PMID- 25684476 TI - Effect of web-supported health education on knowledge of health and healthy living behaviour of female staff in a Turkish university. AB - BACKGROUND: Once limited with face-to face courses, health education has now moved into the web environment after new developments in information technology This study was carried out in order to give training to the university academic and administrative female staff who have difficulty in attending health education planned for specific times and places. The web-supported training focuses on healthy diet, the importance of physical activity, damage of smoking and stress management. MATERIALS AND METHODS: The study was carried out in Sakarya University between the years 2012-2013 as a descriptive and quasi experimental study. The sample consisted of 30 participants who agreed to take part in the survey, filled in the forms and completed the whole training. The data were collected via a "Personel Information Form", "Health Promotion Life-Style Profile (HPLSP)", and "Multiple Choice Questionnaire (MCQ). RESULTS: There was a statistically significant difference between the total points from "Health Promotion Life-Style Profile" and the total points from the sub-scale after and before the training (t=3.63, p=0.001). When the points from the multiple choice questionnaire after and before training were compared, it was seen that the average points were higher after the training (t=8.57, p<0.001). CONCLUSIONS: It was found that web-supported health training has a positive effect on the healthy living behaviour of female staff working at a Turkish university and on their knowledge of health promotion. PMID- 25684475 TI - Manganese superoxide dismutase (MnSOD Val-9Ala) gene polymorphism and susceptibility to gastric cancer. AB - BACKGROUND: Oxidative stress caused by the generation of reactive oxygen species plays an important role in human carcinogenesis. Manganese superoxide dismutase (MnSOD) Val-9Ala in the mitochondrial target sequence is the best known polymorphism of this enzyme. The purpose of the current research was to assess the association of MnSOD Val-9Ala genotypes with the risk of gastric cancer. MATERIALS AND METHODS: This case- control study covered 54 gastric cancer patients compared to 100 cancer free subjects as controls. Extraction of DNA was performed on bioptic samples and genotypes were identified with a polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP) method. RESULTS: The frequencies of MnSOD Ala/Ala, Ala/Val and Val/Val genotypes in healthy individuals were 24.3, 66.7 and 9%, respectively. However, in gastric cancer patients, Ala/Ala, Ala/Val and Val/Val were observed in 24.0, 48.0 and 28.0% (p=0.01). In patients the frequency of MnSOD Val allele was higher (52%) compared to that in controls (42%). CONCLUSIONS: The results of this study show a positive association between MnSOD Val-9Ala gene polymorphism and risk of gastric cancer disease in Iranian population. PMID- 25684477 TI - Updated assessment of the association of the XRCC1 Arg399Gln polymorphism with lung cancer risk in the Chinese population. AB - BACKGROUND: Published studies have reported relationships between X-ray repair cross-complementing group 1 (XRCC1) Arg399Gln polymorphism and lung cancer risk in Chinese population. However, the epidemiological results remained controversial. The objective of this study was to clarify the association of XRCC1 Arg399Gln polymorphism with lung cancer risk in the Chinese population. MATERIALS AND METHODS: Systematic searches were performed through the database of Medline/Pubmed, Web of Science, Embase, CNKI and WanFang Medical Online. Odds ratios (ORs) with 95% confidence interval (95%CI) were calculated to estimate the strength of the association. RESULTS: Overall, we observed an increased lung cancer risk among subjects carrying XRCC1 codon 399 Gln/Gln genotype (OR=1.36, 95%CI: 1.09-1.71) in the Chinese population on the basis of 19 studies with 5,416 cases and 5,782 controls. We did not observe any association between XRCC1 codon 399 Arg/Gln and Arg/Gln+Gln/Gln polymorphisms and lung cancer risk (OR=1.00, 95%CI: 0.92-1.08 and OR=1.05, 95%CI: 0.97- 1.13, respectively). Limiting the analysis to studies with controls in agreement with Hardy-Weinberg equilibrium (HWE), we observed an increased lung cancer risk among subjects carrying XRCC1 codon 399 Gln/Gln genotype (OR=1.18, 95%CI: 1.01-1.38). When stratified by source of control, we observed an increased lung cancer risk among subjects carrying XRCC1 codon 399 Arg/Gln+Gln/Gln genotype on the basis of hospitalized patient based controls (OR=1.21, 95%CI: 1.04-1.42) and among subjects carrying XRCC1 codon 399 Gln/Gln genotype on the basis of healthy subject-based controls (OR=1.22, 95%CI: 1.04-1.43). CONCLUSIONS: Our findings indicated that certain XRCC1 Arg399Gln variants might affect the susceptibility of lung cancer in Chinese population. Larger sample size studies are required to confirm our findings. PMID- 25684478 TI - Evaluation of the National Train-the-Trainer Program for Hospice and Palliative Care in Korea. AB - BACKGROUND: To evaluate the effectiveness of the National Train-the-Trainers Program for Hospice and Palliative Care Experts (TTHPC) sponsored by the National Cancer Center of Korea between 2009 and 2012. This program was developed to improve the teaching skills of those in the field of hospice and palliative care (HPC). MATERIALS AND METHODS: Training was offered in eight 1-day sessions between 2009 and 2012. The effect of the program was measured using Kirkpatrick's model of educational outcomes. First, levels 1 and 2 were evaluated immediately after the 1-day program (n=120). In 2012, the level-3 evaluation test was administered to trainers who offered at least one HPC training (n=78) as well as to their trainees (n=537). RESULTS: The level-1 evaluation addressed participant reactions to and satisfaction with the program. Participants (n=120) were generally satisfied with the content, the method, and the overall course (mean range: 3.94-4.46 on a five-point Likert scale). The level-2 evaluation (learning) showed that participants gained knowledge and confidence related to teaching HPC (4.24 vs. 4.00). The level-3 evaluation (behavioral), which assessed trainers' application of teaching skills to HPC, showed that trainees rated the teaching methods of trainers (mean range: 4.03-4.08) more positively than did trainers (p<0.05). Female trainers were more likely than were male trainers to plan sessions in consideration of their trainees' characteristics (4.11 vs. 3.58; p<0.05), and nurse trainers were more likely than physician trainers to use a variety of instructional methods (4.05 vs. 3.36; p<0.05) CONCLUSIONS: We conducted systematic evaluations based on Kirkpatrick's model to assess the effectiveness of our train-the- trainers program. Our educational program was practical, effective, and followed by our HPC experts, who needed guidance to learn and improve their clinical teaching skills. PMID- 25684479 TI - Living experiences of Indian adult cancer survivors--a brief report. AB - BACKGROUND: This pilot study looked into the physical, social, psychological and economic issues of Indian adult cancer survivors. MATERIALS AND METHODS: Assumed cancer free patients, after cancer directed therapy (CDT), were assessed on the basis of a questionnaire developed by the investigators. The mental status of the survivors was elicited by modified MINI international neuro-psychiatric interview. This cross sectional assessment was conducted as a direct interaction with each patient for 30 to 45 minutes at a cancer hospital in 2012. RESULTS: Thirty one adult cancer survivors participated in this study. Median age was 53 years with a median follow up duration of 21.8 months (Range 2.3-194.1 months). The majority (68%) did not receive financial support for treatment. Median interval after CDT to start of activity of daily living was 1.5 months (range: 0 24 months). Fatigue and loss of appetite were reported by 52% and 29% respectively. The cancer diagnosis and its treatment adversely impacted the financial condition in 42% of patients. Nineteen percent each showed social anxiety and post-traumatic stress disorder and another 13% patients reported depression. CONCLUSIONS: This prospective assessment highlights survivorship issues and the need to address those issues particularly in the context of developing countries where resources and manpower are limited. PMID- 25684480 TI - Expression of HERC4 in lung cancer and its correlation with clinicopathological parameters. AB - BACKGROUND: Growing evidence suggests that the members of the ubiquitin proteasome system (UPS) are important for tumorigenesis. HERC4, one component, is a recently identified ubiqutin ligase. However, the expression level and function role of HERC4 in lung cancer remain unknown. Our objective was to investigate any correlation between HERC4 and development of lung cancer and its clinical significance. MATERIALS AND METHODS: To determine HERC4 expression in lung cancer, an immunohistochemistry analysis of a tissue microarray containing samples of 10 lung normal tissues, 15 pulmonary neuroendocrine carcinomas, 45 squamous epithelial cancers and 50 adenocarcinomas was conducted. Receiver operating characteristic (ROC) curve analysis was applied to obtain a cut-off point of 52.5%, above which the expression of HERC4 was regarded as "positive". RESULTS: On the basis of ROC curve analysis, positive expression of HERC4 was detected in 0/10 (0.0%) of lung normal tissues, in 4/15 (26.7%) of pulmonary neuroendocrine carcinomas, in 13/45 (28.9%) of squamous epithelial cancers and in 19/50 (38.0%) of adenocarcinomas. It showed that lung tumors expressed more HERC4 protein than adjacent normal tissues (chi2=4.675, p=0.031). Furthermore, HERC4 positive expression had positive correlation with pT status (chi2=44.894, p=0.000), pN status (chi2=43.628, p=0.000), histological grade (chi2=7.083, p=0.029) and clinical stage (chi2=72.484, p=0.000), but not age (chi2=0.910, p=0.340). CONCLUSIONS: Our analysis suggested that HERC4 is likely to be a diagnostic biomarker for lung cancer. PMID- 25684481 TI - Comparison of myometrial invasion and tumor free distance from uterine serosa in endometrial cancer. AB - BACKGROUND: We aimed to investigate whether the tumor free distance (the distance between the uterine serosa and the tumor at its deepest point) is useful in surgical staging and in predicting prognosis. MATERIALS AND METHODS: Data from patients who underwent complete surgical staging for endometrial cancer between January 2006 and June 2011 were reviewed retrospectively. All demographic findings, surgical stages, histological type and grade, myometrial invasion, lymphovascular space invasion as well as abdominal cytology, cervical, adnexal, and omental involvement, and lymph node metastasis were recorded. The relations between myometrial invasion and tumor free distance from uterine serosa with prognostic factors were investigated. RESULTS: Seventy patients were included in the study. Sixty-four (91.5%) had endometrioid type cancers and forty-four (62.9%) were grade 1. The deepest myometrial invasion was less than 1/2 in 42 patients (60%). In 18 patients (25.8%) lymphovascular invasion was noted. Eight (11.4%) were found to have cervical involvement, five (7.1%) had adnexal involvement and in 4 cases (5.7%) the peritoneal washings included malignant cells. Four patients had pelvic and one para-aortic node metastasis. We recognized that an invasion of more than 1/2 was correlated significantly with lymphovascular space involvement, histological grade, positive abdominal washing cytology, nodal and cervical involvement, but not with adnexal involvement. Tumor free myometrial thickness was negative and statistically significant correlated with surgical stage, histological grade, lymphovascular space involvement, positive abdominal washing cytology, cervical and adnexal involvement. The importance of tumor- free myometrial thickness in determinating the lymphovascular space invasion was found to be highest in terms of sensitivity and specificity when crossing the ROC curve at 11 millimeters. CONCLUSIONS: Depth of myometrial invasion is more valuable for predicting lymph node metastasis than tumor-free myometrial thickness. The tumor-free myometrial thickness provides a better prediction for adnexal involvement. PMID- 25684482 TI - Developing a scale for quality of life in pediatric oncology patients aged 7-12- children and parent forms. AB - BACKGROUND: This study was planned in an attempt to develop a scale for the quality of life in pediatric oncology patients aged 7-12, with child and parents forms. MATERIALS AND METHODS: In collecting the study data, we used the Child and Parent Information Form, Visual Quality of Life Scale, Scale for Quality of Life Pediatric Oncology Patients Aged 7-12 and the Scale for the Quality of Life in Pediatric Oncology Patients Aged 7-12 for Parents. We also used Pearson correlation analysis, the Cronbach alpha coefficient, factor analysis and ROC analysis for the study data. RESULTS: In this study, the total Cronbach alpha value of the parent form was 0.96, the total factor load being 0.54-0.90 and the total variance explained was 82.5%. The cutoff point of the parent form was 93 points. The total Cronbach alpha value for the child form was 0.96, with a total factor load of 0.55-0.91 and the total variance being explained was 78.3%. The cutoff point of the child form was 65 points. CONCLUSIONS: This study suggests that the Scale for Quality of Life in Pediatric Oncology Patients Aged 7-12 Child and Parents Forms are valid and reliable instruments in assessing the quality of life of children. PMID- 25684483 TI - Effect of grape seed proanthocyanidins on tumor vasculogenic mimicry in human triple-negative breast cancer cells. AB - Vasculogenic mimicry (VM) refers to the unique ability of highly aggressive tumor cells to mimic the pattern of embryonic vasculogenesis, which was associated with invasion and metastasis. The grape seed proanthocyanidins (GSPs) had attracted much attention as a potential bioactive anti-carcinogenic agent. However, GSPs regulation of VM and its possible mechanisms in a triple-negative breast cancer cells (TNBCs) remain not clear. Therefore, we examined the effect of GSPs on VM information in HCC1937 cell model. In this study, we identified the VM structure via the three-dimensional (3D) matrix in vitro. Cell viability was measured using the CCK8 assay. The effects of GSPs on human triple-negative breast cancer cells (TNBCs) HCC1937 in terms of related proteins of VM information were determined using western blot analysis. In vitro, the tubular networks were found in highly invasive HCC1937 cells but not in the non-invasive MCF-7 cells when plated on matrigel. The number of vascular channels was significantly reduced when cells were exposed in GSPs (100 MUg/ml) and GSPs (200 MUg/ml) groups (all p<0.001). Furthermore, we found that treatment with GSPs promoted transition of the mesenchymal state to the epithelial state in HCC1937 cells as well as reducing the expression of Twist1 protein, a master EMT regulator.GSPs has the ability to inhibit VM information by the suppression of Twist1 protein that could be related to the reversal of epithelial-to-mesenchymal (EMT) process. It is firstly concluded that GSPs may be an potential anti-VM botanical agent for human TNBCs. PMID- 25684484 TI - Awareness of ovarian cancer risk factors among women in Malaysia: a preliminary study. AB - BACKGROUND: Ovarian cancer is recognized as the fourth leading cancer in Malaysia. However, women do not always seek help in a timely manner and gaps in awareness may influence screening uptake and presentation. The purpose of this study was to determine levels of awareness of ovarian cancer risk factors in female population in Penang, Malaysia. MATERIALS AND METHODS: A cross-sectional study was conducted in Penang, Malaysia from January until February 2014. Eighty seven women were selected by convenient sampling. Awareness of risk factors of ovarian cancer was assessed using a self-administered questionnaire. Data were analyzed using statistical package for the social sciences (SPSS) version 20.0 for descriptive statistics and Pearson chi-square test for the association between socio-demographic data and awareness. A p value <=0.05 was considered statistically significant. RESULTS: In all, 74.7% of participants answered correctly for the risk factor of increasing age, although 94.3% were unaware of increased risk of tall women. A majority, 71.3%, had a low level of awareness of ovarian cancer risk factors. There was a significant association between age and knowledge (p=0.047). Additionally, there was a significant association between higher education level and level of awareness of ovarian cancer risk factors (p=0.039). CONCLUSIONS: This study revealed that awareness of ovarian cancer risk factors among Malaysian women is low. The results show a need for improved public understanding about ovarian cancer risks and provision of important information for health professionals about initiatives needed for future awareness, prevention and screening programs. PMID- 25684485 TI - Increased hypermethylation of glutathione S-transferase P1, DNA-binding protein inhibitor, death associated protein kinase and paired box protein-5 genes in triple-negative breast cancer Saudi females. AB - Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer (BC) with higher metastatic rate and both local and systemic recurrence compared to non-TNBC. The generation of reactive oxygen species (ROS) secondary to oxidative stress is associated with DNA damage, chromosomal degradation and alterations of both hypermethylation and hypomethylation of DNA. This study concerns differential methylation of promoter regions in specific groups of genes in TNBC and non-TNBC Saudi females in an effort to understand whether epigenetic events might be involved in breast carcinogenesis, and whether they might be used as markers for Saudi BCs. Methylation of glutathione S-transferase P1 (GSTP1), T cadherin (CDH13), Paired box protein 5 (PAX5), death associated protein kinase (DAPK), twist-related protein (TWIST), DNA-binding protein inhibitor (ID4), High In Normal-1 (HIN-1), cyclin-dependent kinase inhibitor 2A (p16), cyclin D2 and retinoic acid receptor-beta (RARbeta1) genes was analyzed by methylation specific polymerase chain reaction (MSP) in 200 archival formalin- fixed paraffin embedded BC tissues divided into 3 groups; benign breast tissues (20), TNBC (80) and non TNBC (100). The relationships between methylation status, and clinical and pathological characteristics of patients and tumors were assessed. Higher frequencies of GSTP1, ID4, TWIST, DAPK, PAX5 and HIN-1 hypermethylation were found in TNBC than in non-TNBC. Hypermethylation of GSTP1, CDH13, ID4, DAPK, HIN 1 and PAX5 increased with tumor grade increasing. Other statistically significant correlations were identified with studied genes. Data from this study suggest that increased hypermethylation of GSTP1, ID4, TWIST, DAPK, PAX5 and HIN-1 genes in TNBC than in non-TNBC can act as useful biomarker for BCs in the Saudi population. The higher frequency of specific hypermethylated genes paralleling tumor grade, size and lymph node involvement suggests contributions to breast cancer initiation and progression. PMID- 25684486 TI - Roles of immunohistochemical staining in diagnosing pulmonary squamous cell carcinoma. AB - BACKGROUND: Differentiating morphologic features based on hematoxylin-eosin (HE) staining is the most common method to classify pathological subtypes of non-small cell lung cancer (NSCLC). However, its accuracy and inter-observer reproducibility in pathological diagnosis of poorly differentiated NSCLC remained to be improved. MATERIALS AND METHODS: We attempted to explore the role of immunohistochemistry (IHC) staining in diagnosing pulmonary squamous cell carcinoma (SQCC) with poorly differentiated features by HE staining or with elevated serum adenocarcinoma-specific tumor markers (AD-TMs). We also compared the difference of epidermal growth factor receptor (EGFR) mutation rate between patients with confirmed SQCC and those with revised pathological subtype. Logistic regression analyses were used to test the association between different factors and diagnostic accuracy. RESULTS: A total of 132 patients who met the eligible criteria and had adequate specimens for IHC confirmation were included. Pathological revised cases in poor differentiated subgroup, biopsy samples and high-level AD-TMs cases were more than those with high/moderate differentiation, surgical specimens and normal-level AD-TMs. Moreover, biopsy sample was a significant factor decreasing diagnostic accuracy of pathological subtype (OR, 4.037; 95% CI 1.446-11.267, p=0.008). Additionally, EGFR mutation rate was higher in patients with pathological diagnostic changes than those with confirmed SQCC (16.7% vs 4.4%, p=0.157). CONCLUSIONS: Diagnosis based on HE staining only might cause pathological misinterpretation in NSCLC patients with poor differentiation or high-level AD-TMs, especially those with biopsy samples. HE staining and IHC should be combined as pathological diagnostic standard. The occurrence of EGFR mutations in pulmonary SQCC might be overestimated. PMID- 25684487 TI - Assessment of the reliability of a novel self-sampling device for performing cervical sampling in Malaysia. AB - BACKGROUND: The participation of women in cervical cancer screening in Malaysia is low. Self-sampling might be able to overcome this problem.The aim of this study was to assess the reliability of self-sampling for cervical smear in our country. MATERIALS AND METHODS: This cross-sectional study was conducted on 258 community dwelling women from urban and rural settings who participated in health campaigns. In order to reduce the sampling bias, half of the study population performed the self-sampling prior to the physician sampling while the other half performed the self-sampling after the physician sampling, randomly. Acquired samples were assessed for cytological changes as well as HPV DNA detection. RESULTS: The mean age of the subjects was 40.4+/-11.3 years. The prevalence of abnormal cervical changes was 2.7%. High risk and low risk HPV genotypes were found in 4.0% and 2.7% of the subjects, respectively. A substantial agreement was observed between self-sampling and the physician obtained sampling in cytological diagnosis (k=0.62, 95%CI=0.50, 0.74), micro-organism detection (k=0.77, 95%CI=0.66, 0.88) and detection of hormonal status (k=0.75, 95%CI=0.65, 0.85) as well as detection of high risk (k=0.77, 95%CI=0.4, 0.98) and low risk (K=0.77, 95%CI=0.50, 0.92) HPV. Menopausal state was found to be related with 8.39 times more adequate cell specimens for cytology but 0.13 times less adequate cell specimens for virological assessment. CONCLUSIONS: This study revealed that self sampling has a good agreement with physician sampling in detecting HPV genotypes. Self-sampling can serve as a tool in HPV screening while it may be useful in detecting cytological abnormalities in Malaysia. PMID- 25684488 TI - Inhibitory effects of Cyrtopodion scabrum extract on growth of human breast and colorectal cancer cells. AB - Breast and colorectal cancers rank high in Iran as causes of mortality. Most of the current treatments are expensive and non-specific. The potential anticancer properties of common home gecko, Cyrtopodion scabrum, were investigated in this study. The effects of C. scabrum extract on proliferation, viability and migration of the colorectal cancer (SW-742), breast cancer (MCF-7) and normal (MSC) cell lines were investigated using MTT and in vitro wound healing assay. IC50 values calculated for the extract were 559+/-28.9 MUg/ml for MCF-7 and 339+/ 11.3 MUg/ml for SW-742. No toxic effects on the normal control cells were observed. MCF-7 and SW-742 cell growth was inhibited by 32.6% and 62%, under optimum conditions, compared to the untreated control cells. The extract also decreased the motility and migration ability of both cancer cell lines, with no significant effects on the normal control cells. Data suggest C. scabrum extract as a useful natural resource for targeting cancer cells specifically. PMID- 25684489 TI - Dendritic cells induce specific cytotoxic T lymphocytes against prostate cancer TRAMP-C2 cells loaded with freeze- thaw antigen and PEP-3 peptide. AB - Prostate cancer is the most common cancer in men. In this study, we investigated immune responses of cytotoxic T lymphocytes (CTLs) against TRAMP-C2 prostate cancer cells after activation by dendritic cells (DCs) loaded with TRAMP-C2 freeze-thaw antigen and/or PEP-3 peptide in vitro. Bone marrow-derived DC from the bone marrow of the C57BL/6 were induced to mature by using the cytokine of rhGM-CSF and rhIL-4, and loaded with either the freeze-thaw antigen or PEP-3 peptide or both of them. Maturation of DCs was detected by flow cytometry. The killing efficiency of the CTLs on TRAMP-C2 cells were detected by flow cytometry, CCK8, colony formation, transwell migration, and wound-healing assay. The levels of the IFN-gamma, TNF-beta and IL-12 were measured by enzyme-linked immunosorbent assay (ELISA). Compared with the unloaded DCs, the loaded DCs had significantly increased expression of several phenotypes related to DC maturation. CTLs activated by DCs loaded with freeze-thaw antigen and PEP-3 peptide had more evident cytotoxicity against TRAMP-C2 cells in vitro. The secretion levels of IFN gamma, TNF-beta and IL-12, secreted by DCs loaded with antigen and PEP-3 and interaction with T cells, were higher than in the other groups. Our results suggest that the CTLs activated by DCs loaded with TRAMP-C2 freeze-thaw antigen and PEP-3 peptide exert a remarkable killing efficiency against TRAMP-C2 cells in vitro. PMID- 25684490 TI - Manual liquid based cytology for Pap smear preparation and HPV detection by PCR in Pakistan. AB - This study was conducted on female patients with different gynecological problems attending the gynecology out-patient departments of two tertiary care hospitals in Peshawar city of Khyber Pakhtunkhwa, Pakistan between August 2012 and October 2013. The 200 patients had an age range of 21-65 years. Smears were taken with cervical brushes and preserved in preservative medium and processed for manual liquid based cytology (MLBC) for Pap staining. Out of 200 collected samples, 30 samples were found inadequate on cytology. Of the remaining 170 samples, 164 (96.47%) were normal, 5 (2.94%) were of atypical squamous cells of unknown significance (ASCUS) and 1 (0.6%) was of high grade squamous intraepithelial lesion (HSIL). On PCR all the samples were positive for beta globin gene fragment including those reported inadequate on cytology. Out of the 5 ASCUS samples, 2 samples were positive for HPV, one each for HPV 16 and HPV 18, and the rest of the 3 samples were negative for HPV DNA. The 1 sample of HSIL was positive for HPV 16 on PCR. Out of 164 normal samples on cytology, only 1 sample was HPV 16 positive. So overall, 4 (2%) out of 200 samples were positive for HPV DNA, where 3 were HPV 16 (1.5%), and 1 was HPV 18 (0.5%) positive, and thus the ratio of infection with of HPV 16 to HPV 18 was 3:1 in the general population. In conclusion, PCR based HPV detection is a more sensitive method for screening of HPV infection than cytology as sample inadequacy does not affect the results. However, it can be combined with cytology methods in a HPV positive female to achieve the maximum results. PMID- 25684491 TI - Associations among physical activity, comorbidity, functional capacity, peripheral muscle strength and depression in breast cancer survivors. AB - Physical inactivity may an important outcome in the prognosis of breast cancer. Physical activity levels decrease significantly for breast cancer patients following the treatment and remain low after oncology treatment is completed. The aim of this study was to determine physical activity levels and to examine associations among physical activity, comorbidity, functional capacity, peripheral muscle strength, and psychosocial status in breast cancer patients. Forty breast cancer survivors were included in this study. Demographic and clinical characteristics were recorded. Physical activity was assessed with a short form of the International Physical Activity Questionnaire (IPAQ). We defined comorbid diseases according to the Charlson Comorbidity Index (CCI). Functional capacity was evaluated with a six-minute walk test (6MWT). Peripheral muscle strength was measured for quadriceps femoris muscle with a hand-held dynamometer. Psychosocial status was measured with the Hospital Anxiety Depression Scale (HADS). Forty percent of patients were inactive. The IPAQ total score was significantly related with quadriceps muscle strength (r=0.492; p<0.001) and HADS depression score (r=0.341; p<0.05). Marked correlations were also observed between IPAQ walking score and quadriceps muscle strength (r=0.449; p<0.001), HADS depression score (r=0.341; p<0.05), and CCI (r=-0.433; p<0.001). The CCI score was also markedly associated with quadriceps muscle strength (r= 0.413; p<0.001). 6MWT distance was not significantly correlated with any of the parameters. Regression analyses revealed that psychosocial status and peripheral muscle strength were significant predictors of physical activity estimated with the IPAQ short form and when combined, they explained 35% of the variance. Comorbidities, peripheral muscle strength and psychosocial status partially explain the variability of physical activity level in breast cancer survivors. These results suggest that physical inactivity contributes to worsening health in breast cancer survivors. PMID- 25684492 TI - Prognostic value of ALDH1A3 promoter methylation in gliob;astoma: a single center experience in Western China. AB - BACKGROUND: Aberrations in gene methylation patterns play important roles in gliomagenesis. However, whether the ALDH1A3 promoter methylation is related to prognoses of primary glioblastomas (GBMs) in Western China remains unclear. MATERIALS AND METHODS: Methylation levels of ALDH1A3 CpG island in 36 GBMs were identified by pyrophosphate sequencing, while ALDH1A3 expression was assessed with matched paraffin section immunohistochemistry. Survival curves were analysed by Kaplan-Meier. RESULTS: The hypermethylation status of ALDH1A3 promoter predicted a better prognosis accompanied with low expression of ALDH1A3 protein. CONCLUSIONS: Our results indicate ALDH1A3 promoter methylation correlates with prognosis in primary GBMs. PMID- 25684493 TI - Metformin association with lower prostate cancer recurrence in type 2 diabetes: a systematic review and meta-analysis. AB - BACKGROUND: Accumulating evidence suggests that metformin possesses anticarcinogenic properties, and its use is associated with favorable outcomes in several cancers. However, it remains unclear whether metformin influences prognosis in prostate cancer (PCa) with concurrent type 2 diabetes (T2D). MATERIALS AND METHODS: We searched PubMed, EMBASE, and the Cochrane Library from database inception to April 16, 2014 without language restrictions to identify studies investigating the effect of metformin treatment on outcomes of PCa with concurrent T2D. We conducted a meta-analysis to quantify the risk of recurrence, progression, cancer-specific mortality, and all-cause mortality. Summary relative risks (RRs) with corresponding 95% confidence intervals (CIs) were calculated. Publication bias was assessed by Begg's rank correlation test. RESULTS: A total of eight studies fulfilled the eligibility criteria. We found that diabetic PCa patients who did not use metformin were at increased risk of cancer recurrence (RR, 1.20; 95%CI, 1.00-1.44), compared with those who used metformin. A similar trend was observed for other outcomes, but their relationships did not reach statistical significance. Funnel plot asymmetry was not observed among studies reporting recurrence (p=0.086). CONCLUSIONS: Our results suggest that metformin may improve outcomes in PCa patients with concurrent T2D. Well-designed large studies and collaborative basic research are warranted. PMID- 25684494 TI - Prostate cancer screening in the fit Chilean elderly: a head to head comparison of total serum PSA versus age adjusted PSA versus primary circulating prostate cells to detect prostate cancer at initial biopsy. AB - BACKGROUND: Prostate cancer is predominately a disease of older men, with a median age of diagnosis of 68 years and 71% of cancer deaths occurring in those over 75 years of age. While prostate cancer screening is not recommended for men>70 years, fit elderly men with controlled comorbidities may have a relatively long life expectancy. We compare the use of age related PSA with the detection of primary malignant circulating prostate cells mCPCs to detect clinically significant PC in this population. MATERIALS AND METHODS: All men undergoing PC screening with a PSA>4.0 ng/ml underwent TRUS 12 core prostate biopsy (PB). Age, PSA, PB results defined as cancer/no-cancer, Gleason, number of positive cores and percentage infiltration were registered. Men had an 8 ml blood sample taken for mCPC detection; mononuclear cells were obtained using differential gel centrifugation and mCPCs were identified using immunocytochemistry with anti-PSA and anti-P504S. A mCPC was defined as a cell expressing PSA and P504S; a positive test as at least one mCPC detected/sample. Diagnostic yields for subgroups were calculated and the number of avoided PBs registered. Esptein criteria were used to define small grade tumours. RESULTS: A total of 610 men underwent PB, 398 of whom were aged <70 yrs. Men over 70 yrs had: a higher median PSA, 6.24 ng/ml versus 5.59 ng/ml (p=0.04); and a higher frequency of cancer detected 90/212 (43%) versus 134/398 (34%) (p=0.032). Some 34/134 cancers in men<70 yrs versus 22/90 (24%) of men>70 yrs complied with criteria for active surveillance. CPC detection: 154/398 (39%) men<70 yrs were CPC (+), specificity for cancer 86%, sensitivity 88%, 14/16 with a false (-) result had a small low grade PC. In men>70 years, 88/212 (42%) were CPC (+); specificity 92%, sensitivity 87%, 10/12 with a false (-) had small low grade tumours. False (+) results were more common in younger men 36/154 versus 10/88 (p<0.02). With a PSA cutoff of 6.5 ng/ml, in men<70 yrs, 108 PB would be avoided, missing 56 cancers of which 48 were clinically significant. Using CPC detection, 124 biopsies would be avoided, missing only 2 clinically significant cancers. In men>70 yrs using a PSA>6.5 ng/ml would have resulted in 108 PB with 34 PC detected, of which 14(41%) were small low grade tumours. CONCLUSIONS: The use of CPC detection in the fit elderly significantly decreases the number of PBs without missing clinically significant cancers, indicating superiority to the use of age-related PSA. PMID- 25684495 TI - Influence of hazy weather on patient presentation with respiratory diseases in Beijing, China. AB - BACKGROUND: Chronic respiratory disease is an important factor for development of lung cancer. To explore the influence of hazy weather on respiratory diseases and its variation the present study was conducted. MATERIALS AND METHODS: Data from air pollution surveillance from January to October 2014 and case records of visiting patients in the 263th Hospital of Chinese PLA in the corresponding period were collected to analyze the relevance between different degrees of air pollution (hazy weather) and the number of visiting patients in Department of Respiratory Disease. RESULTS: Air quality index (AQI) of hazy weather had significantly positive association with particulate matter 2.5 (PM2.5) and the number of patients with 5 kinds of respiratory diseases i and different pollutants had distinct influences on various respiratory diseases. CONCLUSIONS: The degree of air pollution in Beijing City is in close association with the number of patients with respiratory diseases, in which PM2.5 and SO2 are in more significant influences on all respiratory diseases. This could have essential implications for lung cancer development in China. PMID- 25684496 TI - Predictive value of serum insulin-like growth factor-1 in hepatocellular carcinoma. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is the commonest primary malignant cancer of the liver in the world. Insulin-like growth factor-1 (IGF-1) levels reflect hepatic function and are inversely correlated with the severity of background chronic liver disease. OBJECTIVE: This study evaluated whether basal serum IGF-1 levels can predict prognosis of HCC patients according to different risks of disease progression. MATERIALS AND METHODS: A total of 89 patients with hepatocellular carcinoma (HCC) were recruited in 3 groups: Group I, 30 HCC patients receiving sorafinib; Group II, 30 HCC patients with best supportive care; and Group III include 29 patients undergoing transcatheter arterial chemoembolization (TACE). All patients were investigated for serum levels of AST, ALP, Bb, Cr, BUN, AFP and IGF-I. RESULTS: Patients with disease control had significantly higher baseline IGF-1 levels 210 (185-232.5) ng/mL (p value<0.01) than did patients without disease control. Low basal IGF-1 levels were associated with advanced HCC, such as multiple tumors and advanced stage, and low IGF-1 levels predicted shorter TTP and overall survival in patients treated with TACE. CONCLUSIONS: The levels of serum IGF-1, expressed as continuous values, may be helpful for accurately assessing hepatic function and the prognostic stratification of patients with HCC. PMID- 25684497 TI - Opportunistic insights into occupational health hazards associated with waterpipe tobacco smoking premises in the United Kingdom. AB - BACKGROUND: Smokefree laws aim to protect employees and the public from the dangers of secondhand smoke. Waterpipe premises have significantly increased in number in the last decade, with anecdotal reports of poor compliance with the smokefree law. The literature is bereft of information pertaining to waterpipe premise employees. This study aimed to opportunistically gather knowledge about the occupational health hazards associated with working in waterpipe premises in London, England. MATERIALS AND METHODS: Employees from seven convenience-sampled, smokefree-compliant waterpipe premises in London were observed for occupational activities. Opportunistic carbon monoxide (CO) measurements were made among those with whom a rapport had developed. Observations were thematically coded and analysed. RESULTS: Occupational hazards mainly included environmental smoke exposure. Waterpipe-serving employees were required to draw several puffs soon after igniting the coals, thereby providing quality assurance of the product. Median CO levels were 27.5 ppm (range 21-55 ppm) among these employees. Self reported employee health was poor, with some suggestion that working patterns and smoke exposure was a contributory factor. CONCLUSIONS: The smokefree law in England does not appear to protect waterpipe premise employees from high levels of CO. Continued concerns surrounding chronic smoke exposure may contribute to poor self-reported physical and mental wellbeing. PMID- 25684498 TI - Parecoxib: an enhancer of radiation therapy for colorectal cancer. AB - BACKGROUND: To study the effect of parecoxib, a novel cyclooxygenase-2 selective inhibitor, on the radiation response of colorectal cancer (CRC) cells and its underlying mechanisms. MATERIALS AND METHODS: Both in vitro colony formation and apoptosis assays as well as in vivo mouse xenograft experiments were used to explore the radiosensitizing effects of parecoxib in human HCT116 and HT29 CRC cells. RESULTS: Parecoxib sensitized CRC cells to radiation in vitro with a sensitivity enhancement ratio of 1.32 for HCT116 cells and 1.15 for HT29 cells at a surviving fraction of 0.37. This effect was partially attributable to enhanced apoptosis induction by parecoxib combined with radiation, as illustrated using an in vitro apoptosis assays. Parecoxib augmented the tumor response of HCT116 xenografts to radiation, achieving growth delay more than 20 days and an enhancement factor of 1.53. In accordance with the in vitro results, parecoxib combined with radiation resulted in less proliferation and more apoptosis in tumors than radiation alone. Radiation monotherapy decreased microvessel density (MVD) and microvessel intensity (MVI), but increased the hypoxia level in xenografts. Parecoxib did not affect MVD, but it increased MVI and attenuated hypoxia. CONCLUSIONS: Parecoxib can effectively enhance radiation sensitivity in CRC cells through direct effects on tumor cells and indirect effects on tumor vasculature. PMID- 25684499 TI - Factors associated with delayed diagnosis of cervical cancer in Iran--a survey in Isfahan City. AB - BACKGROUND: In the absence of routine screening program for cervical cancer in Iran and high rate of diagnosed cancer in its advanced stage, recognition of sociodemographic factors related to delayed diagnosis of cancer in Iran could be helpful in reducing the burden of disease in our community. The aim of this study was to determine the stage of cervical cancer at diagnosis and factors related to delayed diagnosis of cervical cancer in Isfahan, Iran. MATERIALS AND METHODS: In this cross sectional study women diagnosed with cervical cancer for the first time by histo-pathological examination were enrolled. According to the clinical and paraclinical findings and staging of the cancer, they were classified into early and delayed diagnosis of cervical cancer. Sociodemographic factors were compared in the two groups. RESULTS: In this study of 55 women mean age was 48.3+/-12.0. According to our classification 6/55 (10.9%) and 49/55 (89.1%) of them had early and delayed diagnosis of cervical cancer. Delayed diagnosis of the cancer was significantly higher in patients with lower degree of education, lower socioeconomic status, having smoker and addict husband and those who did not have a history of Pap smear test (p<0.05). CONCLUSIONS: The results of this study indicated risk factors related to delayed diagnosis of cervical cancer. The affected women should be targeted for implementation of specialized educational programmes for improving knowledge and screening test. PMID- 25684500 TI - Post-traumatic stress disorder and post-traumatic growth in breast cancer patients--a systematic review. AB - Breast cancer (BC) is potentially a traumatic stressor which may be associated with negative outcomes, such as post-traumatic stress disorder (PTSD) or positive changes, such as post-traumatic growth (PTG). This study aims to identify the core issues of BC related PTSD, PTG and psychological distress by interrogating the literature in BC survivors. We have also highlighted issues related to the assessment, diagnosis and clinical management of PTSD and PTG. The authors systematically reviewed studies published from 1985 to 2014 pertaining to PTSD, psychological distress and PTG in BC survivors with particular attention paid to incidence rates and causative factors. Multiple studies intimated that women with BC have evidence of PTSD at the initial stages of diagnosis, whereas PTG develops once patients undergo treatment. Early diagnosis and treatment of PTSD/PTG is paramount from literature review but the previously mentioned relationship between PTSD and PTG in BC patients could not be verified. It is evident from the literature that a small percentage of BC patients experience PTSD, while the majority experience PTG after BC diagnosis and treatment. Future research should include prospective studies focusing on high-risk patients, causative factors and the development of psychological interventions. PMID- 25684501 TI - Screening for patients with non-small cell lung cancer who could survive long term chemotherapy. AB - BACKGROUND: Lung cancer was one of the most common cancers in both men and women all over the world. In this study, we aimed to clarify who could survive after long term chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). METHODS: We enrolled 186 patients with stage IV NSCLC after long term chemotherapy from Jun 2006 to Nov 2014 diagnosed in Jiangsu Cancer Hospital. Multiple variables like age, gender, smoking, histology of adenocarcinoma and squamous-cell cancer, number of metastatic sites, metastatic sites (e.g. lung, brain, bone, liver and pleura), hemoglobin, lymphocyte rate (LYR), Change of LYR during multiple therapies, hypertension, diabetes, chronic bronchitis, treatments (e.g.radiotherapy and targeted therapy) were selected. For consideration of factors influencing survival and response for patients with advanced NSCLC, logistic regression analysis and Cox regression analysis were used in an attempt to develop a screening module for patients with elevated survival after long term chemotherapy become possible. RESULTS: Of the total of 186 patients enrolled, 69 survived less than 1 year (short-term group), 45 one to two years, and 72 longer than 3 years (long-term group). For logistic regression analysis, the short-term group was taken as control group and the long-term group as the case group. We found that age, histology of adenocarcinoma, metastatic site (e.g. lung and liver), treatments (e.g. targeted therapy and radiotherapy), LYR, a decreasing tendency of LYR and chronic bronchitis were individually associated with overall survival by Cox regression analysis. A multivariable Cox regression model showed that metastatic site (e.g. lung and liver), histology of adenocarcinoma, treatments (e.g. targeted therapy and radiotherapy) and chronic bronchitis were associated with overall survival. Thus metastatic site (e.g. lung and liver) and chronic bronchitis may be important risk factors for patients with advanced NSCLC. Gender, metastatic site (e.g. lung and liver), LYR and the decreasing tendency of LYR were significantly associated with long-term survival in the individual-variable logistic regression model (P<0.05). On multivariate logistic regression analysis, gender, metastatic site (e.g. lung and liver) and the decreasing tendency of LYR associated with long-term survival. CONCLUSIONS: In conclusion, female patients with stage IV adenocarcinoma of NSCLC who had decreasing tendency of LYR during the course therapy and had accepted multiple therapies e.g. more than third-line chemotherapy, radiotherapy and/or targeted therapy might be expected to live longer. PMID- 25684502 TI - Immunohistochemical expression of cytokeratins and epithelial membrane protein 2 in nasopharyngeal carcinoma and its potential implications. AB - BACKGROUND: Nasopharyngeal carcinoma (NPC) is an aggressive disease and tends to involve surrounding tissues, and biomarkers for better management are yet to be identified. MATERIALS AND METHODS: One hundred and fifty tissue samples with NPC diagnosis were were investigated using pan cytokeratin (CK) and epithelial membrane protein 2 (EMP2) antibodies. RESULTS: Immunohistochemical expression of CK was identified in 144/150 (96%) and of EMP2 in 120/150 (80%). CONCLUSIONS: There is a high loss of EMP2 in NPC, especially high grade examples. Loss of CK expression is also linked to high grade NPC types. PMID- 25684503 TI - Reliability of stool antigen tests: investigation of the diagnostic value of a new immunochromatographic Helicobacter pylori approach in dyspeptic patients. AB - BACKGROUND: A diagnosis of H. pylori infection can be made by invasive or non invasive methods. Several noninvasive diagnostic tests based on the detection of H. pylori stool antigen (HpSA) have been developed. The Genx H. pylori stool antigen card test is a new rapid, non-invasive test that is based on monoclonal immunochromatographic assay. The aim of this study was to determine its sensitivity, specificity, and diagnostic accuracy for diagnosing H. pylori infection in adult patients. MATERIALS AND METHODS: A total of 162 patients were included in the study. A gastric biopsy was collected for histopathology and rapid urease testing. Stool specimens for HpSA testing were also collected. Patients were considered H. pylori positive if two invasive tests (histological and rapid urease tests) were positive. RESULTS: Using the reference test, 50.6% of the samples were positive for H. pylori infection. The Genx H. pylori antigen test was positive in 19.7% of patients. The sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy of the Genx H. pylori antigen test were 51.6%, 96.0%, 88.8%, 76.1%, and 79.0%, respectively. CONCLUSIONS: The Genx H. pylori stool antigen card test is a new non-invasive method that is fast and simple to perform but provides less reliable results. PMID- 25684504 TI - Normalization of CA19-9 following resection for pancreatic ductal adenocarcinoma is not tantamount to being cured? AB - BACKGROUND: Postoperative carbohydrate antigen 19-9 (CA19-9) is an independent predictor of survival for pancreatic ductal adenocarcinoma (PDAC), and more powerful than preoperative CA19-9. However, making decisions just dependent on postoperative CA19-9 may result in necessary treatments not being performed. MATERIALS AND METHODS: A total of 178 patients with resected PDAC were eligible for this retrospective study, classified into two corresponding subgroups according to postoperative CA19-9. Prognostic significance of all clinicopathologic factors was evaluated by univariate and multivariate analyses. RESULTS: Postoperative CA19-9, preoperative CA125 and lymph node status were independent predictors. Better predictive performances for overall survival (OS) and recurrence-free survival (RFS) were achieved by postoperative CA19-9 compared to preoperative CA125 and lymph node status. Particularly, preoperative CA125 was associated with poor OS (p<0.001 for the normalized CA19-9 patients, p=0.012 for the elevated) and RFS (p=0.005 for the normalized, p=0.004 for the elevated). Moreover, preoperative CA125 levels related with survival in double- negative patients. CONCLUSIONS: Normalization of CA19-9 is not tantamount to be cured. Preoperative CA125 is a critical predictor for PDAC patients, especially in double-negative patients. PMID- 25684505 TI - Attitudes towards colorectal cancer (CRC) and CRC screening tests among elderly Malay patients. AB - BACKGROUND: Colorectal cancer (CRC) is the third most common malignancy in Malaysia, where data are limited regarding knowledge and barriers in regard to CRC and screening tests. The aim of the study was to assess these parameters among Malaysians. MATERIALS AND METHODS: The questionnaires were distributed in the Umra Private Hospital in Selangor. The questionnaire had four parts and covered social-demographic questions, respondent knowledge about CRC and colorectal tests, attitude towards CRC and respondentaction regarding CRC. More than half of Malay participants (total n=187) were female (57.2%) and 36.9% of them were working as professionals. RESULTS: The majority of the participants (93.6%) never had a CRC screening test. The study found that only 10.2% of the study participants did not consider that their chances of getting CRC were high. A high percentage of the participants (43.3%) believed that they would have good chance of survival if the cancer would be found early. About one third of the respondents did not want to do screening because of fear of cancer, and concerns of embarrassment during the procedure adversely affected attitude to CRC screening as well. Age, gender, income, family history of CRC, vegetable intake and physical activity were found to be significant determinants of knowledge on CRC. CONCLUSIONS: The major barriers identified towards CRC screening identified in our study were fear of pain and embarrassment. The findings have implications for understanding of similarities and differences in attitude to CRC amongst elderly patients in other cultural/ geographic regions. PMID- 25684506 TI - Elevated fasting blood glucose is associated with increased risk of breast cancer: outcome of case-control study conducted in Karachi, Pakistan. AB - BACKGROUND: There are several validated risk factors for breast cancer. However the legitimacy of elevated fasting blood glucose (FBG) is not well established. This study was designed to assess this parameter as a risk factor for breast cancer among pre- and post-menopausal women. MATERIALS AND METHODS: This case control study was conducted at Department of Biochemistry, University of Karachi from June 2010 to August 2014. Simple random sampling technique was used to collect data of study subjects comprising 175 diagnosed breast cancer patients with positive histopathology from Breast Clinic, surgical unit-1, Civil Hospital, Karachi and 175 healthy controls from various screening programs. Blood samples were analyzed for FBG and serum insulin. RESULTS: FBG, HOMA-IR, systolic and diastolic blood pressure were significantly raised in breast cancer cases when compared to control subjects. Cases and controls were further categorized in to two groups using cutoff value of 110 mg/dl to distinguish subjects into normal fasting glucose (<110 mg/dl) and having impaired fasting glucose (>=110-<=125 mg/dl) or diabetes (>=126 mg/dl). Odds ratios were found to be 1.57, 2.15 and 1.17 in overall, pre-menopausal and post-menopausal groups, respectively. (all p<0.05). CONCLUSIONS: A statistically significant risk of breast cancer exists in women having elevated fasting blood glucose levels, corresponding to prediabetes and diabetes, among pre and postmenopausal ages, with comparatively greater effects in the premenopausal group. PMID- 25684507 TI - Expression of IER3 in primary hepatocarcinoma: correlation with clinicopathological parameters. AB - BACKGROUND: Studies indicate the immediate early response gene 3 (IER3) is involved in many biological processes. Recently, it was discovered that IER3 plays an important role in tumorigenesis and tumor progression. Thus it may be a valuable biomarker in tumor. This study was designed to investigate the expression status of IER3 in primary hepatocarcinoma (PHC) and correlation with clinicopathological parameters. MATERIALS AND METHODS: Real-time PCR was performed to evaluate the expression levels of IER3 in 62 pathologically diagnosed human PHC specimens. RESULTS: A statistically significant association was disclosed between the expression of IER3 and P53 mutant protein (short for P53), Ki-67, EGFR and the biggest diameter, differentiation grade of tumor. CONCLUSIONS: This work is the first to shed light on the potential clinical usefulness of IER3, as an efficient tumor biomarker in PHC. PMID- 25684508 TI - Dietary aloe vera gel powder and extract inhibit azoxymethane- induced colorectal aberrant crypt foci in mice fed a high- fat diet. AB - Aloe vera gel exhibits protective effects against insulin resistance as well as lipid-lowering and anti-diabetic effects. The anti-diabetic compounds in this gel were identified as Aloe-sterols. Aloe vera gel extract (AVGE) containing Aloe sterols has recently been produced using a new procedure. We previously reported that AVGE reduced large-sized intestinal polyps in Apc-deficient Min mice fed a high fat diet (HFD), suggesting that Aloe vera gel may protect against colorectal cancer. In the present study, we examined the effects of Aloe vera gel powder (AVGP) and AVGE on azoxymethane-induced colorectal preneoplastic aberrant crypt foci (ACF) in mice fed a HFD. Male C57BL/6J mice were given a normal diet (ND), HFD, HFD containing 0.5% carboxymethyl cellulose solution, which was used as a solvent for AVGE (HFDC), HFD containing 3% or 1% AVGP, and HFDC containing 0.0125% (H-) or 0.00375% (L-) AVGE. The number of ACF was significantly lower in mice given 3% AVGP and H-AVGE than in those given HFD or HFDC alone. Moreover, 3% AVGP, H-AVGE and L-AVGE significantly decreased the mean Ki-67 labeling index, assessed as a measure of cell proliferation in the colonic mucosa. In addition, hepatic phase II enzyme glutathione S-transferase mRNA levels were higher in the H-AVGE group than in the HFDC group. These results suggest that both AVGP and AVGE may have chemopreventive effects on colorectal carcinogenesis under the HFD condition. Furthermore, the concentration of Aloe-sterols was similar between 3% AVGP and H-AVGE, suggesting that Aloe-sterols were the main active ingredients in this experiment. PMID- 25684509 TI - Frequency of EGFR mutations in non-small cell lung cancer patients: screening data from West Siberia. AB - BACKGROUND: Incorporation of molecular analysis of the epidermal growth factor receptor (EGFR) gene into routine clinical practice has shown great promise to provide personalized therapy of the non-small cell lung cancer (NSCLC) in the developed world. However, the genetic testing of EGFR mutations has not yet become routine clinical practice in territories remote from the central regions of Russia. Therefore, we aimed to study the frequency of major types of activating mutations of the EGFR gene in NSCLC patients residing in West Siberia. MATERIALS AND METHODS: We examined EGFR mutations in exons 19 and 21 in 147 NSCLC patients (excluding squamous cell lung carcinomas) by real time polymerase chain reaction. RESULTS: EGFR mutations were detected in 28 of the 147 (19%) patients. There were 19 (13%) cases with mutations in exon 19 and 9 cases (6%) in exon 21. Mutations were more frequently observed in women (42%, p=0.000) than in men (1%). A significantly higher incidence of EGFR mutations was observed in bronchioloalveolar carcinomas (28%, p=0.019) and in adenocarcinomas (21%, p=0.024) than in large cell carcinomas, mixed adenocarcinomas, and NOS (4%). The EGFR mutation rate was much higher in never-smokers than in smokers: 38% vs. 3% (p=0.000). The frequency of EGFR mutations in the Kemerovo and Tomsk regions was 19%. CONCLUSIONS: The incorporation of molecular analysis of the EGFR gene into routine clinical practice will allow clinicians to provide personalised therapy, resulting in a significant increase in survival rates and improvement in life quality of advanced NSCLC patients. PMID- 25684510 TI - Human telomerase gene and high-risk human papillomavirus infection are related to cervical intraepithelial neoplasia. AB - Our aims were to evaluate the clinical performance of human telomerase RNA gene component (hTERC gene) amplification assay with high-risk human papillomavirus (HR-HPV) DNA test of Hybrid Capture 2 DNA test (HC2), for the detection of high grade cervical precancerous lesions and cancer (CIN 2+). In addition, the association shown between hTERC gene amplification and HPV DNA test positive in women with and without cervical neoplasia was assessed. There were 92 women who underwent cytology, HR-HPV DNA test, hTERC gene amplification test, colposcopy and biopsy. We compared the clinical performance of hTERC gene test along with HR HPV DNA test of women with colposcopy and routine screening. The samples were histology- confirmed high-grade cervical intraepithelial neoplasia (CIN 2) or worse (CIN2+) as the positive criterion. The test of hTERC gene showed the hTERC gene amplification positivity increased with the severity of histological abnormality and cytological abnormality. The test of hTERC gene showed higher specificity than HR-HPV DNA test for high-grade lesions (84.4% versus 50%) and also higher positive predictive value (90.4% versus 76.5%). Our results predicted that hTERC gene amplification demonstrated more specific performance for predicting the risk of progression and offer a strong potential as a tool for triage in cervical cancer screening, with the limited sensitive as HR-HPV DNA test. PMID- 25684511 TI - Treatment of vemurafenib-resistant SKMEL-28 melanoma cells with paclitaxel. AB - Vemurafenib has recently been used as drug for treatment of melanomas with BRAFV600E mutation. Unfortunately, treatment with only vemurafenib has not been sufficiently effective, with recurrence after a short period. In this study, three vemurafenib-resistant BRAFV600E melanoma cell lines, A375PR, A375MR and SKMEL-28R, were established from the original A375P, A375M and SKMEL-28 cell lines. Examination of the molecular mechanisms showed that the phosphorylation levels of MEK and ERK, which play key roles in the RAS/RAF/MEK/ERK signaling pathway, were reduced in these three cell lines, with increased phosphorylation levels of pAKTs limited to SKMEL-28R cells. Treatment of SKMEL-28R cells with 100 nM paclitaxel resulted in increased apoptosis and decreased cellular proliferation, invasion and colony formation via reduction of expression levels of EGFR and pAKTs. Moreover, vemurafenib-induced pAKTs in SKMEL-28R were decreased by treatment with an AKT inhibitor, MK-2206. Taken together, our results revealed that resistance mechanisms of BRAFV600E-mutation melanoma cells to vemurafenib depended on the cell type. Our results suggested that paclitaxel should be considered as a drug in combination with vemurafenib to treat melanoma cells. PMID- 25684512 TI - A logistic model including risk factors for lymph node metastasis can improve the accuracy of magnetic resonance imaging diagnosis of rectal cancer. AB - BACKGROUND: To evaluate use of magnetic resonance imaging (MRI) and a logistic model including risk factors for lymph node metastasis for improved diagnosis. MATERIALS AND METHODS: The subjects were 176 patients with rectal cancer who underwent preoperative MRI. The longest lymph node diameter was measured and a cut-off value for positive lymph node metastasis was established based on a receiver operating characteristic (ROC) curve. A logistic model was constructed based on MRI findings and risk factors for lymph node metastasis extracted from logistic-regression analysis. The diagnostic capabilities of MRI alone and those of the logistic model were compared using the area under the curve (AUC) of the ROC curve. RESULTS: The cut-off value was a diameter of 5.47 mm. Diagnosis using MRI had an accuracy of 65.9%, sensitivity 73.5%, specificity 61.3%, positive predictive value (PPV) 62.9%, and negative predictive value (NPV) 72.2% [AUC: 0.6739 (95%CI: 0.6016-0.7388)]. Age (<59) (p=0.0163), pT (T3+T4) (p=0.0001), and BMI (<23.5) (p=0.0003) were extracted as independent risk factors for lymph node metastasis. Diagnosis using MRI with the logistic model had an accuracy of 75.0%, sensitivity 72.3%, specificity 77.4%, PPV 74.1%, and NPV 75.8% [AUC: 0.7853 (95%CI: 0.7098-0.8454)], showing a significantly improved diagnostic capacity using the logistic model (p=0.0002). CONCLUSIONS: A logistic model including risk factors for lymph node metastasis can improve the accuracy of MRI diagnosis of rectal cancer. PMID- 25684513 TI - DNA repair gene polymorphisms do not predict response to radiotherapy-based multimodality treatment of patients with rectal cancer: a meta-analysis. AB - BACKGROUND: : A number of association studies have been carried out to investigate the relationship between genetic polymorphisms in DNA repair genes and response to radiotherapy-based multimodality treatment of patients with rectal cancer. However, their conclusions were inconsistent. The objective of the present study was to assess the role of DNA repair gene genetic polymorphisms in predicting genetic biomarkers of the response in rectal cancer patients treated with neoadjuvant chemoradiation. MATERIALS AND METHODS: Studies were retrieved by searching the PubMed database, Cochrane Library, Embase, and ISI Web of Knowledge. We conducted a meta-analysis to evaluate the association between genetic polymorphisms and the response in rectal cancer treated with neoadjuvant chemoradiation by checking odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Data were extracted from 5 clinical studies for this meta-analysis. The results showed that XRCC1 RS25487, XRCC1 RS179978, XRCC3 RS861539, ERCC1 RS11615 and ERCC2 RS13181 were not associated with the response in the radiotherapy-based multimodality treatment of patients with rectal cancer (p>0.05). CONCLUSIONS: This study shows that DNA repair gene common genetic polymorphisms are not significantly correlated with the radiotherapy-based multimodality treatment in rectal cancer patients. PMID- 25684514 TI - Tumor markers in serum and ascites in the diagnosis of benign and malignant ascites. AB - OBJECTIVE: To evaluate the values of 4 tumor markers in serum and ascites and their ascites/serum ratios in the identification and diagnosis of benign and malignant ascites. MATERIALS AND METHODS: A total of 76 patients were selected as subjects and divided into malignant ascites group (45 cases) and benign ascites group (31 cases). Samples of ascites and serum of all hospitalized patients were collected before treatment. The levels of carcinoembryonic antigen (CEA), alpha fetoprotein (AFP), cancer antigen 125 (CA125) and carbohydrate antigen 19-9 (CA19 9) were detected by chemiluminescence (CLIA) . RESULTS: CEA, AFP and CA19-9 in both serum and ascites as well as CA125 in ascites were evidently higher in the malignant ascites group than in the benign ascites group (P<0.01). Malignant ascites was associated with elevated ascites/serum ratios for AFP and CA125 (P<0.01). The areas under receiver operating characteristic (AUROCs) of CEA and CA125 in ascites and the ratios of ascites/serum of AFP, CEA, CA125 and CA19-9 were all >0.7, suggesting certain values, while those of ascites CA19-9 and serum CEA were 0.697 and 0.629 respectively, indicating low accuracy in the identification and diagnosis of benign and malignant ascites. However, the AUROCs of the remaining indexes were <0.5, with no value for identification and diagnosis. Compared with single index, the sensitivity of combined detection increased significantly (P<0.05), in which the combined detection of CEA, CA19-9 and CA125 in ascites as well as the ratio of ascites/serum of CEA, CA19-9, CA125 and AFP had the highest sensitivity (98.4%) but with relevantly low specificity. Both sensitivity and specificity of combined detection should be comprehensively considered so as to choose the most appropriate index. CONCLUSIONS: Compared with single index, combined detection of tumor markers in serum and ascites can significantly improve the diagnostic sensitivity and specificity. PMID- 25684515 TI - Symptom experiences and coping strategies among multi- ethnic solid tumor patients undergoing chemotherapy in Malaysia. AB - BACKGROUND: This study was performed to assess patient symptoms prevalence, frequency and severity, as well as distress and coping strategies used, and to identify the relationships between coping strategies and psychological and physical symptoms distress and demographic data of cancer patients. This cross sectional descriptive study involved a total of 268 cancer patients with various types of cancer and chemotherapy identified in the oncology unit of an urban tertiary hospital. MATERIALS AND METHODS: Data were collected using questionnaires (demographic questionnaire, Medical characteristics, Memorial Symptom Assessment Scale (MSAS) and Brief COPE scales and analyzed for demographic, and disease-related variable effects on symptom prevalence, severity, distress and coping strategies. RESULTS: Symptom prevalence was relatively high and ranged from 14.9% for swelling of arms and legs to 88.1% for lack of energy. This latter was the highest rated symptom in the study. The level of distress was found to be low in three domains. Problem-focused coping strategies were found to be more commonly employed compared to emotion-focused strategies, demonstrating significant associations with sex, age group, educational levels and race. However, there was a positive correlation between emotion-focused strategies and physical and psychological distress, indicating that patients would choose emotion-focused strategies when symptom distress increased. CONCLUSIONS: These findings demonstrate that high symptom prevalence rates and coping strategies used render an improvement in current nursing management. Therefore development of symptoms management groups, encouraging the use of self-care diaries and enhancing the quality of psycho- oncology services provided are to be recommended. PMID- 25684516 TI - Cancer risk factors in Korean news media: a content analysis. AB - BACKGROUND: Little is known about the news coverage of cancer risk factors in Korea. This study aimed to examine how the news media encompasses a wide array of content regarding cancer risk factors and related cancer sites, and investigate whether news coverage of cancer risk factors is congruent with the actual prevalence of the disease. MATERIALS AND METHODS: A content analysis was conducted on 1,138 news stories covered during a 5-year period between 2008 and 2012. The news stories were selected from nationally representative media in Korea. Information was collected about cancer risk factors and cancer sites. RESULTS: Of various cancer risk factors, occupational and environmental exposures appeared most frequently in the news. Breast cancer was mentioned the most in relation to cancer sites. Breast, cervical, prostate, and skin cancer were overrepresented in the media in comparison to incidence and mortality cases, whereas lung, thyroid, liver, and stomach cancer were underrepresented. CONCLUSIONS: To our knowledge, this research is the first investigation dealing with news coverage about cancer risk factors in Korea. The study findings show occupational and environmental exposures are emphasized more than personal lifestyle factors; further, more prevalent cancers in developed countries have greater media coverage, not reflecting the realities of the disease. The findings may help health journalists and other health storytellers to develop effective ways to communicate cancer risk factors. PMID- 25684517 TI - Factors affecting disease-free status of differentiated thyroid carcinoma patients. AB - PURPOSE: The study aim was to assess factors that impact on the outcome of radioiodine therapy in patients diagnosed with differentiated thyroid carcinoma (DTC). MATERIALS AND METHODS: We performed a retrospective cohort study on 256 patients with DTC who underwent thyroidectomy and received radioiodine therapy during December 2003 to January 2012. All patients were followed up for at least 1 year. They were considered disease- free by the criteria of the revised American Thyroid Association Management Guideline for Patients with Thyroid nodules and DTC (ATA guideline 2009). RESULTS: On Cox univariate analysis, factors associated with disease-free status were age<45, stage I tumor, low risk group by histopathology, unifocal tumor involvement, stimulated serum Tg level at 1st dose of radioiodine therapy and no distant metastasis from 1st post-treatment WBS (post RxWBS). On multivariate analysis, stage I tumor and stimulated serum Tg level at 1st dose of radioiodine therapy<30 ng/mL were the significant prognostic factors that increased disease-free rate by 1.73 times and 2.60 times, respectively (P-value<0.05). CONCLUSIONS: Factors affecting the outcome of radioiodine therapy in our study were age, stage, risk of recurrence by histopathology, unifocal tumor involvement and 1st postRxWBS findings. From these factors, stage I tumor and stimulated serum Tg level at 1st dose of radioiodine therapy were independent prognostic factors that substantial increase the disease free rate. PMID- 25684518 TI - Exogenous p53 upregulated modulator of apoptosis (PUMA) decreases growth of lung cancer A549 cells. AB - PURPOSE: To investigate the influence of exogenous p53 upregulated modulator of apoptosis (PUMA) expression on cell proliferation and apoptosis in human non small cell lung cancer A549 cells and transplanted tumor cell growth in nude mice. MATERIALS AND METHODS: A549 cells were divided into the following groups: control, non- carrier (NC), PUMA (transfected with pCEP4- (HA) 2-PUMA plasmid), DDP (10 MUg/mL cisplatin treatment) and PUMA+DDP (transfected with pCEP4-(HA)2 PUMA plasmid and 10 MUg/mL cisplatin treatment). The MTT method was used to detect the cell survival rate. Cell apoptosis rates were measured by flow cytometry, and PUMA, Bax and Bcl-2 protein expression levels were measured by Western blotting. RESULTS: Compared to the control group, the PUMA, DDP and PUMA+DDP groups all had significantly decreased A549 cell proliferation (p<0.01), with the largest reduction in the PUMA+DDP group. Conversely, the apoptosis rates of the three groups were significantly increased (P<0.01), and the PUMA and DDP treatments were synergistic. Moreover, Bax protein levels significantly increased (p<0.01), while Bcl-2 protein levels significantly decreased (p<0.01). Finally, both the volume and the weights of transplanted tumors were significantly reduced (p<0.01), and the inhibition ratio of the PUMA+DDP group was significantly higher than in the single DDP or PUMA groups. CONCLUSIONS: Exogenous PUMA effectively inhibited lung cancer A549 cell proliferation and transplanted tumor growth by increasing Bax protein levels and reducing Bcl-2 protein levels. PMID- 25684519 TI - A prognostic model to predict survival in stage III colon cancer patients based on histological grade, preoperative carcinoembryonic antigen level and the neutrophil lymphocyte ratio. AB - BACKGROUND: Stage III colon cancer patients demonstrate diverse clinical outcomes. The aim of this study was to develop a prognostic model in order to better predict their survival. MATERIALS AND METHODS: From 2004 to 2010, 548 patients were retrospectively analyzed, among whom 328 were defined as the study group and the remaining 220 served as a validation group. Clinico-pathologic features, including age, gender, histological grade, T stage, number of positive lymph nodes, number of harvest lymph nodes, pretreatment carcinoembryonic antigen (CEA) levels and pretreatment neutrophil lymphocyte ratio (NLR), were collected. Kaplan-Meier survival curves were used to detect prognostic factors and multivariate analysis was applied to identify independent examples on which to develop a prognostic model. Finally, the model was further validated with the validation group. RESULTS: Histological grade (p=0.002), T stage (p=0.011), number of positive lymph nodes (p=0.003), number of harvested lymph nodes (p=0.020), CEA (p=0.005), and NLR (p<0.001) were found as prognostic factors while histological grade [RR(relative risk):0.632, 95%CI (Confidence interval) 0.405~0.985, p=0.043], CEA (RR:0.644, 95%CI:0.431~0.964, p=0.033) and NLR (RR:0.384, 95%CI:0.255~0.580, p<0.001) levels were independent. The prognostic model based on these three factors was able to classify patients into high risk, intermediate and low risk groups (p<0.001), both in study and validation groups. CONCLUSIONS: Histological grade, pretreatment CEA and NLR levels are independent prognostic factors in stage III colon cancer patients. A prognostic model based on these factors merits attention in future clinical practice. PMID- 25684520 TI - Is early detection of colon cancer possible with red blood cell distribution width? AB - BACKGROUND: Red cell distribution width (RDW) is one of the standard parameters with blood cell counts. Much previous research has indicated that it increases in cases of systemic inflammation or cardiametabolic incident. However, information on the relation of RDW with solid tumors causing systemic inflammation is limited. In the present research, we examined the relation of RDW with malignant and benign lesions of the colon. MATERIALS AND METHODS: 115 patients with colon polyps (group 1), and 30 with colon cancer (group 2) who were diagnosed histopathologically in our clinic between January 2010-January 2013 were scanned retrospectively. Patients with anemia, hematologic diseases and active inflammation were excluded. RDW, mean corpuscular volume (MCV), hemoglobin (Hgb) and platelet (Plt) measurements were recorded and their relations with the malignant and benign lesions of the colon were examined. RESULTS: Both groups were similar in age and gender distribution. RDW values of patients with colon cancer were significantly higher than the patients with colon polyp (p=0,01). No significant differences were detected between the two groups in terms of MCV and Plt values (p>0,05). CONCLUSIONS: RDW can be used as an early warning biomarker for solid colon tumors. Further prospective research is required on the relations of cheap and easily measured RDW parameters with colon malignancies. PMID- 25684521 TI - Rhabdomyosarcoma--an epidemiological and histopathologic study of 277 cases from a major tertiary care center in Karachi, Pakistan. AB - AIM: To present the epidemiologic data (age, gender, size etc) and histopathologic and immunohistochemical features of cases of rhabdomyosarcoma (RMS) reported in our department. SETTINGS: Section of Histopathology, Department of Pathology and Microbiology, Aga Khan University Hospital, Karachi, Pakistan. DURATION: All cases of RMS diagnosed between January 1, 2003 and December 31, 2012 were included in the study. RESULTS: A total of 277 cases were included. Embryonal rhabdomyosarcoma (ERMS) was by far the dominant histologic type (87.4%) followed by alveolar type (ARMS)(9.4%). ERMS was much more common in males (64.0%)and over 65% of cases occurred in the first decade of life (over 90% in the first two decades). Head and neck region was commonest site for ERMS (46.7%), followed by the genitourinary system (16.1%). Over 65% cases of ARMS occurred in the extremities. Over 80% cases of ARMS occurred in the first 3 decades of life. Immunohistochemical staining for Desmin and MyoD1 was positive in 96.7% and 85.4% respectively. CONCLUSIONS: The epidemiologic data and microscopic findings in our patients are similar to international published data on rhabdomyosarcoma. PMID- 25684522 TI - Wild carrot oil extract is selectively cytotoxic to human acute myeloid leukemia cells. AB - BACKGROUND: In this study, we used Daucus carota oil extract (DCOE) to target acute myeloid leukemia (AML) cells. All the AML cell lines tested were sensitive to the extract while peripheral mononuclear cells were not. Analysis of mechanism of cell death showed an increase in cells positive for annexinV and for active caspases, indicating that DCOE induces apoptotic cell death in AML. Inhibition of the MAPK pathway decreased sensitivity of AML cells to DCOE, indicating that cytotoxicity may be dependent on its activity. In conclusion, DCOE induces selective apoptosis in AML cells, possibly through a MAPK-dependent mechanism. PMID- 25684523 TI - Fibulin-5 is a prognostic marker that contributes to proliferation and invasion of human glioma cells. AB - Fibulin-5 has recently been considered as a potential tumor suppressor in human cancers. Several studies have shown that it is down-regulated in a variety of tumor types and inhibits tumor growth and metastasis. This study was aimed to investigate the clinical significance of fibulin-5 in glioma and its role in cell proliferation and invasion. We found that the expression of fibulin-5 in glioma tissues was significantly lower than those in normal brain (NB) tissues. Negative expression was significantly correlated with advanced clinical stage (grade III+IV). Furthermore, Fibulin-5 negative expression was correlated with a shorter overall survival of glioma patients. Multivariate Cox repression analysis indicated that fibulin-5 was an independent factor for predicting overall survival of glioma patients. Overexpression obviously inhibited cell proliferation in U251 and U87 cells. Furthermore, it significantly reduced the number of migrating and invading glioma cells. In conclusion, impaired expression of fibulin-5 is correlated with the advanced tumor stage in glioma. Otherwise, Fibulin-5 is an independent prognostic marker for predicting overall survival of glioma patients. Mechanistically, it may function as a tumor suppressor via inhibiting cell proliferation and invasion in gliomas. PMID- 25684524 TI - RB1 polymorphism contributes to the efficacy of platinum-taxanes in advanced squamous cell lung cancer. AB - BACKGROUND: RB1 (retinoblastoma 1) was reportedly one of the major determinative factors for sensitivity to taxanes in previous studies. In this study, we investigated the influence of RB1 single nucleotide polymorphisms (SNPs) on the efficacy of platinum-taxane regimens in advanced NSCLC patients. MATERIALS AND METHODS: 234 cases of patients with advanced NSCLC who were treated with first line platinum-taxane agents were enrolled in this study. Genomic DNA was extracted from patients' peripheral blood samples using a QIAamp DNA Maxi Kit, and genotyped by iSelect HD Bead-Chip. RESULTS: Regression analyses were conducted through the univariate and multivariate Cox proportional hazards model in the 234 patients. The results showed that of the eight RB1 tagSNPs, only rs4151510 was a positive predictive factor for the advanced NSCLC patients treated with platinum taxanes regimen. The patients with G/G genotype of RB rs4151510 had longer overall survival (OS) than the non-G/G genotype (p=0.018). The histology was also correlated with OS in the whole advanced NSCLC patients. Three tagSNPs of RB1, rs4151510, rs4151465, rs9568036 were significantly associated with OS in the advanced NSCLC patients with squamous cell histology using Kaplan-Meier overall survival analysis stratified by histology. CONCLUSIONS: RB1 genomic variants were correlated with the efficacy of platinum taxanes regimen. RB rs4151510 is an independent factor of the prognosis of NSCLC patients receiving platinum-taxane chemotherapy. PMID- 25684525 TI - Hospitalization risk according to geriatric assessment and laboratory parameters in elderly hematologic cancer patients. AB - BACKGROUND: Utilizing geriatric screening tools for the identification of vulnerable older patients with cancer is important. The aim of this study is to evaluate the hospitalization risk of elderly hematologic cancer patients based on geriatric assessment and laboratory parameters. MATERIALS AND METHODS: In this cross sectional study 61 patients with hematologic malignancies, age 65 years and older, were assessed at a hematology outpatient clinic. Standard geriatric screening tests; activities of daily living (ADL), instrumental activities of daily living (IADL), Mini Nutritional Assessment (MNA), Mini Mental State Examination (MMSE), timed up and go test (TUG), geriatrics depression scale (GDS) were administered. Demographic and medical data were obtained from patient medical records. The number of hospitalizations in the following six months was then recorded to allow analysis of associations with geriatric assessment tools and laboratory parameters. RESULTS: The median age of the patients, 37 being males, was 66 years. Positive TUG test and declined ADL was found as significant risk factors for hospitalization (p=0.028 and p=0.015 respectively). Correlations of hospitalization with thrombocytopenia, vitamin B12 and folic acid deficiency were statistically significant (p=0.004, p=0.011 and p=0.05 respectively). CONCLUSIONS: In this study, geriatric conditions which are usually unrecognized in a regular oncology office visit were identified. Our study indicates TUG and ADL might be use as predictive tests for hospitalization in elderly oncology populations. Also thrombocytopenia, and vitamin B12 and folic acid deficiencies are among the risk factors for hospitalization. The importance of vitamin B12 and folic acid vitamin replacement should not be underestimated in this population. PMID- 25684526 TI - Lack of association between using aspirin and development of non-Hodgkins lymphoma: a meta-analysis. AB - BACKGROUND: Non-Hodgkins lymphoma (NHL) is a heterogeneous group of malignancies, originating in the lymphatic organs, whose incidence is increasing in developed as well as developing countries. Epidemiological evidence suggests that aspirin may reduce the incidence and mortality of several cancers. The main objective of this study was to evaluate the potential relationship between using aspirin and development of NHL with a meta-analysis. MATERIALS AND METHODS: A total of 7 studies were included. Outcome was calculated and reported as odds ratios (ORs). Heterogeneity was assessed with Cochrane Q and I2 statistics. Dissemination bias was evaluated by funnel plot visualization and trim-and-fill analysis. RESULTS: Our analysis showed OR of developing NHL overall of 1(95% CI: 0.87-1.16, p=0.9), and in females this was 0.81 (95%CI: 0.72-.92, p=0.001) and in males 1.01 (95%CI: 0.82-1.26, p=0.86). The odds ratio (OR) of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) was 0.85 (95%CI: 0.75-0.97, p=0.02), The ORs of follicular lymphoma (FL) and large B-cell lymphoma (DLBCL) in individuals exposed to aspirin were 1.12 (95%CI: 0.86-1.45, p=0.37) and 1.03 (95%CI: 0.9-1.19, p=0.6) respectively. CONCLUSIONS: In conclusion, individuals taking aspirin do not demonstrate any change in risk of Non-Hodgkins lymphoma. PMID- 25684527 TI - Clinico-hematological profile of patients with B-chronic lymphoid leukemia in Pakistan. AB - BACKGROUND: Chronic lymphoid leukemia (CLL) is not an uncommon hematological malignancy which primarily affects elderly individuals. It is more common in developed world than in developing countries. The rational of this study was to determine the clinico-hematological profile in Pakistan. MATERIALS AND METHODS: In this prospective cross sectional study, sixty patients with CLL were enrolled from January 2011 to June 2013. Data were analyzed with SPSS version 21. RESULTS: The mean age was 59.0+/-9.2 years (range 40-82) and the male to female ratio was 2.1:1. Peak age group was 60-70 years (38.3%) and 18.3% were under 50 years old. Major complaints were weakness (51.7%), fever (18.3%) and abdominal discomfort (13.3%). Main clinical findings were splenomegaly (46.6%), lymphadenopathy (36.6%) and pallor (26.7%). Some 16.7% were diagnosed incidentally. The mean hemoglobin was 10.8+/-2.4 g/dl, with a total leukocyte count of 91.5+/ 87.8x10(9)/l and platelets 197.8+/-103.2x10(9)/l. Anemia and thrombocytopenia were seen in 26.7% and 21.7% of cases, respectively. High LDH and hyperuricemia were detected in 15% each and elevated serum creatinine was seen in 11.6%. According to Rai staging 11.6% were in stage 0, 13.3% stage 1, 26.7% each for stage II and stage III while 21.7% patients were in stage IV. CONCLUSIONS: CLL in our patients in Pakistan, unlike in the West, is seen in a relatively young population with male predominance. Primarily disease is of B- cell origin and about 2/3 of the patients present at advanced stage. PMID- 25684528 TI - Perfusion computed tomography in predicting treatment response of advanced esophageal squamous cell carcinomas. AB - BACKGROUND: The purpose of this study was to prospectively evaluate the predictive value of perfusion computed tomography (CT) for response of local advanced esophageal carcinoma to radiotherapy and chemotherapy. MATERIALS AND METHODS: Before any treatment, forty-three local advanced esophageal squamous cell carcinomas were prospectively evaluated by perfusion scan with 16-row CT from June 2009 to January 2012. Perfusion parameters, including perfusion (BF), peak enhanced density (PED), blood volume (BV), and time to peak (TTP) were measured using Philips perfusion software. Seventeen cases received definitive radiotherapy and 26 received concurrent chemo-radiotherapy. The response was evaluated by CT scan and esophagography. Differences in perfusion parameters between responders and non-responders were analyzed, and ROCs were used to assess predictive value of the baseline parameters for treatment response. RESULTS: There were 25 responders (R) and 18 non-responders (NR). Responders showed significantly higher BF (R:34.1 ml/100 g/min vs NR: 25.0 ml/100 g/min, p=0.001), BV (23.2 ml/100g vs 18.3 ml/100g, p=0.009) and PED (32.5 HU vs 28.32 HU, P=0.003) than non-responders. But the baseline TTP (R: 38.2 s vs NR: 44.10 s, p=0.172) had no difference in the two groups. For baseline BF, a threshold of 36.1 ml/100 g/min achieved a sensitivity of 56%, and a specificity of 94.4% for detection of clinical responders from non-responders. CONCLUSIONS: The results suggest that the perfusion CT can provide some helpful information for identifying tumors that may respond to radio-chemotherapy. PMID- 25684529 TI - Association of paraoxonase-1(Q192R and L55M) gene polymorphisms and activity with colorectal cancer and effect of surgical intervention. AB - BACKGROUND: Colorectal cancer (CRC) is a leading cause of cancer-related death. Oxidative DNA damage may contribute to cancer risk and the antioxidant paraoxonase is one endogenous free radical scavenger in the human body which could therefore exert an influeence. PURPOSE: Aim of this study was to determine the role of serum arylesterase (ARE) and paraoxonase 1(PON1) activities in CRC patients and to find any association between (PON1) Q192R and L55M gene polymorphisms in CRC patients. Also the serum ARE and PON1 activities in CRC patients will be investigated before and after surgery Materials and Methods: This study involved a total of 50 patients with newly diagnosed CRC and 80 healthy controls. PON1 and ARE activities were determined using an enzymatic spectrophotometric method. PON1 Q192R and L55M gene polymorphisms were determined using polymerase chain reaction-restriction fragment length polymorphism (PCR RFLP) based restriction fragment analysis. The restriction enzyme AlwI was used to examine the Q192R polymorphism and Hsp92II for the L55M polymorphism. RESULTS: Significant differences in the PON1 Q192R polymorphism were found between patients and controls. The Q allele was more frequent in the patient group than in controls, while the R allele was more frequent in the controls. Significant differences were found in the L55M polymorphism. Additionally, there were significant differences in L and M allele frequencies (p=0.001). The serum activities of PON1 and ARE were low in QQ and MM genotype. CONCLUSIONS: serum PON1 and ARE activities were significantly lower in CRC patients compared to healthy subjects. The R allele may protect against colorectal cancer. PMID- 25684530 TI - Community based intervention for tobacco cessation: a pilot study experience, north East India. AB - BACKGROUND: North East India has a high prevalence of tobacco consumption, but only few individualsseek help for tobacco cessation. Impact of community based tobacco cessation intervention in this part needs more research. MATERIALS AND METHODS: Retrospective analysis was done on the dataset from a community-based tobacco cessation intervention pilot project conducted in Guwahati metro during 2009-10. Subjects, both male and female tobacco users, age>15 years, permanent residents of these blocks giving consent were included in the study. RESULTS: The sample was 800 tobacco users, of whom 25% visited any health care provider during last 12 months and 3% received tobacco cessation advice. An 18% quit rate was observed at six weeks follow up, more than the National average, with a 47% quit rate at eight months, while 52% of subjects reduced use. CONCLUSIONS: Higher tobacco quit rate and reduced tobacco use, no loss to follow up and negligible relapse was observed with this community based intervention design. Such designs should be given more emphasis for implementation in specified communities with very high tobacco consumption rates, cultural acceptance of tobacco and less motivation towards quitting. PMID- 25684531 TI - Lung cancer in women, a different disease: survival differences by sex in Turkey. AB - PURPOSE: In this study, we aimed to evaluate the effects of sex-based non-small cell lung cancer (NSCLC) varieties on survival rates. MATERIALS AND METHODS: A retrospective study was performed in patients with NSCLC who were diagnosed by histological methods between the years 2000 and 2010. A chi-square test was used to compare variables. Overall survival (OS) was estimated by the Kaplan-Meier method. RESULTS: Of the 844 patients, 117 (13.9%) were women and 727 (86.1%) were men. Adenocarcinoma was more common in women than in men (p<0.0001). There were more women non-smokers than men (p<0.0001). There was no statistically significant difference in ECOG PS, weight loss>10%, stage, LDH, albumin and treatment between women and men. Women younger than 65 years (17.0 vs 12.0 months; p=0.03), who had adenocarcinoma histology (15.0 vs 10.0 months; p=0.006) and who had a hemoglobin level>=12 g/dL (18.0 vs 12.0 months; p=0.01) were found to have a better median OS rate than men. Median OS rates were found to be 13.0 months in females and 12.0 months in males (p=0.14). Among metastatic patients, the median OS was 11.0 months in females and 8.0 months in males (p=0.005). Among stage IIIB and stage IV patients who had first line platinum-based chemotherapy, the median OS was 17.0 months in women and 11.0 months in men (p=0.002). The response rate of chemotherapy was higher in women than in men (p=0.03). CONCLUSIONS: In our study, we found that survival duration is longer and chemotherapy response is better in women with NSCLC who do not have anemia or comorbidities and who are mostly non-smokers with adenocarcinomas. Further studies regarding the causes of these differences may provide clarity on this subject. PMID- 25684532 TI - Relation between Ki-67, ER, PR, Her2/neu, p21, EGFR, and TOP II-alpha expression in invasive ductal breast cancer patients and correlations with prognosis. AB - The aim of the present study was to investigate the expression of the transcription factor Ki-67, ER, PR, Her2/neu, p21, EGFR, and TOP II-alpha in the tumor tissue of patients with invasive ductal carcinoma(IDC); in addition, we examined correlations between these markers. Two hundred and sixteen IDC patients, who were not previously been treated with chemo- or radiotherapy, were included in the study. All tumors were grade I-III. Expression of molecular markers was determined by immunohistochemical analysis on paraffin-embedded tissue sections. Follow-up data were collected for 3 months to 10 years and analyzed for tumor recurrence, survival time, and prognostic risk factors. We determined Ki-67 expression correlates with the expression of ER, PR, HER-2, EGFR, and TOP-alpha, as well as lymph node involvement, high tumor grade, lymphovascular invasion, high tumor stage, and high TNM stage in IDC. Positive Ki 67 expression was a risk factor for rapid tumor recurrence and may help tumor progression, leading to poor prognosis in IDC. Ki-67 was directly correlated with EGFR, TOP II-alpha, lymph node involvement, high tumor grade, lymphovascular invasion, high tumor stage, and high TNM stage in the hormone receptor subtypes of breast cancer. In triple negative breast cancer, Ki-67 correlated with TOP II alpha. Expression of Ki-67 correlated with that of ER, PR, HER-2, EGFR, TOP II alpha, and p21. In addition, the biomarker Ki-67 has a role as a prognostic factor and indicates a poor prognosis in IDC. PMID- 25684533 TI - Inhibitory effects of dunning rat prostate tumor fluid on proliferation of the metastatic MAT-LyLu cell line. AB - Tumor fluid accumulation occurs in both human cancer and experimental tumor models. Solid tumors show a tendency to tumor fluid accumulation because of their anatomical and physiological features and this may be influenced by molecular factors. Fluid accumulation in the peri-tumor area also occurs in the Dunning model of rat prostate cancer as the tumor grows. In this study, the effects of tumor fluids that were obtained from Dunning prostate tumor-bearing Copenhagen rats on the strongly metastatic MAT-LyLu cell line were investigatedby examining the cell's migration and tumor fluid's toxicity and the kinetic parameters such as cell proliferation, mitotic index, and labelling index. In this research, tumor fluids were obtained from rats injected with 25105 MAT- LyLu cells and treated with saline solution, and 200 nM tetrodotoxin (TTX), highly specific sodium channel blocker was used. Sterilized tumor fluids were added to medium of MAT-LyLu cells with the proportion of 20% in vitro. Consequently, it was demonstrated that Dunning rat prostate tumor fluid significantly inhibited proliferation (up to 50%), mitotic index, and labeling index of MAT-LyLu cells (up to 75%) (p<0.05) but stimulated the motility of the cells in vitro. PMID- 25684534 TI - The myth of not disclosing the diagnosis of cancer: does it really protect elderly patients from depression? AB - BACKGROUND: The disclosure of a diagnosis of cancer is complex, particularly in older patients. The aim of this study was to investigate the association between age and not knowing the diagnosis, and its impact on mood. MATERIALS AND METHODS: The study included 70 patients with various types of solid and hematologic cancer in early stages, which were followed up in an outpatient oncology/hematology clinic in Turkey between January, 2014 and June, 2014. Initially the caregivers of patients were asked whether the patients knew their diagnosis or not. A questionnaire for the Geriatric Depression Scale was then administered to the patients. Patient age, gender, marital status and education level were noted and analyzed with respect to knowing the diagnosis and depression. RESULTS: Of the 70 patients, 40% of them were female. The mean age was 68.2+/-8.9. The rate of the patients who does not know their diagnosis was 37.1% (n=26). The overall depression rate with GDS was found 37.1% (n=26) among the participants. There was no association with knowing the diagnosis (p=0.208) although the association between not knowing the diagnosis and age was significant (p=0.01). CONCLUSIONS: In this study we revealed no association between not knowing the diagnosis and depression in elderly patients. Contrary to what some has thought, the patient is not protected from psychological distress by not being informed about the diagnosis. We believe this study and similar ones will help to discuss and further explore patient autonomy, the principle of respect to self-determination and end of life issues in different cultures. PMID- 25684535 TI - IL-1B (C+3954T) gene polymorphism and susceptibility to gastric cancer in the Iranian population. AB - BACKGROUND: Gastric cancer as one of the most important diseases affecting health in all worldwide. Current studies have confirmed associations of cytokine gene polymorphisms with the risk of gastric cancer development. The current research aimed to assess the association of IL-1B+3954 genotypes with the risk of gastric cancer in the Iranian population. MATERIALS AND METHODS: This case-control study covered 49 gastric cancer patients compared to 53 cancer free individuals as a control group. Genomic-DNA extraction was carried out from bioptic samples of patients and peripheral blood of healthy volunteers. Polymorphism of IL-1B +3954 genotypes were analysed with a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. RESULTS: The frequencies of IL-1B +3954 A1A1, A1A2 and A2A2 genotypes in healthy individuals were 26.4, 66 and 7.6 %, respectively. However, in gastric cancer patients, A1A1, A1A2 and A2A2 with 4.1, 51 and 44.9% were observed (p<0.05). CONCLUSIONS: The findings of our results show a positive association between the IL-1B+3954 genotype distribution and the risk of gastric cancer disease in the Iranian population. PMID- 25684536 TI - Illness representations of cancer among healthy residents of Kolkata, India. AB - Cancer illness representations and screening history among residents of Kolkata, India, were investigated along with socio-demographic characteristics in an effort to understand possible motivations for health behavior. A total of 106 participants were recruited from community locations in Kolkata, India and completed surveys including demographics, the illness perception questionnaire revised (IPQ-R), and previous experience with cancer and screening practices. Participants were 51.5% college educated, 57% female, 51.5% full-time employed with average age of 32.7 years (R: 18-60 years). Descriptive statistics were generated for the subscales of the IPQ-R, cancer-screening practices and cancer experience. Correlation analyses were conducted to investigate associations between cancer representations and socio-demographic variables. Univariate ANOVAs were calculated to determine gender differences in IPQ-R subscales and differences between participants who knew someone diagnosed with cancer versus those who did not. While 76% of participants knew someone with cancer, only 5% of the sample engaged in cancer screening. Participants perceived cancer as a serious illness with negative emotional valence. Younger age (r(100)=-.36, p<0.001) and male gender (F(1, 98)=5.22, p=0.01, eta2=0.05) were associated with better illness coherence. Males also reported greater personal control (F(1, 98)=5.34, p=0.02, eta2=0.05) were associated with better illness coherence. Low screening rates precluded analyses of the relationship between illness representations and cancer screening. Cancer was viewed as a threatening and uncontrollable disease among this sample of educated, middle class Kolkata residents. This view may act as a barrier to seeking cancer screening. Public awareness campaigns aimed at improving understanding of the causes, symptoms and consequences of cancer might reduce misunderstandings and fear, especially among women and older populations, who report less comprehension of cancer. PMID- 25684537 TI - Administration of CoQ10 analogue ameliorates dysfunction of the mitochondrial respiratory chain in a mouse model of Angelman syndrome. AB - Genetic defects in the UBE3A gene, which encodes for the imprinted E6-AP ubiquitin E3 ligase (UBE3A), is responsible for the occurrence of Angelman syndrome (AS), a neurodegenerative disorder which arises in 1 out of every 12,000 20,000 births. Classical symptoms of AS include delayed development, impaired speech, and epileptic seizures with characteristic electroencephalography (EEG) readings. We have previously reported impaired mitochondrial structure and reduced complex III in the hippocampus and cerebellum in the Ube3a(m-/p+) mice. CoQ10 supplementation restores the electron flow to the mitochondrial respiratory chain (MRC) to ultimately increase mitochondrial antioxidant capacity. A number of recent studies with CoQ10 analogues seem promising in providing therapeutic benefit to patients with a variety of disorders. CoQ10 therapy has been reported to be safe and relatively well-tolerated at doses as high as 3000mg/day in patients with disorders of CoQ10 biosynthesis and MRC disorders. Herein, we report administration of idebenone, a potent CoQ10 analogue, to the Ube3a(m-/p+) mouse model corrects motor coordination and anxiety levels, and also improves the expression of complexes III and IV in hippocampus CA1 and CA2 neurons and cerebellum in these Ube3a(m-/p+) mice. However, treatment with idebenone illustrated no beneficial effects in the reduction of oxidative stress. To our knowledge, this is the first study to suggest an improvement in mitochondrial respiratory chain dysfunction via bioenergetics modulation with a CoQ10 analogue. These findings may further elucidate possible cellular and molecular mechanism(s) and ultimately a clinical therapeutic approach/benefit for patients with Angelman syndrome. PMID- 25684538 TI - Genetic and biochemical intricacy shapes mitochondrial cytopathies. AB - The major progress made in the identification of the molecular bases of mitochondrial disease has revealed the huge diversity of their origin. Today up to 300 mutations were identified in the mitochondrial genome and about 200 nuclear genes are possibly mutated. In this review, we highlight a number of features specific to mitochondria which possibly participate in the complexity of these diseases. These features include both the complexity of mitochondrial genetics and the multiplicity of the roles ensured by the organelles in numerous aspects of cell life and death. This spectacular complexity presumably accounts for the present lack of an efficient therapy in the vast majority of cases. PMID- 25684539 TI - Motor and behavioral phenotype in conditional mutants with targeted ablation of cortical D1 dopamine receptor-expressing cells. AB - D1-dopamine receptors (Drd1a) are highly expressed in the deep layers of the cerebral cortex and the striatum. A number of human diseases such as Huntington disease and schizophrenia are known to have cortical pathology involving dopamine receptor expressing neurons. To illuminate their functional role, we exploited a Cre/Lox molecular paradigm to generate Emx-1(tox) MUT mice, a transgenic line in which cortical Drd1a-expressing pyramidal neurons were selectively ablated. Emx 1(tox) MUT mice displayed prominent forelimb dystonia, hyperkinesia, ataxia on rotarod testing, heightened anxiety-like behavior, and age-dependent abnormalities in a test of social interaction. The latter occurred in the context of normal working memory on testing in the Y-maze and for novel object recognition. Some motor and behavioral abnormalities in Emx-1(tox) MUT mice overlapped with those in CamKIIalpha(tox) MUT transgenic mice, a line in which both striatal and cortical Drd1a-expressing cells were ablated. Although Emx 1(tox) MUT mice had normal striatal anatomy, both Emx-1(tox) MUT and CamKIIalpha(tox) MUT mice displayed selective neuronal loss in cortical layers V and VI. This study shows that loss of cortical Drd1a-expressing cells is sufficient to produce deficits in multiple motor and behavioral domains, independent of striatal mechanisms. Primary cortical changes in the D1 dopamine receptor compartment are therefore likely to model a number of core clinical features in disorders such as Huntington disease and schizophrenia. PMID- 25684540 TI - Blistering psoriatic plaques during narrowband UVB phototherapy. PMID- 25684541 TI - Therapeutic outcomes of neoadjuvant and concurrent androgen-deprivation therapy and intensity-modulated radiation therapy with gold marker implantation for intermediate-risk and high-risk prostate cancer. AB - OBJECTIVES: To investigate the therapeutic outcomes of neoadjuvant and concurrent androgen-deprivation therapy and intensity-modulated radiation therapy with gold marker implantation for intermediate- and high-risk prostate cancer. METHODS: This was a retrospective study of 325 patients with intermediate- or high-risk prostate cancer according to the National Comprehensive Cancer Network guidelines who underwent androgen-deprivation therapy and intensity-modulated radiation therapy (76 Gy) after gold marker implantation between 2001 and 2010. RESULTS: The 5-year distant metastasis-free survival rate was significantly lower for very high-risk patients than for intermediate- and high-risk patients (82.6% vs 99.4% and 96.5%, respectively; P < 0.01). The 5-year biochemical relapse-free survival rates significantly declined with increasing prostate cancer risk (P < 0.01), and were 95.9%, 87.2%, and 73.1% for the intermediate-risk, high-risk and very high-risk patients, respectively. Acute genitourinary and gastrointestinal toxicity grade >=3 were not observed in any of the patients. Late grade 3 genitourinary toxicity occurred in 0.3% of patients. CONCLUSION: Combination androgen-deprivation therapy and 76-Gy intensity-modulated radiation therapy with gold marker implantation offers good therapeutic outcomes with few serious complications in patients with intermediate- and high-risk prostate cancer. PMID- 25684542 TI - A new chiral C1-symmetric NHC-catalyzed addition to alpha-aryl substituted alpha,beta-disubstituted enals: enantioselective synthesis of fully functionalized dihydropyranones. AB - The first enantioselective NHC-catalyzed activation of alpha-aryl substituted alpha,beta-disubstituted unsaturated aldehyde is successfully developed via a highly-active acyl azolium intermediate. The new C1-symmetric biaryl-saturated imidazolium exhibits a superior ability to enable previously unavailable transformation, and the corresponding fully functionalized dihydropyranones are efficiently synthesized in high yields with excellent enantioselectivities. PMID- 25684543 TI - hiPS-MSCs differentiation towards fibroblasts on a 3D ECM mimicking scaffold. AB - Fibroblasts are ubiquitous cells that constitute the stroma of virtually all tissues and play vital roles in homeostasis. The poor innate healing capacity of fibroblastic tissues is attributed to the scarcity of fibroblasts as collagen producing cells. In this study, we have developed a functional ECM mimicking scaffold that is capable to supply spatial allocation of stem cells as well as anchorage and storage of growth factors (GFs) to direct stem cells differentiate towards fibroblasts. Electrospun PCL fibers were embedded in a PEG-fibrinogen (PF) hydrogel, which was infiltrated with connective tissue growth factor (CTGF) to form the 3D nanocomposite PFP-C. The human induced pluripotent stem cells derived mesenchymal stem cells (hiPS-MSCs) with an advance in growth over adult MSCs were applied to validate the fibrogenic capacity of the 3D nanocomposite scaffold. The PFP-C scaffold was found not only biocompatible with the hiPS-MSCs, but also presented intriguingly strong fibroblastic commitments, to an extent comparable to the positive control, tissue culture plastic surfaces (TCP) timely refreshed with 100% CTGF. The novel scaffold presented not only biomimetic ECM nanostructures for homing stem cells, but also sufficient cell-approachable bio signaling cues, which may synergistically facilitate the control of stem cell fates for regenerative therapies. PMID- 25684544 TI - Visual working memory modulates within-object metrics of saccade landing position. AB - In two experiments, we examined the influence of visual working memory (VWM) on oculomotor selection, testing whether the landing positions of rapidly generated saccades are biased toward the region of an object that matches a feature held in VWM. Participants executed a saccade to the center of a single saccade target, divided into two colored regions and presented on the horizontal midline. Concurrently, participants maintained a color in VWM for an unrelated memory task. This color either matched one of the two regions or neither of the regions. Relative to the no-match baseline, the landing positions of rapidly generated saccades (mean latency < 150 ms) were biased toward the region that matched the remembered color. The results support the hypothesis that VWM modulates early, spatially organized sensory representations to bias selection toward locations with features that match VWM content. In addition, the results demonstrate that saccades to spatially extended objects are sensitive to within-object differences in salience. PMID- 25684545 TI - Clumpak: a program for identifying clustering modes and packaging population structure inferences across K. AB - The identification of the genetic structure of populations from multilocus genotype data has become a central component of modern population-genetic data analysis. Application of model-based clustering programs often entails a number of steps, in which the user considers different modelling assumptions, compares results across different predetermined values of the number of assumed clusters (a parameter typically denoted K), examines multiple independent runs for each fixed value of K, and distinguishes among runs belonging to substantially distinct clustering solutions. Here, we present Clumpak (Cluster Markov Packager Across K), a method that automates the postprocessing of results of model-based population structure analyses. For analysing multiple independent runs at a single K value, Clumpak identifies sets of highly similar runs, separating distinct groups of runs that represent distinct modes in the space of possible solutions. This procedure, which generates a consensus solution for each distinct mode, is performed by the use of a Markov clustering algorithm that relies on a similarity matrix between replicate runs, as computed by the software Clumpp. Next, Clumpak identifies an optimal alignment of inferred clusters across different values of K, extending a similar approach implemented for a fixed K in Clumpp and simplifying the comparison of clustering results across different K values. Clumpak incorporates additional features, such as implementations of methods for choosing K and comparing solutions obtained by different programs, models, or data subsets. Clumpak, available at http://clumpak.tau.ac.il, simplifies the use of model-based analyses of population structure in population genetics and molecular ecology. PMID- 25684546 TI - The prognostic role of the epithelial-mesenchymal transition markers E-cadherin and Slug in laryngeal squamous cell carcinoma. AB - AIMS: Laryngeal squamous cell carcinoma (LSCC) prognosis is definitely related to lymph node metastasis. Epithelial-mesenchymal transition (EMT) allows neoplastic cells to gain the plasticity and motility required for tumour progression and metastasis. The aim of this study was to investigate the role of EMT in the prognosis of LSCC. METHODS AND RESULTS: Immunohistochemical analysis of E cadherin, N-cadherin, Snail, Slug, ZEB1, and ZEB2 was performed in 37 consecutive LSCC cases. Low E-cadherin levels and high Slug levels correlated with both disease recurrence (P = 0.02 and P =0.01, respectively) and shorter disease-free survival (DFS) (P = 0.04 and P = 0.02, respectively). Relative expression levels of CDH1, SNAI2, miR-1 and the miR-200 family were also evaluated. CDH1, miR-200a and miR-200c down-regulation and SNAI2 overexpression were significantly associated with disease recurrence (P = 0.03, P = 0.02, P = 0.04, and P = 0.04, respectively). CONCLUSIONS: EMT increases tumour recurrence risk and shortens DFS in LSCC. E-cadherin and Slug immunohistochemical analysis could be useful for identifying patients requiring more aggressive treatment after surgery. PMID- 25684547 TI - Reduced compensatory effects explain the nitrogen-mediated reduction in stability of an alpine meadow on the Tibetan Plateau. AB - Many ecosystems are facing strong perturbations such as nitrogen (N) fertilization, which can greatly alter ecosystem stability via different mechanisms. Understanding such mechanisms is critical for predicting how ecosystems will function in the face of global changes. We examined how 8 yr of N fertilization with different N rates (no N addition or N addition at a low, medium or high rate) and different forms of N (ammonium, nitrate or ammonium nitrate) affected the temporal stability of the aboveground biomass of an alpine meadow on the Tibetan Plateau, and tested four mechanisms (diversity effect, mean variance scaling, compensatory dynamics and dominance effect) that may alter stability. Compared with the control (no N addition), a high N rate did not affect the diversity effect, the mean-variance scaling or the dominance effect, but significantly decreased compensatory dynamics among species and functional groups, which contributed to the reduction in community stability of the alpine meadow. The form of N did not affect any of the four mechanisms and thus did not affect community stability. A high N rate can change community stability by altering compensatory dynamics, whereas the form of N may not have an effect. PMID- 25684548 TI - Inhibitory effects of autologous gamma-irradiated cell conditioned medium on osteoblasts in vitro. AB - Skeletal complications from radiation therapy have been reported in patients with breast, brain and pelvic cancer, and types of blood cancer. However, it remains to be elucidated whether localized radiotherapy may result in systemic adverse effects on the unirradiated skeleton through an abscopal mechanism. The present study investigated the abscopal effect of radiation on osteoblasts mediated by autologous gamma-irradiated cell conditioned medium. Osteoblasts obtained from calvarial bones were incubated with irradiated cell conditioned medium (ICCM) and changes in cell viability, alkaline phosphatase (ALP) activity, mineralization ability, cell apoptosis and the gene expression levels of ALP, osteocalcin (BGP), osteoprotegerin (OPG), receptor activator of nuclear factor-kappaB ligand (RANKL) and caspase 3 were observed. Notably, ICCM regulated osteoblast function, inhibiting viability and differentiation, resulting in apoptosis or cell death. ICCM at 10 or 20%, from osteoblasts irradiated with 10 Gy gamma-rays, significantly inhibited the proliferation of osteoblastic cells (P<0.001). In addition, an increase in apoptosis was noted in the osteoblasts incubated with ICCM at 40% with increasing doses of radiation, accompanied by an upregulation in the mRNA expression of caspase 3. In addition, ICCM at 20% inhibited the ALP activity in the 5 and 10 Gy groups and osteoblast mineralization, particularly at 10 Gy ICCM. Additionally, the mRNA expression levels of ALP, BGP, OPG and RANKL of the cells treated with ICCM at 20% were downregulated significantly compared with those treated with medium from unirradiated cells. The present study provided novel evidence to elucidate radiation-therapy-associated side effects on the skeleton. PMID- 25684550 TI - Examination of lifestyle factors and diseases in teaching periodontology in dental education in the Nordic countries. AB - INTRODUCTION: Lifestyle and general diseases are important for the development of periodontitis and other diseases in the oral cavity. Therefore, knowledge on lifestyle factors must be part of the dental curriculum. However, a search for information in the literature databases gave meagre results. The aim of this study was to describe education of lifestyle in relation to diseases in the oral cavity with focus on periodontitis and to elucidate how education is practiced and reflected in dental education in the Nordic countries. MATERIALS AND METHODS: A questionnaire, which consisted of 18 questions, was sent to the chairs of the departments of periodontology in the Nordic countries. The questions concerned extent, curriculum structure, educational method, content, assessment and evaluation of the education. RESULTS: Education on lifestyle factors took place at all dental schools, but the extent, content and placement in the curriculum varied. In some schools, more than 10 lessons were scheduled; two schools had only 3-5 lessons. The education of lifestyle factors was prioritised highest in the departments of periodontology followed by cariology and general health. Despite differences in the content across the dental schools, there were also similarities. So, at all schools smoking, medication, cardiovascular diseases and diabetes type 2 had a high priority. Education of other factors such as alcohol, psychological stress, oral hygiene habits, hypotension and obesity varied. CONCLUSION: Despite the general view that understanding of odontology is considered to be rather homogenous in the Nordic countries, the education varies across the dental schools. This variation may inspire dental educators in the future planning dental curricula. PMID- 25684549 TI - Pharmacological and electrophysiological characterization of AZSMO-23, an activator of the hERG K(+) channel. AB - BACKGROUND AND PURPOSE: We aimed to characterize the pharmacology and electrophysiology of N-[3-(1H-benzimidazol-2-yl)-4-chloro-phenyl]pyridine-3 carboxamide (AZSMO-23), an activator of the human ether-a-go-go-related gene (hERG)-encoded K(+) channel (Kv 11.1). EXPERIMENTAL APPROACH: Automated electrophysiology was used to study the pharmacology of AZSMO-23 on wild-type (WT), Y652A, F656T or G628C/S631C hERG, and on other cardiac ion channels. Its mechanism of action was characterized with conventional electrophysiology. KEY RESULTS: AZSMO-23 activated WT hERG pre-pulse and tail current with EC50 values of 28.6 and 11.2 MUM respectively. At 100 MUM, pre-pulse current at +40 mV was increased by 952 +/- 41% and tail current at -30 mV by 238 +/- 13% compared with vehicle values. The primary mechanism for this effect was a 74.5 mV depolarizing shift in the voltage dependence of inactivation, without any shift in the voltage dependence of activation. Structure-activity relationships for this effect were remarkably subtle, with close analogues of AZSMO-23 acting as hERG inhibitors. AZSMO-23 blocked the mutant channel, hERG Y652A, but against another mutant channel, hERG F656T, its activator activity was enhanced. It inhibited activity of the G628C/S631C non-inactivating hERG mutant channel. AZSMO-23 was not hERG selective, as it blocked hKv 4.3-hKChIP2.2, hCav 3.2 and hKv 1.5 and activated hCav 1.2/beta2/alpha2delta channels. CONCLUSION AND IMPLICATIONS: The activity of AZSMO-23 and those of its close analogues suggest these compounds may be of value to elucidate the mechanism of type 2 hERG activators to better understand the pharmacology of this area from both a safety perspective and in relation to treatment of congenital long QT syndrome. PMID- 25684551 TI - Self-assembly of amphiphilic block copolymer-tethered nanoparticles: a new approach to nanoscale design of functional materials. AB - Colloidal molecules constructed from polymers and nanoparticles (NPs) have recently emerged as a novel class of building blocks for assembling functional hybrid materials. Particularly, self-assembly of amphiphilic block copolymer (BCP)-tethered NPs (BNPs) has shown great promise in the nanoscale design of functional hybrid materials. On the one hand, structurally the BNPs can be considered as molecular equivalents that are capable of self-assembly at multiple hierarchical levels. On the other hand, the assembly of BNPs shows significant differences from molecular assembly due to their large dimension, complex geometry, and multi-scale interactions involved in the assembly process. The manipulation of BCPs localized near the surface of the NPs offers an effective tool for engineering the interactions between NPs and hence the complexity of NP assembly. In this Feature Article, recent progresses on the self-assembly of BNPs into functional materials are summarized. First, major strategies for assembling amphiphilic BNPs are highlighted. Secondly, the application of hybrid nanostructures (e.g., vesicles) assembled from BNPs in the field of biomedical imaging and delivery is discussed. Finally, current challenges and perspectives at this frontier are outlined. PMID- 25684553 TI - Recurrent adaptation in a low-dispersal trait. AB - The study of natural populations from contrasting environments has greatly enhanced our understanding of ecological-dependent selection, adaptation and speciation. Cases of parallel evolution in particular have facilitated the study of the molecular and genetic basis of adaptive variation. This includes the type and number of genes underlying adaptive traits, as well as the extent to which these genes are exchanged among populations and contribute repeatedly to parallel evolution. Yet, surprisingly few studies provide a comprehensive view on the evolutionary history of adaptive traits from mutation to widespread adaptation. When did key mutations arise, how did they increase in frequency, and how did they spread? In this issue of Molecular Ecology, Van Belleghem et al. (2015) reconstruct the evolutionary history of a gene associated with wing size in the salt marsh beetle Pogonus chalceus. Screening the entire distribution range of this species, they found a single origin for the allele associated with the short winged ecotype. This allele seemingly evolved in an isolated population and rapidly introgressed into other populations. These findings suggest that the adaptive genetic variation found in sympatric short- and long-winged populations has an allopatric origin, confirming that allopatric phases may be important at early stages of speciation. PMID- 25684555 TI - Chitosan leads to downregulation of YKL-40 and inflammasome activation in human macrophages. AB - Chitosan, the deacetylated derivative of chitin, is used as biomaterial in diverse settings. It is also found on pathogens and can be proinflammatory. Shorter derivatives of chitosan can be generated chemically or enzymatically, chitosan oligosaccharides (ChOS). There is variation in the chemical composition of ChOS, including size distribution, but in general, they have been described as inert or anti-inflammatory. Active human chitinases can cleave chitin and chitosan, while inactive chitinases bind both but do not cleave. Both active and inactive chitinases have important roles in the immune response. The inactive chitinase YKL-40 is expressed highly during inflammation and has been proposed as a marker of poor prognosis. YKL-40 acts as a negative regulator of the inflammasome and as a positive regulator of angiogenesis. Levels of YKL-40 can therefore regulate levels of inflammation, the extent of angiogenesis, and the process of inflammation resolution. This study shows that chitosan leads to reduced secretion of YKL-40 by primary human macrophages and that this is concomitant with inflammasome activation. This was most pronounced with a highly deacetylated ChOS. No effect on the secretion of the active chitinase Chit-1 was detected. Smaller and more acetylated ChOS did not affect YKL-40 levels nor inflammasome activation. We conclude that this effect on the levels of YKL-40 is a part of the proinflammatory mechanisms of chitosan and its derivatives. PMID- 25684554 TI - Neuroimaging findings in treatment-resistant schizophrenia: A systematic review: Lack of neuroimaging correlates of treatment-resistant schizophrenia. AB - BACKGROUND: Recent developments in neuroimaging have advanced the understanding of biological mechanisms underlying schizophrenia. However, neuroimaging correlates of treatment-resistant schizophrenia (TRS) and superior effects of clozapine on TRS remain unclear. METHODS: Systematic search was performed to identify neuroimaging characteristics unique to TRS and ultra-resistant schizophrenia (i.e. clozapine-resistant [URS]), and clozapine's efficacy in TRS using Embase, Medline, and PsychInfo. Search terms included (schizophreni*) and (resistan* OR refractory OR clozapine) and (ASL OR CT OR DTI OR FMRI OR MRI OR MRS OR NIRS OR PET OR SPECT). RESULTS: 25 neuroimaging studies have investigated TRS and effects of clozapine. Only 5 studies have compared TRS and non-TRS, collectively providing no replicated neuroimaging finding specific to TRS. Studies comparing TRS and healthy controls suggest that hypometabolism in the prefrontal cortex, hypermetabolism in the basal ganglia, and structural anomalies in the corpus callosum contribute to TRS. Clozapine may increase prefrontal hypoactivation in TRS although this was not related to clinical improvement; in contrast, evidence has suggested a link between clozapine efficacy and decreased metabolism in the basal ganglia and thalamus. CONCLUSION: Existing literature does not elucidate neuroimaging correlates specific to TRS or URS, which, if present, might also shed light on clozapine's efficacy in TRS. This said, leads from other lines of investigation, including the glutamatergic system can prove useful in guiding future neuroimaging studies focused on, in particular, the frontocortical-basal ganglia-thalamic circuits. Critical to the success of this work will be precise subtyping of study subjects based on treatment response/nonresponse and the use of multimodal neuroimaging. PMID- 25684557 TI - Surgical treatment of glottic cancer: retrospective analysis of 192 cases in a multidisciplinary tertiary care centre in Pune, India. AB - OBJECTIVES: A multidisciplinary team approach is required for the preservation of voice and appropriate management of glottic cancer. This study aimed to investigate the outcomes of surgically treated glottic cancers of all stages. All aspects of surgical management, such as laser cordectomy, partial laryngectomy, total laryngectomy with voice prosthesis, and salvage laryngectomy, conducted at a single tertiary care institute in India, were reviewed. METHOD: A retrospective analysis of hospital records was performed for 192 glottic cancer patients who were surgically treated between 2003 and 2007. RESULTS: Patients with tumour stages 1 or 2 glottic cancer treated with laser cordectomy had a local control rate of 85 per cent and five-year survival rate of 98.6 per cent. The findings suggest that the number of partial laryngectomies performed for stage 3 tumours is declining. Patients with a tumour stage 3 lesion with a fixed hemilarynx or a tumour stage 4 lesion, treated with total laryngectomy, were found to have a five year survival rate of 61.6 per cent. Nodal status was significantly associated with five-year survival rate. CONCLUSION: Surgery offers a viable five-year survival rate in glottic cancer patients. PMID- 25684556 TI - Functional consequences of cocaine expectation: findings in a non-human primate model of cocaine self-administration. AB - Exposure to stimuli and environments associated with drug use is considered one of the most important contributors to relapse among substance abusers. Neuroimaging studies have identified neural circuits underlying these responses in cocaine-dependent subjects. But these studies are often difficult to interpret because of the heterogeneity of the participants, substances abused, and differences in drug histories and social variables. Therefore, the goal of this study was to assess the functional effects of exposure to cocaine-associated stimuli in a non-human primate model of cocaine self-administration, providing precise control over these variables, with the 2-[(14) C]deoxyglucose method. Rhesus monkeys self-administered 0.3 mg/kg/injection cocaine (n = 4) under a fixed-interval 3-minute (FI 3-min) schedule of reinforcement (30 injections/session) for 100 sessions. Control animals (n = 4) underwent identical schedules of food reinforcement. Sessions were then discontinued for 30 days, after which time, monkeys were exposed to cocaine- or food-paired cues, and the 2 [(14) C]deoxyglucose experiment was conducted. The presentation of the cocaine paired cues resulted in significant increases in functional activity within highly restricted circuits that included portions of the pre-commissural striatum, medial prefrontal cortex, rostral temporal cortex and limbic thalamus when compared with control animals presented with the food-paired cues. The presentation of cocaine-associated cues increased brain functional activity in contrast to the decreases observed after cocaine consumption. Furthermore, the topography of brain circuits engaged by the expectation of cocaine is similar to the distribution of effects during the earliest phases of cocaine self administration, prior to the onset of neuroadaptations that accompany chronic cocaine exposure. PMID- 25684558 TI - Exercise is medicine: a call to action for physicians to assess and prescribe exercise. AB - Engaging in regular physical activity is one of the major determinants of health. Studies have demonstrated the benefits of exercise in the treatment and prevention of most every common medical problem seen today. It is clear that patients who engage in an active and fit way of life, live longer, healthier, and better lives. For these reasons, every patient should be asked about exercise at every visit using an exercise vital sign (EVS) and, when needed, provided with an exercise prescription that encourages them to get 150 minutes or more moderate-to vigorous physical activity. Physicians have an obligation to assess each patients exercise habits and inform them of the risks of being sedentary. Such an approach is critical to help stem the rising tide of deaths around the world due to noncommunicable diseases, which are so closely associated with a sedentary lifestyle. PMID- 25684559 TI - Individualized anatomic anterior cruciate ligament reconstruction. AB - Anterior cruciate ligament (ACL) injuries are often seen in young participants in sports such as soccer, football, and basketball. Treatment options include conservative management as well as surgical intervention, with the goal of enabling the patient to return to cutting and pivoting sports and activities. Individualized anatomic ACL reconstruction is a surgical technique that tailors the procedure to the individual patient using preoperative measurements on plain radiographs and magnetic resonance imaging and intraoperative measurement to map the patients' native ACL anatomy in order to replicate it as closely as possible. Anatomic ACL reconstruction, therefore, is defined as reconstruction of the ACL to its native dimensions, collagen orientation, and insertion site. The surgical reconstruction is followed by a specific rehabilitation protocol that is designed to enable the patient to regain muscle strength and proprioception while facilitating healing of the reconstructed ACL prior to the patient's returning to sports activities. PMID- 25684560 TI - Fourth annual meeting of the European Society for the study of human evolution. PMID- 25684561 TI - Applying evolutionary anthropology. AB - Evolutionary anthropology provides a powerful theoretical framework for understanding how both current environments and legacies of past selection shape human behavioral diversity. This integrative and pluralistic field, combining ethnographic, demographic, and sociological methods, has provided new insights into the ultimate forces and proximate pathways that guide human adaptation and variation. Here, we present the argument that evolutionary anthropological studies of human behavior also hold great, largely untapped, potential to guide the design, implementation, and evaluation of social and public health policy. Focusing on the key anthropological themes of reproduction, production, and distribution we highlight classic and recent research demonstrating the value of an evolutionary perspective to improving human well-being. The challenge now comes in transforming relevance into action and, for that, evolutionary behavioral anthropologists will need to forge deeper connections with other applied social scientists and policy-makers. We are hopeful that these developments are underway and that, with the current tide of enthusiasm for evidence-based approaches to policy, evolutionary anthropology is well positioned to make a strong contribution. PMID- 25684562 TI - Evolution of the hominoid vertebral column: The long and the short of it. AB - The postcranial axial skeleton exhibits considerable morphological and functional diversity among living primates. Particularly striking are the derived features in hominoids that distinguish them from most other primates and mammals. In contrast to the primitive catarrhine morphotype, which presumably possessed an external (protruding) tail and emphasized more pronograde trunk posture, all living hominoids are characterized by the absence of an external tail and adaptations to orthograde trunk posture. Moreover, modern humans evolved unique vertebral features that satisfy the demands of balancing an upright torso over the hind limbs during habitual terrestrial bipedalism. Our ability to identify the evolutionary timing and understand the functional and phylogenetic significance of these fundamental changes in postcranial axial skeletal anatomy in the hominoid fossil record is key to reconstructing ancestral hominoid patterns and retracing the evolutionary pathways that led to living apes and modern humans. Here, we provide an overview of what is known about evolution of the hominoid vertebral column, focusing on the currently available anatomical evidence of three major transitions: tail loss and adaptations to orthograde posture and bipedal locomotion. PMID- 25684563 TI - Role of serum toll-like receptors 2 and 4 in non-alcoholic steatohepatitis and liver fibrosis. AB - BACKGROUND AND AIM: Non-alcoholic fatty liver disease is a common cause of chronic liver disease, including non-alcoholic steatohepatitis (NASH). Our aim was to investigate whether serum toll-like receptors 2 and 4 (TLR2 and TLR4) levels are correlated with NASH and able to predict liver fibrosis, as well as to compare these markers with other non-invasive fibrosis scores (aspartate aminotransferase [AST] to alanine aminotransferase ratio, AST to platelet ratio index, fibrosis index, fibrosis 4, and fibrosis cirrhosis index). METHODS: Serum samples were obtained from consecutive biopsy proven NASH patients and healthy controls. Serum TLR2 and TLR4 were measured using ELISA. Stage of fibrosis was evaluated using the Brunt Criteria. The different non-invasive fibrosis scores were compared using areas under the curve. RESULTS: Fifty-seven patients with NASH and 57 healthy individuals were enrolled in the study. Serum TLR2 levels were not significantly different between the healthy controls and NASH patients. The medians were 3.88 ng/mL +/- 0.29 versus 3.81 ng/mL +/- 0.32, respectively (P = 0.587). In comparing the levels of TLR4 between groups, the medians were 1.05 ng/mL +/- 0.13 versus 1.46 ng/mL +/- 0.27, respectively (P < 0.001). In NASH patients, the levels of serum TLR4 increased with the stage of fibrosis: TLR4 medians were F0:1.01, F1:1.46, F2:2.14, F3:3.74, F4:5.83 (P < 0.001). TLR4 produced AUCs for >= F1, >= F2, and >= F3 of 0.862, 0.810, and 0.905, respectively (P < 0.001). TLR4 levels were more predictive than other non invasive fibrosis scores in liver fibrosis. CONCLUSION: Serum TLR4 levels but not TLR2 were elevated in NASH patients in comparison with healthy controls. And in NASH patients, serum TLR4 levels both correlated with and were able to predict liver fibrosis. PMID- 25684564 TI - Surface site coordination dependent responses resolved in free clusters: applications for neutral sub-nanometer cluster studies. AB - In this paper we demonstrate how surface site specific experimental information can be obtained from free low nanometer scale clusters using photoelectron spectroscopy utilising synchrotron radiation. In addition, we show how it can be used to gain insight into the geometry and surface structure of the clusters. The present experiments were conducted on alkali metal halides, RbCl and CsCl, which were chosen as advantageous test cases due to their simple electronic and geometric structures. These heavy alkali metal salts provide additional clarity since the surface and bulk responses can be separated, which is not the case for clusters of lighter alkali metal salts. Computational chemical shift calculations and simple alkali halide cluster size modelling were used to interpret the experimental results. PMID- 25684565 TI - Galectin-3 and histological, molecular and biochemical aspects of myocardial fibrosis in heart failure of hypertensive origin. AB - AIMS: The aim of this study was to investigate whether galectin-3 (Gal-3) is associated with myocardial histological and molecular parameters related to fibrosis and with the circulating biomarkers of the extracellular generation of mature fibril-forming collagen types I (C-terminal propeptide of procollagen type I, PICP) and III (N-terminal propeptide of procollagen type III, PIIINP) in two independent studies of hypertensive patients with heart failure (HF). METHODS AND RESULTS: Endomyocardial biopsies and blood samples from 39 HF patients (invasive study), and blood samples from 220 HF patients (non-invasive study) were analysed. Necropsies (n = 7) and blood samples (n = 20) from healthy subjects were used as controls. In the invasive study myocardial mRNA and protein expression of Gal-3 and collagen types I and III, plasma Gal-3 and serum PICP and PIIINP were all significantly increased in patients compared with controls. Neither myocardial nor plasma Gal-3 were correlated with myocardial collagen and circulating biomarkers; whereas PICP was correlated with myocardial total (r = 0.819, P < 0.001) and collagen type I (r = 0.744, P < 0.001) deposition, PIIINP was not. In the non-invasive study both plasma Gal-3 and serum PICP were increased (P < 0.001) in patients compared with controls. No correlation was found between Gal-3 and PICP in HF patients. CONCLUSIONS: These findings show that although an excess of cardiac and systemic Gal-3 is present in patients with HF of hypertensive origin, this molecule is not associated with histological, molecular and biochemical parameters related to myocardial fibrosis in these patients. PMID- 25684566 TI - Increased anxiety-like behavior and selective learning impairments are concomitant to loss of hippocampal interneurons in the presymptomatic SOD1(G93A) ALS mouse model. AB - Amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease primarily characterized by motor neuron death, causes damages beyond motor-related areas. In particular, cognitive impairments and hippocampal damage have been reported in ALS patients. We investigated spatial navigation learning and hippocampal interneurons in a mutant SOD1(G93A) mouse (mSOD1) model of ALS. Behavioral tests were performed by using presymptomatic mSOD1 mice. General motor activity was comparable to that of wild-type mice in the open-field test, in which, however mSOD1 exhibited increased anxiety-like behavior. In the Barnes maze test, mSOD1 mice displayed a delay in learning, outperformed wild-type mice during the first probe trial, and exhibited impaired long-term memory. Stereological counts of parvalbumin-positive interneurons, which are crucial for hippocampal physiology and known to be altered in other central nervous system regions of mSOD1 mice, were also performed. At postnatal day (P) 56, the population of parvalbumin positive interneurons in mSOD1 mice was already reduced in CA1 and in CA3, and at P90 the reduction extended to the dentate gyrus. Loss of parvalbumin-positive hippocampal interneurons occurred mostly during the presymptomatic stage. Western blot analysis showed that hippocampal parvalbumin expression levels were already reduced in mSOD1 mice at P56. The hippocampal alterations in mSOD1 mice could at least partly account for the increased anxiety-like behavior and deficits in spatial navigation learning. Our study provides evidence for cognitive alterations and damage to the gamma-aminobutyric acid (GABA)ergic system in the hippocampus of murine ALS, thereby revealing selective deficits antecedent to the onset of motor symptoms. PMID- 25684567 TI - Ocean zoning for conservation, fisheries and marine renewable energy: assessing trade-offs and co-location opportunities. AB - Oceans, particularly coastal areas, are getting busier and within this increasingly human-dominated seascape, marine biodiversity continues to decline. Attempts to maintain and restore marine biodiversity are becoming more spatial, principally through the designation of marine protected areas (MPAs). MPAs compete for space with other uses, and the emergence of new industries, such as marine renewable energy generation, will increase competition for space. Decision makers require guidance on how to zone the ocean to conserve biodiversity, mitigate conflict and accommodate multiple uses. Here we used empirical data and freely available planning software to identified priority areas for multiple ocean zones, which incorporate goals for biodiversity conservation, two types of renewable energy, and three types of fishing. We developed an approached to evaluate trade-offs between industries and we investigated the impacts of co locating some fishing activities within renewable energy sites. We observed non linear trade-offs between industries. We also found that different subsectors within those industries experienced very different trade-off curves. Incorporating co-location resulted in significant reductions in cost to the fishing industry, including fisheries that were not co-located. Co-location also altered the optimal location of renewable energy zones with planning solutions. Our findings have broad implications for ocean zoning and marine spatial planning. In particular, they highlight the need to include industry subsectors when assessing trade-offs and they stress the importance of considering co location opportunities from the outset. Our research reinforces the need for multi-industry ocean-zoning and demonstrates how it can be undertaken within the framework of strategic conservation planning. PMID- 25684568 TI - Bisphenol-A removal in various wastewater treatment processes: operational conditions, mass balance, and optimization. AB - Bisphenol-A (BPA) was analyzed in 499 liquid and 347 solid samples collected from twenty-five wastewater treatment plants (WWTPs) to investigate parameters affecting BPA occurrence, removal, and fate. Lagoons, chemically-assisted primary treatment, secondary treatment, and advanced treatment processes were included. Median BPA concentrations in influent and final effluent were 400 ng/L and 150 ng/L, respectively. Median removal efficiencies ranged from 1 to 77%. Respective median BPA levels in primary sludge, secondary biological sludge, and biosolids were 230, 260, and 460 ng/g with digested biosolids having the highest concentrations. The biological aerated filter and membrane bioreactor processes showed the best performance, while chemically-assisted primary treatment achieved the lowest removal. Biodegradation and sorption contributing to BPA removal were influenced by operational conditions: hydraulic retention time (HRT), solids retention time (SRT), and mixed liquor suspended solids (MLSS). The influence of HRT, SRT, and MLSS in the bioreactor was stronger during cold temperatures. In order to achieve above 80% removal, the required conditions for HRT, SRT, and MLSS were 13 h, 7 days, and 1600 mg/L during summer (median temperature 19 degrees C) and 13 h, 17 days, and 5300 mg/L during winter (median temperature 10 degrees C); indicating that longer SRT and higher MLSS were needed during winter. BPA's sorption tendency to sludge was strongly influenced by the degree of nitrification and HRT. PMID- 25684569 TI - Crescentic glomerulonephritis: data from the Spanish Glomerulonephritis Registry. AB - BACKGROUND: Crescentic glomerulonephritis (CGN) is a histological finding that implies rapid deterioration of renal function and can be related to different diseases, such as type 1 or anti-glomerular basement membrane antibody (Goodpasture) disease, type 2 or immune complex CGN and type 3 or pauci-immune disease. AIM: The present study describes CGN and its characteristics based on the data from the Spanish Glomerulonephritis Registry. METHODS: An analysis was made of all native renal biopsies obtained from patients during 1994-2013 and classified as CGN. A patient epidemiological and clinical data questionnaire was completed by the 120 centres involved. RESULTS: A total of 21,774 biopsies was performed, of which 2089 (8.1%) corresponded to CGN (211 type 1, 177 type 2 and 1701 type 3). Renal function was poorer in type 1 compared with types 2 and 3, and proteinuria was higher in type 2 compared to types 1 and 3. Patients diagnosed with CGN type 3 were older than those with types 1 and 2, but less hypertensive than the type 2 patients. No differences in the urine test findings were found between types 1 and 2. Microhaematuria was the most frequent feature in general, as well as in type 3 compared with types 1 and 2. The main indication for biopsy was acute renal injury. Age was the only difference between type 1 patients with and without alveolar haemorrhage (53 [33-67] vs 64 [46-73], P = 0.008). CONCLUSION: Although classified as the same entity, the different types of CGN have different features that must be taken into account. PMID- 25684570 TI - SAfety of Fondaparinux in transoesophageal echocardiography-guided Electric cardioversion of Atrial Fibrillation (SAFE-AF) study: a pilot study. AB - BACKGROUND: Current guidelines recommend unfractionated heparin (UFH) or low molecular-weight heparin plus an oral anticoagulant for the prevention of thromboembolism in patients undergoing electric cardioversion of atrial fibrillation (AF). Selective factor Xa inhibitors, such as fondaparinux, which has a favourable benefit-risk profile in the prevention and treatment of venous thromboembolism and the management of acute coronary syndromes, have not been systematically evaluated in this setting. AIM: To evaluate the efficacy and safety of fondaparinux versus standard treatment in patients undergoing echocardiographically-guided cardioversion of AF. METHODS: In this multicentre, randomized, open-label, controlled, two-parallel-group, phase II pilot study, patients with AF undergoing electric cardioversion following transoesophageal echocardiography (TEE) were randomized to fondaparinux or standard therapy (UFH plus vitamin K antagonist [VKA]). Patients showing an atrial thrombus in the first TEE (clot-positive) were randomized to treatment with fondaparinux or standard care for 4 weeks before cardioversion. RESULTS: The primary endpoint (combined rate of cerebral neurological events, systemic thromboembolism, all cause death and major bleeding events) occurred in 3 of 174 (1.7%) patients on fondaparinux and 2 of 170 (1.2%) patients on UFH+VKA. The rate of thrombus disappearance among clot-positive patients was higher in the fondaparinux arm (11 of 14; 78.6%) than in the UFH+VKA arm (7 of 14; 50.0%). Incidences of adverse events were similar (45.4% with fondaparinux and 46.5% with UFH+VKA). CONCLUSION: In this pilot study in patients with TEE-guided cardioversion, the use of fondaparinux appeared to be well tolerated, with similar efficacy to UFH+VKA. Furthermore, a trend to greater thrombus resolution was observed. PMID- 25684571 TI - Protective effects of cyanidin-3-rutinoside against monosaccharides-induced protein glycation and oxidation. AB - Cyanidin-3-rutinoside (C3R), a naturally occurring anthocyanin, is present in various fruits and vegetables as a colorant. C3R has been well characterized and demonstrated a number of biological activities attributed to its antioxidant properties. The present study compared the effectiveness of C3R against monosaccharide-induced protein glycation and oxidation in vitro using bovine serum albumin (BSA).The results demonstrated that C3R (0.125-1.00 mM) inhibited the formation of fluorescent AGEs in ribose-glycated BSA (2-52%), fructose glycated BSA (81-93%), glucose-glycated BSA (30-74%) and galactose-glycated BSA (6-79%).Correspondingly, C3R (1.00 mM) decreased the level of N(E) (carboxymethyl) lysine (56-86%) in monosaccharide-induced glycation in BSA. C3R also reduced the level of fructosamine, beta-amyloid cross structure, protein carbonyl content as well as the depletion of thiol in BSA/monosaccharide system. In summary, C3R might offer a new promising antiglycation agent for the prevention of diabetic complications by inhibiting AGE formation and oxidation dependent protein damage. PMID- 25684572 TI - Size-dependent tuning of horseradish peroxidase bioreactivity by gold nanoparticles. AB - Molecules with diverse biological functions, such as heme peroxidases, can be useful tools for identifying potential biological effects of gold nanoparticles (AuNPs) at the molecular level. Here, using UV-Vis, circular dichroism, dynamic light scattering, and electron spin resonance spectroscopy, we report tuning of horseradish peroxidase (HRP) bioactivity by reactant-free AuNPs with diameters of 5, 10, 15, 30 and 60 nm (Au-5 nm, Au-10 nm, Au-15 nm, Au-30 nm and Au-60 nm). HRP conjugation to AuNPs was observed with only Au-5 nm and Au-10 nm prominently increasing the alpha-helicity of the enzyme to extents inversely related to their size. Au-5 nm inhibited both HRP peroxidase activity toward 3,3',5,5' tetramethylbenzidine and HRP compound I/II reactivity toward 5,5-dimethyl-1 pyrroline N-oxide. Au-5 nm enhanced the HRP peroxidase activity toward ascorbic acid and the HRP compound I/II reactivity toward redox-active residues in the HRP protein moiety. Further, Au-5 nm also decreased the catalase- and oxidase-like activities of HRP. Au-10 nm showed similar, but weaker effects, while Au-15 nm, Au-30 nm and Au-60 nm had no effect. Results suggest that AuNPs can size dependently enhance or inhibit HRP bioreactivity toward substrates with different redox potentials via a mechanism involving extension of the HRP substrate access channel and decline in the redox potentials of HRP catalytic intermediates. PMID- 25684574 TI - Structure of human N-acylphosphatidylethanolamine-hydrolyzing phospholipase D: regulation of fatty acid ethanolamide biosynthesis by bile acids. AB - The fatty acid ethanolamides (FAEs) are lipid mediators present in all organisms and involved in highly conserved biological functions, such as innate immunity, energy balance, and stress control. They are produced from membrane N acylphosphatidylethanolamines (NAPEs) and include agonists for G protein-coupled receptors (e.g., cannabinoid receptors) and nuclear receptors (e.g., PPAR-alpha). Here, we report the crystal structure of human NAPE-hydrolyzing phospholipase D (NAPE-PLD) at 2.65 A resolution, a membrane enzyme that catalyzes FAE formation in mammals. NAPE-PLD forms homodimers partly separated by an internal ~ 9-A-wide channel and uniquely adapted to associate with phospholipids. A hydrophobic cavity provides an entryway for NAPE into the active site, where a binuclear Zn(2+) center orchestrates its hydrolysis. Bile acids bind with high affinity to selective pockets in this cavity, enhancing dimer assembly and enabling catalysis. These elements offer multiple targets for the design of small-molecule NAPE-PLD modulators with potential applications in inflammation and metabolic disorders. PMID- 25684573 TI - Fermented Rhizoma Atractylodis Macrocephalae alleviates high fat diet-induced obesity in association with regulation of intestinal permeability and microbiota in rats. AB - Accumulating evidence suggests the anti-inflammatory and anti-obesity activities of Rhizoma Atractylodis Macrocephalae (RAM). Here, we evaluated the anti-obesity impact of unfermented (URAM) versus fermented RAM (FRAM) using both in vitro and in vivo models. Both URAM and FRAM exhibited marked anti-inflammatory, anti adipogenic, and anti-obesity activities, and modulation of the gut microbial distribution. However, FRAM, compared to URAM, resulted in more efficient suppression of NO production and normalization of transepithelial electrical resistance in LPS-treated RAW 264.7 and HCT 116 cells, respectively. Compared to URAM, FRAM more effectively reduced the adipose tissue weight; ameliorated the serum triglyceride and aspartate transaminase levels; restored the serum HDL level and intestinal epithelial barrier function in the LPS control group. The relative abundance of Bifidobacterium and Akkermansia as well as Bacteriodetes/Firmicutes ratio in the gut of the LPS control group was significantly enhanced by both URAM and FRAM. However, FRAM, but not URAM, resulted in a significant increase in the distribution of Bacteriodetes and Lactobacillus in the gut of the HFD + LPS group. Our results suggest that FRAM with probiotics can exert a greater anti-obesity effect than URAM, which is probably mediated at least in part via regulation of the intestinal microbiota and gut permeability. PMID- 25684575 TI - Allosteric effects of the oncogenic RasQ61L mutant on Raf-RBD. AB - The Ras/Raf/MEK/ERK signal transduction pathway is a major regulator of cell proliferation activated by Ras-guanosine triphosphate (GTP). The oncogenic mutant RasQ61L is not able to hydrolyze GTP in the presence of Raf and thus is a constitutive activator of this mitogenic pathway. The Ras/Raf interaction is essential for the activation of the Raf kinase domain through a currently unknown mechanism. We present the crystal structures of the Ras-GppNHp/Raf-RBD and RasQ61L-GppNHp/Raf-RBD complexes, which, in combination with MD simulations, reveal differences in allosteric interactions leading from the Ras/Raf interface to the Ras calcium-binding site and to the remote Raf-RBD loop L4. In the presence of Raf, the RasQ61L mutant has a rigid switch II relative to the wild type and increased flexibility at the interface with switch I, which propagates across Raf-RBD. We show that in addition to local perturbations on Ras, RasQ61L has substantial long-range effects on the Ras allosteric lobe and on Raf-RBD. PMID- 25684576 TI - Structure of EspB from the ESX-1 type VII secretion system and insights into its export mechanism. AB - Mycobacterium tuberculosis (Mtb) uses the ESX-1 type VII secretion system to export virulence proteins across its lipid-rich cell wall, which helps permeabilize the host's macrophage phagosomal membrane, facilitating the escape and cell-to-cell spread of Mtb. ESX-1 membranolytic activity depends on a set of specialized secreted Esp proteins, the structure and specific roles of which are not currently understood. Here, we report the X-ray and electron microscopic structures of the ESX-1-secreted EspB. We demonstrate that EspB adopts a PE/PPE like fold that mediates oligomerization with apparent heptameric symmetry, generating a barrel-shaped structure with a central pore that we propose contributes to the macrophage killing functions of EspB. Our structural data also reveal unexpected direct interactions between the EspB bipartite secretion signal sequence elements that form a unified aromatic surface. These findings provide insight into how specialized proteins encoded within the ESX-1 locus are targeted for secretion, and for the first time indicate an oligomerization-dependent role for Esp virulence factors. PMID- 25684578 TI - Lipopolysaccharide is inserted into the outer membrane through an intramembrane hole, a lumen gate, and the lateral opening of LptD. AB - Lipopolysaccharide (LPS) is essential for the vitality of most Gram-negative bacteria and plays an important role in bacterial multidrug resistance. The LptD/E translocon inserts LPS into the outer leaflet, the mechanism of which is poorly understood. Here, we report mutagenesis, functional assays, and molecular dynamics simulations of the LptD/E complex, which suggest two distinct pathways for the insertion of LPS. The N-terminal domain of LptD comprises a hydrophobic slide that injects the acyl tails of LPS directly into the outer membrane through an intramembrane hole, while the core oligosaccharide and O-antigen pass a lumen gate that triggers the unzipping of the lateral opening between strands beta1C and beta26C of the barrel of LptD, to finalize LPS insertion. Mutation of the LPS transport related residues or block of the LPS transport pathways results in the deaths of Escherichia coli. These findings are important for the development of novel antibiotics. PMID- 25684577 TI - A bipartite interaction between Hsp70 and CHIP regulates ubiquitination of chaperoned client proteins. AB - The ubiquitin ligase CHIP plays an important role in cytosolic protein quality control by ubiquitinating proteins chaperoned by Hsp70/Hsc70 and Hsp90, thereby targeting such substrate proteins for degradation. We present a 2.91 A resolution structure of the tetratricopeptide repeat (TPR) domain of CHIP in complex with the alpha-helical lid subdomain and unstructured tail of Hsc70. Surprisingly, the CHIP-TPR interacts with determinants within both the Hsc70-lid subdomain and the C-terminal PTIEEVD motif of the tail, exhibiting an atypical mode of interaction between chaperones and TPR domains. We demonstrate that the interaction between CHIP and the Hsc70-lid subdomain is required for proper ubiquitination of Hsp70/Hsc70 or Hsp70/Hsc70-bound substrate proteins. Posttranslational modifications of the Hsc70 lid and tail disrupt key contacts with the CHIP-TPR and may regulate CHIP-mediated ubiquitination. Our study shows how CHIP docks onto Hsp70/Hsc70 and defines a bipartite mode of interaction between TPR domains and their binding partners. PMID- 25684579 TI - Serum luteinizing hormone concentration is significantly associated with recovery of urinary function after radical prostatectomy. AB - OBJECTIVE: To perform a longitudinal investigation of the correlation between functional recovery and sex hormone concentrations after radical prostatectomy (RP). PATIENTS AND METHODS: A total of 72 consecutive patients undergoing RP between January 2012 and June 2013 were prospectively included and serially followed after surgery for comparative analysis. Their luteinizing hormone (LH) and total testosterone (TT) concentrations were measured before surgery and 3 and 12 months after surgery. They also filled out a health-related quality of life questionnaire before and at 1, 3, 6 and 12 months after surgery. RESULTS: The mean LH concentration increased from 4.28 U/L at baseline to 5.53 U/L at 3 months and remained high at 12 months after RP (both P < 0.001). There were no significant changes in the TT concentration after RP. LH at baseline was negatively correlated with the urinary function (UF) score at 3 and 12 months after RP (P = 0.030 and 0.032, respectively). After RP, subjects with high baseline LH (n = 37) were more likely than those with low LH concentrations to report lower UF scores (P = 0.014). Multivariate analysis of variance in an interaction of time * LH concentration for UF scores indicated a significant relationship between changes in UF score and LH concentration (P = 0.004). CONCLUSIONS: Radical prostatectomy affects sex hormones by increasing LH concentrations, while TT concentrations remain stable after surgery. Baseline LH concentrations are significantly associated with the recovery of urinary outcomes after RP. PMID- 25684580 TI - What is the best training for vascular access surgery? AB - Questions have been raised whether there is a lack of appropriate training in access creation and maintenance, and if training juniors in arteriovenous (AV) fistulas may affect the outcome. A survey was undertaken to study "experts" opinion in access training using a closed questionnaire. The majority of "experts" consented that there is a lack of appropriate training in access creation and maintenance in a great extent, although they located the main deficit regarding access training in the preoperative planning and decision making. Regarding the second question, a literature search revealed only four studies, comparing the outcomes of AV fistulas created either by consultant surgeons or trainees. A meta-analysis performed revealed that 1-year patency rate was not statistically significant different among access procedures created either by consultants or trainees. Access surgery shares the same basic principles with vascular surgery and provides a valuable workload for the trainees and is a necessity to become a building component in all "core" vascular curricula; the required skills can be acquired with the trainees operating independently simple cases, as the latter is not leading to suboptimal outcomes. PMID- 25684581 TI - Fibrin sheath formation and intimal thickening after catheter placement in dog model: role of hemodynamic wall shear stress. AB - PURPOSE: To investigate the role of wall shear stress in aspects of the formation of fibrin sheath and intimal thickening in a dog model. METHODS: Tunneled silicone 14.5-F catheters were inserted into the left internal jugular vein in eight dogs. The dogs were separated into two groups according to catheter indwelling time of 14 and 28 days. All dogs underwent extracorporeal circulation three times a week. Multidetector computed tomography venography (MDCTV) examination was used to examine the catheter tip thrombus. After the animals were sacrificed, histological and immunohistochemistry evaluations were performed to confirm specific cell populations. We used computer modeling to generate wall shear stress profiles for the blood flow through the catheter. RESULTS: Catheter related sheaths were identified in all catheter specimens, but there was no fibrin sheath around the catheter tip. There were also differences in wall shear stress between the different venous wall sites. Differences in vein wall thickening at different sites have been found at both 14 days (intima to media (I/M) ratio S1 vs S2: p = 0.01, S3 vs S4: p<0.01) and 28 days (I/M ratio S1 vs S2: p<0.01, S3 vs S4: p<0.05). CONCLUSIONS: After catheter placement, fibrin sheath formation partially covered the catheter. Meanwhile, focal areas of intimal thickening were also seen in the venous wall adjacent to the sites of high wall shear stress. These findings indicate an important role of wall shear stress profiles in fibrin sheath formation and intimal thickening. PMID- 25684582 TI - The geographic distribution and ecological preferences of the American dog tick, Dermacentor variabilis (Say), in the U.S.A. AB - Equine piroplasmosis (EP), caused by two parasitic organisms, Theileria equi and Babesia caballi, is a tick-borne disease of recent concern in horses in the U.S.A. Outbreaks of EP have been detected in Florida, Missouri, Kansas and Texas. In 2009, EP transmission in Texas occurred through the adults of two tick species, Amblyomma mixtum [formerly known as Amblyomma cajennense (Fabricius, 1787)] Koch (Ixodida: Ixodidae) and Dermacentor variabilis (Say) (Ixodida: Ixodidae), the American dog tick (ADT). In this study, we developed a continent scale map for the distribution of the EP vector species D. variabilis, using a presence-only modelling approach to assess the habitat preferences of this tick. We used identification records from our tick geodatabase of locations in which the presence of the ADT had been noted. The potential distribution of the ADT in the U.S.A. was estimated from environmental factors using the maximum entropy approach based on localities in which there is a high probability of occurrence according to habitat suitability. Elevation and temperature were found to be biologically significant environmental variables influencing the presence of this tick species. Properly designed and constructed probability surfaces using maximum entropy offer one useful approach to the mapping of distribution ranges of tick species based on suitable habitat in the U.S.A. PMID- 25684583 TI - Digestive tract mycobiota: a source of infection. AB - The human mycobiome includes 390 fungal species detected on the skin, in the vagina, in the oral cavity, and in the digestive tract that includes 335 species and 158 genera. Among these, 221 species are found only in the digestive tract, 88 only in the oral cavity, and 26 in both. These species belong to 126 genera of yeast and filamentous fungi, of the Ascomycota, Basidiomycota, and Zygomycota phyla. Forty species were identified only by culture, 188 species by molecular techniques, and 19 species with both techniques. Fungal diversity does not differ significantly according to sex but Basidiobolus ranarum is significantly more prevalent in male individuals and Paecilomyces fumosoroseus in female individuals. Fungal diversity is significantly higher in adults than in infants. Only 42 species are identified in the course of inflammatory bowel disease, with 27 species specific to IBD. Twenty-nine are identified in HBV infected patients including 17 specific species, and 11 in HIV-infected patients with the specific Histoplasma capsulatum. Genotyping proved that the gut mycobiome was a source of fungal infection caused by Candida albicans and Candida glabrata. The authors suggest updating the repertoire of the human digestive tract in healthy individuals and patients. Fungal culturomics must be intensified to complete this repertoire. PMID- 25684584 TI - Ageing and inflammation - A central role for mitochondria in brain health and disease. AB - To develop successful therapies that prevent or treat neurodegenerative diseases requires an understanding of the upstream events. Ageing is by far the greatest risk factor for most of these diseases, and to clarify their causes will require an understanding of the process of ageing itself. Starting with the question Why do we age as individual organisms, but the line of pluripotent embryonic stem cells and germ cells carried by individuals and transmitted to descendants is immortal? this review discusses how the process of cellular differentiation leads to the accumulation of biological imperfections with ageing, and how these imperfections may be the cause of chronic inflammatory responses to stress that undermine cellular function. Both differentiation and inflammation involve drastic metabolic changes associated with alterations in mitochondrial dynamics that shift the balance between aerobic glycolysis and oxidative phosphorylation. With ageing, mitochondrial dysfunction can be both the cause and consequence of inflammatory processes and elicit metabolic adaptations that might be either protective or become progressively detrimental. It is argued here that an understanding of the relationship between metabolism, differentiation and inflammation is essential to understand the pathological mechanisms governing brain health and disease during ageing. PMID- 25684586 TI - Effect of roflumilast on exacerbations in patients with severe chronic obstructive pulmonary disease uncontrolled by combination therapy (REACT): a multicentre randomised controlled trial. AB - BACKGROUND: Roflumilast reduces exacerbations in patients with severe chronic obstructive pulmonary disease. Its effect in patients using fixed combinations of inhaled corticosteroids and longacting beta2 agonists is unknown. We postulated that roflumilast would reduce exacerbations in patients with severe chronic obstructive pulmonary disease at risk for exacerbations, even in combination with inhaled corticosteroid and longacting beta2 agonist treatment. METHODS: For this 1-year double-blind, placebo-controlled, parallel group, multicentre, phase 3-4 trial, the Roflumilast and Exacerbations in patients receiving Appropriate Combination Therapy (REACT) study, we enrolled patients with severe chronic obstructive pulmonary disease from 203 centres (outpatient clinics, hospitals, specialised pulmonologists, and family doctors) in 21 countries. Eligible patients were 40 years of age or older with a smoking history of at least 20 pack years and a diagnosis of chronic obstructive pulmonary disease with severe airflow limitation, symptoms of chronic bronchitis, and at least two exacerbations in the previous year. We used a computerised central randomisation system to randomly assign patients in a 1:1 ratio to the two treatment groups: roflumilast 500 MUg or placebo given orally once daily together with a fixed inhaled corticosteroid and longacting beta2 agonist combination. Background tiotropium treatment was allowed. All patients and investigators were masked to group assignment. The primary outcome was the rate of moderate to severe chronic obstructive pulmonary disease exacerbations per patient per year, analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01329029. FINDINGS: Between April 3, 2011, and May 27, 2014, we enrolled 1945 eligible participants and randomly assigned 973 to the roflumilast group and 972 to the placebo group. The rate of moderate-to-severe chronic obstructive pulmonary disease exacerbations was 13.2% lower in the roflumilast group than in the placebo group according to a Poisson regression analysis (roflumilast 0.805 vs placebo 0.927; rate ratio [RR] 0.868 [95% CI 0.753-1.002], p=0.0529), and 14.2% lower according to a predefined sensitivity analysis using negative binomial regression (0.823 vs 0.959; 0.858 [0.740-0.995], p=0.0424). Adverse events were reported by 648 (67%) of 968 patients receiving roflumilast and by 572 (59%) of 967 patients in the placebo group; adverse event-associated patient withdrawal from the study was also more common in the roflumilast group (104/968 [11%]) than in the placebo group (52/967 [5%]). The most frequently reported serious adverse events were chronic obstructive pulmonary disease exacerbations and pneumonia, and 17 (1.8%) deaths occurred in the roflumilast group compared with 18 (1.9%) in the placebo group. INTERPRETATION: Our findings suggest that roflumilast reduces exacerbations and hospital admissions in patients with severe chronic obstructive pulmonary disease and chronic bronchitis who are at risk of frequent and severe exacerbations despite inhaled corticosteroid and longacting beta2 agonist therapy, even in combination with tiotropium. FUNDING: Takeda. PMID- 25684587 TI - Can mass media interventions reduce child mortality? AB - Many people recognise that mass media is important in promoting public health but there have been few attempts to measure how important. An ongoing trial in Burkina Faso (ClinicalTrials.gov, NCT01517230) is an attempt to bring together the very different worlds of mass media and epidemiology: to measure rigorously, using a cluster-randomised design, how many lives mass media can save in a low income country, and at what cost. Application of the Lives Saved Tool predicts that saturation-based media campaigns could reduce child mortality by 10-20%, at a cost per disability-adjusted life-year that is as low as any existing health intervention. In this Viewpoint we explain the scientific reasoning behind the trial, while stressing the importance of the media methodology used. PMID- 25684588 TI - Hormone therapy: short-term relief, long-term consequences. PMID- 25684585 TI - Menopausal hormone use and ovarian cancer risk: individual participant meta analysis of 52 epidemiological studies. AB - BACKGROUND: Half the epidemiological studies with information about menopausal hormone therapy and ovarian cancer risk remain unpublished, and some retrospective studies could have been biased by selective participation or recall. We aimed to assess with minimal bias the effects of hormone therapy on ovarian cancer risk. METHODS: Individual participant datasets from 52 epidemiological studies were analysed centrally. The principal analyses involved the prospective studies (with last hormone therapy use extrapolated forwards for up to 4 years). Sensitivity analyses included the retrospective studies. Adjusted Poisson regressions yielded relative risks (RRs) versus never-use. FINDINGS: During prospective follow-up, 12 110 postmenopausal women, 55% (6601) of whom had used hormone therapy, developed ovarian cancer. Among women last recorded as current users, risk was increased even with <5 years of use (RR 1.43, 95% CI 1.31 1.56; p<0.0001). Combining current-or-recent use (any duration, but stopped <5 years before diagnosis) resulted in an RR of 1.37 (95% CI 1.29-1.46; p<0.0001); this risk was similar in European and American prospective studies and for oestrogen-only and oestrogen-progestagen preparations, but differed across the four main tumour types (heterogeneity p<0.0001), being definitely increased only for the two most common types, serous (RR 1.53, 95% CI 1.40-1.66; p<0.0001) and endometrioid (1.42, 1.20-1.67; p<0.0001). Risk declined the longer ago use had ceased, although about 10 years after stopping long-duration hormone therapy use there was still an excess of serous or endometrioid tumours (RR 1.25, 95% CI 1.07 1.46, p=0.005). INTERPRETATION: The increased risk may well be largely or wholly causal; if it is, women who use hormone therapy for 5 years from around age 50 years have about one extra ovarian cancer per 1000 users and, if its prognosis is typical, about one extra ovarian cancer death per 1700 users. FUNDING: Medical Research Council, Cancer Research UK. PMID- 25684589 TI - Dual anti-inflammatory agents prevent COPD exacerbations. PMID- 25684590 TI - Prevalent and up-regulated vimentin expression in micropapillary components of lung adenocarcinomas and its adverse prognostic significance. AB - The factors conferring the increased malignancy on lung adenocarcinoma with micropapillary component (AC-MPC) remain to be elucidated. On proteomics based on 2-dimensional gel electrophoresis, 19 proteins differentially expressed by more than 1.5-fold between AC-MPC and conventional adenocarcinoma (CAC); in particular, vimentin, one of the proteins, was 3.5-fold up-regulated in AC-MPC. Subsequent semi-quantitative investigation by immunohistochemistry with large cohorts comprised 101 AC-MPC and 119 CAC, respectively, of different stages revealed that vimentin was expressed in MPC of 95 (94.1%) AC-MPC and the expression scores were higher than those of well- and moderately differentiated CAC, as well as the background non-MPC of the AC-MPC (P < 0.0001), but not significantly different from those of poorly differentiated CAC (P = 0.561). Even within the AC-MPC entity, higher vimentin expression was correlated with more frequent vascular invasion and more advanced node metastasis (P < 0.02), and multivariate analysis showed that high vimentin expression and worse node statuses were independent indicators of adverse prognosis (P < 0.048). In conclusion, vimentin expression is prevalent and markedly up-regulated in MPC, which might reflect the biological essence of poorer differentiation or dedifferentiation of MPC, and this might have a role in the acquisition and increase of invasiveness and consequent more malignant nature of MPC. PMID- 25684591 TI - Assessing shelf aggregate environmental compatibility and suitability for beach nourishment: a case study for Tuscany (Italy). AB - Beach nourishment practices are a key aspect in coastal management plans for stakeholders and communities. Stemming from a concrete case-study (Tuscany), this research analyzes: (i) principal problems of current law regulating dredging, (ii) gaps in technical guidelines, (iii) advantages of integrated approaches to the decision-making process, (iv) possible applicable nourishment options and their costs and benefits. Our results show that sand compatibility is driven mainly by grain-size stability due to the occurrence of lower pollution levels in off-shore deposits than in threatened beaches, thus current laws and guidelines should be improved to fill the evident gap in the evaluation process and to include a more complete approach to data evaluation and an integrated approach to ecotoxicity evaluation, which is relevant in cases of geochemical anomalies. The cost-benefit analysis performed indicates that only dredging intended to manage more than 1 million m(3) of aggregates would represent a real advantage for local communities. PMID- 25684592 TI - Investigation of trophic level and niche partitioning of 7 cetacean species by stable isotopes, and cadmium and arsenic tissue concentrations in the western Pacific Ocean. AB - A total of 24 stranded or bycatch cetaceans, including Balaenoptera omurai, Lagenodelphis hosei, Kogia sima, Stenella attenuata, Grampus griseus, Neophocaena phocaenoides, and Sousa chinensis, were collected from 2001 to 2011 in Taiwan. Using the muscular delta(13)C and delta(15)N data, three ecological groups were identified as the oceanic baleen whale, the neritic, and the coastal toothed whale groups, coinciding with their taxonomy, feeding habits and geographical distribution. A horizontal inshore to offshore distribution was found for the sympatric neritic toothed dolphins, G. griseus, K. sima, S. attenuata, and L. hosei in the outermost offshore waters, accompanying their growth. For the first time we identify Taiwan's Chinese white dolphin, S. chinensis, as an exclusive fish eater. Cd and As bioaccumulated in the G. griseus, L. hosei and S. attenuata increase as they grow. Prey-derived As- and Cd-induced health threats were found in L. hosei, and G. griseus. PMID- 25684593 TI - Noninvasive Qureshi Grading Scheme Predicts 90-Day mRS in Patients with Acute Ischemic Stroke. AB - BACKGROUND: The Qureshi grading scheme is an effective classification system for evaluating the severity of acute arterial occlusion. However, this scheme is of limited utility because it is based on invasive angiography. In this study, we assessed whether a relationship between a noninvasive Qureshi score, based on magnetic resonance angiography (MRA) or computed tomography angiography (CTA), and 90-day functional outcome could be observed in patients with acute ischemic stroke. METHODS: A stroke neurologist evaluated all patients with acute ischemic stroke who presented to the emergency room within 12 hour of symptom onset. Two neurologists independently assessed the noninvasive Qureshi score from initial MRA or CTA. We assessed the relationship between the noninvasive Qureshi grading scheme and clinical outcome on day 90. RESULTS: Of a total 125 patients, 75 underwent MRA and 50 underwent CTA. Interobserver reliability showed good agreement (kappa = .62). The noninvasive Qureshi score for MRA or CTA and that for CTA alone were directly associated with a good 90-day functional outcome (odds ratio, .672; P = .016 and odds ratio, .511; P = .042). CONCLUSIONS: The noninvasive Qureshi scheme using MRA or CTA provides meaningful information about long-term functional outcomes in patients with acute ischemic stroke. PMID- 25684594 TI - FAST: framework for heterogeneous medical image computing and visualization. AB - PURPOSE: Computer systems are becoming increasingly heterogeneous in the sense that they consist of different processors, such as multi-core CPUs and graphic processing units. As the amount of medical image data increases, it is crucial to exploit the computational power of these processors. However, this is currently difficult due to several factors, such as driver errors, processor differences, and the need for low-level memory handling. This paper presents a novel FrAmework for heterogeneouS medical image compuTing and visualization (FAST). The framework aims to make it easier to simultaneously process and visualize medical images efficiently on heterogeneous systems. METHODS: FAST uses common image processing programming paradigms and hides the details of memory handling from the user, while enabling the use of all processors and cores on a system. The framework is open-source, cross-platform and available online. RESULTS: Code examples and performance measurements are presented to show the simplicity and efficiency of FAST. The results are compared to the insight toolkit (ITK) and the visualization toolkit (VTK) and show that the presented framework is faster with up to 20 times speedup on several common medical imaging algorithms. CONCLUSIONS: FAST enables efficient medical image computing and visualization on heterogeneous systems. Code examples and performance evaluations have demonstrated that the toolkit is both easy to use and performs better than existing frameworks, such as ITK and VTK. PMID- 25684595 TI - Left Ventricular Septolateral Mechanical Delay Is Associated with Reduced Long Term Survival in Systolic Heart Failure with Narrow QRS Duration: Nine-Year Outcome in 109 Patients. AB - BACKGROUND: The long-term prognostic importance of left ventricular (LV) dyssynchrony in patients with systolic heart failure is not known. We investigated this question in 109 consecutive patients with systolic heart failure with an LV ejection fraction (EF) <=35% and QRS duration <130 ms. METHODS: The cohort is a prospective series of 109 patients with EF <=35% and QRS duration <130 ms who did not receive a defibrillator. Onset to onset septolateral and anteroposterior mechanical delays were computed from tissue Doppler velocity signals of the four quadrants of the mitral annulus and related to mortality. RESULTS: Patient characteristics included age 53 +/- 12 years, 73% male, 23% with coronary artery disease, LVEF 24 +/- 7%, LV end-diastolic dimension 64 +/- 9 mm, LV end-systolic dimension 55 +/- 9 mm, QRS duration 107 +/- 30 ms, and 92 with QRS duration <120 ms. Over a follow-up of 9 years, there were 51 deaths. Univariate predictors of mortality included LV septolateral delay (HR 1.01 per ms, P < 0.0001), anteroposterior delay (P = 0.003), and age (P = 0.005), but not EF, LV size, or QRS duration. Using Cox regression analysis, LV septolateral delay was an independent predictor of higher mortality (P = 0.0005) after adjusting for age, gender, EF, LV size, QRS duration, coronary artery disease, diabetes mellitus, and use of beta blockers or angiotensin-converting enzyme inhibitors. CONCLUSION: In patients with heart failure, LVEF <=35% and QRSd < 130 ms, LV mechanical dyssynchrony is a strong and independent predictor of long-term mortality. PMID- 25684596 TI - Bundle Branch Reentry Beats, Hisian Ectopics, or Dual AV Nodal Physiology? Ablating to Achieve 100% Biventricular Pacing. PMID- 25684597 TI - Community participation for rural healthcare design: description and critique of a method. AB - This paper outlines a community participation process that was developed to engage rural community stakeholders in designing new health services. The paper explains what led up to the process and provides critique around applying the process for other health services and in other communities. Internationally, community participation is widely invoked, but it is only broadly explained in the literature, other than reviews of outcomes or descriptions of problems. This paper provides an actual process, derived from iterative research, that others could use, but explains caveats in the method and its application. From developing this method of community participation for service design, we conclude that rather than being a benign and inherently 'good thing', community participation is a process into which health services managers and communities should enter cautiously. Stronger parameters around desirable outcomes and awareness of potential pitfalls in the process are important to address. PMID- 25684599 TI - Correlation of quinone reductase activity and allyl isothiocyanate formation among different genotypes and grades of horseradish roots. AB - Horseradish (Armoracia rusticana) is a perennial crop and its ground root tissue is used in condiments because of the pungency of the glucosinolate (GS) hydrolysis products allyl isothiocyanate (AITC) and phenethyl isothiocyanate (PEITC) derived from sinigrin and gluconasturtiin, respectively. Horseradish roots are sold in three grades: U.S. Fancy, U.S. No. 1, and U.S. No. 2 according to the USDA standards. These grading standards are primarily based on root diameter and length. There is little information on whether root grades vary in their phytochemical content or potential health promoting properties. This study measured GS, GS-hydrolysis products, potential anticancer activity (as quinone reductase inducing activity), total phenolic content, and antioxidant activities from different grades of horseradish accessions. U.S. Fancy showed significantly higher sinigrin and AITC concentrations than U.S. No. 1 ,whereas U.S. No. 1 showed significantly higher concentrations of 1-cyano 2,3-epithiopropane, the epithionitrile hydrolysis product of sinigrin, and significantly higher total phenolic concentrations than U.S. Fancy. PMID- 25684598 TI - Isoguanine and 5-methyl-isocytosine bases, in vitro and in vivo. AB - The synthesis, base-pairing properties and in vitro and in vivo characteristics of 5-methyl-isocytosine (isoC(Me) ) and isoguanine (isoG) nucleosides, incorporated in an HNA(h) (hexitol nucleic acid)-DNA(d) mosaic backbone, are described. The required h-isoG phosphoramidite was prepared by a selective deamination as a key step. As demonstrated by Tm measurements the hexitol sugar showed slightly better mismatch discrimination against dT. The d-isoG base mispairing follows the order T>G>C while the h-isoG base mispairing follows the order G>C>T. The h- and d-isoC(Me) bases mainly mispair with G. Enzymatic incorporation experiments show that the hexitol backbone has a variable effect on selectivity. In the enzymatic assays, isoG misincorporates mainly with T, and isoC(Me) misincorporates mainly with A. Further analysis in vivo confirmed the patterns of base-pair interpretation for the deoxyribose and hexitol isoC(Me) /isoG bases in a cellular context, through incorporation of the bases into plasmidic DNA. Results in vivo demonstrated that mispairing and misincorporation was dependent on the backbone scaffold of the base, which indicates rational advances towards orthogonality. PMID- 25684600 TI - A case of hypertrichotic smooth muscle hamartoma: is it an amelanotic Becker naevus? PMID- 25684601 TI - Yet another way that phage lambda manipulates its Escherichia coli host: lambdarexB is involved in the lysogenic-lytic switch. AB - The life cycle of phage lambda has been studied extensively. Of particular interest has been the process leading to the decision of the phage to switch from lysogenic to lytic cycle. The principal participant in this process is the lambdacI repressor, which is cleaved under conditions of DNA damage. Cleaved lambdacI no longer acts as a repressor, allowing phage lambda to switch from its lysogenic to lytic cycle. The well-known mechanism responsible for lambdacI cleavage is the SOS response. We have recently reported that the Escherichia coli toxin-antitoxin mazEF pathway inhibits the SOS response; in fact, the SOS response is permitted only in E. coli strains deficient in the expression of the mazEF pathway. Moreover, in strains lysogenic for prophage lambda, the SOS response is enabled by the presence of lambdarexB. lambdaRexB had previously been found to inhibit the degradation of the antitoxin MazE, thereby preventing the toxic action of MazF. Thus, phage lambda rexB gene not only safeguards the prophage state by preventing death of its E. coli host but is also indirectly involved in the lysogenic-lytic switch. PMID- 25684602 TI - Is orthodontics prior to 11 years of age evidence-based? A systematic review and meta-analysis. AB - OBJECTIVES: To determine whether interceptive orthodontics prior to the age of 11 years is more effective than later treatment in the short- and long-term. DATA AND SOURCES: Multiple electronic databases were searched, authors were contacted as required and reference lists of included studies were screened. STUDY SELECTION: Randomised and quasi-randomised controlled trials were included, comparing children under the age of 11 years requiring interceptive orthodontic correction for a range of occlusal problems, to an untreated or positive control group. Data extraction and quality assessment were performed independently and in duplicate. RESULTS: Twenty-two studies were potentially eligible for meta analysis, the majority related to growth modification. Other outcomes considered included correction of unilateral posterior crossbite, anterior openbite, extractions and ectopic maxillary canines. Meta-analysis was possible for 11 comparisons. For Class II correction in the short-term, meta-analyses demonstrated a statistically significant reduction in ANB (-1.4 degrees, 95 CI: 2.17, -0.64) and overjet (-5.81mm, 95 CI: -6.37, -5.25) with both functional appliances and headgear versus control. In the long-term, however, statistical significance was not found for the same outcomes. Treatment duration was prolonged with both functional appliances (6.85 months, 95 CI: 3.24, 10.45) and headgear (12.47 months, 95 CI: 8.67, 16.26) compared to adolescent treatments. Meta-analyses were not possible for comparisons of other interceptive treatments due to heterogeneity and methodological limitations. CONCLUSIONS: The results suggest a lack of evidence to prove that early treatment carries additional benefit over and above that achieved with treatment commencing later; however, this does not necessarily imply that early treatment is ineffective. Further high quality trials are required to assess the effectiveness of early treatment compared to later intervention. CLINICAL SIGNIFICANCE: Interceptive orthodontics is variously recommended for a range of malocclusions both of skeletal and dental aetiology. The merits of interceptive treatment, however, are often disputed. Further high quality trials are required to assess the effectiveness of early treatment compared to later intervention. PMID- 25684603 TI - Age-specific prevalence of erosive tooth wear by acidic diet and gastroesophageal reflux in Japan. AB - OBJECTIVES: To evaluate the age-specific prevalence of erosive tooth wear in Japanese adults. METHODS: The study sample consisted of a total of 1108 adults aged 15-89 yrs in Tokyo, Japan. The subjects were asked to complete a self administered nutrition-related questionnaire. Two examiners evaluated tooth wear in a full-mouth recording, using a modified tooth wear index developed based on the Smith and Knight Tooth Wear index. Subjects who had frequent acid consumption or gastric reflux and at least one tooth with an initial enamel wear were placed in an erosive wear positive group, and the rest of subjects were placed in the erosive wear negative group. RESULTS: The median (IQR) prevalence of erosion was 19.1 (1.8) at enamel level and 6.5 (3.7) with dentin exposure. There were statistical differences in prevalence of erosive wear among different age groups (p<0.05). Dietary habits found to be frequent in erosive wear positive group included acidic juices for younger subjects (15-39 yrs), and acidic fruits for older subjects (60-89 yrs). The prevalence of gastroesophageal reflux and eating disorder was 3.5%. A severe loss of dental tissue was observed on labial and incisal surfaces of anterior teeth in the erosive wear positive group. CONCLUSIONS: In the studied sample of Japanese adults, 26.1% had signs of erosive wear. CLINICAL SIGNIFICANCE: Erosive wear, in combination with abrasion and attrition, results in severe loss of tooth tissue. Frequent consumption of acidic fruits and drinks was significantly associated with erosive tooth wear at different age groups. PMID- 25684604 TI - Liraglutide pharmacokinetics and dose-exposure response in Asian subjects with Type 2 diabetes from China, India and South Korea. AB - AIMS: To investigate the population pharmacokinetics and exposure-response relationship of liraglutide, a human glucagon-like peptide-1 (GLP-1) analogue, in Asian subjects with Type 2 diabetes mellitus. METHODS: Data were derived from a published 16-week, randomized, double-blind, double-dummy, active-controlled, parallel-group trial of liraglutide in China, India and South Korea. The analysis utilized 2061 pharmacokinetic (PK) samples from 605 subjects exposed to liraglutide 0.6, 1.2 or 1.8 mg once daily. Demographic factors (body weight, age, gender, country) of importance for liraglutide clearance were evaluated. An exploratory exposure-response analysis was conducted to investigate effects on glycated haemoglobin (HbA1c) and body weight. RESULTS: Estimated liraglutide exposure (area under the curve; AUC) appeared to increase proportionally with increasing liraglutide dose (0.6-1.8 mg). The covariate analysis confirmed previous findings in a global clinical trial. Body weight was a predictor of liraglutide exposure; compared to a reference subject of 67 kg, exposure was 32% lower for maximum (115 kg) and 54% higher for minimum (37 kg) observed body weights. Gender, age and country had no relevant effect on exposure. Exposure response analysis supported the use of 1.2mg as maintenance dose with the option of individual dose escalation to 1.8 mg to optimize treatment outcomes. CONCLUSIONS: Exposure appeared to increase proportionally with increasing liraglutide dose in Asian subjects with Type 2 diabetes mellitus. The only PK relevant predictor of exposure was body weight. The exposure-response relationships for HbA1c and body weight in Asian subjects were similar to observations in global populations. PMID- 25684605 TI - Impact of carbamylation on three different methods, HPLC, capillary electrophoresis and TINIA of measuring HbA1c levels in patients with kidney disease. AB - AIMS: Aim of this study was to investigate whether established IFCC traceable routine measurements of HbA1c levels in patients with kidney diseases result in comparable and valid results. Additionally, the influence of carbamylation as a marker of uremia on the measurement methods was assessed. METHODS: We compared three different measurement methods (high-performance liquid chromatography (HPLC), capillary electrophoresis and turbidimetric inhibition immunoassay (TINIA)) based on 407 nephrology samples for HbA1c determination with specific analysis of the threshold areas where different HbA1c measurements could result in different diagnoses (diabetes mellitus vs prediabetes and prediabetes vs non diabetes). Indirectly, a potential effect of carbamylated hemoglobin was assessed based on determination of BUN levels in serum. RESULTS: In nephrological samples, we were able to show that three different measurement methods provide similar results regarding HbA1c in routine diagnostics. Our results show that with BUN concentrations <80 mg/dl and >=80 mg/dl, similar HbA1c levels were determined, independent of measurement method. CONCLUSION/DISCUSSION: While routine measurements follow IFCC standards, many interfering factors remain which can influence HbA1c determination, e.g. carbamylation of proteins. As kidney disease is the most common complication in patients with diabetes mellitus, interference in the measurement of HbA1c due to carbamylated proteins as markers of uremia must be recognized and if necessary corrected. We found not only a weak influence of carbamylation on all methods of HbA1c determination, but also that, in nephrological samples, the three different measurement methods provided similar results regarding HbA1c in routine diagnostics. PMID- 25684606 TI - Brain interventions and neuroethics must coexist peacefully. PMID- 25684607 TI - Hand on the wheel, mind on the mobile: an analysis of social factors contributing to texting while driving. AB - In an era defined by social technology, mobile phones provide constant connection to others. However, they also present a very dangerous situation when people choose to use their mobile phones while driving. In particular, exchanging text messages while driving has resulted in numerous accidents and fatalities. The purpose of this study is to examine social factors that lead people to text while driving. Specifically, using a multivariate logistic regression analysis of data from a 2010 survey by the Pew Research Center, variables for general mobile talk, driving while talking on a mobile, using the Internet on a mobile, sexting, and various motivations for texting were examined to determine factors that increase the likelihood of texting while driving. The findings suggest that people engage in mobile multiplexing (i.e., communication using two or more media on the mobile) while driving. Additionally, exchanging text messages in public, and consequently texting while driving, has become normalized. Furthermore, people are socialized into such behaviors through observing others texting while driving and using a mobile recklessly while driving. Finally, a number of motivations for texting were found to increase the likelihood of texting while driving significantly. Ultimately, the author contends that texting while driving has become a cultural artifact in the United States, which conflicts with driver safety as well as laws prohibiting texting while driving. The findings of this study could inform future awareness campaigns and technology developers to help establish a safer driving environment within the multitasking culture. PMID- 25684608 TI - Cyberbullying, depression, and problem alcohol use in female college students: a multisite study. AB - Cyberbullying and its effects have been studied largely in middle and high school students, but less is known about cyberbullying in college students. This cross sectional study investigated the relationship between involvement in cyberbullying and depression or problem alcohol use among college females. Two hundred and sixty-five female students from four colleges completed online surveys assessing involvement in cyberbullying behaviors. Participants also completed the Patient Health Questionnaire-9 (PHQ-9) to assess depressive symptoms and the Alcohol Use Disorder Identification Test (AUDIT) to assess problem drinking. Logistic regression tested associations between involvement in cyberbullying and either depression or problem drinking. Results indicated that 27% of participants had experienced cyberbullying in college; 17.4% of all participants met the criteria for depression (PHQ-9 score >=10), and 37.5% met the criteria for problem drinking (AUDIT score >=8). Participants with any involvement in cyberbullying had increased odds of depression. Those involved in cyberbullying as bullies had increased odds of both depression and problem alcohol use. Bully/victims had increased odds of depression. The four most common cyberbullying behaviors were also associated with increased odds for depression, with the highest odds among those who had experienced unwanted sexual advances online or via text message. Findings indicate that future longitudinal study of cyberbullying and its effects into late adolescence and young adulthood could contribute to the prevention of associated comorbidities in this population. PMID- 25684609 TI - Examining how gender and emoticons influence Facebook jealousy. AB - Facebook use among young adults is widespread, and understanding how it affects romantic relationships has practical, real world implications. Both gender and amount of time spent on Facebook have been associated with online jealousy. Emoticons can be used online to clarify messages and are often used in mixed gender interactions. A series of studies was used to examine whether gender and emoticons interacted to influence Facebook jealousy. Interestingly, results differed based on qualitative and quantitative responses. With quantitative responses, a main effect was found only for gender. Females displayed more Facebook jealousy than males. With qualitative responses, an interaction was found. Males were more jealous when a winking emoticon was present, while females were more jealous when no emoticon was present. This research supports evolutionary work in suggesting that specific cues may differentially influence jealousy responses in males and females. It should be mentioned that although differences were noticed, they may be contingent upon the research methods utilized and that mixed methods may best address issues involving jealousy in young adults. PMID- 25684610 TI - Tweeting badges: user motivations for displaying achievement in publicly networked environments. AB - Badge systems, a common mechanism for gamification on social media platforms, provide a way for users to present their knowledge or experience to others. This study aims to contribute to the understanding of why social media users publicize their achievements in the form of online badges. Five motivational factors for badge display in public networked environments are distinguished-self-efficacy, social incentives, networked support, passing time, and inattentive sharing-and it is suggested that different badge types are associated with different motivations. System developers are advised to consider these components in their designs, applying the elements most appropriate to the communities they serve. Comparing user motivations associated with badges shared across boundaries provides a better understanding of how online badges relate to the larger social media ecosystem. PMID- 25684611 TI - Using a digital game for training desirable behavior in cognitive-behavioral therapy of burnout syndrome: a controlled study. AB - Burnout is a globally increasing illness, and as a result, many forms of burnout therapy have arisen. The use of digital games can be psychotherapeutically effective because they can transform exercises that are by themselves unattractive into intrinsically motivated action. This pilot study aims to test whether a specially designed game contributes to patients learning desired behavior and achieving other specific therapeutic goals in an online cognitive behavioral therapy (CBT)-based burnout treatment context. In total, 101 participants took part in the experiment, under four conditions: (a) Game+Therapy, (b) Therapy Only, (c) Game Only, and (d) No Game+No Therapy. Pre- and postmeasures were taken online. Results showed that the two therapy conditions (Game+Therapy and Therapy Only) showed a greater decrease in complaints and disengagement, and a stronger increase in coping skills than the nontherapy conditions (Game Only and No Game+No Therapy). As expected, the Game+Therapy condition outperformed the Therapy Only condition on combined improvement measures of burnout symptoms. However, analyses of individual measures showed no effects. It can be cautiously concluded that the therapeutic digital game may be a useful tool when embedded in a therapeutic burnout treatment program and is probably more efficient than CBT, as it is used in current practice. PMID- 25684612 TI - Evaluation of the psychometric properties of the Italian Internet Addiction Test. AB - Since the diffusion of Internet addiction has emerged in several cultural contexts, it seems relevant to study the properties of the Internet Addiction Test (IAT)-the most widely used screening instrument-across various cultures. In Italy, only one study has examined the IAT factor validity, and a comprehensive investigation of its psychometric characteristics is so far lacking. The purpose of this study was to perform a psychometric analysis of the Italian IAT. A total of 840 students (Mage=18.65 years, SD=3.85 years; 59% female) were recruited. Pertaining to scale dimensionality, the best-fit measurement model includes two factors: "Emotional and cognitive preoccupations with the Internet and social consequences" and "Loss of control and interference with daily duties" (chi(2)/df=3.38; comparative fit index=0.88; Tucker-Lewis Index=0.87; root mean square error of approximation=0.07), which together explained 45.59% of the variance. Internal consistency Cronbach's alpha values ranged from 0.83 to 0.86. Convergent validity was demonstrated, with significant correlations between IAT and Generalized Problematic Internet Use Scale 2 scores. The Italian version of the IAT was found to have good psychometric properties and a two-factorial structure. Identification of the IAT dimensions may help to define the construct better and develop intervention strategies. PMID- 25684613 TI - Versatility and addiction in gaming: the number of video-game genres played is associated with pathological gaming in male adolescents. AB - This study tested the predictive power of gaming versatility (i.e., the number of video game genres engaged in) on game addiction in male adolescents, controlling for time spent on gaming. Participants were 701 male adolescents attending high school (Mage=15.6 years). Analyses showed that pathological gaming was predicted not only by higher time spent on gaming, but also by participation in a greater number of video game genres. Specifically, the wider the array of video game genres played, the higher were the negative consequences caused by gaming. Findings show that versatility can be considered as one of the behavioral risk factors related to gaming addiction, which may be characterized by a composite and diversified experience with video games. This study suggests that educational efforts designed to prevent gaming addiction among youth may also be focused on adolescents' engagement in different video games. PMID- 25684616 TI - Vector-mediated microRNA-21 silencing ameliorates granulomatous liver fibrosis in Schistosoma japonicum infection. PMID- 25684617 TI - Conceptualizing splitting: On the different meanings of splitting and their implications for the understanding of the person and the analytic process. AB - While "splitting" is a familiar concept, its meaning is not as self-evident as is commonly assumed. In different contexts, it refers to different phenomena and is supported by different understandings of psychic dynamics. In this paper, the author presents four different conceptualizations of splitting, which capture the essential aspects of contemporary psychoanalytic discourse on the concept. There is a dissociative kind of splitting, which involves splitting off, in the face of trauma, whole personalities, which to some extent remain accessible to consciousness; there is a disavowal kind of splitting that splits off our awareness of disturbing realities or their meanings in our efforts to avoid the inner restraints imposed by repression; and there are two forms of splitting of the object into good and bad-one focusing on the splitting of representations of the object due to ego weakness and environmental determinants, and the other on the splitting of the mind itself in a primarily destructive act aimed at sparing the good from the destructiveness of our death instinct. All four conceptualizations have their origins in Freud's writing and then are further developed in the work of later analysts. The author argues that understanding the nature of these various conceptualizations of splitting can contribute to analytic theory and practice. It also sheds light on the essential nature of analytic approaches and how they offer different perspectives on the unity and disunity of man's basic nature. PMID- 25684618 TI - Does the expectation or perception of noncontraceptive benefits lead to higher rates of short-acting reversible contraceptive continuation for adolescents and young adult women? AB - OBJECTIVE: Continuation rates of short-acting contraception among young women are low; we attempted to determine if continuation is higher when women expect noncontraceptive benefits at initiation or perceive benefits 6 months later. STUDY DESIGN: A total of 243 young women ages 13-24 years initiating short-acting methods in an adolescent-only family planning clinic completed post-visit surveys that included directed and open-ended questions about anticipated noncontraceptive benefits. The study participants were contacted 6 months later. We compared contraceptive continuation between those who expected noncontraceptive benefits and those who did not and between those who reported experiencing benefits and those who did not. We examined the concordance between expectations and reported experiences. RESULTS: Six months after initiation, 69.3% of women were using the same method. Baseline expectation of noncontraceptive benefits was not associated with 6-month continuation. The experience of any benefit listed by the patient (odds ratio=2.69, 95% confidence interval 1.1, 6.0) was associated with greater continuation. Concordance between expectation and perception of noncontraceptive benefits was low (Kappa=0.2). CONCLUSIONS: Women who experienced noncontraceptive benefits at 6 months of use were more likely to continue short-acting contraception. Women who expected benefits when initiating were not more likely to report experiencing them, and many women who did not expect benefits reported them and were more likely to continue. These findings imply that building expectations of noncontraceptive benefits, e.g., through counseling, may not improve continuation and that new contraceptive development should include consideration of tangible noncontraceptive benefits. IMPLICATIONS: Although adolescents and young women who perceive noncontraceptive benefits after 6 months of use are more likely to continue, the expectation of such benefits does not correlate with continuation. PMID- 25684619 TI - Enhancing low-grade thermal energy recovery in a thermally regenerative ammonia battery using elevated temperatures. AB - A thermally regenerative ammonia battery (TRAB) is a new approach for converting low-grade thermal energy into electricity by using an ammonia electrolyte and copper electrodes. TRAB operation at 72 degrees C produced a power density of 236 +/- 8 Wm(-2), with a linear decrease in power to 95 +/- 5 Wm(-2) at 23 degrees C. The improved power at higher temperatures was due to reduced electrode overpotentials and more favorable thermodynamics for the anode reaction (copper oxidation). The energy density varied with temperature and discharge rates, with a maximum of 650 Wh m(-3) at a discharge energy efficiency of 54% and a temperature of 37 degrees C. The energy efficiency calculated with chemical process simulation software indicated a Carnot-based efficiency of up to 13% and an overall thermal energy recovery of 0.5%. It should be possible to substantially improve these energy recoveries through optimization of electrolyte concentrations and by using improved ion-selective membranes and energy recovery systems such as heat exchangers. PMID- 25684620 TI - [Medical and economic impact of a haemostatic sealant on the rate of transfusion after total knee arthroplasty]. AB - OBJECTIVES: Blood loss reduction in total knee arthroplasty (TKA) contributes to the prevention of morbidity and mortality and in the management of health care costs. Fibrin haemostatic sealant have controversial effectiveness in reducing postoperative blood loss and transfusion requirements. Our study evaluated the medical and economic benefits of this treatment with the assumption that it decreases the frequency of blood transfusion after TKA. METHODS AND PATIENTS: Our single-center and randomized study included 60 patients pose unilateral primary TKA for osteoarthritis. Distribution was done in 2 groups of 30 patients each. Group 1 patients treated with a dose of 5 mL Evicel(r), compared to untreated group 2. Were collected the number of patients transfused. The treatment cost was compared to the sealant cost. RESULTS: Results are not statistically significant. Two patients were transfused in group 1 and 3 in group 2 (P=0.64). The treatment cost for 30 patients is 13,500 ?, for a savings of cells packed at 187 ?, an additional cost of 13,313 ? in group 1. CONCLUSION: The use of fibrin haemostatic sealant in TKA did not induce a significant difference in terms of blood or transfusion savings, with a significant cost. We do not recommend its routine use in TKA. PMID- 25684621 TI - Renal tubular epithelial vacuoles-a marker for both hyperlipidemia and ketoacidosis at autopsy. AB - Review of 15 cases of nephrotic syndrome found that eight had significant hyperlipidemia with serum cholesterol levels ranging between 10.59 and 18.60 mmol/L (mean 12.88) and serum triglyceride levels between 2.30 and 9.92 mmol/L (mean 4.58); all of these cases displayed basal lipid vacuolization. Seven of the 15 study cases had normal-mild hyperlipidemia with serum cholesterol levels ranging between 4.71 and 7.54 mmol/L (mean 6.02) and serum triglyceride levels between 0.65 and 4.1 mmol/L (mean 1.57). Six of the seven cases had basal lipid vacuoles (86%). Of these, five cases were hyperlipidemic and one case had borderline hyperlipidemia with a serum cholesterol level of 4.71 mmol/L. Although hyperlipidemia was associated with renal tubular epithelial vacuolization, the vacuoles appeared morphologically different to those found in ketoacidosis. This study has shown that while hyperlipidemia in isolation may result in basal lipid vacuolization within renal tubular epithelial cells, the phenotype differs from that observed in ketoacidosis. PMID- 25684622 TI - Virulence determinants of the human pathogenic fungus Aspergillus fumigatus protect against soil amoeba predation. AB - Filamentous fungi represent classical examples for environmentally acquired human pathogens whose major virulence mechanisms are likely to have emerged long before the appearance of innate immune systems. In natural habitats, amoeba predation could impose a major selection pressure towards the acquisition of virulence attributes. To test this hypothesis, we exploited the amoeba Dictyostelium discoideum to study its interaction with Aspergillus fumigatus, two abundant soil inhabitants for which we found co-occurrence in various sites. Fungal conidia were efficiently taken up by D. discoideum, but ingestion was higher when conidia were devoid of the green fungal spore pigment dihydroxynaphtalene melanin, in line with earlier results obtained for immune cells. Conidia were able to survive phagocytic processing, and intracellular germination was initiated only after several hours of co-incubation which eventually led to a lethal disruption of the host cell. Besides phagocytic interactions, both amoeba and fungus secreted cross inhibitory factors which suppressed fungal growth or induced amoeba aggregation with subsequent cell lysis, respectively. On the fungal side, we identified gliotoxin as the major fungal factor killing Dictyostelium, supporting the idea that major virulence attributes, such as escape from phagocytosis and the secretion of mycotoxins are beneficial to escape from environmental predators. PMID- 25684623 TI - Mini invasive transoral approach to the glenoid fossa: Benign lesion removal using endoscopy. AB - OBJECTIVE: We describe an endoscopic transoral approach for treating benign lesions of the glenoid fossa with or without infratemporal fossa involvement. STUDY DESIGN: Description and validation of surgical technique on living humans. METHODS: Excision of benign lesions arising from the glenoid fossa was achieved in five patients through a transoral endoscopic approach. Using 0- and 45-degree angled 4-mm optics, the entire middle skull base and infratemporal fossa were explored without damaging the nearby neurovascular structures. RESULTS: Three of the five patients had complete removal of osteochondroma. In the remaining two patients, the lesion removed was diagnosed as osteoma. In one patient, postoperative numbness of the alveolar nerve was observed. No infections were reported. The surgical approach utilized was determined to be valid not only for glenoid fossa exposure but also for management of the middle skull base and infratemporal fossa. CONCLUSION: The described approach to the glenoid fossa offers direct and minimally invasive access to benign lesions within this region. Further use of this approach will allow us to determine its potential in treating malignancies. LEVEL OF EVIDENCE: 4. PMID- 25684624 TI - Gregarious pupation act as a defensive mechanism against cannibalism and intraguild predation. AB - Coccinellid pupae use an array of defensive strategies against their natural enemies. This study aims to assess the efficiency of gregarious pupation as a defensive mechanism against intraguild predators and cannibals in coccinellid. The study was designed specifically (i) to determine the natural occurrence of gregarious pupation in the field for different coccinellid species, and (ii) to evaluate the adaptive value of gregarious pupation as a defensive mechanism against 2 types of predators (i.e., cannibals and intraguild predators). In the field, gregarious pupation consisted of a group of 2-5 pupae. The proportion of gregarious pupation observed varied according to species, the highest rate being observed with Harmonia axyridis Pallas (Coccinellidae; 14.17%). Gregarious pupation had no impact on the probability that intraguild predators and cannibals locate pupae. Intraguild predation occurred more often in site with gregarious pupation, while cannibalism occurred as often in site with gregarious pupation as in site with isolated pupa. However, for a specific pupa, the mortality rate was higher for isolated pupae than for pupae located in a gregarious pupation site both in the presence of intraguild predators and in the presence of cannibals. The spatial location of pupae within the group had no impact on mortality rate. Since it reduces the risk of predation, it is proposed that gregarious pupation act as a defensive mechanism for H. axyridis pupae. PMID- 25684625 TI - Sustained Modeling-Based Bone Formation During Adulthood in Cynomolgus Monkeys May Contribute to Continuous BMD Gains With Denosumab. AB - Denosumab (DMAb) administration to postmenopausal women with osteoporosis is associated with continued bone mineral density (BMD) increases and low fracture incidence through 8 years, despite persistently reduced bone turnover markers and limited fluorochrome labeling in iliac crest bone biopsies. BMD increases were hypothesized to result from additional accrual of bone matrix via modeling-based bone formation-a hypothesis that was tested by examining fluorochrome labeling patterns in sections from ovariectomized (OVX) cynomolgus monkeys (cynos) treated with DMAb for 16 months. Mature OVX or Sham cynos were treated monthly with vehicle for 16 months, whereas other OVX cynos received monthly 25 or 50 mg/kg DMAb. DMAb groups exhibited very low serum bone resorption and formation biomarkers and near-absent fluorochrome labeling in proximal femur cancellous bone. Despite these reductions, femoral neck dual-energy X-ray absorptiometry (DXA) BMD continued to rise in DMAb-treated cynos, from a 4.6% increase at month 6 to 9.8% above baseline at month 16. Further examination of cortical bone in the proximal femur demonstrated consistent and prominent labeling on the superior endocortex and the inferior periosteal surface, typically containing multiple superimposed labels from month 6 to 16 over smooth cement lines, consistent with continuous modeling-based bone formation. These findings were evident in all groups. Quantitative analysis at another modeling site, the ninth rib, demonstrated that DMAb did not alter the surface extent of modeling-based labels, or the cortical area bound by them, relative to OVX controls, while significantly reducing remodeling-based bone formation and eroded surface. This conservation of modeling-based formation occurred concomitantly with increased femoral neck strength and, when coupled with a reduction in remodeling-based bone loss, is likely to contribute to increases in bone mass with DMAb treatment. Thus, this study provides preclinical evidence for a potential mechanism that could contribute to the clinical observations of continued BMD increases and low fracture rates with long-term DMAb administration. PMID- 25684626 TI - Montelukast potentiates the anticonvulsant effect of phenobarbital in mice: an isobolographic analysis. AB - Although leukotrienes have been implicated in seizures, no study has systematically investigated whether the blockade of CysLT1 receptors synergistically increases the anticonvulsant action of classic antiepileptics. In this study, behavioral and electroencephalographic methods, as well as isobolographic analysis, are used to show that the CysLT1 inverse agonist montelukast synergistically increases the anticonvulsant action of phenobarbital against pentylenetetrazole-induced seizures. Moreover, it is shown that LTD4 reverses the effect of montelukast. The experimentally derived ED50mix value for a fixed-ratio combination (1:1 proportion) of montelukast plus phenobarbital was 0.06+/-0.02 MUmol, whereas the additively calculated ED50add value was 0.49+/ 0.03 MUmol. The calculated interaction index was 0.12, indicating a synergistic interaction. The association of montelukast significantly decreased the antiseizure ED50 for phenobarbital (0.74 and 0.04 MUmol in the absence and presence of montelukast, respectively) and, consequently, phenobarbital-induced sedation at equieffective doses. The demonstration of a strong synergism between montelukast and phenobarbital is particularly relevant because both drugs are already used in the clinics, foreseeing an immediate translational application for epileptic patients who have drug-resistant seizures. PMID- 25684627 TI - Trends in darunavir resistance-associated mutations and phenotypic resistance in commercially tested United States clinical samples between 2006 and 2012. AB - HIV-1 samples submitted by clinicians from the United States for routine drug susceptibility testing (PhenoSense GT) were evaluated for genotypic and phenotypic resistance to darunavir and other protease inhibitors (PIs). Among these samples (Monogram Biosciences database January 2006-June 2012; N=78,843), isolates harboring zero IAS-USA darunavir resistance-associated mutations (RAMs) increased from 77.7% in 2006 to 92.8% through the first half of 2012 (H1 2012; upward trend, p=0.0008); a downward trend seen for samples with three or more darunavir RAMs (7.5% in 2006 and 2.6% in H1 2012; p=0.002). Among samples with any PI resistance (N=15,932), samples harboring zero darunavir RAMs gradually increased (39.9% in 2006 vs. 55.0% in H1 2012; upward trend, p=0.005), but three or more darunavir RAMs did not change over time (21.7% in 2006 and 19.2% in H1 2012; p=0.27). During this period, the frequency of the 11 individual darunavir RAMs (IAS-USA 2011 list) decreased among all samples. The frequency of each darunavir RAM in PI-resistant samples decreased or remained relatively stable. The prevalence of samples with phenotypic resistance to darunavir (partial-to full) decreased over time in all samples (8.2% in 2006 vs. 2.3% in H1 2012), as did resistance to other PIs (p<0.006 for all PIs). Phenotypic resistance to darunavir and other PIs also decreased in PI-resistant samples (darunavir: 23.9% in 2006 vs. 17.1% in H1 2012; p<0.013 for all PIs). Since approval of darunavir in 2006, there was a significant decrease in prevalence of samples with genotypic and phenotypic resistance to darunavir in commercially tested HIV-1 isolates. Furthermore, the prevalence of phenotypic resistance to darunavir was lower than all other PIs. PMID- 25684628 TI - The dramatic effect of the annealing temperature and dielectric functionalization on the electron mobility of indene-C60 bis-adduct thin films. AB - Herein we report on the charge transport properties of spin-coated thin films of an n-type fullerene derivative, i.e. the indene-C60 bis-adduct (ICBA). In particular, the effects of annealing temperature and duration as well as surface functionalization are explored. Electron mobilities approaching 0.1 cm(2) V(-1) s(-1) are reported. PMID- 25684629 TI - A safe and efficient model for ultraviolet radiation-induced herpes simplex labialis. PMID- 25684631 TI - Sirolimus-induced interstitial lung disease following pediatric stem cell transplantation. AB - Sirolimus-induced ILD is a known but rare complication in adults who have undergone SOT. However, little is known about this adverse effect in children. Diagnosis of sirolimus-induced ILD can be challenging, especially in patients who have difficulty participating in lung function testing. We present a case of presumed sirolimus-induced ILD in a pediatric stem cell transplant patient who developed polycythemia and hypoxemia. To our knowledge, no other cases of sirolimus-induced pulmonary toxicity in children after HCT have been reported. PMID- 25684630 TI - Tissue heterogeneity in structure and conductivity contribute to cell survival during irreversible electroporation ablation by "electric field sinks". AB - Irreversible electroporation (IRE) is an emerging, minimally invasive technique for solid tumors ablation, under clinical investigation for cancer therapy. IRE affects only the cell membrane, killing cells while preserving the extracellular matrix structure. Current reports indicate tumors recurrence rate after IRE averaging 31% of the cases, of which 10% are local recurrences. The mechanisms for these recurrences are not known and new explanations for incomplete cell death are needed. Using finite elements method for electric field distribution, we show that presence of vascular structures with blood leads to the redistribution of electric fields leading to the areas with more than 60% reduced electric field strength in proximity to large blood vessels and clustered vessel structures. In an in vivo rat model of liver IRE ablation, we show that cells located in the proximity of larger vessel structures and in proximity of clustered vessel structures appear less affected by IRE ablation than cells in the tissue parenchyma or in the proximity of small, more isolated vessels. These findings suggest a role for "electric field sinks" in local tumors recurrences after IRE and emphasize the importance of the precise mapping of the targeted organ structure and conductivity for planning of electroporation procedures. PMID- 25684632 TI - Synergistic combination of histone deacetylase inhibitor suberoylanilide hydroxamic acid and oncolytic adenovirus ZD55-TRAIL as a therapy against cervical cancer. AB - Oncolytic adenoviruses (OA) have been investigated as virotherapeutic agents for the treatment of cervical cancer and thus far results are promising. However, the cytotoxicity of the viruses requires improvement. The present study demonstrated that this can be achieved by combining ZD55-TRAIL, an OA containing the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene, with the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA). It was demonstrated that these agents act synergistically to kill HeLa cells by inducing G2 growth arrest and apoptosis. Notably, in a mouse xenograft model, ZD55-TRAIL/SAHA combination inhibited tumor growth. At the molecular level, it was found that upregulation of IkappaBalpha and the p50 and p65 subunits of nuclear factor kappaB induced by ZD55-TRAIL, can be abrogated by SAHA treatment. These data strongly suggested that ZD55-TRAIL/SAHA co-treatment may serve as an effective therapeutic strategy against cervical cancer. PMID- 25684634 TI - Templateless synthesis of polyacrylamide-based Nanogels via RAFT dispersion polymerization. AB - This paper reports on the synthesis of well-defined polyacrylamide-based nanogels via reversible addition-fragmentation chain transfer (RAFT) dispersion polymerization, highlighting a templateless route for the efficient synthesis of nanogels based on water-soluble polymers. RAFT dispersion polymerization of acrylamide in co-nonsolvents of water-tert-butanol mixtures by chain extension from poly(dimethylacrylamide) shows well-controlled polymerization process, uniform nanogel size, and excellent colloidal stability. The versatility of this approach is further demonstrated by introducing a hydrophobic co-monomer (butyl acrylate) without disturbing the dispersion polymerization process. PMID- 25684635 TI - Effects of receptor tyrosine kinase inhibitors on VEGF165 a- and VEGF165 b stimulated gene transcription in HEK-293 cells expressing human VEGFR2. AB - BACKGROUND AND PURPOSE: Receptor tyrosine kinase inhibitors (RTKIs) targeted at VEGF receptor 2 (VEGFR2) have proved to be attractive approaches to cancer therapy based on their ability to reduce angiogenesis. Here we have undertaken a quantitative analysis of the interaction of RTKIs and two VEGF splice variants, VEGF(165)a and VEGF(165)b, with VEGFR2 by studying nuclear factor of activated T cells (NFAT) reporter gene activity in live HEK-293 cells. EXPERIMENTAL APPROACH: HEK-293 cells expressing the human VEGFR2 and a firefly luciferase reporter gene regulated by an NFAT response element were used for quantitative analysis of the effect of RTKIs on VEGF(165)a- and VEGF(165)b-stimulated luciferase gene expression. KEY RESULTS: VEGF(165)a produced a concentration-dependent activation of the NFAT-luciferase reporter gene in living cells that was inhibited in a non competitive fashion by four different RTKIs (cediranib, pazopanib, sorafenib and vandetanib). The potency obtained for each RTKI from this analysis was similar to those obtained in binding studies using purified VEGFR2 kinase domains. VEGF(165)b was a lower-efficacy agonist of the NFAT-luciferase response when compared with VEGF(165)a. Analysis of the concentration-response data using the operational model of agonism indicated that both VEGF(165) isoforms had similar affinity for VEGFR2. CONCLUSIONS AND IMPLICATIONS: Quantitative pharmacological analysis of the interaction of VEGF(165) isoforms and RTKIs with VEGFR2 in intact living cells has provided important insights into the relative affinity and efficacy of VEGF(165)a and VEGF(165)b for activation of the calcineurin- NFAT signalling pathway by this tyrosine kinase receptor. PMID- 25684636 TI - Recent trends in testosterone testing, low testosterone levels, and testosterone treatment among Veterans. AB - Low serum testosterone (T) is common and increasingly prevalent with increased age. Recent studies report an 'epidemic' of T prescribing and concern about unnecessary T treatment. We investigated the number of men tested for T, the prevalence of low serum T levels, and initiation of T treatment among those with low T levels in men treated at Veterans Affairs (VA) facilities in the Northwest US (VISN 20). We identified male Veterans aged 40-89 years and examined yearly proportions of men tested for T, found to have low T levels (total T < 280 ng/dL, free T < 34 pg/mL, or bioavailable T < 84 ng/dL), and subsequently treated with T from 2002 to 2011. We excluded men who had T treatment in the year prior and men with diagnoses of prostate or breast cancer. Treatment initiation was defined as the first prescription for T within a year following a low T test. From 2002 to 2011, the yearly population of eligible men in VISN 20 increased from 129 247 to 163 572. The proportion of men who had serum T tests increased from 3.2% in 2002 to 5.8% in 2011. Among the tested men, the percentage of men with low T levels increased from 35.0 to 47.3%. However, the proportion of men with low T levels who were given T treatment within a year decreased from 31.0 to 28.0%. Despite large increases in T testing, and detection of men with low T levels, there was a slight decrease in the proportion of men with low T levels who were treated with T. The decrease in T treatment during this time period contrasts with other studies and may be related to higher comorbidity in Veterans and/or VA formulary restrictions on the use of transdermal T formulations. PMID- 25684637 TI - Glutathione S-transferase-pi protein expression in prostate cancer--not always a useful diagnostic tool. PMID- 25684638 TI - Chemotherapy of respiratory syncytial virus infections: the final breakthrough. AB - Respiratory syncytial virus (RSV) infection is the leading cause of hospitalisation for children under 5 years of age and causes excess mortality in the elderly. There is still no approved vaccine available, although the disease can be curtailed by RSV-specific monoclonal antibody. The only antiviral drug approved for the treatment of RSV infection is ribavirin aerosol, but this treatment is cumbersome and its efficacy is questionable. A new antiviral, GS 5806, which interferes with virus-cell fusion, has proven efficacious in experimental RSV infections in adults. PMID- 25684639 TI - Movement disorders and other motor abnormalities in adults with 22q11.2 deletion syndrome. AB - Movement abnormalities are frequently reported in children with 22q11.2 deletion syndrome (22q11.2DS), but knowledge in this area is scarce in the increasing adult population. We report on five individuals illustrative of movement disorders and other motor abnormalities in adults with 22q11.2DS. In addition to an increased susceptibility to neuropsychiatric disorders, seizures, and early onset Parkinson disease, the underlying brain dysfunction associated with 22q11.2DS may give rise to an increased vulnerability to multiple movement abnormalities, including those influenced by medications. Movement abnormalities may also be secondary to treatable endocrine diseases and congenital musculoskeletal abnormalities. We propose that movement abnormalities may be common in adults with 22q11.2DS and discuss the implications and challenges important to clinical practice. PMID- 25684640 TI - Unusual kinetics of poly(ethylene glycol) oxidation with cerium(IV) ions in sulfuric acid medium and implications for copolymer synthesis. AB - The cerium(IV)-alcohol couple in an acidic medium is an example of a redox system capable of initiating free radical polymerization. When the alcohol has a polymeric nature, the outcome of such a process is a block copolymer, a member of a class of compounds possessing many useful properties. The most common polymer with a terminal -OH group is poly(ethylene glycol) (PEG); however, the detailed mechanism of its reaction with cerium(IV) remains underexplored. In this paper, we report our findings for this reaction based on spectrophotometric measurements and kinetic modeling. We find that both the reaction order and the net rate constant for the oxidation process depend strongly on the nature of the acidic medium used. In order to account for the experimental observations, we postulate that protonation of PEG decreases its affinity for some of the cerium(IV)-sulfate complexes formed in the system. PMID- 25684642 TI - Do statins reduce the risk of myocardial infarction in patients with heart failure? A pooled individual-level reanalysis of CORONA and GISSI-HF. AB - AIMS: Current guidelines do not explicitly recommend statin use in heart failure (HF). Relatively low numbers of atherothrombotic events among HF patients, in the context of their elevated competing risks for non-atherothrombotic causes of death, may have prevented previous analyses of clinical trials from detecting a benefit for statins. We pooled data from two landmark trials of HF patients not on statin therapy randomized to rosuvastatin 10 mg daily vs. placebo, CORONA and GISSI-HF, in order to improve our power to detect statistically significant differences in atherothrombotic events. We also accounted for competing risks from other causes of death. METHODS AND RESULTS: We used competing risks analyses to evaluate atherothrombotic events in the context of death from other cardiovascular and non-cardiovascular causes. We also performed traditional Cox survival analyses of the same data with the intention that these statistical approaches would be complementary. CORONA participants (n = 5011, median follow up 32.8 months) were older and sicker than GISSI-HF participants (n = 4574, median follow-up 46.9 months) by design. Rosuvastatin decreased risk for myocardial infarction (MI) among CORONA and GISSI-HF participants with ischaemic aetiology of HF (hazard ratio 0.81, 95% confidence interval 0.66-0.99, P < 0.05). There were no significant differences between rosuvastatin and placebo in risks for stroke or death from other causes. CONCLUSION: This individual-level reanalysis of two landmark trials demonstrates a small but statistically significant decreased risk for MI among patients with ischaemic HF randomized to rosuvastatin vs. placebo. Rosuvastatin appears to be effective in preventing MI in ischaemic HF patients not already on statins. PMID- 25684641 TI - Internal organization of medial rectus and inferior rectus muscle neurons in the C group of the oculomotor nucleus in monkey. AB - Mammalian extraocular muscles contain singly innervated twitch muscle fibers (SIF) and multiply innervated nontwitch muscle fibers (MIF). In monkey, MIF motoneurons lie around the periphery of oculomotor nuclei and have premotor inputs different from those of the motoneurons inside the nuclei. The most prominent MIF motoneuron group is the C group, which innervates the medial rectus (MR) and inferior rectus (IR) muscle. To explore the organization of both cell groups within the C group, we performed small injections of choleratoxin subunit B into the myotendinous junction of MR or IR in monkeys. In three animals the IR and MR myotendinous junction of one eye was injected simultaneously with different tracers (choleratoxin subunit B and wheat germ agglutinin). This revealed that both muscles were supplied by two different, nonoverlapping populations in the C group. The IR neurons lie adjacent to the dorsomedial border of the oculomotor nucleus, whereas MR neurons are located farther medially. A striking feature was the differing pattern of dendrite distribution of both cell groups. Whereas the dendrites of IR neurons spread into the supraoculomotor area bilaterally, those of the MR neurons were restricted to the ipsilateral side and sent a focused bundle dorsally to the preganglionic neurons of the Edinger Westphal nucleus, which are involved in the "near response." In conclusion, MR and IR are innervated by independent neuron populations from the C group. Their dendritic branching pattern within the supraoculomotor area indicates a participation in the near response providing vergence but also reflects their differing functional roles. PMID- 25684643 TI - Efficacy of non-invasive mechanical ventilation in the general ward in patients with chronic obstructive pulmonary disease admitted for hypercapnic acute respiratory failure and pH < 7.35: a feasibility pilot study. AB - AIM: To date non-invasive (NIV) mechanical ventilation use is not recommended in chronic obstructive pulmonary disease (COPD) patients with acute respiratory failure (ARF) and pH < 7.30 outside a 'protected environment'. We assessed NIV efficacy and feasibility in improving arterial blood gases (ABG) and in-hospital outcome in patients with ARF and severe respiratory acidosis (RA) admitted to an experienced rural medical ward. METHODS: This paper is a prospective pilot cohort study conducted in the General Medicine Ward of Budrio's District Hospital. Two hundred and seventy-two patients with ARF were admitted to our Department, 112, meeting predefined inclusion criteria (pH < 7.35, PaCO2 > 45 mmHg). Patients were divided according to the severity of acidosis into: group A (pH < 7.26), group B (7.26 <= pH < 7.30) and group C (7.30 <= pH < 7.35). ABG were assessed at admission, at 2-6 h, 24 h, 48 h and at discharge. RESULTS: Group A included 55 patients (24 men, mean age: 80.8 +/- 8.3 years), group B 31 (12 men, mean age: 80.3 +/- 9.4 years) and group C 26 (15 men, mean age: 78.6 +/- 9.9 years). ABG improved within the first hours in 92/112 (82%) patients, who were all successfully discharged. Eighteen percent (20/112) of the patients died during the hospital stay, no significant difference emerged in mortality rate (MR) within the groups (23%, 16% and 8%, for groups A, B and C, respectively) and between patients with or without pneumonia: 8/29 (27%) versus 12/83 (14%). On multivariable analysis, only age and Glasgow Coma Scale had an impact on the clinical outcome. CONCLUSION: In a non-'highly protected' environment such as an experienced medical ward of a rural hospital, NIV is effective not only in patients with mild, but also with severe forms of RA. MR did not vary according to the level of initial pH. PMID- 25684644 TI - Reconstruction of the descending thoracic aorta by multiview compounding of 3-D transesophageal echocardiographic aortic data sets for improved examination and quantification of atheroma burden. AB - A robust and efficient approach to reconstruction of the descending thoracic aorta from contiguous 3-D transesophageal echocardiographic (TEE) images is proposed. An ad hoc image acquisition protocol was designed to acquire ordered and partially overlapped 3-D TEE data sets, followed by dedicated image processing to align and fuse all acquired data sets. Alignment strategy implemented pairwise rigid registration guided by a priori knowledge, and it was validated using artificially misaligned images. Image fusion was finally performed to enable visualization and analysis of extended field-of-view of the acquired aorta. The application of different fusion techniques was also investigated. The method was applied to a population of 17 consecutive patients. Qualitative and quantitative results supported the feasibility and accuracy of the proposed approach. In a clinical scenario, its application could allow the quantitative assessment of aortic plaque burden in the descending thoracic aorta from 3-D TEE images. PMID- 25684645 TI - Reply to Reliability of automatic vibratory equipment for ultrasonic strain measurement of the median nerve: common mistake. PMID- 25684646 TI - Random biopsy in colposcopy-negative quadrant is not effective in women with positive colposcopy in practice. AB - AIM: To assess the efficacy of random biopsy in diagnosing those high-grade squamous intraepithelial lesions or carcinomas (HSIL+) missed by colposcopy directed biopsy, and to identify the scenarios of cervical cancer screening when random biopsy is necessary. PATIENTS/INTERVENTIONS: Data from 1997 women who participated in the Shanxi Province Cervical Cancer Screening Study I (SPOCCS I) were reviewed. Each woman received human papillomavirus (HPV) testing with the second-generation hybrid capture, liquid-based cytology, four-quadrant biopsy and endocervical curettage. The final diagnosis was based on the most severe pathological result obtained. The efficacy of random biopsy and colposcopy directed biopsy was evaluated on the basis of the final pathological results. RESULTS: For women with severe cytological abnormalities (HSIL+) and negative colposcopy, the yield of HSIL+ diagnosed by random biopsy was 25%. On the other hand, the yield of HSIL+ diagnosed by random biopsies in the negative quadrant was no more than 4% when the colposcopy was positive, regardless of the cytological findings. For women with negative HPV, no HSIL+ was found by random biopsy. For women with severe cytological abnormalities (HSIL+) and positive HPV, the yield of HSIL+ diagnosed by random biopsy was 35% when colposcopy was negative. For women with low-grade intraepithelial lesion (LSIL) and positive HPV, the yield of HSIL+ diagnosed by random biopsy was 12.5% when colposcopy was negative. CONCLUSION: Random biopsy is not effective in the negative quadrant in women with positive colposcopy, but should be performed in women with cytological HSIL+ but negative colposcopy, or in those with cytological LSIL or HGSL+ and positive HPV but negative colposcopy. PMID- 25684647 TI - Synthesis of ordered mesoporous crystalline CuS and Ag2S materials via cation exchange reaction. AB - Cation exchange reaction is a strong tool for the synthesis of new ionic nanomaterials. Most of them are isolated nanoparticles with simple geometric features, such as nanodots, nanorods and nanospheres. In this work, we demonstrated that ordered mesoporous CdS with a complex cubic Ia3d gyroidal 3D bicontinuous porous structure and large particle size can be successfully converted to crystalline CuS and Ag2S materials via cation exchange reaction without destroying the well-defined nanostructure. The change in crystal structure is an important factor for a successful conversion when the reaction is carried out without the presence of a silica template. In addition, the cation exchange reaction is sufficient for a complete compositional conversion, even when the mesostructured CdS precursor is embedded inside a mesoporous silica matrix. Our results indicate that cation exchange reaction may be applied to highly complex nanostructures with extremely large particle sizes. PMID- 25684648 TI - Carnival or football, is there a real risk for acquiring dengue fever in Brazil during holidays seasons? AB - More than 600,000 football fans, coming from all over the world, were expected to visit Brazil during the FIFA World Cup 2014. International travel can become a public health problem when the visitors start to become sick, needing medical intervention and eventually hospitalization. The occurrence of dengue fever infections in Brazil is persistent and has been increasing since the 1980s, and the health authorities were expected to take preventive measures and to warn the visitors about the risks during the tournament period. Before the World Cup started, studies have been published stating that dengue could be a significant problem in some of the Brazilian cities hosting the games. These conclusions were taken after a brief observation of the available data, analyzing its mean and standard deviation only, or based on seasonal climate forecasts, causing alarm for the world cup in Brazil. Here, with a more careful data analysis, we show that the seasonality of the disease plays a major role in dengue transmission. The density of dengue cases in Brazil is residual during winter in the Southern hemisphere (mid June to mid September) and the fans of football were not likely to get dengue during the tournament period. PMID- 25684649 TI - The effect of macrocyclic chelators on the targeting properties of the 68Ga labeled gastrin releasing peptide receptor antagonist PEG2-RM26. AB - INTRODUCTION: Overexpression of gastrin-releasing peptide receptors (GRPR) has been reported in several cancers. Bombesin (BN) analogs are short peptides with a high affinity for GRPR. Different BN analogs were evaluated for radionuclide imaging and therapy of GRPR-expressing tumors. We have previously investigated an antagonistic analog of BN (D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH(2), RM26) conjugated to NOTA via a PEG(2) spacer (NOTA-PEG(2)-RM26) labeled with (68)Ga, (111)In and Al(18)F. (68)Ga-labeled NOTA-PEG(2)-RM26 showed high tumor-to-organ ratios. METHODS: The influence of different macrocyclic chelators (NOTA, NODAGA, DOTA and DOTAGA) on the targeting properties of (68)Ga-labeled PEG(2)-RM26 was studied in vitro and in vivo. RESULTS: All conjugates were labeled with generator produced (68)Ga with high yields and demonstrated high stability and specific binding to GRPR. The IC(50) values of (nat)Ga-X-PEG(2)-RM26 (X = NOTA, DOTA, NODAGA, DOTAGA) were 2.3 +/- 0.2, 3.0 +/- 0.3, 2.9 +/- 0.3 and 10.0 +/- 0.6 nM, respectively. The internalization of the conjugates by PC-3 cells was low. However, the DOTA-conjugated analog demonstrated a higher internalization rate compared to other analogs. GRPR-specific uptake was found in receptor-positive normal tissues and PC-3 xenografts for all conjugates. The biodistribution of the conjugates was influenced by the choice of the chelator moiety. Although all radiotracers cleared rapidly from the blood, [(68)Ga]Ga-NOTA-PEG(2)-RM26 showed significantly lower uptake in lung, muscle and bone compared to the other analogs. The uptake in tumors (5.40 +/- 1.04 %ID/g at 2 h p.i.) and the tumor-to organ ratios (25 +/- 3, 157 +/- 23 and 39 +/- 4 for blood, muscle and bone, respectively) were significantly higher for the NOTA-conjugate than the other analogs. CONCLUSIONS: Chelators had a clear influence on the biodistribution and targeting properties of (68)Ga-labeled antagonistic BN analogs. Positively charged [(68)Ga]Ga-NOTA-PEG(2)-RM26 provided a low kidney radioactivity uptake, high affinity, high tumor uptake and high image contrast. PMID- 25684650 TI - Evaluation of nitrogen-rich macrocyclic ligands for the chelation of therapeutic bismuth radioisotopes. AB - INTRODUCTION: The use of alpha-emitting isotopes for radionuclide therapy is a promising treatment strategy for small micro-metastatic disease. The radioisotope (213)Bi is a nuclide that has found substantial use for targeted alpha-therapy (TAT). The relatively unexplored aqueous chemistry of Bi(3+), however, hinders the development of bifunctional chelating agents that can successfully deliver these Bi radioisotopes to the tumor cells. Here, a novel series of nitrogen-rich macrocyclic ligands is explored for their potential use as Bi-selective chelating agents. METHODS: The ligands, 1,4,7,10-tetrakis(pyridin-2-ylmethyl)-1,4,7,10 tetraazacyclododecane (L(py)), 1,4,7,10-tetrakis(3-pyridazylmethyl)-1,4,7,10 tetraazacyclododecane (L(pyd)), 1,4,7,10-tetrakis(4-pyrimidylmethyl)-1,4,7,10 tetraazacyclododecane (L(pyr)), and 1,4,7,10-tetrakis(2-pyrazinylmethyl)-1,4,7,10 tetraazacyclododecane (L(pz)), were prepared by a previously reported method and investigated here for their abilities to bind Bi radioisotopes. The commercially available and commonly used ligands 1,4,7,10-tetraazacyclododecane-1,4,7,10 tetraacetic acid (DOTA) and N-[(R)-2-amino-3-(p-isothiocyanato-phenyl)propyl] trans-(S,S)- cyclohexane-1,2-diamine-N,N,N',N",N"-pentaacetic acid (CHX-A''-DTPA) were also explored for comparative purposes. Radio-thin-layer chromatography (TLC) was used to measure the binding kinetics and stabilities of the complexes formed. The long-lived isotope, (207)Bi (t(1/2)=32 years), was used for these studies. Density functional theory (DFT) calculations were also employed to probe the ligand interactions with Bi(3+) and the generator parent ion Ac(3+). RESULTS: In contrast to DOTA and CHX-A''-DTPA, these nitrogen-rich macrocycles selectively chelate Bi(3+) in the presence of the parent isotope Ac(3+). Among the four tested, L(py) was found to exhibit optimal Bi(3+)-binding kinetics and complex stability. L(py) complexes Bi(3+) more rapidly than DOTA, yet the resulting complexes are of similar stability. DFT calculations corroborate the experimentally observed selectivity of these ligands for Bi(3+) over Ac(3+). CONCLUSION: Taken together, these data implicate L(py) as a valuable chelating agent for the delivery of (213)Bi. Its selectivity for Bi(3+) and rapid and stable labeling properties warrant further investigation and biological studies. PMID- 25684651 TI - Choosing a single target as a biomarker or therapeutic using radioactive probes. PMID- 25684652 TI - Optical sensing and analyte manipulation in solid-state nanopores. AB - The field of nanopore sensing has been gaining increasing attention. Much progress has been made towards biotechnological applications that involve electrical measurements of temporal changes in the ionic current flowing through the pore. But in many cases the electrical signal is restricted by the non-ideal noise components, limited throughput, and insufficient temporal or spatial resolutions. To address these limitations, high-sensitivity optical detection techniques that complement the electrical measurements have been developed. The optical techniques involve high-bandwidth, multicolor and high-throughput measurements. Here we review the recent advancements and developments that have been taking place in the field of optical sensing in solid-state nanopores. We describe the main optical methods used in this field involving total internal reflection and confocal microscopy in addition to sophisticated background suppression strategies. We further present the phenomenon of light induced analyte manipulation at the pore and the contribution of the optical sensing approach to possible nanopore sensing applications such as optical based DNA sequencing using nanopores. PMID- 25684653 TI - Organic light emitting diode improves diabetic cutaneous wound healing in rats. AB - A major complication for diabetic patients is chronic wounds due to impaired wound healing. It is well documented that visible red wavelengths can accelerate wound healing in diabetic animal models and patients. In vitro and in vivo diabetic models were used to investigate the effects of organic light emitting diode (OLED) irradiation on cellular function and cutaneous wound healing. Human dermal fibroblasts were cultured in hyperglycemic medium (glucose concentration 180 mM) and irradiated with an OLED (623 nm wavelength peak, range from 560 to 770 nm, power density 7 or 10 mW/cm2 at 0.2, 1, or 5 J/cm2). The OLED significantly increased total adenosine triphosphate concentration, metabolic activity, and cell proliferation compared with untreated controls in most parameters tested. For the in vivo experiment, OLED and laser (635 +/- 5 nm wavelength) treatments (10 mW/cm2 , 5 J/cm2 daily for a total of seven consecutive days) for cutaneous wound healing were compared using a genetic, diabetic rat model. Both treatments had significantly higher percentage of wound closure on day 6 postinjury and higher total histological scores on day 13 postinjury compared with control. No statistical difference was found between the two treatments. OLED irradiation significantly increased fibroblast growth factor 2 expression at 36-hour postinjury and enhanced macrophage activation during initial stages of wound healing. In conclusion, the OLED and laser had comparative effects on enhancing diabetic wound healing. PMID- 25684654 TI - A Gene Expression Profiling of Early Rice Stamen Development that Reveals Inhibition of Photosynthetic Genes by OsMADS58. AB - Stamen is a unique plant organ wherein germ cells or microsporocytes that commit to meiosis are initiated from somatic cells during its early developmental process. While genes determining stamen identity are known according to the ABC model of floral development, little information is available on how these genes affect germ cell initiation. By using the Affymetrix GeneChip Rice Genome Array to assess 51 279 transcripts, we established a dynamic gene expression profile (GEP) of the early developmental process of rice (Oryza sativa) stamen. Systematic analysis of the GEP data revealed novel expression patterns of some developmentally important genes including meiosis-, tapetum-, and phytohormone related genes. Following the finding that a substantial amount of nuclear genes encoding photosynthetic proteins are expressed at the low levels in early rice stamen, through the ChIP-seq analysis we found that a C-class MADS box protein, OsMADS58, binds many nuclear-encoded genes participated in photosystem and light reactions and the expression levels of most of them are increased when expression of OsMADS58 is downregulated in the osmads58 mutant. Furthermore, more pro chloroplasts are observed and increased signals of reactive oxygen species are detected in the osmads58 mutant anthers. These findings implicate a novel link between stamen identity determination and hypoxia status establishment. PMID- 25684655 TI - The Splicing Factor PRP31 Is Involved in Transcriptional Gene Silencing and Stress Response in Arabidopsis. AB - Although DNA methylation is known to play an important role in the silencing of transposable elements (TEs) and introduced transgenes, the mechanisms that generate DNA methylation-independent transcriptional silencing are poorly understood. Previous studies suggest that RNA-directed DNA methylation (RdDM) is required for the silencing of the RD29A-LUC transgene in the Arabidopsis ros1 mutant background with defective DNA demethylase. Loss of function of ARGONAUTE 4 (AGO4) gene, which encodes a core RdDM component, partially released the silencing of RD29A-LUC in the ros1/ago4 double mutant plants. A forward genetic screen was performed to identify the mutants with elevated RD29A-LUC transgene expression in the ros1/ago4 mutant background. We identified a mutation in the homologous gene of PRP31, which encodes a conserved pre-mRNA splicing factor that regulates the formation of the U4/U6.U5 snRNP complex in fungi and animals. We previously demonstrated that the splicing factors ZOP1 and STA1 contribute to transcriptional gene silencing. Here, we reveal that Arabidopsis PRP31 associates with ZOP1, STA1, and several other splicing-related proteins, suggesting that these splicing factors are both physically and functionally connected. We show that Arabidopsis PRP31 participates in transcriptional gene silencing. Moreover, we report that PRP31, STA1, and ZOP1 are required for development and stress response. Under cold stress, PRP31 is not only necessary for pre-mRNA splicing but also for regulation of cold-responsive gene expression. Our results suggest that the splicing machinery has multiple functions including pre-mRNA splicing, gene regulation, transcriptional gene silencing, and stress response. PMID- 25684656 TI - Vitamin D rescues dysfunction of fetal endothelial colony forming cells from individuals with gestational diabetes. AB - INTRODUCTION: Gestational diabetes (GDM) is associated with long-term cardiovascular and metabolic diseases in offspring. However, the mechanisms are not well understood. We explored whether fetal exposure to a diabetic environment is associated with fetal endothelial progenitor cell dysfunction, and whether vitamin D can reverse the impairment. METHODS: Nineteen women with uncomplicated pregnancies and 18 women with GDM were recruited before delivery. Time to first appearance of endothelial colony forming cell (ECFC) colonies and number of ECFC colonies formed from culture of cord peripheral blood mononuclear cells were determined. Angiogenesis-related functions of ECFCs in vitro were tested in the presence or absence of vitamin D. RESULTS: Fetal ECFCs from GDM pregnancies formed fewer colonies in culture (P = 0.04) and displayed reduced proliferation (P = 0.02), migration (P = 0.04) and tubule formation (P = 0.03) compared to uncomplicated pregnancies. Fetal ECFCs exposed to hyperglycemia in vitro exhibited less migration (P < 0.05) and less tubule formation (P < 0.05) than normoglycemic control. Vitamin D significantly improved the dysfunction of fetal ECFCs from pregnancies complicated by GDM or after exposure of healthy ECFCs to hyperglycemia. DISCUSSION: Fetal ECFCs from GDM pregnancies or ECFCs exposed to hyperglycemia in vitro exhibit reduced quantity and impaired angiogenesis-related functions. Vitamin D significantly rescues these functions. These findings may have implications for vascular function of infants exposed to a diabetic intrauterine environment. PMID- 25684657 TI - Strong hypoxia reduces leptin synthesis in purified primary human trophoblasts. AB - INTRODUCTION: Oxygen availability severely affects placental function. During placental hypoxia, stabilization of hypoxia inducible factors (HIFs) affects transcription, and leptin gene expression concomitantly increases in vivo and in vitro. However, a causal relationship is uncertain. METHODS: We investigated the effect of oxygen availability on HIF-1 alpha (HIF1A) and leptin regulation in primary human trophoblasts isolated from six normal term placentae cultured at 0.1%, 1%, 3%, and 8% oxygen for 6 h, 24 h and 48 h. Gene expressions of leptin (LEP), leptin receptors (LEPR), HIF1A, insulin receptor (INSR) and further genes relevant in hypoxia (VEGFA, EPO, NOS2) or apoptosis (BCL2, BAX, Tp53) were examined. Leptin, HIF1A, INSR, phospho-AKT/AKT (insulin receptor signaling), caspase 3 and cleaved caspase 3 (apoptosis) proteins were measured. RESULTS: A hypoxic reaction with stabilization of HIF1A protein as well as up-regulation of HIF1A and VEGFA gene expressions, but without any hint for apoptosis, was present at 0.1% and 1% oxygen. However, leptin protein concentration (cell supernatants) peaked at 8% oxygen (normoxia) and was significantly reduced at 0.1% oxygen. There was no significant correlation between leptin and HIF1A, neither on the gene nor on the protein level. DISCUSSION: Elevated leptin gene expression in hypoxic placentas may not originate from trophoblasts, but from other placental cells, or from interaction of trophoblasts with other cells. Not only fetal hyperleptinemia, but also fetal hypoleptinemia under hypoxic conditions is conceivable. Strategies to prevent leptin dysregulation during pregnancy should be elucidated to protect the offspring from fetal programming of leptin resistance and adiposity in later life. PMID- 25684658 TI - Metabolic syndrome burden in apparently healthy adolescents is adversely associated with cardiac autonomic modulation--Penn State Children Cohort. AB - BACKGROUND: Reduced cardiac autonomic modulation (CAM) has been associated with metabolic syndrome (MetS) in adults. However, the association between MetS component cluster and CAM has not been examined in adolescents. METHODS: We conducted a cross-sectional analysis using data from the Penn State Child Cohort follow-up examination. CAM was assessed by heart rate variability (HRV) analysis of 39-h RR intervals, including frequency (high frequency, HF; low frequency, LF; and LF/HF ratio) and time (SDNN, standard deviation of all RR intervals; RMSSD, square root of the mean of the sum of the squares of differences between adjacent RR intervals; and HR, heart rate) domain variables. To assess the MetS burden, we used continuous MetS score (cMetS)--sum of the age and sex-adjusted standardized residual (Z-score) of five established MetS components. Linear mixed-effect models were used to analyze the association between cMetS and CAM in the entire population and stratified by gender. RESULTS: After adjusting for age, sex, and race, cMetS was significantly associated with reduced HRV and higher HR. With 1 standard deviation increase in cMetS, there was a significant decrease in HF ( 0.10 (SE = 0.02)), LF (-0.07 (SE = 0.01)), SDNN (-1.97 (SE = 0.50)), and RMSSD ( 1.70 (SE = 0.72)), and increase in LF/HF (0.08 (SE = 0.02)) and HR (1.40 (SE = 0.26)). All cMetS components, with the exception of high-density lipoprotein (HDL), were associated with significantly decreased HRV and increased HR. High blood pressure (MAP) and triglyceride (TG) levels were also associated with an increase in LF/HF and decrease in RMSSD. An increase in high-density lipoprotein was only associated with higher LF and SDNN. Moreover, cMetS and HRV associations were more pronounced in males than in females. The associations between HRV and. MAP, TG, and HDL were more pronounced in females. CONCLUSIONS: cMetS score is associated with lower HRV, suggesting an adverse impact on CAM, even in apparently healthy adolescents. PMID- 25684659 TI - Maternal risk factors for gastroschisis in Canada. AB - BACKGROUND: Gastroschisis is a congenital abdominal wall defect that occurs in one per 2200 pregnancies. Birth defect surveillance in Canada has shown that the prevalence of gastroschisis has increased threefold over the past 10 years. The purpose of this study was to compare maternal exposures data from a national gastroschisis registry with pregnancy exposures from vital statistics to understand maternal risk factor associations with the occurrence of gastroschisis. METHODS: Using common definitions, pregnancy cohorts were developed from two databases. The Canadian Pediatric Surgery Network database, a population-based dataset was used to record maternal exposures for women who experienced a gastroschisis pregnancy, while a contemporaneous, geographically cross-sectional "control" cohort of pregnant women and their exposures was developed from Canadian Community Health Survey data. Groups comparison of maternal risk factors was performed using univariate and multivariate logistic generalized estimating equation techniques. RESULTS: A total of 692 gastroschisis pregnancies (from Canadian Pediatric Surgery Network) and 4708 pregnancies from Canadian Community Health Survey were compared. Younger maternal age (odds ratio, 0.85; 95% confidence interval, 0.83-0.87; p < 0.0001), smoking (odds ratio, 2.86; 95% confidence interval, 2.22-3.66; p < 0.0001), a history of pregestational or gestational diabetes (odds ratio, 2.81; 95% confidence interval, 1.42-5.5; p = 0.0031), and use of medication to treat depression (odds ratio, 4.4; 95% confidence interval, 1.38-11.8; p = 0.011) emerged as significant associations with gastroschisis pregnancies. CONCLUSION: Gastroschisis in Canada is associated with maternal risk factors, some of which are modifiable. Further studies into sociodemographic birth defect risk are necessary to allow targeted improvements in perinatal health service delivery and health policy. PMID- 25684660 TI - Polyoxometalate-mediated one-pot synthesis of Pd nanocrystals with controlled morphologies for efficient chemical and electrochemical catalysis. AB - Polyoxometalates (POMs), as inorganic ligands, can endow metal nanocrystals (NCs) with unique reactivities on account of their characteristic redox properties. In the present work, we present a facile POM-mediated one-pot aqueous synthesis method for the production of single-crystalline Pd NCs with controlled shapes and sizes. The POMs could function as both reducing and stabilizing agents in the formation of NCs, and thus gave a fine control over the nucleation and growth kinetics of NCs. The prepared POM-stabilized Pd NCs exhibited excellent catalytic activity and stability for electrocatalytic (formic acid oxidation) and catalytic (Suzuki coupling) reactions compared to Pd NCs prepared without the POMs. This shows that the POMs play a pivotal role in determining the catalytic performance, as well as the growth, of NCs. We envision that the present approach can offer a convenient way to develop efficient NC-based catalyst systems. PMID- 25684662 TI - Is Intracardiac Echocardiography Essential for Monitoring Stent Deployment across Aortic Coarctation? PMID- 25684661 TI - Yersinia pseudotuberculosis YopD mutants that genetically separate effector protein translocation from host membrane disruption. AB - The Yersinia type III secretion system (T3SS) translocates Yop effector proteins into host cells to manipulate immune defenses such as phagocytosis and reactive oxygen species (ROS) production. The T3SS translocator proteins YopB and YopD form pores in host membranes, facilitating Yop translocation. While the YopD amino and carboxy termini participate in pore formation, the role of the YopD central region between amino acids 150-227 remains unknown. We assessed the contribution of this region by generating Y. pseudotuberculosis yopD(Delta150 170) and yopD(Delta207-227) mutants and analyzing their T3SS functions. These strains exhibited wild-type levels of Yop secretion in vitro and enabled robust pore formation in macrophages. However, the yopDDelta150-170 and yopD(Delta207 227) mutants were defective in Yop translocation into CHO cells and splenocyte derived neutrophils and macrophages. These data suggest that YopD-mediated host membrane disruption and effector Yop translocation are genetically separable activities requiring distinct protein domains. Importantly, the yopD(Delta150 170) and yopD(Delta207-227) mutants were defective in Yop-mediated inhibition of macrophage cell death and ROS production in neutrophil-like cells, and were attenuated in disseminated Yersinia infection. Therefore, the ability of the YopD central region to facilitate optimal effector protein delivery into phagocytes, and therefore robust effector Yop function, is important for Yersinia virulence. PMID- 25684663 TI - Restoration of TRAIL-induced apoptosis in resistant human pancreatic cancer cells by a novel FAK inhibitor, PH11. AB - Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) emerges as one of the most-promising experimental cancer therapeutic drugs and is currently being tested in clinical trials. However, both intrinsic and acquired resistance of human cancer cells to TRAIL-induced apoptosis poses a huge problem in establishing clinically efficient TRAIL therapies. To assess the regulation of TRAIL-resistance in human pancreatic cancer cells, we studied the TRAIL resistant pancreatic cell line PANC-1. We show that treatment with PH11, a novel Focal Adhesion Kinase (FAK) inhibitor in association with TRAIL rapidly induces apoptosis in TRAIL-resistant PANC-1 cells, but not in normal human fibroblast cells. To explain sensitization, we showed that PH11 restores TRAIL apoptotic pathway in PANC-1 cells through down-regulation of c-FLIP via inhibition of FAK and the phosphatidylinositol-3 kinase (PI3K)/AKT pathways. These findings suggest that this combined treatment may offer an attractive therapeutic strategy for safely and efficiently treating pancreatic cancer. PMID- 25684664 TI - Nanoparticle delivery of an SN38 conjugate is more effective than irinotecan in a mouse model of neuroblastoma. AB - Neuroblastoma (NB) is the most common and deadly solid tumor in children. The majority of NB patients have advanced stage disease with poor prognosis, so more effective, less toxic therapy is needed. We developed a novel nanocarrier-based strategy for tumor-targeted delivery of a prodrug of SN38, the active metabolite of irinotecan. We formulated ultrasmall-sized (<100 nm) biodegradable poly(lactide)-poly(ethylene glycol) based nanoparticles (NPs) containing SN38 conjugated to tocopherol succinate (SN38-TS). Alternative dosing schedules of SN38-TS NPs were compared to irinotecan. Comparison of SN38-TS NPs (2 doses) with irinotecan (20 doses) showed equivalent efficacy but no cures. Comparison of SN38 TS NPs (8, 8, and 16 doses, respectively) to irinotecan (40 doses) showed that all SN38-TS NP regimens were far superior to irinotecan, and "cures" were obtained in all NP arms. SN38-TS NP delivery resulted in 200* the amount of SN38 in NB tumors at 4 hr post-treatment, compared to SN38 detected for the irinotecan arm; no toxicity was seen with NPs. We conclude that this SN38-TS NP formulation improved delivery, retention, and efficacy, without causing systemic toxicity. PMID- 25684665 TI - Cofilin-phosphatase slingshot-1L (SSH1L) is over-expressed in pancreatic cancer (PC) and contributes to tumor cell migration. AB - Slingshot-1L (SSH1L), a cofilin-phosphatase, plays a role in actin dynamics and cell migration by reactivating cofilin-1. However, the expression of SSH1L in malignant diseases is poorly understood. The overexpression of SSH1L in cancerous tissue compared to the matched surrounding non-cancerous tissues from patients with late stages (III-IV) of PC was detected in 90% (9/10) of cases by western blotting. The expression of SSH1L was shown to be upregulated in tumor cells from 10.7% (11/102) of patients with pancreatic cancer (PC) by immunohistochemistry (IHC). The positive rate of SSH1L in patients with PC at stage VI (TNM) categorized as grade 3 was of 50% (2/4) and 15% (6/40), respectively. Moreover, SSH1L expression was shown to be up-regulated in the PC cell lines (KLM1, PANC-1 and MIAPaCa-2) with high metastatic potential. Loss of SSH1L expression was associated with an increase in the phosphorylation of cofilin-1 at serine-3 and further inhibited cell migration (but not proliferation) in KLM1, PANC-1 and MIAPaCa-2. Actin polymerization inhibitor cytochalasin-D was sufficient to abrogate cell migration of PC without changing SSH1L expression. These results reveal that SSH1L is upregulated in a subset of PCs and that the SSH1L/cofilin-1 signal pathway is associated positively in PC with cell migration. Our study may thus provide potential targets to prevent and/or treat PC invasion and metastasis in patients with SSH1L-positive PC. PMID- 25684666 TI - Improvement of predictive models of risk of disease progression in chronic hepatitis C by incorporating longitudinal data. AB - Existing predictive models of risk of disease progression in chronic hepatitis C have limited accuracy. The aim of this study was to improve upon existing models by applying novel statistical methods that incorporate longitudinal data. Patients in the Hepatitis C Antiviral Long-term Treatment Against Cirrhosis trial were analyzed. Outcomes of interest were (1) fibrosis progression (increase of two or more Ishak stages) and (2) liver-related clinical outcomes (liver-related death, hepatic decompensation, hepatocellular carcinoma, liver transplant, or increase in Child-Turcotte-Pugh score to >=7). Predictors included longitudinal clinical, laboratory, and histologic data. Models were constructed using logistic regression and two machine learning methods (random forest and boosting) to predict an outcome in the next 12 months. The control arm was used as the training data set (n = 349 clinical, n = 184 fibrosis) and the interferon arm, for internal validation. The area under the receiver operating characteristic curve for longitudinal models of fibrosis progression was 0.78 (95% confidence interval [CI] 0.74-0.83) using logistic regression, 0.79 (95% CI 0.77-0.81) using random forest, and 0.79 (95% CI 0.77-0.82) using boosting. The area under the receiver operating characteristic curve for longitudinal models of clinical progression was 0.79 (95% CI 0.77-0.82) using logistic regression, 0.86 (95% CI 0.85-0.87) using random forest, and 0.84 (95% CI 0.82-0.86) using boosting. Longitudinal models outperformed baseline models for both outcomes (P < 0.0001). Longitudinal machine learning models had negative predictive values of 94% for both outcomes. CONCLUSIONS: Prediction models that incorporate longitudinal data can capture nonlinear disease progression in chronic hepatitis C and thus outperform baseline models. Machine learning methods can capture complex relationships between predictors and outcomes, yielding more accurate predictions; our models can help target costly therapies to patients with the most urgent need, guide the intensity of clinical monitoring required, and provide prognostic information to patients. PMID- 25684667 TI - DMRT1 is required for Mullerian duct formation in the chicken embryo. AB - DMRT1 is a conserved transcription factor with a central role in gonadal sex differentiation. In all vertebrates studied, DMRT1 plays an essential function in testis development and/or maintenance. No studies have reported a role for DMRT1 outside the gonads. Here, we show that DMRT1 is expressed in the paired Mullerian ducts in the chicken embryo, where it is required for duct formation. DMRT1 mRNA and protein are expressed in the early forming Mullerian ridge, and in cells undergoing an epithelial to mesenchyme transition during duct morphogenesis. RNAi mediated knockdown of DMRT1 in ovo causes a greatly reduced mesenchymal layer, which blocks caudal extension of the duct luminal epithelium. Critical markers of Mullerian duct formation in mammals, Pax2 in the duct epithelium and Wnt4 in the mesenchyme, are conserved in chicken and their expression disrupted in DMRT1 knockdown ducts. We conclude that DMRT1 is required for the early steps of Mullerian duct development. DMRT1 regulates Mullerian ridge and mesenchyme formation and its loss blocks caudal extension of the duct. While DMRT1 plays an important role during testis development and maintenance in many vertebrate species, this is the first report showing a requirement for DMRT1 in Mullerian duct development. PMID- 25684668 TI - The N-terminal fragment of PA subunit of the influenza A virus effectively inhibits ribonucleoprotein (RNP) activity via suppression of its RNP expression. AB - The influenza RNP, which is formed from PB1, PB2, PA, NP subunits, and vRNA, is autonomously replicated and transcribed in the infected cell. The simplest method to inhibit RNP activity is to impair the formation of the RNP. Thereupon we confirmed whether the peptides/fragments mimicking one of RNP components can interfere with their formation. During the process of this inhibitory study we found interesting suppression of protein expression of the RNP components by the N-terminal fragment of PA subunit. Especially, we found two residues (D108 and K134) on the fragment that were critical for the suppression. Furthermore, we determined the combination of three amino acids (P28, M86 and E100) on the fragment that are important for the strong suppression, and identified the minimum essential region (residues from 1 to 188) of the PA subunit that allowed its suppression. Our findings indicate that the N-terminal fragment of PA subunit may become one of candidates for an effective inhibitor of influenza RNP activity. PMID- 25684669 TI - US adults recommended for weight reduction by 1998 and 2013 obesity guidelines, NHANES 2007-2012. AB - OBJECTIVE: To determine the number and proportion of American adults recommended for weight loss treatment under the 1998 and 2013 guidelines on the management of overweight and obesity in adults and to compare characteristics of individuals recommended for treatment. METHODS: A total of 6,692 adult, non-pregnant participants in the National Health and Nutrition Examination Survey 2007-2012 with complete data on demographics, anthropometrics, and biomedical measures were analyzed. RESULTS: Compared to the 1998 guidelines, the 2013 guidelines increased the number of adults recommended for weight loss treatment by 20.9% from 116.0 million to 140.2 million, making 64.5% of non-pregnant, non-institutionalized US adults candidates for treatment. The new guidelines recommended treatment for a larger proportion of those overweight, having only one risk factor, or having a large waist circumference. Up to 53.4% of adults could be considered for pharmacologic therapy in addition to lifestyle therapy, and up to 14.7% could be considered for bariatric surgery. CONCLUSIONS: The 2013 guidelines increased the number of adults to be treated with weight loss by 24.2 million, with the increases spread across groups that differ in socio demographic characteristics. PMID- 25684670 TI - Aberrant methylation of APC and RARbeta2 genes in breast cancer patients. AB - Changes in the status of DNA methylation are one of the most common molecular alterations in human neoplasia. We aimed to identify epigenetic molecular markers in serum for early detection of breast cancer. Authors analyzed retrospectively the methylation status of RARbeta2 and APC genes in serum samples from 121 breast cancer patients, 79 patients with benign breast diseases, and 66 healthy volunteers using methylation-specific PCR. The methylated APC and RARbeta2 were significantly higher in breast cancer patients (93.4%, 95.6%) than benign (7.8%, 14.5%) but not detected in healthy volunteers (0%) at (P < 0.0001). Both methylated genes showed no significant difference among clinicopathological factors apart from triple negative breast cancer patients as all of them (chi(2) = 7.4, P = 0.007) reported to be methylated RARbeta2 genes. Both methylated genes were detected in all grades and stages. Both sensitivities and specificities of the methylated genes for breast cancer detection were superior to traditional tumor markers in detection of breast cancer, early stage, low grade tumors, and triple negative breast cancer patients. Thus methylated APC and RARbeta2 genes might be valuable serum-based molecular markers for early detection of breast cancer. PMID- 25684671 TI - Improving forecasting accuracy of medium and long-term runoff using artificial neural network based on EEMD decomposition. AB - Hydrological time series forecasting is one of the most important applications in modern hydrology, especially for the effective reservoir management. In this research, an artificial neural network (ANN) model coupled with the ensemble empirical mode decomposition (EEMD) is presented for forecasting medium and long term runoff time series. First, the original runoff time series is decomposed into a finite and often small number of intrinsic mode functions (IMFs) and a residual series using EEMD technique for attaining deeper insight into the data characteristics. Then all IMF components and residue are predicted, respectively, through appropriate ANN models. Finally, the forecasted results of the modeled IMFs and residual series are summed to formulate an ensemble forecast for the original annual runoff series. Two annual reservoir runoff time series from Biuliuhe and Mopanshan in China, are investigated using the developed model based on four performance evaluation measures (RMSE, MAPE, R and NSEC). The results obtained in this work indicate that EEMD can effectively enhance forecasting accuracy and the proposed EEMD-ANN model can attain significant improvement over ANN approach in medium and long-term runoff time series forecasting. PMID- 25684672 TI - Nasopharyngeal venous malformation: A rare condition managed with Nd:YAG laser. AB - Venous malformations are benign but symptomatic vascular lesions of the head and neck that undergo soft tissue infiltration and relentless growth. Here we present a 31-year-old female referred for an obstructing and painful right posterior nasal mass. Flexible nasopharyngoscopy and magnetic resonance imaging demonstrated a 3 cm * 4 cm enhancing mucosal and submucosal venous malformation of the nasopharynx and oropharynx. Three staged episodes of transnasal endoscopically guided Nd:YAG laser therapy were performed with dramatic and sustained reduction in size and symptoms. No bleeding or complications occurred. Nd:YAG laser treatment of nasopharyngeal venous malformations is a safe and effective alternative to open surgical excision and sclerotherapy. PMID- 25684674 TI - Intestinal lymphoid nodular hyperplasia in children: the relationship to food allergy. AB - BACKGROUND: Lymphoid nodular hyperplasia (LNH) of the lower gastrointestinal tract is a common finding during paediatric colonoscopies, and its clinical significance has not yet been clearly established. OBJECTIVE: The purpose of this prospective, parallel multi-arm, randomized clinical trial was to study relationship between food allergy and LNH. METHODS: We recruited 268 children who had undergone a diagnostic colonoscopy between 1 January 2009 and 30 September 2011. The inclusion criteria were the following: (i) demonstration of LNH; (ii) no concomitant inflammatory or immune disease; (iii) no treatment since the clinical onset. The patients were assigned 1:1:1 to elimination diet (Group A), mesalamine (Group B) or symptomatic treatment with antispasmodics or antidiarrhoeal drugs (Group C) for an 8-wk period. Patients were followed for 24 months. RESULTS: We enrolled 72 of 97 children with intestinal LNH who were referred for haematochezia (76%), recurrent abdominal pain (68%) and/or chronic diarrhoea (32%). Clinical improvement was observed in 75%, 83% and 79% of the patients in Groups A, B and C, respectively. The difference in the response to treatment among the groups and the association to the clinical, endoscopic and allergic features of the patients were not statistically significant. CONCLUSIONS: Intestinal LNH should be considered a benign finding in children without red flags, because the symptoms are largely self-limiting. The use of mesalamine or elimination diet does not modify the clinical outcome compared to symptomatic therapy. The presence of food allergy was not predicted by allergy skin testing and was found in a minority of patients. PMID- 25684675 TI - Tribolium castaneum immune defense genes are differentially expressed in response to Bacillus thuringiensis toxins sharing common receptor molecules and exhibiting disparate toxicity. AB - In Tribolium castaneum larvae we have demonstrated by RNA interference knockdown that the Bacillus thuringiensis Cry3Ba toxin receptors Cadherin-like and Sodium solute symporter proteins are also functional receptors of the less active Cry3Aa toxin. Differences in susceptibility to B. thuringiensis infection might not only rely on toxin-receptor interaction but also on host defense mechanisms. We compared the expression of the immune related genes encoding Apolipophorin-III and two antimicrobial peptides, Defensin3 and Defensin2 after B. thuringiensis challenge. All three genes were up-regulated following Cry3Ba spore-crystal intoxication whereas only Defensins gene expression was induced upon Cry3Aa spore crystal treatment, evidencing a possible association between host immune response and larval susceptibility to B. thuringiensis. We assessed the antimicrobial activity spectra of T. castaneum defensins peptide fragments and found that a peptide fragment of Defensin3 was effective against the human microbial pathogens, Escherichia coli, Staphylococcus aureus and Candida albicans, being S. aureus the most susceptible one. PMID- 25684676 TI - The microtubule-stabilizing drug Epothilone D increases axonal sprouting following transection injury in vitro. AB - Neuronal cytoskeletal alterations, in particular the loss and misalignment of microtubules, are considered a hallmark feature of the degeneration that occurs after traumatic brain injury (TBI). Therefore, microtubule-stabilizing drugs are attractive potential therapeutics for use following TBI. The best-known drug in this category is Paclitaxel, a widely used anti-cancer drug that has produced promising outcomes when employed in the treatment of various animal models of nervous system trauma. However, Paclitaxel is not ideal for the treatment of patients with TBI due to its limited blood-brain barrier (BBB) permeability. Herein we have characterized the effect of the brain penetrant microtubule stabilizing agent Epothilone D (Epo D) on post-injury axonal sprouting in an in vitro model of CNS trauma. Epo D was found to modulate axonal sprout number in a dose dependent manner, increasing the number of axonal sprouts generated post injury. Elevated sprouting was observed when analyzing the total population of injured neurons, as well as in selective analysis of Thy1-YFP-labeled excitatory neurons. However, we found no effect of Epo D on axonal sprout length or outgrowth speed. These findings indicate that Epo D specifically affects injury induced axonal sprout generation, but not net growth. Our investigation demonstrates that primary cultures of cortical neurons are tolerant of Epo D exposure, and that Epo D significantly increases their regenerative response following structural injury. Therefore Epo D may be a potent therapeutic for enhancing regeneration following CNS injury. This article is part of a Special Issue entitled 'Traumatic Brain Injury'. PMID- 25684677 TI - The pathophysiology of repetitive concussive traumatic brain injury in experimental models; new developments and open questions. AB - In recent years, there has been an increasing interest in the pathophysiology of repetitive concussive traumatic brain injury (rcTBI) in large part due to the association with dramatic cases of progressive neurological deterioration in professional athletes, military personnel, and others. However, our understanding of the pathophysiology of rcTBI is less advanced than for more severe brain injuries. Most prominently, the mechanisms underlying traumatic axonal injury, microglial activation, amyloid-beta accumulation, and progressive tau pathology are not yet known. In addition, the role of injury to dendritic spine cytoskeletal structures, vascular reactivity impairments, and microthrombi are intriguing and subjects of ongoing inquiry. Methods for quantitative analysis of axonal injury, dendritic injury, and synaptic loss need to be refined for the field to move forward in a rigorous fashion. We and others are attempting to develop translational approaches to assess these specific pathophysiological events in both animals and humans to facilitate clinically relevant pharmacodynamic assessments of candidate therapeutics. In this article, we review and discuss several of the recent experimental results from our lab and others. We include new initial data describing the difficulty in modeling progressive tau pathology in experimental rcTBI, and results demonstrating that sertraline can alleviate social interaction deficits and depressive-like behaviors following experimental rcTBI plus foot shock stress. Furthermore, we propose a discrete set of open, experimentally tractable questions that may serve as a framework for future investigations. In addition, we also raise several important questions that are less experimentally tractable at this time, in hopes that they may stimulate future methodological developments to address them. This article is part of a Special Issue entitled "Traumatic Brain Injury". PMID- 25684678 TI - Chemoresistance to doxorubicin induces epithelial-mesenchymal transition via upregulation of transforming growth factor beta signaling in HCT116 colon cancer cells. AB - Doxorubicin (Dox) is a commonly used chemotherapeutic drug in human colon cancer. However, it becomes increasingly ineffective with tumor progression, the underlying mechanism of which remains to be elucidated. Emerging evidence has led to the identification of an association between chemoresistance and the acquisition of epithelial-mesenchymal transition (EMT) in cancer. However, it remains to be elucidated whether this process is involved in the development of resistance to Dox in colon cancer. In HCT116 human colon cancer cells treated with Dox (50 nmol/l), EMT was induced, and transforming growth factor (TGF)beta signaling and multi-drug resistant plasma membrane glycoprotein levels were significantly increased. By contrast, silencing of Smad4, using stable RNA interference, inhibited TGFbeta signaling, reversed the process of EMT and markedly increased the sensitivity of HCT116 cells to Dox. The results of the present study suggested that the combination of Dox with the downregulation of TGFbeta signaling may be a potential novel therapeutic strategy with which to overcome chemoresistance during colon cancer chemotherapy. PMID- 25684679 TI - Characterization of the Bombyx mori Cecropin A1 promoter regulated by IMD pathway. AB - Cecropin A1 (CecA1) promoter from Bombyx mori was cloned and characterized to provide insight into the transcriptional control of this antimicrobial peptide gene upon immune challenges. Reporter gene assays demonstrated that both Escherichia coli and lipopolysaccharide could induce expression in BmE cells but B. bombyseptieus or peptidoglycan failed, and the induction pattern of the reporter gene was coincident with the endogenous CecA1. Analysis of deletion and mutation constructs revealed that the regulatory region was the kappaB motif located between -176 and -166, and no other predicted elements on CecA1 promoter affected its inducibility. Insertion of additional kappaB motifs increased the activity of CecA1 promoter. Furthermore, binding of Relish to kappaB motif was confirmed by electrophoretic mobility shift assay. These findings indicate the regulatory mechanism of CecA1 expression in IMD pathway and suggest an approach of engineering antimicrobial peptide promoter with enhanced activities that may lead to broad applications. PMID- 25684680 TI - Resveratrol in spermatogenesis. PMID- 25684681 TI - Visualization of endogenous and exogenous hydrogen peroxide using a lysosome targetable fluorescent probe. AB - Reactive oxygen species (ROS) play crucial roles in diverse physiological processes; therefore, the efficient detection of ROS is very crucial. In this study, we report a boronate-based hydrogen peroxide (H2O2) probe having naphthalimide fluorophore. This probe also contained a morpholine moiety as a directing group for lysosome. The recognition property indicated that the probe exhibited high selectivity towards H2O2 not only in the solution but also in the living cells. Furthermore, it was used to monitor the level of endogenous and exogenous H2O2. These results support that the probe can function as an efficient indicator to detect H2O2. PMID- 25684682 TI - Bangladeshi women's experiences of infant feeding in the London Borough of Tower Hamlets. AB - This study examined the main factors that influence Bangladeshi women living in London's decisions to partially breastfeed their children, including the influence of older women within the community. Fifty-seven women of Bangladeshi origin living in the London Borough of Tower Hamlets took part in seven discussion groups between April and June 2013. Five groups were held with women of child-bearing age and two groups with older women in the community. A further eight younger women and three older women took part in one-on-one interviews. Interviews were also carried out with eight local health care workers, including public health specialists, peer support workers, breastfeeding coordinators and a health visitor. The influences on women's infant feeding choices can be understood through a 'socio-ecological model', including public health policy; diverse cultural influences from Bangladesh, London and the Bangladeshi community in London; and the impacts of migration and religious and family beliefs. The women's commitment to breastfeeding was mediated through the complexity of their everyday lives. The tension between what was 'best' and what was 'possible' leads them not only to partially breastfeed but also to sustain partial breastfeeding in a way not seen in other socio-cultural groups in the United Kingdom. PMID- 25684683 TI - Non-exponential resistive switching in Ag2S memristors: a key to nanometer-scale non-volatile memory devices. AB - The dynamics of resistive switchings in nanometer-scale metallic junctions formed between an inert metallic tip and an Ag film covered by a thin Ag2S layer are investigated. Our thorough experimental analysis and numerical simulations revealed that the resistance change upon a switching bias voltage pulse exhibits a strongly non-exponential behaviour yielding markedly different response times at different bias levels. Our results demonstrate the merits of Ag2S nanojunctions as nanometer-scale non-volatile memory cells with stable switching ratios, high endurance as well as fast response to write/erase, and an outstanding stability against read operations at technologically optimal bias and current levels. PMID- 25684684 TI - Increased pulmonary vascular resistance, right ventricular dysfunction, and reversible pulmonary vasoconstriction in type 2 pulmonary hypertension: who has it and are we missing a potential therapeutic target in patients with heart failure? PMID- 25684685 TI - Cross-sectional study of the sperm quality in semen samples from spinal cord injured men after long-term cryopreservation. AB - The deterioration of semen quality occurs very early after spinal cord injury (SCI). Thus, routine cryopreservation of semen early after injury has been recommended. However, there is currently a lack of data concerning the effects of long-term cryopreservation on the quality of spermatozoa from SCI men. We have therefore investigated the quality of spermatozoa from SCI men before and after long-term cryopreservation. The semen cryobank of a SCI rehabilitation center was screened for samples with a storage duration of more than 3 years, to carry out a cross-sectional study regarding the sperm quality of semen samples from SCI men. Semen quality analysis was carried out according to the WHO-Guidelines. The quality of 28 semen samples from 16 SCI men was investigated prior to and a median 11 years (95% CI 7-13 years) after cryopreservation. Prior to cryopreservation, ejaculate volume (median = 1.7 mL, 95% CI 1-3 mL) and sperm concentration (median = 106 * 10(6) /mL, 95% CI 82-132 * 10(6) /mL) were within normal limits, but total sperm motility (median = 19%, 95% CI 13-22%) and viability (median = 27%, 95% CI 19-45%) were reduced. Cryopreservation resulted in a significant (p < 0.0001) decrease in total sperm motility (median = 2.5%, 95% CI 0-4%) and viability (median = 7%, 95% CI 6-13%). There were no significant (p = 0.75) differences between the semen parameters of samples collected early (up to 3 weeks) after SCI and those collected later. Complete SCI had a significantly (p < 0.0001) negative effect on the sperm viability of the fresh semen samples, and tetraplegia had a significantly (p < 0.035) negative effect on both pre-cryopreservation sperm viability and post-cryopreservation motility. The assisted ejaculation technique had no significant (p > 0.053) effect on semen quality. Long-term cryopreservation of semen from SCI men results in essentially immotile sperm with minimal viability. Thus, routine long-term cryobanking of semen harvested early after SCI cannot be recommended. PMID- 25684686 TI - Bombesin staining in neuroendocrine cell hyperplasia of infancy (NEHI) and other childhood interstitial lung diseases (chILD). AB - AIMS: We have analysed levels of bombesin-positive neuroendocrine cells (NECs) in neuroendocrine cell hyperplasia of infancy (NEHI) and other childhood interstitial lung diseases (chILDs) in order to validate proposed histological criteria for NEHI and investigate its aetiology. METHODS AND RESULTS: The extent of bombesin-positive cells within airway epithelium was analysed in lung biopsies from seven patients diagnosed with NEHI, including two classified previously as non-diagnostic, and other chILDs (n = 64) with age ranges of 1 month-18 years. NECs were counted and calculated as a percentage of airways containing NECs, average percentage of NECs per airway, percentage of airways with >10% NECs and number of neuroendocrine bodies (NEBs). Correlation with age and gender was also undertaken. Patients with NEHI had the highest average percentage of bombesin positive NECs per airway compared to other chILDs. However, NEH was also seen in many other chILDs, and appears to be most prominent in disorders associated with lung immaturity such as histological patterns associated with surfactant protein related disorders and pulmonary interstitial glycogenosis. CONCLUSIONS: NEH may, to a degree, be a marker of airway immaturity rather than the direct cause of NEHI. This possibility is supported by the fact that the number of bombesin positive NECs decreased with age in this cohort, independent of disease type. The average percentage of bombesin-positive NECs per airway appears to be the best histological criterion for assessing the extent of NECs in the context of NEHI. PMID- 25684688 TI - Interactions of carbon nanotubes with the nitromethane-water mixture governing selective adsorption of energetic molecules from aqueous solution. AB - The structure and dynamics of the nitromethane-water (NM-WT) binary mixture surrounding single walled carbon nanotubes (SWNTs) have been investigated by molecular dynamics simulations. The simulation trajectories show that the NM molecules can be selectively adsorbed both outside the surface and inside the cavity of SWNTs mainly dominated by van der Waals attractions because SWNTs have a higher binding affinity for NM than WT. The binding energies of SWNTs with NM and WT obtained from electronic structure calculations at the M06-2X/6-31+G* level are 15.31 and 5.51 kcal mol(-1), respectively. Compared with the SWNT exterior, the selective adsorption of NM is preferentially occurred in the SWNT interior due to the hydrophobic interactions and the dipole-dipole interactions, which induces the decrease of the hydrogen-bond number of NM with WT and ordered structures of NM with preferred intermolecular orientation in the SWNT cavity. Furthermore, the selective adsorption dynamics of NM from the aqueous solution is regardless of the chirality and radius of SWNTs. The SWNT radius plays a negligible role in the mass density distributions of NM outside the SWNTs, while the mass density of NM in the SWNT interior decreases gradually as the SWNT radius increases. The structural arrangements and intermolecular orientations of NM in the SWNT cavity are greatly dependent on the SWNT radius due to the size effect. PMID- 25684687 TI - Independent and combined effects of cognitive and physical activity on incident MCI. AB - INTRODUCTION: The objective of this study was to examine the independent and combined influences of late-life cognitive activity (CA) and physical activity (PA) on the risk of incident mild cognitive impairment (MCI). METHODS: We used interval censored survival modeling to examine the risk of incident MCI (Clinical Dementia Rating [CDR] = 0.5) as a function of CA (high vs. low) and at least moderate intensity PA (any vs. none) among 864 cognitively normal (CDR = 0) older adults. RESULTS: During three annual follow-up waves, 72 participants developed MCI. Compared with low CA with no PA, significant reductions in risk for MCI were observed for high CA with any PA (hazards ratio (HR) = 0.20, 95% confidence interval (CI) 0.07-0.52) and low CA with any PA (HR = 0.52, 95% CI 0.29-0.93), but not for high CA without PA (HR = 0.94, 95% CI 0.45-1.95). DISCUSSION: These findings suggest that a combination of CA and PA may be most efficacious at reducing the risk for cognitive impairment. PMID- 25684690 TI - Solid-Supported Synthesis and 5-HT7 /5-HT1A Receptor Affinity of Arylpiperazinylbutyl Derivatives of 4,5-dihydro-1,2,4-triazine-6-(1H)-one. AB - A series of arylpiperazinylbutyl derivatives of 4,5-dihydro-1,2,4-triazine-6(1H) ones was designed and synthesized according to the new solid-supported methodology. In this approach, triazinone scaffold was constructed from the Fmoc protected glycine. The library representatives showed different levels of affinity for 5-HT7 and 5-HT1A receptors; compounds 13, 14 and 18-20 were classified as dual 5-HT7 /5-HT1A receptors ligands. The structure-affinity relationship analysis revealed that the receptor affinity and selectivity of the tested compounds depended on the kind of substituent in position 3 of triazinone fragment as well as substitution pattern of the phenylpiperazine moiety. PMID- 25684689 TI - Association of clinical practice guidelines with emergency department management of febrile infants <=56 days of age. AB - BACKGROUND: Differences among febrile infant institutional clinical practice guidelines (CPGs) may contribute to practice variation and increased healthcare costs. OBJECTIVE: Determine the association between pediatric emergency department (ED) CPGs and laboratory testing, hospitalization, ceftriaxone use, and costs in febrile infants. DESIGN: Retrospective cross-sectional study in 2013. SETTING: Thirty-three hospitals in the Pediatric Health Information System. PATIENTS: Infants aged <=56 days with a diagnosis of fever. EXPOSURES: The presence and content of ED-based febrile infant CPGs assessed by electronic survey. MEASUREMENTS: Using generalized estimating equations, we evaluated the association between CPG recommendations and rates of urine, blood, cerebrospinal fluid (CSF) testing, hospitalization, and ceftriaxone use at ED discharge in 2 age groups: <=28 days and 29 to 56 days. We also assessed CPG impact on healthcare costs. RESULTS: We included 9377 ED visits; 21 of 33 EDs (63.6%) had a CPG. For neonates <=28 days, CPG recommendations did not vary and were not associated with differences in testing, hospitalization, or costs. Among infants 29 to 56 days, CPG recommendations for CSF testing and ceftriaxone use varied. CSF testing occurred less often at EDs with CPGs recommending limited testing compared to hospitals without CPGs (adjusted odds ratio: 0.5, 95% confidence interval: 0.3-0.8). Ceftriaxone use at ED discharge varied significantly based on CPG recommendations. Costs were higher for admitted and discharged infants 29 to 56 days old at hospitals with CPGs. CONCLUSIONS: CPG recommendations for febrile infants 29 to 56 days old vary across institutions for CSF testing and ceftriaxone use, correlating with observed practice variation. CPGs were not associated with lower healthcare costs. PMID- 25684691 TI - Nucleotide-dependent structural fluctuations and regulation of microtubule binding affinity of KIF1A. AB - Molecular motors such as kinesin regulate affinity to a rail protein during the ATP hydrolysis cycle. The regulation mechanism, however, is yet to be determined. To understand this mechanism, we investigated the structural fluctuations of the motor head of the single-headed kinesin called KIF1A in different nucleotide states using molecular dynamics simulations of a Go-like model. We found that the helix alpha4 at the microtubule (MT) binding site intermittently exhibits a large structural fluctuation when MT is absent. Frequency of this fluctuation changes systematically according to the nucleotide states and correlates strongly with the experimentally observed binding affinity to MT. We also showed that thermal fluctuation enhances the correlation and the interaction with the nucleotide suppresses the fluctuation of the helix alpha4. These results suggest that KIF1A regulates affinity to MT by changing the flexibility of the helix alpha4 during the ATP hydrolysis process: the binding site becomes more flexible in the strong binding state than in the weak binding state. PMID- 25684692 TI - Emotion processing in joint hypermobility: A potential link to the neural bases of anxiety and related somatic symptoms in collagen anomalies. AB - BACKGROUND: Joint hypermobility syndrome (JHS) has repeatedly been associated with anxiety and anxiety disorders, fibromyalgia, irritable bowel syndrome and temporomandibular joint disorder. However, the neural underpinnings of these associations still remain unclear. This study explored brain responses to facial visual stimuli with emotional cues using fMRI techniques in general population with different ranges of hypermobility. METHODS: Fifty-one non-clinical volunteers (33 women) completed state and trait anxiety questionnaire measures, were assessed with a clinical examination for hypermobility (Beighton system) and performed an emotional face processing paradigm during functional neuroimaging. RESULTS: Trait anxiety scores did significantly correlate with both state anxiety and hypermobility scores. BOLD signals of the hippocampus did positively correlate with hypermobility scores for the crying faces versus neutral faces contrast in ROI analyses. No results were found for any of the other studied ROIs. Additionally, hypermobility scores were also associated with other key affective processing areas (i.e. the middle and anterior cingulate gyrus, fusiform gyrus, parahippocampal region, orbitofrontal cortex and cerebellum) in the whole brain analysis. CONCLUSIONS: Hypermobility scores are associated with trait anxiety and higher brain responses to emotional faces in emotion processing brain areas (including hippocampus) described to be linked to anxiety and somatic symptoms. These findings increase our understanding of emotion processing in people bearing this heritable variant of collagen and the mechanisms through which vulnerability to anxiety and somatic symptoms arises in this population. PMID- 25684693 TI - The role of memory for visual search in scenes. AB - Many daily activities involve looking for something. The ease with which these searches are performed often allows one to forget that searching represents complex interactions between visual attention and memory. Although a clear understanding exists of how search efficiency will be influenced by visual features of targets and their surrounding distractors or by the number of items in the display, the role of memory in search is less well understood. Contextual cueing studies have shown that implicit memory for repeated item configurations can facilitate search in artificial displays. When searching more naturalistic environments, other forms of memory come into play. For instance, semantic memory provides useful information about which objects are typically found where within a scene, and episodic scene memory provides information about where a particular object was seen the last time a particular scene was viewed. In this paper, we will review work on these topics, with special emphasis on the role of memory in guiding search in organized, real-world scenes. PMID- 25684694 TI - Ticks on dogs and cats: a pet owner-based survey in a rural town in northeastern Switzerland. AB - Changes in the endemic foci of tick populations and invasions of tick species to new areas have become evident in Europe, leading to changes in the epidemiology of tick-transmitted diseases. However, data about tick infestations of pet animals are limited. Following the recent identification of a new focus of canine babesiosis in northeastern Switzerland, we investigated the occurrence of tick vectors in this region by using a pet owner-based sampling strategy. All dog owners in a rural town were sent postal requests to send ticks from their dogs and cats over two consecutive years, beginning in April 2012. In total 3003 ticks were submitted for identification from 249 dogs (approximately 20% of the resident dog population) and from 117 cats. Ixodes ricinus was the most abundant species identified in 96.8% (n=2124) and 74.3% (n=601) of the individual samples submitted from dogs and cats, respectively. Two other tick species, I. hexagonus and Dermacentor reticulatus, were recorded on both host species, with host infestation prevalences below 2%. On cats (but not on dogs), as many as 24.0% (n=194) of the specimens were identified as a fourth tick species, I. trianguliceps. Overall, 93.5% of the ticks were adults (93.8% and 93.0% in dogs and cats), 4.4% nymphs (5.7% in dogs and 1% in cats) and 2% larvae (0.5% and 6.0% in dogs and cats), respectively. The highest infestation intensity was 49 I. ricinus ticks from an individual dog. However, 55.6% of the submissions from dogs and 24.8% from cats contained only one tick. This survey demonstrated that pet owners can contribute to a cost-effective tick surveillance and identified a new tick focus of D. reticulatus. The finding of I. trianguliceps exclusively on cats might be related to behavioural traits of the cats or to a more readily detection of these very small ticks during petting by their owners. PMID- 25684696 TI - Nano-sized Mn oxide: A true catalyst in the water-oxidation reaction. AB - The short perspective highlights new results by water-oxidizing Mn-based catalysts in artificial photosynthetic systems. PMID- 25684695 TI - Evaluation of the prognostic significance of perirenal fat invasion and tumor size in patients with pT1-pT3a localized renal cell carcinoma in a comprehensive multicenter study of the CORONA project. Can we improve prognostic discrimination for patients with stage pT3a tumors? AB - BACKGROUND: The current TNM system for renal cell carcinoma (RCC) merges perirenal fat invasion (PFI) and renal vein invasion (RVI) as stage pT3a despite limited evidence concerning their prognostic equivalence. In addition, the prognostic value of PFI compared to pT1-pT2 tumors remains controversial. OBJECTIVE: To analyze the prognostic significance of PFI, RVI, and tumor size in pT1-pT3a RCC. DESIGN, SETTING, AND PARTICIPANTS: Data for 7384 pT1a-pT3a RCC patients were pooled from 12 centers. Patients were grouped according to stages and PFI/RVI presence as follows: pT1-2N0M0 (n=6137; 83.1%), pT3aN0M0 + PFI (n=1036; 14%), and pT3aN0M0 (RVI +/- PFI; n=211; 2.9%). INTERVENTION: Radical nephrectomy or nephron-sparing surgery (NSS) (1992-2010). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Cancer-specific survival was estimated using the Kaplan Meier method. Univariate and multivariate Cox proportional-hazards regression models, as well as sensitivity and discrimination analyses, were used to evaluate the impact of clinicopathologic parameters on cancer-specific mortality (CSM). RESULTS AND LIMITATIONS: Compared to stage pT1-2, patients with stage pT3a RCC were significantly more often male (59.4% vs 53.1%) and older (64.9 vs 62.1 yr), more often had clear cell RCC (85.2% vs 77.7%), Fuhrman grade 3-4 (29.4% vs 13.4%), and tumor size >7 cm (39.1% vs 13%), and underwent NSS less often (7.5% vs 36.6%; all p<0.001). According to multivariate analysis, CSM was significantly higher for the PFI and RVI +/- PFI groups compared to pT1-2 patients (hazard ratio [HR] 1.94 and 2.12, respectively; p<0.001), whereas patients with PFI only and RVI +/- PFI did not differ (HR 1.17; p=0.316). Tumor size instead enhanced CSM by 7% per cm in stage pT3a (HR 1.07; p<0.001) with a 7 cm cutoff yielding the highest prediction accuracy. CONCLUSIONS: Since the prognostic impact of PFI and RVI on CSM seems to be comparable, merging both as stage pT3a RCC might be justified. Enhanced prognostic discrimination of stage pT3a RCC appears to be possible by applying a tumor size cutoff of 7 cm within an alternative staging system. PATIENT SUMMARY: Prognosis prediction for patients with localized renal cell carcinoma up to stage pT3a can be enhanced by including tumor size with a cutoff of 7 cm as an additional parameter in the TNM classification system. PMID- 25684697 TI - Observation of coherent oscillation in single-passage Landau-Zener transitions. AB - Landau-Zener transition (LZT) has been explored in a variety of physical systems for coherent population transfer between different quantum states. In recent years, there have been various proposals for applying LZT to quantum information processing because when compared to the methods using ac pulse for coherent population transfer, protocols based on LZT are less sensitive to timing errors. However, the effect of finite range of qubit energy available to LZT based state control operations has not been thoroughly examined. In this work, we show that using the well-known Landau-Zener formula in the vicinity of an avoided energy level crossing will cause considerable errors due to coherent oscillation of the transition probability in a single-passage LZT experiment. The data agree well with the numerical simulations which take the transient dynamics of LZT into account. These results not only provide a closer view on the issue of finite-time LZT but also shed light on its effects on the quantum state manipulation. PMID- 25684699 TI - Self-assembly of fluorescent carbon dots in a N,N-dimethylmethanamide solution via Schiff base reaction. AB - The transition from nanoparticles suspended in aqueous solutions into solid fluorescent structures is developed for application in solid functional devices. The presented approach enables the organization of carbon dots into rod-like shapes that can still be re-dispersed into aqueous solution. Schiff bases forming at the surface of carbon dots not only protect their surface states, but also provide sites for tethering to other carbon dots. As a consequence, the large assemblies of CDs can come together to form regular, well ordered structures whilst still maintaining their photoluminescence properties. This opens up enormous possibilities for device manufacture, as these self-assemblies could be grown or grafted onto templates forming regular structures, and find innumerable applications ranging from optoelectronic devices, light harvesting to artificial photosynthesis. PMID- 25684698 TI - Development of thymic Foxp3(+) regulatory T cells: TGF-beta matters. AB - CD4(+) regulatory T cells expressing the transcription factor Foxp3 can be generated in the thymus (tTreg cells), but the cellular and molecular pathways driving their development remain incompletely understood. TGF-beta is essential for the generation of Foxp3(+) Treg cells converted from peripheral naive CD4(+) T cells (pTreg cells), yet a role for TGF-beta in tTreg-cell development was initially refuted. Nevertheless, recent studies have unmasked a requirement for TGF-beta in the generation of tTreg cells. Experimental evidence reveals that TGF beta in the context of TCR stimulation induces Foxp3 gene transcription in thymic Treg precursors, CD4(+) CD8(-) CD25(-) semimature and mature single-positive thymocytes. Intriguingly, thymic apoptosis was found to be intrinsically linked to the generation of tTreg cells, as apoptosis induced expression of TGF-beta intrathymically. In this short review, we will highlight key data, discuss the experimental evidence and propose a modified model of tTreg-cell development involving TGF-beta. We will also outline the remaining unresolved questions concerning generation of thymic Foxp3(+) Treg cells and provide our personal perspectives on the mechanisms controlling tTreg-cell development. PMID- 25684700 TI - Urine metabolic fingerprinting using LC-MS and GC-MS reveals metabolite changes in prostate cancer: A pilot study. AB - Prostate cancer (CaP) is a leading cause of cancer deaths in men worldwide. The alarming statistics, the currently applied biomarkers are still not enough specific and selective. In addition, pathogenesis of CaP development is not totally understood. Therefore, in the present work, metabolomics study related to urinary metabolic fingerprinting analyses has been performed in order to scrutinize potential biomarkers that could help in explaining the pathomechanism of the disease and be potentially useful in its diagnosis and prognosis. Urine samples from CaP patients and healthy volunteers were analyzed with the use of high performance liquid chromatography coupled with time of flight mass spectrometry detection (HPLC-TOF/MS) in positive and negative polarity as well as gas chromatography hyphenated with triple quadruple mass spectrometry detection (GC-QqQ/MS) in a scan mode. The obtained data sets were statistically analyzed using univariate and multivariate statistical analyses. The Principal Component Analysis (PCA) was used to check systems' stability and possible outliers, whereas Partial Least Squares Discriminant Analysis (PLS-DA) was performed for evaluation of quality of the model as well as its predictive ability using statistically significant metabolites. The subsequent identification of selected metabolites using NIST library and commonly available databases allows for creation of a list of putative biomarkers and related biochemical pathways they are involved in. The selected pathways, like urea and tricarboxylic acid cycle, amino acid and purine metabolism, can play crucial role in pathogenesis of prostate cancer disease. PMID- 25684701 TI - Statistical shear lag model - unraveling the size effect in hierarchical composites. AB - Numerous experimental and computational studies have established that the hierarchical structures encountered in natural materials, such as the brick-and mortar structure observed in sea shells, are essential for achieving defect tolerance. Due to this hierarchy, the mechanical properties of natural materials have a different size dependence compared to that of typical engineered materials. This study aimed to explore size effects on the strength of bio inspired staggered hierarchical composites and to define the influence of the geometry of constituents in their outstanding defect tolerance capability. A statistical shear lag model is derived by extending the classical shear lag model to account for the statistics of the constituents' strength. A general solution emerges from rigorous mathematical derivations, unifying the various empirical formulations for the fundamental link length used in previous statistical models. The model shows that the staggered arrangement of constituents grants composites a unique size effect on mechanical strength in contrast to homogenous continuous materials. The model is applied to hierarchical yarns consisting of double-walled carbon nanotube bundles to assess its predictive capabilities for novel synthetic materials. Interestingly, the model predicts that yarn gauge length does not significantly influence the yarn strength, in close agreement with experimental observations. PMID- 25684702 TI - Role of endogenous PDGF-BB in cultured cardiomyocytes exposed to hypoxia. AB - Platelet-derived growth factor-BB (PDGF-BB) plays a critical role in cell proliferation, angiogenesis and fibrosis. However, its exact role in cardiomyocytes exposed to hypoxia is not well known. This study was therefore designed to detect whether PDGF-BB expression was changed in a hypoxic condition, then the possible role of endogenous PDGF-BB in cardiomyocytes was explored, with interference RNA in a lentiviral vector ex vivo. The results showed that cultured cardiomyocytes exhibited an optimal proliferation from 3 to 10 days. However, LDH level was significantly increased but the heart rhythm was not altered in cardiomyocytes exposed to hypoxia for 24 hours. PDGF-BB expression was substantially upregulated in hypoxic cardiomyocytes. In order to know the role of PDGF-BB, we performed PDGF-BB knockdown in cultured cardiomyocytes. The number of apoptotic cells and the level of LDH were significantly increased but the beat rhythm was reduced in cardiomyocytes with PDGF-BB knockdown. These findings suggest that endogenous PDGF-BB exerts a crucial protective effect to cultured cardiomyocytes exposed to hypoxia. PMID- 25684703 TI - Surveillance of congenital malformations in infants conceived through assisted reproductive technology or other fertility treatments. AB - BACKGROUND: As assisted reproductive technology (ART) becomes more common, it is important to understand the associated risks. The objective of this study was to determine if congenital malformations are associated with ART or other fertility treatments in New York. METHODS: In a retrospective cohort study of all live births in upstate New York from 1997 to 2005, exposure was defined using ART or other fertility treatments as noted on birth certificates. Outcomes were assessed from the New York State Congenital Malformations Registry. Specific malformations were examined to determine if there is elevated risk for exposed singleton infants compared with infants conceived naturally. RESULTS: The study included 7120 in the ART group, 11,890 in the other fertility treatments group and 1,118,162 in the comparison group. The relative risk for a congenital malformation was 1.43 (95% CI 1.19-1.72) for singleton infants conceived through ART compared with singleton infants conceived naturally. The specific defects associated with ART were patent ductus arteriosus, hypospadias, and obstructive defect in the renal pelvis and ureter, while spina bifida, other specific anomalies of the spinal cord, atresia or stenosis of the pulmonary valve, hypospadias, and obstructive defects of the renal pelvis and ureter were associated with other fertility treatment. CONCLUSION: Assisted reproductive technology is associated with a slight excess risk of birth defects. The specific congenital malformations with elevated risks for singleton infants vary depending on the exposure. Further research is necessary to understand the mechanism related to the increase in risk. PMID- 25684704 TI - Investigation of CYP3A4 and CYP2D6 Interactions of Withania somnifera and Centella asiatica in Human Liver Microsomes. AB - Withania somnifera is commonly used as a rejuvenator, whereas Centella asiatica is well known for its anxiolytic and nootropic effects. The present study aims at investigating the effect of crude extracts and principal phytoconstituents of both the medicinal plants with CYP3A4 and CYP2D6 enzyme activity in human liver microsomes (HLM). Phytoconstituents were quantified in the crude extracts of both the medicinal plants using reverse phase HPLC. Crude extracts and phytoconstituents of W. somnifera showed no significant interaction with both CYP3A4 and CYP2D6 enzymes in HLM. Of the crude extracts of C. asiatica screened in vitro, methanolic extract showed potent noncompetitive inhibition of only CYP3A4 enzyme (Ki-64.36 +/- 1.82 ug/mL), whereas ethanol solution extract showed potent noncompetitive inhibition of only CYP2D6 enzyme (Ki-36.3 +/- 0.44 ug/mL). The flavonoids, quercetin, and kaempferol showed potent (IC50 values less than 100 MUM) inhibition of CYP3A4 activity, whereas quercetin alone showed potent inhibition of CYP2D6 activity in HLM. Because methanolic extract of C. asiatica showed a relatively high percentage content of quercetin and kaempferol than ethanol solution extract, the inhibitory effect of methanolic extract on CYP3A4 enzyme activity could be attributed to the flavonoids. Thus, co-administration of the alcoholic extracts of C. asiatica with drugs that are substrates of CYP3A4 and CYP2D6 enzymes may lead to undesirable herb-drug interactions in humans. PMID- 25684705 TI - Decision solution, data manipulation and trust: The (un-)willingness to donate organs in Germany in critical times. AB - In 2011 and 2012 a change of rules and a data-manipulation scandal focused German public attention on organ donation. This increased citizens' background knowledge as well as their willingness to respond to surveys. The present study is an effort to seize this research opportunity and to create evidence on which policy recommendations can be conceivably based. It uses data from two major representative surveys from 2011 to 2012 to address four central questions: Which characteristics, experiences and attitudes correlate with the written or unwritten willingness of individuals to donate (WTD) their own organs post mortem? How has the WTD changed over time? To what extent does the WTD depend on normative trust? Which factors correlate with trust? The data is analyzed through summary statistics and regression models. Several hypotheses regarding factors connected with the WTD are confirmed in the survey results. Altruistic motives, relevant knowledge and trust are decisive. The special role of trust is corroborated by the data. As current German politics prevents the introduction of post-mortem donation incentives, potential policy making proposals are restricted to institutional changes to regain trust including the implementation of an organ donor registry and the advancement of counselling talks with general practitioners. PMID- 25684706 TI - Purification, characterization, and gene cloning of a chitinase from Stenotrophomonas maltophilia N4. AB - The Stenotrophomonas maltophilia synthesises high-activity chitinase in response to chitin or chitosan induction. The enzyme was purified 8.5 fold and subjected to characterisation. The optimum hydrolysis conditions for this enzyme when using colloidal chitin as substrate were pH 5.6 and temperature of 45 degrees C. The enzyme demonstrated high thermal stability at 45 degrees C within 2 h. The studied chitinase exhibited high activity towards colloidal chitin, glycol chitin and chitosan, while it did not hydrolyse glycosidic bonds in carboxymethylcellulose. The enzyme exhibited the highest activity, equalling 90 U/ml, towards Nitrophenyl beta-D-N,N',N"-triacetylchitotriose and activity of 37 U/ml towards 4-Nitrophenyl N,N'-diacetyl-beta-D-chitobioside. The K(m) value in the presence of the two former substrates was:1.2 and 3.9 mM, respectively, which classifies the studied enzyme as an endochitinase. Cysteine and 2-mercaptoethanol stimulated to a small degree the activity of the chitinase which may indicate the involvement of cysteine residues in the catalysis mechanism. The full length of the nucleotide sequence of this chitinase gene is 2106 bp, which amounts to 702 amino acids. PMID- 25684707 TI - Tests of calibration and goodness-of-fit in the survival setting. AB - To access the calibration of a predictive model in a survival analysis setting, several authors have extended the Hosmer-Lemeshow goodness-of-fit test to survival data. Gronnesby and Borgan developed a test under the proportional hazards assumption, and Nam and D'Agostino developed a nonparametric test that is applicable in a more general survival setting for data with limited censoring. We analyze the performance of the two tests and show that the Gronnesby-Borgan test attains appropriate size in a variety of settings, whereas the Nam-D'Agostino method has a higher than nominal Type 1 error when there is more than trivial censoring. Both tests are sensitive to small cell sizes. We develop a modification of the Nam-D'Agostino test to allow for higher censoring rates. We show that this modified Nam-D'Agostino test has appropriate control of Type 1 error and comparable power to the Gronnesby-Borgan test and is applicable to settings other than proportional hazards. We also discuss the application to small cell sizes. PMID- 25684708 TI - Comparison of the kinetic parameters of the truncated catalytic subunit and holoenzyme of human DNA polymerase E. AB - Numerous genetic studies have provided compelling evidence to establish DNA polymerase E (PolE) as the primary DNA polymerase responsible for leading strand synthesis during eukaryotic nuclear genome replication. PolE is a heterotetramer consisting of a large catalytic subunit that contains the conserved polymerase core domain as well as a 3'->5' exonuclease domain common to many replicative polymerases. In addition, PolE possesses three small subunits that lack a known catalytic activity but associate with components involved in a variety of DNA replication and maintenance processes. Previous enzymatic characterization of the PolE heterotetramer from budding yeast suggested that the small subunits slightly enhance DNA synthesis by PolE in vitro. However, similar studies of the human PolE heterotetramer (hPolE) have been limited by the difficulty of obtaining hPolE in quantities suitable for thorough investigation of its catalytic activity. Utilization of a baculovirus expression system for overexpression and purification of hPolE from insect host cells has allowed for isolation of greater amounts of active hPolE, thus enabling a more detailed kinetic comparison between hPolE and an active N-terminal fragment of the hPolE catalytic subunit (p261N), which is readily overexpressed in Escherichia coli. Here, we report the first pre steady-state studies of fully-assembled hPolE. We observe that the small subunits increase DNA binding by hPolE relative to p261N, but do not increase processivity during DNA synthesis on a single-stranded M13 template. Interestingly, the 3'->5' exonuclease activity of hPolE is reduced relative to p261N on matched and mismatched DNA substrates, indicating that the presence of the small subunits may regulate the proofreading activity of hPolE and sway hPolE toward DNA synthesis rather than proofreading. PMID- 25684710 TI - Autophagic bulk sequestration of cytosolic cargo is independent of LC3, but requires GABARAPs. AB - LC3, a mammalian homologue of yeast Atg8, is assumed to play an important part in bulk sequestration and degradation of cytoplasm (macroautophagy), and is widely used as an indicator of this process. To critically examine its role, we followed the autophagic flux of LC3 in rat hepatocytes during conditions of maximal macroautophagic activity (amino acid depletion), combined with analyses of macroautophagic cargo sequestration, measured as transfer of the cytosolic protein lactate dehydrogenase (LDH) to sedimentable organelles. To accurately determine LC3 turnover we developed a quantitative immunoblotting procedure that corrects for differential immunoreactivity of cytosolic and membrane-associated LC3 forms, and we included cycloheximide to block influx of newly synthesized LC3. As expected, LC3 was initially degraded by the autophagic-lysosomal pathway, but, surprisingly, autophagic LC3-flux ceased after ~2h. In contrast, macroautophagic cargo flux was well maintained, and density gradient analysis showed that sequestered LDH partly accumulated in LC3-free autophagic vacuoles. Hepatocytic macroautophagy could thus proceed independently of LC3. Silencing of either of the two mammalian Atg8 subfamilies in LNCaP prostate cancer cells exposed to macroautophagy-inducing conditions (starvation or the mTOR-inhibitor Torin1) confirmed that macroautophagic sequestration did not require the LC3 subfamily, but, intriguingly, we found the GABARAP subfamily to be essential. PMID- 25684709 TI - Steric gate residues of Y-family DNA polymerases DinB and pol kappa are crucial for dNTP-induced conformational change. AB - Discrimination against ribonucleotides by DNA polymerases is critical to preserve DNA integrity. For many DNA polymerases, including those of the Y family, rNTP discrimination has been attributed to steric clashes between a residue near the active site, the steric gate, and the 2'-hydroxyl of the incoming rNTP. Here we used hydrogen/deuterium exchange (HDX) mass spectrometry (MS) to probe the effects of the steric gate in the Y-family DNA polymerases Escherichia coli DinB and human DNA pol kappa. Formation of a ternary complex with a G:dCTP base pair in the active site resulted in slower hydrogen exchange relative to a ternary complex with G:rCTP in the active site. The protection from exchange was localized to regions both distal and proximal to the active site, suggesting that DinB and DNA pol kappa adopt different conformations depending on the sugar of the incoming nucleotide. In contrast, when the respective steric gate residues were mutated to alanine, the differences in HDX between the dNTP- and rNTP-bound ternary complexes were attenuated such that for DinB(F13A) and pol kappa(Y112A), ternary complexes with either G:dCTP or G:rCTP base pairs had similar HDX profiles. Furthermore, the HDX in these ternary complexes resembled that of the rCTP-bound state rather than the dCTP-bound state of the wild-type enzymes. Primer extension assays confirmed that DinB(F13A) and pol kappa(Y112A) do not discriminate against rNTPs to the same extent as the wild-type enzymes. Our observations indicate that the steric gate is crucial for rNTP discrimination because of its role in specifically promoting a dNTP-induced conformational change and that rNTP discrimination occurs in a relatively closed state of the polymerases. PMID- 25684711 TI - Phosphate uptake-independent signaling functions of the type III sodium-dependent phosphate transporter, PiT-1, in vascular smooth muscle cells. AB - Vascular calcification (VC) is prevalent in chronic kidney disease and elevated serum inorganic phosphate (Pi) is a recognized risk factor. The type III sodium dependent phosphate transporter, PiT-1, is required for elevated Pi-induced osteochondrogenic differentiation and matrix mineralization in vascular smooth muscle cells (VSMCs). However, the molecular mechanism(s) by which PiT-1 promotes these processes is unclear. In the present study, we confirmed that the Pi concentration required to induce osteochondrogenic differentiation and matrix mineralization of mouse VSMCs was well above that required for maximal Pi uptake, suggesting a signaling function of PiT-1 that was independent of Pi transport. Elevated Pi-induced signaling via ERK1/2 phosphorylation was abrogated in PiT-1 deficient VSMCs, but could be rescued by wild-type (WT) and a Pi transport deficient PiT-1 mutant. Furthermore, both WT and transport-deficient PiT-1 mutants promoted osteochondrogenic differentiation as measured by decreased SM22alpha and increased osteopontin mRNA expression. Finally, compared to vector alone, expression of transport-deficient PiT-1 mutants promoted VSMC matrix mineralization, but not to the extent observed with PiT-1 WT. These data suggest that both Pi uptake-dependent and -independent functions of PiT-1 are important for VSMC processes mediating vascular calcification. PMID- 25684712 TI - Estimation of sex in Japanese cadavers based on sternal measurements using multidetector computed tomography. AB - This study assessed the sex-discrimination potential of the sternum in a Japanese population using three-dimensional (3D) computed tomographic (CT) images. A total of 200 cadavers (100 males, 100 females) who underwent postmortem CT and subsequent forensic autopsy between December 2011 and June 2014 were used. Five measurements of each sternum were performed on 3D CT reconstructed images that extracted only bone data, and two sternal dimensions and three indices were calculated. Univariate discriminant function analyses using these linear measurements and calculated sternal dimensions and indices yielded sex classification accuracy rates of 62.5-84.0%, and 63.0-90.5%, respectively. The results of this study indicate that sternal measurements may be useful for the forensic assessment of sex in Japanese individuals, particularly in cases where better predictors, such as the pelvis or skull, are unavailable. PMID- 25684714 TI - Elevated biomarkers and contrast-induced acute kidney failure: what comes first the chicken or the egg? PMID- 25684713 TI - Residential property values predict prevalent obesity but do not predict 1-year weight change. AB - OBJECTIVE: Lower socio economic status (SES) has been linked with higher obesity rates but not with weight gain. This study examined whether SES can predict short term weight change. METHODS: The Seattle Obesity Study II was based on an observational cohort of 440 adults. Weights and heights were measured at baseline and at 1 year. Self-reported education and incomes were obtained by questionnaire. Home addresses were linked to tax parcel property values from the King County, Washington, tax assessor. Associations among SES variables, prevalent obesity, and 1-year weight change were examined using multivariable linear regressions. RESULTS: Low residential property values at the tax parcel level predicted prevalent obesity at baseline and at 1 year. Living in the top quartile of house prices reduced obesity risk by 80% at both time points. At 1 year, about 38% of the sample lost >1 kg body weight; 32% maintained (+/- 1 kg); and 30% gained >1 kg. In adjusted models, none of the baseline SES measures had any impact on 1-year weight change. CONCLUSIONS: SES variables, including tax parcel property values, predicted prevalent obesity but did not predict short term weight change. These findings, based on longitudinal cohort data, suggest other mechanisms are involved in short-term weight change. PMID- 25684715 TI - Gender equity in STEMI: not so simple! PMID- 25684716 TI - Can femoral access bleeding outcomes be improved? PMID- 25684717 TI - How to improve your "STAR quality". PMID- 25684718 TI - Fluoroscopic time: necessary but not sufficient. PMID- 25684719 TI - Once normal coronary arteries, always normal coronary arteries? PMID- 25684720 TI - Covered stents--we need them, but it would be better if we didn't. PMID- 25684721 TI - TAVI mixed with acute kidney injury: a recipe for increased mortality. PMID- 25684722 TI - A rocky road to LV recovery post TAVI. PMID- 25684723 TI - Atrial fibrillation after transcatheter aortic valve replacement: room for improvement. PMID- 25684724 TI - The TAVI stent frame: minimum security prison for the coronary arteries. PMID- 25684725 TI - Novel treatment of neonates with congenital nasal pyriform aperture stenosis. PMID- 25684726 TI - A systematic review of molecular imaging (PET and SPECT) in autism spectrum disorder: current state and future research opportunities. AB - Non-invasive positron emission tomography (PET) and single-photon emission computed tomography (SPECT) are techniques used to quantify molecular interactions, biological processes and protein concentration and distribution. In the central nervous system, these molecular imaging techniques can provide critical insights into neurotransmitter receptors and their occupancy by neurotransmitters or drugs. In recent years, there has been an increase in the number of studies that have investigated neurotransmitters in autism spectrum disorder (ASD), while earlier studies mostly focused on cerebral blood flow and glucose metabolism. The underlying and contributing mechanisms of ASD are largely undetermined and ASD diagnosis relies on the behavioral phenotype. Discovery of biochemical endophenotypes would represent a milestone in autism research that could potentially lead to ASD subtype stratification and the development of novel therapeutic drugs. This review characterizes the prior use of molecular imaging by PET and SPECT in ASD, addresses methodological challenges and highlights areas of future opportunity for contributions from molecular imaging to understand ASD pathophysiology. PMID- 25684729 TI - New insights into the neural network mediating reading processes provided by cortico-subcortical electrical mapping. AB - OBJECTIVES: To ascertain the neural network mediating reading using intraoperative electrostimulation. EXPERIMENTAL DESIGN: A cortical and axonal intraoperative electrical mapping of reading processes was achieved in seven patients who underwent awake surgery for a left occipitotemporal glioma. We performed resection cavity overlapping and superimposition with a diffusion tensor imaging-based white matter atlas. We assessed the relationship between the location of resection cavities and the occurrence of reading impairments of regular, irregular, and pseudowords. PRINCIPAL OBSERVATIONS: Intraoperative stimulation of the left posterior inferior temporal cortex (ITCp) elicited reading disturbances. Subcortical stimulation at the anterior portion of the visual word form area (VWFA) induced addressed phonology (irregular words reading) disturbances. Subcortical stimulation of the connection between VWFA and the posterior segment of the arcuate fascicle (AFp) induced both addressed and assembled phonology (irregular and pseudowords reading) disturbances. Postoperative assessment showed that resection of the posterior portion of the inferior longitudinal fascicle (ILFp), connecting the visual cortex to VWFA, induced long-term and global reading impairment. Resection of the terminations of left AFp in the ITCp-induced irregular and pseudowords reading disturbances with no impairment of regular words reading. Resection of the anterior portion of ILF did not induce reading impairment. CONCLUSIONS: Our data support an inner posterior-to-anterior hierarchical coding of letter strings in the VWFA and a crucial role of the left ILFp to provide visual inputs to the VWFA. Furthermore, we suggest that the AFp is involved in an interactive feedback system between visual and nonvisual information, recruited when reading irregular and pseudowords. PMID- 25684730 TI - Repression of metadherin inhibits biological behavior of prostate cancer cells and enhances their sensitivity to cisplatin. AB - Metadherin (MTDH), also known as astrocyte-elevated gene-1, was first cloned in 2002 and has been confirmed as an oncogene in numerous types of cancer by previous studies. Overexpression of MTDH has been observed in multiple types of cancer, including breast, esophageal, prostate, cervical and non-small-cell lung cancer, as well as neuroblastoma and hepatocellular carcinoma. However, at present, few investigations into MTDH-associated prostate cancer have been performed. A previous study suggested that MTDH was expressed at higher levels in prostate cancer samples, compared with those of benign prostatic hyperplasia. The present study aimed to elucidate the effects of MTDH as an oncogene associated with the biological behavior of prostate cancer cells and chemotherapy sensitivity to cisplatin in vitro. It was demonstrated that the inhibition of MTDH expression promoted cell apoptosis, reduced cell viability and weakened the invasive ability of prostate cancer cells. In addition, the suppression of MTDH expression increased cell sensitivity to cisplatin. Furthermore, it was demonstrated that MTDH-associated phosphoinositide 3-kinase/Akt signaling pathways may be involved in mediating the biological behavior of prostate cancer. PMID- 25684731 TI - Phosphate ytterbium-doped single-mode all-solid photonic crystal fiber with output power of 13.8 W. AB - Single-mode ytterbium-doped phosphate all-solid photonic crystal fiber (AS-PCF) with 13.8 W output power and 32% slope efficiency was reported. By altering the diameter of the rods around the doped core and thus breaking the symmetry of the fiber, a polarization-maintaining AS-PCF with degree of polarization of >85% was also achieved, for the first time to knowledge, in a phosphate PCF. PMID- 25684732 TI - Advanced biotechnology: metabolically engineered cells for the bio-based production of chemicals and fuels, materials, and health-care products. AB - Corynebacterium glutamicum, Escherichia coli, and Saccharomyces cerevisiae in particular, have become established as important industrial workhorses in biotechnology. Recent years have seen tremendous progress in their advance into tailor-made producers, driven by the upcoming demand for sustainable processes and renewable raw materials. Here, the diversity and complexity of nature is simultaneously a challenge and a benefit. Harnessing biodiversity in the right manner through synergistic progress in systems metabolic engineering and chemical synthesis promises a future innovative bio-economy. PMID- 25684733 TI - Designer steroids - over-the-counter supplements and their androgenic component: review of an increasing problem. AB - Colloquially referred to by various misleading monikers ('pro-hormones', 'natural steroids', 'testosterone boosters', etc.) designer anabolic steroids have been popular now for over a decade as a way to achieve classic anabolic steroid-like results from products sold in the legal marketplace. Recent evidence suggests that anabolic steroid use may be the most common cause of hypogonadism in men of reproductive age. Despite recent regulatory efforts that have banned specific compounds, many anabolic-androgenic steroids (AAS) remain available in over-the counter dietary supplements that are legally sold in the United States. Severe side effects including hepatotoxicity, cholestasis, renal failure, hypogonadism, gynecomastia, and infertility have been reported secondary to the use of these products. While some of these side effects may be reversible, more aggressive use may result in more permanent end-organ damage as has been previously described for the case of aggressive AAS users (Rahnema et al., Fertil Steril, 2014). Designer AAS remain easily available for purchase in over-the-counter bodybuilding supplements and these products appear to be increasingly popular, despite the known health risks associated with their use. We conducted a systematic search to identify the designer steroids that are most commonly sold in dietary supplements as of April 2014 and review what is known regarding their potency and toxicity. We propose that the impact of AAS use on the reproductive and hormonal health of men is underestimated in the literature owing to previous studies' failure to account for designer steroid use. Lastly, we make clinical recommendations to help physicians steer patients away from potentially harmful supplements, and summarize key regulatory obstacles that have allowed potent androgens to remain unregulated in the legal marketplace. PMID- 25684727 TI - Toward sophisticated basal ganglia neuromodulation: Review on basal ganglia deep brain stimulation. AB - This review presents state-of-the-art knowledge about the roles of the basal ganglia (BG) in action-selection, cognition, and motivation, and how this knowledge has been used to improve deep brain stimulation (DBS) treatment of neurological and psychiatric disorders. Such pathological conditions include Parkinson's disease, Huntington's disease, Tourette syndrome, depression, and obsessive-compulsive disorder. The first section presents evidence supporting current hypotheses of how the cortico-BG circuitry works to select motor and emotional actions, and how defects in this circuitry can cause symptoms of the BG diseases. Emphasis is given to the role of striatal dopamine on motor performance, motivated behaviors and learning of procedural memories. Next, the use of cutting-edge electrochemical techniques in animal and human studies of BG functioning under normal and disease conditions is discussed. Finally, functional neuroimaging studies are reviewed; these works have shown the relationship between cortico-BG structures activated during DBS and improvement of disease symptoms. PMID- 25684734 TI - Where to place the positive muon in the Periodic Table? AB - In a recent study it was suggested that the positively charged muon is capable of forming its own "atoms in molecules" (AIM) in the muonic hydrogen-like molecules, composed of two electrons, a muon and one of the hydrogen's isotopes, thus deserves to be placed in the Periodic Table [Phys. Chem. Chem. Phys., 2014, 16, 6602]. In the present report, the capacity of the positively charged muon in forming its own AIM is considered in a large set of molecules replacing muons with all protons in the hydrides of the second and third rows of the Periodic Table. Accordingly, in a comparative study the wavefunctions of both sets of hydrides and their muonic congeners are first derived beyond the Born-Oppenheimer (BO) paradigm, assuming protons and muons as quantum waves instead of clamped particles. Then, the non-BO wavefunctions are used to derive the AIM structures of both hydrides and muonic congeners within the context of the multi-component quantum theory of atoms in molecules. The results of the analysis demonstrate that muons are generally capable of forming their own atomic basins and the properties of these basins are not fundamentally different from those AIM containing protons. Particularly, the bonding modes in the muonic species seem to be qualitatively similar to their congener hydrides and no new bonding model is required to describe the bonding of muons to a diverse set of neighboring atoms. All in all, the positively charged muon is similar to a proton from the structural and bonding viewpoint and deserves to be placed in the same box of hydrogen in the Periodic Table. This conclusion is in line with a large body of studies on the chemical kinetics of the muonic molecules portraying the positively charged muon as a lighter isotope of hydrogen. PMID- 25684735 TI - Synthesis of Trimagnetic Multishell MnFe2 O4 @CoFe2 O4 @NiFe2 O4 Nanoparticles. AB - The synthesis and characterization of original ferrite multishell magnetic nanoparticles made of a soft core (manganese ferrite) covered with two successive shells, a hard one (cobalt ferrite) and then a soft one (nickel ferrite), are described. The results demonstrate the modulation of the coercivity when new magnetic shells are added. PMID- 25684736 TI - Similar serotonin-2A receptor binding in rats with different coping styles or levels of aggression. AB - Individual differences in coping style emerge as a function of underlying variability in the activation of a mesocorticolimbic brain circuitry. Particularly serotonin seems to play an important role. For this reason, we assessed serotonin-2A receptor (5-HT2A R) binding in the brain of rats with different coping styles. We compared proactive and reactive males of two rat strains, Wild-type Groningen (WTG) and Roman high- and low avoidance (RHA, RLA). 5-HT2A R binding in (pre)frontal cortex (FC) and hippocampus was investigated using a radiolabeled antagonist ([(3) H]MDL-100907) and agonist ([(3) H]Cimbi-36) in binding assays. No differences in 5-HT2A R binding were observed in male animals with different coping styles. [(3) H]MDL-100907 displayed a higher specific-to-nonspecific binding ratio than [(3) H]Cimbi-36. Our findings suggest that in these particular rat strains, 5-HT2A R binding is not an important molecular marker for coping style. Because neither an antagonist nor an agonist tracer showed any binding differences, it is unlikely that the affinity state of the 5-HT2A R is co-varying with levels of aggression or active avoidance in WTG, RHA and RLA. PMID- 25684737 TI - Tailoring of the titanium surface by preparing cardiovascular endothelial extracellular matrix layer on the hyaluronic acid micro-pattern for improving biocompatibility. AB - It has been proved that high molecular weight hyaluronic acid (HMW-HA, 1*10(6) Da) micro-strips on titanium (Ti) surface can elongate the human vascular endothelial cell (EC) morphology, subsequently enhance endothelial extracellular matrix (ECM) deposition in our previous work. The HMW-HA micro-strips were anticipated to possess good hemocompatibility and EC compatibility simultaneously. However, the single HMW-HA micro-strips on Ti substrate showed bad hemocompatibility. To solve this problem, a method combining HA micro-pattern and EC decellularization was developed, and the endothelial extracellular matrix layer on the HA micro-pattern (ECM/HAP) showed excellent hemocompatibility and endothelial progenitor cells (EPCs) compatibility (cell number: 14.3+/-0.5*10(5) cells/cm2>2.2+/-0.7*10(5) cells/cm2 on ECM/TiOH, 7.5+/-1.3*10(5) cells/cm2 on TiOH, 3.4+/-0.9*10(5) cells/cm2 on TiOH/HAP and 3.6+/-1.2*10(5) cells/cm2 on Ti). We also found that the ECM/HAP coating could significantly inhibit the excessive proliferation of smooth muscle cells (SMCs) (cck-8 absorption: 0.25+/-0.06<1.18+/ 0.09 A.U. on ECM/TiOH, 0.87+/-0.15 A.U. on TiOH and 1.55+/-0.11 A.U. on Ti) and the attachment of macrophages (cell number: 1.3+/-0.1*10(3)<9.2+/-1.5*10(3) cells/cm2 on ECM/TiOH, 8.8+/-0.3*10(3) cells/cm2 on TiOH, 7.3+/-0.7*10(3) cells/cm2 on TiOH/HAP and 9.6+/-0.9*10(3) cells/cm2 on Ti in 12 h). These data suggest that the multifunctional ECM/HAP coating can be used to build the bionic human endothelial ECM on the biomaterials surface, which might provide a potential and effective method for surface modification of cardiovascular devices. PMID- 25684738 TI - Characterizing preclinical model of ischemic heart failure: difference between LAD and LCx infarctions. PMID- 25684739 TI - Reply to "Letter to the editor: Characterizing preclinical model of ischemic heart failure: difference between LAD and LCx infarctions". PMID- 25684740 TI - The impact of complete denture making instructional videos on self-directed learning of clinical skills. AB - PURPOSE: The aim of this research was to evaluate the effectiveness of a clinical instructional video with a structured worksheet for independent self-study in a complete denture program. METHODS: 47 multilingual dental students completed a task by watching an instructional video with subtitles regarding clinical complete denture procedures. After completion, students evaluated their learning experience, and 11 students participated in focus group interviews to gain further insight. A mixed-methods approach to data collection and analysis provided descriptive statistical results and a grounded theory approach to coding identified key concepts and categories from the qualitative data. RESULTS: Over 70% of students had favorable opinions of the learning experience and indicated that the speed and length of the video were appropriate. Highly positive and conflicting negative comments regarding the use of subtitles showed both preferences for subtitles over audio and vice versa. The use of a video resource was considered valuable as the replay and review functions allowed better visualization of the procedures, which was considered a good recap tool for the clinical demonstration. It was also a better revision aid than textbooks. So, if the students were able to view these videos at will, they believed that videos supplemented their self-study. Despite the positive response, videos were not considered to replace live clinical demonstrations. CONCLUSIONS: While students preferred live demonstrations over the clinical videos they did express a realization of these as a supplemental learning material for self-study based on their ease of access, use for revision, and prior to clinical preparation. PMID- 25684742 TI - Risk factors for ground-level falls differ by sex. AB - BACKGROUND: The populations of many developed countries have been aging in recent years, resulting in increasing numbers of elderly-related injuries. Conventionally regarded as minor, injuries from ground-level falls are now associated with a higher risk of death for elderly people. METHODS: The subjects of this study were 15662 adult patients with injuries from ground-level falls who were registered in the Japan Trauma Data Bank between 2007 and 2013. Logistic regression analysis was used to evaluate the effects of age, sex, Injury Severity Score, and Revised Trauma Score (RTS) on inhospital mortality. Patients aged 60 years or older were further categorized into 4 subgroups by age and sex, and the effect of the presence of injuries of Abbreviated Injury Scale greater than or equal to 3 in each region on inhospital mortality was analyzed. RESULTS: Logistic regression analysis for inhospital mortality showed significant interactions between sex and age and between sex and RTS, and subgroup analysis by sex was, therefore, performed. The odds ratio (95% confidence interval) for inhospital mortality compared with patients older than 60 years was 2.75 (1.90-3.96) for men aged 60 to 79 years and 5.44 (3.77-7.85) for men 80 years or older and 1.46 (0.83 2.58) for women aged 60 to 79 years and 2.32 (1.35-4.01) for women 80 years or older. The odds ratios (95% confidence interval) for RTS less than 7.840 was 6.89 (5.56-8.55) for men and 9.97 (7.59-13.10) for women. CONCLUSIONS: The effects of age and RTS on inhospital mortality of patients after ground-level falls differed by sex. PMID- 25684743 TI - Acute vertebrobasilar ischemic stroke due to electric injury. AB - Electrical injuries are most commonly due to household accidents.Various factors determine the severity of electric injury, including type of current, amperage, voltage, tissue resistance, pathway of current,and duration of contact with the body. Various types of neurologic damage due to electrical injury have been described in literature. It may manifest as peripheral nerve injury, spinal cord damage, seizures, cerebellarataxia, hypoxic encephalopathy, and intracerebral hemorrhage. Acute ischemic stroke is an infrequent complication of electrical injury. Herein,we report a case of middle-aged man, who accidentally sustained high voltage electrical injury followed by acute vertebrobasilar ischemic stroke. Magnetic resonance imaging of the brain showed acute infarctin bilateral cerebellar and medial occipital regions. Computed tomographic angiogram of the brain and neck vessels was normal. Possibly,in our patient, the mechanism could be related to direct vascular injury due to electric current. PMID- 25684744 TI - Fluid necessity should be followed by central venous pressure. PMID- 25684745 TI - Allometric scaling and locomotor function in the primate pelvis. AB - Identification of positional behavior adaptation in the pelvis of primates is complicated by possible confounding effects of body size and phylogeny. Previous work on primate pelvic allometry has focused primarily on sexual dimorphism and its relationship to obstetric constraints in species with large fetal size relative to maternal size. This study investigates patterns of pelvic scaling with a specific aim to understand how pelvic scaling relates to locomotor function. Patterns of scaling of nine pelvic dimensions were examined in a broad comparative sample of 40 species of primates, covering both haplorhines and strepsirrhines, while accounting for phylogenetic nonindependence. Phylogenetic reduced major axis regressions on pelvic scaling patterns suggest that primate wide patterns are reflected in haplorhine- and strepsirrhine-specific analyses. Many measures scale isometrically with pelvis size, but notably, features of the ilium tend to scale allometrically. As predicted, ilium width and lower ilium cross-sectional area scale with positive allometry, while lower iliac height scales with negative allometry. Further regression analyses by locomotor group suggest that these ilium measures, as well as pubic symphysis and ischium lengths, differ in their scaling patterns according to locomotor mode. These results suggest that scaling differences within primates, when present, are related to functional differences in locomotor behavior and mechanics. This study supports recent work that identifies adaptations to locomotor loading in the ilium and highlights the need for a better understanding of the relationship between pelvic structural mechanics and the mechanical requirements of primate locomotion. PMID- 25684746 TI - Anti-Gal IgM, IgA and IgG natural antibodies in childhood. AB - The target for the most abundant xenoreactive natural antibodies in humans is the alpha-Gal epitope. Anti-Gal could provide natural immune defense against pathogens that express the alpha-Gal epitope. Anti-Gal natural antibodies are usually studied in adult individuals. Data demonstrating the incidence and concentration of anti-Gal natural antibodies in childhood are in short supply and incomplete. In the present study we prospectively quantified anti-Gal IgM, IgA and IgG levels in different age groups of children from delivery to 24 months of age and compared these levels to the level of these antibodies in their respective mothers. Measurement of anti-Gal antibodies may broaden the spectrum of specific antibodies that are available for determination of specific antibody responses in physiological and pathological conditions in children. Plasma was collected from umbilical cord blood of full term newborn, from blood of infants at age 6, 12 and 24 months and from their respective mothers at time of delivery. Quantitative determination of anti-Gal antibodies IgM, IgA and IgG were made with the enzyme immunoassays Human Anti-Alpha Galactosyl IgM ELISA, IgG ELISA and IgA ELISA. Hemagglutination activity was titrated against rabbit erythrocytes. The kinetic processes for the formation of natural antibodies in the first two years of life, in general, compared with the kinetics for the formation of total immunoglobulins IgM, IgA and IgG. There were no detectable anti-Gal IgM and IgA in the cord blood, whereas anti-Gal IgG were found at similar levels in both neonate cord blood and peripheral blood of their respective mothers. When comparing the percentage of natural antibodies in the plasma of children, the level of natural antibodies in children at the age of two years was approximately 37% for IgM, 25% for IgG and 15% for IgA. The titration of antibodies required for agglutination of rabbit red blood cells over the 24 month period followed the same trend observed for the formation of natural antibodies. Our study demonstrates the kinetics of formation of anti-Gal IgM, IgA and IgG natural antibodies in the first two years of life. The relative lack of these antibodies in this period should be taken into account when assessing for humoral immunodeficiencies, particularly with regards to the potential for children to mount an anti-carbohydrate response. PMID- 25684747 TI - Thickness dependent effective viscosity of a polymer solution near an interface probed by a quartz crystal microbalance with dissipation method. AB - The solution viscosity near an interface, which affects the solution behavior and the molecular dynamics in the solution, differs from the bulk. This paper measured the effective viscosity of a dilute poly (ethylene glycol) (PEG) solution adjacent to a Au electrode using the quartz crystal microbalance with dissipation (QCM-D) technique. We evidenced that the effect of an adsorbed PEG layer can be ignored, and calculated the zero shear rate effective viscosity to remove attenuation of high shear frequency oscillations. By increasing the overtone n from 3 to 13, the thickness of the sensed polymer solution decreased from ~70 to 30 nm. The zero shear rate effective viscosity of the polymer solution and longest relaxation time of PEG chains within it decrease with increasing solution thickness. The change trends are independent of the relation between the apparent viscosity and shear frequency and the values of the involved parameter, suggesting that the polymer solution and polymer chains closer to a solid substrate have a greater effective viscosity and slower relaxation mode, respectively. This method can study the effect of an interface presence on behavior and phenomena relating to the effective viscosity of polymer solutions, including the dynamics of discrete polymer chains. PMID- 25684748 TI - The relation between alpha-synuclein and microglia in Parkinson's disease: Recent developments. AB - Recent research suggests a complex role for microglia not only in Parkinson's disease but in other disorders involving alpha-synuclein aggregation, such as multiple system atrophy. In these neurodegenerative processes, the activation of microglia is a common pathological finding, which disturbs the homeostasis of the neuronal environment otherwise maintained, among others, by microglia. The term activation comprises any deviation from what otherwise is considered normal microglia status, including cellular abundance, morphology or protein expression. The microglial response during disease will sustain survival or otherwise promote cell degeneration. The novel concepts of alpha-synuclein being released and uptaken by neighboring cells, and their importance in disease progression, positions microglia as the main cell that can clear and handle alpha-synuclein efficiently. Microglia's behavior will therefore be a determinant on the disease's progression. For this reason we believe that the better understanding of microglia's response to alpha-synuclein pathological accumulation across brain areas and disease stages is essential to develop novel therapeutic tools for Parkinson's disease and other alpha-synucleinopathies. In this review we will revise the most recent findings and developments with regard to alpha-synuclein and microglia in Parkinson's disease. PMID- 25684749 TI - Morphine causes persistent induction of nitrated neurofilaments in cortex and subcortex even during abstinence. AB - Morphine has a profound role in neurofilament (NF) expression. However, there are very few studies on the fate of NFs during morphine abstinence coinciding with periods of relapse. Mice were treated chronically with morphine to render them tolerant to and dependent on morphine and sacrificed thereafter while another group, treated similarly, was left for 2 months without morphine. A long-lasting alteration in the stoichiometric ratio of the three NFs was observed under both conditions in both the cortex and subcortex. Morphine abstinence caused significant alterations in the phosphorylated and nitrated forms of the three NF subunits. Nitrated neurofilament light polypeptide chain (NFL) was significantly increased during chronic morphine treatment which persisted even after 2 months of morphine withdrawal. Mass spectrometric analysis following two-dimensional gel electrophoresis (2DE)-gel electrophoresis of cytoskeleton fractions of both cortex and subcortex regions identified enzymes associated with energy metabolism, cytoskeleton-associated proteins as well as NFs which showed sustained regulation even after abstinence of morphine for 2 months. It is suggestive that alteration in the levels of some of these proteins may be instrumental in the increased nitration of NFL during morphine exposure. Such gross alteration in NF dynamics is indicative of a concerted biological process of neuroadaptation during morphine abstinence. PMID- 25684750 TI - The basolateral nucleus of the amygdala mediates caloric sugar preference over a non-caloric sweetener in mice. AB - Neurobiological and genetic mechanisms underlying increased intake of and preference for nutritive sugars over non-nutritive sweeteners are not fully understood. We examined the roles of subnuclei of the amygdala in the shift in preference for a nutritive sugar. Food-deprived mice alternately received caloric sucrose (1.0 M) on odd-numbered training days and a non-caloric artificial sweetener (2.5 mM saccharin) on even-numbered training days. During training, mice with sham lesions of the basolateral (BLA) or central (CeA) nucleus of the amygdala increased their intake of 1.0 M sucrose, but not saccharin. Trained mice with sham lesions showed a significant shift in preference toward less concentrated sucrose (0.075 M) over the saccharin in a two-bottle choice test, although the mice showed an equivalent preference for these sweeteners before training. No increased intake of or preference for sucrose before and after the alternating training was observed in non-food-deprived mice. Excitotoxic lesions centered in the BLA impaired the increase in 1.0M sucrose intake and shift in preference toward 0.075 M sucrose over saccharin. Microlesions with iontophoretic excitotoxin injections into the CeA did not block the training-dependent changes. These results suggest that food-deprived animals selectively shift their preference for a caloric sugar over a non-caloric sweetener through the alternate consumption of caloric and non-caloric sweet substances. The present data also suggest that the BLA, but not CeA, plays a role in the selective shift in sweetener preference. PMID- 25684751 TI - NAMPT inhibitor and metabolite protect mouse brain from cryoinjury through distinct mechanisms. AB - Nicotinamide phosphoribosyltransferase (NAMPT) is the key enzyme in the biosynthesis of nicotinamide adenine dinucleotide (NAD). In the brain, NAMPT is primarily expressed in neurons and can prevent neuronal degeneration. NAMPT is also highly expressed in inflammatory cells, and is responsible for their activation. Since inflammation following traumatic brain injury enhances neuronal damage, we assessed the effects of nicotinamide mononucleotide (NMN), the direct NAMPT metabolite, and FK866, a potent NAMPT inhibitor, on brain injury in a cryoinjury mouse model. Twenty-four hours after brain cryoinjury, the density of neuron and the level of NAD decreased. Both NMN and FK866 alleviated the neuronal loss and decreased the lesion volume. NMN prevented the cryoinjury-induced decrease of NAD level, and FK866 decreased it further. On day 14 after cryoinjury, further neuronal loss occurred, astrocytes and Iba1-positive macrophage/microglia activated, and the NAD level increased. At this time-point, NAMPT expression was strongly induced in Iba1-positive macrophages/microglia in the lesion core. NMN and FK866 also alleviated the neuronal loss and decreased the lesion volume. In addition, FK866 significantly attenuated the activation of astrocytes and Iba1-positive macrophages/microglia, and decreased the NAD, while NMN had no such effects. Taken together, both FK866 and NMN attenuate traumatic brain injury. However, FK866 acts via the inhibition of the NAMPT activity in inflammatory cells resulting in the inhibition of inflammation, whereas NMN is effective via replenishing NAD. PMID- 25684752 TI - Synaptic plasticity-related neural oscillations on hippocampus-prefrontal cortex pathway in depression. AB - It is believed that phase synchronization facilitates neural communication and neural plasticity throughout the hippocampal-cortical network, and further supports cognition and memory. The pathway from the ventral hippocampus to the medial prefrontal cortex (mPFC) is thought to play a significant role in emotional memory processing. Therefore, the information transmission on the pathway was hypothesized to be disrupted in the depressive state, which could be related to its impaired synaptic plasticity. In this study, local field potentials (LFPs) from both ventral CA1 (vCA1) and mPFC were recorded in both normal and chronic unpredictable stress (CUS) model rats under urethane anesthesia. LFPs of all rats were recorded before and after the long-term potentiation (LTP) induced on the vCA1-mPFC pathway in order to figure out the correlation of oscillatory synchronization of LFPs and synaptic plasticity. Our results showed the vCA1-to-mPFC unidirectional phase coupling of the theta rhythm, rather than the power of either region, was significantly enhanced by LTP induction, with less enhancement in the CUS model rats compared to that in the normal rats. In addition, theta phase coupling was positively correlated with synaptic plasticity on vCA1-mPFC pathway. Moreover, the theta-slow gamma phase amplitude coupling in vCA1 was long-term enhanced after high frequency stimulation. These results suggest that the impaired synaptic plasticity in vCA1 mPFC pathway could be reflected by the attenuated theta phase coupling and theta gamma cross frequency coupling of LFPs in the depression state. PMID- 25684753 TI - Sensing remote chirality: stereochemical determination of beta-, gamma-, and delta-chiral carboxylic acids. AB - Determining the absolute stereochemisty of small molecules bearing remote nonfunctionalizable stereocenters is a challenging task. Presented is a solution in which appropriately substituted bis(porphyrin) tweezers are used. Complexation of a suitably derivatized beta-, gamma-, or delta-chiral carboxylic acid to the tweezer induces a predictable helicity of the bis(porphyrin), which is detected as a bisignate Cotton Effect (ECCD). The sign of the ECCD curve is correlated with the absolute stereochemistry of the substrate based on the derived working mnemonics in a predictable manner. PMID- 25684754 TI - Biology Open: The story so far.... PMID- 25684757 TI - Last Word on Viewpoint: What is the relationship between the acute muscle protein synthetic response and changes in muscle mass? PMID- 25684755 TI - Common genetic variants and response to atrial fibrillation ablation. AB - BACKGROUND: Common single nucleotide polymorphisms (SNPs) at chromosomes 4q25 (rs2200733, rs10033464 near PITX2), 1q21 (rs13376333 in KCNN3), and 16q22 (rs7193343 in ZFHX3) have consistently been associated with the risk of atrial fibrillation (AF). Single-center studies have shown that 4q25 risk alleles predict recurrence of AF after catheter ablation of AF. Here, we performed a meta analysis to test the hypothesis that these 4 AF susceptibility SNPs modulate response to AF ablation. METHODS AND RESULTS: Patients underwent de novo AF ablation between 2008 and 2012 at Vanderbilt University, the Heart Center Leipzig, and Massachusetts General Hospital. The primary outcome was 12-month recurrence, defined as an episode of AF, atrial flutter, or atrial tachycardia lasting >30 seconds after a 3-month blanking period. Multivariable analysis of the individual cohorts using a Cox proportional hazards model was performed. Summary statistics from the 3 centers were analyzed using fixed effects meta analysis. A total of 991 patients were included (Vanderbilt University, 245; Heart Center Leipzig, 659; and Massachusetts General Hospital, 87). The overall single procedure 12-month recurrence rate was 42%. The overall risk allele frequency for these SNPs ranged from 12% to 35%. Using a dominant genetic model, the 4q25 SNP, rs2200733, predicted a 1.4-fold increased risk of recurrence (adjusted hazard ratio,1.3 [95% confidence intervals, 1.1-1.6]; P=0.011). The remaining SNPs, rs10033464 (4q25), rs13376333 (1q21), and rs7193343 (16q22) were not significantly associated with recurrence. CONCLUSIONS: Among the 3 genetic loci most strongly associated with AF, the chromosome 4q25 SNP rs2200733 is significantly associated with recurrence of atrial arrhythmias after catheter ablation for AF. PMID- 25684758 TI - Corrigendum. PMID- 25684759 TI - Corrigendum. PMID- 25684760 TI - A natural substrate-based fluorescence assay for inhibitor screening on diacylglycerol lipase alpha. AB - The endocannabinoid 2-arachidonoylglycerol (2-AG) is predominantly biosynthesized by sn-1-diacylglycerol lipase alpha (DAGL-alpha) in the CNS. Selective inhibitors of DAGL-alpha will provide valuable insights in the role of 2-AG in endocannabinoid signaling processes and are potential therapeutics for the treatment of obesity and neurodegenerative diseases. Here, we describe the development of a natural substrate-based fluorescence assay for DAGL-alpha, using a coupled enzyme approach. The continuous setup of our assay allows monitoring of DAGL-alpha activity in real-time and in a 96-well plate format. This constitutes a major improvement to the currently available radiometric and LC/MS-based methods, which can be executed only in low-throughput formats. In addition, our assay circumvents the use of radioactive material. We demonstrate that our assay can be used to screen inhibitors of DAGL-alpha activity, using 1-stearoyl-2 arachidonoyl-sn-glycerol as the physiologically relevant natural substrate of DAGL-alpha. Furthermore, our method can be employed to measure DAGL activity and inhibition in the mouse brain membrane proteome. Consequently, our assay should serve as a valuable tool for rapid hit validation and lead optimization of DAGL alpha inhibitors. PMID- 25684761 TI - Overview and introduction: thematic review series on intestinal lipid metabolism. PMID- 25684762 TI - Sustained Remission in Tumor Necrosis Factor Inhibitor-treated Patients with Rheumatoid Arthritis: A Population-based Cohort Study. AB - OBJECTIVE: To study frequency, possible baseline predictors, timing, and duration of sustained remission [SR; defined as 28-joint Disease Activity Score (DAS28) < 2.6 for at least 6 mos] in patients with established rheumatoid arthritis (RA) treated with different tumor necrosis factor (TNF) inhibitors [etanercept (ETN), infliximab (IFX), adalimumab (ADA)]. In addition, the aim was to compare (head-to head) the effectiveness of individual drugs in patients receiving their first anti-TNF treatment. METHODS: All anti-TNF-treated patients with RA included in the observational South Swedish Arthritis Group register were eligible. We identified the patients' first SR periods (time between first visit after treatment initiation with DAS28 < 2.6 and subsequent visit with DAS28 >= 2.6). Baseline predictors of SR in biologic-naive patients were studied using multivariate regression models. Remission duration and timing of remission start was estimated with Kaplan-Meier curves. RESULTS: Of the 2416 patients included, 382 (15.8%) fulfilled the criteria for SR. Median estimated duration of SR was 5.25 years. Predictors for SR were male sex, low Health Assessment Questionnaire, low DAS28, methotrexate (MTX) treatment, and the calendar year of treatment start. OR for achieving SR within the first 12 months of treatment were 1.86 for ETN (95% CI 1.33-2.61) compared to IFX. HR for 4 years of SR were 1.32 for ETN (95% CI 1.01-1.74) and 1.84 for ADA (95% CI 1.23-2.78), with IFX as the reference drug. CONCLUSION: SR was uncommon in patients with RA treated with anti-TNF in clinical practice. However, patients remained in SR for a substantial period of time. Concomitant MTX treatment predicts remission. ETN and ADA were more likely in reaching SR. PMID- 25684763 TI - Four Anti-dsDNA Antibody Assays in Relation to Systemic Lupus Erythematosus Disease Specificity and Activity. AB - OBJECTIVE: Analysis of antibodies against dsDNA is an important diagnostic tool for systemic lupus erythematosus (SLE), and changes in anti-dsDNA antibody levels are also used to assess disease activity. Herein, 4 assays were compared with regard to SLE specificity, sensitivity, and association with disease activity variables. METHODS: Cross-sectional sera from 178 patients with SLE, of which 11 were followed consecutively, from a regional Swedish SLE register were analyzed for immunoglobulin G (IgG) anti-dsDNA by bead-based multiplex assay (FIDIS; Theradig), fluoroenzyme-immunoassay (EliA; Phadia/Thermo Fisher Scientific), Crithidia luciliae immunofluorescence test (CLIFT; ImmunoConcepts), and line blot (EUROLINE; Euroimmun). All patients with SLE fulfilled the 1982 American College of Rheumatology and/or the 2012 Systemic Lupus International Collaborating Clinics (SLICC-12) classification criteria. Healthy individuals (n = 100), patients with rheumatoid arthritis (n = 95), and patients with primary Sjogren syndrome (n = 54) served as controls. RESULTS: CLIFT had the highest SLE specificity (98%) whereas EliA had the highest sensitivity (35%). When cutoff levels for FIDIS, EliA, and EUROLINE were adjusted according to SLICC-12 (i.e., double the reference limit when using ELISA), the specificity and sensitivity of FIDIS was comparable to CLIFT. FIDIS and CLIFT also showed the highest concordance (84%). FIDIS performed best regarding association with disease activity in cross-sectional and consecutive samples. Fisher's exact test revealed striking differences between methods regarding associations with certain disease phenotypes. CONCLUSION: CLIFT remains a good choice for diagnostic purposes, but FIDIS performs equally well when the cutoff is adjusted according to SLICC-12. Based on results from cross-sectional and consecutive analyses, FIDIS can also be recommended to monitor disease activity. PMID- 25684764 TI - Feasibility and Domain Validation of Rheumatoid Arthritis (RA) Flare Core Domain Set: Report of the OMERACT 2014 RA Flare Group Plenary. AB - OBJECTIVE: The Outcome Measures in Rheumatology (OMERACT) Rheumatoid Arthritis (RA) Flare Group was established to develop an approach to identify and measure RA flares. An overview of our OMERACT 2014 plenary is provided. METHODS: Feasibility and validity of flare domains endorsed at OMERACT 11 (2012) were described based on initial data from 3 international studies collected using a common set of questions specific to RA flare. Mean flare frequency, severity, and duration data were presented, and domain scores were compared by flare status to examine known-groups validity. Breakout groups provided input for stiffness, self management, contextual factors, and measurement considerations. RESULTS: Flare data from 501 patients in an observational study indicated 39% were in flare, with mean (SD) severity of 6.0 (2.6) and 55% lasting > 14 days. Pain, physical function, fatigue, participation, and stiffness scores averaged >= 2 times higher (2 of 11 points) in flaring individuals. Correlations between flare domains and corresponding legacy instruments were obtained: r = 0.46 to 0.93. A combined definition (patient report of flare and 28-joint Disease Activity Score increase) was evaluated in 2 other trials, with similar results. Breakout groups debated specific measurement issues. CONCLUSION: These data contribute initial evidence of feasibility and content validation of the OMERACT RA Flare Core Domain Set. Our research agenda for OMERACT 2016 includes establishing duration/intensity criteria and developing criteria to identify RA flares using existing disease activity measures. Ongoing work will also address discordance between patient and physician ratings, facilitate application of flare criteria to clinical care, elucidate the role of self-management, and finalize recommendations for RA flare measurement. PMID- 25684765 TI - Prediction of clinical response after 1 year of infliximab therapy in rheumatoid arthritis based on disease activity at 3 months: posthoc analysis of the RISING study. AB - OBJECTIVE: To investigate the probability of clinical remission (REM) or low disease activity (LDA) after 1 year of infliximab (IFX) therapy based on disease activity at 3 months in patients with rheumatoid arthritis (RA). METHODS: Methotrexate-refractory patients with RA received 3 mg/kg of IFX at weeks 0, 2, and 6, followed by 3 mg/kg, 6 mg/kg, or 10 mg/kg every 8 weeks from Week 14 (W14) to Week 46. Correlation of disease activity at W14 with disease activity at W54 and probability of REM/LDA at W54 were analyzed in each dosing group. RESULTS: Disease activities at W14 were significantly correlated with both disease activity at W54 and probability of REM/LDA at W54 in patients continuing 3 mg/kg as well as in those receiving 6 mg/kg or 10 mg/kg therapy from W14. Results showed that, if approximate REM or LDA had not been achieved by W14, > 50% of patients continuing 3 mg/kg therapy would not be able to achieve REM or LDA at W54. However, even in patients with high or moderate disease activity at W14, dose escalation to 6 mg/kg or 10 mg/kg enabled many to achieve REM/LDA. CONCLUSION: Disease activity at W14 in standard-dose IFX therapy enabled the prediction of longterm clinical response at continued standard dose, as well as subsequent escalated-dose regimens. Disease activity at W14 was hypothesized to be an important index for IFX treatment strategy. PMID- 25684766 TI - Mortality in American Veterans with the HLA-B27 gene. AB - OBJECTIVE: To compare survival in American veterans with and without the HLA-B27 (B27) gene. METHODS: Mortality was evaluated in a national cohort of veterans with clinically available B27 test results between October 1, 1999, and December 31, 2011. The primary outcome was the mortality difference between B27-positive and B27-negative veterans, adjusted for age, sex, race, and diagnoses codes for diseases that may have influenced both B27 testing and mortality, including psoriasis, inflammatory bowel disease, spondyloarthritis (SpA), and other types of inflammatory arthritis. The secondary outcomes were the adjusted mortality HR for B27+ and B27- veterans, in subgroups with and without SpA. RESULTS: Among veterans with available B27 test results, 27,652 (84.7%) were B27- and 4978 (15.3%) were B27+. The mean followup time was 4.6 years. Mortality was higher in the B27+ group than in the B27- group (HR 1.15, 95% CI 1.03-1.27). Mortality was also higher in the B27+ subgroups with SpA (HR 1.35, 95% CI 1.06-1.72) and without SpA (HR 1.11, 95% CI 0.99-1.24), but the difference was significant only in the subgroup with SpA. CONCLUSION: B27 positivity was associated with an increased mortality rate in a cohort of veterans clinically selected for B27 testing, after adjustment for SpA. In the subgroup with SpA, the mortality rate was associated with B27 positivity, and in the subgroup without SpA, there was a nonsignificant association between B27+ and mortality. PMID- 25684767 TI - Macrophage Activation Syndrome in Patients with Systemic Juvenile Idiopathic Arthritis under Treatment with Tocilizumab. AB - OBJECTIVE: To identify macrophage activation syndrome (MAS) in patients with systemic juvenile idiopathic arthritis (sJIA) undergoing tocilizumab (TCZ) treatment, and to confirm laboratory marker changes and responses to treatment in patients with MAS receiving TCZ. METHODS: In Japan, 394 patients with sJIA were registered in an all-patient registry surveillance of TCZ as of January 15, 2012. TCZ (8 mg/kg) was administered every 2 weeks to patients with sJIA. MAS, hemophagocytic lymphohistiocytosis, or Epstein-Barr virus-associated hemophagocytic syndrome (EB-VAHS) was reported in 23 of these patients (25 events). The Safety Evaluation Committee of Tocilizumab for JIA reviewed these cases and clinically evaluated the data and laboratory findings using their own therapeutic experience. Events were categorized into 4 groups: definitive MAS, probable MAS, EB-VAHS, and non-MAS. RESULTS: The committee's review revealed 3 events of definitive MAS in 3 patients, 12 events of probable MAS in 11 patients, 2 events of EB-VAHS in 2 patients, and 8 events of non-MAS in 8 patients. There were 2 patients who developed 2 events: 2 events in 1 patient were classified into definitive MAS and probable MAS, and 2 events in another patient were classified into probable MAS. In patients with definitive or probable MAS, common clinical manifestations and laboratory findings of MAS were observed. Changes in laboratory data observed in patients with EB-VAHS were similar to those observed in patients with MAS. CONCLUSION: These results suggest that the clinical/laboratory features in the course of MAS appear to be similar among patients regardless of whether TCZ is administered. Similarities in the pathophysiological background of MAS and EB-VAHS were also suggested. PMID- 25684768 TI - 2014 Update of the Canadian Rheumatology Association/Spondyloarthritis Research Consortium of Canada Treatment Recommendations for the Management of Spondyloarthritis. Part II: Specific Management Recommendations. AB - OBJECTIVE: The Canadian Rheumatology Association (CRA) and the Spondyloarthritis Research Consortium of Canada (SPARCC) have collaborated to update the recommendations for the management of spondyloarthritis (SpA). METHODS: A working group was assembled and consisted of the SPARCC executive committee, rheumatologist leaders from SPARCC collaborating sites, Canadian rheumatologists from across the country with an interest in SpA (both academic and community), a rheumatology trainee with an interest in SpA, an epidemiologist/health services researcher, a member of the CRA executive, a member of the CRA therapeutics committee, and a patient representative from the Canadian Spondylitis Association. An extensive review was conducted of literature published from 2007 to 2014 involving the management of SpA. The working group created draft recommendations using multiple rounds of Web-based surveys and an in-person conference. RESULTS: Recommendations for the management of SpA were created. Part II: Specific Management Recommendations addresses management with nonpharmacologic methods, nonsteroidal anti-inflammatories and analgesics, disease-modifying antirheumatic drugs, antibiotics, tumor necrosis factor inhibitors, other biologic agents, and surgery. Also included are 10 modifications for application to juvenile SpA. CONCLUSION: These recommendations were developed based on current literature and applied to a Canadian healthcare context. It is hoped that implementation of these recommendations will promote best practices in the treatment of SpA. PMID- 25684769 TI - The cost of research: a survey of participating sites in a nationwide registry. AB - OBJECTIVE: Much attention has been placed upon decreasing costs of clinical research. However, little has been studied about the effects on research completion. METHODS: A survey was sent to all registry investigators and coordinators to determine the cost of enrollment in a national registry, whether sites had to supplement using their own funds, and whether the cost affected enrollment. RESULTS: Results indicate that a majority of sites supplemented enrollment with their own funding (88%) and diagnoses requiring a lot of time to enroll were avoided. CONCLUSION: This survey showed that reimbursement rates were well below the costs of enrollment. PMID- 25684770 TI - 2014 Update of the Canadian Rheumatology Association/spondyloarthritis research consortium of Canada treatment recommendations for the management of spondyloarthritis. Part I: principles of the management of spondyloarthritis in Canada. AB - OBJECTIVE: The Canadian Rheumatology Association (CRA) and the Spondyloarthritis Research Consortium of Canada (SPARCC) have collaborated to update the recommendations for the management of spondyloarthritis (SpA). METHODS: A working group was assembled and consisted of the SPARCC executive committee, rheumatologist leaders from SPARCC collaborating sites, Canadian rheumatologists from across the country with an interest in SpA (both academic and community), a rheumatology trainee with an interest in SpA, an epidemiologist/health services researcher, a member of the CRA executive, a member of the CRA therapeutics committee, and a patient representative from the Canadian Spondylitis Association. An extensive review was conducted of literature published from 2007 to 2014 involving the management of SpA. The working group created draft recommendations using multiple rounds of Web-based surveys and an in-person conference. A survey was sent to the membership of the CRA to obtain an extended review that was used to finalize the recommendations. RESULTS: Guidelines for the management of SpA were created. Part I focuses on the principles of management of SpA in Canada and includes 6 general management principles, 5 ethical considerations, target groups for treatment recommendations, 2 wait time recommendations, and recommendations for disease monitoring. Also included are 6 modifications for application to juvenile SpA. CONCLUSION: These recommendations were developed based on current literature and applied to a Canadian healthcare context. It is hoped that the implementation of these recommendations will promote best practices in the treatment of SpA. PMID- 25684771 TI - The OMERACT MRI in Arthritis Working Group - Update on Status and Future Research Priorities. AB - OBJECTIVE: To provide an update on the status and future research priorities of the Outcome Measures in Rheumatology (OMERACT) magnetic resonance imaging (MRI) in arthritis working group. METHODS: A summary is provided of the activities of the group within rheumatoid arthritis (RA), psoriatic arthritis (PsA), and osteoarthritis (OA), and its research priorities. RESULTS: The OMERACT RA MRI score (RAMRIS) evaluating bone erosion, bone edema (osteitis), and synovitis is now the standard method of quantifying articular pathology in RA trials. Cartilage loss is another important part of joint damage, and at the OMERACT 12 conference, we provided longitudinal data demonstrating reliability and sensitivity to change of the RAMRIS JSN component score, supporting its use in future clinical trials. The MRI group has previously developed a PsA MRI score (PsAMRIS). At OMERACT 12, PsAMRIS was evaluated in a randomized placebo controlled trial of patients with PsA, demonstrating the responsiveness and discriminatory ability of applying the PsAMRIS to hands and feet. A hand OA MRI score (HOAMRIS) was introduced at OMERACT 11, and has subsequently been further validated. At OMERACT 12, good cross-sectional interreader reliability, but variable reliability of change scores, were reported. Potential future research areas were identified at the MRI session at OMERACT 12 including assessment of tenosynovitis in RA and enthesitis in PsA and focusing on alternative MRI techniques. CONCLUSION: MRI has been further developed and validated as an outcome measure in RA, PsA, and OA. The group will continue its efforts to optimize the value of MRI as a robust biomarker in rheumatology clinical trials. PMID- 25684772 TI - Remission in Rheumatoid Arthritis: Working Toward Incorporation of the Patient Perspective at OMERACT 12. AB - OBJECTIVE: The treatment of rheumatoid arthritis (RA) should target patient relevant outcomes, making patient perspective on remission essential. In 2010, patients, physicians, health professionals, and researchers at the Outcome Measures in Rheumatology (OMERACT) conference developed an ambitious research agenda to study the concept of remission. Qualitative research has since helped us understand the concept of remission from the patient perspective. METHODS: During OMERACT 12, the OMERACT working group on patient perspective on remission in RA elaborated on data generated to date and discussed the methodological challenges ahead. Challenges included (1) selection of domains, (2) choice of a patient remission definition or a single domain to add to the current remission definition, and (3) the importance of pain in defining remission from a patient perspective. RESULTS: Focus in the coming years will be on increasing our understanding by identifying the most important domains from the patient perspective regarding remission and investigating how these domains can be measured. Investigation into the Rheumatoid Arthritis Impact of Disease questionnaire, disease flare, as well as the concordance of domains from our ongoing remission survey is appropriate. More data and further discussions are needed to decide on the next steps. CONCLUSION: Progress summarized over 4 years highlights the main methodological challenges discussed within the working group on patient perspective on remission in RA during OMERACT 12. PMID- 25684773 TI - Validation of the OMERACT Magnetic Resonance Imaging Joint Space Narrowing Score for the Wrist in a Multireader Longitudinal Trial. AB - OBJECTIVE: To assess the intrareader and interreader agreement and sensitivity to change of the Outcome Measures in Rheumatology (OMERACT) Rheumatoid Arthritis Magnetic Resonance Imaging Joint Space Narrowing (RAMRIS-JSN) score in the rheumatoid arthritis (RA) wrist in a longitudinal multireader exercise. METHODS: Coronal T1-weighted MR image sets of 1 wrist from 20 patients with early RA were assessed twice for JSN at 17 sites at baseline and after 36 or 60 months by 4 readers blinded to patient data but not time order. The joints were scored 0-4 according to the OMERACT RAMRIS-JSN score. Intraclass correlation coefficients (ICC), smallest detectable change (SDC), percentage exact/close agreement (PEA/PCA), and standardized response mean (SRM) were calculated. RESULTS: Median baseline and change score was 10.3 and 1.9, respectively. Intrareader ICC for baseline and change scores was good (>= 0.50) to very good (>= 0.80) for all and 3 of 4 readers, respectively. Interreader ICC was very good for change (0.93), while poor for baseline score if all 4 readers were included (0.36), but very good if 1 reader was excluded (0.87). Intrareader and interreader SDC was low (2.34-3.18), except for the intrareader SDC for 1 reader (6.75). The mean PEA/PCA was high for baseline and change scores both within and between the readers (51.5 99.2), except for interreader baseline PEA (14.4). SRM was moderate for all readers (0.55-0.77). CONCLUSION: The OMERACT RAMRIS-JSN score showed high overall intrareader and interreader reliability, and moderate sensitivity to change, supporting inclusion of the measure as part of the OMERACT RAMRIS system. PMID- 25684774 TI - Synthesis of Transesterified Palm Olein-Based Polyol and Rigid Polyurethanes from this Polyol. AB - Transesterification of palm olein with glycerol can increase the functionality by introducing additional hydroxyl groups to the triglyceride structure, an advantage compared to using palm olein directly as feedstock for producing palm based polyol. The objective of this study was to synthesize transesterified palm olein-based polyol via a three-step reaction: (1) transesterification of palm olein, (2) epoxidation and (3) epoxide ring opening. Transesterification of palm olein yielded approximately 78 % monoglyceride and has an hydroxyl value of approximately 164 mg KOH g-1. The effect of formic acid and hydrogen peroxide concentrations on the epoxidation reaction was studied. The relationships between epoxide ring-opening reaction time and residual oxirane oxygen content and hydroxyl value were monitored. The synthesized transesterified palm olein-based polyol has hydroxyl value between 300 and 330 mg KOH g-1 and average molecular weight between 1,000 and 1,100 Da. On the basis of the hydroxyl value and average molecular weight of the polyol, the transesterified palm olein-based polyol is suitable for producing rigid polyurethane foam, which can be designed to exhibit desirable properties. Rigid polyurethane foams were synthesized by substituting a portion of petroleum-based polyol with the transesterified palm olein-based polyol. It was observed that by increasing the amount of transesterified palm olein-based polyol, the core density and compressive strength were reduced but at the same time the insulation properties of the rigid polyurethane foam were improved. PMID- 25684775 TI - Detection, identification and differentiation of Pectobacterium and Dickeya species causing potato blackleg and tuber soft rot: a review. AB - The soft rot Enterobacteriaceae (SRE) Pectobacterium and Dickeya species (formerly classified as pectinolytic Erwinia spp.) cause important diseases on potato and other arable and horticultural crops. They may affect the growing potato plant causing blackleg and are responsible for tuber soft rot in storage thereby reducing yield and quality. Efficient and cost-effective detection and identification methods are essential to investigate the ecology and pathogenesis of the SRE as well as in seed certification programmes. The aim of this review was to collect all existing information on methods available for SRE detection. The review reports on the sampling and preparation of plant material for testing and on over thirty methods to detect, identify and differentiate the soft rot and blackleg causing bacteria to species and subspecies level. These include methods based on biochemical characters, serology, molecular techniques which rely on DNA sequence amplification as well as several less-investigated ones. PMID- 25684776 TI - Observations of nitrogen isotope fractionation in deeply embedded protostars. AB - CONTEXT: The terrestrial planets, comets, and meteorites are significantly enriched in 15N compared to the Sun and Jupiter. While the solar and jovian nitrogen isotope ratio is believed to represent the composition of the protosolar nebula, a still unidentified process has caused 15N-enrichment in the solids. Several mechanisms have been proposed to explain the variations, including chemical fractionation. However, observational results that constrain the fractionation models are scarce. While there is evidence of 15N-enrichment in prestellar cores, it is unclear how the signature evolves into the protostellar phases. AIMS: The aim of this study is to measure the 14N/15N ratio around three nearby, embedded low- to intermediate-mass protostars. METHODS: Isotopologues of HCN and HNC were used to probe the 14N/15N ratio. A selection of J = 3-2 and 4-3 transitions of H13CN, HC15N, HN13C, and H15NC was observed with the Atacama Pathfinder EXperiment telescope (APEX). The 14N/15N ratios were derived from the integrated intensities assuming a standard 12C/13C ratio. The assumption of optically thin emission was verified using radiative transfer modeling and hyperfine structure fitting. RESULTS: Two sources, IRAS 16293A and R CrA IRS7B, show 15N-enrichment by a factor of ~1.5-2.5 in both HCN and HNC with respect to the solar composition. IRAS 16293A falls in the range of typical prestellar core values. Solar composition cannot be excluded for the third source, OMC-3 MMS6. Furthermore, there are indications of a trend toward increasing 14N/15N ratios with increasing outer envelope temperature. CONCLUSIONS: The enhanced 15N abundances in HCN and HNC found in two Class 0 sources (14N/15N ~ 160-290) and the tentative trend toward a temperature-dependent 14N/15N ratio are consistent with the chemical fractionation scenario, but 14N/15N ratios from additional tracers are indispensable for testing the models. Spatially resolved observations are needed to distinguish between chemical fractionation and isotope-selective photochemistry. PMID- 25684777 TI - From the History of Science to the History of Knowledge - and Back. AB - The history of science can be better understood against the background of a history of knowledge comprising not only theoretical but also intuitive and practical knowledge. This widening of scope necessitates a more concise definition of the concept of knowledge, relating its cognitive to its material and social dimensions. The history of knowledge comprises the history of institutions in which knowledge is produced and transmitted. This is an essential but hitherto neglected aspect of cultural evolution. Taking this aspect into account one is led to the concept of extended evolution, which integrates the perspectives of niche construction and complex regulative networks. The paper illustrates this concept using four examples: the emergence of language, the Neolithic revolution, the invention of writing and the origin of mechanics. PMID- 25684778 TI - Electrohydrodynamic atomization: A two-decade effort to produce and process micro /nanoparticulate materials. AB - Electrohydrodynamic atomization (EHDA), also called electrospray technique, has been studied for more than one century. However, since 1990s it has begun to be used to produce and process micro-/nanostructured materials. Owing to the simplicity and flexibility in EHDA experimental setup, it has been successfully employed to generate particulate materials with controllable compositions, structures, sizes, morphologies, and shapes. EHDA has also been used to deposit micro- and nanoparticulate materials on surfaces in a well-controlled manner. All these attributes make EHDA a fascinating tool for preparing and assembling a wide range of micro- and nanostructured materials which have been exploited for use in pharmaceutics, food, and healthcare to name a few. Our goal is to review this field, which allows scientists and engineers to learn about the EHDA technique and how it might be used to create, process, and assemble micro-/nanoparticulate materials with unique and intriguing properties. We begin with a brief introduction to the mechanism and setup of EHDA technique. We then discuss issues critical to successful application of EHDA technique, including control of composition, size, shape, morphology, structure of particulate materials and their assembly. We also illustrate a few of the many potential applications of particulate materials, especially in the area of drug delivery and regenerative medicine. Next, we review the simulation and modeling of Taylor cone-jet formation for a single and co-axial nozzle. The mathematical modeling of particle transport and deposition is presented to provide a deeper understanding of the effective parameters in the preparation, collection and pattering processes. We conclude this article with a discussion on perspectives and future possibilities in this field. PMID- 25684780 TI - Smart Nanoparticles for Drug Delivery: Boundaries and Opportunities. AB - Various pharmaceutical particles have been used in developing different drug delivery systems ranging from traditional tablets to state-of-the-art nanoparticle formulations. Nanoparticle formulations are unique in that the small size with huge surface area sometimes provides unique properties that larger particles and bulk materials do not have. Nanoparticle formulations have been used in improving the bioavailability of various drugs, in particular, poorly soluble drugs. Nanoparticle drug delivery systems have found their unique applications in targeted drug delivery to tumors. While nanoparticle formulations have been successful in small animal xenograft models, their translation to clinical applications has been very rare. Developing nanoparticle systems designed for targeted drug delivery, e.g., treating tumors in humans, requires clear understanding of the uniqueness of nanoparticles, as well as limitations and causes of failures in clinical applications. It also requires designing novel smart nanoparticle delivery systems that can increase the drug bioavailability and at the same time reduce the drug's side effects. PMID- 25684781 TI - Platinum stable isotope analysis of geological standard reference materials by double-spike MC-ICPMS. AB - We report a method for the chemical purification of Pt from geological materials by ion-exchange chromatography for subsequent Pt stable isotope analysis by multiple-collector inductively coupled plasma mass spectrometry (MC-ICPMS) using a 196Pt-198Pt double-spike to correct for instrumental mass bias. Double-spiking of samples was carried out prior to digestion and chemical separation to correct for any mass-dependent fractionation that may occur due to incomplete recovery of Pt. Samples were digested using a NiS fire assay method, which pre-concentrates Pt into a metallic bead that is readily dissolved in acid in preparation for anion-exchange chemistry. Pt was recovered from anion-exchange resin in concentrated HNO3 acid after elution of matrix elements, including the other platinum group elements (PGE), in dilute HCl and HNO3 acids. The separation method has been calibrated using a precious metal standard solution doped with a range of synthetic matrices and results in Pt yields of >=90% with purity of >=95%. Using this chemical separation technique, we have separated Pt from 11 international geological standard reference materials comprising of PGE ores, mantle rocks, igneous rocks and one sample from the Cretaceous-Paleogene boundary layer. Pt concentrations in these samples range from ca. 5 ng g-1 to 4 MUg g-1. This analytical method has been shown to have an external reproducibility on delta198Pt (permil difference in the 198Pt/194Pt ratio from the IRMM-010 standard) of +/-0.040 (2 sd) on Pt solution standards (Creech et al., 2013, J. Anal. At. Spectrom. 28, 853-865). The reproducibility in natural samples is evaluated by processing multiple replicates of four standard reference materials, and is conservatively taken to be ca. +/-0.088 (2 sd). Pt stable isotope data for the full set of reference materials have a range of delta198Pt values with offsets of up to 0.40/00 from the IRMM-010 standard, which are readily resolved with this technique. These results demonstrate the potential of the Pt isotope system as a tracer in geochemical systems. PMID- 25684779 TI - Controlled Drug Release from Pharmaceutical Nanocarriers. AB - Nanocarriers providing spatiotemporal control of drug release contribute to reducing toxicity and improving therapeutic efficacy of a drug. On the other hand, nanocarriers face unique challenges in controlling drug release kinetics, due to the large surface area per volume ratio and the short diffusion distance. To develop nanocarriers with desirable release kinetics for target applications, it is important to understand the mechanisms by which a carrier retains and releases a drug, the effects of composition and morphology of the carrier on the drug release kinetics, and current techniques for preparation and modification of nanocarriers. This review provides an overview of drug release mechanisms and various nanocarriers with a specific emphasis on approaches to control the drug release kinetics. PMID- 25684782 TI - "Whatever average is:" understanding African-American mothers' perceptions of infant weight, growth, and health. AB - Biomedical researchers have raised concerns that mothers' inability to recognize infant and toddler overweight poses a barrier to stemming increasing rates of overweight and obesity, particularly among low-income or minority mothers. Little anthropological research has examined the sociocultural, economic or structural factors shaping maternal perceptions of infant and toddler size or addressed biomedical depictions of maternal misperception as a "socio-cultural problem." We use qualitative and quantitative data from 237 low-income, African-American mothers to explore how they define 'normal' infant growth and infant overweight. Our quantitative results document that mothers' perceptions of infant size change with infant age, are sensitive to the size of other infants in the community, and are associated with concerns over health and appetite. Qualitative analysis documents that mothers are concerned with their children's weight status and assess size in relation to their infants' cues, local and societal norms of appropriate size, interactions with biomedicine, and concerns about infant health and sufficiency. These findings suggest that mothers use multiple models to interpret and respond to child weight. An anthropological focus on the complex social and structural factors shaping what is considered 'normal' and 'abnormal' infant weight is critical for shaping appropriate and successful interventions. PMID- 25684783 TI - Uranium isotopes distinguish two geochemically distinct stages during the later Cambrian SPICE event. AB - Anoxic marine zones were common in early Paleozoic oceans (542-400 Ma), and present a potential link to atmospheric pO2 via feedbacks linking global marine phosphorous recycling, primary production and organic carbon burial. Uranium (U) isotopes in carbonate rocks track the extent of ocean anoxia, whereas carbon (C) and sulfur (S) isotopes track the burial of organic carbon and pyrite sulfur (primary long-term sources of atmospheric oxygen). In combination, these proxies therefore reveal the comparative dynamics of ocean anoxia and oxygen liberation to the atmosphere over million-year time scales. Here we report high-precision uranium isotopic data in marine carbonates deposited during the Late Cambrian 'SPICE' event, at ca. 499 Ma, documenting a well-defined -0.180/00 negative delta238U excursion that occurs at the onset of the SPICE event's positive delta13C and delta34S excursions, but peaks (and tails off) before them. Dynamic modelling shows that the different response of the U reservoir cannot be attributed solely to differences in residence times or reservoir sizes - suggesting that two chemically distinct ocean states occurred within the SPICE event. The first ocean stage involved a global expansion of euxinic waters, triggering the spike in U burial, and peaking in conjunction with a well-known trilobite extinction event. During the second stage widespread euxinia waned, causing U removal to tail off, but enhanced organic carbon and pyrite burial continued, coinciding with evidence for severe sulfate depletion in the oceans (Gill et al., 2011). We discuss scenarios for how an interval of elevated pyrite and organic carbon burial could have been sustained without widespread euxinia in the water column (both non-sulfidic anoxia and/or a more oxygenated ocean state are possibilities). Either way, the SPICE event encompasses two different stages of elevated organic carbon and pyrite burial maintained by high nutrient fluxes to the ocean, and potentially sustained by internal marine geochemical feedbacks. PMID- 25684784 TI - MORTALITY AFTER CLINICAL MANAGEMENT OF AIDS-ASSOCIATED CRYPTOCOCCAL MENINGITIS IN KENYA. AB - BACKGROUND: Cryptococcal meningitis (CM) is an increasingly prevalent infection among HIV/AIDS patients and is becoming a leading cause of morbidity and mortality in Africa. The short-term prognosis and management of patients with CM may be improved by identifying factors leading to mortality in patients with CM. OBJECTIVE: To assess the clinical management and mortality associated with cryptococcal meningitis (CM) in patients with acquired immunodeficiency syndrome (AIDS) in Kenya. DESIGN: A retrospective study. SETTING: Kenyatta National Hospital and Mbagathi District Hospital, between August 2008 and March 2009. SUBJECTS: Seventy six HIV-infected patients confirmed to be CM positive. RESULTS: Results show that 30 (40%) of 76 patients diagnosed with CM died during hospitalisation after a median hospital stay of ten days (range, 2-73 days). Significant predictors of mortality in the univariate model were Mycobacterium tuberculosis (TB) co-infection (P = 0.04), having been diagnosed with a co-morbid condition such as diabetes mellitus, oral candidiasis and hypertension (P = 0.01), and a low median CD4+ T lymphocyte count (P < 0.001). The multivariable model revealed that male sex, previous or current anti-retroviral therapy (ART) at admission and CD4+ T lymphocyte count less than 50 were significant predictors of mortality. Conversely, a minimum of two weeks of amphotericin B treatment (P < 0.001), initiation of ART (P = 0.007) and monitoring of creatinine and electrolyte levels (P = 0.02) were significantly associated with survival in the univariate model. CONCLUSIONS: CM-associated mortality in Kenya is high; there is an opportunity to improve the management and the short-term outcomes of hospitalised HIV positive patients with CM in Kenya. PMID- 25684785 TI - Morphology of hydrothermally synthesized ZnO nanoparticles tethered to carbon nanotubes affects electrocatalytic activity for H2O2 detection. AB - We describe the synthesis of zinc oxide (ZnO) nanoparticles and demonstrate their attachment to multiwalled carbon tubes, resulting in a composite with a unique synergistic effect. Morphology and size of ZnO nanostructures were controlled using hydrothermal synthesis, varying the hydrothermal treatment temperature, prior to attachment to carboxylic acid functionalized multi-walled carbon nanotubes for sensing applications. A strong dependence of electrocatalytic activity on nanosized ZnO shape was shown. High activity for H2O2 reduction was achieved when nanocomposite precursors with a roughly semi-spherical morphology (no needle-like particles present) formed at 90 degrees C. A 2.4-fold increase in cyclic voltammetry current accompanied by decrease in overpotential from the composites made from the nanosized, needle-like-free ZnO shapes was observed as compared to those composites produced from needle-like shaped ZnO. Electrocatalytic activity varied with pH, maximizing at pH 7.4. A stable, linear response for H2O2 concentrations was observed in the 1-20 mM concentration range. PMID- 25684786 TI - Biomarkers in Patients with Metastatic Breast Cancer and the PRAEGNANT Study Network. AB - Progress has been made in the treatment of metastatic breast cancer in recent decades, but very few therapies use patient or tumor-specific characteristics to tailor individualized treatment. More than ten years after the publication of the reference human genome sequence, analysis methods have improved enormously, fostering the hope that biomarkers can be used to individualize therapies and offer precise treatment based on tumor and patient characteristics. Biomarkers at every level of the system (genetics, epigenetics, gene expression, micro-RNA, proteomics and others) can be used for this. This has led to changes in clinical study designs, with drug developments often only focusing on small or very small subgroups of patients and tumors. The screening and registration of patients and their molecular tumor data has therefore become very important for the successful completion of clinical studies. This new form of medicine presents particular challenges for patients and physicians. Even in this new age of genome-wide analysis, the focus should still be on the patients' quality of life. This review summarizes recent developments and describes how the PRAEGNANT study network manages the aforementioned medical challenges and changes to create a professional infrastructure for patients and physicians. PMID- 25684787 TI - Fertility and Pregnancy Outcome after Myoma Enucleation by Minilaparotomy under Microsurgical Conditions in Pronounced Uterus Myomatosus. AB - Introduction: Besides the typical complaints and symptoms, myomas can cause sterility, infertility and complications during pregnancy. Laparoscopic interventions reach their limits with regard to organ preservation and the simultaneous desire to have children in the removal of multiple and larger intramural myoma nodes. The aim of this study is to examine fertility status and pregnancy outcome after myoma removal by minilaparotomy (skin incision maximal 8 cm) in women with pronounced uterus myomatosus. Materials and Methods: This retrospective study makes use of the data from 160 patients with an average age of 34.6 years. Factors analysed include number, size and localisation of the myomas, complaints due to the myoma, pre- and postoperative gravidity, mode of delivery, and complications of birth. Results: Indications for organ-sparing myoma enucleation were the desire to have children (72.5 %), bleeding disorders (60 %) and pressure discomfort (36.5 %). On average 4.95 (SD +/- 0.41), maximally 46 myomas were removed. The largest myoma had a diameter of 6.64 cm (SD +/- 2.74). 82.5 % of the patients had transmural myomas, in 17.5 % the uterine cavity was inadvertently opened. On average the operating time was 163 minutes (SD +/- 45.47), the blood loss 1.59 g/dL (SD +/- 0.955). 60.3 % of the patients with the desire to have children became pregnant postoperatively. 75.3 % of the pregnancies were on average carried through to the 38th week (28.4 % vaginal deliveries, 71.6 % Caesarean sections). In the postoperative period there was one case of uterine rupture in the vicinity of a previous scar. Discussion: By means of the microsurgical "mini-laparotomy" even extensive myomatous uterine changes can, in the majority of cases, be operated in an organ-sparing manner with retention of the ability to conceive and to carry a pregnancy through to maturity of the infant. The risk for a postoperative uterine rupture in a subsequent pregnancy and during delivery is minimal. PMID- 25684788 TI - Smoking during Pregnancy Is a Risk Factor for Executive Function Deficits in Preschool-aged Children. AB - Introduction: Maternal nicotine use during pregnancy has a negative impact on the child. Numerous studies have demonstrated an association between smoking during pregnancy and psychological deficits. This study looks at deficits in executive functioning in preschool-aged children. Methods: The executive functioning of preschool children was assessed by asking parents to complete the parental form of the Behavior Rating Inventory of Executive Functions - Preschool Version (BRIEF-P, German version). The results for preschool children whose mothers had smoked during pregnancy (n = 71) were compared with those of a control group. In a subsample, parental assessments of children of smokers (n = 42) and non-smokers (n = 27) were complemented by the teacher form of the BRIEF-P (German version), which allowed inter-rater agreement (parents vs. preschool teachers) to be assessed. Results: An increased incidence of executive function deficits was noted in the children of smokers, based on parental assessment. Clinically relevant deficits were particularly evident with regard to inhibition, with inhibitory deficits in children of smokers found to be almost four times higher than in the control group (p = 0.006). Inhibitory deficits were reported both by parents and by preschool teachers. Discussion: The increased percentage of executive function deficits described here, particularly the increased inhibitory deficits, confirms the current state of research on smoking during pregnancy. Poor inhibition or impulse control is a key symptom of ADHD. PMID- 25684789 TI - Comparison of Sonography versus Digital Breast Tomosynthesis to Locate Intramammary Marker Clips. AB - Introduction: This study aimed to compare the accuracy of sonography versus digital breast tomosynthesis to locate intramammary marker clips placed under ultrasound guidance. Patients and Methods: Fifty patients with suspicion of breast cancer (lesion diameter less than 2 cm [cT1]) had ultrasound-guided core needle biopsy with placement of a marker clip in the center of the tumor. Intramammary marker clips were subsequently located with both sonography and digital breast tomosynthesis. Results: Sonography detected no dislocation of intrammammary marker clips in 42 of 50 patients (84 %); dislocation was reported in 8 patients (16 %) with a maximum dislocation of 7 mm along the x-, y- or z axis. Digital breast tomosynthesis showed accurate placement without dislocation of the intramammary marker clip in 48 patients (96 %); 2 patients (4 %) had a maximum clip dislocation of 3 mm along the x-, y- or z-axis (p < 0.05). Conclusion: The use of digital breast tomosynthesis could improve the accuracy when locating intramammary marker clips compared to sonography and could, in future, be used to complement or even completely replace sonography. PMID- 25684790 TI - Evidence for nucleosynthetic enrichment of the protosolar molecular cloud core by multiple supernova events. AB - The presence of isotope heterogeneity of nucleosynthetic origin amongst meteorites and their components provides a record of the diverse stars that contributed matter to the protosolar molecular cloud core. Understanding how and when the solar system's nucleosynthetic heterogeneity was established and preserved within the solar protoplanetary disk is critical for unraveling the earliest formative stages of the solar system. Here, we report calcium and magnesium isotope measurements of primitive and differentiated meteorites as well as various types of refractory inclusions, including refractory inclusions (CAIs) formed with the canonical 26Al/27Al of ~5 * 10-5 (26Al decays to 26Mg with a half life of ~0.73 Ma) and CAIs that show fractionated and unidentified nuclear effects (FUN-CAIs) to understand the origin of the solar system's nucleosynthetic heterogeneity. Bulk analyses of primitive and differentiated meteorites along with canonical and FUN-CAIs define correlated, mass-independent variations in 43Ca, 46Ca and 48Ca. Moreover, sequential dissolution experiments of the Ivuna carbonaceous chondrite aimed at identifying the nature and number of presolar carriers of isotope anomalies within primitive meteorites have detected the presence of multiple carriers of the short-lived 26Al nuclide as well as carriers of anomalous and uncorrelated 43Ca, 46Ca and 48Ca compositions, which requires input from multiple and recent supernovae sources. We infer that the solar system's correlated nucleosynthetic variability reflects unmixing of old, galactically-inherited homogeneous dust from a new, supernovae-derived dust component formed shortly prior to or during the evolution of the giant molecular cloud parental to the protosolar molecular cloud core. This implies that similarly to 43Ca, 46Ca and 48Ca, the short-lived 26Al nuclide was heterogeneously distributed in the inner solar system at the time of CAI formation. PMID- 25684791 TI - Predicting Regional Self-identification from Spatial Network Models. AB - Social scientists characterize social life as a hierarchy of environments, from the micro level of an individual's knowledge and perceptions to the macro level of large-scale social networks. In accordance with this typology, individuals are typically thought to reside in micro- and macro-level structures, composed of multifaceted relations (e.g., acquaintanceship, friendship, and kinship). This article analyzes the effects of social structure on micro outcomes through the case of regional identification. Self identification occurs in many different domains, one of which is regional; i.e., the identification of oneself with a locationally-associated group (e.g., a "New Yorker" or "Parisian"). Here, regional self-identification is posited to result from an influence process based on the location of an individual's alters (e.g., friends, kin or coworkers), such that one tends to identify with regions in which many of his or her alters reside. The structure of this paper is laid out as follows: initially, we begin with a discussion of the relevant social science literature for both social networks and identification. This discussion is followed with one about competing mechanisms for regional identification that are motivated first from the social network literature, and second by the social psychological and cognitive literature of decision making and heuristics. Next, the paper covers the data and methods employed to test the proposed mechanisms. Finally, the paper concludes with a discussion of its findings and further implications for the larger social science literature. PMID- 25684792 TI - Critical care series. PMID- 25684793 TI - Compatibility of daptomycin with commercially available syringe filters. PMID- 25684794 TI - Compounded Pain Creams and Adverse Effects; Postanesthesia Care Unit ADC Selection Error; Docetaxel Product Has Unusual Concentration; Tragic Vaccine Diluent Mix-ups. AB - These medication errors have occurred in health care facilities at least once. They will happen again-perhaps where you work. Through education and alertness of personnel and procedural safeguards, they can be avoided. You should consider publishing accounts of errors in your newsletters and/or presenting them at your inservice training programs. Your assistance is required to continue this feature. The reports described here were received through the Institute for Safe Medication Practices (ISMP) Medication Errors Reporting Program. Any reports published by ISMP will be anonymous. Comments are also invited; the writers' names will be published if desired. ISMP may be contacted at the address shown below. Errors, close calls, or hazardous conditions may be reported directly to ISMP through the ISMP Web site (www.ismp.org), by calling 800-FAIL-SAFE, or via e mail at ismpinfo@ismp.org. ISMP guarantees the confidentiality and security of the information received and respects reporters' wishes as to the level of detail included in publications. PMID- 25684795 TI - Patient with terbinafine-induced subacute cutaneous lupus erythematosus followed by thalidomide-induced orofacial neuropathy; Beta blocker use, hypertension, and the risk of psoriasis; eczematous reaction to intravenous immunoglobulin; nicolau syndrome after intra-articular glucocorticoid injection; troponin leak associated with drug-induced methemoglobinemia. AB - The purpose of this feature is to heighten awareness of specific adverse drug reactions (ADRs), discuss methods of prevention, and promote reporting of ADRs to the US Food and Drug Administration's (FDA's) MedWatch program (800-FDA-1088). If you have reported an interesting, preventable ADR to MedWatch, please consider sharing the account with our readers. Write to Dr. Mancano at ISMP, 200 Lakeside Drive, Suite 200, Horsham, PA 19044 (phone: 215-707-4936; e-mail: mmancano@temple.edu). Your report will be published anonymously unless otherwise requested. This feature is provided by the Institute for Safe Medication Practices (ISMP) in cooperation with the FDA's MedWatch program and Temple University School of Pharmacy. ISMP is an FDA MedWatch partner. PMID- 25684796 TI - An evaluation of intravenous vitamin k for warfarin reversal: are guideline recommendations being followed? AB - BACKGROUND: Vitamin K antagonists (eg, warfarin) remain the mainstay of anticoagulation therapy in the United States, with over 22 million prescriptions being filled annually. Unfortunately, warfarin therapy is difficult to manage and increases bleeding risk. The 2012 American College of Chest Physicians guidelines created a warfarin reversal algorithm that suggested the stringent use of intravenous vitamin K. OBJECTIVE: The purpose of this evaluation was to determine the rates of adherence with guideline recommendations in clinical practice. METHOD: A convenience sample of 3 months of intravenous vitamin K medication administration data (September to November 2013) was obtained to conduct a retrospective review. Patients with underlying hepatic dysfunction or lack of warfarin therapy were excluded. Vitamin K use was evaluated for consistency with the 2012 guidelines. RESULTS: A total of 364 patients were reviewed and 119 were included. Vitamin K utilization was consistent with guideline recommendations for a total of 30 (25.2%) patients. The most common site of active bleeding requiring reversal was head bleeds, consisting of 56.6% of bleeds. A single dose of 10 mg of vitamin K was the most frequently used dosing strategy. Fresh frozen plasma (73.3%) and four-factor prothrombin complex concentrate (36.7%) were the most commonly used factor products. CONCLUSION: This evaluation demonstrates that there is a difference between clinical judgment and guideline adherence. True adherence with the guidelines may not be necessary; however, there is room for improvement in both the appropriateness and safety of intravenous vitamin K use. PMID- 25684797 TI - Bortezomib, Melphalan, and Prednisone (VMP) Regimen for Multiple Myeloma. AB - The complexity of cancer chemotherapy requires pharmacists be familiar with the complicated regimens and highly toxic agents used. This column reviews various issues related to preparation, dispensing, and administration of antineoplastic therapy, and the agents, both commercially available and investigational, used to treat malignant diseases. Questions or suggestions for topics should be addressed to Dominic A. Solimando, Jr, President, Oncology Pharmacy Services, Inc., 4201 Wilson Blvd #110-545, Arlington, VA 22203, e-mail: OncRxSvc@comcast.net; or J. Aubrey Waddell, Professor, University of Tennessee College of Pharmacy; Oncology Pharmacist, Pharmacy Department, Blount Memorial Hospital, 907 E. Lamar Alexander Parkway, Maryville, TN 37804, e-mail: waddfour@charter.net. PMID- 25684798 TI - Tamsulosin: ureteral stones (distal). AB - This Hospital Pharmacy feature is extracted from Off-Label Drug Facts, a publication available from Wolters Kluwer Health. Off-Label Drug Facts is a practitioner-oriented resource for information about specific drug uses that are unapproved by the US Food and Drug Administration. This new guide to the literature enables the health care professional or clinician to quickly identify published studies on off-label uses and determine if a specific use is rational in a patient care scenario. References direct the reader to the full literature for more comprehensive information before patient care decisions are made. Direct questions or comments regarding Off-Label Drug Uses to jgeneral@ku.edu. PMID- 25684799 TI - Electronic inventory systems and barcode technology: impact on pharmacy technical accuracy and error liability. AB - PURPOSE: To measure the effects associated with sequential implementation of electronic medication storage and inventory systems and product verification devices on pharmacy technical accuracy and rates of potential medication dispensing errors in an academic medical center. METHODS: During four 28-day periods of observation, pharmacists recorded all technical errors identified at the final visual check of pharmaceuticals prior to dispensing. Technical filling errors involving deviations from order-specific selection of product, dosage form, strength, or quantity were documented when dispensing medications using (a) a conventional unit dose (UD) drug distribution system, (b) an electronic storage and inventory system utilizing automated dispensing cabinets (ADCs) within the pharmacy, (c) ADCs combined with barcode (BC) verification, and (d) ADCs and BC verification utilized with changes in product labeling and individualized personnel training in systems application. RESULTS: Using a conventional UD system, the overall incidence of technical error was 0.157% (24/15,271). Following implementation of ADCs, the comparative overall incidence of technical error was 0.135% (10/7,379; P = .841). Following implementation of BC scanning, the comparative overall incidence of technical error was 0.137% (27/19,708; P = .729). Subsequent changes in product labeling and intensified staff training in the use of BC systems was associated with a decrease in the rate of technical error to 0.050% (13/26,200; P = .002). CONCLUSIONS: Pharmacy ADCs and BC systems provide complementary effects that improve technical accuracy and reduce the incidence of potential medication dispensing errors if this technology is used with comprehensive personnel training. PMID- 25684800 TI - Adherence to and Outcomes Associated with a Clostridium difficile Guideline at a Large Teaching Institution. AB - PURPOSE: The incidence and virulence of Clostridium difficile infection (CDI) has recently increased. National CDI treatment guidelines stratify patients based on clinical symptoms and recommend treatment based on severity of illness. In 2009, Advocate Lutheran General Hospital (Park Ridge, Illinois) adopted guidelines with treatment algorithms identical to the national guidelines. The purpose of this study was to determine whether patients were being treated in accordance with the CDI guidelines and whether adherence impacted patient outcomes. METHODS: This was a retrospective, descriptive study. Subjects were identified by CDI-associated ICD-9 codes from July 1, 2009 to June 30, 2011 and stratified by disease severity. Guideline adherence was assessed based on initial treatment selection, and subjects were then further categorized as undertreated (UT), overtreated (OT), or appropriately treated (AT). Secondary endpoints included need for therapy escalation, clinical cure, recurrence rates, 90-day all-cause mortality, proton pump inhibitor (PPI), and antimicrobial use. RESULTS: Two hundred fifty subjects totaling 324 encounters were analyzed. Overall guideline adherence was 42.9%. Adherence rates by CDI severity were mild-moderate, 53.9%; severe, 39.0%; and severe-complicated, 17.9% (P < .001). Of all the subjects, 42.9% were AT, 30.9% were OT, and 26.2% were UT. Clinical outcomes between UT versus AT subjects were as follows: therapy escalation required, 34.1% versus 27.5% (P = .289); clinical cure, 41.2% versus 55.7% (P = .033); mortality, 24.7% versus 10.1% (P = .003); and recurrence, 44.7% versus 24.8% (P < .02). Clinical outcomes between AT versus OT subjects were as follows: therapy escalation required 27.5% versus 14.4% (P < .02); clinical cure, 55.7% versus 66.7% (P = .089); mortality, 10.1% versus 7.8% (P = .553); recurrence, 24.8% versus 27.8% (P = .871). CONCLUSIONS: The majority of subjects were not treated according to CDI guidelines, particularly those with severe and severe-complicated disease. UT subjects had worse clinical outcomes and OT subjects failed to show significant improvements in clinical outcomes compared to AT subjects. Emphasis should be placed on CDI guideline adherence as this may be associated with improved outcomes. PMID- 25684801 TI - Comparison of practice patterns between inpatient cardiology pharmacists with and without added qualifications in cardiology. AB - BACKGROUND: There is a paucity of data comparing practice patterns between board certified specialists with added qualifications in cardiology (AQCV) and cardiovascular pharmacists without these credentials. PURPOSE: The purpose is to characterize differences in practice between inpatient pharmacists with and without AQCV. METHODS: We conducted a multicenter, retrospective, cross sectional, case-controlled survey. An AQCV pharmacist list was extracted from the Board of Pharmacy Specialties Web site. Hospitals with AQCV pharmacists comprised the case group. Hospitals were excluded if the AQCV pharmacists did not provide direct patient care, practiced in the outpatient setting, or were in a Veterans Affairs hospital. Each case hospital was matched to hospitals without an AQCV pharmacist in a 1:3 ratio (case:control) by region, cardiovascular discharges, and teaching hospital status. Institutions completed a survey characterizing their pharmacy services. RESULTS: Fifty-six hospitals completed the survey (21 AQCV, 35 non-AQCV). More AQCV pharmacists participated on rounds (100% vs 82.9%, P = .04) and devoted more time performing administrative tasks (20.5% +/- 15.3% vs 11.1% +/- 8.1%, P = .001) than non-AQCV pharmacists. Conversely, AQCV pharmacists spent less time providing clinical care (52.4% +/- 14.5% vs 66.2% +/- 19.8%, P = .007), were less involved with drug protocol management (71.4% vs 91.4%, P = .05), and performed less order verification than non-AQCV pharmacists. CONCLUSIONS: Practice patterns differ between inpatient pharmacists with and without AQCV. Further research is needed to determine whether AQCV credentialing improves patient outcomes and to delineate what specific tasks performed by inpatient cardiology pharmacists may improve patient outcomes. PMID- 25684802 TI - Suvorexant. AB - Each month, subscribers to The Formulary Monograph Service receive 5 to 6 well documented monographs on drugs that are newly released or are in late phase 3 trials. The monographs are targeted to Pharmacy & Therapeutics Committees. Subscribers also receive monthly 1-page summary monographs on agents that are useful for agendas and pharmacy/nursing in-services. A comprehensive target drug utilization evaluation/medication use evaluation (DUE/MUE) is also provided each month. With a subscription, the monographs are sent in print and are also available on-line. Monographs can be customized to meet the needs of a facility. A drug class review is now published monthly with The Formulary Monograph Service. Through the cooperation of The Formulary, Hospital Pharmacy publishes selected reviews in this column. For more information about The Formulary Monograph Service, call The Formulary at 800-322-4349. The January 2015 monograph topics are ledipasvir/sofosbuvir, eliglustat, naloxegol, pembrolizumab, and dulaglutide injection. The Safety MUE is on ledipasvir/sofosbuvir. PMID- 25684803 TI - Approvals, Submission, and Important Labeling Changes for US Marketed Pharmaceuticals. AB - This monthly feature will help readers keep current on new drugs, new indications, dosage forms, and safety-related changes in labeling or use. Efforts have been made to ensure the accuracy of this information; however, if there are any questions, please let me know at danial.baker@wsu.edu. PMID- 25684804 TI - Applying leadership qualities of great people to your department: sir winston churchill. AB - As pharmacy leaders develop health-system pharmacy services, it is important for them to understand successful leadership behaviors and apply them effectively to be successful in managing the challenges of health care. Directors can learn various skills from leaders both in and outside of pharmacy. Learning from these great leaders can provide pharmacy directors with guidance on how to shape various aspects of their leadership style. Winston Churchill is considered to be one of history's greatest leaders; without his leadership, the outcome of World War II may have been completely different. Leadership qualities that made him successful include the use of clear and simple communication, decisiveness, willingness to take risks and learn from failure, commitment to self-improvement, and the ability to inspire and lead others. This article describes these leadership characteristics displayed by Winston Churchill and discusses ways these qualities can be used effectively by today's pharmacy leaders in building patient-centered services. PMID- 25684805 TI - Tech trends we are watching in 2015: health information technology developments. AB - As a new year begins, we look ahead to several important topics that we will closely follow over the next 12 months. The list is certainly not exhaustive, but we believe these topics should be on all hospital pharmacy staff members' radar screens. PMID- 25684806 TI - Case for local infiltration analgesia: Is all the evidence in black and white? PMID- 25684807 TI - Targeted temperature management in brain protection: An evidence-based review. AB - Targeted temperature management (TTM) for neuroprotection involves maintaining the temperature of the brain at predetermined levels by various techniques. It is aimed at avoiding the harmful effects of hyperthermia on the brain and at exploiting the protective effects of lower tissue temperature. There has been an explosion in the use of TTM for neuroprotection in a variety of clinical scenarios apart from the commonly accepted fields of resuscitation and ischaemic, hypoxic encephalopathy. This review briefly discusses the evidence base for TTM. The focus is on various areas of application for neuroprotection, the practical issues pertaining to TTM implementation, the recent data that support it and the present areas of controversy. PMID- 25684808 TI - Role of wound instillation with bupivacaine through surgical drains for postoperative analgesia in modified radical mastectomy. AB - BACKGROUND AND AIMS: Modified Radical Mastectomy (MRM) is the commonly used surgical procedure for operable breast cancer, which involves extensive tissue dissection. Therefore, wound instillation with local anaesthetic may provide better postoperative analgesia than infiltration along the line of incision. We hypothesised that instillation of bupivacaine through chest and axillary drains into the wound may provide postoperative analgesia. METHODS: In this prospective randomised controlled study 60 patients aged 45-60 years were divided into three groups. All patients were administered general anaesthesia. At the end of the surgical procedure, axillary and chest wall drains were placed before closure. Group C was the control with no instillation; Group S received 40 ml normal saline, 20 ml through each drain; and Group B received 40 ml of 0.25% bupivacaine and the drains were clamped for 10 min. After extubation, pain score for both static and dynamic pain was evaluated using visual analog scale and then 4(th) hourly till 24 h. Rescue analgesia was injection tramadol, if the pain score exceeds 4. Statistical analysis was performed using SPSS version 13. RESULTS: There was a significant difference in the cumulative analgesic requirement and the number of analgesic demands between the groups (P: 0.000). The mean duration of analgesia in the bupivacaine group was 14.6 h, 10.3 in the saline group and 4.3 h in the control group. CONCLUSION: Wound instillation with local anaesthetics is a simple and effective means of providing good analgesia without any major side-effects. PMID- 25684809 TI - Evaluation of continuous non-invasive arterial pressure monitoring during induction of general anaesthesia in patients undergoing cardiac surgery. AB - BACKGROUND AND AIMS: Continuous arterial pressure monitoring is essential in cardiac surgical patients during induction of general anaesthesia (GA). Continuous non-invasive arterial pressure (CNAP) monitoring is fast gaining importance due to complications associated with the invasive arterial monitoring. Recently, a new continuous non-invasive arterial pressure device (CNAPTM) has been validated perioperatively in non-cardiac surgeries. The aim of our study is to compare and assess the performance of CNAP during GA with invasive arterial pressure (IAP) in patients undergoing cardiac surgeries. METHODS: Sixty patients undergoing cardiac surgery were included. Systolic, diastolic, and mean arterial pressure (MAP) data were recorded every minute for 20 min simultaneously for both IAP and CNAPTM. Statistical analysis was performed using mountain plot and Bland Altman plots for assessing limits of agreement and bias (accuracy) calculation. Totally 1200 pairs of data were analysed. RESULTS: The CNAPTM systolic, diastolic and MAP bias was 5.98 mm Hg, -3.72 mm Hg, and - 0.02 mm Hg respectively. Percentage within limits of agreement was 96.0%, 95.2% and 95.7% for systolic, diastolic and MAP. The mountain plot showed similar results as the Bland Altman plots. CONCLUSION: We conclude CNAPTM provides real-time estimates of arterial pressure comparable to IAP during induction of GA for cardiac surgery. We recommend CNAP can be used as an alternative to IAP in situations such as cardiac patients coming for non-cardiac surgeries, cardiac catheterization procedures, positive Allen's test, inability to cannulate radial artery and vascular diseases, where continuous blood pressure monitoring is required. PMID- 25684810 TI - Dexmedetomidine infusion during middle ear surgery under general anaesthesia to provide oligaemic surgical field: A prospective study. AB - BACKGROUND AND AIMS: Middle ear surgery requires bloodless surgical field for better operating conditions, deep level of anaesthesia and rapid emergence. Recent studies suggest that alpha2 agonists could provide desired surgical field, sedation and analgesia. The present study was aimed to evaluate the clinical effects of dexmedetomidine infusion as anaesthetic adjuvant during middle ear surgery using operating microscope. METHODS: Sixty four adult patients aged 18-58 years, American Society of Anaesthesiologists Grades I and II, of both gender were randomised into two comparable equal groups of 32 patients each for middle ear surgery under general anaesthesia with standard anaesthetic technique. After induction of general anaesthesia, patients of Group I were given dexmedetomidine infusion of 0.5 MUg/kg/h and patients of Group II were given placebo infusion of normal saline. Isoflurane concentration was titrated to achieve a systolic blood pressure 30% below the baseline value. All patients were assessed intra operatively for bleeding at surgical field, haemodynamic changes, awakening time and post-operative recovery. RESULTS: Statistically significant reduction was observed in the required percentage of isoflurane (0.8 +/- 0.6%) to maintain the systolic blood pressure 30% below the baseline values in patients receiving dexmedetomidine infusion when compared to those receiving placebo infusion (1.6 +/- 0.7%). Patients receiving dexmedetomidine infusion had statistically significant lesser bleeding at surgical field (P < 0.05). The mean awakening time and recovery from anaesthesia did not show any significant difference between the groups. CONCLUSION: Dexmedetomidine infusion can be safely used to provide oligaemic surgical field for better visualization using operating microscope for middle ear surgery. PMID- 25684811 TI - A prospective study to determine the circumstances, incidence and outcome of cardiopulmonary resuscitation in a referral hospital in India, in relation to various factors. AB - BACKGROUND AND AIMS: Cardiac arrest has multifactorial aetiology and the outcome depends on timely and correct interventions. We decided to investigate the circumstances, incidence and outcome of cardiopulmonary resuscitation (CPR) at a tertiary hospital in India, in relation to various factors, including extensive basic life support and advanced cardiac life support training programme for all nurses and doctors. METHODS: It has been over a decade and a half with periodical updates and implementation of newer guidelines prepared by various societies across the world about CPR for both in-hospital and out-of hospital cardiac arrests (IHCA and OHCA). We conducted a prospective study wherein all cardiac arrests reported in the hospital consecutively for 12 months were registered for the study and followed their survival up to 1-year. Statistical analysis was performed by using Chi-square test for significant differences in proportions applied to various parameters of the study. RESULTS: The main outcome measures were; (following CPR) return of spontaneous circulation, survival for 24 h, survival from 24 h to 6 weeks or discharge, alive at 1-year. For survivors, an assessment was made about their cerebral performance and overall performance and accordingly graded. All these data were tabulated. Totally 419 arrests were reported in the hospital, out of which 413 were in-hospital arrests. Out of this 260 patients were considered for resuscitation, we had about 27 survivors at the end of 1-year follow-up (10.38%). CONCLUSION: We conclude by saying there are many factors involved in good clinical outcomes following IHCAs and these variable factors need to be researched further. PMID- 25684812 TI - Nebulized ketamine decreases incidence and severity of post-operative sore throat. AB - BACKGROUND AND AIMS: Post-operative sore throat (POST) occurs in 21-65% of patients. Ketamine used earlier as gargle for reducing POST has limitations. The aim of this study was to see if nebulised ketamine reduces POST. METHODS: We conducted a prospective, randomised, placebo-control, and double-blind controlled trial. After written informed consent, 100 patients belonging to American Society of Anaesthesiologists physical status I-II in the age group 20-60 years, of either sex undergoing surgery under general anaesthesia (GA) were enrolled. Patients were randomised into two groups; group saline (S) received saline nebulisation 5.0 ml and group ketamine (K) received ketamine 50 mg (1.0 ml) with 4.0 ml of saline nebulisation for 15 min. GA was induced 10 min after completion of nebulisation in the patients. The POST and haemodynamic monitoring were done pre-nebulization, pre-induction, on reaching post-anaesthesia care unit, and at 2, 4, 6, 8, 12 and 24 h post-operatively. POST was graded on a four-point scale (0-3). RESULTS: The overall incidence of POST was 33%; 23 patients (46%) in saline and 10 patients (20%) in ketamine group experienced POST (Fisher's exact P = 0.01). The use of ketamine nebulization attenuated POST at 2 h and 4 h post operatively (P < 0.05). The primary outcome was incidence of POST at 4 h; 13 patients in group S versus 4 patients in group K (P = 0.03) experienced POST at 4 h. The moderate sore throat occurred in 6 patients in group S and none in group K at 2 h, post-operatively (P = 0.02). CONCLUSION: Ketamine nebulization significantly attenuated the incidence and severity of POST, especially in the early post-operative period, with no adverse effects. PMID- 25684813 TI - Anaesthetic management of a child with panthothenate kinase-associated neurodegeneration. AB - Panthothenate kinase-associated neurodegeneration (PKAN) (Hallervorden-Spatz disease) is a rare autosomal recessive chromosomal disorder characterised by progressive neuroaxonal dystrophy. The characteristic features include involuntary movements, rigidity, mental retardation, seizures, emaciation. The anaesthetic concerns include difficult airway, aspiration pneumonia, dehydration, and post-operative respiratory, and renal insufficiency. We report successful anaesthetic management of a 9-year-old intellectually disabled male child with PKAN, scheduled for ophthalmic surgery under general anaesthesia. PMID- 25684814 TI - Uncontrolled seizures and unusual rise in leucocyte counts: transfluthrin, liquid mosquito repellent suicidal poisoning. AB - Transfluthrin is being used as fast acting insecticide and liquid mosquito repellent. This is a case report of poisoning with transfluthrin (90 ml liquid containing 792 mg of transfluthrin) by a 25-year-old female. Tonic-clonic convulsions were not controlled with conventional drugs. In intensive care unit, patient was managed with muscle paralysis by neuromuscular blocking drug vecuronium and elective mechanical ventilation for more than 48 h under care of the anaesthesiologist with uneventful recovery. PMID- 25684815 TI - Successful management of difficult airway in children with the use of adult fibreoptic bronchoscope. PMID- 25684816 TI - Intramyometrial vasopressin as a haemostatic agent: Is it really safe? PMID- 25684817 TI - Effects of intravenous clonidine on haemodynamics and on plasma cortisol level during laparoscopic cholecystectomies. PMID- 25684818 TI - Anaesthetic management for laparoscopic cholecystectomy in patient with situs inversus totalis. PMID- 25684819 TI - Anaesthetic management of intraoperative airway obstruction by ruptured hydatid cyst of right lung and barotrauma induced pneumothorax of the contralateral lung. PMID- 25684820 TI - Innovative way of making intubating laryngeal mask airway stabilizer rod. PMID- 25684821 TI - The big "little problem" with postoperative nausea and vomiting prophylaxis. PMID- 25684822 TI - Peripheral nerve block needle defect. PMID- 25684823 TI - Emaciated, Exhausted and Excited: The Bodies and Minds of the Irish in Nineteenth Century Lancashire Asylums. AB - Drawing on asylum reception orders, casebooks and annual reports, as well as County Council notebooks recording the settlement of Irish patients, this article examines a deeply traumatic and enduring aspect of the Irish migration experience, the confinement of large numbers of Irish migrants in the Lancashire asylum system between the 1850s and the 1880s. This period saw a massive influx of impoverished Irish into the county, particularly in the post-Famine years. Asylum superintendents commented on the impact of Irish patients in terms of resulting management problems in what became, soon after their establishment, overcrowded and overstretched asylums. The article examines descriptions of Irish patients, many of whom were admitted in a poor state of health. They were also depicted as violent and difficult to manage, though reporting of this may have been swayed by anti-Irish sentiment. The article suggests that a hardening of attitudes took place in the 1870s and 1880s, when theories of degeneration took hold and the Irish in Ireland exhibited exceptionally high rates of institutionalization. It points to continuities across this period: the ongoing association between mental illness and migration long after the massive Famine influx had abated, and claims that the Irish, at one and the same time referred to as volatile and vulnerable, were particularly susceptible to the challenges of urban life, marked by their intemperance, liability to general paralysis, turbulence and immorality. Asylum superintendents also noted the relative isolation of the Irish, which led to their long-term incarceration. The article suggests that commentary about Irish asylum patients provides traction in considering broader perceptions of the Irish body, mobility and Irishness in nineteenth-century England, and a deeper understanding of institutionalization. PMID- 25684824 TI - The static allometry of sexual and non-sexual traits in vervet monkeys. AB - Sexual traits vary tremendously in static allometry. This variation may be explained in part by body size-related differences in the strength of selection. We tested this hypothesis with in two populations of vervet monkeys, using estimates of the level of condition dependence for different morphological traits as a proxy for body size-related variation in the strength of selection. In support of the hypothesis, we found that the steepness of allometric slopes increased with the level of condition dependence. One trait of particular interest, the penis, had shallow allometric slopes and low levels of condition dependence, in agreement with one of the most consistent patterns yet detected in the study of allometry, that of genitalia exhibitting shallow allometries. PMID- 25684827 TI - Enhancing the Careers of Under-Represented Junior Faculty in Biomedical Research: The Summer Institute Program to Increase Diversity (SIPID). AB - The Summer Institute Program to Increase Diversity (SIPID) in Health-Related Research is a career advancement opportunity sponsored by the National Heart, Lung, and Blood Institute. Three mentored programs address difficulties experienced by junior investigators in establishing independent research careers and academic advancement. Aims are to increase the number of faculty from under represented minority groups who successfully compete for external research funding. Data were collected using a centralized data-entry system from three Summer Institutes. Outcomes include mentees' satisfaction rating about the program, grant and publications productivity and specific comments. Fifty-eight junior faculty mentees (38% male) noticeably improved their rates of preparing/submitting grant applications and publications, with a 18-23% increase in confidence levels in planning and conducting research. According to survey comments, the training received in grantsmanship skills and one-on-one mentoring were the most valuable program components. The SIPID mentoring program was highly valued by the junior faculty mentees. The program will continue in 2011-2014 as PRIDE (PRogram to Increase Diversity among individuals Engaged in health-related research). Long-term follow-up of current mentees will be indexed at five years post training (2013). In summary, these mentoring programs hope to continue increasing the diversity of the next generation of scientists in biomedical research. PMID- 25684828 TI - Understanding Subgroup Fertility Differentials in Nigeria. AB - As Nigeria enters a period of potentially rapid economic growth due to the increase in the working age population, it is critical to understand why fertility remains so high there. Nigeria's current total fertility rate (TFR) of 5.5 (0.2 fewer children per woman than the TFR of 5.7 reported in both the 2003 and 2008 NDHS surveys) is projected to continue to decline, but questions remain about whether this decline is inevitable and whether it will continue apace. Regardless, Nigeria's population growth will continue through at least 2050 due to simple population momentum. Other challenges are the persistent and vast fertility differentials; many groups remain above replacement fertility across various social and geographical sub-units of the country. Using data primarily from the 2013 Demographic and Health Survey (DHS), as well as from 2003 and 2008 surveys, we document that many population subgroups and zones of the country are finally beginning to show signs of fertility convergence and decline. Nevertheless, some population subgroups still have higher fertility, especially: Hausa/Fulani/Kanuri women, women who live in the North West geopolitical zone, Muslim and traditionalist women, women who live in poor households, women who have lower levels of education, women who are opposed to family planning, women who marry early, and women who give birth early. In order for the projected decline in the TFR to continue, these subgroups must be highlighted, understood, and targeted with fertility- and poverty-reducing interventions. PMID- 25684830 TI - Photoperiodic flowering regulation in Arabidopsis thaliana. AB - Photoperiod, or the duration of light in a given day, is a critical cue that flowering plants utilize to effectively assess seasonal information and coordinate their reproductive development in synchrony with the external environment. The use of the model plant, Arabidopsis thaliana, has greatly improved our understanding of the molecular mechanisms that determine how plants process and utilize photoperiodic information to coordinate a flowering response. This mechanism is typified by the transcriptional activation of FLOWERING LOCUS T (FT) gene by the transcription factor CONSTANS (CO) under inductive long-day conditions in Arabidopsis. FT protein then moves from the leaves to the shoot apex, where floral meristem development can be initiated. As a point of integration from a variety of environmental factors in the context of a larger system of regulatory pathways that affect flowering, the importance of photoreceptors and the circadian clock in CO regulation throughout the day has been a key feature of the photoperiodic flowering pathway. In addition to these established mechanisms, the recent discovery of a photosynthate derivative trehalose-6-phosphate as an activator of FT in leaves has interesting implications for the involvement of photosynthesis in the photoperiodic flowering response that were suggested from previous physiological experiments in flowering induction. PMID- 25684831 TI - Emotional learning and the development of differential moralities: implications from research on psychopathy. AB - In this paper, we will argue that (1) four classes of norm can be distinguished from a neuro-cognitive perspective; (2) learning the prohibitive power of these norms relies on relatively independent emotional systems; (3) individuals with psychopathy show selective impairment for one of these emotional learning systems and two classes of norm: care based and justice based; and (4) while emotional learning systems are necessary for appropriate moral development/reasoning, they are not sufficient for moral development/reasoning. PMID- 25684832 TI - Was Bob Seger Right? Relation Between Boredom in Leisure and [Risky] Sex. AB - This article examines the association between boredom in leisure and risky sexual behaviors among South African youth (N = 1695) using longitudinal data. We hypothesized that youth who were higher on boredom in leisure at the end of ninth grade would be more likely to report engaging in risky sexual behaviors at the beginning of tenth grade. Chi-square results indicate youth, especially male youth who experience high levels of leisure boredom in ninth grade, are more likely to engage in risky sexual behaviors in tenth grade. These findings have implications for prevention programs that aim to delay sexual initiation, reduce sexual risk behaviors, and decrease the transmission of HIV and AIDS. The findings support the need for additional research on how the reduction of leisure boredom may be a potential target for reducing sexual risk among youth. PMID- 25684829 TI - Syntheses of Cyclic Guanidine-Containing Natural Products. AB - Naturally occurring guanidine derivatives frequently display medicinally useful properties. Among them, the higher order pyrrole-imidazole alkaloids, the dragmacidins, the crambescidins/batzelladines, and the saxitoxins/tetradotoxins have stimulated the development of many new synthetic methods over the past decades. We provide here an overview of the syntheses of these cyclic guanidine containing natural products. PMID- 25684833 TI - Race and History: Comments from an Epistemological Point of View. AB - The historiography of race is usually framed by two discontinuities: The invention of race by European naturalists and anthropologists, marked by Carl Linnaeus's Systema naturae (1735); and the demise of racial typologies after WWII in favor of population-based studies of human diversity. This framing serves a similar function as the quotation marks that almost invariably surround the term. "Race" is placed outside of rational discourse as a residue of outdated essentialist and hierarchical thinking. I will throw doubt on this underlying assumption, not in order to re-legitimate race, but in order to understand better why race has been, and continues to be, such a politically powerful and explosive concept. PMID- 25684835 TI - [Review of] "Lorraine Daston and Elisabeth Lunbeck (eds.), Histories of Scientific Observation, Chicago, 2011" PMID- 25684834 TI - Practical Considerations for Implementing Research Recruitment Etiquette. PMID- 25684836 TI - Identification and Active Exploration of Deformable Object Boundary Constraints through Robotic Manipulation. AB - Robotic motion planning algorithms for manipulation of deformable objects, such as in medical robotics applications, rely on accurate estimations of object deformations that occur during manipulation. An estimation of the tissue response (for off-line planning or real-time on-line re-planning), in turn, requires knowledge of both object constitutive parameters and boundary constraints. In this paper, a novel algorithm for estimating boundary constraints of deformable objects from robotic manipulation data is presented. The proposed algorithm uses tissue deformation data collected with a vision system, and employs a multi-stage hill climbing procedure to estimate the boundary constraints of the object. An active exploration technique, which uses an information maximization approach, is also proposed to extend the identification algorithm. The effects of uncertainties on the proposed methods are analyzed in simulation. The results of experimental evaluation of the methods are also presented. PMID- 25684837 TI - Lay Religion and Pastoral Care in Thirteenth-Century England: the Evidence of a Group of Short Confession Manuals. PMID- 25684838 TI - Why are there so many species in the tropics? AB - Known for centuries, the geographical pattern of increasing biodiversity from the poles to the equator is one of the most pervasive features of life on Earth. A longstanding goal of biogeographers has been to understand the primary factors that generate and maintain high diversity in the tropics. Many 'historical' and 'ecological' hypotheses have been proposed and debated, but there is still little consensus. Recent discussions have centred around two main phenomena: phylogenetic niche conservatism and ecological productivity. These two factors play important roles, but accumulating theoretical and empirical studies suggest that the single most important factor is kinetics: the temperature dependence of ecological and evolutionary rates. The relatively high temperatures in the tropics generate and maintain high diversity because 'the Red Queen runs faster when she is hot'. PMID- 25684839 TI - Extensive Operation as One of the Solution for Patients with the Insufficient Proximal Landing Zone for TEVAR in Aortic Dissection - short term results. AB - OBJECTIVE: In our study we wanted to showed the safety, feasibility, efficacy and way how to solve the problems of endovascular repair for aortic dissection with insufficient proximal Landing Zone. METHODS: The clinical data of all the patients with insufficient proximal Landing Zone (PLZ) for endovascular repair for aortic aneurism and dissection Stanford type B for the period from October 2013 to June 2014 was prospectively reviewed. According to the classification proposed by Mitchell et al, aortic Zone 0 was involved in 3 cases, Zone 1 in 1 case, Zone 2 in 9 cases and Zone 3 in 6 cases (19 patients in total). A hybrid surgical procedure of supraortic debranching and revascularization, with direct anastomosed truncus brachiocephalicus and left common carotid artery, were performed to obtain an adequate aortic PLZ. Revascularization of the left subclavian artery was carried out on the patient with dissection Stanford type B and short PLZ 2. RESULTS: There was no significant difference of risk factors between Zone 0, Zone 1, and Zone 2 (Table 1.), but the length of the PLZ significantly differed between groups (p<0.01) and there is no significant difference in technical and clinical success rate among the groups. CONCLUSION: The procedure of extending insufficient PLZ for endovascular repair for aortic arch pathology is feasible and relatively safe. The TEVAR applicability in such aortic disorders could be extended. PMID- 25684840 TI - Metabolic syndrome in patients undergoing coronary angiography. AB - INTRODUCTION: Metabolic Syndrome (MetS) is basically a cluster of cardiovascular risks that involve changes in metabolic and hemodynamic indicators; various organizations have defined it with small differences. Metabolic syndrome is a lethal endocrinopathy starting with insulin resistance and inviting a chain of systemic disorders such as abdominal obesity, glucose intolerance or diabetes mellitus (DM), dyslipidemia, hypertension (HT) and coronary artery disease (CAD). MATERIAL AND METHODS: This prospective and descriptive study was conducted at the Cardiology Clinic of a Private Hospital in Osmaniye between January 2014 and May 2014. The study population included all patients who were administered a CA procedure at the Cardiology Clinic of Private New Life Hospital in Osmaniye in 2014. RESULTS: The majority of the patients were male (63.3%), the mean age was 59.09+/-10.98, vast majority of them had social security (98.5%), 32.8% of them smoked, 7.2% had peripheral arterial disease (PAD), 52.5% were diagnosed with DM, 24.8% with HT, percutaneous transluminal coronary angioplasty (PTCA) or stent was administered to 40.3% of the patients who underwent CA and coronary artery bypass grafting (CABG) was decided for 15.5% of them. 41.8% of the patients met the MetS diagnosis criteria. The mean BMI was found to be 28.61+/-4.68, the mean FBS to be 143.20+/-74.83, the mean triglyceride value to be 168.73+/-96.94 and the mean HDL value to be 37.04+/-9.20. Although male gender came first among the patients who underwent CA, the prevalence of MetS did not show a statistically significant correlation with gender, mean age or smoking. The prevalence of HT, PAD and DM was significantly higher in the patients who met the MetS criteria. The mean values of FBS, HDL, CK-MB, triglyceride and cholesterol were also significantly higher in the patients who met the MetS criteria. As BMI increased, the rate at which MetS criteria are met also increased. CONCLUSION: The objective is to prevent diabetes and cardiovascular diseases. Weight loss achieved with proper nutrition and an exercise program will have a reversing effect on all the disorders seen in metabolic syndrome. PMID- 25684841 TI - Laser Hemorrhoidoplasty Procedure vs Open Surgical Hemorrhoidectomy: a Trial Comparing 2 Treatments for Hemorrhoids of Third and Fourth Degree. AB - OBJECTIVE: According to the ''vascular'' theory, arterial overflow in the superior hemorrhoidal arteries would lead to dilatation of the hemorrhoidal venous plexus. Hemorrhoid laser procedure (LHP) is a new laser procedure for outpatient treatment of hemorrhoids in which hemorrhoidal arterial flow feeding the hemorrhoidal plexus is stopped by laser coagulation. AIM: Our aim was to compare the hemorrhoid laser procedure with open surgical procedure for outpatient treatment of symptomatic hemorrhoids. MATERIAL AND METHOD: A comparison trial between hemorrhoid laser procedure or open surgical hemorrhoidectomy was made. This study was conducted at Aloka hospital in Kosovo. Patients with symptomatic grade III or grade IV hemorrhoids with minimal or complete mucosal prolapse were eligible for the study: 20 patients treated with the laser hemorrhoidoplasty, and 20 patients-with open surgery hemorrhoidectomy. Operative time and postoperative pain with visual analog scale, were evaluated. RESULTS: A total number of 40 patients (23 men and 17 women, mean age, 46 years) entered the trial. Significant differences between laser hemorrhoidoplasty and open surgical procedure were observed in operative time and early postoperative pain. There was a statistically significant difference between the two groups regarding the early postoperative period: 1 week, 2 weeks, 3 weeks and 1 month after respective procedure (p<0.01). The procedure time for LHP was 15.94 min vs. 26.76 min for open surgery (p<0.01). CONCLUSION: The laser hemorrhoidoplasty procedure was more effective than open surgical hemorrhoidectomy. Postoperative pain and duration time are only two indicators for this difference between there procedures. PMID- 25684842 TI - Effects of programmed kinesiologic stimulus to hemodynamics at peripheral artery disease of lower limbs. AB - GOAL: The goal of the article is to examine level of hemodynamic improvement in the peripheral artery diseases of lower limbs among patients on medication therapy and patients included in programmed physical activities simultaneously with the medication therapy. MATERIAL AND METHODS: Prospective-retrospective study includes 100 patients of the Clinic for Vascular Disease, Clinical Center of Sarjevo University (CCUS). It has been found out that the majority of patients in both groups were males. Average age of patients in control group was 48.60+/ 3.82. Average value of claudication distance for patients in control group was 277 m, while the value for patients in test group was 270 m. RESULTS: At the end of research the analysis of average PSV values proved significant difference in relation to examined groups (p<0.05). Average PSV value statistically significantly decreased in both groups after the treatment. According to the obtained results it was determined that the claudication distance of control group was statistically considerably smaller in comparison to the average claudication distance in the test group. CONCLUSION: It was established that the chance for the patients to have claudication distance within reference values is 2.57 times higher in the test group in comparison with the patients in the control group after the treatment. PMID- 25684843 TI - Ovarian reserve after laparoscopic treatment of unilateral ovarian endometrioma. AB - AIM: To evaluate the effect of laparoscopic treatment of unilateral ovarian endometrioma on ovarian reserve using ultrasonographic markers, ovarian volume and antral follicle count (AFC), and two biochemical markers, serum levels of Follicle-stimulating hormone (FSH) and Estradiol (E2). MATERIAL AND METHODS: This prospective study included 40 patients in their reproductive age, between 18 and 40 years old. They were treated laparoscopically for unilateral ovarian endometrioma. Markers of ovarian reserve were investigated before and three months after surgery. Transvaginal ultrasound examination was used for measurement of ovarian volume and AFC. Biochemical markers (FSH and E2 levels) were determined by chemiluminescent tests. RESULTS: Ovarian volume was significantly reduced after surgery. There was significant increase of AFC and non-significant increase of E2 levels in treated patients after three months. CONCLUSIONS: Laparoscopic cystectomy of unilateral ovarian endometrioma decreased ovarian reserve immediately after surgery with decrease of ovarian volume. But ovarian reserve was increased after three months with increase of AFC and estradiol levels. PMID- 25684844 TI - Pedobarography in diagnosis and clinical application. AB - INTRODUCTION: Pedobarography as a new diagnostic tool enables measuring the pressure between the foot and the floor during dynamic loading. Dynamic analysis of the foot shows advantage over static analysis due to its capabilities for detecting high load points in certain diseases and in certain phases of walking. Pedobarography as a new method in the context of rehabilitation include wide range of clinical entities. GOAL: To show the advantages of pedobarography as new diagnostic and rehabilitation method in prevention programs. MATERIAL AND METHODS: A prospective study included 100 patients with diabetes mellitus type 2. Research was conducted in the Primary Health Care Center of the Sarajevo Canton and the Center for Physical Medicine and Rehabilitation. The test parameters were: Test of balance-symmetric load for the test, the number of comorbidity, clinical examination of foot deformity, test with 10 g monofilament, HbA1c. From the total sample 45 patients (Group I) were selected, aged 50-65 years, which underwent pedobarography (on the appliance Novel Inc., Munich with EMEDTM platform) and robotic fabrication of individual orthopedic insoles, followed by control pedobarography. Plantar pressure was determined using standard pedobarography, computer recorded parameters: peak pressure (kPa), force (Ns), area (cm). RESULTS: The average age of the respondents was 59.4+/-11.38 years; altered results on the balance test were present in 34% of patients; 61% of respondents have <=2 comorbidity. In the total sample, the average number of foot deformity was 2.84. Flat feet have 66% of respondents, and valgus position 57%. The average HbA1c values were 7.783+/-1.58% (min.5-max.15.0). All subjects (45) after the first, and after the second measurement of peak pressure, have values above 200 kPa, or are in the designated zone of peak pressure that needs to be corrected. In a study was determined the correlation between the number of deformities and peak pressure, the number of deformities and the area upon which plantar pressure act, test with 10g monofilament and peak pressure. CONCLUSION: Within the framework of prevention programs early diagnosis, detection of sensitivity disorders, adequate treatment and taking load from the feet with the help of pedobarography, are of great importance for the patient suffering from diabetes. PMID- 25684845 TI - Implementation of internet training on posture reform of computer users in iran. AB - BACKGROUND AND PURPOSE: Musculoskeletal disorders are of common problems among computer (PC) users. Training of posture reform plays a significant role in the prevention of the emergence, progression and complications of these diseases. The present research was performed to study the effect of the Internet training on the posture reform of the Internet users working in two Iranian universities including Sistan and Baluchestan University and Islamic Azad University of Zahedan in 2014. MATERIALS AND METHOD: This study was a quasi-experimental intervention with control group and conducted in two Iranian universities including Sistan and Baluchestan University and Islamic Azad University of Zahedan. The study was done on 160 PC users in the two groups of intervention (80 people) and control (80 people). Training PowerPoint was sent to the intervention group through the Internet and a post test was given to them after 45 days. Statistical software of SPSS 19 and statistical tests of Kolmogrov, t-test, Fisher Exact test, and correlation coefficient were used for data analysis. RESULTS: After the training, the mean scores of knowledge, attitude, performance and self-efficacy in the intervention group were 24.21 +/- 1.34, 38.36 +/- 2.89, 7.59 +/- 1.16, and 45.06 +/- 4.11, respectively (P <0.001). The mean scores of knowledge in the intervention group 5.45+/-2.81 and in the control group 1.20 +/- 1.07 showed a significant change. Mean scores of attitude in the intervention group 3.60 +/- 3.59 and in the control group 0.48+/- 1.03 showed a significant change as well. Mean scores of self-efficacy in the intervention group 14.83 +/- 4.67 and in the control group 0.88 +/- 1.93 indicated a significant change and mean scores of performance in the intervention group 5.28 +/- 1.24 and in the control group 0.62 +/- 0.73 indicated a significant change (P <0.001). DISCUSSION: The results of the study showed that training through the Internet had a significant impact on the posture reform of the PC users. According to the findings observed, there was a significant relationship between the scores of self-efficacy-performance after training. Therefore, based on the findings of the study, it is suggested that Internet training to increase self-efficacy approach in the successive periods can be effective to reform the postures of PC users. PMID- 25684846 TI - Factors Affecting Journal Quality Indicator in Scopus (SCImago Journal Rank) in Obstetrics and Gynecology Journals: a Longitudinal Study (1999-2013). AB - INTRODUCTION: Awareness of the latest scientific research and publishing articles in top journals is one of the major concerns of health researchers. In this study, we first introduced top journals of obstetrics and gynecology field based on their Impact Factor (IF), Eigenfactor Score (ES) and SCImago Journal Rank (SJR) indicator indexed in Scopus databases and then the scientometric features of longitudinal changes of SJR in this field were presented. METHOD AND MATERIAL: In our analytical and bibiliometric study, we included all the journals of obstetrics and gynecology field which were indexed by Scopus from 1999 to 2013. The scientometric features in Scopus were derived from SCImago Institute and IF and ES were obtained from Journal Citation Report through the Institute for Scientific Information. Generalized Estimating Equation was used to assess the scientometric features affecting SJR. RESULT: From 256 journals reviewed, 54.2% and 41.8% were indexed in the Pubmed and the Web of Sciences, respectively. Human Reproduction Update based on the IF (5.924+/-2.542) and SJR (2.682+/-1.185), and American Journal of obstetrics and gynecology based on the ES (0.05685+/-0.00633) obtained the first rank among the other journals. Time, Index in Pubmed, H_index, Citable per Document, Cites per Document, and IF affected changes of SJR in the period of study. DISCUSSION: Our study showed a significant association between SJR and scientometric features in obstetrics and gynecology journals. According to this relationship, SJR may be an appropriate index for assessing journal quality. PMID- 25684847 TI - Real Time Processing and Transferring ECG Signal by a Mobile Phone. AB - The real-time ECG signal processing system based on mobile phones is very effective in identifying continuous ambulatory patients. It could monitor cardiovascular patients in their daily life and warns them in case of cardiac arrhythmia. An ECG signal of a patient is processed by a mobile phone with this proposed algorithm. An IIR low-pass filter is used to remove the noise and it has the 55 Hz cutoff frequency and order 3. The obtained SNR showed a desirable noise removal and it helps physicians in their diagnosis. In this paper, Hilbert transform was used and the R peaks are important component to differ normal beats from abnormal ones. The results of sensitivity and positive predictivity of algorithm are 96.97% and 95.63% respectively. If an arrhythmia occurred, 4 seconds of this signal is displayed on the mobile phone then it will be sent to a remote medical center by TCP/IP protocol. PMID- 25684848 TI - The Amount of Media and Information Literacy Among Isfahan University of Medical Sciences' Students Using Iranian Media and Information Literacy Questionnaire (IMILQ). AB - INTRODUCTION: Media and Information literacy (MIL) enables people to interpret and make informed judgments as users of information and media, as well as to become skillful creators and producers of information and media messages in their own right. The purpose of this research was to determine the amount of Media and Information Literacy among Isfahan University of Medical Sciences' students using Iranian Media and Information Literacy Questionnaire (IMILQ). METHODS: This is an applied analytical survey research in which the data were collected by a researcher made questionnaire, provided based on specialists' viewpoints and valid scientific works. Its validity and reliability were confirmed by Library and Information Sciences specialists and Cronbach's alpha (r=0.89) respectively. Statistical population consisted of all students in Isfahan University of Medical Sciences (6000 cases) and the samples were 361. Sampling method was random stratified sampling. Data were analyzed by descriptive and inferential statistics. RESULTS: The findings showed that the mean level of Media and Information Literacy among Isfahan University of Medical Sciences' students was 3.34+/-0.444 (higher than average). The highest mean was promotion of scientific degree with 3.84+/-0.975 and the lowest mean was difficulties in starting research with 2.50+/-1.08. There was significant difference between educational degree, college type and family's income and amount of Media and Information Literacy. CONCLUSION: The results showed that the students didn't have enough skills in starting the research, defining the research subject as well as confining the research subject. In general, all students and education practitioners should pay special attention to factors affecting in improving Media and Information Literacy as a main capability in using printed and electronic media. PMID- 25684849 TI - Development of hospital information systems: user participation and factors affecting it. AB - INTRODUCTION: Given the large volume of data generated in hospitals, in order to efficiently management them; using hospital information system (HIS) is critical. User participation is one of the major factors in the success of HIS that in turn leads Information needs and processes to be correctly predicted and also their commitment to the development of HIS to be augmented. The purpose of this study is to investigate the participation rate of users in different stages of HIS development as well as to identify the factors affecting it. METHOD AND MATERIALS: This is a descriptive-cross sectional study which was inducted in 2014. The study population consists of 140 HIS users (from different types of job including physicians, nurses, laboratory, radiology and HIM staffs) from Teaching Hospitals Affiliated to Urmia University of Medical Sciences. Data were collected using a self-structured questionnaire which was estimated as both reliable and valid. The data were analyzed by SPSS software descriptive statistics and analytical statistics (t-test and chi-square). RESULTS: The highest participation rate of users in the four-stage development of the HIS was related to the implementation phase (2.88) and the lowest participation rate was related to analysis (1.23). The test results showed that the rate of user participation was not satisfactory in none of the stages of development (P< 0.05). The most important factors in increasing user participation include established teamwork from end-users and the support of top managers from HIS development. CONCLUSION: According to the results obtained from the study, it seems that health care administrators must have a detailed plan for user participation prior to the development and purchase of HIS so that they identify the real needs as well as increase their commitment and motivations to develop, maintain and upgrade the system, and in this way, the success of the system will be assured. PMID- 25684850 TI - Health Based Geographic Information Systems (GIS) and their Applications. AB - Medical researches as well as the study of the Earth's surface, better still, geography are interlinked with each other; their relationship dates from antiquity. The science of Geographic Information Systems and, by extension, Geomatics engineering belongs to a discipline which is constantly developing at a global level. This sector has many applications regarding medical / epidemiological research and generally, the social sciences. Furthermore, this discipline may act as a decision making tool in the healthcare sector and it might contribute to the formulation of policies into the healthcare sector. The use of GIS so as to solve public health issues has an exponential increase and has been vital to the understanding and treatment of health problems in different geographic areas. In recent years, the use of various information technology services and software has lead health professionals to work more effectively. PMID- 25684851 TI - Muscle atrophy in intensive care unit patients. AB - INTRODUCTION: The muscle atrophy is one of the most important and frequent problems observed in patients in Intensive Care Units. The term describes the disorder in the structure and in the function of the muscle while incidence rates range from 25-90 % in patients with prolonged hospitalization. PURPOSE: This is a review containing all data related to the issue of muscle atrophy and is especially referred to its causes and risk factors. The importance of early diagnosis and early mobilization are also highlighted in the study. MATERIAL AND METHODS: a literature review was performed on valid databases such as Scopus, PubMed, Cinhal for the period 2000-2013 in English language. The following keywords were used: loss of muscle mass, ICU patients, immobilization, bed rest. RESULTS: From the review is concluded that bed rest and immobilization in order to reduce total energy costs, are the main causes for the appearance of the problem. The results of the reduction of the muscle mass mainly affect the musculoskeletal, cardiovascular and respiratory system. The administration of the cortisone, the immobility, the sepsis and hyperglycemia are included in the risk factors. The prevention is the primary therapeutic agent and this is achieved due to the early mobilization of the patients, the use of neuromuscular electrical stimulation and the avoidance of exposure to risk factors. CONCLUSIONS: The prevention of muscle atrophy is a primary goal of treatment for the patients in the ICU, because it reduces the incidence of the disease, reduces the time spent in ICU and finally improves the quality of patients' life. PMID- 25684852 TI - Effect Transformation of the Micro Electrode Recording (MER) Data to Fast Fourier Transform (FFT) for the Main Target Nucleus Determination for STN-DBS. AB - INTRODUCTION: Advanced PD stimulation of the STN reduces tremor, rigidity, and bradykinesia. Due to hemorrhagic complications the use of micro electrode recordings during DBS operation was still questioning for some of surgeons. But use micro electrodes were still the best choice for the positioning during surgery of DBS. AIM: The aim of the current study was to investigate the effect transformation of the micro electrode recording data to fast fourier transform for the main target nucleus determination. This process needs a multidisciplinary approach from neurosurgery, neurology and specialists on electrophysiology such as biophysics. CASE REPORT: We present the case of a 63 year-old male with medically intractable PD is focused on behalf of the surgical treatment. Patient had a 4-year history of progressively severe hand tremor on right side. The patient was successfully treated unilaterally with the STN DBS. PMID- 25684853 TI - Vision Loss and RNFL Thinning after Internal Carotid Arter Occlusion and Middle Cerebral Artery Infarction. AB - INTRODUCTION: Ischaemic, traumatic or neoplasmic damage to the optic chiasm, optic tract or lateral geniculate nucleus affects the retinal ganglion cell (RGC) axons, detected as reduced retinal nerve fiber layer (RNFL) thickness around the optic nerve head. We report a case of vision loss and reduced RNFL thickness after internal carotid artery (ICA) occlusion and middle cerebral artery (MCA) infarction. CASE REPORT: A 33-year-old woman with a 3-month history of vision loss in right eye and left hemiplegia. The best corrected visual acuity was 1.0 in left eye and there was no light perception in the right eye. Ocular motility, intra-ocular pressure, anterior segments were normal in the both eyes. Her fundus examinations were normal except optic atrophy in the right eye. Visual field test was not performed because of cooperation difficulties. Magnetic resonance imaging (MRI) revealed an infarction of the right MCA. Computed tomographic angiography showed right ICA occlusion. Optical coherence tomography (OCT) demonstrated 6 clock hours of RNFL thinning in the right eye. Average RNFL thickness of the right and left eyes were 53um, 96 um respectively. CONCLUSIONS: Our findings show that a relatively short period of ICA occlusion and MCA infarction can cause vision loss and thinning of the RNFL. PMID- 25684854 TI - The most influential scientists in the development of the medical informatics (3): peter leo reichertz. PMID- 25684855 TI - Controlling for Landform Age When Determining the Settlement History of the Kuril Islands. AB - Archaeological investigations of settlement patterns in dynamic landscapes can be strongly biased by the evolution of the Earth's surface. The Kuril Island volcanic arc exemplifies such a dynamic landscape, where landscape-modifying geological forces were active during settlement, including sea-level changes, tectonic emergence, volcanic eruptive processes, coastal aggradation, and dune formation. With all these ongoing processes, in this paper we seek to understand how new landscape formation in the Holocene might bias archaeological interpretations of human settlement in the Kurils. Resolving this issue is fundamental to any interpretation of human settlement history derived from the distribution and age of archaeological sites from the region. On the basis of a comparison of landform ages and earliest archaeological occupation ages on those landforms, we conclude that landform creation did not significantly bias our aggregate archaeological evidence for earliest settlement. Some sections of the archipelago have larger proportions of landform creation dates closer to archaeological evidence of settlement and undoubtedly some archaeological sites have been lost to geomorphic processes. However, comparisons between regions reveal comparable archaeological establishment patterns irrespective of geomorphic antiquity. PMID- 25684856 TI - Reciprocity in Adolescent and Caregiver Violence. AB - Over a 2-year period, with assessments every six months, the reciprocity in violent behaviors (verbal and physical) was investigated in a sample of 161 adolescents, who met the criteria for substance or alcohol abuse or dependence, and their caregivers, who participated in a clinical trial for family treatment for adolescent substance abuse. Using observed variables in a structural equation model with panel data, there was very little stability in violent behaviors across time from the perspectives of both the adolescents and caregivers. Evidence for violence reciprocity between adolescent and caregiver was demonstrated toward the end of the study period. The results are discussed in the context of previous literature about adolescent-to-parent violence. PMID- 25684857 TI - PATH OPTIMIZATION AND CONTROL OF A SHAPE MEMORY ALLOY ACTUATED CATHETER FOR ENDOCARDIAL RADIOFREQUENCY ABLATION. AB - This paper introduces a real-time path optimization and control strategy for shape memory alloy (SMA) actuated cardiac ablation catheters, potentially enabling the creation of more precise lesions with reduced procedure times and improved patient outcomes. Catheter tip locations and orientations are optimized using parallel genetic algorithms to produce continuous ablation paths with near normal tissue contact through physician-specified points. A nonlinear multivariable control strategy is presented to compensate for SMA hysteresis, bandwidth limitations, and coupling between system inputs. Simulated and experimental results demonstrate efficient generation of ablation paths and optimal reference trajectories. Closed-loop control of the SMA-actuated catheter along optimized ablation paths is validated experimentally. PMID- 25684858 TI - Medical Magic and the Church in Thirteenth-Century England. PMID- 25684859 TI - Effects of Person- and Process-Focused Feedback on Prosocial Behavior in Middle Childhood. AB - Effects of person- and process-focused feedback, parental lay theories, and prosocial self-concept on children's prosocial behavior were investigated with 143 9- and 10-year-old children who participated in a single session. Parents reported entity (person-focused) and incremental (process-focused) beliefs related to prosocial behavior. Children completed measures of prosocial self concept, then participated in a virtual online chat with child actors who asked for help with service projects. After completing the chat, children could assist with the service projects. In the first cohort, children were randomly assigned to receive person-focused, process-focused, or control feedback about sympathy. In the second cohort, with newly-recruited families, children received no feedback. When given process-focused feedback, children spent less time spent helping and worked on fewer service projects. When given no feedback, children spent less time helping when parents held incremental (process-focused) beliefs. Children with higher prosocial self-concept who received no feedback worked on more service projects. PMID- 25684860 TI - Protection from endotoxic uveitis by intravitreal Resolvin D1: involvement of lymphocytes, miRNAs, ubiquitin-proteasome, and M1/M2 macrophages. AB - This study investigated the protective effects of intravitreal Resolvin D1 (RvD1) against LPS-induced rat endotoxic uveitis (EIU). RvD1 was administered into the right eye at a single injection of 5 MUL volume containing 10-100-1000 ng/kg RvD1 1 h post-LPS injection (200 MUg, Salmonella minnesota) into thefootpad of Sprague Dawley rats. 24 h later, the eye was enucleated and examined for clinical, biochemical, and immunohistochemical evaluations. RvD1 significantly and dose dependently decreased the clinical score attributed to EIU, starting from the dose of 10 ng/kg and further decreased by 100 and 1000 ng/kg. These effects were accompanied by changes in four important determinants of the immune-inflammatory response within the eye: (i) the B and T lymphocytes, (ii) the miRNAs pattern, (iii) the ubiquitin-proteasome system (UPS), and (iv) the M1/M2 macrophage phenotype. LPS+RvD1 treated rats showed reduced presence of B and T lymphocytes and upregulation of miR-200c-3p, miR 203a-3p, miR 29b-3p, and miR 21-5p into the eye compared to the LPS alone. This was paralleled by decreases of the ubiquitin, 20S and 26S proteasome subunits, reduced presence of macrophage M1, and increased presence of macrophage M2 in the ocular tissues. Accordingly, the levels of the cytokine TNF-alpha, the chemokines MIP1-alpha and NF-kappaB were reduced. PMID- 25684861 TI - Decreased regulatory T cells in vulnerable atherosclerotic lesions: imbalance between pro- and anti-inflammatory cells in atherosclerosis. AB - Atherosclerosis is a chronic inflammatory disease of the arterial wall in which presentation of autoantigens by dendritic cells (DCs) leads to the activation of T cells. Anti-inflammatory cells like Tregs counterbalance inflammation in atherogenesis. In our study, human carotid plaque specimens were classified as stable (14) and unstable (15) according to established morphological criteria. Vessel specimens (n = 12) without any signs of atherosclerosis were used as controls. Immunohistochemical staining was performed to detect different types of DCs (S100, fascin, CD83, CD209, CD304, and CD123), proinflammatory T cells (CD3, CD4, CD8, and CD161), and anti-inflammatory Tregs (FoxP3). The following results were observed: in unstable lesions, significantly higher numbers of proinflammatory cells like DCs, T helper cells, cytotoxic T cells, and natural killer cells were detected compared to stable plaques. Additionally, there was a significantly higher expression of HLA-DR and more T cell activation (CD25, CD69) in unstable lesions. On the contrary, unstable lesions contained significantly lower numbers of Tregs. Furthermore, a significant inverse correlation between myeloid DCs and Tregs was shown. These data suggest an increased inflammatory state in vulnerable plaques resulting from an imbalance of the frequency of local pro- and anti-inflammatory immune cells. PMID- 25684862 TI - Moderate exercise training attenuates the severity of experimental rodent colitis: the importance of crosstalk between adipose tissue and skeletal muscles. AB - Although progress has been recently made in understanding of inflammatory bowel diseases (IBD), their etiology is unknown apart from several factors from adipose tissue and skeletal muscles such as cytokines, adipokines, and myokines were implicated in the pathogenesis of ulcerative colitis. We studied the effect high fat diet (HFD; cholesterol up to 70%), low-fat diet (LFD; cholesterol up to 10%), and the normal diet (total fat up to 5%) in rats with TNBS colitis forced to treadmill running exercise (5 days/week) for 6 weeks. In nonexercising HFD rats, the area of colonic damage, colonic tissue weight, the plasma IL-1beta, TNF alpha, TWEAK, and leptin levels, and the expression of IL-1beta-, TNF-alpha-, and Hif1alpha mRNAs were significantly increased and a significant fall in plasma adiponectin and irisin levels was observed as compared to LFD rats. In HFD animals, the exercise significantly accelerated the healing of colitis, raised the plasma levels of IL-6 and irisin, downregulated the expression of IL-1beta, TNF-alpha, and Hif1alpha, and significantly decreased the plasma IL-1beta, TNF alpha, TWEAK, and leptin levels. We conclude that HFD delays the healing of colitis in trained rats via decrease in CBF and plasma IL-1beta, TNF-alpha, TWEAK, and leptin levels and the release of protective irisin. PMID- 25684863 TI - Prostacyclin synthase: upregulation during renal development and in glomerular disease as well as its constitutive expression in cultured human mesangial cells. AB - Prostacyclin (PGI2) plays a critical role in nephrogenesis and renal physiology. However, our understanding of how prostacyclin release in the kidney is regulated remains poorly defined. We studied expression of prostacyclin synthase (PGIS) in developing and adult human kidneys, and also in selected pediatric renal diseases. We also examined PGI2 formation in human mesangial cells in vitro. We observed abundant expression of PGIS in the nephrogenic cortex in humans and in situ hybridization revealed an identical pattern in mice. In the normal adult kidney, PGIS-immunoreactive protein and mRNA appear to localize to mesangial fields and endothelial and smooth muscle cells of arteries and peritubular capillaries. In kidney biopsies taken from pediatric patients, enhanced expression of PGIS-immunoreactive protein was noted mainly in endothelial cells of patients with IgA-nephropathy. Cultured human mesangial cells produce primarily PGI2 and prostaglandin E2, followed by prostaglandin F2 alpha Cytokine stimulation increased PGI2 formation 24-fold. Under these conditions expression of PGIS mRNA and protein remained unaltered whereas mRNA for cyclooxygenase-2 was markedly induced. In contrast to its constitutive expression in vitro, renal expression of prostacyclin-synthase appears to be regulated both during development and in glomerular disease. Further research is needed to identify the factors involved in regulation of PGIS-expression. PMID- 25684864 TI - Understanding podocytopathy and its relevance to clinical nephrology. AB - Podocytopathies are the most common group of glomerular disorder leading to proteinuria. On the basis of pathophysiology, light microscopic and ultrastructural evaluation, the podocytopathies include minimal change disease, diffuse mesangial sclerosis, focal segmental glomerulosclerosis and collapsing glomerulopathy. The present review summarizes the basic etiopathogenesis of podocytopthies, highlights the common genetic and acquired factors in its causation, puts forth various diagnostic modalities and discusses the role of emerging agents or treatment. PMID- 25684865 TI - Incidence and profile of C3 Glomerulopathy: A single center study. AB - C3 glomerulopathy has recently been described as a distinct entity. The underlying mechanism is unregulated activation of the alternate pathway of the complement system. The most common presentation is with an acute nephritic syndrome. The diagnosis is made on immunofluoroscence by the presence of isolated or dominant C3 staining. In this retrospective study, renal biopsy data were collected from 2010 to 2013 patients with C3 glomerulopathy identified and their clinical and biochemical parameters analyzed. Out of 514 biopsies available for analysis, the incidence of C3 glomerulopathy was 1.16% (n = 6). The mean age of the presentation was 26 years and the average estimated glomerular filtration rate was 30.65 ml/min/1.73 m(2). The most common histopathological pattern was membranoproliferative glomerulonephritis (n = 4). PMID- 25684866 TI - Study of hypothalamic pituitary adrenal axis in patients of membranous nephropathy receiving modified Ponticelli regimen. AB - Pulse methyl prednisolone followed by oral prednisolone and abrupt switch to chlorambucil/cyclophosphamide (Ponticelli/modified Ponticelli regimen) is used in patients with idiopathic membranous nephropathy. This therapy where steroids are stopped abruptly is unphysiologic and expected to have hypothalamic pituitary adrenal (HPA) axis suppression; however, this has not been evaluated. A total of 13 consecutive adult patients with idiopathic membranous nephropathy who had completed modified Ponticelli regimen were studied. The regimen included administration of pulse methylprednisolone 1 g for 3 days followed by oral prednisolone 0.5 mg/kg/day for 27 days followed by oral cyclophosphamide at a dose of 2 mg/kg/day for the next month. This was repeated for three courses. Patients who had received corticosteroids prior to therapy were excluded. The HPA axis was evaluated after 1 month of completing the last course of steroid therapy. The evaluation was done using a low-dose adrenocorticotropic hormone stimulation test. A single intravenous bolus dose of synacthen (1 MUg) was given at 9.00 am and the serum cortisol levels were estimated by radioimmunoassay at 0, 30, and 60 min. A peak cortisol level of 550 nmol/L or higher was considered as normal. Mean baseline cortisol levels was 662.3 +/- 294.6 nmol/L and peak cortisol level was 767 +/- 304.4 nmol/L. A total of 6 patients (46.2%) had low basal cortisol levels, only 3 (23%) had both basal and peak cortisol levels < 550 nmol/L suggestive of HPA axis suppression. To conclude, 23% of patients had suppression of HPA axis after modified Ponticelli regimen. PMID- 25684867 TI - Comparison of vascular access use in hemodialysis patients in Isfahan in 2003 and 2013. AB - Vascular access (VA) complications are the leading cause of morbidity in the hemodialysis (HD) population and responsible for high health care costs. This study was designed to compare the profile of VA use for HD in Isfahan dialysis units in 2003 and 2013. A cross-sectional observational study was conducted between January and March 2013 on 536 HD patients in seven units. The patients data about VA type, number, survival, and demographic characteristics were collected and compared with the data collected in year 2003 on 320 patients in the same city units. The mean age of patients increased from 51 +/- 17 to 58 +/- 15 years (P < 0.001). The most common etiology of end-stage renal disease was diabetes mellitus, but the percentage increased in 2013 (P = 0.001).The use of an arteriovenous fistula (AVF) as a first dialysis access fell from 60.6% in 2003 to 35.4% in 2013 (P < 0.001). At the time of study, AVFs were used in 92.2% of patients in 2003 versus 56.5% in 2013 (P < 0.001). The 1, 2, 3 and 5 years AVF survival was 80%, 78%, 73%, and 69%, respectively in 2003 versus 79.4%, 61.2%, 47.3%, and 31.5% in 2013. The AVFs proportions decreased and the tunneled catheters proportions increased while the proportion of temporary catheters decreased in 2013 compared with 2003. PMID- 25684868 TI - Measurement of arterial stiffness in subjects with and without renal disease: Are changes in the vessel wall earlier and more sensitive markers of cardiovascular disease than intima media thickness and pulse pressure? AB - There is increased cardiovascular (CV) mortality in subjects with chronic kidney disease (CKD). Arterial stiffness in these subjects is increased when compared to a healthy population. Markers of arterial stiffness and intima media thickness (IMT) are predictors of CV mortality. The aim of this study was to investigate whether there is any difference in markers of arterial stiffness and IMT between subjects with normal renal function and those with mild renal disease. The arterial distension waveform, IMT, diameter, and brachial blood pressure were measured to calculate Young's modulus (E) and elastic modulus (Ep) in the common carotid arteries of subjects with normal kidney function (estimated glomerular filtration rate [eGFR] >90) and those mild CKD (stage 2, eGFR 89-60). Data were available for 15 patients with normal kidney function and 29 patients with mild CKD. The subjects with mild CKD were older, but other co-variables were not significantly different. Both arterial wall stiffness parameters (E and Ep), but not IMT were significantly higher in the mild CKD group. Logistic regression demonstrated that only the arterial wall stiffness parameters (Ep and E) were independently associated with mild renal disease compared with normal, in a model adjusting for sex, age and diabetes and history of cardiovascular disease (CVD). E and Ep may be early markers of CVD in subjects with mild CKD that may manifest change before other more recognized markers such as IMT and pulse pressure. PMID- 25684869 TI - Impact of killer immunoglobulin-like receptor-human leukocyte antigens ligand incompatibility among renal transplantation. AB - Killer immunoglobulin-like receptor (KIR) gene shows a high degree of polymorphism. Natural killer cell receptor gets activated once they bind to self human leukocyte antigens (HLAs) with specific ligand. KIR gene and HLA ligand incompatibility due to the presence/absence of KIR in the recipient and the corresponding HLA ligand in the allograft may impact graft survival in solid organ transplantation. This study evaluates the effect of matches between KIR genes and known HLA ligands. KIR genotypes were determined using sequence specific primer polymerase chain reaction. Presence of certain KIR in a recipient, where the donor lacked the corresponding HLA ligand was considered a mismatch. The allograft was considered matched when both KIR receptor and HLA alloantigen reveald compatibility among recipient and donor. The data revealed better survival among individuals with matched inhibitory KIR receptors and their corresponding HLA ligands (KIR2DL2/DL3-HLAC2, KIR3DL1-HLABw4). On the contrary, no adverse effect was seen for matched activating KIR receptors and their corresponding HLA ligands. One of the activating gene KIR2DS4 showed risk (P = 0.0413, odds ratio = 1.91, 95% confidence interval = 1.02-3.57) association with renal allograft rejection. We conclude that the presence of inhibitory KIR gene leads to better survival; whereas activating motifs show no significant role in renal allograft survival. PMID- 25684870 TI - Interleukin-1 gene cluster variants in hemodialysis patients with end stage renal disease: An association and meta-analysis. AB - We evaluated whether polymorphisms in interleukin (IL-1) gene cluster (IL-1 alpha [IL-1A], IL-1 beta [IL-1B], and IL-1 receptor antagonist [IL-1RN]) are associated with end stage renal disease (ESRD). A total of 258 ESRD patients and 569 ethnicity matched controls were examined for IL-1 gene cluster. These were genotyped for five single-nucleotide gene polymorphisms in the IL-1A, IL-1B and IL-1RN genes and a variable number of tandem repeats (VNTR) in the IL-1RN. The IL 1B - 3953 and IL-1RN + 8006 polymorphism frequencies were significantly different between the two groups. At IL-1B, the T allele of - 3953C/T was increased among ESRD (P = 0.0001). A logistic regression model demonstrated that two repeat (240 base pair [bp]) of the IL-1Ra VNTR polymorphism was associated with ESRD (P = 0.0001). The C/C/C/C/C/1 haplotype was more prevalent in ESRD = 0.007). No linkage disequilibrium (LD) was observed between six loci of IL-1 gene. We further conducted a meta-analysis of existing studies and found that there is a strong association of IL-1 RN VNTR 86 bp repeat polymorphism with susceptibility to ESRD (odds ratio = 2.04, 95% confidence interval = 1.48-2.82; P = 0.000). IL 1B - 5887, +8006 and the IL-1RN VNTR polymorphisms have been implicated as potential risk factors for ESRD. The meta-analysis showed a strong association of IL-1RN 86 bp VNTR polymorphism with susceptibility to ESRD. PMID- 25684871 TI - Rapidly progressive renal failure in a patient with extranodal non-Hodgkin's lymphoma. AB - A 60-year male was admitted with advanced renal failure and bilaterally enlarged kidneys. Kidney biopsy revealed diffuse interstitial infiltration by CD20 + lymphomatous cells suggestive of diffuse large B-cell, non-Hodgkin's lymphoma. Bone marrow examination was negative for malignant cells. Positron emission tomography-computed tomography showed uniformly diffuse and avid flurodeoxy glucose uptake in both kidneys, multiple hypodense areas of both lobes of liver, and axial and appendicular skeleton. Patient was treated with rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine and prednisolone, became afebrile and serum creatinine normalized. PMID- 25684872 TI - Successful induction of granulomatosis with polyangiitis with tacrolimus. AB - We report a 50-year-old female who presented with inflammatory arthritis, upper respiratory tract symptoms, and microscopic hematuria with nephrotic range proteinuria. Antineutrophil cytoplasmic antibodies (ANCA) were detectable and kidney biopsy showed pauci-immune focal necrotizing crescentic glomerulonephritis. She was treated with pulse intravenous cyclophosphamide (CYC) and prednisolone. Patient developed severe leucopenia after the first dose and subsequently had leucopenia to low dose CYC, mycophenolate mofetil and azathioprine were also tried. However, patient developed leukopenia with all the above agents. Initiation of tacrolimus (TAC) was followed by dramatic response: Proteinuria decreased, serum albumin normalized and C-ANCA and anti-PR3 ANCA assays became negative. This is the first successful case of TAC as an induction agent in a patient with GPA (ANCA associated vasculitis with renal involvement). PMID- 25684873 TI - Monoclonal gammopathy associated membranous glomerulonephritis: A rare entity. AB - A 40-year-old male presented with nephrotic syndrome. Light microscopic analysis of the renal biopsy showed thickening of the glomerular capillary wall. Immunofluorescence examination revealed granular deposition of monoclonal immunoglobulin (Ig) G3-kappa and complement C3 along the glomerular basement membrane. Electron microscopy showed subepithelial electron dense deposits, thus confirming membranous glomerulonephritis (MGN) with monoclonal gammopathy. MGN with monoclonal gammopathy is an extremely rare but distinctive entity. This patient was treated with a combination of bortezomib, thalidomide and dexamethasone and showed partial remission of his nephrotic state and dysproteinemia. PMID- 25684874 TI - Acute interstitial nephritis due to statin and its class effect. AB - Recent reports indicate that statins can cause nephrotoxicity. However, the mechanisms of nephrotoxicity remain unclear. We report a case of acute kidney injury (AKI) in a 54-year-old man following the administration of atorvastatin Renal biopsy showed acute interstitial nephritis. Atorvastatin was withdrawn and he was treated with corticosteroid following which renal function recovered. When he was rechallenged with rosuvastatin 6 months later following an episode of acute myocardial infarction, he developed AKI again indicating class effect of statin for nephrotoxicity. PMID- 25684875 TI - Recurrent lactic acidosis secondary to hand sanitizer ingestion. AB - Due to their ability to decrease the spread of infection, hand sanitizers are now ubiquitous in health care settings. We present the case of a 50-year-old woman who was admitted with acute alcohol intoxication and had near complete recovery in 12 hrs. Subsequently, she was found unresponsive on the floor of her hospital room on two separate occasions. Evaluations revealed repeatedly elevated levels of ethanol, acetone, and lactate as well as increased anion gap and hypotension, requiring intensive care unit evaluation and intubation for airway protection. During the second episode, she was found next to an empty bottle of ethanol-based hospital hand sanitizer. She confirmed ingesting hand sanitizer in order to become intoxicated. PMID- 25684876 TI - Use of diffusion-weighted magnetic resonance imaging in the management of infected renal cyst in polycystic kidney disease. PMID- 25684877 TI - Ceftazidime-induced myoclonus and encephalopathy in hemodialysis patient. PMID- 25684878 TI - S-amlodipine-induced gingival enlargement. PMID- 25684879 TI - Partnership in healthcare: What can the west learn from the delivery of pediatric cardiac care in low- and middle-income countries. PMID- 25684880 TI - Tetralogy of Fallot with subarterial ventricular septal defect: Surgical outcome in the current era. AB - BACKGROUND: Tetralogy of Fallot (TOF) with subarterial ventricular septal defect (VSD) is more common among Asians than Caucasians. Compared with the regular subaortic VSD postoperative right ventricular outflow obstruction is more common because of the sub-pulmonary extension of the defect. The objective of this study is to analyze the surgical implications and outcomes of patients with TOF - subarterial VSD in the current era. PATIENTS AND METHODS: In all, 539 consecutive operated patients with TOF from May 2005 to September 2012 were retrospectively reviewed. Eighty-five patients had subarterial VSD. Seventy-nine of these underwent intracardiac repair. Preoperative clinical, echocardiographic features, operative and postoperative variables were assessed. RESULTS: The median age at surgery was 6 years and the median weight was 14 kilograms. The male to female ratio was 1.7:1. TOF with subarterial VSD was associated with frequent use of transannular patch (74.6%). The early mortality was 2.5%. Follow up was 92% complete with a mean duration of 20 months with actuarial survival of 97.3% at 5 years. Two patients required reoperation for significant right ventricular outflow tract obstruction (RVOTO) at one year and three years, respectively. CONCLUSIONS: Intra cardiac repair for TOF with subarterial VSD has low perioperative mortality and morbidity. Transannular patch augmentation of the right ventricular outflow tract (RVOT) is required in a significant proportion of these patients. Precise suturing of the VSD patch, adequate infundibular resection and lower threshold for a transannular patch placement ensures a smooth early postoperative recovery. PMID- 25684881 TI - e-Teaching in pediatric cardiology: A paradigm shift. AB - BACKGROUND: Training of postgraduate students has traditionally been done in person in a hospital setting with hands-on training with each faculty member imparting knowledge to 2 to 4 students per year. Supplementing their practical education with online instruction could make a significant difference in standardizing pediatric cardiology education in India. OBJECTIVE: To present the rationale, methods and survey results of a live e-Teaching methodology implemented for Pediatric cardiology trainees in association with the National Board of Examinations, India. MATERIALS AND METHODS: Between March 2010 and March 2014, 310 e-classes were conducted in the Pediatric cardiac sciences by 24 e teachers. Content of the e-Learning program was based on a 2-year pediatric cardiology curriculum and included twice-weekly live online video training sessions, a library of recorded sessions and online test quizzes for the students. A total of 231 students accessed the program at various times over the 4-year period. RESULTS: In our study, requests for access to the e-lectures increased from 10/year the first year to 100/year by the fourth year with feedback surveys conveying a high satisfaction level from the students and a high need for this knowledge. The advantages of virtual live e-Learning included the fact that one teacher can teach multiple students in multiple geographic locations at the same time, obviating the issue of quality teacher shortage and the same content can be disseminated to all students undergoing specialist training so there is a national consensus on diagnostic and management approach among all trainees. Additionally, the e-classes can be recorded and replayed so they can be viewed repeatedly by the same group or new trainees. CONCLUSION: This is the first sustained use of e-Teaching in a medical super-specialty in India. We believe that e-Teaching is an innovative solution that can be applied, not just to Pediatric Cardiology as we have done, but to all branches of specialist and super-specialist medical training in India and globally. PMID- 25684882 TI - Association of temporary complete AV block and junctional ectopic tachycardia after surgery for congenital heart disease. AB - AIM: Junctional ectopic tachycardia (JET) is a postoperative complication with a mortality rate of up to 14% after surgery for congenital heart disease. This study evaluated the risk factors of JET and explored the association of postoperative temporary third degree atrioventricular (AV) block and the occurrence of JET. MATERIALS AND METHODS: Data were collected retrospectively from 1158 patients who underwent surgery for congenital heart disease. RESULTS: The overall incidence of JET was 2.8%. Temporary third degree AV block occurred in 1.6% of cases. Permanent third degree AV block requiring pacemaker implantation occurred in 1% of cases. In all, 56% of patients with JET had temporary AV block (P < 0.001), whereas no case of postoperative JET was reported in patients with permanent AV block (P = 0.56). temporary third degree AV block did not suffer from JET. CONCLUSIONS: A correlation between temporary third degree AV block and postoperative JET could be observed. The risk factors identified for JET include younger age groups at the time of surgery, longer aortic cross clamping time and surgical procedures in proximity to the AV node. PMID- 25684883 TI - Pediatric echocardiograms performed at primary centers: Diagnostic errors and missing links! AB - AIM: The present study was undertaken to assess the accuracy of pediatric echocardiograms done at non-tertiary centers and to evaluate the relationship of inaccurate interpretations with age, echocardiogram performer and complexity of congenital heart disease (CHD). MATERIALS AND METHODS: The echocardiogram reports of 182 consecutive children with CHD (5 days-16 years) who were evaluated at a non-tertiary center and subsequently referred to our center were reviewed. Age of the child at echocardiogram, echocardiogram performer and complexity of CHD were noted. These reports were compared with echocardiogram done at our center. Discrepancies were noted and categorized. To assess our own error rate, we compared our echocardiogram reports with the findings obtained during surgery (n = 172), CT scan (n = 9) or cardiac catheterization reports (n = 1). RESULTS: Most of the children at the non-tertiary center (92%) underwent echocardiogram by personnel other than a pediatric cardiologist. Overall, diagnostic errors were found in 69/182 (38%) children. Moderate and major discrepancies affecting the final management were found in 42/182 (23%) children. Discrepancies were higher when the echocardiogram was done by personnel other than pediatric cardiologist (P < 0.01) and with moderate and high complexity lesions (P = 0.0001). There was no significant difference in proportion of these discrepancies in children <= 1 year vs. >1 year of age. CONCLUSIONS: A significant number of pediatric echocardiograms done at non-tertiary centers had discrepancies that affected the management of these children. More discrepancies were seen when the echocardiogram performer was not a pediatric cardiologist and with complex CHD. PMID- 25684885 TI - Atrial septal stenting - How I do it? AB - A wide atrial communication is important to maintain hemodynamics in certain forms of congenital and acquired heart defects. In comparison to balloon septostomy or blade septostomy, atrial septal stenting provides a controlled, predictable, and long-lasting atrial communication. It often needs a prior Brockenbrough needle septal puncture to obtain a stable stent position. A stent deployed across a previously dilated and stretched oval foramen or tunnel form of oval foramen carries higher risk of embolization. This review provides technical tips to achieve a safe atrial septal stenting. Even though this is a "How to do it article," an initial discussion about the indications for atrial septal stenting is vital as the resultant size of the atrial septal communication should be tailored for each indication. PMID- 25684884 TI - Aortopathy associated with congenital heart disease: A current literature review. AB - In patients born with congenital heart disease, dilatation of the aorta is a frequent feature at presentation and during follow-up after surgical intervention. This review provides an overview of the pathologies associated with aortopathy, and discusses the current knowledge on pathophysiology, evolution, and treatment guidelines of the aortic disease associated with congenital heart defects. PMID- 25684886 TI - Challenges in the management of congenital heart disease in Vietnam: A single center experience. AB - Vietnam, in Asia, is a low middle-income country with a relatively large population to cater to. Not many know about Vietnam, or its healthcare sector especially the field of pediatric cardiology and congenital heart disease. In contrast to the developed world, congenital heart disease (CHD) is not diagnosed early. Since most of the patients visit the hospital only in later stages of the disease there are many complications during the operation and post-operatively. But during the past 5 years (from 2009), there has been major improvement in the treatment of CHD, both by intervention and surgery. At present, all kinds of CHD, both simple and complex are being successfully treated in our country. Today in Vietnam, all children under 6 years of age have health insurance coverage, under which almost all operations and catheter interventions are done free in government hospitals. It is helping many patients, especially those from the poor socioeconomic background. However, the present infrastructure is inadequate and a long waiting list has accumulated for treatment of CHD. PMID- 25684887 TI - Spontaneous expectoration of a Blalock-Taussig shunt a decade after operation. AB - An eleven-year-old boy expectorated a foreign body in cough that was identified as the prosthetic graft used for a Blalock-Taussig shunt. The shunt procedure was done 10 years earlier, and a definitive repair for tetralogy of Fallot was done a year later. He had no other symptoms, and a computed tomography (CT) angiogram did not reveal any other significant anomaly. The reason for this extremely rare event is unclear. PMID- 25684888 TI - Cardiovascular collapse during amiodarone infusion in a hemodynamically compromised child with refractory supraventricular tachycardia. AB - We describe a 7-week-old female infant who presented with refractory supraventricular tachycardia (SVT). During amiodarone infusion, she developed hypotension and cardiac arrest requiring extracorporeal membrane oxygenation (ECMO) support. After successful control of SVT using procainamide infusion, she was weaned from ECMO and discharged home on oral flecainide. We conclude that infants with acidosis, ventricular dysfunction, and prolonged refractory SVT may poorly tolerate intravenous amiodarone. PMID- 25684889 TI - Management of iatrogenic RV injury - RV packing and CPB through PTFE graft attached to femoral artery. AB - Cardiac injuries during repeat sternotomy are rare. While undergoing debridement for chronic osteomyelitis (post arterial septal defect closure), a 4-year-old girl sustained significant right ventricular (RV) injury. Bleeding from the RV was controlled by packing the injury site, which helped in maintaining stable hemodynamics till arrangements were made for instituting cardiopulmonary bypass (CPB). Since the femoral artery was very small and unsuitable for direct cannulation, a polytetrafluoroethylene (PTFE) graft sutured end-to-side to the femoral artery was used for establishing CPB. The injury was successfully repaired. PMID- 25684890 TI - Uncommon variants of the scimitar syndrome in two siblings. AB - The Scimitar syndrome is a complex association of cardiovascular and bronchopulmonary abnormalities, with the main feature a partial or total anomalous right pulmonary venous drainage to the inferior vena cava. A number of cases that lack of all the features of the typical syndrome have been described as Scimitar variant, but the incidence is rare. Familial occurrence is exceptional and limited to few cases in literature. We report two sibling diagnosed with an uncommon variant of the Scimitar syndrome. PMID- 25684891 TI - Lessons learnt from a series of hemodynamic and interventional complications during pulmonary valvotomy and device closure of ventricular septal defect. AB - In an adolescent girl with coexistent valvar pulmonary stenosis (PS) and muscular ventricular septal defect (VSD) causing right to left shunt and severe cyanosis, a series of complications were encountered during transcatheter intervention. After balloon pulmonary valvotomy (BPV) and device closure of the VSD, dynamic infundibular hypercontractility elevated the right ventricular (RV) systolic pressures leading to embolization of the device into the left ventricle. During retrieval of the device from the left ventricular outflow tract (LVOT), there was injury to the atrioventricular nodal tissue resulting in transient complete heart block. Even though the device was successfully retrieved out from the right femoral arterial access, there was a retroperitoneal hematoma causing severe anemia. A combination of dynamic infundibular obstruction, intravascular volume depletion caused by hemorrhage, low oxygen carrying capacity due to anemia, and inotropes resulted in a life-threatening hypercyanotic spell. Once this combination of suicidal hypercontractile right ventricle, anemia, and dehydration was recognized; management of the pathophysiology resulted in recovery of the patient. On a subsequent day, device closure of the VSD was complicated by unstable device position, but was finally achieved by an innovative device stabilization technique. We propose to explain the basis of hemodynamic and procedural complications, their recognition, and management. During preparatory stage before interventions in patients with multiple defects, which are linked by strong hemodynamic interdependence, meticulous planning should be done and multiple untoward events should be foreseen. While a few complications were completely unanticipated, some others could have been predicted. PMID- 25684892 TI - Abernethy syndrome, a rare cause of hypoxemia: A case report. AB - Abernethy syndrome (congenital extrahepatic portosystemic shunt (CEPS II)) as an etiology of hepatopulmonary syndrome (HPS) is uncommon. The severe hypoxemia and its consequences become incapacitating for the patient. Early shunt closure resolves hypoxemia and clinical symptomatology and prevents irreversible changes in pulmonary vasculature. PMID- 25684893 TI - A novel approach to the management of critically ill neonatal Ebstein's anomaly: Veno-venous extracorporeal membrane oxygenation to promote right ventricular recovery. AB - This is the first report of the use of veno-venous extracorporeal membrane oxygenation in a neonate with severe Ebstein's anomaly. The report suggests the use of veno-venous extracorporeal membrane oxygenation in the immediate neonatal period may be a useful therapy in severe Ebstein's anomaly. By providing adequate oxygenation independent of the patient's native pulmonary blood flow, veno-venous extracorporeal membrane oxygenation allows the pulmonary vascular resistance to decrease and may promote right ventricular recovery. PMID- 25684894 TI - Uhl's anomaly: Absence of the right ventricular myocardium. AB - We report a case of Uhl's anomaly in a 3-week-old infant that underwent central shunt placement, patent duct us arteriosus and main pulmonary artery ligation. The infant presented with room air saturation of 43%, dilated right ventricle with decreased function and dilated right atrium. Diagnosis was established with a myocardial biopsy. PMID- 25684895 TI - Hybrid closure of atrial septal defect: A modified approach. AB - A 3.5-year-old girl underwent transcatheter closure of patent ductus arteriosus in early infancy during which time her secundum atrial septal defect (ASD) was left alone. When she came for elective closure of ASD, she was found to have bilaterally blocked femoral veins. The defect was successfully closed with an Amplatzer septal occluder (ASO; St. Jude Medical, Plymouth, MN, USA) using a hybrid approach via a sub-mammary mini-thoracotomy incision without using cardiopulmonary bypass. At the end of 1-year follow-up, the child is asymptomatic with device in a stable position without any residual shunt. PMID- 25684896 TI - Double orifice tricuspid valve in an infant with partial atrioventricular septal defect. AB - Double orifice Tricuspid Valve is an extremely rare malformation with few case reports. We report such a case in an infant associated with atrioventricular septal defect. PMID- 25684897 TI - Intermittent' restrictive ventricular septal defect in Tetralogy of Fallot. AB - Ventricular septal defect (VSD) in Tetralogy of Fallot (TOF) is usually large and non-restrictive with equalization of right and left ventricular pressures. Restrictive VSD in TOF is rare. We present an unusual case of TOF with restriction to VSD caused by accessory tricuspid valve tissue that varied with respiration. PMID- 25684898 TI - Selected summaries. PMID- 25684899 TI - A report on 5(th) congress of Asia Pacific Pediatric Cardiac Society, New Delhi, India, 6-9 March 2014. AB - The 5(th) Congress of Asia Pacific Pediatric Cardiac Society was held in New Delhi from 6-9 March 2014. This article describes the journey of preparing and hosting one of the largest international events in the specialty of Pediatric Cardiac Care ever held in India. A total of 938 delegates, including 400 from outside India, participated. The scientific program was inclusive keeping in mind the diverse background of delegates from the member nations. Large numbers of research papers were presented, mostly by fellows in training. PMID- 25684900 TI - A "non-rheumatic" giant left atrium. PMID- 25684901 TI - Changing patient safety in India: Mandatory hepatitis B immunity. PMID- 25684902 TI - Cancer: Forbidden cures? PMID- 25684903 TI - Accuracy of Demirjian's 8 teeth method for age prediction in South Indian children: A comparative study. AB - INTRODUCTION: Demirjian's method of tooth development is most commonly used to assess age in individuals with emerging teeth. However, its application on numerous populations has resulted in wide variations in age estimates and consequent suggestions for the method's adaptation to the local sample. Original Demirjian's method utilized seven mandibular teeth, to which recently third molar is added so that the method can be applied on a wider age group. Furthermore, the revised method developed regression formulas for assessing age. In Indians, as these formulas resulted in underestimation, India-specific regression formulas were developed recently. The purpose of this cross-sectional study was to evaluate the accuracy and applicability of original regression formulas (Chaillet and Demirjian 2004) and India-specific regression formulas (Acharya 2010) using Demirjian's 8 teeth method in South Indian children of age groups 9-20 years. METHODS: The present study consisted of 660 randomly selected subjects (330 males and 330 females) were in the aged ranging from 9 to 20 years divided into 11 groups according to their age. Demirjian's 8 teeth method was used for staging of teeth. RESULTS: Demirjian's method underestimated the dental age (DA) by 1.66 years for boys and 1.55 years for girls and 1.61 years in total. Acharya's method over estimated DA by 0.21 years for boys and 0.85 years for girls and 0.53 years in total. The absolute accuracy was better for Acharya's method compared with Demirjian method. CONCLUSION: This study concluded that both the Demirjian and Indian regression formulas were reliable in assessing age making Demirjian's 8 teeth method applicable for South Indians. PMID- 25684904 TI - Periotest values: Its reproducibility, accuracy, and variability with hormonal influence. AB - Tooth mobility can be assessed by both subjective and objective means. The use of subjective measures may lead to bias and hence it becomes imperative to use objective means to assess tooth mobility. It has also been observed that hormonal fluctuations may have significantly influence tooth mobility. AIMS: The study was undertaken to assess the reproducibility of periotest in the assessment of tooth mobility and, to unravel the obscurity associated with the hormonal influence on tooth mobility. MATERIALS AND METHODS: 100 subjects were included in the study and were divided equally into two groups based on their age, group I (11-14 years) and group II(16-22 years). RESULTS: There was no statistical significant difference between the periotest values (PTV) taken at two different time periods with a time difference of 20 minutes. PTV of group I was found to have a statistical significant greater PTV than group II. CONCLUSION: Periotest can reliably measure tooth mobility. Tooth mobility is greater during puberty as compared to adolescence and during adolescence mobility was slightly greater in males. PMID- 25684905 TI - Comparative study of mechanical properties of direct core build-up materials. AB - BACKGROUND AND OBJECTIVES: The strength greatly influences the selection of core material because core must withstand forces due to mastication and para-function for many years. This study was conducted to evaluate certain mechanical properties of commonly used materials for direct core build-up, including visible light cured composite, polyacid modified composite, resin modified glass ionomer, high copper amalgam, and silver cermet cement. MATERIALS AND METHODS: All the materials were manipulated according to the manufacturer's recommendations and standard test specimens were prepared. A universal testing machine at different cross-head speed was used to determine all the four mechanical properties. Mean compressive strength, diametral tensile strength, flexural strength, and elastic modulus with standard deviations were calculated. Multiple comparisons of the materials were also done. RESULTS: Considerable differences in compressive strength, diametral tensile strength, and flexural strength were observed. Visible light cured composite showed relatively high compressive strength, diametral tensile strength, and flexural strength compared with the other tested materials. Amalgam showed the highest value for elastic modulus. Silver cermet showed less value for all the properties except for elastic modulus. CONCLUSIONS: Strength is one of the most important criteria for selection of a core material. Stronger materials better resist deformation and fracture provide more equitable stress distribution, greater stability, and greater probability of clinical success. PMID- 25684906 TI - Visibility of lamina dura and periodontal space on periapical radiographs and its comparison with cone beam computed tomography. AB - OBJECTIVES: To retrospectively evaluate the subjective quality of images of cone beam computed tomography and compare with periapical radiographs (PR) to determine whether lamina dura (LD) and periodontal ligament (PDL) space can be detected and reported. STUDY DESIGN: Sixty scans for anterior and posterior teeth with PR were included and scored on four point subjective scale. Scores assessed using Wilcoxon Signed rank test with the level of statistical significance P < 0.05. RESULTS: Maximum number of ties for LD in anteriors was seen in coronal section (16) and in posteriors with sagittal section (17). Assessing PDL space in anteriors, high number of ties was seen with coronal section (25) and sagittal section (21), while for posteriors showed a high number of ties in all sections. CONCLUSIONS: LD could be observed and reported in coronal section for anteriors and in sagittal section for posteriors and PDL space in all the sections for both anteriors and posteriors. PMID- 25684907 TI - Effect of advanced irrigation protocols on self-expanding Smart-Seal obturation system: A scanning electron microscopic push-out bond strength study. AB - INTRODUCTION: The aim of this study was to evaluate the effect of different final irrigation activation techniques affect the bond strength of self-expanding Smart Seal obturation at the different thirds of root canal space. MATERIALS AND METHODS: One hundred single-rooted human teeth were prepared using the Pro-Taper system to size F3, and a final irrigation regimen using 3% sodium hypochlorite and 17% EDTA was performed. The specimens were randomly divided into five groups (n = 20) according to the final irrigation activation technique used as follows: No activation (control), manual dynamic activation (MDA), CanalBrush activation, ultrasonic activation (UA) and EndoActivator. Five specimens from each group were subjected to scanning electron microscopic observation for assessment of the smear layer removal after the final irrigation procedures. All remaining roots were then obturated with Smart-Seal obturation system. A push-out test was used to measure the bond strength between the root canal dentin and Smart-Seal paste. The data obtained from the push-out test were analyzed using two-way analysis of variance and Tukey post-hoc tests. CONCLUSIONS: It was observed that UA improved the bond strength of Smart-Seal obturation in the coronal and middle third and MDA/EndoActivator in the apical third of the root canal space. PMID- 25684908 TI - Dimensional changes in height of labial alveolar bone of proclined lower incisor after lingual positioning by orthodontic treatment: A cephalometric study on adult Bengali population. AB - AIM: The study aims to know whether modern orthodontic treatment procedure do actually cause permanent bone loss at the alveolar bone crest or improve alveolar bone morphology on labial aspect of permanent incisors which are to be moved lingually. SETTINGS AND DESIGN: Manual tracings of pre and post treatment lateral cephalometric radiographs were used. MATERIAL AND METHOD: The cephalometric radiographs of 34 adult bengali subjects whose orthodontic treatment involved lingual positioning of procumbent mandibular central incisors were examined to determine the morphologic changes (bone height) in the labial alveolar bone that resulted from orthodontic treatment. RESULT: Comparison of tracings of radiographs taken before and after treatment indicated that 57.6% shows an increase in labial alveolar bone height, 30.3% shows decreased value and 12.1% shows no change with the decrease in the angulation between long axis of lower incisor and mandibular plane (GoGn). In the increase group there is a significant increase in the distance 'incisal edge to D point' whereas this dimension decreased significantly in the rest of the cases. In addition, a significant positive correlation (r = 0.56) was found between the changes in the distance from the incisal edge to the 'D' point and the alveolar bone height. But no significant relation was found between alveolar bone height and decrease in angulation of lower incisor either in the 'increase group' (r = 0.13, p > 0.05) or in the 'decrease group' (r = 0.37, p > 0.05). CONCLUSION: These findings indicate that during orthodontic treatment that involves lingual positioning of procumbent teeth but no intrusion, an increase in the amount of buccal alveolar bone may take place. PMID- 25684909 TI - Comparative assessment of Cranberry and Chlorhexidine mouthwash on streptococcal colonization among dental students: A randomized parallel clinical trial. AB - BACKGROUND: Chlorhexidine gluconate mouthwash has earned an eponym of the gold standard against oral infections, but with certain limitations. There is no effective alternative to Chlorhexidine. Cranberry is known to inhibit bacterial adhesion in various systemic infections and acts as a strong antioxidant. However, it is less explored for its dental use. Hence, there is a need to evaluate its effect against oral infections. AIM: The aim was to compare the efficacy of 0.2% Chlorhexidine mouthwash with 0.6% Cranberry mouthwash on Streptococcus mutans. MATERIALS AND METHODS: This was a double-blind, randomized parallel group clinical trial. Total sample of 50 subjects, aged 18-20 years, were randomly divided into two groups, Group A (25) and Group B (25) were given 10 mL of Chlorhexidine mouthwash and Cranberry mouthwash twice daily, respectively, for 14 days each. The plaque samples, which were taken from the subjects on 1(st) day and 14(th) day, were inoculated on blood agar plates and incubated at 37 degrees C for 24-48 h. Number of streptococcal colony forming units were calculated using digital colony counter. The data were subjected to paired t-test and unpaired t-test at a 5% significance level. RESULTS: (1) Chlorhexidine mouthwash showed 69% reduction whereas Cranberry mouthwash showed 68% reduction in S. mutans count. (2) No significant difference was seen between Chlorhexidine and Cranberry mouthwash on streptococci. CONCLUSION: Cranberry mouthwash is equally effective as Chlorhexidine mouthwash with beneficial local and systemic effect. Hence, it can be used effectively as an alternative to Chlorhexidine mouthwash. PMID- 25684910 TI - Evaluation of specifically designed implants placed in the low-density jaw bones: A clinico-radiographical study. AB - AIM: In the less dense bone, it is difficult to obtain implant anchorage. The present study was undertaken to determine the survival rate of MaestroTM implants placed in d3 and d4 bones. MATERIALS AND METHODS: Fourteen patients (10 males and 4 females) were selected for the study and implants were evaluated for posttreatment changes in at 3, 6, 9 and 12 months from implant placement. The implant probing depth and mobility were recorded 3 and 6 months after prosthesis placement. Also, peri-implant bone level was assessed at the baseline and 12 months postoperatively, followed by a statistical analysis. RESULTS: The mean plaque and gingival indices showed a reduction at repeated intervals. The mean sulcular bleeding showed a slight reduction which was statistically significant. An overall mean bone loss was observed after 12 months follow-up, which was statistically not significant. The overall survival rate of implants was reported as 92.3%. CONCLUSION: The specific implant used in the study is advantageous in the soft bone condition. CLINICAL SIGNIFICANCE: Although, there is a great evidence of implant failure in compromised jaw quality, the newer designs and approaches suggest that the poor quality is not a contraindication. PMID- 25684911 TI - Estimation of changes in nickel and chromium content in nickel-titanium and stainless steel orthodontic wires used during orthodontic treatment: An analytical and scanning electron microscopic study. AB - INTRODUCTION: The biocompatibility of orthodontic dental alloys has been investigated over the past 20 years, but the results have been inconclusive. The study compares standard 3 M Unitek nickel-titanium (NiTi) and stainless steel archwires with locally available JJ orthodontics wires. Scanning electron microscope (SEM) study of surface changes and complexometric titration to study compositional change was performed. MATERIALS AND METHODS: Ten archwires each of group 1-3 M 0.016" NiTi, group 2-JJ 0.016" NiTi, group 3-3 M 0.019" *0.025" SS and group 4-JJ SS contributed a 10 mm piece of wire for analysis prior to insertion in the patient and 6 weeks post insertion. SEM images were recorded at *2000, *4000 and *6000 magnification. The same samples were subjected to complexiometric titration using ethylenediaminetetraacetic acid to gauge the actual change in the composition. OBSERVATIONS AND RESULTS: The SEM images of all the archwires showed marked changes with deep scratches and grooves and dark pitting corrosion areas post intraoral use. 3M wires showed an uniform criss cross pattern in as received wires indicating a coating which was absent after intraoral use. There was a significant release of Nickel and Chromium from both group 3 and 4. Group 2 wires released ions significantly more than group 1 (P = 0.0). CONCLUSION: Extensive and stringent trials are required before certifying any product to be used in Orthodontics. PMID- 25684912 TI - Dental arch changes associated with rapid maxillary expansion: A retrospective model analysis study. AB - INTRODUCTION: Transverse deficiency of the maxilla is a common clinical problem in orthodontics and dentofacial orthopedics. Transverse maxillary deficiency, isolated or associated with other dentofacial deformities, results in esthetic and functional impairment giving rise to several clinical manifestations such as asymmetrical facial growth, positional and functional mandibular deviations, altered dentofacial esthetics, adverse periodontal responses, unstable dental tipping, and other functional problems. Orthopedic maxillary expansion is the preferred treatment approach to increase the maxillary transverse dimension in young patients by splitting of the mid palatal suture. This orthopedic procedure has lately been subject of renewed interest in orthodontic treatment mechanics because of its potential for increasing arch perimeter to alleviate crowding in the maxillary arch without adversely affecting facial profile. Hence, the present investigation was conducted to establish a correlation between transverse expansion and changes in the arch perimeter, arch width and arch length. METHODS: For this purpose, 10 subjects (five males, five females) were selected who had been treated by rapid maxillary expansion (RME) using hyrax rapid palatal expander followed by fixed mechanotherapy (PEA). Pretreatment (T1), postexpansion (T2), and posttreatment (T3) dental models were compared for dental changes brought about by RME treatment and its stability at the end of fixed mechanotherapy. After model measurements were made, the changes between T1-T2, T2 T3 and T1-T3 were determined for each patient. The mean difference between T1-T2, T2-T3 and T1-T3 were compared to assess the effects of RME on dental arch measurements. Results are expressed as mean +/- standard deviation and are compared by repeated measures analysis of variance followed by a post-hoc test. Arch perimeter changes are correlated with changes in arch widths at the canine, premolar and molar regions. RESULTS: The intercanine arch width increased by 2.9 mm, inter first premolar width increased by 3.2 mm, inter second premolar width increased by 4.6 mm, intermolar width increased by 4.4 mm, arch perimeter increased by 3.2 mm, arch length decreased by 1.8 mm from pretreatment to posttreatment. There is a strong positive correlation of arch perimeter with intercanine width (r (2) = 0.99), interpremolar width (r (2) = 0.99) and intermolar width (r (2) = 0.98), indicating that there is a significant increase in arch perimeter with increase in arch width at the canine, premolars and molar regions. CONCLUSION: Findings of this study demonstrate that there was a significant increase in the intercanine, inter first premolar, inter second premolar intermolar arch width and arch perimeter from pretreatment to postexpansion, which was stable at the end of fixed mechanotherapy (PEA). There was a nonsignificant decrease in arch length from pretreatment to postexpansion that further decreased nonsignificantly from postexpansion to posttreatment. PMID- 25684913 TI - Comparison of risk indicators of dental caries in children with and without cleft lip and palate deformities. AB - OBJECTIVE: To test the hypothesis that there are no differences in various risk factors of dental caries among children with cleft lip and palate when compared to non-cleft high caries risk and non-cleft caries free children. DESIGN: Seventy three children in the age range of 4-9 years comprised three groups; Group-I (n = 23, children with cleft lip and palate), Group-II (n = 25, non-cleft high caries risk children) and Group-III (n = 25, non-cleft caries free children). Various risk factors for dental caries like type of oral hygiene practice, sugar exposures/day, developmental defects of enamel, caries activity, salivary streptococci mutans levels and lactobacilli levels were evaluated and compared among the three groups of children. RESULTS: The mean deft score among Group-II children was significantly more (P < 0.01) as compared to the Group-I children. The mean deft + DMFT score among Group-I and Group-II children was comparable (P = 0.149). Developmental enamel defects were more among Group-I children as compared to Group-II and Group-III children (P < 0.01). Hypoplasia of the maxillary anterior teeth was more common among Group-I children as compared to Group-II (P < 0.05) and Group-III children (P < 0.001). The association between hypoplastic teeth and dental caries was significant (P < 0.05). The salivary acidogenic potential as evaluated by Snyder test was comparable among Group-I and Group-II children. The salivary streptococcus mutans levels in Group-I and Group II children were higher when compared to lactobacillus counts. CONCLUSION: The risk factors of dental caries among children with cleft lip and palate were more as compared to non-cleft high caries risk and non-cleft caries free children. PMID- 25684914 TI - A comparative evaluation of the blood clot, platelet-rich plasma, and platelet rich fibrin in regeneration of necrotic immature permanent teeth: A clinical study. AB - INTRODUCTION: This study was designed as a clinical trial to evaluate and compare the regenerative potential of platelet-rich fibrin (PRF), platelet-rich plasma (PRP), and blood clot in immature necrotic permanent teeth with or without associated apical periodontitis. METHODS: Access preparation was done under rubber dam isolation. Copious irrigation was done with 2.5% NaOCl and triple antibiotic paste was placed as an intracanal medicament. After 4 weeks, the cases were divided into four groups with five patients in each group. The study design had three test arms and one control arm. Group I in which mineral trioxide aggregate apexification was carried out and it was kept as control group to evaluate the regenerative potential of blood clot and platelet concentrates, Group II in which blood clot was used as scaffold in the canal, Group III in PRF was used as scaffold, and Group IV in which PRP carried on collagen was used as a scaffold. RESULTS: The clinical and radiographic evaluation after 6 and 18 months was done by two independent observers who were blinded from the groups. The scoring was done as: None score was denoted by, Fair by 1, Good by 2, and Excellent by 3. The data were then analyzed statistically by Fisher's exact test using Statistics and Data 11.1(PRP Using harvest Smart PReP2) which showed statistically significant values in Group III as compared to other Groups. CONCLUSION: PRF has huge potential to accelerate the growth characteristics in immature necrotic permanent teeth as compared to PRP and blood clot. PMID- 25684915 TI - Prevalence of early childhood caries among preschool children in Trivandrum and its association with various risk factors. AB - BACKGROUND: Early childhood caries (ECC) is a severe form of dental decay with multi-factorial origin. OBJECTIVES: The aim of this cross-sectional study was to determine the prevalence and related risk factors of ECC among preschool children residing in rural and urban areas of Trivandrum district in Kerala. METHODS: A sample size of 1329 preschool children of <60 months of age was randomly selected from rural and urban areas of Trivandrum and decayed missing filled teeth indices were recorded. A standardized questionnaire was distributed to the parents. The data were subjected to SPSS version 16 and statistically analyzed with Chi-square test. RESULTS: Prevalence of ECC in the study sample was found to be 54%. Furthermore, a positive association was obtained between ECC and age of the child, location of residence, dietary habits, and oral hygiene habits. CONCLUSION: There is an urgent need to implement preventive and curative oral health programs for preschool children in rural and urban areas. PMID- 25684916 TI - Frequency of second mesiobuccal canal in permanent maxillary first molars using the operating microscope and selective dentin removal: A clinical study. AB - PURPOSE: The aim of this study was to investigate whether the combination of operating microscope and selective dentin removal increased the frequency of second mesiobuccal (MB2) canal detection in permanent maxillary first molar teeth. MATERIALS AND METHODS: One hundred fifty permanent maxillary first molars indicated for root canal treatment were randomly selected from patients belonging to the age group of 18-45 years irrespective of gender. After access cavity preparation and location of main canals, the MB2 canal orifice was sought in all teeth with an endodontic explorer under direct vision (Stage I), then under magnification with the aid of operating microscope (Stage II) and finally with the combined use of operating microscope and selective dentin removal (Stage III). RESULTS: MB2 canals were detected in 36%, 54% and 72% of the teeth in Stages I-III, respectively. CONCLUSION: This study demonstrated that dental operating microscope when used along with adjunctive aids such as selective dentin removal/troughing and good clinical knowledge will increase the ability of dental clinician to locate MB2 canals. PMID- 25684917 TI - A comparative evaluation of root canal area increase using three different nickel titanium rotary systems: An ex vivo cone-beam computed tomographic analysis. AB - BACKGROUND AND OBJECTIVES: The present study was undertaken to compare and evaluate the area increase of root canals with ProTaper, iRaCe and Revo-S systems using cone beam computed tomography for analysis. MATERIALS AND METHODOLOGY: Forty five extracted human mandibular premolars having single canal and straight root were collected. Teeth were randomly assigned to three groups (n=15). Samples were decoronized by maintaining root length at 14 mm. Pre-instrumentation cone beam computed tomography scan was done after stabilizing the samples on wax blocks. The working length was determined at 1 mm short from the apical foramen by using a ISO 15 K-file tip protruding at apical foramen. Preparation was carried out according to the manufacturer's instructions. Finally, canals were instrumented upto 30/.06 apically for each group. After each instrumentation, root canals were irrigated with 2ml of 3% sodium hypochlorite solution followed by 2 ml of 17% EDTA solution. Final irrigation was done with 5ml of saline. Post instrumentation cone beam computed tomography scans of all samples in the 3 groups were acquired. RESULTS: Mean percentage of area increase in different thirds of the canal was highest for ProTaper followed by i-RaCe and Revo-s system which was statistically significant. INTERPRETATION AND CONCLUSION: Root canal area increase was highest for ProTaper followed by i-Race and Revo-S systems. PMID- 25684918 TI - Reconstruction of pink esthetics: The periodontal way. AB - Cosmetic procedures involving gingival reconstruction have become an integral part of current periodontal practice. The ability to cover unsightly exposed, sensitive roots and recontour soft tissue recessions have added an esthetic angle to the traditional concept of biological and functional periodontal health. The recession of the gingiva, either localized or generalized, may be associated with one or more surfaces, resulting in attachment loss and root exposure, which can lead to clinical problems such as diminished cosmetic appeal and aesthetic concern. Marginal gingival recession, therefore, can cause major functional and aesthetic problems and should not be viewed as merely a soft tissue defect, but rather as the destruction of both the soft and hard tissue. Treatment proposals for this type of defect have evolved based on the knowledge for healing the gingiva and the attachment system. This case report describes a clinical case of severe Miller Class II gingival recession treated by two stages of surgery that combined a free gingival graft and connective tissue grafting. First, a free gingival graft (FGG) was performed to obtain an adequate keratinized tissue level. Three months later, a connective tissue graft (CTG)was performed to obtain root coverage. The results indicated that the FGG allows for a gain in the keratinized tissue level and the CTG allows for root coverage with decreased recession level after 6 months. Therefore, for this type of specific gingival recession, the combined use of FGG and CTG still serves as a Gold Standard in predictable root coverage. PMID- 25684919 TI - Management of grossly destroyed endodontically treated teeth with lock and key custom modified cast post and core design: A case series. AB - The purpose of this paper is to demonstrate a more retentive custom modified lock and key design of metal cast post and core for the restoration of grossly destroyed endodontically treated molar tooth. The lock and key metal cast post consists of two parts, one in the distal canal (primary post) and the other one in mesio-lingual canal (secondary post). The primary post has a lock design, while the secondary post contains the key design, both of which interlock together. Lock and key cast post, mentioned in this report can be an effective design for the management of grossly destroyed molar teeth. PMID- 25684920 TI - Ridge split and implant placement in deficient alveolar ridge: Case report and an update. AB - Dr. Hilt Tatum 1970s introduced a method of ridge splitting or bone spreading, which over a period have been used in implant dentistry for esthetic rehabilitation and implant site preparation in cases of deficient alveolar ridges to satisfy the basic ideal need of hard tissue augmentation for functional and esthetic outcome of implant. In this case report, we describe a case of horizontal ridge augmentation using ridge split and simultaneous implant placement in esthetic maxillary premolar zone. PMID- 25684921 TI - Juvenile Nasopharyngeal Angiofibroma: Case report with review on role of imaging in diagnosis. AB - Juvenile nasopharyngeal angiofibroma is a locally aggressive benign vascular neoplasm, composed of vasogenic and myofibroblastic elements, accounts for 0.05 0.5% of all the head and neck neoplasms. There are very few case reports of nasopharyngeal angiofibroma involving the oral cavity; we report a case involving both the maxilla and mandible in a 17-year-old patient who reported with a large firm swelling on right side of face with recurrent epistaxis and headache. Magnetic resonance angiography revealed a large lobulated enhancing soft tissue mass, which was hypointense on T1-weighted image and heterogeneously hyperintense on T2-weighted image causing expansion of pterygopalatine fossa and sphenopalatine foramen with extension into the sphenoid sinus, ethmoid air cells, right nasal cavity, right infratemporal fossa and right maxillary sinus with remodeling of right zygomatic arch and part of body and ramus of mandible. It was supplied by the right external carotid artery. Patient was referred to the department of neurosurgery for further management. The diagnosis at an early stage is important because it is associated with high risk of morbidity, but advances in imaging, and surgical methods of treatment have changed the sites associated with high risk of morbidity. PMID- 25684922 TI - Hereditary sensory and autonomic neuropathy type V: Report of a rare case. AB - Hereditary sensory and autonomic neuropathy (HSAN) type V is a rare inherited disease caused by a mutation in the neurotrophic tyrosine kinase receptor, type 1 gene located on chromosome 1 (1q21-q22). It is characterized by pain insensitivity, partial anhydrosis without mental retardation and unimpaired touch and pressure sensitivity. Self-mutilation injury involving the teeth, lips, tongue, ears, eyes, nose, and fingers are invariable feature of this disorder. The purpose of this paper was to discuss the diagnosis and oral management of 18 month-old girl with HSAN type V, having typical oral manifestation of bitten tongue and auto-extraction of primary teeth. Modified bite guard was given to the patient to prevent further self-mutilating injuries to the tongue. PMID- 25684923 TI - Low dose amlodipine-induced gingival enlargement: A clinical case series. AB - Gingival enlargement sometimes has an adverse effect of certain systemic drugs such as the use of anticonvulsants, phenytoin, antihypertensive, calcium channel blockers and immunosuppressant, cyclosporine. Amlodipine, a relatively newer calcium channel blocker drugs, exhibit adverse effect of gingival enlargement in middle to older aged adults. There are very few reports of amlodipine-induced gingival enlargement at a lower dose (5 mg). In this article, three cases of amlodipine-induced gingival enlargement in the age range of 50-65 years old hypertensive patient with a lower dose of amlodipine (5 mg). PMID- 25684924 TI - Hypohidrotic ectodermal dysplasia with ankylosis of temporomandibular joint and cleft palate: A rare presentation. AB - The ectodermal dysplasias are a heterogenous group of diseases, which have one or more anomalies of the hair, teeth, nails, and sweat glands. Hypohidrotic ectodermal dysplasia (HED) is the most common type and is usually transmitted as an X-linked recessive trait. It is characterized by classical triad of hypotrichosis, anhidrosis/hypohidrosis, and hypodontia/anodontia. Here, we describe an Indian boy affected with HED and rare features including ankylosis of temporomandibular joint and cleft palate. PMID- 25684925 TI - Rhabdomyosarcoma in a pediatric patient: A rare case report. AB - Rhabdomyosarcoma (RMS), a tumor of skeletal muscle origin, is the second most common soft tissue sarcoma encountered in childhood after osteosarcoma. The common sites of occurrence are the head and neck region, genitourinary tract, retroperitoneum, and to a lesser extent, the extremities. Site predilections in the oral cavity are a soft palate, maxillary sinus and alveolus, posterior mandibular region, cheek and lip, and possibly tongue. RMS is a highly malignant tumor with extensive local invasions and early hemorrhagic and lymphatic dissemination. Despite aggressive approaches incorporating surgery, dose intensive combination chemotherapy, and radiation therapy, the outcome for patients with metastatic disease remains poor. Here, we report a case of oral RMS in a 1-year-old child and describe the clinical, radiological, histopathological, and immunohistochemical findings. PMID- 25684926 TI - Radiation-induced thumbs carcinoma due to practicing dental X-ray. AB - Dealing with diagnostic X-ray radiation may result in serious health problems, unless protection guidelines are followed. This became prevalent immediately a decade following the invention of X-ray radiation, where it had not been known that the accumulative exposure to X-ray radiation may carry huge health hazards. The reoccurrence of various fatal cancer cases compelled the concerned health authorities to develop safety standards to be followed by all X-ray clinics and technicians worldwide. This report documents the clinical case of a dental radiographer, who developed thumbs carcinoma after 15 years of practicing the profession, most likely due to his neglect of the X-ray radiation protection guidelines. PMID- 25684927 TI - Second premolar extraction: Not always a second choice. AB - Extraction is a recognized and widely accepted procedure in orthodontic treatment. The selection of teeth for orthodontic extraction is an important decision and they are modified according to the individual patient. This case report describes the management of 18-year old female patient with moderate crowding which was treated with second bicuspid extraction. At the end of treatment, patient had pleasing profile, good intercuspation, ideal overjet, and overbite. The occlusion remained stable even 3 years after orthodontic treatment. PMID- 25684928 TI - Rheumatoid arthritis affecting temporomandibular joint. AB - Rheumatoid arthritis (RA) is a chronic, systemic, autoimmune inflammatory disorder that is characterized by joint inflammation, erosive properties and symmetric multiple joint involvement. Temporomandibular joint (TMJ) is very rare to be affected in the early phase of the disease, thus posing diagnostic challenges for the dentist. Conventional radiographs fail to show the early lesions due to its limitations. More recently cone-beam computed tomography (CBCT) has been found to diagnose the early degenerative changes of TMJ and hence aid in the diagnosis of the lesions more accurately. Our case highlights the involvement of TMJ in RA and the role of advanced imaging (CBCT) in diagnosing the bony changes in the early phase of the disease. PMID- 25684929 TI - Surgical management of peripheral variant of adenomatoid odontogenic tumor: A rare case report with review. AB - The adenomatoid odontogenic tumour (AOT) is a relatively uncommon lesion constituting around 3% of all odontogenic tumours and often misdiagnosed as an odontogenic cyst. It manifests as a beningn growth which affects young individuals, with a female predeliction usually in the second decade of life, exhibiting more often in the anterior region of maxilla. The current article enumerates the clinical, radiographic and histopathological features of a rare case of extraosseous AOT with its therapeutic consideration. PMID- 25684930 TI - Odontogenic myxoma of maxilla: A review discussion with two case reports. AB - Odontogenic myxoma (OM) is a rare entity of slowly growing benign neoplasm of ectomesenchymal origin, comprising of 3-6% of all odontogenic tumors that histologically presenting spindle-shaped, stellate and round cells within loosely arranged myxomatous tissue stroma. OM originates from the dental papilla, follicle or periodontal ligament with an exclusive location in the tooth-bearing areas of the jaws, association with missing or unerupted teeth. Clinically and radiographically the reported incidence and demographic information of this tumor has wide variability. Most common clinical variant is associated with the impacted tooth and shows local invasion with destruction of adjacent structures and displacement of teeth. Radiographically, common manifestations are multilocular radiolucent areas with well-defined borders and typical soap bubble or tennis racket appearances. This paper presents two rare case reports of OM of maxilla along with review discussion. PMID- 25684931 TI - Sharp tooth induced sublingual hematoma in a patient with elevated international normalized ratio. AB - Sublingual hematoma secondary to anticoagulation is a rare fatal condition. Hemorrhagic complications of warfarin are well-known. This particular case is unique because the patient was on warfarin for the past 2 years but did not develop the sublingual hematoma. However, a trauma by an attrited sharp cusp triggered the episode of the sublingual hematoma in this patient. Being a medical emergency, patient was promptly hospitalized in cardiac care unit and managed by medical team. The patient was transfused with 2 units of fresh frozen plasma and warfarin was temporarily stopped for 4 days. Alternate day regimen of warfarin was started after 4 days, and international normalized ratio dropped to 3. In dental management, enameloplasty of the mandibular first molar tooth was done to prevent trauma and ulcer development in the floor of the mouth. The hematoma resolved, and no new hematoma formation was observed for a period of 6 months. PMID- 25684932 TI - Massive ossifying pleomorphic adenoma of the maxillary antrum: A rare presentation. AB - Pleomorphic adenoma is the most common benign neoplasm of salivary gland origin involving both major and minor glands. Though parotid is the most common site of origin, it has been reported to arise from various unusual locations. Incidence of its origin in the respiratory tract is extremely rare, and the occurrence is even lower in the maxillary sinus. We report a case of a huge antral pleomorphic adenoma in a 33-year-old male patient presented as a swelling in the maxilla which was mistaken of odontogenic origin. Histological findings showed extensive ossification and hyalinization of the stroma as a striking feature. The patient has undergone hemimaxillectomy and is in 8 months follow-up without any sign and symptom of recurrence. PMID- 25684933 TI - Gut microbiota and liver diseases. AB - Several studies revealed that gut microbiota are associated with various human diseases, e.g., metabolic diseases, allergies, gastroenterological diseases, and liver diseases. The liver can be greatly affected by changes in gut microbiota due to the entry of gut bacteria or their metabolites into the liver through the portal vein, and the liver-gut axis is important to understand the pathophysiology of several liver diseases, especially non-alcoholic fatty liver disease and hepatic encephalopathy. Moreover, gut microbiota play a significant role in the development of alcoholic liver disease and hepatocarcinogenesis. Based on these previous findings, trials using probiotics have been performed for the prevention or treatment of liver diseases. In this review, we summarize the current understanding of the changes in gut microbiota associated with various liver diseases, and we describe the therapeutic trials of probiotics for those diseases. PMID- 25684934 TI - Robotic assisted Roux-en-Y hepaticojejunostomy in a post-cholecystectomy type E2 bile duct injury. AB - Roux-en-Y hepaticojejunostomy anastomosis is the treatment of choice for common hepatic duct injury type E2. It has been performed laparoscopically with the advancement of laparoscopic skill. Recently, a telemanipulative robotic surgical system was introduced, providing laparoscopic instruments with wrist-arm technology and 3-dimensional visualization of the operative field. We present a case of 36-year-old female patient who had undergone elective cholecystectomy 2 mo ago for gall stones and had a common bile duct injury during surgery. As the stricture was old and complete it could not be tackled endoscopically. We did a laparoscopic assisted adhesiolysis followed by robotic Roux-en-Y hepaticojejunostomy. No intraoperative complications or technical problems were encountered. Postoperative period was uneventful and she was discharged on the 4th postoperative day. At follow-up, she is doing well without evidence of jaundice or cholangitis. This is the first reported case of robotic hepaticojejunostomy following common bile duct injury. The hybrid technique gives the patient benefit of laparoscopic adhesiolysis and robotic suturing. PMID- 25684936 TI - Vitamin D: a new player in non-alcoholic fatty liver disease? AB - Vitamin D through its active form 1a-25-dihydroxyvtamin D [1,25(OH)2D] is a secosteroid hormone that plays a key role in mineral metabolism. Recent years have witnessed a significant scientific interest on vitamin D and expanded its actions to include immune modulation, cell differentiation and proliferation and inflammation regulation. As our understanding of the many functions of vitamin D has grown, the presence of vitamin D deficiency has become one of the most prevalent micronutrient deficiencies worldwide. Concomitantly, non-alcoholic fatty liver disease (NAFLD) has become the most common form of chronic liver disease in western countries. NAFLD and vitamin D deficiency often coexist and epidemiologic evidence has shown that both of these conditions share several cardiometabolic risk factors. In this article we provide an overview of the epidemiology and pathophysiology linking NAFLD and vitamin D deficiency, as well as the available evidence on the clinical utility of vitamin D supplementation in NAFLD. PMID- 25684935 TI - Pancreatic cancer early detection: expanding higher-risk group with clinical and metabolomics parameters. AB - Pancreatic ductal adenocarcinoma (PDAC) is the fourth and fifth leading cause of cancer death for each gender in developed countries. With lack of effective treatment and screening scheme available for the general population, the mortality rate is expected to increase over the next several decades in contrast to the other major malignancies such as lung, breast, prostate and colorectal cancers. Endoscopic ultrasound, with its highest level of detection capacity of smaller pancreatic lesions, is the commonly employed and preferred clinical imaging-based PDAC detection method. Various molecular biomarkers have been investigated for characterization of the disease, but none are shown to be useful or validated for clinical utilization for early detection. As seen from studies of a small subset of familial or genetically high-risk PDAC groups, the higher yield and utility of imaging-based screening methods are demonstrated for these groups. Multiple recent studies on the unique cancer metabolism including PDAC, demonstrate the potential for utility of the metabolites as the discriminant markers for this disease. In order to generate an early PDAC detection screening strategy available for a wider population, we propose to expand the population of higher risk PDAC group with combination clinical and metabolomics parameters. PMID- 25684937 TI - Biological therapy in inflammatory bowel diseases: access in Central and Eastern Europe. AB - Biological drugs opened up new horizons in the management of inflammatory bowel diseases (IBD). This study focuses on access to biological therapy in IBD patients across 9 selected Central and Eastern European (CEE) countries, namely Bulgaria, the Czech Republic, Estonia, Hungary, Latvia, Lithuania, Poland, Romania and Slovakia. Literature data on the epidemiology and disease burden of IBD in CEE countries was systematically reviewed. Moreover, we provide an estimation on prevalence of IBD as well as biological treatment rates. In all countries with the exception of Romania, lower biological treatment rates were observed in ulcerative colitis (UC) compared to Crohn's disease despite the higher prevalence of UC. Great heterogeneity (up to 96-fold) was found in access to biologicals across the CEE countries. Poland, Bulgaria, Romania and the Baltic States are lagging behind Hungary, Slovakia and the Czech Republic in their access to biologicals. Variations of reimbursement policy may be one of the factors explaining the differences to a certain extent in Bulgaria, Latvia, Lithuania, and Poland, but association with other possible determinants (differences in prevalence and incidence, price of biologicals, total expenditure on health, geographical access, and cost-effectiveness results) was not proven. We assume, nevertheless, that health deterioration linked to IBD might be valued differently against other systemic inflammatory conditions in distinct countries and which may contribute to the immense diversity in the utilization of biological drugs for IBD. In conclusion, access to biologicals varies widely among CEE countries and this difference cannot be explained by epidemiological factors, drug prices or total health expenditure. Changes in reimbursement policy could contribute to better access to biologicals in some countries. PMID- 25684938 TI - Management of patients with hepatitis B in special populations. AB - The development of effective nucleos(t)ide analogs (NAs) against hepatitis B virus (HBV) has improved the outcome of patients with chronic hepatitis B (CHB). This review updates issues related to the management of CHB patients included in special populations. Entecavir (ETV) and tenofovir (TDF) represent the currently recommended first-line NAs in patients with HBV decompensated cirrhosis. The combination of HBV immunoglobulin (usually for a finite duration) and NA is considered the standard of care for prophylaxis against HBV recurrence after liver transplantation. TDF is the best choice for hemodialysis patients and in patients with chronic kidney disease with nucleoside resistance. ETV and telbivudine are the preferred options in naive renal transplant recipients and with low viremia levels, respectively. All hepatitis B surface antigen (HBsAg) positive candidates should be treated with NAs before renal transplantation to achieve undetectable HBV DNA at the time of transplantation. Conventional interferon or NAs can also be used in children, on the basis of well-established therapeutic indication. Pregnant women at high risk of perinatal transmission could be treated with lamivudine, telbivudine or TDF in the last trimester of pregnancy. HBsAg-positive patients under immunosuppression should receive NA pre emptively (regardless of HBV DNA levels) up to 12 mo after its cessation. In HBsAg negative, anti-HBc positive patients under immunosuppression, further studies are needed to form a final conclusion; however, it seems that anti-HBV prophylaxis is justified in such patients with hematological diseases and/or for those receiving rituximab-containing regimens, regardless of their anti-HBs or serum HBV DNA status. PMID- 25684939 TI - Immunohistochemical expression of SP-NK-1R-EGFR pathway and VDR in colonic inflammation and neoplasia. AB - AIM: To determine the expression of neurokinin-1 receptor (NK-1R), phosphorylated epidermal growth factor receptor (pEGFR), cyclooxygenase-2 (Cox-2), and vitamin D receptor (VDR) in normal, inflammatory bowel disease (IBD), and colorectal neoplasia tissues from Puerto Ricans. METHODS: Tissues from patients with IBD, colitis-associated colorectal cancer (CAC), sporadic dysplasia, and sporadic colorectal cancer (CRC), as well as normal controls, were identified at several centers in Puerto Rico. Archival formalin-fixed, paraffin-embedded tissues were de-identified and processed by immunohistochemistry for NK-1R, pEGFR, Cox-2, and VDR. Pictures of representative areas of each tissues diagnosis were taken and scored by three observers using a 4-point scale that assessed intensity of staining. Tissues with CAC were further analyzed by photographing representative areas of IBD and the different grades of dysplasia, in addition to the areas of cancer, within each tissue. Differences in the average age between the five patient groups were assessed with one-way analysis of variance and Tukey-Kramer multiple comparisons test. The mean scores for normal tissues and tissues with IBD, dysplasia, CRC, and CAC were calculated and statistically compared using one way analysis of variance and Dunnett's multiple comparisons test. Correlations between protein expression patterns were analyzed with the Pearson's product moment correlation coefficient. Data are presented as mean +/- SE. RESULTS: On average, patients with IBD were younger (34.60 +/- 5.81) than normal (63.20 +/- 6.13, P < 0.01), sporadic dysplasia (68.80 +/- 4.42, P < 0.01), sporadic cancer (74.80 +/- 4.91, P < 0.001), and CAC (57.50 +/- 5.11, P < 0.05) patients. NK-1R in cancer tissue (sporadic CRC, 1.73 +/- 0.34; CAC, 1.57 +/- 0.53) and sporadic dysplasia (2.00 +/- 0.45) were higher than in normal tissues (0.73 +/- 0.19). pEGFR was significantly increased in sporadic CRC (1.53 +/- 0.43) and CAC (2.25 +/- 0.47) when compared to normal tissue (0.07 +/- 0.25, P < 0.05, P < 0.001, respectively). Cox-2 was significantly increased in sporadic colorectal cancer (2.20 +/- 0.23 vs 0.80 +/- 0.37 for normal tissues, P < 0.05). In comparison to normal (2.80 +/- 0.13) and CAC (2.50 +/- 0.33) tissues, VDR was significantly decreased in sporadic dysplasia (0.00 +/- 0.00, P < 0.001 vs normal, P < 0.001 vs CAC) and sporadic CRC (0.47 +/- 0.23, P < 0.001 vs normal, P < 0.001 vs CAC). VDR levels negatively correlated with NK-1R (r = -0.48) and pEGFR (r = -0.56) in normal, IBD, sporadic dysplasia and sporadic CRC tissue, but not in CAC. CONCLUSION: Immunohistochemical NK-1R and pEGFR positivity with VDR negativity can be used to identify areas of sporadic colorectal neoplasia. VDR immunoreactivity can distinguish CAC from sporadic cancer. PMID- 25684940 TI - Beta-7 integrin controls enterocyte migration in the small intestine. AB - AIM: To hypothesize that beta-7 integrin affects cellular migration of both, lymphocytes and enterocytes. METHODS: The nucleoside analog BrdU was ip injected in beta-7-deficient mice (C57BL/6-Itgb(tmlcgn)/J) of male gender and age-matched male C57BL/J J mice (wild type) 4, 20, or 40 h before analysis. The total small intestine was isolated, dissected, and used for morphometrical studies. BrdU positive epithelial cells were numbered in at least 15 hemi-crypts per duodenum, jejunum, and ileum of each animal. The outer most BrdU-positive cell (cell(max)) was determined per hemi-crypt, numerically documented, and statistically analysed. RESULTS: Integrins containing the beta-7-chain were exclusively expressed on leukocytes. In the small intestinal mucosa of beta-7 integrin deficient mice the number of intraepithelial lymphocytes was drastically decreased. Moreover, the Peyer's patches of beta-7 integrin-deficient mice appeared hypoplastic. In beta-7 integrin-deficient mice the location of cell(max) was found in a higher position than it was the case for the controls. The difference was already detected at 4 h after BrdU application, but significantly increased with time (40 h after BrdU injection) in all small intestinal segments investigated, i.e., duodenum, jejunum, and ileum. Migration of small intestinal enterocytes was different between the experimental groups measured by cell(max) locations. CONCLUSION: The E-cadherin beta-7 integrin pathway probably controls migration of enterocytes within the small intestinal surface lining epithelial layer. PMID- 25684941 TI - Sirtuin 1 in rat orthotopic liver transplantation: an IGL-1 preservation solution approach. AB - AIM: To investigate the possible involvement of Sirtuin 1 (SIRT1) in rat orthotopic liver transplantation (OLT), when Institute Georges Lopez 1 (IGL-1) preservation solution is enriched with trimetazidine (TMZ). METHODS: Male Sprague Dawley rats were used as donors and recipients. Livers were stored in IGL-1 preservation solution for 8h at 4 degrees C, and then underwent OLT according to Kamada's cuff technique without arterialization. In another group, livers were stored in IGL-1 preservation solution supplemented with TMZ, at 10(-6) mol/L, for 8 h at 4 degrees C and then underwent OLT. Rats were sacrificed 24 h after reperfusion, and liver and plasma samples were collected. Liver injury (transaminase levels), mitochondrial damage (glutamate dehydrogenase activity) oxidative stress (malondialdehyde levels), and nicotinamide adenine dinucleotide (NAD(+)), the co-factor necessary for SIRT1 activity, were determined by biochemical methods. SIRT1 and its substrates (ac-FoxO1, ac-p53), the precursor of NAD(+), nicotinamide phosphoribosyltransferase (NAMPT), as well as the phosphorylation of adenosine monophosphate activated protein kinase (AMPK), p mTOR, p-p70S6K (direct substrate of mTOR), autophagy parameters (beclin-1, LC3B) and MAP kinases (p-p38 and p-ERK) were determined by Western blot. RESULTS: Liver grafts preserved in IGL-1 solution enriched with TMZ presented reduced liver injury and mitochondrial damage compared with those preserved in IGL-1 solution alone. In addition, livers preserved in IGL-1 + TMZ presented reduced levels of oxidative stress. This was consistent with enhanced SIRT1 protein expression and elevated SIRT1 activity, as indicated by decreased acetylation of p53 and FoxO1. The elevated SIRT1 activity in presence of TMZ can be attributed to the enhanced NAMPT protein and NAD(+)/NADH levels. Up-regulation of SIRT1 was consistent with activation of AMPK and inhibition of phosphorylation of mTOR and its direct substrate (p-p70S6K). As a consequence, autophagy mediators (beclin-1 and LC3B) were over-expressed. Furthermore, MAP kinases were regulated in livers preserved with IGL-1 + TMZ, as they were characterized by enhanced p-ERK and decreased p p38 protein expression. CONCLUSION: Our study shows that IGL-1 preservation solution enriched with TMZ protects liver grafts from the IRI associated with OLT, through SIRT1 up-regulation. PMID- 25684942 TI - Nitrite, a novel method to decrease ischemia/reperfusion injury in the rat liver. AB - AIM: To investigate whether nitrite administered prior to ischemia/reperfusion (I/R) reduces liver injury. METHODS: Thirty-six male Sprague-Dawley rats were randomized to 3 groups, including sham operated (n = 8), 45-min segmental ischemia of the left liver lobe (IR, n = 14) and ischemia/reperfusion (I/R) preceded by the administration of 480 nmol of nitrite (n = 14). Serum transaminases were measured after 4 h of reperfusion. Liver microdialysate (MD) was sampled in 30-min intervals and analyzed for glucose, lactate, pyruvate and glycerol as well as the total nitrite and nitrate (NOx). The NOx was measured in serum. RESULTS: Aspartate aminotransferase (AST) at the end of reperfusion was higher in the IR group than in the nitrite group (40 +/- 6.8 MUkat/L vs 22 +/- 2.6 MUkat/L, P = 0.022). Similarly, alanine aminotransferase (ALT) was also higher in the I/R group than in the nitrite group (34 +/- 6 MUkat vs 14 +/- 1.5 MUkat, P = 0.0045). The NOx in MD was significantly higher in the nitrite group than in the I/R group (10.1 +/- 2.9 MUmol/L vs 3.2 +/- 0.9 MUmol/L, P = 0.031) after the administration of nitrite. During ischemia, the levels decreased in both groups and then increased again during reperfusion. At the end of reperfusion, there was a tendency towards a higher NOx in the I/R group than in the nitrite group (11.6 +/- 0.7 MUmol/L vs 9.2 +/- 1.1 MUmol/L, P = 0.067). Lactate in MD was significantly higher in the IR group than in the nitrite group (3.37 +/- 0.18 mmol/L vs 2.8 +/- 0.12 mmol/L, P = 0.01) during ischemia and the first 30 min of reperfusion. During the same period, glycerol was also higher in the IRI group than in the nitrite group (464 +/- 38 MUmol/L vs 367 +/- 31 MUmol/L, P = 0.049). With respect to histology, there were more signs of tissue damage in the I/R group than in the nitrite group, and 29% of the animals in the I/R group exhibited necrosis compared with none in the nitrite group. Inducible nitric oxide synthase transcription increased between early ischemia (t = 15) and the end of reperfusion in both groups. CONCLUSION: Nitrite administered before liver ischemia in the rat liver reduces anaerobic metabolism and cell necrosis, which could be important in the clinical setting. PMID- 25684943 TI - In vitro identification of nonalcoholic fatty liver disease-related protein hnRNPM. AB - AIM: To study the formation of intracellular glyceraldehyde-derived advanced glycation end products (Glycer-AGEs) in the presence of high concentrations of fructose. METHODS: Cells of the human hepatocyte cell line Hep3B were incubated with or without fructose for five days, and the corresponding cell lysates were separated by two-dimensional gradient sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Glycer-AGEs were detected with the anti-Glycer-AGEs antibody. Furthermore, the identification of the proteins that are modified by glyceraldehyde in the presence of high concentrations of fructose was conducted using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). The protein and mRNA levels were determined by Western blotting and real-time reverse transcription PCR, respectively. RESULTS: The results of the two-dimensional gradient sodium dodecyl sulfate-polyacrylamide gel electrophoresis indicated a greater amount of Glycer-AGEs in the sample exposed to high concentrations of fructose than in the control. The detected Glycer-AGEs showed isoelectric points in the range of 8.0-9.0 and molecular weights in the range of 60-80 kDa. The heterogeneous nuclear ribonucleoprotein M (hnRNPM), which plays an important role in regulating gene expression by processing heterogeneous nuclear RNAs to form mature mRNAs, was identified as a modified protein using MALDI-TOF-MS. Increasing the concentration of fructose in the medium induced a concentration-dependent increase in the generated Glycer AGEs. Furthermore, in an experiment using glyceraldehyde, which is a precursor of Glycer-AGEs, hnRNPM was found to be more easily glycated than the other proteins. CONCLUSION: The results suggest that glyceraldehyde-modified hnRNPM alters gene expression. This change may cause adverse effects in hepatocytes and may serve as a target for therapeutic intervention. PMID- 25684944 TI - Occult infection related hepatitis B surface antigen variants showing lowered secretion capacity. AB - AIM: To elucidate the molecular mechanisms underlying hepatitis B virus (HBV) occult infection of genotype C. METHODS: A total of 10 types of hepatitis B surface antigen (HBsAg) variants from a Korean occult cohort were used. After a complete HBV genome plasmid mutated such that it does not express HBsAg and plasmid encoding, each HBsAg variant was transiently co-transfected into HuH-7 cells. The secretion capacity and intracellular expression of the HBV virions and HBsAgs in their respective variants were analyzed using real-time quantitative polymerase chain reaction assays and commercial HBsAg enzyme-linked immunosorbent assays, respectively. RESULTS: All variants exhibited lower levels of HBsAg secretion into the medium compared with the wild type. In particular, in eight of the ten variants, very low levels of HBsAg secretion that were similar to the negative control were detected. In contrast, most variants (9/10) exhibited normal virion secretion capacities comparable with, or even higher than, the wild type. This provided new insight into the intrinsic nature of occult HBV infection, which leads to HBsAg sero-negativeness but has horizontal infectivity. Furthermore, most variants generated higher reactive oxidative species production than the wild type. This finding provides potential links between occult HBV infection and liver disease progression. CONCLUSION: The presently obtained data indicate that deficiency in the secretion capacity of HBsAg variants may have a pivotal function in the occult infections of HBV genotype C. PMID- 25684945 TI - Overexpression of B7-H3 augments anti-apoptosis of colorectal cancer cells by Jak2-STAT3. AB - AIM: To investigate the role of the overexpression of B7-H3 in apoptosis in colorectal cancer cell lines and the underlying molecular mechanisms. METHODS: SW620 cells that highly overexpressed B7-H3 (SW620-B7-H3-EGFP) and HCT8 cells stably transfected with B7-H3 shRNA (HCT8-shB7-H3) were previously constructed in our laboratory. Cells transfected with pIRES2-EGFP were used as negative controls (SW620-NC and HCT8-NC). Real-time PCR and western blotting analysis were used to detect the mRNA and protein expressions of the apoptosis regulator proteins Bcl 2, Bcl-xl and Bax. A cell proliferation assay was used to evaluate the survival rate and drug sensitivity of the cells. The effect of drug resistance was detected by a cell cycle assay. Active caspase-3 western blotting was used to reflect the anti-apoptotic ability of cells. Western blotting was also performed to determine the expression of proteins associated with the Jak2-STAT3 signaling pathway and the apoptosis regulator proteins after the treatment with AG490, a Jak2 specific inhibitor, in B7-H3 overexpressing cells. The data were analyzed by GraphPad Prism 6 using a non-paired t-test. RESULTS: Whether by overexpression in SW620 cells or downregulation in HCT8, B7-H3 significantly affected the expression of anti- and pro-apoptotic proteins, at both the transcriptional and translational levels, compared with the negative control (P < 0.05). A cell proliferation assay revealed that B7-H3 overexpression increased the drug resistance of cells and resulted in a higher survival rate (P < 0.05). In addition, the results of cell cycle and active caspase-3 western blotting proved that B7-H3 overexpression inhibited apoptosis in colorectal cancer cell lines (P < 0.05). B7-H3 overexpression improved Jak2 and STAT3 phosphorylation and, in turn, increased the expression of the downstream anti-apoptotic proteins B-cell CLL/lymphoma 2 (Bcl-2) and Bcl-xl, based on western blotting (P < 0.05). After treating B7-H3 overexpressing cells with the Jak2-specific inhibitor AG490, the phosphorylation of Jak2 and STAT3, and the expression of Bcl-2 and Bcl-xl, decreased accordingly (P < 0.05). This finding suggested that the Jak2-STAT3 pathway is involved in the mechanism mediating the anti-apoptotic ability of B7 H3. CONCLUSION: The overexpression of B7-H3 induces resistance to apoptosis in colorectal cancer cell lines by upregulating the Jak2-STAT3 signaling pathway, potentially providing new approaches to the treatment of colorectal cancer. PMID- 25684946 TI - Overexpression of Csk-binding protein decreases growth, invasion, and migration of esophageal carcinoma cells by controlling Src activation. AB - AIM: To investigate the mechanisms by which Csk-binding protein (CBP) inhibits tumor progression in esophageal carcinoma. METHODS: A CBP overexpressing esophageal carcinoma cell line (TE-1) was established. The growth, invasion, and migration of CBP-TE-1 cells, as well as the expression of Src were then determined and compared with those in normal TE-1 cells. RESULTS: The expression of Src was decreased by the overexpression of CBP in TE-1 cells. The growth, invasion, and migration of TE-1 cells were decreased by the overexpression of CBP. CONCLUSION: This study indicates that CBP may decrease the metastasis of esophageal carcinoma by inhibiting the activation of Src. CBP may be a potential tumor suppressor and targeting the CBP gene may be an alternative strategy for the development of therapies for esophageal carcinoma. PMID- 25684947 TI - New parameter in diagnosis of acute appendicitis: platelet distribution width. AB - AIM: To investigate the diagnostic accuracy of the mean platelet volume and platelet distribution width in acute appendicitis. METHODS: This retrospective, case-controlled study compared 295 patients with acute appendicitis (Group I, 100 patients with other intra-abdominal infections (Group II), and 100 healthy individuals (Group III) between January 2012 and January 2013. The age, gender, and white blood cell count, neutrophil percentage, mean platelet volume, and platelet distribution width values from blood samples were compared among the groups. Statistical analyses were performed using SPSS for Windows 21.0 software. In addition, the sensitivity, specificity, positive and negative predictive values and likelihood ratios, and diagnostic accuracy were calculated. RESULTS: The mean ages of patients were 29.9 +/- 12.0 years for Group I, 31.5 +/- 14.0 years for Group II, and 30.4 +/- 13.0 years for Group III. Demographic features such as age and gender were not significantly different among the groups. White blood cell count, neutrophil percentage and platelet distribution width were significantly higher in Group I compared to groups II and III (P < 0.05). Diagnostically, the sensitivity, specificity and diagnostic accuracy were 73.1%, 94.0%, and 78% for white blood cell count, 70.0%, 96.0%, and 76.0% for neutrophil percentage, 29.5%, 49.0%, and 34.0% for mean platelet volume, and 97.1%, 93.0%, and 96.0% for platelet distribution width, respectively. The highest diagnostic accuracy detected was for platelet distribution width between Group I and Group III (P < 0.01). CONCLUSION: Platelet distribution width analysis can be used for diagnosis of acute appendicitis without requiring additional tests, thus reducing the cost and loss of time. PMID- 25684948 TI - Digitally reinforced hematoxylin-eosin polarization technique in diagnosis of rectal amyloidosis. AB - AIM: To investigate the efficacy of the digitally reinforced hematoxylin-eosin polarization (DRHEP) technique for detection of amyloidosis in rectal biopsies. METHODS: One hundred hematoxylin-eosin (HE) stained rectal biopsies with Congo red (CR)-positive amyloid depositions and 50 control cases with CR-negative amyloid-mimicking areas were scanned blinded to the CR results for amyloid depositions under both bright and polarized light, and digitally photographed using the DRHEP technique, to accentuate the faint birefringence observed in HE slides under polarization. The results of DRHEP and HE evaluation were statistically correlated with CR polarization results with respect to presence and localization of amyloid deposits as well as amyloid types. RESULTS: Amyloid deposits showed yellowish-green birefringence by DRHEP, which allowed identification of amyloidosis in 41 HE-unsuspected cases (P = 0.016), 31 of which only had vascular deposits. True positivity was higher, and false negativity and positivity were lower by DRHEP, compared to evaluation by HE (69%, 31%, and 0.8% vs 33%, 67%, and 33%, respectively; P < 0.0001). The sensitivity, specificity, accuracy, and positive and negative predictive values for DRHEP were 69%, 98%, 78.6%, 98.5%, and 61.25%, respectively. Reasons for DRHEP false negativity were presence of extensive background birefringence in 12 cases, absence of CR birefringent vessel in 3 cases, and missing of the tiny deposits in 9 cases, which could be improved by experience, especially in the latter case. No correlation was found between age, gender, sites of deposits, or amyloid types. CONCLUSION: The DRHEP technique improves diagnostic accuracy when used as an adjunct or a prior step to CR staining, especially for cases with limited tissues for further analysis. PMID- 25684949 TI - Fibroblast growth factor receptor 4 protein expression and clinicopathological features in gastric cancer. AB - AIM: To investigate fibroblast growth factor receptor 4 (FGFR4) protein expression in Chinese patients with resectable gastric cancer (GC) and the association with clinicopathological characteristics and survival. METHODS: One hundred and seventy-five GC patients who underwent curative surgical procedures were enrolled in this study. The protein expression of FGFR4 in formalin-fixed, paraffin-embedded (FFPE) GC tissues was determined by immunohistochemical (IHC) analysis. Patient clinicopathological data and survival information were also collected and chi(2) statistical analysis was performed to analyze FGFR4 protein expression in the subgroups with differing clinicopathological characteristics including; gender, age, tumor location, differentiation, tumor-node-metastasis stage, macroscopic type, depth of invasion, lymph node metastases, distant metastasis, neural invasion and vascular invasion. Furthermore, some common molecular markers of GC in our cancer center, including p53, p27, topoisomerase IIalpha (Topo IIalpha) were also determined by IHC and their association with FGFR4 protein expression evaluated. The probability of survival for different subgroups with different clinicopathological characteristics was calculated using the Kaplan-Meier method and survival curves plotted using the log rank test. RESULTS: Seventy seven cases (44%) were found to have high expression of FGFR4 protein. Significantly different FGFR4 expression was observed between gastric cancers with differing expression of Topo IIalpha (log rank chi(2) = 9.4760, P = 0.0236). No significant differences were observed between subgroups defined by any of the other clinicopathological characteristics. The median survival time of the FGFR4 high expression (77 cases) and low expression groups (98 cases) was 27 mo and 39 mo, respectively. The five-year survival rates and median survival times of gastric cancers with high FGFR4 expression were worse than those with low expression (30.8% vs 39.2%, 27 mo vs 39 mo), respectively, however, no significant difference was observed in survival time (log rank chi(2) = 1.0477, P = 0.3060). Survival analysis revealed that high expression of FGFR4 was a predictor of poor outcome in GC patients if the tumor was small (less than or equal to 3 cm in size) (log rank chi(2) = 5.5033, P = 0.0190), well differentiated (log rank chi(2) = 7.9757, P = 0.0047), and of T1 or T2 stage invasion depth (log rank chi(2) = 4.8827, P = 0.0271). CONCLUSION: Our results suggest that high tumor expression of FGFR4 protein is not an independent risk factor for GC cancer initiation, but is a useful prognostic marker for GC patients when the tumor is relatively small, well differentiated, or in the early stages of invasion. PMID- 25684950 TI - Retrospective analysis of extra-gastrointestinal stromal tumors. AB - AIM: To investigate the clinicopathologic features of patients with extra gastrointestinal stromal tumors (EGISTs) in South Korea. METHODS: A total of 51 patients with an EGIST were identified. The clinicopathologic features, including sex, age, location, tumor size, histology, mitotic rate, immunohistochemical features, genetic status and survival data, were analyzed. RESULTS: The median age was 55 years (range: 29-80 years), and male:female ratio was 1:1.04. The most common site was in the mesentery (n = 15) followed by the retroperitoneum (n = 13) and omentum (n = 8). The median tumor size was 9.0 cm (range: 2.6-30.0 cm) and the median mitotic rate was 5.0/50HPF. (1/50 - 185/50). KIT was analyzed in 16, which revealed 10 cases with wild-type KIT and 6 cases with an exon 11 mutation. Among 51 patients, 31 patients had undergone surgery, and 10 had unresectable disease and had taken palliative imatinib, which resulted in 22.7 mo of progression-free survival. Of the patients who had undergone surgery, 18 did not take adjuvant imatinib, and 8 of these were categorized as "high risk" according to the risk criteria. However, the relapse-free survival was not different (P = 0.157) between two groups. CONCLUSION: Because the biologic behaviors of GISTs differ according to the location of the tumor, a more stratified strategy is required for managing EGISTs including incorporation of molecular features. PMID- 25684951 TI - Tumor regression grades: potential outcome predictor of locally advanced rectal adenocarcinoma after preoperative radiotherapy. AB - AIM: To analyze tumor regression grade (TRG) for prognosis of locally advanced rectal adenocarcinoma (LARA) treated with preoperative radiotherapy. METHODS: One hundred and ninety patients with clinical stage II/III LARA were studied. All patients underwent radical surgery (between 2004 and 2010) after 30-Gy/10 fraction preoperative radiotherapy (pre-RT). All 190 patients received a short course of pre-RT and were reassessed for disease recurrence and survival; the slides of surgical specimens were reviewed and classified according to Mandard TRG. We compared patients with good response (Mandard TRG1 or TRG2) vs patients with bad/poor response (Mandard TRG3-5). Outcomes evaluated were 5-year overall survival (OS), 5-year disease-free survival (DFS), and local, distant and mixed recurrence. Fisher's exact test or chi(2) test, log-rank test and proportional hazards regression analysis were used to calculate the probability that Mandard TRG was associated with patient outcomes. RESULTS: One hundred and sixty-six of 190 patients (87.4%) were identified as Mandard bad responders (TRG3-5). High Mandard grade was correlated with tumor height (41.7% < 6 cm vs 58.3% >= 6 cm, P = 0.050), ypT stage (75% ypT0-2 vs 25% ypT3-4, P = 0.000), and ypN stage (75% ypN0 vs 25% ypN1, P = 0.031). In univariate survival analysis, Mandard grade bad responders had significantly worse OS and DFS than good responders (TRG1/2) (OS, 83.1% vs 96.4%, P = 0.000; DFS, 72.3% vs 92.0%, P = 0.002). In multivariate survival analysis, Mandard bad responders had significantly worse DFS than Mandard good responders (DFS 3.8 years (95%CI: 1.2-12.2 years, P = 0.026). CONCLUSION: Mandard grade good responders had a favorable prognosis. TRG may be a potential predictor for DFS in LARA after pre-RT. PMID- 25684952 TI - Prediction of synchronous colorectal cancers by computed tomography in subjects receiving an incomplete colonoscopy: a single-center study. AB - AIM: To assess the value of computed tomography (CT) for diagnosis of synchronous colorectal cancers (SCRCs) involving incomplete colonoscopy. METHODS: A total of 2123 cases of colorectal cancer (CRC) were reviewed and divided into two groups according to whether a complete or incomplete colonoscopy was performed. CT results and final histological findings were compared to calculate the sensitivity and specificity associated with CT for detection of SCRCs following complete vs incomplete colonoscopy. Factors affecting the CT detection were also analyzed. RESULTS: Three hundred and seventy-four CRC patients underwent incomplete colonoscopy and 1749 received complete colonoscopy. Fifty-six cases of SCRCs were identified by CT, and 36 were missed. In the incomplete colonoscopy group, the sensitivity and specificity of CT were 44.8% and 93.6%, respectively. The positive and negative predictive values were 23.6% and 95.0%, respectively. In contrast, the sensitivity and specificity of CT for the complete colonoscopy group were 68.3% and 97.0%, while the positive and negative predictive values were 22.2% and 98.7%, respectively. In both groups, the mean maximum dimension of the concurrent cancers identified in the CT-negative cases was shorter than in the CT-positive cases (incomplete group: P = 0.02; complete group: P < 0.01) Topographical proximity to synchronous cancers was identified as a risk factor for missed diagnosis (P = 0.03). CONCLUSION: CT has limited sensitivity in detecting SCRCs in patients receiving incomplete colonoscopy. Patients with risk factors and negative CT results should be closely examined and monitored. PMID- 25684953 TI - Prognostic factors and survival in patients with gastric stump cancer. AB - AIM: To elucidate the clinicopathological characteristics and prognostic factors of gastric stump cancer (GSC). METHODS: The clinical data for 92 patients with GSC were collected at Fudan University Shanghai Cancer Center. The prognostic factors were analyzed with Cox proportional hazard models. RESULTS: GSC tended to occur within 25 years following the primary surgery, when the initial disease is benign, whereas it primarily occurred within the first 15 years post-operation for gastric cancer. Patients with regular follow-up after primary surgery had a better survival rate. The multivariate Cox regression analysis revealed that Borrmann type I/II (HR = 3.165, 95%CI: 1.055-9.500, P = 0.040) and radical resection (HR = 1.780, 95%CI: 1.061-2.987, P = 0.029) were independent prognostic factors for GSC. The overall 1-, 3-, and 5-year survival rates of the 92 patients were 78.3%, 45.6% and 27.6%, respectively. The 1-, 3-, and 5-year survival rates of those undergoing radical resection were 79.3%, 52.2%, and 37.8%, respectively. The 5-year survival rates for stages I, II, III, and IV were 85.7%, 47.4%, 16.0%, and 13.3%, respectively (P = 0.005). CONCLUSION: The appearance of GSC occurs sooner in patients with primary malignant cancer than in patients with a primary benign disease. Therefore, close follow-up is necessary. The overall survival of patients with GSC is poor, and curative resection can improve their prognosis. PMID- 25684954 TI - Application of air insufflation to prevent clinical pancreatic fistula after pancreaticoduodenectomy. AB - AIM: To introduce an air insufflation procedure and to investigate the effectiveness of air insufflation in preventing pancreatic fistula (PF). METHODS: From March 2010 to August 2013, a total of 185 patients underwent pancreaticoduodenectomy (PD) at our institution, and 74 patients were not involved in this study for various reasons. The clinical outcomes of 111 patients were retrospectively analyzed. The air insufflation test was performed in 46 patients to investigate the efficacy of the pancreaticojejunal anastomosis during surgery, and 65 patients who did not receive the air insufflation test served as controls. Preoperative assessments and intraoperative outcomes were compared between the 2 groups. Univariate and multivariate analyses were performed to identify the risk factors for PF. RESULTS: The two patient groups had similar baseline demographics, preoperative assessments, operative factors, pancreatic factors and pathological results. The overall mortality, morbidity, and PF rates were 1.8%, 48.6%, and 26.1%, respectively. No significant differences were observed in either morbidity or mortality between the two groups. The rate of clinical PF (grade B and grade C PF) was significantly lower in the air insufflation test group, compared with the non-air insufflation test group (6.5% vs 23.1%, P = 0.02). Univariate analysis identified the following parameters as risk factors related to clinical PF: estimated blood loss; pancreatic duct diameter <= 3 mm; invagination anastomosis technique; and not undergoing air insufflation test. By further analyzing these variables with multivariate logistic regression, estimated blood loss, pancreatic duct diameter <= 3 mm and not undergoing air insufflation test were demonstrated to be independent risk factors. CONCLUSION: Performing an air insufflation test could significantly reduce the occurrence of clinical PF after PD. Not performing an air insufflation test was an independent risk factor for clinical PF. PMID- 25684955 TI - Effects of oral tacrolimus as a rapid induction therapy in ulcerative colitis. AB - AIM: To determine the efficacy and safety of rapid induction therapy with oral tacrolimus without a meal in steroid-refractory ulcerative colitis (UC) patients. METHODS: This was a prospective, multicenter, observational study. Between May 2010 and August 2012, 49 steroid-refractory UC patients (55 flare-ups) were consecutively enrolled. All patients were treated with oral tacrolimus without a meal at an initial dose of 0.1 mg/kg per day. The dose was adjusted to maintain trough whole-blood levels of 10-15 ng/mL for the first 2 wk. Induction of remission at 2 and 4 wk after tacrolimus treatment initiation was evaluated using Lichtiger's clinical activity index (CAI). RESULTS: The mean CAI was 12.6 +/- 3.6 at onset. Within the first 7 d, 93.5% of patients maintained high trough levels (10-15 ng/mL). The CAI significantly decreased beginning 2 d after treatment initiation. At 2 wk, 73.1% of patients experienced clinical responses. After tacrolimus initiation, 31.4% and 75.6% of patients achieved clinical remission at 2 and 4 wk, respectively. Treatment was well tolerated. CONCLUSION: Rapid induction therapy with oral tacrolimus shortened the time to achievement of appropriate trough levels and demonstrated a high remission rate 28 d after treatment initiation. Rapid induction therapy with oral tacrolimus appears to be a useful therapy for the treatment of refractory UC. PMID- 25684956 TI - Assessing cultural competency skills in gastroenterology fellowship training. AB - AIM: To assess and teach cultural competency skills at the fellowship training level through the use of objective structured clinical examinations (OSCEs). METHODS: We revised four scenarios to infuse a specific focus on cross-cultural care, and to render them appropriate for gastroenterology fellows. Three are discussed here: (1) Poor Health Literacy; (2) Disclosing/Apologizing for a Complication to a Patient Who Mistrusts the Healthcare System; and (3) Breaking Bad News to a Fatalistic Patient. A fourth case emphasizing shared decision making will be described elsewhere. Four stations were completed by fellows and observed live by four faculty members, and the fellows' performance was assessed. RESULTS: Eleven fellows from four programs participated in the four OSCE. In the "Poor Health Literacy" case, 18% (2/11) of participants recognized that the standardized patient (SP) had below-basic health literacy. None successfully evaluated the SP's reading skills in a culturally-sensitive manner. In "Disclosing/Apologizing for a Complication", 4/11 (36%) personally apologized for the complication. 1/11 recognized the SP's mistrust of the medical system. With "Breaking Bad News", 27% (3/11) explored the patient's values to identify her fatalistic beliefs. CONCLUSION: OSCEs can be used to assess deficiencies in culturally-competent care at the fellowship level. OSCEs also afford fellowships the opportunity to inform future training curricula. PMID- 25684957 TI - Snapshot of an integrated psychosocial gastroenterology service. AB - AIM: To characterize the patients utilizing a gastroenterology behavioral medicine service and examine the effect of treatment on health care utilization. METHODS: Patients were referred by their gastroenterologists for psychological treatment during a 15 mo period. Patients seen for an intake with a psychologist completed the Brief Symptom Inventory (BSI) and a checklist of psychosocial concerns. A subset of patients with functional bowel disorders also completed a disease specific quality of life measure. Chart review was conducted to obtain information on type and frequency of sessions with the psychologist, the number of outpatient gastroenterology visits, and number of gastroenterology-related medical procedures during the 6 mo following psychological intake. RESULTS: Of 259 patients referred for treatment, 118 (46%) completed an intake with a psychologist. Diagnoses included: irritable bowel syndrome (42%), functional dyspepsia (20%), inflammatory bowel diseases (20%), esophageal symptoms (10%), and "other" (8%). Demographic variables and disease type did not differentiate between those who did and did not schedule an intake. Mean t-scores for the BSI global score index and the depression, anxiety, and somatization subscales fell below the cutoff for clinical significance (t = 63). Treatments were predominantly gut-directed hypnosis (48%) and cognitive behavioral therapy (44%). Average length of treatment was 4 sessions. Among functional gastrointestinal (GI) patients, those patients who initiated treatment received significantly fewer GI-related medical procedures during the 6 mo following the referral than patients who did not schedule an intake [t (197) = 2.69, P < 0.01]. CONCLUSION: Patients are receptive to psychological interventions for GI conditions and there is preliminary evidence that treatment can decrease health-care utilization among patients with functional GI conditions. PMID- 25684958 TI - Measures of patient radiation exposure during endoscopic retrograde cholangiography: beyond fluoroscopy time. AB - AIM: To determine whether fluoroscope time is a good predictor of patient radiation exposure during endoscopic retrograde cholangiopancreatography. METHODS: This is a prospective observational study of consecutive patients undergoing endoscopic retrograde cholangiopancreatography in a tertiary care setting. Data related to radiation exposure were collected. The following measures were obtained: Fluoroscopy time (FT), dose area product (DAP) and dose at reference point (DOSERP). Coefficients of determination were calculated to analyze the correlation between FT, DAP and DOSRP. Agreement between FT and DAP/DOSRP was assessed using Bland Altman plots. RESULTS: Four hundred sixty three data sets were obtained. Fluoroscopy time average was 7.3 min. Fluoroscopy related radiation accounted for 86% of the total DAP while acquisition films related radiation accounted for 14% of the DAP. For any given FT there are wide ranges of DAP and DOSERP and the variability in both increases as fluoroscopy time increases. The coefficient of determination (R(2)) on the non transformed data for DAP and DOSERP versus FT were respectively 0.416 and 0.554. While fluoroscopy use was the largest contributor to patient radiation exposure during endoscopic retrograde cholangiography (ERCP), there is a wide variability in DAP and DOSERP that is not accounted for by FT. DAP and DOSERP increase in variability as FT increases. This translates into poor accuracy of FT in predicting DAP and DOSERP at higher radiation doses. CONCLUSION: DAP and DOSERP in addition to FT should be adopted as new ERCP quality measures to estimate patient radiation exposure. PMID- 25684959 TI - Significance of low level infliximab in the absence of anti-infliximab antibodies. AB - AIM: To evaluate the prevalence of double negative (DN) sera and the mechanisms responsible for DN status. METHODS: Sera of inflammatory bowel disease patients treated with infliximab (IFX) were tested for drug/antibodies to infliximab (ATI) trough levels and the proportion of DN results was compared between a commercially available double antigen ELISA (with labeled IFX as the detection antibody) and an anti-lambda ELISA (with anti-human lambda chain detection antibody). Repeat testing with lower than customary serum dilution (1:10) was performed. Patients with DN status were matched with IFX+/ATI- controls and were followed-up for subsequent development of non-transient ATI to investigate if DN status precedes ATI. RESULTS: Of 67 sera obtained at time of loss of response, only 6/67 (9%) were DN by anti-lambda ELISA compared to 27/67 (40%) with double antigen ELISA (P < 0.001, Fisher's Exact test). Of the latter 27 sera, 22% were also DN by anti-lambda ELISA, whereas 44% were actually IFX positive (IFX+ATI-), 30% were ATI positive (IFX-ATI+) and 4% were double positive (IFX+ATI+). Re testing using a 1:10 dilution converted most DN results into IFX+ and /or ATI+ status. Patients with DN status had shorter survival free of non-transient ATI compared with matched controls (log rank test, P < 0.001). In 9/30 (30%) of these patients, non transient ATI occurred before and after the event at which the DN serum was obtained, supporting the view that a DN result may represent a particular time-point along the two curves of ATI titer rise and infliximab drug level decline. CONCLUSION: DN status may result from false negative detection of IFX or ATI by double antigen ELISA, suggesting a transitional state of low-level immunogenicity, rather than non-immunological clearance. PMID- 25684961 TI - Acute fatty liver of pregnancy: over six months follow-up study of twenty-five patients. AB - AIM: To evaluate the prognosis of patients with acute fatty liver of pregnancy (AFLP) 6 mo or longer after discharge. METHODS: The records of pregnant patients diagnosed with AFLP at Beijing Ditan Hospital over a 16-year period were reviewed in November 2012. Patients were monitored using abdominal ultrasound, liver and kidney functions, and routine blood examination. RESULTS: A total of 42 patients were diagnosed with AFLP during the study period, and 25 were followed. The mean follow-up duration was 54.5 mo (range: 6.5-181 mo). All patients were in good physical condition, but one patient had gestational diabetes. The renal and liver functions normalized in all patients after recovery, including in those with pre existing liver or kidney failure. The ultrasound findings were normal in 12 patients, an increasingly coarsened echo-pattern and increased echogenicity of the liver in 10 patients, and mild to moderate fatty liver infiltration in 3 patients. Cirrhosis or liver nodules were not observed in any patient. CONCLUSION: Acute liver failure and acute renal failure in AFLP patients is reversible. Patients do not require any specific long-term follow-up after recovery from AFLP if their liver function tests have normalized and they remain well. PMID- 25684960 TI - Human cytomegalovirus and Epstein-Barr virus infection in inflammatory bowel disease: need for mucosal viral load measurement. AB - AIM: To evaluate the best diagnostic technique and risk factors of the human Cytomegalovirus (HCMV) and Epstein-Barr virus (EBV) infection in inflammatory bowel disease (IBD). METHODS: A cohort of 40 IBD patients (17 refractory) and 40 controls underwent peripheral blood and endoscopic colonic mucosal sample harvest. Viral infection was assessed by quantitative real-time polymerase chain reaction and immunohistochemistry, and correlations with clinical and endoscopic indexes of activity, and risk factors were investigated. RESULTS: All refractory patients carried detectable levels of HCMV and/or EBV mucosal load as compared to 13/23 (56.5%) non-refractory and 13/40 (32.5%) controls. The median DNA value was significantly higher in refractory (HCMV 286 and EBV 5.440 copies/10(5) cells) than in non-refractory (HCMV 0 and EBV 6 copies/10(5) cells; P < 0.05 and < 0.001) IBD patients and controls (HCMV and EBV 0 copies/10(5) cells; P < 0.001 for both). Refractory patients showed DNA peak values >= 10(3) copies/10(5) cells in diseased mucosa in comparison to non-diseased mucosa (P < 0.0121 for HCMV and < 0.0004 for EBV), while non-refractory patients and controls invariably displayed levels below this threshold, thus allowing us to differentiate viral colitis from mucosal infection. Moreover, the mucosal load positively correlated with the values found in the peripheral blood, whilst no correlation with the number of positive cells at immunohistochemistry was found. Steroid use was identified as a significant risk factor for both HCMV (P = 0.018) and EBV (P = 0.002) colitis. Finally, a course of specific antiviral therapy with ganciclovir was successful in all refractory patients with HCMV colitis, whilst refractory patients with EBV colitis did not show any improvement despite steroid tapering and discontinuation of the other medications. CONCLUSION: Viral colitis appeared to contribute to mucosal lesions in refractory IBD, and its correct diagnosis and management require quantitative real-time polymerase chain reaction assay of mucosal specimens. PMID- 25684962 TI - Incidence and psychological-behavioral characteristics of refractory functional dyspepsia: a large, multi-center, prospective investigation from China. AB - AIM: To explore the incidence and psychological and behavioral characteristics of refractory functional dyspepsia (RFD) in China. METHODS: The subjects of this study were 1341 new outpatients with functional dyspepsia (FD) who were diagnosed according to the Rome III criteria at four hospitals in Guangdong Province between June and September 2012, and 100 healthy volunteers. All subjects completed questionnaires and scales administered. RESULTS: Three-hundred and twenty-seven of the 1341 patients with FD had RFD (24.4%). Patients with RFD had a longer disease duration and a more severe form of the disease than patients with non-refractory FD (NRFD). The prevalence of depression and anxiety symptoms was higher in patients with RFD than in patients with NRFD. The prevalence of unhealthy eating behaviors, lack of physical activity, and sleeping disorders was higher in patients with RFD than in patients with NRFD. Patients with RFD sought medical advice on more occasions and spent more money on treatment than patients with NRFD. Finally, patients with RFD had poorer quality of life than patients with NRFD. CONCLUSION: RFD is not rare in clinical practice and should get attention by patients and doctors because of its long duration, severe symptoms, and associations with abnormal psychology and poor quality of life. PMID- 25684963 TI - Split-dose menthol-enhanced PEG vs PEG-ascorbic acid for colonoscopy preparation. AB - AIM: To compare the efficacy and palatability of 4 L polyethylene glycol electrolyte (PEG) plus sugar-free menthol candy (PEG + M) vs reduced-volume 2 L ascorbic acid-supplemented PEG (AscPEG). METHODS: In a randomized controlled trial setting, ambulatory patients scheduled for elective colonoscopy were prospectively enrolled. Patients were randomized to receive either PEG + M or AscPEG, both split-dosed with minimal dietary restriction. Palatability was assessed on a linear scale of 1 to 5 (1 = disgusting; 5 = tasty). Quality of preparation was scored by assignment-blinded endoscopists using the modified Aronchick and Ottawa scales. The main outcomes were the palatability and efficacy of the preparation. Secondary outcomes included patient willingness to retake the same preparation again in the future and completion of the prescribed preparation. RESULTS: Overall, 200 patients were enrolled (100 patients per arm). PEG + M was more palatable than AscPEG (76% vs 62%, P = 0.03). Completing the preparation was not different between study groups (91% PEG + M vs 86% AscPEG, P = 0.38) but more patients were willing to retake PEG + M (54% vs 40% respectively, P = 0.047). There was no significant difference between PEG + M vs AscPEG in adequate cleansing on both the modified Aronchick (82% vs 77%, P = 0.31) and the Ottawa scale (85% vs 74%, P = 0.054). However, PEG + M was superior in the left colon on the Ottawa subsegmental score (score 0-2: 94% for PEG + M vs 81% for AscPEG, P = 0.005) and received significantly more excellent ratings than AscPEG on the modified Aronchick scale (61% vs 43%, P = 0.009). Both preparations performed less well in afternoon vs morning examinations (inadequate: 29% vs 15.2%, P = 0.02). CONCLUSION: 4 L PEG plus menthol has better palatability and acceptability than 2 L ascorbic acid- PEG and is associated with a higher rate of excellent preparations; Clinicaltrial.gov identifier: NCT01788709. PMID- 25684964 TI - Gastrointestinal neuroendocrine tumors treated with high dose octreotide-LAR: a systematic literature review. AB - AIM: To review literature on efficacy and safety of octreotide-long-acting repeatable (LAR) used at doses higher than the Food and Drug Administration (FDA) approved 30 mg/mo for treatment of neuroendocrine tumors (NETs). METHODS: We searched PubMed and Cochrane Library from 1998-2012, 5 conferences (American Society of Clinical Oncology, Endocrine Society, European Neuroendocrine Tumor Society, European Society for Medical Oncology, North American Neuroendocrine Tumor Society) from 2000-2013 using MeSH and keyterms including neuroendocrine tumors, carcinoid tumor, carcinoma, neuroendocrine, and octreotide. Bibliographies of accepted articles were also searched. Two reviewers reviewed titles, abstracts, and full-length articles. Studies that reported data on efficacy and safety of >= 30 mg/mo octreotide-LAR for NETs in human subjects, published in any language were included in the review. RESULTS: The search identified 1086 publications, of which 238 underwent full-text review (20 were translated into English); 17 were included in the review. Studies varied in designs, subjects, octreotide-LAR regimens, and definition of outcomes. Eleven studies reported use of higher doses to control symptoms and tumor progression, although symptom severity and formal quality-of-life analysis were not quantitatively measured. Ten studies reported efficacy, describing 260 subjects with doses ranging from 40 mg/mo or 30 mg/3 wk up to 120 mg/mo. Eight studies reported expert clinical opinion that supported dose escalation of octreotide-LAR up to 60 mg/mo for symptom control and suggested increased doses may be effective at preventing tumor progression. Eight studies reported safety; there was no evidence of increased toxicity associated with doses of octreotide-LAR > 30 mg/mo. CONCLUSION: As reported in this review, octreotide-LAR at doses > 30 mg/mo is being prescribed for symptom and tumor control in NET patients. Furthermore, expert clinical opinion provided support for escalation of somatostatin analogs for refractory hormonal symptoms. PMID- 25684965 TI - Distinctive inflammatory bowel disease phenotype in primary sclerosing cholangitis. AB - AIM: To review the current literature for the specific clinical characteristics of inflammatory bowel disease (IBD) associated with primary sclerosing cholangitis (PSC). METHODS: A systematical review for clinical characteristics of IBD in PSC was performed by conducting a broad search for "primary sclerosing cholangitis" in Pubmed. "Clinical characteristics" were specified into five predefined subthemes: epidemiology of IBD in PSC, characteristics of IBD in PSC (i.e., location, disease behavior), risk of colorectal cancer development, IBD recurrence and de novo disease after liver transplantation for PSC, and safety and complications after proctocolectomy with ileal pouch-anal anastomosis. Papers were selected for inclusion based on their relevance to the subthemes, and were reviewed by two independent reviewers. Only full papers relevant to PSC-IBD were included. Additionally the references of recent reviews for PSC (< 5 years old) were scrutinized for relevant articles. RESULTS: Initial literature search for PSC yielded 4704 results. After careful review 65 papers, comprising a total of 11406 PSC-IBD patients, were selected and divided according to subtheme. Four manuscripts overlapped and were included in two subthemes. Prevalence of IBD in PSC shows a large variance, ranging from 46.5% to 98.7% with ulcerative colitis (UC) being the most common type (> 75%). The highest IBD rates in PSC are found in papers reviewing both endoscopic and histological data for IBD diagnosis. Although IBD in PSC is found to be a quiescent disease, pancolitis occurs often, with rates varying from 35% to 95%. Both backwash ileitis and rectal sparing are observed infrequently. The development of dysplasia or colorectal carcinoma is increased in PSC-IBD; the cumulative 10 years risk varying between 0% and 11%. Exacerbation of IBD is common after liver transplantation for PSC and de novo disease is seen in 1.3% to 31.3% of PSC-IBD patients. The risk for development of pouchitis in PSC-IBD is found to be significant, affecting 13.8% to 90% of the patients after proctocolectomy with ileo anal-pouch anastomosis. CONCLUSION: IBD in primary sclerosing cholangitis represents a distinct phenotype that differs from UC and Crohn's disease and therefore requires specialized management. PMID- 25684966 TI - Chronic hepatitis C genotype 1 treatment roadmap for resource constrained settings. AB - AIM: To use existing hepatitis C virus (HCV) antiviral therapies as access to new treatments is limited. METHODS: A PubMed search for randomised control trials or meta-analysis related to response-guided therapy of HCV genotype 1 patients was undertaken using pegylated interferon and ribavirin (PR), boceprevir (B) and telaprevir (T) and lead-in where response-guided therapy at TW4(TW4), 8(TW8), 10(TW10), or 12(TW12) based on HCVRNA(+) or HCVRNA(-). Studies presented at major conferences were also used. Where necessary, a post-hoc analysis was performed. A response-guided management roadmap was created based on sustained virological response (SVR). RESULTS: Starting with PR, those with HCVRNA(-) at TW4 have > 86% SVR, while those are HCVRNA(+) have 34%-41.7% SVR. HCVRNA(-) TW4 patients can have 24 wk PR if HCVRNA < 400000 IU/mL. Alternatively, 28 wk BPR has similar SVR. If HCVRNA(+) at TW4, 72 wk PR leads to 53% SVR, hence BPR is a better option, and if HCVRNA(-) by TW8, 28 wk therapy is sufficient. If HCVRNA(+) at TW8, then HCVRNA should be checked at TW10 and TW12. By TW12, HCVRNA >= 100 IU/mL activates the stopping rule. This roadmap is applicable for treatment-naive, treatment failures and cirrhotic patients. Validation from an Asia Pacific early access boceprevir program confirmed the findings that HCVRNA(-) at TW4, or TW8 conferred > 80% SVR, leading to the "80-80" rule. CONCLUSION: Using a roadmap based on HCVRNA(-) at TW4 or TW8 (the "80-80" rule), high SVR can be achieved, and guide the best choices for treatment, and also reduces drug exposure in poor responders. PMID- 25684967 TI - Successful treatment of conversion chemotherapy for initially unresectable synchronous colorectal liver metastasis. AB - A 72-year-old woman with a sigmoid colon cancer and a synchronous colorectal liver metastasis (CRLM), which involved the right hepatic vein (RHV) and the inferior vena cava (IVC), was referred to our hospital. The metastatic lesion was diagnosed as initially unresectable because of its invasion into the confluence of the RHV and IVC. After she had undergone laparoscopic sigmoidectomy for the original tumor, she consequently had 3 courses of modified 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) plus cetuximab. Computed tomography revealed a partial response, and the confluence of the RHV and IVC got free from cancer invasion. After 3 additional courses of mFOLFOX6 plus cetuximab, preoperative percutaneous transhepatic portal vein embolization (PTPE) was performed to secure the future remnant liver volume. Finally, a right hemihepatectomy was performed. The postoperative course was uneventful. The patient was discharged from the hospital on postoperative day 13. She had neither local recurrence nor distant metastasis 18 mo after the last surgical intervention. This multidisciplinary strategy, consisting of conversion chemotherapy using FOLFOX plus cetuximab and PTPE, could contribute in facilitating curative hepatic resection for initially unresectable CRLM. PMID- 25684968 TI - Rapidly aggravated skeletal muscle metastases from an intrahepatic cholangiocarcinoma. AB - We present a rare case of intrahepatic cholangiocarcinoma (ICC) with multiple skeletal muscle metastases. The patient was a 55-year-old Asian woman presenting with abdominal pain; abdominal and pelvic computed tomography and magnetic resonance cholangiopancreatography revealed an unresectable ICC with hepatic metastasis and metastastatic lymphadenopathy in the porto-caval area. After 3 mo of treatment with palliative radiotherapy and chemotherapy, magnetic resonance imaging of the thoracolumbar spine detected right psoas muscle and paraspinous muscle metastases. We performed an ultrasound-guided percutaneous fine-needle biopsy that confirmed a similar pattern of poorly differentiated adenocarcinoma. The patient treated with palliative chemotherapy and achieved 10 mo of survival. Here we report the first case quickly spread to multiple sites of muscle even though the three-month treatment, compare to the other cases reported muscle metastases at diagnosis. PMID- 25684969 TI - Retreatment with peginterferon and ribavirin in chronic hepatitis C. AB - The development of boceprevir and telaprevir was a major step forward in the treatment of chronic hepatitis C. In addition, the treatment of these infections has been recently revolutionized by the approval of sofosbuvir and simeprevir. However, there are several challenges associated with the application of novel drugs, such as new and more frequent adverse events, new drug interactions, and excessively high treatment costs. An additional concern is viral resistance. These considerations highlight the fact that direct-acting antiviral agents are not a panacea and may not be the best option for all patients who are in need of therapy. This retrospective study revealed that the sustained virologic response was not significantly reduced following peginterferon and ribavirin retreatment compared with the new therapy. We suggest that patients who experience relapse shortly after completing treatment with peginterferon and ribavirin have a reasonable chance of achieving a sustained virologic response when retreated with these drugs alone. PMID- 25684971 TI - Sparse PCA with Oracle Property. AB - In this paper, we study the estimation of the k-dimensional sparse principal subspace of covariance matrix Sigma in the high-dimensional setting. We aim to recover the oracle principal subspace solution, i.e., the principal subspace estimator obtained assuming the true support is known a priori. To this end, we propose a family of estimators based on the semidefinite relaxation of sparse PCA with novel regularizations. In particular, under a weak assumption on the magnitude of the population projection matrix, one estimator within this family exactly recovers the true support with high probability, has exact rank-k, and attains a [Formula: see text] statistical rate of convergence with s being the subspace sparsity level and n the sample size. Compared to existing support recovery results for sparse PCA, our approach does not hinge on the spiked covariance model or the limited correlation condition. As a complement to the first estimator that enjoys the oracle property, we prove that, another estimator within the family achieves a sharper statistical rate of convergence than the standard semidefinite relaxation of sparse PCA, even when the previous assumption on the magnitude of the projection matrix is violated. We validate the theoretical results by numerical experiments on synthetic datasets. PMID- 25684970 TI - Successful treatment of complex cholangiolithiasis following orthotopic liver transplantation with interventional radiology. AB - Bile duct stones are a serious and the third most common complication of the biliary system that can occur following liver transplantation. The incidence rate of bile duct stones after liver transplantation is 1.8%-18%. The management of biliary stones is usually performed with endoscopic techniques; however, the technique may prove to be challenging in the treatment of the intrahepatic bile duct stones. We herein report a case of a 40-year-old man with rare, complex bile duct stones that were successfully eliminated with percutaneous interventional techniques. The complex bile duct stones were defined as a large number of bile stones filling the intra- and extrahepatic bile tracts, resulting in a cast formation within the biliary tree. Common complications such as hemobilia and acute pancreatitis were not present during the perioperative period. The follow up period was 20 mo long. During the postoperative period, the patient maintained normal temperature, and normal total bilirubin and direct bilirubin levels. The patient is now living a high quality life. This case report highlights the safety and efficacy of the percutaneous interventional approach in the removal of complex bile duct stones following liver transplantation. PMID- 25684972 TI - Deconvolution of High Dimensional Mixtures via Boosting, with Application to Diffusion-Weighted MRI of Human Brain. AB - Diffusion-weighted magnetic resonance imaging (DWI) and fiber tractography are the only methods to measure the structure of the white matter in the living human brain. The diffusion signal has been modelled as the combined contribution from many individual fascicles of nerve fibers passing through each location in the white matter. Typically, this is done via basis pursuit, but estimation of the exact directions is limited due to discretization [1, 2]. The difficulties inherent in modeling DWI data are shared by many other problems involving fitting non-parametric mixture models. Ekanadaham et al. [3] proposed an approach, continuous basis pursuit, to overcome discretization error in the 1-dimensional case (e.g., spike-sorting). Here, we propose a more general algorithm that fits mixture models of any dimensionality without discretization. Our algorithm uses the principles of L2-boost [4], together with refitting of the weights and pruning of the parameters. The addition of these steps to L2-boost both accelerates the algorithm and assures its accuracy. We refer to the resulting algorithm as elastic basis pursuit, or EBP, since it expands and contracts the active set of kernels as needed. We show that in contrast to existing approaches to fitting mixtures, our boosting framework (1) enables the selection of the optimal bias-variance tradeoff along the solution path, and (2) scales with high dimensional problems. In simulations of DWI, we find that EBP yields better parameter estimates than a non-negative least squares (NNLS) approach, or the standard model used in DWI, the tensor model, which serves as the basis for diffusion tensor imaging (DTI) [5]. We demonstrate the utility of the method in DWI data acquired in parts of the brain containing crossings of multiple fascicles of nerve fibers. PMID- 25684973 TI - Acute infectious morbidity in multiple gestation. AB - OBJECTIVES: Physiologic and immunologic changes in pregnancy result in increased susceptibility to infection. These shifts are more pronounced in pregnancies complicated by multiple gestation. The objective of this study was to determine the association between multiple gestation and risk of infectious morbidity. STUDY DESIGN: The Nationwide Inpatient Sample for the years 2008-2010 was used to identify pregnant women during admission for delivery with International Classification of Diseases codes. Logistic regression was used to compute odds ratios and 95% confidence intervals for demographic data, preexisting medical conditions, and acute medical and infectious complications for women with multiple versus singleton gestations. RESULTS: Among women with multiple gestation, 38.4 per 1,000 women had an infectious complication compared to 12.8 per 1,000 women with singletons. The most significant infectious morbidity associated with multiple gestation was intestinal infections, pyelonephritis, influenza, and pneumonia. After controlling for confounding variables, infectious complications at delivery persisted for women with multiples, though the association was dependent on mode of delivery. CONCLUSIONS: Women with multiple gestations are at increased risk for infectious morbidity identified at the time of delivery. This association was diminished among women who had a cesarean suggesting that operative delivery is not responsible for this association. PMID- 25684974 TI - Cluster analysis of multiplex ligation-dependent probe amplification data in choroidal melanoma. AB - PURPOSE: To determine underlying correlations in multiplex ligation-dependent probe amplification (MLPA) data and their significance regarding survival following treatment of choroidal melanoma (CM). METHODS: MLPA data were available for 31 loci across four chromosomes (1p, 3, 6, and 8) in tumor material obtained from 602 patients with CM treated at the Liverpool Ocular Oncology Center (LOOC) between 1993 and 2012. Data representing chromosomes 3 and 8q were analyzed in depth since their association with CM patient survival is well-known. Unsupervised k-means cluster analysis was performed to detect latent structure in the data set. Principal component analysis (PCA) was also performed to determine the intrinsic dimensionality of the data. Survival analyses of the identified clusters were performed using Kaplan-Meier (KM) and log-rank statistical tests. Correlation with largest basal tumor diameter (LTD) was investigated. RESULTS: Chromosome 3: A two-cluster (bimodal) solution was found in chromosome 3, characterized by centroids at unilaterally normal probe values and unilateral deletion. There was a large, significant difference in the survival characteristics of the two clusters (log-rank, p<0.001; 5-year survival: 80% versus 40%). Both clusters had a broad distribution in LTD, although larger tumors were characteristically in the poorer outcome group (Mann-Whitney, p<0.001). Threshold values of 0.85 for deletion and 1.15 for gain optimized the classification of the clusters. PCA showed that the first principal component (PC1) contained more than 80% of the data set variance and all of the bimodality, with uniform coefficients (0.28+/-0.03). Chromosome 8q: No clusters were found in chromosome 8q. Using a conventional threshold-based definition of 8q gain, and in conjunction with the chromosome 3 clusters, three prognostic groups were identified: chromosomes 3 and 8q both normal, either chromosome 3 or 8q abnormal, and both chromosomes 3 and 8q abnormal. KM analysis showed 5-year survival figures of approximately 97%, 80%, and 30% for these prognostic groups, respectively (log-rank, p<0.001). All MLPA probes within both chromosomes were significantly correlated with each other (Spearman, p<0.001). CONCLUSIONS: Within chromosome 3, the strong correlation between the MLPA variables and the uniform coefficients from the PCA indicates a lack of evidence for a signature gene that might account for the bimodality we observed. We hypothesize that the two clusters we found correspond to binary underlying states of complete monosomy or disomy 3 and that these states are sampled by the complete ensemble of probes. Consequently, we would expect a similar pattern to emerge in higher-resolution MLPA data sets. LTD may be a significant confounding factor. Considering chromosome 8q, we found that chromosome 3 cluster membership and 8q gain as traditionally defined have an indistinguishable impact on patient outcome. PMID- 25684975 TI - The effects of actomyosin disruptors on the mechanical integrity of the avian crystalline lens. AB - PURPOSE: Actin and myosin within the crystalline lens maintain the structural integrity of lens fiber cells and form a hexagonal lattice cradling the posterior surface of the lens. The actomyosin network was pharmacologically disrupted to examine the effects on lenticular biomechanics and optical quality. METHODS: One lens of 7-day-old White Leghorn chickens was treated with 10 uM of a disruptor and the other with 0.01% dimethyl sulfoxide (vehicle). Actin, myosin, and myosin light chain kinase (MLCK) disruptors were used. The stiffness and the optical quality of the control and treated lenses were measured. Western blotting and confocal imaging were used to confirm that treatment led to a disruption of the actomyosin network. The times for the lenses to recover stiffness to match the control values were also measured. RESULTS: Disruptor-treated lenses were significantly less stiff than their controls (p<=0.0274 for all disruptors). The disruptors led to changes in the relative protein amounts as well as the distributions of proteins within the lattice. However, the disruptors did not affect the clarity of the lenses (p>=0.4696 for all disruptors), nor did they affect spherical aberration (p = 0.02245). The effects of all three disruptors were reversible, with lenses recovering from treatment with actin, myosin, and MLCK disruptors after 4 h, 1 h, and 8 min, respectively. CONCLUSIONS: Cytoskeletal protein disruptors led to a decreased stiffness of the lens, and the effects were reversible. Optical quality was mostly unaffected, but the long-term consequences remain unclear. Our results raise the possibility that the mechanical properties of the avian lens may be actively regulated in vivo via adjustments to the actomyosin lattice. PMID- 25684976 TI - Localization of complement factor H gene expression and protein distribution in the mouse outer retina. AB - PURPOSE: To determine the localization of complement factor H (Cfh) mRNA and its protein in the mouse outer retina. METHODS: Quantitative real-time PCR (qPCR) was used to determine the expression of Cfh and Cfh-related (Cfhr) transcripts in the RPE/choroid. In situ hybridization (ISH) was performed using the novel RNAscope 2.0 FFPE assay to localize the expression of Cfh mRNA in the mouse outer retina. Immunohistochemistry (IHC) was used to localize Cfh protein expression, and western blots were used to characterize CFH antibodies used for IHC. RESULTS: Cfh and Cfhr2 transcripts were detected in the mouse RPE/choroid using qPCR, while Cfhr1, Cfhr3, and Cfhrc (Gm4788) were not detected. ISH showed abundant Cfh mRNA in the RPE of all mouse strains (C57BL/6, BALB/c, 129/Sv) tested, with the exception of the Cfh(-/-) eye. Surprisingly, the Cfh protein was detected by immunohistochemistry in photoreceptors rather than in RPE cells. The specificity of the CFH antibodies was tested by western blotting. Our CFH antibodies recognized purified mouse Cfh protein, serum Cfh protein in wild-type C57BL/6, BALB/c, and 129/Sv, and showed an absence of the Cfh protein in the serum of Cfh( /-) mice. Greatly reduced Cfh protein immunohistological signals in the Cfh(-/-) eyes also supported the specificity of the Cfh protein distribution results. CONCLUSIONS: Only Cfh and Cfhr2 genes are expressed in the mouse outer retina. Only Cfh mRNA was detected in the RPE, but no protein. We hypothesize that the steady-state concentration of Cfh protein is low in the cells due to secretion, and therefore is below the detection level for IHC. PMID- 25684977 TI - Ophthalmological phenotype associated with homozygous null mutation in the NEUROD1 gene. AB - PURPOSE: NEUROD1 is a tissue-specific basic helix loop helix (bHLH) protein involved in the development and maintenance of the endocrine pancreas and neuronal elements. Loss of NEUROD1 causes ataxia, cerebellar hypoplasia, sensorineural deafness, and severe retinal dystrophy in mice. Heterozygous loss of-function mutations in NEUROD1 have previously been described as a cause of maturity-onset diabetes of the young (MODY) and late-onset diabetes. To date, homozygous loss-of-function NEUROD1 mutations have only been detected in two patients. Both mutations caused permanent neonatal diabetes and severe neurologic defects, including visual impairment. However, a detailed ophthalmological phenotype of this novel syndrome has not yet been reported. Our aim was to characterize the ophthalmological phenotype associated with the previously reported homozygous c.427_428CT mutation in the NEUROD1 gene. METHODS: The female patient was investigated on multiple occasions between 2009 (age 14) and 2014 (age 19), including visual acuity testing, automated perimetry, funduscopy, anterior-segment imaging, optical coherence tomography of the posterior pole, standard full-field electroretinography, and fundus-autofluorescence imaging. RESULTS: The patient had nyctalopia, blurry vision, and visual field constriction from early childhood. Her best corrected visual acuity ranged between 20/25 and 15/25 during the investigation period. Perimetry showed concentric constriction of the visual field, sparing only the central 30 degrees in both eyes. The anterior segment did not show any morphological changes. Optical coherence tomography revealed total absence of the photoreceptor layer of the retina outside the fovea, where a discoid remnant of cone photoreceptors could be detected. Neither setting of the standard full-field electroretinography could detect any electrical response from the retina. Color fundus photos presented peripheral chorioretinal atrophy and central RPE mottling. A hyperreflective parafoveal ring was detected on fundus autofluorescent photos, a characteristic sign of hereditary retinal dystrophies. CONCLUSIONS: To the best of our knowledge, this is the first report on the ophthalmological phenotype associating with a homozygous NEUROD1 null mutation in humans. Our results indicate that the loss of NEUROD1 has similar functional and anatomic consequences in the human retina as those described in mice. The present description can help the diagnosis of future cases and provide clues on the rate of disease progression. PMID- 25684978 TI - Ocular inflammation in HLA-B27 transgenic mice reveals a potential role for MHC class I in corneal immune privilege. AB - PURPOSE: HLA-B27 is a major histocompatibility complex class I (MHCI) allele that has been closely associated with the development of ankylosing spondylitis and acute anterior uveitis (AAU), the most common form of uveitis worldwide. We have been characterizing the phenotypes of transgenic mice carrying a human HLA-B27 allele, but that are deficient in endogenous mouse MHCI genes (H-2K(-/-) and H 2D(-/-) double knockout, or DKO) to create the HLA-B27/DKO line. In maintaining and expanding this colony, we observed a rare sporadic severe central keratitis that developed in transgenic animals, but that was not present in wild-type (WT) animals. METHODS: The corneas of affected HLA-B27/DKO and DKO mice were compared to their WT counterparts by staining with standard histological methods for markers of inflammation and neovascularization. A model of experimental corneal inflammation was subsequently used to test the responses of each genotype to insult. RESULTS: We identified a previously unreported corneal pathology in naive HLA-B27/DKO mice, and we describe significantly prolonged CD4(+)- and CD8(+) associated inflammation in these animals following an experimentally induced corneal injury. CONCLUSIONS: These results demonstrate an increased T-cell response in B27/DKO corneas due to the expression of the HLA-B27 allele, suggesting that low MHCI expression in WT corneas is an important contributor to immune privilege. PMID- 25684979 TI - Chondrogenesis in scleral stem/progenitor cells and its association with form deprived myopia in mice. AB - PURPOSE: Previously, we demonstrated that scleral stem/progenitor cells (SSPCs) from mice have a chondrogenic differentiation potential, which is stimulated by transforming growth factor-beta (TGF-beta). In the present study, we hypothesized that chondrogenesis in the sclera could be a possible mechanism in myopia development. Therefore, we investigated the association of form-deprivation myopia (FDM) with expressions in mice sclera representing the chondrogenic phenotype: collagen type II (Col2) and alpha-smooth muscle actin (alpha-SMA). METHODS: The mRNA levels of alpha-SMA and Col2 in cultured murine SSPCs during chondrogenesis stimulated by TGF-beta2 were determined by real-time quantitative RT-PCR (qRT-PCR). The expression patterns of alpha-SMA and Col2 were assessed by immunohistochemistry in a three dimensional pellet culture. In an FDM mouse model, a western blot analysis and immunofluorescence study were used to detect the changes in the alpha-SMA and Col2 protein expressions in the sclera. In the RPE-choroid complex, qRT-PCR was used to detect any changes in the TGF-beta mRNA expression. RESULTS: The treatment of SSPCs in vitro with TGF-beta2 for 24 h at 1 or 10 ng/ml led to increased levels of both the alpha-SMA and Col2 expressions. In addition, we observed the formation of cartilage-like pellets from TGF-beta2 treated SSPCs. Both alpha-SMA and Col2 were expressed in the pellet. In an in vivo study, the alpha-SMA and Col2 protein expressions were significantly increased in the sclera of FDM eyes in comparison to contralateral control eyes. Similarly, the levels of TGF-beta in the RPE-choroid complex of an FDM eye were also significantly elevated. CONCLUSION: Based on the concept of stem cells possessing multipotent differentiation potentials, scleral chondrogenesis induced by SSPCs may play a role in myopia development. The increased expressions of the cartilage-associated proteins Col2 and alpha-SMA during scleral chondrogenesis may be potential markers for myopia development. In addition, the increased levels of TGF-beta mRNA in the RPE-choroid complex might induce the chondrogenic change in the sclera during myopia development. PMID- 25684980 TI - Ablation of Kcnj10 expression in retinal explants revealed pivotal roles for Kcnj10 in the proliferation and development of Muller glia. AB - PURPOSE: We previously found that Kcnj10, an inwardly-rectifying potassium channel, is a gene expressed in c-kit-positive retinal progenitor cells on P1. The shRNA-mediated screening of the functions of the genes for retinal development in retinal explant culture suggested a role for Kcnj10 in the differentiation of 23Muller glia. In the present study, we extended the work and focused on analyzing the role of Kcnj10 in retinal development. METHODS: shRNA mediated downregulation of Kcnj10 in retinal explants and the in vivo mouse retina at the P1 stage was performed. Differentiation and proliferation of the retina were examined with immunohistochemistry. The effect of barium (Ba(2+)) treatment, which inhibits potassium currents by blocking potassium channels, on retinal development was examined. RESULTS: When Kcnj10 was downregulated at E18, cellular proliferation and morphological differentiation were perturbed; in particular, a decreased number of Muller glial cells with abnormal morphological maturation was observed. The overexpression of Kcnj10 in retinal progenitors did not result in gross abnormality during retinal development, but rescued the abnormal differentiation induced with sh-Kcnj10. The presence of Ba(2+) in the retinal explant medium led to a phenotype similar to that seen with sh-Kcnj10. Ba(2+) exerts an effect mainly during late retinal development, and sh-Kcnj10 in the P1 retina affected Muller glia maturation, suggesting that Kcnj10 plays a pivotal role in the maturation of retinal cell subsets. A previous study of Kcnj10-knockout mice showed no obvious abnormality in retinal differentiation, especially of Muller glia. We examined the effects of the downregulation of Kcnj10 with in vivo electroporation of sh-Kcnj10 in the P1 retina. Retinal differentiation was perturbed, as seen following the in vitro downregulation of Kcnj10, suggesting that compensatory gene expression and/or signaling occurred in the Kcnj10-knockout mice in the retina, leading to normal eye development. CONCLUSION: Kcnj10 plays a role in Muller glia maturation during retinal development probably through ionic channel activities. PMID- 25684981 TI - Modified Newton-Raphson method to tune feedback gains of control system for standing by functional neuromuscular stimulation following spinal cord injury. AB - BACKGROUND: Functional neuromuscular stimulation (FNS) can restore standing capabilities following spinal cord injury. Feedback control of these systems can optimize performance by reducing the required upper extremity support. However, tuning these control systems can be intensive and clinically inconvenient. OBJECTIVE: This case study investigated a clinical method to efficiently tune feedback gains for a control system utilizing feedback of total body center of mass acceleration to modulate stimulation levels to targeted paralyzed musculature of the lower extremities and trunk. METHODS: Gains for this control system were tuned to minimize the stabilization loading by one arm against internal postural perturbations volitionally-generated during manipulation of an object using the other arm. An algorithm based on a modified form of the Newton Raphson method was employed to find the optimal feedback gains with lower subject effort than that to determine the original tuning curves. RESULTS: This method accurately (<6.2% error) approximated the optimal gains with 70% fewer manipulations by the subject. CONCLUSIONS: These results suggest that optimal feedback gains for the specific FNS control system can be determined systematically with considerably less effort than heuristic gain tuning. This demonstrates the potential for devising simple, convenient methods for effective system re-tuning during clinical usage. PMID- 25684982 TI - Tumour inflammatory response: adding fuel to the fire? PMID- 25684983 TI - In 2124, half of all men can count on developing prostate cancer. PMID- 25684984 TI - Yoga in adult cancer: a pilot survey of attitudes and beliefs among oncologists. AB - BACKGROUND: Depending on interest, knowledge, and skills, oncologists are adapting clinical behaviour to include integrative approaches, supporting patients to make informed complementary care decisions. The present study sought to improve the knowledge base in three ways: Test the acceptability of a self reported online survey for oncologists.Provide preliminary data collection concerning knowledge, attitudes, beliefs, and current referral practices among oncologists with respect to yoga in adult cancer.List the perceived benefits of and barriers to yoga intervention from a clinical perspective. METHODS: A 38-item self-report questionnaire was administered online to medical, radiation, and surgical oncologists in British Columbia. RESULTS: Some of the 29 oncologists who completed the survey (n = 10) reported having recommended yoga to patients to improve physical activity, fatigue, stress, insomnia, and muscle or joint stiffness. Other responding oncologists were hesitant or unlikely to suggest yoga for their patients because they had no knowledge of yoga as a therapy (n = 15) or believed that scientific evidence to support its use is lacking (n = 11). All 29 respondents would recommend that their patients participate in a clinical trial to test the efficacy of yoga. In qualitative findings, oncologists compared yoga with exercise and suggested that it might have similar psychological and physical health benefits that would improve patient capacity to endure treatment. Barriers to and limitations of yoga in adult cancer are also discussed. CONCLUSIONS: An online self-report survey is feasible, but has response rate limitations. A small number of oncologists are currently recommending yoga to improve health-related outcomes in adult cancer. Respondents would support clinical yoga interventions to improve the evidence base in cancer patients, including men and women in all tumour groups. PMID- 25684985 TI - Serum C-reactive protein predicts poor prognosis in patients with locoregionally advanced nasopharyngeal carcinoma treated with chemoradiotherapy. AB - BACKGROUND: We aimed to evaluate the association of serum C-reactive protein (crp) with prognosis in patients with locoregionally advanced nasopharyngeal carcinoma treated with chemoradiotherapy. METHODS: We retrospectively reviewed 79 patients with locoregionally advanced nasopharyngeal carcinoma (cT3-4N0-3M0) treated with chemoradiotherapy. Chemoradiotherapy consisted of external-beam radiotherapy to the nasopharynx (70-80 Gy), the lymph node-positive area (60-70 Gy), and the lymph node-negative area (50-60 Gy) combined with 3 cycles of various platinum-based regimens delivered at 3-week intervals. Elevated crp was defined as more than 8 mg/L. The survival rate was calculated using the Kaplan Meier method, and univariate and multivariate analyses (Cox proportional hazards model) were used to identify factors significantly associated with prognosis. RESULTS: During the median follow-up of 3.9 years (range: 1-5.5 years), 23 patients died from nasopharyngeal cancer. The 5-year cancer-specific survival (css) rate was 62.90%. Before chemoradiotherapy, 18 patients had high serum crp; the css rate in that subgroup was significantly worse than the rate in the remaining patients (p = 0.0002). Multivariate analysis showed that crp was an independent prognostic indicator of css, with a hazard ratio of 3.04 (95% confidence interval: 1.22 to 7.55; p = 0.017). Among the 18 patients with elevated serum crp, 9 achieved normal serum crp after chemoradiotherapy, of whom 5 remained living with no evidence of recurrence or metastasis during follow-up. By contrast, the remaining 9 patients in whom serum crp did not normalize after chemoradiotherapy died within 4.2 years. CONCLUSIONS: Elevated serum crp before treatment predicts poor prognosis in patients with locoregionally advanced nasopharyngeal carcinoma treated with chemoradiotherapy. PMID- 25684986 TI - Concurrent chemoradiotherapy for locally advanced breast cancer-time for a new paradigm? AB - BACKGROUND: In cases of locally advanced breast cancer (labc), preoperative ("neoadjuvant") therapy was traditionally reserved to render the patient operable. More recently, neoadjuvant therapy, particularly chemotherapy, is being used in patients with operable disease to increase the opportunity for breast conservation. Despite the increasing use of preoperative chemotherapy, rates of pathologic complete response, a surrogate marker for disease-free survival, remain modest in patients with locally advanced disease and particularly so when the tumour is estrogen or progesterone receptor-positive and her2-negative. A new paradigm for labc patients is needed. In other solid tumours (for example, rectal, esophageal, and lung cancers), concurrent chemoradiotherapy (ccrt) is routinely used in neoadjuvant and adjuvant treatment protocols alike. RESULTS: The literature suggests that ccrt in labc patients with inoperable disease is associated with response rates higher than would be anticipated with systemic therapy alone. CONCLUSIONS: Ongoing trials in this field are eagerly awaited to determine if ccrt should become the new paradigm. PMID- 25684987 TI - Novel agents and associated toxicities of inhibitors of the pi3k/Akt/mtor pathway for the treatment of breast cancer. AB - The pi3k/Akt/mtor (phosphatidylinositol 3 kinase/ Akt/mammalian target of rapamycin) signalling pathway is an established driver of oncogenic activity in human malignancies. Therapeutic targeting of this pathway holds significant promise as a treatment strategy. Everolimus, an mtor inhibitor, is the first of this class of agents approved for the treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. Everolimus has been associated with significant improvements in progression-free survival; however, it is also associated with increased toxicity related to its specific mechanism of action. METHODS: A comprehensive review of the literature conducted using a focused medline search was combined with a search of current trials at http://ClinicalTrials.gov/. Summary tables of the toxicities of the various classes of pi3k/Akt/mtor inhibitors were created. A broad group of Canadian health care professionals was assembled to review the data and to produce expert opinion and summary recommendations for possible best practices in managing the adverse events associated with these pathway inhibitors. RESULTS: Differing toxicities are associated with the various classes of pi3k/Akt/mtor pathway inhibitors. The most common unique adverse events observed in everolimus clinical trials in breast cancer include stomatitis (all grades: approximately 60%), noninfectious pneumonitis (15%), rash (40%), hyperglycemia (15%), and immunosuppression (40%). To minimize grades 3 and 4 toxicities and to attempt to attain optimal outcomes, effective management of those adverse events is critical. Management should be interdisciplinary and should use approaches that include education, early recognition, active intervention, and potentially prophylactic strategies. DISCUSSION: Everolimus likely represents the first of many complex oral targeted therapies for the treatment of breast cancer. Using this agent as a template, it is essential to establish best practices involving and integrating multiple disciplines for the management of future pi3k/Akt/mtor signalling pathway inhibitors. PMID- 25684988 TI - Clinical challenges in patients with cancer-associated thrombosis: Canadian expert consensus recommendations. AB - Venous thromboembolism is a common complication in cancer patients, and thromboembolism is the second most common cause of death after cancer progression. A number of clinical practice guidelines provide recommendations for the management of cancer-associated thrombosis. However, the guidelines lack recommendations covering commonly encountered clinical challenges (for example, thrombocytopenia, recurrent venous thromboembolism, etc.) for which little or no evidence exists. Accordingly, recommendations were developed to provide expert guidance to medical oncologists and other health care professionals caring for patients with cancer-associated thrombosis. The current expert consensus was developed by a team of 21 clinical experts. For each identified clinical challenge, the literature in medline, embase, and Evidence Based Medicine Reviews was systematically reviewed. The quality of the evidence was assessed, summarized, and graded. Consensus statements were generated, and the experts voted anonymously using a modified Delphi process on their level of agreement with the various statements. Statements were progressively revised through separate voting iterations and were then finalized. Clinicians using these recommendations and suggestions should tailor patient management according to the risks and benefits of the treatment options, patient values and preferences, and local cost and resource allocations. PMID- 25684989 TI - Rectal cancer resection and circumferential margin rates in Canada: a population based study. PMID- 25684990 TI - Adherence to abiraterone among the first 86 recipients after release in Saskatchewan. AB - Metastatic castration-resistant prostate cancer is now commonly treated with abiraterone, an orally administered chronic medication. Although abiraterone has certain advantages over docetaxel-based therapy, patients are now responsible for ensuring optimal adherence to their medication. To our knowledge, adherence to abiraterone in a real-world setting has never been described. The objective of the present study was to measure adherence to abiraterone among the first patients to receive the drug in Saskatchewan. Electronic pharmacy claims were obtained from the Saskatchewan Cancer Agency after removal of patient names and identifiers. All patients with at least 1 dispensation for abiraterone between August 2011 and October 2013 were eligible. The primary endpoint was the percentage of patients achieving optimal adherence at 6 months, defined as a medication possession ratio (mpr) of 80% or better. During the study period, 141 patients received abiraterone, among whom 86 could be followed for at least 6 months. Optimal adherence was achieved in 82.6% of patients (71 of 86) at 6 months, with 79.1% achieving a mpr of at least 90%. Of patients with available follow-up to 1 year, 81.6% (31 of 38) maintained optimal adherence during the entire period. PMID- 25684991 TI - Publishing clinical research: ten pearls for oncology trainees and junior oncologists. PMID- 25684992 TI - Distribution and clinical significance of tumour-associated macrophages in pancreatic ductal adenocarcinoma: a retrospective analysis in China. AB - BACKGROUND: We aimed to characterize the localization and prognostic significance of tumour-associated macrophages (tams) in pancreatic ductal adenocarcinoma (pdac). METHODS: Tumour specimens from 70 patients with pdac and inflammatory specimens from 13 patients with chronic pancreatitis were collected and analyzed for tam and M2 macrophage counts by immunohistochemistry. Correlations between tam distributions and clinicopathologic features were determined. RESULTS: Immunohistochemical analysis showed that tam and M2 macrophage counts were higher in tissues from pdac than from chronic pancreatitis. The tams and M2 macrophages both infiltrated more into peritumour. Both macrophage types were positively associated with lymph node metastasis (p = 0.041 for tams in peritumour, p = 0.013 for M2 macrophages in introtumour, p = 0.006 for M2 macrophage in peritumour). In addition, abdominal pain was significantly more frequent in pdac patients with a greater tams count. The survival rate was much lower in patients having high infiltration by M2 macrophages than in those having low infiltration. CONCLUSIONS: The tam count might be associated with neural invasion in pdac, and M2 macrophages might play an important role in lymph node metastasis. Higher counts of either macrophage type were associated with increased risk of lymph node metastasis, and the M2 macrophage count could potentially be a marker for evaluating prognosis. PMID- 25684993 TI - Urologist referral delay and its impact on survival after radical cystectomy for bladder cancer. AB - BACKGROUND: Evidence shows that wait times before bladder cancer surgery have been increasing, and wait time can negatively affect survival. We aimed to determine if a long delay caused by an indirect referral before a first urologist visit affects the survival of patients undergoing radical cystectomy for bladder cancer. METHODS: We analyzed data from 1271 patients who underwent surgery for bladder cancer during the decade 2000-2009. The cohort was obtained by linking two administrative databases in the province of Quebec. Patients were considered to have been directly referred to a urologist if they had 5 or fewer visits with a general practitioner before their first urologist visit; otherwise, they were considered to have been indirectly referred. The effect on survival after surgery of a longer delay before a first urologist visit was assessed using Cox regression models. RESULTS: Median referral delay for the study population was 30 days (56 days for women, 23 days for men; p < 0.0001). Indirect referral was observed for 49% of women and 33% of men. Compared with patients who were directly referred, those who were indirectly referred after first symptoms of bladder cancer experienced poorer survival (hazard ratio: 1.29; 95% confidence interval: 1.10 to 1.52). Women who were indirectly referred had a significant 47% greater risk of death after radical cystectomy. Men who were indirectly referred also experienced decreased survival (adjusted hazard ratio: 1.25; 95% confidence interval: 1.03 to 1.51). CONCLUSIONS: Patients indirectly referred to a urologist had an increased risk of mortality after surgery. Compared with men, women had longer wait times and poorer survival. PMID- 25684994 TI - Safe handling of cytotoxics: guideline recommendations. AB - BACKGROUND: This evidence-based practice guideline was developed to update and address new issues in the handling of cytotoxics, including the use of oral cytotoxics; the selection and use of personal protective equipment; and treatment in diverse settings, including the home setting. METHODS: The guideline was developed primarily from an adaptation and endorsement of an existing guideline and from three systematic reviews. Before publication, the guideline underwent a series of peer and external reviews to gather feedback. All comments were addressed, and the guideline was amended when required. The guideline applies to health care workers who could come into contact with cytotoxic drugs at any point in the medication circuit. The intended users are hospital administrators, educators, and managers; occupational health and safety services; and pharmacy and health care workers. RESULTS: The recommendations represent a reasonable and practical set of procedures that the intended users of this guideline should implement to minimize opportunities for accidental exposure. They are not limited to just the point of care; they cover the entire chain of cytotoxics handling from the time such agents enter the institution until they leave in the patient or as waste. CONCLUSIONS: Reducing the likelihood of accidental exposure to cytotoxic agents within the medication circuit is the main objective of this evidenced-based guideline. The recommendations differ slightly from earlier guidelines because of the availability of new evidence. PMID- 25684995 TI - Overdiagnosis in breast cancer chemoprevention trials. PMID- 25684996 TI - New species of Daidalotarsonemus and Excelsotarsonemus (Acari, Tarsonemidae) from the Brazilian rainforest. AB - Three new species of Tarsonemidae, Daidalotarsonemusoliveirai Rezende, Lofego & Ochoa, sp. n., Excelsotarsonemuscaravelis Rezende, Lofego & Ochoa, sp. n. and Excelsotarsonemustupi Rezende, Lofego & Ochoa, sp. n. are described and illustrated. Measurements for these species are provided, as well as drawings, phase contrast (PC), differential interference contrast (DIC) and low temperature scanning electron microscopy (LT-SEM) micrographs. Some characters, which have not been used or clearly understood, are described herein. Biological, ecological and agricultural aspects about the role of these species in the rainforest and its surrounding environment are briefly discussed. PMID- 25684997 TI - The blattodeas.s. (Insecta, dictyoptera) of the Guiana shield. AB - Here we provide a checklist of cockroach species known from areas within the Guiana Shield based on literature records and new field collection. We give records of sixteen species collected in Guyana, eight of which are new records for Guyana and one of which is a new generic record for the entire Guiana Shield. We also provide a description for a geographically disparate species of Calhypnorna Stal, and the new species Xestoblattaberenbaumae. The complete checklist contains 234 species of Blattodeas.s. currently known in the shield. This checklist shows particularly low richness in Guianan Venezuela, Roraima and Amapa Brazil, but this is likely an artifact due to under-sampling. Indeed, based on previously published data and current fieldwork, we believe that most regions of the Guiana Shield are under-sampled for cockroaches. Despite this, French Guiana (151 spp.) and Suriname (136 spp.) rank as the second and sixth most species dense faunas of cockroaches in the neotropics. PMID- 25684998 TI - A new species of the genus Sulawesifulvius Gorczyca, Cherot, & Stys, 2004 (Insecta, Heteroptera, Miridae, Cylapinae) from India. AB - A new species, Sulawesifulviusindicus sp. n., is described from Bangalore, India. It is easily separated from the type species SulawesifulviusschuhiGorczyca et al., 2004, the only other species of the genus, by the small size, dorsal coloration, and the male genital structures. The discovery of a new species of Sulawesifulvius in southern India considerably extends the distribution of the genus, previously recorded only from Sulawesi, Indonesia. PMID- 25684999 TI - Revision of the ant genus Proceratium Roger (Hymenoptera, Proceratiinae) in Fiji. AB - The Fiji archipelago harbours a surprisingly diverse and endemic ant fauna, despite its isolated and remote location in the South Pacific. The ant genus Proceratium is present on Fiji with three endemic species, of which Proceratiumoceanicum De Andrade, 2003 and Proceratiumrelictum Mann, 1921 were previously known. In this study we describe the third species: Proceratiumvinaka sp. n. All three species are members of the widespread and species-rich Proceratiumsilaceum clade. In order to integrate the new species into the current taxonomic system, we present an illustrated identification key to the worker caste of the three Fijian species. In addition, we provide a detailed description of Proceratiumvinaka, as well as species accounts for the other two species, which include diagnoses, taxonomic discussions, specimen photographs, and a distribution map. PMID- 25685000 TI - A new species of Metaeuchromius (Lepidoptera, Crambidae) from the Tibetan glacier area of China. AB - Metaeuchromiusglacialis Li, sp. n. is described from the Tibetan glacier area of China. The new species is similar to Metaeuchromiuscirce Bleszynski by the distal projection of costa exceeding the apex of valva, and the phallus with strong spine-like cornuti in the male genitalia. Images of male adult, tympanal and scent organs as well as genitalia of the new species are provided. PMID- 25685001 TI - VIS - A database on the distribution of fishes in inland and estuarine waters in Flanders, Belgium. AB - The Research Institute for Nature and Forest (INBO) has been performing standardized fish stock assessments in Flanders, Belgium. This Flemish Fish Monitoring Network aims to assess fish populations in public waters at regular time intervals in both inland waters and estuaries. This monitoring was set up in support of the Water Framework Directive, the Habitat Directive, the Eel Regulation, the Red List of fishes, fish stock management, biodiversity research, and to assess the colonization and spreading of non-native fish species. The collected data are consolidated in the Fish Information System or VIS. From VIS, the occurrence data are now published at the INBO IPT as two datasets: 'VIS - Fishes in inland waters in Flanders, Belgium' and 'VIS - Fishes in estuarine waters in Flanders, Belgium'. Together these datasets represent a complete overview of the distribution and abundance of fish species pertaining in Flanders from late 1992 to the end of 2012. This data paper discusses both datasets together, as both have a similar methodology and structure. The inland waters dataset contains over 350,000 fish observations, sampled between 1992 and 2012 from over 2,000 locations in inland rivers, streams, canals, and enclosed waters in Flanders. The dataset includes 64 fish species, as well as a number of non target species (mainly crustaceans). The estuarine waters dataset contains over 44,000 fish observations, sampled between 1995 and 2012 from almost 50 locations in the estuaries of the rivers Yser and Scheldt ("Zeeschelde"), including two sampling sites in the Netherlands. The dataset includes 69 fish species and a number of non-target crustacean species. To foster broad and collaborative use, the data are dedicated to the public domain under a Creative Commons Zero waiver and reference the INBO norms for data use. PMID- 25685002 TI - The New World whirligig beetles of the genus Dineutus Macleay, 1825 (Coleoptera, Gyrinidae, Gyrininae, Dineutini). AB - All New World members of the whirligig beetle genus Dineutus Macleay, 1825 are treated. The New World Dineutus are found to be composed of 18 species and 6 subspecies: one species, Dineutusmexicanus Ochs, 1925, stat. n. is elevated from subspecies to species rank, and the subspecies Dineutuscarolinusmutchleri Ochs, 1925, syn. n. is synonymized here with the typical form. Lectotypes are designated for Dineutusdiscolor Aube, 1838, Dineutesmetallicus Aube, 1838, Dineutussolitarius Aube, 1838, Dineutesanalis Regimbart, 1883, and Gyrinuslongimanus Olivier, 1795. Each taxonomic unit is provided with a taxonomic history, type locality, diagnosis, distribution, habitat information, and a discussion section. The aedeagus and male mesotarsal claws are illustrated, and dorsal and ventral habitus images of both sexes, for each species and subspecies are provided. General distribution maps are provided for all taxonimc units. A key to the genera of New World Gyrinidae, as well as all the New World Dineutus species is provided. General Dineutus anatomy as well as a clarification of homology and anatomical terms is included. PMID- 25685003 TI - A new species of Metagovea Rosas Costa, 1950 from Napo Province, Ecuador (Opiliones, Cyphophthalmi, Neogoveidae). AB - As a result of an expedition to Ecuador in 2014, a new species of mite harvestman was discovered. This new species belonging to the genus Metagovea Rosas Costa, 1950 - Metagovealigiae sp. n. - is described, based on male and female specimens from Napo Province, Ecuador. This is the fourth species described for the genus and the second from Ecuador. A simple terminology is proposed for the microtrichiae of the spermatopositor and genital characters in the family are discussed. The genus Brasiliogovea Martens, 1969 is consistently misspelled in the literature as Brasilogovea. The description of Metagovealigiae offered opportunity to discuss some aspects of systematics of the family. PMID- 25685004 TI - New records of ant species from Yunnan, China. AB - As with many other regions of the world, significant collecting, curation, and taxonomic efforts will be needed to complete the inventory of China's ant fauna. This is especially true for the highly diverse tropical regions in the south of the country, where moist tropical forests harbor high species richness typical of the Southeast Asian region. We inventoried ants in the Xingshuangbanna prefecture, Yunnan, in June 2013, using a variety of methods including Winkler extraction and hand collection to sample ant diversity. We identified 213 species/morphospecies of ants from 10 subfamilies and 61 genera. After identification of 148 valid species of the 213 total species collected, 40 species represent new records for Yunnan province and 17 species are newly recorded for China. This increases the total number of named ant species in Yunnan and China to 447 and 951 respectively. The most common species collected were Brachyponeraluteipes and Vollenhoviaemeryi. Only one confirmed exotic species Strumigenysmembranifera, was collected, although several others were potentially introduced by humans. These results highlight the high biodiversity value of the region, but also underscore how much work remains to fully document the native myrmecofauna. PMID- 25685005 TI - Taxonomic revision of genus Ablattaria Reitter (Coleoptera, Silphidae) using geometric morphometrics. AB - The genus Ablattaria Reitter, 1884 (Coleoptera: Silphidae: Silphinae) is revised. Four taxa are recognized as valid species: Ablattariaarenaria (Kraatz, 1876), Ablattariacribrata (Menetries, 1832), Ablattarialaevigata (Fabricius, 1775) and Ablattariasubtriangula Reitter, 1905. Ablattarialaevigatavar.meridionalis Ganglbauer, 1899 is newly treated as a junior subjective synonym of Ablattarialaevigata. Lectotypes are designated for Phosphugaarenaria Kraatz, 1876, Ablattariaarenariavar.punctigera Reitter, 1884, Ablattariaarenariavar.alleoni Portevin, 1926, Silphacribrata Menetries, 1832, Silphalaevigata Fabricius, 1775, Silphagibba Brulle, 1832, Ablattariagibbavar.costulata Portevin, 1926, Ablattariagibbavar.distinguenda Portevin, 1926, Ablattariagibbavar.punctata Portevin, 1926 and Ablattariasubtriangula Reitter, 1905. The distribution of all taxa is mapped, based on material examined. Geometric morphometric methods were used to evaluate shape variability in Ablattaria. Results indicated sexual dimorphism in all species. Shape inconsistency was found between the sexes of all taxa when tested independently. The first two relative warp axes indicated 65.17% shape variation in males and 65.72% in females. Canonical variate analysis separated the taxa studied. There was minimal overlap between some groups in both sexes. Differences in body shape between populations of Ablattarialaevigata from Central Europe, Italy and Greece + Turkey were also examined. Relative warps implied 58.01% shape variability on both axes in males and 64.78% in females. CVA revealed noticeable overlaps between the groups, although the Italian population demonstrated a higher separation in both sexes. PMID- 25685006 TI - A new species of bromeliad-feeding Cephaloleia Chevrolat (Coleoptera, Chrysomelidae, Cassidinae) from Costa Rica: evidence from DNA barcodes, larval and adult morphology and insect diets. AB - The Neotropical genus Cephaloleia Chevrolat (Coleoptera: Chrysomelidae: Cassidinae) includes 214 species distributed from the south of Mexico to Argentina. Cephaloleia beetles feed mostly on plants from the order Zingiberales. The interactions between Cephaloleia beetles and their Zingiberales host plants is proposed as one of the oldest and most conservative associations. Here we describe a new species of Cephaloleia (Cephaloleiakuprewiczae sp. n.) that feeds on two species of bromeliads (Pitcairniaarcuata and Pitcairniabrittoniana, Bromeliaceae: Pitcairnioideae). Cephaloleiakuprewiczae was previously described as Cephaloleiahistrionica. This study includes evidence from DNA barcodes (COI), larval and adult morphology and insect diets that separates Cephaloleiakuprewiczae from Cephaloleiahistrionica as a new species. PMID- 25685007 TI - One new species of the subgenus Hexatoma (Eriocera) Macquart (Diptera, Limoniidae) from China with a key to Chinese species. AB - One new species of the subgenus Eriocera Macquart, 1838, Hexatoma (Eriocera) cleopatroides Men, sp. n. (Southern China: Anhui) is described and illustrated. A key to all of 78 known species from China in the subgenus is provided, which was solely based on literatures. The new species is similar to Hexatoma (Eriocera) cleopatra Alexander, 1933, but distinguishes from the latter by the prescutum entirely black with two ill-defined gray stripes, by the legs with fore and middle femora brown in basal half, black in apical half, with hind femora brown in basal one-fourth, and by the wings with cells c and sc more yellowish brown than the ground color. PMID- 25685008 TI - Descriptions of two azooxanthellate Palythoa species (Subclass Hexacorallia, Order Zoantharia) from the Ryukyu Archipelago, southern Japan. AB - Two new species of zoantharians (Hexacorallia, Zoantharia, Sphenopidae), Palythoamizigama sp. n. and Palythoaumbrosa sp. n., are described from the Ryukyu Archipelago, southern Japan. Unlike almost all other known Palythoa spp., both species are azooxanthellate and inhabit low-light environments such as floors or sides of caves, crevasses, or hollows of shallow coral reefs. The two species were initially considered to be the same species from their similar habitat environments and highly similar morphological features. However, phylogenetic analyses of nuclear internal transcribed spacer (ITS) ribosomal DNA, mitochondrial 16S ribosomal DNA, and cytochrome oxidase subunit I (COI) sequences revealed that these two species have a genetically distant relationship within the genus Palythoa. Morphological characteristics, including polyp size, tentacle number, external/internal coloration, and types and sizes of cnidae were examined in this study. As a result, only tentacle coloration was found to be useful for the morphological distinction between the two species. Palythoamizigama possesses white tentacles with black horizontal stripes while Palythoaumbrosa possesses white tentacles without any stripe patterns. Considering their distant phylogenetic relationship, it can be assumed that their unique yet similar morphological and ecological characteristics developed independently in each species as an example of parallel evolution. PMID- 25685010 TI - Phylogeny and biogeography of Asthenopodinae with a revision of Asthenopus, reinstatement of Asthenopodes, and the description of the new genera Hubbardipes and Priasthenopus (Ephemeroptera, Polymitarcyidae). AB - The Neotropical species of Asthenopodinae are revised in a formal phylogenetic context. The five known species of Asthenopus Eaton, 1871, together with other five new species were included in a cladistic analysis using morphological characters (continuous and discretes). Representatives of the Afro-Oriental group of the subfamily (Povilla Navas, 1912 and Languidipes Hubbard, 1984) were also included to test the monophyletic hypothesis traditionally accepted for the group. Additional taxa representing the other subfamilies of Polymitarcyidae were incorparated: Ephoron Williamson, 1802 (Polymitarcyinae) and Campsurus Eaton, 1868, Tortopus Needham & Murphy, 1924 and Tortopsis Molineri, 2010 (Campsurinae). A matrix of 17 taxa and 72 characters was analyzed under parsimony resulting in a single tree supporting the monophyly of the subfamily Asthenopodinae. Other results include the monophyly of the Afro-Oriental taxa (Povilla and Languidipes), the paraphyletic nature of Neotropical Asthenopodinae, and the recognition of four South American genera: Asthenopus (including Asthenopuscurtus (Hagen), 1861, Asthenopusangelae de Souza & Molineri, 2012, Asthenopusmagnus sp. n., Asthenopushubbardi sp. n., Asthenopusguarani sp. n.), Asthenopodes Ulmer, 1924, stat. n. (including Asthenopuspicteti Hubbard, 1975, stat. n., Asthenopodestraverae sp. n., Asthenopodeschumuco sp. n.), Priasthenopus gen. n. (including Priasthenopusgilliesi (Dominguez), 1988, comb. n.), and Hubbardipes gen. n. (including Hubbardipescrenulatus (Molineri et al.), 2011, comb. n.). Descriptions, diagnoses, illustrations and keys are presented for all Neotropical taxa of Asthenopodinae (adults of both sexes, eggs and nymphs). Additionally a key to the subfamilies and genera of Polymitarcyidae is included. A quantitative biogeographic analysis of vicariance is presented and discussed through the study of the "taxon history" of the group. PMID- 25685009 TI - Molecular identification of blood meal sources of ticks (Acari, Ixodidae) using cytochrome b gene as a genetic marker. AB - Blood meal analysis (BMA) from ticks allows for the identification of natural hosts of ticks (Acari: Ixodidae). The aim of this study is to identify the blood meal sources of field collected on-host ticks using PCR analysis. DNA of four genera of ticks was isolated and their cytochrome b (Cyt b) gene was amplified to identify host blood meals. A phylogenetic tree was constructed based on data of Cyt b sequences using Neighbor Joining (NJ) and Maximum Parsimony (MP) analysis using MEGA 5.05 for the clustering of hosts of tick species. Twenty out of 27 samples showed maximum similarity (99%) with GenBank sequences through a Basic Local Alignment Search Tool (BLAST) while 7 samples only showed a similarity range of between 91-98%. The phylogenetic trees showed that the blood meal samples were derived from small rodents (Leopoldamyssabanus, Rattustiomanicus and Sundamysmuelleri), shrews (Tupaiaglis) and mammals (Tapirusindicus and Prionailurusbengalensis), supported by 82-88% bootstrap values. In this study, Cyt b gene as a molecular target produced reliable results and was very significant for the effective identification of ticks' blood meal. The assay can be used as a tool for identifying unknown blood meals of field collected on-host ticks. PMID- 25685011 TI - First record of the genus Gratia Thomas (Ephemeroptera, Baetidae) from China with the description of a new species. AB - A new species of Baetidae, Gratiabaibungensis sp. n., is described and illustrated based on nymphal stage collected from the southeastern Tibet (Xizang) and the genus is reported for the first time from China. This new species can be readily differentiated from its congeners by the absence of a protuberance on the posterior margin of the abdominal tergum X, glabrate simple submarginal setae on the labrum, and the posterior margin of sterna VI-IX having much longer spatulate setae. PMID- 25685012 TI - A new species of the genus Seticornuta Morley (Hymenoptera, Ichneumonidae, Metopiinae) from South Korea. AB - Old World species of the genus Seticornuta Morley are reviewed. Seven species of this genus were recorded worldwide, but only one species, Seticornutaalbopilosa (Cameron), was known from the Old World. Here, we report one new species, Seticornutakoreana sp. n., from South Korea, and redescribe the other known Old World species, Seticornutaalbopilosa, with photographs. PMID- 25685013 TI - New substitute name for the genus Poliocoris Slater, 1994 (Hemiptera, Heteroptera, Rhyparochromidae). AB - Neopoliocoris nom. n., a new substitute name is proposed for Poliocoris Slater, 1994 (Hemiptera: Heteroptera: Rhyparochromidae), preoccupied by Poliocoris Kirkaldy, 1910 (Hemiptera: Heteroptera: Pentatomidae). A new combination, Neopoliocorisumbrosus (Slater, 1994), comb. n. is proposed for Poliocorisumbrosus Slater, 1994. PMID- 25685014 TI - First record of harpacticoid copepods from Lake Tahoe, United States: two new species of Attheyella (Harpacticoida, Canthocamptidae). AB - Benthic harpacticoids were collected for the first time at Lake Tahoe, California Nevada, United States. Two species were identified as members of the genus Attheyella Brady, 1880. The genus Attheyella comprises about 150 species within six subgenera, but only twelve species have previously been reported from North American freshwater habitats. The two new species of Attheyella described here have a 3-segmented endopod on P1 and 2-segmented P2-P4 endopods, the distal segment of exopod of P2-P4 has three outer spines, and the P5 has five setae on the exopod and six setae on the baseoendopod. Attheyella (Attheyella) tahoensissp. n. most closely resembles Attheyella (Attheyella) idahoensis (Marsh, 1903) from Idaho, Montana, and Alaska (United States) and Attheyella (Attheyella) namkungi Kim, Soh & Lee, 2005 from Gosu Cave in South Korea. They differ mainly by the number of setae on the distal endopodal segment of P2-P4. In addition, intraspecific variation has been observed on the caudal rami. Attheyella (Neomrazekiella) tessiaesp. n. is characterized by the extension of P5 baseoendopod, 2-segmented endopod of female P2-P3, and naked third seta of male P5 exopod. The two new species are likely endemic to Lake Tahoe, an isolated alpine lake within the Great Basin watershed in the western United States. PMID- 25685015 TI - A taxonomic study of Ooctonus (Hymenoptera, Mymaridae) from Heilongjiang, China. AB - Five species of Ooctonus Haliday (Hymenoptera, Mymaridae) from Heilongjiang Province, China, are reviewed. One species, Ooctonushuberi sp. n., is described as new, and four species, Ooctonusorientalis Doutt, Ooctonussaturn Triapitsyn, Ooctonussublaevis Forster and Ooctonusvulgatus Haliday are reported as new to China. A key to the females of the 10 described Chinese species is given. All the specimens are deposited in the insect collections of Northeast Forestry University, China. PMID- 25685016 TI - Temnothoraxcrasecundus sp. n. - a cryptic Eurocaucasian ant species (Hymenoptera, Formicidae) discovered by Nest Centroid Clustering. AB - The paper integrates two independent studies of numeric morphology-based alpha taxonomy of the cryptic ant species Temnothoraxcrassispinus (Karavajev, 1926) and Temnothoraxcrasecundus sp. n. conducted by different investigators, using different equipment, considering different character combinations and evaluating different samples. Samples investigated included 603 individual workers from 203 nests - thereof 104 nest samples measured by Seifert and 99 by Csosz. The material originated from Europe, Asia Minor and Caucasia. There was a very strong interspecific overlap in any of the 29 shape characters recorded and subjective expert determination failed in many cases. Primary classification hypotheses were formed by the exploratory data analysis Nest Centroid (NC) clustering and corrected to final species hypotheses by an iterative linear discriminant analysis algorithm. The evaluation of Seifert's and Csosz's data sets arrived at fully congruent conclusions. NC-Ward and NC-K-means clustering disagreed from the final species hypothesis in only 1.9 and 1.9% of the samples in Seifert's data set and by 1.1 and 2.1% in Csosz's data set which is a strong argument for heterospecificity. The type series of Temnothoraxcrassispinus and Temnothoraxcrasecundus sp. n. were allocated to different clusters with p = 0.9851 and p = 0.9912 respectively. The type series of the junior synonym Temnothoraxslavonicus (Seifert, 1995) was allocated to the Temnothoraxcrassispinus cluster with p = 0.9927. Temnothoraxcrasecundus sp. n. and Temnothoraxcrassispinus are parapatric species with a long contact zone stretching from the Peloponnisos peninsula across Bulgaria northeast to the southern Ukraine. There is no indication for occurrence of interspecifically mixed nests or intraspecific polymorphism. However, a significant reduction of interspecific morphological distance at sites with syntopic occurrence of both species indicates local hybridization. The results are discussed within the context of the Pragmatic Species Concept of Seifert (2014). The taxonomic description and a differential diagnosis of Temnothoraxcrasecundus sp. n. are given. PMID- 25685017 TI - Revision of the genus Exaesiopus Reichardt, 1926 (Coleoptera, Histeridae, Saprininae). AB - The genus Exaesiopus Reichardt, 1926 is revised herein. It now contains seven species; one new combination is proposed: Pachylopusglaucus = Exaesiopusglaucus (Bickhardt, 1914), comb. n., and one species is described as new: Exaesiopustherondi sp. n. from Afghanistan. Subspecies Exaesiopusgrossipesberberus Peyerimhoff, 1936 is sunk in synonymy with Exaesiopusgrossipes (Marseul, 1855), syn. n. Lectotypes and paralectotypes, respectively, for Saprinusgrossipes Marseul, 1855, Exaesiopusgrossipesberberus Peyerimhoff, 1936 and a neotype for Pachylopusglaucus Bickhardt, 1914 are designated. Exaesiopusgrossipes is re-described; other species are provided with diagnostic descriptions and supplemented by SEM micrographs, colour images, and line drawings of their male genitalia. A key to species is given. Exaesiopusglaucus (Bickhardt, 1914) is newly recorded from the Republic of South Africa; Exaesiopustorvus Reichardt, 1926 is new to Uzbekistan and Russia; Exaesiopusatrovirens Reichardt, 1926 is new to Ukraine and Tajikistan; and Exaesiopushenoni (Schmidt, 1896) is new to Libya and Djibouti. PMID- 25685018 TI - Two new species of Stenochironomus Kieffer (Diptera, Chironomidae) from Zhejiang, China. AB - Two new species of Stenochironomus Kieffer (Diptera: Chironomidae: Chironominae), Stenochironomusbrevissimus sp. n. and Stenochironomuslinanensis sp. n., are described from China and the male imagines are illustrated. Stenochironomusbrevissimus sp. n. can be separated from the so far known species by having very short and small, spatulate superior volsella with two long setae, whereas Stenochironomuslinanensis sp. n. is easily separated from the other species of Stenochironomus by the following characters: wings transparent, body yellow, superior volsella finger-like, with nine long setae, elongated inferior volsella with four long setae and one well developed terminal spine; tergite IX with 10-15 long setae medially. A key to the males of Stenochironomus occurring in China is given. PMID- 25685019 TI - Description of Telamoptiliagrewiae sp. n. and the consequences for the definition of the genera Telamoptilia and Spulerina (Lepidoptera, Gracillariidae, Gracillariinae). AB - The new species Telamoptiliagrewiae, reared from leafmines on Grewiabiloba (Malvaceae) is described with details on adult and immature stages. The larval head and the pupa are described for the first time in Telamoptilia Kumata & Kuroko, 1988, and are illustrated with scanning electron micrographs and line drawings. Photographs of adult habitus, wing venation, male and female genitalia, as well as host plant and mines are provided. The apomorphic adult and larval characters of the new species in Telamoptilia are discussed in relation to the recognition of the genera Telamoptilia and Spulerina Vari, 1961. PMID- 25685020 TI - New species of Rissoidae (Mollusca, Gastropoda) from the Archipelago of the Azores (northeast Atlantic) with an updated regional checklist for the family. AB - Four new species of shallow-water marine gastropods belonging to the family Rissoidae are described from the Archipelago of the Azores: Setiaalexandrae sp. n., Setiaermelindoi sp. n., Setianetoae sp. n., and Manzoniamartinsi sp. n. These novelties increase the regional rissoid fauna to 39 species, of which 29 live in shallow-water habitats. A list of the species of Rissoidae from the Azores is presented based on data from the literature and new material examined. PMID- 25685021 TI - Two new species of Bryobia (Acarina, Prostigmata, Tetranychidae) from South France. AB - Two new species of Tetranychidae belonging to the genus Bryobia are reported from France. Bryobiabelliloci sp. n. and Bryobiagigas sp. n. collected on Genistacinerea and Bituminariabituminosa, respectively, are described and illustrated in the present work. Additional data to the original description of Bryobiacinereae are given and an identification key to known Bryobia species from France is also provided. PMID- 25685022 TI - One new species of the genus Belisana Thorell, 1898 (Araneae, Pholcidae) from northern Vietnam. AB - One new species Belisanadenticulata sp. n. (?) is reported from northern Vietnam based on material collected by fogging the forest canopy. This species resembles Belisanascharffi Huber, 2005, but can be distinguished by relatively long distance between proximal parts of proximo-lateral apophysis and distal apophysis on male chelicerae, by presence of a nearly saddle-shaped prolateral sclerite on procursus, and by different shape of retrolateral membranous flap on procursus. Type specimens are deposited in the Vietnam Academy of Science and Technology in Hanoi. PMID- 25685023 TI - Additions to the review of Chinese Enochrus, with description of a new species (Coleoptera, Hydrophilidae, Enochrinae). AB - A new species, Enochrus (Methydrus) limbourgisp. n., is described from Jiangxi Province, Southeast China, and illustrated. Subgenus Enochrus s. str. Thomson, 1859 is recorded for the first time in China, based on the record of Enochrus(s. str.)melanocephalus (Olivier, 1792) from Inner Mongolia. The male of Enochrus (Hydatotrephis) liangi Jia & Zhao, 2007 is described for the first time. PMID- 25685024 TI - A review of the genus Toxorhina Loew from China, with descriptions of three new species (Diptera, Limoniidae, Limoniinae). AB - The genus Toxorhina Loew from China is reviewed. Seven species belonging to the subgenus Ceratocheilus Wesche are recognized, of which three species, Toxorhina (Ceratocheilus) huanglicasp. n., Toxorhina (Ceratocheilus) omnifuscasp. n. and Toxorhina (Ceratocheilus) univirgatasp. n., are described as new to science, Toxorhina (Ceratocheilus) fuscolimbata Alexander is recorded from China for the first time, and three known species are redescribed and illustrated. PMID- 25685025 TI - A new species of Telmatobius (Amphibia, Anura, Telmatobiidae) from the Pacific slopes of the Andes, Peru. AB - We describe a new species of Telmatobius from the Pacific slopes of the Andes in central Peru. Specimens were collected at 3900 m elevation near Huaytara, Huancavelica, in the upper drainage of the Pisco river. The new species has a snout-vent length of 52.5 +/- 1.1 mm (49.3-55.7 mm, n = 6) in adult females, and 48.5 mm in the single adult male. The new species has bright yellow and orange coloration ventrally and is readily distinguished from all other central Peruvian Andean species of Telmatobius but Telmatobiusintermedius by having vomerine teeth but lacking premaxillary and maxillary teeth, and by its slender body shape and long legs. The new species differs from Telmatobiusintermedius by its larger size, flatter head, and the absence of cutaneous keratinized spicules (present even in immature females of Telmatobiusintermedius), and in males by the presence of minute, densely packed nuptial spines on dorsal and medial surfaces of thumbs (large, sparsely packed nuptial spines in Telmatobiusintermedius). The hyper-arid coastal valleys of Peru generally support low species richness, particularly for groups such as aquatic breeding amphibians. The discovery of a new species in this environment, and along a major highway crossing the Andes, shows that much remains to be done to document amphibian diversity in Peru. PMID- 25685026 TI - Three new species of saddled loricariid catfishes, and a review of Hemiancistrus, Peckoltia, and allied genera (Siluriformes). AB - Three new species of saddled hypostomine loricariids are described. According to a recent phylogenetic analysis, these species are members of the genus Peckoltia. The species differ from all described Peckoltia except Peckoltiafurcata and Peckoltiasabaji by having the dentaries meet at an angle greater than 90 degrees . The species also have similarities to Hemiancistrus, and can be separated from all described species by having dorsal saddles. We discuss the taxonomy of Peckoltia, Hemiancistrus, and allied genera and recognize Ancistomus as valid for Peckoltiafeldbergae, Hemiancistrusmicrommatos, Ancistrussnethlageae, Hemiancistrusspilomma, and Hemiancistrusspinosissimus. We recommend descriptions of genera for several clades of Hemiancistrus and restriction of Hemiancistrus to the type species of the genus, Hemiancistrusmedians. Chaetostomusmacrops is transferred to Pseudancistrus and recognized as a junior synonym of Pseudancistrusmegacephalus. The Hemiancistrusannectens group of species (Hemiancistrusannectens, Hemiancistrusargus, Hypostomusaspidolepis, Hemiancistrusfugleri, Hemiancistrusholostictus, Hemiancistrusmaracaiboensis, Hemiancistruspanamensis, Hemiancistruswilsoni) are recognized in Hypostomus. Multivariate analysis reveals that the newly described species differ from one another in shape space, but overlap broadly with other Peckoltia (Peckoltialujani), narrowly with other Peckoltia (Peckoltiagreedoi), or broadly with Etsaputu (Peckoltiaephippiata). PMID- 25685027 TI - Crowdsourcing the identification of organisms: A case-study of iSpot. AB - Accurate species identification is fundamental to biodiversity science, but the natural history skills required for this are neglected in formal education at all levels. In this paper we describe how the web application ispotnature.org and its sister site ispot.org.za (collectively, "iSpot") are helping to solve this problem by combining learning technology with crowdsourcing to connect beginners with experts. Over 94% of observations submitted to iSpot receive a determination. External checking of a sample of 3,287 iSpot records verified > 92% of them. To mid 2014, iSpot crowdsourced the identification of 30,000 taxa (>80% at species level) in > 390,000 observations with a global community numbering > 42,000 registered participants. More than half the observations on ispotnature.org were named within an hour of submission. iSpot uses a unique, 9 dimensional reputation system to motivate and reward participants and to verify determinations. Taxon-specific reputation points are earned when a participant proposes an identification that achieves agreement from other participants, weighted by the agreers' own reputation scores for the taxon. This system is able to discriminate effectively between competing determinations when two or more are proposed for the same observation. In 57% of such cases the reputation system improved the accuracy of the determination, while in the remainder it either improved precision (e.g. by adding a species name to a genus) or revealed false precision, for example where a determination to species level was not supported by the available evidence. We propose that the success of iSpot arises from the structure of its social network that efficiently connects beginners and experts, overcoming the social as well as geographic barriers that normally separate the two. PMID- 25685028 TI - New Bythinella (Gastropoda, Bythinellidae) species from western Turkey. AB - Bythinellaanatolica sp. n., Bythinellaistanbulensis sp. n., Bythinellamagdalenae sp. n., and Bythinellawilkei sp. n. from western Turkey are described herein. Illustrations of the shell and genitalia of the newly described taxa, together with comparisons with previously known Bythinella taxa and a key to the species from western Turkey, are also provided. PMID- 25685029 TI - A pioneer survey and DNA barcoding of some commonly found gastropod molluscs on Robben Island. AB - Nineteen species of abundant gastropods were collected at Robben Island, including introduced dune snails and European brown garden snails. They were identified using morphology and DNA barcoding. It was expected that the species recorded would be similar to those from the Cape peninsula, South Africa, but we were surprised to find some exceptions: the very abundant invasive mussel species in South Africa, the South American bisexual mussel (Semimytilusalgosus), and the beaded topshells (Oxysteleimpervia) were not found on Robben Island. Possible explanations are presented for these differences. PMID- 25685030 TI - A new species of Hyalella (Crustacea, Amphipoda, Dogielinotidae) from the Atlantic Forest of Misiones, Argentina. AB - The freshwater genus Hyalella Smith, 1874 has a distribution restricted to the Western Hemisphere with most species being found in South America. In this report we describe a new species of Hyalella from the Atlantic Forest of the Misiones province, Argentina. PMID- 25685031 TI - A review of Solenysa spiders from Japan (Araneae, Linyphiidae), with a comment on the type species S.mellotteei Simon, 1894. AB - The present paper gives a review of Solenysa species from Japan and provides a solution for the species bearing the generotype name Solenysamellotteei Simon, 1894. A total of six species are recorded, including two new species Solenysamacrodonta sp. n. and Solenysatrunciformis sp. n. The species collected from Kawasaki (NSMT-Ar 11154) and Hachioji should be the generotype Solenysamellotteei, with Solenysaakihisai Tu, 2011, syn. n. as its junior synonym. To distinguish these congeneric species from each other, their genital characters are provided in detail based on images collected by scanning electron microscopy and light microscopy. PMID- 25685032 TI - Trophic relations of Opatrumsabulosum (Coleoptera, Tenebrionidae) with leaves of cultivated and uncultivated species of herbaceous plants under laboratory conditions. AB - We carried out a quantitative assessment of the consumption of herbaceous plants by Opatrumsabulosum (Linnaeus, 1761) - a highly significant agricultural pest species. We researched the feeding preferences of this pest species with respect to 33 uncultivated and 22 cultivated plant species. This species of darkling beetle feeds on many uncultivated plant species, including those with hairy leaves and bitter milky sap, such as Scabiosaucrainca (5.21 mg/specimen/24 hours), Euphorbiavirgata (3.45), Solanumnigrum (3.32), Centauriascabiosa (2.47), Lamiumalbum (2.41), Aristolochiaclematitis (1.76), Chenopodiumalbum (1.73), Arctiumlappa (1.51), Asperulaodorata (1.20). A high rate of leaf consumption is also characteristic for cultivated species, for example, Perillanankinensis (5.05 mg/specimen/24 hours), Lycopersiconesculentum (3.75), Tropaeolummajus (3.29), Nicotianatabacum (2.66), Rumexacetosa (1.96), Betavulgaris (1.27). Opatrumsabulosum is capable of feeding on plants which are poisonous to cattle. This species of darkling beetle consumes 95.5% of the cultivated and 48.5% of the uncultivated herbaceous plants researched. PMID- 25685033 TI - The bostrichidae of the maltese islands (coleoptera). AB - The Bostrichidae of the Maltese Islands are reviewed. Ten species are recorded with certainty from this Archipelago, of which 6 namely, Trogoxylonimpressum (Comolli, 1837), Amphicerusbimaculatus (A.G. Olivier, 1790), Heterobostrychusaequalis (Waterhouse, 1884), Sinoxylonunidentatum (Fabricius, 1801), Xyloperthellapicea (A.G. Olivier, 1790) and Apatemonachus Fabricius, 1775 are recorded for the first time. Two of the mentioned species (Heterobostrychusaequalis and Sinoxylonunidentatum) are alien and recorded only on the basis of single captures and the possible establishment of these species is discussed. Earlier records of Scobiciapustulata (Fabricius, 1801) from Malta are incorrect and should be attributed to Scobiciachevrieri (A. Villa & J.B. Villa, 1835). A zoogeographical analysis and an updated checklist of the 12 species of Bostrichidae recorded from the Maltese Islands and neigbouring Sicilian islands (Pantelleria, Linosa and Lampedusa) are also provided. Rhizoperthadominica(Fabricius, 1792)formgranulipennis Lesne in Beeson & Bhatia, 1937 from Uttarakhand (northern India) was overlooked by almost all subsequent authors. Its history is summarized and the following new synonymy is established: Rhizoperthadominica(Fabricius, 1792)formgranulipennis Lesne in Beeson & Bhatia, 1937 = Rhyzoperthadominica (Fabricius, 1792), syn. n. Finally, records of Amphicerusbimaculatus from Azerbaijan, of Bostrichuscapucinus (Linnaeus, 1758) from Jordan and Syria, of Scobiciachevrieri from Jordan and Italy, of Xyloperthellapicea from Italy, and of Apatemonachus from Corsica (France) and Italy, are also provided. PMID- 25685034 TI - Rhinolekoscapetinga: a new cascudinho species (Loricariidae, Otothyrinae) from the rio Tocantins basin and comments on its ancestral dispersal route. AB - The present study deals with the description of a new species of Rhinolekos. It can be distinguished from its congeners by having 31 vertebrae, the anterior portion of the compound supraneural-first dorsal-fin proximal radial contacting the neural spine of the 9(th) vertebra, the absence of transverse dark bands in the pectoral, pelvic and anal-fin rays, 24-28 plates in the dorsal series, the lack of odontodes on the ventral tip of the snout, the absence of accessory teeth, a greater prenasal length, a smaller head length, and by a greater snout length. Rhinolekoscapetinga is restricted to the headwaters of the rio Tocantins and it is the first species of this genus in the Amazon basin. Additionally, we present a brief discussion of a biogeographic scenario that may explain the dispersal of the new species from the rio Paranaiba to the rio Tocantins basin. We suggest that the ancestral lineage of Rhinolekoscapetinga reached the rio Tocantins from portions of the rio Paranaiba at the end of the Miocene, about 6.3 Mya (4.1-13.9 Mya 95% HPD), probably as a result of headwater capture processes among adjacent drainages. PMID- 25685035 TI - IMp: The customizable LEGO((r)) Pinned Insect Manipulator. AB - We present a pinned insect manipulator (IMp) constructed of LEGO(r) building bricks with two axes of movement and two axes of rotation. In addition we present three variants of the IMp to emphasise the modular design, which facilitates resizing to meet the full range of pinned insect specimens, is fully customizable, collapsible, affordable and does not require specialist tools or knowledge to assemble. PMID- 25685036 TI - Systemic review on drug related hospital admissions - A pubmed based search. AB - BACKGROUND: Drug related admissions have significantly increased over the past few decades. According to various studies on drug related hospital admissions, it was estimated that around 5-10% of hospital admissions were due to drug related problems (DRP), in which 50% of them are avoidable. OBJECTIVE: The objective of the study was to derive results from various studies conducted on drug related hospital admissions and have an overall view about the incidence, frequency, cost of treatment, major causative drugs, problems for drug related hospital admissions, and preventable drug related admissions and summarize the factors responsible for the occurrence of DRP. METHOD: Relevant literatures related to 'drug related hospital admissions' were obtained from PubMed database. Articles that were published from October 2007 to September 2012 were collected. All the studies being shown in the search results were considered for the study irrespective of the specialty department. RESULTS: A total of 366 articles were found based on the keyword 'drug related hospital admission', 'drug related problem admission', and 'adverse drug event admissions' search. Out of which 49 articles were identified to be showing relevance to the study. Non-English, abstract-only articles, and out-patient adverse drug reaction (ADR) studies were filtered from 49 articles. Finally 15 articles were taken up for the study. Systemic analysis was made on these articles and the results were summarized. CONCLUSION: Most of DRP studies were retrospective, multicenter studies conducted in general populations in Europe. The main objective of the studies was to estimate DRP frequency, incidence, risk factors and trends of DRP hospital admissions. Anti-neoplastic agents, CVS drugs and CNS drugs were related to most of the drug related problems. These studies concluded polypharmacy and older age were the major risk factors for developing drug related problems. It was found that the cost for the management of DRP was directly proportional to severity. PMID- 25685037 TI - Importance and globalization status of good manufacturing practice (GMP) requirements for pharmaceutical excipients. AB - Pharmaceutical excipients are no longer inert materials but it is effective and able to improve the characteristics of the products' quality, stability, functionality, safety, solubility and acceptance of patients. It can interact with the active ingredients and alter the medicament characteristics. The globalization of medicines' supply enhances the importance of globalized good manufacturing practice (GMP) requirements for pharmaceutical excipients. This review was intended to assess the globalization status of good manufacturing practice (GMP) requirements for pharmaceutical excipients. The review outcomes demonstrate that there is a lack of accurately defined methods to evaluate and measure excipients' safety. Furthermore good manufacturing practice requirements for excipients are not effectively globalized. PMID- 25685038 TI - Can an oral antidiabetic (rosiglitazone) be of benefit in leukemia treatment? AB - PPARs are ligand-regulated transcription factors and regulate expression of several gene products. Therefore, PPARs are being studied for their possible contribution to the treatment of cancer, atherosclerosis, inflammation, infertility and demyelinating diseases. Primary AML patients were observed to have significantly elevated PPARgamma mRNA expression compared to normal peripheral blood or bone marrow mononuclear cells. This study investigated the cytotoxic effects of rosiglitazone maleate, a pure PPARgamma agonist, in vitro in HL-60 cell line. This study obtained results which can provide guidance for future studies. Whether the PPARy agonist rosiglitazone maleate may provide additive effects in refractory or relapsing cases of acute leukemia may be set as an objective for the future studies. PMID- 25685039 TI - Evaluation of T2DM related knowledge and practices of Omani patients. AB - BACKGROUND: The prevalence of diabetes mellitus (DM) has increased alarmingly mainly due to the life style changes and obesity factor. Approximately 10% of the Omani population is suffering from this chronic disease and according to World Health Organization, number of subjects living with diabetes in Oman will rise from 75,000 in 2000 to 217,000 in 2025. It has been well established that data on KP of diabetic patients reveal aspects of education that need to be reinforced and addressed in order to improve diabetes management. OBJECTIVE: The aim of this cross sectional study was to assess the diabetes mellitus type 2 related knowledge and practices (KP) of Omani adult patients. MATERIALS AND METHODS: Diabetic patients were recruited using the convenient sampling method from Outpatient diabetes clinic of various primary health care centers and private hospitals in Muscat region of Sultanate of Oman. KP of patients who agreed to participate in the study were assessed by administering a self designed questionnaire containing 15 close ended or multiple choice type questions in face to face interviews. The collected data were analyzed by SPSS software. RESULTS AND DISCUSSION: 106 patients with T2DM participated in this study (42 men and 64 women). Majority of them were; married (83%), above 50 years (64.2%), on oral hypoglycemic (56.6%), having family history of diabetes (66%). The mean +/- SD knowledge score of participants was found to be 4.92 +/- 1.22 out of maximum possible score of 8. CONCLUSION: Omani patients seemed aware and displayed satisfactory diabetes knowledge and good practices except adherence to regular exercise. We recommend to design and develop diabetes educational programs that could help Omani patients in diabetes management and improvement of quality of life. PMID- 25685040 TI - Use of an entacapone-containing drug combination and risk of death: Analysis of the FDA AERS (FAERS) database. AB - To assess the signal of death associated with the use of an entacapone-containing drug combination in the FDA Adverse Event Reporting System (FAERS) database. Reports of death events submitted between January 2004 and December 2010 were retrieved and analysed by the reporting odds ratio (ROR). The ROR of case/non case reports of death associated with an entacapone-containing drug combination was compared with the levodopa/carbidopa combination using the FDA AERS database. Eighty-seven reports linked the entacapone-containing drug combination to death, compared to 27 reports of death linking the levodopa/carbidopa combination. The ROR was statistically significant for the association between deaths with the use of an entacapone-containing drug combination (1.86 [95% CI 1.50-2.31]). In contrast, the ROR of death associated with the combination of levodopa and carbidopa was not statistically significant (0.89 [95% CI 0.61-1.30)]. Based on analysing reports in the FAERS database, there is a risk of death with the use of an entacapone-containing drug combination. These results generated a signal of death with the use of this drug. However, epidemiological studies are required to confirm this association. PMID- 25685041 TI - Adherence to medication among outpatient adolescents with epilepsy. AB - BACKGROUND AND OBJECTIVE: The promotion of medication adherence is considered as an integral component of pharmaceutical care practice and patient healthcare. An approach which focuses on the choice and dose of antiepileptic drug will have limited success without medication adherence. This study sought to assess medication adherence for improvement among adolescents who are suffering from epilepsy. METHODS: A total of 116 patients affected with idiopathic epilepsy and fulfilled the inclusion criteria were recruited in the current study. Adherence to the treatment was evaluated during patients' hospitalization in the Department of Neurology at Riyadh National Hospital, Riyadh, Saudi Arabia, between December 2011 and January 2014. The medication adherence has been assessed during semi structured interviews with each patient and/or his parents using a multiple choice graded questionnaire. RESULTS: From the selected group of patients, only 94 patients (81.0%) fulfilled the inclusion criteria within the study period. Thirty-six of respondents (38.3%) were non adherent to antiepileptic treatment. No statistical differences were found between males and females regarding their ages, age at diagnosis of epilepsy, mother age, epilepsy duration, family numbers, number of poor-adherents or seizure frequency. The most important factors that were significantly affecting patients' adherence to the prescribed medications were age of mother, family number, number of administered drugs, the stability of parents' marriage, family support, and seizure frequency as well as the regularity of the relationship between patients and their healthcare providers. Forgetfulness was the most common cause of non-adherence among this group of patients followed by inability to obtain medication and fear from side effects of drugs. Our results revealed also that the number of patients who felt to be stigmatized is significantly more in non-adherent group as compared to patients with a strong sense of normality (P < 0.05). A positive relationship between adherence and the necessity and benefit scales at which patients have a stronger belief in the necessity of medication for controlling illness was associated with good adherence. CONCLUSION: The assessment of medication adherence among epileptic patients should be a routine part of the management process to improve the health care and quality of lives of those patients. PMID- 25685042 TI - An example of using a decision making framework designed for non-medical prescribers as a method for enhancing prescribing safety for inhaled corticosteroids (ICS). AB - Non-medical prescribing is needed especially with the increased demand for health care and the physicians' time constrains. Also, it is not well regulated in Saudi Arabia unlike the United Kingdom. This report aims to demonstrate the urged need for regulations to maintain a safe non-medical prescribing process. It also adapts the single competency framework provided by the United Kingdom national prescribing centre (NPC, 2012) to be utilised by the respiratory therapist for a safe prescribing process for inhaled corticosteroids (ICS) to control adult asthma as an example. The framework is thought to be an effective tool for safe non-medical prescribing and it is highly recommended to develop a national Saudi framework to maintain the patients' safety and utilise resources. PMID- 25685043 TI - Blood viscosity as a sensitive indicator for paclitaxel induced oxidative stress in human whole blood. AB - In this study, the in vitro effects of paclitaxel (PTX) and Cremophor-EL (CrEL) on blood viscosity and oxidative stress markers were investigated. Whole-blood samples were collected from healthy volunteers and co-incubated with PTX, CrEL or their combination then compared with control blood samples. After a 24 h incubation time, the whole-blood viscosity (WBV), erythrocyte sedimentation rate (ESR), levels of whole-blood malondialdehyde (MDA), protein carbonyl content (PCC) and reduced glutathione (GSH) were determined. Moreover, plasma nitrite and plasma sialic acid (SA) values were measured. The present results revealed that the incubation of blood samples with PTX, CrEL or PTX plus CrEL significantly increased the values of WBV, ESR, MDA and PCC compared to control samples. In contrast, a significant decrease in levels of GSH, SA and nitrite was observed after incubation of blood samples with tested agents compared to control. The effects of tested agents on the measured parameters were more pronounced in the case of blood samples treated with PTX plus CrEL. The present study demonstrates that PTX-induced oxidative stress is associated with an increase of WBV. PMID- 25685044 TI - The effect of antifungal combination on transcripts of a subset of drug resistance genes in clinical isolates of Candida species induced biofilms. AB - Biofilm formation is often associated with increased Candida resistance toward antifungal agents. Therefore, the current study aimed to assess the incidence of biofilm formation among Candida isolates and to investigate the effect of high doses of fluconazole {FLC}, voriconazole {VOC} and amphotericin B {AMB}, singly and in combination on mature biofilms. Moreover, it aimed to assess the expression of selected genes (CDR1, KRE1 and SKN1) responsible for Candida biofilm resistance. The study included 49 patients; samples were collected from the King Khalid Hospital, Riyadh, Saudi Arabia. Isolates were prepared for biofilm formation and quantification using 0.4% (w/v) crystal violet. Minimum Inhibitory concentration (MIC) and fractional inhibitory concentration (FIC) were conducted by the broth microdilution method. Biofilm eradication was evaluated using counting, XTT stain intensity and observed under the inverted microscope. Selected genes were evaluated in Candida biofilms under the effect of antifungal exposure using QPCR. The major isolates were Candida albicans (65.3%) followed by Candida tropicalis and Candida glabrata. 77.6% of the strains were biofilm formers. AMB showed susceptibility in 87.8% of isolates, followed by VOC (77.6%) and FLC (67.3%). MIC50 and MIC90 were (0.03, 0.125), (0.5, 8), (2, >128) MUg/ml for AMB, VOC and FLC, respectively. 34.7% and 18.4% of the isolates were antagonistic to AMB/FLC and AMB/VOC, respectively. Mature biofilms of ten selected isolates were found resistant to FLC (1000 MUg/ml). VOR and AMB concentration required to inhibit biofilm formation was 16-250 fold higher than the MIC for planktonic cells. Isolates showed significant reduction with antifungal combination when compared with the untreated controls (p value ? 0.01), or using fluconazole alone (p value ? 0.05). High doses of the antifungals were employed to assess the effect on the persisters' selected gene expression. Marked over expression of SKN1 and to a lesser extent KRE1 was noticed among the mature biofilms treated with AMB alone or in combination after 1 h of exposure, and SKN1 expression was even more sharply induced after 24 h. No statistically significant over expression of CDR1 was observed in biofilms after exposure to high doses of FLC, VOC or any of the combinations used. PMID- 25685045 TI - Penetration enhancers in proniosomes as a new strategy for enhanced transdermal drug delivery. AB - The aim of this work is to investigate penetration enhancers in proniosomes as a transdermal delivery system for nisoldipine. This was performed with the goal of optimising the composition of proniosomes as transdermal drug delivery systems. Plain proniosomes comprising sorbitan monostearate, cholesterol, ethanol and a small quantity of water were initially prepared. Subsequently, proniosomes containing lecithin or skin penetration enhancers were prepared and evaluated for transdermal delivery of nisoldipine. The plain proniosomes significantly enhanced the transdermal flux of nisoldipine to reach 12.18 MUg cm(-2) h(-1) compared with a saturated aqueous drug solution which delivered the drug at a rate of 0.46 MUg cm(-2) h(-1). Incorporation of lecithin into such proniosomes increased the drug flux to reach a value of 28.51 MUg cm(-2) h(-1). This increase can be attributed to the penetration enhancing effect of lecithin fatty acid components. Replacing lecithin oleic acid (OA) produced proniosomes of comparable efficacy to the lecithin containing system. The transdermal drug flux increased further after incorporation of propylene glycol into the OA based proniosomes. Similarly, incorporation of isopropyl myristate into plain proniosomes increased drug flux. The study introduced enhanced proniosomes as a promising transdermal delivery carrier and highlighted the role of penetration enhancing mechanisms in enhanced proniosomal skin delivery. The study opened the way for another line of optimisation of niosome proconcentrates. PMID- 25685046 TI - Charge-transfer reaction of 2,3-dichloro-1,4-naphthoquinone with crizotinib: Spectrophotometric study, computational molecular modeling and use in development of microwell assay for crizotinib. AB - The reaction of 2,3-dichloro-1,4-naphthoquinone (DCNQ) with crizotinib (CZT; a novel drug used for treatment of non-small cell lung cancer) was investigated in different solvents of varying dielectric constants and polarity indexes. The reaction produced a red-colored product. Spectrophotometric investigations confirmed that the reaction proceeded through charge-transfer (CT) complex formation. The molar absorptivity of the complex was found to be linearly correlated with the dielectric constant and polarity index of the solvent; the correlation coefficients were 0.9567 and 0.9069, respectively. The stoichiometric ratio of DCNQ:CZT was found to be 2:1 and the association constant of the complex was found to be 1.07 * 10(2) l/mol. The kinetics of the reaction was studied; the order of the reaction, rate and rate constant were determined. Computational molecular modeling for the complex between DCNQ and CZT was conducted, the sites of interaction on CZT molecule were determined, and the mechanism of the reaction was postulated. The reaction was employed as a basis in the development of a novel 96-microwell assay for CZT in a linear range of 4-500 MUg/ml. The assay limits of detection and quantitation were 2.06 and 6.23 MUg/ml, respectively. The assay was validated as per the guidelines of the International Conference on Harmonization (ICH) and successfully applied to the analysis of CZT in its bulk and capsules with good accuracy and precision. The assay has high throughput and consumes a minimum volume of organic solvents thus it reduces the exposures of the analysts to the toxic effects of organic solvents, and significantly reduces the analysis cost. PMID- 25685047 TI - Development and validation of stability-indicating high performance liquid chromatography method to analyze gatifloxacin in bulk drug and pharmaceutical preparations. AB - Quantitative determination of gatifloxacin in tablets, solid lipid nanoparticles (SLNs) and eye-drops using a very simple and rapid chromatographic technique was validated and developed. Formulations were analyzed using a reverse phase SUPELCO(r) 516 C-18-DB, 50306-U, HPLC column (250 mm * 4.6 mm, 5 MUm) and a mobile phase consisting of disodium hydrogen phosphate buffer:acetonitrile (75:25, v/v) and with orthophosphoric acid pH was adjusted to 3.3 The flow rate was 1.0 mL/min and analyte concentrations were measured using a UV-detector at 293 nm. The analyses were performed at room temperature (25 +/- 2 degrees C). Gatifloxacin was separated in all the formulations within 2.767 min. There were linear calibration curves over a concentration range of 4.0-40 MUg.mL(-1) and correlation coefficients of 0.9998 with an average recovery above 99.91%. Detection of analyte from different dosage forms at the same Rt indicates the specificity and stability of the developed method. PMID- 25685048 TI - Formulation and optimization of potassium iodide tablets. AB - The use of potassium iodide (KI) as a protective agent against accidental radioactive exposure is well established. In this study, we aimed to prepare a KI tablet formulation using a direct compression method. We utilized Design of Experiment (DoE)/mixture design to define the best formulation with predetermined physical qualities as to its dissolution, hardness, assay, disintegration, and angle of repose. Based on the results from the DoE, the formulation had the following components (%w/w): Avicel 48.70%, silicon dioxide 0.27%, stearic acid (1.00%), magnesium stearate 2.45%, and dicalcium phosphate 18.69%, in addition to potassium iodide 28.89% (130 mg/tablet). This formulation was scaled-up using two tablet presses, a single-punch press and a rotary mini tablet press. The final scaled-up formulation was subjected to a variety of quality control tests, including photo-stability testing. The results indicate that potassium iodide tablets prepared by a rotary mini tablet press had good pharmaceutical characteristics and a shelf-life of 25 days when stored at room temperature protected from light. PMID- 25685049 TI - Exploring medication use by blind patients in Saudi Arabia. AB - OBJECTIVE: To explore the characteristics of medication use and challenges experienced by the blind patients. METHODS: This cross-sectional descriptive study included blind persons living in Saudi Arabia who were at least 18 years of age. Participants were recruited through a number of nongovernmental blind associations (in the central, western, eastern regions), universities, social networks, and specialized websites for the blind. A questionnaire was designed and administered via face-to-face meetings with participants and made available online through Google Docs. RESULTS: There were a total of 121 respondents of which 26 were excluded based on their ability to visually identify their medications or being <18 years old. The majority of the respondents were 18-29 years old (68%), 49% were male and 51% were female. Around 57% had a college degree while 27% had a high school degree. Diagnosis with a chronic disease was reported by 71 participants (79%, 5 missing). The most common diseases were diabetes and asthma (22%) followed by hypertension (17%). Most blind patients (75%) believed that physicians were the most reliable source of medication information. The medication information and services provided by pharmacists were viewed as inadequate by 46%. The most common challenges encountered by blind patients were linked to drug identification (75%), dose recognition (82%), and identification of expiration date (92%). A large number of patients had to rely on persons with normal vision for dispensing and administering the medications. CONCLUSIONS: Pharmacists can no longer ignore the medication use problems encountered by the blind people. This study may serve as an initial step for planning improvements in pharmaceutical services provided to blind patients. The government, pharmaceutical companies and pharmacists must work in collaboration to address the special needs of the blind. PMID- 25685050 TI - Air quality in the Industrial Heartland of Alberta, Canada and potential impacts on human health. AB - The "Industrial Heartland" of Alberta is Canada's largest hydrocarbon processing center, with more than 40 major chemical, petrochemical, and oil and gas facilities. Emissions from these industries affect local air quality and human health. This paper characterizes ambient levels of 77 volatile organic compounds (VOCs) in the region using high-precision measurements collected in summer 2010. Remarkably strong enhancements of 43 VOCs were detected, and concentrations in the industrial plumes were often similar to or even higher than levels measured in some of the world's largest cities and industrial regions. For example maximum levels of propene and i-pentane exceeded 100 ppbv, and 1,3-butadiene, a known carcinogen, reached 27 ppbv. Major VOC sources included propene fractionation, diluent separation and bitumen processing. Emissions of the measured VOCs increased the hydroxyl radical reactivity (kOH), a measure of the potential to form downwind ozone, from 3.4 s-1 in background air to 62 s-1 in the most concentrated plumes. The plume value was comparable to polluted megacity values, and acetaldehyde, propene and 1,3-butadiene contributed over half of the plume kOH. Based on a 13-year record (1994-2006) at the county level, the incidence of male hematopoietic cancers (leukemia and non-Hodgkin lymphoma) was higher in communities closest to the Industrial Heartland compared to neighboring counties. While a causal association between these cancers and exposure to industrial emissions cannot be confirmed, this pattern and the elevated VOC levels warrant actions to reduce emissions of known carcinogens, including benzene and 1,3 butadiene. PMID- 25685051 TI - The Tears of Mr Justice Willes. PMID- 25685052 TI - Hispanic Use of Juramentos and Roman Catholic Priests as Auxiliaries to Abstaining from Alcohol Use/Misuse. AB - This self-administered mail survey study conducted along the US-Mexico border replicates and expands on research conducted in Florida regarding the prevalence of juramento use as an intervention technique for alcohol misuse. Juramentos are pledges to abstain from alcohol use for a time determined by the user. The pledge is usually to the Virgin of Guadalupe and is often done in the presence of a Roman Catholic Priest. As in Florida, the majority of Priests along the border reported they were familiar with the practice of juramentos and had already witnessed at least one. The majority of Priests who had done juramentos viewed them as effective. Since the vast majority of Priest indicated that they would begin or continue witnessing juramentos, this makes juramentos and Roman Catholic Priests a viable culturally sensitive aide for treatment among Hispanics, in particular those of Mexican descent. PMID- 25685053 TI - Why do lifespan variability trends for the young and old diverge? A perturbation analysis. AB - BACKGROUND: Variation in lifespan has followed strikingly different trends for the young and old: while total lifespan variability has decreased as life expectancy at birth has risen, the variability conditional on survival to older ages has increased. These diverging trends reflect changes in the underlying demographic parameters determining age-specific mortality. OBJECTIVE: We ask why the variation in the ages at death after survival to adult ages has followed a different trend than the variation at younger ages, and aim to explain the divergence in terms of the age pattern of historical mortality changes. METHODS: Using simulations, we show that the empirical trends in lifespan variation are well characterized using the Siler model, which describes the mortality trajectory using functions representing early-life, later-life, and background mortality. We then obtain maximum likelihood estimates of the Siler parameters for Swedish females from 1900 to 2010. We express mortality in terms of a Markov chain model, and apply matrix calculus to compute the sensitivity of age-specific variance trends to the changes in Siler model parameters. RESULTS: Our analysis quantifies the influence of changing demographic parameters on lifespan variability at all ages, highlighting the influence of declining childhood mortality on the reduction of lifespan variability, and the influence of subsequent improvements in adult survival on the rising variability of lifespans at older ages. CONCLUSIONS: These findings provide insight into the dynamic relationship between the age pattern of survival improvements and time trends in lifespan variability. PMID- 25685054 TI - Tocopherol and tocotrienol homologs in parenteral lipid emulsions. AB - : Parenteral lipid emulsions, which are made of oils from plant and fish sources, contain different types of tocopherols and tocotrienols (vitamin E homologs). The amount and types of vitamin E homologs in various lipid emulsions vary considerably and are not completely known. The objective of this analysis was to develop a quantitative method to determine levels of all vitamin E homologs in various lipid emulsions. An HPLC system was used to measure vitamin E homologs using a Pinnacle DB Silica normal phase column and an isocratic, n-hexane:1,4 dioxane (98:2) mobile phase. An optimized protocol was used to report vitamin E homolog concentrations in soybean oil-based (Intralipid(r), Ivelip(r), Lipofundin(r) N, Liposyn(r) III, and Liposyn(r) II), medium- and long-chain fatty acid-based (Lipofundin(r), MCT and Structolipid(r)), olive oil-based (ClinOleic(r)), and fish oil-based (Omegaven(r)) and mixture of these oils-based (SMOFlipid(r), Lipidem(r)) commercial parenteral lipid emulsions. Total content of all vitamin E homologs varied greatly between different emulsions, ranging from 57.9 to 383.9 ug/mL. Tocopherols (alpha, beta, gamma, delta) were the predominant vitamin E homologs for all emulsions, with tocotrienol content < 0.3%. In all of the soybean emulsions, except for Lipofundin(r) N, the predominant vitamin E homolog was gamma-tocopherol, which ranged from 57-156 ug/mL. ClinOleic(r) predominantly contained alpha-tocopherol (32 ug/mL), whereas alpha-tocopherol content in Omegaven(r) was higher than most of the other lipid emulsions (230 ug/mL). PRACTICAL APPLICATIONS: The information on the types and quantity of vitamin E homologs in various lipid emulsions will be extremely useful to physicians and healthcare personnel in selecting appropriate lipid emulsions that are exclusively used in patients with inadequate gastrointestinal function, including hospitalized and critically ill patients. Some emulsions may require vitamin E supplementation in order to meet minimal human requirements. PMID- 25685055 TI - Causal diagrams for empirical legal research: a methodology for identifying causation, avoiding bias and interpreting results. AB - In this paper we introduce methodology-causal directed acyclic graphs-that empirical researchers can use to identify causation, avoid bias, and interpret empirical results. This methodology has become popular in a number of disciplines, including statistics, biostatistics, epidemiology and computer science, but has yet to appear in the empirical legal literature. Accordingly we outline the rules and principles underlying this new methodology and then show how it can assist empirical researchers through both hypothetical and real-world examples found in the extant literature. While causal directed acyclic graphs are certainly not a panacea for all empirical problems, we show they have potential to make the most basic and fundamental tasks, such as selecting covariate controls, relatively easy and straightforward. PMID- 25685056 TI - The effect of preoperative suggestions on perioperative dreams and dream recalls after administration of different general anesthetic combinations: a randomized trial in maxillofacial surgery. AB - BACKGROUND: Images evoked immediately before the induction of anesthesia with the help of suggestions may influence dreaming during anesthesia.The aim of the study was to assess the incidence of evoked dreams and dream recalls by employing suggestions before induction of anesthesia while administering different general anesthetic combinations. METHODS: This is a single center, prospective randomized including 270 adult patients scheduled for maxillofacial surgical interventions. Patients were assigned to control, suggestion and dreamfilm groups according to the psychological method used. According to the anesthetic protocol there were also three subgroups: etomidate & sevoflurane, propofol & sevoflurane, propofol & propofol groups. Primary outcome measure was the incidence of postoperative dreams in the non-intervention group and in the three groups receiving different psychological interventions. Secondary endpoint was to test the effect of perioperative suggestions and dreamfilm-formation training on the occurrance of dreams and recallable dreams in different general anesthesiological techniques. RESULTS: Dream incidence rates measured in the control group did not differ significantly (etomidate & sevoflurane: 40%, propofol & sevoflurane: 26%, propofol & propofol: 39%). A significant increase could be observed in the incidence rate of dreams between the control and suggestion groups in the propofol & sevoflurane (26%-52%) group (p = 0.023). There was a significant difference in the incidence of dreams between the control and dreamfilm subgroup in the propofol & sevoflurane (26% vs. 57%), and in the propofol & propofol group (39% vs.70%) (p = 0.010, and p = 0.009, respectively). Similar to this, there was a significant difference in dream incidence between the dreamfilm and the suggestion subgroups (44% vs. 70%) in the propofol & propofol group (p = 0.019). Propofol as an induction agent contributed most to dream formation and recalls (chi2-test p value: 0.005). The content of images and dreams evoked using suggestions showed great agreement using all three anesthetic protocols. CONCLUSION: The psychological method influenced dreaming during anesthesia. The increase of the incidence rate of dreams was dependent on the anesthetic agent used, especially the induction agent. The study was registered in ClinicalTrials.gov. Identifier: NCT01839201. PMID- 25685057 TI - Cardiac surgery in 260 octogenarians: a case series. AB - BACKGROUND: The elderly undergo cardiac surgery more and more frequently, often present multiple comorbidities, assume chronic therapies, and present a unique physiology. Aim of our study was to analyze the experience of a referral cardiac surgery center with all types of cardiac surgery interventions performed in patients >=80 years old over a six years' period. METHODS: A retrospective observational study performed in a university hospital. 260 patients were included in the study (3.5% of the patients undergoing cardiac surgery in the study period). RESULTS: Mean age was 82 +/- 1.8 years. Eighty-five percent of patients underwent elective surgery, 15% unplanned surgery and 4.2% redo surgery. Intervention for aortic valve pathology and coronary artery bypass grafting were performed in 51% and 46% of the patients, respectively. Interventions involving the mitral valve were the 26% of the total, those on the tricuspid valve were 13% and those on the ascending aortic arch the 9.6%. Postoperative low output syndrome was identified in 44 patients (17%). Mortality was 3.9% and most of the patients (91%) were discharged from hospital in good clinical conditions. Hospital mortality was lower in planned vs unplanned surgery: 3.8% vs 14% respectively. Chronic obstructive pulmonary disease (OR 9.106, CI 2.275 - 36.450) was the unique independent predictor of mortality. CONCLUSIONS: Clinicians should be aware that cardiac surgery can be safely performed at all ages, that risk stratification is mandatory and that hemodynamic treatment to avoid complications is expected. PMID- 25685058 TI - Temperature modulation with an esophageal heat transfer device - a pediatric swine model study. AB - BACKGROUND: An increasing number of conditions appear to benefit from control and modulation of temperature, but available techniques to control temperature often have limitations, particularly in smaller patients with high surface to mass ratios. We aimed to evaluate a new method of temperature modulation with an esophageal heat transfer device in a pediatric swine model, hypothesizing that clinically significant modulation in temperature (both increases and decreases of more than 1 degrees C) would be possible. METHODS: Three female Yorkshire swine averaging 23 kg were anesthetized with inhalational isoflurane prior to placement of the esophageal device, which was powered by a commercially available heat exchanger. Swine temperature was measured rectally and cooling and warming were performed by selecting the appropriate external heat exchanger mode. Temperature was recorded over time in order to calculate rates of temperature change. Histopathology of esophageal tissue was performed after study completion. RESULTS: Average swine baseline temperature was 38.3 degrees C. Swine #1 exhibited a cooling rate of 3.5 degrees C/hr; however, passive cooling may have contributed to this rate. External warming blankets maintained thermal equilibrium in swine #2 and #3, demonstrating maximum temperature decrease of 1.7 degrees C/hr. Warming rates averaged 0.29 degrees C/hr. Histopathologic analysis of esophageal tissue showed no adverse effects. CONCLUSIONS: An esophageal heat transfer device successfully modulated the temperature in a pediatric swine model. This approach to temperature modulation may offer a useful new modality to control temperature in conditions warranting temperature management (such as maintenance of normothermia, induction of hypothermia, fever control, or malignant hyperthermia). PMID- 25685059 TI - Patterns of cancer cell sphere formation in primary cultures of human oral tongue squamous cell carcinoma and neck nodes. AB - Recently a sub-population of cells with stem cell characteristics, reported to be associated with initiation, growth, spread and recurrence, has been identified in several solid tumors including oral tongue squamous cell carcinoma (OTSCC). The aim of our pilot study was to isolate CD44+ cancer stem cells from primary cultures of OTSCC and neck node Level I (node-I) biopsies, grow cell spheres and observe their characteristics in primary cultures. Parallel cultures of hyperplastic lesions of tongue (non-cancer) were set up as a control. Immunohistochemistry was used to detect CD44/CD24 expression and magnetic activated cell sorting to isolate CD44+ cell populations followed by primary cell culturing. Both OTSCC and node-I biopsies produced floating spheres in suspension, however those grown in hyperplastic and node-I primary cultures did not exhibit self-renewal properties. Lymph node metastatic OTSCC, express higher CD44/CD24 levels, produce cancer cell spheres in larger number and rapidly (24 hours) compared to node negative OTSCC (1 week) and non-cancer specimens (3 weeks). In addition, metastatic OTSCC have the capacity for proliferation for up to three generations in primary culture. This in vitro system will be used to study cancer stem cell behavior, therapeutic drug screening and optimization of radiation dose for elimination of resistant cancer cells. PMID- 25685060 TI - Understanding the colon cancer stem cells and perspectives on treatment. AB - An area of research that has been recently gaining attention is the relationship between cancer stem cell (CSC) biology and chemo-resistance in colon cancer patients. It is well recognized that tumor initiation, growth, invasion and metastasis are promoted by CSCs. An important reason for the widespread interest in the CSC model is that it can comprehensibly explain essential and poorly understood clinical events, such as therapy resistance, minimal residual disease, and tumor recurrence. This review discusses the recent advances in colon cancer stem cell research, the genes responsible for CSC chemoresistance, and new therapies against CSCs. PMID- 25685061 TI - The multifaceted role of CD146/MCAM in the promotion of melanoma progression. AB - Human malignant melanoma is a common primary malignant cutaneous tumour derived from transformed epidermal melanocytes. Patients with melanoma have a high rate of mortality due to resistance to chemotherapeutic drugs, a major obstacle to a successful treatment. Several reports have suggested that CD146 plays an important role as a signalling molecule in human melanoma. This role includes CD146 as a participant in inflammation, differentiation, adhesion, tumourigenicity, metastasis, invasion and angiogenesis among other processes, which suggests that this molecule promotes the progression of human melanoma as a multifaceted regulator. In this article, we explore the effects and corresponding mechanisms with respect to the role of CD146/MUC18 in the promotion of human melanoma progression. Collectively, the studies indicated that targeting CD146, because it is a suitable marker of poor patient outcome, might be useful in the design of future strategies for the prevention and treatment of human melanoma. PMID- 25685062 TI - EHMT2 inhibitor BIX-01294 induces apoptosis through PMAIP1-USP9X-MCL1 axis in human bladder cancer cells. AB - BIX-01294, an euchromatic histone-lysine N-methyltransferase 2 (EHMT2) inhibitor, has been reported to induce apoptosis in human neuroblastoma cells and inhibit the proliferation of bladder cancer cells. However, the definite mechanism of the apoptosis mediated by BIX-01294 in bladder cancer cells remains unclear. In the present study, we found that BIX-01294 induced caspase-dependent apoptosis in human bladder cancer cells. Moreover, our data show BIX-01294 stimulates endoplasmic reticulum stress (ER stress) and up-regulated expression of PMAIP1 through DDIT3 up-regulation. Furthermore, down-regulation of the deubiquitinase USP9X by BIX-01294 results in downstream reduction of MCL1 expression, leading to apoptosis eventually. Thus, our findings demonstrate PMAIP1-USP9X-MCL1 axis may contribute to BIX-01294-induced apoptosis in human bladder cancer cells. PMID- 25685063 TI - Antihelminthic benzimidazoles potentiate navitoclax (ABT-263) activity by inducing Noxa-dependent apoptosis in non-small cell lung cancer (NSCLC) cell lines. AB - BACKGROUND: Evasion of apoptosis is a hallmark of cancer cells. One mechanism to deregulate the apoptotic pathway is by upregulation of the anti-apoptotic Bcl-2 family members. Navitoclax (ABT-263) is a Bcl-2/Bcl-xL inhibitor that restores the ability of cancer cells to undergo apoptosis. METHODS: In this study we performed a high-throughput screen with 640 FDA-approved drugs to identify potential therapeutic combinations with navitoclax in a non-small cell lung cancer (NSCLC) cell line. RESULTS: Other than a panel of cancer compounds such as doxorubicin, camptothecin, and docetaxel, four antihelminthic compounds (benzimidazoles) potentiated navitoclax activity. Treatment with benzimidazoles led to induction of the pro-apoptotic protein Noxa at the mRNA and protein level. Noxa binds and antagonizes antiapoptotic protein Mcl-1. siRNA-mediated knock-down of Noxa completely rescued benzimidazole-potentiated navitoclax activity. In addition, inhibiting caspase 3 and 9 partially rescued benzimidazole-potentiated navitoclax activity. CONCLUSIONS: We have identified compounds and mechanisms which potentiate navitoclax activity in lung cancer cell lines. Further validation of the benzimidazole-potentiated navitoclax effect in vivo is required to evaluate the potential for translating this observation into clinical benefit. PMID- 25685064 TI - The role of individual caspases in cell death induction by taxanes in breast cancer cells. AB - BACKGROUND: In previous study we showed that caspase-2 plays the role of an apical caspase in cell death induction by taxanes in breast cancer cells. This study deals with the role of other caspases. We tested breast cancer cell lines SK-BR-3 (functional caspase-3) and MCF-7 (nonfunctional caspase-3). METHODS AND RESULTS: Using western blot analysis we demonstrated the activation of initiator caspase-8 and -9 as well as executioner caspase-6 and -7 in both tested cell lines after application of taxanes (paclitaxel, SB-T-1216) at death-inducing concentrations. Caspase-3 activation was also found in SK-BR-3 cells. Employing specific siRNAs after taxane application, suppression of caspase-3 expression significantly increased the number of surviving SK-BR-3 cells. Inhibition of caspase-7 expression also increased the number of surviving SK-BR-3 and MCF-7 cells. On the other hand, suppression of caspase-8 and caspase-9 expression had no significant effect on cell survival. However, caspase-9 seemed to be involved in the activation of caspase-3 and caspase-7. Caspase-3 and caspase-7 appeared to activate mutually. Furthermore, we observed a significant decrease in mitochondrial membrane potential (flow cytometric analysis) and cytochrome c release (confocal microscopy, western blot after cell fractionation) from mitochondria in SK-BR-3 cells. No such changes were observed in MCF-7 cells after taxane treatment. CONCLUSION: We conclude that the activation of apical caspase-2 results in the activation of caspase-3 and -7 without the involvement of mitochondria. Caspase-9 can be activated directly via caspase-2 or alternatively after cytochrome c release from mitochondria. Subsequently, caspase-9 activation can also lead to caspase-3 and -7 activations. Caspase-3 and caspase-7 activate mutually. It seems that there is also a parallel pathway involving mitochondria that can cooperate in taxane-induced cell death in breast cancer cells. PMID- 25685065 TI - Variant RONDelta160 of the RON receptor tyrosine kinase promotes the growth and invasion in vitro and in vivo in gastric cancer cell lines. AB - BACKGROUND: Recepteur d'origine nantais (RON) is a receptor tyrosine kinase whose overexpression has been observed in human gastric cancers. This study aimed to determine whether overexpression of the variant RONDelta160 could induce tumorigenicity of gastric cancer cells in vitro or in vivo, and whether its specific small molecule inhibitor (Compound I) could inhibit the effect of RONDelta160. METHODS: We constructed human gastric cancer cell line MGC-803 that was stably transfected with a recombinant plasmid expressing RONDelta160, and the effect of RONDelta160 overexpression and macrophage-stimulating protein (MSP) activation on proliferation, migration and invasion abilities of MGC-803 cells were evaluated. Tumor-bearing mice with gastric cancer cells were used to analyze the effects of RONDelta160 overexpression and Compound I on implanted tumor growth. RESULTS: In vitro, overexpression of RONDelta160 in MGC-803 cells resulted changes to their cell morphology, and promoted cell proliferation, migration and invasion. In addition, overexpression of RONDelta160 increased the proportion of cells in the S phase. The effect of RONDelta160 was significantly enhanced by induction of MSP inducing (p < 0.05). In vivo, RONDelta160 promoted the growth of MGC-803 cells in nude mice, including increased tumor size and weight, and lower tumor incubation period. The Compound I inhibited the tumorigenic abilities of RONDelta160 (p <0.05). CONCLUSIONS: The results indicate that overexpression of the variant RONDelta160 altered the phenotype and tumorigenicity of MGC-803 cells. Its specific small molecule inhibitor could inhibit the effect of RONDelta160. Therefore, the variant RONDelta160 may become a potential therapeutic target for gastric cancer. PMID- 25685066 TI - Antiproliferative and apoptosis-inducing activity of schisandrin B against human glioma cells. AB - BACKGROUND: Malignant glioma is the most devastating and aggressive tumour in the brain and is characterised by high morbidity, high mortality and extremely poor prognosis. The main purpose of the present study was to investigate the effects of schisandrin B (Sch B) on glioma cells both in vitro and in vivo and to explore the possible anticancer mechanism underlying Sch B-induced apoptosis and cell cycle arrest. METHODS: The anti-proliferative ability of Sch B on glioma cells were assessed by MTT and clony formation assays. Flow cytometric analysis was used to detect cell cycle changes. Apoptosis was determined by Hoechst 33342 staining and annexin V/PI double-staining assays. The mitochondrial membrane potential was detected by Rhodamine 123 staining. The in vivo efficacy of Sch B was measured using a U87 xenograft model in nude mice. The expressions of the apoptosis-related and cell cycle-related proteins were analysed by western blot. Student's t-test was used to compare differences between treated groups and their controls. RESULTS: We found that Sch B inhibited growth in a dose- and time dependent manner as assessed by MTT assay. In U87 and U251 cells, the number of clones was strongly suppressed by Sch B. Flow cytometric analysis revealed that Sch B induced cell cycle arrest in glioma cells at the G0/G1 phase. In addition, Sch B induced glioma cell apoptosis and reduced mitochondrial membrane potential (DeltaPsim) in a dose-dependent manner. Mechanically, western blot analysis indicated that Sch B induced apoptosis by caspase-3, caspase-9, PARP, and Bcl-2 activation. Moreover, Sch B significantly inhibited tumour growth in vivo following the subcutaneous inoculation of U87 cells in athymic nude mice. COCLUSIONS: In summary, Sch B can reduce cell proliferation and induce apoptosis in glioma cells and has potential as a novel anti-tumour therapy to treat gliomas. PMID- 25685067 TI - Treatment with the PARP inhibitor, niraparib, sensitizes colorectal cancer cell lines to irinotecan regardless of MSI/MSS status. AB - BACKGROUND: Cells with homologous recombination (HR) deficiency, most notably caused by mutations in the BRCA1 or BRCA2 genes, are sensitive to PARP inhibition. Microsatellite instability (MSI) accounts for 10-15% of colorectal cancer (CRC) and is hypothesized to lead to HR defects due to altered expression of Mre11, a protein required for double strand break (DSB) repair. Indeed, others have reported that PARP inhibition is efficacious in MSI CRC. METHODS: Here we examine the response to niraparib, a potent PARP-1/PARP-2 inhibitor currently under clinical evaluation, in MSI versus microsatellite stable (MSS) CRC cell lines in vitro and in vivo. We compiled a large panel of MSI and MSS CRC cell lines and evaluated the anti-proliferative activity of niraparib. In addition to testing single agent cytotoxic activity of niraparib, we also tested irinotecan (or SN-38, the active metabolite of irinotecan) activity alone and in combination with niraparib in vitro and in vivo. RESULTS: In contrast to earlier reports, MSI CRC cell lines were not more sensitive to niraparib than MSS CRC cell lines suggesting that the MSI phenotype does not sensitize CRC cell lines to PARP inhibition. Moreover, even the most sensitive MSI cell lines had niraparib EC50s greater than 10 fold higher than BRCA-deficient cell lines. However, MSI lines were more sensitive to SN-38 than MSS lines, consistent with previous findings. We have also demonstrated that combination of niraparib and irinotecan was more efficacious than either agent alone in both MSI and MSS cell lines both in vitro and in vivo, and that niraparib potentiates the effect of irinotecan regardless of MSI status. CONCLUSIONS: Our results support the clinical evaluation of this combination in all CRC patients, regardless of MSI status. PMID- 25685068 TI - Inhibition of miR-191 contributes to radiation-resistance of two lung cancer cell lines by altering autophagy activity. AB - BACKGROUND: Lung cancer is the leading cause of cancer-related morbidity and mortality all over the world. Surgery resection, radiotherapy, chemotherapy, immunotherapy and combined treatments have been discovered and well established for treatments. However, low survival rate of five years after clinical treatments mainly due to recurrence of stress-resistant cancer cells calls for better understanding and new ideas. Our project aimed to understand the forming process of stress resistant lung cancer cells after radiotherapy. METHODS: Two classic non-small cell lung cancer (NSCLC) cell lines A549 and H1299 initially were radiated with a (137)Cs gamma-ray source with doses ranging from 0 to 12 Gy to generate radiation-resistant cancer cells. 8 Gy of radiation was regard as a standard dosage since it provides effective killing as well as good amount of survivals. The expression levels of autophagy-related proteins including Beclin 1, LC3-II and p62 were studied and measured by both western blot and quantitative real-time polymerase chain reaction (real-time RT-PCR). RESULTS: Increased Beclin 1, LC3-II and decreased p62 have been observed in radiation-resistant cells indicating elevated autophagy level. Decreased miR-191 in radiation-resistant cells performed by Taqman qRT-PCR also has been seen. Two binding sites between Beclin-1 and miR-191 suggest potential association between. CONCLUSIONS: It is reasonable to speculate that inhibition of miR-191 expression in lung cancer cells would contribute to the establishment of radiation-resistant cells via mediating cellular autophagy. Therefore, miR-191 is a potential target for therapy in treating radiation-resistant lung cancer. PMID- 25685069 TI - The association between expressions of Ras and CD68 in the angiogenesis of breast cancers. AB - OBJECTIVE: Angiogenesis is a critical step of breast cancer metastasis. Oncogenic Ras promotes the remodeling of cancer microenviroment. Tumor-associated macrophages (TAMs) are a prominent inflammatory cell population emerging in the microenviroment and facilitating the angiogenesis and metastasis. In the present study, we tried to investigate the relationship between the expression of Ras and infiltration of TAM, both of which could further promote angiogenesis. METHODS: Expressions of Ras, CD68 and CD34 were assessed by immunohistochemistry. The infiltration of macrophages was evaluated by counting the number of CD68(+) cells. Vessel endothelial cells were defined as CD34(+) cells. Angiogenesis vascularity was defined by microvessel density (MVD) assay through counting the number of vessels per field counted in the area of highest vascular density. The Kaplan-Meier survival analysis was used to estimate the overall survival (OS). Macrophages were derived from monocytes in the presence of macrophage colony stimulating-factor (MCSF). Breast cancer cells were treated with macrophage conditioned medium (MCM) and tested the expressions of K-, H- and N-Ras by using realtime-PCR. RESULTS: Ras positive status was correlated with ER, PR and Her-2 positivity, larger tumour size and lymph node metastasis, as well as higher TNM stages. A higher number of CD68(+) cells was correlated with larger tumour size, higher TNM stages and Her-2 positivity. Both Ras positivity and infiltration of CD68(+) macrophages correlated with poor OS. The number of CD68(+) cells was positively correlated with the expression of Ras. Treatment with MCM did not up regulate but repressed the expression of Ras. Both up-regulation of Ras and infiltration of TAMs correlated with increased MVD. CONCLUSION: Expression of Ras and infiltration of TAM were positively correlated, and both participated in angiogenesis. Elevated Ras could be responsible for the infiltration of TAM. PMID- 25685070 TI - Targeting CD226/DNAX accessory molecule-1 (DNAM-1) in collagen-induced arthritis mouse models. AB - BACKGROUND: Genetic studies have pointed out that CD226 variants, encoding DNAM 1, could be associated with susceptibility to rheumatoid arthritis. Therefore, we aimed to determine the influence of DNAM-1 on the development of arthritis using the collagen-induced arthritis (CIA) mouse model. METHODS: CIA was induced in mice on a DBA/1 background, treated in parallel with a DNAM-1 neutralizing monoclonal antibody, a control IgG and PBS, respectively. CIA was also induced in mice deficient for DNAM-1(dnam1-/-) and control dnam-1+/+ mice on a C57/BL6 background. Mice were monitored for clinical and ultrasound signs of arthritis. Histological analysis was performed to search for inflammatory infiltrates and erosions. The Mann-Whitney U test for non-related samples was used for statistical analysis. RESULTS: There was a non-significant trend for a less arthritic phenotype in mice receiving anti-DNAM-1 mAb at both clinical, ultrasound and histological assessments. But, we did not observe any difference between dnam1+/+ and dnam1-/- mice for incidence nor severity of clinical arthritis. Histological analysis revealed inflammatory scores similar in both groups, without evidence of erosion. Collagen antibodies levels were similar in all mice, confirming immunization with collagen. CONCLUSION: Despite some clues suggesting a role of DNAM-1 in arthritis, these complementary approaches demonstrate no contribution of CD226/DNAM-1 in the arthritic phenotype. These results contrast with previous studies showing a role in vivo of DNAM-1 in some autoimmune disorders. PMID- 25685071 TI - Antioxidant polyphenol-rich extracts from the medicinal plants Antirhea borbonica, Doratoxylon apetalum and Gouania mauritiana protect 3T3-L1 preadipocytes against H2O2, TNFalpha and LPS inflammatory mediators by regulating the expression of superoxide dismutase and NF-kappaB genes. AB - BACKGROUND: Adipose cells responsible for fat storage are the targets of reactive oxygen species (ROS) like H2O2 and pro-inflammatory agents including TNFalpha and LPS. Such mediators contribute to oxidative stress and alter inflammatory processes in adipose tissue, leading to insulin resistance during obesity. Thus, the identification of natural compounds such as plant polyphenols able to increase the antioxidant and anti-inflammatory capacity of the body is of high interest. We aimed to evaluate the biological properties of polyphenol-rich extracts from the medicinal plants A. borbonica, D. apetalum and G. mauritiana on preadipocytes exposed to H2O2, TNFalpha or LPS mediators. METHODS: Medicinal plant extracts were analysed for their polyphenol contents by Folin-Ciocalteu and UPLC-ESI-MS methods as well as for their free radical-scavenging activities by DPPH and ORAC assays. To assess the ability of polyphenol-rich extracts to protect 3T3-L1 preadipocytes against H2O2, TNFalpha or LPS mediators, several parameters including cell viability (MTT and LDH assays), ROS production (DCFH-DA test), IL-6 and MCP-1 secretion (ELISA) were evaluated. Moreover, the expression of superoxide dismutase, catalase and NF-kappaB genes was explored (RT-QPCR). RESULTS: All medicinal plants exhibited high levels of polyphenols with free radical-scavenging capacities. Flavonoids such as quercetin, kaempferol, epicatechin and procyanidins, and phenolic acids derived from caffeic acid including chlorogenic acid, were detected. Polyphenol-rich plant extracts did not exert a cytotoxic effect on preadipocytes but protected them against H2O2 anti proliferative action. Importantly, they down-regulated ROS production and the secretion of IL-6 and MCP-1 pro-inflammatory markers induced by H2O2, TNFalpha and LPS mediators. Such a protective action was associated with an increase in superoxide dismutase antioxidant enzyme gene expression and a decrease in mRNA levels of NF-kappaB pro-inflammatory transcription factor. CONCLUSION: This study highlights that antioxidant strategies based on polyphenols derived from medicinal plants tested could contribute to regulate adipose tissue redox status and immune process, and thus participate to the improvement of obesity-related oxidative stress and inflammation. PMID- 25685072 TI - Silencing collapsin response mediator protein-2 reprograms macrophage phenotype and improves infarct healing in experimental myocardial infarction model. AB - BACKGROUND: Delayed M1 toward M2 macrophage phenotype transition is considered one of the major causes for the impaired healing after myocardial infarction (MI). While searching for molecules that modulate M1 and M2 macrophage polarization, we identified collapsin response mediator protein-2 (CRMP2) as a novel molecule involved in macrophage polarization to M1. In this study, we evaluated the effect of silencing CRMP2 on macrophage polarization, inflammation and fibrosis post myocardial infarction. METHODS: CRMP2 expression was assessed with Western blotting or immunohistochemistry. Macrophage phenotypes were measured with flow cytometry, quantitative real-time PCR (qPCR), Western blotting or immunohistochemistry. CRMP2 siRNA was delivered into the macrophages infiltrated in the wound of ApoE(-/-) mice through lipidoid nanoparticle, and fibrosis, leukocyte infiltration and inflammation parameters were measured with qPCR. Infarct size was measured with Masson's trichrome staining. Echocardiography was performed to assess ventricular systolic dimension, left ventricular diastolic dimension, anterior wall thickness and posterior wall thickness. Student's t-test (for 2 groups) and ANOVA (for > 2 groups) were used for statistical analyses. RESULTS: CRMP2 was expressed in a higher level in M1 macrophages than M2 subsets, and CRMP2 RNA interference (RNAi) resulted in a switch of bone marrow-derived macrophages from M1 to M2 phenotype. High level of CRMP2 was also observed in the macrophages infiltrated in the infarct area 3 days post MI in both wildtype (WT) and ApoE(-/-) mice, and the expression of CRMP2 retained in the infiltrated macrophages of ApoE(-/-) mice but not in that of WT mice 10 days after MI. Nanoparticle-mediated delivery of CRMP2 siRNA to ApoE(-/-) mice with MI resulted in dramatic switch of wound macrophages from M1 to M2 phenotype, marked decrease in inflammation and fibrosis, and significant attenuation of post-MI heart failure and mortality. CONCLUSION: CRMP2 is highly expressed in M1 macrophages and silencing CRMP2 reprograms macrophage phenotype and improves infarct healing in atherosclerotic mice. PMID- 25685073 TI - Negotiating technology-mediated interaction in health care. AB - The health-care sector is increasingly faced with different forms of technology that are introduced to mediate interaction, thus fully or partially replacing face-to-face meetings. In this article we address health personnel's experiences with three such technologies, namely: electronic messages, video conferences and net-based discussion forums. Drawing on Goffman's perspectives on interaction and frame, we argue that when technologies are introduced to mediate interaction, new frames for understanding and making sense of situations are created. These new frames imply new ways of organising and making sense of experience, and require work by the participants in the interaction. In this article, based on interviews from two Norwegian research projects, we investigate health personnel's work to make sense of technology-mediated interaction in health care. We discuss this work represented in four categories: how to perform in a competent manner, how to negotiate immediacy, how to enable social cues and how to establish and maintain commitment. Concluding, we argue that the introduction of mediating technologies redefines what is considered up-to-date, 'good' health-care work and challenges health personnel to change (some of) their work practices and moves, as a result, far beyond simple interventions aimed at making work more efficient. PMID- 25685074 TI - Salud Mesoamerica 2015 Initiative: design, implementation, and baseline findings. AB - BACKGROUND: Health has improved markedly in Mesoamerica, the region consisting of southern Mexico and Central America, over the past decade. Despite this progress, there remain substantial inequalities in health outcomes, access, and quality of medical care between and within countries. Poor, indigenous, and rural populations have considerably worse health indicators than national or regional averages. In an effort to address these health inequalities, the Salud Mesoamerica 2015 Initiative (SM2015), a results-based financing initiative, was established. METHODS: For each of the eight participating countries, health targets were set to measure the progress of improvements in maternal and child health produced by the Initiative. To establish a baseline, we conducted censuses of 90,000 households, completed 20,225 household interviews, and surveyed 479 health facilities in the poorest areas of Mesoamerica. Pairing health facility and household surveys allows us to link barriers to care and health outcomes with health system infrastructure components and quality of health services. RESULTS: Indicators varied significantly within and between countries. Anemia was most prevalent in Panama and least prevalent in Honduras. Anemia varied by age, with the highest levels observed among children aged 0 to 11 months in all settings. Belize had the highest proportion of institutional deliveries (99%), while Guatemala had the lowest (24%). The proportion of women with four antenatal care visits with a skilled attendant was highest in El Salvador (90%) and the lowest in Guatemala (20%). Availability of contraceptives also varied. The availability of condoms ranged from 83% in Nicaragua to 97% in Honduras. Oral contraceptive pills and injectable contraceptives were available in just 75% of facilities in Panama. IUDs were observed in only 21.5% of facilities surveyed in El Salvador. CONCLUSIONS: These data provide a baseline of much-needed information for evidence-based action on health throughout Mesoamerica. Our baseline estimates reflect large disparities in health indicators within and between countries and will facilitate the evaluation of interventions and investments deployed in the region over the next three to five years. SM2015's innovative monitoring and evaluation framework will allow health officials with limited resources to identify and target areas of greatest need. PMID- 25685075 TI - Key activities used by community based primary care practices to improve the quality of diabetes care in response to practice facilitation. AB - BACKGROUND: A recent systematic review suggests that practice facilitation (PF) is a robust intervention for implementing evidence-based preventive care guidelines in primary care, but the ability of PF to improve chronic illness care remains unclear. AIMS: To examine the specific activities and Chronic Care model (CCM) components that primary care practices implemented and sustained in response to a 12-month PF intervention. METHODS: The ABC trial tested the effectiveness of PF to improve care for diabetes in 40 small community-based primary care practices that were randomized to "initial" or "delayed" intervention arms. A trained facilitator met with each practice over 12-months. Facilitators used interactive consensus building to help practices implement one or more of quality improvement activities based on the CCM. Facilitators prospectively recorded implementation activities reported by practice teams during monthly meetings and confirmed which of these were sustained at the end of the intervention. RESULTS: 37 practices implemented and sustained a total of 43 unique activities [range 1-15, average 6.5 (SD=2.9)]. The number (%) of practices that implemented 1 or more key activities in each CCM component varied: Patient Self-Management Support: 37 (100%); Clinical Information Systems: 24 (64.9%), Delivery System Design: 14 (37.8%), Decision Support: 13 (35.1%), Community Linkages: 2 (5.4%); Healthcare System Support: 2 (2.7%). The majority of practices (59%) only implemented activities from 1 or 2 CCM components. The number of sustained activities was associated with the number of PF visits, but not with practice characteristics. CONCLUSIONS: In spite of the PF intervention, it was difficult for these small practices to implement comprehensive CCM changes. Although practices implemented and sustained a remarkable number and variety of key activities, the majority of these focused on patient self management support, as opposed to other components of the CCM, such as clinical information systems, decision support, delivery system redesign, and community linkages. PMID- 25685076 TI - Study on research anxiety among faculty members of isfahan university of medical sciences. AB - INTRODUCTION: One of the most common anxieties in higher education is research anxiety. The purpose of this study was to determine the research anxiety level among the faculty members of Isfahan University of Medical Sciences (IUMS). METHODS: this was survey- analytical study. The stratified random sampling method was used and a sample of 212 people was selected. For data collection was used a questionnaire. Data were analyzed with descriptive and analytical (T Test, ANOVA and LSD) statistics. FINDINGS: The average anxiety research in IUMS was about 3.27 +/-0.536. Among factors, highest scores in descending order are related to lack of timely payment of fees (3.97+/-0.961), the long approval process of proposals and research project reporting (3.86.+/-0.99) and lack of research efficiency on the part of faculty (3.70+/-1.00). The lowest scores were related to having insufficient funds to conduct research (2.67+/-1.08), another's understanding of inability for researching (2.84+/-1.192), and unfriendly behavior from journals and research center staffs (2.89+/-0.802). CONCLUSION: The mean level of research anxiety among faculty members of IUMS was found higher than average. So it's essential that authorities pay greater attention to the factors that cause research anxiety. PMID- 25685077 TI - The Effects of Problem-Solving Teaching on Creative Thinking among District 2 High School Students in Sari City. AB - INTRODUCTION: Nowadays, regarding the learners' needs and social conditions, it is obviously needed to revise and reconsider the traditional methods and approaches in teaching. The problem solving approach is one of the new ways in Teaching and learning process. This study aimed at studying and examining the effect of "problem-solving" approach on creative thinking of high school female students. METHODS: An experimental method is used for this research. In this research, 342 out of 3047 female-students from Sari high schools were randomly selected. These 342 students were divided into two groups (experimental and control) in which there were seven classrooms. The total number of students in every group was about 171. After testing them with Jamal Abedi creativity test, it was revealed that two groups were equal in creativity score. The tests were done through Requirements. The experimental group was taught by problem solving method for three months while the control group was taught by traditional method. RESULTS: The research results showed that using descriptive indices and t-test for the two independent sample groups in which problem solving teaching method was used in teaching processes had an effect on creativity level in comparison with traditional method used in the control group. CONCLUSION: Considering the results of this study, the application of problem-solving teaching methods increased the creativity and its components (fluidity, expansion, originality and flexibility) in learners, therefore, it is recommended that students be encouraged to take classes on frequent responses on various topics (variability) and draw attention on different issues, and expand their analysis on elements in particular courses like art (expansion). To enhance the learner's mental flexibility and attention to various aspects, they are encouraged to provide a variety of responses. PMID- 25685078 TI - Effects of sulphate-sulphide mineral water "mljecanica" in patients with hypertension. AB - INTRODUCTION: Arterial hypertension is the main independent risk factor for cardiovascular (CV) disease and death. It affects development and course of cerebrovascular insult (CVI) and chronic kidney disease (CKD). Balneotherapy with sulphide baths was administered to patients having stage I hypertension (BP values 140-159/90-99), with no arrhythmia or pronounced coronary disease. Baths also had advantage in patients having hypertension joined with obesity, diabetes, microangiopathy, and atherosclerosis of peripheral arteries. GOAL: Determine the effects of sulphate-sulphide mineral baths on stage I hypertension after 10 days therapy. MATERIALS AND METHODS: Patients having stage I hypertension were sent to "Mljecanica" Institute for rehabilitation. All subjects were treated with kinesitherapy and electrotherapy, while experimental group (n=30) was also treated with 20 minute baths, daily, for period of 10 days. RESULTS: In experimental group BP level lowered in average 10 mmHg after 10-day therapy, and change was evident even after only 5 days. CONCLUSION: Sulphate-sulphide mineral water "Mljecanica" caused significant (p<0.05) lowering of arterial BP level after 10 days of therapy in patients who had stage I hypertension. PMID- 25685079 TI - Reproductive outcome following hysteroscopic treatment of uterine septum. AB - BACKGROUND: Septate uterus is the most common uterine anomaly and a cause for miscarriage and infertility. Existing data suggested a better reproductive outcome of uterine septum following hysteroscopic septum resection. OBJECTIVE: Current study was administered to share our experience in hystroscopic septum resection for reproductive outcome following hysteroscopic treatment of uterine septum and specifically focusing on different treatment protocols after hysteroscopic septum resection. METHODS& MATERIALS: This study was a cross sectional study based on secondary data that was obtained from medical records of infertile women who had undergone transvaginal hysteroscopy and used different treatment protocols after hysteroscopic correction of uterine septum in Infertility and Reproductive Health Research Center between April 2005 and February 2014. RESULTS: The total number of infertile women underwent hysteroscopy uterine septoplasty was 106. The hysteroscopy septoplasty resulted in an overall pregnancy rate of 67% and a live birth 57.5%. Pregnancy rate for patients who had not male infertility was 92.1%. The chi-square test did not reveal any statistically significant difference in side affect, pregnancy, live birth, abortion, preterm deliveries, and term deliveries rate between these patients either with consistent hormone therapy plus IUD insertion or with alternate hormone therapy plus IUD after hysteroscopic metroplasty. CONCLUSION: The findings of the present study indicated hysteroscopic septum resection to remove a uterine septum in women with infertility is safe and may be an efficacious procedure. Treatment following hysteroscopic septum resection, either the consistent or the alternate protocol is both beneficial to improve pregnancy rate. PMID- 25685080 TI - Evaluaton of healthy lifestyle behaviors of female students in a public accommodation center from kirsehir, Turkey. AB - GOAL: This study is a descriptive analysis aiming to determine the healthy lifestyle behaviors of students staying in a female dormitory in the Central Anatolia region. METHODS: A total of 295 students staying in a state-run female dormitory were included in the study. Data was collected with a personal information form and a "Healthy Lifestyle Behavior Scale" between March and May 2014. The dependent variables of the study were the HLBS points and subscales. The independent variables were age, class, department, family structure, place of longest residence, family education and occupation, perception of income, sport, academic success, BMI and nutrition. RESULTS: The average age of students participating in the study was 19.92+/-1.39 (17-26) years. The average HLBS points of the students in the study were determined to be 120.24+/-16.99 (85 170). There was a statistically significant difference found between the students' regular participation in sport, use of cigarettes, department they studied in and academic success levels with healthy lifestyle behavior and subscales (p<0.05). CONCLUSION: We determined that student' scores taken from healthy lifestyle behaviors scale was moderate level. We consider that regular and continuous education to develop healthy lifestyle behavior during undergraduate education will benefit students who will become the health professionals of the future. PMID- 25685081 TI - A review of affecting factors on sexual satisfaction in women. AB - BACKGROUND: Sex is a complex, important and sensitive issue in human being and interwoven with the whole of human existence. Given the serious changes in attitude, function and behavior in sex, the need to address sexual function, especially sexual satisfaction, is felt completely. Sexual satisfaction has a very important role in creating marital satisfaction and any defect in sexual satisfaction is significantly associated with risky sexual behaviors, serious mental illness, social crimes and ultimately divorce. AIM: The aim of this study was to explore affecting factors on sexual satisfaction in women based on an overview in scientific database. METHODS: In this narrative review the researchers searched MEDLINE database, Google Scholar and Science Direct as well as Persian database like Scientific Information Database with search terms of sexual satisfaction and sexual function, restricted to English/ Persian language, during the 20 years ago. Then those articles written by renowned experts were selected. In this regard, 57 articles have been reviewed, which 30 articles related to this research have been extracted. RESULTS: The findings were divided in to four categories including: Demographic factors, Pathophysiological factors, Psychological factors and Sociocultural factors. CONCLUSIONS: Sexuality, especially sexual intimacy is sophisticated and yet elegant affair that the other persons has different definitions and different functions. Discrepancies in the results of the studies show that analysis of factors affecting sexual satisfaction regardless of the women's' sociocultural context, religious beliefs, and personal attitudes is undoubtedly inefficient, unscientific and irrational. PMID- 25685082 TI - The impact of war on vaccine preventable diseases. AB - INTRODUCTION: During the war in Bosnia and Herzegovina, which lasted from 1992 1995, the functioning of all sectors was disturbed, including the health sector. The priority of the heath sector was treatment and less attention was paid to prevention, and this applies also to the Program of implementation of obligatory immunization, as one of the most important prevention measures. This program was conducted with difficulty and sometimes was completely interrupted because of the lack of necessary vaccines and the inability of adequate maintenance of the cold chain. It was difficult and sometimes completely impossible to bring children to vaccination. Because of these problems, a great number of children stayed unvaccinated so they suffered from vaccine-preventable diseases several years after the war. MATERIALS AND METHODS: This is a retrospective epidemiological study. We analyzed data from January 1994 to July 2014 in Canton Sarajevo, and data about measles outbreak in 2014. RESULTS: In the period from January 1994 to July 2014, 3897 vaccine-preventable diseases were registered in Canton Sarajevo. Among them measles, rubella and mumps were the most frequent. In March 2014, measles outbreak was registered. Almost all cases are unvaccinated (99%) and 43% of all cases are connected with failure of vaccination during the war. CONCLUSION: During the war, routine immunization program was disrupted in Bosnia and Herzegovina (also in Canton Sarajevo). The consequences are presented as vaccine preventable diseases cases. PMID- 25685083 TI - Effects of salt intake on blood pressure in banovici coal mine workers. AB - INTRODUCTION: High blood pressure is the cause of almost 13 % of all deaths in the world. DASH (Dietary Approaches to Stop Hypertension) is "gold standard" in diet recommended by American Society of Hypertension, American Heart Association and Dietary Guidelines for Americans 2010 for reduction many CV risk factors including hypertension. Non-pharmacological treatment of hypertension through DASH dietary program with reduction of salt intake can significantly reduce high values of blood pressure and decrease general cardiovascular risks. GOAL: The aim of this research is to determine the prevalence of hypertension among miners in Banovici coal mine and amount of salt taken in meals during work time. MATERIAL AND METHODS: We inspected the medical documentation and registers for all employees in coal mine Banovici in order to provide calculation of hypertension prevalence. Based on reports and company standards on grocery usage and average amount of salt used in preparation of one meal in coal mine kitchen, we have calculated the average consumption of salt of one employee per meal. RESULTS: There are 2700 of employees in coal mine Banovici with average life age of 46 years. From them 694 (25.7%) miners have arterial hypertension. Also 707023 kg of salt is being spent for preparation of meals in coal mine kitchen on yearly basis. Employees take between 4-9 grams of salt per one meal excluding the salt contained in bread. CONCLUSION: the amount of salt intake per one meal in the coal mine kitchen is larger from daily doses recommended by ACC/AHA. PMID- 25685084 TI - Smoking cessation in school children in the Federation of bosnia and herzegovina. AB - INTRODUCTION: Quitting tobacco use has many benefits for both individuals and society. For individuals, quitting of smoking provides immediate and long-term benefits to health. Higher levels of nicotine addiction and start smoking at a younger age are factors consider as strongly influence on quit smoking. Access to youth friendly quit lines increases a smoking cessation of school children. GOAL: Monitoring of trends of age of initiation of smoking and current smoking cigarettes as good motivation for smoking cessation among school children in the Federation of BiH. METHODS: Analysis of survey's findings performed in the Federation of BiH in period 2008-2013, with particular focus on indicators of every smokers, currents smokers, start to smoke before age of ten, signs of smoking dependence and motivation for quitting smoking in school children. Surveys involves two-stage cluster sample design aimed to enroll students in grades 7, 8 and 9(th) of primary and 1(th) grade of secondary school. RESULTS: A survey findings indicates ever cigarettes smokers decreases from 45.9% in 2008 to 43.2% in 2013, as well decreases of current cigarette smoking from 14.3% in 2008 to 12.7% in 2013, both boys and girls. However, survey data shows decrease of current smoking students who want to stop smoking now from 50.5% in 2008 to 45.8% in 2013. CONCLUSIONS: Collected data confirmed decreases of current cigarette smoking in school children in the Federation of BiH in period 2008-2013. Access to available smoking cessation services and quit lines for school children and youth considers should be a significant part of tobacco control measure in the Federation of BiH. PMID- 25685085 TI - Oral health status of children with disability living in Albania. AB - INTRODUCTION: This study was carried out at nine (9) special schools for disabled children in Albania. The aim of the study is to determine the caries prevalence and oral hygiene status of children with different disabilities attending different schools for disabled at Albania. METHODS: Participants are grouped according disability Autistic Spectrum Disorder, Down syndrome, Cerebral Palsy, Mental Retarded, Blind, Deaf-Mute and age group (0-5, 6-10, 11-14, 15-18 years old children). Caries and oral health status were examined and assessed according WHO 1997 criteria. RESULTS: Overall caries prevalence at permanent dentition for all groups is 85.3% and for primary dentition 72%. The mean deft index is 3.4 +/- 3.5(p<=0.029), mean DMFT= 4.9+/-4.6 (p<=0.001) with significance difference across type of disability (Kruskal-Wallis test) for both dentition. The mean OHI S of total population is 1.91; there is significant difference across disability type (p<=0.001, Anova test) for OHI-S index. In total 43.2 % have good, 49.4% fair and 7.4% bad oral hygiene. CONCLUSIONS: The subjects in this study had a high prevalence of dental caries, poor oral hygiene and need for restorative care. PMID- 25685086 TI - Symptomatic Epilepsies due to Cerebrovascular Diseases. AB - INTRODUCTION: Cerebro-vascular diseases (CVD) are the leading cause of symptomatic epilepsies. This study aims to investigate: a) Frequency of epilepsy in patients with CVD; b) Correlation of epilepsy with the type of CVD (ischemic and hemorrhage) and with age. METHODOLOGY: It is analyzed medical documentation of 816 hospitalized patients with CVD in the clinic of Neurology in University Clinical Center (UCC) during the period January - December 2010. The study included data on patients presenting with epileptic seizures after CVD, and those with previously diagnosed epilepsy, are not included in the study. The diagnosis of CVD, are established in clinical neurological examination and the brain imaging (computer tomography and magnetic resonance imaging). The diagnosis of epilepsy is established by the criteria of ILAE (International League against Epilepsy) 1983, and epileptic seizures are classified according to the ILAE classification, of 1981. RESULTS: Out of 816 patients with CVD, 692 were with ischemic stroke and 124 with hemorrhage. From 816 patients, epileptic seizures had 81 (10%), of which 9 patients had been diagnosed with epilepsy earlier and they are not included in the study. From 72 (99%) patients with seizures after CVD 25 (33%) have been with ischemia, whereas 47 (67%) with hemorrhage. CONCLUSION: CVD present fairly frequent cause of symptomatic epilepsies among patients treated in the clinic of Neurology at UCC (about 10%). The biggest number of patients with epilepsy after CVD was with intracerebral hemorrhage. PMID- 25685087 TI - Local irrigation of the surgical field with antibiotics in the end of procedure reduces the infection rate in herniated lumbar disc surgery. AB - INTRODUCTION: Reported rate of infections after lumbar discectomy is 1%-15 %. This complication may result in disability or even the death. AIM: The aim of the study is to assess the rate of infection associated with lumbar discectomies when combined systemic and local antibiotic prophylaxis was employed. PATIENTS AND METHODS: In this retrospective study we analyzed all patients operated for herniated lumbar disc from 2009 -2012 in our institute. Beside of receiving systemic prophylaxis with 2g of Cefazoline, all patients had their operative field irrigated at the end of operation with Amikacin sulfate injection. Wound was considered infected when local and systemic signs of infection were revealed and were associated with elevated ESR, leukocytosis and elevated CRP. Assessment of infection is done by neurosurgeon during the hospitalization and later at outpatient's clinic along postoperative course of three months. RESULTS: A total of 604 patients were operated, of those 285 patients (47.2 %) females and 319 males (52.8 %), 12 patients were operated on two levels (1.98 %). Average patient age was 32.5 years (range 20-65 years) Localization of herniated disc was: in L/2 L/3 20 patients or 3.3 %, the L/3-L/4 level 42 patients or 7 % , the L/4 -L /5 262 patients or 43.3 % at the level L/V- S/1 280 patients or 46.3 %. Three patients (0.49%) developed wound infection, two of them superficial infection only with local signs: local pain, redness and leakage. They were treated with oral antibiotics. One with deep wound infection. He presented with local and systemic signs and treated with i.v antibiotics. All the cultures from wound swab revealed staphylococcus aureus. CONCLUSION: Prophylaxis with systemic antibiotic (Cefazoline 2.0) intravenous administration 30 minutes before the incision and irrigation of operative field with local antibiotic Amikacine sulfate at the end of procedure reduces the infection rate in patients operated for herniated lumbar disc when compared with systemic antibiotic prophylaxis only. PMID- 25685088 TI - Exercise-induced Anaphylaxis: the Role of Cofactors. AB - INTRODUCTION: Anaphylaxis is a dramatic clinical emergency. It is a very severe, life-threatening generalized or systemic hypersensitivity reaction. Based on immunologic mechanism the anaphylaxis is divided in IgE, IgG, complement, or immune complexes-mediated vs non allergic anaphylaxis. There are a lot of etiologic factors of anaphylaxis, but the three principal immunologic triggers are drugs, insect stings, and foods. Regarding the clinical severity there are several proposed grading systems. The diagnosis of anaphylaxis is mainly clinical. DISCUSSION: The anaphylaxis markers measured in clinical laboratories are total tryptase and histamine. There are some conditions that modulate the onset of anaphylaxis, acting as co- or augmentation factors, which significantly lower the allergen dose necessary for triggering anaphylaxis. The well-documented cofactors of anaphylaxis are physical exercise, alcohol consumption, some foods, co-administration of nonsteroidal anti-inflammatory drugs (NSAID), and concomitant infectious diseases. Development of anaphylaxis depends on the sensitization pattern, the proportion of the involved immunoglobulin classes, characteristics of the allergen, the proportion of the involved immunoglobulin classes, the avidity and affinity of immunoglobulins to bind an allergen, the route of allergen application, and, last but not least, the presence of cofactors of anaphylaxis. CONCLUSION: Anaphylaxis remains a continuous challenge for the diagnosis and treatment. The adequate management of anaphylaxis requires rapid diagnosis, implementation of primary and secondary prevention measures, and immediate administration of subcutaneous epinephrine. PMID- 25685089 TI - Motivation, leadership, empowerment and confidence: their relation with nurses' burnout. AB - INTRODUCTION: Burnout is usually defined as a state of physical, emotional and mental exhaustion that results from long-term involvement in work situations that are emotionally demanding. A great deal of researches has been devoted to the understanding of factors contributing to burnout and the negative effects that burnout has in the cost and the quality of the provided healthcare. DISCUSSION: Many researchers believe that in difficult and stressful working conditions the work environment should be changed in order to reduce burnout levels successfully. Indeed, recent studies have highlighted the role of human resources management in burnout. It has been widely recognized that human resource management policies should be at the core of any sustainable solution that aims to increase health care systems performance and efficient. CONCLUSION: Motivation, leadership, empowerment and confidence are very important factors that should be considered in this direction because they are strongly related with burnout levels. PMID- 25685090 TI - Comparative Review of Education Programs of Family Medicine (FM) in Bosnia and Herzegovina and Several Transition Countries. AB - Family Medicine as an independent medical discipline is relatively young in the countries of Southeast Europe. Still are used the old models of all forms of education in this module, although most countries accepted Bologna undergraduate teaching concept and already implement it with greater or lesser success. Measuring the effects of the qualities of these concepts and models is not done systematically nor in uniform manner, so it could not be compared by the unique variables measuring the quality of education curricula, and especially the quality of education level of the graduates at the first, second and third degree courses and other forms of education. This paper provides a comparative overview of the state of education in the area of family medicine in the region. It creates comparison according to the study duration for undergraduate and postgraduate studies, doctoral studies and specialized studies in specified areas. What stand out are the proposals to improve education in the field of family medicine in the region. PMID- 25685091 TI - Publication on health policy worldwide from 1898 to 2013: identifying position of iran. AB - BACKGROUND: As the field of health policy continues to evolve and grow, it is important to examine the trend of scientific output generated in this domain. Scientific outputs can also be used to evaluate academic progress of the field in each country or over a given period of time. OBJECTIVE: Aim of this study is to depict trend of publication on topics of health policy world-wide and to highlight contribution of Iran in this field. METHODS: The web of science database was used to identify all relevant published papers worldwide The search was conducted on documents published from January 1898 to December 2013. The criteria for retrieval were set to be "health policy" in topics. Then the retrieved papers were filtered in terms of distinct years, countries, source titles, and languages. RESULTS: Findings revealed an increasing trend of publication on health policy over past decades. English was the first most dominant language of publication. USA had the highest number of publication with 5347 papers; however Switzerland ranked first after considering publication number in terms of countries' population. BMJ was the source title with highest number of publication on topics of health policy. Number of publication by Iranian authors was 87 from January 1898 to December 2013. CONCLUSION: It seems discipline of health policy has started its evolution worldwide long time ago while Iran is in its initial phases. PMID- 25685092 TI - Eupha strategy 2014-2020*. PMID- 25685093 TI - Children with Imaginary Companions Focus on Mental Characteristics When Describing Their Real-Life Friends. AB - Relations between having an imaginary companion (IC) and (i) descriptions of a real-life friend, (ii) theory of mind performance, and (iii) reported prosocial behaviour and behavioural difficulties were investigated in a sample of 5-year olds (N = 159). Children who had an IC were more likely than their peers without an IC to describe their best friends with reference to their mental characteristics, but IC status was unrelated to children's theory of mind performance and reported prosocial behaviour and behavioural difficulties. These findings are discussed in the context of the proposal that there is a competence performance gap in children's mentalizing abilities. (c) 2014 The Authors. Infant and Child Development published by John Wiley & Sons Ltd. PMID- 25685094 TI - Trajectories of regulatory behaviors in early infancy: Determinants of infant self-distraction and self-comforting. AB - The ability to effectively regulate emotions is an important marker for early socioemotional development. The uses of self-comforting behaviors and self distraction have been empirically supported as effective regulatory strategies for infants, though research on determinants of such behaviors is scarce. Thus, a more thorough examination of the development of regulatory behaviors is needed. For the current study, 135 mothers, fathers, and their infants participated in laboratory visits at 3-, 5-, and 7-months of age where parent sensitivity and infant regulatory strategies were coded from the Still Face Paradigm. Parents also filled out questionnaires about infant temperament and parental involvement. Using multi-level modeling to examine levels and trajectories of self-comforting and self-distraction, the current study found: 1) infants higher in temperamental surgency used more self-distraction and self-comforting, 2) infants lower in surgency with highly involved parents increased in self-distraction at a faster rate, particularly with highly involved fathers, and 3) infants used self comforting more than average with fathers when the infant was also lower in temperamental regulation. In addition, we examined trajectories of parent involvement and temperament in relation to infant regulatory strategy. PMID- 25685095 TI - Self-Conscious Shyness: Growth during Toddlerhood, Strong Role of Genetics, and No Prediction from Fearful Shyness. AB - Fearful and self-conscious subtypes of shyness have received little attention in the empirical literature. Study aims included: 1) determining if fearful shyness predicted self-conscious shyness, 2) describing development of self-conscious shyness, and 3) examining genetic and environmental contributions to fearful and self-conscious shyness. Observed self-conscious shyness was examined at 19, 22, 25, and 28 months in same-sex twins (MZ = 102, DZ = 111, missing zygosity = 3 pairs). Self-conscious shyness increased across toddlerhood, but onset was earlier than predicted by theory. Fearful shyness (observed [6 and 12 months] and parents' reports [12 and 22 months]) was not predictive of self-conscious shyness. Independent genetic factors made strong contributions to parent-reported (but not observed) fearful shyness (additive genetic influence = .69 and .72 at 12 and 22 months, respectively) and self-conscious shyness (additive genetic influence = .90 for the growth model intercept). Results encourage future investigation of patterns of change and interrelations in shyness subtypes. PMID- 25685096 TI - Morad askari, MD, and steven L. Moran, MD. PMID- 25685097 TI - Complex upper extremity reconstruction. PMID- 25685098 TI - Approach to complex upper extremity injury: an algorithm. AB - Patients with complex upper extremity injuries represent a unique subset of the trauma population. In addition to extensive soft tissue defects affecting the skin, bone, muscles and tendons, or the neurovasculature in various combinations, there is usually concomitant involvement of other body areas and organ systems with the potential for systemic compromise due to the underlying mechanism of injury and resultant sequelae. In turn, this has a direct impact on the definitive reconstructive plan. Accurate assessment and expedient treatment is thus necessary to achieve optimal surgical outcomes with the primary goal of limb salvage and functional restoration. Nonetheless, the characteristics of these injuries places such patients at an increased risk of complications ranging from limb ischemia, recalcitrant infections, failure of bony union, intractable pain, and most devastatingly, limb amputation. In this article, the authors present an algorithmic approach toward complex injuries of the upper extremity with due consideration for the various reconstructive modalities and timing of definitive wound closure for the best possible clinical outcomes. PMID- 25685099 TI - Ballistic trauma: lessons learned from iraq and afghanistan. AB - Management of upper extremity injuries secondary to ballistic and blast trauma can lead to challenging problems for the reconstructive surgeon. Given the recent conflicts in Iraq and Afghanistan, advancements in combat-casualty care, combined with a high-volume experience in the treatment of ballistic injuries, has led to continued advancements in the treatment of the severely injured upper extremity. There are several lessons learned that are translatable to civilian trauma centers and future conflicts. In this article, the authors provide an overview of the physics of ballistic injuries and principles in the management of such injuries through experience gained from military involvement in Iraq and Afghanistan. PMID- 25685100 TI - New options for vascularized bone reconstruction in the upper extremity. AB - Originally described in the 1970s, vascularized bone grafting has become a critical component in the treatment of bony defects and non-unions. Although well established in the lower extremity, recent years have seen many novel techniques described to treat a variety of challenging upper extremity pathologies. Here the authors review the use of different techniques of vascularized bone grafts for the upper extremity bone pathologies. The vascularized fibula remains the gold standard for the treatment of large bone defects of the humerus and forearm, while also playing a role in carpal reconstruction; however, two other important options for larger defects include the vascularized scapula graft and the Capanna technique. Smaller upper extremity bone defects and non-unions can be treated with the medial femoral condyle (MFC) free flap or a vascularized rib transfer. In carpal non-unions, both pedicled distal radius flaps and free MFC flaps are viable options. Finally, in skeletally immature patients, vascularized fibular head epiphyseal transfer can provide growth potential in addition to skeletal reconstruction. PMID- 25685101 TI - Principles of tendon reconstruction following complex trauma of the upper limb. AB - Reconstruction of tendons following complex trauma to the upper limb presents unique clinical and research challenges. In this article, the authors review the principles guiding preoperative assessment, surgical reconstruction, and postoperative rehabilitation and management of the upper extremity. Tissue engineering approaches to address tissue shortages for tendon reconstruction are also discussed. PMID- 25685102 TI - Principles of nerve repair in complex wounds of the upper extremity. AB - Peripheral nerve injuries are common in the setting of complex upper extremity trauma. Early identification of nerve injuries and intervention is critical for maximizing return of function. In this review, the principles of nerve injury, patient evaluation, and surgical management are discussed. An evidence-based approach to nerve reconstruction is reviewed, including the benefits and limitations of direct repair and nerve gap reconstruction with the use of autografts, processed nerve allografts, and conduits. Further, the principles and indications of commonly used nerve transfers in proximal nerve injuries are also addressed. PMID- 25685103 TI - Soft tissue coverage of the mangled upper extremity. AB - Mangled upper extremity injuries usually involve high-impact trauma with crushing and tearing of the limb and its associated soft tissue structures. Such trauma is particularly mutilating because of the nature of the injury and the involvement of structures vital for proper function. Although advancements in flap technique and improvements in bone fixation methods have enabled good functional and clinical outcomes in limb salvage reconstruction, this remains a challenging area. Attempts at limb preservation should be fully exhausted before consideration is given for amputation, which results in significantly decreased function. Here the authors focus on the various modalities of soft tissue coverage available including allogenic substitutes, the adjunctive use of negative pressure wound therapy, and the design and utilization of flaps to address various defect configurations for the goals of wound healing, aesthetics, and functional restoration in the mangled upper extremity. PMID- 25685104 TI - Upper extremity amputations and prosthetics. AB - Upper extremity amputations are most frequently indicated by severe traumatic injuries. The location of the injury will determine the level of amputation. Preservation of extremity length is often a goal. The amputation site will have important implications on the functional status of the patient and options for prosthetic reconstruction. Advances in amputation techniques and prosthetic reconstructions promote improved quality of life. In this article, the authors review the principles of upper extremity amputation, including techniques, amputation sites, and prosthetic reconstructions. PMID- 25685105 TI - Targeted muscle reinnervation and advanced prosthetic arms. AB - Targeted muscle reinnervation (TMR) is a surgical procedure used to improve the control of upper limb prostheses. Residual nerves from the amputated limb are transferred to reinnervate new muscle targets that have otherwise lost their function. These reinnervated muscles then serve as biological amplifiers of the amputated nerve motor signals, allowing for more intuitive control of advanced prosthetic arms. Here the authors provide a review of surgical techniques for TMR in patients with either transhumeral or shoulder disarticulation amputations. They also discuss how TMR may act synergistically with recent advances in prosthetic arm technologies to improve prosthesis controllability. Discussion of TMR and prosthesis control is presented in the context of a 41-year-old man with a left-side shoulder disarticulation and a right-side transhumeral amputation. This patient underwent bilateral TMR surgery and was fit with advanced pattern recognition myoelectric prostheses. PMID- 25685106 TI - Rehabilitation of the upper extremity following nerve and tendon reconstruction: when and how. AB - Following upper extremity nerve and tendon reconstruction, rehabilitation is necessary to achieve optimal function and outcome. In this review, the authors present current evidence and literature regarding the strategies and techniques of rehabilitation following peripheral nerve and tendon reconstruction. PMID- 25685107 TI - Chemical Complexity and the Genetics of Aging. AB - We examine how aging is impacted by various chemical challenges that organisms face and by the molecular mechanisms that have evolved to regulate lifespan in response to them. For example, environmental information, which is detected and processed through sensory systems, can modulate lifespan by providing information about the presence and quality of food as well as presence and density of conspecifics and predators. In addition, the diverse forms of molecular damage that result from constant exposure to damaging chemicals that are generated from the environment and from metabolism pose an informatic and energetic challenge for detoxification systems, which are important in ensuring longevity. Finally, systems of innate immunity are vital for recognizing and combating pathogens but are also seen as of increasing importance in causing the aging process. Integrating ideas of molecular mechanism with context derived from evolutionary considerations will lead to exciting new insights into the evolution of aging. PMID- 25685108 TI - Successful treatment with tocilizumab every 4 weeks of a low disease activity group who achieve a drug-free remission in patients with systemic-onset juvenile idiopathic arthritis. AB - BACKGROUND: Systemic juvenile idiopathic arthritis (SoJIA) is the most striking form of juvenile idiopathic arthritis. The aim of our study was to evaluate the clinical responses and outcomes of children with SoJIA to IL-6 blockade using two different tocilizumab (TCZ) treatment protocols designed for milder and more severe SoJIA patient groups, and evaluate the possibility of achieving biologic free remission. METHODS: Thirty-seven active SoJIA children who have failed treatment with corticosteroids and other DMARDs were included in our retrospective study. TCZ doses were prescribed in two treatment approaches: every 2 weeks TCZ dosing (Q2W) and every 4 weeks TCZ dosing (Q4W). The patients were assigned to these two groups by the study physicians depending on the severity of the SoJIA disease as judged by each clinician. RESULTS: Thirty-three of the 37 children successfully completed the trial. TCZ was discontinued in 11patients during the trial. Seven children achieved inactive disease and were allowed to stop the TCZ and 4 had severe adverse events requiring drug cessation. Currently 7 patients continue to have TCZ-free remission [4/7 remission off-medication, 3/7still on methotrexate (MTX)]. This mixed group had a median treatment duration of 1002 days. The children in remission off of all medications, TCZ and MTX, had a median remission duration of 1162 days (ranged 932-1301 days). Compared to the patients assigned to the Q2W TCZ treatment group, the patients assigned to the Q4W TCZ group had a milder SoJIA course. The patients had higher levels of hemoglobin, total proteins, and serum albumins. They had lower white blood cell counts (WBC), % granulocytes, CRP, ESR, ferritins, and LDH. These children had a lower frequency of internal organ involvement, fewer relapses during TCZ treatment, and no macrophage activation syndrome episodes. CONCLUSIONS: Our experience with TCZ for SoJIA supports the excellent result of other studies. What may be novel is our finding that thisIL-6 blockade with TCZ may be able to be utilized at a less frequent dosing schedule in mild SoJIA compared to severe SoJIA. We discuss other factors that may increase the probability of a patient reaching TCZ-free remission. PMID- 25685109 TI - The implications of low testosterone on mortality in men. AB - Testosterone levels in men slowly decline with aging and also decline more abruptly due to medical illness or medications. Prescriptions for testosterone have increased dramatically over the past decade, since a testosterone-gel formulation was approved and since numerous studies reported an association between low serum testosterone and increased mortality. However, recent observational studies of testosterone treatment have reported conflicting results with some studies reporting decreased risks for mortality while others reported increased mortality risks with testosterone treatment. This paper will summarize recent studies of low serum testosterone and mortality and testosterone treatment and mortality and what the potential implications of these studies are for the clinician. PMID- 25685110 TI - Glutathione supplementation suppresses muscle fatigue induced by prolonged exercise via improved aerobic metabolism. AB - BACKGROUNDS: Glutathione is an endogenous redox couple in animal cells and plays important roles in antioxidant defense and detoxification, although it is unknown if oral glutathione supplementation affects exercise-induced physiological changes. The present study investigated the effect of glutathione intake on exercise-induced muscle metabolism and fatigue in mice and humans. METHODS: ICR mice were divided into 4 groups: sedentary control, sedentary supplemented with glutathione (2.0%, 5 MUL/g body weight), exercise control, and exercise supplemented with glutathione. After 2 weeks, the exercise groups ran on a treadmill at 25 m/min for 30 min. Immediately post-exercise, intermuscular pH was measured, and hind limb muscle and blood samples were collected to measure biochemical parameters. In a double-blind, cross-over study, 8 healthy men (35.9 +/- 2.0 y) were administered either glutathione (1 g/d) or placebo for 2 weeks. Then, they exercised on a cycle ergometer at 40% maximal heart rate for 60 min. Psychological state and blood biochemical parameters were examined after exercise. RESULTS: In the mouse experiment, post-exercise plasma non-esterified fatty acids were significantly lower in the exercise supplemented with glutathione group (820 +/- 44 mEq/L) compared with the exercise control group (1152 +/- 61 mEq/L). Intermuscular pH decreased with exercise (7.17 +/- 0.01); however, this reduction was prevented by glutathione supplementation (7.23 +/- 0.02). The peroxisome proliferator-activated receptor-gamma coactivator-1alpha protein and mitochondrial DNA levels were significantly higher in the sedentary supplemented with glutathione group compared with the sedentary control group (25% and 53% higher, respectively). In the human study, the elevation of blood lactate was suppressed by glutathione intake (placebo, 3.4 +/- 1.1 mM; glutathione, 2.9 +/- 0.6 mM). Fatigue-related psychological factors were significantly decreased in the glutathione trial compared with the placebo trial. CONCLUSIONS: These results suggest that glutathione supplementation improved lipid metabolism and acidification in skeletal muscles during exercise, leading to less muscle fatigue. PMID- 25685111 TI - Becoming the Parent of a GLB Son or Daughter. AB - Recent research has documented the importance of parental reactions to disclosure for sexual minority youth (SMY) (e.g., Ryan, Huebner, Diaz, & Sanchez, 2009). The purpose of this study was to develop a deeper understanding of the parent perspective of the disclosure to family experience of SMY ages 14-21. In-depth interviews were conducted with eight parents in the United States who had experienced a child disclose their lesbian, gay, or bisexual (LGB) orientation to them. Constructivist grounded theory and symbolic interaction theory informed the methodology and data analysis for the project. Analysis revealed that the process of becoming the parent of an LGB son or daughter is an appropriate narrative to conceptualize the parental experience of the disclosure to family process. The findings highlight how disclosure introduces new roles into the existing family system, which affects the consideration and interpretation of the salience of particular identities, such as being the parent of an LGB son or daughter. Understanding how parents experience the disclosure to family process - particularly, how they understand and re-envision the meaning of being a parent - is crucial for research and intervention to help families become supportive of SMY. Limitations and suggestions for future research are presented. PMID- 25685112 TI - RS-Forest: A Rapid Density Estimator for Streaming Anomaly Detection. AB - Anomaly detection in streaming data is of high interest in numerous application domains. In this paper, we propose a novel one-class semi-supervised algorithm to detect anomalies in streaming data. Underlying the algorithm is a fast and accurate density estimator implemented by multiple fully randomized space trees (RS-Trees), named RS-Forest. The piecewise constant density estimate of each RS tree is defined on the tree node into which an instance falls. Each incoming instance in a data stream is scored by the density estimates averaged over all trees in the forest. Two strategies, statistical attribute range estimation of high probability guarantee and dual node profiles for rapid model update, are seamlessly integrated into RS-Forest to systematically address the ever-evolving nature of data streams. We derive the theoretical upper bound for the proposed algorithm and analyze its asymptotic properties via bias-variance decomposition. Empirical comparisons to the state-of-the-art methods on multiple benchmark datasets demonstrate that the proposed method features high detection rate, fast response, and insensitivity to most of the parameter settings. Algorithm implementations and datasets are available upon request. PMID- 25685113 TI - Exploring the Factors that Influence Nurse Practitioner Role Transition. AB - The transition from registered nurse (RN) to nurse practitioner (NP) is often a stressful career change. Data are lacking on the factors affecting NP role transition. This study examined the relationships between NP role transition, prior RN experience, and a formal orientation. From a sample of 352 NPs, only a formal orientation contributed significantly to the regression model indicating a positive relationship with NP role transition (b = 6.24, p < .001). Knowledge of the factors that explain NP role transition is important to inform the discipline how best to support NPs during entry into practice. PMID- 25685114 TI - Interaction of graphene family materials with Listeria monocytogenes and Salmonella enterica. AB - Graphene family materials have unique properties, which make them valuable for a range of applications. The antibacterial properties of graphene have been reported; however, findings have been contradictory. This study reports on the antimicrobial proprieties of three different graphene materials (pristine graphene (pG), graphene oxide (GO), and reduced graphene oxide (rGO)) against the food-borne bacterial pathogens Listeria monocytogenes and Salmonella enterica. A high concentration (250 MUg/mL) of all the analyzed graphenes completely inhibited the growth of both pathogens, despite their difference in bacterial cell wall structure. At a lower concentration (25 MUg/mL), similar effects were only observed with GO, as growth inhibition decreased with pG and rGO at the lower concentration. Interaction of the nanoparticles with the pathogenic bacteria was found to differ depending on the form of graphene. Microscopic imaging demonstrated that bacteria were arranged at the edges of pG and rGO, while with GO, they adhered to the nanoparticle surface. GO was found to have the highest antibacterial activity. PMID- 25685115 TI - Chiropractic management of pubic symphysis shear dysfunction in a patient with overactive bladder. AB - OBJECTIVE: The purpose of this case report is to describe chiropractic management of a patient with overactive bladder (OAB) and to describe an hypothetical anatomical basis for a somato-vesical reflex and possible clinical link between pelvic and symphysis pubis dysfunction to OAB. CLINICAL FEATURES: A 24-year-old nulliparous female with idiopathic OAB, with a primary complaint of nocturia presented for chiropractic care. Her sleep was limited to 2 consecutive hours due to bladder urgency. Pubic symphysis shear dysfunction was observed on physical examination. INTERVENTION AND OUTCOMES: The primary treatment modality used was chiropractic side-posture drop-table manipulation designed to reduce pubic shear dysfunction. After 8 treatments in 1 month, the pubic shear gradually reduced while nocturia diminished and consecutive sleep hours increased from 2 to 7. At 1 year follow-up, the nocturia remained resolved. CONCLUSION: The patient reported in this case responded favorably to chiropractic care, which resulted in reduced nocturia and increased sleep continuity. PMID- 25685116 TI - Recognition of spontaneous vertebral artery dissection preempting spinal manipulative therapy: a patient presenting with neck pain and headache for chiropractic care. AB - OBJECTIVE: The purpose of this case report is to describe a patient who presented to a chiropractic physician for evaluation and treatment of neck pain and headache. CLINICAL FEATURES: A 45-year-old otherwise healthy female presented for evaluation and treatment of neck pain and headache. Within minutes, non-specific musculoskeletal symptoms progressed to neurological deficits, including limb ataxia and cognitive disturbances. Suspicion was raised for cerebrovascular ischemia and emergent referral was initiated. INTERVENTION AND OUTCOME: Paramedics were immediately summoned and the patient was transported to a local hospital with a working diagnosis of acute cerebrovascular ischemia. Multiplanar computed tomographic and magnetic resonance imaging with contrast revealed vertebral artery dissection of the V2 segment in the right vertebral artery. Anticoagulation therapy was administered and the patient was discharged without complications after 5 days in the hospital. CONCLUSION: This case highlights the potential for patients with vertebral artery dissection to present with nonspecific musculoskeletal complaints. Neurological symptoms may not manifest initially, but their sudden onset indicates the possibility of an ischemic cerebrovascular event. We suggest that early recognition and emergent referral for this patient avoided potential exacerbation of an evolving pre-existing condition and resulted in timely anticoagulation treatment. PMID- 25685117 TI - Treatment of Bell's Palsy Using Monochromatic Infrared Energy: A Report of 2 Cases. AB - OBJECTIVE: The purpose of the study is to describe the use of monochromatic infrared energy (MIRE) therapy in the management of 2 patients with Bell's palsy. CLINICAL FEATURES: Two patients presented to a chiropractic clinic with Bell's palsy that was diagnosed by a medical physician. Both patients were treated using MIRE. The acute patient was a 32-year-old male. He presented with left facial palsy 1 day before the consultation. He was unable to puff the left cheek and close the left eyelid. He had difficulty raising the left eyebrow. The chronic case was a 46-year-old lady. Prior to the first consultation, she was treated with corticosteroid and electro-acupuncture for one and a half years, with incomplete recovery. When first seen, the left corner of mouth drooped and she had difficulty raising her left eyebrow. INTERVENTION AND OUTCOME: Monochromatic infrared energy therapy, emitting 890 nm infrared light, was placed on the post auricular area, pre-auricular area, the temple and mandibular area of the affected side. Each treatment lasted 30 minutes. Photographs were taken every week to document changes. The acute case received 19 treatments in 6 weeks. He reported an improvement of 95%. The chronic case received a total of 45 treatments in 9 months. She rated an improvement of 50%. At the conclusion of treatment, she was able to close her left eyelid and puff her left cheek but still could not raise her left eyebrow. CONCLUSION: These 2 patients seemed to respond to a different degree to the MIRE therapy. As 71% of patients with Bell's palsy recover uneventfully without any treatment, the present study describes the course of care but cannot confirm the effectiveness of MIRE therapy in the management of Bell's palsy. PMID- 25685118 TI - Chiropractic treatment of lateral epicondylitis: a case report utilizing active release techniques. AB - OBJECTIVE: The purpose of this report is to describe the chiropractic management of a case of lateral epicondylitis with active release techniques (ART). CLINICAL FEATURES: A 48-year-old white man presented to a chiropractic clinic with a complaint of left lateral elbow pain that began 2 years previous with insidious onset. The patient reported an inability to play 18 consecutive holes of golf due to the pain. INTERVENTION AND OUTCOME: Treatment consisted of 5 sessions of ART (a soft tissue technique that is applied to muscles, fascia, tendons, ligaments, and nerves) applied to the left elbow soft tissue over a duration of 3 weeks. The patient reported an absence of pain and ability to consistently play 18 consecutive holes of golf up to 3 times per week at 4 and 8 weeks post-treatment. CONCLUSION: This patient with lateral epicondylitis responded favorably to chiropractic treatment using the application of ART, as demonstrated by reduced pain and increased functional outcomes. PMID- 25685119 TI - Cox decompression manipulation and guided rehabilitation of a patient with a post surgical c6-c7 fusion with spondylotic myelopathy and concurrent L5-s1 radiculopathy. AB - OBJECTIVE: The purpose of this case report is to describe combined treatment utilizing Cox distraction manipulation and guided rehabilitation for a patient with spine pain and post-surgical C6-7 fusion with spondylotic myelopathy and L5 S1 radiculopathy. CLINICAL FEATURES: A 38-year-old man presented to a chiropractic clinic with neck pain and a history of an anterior cervical spine plate fusion at C6-7 after a work related accident 4 years earlier. He had signs and symptoms of spondolytic myelopathy and right lower back, right posterior thigh pain and numbness. INTERVENTION AND OUTCOME: The patient was treated with Cox technique and rehabilitation. The patient experienced a reduction of pain on a numeric pain scale from 8/10 to 3/10. The patient was seen a total of 12 visits over 3 months. No adverse effects were reported. CONCLUSIONS: A patient with a prior C6-7 fusion with spondylotic myelopathy and concurrent L5-S1 radiculopathy improved after a course of rehabilitation and Cox distraction manipulation. Further research is needed to establish its efficiency. PMID- 25685120 TI - Chiropractic management of an 81-year-old man with Parkinson disease signs and symptoms. AB - OBJECTIVE: The purpose of this case report is to describe the chiropractic management of a patient with Parkinson disease. CLINICAL FEATURES: An 81-year-old male with a 12-year history of Parkinson disease sought chiropractic care. He had a stooped posture and a shuffling gait. He was not able to ambulate comfortably without the guidance of his walker. The patient had a resting tremor, most notably in his right hand. Outcome measures were documented using the Parkinson's Disease Questionaire-39 (PDQ-39) and patient subjective reports. INTERVENTION AND OUTCOME: The patient was treated with blue-lensed glasses, vibration stimulation therapy, spinal manipulation, and eye-movement exercises. Within the first week of treatment, there was a reduction in symptoms, improvement in ambulation, and tremor. CONCLUSION: For this particular patient, the use of alternative treatment procedures appeared to help his Parkinson disease signs and symptoms. PMID- 25685121 TI - Interdisciplinary management of deep vein thrombosis during rehabilitation of acute rupture of the anterior cruciate ligament: a case report. AB - OBJECTIVE: The purpose of this case report is to describe a patient who experienced deep venous thrombosis (DVT) during pre-operative rehabilitation of an acute rupture of an anterior cruciate ligament (ACL) reconstruction graft, to increase awareness of DVT occurring in a healthy individual after periodic immobilization, and to describe the interdisciplinary management for this patient. CLINICAL FEATURES: A 30-year-old male was referred to a chiropractic clinic for presurgical treatment of a left ACL rupture and medial meniscus tear confirmed at magnetic resonance imaging. During the course of preoperative rehabilitation, the patient became limited in ambulation and presented for a routine rehabilitation visit. During this visit, he experienced increased leg swelling, pain and tenderness. The patient was assessed for DVT and was referred to the local emergency department for further evaluation where multiple DVTs were found in the left popliteal, posterior tibial, and peroneal veins. INTERVENTION/OUTCOME: The patient was treated with a 17-week course of warfarin during which time the clinical signs and symptoms of DVT resolved. Meanwhile, the patient completed the rehabilitation treatment plan in preparation for ACL reconstruction without further complications. CONCLUSIONS: This case raises awareness that DVT may occur in a healthy individual after periodic immobilization. While there may be controversy regarding the appropriate application of pharmaceutical anticoagulants in patients with DVT of the leg, the most risk averse strategy is for a short duration prescription medication with compression stockings. Through interdisciplinary management, the patient experienced a successful outcome. PMID- 25685122 TI - Elongated styloid processes and calcified stylohyoid ligaments in a patient with neck pain: implications for manual therapy practice. AB - OBJECTIVE: The purpose of this paper is to present a case of a patient with neck pain, tinnitus, and headache in the setting of bilateral elongated styloid processes (ESP) and calcified stylohyoid ligaments (CSL), how knowledge of this anatomical variation and symptomatic presentation affected the rehabilitation management plan for this patient, and to discuss the potential relevance of ESPs and CSLs to carotid artery dissection. CLINICAL FEATURES: A 29-year-old male military helicopter mechanic presented for chiropractic care for chronic pain in the right side of his neck and upper back, tinnitus, and dizziness with a past history of right side parietal headaches and tonsillitis. Conventional radiographs showed C6 and C7 spinous process fractures, degenerative disc disease at C6/7, and an elongated right styloid process with associated calcification of the left stylohyoid ligament. Volumetric computerized tomography demonstrated calcification of the stylohyoid ligaments bilaterally. INTERVENTION AND OUTCOME: Given the proximity of the calcified stylohyoid apparatus to the carotid arteries, spinal manipulation techniques were modified to minimize rotation of the neck. Rehabilitation also included soft tissue mobilization and stretching, corrective postural exercises, and acupuncture. An otolaryngologist felt that the symptoms were not consistent with Eagle syndrome and the tinnitus was associated with symmetric high frequency hearing loss, likely due to occupational noise exposure. Initially, the patient's symptoms improved but plateaued by the fifth visit. CONCLUSION: Neck pain in the presence of ESPs and CSLs can be associated with Eagle syndrome, which can include ipsilateral head and neck pain, odynophagia, dysphagia, and cerebrovascular symptoms. This case, initially thought to be Eagle syndrome, highlights proper diagnostic workup for this condition and presents potential contraindications to consider with regard to cervical spine manipulation in such patients. Manual therapy precautions pertaining to cervical spine manipulation may be appropriate in cases involving ESPs and calcified stylohyoid ligaments. PMID- 25685123 TI - Ultrasonography and radiography to identify early post traumatic myosistis ossificans in an 18-year-old male: a case report. AB - OBJECTIVE: The purpose of this case report is to describe a patient with post traumatic myositis ossificans (PTMO) of the anterior thigh following blunt trauma and discuss the incidence, clinical presentation, management, and imaging findings. CLINICAL FEATURES: An 18-year-old male presented to a chiropractic clinic with a chief complaint of left knee pain and reduced range of motion after an impact injury to his left anterior thigh during hurdling 6 weeks earlier. Immediately after the injury, he presented to the emergency department where radiography of the left knee was negative and he was diagnosed with a muscle sprain. Follow-up radiography and ultrasonography of the left knee in a chiropractic radiology department revealed ossification consistent with PTMO within his vastus intermedius. INTERVENTION AND OUTCOME: The patient underwent a course of rehabilitation for 2 months including ice, class IV cold laser and vibration applied to his anterior thigh, and myofascial release of his quadriceps musculature with targeted and progressive rehabilitative exercises. His left knee pain resolved within 2 weeks of care. He resumed sports participation (American football) pain-free, while wearing protective padding over the affected thigh, 1 month after presentation, which was approximately 2 1/2 months following his injury. CONCLUSION: This case demonstrates that ultrasonography may have the capability to detect early phases of PTMO approximately 2 weeks prior to radiographic evidence and to monitor progression throughout its course. PMID- 25685124 TI - Sonography of occult rib and costal cartilage fractures: a case series. AB - OBJECTIVE: The purpose of this case series is to describe the use of diagnostic ultrasound (US) in the detection of occult rib and costal cartilage fractures presenting as chest wall pain to a chiropractic clinic. CLINICAL FEATURES: Three patients presented with chest wall pain and tenderness. Two of the patients presented with acute chest wall injury and 1 carried a previous diagnosis of rib fracture after trivial trauma 2 months earlier. INTERVENTION AND OUTCOMES: Diagnostic US was selected as a non-ionizing imaging tool for these patients after negative digital radiography studies. All fractures were considered isolated as there was no associated injury, such as pneumothorax. Both of the acute cases were followed up to complete healing (evidence of osseous union) using US. All patients eventually achieved pain-free status. CONCLUSION: In these cases, US was more sensitive than radiography for diagnosing these cases of acute rib and costal cartilage fractures. Early recognition of rib injury could avoid potential complications from local manipulative therapy. PMID- 25685125 TI - A 69-year-old presenting with musculoskeletal low back pain: a case of lumbosacral chordoma. AB - OBJECTIVE: The purpose of this case report is to describe the presentation of a patient with lumbosacral chordoma characterized by somatic chronic low back pain and intermittent sacral nerve impingement. CASE REPORT: A 69-year-old male presenting to an emergency department (ED) with low back pain was provided analgesics and muscle relaxants then referred for a series of chiropractic treatments. Chiropractic treatment included manipulation, physical therapy, and rehabilitation. After 3 times per week for a total of 4 weeks, re-examination showed little relief of his symptoms. His pain symptoms worsened and he presented to the ED for the second time. Magnetic resonance imaging was performed and revealed a high intensity mass. INTERVENTION AND OUTCOME: The soft tissue mass identified on magnetic resonance imaging was surgically removed. Shortly after the surgery, the patient developed post-operative bleeding and was returned to surgery. During the second procedure, he developed a post-operative hemorrhage related to the development of disseminated intravascular coagulation and subsequently died during the second procedure. A malignant lumbosacral chordoma was diagnosed on pathologic examination. CONCLUSION: This case report describes the presentation of a patient with lumbosacral chordoma presenting with musculoskeletal low back pain. Chordomas are rare with few prominent manifestations. An early diagnosis can potentially make a difference in morbidity and mortality. Due to its insidious nature, it is a difficult diagnosis and one that is often delayed. PMID- 25685126 TI - A Community Care Model of Intravenous Antibiotic Therapy for Injection Drug Users with Deep Tissue Infection for "Reduce Leaving Against Medical Advice" AB - Deep tissue infection is a serious sequela that often demands intravenous (IV) antibiotic treatment. With respect to IV drug users (IDU's), research and lived experience demonstrates a trend of failed treatment outcomes, most notably associated with leaving hospital against medical advice (LAMA) prior to treatment completion, increased adverse outcomes and patient hardship. This paper examines an alternative model for delivering and completing IV antibiotic treatment to IDU's in a community care setting. A retrospective study was designed to review client characteristics. A total of 33 in-depth interviews were conducted with clients, clinicians and with staff. The impact of treatment adherence and completion, as well as client satisfaction of care was explored. A total of 165 patients were admitted during the study period. Osteomyelitis was the primary cause for IV antibiotics. Risk of leaving AMA was significantly lower for community model (p value <0.0000). Qualitative narrative analysis is also described with respect to satisfaction, stigma and the need for better models of care. With lower rates of LAMA a community model ought to be considered on a wider scale for provision of comprehensive support for populations with complex underlying health needs. PMID- 25685127 TI - Palladium-Catalyzed Direct alpha-Aryation of Benzyl Thioethers with Aryl Bromides. AB - The arylation of sp3-hybridized C-H's bonds is a powerful strategy to build molecular complexity and diversity. A novel and efficient palladium-catalyzed direct sp3 C-H arylation of aryl and alkyl benzyl thioether derivatives with aryl bromides is reported. The reaction involves reversible deprotonation of the benzylic C-H's of the thioether with either LiN(SiMe3)2 or NaN(SiMe3)2 and subsequent cross-coupling to provide the functionalized products in up to 97% yield. A screen of 24 of the most successful ligands in cross-coupling chemistry led to the identification of NiXantPhos as the only viable ligand for this challenging coupling. PMID- 25685128 TI - Appendiceal Abscesses Reduced in Size by Drainage of Pus from the Appendiceal Orifice during Colonoscopy: A Report of Three Cases. AB - Interval appendectomy (IA) for appendiceal abscesses is useful for avoiding extended surgery and preventing postoperative complications. However, IA has problems in that it takes time before an abscess is reduced in size in some cases and in that elective surgery may result in a delay in treatment in patients with a malignant tumor of the appendix. In order to rule out malignancy, we performed colonoscopy on three patients with an appendiceal abscess that did not decrease in size 5 or more days after IA. After malignancy had been ruled out by examination of the area of the appendiceal orifice, the appendiceal orifice was compressed with a colonoscope, and a catheter was inserted through the orifice. Then, drainage of pus was observed from the appendiceal orifice into the cecal lumen. Computed tomography performed 3 days after colonoscopy revealed a marked reduction in abscess size in all patients. No endoscopy-related complication was noted. Colonoscopy in patients with an appendiceal abscess may not only differentiate malignant tumors, but also accelerate reduction in abscess size. PMID- 25685129 TI - Gastroduodenal Intussusception, Intermittent Biliary Obstruction and Biochemical Pancreatitis due to a Gastric Hyperplastic Polyp. AB - We present the case of a 76-year-old man with gastroduodenal intussusception secondary to a gastric hyperplastic polyp. Intussusception in the adult population occurs infrequently. Our patient presented with gastroduodenal intussusception, which is very uncommon and accounts for <10% of all types of intussusception. This case is unique in that partial endoscopic resection of the gastric hyperplastic polyp resolved the patient's gastroduodenal intussusception, biliary obstruction and biochemical pancreatitis without the need for surgical intervention. PMID- 25685130 TI - Clostridium perfringens Bacteremia in an 85-Year-Old Diabetic Man. AB - Emphysematous cholecystitis is an uncommon and dangerous complication of acute cholecystitis. Common risk factors for this disease include male gender, old age, presence of diabetes mellitus and cholelithiasis. The disease is best treated with emergent surgery and parenteral antibiotics. We present the case of an 85 year-old nursing home resident who presented to our institution with a 3-day history of gradually worsening abdominal discomfort. PMID- 25685131 TI - Rapid partial repigmentation of vitiligo in a young female adult with a gluten free diet. AB - Vitiligo is a common pigmentary skin condition with a profound impact. Despite a number of therapeutic modalities, few have been demonstrated to result in significant repigmentation within a brief period of time. Reported dietary interventions are sparse. Following exclusion of gluten in the diet, early and extensive repigmentation of facial lesions were noted in a young female adult of Asian ethnicity with acrofacial vitiligo. The majority of the benefits occurred within the first month and stabilized at 4 months. Previous topical and phototherapy had not been found to be effective. The patient was maintained on the previously prescribed dapsone therapy. Dietary elimination can potentially be a disease-modifying intervention for vitiligo and should be considered even in patients without concomitant celiac disease. PMID- 25685132 TI - Calcinosis cutis long after rhinoplasty with silicone. AB - Rhinoplasty is a plastic surgery procedure to reconstruct the nose. Silicone alloplastic materials are most widely used as implants for rhinoplasty, but calcification on the surface occurs with long-term usage. Herein, we report a case of gruel-like calcification approximately 50 years after silicone implant rhinoplasty. In this case, calcification on the silicone surface might have transformed into gruel-like deposits, which presented as a subcutaneous mass at the dorsal area of the nose. The precise mechanism is unclear; a pH change in the tissue might have occurred during the process of inflammation, leading to the dissolution of calcified deposits. PMID- 25685133 TI - Angioimmunoblastic T-cell lymphoma: a diagnostic challenge. AB - Angioimmunoblastic T-cell lymphoma (AITL) accounts for 15-20% of all peripheral T cell lymphomas. It is a rare subtype of CD4 T-cell peripheral lymphoma that affects aged individuals, causing B symptoms, generalized lymphadenopathy and hepatosplenomegaly. Its pathogenesis is still unclear, but in some cases it has been associated with infection, allergic reaction or drug exposure. The majority of patients are diagnosed in an advanced stage and anthracycline based regimen is considered the first-line therapy. Skin involvement is not well characterized, occurring in up to 50% of patients and presenting as nonspecific rash, macules, papules, petechiae, purpura, nodules and urticaria. We present the illustrative case of a 55-year-old woman with an AITL who presented prominent skin findings, arthritis, lymphadenopathy and hypereosinophilia. Skin biopsy reported a T-cell lymphoma and the diagnosis of AITL was confirmed by an axillary lymph node biopsy, which was also positive for Epstein-Barr virus. Chemotherapy with CHOP-21 and thalidomide was given, accomplishing complete remission after six cycles. PMID- 25685134 TI - Successful interventional treatment for arterioportal fistula caused by radiofrequency ablation for hepatocellular carcinoma. AB - Radiofrequency ablation (RFA) is commonly used as a treatment for small hepatocellular carcinoma (HCC). Although several complications such as intraperitoneal bleeding are often observed after RFA, hepatic arterioportal fistula (APF) is a less frequently occurring complication. In this study, we describe two cases of APF caused by RFA, which was successfully occluded by an interventional approach. Case 1 involved a 68-year-old man with solitary HCC in segment VIII of the liver. Both contrast-enhanced computed tomography and color Doppler sonography indicated an APF between the anterosuperior branch of the right hepatic artery (A8) and the portal branch (P8). Concordant with these findings, digital subtraction angiography (DSA) revealed an APF in segment VIII of the liver. Subsequently, the APF was successfully occluded by transarterial embolization (TAE) using gelatin sponge particles. Case 2 involved a 67-year-old man with solitary HCC in segment VII of the liver. Although he developed obstructive jaundice because of hemobilia after RFA, it was improved by endoscopic nasobiliary drainage and the systemic administration of antibiotics. In addition, color Doppler sonography revealed a disturbed flow of the right branch of the portal vein. Similar to case 1, DSA showed an APF between A8 and P8. The APF was successfully embolized by TAE using microcoils. In conclusion, it appears that the formation of APF should be checked after RFA. It is preferable to treat RFA-induced APF promptly by an interventional approach to avoid secondary complications such as portal hypertension and liver dysfunction. PMID- 25685135 TI - A case of carcinoma showing thymus-like differentiation with a rapidly lethal course. AB - A 55-year-old woman underwent a total thyroidectomy for carcinoma showing thymus like differentiation (CASTLE). The patient was referred to our hospital after the tumor was found to have directly invaded the cervical esophagus and the entire circumference of the trachea. A total thyroidectomy was performed, followed by end-to-end anastomosis of the trachea, suprahyoid release and dissection of bilateral pulmonary ligaments. No major complications, including anastomotic dehiscence or stenosis, were observed. The patient experienced some swallowing disturbances and hoarseness during the perioperative period but fully recovered. Radiotherapy to the neck was performed as an adjuvant therapy. Eleven months after surgery, lower back pain and right leg numbness developed and led to gait inability. Multiple lung and bone recurrences were observed, but no local recurrence. Palliative radiotherapy to the bone metastasis was performed. The patient died of pleural metastasis 14 months after the initial diagnosis of CASTLE. PMID- 25685136 TI - Hereditary Neuropathy with Liability to Pressure Palsy Presenting as an Acute Brachial Plexopathy: A Lover's Palsy. AB - It is generally regarded that patients with hereditary neuropathy to pressure palsies, due to a deletion in the PMP22 gene, show recurrent pressure palsy and generalised peripheral neuropathy (pes cavus and hammer toes sometimes develop). Brachial plexopathy is rarely identified as a first presentation of hereditary neuropathy to pressure palsies. We describe a young man who developed a painless flail upper limb with a clinical diagnosis of a brachial plexopathy after his partner slept on his arm - a PMP22 deletion was found. His father, who had a symmetrical polyneuropathy without recurrent mononeuropathies, shared the PMP22 deletion. PMID- 25685137 TI - Very late-onset friedreich ataxia with laryngeal dystonia. AB - Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder characterized by progressive gait and limb ataxia, cerebellar, pyramidal and dorsal column involvement, visual defects, scoliosis, pes cavus and cardiomyopathy. It is caused by a homozygous guanine-adenine-adenine (GAA) trinucleotide repeat expansion in intron 1 of the frataxin gene (FXN) on chromosome 9q13-q21.1. Onset is usually in the first or second decade of life; however, late-onset cases of Freidreich ataxia (LOFA), after the age of 25 years, and very late-onset cases of Freidreich ataxia (VLOFA), after the age of 40 years, have been reported. VLOFA is quite rare and usually presents a milder progression of the disease. We report the case of a 64-year-old woman affected with VLOFA whose first symptoms (balance and gait disturbances) occurred at the age of 44 years. At the age of 62 years, she started complaining of a slowly progressive dysphonia showing the clinical aspects of laryngeal dystonia. Molecular analysis showed a 210- and 230-trinucleotide GAA repeat expansion in the two alleles of the FXN gene. Laryngeal dystonia has been reported only in very few cases of ataxia syndrome and never before in FRDA patients. It may represent a rare clinical manifestation of VLOFA thus confirming the high variability of the clinical spectrum of FRDA. PMID- 25685138 TI - Anti-glutamate ?2 receptor antibody-positive and anti-N-methyl-d-aspartate receptor antibody-negative lobar encephalitis presenting as global aphasia and swallowing apraxia. AB - BACKGROUND: Little is known about the difference between anti-N-methyl-D aspartate receptor (NMDAR) antibody-positive encephalitis and anti-glutamate receptor (GluR) antibody-positive encephalitis. OBJECTIVES: To characterize anti GluR antibody-positive encephalitis. METHODS: We report a 33-year-old man with nonparaneoplastic anti-GluR ?2, zeta1 and delta2 antibody-positive and anti-NMDAR antibody-negative encephalitis, using neuropsychological tests and imaging studies including magnetic resonance imaging and single photon emission computed tomography (SPECT) with a (99m)Tc-ethylcysteinate dimer. RESULTS: The patient exhibited global aphasia and swallowing apraxia (inability to transfer food to the pharyngeal cavity without sialorrhea). He was treated with 3 courses of corticosteroid pulse therapy and had recovered markedly 3 weeks after onset. Magnetic resonance diffusion-weighted images revealed hyperintensity in the bilateral frontal and left parietal cortices. Seven months later, a small area of hyperintensity in the left supramarginal gyrus remained. SPECT revealed hypoperfusion in extensive regions of the bilateral frontal lobes and left supramarginal gyrus. Thirteen months later, blood flow reduction was restricted to diffuse areas in the frontal lobes. CONCLUSIONS: Frontal lobar encephalitis without medial temporal involvement, marked cognitive impairment with a relatively preserved level of consciousness, and a favorable response to corticosteroid therapy, with nearly reversible cortical damage, may characterize anti-GluR antibody-positive encephalitis. PMID- 25685139 TI - Associations between Dementia Outcomes and Depressive Symptoms, Leisure Activities, and Social Support. AB - BACKGROUND: Social relations and depressive symptoms are intertwined. They both predict subsequent dementia, but only few studies on the association between social life aspects and subsequent dementia exist. METHODS: The risk of subsequent dementia was estimated over 2 follow-up assessments, each 18 months apart, depending on leisure activity, social support (general scale and the 3 factors emotional support, practical support, and social integration), and depressive symptoms, using proportional hazard models in a cohort of elderly patients (n = 2,300, with a mean age of 82.45 years) recruited for the study by their general practitioners. RESULTS: Higher depressive symptoms and lower cognitive and physical activity were associated with an increased risk of subsequent all-cause dementia and Alzheimer's dementia (AD). While neither social engagement nor the general social support scale was associated with subsequent dementia, a higher level of social integration was associated with a lower dementia risk. In combined models, the results for activity variables remained similar, but the strength of the association between depressive symptoms and the subsequent risk of dementia decreased, and the association with social integration disappeared. CONCLUSIONS: Depressive symptoms increased and activity variables decreased the risk of subsequent dementia; however, activity variables, namely cognitive and physical activity, partly mediated the effect of depressive symptoms on the subsequent risk of all-cause dementia and AD. In many cases, social support was not associated with a risk of subsequent dementia. PMID- 25685140 TI - The Progression of Alzheimer's Disease Can Be Assessed with a Short Version of the CERAD Neuropsychological Battery: The Kuopio ALSOVA Study. AB - BACKGROUND/AIMS: Measuring and predicting Alzheimer's disease (AD) progression is important in order to adjust treatment and allocate care resources. We aimed to identify a combination of subtests from the Consortium to Establish a Registry for Alzheimer's Disease Neuropsychological Battery (CERAD-NB) that best correlated with AD progression in follow-up as well as to predict AD progression. METHOD: A total of 236 participants with very mild [Clinical Dementia Rating (CDR) = 0.5] or mild AD (CDR = 1.0) at baseline were followed up for 3 years. The CERAD-NB and Mini-Mental State Examination (MMSE) were used to assess cognition, and the CDR scale sum of boxes (CDR-sb) was employed to evaluate AD progression. Generalized estimating equations were used to develop models to predict and follow up disease progression. RESULTS: Performance declined on all CERAD-NB subtests. The ability of the separate subtests to distinguish between groups (baseline CDR = 0.5 or 1.0) diminished during follow-up. The best combination of subtests that explained 62% of CDR-sb variance in follow-up included verbal fluency, constructional praxis, the clock drawing test, and the MMSE. Baseline values of the same combination predicted 37% of the CDR-sb change. CONCLUSION: A short version of the CERAD-NB subtests provides a promising and time-efficient alternative for measuring cognitive deterioration during AD follow-up. Although the initial signs of AD include memory difficulties, it may be useful to assess non-memory tasks in follow-up. PMID- 25685141 TI - The Alzheimer's disease cooperative study prevention instrument project: longitudinal outcome of behavioral measures as predictors of cognitive decline. AB - BACKGROUND/METHODS: The Alzheimer's Disease Cooperative Study Prevention Instrument Project is a longitudinal study that recruited 644 cognitively healthy older subjects (aged between 75 and 93 years, 58% women) at baseline and evaluated their cognitive change over 4 years. The study was structured like a clinical trial to anticipate a prevention trial and to determine the performance of novel trial instruments in a longitudinal non-interventional trial framework. Behavioral symptoms were assessed at baseline. RESULTS: The existence of participant-reported behavioral symptoms at baseline predicted conversion to Clinical Dementia Rating scale score >=0.5 over the 4-year period. CONCLUSIONS: The results imply that early anxiety and depression may be harbingers of future cognitive decline, and that patients exhibiting such symptoms, even in the absence of co-occurring cognitive symptoms, should be closely followed over time. PMID- 25685142 TI - Incidence of Brain Abnormalities Detected on Preoperative Brain MR Imaging and Their Effect on the Outcome of Cochlear Implantation in Children with Sensorineural Hearing Loss. AB - The incidence of sensorineural hearing loss (SNHL) increased gradually in the past decades. High-resolution computed tomography (HRCT) and magnetic resonance (MR) imaging, as an important part of preimplantation evaluation for children with SNHL, could provide the detailed information about the inner ear, the vestibulocochlear nerve, and the brain, so as to select suitable candidate for cochlear implantation (CI). Brain abnormalities were not rare in the brain MR imaging of SNHL children; however, its influence on the effect of CI has not been clarified. After retrospectively analyzing the CT and MR imaging of 157 children with SNHL that accepted preoperative evaluation from June 2011 to February 2013 in our hospital and following them during a period of 14.09 +/- 5.08 months, we found that the white matter change, which might be associated with the history of medical condition, was the most common brain abnormality. Usually CI was still beneficial to the children with brain abnormalities, and the short-term hearing improvement could be achieved. Further study with more patients and longer follow up time was needed to confirm our results. PMID- 25685143 TI - Automated classification of glandular tissue by statistical proximity sampling. AB - Due to the complexity of biological tissue and variations in staining procedures, features that are based on the explicit extraction of properties from subglandular structures in tissue images may have difficulty generalizing well over an unrestricted set of images and staining variations. We circumvent this problem by an implicit representation that is both robust and highly descriptive, especially when combined with a multiple instance learning approach to image classification. The new feature method is able to describe tissue architecture based on glandular structure. It is based on statistically representing the relative distribution of tissue components around lumen regions, while preserving spatial and quantitative information, as a basis for diagnosing and analyzing different areas within an image. We demonstrate the efficacy of the method in extracting discriminative features for obtaining high classification rates for tubular formation in both healthy and cancerous tissue, which is an important component in Gleason and tubule-based Elston grading. The proposed method may be used for glandular classification, also in other tissue types, in addition to general applicability as a region-based feature descriptor in image analysis where the image represents a bag with a certain label (or grade) and the region based feature vectors represent instances. PMID- 25685144 TI - An extended affinity propagation clustering method based on different data density types. AB - Affinity propagation (AP) algorithm, as a novel clustering method, does not require the users to specify the initial cluster centers in advance, which regards all data points as potential exemplars (cluster centers) equally and groups the clusters totally by the similar degree among the data points. But in many cases there exist some different intensive areas within the same data set, which means that the data set does not distribute homogeneously. In such situation the AP algorithm cannot group the data points into ideal clusters. In this paper, we proposed an extended AP clustering algorithm to deal with such a problem. There are two steps in our method: firstly the data set is partitioned into several data density types according to the nearest distances of each data point; and then the AP clustering method is, respectively, used to group the data points into clusters in each data density type. Two experiments are carried out to evaluate the performance of our algorithm: one utilizes an artificial data set and the other uses a real seismic data set. The experiment results show that groups are obtained more accurately by our algorithm than OPTICS and AP clustering algorithm itself. PMID- 25685146 TI - Impact of clinical experience and diagnostic performance in patients with acute abdominal pain. AB - Background. The aims were to evaluate the importance of the formal competence of the emergency department physician, the patient's time of arrival at the emergency department, and the use of a structured schedule for investigation of patients with acute abdominal pain. Methods. Patients attending the Mora Hospital with acute abdominal pain from 1997 to 2000 were registered prospectively according to a structured schedule. Registration included history, symptoms, signs, preliminary diagnosis, surgery and final diagnosis after at least one year. Results. 3073 acute abdominal pain patients were included. The preliminary diagnosis, as compared with the final diagnosis, was correct in 54% (n = 1659). Previously, during 1996, a base-line registration of 790 patients had a 58% correct diagnoses (n = 458). A majority of the patients (n = 2699; 88%) were managed by nonspecialists. The proportion of correct diagnoses was 54% (n = 759) for pre-registrar house officers and 55% (n = 443) for senior house officers. Diagnostic performance at the emergency department was independent of patient's time of arrival. Conclusions. A structured schedule for investigation did not improve the diagnostic precision at the emergency department in patients with acute abdominal pain. The diagnostic performance was independent of the formal competence of the physician and the patient's time of arrival. PMID- 25685145 TI - Five-aminosalicylic Acid: an update for the reappraisal of an old drug. AB - Inflammatory bowel disease (IBD) comprises several conditions with chronic or recurring immune response and inflammation of the gastrointestinal apparatus, of which ulcerative colitis and Crohn's disease are the commonest forms. This disease has a significant prevalence and it is of an unknown aethiology. Five aminosalicylic acid (5-ASA) and its derivatives are among the oldest drugs approved for the treatment of the IBD. In this review we reapprise aspects of 5 ASA mechanism of action, safety, and efficacy that in our opinion make it a valuable drug that can be fruitfully tailored in personalised treatments as a therapeutic option alongside other immune-modifying agents. PMID- 25685147 TI - Determinants of vitamin d levels in children and adolescents with down syndrome. AB - Background. Poor studies have evaluated 25-hydroxycholecalciferol (25(OH)D) levels in Down syndrome (DS). Objective. To assess in DS subjects serum 25(OH)D value, to identify risk factors for vitamin D deficiency, and to evaluate whether a normal 25(OH)D value can be restored with a 400 I.U. daily supplement of cholecalciferol in respect to controls. Methods. We have longitudinally evaluated 31 DS patients (aged 4.5-18.9 years old) and 99 age- and sex-matched healthy controls. In these subjects, we analysed calcium, phosphate, parathyroid hormone (PTH), 25(OH)D concentrations, and calcium and 25(OH)D dietary intakes, and we quantified outdoor exposure. After 12.3 months (range 8.1-14.7 months) of 25(OH)D supplementation, we reevaluated these subjects. Results. DS subjects showed reduced 25(OH)D levels compared to controls (P < 0.0001), in particular DS subjects with obesity (P < 0.05) and autoimmune diseases history (P < 0.005). PTH levels were significantly higher in DS subjects than controls (P < 0.0001). After cholecalciferol supplementation, 25(OH)D levels were significantly ameliorated (P < 0.05), even if reduced compared to controls (P < 0.0001), in particular in DS subjects with obesity (P < 0.05) and autoimmune diseases (P < 0.001). Conclusions. Hypovitaminosis D is very frequent in DS subjects, in particular in presence of obesity and autoimmune diseases. In these subjects, there could be a need for higher cholecalciferol supplementation. PMID- 25685148 TI - Non-Small-Cell Lung Cancer Clinicopathologic Features and Survival Outcomes in Asian Pacific Islanders Residing in the United States: A SEER Analysis. AB - Background. The objective of our study was to ascertain racial/ethnic disparities in Asian/Pacific Islanders (API) for non-small-cell lung cancer (NSCLC) clinicopathologic features and survival outcomes based on various tumor characteristics and treatment modalities. Method. SEER database identified invasive NSCLC cases from 2004 to 2010. Variables included American Joint Committee on Cancer (AJCC) stage 7, tumor grade, tumor size, histology, age, marital status, radiation, surgery, and reason for no surgery. The Kruskall Wallis test and the Z test were used to examine differences between races/ethnicities and the referent, non-Hispanic white (NHW). Multivariate Cox proportional analyses were used to establish the weight of the prognostic significance contributing to disease-specific survival (DSS) in each AJCC stage. Result. Improved DSS was seen in API across stage I (HR: 0.78), stage II (HR: 0.79), and stage IV (HR: 0.86), respectively, compared to the referent NHW (P < 0.01). Prognosis was improved by being married, being female gender, AIS histology, and birth outside the US (P < 0.01). Conclusion. We have demonstrated improved survival among API in early stage and stage IV NSCLC. Further research is necessary to clarify the role of lifestyle and tumor biology for these differences. PMID- 25685149 TI - Colorectal cancer in iran: molecular epidemiology and screening strategies. AB - Purpose. The increasing incidence of colorectal cancer (CRC) in the past three decades in Iran has made it a major public health burden. This study aimed to report its epidemiologic features, molecular genetic aspects, survival, heredity, and screening pattern in Iran. Methods. A comprehensive literature review was conducted to identify the relevant published articles. We used medical subject headings, including colorectal cancer, molecular genetics, KRAS and BRAF mutations, screening, survival, epidemiologic study, and Iran. Results. Age standardized incidence rate of Iranian CRCs was 11.6 and 10.5 for men and women, respectively. Overall five-year survival rate was 41%, and the proportion of CRC among the younger age group was higher than that of western countries. Depending on ethnicity, geographical region, dietary, and genetic predisposition, mutation genes were considerably diverse and distinct among CRCs across Iran. The high occurrence of CRC in records of relatives of CRC patients showed that family history of CRC was more common among young CRCs. Conclusion. Appropriate screening strategies for CRC which is amenable to early detection through screening, especially in relatives of CRCs, should be considered as the first step in CRC screening programs. PMID- 25685150 TI - Edible mushrooms: improving human health and promoting quality life. AB - Mushrooms have been consumed since earliest history; ancient Greeks believed that mushrooms provided strength for warriors in battle, and the Romans perceived them as the "Food of the Gods." For centuries, the Chinese culture has treasured mushrooms as a health food, an "elixir of life." They have been part of the human culture for thousands of years and have considerable interest in the most important civilizations in history because of their sensory characteristics; they have been recognized for their attractive culinary attributes. Nowadays, mushrooms are popular valuable foods because they are low in calories, carbohydrates, fat, and sodium: also, they are cholesterol-free. Besides, mushrooms provide important nutrients, including selenium, potassium, riboflavin, niacin, vitamin D, proteins, and fiber. All together with a long history as food source, mushrooms are important for their healing capacities and properties in traditional medicine. It has reported beneficial effects for health and treatment of some diseases. Many nutraceutical properties are described in mushrooms, such as prevention or treatment of Parkinson, Alzheimer, hypertension, and high risk of stroke. They are also utilized to reduce the likelihood of cancer invasion and metastasis due to antitumoral attributes. Mushrooms act as antibacterial, immune system enhancer and cholesterol lowering agents; additionally, they are important sources of bioactive compounds. As a result of these properties, some mushroom extracts are used to promote human health and are found as dietary supplements. PMID- 25685151 TI - A Reappraisal of Women's Health Initiative Estrogen-Alone Trial: Long-Term Outcomes in Women 50-59 Years of Age. AB - The Women's Health Initiative (WHI) Estrogen-Alone Trial randomized postmenopausal women, 50 to 79 years of age, with prior hysterectomy, to conjugated equine estrogens (CEE) or placebo with a 5.9-year median duration of CEE use. In 2013, the WHI published outcomes for additional extended follow-up. Reported here for the first time is an analysis of the number needed to treat with CEE rather than placebo for younger women (50-59 years) to prevent an adverse long-term outcome. For every 76 women randomized to CEE at 50-59 years, one less myocardial infarction occurred during the 13-year cumulative long-term follow-up. For every 37 women randomized to CEE at 50-59 years, one less woman experienced a global index endpoint (including coronary heart disease, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, hip fracture, and death) during the 13-year follow-up. Younger women (50-59 years), compared to older women, had more favorable cumulative long-term outcomes for MI and global index. Though a subgroup analysis is not an adequate basis for making primary prevention guideline recommendations, the WHI Estrogen-Alone Trial outcomes strongly suggest that a similar course of estrogen initiated at 50-59 years in postmenopausal women with prior hysterectomy results in significant long-term health benefit. PMID- 25685152 TI - A Case of IFAP Syndrome with Severe Atopic Dermatitis. AB - Introduction. The IFAP syndrome is a rare X-linked genetic disorder characterized by the triad of follicular ichthyosis, atrichia, and photophobia. Case Report. A three-month-old Caucasian, male patient was observed with noncicatricial universal alopecia and persistent eczema from birth. He had dystrophic nails, spiky follicular hyperkeratosis, and photophobia which became apparent at the first year of life. Short stature and psychomotor developmental delay were also noticed. Histopathological examination of skin biopsy on left thigh showed epidermis with irregular acanthosis, lamellar orthokeratotic hyperkeratosis, and hair follicles fulfilled by parakeratotic hyperkeratosis. The chromosomal study showed a karyotype 46, XY. Total IgE was 374 IU/mL. One missense mutation c.1360G>C (p.Ala454Pro) in hemizygosity was detected on the MBTPS2 gene thus confirming the diagnosis of IFAP syndrome. Conclusions. We describe a boy with a typical clinical presentation of IFAP syndrome and severe atopic manifestations. A novel missense mutation c.1360G>C (p.Ala454Pro) in MBTPS2 gene was observed. The phenotypic expression of disease is quantitatively related to a reduced function of a key cellular regulatory system affecting cholesterol and endoplasmic reticulum homeostasis. It can cause epithelial disturbance with failure in differentiation of epidermal structures and abnormal skin permeability barrier. However, no correlation phenotype/genotype could be established. PMID- 25685153 TI - Guide catheter-induced aortic dissection complicated by pericardial effusion with pulsus paradoxus: a case report of successful medical management. AB - Aortic dissection is a rare but potentially fatal complication of percutaneous coronary intervention (PCI). Management strategies of PCI induced dissection are not clearly identified in literature; such occurrences often mandate surgical repair of the aortic root with reimplantation of the coronary arteries. Another trend seen in case reports is the use of coronary-aortic stenting if such lesions permit. Several factors impact the management decision including the hemodynamic stability of the patient; mechanism of aortic injury; size, severity, and direction of propagation of the dissection; presence of an intimal flap; and preexisting atherosclerotic disease. We describe a case of a 65-year-old woman who underwent PCI for a chronic right coronary artery (RCA) occlusion, which was complicated by aortic dissection and pericardial effusion. Our case report suggests that nonsurgical management may also be appropriate for PCI induced dissections, and potentially even those associated with new pericardial effusion. PMID- 25685154 TI - A rare case of unrecognized and uncommon bladder perforation after transobturator tape procedure. AB - The transobturator tape (TOT) procedure has become practically widespread worldwide. Complications seem to be rare, but recognizing them intraoperatively is the most significant step because some of the complications which may appear in postoperative period can be challenging for both physicians and patients. The purpose of this case, with this patient who was operated on with open surgery, is to evaluate this rarely seen unrecognized and uncommon bladder perforation after TOT procedure and thus make some contribution to the literature. Here, we present a case report about the treatment of a 48-year-old woman patient with unrecognized and uncommon bladder perforation after TOT procedure, 5 months postoperatively. Cystoscopic evaluation is not recommended routinely, but it must be performed if the patient is complicated enough to create doubt and also the surgeon's skill and ability are not sufficient enough to operate decently. PMID- 25685155 TI - Recurrent syncope attributed to left main coronary artery severe stenosis. AB - Patients with acute coronary syndrome (ACS) rarely manifest as recurrent syncope due to malignant ventricular arrhythmia. We report a case of a 56-year-old Chinese male with complaints of paroxysmal chest burning sensation and distress for 2 weeks as well as loss of consciousness for 3 days. The electrocardiogram (ECG) revealed paroxysmal multimorphologic ventricular tachycardia during attack and normal heart rhythm during intervals. Coronary angiograph showed 90% stenosis in left main coronary artery and 80% stenosis in anterior descending artery. Two stents sized 4.0*18 mm and 2.75*18 mm were placed at left main coronary artery and anterior descending artery, respectively, during percutaneous coronary intervention (PCI). The patient was discharged and never had ventricular arrhythmia again during a 3-month follow-up since the PCI. This indicated that ventricular tachycardia was correlated with persistent severe myocardial ischemia. Coronary vasospasm was highly suspected to be the reason of the sudden attack and acute exacerbation. PCI is recommended in patients with both severe coronary artery stenosis and ventricular arrhythmia. Removing myocardial ischemia may stop or relieve ventricular arrhythmia and prevent cardiac arrest. PMID- 25685156 TI - Management of six root canals in mandibular first molar. AB - Success in root canal treatment is achieved after thorough cleaning, shaping, and obturation of the root canal system. This clinical case describes conventional root canal treatment of an unusual mandibular first molar with six root canals. The prognosis for endodontic treatment in teeth with abnormal morphology is unfavorable if the clinician fails to recognize extra root canals. PMID- 25685157 TI - Multiglandular hormone deficiency in a patient with systemic capillary leak syndrome. AB - Systemic capillary leak syndrome (SCLS) is a rare but potentially fatal disorder characterized by a loss of fluid and proteins into the interstitial space leading to intravascular hypovolemia up to the point of hypovolemic shock. We report the case of a 64-year-old man with SCLS and multiple hormone abnormalities (primary hypothyroidism, hypoadrenalism, and hypogonadism), deficiency of hormone binding globulins, and hypogammaglobulinemia. The patient was successfully treated with intravenous immunoglobulins, theophylline, and terbutaline. Strikingly, with the dissolution of peripheral edema, hormone levels improved. To our knowledge, this is the first reported case of SCLS associated with polyglandular abnormalities. PMID- 25685159 TI - Mesenchymal Stem Cells Pretreated with HGF and FGF4 Can Reduce Liver Fibrosis in Mice. AB - Stem cells have opened a new avenue to treat liver fibrosis. We investigated in vitro and in vivo the effect of cytokine (HGF and FGF4) pretreated MSCs in reduction of CCl4 liver injury. Mouse MSCs were pretreated with cytokines to improve their ability to reduce CCl4 injury. In vitro we gave CCl4 injury to mouse hepatocytes and cocultured it with untreated and cytokines pretreated MSCs. For in vivo study we labeled MSCs with PKH-26 and transplanted them into CCl4 injured mice by direct injection into liver. In vitro data showed that cytokines pretreated MSCs significantly reduce LDH level and apoptotic markers in CCl4 injured hepatocytes cocultured model. Furthermore the cytokines pretreated MSCs also improved cell viability and enhanced hepatic and antiapoptotic markers in injured hepatocytes cocultured model as compared to untreated MSCs. In vivo data in cytokines pretreated group demonstrated greater homing of MSCs in liver, restored glycogen storage, and significant reduction in collagen, alkaline phosphatase, and bilirubin levels. TUNEL assay and real time PCR also supported our hypothesis. Therefore, cytokines pretreated MSCs were shown to have a better therapeutic potential on reduction of liver injury. These results demonstrated the potential utility of this novel idea of cytokines pretreated MSCs for the treatment of liver fibrosis. PMID- 25685158 TI - Bone marrow-derived multipotent stromal cells promote myocardial fibrosis and reverse remodeling of the left ventricle. AB - Cell therapy is increasingly recognized as a beneficial practice in various cardiac conditions, but its fundamentals remain largely unclear. The fates of transplanted multipotent stromal cells in postinfarction cardiac microenvironments are particularly understudied. To address this issue, labeled multipotent stromal cells were infused into rat myocardium at day 30 after myocardial infarction, against the background of postinfarction cardiosclerosis. Therapeutic effects of the transplantation were assessed by an exercise tolerance test. Histological examination at 14 or 30 days after the transplantation was conducted by means of immunostaining and quantitative image analysis. An improvement in the functional status of the cardiovascular system was observed after both the autologous and the allogeneic transplantations. Location of the label-positive cells within the heart was restricted to the affected part of myocardium. The transplanted cells could give rise to fibroblasts or myofibroblasts but not to cardiac myocytes or blood vessel cells. Both types of transplantation positively influenced scarring processes, and no expansion of fibrosis to border myocardium was observed. Left ventricular wall thickening associated with reduced dilatation index was promoted by transplantation of the autologous cells. According to the results, multipotent stromal cell transplantation prevents adverse remodeling and stimulates left ventricular reverse remodeling. PMID- 25685161 TI - Allopurinol desensitization with A 2 weeks modified protocol in an elderly patients with multiple comorbidities: a case report. AB - BACKGROUND: Allopurinol is an effective urate-lowering drug that is well tolerated by the majority of patients. Patients with chronic renal insufficiency have an increased risk of hypersensitivity reactions with allopurinol. CASE PRESENTATION: 75 year old male patient with gout, renal insufficiency, history of metastatic colorectal carcinoma status post-resection was referred to Allergy clinic for a maculopapular eruption that developed 1 week after initiating therapy with allopurinol. The rash resolved with discontinuation of allopurinol. However, his serum urate level rose to 19.9 mg/dl. We initially proposed a slow 4 week oral allopurinol desensitization. The treating nephrologist felt it was critical to lower urate more rapidly. As a result, we modified the dose and standard 4 week protocol down to 2 weeks. A suspension of allopurinol was prepared by the allergy nurse practitioner with a 300 mg allopurinol tablet. The sensitization protocol was modified as a starting dose of 0.3 mg escalating to a final dose of 300 mg/day in 2 weeks. There was no reaction during or after the desensitization. The patient's urate level normalized (6.3 mg/dl) and has continued on 300 mg allopurinol daily without reaction. CONCLUSION: A 2 week modified allopurinol desensitization protocol is a safe alternative for elderly patients with multiple comorbidities. PMID- 25685160 TI - Residential exposure to urban traffic is associated with increased carotid intima media thickness in children. AB - Chronic exposure to urban traffic pollution is documented to promote atherosclerosis in adults but little is known about its potential effects in children. Our study examined the association of long-term exposure to traffic with carotid intima-media thickness (cIMT) in 287 healthy children. Residential proximity and distance-weighted traffic density (DWTD) were used as proximity markers for traffic-related air pollution exposure. The multivariable analyses revealed that children residing <100 meters from the nearest heavily trafficked road had cIMT mean and maximum measurements that were increased by 15% and 11% compared to those living >= 200 meters away (P = 0.0001). Similar increases in cIMT were identified for children in the highest versus lowest DWTD tertile. Children who resided 100-199 meters from traffic or in the middle DWTD tertile also exhibited increased cIMT but these differences were not statistically significant. No statistically significant differences were identified between residential distance to traffic or DWTD and systemic inflammation indicators (CRP, IL-6). The study results suggest that exposure to urban traffic promotes arterial remodeling in children. This finding is important since even small increases in cIMT over time can potentially lead to earlier progression to atherosclerosis. It is also important because traffic-related pollution is potentially modifiable. PMID- 25685162 TI - The efficacy and safety of the Timothy grass allergy sublingual immunotherapy tablet in Canadian adults and children. AB - BACKGROUND: The effect of sublingual Timothy grass immunotherapy tablet 2800 BAU (grass SLIT-T) has been evaluated in three North American trials in adults and children who have allergic rhinitis with or without conjunctivitis (AR/C). This paper examines the effects of grass SLIT-T in Canadians. METHODS: Data for grass allergic Canadians in three randomized, placebo-controlled, double-blind trials were analyzed post hoc: 1) adults >=18 y, grass-pollen season [GPS] 2009; 2) children 5- <18 y, 2009; and 3) adults 18-65 y and children 5- <18 y, GPS 2012. Data from the GPS 2009 trials were pooled to provide a more precise estimate of treatment effects than the individual studies would provide. In every trial, participants received once-daily grass SLIT-T or placebo approximately 12 weeks before and continuing throughout the GPS. Participants used daily electronic diaries to record AR/C symptoms and medication use for treatment of symptoms. The therapeutic effect of grass SLIT-T was measured as a total combined score (TCS = daily symptom score + daily medication score) averaged over the entire GPS. Safety was assessed by monitoring adverse events (AEs). RESULTS: In the three trials, 386 Canadian participants were randomized; the overall population had 2284 participants. Canadian participants treated with grass SLIT-T in the pooled adult-pediatric 2009 trials showed a 38% mean TCS reduction relative to placebo ( 2.06 difference [95% CI: -3.72, -0.39]; 3.32 vs. 5.37). Participants treated with grass SLIT-T in the adult-pediatric 2012 trial showed a 37% median TCS reduction relative to placebo (-1.53 difference [95% CI: -2.1, -0.3]; 2.58 vs. 4.11). Similar efficacy findings were observed over the peak GPS. Approximately 90% of treatment-related AEs were mild or moderate in severity. Two Canadian participants had moderate systemic allergic reactions (skin, respiratory, abdominal symptoms) to grass SLIT-T; symptoms resolved within 1 hour without medical intervention or treatment. No serious or life-threatening treatment related AEs occurred. CONCLUSION: The 2800 BAU Timothy grass SLIT-T significantly improved AR/C induced by Timothy grass pollen in adults and children >=5 y in Canadians, which was consistent with the robust efficacy observed in the overall trial population. The treatment was generally well tolerated. TRIAL REGISTRATION: Clinicaltrials.gov identifiers NCT00562159, NCT00550550, NCT01385371. PMID- 25685163 TI - Letter to the editor for the article "Auto-injector needle length may be inadequate to deliver epinephrine intramuscularly in women with confirmed food allergy". AB - Letter to the Editor for "Auto-injector needle length may be inadequate to deliver epinephrine intramuscularly in women with confirmed food allergy" by Tsai et al. There are limitations of this study note mentioning such as method of compression, role of propulsion, defining those patients who are at risk of prophylaxis and future studies. PMID- 25685164 TI - Prevalence of hepatitis C virus genotypes in Iranian patients: a systematic review and meta-analysis. AB - CONTEXT: Hepatitis C virus (HCV) is a global public health problem and a major etiology of chronic liver disease, which may develop into cirrhosis and hepatocellular carcinoma. Genotypes of HCV indicate the route of acquisition, the clinical outcome, response to treatment, prognosis and control strategies. OBJECTIVES: The aim of this study was to estimate the overall prevalence and trend of HCV genotypes or subtypes in Iran. DATA SOURCES: A literature review was done for papers reporting HCV genotypes in Iranian patients in PubMed, Magiran, IranMedex, Scientific Information Databank, and Google scholar databases. STUDY SELECTION: Data were selected according to inclusion and exclusion criteria. DATA EXTRACTION: Data were abstracted by two independent authors. Data were analyzed based on random-effects model using the Meta R. Pooled statistical software. Prevalence of HCV genotypes in cities and provinces of Iran with 95% confidence interval (CI) were calculated. RESULTS: Fifty-three articles published between 1999 and 31 June 2014 including 22952 HCV infected individuals were included in the meta-analysis. Subtype 1a was predominant with a rate of 39% (95% CI: 34 44%); followed by subtype 3a, 32% (95% CI: 26-39%); subtype 1b, 13% (95% CI: 10 15%); genotype 4, 5.18% (95% CI: 3.27-7.5%); and genotype 2, 3.6% (95% CI: 1.6 8.3%). Untypeable HCV had a rate of 0.11% (95% CI: 0.07-0.16%). CONCLUSIONS: The most frequent subtypes of HCV in Iran were 1a, 3a and 1b, respectively. This frequency differed in various provinces of Iran and fluctuated with time. It is important to determine the distribution of HCV genotypes in different geographical areas and its trend with time for epidemiological and patients' management purposes. PMID- 25685165 TI - Association of Upregulated HMGB1 and c-IAP2 Proteins With Hepatocellular Carcinoma Development and Progression. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most important health problems in China. OBJECTIVES: This study analyzed expression of high-mobility group protein B1 (HMGB1) and inhibitor of apoptosis protein-2 (c-IAP2) proteins in HCC compared to paired para-tumor tissue samples to assess the association with HCC pathogenesis and progression. MATERIALS AND METHODS: Sixty-eight HCC and para-tumor tissue samples were collected for Western blot, qRT-PCR and immunohistochemical analyses of HMGB1 and c-IAP2. RESULTS: HMGB1 and c-IAP2 proteins were highly expressed in HCC tissue samples [85.3% (58/68) and 82.4% (56/68), respectively] compared to para-tumor tissue samples [32.3% and 27.9%, respectively]. Furthermore, expression of HMGB1 was significantly associated with enhanced c-IAP2 expression in HCC tissue samples (r = 0.878, P < 0.01). Expression of HMGB1 was associated with tumor multiplicity and size, alpha fetoprotein (AFP) level and advanced TNM stage, while expression of c-IAP2 was associated with tumor size, AFP level and advanced TNM stage. CONCLUSIONS: Expression of HMGB1 and c-IAP2 proteins was associated with HCC development and progression, and the expression of HMGB1 and c-IAP2 proteins in HCC were significantly associated with each other. Additionally, these proteins may show promise as biomarkers to predict HCC progression. PMID- 25685166 TI - Distribution of hepatitis B virus genotypes in azerbaijani patients with chronic hepatitis B infection. AB - BACKGROUND: Hepatitis B virus (HBV) has been classified into ten genotypes (A-J) based on genome sequence divergence, which is very important for etiological and clinical investigations. HBV genotypes have distinct geographical distributions worldwide. OBJECTIVES: The aim of this study was to investigate the distribution of HBV genotypes among Azerbaijani patients with chronic hepatitis B, came from the Republic of Azerbaijan country to Iran to receive medical care. PATIENTS AND METHODS: One hundred and three patients with chronic HBV infection, referred to hospitals related to Iran University of Medical Sciences and Tehran Hepatitis Center from August 2011 to July 2014, were enrolled in this cross sectional study. About 3-milliliter of peripheral blood was taken from each patient. After viral DNA extraction, HBV genotypes were tested using the INNO-LiPATM HBV kit (Innogenetics, Ghent, Belgium). HBV genotyping was confirmed using sequencing of hepatitis B surface antigen (HBsAg) and polymerase (pol) regions of HBV. RESULTS: The mean age of patients was 35.9 +/- 11.7 years (19-66). Of 103 patients, 72 (69.9%) were male. In the present study, the predominant HBV genotype was D (93.2%) followed by genotype A (5.8%) and concurrent infection with A and D genotypes (0.97%). CONCLUSIONS: The main and frequent HBV genotype among Azerbaijani patients with chronic hepatitis B virus infection was genotype D followed by genotype A. PMID- 25685167 TI - Identifying chinese herbal medicine network for eczema: implications from a nationwide prescription database. AB - Eczema is a highly prevalent dermatological disease that can severely affect the patient's quality of life. Chinese herbal medicine (CHM) is commonly used in combination for eczema due to the complicated pathogenesis. This study aimed to identify a CHM network for the treatment of eczema by using a nationwide database. During 2011, 381,282 CHM prescriptions made for eczema (ICD-9-CM 692.x) were obtained from the National Health Insurance Research Database (NHIRD) in Taiwan and analyzed by using association rule mining and social network analysis. Among 661 available CHMs, 44 important combinations were identified. Among the CHM networks, seven clusters with the predominant traditional Chinese medicine (TCM) pattern were recognized. The largest CHM cluster was used to treat the wind dampness-heat pattern, and Xiao-Feng-San (24.1% of all prescriptions) was the core of this cluster with anti-inflammation, antioxidation, and antiallergic effects. Lonicera japonica (11.0% of all prescriptions) with Forsythia suspense (17.0% of all prescriptions) was the most commonly used CHM combination and was also the core treatment for treating the heat pattern, in which an antimicrobial effect is found. CHM network analysis is helpful for TCM doctors or researchers to choose candidates for clinical practice or further studies. PMID- 25685168 TI - Cytotoxic and Antimigratory Activities of Phenolic Compounds from Dendrobium brymerianum. AB - Chromatographic separation of a methanol extract prepared from the whole plant of Dendrobium brymerianum led to the isolation of eight phenolic compounds. Among the isolated compounds (1-8), moscatilin (1), gigantol (3), lusianthridin (4), and dendroflorin (6) showed appreciable cytotoxicity against human lung cancer cell lines with IC50 values of 196.7, 23.4, 65.0, and 125.8 MUg/mL, respectively, and exhibited antimigratory property at nontoxic concentrations. This study is the first report on the biological activities of this plant. PMID- 25685169 TI - Transmitted drug resistance in recently infected HIV-positive Individuals from four urban locations across Asia (2007-2010) - TASER-S. AB - BACKGROUND: The availability of HIV antiretroviral therapy (ART) has been associated with the development of transmitted drug resistance-associated mutations (TDRM). TDRM can compromise treatment effectiveness in patients initiating ART and the prevalence can vary in different clinical settings. In this study, we investigated the proportion of TDRM in treatment-naive, recently infected HIV-positive individuals sampled from four urban locations across Asia between 2007-2010. METHODS: Patients enrolled in the TREAT Asia Studies to Evaluate Resistance - Surveillance Study (TASER-S) were genotyped prior to ART initiation, with resulting resistance mutations analysed according to the WHO 2009 list. RESULTS: Proportions of TDRM from recently infected individuals from TASER-S ranged from 0% to 8.7% - Hong Kong: 3/88 (3.4%, 95% CI (0.71%-9.64%)); Thailand: Bangkok: 13/277 (4.7%, 95% CI (2.5%-7.9%)), Chiang Mai: 0/17 (0%, 97.5% CI (0%-19.5%)); and the Philippines: 6/69 (8.7%, 95% CI (3.3%-18.0%)). There was no significant increase in TDRM over time across all four clinical settings. CONCLUSIONS: The observed proportion of TDRM in TASER-S patients from Hong Kong, Thailand and the Philippines was low to moderate during the study period. Regular monitoring of TDRM should be encouraged, especially with the scale-up of ART at higher CD4 levels. PMID- 25685170 TI - Fine-needle aspiration detects primary neuroendocrine carcinoma of the breast in a patient with breast implants. AB - Breast augmentation with implantation represents a challenge for subsequent radiographic imaging and pathological sampling. Fine-needle aspiration biopsy (FNAB) is an excellent technique to sample suspicious lesions that are adjacent to fragile implants. We report a case of a 51-year-old woman with breast implants presenting with an initial diagnosis of fibroadenoma by imaging studies. A definite diagnosis of mammary carcinoma with plasmacytoid cells was made on ultrasound (US)-guided FNAB of the breast mass with rapid on-site evaluation which initiated core needle biopsy of the mass and subsequent mastectomy with sentinel lymph node biopsy. Our case exemplifies the role of US-guided FNAB for the initial investigation of breast masses in patients with implants. In addition, the case illustrates the cytomorphological features of the tumor cells in primary neuroendocrine carcinoma of the breast. PMID- 25685171 TI - Comparative study of ProEx C immunocytochemistry and UroVysion fluorescent in situ hybridization assays on urine cytology specimens. AB - BACKGROUND: Detection of urothelial carcinoma (UC) by urine cytology can be challenging. Recently, ProEx C has been studied as a marker to improve detection of UC. ProEx C is an assay targeting expression of topoisomerase IIa and minichromosome maintenance protein-2 and is currently utilized to assist in diagnoses of the gynecological specimens. In this study, we compared the utility of ProEx C and UroVysion in urine specimens. MATERIALS AND METHODS: Twenty-seven urine specimens with UroVysion assay analysis and surgical biopsy follow-up were selected. The smears were stained with ProEx C. ProEx C and UroVysion assay results were separated into two categories based on surgical biopsy follow-up (benign or neoplastic). Surgical biopsy diagnoses were used as the gold standard for comparative evaluation of the two assays. The surgical follow-up was 9 benign, 2 low grade, and 16 high grade UCs. RESULTS: The sensitivity was 88.9% for ProEx C and 55.6% for UroVysion, while the specificity was 77.8% for ProEx C and 44.4% for UroVysion. Positive predictive value was 88.9% for ProEx C and 66.7% for UroVysion. Negative predictive value was 77.8% and 33.3% for ProEx C and UroVysion, respectively. Using the two-tailed paired t-test, P value of 0.033 was obtained when ProEx C stain was compared with the UroVysion assay. CONCLUSION: ProEx C immunocytochemistry has a more favorable performance than fluorescent in-situ hybridization with a significant difference between the two assays using paired two-tail t-test (P = 0.0033). PMID- 25685172 TI - Smoking reduction in psychiatric inpatients is feasible: results from a 12-month prospective study. AB - BACKGROUND: Despite the fact that smoking is a crucial morbidity factor among psychiatric patients, little progress has been made in order to reduce smoking during psychiatric hospitalization. METHODS: We studied the smoking behaviour of patients admitted to a non-smoking psychiatric ward, after monitoring them for smoking habits and helping them cope in order to modify their smoking behaviour. For a period of 12 months, we conducted a prospective study of simple smoking avoidance measures in the 2nd Department of Psychiatry of Attikon University Hospital in Athens. RESULTS: From 330 admitted patients, 170 (51.5%) were smokers; they were monitored for their smoking habits and encouraged by the nursing staff to reduce smoking. The mean number of cigarettes per day (CPD) at admission was 32.2 (sd 22.1) and upon discharge 14.1 (sd 14.8) (t = 11.7, p < 0.001). Most of the smokers, 142 (83.5%), managed to reduce their cigarette consumption per day. Diagnosis did not affect the reduction or increase in CPD. The only factor that predicted reduction in CPD was the female sex. CONCLUSIONS: Our findings indicate that seriously mentally ill psychiatric inpatients despite negative preconceptions and stereotypes respond well to simple measures aiming to reduce their smoking and modify their behaviour. PMID- 25685173 TI - Claude Levi-Strauss on Race, History, and Genetics. AB - In 1952, the French anthropologist Claude Levi-Strauss published a small booklet titled Race and History. It formed part of a series of pamphlets on the so-called "race-question" by leading anthropologists and geneticists, which UNESCO published as part of its campaign against racism. Roughly twenty years later, in 1971, UNESCO invited Levi-Strauss to give a lecture to open the International Year of Action to Combat Racism and Racial Discrimination. This time the lecture, titled "Race and culture," caused a scandal. In 2005, on occasion of the Organisation's 60th anniversary, Levi-Strauss was once again invited by UNESCO to give a lecture. It followed the same lines as his 1971 speech, but now met with acclaim. In my paper I will analyze Levi-Strauss' interventions with respect to their reliance on contemporary genetics. Levi-Strauss always saw a close analogy between structuralist anthropology and genetics, and derived his anti evolutionary stance from the combinatory logic that both disciplines endorsed. I will argue, that it was this combinatory logic which created room for historical contingency and agency in Levi-Strauss' understanding of the history of humankind. PMID- 25685174 TI - Extraction of heart rate variability from smartphone photoplethysmograms. AB - Heart rate variability (HRV) is a useful clinical tool for autonomic function assessment and cardiovascular diseases diagnosis. It is traditionally calculated from a dedicated medical electrocardiograph (ECG). In this paper, we demonstrate that HRV can also be extracted from photoplethysmograms (PPG) obtained by the camera of a smartphone. Sixteen HRV parameters, including time-domain, frequency domain, and nonlinear parameters, were calculated from PPG captured by a smartphone for 30 healthy subjects and were compared with those derived from ECG. The statistical results showed that 14 parameters (AVNN, SDNN, CV, RMSSD, SDSD, TP, VLF, LF, HF, LF/HF, nLF, nHF, SD1, and SD2) from PPG were highly correlated (r > 0.7, P < 0.001) with those from ECG, and 7 parameters (AVNN, TP, VLF, LF, HF, nLF, and nHF) from PPG were in good agreement with those from ECG within the acceptable limits. In addition, five different algorithms to detect the characteristic points of PPG wave were also investigated: peak point (PP), valley point (VP), maximum first derivative (M1D), maximum second derivative (M2D), and tangent intersection (TI). The results showed that M2D and TI algorithms had the best performance. These results suggest that the smartphone might be used for HRV measurement. PMID- 25685175 TI - Surgical management of moderate adolescent idiopathic scoliosis with ApiFix(r): a short peri- apical fixation followed by post-operative curve reduction with exercises. AB - Surgery in adolescent idiopathic scoliosis (AIS) is a major operative intervention where 10-12 vertebrae are instrumented and fused. A smaller motion preserving surgery would be more desirable for these otherwise healthy adolescents. The ApiFix(r) system is a novel less invasive short segment pedicle screw based instrumentation inserted around the apex of the main curve. The system has a ratchet mechanism that enables gradual postoperative device elongation and curve correction. The ratchet is activated by performing specific spinal exercises. The unique features of the device allow curve correction without fusion. The system which has a CE approval was employed in adolescents with main thoracic curves. More than a dozen of ApiFix surgeries have been performed so far. The preoperative Cobb angle was 45 degrees +/- 8, and 25 degrees +/- 8 at final follow up. The following is a report on three adolescent females aged 13-16 years with curves between 43 degrees -53 degrees and Risser sign of 1-4 who underwent surgery with ApiFix(r). Two pedicle screws were inserted around the curve apex and the ratchet based device with polyaxial ring connectors was attached to the screws. No fusion attempt was made. Operative time was around one hour. Two weeks after surgery the patients were instructed to perform Schroth like daily exercises with the aim of rod elongation and gradual curve correction. Patients were followed between 6 months to 2 years. Curves were reduced and maintained between 22- 33 degrees . Patients were pain free and were able to perform their spinal exercises. Postoperative gradual elongation of the device was observed. No screw loosening or rod breakage were observed. No adding on or curve progression was seen. Three factors may contribute to the ApiFix(r) success: polyaxial connections that prevent mechanical failure, gradual curve correction by spinal motion and spinal growth modulation. The ApiFix(r) system allows managing moderate AIS with a simple and minor surgical intervention. Recovery is rapid with negligible motion loss. It allows gradual and safe curve correction with high patient satisfaction. It may also serve as an internal brace for AIS. PMID- 25685176 TI - Estimating evolutionary distances between genomic sequences from spaced-word matches. AB - Alignment-free methods are increasingly used to calculate evolutionary distances between DNA and protein sequences as a basis of phylogeny reconstruction. Most of these methods, however, use heuristic distance functions that are not based on any explicit model of molecular evolution. Herein, we propose a simple estimator d N of the evolutionary distance between two DNA sequences that is calculated from the number N of (spaced) word matches between them. We show that this distance function is more accurate than other distance measures that are used by alignment-free methods. In addition, we calculate the variance of the normalized number N of (spaced) word matches. We show that the variance of N is smaller for spaced words than for contiguous words, and that the variance is further reduced if our spaced-words approach is used with multiple patterns of 'match positions' and 'don't care positions'. Our software is available online and as downloadable source code at: http://spaced.gobics.de/. PMID- 25685177 TI - Hospital tests and patient related factors influencing time-to-theatre in 1000 cases of suspected appendicitis: a cohort study. AB - BACKGROUND: Acute appendicitis is increasingly being managed in the setting of a dedicated emergency theatre. However understanding of hospital factors that influence time-to-theatre (TTT) is poor. Thus, the aim of this study is to identify factors that influence TTT and to observe the effect of prolonged TTT on patient outcome. METHODS: A retrospective review of an electronic prospectively maintained database was performed over a 2 year period. Factors thought to influence TTT were highlighted. A delay was defined as TTT >8 hours. Data analysis was performed using SPSS 20. RESULTS: 1,000 cases of suspected acute appendicitis were identified. Median age was 19 years. Appendicectomy was performed in 90.7%. 68.1% underwent laparoscopic appendicectomy. Overall mean TTT was 12 hours, 27 minutes. There was a significant association between delayed TTT and female gender (p = 0.017), older age (p = 0.001), pre-operative radiology (<0.001), normal WCC (p < 0.001), normal neutrophils (p < 0.001) and histological non-perforated appendix (p < 0.001). However, on multivariate analysis, younger age, a neutrophilia and presence of a perforation had a shorter TTT. Delayed TTT did not affect outcome variables including post-operative collection (3.59% v 4.38%, p = 0.528), readmission rate (6.54% v 5.72%, p = 0.403) and length of stay (3.1 days v 3.34 days, p = 0.823). CONCLUSIONS: This study highlights key hospital factors that influence TTT in patients with suspected appendicitis. Identification of these influential factors adds greatly to our understanding of patient prioritisation. Finally, TTT delays greater than 8 hour do not appear to affect short-term patient outcomes. PMID- 25685178 TI - Airborne lidar-based estimates of tropical forest structure in complex terrain: opportunities and trade-offs for REDD+ AB - BACKGROUND: Carbon stocks and fluxes in tropical forests remain large sources of uncertainty in the global carbon budget. Airborne lidar remote sensing is a powerful tool for estimating aboveground biomass, provided that lidar measurements penetrate dense forest vegetation to generate accurate estimates of surface topography and canopy heights. Tropical forest areas with complex topography present a challenge for lidar remote sensing. RESULTS: We compared digital terrain models (DTM) derived from airborne lidar data from a mountainous region of the Atlantic Forest in Brazil to 35 ground control points measured with survey grade GNSS receivers. The terrain model generated from full-density (~20 returns m-2) data was highly accurate (mean signed error of 0.19 +/- 0.97 m), while those derived from reduced-density datasets (8 m-2, 4 m-2, 2 m-2 and 1 m-2) were increasingly less accurate. Canopy heights calculated from reduced-density lidar data declined as data density decreased due to the inability to accurately model the terrain surface. For lidar return densities below 4 m-2, the bias in height estimates translated into errors of 80-125 Mg ha-1 in predicted aboveground biomass. CONCLUSIONS: Given the growing emphasis on the use of airborne lidar for forest management, carbon monitoring, and conservation efforts, the results of this study highlight the importance of careful survey planning and consistent sampling for accurate quantification of aboveground biomass stocks and dynamics. Approaches that rely primarily on canopy height to estimate aboveground biomass are sensitive to DTM errors from variability in lidar sampling density. PMID- 25685179 TI - Prevalence of human cytomegalovirus, polyomaviruses, and oncogenic viruses in glioblastoma among Japanese subjects. AB - BACKGROUND: The association between human cytomegalovirus (HCMV) and glioblastoma multiforme (GBM) is becoming a new concept. However, information on the geographic variability of HCMV prevalence in GBM remains scarce. Moreover, the potential roles of various viruses, such as polyomaviruses and oncogenic viruses, in gliomagenesis remain unclear. Our aim was to investigate the prevalence of HCMV in GBM among Japanese patients. Furthermore, this was the first study that evaluated infection with four new human polyomaviruses in GBMs. This study also provided the first data on the detection of human papillomavirus (HPV) in GBM in the Eastern world. METHODS: We measured the number of various viral genomes in GBM samples from 39 Japanese patients using real-time quantitative PCR. The tested viruses included HCMV, Merkel cell polyomavirus, human polyomavirus (HPyV) 6, HPyV7, HPyV9, Epstein-Barr virus, human herpesvirus 8, and HPV. Our quantitative PCR analysis led to the detection of eight copies of the HCMV DNA mixed with DNA extracted from 10(4) HCMV-negative cells. The presence of HCMV and HPV genomes was also assessed by nested PCR. Immunohistochemical study was also carried out to detect HPV-derived protein in GBM tissues. RESULTS: The viral DNAs were not detectable, with the exception of HPV, which was present in eight out of 39 (21%) GBMs. All HPV-positive cases harbored high-risk-type HPV (HPV16 and HPV18). Moreover, the HPV major capsid protein was detected in GBM tumor cells. CONCLUSIONS: In contrast with previous reports from Caucasian patients, we did not obtain direct evidence in support of the association between HCMV and GBM. However, high-risk-type HPV infection may play a potential etiological role in gliomagenesis in a subset of patients. These findings should prompt further worldwide epidemiological studies aimed at defining the pathogenicity of virus associated GBM. PMID- 25685180 TI - HIV and cancer: a comparative retrospective study of Brazilian and U.S. clinical cohorts. AB - BACKGROUND: With successful antiretroviral therapy, non-communicable diseases, including malignancies, are increasingly contributing to morbidity and mortality among HIV-infected persons. The epidemiology of AIDS-defining cancers (ADCs) and non-AIDS-defining cancers (NADCs) in HIV-infected populations in Brazil has not been well described. It is not known if cancer trends in HIV-infected populations in Brazil are similar to those of other countries where antiretroviral therapy is also widely available. METHODS: We performed a retrospective analysis of clinical cohorts at Instituto Nacional de Infectologia Evandro Chagas (INI) in Rio de Janeiro and Vanderbilt Comprehensive Care Clinic (VCCC) in Nashville from 1998 to 2010. We used Poisson regression and standardized incidence ratios (SIRs) to examine incidence trends. Clinical and demographic predictors of ADCs and NADCs were examined using Cox proportional hazards models. RESULTS: This study included 2,925 patients at INI and 3,927 patients at VCCC. There were 57 ADCs at INI (65% Kaposi sarcoma), 47 at VCCC (40% Kaposi sarcoma), 45 NADCs at INI, and 82 at VCCC. From 1998 to 2004, incidence of ADCs remained statistically unchanged at both sites. From 2005 to 2010, ADC incidence decreased in both cohorts (INI incidence rate ratio per year = 0.74, p < 0.01; VCCC = 0.75, p < 0.01). Overall Kaposi sarcoma incidence was greater at INI than VCCC (3.0 vs. 1.2 cases per 1,000 person-years, p < 0.01). Incidence of NADCs remained constant throughout the study period (overall INI incidence 3.6 per 1,000 person-years and VCCC incidence 5.3 per 1,000 person-years). Compared to general populations, overall risk of NADCs was increased at both sites (INI SIR = 1.4 [95% CI 1.1-1.9] and VCCC SIR = 1.3 [1.0-1.7]). After non-melanoma skin cancers, the most frequent NADCs were anal cancer at INI (n = 7) and lung cancer at VCCC (n = 11). In multivariate models, risk of ADC was associated with male sex and immunosuppression. Risk of NADC was associated with increased age. CONCLUSIONS: In both cohorts, ADCs have decreased over time, though incidence of KS was higher at INI than VCCC. Rates of NADCs remained constant over time at both sites. PMID- 25685181 TI - Interaction between GSTT1 and GSTP1 allele variants as a risk modulating-factor for autism spectrum disorders. AB - We investigated the role of glutathione S-transferase (GST) genes in Autism Spectrum Disorder (ASD). We used data from 111 pairs of age- and sex-matched ASD cases and typically developing (TD) controls between 2-8 years of age from Jamaica to investigate the role of GST pi 1 (GSTP1), GST theta 1 (GSTT1), and GST mu 1 (GSTM1) polymorphisms in susceptibility to ASD. In univariable conditional logistic regression models we did not observe significant associations between ASD status and GSTT1, GSTM1, or GSTP1 genotype (all P > 0.15). However, in multivariable conditional logistic regression models, we identified a significant interaction between GSTP1 and GSTT1 in relation to ASD. Specifically, in children heterozygous for the GSTP1 Ile105Val polymorphism, the odds of ASD was significantly higher in those with the null GSTT1 genotype than those with the other genotypes [Matched Odds Ratio (MOR) = 2.97, 95% CI (1.09, 8.01), P = 0.03]. Replication in other populations is warranted. PMID- 25685182 TI - On the mean and variance of the writhe of random polygons. AB - We here address two problems concerning the writhe of random polygons. First, we study the behavior of the mean writhe as a function length. Second, we study the variance of the writhe. Suppose that we are dealing with a set of random polygons with the same length and knot type, which could be the model of some circular DNA with the same topological property. In general, a simple way of detecting chirality of this knot type is to compute the mean writhe of the polygons; if the mean writhe is non-zero then the knot is chiral. How accurate is this method? For example, if for a specific knot type K the mean writhe decreased to zero as the length of the polygons increased, then this method would be limited in the case of long polygons. Furthermore, we conjecture that the sign of the mean writhe is a topological invariant of chiral knots. This sign appears to be the same as that of an "ideal" conformation of the knot. We provide numerical evidence to support these claims, and we propose a new nomenclature of knots based on the sign of their expected writhes. This nomenclature can be of particular interest to applied scientists. The second part of our study focuses on the variance of the writhe, a problem that has not received much attention in the past. In this case, we focused on the equilateral random polygons. We give numerical as well as analytical evidence to show that the variance of the writhe of equilateral random polygons (of length n) behaves as a linear function of the length of the equilateral random polygon. PMID- 25685183 TI - Evaluations of reproductive health programs in humanitarian settings: a systematic review. AB - Provision of reproductive health (RH) services is a minimum standard of health care in humanitarian settings; however access to these services is often limited. This systematic review, one component of a global evaluation of RH in humanitarian settings, sought to explore the evidence regarding RH services provided in humanitarian settings and to determine if programs are being evaluated. In addition, the review explored which RH services receive more attention based on program evaluations and descriptive data. Peer-reviewed papers published between 2004 and 2013 were identified via the Ovid MEDLINE database, followed by a PubMed search. Papers on quantitative evaluations of RH programs, including experimental and non-experimental designs that reported outcome data, implemented in conflict and natural disaster settings, were included. Of 5,669 papers identified in the initial search, 36 papers describing 30 programs met inclusion criteria. Twenty-five papers described programs in sub-Saharan Africa, six in Asia, two in Haiti and three reported data from multiple countries. Some RH technical areas were better represented than others: seven papers reported on maternal and newborn health (including two that also covered family planning), six on family planning, three on sexual violence, 20 on HIV and other sexually transmitted infections and two on general RH topics. In comparison to the program evaluation papers identified, three times as many papers were found that reported RH descriptive or prevalence data in humanitarian settings. While data demonstrating the magnitude of the problem are crucial and were previously lacking, the need for RH services and for evaluations to measure their effectiveness is clear. Program evaluation and implementation science should be incorporated into more programs to determine the best ways to serve the RH needs of people affected by conflict or natural disaster. Standard program design should include rigorous program evaluation, and the results must be shared. The papers demonstrated both that RH programs can be implemented in these challenging settings, and that women and men will use RH services when they are of reasonable quality. PMID- 25685184 TI - Regioselective synthesis of 2-(bromomethyl)-5-aryl-thiophene derivatives via palladium (0) catalyzed suzuki cross-coupling reactions: as antithrombotic and haemolytically active molecules. AB - BACKGROUND: It is seen that the regioselective functionalizations of halogenated heterocycles play an important role in the synthesis of several types of organic compounds. In this domain, the Suzuki-Miyaura reaction has emerged as a convenient way to build carbon-carbon bonds in synthesizing organic compounds. Some of the most important applications of these reactions can be seen in the synthesis of natural products, and in designing targeted pharmaceutical compounds. Herein, we present the regioselective synthesis of the novel series of 2-(bromomethyl)-5-aryl-thiophenes 3a-i, via Suzuki cross-coupling reactions of various aryl boronic acids with 2-bromo-5-(bromomethyl)thiophene (2). RESULTS: The synthesized compounds were screened for their haemolytic and antithrombolytic activities. The novel compounds 3f, 3i showed highest 69.7, 33.6% haemolysis of blood cells, respectively. The antithrombolytic activity of the compounds was found to be within low to moderate against human blood clot. The compound 3i showed potent clot lysis (31.5%). CONCLUSIONS: Considering these results, it is concluded that the synthesized compounds can be used as a promising source of therapeutic agents. PMID- 25685185 TI - Knowledge transfer in the field of parental mental illness: objectives, effective strategies, indicators of success, and sustainability. AB - BACKGROUND: Mental health problems are often transmitted from one generation to the next. However, transferring knowledge about interventions that reduce intergenerational transmission of disease to the field of parental mental illness has been very difficult. One of the most critical issues in mental health services research is the gap between what is generally known about effective treatment and what is provided to consumers in routine care. DISCUSSION: In this article we discuss several aspects of knowledge transfer in the field of parental mental illness. Effective strategies and implementation prerequisites are explored, and we also discuss indicators of success and sustainability. SUMMARY: Altogether, this article presents a rationale for the importance of preventive strategies for children of mentally ill parents. Furthermore, the discussion shows how complex it is to change clinical practice. PMID- 25685186 TI - Defining outcome measures of hospitalization for assessment in the Japanese forensic mental health scheme: a Delphi study. AB - BACKGROUND: A new legislation concerning forensic mental health was established by the Japanese Government in 2005, the "Act on Medical Care and Treatment for the Persons Who Had Caused Serious Cases under the Condition of Insanity," or the Medical Treatment and Supervision (MTS) Act. Since it was passed, however, there has been broad controversy over Hospitalization for Assessment (HfA), the first stage of the MTS scheme. METHODS: Following a comprehensive literature search to assemble a list of candidates, we conducted a Delphi study to establish standard outcome measures for HfA. RESULTS: Five Delphi rounds were conducted by 19 panelists including medical practitioners and lawyers. A total of 139 items were accepted as outcome measures for HfA based on panel agreement. CONCLUSION: The Delphi study established a list of HfA outcome measures for the MTS act, which will contribute to the optimization of the new forensic mental health system in Japan. PMID- 25685187 TI - Psychosocial correlates of using faith healing services in Riyadh, Saudi Arabia: a comparative cross-sectional study. AB - BACKGROUND: In this study, we compared the prevalence of psychiatric disorders and the characteristics of those who either use or do not use faith healers (FHs) services. We also assessed the independent factors of study subjects associated with using FHs. METHODS: This cross-sectional study compared those who use FHs (n = 383) with a control group of those who do not use them (i.e., shopping mall visitors, n = 424) using a survey of sociodemographic characteristics and a validated Arabic version of the Mini International Neuropsychiatric Interview (MINI 6.0). RESULTS: Participants who ranked higher among FH users included males, people who were either married, divorced, or widowed, those with less education, and those with lower income. They were more likely to report past medical and psychiatric history. Those with diagnosable psychiatric disorders were more likely to visit FHs, especially if the diagnosis was of psychotic and bipolar disorders. The prevalence of psychiatric disorders was higher among FH users, and depressive and anxiety disorders were the most prevalent. CONCLUSIONS: The study showed that having past psychiatric history and a current psychiatric disorder are risk factors for using FHs. Also, a high percentage of FH users had a diagnosable psychiatric disorder. Further research should assess how to facilitate their access to the mental health system. PMID- 25685188 TI - Research highlights for issue 2: recent applications in molecular evolution. PMID- 25685189 TI - Seed fates in crop-wild hybrid sunflower: crop allele and maternal effects. AB - Domestication has resulted in selection upon seed traits found in wild populations, yet crop-wild hybrids retain some aspects of both parental phenotypes. Seed fates of germination, dormancy, and mortality can influence the success of crop allele introgression in crop-wild hybrid zones, especially if crop alleles or crop-imparted seed coverings result in out-of-season germination. We performed a seed burial experiment using crop, wild, and diverse hybrid sunflower (Helianthus annuus) cross types to test how a cross type's maternal parent and nuclear genetic composition might affect its fate under field conditions. We observed higher maladaptive fall germination in the crop- and F1- produced seeds than wild-produced seeds and, due to an interaction with percent crop alleles, fall germination was higher for cross types with more crop-like nuclear genetics. By spring, crop-produced cross types had the highest overwintering mortality, primarily due to higher fall germination. Early spring germination was identical across maternal types, but germination continued for F1 produced seeds. In conclusion, the more wild-like the maternal parent or the less proportion of the cross type's genome contributed by the crop, the greater likelihood a seed will remain ungerminated than die. Wild-like dormancy may facilitate introgression through future recruitment from the soil seed bank. PMID- 25685190 TI - Transcriptomic responses to emamectin benzoate in Pacific and Atlantic Canada salmon lice Lepeophtheirus salmonis with differing levels of drug resistance. AB - Salmon lice Lepeophtheirus salmonis are an ecologically and economically important parasite of wild and farmed salmon. In Scotland, Norway, and Eastern Canada, L. salmonis have developed resistance to emamectin benzoate (EMB), one of the few parasiticides available for salmon lice. Drug resistance mechanisms can be complex, potentially differing among populations and involving multiple genes with additive effects (i.e., polygenic resistance). Indicators of resistance development may enable early detection and countermeasures to avoid the spread of resistance. Here, we collect sensitive Pacific L. salmonis and sensitive and resistant Atlantic L. salmonis from salmon farms, propagate in laboratory (F1), expose to EMB in bioassays, and evaluate either baseline (Atlantic only) or induced transcriptomic differences between populations. In all populations, induced responses were minor and a cellular stress response was not identified. Pacific lice did not upregulate any genes in response to EMB, but downregulated degradative enzymes and transport proteins at 50 ppb EMB. Baseline differences between sensitive and now resistant Atlantic lice were much greater than responses to exposures. All resistant lice overexpressed degradative enzymes, and resistant males, the most resistant group, overexpressed collagenases to the greatest extent. These results indicate an accumulation of baseline expression differences related to resistance. PMID- 25685191 TI - Intercontinental genetic structure and gene flow in Dunlin (Calidris alpina), a potential vector of avian influenza. AB - Waterfowl (Anseriformes) and shorebirds (Charadriiformes) are the most common wild vectors of influenza A viruses. Due to their migratory behavior, some may transmit disease over long distances. Migratory connectivity studies can link breeding and nonbreeding grounds while illustrating potential interactions among populations that may spread diseases. We investigated Dunlin (Calidris alpina), a shorebird with a subspecies (C. a. arcticola) that migrates from nonbreeding areas endemic to avian influenza in eastern Asia to breeding grounds in northern Alaska. Using microsatellites and mitochondrial DNA, we illustrate genetic structure among six subspecies: C. a. arcticola,C. a. pacifica,C. a. hudsonia,C. a. sakhalina,C. a. kistchinski, and C. a. actites. We demonstrate that mitochondrial DNA can help distinguish C. a. arcticola on the Asian nonbreeding grounds with >70% accuracy depending on their relative abundance, indicating that genetics can help determine whether C. a. arcticola occurs where they may be exposed to highly pathogenic avian influenza (HPAI) during outbreaks. Our data reveal asymmetric intercontinental gene flow, with some C. a. arcticola short stopping migration to breed with C. a. pacifica in western Alaska. Because C. a. pacifica migrates along the Pacific Coast of North America, interactions between these subspecies and other taxa provide route for transmission of HPAI into other parts of North America. PMID- 25685192 TI - Relating adaptive genetic traits to climate for Sandberg bluegrass from the intermountain western United States. AB - Genetic variation for potentially adaptive traits of the key restoration species Sandberg bluegrass (Poa secunda J. Presl) was assessed over the intermountain western United States in relation to source population climate. Common gardens were established at two intermountain west sites with progeny from two maternal parents from each of 130 wild populations. Data were collected over 2 years at each site on fifteen plant traits associated with production, phenology, and morphology. Analyses of variance revealed strong population differences for all plant traits (P < 0.0001), indicating genetic variation. Both the canonical correlation and linear correlation established associations between source populations and climate variability. Populations from warmer, more arid climates had generally lower dry weight, earlier phenology, and smaller, narrower leaves than those from cooler, moister climates. The first three canonical variates were regressed with climate variables resulting in significant models (P < 0.0001) used to map 12 seed zones. Of the 700 981 km(2) mapped, four seed zones represented 92% of the area in typically semi-arid and arid regions. The association of genetic variation with source climates in the intermountain west suggested climate driven natural selection and evolution. We recommend seed transfer zones and population movement guidelines to enhance adaptation and diversity for large-scale restoration projects. PMID- 25685193 TI - Drug-resistant HIV-1 protease regains functional dynamics through cleavage site coevolution. AB - Drug resistance is caused by mutations that change the balance of recognition favoring substrate cleavage over inhibitor binding. Here, a structural dynamics perspective of the regained wild-type functioning in mutant HIV-1 proteases with coevolution of the natural substrates is provided. The collective dynamics of mutant structures of the protease bound to p1-p6 and NC-p1 substrates are assessed using the Anisotropic Network Model (ANM). The drug-induced protease mutations perturb the mechanistically crucial hinge axes that involve key sites for substrate binding and dimerization and mainly coordinate the intrinsic dynamics. Yet with substrate coevolution, while the wild-type dynamic behavior is restored in both p1-p6 ((LP) (1'F)p1-p6D30N/N88D) and NC-p1 ((AP) (2) (V)NC p1V82A) bound proteases, the dynamic behavior of the NC-p1 bound protease variants (NC-p1V82A and (AP) (2) (V)NC-p1V82A) rather resemble those of the proteases bound to the other substrates, which is consistent with experimental studies. The orientational variations of residue fluctuations along the hinge axes in mutant structures justify the existence of coevolution in p1-p6 and NC-p1 substrates, that is, the dynamic behavior of hinge residues should contribute to the interdependent nature of substrate recognition. Overall, this study aids in the understanding of the structural dynamics basis of drug resistance and evolutionary optimization in the HIV-1 protease system. PMID- 25685194 TI - Modelling interspecific hybridization with genome exclusion to identify conservation actions: the case of native and invasive Pelophylax waterfrogs. AB - Interspecific hybridization occurs in nature but can also be caused by human actions. It often leads to infertile or fertile hybrids that exclude one parental genome during gametogenesis, escaping genetic recombination and introgression. The threat that genome-exclusion hybridization might represent on parental species is poorly understood, especially when invasive species are involved. Here, we show how to assess the effects of genome-exclusion hybridization and how to elaborate conservation actions by simulating scenarios using a model of nonintrogressive hybridization. We examine the case of the frog Pelophylax ridibundus, introduced in Western Europe, which can hybridize with the native Pelophylax lessonae and the pre-existing hybrid Pelophylax esculentus, maintained by hybridogenesis. If translocated from Southern Europe, P. ridibundus produces new sterile hybrids and we show that it mainly threatens P. esculentus. Translocation from Central Europe leads to new fertile hybrids, threatening all native waterfrogs. Local extinction is demographically mediated via wasted reproductive potential or via demographic flow through generations towards P. ridibundus. We reveal that enlarging the habitat size of the native P. lessonae relative to that of the invader is a promising conservation strategy, avoiding the difficulties of fighting the invader. We finally stress that nonintrogressive hybridization is to be considered in conservation programmes. PMID- 25685196 TI - The 'Aachen Falls Prevention Scale' - development of a tool for self-assessment of elderly patients at risk for ground level falls. AB - BACKGROUND: The incidence of falls in the elderly population is difficult to determine and therefore potentially underestimated. Screening algorithms usually have in common that the evaluation is undertaken by trained individuals in a hospital setting. This leads to the inclusion of a high proportion of low-risk people and a waste of resources. It would be advantageous to pretest the individuals at risk in their own environment using a simple self-assessment approach. METHODS: The consensus process of our group of clinicians and physical therapists included: 1. a preparative literature review about risk profiles and assessment tools for ground level falls; 2. a selection of appropriate questions that cover all health aspects involved in an increased risk for falling; and 3. a selection of a simple physical test that can be used at home without the need of a health care professional. We thus searched to develop a scale that can be used by older citizen at higher risk of falling. The current manuscript summarizes the results of this review, consensus and selection process. RESULTS: The literature search was undertaken between March and August 1, 2013. The selection process for the questions used (Part I) lasted between March 2013 and January 2014. Among all tests evaluated the 20 second standing test (Part II) was deemed to be safe to be performed even by an individual at risk for a fall, as it closely resembles activities of daily living. The 'Aachen Falls Prevention Scale' finally uses a self-assessment tool grading falls risk on a scale of 1 to 10 by the individual itself after completion of Part I and Part II. In summary, we present a scale that might offer a self-assessment option to improve the measures of falls prevention pass for elderly citizens. CONCLUSIONS: The introduction of the 'Aachen Falls Prevention Scale' which combines a simple questionnaire with a safe and quick balance tool, meets the criteria to identify whether or not a balance problem exists - the first step in evaluation of falls risk. Further studies will have to assess the ability of an individual to estimate his or her individual falls risk on a longitudinal basis and possibly trigger the necessity for the assessment by a physician. PMID- 25685197 TI - Differential co-expression network centrality and machine learning feature selection for identifying susceptibility hubs in networks with scale-free structure. AB - BACKGROUND: Biological insights into group differences, such as disease status, have been achieved through differential co-expression analysis of microarray data. Additional understanding of group differences may be achieved by integrating the connectivity structure of the differential co-expression network and per-gene differential expression between phenotypic groups. Such a global differential co-expression network strategy may increase sensitivity to detect gene-gene interactions (or expression epistasis) that may act as candidates for rewiring susceptibility co-expression networks. METHODS: We test two methods for inferring Genetic Association Interaction Networks (GAIN) incorporating both differential co-expression effects and differential expression effects: a generalized linear model (GLM) regression method with interaction effects (reGAIN) and a Fisher test method for correlation differences (dcGAIN). We rank the importance of each gene with complete interaction network centrality (CINC), which integrates each gene's differential co-expression effects in the GAIN model along with each gene's individual differential expression measure. We compare these methods with statistical learning methods Relief-F, Random Forests and Lasso. We also develop a mixture model and permutation approach for determining significant importance score thresholds for network centralities, Relief-F and Random Forest. We introduce a novel simulation strategy that generates microarray case-control data with embedded differential co-expression networks and underlying correlation structure based on scale-free or Erdos-Renyi (ER) random networks. RESULTS: Using the network simulation strategy, we find that Relief-F and reGAIN provide the best balance between detecting interactions and main effects, plus reGAIN has the ability to adjust for covariates and model quantitative traits. The dcGAIN approach performs best at finding differential co expression effects by design but worst for main effects, and it does not adjust for covariates and is limited to dichotomous outcomes. When the underlying network is scale free instead of ER, all interaction network methods have greater power to find differential co-expression effects. We apply these methods to a public microarray study of the differential immune response to influenza vaccine, and we identify effects that suggest a role in influenza vaccine immune response for genes from the PI3K family, which includes genes with known immunodeficiency function, and KLRG1, which is a known marker of senescence. PMID- 25685198 TI - Expression of follicle stimulating hormone receptors (FSHR) in thyroid tumours - a marker of malignancy? AB - BACKGROUND: In normal conditions FSHR are expressed in granulosa cells of the ovary and Sertoli cells of the testis. They can be expressed also in gonadal tumours. However, recently the expression of FSHR was found in tumoral cells and intra-tumoral blood vessels of many other tumours, including thyroid tumours. Aim of this study was to see whether the expression of FSHR can be useful in the differentiation of benign and malignant thyroid lesions. METHODS: 44 samples of surgically excised thyroids were immunostained with anti- FSHR antibody raised against 1-190 amino acid sequence from the human FSHR. RESULTS: Non-neoplastic thyroid follicles (i.e. the follicles situated outside the tumour) do not show the immunostaining for FSHR. The same concerns the majority of follicular adenomas. In contrast, 87.5% of follicular cancers, the same percentage of papillary cancers and all the examined undifferentiated cancers showed the FSHR immunopositivity of tumoral cells. A tendency towards the higher frequency of FSHR - positive blood vessels also concerns malignant thyroid tumours. CONCLUSIONS: The ectopic FSHR immunostaining seems to be useful to differentiate malignant from benign lesions, especially follicular cancers from follicular adenomas. However, the further studies on larger material are needed. PMID- 25685199 TI - Synthesis and click chemistry of a new class of biodegradable polylactide towards tunable thermo-responsive biomaterials. AB - A new class of clickable and biodegradable polylactide was designed and prepared via bulk polymerization of 3,6-dipropargyloxymethyl-1,4-dioxane-2,5-dione (1) which was synthesized from easily accessible propargyloxylactic acid (5). A homopolymer of 1 and random copolymer of 1 with l-lactide were obtained as amorphous materials and exhibit low Tg of 8.5 and 34 degrees C, respectively, indicating their promising potentials for biomedical applications. The statistical nature of random copolymers was investigated by DSC analysis and 13C NMR spectroscopy, which implies the random distribution of terminal alkyne groups along the back bone of copolymers. The efficient click post-modification of this new class of polylactide with alkyl and mPEG azides affords novel hydrophilic biomaterials, which exhibit reversible thermo-responsive properties as evidenced by their tunable LCST ranging from 22 to 69 degrees C depending on the balance of the incorporated hydrophilic/hydrophobic side chains. These results indicate the generality of this new class of clickable polylactide in preparing novel smart biomaterials in a simple and efficient manner via click chemistry. PMID- 25685200 TI - Descending colo-colonic intussusception secondary to signet ring cell carcinoma: A case report. AB - The incidence of intussusception is low in adults, particularly in the descending colon, due to the anatomical attachment of the descending colon to the retroperitoneum. Signet ring cell histology represents ~1% of colon adenocarcinomas and is associated with young patients and a poor clinical outcome. The present study describes a case of descending colo-colonic intussusception caused by signet ring cell carcinoma in a 27-year-old male. The patient presented with a history of intermittent left upper-quadrant abdominal pain for more than six months without any evident etiology. A computed tomography scan of the abdomen revealed left-sided colo-colonic intussusception. Upon laparotomy, a left hemicolectomy was performed according to intraoperative frozen section pathology. Post-operative pathological evaluation revealed signet ring cell carcinoma invasion of the serosa, and 31.8% (7/22) of the regional lymph nodes were positive for cancerous cells. The post-operative course was uneventful and the patient was discharged on the tenth post-operative day. PMID- 25685201 TI - Better Glasgow outcome score, cerebral perfusion pressure and focal brain oxygenation in severely traumatized brain following direct regional brain hypothermia therapy: A prospective randomized study. AB - BACKGROUND: Induced hypothermia for treatment of traumatic brain injury is controversial. Since many pathways involved in the pathophysiology of secondary brain injury are temperature dependent, regional brain hypothermia is thought capable to mitigate those processes. The objectives of this study are to assess the therapeutic effects and complications of regional brain cooling in severe head injury with Glasgow coma scale (GCS) 6-7. MATERIALS AND METHODS: A prospective randomized controlled pilot study involving patients with severe traumatic brain injury with GCS 6 and 7 who required decompressive craniectomy. Patients were randomized into two groups: Cooling and no cooling. For the cooling group, analysis was made by dividing the group into mild and deep cooling. Brain was cooled by irrigating the brain continuously with cold Hartmann solution for 24-48 h. Main outcome assessments were a dichotomized Glasgow outcome score (GOS) at 6 months posttrauma. RESULTS: A total of 32 patients were recruited. The cooling-treated patients did better than no cooling. There were 63.2% of patients in cooling group attained good GOS at 6 months compared to only 15.4% in noncooling group (P = 0.007). Interestingly, the analysis at 6 months post-trauma disclosed mild-cooling-treated patients did better than no cooling (70% vs. 15.4% attained good GOS, P = 0.013) and apparently, the deep-cooling-treated patients failed to be better than either no cooling (P = 0.074) or mild cooling group (P = 0.650). CONCLUSION: Data from this pilot study imply direct regional brain hypothermia appears safe, feasible and maybe beneficial in treating severely head injured patients. PMID- 25685202 TI - Early experience in endoscopic management of massive intraventricular hemorrhage with literature review. AB - Massive intraventricular hemorrhage (IVH) is nearly always associated with hydrocephalus and is often treated with prolonged external ventricular drainage (EVD); however this procedure can lead to bacterial ventriculitis and meningitis, which can worsen the clinical outcomes. Endoscopic burr hole surgery to remove the hematomas in lateral and third ventricles is an alternative treatment option. We describe the surgical techniques and benefits of endoscopic surgery for acute massive IVH in four patients and discuss the current published literature-related to this condition. Four patients were treated endoscopically for massive IVH. Three patients presented with secondary IVH due to vascular malformation, tumoral bleed and chronic hypertension, while one case presented as massive primary IVH. Endoscopic wash out and removal of hematomas was normally performed together with an endoscopic third ventriculostomy. Recombinant factor VIIa was only administered prior to surgery for IVH secondary to vascular malformation and for cases with postoperative rebleeding which required second endoscopic surgery. Weaning from ventilator and EVD commenced on day 4 postoperatively. All treated patients recovered and did not require further shunt surgery. Good outcomes obtained may be related to early removal of hematomas, creation of new cerebrospinal fluid diversion pathway after thorough wash-out, early weaning from ventilator and EVD. Endoscopic surgery is beneficial in treating poor grade IVH with Graeb score of more than 6. PMID- 25685203 TI - The impact of immunohistochemical markers of Ki-67 and p53 on the long-term outcome of growth hormone-secreting pituitary adenomas: A cohort study. AB - BACKGROUND AND OBJECTIVES: The tumoral biomarkers have a rather well known effect upon the tumor control period of several types of malignant lesions. The aim of this study was to evaluate the impact of immunohistochemical (IHC) markers of Ki 67 and p53 on the long-term outcome of growth hormone (GH)-secreting pituitary adenomas treated surgically. MATERIALS AND METHODS: We conducted and followed a cohort of 47 consecutive patients with GH-secreting pituitary adenomas referred to our department during a 4 year period for trans-sphenoidal microsurgical adenomectomy. The expression levels of Ki-67 and p53 were determined by IHC study of the tissue samples. Periodical pituitary magnetic resonance imaging (MRI), visual field studies and hormonal evaluations (GH and insulin-like growth factor 1 [IGF-1]) performed during the follow-up period were the outcome measures. RESULTS: The level of Ki-67 expression was higher among patients with postoperative residual tumor (3.5 vs. 1.7%) and those with a hormonal recurrence (4.3 vs. 1.6%). The p53 expression level was remarkably higher in patients with radiological recurrence (18 vs. 6.3%). Patients with invasive features (i.e. cavernous sinus and suprasellar invasion) had significantly higher p53 and Ki-67 values and higher IGF-1 levels during the follow-up period. The patients younger than 30 years of age and those with mixed GH-prolactin secreting adenomas had significantly higher hormonal remission and lower radiological recurrence rates. CONCLUSION: Each of the biomarkers, Ki-67 and p53, along with patient's age and mixed GH-prolactin secretion showed a kind of correlation with each of aspects of the clinical, hormonal and radiologic outcome of GH-secreting pituitary adenomas in this series. PMID- 25685204 TI - A decade after International Subarachnoid Aneurysm Trial: Coiling as a first choice treatment in the management of intracranial aneurysms - Technical feasibility and early management outcomes. AB - PURPOSE: The technique of coiling has evolved in the last decade with evolution in both equipment and material. The preferable treatment of intracranial aneurysms at our center is endovascular coiling. We discuss the technical and management outcomes of consecutive patients treated with this approach and compare our results with a decade old International Subarachnoid Aneurysm Trial. MATERIALS AND METHODS: Between January 2006 and November 2011, a total of 324 aneurysms in 304 consecutive patients were treated. Endovascular treatment was done in 308 aneurysms (95.0%) in 288 patients while 16 patients (5%) underwent surgical clipping. Of the 308 aneurysms treated endovascularly, 269 (87.3%) were ruptured, and 39 (12.7%) were unruptured aneurysms. RESULTS: The endovascular coiling was feasible in all (99.6%) but 1 case. The immediate postoperative occlusion status was complete occlusion in 240 aneurysms (77.9%), neck remnant in 57 aneurysms (18.5%), and aneurysm remnant in 11 aneurysms (3.6%). Technical issues - with or without clinical effect-were encountered in 20 patients (6.9%). They included 18 thromboembolic events (6.2%) and intraprocedural aneurysmal rupture in 2 cases (0.7%). In "good grade" patients, H and H grade 1-3, a good outcome (modified Rankin score [mRS] 0-2) was in 87.6% patients while the bad outcome (mRS 3-5) was in 10.2% patients and mortality of 2.2%. In "bad grade" patients, H and H grade 3-5, a good outcome was in 29.2%, and bad outcome was in 41.7% patients with mortality was 29.1%. In the unruptured aneurysm group, the good outcome was seen in 97.7% and bad outcome in 2.3% with no mortality. CONCLUSIONS: In the current era, the favorable results of coiling demonstrated in previous studies may be applicable to the larger proportion of patients. In our series of consecutively treated patients using latest advances, such as three dimensional imaging and the interventional material, endovascular management as first choice was feasible in 95% of patients with good technical and management outcomes. PMID- 25685205 TI - Neural oscillation, network, eloquent cortex and epileptogenic zone revealed by magnetoencephalography and awake craniotomy. AB - BACKGROUND: Magnetoencephalography (MEG) is a method of functional neuroimaging. The concomitant use of MEG and electrocorticography has been found to be useful in elucidating neural oscillation and network, and to localize epileptogenic zone and functional cortex. We describe our early experience using MEG in neurosurgical patients, emphasizing on its impact on patient management as well as the enrichment of our knowledge in neurosciences. MATERIALS AND METHODS: A total of 10 subjects were included; five patients had intraaxial tumors, one with an extraaxial tumor and brain compression, two with arteriovenous malformations, one with cerebral peduncle hemorrhage and one with sensorimotor cortical dysplasia. All patients underwent evoked and spontaneous MEG recordings. MEG data was processed at band-pass filtering frequency of between 0.1 and 300 Hz with a sampling rate of 1 kHz. MEG source localization was performed using either overdetermined equivalent current dipoles or underdetermined inversed solution. Neuromag collection of events software was used to study brain network and epileptogenic zone. The studied data were analyzed for neural oscillation in three patients; brain network and clinical manifestation in five patients; and for the location of epileptogenic zone and eloquent cortex in two patients. RESULTS: We elucidated neural oscillation in three patients. One demonstrated oscillatory phenomenon on stimulation of the motor-cortex during awake surgery, and two had improvement in neural oscillatory parameters after surgery. Brain networks corresponding to clinico-anatomical relationships were depicted in five patients, and two networks were illustrated here. Finally, we demonstrated epilepsy cases in which MEG data was found to be useful in localizing the epileptogenic zones and functional cortices. CONCLUSION: The application of MEG while enhancing our knowledge in neurosciences also has a useful role in epilepsy and awake surgery. PMID- 25685206 TI - Cervical puncture and perimedullary cistern shunt placement for idiopathic intracranial hypertension: An alternative to lumbar cistern or cerebral ventricular catheter placement a report of two cases. AB - OBJECTIVE: Idiopathic intracranial hypertension (IIH) is a syndrome characterized by increased intracranial pressure (ICP) in the absence of an identifiable cause, and if untreated, can result in permanent vision loss. In symptomatic IIH patients, cerebrospinal fluid (CSF) diversion can lower ICP and protect vision; however, currently used CSF diversion systems are prone to malfunction in this population. MATERIALS AND METHODS: In two IIH patients with histories of numerous prior shunt revisions that presented with proximal ventriculoperitoneal shunt malfunction, ICP reduction was achieved by an alternative surgical cerebrospinal fluid (CSF) diversion technique: Fluoroscopically guided, percutaneous placement of a catheter in the premedullary cistern and subsequent connection to the valve and distal shunt system. RESULTS: Postoperatively, both patients' papilledema resolved, headaches improved, and the shunts were working well at 3-month follow up. At 1-year follow-up, one patient was well without papilledema or symptom recurrence, and the second patient had the shunt system removed by an outside surgeon. CONCLUSION: This technique may hold promise as an alternative shunting strategy in IIH patients with numerous proximal shunt failures or who are poor candidates for ventricular and lumbar shunts. PMID- 25685207 TI - A giant occipital encephalocele with spontaneous hemorrhage into the sac: A rare case report. AB - In giant encephalocele, head size is smaller than the encelphalocele. Occipital encephalocele is the commonest of all encephalocele. In our case, there was rare association with giant encephalocele with old hemorrhage in the sac. This was a unique presentation. In world literature, there was rare association with giant encephalocele with hemorrhage. PMID- 25685208 TI - Remote cerebellar hemorrhage: Report of 2 cases and review of literature. AB - Remote cerebellar hemorrhage (RCH) is an extremely rare and potentially devastating complication of supratentorial and spinal surgeries. While there are numerous postulates explaining the patho-physiology behind this phenomenon, including the most popular CSF over drainage theory, the exact cause for the same is still largely unknown. In this report, we present 2 cases of remote cerebellar hemorrhage encountered following 2 different surgical procedures. One patient had preceding pterional craniotomy for ruptured anterior communicating artery aneurysm while the other one developed RCH after placement of EVD. Both of them had history of poorly controlled hypertension, contrary to most reports where hypertension has not been found to be commonly associated with it. Moreover, while most cases have been reported to occur following supratentorial craniotomies and spinal surgeries, one of our patients developed the same after placement of the EVD, which, to the best of our knowledge, has not been reported earlier. PMID- 25685209 TI - Chronic subdural hematoma associated with moyamoya disease. AB - Chronic subdural hematomas (SDHs) associated with non-operated moyamoya disease are extremely rare. A 68-year-old woman underwent burr-hole surgery for a right SDH, which resolved completely. On day 3, however, the patient suffered cerebral infarction in the right parietal lobe. Cerebral angiography demonstrated total occlusion of the bilateral internal carotid arteries with transdural anastomoses via branches of the right occipital artery and middle meningeal artery, feeding the left parietal cortex. A branch of the right middle meningeal artery passed near the burr hole, but was preserved. The patient was diagnosed of moyamoya disease. We thought that the main cause of chronic SDH might be the disruption of transdural anastomoses. Furthermore, we also hypothesized that we might have coagulated the small vessels of the transdural anastomoses which were undetectable by postoperative angiography, and that cerebral infarction might occur. PMID- 25685210 TI - Spontaneous chronic subdural hematoma associated with arachnoid cyst in children and young adults. AB - Arachnoid cysts are clear, colorless fluid-filled cysts that arise during brain and skull development from the splitting of the arachnoid membrane. Chronic subdural hematoma (CSDH) is an encapsulated collection of old blood, mostly or totally liquefied and located between the dura mater and the arachnoid mater. Trauma is an important factor in the development of CSDH. Here, we report four patients, previously asymptomatic, revealing CSDH with AC on computed tomography (CT) and magnetic resonance imaging (MRI) of the brain. All patients underwent craniotomy with evacuation of hematoma and resection of the cystic membrane that was then connected to the basal cistern under the operating microscope. Postoperatively, all patients were symptom-free. Presentation of an AC with chronic subdural hematoma in the absence of preceding head trauma is considered to be rare in children and young adults. PMID- 25685211 TI - A extremely rare case of cervical intramedullary granuloma due to Brucella accompanied by Chiari Type-1 malformation. AB - Chiari Type-1 malformation is displacement of the cerebellar tonsils through the foramen magnum into the cervical spine and usually does not exceed the level of C2. It is 50-70% associated with syringomyelia. Nervous system involvement due to brucellosis is called neurobrucellosis, and neurological involvement rate has been reported an average of 3-5%, ranging between 3% and 25% at different series. Intramedullary abscess or granuloma due to Brucella is extremely rare. Hence far, six cases have been reported in the literature and only two of these cases were reported as intramedullary granuloma. This case is presented in order to remind the importance of the cervical cord granuloma which was presented once before in the literature and to emphasize the importance of evaluation of patient history, clinical and radiological findings together in the evaluation of a patient. PMID- 25685212 TI - Management and functional outcome of intramedullary spinal cord tumors: A prospective clinical study. AB - AIM: Intramedullary spinal cord tumors (IMSCT) are rare neoplasms of central nervous system but require proper evaluation and management to ensure a good outcome. This study was carried out to evaluate the functional outcome of IMSCT following surgery and to decipher the factors affecting optimal outcome of these cases. MATERIALS AND METHODS: A prospective clinical study was carried out at a tertiary care center from 2003 to 2012. Forty three patients with intramedullary tumors diagnosed on magnetic resonance imaging were included. Their clinical details, neurological findings and demographic data were recorded. The patients were then subjected to surgery and adjuvant radiotherapy. The patients were followedup clinically and radiologically, and all parameters examined and recorded. RESULTS: Sensory and motor impairment was present preoperatively in majority of patients (n = 39 and n = 38, 90.7% and 88.4%, respectively). Gross total excision was performed in 30 cases (69.76%). The most common histological diagnosis was ependymoma (n = 21, 48.8%). Postoperatively 32 patients (74.4%) were in McCormick functional Grade I or II improving from 13 cases (30.2%) in Grade I or II preoperatively. Fifteen of 17 patients in Medical Research Council (MRC) Grade III and 10 out of 12 patients in Grade MRC IV improved. No mortality was recorded during the entire period of follow-up (mean: 22, range: 3-96 months). Eight patients (18.6%) had recurrence till the last follow-up visit. CONCLUSIONS: Preoperative neurological grade was the most important predictor of functional outcome. Gross tumor excision was the best surgical modality to improve event free survival. High-grade tumors had higher rates of recurrence but no effect on functional outcome. PMID- 25685213 TI - Role of sertraline in posttraumatic brain injury depression and quality-of-life in TBI. AB - INTRODUCTION: Traumatic brain injury (TBI) is a major cause of disability. Depression is one of the major squeal of TBI in both in-patient and out-patient populations. Depression is associated with numerous negative outcomes, thus affecting quality-of-life (QOL) adversely in these patients. Addressing depression in treatment regimen of TBI may improve QOL of these patients. OBJECTIVE: The present study is designed to evaluate the role of sertraline in post TBI depression and its impact on QOL. MATERIALS AND METHODS: Eighty male patients with post TBI depression were included in the study among the 250 male patients of mild to moderate TBI recruited for the evaluation. Half of the patients were given sertraline 50 mg PO, whereas other half served as control without sertraline treatment. Participants were assessed on Glasgow Coma scale, Patient Health Questionnaire-9 (PHQ-9) and World Health Organization QOL (WHOQOL) at regular interval till the end of 6 months. RESULT: Depression was found in 35.6% of total patients recruited. Most of the patients (63.1%) were below 35 years of age. Depression was more common in mild TBI cases than those with moderate TBI (53.7% vs. 46.25%, P = 0.04). Left side brain injury (56.25%) with cerebral contusions was more commonly associated with depression (P = 0.04). Patients in sertraline group responded well to treatment with significant improvement in mod symptoms (PHQ-9 score 14.88 +/- 3.603 vs. 5.33 +/- 2.98, P = 0.04)). All the four domains of QOL improved significantly in sertraline group than the control group with sertraline treatment. CONCLUSION: Management of TBI should also focus on treatment of associated mood symptoms, which is likely to be associated with poor QOL in these patients. Sertraline has been found to be effective in the treatment of depression with significant improvement in QOL in TBI patients. PMID- 25685214 TI - Single port microsurgical technique for excision of third ventricular colloid cysts. AB - INTRODUCTION: Colloid cysts are benign space-occupying lesions that account for 0.5-1.0% of brain tumors and arise from the velum interpositum or the choroid plexus of the third ventricle. MATERIAL AND METHODS: We are describing a modified surgical technique that combines the positive attributes of being minimalistic, while retaining the effectiveness of microsurgery. In all 20 consecutive symptomatic patients with a preoperative magnetic resonance imaging (MRI) diagnosis of colloid cyst who came to the senior author between 2008 and 2011 were included in the study. The patient was kept supine with the head positioned neutrally in the sagittal plane and neck flexed at 20 degrees . The tube of a 5 ml plastic syringe having an external diameter of 13 mm and an internal diameter of 12.6 mm was cut toward the nozzle end to the appropriate length depending upon the cortical thickness measured on the preoperative MRI. RESULTS: The average operative time was around 90 min with maximum of 120 min. None of the patients had seizures preoperatively or postoperatively and in all cases antiepileptic medication could be stopped after 3-6 month of surgery. Two patients had short term memory impairment which returned to near normal by 1-year following surgery. CONCLUSION: A volume of 5 ml plastic syringe port technique decreases the operative morbidity and operative time. The wider corridor of working makes the simultaneously maneuverability of two surgical instruments feasible enhancing safety and completeness of excision. PMID- 25685215 TI - Determining the critical size of intracranial aneurysm predisposing to subarachnoid hemorrhage in the Saudi population. AB - INTRODUCTION: Aneurysmal subarachnoid hemorrhage (SAH) is a devastating event with a high rate of morbidity and mortality. With the improvement of diagnostic modalities and the adoption of different screening strategies, more aneurysms are being diagnosed prior to rupture. Based on large multi-center trials, size has become the most important determinant of treatment decisions. Unfortunately, these studies did not take into account the regional and racial variations, challenging the generalizability of their results. MATERIAL AND METHODS: We conducted a retrospective analysis on a series of 192 patients harboring 213 aneurysms. RESULTS: The critical finding in our study is that the majority of patients presenting with SAH due to ruptured aneurysms are <10 mm in size. CONCLUSION: Decision to treatment of a given unruptured intracranial aneurysm should be individually assessed and not taken from general international literature as this may mistakenly apply factors from one population to another. PMID- 25685216 TI - Surgical outcome in patients with cervical ossified posterior longitudinal ligament: A single institutional experience. AB - OBJECTIVE: Ossification of the posterior longitudinal ligament (OPLL) is a complex multi-factorial disease process having both metabolic and biomechanical factors. The role of surgical intervention as well as the choice of approach weather anterior or posterior is ambiguous. The objective of this study was to assess the surgical out come and post operative functional improvement in patients with cervical OPLL at a tertiary care centre. PATIENTS AND METHODS: This prospective study included 63 patients of cervical OPLL who underwent either anterior and/or posterior surgeries in Department of Neurosurgery, Nizam's Institute of Medical Sciences, Hyderabad between June 2009 to May 2011. Patient's data including age, sex, pre and post operative functional status, radiographic findings and OPLL subtypes were recorded and analyzed over a follow up ranging up to minimum two years. RESULTS: The mean age of the patients was 51.1 (range 30-80 years) involving 14 women and 49 men. Out of 63 patients, 14 patients underwent surgery by anterior approach (corpectomy and fusion) and all of them improved (P = 0.52). 49 patients underwent surgery by posterior approach where decompressive laminectomy was performed in 40, laminectomy with instrumentation was done in 5, laminoplasty was done in 3 and 1 patient underwent both anterior and posterior surgeries. Of those who underwent posterior surgery, 40 patients improved, 7 remained the same as their preoperative status (who were having signal intensity changes on T2W MRI) and 2 patients deteriorated in the immediate post operative period and then showed gradual improvement. All the patients were followed up for 24 months. The mean pre-operative Nurick grade was 2.82 which later on improved to 2.03 post surgery (P < 0.05). Minor complications included wound infections in two patients (1.26%). CONCLUSIONS: Anterior cervical decompression and reconstruction is a safe and appropriate treatment for cervical spondylitic myelopathy in the setting of single or two level OPLL. Laminectomy or laminoplasty is indicated in patients with preserved cervical lordosis having three or more levels of involvement. Younger patients with good pre operative functional status and less than 2 levels of involvement have better outcome following anterior surgery. PMID- 25685217 TI - Factors prognosticating the outcome of decompressive craniectomy in severe traumatic brain injury: A Malaysian experience. AB - OBJECTIVE: The objective of this prospective cohort study was to analyse the characteristics of severe Traumatic Brain Injury (TBI) in a regional trauma centre Hospital Kuala Lumpur (HKL) along with its impact of various prognostic factors post Decompressive Craniectomy (DC). MATERIALS AND METHODS: Duration of the study was of 13 months in HKL. 110 consecutive patients undergoing DC and remained in our centre were recruited. They were then analysed categorically with standard analytical software. RESULTS: Age group have highest range between 12-30 category with male preponderance. Common mechanism of injury was motor vehicle accident involving motorcyclist. Univariate analysis showed statistically significant in referral area (P = 0.006). In clinical evaluation statistically significant was the motor score (P = 0.040), pupillary state (P = 0.010), blood pressure stability (P = 0.013) and evidence of Diabetes Insipidus (P < 0.001). In biochemical status the significant statistics included evidence of coagulopathy (P < 0.001), evidence of acidosis (P = 0.003) and evidence of hypoxia (P = 0.030). In Radiological sector, significant univariate analysis proved in location of the subdural clot (P < 0.010), location of the contusion (P = 0.045), site of existence of both type of clots (P = 0.031) and the evidence of edema (P = 0.041). The timing of injury was noted to be significant as well (P = 0.061). In the post operative care was, there were significance in the overall stability in intensive care (P < 0.001), the stability of blood pressure, cerebral perfusion pressure, pulse rates and oxygen saturation (all P < 0.001)seen individually, post operative ICP monitoring in the immediate (P = 0.002), within 24 hours (P < 0.001) and within 24-48 hours (P < 0.001) period, along with post operative pupillary size (P < 0.001) and motor score (P < 0.001). Post operatively, radiologically significant statistics included evidence of midline shift post operatively in the CT scan (P < 0.001). Multivariate logistic regression with stepwise likelihood ratio (LR) method concluded that hypoxia post operatively (P = 0.152), the unmaintained Cerebral Perfusion Pressure (CPP) (P = 0.007) and unstable blood pressure (BP) (P = <0.001). Poor outcome noted 10.2 times higher in post operative hypoxia [OR10.184; 95% CI: 0.424, 244.495]. Odds of having poor outcome if CPP unmaintained was 13.8 times higher [OR: 13.754; CI: 2.050, 92.301]. Highest predictor of poor outcome was the unstable BP, 32 times higher [OR 31.600; CI: 4.530, 220440]. CONCLUSION: Our series represent both urban and rural population, noted to be the largest series in severe TBI in this region. Severe head injury accounts for significant proportion of neurosurgical admissions, resources with its impact on socio-economic concerns to a growing population like Malaysia. This study concludes that the predictors of outcome in severe TBI post DC were postoperative hypoxia, unmaintained cerebral perfusion pressure and unstable blood pressure as independent predictors of poor outcome. Key words: Decompressive craniectomy, prognostication of decompressive craniectomy, prognostication of severe head injury, prognostication of traumatic brain injury, severe head injury, severe traumatic brain injury, traumatic brain injury. PMID- 25685218 TI - Long term preservation of motion with artificial cervical disc implants: A comparison between cervical disc replacement and rigid fusion with cage. AB - BACKGROUND: With the advancement of technologies there is more interest in the maintenance of the spine's biomechanical properties focusing on the preservation of the functional motion segment. In present article we describe our experience with 25 cases managed with artificial cervical discs with 28 Solis cage following cervical discectomy with a mean follow-up period of 7.5 year. MATERIALS AND METHODS: All surgeries were performed by single surgeon from March 2004 to June 2005 with a follow-up till date. Patients with symptomatic single or multiple level diseases that had no prior cervical surgery were candidates for the study. Cohort demographics were comparable. Standardized clinical outcome measures and radiographic examinations were used at prescribed post-operative intervals to compare the treatment groups. Relief in radicular pain, cervical spine motion, and degenerative changes at follow-up were noted. RESULTS: In a total 53 cases, the mean age in prosthesis group was 47 years (age range: 30-63 years) and mean age in cage group was 44 years (32-62 years). Mean hospital stay was 2.7 days in both the groups. At 4 weeks complete cervical movements could be achieved in 19 cases in artificial disc group. Maintenance of movement after 7.5 years was in 76% of these patients. Lordosis was maintained in all cases till date. There was no mortality or wound infection in our series. CONCLUSIONS: We conclude that artificial cervical disc could be an alternative to fixed spinal fusion as it represents the most physiological substitute of disc. However, there is need for further studies to support the use of artificial cervical disc prosthesis. PMID- 25685219 TI - Are acute subdural hematomas possible without head trauma? AB - Acute subdural hematomas (ASDHs) are rarely reported in the literature. In general, it is due to head trauma, but if the traumatic event is very mild, it is inadequate to explain the ASDH occurrence. Risk factors for the development of spontaneous ASDH include hypertension, vascular abnormalities and deficit of coagulation. We present two cases of ASDH in patients with the coagulation deficit and review of the literature to understand the coagulation factors role and platelet role in the management of ASDHs. PMID- 25685220 TI - Extramedullary foramen magnum tumors and their surgical management: An experience with 29 cases. AB - INTRODUCTION: Surgical management of foramen magnum (FM) tumors is challenging by virtue of their location and vital neurovascular relationships. The ideal approach to anterior/anterolateral tumors continue to evoke controversy even in the modern era. In this article, we present and discuss our experience in the surgical management of these tumors. MATERIALS AND METHODS: This retrospective study includes 29 consecutive patients (mean age 36.6 years, M: F = 2.63:1) of extramedullary tumors at the surgical foramen magnum, operated at our center, between 2007 and 2012. RESULTS: Their mean duration of symptoms was 14. 6 months. A majority of the patients presented with motor symptoms (quadri/paraparesis, n = 21, 72.4%), neck pain with/without suboccipital radiation (n = 16, 55.2%) and sensory symptoms like tingling/numbness (n = 16, 55.2%). There were nine extradural (31%) and 20 intradural tumors (69%). Most of the tumors were located posterolateral to the neuraxis (n = 13, 44.8%). Nerve sheath tumors (n = 11, 38%) and meningiomas (n = 5, 17.2%) were the most commonly encountered histologies in our series. The standard posterior approach was the most frequently employed surgical approach (n = 20, 69%). Operative mortality and morbidity were 3.4 and 18.9%, respectively. At a mean follow-up of 27.3 months, 13 out of the 18 available patients improved. CONCLUSION: A majority of the foramen magnum tumors are amenable to excision via the standard posterior approach. Small anterior dural-based meningiomas/recurrent tumors may require a lateral approach like the far lateral approach. PMID- 25685221 TI - Can a head get bigger than this? Report of a neglected case of hydrocephalus. PMID- 25685222 TI - Trigeminocardiac reflex may mimic symptoms of air embolism! PMID- 25685223 TI - Sino-nasal T-cell lymphoma invading the brain: A case study. AB - Lesions occupying the anterior cranial fossa may arise de novo or are extensions from the sino-nasal areas with a handful of differentials in either group. The imaging findings, though to a large extent standardized are not full proof. Primary central nervous system lymphoma and sino-nasal lymphoma are uncommon variants of extranodal non-Hodgkin's lymphoma (NHL). We encountered a 35-year-old lady presenting with headache and seizures with a mass lesion involving the ethmoids with invasion into the anterior cranial fossa diagnosed as T-cell extranodal NHL. Gross total resection and reconstruction of the skull base were done. She was treated with chemotherapy and radiotherapy and is doing well at 6 months follow-up. This is the first report of a sino-nasal T-cell lymphoma invading the brain-parenchyma in an immuno-competent person. Sino-nasal primary T cell lymphoma presenting as skull base pathology should form an essential differential diagnosis along with other routine lesions of anterior cranial fossa. Since these lesions have a good response to chemo and radiotherapy, a trans-nasal biopsy may obviate the need of a craniotomy if neurosurgeons are aware of this rare entity. PMID- 25685224 TI - Importance of C1 laminectomy in foramen magnum decompression surgery: A technical note. AB - Arnold-Chiari malformations (ACM) of the brain result from aberrations in the development of the posterior fossa resulting in its smaller volume leading to tonsillar herniation. The most common type includes Type I ACM where tonsillar descent reaches up to either C1 or C2 along with cervico-dorsal syringomyelia. The surgery (foramen magnum decompression, [FMD]) is usually straight forward and includes sub-occipital craniectomy and cervical laminectomy based on the level of descent. Rarely inadequate cervical laminectomy of C1 arch may result in residual compression at the level of obex even after "lax" duraplasty. A cervico-dural angle (angle between the neo-dura and cervical dura) at level foramen magnum can be observed in these patients. This angle is usually obtuse in imaging of cranio vertebral junction (CVJ) of normal people and in postoperative patients of Chiari malformations where normal anatomy is restored. Inadequate C1 laminectomy may result in an acute cervico-dural angle with residual compression at the level of CVJ. Therefore, C1 laminectomy becomes a key step in FMD surgery that is often underemphasized, and neurosurgeons should be careful in doing it adequately. PMID- 25685225 TI - Endoscopic endonasal transsphenoidal approach for resection of a coexistent pituitary macroadenoma and a tuberculum sellae meningioma. AB - The coexistence of a pituitary macroadenoma and a tuberculum sellae meningioma is very rare. This article demonstrates the surgical technique of the simultaneous resection of a pituitary macroadenoma and a tuberculum sellae meningioma using an endoscopic, endonasal, biportal, transsphenoidal approach. A 36-year-old woman presented with frontal headache and extended visual field loss of the right eye. She underwent cranial magnetic resonance imaging (MRI) revealing a 2 * 2 * 2.5 mm contrast-enhancing intrasellar and suprasellar lesion with compression of the optic chiasma. The coexistence of a pituitary macroadenoma and meningioma was suggested. A biportal endoscopic endonasal transsphenoidal approach was performed to remove both lesions. The histological results confirmed the coexistence of the pituitary macroadenoma and meningioma, World Health Organization (WHO) grade I. The endoscopic, endonasal, transsphenoidal approach is a safe and reliable minimal invasive surgical alternative for resection of the intra-, supra- and parasellar lesions, avoiding additional craniotomy. PMID- 25685226 TI - Diffuse neurofibroma of scalp. AB - A 22-year-old man presented with a large, soft, compressible swelling in the right occipito-parietal region. Fine needle aspiration cytology revealed blood only. The lesion was excised and histopathology studies revealed it to be a diffuse neurofibroma. PMID- 25685227 TI - Does the occurrence of pleomorphic xanthoastrocytoma in the elderly carries a poor prognosis: A case report and review of literature. AB - Pleomorphic xanthoastrocytoma (PXA) is a rare slow growing tumor which accounts for <1% of all astrocytic neoplasms. PXA usually affects young patients in their second decade of life and carries a favorable prognosis. We present the clinical, radiological and histopathological features of PXA involving the left temporal lobe in an 84-year-old male with right upper motor neuron facial paresis of 2 weeks duration. Histopathology confirmed the diagnosis of PXA. Our case is unique in that our patient is the oldest one reported in the literature with favorable histopathological features. The occurrence of these tumors in elderly patients may indicate an aggressive behavior with unfavorable outcome. Gross total resection achieves higher recurrence free and overall survival rates. PMID- 25685228 TI - Choroid plexus papilloma of posterior third ventricle: A case report and review of literature. AB - Choroid plexus papillomas (CPPs) are rare intracranial neoplasms, especially in the third ventricle. The most common site of presentation of these lesions is in the fourth ventricle in adults and lateral ventricles in children. We report a male child with a posterior third ventricular CPP who presented with the symptoms of increased intracranial pressure. Magnetic resonance imaging revealed hydrocephalus related to a mass in the posterior third ventricle, occluding the aqueduct of Sylvius. After endoscopic third ventriculostomy, tumor was approached through the infratentorial-supracerebellar approach and completely excised. Pathological examination revealed a typical CPP. This entity should be considered an extremely rare cause of a lesion in the posterior third ventricle. PMID- 25685229 TI - Juvenile Xanthogranuloma of adult spine: A rare case and review of literature. AB - Juvenile Xanthogranuloma (JXG) is a rare disorder of central nervous system. It rarely produces compressive myelopathy. On reviewing world literature, we could find only nine cases of this disease involving spine and of which only four cases were in adults' i.e., 18 years and above. We are presenting a case of Spinal JXG in an 18-year-old male with thoracic compressive myelopathy presenting as short duration progressive paraparesis. Magnetic Resonance Imaging of Spine showed mass lesion in epidural space compressing cord from behind without any bony involvement at D7 to D10 vertebral segment. It was isointense on T1 and hyperintense on T2 with no contrast enhancement. D7 to D10 Laminectomy with complete excision of firm epidural mass was carried out. The histopathology with tumor markers confirmed the diagnosis of JXG. Post-operative neurological recovery in this patient was good. His power improved to grade 5/5 with decreased spasticity. Follow-up MRI at 3 months showed no residual tumor. This case appears to be the first in the series with entirely extradural component in adult thoracic spine. PMID- 25685230 TI - Bilateral large traumatic hemorrhage of the basal ganglion. AB - Traumatic bilateral basal ganglia bleed is extremely rare. It is defined as a hemorrhagic lesion located in the basal ganglia or neighboring structures such as the internal capsule and the thalamus. This report describes a 37-year-old man who had large bilateral basal ganglia hemorrhage (BGH) with subdural hematoma and traumatic subarachnoid hemorrhage. With regards to an etiology of bilateral hemorrhage of the basal ganglia, we could not disclose any possible cause except head injury in spite of full diagnostic work-up. Our final diagnosis was bilateral traumatic BGH (TBGH). The pathomechanism of such injuries is still not clear and it is proposed to be due to shear injury to the lenticulostriate and choroidal arteries. Rather than any features of the TBGH itself, duration of coma and/or associated temporal herniation predicted slower recovery and worse outcome. Bilateral TBGH is an extremely rare entity, compatible with a favorable recovery, if not associated with damage to other cortical and subcortical structures and occurring in isolation. TBGH can be considered as a marker of poor outcome rather than its cause. The BGHs seem to be hemorrhagic contusions resulting from a shearing injury, due to high velocity impact. PMID- 25685231 TI - Penetrating Marjolin's ulcer of scalp with intracranial extension: A multidisciplinary experience. AB - Marjolin's ulcer invading the skull, dura mater, and the brain is quite exceptional. We report such a rare case of massive Marjolin's ulcer arising in the chronic scar tissue of the scalp of an elderly male. The ulcer had invaded the skull, dura mater, and underlying brain tissue. The patient was managed successfully by wide excision and scalp reconstruction. The importance of appropriate and timely wound management of scar ulcers with high malignant potential is highlighted. The role of multidisciplinary approach in the scalp reconstruction is discussed. PMID- 25685232 TI - Granulocytic sarcoma presenting as presenting as monoparesis: A rare case report. AB - Granulocytic sarcomas (GSs) or myeloid sarcoma or chloroma are rare, destructive, extramedullary tumor masses that consist of immature granulocytic cells. We present case of a 35-year-old man presenting as monoparesis, diagnosed to have cervical intradural extramedullary mass lesion with an extradural extension. Although the history or physical examination had no symptoms and signs suggestive of leukemia, bone marrow study and blood picture indicated chronic myeloid leukemia. Surgical decompression was done, and histopathological examination was consistent with GS. GSs have been observed in patients with acute myelogenous leukemia, chronic myelogenous leukemia, and other myeloproliferative disorders, but rarely have been reported as first presentation of the disease. PMID- 25685233 TI - Recurrent primary retro-bulbar hydatid cysts. AB - Retro-bulbar hydatid cysts are extremely uncommon, while nonorbital forms are frequently encountered disease in underdeveloped countries. Most of these are situated in the superolateral and superomedial angle of the orbit. We report a case of recurrent primary hydatid cysts of the orbit, situated in different locations in the orbit. A 35-year-old female patient was admitted to Department of Neurosurgery with proptosis, ptosis and watering from left eye. She also complained for headache with excruciating pain in left eye and loss of vision in left eye. Neurological examination revealed limited ocular mobility in all directions. Visual acuity was reduced to finger counting at 2-feet distance. Papilledema was found in ophthalmic examination. This case was considered as recurrence of primary infection because there was no previous history of hydatid disease and no finding of liver and lung cysts on radiological examinations. Treatment of orbital hydatid cyst, early diagnosis, surgical excision and systemic use of albendazole are suggested. PMID- 25685234 TI - Calvarial metastasis from endometrial carcinoma: Case report and review of the literature. AB - Hematogenous bone metastases from endometrial carcinoma are not frequent and their treatment is a matter of debate. We describe an extremely rare case of calvarial metastasis from endometrial carcinoma in an 80-year-old woman treated by means of one-step surgical radical resection and heterologous cranioplasty, along with a review of the literature regarding epidemiology, clinico radiological features, prognosis, and management of skull metastases. PMID- 25685235 TI - Anterior petrosal approach for brainstem cavernoma. AB - Brainstem cavernomas (BC) comprise about 5-18% of intracranial vascular malformations. The annual hemorrhage rate varies depending on the study design ranging from as low as 0.25% per patient-year in a retrospective study[2] to 1.6 3.1% per patient-year in prospective studies.[45] The annual event rate is significantly higher in deep (brainstem, diencephalon) and infratentorial cavernomas when compared to their counterparts in other locations.[5] The management of BC can be conservative or surgical depending upon the mode of clinical presentation. Surgical excision of a BC is a challenge because of critical anatomy. We present a case of BC, which was totally excised with anterior petrosal approach. Anterior petrosal approach has been used for excision of BC in only 17 cases until now.[6] The use of preoperative diffusion tensor imaging, tractography, intra-operative navigation, and cranial nerve monitoring will help in reducing the morbidity. PMID- 25685236 TI - Giant intradural intramedullary epidermoid cyst Report of two cases with varied presentations. AB - We report two cases with giant intramedullary epidermoid cysts in the thoracolumbosacral and lumbosacral regions with varied presentations. Magnetic resonance (MR) imaging of the thoraco lumbar spine in case 1revealed an intramedullary elongated mass extending from T10 to S2 level causing significant widening of the spinal canal while MR imaging of lumbosacral spine in case 2 showed straightening of the lumbar spine and spina bifida at L5 level with conus at L3 and a lobulated long segment intramedullary solid cystic lesion extending from L2 to S2 veterbrae. The lesion was surgically resected and the pathology revealed an epidermoid cyst. Epidermoid cysts of the spinal cord are rare tumours in the adult population which may be congenital or acquired. Symptoms arising from epidermoid cysts vary with the level of involvement. The treatment of epidermoid cysts is surgical and if possible, complete removal is the goal. PMID- 25685237 TI - Recurrent artery of Heubner aneurysm. AB - True Recurrent artery of Heubner (RAH) aneurysms are extremely rare and only three cases have been reported in the literature. We report a case of RAH aneurysm in a patient with World Federation of Neurosurgical Societies grade one subarachnoid hemorrhage (SAH), detected only on delayed cerebral angiography. We propose that an aneurysm in this location should be considered in the differential diagnosis of angiogram-negative SAH, and all vascular imaging studies be carefully scrutinized for RAH aneurysm. PMID- 25685238 TI - Cerebral nocardiosis. AB - Cerebral Nocardiosis is a rare, challenging, opportunistic infectious disease of the central nervous system occurring in both immunocompetent and immunocompromised hosts. It often results in intraparenchymal abscess formation, which represents only 2% of all cerebral abscesses. The diagnosis of cerebral Nocardiosis is seldom based on imaging. Bacteriological diagnosis is often reached only after surgical excision of the abscess. We report a rare case of brain abscess caused by Nocardia species in a 20-year-old immunocompromised lady. Total surgical excision of the abscess, prompt bacteriological diagnosis based on smear and culture of the pus and initiation of specific antimicrobial therapy (trimethoprim and sulfamethoxazole) resulted in good clinical outcome. PMID- 25685239 TI - L'hermitte-Duclos disease in an elderly patient: A case report and review of the literature. AB - L'hermitte-Duclos disease (LDD) is an extremely rare cerebellar lesion of uncertain etiology. Occasionally, the patients with LDD may even have sudden neurological deterioration due to acute heniation as seen in the present case report. It is also imperative to distinguish this disease from other malignant lesion of the cerebellum and cerebellar malformations with its varied natural course of history and hence better ability to prognosticate such patients. Herein, we reported a successfully treated case of LDD following a long history of vaguely defined neurological complaints in an elderly patient and reviewed the literature. PMID- 25685240 TI - Model of the Reticular Formation of the Brainstem Based on Glial-Neuronal Interactions. AB - A new model of the reticular formation of the brainstem is proposed. It refers to the neuronal and glial cell systems. Thus, it is biomimetically founded. The reticular formation generates modes of behavior (sleeping, eating, etc.) and commands all behavior according to the most appropriate environmental information. The reticular formation works on an abductive logic and is dominated by a redundancy of potential command. Formally, a special mode of behavior is represented by a comprehensive cycle (Hamilton loop) located in the glial network (syncytium) and embodied in gap junctional plaques. Whereas for the neuronal network of the reticular formation, a computer simulation has already been presented; here, the necessary devices for computation in the whole network are outlined. PMID- 25685243 TI - Identification of novel long non-coding RNAs in clear cell renal cell carcinoma. AB - BACKGROUND: Long non-coding RNAs (lncRNA) play an important role in carcinogenesis; knowledge on lncRNA expression in renal cell carcinoma is rudimental. As a basis for biomarker development, we aimed to explore the lncRNA expression profile in clear cell renal cell carcinoma (ccRCC) tissue. RESULTS: Microarray experiments were performed to determine the expression of 32,183 lncRNA transcripts belonging to 17,512 lncRNAs in 15 corresponding normal and malignant renal tissues. Validation was performed using quantitative real-time PCR in 55 ccRCC and 52 normal renal specimens. Computational analysis was performed to determine lncRNA-microRNA (MiRTarget2) and lncRNA-protein (catRAPID omics) interactions. We identified 1,308 dysregulated transcripts (expression change >2-fold; upregulated: 568, downregulated: 740) in ccRCC tissue. Among these, aberrant expression was validated using PCR: lnc-BMP2-2 (mean expression change: 37-fold), lnc-CPN2-1 (13-fold), lnc-FZD1-2 (9-fold), lnc-ITPR2-3 (15 fold), lnc-SLC30A4-1 (15-fold), and lnc-SPAM1-6 (10-fold) were highly overexpressed in ccRCC, whereas lnc-ACACA-1 (135-fold), lnc-FOXG1-2 (19-fold), lnc-LCP2-2 (2-fold), lnc-RP3-368B9 (19-fold), and lnc-TTC34-3 (314-fold) were downregulated. There was no correlation between lncRNA expression with clinical pathological parameters. Computational analyses revealed that these lncRNAs are involved in RNA-protein networks related to splicing, binding, transport, localization, and processing of RNA. Small interfering RNA (siRNA)-mediated knockdown of lnc-BMP2-2 and lnc-CPN2-1 did not influence cell proliferation. CONCLUSIONS: We identified many novel lncRNA transcripts dysregulated in ccRCC which may be useful for novel diagnostic biomarkers. PMID- 25685244 TI - Central pressure should not be used in clinical practice. AB - The heart, brain and kidneys are key targets of pulsatile damage in older people and in patients with longstanding hypertension. These central organs are exposed to central systolic and pulse pressures, which may differ from the corresponding peripheral pressures measured in the brachial artery. Studies employing the generalized transfer function as a means to estimate central pressure have demonstrated a large difference between central and peripheral systolic and pulse pressure that diminishes with age but remains substantial even in octogenarians. As a result of this persistent difference, some have advocated that central pressure may represent a more robust indicator of risk for target organ damage and major cardiovascular disease events. From the perspective of risk prediction, it is important to acknowledge that a new technique must add incremental predictive value to what is already commonly measured. Thus, in order to justify the added complexity and expense implicit in the measurement, central pressure must be shown to add significantly to a risk factor model that includes standard cardiovascular disease risk factors. A limited number of studies have shown marginally better correlations between central pressure pulsatility and continuous measures of target organ damage in the heart. A similarly limited number of prospective studies in unique cohorts have suggested that central pressure may provide marginally better risk stratification, although no reclassification analysis has been published. Thus, currently available evidence does not provide sufficient justification for widespread adoption and routine use of central pressure measurements in clinical practice. PMID- 25685245 TI - HEALS Hypertension Control Program: Training Church Members as Program Leaders. AB - INTRODUCTION: Health disparities related to cardiovascular diseases (CVDs) including stroke have remained higher in the African-Americans (AAs) than in other populations. HEALS is a faith-based hypertension (HTN) control program modified according to AA community needs, and delivered by the church-lay members called church health advisors (CHAs). This study examined the feasibility and acceptability of training CHAs as HEALS program leaders. DESIGN: Four CHAs completed a 10-hour HEALS program training workshop at the Church, conducted by the nutrition experts. Workshop was evaluated by CHAs on their level of satisfaction, clarity of contents covered and comfort in delivery the program to the church congregation. RESULTS: The overall six main HEALS curriculum components were completed. Workshop was highly evaluated by CHAs on length of training, balance between content and skills development, and level of satisfaction with program delivery. CONCLUSION: Church-based culturally modified health promotion interventions conducted by the community lay members may be a way to reduce health disparities in ethnic minorities. PMID- 25685246 TI - Pathogens in Urine from a Female Patient with Overactive Bladder Syndrome Detected by Culture-independent High Throughput Sequencing: A Case Report. AB - INTRODUCTION: Overactive bladder syndrome (OAB) is described as urgency, with or without urgency incontinence. A range of medical conditions shares the symptoms of OAB, however the diagnosis is contingent on the exclusion of urinary tract infection (UTI). Knowing that urine dipstick and routine culture of bacteria can miss UTI diagnosis caused by low-count bacteriuria or "difficult-to-culture" pathogens, we examined a case of OAB with a culture-independent approach. CASE PRESENTATION: A 61-year-old Norwegian female with a long history of urinary symptoms and a diagnosis of OAB was selected as a suitable subject for a culture independent 16S rDNA analysis on the patient's urine. The patient's medical records showed no history of recurrent UTI, however, when the urine specimen was sent to routine culture at the time of study it showed a significant bacteriuria caused by a single bacterium, and the patient was prescribed antibiotics. The 16S rDNA analysis revealed not one, but many different bacteria, including a considerable amount of fastidious bacteria, indicating a polymicrobial state. One year later, the subject was still experiencing severe symptoms, and a follow-up analysis was performed. This time the urine-culture was negative, however, the 16S rDNA profile was quite similar to that of the first sample, again displaying a complex bacterial profile. CONCLUSION: The use of 16S rDNA pyrosequencing and sequence analysis to uncover "difficult-to-culture" bacteria should be considered when examining patients with chronic urinary symptoms. These methods may contribute to further elucidation of the etiology of overactive bladder syndrome and other urinary syndromes. PMID- 25685247 TI - Live Attenuated Influenza H7N3 Vaccine is Safe, Immunogenic and Confers Protection in Animal Models. AB - BACKGROUND: In 2003 the outbreak of highly pathogenic H7 avian influenza occurred in the Netherlands. The avian H7 virus causing the outbreak was also detected in humans; one person died of pneumonia and acute respiratory distress syndrome. Our paper describes preclinical studies of a H7N3 live attenuated influenza A vaccine (LAIV) candidate in various animal models. OBJECTIVES: To study safety, immunogenicity and protection of H7N3 LAIV candidate in mice, ferrets and chickens. METHODS: The vaccine was generated by a classical reassortment between low pathogenicity A/mallard/Netherlands/00 (H7N3) virus and A/Leningrad4/17/57 (H2N2) master donor virus (MDV). RESULTS: Immunogenicity was found that H7N3 LAIV was similar to the MDV in terms of replication in the respiratory organs of mice and failed to replicate in mouse brains. One dose of a H7N3 LAIV elicited measurable antibody response and it was further boosted with a second vaccine dose. Immunization of mice with H7N3 LAIV provided protection against infection following a homologous challenge with wild type H7N3 virus. Attenuated phenotype of H7N3 LAIV has been confirmed in ferrets. Immunogenicity and protective efficacy of H7N3 LAIV in ferrets were also demonstrated. The vaccine protected animals from subsequent infection with wild type H7N3 virus. The results of histopathology study revealed that inoculation of H7N3 LAIV in ferrets did not cause any inflammation or destructive changes in lungs. Lack of H7N3 LAIV replication in chicken demonstrated complete safety of this preparation for poultry. CONCLUSION: Results of our study suggest that new H7N3 LAIV candidate is safe, immunogenic and protects from homologues influenza virus infection in mice and ferrets. PMID- 25685248 TI - Early complications following cemented modular hip hemiarthroplasty. AB - INTRODUCTION: Hemiarthroplasty is the recommended treatment for displaced, intracapsular, femoral neck fractures. This study aimed to evaluate the early complications following insertion of the JRI Furlong cemented hemiarthroplasty, a contemporary, modular, double tapered, polished prosthesis. METHOD: A series of 459 consecutive patients (May 2006 - June 2009) treated with a JRI hemiarthroplasty with a minimum of one-year (1-4years) follow-up were evaluated. Data collected retrospectively from clinical records and hospital databases included patient demographics, mortality, deep infection, dislocation, periprosthetic fracture, and any requirement for revision or complications related to the prosthesis. RESULTS: Full data were available for 429 of 459 (93%), partial data for 30 (7%). Average age was 83 years (52-100), 76% were female. One-year mortality was 24%. Intraoperative fractures occurred in 17 patients (3.7%). There were two intraoperative deaths. There were nine early deep wound infections (2%). There were two revisions to total hip replacement (THR), four patients required conversion to THR and one underwent an excision arthroplasty procedure. DISCUSSION: Early surgical outcomes for the JRI hemiarthroplasty prosthesis are equivalent or superior to other major hemiarthroplasty prostheses previously reported however, there was a high intraoperative fracture rate of 3.7%. We recommend using a stem one size smaller than the final broach in fragile, osteoporotic bone. No patients re-presented with aseptic loosening or stem failure. PMID- 25685249 TI - Age-related differences of tooth enamel morphochemistry in health and dental caries. AB - Currently, dental caries is the main reason of patient visits to dentists. A great deal of scientific work is dedicated to the study of enamel caries. The reason for this is the necessity for more detailed study of the pathogenesis of dental caries and other pathological processes occurring in tooth enamel. The application of modern high-technological methods of research has made it possible to study enamel structure in detail. Hard dental tissues are composed of organic and inorganic components and water. The organic substance consists of proteins, lipids, and carbohydrates. At different ages, caries intensity may vary. The carious process often develops during the first months after the tooth eruption but much less in adulthood and old age. These processes are mainly associated with the mechanisms of ionic exchange between the oral cavity and hard dental tissues. Different groups of teeth are differently affected by the carious process. Previous studies have revealed that age is an important factor influencing on the structure and chemical composition of hard dental tissues. Various recent works at the Department of Therapeutic Dentistry of Voronezh N.N. Burdenko State Medical Academy (VSMA) have studied not only the structural morphological features of the enamel in children and adults but also the level of metabolic processes inside it. As a result of aging, teeth change both the enamel structure and the level of its ionic processes, but unfortunately, these changes have not been well characterized in teeth with conventional age-specific differences. PMID- 25685250 TI - Population Declines of Mountain Coqui (Eleutherodactylus portoricensis) in the Cordillera Central of Puerto Rico. AB - The Mountain Coqui (Eleutherodactylus portoricensis) is a frog endemic to montane rainforests in the Cordillera Central and Luquillo Mountains of Puerto Rico. Classified as endangered by the IUCN Red List and as vulnerable by the Department of Natural and Environmental Resources of Puerto Rico, this species has undergone considerable decline in the Luquillo Mountains. To evaluate the population status of E. portoricensis across its entire range, we conducted ~87 hours of surveys at 18 historical localities and 25 additional localities that we considered suitable for this species. We generated occupancy models to estimate the probability of occurrence at surveyed sites and to identify geographic and climatic factors affecting site occupancy. We also constructed a suitability map to visualize population status in relation to the presence of land cover at elevations where the species has been documented, and determined the dates when populations were last detected at historical localities. Eleutherodactylus portoricensis was detected at 14 of 43 localities, including 10 of 18 historical localities, but it was not detected at any localities west of Aibonito (western Cordillera Central). Occupancy models estimated the probability of occurrence for localities in the western Cordillera Central as zero. Site occupancy was positively associated with montane cloud forest, and negatively associated with the western Cordillera Central, maximum temperature, and precipitation seasonality. The suitability map suggests that declines have occurred despite the presence of suitable habitat. We suggest upgrading the extinction risk of E. portoricensis and potentially developing a captive breeding program for this species. PMID- 25685251 TI - Large-Scale Chromosomal Changes and Associated Fitness Consequences in Pathogenic Fungi. AB - Pathogenic fungi encounter many different host environments to which they must adapt rapidly to ensure growth and survival. They also must be able to cope with alterations in established niches during long-term persistence in the host. Many eukaryotic pathogens have evolved a highly plastic genome, and large-scale chromosomal changes including aneuploidy, and loss of heterozygosity (LOH) can arise under various in vitro and in vivo stresses. Both aneuploidy and LOH can arise quickly during a single cell cycle, and it is hypothesized that they provide a rapid, albeit imprecise, solution to adaptation to stress until better and more refined solutions can be acquired by the organism. While LOH, with the extreme case of haploidization in Candida albicans, can purge the genome from recessive lethal alleles and/or generate recombinant progeny with increased fitness, aneuploidy, in the absence or rarity of meiosis, can serve as a non Mendelian mechanism for generating genomic variation. PMID- 25685252 TI - Predictors of Successful Telephone Contact After Emergency Department-based Recruitment into a Multicenter Smoking Cessation Cohort Study. AB - INTRODUCTION: Emergency department (ED) studies often require follow-up with subjects to assess outcomes and adverse events. Our objective was to identify baseline subject characteristics associated with successful contact at 3 time points after the index ED visit within a sample of cigarette smokers. METHODS: This study is a secondary analysis of a prospective cohort. We recruited current adult smokers at 10 U.S. EDs and collected baseline demographics, smoking profile, substance abuse, health conditions, and contact information. Site investigators attempted contact at 2 weeks, 3 months, and 6 months to assess smoking prevalence and quit attempts. Subjects were paid $20 for successful follow-up at each time point. We analyzed data using logistic and Poisson regressions. RESULTS: Of 375 recruited subjects, 270 (72%) were contacted at 2 weeks, 245 (65%) at 3 months, and 217 (58%) at 6 months. Overall, 175 (47%) were contacted at 3 of 3, 71 (19%) at 2 of 3, 62 (17%) at 1 of 3, and 66 (18%) at 0 of 3 time points. At 6 months, predictors of successful contact were: older age (adjusted odds ratio [AOR] 1.2 [95%CI, 0.99-1.5] per ?10 years); female sex (AOR 1.7 [95%CI, 1.04-2.8]); non-Hispanic black (AOR 2.3 [95%CI, 1.2-4.5]) vs Hispanic; private insurance (AOR 2.0 [95%CI, 1.03-3.8]) and Medicare (AOR 5.7 [95%CI, 1.5-22]) vs no insurance; and no recreational drug use (AOR 3.2 [95%CI; 1.6-6.3]). The characteristics independently predictive of the total number of successful contacts were: age (incidence rate ratio [IRR] 1.06 [95%CI, 1.00-1.13] per ?10 years); female sex (IRR 1.18 [95%CI, 1.01-1.40]); and no recreational drug use (IRR 1.37 [95%CI, 1.07-1.74]). Variables related to smoking cessation (e.g., cigarette packs-years, readiness to quit smoking) and amount of contact information provided were not associated with successful contact. CONCLUSION: Successful contact 2 weeks after the ED visit was 72% but decreased to 58% by 6 months, despite modest financial incentives. Older, female, and non-drug abusing participants were the most likely to be contacted. Strategies to optimize longitudinal follow-up rates, with limited sacrifice of generalizability, remain an important challenge for ED-based research. This is particularly true for studies on substance abusers and other difficult-to-reach populations. PMID- 25685253 TI - The Culture of Translational Science Research: Participants' Stories. AB - We apply a symbolic interactionist framework and a qualitative methodology to the examination of the everyday reality of translational science research (TSR). This is a growing scientific movement that aims to facilitate the efficient application of basic research to clinical service design and delivery. We describe the emerging culture of translational research at a mid-size medical center that received a Clinical and Translational Science Award from the National Institutes of Health. The stories related by scientists, clinicians, and students in interviews indicate that they make sense of the emerging inter- and cross disciplinary, team-oriented culture of TSR through the refinement and redefinition of the significant symbols that inform their work while they attempt to master translational research by addressing the dilemmas it produces for them and their work. We see the strength, currency, adaptability, and energy of the core self-definition of "scientist" to be significant in shaping the emerging culture of translational research. We conclude by celebrating the value of interpretive ethnography for evaluation research. PMID- 25685255 TI - The synergistic effects of heat shock protein 70 and ginsenoside Rg1 against tert butyl hydroperoxide damage model in vitro. AB - Neural stem cells (NSCs) transplanted is one of the hottest research to treat Alzheimer's disease (AD), but cholinergic neurons from stem cells were also susceptible to cell death which Heat shock protein 70 (HSP70) was affirmed to reverse. Related to cognitive impairment, cholinergic nervous cells should be investigated and ginsenoside Rg1 (G-Rg1) was considered to increase them. We chose tert-butyl hydroperoxide (t-BHP) damage model to study in vitro. Functional properties of our recombination plasmid pEGFP-C2-HSP70 were affirmed by SH-SY5Y cells. To opposite the transitory appearance of HSP70, NSCs used as the vectors of HSP70 gene overexpressed HSP70 for at least 7 days in vitro. After transfection for 3 days, G-Rg1 pretreatment for 4 hours, and coculture for 3 days, the expression of acetylcholinesterase (ChAT), synaptophysin, and the ratio of NeuN and GFAP were assessed by western blot; Morphological properties were detected by 3D reconstruction and immunofluorescence. ChAT was markedly improved in the groups contained G-Rg1. In coculture system, the ratio of neurons/astrocytes and the filaments of neurons were increased; apoptosis cells were decreased, compared to monotherapy (P < 0.05). In conclusion, we demonstrated that, as a safe cotreatment affirmed in vitro, overexpression of HSP70 in NSCs plus G-Rg1 promoted nervous cells regeneration from chronic oxidative damage. PMID- 25685254 TI - New antioxidant drugs for neonatal brain injury. AB - The brain injury concept covers a lot of heterogeneity in terms of aetiology involving multiple factors, genetic, hemodynamic, metabolic, nutritional, endocrinological, toxic, and infectious mechanisms, acting in antenatal or postnatal period. Increased vulnerability of the immature brain to oxidative stress is documented because of the limited capacity of antioxidant enzymes and the high free radicals (FRs) generation in rapidly growing tissue. FRs impair transmembrane enzyme Na(+)/K(+)-ATPase activity resulting in persistent membrane depolarization and excessive release of FR and excitatory aminoacid glutamate. Besides being neurotoxic, glutamate is also toxic to oligodendroglia, via FR effects. Neuronal cells die of oxidative stress. Excess of free iron and deficient iron/binding metabolising capacity are additional features favouring oxidative stress in newborn. Each step in the oxidative injury cascade has become a potential target for neuroprotective intervention. The administration of antioxidants for suspected or proven brain injury is still not accepted for clinical use due to uncertain beneficial effects when treatments are started after resuscitation of an asphyxiated newborn. The challenge for the future is the early identification of high-risk babies to target a safe and not toxic antioxidant therapy in combination with standard therapies to prevent brain injury and long-term neurodevelopmental impairment. PMID- 25685256 TI - Naphthoquinone derivative PPE8 induces endoplasmic reticulum stress in p53 null H1299 cells. AB - Endoplasmic reticulum (ER) plays a key role in synthesizing secretory proteins and sensing signal function in eukaryotic cells. Responding to calcium disturbance, oxidation state change, or pharmacological agents, ER transmembrane protein, inositol-regulating enzyme 1 (IRE1), senses the stress and triggers downstream signals. Glucose-regulated protein 78 (GRP78) dissociates from IRE1 to assist protein folding and guard against cell death. In prolonged ER stress, IRE1 recruits and activates apoptosis signal-regulating kinase 1 (ASK1) as well as downstream JNK for cell death. Naphthoquinones are widespread natural phenolic compounds. Vitamin K3, a derivative of naphthoquinone, inhibits variant tumor cell growth via oxygen uptake and oxygen stress. We synthesized a novel naphthoquinone derivative PPE8 and evaluated capacity to induce ER stress in p53 null H1299 and p53 wild-type A549 cells. In H1299 cells, PPE8 induced ER enlargement, GRP78 expression, and transient IER1 activation. Activated IRE1 recruited ASK1 for downstream JNK phosphorylation. IRE1 knockdown by siRNA attenuated PPE8-induced JNK phosphorylation and cytotoxicity. Prolonged JNK phosphorylation may be involved in PPE8-induced cytotoxicity. Such results did not arise in A549 cells, but p53 knockdown by siRNA restored PPE8-induced GRP78 expression and JNK phosphorylation. We offer a novel compound to induce ER stress and cytotoxicity in p53-deficient cancer cells, presenting an opportunity for treatment. PMID- 25685257 TI - Genome sequence and description of the mosquitocidal and heavy metal tolerant strain Lysinibacillus sphaericus CBAM5. AB - Lysinibacillus sphaericus CBAM5, was isolated from subsurface soil of oil well explorations in the Easter Planes of Colombia. This strain has potential in bioremediation of heavy-metal polluted environments and biological control of Culex quinquefasciatus. According to the phylogenetic analysis of 16S rRNA gene sequences, the strain CBAM5 was assigned to the Lysinibacillus sphaericus taxonomic group 1 that comprises mosquito pathogenic strains. After a combination assembly-integration, alignment and gap-filling steps, we propose a 4,610,292 bp chromosomal scaffold. The whole genome (consisting of 5,146,656 bp long, 60 contigs and 5,209 predicted-coding sequences) revealed strong functional and syntenial similarities to the L. sphaericus C3-41 genome. Mosquitocidal (Mtx), binary (Bin) toxins, cereolysin O, and heavy metal resistance clusters from nik, ars, czc, mnt, ter, cop, cad, and znu operons were identified. PMID- 25685258 TI - Complete genome sequence of the fish pathogen Flavobacterium psychrophilum ATCC 49418(T.). AB - Flavobacterium psychrophilum is the causative agent of bacterial cold water disease and rainbow trout fry mortality syndrome in salmonid fishes and is associated with significant losses in the aquaculture industry. The virulence factors and molecular mechanisms of pathogenesis of F. psychrophilum are poorly understood. Moreover, at the present time, there are no effective vaccines and control using antimicrobial agents is problematic due to growing antimicrobial resistance and the fact that sick fish don't eat. In the hopes of identifying vaccine and therapeutic targets, we sequenced the genome of the type strain ATCC 49418 which was isolated from the kidney of a Coho salmon (Oncorhychus kisutch) in Washington State (U.S.A.) in 1989. The genome is 2,715,909 bp with a G+C content of 32.75%. It contains 6 rRNA operons, 49 tRNA genes, and is predicted to encode 2,329 proteins. PMID- 25685259 TI - Complete genome sequence of Pseudomonas fluorescens strain PICF7, an indigenous root endophyte from olive (Olea europaea L.) and effective biocontrol agent against Verticillium dahliae. AB - Pseudomonas fluorescens strain PICF7 is a native endophyte of olive roots. Previous studies have shown this motile, Gram-negative, non-sporulating bacterium is an effective biocontrol agent against the soil-borne fungus Verticillium dahliae, the causal agent of one of the most devastating diseases for olive (Olea europaea L.) cultivation. Here, we announce and describe the complete genome sequence of Pseudomonas fluorescens strain PICF7 consisting of a circular chromosome of 6,136,735 bp that encodes 5,567 protein-coding genes and 88 RNA only encoding genes. Genome analysis revealed genes predicting factors such as secretion systems, siderophores, detoxifying compounds or volatile components. Further analysis of the genome sequence of PICF7 will help in gaining insights into biocontrol and endophytism. PMID- 25685260 TI - A Genomic Encyclopedia of the Root Nodule Bacteria: assessing genetic diversity through a systematic biogeographic survey. AB - Root nodule bacteria are free-living soil bacteria, belonging to diverse genera within the Alphaproteobacteria and Betaproteobacteria, that have the capacity to form nitrogen-fixing symbioses with legumes. The symbiosis is specific and is governed by signaling molecules produced from both host and bacteria. Sequencing of several model RNB genomes has provided valuable insights into the genetic basis of symbiosis. However, the small number of sequenced RNB genomes available does not currently reflect the phylogenetic diversity of RNB, or the variety of mechanisms that lead to symbiosis in different legume hosts. This prevents a broad understanding of symbiotic interactions and the factors that govern the biogeography of host-microbe symbioses. Here, we outline a proposal to expand the number of sequenced RNB strains, which aims to capture this phylogenetic and biogeographic diversity. Through the Vavilov centers of diversity (Proposal ID: 231) and GEBA-RNB (Proposal ID: 882) projects we will sequence 107 RNB strains, isolated from diverse legume hosts in various geographic locations around the world. The nominated strains belong to nine of the 16 currently validly described RNB genera. They include 13 type strains, as well as elite inoculant strains of high commercial importance. These projects will strongly support systematic sequence-based studies of RNB and contribute to our understanding of the effects of biogeography on the evolution of different species of RNB, as well as the mechanisms that determine the specificity and effectiveness of nodulation and symbiotic nitrogen fixation by RNB with diverse legume hosts. PMID- 25685261 TI - Draft genome sequence of Bacillus azotoformans MEV2011, a (Co-) denitrifying strain unable to grow with oxygen. AB - Bacillus azotoformans MEV2011, isolated from soil, is a microaerotolerant obligate denitrifier, which can also produce N2 by co-denitrification. Oxygen is consumed but not growth-supportive. The draft genome has a size of 4.7 Mb and contains key genes for both denitrification and dissimilatory nitrate reduction to ammonium. PMID- 25685262 TI - Complete genome sequence of Roseophage vB_DshP-R1, which infects Dinoroseobacter shibae DFL12. AB - The Roseophages, a group of marine viruses that uniquely infect the Roseobacter clade of bacteria, play a significant role in marine ecosystems. Here we present a complete genomic sequence of an N4 phage 'vB_DshP-R1', which infects Dinoroseobacter shibae DFL12, together with its structural and genomic features. vB_DshP-R1 has an ~ 75 nm diameter icosahedral structure and a complete genome of 75,028 bp. This is the first genome sequence of a lytic phage of the genus Dinoroseobacter. PMID- 25685263 TI - Reappraisal of endoscopic papillary balloon dilation for the management of common bile duct stones. AB - Although endoscopic sphincterotomy (EST) is still considered as a gold standard treatment for common bile duct (CBD) stones in western guideline, endoscopic papillary balloon dilation (EPBD) is commonly used by the endoscopists in Asia as the first-line treatment for CBD stones. Besides the advantages of a technical easy procedure, endoscopic papillary large balloon dilation (EPLBD) can facilitate the removal of large CBD stones. The indication of EPBD is now extended from removal of the small stones by using traditional balloon, to removal of large stones and avoidance of lithotripsy by using large balloon alone or after EST. According to the reports of antegrade papillary balloon dilatation, balloon dilation itself is not the cause of pancreatitis. On the contrary, adequate dilation of papillary orifice can reduce the trauma to the papilla and pancreas by the basket or lithotripter during the procedure of stone extraction. EPLBD alone is as effective as EPLBD with limited EST. Longer ballooning time may be beneficial in EPLBD alone to achieve adequate loosening of papillary orifice. The longer ballooning time does not increase the risk of pancreatitis but may reduce the bleeding episodes in patients with coagulopathy. Slowly inflation of the balloon, but not exceed the diameter of bile duct and tolerance of the patients are important to prevent the complication of perforation. EPBLD alone or with EST are not the sphincter preserved procedures, regular follow up is necessary for early detection and management of CBD stones recurrence. PMID- 25685264 TI - Current status of minimally invasive endoscopic management for Zenker diverticulum. AB - Surgical resection has been the mainstay of treatment of pharyngoesophageal (Zenker) diverticula over the past century. Developments in minimally invasive surgery and new endoscopic devices have led to a paradigm change. The concept of dividing the septum between the esophagus and the pouch rather than resecting the pouch itself has been revisited during the last three decades and new technologies have been investigated to make the transoral operation safe and effective. The internal pharyngoesophageal myotomy accomplished through the transoral stapling approach has been shown to effectively relieve outflow obstruction and restore physiological bolus transit in patients with medium size diverticula. Transoral techniques, either through a rigid device or by flexible endoscopy, are gaining popularity over the open surgical approach due the low morbidity, the fast recovery time and the fact that the procedure can be safely repeated. We provide an analysis of the the current status of minimally invasive endoscopic management of Zenker diverticulum. PMID- 25685265 TI - Colonoscopy appropriateness: Really needed or a waste of time? AB - Technical and quality improvements in colonoscopy along with the widespread implementation of population screening programs and the development of open access units have resulted in an exponential increase in colonoscopy demands, forcing endoscopy units to bear an excessive burden of work. The American Society for Gastrointestinal Endoscopy appropriateness guideline and the European panel appropriateness of gastrointestinal endoscopy guideline have appeared as potential solutions to tackle this problem and to increase detection rates of relevant lesions. Inappropriate indications based on either guideline are as high as 30%. Strategies based on these clinical criteria or other systems may be used to reduce inappropriate indications, thus decreasing waiting lists for outpatient colonoscopy, saving costs, prioritizing colonoscopy referrals and subsequently decreasing interval times from diagnosis to treatment. Despite the potential role of appropriateness guidelines, they have not been widely adopted partly due to fear of missing significant lesions detected in inappropriate indications. We review the main appropriateness and prioritising systems, their usefulness for detecting relevant lesions, as well as interventions based on those systems and cost-effectiveness. PMID- 25685266 TI - Sedation in gastrointestinal endoscopy: Where are we at in 2014? AB - Gastrointestinal endoscopies are invasive and unpleasant procedures that are increasingly being used worldwide. The importance of high quality procedures (especially in colorectal cancer screening), the increasing patient awareness and the expectation of painless examination, increase the need for procedural sedation. The best single sedation agent for endoscopy is propofol which, due to its' pharmacokinetic/dynamic profile allows for a higher patient satisfaction and procedural quality and lower induction and recovery times, while maintaining the safety of traditional sedation. Propofol is an anesthetic agent when used in higher doses than those needed for endoscopy. Because of this important feature it may lead to cardiovascular and respiratory depression and, ultimately, to cardiac arrest and death. Fueled by this argument, concern over the safety of its administration by personnel without general anesthesia training has arisen. Propofol usage seems to be increasing but it's still underused. It is a safe alternative for simple endoscopic procedures in low risk patients even if administered by non-anesthesiologists. Evidence on propofol safety in complex procedures and high risk patients is less robust and in these cases, the presence of an anesthetist should be considered. We review the existing evidence on the topic and evaluate the regional differences on sedation practices. PMID- 25685267 TI - Narrow-band imaging with magnifying endoscopy for the evaluation of gastrointestinal lesions. AB - Narrow band imaging (NBI) endoscopy is an optical image enhancing technology that allows a detailed inspection of vascular and mucosal patterns, providing the ability to predict histology during real-time endoscopy. By combining NBI with magnification endoscopy (NBI-ME), the accurate assessment of lesions in the gastrointestinal tract can be achieved, as well as the early detection of neoplasia by emphasizing neovascularization. Promising results of the method in the diagnosis of premalignant and malignant lesions of gastrointestinal tract have been reported in clinical studies. The usefulness of NBI-ME as an adjunct to endoscopic therapy in clinical practice, the potential to improve diagnostic accuracy, surveillance strategies and cost-saving strategies based on this method are summarized in this review. Various classification systems of mucosal and vascular patterns used to differentiate preneoplastic and neoplastic lesions have been reviewed. We concluded that the clinical applicability of NBI-ME has increased, but standardization of endoscopic criteria and classification systems, validation in randomized multicenter trials and training programs to improve the diagnostic performance are all needed before the widespread acceptance of the method in routine practice. However, published data regarding the usefulness of NBI endoscopy are relevant in order to recommend the method as a reliable tool in diagnostic and therapy, even for less experienced endoscopists. PMID- 25685268 TI - Circumstance of endoscopic and laparoscopic treatments for gastric cancer in Japan: A review of epidemiological studies using a national administrative database. AB - Currently, endoscopic submucosal dissection (ESD) and laparoscopic gastrectomy (LG) have become widely accepted and increasingly play important roles in the treatment of gastric cancer. Data from an administrative database associated with the diagnosis procedure combination (DPC) system have revealed some circumstances of ESD and LG in Japan. Some studies demonstrated that medical costs or length of stay of patients receiving ESD for gastric cancer had become significantly reduced while length of hospitalization and costs were significantly increased in older patients. With respect to LG, some recent reports have shown that this has been a cost-beneficial treatment for patients compared with open gastrectomy while simultaneous LG and cholecystectomy is a safe procedure for patients with both gastric cancer and gallbladder stones. These epidemiological studies using the administrative database in the DPC system closely reflect clinical circumstances of endoscopic and surgical treatment for gastric cancer in Japan. However, DPC database does not contain detailed clinical data such as histological types and lesion size of gastric cancer. The link between the DPC database and another detailed clinical database may be vital for future research into endoscopic and laparoscopic treatments for gastric cancer. PMID- 25685269 TI - Endoscopic retrograde cholangiopancreatography for suspected choledocholithiasis: From guidelines to clinical practice. AB - AIM: To study the practical applicability of the American Society for Gastrointestinal Endoscopy guidelines in suspected cases of choledocholithiasis. METHODS: This was a retrospective single center study, covering a 4-year period, from January 2010 to December 2013. All patients who underwent endoscopic retrograde cholangiopancreatography (ERCP) for suspected choledocholithiasis were included. Based on the presence or absence of predictors of choledocholithiasis (clinical ascending cholangitis, common bile duct (CBD) stones on ultrasonography (US), total bilirubin > 4 mg/dL, dilated CBD on US, total bilirubin 1.8-4 mg/dL, abnormal liver function test, age > 55 years and gallstone pancreatitis), patients were stratified in low, intermediate or high risk for choledocholithiasis. For each predictor and risk group we used the chi(2) to evaluate the statistical associations with the presence of choledocolithiasis at ERCP. Statistical analysis was performed using SPSS version 21.0. A P value of less than 0.05 was considered statistically significant. RESULTS: A total of 268 ERCPs were performed for suspected choledocholithiasis. Except for gallstone pancreatitis (P = 0.063), all other predictors of choledocholitiasis (clinical ascending cholangitis, P = 0.001; CBD stones on US, P <= 0.001; total bilirubin > 4 mg/dL, P = 0.035; total bilirubin 1.8-4 mg/dL, P = 0.001; dilated CBD on US, P <= 0.001; abnormal liver function test, P = 0.012; age > 55 years, P = 0.002) showed a statistically significant association with the presence of choledocholithiasis at ERCP. Approximately four fifths of patients in the high risk group (79.8%, 154/193 patients) had confirmed choledocholithiasis on ERCP, vs 34.2% (25/73 patients) and 0 (0/2 patients) in the intermediate and low risk groups, respectively. The definition of "high risk group" had a sensitivity of 86%, positive predictive value 79.8% and specificity 56.2% for the presence of choledocholithiasis at ERCP. CONCLUSION: The guidelines should be considered to optimize patients' selection for ERCP. For high risk patients specificity is still low, meaning that some patients perform ERCP unnecessarily. PMID- 25685270 TI - Clinical outcomes of self-expandable stent placement for benign esophageal diseases: A pooled analysis of the literature. AB - AIM: To analyze the outcomes of self-expandable stent placement for benign esophageal strictures and benign esophageal leaks in the literature. METHODS: The PubMed, Embase and Cochrane databases were searched for relevant articles published between January 2000 and July 2014. Eight prospective studies were identified that analyzed the outcomes of stent placement for refractory benign esophageal strictures. The outcomes of stent placement for benign esophageal leaks, perforations and fistulae were extracted from 20 retrospective studies that were published after the inclusion period of a recent systematic review. Data were pooled and analyzed using descriptive statistics. RESULTS: Fully covered self-expandable metal stents (FC SEMS) (n = 85), biodegradable (BD) stents (n = 77) and self-expandable plastic stents (SEPS) (n = 70) were inserted in 232 patients with refractory benign esophageal strictures. The overall clinical success rate was 24.2% and according to stent type 14.1% for FC SEMS, 32.9% for BD stents and 27.1% for SEPS. Stent migration occurred in 24.6% of cases. The overall complication rate was 31.0%, including major (17.7%) and minor (13.4%) complications. A total of 643 patients were treated with self-expandable stents mainly for postsurgical leaks (64.5%), iatrogenic perforations (19.6%), Boerhaave's syndrome (7.8%) and fistulae (3.7%). FC SEMS and partially covered SEMS were used in the majority of patients. Successful closure of the defect was achieved in 76.8% of patients and according to etiology in 81.4% for postsurgical leaks, 86.0% for perforations and 64.7% for fistulae. The pooled stent migration rate was 16.5%. Stent-related complications occurred in 13.4% of patients, including major (7.8%) and minor (5.5%) complications. CONCLUSION: The outcomes of stent placement for refractory benign esophageal strictures were poor. However, randomized trials are needed to put this into perspective. The evidence on successful stent placement for benign esophageal leaks, perforations and fistulae is promising. PMID- 25685271 TI - Rare case of dysphagia, skin blistering, missing nails in a young boy. AB - Epidermolysis bullosa is a group of genetic disorders with an autosomal dominant or an autosomal recessive mode of inheritance and more than 300 mutations. The disorder is characterized by blistering mucocutaneous lesions and has several varying phenotypes due to anchoring defect between the epidermis and dermis. The variation in phenotypic expression depends on the involved structural protein that mediates cell adherence between different layers of the skin. Epidermolysis bullosa can also involve extra-cutaneous sites including eye, nose, ear, upper airway, genitourinary tract and gastrointestinal tract. The most prominent feature of the gastrointestinal tract involvement is development of esophageal stricture. The stricture results from recurrent esophageal mucosal blistering with consequent scarring and most commonly involves the upper esophagus. Here we present a case of a young boy with dominant subtype of dystrophic epidermolysis bullosa who presented with dysphagia, extensive skin blistering and missing nails. Management of an esophageal stricture eventually requires dilatation of the stricture or placement of a gastrostomy tube to keep up with the nutritional requirements. Gastrostomy tube also provides access for esophageal stricture dilatation in cases where antegrade approach through the mouth has failed. PMID- 25685272 TI - Radiofrequency ablation of pancreatic ductal adenocarcinoma: The past, the present and the future. AB - Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers with a grim overall 5-year survival rate of 5%. Advances in surgical techniques, critical care, molecular diagnosis, diagnostic imaging, endosonology and adjuvant therapy have improved outcomes; but still more needs to be achieved. There is an urgent need to discover new avenues that may impact survival. Radiofrequency ablation (RFA) has attracted attention as an adjunctive treatment in PDAC. A review of English literature in PubMed was done using the MESH terms for PDAC and RFA. All the articles were reviewed and core information was tabulated for reference. After a comprehensive review of all articles the data was evaluated to discover the role of RFA in PDAC management. Indications, contraindications, feasibility, success rate, safety, complications and impact on survival were reviewed and are discussed further. RFA appears to be an attractive option for non-metastatic locally advanced PDAC. RFA is feasible but has a significant morbidity. At the present time the integration of RFA into the management of pancreatic ductal adenocarcinoma is evolving. It should be considered as having a complimentary role to current standard therapy in the multimodal management care model. It is likely that indications and patient selection for pancreatic RFA will expand. PMID- 25685273 TI - One center in Brussels has consistently had the lowest HbA1c values in the 4 studies (1994-2009) by the Hvidoere International Study Group on Childhood Diabetes: What are the "recipes"? AB - The principal aims of therapeutic management of the child, adolescent and adult with type 1 diabetes are to allow good quality of life and to avoid long-term complications (retinopathy, neuropathy, nephropathy, cardiovascular disease, etc.) by maintaining blood glucose concentrations close to normal level. Glycated hemoglobin levels (HbA1c) provide a good criterion of overall glycemic control. The Hvidoere Study Group (HSG) on Childhood Diabetes, founded in 1994, is an international group representing about twenty highly experienced pediatric centers from Europe, North America, Japan and Australia. Four international comparisons of metabolic control (1995, 1998, 2005, 2009) have been performed. The one center that has consistently had the lowest HbA1c values (approximate 7.3% or 56.3 mmol/mol) is my center in Brussels. This is more often obtained with a twice-daily free-mixed regimen with additional supplemental fast insulins ad hoc. The so-called "Dorchy's recipes" are summarized. The conclusion is that the number of daily insulin injections, 2 or >= 4, or the use of pumps, by itself does not necessarily give better results. Intensified therapy should not depend upon the number of insulin doses per day, by syringe, pen or pump but rather should be redefined as to intent-to-treat ascertainment (i.e., goals). When there are no mutually agreed upon goals for BG and/or HbA1c, when there is insufficient education and psychosocial support by the medical team or at home, there is likely to be poor outcomes, as shown by the HSG. One of our recipes is not to systematically replace rapid-acting human insulins by fast-acting analogues. Because the multicenter studies of the HSG, performed in developed countries without financial restriction, show that treatment of childhood diabetes is inadequate in general and that levels of HbA1c are very different, diabetes treatment teams should individually explore the reasons for failure, without any prejudice or bias. Any dogmatism must be avoided. Treatment cost vs results must also be taken into account. PMID- 25685274 TI - Insulin sensitivity and complications in type 1 diabetes: New insights. AB - Despite improvements in glucose, lipids and blood pressure control, vascular complications remain the most important cause of morbidity and mortality in patients with type 1 diabetes. For that reason, there is a need to identify additional risk factors to utilize in clinical practice or translate to novel therapies to prevent vascular complications. Reduced insulin sensitivity is an increasingly recognized component of type 1 diabetes that has been linked with the development and progression of both micro- and macrovascular complications. Adolescents and adults with type 1 diabetes have reduced insulin sensitivity, even when compared to their non-diabetic counterparts of similar adiposity, serum triglycerides, high-density lipoprotein cholesterol, level of habitual physical activity, and in adolescents, pubertal stage. Reduced insulin sensitivity is thought to contribute both to the initiation and progression of macro- and microvascular complications in type 1 diabetes. There are currently clinical trials underway examining the benefits of improving insulin sensitivity with regards to vascular complications in type 1 diabetes. Reduced insulin sensitivity is an increasingly recognized component of type 1 diabetes, is implicated in the pathogenesis of vascular complications and is potentially an important therapeutic target to prevent vascular complications. In this review, we will focus on the pathophysiologic contribution of insulin sensitivity to vascular complications and summarize related ongoing clinical trials. PMID- 25685275 TI - Utility of different glycemic control metrics for optimizing management of diabetes. AB - The benchmark for assessing quality of long-term glycemic control and adjustment of therapy is currently glycated hemoglobin (HbA1c). Despite its importance as an indicator for the development of diabetic complications, recent studies have revealed that this metric has some limitations; it conveys a rather complex message, which has to be taken into consideration for diabetes screening and treatment. On the basis of recent clinical trials, the relationship between HbA1c and cardiovascular outcomes in long-standing diabetes has been called into question. It becomes obvious that other surrogate and biomarkers are needed to better predict cardiovascular diabetes complications and assess efficiency of therapy. Glycated albumin, fructosamin, and 1,5-anhydroglucitol have received growing interest as alternative markers of glycemic control. In addition to measures of hyperglycemia, advanced glucose monitoring methods became available. An indispensible adjunct to HbA1c in routine diabetes care is self-monitoring of blood glucose. This monitoring method is now widely used, as it provides immediate feedback to patients on short-term changes, involving fasting, preprandial, and postprandial glucose levels. Beyond the traditional metrics, glycemic variability has been identified as a predictor of hypoglycemia, and it might also be implicated in the pathogenesis of vascular diabetes complications. Assessment of glycemic variability is thus important, but exact quantification requires frequently sampled glucose measurements. In order to optimize diabetes treatment, there is a need for both key metrics of glycemic control on a day-to day basis and for more advanced, user-friendly monitoring methods. In addition to traditional discontinuous glucose testing, continuous glucose sensing has become a useful tool to reveal insufficient glycemic management. This new technology is particularly effective in patients with complicated diabetes and provides the opportunity to characterize glucose dynamics. Several continuous glucose monitoring (CGM) systems, which have shown usefulness in clinical practice, are presently on the market. They can broadly be divided into systems providing retrospective or real-time information on glucose patterns. The widespread clinical application of CGM is still hampered by the lack of generally accepted measures for assessment of glucose profiles and standardized reporting of glucose data. In this article, we will discuss advantages and limitations of various metrics for glycemic control as well as possibilities for evaluation of glucose data with the special focus on glycemic variability and application of CGM to improve individual diabetes management. PMID- 25685276 TI - Causative anti-diabetic drugs and the underlying clinical factors for hypoglycemia in patients with diabetes. AB - Recent clinical trials indicated that the intensive glycemic control do not reduce cardiovascular disease mortality among diabetic patients, challenging a significance of the strict glycemic control in diabetes management. Furthermore, retrospective analysis of the Action to Control Cardiovascular Risk in Diabetes study demonstrated a significant association between hypoglycemia and mortality. Here, we systematically reviewed the drug-induced hypoglycemia, and also the underlying clinical factors for hypoglycemia in patients with diabetes. The sulfonylurea use is significantly associated with severe hypoglycemia in patients with type 2 diabetes. The use of biguanide (approximately 45%-76%) and thiazolidinediones (approximately 15%-34%) are also highly associated with the development of severe hypoglycemia. In patients treated with insulin, the intensified insulin therapy is more frequently associated with severe hypoglycemia than the conventional insulin therapy and continuous subcutaneous insulin infusion. Among the underlying clinical factors for development of severe hypoglycemia, low socioeconomic status, aging, longer duration of diabetes, high HbA1c and low body mass index, comorbidities are precipitating factors for severe hypoglycemia. Poor cognitive and mental functions are also associated with severe hypoglycemia. PMID- 25685277 TI - Literature review on the management of diabetic foot ulcer. AB - Diabetic foot ulcer (DFU) is the most costly and devastating complication of diabetes mellitus, which affect 15% of diabetic patients during their lifetime. Based on National Institute for Health and Clinical Excellence strategies, early effective management of DFU can reduce the severity of complications such as preventable amputations and possible mortality, and also can improve overall quality of life. The management of DFU should be optimized by using a multidisciplinary team, due to a holistic approach to wound management is required. Based on studies, blood sugar control, wound debridement, advanced dressings and offloading modalities should always be a part of DFU management. Furthermore, surgery to heal chronic ulcer and prevent recurrence should be considered as an essential component of management in some cases. Also, hyperbaric oxygen therapy, electrical stimulation, negative pressure wound therapy, bio-engineered skin and growth factors could be used as adjunct therapies for rapid healing of DFU. So, it's suggested that with appropriate patient education encourages them to regular foot care in order to prevent DFU and its complications. PMID- 25685278 TI - Pathogenesis of diabetic cerebral vascular disease complication. AB - Diabetes mellitus is one of the most potent independent risk factors for the development of diabetic cerebral vascular disease (CVD). Many evidences suggested that hyperglycemia caused excess free fatty acids, the loss of endothelium derived nitric oxide, insulin resistance, the prothrombotic state, endothelial dysfunction, the abnormal release of endothelial vasoactivators, vascular smooth muscle dysfunction, oxidative stress, and the downregulation of miRs participated in vessel generation and recovery as well as the balance of endotheliocytes. In turn, these abnormalities, mainly via phosphatidylinositol 3 kinase, mitogen activated protein kinase, polyol, hexosamine, protein kinase C activation, and increased generation of advanced glycosylation end products pathway, play an important role in inducing diabetic CVD complication. A deeper comprehension of pathogenesis producing diabetic CVD could offer base for developing new therapeutic ways preventing diabetic CVD complications, therefore, in the paper we mainly reviewed present information about the possible pathogenesis of diabetic CVD complication. PMID- 25685279 TI - Type 1 diabetes and polyglandular autoimmune syndrome: A review. AB - Type 1 diabetes (T1D) is an autoimmune disorder caused by inflammatory destruction of the pancreatic tissue. The etiopathogenesis and characteristics of the pathologic process of pancreatic destruction are well described. In addition, the putative susceptibility genes for T1D as a monoglandular disease and the relation to polyglandular autoimmune syndrome (PAS) have also been well explored. The incidence of T1D has steadily increased in most parts of the world, especially in industrialized nations. T1D is frequently associated with autoimmune endocrine and non-endocrine diseases and patients with T1D are at a higher risk for developing several glandular autoimmune diseases. Familial clustering is observed, which suggests that there is a genetic predisposition. Various hypotheses pertaining to viral- and bacterial-induced pancreatic autoimmunity have been proposed, however a definitive delineation of the autoimmune pathomechanism is still lacking. In patients with PAS, pancreatic and endocrine autoantigens either colocalize on one antigen-presenting cell or are expressed on two/various target cells sharing a common amino acid, which facilitates binding to and activation of T cells. The most prevalent PAS phenotype is the adult type 3 variant or PAS type III, which encompasses T1D and autoimmune thyroid disease. This review discusses the findings of recent studies showing noticeable differences in the genetic background and clinical phenotype of T1D either as an isolated autoimmune endocrinopathy or within the scope of polyglandular autoimmune syndrome. PMID- 25685280 TI - Diabetes and cardiac autonomic neuropathy: Clinical manifestations, cardiovascular consequences, diagnosis and treatment. AB - Cardiac autonomic neuropathy (CAN) is a frequent chronic complication of diabetes mellitus with potentially life-threatening outcomes. CAN is caused by the impairment of the autonomic nerve fibers regulating heart rate, cardiac output, myocardial contractility, cardiac electrophysiology and blood vessel constriction and dilatation. It causes a wide range of cardiac disorders, including resting tachycardia, arrhythmias, intraoperative cardiovascular instability, asymptomatic myocardial ischemia and infarction and increased rate of mortality after myocardial infarction. Etiological factors associated with autonomic neuropathy include insufficient glycemic control, a longer period since the onset of diabetes, increased age, female sex and greater body mass index. The most commonly used methods for the diagnosis of CAN are based upon the assessment of heart rate variability (the physiological variation in the time interval between heartbeats), as it is one of the first findings in both clinically asymptomatic and symptomatic patients. Clinical symptoms associated with CAN generally occur late in the disease process and include early fatigue and exhaustion during exercise, orthostatic hypotension, dizziness, presyncope and syncope. Treatment is based on early diagnosis, life style changes, optimization of glycemic control and management of cardiovascular risk factors. Medical therapies, including aldose reductase inhibitors, angiotensin-converting enzyme inhibitors, prostoglandin analogs and alpha-lipoic acid, have been found to be effective in randomized controlled trials. The following article includes the epidemiology, clinical findings and cardiovascular consequences, diagnosis, and approaches to prevention and treatment of CAN. PMID- 25685283 TI - Roles of interstitial fluid pH in diabetes mellitus: Glycolysis and mitochondrial function. AB - The pH of body fluids is one the most important key factors regulating various cell function such as enzyme activity and protein-protein interaction via modification of its binding affinity. Therefore, to keep cell function normal, the pH of body fluids is maintained constant by various systems. Insulin resistance is one of the most important, serious factors making the body condition worse in diabetes mellitus. I have recently found that the pH of body (interstitial) fluids is lower in diabetes mellitus than that in non-diabetic control, and that the lowered pH is one of the causes producing insulin resistance. In this review article, I introduce importance of body (interstitial) fluid pH in regulation of body function, evidence on abnormal regulation of body fluid pH in diabetes mellitus, and relationship between the body fluid pH and insulin resistance. Further, this review proposes perspective therapies on the basis of regulation of body fluid pH including propolis (honeybee product) diet. PMID- 25685282 TI - beta-cell dysfunction: Its critical role in prevention and management of type 2 diabetes. AB - Type 2 diabetes (T2DM) is characterized by insulin resistance and beta-cell dysfunction. Although, in contrast to type 1 diabetes, insulin resistance is assumed to be a major pathophysiological feature of T2DM, T2DM never develops unless beta-cells fail to compensate insulin resistance. Recent studies have revealed that a deficit of beta-cell functional mass is an essential component of the pathophysiology of T2DM, implying that beta-cell deficit is a common feature of both type 1 and type 2 diabetes. beta-cell dysfunction is present at the diagnosis of T2DM and progressively worsens with disease duration. beta-cell dysfunction is associated with worsening of glycemic control and treatment failure; thus, it is important to preserve or recover beta-cell functional mass in the management of T2DM. Since beta-cell regenerative capacity appears somewhat limited in humans, reducing beta-cell workload appears to be the most effective way to preserve beta-cell functional mass to date, underpinning the importance of lifestyle modification and weight loss for the treatment and prevention of T2DM. This review summarizes the current knowledge on beta-cell functional mass in T2DM and discusses the treatment strategy for T2DM. PMID- 25685281 TI - Ocular complications of diabetes mellitus. AB - Diabetes mellitus (DM) is a important health problem that induces ernestful complications and it causes significant morbidity owing to specific microvascular complications such as, retinopathy, nephropathy and neuropathy, and macrovascular complications such as, ischaemic heart disease, and peripheral vasculopathy. It can affect children, young people and adults and is becoming more common. Ocular complications associated with DM are progressive and rapidly becoming the world's most significant cause of morbidity and are preventable with early detection and timely treatment. This review provides an overview of five main ocular complications associated with DM, diabetic retinopathy and papillopathy, cataract, glaucoma, and ocular surface diseases. PMID- 25685284 TI - Ipragliflozin: A novel sodium-glucose cotransporter 2 inhibitor developed in Japan. AB - Sodium-glucose cotransporter 2 (SGLT2) inhibition induces glucosuria and decreases blood glucose levels in diabetic patients and lowers hypoglycemic risk. SGLT1 is expressed in the kidney and intestine; SGLT1 inhibition causes abdominal symptoms such as diarrhea and reduces incretin secretion. Therefore, SGLT2 selectivity is important. Ipragliflozin is highly selective for SGLT2. In type 2 diabetes mellitus (T2DM), urinary glucose excretion increased to 90 g/24 h after 28 d of treatment with ipragliflozin 300 mg/d. Twelve weeks of ipragliflozin 50 mg/d vs placebo reduced glycated hemoglobin and body weight by 0.65% and 0.66 kg, respectively, in Western T2DM patients, and by 1.3% and 1.89 kg, respectively, in Japanese patients. Ipragliflozin (highly selective SGLT2 inhibitor) improves glycemic control and reduces body weight and lowers hypoglycemic risk and abdominal symptoms. Ipragliflozin can be a novel anti-diabetic and anti-obesity agent. PMID- 25685285 TI - Pathological consequences of C-peptide deficiency in insulin-dependent diabetes mellitus. AB - Diabetes is associated with several complications such as retinopathy, nephropathy, neuropathy and cardiovascular diseases. Currently, insulin is the main used medication for management of insulin-dependent diabetes mellitus (type 1 diabetes). In this metabolic syndrome, in addition to decrease of endogenous insulin, the plasma level of connecting peptide (C-peptide) is also reduced due to beta cell destruction. Studies in the past decade have shown that C-peptide is much more than a byproduct of insulin biosynthesis and possess different biological activities. Therefore, it may be possible that C-peptide deficiency be involved, at least in part, in the development of different complications of diabetes. It has been shown that a small level of remaining C-peptide is associated with significant metabolic benefit. The purpose of this review is to describe beneficial effects of C-peptide replacement on pathological features associated with insulin-dependent diabetes. Also, experimental and clinical findings on the effects of C-peptide on whole-body glucose utilization, adipose tissue metabolism and tissues blood flow are summarized and discussed. The hypoglycemic, antilipolytic and vasodilator effects of C-peptide suggest that it may contribute to fine-tuning of the tissues metabolism under different physiologic or pathologic conditions. Therefore, C-peptide replacement together with the classic insulin therapy may prevent, retard, or ameliorate diabetic complications in patients with type-1 diabetes. PMID- 25685286 TI - Adiponectin: Probe of the molecular paradigm associating diabetes and obesity. AB - Type 2 diabetes is an emerging health challenge all over the world as a result of urbanization, high prevalence of obesity, sedentary lifestyle and other stress related factors compounded with the genetic prevalence. The health consequences and economic burden of the obesity and related diabetes mellitus epidemic are enormous. Different signaling molecules secreted by adipocytes have been implicated in the development of obesity and associated insulin resistance in type 2 diabetes. Human adiponectin, a 244-amino acid collagen-like protein is solely secreted by adipocytes and acts as a hormone with anti-inflammatory and insulin-sensitizing properties. Adiponectin secretion, in contrast to secretion of other adipokines, is paradoxically decreased in obesity which may be attributable to inhibition of adiponectin gene transcription. There are several mechanisms through which adiponectin may decrease the risk of type 2 diabetes, including suppression of hepatic gluconeogenesis, stimulation of fatty acid oxidation in the liver, stimulation of fatty acid oxidation and glucose uptake in skeletal muscle, and stimulation of insulin secretion. To date, no systematic review has been conducted that evaluate the potential importance of adiponectin metabolism in insulin resistance. In this review attempt has been made to explore the relevance of adiponectin metabolism for the development of diabetes mellitus. This article also identifies this novel target for prospective therapeutic research aiming successful management of diabetes mellitus. PMID- 25685287 TI - Rare complications of pediatric diabetic ketoacidosis. AB - The incidence of type 1 diabetes (T1D) among youth is steadily increasing across the world. Up to a third of pediatric patients with T1D present with diabetic ketoacidosis, a diagnosis that continues to be the leading cause of death in this population. Cerebral edema is the most common rare complication of diabetic ketoacidosis in children. Accordingly, treatment and outcome measures of cerebral edema are vastly researched and the pathophysiology is recently the subject of much debate. Nevertheless, cerebral edema is not the only sequela of diabetic ketoacidosis that warrants close monitoring. The medical literature details various other complications in children with diabetic ketoacidosis, including hypercoagulability leading to stroke and deep vein thrombosis, rhabdomyolysis, pulmonary and gastrointestinal complications, and long-term memory dysfunction. We review the pathophysiology, reported cases, management, and outcomes of each of these rare complications in children. As the incidence of T1D continues to rise, practitioners will care for an increasing number of pediatric patients with diabetic ketoacidosis and should be aware of the various systems that may be affected in both the acute and chronic setting. PMID- 25685288 TI - Transcriptional factors, Mafs and their biological roles. AB - The Maf family of transcription factors is characterized by a typical bZip structure; these transcription factors act as important regulators of the development and differentiation of many organs and tissues, including the kidney. The Maf family consists of two subgroups that are characterized according to their structure: large Maf transcription factors and small Maf transcription factors. The large Maf subgroup consists of four proteins, designated as MAFA, MAFB, c-MAF and neural retina-specific leucine zipper. In particular, MAFA is a distinct molecule that has been attracting the attention of researchers because it acts as a strong transactivator of insulin, suggesting that Maf transcription factors are likely to be involved in systemic energy homeostasis. In this review, we focused on the regulation of glucose/energy balance by Maf transcription factors in various organs. PMID- 25685289 TI - Coronary atherosclerosis is already ongoing in pre-diabetic status: Insight from intravascular imaging modalities. AB - Diabetes mellitus is a powerful risk factor of coronary artery disease (CAD), leading to death and disability. In recent years, given the accumulating evidence that prediabetes is also related to increasing risk of CAD including cardiovascular events, a new guideline has been proposed for the treatment of blood cholesterol for primary prevention of cardiovascular events. This guideline recommends aggressive lipid-lowering statin therapy for primary prevention in diabetes and other patients. The ultimate goal of patient management is to inhibit progression of systemic atherosclerosis and prevent fatal cardiovascular events such as acute coronary syndrome (ACS). Because disruption of atherosclerotic coronary plaques is a trigger of ACS, the high-risk atheroma is called a vulnerable plaque. Several types of novel diagnostic imaging technologies have been developed for identifying the characteristics of coronary atherosclerosis before the onset of ACS, especially vulnerable plaques. According to coronary angioscopic evaluation, atherosclerosis severity and plaque vulnerability were more advanced in prediabetic than in nondiabetic patients and comparable to that in diabetic patients. In addition, pharmacological intervention by statin therapy changed plaque color and complexity, and the dynamic changes in plaque features are considered plaque stabilization. In this article, we review the findings of atherosclerosis in prediabetes, detected by intravascular imaging modalities, and the therapeutic implications. PMID- 25685290 TI - Literature review of type 2 diabetes mellitus among minority Muslim populations in Israel. AB - This review surveys the literature published on the characteristics and implications of pre-diabetes and type 2 diabetes mellitus (T2DM) for the Arab and Bedouin populations of Israel. T2DM is a global health problem. The rapid rise in its prevalence in the Arab and Bedouin populations in Israel is responsible for their lower life expectancy compared to Israeli Jews. The increased prevalence of T2DM corresponds to increased rates of obesity in these populations. A major risk group is adult Arab women aged 55-64 years. In this group obesity reaches 70%. There are several genetic and nutritional explanations for this increase. We found high hospitalization rates for micro and macrovascular complications among diabetic patients of Arab and Bedouin origin. Despite the high prevalence of diabetes and its negative health implications, there is evidence that care and counseling relating to nutrition, physical activity and self-examination of the feet are unsatisfactory. Economic difficulties are frequently cited as the reason for inadequate medical care. Other proposed reasons include faith in traditional therapy and misconceptions about drugs and their side effects. In Israel, the quality indicators program is based on one of the world's leading information systems and deals with the management of chronic diseases such as diabetes. The program's baseline data pointed to health inequality between minority populations and the general population in several areas, including monitoring and control of diabetes. Based on these data, a pilot intervention program was planned, aimed at minority populations. This program led to a decrease in inequality and served as the basis for a broader, more comprehensive intervention that has entered the implementation stage. Interventions that were shown to be effective in other Arabic countries may serve as models for diabetes management in the Arab and Bedouin populations in Israel. PMID- 25685291 TI - Obesity and cardiometabolic disease risk factors among US adolescents with disabilities. AB - AIM: To generate prevalence estimates of weight status and cardiometabolic disease risk factors among adolescents with and without disabilities. METHODS: Analysis of the 1999-2010 National Health and Nutrition Examination Survey data was conducted among 12-18 years old with (n = 256) and without disabilities (n = 5020). Mean values of waist circumference, fasting glucose, high-density lipoprotein cholesterol, triglycerides, systolic and diastolic blood pressure and metabolic syndrome (MetS, >= 3 risk factors present) were examined by the following standardized body mass index (BMI) categories for those with and without disabilities; overweight (BMI >= 85(th) - < 95(th) percentile for age and sex), obesity (BMI >= 95(th) percentile) and severe obesity (BMI >=35 kg/m(2)). Linear regression models were fit with each cardiometabolic disease risk factor independently as continuous outcomes to show relationships with disability status. RESULTS: Adolescents with disabilities were significantly more likely to be overweight (49.3%), obese (27.6%) and severely obese (12%) vs their peers without disabilities (33.1%, 17.5% and 3.6%, respectively, P <= 0.01 for all). A higher proportion of overweight, obese and severely obese children with disabilities had abnormal SBP, fasting lipids and glucose as well as MetS (18.9% of overweight, 32.3% of obese, 55% of severely obese) vs their peers without disabilities (9.7%, 16.8%, 36.3%, respectively). US adolescents with disabilities are over three times as likely to have MetS (OR = 3.45, 95%CI: 1.08-10.99, P = 0.03) vs their peers with no disabilities. CONCLUSION: Results show that adolescents with disabilities are disproportionately affected by obesity and poor cardiometabolic health vs their peers with no disabilities. Health care professionals should monitor the cardiometabolic health of adolescents with disabilities. PMID- 25685292 TI - Glycaemic control, treatment satisfaction and quality of life in type 2 diabetes patients in Greece: The PANORAMA study Greek results. AB - AIM: To provide an update on glycaemic control in European patients with type 2 diabetes mellitus (T2DM). We present the Greek population data of the study. METHODS: An observational multicenter, cross-sectional study evaluating glycaemic control and a range of other clinical and biological measures as well as quality of life (QoL) and treatment satisfaction in 375 patients with T2DM enrolled by 25 primary care sites from Greece. RESULTS: The mean age of the patients was 63.5 years and the male/female ratio 48.9%/51.1%. 79.7% of the patients exerted none or light physical activity, 82.4% were overweight or obese and 32.9% did not meet HbA1c target of less than 7.0% (53 mmol/mol). Patients reported high satisfaction to continue with treatment, high satisfaction with administered treatment and increased willingness to recommend treatment to others (mean Diabetes Treatment Satisfaction Questionnaire score 29.1 +/- 5.6). However, 80% of the patients reported that their QoL would be better without diabetes. Finally, the most challenging parameter reported was the lack of freedom to eat and drink. CONCLUSION: This analysis of the Greek Panorama study results showed that a considerable percentage of T2DM patients in Greece do not achieve glycaemic target levels, despite the favourably reported patient satisfaction from administered therapy. Additionally, the majority of primary care T2DM patients in Greece depict the negative effect of the disease in their QoL. PMID- 25685293 TI - Modelling of photo-thermal control of biological cellular oscillators. AB - We study the transient dynamics of biological oscillators subjected to brief heat pulses. A prospective well-defined experimental system for thermal control of oscillators is the peripheral electroreceptors in paddlefish. Epithelial cells in these receptors show spontaneous voltage oscillations which are known to be temperature sensitive. We use a computational model to predict the effect of brief thermal pulses in this system. In our model thermal stimulation is realized through the light excitation of gold nanoparticles delivered in close proximity to epithelial cells and generating heat due to plasmon resonance. We use an ensemble of modified Morris-Lecar systems to model oscillatory epithelial cells. First, we validate that the model quantitatively reproduces the dynamics of epithelial oscillations in paddlefish electroreceptors, including responses to static and slow temperature changes. Second, we use the model to predict transient responses to short heat pulses generated by the light actuated gold nanoparticles. The model predicts that the epithelial oscillators can be partially synchronized by brief 5 - 15 ms light stimuli resulting in a large amplitude oscillations of the mean field potential. PMID- 25685294 TI - Next generation sequencing and urologic cancer. PMID- 25685295 TI - Clinically relevant genetic characterization of prostate tumors: how close are we to the goal? AB - Substantial efforts are being made in research on the molecular genetic characterization of prostate cancer. The number of fundamental research programs in prostate cancer molecular biology and genetics is overwhelming. However, a significant gap appears to exist between the huge number of studies on the genetic characterization of prostate cancer, which often have limited translation into clinical practice or simply were not conceived to be so translated, and clinical practice. From a clinical point of view, this balance should be urgently shifted towards rapid translation into urological practice. However, prostate cancer is characterized by prominent genetic heterogeneity, which could be a very difficult barrier to overcome. In this review, we discuss the possible clinical applications of scientific data from fundamental studies of prostate cancer genetics, the main problems with the translation of these data to clinics, and future perspectives. PMID- 25685296 TI - Current status of penile rehabilitation after radical prostatectomy. AB - Although disease-free survival remains the primary goal of prostate cancer treatment, erectile dysfunction (ED) remains a common complication that affects the quality of life. Even though several preventive and therapeutic strategies are available for ED after radical prostatectomy (RP), no specific recommendations have been made on the optimal rehabilitation or treatment strategy. Several treatment options are available, including phosphodiesterase-5 inhibitors, vacuum erection devices, intracavernosal or intraurethral prostaglandin injections, and penile prostheses. Urologists must consider more effective ways to establish optimal treatments for ED after RP. ED is an important issue among patients with prostate cancer, and many patients hope for early ED recovery after surgery. This review highlights the currently available treatment options for ED after RP and discusses the limitations of each. PMID- 25685297 TI - A clinicogenetic model to predict lymph node invasion by use of genome-based biomarkers from exome arrays in prostate cancer patients. AB - PURPOSE: Genetic variations among prostate cancer (PCa) patients who underwent radical prostatectomy (RP) and pelvic lymph node dissection were evaluated to predict lymph node invasion (LNI). Exome arrays were used to develop a clinicogenetic model that combined clinical data related to PCa and individual genetic variations. MATERIALS AND METHODS: We genotyped 242,186 single-nucleotide polymorphisms (SNPs) by using a custom HumanExome BeadChip v1.0 (Illumina Inc.) from the blood DNA of 341 patients with PCa. The genetic data were analyzed to calculate an odds ratio as an estimate of the relative risk of LNI. We compared the accuracies of the multivariate logistic model incorporating clinical factors between the included and excluded selected SNPs. The Cox proportional hazard models with or without genetic factors for predicting biochemical recurrence (BCR) were analyzed. RESULTS: The genetic analysis indicated that five SNPs (rs75444444, rs8055236, rs2301277, rs9300039, and rs6908581) were significant for predicting LNI in patients with PCa. When a multivariate model incorporating clinical factors was devised to predict LNI, the predictive accuracy of the multivariate model was 80.7%. By adding genetic factors in the aforementioned multivariate model, the predictive accuracy increased to 93.2% (p=0.006). These genetic variations were significant factors for predicting BCR after adjustment for other variables and after adding the predictive gain to BCR. CONCLUSIONS: Based on the results of the exome array, the selected SNPs were predictors for LNI. The addition of individualized genetic information effectively enhanced the predictive accuracy of LNI and BCR among patients with PCa who underwent RP. PMID- 25685298 TI - Renal cryoablation of small renal masses: a Korea University experience. AB - PURPOSE: To evaluate the perioperative, functional, and oncological outcomes of renal cryoablation (RC) of small renal masses (SRMs) performed in Korea University Hospital. MATERIALS AND METHODS: We reviewed an Institutional Review Board-approved database of 70 patients who underwent RC and were followed up for a minimum of 3 months by a single surgeon in Korea University Hospital from August 2007 to May 2014. Among these patients, 68 patients (79 renal masses) were enrolled in our research. We evaluated perioperative, functional, and oncologic outcomes of RC. RESULTS: A total of 68 patients (79 renal masses) underwent RC in our institution. The mean age of the patients was 62.0 years. The mean tumor size was 2.25 cm. Among the 59 patients who underwent laparoscopic surgery, only 1 patient (1.47%) was converted to open surgery. No other perioperative complications occurred. The mean preoperative and 1-month postoperative estimated glomerular filtration ratio (eGFR) were 71.8 and 68.3 mL/min/1.73 m(2), respectively (p=0.19). The mean 1-year postoperative eGFR was 65.0 mL/min/1.73 m(2) (p=0.25). The mean follow-up period was 59.76 months (range, 3-119 months). Local tumor recurrence occurred in eight tumors (15.4%; a total of 52 renal cell carcinomas). Concerning treatment in the patients with recurrence, five patients underwent re-treatment and three patients are under active surveillance. None of the eight patients who experienced local recurrence had additional recurrence or tumor progression during the follow-up period. In our study, the recurrence-free rate was 83.0% and the cancer-specific survival rate was 100%. Moreover, the 5- and 10-year overall survival rates were both 100%. CONCLUSIONS: Long-term experience with RC in our institution demonstrates that RC is a safe and effective treatment for patients with SRMs. PMID- 25685299 TI - Lessons learnt in the management of primary invasive penile cancer in an Australian tertiary referral centre: clinical outcomes with a minimum 48 months follow-up study. AB - PURPOSE: To report on lessons learnt in the management of primary invasive penile cancer in a major tertiary hospital in Australia. MATERIALS AND METHODS: Medical records for all patients who underwent surgery for primary invasive penile cancer between January 2000 and January 2011 were obtained. Patient demographics, clinical status of inguinal node, cancer stage and clinical outcomes were reviewed. All patients were followed up for a minimum of 48 months postoperative unless patient deceased within the first 48 months from the time of penile cancer surgery. RESULTS: Over the 11-year period, a total of 23 cases of invasive penile cancer were identified. Partial penectomy was the most common form of organ preserving surgery and the majority of patients have pT1b disease. Of the 9 patients with clinically palpable inguinal nodes, 7 patients were diagnosed with pN3 disease following inguinal lymphadenectomy. The Kaplan-Meier cancer-specific survival at 72 months showed decreasing survival based on tumour stage (83% in pT1, 79% in pT2, and 64% in pT3 disease) and nodal disease (100% in node negative, 50% in superficial inguinal lymphadenopathy, and 38% in patients with deep inguinal and/or pelvic lymphadenopathy) (p=0.082). The Kaplan-Meier cancer specific survival revealed statistically significant difference in survival outcome in patients with local recurrence vs. systemic metastasis disease (33% vs. 17%, p=0.008). CONCLUSIONS: The presence of high risk features such as tumour stage, lymph node involvement and distant metastasis carries a significant higher risk of death and tumour recurrence in patients with penile cancer and inguinal lymph node metastasis. PMID- 25685300 TI - Robotic or open radical prostatectomy after previous open surgery in the pelvic region. AB - PURPOSE: We sought to evaluate the feasibility and safety of open or robotic radical prostatectomy (RP) after rectum, sigmoid, or colon surgery. MATERIALS AND METHODS: Sixty-four patients with a median age of 65 years (range, 46-73 years) who underwent RP after previous pelvic surgery were included. Twenty-four patients (38%) underwent robotic RP and 40 patients (62%) underwent open RP. Bilateral lymph node dissection and nerve preservation were performed in 50 patients (78%) and 35 patients (55%), respectively. Variables evaluated included demographic characteristics, perioperative complications, and functional and oncological outcomes. The median hospitalization and follow-up periods were 2 days (range, 1-12 days) and 21 months (range, 1-108 months), respectively. RESULTS: No conversions from robotic to open surgery were performed and there were no intraoperative complications. Surgical margins were positive in 13 patients (20%), seminal vesicle involvement was detected in 6 patients (9%), and lymph node involvement was found in 2 patients (3%). Postoperative complications included lymphocele in 1 patient, urethral stricture in 1 patient, and bowel obstruction and persistent bladder leakage in 2 patients. Eighty-eight percent of the patients were continent at 7 months and 80% of patients were able to achieve erection with or without medical aid. CONCLUSIONS: Open or robotic RP can be done safely and effectively in patients who have previously undergone pelvic surgery. Although prior pelvic surgery of the large intestine was associated with increased morbidity, it should not be considered a contraindication for robotic or open RP. PMID- 25685301 TI - Predictive factors for flexible ureterorenoscopy requirement after rigid ureterorenoscopy in cases with renal pelvic stones sized 1 to 2 cm. AB - PURPOSE: To evaluate the outcomes of rigid ureterorenoscopy (URS) for renal pelvic stones (RPS) sized 1 to 2 cm and to determine the predictive factors for the requirement for flexible URS (F-URS) when rigid URS fails. MATERIALS AND METHODS: A total of 88 patients were included into the study. In 48 patients, the RPS were totally fragmented with rigid URS and F-URS was not required (group 1). In 40 patients, rigid URS was not able to access the renal pelvis or fragmentation of the stones was not completed owing to stone position or displacement and F-URS was utilized for retrograde intrarenal surgery (RIRS) (group 2). The predictive factors for F-URS requirement during RIRS for RPS were evaluated. Both groups were compared regarding age, height, sex, body mass index, stone size, stone opacity, hydronephrosis, and previous treatments. RESULTS: The mean patient age was 48.6+/-16.5 years and the mean follow-period was 39+/-11.5 weeks. The overall stone-free rate in the study population was 85% (75 patients). In groups 1 and 2, the overall stone-free rates were 83% (40 patients) and 87% (35 patients), respectively (p>0.05). The independent predictors of requirement for F-URS during RIRS were male gender, patient height, and higher degree of hydronephrosis. CONCLUSIONS: Rigid URS can be utilized in selected patients for the fragmentation of RPS sized 1 to 2 cm with outcomes similar to that of F-URS. In case of failure of rigid URS, F-URS can be performed successfully in this group of patients. PMID- 25685302 TI - Efficacy of scrotal Doppler ultrasonography with the Valsalva maneuver, standing position, and resting-Valsalva ratio for varicocele diagnosis. AB - PURPOSE: To determine effectiveness of Valsalva maneuver and standing position on scrotal color Doppler ultrasound (CDU) for the varicocele diagnosis. MATERIALS AND METHODS: We reviewed the physical examination and CDU finding in 87 patients who visited National Police Hospital from January 2011 to April 2014. Diameters of pampiniform plexus were measured bilaterally during resting and Valsalva maneuver in the supine position and standing position. We calculated the ratio of mean of maximal vein diameter (mMVD) during resting and Valsalva maneuver (resting-Valsalva ratio) and compared in the both position. RESULTS: In the resting and supine position, mMVD of varicocele testis units were 1.8 mm, 2.1 mm, 2.6 mm (grades I, II, III, respectively), and that of normal testis units (NTU) 1.2 mm. During Valsalva maneuver in the supine position, mMVD were 3.0 mm, 3.4 mm, 4.2 mm (grades I, II, III) vs 1.8 mm (NTU) (p=0.007, p<0.001, p<0.001, respectively). Average of resting-Valsalva ratio in the supine position were 0.69, 0.74, 0.74 (grades I, II, III) and 0.67 (NTU). Whereas in the resting and standing position, mMVD were 2.8 mm, 3.3 mm, 3.8 mm (grades I, II, III) and 1.8 mm (NTU) (p=0.002, p<0.001, p<0.001). During Valsalva maneuver in the standing position, mMVD were 5.0 mm, 5.8 mm, 6.6 mm (grades I, II, III) and 2.5 mm (NTU) (p=0.002, p<0.001, p<0.001). And average resting-Valsalva ratio were 0.76, 0.90, 0.71 (grades I, II, III) and 0.26 (NTU), which showed significant differences from all grades (p<0.001, p<0.001, p<0.001). CONCLUSIONS: It is suggested that the standing position and Valsalva maneuver during CDU could improve diagnostic ability for varicocele. Resting-Valsalva ratio in the standing position could be a new diagnostic index for varicocele diagnosis using CDU. PMID- 25685303 TI - Evaluation of holmium laser for transurethral deroofing of severe and multiloculated prostatic abscesses. AB - PURPOSE: Our objective was to evaluate the use of a holmium laser for transurethral deroofing of a prostatic abscess in patients with severe and multiloculated prostatic abscesses. MATERIALS AND METHODS: From January 2011 to April 2014, eight patients who were diagnosed with prostatic abscesses and who underwent transurethral holmium laser deroofing at Pusan National University Hospital were retrospectively reviewed. RESULTS: Multiloculated or multifocal abscess cavities were found on the preoperative computed tomography (CT) scan in all eight patients. All patients who underwent transurethral holmium laser deroofing of a prostatic abscess had successful outcomes, without the need for secondary surgery. Of the eight patients, seven underwent holmium laser enucleation of the prostate (HoLEP) for the removal of residual adenoma. Markedly reduced multiloculated abscess cavities were found in the follow-up CT in all patients. No prostatic abscess recurrence was found. Transient stress urinary incontinence was observed in three patients. The stress urinary incontinence subsided within 3 weeks in two patients and improved with conservative management within 2 months in the remaining patient. CONCLUSIONS: Transurethral holmium laser deroofing of prostatic abscesses ensures successful drainage of the entire abscess cavity. Because we resolved the predisposing conditions of prostatic abscess, such as bladder outlet obstruction and prostatic calcification, by simultaneously conducting HoLEP, there was no recurrence of the prostatic abscesses after surgery. We recommend our method in patients requiring transurethral drainage. PMID- 25685304 TI - Delayed redo pyeloplasty fails to recover lost renal function after failed pyeloplasty: early sonographic changes that correlate with a loss of differential renal function. AB - PURPOSE: To evaluate changes in differential renal function (DRF), as a functional outcome, in children who underwent redo pyeloplasty for management of failed pyeloplasty and to examine the factors that affect functional outcomes. MATERIALS AND METHODS: Between January 2002 and November 2010, a total of 18 patients who underwent redo pyeloplasty for persistent ureteropelvic junction obstruction after failed pyeloplasty were enrolled in this study. We assessed perioperative factors and evaluated changes in renal cortical thickness (RCT), renal function, and hydronephrosis by use of serial ultrasound and diuretic renography. RESULTS: The mean follow-up period was 44.83+/-28.86 months. After redo pyeloplasty, prevention of further functional deterioration was observed in only 12 of the 18 patients. After dividing the patients according to this observation, we discovered significant differences in both change in DRF (dDRF) and change in RCT (dRCT) (difference between before and after initial pyeloplasty) between the two groups (p<0.001). Additionally, we noted a significant positive correlation between dRCT and dDRF. All patients showed improvements in hydronephrosis grade and relief of symptoms compared with before redo pyeloplasty. CONCLUSIONS: Redo pyeloplasty should be considered in cases of failed pyeloplasty to preserve renal function and obtain relief from symptoms. If patients show severe deterioration of DRF or a decrease in RCT after initial pyeloplasty, preservation of DRF in these patients after redo pyeloplasty could be difficult. Therefore, redo pyeloplasty should be performed before severe deterioration of DRF or decrease in RCT. PMID- 25685305 TI - Ventral inlay buccal mucosal graft urethroplasty: a novel surgical technique for the management of urethral stricture disease. AB - To describe the novel technique of ventral inlay substitution urethroplasty for the management of male anterior urethral stricture disease. A 58-year-old gentleman with multifocal bulbar stricture disease measuring 7 cm in length was treated using a ventral inlay substitution urethroplasty. A dorsal urethrotomy was created, and the ventral urethral plated was incised. The edges of the urethral plate were mobilized without violation of the ventral corpus spongiosum. A buccal mucosa graft was harvested and affixed as a ventral inlay to augment the caliber of the urethra. The dorsal urethrotomy was closed over a foley catheter. No intraoperative or postoperative complications occurred. Postoperative imaging demonstrated a widely patent urethra. After three years of follow-up, the patient continues to do well with no voiding complaints and low postvoid residuals. Ventral inlay substitution urethroplasty appears to be a safe and feasible technique for the management of bulbar urethral strictures. PMID- 25685306 TI - A pilot controlled trial of insulin-like growth factor-1 in children with Phelan McDermid syndrome. AB - BACKGROUND: Autism spectrum disorder (ASD) is now understood to have multiple genetic risk genes and one example is SHANK3. SHANK3 deletions and mutations disrupt synaptic function and result in Phelan-McDermid syndrome (PMS), which causes a monogenic form of ASD with a frequency of at least 0.5% of ASD cases. Recent evidence from preclinical studies with mouse and human neuronal models of SHANK3 deficiency suggest that insulin-like growth factor-1 (IGF-1) can reverse synaptic plasticity and motor learning deficits. The objective of this study was to pilot IGF-1 treatment in children with PMS to evaluate safety, tolerability, and efficacy for core deficits of ASD, including social impairment and restricted and repetitive behaviors. METHODS: Nine children with PMS aged 5 to 15 were enrolled in a placebo-controlled, double-blind, crossover design study, with 3 months of treatment with IGF-1 and 3 months of placebo in random order, separated by a 4-week wash-out period. RESULTS: Compared to the placebo phase, the IGF-1 phase was associated with significant improvement in both social impairment and restrictive behaviors, as measured by the Aberrant Behavior Checklist and the Repetitive Behavior Scale, respectively. IGF-1 was found to be well tolerated and there were no serious adverse events in any participants. CONCLUSIONS: This study establishes the feasibility of IGF-1 treatment in PMS and contributes pilot data from the first controlled treatment trial in the syndrome. Results also provide proof of concept to advance knowledge about developing targeted treatments for additional causes of ASD associated with impaired synaptic development and function. PMID- 25685307 TI - Atypical integration of social cues for orienting to gaze direction in adults with autism. AB - BACKGROUND: Gaze direction provides important information about social attention, and people tend to reflexively orient in the direction others are gazing. Perceiving the gaze of others relies on the integration of multiple social cues, which include perceptual information related to the eyes, gaze direction, head position, and body orientation of others. Autism spectrum conditions (ASC) are characterised by social and emotional deficits, including atypical gaze behaviour. The social-emotional deficits may emerge from a reliance on perceptual information involving details and features, at the expense of more holistic processing, which includes the integration of features. While people with ASC are often able to physically compute gaze direction and show intact reflexive orienting to others' gaze, they show deficits in reading mental states from the eyes. METHODS: The present study recruited 23 adult males with a diagnosis of ASC and 23 adult males without ASC as a control group. They were tested using a spatial cuing paradigm involving head and body cues in a photograph of a person followed by a laterally presented target. The task manipulated the orientation of head with respect to body orientation to test subsequent shifts of attention in observers. RESULTS: The results replicated previous findings showing facilitated shifts of attention by the healthy control participants toward laterally presented targets cued by a congruently rotated head combined with a front view of a body. In contrast, the ASC group showed facilitated orienting to targets when both the head and body were rotated towards the target. CONCLUSIONS: The findings reveal atypical integration of social cues in ASC for orienting of attention. This is suggested to reflect abnormalities in cognitive and neural mechanisms specialized for processing of social cues for attention orienting in ASC. PMID- 25685308 TI - Synthesis, Structure-Activity Relationship, and Mechanistic Investigation of Lithocholic Acid Amphiphiles for Colon Cancer Therapy. AB - We report a structure-activity relationship of lithocholic acid amphiphiles for their anticancer activities against colon cancer. We synthesized ten cationic amphiphiles differing in nature of cationic charged head groups using lithocholic acid. We observed that anticancer activities of these amphiphiles against colon cancer cell lines are contingent on nature of charged head group. Lithocholic acid based amphiphile possessing piperidine head group (LCA-PIP1 ) is ~10 times more cytotoxic as compared to its precursor. Biochemical studies revealed that enhanced activity of LCA-PIP1 as compared to lithocholic acid is due to greater activation of apoptosis.LCA-PIP1 induces sub G0 arrest and causes cleavage of caspases. A single dose of lithocholic acid-piperidine derivative is enough to reduce the tumor burden by 75% in tumor xenograft model. PMID- 25685309 TI - EVALUATION OF AROMATIC 6-SUBSTITUTED THIENOPYRIMIDINES AS SCAFFOLDS AGAINST PARASITES THAT CAUSE TRYPANOSOMIASIS, LEISHMANIASIS, AND MALARIA. AB - Target repurposing is a proven method for finding new lead compounds that target Trypanosoma brucei, the causative agent of human African trypanosomiasis. Due to the recent discovery of a lapatinib-derived analog 2 with excellent potency against T. brucei (EC50 = 42 nM) and selectivity over human host cells, we have explored other classes of human tyrosine kinase inhibitor scaffolds in order to expand the range of chemotypes for pursuit. Following library expansion, we found compound 11e to have an EC50 of 84 nM against T. brucei cells while maintaining selectivity over human hepatocytes. In addition, the library was tested against causative agents of Chagas' disease, leishmaniasis, and malaria. Two analogs with sub-micromolar potencies for T. cruzi (4j) and Plasmodium falciparum (11j) were discovered, along with an analog with considerable potency against Leishmania major amastigotes (4e). Besides identifying new and potent protozoan growth inhibitors, these data highlight the value of concurrent screening of a chemical library against different protozoan parasites. PMID- 25685310 TI - Decomposing changes in phylogenetic and functional diversity over space and time. AB - The alpha, beta, gamma diversity decomposition methodology is commonly used to investigate changes in diversity over space or time but rarely conjointly. However, with the ever-increasing availability of large-scale biodiversity monitoring data, there is a need for a sound methodology capable of simultaneously accounting for spatial and temporal changes in diversity.Using the properties of Chao's index, we adapted Rao's framework of diversity decomposition between orthogonal dimensions to a multiplicative alpha, beta, gamma decomposition of functional or phylogenetic diversity over space and time, thereby combining their respective properties. We also developed guidelines for interpreting both temporal and spatial beta-diversities and their interaction.We characterised the range of beta-diversity estimates and their relationship to the nested decomposition of diversity. Using simulations, we empirically demonstrated that temporal and spatial beta-diversities are independent from each other and from alpha and gamma-diversities when the study design is balanced, but not otherwise. Furthermore, we showed that the interaction term between the temporal and the spatial beta-diversities lacked such properties.We illustrated our methodology with a case study of the spatio-temporal dynamics of functional diversity in bird assemblages in four regions of France. Based on these data, our method makes it possible to discriminate between regions experiencing different diversity changes in time. Our methodology may therefore be valuable for comparing diversity changes over space and time using large-scale datasets of repeated surveys. PMID- 25685311 TI - Non-Directed Allylic C-H Acetoxylation in the Presence of Lewis Basic Heterocycles. AB - We outline a strategy to enable non-directed Pd(II)-catalyzed C-H functionalization in the presence of Lewis basic heterocycles. In a high throughput screen of two Pd-catalyzed C-H acetoxylation reactions, addition of a variety of N-containing heterocycles is found to cause low product conversion. A pyridine-containing test substrate is selected as representative of heterocyclic scaffolds that are hypothesized to cause catalyst arrest. We pursue two approaches in parallel that allow product conversion in this representative system: Lewis acids are found to be effective in situ blocking groups for the Lewis basic site, and a pre-formed pyridine N-oxide is shown to enable high yield of allylic C-H acetoxylation. Computational studies with density functional theory (M06) of binding affinities of selected heterocycles to Pd(OAc)2 provide an inverse correlation of the computed heterocycle-Pd(OAc)2 binding affinities with the experimental conversions to products. Additionally, 1H NMR binding studies provide experimental support for theoretical calculations. PMID- 25685312 TI - Cobalt co-catalysis for cross-electrophile coupling: diarylmethanes from benzyl mesylates and aryl halides. AB - The nickel-catalyzed cross-coupling of aryl halides with alkyl radicals derived from alkyl halides has recently been extended to couplings with carbon radicals generated by a co-catalyst. In this study, a new co-catalyst, cobalt phthalocyanine (Co(Pc)), is introduced and demonstrated to be effective for coupling substrates not prone to homolysis. This is because Co(Pc) reacts with electrophiles by an SN2 mechanism instead of by the electron-transfer or halogen abstraction mechanisms previously explored. Studies demonstrating the orthogonal reactivity of (bpy)Ni and Co(Pc), applying this selectivity to the coupling of benzyl mesylates with aryl halides, and the adaptation of these conditions to the less reactive benzyl phosphate ester and an enantioconvergent reaction are presented. PMID- 25685313 TI - A dual catalytic strategy for carbon-phosphorus cross-coupling via gold and photoredox catalysis. AB - A new method for the P-arylation of aryldiazonium salts with H-phosphonates via dual gold and photoredox catalysis is described. The reaction proceeds smoothly at room temperature in the absence of base and/or additives, and offers an efficient approach to arylphosphonates. The reaction is proposed to proceed through a photoredox-promoted generation of an electrophilic arylgold(III) intermediate that undergoes coupling with the H-phosphonate nucleophile. PMID- 25685314 TI - Stereoselective Radical C-H Alkylation with Acceptor/Acceptor-Substituted Diazo Reagents via Co(II)-Based Metalloradical Catalysis. AB - Co(II)-based metalloradical catalysis has been, for the first time, successfully applied for asymmetric intramolecular C-H alkylation of acceptor/acceptor substituted diazo reagents. Through the design and synthesis of a new D2 symmetric chiral amidoporphyrin as the supporting ligand, the Co(II)-based metalloradical system, which operates at room temperature, is capable of 1,5-C-H alkylation of alpha-methoxycarbonyl-alpha-diazosulfones with a broad range of electronic properties, providing the 5-membered sulfolane derivatives in high yields with excellent diastereoselectivity and enantioselectivity. In addition to complete chemoselectivity toward allylic and allenic C-H bonds, the Co(II)-based metalloradical catalysis for asymmetric C-H alkylation features a remarkable degree of functional group tolerance. PMID- 25685315 TI - Rational Coupled Dynamics Network Manipulation Rescues Disease-Relevant Mutant Cystic Fibrosis Transmembrane Conductance Regulator. AB - Many cellular functions necessary for life are tightly regulated by protein allosteric conformational change, and correlated dynamics between protein regions has been found to contribute to the function of proteins not previously considered allosteric. The ability to map and control such dynamic coupling would thus create opportunities for the extension of current therapeutic design strategy. Here, we present an approach to determine the networks of residues involved in the transfer of correlated motion across a protein, and apply our approach to rescue disease-causative mutant cystic fibrosis transmembrane regulator (CFTR) ion channels, DeltaF508 and DeltaI507, which together constitute over 90% of cystic fibrosis cases. We show that these mutations perturb dynamic coupling within the first nucleotide-binding domain (NBD1), and uncover a critical residue that mediates trans-domain coupled dynamics. By rationally designing a mutation to this residue, we improve aberrant dynamics of mutant CFTR as well as enhance surface expression and function of both mutants, demonstrating the rescue of a disease mutation by rational correction of aberrant protein dynamics. PMID- 25685316 TI - Evolution of transcription factor function as a mechanism for changing metazoan developmental gene regulatory networks. AB - The form that an animal takes during development is directed by gene regulatory networks (GRNs). Developmental GRNs interpret maternally deposited molecules and externally supplied signals to direct cell-fate decisions, which ultimately leads to the arrangements of organs and tissues in the organism. Genetically encoded modifications to these networks have generated the wide range of metazoan diversity that exists today. Most studies of GRN evolution focus on changes to cis-regulatory DNA, and it was historically theorized that changes to the transcription factors that bind to these cis-regulatory modules (CRMs) contribute to this process only rarely. A growing body of evidence suggests that changes to the coding regions of transcription factors play a much larger role in the evolution of developmental gene regulatory networks than originally imagined. Just as cis-regulatory changes make use of modular binding site composition and tissue-specific modules to avoid pleiotropy, transcription factor coding regions also predominantly evolve in ways that limit the context of functional effects. Here, we review the recent works that have led to this unexpected change in the field of Evolution and Development (Evo-Devo) and consider the implications these studies have had on our understanding of the evolution of developmental processes. PMID- 25685317 TI - Exploring the tumors of multiple endocrine neoplasia type 1 in mouse models for basic and preclinical studies. AB - Most patients (70-90%) with the multiple endocrine neoplasia type 1 (MEN1) syndrome possess germline heterozygous mutations in MEN1 that predisposes to tumors of multiple endocrine and nonendocrine tissues. Some endocrine tumors of the kinds seen in MEN1 that occur sporadically in the general population also possess somatic mutations in MEN1. Interestingly, the endocrine tumors of MEN1 are recapitulated in mouse models of Men1 loss that serve as a valuable resource to understand the pathophysiology and molecular basis of tumorigenesis. Exploring these endocrine tumors in mouse models using in vivo, ex vivo and in vitro methods can help to follow the process of tumorigenesis, and can be useful for preclinical testing of therapeutics and understanding their mechanisms of action. PMID- 25685318 TI - Identification of active chemotherapy regimens in advanced biliary tract carcinoma: a review of chemotherapy trials in the past two decades. AB - Biliary tract carcinoma is a rare malignancy. We performed a comprehensive analysis of published prospective clinical trials in advanced biliary tract carcinoma in an attempt to identify active regimens in this setting. We searched PubMed and abstracts presented at the American Society of Clinical Oncology, Gastrointestinal Cancer Symposium, European Society of Medical Oncology and European Cancer Organization conferences for clinical trials in this disease. We found 83 trials. The effect of gemcitabine on overall survival benefit showed a strong trend (p = 0.014) and an improvement in progression-free survival (p = 0.003). Gemcitabine-based regimens containing 5-fluorouracil showed a trend toward an improved overall survival (p = 0.047) relative to platinum agents. Our findings support gemcitabine as the chemotherapy backbone for the treatment of patients with cholangiocarcinoma. Gemcitabine plus 5-fluorouracil combinations warrant further investigations. PMID- 25685319 TI - Kaolin-induced chronic hydrocephalus accelerates amyloid deposition and vascular disease in transgenic rats expressing high levels of human APP. AB - BACKGROUND: Normal pressure hydrocephalus (NPH) is most common in the elderly and has a high co-morbidity with Alzheimer's disease (AD) and cerebrovascular disease (CVD). To understand the relationship between NPH, AD and CVD, we investigated how chronic hydrocephalus impacts brain amyloid-beta peptide (Abeta) accumulation and vascular pathology in an AD transgenic rodent model. Previously we showed that the altered CSF physiology produced by kaolin-hydrocephalus in older wild type Sprague-Dawley rats increased Abeta and hyperphosphorylated Tau (Silverberg et. al. Brain Res. 2010, 1317:286-296). We postulated that hydrocephalus would similarly affect an AD rat model. METHODS: Thirty-five transgenic rats (tgAPP21) that express high levels of human APP and naturally overproduce Abeta40 were used. Six- (n = 7) and twelve-month-old (n = 9) rats had hydrocephalus induced by cisternal kaolin injection. We analyzed Abeta burden (Abeta40, Abeta42 and oligomeric Abeta) and vascular integrity (Masson trichrome and Verhoeff-Van Gieson) by immunohistochemistry and chemical staining at 10 weeks (n = 8) and 6 months (n = 5) post hydrocephalus induction. We also analyzed whether the vascular pathology seen in tgAPP21 rats, which develop amyloid angiopathy, was accelerated by hydrocephalus. Age-matched naive and sham-operated tgAPP21 rats served as controls (n = 19). RESULTS: In hydrocephalic tgAPP21 rats, compared to naive and sham-operated controls, there was increased Abeta 40 and oligomeric Abeta in hippocampal and cortical neurons at 10 weeks and 6 months post hydrocephalus induction. No dense-core amyloid plaques were seen, but diffuse Abeta immunoreactivity was evident in neurons. Vascular pathology was accelerated by the induction of hydrocephalus compared to controls. In the six-month-old rats, subtle degenerative changes were noted in vessel walls at 10 weeks post kaolin, whereas at six months post-kaolin and in the 12-month-old hydrocephalic rats more pronounced amyloid angiopathic changes were seen, with frequent large areas of infarction noted. CONCLUSIONS: Kaolin-hydrocephalus can accelerate intraneuronal Abeta40 accumulation and vascular pathology in tgAPP21 rats. In addition, disrupted CSF production and reduced CSF turnover results in impaired Abeta clearance and accelerated vascular pathology in chronic hydrocephalus. The high co-morbidity seen in NPH, AD and CVD is likely not to be an age-related coincidence, but rather a convergence of pathologies related to diminished CSF clearance. PMID- 24860646 TI - edgeR: a versatile tool for the analysis of shRNA-seq and CRISPR-Cas9 genetic screens. AB - Pooled library sequencing screens that perturb gene function in a high-throughput manner are becoming increasingly popular in functional genomics research. Irrespective of the mechanism by which loss of function is achieved, via either RNA interference using short hairpin RNAs (shRNAs) or genetic mutation using single guide RNAs (sgRNAs) with the CRISPR-Cas9 system, there is a need to establish optimal analysis tools to handle such data. Our open-source processing pipeline in edgeR provides a complete analysis solution for screen data, that begins with the raw sequence reads and ends with a ranked list of candidate genes for downstream biological validation. We first summarize the raw data contained in a fastq file into a matrix of counts (samples in the columns, genes in the rows) with options for allowing mismatches and small shifts in sequence position. Diagnostic plots, normalization and differential representation analysis can then be performed using established methods to prioritize results in a statistically rigorous way, with the choice of either the classic exact testing methodology or generalized linear modeling that can handle complex experimental designs. A detailed users' guide that demonstrates how to analyze screen data in edgeR along with a point-and-click implementation of this workflow in Galaxy are also provided. The edgeR package is freely available from http://www.bioconductor.org. PMID- 25685321 TI - Longevity of Atlantic Sharpnose Sharks Rhizoprionodon terraenovae and Blacknose Sharks Carcharhinus acronotus in the western North Atlantic Ocean based on tag recapture data and direct age estimates. AB - Longevity of Rhizoprionodon terraenovae and Carcharhinus acronotus in the western North Atlantic Ocean was examined using direct age estimates from vertebral sections and tag-recapture data. Time-at-liberty ranged from 7.7-12.1 years (mean =9.2) for R. terraenovae and 10.9-12.8 years (mean =11.9) for C. acronotus. Maximum estimated longevity was determined to be 19.8 years through tag-recapture data and 18.5 years from direct age estimates for R. terraenovae and 22.8 years through tag-recapture data and 20.5 years through direct age estimates for C. acronotus. These longevity estimates represent a large increase over previous estimates and may have significant effects on analyses that depend on longevity including lifetime fecundity, mortality rates, demographic analyses and stock assessments. PMID- 25685322 TI - ABS-Scan: In silico alanine scanning mutagenesis for binding site residues in protein-ligand complex. AB - Most physiological processes in living systems are fundamentally regulated by protein-ligand interactions. Understanding the process of ligand recognition by proteins is a vital activity in molecular biology and biochemistry. It is well known that the residues present at the binding site of the protein form pockets that provide a conducive environment for recognition of specific ligands. In many cases, the boundaries of these sites are not well defined. Here, we provide a web server to systematically evaluate important residues in the binding site of the protein that contribute towards the ligand recognition through in silico alanine scanning mutagenesis experiments. Each of the residues present at the binding site is computationally mutated to alanine. The ligand interaction energy is computed for each mutant and the corresponding DeltaDeltaG values are computed by comparing it to the wild type protein, thus evaluating individual residue contributions towards ligand interaction. The server will thus provide clues to researchers about residues to obtain loss-of-function mutations and to understand drug resistant mutations. This web-tool can be freely accessed through the following address: http://proline.biochem.iisc.ernet.in/abscan/. PMID- 25685323 TI - Diversity of two-component systems: insights into the signal transduction mechanism by the Staphylococcus aureus two-component system GraSR. AB - The response to cationic antimicrobial peptides (CAMPs) in Staphylococcus aureus relies on a two-component system (TCS), GraSR, an auxiliary protein GraX and an ATP-binding cassette (ABC) transporter, VraF/G. To understand the signal transduction mechanism by GraSR, we investigated the kinase activity of the cytoplasmic domain of histidine kinase GraS and the interaction with its cognate response regulator GraR. We also investigated interactions among the auxiliary protein GraX, GraS/R and the ATPase protein of the ABC transporter, VraF. We found that GraS lacks autophosphorylation activity, unlike a similar histidine kinase, BceS, of Bacillus subtilis. In addition, the interaction between GraS and GraR is very weak in comparison to the stronger interaction observed between BceS and its conjugated response regulator, BceR, suggesting that CAMP signaling may not flow directly from GraS to GraR. We found that the auxiliary protein GraX interacts with VraF and GraR, and requires the histidine phosphotransfer and dimerization domain of GraS to interact with this protein. Further, VraF requires the GraS region that connects the membrane-bound domain with the cytoplasmic domain of this protein for interaction with GraS. The interactions of GraX with GraS/R and VraF indicate that GraX may serve as a scaffold to bring these proteins in close proximity to GraS, plausibly to facilitate activation of GraS to ultimately transduce the signal to GraR. PMID- 25685324 TI - Collaboration for rare disease drug discovery research. AB - Rare disease research has reached a tipping point, with the confluence of scientific and technologic developments that if appropriately harnessed, could lead to key breakthroughs and treatments for this set of devastating disorders. Industry-wide trends have revealed that the traditional drug discovery research and development (R&D) model is no longer viable, and drug companies are evolving their approach. Rather than only pursue blockbuster therapeutics for heterogeneous, common diseases, drug companies have increasingly begun to shift their focus to rare diseases. In academia, advances in genetics analyses and disease mechanisms have allowed scientific understanding to mature, but the lack of funding and translational capability severely limits the rare disease research that leads to clinical trials. Simultaneously, there is a movement towards increased research collaboration, more data sharing, and heightened engagement and active involvement by patients, advocates, and foundations. The growth in networks and social networking tools presents an opportunity to help reach other patients but also find researchers and build collaborations. The growth of collaborative software that can enable researchers to share their data could also enable rare disease patients and foundations to manage their portfolio of funded projects for developing new therapeutics and suggest drug repurposing opportunities. Still there are many thousands of diseases without treatments and with only fragmented research efforts. We will describe some recent progress in several rare diseases used as examples and propose how collaborations could be facilitated. We propose that the development of a center of excellence that integrates and shares informatics resources for rare diseases sponsored by all of the stakeholders would help foster these initiatives. PMID- 25685325 TI - Slow progression of exudative age related macular degeneration associated with hypertrophy of the retinal pigment epithelium. AB - RATIONALE: Choroidal neovascular (CNV) lesions in younger patients are often accompanied by the appearance of a surrounding ring of pigment that is associated with disease regression or slowed disease progression. In older patients with age related macular degeneration (AMD), however, hypertrophy of the retinal pigment epithelium (RPE) is known to occur but has not previously been reported to be associated with CNV regression. This report describes the clinical course of a case series of AMD patients with pigment hypertrophy adjacent to CNV associated with stabilization of the CNV lesion. METHODS: A retrospective analysis of exudative AMD patients seen by a single retina specialist over a 7-year period. RESULTS: Retrospective analysis of 955 exudative AMD patients revealed pigment hypertrophy associated with CNV in 33 patients. A ring of pigment surrounded CNV in 6 of these. Three representative patients are presented to illustrate the decrease in macular edema, reduced fluorescein leakage and slowed CNV progression that was associated with a pigment ring around CNV in AMD. Pigment hypertrophy was associated with blocked fluorescein leakage and exudative AMD patients with a complete pigment ring maintained stable visual acuity, macular edema, fluorescein leakage and CNV lesion size without treatment for intervals of up to 21 months. CONCLUSION: We report slowed disease progression in AMD patients who develop pigment around CNV. The slow rate of disease progression in the AMD patient subgroup having a pigment ring is a factor to consider in determining the treatment interval for exudative AMD patients. PMID- 25685326 TI - Case Report: Large nested variant urothelial carcinoma -invasive malignancy masquerading as low grade disease. AB - Introduction The large nested variant of urothelial carcinoma (LNVUC) is a newly described and rare subtype of urothelial carcinoma. It is characterised by bland cytological features and a large nested architecture similar in appearance to low grade urothelial carcinoma with an inverted growth pattern. To date only 23 cases in a single series have been described. Case Report We describe the case of a 59 year old male with LNVUC whose tumour was initially misdiagnosed as a non invasive low grade urothelial carcinoma. At a subsequent re-resection, his tumour was correctly re-classified as LNVUC with extensive invasion of the muscularis propria. Radical cystectomy and formation of an ileal conduit was performed. His operative specimen revealed invasion of prostatic stroma and perivesical fat, with all surgical margins clear. He is currently free from clinical recurrence 12 months after his cystectomy. Conclusion LNVUC is a newly described and rare urothelial carcinoma subtype. It characteristically possesses bland cytological features and may mimic low grade urothelial cancer. Despite its bland appearance it behaves aggressively with invasion, metastasis and death being common. PMID- 25685327 TI - Capsaicin from chili ( Capsicum spp.) inhibits vascular smooth muscle cell proliferation. AB - Accelerated vascular smooth muscle cell (VSMC) proliferation is implied in cardiovascular disease and significantly contributes to vessel lumen reduction following surgical interventions such as percutaneous transluminal coronary angioplasty or bypass surgery. Therefore, identification and characterization of compounds and mechanisms able to counteract VSMC proliferation is of potential therapeutic relevance. This work reveals the anti-proliferative effect of the natural product capsaicin from Capsicum spp. by quantification of metabolic activity and DNA synthesis in activated VSMC. The observed in vitro activity profile of capsaicin warrants further research on its mechanism of action and potential for therapeutic application. PMID- 25685328 TI - Cellular binding of nanoparticles disrupts the membrane potential. AB - All cells generate an electrical potential across their plasma membrane driven by a concentration gradient of charged ions. A typical resting membrane potential ranges from -40 to -70 mV, with a net negative charge on the cytosolic side of the membrane. Maintenance of the resting membrane potential depends on the presence of two-pore-domain potassium "leak" channels, which allow for outward diffusion of potassium ions along their concentration gradient. Disruption of the ion gradient causes the membrane potential to become more positive or more negative relative to the resting state, referred to as "depolarization" or "hyperpolarization," respectively. Changes in membrane potential have proven to be pivotal, not only in normal cell cycle progression but also in malignant transformation and tissue regeneration. Using polystyrene nanoparticles as a model system, we use flow cytometry and fluorescence microscopy to measure changes in membrane potential in response to nanoparticle binding to the plasma membrane. We find that nanoparticles with amine-modified surfaces lead to significant depolarization of both CHO and HeLa cells. In comparison, carboxylate modified nanoparticles do not cause depolarization. Mechanistic studies suggest that this nanoparticle-induced depolarization is the result of a physical blockage of the ion channels. These experiments show that nanoparticles can alter the biological system of interest in subtle, yet important, ways. PMID- 25685329 TI - Goal-directed therapy: what we know and what we need to know. AB - Goal-directed therapy (GDT) utilizes monitoring techniques to help guide clinicians with administering fluids, vasopressors, inotropes, or other treatments to patients in various clinical settings. Multiple studies have investigated the potential benefits of GDT, but no consensus on the use of GDT exists. Future trials which address fluid and inotrope choice as well as expanding the results to evaluate patient-centered outcomes in addition to survival are warranted. PMID- 25685331 TI - Ten recommendations for software engineering in research. AB - Research in the context of data-driven science requires a backbone of well written software, but scientific researchers are typically not trained at length in software engineering, the principles for creating better software products. To address this gap, in particular for young researchers new to programming, we give ten recommendations to ensure the usability, sustainability and practicality of research software. PMID- 25685330 TI - Clinical outcome of preimplantation genetic diagnosis and screening using next generation sequencing. AB - BACKGROUND: Next generation sequencing (NGS) is now being used for detecting chromosomal abnormalities in blastocyst trophectoderm (TE) cells from in vitro fertilized embryos. However, few data are available regarding the clinical outcome, which provides vital reference for further application of the methodology. Here, we present a clinical evaluation of NGS-based preimplantation genetic diagnosis/screening (PGD/PGS) compared with single nucleotide polymorphism (SNP) array-based PGD/PGS as a control. RESULTS: A total of 395 couples participated. They were carriers of either translocation or inversion mutations, or were patients with recurrent miscarriage and/or advanced maternal age. A total of 1,512 blastocysts were biopsied on D5 after fertilization, with 1,058 blastocysts set aside for SNP array testing and 454 blastocysts for NGS testing. In the NGS cycles group, the implantation, clinical pregnancy and miscarriage rates were 52.6% (60/114), 61.3% (49/80) and 14.3% (7/49), respectively. In the SNP array cycles group, the implantation, clinical pregnancy and miscarriage rates were 47.6% (139/292), 56.7% (115/203) and 14.8% (17/115), respectively. The outcome measures of both the NGS and SNP array cycles were the same with insignificant differences. There were 150 blastocysts that underwent both NGS and SNP array analysis, of which seven blastocysts were found with inconsistent signals. All other signals obtained from NGS analysis were confirmed to be accurate by validation with qPCR. The relative copy number of mitochondrial DNA (mtDNA) for each blastocyst that underwent NGS testing was evaluated, and a significant difference was found between the copy number of mtDNA for the euploid and the chromosomally abnormal blastocysts. So far, out of 42 ongoing pregnancies, 24 babies were born in NGS cycles; all of these babies are healthy and free of any developmental problems. CONCLUSIONS: This study provides the first evaluation of the clinical outcomes of NGS-based pre-implantation genetic diagnosis/screening, and shows the reliability of this method in a clinical and array-based laboratory setting. NGS provides an accurate approach to detect embryonic imbalanced segmental rearrangements, to avoid the potential risks of false signals from SNP array in this study. PMID- 25685332 TI - The birds of Genome10K. AB - Everyone loves the birds of the world. From their haunting songs and majesty of flight to dazzling plumage and mating rituals, bird watchers - both amateurs and professionals - have marveled for centuries at their considerable adaptations. Now, we are offered a special treat with the publication of a series of papers in dedicated issues of Science, Genome Biology and GigaScience (which also included pre-publication data release). These present the successful beginnings of an international interdisciplinary venture, the Avian Phylogenomics Project that lets us view, through a genomics lens, modern bird species and the evolutionary events that produced them. PMID- 25685333 TI - Multidrug-resistant tuberculosis in Ethiopia: efforts to expand diagnostic services, treatment and care. AB - The emergence of drug-resistant tuberculosis (TB), particularly multidrug resistant (MDR) and extensively drug-resistant (XDR) TB, is a major public health problem. The purpose of this review is to describe the current status of MDR-TB and factors that increase the risk of this infection. We conducted a systematic review of the literature on MDR-TB in Ethiopia. Out of 766 articles, 23 were found to meet eligibility criteria and included in this review. Among the 23 papers, six of them reported high prevalence of MDR-TB in the range of 3.3% 46.3%. Likewise, two studies reported XDR-TB in the range of 1% - 4.4% in Ethiopia. The most powerful predictor of the emergence of MDR-TB reported in Ethiopia is previous exposure to anti-TB drug treatment. This review indicated that MDR-TB in Ethiopia is a serious public health problem that needs to be addressed urgently. Strengthening early case detection and proper treatment of drug-susceptible TB in accordance with World Health Organization (WHO) treatment guidelines to ensure adequate treatment success rates is critical. Consequently, efforts have been made to a rapidly increase MDR-TB diagnosis as well as the number of treatment sites to implement a directly observed treatment, short course (DOTS) plus strategy to interrupt transmission of MDR-TB. PMID- 25685334 TI - Hand hygiene and aseptic techniques during routine anesthetic care - observations in the operating room. AB - BACKGROUND: More knowledge is needed about task intensity in relation to hand hygiene in the operating room during anesthetic care in order to choose effective improvement strategies. The aim of this study was to explore the indications and occurrence of hand hygiene opportunities and the adherence to hand hygiene guidelines during routine anesthetic care in the operating room. METHODS: Structured observational data on hand hygiene during anesthetic care during 94 surgical procedures was collected using the World Health Organization's observational tool in a surgical department consisting of 16 operating rooms serving different surgical specialties such as orthopedic, gynecological, urological and general surgery. RESULTS: A total of 2,393 opportunities for hand hygiene was recorded. The number of hand hygiene opportunities when measured during full-length surgeries was mean = 10.9/hour, SD 6.1 with an overall adherence of 8.1%. The corresponding numbers for the induction phase were, mean =77.5/h, SD 27.4 with an associated 3.1% adherence to hand hygiene guidelines. Lowest adherence was observed during the induction phase before an aseptic task (2.2%) and highest during full-length surgeries after body fluid exposure (15.9%). CONCLUSIONS: There is compelling evidence for low adherence to hand hygiene guidelines in the operating room and thus an urgent need for effective improvement strategies. The conclusion of this study is that any such strategy should include education and practical training in terms of how to carry out hand hygiene and aseptic techniques and how to use gloves correctly. Moreover it appears to be essential to optimize the work processes in order to reduce the number of avoidable hand hygiene opportunities thereby enhancing the possibilities for adequate use of HH during anesthetic care. PMID- 25685335 TI - Characteristics of language impairment in Parkinson's disease and its influencing factors. AB - BACKGROUND: Language impairment is relatively common in Parkinson's disease (PD), but not all PD patients are susceptible to language problems. In this study, we identified among a sample of PD patients those pre-disposed to language impairment, describe their clinical profiles, and consider factors that may precipitate language disability in these patients. METHODS: A cross-sectional cohort of 31 PD patients and 20 controls were administered the Chinese version of the Western Aphasia Battery (WAB) to assess language abilities, and the Montreal Cognitive Assessment (MoCA) to determine cognitive status. PD patients were then apportioned to a language-impaired PD (LI-PD) group or a PD group with no language impairment (NLI-PD). Performance on the WAB and MoCA was investigated for correlation with the aphasia quotient deterioration rate (AQDR). RESULTS: The PD patients scored significantly lower on most of the WAB subtests than did the controls. The aphasia quotient, cortical quotient, and spontaneous speech and naming subtests of the WAB were significantly different between LI-PD and NLI-PD groups. The AQDR scores significantly and positively correlated with age at onset and motor function deterioration. CONCLUSION: A subset group was susceptible to language dysfunction, a major deficit in spontaneous speech. Once established, dysphasia progression is closely associated with age at onset and motor disability progression. PMID- 25685336 TI - Case of intraperitoneal sepsis secondary to rupture of the appendix on the background of pseudomyxoma peritonei. AB - INTRODUCTION: Pseudomyxoma peritonei (PMP) is characterised by gelatinous ascites and pools of mucin associated with neoplastic mucinous epithelium within the peritoneal cavity. It can rarely present as acute intraperitoneal sepsis, requiring urgent medical attention. PRESENTATION OF CASE: A 59-year old male was referred to our centre in February 2014 following a diagnostic laparotomy, which showed jelly-like material with occasional epithelial cells. He was listed for peritonectomy in a month's time at our centre. Three weeks later, he was admitted urgently to our hospital due to generalised abdominal pain and watery diarrhoea. Examination at admission was unremarkable. On the following day, he became haemodynamically unstable and was suspected to have intraperitoneal sepsis due to infected PMP. At emergency laparotomy, we found gross intraperitoneal sepsis and did extensive debulking of tumour, appendectomy and extensive division of adhesions. Another laparotomy was done 24 h later for washout. He was discharged three weeks after. DISCUSSION: Although we have done 780 peritonectomy procedures, this was the first patient with this presentation of widerspread intraperitoneal sepsis. Continuous mucous production of appendiceal adenoma can lead to appendiceal rupture. The appendix may decompress by perforation and then reseal. However, one episode of appendiceal rupture can cause bacterial contamination of PMP, leading to sepsis. CONCLUSION: Intraperitoneal sepsis secondary to appendiceal rupture is rare. Hence surgeons may face an emergency of intraperitoneal sepsis during waiting period of planned CRS or as a primary presentation. With combined therapy of CRS and PIC, the prognosis of mucinous appendiceal adenoma is excellent. PMID- 25685337 TI - The preoperative evaluation prevent the postoperative complications of thyroidectomy. AB - OBJECTIVE: Thyroid surgery is generally a safe surgery but its complications are still common. We wish to identify preoperative factors that predict postoperative complications. METHODS: A nationwide survey was conducted by senior surgeons from 16 medical centers and 5 regional hospitals in Taiwan to thyroid operations performed over 3 years. 3846 cases were retrospectively examined to identify factors influencing complications: indication for surgery, preoperative evaluation, such as ultrasonography, chest X-ray, computed tomography and magnetic resonance imaging, isotope scanning, fine-needle aspiration cytology (FNAC) and thyroid function test, and patient characteristics. RESULTS: Eighty four percent of patients were female. Seven percent of the patients had immediate postoperative hypocalcemia (mild and severe) and 2.3%, hoarseness (recurrent laryngeal nerve (RLN) injury, temporary/permanent). Logistic regression analysis identified an association between hypocalcemia and RLN injury with age, hospital category, surgical procedure types (total thyroidectomy, unilateral, bilateral subtotal or total resection). A lower incidence of hypocalcemia was related to preoperative neck ultrasound and FNAC analysis (the odds ratio (OR) = 0.5 and 0.65, [95% confidence interval (CI) 0.331-0.768 and 0.459-0.911], P = 0.0014 and 0.0127, respectively), while RLN injury was not associated with any preoperative evaluation. The ORs of hypocalcemia and RLN injury for patients older than 50 years were 0.55 and 2.15, [0.393-0.763 and 1.356-3.4], P < 0.001 and 0.0012, respectively. CONCLUSIONS: The success of thyroid surgery depends on careful preoperative planning, including a preoperative neck ultrasound to determine the proximity of the nodule to the recurrent laryngeal nerve course, and the consideration of the type of anesthesia, adjuvant devices for intra-op monitoring of the RLN, and surgical modalities. Our results suggest that preoperative evaluation implementations are positively associated with strategy of surgery and postoperative hypocalcemia prevention. PMID- 25685338 TI - Patient factors may predict anastomotic complications after rectal cancer surgery: Anastomotic complications in rectal cancer. AB - PURPOSE: Anastomotic complications following rectal cancer surgery occur with varying frequency. Preoperative radiation, BMI, and low anastomoses have been implicated as predictors in previous studies, but their definitive role is still under review. The objective of our study was to identify patient and operative factors that may be predictive of anastomotic complications. METHODS: A retrospective review was performed on patients who had sphincter-preservation surgery performed for rectal cancer at a tertiary medical center between 2005 and 2011. RESULTS: 123 patients were included in this study, mean age was 59 (26-86), 58% were male. There were 33 complications in 32 patients (27%). Stenosis was the most frequent complication (24 of 33). 11 patients required mechanical dilatation, and 4 had operative revision of the anastomosis. Leak or pelvic abscess were present in 9 patients (7.3%); 4 were explored, 2 were drained and 3 were managed conservatively. 4 patients had permanent colostomy created due to anastomotic complications. Laparoscopy approach, BMI, age, smoking and tumor distance from anal verge were not significantly associated with anastomotic complications. After a multivariate analysis chemoradiation was significantly associated with overall anastomotic complications (Wall = 0.35, p = 0.05), and hemoglobin levels were associated with anastomotic leak (Wald = 4.09, p = 0.04). CONCLUSION: Our study identifies preoperative anemia as possible risk factor for anastomotic leak and neoadjuvant chemoradiation may lead to increased risk of complications overall. Further prospective studies will help to elucidate these findings as well as identify amenable factors that may decrease risk of anastomotic complications after rectal cancer surgery. PMID- 25685339 TI - Do surgery journals insist on reporting by CONSORT and PRISMA? A follow-up survey of 'instructions to authors'. AB - AIMS: Guidance has been published on how best to report randomised controlled trials (Consolidated Standards of Reporting Trials - CONSORT) and systematic reviews (Preferred Reporting Items for Systematic Reviews and Meta-analysis - PRISMA). In 2011, we reported a low rate of enforcement by surgery journals for submitted manuscripts to conform to these guidelines. The aim of this follow-up study is to establish whether there has been any improvement. METHODS: We studied the 134 surgery journals indexed in the Journal Citation Report. The 'Instructions to Authors' were scrutinised for inclusion of the following guidance: CONSORT, PRISMA, clinical trial registration and systematic review registration. RESULTS: Compared to 2011, there has been an improvement in the endorsement of reporting guidance in journals' 'Instructions to Authors' in 2014, as follows: trial registration (42% vs 33%), CONSORT (42% vs 30%) and PRISMA (19% vs 10%, all p < 0.001). As in 2011, journals with a higher impact were more likely to adopt trial registration (p < 0.001), CONSORT (p < 0.001) and PRISMA (p = 0.002). Journals with editorial offices in the UK were more likely to endorse guidance compared to those outside the UK (p < 0.05). Only one journal mentioned registration for systematic reviews. CONCLUSIONS: Surgery journals are presently more likely to require submitted manuscripts to follow published reporting guidance compared to three years ago. However, overall concordance rates are still low, and an improvement is required to help enhance the quality of reporting - and ultimately the conduct - of randomised control trials and systematic reviews in surgery. PMID- 25685340 TI - Health-Related Quality-of-Life in a cohort undergoing cholecystectomy. AB - INTRODUCTION: Patient-related outcome measures are crucial when assessing outcome from surgical intervention registers. The aim of this study was to analyse what factors affect Health-Related Quality of Life (HRQoL) in patients undergoing cholecystectomy, and to assess the feasibility of SF-36 as a HRQoL instrument in a patient register. METHODS: The SF-36 questionnaire was distributed to patients preoperatively and 6-9 months after surgery. The outcome of patients who had undergone planned surgery between January 1, 2010 and June 30, 2011 at six units, with response rates of at least 100 per year, formed the basis for the present study. Expected outcome from a background population was determined from a Swedish cohort assembled previously. RESULTS: Altogether 919 patients (646 women, 273 men) at the six units answered the questionnaire. Mean age was 52 years, standard deviation 15 years. Preoperatively, the surgery cohort rated lower on all subscales of the SF-36 than the age- and gender-matched background population. Postoperatively, they did not rate lower in any of the subscales. High age was associated with a significantly lower increase in bodily pain and Physical Component Summary (both p < 0.05). Open surgery was associated with a significantly lower increase in the Physical Component Summary (p < 0.05). DISCUSSION: Regardless of indication for surgery, high age is associated with less benefit from surgery according to this questionnaire study. SF-36 is appropriate for measuring the impact of gallstone surgery on HRQoL. PMID- 25685341 TI - Atypical presentation of congenital cholesteatoma in an adult case with good hearing result. AB - INTRODUCTION: Congenital cholesteatoma is thought to be caused by inadequate folding of the epidermoid formation inside the middle ear cleft. During development of the middle ear mucosa, stratified squamous epithelium accumulates in the embryonic life. Its typical appearance is a "pearl" beneath the anterosuperior quadrant of the tympanic membrane. PRESENTATION OF CASE: We report 28 years-old case with congenital cholesteatoma in the posterosuperior quadrant of middle ear cavity. The main complaint was the hearing loss which had developed slowly over several years. DISCUSSION: The case was surgically treated. Postoperative hearing result was satisfactory. CONCLUSION: Congenital cholesteatoma may occur in atypical locations and ages. Many authors prefer canal wall down tympanomastoidectomy. But it can also be treated successfully by intact canal wall tympanomastoidectomy with good hearing results. PMID- 25685342 TI - Induction of continuous expanding infrarenal aortic aneurysms in a large porcine animal model. AB - BACKGROUND: A large animal model with a continuous expanding infrarenal aortic aneurysm gives access to a more realistic AAA model with anatomy and physiology similar to humans, and thus allows for new experimental research in the natural history and treatment options of the disease. METHODS: 10 pigs (group A) underwent infrarenal aortic dissection, balloon dilatation, infusion of elastase into the lumen and placement of a stenosing cuff around the aorta. 10 control pigs (group B) underwent a sham procedure. The subsequent 28 days the AP diameters of the aneurysms were measured using ultrasound, hereafter the pigs were euthanized for inspection and AAA wall sampling for histological analysis. RESULTS: In group A, all pigs developed continuous expanding AAA's with a mean increase in AP-diameter to 16.26 +/- 0.93 mm equivalent to a 57% increase. In group B the AP-diameters increased to 11.33 +/- 0.13 mm equivalent to 9.3% which was significantly less than in group A (p < 0.001). In group A, a significant negative association between the preoperative weight and the resulting AP diameters was found. Histology shoved more or less complete resolution of the elastic tissue in the tunica media in group A. The most frequent complication was a neurological deficit in the lower limbs. CONCLUSION: In pigs it's possible to induce continuous expanding AAA's based upon proteolytic degradation and pathological flow, resembling the real life dynamics of human aneurysms. Because the lumbars are preserved, it's also a potential model for further studies of novel endovascular devices and their complications. PMID- 25685343 TI - Gastrointestinal surgery and the acquired immune deficiency syndrome. AB - Acquired immune-deficiency syndrome (AIDS) is becoming an increasing problem to the surgeon. The impact of HIV/AIDS on surgical practice include the undoubted risk to which the surgeon will expose him or herself, the atypical conditions that may be encountered and the outcome and long term benefit of the surgical treatment in view of disease progression. The two factors most associated with surgical outcome and poor wound healing were AIDS and poor performance status (ASA score). This article questions whether gastrointestinal surgical procedures can be safe and effective therapeutic measures in HIV/AIDS patients and if surgical outcome is worthy of the surgeon's ethical responsibility to treat. As HIV/AIDS patients are not a homogeneous group, with careful patient selection, emergency laparotomy for peritonitis confers worthwhile palliation. However, aggressive surgical intervention must be undertaken with caution and adequate peri-operative care is required. Symptomatic improvement of anorectal pathology may make delayed wound healing an acceptable complication. Alternatives to surgery can be contemplated for diagnosis, prophylaxis or palliation. PMID- 25685344 TI - Abdominal trauma by ostrich. AB - INTRODUCTION: Ostriches typically avoid humans in the wild, since they correctly assess humans as potential predators, and, if approached, often run away. However, ostriches may turn aggressive rather than run when threatened, especially when cornered, and may also attack when they feel the need to defend their offspring or territories. PRESENTATION OF CASE: A 71-year-old male patient presented with intra abdominal injury sustained from being kicked in the abdominal wall by an ostrich. During laparotomy, were found free peritoneal effusion and perforation of the small intestine. DISCUSSION: The clinical history and physical examination are extremely important for diagnostic and therapeutic decision making. CT-scan is the most accurate exam for making diagnosis. Surgery is the treatment of choice, and is always indicated when there is injury to the hollow viscera. In general it is possible to suture the defect. CONCLUSION: In cases of blunt abdominal trauma by animals is necessary to have a low threshold of suspicion for acute abdomen. PMID- 25685345 TI - Revisiting closure options for heavily irradiated tissue following Mohs excision: A case report and review of literature. AB - INTRODUCTION: Squamous cell carcinoma is a cancer of the squamous cells of the epithelium, often treated with radiation therapy or surgical resection. Patients who undergo Mohs excision on the face are left with defects that require thoughtful reconstruction, especially if previously treated with radiotherapy. CASE PRESENTATION: We report a patient who suffered from squamous cell carcinoma of the skin overlying his right cheek. After receiving upwards of 10,000 cGY of radiotherapy, he underwent Mohs excision. Despite conventional therapy protocols, which would normally consist of a free-tissue transfer, a successful rhomboid flap was performed to cover the defect. DISCUSSION: Conventional reconstruction of a previously irradiated area would consist of using non-irradiated tissue. Data on whether such a large, heavily irradiated defect of the face could be repaired using a local flap is practically non-existent. CONCLUSION: This case demonstrates that a local flap can still be successful even with large facial defects and previously radiation therapy, sparing the patient from free-tissue transfer and its possible complications, while leaving the option of a free tissue transfer available in case of flap failure. This case serves as a reminder that local flaps are still viable options for such defects. PMID- 25685346 TI - Assessment of research productivity of Arab countries in the field of infectious diseases using Web of Science database. AB - BACKGROUND: To meet the future challenges of infectious diseases and limit the spread of multidrug resistant microorganisms, a better understanding of published studies in the field of infectious diseases is needed. The objective of this study was to analyze the quantity and quality of research activity in the field of infectious diseases in Arab countries and compare it with that in non-Arab countries. METHODS: Documents published in Arab countries within the research category of "infectious diseases" were extracted and analyzed using the Web of Science database. The data analyzed represent research productivity during the time interval between 1900 - 2012. RESULTS: Worldwide, the total number of documents published in the field of infectious diseases up to 2012 was 227,188. A total of 2,408 documents in the field of infectious diseases were published in Arab countries, which represents 1.06% of worldwide research output. Research output from Arab countries in the field of infectious diseases was low for decades. However, approximately a five-fold increase was observed in the past decade. Arab countries ranked 56(th) to 218(th) on the standard competition ranking (SCR) in worldwide publications in the field of infectious diseases. Egypt, with a total publication of 464 (19.27%) documents ranked first among Arab countries, while Kuwait University was the most productive institution with a total of 158 (6.56%) documents. Average citation per document published in Arab countries was 13.25 and the h-index was 64. Tuberculosis (230; 9.55%), malaria (223; 9.26%), and hepatitis (189; 7.8%) were the top three infectious diseases studied as according to the retrieved documents. CONCLUSION: The present data reveals that some Arab countries contribute significantly to the field of infectious diseases. However, Arab countries need to work harder to bridge the gap in this field. Compared with non-Arab countries in the Middle East, research output from Arab countries was high, but more efforts are needed to enhance the quality of this output. Future research in the field should be encouraged and correctly directed. PMID- 25685347 TI - Incidence of human rabies exposure and associated factors at the Gondar Health Center, Ethiopia: a three-year retrospective study. AB - BACKGROUND: Rabies is one of the oldest known and most feared human diseases. Epidemiological studies provide basic information about the burden of the disease and underline the importance of prevention and control interventions. However, there have been limited studies conducted regarding the incidence of rabies and associated factors in Ethiopia, in general, and in this study area, in particular. Therefore, the aim of this study was to assess the incidence of human rabies exposure and associated factors at the Gondar Health Center, Ethiopia. METHODS: A retrospective cross-sectional study was conducted at the Gondar Health Center where post-exposure prophylaxis (PEP) for rabies was available for the whole population in the North Gondar Zone catchment area. Data of human rabies exposure cases between 2011 and 2013 were collected from the rabies PEP registration book using data abstraction sheets. The data was entered and analyzed using SPSS version 16 statistical software. RESULT: A total of 261 cases of human rabies exposure were reported to the Gondar Health Center from 2011 to 2013. The sex and age specific distribution showed that the majority of these cases were among males (142/226, 62.8%) and children under 15 years of age (87/226, 38.5%). A predominant number of cases were observed in individuals from rural areas (161/220, 73.2%), and during fall and winter seasons (67/222, 30.18%). A significant number of people exposed to rabies (23.2%) came to the health center for PEP two or more weeks after the injury. The incidence of human rabies exposure cases was 4.6, 2.61, and 1.27 per 100, 000 population in 2011, 2012, and 2013, respectively. Being male and living in an urban setting were found to be risk factors for human rabies exposure in 2011. CONCLUSION: A significant number of human rabies exposure cases were reported to the Gondar Health Center. Being male and living in an urban setting were found to be associated with rabies exposure. A community-based follow-up study is recommended to more accurately estimate the incidence of human rabies exposure. PMID- 25685348 TI - Ebola wreaks havoc in Sierra Leone. AB - BACKGROUND: Ebola virus disease has taken a toll on more than 8,000 lives in West Africa in 2014. The most affected countries are Guinea, Liberia, and Sierra Leone. The number of people infected by Ebola in Sierra Leone surpassed that of Liberia in the last month in this year and almost half of human cases are distributed in this country. DISCUSSION: The ignorance on Ebola among people, including health workers at the early stage, plaid an important role in spread of Ebola virus disease. Subsequently, Ebola ravages urban settings for the first time and takes a huge toll on the lives. The government and international partners do make efforts to control the epidemic, however, lack of synergy make them lip service. SUMMARY: The leading role of government in the response to the epidemic should be emphasized. Basic information of Ebola should be quickly spread among communities by health education programme and social mobilization should be a basic measure for Ebola control. PMID- 25685349 TI - Family-based treatment with transition age youth with anorexia nervosa: a qualitative summary of application in clinical practice. AB - BACKGROUND: Family based treatment (FBT) has been empirically investigated in adolescents between the ages of 12 and 19 years of age. Although parental control over eating symptoms and the weight gain process are temporary and necessary due to serious medical complications, FBT may be developmentally inappropriate when working with older adolescents. To date, there are no studies identifying how the principles of this model are used differentially across different stages of adolescence. This study aimed to identify how clinicians informed by FBT employ this model with transition age youth (TAY) (16-21) with an eating disorder. METHODS: Using content analysis, seven individual interviews and six focus groups were conducted with 34 clinicians from specialized Eating Disorder Treatment programs across Ontario, Canada. RESULTS: Participants consistently reported modifying FBT to increase its developmental appropriateness with TAY in the following ways: working more collaboratively with the patient, increasing individual time spent with the patient prior to the family meeting, providing greater opportunities for the individual to practice eating without parental support and introducing relapse prevention in the latter phase of the treatment. CONCLUSIONS: In all adaptations of the model, participants in focus groups and individual interviews cited the age of the individual with the eating disorder, their level of autonomy and independence in all areas of their lives, and their pending transfer of care from paediatric to adult eating disorder programs as main factors that influenced the modification of FBT with TAY. While adaptations were made across all three phases of FBT, adherence to the model progressively declined over the course of treatment with adaptations increasing significantly in the later phases. Future research is needed to evaluate the effectiveness of an adapted version of FBT with TAY. PMID- 25685350 TI - Student-teacher relationship trajectories and mental health problems in young children. AB - BACKGROUND: This longitudinal study classified groups of children experiencing different trajectories of student-teacher relationship quality over the transition from preschool into school, and determined the strength of the association between different student-teacher relationship trajectories and childhood mental health problems in the second year of primary school. METHODS: A community sample of 460 Australian children were assessed in preschool (age 4), the first school year (age 5), and second school year (age 6). Teachers at all three assessments reported on student-teacher relationship quality with the Student Teacher Relationship Scale. When the children were at preschool and in their second school year, parents and teachers rated children's mental health problems using the Strengths and Difficulties Questionnaire. RESULTS: Latent class growth modelling identified two trajectories of student-teacher relationship quality: (1) a stable-high student-teacher relationship quality and (2) a moderate/declining student-teacher relationship quality trajectory. Generalised linear models found that after adjusting for family demographic characteristics, having a stable high quality student-teacher relationship trajectory was associated with fewer parent-rated and teacher-rated total mental health problems, and fewer conduct, hyperactivity, and peer problems, and greater prosocial behaviour at age 6. A stable high quality trajectory was also associated with fewer teacher-rated, but not parent-rated emotional symptoms. These effects remained after adjustment for levels of mental health problems at age 4. CONCLUSIONS: Findings suggest that early intervention and prevention strategies that focus on building stable high quality student-teacher relationships during preschool and children's transition into formal schooling, may help reduce rates of childhood mental health problems during the early school years. PMID- 25685351 TI - Adaptation and testing of psychosocial assessment instruments for cross-cultural use: an example from the Thailand Burma border. AB - BACKGROUND: The purpose of this study was to develop valid and reliable instruments to assess priority psychosocial problems and functioning among adult survivors of systematic violence from Burma living in Thailand. METHODS: The process involved four steps: 1) instrument drafting and piloting; 2) reliability and validity testing; 3) instrument revision; and 4) retesting revised instrument. RESULTS: A total of N = 158 interviews were completed. Overall subscales showed good internal consistency (0.73-0.92) and satisfactory combined test-retest/inter rater reliability (0.63-0.84). Criterion validity, was not demonstrated for any scale. The alcohol and functioning scales underperformed and were revised (step 3) and retested (step 4). Upon retesting, the function scale showed good internal consistency reliability (0.91-0.92), and the alcohol scale showed acceptable internal consistency (0.79) and strong test-retest/inter-rater reliability (0.86-0.89). CONCLUSIONS: This paper describes the importance and process of adaptation and testing, illustrated by the experiences and results for selected instruments in this population. PMID- 25685352 TI - Test-retest reliability of Common Mental Disorders Questionnaire (CMDQ) in patients with total hip replacement (THR). AB - BACKGROUND: The Common Mental Disorders Questionnaire (CMDQ) is used to assess patients' mental health. It has previously been shown to provide a sensitive and specific instrument for general practitioner setting but has so far not been tested in hospital setting or for changes over time (test-retest). The aim of this study is, by means of a test-retest method, to investigate the reliability of the instrument over time with total hip replacement (THR) patients. METHODS: Forty-nine hip osteoarthritis patients who had undergone THR answered the questionnaire twelve months after their operation. Fourteen days later they completed it again. Covering emotional disorder, anxiety, depression, concern, somatoform disorder and alcohol abuse, the questionnaire consists of 38 items with six subscales, each of which has between 4 to 12 items. A five-point Likert scale (from 0-4) is used. RESULTS: For each of the 38 questions, a quadratic weighted Kappa coefficient of 0.42 (0.68 - 0.16) to 0.98 (1.00 - 0.70) was found. A Cronbach's alpha of 0.94 for all the questions indicated high internal consistency. CONCLUSION: The results showed a moderate to almost perfect reliability of CMDQ of this specific population. TRIAL REGISTRATION: Current Controlled Trials: NCT01205295. PMID- 25685353 TI - Study protocol: psychological and physiological consequences of exposure to mass media in young women - an experimental cross-sectional and longitudinal study and the role of moderators. AB - BACKGROUND: Repeated exposure to thin beauty ideals is part of the daily routine. Exposure to thin ideals via mass media plays an important role in the development and maintenance of eating disorders (EDs), low self-esteem, depressive or anxious feelings in young females. It is important to elucidate the circumstances under which exposure to thin ideals develops its detrimental impact and to investigate whether these features are more pronounced in EDs than in other mental disorders also related to negative body image. METHODS/DESIGN: We investigate the following key questions: (1) Does laboratory induced exposure to thin ideals (waiting room design) relate to impairments in terms of body image, affect and eating behavior and biological stress response (salivary alpha-amylase, salivary cortisol, heart rate and heart rate variability) in 18 to 35 year old female suffering from anorexia and bulimia nervosa (AN, BN) compared to female healthy controls and to a sample of females suffering from mixed mental disorders (depression, anxiety and somatic symptom disorder (SSD) disorders)? (2) How do moderators such as cognitive distortions ("Thought-Shape Fusion, TSF"), and correlates of emotion regulation (ER) moderate the influence of the exposure? (3) Are these characteristics amenable to change after treatment? Altogether 250 female participants including patients with AN, BN, depressive, anxiety and SSD disorders, and healthy women will be recruited in Switzerland and Germany. DISCUSSION: The findings will provide knowledge about the role of moderators influencing the effects of exposure to thin ideals promoted by mass media in eating disorder (ED) patients, patients suffering from mixed mental disorders and healthy controls. Evaluating their differential susceptibility will contribute to a better understanding of the role of negative body image in the maintenance of not only symptoms of ED, but also of depression, anxiety and SSD. Additionally our results will shed light on the stability of effects in healthy controls as well as in the patient groups before and after treatment as usual. Findings foster the development of tailored interventions including a training in specific ER strategies as well as cognitive restructuring of distorted beliefs about the own body when confronted with thin ideals. TRIAL REGISTRATION: German Clinical Trials Register: DRKS00005709. Date of registration: 6(th) of February, 2014. PMID- 25685355 TI - Translation and cultural adaptation of the Illness Invalidation Inventory for use in Sweden. AB - BACKGROUND: This study describes the translation and cultural adaptation procedure and guidelines for the Illness Invalidation Inventory for use in Sweden. Invalidation includes responses to negative social interactions and to the lack of positive social interactions, responses that can negatively affect health and suffering. Although invalidation is a recognized phenomenon, in Sweden no instruments exist that describe and measure invalidation. To this end, this study evaluates the translation and adaptation of the Illness Invalidation Inventory as an instrument for measuring invalidation in a Swedish context. METHODS: Internationally recognized ten-step guidelines were used. Both forward and back translations were performed. Patients from a patient organization for chronic pain were recruited and cognitive interviews were performed using concurrent think aloud protocols, probing techniques and observations of behaviour. Analysis of data collected from cognitive interviews was inspired by the generic response model and a centralized review procedure and thorough documentation was emphasized. RESULTS: Although difficulties regarding concepts were found, these issues were solved during the process. The Swedish version contains the same number of items as the original questionnaire. Four of eight items required revision after cognitive interviews. CONCLUSIONS: The study highlights the importance of using guidelines to produce translations and to ensure validity and results. The results indicate that the Illness Invalidation Inventory can be used in Sweden to measure invalidation. PMID- 25685354 TI - Short-term efficacy of repetitive transcranial magnetic stimulation (rTMS) in depression- reanalysis of data from meta-analyses up to 2010. AB - BACKGROUND: According to a narrative review of 13 meta-analyses (published up to 2010), repetitive transcranial magnetic stimulation (rTMS) has a moderate, short term antidepressant effect in the treatment of major depression. The aim of the current study was to reanalyse the data from these 13 meta-analyses with a uniform meta-analytical procedure and to investigate predictors of such an antidepressant response. METHODS: A total of 40 double-blind, randomised, sham controlled trials with parallel designs, utilising rTMS of the dorsolateral prefrontal cortex in the treatment of major depression, was included in the current meta-analysis. The studies were conducted in 15 countries on 1583 patients and published between 1997-2008. Depression severity was measured using the Hamilton Depression Rating Scale, Beck Depression Inventory, or Montgomery Asberg Depression Rating Scale at baseline and after the last rTMS. A random effects model with the inverse-variance weights was used to compute the overall mean weighted effect size, Cohen's d. RESULTS: There was a significant and moderate reduction in depression scores from baseline to final, favouring rTMS over sham (overall d = -.54, 95% CI: -.68, -.41, N = 40 studies). Predictors of such a response were investigated in the largest group of studies (N = 32) with high-frequency (>1 Hz) left (HFL) rTMS. The antidepressant effect of HFL rTMS was present univariately in studies with patients receiving antidepressants (at stable doses or started concurrently with rTMS), with treatment-resistance, and with unipolar (or bipolar) depression without psychotic features. Univariate meta regressions showed that depression scores were significantly lower after HFL rTMS in studies with higher proportion of female patients. There was little evidence for publication bias in the current analysis. CONCLUSIONS: Daily rTMS (with any parameters) has a moderate, short-term antidepressant effect in studies published up to 2008. The clinical efficacy of HFL rTMS may be better in female patients not controlling for any other study parameters. PMID- 25685356 TI - The relationship between trait empathy and memory formation for social vs. non social information. AB - BACKGROUND: To navigate successfully through their complex social environment, humans need both empathic and mnemonic skills. Little is known on how these two types of psychological abilities relate to each other in humans. Although initial clinical findings suggest a positive association, systematic investigations in healthy subject samples have not yet been performed. Differentiating cognitive and affective aspects of empathy, we assumed that cognitive empathy would be positively associated with general memory performance, while affective empathy, due to enhanced other-related emotional reactions, would be related to a relative memory advantage for information of social as compared to non-social relevance. METHODS: We investigated in young healthy participants the relationship between dispositional cognitive and affective empathy, as measured by Davis' Interpersonal Reactivity Index (Journal of Personality and Social Psychology, 44, 113-126, 1983), and memory formation for stimuli (numbers presented in a lottery choice task) that could be encoded in either a social (other-related) or a non social (self-related) way within the task. RESULTS: Cognitive empathy, specifically perspective taking, correlated with overall memory performance (regardless of encoding condition), while affective empathy, specifically empathic personal distress, predicted differential memory for socially vs. non socially encoded information. CONCLUSION: Both cognitive and affective empathy are associated with memory formation, but in different ways, depending on the social nature of the memory content. These results open new and so far widely neglected avenues of psychological research on the relationship between social and cognitive skills. PMID- 25685357 TI - Inhibition of atherosclerosis-promoting microRNAs via targeted polyelectrolyte complex micelles. AB - Polyelectrolyte complex micelles have great potential as gene delivery vehicles because of their ability to encapsulate charged nucleic acids forming a core by neutralizing their charge, while simultaneously protecting the nucleic acids from non-specific interactions and enzymatic degradation. Furthermore, to enhance specificity and transfection efficiency, polyelectrolyte complex micelles can be modified to include targeting capabilities. Here, we describe the design of targeted polyelectrolyte complex micelles containing inhibitors against dys regulated microRNAs (miRNAs) that promote atherosclerosis, a leading cause of human mortality and morbidity. Inhibition of dys-regulated miRNAs in diseased cells associated with atherosclerosis has resulted in therapeutic efficacy in animal models and has been proposed to treat human diseases. However, the non specific targeting of microRNA inhibitors via systemic delivery has remained an issue that may cause unwanted side effects. For this reason, we incorporated two different peptide sequences to our miRNA inhibitor containing polyelectrolyte complex micelles. One of the peptides (Arginine-Glutamic Acid-Lysine-Alanine or REKA) was used in another micellar system that demonstrated lesion-specific targeting in a mouse model of atherosclerosis. The other peptide (Valine Histidine-Proline-Lysine-Glutamine-Histidine-Arginine or VHPKQHR) was identified via phage display and targets vascular endothelial cells through the vascular cell adhesion molecule-1 (VCAM-1). In this study we have tested the in vitro efficacy and efficiency of lesion- and cell-specific delivery of microRNA inhibitors to the cells associated with atherosclerotic lesions via peptide targeted polyelectrolyte complex micelles. Our results show that REKA-containing micelles (fibrin-targeting) and VHPKQHR-containing micelles (VCAM-1 targeting) can be used to carry and deliver microRNA inhibitors into macrophages and human endothelial cells, respectively. Additionally, the functionality of miRNA inhibitors in cells was demonstrated by analyzing miRNA expression as well as the expression or the biological function of its downstream target protein. Our study provides the first demonstration of targeting dys-regulated miRNAs in atherosclerosis using targeted polyelectrolyte complex micelles and holds promising potential for translational applications. PMID- 25685358 TI - Reduction in Thrombosis and Bacterial Adhesion with 7 Day Implantation of S Nitroso-N-acetylpenicillamine (SNAP)-Doped Elast-eon E2As Catheters in Sheep. AB - Thrombosis and infection are two common problems associated with blood-contacting medical devices such as catheters. Nitric oxide (NO) is known to be a potent antimicrobial agent as well as an inhibitor of platelet activation and adhesion. Healthy endothelial cells that line the inner walls of all blood vessels exhibit a NO flux of 0.5~4*10-10 mol cm-2 min-1 that helps prevent thrombosis. Materials with a NO flux that is equivalent to this level are expected to exhibit similar anti-thrombotic properties. In this study, NO-releasing catheters were fabricated by incorporating S-nitroso-N-acetylpenicillamine (SNAP) in the Elast-eon E2As polymer. The SNAP/E2As catheters release physiological levels of NO for up to 20 d, as measured by chemiluminescence. Furthermore, SNAP is stable in the E2As polymer, retaining 89% of the initial SNAP after ethylene oxide (EO) sterilization. The SNAP/E2As and E2As control catheters were implanted in sheep veins for 7 d to examine the effect on thrombosis and bacterial adhesion. The SNAP/E2As catheters reduced the thrombus area when compared to the control (1.56 +/- 0.76 and 5.06 +/- 1.44 cm2, respectively). A 90% reduction in bacterial adhesion was also observed for the SNAP/E2As catheters as compared to the controls. The results suggest that the SNAP/E2As polymer has the potential to improve the hemocompatibility and bactericidal activity of intravascular catheters, as well as other blood-contacting medical devices (e.g., vascular grafts, extracorporeal circuits). PMID- 25685359 TI - Response to Letter to the Editor regarding 'establishing advanced practice for medical imaging in New Zealand' PMID- 25685360 TI - High sensitivity C reactive protein as a prognostic marker in patients with mild to moderate aortic valve stenosis during lipid-lowering treatment: an SEAS substudy. AB - AIMS: To assess the prognostic importance of high-sensitive C reactive protein (hsCRP) in patients with mild to moderate aortic valve stenosis during placebo or simvastatin/ezetimibe treatment in Simvastatin and Ezetimibe in Aortic Stenosis (SEAS). METHODS AND RESULTS: In 1620 SEAS patients, we measured lipids and hsCRP at baseline and after 1 year of treatment and registered during 4 years of follow up major cardiovascular events (MCE) composed of ischaemic cardiovascular events (ICE) and aortic valve-related events (AVE). Simvastatin/ezetimibe reduced low density lipoprotein cholesterol (3.49 (2.94 to 4.15) to 1.32 (1.02 to 1.69) vs 3.46 (2.92 to 4.08) to 3.34 (2.81 to 3.92) mmol/L) and hsCRP (2.1 (0.9 to 4.1) to 1.2 (0.6 to 2.4) vs 2.2 (0.9 to 4.9) to 1.8 (0.85 to 4.35) mg/L, all p<0.05) during the first year of treatment. In multivariable Cox regression analysis adjusting for traditional risk factors and baseline hsCRP, ICE was associated with a 1-year increase of hsCRP (HR=1.19 (95% CI 1.12 to 1.25), p<0.001) but not with active treatment (HRTreatment=0.86 (0.67 to 1.13), p=0.28). Patients in the top quartile of baseline hsCRP versus the rest were associated with a higher risk of MCE (HR=1.34(1.09 to 1.64), p=0.02). The prognostic benefit of reduction in hsCRP after 1 year was significantly larger (p<0.01 for interaction) in patients with high versus low baseline hsCRP; hence, a reduction in hsCRP abolished the difference in incidence of MCE between high versus low baseline hsCRP in patients with reduced hsCRP (31.1 vs 31.9%, NS) in contrast to patients with increased hsCRP. CONCLUSIONS: The treatment-associated reduction in ICE was in part related to a reduction in hsCRP but not in lipids. hsCRP reduction was associated with less MCE, especially in patients with high baseline hsCRP. TRIAL REGISTRATION: NCT00092677. PMID- 25685361 TI - Exercise-based rehabilitation for heart failure: systematic review and meta analysis. AB - OBJECTIVE: To update the Cochrane systematic review of exercise-based cardiac rehabilitation (CR) for heart failure. METHODS: A systematic review and meta analysis of randomised controlled trials was undertaken. MEDLINE, EMBASE and the Cochrane Library were searched up to January 2013. Trials with 6 or more months of follow-up were included if they assessed the effects of exercise interventions alone or as a component of comprehensive CR programme compared with no exercise control. RESULTS: 33 trials were included with 4740 participants predominantly with a reduced ejection fraction (<40%) and New York Heart Association class II and III. Compared with controls, while there was no difference in pooled all cause mortality between exercise CR with follow-up to 1 year (risk ratio (RR) 0.93; 95% CI 0.69 to 1.27, p=0.67), there was a trend towards a reduction in trials with follow-up beyond 1 year (RR 0.88; 0.75 to 1.02, 0.09). Exercise CR reduced the risk of overall (RR 0.75; 0.62 to 0.92, 0.005) and heart failure specific hospitalisation (RR 0.61; 0.46 to 0.80, 0.0004) and resulted in a clinically important improvement in the Minnesota Living with Heart Failure questionnaire (mean difference: -5.8 points, -9.2 to -2.4, 0.0007). Univariate meta-regression analysis showed that these benefits were independent of the type and dose of exercise CR, and trial duration of follow- up, quality or publication date. CONCLUSIONS: This updated Cochrane review shows that improvements in hospitalisation and health-related quality of life with exercise-based CR appear to be consistent across patients regardless of CR programme characteristics and may reduce mortality in the longer term. An individual participant data meta analysis is needed to provide confirmatory evidence of the importance of patient subgroup and programme level characteristics (eg, exercise dose) on outcome. PMID- 25685362 TI - Underuse of an invasive strategy for patients with diabetes with acute coronary syndrome: a nationwide study. AB - BACKGROUND: Guidelines recommend an early invasive strategy for patients with diabetes with acute coronary syndromes (ACS). We investigated if patients with diabetes with ACS are offered coronary angiography (CAG) and revascularisation to the same extent as patients without diabetes. METHODS AND RESULTS: The study is a nationwide cohort study linking Danish national registries containing information on healthcare. The study population comprises all patients hospitalised with first-time ACS in Denmark during 2005-2007 (N=24 952). Diabetes was defined as claiming of a prescription for insulin and/or oral hypoglycaemic agents within 6 months prior to the ACS event. Diabetes was present in 2813 (11%) patients. Compared with patients without diabetes, patients with diabetes were older (mean 69 vs 67 years, p<0.0001), less often males (60% vs 64%, p=0.0001) and had more comorbidity. Fewer patients with diabetes underwent CAG: cumulative incidence 64% vs 74% for patients without diabetes, HR=0.72 (95% CI 0.69 to 0.76, p<0.0001); adjusted for age, sex, previous revascularisation and comorbidity HR=0.78 (95% CI 0.74 to 0.82, p<0.0001). More patients with diabetes had CAG showing two-vessel or three-vessel disease (53% vs 38%, p<0.0001). However, revascularisation after CAG revealing multivessel disease was less likely in patients with diabetes (multivariable adjusted HR=0.76, 95% CI 0.68 to 0.85, p<0.0001). CONCLUSIONS: In this nationwide cohort of patients with incident ACS, patients with diabetes were found to be less aggressively managed by an invasive treatment strategy. The factors underlying the decision to defer an invasive strategy in patients with diabetes are unclear and merit further investigation. PMID- 25685363 TI - Evidence from randomised controlled trials did not support the introduction of dietary fat guidelines in 1977 and 1983: a systematic review and meta-analysis. AB - OBJECTIVES: National dietary guidelines were introduced in 1977 and 1983, by the US and UK governments, respectively, with the ambition of reducing coronary heart disease (CHD) by reducing fat intake. To date, no analysis of the evidence base for these recommendations has been undertaken. The present study examines the evidence from randomised controlled trials (RCTs) available to the US and UK regulatory committees at their respective points of implementation. METHODS: A systematic review and meta-analysis were undertaken of RCTs, published prior to 1983, which examined the relationship between dietary fat, serum cholesterol and the development of CHD. RESULTS: 2467 males participated in six dietary trials: five secondary prevention studies and one including healthy participants. There were 370 deaths from all-cause mortality in the intervention and control groups. The risk ratio (RR) from meta-analysis was 0.996 (95% CI 0.865 to 1.147). There were 207 and 216 deaths from CHD in the intervention and control groups, respectively. The RR was 0.989 (95% CI 0.784 to 1.247). There were no differences in all-cause mortality and non-significant differences in CHD mortality, resulting from the dietary interventions. The reductions in mean serum cholesterol levels were significantly higher in the intervention groups; this did not result in significant differences in CHD or all-cause mortality. Government dietary fat recommendations were untested in any trial prior to being introduced. CONCLUSIONS: Dietary recommendations were introduced for 220 million US and 56 million UK citizens by 1983, in the absence of supporting evidence from RCTs. PMID- 25685364 TI - Acarbose, lente carbohydrate, and prebiotics promote metabolic health and longevity by stimulating intestinal production of GLP-1. AB - The alpha-glucosidase inhibitor acarbose, which slows carbohydrate digestion and blunts postprandial rises in plasma glucose, has long been used to treat patients with type 2 diabetes or glucose intolerance. Like metformin, acarbose tends to aid weight control, postpone onset of diabetes and decrease risk for cardiovascular events. Acarbose treatment can favourably affect blood pressure, serum lipids, platelet aggregation, progression of carotid intima-media thickness and postprandial endothelial dysfunction. In mice, lifetime acarbose feeding can increase median and maximal lifespan-an effect associated with increased plasma levels of fibroblast growth factor 21 (FGF21) and decreased levels of insulin like growth factor-I (IGF-I). There is growing reason to suspect that an upregulation of fasting and postprandial production of glucagon-like peptide-1 (GLP-1)-stemming from increased delivery of carbohydrate to L cells in the distal intestinal tract-is largely responsible for the versatile health protection conferred by acarbose. Indeed, GLP-1 exerts protective effects on vascular endothelium, the liver, the heart, pancreatic beta cells, and the brain which can rationalise many of the benefits reported with acarbose. And GLP-1 may act on the liver to modulate its production of FGF21 and IGF-I, thereby promoting longevity. The benefits of acarbose are likely mimicked by diets featuring slowly-digested 'lente' carbohydrate, and by certain nutraceuticals which can slow carbohydrate absorption. Prebiotics that promote colonic generation of short-chain fatty acids represent an alternative strategy for boosting intestinal GLP-1 production. The health benefits of all these measures presumably would be potentiated by concurrent use of dipeptidyl peptidase 4 inhibitors, which slow the proteolysis of GLP-1 in the blood. PMID- 25685365 TI - The evidence base for fat guidelines: a balanced diet. PMID- 25685366 TI - Dialogue: Vitamin D, statins and atherosclerotic progression in paediatric lupus. PMID- 25685367 TI - Combined Positron Emission Tomography and Computed Tomography: Option or necessity? PMID- 25685368 TI - Perceived Benefits of Pre-Clinical Simulation-based Training on Clinical Learning Outcomes among Omani Undergraduate Nursing Students. AB - OBJECTIVES: This study aimed to explore the benefits perceived by Omani undergraduate maternity nursing students regarding the effect of pre-clinical simulation-based training (PSBT) on clinical learning outcomes. METHODS: This non experimental quantitative survey was conducted between August and December 2012 among third-year baccalaureate nursing students at Sultan Qaboos University in Muscat, Oman. Voluntary participants were exposed to faculty-guided PSBT sessions using low- and medium-fidelity manikins, standardised scenarios and skill checklists on antenatal, intranatal, postnatal and newborn care and assessment. Participants answered a purposely designed self-administered questionnaire on the benefits of PSBT in enhancing learning outcomes. Items were categorised into six subscales: knowledge, skills, patient safety, academic safety, confidence and satisfaction. Scores were rated on a four-point Likert scale. RESULTS: Of the 57 participants, the majority (95.2%) agreed that PSBT enhanced their knowledge. Most students (94.3%) felt that their patient safety practices improved and 86.5% rated PSBT as beneficial for enhancing skill competencies. All male students and 97% of the female students agreed that PSBT enhanced their confidence in the safe holding of newborns. Moreover, 93% of participants were satisfied with PSBT. CONCLUSION: Omani undergraduate nursing students perceived that PSBT enhanced their knowledge, skills, patient safety practices and confidence levels in providing maternity care. These findings support the use of simulation training as a strategy to facilitate clinical learning outcomes in future nursing courses in Oman, although further research is needed to explore the objective impact of PSBT on learning outcomes. PMID- 25685369 TI - Trends in Epithelial Cell Abnormalities Observed on Cervical Smears over a 21 Year Period in a Tertiary Care Hospital in Kuwait. AB - OBJECTIVES: This study aimed to analyse trends in epithelial cell abnormalities (ECAs) in cervical cytology at a tertiary care hospital in Kuwait. METHODS: ECAs in 135,766 reports were compared over three seven-year periods between 1992 and 2012. Conventional Papanicolaou (Pap) smear tests were used in the first two periods and ThinPrep (Hologic Corp., Bedford, Massachusetts, USA) tests were used in the third. RESULTS: Significant increases in satisfactory smears, atypical squamous cells of undetermined significance (ASCUS) and atypical glandular cells of undetermined significance/atypical glandular cells (AGUS/AGCs) were seen in the second and third periods (P <0.001). No significant increases were observed among low-grade squamous intraepithelial lesions (LSILs) or high-grade squamous intraepithelial lesions (HSILs) (P >0.05). An increase was noted in carcinomas between the first and second periods although a significant decline was seen in the third (P <0.014). CONCLUSION: Satisfactory smears, ASCUS and AGUS/AGC increased during the study period although no significant increases in LSILs, HSILs or carcinomas were observed. PMID- 25685370 TI - Does Sickle Cell Disease Protect Against Diabetes Mellitus?: Cross-sectional study. AB - OBJECTIVES: The co-existence of diabetes mellitus (DM) and sickle cell disease (SCD) is rare. This study aimed to explore whether SCD patients have the same DM prevalence as the general population in a country with a high prevalence of DM. METHODS: This cross-sectional study included all SCD adult patients admitted to Salmaniya Medical Complex, Bahrain, between 2003 and 2010 (n = 2,204). A random sample (n = 520) was taken to establish the prevalence of DM. Laboratory records were examined to determine the presence of DM. RESULTS: There were 376 SCD patients with complete records; of these, 24 (6.4%) had DM. The age- and sex standardised prevalence of DM was 8.3%. CONCLUSION: While the prevalence of DM in SCD patients in Bahrain was high, it was lower than expected in this population. SCD may have a protective effect towards DM development. However, the impact of these two conditions on vascular diseases suggest a need for screening and aggressive treatment in this population. PMID- 25685371 TI - Adrenocorticotropic Hormone-Dependent Cushing's Syndrome: Use of an octreotide trial to distinguish between pituitary or ectopic sources. AB - OBJECTIVES: Adrenocorticotropic hormone (ACTH) overproduction is usually due to a pituitary tumour which is often not visible on magnetic resonance imaging (MRI). However, ACTH overproduction may be due to an ectopic source. This study aimed to develop a simple non-invasive technique to differentiate these sources. METHODS: This study took place in King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia, and Sultan Qaboos University Hospital, Muscat, Oman, between 1988 and 2012. Serum cortisol levels were measured in nine patients with ACTH-dependent Cushing's syndrome before and during a 72-hour trial of octreotide. All patients underwent computed tomography (CT) scans. MRI scans were performed on six patients. RESULTS: CT scans were abnormal in three patients with ectopic ACTH production. MRI scans showed that three patients had pituitary microadenomas. Serum cortisol levels returned to normal in those with confirmed ectopic ACTH production. No response was found in the other six patients. CONCLUSION: A 72-hour trial of octreotide is recommended for patients with ACTH dependent Cushing's syndrome and a normal pituitary MRI. This trial will be a useful alternative to petrosal sinus sampling. PMID- 25685372 TI - Heerfordt's Syndrome Presenting with Recurrent Facial Nerve Palsy: Case report and 10-year literature review. AB - Heerfordt's syndrome is defined as a combination of facial palsy, parotid swelling, uveitis and fever in sarcoidosis cases. Heerfordt's syndrome as a cause of facial palsy is very rare. We report a case of alternating facial nerve palsy in a 52-year-old female initially treated for Bell's palsy. The patient was referred to the All India Institute of Medical Sciences, Bhubaneswar, India, in January 2013 for clinical evaluation. She was found to have a parotid swelling and anterior intermediate uveitis. A pathoradiological evaluation suggested sarcoidosis and a final diagnosis of Heerfordt's syndrome was made. Steroid treatment was initiated which led to an improvement in the facial palsy and uveitis as well as the disappearance of the parotid swelling with a corresponding decrease in angiotensin-converting enzyme levels. An English literature review was carried out to analyse the varied presentation of this syndrome. The analysis focused on presenting symptoms, biochemical markers and radiological findings of Heerfordt's syndrome cases. PMID- 25685373 TI - Trichilemmal cyst of the penis in a paediatric patient. AB - Paediatric penile cysts are uncommon. We report a five-year-old child with an asymptomatic progressively growing cyst on the ventral aspect of the penis after a hypospadias repair. The patient presented to the Cooper Health Clinic, Dubai, United Arab Emirates, in March 2012. A complete excision of the cyst was performed. Histology results delineated a capsulated benign trichilemmal cyst. No recurrence or complications were reported in the 26 months following the excision. We recommend an early and complete excision of all penile cysts to prevent the risk of urethral obstruction, infection, inflammation and rare malignant changes. This is the first reported case of a penile trichilemmal cyst in a child. PMID- 25685374 TI - Cerebellar mutism following closed head injury in a child. AB - Cerebellar mutism is a rare occurrence following paediatric trauma. Although it is quite common after posterior fossa surgery in children, this phenomenon has rarely been reported following other insults, such as trauma, and its pathophysiology remains poorly understood. We report a seven-year-old child who presented to the casualty department of Sultan Qaboos University Hospital in Muscat, Oman, in May 2013 with a traumatic right cerebellar contusion. The child presented with clinical features of cerebellar mutism but underwent a rapid and spontaneous recovery. The possible mechanism of this occurrence is discussed. PMID- 25685375 TI - Vascular Anomalies in Children Misdiagnosed with Asthma: Case series. AB - In most asthmatic children, inhaled steroids can relieve and control the symptoms of asthma. Persistent wheezing and respiratory symptoms in young children despite appropriate treatment may indicate other diagnostic considerations. Delays in this diagnosis can result in unnecessary investigations, inappropriate treatment and further complications. We report three patients who presented to Sultan Qaboos University Hospital, Muscat, Oman, in the period between September 2010 and May 2012 with persistent wheezing due to compression of the trachea caused by vascular anomalies. All patients had double aortic arches putting pressure on the trachea, leading to respiratory manifestations and feeding problems. Following surgery, all cases showed improvement and no longer required medication. Without clinical suspicion and appropriate imaging, congenital vascular anomalies may remain undetected for years. Infants and children with chronic wheezing should be evaluated for vascular anomalies as soon as possible. General practitioners should refer all such patients to a tertiary-level hospital for further investigations and management. PMID- 25685376 TI - Utility of magnetic resonance imaging t2(*) in diagnosing and monitoring severe cardiac and hepatic siderosis. PMID- 25685377 TI - Bart syndrome with ear malformation. PMID- 25685378 TI - Sodium valproate-induced myopathy in a child. PMID- 25685379 TI - Re: Pregnancy Outcomes in Women with Homozygous Beta Thalassaemia: A single centre experience from Oman. PMID- 25685380 TI - Paget's Disease of Bone among Various Ethnic Groups. AB - Paget's disease of bone (PDB) is a relatively benign disease common among many European populations, including those in the UK, Italy and Spain. However, it appears to be rare among Scandinavians and non-European immigrants living in Europe. The prevalence among Asian populations may be underestimated because a large number of reported cases were discovered incidentally. There is a need for surveys addressing the prevalence rate and consequences of PDB to be carried out in various parts of the world, particularly Asia. PMID- 25685381 TI - Health Workforce Planning: An overview and suggested approach in Oman. AB - In most countries, the lack of explicit health workforce planning has resulted in imbalances that threaten the capacity of healthcare systems to attain their objectives. This has directed attention towards the prospect of developing healthcare systems that are more responsive to the needs and expectations of the population by providing health planners with a systematic method to effectively manage human resources in this sector. This review analyses various approaches to health workforce planning and presents the Six-Step Methodology to Integrated Workforce Planning which highlights essential elements in workforce planning to ensure the quality of services. The purpose, scope and ownership of the approach is defined. Furthermore, developing an action plan for managing a health workforce is emphasised and a reviewing and monitoring process to guide corrective actions is suggested. PMID- 25685382 TI - A Brief History of Breast Cancer: Part III - Tumour biology lays the foundation for medical oncology. PMID- 25685383 TI - Trends in the Risk for Cardiovascular Disease among Adults with Diabetes in Oman. AB - OBJECTIVES: This study aimed to investigate trends in the estimated 10-year risk for developing cardiovascular disease (CVD) among adults with diagnosed diabetes in Oman. In addition, the effect of hypothetical risk reductions in this population was examined. METHODS: Data from 1,077 Omani adults aged >=40 years with diagnosed diabetes were collected and analysed from three national surveys conducted in 1991, 2000 and 2008 across all regions of Oman. The estimated 10 year CVD risk and hypothetical risk reductions were calculated using risk prediction algorithms from the Systematic COronary Risk Evaluation (SCORE), Diabetes Epidemiology Collaborative Analysis of Diagnostic Criteria in Europe (DECODE) and World Health Organization/International Society of Hypertension (WHO/ISH) risk tools. RESULTS: Between 1991 and 2008, the estimated 10-year risk of CVD increased significantly in the total sample and among both genders, regardless of the risk prediction algorithm that was used. Hypothetical risk reduction models for three scenarios (eliminating smoking, controlling systolic blood pressure and reducing total cholesterol) identified that reducing systolic blood pressure to <=130 mmHg would lead to the largest reduction in the 10-year risk of CVD in subjects with diabetes. CONCLUSION: The estimated 10-year risk for CVD among adults with diabetes increased significantly between 1991 and 2008 in Oman. Focused public health initiatives, involving recognised interventions to address behavioural and biological risks, should be a national priority. Improvements in the quality of care for diabetic patients, both at the individual and the healthcare system level, are required. PMID- 25685384 TI - Sleep Deprivation and Depression: A bi-directional association. PMID- 25685385 TI - Prevalence of Hepatitis C among Multi-transfused Thalassaemic Patients in Oman: Single centre experience. AB - OBJECTIVES: Regular blood transfusions are essential for patients with thalassaemia major. However, infections with hepatotropic viruses remain a major concern. The objective of this study was to evaluate the prevalence and characteristics of hepatitis C viral (HCV) infection among patients with homozygous beta thalassaemia in a single centre in Oman. METHODS: A retrospective chart review of 200 patients treated at the Thalassemia Unit of Sultan Qaboos University Hospital (SQUH) in Muscat, Oman, between August 1991 and December 2011 was performed. Relevant demographic and clinical characteristics were collected, including age, gender, HCV status and the presence of endocrinopathies. RESULTS: A total of 81 patients (41%) were found to be anti-HCV-antibody (anti-HCV) positive. HCV ribonucleic acid tests were performed on 65 anti-HCV-positive patients and were positive among 33 (51%); the remaining 16 patients died before these tests were available. Anti-HCV-positive patients were significantly older than anti-HCV-negative patients (P <0.001) and were more likely to be diabetic than anti-HCV-negative patients (27% versus 8%; P <0.001). A total of 100 patients had been transfused before they were transferred to SQUH in 1991; of these, 70 (70%) were anti-HCV-positive. Only 11 (11.5%) of the 96 patients who were seronegative in 1991, or who were transfused later, became seropositive. CONCLUSION: It is likely that the high prevalence of HCV among multi-transfused thalassaemic patients in Oman is due to blood transfusions dating from before the implementation of HCV screening in 1991 as the risk of HCV-associated transfusions has significantly reduced since then. Additionally, results showed that anti-HCV-positive patients were more likely to be diabetic than anti-HCV negative patients. PMID- 25685386 TI - Selective Use of (18)F-Fluorodeoxyglucose-Positron Emission Tomography and Computed Tomography in the Management of Metastatic Disease from Colorectal Cancer: Results from a regional centre. AB - OBJECTIVES: Computed tomography (CT) scans are routinely used for primary staging and disease surveillance in patients with colorectal cancer. However, these scans have limited sensitivity in some organs and can only detect lesions with morphological changes, whereas (18)F-fluorodeoxyglucose-positron emission tomography ((18)F-FDG-PET) scans are able to detect areas of metabolic change before morphological changes appear. The aim of this study was to evaluate the impact of (18)F-FDG-PET/CT scans over conventional imaging during preoperative work-ups or follow-ups in a selected group of patients. METHODS: This retrospective cohort study, which took place between July 2009 and May 2011, assessed 1,043 patient records from the South East Scotland Cancer Network colorectal cancer database. A total of 102 patients who underwent (18)F-FDG PET/CT scans in addition to conventional imaging were included in the study. These patients had potentially resectable metastases, equivocal findings on CT scans and elevated carcinoembryonic antigen levels with negative conventional imaging. RESULTS: Of the 102 patients included in the study, 22 underwent a preoperative (18)F-FDG-PET/CT scan and 80 underwent a follow-up 18F-FDG-PET/CT scan. In the preoperative scan group, the (18)F-FDG-PET/CT scan had a major impact on 16 patients (72.75%) and no impact on six patients (27.25%). In the follow-up scan group, the (18)F-FDG-PET/CT scan had a major impact on 51 (63.75%), a minor impact on four (5%), no impact on 22 (27.5%) and a negative impact on three (3.75%) patients. CONCLUSION: The results of this study demonstrated that (18)F-FDG-PET/CT scans have a considerable effect on disease management when undertaken among indicated colorectal cancer patients. PMID- 25685387 TI - Diagnostic Screening Workflow for Mutations in the BRCA1 and BRCA2 Genes. AB - OBJECTIVES: Screening for mutations in large genes is challenging in a molecular diagnostic environment. Sanger-based DNA sequencing methods are largely used; however, massively parallel sequencing (MPS) can accommodate increasing test demands and financial constraints. This study aimed to establish a simple workflow to amplify and screen all coding regions of the BRCA1 and BRCA2 (BRCA1/2) genes by Sanger-based sequencing as well as to assess a MPS approach encompassing multiplex polymerase chain reaction (PCR) and pyrosequencing. METHODS: This study was conducted between July 2011 and April 2013. A total of 20 patients were included in the study who had been referred to Genetic Health Services New Zealand (Northern Hub) for BRCA1/2 mutation screening. Patients were randomly divided into a MPS evaluation and validation cohort (n = 10 patients each). Primers were designed to amplify all coding exons of BRCA1/2 (28 and 42 primer pairs, respectively). Primers overlying known variants were avoided to circumvent allelic drop-out. The MPS approach necessitated utilisation of a complementary fragment analysis assay to eliminate apparent false-positives at homopolymeric regions. Variants were filtered on the basis of their frequency and sequence depth. RESULTS: Sanger-based sequencing of PCR-amplified coding regions was successfully achieved. Sensitivity and specificity of the combined MPS/homopolymer protocol was determined to be 100% and 99.5%, respectively. CONCLUSION: In comparison to traditional Sanger-based sequencing, the MPS workflow led to a reduction in both cost and analysis time for BRCA1/2 screening. MPS analysis achieved high analytical sensitivity and specificity, but required complementary fragment analysis combined with Sanger-based sequencing confirmation in some instances. PMID- 25685388 TI - Heerfordt's Syndrome: An interesting and under-recognised manifestation of sarcoidosis. PMID- 25685389 TI - Reliability of the Emergency Severity Index: Meta-analysis. AB - OBJECTIVES: Although triage systems based on the Emergency Severity Index (ESI) have many advantages in terms of simplicity and clarity, previous research has questioned their reliability in practice. Therefore, the aim of this meta analysis was to determine the reliability of ESI triage scales. METHODS: This meta-analysis was performed in March 2014. Electronic research databases were searched and articles conforming to the Guidelines for Reporting Reliability and Agreement Studies were selected. Two researchers independently examined selected abstracts. Data were extracted in the following categories: version of scale (latest/older), participants (adult/paediatric), raters (nurse, physician or expert), method of reliability (intra/inter-rater), reliability statistics (weighted/unweighted kappa) and the origin and publication year of the study. The effect size was obtained by the Z-transformation of reliability coefficients. Data were pooled with random-effects models and a meta-regression was performed based on the method of moments estimator. RESULTS: A total of 19 studies from six countries were included in the analysis. The pooled coefficient for the ESI triage scales was substantial at 0.791 (95% confidence interval: 0.787-0.795). Agreement was higher with the latest and adult versions of the scale and among expert raters, compared to agreement with older and paediatric versions of the scales and with other groups of raters, respectively. CONCLUSION: ESI triage scales showed an acceptable level of overall reliability. However, ESI scales require more development in order to see full agreement from all rater groups. Further studies concentrating on other aspects of reliability assessment are needed. PMID- 25685390 TI - Prevalence of Sleep Deprivation and Relation with Depressive Symptoms among Medical Residents in King Fahd University Hospital, Saudi Arabia. AB - OBJECTIVES: Sleep deprivation is common among medical residents of all specialties. This study aimed to determine the prevalence of sleep deprivation and depressive symptoms among medical residents in King Fahd University Hospital (KFUH) in Al Khobar, Saudi Arabia. Furthermore, the association between sleep deprivation, sleepiness and depressive symptoms was examined. METHODS: This cross sectional study took place between February and April 2012 and involved 171 KFUH medical residents of different specialties. Data were collected using a specifically designed questionnaire eliciting demographic information, working hours and number of hours of sleep. In addition, validated Arabic versions of the Epworth Sleepiness Scale and the Beck Depression Inventory-2 (BDI-2) were used. RESULTS: The prevalence of acute sleep deprivation and chronic sleep deprivation among residents in KFUH was 85.9% and 63.2%, respectively. The prevalence of overall sleepiness was 52%; 43.3% reported being excessively sleepy in certain situations while 8.8% reported being excessively sleepy regardless of the situation. Based on the BDI-2, the prevalence of mild, moderate and severe depressive symptoms was 43.3%, 15.2% and 4.7%, respectively. Significant associations were found between sleep deprivation and depressive symptoms; depressive symptoms and sleepiness, and depressive symptoms and being a female resident. CONCLUSION: The vast majority of medical residents had acute sleep deprivation, with more than half suffering from chronic sleep deprivation. The number of hours and quality of sleep among the residents were strongly associated with depressive symptoms. New regulations are recommended regarding the number of working hours and night duties for medical residents. Further studies should assess these new regulations on a regular basis. PMID- 25685391 TI - Hepatoblastomas in Oman: Unveiling success. AB - OBJECTIVES: Primary malignant liver tumours account for more than 1% of all paediatric malignancies, with the most common form being hepatoblastomas (HB). Such malignancies among Arab populations have rarely been addressed in the literature. Using data from Oman's sole national referral centre for childhood solid malignancies, this study aimed to present the nationwide Omani experience with HB over the past 21 years. METHODS: This retrospective study reviewed the medical records of all children with HB who were managed in the Royal Hospital, Muscat, Oman, between January 1991 and April 2012. Clinical, radiological and laboratory characteristics were examined as well as treatments and outcomes. RESULTS: During the study period, 15 patients with HB were treated. Of these, 10 have survived to date. Nine of the survivors were no longer receiving treatment and one patient still had the disease but was in a stable condition. Of the remaining five patients, three did not survive and two were lost to follow-up. The survival rate among patients who completed therapy was 91%. CONCLUSION: HB has an excellent prognosis in Oman. The main obstacle to improving outcomes among Omani patients is non-compliance with therapy. PMID- 25685392 TI - The Role of Damage-Associated Molecular Patterns in Human Diseases: Part I - Promoting inflammation and immunity. AB - There is increasing interest by physicians in the impact of the innate immune system on human diseases. In particular, the role of the molecules that initiate and amplify innate immune pathways, namely damage-associated molecular patterns (DAMPs), is of interest as these molecules are involved in the pathogenesis of many human disorders. The first part of this review identifies five classes of cell stress/tissue injury-induced DAMPs that are sensed by various recognition receptor-bearing cells of the innate immune system, thereby mounting inflammation, promoting apoptosis and shaping adaptive immune responses. The DAMPs activate and orchestrate several innate immune machineries, including inflammasomes and the unfolded protein response that synergistically operates to induce inflammatory, metabolic and adaptive immune pathologies. Two examples of autoimmune diseases are discussed as they represent a typical paradigm of the intimate interplay between innate and adaptive immune responses. PMID- 25685393 TI - Factors responsible for the prolonged stay of surgical neonates in intensive care units. AB - OBJECTIVES: The length of hospital stay (HS) for patients is a major concern due to its social, economic and administrative implications; this is particularly important for neonates admitted to intensive care units (ICUs). This study aimed to determine the factors responsible for prolonged HS in surgical neonates. METHODS: This retrospective study was conducted at Sultan Qaboos University Hospital, in Muscat, Oman. The medical records of 95 neonates admitted to the neonatal ICU who underwent general surgical procedures between July 2009 and June 2013 were reviewed. Mann-Whitney U and Pearson's Chi-squared tests were used for non-parametric numerical and categorical variables, respectively. A multiple regression analysis was performed to find a relationship between the variables and to detect the most important factor responsible for prolonged HS. A P value of <0.05 was considered statistically significant. RESULTS: Gestational age, birth weight, number of days on a ventilator and postoperative morbidity were associated with prolonged HS. Furthermore, the age of neonates at first full enteral feed was associated with increased HS using both independent and multiple regression analyses. CONCLUSION: Prolonged HS can occur as a result of many factors. In this study, a number of factors were identified, including low gestational age, low birth weight, increased number of days on a ventilator and postoperative morbidity. Additionally, neonate age at first full enteral feeds also correlated with increased HS. Further research on this topic is suggested to explore this correlation in more detail and to inform future practices. PMID- 25685394 TI - Voluntary Fasting to Control Post-Ramadan Weight Gain among Overweight and Obese Women. AB - OBJECTIVES: This study aimed to examine the effectiveness of an Islamic voluntary fasting intervention to control post-Ramadan weight gain. METHODS: This study was conducted between July and November 2011. Two weight loss intervention programmes were developed and implemented among groups of overweight or obese Malay women living in the Malaysian cities of Putrajaya and Seremban: a standard programme promoting control of food intake according to national dietary guidelines (group B) and a faith-based programme promoting voluntary fasting in addition to the standard programme (group A). Participants' dietary practices (i.e., voluntary fasting practices, frequency of fruit/vegetable consumption per week and quantity of carbohydrates/protein consumed per day), body mass index (BMI), blood pressure, fasting blood high-density lipoprotein cholesterol (HDL-C) and total cholesterol (TC):HDL-C ratio were assessed before Ramadan and three months post Ramadan. RESULTS: Voluntary fasting practices increased only in group A (P <0.01). Additionally, the quantity of protein/carbohydrates consumed per day, mean diastolic pressure and TC:HDL-C ratio decreased only in group A (P <0.01, 0.05, 0.02 and <0.01, respectively). Frequency of fruit/vegetable consumption per week, as well as HDL-C levels, increased only in group A (P = 0.03 and <0.01, respectively). Although changes in BMI between the groups was not significant (P = 0.08), BMI decrease among participants in group A was significant (P <0.01). CONCLUSION: Control of post-Ramadan weight gain was more evident in the faith based intervention group. Healthcare providers should consider faith-based interventions to encourage weight loss during Ramadan and to prevent post-Ramadan weight gain among patients. PMID- 25685395 TI - Intrastromal corneal ring segment implantation (keraring 355 degrees ) in patients with central keratoconus: 6-month follow-up. AB - We evaluate the efficacy and safety of Keraring 355 degrees intrastromal corneal ring segment (ICRS) implantation aided by PocketMaker microkeratome for the correction of keratoconus. Patients underwent ICRS insertion using mechanical dissection with PocketMaker microkeratome and completed 6 months of follow-up. Uncorrected visual acuity (UCVA), best spectacle-corrected visual acuity (BSCVA), refraction, topographic findings, safety, efficacy index, and adverse events were reported for six months postoperatively. We evaluated 15 eyes of 15 patients (12 men) with a mean age of 28.87 +/- 6.94 years (range 21-49 years). At final postoperative examination, there was a statistically significant reduction in the spherical equivalent refractive error compared to preoperative measurements ( 5.46 +/- 1.52 to -2.01 +/- 1.63 D, P < 0.001). Mean preoperative UCVA (logMAR) before implantation was 0.79 +/- 0.48, and postoperative UCVA was 0.28 +/- 0.15, P = 0.001. Mean preoperative BSCVA (logMAR) before implantation was 0.36 +/- 0.21; at final follow-up examination BSCVA was 0.18 +/- 0.9, P = 0.009. Mean K decreased from 48.33 to 43.31 D, P < 0.001. All patients were satisfied with ICRS implantation; 86.7% were moderately to very happy with the results. No intraoperative or postoperative complications were demonstrated. This preliminary study shows that ICRS (Keraring 355 degrees ) implantation is an efficient, cost effective, and minimally invasive procedure for improving visual acuity in nipple type keratoconic corneas. PMID- 25685396 TI - Two integrator loop quadrature oscillators: A review. AB - A review of the two integrator loop oscillator circuits providing two quadrature sinusoidal output voltages is given. All the circuits considered employ the minimum number of capacitors namely two except one circuit which uses three capacitors. The circuits considered are classified to four different classes. The first class includes floating capacitors and floating resistors and the active building blocks realizing these circuits are the Op Amp or the OTRA. The second class employs grounded capacitors and includes floating resistors and the active building blocks realizing these circuits are the DCVC or the unity gain cells or the CFOA. The third class employs grounded capacitors and grounded resistors and the active building blocks realizing these circuits are the CCII. The fourth class employs grounded capacitors and no resistors and the active building blocks realizing these circuits are the TA. Transformation methods showing the generation of different classes from each other is given in details and this is one of the main objectives of this paper. PMID- 25685397 TI - Diversity of bacteria nesting the plant cover of north Sinai deserts, Egypt. AB - North Sinai deserts were surveyed for the predominant plant cover and for the culturable bacteria nesting their roots and shoots. Among 43 plant species reported, 13 are perennial (e.g. Fagonia spp., Pancratium spp.) and 30 annuals (e.g. Bromus spp., Erodium spp.). Eleven species possessed rhizo-sheath, e.g. Cyperus capitatus, Panicum turgidum and Trisetaria koelerioides. Microbiological analyses demonstrated: the great diversity and richness of associated culturable bacteria, in particular nitrogen-fixing bacteria (diazotrophs); the majority of bacterial residents were of true and/or putative diazotrophic nature; the bacterial populations followed an increasing density gradient towards the root surfaces; sizeable populations were able to reside inside the root (endorhizosphere) and shoot (endophyllosphere) tissues. Three hundred bacterial isolates were secured from studied spheres. The majority of nitrogen-fixing bacilli isolates belonged to Bacillus megaterium, Bacillus pumilus, Bacillus polymexa, Bacillus macerans, Bacillus circulans and Bacillus licheniformis. The family Enterobacteriaceae represented by Enterobacter agglomerans, Enterobacter sackazakii, Enterobacter cloacae, Serratia adorifera, Serratia liquefaciens and Klebsiella oxytoca. The non-Enterobacteriaceae population was rich in Pantoae spp., Agrobacterium rdiobacter, Pseudomonas vesicularis, Pseudomonas putida, Stenotrophomonas maltophilia, Ochrobactrum anthropi, Sphingomonas paucimobilis and Chrysemonas luteola. Gluconacetobacter diazotrophicus were reported inside root and shoot tissues of a number of tested plants. The dense bacterial populations reported speak well to the very possible significant role played by the endophytic bacterial populations in the survival, in respect of nutrition and health, of existing plants. Such groups of diazotrophs are good candidates, as bio-preparates, to support the growth of future field crops grown in deserts of north Sinai and irrigated by the water of El-Salam canal. PMID- 25685398 TI - Optimization of cold rolling process parameters in order to increasing rolling speed limited by chatter vibrations. AB - Chatter has been recognized as major restriction for the increase in productivity of cold rolling processes, limiting the rolling speed for thin steel strips. It is shown that chatter has close relation with rolling conditions. So the main aim of this paper is to attain the optimum set points of rolling to achieve maximum rolling speed, preventing chatter to occur. Two combination methods were used for optimization. First method is done in four steps: providing a simulation program for chatter analysis, preparing data from simulation program based on central composite design of experiment, developing a statistical model to relate system tendency to chatter and rolling parameters by response surface methodology, and finally optimizing the process by genetic algorithm. Second method has analogous stages. But central composite design of experiment is replaced by Taguchi method and response surface methodology is replaced by neural network method. Also a study on the influence of the rolling parameters on system stability has been carried out. By using these combination methods, new set points were determined and significant improvement achieved in rolling speed. PMID- 25685399 TI - Vortex-assisted ionic liquid microextraction coupled to flame atomic absorption spectrometry for determination of trace levels of cadmium in real samples. AB - A simple and rapid vortex assisted ionic liquid based liquid-liquid microextraction technique (VALLME) was proposed for preconcentration of trace levels of cadmium. According to this method, the extraction solvent was dispersed into the aqueous samples by the assistance of vortex agitator. Cadmium preconcentration was mediated by chelation with the 8-hydroxyquinoline (oxine) reagent and an IL, 1-octyl-3-methylimidazolium hexafluorophosphate ([Omim][PF6]) was chosen as the extraction solvent to extract the hydrophobic complex. Several variables such as sample pH, concentration of oxine, volume of [Omim][PF6] and extraction time were investigated in details and optimum conditions were selected. Under the optimum conditions, the limit of detection (LOD) was 2.9 MUg L(-1) for Cd (II) and relative standard deviation (RSD%) for five replicate determinations of 125 MUg L(-1) was 4.1%. The method was successfully applied to the determination of cadmium in tap water, apple and rice samples. PMID- 25685400 TI - The validity of spinal mobility for prediction of functional disability in male patients with low back pain. AB - Clinical assessment of functional disability is an integral part of management in patients with low back pain (LBP). The range of spinal motion is one of LBP disability measure. The aim of this study was to investigate the validity of spinal range of motion as a predictable measure of disability and to analyze the intrarater reliability of back range of motion (BROM) instrument for measurement of active lumber spine range of motion. Forty men patients with chronic low back pain over 6 month's duration were participated in the study. Their ages ranged from 20 to 40 years. Lumber range of motion was measured with BROM device and disability was evaluated by self reported Roland Morris disability questionnaire (RMDQ). Data were analyzed using Spearman's correlation, multiple regression analysis models and ICC. Statistical analysis revealed that there was a highly significant moderate to good relation between forward trunk flexion and RMDQ score (rho = -0.59, p < 0.001). While there was a weak correlation between trunk extensions, lateral trunk flexion and trunk rotation with the RMDQ scores (p > 0.05). The main predictors of disability were forward and lateral trunk flexion. Furthermore, intrarater reliability for forward trunk flexion was good (ICC, 0.84), for extension was high (ICC, 0.91), for rotation was good (ICC range, 0.86 0.88), and for lateral flexion was good (ICC range, 0.81-0.82). It was suggested that spinal ROM do not appear to be a valid measure for prediction of the functional disability in patients with chronic low back pain. PMID- 25685401 TI - Spectrophotometric and TLC-densitometric methods for the simultaneous determination of Ezetimibe and Atorvastatin calcium. AB - Three sensitive methods were developed for simultaneous determination of Ezetimibe (EZB) and Atorvastatin calcium (ATVC) in binary mixtures. First derivative (D(1)) spectrophotometry was employed for simultaneous determination of EZB (223.8 nm) and ATVC (233.0 nm) with a mean percentage recovery of 100.23 +/- 1.62 and 99.58 +/- 0.84, respectively. Linearity ranges were 10.00-30.00 MUg mL(-1) and 10.00-35.00 MUg mL(-1), respectively. Isosbestic point (IS) spectrophotometry, in conjunction with second derivative (D(2)) spectrophotometry was employed for analysis of the same mixture. Total concentration was determined at IS, 224.6 nm and 238.6 nm over a concentration range of 10.00-35.00 MUg mL(-1) and 5.00-30.00 MUg mL(-1), respectively. ATVC concentration was determined using D(2) at 313.0 nm (10.00-35.00 MUg mL(-1)) with a mean recovery percentage of 99.72 +/- 1.36, while EZB was determined mathematically at 224.6 nm (99.75 +/- 1.43) and 238.6 nm (99.80 +/- 0.95). TLC-densitometry was employed for the determination of the same mixture; 0.10-0.60 MUg band(-1) for both drugs. Separation was carried out on silica gel plates using diethyl ether-ethyl acetate (7:3 v/v). EZB and ATVC were resolved with Rf values of 0.78 and 0.13. Determination was carried out at 254.0 nm with a mean percentage recovery of 99.77 +/- 1.30 and 99.86 +/- 0.97, respectively. Methods were validated according to ICH guidelines and successfully applied for analysis of bulk powder and pharmaceutical formulations. Results were statistically compared to a reported method and no significant difference was noticed regarding accuracy and precision. PMID- 25685402 TI - Effect of endodontic irrigation and dressing procedures on the shear bond strength of composite to coronal dentin. AB - This study aimed to evaluate the effects of three sodium hypochlorite (NaOCl) endodontic irrigation procedures used alone or in combinations with two intermediate dressing materials on bond strengths of two adhesive composite systems to coronal dentin. Surfaces were treated with NaOCl or NaOCl-Glyde-File Prep (H2O2 and EDTA) with or without chlorhexidine (CHX) as a final rinse. Intermediate dressing materials of calcium hydroxide (Ca(OH)2) and sodium perborate (SP) were combined with surface treatments. Surface treatment groups (n = 10/group) included (1) distilled water (control), (2) 5.25% NaOCl (30 min), (3) NaOCl/Glyde (30 min), (4) NaOCl/Glyde (30 min) + CHX (2 min), (5) NaOCl/Glyde (30 min) + Ca(OH)2 (5 days) + CHX (2 min), and (6) NaOCl/Glyde (30 min) + SP (9 days) + CHX (2 min). For each surface treatment group, dentin shear bond strengths of two different composite systems (Excite/Tetric Flow Chroma, [EX/TFC], and Clearfil Protect Bond/Protect Liner F [PB/PLF]) were evaluated. Median shear bond strengths (EX/TFC, PB/PLF) for each surface treatment group in MPa were (1) 21, 18; (2) 26, 18; (3) 21, 17; (4) 22, 16; (5) 17, 11; and (6) 14, 11, respectively. NaOCl significantly increased the bond strength of EX/TFC (p < 0.05), but did not significantly affect that of PB/PLF. The use of NaOCl/Glyde with CHX did not significantly affect EX/TFC (p > 0.05), whereas it significantly decreased PB/PLF (p < 0.05). Ca(OH)2 and SP significantly decreased the bond strengths of both adhesive systems (p < 0.05). Adhesion to coronal dentin is dependent upon the irrigation regimen and the type of adhesive. PMID- 25685403 TI - Synthesis, characterization and RHF/ab initio simulations of 2-amino-1,3,4 thiadiazole and its annulated ring junction pyrimidine derivatives. AB - Michael addition reaction of the 2-amino-1,3,4-thiadiazole to chalcone as biselectrophile afforded 5,7-diphenyl-6-[1,3-diphenylpropan-1-on-3 yl][1,3,4]thiadiazolo[3,2-a]pyrimidine (3) instead of 5,7-diphenyl-5H [1,3,4]thiadiazolo[3,2-a]pyrimidine (5) via further Michael addition at C5 in pyrimidine moiety. The structure 3 was established through the aspect of ab initio calculations, elemental analysis and spectral data. PMID- 25685404 TI - Synthesis and characterization of laminated Si/SiC composites. AB - Laminated Si/SiC ceramics were synthesized from porous preforms of biogenous carbon impregnated with Si slurry at a temperature of 1500 degrees C for 2 h. Due to the capillarity infiltration with Si, both intrinsic micro- and macrostructure in the carbon preform were retained within the final ceramics. The SEM micrographs indicate that the final material exhibits a distinguished laminar structure with successive Si/SiC layers. The produced composites show weight gain of ~5% after heat treatment in air at 1300 degrees C for 50 h. The produced bodies could be used as high temperature gas filters as indicated from the permeability results. PMID- 25685405 TI - Analytical study for deformability of laminated sheet metal. AB - While a freestanding high-strength sheet metal subject to tension will rupture at a small strain, it is anticipated that lamination with a ductile sheet metal will retard this instability to an extent that depends on the relative thickness, the relative stiffness, and the hardening exponent of the ductile sheet. This paper presents an analytical study for the deformability of such laminate within the context of necking instability. Laminates of high-strength sheet metal and ductile low-strength sheet metal are studied assuming: (1) sheets are fully bonded; and (2) metals obey the power law material model. The effect of hardening exponent, volume fraction and relative stiffness of the ductile component has been studied. In addition, stability of both uniform and nonuniform deformations has been investigated under plane strain condition. The results have shown the retardation of the high-strength layer instability by lamination with the ductile layer. This has been achieved through controlling the aforementioned key parameters of the ductile component, while the laminate exhibits marked enhancement in strength-ductility combination that is essential for metal forming applications. PMID- 25685406 TI - Vibration analysis of structural elements using differential quadrature method. AB - The method of differential quadrature is employed to analyze the free vibration of a cracked cantilever beam resting on elastic foundation. The beam is made of a functionally graded material and rests on a Winkler-Pasternak foundation. The crack action is simulated by a line spring model. Also, the differential quadrature method with a geometric mapping are applied to study the free vibration of irregular plates. The obtained results agreed with the previous studies in the literature. Further, a parametric study is introduced to investigate the effects of geometric and elastic characteristics of the problem on the natural frequencies. PMID- 25685407 TI - Clinical and biomechanical evaluation of three bioscaffold augmentation devices used for superficial digital flexor tenorrhaphy in donkeys (Equus asinus): An experimental study. AB - The present study was designed to carry out an in vivo and in vitro comparative evaluation of three bio-scaffold augmentation devices used for superficial digital flexor tenorrhaphy in donkeys. Twenty-four clinically healthy donkeys were assigned for three treatment trials (n = 8) using one of three bioscaffold materials (glycerolized bovine pericardium xenograft, tendon allograft and allograft with glycerolized by bovine pericardium). In addition, eight clinically healthy donkeys were selected to serve as control. Clinical signs of each animal were scored and the sum of all clinical indexes was calculated at each time point of the experiment. Four donkeys from each group were euthanized at 45 and 90 days postoperatively, respectively, for biomechanical and histopathological evaluation of treated superficial digital flexor tendon (SDFT). The failure stress in allograft shielding group significantly increased compared to the corresponding values of the other groups at 45 (62.7 +/- 6.5 N mm(-2)) and 90 (88.8 +/- 3.5 N mm(-2)) days postoperatively. The fetlock angle in the allograft shielding group at both 45 (112.8 degrees +/- 4.4) and 90 (123.8 degrees +/- 1.1) days postoperatively showed a significant increase (p < 0.05) relative to the values of the other groups and a significant decrease (p < 0.05) when compared to normal angle (125 degrees +/- 0). However, the histomorphological findings revealed no remarkable changes between the treatment groups. In conclusion, the failure stress, fetlock angle and histomorphological findings may provide useful information about the healing characteristics of SDFT tenorrhaphy. The bio scaffold augmentation devices, either xenogenic or allogenic, provide good alternative techniques accelerating SDFT healing with minimal adhesions in donkeys. PMID- 25685408 TI - Facile construction of substituted pyrimido[4,5-d]pyrimidones by transformation of enaminouracil. AB - The reaction of 6-amino-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (1) as a binucleophile with primary aromatic or heterocyclic amines and formaldehyde or aromatic (heterocyclic) aldehydes in a molar ratio (1:1:2) gave the pyrimido[4,5 d]pyrimidin-2,4-dione ring systems 2-5. Treatment of 1 with diamines and formalin in molar ratio (2:1:4) gave the bis-pyrimido[4,5-d]pyrimidin-2,4-diones 6-8. Furthermore, substituted pyrimido[4,5-d]pyrimidin-2,4-diones with uracil derivative 11 or spiro indole 16 were synthesized. Synthesis of pyrimido[4,5 d]pyrimidin-2,4-diones with different substitution at C-5 and C-7 was achieved to give 13 and 18, respectively. PMID- 25685409 TI - Canal configuration of mandibular first premolars in an Egyptian population. AB - The purpose of this study was to investigate canal configuration of mandibular first premolars in an Egyptian population. Two hundred fifty human extracted mandibular first premolars were collected from Egyptian patients and a small hole in the center of the occlusal surface of each tooth was made perforating the roof of the pulp chamber. Teeth were decalcified by immersing in nitric acid and dehydrated in ascending concentrations of ethyl alcohol. A waterproof black ink was passively injected from the occlusal hole into pulp system and stained teeth were immersed in methyl salicylate solution for clearing. Standardized pictures of the cleared teeth were obtained and anatomical features of the root canal were observed. The average length of the mandibular first premolar teeth was 22.48 +/- 1.74 mm, one-rooted teeth were 96.8% and the two-rooted were 3.2%. Vertucci Type I canal configuration represented the highest percentage (61.2%) followed by Type V (16.4%), Type IV (13.2%), Type II (5.6%) and Type III (2.8%). Vertucci Type VI canal configuration represented the lowest percentage (0.4%) and a complex configuration was found in one tooth. Accessory canals were detected in 22.8% and inter-canal connections were observed in 24.8% while 54% showed apical delta. Such knowledge is clinically useful for localization and negotiation of canals of mandibular first premolar, as well as their subsequent management in Egyptian population. PMID- 25685410 TI - Isotope effects of neodymium in different ligands exchange systems studied by ion exchange displacement chromatography. AB - The isotope effects of neodymium in Nd-glycolate ligand exchange system were studied by using ion exchange chromatography. The separation coefficients of neodymium isotopes, epsilon's, were calculated from the observed isotopic ratios at the front and rear boundaries of the neodymium adsorption band. The values of separation coefficients of neodymium isotopes, epsilon's, for the Nd-glycolate ligand exchange system were compared with those of Nd-malate and Nd-citrate, which indicated that the isotope effects of neodymium as studied by the three ligands takes the following direction Malate > Citrate > Glycolate. This order agrees with the number of available sites for complexation of each ligand. The values of the plate height, HETP of Nd in Nd-ligand exchange systems were also calculated. PMID- 25685411 TI - Semi-empirical correlation for binary interaction parameters of the Peng-Robinson equation of state with the van der Waals mixing rules for the prediction of high pressure vapor-liquid equilibrium. AB - Peng-Robinson equation of state is widely used with the classical van der Waals mixing rules to predict vapor liquid equilibria for systems containing hydrocarbons and related compounds. This model requires good values of the binary interaction parameter kij . In this work, we developed a semi-empirical correlation for kij partly based on the Huron-Vidal mixing rules. We obtained values for the adjustable parameters of the developed formula for over 60 binary systems and over 10 categories of components. The predictions of the new equation system were slightly better than the constant-kij model in most cases, except for 10 systems whose predictions were considerably improved with the new correlation. PMID- 25685412 TI - Pullout capacity of batter pile in sand. AB - Many offshore structures are subjected to overturning moments due to wind load, wave pressure, and ship impacts. Also most of retaining walls are subjected to horizontal forces and bending moments, these forces are due to earth pressure. For foundations in such structures, usually a combination of vertical and batter piles is used. Little information is available in the literature about estimating the capacity of piles under uplift. In cases where these supporting piles are not vertical, the behavior under axial pullout is not well established. In order to delineate the significant variables affecting the ultimate uplift shaft resistance of batter pile in dry sand, a testing program comprising 62 pullout tests was conducted. The tests are conducted on model steel pile installed in loose, medium, and dense sand to an embedded depth ratio, L/d, vary from 7.5 to 30 and with various batter angles of 0 degrees , 10 degrees , 20 degrees , and 30 degrees . Results indicate that the pullout capacity of a batter pile constructed in dense and/or medium density sand increases with the increase of batter angle attains maximum value and then decreases, the maximum value of Palpha occurs at batter angle approximately equal to 20 degrees , and it is about 21-31% more than the vertical pile capacity, while the pullout capacity for batter pile that constructed in loose sand decreases with the increase of pile inclination. The results also indicated that the circular pile is more resistant to pullout forces than the square and rectangular pile shape. The rough model piles tested is experienced 18-75% increase in capacity compared with the smooth model piles. The suggested relations for the pullout capacity of batter pile regarding the vertical pile capacity are well predicted. PMID- 25685413 TI - Preparation and physical properties of (PVA)0.7(NaBr)0.3(H3PO4) x M solid acid membrane for phosphoric acid - Fuel cells. AB - A solid acid membranes based on poly (vinyl alcohol) (PVA), sodium bromide (NaBr) and phosphoric acid (H3PO4) were prepared by a solution casting method. The morphological, IR, electrical and optical properties of the (PVA)0.7(NaBr)0.3(H3PO4) x M solid acid membranes where x = 0.00, 0.85, 1.7, 3.4, 5.1 M were investigated. The variation of film morphology was examined by scanning electron microscopy (SEM) studies. FTIR spectroscopy has been used to characterize the structure of polymer and confirms the complexation of phosphoric acid with host polymeric matrix. The temperature dependent nature of ionic conductivity and the impedance of the polymer electrolytes were determined along with the associated activation energy. The ionic conductivity at room temperature was found to be strongly depends on the H3PO4 concentration which it has been achieved to be of the order 4.3 * 10(-3) S/cm at ambient temperature. Optical measurements showed a decrease in optical band gap and an increase in band tail width with the increase of phosphoric acid. The data shows that the (PVA)0.7(NaBr)0.3(H3PO4) x M solid acid membrane is promising for intermediate temperature phosphoric acid fuel cell applications. PMID- 25685414 TI - On some generalized discrete logistic maps. AB - Recently, conventional logistic maps have been used in different vital applications like modeling and security. However, unfortunately the conventional logistic maps can tolerate only one changeable parameter. In this paper, three different generalized logistic maps are introduced with arbitrary powers which can be reduced to the conventional logistic map. The added parameter (arbitrary power) increases the degree of freedom of each map and gives us a versatile response that can fit many applications. Therefore, the conventional logistic map is considered only a special case from each proposed map. This new parameter increases the flexibility of the system, and illustrates the performance of the conventional system within any required neighborhood. Many cases will be illustrated showing the effect of the arbitrary power and the equation parameter on the number of equilibrium points, their locations, stability conditions, and bifurcation diagrams up to the chaotic behavior. PMID- 25685415 TI - Simultaneous determination of olanzapine and fluoxetine hydrochloride in capsules by spectrophotometry, TLC-spectrodensitometry and HPLC. AB - This paper describes sensitive, accurate and precise spectrophotometric, TLC spectrodensitometric and high performance liquid chromatographic (HPLC) methods for simultaneous determination of olanzapine and fluoxetine HCl. Two spectrophotometric methods were developed, namely; first derivative (D (1)) and derivative ratio (DD (1)) methods. The TLC method employed aluminum TLC plates precoated with silica gel GF254 as the stationary phase and methanol:toluene:ammonia (7:3:0.1, by volume) as the mobile phase, where the chromatogram was scanned at 235 nm. The developed HPLC method used a reversed phase C18 column with isocratic elution. The mobile phase composed of phosphate buffer pH 4.0:acetonitrile:triethylamine (53:47:0.03, by volume) at flow rate of 1.0 mL min(-1). Quantitation was achieved with UV detection at 235 nm. The methods were validated according to the International Conference on Harmonization (ICH) guidelines. The selectivity of the proposed methods was tested using laboratory-prepared mixtures. The developed methods were successfully applied for the determination of olanzapine and fluoxetine HCl in bulk powder and combined capsule dosage form. PMID- 25685416 TI - Non-thermal continuous and modulated electromagnetic radiation fields effects on sleep EEG of rats. AB - In the present study, the alteration in the sleep EEG in rats due to chronic exposure to low-level non-thermal electromagnetic radiation was investigated. Two types of radiation fields were used; 900 MHz unmodulated wave and 900 MHz modulated at 8 and 16 Hz waves. Animals has exposed to radiation fields for 1 month (1 h/day). EEG power spectral analyses of exposed and control animals during slow wave sleep (SWS) and rapid eye movement sleep (REM sleep) revealed that the REM sleep is more susceptible to modulated radiofrequency radiation fields (RFR) than the SWS. The latency of REM sleep increased due to radiation exposure indicating a change in the ultradian rhythm of normal sleep cycles. The cumulative and irreversible effect of radiation exposure was proposed and the interaction of the extremely low frequency radiation with the similar EEG frequencies was suggested. PMID- 25685417 TI - Correlation between changes in diastolic dysfunction and health-related quality of life after cardiac rehabilitation program in dilated cardiomyopathy. AB - Chronic heart failure (CHF) is a complex syndrome characterized by progressive decline in left ventricular function, low exercise tolerance and raised mortality and morbidity. Left ventricular diastolic dysfunction plays a major role in CHF and progression of most cardiac diseases. The current recommended goals can theoretically be accomplished via exercise and pharmacological therapy so the aim of the present study was to evaluate the impact of cardiac rehabilitation program on diastolic dysfunction and health related quality of life and to determine the correlation between changes in left ventricular diastolic dysfunction and domains of health-related quality of life (HRQoL). Forty patients with chronic heart failure were diagnosed as having dilated cardiomyopathy (DCM) with systolic and diastolic dysfunction. The patients were equally and randomly divided into training and control groups. Only 30 of them completed the study duration. The training group participated in rehabilitation program in the form of circuit interval aerobic training adjusted according to 55-80% of heart rate reserve for a period of 7 months. Circuit training improved both diastolic and systolic dysfunction in the training group. On the other hand, only a significant correlation was found between improvement in diastolic dysfunction and health related quality of life measured by Kansas City Cardiomyopathy Questionnaire. It was concluded that improvement in diastolic dysfunction as a result of rehabilitation program is one of the important underlying mechanisms responsible for improvement in health-related quality of life in DCM patients. PMID- 25685419 TI - Special issue on "Heliospheric Physics during and after a deep solar minimum". PMID- 25685418 TI - On the oscillation of higher order dynamic equations. AB - We present some new criteria for the oscillation of even order dynamic equation[Formula: see text]on time scale T, where alpha is the ratio of positive odd integers a and q is a real valued positive rd-continuous functions defined on T. PMID- 25685420 TI - Deep solar minimum and global climate changes. AB - This paper examines the deep minimum of solar cycle 23 and its potential impact on climate change. In addition, a source region of the solar winds at solar activity minimum, especially in the solar cycle 23, the deepest during the last 500 years, has been studied. Solar activities have had notable effect on palaeoclimatic changes. Contemporary solar activity are so weak and hence expected to cause global cooling. Prevalent global warming, caused by building-up of green-house gases in the troposphere, seems to exceed this solar effect. This paper discusses this issue. PMID- 25685421 TI - Sources of solar wind over the solar activity cycle. AB - Fast solar wind has been recognized, about 40 years ago, to originate in polar coronal holes (CHs), that, since then, have been identified with sources of recurrent high speed wind streams. As of today, however, there is no general consensus about whether there are, within CHs, preferential locations where the solar wind is accelerated. Knowledge of slow wind sources is far from complete as well. Slow wind observed in situ can be traced back to its solar source by backward extrapolation of magnetic fields whose field lines are streamlines of the outflowing plasma. However, this technique often has not the necessary precision for an indisputable identification of the region where wind originates. As the Sun progresses through its activity cycle, different wind sources prevail and contribute to filling the heliosphere. Our present knowledge of different wind sources is here summarized. Also, a Section addresses the problem of wind acceleration in the low corona, as inferred from an analysis of UV data, and illustrates changes between fast and slow wind profiles and possible signatures of changes along the solar cycle. A brief reference to recent work about the deep roots of solar wind and their changes over different solar cycles concludes the review. PMID- 25685422 TI - Solar origins of solar wind properties during the cycle 23 solar minimum and rising phase of cycle 24. AB - The solar wind was originally envisioned using a simple dipolar corona/polar coronal hole sources picture, but modern observations and models, together with the recent unusual solar cycle minimum, have demonstrated the limitations of this picture. The solar surface fields in both polar and low-to-mid-latitude active region zones routinely produce coronal magnetic fields and related solar wind sources much more complex than a dipole. This makes low-to-mid latitude coronal holes and their associated streamer boundaries major contributors to what is observed in the ecliptic and affects the Earth. In this paper we use magnetogram based coronal field models to describe the conditions that prevailed in the corona from the decline of cycle 23 into the rising phase of cycle 24. The results emphasize the need for adopting new views of what is 'typical' solar wind, even when the Sun is relatively inactive. PMID- 25685423 TI - Voyager observations of the interaction of the heliosphere with the interstellar medium. AB - This paper provides a brief review and update on the Voyager observations of the interaction of the heliosphere with the interstellar medium. Voyager has found many surprises: (1) a new energetic particle component which is accelerated at the termination shock (TS) and leaks into the outer heliosphere forming a foreshock region; (2) a termination shock which is modulated by energetic particles and which transfers most of the solar wind flow energy to the pickup ions (not the thermal ions); (3) the heliosphere is asymmetric; (4) the TS does not accelerate anomalous cosmic rays at the Voyager locations; and (5) the plasma flow in the Voyagers 1 (V1) and 2 (V2) directions are very different. At V1 the flow was small after the TS and has recently slowed to near zero, whereas at V2 the speed has remained constant while the flow direction has turned tailward. V1 may have entered an extended boundary region in front of the heliopause (HP) in 2010 in which the plasma flow speeds are near zero. PMID- 25685424 TI - The Space Weather and Ultraviolet Solar Variability (SWUSV) Microsatellite Mission. AB - We present the ambitions of the SWUSV (Space Weather and Ultraviolet Solar Variability) Microsatellite Mission that encompasses three major scientific objectives: (1) Space Weather including the prediction and detection of major eruptions and coronal mass ejections (Lyman-Alpha and Herzberg continuum imaging); (2) solar forcing on the climate through radiation and their interactions with the local stratosphere (UV spectral irradiance from 180 to 400 nm by bands of 20 nm, plus Lyman-Alpha and the CN bandhead); (3) simultaneous radiative budget of the Earth, UV to IR, with an accuracy better than 1% in differential. The paper briefly outlines the mission and describes the five proposed instruments of the model payload: SUAVE (Solar Ultraviolet Advanced Variability Experiment), an optimized telescope for FUV (Lyman-Alpha) and MUV (200-220 nm Herzberg continuum) imaging (sources of variability); UPR (Ultraviolet Passband Radiometers), with 64 UV filter radiometers; a vector magnetometer; thermal plasma measurements and Langmuir probes; and a total and spectral solar irradiance and Earth radiative budget ensemble (SERB, Solar irradiance & Earth Radiative Budget). SWUSV is proposed as a small mission to CNES and to ESA for a possible flight as early as 2017-2018. PMID- 25685425 TI - How unprecedented a solar minimum was it? AB - The end of the last solar cycle was at least 3 years late, and to date, the new solar cycle has seen mainly weaker activity since the onset of the rising phase toward the new solar maximum. The newspapers now even report when auroras are seen in Norway. This paper is an update of our review paper written during the deepest part of the last solar minimum [1]. We update the records of solar activity and its consequent effects on the interplanetary fields and solar wind density. The arrival of solar minimum allows us to use two techniques that predict sunspot maximum from readings obtained at solar minimum. It is clear that the Sun is still behaving strangely compared to the last few solar minima even though we are well beyond the minimum phase of the cycle 23-24 transition. PMID- 25685426 TI - The long-term variability of cosmic ray protons in the heliosphere: A modeling approach. AB - Galactic cosmic rays are charged particles created in our galaxy and beyond. They propagate through interstellar space to eventually reach the heliosphere and Earth. Their transport in the heliosphere is subjected to four modulation processes: diffusion, convection, adiabatic energy changes and particle drifts. Time-dependent changes, caused by solar activity which varies from minimum to maximum every ~11 years, are reflected in cosmic ray observations at and near Earth and along spacecraft trajectories. Using a time-dependent compound numerical model, the time variation of cosmic ray protons in the heliosphere is studied. It is shown that the modeling approach is successful and can be used to study long-term modulation cycles. PMID- 25685427 TI - Geomagnetism during solar cycle 23: Characteristics. AB - On the basis of more than 48 years of morphological analysis of yearly and monthly values of the sunspot number, the aa index, the solar wind speed and interplanetary magnetic field, we point out the particularities of geomagnetic activity during the period 1996-2009. We especially investigate the last cycle 23 and the long minimum which followed it. During this period, the lowest values of the yearly averaged IMF (3 nT) and yearly averaged solar wind speed (364 km/s) are recorded in 1996, and 2009 respectively. The year 2003 shows itself particular by recording the highest value of the averaged solar wind (568 km/s), associated to the highest value of the yearly averaged aa index (37 nT). We also find that observations during the year 2003 seem to be related to several coronal holes which are known to generate high-speed wind stream. From the long time (more than one century) study of solar variability, the present period is similar to the beginning of twentieth century. We especially present the morphological features of solar cycle 23 which is followed by a deep solar minimum. PMID- 25685428 TI - An early prediction of the maximum amplitude of the solar cycle 25. AB - A solar activity precursor technique of spotless event has been currently used to predict the strengths and the times of rise of the 11-year coming cycles. This simple statistical method has been previously applied to predict the maximum amplitudes and the times of rises of cycles 22 and 23. The results obtained are successful for both cycles. A developed version of the suggested method was previously used to make an early forecast of the characteristic parameters of the cycle 24. In this work the preliminarily predicted parameters of the cycle 24 are checked using observed values of the spotless events. In addition, the developed method is also applied to forecast the maximum amplitude and time of rise of the 25th solar cycle. The maximum Wolf number and time of rise of the latter cycle are found to be 118.2 and 4.0 years respectively. PMID- 25685429 TI - The sunspot cycle no. 24 in relation to long term solar activity variation. AB - The solar minimum between solar cycles 23 and 24 during the period 2007-2009 has been the longest and deepest one at least since for the last 100 years. We suggest that the Sun is going to his next supercenturial minimum. The main aim of this paper is to tell about arguments concerning this statement. They are based on series of studies, which have been provided during the period since 1997 up to 2010. The progress of solar cycle 24 since its minimum at the end of 2008 up to the end of October 2011 in the light of long term solar activity dynamics is analyzed. PMID- 25685430 TI - Influence of projection effects on the observed differential rotation rate in the UV corona. AB - Following previous investigations by Giordano and Mancuso [1] and Mancuso and Giordano [2,3] on the differential rotation of the solar corona as obtained through the analysis of the intensity time series of the O VI 1032 A spectral line observed by the UVCS/SOHO telescope during solar cycle 23, we analysed the possible influence of projection effects of extended coronal structures on the observed differential rotation rate in the ultraviolet corona. Through a simple geometrical model, we found that, especially at higher latitudes, the differential rotation may be less rigid than observed, since features at higher latitudes could be actually linked to much lower coronal structures due to projection effects. At solar maximum, the latitudinal rigidity of the UV corona, with respect to the differential rotating photosphere, has thus to be considered as an upper limit of the possible rigidity. At solar minimum and near the equatorial region throughout the solar cycle, projection effects are negligible. PMID- 25685431 TI - Super- and sub-critical regions in shocks driven by radio-loud and radio-quiet CMEs. AB - White-light coronagraphic images of Coronal Mass Ejections (CMEs) observed by SOHO/LASCO C2 have been used to estimate the density jump along the whole front of two CME-driven shocks. The two events are different in that the first one was a "radio-loud" fast CME, while the second one was a "radio quiet" slow CME. From the compression ratios inferred along the shock fronts, we estimated the Alfven Mach numbers for the general case of an oblique shock. It turns out that the "radio-loud" CME shock is initially super-critical around the shock center, while later on the whole shock becomes sub-critical. On the contrary, the shock associated with the "radio-quiet" CME is sub-critical at all times. This suggests that CME-driven shocks could be efficient particle accelerators at the shock nose only at the initiation phases of the event, if and when the shock is super critical, while at later times they lose their energy and the capability to accelerate high energetic particles. PMID- 25685432 TI - Plasma properties from the multi-wavelength analysis of the November 1st 2003 CME/shock event. AB - The analysis of the spectral properties and dynamic evolution of a CME/shock event observed on November 1st 2003 in white-light by the LASCO coronagraph and in the ultraviolet by the UVCS instrument operating aboard SOHO, has been performed to compute the properties of some important plasma parameters in the middle corona below about 2R ?. Simultaneous observations obtained with the MLSO/Mk4 white-light coronagraph, providing both the early evolution of the CME expansion in the corona and the pre-shock electron density profile along the CME front, were also used to study this event. By combining the above information with the analysis of the metric type II radio emission detected by ground-based radio spectrographs, we finally derive estimates of the values of the local Alfven speed and magnetic field strength in the solar corona. PMID- 25685433 TI - Comparison of COSMIC measurements with the IRI-2007 model over the eastern Mediterranean region. AB - This paper presents a comparison of the International Reference Ionosphere (IRI 2007) model over the eastern Mediterranean region with peak ionospheric characteristics (foF2-hmF2) and electron density profiles measured by FORMOSAT 3/COSMIC satellites in terms of GPS radio occultation technique and the Cyprus digisonde. In the absence of systematic ionosonde measurements over this area, COSMIC measurements provide an opportunity to perform such a study by considering observations for year 2010 to investigate the behaviour of the IRI-2007 model over the eastern Mediterranean area. PMID- 25685434 TI - Solar quiet day ionospheric source current in the West African region. AB - The Solar Quiet (Sq) day source current were calculated using the magnetic data obtained from a chain of 10 magnetotelluric stations installed in the African sector during the French participation in the International Equatorial Electrojet Year (IEEY) experiment in Africa. The components of geomagnetic field recorded at the stations from January-December in 1993 during the experiment were separated into the source and (induced) components of Sq using Spherical Harmonics Analysis (SHA) method. The range of the source current was calculated and this enabled the viewing of a full year's change in the source current system of Sq. PMID- 25685435 TI - Helium shells and faint emission lines from slitless flash spectra. AB - At the time of the two last solar total eclipses of August 1st, 2008 in Siberia and July 11th, 2010 in French Polynesia, high frame rate CCD flash spectra were obtained. These eclipses occurred in quiet Sun period and after. The slitless flash spectra show two helium shells, in the weak Paschen alpha 4686 A line of the ionized helium HeII and in the neutral helium HeI line at 4713 A. The extensions of these helium shells are typically 3 Mm. In prominences, the extension of the interface with the corona is much more extended. The observations and analysis of these lines can properly be done only in eclipse conditions, when the intensity threshold reaches the coronal level, and the parasitic scattered light is virtually zero. Under the layers of 1 Mm above the limb, many faint low FIP lines were also seen in emission. These emission lines are superposed on the continuum containing absorption lines. The solar limb can be defined using the weak continuum appearing between the emission lines at the time of the second and third contact. The variations of the singly ionized iron line, the HeI and HeII lines and the continuum intensity are analyzed. The intensity ratio of ionized to neutral helium is studied for evaluating the ionization rate in low layers up to 2 Mm and also around a prominence. PMID- 25685436 TI - Education and public outreach at the Carl Sagan Solar Observatory of the University of Sonora. AB - We discuss the importance of small solar observatories for EPO (Education and Public Outreach), mentioning why they are relevant and what kind of equipment and software require. We stress the fact that technological advances have made them affordable and that they should be widely available. This work is a result of our experience with one: The Carl Sagan Solar Observatory (CSSO). We briefly describe its status and the solar data obtained daily with students participation. We present examples of the data obtained in the visible, Ca II and two in Halpha. Data which is widely used for education. Finally we talk about the capability for remote operation as an open invitation for collaboration in educational and scientific projects. PMID- 25685437 TI - Boundary conditions for hyperbolic systems of partial differentials equations. AB - An easy-to-apply algorithm is proposed to determine the correct set(s) of boundary conditions for hyperbolic systems of partial differential equations. The proposed approach is based on the idea of the incoming/outgoing characteristics and is validated by considering two problems. The first one is the well-known Euler system of equations in gas dynamics and it proved to yield set(s) of boundary conditions consistent with the literature. The second test case corresponds to the system of equations governing the flow of viscoelastic liquids. PMID- 25685438 TI - QRS detection using K-Nearest Neighbor algorithm (KNN) and evaluation on standard ECG databases. AB - The performance of computer aided ECG analysis depends on the precise and accurate delineation of QRS-complexes. This paper presents an application of K Nearest Neighbor (KNN) algorithm as a classifier for detection of QRS-complex in ECG. The proposed algorithm is evaluated on two manually annotated standard databases such as CSE and MIT-BIH Arrhythmia database. In this work, a digital band-pass filter is used to reduce false detection caused by interference present in ECG signal and further gradient of the signal is used as a feature for QRS detection. In addition the accuracy of KNN based classifier is largely dependent on the value of K and type of distance metric. The value of K = 3 and Euclidean distance metric has been proposed for the KNN classifier, using fivefold cross validation. The detection rates of 99.89% and 99.81% are achieved for CSE and MIT BIH databases respectively. The QRS detector obtained a sensitivity Se = 99.86% and specificity Sp = 99.86% for CSE database, and Se = 99.81% and Sp = 99.86% for MIT-BIH Arrhythmia database. A comparison is also made between proposed algorithm and other published work using CSE and MIT-BIH Arrhythmia databases. These results clearly establishes KNN algorithm for reliable and accurate QRS detection. PMID- 25685439 TI - Bactericidal efficacy of elevated pH on fish pathogenic and environmental bacteria. AB - Ship ballast water is a recognized medium for transfer and introductions of nonindigenous species. There is a need for new ballast water treatment methods that effectively and safely eliminate or greatly minimize movements of these species. The present study employed laboratory methods to evaluate the bactericidal efficacy of increased pH (pH 10.0-12.0) for exposure durations of up to 72 h to kill a variety of Gram-negative and Gram-positive bacteria including fish pathogens (Aeromonas spp., Yersinia ruckeri, Edwardsiella ictaluri, Serratia liquefaciens, Carnobacterium sp.), other common aquatic-inhabitant bacteria (Serratia marcescens, Pseudomonas fluorescens, Staphylococcus sp., Bacillus sp.) and indicators listed in International Maritime Organization D2 Standards; namely, Vibrio cholera (an environmental isolate from fish), Escherichia coli and Enterococcus faecalis. Volumes of 5 N NaOH were added to tryptic soy broth to obtain desired pH adjustments. Viable cells were determined after 0, 4, 12, 24, 48, and 72 h. Initial (0 h) cell numbers ranged from 3.40 * 10(4) cfu/mL for Bacillus sp. to 2.44 * 10(7) cfu/mL for E. faecalis. The effective endpoints of pH and treatment duration necessary to realize 100% bactericidal effect varied; however, all bacteria tested were killed within 72 h at pH 12.0 or lower. The lowest parameters examined, 4 h at pH 10.0, were bactericidal to V. cholera, E. ictaluri, three of four isolates of E. coli, and (three of four) Aeromonas salmonicida subsp. salmonicida. Bactericidal effect was attained at pH 10.0 within 12 h for the other A. salmonicida subsp. salmonicida, and within 24 h for P. fluorescens, and the remaining E. coli. PMID- 25685440 TI - Analgesic effect of intra-articular magnesium sulphate compared with bupivacaine after knee arthroscopic menisectomy. AB - This work aimed to evaluate the analgesic efficacy of intra-articular injection of magnesium sulphate (4%) compared with equivalent volume of bupivacaine (0.5%) after outpatient knee arthroscopic meniscectomy. Forty patients were randomly assigned to two groups. Group M (n = 20) received intra-articular magnesium sulphate 4%, group B (n = 20) received bupivacaine (0.5%). Analgesic effect was evaluated by analgesic duration, and by measuring pain intensity at 1, 2, 4, 6, 12, 24 h both at rest and on knee movement to 90 degrees . The primary outcome variable was pain intensity on the VAS at 1, 2, 4, 6, 12, 24 h post arthroscopy at rest and on movement (flexion of knee to 90 degrees ), although the magnesium group had lower time weighted averages (TWAs) at rest and on movement, these TWAs were not statistically significant. The median duration of postoperative analgesia was significantly longer in the patients treated with magnesium sulphate (528 min) than in the bupivacaine group (317 min) (p < 0.0001), with less number of patients needing supplementary analgesia in magnesium group (8/20) than those of the bupivacaine group (16/20) (p < 0.022). Also analgesic consumption was significantly lower in the magnesium sulphate group (p < 0.002). We concluded that the use of magnesium sulphate is rational and effective in reducing pain, and is more physiological and shortens convalescence after outpatient arthroscopic meniscectomy, however our hypotheses that analgesic efficacy of intra-articular isotonic magnesium sulphate would be superior to intra-articular local anaesthetic cannot be supported with this study. PMID- 25685441 TI - Preconcentration of lead using solidification of floating organic drop and its determination by electrothermal atomic absorption spectrometry. AB - A simple microextraction method based on solidification of a floating organic drop (SFOD) was developed for preconcentration of lead prior to its determination by electrothermal atomic absorption spectrometry (ETAAS). Ammonium pyrolidinedithiocarbamate (APDC) was used as complexing agent, and the formed complex was extracted into a 20 MUL of 1-undecanol. The extracted complex was diluted with ethanol and injected into a graphite furnace. An orthogonal array design (OAD) with OA16 (4(5)) matrix was employed to study the effects of different parameters such as pH, APDC concentration, stirring rate, sample solution temperature and the exposure time on the extraction efficiency. Under the optimized experimental conditions the limit of detection (based on 3 s) and the enhancement factor were 0.058 MUg L(-1) and 113, respectively. The relative standard deviation (RSD) for 8 replicate determinations of 1 MUg L(-1) of Pb was 8.8%. The developed method was validated by the analysis of certified reference materials and was successfully applied to the determination of lead in water and infant formula base powder samples. PMID- 25685442 TI - Biosorption of cadmium and lead from aqueous solution by fresh water alga Anabaena sphaerica biomass. AB - The present work represents the biosorption of Cd(II) and Pb(II) from aqueous solution onto the biomass of the blue green alga Anabaena sphaerica as a function of pH, biosorbent dosage, contact time, and initial metal ion concentrations. Freundlich, Langmuir, and Dubinin-Radushkevich (D-R) models were applied to describe the biosorption isotherm of both metals by A. sphaerica biomass. The biosorption isotherms studies indicated that the biosorption of Cd(II) and Pb(II) follows the Langmuir and Freundlish models. The maximum biosorption capacities (qmax ) were 111.1 and 121.95 mg/g, respectively, at the optimum conditions for each metal. From the D-R isotherm model, the mean free energy was calculated to be 11.7 and 14.3 kJ/mol indicating that the biosorption mechanism of Cd(II) and Pb(II) by A. sphaerica was chemisorption. The FTIR analysis for surface function group of algal biomass revealed the existence of amino, carboxyl, hydroxyl, and carbonyl groups, which are responsible for the biosorption of Cd(II) and Pb(II). The results suggested that the biomass of A. sphaerica is an extremely efficient biosorbent for the removal of Cd(II) and Pb(II) from aqueous solutions. PMID- 25685443 TI - The effect of streptozotocin-induced diabetes on the EDHF-type relaxation and cardiac function in rats. AB - The endothelium-derived hyperpolarizing factor (EDHF) response is a critical for the functioning of small blood vessels. We investigated the effect of streptozotocin-induced diabetes on the EDHF response and its possible role in the regulation of cardiac function. The vasorelaxant response to ACh- or NS309- (direct opener endothelial small- (SKCa)- and intermediate-conductance (IKCa) calcium-activated potassium channels; main components of EDHF response) were measured in pressurized mesenteric arteries (diameter 300-350 MUm). The response to 1 MUM ACh was reduced in diabetes (84.8 +/- 2.8% control vs 22.5 +/- 5.8% diabetics; n ? 8; P < 0.001). NS309 (1 MUM) relaxations were also decreased in diabetic arteries (78.5 +/- 8.7% control vs 32.1 +/- 5.8% diabetics; n ? 5; P < 0.001). SKCa and IKCa-mediated EDHF relaxations in response ACh or NS309 were also significantly reduced by diabetes. Ruthenium red, RuR, a blocker of TRP channels, strongly depress the response to ACh and NS309 in control and diabetic arteries. RuR decreased SKCa and IKCa-mediated EDHF vasodilatation in response to NS309 but not to ACh. An elevation in systolic blood pressure was observed in diabetic animals. ECG recording of control hearts showed shortening of PR interval. RuR reduced PR interval and R wave amplitude in diabetic hearts. In conclusion, the reduced EDHF-type relaxations in STZ-induced diabetes is due impairment of KCa channels function. TRP channels possibly contribute to EDHF vasodilatation via direct opening of endothelial KCa. It is possible that EDHF and TRP channels contribute to the regulation of cardiac function and therefore can be considered as therapeutic targets to improve cardiovascular complications of diabetes. PMID- 25685444 TI - Synthesis and corrosion protection properties of poly(o-phenylenediamine) nanofibers. AB - The present study shows a novel method for the synthesis of uniformly-shaped poly(othophenylediamine) (PoPD) nanofibers by chemical oxidative polymerization method for application towards smart corrosion resistance coatings. Transmission Electron Microscopy (TEM) and Scanning Electron Microscopy (SEM) studies confirm morphology of PoPD with three dimensional (3D) networked dendritic superstructures having average diameter of 50-70 nm and several hundred meters of length. UV-vis and FTIR spectral results shows the formation of PoPD nanofibers containing phenazine ring ladder-structure with benzenoid and quinoid imine units. Thermogravimetric analyses (TGA) of PoPD nanofibers possess good thermal stability. The anti-corrosion behavior of PoPD nanofibers on 316L SS was investigated in 3.5% NaCl solution using potentiodynamic polarization and electrochemical impedance spectroscopic (EIS) measurements. The PoPD coated 316L SS exhibits higher corrosion potential when compared to uncoated specimen. EIS studies, clearly ascertain that PoPD nanofiber coatings exhibits excellent potential barrier to protect the 316L SS against corrosion in 3.5% NaCl. PMID- 25685445 TI - Efficacy of a pyrimidine derivative to control spot disease on Solanum melongena caused by Alternaria alternata. AB - The pyrimidine derivative (4,6-dimethyl-N-phenyldiethyl pyrimidine, DPDP) was tested as a foliar spray fungicide at 50 mg l(-1) for protection of eggplant (Solanum melongena) from spot disease caused by Alternaria alternata. Varied concentrations of DPDP (10-50 mg l(-1)) differentially inhibited mycelial growth, conidial count and conidial germination of A. alternata growth in vitro; the magnitude of inhibition increased with increasing concentration. In vivo, an experiment was conducted in pots using a complete block randomized design and repeated twice with three replications and four treatments (control, A. alternata alone, DPDP alone and combination of DPDP and A. alternata) for 5 weeks (1 plant in pot * 3 pots per set (3 replications per treatment) * 4 sets (4 treatments) * 5 weeks * 2 experimental repetitions = 120 pots). In this experiment, 10-day-old eggplant seedlings were transplanted in pots and then inoculated with A. alternata, DPDP or their combination 1 week later. Leaves of the A. alternata infected eggplant suffered from chlorosis, necrosis and brown spots during the subsequent 5 weeks. Disease intensity was obvious in infected leaves but withdrawn by DPDP. There were relationships between incidence and severity, greater in plant leaves infected A. alternata alone and diminished with the presence of DPDP. Moreover, the infection resulted in reductions in growth, decreases in contents of anthocyanins, chlorophylls, carotenoids and thiols as well as inhibitions in activities of superoxide dismutase (SOD), glutathione peroxidase (GPX) and glutathione-S-transferase (GST). Nonetheless, the application of DPDP at 50 mg led to a recovery of the infected eggplant; the infection-induced deleterious effects were mostly reversed by DPDP. However, treatment with DPDP alone seemed with no significant impacts. Due to its safe use to host and the inhibition for the pathogen, DPDP could be suggested as an efficient fungicide for protection of eggplant to control A. alternata spot disease. PMID- 25685446 TI - Efficient modeling of vector hysteresis using a novel Hopfield neural network implementation of Stoner-Wohlfarth-like operators. AB - Incorporation of hysteresis models in electromagnetic analysis approaches is indispensable to accurate field computation in complex magnetic media. Throughout those computations, vector nature and computational efficiency of such models become especially crucial when sophisticated geometries requiring massive sub region discretization are involved. Recently, an efficient vector Preisach-type hysteresis model constructed from only two scalar models having orthogonally coupled elementary operators has been proposed. This paper presents a novel Hopfield neural network approach for the implementation of Stoner-Wohlfarth-like operators that could lead to a significant enhancement in the computational efficiency of the aforementioned model. Advantages of this approach stem from the non-rectangular nature of these operators that substantially minimizes the number of operators needed to achieve an accurate vector hysteresis model. Details of the proposed approach, its identification and experimental testing are presented in the paper. PMID- 25685447 TI - In vivo wound healing and antiulcer properties of white sweet potato (Ipomoea batatas). AB - The potential of tuber flour of Ipomoea batatas (L.) Lam. cv. Brazlandia Branca (white sweet potato) as wound healing and antiulcerogenic agent was investigated in vivo in animal model. Excision on the back of Wistar rats was performed to induce wounds that were topically treated with Beeler's base containing tuber flour of white sweet potato at 2.5%. Number of cells undergoing metaphase and the degree of tissue re-epithelialization were investigated 4, 7 and 10 days post treatment. The protective effect of aqueous suspension of tuber flour (75 and 100 mg/kg animal weight) on gastric mucosa of Wistar rats was also studied by using the ethanol-induced ulceration model. Ointment based on white sweet potato at 2.5% effectively triggered the healing of cutaneous wound as attested by the increased number of cells undergoing metaphase and tissue re-epithelialization regardless the time of wound treatment. Tuber flour potentially prevented ethanol induced gastric ulceration by suppressing edema formation and partly protecting gastric mucosa wrinkles. Crude extracts also exhibited potential as free radical scavengers. The results from animal model experiments indicate the potential of tuber flour of white sweet potato to heal wounds. PMID- 25685448 TI - Cytotoxic effect of commercial Humulus lupulus L. (hop) preparations - In comparison to its metabolomic fingerprint. AB - Hops (Humulus lupulus L. Cannabaceae) is an economically important crop, that has drawn more attention in recent years due to its potential pharmaceutical applications. Bitter acids (prenylated polyketides) and prenylflavonoids are the primary phytochemical components that account for hops resins medicinal value. We have previously reported on utilizing untargeted NMR and MS metabolomics for analysis of 13 hops cultivars, revealing for differences in alpha- versus beta bitter acids composition in derived resins. In this study, effect of ratios of bitter alpha- to beta-acids in hop resins to cytotoxicity of hop resins was investigated. In vitro cell culture assays revealed that beta-acids were more effective than alpha-acids in growth inhibition of PC3 and HT29 cancer cell lines. Nevertheless, hop resins enriched in beta-acids showed comparable growth inhibition patterns to alpha-enriched resins and suggesting that bioactivity may not be easily predicted by metabolomics and/or gross metabolic profiling in hops. PMID- 25685449 TI - Epidemiology of Schistosomiasis in Egypt: Travel through Time: Review. AB - Schistosomiasis is a parasitic disease caused by blood flukes (Trematodes) of the genus Schistosoma (S.). It is well documented that schistosomiasis haematobium was endemic in Ancient Egypt. Infection was diagnosed in mummies 3000, 4000 and 5000 years old. Scott was the first to describe the pattern of schistosomiasis infection in Egypt. Schistosomiasis haematobium was highly prevalent (60%) both in the Nile Delta and Nile Valley South of Cairo in districts of perennial irrigation while it was low (6%) in districts of basin irrigation. Schistosoma mansoni infected 60% of the population in the Northern and Eastern parts of the Nile Delta and only 6% in the Southern part. Neither S. mansoni cases nor its snail intermediate host were found in the Nile Valley South of Cairo. The building of the Aswan High Dam -which was completed in 1967 - did not cause any increase in schistosomiasis prevalence. In 1990, a study conducted in nine governorates of Egypt confirmed the change in the pattern of schistosomiasis transmission in the Delta. There was an overall reduction in S. mansoni prevalence while Schistosoma haematobium had continued to disappear. In Middle and Upper Egypt there was consistent reduction in the prevalence of S. haematobium except in Sohag, Qena, and Aswan governorates. However, foci of S. mansoni were detected in Giza, Fayoum, Menya and Assiut. All schistosomiasis control projects implemented in Egypt from 1953 to 1985 adopted the strategy of transmission control and were based mainly on snail control supplemented by anti bilharzial chemotherapy. In 1997, the National Schistosomiasis Control Program (NSCP) was launched in the Nile Delta. It adopted morbidity control strategy with Praziquantel mass treatment as the main component. In 1996, before the NSCP, 168 villages had S. mansoni prevalence >30%, 324 villages 20-30% and 654 villages 10 20%. By the end of 2010, in the whole country only 29 villages had prevalence >3% and none had more than 10%. PMID- 25685450 TI - Human schistosomiasis: clinical perspective: review. AB - The clinical manifestations of schistosomiasis pass by acute, sub acute and chronic stages that mirror the immune response to infection. The later includes in succession innate, TH1 and TH2 adaptive stages, with an ultimate establishment of concomitant immunity. Some patients may also develop late complications, or suffer the sequelae of co-infection with other parasites, bacteria or viruses. Acute manifestations are species-independent; occur during the early stages of invasion and migration, where infection-naivety and the host's racial and genetic setting play a major role. Sub acute manifestations occur after maturity of the parasite and settlement in target organs. They are related to the formation of granulomata around eggs or dead worms, primarily in the lower urinary tract with Schistosoma haematobium, and the colon and rectum with Schistosoma mansoni, Schistosoma japonicum, Schistosoma intercalatum and Schistosoma mekongi infection. Secondary manifestations during this stage may occur in the kidneys, liver, lungs or other ectopic sites. Chronic morbidity is attributed to the healing of granulomata by fibrosis and calcification at the sites of oval entrapment, deposition of schistosomal antigen-antibody complexes in the renal glomeruli or the development of secondary amyloidosis. Malignancy may complicate the chronic lesions in the urinary bladder or colon. Co-infection with salmonella or hepatitis viruses B or C may confound the clinical picture of schistosomiasis, while the latter may have a negative impact on the course of other co-infections as malaria, leishmaniasis and HIV. Prevention of schistosomiasis is basically geared around education and periodic mass treatment, an effective vaccine being still experimental. Praziquantel is the drug of choice in the treatment of active infection by any species, with a cure rate of 80%. Other antischistosomal drugs include metrifonate for S. haematobium, oxamniquine for S. mansoni and Artemether and, possibly, Mirazid for both. Surgical treatment may be needed for fibrotic lesions. PMID- 25685451 TI - Hepatic and intestinal schistosomiasis: review. AB - Schistosomiasis is an endemic disease in Egypt caused by the trematode Schistosoma which has different species. Hepatic schistosomiasis represents the best known form of chronic disease with a wide range of clinical manifestations. The pathogenesis of schistosomiasis is related to the host cellular immune response. This leads to granuloma formation and neo angiogenesis with subsequent periportal fibrosis manifested as portal hypertension, splenomegaly and esophageal varices. Intestinal schistosomiasis is another well identified form of chronic schistosomal affection. Egg deposition and granuloma formation eventually leads to acute then chronic schistosomal colitis and is commonly associated with polyp formation. It frequently presents as abdominal pain, diarrhea, tenesmus and anal pain. Definite diagnosis of schistosomiasis disease depends on microscopy and egg identification. Marked progress regarding serologic diagnosis occurred with development of recent PCR techniques that can confirm schistosomal affection at any stage. Many antischistosomal drugs have been described for treatment, praziquantel being the most safe and efficient drug. Still ongoing studies try to develop effective vaccines with identification of many target antigens. Preventive programs are highly needed to control the disease morbidity and to break the cycle of transmission. PMID- 25685452 TI - Urinary schistosomiasis: review. AB - In this review, the clinical manifestations of urinary schistosomiasis are displayed from a pathogenetic perspective. According to the prevailing host's immune response profile, urinary schistosomiasis may be broadly categorized into cell-mediated and immune-complex-mediated disorders. The former, usually due to Schistosoma haematobium infection, are attributed to the formation of granulomata along the entire urinary tract. As they heal with excessive fibrosis, they may lead to strictures, calcifications and urodynamic abnormalities. The main impact is lower urinary, the site of heaviest ovi-position. Secondary bacterial or viral infection is common, any may be incriminated in secondary stone formation of the development of bladder malignancy. Immune-complex mediated lesions are usually associated with hepatosplenic schistosomiasis due to Schistosoma mansoni infection. Circulating complexes composed of schistosomal gut antigens and different classes of immunoglobulins deposit in the kidneys leading to several patterns of glomerular pathology. The latter have been categorized under six classes based on the histological and immunofluorescence profile. These classes have been linked to respective clinical manifestations and depend on the stage of evolution of the host's immune response, extent of associated hepatic fibrosis and co-infection with salmonella or hepatitis C. Secondary amyloidosis develops in 15% of such patients, representing a critical impairment of macrophage function. CONCLUSION: The wide clinicopathological spectrum of urinary schistosomiasis mirrors the evolution of the host's immune response according to chronicity of infection, bacterial or viral co-infection and, in the case of glomerulonephritis, to the extent of hepatic co-morbidity. PMID- 25685453 TI - Schistosomiasis and cancer in egypt: review. AB - Schistosomiasis is not known to be associated with any malignant disease other than bladder cancer. Bladder cancer is still the most common malignant tumor among males in Egypt and some African and Middle East countries. However, the frequency rate of bladder cancer has declined significantly during the last 25 years. This drop is mainly related to the control of Schistosomiasis. Many studies have elucidated the pathogenic events of Schistosomal-related bladder cancer with a suggested theory of pathogenesis. Furthermore, the disease presents with a distinct clinicopathologic profile that is quite different from bladder cancer elsewhere with younger age at presentation, more male predominance, more invasive stages, and occurrence of squamous cell carcinoma pathologic subtype. However, recent data suggest that this profile has been dramatically changed over the past 25 years leading to minimization of the differences between its features in Egypt and that in Western countries. Management of muscle-invasive localized disease is mainly surgery with 5-year survival rates of 30-50%. Although still a debatable issue, adjuvant and neoadjuvant chemotherapy and radiotherapy have improved treatment outcomes including survival and bladder preservation rates in most studies. This controversy emphasizes the need of individualized treatment options based on a prognostic index or other factors that can define the higher risk groups where more aggressive therapy is needed. The treatment for locally advanced and/or metastatic disease has passed through a series of clinical trials since 1970s. These phase II and III trials have included the use of single agent and combination of chemotherapy and radiotherapy regimens. The current standard of systemic chemotherapy of generally fit patients is now the gemcitabine cisplatin combination. In conclusion, a changing pattern of bladder cancer in Egypt is clearly observed. This is mainly due to the success in the control of Schistosomiasis. It may also be due to increased exposure to other etiologic factors that include smoking, pesticides, and/or other causative agents. This change will ultimately affect disease management. PMID- 25685455 TI - Beneficial role of ZnO photocatalyst supported with porous activated carbon for the mineralization of alizarin cyanin green dye in aqueous solution. AB - The present investigation depicts the development of a simple and low cost method for the removal of color from textile dyeing and printing wastewater using ZnO as photocatalyst supported with porous activated carbon (AC). Photocatalytic degradation studies were carried out for water soluble toxic alizarin cyanin green (ACG) dye in aqueous suspension along with activated carbon (AC) as co adsorbent. Different parameters like concentration of ACG dye, irradiation time, catalyst concentration and pH have also been studied. The pseudo first order kinetic equation was found to be applicable in the present dye-catalyst systems. It was observed that photocatalytic degradation by ZnO along with AC was a more effective and faster mode of removing ACG from aqueous solutions than the ZnO alone. PMID- 25685456 TI - Kinesio arm taping as prophylaxis against the development of Erb's Engram. AB - An Erb's Engram is a common debility that develops in recovering children with Erb's palsy. The purpose of this study was to investigate the effect of kinesiotaping over the deltoid and the forearm on the development of proper upper extremity function in children recovering from Erb's palsy. Thirty patients with Erb's palsy participated for 3 months in this study and were equally divided into two groups; control group A and study group B. The two groups received the same designed physical therapy program, while group B along the program, received kinesiotaping over the deltoid and the forearm. The subjects were evaluated, pre and post-treatment, and scored functionally, using the Toronto Active Motion Scale, and objectively, using an EMG device utilized to obtain the percentages of degeneration of the deltoid and the biceps muscles. Post-treatment values of six out of nine measured variables, between the two groups, revealed significant difference in favor of group B. The obtained results strongly support the introduction of kinesiotaping of the deltoid and the forearm as an adjunct to the treatment program of Erb's palsied children. PMID- 25685457 TI - Effect of air injection under subsurface drip irrigation on yield and water use efficiency of corn in a sandy clay loam soil. AB - Subsurface drip irrigation (SDI) can substantially reduce the amount of irrigation water needed for corn production. However, corn yields need to be improved to offset the initial cost of drip installation. Air-injection is at least potentially applicable to the (SDI) system. However, the vertical stream of emitted air moving above the emitter outlet directly toward the surface creates a chimney effect, which should be avoided, and to ensure that there are adequate oxygen for root respiration. A field study was conducted in 2010 and 2011, to evaluate the effect of air-injection into the irrigation stream in SDI on the performance of corn. Experimental treatments were drip irrigation (DI), SDI, and SDI with air injection. The leaf area per plant with air injected was 1.477 and 1.0045 times greater in the aerated treatment than in DI and SDI, respectively. Grain filling was faster, and terminated earlier under air-injected drip system, than in DI. Root distribution, stem diameter, plant height and number of grains per plant were noticed to be higher under air injection than DI and SDI. Air injection had the highest water use efficiency (WUE) and irrigation water use efficiency (IWUE) in both growing seasons; with values of 1.442 and 1.096 in 2010 and 1.463 and 1.112 in 2011 for WUE and IWUE respectively. In comparison with DI and SDI, the air injection treatment achieved a significantly higher productivity through the two seasons. Yield increases due to air injection were 37.78% and 12.27% greater in 2010 and 38.46% and 12.5% in 2011 compared to the DI and SDI treatments, respectively. Data from this study indicate that corn yield can be improved under SDI if the drip water is aerated. PMID- 25685454 TI - Novel therapeutic and prevention approaches for schistosomiasis: review. AB - Schistosomiasis is a debilitating disease affecting approximately 600 million people in 74 developing countries, with 800 million, mostly children at risk. To circumvent the threat of having praziquantel (PZQ) as the only drug used for treatment, several PZQ derivatives were synthesized, and drugs destined for other parasites were used with success. A plethora of plant-derived oils and extracts were found to effectively kill juvenile and adult schistosomes, yet none was progressed to pre- and clinical studies except an oleo-gum resin extracted from the stem of Commiphora molmol, myrrh, which action was challenged in several trials. We have proposed an essential fatty acid, a component of our diet and cells, the polyunsaturated fatty acid arachidonic acid (ARA) as a remedy for schistosomiasis, due to its ability to activate the parasite tegument-bound neutral sphingomyelinase, with subsequent hydrolysis of the apical lipid bilayer sphingomyelin molecules, allowing access of specific antibody molecules, and eventual worm attrition. This concept was convincingly supported using larval and adult Schistosoma mansoni and Schistosoma haematobium worms in in vitro experiments, and in vivo studies in inbred mice and outbred hamsters. Even if ARA proves to be an entirely effective and safe therapy for schistosomiasis, it will not prevent reinfection, and accordingly, the need for developing an effective vaccine remains an urgent priority. Our studies have supported the status of S. mansoni calpain, glutathione-S-transferase, aldolase, triose phosphate isomerase, glyceraldehyde 3-phosphate dehydrogenase, enolase, and 2-cys peroxiredoxin as vaccine candidates, as they are larval excreted-secreted products and, contrary to the surface membrane molecules, are entirely accessible to the host immune system effector elements. We have proposed that the use of these molecules, in conjunction with Th2 cytokines-inducing adjuvants for recruiting and activating eosinophils and basophils, will likely lead to development and implementation of a sterilizing vaccine in a near future. PMID- 25685458 TI - Multiproperty empirical isotropic interatomic potentials for CH4-inert gas mixtures. AB - An approximate empirical isotropic interatomic potentials for CH4-inert gas mixtures are developed by simultaneously fitting the Exponential-Spline-Morse Spline-van der Waals (ESMSV) potential form to viscosity, thermal conductivity, thermal diffusion factors, diffusion coefficient, interaction second pressure virial coefficient and scattering cross-section data. Quantum mechanical lineshapes of collision-induced absorption (CIA) at different temperatures for CH4-He and at T = 87 K for CH4-Ar are computed using theoretical values for overlap, octopole and hexadecapole mechanisms and interaction potential as input. Also, the quantum mechanical lineshapes of collision-induced light scattering (CILS) for the mixtures CH4-Ar and CH4-Xe at room temperature are calculated. The spectra of scattering consist essentially of an intense, purely translational component which includes scattering due to free pairs and bound dimers, and the other is due to the induced rotational scattering. These spectra have been interpreted by means of pair-polarizability terms, which arise from a long-range dipole-induced-dipole (DID) with small dispersion corrections and a short-range interaction mechanism involving higher-order dipole-quadrupole A and dipole octopole E multipole polarizabilities. Good agreement between computed and experimental lineshapes of both absorption and scattering is obtained when the models of potential, interaction-induced dipole and polarizability components are used. PMID- 25685459 TI - Sonochemical synthesis of 1,2,4,5-tetrasubstituted imidazoles using nanocrystalline MgAl2O4 as an effective catalyst. AB - An efficient four-component synthesis of 1,2,4,5-tetrasubstituted imidazoles is described by one-step condensation of an aldehyde, benzil, ammonium acetate and primary aromatic amine with nanocrystalline magnesium aluminate in ethanol under ultrasonic irradiation. High yields, short reaction times, mild conditions, simplicity of operation and easy work-up are some advantages of this protocol. PMID- 25685460 TI - Impact of highway geometry and posted speed on operating speed at multi-lane highways in Egypt. AB - The paper presents an analysis of roadway factors and posted speed limits that affect the operating speed at multi-lane highways in Egypt. Field data on multi lane highways in Egypt are used in this investigation. The analysis considers two categories of highways. The first consists of two desert roads (Cairo-Alexandria and Cairo-Ismailia desert roads) and the second consists of two agricultural roads (Cairo-Alexandria and Tanta-Damietta agricultural roads). The paper includes three separate relevant analyses. The first analysis uses the regression models to investigate the relationships between operating speed (V 85) as dependent variable, and roadway factors and posted speed as independent variables. The road factors are lane width, shoulder width, pavement width, median width, number of lanes in each direction, and existence of side access along each section. The second analysis uses the Artificial Neural Network (ANN) to explore the previous relationships while the third one examines the suitability of the posted speed limits on the roads under study. It is found that the ANN modeling gives the best model for predicting the operating speed and the most influential variables on V 85 are the pavement width, followed by the median width and the existence of side access along section. It is also found that the posted speed limit has a very small effect on the operating speed due to the bad behavior of drivers in Egypt. These results are so important for controlling V 85 on multi-lane rural highways in Egypt. PMID- 25685461 TI - Synthesis and photophysical properties of aluminium tris-(4-morpholine-8 hydroxyquinoline). AB - Aluminium tris(4-morpholinyl-8-hydroxyquinoline) has been synthesized and characterized. The photoluminescence measurements showed that the new derivative is blue shifted and has relative photoluminescence quantum yield two times higher compared to the pristine Al tris(8-hydroxyquinoline). Deferential scanning colorimetric studies revealed that the newly synthesized Alq3 derivative in this work is amorphous material with the highest transition glass temperature value among the reported amorphous Alq3 derivatives. PMID- 25685462 TI - Electrical conduction and dielectric relaxation in p-type PVA/CuI polymer composite. AB - PVA/CuI polymer composite samples have been prepared and subjected to characterizations using FT-IR spectroscopy, DSC analysis, ac spectroscopy and dc conduction. The FT-IR spectral analysis shows remarkable variation of the absorption peak positions whereas DSC illustrates a little decrease of both glass transition temperature, Tg , and crystallization fraction, chi, with increasing CuI concentration. An increase of dc conductivity for PVA/CuI nano composite by increasing CuI concentration is recoded up to 15 wt%, besides it obeys Arhenuis plot with an activation energy in the range 0.54-1.32 eV. The frequency dependence of ac conductivity showed power law with an exponent 0.33 < s < 0.69 which predicts hopping conduction mechanism. The frequency dependence of both dielectric permittivity and dielectric loss obeys Debye dispersion relations in wide range of temperatures and frequency. Significant values of dipole relaxation time obtained which are thermally activated with activation energies in the range 0.33-0.87 eV. A significant value of hopping distance in the range 3.4-1.2 nm is estimated in agreement with the value of Bohr radius of the exciton. PMID- 25685463 TI - Impact of PIVKA-II in diagnosis of hepatocellular carcinoma. AB - Liver cancer grows silently with mild or no symptoms until advanced. In the absence of an effective treatment for advanced stage of hepatic cancer hope lies in early detection, and screening for high-risk population. Among Egyptians viral hepatitis is the most common risk factor for hepatocellular carcinoma (HCC). The current work was designed to determine the level of prothrombin induced by vitamin K absence-II (PIVKA-II) in sera of patients suffering from HCC and hepatitis C virus (HCV) patients being the most common predisposing factor for HCC. Our ultimate goal is diagnosis of HCC at its early stage. The current study was carried out on 83 individuals within three groups; Normal control, HCV and HCC groups. Patients were subdivided into cirrhotic and non-cirrhotic. Complete clinicopathological examination was carried out for each individual to confirm diagnosis. Individuals' sera were subjected to quantitative determination of alpha-fetoprotein (AFP), PIVKA-II and other parameters. PIVKA-II proved to be superior to AFP for early detection of HCC patients being highly sensitive and specific. Furthermore it has the ability to discriminate between different histopathological grades of HCC and It has a powerful diagnostic validity to evaluate the thrombosis of portal vein and to differentiate between early and late stages of HCC. The direct relation between the level of PIVKA-II and the size of tumor makes it an attractive tool for early HCC diagnosis and surveillance. Using the best cut-off value of AFP (>28), showed a sensitivity of (44%) and specificity of (73.3%). While cut-off value of PIVKA-II (>53.7) showed 100% sensitivity and specificity. PMID- 25685464 TI - Modification of fiber properties through grafting of acrylonitrile to rayon by chemical and radiation methods. AB - Fibrous properties of rayon has been modified through synthesis of graft copolymers of rayon with acrylonitrile (AN) by chemical method using ceric ammonium nitrate (CAN/HNO3) as a redox initiator and gamma radiation mutual method. Percentage of grafting (Pg) was determined as a function of initiator concentration, monomer concentration, irradiation dose, temperature, time of reaction and the amount of water. Maximum percentage of grafting (160.01%) using CAN/HNO3 was obtained at [CAN] = 22.80 * 10(-3) mol/L, [HNO3] = 112.68 * 10(-2) mol/L and [AN] = 114.49 * 10(-2) mol/L in 20 mL of water at 45 degrees C within 120 min while in case of gamma radiation method, maximum Pg (90.24%) was obtained at an optimum concentration of AN of 76.32 * 10(-2) mol/L using 10 mL of water at room temperature with total dose exposure of 3.456 kGy/h. The grafted fiber was characterized by FTIR, SEM, TGA and XRD studies. Swelling behavior of grafted rayon in different solvents such as water, methanol, ethanol, DMF and acetone was studied and compared with the unmodified rayon. Dyeing behavior of the grafted fiber was also investigated. PMID- 25685465 TI - Detection of haptoglobin in seminal plasma of Awassi rams and the relation with its level in serum and some semen parameters. AB - The study was conducted to detect haptoglobin in seminal plasma (SP-Hp) of Awassi rams and the effect of the breeding season on its concentration, along with determining the correlation with its concentration in serum (S-Hp) and main semen variables. Pre-warmed artificial vagina was used to collect semen samples biweekly from five Awassi rams. Semen samples were evaluated for volume, concentration and sperm motility. Blood samples were collected 10-30 min after semen collection. The concentration of serum and seminal plasma Hp was determined using ELISA. The mean +/- SESP-Hp concentrations ranged from 0.25 +/- 0.05 to 0.81 +/- 0.44 MUg/ml, whereas those of S-Hp-ranged from 0.99 +/- 0.29 to 2.99 +/- 0.18 mg/ml. There was a significant (P < 0.05) positive correlation (r = 0.329) between SP-Hp and S-Hp concentrations. Both SP-Hp and S-Hp concentrations were significantly (P < 0.05) higher in winter as compared with the other seasons. The concentrations of SP-Hp and S-Hp during the breeding season were significantly lower (P < 0.01) than those of the out season period. SP-Hp concentration negatively correlated with semen volume and sperm concentration (r = -0.164 and 0.121), whereas sperm concentration positively correlated with individual sperm motility (r = 0.100). No significant correlation was detected between SP-Hp and semen parameters. It can be concluded that, Hp is present in ram seminal plasma and its concentration was about 2000 folds lower than that of the serum, and Hp concentration was lower during the breeding season, but its concentration in seminal plasma has no significant correlation with semen parameters. PMID- 25685466 TI - Application and evaluation of a molecular approach for detection of the schistosomicidal effect of Mirazid(r) (myrrh) in the murine model. AB - The conventional PCR technique was used for studying the schistosomicidal effect of Mirazid(r) in the murine model. Results of the molecular study were compared with the parasitological results (ova and worm count). The used PCR technique was more sensitive than the Kato-Katz thick smears. Mirazid(r) showed some schistosomicidal effects against murine Schistosoma mansoni. However, it was not efficient enough to cure any of the studied mice. PMID- 25685467 TI - 1,3,4-Thiadiazoles of pharmacological interest: Recent trends in their synthesis via tandem 1,3-dipolar cycloaddition: Review. AB - This review article presents a survey of the utility of a new synthetic strategy for 1,3,4-thiadiazole derivatives based on reactions of nitrilimines with various functionalized sulfur dipolarophiles which proceed via tandem in situ 1,3-dipolar cycloaddition and beta-elimination of simple molecule from the initially formed cycloadduct. The biological activities of some of the compounds prepared by such a strategy are pointed out. Only the literature reports within the period from 2000 to mid 2012 are covered. PMID- 25685468 TI - Modification of the photocatalytic activity of TiO2 by beta-Cyclodextrin in decoloration of ethyl violet dye. AB - The photocatalytic decoloration of an organic dye, ethyl violet (EV), has been studied in the presence of TiO2 and the addition of beta-Cyclodextrin (beta-CD) with TiO2 (TiO2-beta-CD) under UV-A light irradiation. The different operating parameters like initial concentration of dye, illumination time, pH and amount of catalyst used have also been investigated. The photocatalytic decoloration efficiency is more in the TiO2-beta-CD/UV-A light system than TiO2/UV-A light system. The mineralization of EV has been confirmed by Chemical Oxygen Demand (COD) measurements. The complexation patterns have been confirmed with UV-Visible and FT-IR spectral data and the interaction between TiO2 and beta-CD have been characterized by powder XRD analysis and UV-Visible diffuse reflectance spectroscopy. PMID- 25685469 TI - Methylation of multiple genes in hepatitis C virus associated hepatocellular carcinoma. AB - We studied promoter methylation (PM) of 11 genes in Peripheral Blood Lymphocytes (PBLs) and tissues of hepatitis C virus (HCV) associated hepatocellular carcinoma (HCC) and chronic hepatitis (CH) Egyptian patients. The present study included 31 HCC with their ANT, 38 CH and 13 normal hepatic tissue (NHT) samples. In all groups, PM of APC, FHIT, p15, p73, p14, p16, DAPK1, CDH1, RARbeta, RASSF1A, O(6)MGMT was assessed by methylation-specific PCR (MSP). APC and O6-MGMT protein expression was assessed by immunohistochemistry (IHC) in the studied HCC and CH (20 samples each) as well as in a different HCC and CH set for confirmation of MSP results. PM was associated with progression from CH to HCC. Most genes showed high methylation frequency (MF) and the methylation index (MI) increased with disease progression. MF of p14, p73, RASSF1A, CDH1 and O(6)MGMT was significantly higher in HCC and their ANT. MF of APC was higher in CH. We reported high concordance between MF in HCC and their ANT, MF in PBL and CH tissues as well as between PM and protein expression of APC and O(6)MGMT. A panel of 4 genes (APC, p73, p14, O(6)MGMT) classifies the cases independently into HCC and CH with high accuracy (89.9%), sensitivity (83.9%) and specificity (94.7%). HCV infection may contribute to hepatocarcinogenesis through enhancing PM of multiple genes. PM of APC occurs early in the cascade while PM of p14, p73, RASSF1A, RARB, CDH1 and O(6)MGMT are late changes. A panel of APC, p73, p14, O6-MGMT could be used in monitoring CH patients for early detection of HCC. Also, we found that, the methylation status is not significantly affected by whether the tissue was from the liver or PBL, indicating the possibility of use PBL as indicator to genetic profile instead of liver tissue regardless the stage of disease. PMID- 25685470 TI - Bio-preparates support the productivity of potato plants grown under desert farming conditions of north Sinai: Five years of field trials. AB - Organic agriculture as well as good agricultural practices (GAPs) intrigues the concern of both consumers and producers of agricultural commodities. Bio preparates of various rhizospheric microorganisms (RMOs) are potential sources of biological inputs supporting plant nutrition and health. The response of open field potatoes to the application of RMO bio-preparates, the biofertilizer "Biofertile" and the bioagent "Biocontrol", were experimented over 5 successive years under N-hunger of north Sinai desert soils. Both vegetative and tuber yields of a number of tested cultivars were significantly improved due to rhizobacterial treatments. In the majority of cases, the biofertilizer "Biofertile" did successfully supply ca. 50% of plant N requirements, as the yield of full N-fertilized plants was comparable to those received 50% N simultaneously with bio-preparates treatment. The magnitude of inoculation was cultivar-dependent; cvs. Valor and Oceania were among the most responsive ones. Bio-preparate introduction to the plant-soil system was successful via soaking of tubers and/or spraying the plant canopy. The "Biocontrol" formulation was supportive in controlling plant pathogens and significantly increased the fruit yields. The cumulative effect of both bio-preparates resulted in tuber yield increases of ca. 25% over control. PMID- 25685471 TI - Analyzing delay causes in Egyptian construction projects. AB - Construction delays are common problems in civil engineering projects in Egypt. These problems occur frequently during project life-time leading to disputes and litigation. Therefore, it is essential to study and analyze causes of construction delays. This research presents a list of construction delay causes retrieved from literature. The feedback of construction experts was obtained through interviews. Subsequently, a questionnaire survey was prepared. The questionnaire survey was distributed to thirty-three construction experts who represent owners, consultants, and contractor's organizations. Frequency Index, Severity Index, and Importance Index are calculated and according to the highest values of them the top ten delay causes of construction projects in Egypt are determined. A case study is analyzed and compared to the most important delay causes in the research. Statistical analysis is carried out using analysis of variance ANOVA method to test delay causes, obtained from the survey. The test results reveal good correlation between groups while there is significant difference between them for some delay causes and finally roadmap for prioritizing delay causes groups is presented. PMID- 25685472 TI - New fast least-squares algorithm for estimating the best-fitting parameters due to simple geometric-structures from gravity anomalies. AB - A new fast least-squares method is developed to estimate the shape factor (q parameter) of a buried structure using normalized residual anomalies obtained from gravity data. The problem of shape factor estimation is transformed into a problem of finding a solution of a non-linear equation of the form f(q) = 0 by defining the anomaly value at the origin and at different points on the profile (N-value). Procedures are also formulated to estimate the depth (z-parameter) and the amplitude coefficient (A-parameter) of the buried structure. The method is simple and rapid for estimating parameters that produced gravity anomalies. This technique is used for a class of geometrically simple anomalous bodies, including the semi-infinite vertical cylinder, the infinitely long horizontal cylinder, and the sphere. The technique is tested and verified on theoretical models with and without random errors. It is also successfully applied to real data sets from Senegal and India, and the inverted-parameters are in good agreement with the known actual values. PMID- 25685473 TI - Strengthening of defected beam-column joints using CFRP. AB - This paper presents an experimental study for the structural performance of reinforced concrete (RC) exterior beam-column joints rehabilitated using carbon fiber-reinforced polymer (CFRP). The present experimental program consists of testing 10 half-scale specimens divided into three groups covering three possible defects in addition to an adequately detailed control specimen. The considered defects include the absence of the transverse reinforcement within the joint core, insufficient bond length for the beam main reinforcement and inadequate spliced implanted column on the joint. Three different strengthening schemes were used to rehabilitate the defected beam-column joints including externally bonded CFRP strips and sheets in addition to near surface mounted (NSM) CFRP strips. The failure criteria including ultimate capacity, mode of failure, initial stiffness, ductility and the developed ultimate strain in the reinforcing steel and CFRP were considered and compared for each group for the control and the CFRP strengthened specimens. The test results showed that the proposed CFRP strengthening configurations represented the best choice for strengthening the first two defects from the viewpoint of the studied failure criteria. On the other hand, the results of the third group showed that strengthening the joint using NSM strip technique enabled the specimen to outperform the structural performance of the control specimen while strengthening the joints using externally bonded CFRP strips and sheets failed to restore the strengthened joints capacity. PMID- 25685474 TI - Effect of ethylene carbonate as a plasticizer on CuI/PVA nanocomposite: Structure, optical and electrical properties. AB - Layers of ethylene carbonate (EC) modified CuI/PVA polymer composites were prepared by growth of CuI nano-particles in an aqueous solution of PVA followed by casting at room temperature. The structural, thermal, optical, electrical and di-electrical characterization of polymer composites was investigated using different techniques. These investigations confirm the growth of CuI nano particles and reduction of PVA crystallinity by increasing ethylene carbonate concentration. These results show that energy band gap and bulk conductivity increase while activation energy reduces with the increase of EC concentration in the composite. Moreover, the variation of the dielectric permittivity and dielectric loss with EC content are found to obey Debye dispersion relations. PMID- 25685475 TI - Experimental performance study of a proposed desiccant based air conditioning system. AB - An experimental investigation on the performance of a proposed hybrid desiccant based air conditioning system referred as HDBAC is introduced in this paper. HDBAC is mainly consisted of a liquid desiccant dehumidification unit integrated with a vapor compression system (VCS). The VCS unit has a cooling capacity of 5.27 kW and uses 134a as refrigerant. Calcium chloride (CaCl2) solution is used as the working desiccant material. HDBAC system is used to serve low sensible heat factor applications. The effect of different parameters such as, process air flow rate, desiccant solution flow rate, evaporator box and condenser box solution temperatures, strong solution concentration and regeneration temperature on the performance of the system is studied. The performance of the system is evaluated using some parameters such as: the coefficient of performance (COPa), specific moisture removal and energy saving percentage. A remarkable increase of about 54% in the coefficient of performance of the proposed system over VCS with reheat is achieved. A maximum overall energy saving of about 46% is observed which emphasizes the use of the proposed system as an energy efficient air conditioning system. PMID- 25685476 TI - Predicting morphological changes DS New Naga-Hammadi Barrage for extreme Nile flood flows: A Monte Carlo analysis. AB - While construction of the Aswan High Dam (AHD) has stopped concurrent flooding events, River Nile is still subject to low intensity flood waves resulting from controlled release of water from the dam reservoir. Analysis of flow released from New Naga-Hammadi Barrage, which is located at 3460 km downstream AHD indicated an increase in magnitude of flood released from the barrage in the past 10 years. A 2D numerical mobile bed model is utilized to investigate the possible morphological changes in the downstream of Naga-Hammadi Barrage from possible higher flood releases. Monte Carlo simulation analyses (MCS) is applied to the deterministic results of the 2D model to account for and assess the uncertainty of sediment parameters and formulations in addition to sacristy of field measurements. Results showed that the predicted volume of erosion yielded the highest uncertainty and variation from deterministic run, while navigation velocity yielded the least uncertainty. Furthermore, the error budget method is used to rank various sediment parameters for their contribution in the total prediction uncertainty. It is found that the suspended sediment contributed to output uncertainty more than other sediment parameters followed by bed load with 10% less order of magnitude. PMID- 25685477 TI - Crossed ring anchored disk resonator for self-alignment of the anchor. AB - Misalignment is a problematic challenge in RF MEMS resonators. It causes asymmetry in the ultra symmetric radial contour mode disk resonators and degrades their performance by increasing the insertion loss and decreasing their quality factors (Q). Self-alignment method seems to be a good solution for misalignment problem, but it cannot be directly applied on high performance ring shape anchored resonators. This paper discusses misalignment effects for the ring shape anchored resonators and proposes a method for reconfiguring its anchor to be compatible with self-alignment process. Simulation results validate that the crossed ring anchor structure has the same resonance characteristics with the complete ring shape anchored resonator. PMID- 25685478 TI - Protein kinase expression as a predictive factor for interferon response in chronic hepatitis C patients. AB - Egypt has the highest prevalence of hepatitis C virus (HCV) worldwide. Currently, combined pegylated interferon and ribavirin therapy are the standard treatment. The biological activity of interferon (IFN) is mediated by the induction of intracellular antiviral proteins, such as 2'-5' oligoadenylate synthetase, and dsRNA-activated protein kinase. IFN-inducible double-stranded RNA-activated protein kinase (PKR) is thought to play a key antiviral role against HCV. Some studies observed that PKR expression was higher in sustained viral responders compared with the non-responders. The PKR is considered as antiviral toward HCV and responsible for IFN's effect against HCV while others have showed that, there were kinetic results indicate that HCV infection is not altered by reduced levels of PKR, indicating that HCV is resistant to the translational inhibitory effects of the phosphorylated forms of PKR. This study was conducted on 50 consecutive patients with chronic HCV infection (CHC) and 20 healthy controls. All the patients were subjected to clinical and laboratory assessment, abdominal ultrasound, and liver biopsy. Determination of PKR gene quantity by using a real time PCR was done at the baseline and at the end of treatment for all patients and controls. Pre-treatment levels of protein kinase gene were significantly higher in responders in comparison with non-responders (P < 0.001). It was found that 97.06% of patients who were responding to treatment had the expression of protein kinase gene greater than 2(6) cycle threshold. PMID- 25685479 TI - Control and switching synchronization of fractional order chaotic systems using active control technique. AB - This paper discusses the continuous effect of the fractional order parameter of the Lu system where the system response starts stable, passing by chaotic behavior then reaching periodic response as the fractional-order increases. In addition, this paper presents the concept of synchronization of different fractional order chaotic systems using active control technique. Four different synchronization cases are introduced based on the switching parameters. Also, the static and dynamic synchronizations can be obtained when the switching parameters are functions of time. The nonstandard finite difference method is used for the numerical solution of the fractional order master and slave systems. Many numeric simulations are presented to validate the concept for different fractional order parameters. PMID- 25685480 TI - The potential effects of Spirulina platensis (Arthrospira platensis) on tissue protection of Nile tilapia (Oreochromis niloticus) through estimation of P53 level. AB - The current study was designed to investigate the potential effect of Spirulina platensis, Arthrospira platensis, (SP) on tissue protection of Nile tilapia (Oreochromis niloticus) through estimation of P53 level. Five isonitrogenous and isocaloric rations containing graded levels of dried SP 5, 7.5,10, 15, and 20 g/kg diet were fed separately to five equal groups of O. niloticus fingerlings, additional control group was assigned for 3 months. Liver samples were separately collected from each group by the end of each month. The expression level of P53 showed a substantial decrease among the treated groups in a time-dependent manner. It is therefore advisable to incorporate SP in diets for tissue protection and antioxidant effects in cultured O. niloticus. PMID- 25685482 TI - Limitations of navigation through Nubaria canal, Egypt. AB - Alexandria port is the main Egyptian port at the Mediterranean Sea. It is connected to the Nile River through Nubaria canal, which is a main irrigation canal. The canal was designed to irrigate eight hundred thousand acres of agricultural lands, along its course which extends 100 km. The canal has three barrages and four locks to control the flow and allow light navigation by some small barges. Recently, it was decided to improve the locks located on the canal. More than 40 million US$ was invested in these projects. This decision was taken to allow larger barges and increase the transported capacity through the canal. On the other hand, navigation through canals and restricted shallow waterways is affected by several parameters related to both the channel and the vessel. Navigation lane width as well as vessel speed and maneuverability are affected by both the channel and vessel dimensions. Moreover, vessel dimensions and speed will affect the canal stability. In Egypt, there are no guide rules for navigation through narrow and shallow canals such Nubaria. This situation threatens the canal stability and safety of navigation through it. This paper discussed the characteristics of Nubaria canal and the guide rules for navigation in shallow restricted water ways. Dimensions limitation for barges navigating through Nubaria canal is presented. New safe operation rules for navigation in Nubaria canal are also presented. Moreover, the implication of navigation through locks on canal discharge is estimated. PMID- 25685481 TI - Cannabinoid receptor 1 signaling in cardiovascular regulating nuclei in the brainstem: A review. AB - Cannabinoids elicit complex hemodynamic responses in experimental animals that involve both peripheral and central sites. Centrally administered cannabinoids have been shown to predominantly cause pressor response. However, very little is known about the mechanism of the cannabinoid receptor 1 (CB1R)-centrally evoked pressor response. In this review, we provided an overview of the contemporary knowledge regarding the cannabinoids centrally elicited cardiovascular responses and the possible underlying signaling mechanisms. The current review focuses on the rostral ventrolateral medulla (RVLM) as the primary brainstem nucleus implicated in CB1R-evoked pressor response. PMID- 25685483 TI - CCII based fractional filters of different orders. AB - This paper aims to generalize the design of continuous-time filters to the fractional domain with different orders and validates the theoretical results with two different CCII based filters. In particular, the proposed study introduces the generalized formulas for the previous fractional-order analysis of equal orders. The fractional-order filters enhance the design flexibility and prove that the integer-order performance is a very narrow subset from the fractional-order behavior due to the extra degrees of freedom. The general fundamentals of these filters are presented by calculating the maximum and minimum frequencies, the half power frequency and the right phase frequency which are considered a critical issue for the filter design. Different numerical solutions for the generalized fractional order low pass filters with two different fractional order elements are introduced and verified by the circuit simulations of two fractional-order filters: Kerwin-Huelsman-Newcomb (KHN) and Tow-Tomas CCII-based filters, showing great matching. PMID- 25685484 TI - Reinforcement of natural rubber hybrid composites based on marble sludge/Silica and marble sludge/rice husk derived silica. AB - A research has been carried out to develop natural rubber (NR) hybrid composites reinforced with marble sludge (MS)/Silica and MS/rice husk derived silica (RHS). The primary aim of this development is to scrutinize the cure characteristics, mechanical and swelling properties of such hybrid composite. The use of both industrial and agricultural waste such as marble sludge and rice husk derived silica has the primary advantage of being eco-friendly, low cost and easily available as compared to other expensive fillers. The results from this study showed that the performance of NR hybrid composites with MS/Silica and MS/RHS as fillers is extremely better in mechanical and swelling properties as compared with the case where MS used as single filler. The study suggests that the use of recently developed silica and marble sludge as industrial and agricultural waste is accomplished to provide a probable cost effective, industrially prospective, and attractive replacement to the in general purpose used fillers like china clay, calcium carbonate, and talc. PMID- 25685485 TI - A simple analytical method to estimate all exit parameters of a cross-flow air dehumidifier using liquid desiccant. AB - The dehumidifier is a key component in liquid desiccant air-conditioning systems. Analytical solutions have more advantages than numerical solutions in studying the dehumidifier performance parameters. This paper presents the performance results of exit parameters from an analytical model of an adiabatic cross-flow liquid desiccant air dehumidifier. Calcium chloride is used as desiccant material in this investigation. A program performing the analytical solution is developed using the engineering equation solver software. Good accuracy has been found between analytical solution and reliable experimental results with a maximum deviation of +6.63% and -5.65% in the moisture removal rate. The method developed here can be used in the quick prediction of the dehumidifier performance. The exit parameters from the dehumidifier are evaluated under the effects of variables such as air temperature and humidity, desiccant temperature and concentration, and air to desiccant flow rates. The results show that hot humid air and desiccant concentration have the greatest impact on the performance of the dehumidifier. The moisture removal rate is decreased with increasing both air inlet temperature and desiccant temperature while increases with increasing air to solution mass ratio, inlet desiccant concentration, and inlet air humidity ratio. PMID- 25685486 TI - Experimental study of heat transfer and thermal performance with longitudinal fins of solar air heater. AB - The thermal performance of a single pass solar air heater with five fins attached was investigated experimentally. Longitudinal fins were used inferior the absorber plate to increase the heat exchange and render the flow fluid in the channel uniform. The effect of mass flow rate of air on the outlet temperature, the heat transfer in the thickness of the solar collector, and the thermal efficiency were studied. Experiments were performed for two air mass flow rates of 0.012 and 0.016 kg s(-1). Moreover, the maximum efficiency values obtained for the 0.012 and 0.016 kg s(-1) with and without fins were 40.02%, 51.50% and 34.92%, 43.94%, respectively. A comparison of the results of the mass flow rates by solar collector with and without fins shows a substantial enhancement in the thermal efficiency. PMID- 25685487 TI - Effectiveness of acupressure versus isometric exercise on pain, stiffness, and physical function in knee osteoarthritis female patients. AB - Osteoarthritis (OA) is the most common form of arthritis and a leading cause of disability in older adults. Conservative non-pharmacological strategies, particularly exercise, are recommended by clinical guidelines for its management. The aim of this study was to assess the effectiveness of acupressure versus isometric exercise on pain, stiffness, and physical function in knee OA female patients. This quasi experimental study was conducted at the inpatient and outpatient sections at Al-kasr Al-Aini hospital, Cairo University. It involved three groups of 30 patients each: isometric exercise, acupressure, and control. Data were collected by an interview form and the Western Ontario and McMaster Universities Osteoarthritis index (WOMAC) scale. The study revealed high initial scores of pain, stiffness, and impaired physical functioning. After the intervention, pain decreased in the two intervention groups compared to the control group (p < 0.001), while the scores of stiffness and impaired physical function were significantly lower in the isometric group (p < 0.001) compared to the other two groups. The decrease in the total WOMAC score was sharper in the two study groups compared to the control group. In multiple linear regression, the duration of illness was a positive predictor of WOMAC score, whereas the intervention is associated with a reduction in the score. In conclusion, isometric exercise and acupressure provide an improvement of pain, stiffness, and physical function in patients with knee OA. Since isometric exercise leads to more improvement of stiffness and physical function, while acupressure acts better on pain, a combination of both is recommended. The findings need further confirmation through a randomized clinical trial. PMID- 25685488 TI - In vitro study of nano-hydroxyapatite/chitosan-gelatin composites for bio applications. AB - The present work aims to study the in vitro properties of nano hydroxyapatite/chitosan-gelatin composite materials. In vitro behavior was performed in simulated body fluid (SBF) to verify the formation of apatite layer onto the composite surfaces. The in vitro data proved the deposition of calcium and phosphorus ions onto hydroxyapatite /polymeric composite surfaces especially those containing high concentrations of polymer content. The degradation of the composites decreased with increase in the polymeric matrix content and highly decreased in the presence of citric acid (CA), especially these composites which contain 30% polymeric content. The water absorption of the composites increased with increase in the polymeric content and highly increased with CA addition. The Fourier transformed infrared reflectance (FT-IR) and scanning electron microscope (SEM) for the composites confirmed the formation of bone-like apatite layer on the composite surfaces, especially those containing high content of polymers (30%) with 0.2 M of CA. These promising composites have suitable properties for bio-applications such as bone grafting and bone tissue engineering applications in the future. PMID- 25685489 TI - Pentafluorophenylammonium triflate (PFPAT) catalyzed facile construction of substituted chromeno[2,3-d]pyrimidinone derivatives and their antimicrobial activity. AB - A new, simple thermally efficient and solvent-free condensation of 2-amino-3 cyano-6-methyl-4-phenyl-4H-pyran-5-ethylcarboxylate derivatives with coumarin-3 carboxylic acid employing pentafluorophenylammonium triflate (PFPAT) as an inexpensive organocatalyst for the synthesis of a series of ethyl 4,5-dihydro 7 methyl-2-(2-oxo-2H-chromen-3-yl)-4-oxo-5-aryl-3H-chromeno[2,3-d]pyrimidine-6 carboxylate derivatives is described. This method has the advantages of high yields, a cleaner reaction, simple methodology, short reaction times, easy workup, and greener conditions. All the compounds were evaluated for their in vitro antimicrobial activity against different bacterial and fungal strains. PMID- 25685490 TI - Proteomics of old world camelid (Camelus dromedarius): Better understanding the interplay between homeostasis and desert environment. AB - Life is the interplay between structural-functional integrity of biological systems and the influence of the external environment. To understand this interplay, it is useful to examine an animal model that competes with harsh environment. The dromedary camel is the best model that thrives under severe environment with considerable durability. The current proteomic study on dromedary organs explains a number of cellular mysteries providing functional correlates to arid living. Proteome profiling of camel organs suggests a marked increased expression of various cytoskeleton proteins that promote intracellular trafficking and communication. The comparative overexpression of alpha-actinin of dromedary heart when compared with rat heart suggests an adaptive peculiarity to sustain hemoconcentration-hemodilution episodes associated with alternative drought-rehydration periods. Moreover, increased expression of the small heat shock protein, alpha B-crystallin facilitates protein folding and cellular regenerative capacity in dromedary heart. The observed unbalanced expression of different energy related dependent mitochondrial enzymes suggests the possibility of mitochondrial uncoupling in the heart in this species. The evidence of increased expression of H+-ATPase subunit in camel brain guarantees a rapidly usable energy supply. Interestingly, the guanidinoacetate methyltransferase in camel liver has a renovation effect on high energy phosphate with possible concomitant intercession of ion homeostasis. Surprisingly, both hump fat tissue and kidney proteomes share the altered physical distribution of proteins that favor cellular acidosis. Furthermore, the study suggests a vibrant nature for adipose tissue of camel hump by the up-regulation of vimentin in adipocytes, augmenting lipoprotein translocation, blood glucose trapping, and challenging external physical extra-stress. The results obtained provide new evidence of homeostasis in the arid habitat suitable for this mammal. PMID- 25685491 TI - Behavior of concentrically loaded CFT braces connections. AB - Concrete filled tubes (CFTs) composite columns have many economical and esthetic advantages, but the behavior of their connections is complicated. Through this study, it is aimed to investigate the performance and behavior of different connection configurations between concrete filled steel tube columns and bracing diagonals through an experimental program. The study included 12 connection subassemblies consisting of a fixed length steel tube and gusset plate connected to the tube end with different details tested under half cyclic loading. A notable effect was observed on the behavior of the connections due to its detailing changes with respect to capacity, failure mode, ductility, and stress distribution. PMID- 25685492 TI - Numerical simulation of fractional Cable equation of spiny neuronal dendrites. AB - In this article, numerical study for the fractional Cable equation which is fundamental equations for modeling neuronal dynamics is introduced by using weighted average of finite difference methods. The stability analysis of the proposed methods is given by a recently proposed procedure similar to the standard John von Neumann stability analysis. A simple and an accurate stability criterion valid for different discretization schemes of the fractional derivative and arbitrary weight factor is introduced and checked numerically. Numerical results, figures, and comparisons have been presented to confirm the theoretical results and efficiency of the proposed method. PMID- 25685493 TI - An efficient reliable method to estimate the vaporization enthalpy of pure substances according to the normal boiling temperature and critical properties. AB - The heat of vaporization of a pure substance at its normal boiling temperature is a very important property in many chemical processes. In this work, a new empirical method was developed to predict vaporization enthalpy of pure substances. This equation is a function of normal boiling temperature, critical temperature, and critical pressure. The presented model is simple to use and provides an improvement over the existing equations for 452 pure substances in wide boiling range. The results showed that the proposed correlation is more accurate than the literature methods for pure substances in a wide boiling range (20.3-722 K). PMID- 25685494 TI - Comparative sequence analysis of double stranded RNA binding protein encoding gene of parapoxviruses from Indian camels. AB - The dsRNA binding protein (RBP) encoding gene of parapoxviruses (PPVs) from the Dromedary camels, inhabitating different geographical region of Rajasthan, India were amplified by polymerase chain reaction using the primers of pseudocowpoxvirus (PCPV) from Finnish reindeer and cloned into pGEM-T for sequence analysis. Analysis of RBP encoding gene revealed that PPV DNA from Bikaner shared 98.3% and 76.6% sequence identity at the amino acid level, with Pali and Udaipur PPV DNA, respectively. Reference strains of Bovine papular stomatitis virus (BPSV) and PCPV (reindeer PCPV and human PCPV) shared 52.8% and 86.9% amino acid identity with RBP gene of camel PPVs from Bikaner, respectively. But different strains of orf virus (ORFV) from different geographical areas of the world shared 69.5-71.7% amino acid identity with RBP gene of camel PPVs from Bikaner. These findings indicate that the camel PPVs described are closely related to bovine PPV (PCPV) in comparison to caprine and ovine PPV (ORFV). PMID- 25685496 TI - Prediction models in in vitro fertilization; where are we? A mini review. AB - Since the introduction of in vitro fertilization (IVF) in 1978, over five million babies have been born worldwide using IVF. Contrary to the perception of many, IVF does not guarantee success. Almost 50% of couples that start IVF will remain childless, even if they undergo multiple IVF cycles. The decision to start or pursue with IVF is challenging due to the high cost, the burden of the treatment, and the uncertain outcome. In optimal counseling on chances of a pregnancy with IVF, prediction models may play a role, since doctors are not able to correctly predict pregnancy chances. There are three phases of prediction model development: model derivation, model validation, and impact analysis. This review provides an overview on predictive factors in IVF, the available prediction models in IVF and provides key principles that can be used to critically appraise the literature on prediction models in IVF. We will address these points by the three phases of model development. PMID- 25685497 TI - Physiological, biochemical and histometric responses of Nile tilapia (Oreochromis niloticus L.) by dietary organic chromium (chromium picolinate) supplementation. AB - Chromium has been recognized as a new and important micro-nutrient, essential for both human and animal nutrition. This study was conducted to evaluate the appropriateness and/or the use of safety level of dietary chromium picolinate (Cr Pic), and its effects on the physiological responses, the histometric characteristics, and the chemical analysis of dorsal muscles of mono-sex Nile tilapia, Oreochromis niloticus. A total of 420 fingerlings (28.00 +/- 0.96 g) were randomly distributed into 21 fiberglass tanks representing seven treatments at a rate of 20 fish m(-3). The control fish group (T1) was fed a Cr-Pic free basal diet. Other fish groups were fed the basal diet supplemented with 200 (T2), 400 (T3), 600 (T4), 800 (T5), 1000 (T6) and 1200 MUg Cr-Pic kg(-1) diet (T7). Diets were offered to fish at a feeding rate of 3% of life body weight for 12 weeks. Results revealed that blood hematological parameters (hemoglobin, red blood cells, packed cell volume, mean corpuscular hemoglobin concentration, blood platelets, and white blood cells lymphocytes); serum biochemical measurements (total testosterone, high density lipoprotein, total protein, albumin, and globulin); and the dry matter and crude protein of the fish dorsal muscles all have significantly increased (P ? 0.05) in the T3 treatment compared with the other treatments. Meanwhile, no significant differences were found among all treatments with regard to the histometric characteristics. It can be concluded that Cr-Pic at 400 MUg kg(-1) diet (T3) seems to be the most appropriate level for O. niloticus fingerlings. PMID- 25685498 TI - Molten salt-supported polycondensation of optically active diacid monomers with an aromatic thiazole-bearing diamine using microwave irradiation. AB - Microwave heating was used to prepare optically active thiazole-bearing poly(amide-imide)s. Polymerization reactions were carried out in the molten tetrabutylammonium bromide as a green molten salt medium and triphenyl phosphite as the homogenizer. Structural elucidation of the compounds was performed by Fourier transform infrared and NMR spectroscopic data and elemental analysis results. The polymeric samples were readily soluble in various organic solvents, forming low-colored and flexible thin films via solution casting. They showed high thermal stability with decomposition temperature being above 360 degrees C. They were assembled randomly in a nanoscale size. PMID- 25685495 TI - Current concept in neural regeneration research: NSCs isolation, characterization and transplantation in various neurodegenerative diseases and stroke: A review. AB - Since last few years, an impressive amount of data has been generated regarding the basic in vitro and in vivo biology of neural stem cells (NSCs) and there is much far hope for the success in cell replacement therapies for several human neurodegenerative diseases and stroke. The discovery of adult neurogenesis (the endogenous production of new neurons) in the mammalian brain more than 40 years ago has resulted in a wealth of knowledge about stem cells biology in neuroscience research. Various studies have done in search of a suitable source for NSCs which could be used in animal models to understand the basic and transplantation biology before treating to human. The difficulties in isolating pure population of NSCs limit the study of neural stem behavior and factors that regulate them. Several studies on human fetal brain and spinal cord derived NSCs in animal models have shown some interesting results for cell replacement therapies in many neurodegenerative diseases and stroke models. Also the methods and conditions used for in vitro culture of these cells provide an important base for their applicability and specificity in a definite target of the disease. Various important developments and modifications have been made in stem cells research which is needed to be more specified and enrolment in clinical studies using advanced approaches. This review explains about the current perspectives and suitable sources for NSCs isolation, characterization, in vitro proliferation and their use in cell replacement therapies for the treatment of various neurodegenerative diseases and strokes. PMID- 25685499 TI - Tissue specific structural variations of mitochondria of fish ectoparasite Argulus bengalensis Ramakrishna, 1951 (Crustacea: Branchiura): Functional implications. AB - We studied the fine structure of some classical and six variant mitochondria from different tissues viz. proboscis gland, spinal gland, ovary, testis, and muscle of a fish ectoparasite, Argulus bengalensis. In the proboscis gland and spinal gland, mitochondria are protected within vesicle to preserve their structure and activity from exposure to glandular synthesis for its parasitic mode of feeding. In the oocytes, mitochondria are larger and cylindrical in appearance. Oocyte mitochondria are highly dynamic and exhibit frequent fission and fusion. Those are clustered in the cytoplasm of previtellogenic oocytes which prepare for different synthetic activities for successful reproductive investment. In contrast, mitochondrial abundance is less in the male gametic lineage. The spermatocytes and the nurse cells in the testis have an unusual type of mitochondria, nebenkern which is formed by the fusions of number of mitochondria. A completely different type of mitochondrion is discovered in the flagellum of the spermatozoa. It is provided with fifteen numbers of singlet microtubules at its outer periphery which is a salient feature of the flagellum of this Branchiuran genus. This unique mitochondrion uses the microtubule tract for its movement to distribute energy efficiently along the axoneme. Such mitochondrion and microtubular association provide evidence in favor of phylogenetic relationship between Argulus and pentastomid Raillietiella. In striated muscle of thoracic appendages, mitochondria maintain tight junctions with the endoplasmic reticulum and remain in close apposition of the myofibrils which helps in Ca(2+) uptake for stimulating continuous muscular activity required for ventilation of respiratory structures of the parasites. PMID- 25685500 TI - Determination of kresoxim-methyl and its thermolabile metabolites in pear utilizing pepper leaf matrix as a protectant using gas chromatography. AB - Kresoxim-methyl and its two thermolabile metabolites, BF 490-2 and BF 490-9, were analyzed in pear using a pepper leaf matrix protection to maintain the metabolites inside the gas chromatography system. Samples were extracted with a mixture of ethyl acetate and n-hexane (1:1, v/v) and purified and/or separated using a solid phase extraction procedure. The pepper leaf matrix was added and optimized with cleaned pear extract to enhance metabolite sensitivity. Matrix matched calibration was used for kresoxim-methyl in the pear matrix and for metabolites in the pear mixed with pepper leaf matrix. Good linearity was obtained for all analytes with a coefficient of determination, r (2) ? 0.992. Limits of detection (LOD) and quantification (LOQ) were 0.006 and 0.02 mg kg(-1) and 0.02 and 0.065 mg kg(-1) for kresoxim-methyl and the metabolites, respectively. Recoveries were carried out at two concentration levels and were 85.6-97.9% with a relative standard deviation <2.5%. The method was successfully applied to field incurred pear samples, and only kresoxim-methyl was detected at a concentration of 0.03 mg kg(-1). PMID- 25685501 TI - Synthesis and biological activity of novel series of 4-methoxy, and 4,9-dimethoxy 5-substituted furo[2,3-g]-1,2,3-benzoxathiazine-7,7-dioxide derivatives. AB - A novel series of 4-methoxy, and 4,9-dimethoxy-5-substituted furo[2,3-g]-1,2,3 benzoxathiazine-7,7-dioxide derivatives 3a,b, 10a-g and 11a-g were prepared in good yields via the reaction of 4-methoxy (1a) and 4,7-dimethoxy-5-acetyl-6 hydroxybenzofurans (1b) and their alpha,beta-unsaturated keto derivatives 6a-g and 7a-g with chlorosulfonyl isocyanate (CSI). On the other hand, N chlorosulfonyl carbamate derivatives 4a,b, 12a,b and 13a,b were prepared and allowed to react with piperidine to give the corresponding N-piperidinosulfonyl carbamate derivatives 5a,b, 14a,b and 15a,b, respectively. Sixteen new target compounds 3a,b, 10a-g, and 11a-g were tested for their DPPH radical-scavenging, and in vitro antiproliferative activity against A-549, MCF7 and HCT-116 cancer cell lines. Compounds 10a, 11c, 11e, and 11g showed moderate DPPH radical scavenging activity compared to ascorbic acid at 100 MUg/mL. 4,9-Dimethoxy-5 substituted styrylfuro[3,2-g]-1,2,3-benzoxathiazine-7,7-dioxides 11a, 11b, and 11c were found to be highly active against A-549 and HCT-116 cancer cell lines with IC50 values ranging from 0.02 to 0.08 MUmol/mL compared to doxorubicin with IC50 = 0.04 and 0.06 MUmol/mL, respectively. PMID- 25685502 TI - Feasibility of optimizing trimetazidine dihydrochloride release from controlled porosity osmotic pump tablets of directly compressed cores. AB - The aim of this study was to develop and optimize Trimetazidine dihydrochloride (TM) controlled porosity osmotic pump (CPOP) tablets of directly compressed cores. A 2(3) full factorial design was used to study the influence of three factors namely: PEG400 (10% and 25% based on coating polymer weight), coating level (10% and 20% of tablet core weight) and hole diameter (0 "no hole" and 1 mm). Other variables such as tablet cores, coating mixture of ethylcellulose (4%) and dibutylphthalate (2%) in 95% ethanol and pan coating conditions were kept constant. The responses studied (Yi ) were cumulative percentage released after 2 h (Q%2h), 6 h (Q%6h), 12 h (Q%12h) and regression coefficient of release data fitted to zero order equation (RSQzero), for Y 1, Y 2, Y 3, and Y 4, respectively. Polynomial equations were used to study the influence of different factors on each response individually. Response surface methodology and multiple response optimization were used to search for an optimized formula. Response variables for the optimized formula were restricted to 10% ? Y 1 ? 20%, 40% ? Y 2 ? 60%, 80% ? Y 3 ? 100%, and Y 4 > 0.9. The statistical analysis of the results revealed that PEG400 had positive effects on Q%2h, Q%6h and Q%12h, hole diameter had positive effects on all responses and coating level had positive effect on Q%6h, Q%12h and negative effect on RSQzero. Full three factor interaction (3FI) equations were used for representation of all responses except Q%2h which was represented by reduced (3FI) equation. Upon exploring the experimental space, no formula in the tested range could satisfy the required constraints. Thus, direct compression of TM cores was not suitable for formation of CPOP tablets. Preliminary trials of CPOP tablets with wet granulated cores were promising with an intact membrane for 12 h and high RSQzero. Further improvement of these formulations to optimize TM release will be done in further studies. PMID- 25685503 TI - Chemical kinetic simulation of kerosene combustion in an individual flame tube. AB - The use of detailed chemical reaction mechanisms of kerosene is still very limited in analyzing the combustion process in the combustion chamber of the aircraft engine. In this work, a new reduced chemical kinetic mechanism for fuel n-decane, which selected as a surrogate fuel for kerosene, containing 210 elemental reactions (including 92 reversible reactions and 26 irreversible reactions) and 50 species was developed, and the ignition and combustion characteristics of this fuel in both shock tube and flat-flame burner were kinetic simulated using this reduced reaction mechanism. Moreover, the computed results were validated by experimental data. The calculated values of ignition delay times at pressures of 12, 50 bar and equivalence ratio is 1.0, 2.0, respectively, and the main reactants and main products mole fractions using this reduced reaction mechanism agree well with experimental data. The combustion processes in the individual flame tube of a heavy duty gas turbine combustor were simulated by coupling this reduced reaction mechanism of surrogate fuel n-decane and one step reaction mechanism of surrogate fuel C12H23 into the computational fluid dynamics software. It was found that this reduced reaction mechanism is shown clear advantages in simulating the ignition and combustion processes in the individual flame tube over the one step reaction mechanism. PMID- 25685504 TI - Design of an ultra low power third order continuous time current mode SigmaDelta modulator for WLAN applications. AB - This paper presents a third order continuous time current mode SigmaDelta modulator for WLAN 802.11b standard applications. The proposed circuit utilized feedback architecture with scaled and optimized DAC coefficients. At circuit level, we propose a modified cascade current mirror integrator with reduced input impedance which results in more bandwidth and linearity and hence improves the dynamic range. Also, a very fast and precise novel dynamic latch based current comparator is introduced with low power consumption. This ultra fast comparator facilitates increasing the sampling rate toward GHz frequencies. The modulator exhibits dynamic range of more than 60 dB for 20 MHz signal bandwidth and OSR of 10 while consuming only 914 MUW from 1.8 V power supply. The FoM of the modulator is calculated from two different methods, and excellent performance is achieved for proposed modulator. PMID- 25685505 TI - Resilient guaranteed cost control of a power system. AB - With the development of power system interconnection, the low-frequency oscillation is becoming more and more prominent which may cause system separation and loss of energy to consumers. This paper presents an innovative robust control for power systems in which the operating conditions are changing continuously due to load changes. However, practical implementation of robust control can be fragile due to controller inaccuracies (tolerance of resistors used with operational amplifiers). A new design of resilient (non-fragile) robust control is given that takes into consideration both model and controller uncertainties by an iterative solution of a set of linear matrix inequalities (LMI). Both uncertainties are cast into a norm-bounded structure. A sufficient condition is derived to achieve the desired settling time for damping power system oscillations in face of plant and controller uncertainties. Furthermore, an improved controller design, resilient guaranteed cost controller, is derived to achieve oscillations damping in a guaranteed cost manner. The effectiveness of the algorithm is shown for a single machine infinite bus system, and then, it is extended to multi-area power system. PMID- 25685506 TI - Three-dimensional linear and volumetric analysis of maxillary sinus pneumatization. AB - Considering the anatomical variability related to the maxillary sinus, its intimate relation to the maxillary posterior teeth and because of all the implications that pneumatization may possess, three-dimensional assessment of maxillary sinus pneumatization is of most usefulness. The aim of this study is to analyze the maxillary sinus dimensions both linearly and volumetrically using cone beam computed tomography (CBCT) to assess the maxillary sinus pneumatization. Retrospective analysis of 30 maxillary sinuses belonging to 15 patients' CBCT scans was performed. Linear and volumetric measurements were conducted and statistically analyzed. The maximum craniocaudal extension of the maxillary sinus was located around the 2nd molar in 93% of the sinuses, while the maximum mediolateral and antroposterior extensions of the maxillary sinus were located at the level of root of zygomatic complex in 90% of sinuses. There was a high correlation between the linear measurements of the right and left sides, where the antroposterior extension of the sinus at level of the nasal floor had the largest correlation (0.89). There was also a high correlation between the Simplant and geometric derived maxillary sinus volumes for both right and left sides (0.98 and 0.96, respectively). The relations of the sinus floor can be accurately assessed on the different orthogonal images obtained through 3D CBCT scan. The geometric method offered a much cheaper, easier, and less sophisticated substitute; therefore, with the availability of software, 3D volumetric measurements are more facilitated. PMID- 25685507 TI - A new technique based on Artificial Bee Colony Algorithm for optimal sizing of stand-alone photovoltaic system. AB - One of the most recent optimization techniques applied to the optimal design of photovoltaic system to supply an isolated load demand is the Artificial Bee Colony Algorithm (ABC). The proposed methodology is applied to optimize the cost of the PV system including photovoltaic, a battery bank, a battery charger controller, and inverter. Two objective functions are proposed: the first one is the PV module output power which is to be maximized and the second one is the life cycle cost (LCC) which is to be minimized. The analysis is performed based on measured solar radiation and ambient temperature measured at Helwan city, Egypt. A comparison between ABC algorithm and Genetic Algorithm (GA) optimal results is done. Another location is selected which is Zagazig city to check the validity of ABC algorithm in any location. The ABC is more optimal than GA. The results encouraged the use of the PV systems to electrify the rural sites of Egypt. PMID- 25685508 TI - Treatment for resistant subphrenic abscess by combined intracavitary doxycycline and cyanoacrylate injection. AB - We report the case of a male patient with resistant subphrenic abscess complicating radiofrequency ablation (RFA) of two left lobe hepatocellular carcinoma (HCCs). The causative organism was multidrug resistant Escherichia coli. Percutaneous pigtail drainage together with IV antibiotics failed to resolve the abscess which persisted for 4 months. Intracavitary doxycycline injection causes moderate reduction in the volume of the drained fluid. This was followed by percutaneous cyanoacrylate injection inside the abscess cavity and the fistulous tract which causes complete resolution of the abscess. PMID- 25685509 TI - Special issue on "Cyber Security". PMID- 25685510 TI - DoS detection in IEEE 802.11 with the presence of hidden nodes. AB - The paper presents a novel technique to detect Denial of Service (DoS) attacks applied by misbehaving nodes in wireless networks with the presence of hidden nodes employing the widely used IEEE 802.11 Distributed Coordination Function (DCF) protocols described in the IEEE standard [1]. Attacker nodes alter the IEEE 802.11 DCF firmware to illicitly capture the channel via elevating the probability of the average number of packets transmitted successfully using up the bandwidth share of the innocent nodes that follow the protocol standards. We obtained the theoretical network throughput by solving two-dimensional Markov Chain model as described by Bianchi [2], and Liu and Saadawi [3] to determine the channel capacity. We validated the results obtained via the theoretical computations with the results obtained by OPNET simulator [4] to define the baseline for the average attainable throughput in the channel under standard conditions where all nodes follow the standards. The main goal of the DoS attacker is to prevent the innocent nodes from accessing the channel and by capturing the channel's bandwidth. In addition, the attacker strives to appear as an innocent node that follows the standards. The protocol resides in every node to enable each node to police other nodes in its immediate wireless coverage area. All innocent nodes are able to detect and identify the DoS attacker in its wireless coverage area. We applied the protocol to two Physical Layer technologies: Direct Sequence Spread Spectrum (DSSS) and Frequency Hopping Spread Spectrum (FHSS) and the results are presented to validate the algorithm. PMID- 25685511 TI - Unsupervised, low latency anomaly detection of algorithmically generated domain names by generative probabilistic modeling. AB - We propose a method for detecting anomalous domain names, with focus on algorithmically generated domain names which are frequently associated with malicious activities such as fast flux service networks, particularly for bot networks (or botnets), malware, and phishing. Our method is based on learning a (null hypothesis) probability model based on a large set of domain names that have been white listed by some reliable authority. Since these names are mostly assigned by humans, they are pronounceable, and tend to have a distribution of characters, words, word lengths, and number of words that are typical of some language (mostly English), and often consist of words drawn from a known lexicon. On the other hand, in the present day scenario, algorithmically generated domain names typically have distributions that are quite different from that of human created domain names. We propose a fully generative model for the probability distribution of benign (white listed) domain names which can be used in an anomaly detection setting for identifying putative algorithmically generated domain names. Unlike other methods, our approach can make detections without considering any additional (latency producing) information sources, often used to detect fast flux activity. Experiments on a publicly available, large data set of domain names associated with fast flux service networks show encouraging results, relative to several baseline methods, with higher detection rates and low false positive rates. PMID- 25685512 TI - An efficient method to detect periodic behavior in botnet traffic by analyzing control plane traffic. AB - Botnets are large networks of bots (compromised machines) that are under the control of a small number of bot masters. They pose a significant threat to Internet's communications and applications. A botnet relies on command and control (C2) communications channels traffic between its members for its attack execution. C2 traffic occurs prior to any attack; hence, the detection of botnet's C2 traffic enables the detection of members of the botnet before any real harm happens. We analyze C2 traffic and find that it exhibits a periodic behavior. This is due to the pre-programmed behavior of bots that check for updates to download them every T seconds. We exploit this periodic behavior to detect C2 traffic. The detection involves evaluating the periodogram of the monitored traffic. Then applying Walker's large sample test to the periodogram's maximum ordinate in order to determine if it is due to a periodic component or not. If the periodogram of the monitored traffic contains a periodic component, then it is highly likely that it is due to a bot's C2 traffic. The test looks only at aggregate control plane traffic behavior, which makes it more scalable than techniques that involve deep packet inspection (DPI) or tracking the communication flows of different hosts. We apply the test to two types of botnet, tinyP2P and IRC that are generated by SLINGbot. We verify the periodic behavior of their C2 traffic and compare it to the results we get on real traffic that is obtained from a secured enterprise network. We further study the characteristics of the test in the presence of injected HTTP background traffic and the effect of the duty cycle on the periodic behavior. PMID- 25685513 TI - Supporting secure programming in web applications through interactive static analysis. AB - Many security incidents are caused by software developers' failure to adhere to secure programming practices. Static analysis tools have been used to detect software vulnerabilities. However, their wide usage by developers is limited by the special training required to write rules customized to application-specific logic. Our approach is interactive static analysis, to integrate static analysis into Integrated Development Environment (IDE) and provide in-situ secure programming support to help developers prevent vulnerabilities during code construction. No additional training is required nor are there any assumptions on ways programs are built. Our work is motivated in part by the observation that many vulnerabilities are introduced due to failure to practice secure programming by knowledgeable developers. We implemented a prototype interactive static analysis tool as a plug-in for Java in Eclipse. Our technical evaluation of our prototype detected multiple zero-day vulnerabilities in a large open source project. Our evaluations also suggest that false positives may be limited to a very small class of use cases. PMID- 25685514 TI - Capturing security requirements for software systems. AB - Security is often an afterthought during software development. Realizing security early, especially in the requirement phase, is important so that security problems can be tackled early enough before going further in the process and avoid rework. A more effective approach for security requirement engineering is needed to provide a more systematic way for eliciting adequate security requirements. This paper proposes a methodology for security requirement elicitation based on problem frames. The methodology aims at early integration of security with software development. The main goal of the methodology is to assist developers elicit adequate security requirements in a more systematic way during the requirement engineering process. A security catalog, based on the problem frames, is constructed in order to help identifying security requirements with the aid of previous security knowledge. Abuse frames are used to model threats while security problem frames are used to model security requirements. We have made use of evaluation criteria to evaluate the resulting security requirements concentrating on conflicts identification among requirements. We have shown that more complete security requirements can be elicited by such methodology in addition to the assistance offered to developers to elicit security requirements in a more systematic way. PMID- 25685515 TI - Fast Flux Watch: A mechanism for online detection of fast flux networks. AB - Fast flux networks represent a special type of botnets that are used to provide highly available web services to a backend server, which usually hosts malicious content. Detection of fast flux networks continues to be a challenging issue because of the similar behavior between these networks and other legitimate infrastructures, such as CDNs and server farms. This paper proposes Fast Flux Watch (FF-Watch), a mechanism for online detection of fast flux agents. FF-Watch is envisioned to exist as a software agent at leaf routers that connect stub networks to the Internet. The core mechanism of FF-Watch is based on the inherent feature of fast flux networks: flux agents within stub networks take the role of relaying client requests to point-of-sale websites of spam campaigns. The main idea of FF-Watch is to correlate incoming TCP connection requests to flux agents within a stub network with outgoing TCP connection requests from the same agents to the point-of-sale website. Theoretical and traffic trace driven analysis shows that the proposed mechanism can be utilized to efficiently detect fast flux agents within a stub network. PMID- 25685516 TI - Cyber-physical security of Wide-Area Monitoring, Protection and Control in a smart grid environment. AB - Smart grid initiatives will produce a grid that is increasingly dependent on its cyber infrastructure in order to support the numerous power applications necessary to provide improved grid monitoring and control capabilities. However, recent findings documented in government reports and other literature, indicate the growing threat of cyber-based attacks in numbers and sophistication targeting the nation's electric grid and other critical infrastructures. Specifically, this paper discusses cyber-physical security of Wide-Area Monitoring, Protection and Control (WAMPAC) from a coordinated cyber attack perspective and introduces a game-theoretic approach to address the issue. Finally, the paper briefly describes how cyber-physical testbeds can be used to evaluate the security research and perform realistic attack-defense studies for smart grid type environments. PMID- 25685517 TI - Cyber security challenges in Smart Cities: Safety, security and privacy. AB - The world is experiencing an evolution of Smart Cities. These emerge from innovations in information technology that, while they create new economic and social opportunities, pose challenges to our security and expectations of privacy. Humans are already interconnected via smart phones and gadgets. Smart energy meters, security devices and smart appliances are being used in many cities. Homes, cars, public venues and other social systems are now on their path to the full connectivity known as the "Internet of Things." Standards are evolving for all of these potentially connected systems. They will lead to unprecedented improvements in the quality of life. To benefit from them, city infrastructures and services are changing with new interconnected systems for monitoring, control and automation. Intelligent transportation, public and private, will access a web of interconnected data from GPS location to weather and traffic updates. Integrated systems will aid public safety, emergency responders and in disaster recovery. We examine two important and entangled challenges: security and privacy. Security includes illegal access to information and attacks causing physical disruptions in service availability. As digital citizens are more and more instrumented with data available about their location and activities, privacy seems to disappear. Privacy protecting systems that gather data and trigger emergency response when needed are technological challenges that go hand-in-hand with the continuous security challenges. Their implementation is essential for a Smart City in which we would wish to live. We also present a model representing the interactions between person, servers and things. Those are the major element in the Smart City and their interactions are what we need to protect. PMID- 25685518 TI - System-level protection and hardware Trojan detection using weighted voting. AB - The problem of hardware Trojans is becoming more serious especially with the widespread of fabless design houses and design reuse. Hardware Trojans can be embedded on chip during manufacturing or in third party intellectual property cores (IPs) during the design process. Recent research is performed to detect Trojans embedded at manufacturing time by comparing the suspected chip with a golden chip that is fully trusted. However, Trojan detection in third party IP cores is more challenging than other logic modules especially that there is no golden chip. This paper proposes a new methodology to detect/prevent hardware Trojans in third party IP cores. The method works by gradually building trust in suspected IP cores by comparing the outputs of different untrusted implementations of the same IP core. Simulation results show that our method achieves higher probability of Trojan detection over a naive implementation of simple voting on the output of different IP cores. In addition, experimental results show that the proposed method requires less hardware overhead when compared with a simple voting technique achieving the same degree of security. PMID- 25685519 TI - Fetal MRI: An approach to practice: A review. AB - MRI has been increasingly used for detailed visualization of the fetus in utero as well as pregnancy structures. Yet, the familiarity of radiologists and clinicians with fetal MRI is still limited. This article provides a practical approach to fetal MR imaging. Fetal MRI is an interactive scanning of the moving fetus owed to the use of fast sequences. Single-shot fast spin-echo (SSFSE) T2 weighted imaging is a standard sequence. T1-weighted sequences are primarily used to demonstrate fat, calcification and hemorrhage. Balanced steady-state free precession (SSFP), are beneficial in demonstrating fetal structures as the heart and vessels. Diffusion weighted imaging (DWI), MR spectroscopy (MRS), and diffusion tensor imaging (DTI) have potential applications in fetal imaging. Knowing the developing fetal MR anatomy is essential to detect abnormalities. MR evaluation of the developing fetal brain should include recognition of the multilayered-appearance of the cerebral parenchyma, knowledge of the timing of sulci appearance, myelination and changes in ventricular size. With advanced gestation, fetal organs as lungs and kidneys show significant changes in volume and T2-signal. Through a systematic approach, the normal anatomy of the developing fetus is shown to contrast with a wide spectrum of fetal disorders. The abnormalities displayed are graded in severity from simple common lesions to more complex rare cases. Complete fetal MRI is fulfilled by careful evaluation of the placenta, umbilical cord and amniotic cavity. Accurate interpretation of fetal MRI can provide valuable information that helps prenatal counseling, facilitate management decisions, guide therapy, and support research studies. PMID- 25685521 TI - Design flow factors for sewerage systems in small arid communities. AB - Reliable estimation of sewage flow rates is essential for the proper design of sewers, pumping stations, and treatment plants. The design of the various components of the sewerage system should be based on the most critical flow rates with a focus on extremely low and peak flow rates that would be sustained for a duration related to the acceptable limits of behavior of the components under consideration. The extreme flow conditions and to what extent they differ from the average values are closely related to the size of the community or network, and the socioeconomic conditions. A single pumping station is usually sufficient to pump flow from small community in either flat or non-undulating topography. Therefore, the hydraulic loading on the wastewater treatment plant (WWTP) results from the pumped flow from the pumping station rather than the trunk sewer flow. The intermittent operation of the pumping units further accentuates the sewage hydrograph in the final trunk sewer. Accordingly, the design flow for the various components of the WWTP should be determined based on their relevant flow factors. In this study, analysis of one representative small community out of five monitored small communities in Egypt and the Kingdom of Saudi Arabia is presented. Pumped sewage flow rates were measured and the sewer incoming flows were hydraulically derived. The hourly and daily sewer and pumped flow records were analyzed to derive the relationship between the flow factors that would be sustained for various durations (instantaneously, 1 h, 2 h, etc.) and their probability of non-exceedance. The resulting peaking factors with a consideration for their sustained flow duration and specified probability would permit the design of the various components of the treatment plant using more accurate critical flows. PMID- 25685522 TI - Effect of P2O5 and MnO2 on crystallization of magnetic glass ceramics. AB - This work pointed out the effect of adding P2O5 and/or MnO2 on the crystallization behavior of magnetic glass ceramic in the system Fe2O3.ZnO.CaO.SiO2.B2O3. The differential thermal analysis of the quenched samples revealed decrease in the thermal effects by adding P2O5 and/or MnO2 to the base sample. The X-ray diffraction patterns show the development of nanometric magnetite crystals in a glassy matrix. Heat treatment at 800 degrees C for 2 h, under reducing atmosphere, caused an increase in the amount of the crystallized magnetite with the appearance of minor hematite and Ca2SiO4. The transmission electron microscope revealed a crystallite size in the range 10-30 nm. Magnetic hysteresis cycles were analyzed with a maximum applied field of 25 kOe at room temperature. The prepared magnetic glass ceramics are expected to be useful for localized treatment of cancer. PMID- 25685520 TI - Inflammatory breast cancer: New factors contribute to disease etiology: A review. AB - Inflammatory breast cancer (IBC) is a highly metastatic and fatal form of breast cancer. In fact, IBC is characterized by specific morphological, phenotypic, and biological properties that distinguish it from non-IBC. The aggressive behavior of IBC being more common among young women and the low survival rate alarmed researchers to explore the disease biology. Despite the basic and translational studies needed to understand IBC disease biology and identify specific biomarkers, studies are limited by few available IBC cell lines, experimental models, and paucity of patient samples. Above all, in the last decade, researchers were able to identify new factors that may play a crucial role in IBC progression. Among identified factors are cytokines, chemokines, growth factors, and proteases. In addition, viral infection was also suggested to participate in the etiology of IBC disease. In this review, we present novel factors suggested by different studies to contribute to the etiology of IBC and the proposed new therapeutic insights. PMID- 25685523 TI - Development and validation of a lead emission inventory for the Greater Cairo area. AB - Studies that investigate the environmental health risks to Cairo residents invariably conclude that lead is one of the area's major health hazards. The Cairo Air Improvement Project (CAIP), which was implemented by a team led by Chemonics International, funded by USAID in partnership with the Egyptian Environmental Affairs Agency (EEAA), started developing a lead emission inventory for the greater Cairo (GC) area in 1998. The inventory contains a list by major source of the annual lead emissions in the GC area. Uses of the inventory and associated database include developing effective regulatory and control strategies, assessing emissions trends, and conducting modeling exercises. This paper describes the development of the current lead emissions inventory (1999 2010), along with an approach to develop site specific emission factors and measurements to validate the inventory. This paper discusses the major sources of lead in the GC area, which include lead smelters, Mazout (heavy fuel oil) combustion, lead manufacturing batteries factories, copper foundries, and cement factories. Included will be the trend in the lead emissions inventory with regard to the production capacity of each source category. In addition, the lead ambient measurements from 1999 through 2010 are described and compared with the results of Source Attribution Studies (SAS) conducted in 1999, 2002, and 2010. Due to EEAA/CAIP efforts, a remarkable decrease in more than 90% in lead emissions was attained for 2007. PMID- 25685524 TI - Profile of cystic fibrosis in a single referral center in Egypt. AB - It was generally believed that Cystic fibrosis (CF) is rare among Arabs; however, the few studies available from Egypt and other Arabic countries suggested the presence of many undiagnosed patients. The aim of the present study was to determine the frequency of CF patients out of the referred cases in a single referral hospital in Egypt. A total of 100 patients clinically suspected of having CF were recruited from the CF clinic of the Allergy and Pulmonology Unit, Children's Hospital, Cairo University, Egypt, throughout a 2 year period. Sweat chloride testing was done for all patients using the Wescor macroduct system for collection of sweat. Quantitative analysis for chloride was then done by the thiocyanate colorimetric method. Patients positive for sweat chloride (?60 mmol/L) were tested for the DeltaF508 mutation using primer specific PCR for cystic fibrosis transmembrane conductance regulator (CFTR) gene. Thirty-six patients (36%) had a positive sweat chloride test. The main clinical presentations in patients were chronic cough in 32 (88.9%), failure to thrive in 27 (75%), steatorrhea in 24 (66.7%), and hepatobiliary involvement in 5 (13.9%). Positive consanguinity was reported in 50% of CF patients. Thirty-two patients were screened for DeltaF508 mutation. Positive DeltaF508 mutation was detected in 22 (68.8%) patients, 8 (25%) were homozygous, 14 (43.8%) were heterozygous, and 10 (31.3%) tested were negative. CF was diagnosed in more than third of patients suspected of having the disease on clinical grounds. This high frequency of CF among referred patients indicates that a high index of suspicion and an increasing availability of diagnostic tests lead to the identification of a higher number of affected individuals. PMID- 25685525 TI - Risk assessment of desert pollution on composite high voltage insulators. AB - Transmission lines located in the desert are subjected to desert climate, one of whose features is sandstorms. With long accumulation of sand and with the advent of moisture from rain, ambient humidity and dew, a conductive layer forms and the subsequent leakage current may lead to surface discharge, which may shorten the insulator life or lead to flashover thus interrupting the power supply. Strategically erected power lines in the Egyptian Sinai desert are typically subject to such a risk, where sandstorms are known to be common especially in the spring. In view of the very high cost of insulator cleaning operation, composite (silicon rubber) insulators are nominated to replace ceramic insulators on transmission lines in Sinai. This paper examines the flow of leakage current on sand-polluted composite insulators, which in turn enables a risk assessment of insulator failure. The study uses realistic data compiled and reported in an earlier research project about Sinai, which primarily included grain sizes of polluting sand as well as their salinity content. The paper also uses as a case study an ABB-designed composite insulator. A three-dimensional finite element technique is used to simulate the insulator and seek the potential and electric field distribution as well as the resulting leakage current flow on its polluted surface. A novel method is used to derive the probabilistic features of the insulator's leakage current, which in turn enables a risk assessment of insulator failure. This study is expected to help in critically assessing - and thus justifying - the use of this type of insulators in Sinai and similar critical areas. PMID- 25685526 TI - Microbially induced sedimentary structures in evaporite-siliciclastic sediments of Ras Gemsa sabkha, Red Sea Coast, Egypt. AB - The coastal sabkha in Ras Gemsa, Red Sea coast with its colonizing microbial mats and biofilms was investigated. The sabkha sediments consist mainly of terrigenous siliciclastic material accompanied by the development of evaporites. Halite serves as a good conduit for light and reduces the effect of intensive harmful solar radiation, which allows microbial mats to survive and flourish. The microbial mats in the evaporite-siliciclastic environments of such sabkha display distinctive sedimentary structures (microbially induced sedimentary structures), including frozen multidirected ripple marks, salt-encrusted crinkle mats, jelly roll structure, and petee structures. Scanning electron microscopy of the sediment surface colonized by cyanobacteria revealed that sand grains of the studied samples are incorporated into the biofilm by trapping and binding processes. Filamentous cyanobacteria and their EPS found in the voids in and between the particles construct a network that effectively interweaves and stabilizes the surface sediments. In advanced stages, the whole surface is covered by a spider web-like structure of biofilm, leading to a planar surface morphology. Sabkha with its chemical precipitates is a good model for potential preservation of life signatures. It is worthy to note that the available, published works on the subject of the present work are not numerous. PMID- 25685527 TI - Enhanced efficacy and reduced side effects of diazepam by kava combination. AB - The long term use of antiepileptic drugs possesses many unwanted effects; thus, new safe combinations are urgently mandated. Hence, the present study aimed to investigate the anticonvulsant effect of kava alone or in combination with a synthetic anticonvulsant drug, diazepam (DZ). To this end, female Wistar rats were divided into two subsets, each comprising 6 groups as follows: group (i) received 1% Tween 80 p.o. and served as control, while groups (ii) and (iii) received kava at two dose levels (100 and 200 mg/kg, p.o.). The remaining three groups received (iv) DZ alone (10 mg/kg p.o.) or kava in combination with DZ (v) (5 mg/kg, p.o.) or (vi) (10 mg/kg, p.o.). Results of the present study revealed that kava increased the maximal electroshock seizure threshold (MEST) and enhanced the anticonvulsant effect of diazepam following both acute and chronic treatment. Moreover, neither kava nor its combination with DZ impaired motor co ordination either acutely or chronically. Furthermore, kava ameliorated both the reduction in locomotor activity as well as changes in liver function tests induced by chronic administration of DZ. Moreover, no elevation was shown in the creatinine concentration vs. control group following chronic administration of kava or DZ either alone or in combination with kava. In conclusion, the present study suggests the possibility of combining a low dose DZ with kava to reduce harmful effects and might be recommended for clinical use in patients chronically treated with this synthetic anticonvulsant drug. PMID- 25685528 TI - Pilot study on molecular quantitation and sequencing of endometrial cytokines gene expression and their effect on the outcome of in vitro fertilization (IVF) cycle. AB - Human trophoblast invasion and differentiation are essential for successful pregnancy outcome. The molecular mechanisms, however, are poorly understood. Interleukin (IL)-11, a cytokine, regulates endometrial epithelial cell adhesion. Leukemia inhibitory factor (LIF) is one of the key cytokines in the embryo implantation regulation. The present study aimed to assess the levels of LIF, IL 11, and IL-11 alpha receptor gene expression in the endometrium of women undergoing IVF and correlate their levels with the IVF pregnancy outcome. Also, the study aimed to detect any mutation in these three genes among IVF pregnant and non-pregnant women versus control menstrual blood of fertile women. Endometrial tissue biopsies were taken from 15 women undergoing IVF on the day of oocyte retrieval. The quantitative expression of IL-11, IL-11Ralpha, and LIF genes was assessed by real-time PCR and PCR products were sequenced. Menstrual blood from 10 fertile women was used as control to compare the DNA sequence versus DNA sequence of the studied genes in endometrial biopsies. LH, FSH, and E2 were assessed for enrolled patients by ELISA. Endometrial thickness was also assessed by pelvic ultrasonography. No significant difference was detected between quantitative expression of the three studied genes and pregnancy IVF outcome. Although DNA sequence changes were found in IL-11 and LIF genes of women with negative pregnancy IVF outcome compared to women with positive pregnancy IVF outcome, no DNA sequence changes were detected for IL-11Ralpha. Other studied parameters (e.g., age, LH, FSH, E2, and endometrial thickness) showed no significant differences or correlation of quantitative expression of the three studied involved genes. Data suggested that there were no significant differences between quantitative expression of IL-11, IL-11Ralpha, and LIF genes and the IVF pregnancy outcome. The present study may reveal that changes in IL-11 and LIF genes sequence may contribute in pregnancy IVF outcome. PMID- 25685529 TI - Improvement of the magnetic properties for Mn-Ni-Zn ferrites by rare earth Nd(3+) ion substitution. AB - Single spinel phases of Mn0.5Ni0.1Zn0.4Nd x Fe2- x O4 ferrite samples (x = 0.0, 0.01, 0.02, 0.05, 0.075, and 0.1) have been prepared by ceramic method and the composition dependence of the physical and magnetic properties has been investigated. SEM micrographs and EDX analysis revealed that there is no considerable effect for the Nd(3+) ion substitution on the average grain size or porosity, whereas its concentration in the grain boundaries is higher than that in the grains. Saturation magnetization (M S) increased with the Nd(3+) ion concentration (x) and reached a maximum value at x = 0.05. In addition, both the initial permeability and the magnetic homogeneity increased by increasing the Nd(3+) ion content. The value of Curie temperature increased due to the substitution by Nd(3+) ions to record about 170 K, for the sample with x = 0.05, higher than that of the un-substituted one. PMID- 25685530 TI - Climate change and epidemiology of human parasitosis in Egypt: A review. AB - Climate change is an emerging global issue. It is expected to have significant impacts both in Egypt and around the world. Thus, the country is in need for taking action to prepare for the unavoidable effects of climate change, including the increase in water stress, the rise in sea level, and the rapidly increasing gap between the limited water availability and the escalating demand for water in the country. Also, weather and climate play a significant role in people's health. Direct impacts of climate change on the Egyptians public health may include also increased prevalence of human parasitic diseases. Climate could strongly influence parasitic diseases transmitted through intermediate hosts. The present work reviews the future of such parasitic diseases in the view of the current available evidence and scenarios for climate change in the Egypt. PMID- 25685531 TI - Utilizing neural networks in magnetic media modeling and field computation: A review. AB - Magnetic materials are considered as crucial components for a wide range of products and devices. Usually, complexity of such materials is defined by their permeability classification and coupling extent to non-magnetic properties. Hence, development of models that could accurately simulate the complex nature of these materials becomes crucial to the multi-dimensional field-media interactions and computations. In the past few decades, artificial neural networks (ANNs) have been utilized in many applications to perform miscellaneous tasks such as identification, approximation, optimization, classification and forecasting. The purpose of this review article is to give an account of the utilization of ANNs in modeling as well as field computation involving complex magnetic materials. Mostly used ANN types in magnetics, advantages of this usage, detailed implementation methodologies as well as numerical examples are given in the paper. PMID- 25685532 TI - Inhibitory action of quaternary ammonium bromide on mild steel and synergistic effect with other halide ions in 0.5 M H2SO4. AB - The corrosion inhibition of mild steel in 0.5 M H2SO4 solution has been investigated using electrochemical methods, X-ray diffraction (XRD) and scanning electron microscope (SEM). The adsorption and inhibition action of acid corrosion of mild steel using cetyltrimethylammonium bromide (CTABr) and different halides (NaCl, NaBr and NaI) has shown synergetic effect. The results showed that the protection efficiency (P%) has high values at considerable high concentration of CTABr. However, in the presence of the different halides, the P increases dramatically at low concentration of CTABr. Physisorption was proposed from the the values of [Formula: see text]. The synergism parameter (S theta) is found to be greater than unity indicating that the enhanced P% caused by the addition of the halides to the CTABr is due to a co-operative adsorption of both species. Corrosion products phases and surface morphology were studied using X-ray diffraction (XRD) and scanning electron microscopy (SEM), respectively. PMID- 25685533 TI - CD4(+) CD25(+) cells in type 1 diabetic patients with other autoimmune manifestations. AB - The existence of multiple autoimmune disorders in diabetics may indicate underlying primary defects of immune regulation. The study aims at estimation of defects of CD4(+) CD25(+high) cells among diabetic children with multiple autoimmune manifestations, and identification of disease characteristics in those children. Twenty-two cases with type 1 diabetes associated with other autoimmune diseases were recruited from the Diabetic Endocrine and Metabolic Pediatric Unit (DEMPU), Cairo University along with twenty-one normal subjects matched for age and sex as a control group. Their anthropometric measurements, diabetic profiles and glycemic control were recorded. Laboratory investigations included complete blood picture, glycosylated hemoglobin, antithyroid antibodies, celiac antibody panel and inflammatory bowel disease markers when indicated. Flow cytometric analysis of T-cell subpopulation was performed using anti-CD3, anti-CD4, anti CD8, anti-CD25 monoclonal antibodies. Three cases revealed a proportion of CD4(+) CD25(+high) below 0.1% and one case had zero counts. However, this observation did not mount to a significant statistical difference between the case and control groups neither in percentage nor absolute numbers. Significant statistical differences were observed between the case and the control groups regarding their height, weight centiles, as well as hemoglobin percentage, white cell counts and the absolute lymphocytic counts. We concluded that, derangements of CD4(+) CD25(+high) cells may exist among diabetic children with multiple autoimmune manifestations indicating defects of immune controllers. PMID- 25685534 TI - Frequency and prognostic significant of CYP3A4-A-290G polymorphism in acute myeloid leukemia. AB - Cytochrome P450 3A4 (CYP3A4) is the most plentiful cytochrome P450 in adult human liver and small intestine and is responsible for detoxification of more than 50% of drugs in addition to the metabolic deactivation and metabolism of many carcinogens. Polymorphism of CYP3A4-A-290G considered the only allele that appears to stimulate CYP3A4 expression and has been associated with a number of clinical phenotypes, including prostate cancer, breast cancer, leukemia and the early onset of puberty. In this study, we analyzed the presence of CYP3A4-A-290G polymorphism in 77 newly diagnosed AML cases and 72 healthy control using PCR/RFLP aiming to show CYP3A4-A-290G polymorphism pattern in acute myeloid leukemia patients, and its role in disease severity and progression. A highly statistically significant difference was found between the control and AML groups as regards the heterozygous genotype (p-value = 0.002) and increases the risk of AML 11.4-fold. Also there was a highly significant difference between the control and AML patients regarding variant allele (G in AG and GG genotypes) (p-value 0.001) and increases the risk of AML 19-fold. No statistically significant association found between the CYP3A4-A-290G polymorphism and different clinical or laboratory parameters as well as an initial response to treatment, overall survival and the disease free survival. We concluded that CYP3A4-A-290G polymorphism is a genotypic factor that increases the CYP3A4 enzymatic activity and increases the risk of AML by 18.9-fold. PMID- 25685535 TI - Preparation of ZrO2/Al2O3-montmorillonite composite as catalyst for phenol hydroxylation. AB - Zirconium dispersed in aluminum-pillared montmorillonite was prepared as a catalyst for phenol hydroxylation. The effects of varying the Zr content on the catalyst's physicochemical character and activity were studied with XRD, BET surface area analysis, surface acidity measurements and scanning electron microscopy before investigating the performance for phenol conversion. The zirconia dispersion significantly affects the specific surface area, the total surface acidity and surface acidity distribution related to the formation of porous zirconia particles on the surface. The prepared samples exhibited excellent catalytic activity during phenol hydroxylation. PMID- 25685536 TI - Modulation of genotoxicity and endocrine disruptive effects of malathion by dietary honeybee pollen and propolis in Nile tilapia (Oreochromis niloticus). AB - The present study aimed at verifying the usefulness of dietary 2.5% bee-pollen (BP) or propolis (PROP) to overcome the genotoxic and endocrine disruptive effects of malathion polluted water in Oreochromis niloticus (O. niloticus). The acute toxicity test was conducted in O. niloticus in various concentrations (0-8 ppm); mortality rate was assessed daily for 96 h. The 96 h-LC50 was 5 ppm and therefore 1/5 of the median lethal concentration (1 ppm) was used for chronic toxicity assessment. In experiment (1), fish (n = 8/group) were kept on a diet (BP/PROP or without additive (control)) and exposed daily to malathion in water at concentration of 5 ppm for 96 h "acute toxicity experiment". Protective efficiency against the malathion was verified through chromosomal aberrations (CA), micronucleus (MN) and DNA-fragmentation assessment. Survival rate in control, BP and PROP groups was 37.5%, 50.0% and 100.0%, respectively. Fish in BP and PROP groups showed a significant (P < 0.05) reduction in the frequency of CA (57.14% and 40.66%), MN (53.13% and 40.63%) and DNA-fragmentation (53.08% and 30.00%). In experiment (2), fish (10 males and 5 females/group) were kept on a diet with/without BP for 21 days before malathion-exposure in water at concentration of 0 ppm (control) or 1 ppm (Exposed) for further 10 days "chronic toxicity experiment". BP significantly (P < 0.05) reduced CA (86.33%), MN (82.22%) and DNA-fragmentation (93.11%), prolonged the sperm motility when exposed to 0.01 ppm of pollutant in vitro and increased the estradiol level in females comparing to control. In conclusion, BP can be used as a feed additive for fish prone to be raised in integrated fish farms or cage culture due to its potency to chemo-protect against genotoxicity and sperm-teratogenicity persuaded by malathion-exposure. PMID- 25685537 TI - Pseudo-stir bar hollow fiber solid/liquid phase microextraction combined with anodic stripping voltammetry for determination of lead and cadmium in water samples. AB - A new procedure is presented for the determination of low concentrations of lead and cadmium in water samples. Ligand assisted pseudo-stir bar hollow fiber solid/liquid phase microextraction using sol-gel sorbent reinforced with carbon nanotubes was combined with differential pulse anodic stripping voltammetry for simultaneous determination of cadmium and lead in tap water, and Darongar river water samples. In the present work, differential pulse anodic stripping voltammetry (DPASV) using a hanging mercury drop electrode (HMDE) was used in order to determine the ultra trace level of lead and cadmium ions in real samples. This method is based on accumulation of lead and cadmium ions on the electrode using different ligands; Quinolin-8-ol, 5,7-diiodo quinoline-8-ol, 4,5 diphenyl-1H-imidazole-2(3H)-one and 2-{[2-(2-Hydroxy-ethylamino)-ethylamino] methyl}-phenol as the complexing agent. The optimized conditions were obtained. The relationship between the peak current versus concentration was linear over the range of 0.05-500 ng mL(-1) for Cd (II) and Pb (II). The limits of detection for lead and cadmium were 0.015 ng mL(-1) and 0.012 ng mL(-1), respectively. Under the optimized conditions, the pre-concentration factors are 2440 and 3710 for Cd (II) and Pb (II) in 5 mL of water sample, respectively. PMID- 25685538 TI - Sequence analysis of the Toll-like receptor 2 gene of old world camels. AB - The Toll-like receptor 2 (TLR2) gene of old world camels (Camelus dromedarius and Camelus bactrianus) was cloned and sequenced. The TLR2 gene of the dromedary camel had the highest nucleotide and amino acid identity with pig, i.e., 66.8% and 59.6%, respectively. Similarly, the TLR2 gene of the Bactrian camel also had the highest nucleotide and amino acid identity with pig, i.e., 85.7% and 81.4%, respectively. Dromedary and Bactrian camels shared 77.9% nucleotide and 73.6% amino acid identity with each other. Interestingly, the amidation motif is present in camel (Dromedary and Bactrian) TLR2 only, and the TIR domain is absent in Dromedary camel TLR2. This is the first report of the TLR2 gene sequence of Dromedary and Bactrian camels. PMID- 25685539 TI - Editorial. PMID- 25685540 TI - Two dimensional NMR spectroscopic approaches for exploring plant metabolome: A review. AB - Today, most investigations of the plant metabolome tend to be based on either nuclear magnetic resonance (NMR) spectroscopy or mass spectrometry (MS), with or without hyphenation with chromatography. Although less sensitive than MS, NMR provides a powerful complementary technique for the identification and quantification of metabolites in plant extracts. NMR spectroscopy, well appreciated by phytochemists as a particularly information-rich method, showed recent paradigm shift for the improving of metabolome(s) structural and functional characterization and for advancing the understanding of many biological processes. Furthermore, two dimensional NMR (2D NMR) experiments and the use of chemometric data analysis of NMR spectra have proven highly effective at identifying novel and known metabolites that correlate with changes in genotype or phenotype. In this review, we provide an overview of the development of NMR in the field of metabolomics with special focus on 2D NMR spectroscopic techniques and their applications in phytomedicines quality control analysis and drug discovery from natural sources, raising more attention at its potential to reduce the gap between the pace of natural products research and modern drug discovery demand. PMID- 25685541 TI - Microbial biotransformation as a tool for drug development based on natural products from mevalonic acid pathway: A review. AB - Natural products are structurally and biologically interesting metabolites, but they have been isolated in minute amounts. The syntheses of such natural products help in obtaining them in bulk amounts. The recognition of microbial biotransformation as important manufacturing tool has increased in chemical and pharmaceutical industries. In recent years, microbial transformation is increasing significantly from limited interest into highly active area in green chemistry including preparation of pharmaceutical products. This is the first review published on the usage of microbial biocatalysts for some natural product classes and natural product drugs. PMID- 25685542 TI - An overview on the potential of natural products as ureases inhibitors: A review. AB - Ureases, enzymes that catalyze urea hydrolysis, have received considerable attention for their impact on living organisms' health and life quality. On the one hand, the persistence of urease activity in human and animal cells can be the cause of some diseases and pathogen infections. On the other hand, food production can be negatively affected by ureases of soil microbiota that, in turn, lead to losses of nitrogenous nutrients in fields supplemented with urea as fertilizer. In this context, nature has proven to be a rich resource of natural products bearing a variety of scaffolds that decrease the ureolytic activity of ureases from different organisms. Therefore, this work compiles the state-of-the art researches focused on the potential of plant natural products (present in extracts or as pure compounds) as urease inhibitors of clinical and/or agricultural interests. Emphasis is given to ureases of Helicobacter pylori, Canavalia ensiformis and soil microbiota although the active site of this class of hydrolases is conserved among living organisms. PMID- 25685544 TI - A mini review on pyridoacridines: Prospective lead compounds in medicinal chemistry. AB - Natural products are increasingly being considered "critical and important" in drug discovery paradigms as a number of them such as camptothecin, penicillin, and vincristine serve as "lead molecules" for the discovery of potent compounds of therapeutic interests namely irinotecan, penicillin G, vinblastine respectively. Derived compounds of pharmacological interests displayed a wide variety of activity viz. anticancer, anti-inflammatory, antimicrobial, anti protozoal, etc.; when modifications or derivatizations are performed on a parent moiety representing the corresponding derivatives. Pyridoacridine is such a moiety which forms the basic structure of numerous medicinally important natural products such as, but not limited to, amphimedine, ascididemin, eilatin, and sampangine. Interestingly, synthetic analogues of natural pyridoacridine exhibit diverse pharmacological activities and in view of these, natural pyridoacridines can be considered as "lead compounds". This review additionally provides a brief but critical account of inherent structure activity relationships among various subclasses of pyridoacridines. Furthermore, the current aspects and future prospects of natural pyridoacridines are detailed for further reference and consideration. PMID- 25685545 TI - Control of amphibious weed ipomoea (Ipomoea carnea) by utilizing it for the extraction of volatile fatty acids as energy precursors. AB - Volatile fatty acids (VFAs), comprising mainly of acetic acid and lesser quantities of propionic and butyric acids, are generated when zoomass or phytomass is acted upon by acidogenic and acetogenic microorganisms. VFAs can be utilized by methanogens under anaerobic conditions to generate flammable methane carbon dioxide mixtures known as 'biogas'. Acting on the premise that this manner of VFA utilization for generating relatively clean energy can be easily accomplished in a controlled fashion in conventional biogas plants as well as higher-rate anaerobic digesters, we have carried out studies aimed to generate VFAs from the pernicious weed ipomoea (Ipomoea carnea). The VFA extraction was accomplished by a simple yet effective technology, appropriate for use even by laypersons. For this acid-phase reactors were set, to which measured quantities of ipomoea leaves were charged along with water inoculated with cow dung. The reactors were stirred intermittently. It was found that VFA production started within hours of the mixing of the reactants and peaked by the 10(th) or 11(th) day in all the reactors, effecting a conversion of over 10% of the biomass into VFAs. The reactor performance had good reproducibility and the process appeared easily controllable, frugal and robust. PMID- 25685543 TI - P-glycoprotein inhibitors of natural origin as potential tumor chemo-sensitizers: A review. AB - Resistance of solid tumors to treatment is significantly attributed to pharmacokinetic reasons at both cellular and multi-cellular levels. Anticancer agent must be bio-available at the site of action in a cytotoxic concentration to exert its proposed activity. P-glycoprotein (P-gp) is a member of the ATP dependent membrane transport proteins; it is known to pump substrates out of cells in ATP-dependent mechanism. The over-expression of P-gp in tumor cells reduces the intracellular drug concentrations, which decreases the cytotoxicity of a broad spectrum of antitumor drugs. Accordingly, P-gp inhibitors/blockers are potential enhancer for the cellular bioavailability of several clinically important anticancer drugs such as, anthracyclines, taxanes, vinca alkaloids, and podophyllotoxins. Besides several chemically synthesized P-gp inhibitors/blockers, some naturally occurring compounds and plant extracts were reported for their modulation of multidrug resistance; however, this review will focus only on major classes of naturally occurring inhibitors viz., flavonoids, coumarins, terpenoids, alkaloids and saponins. PMID- 25685546 TI - Functional and antioxidant properties of novel snack crackers incorporated with Hibiscus sabdariffa by-product. AB - The Hibiscus sabdariffa calyxes' residue (HSR) remained after the extraction of beverage is discarded which contributes to environmental pollution. The objective of this study was to explore the suitability of incorporating different amount of HSR (0%, 1.25%, 2.5%, 3.75%, and 5.0%) in crackers to enhance dietary fiber and antioxidant content. Physicochemical properties, antioxidants activity, nutritional quality, sensory profile and microstructure properties of samples containing HSR were examined and compared with control crackers. Cracker protein and fat levels decreased as HSR increased from 0.0% to 5% while ash increased. The total dietary fiber DF increased from 3.36% to 8.17% where the highest DF was reached at 5% HSR. The content of phenols increased from 5.99 to 17.57 mg/g and total flavonoid content increased from 49.36 to 104.63 mg/g of crackers incorporated with 5% HSR. DPPH radical scavenging activity increased two fold by increasing HSR up to 5%. HSR containing crackers exhibited darker L values than none/less HSR containing ones. In sensory ranking tests, acceptable crackers with pleasant flavor were obtained by incorporating up to 3.75% HSR into the cracker's formula. Crackers prepared with 5% HSR received the poorest sensory rating compared to non/less HSR enriched cracker. Scanning electron microscopy (EM) images of the prepared crackers revealed marked changes caused by incorporating HSR as upon HSR addition the surface was observed to be scratched, cracker and rougher. Overall results suggest that HSR is a potential functional food ingredient high in fiber content and antioxidants activity that may be processed into flour and used in food applications, such as baked goods. PMID- 25685547 TI - An investigation of the bactericidal activity of selected essential oils to Aeromonas spp. AB - Diseases of fishes caused by Aeromonas spp. are common, have broad host ranges and may cause high mortality. Treatments of captive-reared populations using antimicrobials are limited with concerns for bacterial resistance development and environmental dissemination. This study was done to determine whether selected plant-derived essential oils were bactericidal to Aeromonas spp. Initially, twelve essential oils were evaluated using a disk diffusion assay to an isolate of A. salmonicida subsp. salmonicida, cause of fish furunculosis. The greatest zones of inhibition were obtained with oils of cinnamon Cinnamomum cassia, oregano Origanum vulgare, lemongrass Cymbopogon citratus and thyme Thymus vulgaris. Minimum bactericidal concentrations (MBC's) were determined for these four oils, Allimed(r) (garlic extract, Allium sativum) and colloidal silver to sixty-nine isolates representing nine Aeromonas spp. The lowest mean MBCs (0.02 0.04%) were obtained with three different sources of cinnamon oil. MBCs for three sources of oregano and lemongrass oils ranged from 0.14% to 0.30% and 0.10% to 0.65%, respectively, and for two thyme oils were 2.11% and 2.22%. The highest concentration (5%) of Allimed(r) tested resulted in MBCs to twelve isolates. A concentration of silver greater than 15 mg/L would be required to determine MBCs for all but one isolate. PMID- 25685548 TI - Unequivocal glycyrrhizin isomer determination and comparative in vitro bioactivities of root extracts in four Glycyrrhiza species. AB - Glycyrrhiza glabra, commonly known as licorice, is a popular herbal supplement used for the treatment of chronic inflammatory conditions and as sweetener in the food industry. This species contains a myriad of phytochemicals including the major saponin glycoside glycyrrhizin (G) of Glycyrrhetinic acid (GA) aglycone. In this study, 2D-ROESY NMR technique was successfully applied for distinguishing 18alpha and 18beta glycyrrhetinic acid (GA). ROESY spectra acquired from G. glabra, Glycyrrhiza uralensis and Glycyrrhiza inflata crude extracts revealed the presence of G in its beta-form. Anti-inflammatory activity of four Glycyrrhiza species, G, glabra, G. uralensis, G. inflata, and G. echinata roots was assessed against COX-1 inhibition revealing that phenolics rather than glycyrrhizin are biologically active in this assay. G. inflata exhibits a strong cytotoxic effect against PC3 and HT29 cells lines, whereas other species are inactive. This study presents an effective NMR method for G isomer assignment in licorice extracts that does not require any preliminary chromatography or any other purification step. PMID- 25685549 TI - Knowledge of Hepatitis B Virus Infection, Immunization with Hepatitis B Vaccine, Risk Perception, and Challenges to Control Hepatitis among Hospital Workers in a Nigerian Tertiary Hospital. AB - Background. Studies had reported high rate of hepatitis B infection among hospital workers with low participation in vaccination programmes, especially those whose work exposes them to the risk of HBV infection. The study assessed knowledge of hepatitis B virus infection, risk perception, vaccination history, and challenges to control hepatitis among health workers. Methods. A descriptive cross-sectional study. Consenting health care workers completed a self administered questionnaire that assessed respondents' general knowledge of HBV, vaccination history and HBsAg status, risk perception, and challenges to control hepatitis. Data was analysed using descriptive and inferential statistics. Results. Three hundred and eighty-two health care workers participated in the study. There were 182 males and 200 females. The respondents comprised 94 (25%) medical doctors, 168 (44%) nurses, 68 (18%) medical laboratory technologists, and 52 (14%) pharmacists. Over 33% had poor knowledge with 35% not immunized against HBV. Predictors of good knowledge include age less than 35 years, male sex, being a medical doctor, previous HBsAg test, and complete HBV immunisation. Identified challenges to control hepatitis include lack of hospital policy (91.6%), poor orientation of newly employed health workers (75.9%), and low risk perception (74.6%). Conclusion. Hospital policy issues and low risk perception of HBV transmission have grave implications for the control of HBV infection. PMID- 25685550 TI - Clinical characteristics and prognosis of incidentally detected lung cancers. AB - OBJECTIVE: To evaluate clinical characteristics and outcomes in incidentally detected lung cancer and in symptomatic lung cancer. MATERIAL AND METHODS: We designed a retrospective study including all patients undergoing pulmonary resection with a curative intention for NSCLC. They were classified into two groups according to the presence or absence of cancer-related symptoms at diagnosis in asymptomatic (ASX)-incidental diagnosis-or symptomatic. RESULTS: Of the 593 patients, 320 (53.9%) were ASX. In 71.8% of these, diagnosis was made by chest X-ray. Patients in the ASX group were older (P = 0.007), had a higher prevalence of previous malignancy (P = 0.002), presented as a solitary nodule more frequently (P < 0.001), and were more likely to have earlier-stage disease and smaller cancers (P = 0.0001). A higher prevalence of incidental detection was observed in the last ten years (P = 0.008). Overall 5-year survival was higher for ASX (P = 0.001). Median survival times in pathological stages IIIB-IV were not significantly different. CONCLUSION: Incidental finding of NSCLC is not uncommon even among nonsmokers. It occurred frequently in smokers and in those with history of previous malignancy. Mortality of incidental diagnosis group was lower, but the better survival was related to the greater number of patients with earlier-stage disease. PMID- 25685551 TI - Evaluating the feasibility of performing window of opportunity trials in breast cancer. AB - BACKGROUND: The waiting period to surgery represents a valuable "window of opportunity" to evaluate novel therapeutic strategies. Interventional studies performed during this period require significant multidisciplinary collaboration to overcome logistical hurdles. We undertook a one-year prospective window of opportunity study to assess feasibility. METHODS: Eligible newly diagnosed postmenopausal, estrogen receptor positive breast cancer patients awaiting primary surgery received anastrozole daily until surgery. Feasibility was assessed by (a) the proportion of patients who consented and (b) completed the study. Comparison of pre- and poststudy Ki67 labelling index and cleaved caspase 3 scores (CC3) was performed. RESULTS: 22/131 (16.8%) patients were confirmed eligible and 20/22 (91%) patients completed the study. 19/20 (95%) patients agreed to undergo optional additional tissue biopsies. The mean duration of anastrozole use was 24.7 (15-44) days. There were a statistically significant decline in mean Ki67 indices of 48.8% (p < 0.001) and a trend towards significance in the decline of CC3 (p = 0.17) when comparing pre- with posttreatment values. CONCLUSION: window of opportunity trials in breast cancer are a feasible way of assessing the biologic efficacy of different therapies in the presurgical setting. The majority of eligible women were willing to participate including undergoing additional tissue biopsies. PMID- 25685552 TI - Clear cell adenocarcinoma of the urethra: review of the literature. AB - BACKGROUND: Clear cell adenocarcinoma of the urethra (CCAU) is extremely rare and a number of clinicians may be unfamiliar with its diagnosis and biological behaviour. AIMS: To review the literature on CCAU. METHODS: Various internet databases were used. RESULTS/LITERATURE REVIEW: (i) CCAU occurs in adults and in women in the great majority of cases. (ii) It has a particular association with urethral diverticulum, which has been present in 56% of the patients; is indistinguishable from clear cell adenocarcinoma of the female genital tract but is not associated with endometriosis; and probably does not arise by malignant transformation of nephrogenic adenoma. (iii) It is usually, readily distinguished from nephrogenic adenoma because of greater cytological a-typicality and mitotic activity and does not stain for prostate-specific antigen or prostatic acid phosphatase. (iv) It has been treated by anterior exenteration in women and cystoprostatectomy in men and at times by radiotherapy; chemotherapy has rarely been given. (v) CCAU is aggressive with low 5-year survival rates. (vi) There is no consensus opinion of treatment options that would improve the prognosis. CONCLUSIONS: Few cases of CCAU have been reported. Urologists, gynaecologists, pathologists, and oncologists should report cases of CCAU they encounter and enter them into a multicentric trial to determine the best treatment options that would improve the prognosis. PMID- 25685553 TI - Changes in identity after aphasic stroke: implications for primary care. AB - Background. Stroke survivors with aphasia experience difficulty associated with their communication disorder. While much has been written about aphasia's impacts on partners/family, we lack data regarding the psychosocial adjustment of aphasic stroke survivors, with a paucity of data from the patients themselves. Methods. Qualitative study of lived experiences of individuals with poststroke aphasia. Each of the stroke survivors with aphasia completed 3-4 semistructured interviews. In most cases, patients' partners jointly participated in interviews, which were transcribed and analyzed using techniques derived from grounded theory. Results. 12 patients were interviewed, with the total of 45 interviews over 18 months. Themes included poststroke changes in patients' relationships and identities, which were altered across several domains including occupational identity, relationship and family roles, and social identity. While all these domains were impacted by aphasia, the impact varied over time. Conclusion. Despite the challenges of interviewing individuals with aphasia, we explored aphasia's impacts on how individuals experience their identity and develop new identities months and years after stroke. This data has important implications for primary care of patients with aphasia, including the importance of the long term primary care relationship in supporting psychosocial adjustment to life after aphasic stroke. PMID- 25685554 TI - Design and synthesis of novel antileishmanial compounds. AB - According to the WHO, infectious diseases, and in particular neglected tropical diseases in poor developing countries, still play a significant role in a vast number of deaths reported worldwide. Among them, leishmaniasis occurs as a complex and clinically diverse illness caused by protozoan Leishmania species which are transmitted through the bite of sandflies. They develop through a complex life cycle, from promastigotes in sandflies to amastigotes in humans. The severity of disease is determined by the type of infecting Leishmania species and also depends strongly on whether the parasite infection leads to a systemic involvement or not. Since the sensitivity towards diverse medicaments highly differs among the Leishmania species, it is advantageous to treat leishmaniasis with species-specific drugs. Towards this goal we report a synthetic methodology and characterization of novel small molecular agents active against both forms of L. major. This synthetic approach allows for rapid access to new active antileishmanial drug templates and their first derivatives in moderate to very good yields. Although the compounds reported here are bioactive, the detailed biological results are part of a more comprehensive study and will be reported separately by our collaborators. PMID- 25685555 TI - Postchemotherapy histopathological evaluation of ovarian carcinoma: a 40-case study. AB - Ovarian carcinomas are conventionally treated with primary debulking surgery followed by chemotherapy. Nowadays neoadjuvant chemotherapy followed by surgery is an upcoming treatment modality for ovarian carcinoma. This study highlights the histopathological changes observed after neoadjuvant chemotherapy. Present study is a 40-case study stressing five histological parameters: residual tumour, fibrosis, necrosis, inflammation, and psammoma bodies. All these parameters carry prognostic significance and they are easily reproducible. Fleiss kappa statistics were used to measure intraobserver agreement between pathologists which was found to be substantial to almost perfect with kappa ranging between 0.621 and 1.00. This study highlights easily reproducible parameters and their incorporation in histopathology report, thus helping in patient management. PMID- 25685556 TI - Prognostic Value of Serum Uric Acid in Patients on the Waiting List before and after Renal Transplantation. AB - Background. High serum uric acid (UA) is associated with increased cardiovascular (CV) risk in the general population. The impact of UA on CV events and mortality in CKD is unclear. Objective. To assess the relationship between UA and prognosis in hemodialysis (HD) patients before and after renal transplantation (TX). Methods. 1020 HD patients assessed for CV risk and followed from the time of inception until CV event, death, or TX (HD) or date of TX, CV event, death, or return to dialysis (TX). Results. 821 patients remained on HD while 199 underwent TX. High UA (>=428 mmol/L) was not associated with either composite CV events or mortality in HD patients. In TX patients high UA predicted an increased risk of events (P = 0.03, HR 1.6, and 95% CI 1.03-2.54) but not with death. In the Cox proportional model UA was no longer significantly associated with CV events. Instead, a reduced GFR (<50 mL/min) emerged as the independent risk factor for events (P = 0.02, HR 1.79, and % CI 1.07-3.21). Conclusion. In recipients of TX an increased posttransplant UA is related to higher probability of major CV events but this association probably caused concurrent reduction in GFR. PMID- 25685557 TI - Comparative proteomic study reveals the molecular aspects of delayed ocular symptoms induced by sulfur mustard. AB - Objective. Sulfur mustard (SM) is a highly reactive alkylating agent which produces ocular, respiratory, and skin damages. Eyes are the most sensitive organ to SM due to high intrinsic metabolic and rapid turnover rate of corneal epithelium and aqueous-mucous interfaces of the cornea and conjunctiva. Here we investigate underlying molecular mechanism of SM exposure delayed effects which is still a controversial issue after about 30 years. Materials and Methods. Following ethical approval, we have analyzed serum proteome of ten severe SM exposed male patients with delayed eye symptoms with two-dimensional electrophoresis followed by matrix-assisted laser desorption/ionization time-of flight/time-of-flight mass spectrometry. The western blotting was used to confirm the proteins that have been identified. Results. We have identified thirteen proteins including albumin, haptoglobin, and keratin isoforms as well as immunoglobulin kappa chain which showed upregulation while transferrin and alpha 1 antitrypsin revealed downregulation in these patients in comparison with healthy control group. Conclusions. Our results elevated participation of free iron circulatory imbalance and local matrix-metalloproteinase activity in development of delayed ocular symptoms induced by SM. It demonstrates that SM induced systemic toxicity leads to some serum protein changes that continually and gradually exacerbate the ocular surface injuries. PMID- 25685558 TI - Reference ranges of amniotic fluid index in late third trimester of pregnancy: what should the optimal interval between two ultrasound examinations be? AB - BACKGROUND: Amniotic fluid index (AFI) is one of the major and deciding components of fetal biophysical profile and by itself it can predict pregnancy outcome. Very low values are associated with intrauterine growth restriction and renal anomalies of fetus, whereas high values may indicate fetal GI anomalies, maternal diabetes mellitus, and so forth. However, before deciding the cut-off standards for abnormal values for a local population, what constitutes a normal range for specific gestational age and the ideal interval of testing should be defined. OBJECTIVES: To establish reference standards for AFI for local population after 34 weeks of pregnancy and to decide an optimal scan interval for AFI estimation in third trimester in low risk antenatal women. MATERIALS AND METHODS: A prospective estimation of AFI was done in 50 healthy pregnant women from 34 to 40 weeks at weekly intervals. The trend of amniotic fluid volume was studied with advancing gestational age. Only low risk singleton pregnancies with accurately established gestational age who were available for all weekly scan from 34 to 40 weeks were included in the study. Women with gestational or overt diabetes mellitus, hypertensive disorders of the pregnancy, prelabour rupture of membranes, and congenital anomalies in the foetus and those who delivered before 40 completed weeks were excluded from the study. For the purpose of AFI measurement, the uterine cavity was arbitrarily divided into four quadrants by a vertical and horizontal line running through umbilicus. Linear array transabdominal probe was used to measure the largest vertical pocket (in cm) in perpendicular plane to the abdominal skin in each quadrant. Amniotic fluid index was obtained by adding these four measurements. Statistical analysis was done using SPSS software (Version 16, Chicago, IL). Percentile curves (5th, 50th, and 95th centiles) were constructed for comparison with other studies. Cohen's d coefficient was used to examine the magnitude of change at different time intervals. RESULTS: Starting from 34 weeks till 40 weeks, 50 ultrasound measurements were available at each gestational age. The mean (standard deviation) of AFI values (in cms) were 34 W: 14.59 (1.79), 35 W: 14.25 (1.57), 36 W: 13.17 (1.56), 37 W: 12.48 (1.52), 38 W: 12.2 (1.7), and 39 W: 11.37 (1.71). The 5th percentile cut-off was 8.7 cm at 40 weeks. There was a gradual decline of AFI values as the gestational age approached term. Significant drop in AFI was noted at two-week intervals. AFI curve generated from the study varied significantly when compared with already published data, both from India and abroad. CONCLUSION: Normative range for AFI values for late third trimester was established. Appreciable changes occurred in AFI values as gestation advanced by two weeks. Hence, it is recommended to follow up low risk antenatal women every two weeks after 34 weeks of pregnancy. The percentile curves of AFI obtained from the present study may be used to detect abnormalities of amniotic fluid for our population. PMID- 25685559 TI - High-Resolution Imaging of Polyethylene Glycol Coated Dendrimers via Combined Atomic Force and Scanning Tunneling Microscopy. AB - Dendrimers have shown great promise as drug delivery vehicles in recent years because they can be synthesized with designed size and functionalities for optimal transportation, targeting, and biocompatibility. One of the most well known termini used for biocompatibility is polyethylene glycol (PEG), whose performance is affected by its actual conformation. However, the conformation of individual PEG bound to soft materials such as dendrimers has not been directly observed. Using atomic force microscopy (AFM) and scanning tunneling microscopy (STM), this work characterizes the structure adopted by PEGylated dendrimers with the highest resolution reported to date. AFM imaging enables visualization of the individual dendrimers, as well as the differentiation and characterization of the dendrimer core and PEG shell. STM provides direct imaging of the PEG extensions with high-resolution. Collectively, this investigation provides important insight into the structure of coated dendrimers, which is crucial for the design and development of better drug delivery vehicles. PMID- 25685560 TI - Green synthesis of silver nanoparticles using extract of oak fruit hull (jaft): synthesis and in vitro cytotoxic effect on mcf-7 cells. AB - A green synthetic approach by using oak fruit hull (Jaft) extract for preparation of silver nanoparticles (AgNPs) was developed and optimized. Parameters affecting the synthesis of AgNPs, such as temperature, extract pH, and concentration of extract (ratio of plant sample to extraction solvent), were investigated and optimized. Optimum conditions for the synthesis of silver nanoparticles are as follows: Ag(+) concentration, 1 mM; extract concentration, 40 g/L (4% w/v); pH = 9 and temperature, 45 degrees C. Biosynthesized silver nanoparticles were characterized using UV-visible absorption spectroscopy (UV-Vis), Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD), dynamic light scattering (DLS), transmission electron microscopy (TEM), and scanning electron microscopy (SEM). TEM and DLS analyses have shown the synthesized AgNPs were predominantly spherical in shape with an average size of 40 nm. The cytotoxic activity of the synthesized AgNPs and Jaft extract containing AgNPs against human breast cancer cell (MCF-7) was investigated and the half maximal inhibitory concentrations (IC50) were found to be 50 and 0.04 MUg/mL at 24 h incubation, respectively. This eco-friendly and cost-effective synthesis method can be potentially used for large-scale production of silver nanoparticles. PMID- 25685561 TI - Challenges and Opportunities to Improve Cervical Cancer Screening Rates in US Health Centers through Patient-Centered Medical Home Transformation. AB - Over the last 50 years, the incidence of cervical cancer has dramatically decreased. However, health disparities in cervical cancer screening (CCS) persist for women from racial and ethnic minorities and those residing in rural and poor communities. For more than 45 years, federally funded health centers (HCs) have been providing comprehensive, culturally competent, and quality primary health care services to medically underserved communities and vulnerable populations. To enhance the quality of care and to ensure more women served at HCs are screened for cervical cancer, over eight HCs received funding to support patient-centered medical home (PCMH) transformation with goals to increase CCS rates. The study conducted a qualitative analysis using Atlas.ti software to describe the barriers and challenges to CCS and PCMH transformation, to identify potential solutions and opportunities, and to examine patterns in barriers and solutions proposed by HCs. Interrater reliability was assessed using Cohen's Kappa. The findings indicated that HCs more frequently described patient-level barriers to CCS, including demographic, cultural, and health belief/behavior factors. System-level barriers were the next commonly cited, particularly failure to use the full capability of electronic medical records (EMRs) and problems coordinating with external labs or providers. Provider-level barriers were least frequently cited. PMID- 25685562 TI - Management of Cerebellar Tonsillar Herniation following Lumbar Puncture in Idiopathic Intracranial Hypertension. AB - Lumbar puncture is performed routinely for diagnostic and therapeutic purposes in idiopathic intracranial hypertension, despite lumbar puncture being classically contraindicated in the setting of raised intracranial pressure. We report the case of a 30-year-old female with known idiopathic intracranial hypertension who had cerebellar tonsillar herniation following therapeutic lumbar puncture. Management followed guidelines regarding treatment of traumatic intracranial hypertension, including rescue decompressive craniectomy. We hypothesize that the changes in brain compliance that are thought to occur in the setting of idiopathic intracranial hypertension are protective against further neuronal injury due to axonal stretch following decompressive craniectomy. PMID- 25685563 TI - Changes in caries risk and activity of a 9-year-old patient with niemann-pick disease type C. AB - Objective. This case report describes the changes in caries risk and activity and dental treatment of a 9-year-old patient who presented with signs and symptoms of Niemann-Pick disease type C (NPC). Treatment. The preventive dental treatment included instructions to caregivers for oral hygiene and diet. A calcium hydroxide pulpotomy and restorative dental treatments were performed in a dental office with desensitization techniques and behavioral management. The patient was attended every 3 months for the control of dental plaque biofilm, for topical fluoride application, and for observing the pulpotomized tooth. Results. The bacterial plaque biofilm was being adequately controlled by the caregiver. After 2 years, the clinical and radiographic examination of the pulpotomized tooth showed the absence of internal root resorption and bone rarefaction, and clinical examination showed tooth sensitivity, dental pain, and gingival swelling. Conclusion. The pulpotomy prevented clinical and radiographic success. Dentists must be aware of and be able to identify systemic and local aspects associated with caries risk of children with NPC disease. Furthermore, dentists must employ stringent preventive measures and provide instructions to caregivers to reduce caries risk. PMID- 25685564 TI - Bilateral molariform mandibular second premolars. AB - Macrodontia is a rare dental anomaly that refers to teeth that appear larger than normal. Generalised macrodontia can be associated with certain medical conditions and syndromes. This case report presents clinical and radiographic findings of isolated bilateral macrodontia in a 14-year-old child. The patient was referred to the clinic with local crowding of maxillary and mandibular teeth. Radiographic findings revealed the presence of impacted macrodont mandibular second premolar on one side and erupted macrodontic premolar on the other side and their distinct morphological appearance, characterized by large, multitubercular, and molariform crowns and tapering, single roots. PMID- 25685565 TI - Thyroid carcinoma with pituitary metastases: 2 case reports and literature review. AB - We present 2 patients with pituitary metastases from thyroid carcinoma-the first from anaplastic thyroid carcinoma and the second from follicular thyroid carcinoma. The first patient, a 50-year-old lady, presented with 2-week history of hoarseness of voice, dysphagia, dyspnoea, and neck swelling. Imaging revealed metastatic thyroid cancer to lymph nodes and bone. Histology from surgery confirmed anaplastic thyroid cancer. She was found to have pituitary metastases postoperatively when she presented with nonvertiginous dizziness. She subsequently underwent radiotherapy and radioiodine treatment but passed away from complications. The second patient, a 65-year-old lady, presented with loss of appetite and weight with increased goitre size and dyspnoea. Surgery was performed in view of compressive symptoms and histology confirmed follicular thyroid carcinoma. Imaging revealed metastases to bone, lung, and pituitary. She also had panhypopituitarism with hyperprolactinemia and diabetes insipidus. She received radioiodine therapy but eventually passed away from complications. PMID- 25685566 TI - Successful desensitization of a patient with rituximab hypersensitivity. AB - Rituximab is a monoclonal antibody which targets CD20 in B cells that is used for the treatment of CD20 positive oncologic and hematologic malignancies. Rituximab causes hypersensitivity reactions during infusions. The delay of treatment or loss of a highly efficient drug can be prevented by rapid drug desensitization method in patients who are allergic to rituximab. We report a low grade B cell non-Hodgkin lymphoma patient with rituximab hypersensitivity successfully treated with rapid drug desensitization. In experienced centers, drug desensitization is a novel modality to break through in case of hypersensitivity that should be considered. PMID- 25685567 TI - Diagnostic challenges of tuberculous lymphadenitis using polymerase chain reaction analysis: a case study. AB - This report presents a case of tuberculous lymphadenitis that was difficult to diagnose using polymerase chain reaction analysis. An 80-year-old Japanese female was hospitalized due to swollen cervical lymph nodes. Her lymph node tests revealed paradoxical polymerase chain reaction results. Polymerase chain reaction analysis of two biopsy tissues using the Cobas TaqMan revealed a positive result for Mycobacterium avium and a negative result for Mycobacterium tuberculosis. However, polymerase chain reaction analysis of a cultured colony of acid-fast bacteria from biopsy tissue using the Cobas TaqMan and an alternative polymerase chain reaction analysis of biopsy tissue yielded discordant results. The patient was diagnosed as having tuberculous lymphadenitis. She was treated with antitubercular drugs and subsequently had a reduction in cervical lymph node swelling. Polymerase chain reaction analysis is not 100% accurate; hence, its use as a diagnostic tool for mycobacterial infection requires increased attention. PMID- 25685568 TI - Severe congenital toxoplasmosis: a case report and strain characterization. AB - We report a fatal congenital toxoplasmosis case in an Iranian woman in the south of Iran. A pregnant mother had been admitted at the 15th week of her pregnancy on account of a febrile illness, symptoms of common cold, and enlargement of submandibular lymph nodes. Serological testing of the mother's serum revealed positive IgG and IgM anti-Toxoplasma antibodies. Amniotic fluid was taken and evaluated by polymerase chain reaction (PCR) assay with a direct amplification of the Toxoplasma URPT gene which was found to be positive. Sequencing and analysis of PCR product revealed that the isolate has the most similarity with type I of Toxoplasma gondii. Fetal scan showed anomaly in fetus including mild hydrocephaly. Termination of the pregnancy was suggested by the physician and pregnancy was terminated 178 days after conception. PMID- 25685569 TI - Subarachnoid hemorrhage secondary to forceful sneeze. AB - Subarachnoid hemorrhage (SAH) is a relatively less common but important neurological condition comprising 5% of all the cerebrovascular accidents. In most populations the reported incidence is 6-7 per 100,000 person-years and one third of survivors become dependent. It is a serious but potentially treatable cause of neurological morbidity. Multiple authors have identified the most unusual novel associations and triggers of subarachnoid bleeds over the past decade. We herein report a rare case of subarachnoid hemorrhage leading to focal neurological deficit in a middle aged man secondary to forceful sneeze. PMID- 25685570 TI - Primary vaginal myeloid sarcoma: a rare case report and review of the literature. AB - Myeloid sarcoma (chloroma, granulocytic sarcoma, or extramedullary myeloid tumour) is an extramedullary mass forming neoplasm composed of myeloid precursor cells. It is usually associated with myeloproliferative disorders but very rarely may precede the onset of leukemia. Here, we are presenting a rare case of primary vaginal myeloid sarcoma in a geriatric female patient without initial presentation of acute myeloid leukemia (AML). A 68-year-old female patient with ECOG Performance Score of 1 presented with pervaginal bleeding for 20 days. On colposcopic examination, she was found to have mass in the anterior fornix of vagina. A punch biopsy specimen revealed chloromatous infiltration of the vagina. LCA (leukocyte common antigen), MPO (myeloperoxidase), and c-kit were strongly positive on IHC (immunohistochemistry). The patient's routine blood investigations were normal including peripheral smear, lactose dehydrogenase, uric acid, 2D echocardiography, conventional cytogenetics, bone marrow aspiration, and biopsy. The patient was given 4 cycles of decitabine (Decitex, manufactured by Sun Pharmaceutical Industries Limited, India), 20 mg/m(2) for 5 days at an interval of 28 days. There was a partial response to decitabine according to RECIST criteria. As decitabine therapy was well tolerated, we are continuing in the same way until disease progression without any complications. The patient is undergoing regular follow-up at our centre. PMID- 25685571 TI - Aggressive extraocular sebaceous carcinoma recurring after mohs micrographic surgery. AB - Sebaceous carcinomas (SC) are rare adnexal tumors with possible aggressive behavior usually arising in the head and neck region of adults in the seventh decade of life. Treatment has traditionally been with surgical excision with 5-6 mm wide margins but Mohs micrographic surgery (MMS) has also been reported as an effective treatment modality. We present a case of a Caucasian female renal transplant patient with a rapidly enlarging nodule on the left preauricular cheek that was excised with MMS with negative margins. The tumor recurred rapidly and metastasized ultimately leading to the death of the patient. There was some disagreement amongst pathologists as to the possible nature of the diagnosis with the original biopsy being labeled as a poorly differentiated carcinoma. We aim to highlight the potential aggressive nature of SC and review the features of the neoplasm including histological features that help in making the diagnosis. PMID- 25685572 TI - Idiopathic bilateral bloody tearing. AB - Bloody tear is a rare and distinct clinic phenomenon. We report a case presenting with the complaint of recurrent episodes of bilateral bloody tearing. A 16-year old girl presented to our clinic with complaint of bloody tearing in both eyes for 3 months. Bloody tearing was not associated with her menses. A blood-stained discharge from the punctum was not observed during the compression of both nasolacrimal ducts. Nasolacrimal passage was not obstructed. Imaging studies such as dacryocystography and gradient-echo magnetic resonance imaging (MRI) of nasolacrimal canal were normal. Intranasal endoscopic evaluation was normal. We collected samples from bloody tears two times and pathological examination was performed. Pathological analysis showed lots of squamous cells and no endometrial cells; dysplastic cells were found. Further evaluations for underlying causes were unremarkable. No abnormalities were found in ophthalmologic, radiologic, and pathologic investigations. This condition is likely a rare abnormality and the least recognized aetiology for the idiopathic phenomenon. PMID- 25685573 TI - Ultrasound-guided quadrilateral space block for the diagnosis of quadrilateral syndrome. AB - Quadrilateral space syndrome (QSS) is a rare nerve entrapment disorder that occurs when the axillary nerve and posterior circumflex humeral artery (PCHA) become compressed in the quadrilateral space. QSS presents as vague posterolateral shoulder pain that is exacerbated upon the abduction and external rotation of the shoulder. Diagnosis of QSS is difficult because of the vague presentation of QSS. In addition, even though MRI and MR angiography can be used in QSS diagnosis, there is currently no "gold standard" diagnostic imaging studies for QSS. In this case report, we describe a novel ultrasound-guided technique for a diagnostic quadrilateral space block and present a case where the diagnostic block was used to diagnose QSS. We believe that a diagnostic block of the quadrilateral space is a useful adjunct in the evaluation of patients with suspected QSS, especially in cases where examination findings and other diagnostic modalities are indeterminate. PMID- 25685574 TI - An easily overlooked presentation of malignant psoas abscess: hip pain. AB - Psoas abscess is a rare infectious disease with nonspecific clinical presentation that frequently causes a diagnostic difficulty. Its insidious onset and occult characteristics can cause diagnostic delays. It is classified as primary or secondary. Staphylococcus aureus is the most commonly causative pathogen in primary psoas abscess. Secondary psoas abscess usually occurs as a result of underlying diseases. A high index of clinical suspicion, the past and recent history of the patient, and imaging studies can be helpful in diagnosing the disease. The delay of the treatment is related with high morbidity and mortality rates. In this paper, 54-year-old patient with severe hip pain having an abscess in the psoas muscle due to metastatic cervical carcinoma is presented. PMID- 25685575 TI - Magnetic Resonance Imaging Visualizes Median Nerve Entrapment due to Radius Fracture and Allows Immediate Surgical Release. AB - Median nerve entrapment with forearm fracture is rare, and surgical exploration in the early stage is rarely performed. We report the case of a 19-year-old man presenting with severe pain and numbness of the thumb, index, and middle fingers and half of the ring finger along with weakness of abduction and opposition of the thumb after fracture of the radial shaft. These symptoms remained unimproved despite precise closed reduction and cast immobilization. The radius fracture was barely displaced, but complaints were increasing, particularly when the wrist and/or fingers were stretched. This suggested direct involvement of the median nerve at the fracture site, so magnetic resonance imaging (MRI) of the forearm was performed to identify any entrapment. Short tau inversion recovery MRI visualized significant deviation and entrapment of the median nerve at the fracture site. Surgical release of the entrapment was performed immediately, and complaints resolved shortly thereafter. A positive Tinel sign from the palm to the fingertips and recovery of abduction and opposition of the thumb were seen at 6 months postoperatively. This report highlights the utility of MRI for detecting median nerve entrapment at a fracture site, allowing immediate surgical release. PMID- 25685576 TI - Superior Mesenteric Artery Syndrome due to a Vertebral Hemangioma and Postpartum Osteoporosis following Treatment. AB - In pregnancy, advanced vertebral hemangiomas may be seen, and these require treatment. The case reported here is of a 35-year-old female in the 32nd week of pregnancy who was admitted to the orthopaedics clinic with a history of backache and difficulty walking. A burst fracture of L1 associated with a vertebral hemangioma was identified with an L3 compression fracture secondary to osteoporosis. The local kyphosis angle between T12 and L2 was 27 degrees . Kyphotic deformity was corrected and postoperatively, the measured T12-L2 local kyphotic angle was 9 degrees . Twelve hours postoperatively, oral nutrition was allowed, but she developed nausea and vomiting and twenty-four hours postoperatively, an electrolyte imbalance developed. Postoperatively, the patient was diagnosed with superior mesenteric artery syndrome. To the best of our knowledge, this is the first reported case of superior mesenteric artery syndrome, which occurred following the correction of a kyphotic deformity that had developed secondary to an advanced hemangioma in pregnancy. PMID- 25685577 TI - Intractable persistent direction-changing geotropic nystagmus improved by lateral semicircular canal plugging. AB - Antigravitational deviation of the cupula of the lateral semicircular canal, which is also called light cupula, evokes persistent direction-changing geotropic nystagmus with a neutral point. No intractable cases of this condition have been reported. In our case, a 67-year-old man complained of positional vertigo 3 months after developing idiopathic sudden hearing loss in the right ear with vertigo. He showed a persistent direction-changing geotropic nystagmus with a leftward beating nystagmus in the supine position. The nystagmus resolved when his head was turned approximately 30 degrees to the right. He was diagnosed with light cupula of the right lateral semicircular canal and was subsequently treated with an antivertiginous agent. However, his symptoms and positional nystagmus did not improve, so the right lateral semicircular canal was plugged by surgery. One month after surgery, his positional vertigo and nystagmus were completely resolved. We speculated that the cause of the patient's intractable light cupula was an enlarged cupula caused by his idiopathic sudden hearing loss. PMID- 25685578 TI - Hair barrette induced cochlear implant receiver stimulator site infection with extrusion. AB - Background. Cochlear implant infections and extrusion are uncommon but potentially devastating complications. Recent literature suggests conservative management can be employed. Local measures inclusive of aggressive surgical debridement with vascularized flaps and parenteral antibiotics represent a viable option and often permit device salvage. However, explantation should be considered if there is evidence of systemic, intracranial, or intractable infection. Method. A Case report and literature review. Case Report. This case illustrates a complicated local wound infection associated with cochlear implantation due to transcutaneous adherence of a ferrous hair barrette to a cochlear implant magnet. Reconstruction of computed tomography (CT) data with 3D volume rendering significantly improved the value of the images and facilitated patient counseling as well as operative planning. Conclusion. Cochlear implant infections can be associated with foreign bodies. CT images are beneficial in the evaluation of cochlear implant complications. 3D CT images provide a comprehensive view of the site of interest, displaying the relationship of the hardware to the skull and soft tissues, while minimizing associated artifacts. Cochlear implant patients should consider use of nonmetallic hair devices. PMID- 25685579 TI - Radiofrequency coblation of congenital nasopharyngeal teratoma: a novel technique. AB - Introduction. Congenital nasopharyngeal teratomas are rare tumours that pose difficulties in diagnosis and surgical management. We report the first use of radiofrequency coblation in the management of such tumours. Case Report. A premature baby with a perinatal diagnosis of a large, obstructing nasooropharyngeal mass was referred to the ENT service for further investigations and management. The initial biopsy was suggestive of a neuroblastoma, but the tumour demonstrated rapid growth despite appropriate chemotherapy. In a novel use of radiofrequency coblation, the nasooropharyngeal mass was completely excised, with the final histopathology revealing a congenital nasopharyngeal teratoma. Conclusion. We report the first use of radiofrequency coblation to excise a congenital nasopharyngeal teratoma and discuss its advantages. PMID- 25685580 TI - A three-generation family with idiopathic facial palsy suggesting an autosomal dominant inheritance with high penetrance. AB - Idiopathic facial palsy (IFP), also known as Bell's palsy, is a common neurologic disorder, but recurrent and familial forms are rare. This case series presents a three-generation family with idiopathic facial palsy. The mode of inheritance of IFP has previously been suggested as autosomal dominant with low or variable penetrance, but the present family indicates an autosomal dominant trait with high or complete penetrance. Chromosome microarray studies did not reveal a pathogenic copy number variation, which could enable identification of a candidate gene. PMID- 25685581 TI - Tumor-to-Tumor Metastasis: Lung Carcinoma Metastasizing to Thyroid Neoplasms. AB - Tumor-to-tumor metastasis is extremely rare in the thyroid glands, and only seven cases of lung carcinoma metastasizing to thyroid tumors have been reported in the literature. We report another two cases of lung carcinoma metastasizing to thyroid neoplasms and review of the literature. The first case was a 64-year-old man presenting with neck mass, hoarseness, and easy choking for 2 months. Image studies showed several nodular lesions within bilateral thyroid glands. A histological examination after radical thyroidectomy revealed lung small cell carcinoma metastasizing to a thyroid follicular adenoma. The second case was a 71 year-old woman with a history of lung adenosquamous carcinoma. The PET/CT scan showed left lower lung cancer and a hypermetabolic area in the right thyroid lobe, highly suspicious for malignancy. Radical thyroidectomy and left lung lobectomy were performed, and the thyroid gland revealed lung adenosquamous carcinoma metastasizing to a papillary thyroid carcinoma. PMID- 25685582 TI - Small bowel dissemination of coccidioidomycosis. AB - Gastrointestinal coccidioidomycosis is extremely rare, with less than 10 cases reported in the literature. We report a case of small bowel dissemination of coccidioidomycosis in a 21-year-old African American male with a history of living in San Joaquin Valley. The patient presented with one week of abdominal pain, nausea, shortness of breath, intermittent fever, and sweat, and one month of abdominal distention. A chest radiograph revealed complete effusion of left lung. A computed tomography scan of the abdomen showed diffuse small bowel thickening and enhancement, as well as omental and peritoneal nodules, and ascites. The coccidioidal complement fixation titer was 1 : 256. The duodenal biopsy revealed many spherules filled with round fungal endospores. Later, blood fungal culture showed positivity for Coccidioides immitis. The final diagnosis is disseminated coccidioidomycosis involving lungs, blood, and duodenum. Despite aggressive antifungal therapy, the patient's clinical situation deteriorated and he succumbed to multisystem organ failure one and half months later. A high index of suspicion for gastrointestinal coccidioidomycosis should be maintained in patients from an endemic area presenting as abdominal distention and pain. PMID- 25685583 TI - Cytological Features of a Variant NUT Midline Carcinoma of the Lung Harboring the NSD3-NUT Fusion Gene: A Case Report and Literature Review. AB - Background. Nuclear protein in testis (NUT) midline carcinoma (NMC) is a very rare and aggressive malignancy. In more than two-thirds of these NMC cases, a fusion between NUT and BRD4 or BRD3 has been documented; other variants are rare. The cytology of NMC itself has been sparsely documented and that of variant NMC has never been reported. Case Presentation. A 36-year-old woman was admitted because of a rapidly progressing lung tumor with metastases to the breast and bone. We recently reported this patient as the first case of a variant NMC of the lung harboring an NSD3-NUT fusion, based on immunohistochemical and genetic analyses. Cytological material was available for the present review. A highly cellular smear contained a predominantly noncohesive pattern of monomorphic cells with diameters 2-2.5 times greater than those of small lymphocytes, with a round to-oval nucleus, slightly irregular nuclear contours, variably prominent nucleoli, scant cytoplasm, and identifiable mitotic figures. Foci of stratification and overt pearl formation, including a dyskeratocyte, were occasionally observed. The necrotic background contained naked nuclei, karyorrhectic debris, apoptotic cells, and macrophages phagocytizing karyorrhectic debris; nuclear crushing was noted. Conclusion. The cytological features of a variant NMC of the lung are described for the first time. PMID- 25685584 TI - Concurrence of Meningomyelocele and Salt-Wasting Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency. AB - Congenital adrenal hyperplasia (CAH) is a group of inherited defects of cortisol biosynthesis. A case of classical CAH due to 21-hydroxylase deficiency (21-OHD) with early onset of salt waste and concurrence of meningomyelocele (MMC) was presented here. The management of salt-wasting crisis which is complicated by a postrenal dysfunction due to neurogenic bladder was described. Possible reasons of growth retardation in the one-year follow-up period were discussed. A significant regression of the phallus with proper medical treatment was also mentioned. PMID- 25685585 TI - Deep Venous Thrombosis of the Leg, Associated with Agenesis of the Infrarenal Inferior Vena Cava and Hypoplastic Left Kidney (KILT Syndrome) in a 14-Year-Old Child. AB - Agenesis of the inferior vena cava (IVC) is a rare anomaly which can be identified as incidental finding or can be associated with iliofemoral vein thrombosis. IVC agenesis has a known association with renal anomalies which are mainly confined to the right kidney. We describe a case of a 14-year-old male who presented with left leg swelling and pain. Ultrasonography confirmed the presence of left leg deep vein thrombosis (DVT). No underlying hematologic risk factors were identified. A CT scan was obtained which demonstrated absent infrarenal IVC and extensive thrombosis in the left deep venous system and development of collateral venous flow into the azygous/hemiazygous system, with extension of thrombus into paraspinal collaterals. An additional finding in the patient was an atrophic left kidney and stenosis of an accessory left renal artery. Agenesis of the IVC should be considered in a young patient presenting with lower extremity DVT, especially in patients with no risk factors for thrombosis. As agenesis of the IVC cannot be corrected, one should be aware that there is a lifelong risk of lower extremity DVT. PMID- 25685586 TI - Fatal cytomegalovirus disease after combination therapy with corticosteroids and rituximab for granulomatosis with polyangiitis. AB - The association of cytomegalovirus (CMV) with autoimmune disease is poorly understood with suggested causality and reported viral reactivation coinciding with active inflammation. We report a case of a patient who presented with diffuse alveolar hemorrhage and acute renal failure from rapidly progressive glomerulonephritis ultimately diagnosed with granulomatosis with polyangiitis (GPA). She was acutely managed with plasmapheresis to reduce antibody-mediated end-organ damage, hemodialysis for worsening hyperkalemia and acidosis, and high dose intravenous methylprednisolone. She was transitioned to oral prednisone and started on weekly rituximab with resultant remission induction over a three-week period at which point she developed reactivation of CMV causing severe fatal lung disease and viremia. The case highlights the multiple factors associated with CMV reactivation in cases of severe systemic inflammatory states and the need for further research to help establish practice guidelines regarding antimicrobial prophylaxis in patients with autoimmune diseases on prolonged courses of corticosteroids and biologic agents. PMID- 25685587 TI - A rare combination of ovarian and uterine leiomyomas with goblet cell carcinoid of the appendix. AB - We present a case of the rare combination of unilateral ovarian leiomyoma, uterine leiomyoma, and goblet cell carcinoid tumor of the appendix in a premenopausal woman who presented with right iliac pain. Immunohistochemistry study for desmin (muscle marker) and chromogranin and synaptophysin (neuroendocrine markers) confirmed immunophenotyping origin. Interestingly, both tumors showed positive reaction for estrogen receptor. To our knowledge, such a combination has not been reported previously in the literature. In this paper, the pathogenesis and differential diagnosis of both types of tumors are discussed. PMID- 25685588 TI - Primary adrenal leiomyosarcoma in an arab male: a rare case report with immunohistochemistry study. AB - Primary adrenal leiomyosarcoma is a rare form of adrenal mesenchymal tumors. Immunohistochemistry (IHC) together with histology takes a major role in determining the tumor type and predicting their biological behavior and differentiating them from adrenal cortical carcinoma. Appropriate radiological investigation is necessary to rule out metastatic disease from primary tumors elsewhere in the body. In this case, we report a primary leiomyosarcoma of the adrenal gland in a 61-year-old Bahraini male clinically presumed to be a renal neoplasm. PMID- 25685589 TI - Rupture of renal transplant. AB - Background. Rupture of renal allograft is a rare and serious complication of transplantation that is usually attributed to acute rejection, acute tubular necrosis, or renal vein thrombosis. Case Presentation. LD, a 26-year-old male with established renal failure, underwent deceased donor transplantation using kidney from a 50-year-old donor with acute kidney injury (Cr 430 mmol/L). LD had a stormy posttransplant recovery and required exploration immediately for significant bleeding. On day three after transplant, he developed pain/graft swelling and another significant haemorrhage with cardiovascular compromise which did not respond to aggressive resuscitation. At reexploration, the renal allograft was found to have a longitudinal rupture and was removed. Histology showed features of type IIa Banff 97 acute vascular rejection, moderate arteriosclerosis, and acute tubular necrosis. Conclusion. Possible ways of avoiding allograft rupture include use of well-matched, good quality kidneys; reducing or managing risk factors that would predispose to delayed graft function; ensuring a technically satisfactory transplant procedure with short cold and warm ischemia times; and avoiding large donor-recipient age gradients. PMID- 25685590 TI - A case of primary renal carcinoid tumor. AB - Primary renal carcinoid tumors are extremely rare kidney lesions, with fewer than 100 reported cases previously. We describe a 75-year-old man with an incidentally detected cystic renal mass. Computed tomography showed a 3 cm tumor with a cystic component enhanced with contrast. No evidence of metastasis was detected. We treated the patient with radical nephrectomy. Pathological examinations revealed a cellular arrangement specific to carcinoid tumor and positive for chromogranin A, neural cell adhesion molecule, and somatostatin receptor type 2. The tumor cells had a mitotic count of 4 mitoses/10 high-power fields, and the level of the proliferation marker Ki-67 was 5%. The pathological diagnosis was renal neuroendocrine tumor grade 2. No local recurrence and no systemic metastasis were detected during the 18-month follow-up period. To our knowledge, this is the 6th case of renal neuroendocrine grade 2 tumor reported thus far. PMID- 25685591 TI - Unusual Response of Subclavian In-Stent Restenosis to Balloon Angioplasty in a Patient with HIV. AB - Human Immunodeficiency Virus (HIV) infection and use of protease inhibitors have been associated with accelerated atherosclerosis. Increased rates of coronary in stent restenosis are reported in these patients. There is limited data available on peripheral vascular disease interventions on these patients. Herein we report an aggressive subclavian in-stent restenosis with an unexpected response to balloon angioplasty treatment with a large, mobile tissue flap formation and its treatment with another stent. PMID- 25685592 TI - Periodontal disease and late-onset aortic prosthetic vascular graft infection. AB - Prosthetic vascular graft infection (PVGI) is a rare but significant complication of arterial reconstructive surgery. Although the relative risk is low, the clinical consequences can be catastrophic. Microbiological data on causative bacteria are limited. We present four cases of late-onset PVGI. Using a culture independent nucleic acid amplification method for analysis of intraoperative samples, the presence of bacteria highly suggestive of an oral source was reported. Examination by an oral health specialist confirmed the presence of chronic periodontal disease. We hypothesize that chronic oral infection may be a previously unreported risk factor for the development of late-onset PVGI. PMID- 25685593 TI - Occurrence of pfatpase6 Single Nucleotide Polymorphisms Associated with Artemisinin Resistance among Field Isolates of Plasmodium falciparum in North Eastern Tanzania. AB - We aimed to determine the current prevalence of four P. falciparum candidate artemisinin resistance biomarkers L263E, E431K, A623E, and S769N in the pfatpase6 gene in a high transmission area in Tanzania in a retrospective cross sectional study using 154 archived samples collected from three previous malaria studies in 2010, 2011 and 2013. Mutations in pfatpase6 gene were detected in parasite DNA isolated from Dried Blood Spots by using PCR-RFLP. We observed overall allelic frequencies for L263E, E431K, A623E, and S769N to be 5.8% (9/154), 16.2% (25/154), 0.0% (0/154), and 3.9% (6/154). The L263E mutation was not detected in 2010 but occurred at 3.9% and 2.6% in 2011 and 2013 respectively. The L263E mutation showed a significant change of frequency between 2010 and 2011, but not between 2011 and 2013 (P < 0.05). Frequency of E431K was highest of all without any clear trend whereas S769N increased from 2.2% in 2010 to 3.6% in 2011 and 5.1% in 2013. A623E mutation was not detected. The worrisome detection and the increase in the frequency of S769N and other mutations calls for urgent assessment of temporal changes of known artemisinin biomarkers in association with in vivo ACT efficacy. PMID- 25685594 TI - Disorders of the oral cavity in Parkinson's disease and parkinsonian syndromes. AB - Awareness of nonmotor symptoms of Parkinson's disease is growing during the last decade. Among these, oral cavity disorders are, although prevalent, often neglected by the patients, their caregivers, and physicians. Some of these disorders include increased prevalence of caries and periodontal disease, sialorrhea and drooling, xerostomia, orofacial pain, bruxism, and taste impairment. Though many of these disorders are not fully understood yet and relatively few controlled trials have been published regarding their treatment, physicians should be aware of the body of evidence that does exist on these topics. This paper reviews current knowledge regarding the epidemiology, pathophysiology, and treatment options of disorders of the oral cavity in Parkinson's disease patients. PMID- 25685595 TI - Morphological and chemical study of pathological deposits in human aortic and mitral valve stenosis: a biomineralogical contribution. AB - Aim of this study was to investigate heart valve calcification process by different biomineralogical techniques to provide morphological and chemical features of the ectopic deposit extracted from patients with severe mitral and aortic valve stenosis, to better evaluate this pathological process. Polarized light microscopy and scanning electron microscopy analyses brought to light the presence of nodular and massive mineralization forms characterized by different levels of calcification, as well as the presence of submicrometric calcified globular cluster, micrometric cavities containing disorganized tissue structures, and submillimeter pockets formed by organic fibers very similar to amyloid formations. Electron microprobe analyses showed variable concentrations of Ca and P within each deposit and the highest content of Ca and P within calcified tricuspid aortic valves, while powder X-ray diffraction analyses indicated in the nanometer range the dimension of the pathological bioapatite crystals. These findings indicated the presence of highly heterogeneous deposits within heart valve tissues and suggested a progressive maturation process with continuous changes in the composition of the valvular tissue, similar to the multistep formation process of bone tissue. Moreover the micrometric cavities represent structural stages of the valve tissue that immediately precedes the formation of heavily mineralized deposits such as bone-like nodules. PMID- 25685597 TI - Blood transfusion, serum ferritin, and iron in hemodialysis patients in Africa. AB - Background and Objectives. There is no data analyzing the outcome of blood transfusions and oral iron therapy in patients with kidneys failure in sub Saharan Africa. The present study aimed to fill that gap and assess the value of ferritin in the diagnosis of iron overload and deficiency. Design. From January to February 2012, we prospectively studied 85 hemodialysis patients (78% of males and 22% of females aged 20 to 79 years) attending the Gabonese National Hemodialysis Centre. Results. Correlation studies showed (a) a strong positive linear relationship between the number of blood transfusions and high serum ferritin in hemodialysis patient (Spearman r : 0.74; P value: 0.0001); (b) a weak association between the number of blood transfusions and serum iron concentrations (Spearman r : 0.32; P value: 0.04); (c) a weak association between serum ferritin and serum iron (Spearman r : 0.32; P value: 0.003). Also, the strength of agreement beyond chance between the levels of ferritin and iron in the serum was poor (kappa = 0.14). The prevalence of iron overload was 10.6%, whereas the prevalence of iron deficiency was 2.3%, comparing (1) patients with a maximum of one transfusion not on iron therapy; (2) patients with a maximum of one transfusion on iron therapy; (3) polytransfused patients not on iron therapy; and (4) polytransfused patients on oral iron therapy. The "Kruskal-Wallis test" showed that ferritin levels varied significantly between the groups (P value: 0.0001). Conclusion. Serum ferritin is not reliable as a marker of iron overload. For patients undergoing regular transfusion we recommend routine serum ferritin measurement and yearly measurement of LIC. PMID- 25685596 TI - Protocol variations and six-minute walk test performance in stroke survivors: a systematic review with meta-analysis. AB - Objective. To investigate the use of the six-minute walk test (6MWT) for stroke survivors, including adherence to 6MWT protocol guidelines and distances achieved. Methods. A systematic search was conducted from inception to March 2014. Included studies reported a baseline (intervention studies) or first instance (observational studies) measure for the 6MWT performed by stroke survivors regardless of time after stroke. Results. Of 127 studies (participants n = 6,012) that met the inclusion criteria, 64 were also suitable for meta analysis. Only 25 studies made reference to the American Thoracic Society (ATS) standards for the 6MWT, and 28 reported using the protocol standard 30 m walkway. Thirty-nine studies modified the protocol walkway, while 60 studies did not specify the walkway used. On average, stroke survivors walked 284 +/- 107 m during the 6MWT, which is substantially less than healthy age-matched individuals. The meta-analysis identified that changes to the ATS protocol walkway are associated with reductions in walking distances achieved. Conclusion. The 6MWT is now widely used in stroke studies. The distances achieved by stroke patients indicate substantially compromised walking ability. Variations to the standard 30 m walkway for the 6MWT are common and caution should be used when comparing the values achieved from studies using different walkway lengths. PMID- 25685598 TI - Hepatitis E in a food handler--a rapid risk assessment to guide the public health response. AB - OBJECTIVE: The Australian Capital Territory Health Directorate was notified of a food handler with hepatitis E virus (HEV) infection. To guide the public health response, a rapid risk assessment was undertaken to determine the risk of transmission of HEV from the infected food handler to restaurant patrons. METHOD: The literature on HEV was reviewed and expert advice sought from clinical and public health specialists. This was supplemented by results of a site investigation and a case interview. The risk rating was determined to be the product of the likelihood of transmission and the consequence of the infection. RESULTS: The food handler was likely to have been infectious at the time he was working at the restaurant. He had handled high-risk foods, and the site inspection revealed potential opportunities for transmission. HEV is not common in Australia and it was assumed that the population was non-immune and hence susceptible to the disease. Therefore, there was a low but possible likelihood of transmission of HEV. If infected, HEV has the potential for major consequences in vulnerable populations especially among women who are pregnant. The overall level of risk was considered to be very high. DISCUSSION: The general public and health practitioners were alerted to enable early identification of symptoms and prompt disease management. There were no secondary cases of HEV associated with this event. In the absence of published guidelines and limited evidence, a risk assessment framework was a useful tool to inform public health decision-making. PMID- 25685599 TI - Investigating an outbreak of acute fever in Chuuk, Federated States of Micronesia. AB - OBJECTIVE: In September 2012, there was an unexpected increase of acute febrile illness (AFI) in Chuuk State of the Federated States of Micronesia. At the same time, dengue outbreaks were occurring in two of the Federated States of Micronesia's other three states. The cause of AFI was suspected to be dengue; however, by the end of October, only one of 39 samples was positive for dengue. The objective of the investigation was to establish the cause of the outbreak. METHODS: A line list was created and data analysed by time, place, person and clinical features. Reported symptoms were compared with the published symptoms of several diagnoses and laboratory testing undertaken. RESULTS: Of the 168 suspected cases, 62% were less than 20 years of age and 60% were male. The clinical features of the cases were not typical for dengue but suggestive of respiratory illness. Nasopharyngeal swabs were subsequently collected and found to be positive for influenza. Public health measures were undertaken and the AFI returned to expected levels. DISCUSSION: Clinical diagnosis of acute febrile illness (AFI) can often be difficult and misleading. This can mean that opportunities for preventive measures early on in an outbreak are missed. In any outbreak, descriptive epidemiological analyses are valuable in helping to ascertain the cause of the outbreak. PMID- 25685600 TI - Seroprevalence survey of brucellosis among rural people in Mongolia. AB - BACKGROUND: After the transition from socialism to a market economy in 1990, human brucellosis re-emerged in Mongolia. The aim of our study was to estimate a representative seroprevalence of Brucella spp. and to determine risk factors for brucellosis seropositivity among rural people. METHODS: A cross-sectional study with multistage random selection was conducted in eight provinces of Mongolia. Study participants were interviewed using a questionnaire to obtain their brucellosis history, current symptoms and likely risk factors. Blood samples were drawn to determine brucellosis seroprevalence. RESULTS: A total of 2856 randomly selected rural people aged four to 90 years were enrolled in the study. The seroprevalence of Brucella spp. was 11.1% (95% confidence interval [CI]: 10.0 12.1), ranging between 2.3% and 22.6% in the eight provinces; 39.2% (n = 609) of nomadic camps had at least one seropositive participant. Risk factors associated with brucellosis seropositivity were being older than 45 years (adjusted odds ratio [AOR] = 6.9, 95% CI = 5.1-8.7) and being a veterinarian (AOR = 2.8, 95% CI = 1.5-5.0). CONCLUSION: Our study confirms that human brucellosis seroprevalence among rural people in Mongolia is high. Human brucellosis can be effectively controlled if high-coverage livestock mass vaccination is implemented with a coverage survey after the vaccinations to ensure completeness. This mass vaccination should be accompanied by public awareness and educational programmes. PMID- 25685601 TI - Seroprevalence survey of avian influenza A(H5N1) among live poultry market workers in northern Viet Nam, 2011. AB - OBJECTIVE: Highly pathogenic avian influenza A(H5N1) is endemic in poultry in Viet Nam. The country has experienced the third highest number of human infections with influenza A(H5N1) in the world. A study in Hanoi in 2001, before the epizootic that was identified in 2003, found influenza A(H5N1) specific antibodies in 4% of poultry market workers (PMWs). We conducted a seroprevalence survey to determine the seroprevalence of antibodies to influenza A(H5N1) among PMWs in Hanoi, Thaibinh and Thanhhoa provinces. METHODS: We selected PMWs from five markets, interviewed them and collected blood samples. These were then tested using a horse haemagglutination inhibition assay and a microneutralization assay with all three clades of influenza A(H5N1) viruses that have circulated in Viet Nam since 2004. RESULTS: The overall seroprevalence was 6.1% (95% confidence interval: 4.6-8.3). The highest proportion (7.2%) was found in PMWs in Hanoi, and the majority of seropositive subjects (70.3%) were slaughterers or sellers of poultry. DISCUSSION: The continued circulation and evolution of influenza A(H5N1) requires comprehensive surveillance of both human and animal sites throughout the country with follow-up studies on PMWs to estimate the risk of avian-human transmission of influenza A(H5N1) in Viet Nam. PMID- 25685602 TI - Ongoing local transmission of dengue in Japan, August to September 2014. PMID- 25685603 TI - Detection of Campylobacter in human faecal samples in Fiji. AB - INTRODUCTION: Data on campylobacteriosis in developed countries are well documented; in contrast, few studies on campylobacteriosis have been conducted in developing countries. This study was undertaken to test for Campylobacter in human faecal samples sent to the two major pathology laboratories in Fiji. METHODS: A total of 408 diarrhoeal faecal samples were collected from the two major hospital pathology laboratories in Central Fiji (Suva) and Western Fiji (Lautoka) between December 2012 and February 2013 and from June to July 2013. Samples were analysed for the presence of Campylobacter using polymerase chain reaction (PCR) based methods. RESULTS: Campylobacter was detected in 241/408 (59.1%) of samples tested using PCR. Samples from children aged less than five accounted for 21.6% of positive cases. DISCUSSION: Campylobacter was detected in 59.1% of diarrhoeal samples collected from the two main laboratories in Fiji. A high proportion of children under five years with Campylobacter has been reported in other countries and could be due to parents being more likely to seek medical attention. Further studies are required to confirm the species of Campylobacter that are predominantly associated with gastroenteritis in Fiji. PMID- 25685604 TI - Drug-resistant tuberculosis in the WHO Western Pacific Region. AB - OBJECTIVE: To review the latest information about tuberculosis (TB) drug resistance and programmatic management of drug-resistant TB in the Western Pacific Region of the World Health Organization (WHO). METHODS: We analysed routine data reported by countries to WHO from 2007 to 2013, focusing on data from the following: surveillance and surveys of drug resistance, management of drug-resistant TB and financing related to multidrug-resistant TB (MDR-TB) management. RESULTS: In the Western Pacific Region, 4% (95% confidence interval [CI]: 3-6) of new and 22% (95% CI: 18-26) of previously treated TB cases were estimated to have MDR-TB; this means that in 2013, there were an estimated 71,000 (95% CI: 47,000-94,000) MDR-TB cases among notified pulmonary TB cases in this Region. The coverage of drug susceptibility testing (DST) among new and previously treated TB cases was 3% and 20%, respectively. In 2013, 11,153 cases were notified--16% of the estimated MDR-TB cases. Among the notified cases, 6926 or 62% were enrolled in treatment. Among all enrolled MDR-TB cases, 34% had second-line DST and of these, 13% were resistant to fluoroquinolones (FQ) and/or second-line injectable agents. The 2011 cohort of MDR-TB showed a 52% treatment success. Over the last five years, case notification and enrolment have increased more than five times, but the gap between notification and enrolment widened. DISCUSSION: The increasing trend in detection and enrolment of MDR-TB cases demonstrates readiness to scale up programmatic management of drug-resistant TB at the country level. However, considerable challenges remain. PMID- 25685605 TI - Sleep quality improved following a single session of moderate-intensity aerobic exercise in older women: Results from a pilot study. AB - BACKGROUND: Poor sleep quality is associated with adverse effects on health outcomes. It is not clear whether exercise can improve sleep quality and whether intensity of exercise affects any of the effects. METHODS: Fifteen healthy, non obese (body mass index = 24.4 +/- 2.1 kg/m2, mean +/- SD), sedentary (<20 min of exercise on no more than 3 times/week) older women (66.1 +/- 3.9 years) volunteered for the study. Peak oxygen consumption (VO2peak) was evaluated using a graded exercise test on a treadmill with a metabolic cart. Following a 7-day baseline period, each participant completed two exercise sessions (separated by 1 week) with equal caloric expenditure, but at different intensities (60% and 45% VO2peak, sequence randomized) between 9:00 and 11:00 am. A wrist ActiGraph monitor was used to assess sleep at baseline and two nights following each exercise session. RESULTS: The average duration of the exercise was 54 and 72 min, respectively at 60% (moderate-intensity) and 45% VO2peak (light-intensity). Wake time after sleep onset was significantly shorter (p = 0.016), the number of awakenings was less (p = 0.046), and total activity counts were lower (p = 0.05) after the moderate-intensity exercise compared to baseline no-exercise condition. CONCLUSION: Our data showed that a single moderate-intensity aerobic exercise session improved sleep quality in older women. PMID- 25685606 TI - Pathogenesis of Crohn's disease: Bug or no bug. AB - The possibility of an infectious origin in inflammatory bowel disease (IBD) has been postulated since the first description of Crohn's disease (CD). Many observations implicate bacteria as a trigger for the development of CD: lesions occur in regions with higher bacterial concentrations; aphthous ulcers occur in Peyer's patches; inflammation resolves when the fecal stream is diverted and is reactivated following reinfusion of bowel contents; severity of the disease is correlated with bacterial density in the mucosa; granulomas can contain bacteria; and susceptible mice raised in germ-free conditions develop inflammation when bacteria are introduced in the 1990's, several studies sought to establish a relationship with viral infections and the onset of IBD, finally concluding that no direct link had been demonstrated. In the past fifteen years, evidence relating IBD pathogenesis to Mycobacterium avium paratuberculosis, salmonella, campylobacter, etc., has been found. The tendency now under discussion to regard microbiota as the primary catalyst has led to the latest studies on microbiota as pathogens, focusing on Escherichia coli, mainly in ileal CD. The present review discusses the literature available on these "bugs". PMID- 25685607 TI - Laboratory markers in ulcerative colitis: Current insights and future advances. AB - Ulcerative colitis (UC) and Crohn's disease (CD) are the major forms of inflammatory bowel diseases (IBD) in man. Despite some common features, these forms can be distinguished by different genetic predisposition, risk factors and clinical, endoscopic and histological characteristics. The aetiology of both CD and UC remains unknown, but several evidences suggest that CD and perhaps UC are due to an excessive immune response directed against normal constituents of the intestinal bacterial flora. Tests sometimes invasive are routine for the diagnosis and care of patients with IBD. Diagnosis of UC is based on clinical symptoms combined with radiological and endoscopic investigations. The employment of non-invasive biomarkers is needed. These biomarkers have the potential to avoid invasive diagnostic tests that may result in discomfort and potential complications. The ability to determine the type, severity, prognosis and response to therapy of UC, using biomarkers has long been a goal of clinical researchers. We describe the biomarkers assessed in UC, with special reference to acute-phase proteins and serologic markers and thereafter, we describe the new biological markers and the biological markers could be developed in the future: (1) serum markers of acute phase response: The laboratory tests most used to measure the acute-phase proteins in clinical practice are the serum concentration of C-reactive protein and the erythrocyte sedimentation rate. Other biomarkers of inflammation in UC include platelet count, leukocyte count, and serum albumin and serum orosomucoid concentrations; (2) serologic markers/antibodies: In the last decades serological and immunologic biomarkers have been studied extensively in immunology and have been used in clinical practice to detect specific pathologies. In UC, the presence of these antibodies can aid as surrogate markers for the aberrant host immune response; and (3) future biomarkers: The development of biomarkers in UC will be very important in the future. The progress of molecular biology tools (microarrays, proteomics and nanotechnology) have revolutionised the field of the biomarker discovery. The advances in bioinformatics coupled with cross-disciplinary collaborations have greatly enhanced our ability to retrieve, characterize and analyse large amounts of data generated by the technological advances. The techniques available for biomarkers development are genomics (single nucleotide polymorphism genotyping, pharmacogenetics and gene expression analyses) and proteomics. In the future, the addition of new serological markers will add significant benefit. Correlating serologic markers with genotypes and clinical phenotypes should enhance our understanding of pathophysiology of UC. PMID- 25685608 TI - Rabeprazole is effective for bile reflux oesophagitis after total gastrectomy in a rat model. AB - AIM: To elucidate the effect of a proton pump inhibitor (PPI, rabeparazole) on oesophageal bile reflux in oesophagitis after total gastrectomy. METHODS: Twenty one 8-week-old male Wistar rats were studied. They were performed oesophagoduodenostomy of total gastrectomy to induce oesophageal reflux of biliary and pancreatic juice. Five rats were performed the sham operation (Sham). On post-operative day 7, they were treated with saline (Control) (n = 8) or PPI (rabeprazole, 30 mg/kg per day, ip ) (n = 8) for 2 wk. On post-operative 21, all rats were sacrificed and each oesophagus was evaluated histologically. Oesophageal injury was evaluated by macroscopic and microscopic findings as well as the expression of cyclooxygenase-2 (COX2). We measured bile acid in the oesophageal lumen and the common bile duct. RESULTS: At 3 wk after surgery, a histological study analysis revealed an increase in the thickness of the epithelium, elongation of the lamina propria and basal cell hyperplasia in the oesophageal mucosa. The macroscopic ulcer score and microscopic ulcer length of the control group were significantly higher compared to those of the rabeprazole- treated group. The expression of COX2 was significantly increased according to the immunostaining in the control group compared to rabeprazole- treated group. Although there was no difference between the control and PPI groups in the total bile acid in the common bile duct, the bile acid activity in the oesophageal lumen was significantly decreased in the rabeprazole- treated group due to augmentation of the duodenal motor complex. CONCLUSION: With this model, rabeprazole is good effect for reflux esophagitis after total gastrectomy from bile reflux. Bile acid is an important factor in the mucosal lesion induced by duodenal reflux. PMID- 25685609 TI - Effectiveness of Ceftriaxone Treatment in Preventing Relapse-like Drinking Behavior Following Long-term Ethanol Dependence in P Rats. AB - OBJECTIVE: To evaluate the effectiveness of ceftriaxone treatment in attenuating relapse-like ethanol drinking behavior in male P rats following 14-weeks of continuous ethanol consumption. METHODS: After 14-weeks of continuous access to free choice of 15% and 30% ethanol, male P rats were deprived of ethanol for two weeks. On the last five days of abstinence period, P rats were treated, once a day, with either saline or ceftriaxone (50 or 200 mg/kg; i.p.). This was followed by re-exposure to ethanol for the next 10 days to simulate the relapse-like ethanol drinking behavior. RESULTS: Ceftriaxone treatment (during abstinence) reduced ethanol intake upon re-exposure to ethanol, compared to the saline treated P rats. This statistically significant reduction in ethanol consumption in P rats following treatment with ceftriaxone (200 mg/kg/day) was observed from Day 2 to Day 9. Similarly, water consumption in P rats treated with ceftriaxone was significantly higher than the saline treated group between Day 2 and Day 7. Importantly, ceftriaxone treatment at both doses did not cause any significant changes in body weight compared to saline treated group. CONCLUSIONS: We report here that ceftriaxone at higher dose has been found to be effective in the attenuation of relapse-like ethanol-drinking behavior in chronic ethanol intake model. This is in accordance with previous data from our lab in cocaine animal model demonstrating that only higher dose of ceftriaxone has been effective in attenuating cocaine relapse. PMID- 25685610 TI - Understanding Biogeochemical Cycling of Trace Elements and Heavy Metals in Estuarine Ecosystems. PMID- 25685611 TI - Implementation of an iPod wireless accelerometer application using machine learning to classify disparity of hemiplegic and healthy patellar tendon reflex pair. AB - The characteristics of the patellar tendon reflex provide fundamental insight regarding the diagnosis of neurological status. Based on the features of the tendon reflex response, a clinician may establish preliminary perspective regarding the global condition of the nervous system. Current techniques for quantifying the observations of the reflex response involve the application of ordinal scales, requiring the expertise of a highly skilled clinician. However, the reliability of the ordinal scale approach is debatable. Highly skilled clinicians have even disputed the presence of asymmetric reflex pairs. An alternative strategy was the implementation of an iPod wireless accelerometer application to quantify the reflex response acceleration waveform. An application enabled the recording of the acceleration waveform and later wireless transmission as an email attachment by connectivity to the Internet. A potential energy impact pendulum enabled the patellar tendon reflex to be evoked in a predetermined and targeted manner. Three feature categories of the reflex response acceleration waveform (global parameters, temporal organization, and spectral features) were incorporated into machine learning to distinguish a subject's hemiplegic and healthy reflex pair. Machine learning attained perfect classification of the hemiplegic and healthy reflex pair. The research findings implicate the promise of machine learning for providing increased diagnostic acuity regarding the acceleration waveform of the tendon reflex response. PMID- 25685612 TI - Constitutive mitochondrial DNA copy number in peripheral blood of melanoma families with and without CDKN2A mutations. AB - Quantitative changes in mitochondrial DNA (mtDNA) have been associated with the risk of a number of human cancers; however, the relationship between constitutive mtDNA copy number in blood and the risk of familial cutaneous malignant melanoma (CMM) has not been reported. We measured mtDNA copy number using quantitative PCR in blood-derived DNA from 136 CMM cases and 302 controls in 53 melanoma-prone families (23 segregating CDKN2A germline mutations). MtDNA copy number did not vary by age, sex, pigmentation characteristics, or CMM status. However, germline CDKN2A mutation carriers had significantly higher mean mtDNA copy number compared to non-carriers, particularly among CMM cases (geometric mean mtDNA copy number of 144 and 111 for carrier versus non-carrier, respectively; P= 0.02). When adjusting for age, sex, and familial correlation, having increasing mtDNA copy number was significantly associated with CDKN2A mutation status among CMM cases (OR=1.47, Ptrend=0.024). In particular, individuals with specific CDKN2A mutations with the potential to inactivate or reduce the level of the p16-INK4 reactive oxygen species (ROS) protective function had significantly increased mtDNA copy number levels (P=0.035). Future research in prospective studies is required to validate these findings and to further investigate mtDNA copy number in both blood and melanoma tissues in relation to CMM risk and CDKN2A mutation status. PMID- 25685613 TI - The UCSC Ebola Genome Portal. AB - BACKGROUND: With the Ebola epidemic raging out of control in West Africa, there has been a flurry of research into the Ebola virus, resulting in the generation of much genomic data. METHODS: In response to the clear need for tools that integrate multiple strands of research around molecular sequences, we have created the University of California Santa Cruz (UCSC) Ebola Genome Browser, an adaptation of our popular UCSC Genome Browser web tool, which can be used to view the Ebola virus genome sequence from GenBank and nearly 30 annotation tracks generated by mapping external data to the reference sequence. Significant annotations include a multiple alignment comprising 102 Ebola genomes from the current outbreak, 56 from previous outbreaks, and 2 Marburg genomes as an outgroup; a gene track curated by NCBI; protein annotations curated by UniProt and antibody-binding epitopes curated by IEDB. We have extended the Genome Browser's multiple alignment color-coding scheme to distinguish mutations resulting from non-synonymous coding changes, synonymous changes, or changes in untranslated regions. DISCUSSION: Our Ebola Genome portal at http://genome.ucsc.edu/ebolaPortal/ links to the Ebola virus Genome Browser and an aggregate of useful information, including a collection of Ebola antibodies we are curating. PMID- 25685614 TI - A three-scale network model for the early growth dynamics of 2014 west Africa ebola epidemic. AB - BACKGROUND: In mid-October 2014, the number of cases of the West Africa Ebola virus epidemic in Guinea, Sierra Leone and Liberia exceeded 9,000 cases. The early growth dynamics of the epidemic has been qualitatively different for each of the three countries. However, it is important to understand these disparate dynamics as trends of a single epidemic spread over regions with similar geographic and cultural aspects, with likely common parameters for transmission rates and reproduction number R0. METHODS: We combine a discrete, stochastic SEIR model with a three-scale community network model to demonstrate that the different regional trends may be explained by different community mixing rates. Heuristically, the effect of different community mixing rates may be understood as the observation that two individuals infected by the same chain of transmission are more likely to share the same contacts in a less-mixed community. Local saturation effects occur as the contacts of an infected individual are more likely to already be exposed by the same chain of transmission. RESULTS: The effects of community mixing, together with stochastic effects, can explain the qualitative difference in the growth of Ebola virus cases in each country, and why the probability of large outbreaks may have recently increased. An increase in the rate of Ebola cases in Guinea in late August, and a local fitting of the transient dynamics of the Ebola cases in Liberia, suggests that the epidemic in Liberia has been more severe, and the epidemic in Guinea is worsening, due to discrete seeding events as the epidemic spreads into new communities. CONCLUSIONS: A relatively simple network model provides insight on the role of local effects such as saturation that would be difficult to otherwise quantify. Our results predict that exponential growth of an epidemic is driven by the exposure of new communities, underscoring the importance of limiting this spread. PMID- 25685615 TI - Is West Africa Approaching a Catastrophic Phase or is the 2014 Ebola Epidemic Slowing Down? Different Models Yield Different Answers for Liberia. AB - An unprecedented epidemic of Zaire ebolavirus (EBOV) has affected West Africa since approximately December 2013, with intense transmission on-going in Guinea, Sierra Leone and Liberia and increasingly important international repercussions. Mathematical models are proving instrumental to forecast the expected number of infections and deaths and quantify the intensity of interventions required to control transmission; however, calibrating mechanistic transmission models to an on-going outbreak is a challenging task owing to limited availability of epidemiological data and rapidly changing interventions. Here we project the trajectory of the EBOV epidemic in Liberia by fitting logistic growth models to the cumulative number of cases. Our model predictions align well with the latest epidemiological reports available as of October 23, and indicates that the exponential growth phase is over in Liberia, with an expected final attack rate of ~0.1-0.12%. Our results indicate that simple phenomenological models can provide complementary insights into the dynamics of an outbreak and capture early signs of changes in population behavior and interventions. In particular, our results underscore the need to treat the effective size of the susceptible population as a dynamic variable rather than a fixed quantity, due to reactive changes in transmission throughout the outbreak. We show that predictions from the logistic model are more variable in the earlier stages of an epidemic (such as the EBOV epidemics in Sierra Leone and Guinea). More research is warranted to compare the performances of mechanistic and phenomenological approaches for disease forecasts, before such predictions can be fully used by public health authorities. PMID- 25685616 TI - Projected impact of vaccination timing and dose availability on the course of the 2014 west african ebola epidemic. AB - BACKGROUND: The 2014 West African Ebola outbreak has evolved into an epidemic of historical proportions and catastrophic scope. Prior outbreaks have been contained through the use of personal protective equipment, but such an approach has not been rapidly effective in the current epidemic. Several candidate vaccines have been developed against the Ebola virus, and are undergoing initial clinical trials. METHODS: As removal of population-level susceptibility through vaccination could be a highly impactful control measure for this epidemic, we sought to estimate the number of vaccine doses and timing of vaccine administration required to reduce the epidemic size. Our base model was fit using the IDEA approach, a single equation model that has been successful to date in describing Ebola growth. We projected the future course of the Ebola epidemic using this model. Vaccination was assumed to reduce the effective reproductive number. We evaluated the potential impact of vaccination on epidemic trajectory under different assumptions around timing of vaccine availability. RESULTS: Using effective reproductive (Re) number estimates derived from this model, we estimate that 3-4 million doses of vaccine, if available and administered, could reduce Re to 0.9 in the interval from January-March 2015. Later vaccination would be associated with a progressively diminishing impact on final epidemic size; in particular, vaccination to the same Re at or after the epidemic is projected to peak (April-May 2015) would have little impact on final epidemic size, though more intensive campaigns (e.g., Re reduced to 0.5) could still be effective if initiated by summer 2015. In summary, there is a closing window of opportunity for the use of vaccine as a tool for Ebola epidemic control. CONCLUSIONS: Effective vaccination, used before the epidemic peaks, would be projected to prevent tens of thousands of deaths; this does not minimize the ethical challenges that would be associated with wide-scale application of vaccines that have undergone only limited evaluation for safety and efficacy. PMID- 25685617 TI - Ebola and indirect effects on health service function in sierra leone. AB - BACKGROUND: The indirect effects of the Ebola epidemic on health service function may be significant but is not known. The aim of this study was to quantify to what extent admission rates and surgery has changed at health facilities providing such care in Sierra Leone during the time of the Ebola epidemic. METHODS: Weekly data on facility inpatient admissions and surgery from admission and surgical theatre register books were retrospectively retrieved during September and October. 21 Community Health Officers enrolled in a surgical task shifting program personally visited the facilities. The study period was January 6 (week 2) to October 12, (week 41) 2014. RESULTS: Data was retrieved from 40 out of 55 facilities. A total of 62,257 admissions and 12,124 major surgeries were registered for the study period. Total admissions in the week of the first Ebola case were 2,006, median 40 (IQR 20-76) compared to 883, median 12 (IQR 4-30) on the last week of the study. This equals a 70% drop in median number of admissions (p=0.005) between May and October. Total number of major surgeries fell from 342, median 6 (IQR 2-14) to 231, median 3 (IQR 0-6) in the same period, equal 50% reduction in median number of major surgeries (p=0.014). CONCLUSIONS: Inpatient health services have been severely affected by the Ebola outbreak. The dramatic documented decline in facility inpatient admissions and major surgery is likely to be an underestimation. Reestablishing such care is urgent and must be a priority. PMID- 25685618 TI - The race to save lives: demonstrating the use of social media for search and rescue operations. AB - IMPORTANCE: Utilizing social media in an emergency can enhance abilities to locate and evacuate casualties more rapidly and effectively, and can contribute towards saving lives following a disaster, through better coordination and collaboration between search and rescue teams. OBJECTIVE: An exercise was conducted in order to test a standard operating procedure (SOP) designed to leverage social media use in response to an earthquake, and study whether social media can improve joint Israeli-Jordanian search and rescue operations following a regional earthquake. DESIGN: First responders from both Jordan and Israel were divided into two mixed groups of eight people each, representing joint (Israeli Jordanian) EMS teams. Simulated patients were dispersed throughout the Ben-Gurion University Campus. The first search and rescue team used conventional methods, while the second team also used social media channels (Facebook and Twitter) to leverage search and rescue operations. PARTICIPANTS: Eighteen EMS and medical professionals from Israel and Jordan, which are members of the Emergency Response Development and Strategy Forum working group, participated in the exercise. RESULTS: The social media team found significantly more mock casualties, 21 out of 22 (95.45%) while the no-media team found only 19 out of 22 (86.36%). Fourteen patients (63.63%) were found by the social media team earlier than the no-media team. The differences between the two groups were analyzed using the Mann-Whitney U-test, and evacuation proved to be significantly quicker in the group that had access to social media. The differences between the three injury severities groups' extraction times in each group were analyzed using the Kruskal-Wallis test for variance. Injury severity influenced the evacuation times in the social media team but no such difference was noted in the no-media team. CONCLUSIONS: Utilizing social media in an emergency situation enables to locate and evacuate casualties more rapidly and effectively. Social media can contribute towards saving lives during a disaster, in national and bi-national circumstances. Due to the small numbers in the groups, this finding requires further verification on a larger study cohort. PMID- 25685619 TI - Communicable diseases surveillance system in East azerbaijan earthquake: strengths and weaknesses. AB - BACKGROUND: A Surveillance System was established for 19 diseases/syndromes in order to prevent and control communicable diseases after 2012 East Azerbaijan earthquakes. This study was conducted to investigate the strengths and weaknesses of the established SS. METHODS: This study was carried out on an interview-based qualitative study using content analysis in 2012. Data was collected by semi structured deep interviews and surveillance data. Fifteen interviews were conducted with experts and health system managers who were engaged in implementing the communicable disease surveillance system in the affected areas. The selection of participants was purposeful. Data saturation supported the sample size. The collected data was analyzed using the principles suggested by Strauss and Corbin. RESULTS: Establishment of the disease surveillance system was rapid and inexpensive. It collected the required data fast. It also increased confidence in health authorities that the diseases would be under control in earthquake-stricken regions. Non estimated denominator for calculating the rates (incidence & prevalence), non-participation of the private sector and hospitals, rapid turnover of health staff and unfamiliarity with the definitions of the diseases were the weak points of the established disease SS. CONCLUSION: During the time when surveillance system was active, no significant outbreak of communicable diseases was reported. However, the surveillance system had some weaknesses. Thus, considering Iran's susceptibility to various natural hazards, repeated exercises should be conducted in the preparedness phase to decrease the weaknesses. In addition, other types of surveillance system such as web-based or mobile-based systems should be piloted in disaster situations for future. PMID- 25685620 TI - One tree to link them all: a phylogenetic dataset for the European tetrapoda. AB - Since the ever-increasing availability of phylogenetic informative data, the last decade has seen an upsurge of ecological studies incorporating information on evolutionary relationships among species. However, detailed species-level phylogenies are still lacking for many large groups and regions, which are necessary for comprehensive large-scale eco-phylogenetic analyses. Here, we provide a dataset of 100 dated phylogenetic trees for all European tetrapods based on a mixture of supermatrix and supertree approaches. Phylogenetic inference was performed separately for each of the main Tetrapoda groups of Europe except mammals (i.e. amphibians, birds, squamates and turtles) by means of maximum likelihood (ML) analyses of supermatrix applying a tree constraint at the family (amphibians and squamates) or order (birds and turtles) levels based on consensus knowledge. For each group, we inferred 100 ML trees to be able to provide a phylogenetic dataset that accounts for phylogenetic uncertainty, and assessed node support with bootstrap analyses. Each tree was dated using penalized-likelihood and fossil calibration. The trees obtained were well supported by existing knowledge and previous phylogenetic studies. For mammals, we modified the most complete supertree dataset available on the literature to include a recent update of the Carnivora clade. As a final step, we merged the phylogenetic trees of all groups to obtain a set of 100 phylogenetic trees for all European Tetrapoda species for which data was available (91%). We provide this phylogenetic dataset (100 chronograms) for the purpose of comparative analyses, macro-ecological or community ecology studies aiming to incorporate phylogenetic information while accounting for phylogenetic uncertainty. PMID- 25685621 TI - Sequential outbreaks due to a new strain of Neisseria meningitidis serogroup C in northern Nigeria, 2013-14. AB - Background Neisseria meningitidis serogroup C (NmC) outbreaks occur infrequently in the African meningitis belt; the most recent report of an outbreak of this serogroup was in Burkina Faso, 1979. Medecins sans Frontieres (MSF) has been responding to outbreaks of meningitis in northwest Nigeria since 2007 with no reported cases of serogroup C from 2007-2012. MenAfrivac(r), a serogroup A conjugate vaccine, was first used for mass vaccination in northwest Nigeria in late 2012. Reactive vaccination using polysaccharide ACYW135 vaccine was done by MSF in parts of the region in 2008 and 2009; no other vaccination campaigns are known to have occurred in the area during this period. We describe the general characteristics of an outbreak due to a novel strain of NmC in Sokoto State, Nigeria, in 2013, and a smaller outbreak in 2014 in the adjacent state, Kebbi. Methods Information on cases and deaths was collected using a standard line-list during each week of each meningitis outbreak in 2013 and 2014 in northwest Nigeria. Initial serogroup confirmation was by rapid Pastorex agglutination tests. Cerebrospinal fluid (CSF) samples from suspected meningitis patients were sent to the WHO Reference Laboratory in Oslo, where bacterial isolates, serogrouping, antimicrobial sensitivity testing, genotype characterisation and real-time PCR analysis were performed. Results In the most highly affected outbreak areas, all of the 856 and 333 clinically suspected meningitis cases were treated in 2013 and 2014, respectively. Overall attack (AR) and case fatality (CFR) rates were 673/100,000 population and 6.8% in 2013, and 165/100,000 and 10.5% in 2014. Both outbreaks affected small geographical areas of less than 150km2 and populations of less than 210,000, and occurred in neighbouring regions in two adjacent states in the successive years. Initial rapid testing identified NmC as the causative agent. Of the 21 and 17 CSF samples analysed in Oslo, NmC alone was confirmed in 11 and 10 samples in 2013 and 2014, respectively. Samples confirmed as NmC through bacterial culture had sequence type (ST)-10217. Conclusions These are the first recorded outbreaks of NmC in the region since 1979, and the sequence (ST)-10217 has not been identified anywhere else in the world. The outbreaks had similar characteristics to previously recorded NmC outbreaks. Outbreaks of NmC in 2 consecutive years in northern Nigeria indicate a possible emergence of this serogroup. Increased surveillance for multiple serogroups in the region is needed, along with consideration of vaccination with conjugate vaccines rather than for NmA alone. PMID- 25685622 TI - Estimation of MERS-Coronavirus Reproductive Number and Case Fatality Rate for the Spring 2014 Saudi Arabia Outbreak: Insights from Publicly Available Data. AB - BACKGROUND: The Middle East Respiratory Syndrome Coronavirus (MERS-CoV) was initially recognized as a source of severe respiratory illness and renal failure in 2012. Prior to 2014, MERS-CoV was mostly associated with sporadic cases of human illness, of presumed zoonotic origin, though chains of person-to-person transmission in the healthcare setting were reported. In spring 2014, large healthcare-associated outbreaks of MERS-CoV infection occurred in Jeddah and Riyadh, Kingdom of Saudi Arabia. To date the epidemiological information published by public health investigators in affected jurisdictions has been relatively limited. However, it is important that the global public health community have access to information on the basic epidemiological features of the outbreak to date, including the basic reproduction number (R0) and best estimates of case-fatality rates (CFR). We sought to address these gaps using a publicly available line listing of MERS-CoV cases. METHODS: R0 was estimated using the incidence decay with exponential adjustment ("IDEA") method, while period specific case fatality rates that incorporated non-attributed death data were estimated using Monte Carlo simulation. RESULTS: 707 cases were available for evaluation. 52% of cases were identified as primary, with the rest being secondary. IDEA model fits suggested a higher R0 in Jeddah (3.5-6.7) than in Riyadh (2.0-2.8); control parameters suggested more rapid reduction in transmission in the former city than the latter. The model accurately projected final size and end date of the Riyadh outbreak based on information available prior to the outbreak peak; for Jeddah, these projections were possible once the outbreak peaked. Overall case-fatality was 40%; depending on the timing of 171 deaths unlinked to case data, outbreak CFR could be higher, lower, or equivalent to pre-outbreak CFR. CONCLUSIONS: Notwithstanding imperfect data, inferences about MERS-CoV epidemiology important for public health preparedness are possible using publicly available data sources. The R0 estimated in Riyadh appears similar to that seen for SARS-CoV, but CFR appears higher, and indirect evidence suggests control activities ended these outbreaks. These data suggest this disease should be regarded with equal or greater concern than the related SARS-CoV. PMID- 25685623 TI - Variables associated with effects on morbidity in older adults following disasters. AB - INTRODUCTION: Older adults are vulnerable to disproportionately higher morbidity following disasters. Reasons for this vulnerability are multifaceted and vary by disaster type as well as patient comorbidities. Efforts to mitigate this increased morbidity require identification of at-risk older adults who can be targeted for intervention. METHODS: A PubMed search was performed using the search terms "geriatric, disaster" and "morbidity, disaster" to identify published articles that reported variables associated with increased morbidity of older adults during and after disasters. A review of article titles and abstracts was then conducted to identify those articles that contained evidence-based variables that render older adults vulnerable to poor health outcomes during disasters. RESULTS: A total of 233 studies was initially identified. After applying exclusion criteria, nine studies were chosen for the comprehensive review. Based on the synthesis of the literature, factors were identified that were repeatedly associated with morbidity and mortality among older adults during and shortly after disasters. CONCLUSION: Older adults, especially those with multiple co-morbidities, are at risk of increased morbidity after disasters and catastrophic events. Factors such as the need for prescription medications, low social support, visual and hearing impairment, impaired mobility, and poor economic status are associated with an increased risk of morbidity. PMID- 25685624 TI - Estimating Potential Incidence of MERS-CoV Associated with Hajj Pilgrims to Saudi Arabia, 2014. AB - Between March and June 2014 the Kingdom of Saudi Arabia (KSA) had a large outbreak of MERS-CoV, renewing fears of a major outbreak during the Hajj this October. Using KSA Ministry of Health data, the MERS-CoV Scenario and Modeling Working Group forecast incidence under three scenarios. In the expected incidence scenario, we estimate 6.2 (95% Prediction Interval [PI]: 1-17) pilgrims will develop MERS-CoV symptoms during the Hajj, and 4.0 (95% PI: 0-12) foreign pilgrims will be infected but return home before developing symptoms. In the most pessimistic scenario, 47.6 (95% PI: 32-66) cases will develop symptoms during the Hajj, and 29.0 (95% PI: 17-43) will be infected but return home asymptomatic. Large numbers of MERS-CoV cases are unlikely to occur during the 2014 Hajj even under pessimistic assumptions, but careful monitoring is still needed to detect possible mass infection events and minimize introductions into other countries. PMID- 25685625 TI - Challenges for resuming normal life after earthquake: a qualitative study on rural areas of iran. AB - BACKGROUND AND OBJECTIVE: Growing evidence is indicating that some of disaster affected people face challenges to resume normal life several months after an earthquake. However, there is no sufficient in-depth understanding of complex process of resuming normal life after an earthquake in Iran, as one of the most disaster-prone countries in the world, and in rural areas as a particular setting. This study aimed to explore challenges of return to normalcy in rural earthquake-stricken areas of Iran. METHODS: The study was conducted using qualitative content analysis method (Graneheim approach). Twenty people from the earthquake-stricken areas and seven qualified experts were selected via purposeful sampling .Data was collected through semi-structured interviews, focus group discussions, and field notes from August 2013 to January 2014. Data collection continued to the point of data saturation (no new information was provided by interviewees). Data saturation supported the sample size. Data analysis was based on qualitative content analysis principles. RESULTS: "Social uncertainty and confusion" was the most prominent challenge of return to the normal life after earthquake, which was categorized into six concepts of social vulnerability, lack of comprehensive rehabilitation plan, incomplete reconstruction, ignorance of local social capital, waste of assets, and psychological problems. CONCLUSIONS: Findings showed that social uncertainty and confusion occurs as a result of negligence of some important social aspects in process of returning to the normal life. This issue, in turn, can greatly interrupt the normal developmental processes. Understanding the challenges of life recovery after disasters will help policy makers consider social rehabilitation as a key factor in facilitation of return to normal life process after earthquakes. KEYWORDS: Disaster; earthquake; social rehabilitation; social uncertainty. PMID- 25685626 TI - Validating indicators of disaster recovery with qualitative research. AB - INTRODUCTION: Recovery from disasters is a critical function of federal, state, and local governments, yet measurable, validated indicators of community recovery remain unidentified. A list of potential recovery indicators was developed by the authors through a literature review, recovery plan review, and case study of two disaster impacted communities. METHODS: To validate the indicators, qualitative data was collected from experts on disaster recovery. Twenty-one key informant interviews and two focus groups were conducted between January and April of 2014 to solicit feedback from disaster recovery practitioners and academics. RESULTS: Five major themes emerged from the qualitative data. These included: the flexibility of the indicators to serve multiple purposes for communities and individuals both pre- and post- disaster; the focus areas are comprehensive, but content and organization can be improved; the importance of seeing the indicators as a self-assessment, rather than a tool for comparing communities; the potential challenges of collecting data for some indicators; and the identification of potential measurement issues with the indicators. DISCUSSION: The proposed recovery indicators can be utilized by both practitioners and researchers to effectively track post-disaster recovery. They capture many of the complexities of community disaster recovery and provide potential opportunities for linkages to the development of disaster recovery plans and other activities that could increase community resilience in the future. PMID- 25685627 TI - Assessment of the risk of ebola importation to australia. AB - OBJECTIVES: To assess the risk of Ebola importation to Australia during the first six months of 2015, based upon the current outbreak in West Africa. METHODOLOGY: We assessed the risk under two distinct scenarios: (i) assuming that significant numbers of cases of Ebola remain confined to Guinea, Liberia and Sierra Leone, and using historic passenger arrival data into Australia; and, (ii) assuming potential secondary spread based upon international flight data. A model appropriate to each scenario is developed, and parameterised using passenger arrival card or international flight data, and World Health Organisation case data from West Africa. These models were constructed based on WHO Ebola outbreak data as at 17 October 2014 and 3 December 2014. An assessment of the risk under each scenario is reported. On 27 October 2014 the Australian Government announced a policy change, that visas from affected countries would be refused/cancelled, and the predicted effect of this policy change is reported. RESULTS: The current probability of at least one case entering Australia by 1 July 2015, having travelled directly from West Africa with historic passenger arrival rates into Australia, is 0.34. Under the new Australian Government policy of restricting visas from affected countries (as of 27 October 2014), the probability of at least one case entering Australia by 1 July 2015 is reduced to 0.16. The probability of at least one case entering Australia by 1 July 2015 via an outbreak from a secondary source country is approximately 0.12. CONCLUSIONS: Our models suggest that if the transmission of Ebola remains unchanged, it is possible that a case will enter Australia within the first six months of 2015, either directly from West Africa (even when current visa restrictions are considered), or via secondary outbreaks elsewhere. Government and medical authorities should be prepared to respond to this eventuality. Control measures within West Africa over recent months have contributed to a reduction in projected risk of a case entering Australia. A significant further reduction of the rate at which Ebola is proliferating in West Africa, and control of the disease if and when it proliferates elsewhere, will continue to result in substantially lower risk of the disease entering Australia. PMID- 25685628 TI - Art of disaster preparedness in European union: a survey on the health systems. AB - INTRODUCTION: Naturally occurring and man-made disasters have been increasing in the world, including Europe, over the past several decades. Health systems are a key part of any community disaster management system. The success of preparedness and prevention depends on the success of activities such as disaster planning, organization and training. The aim of this study is to evaluate health system preparedness for disasters in the 27 European Union member countries. METHOD: A cross-sectional analysis study was completed between June-September 2012. The checklist used for this survey was a modified from the World Health Organization toolkit for assessing health-system capacity for crisis management. Three specialists from each of the 27 European Union countries were included in the survey. Responses to each survey question were scored and the range of preparedness level was defined as 0-100%, categorized in three levels as follows: Acceptable; Transitional; or Insufficient. RESULTS: Response rate was 79.1%. The average level of disaster management preparedness in the health systems of 27 European Union member states was 68% (Acceptable). The highest level of preparedness was seen in the United Kingdom, Luxemburg, and Lithuania. Considering the elements of disaster management system, the highest level of preparedness score was at health information elements (86%), and the lowest level was for hospitals, and educational elements (54%). CONCLUSION: This survey study suggests that preparedness level of European Union countries in 2012 is at an acceptable level but could be improved. Elements such as hospitals and education and training suffer from insufficient levels of preparedness. The European Union health systems need a collective strategic plan, as well as enough resources, to establish a comprehensive and standardized disaster management strategy plan. A competency based training curriculum for managers and first responders is basic to accomplishing this goal. KEYWORDS: Disaster medicine; Disaster preparedness; Disaster epidemiology; Health systems; European Union. PMID- 25685629 TI - Snow Tweets: Emergency Information Dissemination in a US County During 2014 Winter Storms. AB - INTRODUCTION: This paper describes how American federal, state, and local organizations created, sourced, and disseminated emergency information via social media in preparation for several winter storms in one county in the state of New Jersey (USA). METHODS: Postings submitted to Twitter for three winter storm periods were collected from selected organizations, along with a purposeful sample of select private local users. Storm-related posts were analyzed for stylistic features (hashtags, retweet mentions, embedded URLs). Sharing and re tweeting patterns were also mapped using NodeXL. RESULTS: RESULTS indicate emergency management entities were active in providing preparedness and response information during the selected winter weather events. A large number of posts, however, did not include unique Twitter features that maximize dissemination and discovery by users. Visual representations of interactions illustrate opportunities for developing stronger relationships among agencies. DISCUSSION: Whereas previous research predominantly focuses on large-scale national or international disaster contexts, the current study instead provides needed analysis in a small-scale context. With practice during localized events like extreme weather, effective information dissemination in large events can be enhanced. PMID- 25685630 TI - Modeling the impact of interventions on an epidemic of ebola in sierra leone and liberia. AB - BACKGROUND: An Ebola outbreak of unparalleled size is currently affecting several countries in West Africa, and international efforts to control the outbreak are underway. However, the efficacy of these interventions, and their likely impact on an Ebola epidemic of this size, is unknown. Forecasting and simulation of these interventions may inform public health efforts. METHODS: We use existing data from Liberia and Sierra Leone to parameterize a mathematical model of Ebola and use this model to forecast the progression of the epidemic, as well as the efficacy of several interventions, including increased contact tracing, improved infection control practices, the use of a hypothetical pharmaceutical intervention to improve survival in hospitalized patients. FINDINGS: Model forecasts until Dec. 31, 2014 show an increasingly severe epidemic with no sign of having reached a peak. Modeling results suggest that increased contact tracing, improved infection control, or a combination of the two can have a substantial impact on the number of Ebola cases, but these interventions are not sufficient to halt the progress of the epidemic. The hypothetical pharmaceutical intervention, while impacting mortality, had a smaller effect on the forecasted trajectory of the epidemic. INTERPRETATION: Near-term, practical interventions to address the ongoing Ebola epidemic may have a beneficial impact on public health, but they will not result in the immediate halting, or even obvious slowing of the epidemic. A long-term commitment of resources and support will be necessary to address the outbreak. PMID- 25642382 TI - Effects of a Two-Year Intensive Multidisciplinary Rehabilitation Program for Patients with Huntington's Disease: a Prospective Intervention Study. AB - OBJECTIVE: To assess effects of a two year intensive, multidisciplinary rehabilitation program for patients with early- to mid-stage Huntington's disease. DESIGN: A prospective intervention study. SETTING: One inpatient rehabilitation center in Norway. SUBJECTS: 10 patients, with early- to mid-stage Huntington's disease. INTERVENTIONS: A two year rehabilitation program, consisting of six admissions of three weeks each, and two evaluation stays approximately three months after the third and sixth rehabilitation admission. The program focused on physical exercise, social activities, and group/teaching sessions. MAIN OUTCOME MEASURES: Standard measures for motor function, including gait and balance, cognitive function, including MMSE and UHDRS cognitive assessment, anxiety and depression, activities of daily living (ADL), health related quality of life (QoL) and Body Mass Index (BMI). RESULTS: Six out of ten patients completed the full program. Slight, but non-significant, decline was observed for gait and balance from baseline to the evaluation stay after two years. Non-significant improvements were observed in physical QoL, anxiety and depression, and BMI. ADL-function remained stable with no significant decline. None of the cognitive measures showed a significant decline. An analysis of individual cases revealed that four out of the six participants who completed the program sustained or improved their motor function, while motor function declined in two participants. All the six patients who completed the program reported improved or stable QoL throughout the study period. CONCLUSION: Our findings suggest that participation in an intensive rehabilitation program is well tolerated among motivated patients with early to mid-stage HD. The findings should be interpreted with caution due to the small sample size in this study. PMID- 25685632 TI - Projected treatment capacity needs in sierra leone. AB - BACKGROUND: The ongoing outbreak of Ebola Virus Disease in West Africa requires immediate and sustained input from the international community in order to curb transmission. The CDC has produced a model that indicates that to end the outbreak by pushing the reproductive number below one, 25% of the patients must be placed in an Ebola Treatment Unit (ETC) and 45% must be isolated in community settings in which risk of disease transmission is reduced and safe burials are provided. In order to provide firmer targets for the international response in Sierra Leone, we estimated the national and international personnel and treatment capacity that may be required to reach these percentages. METHODS: We developed a compartmental SEIR model that was fitted to WHO data and local data allowing the reproductive number to change every 8 weeks to forecast the progression of the EVD epidemic in Sierra Leone. We used the previously estimated 2.5x correction factor estimated by the CDC to correct for underreporting. Number of personnel required to provide treatment for the predicted number of cases was estimated using UNMEER and UN OCHA requests for resources required to meet the CDC target of 70% isolation. RESULTS: As of today (2014-12-04), we estimate that there are 810 (95% CI=646 to 973) EVD active cases in treatment, with an additional 3751 (95% CI=2778 to 4723) EVD cases unreported and untreated. To reach the CDC targets today, we need 1140 (95% CI=894 to 1387) cases in ETCs and 2052 (95% CI=1608 to 2496) at home or in a community setting with a reduced risk for disease transmission. In 28 days (2015-01-01), we will need 1309 (95% CI=804 to 1814) EVD cases in ETCs and 2356 (95% CI=1447 to 3266) EVD cases at reduced risk of transmission. If the current transmission rate is not reduced, up to 3183 personnel in total will be required in 56 days (2015-01-29) to operate ETCs according to our model. CONCLUSIONS: The current outbreak will require massive input from the international community in order to curb the transmission through traditional containment mechanisms by breaking the chains of transmission in Sierra Leone. If sufficient treatment facilities, healthcare workers and support personnel are not rapidly deployed, the increasing number of cases will be overwhelming.In addition to supporting isolation and treatment mechanisms, other viable control options, such as the development of an effective vaccine, should be supported. PMID- 25685633 TI - The Western Africa ebola virus disease epidemic exhibits both global exponential and local polynomial growth rates. AB - BACKGROUND: While many infectious disease epidemics are initially characterized by an exponential growth in time, we show that district-level Ebola virus disease (EVD) outbreaks in West Africa follow slower polynomial-based growth kinetics over several generations of the disease. METHODS: We analyzed epidemic growth patterns at three different spatial scales (regional, national, and subnational) of the Ebola virus disease epidemic in Guinea, Sierra Leone and Liberia by compiling publicly available weekly time series of reported EVD case numbers from the patient database available from the World Health Organization website for the period 05-Jan to 17-Dec 2014. RESULTS: We found significant differences in the growth patterns of EVD cases at the scale of the country, district, and other subnational administrative divisions. The national cumulative curves of EVD cases in Guinea, Sierra Leone, and Liberia show periods of approximate exponential growth. In contrast, local epidemics are asynchronous and exhibit slow growth patterns during 3 or more EVD generations, which can be better approximated by a polynomial than an exponential function. CONCLUSIONS: The slower than expected growth pattern of local EVD outbreaks could result from a variety of factors, including behavior changes, success of control interventions, or intrinsic features of the disease such as a high level of clustering. Quantifying the contribution of each of these factors could help refine estimates of final epidemic size and the relative impact of different mitigation efforts in current and future EVD outbreaks. PMID- 25685634 TI - Developing a Consensus-based Definition of "Kokoro-no Care" or Mental Health Services and Psychosocial Support: Drawing from Experiences of Mental Health Professionals Who Responded to the Great East Japan Earthquake. AB - OBJECTIVES: In this survey, we aimed to build consensus and gather opinions on 'Kokoro-no care' or mental health services and psychosocial support (MHSPSS) after a disaster, among mental health professionals who engaged in care after the Great East Japan Earthquake. METHODS: We recruited mental health professionals who engaged in support activities after the Great East Japan Earthquake, which included local health professionals in the affected areas and members of mental health care teams dispatched from outside (n = 131). Adopting the Delphi process, we proposed a definition of 'Kokoro-no care', and asked the participants to rate the appropriateness on a 5-point Likert scale. We also solicited free comments based on the participants' experiences during the disaster. After Round 1, we presented the summary statistics and comments, and asked the participants to re rate the definition that had been modified based on their comments. This process was repeated twice, until the consensus criterion of >= 80% of the participants scoring >= 4 on the statement was fulfilled. RESULTS: In Round 1, 68.7% of the respondents rated the proposed definition >= 4 for its appropriateness, and 88.4% did so in Round 2. The comments were grouped into categories (and subcategories) based on those related to the definition in general (Appropriate, Continuum of MHSPSS, Cautions in operation, Alternative categorisation of care components, Whether the care component should be categorised according to the professional involved, Ambiguous use of psychology, and Others), to mental health services (Appropriate, More specification within mental health services, More explicit remarks on mental health services, and Others), and to psychosocial support (Whether the care component should be categorised according to the professional involved, Raising concerns about the terms, and Others), and others. CONCLUSION: We achieved a consensus on the definition of 'Kokoro-no care', and systematically obtained suggestions on the concept, and practical advice on operation, based on the participants' experiences from the Great East Japan Earthquake. This collective knowledge will serve as reference to prepare and respond to future disasters. PMID- 25685635 TI - Global climate anomalies and potential infectious disease risks: 2014-2015. AB - BACKGROUND: The El Nino/Southern Oscillation (ENSO) is a global climate phenomenon that impacts human infectious disease risk worldwide through droughts, floods, and other climate extremes. Throughout summer and fall 2014 and winter 2015, El Nino Watch, issued by the US National Oceanic and Atmospheric Administration, assessed likely El Nino development during the Northern Hemisphere fall and winter, persisting into spring 2015. METHODS: We identified geographic regions where environmental conditions may increase infectious disease transmission if the predicted El Nino occurs using El Nino indicators (Sea Surface Temperature [SST], Outgoing Longwave Radiation [OLR], and rainfall anomalies) and literature review of El Nino-infectious disease associations. RESULTS: SSTs in the equatorial Pacific and western Indian Oceans were anomalously elevated during August-October 2014, consistent with a developing weak El Nino event. Teleconnections with local climate is evident in global precipitation patterns, with positive OLR anomalies (drier than average conditions) across Indonesia and coastal southeast Asia, and negative anomalies across northern China, the western Indian Ocean, central Asia, north-central and northeast Africa, Mexico/Central America, the southwestern United States, and the northeastern and southwestern tropical Pacific. Persistence of these conditions could produce environmental settings conducive to increased transmission of cholera, dengue, malaria, Rift Valley fever, and other infectious diseases in regional hotspots as during previous El Nino events. DISCUSSION AND CONCLUSIONS: The current development of weak El Nino conditions may have significant potential implications for global public health in winter 2014-spring 2015. Enhanced surveillance and other preparedness measures in predicted infectious disease hotspots could mitigate health impacts. PMID- 25685636 TI - A model of the 2014 ebola epidemic in west Africa with contact tracing. AB - A differential equations model is developed for the 2014 Ebola epidemics in Sierra Leone and Liberia. The model describes the dynamic interactions of the susceptible and infected populations of these countries. The model incorporates the principle features of contact tracing, namely, the number of contacts per identified infectious case, the likelihood that a traced contact is infectious, and the efficiency of the contact tracing process. The model is first fitted to current cumulative reported case data in each country. The data fitted simulations are then projected forward in time, with varying parameter regimes corresponding to contact tracing efficiencies. These projections quantify the importance of the identification, isolation, and contact tracing processes for containment of the epidemics. PMID- 25685637 TI - What's the Big Deal? Responder Experiences of Large Animal Rescue in Australia. AB - BACKGROUND: The management of large animals during disasters and emergencies creates difficult operational environments for responders. The aims of this study were to identify the exact challenges faced by Australian emergency response personnel in their interactions with large animals and their owners, and to determine the readiness for large animal rescue (LAR) in Australia. METHODS: A survey tool collected the views and experiences of a broad cross section of emergency services personnel operating across Australia and across all hazards. Data were collected from 156 responders including Australian emergency services personnel, emergency managers such as federal agricultural departments, and local government. RESULTS: Overall, many of the respondents had serious concerns, and felt that there were significant issues in relation to LAR in Australia. These included the coordination of emergency care for animals, physical management of large animals, inter-agency coordination, and dealing with animal owners. Very few respondents had received any formal training in LAR, with an overwhelming majority indicating they would attend formal training if it were made available. DISCUSSION: RESULTS help to guide the development of evidence-informed support tools to assist operational response and community engagement, and the production of professional development resources. PMID- 25685638 TI - Chiapas' Delayed Entry into the International Labour Market: A Story of Peasant Isolation, Exploitation, and Coercion. AB - This manuscript presents a synthetic view of Chiapas' migration history over the last century through a thorough examination of relevant English and Spanish language literature sources. Unlike most Mexican states, Chiapas did not heavily rely upon migration, especially international migration, as an economic strategy until very recently. The reasons that underlie Chiapas' late adoption of economic migration include socio-political and economic structural factors that shaped rural and agrarian policy and demographic trends. This paper evaluates these structural factors with regards to several migration theories to assist our understanding of how and why Chiapans were prevented or discouraged from leaving their native communities. The paper concludes by detailing the perfect cascade of climatic, demographic, economic and political factors that ultimately forced Chiapans to resort to international migration as a major economic diversification strategy. PMID- 25685639 TI - Advances in the Structural Evaluation of Glaucoma with Optical Coherence Tomography. AB - Optical coherence tomography (OCT) is capable of providing quantitative and objective assessments of the optic disc, macula and retinal nerve fiber layer in glaucoma. The recent advent of spectral domain OCT (SD-OCT) has enhanced the resolution, decreased scan acquisition time, and improved the reproducibility of measurements compared to older versions of this technology. However, although OCT has been successfully used for detection of disease and evaluation of progression, the limited agreement between structural and functional tests indicates the strong need for a combined approach for detecting and monitoring the disease. A recently described approach for estimation of rates of retinal ganglion cell loss from a combination of SD-OCT and functional data is a promising method for diagnosing, staging, detecting progression, and estimating rates of glaucomatous deterioration. PMID- 25685640 TI - Epigenetic Developmental Disorders: CHARGE syndrome, a case study. AB - Epigenetic events including chromatin remodeling and histone modifications have recently emerged as important contributors to a variety of neurodevelopmental disorders. This review focuses on CHARGE syndrome, a multiple anomaly condition caused by mutations in the gene encoding CHD7, an ATP-dependent chromatin remodeling protein. CHD7 exhibits pleiotropic effects during embryonic development, consistent with highly variable clinical features in CHARGE syndrome. In this review, a historical description of CHARGE is provided, followed by establishment of diagnostic criteria, gene discovery, and development of animal models. Current understanding of epigenetic CHD7 functions and interacting proteins in cells and tissues is also presented, and final emphasis is placed on challenges and major questions to be answered with ongoing research efforts. PMID- 25685641 TI - Current Diagnostic and Therapeutic Strategies in Microvascular Angina. AB - Microvascular angina is common among patients with signs and symptoms of acute coronary syndrome and is associated with an increased risk of cardiovascular and cerebrovascular events. Unfortunately, microvascular is often under-recognized in clinical settings. The diagnosis of microvascular angina relies on assessment of the functional status of the coronary microvasculature. Invasive strategies include acetylcholine provocation, intracoronary Doppler ultrasound, and intracoronary thermodilution; noninvasive strategies include cardiac positron emission tomography (PET), cardiac magnetic resonance, and Doppler echocardiography. Once the diagnosis of microvascular angina is established, treatment is focused on improving symptoms and reducing future risk of cardiovascular and cerebrovascular events. Pharmacologic options and lifestyle modifications for patients with microvascular angina are similar to those for patients with coronary artery disease. PMID- 25685642 TI - Facial nerve function after the extended translabyrinthine approach. AB - Objective To evaluate facial nerve function after excision of petroclival/anterior cerebellopontine angle (CPA) meningiomas by the extended translabyrinthine (EXTL) approach and compare these with outcomes after the transcochlear and transotic approaches. Design Retrospective chart review. Setting/Participants A search of archived surgical cases at a single institution between January 1, 1995, and January 1, 2012. Main Outcome Measures Facial function measured on the House-Brackmann (HB) scale. Results A total of 16 patients underwent the EXTL approach for primary excision of petroclival meningiomas. Average tumor size was 4.6 cm, and six patients had gross total resection. Average length of follow-up was 36.4 months. Two patients required reoperation for tumor regrowth. Preoperative facial function was HB I or II in all patients with available examinations. Immediate postoperative facial nerve function ranged from HB I to HB VI. In patients with an intact facial nerve at surgery, all but one had long-term facial function of HB I or II. A robust response on intraoperative facial nerve monitoring was prognostic of favorable long-term facial function. Facial function declined in some patients after postoperative radiation or revision surgery. Conclusions The EXTL approach allows excellent exposure of petroclival/anterior CPA lesions and should be favored to improve facial outcomes. PMID- 25685643 TI - A novel graft material for preventing cerebrospinal fluid leakage in skull base reconstruction: technical note of perifascial areolar tissue. AB - Objectives Perifascial areolar tissue (PAT), a layer of loose connective tissue on the deep fascias with a rich vascular plexus, serves as a vital cover over defects with scarce vascularity. We report the usefulness of PAT as a nonvascularized alternative to flaps for reconstruction of dural defects in skull base surgery and transsphenoidal surgery while evaluating its effect on control of cerebrospinal fluid (CSF) leakage. Design A retrospective chart analysis was performed on patients who had undergone repair of a dural defect with PAT during skull base surgery or transsphenoidal surgery between December 2004 and October 2011. Results Twenty-one patients were included: 11 patients had received surgical treatment and/or irradiation. Fourteen of the 21 patients had pre- and/or intraoperative CSF leakage. Only one patient (4.8%) had postoperative CSF leakage requiring additional surgical repair. Ten patients underwent postoperative irradiation from 1 to 15 months after transplant of the PAT. None of the patients had postoperative CSF leakage after irradiation. Conclusion We successfully repaired dural defects using PAT in skull base surgery and transsphenoidal surgery, even in patients with a history of multiple operations and radiotherapy. PAT may serve as a valuable tool for skull base reconstruction. PMID- 25685644 TI - "Round-the-Clock" Surgical Access to the Orbit. AB - Objective To describe an algorithm to guide surgeons in choosing the most appropriate approach to orbital pathology. Methods A review of 12 selected illustrative cases operated on at the neurosurgical department of University of Pittsburgh Medical Center over 3 years from 2009 to 2011 was performed. Preoperative coronal magnetic resonance imaging and/or computed tomography views were compared using a "clock model" of the orbit with its center at the optic nerve. The rationale for choosing an external, endoscopic, or combined approach is discussed for each case. Results Using the right orbit for demonstration of the clock model, the medial transconjunctival approach provides access to the anterior orbit from 1 to 6 o'clock; endoscopic endonasal approaches provide access to the mid and posterior orbit and orbital apex from 1 to 7 o'clock. The lateral micro-orbitotomy gives access to the orbit from 8 to 10 o'clock. The frontotemporal craniotomy with orbital osteotomy accesses the orbit from 9 to 1 o'clock; addition of a zygomatic osteotomy to this extends access from 6 to 8 o'clock. Conclusions Combined, the approaches described provide 360 degrees of access to the entire orbit with the choice of the optimal approach guided primarily by the avoidance of crossing the plane of the optic nerve. PMID- 25685645 TI - Scarless abdominal fat graft harvest for neurosurgical procedures: technical note. AB - Background Abdominal fat grafts are often harvested for use in skull base reconstruction and cerebrospinal fluid (CSF) leak repairs, and for operations traversing the nasal sinuses or mastoid bone. Although the endoscopic transnasal surgery has gained significant popularity, in part because it is considered "scarless," a common adjunct, the abdominal fat graft, can result in a disfiguring scar across the abdomen. Objective This is the first report of a scarless abdominal fat graft technique for skull base reconstruction. Methods Ten patients with a median age of 56.5 years (range: 45-73 years) underwent endoscopic transsphenoidal tumor resection with intraumbilical fat graft harvest. Careful circumferential fat dissection at the umbilicus, with progressive retraction of the graft, was crucial to ensure maximal visualization and to prevent injury to the subcutaneous vessels and rectus fascia. Results Following reconstruction of the sellar skull base, all patients did well postoperatively with no evidence of CSF leak. At 12-week follow-up for all patients, there was no evidence of scar, intracavity hematoma, or wound infection. Conclusions Fat graft harvest through an intraumbilical incision results in a scar-free abdominal harvest, and is a useful procedural adjunct to complement "scarless" brain surgery. PMID- 25685646 TI - Comparing operative exposures of the le fort I osteotomy and the expanded endoscopic endonasal approach to the clivus. AB - Objectives We compare surgical exposures to the clivus by Le Fort I osteotomy (LFO) and the expanded endoscopic endonasal approach (EEEA). Methods Ten cadaveric specimens were imaged with 1.25-mm computed tomography. After stereotactic navigation, EEEA was performed followed by LFO. Clival measurements included lateral and vertical limits to the midline lower extent of exposure (t test). Results For EEFA and LFO, respectively, maximal lateral exposure in millimeters (mean +/- standard deviation) was 24.5 +/- 3.7 and 24.5 +/- - 3.8 (p = 0.99) at the opticocarotid recess (OCR) and 25.1 +/- - 4.1 and 24.1 +/- - 3.0 (p = 0.53) at the foramen lacerum level; lateral reach at the hypoglossal canals was 39.0 +/- - 5.88 and 56.1 +/- - 5.3 (p = 0.0004); and vertical extension was 56.0 +/- - 4.1 and 56.3 +/- - 3.4 (p = 0.78). Conclusions For clival exposures, LFO and EEEA were similar craniocaudally and laterally at the levels of the OCR and foramen lacerum. LFO achieved greater exposure at the level of the hypoglossal canal. PMID- 25685647 TI - Role of squamosal suture as a consistent landmark for middle fossa approach craniotomy: an anatomical study. AB - Objective To establish a consistent surface bony landmark for a middle fossa approach (MFA) lateral craniotomy represented by the squamosal suture (SS). Methods In 60 dried skulls, we assessed the relation between the SS and the external auditory canal (EAC). The lateral portion of the middle cranial fossa floor was also assessed for a possible relation with the anteroposterior diameter (APD) of the squama temporalis (ST). Clinically, we applied our findings on the SS in MFA for different lesions. Results A vertical line at the EAC divided the ST into the anterior part constituting 61% of the APD (i.e., two thirds) and the posterior part forming 39% (i.e., one third). The average ST height was 35.92 mm. The SS posterior limit at the supramastoid crest was located just anterior to the external projection of the petrous ridge in 35 skulls (58%) and exactly corresponded to it in 25 skulls (42%). The APD of the ST equals on average 97% of the APD of the lateral middle cranial fossa. Optimum exposure of the middle fossa was obtained without any further craniotomy extension. Conclusion The SS serves as a consistent natural surface bony landmark for MFA. Optimum craniotomy, two thirds anterior to the EAC and one third posterior, is obtained following SS as a landmark. PMID- 25685648 TI - The costs of skull base surgery in the pediatric population. AB - Objectives To determine the costs of endoscopic endonasal surgery (EES) for pediatric skull base lesions. Methods Retrospective chart review of pediatric patients (ages 1 month to 19 years) treated for skull base lesions with EES from 1999 to 2013. Demographic and operative data were recorded. The cost of care for the surgical day, intensive care unit (ICU), floor, and total overall cost of inpatient stay were acquired from the finance department. Results A total of 160 pediatric patients undergoing EES for skull base lesions were identified. Of these, 55 patients had complete financial data available. The average total inpatient and surgical costs of care were $34, 056 per patient. Angiofibromas were the most costly: $59,051 per patient. Fibro-osseous lesions had the lowest costs: $10,931 per patient. The average ICU stay was 1.8 days at $4,577 per ICU day. The average acute care stay was 3.4 days at $1,961 per day. Overall length of stay was 4.5 days. Three cerebrospinal fluid leaks (4%) and two cases of meningitis (3%) occurred. One tracheostomy was required (1.5%). Conclusions EES is a cost-effective model for removal of skull base lesions in the pediatric population. Costs of care vary according to pathology, staged surgeries, length of ICU stay, and need for second operations. PMID- 25685649 TI - Esthesioneuroblastoma: an update on the UCLA experience, 2002-2013. AB - Objectives To profile the clinical presentation and treatment results of esthesioneuroblastomas at the University of California, Los Angeles (UCLA), from 2002 to 2013. Design Retrospective review. Setting Tertiary academic institution. Participants Forty-one patients with esthesioneuroblastomas treated at UCLA. Main Outcome Measures Overall survival (OS) and recurrence-free survival (RFS). Results Thirty-six patients were included with a mean age of 50.1 years and a median duration of follow-up of 33 months. The 5-year RFS and OS were 54% and 82%, respectively. Modified Kadish stage was the only factor identified to affect OS. Multivariate analysis demonstrated that tumor grade was the only factor that had an independent impact on RFS. There was no statistical difference in survival among the surgical approaches chosen. Conclusions The updated data on the UCLA experience reveals that all three surgical approaches chosen provide comparable survival, although longer follow-up will be needed to ascertain if these findings hold true. The endoscopic approach had a statistically significant decrease in length of hospital stay and a trend toward reduced blood loss, intensive care unit admission, and complications. The modified Kadish staging was the only factor identified to predict OS. Multivariate analysis revealed that tumor grade was an independent predictor of recurrence; therefore, its importance should be emphasized in future staging systems. PMID- 25685650 TI - Endoscopic endonasal surgery for recurrent pituitary tumors: technical challenges to the surgical approach. AB - Objective To review our experience in a series of patients who underwent revision endoscopic pituitary surgery. Methods Retrospective chart review. Results A total of 27 patients were included in the study. Of the 21 patients who required nasoseptal flap reconstruction, a left-sided nasoseptal flap was successfully used in 13 patients. Gross total or near-total resection of tumor was achieved in 74.1%. Cavernous sinus invasion and presentation with residual disease were identified as factors limiting extent of resection (p = 0.002 and 0.009, respectively). A statistically significant difference (p = 0.027) was noted between mean largest tumor dimension in patients with gross total resection and those with near-total or subtotal resection. Complications occurred in 22% and included postoperative temporary diabetes insipidus (n = 2), postoperative hypotension (n = 2), new anterior pituitary insufficiency (n = 1), and right sided abducens palsy (n = 1). Conclusions Revision endoscopic pituitary surgery is advantageous but technically challenging. Cavernous sinus invasion and presentation with residual disease were significant factors limiting extent of resection. Suprasellar extension was not a factor limiting extent of resection and may prove to be an advantage over microscopic speculum-based approaches. Because of the right-sided scarring from prior surgery, a left-sided nasoseptal flap is reliable and advantageous. PMID- 25685651 TI - Quantitative Anatomical Study of Tailored Far-Lateral Approach for the VA-PICA Regions. AB - Objective The extent of the far-lateral approach (FLA) has not yet been quantified for the region of the vertebral and posterior inferior cerebellar arteries (VA-PICA). We quantitatively analyzed six main sequential steps of the FLA. Methods A modified small FLA (msFLA) and a classic large FLA (clFLA) were performed sequentially on both sides of five cadaveric heads. A frameless navigational system was used to quantify the angle of attack for the origin (T1) and lateral medullary segment (T2) of the PICA and the surgical area of exposure above and below the vagus nerve (cranial nerve [CN] X). Results The total area of exposure above CN X increased significantly (p < 0.05) from the msFLA to the clFLA. However, the surgical exposure area below CN X did not change (p > 0.05). C1 hemilaminectomy increased (p < 0.05) the vertical angle of attack, and drilling the posteromedial third of the occipital condyle increased (p < 0.05) the horizontal angle of attack to the origin of the PICA. Conclusions For the VA PICA region, the msFLA offered a similar practical surgical working area and similar angles of attack when compared with the clFLA. The FLA should be tailored based on the location, size, and pathology of lesions and on the exposure required for effective surgical treatment. PMID- 25685652 TI - Meningiomas of the pediatric skull base: a review. AB - Pediatric skull base meningiomas are rare and complex clinical entities. Meningioma is a relatively uncommon brain tumor in children, and only ~ 27% involve the skull base. Some evidence suggests that these tumors are more likely to be atypical or malignant in children than adults. The absence of female preponderance in pediatric meningiomas is reflected in the skull base subpopulation. Skull base meningiomas in children are most likely to be found in the anterior or middle fossa base, or involving the orbit and optic nerve sheath. Petroclival, suprasellar/parasellar, cerebellopontine angle, cavernous sinus, and foramen magnum tumors are very rare. Meningiomas constitute a small proportion of reported cases of pediatric skull base pathology, and they are entirely absent from many case series. Initial gross total resection is consistently associated with superior outcomes. Surgical approaches to the pediatric skull base must take additional factors into consideration including relatively smaller anatomy, immature dentition, incompletely aerated sinuses and air cells, and altered configurations of structures such as the pterional bony complex. Multidisciplinary expertise is essential to optimizing treatment outcomes. PMID- 25685653 TI - Meningiomas of the tuberculum and diaphragma sellae. AB - Introduction Although tuberculum sellae (TS) and diaphragma sellae (DS) meningiomas have different anatomical origins, they are frequently discussed as a single entity. Here we review the radiologic and intraoperative findings of TS and DS meningiomas and propose a radiologic classification. Methods We retrospectively reviewed 10 consecutive TS and DS meningiomas. Data regarding clinical presentation, preoperative imaging, and intraoperative findings were analyzed. Three sellar dimensions were measured on magnetic resonance imaging (MRI): the tuberculum-sellar floor interval (TSFI), the planum-tuberculum interval (PTI), and the total height. Results Three distinct anatomical patterns were recognized: exclusively tubercular meningiomas (type A) were accompanied by elongation of the TSFI and, more significantly, of the PTI; combined TS and DS meningiomas (type B) were associated with relative elongation of both the PTI and TSFI; and the sole exclusively DS meningioma (type C) was associated with elongation of neither PTI nor TSFI. Conclusion Suprasellar meningiomas can be classified as tubercular, combined, or diaphragmatic based on preoperative MRI. Exclusively tubercular meningiomas (type A) require only a supradiaphragmatic approach. Tumor involvement of the sellar diaphragm (type B or C) requires resection of the diaphragm and thus a combined infra- and supradiaphragmatic approach. PMID- 25685654 TI - The Pterional Port in Dual-Port Endoscopy: A 2D and 3D Cadaveric Study. AB - Objective We propose a novel dual-port endonasal and pterional endoscopic approach targeting midline lesions of the anterior cranial fossa with lateral extension beyond the optic nerve. Methods Ten dual-port approaches were performed on five cadaveric heads. All specimens underwent an endoscopic transtuberculum/transplanum approach followed by placement of a pterional port. The endonasal port was combined with an endoscopic extradural pterional keyhole craniectomy. The pterional port was placed at the intersection of the sphenoparietal and coronal sutures. The extradural space was explored using two dimensional and three-dimensional endoscopes. Results The superolateral access provided by the pterional port may improve the ability to achieve a gross total resection of tumors with lateral extensions. The complete opening of the optic canal achieved through the dual-port approach may enable resection of the intracanalicular portion of a tumor, a crucial step in improvement of visual function and reduction of tumor recurrence. Conclusion The pterional port may enhance control of midline anterior skull base lesions with lateral extension beyond the optic nerve and optic canal. Dual-port endoscopy maintains minimally invasiveness and dramatically increases the working limits and control of anatomical structures well beyond what is attainable through single-port neuroendoscopy. PMID- 25685655 TI - New regulations for animal research - a chance to shine for in silico approaches. PMID- 25685656 TI - Congenital Malformations and Consequential Epidemiology. AB - A call for a shift in the discipline of epidemiology, away from those aimed at identifying risk factors and toward those aimed at more directly improving health - so called consequential epidemiology. This call for epidemiologists to engage in solving the biggest public health problems has been heralded for decades by Cates and more recently by Galea [Am J Epidemiol 2013; 178; 1185-94]. In consideration of the consequential epidemiology perspective, the impacts of epidemiologic research of birth defects over the recent decades are evaluated and directions for the field are proposed. While many causal factors have been identified, the causes of the majority of birth defects remain unknown. Folic acid intake notwithstanding, primary prevention of birth defects is elusive. Meanwhile, research that identifies what improves the lives of individuals born with a birth defect and how to ensure those factors are available to all affected would have great impact. In summary, a consequentialist approach to birth defects epidemiology requires a shift in research agendas and teams, but the opportunities are wide open. PMID- 25685657 TI - Clostridium difficile in the Long-Term Care Facility: Prevention and Management. AB - Residents of long-term care facilities are at high risk for Clostridium difficile infection due to frequent antibiotic exposure in a population already rendered vulnerable to infection due to advanced age, multiple comorbid conditions and communal living conditions. Moreover, asymptomatic carriage of toxigenic C. difficile and recurrent infections are prevalent in this population. Here, we discuss epidemiology and management of C. difficile infection among residents of long-term care facilities. Also, recognizing that both the population and culture differs significantly from that of hospitals, we also address prevention strategies specific to LTCFs. PMID- 25685658 TI - Adenovirus serotype 5 E1A expressing tumor cells elicit a tumor-specific CD8+ T cell response independent of NKG2D. AB - The expression of the Adenovirus serotype 2 or serotype 5 (Ad2/5) E1A gene in tumor cells upregulates ligands that are recognized by the NKG2D activating receptor, which is expressed on NK cells and T cells, and reduces their tumorigenicity, a process dependent on NK cells and T cells. In some model systems, the forced overexpression of NKG2D ligands on tumor cells induced antigen-specific CD8+ T cells that mediated anti-tumor immunity. We wanted to determine if the interaction of NKG2D ligands on tumor cells that express E1A with NKG2D on immune cells contributed to the ability of E1A to induce a CD8+ T cell anti-tumor response or reduce tumorigenicity. To address these questions, we used the MCA-205 tumor cell line or MCA-205 cells that expressed Ad5 E1A (MCA-205 E1A cells), a fusion protein of E1A and ovalbumin (MCA-205-E1A-OVA) or OVA (MCA 205-OVA). We found that the expression of E1A or E1A-OVA, but not OVA, upregulated the expression of the NKG2D ligand RAE-1 on the surface of MCA-205 cells. Additionally, MCA-205-E1A cells and MCA-205-E1A-OVA cells were more sensitive to NK cell lysis than MCA-205 or MCA-205-OVA cells in WT B6 mice, but not NKG2D deficient B6 mice. Next, we adoptively transferred WT or NKG2D deficient OT-1 T cells (CD8 T cells that recognize OVA residues 257-264) into WT B6 mice or B6 mice that were deficient in NKG2D respectively and measured the expansion of OT-1 cells following immunization with MCA-205-E1A-OVA or MCA-205 OVA cells. We found that the expansion of OT-1 cells following immunization of either OVA-expressing MCA-205 cell lines was not affected by the presence or absence of NKG2D in B6 mice. Finally, we found that the capacity of E1A to reduce the tumorigenicity of MCA-205 cells was not impaired in B6-NKG2D deficient mice as compared to WT B6 mice. Our results suggest that the ability of E1A to reduce the tumorigenicity of MCA-205 cells, or induce an antigen-specific CD8+ T cell response, is independent of the interaction of NKG2D ligands with the NKG2D receptor. PMID- 25685659 TI - Functional classification and biochemical characterization of a novel rho class glutathione S-transferase in Synechocystis PCC 6803. AB - We report a novel class of glutathione S-transferase (GST) from the model cyanobacterium Synechocystis PCC 6803 (sll1545) which catalyzes the detoxification of the water pollutant dichloroacetate and also shows strong glutathione-dependent peroxidase activity representing the classical activities of zeta and theta/alpha class respectively. Interestingly, sll1545 has very low sequence and structural similarity with these classes. This is the first report of dichloroacetate degradation activity by any bacterial GST. Based on these results we classify sll1545 to a novel GST class, rho. The present data also indicate potential biotechnological and industrial applications of cyanobacterial GST in dichloroacetate-polluted areas. PMID- 25685660 TI - Secretory prostate apoptosis response (Par)-4 sensitizes multicellular spheroids (MCS) of glioblastoma multiforme cells to tamoxifen-induced cell death. AB - Glioblastoma multiforme (GBM) is the most malignant form of brain tumor and is associated with resistance to conventional therapy and poor patient survival. Prostate apoptosis response (Par)-4, a tumor suppressor, is expressed as both an intracellular and secretory/extracellular protein. Though secretory Par-4 induces apoptosis in cancer cells, its potential in drug-resistant tumors remains to be fully explored. Multicellular spheroids (MCS) of cancer cells often acquire multi drug resistance and serve as ideal experimental models. We investigated the role of Par-4 in Tamoxifen (TAM)-induced cell death in MCS of human cell lines and primary cultures of GBM tumors. TCGA and REMBRANT data analysis revealed that low levels of Par-4 correlated with low survival period (21.85 +/- 19.30 days) in GBM but not in astrocytomas (59.13 +/- 47.26 days) and oligodendrogliomas (58.04 +/- 59.80 days) suggesting low PAWR expression as a predictive risk factor in GBM. Consistently, MCS of human cell lines and primary cultures displayed low Par-4 expression, high level of chemo-resistance genes and were resistant to TAM induced cytotoxicity. In monolayer cells, TAM-induced cytotoxicity was associated with enhanced expression of Par-4 and was alleviated by silencing of Par-4 using specific siRNA. TAM effectively induced secretory Par-4 in conditioned medium (CM) of cells cultured as monolayer but not in MCS. Moreover, MCS were rendered sensitive to TAM-induced cell death by exposure to conditioned medium (CM) containing Par-4 (derived from TAM-treated monolayer cells). Also TAM reduced the expression of Akt and PKCzeta in GBM cells cultured as monolayer but not in MCS. Importantly, combination of TAM with inhibitors to PI3K inhibitor (LY294002) or PKCzeta resulted in secretion of Par-4 and cell death in MCS. Since membrane GRP78 is overexpressed in most cancer cells but not normal cells, and secretory Par-4 induces apoptosis by binding to membrane GRP78, secretory Par-4 is an attractive candidate for potentially overcoming therapy-resistance not only in malignant glioma but in broad spectrum of cancers. PMID- 25685661 TI - Piperine, a component of black pepper, decreases eugenol-induced cAMP and calcium levels in non-chemosensory 3T3-L1 cells. AB - This study investigated the effects of an ethanol extract of black pepper and its constituent, piperine, on odorant-induced signal transduction in non-chemosensory cells. An ethanol extract of black pepper decreased eugenol-induced cAMP and calcium levels in preadipocyte 3T3-L1 cells with no toxicity. Phosphorylation of CREB (cAMP response element-binding protein) was down-regulated by the black pepper extract. The concentration (133.8 mg/g) and retention time (5.5 min) of piperine in the ethanol extract were quantified using UPLC-MS/MS. Pretreatment with piperine decreased eugenol-induced cAMP and calcium levels in 3T3-L1 cells. Piperine also decreased the phosphorylation of CREB, which is up-regulated by eugenol. These results suggest that piperine inhibits the eugenol-induced signal transduction pathway through modulation of cAMP and calcium levels and phosphorylation of CREB in non-chemosensory cells. PMID- 25685662 TI - Creation of targeted genomic deletions using TALEN or CRISPR/Cas nuclease pairs in one-cell mouse embryos. AB - The use of TALEN and CRISPR/CAS nucleases is becoming increasingly popular as a means to edit single target sites in one-cell mouse embryos. Nevertheless, an area that has received less attention concerns the engineering of structural genome variants and the necessary religation of two distant double-strand breaks. Herein, we applied pairs of TALEN or sgRNAs and Cas9 to create deletions in the Rab38 gene. We found that the deletion of 3.2 or 9.3 kb, but not of 30 kb, occurs at a frequency of 6-37%. This is sufficient for the direct production of mutants by embryo microinjection. Therefore, deletions up to ~10 kb can be readily achieved for modeling human disease alleles. This work represents an important step towards the establishment of new protocols that support the ligation of remote DSB ends to achieve even larger rearrangements. PMID- 25685663 TI - Role of histamine H3 receptor in glucagon-secreting alphaTC1.6 cells. AB - Pancreatic alpha-cells secrete glucagon to maintain energy homeostasis. Although histamine has an important role in energy homeostasis, the expression and function of histamine receptors in pancreatic alpha-cells remains unknown. We found that the histamine H3 receptor (H3R) was expressed in mouse pancreatic alpha-cells and alphaTC1.6 cells, a mouse pancreatic alpha-cell line. H3R inhibited glucagon secretion from alphaTC1.6 cells by inhibiting an increase in intracellular Ca(2+) concentration. We also found that immepip, a selective H3R agonist, decreased serum glucagon concentration in rats. These results suggest that H3R modulates glucagon secretion from pancreatic alpha-cells. PMID- 25685664 TI - Diffuse binding of Zn(2+) to the denatured ensemble of Cu/Zn superoxide dismutase 1. AB - The stability and structural properties of the metalloprotein superoxide dismutase 1 (SOD1) are found to depend critically on metal ions. Native SOD1 monomers coordinate one structural Zn(2+) and one redox-active Cu(2+/1+) to the active site. To do this, the Zn(2+) ions need to interact with the SOD1 protein on the denatured side of the folding barrier, prior to the formation of the folding nucleus. In this study, we have examined at residue level the nature of this early Zn(2+) binding by NMR studies on the urea denatured-state of SOD1. Nearly complete backbone chemical shift assignments were obtained in 9 M urea at physiological pH, conditions at which NMR studies are scarce. Our results demonstrate that SOD1 is predominantly unstructured under these conditions. Chemical-shift changes upon Zn(2+) titration show that denatured SOD1 retains a significant affinity to Zn(2+) ions, even in 9 M urea. However, the Zn(2+) interactions are not limited to the native metal-binding ligands in the two binding sites, but are seen for all His residues. Moreover, the native Cu(2+/1+) ligand H46 seems not to bind as well as the other His residues, while the nearby non-native H43 does bind, indicating that the binding geometry is relaxed. The result suggests that the Zn(2+)-binding observed to catalyze folding of SOD1 in physiological buffer is initiated by diffuse, non-specific coordination to the coil, which subsequently funnels by ligand exchange into the native coordination geometry of the folded monomer. Altogether, this diffuse binding is a result with fundamental implications for folding of metalloproteins in general. PMID- 25685665 TI - Distinct conformational and functional effects of two adjacent pathogenic mutations in cardiac troponin I at the interface with troponin T. AB - The alpha-helix in troponin I (TnI) at the interface with troponin T (TnT) is a highly conserved structure. A point mutation in this region, A116G, was found in human cardiac TnI in a case of cardiomyopathy. An adjacent dominantly negative mutation found in turkey cardiac TnI (R111C, equivalent to K117C in human and K118C in mouse) decreased diastolic function and blunted beta-adrenergic response in transgenic mice. To investigate the functional importance of the TnI-TnT interface and pathological impact of the cardiac TnI mutations, we engineered K118C and A117G mutations in mouse cardiac TnI for functional studies. Despite their adjacent locations, A117G substitution results in faster mobility of cardiac TnI in SDS-PAGE whereas K118C decreases gel mobility, indicating significant and distinct changes in overall protein conformation. Consistently, monoclonal antibody epitope analysis demonstrated distinct local and remote conformational alterations in the two mutant proteins. Protein binding assays showed that K118C, but not A117G, decreased the relative binding affinity of cardiac TnI for TnT. K118C mutation decreased binding affinity for troponin C in a Ca(2+)-dependent manner, whereas A117G had a similar but less profound effect. Protein kinase A phosphorylation or truncation to remove the cardiac specific N terminal extension of cardiac TnI resulted in similar conformational changes in the region interfacing with TnT and minimized the functional impacts of the mutations. The data demonstrate potent conformational and functional impacts of the TnT-interfacing helix in TnI and suggest a role of the N-terminal extension of cardiac TnI in modulating TnI-TnT interface functions. PMID- 25685666 TI - Ligand binding specificity of RutR, a member of the TetR family of transcription regulators in Escherichia coli. AB - RutR is a member of the large family of TetR transcriptional regulators in Escherichia coli. It was originally discovered as the regulator of the rutABCDEFG operon encoding a novel pathway for pyrimidine utilization, but its highest affinity target is the control region of the carAB operon, encoding carbamoylphosphate synthase. Unlike most other TetR-like regulators, RutR exerts both positive and negative effects on promoter activity. Furthermore, RutR exhibits a very narrow ligand binding specificity, unlike the broad effector specificity that characterizes some of the well-studied multidrug resistance regulators of the family. Here we focus on ligand binding and ligand specificity of RutR. We construct single alanine substitution mutants of amino acid residues of the ligand-binding pocket, study their effect on in vitro DNA binding in absence and presence of potential ligands, and analyse their effect on positive regulation of the carP1 promoter and negative autoregulation in vivo. Although RutR structures have been determined previously, they were deposited in the Protein Data Bank without accompanying publications. All of them have uracil bound in the effector-binding site, representing the inactive form of the regulator. We determined the crystal structure of an unliganded mutant RutR protein and provide a structural basis for the use of uracil as sole effector molecule and the exclusion of the very similar thymine from the ligand-binding pocket. PMID- 25685667 TI - Paired image- and FACS-based toxicity assays for high content screening of spheroid-type tumor cell cultures. AB - Novel spheroid-type tumor cell cultures directly isolated from patients' tumors preserve tumor characteristics better than traditionally grown cell lines. However, such cultures are not generally used for high-throughput toxicity drug screens. In addition, the assays that are commonly used to assess drug-induced toxicity in such screens usually measure a proxy for cell viability such as mitochondrial activity or ATP-content per culture well, rather than actual cell death. This generates considerable assay-dependent differences in the measured toxicity values. To address this problem we developed a robust method that documents drug-induced toxicity on a per-cell, rather than on a per-well basis. The method involves automated drug dispensing followed by paired image- and FACS based analysis of cell death and cell cycle changes. We show that the two methods generate toxicity data in 96-well format which are highly concordant. By contrast, the concordance of these methods with frequently used well-based assays was generally poor. The reported method can be implemented on standard automated microscopes and provides a low-cost approach for accurate and reproducible high throughput toxicity screens in spheroid type cell cultures. Furthermore, the high versatility of both the imaging and FACS platforms allows straightforward adaptation of the high-throughput experimental setup to include fluorescence based measurement of additional cell biological parameters. PMID- 25685668 TI - Dual-camera technique for arthroscopic rotator cuff repair. AB - An all-arthroscopic rotator cuff repair demands a high level of technical skill and is associated with a steep learning curve. It is well accepted that small rotator cuff tears or partial tears can be more difficult than large or even massive tears to repair. Part of the reason is the difficulty in visualizing the tear, as well as important surrounding structures, during repair. To improve visibility during the repair process, we have introduced a second arthroscopic camera. Two cameras allow the surgeon to observe the rotator cuff from both the articular and bursal sides. We find this technique has merit in small or partial thickness rotator cuff tears; however, there may be other applications. PMID- 25685669 TI - Arthroscopic bone graft procedure for anterior inferior glenohumeral instability. AB - There are many described surgical techniques for the treatment of recurrent anterior shoulder instability. Numerous authors have performed anterior bone block procedures with good results for the treatment of anterior shoulder instability with glenoid bone loss. The benefits of using arthroscopic procedures for surgical stabilization of the shoulder include smaller incisions with less soft-tissue dissection, better visualization of the joint, better repair accessibility, and the best possible outcome for external rotation. We describe an arthroscopic anteroinferior shoulder stabilization technique with an iliac crest tricortical bone graft and capsulolabral reconstruction. It is an all arthroscopic technique with the advantage of not using fixation devices, such as screws, but instead using special buttons to fix the bone graft. The steps of the operation are as follows: precise placement of a specific posterior glenoid guide that allows the accurate positioning of the bone graft on the anterior glenoid neck; fixation of the graft flush with the anterior glenoid rim using specific buttons under arthroscopic control; and finally, subsequent capsular, labral, and ligament reconstruction on the glenoid rim using suture anchors and leaving the graft as an extra-articular structure. PMID- 25685670 TI - Ischiofemoral space decompression through posterolateral approach: cutting block technique. AB - Ischiofemoral space impingement has become an increasingly recognized extracapsular cause of atypical hip, deep gluteal, and groin pain that can be treated endoscopically. We present a minimally invasive posterolateral technique that preserves the attachment of the iliopsoas tendon and quadratus femoris insertion while decompressing the ischiofemoral space by resecting the lesser trochanter. Furthermore, we present tips to perform this technique in a manner that minimizes the potential for damage to the sciatic nerve. This technique also allows the surgeon to treat concurrent hip pathology arthroscopically. PMID- 25685671 TI - Arthroscopic lamina-specific double-row fixation for large delaminated rotator cuff tears. AB - Delamination is a commonly observed finding at the time of rotator cuff repair, but few studies have described the surgical techniques used for delaminated rotator cuff tears (RCTs) or their clinical outcomes. We developed a technique using a combination of a double row and an additional row, which we call lamina specific double-row fixation, for large delaminated RCTs. The lamina-specific double-row technique is performed using an additional row (lamina-specific lateral row) of suture anchors placed between the typical medial and lateral rows of suture anchors. The technique is performed as follows: (1) medial-row sutures are passed through the inferior (articular-side) and superior (bursal-side) layers in a mattress fashion; (2) lamina-specific lateral-row simple sutures are passed through the inferior layer; and (3) lateral-row simple sutures are passed through the superior layer. We believe that this technique offers the following advantages: (1) creation of a larger area of contact between the inferior layer and the footprint, (2) higher initial fixation strength of the articular-side components of the repaired rotator cuff tendon, and (3) an adaptation between the superficial and inferior layers. This technique represents an alternative option in the operative treatment of large delaminated RCTs. PMID- 25685672 TI - All-arthroscopic knotless suture anchor repair of triangular fibrocartilage complex fovea tear by the 2-portal technique. AB - After the importance of the deep fiber of the distal radioulnar ligament had been acknowledged, some repair techniques have been introduced. Because the knotless suture anchor does not cause any knot irritation and yields appropriate tension, it is a useful fixation material. All-arthroscopic knotless suture anchor repair of the triangular fibrocartilage complex fovea tear by a 2-portal technique is easier and less vulnerable to ulnar nerve injury than the original Geissler technique. Instead of the suture hook and accessory portal, this technique uses the always-sharp 18-gauge needle and percutaneous route. This change results in the repair of the complex fovea tear having the smallest possible remnant tissue. Repair of triangular fibrocartilage complex fovea tears combined type IB, ID, and IIC tears can reduce the chance of needing to perform distal radioulnar ligament reconstruction. PMID- 25685673 TI - Re-tensioning technique to cover the graft with remnant in anterior cruciate ligament reconstruction. AB - A number of remnant-preserving techniques to restore proprioceptive function in anterior cruciate ligament reconstruction have been described. However, they might not cover the significant amount of the graft with the synovium of the remnant in many cases. We introduce a simple technique that can cover nearly the entire graft with the synovium by re-tensioning the remnant, which might enhance synovialization of the graft and restoration of proprioception. PMID- 25685674 TI - Arthroscopic 4-point suture fixation of anterior cruciate ligament tibial avulsion fractures. AB - Tibial eminence avulsion fractures are rare injuries occurring mainly in adolescents and young adults. When necessary, regardless of patient age, anatomic reduction and stable internal fixation are mandatory for fracture healing and accurate restoration of normal knee biomechanics. Various arthroscopically assisted fixation methods with sutures, anchors, wires, or screws have been described but can be technically demanding, thus elongating operative times. The purpose of this article is to present a technical variation of arthroscopic suture fixation of anterior cruciate ligament avulsion fractures. Using thoracic drain needles over 2.4-mm anterior cruciate ligament tibial guidewires, we recommend the safe and easy creation of four 2.9-mm tibial tunnels at different angles and at specific points. This technique uses thoracic drain needles as suture passage cannulas and offers 4-point fixation stability, avoiding potential complications of bony bridge fracture and tunnel connection. PMID- 25685675 TI - Anterior Cruciate Ligament Reconstruction and Preservation: The Single Anteromedial Bundle Biological Augmentation (SAMBBA) Technique. AB - Preservation of the anterior cruciate ligament (ACL) remnant during ACL reconstruction has the advantages of improved vascularity and synovial encircling of the graft tendon. We describe a technique called single-anteromedial bundle biological augmentation (SAMBBA) using complete preservation of the ACL remnant, as well as preservation of the semitendinosus tibial insertion, that uses standard portals and equipment. PMID- 25685676 TI - Comma sign-directed repair of anterosuperior rotator cuff tears. AB - The comma sign was described as an arthroscopic landmark to identify the torn subscapularis stump to mobilize and repair the tendon in anterosuperior rotator cuff tears. It was hypothesized that it is composed of the humeral attachments of the superior glenohumeral and coracohumeral ligaments. This arthroscopic finding has since become accepted orthopaedic nomenclature pathognomonic for subscapularis tears and a key component of subscapularis tear classification. We propose an alternative theory of the pathoanatomy of the comma sign in anterosuperior rotator cuff tears and present the technique of comma sign directed repairs of combined subscapularis and supraspinatus lesions. After appropriate releases, tendon-to-tendon repair of the distal-superior aspect of the comma sign to the upper border of the remnant subscapularis results in anatomic re-creation of the intra-articular portion of the torn subscapularis with concomitant reduction of the anterior leading edge of the supraspinatus and reconstitution of the rotator cable complex. A tension-free, single-anchor subscapularis repair is then performed to secure the tendon to the lesser tuberosity. After subscapularis repair, the supraspinatus that was previously retracted to the glenoid rim takes the appearance of a crescent-type tear that is easily approximated to its anatomic insertion. PMID- 25685677 TI - Arthroscopic release of the deep medial collateral ligament to assist in exposure of the medial tibiofemoral compartment. AB - Arthroscopy of the knee is a widely used surgical procedure for addressing intra articular pathology. In assessing the intra-articular structures, visualization is of paramount importance. The medial tibiofemoral compartment is often difficult to fully visualize in tight knees in which limited access can compromise surgical efficacy. Poor visualization can increase the possibility of a residual meniscal tear after attempted partial meniscectomy, as well as the possibility of iatrogenic chondral injury from arthroscopic instruments. We describe a technique that allows improved medial tibiofemoral visualization with release of the deep medial collateral ligament. We use standard arthroscopic portals, without the need for further incisions or stab holes and with minimal additional patient morbidity. This procedure allows easier exposure of the medial knee chondral surfaces and meniscus and easier use of arthroscopic instrumentation in the medial compartment. PMID- 25685678 TI - Management of a large acetabular chondrolabral injury in a young patient with femoroacetabular impingement. AB - Patients with mixed-type femoroacetabular impingement syndrome often have concomitant chondrolabral pathology in addition to the characteristic cam and pincer lesions. Unfortunately, these patients are typically young, and the pathology is localized to the weight-bearing dome of the acetabulum. Complete preoperative characterization of labral and cartilage lesions is often not possible even with advanced imaging techniques, and the full extent of the injury may not be appreciated without direct arthroscopic visualization. Thus management decisions regarding intra-articular pathology may not be possible until the time of surgery. Often, the cartilage and labral pathology in these young patients is part of a contiguous complex of tissue that separates from the underlying subchondral bone. We present an arthroscopic management technique for young patients with this pattern of injury. This includes limited debridement of loose labral and chondral tissue, labral repair to restore the suction-seal effect, microfracture to promote reparative tissue formation, and takedown of the underlying pathoanatomic cam and pincer lesions. PMID- 25685679 TI - Hip Arthroscopy for Synovial Chondromatosis: Tips and Tricks. AB - Hip arthroscopy is an important diagnostic and therapeutic tool in the management of synovial chondromatosis. Removal of osteochondral fragments (OCFs) from the central and peripheral compartments is crucial for the relief of mechanical symptoms and subsequent joint destruction. Direct access to the central compartment is often limited because of the ball-and-socket morphology and limitation of traction. We present our surgical technique for removing OCFs and a new method for the removal of a large loose body using a nitinol stone retrieval basket. The technique facilitates removal of difficult-to-access fragments from the central compartment. Moreover, this technique allows removal of far-medial OCFs from the peripheral compartment. PMID- 25685680 TI - Intraosseous infiltration of platelet-rich plasma for severe knee osteoarthritis. AB - We describe a new technique of platelet-rich plasma (PRP) infiltration for the treatment of severe knee osteoarthritis. PRP intra-articular infiltration is a promising treatment for knee osteoarthritis, but it still has some limitations in high-degree osteoarthritis. Diagnosis of osteoarthritis is based on clinical and radiographic findings, and patients with grade III or IV knee tibiofemoral osteoarthritis based on the Ahlback scale are considered candidates for this technique. The technique consists of performing intraosseous infiltration of PRP into the subchondral bone, which acts on this tissue and consequently on cartilage-bone communication. Although the intraosseous injection hinders the conventional knee intra-articular infiltration, it allows an extension of the range of action of the PRP, which acts directly on the subchondral bone, which is involved in the progression of osteoarthritis. Thus this technique involves a new administration of PRP that can delay knee arthroplasty; moreover, it can be applied for not only severe osteoarthritis but also other pathologies in which the subchondral bone is critical in the etiology, such as necrosis and osteochondral lesions. PMID- 25685681 TI - Medial biceps sling takedown may be necessary to expose an occult subscapularis tendon tear. AB - With a systematic approach to diagnosis, including a thorough history, physical examination, advanced imaging, and arthroscopic evaluation, most subscapularis tendon tears may be readily discovered. Occult tears, on the other hand, may escape arthroscopic detection if a high index of suspicion and certain intraoperative examination steps are lacking. We describe an occult tear pattern in which a subscapularis tendon tear was completely hidden by an intact medial biceps tendon sling. Takedown of the sling, which was expendable because a tenodesis was planned, was required to expose this occult tear. Awareness of occult subscapularis tear patterns makes diagnosis and repair possible. PMID- 25685682 TI - Arthroscopy of the nondistractable hip: a novel extracapsular approach. AB - Adequate traction to achieve hip joint distraction is essential for avoiding iatrogenic injury to the joint during hip arthroscopy. An inability to distract the joint is a relative contraindication for hip arthroscopy. This report describes a novel technique involving an extracapsular approach to gain safe access to a hip joint that fails a trial of traction during positioning for hip arthroscopy. The anterolateral portal is established under fluoroscopic guidance. The arthroscope is positioned on the lateral rim of the acetabulum. A shaver, introduced through a modified anterior portal, is used to facilitate capsular exposure. An arthroscopic capsular incision is made proximal to the lateral acetabular rim and extended anteriorly with a radiofrequency probe. Osteoplasty of the anterolateral acetabular rim is carried out with a burr while protecting the labrum. Distraction of the hip is then possible, allowing safe central compartment access and subsequent chondrolabral procedures. PMID- 25685683 TI - Arthroscopic repair of inferior labrum from anterior to posterior lesions associated with multidirectional instability of the shoulder. AB - Multidirectional instability (MDI) of the shoulder may arise spontaneously; however, recent evidence suggests that traumatic events may play a role in this syndrome. Variable degrees of injury around the circumference of the glenoid have been reported, ranging from Bankart and Kim lesions to 270 degrees of injury and even 360 degrees of injury. Hyperabduction injury may cause inferior subluxation of the shoulder and result in traumatic isolated injury to the inferior labrum from anterior to posterior. This particular lesion spans approximately 180 degrees of the inferior hemisphere and may lead to symptomatic MDI. In contrast to open or arthroscopic plication procedures for atraumatic MDI without labral injury, the goal in these cases is anatomic arthroscopic repair of the inferior labrum tear without the need for capsular plication, volume reduction, or rotator interval closure. PMID- 25685684 TI - The good, the bad, and the unknown: Fructose and FGF21. PMID- 25685685 TI - GPR40 (FFAR1) - Combined Gs and Gq signaling in vitro is associated with robust incretin secretagogue action ex vivo and in vivo. AB - OBJECTIVES: GPR40 (FFAR1), a clinically proven anti-diabetes target, is a Gq coupled receptor for long chain fatty acids (LCFA) stimulating insulin secretion directly and mediating a major part of the dietary triglyceride-induced secretion of the incretins GLP-1 and GIP. In phase-II studies the GPR40 agonist TAK-875 decreased blood glucose but surprisingly without stimulating incretins. METHODS AND RESULTS: Here we find that GPR40 can signal through not only Gq and IP3 but also Gs and cAMP when stimulated with certain agonists such as AM-1638 and AM 5262 in contrast to the endogenous LCFA ligands and agonists such as TAK-875 and AM-837, which only signal through Gq. In competition binding against [3H]AM-1638 and [3H]L358 the Gq + Gs and the Gq-only agonists either competed for or showed positive cooperativity by increasing the binding of the two different radio ligands, in opposite ways. Nevertheless, both the Gq-only and the Gq + Gs agonists all docked surprisingly well into the binding site for TAK-875 in the X ray structure of GPR40. In murine intestinal primary cell-cultures the endogenous LCFAs and the Gq-only agonists stimulated GLP-1 secretion with rather poor efficacy as compared with the high efficacy Gq + Gs GPR40 agonists and a prototype GPR119 agonist. Similarly, in fasting both male and female mice the Gq + Gs agonists showed significantly higher efficacy than the Gq-only agonists in respect of increasing plasma GLP-1 and plasma GIP in a GPR40-dependent manner. CONCLUSIONS: It is concluded that stimulation of GPR40 by endogenous LCFAs or by Gq-only synthetic agonists result in a rather limited incretin response, whereas Gq + Gs GPR40 agonists stimulate incretin secretion robustly. PMID- 25685686 TI - Neonatal overnutrition causes early alterations in the central response to peripheral ghrelin. AB - OBJECTIVE: Excess nutrient supply and rapid weight gain during early life are risk factors for the development of obesity during adulthood. This metabolic malprogramming may be mediated by endocrine disturbances during critical periods of development. Ghrelin is a metabolic hormone secreted from the stomach that acts centrally to promote feeding behavior by binding to growth hormone secretagogue receptors in the arcuate nucleus of the hypothalamus. Here, we examined whether neonatal overnutrition causes changes in the ghrelin system. METHODS: We used a well-described mouse model of divergent litter sizes to study the effects of postnatal overfeeding on the central and peripheral ghrelin systems during postnatal development. RESULTS: Mice raised in small litters became overweight during lactation and remained overweight with increased adiposity as adults. Neonatally overnourished mice showed attenuated levels of total and acyl ghrelin in serum and decreased levels of Ghrelin mRNA expression in the stomach during the third week of postnatal life. Normalization of hypoghrelinemia in overnourished pups was relatively ineffective at ameliorating metabolic outcomes, suggesting that small litter pups may present ghrelin resistance. Consistent with this idea, neonatally overnourished pups displayed an impaired central response to peripheral ghrelin. The mechanisms underlying this ghrelin resistance appear to include diminished ghrelin transport into the hypothalamus. CONCLUSIONS: Early postnatal overnutrition results in central resistance to peripheral ghrelin during important periods of hypothalamic development. Because ghrelin signaling has recently been implicated in the neonatal programming of metabolism, these alterations in the ghrelin system may contribute to the metabolic defects observed in postnatally overnourished mice. PMID- 25685687 TI - Maternal high-fat diet and obesity compromise fetal hematopoiesis. AB - OBJECTIVE: Recent evidence indicates that the adult hematopoietic system is susceptible to diet-induced lineage skewing. It is not known whether the developing hematopoietic system is subject to metabolic programming via in utero high-fat diet (HFD) exposure, an established mechanism of adult disease in several organ systems. We previously reported substantial losses in offspring liver size with prenatal HFD. As the liver is the main hematopoietic organ in the fetus, we asked whether the developmental expansion of the hematopoietic stem and progenitor cell (HSPC) pool is compromised by prenatal HFD and/or maternal obesity. METHODS: We used quantitative assays, progenitor colony formation, flow cytometry, transplantation, and gene expression assays with a series of dietary manipulations to test the effects of gestational high-fat diet and maternal obesity on the day 14.5 fetal liver hematopoietic system. RESULTS: Maternal obesity, particularly when paired with gestational HFD, restricts physiological expansion of fetal HSPCs while promoting the opposing cell fate of differentiation. Importantly, these effects are only partially ameliorated by gestational dietary adjustments for obese dams. Competitive transplantation reveals compromised repopulation and myeloid-biased differentiation of HFD programmed HSPCs to be a niche-dependent defect, apparent in HFD-conditioned male recipients. Fetal HSPC deficiencies coincide with perturbations in genes regulating metabolism, immune and inflammatory processes, and stress response, along with downregulation of genes critical for hematopoietic stem cell self renewal and activation of pathways regulating cell migration. CONCLUSIONS: Our data reveal a previously unrecognized susceptibility to nutritional and metabolic developmental programming in the fetal HSPC compartment, which is a partially reversible and microenvironment-dependent defect perturbing stem and progenitor cell expansion and hematopoietic lineage commitment. PMID- 25685688 TI - High fat diet-induced modifications in membrane lipid and mitochondrial-membrane protein signatures precede the development of hepatic insulin resistance in mice. AB - OBJECTIVE: Excess lipid intake has been implicated in the pathophysiology of hepatosteatosis and hepatic insulin resistance. Lipids constitute approximately 50% of the cell membrane mass, define membrane properties, and create microenvironments for membrane-proteins. In this study we aimed to resolve temporal alterations in membrane metabolite and protein signatures during high fat diet (HF)-mediated development of hepatic insulin resistance. METHODS: We induced hepatosteatosis by feeding C3HeB/FeJ male mice an HF enriched with long chain polyunsaturated C18:2n6 fatty acids for 7, 14, or 21 days. Longitudinal changes in hepatic insulin sensitivity were assessed via the euglycemic hyperinsulinemic clamp, in membrane lipids via t-metabolomics- and membrane proteins via quantitative proteomics-analyses, and in hepatocyte morphology via electron microscopy. Data were compared to those of age- and litter-matched controls maintained on a low-fat diet. RESULTS: Excess long-chain polyunsaturated C18:2n6 intake for 7 days did not compromise hepatic insulin sensitivity, however, induced hepatosteatosis and modified major membrane lipid constituent signatures in liver, e.g. increased total unsaturated, long-chain fatty acid containing acyl-carnitine or membrane-associated diacylglycerol moieties and decreased total short-chain acyl-carnitines, glycerophosphocholines, lysophosphatidylcholines, or sphingolipids. Hepatic insulin sensitivity tended to decrease within 14 days HF-exposure. Overt hepatic insulin resistance developed until day 21 of HF-intervention and was accompanied by morphological mitochondrial abnormalities and indications for oxidative stress in liver. HF feeding progressively decreased the abundance of protein-components of all mitochondrial respiratory chain complexes, inner and outer mitochondrial membrane substrate transporters independent from the hepatocellular mitochondrial volume in liver. CONCLUSIONS: We assume HF-induced modifications in membrane lipid- and protein-signatures prior to and during changes in hepatic insulin action in liver alter membrane properties - in particular those of mitochondria which are highly abundant in hepatocytes. In turn, a progressive decrease in the abundance of mitochondrial membrane proteins throughout HF-exposure likely impacts on mitochondrial energy metabolism, substrate exchange across mitochondrial membranes, contributes to oxidative stress, mitochondrial damage, and the development of insulin resistance in liver. PMID- 25685689 TI - Fructose ingestion acutely stimulates circulating FGF21 levels in humans. AB - OBJECTIVE: Fibroblast growth factor 21 (FGF21) is a hormone with pleiotropic metabolic activities which, in rodents, is robustly regulated by fasting and ketogenic diets. In contrast, similar dietary interventions have either no or minimal effects on circulating FGF21 in humans. Moreover, no intervention or dietary challenge has been shown to acutely stimulate circulating FGF21 in either humans or animals. Recent animal data suggest that the transcription factor Carbohydrate Responsive-Element Binding Protein (ChREBP) stimulates hepatic FGF21 expression and that fructose may activate hepatic ChREBP more robustly than glucose. Here, we examined whether fructose ingestion can acutely stimulate FGF21 in humans. METHODS: We measured serum FGF21, glucose, insulin, and triglyceride levels in ten lean, healthy adults and eleven adults with the metabolic syndrome following oral ingestion of 75 g of glucose, fructose, or a combination of the two sugars. RESULTS: FGF21 levels rose rapidly following fructose ingestion, achieved a mean 3.4-fold increase at two hours (P < 0.01), and returned to baseline levels within five hours. In contrast, FGF21 did not increase in the first two hours following ingestion of a glucose load, although more modest increases were observed after three to four hours. Both baseline and fructose stimulated FGF21 levels were 2-3 fold elevated in subjects with metabolic syndrome. CONCLUSIONS: Fructose ingestion acutely and robustly increases serum FGF21 levels in humans in a pattern consistent with a hormonal response. While FGF21 appears to be critical for the adaptive response to fasting or starvation in rodents, these findings suggest that in humans, FGF21 may play an important role in fructose metabolism. PMID- 25685690 TI - Evidence for a novel functional role of astrocytes in the acute homeostatic response to high-fat diet intake in mice. AB - OBJECTIVE: Introduction of a high-fat diet to mice results in a period of voracious feeding, known as hyperphagia, before homeostatic mechanisms prevail to restore energy intake to an isocaloric level. Acute high-fat diet hyperphagia induces astrocyte activation in the rodent hypothalamus, suggesting a potential role of these cells in the homeostatic response to the diet. The objective of this study was to determine physiologic role of astrocytes in the acute homeostatic response to high-fat feeding. METHODS: We bred a transgenic mouse model with doxycycline-inducible inhibition of NFkappaB (NFkappaB) signaling in astrocytes to determine the effect of loss of NFkappaB-mediated astrocyte activation on acute high-fat hyperphagia. ELISA was used to measure the levels of markers of astrocyte activation, glial-fibrillary acidic protein (GFAP) and S100B, in the medial basal hypothalamus. RESULTS: Inhibition of NFkappaB signaling in astrocytes prevented acute high-fat diet-induced astrocyte activation and resulted in a 15% increase in caloric intake (P < 0.01) in the first 24 h after introduction of the diet. CONCLUSIONS: These data reveal a novel homeostatic role for astrocytes in the acute physiologic regulation of food intake in response to high-fat feeding. PMID- 25685691 TI - The class II histone deacetylase HDAC4 regulates cognitive, metabolic and endocrine functions through its expression in osteoblasts. AB - OBJECTIVE: The recently described endocrine functions of osteoblasts raise questions about their transcriptional regulation. Thus far, this aspect of osteoblast biology has been addressed only by examining the role of transcription factors binding to specific cis-acting elements in the promoter of the Osteocalcin gene. METHODS: In contrast, the role of chromatin remodeling enzymes, such as histone deacetylases (HDACs), in this process has not as yet been thoroughly understood. RESULTS: Here we show that through its expression in osteoblasts, one class II HDAC molecule, HDAC4, favors Osteocalcin expression, and as a result, the physiological functions regulated by osteocalcin such as spatial learning, memory, male fertility and insulin secretion. Molecular and genetic evidence indicates that through its expression in osteoblasts HDAC4 fulfills these long-range functions in part by stabilizing the transcription factor ATF4. Remarkably, through its expression in osteoblasts, HDAC4 also enhances appetite, a physiological function that is not regulated by osteocalcin. CONCLUSIONS: These results provide a more in depth molecular understanding of the regulation of the endocrine functions of the osteoblast, and suggest the existence of additional hormones synthesized by osteoblasts that also regulate appetite. PMID- 25685692 TI - Glucose-regulated insulin production in the liver improves glycemic control in type 1 diabetic mice. AB - OBJECTIVE: Type 1 diabetes results from autoimmune destruction of beta-cells in the pancreas. Our objective is to reconstitute a glucose-responsive system in the liver to regulate hepatic insulin production for improving glycemic control in type 1 diabetes. METHODS: We have cloned the glucose-responsive element (GRE) from the promoter of acetyl-CoA carboxylase (ACC), an enzyme that catalyzes the rate-limiting step in fatty acid synthesis in the liver in response to glucose. To increase the amplitude of glucose induction, we quadruplicated the GRE DNA by gene duplication. The resulting GRE multimer (4*GRE) was tested for its ability to drive rat proinsulin cDNA expression in hepatocytes and insulin-deficient diabetic mice. RESULTS: We showed that this GRE multimer-directed glucose responsive system produced insulin in hepatocytes in a glucose-dependent manner. When delivered into the liver by adenovirus-mediated gene transfer, this glucose responsive insulin production system was able to reverse hyperglycemia to a normal range without causing hypoglycemia after glucose challenge or overnight fasting. Insulin vector-treated diabetic mice exhibited significantly improved blood glucose profiles in response to glucose tolerance, correlating with insulin production in the liver. We recapitulated these findings in streptozotocin induced diabetic CD1 mice and autoimmune non-obese diabetic mice. CONCLUSION: Our data characterized the GRE motif from the ACC promoter as a potent glucose responsive element, and provided proof-of-concept that the 4*GRE-mediated hepatic insulin production is capable of correcting insulin deficiency and improving glycemic control in type 1 diabetes. PMID- 25685693 TI - Brain insulin receptors link stress and metabolism. PMID- 25685694 TI - Distinct roles of angiopoietin-like 4 in the regulation of central and peripheral lipid metabolism? PMID- 25685695 TI - Glucagon signaling in the heart: Activation or inhibition? PMID- 25685696 TI - Central insulin signaling modulates hypothalamus-pituitary-adrenal axis responsiveness. AB - OBJECTIVE: Obesity is often accompanied by hyperactivity of the neuroendocrine stress axis and has been linked to an increased risk of psychiatric disorders. Insulin is reciprocally regulated with the stress hormone corticosterone (CORT), raising the possibility that insulin normally provides inhibitory tone to the hypothalamus-adrenal-pituitary (HPA) axis. Here we examined whether disrupting signaling via the insulin receptor (InsR) in hypothalamic subpopulations impacts the neuroendocrine response to acute psychological stress. METHODS: We used Nkx2.1-Cre, Sim1-Cre and Agrp-Cre transgenic driver lines to generate conditional knockouts of InsR signaling throughout the hypothalamus, paraventricular nucleus of the hypothalamus (PVH) and in neurons expressing Agouti-related peptide (AgRP) in the arcuate nucleus of the hypothalamus (ARH), respectively. We used a combination of molecular, behavioral and neuroendocrine criteria to evaluate the consequences on HPA axis responsiveness. RESULTS: Endpoints related to body weight and glucose homeostasis were not altered in any of the conditional mutant lines. Consistent with observations in the neuronal Insr knockout mice (NIRKO), baseline levels of serum CORT were similar to controls in all three lines. In male mice with broad disruptions of InsR signals in Nkx2.1-expressing regions of the hypothalamus (IR(Nkx2.1) KO), we observed elevated arginine vasopressin (AVP) levels at baseline and heightened neuroendocrine responses to restraint stress. IR(Nkx2.1) KO males also exhibited increased anxiety-like behaviors in open field, marble burying, and stress-induced hyperthermia testing paradigms. HPA axis responsivity was not altered in IR(Sim1) KO males, in which InsR was disrupted in the PVH. In contrast to observations in the IR(Nkx2.1) KO males, disrupting InsR signals in ARH neurons expressing Agrp (IR(Agrp) KO) led to reduced AVP release in the median eminence (ME). CONCLUSIONS: We find that central InsR signals modulate HPA responsivity to restraint stress. InsR signaling in AgRP/NPY neurons appears to promote AVP release, while signaling in other hypothalamic neuron(s) likely acts in an opposing fashion. Alterations in InsR signals in neurons that integrate metabolic and psychiatric information could contribute to the high co-morbidity of obesity and mental disorders. PMID- 25685697 TI - Blockade of VEGF-C and VEGF-D modulates adipose tissue inflammation and improves metabolic parameters under high-fat diet. AB - OBJECTIVE: Elevated serum levels of the lymphangiogenic factors VEGF-C and -D have been observed in obese individuals but their relevance for the metabolic syndrome has remained unknown. METHODS: K14-VEGFR-3-Ig (sR3) mice that constitutively express soluble-VEGFR-3-Ig in the skin, scavenging VEGF-C and -D, and wildtype (WT) mice were fed either chow or high-fat diet for 20 weeks. To assess the effect of VEGFR-3 blockage on adipose tissue growth and insulin sensitivity, we evaluated weight gain, adipocyte size and hepatic lipid accumulation. These results were complemented with insulin tolerance tests, FACS analysis of adipose tissue macrophages, in vitro 3T3-L1 differentiation assays and in vivo blocking antibody treatment experiments. RESULTS: We show here that sR3 mice are protected from obesity-induced insulin resistance and hepatic lipid accumulation. This protection is associated with enhanced subcutaneous adipose tissue hyperplasia and an increased number of alternatively-activated (M2) macrophages in adipose tissue. We also show that VEGF-C and -D are chemotactic for murine macrophages and that this effect is mediated by VEGFR-3, which is upregulated on M1 polarized macrophages. Systemic antibody blockage of VEGFR-3 in db/db mice reduces adipose tissue macrophage infiltration and hepatic lipid accumulation, and improves insulin sensitivity. CONCLUSIONS: These results reveal an unanticipated role of the lymphangiogenic factors VEGF-C and -D in the mediation of metabolic syndrome-associated adipose tissue inflammation. Blockage of these lymphangiogenic factors might constitute a new therapeutic strategy for the prevention of obesity-associated insulin resistance. PMID- 25685698 TI - A gut-brain neural circuit controlled by intestinal gluconeogenesis is crucial in metabolic health. AB - OBJECTIVES: Certain nutrients positively regulate energy homeostasis via intestinal gluconeogenesis (IGN). The objective of this study was to evaluate the impact of a deficient IGN in glucose control independently of nutritional environment. METHODS: We used mice deficient in the intestine glucose-6 phosphatase catalytic unit, the key enzyme of IGN (I-G6pc (-/-) mice). We evaluated a number of parameters involved in energy homeostasis, including insulin sensitivity (hyperinsulinemic euglycaemic clamp), the pancreatic function (insulin secretion in vivo and in isolated islets) and the hypothalamic homeostatic function (leptin sensitivity). RESULTS: Intestinal-G6pc (-/-) mice exhibit slight fasting hyperglycaemia and hyperinsulinemia, glucose intolerance, insulin resistance and a deteriorated pancreatic function, despite normal diet with no change in body weight. These defects evoking type 2 diabetes (T2D) derive from the basal activation of the sympathetic nervous system (SNS). They are corrected by treatment with an inhibitor of alpha-2 adrenergic receptors. Deregulation in a key target of IGN, the homeostatic hypothalamic function (highlighted here through leptin resistance) is a mechanistic link. Hence the leptin resistance and metabolic disorders in I-G6pc (-/-) mice are corrected by rescuing IGN by portal glucose infusion. Finally, I-G6pc (-/-) mice develop the hyperglycaemia characteristic of T2D more rapidly under high fat/high sucrose diet. CONCLUSIONS: Intestinal gluconeogenesis is a mandatory function for the healthy neural control of glucose homeostasis. PMID- 25685699 TI - SIRT1 enhances glucose tolerance by potentiating brown adipose tissue function. AB - OBJECTIVE: SIRT1 has been proposed to be a key signaling node linking changes in energy metabolism to transcriptional adaptations. Although SIRT1 overexpression is protective against diverse metabolic complications, especially in response to high-fat diets, studies aiming to understand the etiology of such benefits are scarce. Here, we aimed to identify the key tissues and mechanisms implicated in the beneficial effects of SIRT1 on glucose homeostasis. METHODS: We have used a mouse model of moderate SIRT1 overexpression, under the control of its natural promoter, to evaluate glucose homeostasis and thoroughly characterize how different tissues could influence insulin sensitivity. RESULTS: Mice with moderate overexpression of SIRT1 exhibit better glucose tolerance and insulin sensitivity even on a low fat diet. Euglycemic-hyperinsulinemic clamps and in depth tissue analyses revealed that enhanced insulin sensitivity was achieved through a higher brown adipose tissue activity and was fully reversed by housing the mice at thermoneutrality. SIRT1 did not influence brown adipocyte differentiation, but dramatically enhanced the metabolic transcriptional responses to beta3-adrenergic stimuli in differentiated adipocytes. CONCLUSIONS: Our work demonstrates that SIRT1 improves glucose homeostasis by enhancing BAT function. This is not consequent to an alteration in the brown adipocyte differentiation process, but as a result of potentiating the response to beta3 adrenergic stimuli. PMID- 25685700 TI - Cardiomyocyte glucagon receptor signaling modulates outcomes in mice with experimental myocardial infarction. AB - OBJECTIVE: Glucagon is a hormone with metabolic actions that maintains normoglycemia during the fasting state. Strategies enabling either inhibition or activation of glucagon receptor (Gcgr) signaling are being explored for the treatment of diabetes or obesity. However, the cardiovascular consequences of manipulating glucagon action are poorly understood. METHODS: We assessed infarct size and the following outcomes following left anterior descending (LAD) coronary artery ligation; cardiac gene and protein expression, acylcarnitine profiles, and cardiomyocyte survival in normoglycemic non-obese wildtype mice, and in newly generated mice with selective inactivation of the cardiomyocyte Gcgr. Complementary experiments analyzed Gcgr signaling and cell survival in cardiomyocyte cultures and cell lines, in the presence or absence of exogenous glucagon. RESULTS: Exogenous glucagon administration directly impaired recovery of ventricular pressure in ischemic mouse hearts ex vivo, and increased mortality from myocardial infarction after LAD coronary artery ligation in mice in a p38 MAPK-dependent manner. In contrast, cardiomyocyte-specific reduction of glucagon action in adult Gcgr (CM-/-) mice significantly improved survival, and reduced hypertrophy and infarct size following myocardial infarction. Metabolic profiling of hearts from Gcgr (CM-/-) mice revealed a marked reduction in long chain acylcarnitines in both aerobic and ischemic hearts, and following high fat feeding, consistent with an essential role for Gcgr signaling in the control of cardiac fatty acid utilization. CONCLUSIONS: Activation or reduction of cardiac Gcgr signaling in the ischemic heart produces substantial cardiac phenotypes, findings with implications for therapeutic strategies designed to augment or inhibit Gcgr signaling for the treatment of metabolic disorders. PMID- 25685701 TI - Differential effects of angiopoietin-like 4 in brain and muscle on regulation of lipoprotein lipase activity. AB - OBJECTIVE: Lipoprotein lipase (LPL) is a key regulator of circulating triglyceride rich lipoprotein hydrolysis. In brain LPL regulates appetite and energy expenditure. Angiopoietin-like 4 (Angptl4) is a secreted protein that inhibits LPL activity and, thereby, triglyceride metabolism, but the impact of Angptl4 on central lipid metabolism is unknown. METHODS: We induced type 1 diabetes by streptozotocin (STZ) in whole-body Angptl4 knockout mice (Angptl4(-/ ) ) and their wildtype littermates to study the role of Angptl4 in central lipid metabolism. RESULTS: In type 1 (streptozotocin, STZ) and type 2 (ob/ob) diabetic mice, there is a ~2-fold increase of Angptl4 in the hypothalamus and skeletal muscle. Intracerebroventricular insulin injection into STZ mice at levels which have no effect on plasma glucose restores Angptl4 expression in hypothalamus. Isolation of cells from the brain reveals that Angptl4 is produced in glia, whereas LPL is present in both glia and neurons. Consistent with the in vivo experiment, in vitro insulin treatment of glial cells causes a 50% reduction of Angptl4 and significantly increases LPL activity with no change in LPL expression. In Angptl4(-/-) mice, LPL activity in skeletal muscle is increased 3 fold, and this is further increased by STZ-induced diabetes. By contrast, Angptl4(-/-) mice show no significant difference in LPL activity in hypothalamus or brain independent of diabetic and nutritional status. CONCLUSION: Thus, Angptl4 in brain is produced in glia and regulated by insulin. However, in contrast to the periphery, central Angptl4 does not regulate LPL activity, but appears to participate in the metabolic crosstalk between glia and neurons. PMID- 25685702 TI - The Serum Immunoglobulin G Glycosylation Signature of Gastric Cancer. AB - Biomarkers may facilitate detection of gastric cancer at an earlier stage and reduce mortality. Here we sought to determine if the glycosylation profile of serum immunoglobulin G (IgG) could distinguish patients with non-atrophic gastritis (NAG), duodenal ulcer (DU) and gastric cancer (GC). Serum IgG was released and analyzed using nano-LC-TOF mass spectrometry. Statistically significant false discovery rate (FDR)-adjusted p-values were observed for 18 glycans, eight that differed significantly between NAG and GC, three that distinguished NAG from DU, and eight that differed between DU and GC. The IgG glycosylation signature may be useful as a predictive marker for gastric cancer. PMID- 25685703 TI - Functional connectivity classification of autism identifies highly predictive brain features but falls short of biomarker standards. AB - OBJECTIVES: Autism spectrum disorders (ASD) are diagnosed based on early manifesting clinical symptoms, including markedly impaired social communication. We assessed the viability of resting-state functional MRI (rs-fMRI) connectivity measures as diagnostic biomarkers for ASD and investigated which connectivity features are predictive of a diagnosis. METHODS: Rs-fMRI scans from 59 high functioning males with ASD and 59 age- and IQ-matched typically developing (TD) males were used to build a series of machine learning classifiers. Classification features were obtained using 3 sets of brain regions. Another set of classifiers was built from participants' scores on behavioral metrics. An additional age and IQ-matched cohort of 178 individuals (89 ASD; 89 TD) from the Autism Brain Imaging Data Exchange (ABIDE) open-access dataset (http://fcon_1000.projects.nitrc.org/indi/abide/) were included for replication. RESULTS: High classification accuracy was achieved through several rs-fMRI methods (peak accuracy 76.67%). However, classification via behavioral measures consistently surpassed rs-fMRI classifiers (peak accuracy 95.19%). The class probability estimates, P(ASD|fMRI data), from brain-based classifiers significantly correlated with scores on a measure of social functioning, the Social Responsiveness Scale (SRS), as did the most informative features from 2 of the 3 sets of brain-based features. The most informative connections predominantly originated from regions strongly associated with social functioning. CONCLUSIONS: While individuals can be classified as having ASD with statistically significant accuracy from their rs-fMRI scans alone, this method falls short of biomarker standards. Classification methods provided further evidence that ASD functional connectivity is characterized by dysfunction of large-scale functional networks, particularly those involved in social information processing. PMID- 25685704 TI - MRI-based diagnostic biomarkers for early onset pediatric multiple sclerosis. AB - Currently, it is unclear whether pediatric multiple sclerosis (PMS) is a pathoetiologically homogeneous disease phenotype due to clinical and epidemiological differences between early and late onset PMS (EOPMS and LOPMS). Consequently, the question was raised whether diagnostic guidelines need to be complemented by specific EOPMS markers. To search for such markers, we analyzed cerebral MRI images acquired with standard protocols using computer-based classification techniques. Specifically, we applied classification algorithms to gray (GM) and white matter (WM) tissue probability parameters of small brain regions derived from T2-weighted MRI images of EOPMS patients (onset <12 years), LOPMS patients (onset >=12 years), and healthy controls (HC). This was done for PMS subgroups matched for disease duration and participant age independently. As expected, maximal diagnostic information for distinguishing PMS patients and HC was found in a periventricular WM area containing lesions (87.1% accuracy, p < 2.2 * 10(-5)). MRI-based biomarkers specific for EOPMS were identified in prefrontal cortex. Specifically, a coordinate in middle frontal gyrus contained maximal diagnostic information (77.3%, p = 1.8 * 10(-4)). Taken together, we were able to identify biomarkers reflecting pathognomonic processes specific for MS patients with very early onset. Especially GM involvement in the separation between PMS subgroups suggests that conventional MRI contains a richer set of diagnostically informative features than previously assumed. PMID- 25685705 TI - Usage of fMRI for pre-surgical planning in brain tumor and vascular lesion patients: task and statistical threshold effects on language lateralization. AB - BACKGROUND AND PURPOSE: Functional magnetic resonance imaging (fMRI) is a non invasive pre-surgical tool used to assess localization and lateralization of language function in brain tumor and vascular lesion patients in order to guide neurosurgeons as they devise a surgical approach to treat these lesions. We investigated the effect of varying the statistical thresholds as well as the type of language tasks on functional activation patterns and language lateralization. We hypothesized that language lateralization indices (LIs) would be threshold- and task-dependent. MATERIALS AND METHODS: Imaging data were collected from brain tumor patients (n = 67, average age 48 years) and vascular lesion patients (n = 25, average age 43 years) who received pre-operative fMRI scanning. Both patient groups performed expressive (antonym and/or letter-word generation) and receptive (tumor patients performed text-reading; vascular lesion patients performed text listening) language tasks. A control group (n = 25, average age 45 years) performed the letter-word generation task. RESULTS: Brain tumor patients showed left-lateralization during the antonym-word generation and text-reading tasks at high threshold values and bilateral activation during the letter-word generation task, irrespective of the threshold values. Vascular lesion patients showed left lateralization during the antonym and letter-word generation, and text-listening tasks at high threshold values. CONCLUSION: Our results suggest that the type of task and the applied statistical threshold influence LI and that the threshold effects on LI may be task-specific. Thus identifying critical functional regions and computing LIs should be conducted on an individual subject basis, using a continuum of threshold values with different tasks to provide the most accurate information for surgical planning to minimize post-operative language deficits. PMID- 25685706 TI - Content-based image retrieval for brain MRI: an image-searching engine and population-based analysis to utilize past clinical data for future diagnosis. AB - Radiological diagnosis is based on subjective judgment by radiologists. The reasoning behind this process is difficult to document and share, which is a major obstacle in adopting evidence-based medicine in radiology. We report our attempt to use a comprehensive brain parcellation tool to systematically capture image features and use them to record, search, and evaluate anatomical phenotypes. Anatomical images (T1-weighted MRI) were converted to a standardized index by using a high-dimensional image transformation method followed by atlas based parcellation of the entire brain. We investigated how the indexed anatomical data captured the anatomical features of healthy controls and a population with Primary Progressive Aphasia (PPA). PPA was chosen because patients have apparent atrophy at different degrees and locations, thus the automated quantitative results can be compared with trained clinicians' qualitative evaluations. We explored and tested the power of individual classifications and of performing a search for images with similar anatomical features in a database using partial least squares-discriminant analysis (PLS-DA) and principal component analysis (PCA). The agreement between the automated z score and the averaged visual scores for atrophy (r = 0.8) was virtually the same as the inter-evaluator agreement. The PCA plot distribution correlated with the anatomical phenotypes and the PLS-DA resulted in a model with an accuracy of 88% for distinguishing PPA variants. The quantitative indices captured the main anatomical features. The indexing of image data has a potential to be an effective, comprehensive, and easily translatable tool for clinical practice, providing new opportunities to mine clinical databases for medical decision support. PMID- 25685707 TI - Adolescents with current major depressive disorder show dissimilar patterns of age-related differences in ACC and thalamus. AB - OBJECTIVE: There is little understanding of the neural system abnormalities subserving adolescent major depressive disorder (MDD). In a cross-sectional study we compare currently unipolar depressed with healthy adolescents to determine if group differences in grey matter volume (GMV) were influenced by age and illness severity. METHOD: Structural neuroimaging was performed on 109 adolescents with current MDD and 36 healthy controls, matched for age, gender, and handedness. GMV differences were examined within the anterior cingulate cortex (ACC) and across the whole-brain. The effects of age and self-reported depressive symptoms were also examined in regions showing significant main or interaction effects. RESULTS: Whole-brain voxel based morphometry revealed no significant group differences. At the whole-brain level, both groups showed a main effect of age on GMV, although this effect was more pronounced in controls. Significant group-by age interactions were noted: A significant regional group-by-age interaction was observed in the ACC. GMV in the ACC showed patterns of age-related differences that were dissimilar between adolescents with MDD and healthy controls. GMV in the thalamus showed an opposite pattern of age-related differences in adolescent patients compared to healthy controls. In patients, GMV in the thalamus, but not the ACC, was inversely related with self-reported depressive symptoms. CONCLUSIONS: The depressed adolescent brain shows dissimilar age-related and symptom-sensitive patterns of GMV differences compared with controls. The thalamus and ACC may comprise neural markers for detecting these effects in youth. Further investigations therefore need to take both age and level of current symptoms into account when disaggregating antecedent neural vulnerabilities for MDD from the effects of MDD on the developing brain. PMID- 25685708 TI - Increased in vivo glial activation in patients with amyotrophic lateral sclerosis: assessed with [(11)C]-PBR28. AB - Evidence from human post mortem, in vivo and animal model studies implicates the neuroimmune system and activated microglia in the pathology of amyotrophic lateral sclerosis. The study aim was to further evaluate in vivo neuroinflammation in individuals with amyotrophic lateral sclerosis using [(11)C] PBR28 positron emission tomography. Ten patients with amyotrophic lateral sclerosis (seven males, three females, 38-68 years) and ten age- and [(11)C] PBR28 binding affinity-matched healthy volunteers (six males, four females, 33-65 years) completed a positron emission tomography scan. Standardized uptake values were calculated from 60 to 90 min post-injection and normalized to whole brain mean. Voxel-wise analysis showed increased binding in the motor cortices and corticospinal tracts in patients with amyotrophic lateral sclerosis compared to healthy controls (p FWE < 0.05). Region of interest analysis revealed increased [(11)C]-PBR28 binding in the precentral gyrus in patients (normalized standardized uptake value = 1.15) compared to controls (1.03, p < 0.05). In patients those values were positively correlated with upper motor neuron burden scores (r = 0.69, p < 0.05), and negatively correlated with the amyotrophic lateral sclerosis functional rating scale (r = -0.66, p < 0.05). Increased in vivo glial activation in motor cortices, that correlates with phenotype, complements previous histopathological reports. Further studies will determine the role of [(11)C]-PBR28 as a marker of treatments that target neuroinflammation. PMID- 25685709 TI - Improved nTMS- and DTI-derived CST tractography through anatomical ROI seeding on anterior pontine level compared to internal capsule. AB - Imaging of the course of the corticospinal tract (CST) by diffusion tensor imaging (DTI) is useful for function-preserving tumour surgery. The integration of functional localizer data into tracking algorithms offers to establish a direct structure-function relationship in DTI data. However, alterations of MRI signals in and adjacent to brain tumours often lead to spurious tracking results. We here compared the impact of subcortical seed regions placed at different positions and the influences of the somatotopic location of the cortical seed and clinical co-factors on fibre tracking plausibility in brain tumour patients. The CST of 32 patients with intracranial tumours was investigated by means of deterministic DTI and neuronavigated transcranial magnetic stimulation (nTMS). The cortical seeds were defined by the nTMS hot spots of the primary motor area (M1) of the hand, the foot and the tongue representation. The CST originating from the contralesional M1 hand area was mapped as intra-individual reference. As subcortical region of interests (ROI), we used the posterior limb of the internal capsule (PLIC) and/or the anterior inferior pontine region (aiP). The plausibility of the fibre trajectories was assessed by a-priori defined anatomical criteria. The following potential co-factors were analysed: Karnofsky Performance Scale (KPS), resting motor threshold (RMT), T1-CE tumour volume, T2 oedema volume, presence of oedema within the PLIC, the fractional anisotropy threshold (FAT) to elicit a minimum amount of fibres and the minimal fibre length. The results showed a higher proportion of plausible fibre tracts for the aiP-ROI compared to the PLIC-ROI. Low FAT values and the presence of peritumoural oedema within the PLIC led to less plausible fibre tracking results. Most plausible results were obtained when the FAT ranged above a cut-off of 0.105. In addition, there was a strong effect of somatotopic location of the seed ROI; best plausibility was obtained for the contralateral hand CST (100%), followed by the ipsilesional hand CST (>95%), the ipsilesional foot (>85%) and tongue (>75%) CST. In summary, we found that the aiP-ROI yielded better tracking results compared to the IC-ROI when using deterministic CST tractography in brain tumour patients, especially when the M1 hand area was tracked. In case of FAT values lower than 0.10, the result of the respective CST tractography should be interpreted with caution with respect to spurious tracking results. Moreover, the presence of oedema within the internal capsule should be considered a negative predictor for plausible CST tracking. PMID- 25685710 TI - Relationship of white matter network topology and cognitive outcome in adolescents with d-transposition of the great arteries. AB - Patients with congenital heart disease (CHD) are at risk for neurocognitive impairments. Little is known about the impact of CHD on the organization of large scale brain networks. We applied graph analysis techniques to diffusion tensor imaging (DTI) data obtained from 49 adolescents with dextro-transposition of the great arteries (d-TGA) repaired with the arterial switch operation in early infancy and 29 healthy referent adolescents. We examined whether differences in neurocognitive functioning were related to white matter network topology. We developed mediation models revealing the respective contributions of peri operative variables and network topology on cognitive outcome. Adolescents with d TGA had reduced global efficiency at a trend level (p = 0.061), increased modularity (p = 0.012), and increased small-worldness (p = 0.026) as compared to controls. Moreover, these network properties mediated neurocognitive differences between the d-TGA and referent adolescents across every domain assessed. Finally, structural network topology mediated the neuroprotective effect of longer duration of core cooling during reparative neonatal cardiac surgery, as well as the detrimental effects of prolonged hospitalization. Taken together, worse neurocognitive function in adolescents with d-TGA is mediated by global differences in white matter network topology, suggesting that disruption of this configuration of large-scale networks drives neurocognitive dysfunction. These data provide new insights into the interplay between perioperative factors, brain organization, and cognition in patients with complex CHD. PMID- 25685711 TI - Altered intrinsic functional coupling between core neurocognitive networks in Parkinson's disease. AB - Parkinson's disease (PD) is largely attributed to disruptions in the nigrostriatal dopamine system. These neurodegenerative changes may also have a more global effect on intrinsic brain organization at the cortical level. Functional brain connectivity between neurocognitive systems related to cognitive processing is critical for effective neural communication, and is disrupted across neurological disorders. Three core neurocognitive networks have been established as playing a critical role in the pathophysiology of many neurological disorders: the default-mode network (DMN), the salience network (SN), and the central executive network (CEN). In healthy adults, DMN-CEN interactions are anti-correlated while SN-CEN interactions are strongly positively correlated even at rest, when individuals are not engaging in any task. These intrinsic between-network interactions at rest are necessary for efficient suppression of the DMN and activation of the CEN during a range of cognitive tasks. To identify whether these network interactions are disrupted in individuals with PD, we used resting state functional magnetic resonance imaging (rsfMRI) to compare between-network connectivity between 24 PD participants and 20 age-matched controls (MC). In comparison to the MC, individuals with PD showed significantly less SN-CEN coupling and greater DMN-CEN coupling during rest. Disease severity, an index of striatal dysfunction, was related to reduced functional coupling between the striatum and SN. These results demonstrate that individuals with PD have a dysfunctional pattern of interaction between core neurocognitive networks compared to what is found in healthy individuals, and that interaction between the SN and the striatum is even more profoundly disrupted in those with greater disease severity. PMID- 25685712 TI - Longitudinal assessment of global and regional atrophy rates in Alzheimer's disease and dementia with Lewy bodies. AB - BACKGROUND & OBJECTIVE: Percent whole brain volume change (PBVC) measured from serial MRI scans is widely accepted as a sensitive marker of disease progression in Alzheimer's disease (AD). However, the utility of PBVC in the differential diagnosis of dementia remains to be established. We compared PBVC in AD and dementia with Lewy bodies (DLB), and investigated associations with clinical measures. METHODS: 72 participants (14 DLBs, 25 ADs, and 33 healthy controls (HCs)) underwent clinical assessment and 3 Tesla T1-weighted MRI at baseline and repeated at 12 months. We used FSL-SIENA to estimate PBVC for each subject. Voxelwise analyses and ANCOVA compared PBVC between DLB and AD, while correlational tests examined associations of PBVC with clinical measures. RESULTS: AD had significantly greater atrophy over 1 year (1.8%) compared to DLB (1.0%; p = 0.01) and HC (0.9%; p < 0.01) in widespread regions of the brain including periventricular areas. PBVC was not significantly different between DLB and HC (p = 0.95). There were no differences in cognitive decline between DLB and AD. In the combined dementia group (AD and DLB), younger age was associated with higher atrophy rates (r = 0.49, p < 0.01). CONCLUSIONS: AD showed a faster rate of global brain atrophy compared to DLB, which had similar rates of atrophy to HC. Among dementia subjects, younger age was associated with accelerated atrophy, reflecting more aggressive disease in younger people. PBVC could aid in differentiating between DLB and AD, however its utility as an outcome marker in DLB is limited. PMID- 25685713 TI - The relation of object naming and other visual speech production tasks: a large scale voxel-based morphometric study. AB - We report a lesion-symptom mapping analysis of visual speech production deficits in a large group (280) of stroke patients at the sub-acute stage (<120 days post stroke). Performance on object naming was evaluated alongside three other tests of visual speech production, namely sentence production to a picture, sentence reading and nonword reading. A principal component analysis was performed on all these tests' scores and revealed a 'shared' component that loaded across all the visual speech production tasks and a 'unique' component that isolated object naming from the other three tasks. Regions for the shared component were observed in the left fronto-temporal cortices, fusiform gyrus and bilateral visual cortices. Lesions in these regions linked to both poor object naming and impairment in general visual-speech production. On the other hand, the unique naming component was potentially associated with the bilateral anterior temporal poles, hippocampus and cerebellar areas. This is in line with the models proposing that object naming relies on a left-lateralised language dominant system that interacts with a bilateral anterior temporal network. Neuropsychological deficits in object naming can reflect both the increased demands specific to the task and the more general difficulties in language processing. PMID- 25685714 TI - White matter integrity and its association with affective and interpersonal symptoms in borderline personality disorder. AB - BACKGROUND: Borderline personality disorder (BPD) is a severe psychiatric disorder involving a range of symptoms including marked affective instability and disturbances in interpersonal interactions. Neuroimaging studies are beginning to provide evidence of altered processing in fronto-limbic network deficits in the disorder, however, few studies directly examine structural connections within this circuitry together with their relation to proposed causative processes and clinical features. METHODS: In the current study, we investigated whether individuals with BPD (n = 20) have deficits in white matter integrity compared to a matched group of healthy controls (n = 18) using diffusion tensor MRI (DTI). We hypothesized that the BPD group would have decreased fractional anisotropy (FA), a measure of white matter integrity, compared to the controls in white matter tracts connecting frontal and limbic regions, primarily the cingulum, fornix and uncinate fasciculus. We also investigated the extent to which any such deficits related to childhood adversity, as measured by the childhood trauma questionnaire, and symptom severity as measured by the Zanarini rating scale for BPD. RESULTS: We report decreased white matter integrity in BPD versus controls in the cingulum and fornix. There were no significant relationships between FA and measures of childhood trauma. There were, however, significant associations between FA in the cingulum and clinical symptoms of anger, and in the fornix with affective instability, and measures of avoidance of abandonment from the Zanarini rating scale. CONCLUSIONS: We report deficits within fronto-limbic connections in individuals with BPD. Abnormalities within the fornix and cingulum were related to severity of symptoms and highlight the importance of these tracts in the pathogenesis of the disorder. PMID- 25685716 TI - A49T, R227Q and TA repeat polymorphism of steroid 5 alpha-reductase type II gene and Hypospadias risk in North Indian children. AB - BACKGROUND/AIMS: Hypospadias is a common congenital error of genital development, the frequency of which is increasing. As androgens have a significant role in the development of the male urethra, we sought to investigate the association between functional polymorphisms of SRD5A2 gene in relation to hypospadias. METHODS: We examined DNA samples of 96 cases and 105 controls for SRD5A2-A49T, R227Q and TA repeat gene polymorphisms. RESULT: Absence of 49T locus and 227Q locus was observed in the present study. At the (TA) n repeat site, TA (0) allele was observed to be the most common allele in both cases (91.7%) and controls (90%). TA (9/9) genotype exhibited an odds ratio of 3.03 (95% C.I. = 0.18-50.14, p = 0) with respect to only middle phenotypes. Analysis of the demographic data depicted the agricultural background aspect of the parents of the cases. 72.27% of the cases (affected with Hypospadias) have parents having agriculture as a primary occupation. CONCLUSION: As longer TA repeats are associated with lower enzymatic activity and lower DHT levels as reported among Caucasians, this polymorphism may have an effect (rather small) in predisposing the population of the present study to the risk of Hypospadias of lesser severity. Due to small sample size, the 3.03 O.R. is not significant and a larger sample is needed to validate the results. Large scale screening of Hypospadias and other 46 X,Y disorders of sexual development is needed especially in India, where the majority of the population is from agricultural background. The results of the present study are likely to assist the health planners to initiate screening of Hypospadias among the farmer community to combat the risk of Hypospadias. PMID- 25685715 TI - White matter disruption at the prodromal stage of Alzheimer's disease: relationships with hippocampal atrophy and episodic memory performance. AB - White matter tract alterations have been consistently described in Alzheimer's disease (AD). In particular, limbic fronto-temporal connections, which are critical to episodic memory function, may degenerate early in the course of the disease. However the relation between white matter tract degeneration, hippocampal atrophy and episodic memory impairment at the earliest stages of AD is still unclear. In this magnetic resonance imaging study, white matter integrity and hippocampal volumes were evaluated in patients with amnestic mild cognitive impairment due to AD (Albert et al., 2011) (n = 22) and healthy controls (n = 15). Performance in various episodic memory tasks was also evaluated in each participant. Relative to controls, patients showed a significant reduction of white matter fractional anisotropy (FA) and increase of radial diffusivity (RD) in the bilateral uncinate fasciculus, parahippocampal cingulum and fornix. Within the patient group, significant intra-hemispheric correlations were notably found between hippocampal grey matter volume and FA in the uncinate fasciculus, suggesting a relationship between atrophy and disconnection of the hippocampus. Moreover, episodic recognition scores were related with uncinate fasciculus FA across patients. These results indicate that fronto-hippocampal connectivity is reduced from the earliest pre-demential stages of AD. Disruption of fronto-hippocampal connections may occur progressively, in parallel with hippocampal atrophy, and may specifically contribute to early initial impairment in episodic memory. PMID- 25685717 TI - Single tube tetraplex PCR based screening of a SNP at exon 14 region of bovine ITGB6 among different Zebu breeds. AB - The present study was aimed to screen genetic variation within a SNP (rs136500299) located at exon 14 region of bovine ITGB6 gene among different Zebu cattle breeds. The genotyping method describe in the present study is a tetraplex ARMS PCR, which offers extremely fast, economical, and simple detection tool. The distribution of the ITGB6 genotypes among the different breeds studied suggested that the populations were under Hardy-Weinberg equilibrium. Our findings revealed that TT genotypes are widely distributed among different Zebu cattle breeds, which can be associated with the resistance to FMD virus, as the Bos indicus are more resistant to FMD virus in comparison to Bos taurus. PMID- 25685718 TI - Modeling cardiac arrest and resuscitation in the domestic pig. AB - Cardiac arrest remains a leading cause of death and permanent disability worldwide. Although many victims are initially resuscitated, they often succumb to the extensive ischemia-reperfusion injury inflicted on the internal organs, especially the brain. Cardiac arrest initiates a complex cellular injury cascade encompassing reactive oxygen and nitrogen species, Ca(2+) overload, ATP depletion, pro- and anti-apoptotic proteins, mitochondrial dysfunction, and neuronal glutamate excitotoxity, which injures and kills cells, compromises function of internal organs and ignites a destructive systemic inflammatory response. The sheer complexity and scope of this cascade challenges the development of experimental models of and effective treatments for cardiac arrest. Many experimental animal preparations have been developed to decipher the mechanisms of damage to vital internal organs following cardiac arrest and cardiopulmonary resuscitation (CPR), and to develop treatments to interrupt the lethal injury cascades. Porcine models of cardiac arrest and resuscitation offer several important advantages over other species, and outcomes in this large animal are readily translated to the clinical setting. This review summarizes porcine cardiac arrest-CPR models reported in the literature, describes clinically relevant phenomena observed during cardiac arrest and resuscitation in pigs, and discusses numerous methodological considerations in modeling cardiac arrest/CPR. Collectively, published reports show the domestic pig to be a suitable large animal model of cardiac arrest which is responsive to CPR, defibrillatory countershocks and medications, and yields extensive information to foster advances in clinical treatment of cardiac arrest. PMID- 25685719 TI - Antibiotic stewardship programmes in intensive care units: Why, how, and where are they leading us. AB - Antibiotic usage and increasing antimicrobial resistance (AMR) mount significant challenges to patient safety and management of the critically ill on intensive care units (ICU). Antibiotic stewardship programmes (ASPs) aim to optimise appropriate antibiotic treatment whilst minimising antibiotic resistance. Different models of ASP in intensive care setting, include "standard" control of antibiotic prescribing such as "de-escalation strategies"through to interventional approaches utilising biomarker-guided antibiotic prescribing. A systematic review of outcomes related studies for ASPs in an ICU setting was conducted. Forty three studies were identified from MEDLINE between 1996 and 2014. Of 34 non-protocolised studies, [1 randomised control trial (RCT), 22 observational and 11 case series], 29 (85%) were positive with respect to one or more outcome: These were the key outcome of reduced antibiotic use, or ICU length of stay, antibiotic resistance, or prescribing cost burden. Limitations of non standard antibiotic initiation triggers, patient and antibiotic selection bias or baseline demographic variance were identified. All 9 protocolised studies were RCTs, of which 8 were procalcitonin (PCT) guided antibiotic stop/start interventions. Five studies addressed antibiotic escalation, 3 de-escalation and 1 addressed both. Six studies reported positive outcomes for reduced antibiotic use, ICU length of stay or antibiotic resistance. PCT based ASPs are effective as antibiotic-stop (de-escalation) triggers, but not as an escalation trigger alone. PCT has also been effective in reducing antibiotic usage without worsening morbidity or mortality in ventilator associated pulmonary infection. No study has demonstrated survival benefit of ASP. Ongoing challenges to infectious disease management, reported by the World Health Organisation global report 2014, are high AMR to newer antibiotics, and regional knowledge gaps in AMR surveillance. Improved AMR surveillance data, identifying core aspects of successful ASPs that are transferable, and further well-conducted trials will be necessary if ASPs are to be an effective platform for delivering desired patient outcomes and safety through best antibiotic policy. PMID- 25685720 TI - Diagnosis of deep vein thrombosis, and prevention of deep vein thrombosis recurrence and the post-thrombotic syndrome in the primary care medicine setting anno 2014. AB - The requirement for a safe diagnostic strategy of deep vein thrombosis (DVT) should be based on an overall objective post incidence of venous thromboembolism (VTE) of less than 1% during 3 mo follow-up. Compression ultrasonography (CUS) of the leg veins has a negative predictive value (NPV) of 97%-98% indicating the need of repeated CUS testing within one week. A negative ELISA VIDAS safely excludes DVT and VTE with a NPV between 99% and 100% at a low clinical score of zero. The combination of low clinical score and a less sensitive D-dimer test (Simplify) is not sensitive enough to exclude DVT and VTE in routine daily practice. From prospective clinical research studies it may be concluded that complete recanalization within 3 mo and no reflux is associated with a low or no risk of PTS obviating the need of MECS 6 mo after DVT. Partial and complete recanalization after 3 to more than 6 mo is usually complicated by reflux due to valve destruction and symptomatic PTS. Reflux seems to be a main determinant for PTS and DVT recurrence, the latter as a main contributing factor in worsening PTS. This hypothesis is supported by the relation between the persistent residual vein thrombosis (RVT = partial recanalization) and the risk of VTE recurrence in prospective studies. Absence of RVT at 3 mo post-DVT and no reflux is predicted to be associated with no recurrence of DVT (1.2%) during follow-up obviating the need of wearing medical elastic stockings and anticoagulation at 6 mo post-DVT. The presence or absence of RVT but with reflux at 3 to 6 mo post-DVT is associated with both symptomatic PTS and an increased risk of VTE recurrence in about one third in the post-DVT period after regular discontinuation of anticoagulant treatment. To test this hypothesis we designed a prospective DVT and postthrombotic syndrome (PTS) Bridging the Gap Study by addressing at least four unanswered questions in the treatment of DVT and PTS. Which DVT patient has a clear indication for long-term compression stocking therapy to prevent PTS after the initial anticoagulant treatment in the acute phase of DVT? Is 3 mo the appropriate point in time to determine candidates at risk to develop DVT recurrence and PTS? Which high risk symptomatic PTS patients need extended anticoagulant treatment? PMID- 25685721 TI - Treatment and prevention of gastrointestinal bleeding in patients receiving antiplatelet therapy. AB - Antiplatelet therapy is the standard of care for the secondary prevention of acute coronary syndrome and ischemic stroke, especially after coronary intervention. However, this therapy is associated with bleeding complications such as gastrointestinal bleeding, which is one of the most common life threatening complications. Early endoscopy is recommended for most patients with acute upper gastrointestinal bleeding. After successful endoscopic hemostasis, immediate resumption of antiplatelet therapy with proton-pump inhibitors (PPIs) is recommended to prevent further ischemic events. PPI prophylaxis during antiplatelet therapy reduces the risk of upper gastrointestinal bleeding. The potential negative metabolic interaction between PPIs and clopidogrel is still unclear. PMID- 25685722 TI - Noninvasive ventilation in trauma. AB - Trauma patients are a diverse population with heterogeneous needs for ventilatory support. This requirement depends mainly on the severity of their ventilatory dysfunction, degree of deterioration in gaseous exchange, any associated injuries, and the individual feasibility of potentially using a noninvasive ventilation approach. Noninvasive ventilation may reduce the need to intubate patients with trauma-related hypoxemia. It is well-known that these patients are at increased risk to develop hypoxemic respiratory failure which may or may not be associated with hypercapnia. Hypoxemia in these patients is due to ventilation perfusion mismatching and right to left shunt because of lung contusion, atelectasis, an inability to clear secretions as well as pneumothorax and/or hemothorax, all of which are common in trauma patients. Noninvasive ventilation has been tried in these patients in order to avoid the complications related to endotracheal intubation, mainly ventilator-associated pneumonia. The potential usefulness of noninvasive ventilation in the ventilatory management of trauma patients, though reported in various studies, has not been sufficiently investigated on a large scale. According to the British Thoracic Society guidelines, the indications and efficacy of noninvasive ventilation treatment in respiratory distress induced by trauma have thus far been inconsistent and merely received a low grade recommendation. In this review paper, we analyse and compare the results of various studies in which noninvasive ventilation was applied and discuss the role and efficacy of this ventilator modality in trauma. PMID- 25685723 TI - Checklist for early recognition and treatment of acute illness: International collaboration to improve critical care practice. AB - Processes to ensure world-wide best-practice for critical care delivery are likely to minimize preventable death, disability and costly complications for any healthcare system's sickest patients, but no large-scale efforts have so far been undertaken towards these goals. The advances in medical informatics and human factors engineering have provided possibility for novel and user-friendly clinical decision support tools that can be applied in a complex and busy hospital setting. To facilitate timely and accurate best-practice delivery in critically ill patients international group of intensive care unit (ICU) physicians and researchers developed a simple decision support tool: Checklist for Early Recognition and Treatment of Acute Illness (CERTAIN). The tool has been refined and tested in high fidelity simulated clinical environment and has been shown to improve performance of clinical providers faced with simulated emergencies. The aim of this international educational intervention is to implement CERTAIN into clinical practice in hospital settings with variable resources (included those in low income countries) and evaluate the impact of the tool on the care processes and patient outcomes. To accomplish our aims, CERTAIN will be uniformly available on either mobile or fixed computing devices (as well as a backup paper version) and applied in a standardized manner in the ICUs of diverse hospitals. To ensure the effectiveness of the proposed intervention, access to CERTAIN is coupled with structured training of bedside ICU providers. PMID- 25685724 TI - Has Stewart approach improved our ability to diagnose acid-base disorders in critically ill patients? AB - The Stewart approach-the application of basic physical-chemical principles of aqueous solutions to blood-is an appealing method for analyzing acid-base disorders. These principles mainly dictate that pH is determined by three independent variables, which change primarily and independently of one other. In blood plasma in vivo these variables are: (1) the PCO2; (2) the strong ion difference (SID)-the difference between the sums of all the strong (i.e., fully dissociated, chemically nonreacting) cations and all the strong anions; and (3) the nonvolatile weak acids (Atot). Accordingly, the pH and the bicarbonate levels (dependent variables) are only altered when one or more of the independent variables change. Moreover, the source of H(+) is the dissociation of water to maintain electroneutrality when the independent variables are modified. The basic principles of the Stewart approach in blood, however, have been challenged in different ways. First, the presumed independent variables are actually interdependent as occurs in situations such as: (1) the Hamburger effect (a chloride shift when CO2 is added to venous blood from the tissues); (2) the loss of Donnan equilibrium (a chloride shift from the interstitium to the intravascular compartment to balance the decrease of Atot secondary to capillary leak; and (3) the compensatory response to a primary disturbance in either independent variable. Second, the concept of water dissociation in response to changes in SID is controversial and lacks experimental evidence. In addition, the Stewart approach is not better than the conventional method for understanding acid-base disorders such as hyperchloremic metabolic acidosis secondary to a chloride-rich-fluid load. Finally, several attempts were performed to demonstrate the clinical superiority of the Stewart approach. These studies, however, have severe methodological drawbacks. In contrast, the largest study on this issue indicated the interchangeability of the Stewart and conventional methods. Although the introduction of the Stewart approach was a new insight into acid base physiology, the method has not significantly improved our ability to understand, diagnose, and treat acid-base alterations in critically ill patients. PMID- 25685725 TI - Serum bicarbonate may independently predict acute kidney injury in critically ill patients: An observational study. AB - AIM: To explore whether serum bicarbonate at admission to intensive care unit (ICU) predicted development of acute kidney injury (AKI). METHODS: We studied all patients admitted to our ICU over a 2 year period (February 2010 to 2012). The ICU has a case mix of medical and surgical patients excluding cardiac surgical, trauma and neurosurgical patients. We analysed 2035 consecutive patients admitted to ICU during the study period. Data were collected by two investigators independently and in duplicate using a standardised spread sheet to ensure accuracy. Ambiguous data were checked for accuracy where indicated. AKI was defined using the Kidney Disease Improving Global Outcomes criteria. Patients were divided into two groups; patients who developed AKI or those who did not, in order to compare the baseline characteristics, and laboratory and physiologic data of the two cohorts. Regression analysis was used to identify if serum bicarbonate on admission predicted the development of AKI. RESULTS: Of 2036 patients 152 (7.5%) were excluded due to missing data. AKI developed in 43.1% of the patients. The AKI group, compared to the non-AKI group, was sicker based on their lower systolic, diastolic and mean arterial pressures and a higher acute physiology and chronic health evaluation (APACHE) III and SAPS II scores. Moreover, patients who developed AKI had more co-morbidities and a higher proportion of patients who developed AKI required mechanical ventilation. The multi-regression analysis of independent variables showed that serum bicarbonate on admission (OR = 0.821; 95%CI: 0.796-0.846; P < 0.0001), APACHE III (OR = 1.011; 95%CI: 1.007-1.015; P < 0.0001), age (OR = 1.016; 95%CI: 1.008-1.024; P < 0.0001) and presence of sepsis at ICU admission (OR = 2.819; 95%CI: 2.122-23.744; P = 0.004) were each significant independent predictors of AKI. The area under the ROC curve was 0.8 (95%CI: 0.78-0.83), thereby demonstrating that the predictive model has relatively good discriminating power for predicting AKI. CONCLUSION: Serum bicarbonate on admission may independently be used to make a diagnosis of AKI. PMID- 25685726 TI - Utility of flexible fiberoptic bronchoscopy for critically ill pediatric patients: A systematic review. AB - AIM: To investigate the diagnostic yield, therapeutic efficacy, and rate of adverse events related to flexible fiberoptic bronchoscopy (FFB) in critically ill children. METHODS: We searched PubMed, SCOPUS, OVID, and EMBASE databases through July 2014 for English language publications studying FFB performed in the intensive care unit in children < 18 years old. We identified 666 studies, of which 89 full-text studies were screened for further review. Two reviewers independently determined that 27 of these studies met inclusion criteria and extracted data. We examined the diagnostic yield of FFB among upper and lower airway evaluations, as well as the utility of bronchoalveolar lavage (BAL). RESULTS: We found that FFB led to a change in medical management in 28.9% (range 21.9%-69.2%) of critically ill children. The diagnostic yield of FFB was 82% (range 45.2%-100%). Infectious organisms were identified in 25.7% (17.6%-75%) of BALs performed, resulting in a change of antimicrobial management in 19.1% (range: 12.2%-75%). FFB successfully re-expanded atelectasis or removed mucus plugs in 60.3% (range: 23.8%-100%) of patients with atelectasis. Adverse events were reported in 12.9% (range: 0.5%-71.4%) of patients. The most common adverse effects of FFB were transient hypotension, hypoxia and/or bradycardia that resolved with minimal intervention, such as oxygen supplementation or removal of the bronchoscope. Serious adverse events were uncommon; 2.1% of adverse events required intervention such as bag-mask ventilation or intubation and atropine for hypoxia and bradycardia, normal saline boluses for hypotension, or lavage and suctioning for hemorrhage. CONCLUSION: FFB is safe and effective for diagnostic and therapeutic use in critically ill pediatric patients. PMID- 25685727 TI - Thoracic epidural anesthesia: Effects on splanchnic circulation and implications in Anesthesia and Intensive care. AB - AIM: To evaluate the currently available evidence on thoracic epidural anesthesia effects on splanchnic macro and microcirculation, in physiologic and pathologic conditions. METHODS: A PubMed search was conducted using the MeSH database. Anesthesia, Epidural was always the first MeSH heading and was combined by boolean operator AND with the following headings: Circulation, Splanchnic; Intestines; Pancreas and Pancreatitis; Liver Function Tests. EMBASE, Cochrane library, ClinicalTrials.gov and clinicaltrialsregister.eu were also searched using the same terms. RESULTS: Twenty-seven relevant studies and four ongoing trials were found. The data regarding the effects of epidural anesthesia on splanchnic perfusion are conflicting. The studies focusing on regional macro hemodynamics in healthy animals and humans undergoing elective surgery, demonstrated no influence or worsening of regional perfusion in patients receiving thoracic epidural anesthesia (TEA). On the other hand most of the studies focusing on micro-hemodynamics, especially in pathologic low flow conditions, suggested that TEA could foster microcirculation. CONCLUSION: The available studies in this field are heterogeneous and the results conflicting, thus it is difficult to draw decisive conclusions. However there is increasing evidence deriving from animal studies, that thoracic epidural blockade could have an important role in modifying tissue microperfusion and protecting microcirculatory weak units from ischemic damage, regardless of the effects on macro-hemodynamics. PMID- 25685728 TI - Overcoming access barriers to health services through membership-based microfinance organizations: a review of evidence from South Asia. AB - It is a challenge for the poor to overcome the barriers to accessing health services. Membership-based microfinance with associated health programmes can improve health outcomes for the poor. This study reviewed the evidence published between 1993 and 2013 on the role of membership-based microfinance with associated health programmes in improving health outcomes for the poor in South Asia. A total of 661 papers were identified and 26 selected for inclusion, based on the relevance and rigour of the research methods. Of these 26, five were evidence reviews. Of the remaining 21 papers, 12 were from India, seven from Bangladesh, and one each from Sri Lanka and Indonesia. Three papers addressed more than one theme. Five key themes emerged from the review: (i) the impact of microfinance programmes on the social and economic situation of the poor; (ii) the impact of microfinance programmes on community health; (iii) the impact of integrated microfinance health programmes on raising client awareness; (iv) the impact of integrated microfinance health programmes on financing health care; and (v) the impact of integrated microfinance health programmes on affordable health care products and services. The review provides new evidence on the pathways through which microfinance helps to improve population health and value for money for such programmes. Among countries with large populations in the informal sector, there is a strong case for policy-makers to support these groups in providing access to life-saving health care among the poor. PMID- 25685729 TI - Lycopene as a carotenoid provides radioprotectant and antioxidant effects by quenching radiation-induced free radical singlet oxygen: an overview. AB - Radio-protectors are agents that protect human cells and tissues from undesirable effects of ionizing radiation by mainly scavenging radiation-induced free radicals. Although chemical radio-protectors diminish these deleterious side effects they induce a number of unwanted effects on humans such as blood pressure modifications, vomiting, nausea, and both local and generalized cutaneous reactions. These disadvantages have led to emphasis on the use of some botanical radio-protectants as alternatives. This review has collected and organized studies on a plant-derived radio-protector, lycopene. Lycopene protects normal tissues and cells by scavenging free radicals. Therefore, treatment of cells with lycopene prior to exposure to an oxidative stress, oxidative molecules or ionizing radiation may be an effective approach in diminishing undesirable effects of radiation byproducts. Studies have designated lycopene to be an effective radio-protector with negligible side effects. PMID- 25685730 TI - An overview of the available methods for morphological scoring of pre implantation embryos in in vitro fertilization. AB - Assessment of embryo quality in order to choose the embryos that most likely result in pregnancy is the critical goal in assisted reproductive technologies (ART). The current trend in human in vitro fertilization/embryo transfer (IVF/ET) protocols is to decrease the rate of multiple pregnancies after multiple embryo transfer with maintaining the pregnancy rate at admissible levels (according to laboratory standards). Assessment of morphological feathers as a reliable non invasive method that provides valuable information in prediction of IVF/intra cytoplasmic sperm injection (ICSI) outcome has been frequently proposed in recent years. This article describes the current status of morphological embryo evaluation at different pre-implantation stages. PMID- 25685731 TI - Isolation and enrichment of mouse female germ line stem cells. AB - OBJECTIVE: The existence of female germ-line stem cells (FGSCs) has been the subject of a wide range of recent studies. Successful isolation and culture of FGSCs could facilitate studies on regenerative medicine and infertility treatments in the near future. Our aim in the present study was evaluation of the most commonly used techniques in enrichment of FGSCs and in establishment of the best procedure. MATERIALS AND METHODS: In this experimental study, after digesting neonate ovary from C57Bl/6 mice, we performed 2 different isolation experiments: magnetic activated cell sorting (MACS) and pre-plating. MACS was applied using two different antibodies against mouse vasa homolog (MVH) and stage specific embryonic antigen-1 (SSEA1) markers. After the cells were passaged and proliferated in vitro, colony-forming cells were characterized using reverse transcription-polymerase chain reaction (RT-PCR) (for analysis of expression of Oct4, Nanog, C-kit, Fragilis, Mvh, Dazl, Scp3 and Zp3), alkaline phosphatase (AP) activity test and immunocytochemistry. RESULTS: Data showed that colonies can be seen more frequently in pre-plating technique than that in MACS. Using the SSEA1 antibody with MACS, 1.98 +/- 0.49% (Mean +/- SDV) positive cells were yield as compared to the total cells sorted. The colonies formed after pre-plating expressed pluripotency and germ stem cell markers (Oct4, Nanog, C-kit, Fragilis, Mvh and Dazl) whereas did not express Zp3 and Scp3 at the mRNA level. Immunocytochemistry in these colonies further confirmed the presence of OCT4 and MVH proteins, and AP activity measured by AP-kit showed positive reaction. CONCLUSION: We established a simple and an efficient pre-plating technique to culture and to enrich FGSCs from neonatal mouse ovaries. PMID- 25685732 TI - Comparing The Effects of Small Molecules BIX-01294, Bay K8644, RG-108 and Valproic Acid, and Their Different Combinations on Induction of Pluripotency Marker-Genes by Oct4 in The Mouse Brain. AB - OBJECTIVE: Every cell type is characterized by a specific transcriptional profile together with a unique epigenetic landscape. Reprogramming factors such as Oct4, Klf4, Sox2 and c-Myc enable somatic cells to change their transcriptional profile and convert them to pluripotent cells. Small molecules such as BIX-01294, Bay K8644, RG-108 and valproic acid (VPA) are reported as effective molecules for enhancing induction of pluripotency in vitro, however, their effects during in vivo reprogramming are addressed in this experimental study. MATERIALS AND METHODS: In this experimental study, Oct4 expressing lentiviral particles and small molecules BIX-01294, Bay K8644 and RG-108 were injected into the right ventricle of mice brain and VPA was systematically administered as oral gavages. Animals treated with different combinations of small molecules for 7 or 14 days in concomitant with Oct4 exogenous expression were compared for expression of pluripotency markers. Total RNA was isolated from the rims of the injected ventricle and quantitative polymerase chain reaction (PCR) was performed to evaluate the expression of endogenous Oct4, Nanog, c-Myc, klf4 and Sox2 as pluripotency markers, and Pax6 and Sox1 as neural stem cell (NSC) markers. RESULTS: Results showed that Oct4 exogenous expression for 7 days induced pluripoten- cy slightly as it was detected by significant enhancement in expression of Nanog (p<0.05). Combinatorial administration of Oct4 expressing vector and BIX-01294, Bay K8644 and RG-108 did not affect the expression of pluripotency and NSC markers, but VPA treatment along with Oct4 exogenous expression induced Nanog, Klf4 and c-Myc (p<0.001). VPA treatment before the induction of exogenous Oct4 was more effective and significantly increased the expression of endogenous Oct4, Nanog, Klf4, c-Myc (p<0.01), Pax6 and Sox1 (p<0.001). CONCLUSION: These results suggest VPA as the best enhancer of pluripotency among the chemicals tested, especially when applied prior to pluripotency induction by Oct4. PMID- 25685733 TI - Differentiation potential of o bombay human-induced pluripotent stem cells and human embryonic stem cells into fetal erythroid-like cells. AB - OBJECTIVE: There is constant difficulty in obtaining adequate supplies of blood components, as well as disappointing performance of "universal" red blood cells. Advances in somatic cell reprogramming of human-induced pluripotent stem cells (hiPSCs) have provided a valuable alternative source to differentiate into any desired cell type as a therapeutic promise to cure many human disease. MATERIALS AND METHODS: In this experimental study, we examined the erythroid differentiation potential of normal Bombay hiPSCs (B-hiPSCs) and compared results to human embryonic stem cell (hESC) lines. Because of lacking ABO blood group expression in B-hiPSCs, it has been highlighted as a valuable source to produce any cell type in vitro. RESULTS: Similar to hESC lines, hemangioblasts derived from B-hiPSCs expressed approximately 9% KDR(+)CD31(+) and approximately 5% CD31(+)CD34(+). In semisolid media, iPSC and hESC-derived hemangioblast formed mixed type of hematopoietic colony. In mixed colonies, erythroid progenitors were capable to express CD71(+)GPA(+)HbF(+) and accompanied by endothelial cells differentiation. CONCLUSION: Finally, iPS and ES cells have been directly induced to erythropoiesis without hemangioblast formation that produced CD71(+)HbF(+) erythroid cells. Although we observed some variations in the efficiency of hematopoietic differentiation between iPSC and ES cells, the pattern of differentiation was similar among all three tested lines. PMID- 25685734 TI - SDF-1alpha/CXCR4 Axis Mediates The Migration of Mesenchymal Stem Cells to The Hypoxic-Ischemic Brain Lesion in A Rat Model. AB - OBJECTIVE: Transplantation of mesenchymal stem cells (MSCs) can promote functional recovery of the brain after hypoxic-ischemic brain damage (HIBD). However, the mechanism regulating MSC migration to a hypoxic-ischemic lesion is poorly understood. Interaction between stromal cell-derived factor-1alpha (SDF 1alpha) and its cognate receptor CXC chemokine receptor 4 (CXCR4) is crucial for homing and migration of multiple stem cell types. In this study, we investigate the potential role of SDF-1alpha/CXCR4 axis in mediating MSC migration in an HIBD model. MATERIALS AND METHODS: In this experimental study, we first established the animal model of HIBD using the neonatal rat. Bone marrow MSCs were cultured and labeled with 5-bromo-21-deoxyuridine (BrdU) after which 6*10(6) cells were intravenously injected into the rat. BrdU positive MSCs in the hippocampus were detected by immunohistochemical analyses. The expression of hypoxia-inducible factor-1alpha (HIF-1alpha) and SDF-1alpha in the hippocampus of hypoxic-ischemic rats was detected by Western blotting. To investigate the role of hypoxia and SDF 1alpha on migration of MSCs in vitro, MSCs isolated from normal rats were cultured in a hypoxic environment (PO2=1%). Migration of MSCs was detected by the transwell assay. The expression of CXCR4 was tested using Western blotting and flow cytometry. RESULTS: BrdU-labeled MSCs were found in the rat brain, which suggested that transplanted MSCs migrated to the site of the hypoxic-ischemic brain tissue. HIF-1alpha and SDF-1alpha significantly increased in the hippocampal formations of HIBD rats in a time-dependent manner. They peaked on day 7 and were stably expressed until day 21. Migration of MSCs in vitro was promoted by SDF-1alpha under hypoxia and inhibited by the CXCR4 inhibitor AMD3100. The expression of CXCR4 on MSCs was elevated by hypoxia stimulation as well as microdosage treatment of SDF-1alpha. CONCLUSION: This observation illustrates that SDF-1alpha/CXCR4 axis mediate the migration of MSCs to a hypoxic ischemic brain lesion in a rat model. PMID- 25685735 TI - Neuroplasticity Changes of Rat Brain by Musical Stimuli during Fetal Period. AB - OBJECTIVE: Fetal development of the central nervous system is an important and sensitive stage which is affected by many external and internal stimuli. This study aimed to investigate effect of musical stimuli on fetal rat brain. MATERIALS AND METHODS: In this experimental study, twelve female Wistar rats were selected and evenly assigned to control and musical groups. The females were mated with a male rat of the same genotype. Musical group was exposed to classic music with 60 dB power for 90 minutes twice per day from 2(nd) to 20(th) day of gestation. The control rats were handled similar to the musical group, but were not exposed to music. Before parturition, all the dams were anesthetized, and their blood samples were obtained and used for corticosterone (COS) measurement. They were transcardially perfused by electron microscope (EM) fixative agent. The fetal brains were extracted intact and used for slice preparation. Horizontal slices were made for electron microscope preparation, and images were taken and analyzed in terms of cell density and morphological changes. RESULTS: EM observation indicated significant morphological difference in cellular and intercellular spaces between the two groups. Music-treated fetuses had significantly higher cell density in parietal cortex and music-treated dams had lower COS level. CONCLUSION: It was concluded that prenatal music would have a great impact on neuroplasticity of fetal rat brain, at least indirectly. Although the rat fetuses cannot hear until birth, music-induced reduction in COS blood level of dams might be the reason for neuroplasticity of fetal brain. PMID- 25685736 TI - Equine adipose-derived mesenchymal stem cells: phenotype and growth characteristics, gene expression profile and differentiation potentials. AB - OBJECTIVE: Because of the therapeutic application of stem cells (SCs), isolation and characterization of different types of SCs, especially mesenchymal stem cells (MSCs), have gained considerable attention in recent studies. Adipose tissue is an abundant and accessible source of MSCs which can be used for tissue engineering and in particular for treatment of musculoskeletal disorders. This study was aimed to isolate and culture equine adipose-derived MSCs (AT-MSCs) from little amounts of fat tissue samples and determine some of their biological characteristics. MATERIALS AND METHODS: In this descriptive study, only 3-5 grams of fat tissue were collected from three crossbred mares. Immediately, cells were isolated by mechanical means and enzymatic digestion and were cultured in optimized conditions until passage 3 (P3). The cells at P3 were evaluated for proliferative capacities, expression of specific markers, and osteogenic, chondrogenic and adipogenic differentiation potentials. RESULTS: Results showed that the isolated cells were plastic adherent with a fibroblast-like phenotype. AT-MSCs exhibited expression of mesenchymal cluster of differentiation (CD) markers (CD29, CD44 and CD90) and not major histocompatibility complex II (MHC II) and CD34 (hematopoietic marker). Cellular differentiation assays demonstrated the chondrogenic, adipogenic and osteogenic potential of the isolated cells. CONCLUSION: Taken together, our findings reveal that equine MSCs can be obtained easily from little amounts of fat tissue which can be used in the future for regenerative purposes in veterinary medicine. PMID- 25685737 TI - DNA Methylation and Histone Acetylation Patterns in Cultured Bovine Adipose Tissue-Derived Stem Cells (BADSCs). AB - OBJECTIVE: Many studies have focused on the epigenetic characteristics of donor cells to improve somatic cell nuclear transfer (SCNT). We hypothesized that the epigenetic status and chromatin structure of undifferentiated bovine adipose tissue-derived stem cells (BADSCs) would not remain constant during different passages. The objective of this study was to determine the mRNA expression patterns of DNA methyltransferases (DNMT1, DNMT3a, DNMT3b) and histone deacetyltransferses (HDAC1, HDAC2, HDAC3) in BADSCs. In addition, we compared the measured levels of octamer binding protein-4 expression (OCT4) and acetylation of H3K9 (H3K9ac) in BADSCs cultures and different passages in vitro. MATERIALS AND METHODS: In this experimental study, subcutaneous fat was obtained from adult cows immediately post-mortem. Relative level of DNMTs and HDACs was examined using quantitative real time polymerase chain reaction (q-PCR), and the level of OCT4 and H3K9ac was analyzed by flow cytometry at passages 3 (P3), 5 (P5) and 7 (P7). RESULTS: The OCT4 protein level was similar at P3 and P5 but a significant decrease in its level was seen at P7. The highest and lowest levels of H3K9ac were observed at P5 and P7, respectively. At P5, the expression of HDACs and DNMTs was significantly decreased. In contrast, a remarkable increase in the expression of DNMTs was observed at P7. CONCLUSION: Our data demonstrated that the epigenetic status of BADSCs was variable during culture. The P5 cells showed the highest level of stemness and multipotency and the lowest level of chromatin compaction. Therefore, we suggest that P5 cells may be more efficient for SCNT compared with other passages. PMID- 25685738 TI - Fabrication and characterization of spongy denuded amniotic membrane based scaffold for tissue engineering. AB - OBJECTIVE: As a biological tissue material, amniotic membrane (AM) has low immunogenicity and to date has been widely adopted in clinical practice. However, some features such as low biomechanical consistency and rapid biodegradation is limited the application of AM. Therefore, in this study, we fabricated a novel three-dimensional (3D) spongy scaffold made of the extracellular matrix (ECM) of denuded AM. Due to their unique characteristics which are similar to the skin, these scaffolds can be considered as an alternative option in skin tissue engineering. MATERIALS AND METHODS: In this experimental study, cellular components of human amniotic membrane (HAM) were removed with 0.03% (w/v) sodium dodecyl sulphate (SDS). Quantitative analysis was performed to determine levels of Glycosaminoglycans (GAGs), collagen, and deoxyribonucleic acid (DNA). To increase the low efficiency and purity of the ECM component, especially collagen and GAG, we applied an acid solubilization procedure hydrochloridric acid (HCl 0.1 M) with pepsin (1 mg/ml). In the present experiment 1-ethyl-3-(3-dimethyl aminopropyl) carbodiimide hydrochloride (EDC)/N-hydroxysuccinimide (NHS) cross linker agent was used to improve the mechanical properties of 3D lyophilized AM scaffold. The spongy 3D AM scaffolds were specified, by scanning electron microscopy, hematoxylin and eosin (H&E) staining, a swelling test, and mechanical strength and in vitro biodegradation tests. Human fetal fibroblast culture systems were used to establish that the scaffolds were cytocompatible. RESULTS: Histological analysis of treated human AM showed impressive removal of cellular components. DNA content was diminished after treatment (39 +/- 4.06 MUg/ml vs. 341 +/- 29.60 MUg/ml). Differences were observed between cellular and denude AM in matrix collagen (478 +/- 18.06 MUg/mg vs. 361 +/- 27.47 MUg/mg).With the optimum concentration of 1 mM NHS/EDC ratio1:4, chemical cross-linker agent could significantly increase the mechanical property, and resistance to collagenase digestion. The results of 2, 4, 6-Trinitrobenzenesulfonic acid (TNBS) test showed that cross-linking efficiency of AM derived ECM scaffolds was about 65% +/- 10.53. Scaffolds treated with NHS/EDC cross-linker agent by 100 MUg/ml collagenase, lost 75% of their dry weight after 14 days. The average pore size of 3D spongy scaffold was 160 um measured from scanning electron microscope (SEM) images that it is suitable for cell penetration, nutrients and gas change. In addition, the NHS/ EDC cross-linked AM scaffolds were able to support human fetal fibroblast cell proliferation in vitro. Extracts and contact prepared from the 3D spongy scaffold of AM showed a significant increase in the attachment and proliferation of the human fetal fibroblasts cells. CONCLUSION: The extra cellular matrix of denuded AM-based scaffold displays the main properties required for substitute skin including natural in vitro biodegradation, similar physical and mechanical characterization, nontoxic biomaterial and no toxic effect on cell attachment and cell proliferation. PMID- 25685739 TI - Androgen Stimulation of PCA3 and miR-141 and Their Release from Prostate Cancer Cells. AB - OBJECTIVE: Prostate cancer antigen 3 (PCA3) and microRNA-141 (miR-141) are emerging molecules in prostate cancer (PCa) pathogenesis and have been shown to be involved in androgen signaling. In this original research, we designed an experimental cell model with androgen-sensitive LNCaP cells to comparatively assess the extent of androgen responsiveness of PCA3-mRNA and miR-141 along with prostate specific antigen (PSA)mRNA and their release into culture medium. These molecules were also measured in the plasma of the patients with early PCa which is considered to be analogous to androgenresponsive cells. MATERIALS AND METHODS: In this experimental study, LNCaP cells were exposed to androgen ablation for 48 hours and treated then with dihydrotestosterone (DHT) for 24 hours. Expression of all three RNA molecules in cells, culture medium or plasma was measured by quantitative polymerase chain reaction (qPCR). RESULTS: Our results show that DHT differentially affects the expression of these molecules. PCA3 was the most evidently induced molecule (up to 400-fold, p<0.001), while the effect was moderate for PSA-mRNA (up to 30-fold, p<0.001). In contrast, the stimulation of miR-141 was much weaker (up to 1.5-fold, p>0.05). With regard to the release into culture medium, a similar picture was observed except for PCA3. PCA3 was below the detection level despite its high stimulation. DHT treatment led to a significant release of PSA-mRNA (up to 12-fold). Similar to its induction pattern in LNCaP cells, miR-141 was released at a limited quantity into the medium (up to 1.7- fold, p=0.07). In plasma, only PCA3 differed significantly between the patients and healthy subjects (p=0.001). CONCLUSION: Our findings indicate that PCa-related RNA molecules respond differentially to androgen stimulation suggesting differential regulation by androgens. PMID- 25685740 TI - Enrichment of A Rare Subpopulation of miR-302-Expressing Glioma Cells by Serum Deprivation. AB - OBJECTIVE: MiR-302-367 is a cluster of polycistronic microRNAs that are exclusively expressed in embryonic stem (ES) cells. The miR-302-367 promoter is functional during embryonic development but is turned off in later stages. Motivated by the cancer stem cell hypothesis, we explored the potential expression of miR-302 in brain tumor cell lines. MATERIALS AND METHODS: In the present experimental study, we have tried to expand our knowledge on the expression pattern and functionality of miR302 cluster by quantifying its expression in a series of glioma (A-172, 1321N1, U87MG) and medulloblastoma (DAOY) cell lines. To further assess the functionality of miR-302 in these cell lines, we cloned its promoter core region upstream of the enhanced green fluorescent protein (EGFP) or luciferase encoding genes. RESULTS: Our data demonstrated a very low expression of miR-302 in glioma cell lines, compared with that of embryonal carcinoma cell line NT2 being used as a positive control. The expression of miR-302 promoter-EGFP construct in the aforementioned cell lines demonstrated GFP expression in a rare subpopulation of the cells. Serum deprivation led to the generation of tumorospheres, enrichment of miR-302 positive cells and upregulation of a number of pluripotency genes. CONCLUSION: Taken together, our data suggest that miR-302 could potentially be used as a novel putative cancer stem cell marker to identify and target cancer stem cells within tumor tissues. PMID- 25685741 TI - Association of CD58 Polymorphism with Multiple Sclerosis and Response to Interferon beta Therapy in A Subset of Iranian Population. AB - OBJECTIVE: Multiple sclerosis (MS) is one of the leading neurodegenerative causes of physical disability world-wide. Genetic aberrations of autoimmunity pathway components have been demonstrated to significantly influence MS development. Cluster of Differentiation 58 (CD58) is pertained to a group of genes which had been assayed in several recent association studies. Given the significance of CD58 in modulation of T regulatory cells that control autoimmune responses, the present study was conducted to investigate the frequency of rs12044852 polymorphism and its effect on the outcome of interferon beta (IFN-beta) therapy in a subset of Iranian MS patients. MATERIALS AND METHODS: Two hundred MS patients and equal number of healthy controls were recruited to be genotyped in an experimental case-control based study through polymerase chain reaction using specific sequence primers (PCR-SSP). Relapsing remitting multiple sclerosis (RRMS) patients administered IFN-beta therapy were followed up with clinical visits every three months up to two years. The mean of multiple sclerosis severity score (MSSS) and expanded disability status scale (EDSS) were measured to monitor the change in severity of MS in response to IFN-beta therapy. Pearson's Chi-square and analysis of variance (ANOVA) tests were the main statistical methods used in this study. RESULTS: Strong association was found between the CC genotype and onset of MS (p=0.001, OR=2.22). However, there was no association between rs12044852 and various classifications and severity of MS. Pharmacogenetics-based analysis indicated that carriers of CC genotype had the highest MSSS score compared to others, implying a negative impact of rs12044852 on response to IFN-beta therapy. CONCLUSION: Taken together, our findings revealed the critical effect of rs12044852 polymorphism of CD58 on the progression of MS disease. This indicates that genotyping of MS patients may expedite achieving personalized medical management of MS patients. PMID- 25685742 TI - Effect of nanocrystalline hydroxyapatite socket preservation on orthodontically induced inflammatory root resorption. AB - OBJECTIVE: Orthodontically induced inflammatory root resorption (OIIRR) is considered to be an important sequel associated with orthodontic tooth movement (OTM). OTM after Socket preservation enhances the periodontal condition before orthodontic space closure. The purpose of this study is to investigate the histologic effects of NanoBone(r), a new highly nonsintered porous nano crystalline hydroxyapatite bone on root resorption following OTM. MATERIALS AND METHODS: This experimental study was conducted on four male dogs. In each dog, four defects were created at the mesial aspects of the maxillary and mandibular first premolars. The defects were filled with NanoBone(r). We used the NiTi closed coil for mesial movement of the first premolar tooth. When the experimental teeth moved approximately halfway into the defects, after two months, the animals were sacrificed and we harvested the area of interest. The first premolar root and adjacent tissues were histologically evaluated. The three way ANOVA statistical test was used for comparison. RESULTS: The mean root resorption in the synthetic bone substitute group was 22.87 +/- 11.25*10(-4)mm(2) in the maxilla and 21.41 +/- 11.25*10(-4)mm(2) in the mandible. Statistically, there was no significant difference compared to the control group (p>0.05). CONCLUSION: The use of a substitution graft in the nano particle has some positive effects in accessing healthy periodontal tissue following orthodontic procedures without significant influence on root resorption (RR). Histological evaluation in the present study showed osteoblastic activity and remodeling environment of nanoparticles in NanoBone(r). PMID- 25685743 TI - Effect of Interleukin-29 on Interferon-alpha Secretion by Peripheral Blood Mononuclear Cells. AB - OBJECTIVE: The effect of interleukin (IL)-29, a new therapeutic agent similar to type I interferons (IFNs), on IFN-alpha secretion of human plasmacytoid dendritic cells (pDCs) has not been studied. Therefore, in this study, we aimed to clarify the effect of IL-29 on IFN-alpha secretion of pDCs using human peripheral blood mononuclear cells (PBMCs) in the presence of cytosine-phosphate-guanosinemotif containing oligodeoxy nucleotides (CpG). MATERIALS AND METHODS: In this experimental and prospective study, PBMCs were ob- tained from 11 healthy volunteers and divided into four culture conditions: I. control, II. CpG treatment, III. IL-29 treatment and IV. CpG plus IL-29 treatment. The amount of IFN-alpha secretion was measured from each culture supernatant by flow cytometry using the flowcytomix apparatus (eBioscience, Vienna, Austria). Fractional IFN alpha production of the cultured PBMCs was measured by intracellular staining using the cytomics FC 500 system (Beckman Coulter, Brea, CA, USA) with CXP Software. RESULTS: The mean +/- standard deviation (SD) of supernatant IFN-alpha secretion per pDC/MUL was 5.7 +/- 9.3 pg/mL/count/uL for condition I, 1071.5 +/- 1026.6 pg/mL/count/uL for condition II, 14.1 +/- 21.1 pg/mL/count/uL for condition III, and 1913.9 +/- 1525.9 pg/mL/count/uL for condition IV. There were statistically significant differences between conditions I and II as well as betweenconditions II and IV. Intracellular IFN-alpha production was only detectable in the pDC fraction from one culture; the production amount was similar between the cells treated with CpG and those treated with CpG plus IL-29. Natural killer (NK) cell production of IFN-alpha was observed in two out of three cultures and one culture showed IFN- alpha production in the monocyte fraction. CONCLUSION: IL-29 alone did not show any effect on IFN-alpha secretion of PBMCs. However, the addition of CpG along with IL-29 enhanced IFN-alpha secretion of PBMCs. Given that pDCs are the major secretors of IFN-alpha in peripheral blood, this result has suggested the possibility that IL-29 has an enhancing effect in human pDC IFN-alpha secretion. Although the supernatant IFN-alpha secretion was not directly correlated with pDCs's intracellular IFN-alpha production in this study, prolonged incubation of pDC and other PB subsets with CpG or IL-29 for over 4 hours could be applied in future studies. These studies would help to elucidate the mechanism of action of IL-29 in human pDCs associated with viral infections. PMID- 25685744 TI - Gene expression analysis of VEGF and its receptors and assessment of its serum level in unexplained recurrent spontaneous abortion. AB - OBJECTIVE: Unexplained recurrent spontaneous abortion (URSA) is one of the main complications of pregnancy which is usually defined as three or more consecutive pregnancy losses before the 20(th) week of gestation without a known cause. Vascular endothelial growth factor (VEGF) is a potent angiogenic factor and shown, along with its receptors (VEGFR1, 2), to play important roles in several physiologic processes including reproduction. The aim of the present study was to analyze gene expression of VEGF and VEGF receptors in endometrium of patients with a history of URSA compared with normal fertile women. In addition, serum VEGF concentration was assessed and compared between the two groups at the same time. MATERIALS AND METHODS: In this case control study, endometrial and blood samples were obtained between day 19(th)and 24(th) of menstrual cycle (window of implantation) from 10 women with a history of URSA (case group) and 6 fertile women who had at least one successful pregnancy (control group). Expression of VEGF and VEGFRs was studied by reverse transcription- polymerase chain reaction (RT-PCR) and then quantified by real time PCR. Normalization of expression levels was done by comparison with beta-actin expression level as an internal control. Relative VEGF, VEGFR1 and VEGFR2 expression quantities were compared between the two groups. Enzyme linked immunosorbent assay (ELISA) was used for serum VEGF assay. RESULTS: VEGF, VEGFR1 and VEGFR2 gene expression was detected in endometrial samples of both groups. The mean relative expression of VEGF gene was lower in the case group compared with control women, however, both VEGF receptors were expressed higher in endometrium of the case group. In addition, the serum level of VEGF was significantly higher in the case group compared with the controls. CONCLUSION: Alteration in gene expression of VEGF and its receptors in endometrium and changes of serum VEGF might play important roles in pathogenesis of unexplained RSA. PMID- 25685745 TI - Development of mouse preantral follicle after in vitro culture in a medium containing melatonin. AB - OBJECTIVE: Improvements in cancer treatment have allowed more young women to survive. However, many cancer patients suffer from ovarian failure. Cryopreservation is one of the solutions for fertility restoration in these patients. The cryopreservation of isolated follicles is a more attractive approach in the long term. Many endocrine and paracrine factors can stimulate the granulosa cells of preantral follicles to proliferate. Melatonin acts as direct free radical scavenger and indirect antioxidant. In this study, we investigated the direct effects of melatonin on follicle development and oocyte maturation by exposing in vitro cultured mouse vitrified-warmed ovarian follicles to melatonin. MATERIALS AND METHODS: In an experimental study, preantral follicles with diameter of 150-180 um were isolated from prepubertal mouse ovaries. Follicles were vitrified and thawed using cryolock method. They were then cultured individually for 7 days in droplets supplemented with 0, 10 and 100 pM melatonin, while ovulation was induced using epidermal growth factor (EGF) and human chorionic gonadotropin (hCG). The survival rate of follicles and nuclear maturation of ovulated oocytes were determined. RESULTS: At the end of culture, significant increases in follicle survival (p<0.001) and in diameter (p<0.05) were noticed in 10 pM melatonin group compared to control group. In the 100 pM group, survival rate was not affected by melatonin. It was revealed that after induction of ovulation, total number of metaphase II oocytes in treatment groups were not influenced by melatonin (p>0.05). CONCLUSION: Culture of mouse vitrified warmed preantral follicles in a medium supplemented with 10 pM melatonin increased the number of surviving follicles. PMID- 25685746 TI - Total antioxidant capacity and lipid peroxidation in semen of patient with hyperviscosity. AB - Semen hyperviscosity (SHV) is one of the factors involved in deficiency in sperm function. This research aimed to evaluate seminal plasma total antioxidant capacity (TAC) and malondialdehyde (MDA) levels in infertile patients with hyperviscous and non-hyperviscous semen samples to understand whether hyperviscous semen is associated with oxidative damage in infertile subjects. In this cross sectional study, 59 semen samples were provided by fertile (n=12) individuals as control, infertile patients with normal viscosity (n=25) and infertile patients with hyperviscosity (n=22). After semen parameters examination, semen viscosity was studied by glass pipettes. Seminal plasma TAC and MDA levels were measured by ferric reducing of antioxidant power (FRAP) and thiobarbituric acid reaction (TBAR) methods, respectively. A probability less than 0.05 was considered statistically significant throughout the article. The mean of sperm parameters including: counts, motility and normal morphology in patients with hyperviscosity were significantly lower than those in non hyperviscosity patients (p<0.05, p<0.01 and p<0.001, respectively). The mean of seminal plasma TAC value in seminal plasma of non-hyperviscosity patients (1710.31 +/- 458.67 umol/l) was significantly (p<0.01) higher than that of hyperviscosity group (1230.25 +/- 352 umol/l). A trend toward a higher mean of seminal plasma MDA value was estimated for hyperviscous group compared with non hyperviscous (1.01 +/- 0.41 nmol/ml vs. 0.94 +/- 0.28 nmol/l); however, it was nonsignificant. Hyperviscous semen impairs seminal plasma TAC which is eventually associated with sperm membrane lipid peroxidation. PMID- 25685747 TI - Can Lucifer Yellow Indicate Correct Permeability of Biological Cell Membrane under An Electric and Magnetic Field? AB - The effect of external magnetic and electric fields, in the range of electroporation and magnetoporation, on Lucifer Yellow (LY) fluorescence in the absence of cells is studied. Electric-field-induced quenching and magnetic field induced increase are observed for fluorescence intensity of LY. Regard to the fact that the variation of field-induced fluorescence, even in the absence of cells, can be observed, the application of LY, as a marker, is debatable in electroporation and magnetoporation techniques. PMID- 25685748 TI - Protection of renal tubular cells by antioxidants: current knowledge and new trends. AB - Acute renal damage mainly develops following toxic or ischemic insults and is defined as acute. These damages have largely been attributed to oxidative stress. Recently much attention has been directed toward decreased renal tubular cell regeneration during tubular cell injury. Antioxidants have recently been the focus of researchers and scientists for prevention and treatment of various oxidative stress-related conditions, including renal toxicities. Although free radicals are known to contribute in kidney injury and abundant researches, particularly laboratory trials, have shown the beneficial effects of antioxidants against these complications, long term clinical trials do not uniformly confirm this matter, especially for single antioxidant consumption such as vitamin C. The aim of this paper is to discuss the possible explanation of this matter. PMID- 25685749 TI - Bilateral anterior shoulder dislocation. AB - INTRODUCTION: Unilateral anterior shoulder dislocation is one of the most common problems encountered in orthopedic practice. However, simultaneous bilateral anterior dislocation of the shoulders is quite rare. CASE PRESENTATION: We report a case of a 75-year-old woman presented with simultaneous bilateral anterior shoulder dislocation following a trauma, complicated with a traction injury to the posterior cord of the brachial plexus. CONCLUSIONS: Bilateral anterior shoulder dislocation is very rare. The excessive traction force during closed reduction may lead to nerve palsy. Clear documentation of neurovascular status and adequate imaging before and after a reduction should be performed. PMID- 25685750 TI - Epidemiological pattern of bullying among school children in mazandaran province, iran. AB - BACKGROUND: School bullying, the most common type of school violence, comprises a spectrum of aggressive behaviors that involve both perpetrators and victims. OBJECTIVES: The current study aimed to investigate the extent and nature of school bullying among middle school students in the North of Iran. PATIENTS AND METHODS: A cross-sectional study was conducted on a sample of 834 Iranian middle school students. Participants completed a self-report anonymous questionnaire measuring bullying and victimization (Iranian-Olweus bullying questionnaire). Descriptive statistics and the Pearson's chi-squared test and multinomial logistic regressions with area, gender and grade variables were applied. RESULTS: Prevalence rates of bullying behaviors based on the cut-off point at 2 or 3 times a month were 5.4% for only bully, 22.1% for only victim and 11% for both bully victim. The prevalence of each form of victimization were 24.7% verbal, 15% relational, 10.3% physical and for each form of bullies 11% verbal, 5.3% relational, 6.4% physical. Boys were more involved in all forms of bullying behaviors. The students from rural areas were more involved in bullying .The most common places of victimization were the playground or athletic fields. The majority of victims were bullied by their classmates. CONCLUSIONS: Different forms of bullying have a distinct nature and the epidemiological pattern indicates that bullying exists in the Iranian schools. Thus, the effective bullying prevention and appropriate intervention programs are recommended. PMID- 25685751 TI - Injuries Due to Wedging of Bicycle Wheels in On-road Tram Tracks. AB - BACKGROUND: In cities with trams as public transportation, tram tracks are often on public roads, creating a shared road situation with other road participants like cyclists. Beside the risk of direct collisions, this situation can also lead to bicycle wheels getting wedged in tram tracks, causing cyclists to fall. OBJECTIVES: The aim of this study was to gain more insight in the injury pattern of this trauma mechanism and to draw attention to the risks of the infrastructural situation with on-road tram tracks. PATIENTS AND METHODS: A one year, prospective, observational cohort study was conducted. All patients admitted after presentation to the emergency department of a level 1 trauma center, who got injured because their bicycle wheels got wedged in tram tracks, were included. Data were collected on patient demographics, type of injury and treatment. RESULTS: Ten patients were included. Six were male. The mean age was 38 years. Six patients required surgery, mostly because of extremity injuries. Mean duration of admission was 4 days. Mean injury severity score was 13. One patient died as a result of the injuries sustained in the accident. CONCLUSIONS: Tram tracks on public roads are potentially dangerous and can lead to serious injuries and even mortality amongst cyclist. Operative intervention is frequently needed. PMID- 25685752 TI - Long-Term Therapy with Lenalidomide in a Patient with POEMS Syndrome. AB - Lenalidomide is an effective therapy against malignant plasma cells and a potent agent against proinflammatory and proangiogenic cytokines. The use of lenalidomide in POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein with plasma cells, skin changes) has been reported, but its benefit in long-term use is not well established. A 55-year-old man with POEMS and debilitating polyneuropathy was treated with lenalidomide and dexamethasone followed by maintenance lenalidomide. He remains in haematologic remission and in complete recovery of functional status 3.5 years after diagnosis. This case supports the long-term use of lenalidomide in patients with POEMS syndrome. PMID- 25685753 TI - Reconstruction with fibular osteocutaneous free flap in patients with mandibular osteoradionecrosis. AB - BACKGROUND: Osteoradionecrosis is a delayed complication from radiation therapy which causes chronic pain, infection and constant deformity after necrosis. Most of the osteoradionecrosis occurs spontaneously or after the primary oncologic surgery, dental extraction or by trauma of prosthesis. The treatment of osteoradionecrosis relies on both conservative measures and surgical measures. The fibular osteocutaneous free flap has become more popular choice for reconstruction of maxillofacial defects as a treatment of osteoradionecrosis. METHODS: We presented our experiences from 7 patients with osteoradionecrosis who have had reconstruction surgery with fibular osteocutaneous free flap at National Cancer Center during the recent 5 years. We performed segmental mandibular resection with fibular osteocutaneous free flap for all 7 patients of advanced osteoradionecrosis who were not controlled by conservative treatment such as wound irrigation, debridement, and antibiotics. RESULTS: A wide range of techniques were available for the reconstruction of composite defects resulted from the treatment of advanced mandibular osteoradionecrosis. Significant improvement was noted in relieving pain and treating trismus after the surgery however difficulty in swallowing and xerostomia showed less improvement. CONCLUSIONS: We concluded that fibular osteocutaneous free flap can be performed safely in patients with osteoradionecrosis and yields positive outcomes with significantly increased success rate. The fibular osteocutaneous free flap was our preferred choice for the mandibular reconstruction due to its versatility and predictability. PMID- 25685754 TI - New strategies for treatment of inflammatory bowel disease. AB - The etiology of inflammatory bowel disease (IBD), of which ulcerative colitis (UC) and Crohn's disease (CD) are the two most prevailing entities, is unknown. However, IBD is characterized by an imbalanced synthesis of pro-inflammatory mediators of the inflamed intestine, and for more than a decade tumor necrosis factor-(TNF) alpha has been a major target for monoclonal antibody therapy. However, TNF inhibitors are not useful for one third of all patients (i.e. "primary failures"), and further one third lose effect over time ("secondary failures"). Therefore, other strategies have in later years been developed including monoclonal antibodies targeting the interleukin (IL)-6 family of receptors (the p40 subunit of IL-12/IL-23) as well as monoclonal antibodies inhibiting adhesion molecules (the alpha4beta7 heterodimers), which direct leukocytes to the intestinal mucosa. Recently, small molecules, which are inhibitors of Janus kinases (JAKs), hold promise with a tolerable safety profile and efficacy in UC, and the field of nanomedicine is emerging with siRNAs loaded into polyactide nanoparticles that may silence gene transcripts at sites of intestinal inflammation. Thus, drug development for IBD holds great promise, and patients as well as their treating physicians can be hopeful for the future. PMID- 25685755 TI - State-of-the-Art management of knee osteoarthritis. AB - Osteoarthritis (OA) is the most common type of arthritis found in the United States' population and is also the most common disease of joints in adults throughout the world with the knee being the most frequently affected of all joints. As the United States' population ages along with the increasing trends in obesity prevalence in other parts of the world, it is expected that the burden of OA on the population, healthcare system, and overall economy will continue to increase in the future without making major improvements in managing knee OA. Numerous therapies aim to reduce symptoms of knee OA and continued research has helped to further understand the complex pathophysiology of its disease mechanism attempting to uncover new potential targets for the treatment of OA. This review article seeks to evaluate the current practices for managing knee OA and discusses emerging therapies on the horizon. These practices include non pharmacological treatments such as providing patient education and self management strategies, advising weight loss, strengthening programs, and addressing biomechanical issues with bracing or foot orthoses. Oral analgesics and anti-inflammatories are pharmacologicals that are commonly used and the literature overall supports that some of these medications can be helpful for managing knee OA in the short-term but are less effective for long-term management. Additionally, more prolonged use significantly increases the risk of serious associated side effects that are not too uncommon. Disease-modifying osteoarthritis drugs are being researched as a treatment modality to potentially halt or slow disease progression but data at this time is limited and continued studies are being conducted to further investigate their effectiveness. Intra articular injectables are also implemented to manage knee OA ranging from corticosteroids to hyaluronans to more recently platelet-rich plasma and even stem cells while several other injection therapies are presently being studied. The goal of developing new treatment strategies for knee OA is to prolong the need for total knee arthroplasty which should be utilized only if other strategies have failed. High tibial osteotomy and unicompartmental knee arthroplasty are potential alternatives if only a single compartment is involved with more data supporting unicompartmental knee arthroplasty as a good treatment option in this scenario. Arthroscopy has been commonly used for many years to treat knee OA to address degenerative articular cartilage and menisci, however, several high-quality studies have shown that it is not a very effective treatment for the majority of cases and should generally not be considered when managing knee OA. Improving the management of knee OA requires a multi-faceted treatment approach along with continuing to broaden our understanding of this complex disease so that therapeutic advancements can continue to be developed with the goal of preventing further disease progression and even potentially reversing the degenerative process. PMID- 25685756 TI - Upper aerodigestive tract disorders and gastro-oesophageal reflux disease. AB - A wide variety of symptoms and diseases of the upper aerodigestive tract are associated to gastro-oesophageal reflux disease (GORD). These disorders comprise a large variety of conditions such as asthma, chronic otitis media and sinusitis, chronic cough, and laryngeal disorders including paroxysmal laryngospasm. Laryngo pharyngeal reflux disease is an extraoesophageal variant of GORD that can affect the larynx and pharynx. Despite numerous research efforts, the diagnosis of laryngopharyngeal reflux often remains elusive, unproven and controversial, and its treatment is then still empiric. Aim of this paper is to review the current literature on upper aerodigestive tract disorders in relation to pathologic gastro-oesophageal reflux, focusing in particular on the pathophysiology base and results of the surgical treatment of GORD. PMID- 25685757 TI - Review and update on the molecular basis of Leber congenital amaurosis. AB - Inherited retinal diseases are uncommon pathologies and one of the most harmful causes of childhood and adult blindness. Leber congenital amaurosis (LCA) is the most severe kind of these diseases accounting for approximately 5% of the whole retinal dystrophies and 20% of the children that study on blind schools. Clinical ophthalmologic findings including severe vision loss, nystagmus and ERG abnormalities should be suspected through the first year of life in this group of patients. Phenotypic variability is found when LCA patients have a full ophthalmologic examination. However, a correct diagnosis may be carried out; the determination of ophthalmologic clues as light sensibility, night blindness, fundus pigmentation, among other, join with electroretinographics findings, optical coherence tomography, and new technologies as molecular gene testing may help to reach to a precise diagnosis. Several retinal clinical features in LCA may suggest a genetic or gene particular defect; thus genetic-molecular tools could directly corroborate the clinical diagnosis. Currently, approximately 20 genes have been associated to LCA. In this review, historical perspective, clinical ophthalmological findings, new molecular-genetics technologies, possible phenotype-genotypes correlations, and gene therapy for some LCA genes are described. PMID- 25685758 TI - Dengue and its effects on liver. AB - Dengue has emerged as an important arboviral disease with significant impact on the disease burden in population residing in tropical countries. Dengue is spread by the bite of Aedes mosquito. The virus seems to have some hepatotoxic effects. Affliction of liver in form of derangements in the liver function tests is common and may include mild elevations in serum bilirubin, elevated transaminases and derangements in serum albumin. Although asymptomatic in most cases, clinical manifestations like jaundice, and acute liver failure (ALF) may occasionally complicate the clinical picture. Indeed, dengue has been implicated as an important cause of ALF in endemic countries. The present review focuses on the hepatic manifestations and the pathogenesis of the liver injury in dengue. PMID- 25685759 TI - Role of third molars in orthodontics. AB - The role of third molars in the oral cavity has been extensively studied over the years. Literature includes numerous diagnostic and treatment alternatives regarding the third molars. However, an issue that has not been discussed at the same level is their involvement in orthodontic therapy. The aim of this study is to present a review of the contemporary literature regarding the most broadly discussed aspects of the multifactorial role of third molars in orthodontics and which are of general dental interest too. PMID- 25685760 TI - Clinical outcomes for Conduits and Scaffolds in peripheral nerve repair. AB - The gold standard of peripheral nerve repair is nerve autograft when tensionless repair is not possible. Use of nerve autograft has several shortcomings, however. These include limited availability of donor tissue, sacrifice of a functional nerve, and possible neuroma formation. In order to address these deficiencies, researchers have developed a variety of biomaterials available for repair of peripheral nerve gaps. We review the clinical studies published in the English literature detailing outcomes and reconstructive options. Regardless of the material used or the type of nerve repaired, outcomes are generally similar to nerve autograft in gaps less than 3 cm. New biomaterials currently under preclinical evaluation may provide improvements in outcomes. PMID- 25685761 TI - Role of coronary physiology in the contemporary management of coronary artery disease. AB - Coronary artery disease (CAD) remains the leading cause of death worldwide with approximately 1 in 30 patients with stable CAD experiencing death or acute myocardial infarction each year. The presence and extent of resultant myocardial ischaemia has been shown to confer an increased risk of adverse outcomes. Whilst, optimal medical therapy (OMT) forms the cornerstone of the management of patients with stable CAD, a significant number of patients present with ischaemia refractory to OMT. Historically coronary angiography alone has been used to determine coronary lesion severity in both stable and acute settings. It is increasingly clear that this approach fails to accurately identify the haemodynamic significance of lesions; especially those that are visually "intermediate" in severity. Revascularisation based upon angiographic appearances alone may not reduce coronary events above OMT. Technological advances have enabled the measurement of physiological indices including the fractional flow reserve, the index of microcirculatory resistance and the coronary flow reserve. The integration of these parameters into the routine management of patients presenting to the cardiac catheterization laboratory with CAD represents a critical adjunctive tool in the optimal management of these patients by identifying patients that would most benefit from revascularisation and importantly also highlighting patients that would not gain benefit and therefore reducing the likelihood of adverse outcomes associated with coronary revascularisation. Furthermore, these techniques are applicable to a broad range of patients including those with left main stem disease, proximal coronary disease, diabetes mellitus, previous percutaneous coronary intervention and with previous coronary artery bypass grafting. This review will discuss current concepts relevant to coronary physiology assessment, its role in the management of both stable and acute patients and future applications. PMID- 25685762 TI - Review on microbiota and effectiveness of probiotics use in older. AB - The aim of the present systematic review is to summarize the existing knowledge about the human microbiota in the elderly and the effects of probiotics in elderly population. The elderly subjects, compared to adult population, show a reduction in the diversity of the microbiota, characterized by a large interindividual variability, with lower numbers of Firmicutes, Bifidobacteria, Clostridium cluster XIV, Faecalibacterium Prausnitzii, Blautia coccoides Eubacterium rectal and higher presence of Enterobacteriaceae and Bacteroidetes. These differences of the intestinal microbiota of the elderly may not necessarily be caused by aging, but they could be associated with the decline of the general state of health with malnutrition and with increased need for medication, such as antibiotics and nonsteroidal anti-inflammatory drugs, situations that occur frequently in the elderly. Differences have been demonstrated in the composition of the microbiota between healthy elderly subjects and hospitalized or institutionalized elderly subjects. These findings which further indicates that the living conditions, health status, nutrition and drugs have a significant effect on the composition of the microbiota. According to the available knowledge, the use of probiotics is safe and could represent an useful intervention to prevent or treat antibiotic-associated diarrhea, in addition to reducing the severity of symptoms, other than to help the management of constipation. PMID- 25685763 TI - Conservative strategy for treatment of stable coronary artery disease. AB - Patients with coronary artery disease vary widely in terms of prognosis, which is mainly dependent on ventricular function. In relation to the major outcomes of death and myocardial infarction, it is not clear in the literature if an invasive strategy of myocardial revascularization is superior to a conservative strategy of optimized medical therapy. Moreover, with the exception of patients with left main coronary disease, this similarity in prognosis also occurs in different subgroups of patients. PMID- 25685764 TI - Correlation between hypertension and hyperglycemia among young adults in India. AB - AIM: To assess the correlation between blood pressure levels and fasting plasma glucose levels among young adults attending Chatrapati Shahuji Maharaj University, Kanpur, India. METHODS: The present study was cross-sectional in nature, conducted among students in the Institute of Paramedical Sciences, Chatrapati Shahuji Maharaj University, Kanpur. Study subjects included 185 young adults. Among them, 94 were males and 91 were females, in the age group 17 to 19 years. RESULTS: Mean age among males was 18.5 +/- 1.5 years and among females was 17.9 +/- 1.8 years. Of the total 185 study subjects, 61 (32.9%) were classified as pre-diabetic and 20 (10.8%) as pre-hypertensive. Mean waist circumference, systolic blood pressure and serum high density lipoprotein did not vary significantly between normoglycemic and pre-diabetic subjects. However, the mean diastolic blood pressure of pre-diabetics (82 +/- 5 mmHg) was significantly higher than normoglycemics (79 +/- 6 mmHg). Mean serum cholesterol, serum triglycerides, serum low density lipoprotein (LDL) and serum very low density lipoprotein was also higher among pre-diabetic subjects in comparison to normoglycemic subjects and the difference was statistically significant. Upon multiple linear regression analysis, it was observed that body mass index (BMI) (beta = 0.149), diastolic blood pressure (beta = 0.375) and serum LDL (beta = 0.483) were significantly associated with fasting plasma glucose. Multiple linear regression with diastolic blood pressure as the outcome variable showed that BMI (beta = 0.219), fasting blood glucose (beta = 0.247) and systolic blood pressure (beta = 0.510) were significantly associated. CONCLUSION: A significant prevalence of pre-diabetes and pre-hypertension in young adults is a matter of concern therefore all young adults need to be targeted for screening of diabetes and hypertension and lifestyle modification. PMID- 25685765 TI - Use of steroids for facial nerve paralysis after parotidectomy: A systematic review. AB - AIM: To systematically review the literature to assess the efficacy of corticosteroids in treating post-parotidectomy facial nerve palsy (FNP). METHODS: We searched the Cochrane library, EMBASE and MEDLINE (from inception to 2014) for studies assessing the use of corticosteroids in post-parotidectomy FNP. Studies were assessed for inclusion and quality. Data was extracted from included studies. RESULTS: Two randomised controlled trials met the inclusion criteria. One study assessed the use of dexamethasone and the other prednisolone. None of the studies demonstrated a significant difference in the outcome of FNP post parotidectomy with the use of corticosteroids vs no therapy. The majority of FNP post-parotidectomy is transient. Preoperative factors (size of tumour and malignancy), intraoperative factors (extent of parotidectomy and integrity of facial nerve at the end of the operation) are important in determining prognosis of FNP if it does occur. CONCLUSION: Corticosteroids do not appear to improve FNP prognosis post-parotidectomy. Further studies assessing patients by cohort and with long term follow-up are required to increase scientific evidence. PMID- 25685766 TI - Complete remission of primary hepatic lymphoma in a patient with human immunodeficiency virus. AB - Diffuse large B cell primary hepatic lymphoma is a rare disease with limited available information regarding treatment strategy. Although the liver contains lymphoid tissue and is an important site for lymphocytes activation, primary hepatic lymphoma is rare. Host factors make the liver a poor environment for malignant lymphoma development. Its coexistence with human immunodeficiency virus (HIV) infection increases morbidity and mortality risks. Additionally, jaundice increases chances of developing adverse effects from chemotherapy. Here, we report a case of diffuse large B cell primary hepatic lymphoma in a 32-year-old HIV positive man. Due to elevated liver enzyme levels and jaundice, the patient was initially treated with an R-DHAP regimen, which was replaced with an R-CHOP regimen. Restaging images with a positron emission tomography scan after the latest chemotherapy cycle confirmed remission. This is the first report of complete remission of primary hepatic diffuse large B cell lymphoma in an HIV positive patient in the English literature. PMID- 25685767 TI - Survival in unresectable sinonasal undifferentiated carcinoma treated with concurrent intra-arterial cisplatin and radiation. AB - We report the successful use of RADPLAT to treat a patient with an unresectable T4N0 sinonasal undifferentiated carcinoma. This patient received 4 cycles of weekly intra-arterial cisplatin together with thiosulfate infusion with concurrent radiation therapy. Radiation therapy was given in 28 daily fractions to 54 Gy using intensity-modulated radiation therapy followed by a hypofractionated stereotactic boost of 3 fractions to 13 Gy to a total dose of 67 Gy in 31 fractions to the nasal sinus and bilateral neck. Intra-arterial cisplatin was administered using a bilateral approach due to the midline site of this tumor. Within days of the first intra-arterial cisplatin, there was an obvious decrease in tumor size. She has been followed with magnetic resonance imaging and positron emission tomography, and remains disease-free 47 mo post treatment. Centers with expertise in intra-arterial chemotherapy could consider the RADPLAT approach for patients with unresectable sinonasal undifferentiated carcinoma. PMID- 25685768 TI - Sweet syndrome and differentiation syndrome in a patient with acute promyelocytic leukemia. AB - The differentiation syndrome is an inflammatory reaction with increased capillary permeability that occurs in up to 25% of patients with acute promyelocytic leukemia treated with all-trans retinoic acid. A 50-year-old man with acute promyelocytic leukemia underwent chemotherapy with idarubicin and all-trans retinoic acid. On day +21 the patient developed pruritic prepatelar papules as well as several 10 mm subcutaneous nodules in both thighs accompanied by persistent fever. On the day +25 the patient presented with bilateral pulmonary crackles, infiltrates in the right lower lobe and severe hypotension which required dopamine infusion. Biopsy of one of the thighs nodules was performed. A Sweet syndrome associated to a differentiation syndrome was suspected. All-trans retinoic acid therapy was discontinued and dexamethasone was administered. In 48 h the patient showed remission of the fever and the infiltrates and the skin lesions acquired a residual aspect. It is debatable whether these two syndromes are distinct entities with common mechanisms or whether they are poles of the same spectrum. Dermatologists and hematologists must be aware of these two syndromes and its pathophysiologic association. PMID- 25685769 TI - Gingival unit transfer using in the Miller III recession defect treatment. AB - The most significant factor for the success in soft tissue grafts is the synergistic relation between vascular configuration and involved tissues. In the soft tissue graft procedures, site specific donor tissue is assumed to have improved potential for function and aesthetic survive at recipient sites. On a clinical level, using site specific gingival unit graft that placed on traditionally prepared recipient site, results in predictable root coverage. In this case report the clinical effectiveness of gingival unit transfer (GUT) technique performed on Miller III recession was presented and a similar recession case treated with free gingival graft (FGG) technique for comparison. Probing depth, recession depth, keratinized tissue width and clinical attachment level clinical parameters were measured at baseline and postoperative 8 mo. Percentage of defect coverage was evaluated at postoperative 8 mo. Creeping attachment was assessed at postoperative 1, 3, 6 and 8 mo. The GUT revealed better defect coverage and creeping attachment results than the FGG in the treatment of Miller III defects. PMID- 25685770 TI - Is Takotsubo syndrome in patients receiving chemotherapy drug-specific? AB - In commenting on a case report of a 55-year-old man who suffered Takotsubo syndrome (TTS), in the setting of receiving chemotherapy with cytarabine and daunorubicin for acute myeloid leukemia, the author expresses his views that TTS in the setting of chemotherapy for malignancies may not be chemotherapeutic drug specific (like in the chemotherapeutic drug induced-cardiomyopathy), but may be due to the emotional and physical stresses resulting from the realization of having diagnosed with a malignancy, and the diagnostic testing, and therapeutic management which follows. PMID- 25685771 TI - Pharmacological application of growth factors: basic and clinical. PMID- 25685772 TI - Assessment of duration of staying free from acquiring rehappening opportunistic infections among pre-ART people living with HIV/AIDS between 2008 and 2013. AB - Introduction. In regional state of the study area, HIV (Human Immunodeficiency Virus) prevalence is 2.2% and opportunistic infections (OIs) occurred in 88.9% of pre-ART (Antiretroviral Therapy) people living with HIV/AIDS (PLWHA). Even though OIs are prevalent in the study area, duration of staying free from acquiring rehappening opportunistic infections and its determinant factors are not studied. Method. The study was conducted in randomly selected 341 adult Pre-ART PLWHA who are included in chronic HIV care. OI free duration was estimated using the actuarial life table and Kaplan Meier survival. Cox proportional-hazard model was used to calculate hazard rate. Result. OIs were rediagnosed in three quarters (75.37%) participants. In each week the probability of getting new recurrence OI was about 15.04 per 1000 person weeks. The median duration of not acquiring OI recurrence was 54 weeks. After adjustment, variables associated with recurrence were employment status, marital status, exposure for prophylaxis and adherence to it, CD4 count, and hemoglobin value. Conclusion. Giving prophylaxis and counseling to adhere it, rise in CD4 and hemoglobin level, and enhancing job opportunities should be given for PLWHA who are on chronic HIV care while continuing the care. PMID- 25685773 TI - The benefit of a human bone marrow stem cells concentrate in addition to an inorganic scaffold for bone regeneration: an in vitro study. AB - Background. This work compares the osteoblastic behaviour of a bone marrow (BM) aspirate and a prepared BM concentrate of nucleated cells associated with a glass reinforced hydroxyapatite composite (GRHC) in a microporous pellet formulation. Methods. BM aspirate (30 mL) was collected during 3 orthopedic surgical procedures, and a concentration system was used to achieve 3 rapid preparations of a concentrate of nucleated cells (3 mL) from the BM aspirates. The BM aspirates (53% cell viability; 2.7 * 10(6) nucleated cell/mL) and the BM concentrates (76% cell viability; 2 * 10(7) nucleated cell/mL) were cultured over glass reinforced hydroxyapatite pellets, at the same volume/mass ratio, for 30 days. Cultures performed in standard tissue culture plates were used as control. Results. The colonized BM concentrate/material constructs exhibited a representative osteoblastic proliferation/differentiation pathway, evidenced by a high alkaline phosphatase (ALP) activity, expression of collagen type 1, ALP, BMP 2, M-CSF, RANKL, and OPG, and formation of a calcium phosphate mineralized matrix. A clear improved behaviour was noticed compared to the BM aspirate/material constructs. Conclusions. The results suggest the benefit of using an autologous BM concentrate/material construct in the clinical setting, in bone regeneration applications. PMID- 25685774 TI - Use of early biomarkers in neonatal brain damage and sepsis: state of the art and future perspectives. AB - The identification of early noninvasive biochemical markers of disease is a crucial issue of the current scientific research, particularly during the first period of life, since it could provide useful and precocious diagnostic information when clinical and radiological signs are still silent. The ideal biomarker should be practical and sensitive in the precocious identification of at risk patients. An earlier diagnosis may lead to a larger therapeutic window and improve neonatal outcome. Brain damage and sepsis are common causes of severe morbidity with poor outcome and mortality during the perinatal period. A large number of potential biomarkers, including neuroproteins, calcium binding proteins, enzymes, oxidative stress markers, vasoactive agents, and inflammatory mediators, have been so far investigated. The aim of the present review was to provide a brief overview of some of the more commonly investigated biomarkers used in case of neonatal brain damage and sepsis. PMID- 25685775 TI - Temporal auditory processing and phonological awareness in children with benign epilepsy with centrotemporal spikes. AB - The aim of this research was to analyze temporal auditory processing and phonological awareness in school-age children with benign childhood epilepsy with centrotemporal spikes (BECTS). Patient group (GI) consisted of 13 children diagnosed with BECTS. Control group (GII) consisted of 17 healthy children. After neurological and peripheral audiological assessment, children underwent a behavioral auditory evaluation and phonological awareness assessment. The procedures applied were: Gaps-in-Noise test (GIN), Duration Pattern test, and Phonological Awareness test (PCF). Results were compared between the groups and a correlation analysis was performed between temporal tasks and phonological awareness performance. GII performed significantly better than the children with BECTS (GI) in both GIN and Duration Pattern test (P < 0.001). GI performed significantly worse in all of the 4 categories of phonological awareness assessed: syllabic (P = 0.001), phonemic (P = 0.006), rhyme (P = 0.015) and alliteration (P = 0.010). Statistical analysis showed a significant positive correlation between the phonological awareness assessment and Duration Pattern test (P < 0.001). From the analysis of the results, it was concluded that children with BECTS may have difficulties in temporal resolution, temporal ordering, and phonological awareness skills. A correlation was observed between auditory temporal processing and phonological awareness in the suited sample. PMID- 25685777 TI - Neurodegeneration: etiologies and new therapies. PMID- 25685776 TI - Iron dextran increases hepatic oxidative stress and alters expression of genes related to lipid metabolism contributing to hyperlipidaemia in murine model. AB - The objective of this study was to investigate the effects of iron dextran on lipid metabolism and to determine the involvement of oxidative stress. Fischer rats were divided into two groups: the standard group (S), which was fed the AIN 93M diet, and the standard plus iron group (SI), which was fed the same diet but also received iron dextran injections. Serum cholesterol and triacylglycerol levels were higher in the SI group than in the S group. Iron dextran was associated with decreased mRNA levels of pparalpha, and its downstream gene cpt1a, which is involved in lipid oxidation. Iron dextran also increased mRNA levels of apoB-100, MTP, and L-FABP indicating alterations in lipid secretion. Carbonyl protein and TBARS were consistently higher in the liver of the iron treated rats. Moreover, a significant positive correlation was found between oxidative stress products, lfabp expression, and iron stores. In addition, a negative correlation was found between pparalpha expression, TBARS, carbonyl protein, and iron stores. In conclusion, our results suggest that the increase observed in the transport of lipids in the bloodstream and the decreased fatty acid oxidation in rats, which was promoted by iron dextran, might be attributed to increased oxidative stress. PMID- 25685778 TI - Neural and nonneural contributions to wrist rigidity in Parkinson's disease: an explorative study using the NeuroFlexor. AB - OBJECTIVE: The NeuroFlexor is a novel method incorporating a biomechanical model for the measurement of neural and nonneural contributions to resistance induced by passive stretch. In this study, we used the NeuroFlexor method to explore components of passive movement resistance in the wrist and finger muscles in subjects with Parkinson's disease (PD). METHODS: A cross-sectional comparison was performed in twenty-five subjects with PD with clinically identified rigidity and 14 controls. Neural (NC), elastic (EC), and viscous (VC) components of the resistance to passive extension of the wrist were calculated using the NeuroFlexor. Measurements were repeated during a contralateral activation maneuver. RESULTS: PD subjects showed greater total resistance (P < 0.001) and NC (P = 0.002) compared to controls. EC and VC did not differ significantly between groups. Contralateral activation maneuver resulted in increased NC in the PD group but this increase was due to increased resting tension. Total resistance and NC correlated with clinical ratings of rigidity and with bradykinesia. CONCLUSIONS: The findings suggest that stretch induced reflex activity, but not nonneural resistance, is the major contributor to rigidity in wrist muscles in PD. The NeuroFlexor is a potentially valuable clinical and research tool for quantification of rigidity. PMID- 25685779 TI - Integrating retrogenesis theory to Alzheimer's disease pathology: insight from DTI-TBSS investigation of the white matter microstructural integrity. AB - Microstructural abnormalities in white matter (WM) are often reported in Alzheimer's disease (AD) and may reflect primary or secondary circuitry degeneration (i.e., due to cortical atrophy). The interpretation of diffusion tensor imaging (DTI) eigenvectors, known as multiple indices, may provide new insights into the main pathological models supporting primary or secondary patterns of WM disruption in AD, the retrogenesis, and Wallerian degeneration models, respectively. The aim of this review is to analyze the current literature on the contribution of DTI multiple indices to the understanding of AD neuropathology, taking the retrogenesis model as a reference for discussion. A systematic review using MEDLINE, EMBASE, and PUBMED was performed. Evidence suggests that AD evolves through distinct patterns of WM disruption, in which retrogenesis or, alternatively, the Wallerian degeneration may prevail. Distinct patterns of WM atrophy may be influenced by complex interactions which comprise disease status and progression, fiber localization, concurrent risk factors (i.e., vascular disease, gender), and cognitive reserve. The use of DTI multiple indices in addition to other standard multimodal methods in dementia research may help to determine the contribution of retrogenesis hypothesis to the understanding of neuropathological hallmarks that lead to AD. PMID- 25685780 TI - Prokineticin 2 upregulation in the peripheral nervous system has a major role in triggering and maintaining neuropathic pain in the chronic constriction injury model. AB - The new chemokine Prokineticin 2 (PROK2) and its receptors (PKR1 and PKR2) have a role in inflammatory pain and immunomodulation. Here we identified PROK2 as a critical mediator of neuropathic pain in the chronic constriction injury (CCI) of the sciatic nerve in mice and demonstrated that blocking the prokineticin receptors with two PKR1-preferring antagonists (PC1 and PC7) reduces pain and nerve damage. PROK2 mRNA expression was upregulated in the injured nerve since day 3 post injury (dpi) and in the ipsilateral DRG since 6 dpi. PROK2 protein overexpression was evident in Schwann Cells, infiltrating macrophages and axons in the peripheral nerve and in the neuronal bodies and some satellite cells in the DRG. Therapeutic treatment of neuropathic mice with the PKR-antagonist, PC1, impaired the PROK2 upregulation and signalling. This fact, besides alleviating pain, brought down the burden of proinflammatory cytokines in the damaged nerve and prompted an anti-inflammatory repair program. Such a treatment also reduced intraneural oedema and axon degeneration as demonstrated by the physiological skin innervation and thickness conserved in CCI-PC1 mice. These findings suggest that PROK2 plays a crucial role in neuropathic pain and might represent a novel target of treatment for this disease. PMID- 25685781 TI - Soil as levels and bioaccumulation in Suaeda salsa and Phragmites australis wetlands of the Yellow River Estuary, China. AB - Little information is available on As contamination dynamics in the soil-plant systems of wetlands. Total arsenic (As) in soil and plant samples from Suaeda salsa and Phragmites australis wetlands was measured in the Yellow River Estuary (YRE) in summer and autumn of 2007 to investigate the seasonal changes in As concentrations in different wetlands. The results showed that soil As levels greatly exceeded the global and regional background values. As levels in soil and the roots and stems of both types of plants were much higher in summer than in autumn, whereas leaf As showed higher level in autumn. Soil sulfur was the main factor influencing As levels in Suaeda salsa wetlands, whereas soil porosity was the most important factor for Phragmites australis wetlands. The contamination factor (CF) showed moderately to considerably polluted levels of As in both wetland soils. Plant roots and leaves of Suaeda salsa had higher As concentrations and biological concentration factors (BCFs) than stems, while the leaves and stems of Phragmites australis showed higher As levels and BCFs than roots. Compared to Phragmites australis, Suaeda salsa generally showed higher translocation factor (TF), while TF values for both plant species were higher in summer than in autumn. PMID- 25685782 TI - Natural compounds regulate glycolysis in hypoxic tumor microenvironment. AB - In the early twentieth century, Otto Heinrich Warburg described an elevated rate of glycolysis occurring in cancer cells, even in the presence of atmospheric oxygen (the Warburg effect). Recently it became a therapeutically interesting strategy and is considered as an emerging hallmark of cancer. Hypoxia inducible factor-1 (HIF-1) is one of the key transcription factors that play major roles in tumor glycolysis and could directly trigger Warburg effect. Thus, how to inhibit HIF-1-depended Warburg effect to assist the cancer therapy is becoming a hot issue in cancer research. In fact, HIF-1 upregulates the glucose transporters (GLUT) and induces the expression of glycolytic enzymes, such as hexokinase, pyruvate kinase, and lactate dehydrogenase. So small molecules of natural origin used as GLUT, hexokinase, or pyruvate kinase isoform M2 inhibitors could represent a major challenge in the field of cancer treatment. These compounds aim to suppress tumor hypoxia induced glycolysis process to suppress the cell energy metabolism or enhance the susceptibility of tumor cells to radio- and chemotherapy. In this review, we highlight the role of natural compounds in regulating tumor glycolysis, with a main focus on the glycolysis under hypoxic tumor microenvironment. PMID- 25685783 TI - Clinical significance of neutrophil gelatinase-associated lipocalin in Crimean Congo hemorrhagic Fever. AB - Neutrophil gelatinase-associated lipocalin (NGAL), which is an important prognostic marker for sepsis and inflammatory diseases, is mostly released from neutrophils. Crimean-Congo hemorrhagic fever (CCHF) patients are generally neutropenic. We aimed to investigate whether there is a change in serum NGAL level and to investigate its effect on the recovery time (RT) during the course of CCHF. A total of 40 CCHF patients (19 females and 21 males) and 34 healthy controls (17 females and 17 males) were included in the study. The serum NGAL level and biochemical and hematological parameters were checked. The NGAL level of CCHF patients was significantly higher than that of the healthy controls (P < 0.001). A multivariate analysis showed that the independent prognostic factor for the prediction of the RT is the NGAL level (odds ratio [OR] 0.3, 95% confidence interval [Cl] 0.1-0.4, P < 0.001). An elevated NGAL level was found to be associated with an increased RT in CCHF patients. The NGAL levels of CHHF patients might be elevated due to increased cytokine release, the presence of a tissue injury, and the release of immature neutrophils from the bone marrow into the peripheral stream. This may be a good prognostic factor in CHHF patients. PMID- 25685784 TI - In vitro gender-dependent inhibition of porcine cytochrome p450 activity by selected flavonoids and phenolic acids. AB - We investigated gender-related differences in the ability of selected flavonoids and phenolic compounds to modify porcine hepatic CYP450-dependent activity. Using pools of microsomes from male and female pigs, the inhibition of the CYP families 1A, 2A, 2E1, and 3A was determined. The specific CYP activities were measured in the presence of the following selected compounds: rutin, myricetin, quercetin, isorhamnetin, p-coumaric acid, gallic acid, and caffeic acid. We determined that myricetin and isorhamnetin competitively inhibited porcine CYP1A activity in the microsomes from both male and female pigs but did not affect the CYP2A and CYP2E1. Additionally, isorhamnetin competitively inhibited CYP3A in both genders. Noncompetitive inhibition of CYP3A activity by myricetin was observed only in the microsomes from male pigs, whereas CYP3A in female pigs was not affected. Quercetin competitively inhibited CYP2E1 and CYP1A activity in the microsomes from male pigs and irreversibly CY3A in female pigs. No effect of quercetin on CYP2E1 was observed in the microsomes from female pigs. Neither phenolic acids nor rutin affected CYP450 activities. Taken together, our results suggest that the flavonoids myricetin, isorhamnetin, and quercetin may affect the activities of porcine CYP1A, CYP3A, and CYP2E1 in a gender-dependent manner. PMID- 25685785 TI - Endoscopic transsphenoidal cisternostomy for nonneoplastic sellar cysts. AB - Background and Importance. Sellar arachnoid cysts and Rathke's cleft cysts are benign lesions that produce similar symptoms, including optochiasmatic compression, pituitary dysfunction, and headache. Studies have reported the use of various surgical treatment methods for treating these symptoms, preventing recurrence, and minimizing operative complications. However, the postoperative cerebrospinal fluid (CSF) fistula and recurrence rate remain significant. Clinical Presentation. In this paper, we present 8 consecutive cases involving arachnoid cysts and Rathke's cleft cysts, which were managed by using drainage and cisternostomy, the intentional fenestration of the cyst into the subarachnoid space, and then meticulously closing sellar floor using dural sutures. The postoperative images, CSF fistula rate, and the recurrence rate were favorable. Conclusion. We report this technique and discuss the benefit of this minimally invasive approach. PMID- 25685786 TI - mTOR kinase: a possible pharmacological target in the management of chronic pain. AB - Chronic pain represents a major public health problem worldwide. Current pharmacological treatments for chronic pain syndromes, including neuropathic pain, are only partially effective, with significant pain relief achieved in 40 60% of patients. Recent studies suggest that the mammalian target of rapamycin (mTOR) kinase and downstream effectors may be implicated in the development of chronic inflammatory, neuropathic, and cancer pain. The expression and activity of mTOR have been detected in peripheral and central regions involved in pain transmission. mTOR immunoreactivity was found in primary sensory axons, in dorsal root ganglia (DRG), and in dorsal horn neurons. This kinase is a master regulator of protein synthesis, and it is critically involved in the regulation of several neuronal functions, including the synaptic plasticity that is a major mechanism leading to the development of chronic pain. Enhanced activation of this pathway is present in different experimental models of chronic pain. Consistently, pharmacological inhibition of the kinase activity turned out to have significant antinociceptive effects in several experimental models of inflammatory and neuropathic pain. We will review the main evidence from animal and human studies supporting the hypothesis that mTOR may be a novel pharmacological target for the management of chronic pain. PMID- 25685787 TI - Importance of silicon and mechanisms of biosilica formation in plants. AB - Silicon (Si) is one of the most prevalent macroelements, performing an essential function in healing plants in response to environmental stresses. The purpose of using Si is to induce resistance to distinct stresses, diseases, and pathogens. Additionally, Si can improve the condition of soils, which contain toxic levels of heavy metals along with other chemical elements. Silicon minimizes toxicity of Fe, Al, and Mn, increases the availability of P, and enhances drought along with salt tolerance in plants through the formation of silicified tissues in plants. However, the concentration of Si depends on the plants genotype and organisms. Hence, the physiological mechanisms and metabolic activities of plants may be affected by Si application. Peptides as well as amino acids can effectively create polysilicic species through interactions with different species of silicate inside solution. The carboxylic acid and the alcohol groups of serine and asparagine tend not to engage in any significant role in polysilicates formation, but the hydroxyl group side chain can be involved in the formation of hydrogen bond with Si(OH)4. The mechanisms and trend of Si absorption are different between plant species. Furthermore, the transportation of Si requires an energy mechanism; thus, low temperatures and metabolic repressors inhibit Si transportation. PMID- 25685788 TI - Positive association of vitamin D receptor gene variations with multiple sclerosis in South East Iranian population. AB - Among the factors postulated to play a role in MS susceptibility, the role of vitamin D is outstanding. Since the function of vitamin D receptor (VDR) represents the effect of vitamin D on the body and genetic variations in VDR gene may affect its function, we aim to highlight the association of two VDR gene polymorphisms with MS susceptibility. In current study, we recruited 113 MS patients and 122 healthy controls. TaqI (rs731236) and ApaI (rs7975232) genetic variations in these two groups were evaluated using the polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) technique. All genotype and allele frequencies in both variations showed association with the disease status. However, to find the definite connection between genetic variations in VDR gene and MS disease in a population of South East of Iran, more researches on gene structure and its function with regard to patients' conditions are required. PMID- 25685789 TI - Mechanical stress promotes cisplatin-induced hepatocellular carcinoma cell death. AB - Cisplatin (CisPt) is a commonly used platinum-based chemotherapeutic agent. Its efficacy is limited due to drug resistance and multiple side effects, thereby warranting a new approach to improving the pharmacological effect of CisPt. A newly developed mathematical hypothesis suggested that mechanical loading, when coupled with a chemotherapeutic drug such as CisPt and immune cells, would boost tumor cell death. The current study investigated the aforementioned mathematical hypothesis by exposing human hepatocellular liver carcinoma (HepG2) cells to CisPt, peripheral blood mononuclear cells, and mechanical stress individually and in combination. HepG2 cells were also treated with a mixture of CisPt and carnosine with and without mechanical stress to examine one possible mechanism employed by mechanical stress to enhance CisPt effects. Carnosine is a dipeptide that reportedly sequesters platinum-based drugs away from their pharmacological target-site. Mechanical stress was achieved using an orbital shaker that produced 300 rpm with a horizontal circular motion. Our results demonstrated that mechanical stress promoted CisPt-induced death of HepG2 cells (~35% more cell death). Moreover, results showed that CisPt-induced death was compromised when CisPt was left to mix with carnosine 24 hours preceding treatment. Mechanical stress, however, ameliorated cell death (20% more cell death). PMID- 25685790 TI - Noninvasive physiologic assessment of coronary stenoses using cardiac CT. AB - Coronary CT angiography (CCTA) has become an important noninvasive imaging modality in the diagnosis of coronary artery disease (CAD). CCTA enables accurate evaluation of coronary artery stenosis. However, CCTA provides limited information on the physiological significance of stenotic lesions. A noninvasive "one-stop-shop" diagnostic test that can provide both anatomical significance and functional significance of stenotic lesions would be beneficial in the diagnosis and management of CAD. Recently, with the introduction of novel techniques, such as myocardial CT perfusion, CT-derived fractional flow reserve (FFRCT), and transluminal attenuation gradient (TAG), CCTA has emerged as a noninvasive method for the assessment of both anatomy of coronary lesions and its physiological consequences during a single study. This review provides an overview of the current status of new CT techniques for the physiologic assessments of CAD. PMID- 25685791 TI - Effect of spirulina intervention on oxidative stress, antioxidant status, and lipid profile in chronic obstructive pulmonary disease patients. AB - BACKGROUND AND OBJECTIVE: Oxidative stress is intimately associated with many diseases, including chronic obstructive pulmonary disease (COPD). Study objectives include a comparison of the oxidative stress, antioxidant status, and lipid profile between COPD patients and controls and evaluation of the effect of spirulina intervention on oxidative stress, antioxidant status, and lipid profile of COPD patients. METHODS: 30 patients with COPD and 20 controls with no respiratory problems were selected. Global Initiative for Chronic Obstructive Lung Disease criteria were served as the basis of COPD diagnosis. The serum content of malondialdehyde (MDA), lipid hydroperoxide, glutathione (GSH), vitamin C, cholesterol, triglyceride (TG), and high density lipoprotein (HDL) was measured. The activity of superoxide dismutase (SOD), catalase (CAT), and glutathione-s-transferase (GST) was also measured. Two different doses, (500 * 2) mg and (500 * 4) mg spirulina, were given to two groups, each of which comprises 15 COPD patients. RESULTS: All targeted blood parameters have significant difference (P = 0.000) between COPD patients and controls except triglyceride (TG). Spirulina intake for 30 and 60 days at (500 * 2) mg dose has significantly reduced serum content of MDA, lipid hydroperoxide, and cholesterol (P = 0.000) while increasing GSH, Vit C level (P = 0.000), and the activity of SOD (P = 0.000) and GST (P = 0.038). At the same time, spirulina intake for 30 and 60 days at (500 * 4) mg dose has favorable significant effect (P = 0.000) on all targeted blood parameters except for HDL (P = 0.163). PMID- 25685792 TI - Computational study of correlated domain motions in the AcrB efflux transporter. AB - As active part of the major efflux system in E. coli bacteria, AcrB is responsible for the uptake and pumping of toxic substrates from the periplasm toward the extracellular space. In combination with the channel protein TolC and membrane fusion protein AcrA, this efflux pump is able to help the bacterium to survive different kinds of noxious compounds. With the present study we intend to enhance the understanding of the interactions between the domains and monomers, for example, the transduction of mechanical energy from the transmembrane domain into the porter domain, correlated motions of different subdomains within monomers, and cooperative effects between monomers. To this end, targeted molecular dynamics simulations have been employed either steering the whole protein complex or specific parts thereof. By forcing only parts of the complex towards specific conformational states, the risk for transient artificial conformations during the simulations is reduced. Distinct cooperative effects between the monomers in AcrB have been observed. Possible allosteric couplings have been identified providing microscopic insights that might be exploited to design more efficient inhibitors of efflux systems. PMID- 25685793 TI - Effects of Mentha suaveolens essential oil on Chlamydia trachomatis. AB - Chlamydia trachomatis, the most common cause of sexually transmitted bacterial infection worldwide, has a unique biphasic developmental cycle alternating between the infectious elementary body and the replicative reticulate body. C. trachomatis is responsible for severe reproductive complications including pelvic inflammatory disease, ectopic pregnancy, and obstructive infertility. The aim of our study was to evaluate whether Mentha suaveolens essential oil (EOMS) can be considered as a promising candidate for preventing C. trachomatis infection. Specifically, we investigated the in vitro effects of EOMS towards C. trachomatis analysing the different phases of chlamydial developmental cycle. Our results demonstrated that EOMS was effective towards C. trachomatis, whereby it not only inactivated infectious elementary bodies but also inhibited chlamydial replication. Our study also revealed the effectiveness of EOMS, in combination with erythromycin, towards C. trachomatis with a substantial reduction in the minimum effect dose of antibiotic. In conclusion, EOMS treatment may represent a preventative strategy since it may reduce C. trachomatis transmission in the population and, thereby, reduce the number of new chlamydial infections and risk of developing of severe sequelae. PMID- 25685794 TI - Neuroimaging of brain networks and function. PMID- 25685795 TI - Effects of lordotic angle of a cage on sagittal alignment and clinical outcome in one level posterior lumbar interbody fusion with pedicle screw fixation. AB - This study aims to assess the differences in the radiological and clinical results depending on the lordotic angles of the cage in posterior lumbar interbody fusion (PLIF). We reviewed 185 segments which underwent PLIF using two different lordotic angles of 4 degrees and 8 degrees of a polyetheretherketone (PEEK) cage. The segmental lordosis and total lumbar lordosis of the 4 degrees and 8 degrees cage groups were compared preoperatively, as well as on the first postoperative day, 6th and 12th months postoperatively. Clinical assessment was performed using the ODI and the VAS of low back pain. The pre- and immediate postoperative segmental lordosis angles were 12.9 degrees and 12.6 degrees in the 4 degrees group and 12 degrees and 12.0 degrees in the 8 degrees group. Both groups exhibited no significant different segmental lordosis angle and total lumbar lordosis over period and time. However, the total lumbar lordosis significantly increased from six months postoperatively compared with the immediate postoperative day in the 8 degrees group. The ODI and the VAS in both groups had no differences. Cages with different lordotic angles of 4 degrees and 8 degrees showed insignificant results clinically and radiologically in short level PLIF surgery. Clinical improvements and sagittal alignment recovery were significantly observed in both groups. PMID- 25685796 TI - Does more education always lead to better health? Evidence from rural malaysia. AB - Background. Education is usually associated with improvement in health; there is evidence that this may not be the case if education is not fully utilised at work. This study examines the relationship between education level, occupation, and health outcomes of individuals in rural Malaysia. Results. The study finds that the incidence of chronic diseases and high blood pressure are higher for tertiary educated individuals in agriculture and construction occupations. This brings these individuals into more frequent contact with the health system. These occupations are marked with generally lower levels of education and contain fewer individuals with higher levels of education. Conclusions. Education is not always associated with better health outcomes. In certain occupations, greater education seems related to increased chronic disease and contact with the health system, which is the case for workers in agriculture in rural Malaysia. Agriculture is the largest sector of employment in rural Malaysia but with relatively few educated individuals. For the maintenance and sustainability of productivity in this key rural industry, health monitoring and job enrichment policies should be encouraged by government agencies to be part of the agenda for employers in these sectors. PMID- 25685797 TI - Mammalian cell culture process for monoclonal antibody production: nonlinear modelling and parameter estimation. AB - Monoclonal antibodies (mAbs) are at present one of the fastest growing products of pharmaceutical industry, with widespread applications in biochemistry, biology, and medicine. The operation of mAbs production processes is predominantly based on empirical knowledge, the improvements being achieved by using trial-and-error experiments and precedent practices. The nonlinearity of these processes and the absence of suitable instrumentation require an enhanced modelling effort and modern kinetic parameter estimation strategies. The present work is dedicated to nonlinear dynamic modelling and parameter estimation for a mammalian cell culture process used for mAb production. By using a dynamical model of such kind of processes, an optimization-based technique for estimation of kinetic parameters in the model of mammalian cell culture process is developed. The estimation is achieved as a result of minimizing an error function by a particle swarm optimization (PSO) algorithm. The proposed estimation approach is analyzed in this work by using a particular model of mammalian cell culture, as a case study, but is generic for this class of bioprocesses. The presented case study shows that the proposed parameter estimation technique provides a more accurate simulation of the experimentally observed process behaviour than reported in previous studies. PMID- 25685798 TI - Zero discharge performance of an industrial pilot-scale plant treating palm oil mill effluent. AB - Palm oil is one of the most important agroindustries in Malaysia. Huge quantities of palm oil mill effluent (POME) pose a great threat to aqueous environment due to its very high COD. To make full use of discharged wastes, the integrated "zero discharge" pilot-scale industrial plant comprising "pretreatment-anaerobic and aerobic process-membrane separation" was continuously operated for 1 year. After pretreatment in the oil separator tank, 55.6% of waste oil in raw POME could be recovered and sold and anaerobically digested through 2 AnaEG reactors followed by a dissolved air flotation (DAF); average COD reduced to about 3587 mg/L, and biogas production was 27.65 times POME injection which was used to generate electricity. The aerobic effluent was settled for 3 h or/and treated in MBR which could remove BOD3 (30 degrees C) to less than 20 mg/L as required by Department of Environment of Malaysia. After filtration by UF and RO membrane, all organic compounds and most of the salts were removed; RO permeate could be reused as the boiler feed water. RO concentrate combined with anaerobic surplus sludge could be used as biofertilizer. PMID- 25685799 TI - Correlation of serum levels of endostatin with tumor stage in gastric cancer: a systematic review and meta-analysis. AB - BACKGROUND: We performed a systematic review and meta-analysis to study the association between serum endostatin levels and gastric cancer (GC) progression. METHOD: We searched the MEDLINE, Science Citation Index, Cochrane Library, PubMed, Embase, Current Contents Index, and several Chinese databases for published studies relevant to our study topic. Carefully selected studies were pooled and SMD and its corresponding 95% CI were calculated. Version 12.0 STATA software was used for statistical analysis. RESULTS: Serum endostatin levels were analyzed in 12 case-control studies (736 GC patients and 350 controls). Significant differences in serum endostatin levels were observed between GC patients and the healthy controls (SMD = 1.418, 95% CI = 1.079~1.757, P < 0.001). Importantly, significantly lower levels of serum endostatin were found in I-II grade patients compared to those with III-IV grade tumors (P < 0.001). Further, higher serum endostatin levels were observed in the LN invasion-positive GC subjects in comparison with LN invasion-negative subjects (P < 0.001). CONCLUSION: Patients with GC exhibited elevated levels of serum endostatin than controls and its level showed a statistical correlation with the more aggressive type of GC, exhibiting invasion and LN metastasis. Thus, serum levels of endostatin being a useful prognostic biomarker for GC patients warrants further investigation. PMID- 25685800 TI - The type III secretion system (T3SS) of Chlamydophila psittaci is involved in the host inflammatory response by activating the JNK/ERK signaling pathway. AB - Chlamydophila psittaci (C. psittaci) is a human zoonotic pathogen, which could result in severe respiratory disease. In the present study, we investigated the role and mechanism of the type III secretion system (T3SS) of C. psittaci in regulating the inflammatory response in host cells. C. psittaci-infected THP-1 cells were incubated with the specific T3SS inhibitor INP0007, inhibitors of ERK, p38, or JNK, and the levels of inflammatory cytokines were analyzed using Q-PCR and ELISA. The levels of ERK, p38, and JNK phosphorylation were analyzed by Western blot. Our results verified that INP0007 inhibited chlamydial growth in vitro, but the coaddition of exogenous iron completely reversed the growth deficit. INP0007 inhibited the growth of C. psittaci and decreased the levels of IL-8, IL-6, TNF-alpha, and IL-1beta. Exogenous iron restored the chlamydial growth but not the production of inflammatory cytokines. These results demonstrated that the expression of inflammatory cytokines during infection was associated with the T3SS which reduced by incubation with ERK and JNK inhibitors, but not with p38 inhibitor. We concluded that the T3SS elicited inflammatory responses by activating the JNK or ERK signaling pathways in the infection of C. psittaci. PMID- 25685801 TI - Dual functions in response to heat stress and spermatogenesis: characterization of expression profile of small heat shock proteins 9 and 10 in goat testis. AB - Small heat shock proteins 9 and 10 (HSPB9 and HSPB10) are two testis-specific expressed sHsps. The objective of this study was to investigate the mRNA expression profile of HSPB9 and HSPB10 in goat testis among the different seasons, ages, and environmental temperatures. Allocation of the two sHsps was also performed by immunohistochemistry. The results showed that the transcript levels of HSPB9 and HSPB10 were extremely high in the testis (P < 0.01). The relative expression of HSBP9 and HSPB10 in testis showed a tendency to increase with age and then is maintained at the constant level after sexual maturity. HSPB9 and HSPB10 have significantly higher expression in the breeding season (P < 0.05) and hot season (P < 0.01). Both HSPB9 and HSPB10 were found to be upregulated by high-temperature stress in testis (P < 0.05), and the expressions of Hsp70 and Hsp90 were also increased simultaneously (P < 0.01). Immunohistochemistry analysis localized HSPB9 expressed in spermatogonia, spermatocytes, and round spermatids and HSPB10 expressed in the elongate spermatids. In epididymis, strongly staining signal of HSPB10 was detected in pseudostratified columnar epithelium. In conclusion, the two testis-specific sHsps are closely related to male reproduction and heat tolerance. The results could provide valuable data for the further studies on HSPB9 and HSPB10. PMID- 25685802 TI - DT2008: a promising new genetic resource for improved drought tolerance in soybean when solely dependent on symbiotic N2 fixation. AB - Water deficit is one of the major constraints for soybean production in Vietnam. The soybean breeding research efforts conducted at the Agriculture Genetics Institute (AGI) of Vietnam resulted in the development of promising soybean genotypes, suitable for the drought-stressed areas in Vietnam and other countries. Such a variety, namely, DT2008, was recommended by AGI and widely used throughout the country. The aim of this work was to assess the growth of shoots, roots, and nodules of DT2008 versus Williams 82 (W82) in response to drought and subsequent rehydration in symbiotic association as a means to provide genetic resources for genomic research. Better shoot, root, and nodule growth and development were observed in the cultivar DT2008 under sufficient, water deficit, and recovery conditions. Our results represent a good foundation for further comparison of DT2008 and W82 at molecular levels using high throughput omic technologies, which will provide huge amounts of data, enabling us to understand the genetic network involved in regulation of soybean responses to water deficit and increasing the chances of developing drought-tolerant cultivars. PMID- 25685803 TI - Intracranial biodegradable silica-based nimodipine drug release implant for treating vasospasm in subarachnoid hemorrhage in an experimental healthy pig and dog model. AB - Nimodipine is a widely used medication for treating delayed cerebral ischemia (DCI) after subarachnoid hemorrhage. When administrated orally or intravenously, systemic hypotension is an undesirable side effect. Intracranial subarachnoid delivery of nimodipine during aneurysm clipping may be more efficient way of preventing vasospasm and DCI due to higher concentration of nimodipine in cerebrospinal fluid (CSF). The risk of systemic hypotension may also be decreased with intracranial delivery. We used animal models to evaluate the feasibility of surgically implanting a silica-based nimodipine releasing implant into the subarachnoid space through a frontotemporal craniotomy. Concentrations of released nimodipine were measured from plasma samples and CSF samples. Implant degradation was followed using CT imaging. After completing the recovery period, full histological examination was performed on the brain and meninges. The in vitro characteristics of the implant were determined. Our results show that the biodegradable silica-based implant can be used for an intracranial drug delivery system and no major histopathological foreign body reactions were observed. CT imaging is a feasible method for determining the degradation of silica implants in vivo. The sustained release profiles of nimodipine in CSF were achieved. Compared to a traditional treatment, higher nimodipine CSF/plasma ratios can be obtained with the implant. PMID- 25685804 TI - The correlations between health-related quality of life changes and pain and anxiety in orthodontic patients in the initial stage of treatment. AB - This study aimed to assess generic health-related quality of life (HRQoL), pain intensity, and anxiety levels and the relationship between the three aspects in healthy young Chinese orthodontic patients in the early stage of orthodontic treatment. We enrolled 252 eligible participants (10-29 years old) to complete validated Chinese versions of questionnaires, including the State-Trait Anxiety Inventory (S-AI), the visual analogue scale (VAS), and the Short-Form 36-Item Health Survey (SF-36) at baseline and on days 1, 2, 3, 7, 14, and 30 after initial archwire placement (SF-36 only at baseline and day 30). The response rate was 96% (243 of 252). SF-36 had moderate reliability (Cronbach's alpha coefficient exceeding 0.7, good fit on day 30). Statistical significant changes were observed in physical function (P < 0.01), body pain (P = 0.01), and general health (P < 0.01) domains. Spearman correlation coefficients for SF-36 with S-AI were -0.131~-0.515 (P < 0.05); SF-36 with VAS were -0.141~-0.273 (P < 0.05), indicating significant but moderate negative correlations between HRQoL and pain/anxiety. Overall, the application of SF-36 in assessing HRQoL is reluctantly suitable for young Chinese orthodontic patients in the early stage of orthodontic treatment. Early treatment-related pain and anxiety are important factors in HRQoL. PMID- 25685805 TI - Effectiveness of functional electrical stimulation in improving clinical outcomes in the upper arm following stroke: a systematic review and meta-analysis. AB - BACKGROUND: Different therapeutic methods are being used to prevent or decrease long-term impairments of the upper arm in stroke patients. Functional electrical stimulation (FES) is one of these methods, which aims to stimulate the nerves of the weakened muscles so that the resulting muscle contractions resemble those of a functional task. OBJECTIVES: The objective of this study was to review the evidence for the effect of FES on (1) shoulder subluxation, (2) pain, and (3) upper arm motor function in stroke patients, when added to conventional therapy. METHODS: From the 727 retrieved articles, 10 (9 RCTs, 1 quasi-RCT) were selected for final analysis and were rated based on the PEDro (Physiotherapy Evidence Database) scores and the Sackett's levels of evidence. A meta-analysis was performed for all three considered outcomes. RESULTS: The results of the meta analyses showed a significant difference in shoulder subluxation in experimental groups compared to control groups, only if FES was applied early after stroke. No effects were found on pain or motor function outcomes. CONCLUSION: FES can be used to prevent or reduce shoulder subluxation early after stroke. However, it should not be used to reduce pain or improve upper arm motor function after stroke. PMID- 25685806 TI - Fibroblast growth factors stimulate hair growth through beta-catenin and Shh expression in C57BL/6 mice. AB - Growth factors are involved in the regulation of hair morphogenesis and cycle hair growth. The present study sought to investigate the hair growth promoting activities of three approved growth factor drugs, fibroblast growth factor 10 (FGF-10), acidic fibroblast growth factor (FGF-1), and basic fibroblast growth factor (FGF-2), and the mechanism of action. We observed that FGFs promoted hair growth by inducing the anagen phase in telogenic C57BL/6 mice. Specifically, the histomorphometric analysis data indicates that topical application of FGFs induced an earlier anagen phase and prolonged the mature anagen phase, in contrast to the control group. Moreover, the immunohistochemical analysis reveals earlier induction of beta-catenin and Sonic hedgehog (Shh) in hair follicles of the FGFs-treated group. These results suggest that FGFs promote hair growth by inducing the anagen phase in resting hair follicles and might be a potential hair growth-promoting agent. PMID- 25685807 TI - Synthetic covalently linked dimeric form of H2 relaxin retains native RXFP1 activity and has improved in vitro serum stability. AB - Human (H2) relaxin is a two-chain peptide member of the insulin superfamily and possesses potent pleiotropic roles including regulation of connective tissue remodeling and systemic and renal vasodilation. These effects are mediated through interaction with its cognate G-protein-coupled receptor, RXFP1. H2 relaxin recently passed Phase III clinical trials for the treatment of congestive heart failure. However, its in vivo half-life is short due to its susceptibility to proteolytic degradation and renal clearance. To increase its residence time, a covalent dimer of H2 relaxin was designed and assembled through solid phase synthesis of the two chains, including a judiciously monoalkyne sited B-chain, followed by their combination through regioselective disulfide bond formation. Use of a bisazido PEG7 linker and "click" chemistry afforded a dimeric H2 relaxin with its active site structurally unhindered. The resulting peptide possessed a similar secondary structure to the native monomeric H2 relaxin and bound to and activated RXFP1 equally well. It had fewer propensities to activate RXFP2, the receptor for the related insulin-like peptide 3. In human serum, the dimer had a modestly increased half-life compared to the monomeric H2 relaxin suggesting that additional oligomerization may be a viable strategy for producing longer acting variants of H2 relaxin. PMID- 25685808 TI - Plants coping abiotic and biotic stresses: a tale of diligent management. PMID- 25685809 TI - Effects of calcium phosphate nanocrystals on osseointegration of titanium implant in irradiated bone. AB - Radiotherapy may compromise the integration of implant and cause implant loss. Implant surface modifications have the possibility of promoting cell attachment, cell growth, and bone formation which ultimately enhance the osseointegration process. The present study aimed to investigate the effects of calcium phosphate nanocrystals on implant osseointegration in irradiated bone. Sixteen rabbits were randomly assigned into control and nano-CaP groups, receiving implants with dual acid-etched surface or dual acid-etched surface discretely deposited of nanoscale calcium-phosphate crystals, respectively. The left leg of all the rabbits received 15 Gy radiation, followed by implants placement one week after. Four animals in each group were sacrificed after 4 and 12 weeks, respectively. Implant stability quotient (ISQ), ratio of bone volume to total volume (BV/TV), bone growth rate, and bone-to-implant contact (BIC) were evaluated. The nano-CaP group showed significantly higher ISQ (week 12, P = 0.031) and bone growth rate (week 6, P = 0.021; week 9, P = 0.001) than that in control group. No significant differences in BV/TV and BIC were found between two groups. Titanium implant surface modified with CaP nanocrystals provides a potential alternative to improve bone healing around implant in irradiated bone. PMID- 25685810 TI - Breast MRI in patients with unilateral bloody and serous-bloody nipple discharge: a comparison with galactography. AB - PURPOSE: Assessing the role of breast MRI compared to galactography in patients with unilateral bloody or serous-bloody nipple discharge. MATERIALS AND METHODS: Retrospective study including 53 unilateral discharge patients who performed galactography and MRI. We evaluated the capability of both techniques in identifying pathology and distinguishing between nonmalignant and malignant lesions. Lesions BIRADS 1/2 underwent follow-up, while the histological examination after surgery has been the gold standard to assess pathology in lesions BIRADS 3/4/5. The ROC analysis was used to test diagnostic MRI and galactography ability. RESULTS: After surgery and follow-up, 8 patients had no disease (15%), 23 papilloma (43%), 11 papillomatosis (21%), 5 ductal cancer in situ (10%), and 6 papillary carcinoma (11%) diagnoses. Both techniques presented 100% specificity; MRI sensitivity was 98% versus 49% of galactography. Considering MRI, we found a statistical association between mass enhancement and papilloma (P < 0.001; AUC 0.957; CI 0.888-1.025), ductal enhancement and papillomatosis (P < 0.001; AUC 0.790; CI 0.623-0.958), segmental enhancement and ductal cancer in situ (P = 0.007; AUC 0.750; CI 0.429-1.071), and linear enhancement and papillary cancer (P = 0.011). CONCLUSIONS: MRI is a valid tool to detect ductal pathologies in patients with suspicious bloody or serous-bloody discharge showing higher sensitivity and specificity compared to galactography. PMID- 25685811 TI - The roads to mitochondrial dysfunction in a rat model of posttraumatic syringomyelia. AB - The pathophysiology of posttraumatic syringomyelia is incompletely understood. We examined whether local ischemia occurs after spinal cord injury. If so, whether it causes neuronal mitochondrial dysfunction and depletion, and subsequent energy metabolism impairment results in cell starvation of energy and even cell death, contributing to the enlargement of the cavity. Local blood flow was measured in a rat model of posttraumatic syringomyelia that had received injections of quisqualic acid and kaolin. We found an 86 +/- 11% reduction of local blood flow at C8 where a cyst formed at 6 weeks after syrinx induction procedure (P < 0.05), and no difference in blood flow rate between the laminectomy and intact controls. Electron microscopy confirmed irreversible neuronal mitochondrion depletion surrounding the cyst, but recoverable mitochondrial loses in laminectomy rats. Profound energy loss quantified in the spinal cord of syrinx animals, and less ATP and ADP decline observed in laminectomy rats. Our findings demonstrate that an excitotoxic injury induces local ischemia in the spinal cord and results in neuronal mitochondrial depletion, and profound ATP loss, contributing to syrinx enlargement. Ischemia did not occur following laminectomy induced trauma in which mitochondrial loss and decline in ATP were reversible. This confirms excitotoxic injury contributing to the pathology of posttraumatic syringomyelia. PMID- 25685812 TI - Smaller anterior cruciate ligament diameter is a predictor of subjects prone to ligament injuries: an ultrasound study. AB - PURPOSE: To test if diameter of normal anterior cruciate ligament (ACL) can be measured by ultrasound (US), to see if there is a relationship between smaller ACL diameter and ACL injury, and to assess agreement between radiologists in measuring ACL diameter in cases and matched controls. MATERIALS AND METHODS: In this ethics committee-approved study, maximum diameter of ACL near tibial insertion site was measured by static and dynamic US study in 25 normal contralateral knees of subjects who suffered noncontact ACL injury and in 25 matched control subjects. RESULTS: ACL was visualized as a thick linear hypoechoic band inserted approximately 11 mm caudal to the tibial plateau and the intercondylar eminence. Maximum diameter of contralateral ACL near tibial insertion site among injured subjects was significantly smaller than in noninjured subjects (0.62 +/- 0.07 cm versus 0.81 +/- 0.06 cm; P < 0.0001). In the regression analysis, the diameter of ACL near tibial insertion site was found significantly proportional to body weight and not significantly associated to height, gender, and age. CONCLUSION: Diameter of normal ACL near tibial insertion site can be measured by US and the maximum diameter is significantly smaller among subjects with noncontact ACL injury. US is a promising modality that can be used as an excellent screening test to detect subjects especially aspiring athletes prone to ACL injury. Very strong agreement was observed between radiologists in measuring ACL diameter. PMID- 25685813 TI - Transgenic sugarcane resistant to Sorghum mosaic virus based on coat protein gene silencing by RNA interference. AB - As one of the critical diseases of sugarcane, sugarcane mosaic disease can lead to serious decline in stalk yield and sucrose content. It is mainly caused by Potyvirus sugarcane mosaic virus (SCMV) and/or Sorghum mosaic virus (SrMV), with additional differences in viral strains. RNA interference (RNAi) is a novel strategy for producing viral resistant plants. In this study, based on multiple sequence alignment conducted on genomic sequences of different strains and isolates of SrMV, the conserved region of coat protein (CP) genes was selected as the target gene and the interference sequence with size of 423 bp in length was obtained through PCR amplification. The RNAi vector pGII00-HACP with an expression cassette containing both hairpin interference sequence and cp4-epsps herbicide-tolerant gene was transferred to sugarcane cultivar ROC22 via Agrobacterium-mediated transformation. After herbicide screening, PCR molecular identification, and artificial inoculation challenge, anti-SrMV positive transgenic lines were successfully obtained. SrMV resistance rate of the transgenic lines with the interference sequence was 87.5% based on SrMV challenge by artificial inoculation. The genetically modified SrMV-resistant lines of cultivar ROC22 provide resistant germplasm for breeding lines and can also serve as resistant lines having the same genetic background for study of resistance mechanisms. PMID- 25685814 TI - Virtual screening of acetylcholinesterase inhibitors using the Lipinski's rule of five and ZINC databank. AB - Alzheimer's disease (AD) is a progressive and neurodegenerative pathology that can affect people over 65 years of age. It causes several complications, such as behavioral changes, language deficits, depression, and memory impairments. One of the methods used to treat AD is the increase of acetylcholine (ACh) in the brain by using acetylcholinesterase inhibitors (AChEIs). In this study, we used the ZINC databank and the Lipinski's rule of five to perform a virtual screening and a molecular docking (using Auto Dock Vina 1.1.1) aiming to select possible compounds that have quaternary ammonium atom able to inhibit acetylcholinesterase (AChE) activity. The molecules were obtained by screening and further in vitro assays were performed to analyze the most potent inhibitors through the IC50 value and also to describe the interaction models between inhibitors and enzyme by molecular docking. The results showed that compound D inhibited AChE activity from different vertebrate sources and butyrylcholinesterase (BChE) from Equus ferus (EfBChE), with IC50 ranging from 1.69 +/- 0.46 to 5.64 +/- 2.47 uM. Compound D interacted with the peripheral anionic subsite in both enzymes, blocking substrate entrance to the active site. In contrast, compound C had higher specificity as inhibitor of EfBChE. In conclusion, the screening was effective in finding inhibitors of AChE and BuChE from different organisms. PMID- 25685815 TI - Activation of cannabinoid receptor 2 enhances osteogenic differentiation of bone marrow derived mesenchymal stem cells. AB - Bone marrow derived mesenchymal stem cells (BM-MSCs) are considered as the most promising cells source for bone engineering. Cannabinoid (CB) receptors play important roles in bone mass turnover. The aim of this study is to test if activation of CB2 receptor by chemical agonist could enhance the osteogenic differentiation and mineralization in bone BM-MSCs. Alkaline phosphatase (ALP) activity staining and real time PCR were performed to test the osteogenic differentiation. Alizarin red staining was carried out to examine the mineralization. Small interference RNA (siRNA) was used to study the role of CB2 receptor in osteogenic differentiation. Results showed activation of CB2 receptor increased ALP activity, promoted expression of osteogenic genes, and enhanced deposition of calcium in extracellular matrix. Knockdown of CB2 receptor by siRNA inhibited ALP activity and mineralization. Results of immunofluorescent staining showed that phosphorylation of p38 MAP kinase is reduced by knocking down of CB2 receptor. Finally, bone marrow samples demonstrated that expression of CB2 receptor is much lower in osteoporotic patients than in healthy donors. Taken together, data from this study suggested that activation of CB2 receptor plays important role in osteogenic differentiation of BM-MSCs. Lack of CB2 receptor may be related to osteoporosis. PMID- 25685816 TI - Elevation of Tim-3 and PD-1 expression on T cells appears early in HIV infection, and differential Tim-3 and PD-1 expression patterns can be induced by common gamma -chain cytokines. AB - PURPOSE: To explore the association between differential Tim-3 and PD-1 expression patterns and HIV disease progression, and to investigate the impact of common gamma-chain cytokines on Tim-3 and PD-1 expression patterns on T cells. METHODS: Tim-3/PD-1 expression on the T cells of patients with early and chronic HIV infections was detected. The expression levels and functional profiles of T cells with differential Tim-3 and PD-1 expression patterns induced by gamma-chain cytokines were studied. RESULTS: The elevation of differential Tim-3 and PD-1 expression patterns on T cells appeared early in HIV infection. Co-expression of Tim-3 and PD-1 (Tim-3+PD-1+) correlates with more severe exhaustion of T cells during HIV infection. In vitro stimulation of common gamma-chain cytokines can induce differential expression patterns of Tim-3 and PD-1 on T cells. The enhancement of Tim-3 and PD-1 expression by common gamma-chain IL-2 can inhibit the function of T cells re-stimulated by HIV gag and TCR, not by the re stimulation of IL-2. CONCLUSIONS: The elevation of differential Tim-3 and PD-1 expression patterns on T cells represents a state of T cell exhaustion and can be induced by common gamma-chain cytokines. These findings provide insights into HIV pathogenesis and help inform immune intervention strategies. PMID- 25685817 TI - Zoledronic Acid may reduce intraoperative bleeding in spinal tumors: a prospective cohort study. AB - Between June 2010 and June 2011, 176 patients were divided into 2 groups: a group with spinal metastasis of solid tumors (n = 157) and a group with multiple myeloma (n = 19). Both groups were further divided into 2 subgroups: a group receiving zoledronic acid before surgery and a control group. The zoledronic acid subgroup of the solid tumors group was group A (n = 81), the control subgroup of the solid tumors group was group B (n = 76), the zoledronic acid subgroup of the multiple myeloma group was group C (n = 10), and the control subgroup of the multiple myeloma group was group D (n = 9). The average intraoperative blood loss during spinal surgery was as follows: 1311 +/- 691 mL in group A and 1752 +/- 740 mL in group B (P = 0.000) and 1994 +/- 810 mL in group C and 3134 +/- 795 mL in group D (P = 0.000). Patients receiving zoledronic acid before surgery had significantly less intraoperative bleeding than those who did not receive it. Preoperative use of zoledronic acid can effectively reduce intraoperative bleeding during surgery for the treatment of spinal tumors. PMID- 25685818 TI - Design and delivery of a tailored intervention to implement recommendations for multimorbid patients receiving polypharmacy into primary care practices. AB - Introduction. Managing polypharmacy is particularly demanding for general practitioners as coordinators of care. Recently, a German guideline for polypharmacy in primary care has been published. This paper describes the content and delivery of a tailored intervention, which aims at improving the implementation of guideline recommendations for polypharmacy into practice, considering individual barriers. Materials and Methods. Firstly, barriers for implementation and the corresponding strategies to address them have been identified. On this basis, an intervention consisting of a workshop for health care professionals and educational materials for patients has been developed. The workshop focused on knowledge, awareness, and skills. The educational materials included a tablet computer. Practice teams will elaborate individual concepts of how to implement the recommendations into their practice. The workshop has been evaluated by the participants by means of a questionnaire. Results. During the workshop 41 possible sources of medication errors and 41 strategies to improve medication management have been identified. Participants evaluated the workshop overall positively, certifying its relevancy to practice. Discussion. The concept of the workshop seemed appropriate to impart knowledge about medication management to the participants. It will have to be evaluated, if the intervention finally resulted in an improved implementation of the guideline recommendations. PMID- 25685819 TI - The diagnosis of invasive and noninvasive pulmonary aspergillosis by serum and bronchoalveolar lavage fluid galactomannan assay. AB - The incidence and mortality of invasive pulmonary aspergillosis (IPA) are rising, particularly in critically ill patients and patients with severe chronic obstructive pulmonary disease (COPD). Noninvasive aspergillosis occurring in these patients requires special attention because of the possibility of developing subsequent IPA, given the poor health and worsened immune state of these patients. We compared the performance of the Platelia galactomannan (GM) enzyme immunoassay in the bronchoalveolar lavage fluid (BALF) and serum. The sensitivity, and specificity of BALF-GM were 85.4% and 62.4%, and those of serum GM were 67.9% and 93.5% at the cutoff index of 0.5. As the cutoff index increased, the specificity of BALF-GM detection was increased with the detriment of sensitivity. The area under the ROC curves was 0.817 (95% CI: 0.718-0.916) for BALF-GM and 0.819 (95% CI: 0.712-0.926) for serum-GM. The optimal cutoff index was 1.19 for BALF-GM, and the sensitivity and specificity were 67.9% and 89.2%. The BALF-GM assay is more sensitive in detecting pulmonary aspergillosis than serum-GM assay and fungal cultures. However, BALF-GM assay has a high false positive rate at the cutoff index of 0.5. Hence, the diagnostic cutoff index of the BALF-GM assay should be improved to avoid the overdiagnosis of pulmonary aspergillosis in clinic. PMID- 25685820 TI - Pyrosequencing reveals fungal communities in the rhizosphere of Xinjiang Jujube. AB - Fungi are important soil components as both decomposers and plant symbionts and play a major role in ecological and biogeochemical processes. However, little is known about the richness and structure of fungal communities. DNA sequencing technologies allow for the direct estimation of microbial community diversity, avoiding culture-based biases. We therefore used 454 pyrosequencing to investigate the fungal communities in the rhizosphere of Xinjiang jujube. We obtained no less than 40,488 internal transcribed spacer (ITS) rDNA reads, the number of each sample was 6943, 6647, 6584, 6550, 6860, and 6904, and we used bioinformatics and multivariate statistics to analyze the results. The index of diversity showed greater richness in the rhizosphere fungal community of a 3-year old jujube than in that of an 8-year-old jujube. Most operational taxonomic units belonged to Ascomycota, and taxonomic analyses identified Hypocreales as the dominant fungal order. Our results demonstrated that the fungal orders are present in different proportions in different sampling areas. Redundancy analysis (RDA) revealed a significant correlation between soil properties and the abundance of fungal phyla. Our results indicated lower fungal diversity in the rhizosphere of Xinjiang jujube than that reported in other studies, and we hope our findings provide a reference for future research. PMID- 25685821 TI - Pathogenic potential of two sibling species, Anisakis simplex (s.s.) and Anisakis pegreffii (Nematoda: Anisakidae): in vitro and in vivo studies. AB - The pathogenic potentials of two sibling nematodes Anisakis simplex sensu stricto (s.s.) and A. pegreffii were compared by in vitro and in vivo studies. Live third stage larvae of each species were subjected to agar blocks made using PBS or RPMI 1640, overlaid with different supernatants (artificial gastric juice, PBS, and RPMI-1640), and their penetration ability was compared. Their tolerance of artificial gastric juice was also tested. Further, they were introduced into rats by gastric intubation, and the in vivo locations of them were investigated. A. pegreffii showed higher penetration ability than A. simplex (s.s.) in most of the experimental conditions, except for the RPMI-1640 agar block overlaid with artificial gastric juice. In an acid tolerance test, the mean survival times were 6.1 days for A. simplex (s.s.) and 4.2 days for A. pegreffii. In an animal experiment, A. simplex (s.s.) stayed for a shorter time in the stomachs of rats than A. pegreffii. Some A. pegreffii and A. simplex (s.s.) were embedded in the gastric mucosa or freely existed in the abdominal cavity. All of these results suggest that A. pegreffii has the pathogenic potential to cause anisakidosis in humans when ingested, as does A. simplex (s.s.). PMID- 25685822 TI - Dendrobium chrysotoxum Lindl. alleviates diabetic retinopathy by preventing retinal inflammation and tight junction protein decrease. AB - Diabetic retinopathy (DR) is a serious complication of diabetes mellitus. This study aimed to observe the alleviation of the ethanol extract of Dendrobium chrysotoxum Lindl. (DC), a traditional Chinese herbal medicine, on DR and its engaged mechanism. After DC (30 or 300 mg/kg) was orally administrated, the breakdown of blood retinal barrier (BRB) in streptozotocin- (STZ-) induced diabetic rats was attenuated by DC. Decreased retinal mRNA expression of tight junction proteins (including occludin and claudin-1) in diabetic rats was also reversed by DC. Western blot analysis and retinal immunofluorescence staining results further confirmed that DC reversed the decreased expression of occludin and claudin-1 proteins in diabetic rats. DC reduced the increased retinal mRNA expressions of intercellular adhesion molecule-1 (ICAM-1), tumor necrosis factor alpha (TNFalpha), interleukin- (IL-) 6, and IL-1beta in diabetic rats. In addition, DC alleviated the increased 1 and phosphorylated p65, IkappaB, and IkappaB kinase (IKK) in diabetic rats. DC also reduced the increased serum levels of TNFalpha, interferon-gamma (IFN-gamma), IL-6, IL-1beta, IL-8, IL-12, IL-2, IL 3, and IL-10 in diabetic rats. Therefore, DC can alleviate DR by inhibiting retinal inflammation and preventing the decrease of tight junction proteins, such as occludin and claudin-1. PMID- 25685823 TI - Gait Asymmetries Persist 1 Year After Anterior Cruciate Ligament Reconstruction. AB - BACKGROUND: After anterior cruciate ligament reconstruction (ACLR), motivation to return to previous levels of activity is high. Very few studies have used return to-activity criteria to determine when to permit athletic play. Return-to activity measures objectively evaluate functional limb symmetry; however, previous biomechanical studies have found gait deviations in these individuals that persist up to 2 years after surgery. PURPOSE: To evaluate gait biomechanics in a specific cohort of ACL patients 1 year after surgery and retrospectively compare individuals who pass return-to-activity criteria 6 months after surgery with those who fail. STUDY DESIGN: Prospective analysis. METHODS: A total of 40 athletes who participated regularly (>50 h/y) in cutting, jumping, and pivoting activities and who sustained an isolated, unilateral ACL rupture were included in this study. All participants underwent reconstruction by the same surgeon and received individualized postoperative rehabilitation. Performance-based and self report data were measured 6 months after surgery to assess readiness to return to activity (90% outcome required to pass); 20 subjects passed return-to-activity criteria and 20 subjects did not. Motion analysis was performed 1 year after surgery, and knee flexion angles, moments, and excursions were measured during gait and evaluated for all subjects. RESULTS: There was no limb * group interaction or effect of group for all measures. Decreased knee measures were seen on the involved limb compared with the uninvolved limb for all subjects, and failed subjects demonstrated larger differences between limbs. CONCLUSION: Patients continued to demonstrate biomechanical limb asymmetries 1 year after ACLR, regardless of performance-based measures at 6 months. Early return to activity did not ensure limb symmetry at 1 year. CLINICAL RELEVANCE: Gait asymmetries were seen in all subjects 1 year after surgery regardless of status at 6 months. Potentially prolonging athlete's timelines for returning to activity may prove beneficial for a successful return to activity as well as for long-term knee function. PMID- 25685824 TI - Analysis of iterative region-of-interest image reconstruction for x-ray computed tomography. AB - One of the challenges for iterative image reconstruction (IIR) is that such algorithms solve an imaging model implicitly, requiring a complete representation of the scanned subject within the viewing domain of the scanner. This requirement can place a prohibitively high computational burden for IIR applied to x-ray computed tomography (CT), especially when high-resolution tomographic volumes are required. In this work, we aim to develop an IIR algorithm for direct region-of interest (ROI) image reconstruction. The proposed class of IIR algorithms is based on an optimization problem that incorporates a data fidelity term, which compares a derivative of the estimated data with the available projection data. In order to characterize this optimization problem, we apply it to computer simulated two-dimensional fan-beam CT data, using both ideal noiseless data and realistic data containing a level of noise comparable to that of the breast CT application. The proposed method is demonstrated for both complete field-of-view and ROI imaging. To demonstrate the potential utility of the proposed ROI imaging method, it is applied to actual CT scanner data. PMID- 25685825 TI - Region of interest based Hotelling observer for computed tomography with comparison to alternative methods. AB - We compare several approaches to estimation of Hotelling observer (HO) performance in x-ray computed tomography (CT). We consider the case where the signal of interest is small so that the reconstructed image can be restricted to a small region of interest (ROI) surrounding the signal. This reduces the dimensionality of the image covariance matrix so that direct computation of HO metrics within the ROI is feasible. We propose that this approach is directly applicable to systems optimization in CT; however, many alternative approaches exist, which make computation of HO performance tractable through a range of approximations, assumptions, or estimation strategies. Here, we compare several of these methods, including the use of Laguerre-Gauss channels, discrete Fourier domain computation of the HO (which assumes noise stationarity), and two approaches to HO estimation through samples of noisy images. Since our method computes HO performance exactly within an ROI, this allows us to investigate the validity of the assumptions inherent in various common approaches to HO estimation, such as the stationarity assumption in the case of the discrete Fourier transform domain method. PMID- 25685826 TI - Does screening keep Ebola out of USA? PMID- 25685827 TI - Effects of long-term doxycycline on bone quality and strength in diabetic male DBA/2J mice. AB - In type 1 diabetes, diabetic bone disease (DBD) is characterized by decreased bone mineral density, a state of low bone turnover and an increased risk of fracture. Animal models of DBD demonstrate that acquired alterations in trabecular and cortical bone microarchitecture contribute to decreased bone strength in diabetes. With anti-collagenolytic and anti-inflammatory properties, tetracycline derivatives may prevent diabetes-related decreases in bone strength. To determine if doxycycline, a tetracycline class antibiotic, can prevent the development of DBD in a model of long-term diabetes, male DBA/2J mice, with or without diabetes, were treated with doxycycline-containing chow for 10 weeks (dose range, 28-92 mg/kg/day). Long-term doxycycline exposure was not deleterious to the microarchitecture or biomechanical properties of healthy bone in male DBA/2J mice. Doxycycline treatment also did not prevent or alleviate the deleterious changes in trabecular microarchitecture, cortical structure, and biomechanical properties of bone induced by chronic diabetes. PMID- 25685828 TI - The versatile functions of Sox9 in development, stem cells, and human diseases. AB - The transcription factor Sox9 was first discovered in patients with campomelic dysplasia, a haploinsufficiency disorder with skeletal deformities caused by dysregulation of Sox9 expression during chondrogenesis. Since then, its role as a cell fate determiner during embryonic development has been well characterized; Sox9 expression differentiates cells derived from all three germ layers into a large variety of specialized tissues and organs. However, recent data has shown that ectoderm- and endoderm-derived tissues continue to express Sox9 in mature organs and stem cell pools, suggesting its role in cell maintenance and specification during adult life. The versatility of Sox9 may be explained by a combination of post-transcriptional modifications, binding partners, and the tissue type in which it is expressed. Considering its importance during both development and adult life, it follows that dysregulation of Sox9 has been implicated in various congenital and acquired diseases, including fibrosis and cancer. This review provides a summary of the various roles of Sox9 in cell fate specification, stem cell biology, and related human diseases. Ultimately, understanding the mechanisms that regulate Sox9 will be crucial for developing effective therapies to treat disease caused by stem cell dysregulation or even reverse organ damage. PMID- 25685829 TI - Oncolytic adenoviruses: A thorny path to glioma cure. AB - Glioblastoma Multiforme (GBM) is a rapidly progressing brain tumor. Despite the relatively low percentage of cancer patients with glioma diagnoses, recent statistics indicate that the number of glioma patients may have increased over the past decade. Current therapeutic options for glioma patients include tumor resection, chemotherapy, and concomitant radiation therapy with an average survival of approximately 16 months. The rapid progression of gliomas has spurred the development of novel treatment options, such as cancer gene therapy and oncolytic virotherapy. Preclinical testing of oncolytic adenoviruses using glioma models revealed both positive and negative sides of the virotherapy approach. Here we present a detailed overview of the glioma virotherapy field and discuss auxiliary therapeutic strategies with the potential for augmenting clinical efficacy of GBM virotherapy treatment. PMID- 25685830 TI - An Endotoxin Tolerance Signature Predicts Sepsis and Organ Dysfunction at Initial Clinical Presentation. AB - BACKGROUND: Sepsis involves aberrant immune responses to infection, but the exact nature of this immune dysfunction remains poorly defined. Bacterial endotoxins like lipopolysaccharide (LPS) are potent inducers of inflammation, which has been associated with the pathophysiology of sepsis, but repeated exposure can also induce a suppressive effect known as endotoxin tolerance or cellular reprogramming. It has been proposed that endotoxin tolerance might be associated with the immunosuppressive state that was primarily observed during late-stage sepsis. However, this relationship remains poorly characterised. Here we clarify the underlying mechanisms and timing of immune dysfunction in sepsis. METHODS: We defined a gene expression signature characteristic of endotoxin tolerance. Gene set test approaches were used to correlate this signature with early sepsis, both newly and retrospectively analysing microarrays from 593 patients in 11 cohorts. Then we recruited a unique cohort of possible sepsis patients at first clinical presentation in an independent blinded controlled observational study to determine whether this signature was associated with the development of confirmed sepsis and organ dysfunction. FINDINGS: All sepsis patients presented an expression profile strongly associated with the endotoxin tolerance signature (p < 0.01; AUC 96.1%). Importantly, this signature further differentiated between suspected sepsis patients who did, or did not, go on to develop confirmed sepsis, and predicted the development of organ dysfunction. INTERPRETATION: Our data support an updated model of sepsis pathogenesis in which endotoxin tolerance mediated immune dysfunction (cellular reprogramming) is present throughout the clinical course of disease and related to disease severity. Thus endotoxin tolerance might offer new insights guiding the development of new therapies and diagnostics for early sepsis. PMID- 25685831 TI - The effect of hydroxyl moieties and their oxosubstitution on bile acid association studied in floating monolayers. AB - Bile salt aggregates are promising candidates for drug delivery vehicles due to their unique fat-solubilizing ability. However, the toxicity of bile salts increases with improving fat-solubilizing capability and so an optimal combination of efficient solubilization and low toxicity is necessary. To improve hydrophilicity (and decrease toxicity), we substituted hydroxyl groups of several natural bile acid (BA) molecules for oxogroups and studied their intrinsic molecular association behavior. Here we present the comparative Langmuir trough study of the two-dimensional (2D) association behavior of eight natural BAs and four oxoderivatives (traditionally called keto-derivatives) floated on an aqueous subphase. The series of BAs and derivatives showed systematic changes in the shape of the compression isotherms. Two types of association could be distinguished: the first transition was assigned to the formation of dimers through H-bonding and the second to the hydrophobic aggregation of BA dimers. Hydrophobic association of BA molecules in the films is linked to the ability of forming H-bonded dimers. Both H-bond formation and hydrophobic association weakened with increasing number of hydroxyl groups, decreasing distance between hydroxyl groups, and increasing oxosubstitution. The results also show that the Langmuir trough method is extremely useful in selecting appropriate BA molecules to design drug delivery systems. PMID- 25685832 TI - Exploiting semantic annotations and Q-learning for constructing an efficient hierarchy/graph texts organization. AB - Tremendous growth in the number of textual documents has produced daily requirements for effective development to explore, analyze, and discover knowledge from these textual documents. Conventional text mining and managing systems mainly use the presence or absence of key words to discover and analyze useful information from textual documents. However, simple word counts and frequency distributions of term appearances do not capture the meaning behind the words, which results in limiting the ability to mine the texts. This paper proposes an efficient methodology for constructing hierarchy/graph-based texts organization and representation scheme based on semantic annotation and Q learning. This methodology is based on semantic notions to represent the text in documents, to infer unknown dependencies and relationships among concepts in a text, to measure the relatedness between text documents, and to apply mining processes using the representation and the relatedness measure. The representation scheme reflects the existing relationships among concepts and facilitates accurate relatedness measurements that result in a better mining performance. An extensive experimental evaluation is conducted on real datasets from various domains, indicating the importance of the proposed approach. PMID- 25685833 TI - Temporary redundant transmission mechanism for SCTP multihomed hosts. AB - In SCTP's Concurrent Multipath Transfer, if data is sent to the destined IP(s) without knowledge of the paths condition, packets may be lost or delayed. This is because of the bursty nature of IP traffic and physical damage to the network. To offset these problems, network path status is examined using our new mechanism Multipath State Aware Concurrent Multipath Transfer using redundant transmission (MSACMT-RTv2). Here the status of multiple paths is analyzed, initially and periodically thereafter transmitted. After examination, paths priority is assigned before transmission. One path is temporarily employed as redundant path for the failure-expected path (FEP); this redundant path is used for transmitting redundant data. At the end of predefined period, reliability of the FEP is confirmed. If FEP is ensured to be reliable, temporary path is transformed into normal CMT path. MSACMT-RTv2 algorithm is simulated using the Delaware University ns-2 SCTP/CMT module (ns-2; V2.29). We present and discuss MSACMT-RTv2 performance in asymmetric path delay and with finite receiver buffer (rbuf) size. We extended our experiment to test robustness of this algorithm and inferred exhaustive result. It is inferred that our algorithm outperforms better in terms of increasing the throughput and reducing the latency than existing system. PMID- 25685834 TI - Association between single nucleotide polymorphism of vitamin D receptor gene FokI polymorphism and clinical progress of benign prostatic hyperplasia. AB - BACKGROUND: The aim of the study was to investigate the association between single nucleotide polymorphism (SNP) of vitamin D receptor (VDR) gene and clinical progress of benign prostatic hyperplasia (BPH) in Chinese men. METHODS: The DNA was extracted from blood of 200 BPH patients with operation (progression group) and 200 patients without operation (control group), respectively. The genotypes of VDR gene FokI SNP represented by "F/f" were identified by PCR restriction fragment length polymorphism. The odds ratio (OR) of having progression of BPH for having the genotype were calculated. RESULTS: Our date indicated that the f alleles of the VDR gene FokI SNP associated with the progression of BPH (P = 0.009). CONCLUSION: For the first time, our study demonstrated that VDR gene FokI SNP may be associated with the risk of BPH progress. PMID- 25685835 TI - Prevalence and molecular epidemiological data on Dirofilaria immitis in dogs from Northeastern States of India. AB - The aim of the present study was to determine the prevalence of Dirofilaria immitis in stray, pet, and working dogs (n = 413, 266, and 103, resp.) from Guwahati (Assam) and Aizawl (Mizoram), areas located in two Northeastern States of India. Diagnostic methods applied were microscopy (wet film and Knott's concentration technique), immunological test (Ag ELISA by SNAP 4Dx ELISA kit), and molecular tools (polymerase chain reaction and sequencing), which evidenced 11.38, 18.03, and 13.93% of positive animals, respectively. No significant differences were observed by area (18.23% versus 17.68%) nor by sex (18.1% versus 17.9%), whereas stray dogs proved more infected than other groups (P < 0.05). ELISA test evidenced an overall 22.69% of occult infections, mainly in working dogs (60%), and molecular techniques detected Dirofilaria (Nochtiella) repens in 4 stray dogs from Guwahati. Characterization of D. immitis isolates for ITS-2 region showed close identity with South Asian isolates. PMID- 25685836 TI - The alpaca melanocortin 1 receptor: gene mutations, transcripts, and relative levels of expression in ventral skin biopsies. AB - The objectives of the present study were to characterize the MC1R gene, its transcripts and the single nucleotide polymorphisms (SNPs) associated with coat color in alpaca. Full length cDNA amplification revealed the presence of two transcripts, named as F1 and F2, differing only in the length of their 5' terminal untranslated region (UTR) sequences and presenting a color specific expression. Whereas the F1 transcript was common to white and colored (black and brown) alpaca phenotypes, the shorter F2 transcript was specific to white alpaca. Further sequencing of the MC1R gene in white and colored alpaca identified a total of twelve SNPs; among those nine (four silent mutations (c.126C>A, c.354T>C, c.618G>A, and c.933G>A); five missense mutations (c.82A>G, c.92C>T, c.259A>G, c.376A>G, and c.901C>T)) were observed in coding region and three in the 3'UTR. A 4 bp deletion (c.224 227del) was also identified in the coding region. Molecular segregation analysis uncovered that the combinatory mutations in the MC1R locus could cause eumelanin and pheomelanin synthesis in alpaca. Overall, our data refine what is known about the MC1R gene and provides additional information on its role in alpaca pigmentation. PMID- 25685837 TI - Decolorization of anthraquinonic dyes from textile effluent using horseradish peroxidase: optimization and kinetic study. AB - Two anthraquinonic dyes, C.I. Acid Blue 225 and C.I. Acid Violet 109, were used as models to explore the feasibility of using the horseradish peroxidase enzyme (HRP) in the practical decolorization of anthraquinonic dyes in wastewater. The influence of process parameters such as enzyme concentration, hydrogen peroxide concentration, temperature, dye concentration, and pH was examined. The pH and temperature activity profiles were similar for decolorization of both dyes. Under the optimal conditions, 94.7% of C.I. Acid Violet 109 from aqueous solution was decolorized (treatment time 15 min, enzyme concentration 0.15 IU/mL, hydrogen peroxide concentration 0.4 mM, dye concentration 30 mg/L, pH 4, and temperature 24 degrees C) and 89.36% of C.I. Acid Blue 225 (32 min, enzyme concentration 0.15 IU/mL, hydrogen peroxide concentration 0.04 mM, dye concentration 30 mg/L, pH 5, and temperature 24 degrees C). The mechanism of both reactions has been proven to follow the two substrate ping-pong mechanism with substrate inhibition, revealing the formation of a nonproductive or dead-end complex between dye and HRP or between H2O2 and the oxidized form of the enzyme. Both chemical oxygen demand and total organic carbon values showed that there was a reduction in toxicity after the enzymatic treatment. This study verifies the viability of use of horseradish peroxidase for the wastewaters treatment of similar anthraquinonic dyes. PMID- 25685838 TI - Mechanism of gene amplification via yeast autonomously replicating sequences. AB - The present investigation was aimed at understanding the molecular mechanism of gene amplification. Interplay of fragile sites in promoting gene amplification was also elucidated. The amplification promoting sequences were chosen from the Saccharomyces cerevisiae ARS, 5S rRNA regions of Plantago ovata and P. lagopus, proposed sites of replication pausing at Ste20 gene locus of S. cerevisiae, and the bend DNA sequences within fragile site FRA11A in humans. The gene amplification assays showed that plasmid bearing APS from yeast and human beings led to enhanced protein concentration as compared to the wild type. Both the in silico and in vitro analyses were pointed out at the strong bending potential of these APS. In addition, high mitotic stability and presence of TTTT repeats and SAR amongst these sequences encourage gene amplification. Phylogenetic analysis of S. cerevisiae ARS was also conducted. The combinatorial power of different aspects of APS analyzed in the present investigation was harnessed to reach a consensus about the factors which stimulate gene expression, in presence of these sequences. It was concluded that the mechanism of gene amplification was that AT rich tracts present in fragile sites of yeast serve as binding sites for MAR/SAR and DNA unwinding elements. The DNA protein interactions necessary for ORC activation are facilitated by DNA bending. These specific bindings at ORC promote repeated rounds of DNA replication leading to gene amplification. PMID- 25685839 TI - Efficacy and safety of miltefosine in treatment of post-kala-azar dermal leishmaniasis. AB - BACKGROUND: Long regimens for the treatment of post-kala-azar dermal leishmaniasis (PKDL) result in noncompliance. A safe, effective, and acceptable regimen for the treatment of PKDL is still to be developed. Miltefosine has been found to be effective in the treatment of Visceral Leishmaniasis (VL). Hence, its efficacy was tested in patients of PKDL. METHODS: In this exploratory study, 33 patients with PKDL aged 10 years and above were administered miltefosine (50 mg for those weighing < 25 kg or 100 mg in divided doses for those >= 25 kg and 2.5 mg per kg for children) for 12 weeks and followed up for one year to find out the efficacy. RESULTS: Out of 33 patients, 3 patients withdrew consent. Treatment was stopped due to adverse effect in 1 patient. 28 (96.6%) got cured with complete disappearance of lesion while 1 patient (3.4%) failed treatment by protocol analysis. CONCLUSION: Miltefosine was found to be effective and safe in the treatment of PKDL. PMID- 25685841 TI - A dynamic integrated fault diagnosis method for power transformers. AB - In order to diagnose transformer fault efficiently and accurately, a dynamic integrated fault diagnosis method based on Bayesian network is proposed in this paper. First, an integrated fault diagnosis model is established based on the causal relationship among abnormal working conditions, failure modes, and failure symptoms of transformers, aimed at obtaining the most possible failure mode. And then considering the evidence input into the diagnosis model is gradually acquired and the fault diagnosis process in reality is multistep, a dynamic fault diagnosis mechanism is proposed based on the integrated fault diagnosis model. Different from the existing one-step diagnosis mechanism, it includes a multistep evidence-selection process, which gives the most effective diagnostic test to be performed in next step. Therefore, it can reduce unnecessary diagnostic tests and improve the accuracy and efficiency of diagnosis. Finally, the dynamic integrated fault diagnosis method is applied to actual cases, and the validity of this method is verified. PMID- 25685840 TI - Gender differences in individuals at high-risk of psychosis: a comprehensive literature review. AB - INTRODUCTION: To date, few studies have focused on the characterization of clinical phenomenology regarding gender in population at high-risk of psychosis. This paper is an attempt to summarize the findings found in the scientific literature regarding gender differences in high-risk populations, taking into account parameters studied in populations with schizophrenia and other psychotic disorders, such as incidence, clinical expression, duration of untreated illness (DUI), social functioning, and cognitive impairment prior to full-blown psychosis development. METHOD: Studies were systematically searched in PubMed. Studies using gender variable as a control variable were excluded. 12 studies met inclusion criteria. RESULTS: Most of the studies found a differential pattern between women and men as regards clinical, social, and cognitive variables in the prodromal phase, with worse performance in men except in cognitive functioning (more severe negative symptoms, worse social functioning, and longer DUI in men). Similar conversion rates over time were found between men and women. CONCLUSIONS: Many of the studies analyzed suggest that differences between men and women in the expression of psychosis extend across a continuum, from the subclinical forms of illness to the debut of psychosis. However, the small number of studies and their significant methodological and clinical limitations do not allow for firm conclusions. PMID- 25685842 TI - Geographic tongue and fissured tongue in 348 patients with psoriasis: correlation with disease severity. AB - Geographic tongue (GT) and fissured tongue (FT) are the more frequent oral lesions in patients with psoriasis. The aims of this study were to compare the prevalence of GT/FT between psoriasis group (PG) and healthy controls (HC) and investigate the correlation between GT/FT and psoriasis severity using the PASI and age of psoriasis onset. Three hundred and forty-eight PG and 348 HC were selected. According to the age of psoriasis onset, the individuals were classified as having early psoriasis and late psoriasis. The severity of vulgaris psoriasis was determined according to PASI. A follow-up was conducted in patients with psoriasis vulgaris (PV) with GT to evaluate the progression of oral and cutaneous lesions. The FT and GT were more frequent in PG than in HC. The incidence of GT was higher in patients with early psoriasis and that of FT in late-psoriasis. There is association between psoriasis intensity and GT; and a higher monthly decrease of PASI score in patients without GT. The presence of GT and FT is higher in PG than in the HC. GT is associated with disease severity and may be a marker of the psoriasis severity. PMID- 25685843 TI - Efficacy of nonthermal atmospheric pressure plasma for tooth bleaching. AB - The conventional light source used for tooth bleaching has the potential to cause thermal damage, and the actual role of the light source is doubtful. In this study, we evaluated bleaching efficacy, temperature, and morphological safety after tooth bleaching with nonthermal atmospheric pressure plasma. Tooth bleaching combined with plasma had improved efficacy in providing a higher level of brightness. The temperature of the pulp chamber was maintained around 37 degrees C, indicating that the plasma does not cause any thermal damage. The morphological results of tooth bleaching with plasma did not affect mineral composition under scanning electron microscopy (SEM) observations. On the basis of these results, the application of plasma and low concentration of 15% carbamide peroxide (CP) has a high capability for effective tooth bleaching. It can be documented that plasma is a safe energy source, which has no deleterious effects on the tooth surface. PMID- 25685844 TI - Haemophilia A: pharmacoeconomic review of prophylaxis treatment versus on-demand. AB - OBJECTIVES: Haemophilia A is a congenital disorder of coagulation that mainly affects males and causes a considerable use of resources, especially when hemophilic patients are treated with prophylaxis. The aim of the present review was to discuss and appraise the methodological aspects and results of published economic evaluations of haemophilia A treatments in the last decade. METHODS: The literature search, performed by consulting four engines, covered studies published between 2002 and 2014. Full economic evaluations published in English language were identified and included in the review. A quality assessment of the studies was also carried out based on Drummond's checklist. RESULTS: After careful evaluations of the identified records, 5 studies were reviewed. Primary and secondary prophylaxis resulted cost-effective compared to on-demand therapy: the ICER of primary prophylaxis ranged from ? 40.236 to ? 59.315/QALY gained, while the ICER of secondary prophylaxis was ? 40.229/QALY gained. Furthermore, 60% were high quality and 40% were medium quality studies. CONCLUSIONS: The review underlines the cost-effectiveness of prophylaxis versus on-demand treatment and the different methodological approaches applied. Further economic evaluations are required with models that reflect the clinical reality and consumption of resources in each country. PMID- 25685845 TI - Evidence for negative effects of elevated intra-abdominal pressure on pulmonary mechanics and oxidative stress. AB - OBJECTIVE: To compare the effects of pneumoperitoneum on lung mechanics, end tidal CO2 (ETCO2), arterial blood gases (ABG), and oxidative stress markers in blood and bronchoalveolar lavage fluid (BALF) during laparoscopic cholecystectomy (LC) by using lung-protective ventilation strategy. MATERIALS AND METHODS: Forty six patients undergoing LC and abdominal wall hernia (AWH) surgery were assigned into 2 groups. Measurements and blood samples were obtained before, during pneumoperitoneum, and at the end of surgery. BALF samples were obtained after anesthesia induction and at the end of surgery. RESULTS: Peak inspiratory pressure, ETCO2, and pCO2 values at the 30th minute were significantly increased, while there was a significant decrease in dynamic lung compliance, pH, and pO2 values in LC group. In BALF samples, total oxidant status (TOS), arylesterase, paraoxonase, and malondialdehyde levels were significantly increased; the glutathione peroxidase levels were significantly decreased in LC group. The serum levels of TOS and paraoxonase were significantly higher at the end of surgery in LC group. In addition, arylesterase level in the 30th minute was increased compared to baseline. Serum paraoxonase level at the end of surgery was significantly increased when compared to AWH group. CONCLUSIONS: Our study showed negative effects of pneumoperitoneum in both lung and systemic levels despite lung-protective ventilation strategy. PMID- 25685846 TI - Effects of TGF-beta1 on OPG/RANKL expression of cementoblasts and osteoblasts are similar without stress but different with mechanical compressive stress. AB - INTRODUCTION: This study aimed to explore the effects of TGF-beta1 on regulating activities of cementoblasts and osteoblasts with or without stress. MATERIAL AND METHODS: Human recombinant TGF-beta1 was added with different doses. Immunohistochemical test of osteoprotegerin (OPG)/receptor activator of nuclear factor-kappaB ligand (RANKL) and Alizarin Red-S staining were conducted. Mechanical compressive stress was obtained by increasing the pressure of gaseous phase. OPG/RANKL expression was detected in both cells through quantitative real time PCR. RESULTS: Similar significant differences (P < 0.05) existed in OPG/RANKL change with increasing concentration of TGF-beta1 without mechanical stress for cementoblasts and osteoblasts. However, under 3 h stress, OPG increased and RANKL decreased significantly (P < 0.01) but with similar OPG/RANKL change. Moreover, under 24 h stress, OPG change exhibited no difference (P > 0.05), but RANKL decreased significantly (P < 0.01) at 10 and 100 ng/mL TGF-beta1 in cementoblasts. In osteoblasts, OPG increased significantly (P < 0.01) at 10 and 100 ng/mL, whereas RANKL decreased with statistical difference (P < 0.05) at 1 and 10 ng/mL. CONCLUSIONS: The effects of TGF-beta1 on OPG/RANKL expression of cementoblasts and osteoblasts are similar even without mechanical stress. However, these effects are different under mechanical compressive stress. PMID- 25685847 TI - C1-almost periodic solutions of BAM neural networks with time-varying delays on time scales. AB - On a new type of almost periodic time scales, a class of BAM neural networks is considered. By employing a fixed point theorem and differential inequality techniques, some sufficient conditions ensuring the existence and global exponential stability of C1-almost periodic solutions for this class of networks with time-varying delays are established. Two examples are given to show the effectiveness of the proposed method and results. PMID- 25685848 TI - The "gender factor" in wearing-off among patients with Parkinson's disease: a post hoc analysis of DEEP study. AB - BACKGROUND: The early detection of wearing-off in Parkinson disease (DEEP) observational study demonstrated that women with Parkinson's disease (PD) carry an increased risk (80.1%) for wearing-off (WO). This post hoc analysis of DEEP study evaluates gender differences on WO and associated phenomena. METHODS: Patients on dopaminergic treatment for >= 1 year were included in this multicenter observational cross-sectional study. In a single visit, WO was diagnosed based on neurologist assessment as well as the use of the 19-item wearing-off questionnaire (WOQ-19); WO was defined for scores >= 2. Post hoc analyses were conducted to investigate gender difference for demographic and clinical features with respect to WO. RESULTS: Of 617 patients enrolled, 236 were women and 381 were men. Prevalence of WO was higher among women, according to both neurologists' judgment (61.9% versus 53.8%, P = 0.045) and the WOQ-19 analysis (72.5% versus 64.0%, P = 0.034). In patients with WO (WOQ-19), women experienced >= 1 motor symptom in 72.5% versus 64.0% in men and >= 1 nonmotor symptom in 44.5% versus 36.7%, in men. CONCLUSIONS: Our results suggest WO as more common among women, for both motor and nonmotor symptoms. Prospective studies are warranted to investigate this potential gender-effect. PMID- 25685849 TI - Effects of weather, time, and pollution level on the amount of particulate matter deposited on leaves of Ligustrum lucidum. AB - This paper investigated the spatial and temporal variations in the amounts of PM accumulated on leaves of Ligustrum lucidum, a common evergreen tree species in North China. The effects of rainfall and wind on the amounts of PM deposited on foliage were also determined. The amounts of PM (g . m(-2)) retained by leaves of L. lucidum differed significantly among the sites (from 0.96 to 5.56) and over time (from 2.51 to 4.48). The largest amounts of PM on foliage of L. lucidum were observed on plants growing at the most polluted site. During the year, the highest and lowest accumulation of PM occurred in November and August, respectively. A considerable proportion of the accumulated PM on leaves was removed by rainfall events (28-48% of PM) and strong winds (27-36% of PM), and more precipitation or higher maximum wind speed could remove more PM from leaves. Rainfall removed mainly large and coarse particles, while fine particles adhered more strongly to the foliage. These results suggested that the effects of local weather conditions (e.g., rainfall, strong wind), different seasons, and pollution levels should be considered in evaluating total PM accumulation on leaves. PMID- 25685850 TI - Plasma Fibrinogen as a Biomarker for Mortality and Hospitalized Exacerbations in People with COPD. AB - BACKGROUND: In 2010 the COPD Foundation established the COPD Biomarkers Qualification Consortium (CBQC) as a partnership between the Foundation, the Food and Drug Administration (FDA), and the pharmaceutical industry to pool publicly funded and industry data to develop innovative tools to facilitate the development and approval of new therapies for COPD. We present data from the initial project seeking regulatory qualification of fibrinogen as a biomarker for the stratification of COPD patients into clinical trials. METHODS: This analysis pooled data from 4 publicly-funded studies and 1 industry study into a common database resulting in 6376 individuals with spirometric evidence of COPD. We used a threshold of 350 mg/dL to determine high vs. low fibrinogen, and determined the subsequent risk of hospitalizations from exacerbations and death using Cox proportional hazards models. RESULTS: High fibrinogen levels at baseline were present in 2853 (44.7%) of individuals with COPD. High fibrinogen was associated with an increased risk of hospitalized COPD exacerbations within 12 months (hazard ratio [HR]: 1.64; 95% confidence interval [CI]: 1.39-1.93) among participants in the Atherosclerosis Risk in Communities Study (ARIC), the Cardiovascular Health Study (CHS), and the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study. High fibrinogen was associated with an increased risk of death within 36 months (HR: 1.94; 95% CI: 1.62-2.31) among all participants. CONCLUSIONS: Fibrinogen levels >= 350 mg/dL identify COPD individuals at an increased risk of exacerbations and death and could be a useful biomarker for enriching clinical trials in the COPD population. PMID- 25685851 TI - A Human Papillomavirus Type 16 E6 52-62 CD4 T-Cell Epitope Restricted by the HLA DR11 Molecule Described in an Epitope Hotspot. AB - Cell-mediated immune responses to the human papillomavirus type 16 (HPV 16) E6 protein have been shown to be important in viral clearance and in regression of cervical lesions. Here, detailed analyses of a novel HPV 16 E6 CD4 T-cell epitope from a subject with cervical intraepithelial neoplasia 1 are described. This subject had demonstrated HPV 16 CD4 T-cell responses to multiple regions within the E6 protein. Isolation and cloning of CD4 T-cells were performed by magnetic selection of interferon-gamma secreting cells and limiting dilution. A single HPV 16-specific T-cell clone isolated was shown to have a specificity to HPV 16 E6 52 62 restricted by the HLA-DR11 molecule. Homologous sequences (>=70% amino acid homology) were identified for HPV types 31, 33, 45, 58, 73, but cross-recognition was demonstrated only for HPV 45. Based on work performed by our group and others, it is known that this short peptide contains multiple CD4 and CD8 T-cell HPV epitopes and would be an ideal region to incorporate into a design of vaccines and immunotherapies against HPV-associated malignancies. PMID- 25685852 TI - Evaluation of Patients' Knowledge Regarding Smoking and Chronic Pancreatitis: A Pilot Study. AB - OBJECTIVE: Over the last decade, a strong association has been found between smoking and chronic pancreatitis. Some studies suggest that smoking may be a more important cause of chronic pancreatitis than alcohol and the two are additive. The primary purpose of our study was to test the use of a questionnaire to assess patient's knowledge regarding the association of smoking with pancreatic disease. METHODS: The questionnaire was administered prospectively during a 9 month period in 2013 to patients referred to a pancreas clinic at the University of Alabama Birmingham. The primary purpose of the questionnaire was to investigate patient awareness regarding the association of smoking with pancreatic disease; however, it was also designed for assessing doctor-patient communication regarding smoking in general and pancreatic disease specifically and the patient's stage of change for quitting smoking. RESULTS: Eighteen patients (mean age 52 years; 85% male) were used for the analysis. The data analysis showed that 56% of patients were aware of the relationship between smoking and chronic pancreatitis and 72% were aware about alcohol and pancreatitis. Patients related that physicians were an important reference source for their knowledge regarding the causes of chronic pancreatitis, but only 39% stated that their physician had specifically mention the effect of smoking on the pancreas. CONCLUSION: Elaborate studies involving greater number of study population, are necessary to better define measuring tools and to further assess patient's knowledge regarding the relationship between smoking and chronic pancreatitis. Additionally, efforts should be directed towards enhancing physician's knowledge on this established relationship and the importance of patient education as well. PMID- 25685853 TI - Country Cancer Report. PMID- 25685854 TI - Distribution, Severity and Radiologic Features of Intracranial Stenosis in Asymptomatic Pakistanis. AB - BACKGROUND: Intracranial atherosclerotic disease (ICAD) is the most common ischemic stroke subtype globally. It accounts for 30-50% of all ischemic strokes in Asians. AIMS: The aim of the study is to report the frequency of asymptomatic ICAD and its associated Magnetic Resonance Imaging (MRI) findings. METHODS: 200 adult participants were recruited from the Radiology Departments of two major diagnostic centers in Karachi. Eligible participants were confirmed for the absence of stroke symptoms via the Questionnaire for Verifying Stroke Free Status (QVSFS). QVSFS negative subjects underwent MRI on a 1.5 Tesla scanner. Images were centrally reviewed on Di com Viewer 3.0 with electronic calipers to calculate the degree of ICAD. RESULTS: Mean age of subjects was 37.1 years (S.D 15.1) with 50.5% men (n=101) and 49.5% women (n=99). Asymptomatic ICAD was found in 34.5% (n=69) subjects. Of the 3800 intracranial arteries studied, 2.2% (n=88) had biological disease. 20.5% (n=18) of these vessels had atherosclerotic irregularities, 43.2% (n=38) had mild stenos is, 11.4% (n=10) had moderate stenos is, 5.7% (n=5) had severe stenos is while 19.3% (n=17) were completely occluded. The posterior cerebral artery (42% of stenosed arteries, n=37) was most affected. 23.5% (n=47) of subjects had peri-ventricular lucencies, 10.5% (n=21) had brain atrophy while 3.5% (n=7) had silent brain infarcts. There was a significant association between asymptomatic ICAD and peri ventricular lucencies (PR 1.59; 95% CI 1.35-1.99). CONCLUSION: Asymptomatic ICAD is common in young Pakistanis, with no gender predilection; it preferentially affects the posterior circulation. Silent infarcts are rare compared to peri ventricular lucencies and atrophy. PMID- 25685855 TI - Do Dog Behavioral Characteristics Predict the Quality of the Relationship between Dogs and Their Owners? AB - This paper explores whether dog behavioral characteristics predict the quality of the relationship between dogs and their owners (i.e., owner attachment to dog), and whether relations between dog behavior and owner attachment are moderated by demographic characteristics. In this study, N = 92 children and N = 60 adults from 60 dog-owning families completed questionnaires about their attachment to their pet dog, their level of responsibility for that dog, and their general attitudes toward pets. They also rated their dogs on observable behavioral characteristics. Individuals who held positive attitudes about pets and who provided much of their dog's care reported stronger attachments to their dogs. The strength of owners' attachments to their dogs was associated with dog trainability and separation problems. Relationships between owner attachment and both dog excitability and attention-seeking behavior were further moderated by demographic characteristics: for Caucasians but not for non-Caucasians, dog excitability was negatively associated with owner attachment to dog; and for adults, dog attention-seeking behavior was positively associated with owner attachment, but children tended to be highly attached to their dogs, regardless of their dogs' attention-seeking behaviors. This study demonstrates that certain dog behavioral traits are indeed associated with the strength of owners' attachments to their dogs. PMID- 25685856 TI - A Generative Model for Probabilistic Label Fusion of Multimodal Data. AB - The maturity of registration methods, in combination with the increasing processing power of computers, has made multi-atlas segmentation methods practical. The problem of merging the deformed label maps from the atlases is known as label fusion. Even though label fusion has been well studied for intramodality scenarios, it remains relatively unexplored when the nature of the target data is multimodal or when its modality is different from that of the atlases. In this paper, we review the literature on label fusion methods and also present an extension of our previously published algorithm to the general case in which the target data are multimodal. The method is based on a generative model that exploits the consistency of voxel intensities within the target scan based on the current estimate of the segmentation. Using brain MRI scans acquired with a multiecho FLASH sequence, we compare the method with majority voting, statistical-atlas-based segmentation, the popular package FreeSurfer and an adaptive local multi-atlas segmentation method. The results show that our approach produces highly accurate segmentations (Dice 86.3% across 22 brain structures of interest), outperforming the competing methods. PMID- 25685857 TI - Pembrolizumab: PD-1 inhibition as a therapeutic strategy in cancer. AB - Programmed cell death protein 1 (PD-1) and its ligands, programmed cell death 1 ligand 1 (PD-L1) and 2 (PD-L2) play an important role in regulating immune response through various mechanisms. This inhibitory action is thought to assist in immune evasion by cancer cells as PD-1, PD-L1 and PD-L2 have been found to be abnormally expressed by tumor cells and lymphocytes in the tumor microenvironment. Preclinical studies described PD-1 blockade resulting in tumor growth suppression and even decreased metastasis. This has led to the development of pembrolizumab (MK-3475), a highly selective, humanized monoclonal IgG4-kappa isotype antibody against PD-1. Early clinical trials have shown high tumor response rates and long duration of effect in previously treated advanced melanoma resulting in accelerated FDA approval for the drug in this situation. Pembrolizumab has also had success in non-small cell lung cancer and is being tested in multiple other tumor types. This review will discuss the development, preclinical data, pharmacokinetics and clinical efficacy to date of pembrolizumab. PMID- 25685858 TI - Siltuximab: a new option for the management of Castleman's disease. AB - Castleman's disease is a rare lymphoproliferative disorder the underlying mechanism of which remains unclear. However, interleukin-6 (IL-6) may play a role in the pathogenesis of the disease. Blockade of the IL-6 pathway has been explored in multiple preclinical and clinical studies with promising results for the treatment of different types of cancer and Castleman's disease. Siltuximab is a human/murine chimeric immunoglobulin G1kappa (IgG1kappa) monoclonal antibody against human IL-6. It binds to IL-6 neutralizing its biological activity. Recent phase II clinical studies in patients with multicentric Castleman's disease have shown the efficacy and safety of siltuximab in patients with this condition. Results from this study led to the recent approval of siltuximab for the treatment of Castleman's disease by the FDA and EMA. PMID- 25685859 TI - Tasimelteon for the treatment of non-24-hour sleep-wake disorder. AB - Tasimelteon (Hetlioz(r)), a melatonin receptor agonist, is the first, and, at the time of the publication, the only drug to be approved by the U.S. Food and Drug Administration (FDA) for the treatment of non-24-hour sleep-wake disorder (non 24). This circadian rhythm disorder occurs most commonly in blind individuals without light perception, and it results from their inability to entrain to the 24-hour photoperiod, although the indication does not specify a particular patient population. Non-24 is characterized by a persistent cycle of nighttime insomnia and daytime sleepiness, alternating with asymptomatic periods depending on an individual's degree of circadian rhythm synchronization with the photoperiod at any particular time. Phase II clinical trials in healthy individuals confirmed the circadian phase-shifting potential of tasimelteon. Phase III trials in totally blind subjects diagnosed with non-24 demonstrated the efficacy of tasimelteon in reducing both nighttime wakefulness and daytime napping. Physiologic monitoring revealed that tasimelteon resulted in a higher proportion of individuals becoming entrained to the 24-hour cycle compared with placebo. Safety assessments indicated that tasimelteon is well tolerated, with the most common adverse events being headache, alanine aminotransferase elevation, nightmares or unusual dreams, and upper respiratory or urinary tract infections. Tasimelteon is available as a capsule in a single 20-mg dose and it must be obtained through Vanda Pharmaceutical's HetliozSolutions program with dispensing through a specialty pharmacy. Safety studies in blind individuals diagnosed with non-24 are ongoing and a future clinical trial with Smith-Magenis syndrome patients is planned. PMID- 25685860 TI - The year's new drugs & biologics, 2014: Part I. AB - A year-end wrap-up of new drug approvals and launches reveals that activity in the pharmaceutical industry continues at a high level, with 55 new drugs and biologics introduced on their first markets in 2014 (as of December 23, 2014). Additionally, 29 important new line extensions (new formulations, new combinations or new indications for previously marketed products) also reached their first markets during the year. The most active therapeutic group in terms of new launches was anti-infective therapies, with 11 new drugs and biologics launched, most for the treatment of multidrug-resistant bacterial infections or hepatitis C. The most active market for new launches was again the U.S., site of more than half of all new launches in 2014. However new launch activity increased considerably last year in Japan, which actually pulled ahead of the E.U. for the first time in many years. In another important new development, 15 of the new drugs and biologics launched last year had orphan drug status, 5 had breakthrough therapy designation and 3 had Qualified Infectious Disease Product (QIDP) status. Another 19 products were approved for the first time during the year but not yet launched by close of this article; most are slated for launch in the first months of the new year. PMID- 25685861 TI - Pharmacovigilance Discussion Forum--The European Generic Medicines Association's 8th Annual Meeting (January 21, 2015--London, UK). AB - The practice and science of pharmacovigilance first emerged following the disaster caused by thalidomide in 1961, which led to the initiation of systemic international efforts to address drug safety issues spearheaded by the WHO. Systems were developed in member states of the WHO to analyze cases of adverse drug reactions (ADRs) and collate these data into a central database to aid national drug regulatory authorities in improving safety profiles of medicines. Pharmacovigilance is a key public health function for monitoring all medicinal products to assess their quality, efficacy and safety before and following authorization. These medicines are continually assessed to detect any aspect that could compromise their safety, and ensure that the necessary measures are taken. In July 2012, new legislation for pharmacovigilance in the E.U. came into effect as a result of the changes set out in the Directive 2010/84/EU and the European Commission (EC) implementing Regulation (EU) No 520/2012 to reduce the increasing number of ADRs. The latest developments in pharmacovigilance in Europe, including news on E.U. pharmacovigilance legislation, were discussed at the 8th European Generic Medicines Association (EGA) Pharmacovigilance Discussion Forum. The meeting facilitated constructive dialogue between regulators and industry on a range of topics including how to simplify pharmacovigilance activities and improve the processes of risk management plans, periodic safety update reports, signal detection, joint studies and inspections. PMID- 25685862 TI - Susceptibility to retroactive interference: The effect of context as a function of age and cognition. AB - Previous studies have shown that contextual cues improve memory performance and reduce interference in younger adults. However, it is not clear whether middle aged and older adults can also benefit from contextual cues, or if this ability diminishes with ageing and cognitive decline. In order to test this question, we tested 69 middle-aged adults (aged 30-50 years) and 65 older adults (aged 65-85). Participants completed a retroactive interference paradigm with or without contextual cues. Cognitive functioning of older adults was assessed using the Montreal Cognitive Assessment, which is a sensitive and highly validated tool to detect cognitive decline in older age. The results showed that while middle-aged adults were able to benefit from context to improve recognition and reduce interference, older adults were not able to benefit from it. However, when we compared older adults with lower (<26) and higher (>=26) scores on the Montreal Cognitive Assessment, we found that older adults with high cognitive functioning could benefit from context advantage at retrieval to improve recognition compared to those with lower cognitive functioning. Yet, similar to older adults with lower cognitive functioning, they could not benefit from context advantage at encoding and hence were still susceptible to interference. PMID- 25685863 TI - Binary DNA hairpin-based colorimetric biochip for simultaneous detection of Pb(2+) and Hg(2+) in real-world samples. AB - A microarray-format colorimetric biochip was constructed on plastic using two specially-designed DNA hairpin strands as binary probes and a binding-induced conformational switching strategy as the signal generation protocol. Coupled with single- or dual-color staining, we were able to simultaneously detect and quantitate the trace amounts of Pb(2+) and Hg(2+) in various real-world samples. PMID- 25685864 TI - Occurrence of haemoparasites in cattle in Monduli district, northern Tanzania. AB - Haemoparasite infections are among the most economically important cattle diseases in sub-Saharan Africa. The present study investigated the occurrence of haemoparasites in 295 indigenous cattle from five villages (Mswakini, Lake Manyara, Naitolia, Makuyuni and Nanja) of the Monduli district, a wildlife domestic animal-human interface area in northern Tanzania. The data showed that the overall occurrence of haemoparasites in the sampled cattle was 12.5% (95% CI: 8.7% - 16.3%), involving single and mixed infections with Theileria parva, Anaplasma marginale, Babesia bovis, Trypanosoma vivax and Trypanosoma brucei. The highest haemoparasite occurrence was recorded in Lake Manyara (18.3%; 95% CI: 8.5% - 28.1%), and the lowest was recorded in Nanja (6.5%; 95% CI: 0.4% - 12.6%). This preliminary study, furthermore, provided evidence of the possible arthropod vectors (ticks and tsetse flies) that may be involved in the transmission of haemoparasites to cattle in the Monduli district. It is envisaged that this survey will stimulate more studies to determine the prevalence of haemoparasites in livestock by using more sensitive molecular techniques. PMID- 25685865 TI - Analysis of the Particle Formation Process of Structured Microparticles. AB - The particle formation process for microparticles of cellulose acetate butyrate dried from an acetone solution was investigated experimentally and theoretically. A monodisperse droplet chain was used to produce solution microdroplets in a size range of 55-70 MUm with solution concentrations of 0.37 and 10 mg/mL. As the droplets dried in a laminar air flow with a temperature of 30, 40, or 55 degrees C, the particle formation process was recorded by two independent optical methods. Dried particles in a size range of 10-30 MUm were collected for morphology analysis, showing hollow, elongated particles whose structure was dependent on the drying gas temperature and initial solution concentration. The setup allowed comprehensive measurements of the particle formation process to be made, including the period after initial shell formation. The early particle formation process for this system was controlled by the diffusion of cellulose acetate butyrate in the liquid phase, whereas later stages of the process were dominated by shell buckling and folding. PMID- 25685866 TI - Antigenic characterisation of lyssaviruses in South Africa. AB - There are at least six Lyssavirus species that have been isolated in Africa, which include classical rabies virus, Lagos bat virus, Mokola virus, Duvenhage virus, Shimoni bat virus and Ikoma lyssavirus. In this retrospective study, an analysis of the antigenic reactivity patterns of lyssaviruses in South Africa against a panel of 15 anti-nucleoprotein monoclonal antibodies was undertaken. A total of 624 brain specimens, collected between 2005 and 2009, confirmed as containing lyssavirus antigen by direct fluorescent antibody test, were subjected to antigenic differentiation. The lyssaviruses were differentiated into two species, namely rabies virus (99.5%) and Mokola virus (0.5%). Furthermore, rabies virus was further delineated into two common rabies biotypes in South Africa: canid and mongoose. Initially, it was found that the canid rabies biotype had two reactivity patterns; differential staining was observed with just one monoclonal antibody. This difference was likely to have been an artefact related to sample quality, as passage in cell culture restored staining. Mongoose rabies viruses were more heterogeneous, with seven antigenic reactivity patterns detected. Although Mokola viruses were identified in this study, prevalence and reservoir host species are yet to be established. These data demonstrate the usefulness of monoclonal antibody typing panels in lyssavirus surveillance with reference to emergence of new species or spread of rabies biotypes to new geographic zones. PMID- 25685867 TI - Effect of surface texture on freezing in nanopores: surface-induced versus homogeneous crystallization. AB - Freezing of argon in ordered and disordered carbon pores of a similar diameter D ~ 2.4 nm is investigated using extensive molecular simulations with large system sizes up to 10(4) atoms. While crystallization in the atomistically smooth pore consists in a surface-induced phase transition occurring at a temperature larger than the bulk, crystallization in the disordered pores, which is only partial as it is spatially restricted to the pore center, occurs through homogeneous crystallization. These results shed light on solidification in pores by showing that there is a crossover between surface-induced and homogeneous crystallization upon increasing the surface disorder of the host material. In the latter case, the Gibbs-Thomson equation, in which crystallization is assumed to occur when the crystal size equals the pore size corrected for the thickness of the unfreezable layer at the pore surface, is in reasonable agreement with the observed freezing temperature. PMID- 25685868 TI - CKD in disadvantaged populations. AB - The increased burden of CKD in disadvantaged populations is due to both global factors and population-specific issues. Low socioeconomic status and poor access to care contribute to healthcare disparities and exacerbate the negative effects of genetic or biologic predisposition. Provision of appropriate renal care to these populations requires a two-pronged approach: expanding the reach of dialysis through development of low-cost alternatives that can be practiced in remote locations, and implementation and evaluation of cost-effective prevention strategies. Kidney transplantation should be promoted by expanding both deceased donor transplant programs and the use of inexpensive, generic immunosuppressive drugs. The message of WKD 2015 is that a concerted attack against the diseases that lead to ESRD, by increasing community outreach, better education, improved economic opportunity, and access to preventive medicine for those at highest risk, could end the unacceptable relationship between CKD and disadvantage in these communities. PMID- 25685869 TI - Cystinuria: current concepts and future directions. AB - Cystinuria, an autosomic recessive genetic disorder is an uncommon cause of nephrolithiasis characterized by an impairment of transport of cystine, ornithine, lysine, and arginine (COLA). Of these, only cystine is insoluble enough to cause stone formation. Although a classification exists that categorizes the disease depending on chromosomal mutation, this does not currently alter management which consists of increased fluid intake, urine alkalinization, reduced sodium intake and, if warranted, cystine-binding thiol drugs. Cystine stones are relatively resistant to fragmentation. Intrinsic characteristics on imaging may help in planning surgical treatment. Finally, advances in crystal growth inhibition are encouraging as they may provide a new tool to treat this condition which although uncommon, is treatable and has been associated with lower quality of life and renal function compared to other stone formers. PMID- 25685870 TI - Relationship between relative interdialytic weight gain and serum leptin levels, nutrition, and inflammation in chronic hemodialysis patients. AB - INTRODUCTION: Excessive relative interdialytic weight gain (RIDWG, %) is an important risk factor for long-term adverse cardiovascular outcomes in chronic hemodialysis (HD) patients. On the other hand, it may also be an index of good appetite and nutritional status. We aimed to assess the relationship between RIDWG and appetite, nutrition, inflammation parameters of chronic HD patients. METHODS: 100 chronic anuric HD patients were enrolled in this prospective study between January 2013 and January 2014. Patients with hospitalization, major surgery, obvious infectious/inflammatory disease, end-stage liver disease, malignancies, and malabsorption syndromes were excluded. Patients were divided into 3 groups according to their RIDWG levels; group 1 = RIDWG < 3%, group 2 = RIDWG: 3 - 5%, and group 3 = RIDWG > 5%. RESULTS: Group 3 patients were younger (p = 0.011) and had a lower body mass index (BMI) (p = 0.014). Nutrition and inflammation parameters including malnutrition inflammation score (MIS), serum albumin, prealbumin, triceps skinfold thickness, hs-CRP, and TNF-alpha ere not significantly different between the groups. Leptin and leptin/BMI ratio were significantly lower in group 3 (p = 0.001). RIDWG was negatively correlated with age (p = 0.001, r = -0.371), BMI (p = 0.001, r = -0.372), leptin (p = 0.001, r = 0.369), leptin/BMI (p = 0.001, r = -0.369). After adjustment for BMI in linear regression analyis, leptin/BMI remained significantly correlated with RIDWG (p = 0.024). CONCLUSION: This study revealed that RIDWG was associated with younger age, lower BMI and dry weight, and lower serum leptin levels. More detailed studies are needed to validate and dissect the mechanisms of these findings. PMID- 25685871 TI - Laparoscopic peritoneal dialysis catheter placement is associated with decreased deep organ infection and reoperation. AB - INTRODUCTION: The optimal method for placement of peritoneal dialysis catheters (PDC) is unclear. The objective of this study was to compare the outcomes of laparoscopic and open surgical placement of PDC. MATERIALS AND METHODS: Patients who underwent laparoscopic (LPD) and open (OPD) surgical placement of PDC between 2007 and 2011 were identified from the American College of Surgeons National Surgical Quality Initiative Project (NSQIP) dataset using current procedural terminology (CPT) and international classification of diseases 9th revision (ICD 9) codes. Perioperative outcomes were compared using Fisher's exact test for categorical variables, Student's t-test and Gamma regression were used for continuous variables. Catheter function was not reported in the dataset. RESULTS: There were 1,560 PDC procedures in our study and most were performed laparoscopically (89%). 83% of these procedures were performed by general surgeons, mostly, with the patients under general anesthesia (95%). OPD was associated with a higher rate of perioperative deep organ infection (3.5% vs. 1.1%, p = 0.02) and need for reoperation (10.4% vs. 5.0%, p = 0.007). Operative time was, however, significantly longer with LPD (53.3 vs. 45.5 minutes, p < 0.001). In multivariate analysis, OPD was independently associated with increased risk of perioperative deep organ infection (odds ratio (OR) 3.7,95%, Confidence Interval (CI) 1.3 - 10.2, p = 0.01) and reoperation (OR 2.3, 95% CI 1.3 - 4.1, p = 0.005). CONCLUSIONS: Laparoscopic PDC placement is more commonly performed and is associated with a lower risk of perioperative deep organ infection and reoperation than the open surgical approach. When possible, laparoscopic PDC placement might be preferable over open surgical placement. PMID- 25685872 TI - Parameters of phosphorus homeostasis at normal and reduced GFR: theoretical considerations. AB - AIMS: Influx and reabsorption of phosphorus (IP and TRP) are assessed with fractional excretion and reabsorption (FEP and FTRP, nl <= 20% and >= 80%), or with excretion and reabsorption per volume of filtrate (EP/GFR and TRP/GFR, fasting nl ~ 0.4 and 3.0 mg/dL). We analyzed these parameters at normal and reduced GFR. METHODS: We equated GFR with creatinine clearance (Ccr) to develop necessary equations. We plotted serum phosphorus ([P]s), EP/Ccr, and FEP against their determinants, and TRP/Ccr against EP/Ccr at FEP of 20% or 40%. RESULTS: Linear equations related [P]s to EP/Ccr and TRP/Ccr, and EP/Ccr to [cr]s and [P]u/[cr]u (a surrogate for IP). FEP rose in curvilinear fashion as Esub>P/Ccr rose and TRP/Ccr fell; changes in low values of EP/Ccr and TRP/Ccr induced large changes in FEP. At increased EP/Ccr (as in CKD), maintenance of FEP <= 20% required impossibly high TRP/Ccr; at EP/Ccr of 2.0 mg/dL, FEP and FTRP of 40% and 60% required normal TRP/Ccr. CONCLUSIONS: EP/Ccr varies with IP at normal GFR, and with IP and [cr]s at low GFR. FEP, a function of EP/Ccr and TRP/Ccr, varies primarily with the lower ratio, which is always EP/Ccr at normal GFR. At low GFR, high FEP is inevitable if IP is preserved, and TRP/Ccr may be normal despite low FTRP. Contributions of IP and TRP to [P]s should be assessed with EP/Ccr and TRP/Ccr. FEP and FTRP have limitations at any GFR. PMID- 25685873 TI - Organometallic dimers: application to work-function reduction of conducting oxides. AB - The dimers of pentamethyliridocene and ruthenium pentamethylcyclopentadienyl mesitylene, (IrCp*Cp)2 and (RuCp*mes)2, respectively, are shown here to be effective solution-processable reagents for lowering the work functions of electrode materials; this approach is compared to the use of solution-deposited films of ethoxylated poly(ethylenimine) (PEIE). The work functions of indium tin oxide (ITO), zinc oxide, and gold electrodes can be reduced to 3.3-3.4 eV by immersion in a toluene solution of (IrCp*Cp)2; these values are similar to those that can be obtained by spin-coating a thin layer of PEIE onto the electrodes. The work-function reductions achieved using (IrCp*Cp)2 are primarily attributable to the interface dipoles associated with the formation of submonolayers of IrCp*Cp(+) cations on negatively charged substrates, which in turn result from redox reactions between the dimer and the electrode. The electrical properties of C60 diodes with dimer-modified ITO cathodes are similar to those of analogous devices with PEIE-modified ITO cathodes. PMID- 25685874 TI - Highly efficient synthesis of chiral alpha-CF3 amines via Rh-catalyzed asymmetric hydrogenation. AB - Highly enantioselective catalytic asymmetric hydrogenation of alpha-CF3-enamides has been achieved by employing rhodium-DuanPhos as the catalyst, which provides a readily accessible method for the synthesis of chiral trifluoromethylated amines. The reaction has a broad substrate scope; both aryl- and alkyl-substituted alpha CF3-enamides worked smoothly and afford the corresponding chiral amines in high yields and excellent enantioselectivities (up to 99% ee). PMID- 25685875 TI - Computational mechanistic study of the Julia-Kocienski reaction. AB - This paper describes the first detailed computational mechanistic study of the Julia-Kocienski olefination between acetaldehyde (1) and ethyl 1-phenyl-1H tetrazol-5-yl sulfone (2), considered a paradigmatic example of the reaction between unsubstituted alkyl PT sulfones and linear aliphatic aldehydes. The theoretical study was performed within the density functional approach through calculations at the B3LYP/6-311+G(d,p) level for all atoms except sulfur for which the 6-311+G(2df,p) basis set was used. All the different intermediates and transition states encountered along the reaction pathways leading to final E and Z olefins have been located and the relative energies calculated, both for the reactions with potassium- and lithium-metalated sulfones, in THF and toluene, respectively. We have essentially confirmed the complex multistep mechanistic manifold proposed by others; however, the formation of a spirocyclic intermediate in the Smiles rearrangement was excluded. Instead, we found that this step involves a concerted, though asynchronous, mechanism. Moreover, our calculations nicely fit with the diastereoselectivities observed experimentally for potassium- and lithium-metalated sulfones, in THF and toluene, respectively. PMID- 25685876 TI - Applicability of next generation sequencing technology in microsatellite instability testing. AB - Microsatellite instability (MSI) is a useful marker for risk assessment, prediction of chemotherapy responsiveness and prognosis in patients with colorectal cancer. Here, we describe a next generation sequencing approach for MSI testing using the MiSeq platform. Different from other MSI capturing strategies that are based on targeted gene capture, we utilize "deep resequencing", where we focus the sequencing on only the microsatellite regions of interest. We sequenced a series of 44 colorectal tumours with normal controls for five MSI loci (BAT25, BAT26, BAT34c4, D18S55, D5S346) and a second series of six colorectal tumours (no control) with two mononucleotide loci (BAT25, BAT26). In the first series, we were able to determine 17 MSI-High, 1 MSI-Low and 26 microsatellite stable (MSS) tumours. In the second series, there were three MSI High and three MSS tumours. Although there was some variation within individual markers, this NGS method produced the same overall MSI status for each tumour, as obtained with the traditional multiplex PCR-based method. PMID- 25685878 TI - Explaining religious differentials in family-size preference: Evidence from Nepal in 1996. AB - We examine how religio-ethnic identity, individual religiosity, and family members' religiosity were related to preferred family size in Nepal in 1996. Analyses of survey data from the Chitwan Valley Family Study show that socio economic characteristics and individual experiences can suppress, as well as largely account for, religio-ethnic differences in fertility preference. These religio-ethnic differentials are associated with variance in particularized theologies or general value orientations (like son preference) across groups. In addition, individual and family religiosity are both positively associated with preferred family size, seemingly because of their association with religious beliefs-beliefs that are likely to shape fertility strategies. These findings suggest the need for improvements in how we conceptualize and measure supra individual religious influence in a variety of settings and for a range of demographically interesting outcomes. PMID- 25685879 TI - Sex preference for children in German villages during the fertility transition. AB - In the past, parents' sex preferences for their children have proved difficult to verify. This study used John Knodel's German village genealogies of couples married between 1815 and 1899 to investigate sex preferences for children during the fertility transition. Event history analyses of couples' propensity to progress to a fifth parity was used to test whether the probability of having additional children was influenced by the sex composition of surviving children. It appears that son preference influenced reproductive behaviour: couples having only girls experienced significantly higher transition rates than those having only boys or a mixed sibset. However, couples who married after about 1870 began to exhibit fertility behaviour consistent with the choice to have at least one surviving boy and girl. This result represents a surprisingly early move towards the symmetrical sex preference typical of modern European populations. PMID- 25685881 TI - Noun representation in AAC grid displays: visual attention patterns of people with traumatic brain injury. AB - Clinicians supporting the communication of people with traumatic brain injury (TBI) must determine an efficient message representation method for augmentative and alternative communication (AAC) systems. Due to the frequency with which visual deficits occur following brain injury, some adults with TBI may have difficulty locating items on AAC displays. The purpose of this study was to identify aspects of graphic supports that increase efficiency of target-specific visual searches. Nine adults with severe TBI and nine individuals without neurological conditions located targets on static grids displaying one of three message representation methods. Data collected through eye tracking technology revealed significantly more efficient target location for icon-only grids than for text-only or icon-plus-text grids for both participant groups; no significant differences emerged between participant groups. PMID- 25685882 TI - iPads, mobile technologies, and communication applications: a survey of family wants, needs, and preferences. AB - Families of children with communication disabilities were surveyed to explore wants and preferences relative to mobile media technology, including iPads, as a form of augmentative and alternative communication (AAC). The families surveyed reported wanting information and support from professionals, including speech language pathologists (SLPs), who are knowledgeable about AAC. These families wanted devices to meet their children's individual needs and reported that ease of use and affordability were the most influential characteristics in the purchase of mobile media devices and communication applications. SLPs who understand family decision making can utilize collaborative clinical decision making that respects families' wants and needs, while also focusing on device feature matching and family education. PMID- 25685883 TI - The oral core vocabulary of typically developing English-speaking school-aged children: implications for AAC practice. AB - This study analyzes the core vocabulary used by typically developing school-aged English-speaking children in the United States while participating in a variety of school activities. The language of typically developing children, some of whom spoke English as a second language was recorded, transcribed and analyzed to identify the most frequently used words across samples. An inventory of oral core vocabulary of typically developing school-aged children resulted from this analysis. This inventory can be used as a source list for vocabulary selection for school-aged children with AAC needs. Implications for vocabulary selection are discussed. PMID- 25685884 TI - Conformational change from rigid rod to star: a triple-helical peptide with a linker domain at the C-terminal end. AB - Small-angle X-ray scattering and circular dichroism measurements were made for a triple-helical peptide of which one end was linked by the thermally stable trimerization domain of type XIX collagen. The radius of gyration decreased steeply around the transition temperature while the scattering intensity at zero angle did not significantly change, indicating no molar mass change through the conformational transition. Thus, the data were analyzed in terms of the rigid cylinder model for the data at low temperatures and the wormlike star model at high temperatures. It was confirmed that the peptide molecules behave as a rod like cylinder at low temperature and a semi flexible three-arm star-like chain at high temperature of which the single-coil peptide chain is appreciably extended by the high segment density nearby the linking domain. PMID- 25685885 TI - Copper-catalyzed oxidative N-S bond formation for the synthesis of N sulfenylimines. AB - Despite the remarkable success of the copper-catalyzed oxidative coupling reaction, direct cross-coupling of amines and thiols for the synthesis of N sulfenylimines has not been previously reported. Using commercially available copper catalysts (CuI) and oxygen as an environmentally benign oxidant, synthetically useful N-sulfenylimines were prepared from amines and thiols in good yields without overoxidation of sulfur atoms. PMID- 25685886 TI - Adsorption force of fibronectin on various surface chemistries and its vital role in osteoblast adhesion. AB - The amount, type, and conformation of proteins adsorbed on an implanted biomaterial are believed to influence cell adhesion. Nevertheless, only a few research works have been dedicated to the contribution of protein adsorption force. To verify our hypothesis that the adsorption force of protein on biomaterial is another crucial mediator to cell adhesion, fibronectin (FN) adsorbed on self-assembled monolayers (SAMs) with terminal -OH, -CH3, and -NH2 was quantified for FN adsorption force (F(ad)) by utilizing a sphere/plane adsorption model and parallel plate flow chamber. As revealed, F(ad) on SAMs followed a chemistry-dependence of -NH2 > -CH3 ? -OH. It is further demonstrated that F(ad) together with FN conformation could regulate the late osteoblast adhesion and the consequent reorganization of the adsorbed FN and fibrillogenesis of the endogenous FN. Our study suggests that protein adsorption force plays a key role in cell adhesion and should be involved for better biomaterial design. PMID- 25685887 TI - Two genotypes of infectious bronchitis virus are responsible for serological variation in KwaZulu-Natal poultry flocks prior to 2012. AB - This study describes the isolation, serotyping and genotyping of 54 infectious bronchitis virus (IBV) cases predominantly in KwaZulu-Natal and compared to several isolates from other South African provinces between 2011 and 2012 and several historic isolates. The results indicate the division of isolates into two different genotypes of IBV within the province, Massachusetts (Mass)-like and QX like. The IBV Mass-like genotype was the most prevalent and was detected in 79% of the full spike protein S1 gene sequences. Variation up to 22.3% was detected within local Mass-type strains, supporting the hypothesis that multiple IBV serotypes may co-circulate in the same region simultaneously. Additionally, more conservation was observed amongst Mass serotypes versus QX-like serotypes, implying that vaccine use can influence the variability within the IBV population; this is deduced from the fact that the only live vaccine registered for use in South Africa at the time of the study was of Mass origin and no QX like vaccines were available for use. This study offers the first published consolidation of IBV isolates from an area of South Africa and identifies variation within the IBV population of the broiler flock within the study area over a 2-year period. PMID- 25685888 TI - Migration of epoxidised soybean oil from PVC gaskets of commercial lids: simulation of migration under various conditions and screening of food products from Czech markets. AB - Previous studies have shown that a large number of polyvinylchloride (PVC) lid gaskets exceed the existing migration limits for epoxidised soybean oil (ESBO) and correct prediction of ESBO release into food therefore appears to be a difficult issue. ESBO migration from PVC gaskets of metal closures into food simulants and food products from the Czech market is evaluated during a survey in 2009 and subsequently one in 2012 to assess progress in lid manufacturing and official testing conditions. ESBO migration from lids into various food simulants was studied at various temperatures (25, 40 and 60 degrees C) during storage times up to 12 months. ESBO released into food simulants or food products was transmethylated, derivatised and analysed by GC-MS. The levels of ESBO migration in foodstuffs in 2012 exceeded the specific migration limit (SML) in fewer products in comparison with the previous survey. However, most of the products were analysed at a time far from the expiry date and exceedance of the SML at the end of the product shelf life is not therefore excluded. More severe test conditions (60 degrees C for 10 days) for specific migration given by the current European Union legislation (Regulation (EU) No. 10/2011) still seem to be insufficient for the simulation of ESBO migration during long-term storage. PMID- 25685889 TI - Identification of common genetic variants controlling transcript isoform variation in human whole blood. AB - An understanding of the genetic variation underlying transcript splicing is essential to dissect the molecular mechanisms of common disease. The available evidence from splicing quantitative trait locus (sQTL) studies has been limited to small samples. We performed genome-wide screening to identify SNPs that might control mRNA splicing in whole blood collected from 5,257 Framingham Heart Study participants. We identified 572,333 cis sQTLs involving 2,650 unique genes. Many sQTL-associated genes (40%) undergo alternative splicing. Using the National Human Genome Research Institute (NHGRI) genome-wide association study (GWAS) catalog, we determined that 528 unique sQTLs were significantly enriched for 8,845 SNPs associated with traits in previous GWAS. In particular, we found 395 (4.5%) GWAS SNPs with evidence of cis sQTLs but not gene-level cis expression quantitative trait loci (eQTLs), suggesting that sQTL analysis could provide additional insights into the functional mechanism underlying GWAS results. Our findings provide an informative sQTL resource for further characterizing the potential functional roles of SNPs that control transcript isoforms relevant to common diseases. PMID- 25685890 TI - A single natural nucleotide mutation alters bacterial pathogen host tropism. AB - The capacity of microbial pathogens to alter their host tropism leading to epidemics in distinct host species populations is a global public and veterinary health concern. To investigate the molecular basis of a bacterial host-switching event in a tractable host species, we traced the evolutionary trajectory of the common rabbit clone of Staphylococcus aureus. We report that it evolved through a likely human-to-rabbit host jump over 40 years ago and that only a single naturally occurring nucleotide mutation was required and sufficient to convert a human-specific S. aureus strain into one that could infect rabbits. Related mutations were identified at the same locus in other rabbit strains of distinct clonal origin, consistent with convergent evolution. This first report of a single mutation that was sufficient to alter the host tropism of a microorganism during its evolution highlights the capacity of some pathogens to readily expand into new host species populations. PMID- 25685891 TI - Recombination affects accumulation of damaging and disease-associated mutations in human populations. AB - Many decades of theory have demonstrated that, in non-recombining systems, slightly deleterious mutations accumulate non-reversibly, potentially driving the extinction of many asexual species. Non-recombining chromosomes in sexual organisms are thought to have degenerated in a similar fashion; however, it is not clear the extent to which damaging mutations accumulate along chromosomes with highly variable rates of crossing over. Using high-coverage sequencing data from over 1,400 individuals in the 1000 Genomes and CARTaGENE projects, we show that recombination rate modulates the distribution of putatively deleterious variants across the entire human genome. Exons in regions of low recombination are significantly enriched for deleterious and disease-associated variants, a signature varying in strength across worldwide human populations with different demographic histories. Regions with low recombination rates are enriched for highly conserved genes with essential cellular functions and show an excess of mutations with demonstrated effects on health, a phenomenon likely affecting disease susceptibility in humans. PMID- 25685892 TI - What are the patient's wishes? PMID- 25685893 TI - Developing family-friendly signage in a South African paediatric healthcare setting. AB - BACKGROUND: Multiple renovations and changing flow in a tertiary children's hospital in Cape Town resulted in numerous signs being posted in the corridors and units, making wayfinding extremely complex. A request from nursing management prompted the formation of a learning collaborative of nurses from all departments to improve wayfinding signage. OBJECTIVES: The project aimed to contribute to a family-friendly environment by reviewing the current situation and developing signage to improve wayfinding and convey essential information to parents, caregivers and patients. METHODS: A participative action research method followed a four-stage process to facilitate the development of family-friendly signage. Nurse participants reviewed existing signage and collaboratively developed new signage templates and posted signs. The signage was then evaluated using a rapid appraisal questionnaire involving 50 parents and nurse respondents. At each stage of data collection, thematic content analysis was used to analyse data gathered in process meetings and the reflections of participating nurses. RESULTS: A design template and then 44 new signs were developed and used to replace old signage. Respondents reported that the new signs were noticeable, looked attractive and were easily understandable. CONCLUSION: Intentional and active participation of nurses in clinical paediatric settings ensured collaborative data gathering and analysis. An inclusive research design allowed for insights into the words and tone of posted signs that nurse participants had not noticed previously. The participative redesign of signage resulted in a sense of ownership of the signs.The support and involvement of hospital management throughout ensured that the resulting signage received wide acceptance. PMID- 25685894 TI - Nurses experiences in palliative care of terminally-ill HIV patients in a level 1 district hospital. AB - BACKGROUND: Whilst the discourse of palliative care in HIV management is largely documented and regarded as being an essential component, various authors have further argued that within the context of HIV care in sub-Saharan Africa, palliative care and exploration of the dimensions thereof is largely lacking. This article presents the lived experiences of nurses involved in palliative care, thus providing the perspective of nurses and the multi-faceted dimensions of the nature of caring inherent. OBJECTIVES: This study explored the respondents' understanding of the concepts 'caring' and 'terminal patient' and described the experiences of nurses caring for terminally-ill patients with HIV and how these experiences influence the nature of care rendered. METHODS: Qualitative research using Husserl's approach of phenomenology design underpinned the study and Giorgi's steps of analysis were used to make meaning of the data. RESULTS: The concept 'caring' was experienced by the nurses as transforming the patients' quality of life through supportive care and hope for life. Palliative care made the nurses conscious of their own mortality, enabling them to be more sensitive, compassionate and dedicated to caring for their patients. The findings described the social networking that enabled nurses to collaborate with colleagues in the interdisciplinary teams and shared knowledge, skills and support within the palliative care team in order to optimise patient outcomes. CONCLUSION: Nurses with prolonged involvement in caring for terminally-ill patients with HIV experienced helplessness and emotional stress. Recommendations based on the results are that training in psychological and holistic care of the patient, professional counselling and stress management services are needed to support the nurse in this context. PMID- 25685895 TI - Worldwide prevalence and risk factors for feline hyperthyroidism: A review. AB - Since first reported in the late 1970s, there has been a steady but dramatic increase in the worldwide prevalence of hyperthyroidism in cats. It is now regarded as the most common feline endocrine disorder, with diabetes mellitus coming a close second. Not only is there evidence for an increased worldwide prevalence of feline hyperthyroidism, but also for geographical variation in the prevalence of the disease. Despite its frequency, the underlying cause(s) of this common disease is or are not known, and therefore prevention of the disease is not possible. Due to the multiple risk factors that have been described for feline hyperthyroidism, however, it is likely that more than one factor is involved in its pathogenesis. Continuous, lifelong exposure to environmental thyroid-disruptor chemicals or goitrogens in food or water, acting together or in an additive fashion, may lead to euthyroid goitre and ultimately to autonomous adenomatous hyperplasia, thyroid adenoma and hyperthyroidism. This review aims to summarise the available published evidence for the changes observed in the worldwide prevalence of the disease, as well as risk factors that may contribute to development of hyperthyroidism in susceptible cats. PMID- 25685896 TI - The neuroscience of birth--and the case for Zero Separation. AB - Currently, Western maternal and neonatal care are to a large extent based on routine separation of mother and infant. It is argued that there is no scientific rationale for this practice and a body of new knowledge now exists that makes a case for Zero Separation of mother and newborn. For the infant, the promotion of Zero Separation is based on the need for maternal sensory inputs that regulate the physiology of the newborn. There are harmful effects of dysregulation and subsequent epigenetic changes caused by separation. Skin-to-skin contact is the antithesis to such separation; the mother's body is the biologically 'normal' place of care, supporting better outcomes both for normal healthy babies and for the smallest preterm infants. In the mother, there are needed neural processes that ensure enhanced reproductive fitness, including behavioural changes (e.g. bonding and protection) and improved lactation, which are supported by the practice of Zero Separation. Zero Separation of mother and newborn should thus be maintained at all costs within health services. PMID- 25685897 TI - Functional colloidal micro-sieves assembled and guided above a channel-free magnetic striped film. AB - Colloidal inclusions in lab-on-a-chip devices can be used to perform analytic operations in a non-invasive fashion. We demonstrate here a novel approach to realize fast and reversible micro-sieving operations by manipulating and transporting colloidal chains via mobile domain walls in a magnetic structured substrate. We show that this technique allows one to precisely move and sieve non magnetic particles, to tweeze microscopic cargos or to mechanically compress highly dense colloidal monolayers. PMID- 25685898 TI - Loop diuretics for patients receiving blood transfusions. AB - BACKGROUND: Blood transfusions are associated with significant morbidity and mortality. Prophylactic administration of loop diuretics (furosemide, bumetanide, ethacrynic acid, or torsemide) is common practice, especially among people who are at risk for circulatory overload, pulmonary oedema or both. OBJECTIVES: This review aimed to determine if the prophylactic administration of loop diuretics (furosemide, bumetanide, ethacrynic acid, or torsemide) provides a therapeutic advantage (that is, a favourable risk benefit ratio) in adults and children who are recipients of any blood product transfusion versus placebo, no treatment, or general fluid restriction measures. SEARCH METHODS: We searched the Cochrane Renal Group's Specialised Register to 13 January 2015 through contact with the Trials' Search Co-ordinator using search terms relevant to this review. SELECTION CRITERIA: All randomised controlled trials (RCTs) and quasi-RCTs assessing a loop diuretic in patients receiving any blood transfusion were considered for inclusion. DATA COLLECTION AND ANALYSIS: Two authors independently assessed study quality and extracted data. Study authors were contacted for additional information. Results were to be expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes, and mean difference (MD) and 95% CI for continuous outcomes. Mean effect sizes were to be calculated using the random-effects models. MAIN RESULTS: We included four studies that involved 100 participants. Furosemide was the only diuretic investigated in all four studies.None of the included studies assessed the clinically important outcomes noted in our protocol. The studies focused on various markers of respiratory function. An improvement in fraction of inspired oxygen (in favour of furosemide) was noted in one study. An improvement in pulmonary capillary wedge pressure (in favour of furosemide) was noted in two studies. AUTHORS' CONCLUSIONS: There was insufficient evidence to determine whether premedicating people undergoing blood transfusion with loop diuretics prevents clinically important transfusion-related morbidity. Due to the continued use of prophylactic loop diuretics during transfusions, and because this review highlights the absence of evidence to justify this practice, well-conducted RCTs are needed. Given the high mortality, severe morbidity and increasing incidence of transfusion-associated circulatory overload, determining the therapeutic utility of pre-transfusion loop diuresis is an urgent need. PMID- 25685899 TI - Optical gas sensing properties of nanoporous Nb2O5 films. AB - Nanoporous Nb2O5 has been previously demonstrated to be a viable electrochromic material with strong intercalation characteristics. Despite showing such promising properties, its potential for optical gas sensing applications, which involves the production of ionic species such as H(+), has yet to be explored. Nanoporous Nb2O5 can accommodate a large amount of H(+) ions in a process that results in an energy bandgap change of the material which induces an optical response. Here, we demonstrate the optical hydrogen gas (H2) sensing capability of nanoporous anodic Nb2O5 with a large surface-to-volume ratio prepared via a high temperature anodization method. The large active surface area of the film provides enhanced pathways for efficient hydrogen adsorption and dissociation, which are facilitated by a thin layer of Pt catalyst. We show that the process of H2 sensing causes optical modulations that are investigated in terms of response magnitudes and dynamics. The optical modulations induced by the intercalation process and sensing properties of nanoporous anodic Nb2O5 shown in this work can potentially be used for future optical gas sensing systems. PMID- 25685900 TI - Metallic oxide nanoparticle translocation across the human bronchial epithelial barrier. AB - Inhalation is the most frequent route of unintentional exposure to nanoparticles (NPs). Our aim was to quantify the translocation of different metallic NPs across human bronchial epithelial cells and to determine the factors influencing this translocation. Calu-3 cells forming a tight epithelial barrier when grown on a porous membrane in a two compartment chamber were exposed to fluorescently labelled NPs to quantify the NP translocation. NP translocation and uptake by cells were also studied by confocal and transmission electron microscopy. Translocation was characterized according to NP size (16, 50, or 100 nm), surface charge (negative or positive SiO2), composition (SiO2 or TiO2), presence of proteins or phospholipids and in an inflammatory context. Our results showed that NPs can translocate through the Calu-3 monolayer whatever their composition (SiO2 or TiO2), but this translocation was increased for the smallest and negatively charged NPs. Translocation was not associated with an alteration of the integrity of the epithelial monolayer, suggesting a transcytosis of the internalized NPs. By modifying the NP corona, the ability of NPs to cross the epithelial barrier differed depending on their intrinsic properties, making positively charged NPs more prone to translocate. NP translocation can be amplified by using agents known to open tight junctions and to allow paracellular passage. NP translocation was also modulated when mimicking an inflammatory context frequently found in the lungs, altering the epithelial integrity and inducing transient tight junction opening. This in vitro evaluation of NP translocation could be extended to other inhaled NPs to predict their biodistribution. PMID- 25685901 TI - Isotherm-based thermodynamic model for electrolyte and nonelectrolyte solutions incorporating long- and short-range electrostatic interactions. AB - The activities of solutes and solvents in solutions govern numerous physical phenomena in a wide range of practical applications. In prior work, we used statistical mechanics and multilayer adsorption isotherms to develop a transformative model for capturing thermodynamic properties of multicomponent aqueous solutions over the entire concentration range (Dutcher et al. J. Phys. Chem. 2011, 2012, 2013). That model needed only a few adsorption energy values to represent the solution thermodynamics of each solute. In the current work, we posit that the adsorption energies are due to dipole-dipole electrostatic forces in solute-solvent and solvent-solvent interactions. This hypothesis was tested in aqueous solutions on (a) 37 1:1 electrolytes, over a range of cation sizes, from H(+) to tetrabutylammonium, for common anions including Cl(-), Br(-), I(-), NO3( ), OH(-), ClO4(-), and (b) 20 water-soluble organic molecules including alcohols and polyols. For both electrolytes and organic solutions, the energies of adsorption can be calculated with the dipole moments of the solvent, molecular size of the solvent and solute, and the solvent-solvent and solvent-solute intermolecular bond lengths. Many of these physical properties are available in the literature, with the exception of the solute-solvent intermolecular bond lengths. For those, predictive correlations developed here enable estimation of solute and solvent solution activities for which there are little or no activity data. PMID- 25685902 TI - Molecular differentiation and pathogenicity of Aviadenoviruses isolated during an outbreak of inclusion body hepatitis in South Africa. AB - Fowl adenovirus (FAdV) is a member of the genus Aviadenovirus and causes a number of economically important poultry diseases. One of these diseases, inclusion body hepatitis (IBH), has a worldwide distribution and is characterised by acute mortality (5% - 20%) in production chickens. The disease was first described in the United States of America in 1963 and has also been reported in Canada, the United Kingdom, Australia, France and Ireland, but until now, not in South Africa. Adenoviruses isolated from the first outbreak of IBH in South Africa were able to reproduce the disease in chicken embryo livers. The aim of the present study was to characterise the viruses and determine the pathogenicity of the FAdV strains responsible for the first reported case of IBH in South Africa. Polymerase chain reaction (PCR) amplification of the L1 loop region of the fowl adenovirus hexon gene using degenerate primer pair hexon A/B was used to identify the viruses that were isolated. Restriction fragment length polymorphism (RFLP) of the amplification products was used for the differentiation of 14 isolates of fowl adenovirus. Sequencing of the PCR products followed by amino acid comparison and phylogenetic analysis using the L1 loop region of the hexon protein was done to determine the identity of the isolates. Amino acid sequences of the hexon genes of all the South African isolates were compared with those of reference strains representing FAdV species. Amino acid comparison of 12 South Africa field isolates to FAdV reference strains revealed a high sequence identity (> 93.33%) with reference strains T8-A and 764. Two of the isolates had high sequence identity (93.40%) with reference strains P7-A, C2B and SR48. Phylogenetic analysis of the L1 loop region of the hexon protein of all 14 South African isolates was consistent with their RFLP clusters. The mortality rates of embryos challenged with 106 egg infective doses (EID50) FAdV 2 were 80% - 87% and mortality rates for embryos challenged with 105.95 (EID50) FAdV 8b were 65% - 80%. PMID- 25685903 TI - Theileriosis in six dogs in South Africa and its potential clinical significance. AB - Theileriosis is a tick-borne disease caused by a piroplasma of the genus Theileria that can causeanaemia and thrombocytopenia. Its clinical importance for dogs' remains poorly understood,as only some develop clinical signs. In this study, physical and laboratory findings, treatment and outcomes of six client owned diseased dogs presented at the Onderstepoort Veterinary Academic Hospital are described retrospectively. In the dogs, Theileria species (n = 4) and Theileria equi (n = 2) were detected by a polymerase chain reaction (PCR)-reverse blothybridisation assay in blood samples, whilst PCR for Babesia, Anaplasma and Ehrlichia were negative. The most common physical findings were pale mucous membranes (five out of six dogs), bleeding tendencies (five out of six dogs) and lethargy (three out of six dogs). All dogs were thrombocytopenic [median 59.5 x 10(9)/L (range 13-199)] and five out of six dogs were anaemic [median haematocrit 18% (range 5-32)]. Bone marrow core biopsies performed in two dogs showed myelofibrosis. Theileriosis was treated with imidocarb dipropionate and the suspected secondary immune-mediated haematological disorders with prednisolone and azathioprine. Five dogs achieved clinical cure and post-treatment PCR performed in three out of five dogs confirmed absence of circulating parasitaemia. An immune-mediated response to Theileria species is thought to result in anaemia and/or thrombocytopenia in diseased dogs with theileriosis. A bleeding tendency, most likely secondary to thrombocytopenia and/or thrombocytopathy, was the most significant clinical finding in these cases. The link between thrombocytopenia, anaemia and myelofibrosis in theileriosis requires further investigation and theileriosis should be considered a differential diagnosis for dogs presenting with anaemia and/or thrombocytopenia in endemic tick-borne disease areas. PMID- 25685904 TI - Outbreak investigation and control case report of brucellosis: experience from livestock research centre, Mpwapwa, Tanzania. AB - Brucellosis screening was conducted between 2005 and 2010 at the National Livestock Research Institute headquarters, Mpwapwa, Tanzania, following an abortion storm in cattle. The initial screening targeted breeding herds; 483 cattle were screened using the Rose Bengal Plate Test (RBPT) followed by the Competitive Enzyme-linked Immunosorbent Assay (c-ELISA) as a confirmatory test. The seropositivity on c-ELISA was 28.95% in 2005; it subsequently declined to 6.72%, 1.17%, 0.16% and 0.00% in 2006, 2007, 2009 and 2010, respectively. Brucella seropositivity was not detected in goats. Seropositivity declined following institution of stringent control measures that included: gradual culling of seropositive animals through slaughter; isolation and confinement of pregnant cows close to calving; proper disposal of placentas and aborted foetuses; the use of the S19 vaccine; and restricted introduction of new animals. It was thought that the source of this outbreak was likely to have been from the introduction of infected animals from another farm. Furthermore, humans were found with brucellosis antibodies. Out of 120 people screened, 12 (10%) were confirmed seropositive to brucella antigen exposure by c-ELISA analysis. The majority of the seropositive individuals (80%) were milkers and animal handlers from the farm. Nine individuals had clinical signs suggestive of brucellosis. All cases received medical attention from the district hospital. This achievement in livestock and human health showed that it is possible to control brucellosis in dairy farms, compared to pastoral and agro-pastoral farms, thus providing evidence to adopt these strategies in dairy farms thought to be at risk. PMID- 25685905 TI - Environmental legacy of copper metallurgy and Mongol silver smelting recorded in Yunnan Lake sediments. AB - Geochemical measurements on well-dated sediment cores from Lake Er (Erhai) are used to determine the timing of changes in metal concentrations over 4500 years in Yunnan, a borderland region in southwestern China noted for rich mineral deposits but with inadequately documented metallurgical history. Our findings add new insight into the impacts and environmental legacy of human exploitation of metal resources in Yunnan history. We observe an increase in copper at 1500 BC resulting from atmospheric emissions associated with metallurgy. These data clarify the chronological issues related to links between the onset of Yunnan metallurgy and the advent of bronze technology in adjacent Southeast Asia, subjects that have been debated for nearly half a century. We also observe an increase from 1100 to 1300 AD in a number of heavy metals including lead, silver, zinc, and cadmium from atmospheric emissions associated with silver smelting. Culminating during the rule of the Mongols, known as the Yuan Dynasty (1271-1368 AD), these metal concentrations approach levels three to four times higher than those from industrialized mining activity occurring within the catchment today. Notably, the concentrations of lead approach levels at which harmful effects may be observed in aquatic organisms. The persistence of this lead pollution over time created an environmental legacy that likely contributes to known issues in modern day sediment quality. We demonstrate that historic metallurgical production in Yunnan can cause substantial impacts on the sediment quality of lake systems, similar to other paleolimnological findings around the globe. PMID- 25685906 TI - Communal child-rearing: The role of nurses in school health. AB - BACKGROUND: Child-rearing remains a concern within our communities, especially because families of today lack primary parents due to multifaceted challenges such as working mothers, diseases and violence. Health-promoting school initiatives are necessary because they allow a multifaceted approach to child rearing. They further provide a conducive environment for continued schoolchild rearing moving from home to school. OBJECTIVES: This study promotes an integrated approach to school care using the African concept of Ubuntu - solidarity and sense of community - as a point of departure. The socio-ecological model was used, which includes the work of the school healthcare nurse in contributing to holistic health services. METHOD: An integrative review was conducted in January 2013, which included methodology studies, a theory review and a variety of studies related to school health. The studies were categorised according to school health, Ubuntu and the socio-ecological model. FINDINGS: The role of school healthcare nurses entails acting as a liaison officer between a variety of stakeholders who work together to shape the future of children. CONCLUSION: Ubuntu, together with the socio-ecological model, can assist us to involve an entire community to raise children. This knowledge serves as a background to the planning of a school health programme. The role of the nurse in school health can also assist in collaborative efforts to formulate the programme and develop the competencies that will inform school health nurse training curricula. PMID- 25685907 TI - Indole alkaloids from Catharanthus roseus: bioproduction and their effect on human health. AB - Catharanthus roseus is a medicinal plant belonging to the family Apocynaceae which produces terpenoid indole alkaloids (TIAs) of high medicinal importance. Indeed, a number of activities like antidiabetic, bactericide and antihypertensive are linked to C. roseus. Nevertheless, the high added value of this plant is based on its enormous pharmaceutical interest, producing more than 130 TIAs, some of which exhibit strong pharmacological activities. The most striking biological activity investigated has been the antitumour effect of dimeric alkaloids such as anhydrovinblastine, vinblastine and vincristine which are already in pre-, clinical or in use. The great pharmacological importance of these indole alkaloids, contrasts with the small amounts of them found in this plant, making their extraction a very expensive process. To overcome this problem, researches have looked for alternative sources and strategies to produce them in higher amounts. In this sense, intensive research on the biosynthesis of TIAs and the regulation of their pathways has been developed with the aim to increase by biotechnological approaches, the production of these high added value compounds. This review is focused on the different strategies which improve TIA production, and in the analysis of the beneficial effects that these compounds exert on human health. PMID- 25685908 TI - Structural analysis of metabolites of asiatic acid and its analogue madecassic acid in zebrafish using LC/IT-MSn. AB - Although zebrafish has become a significant animal model for drug discovery and screening, drug metabolism in zebrafish remains largely unknown. Asiatic acid (AA) and madecassic acid (MA), two natural pentacyclic triterpenoids mainly obtained from Centella asiatica (L.) Urban, have been found to possess many pharmacological effects. This study is to probe the metabolic capability of zebrafish via investigation of the drug metabolism of AA and MA in zebrafish, using a sensitive LC/IT-MSn method. In addition, the main fragmentation pathways of AA and MA were reported for the first time. Nineteen metabolites of AA and MA were firstly identified after zebrafish was exposed to the drug, which all were the phase I metabolites and mainly formed from hydroxylation, dehydrogenation, hydroxylation and dehydrogenation, dihydroxylation and dehydrogenation, and dehydroxylation reaction. The results indicated that zebrafish possessed strong metabolic capacity, and the metabolites of AA and MA were formed via similar metabolic pathways and well matched with the known metabolic rules in vivo and in vitro, which supports the widely use of this system in drug metabolism research. This investigation would also contribute to the novel information on the structural elucidation, in vivo metabolites and metabolic mechanism of pentacyclic triterpenoids. PMID- 25685909 TI - Curcumin and omega-3 fatty acids enhance NK cell-induced apoptosis of pancreatic cancer cells but curcumin inhibits interferon-gamma production: benefits of omega 3 with curcumin against cancer. AB - STAT-3 and STAT-1 signaling have opposite effects in oncogenesis with STAT-3 acting as an oncogene and STAT-1 exerting anti-oncogenic activities through interferon-gamma and interferon-alpha. The cytokine IL-6 promotes oncogenesis by stimulation of NFkappaB and STAT-3 signaling. Curcuminoids have bi-functional effects by blocking NFkappaB anti-apoptotic signaling but also blocking anti oncogenic STAT-1 signaling and interferon-gamma production. In our recent study (unpublished work [1]) in pancreatic cancer cell cultures, curcuminoids enhanced cancer cell apoptosis both directly and by potentiating natural killer (NK) cell cytotoxic function. The cytotoxic effects of curcuminoids were increased by incubation of cancer cells and NK cells in an emulsion with omega-3 fatty acids and antioxidants (Smartfish), which enhanced cancer cell apoptosis and protected NK cells against degradation. However, as also shown by others, curcuminoids blocked interferon-gamma production by NK cells. The combined use of curcuminoids and omega-3 in cancer immunotherapy will require deeper understanding of their in vivo interactions with the immune system. PMID- 25685911 TI - New pregnane glycosides from Gymnema sylvestre. AB - Four new pregnane glycosides 1-4 were isolated from the ethanol extract of the stem of Gymnema sylvestre and named gymsylvestrosides A-D. Hydrolysis of compound 1 under the catalysis of Aspergilus niger beta-glucosidase afforded compound 5 (gymsylvestroside E). Their structures were determined by spectroscopic methods such as HRESIMS, 1D and 2D NMR, as well as HMQC-TOCSY experiment. Compounds 1-4 were screened for Saccharomyces cerevisiae alpha-glucosidase inhibitory activity. PMID- 25685910 TI - Inhibitors of the AAA+ chaperone p97. AB - It is remarkable that a pathway as ubiquitous as protein quality control can be targeted to treat cancer. Bortezomib, an inhibitor of the proteasome, was first approved by the US Food and Drug Administration (FDA) more than 10 years ago to treat refractory myeloma and later extended to lymphoma. Its use has increased the survival rate of myeloma patients by as much as three years. This success was followed with the recent accelerated approval of the natural product derived proteasome inhibitor carfilzomib (Kyprolis(r)), which is used to treat patients with bortezomib-resistant multiple myeloma. The success of these two drugs has validated protein quality control as a viable target to fight select cancers, but begs the question why are proteasome inhibitors limited to lymphoma and myeloma? More recently, these limitations have encouraged the search for additional targets within the protein quality control system that might offer heightened cancer cell specificity, enhanced clinical utility, a lower rate of resistance, reduced toxicity, and mitigated side effects. One promising target is p97, an ATPase associated with various cellular activities (AAA+) chaperone. p97 figures prominently in protein quality control as well as serving a variety of other cellular functions associated with cancer. More than a decade ago, it was determined that up-regulation of p97 in many forms of cancer correlates with a poor clinical outcome. Since these initial discoveries, a mechanistic explanation for this observation has been partially illuminated, but details are lacking. Understandably, given this clinical correlation, myriad roles within the cell, and its importance in protein quality control, p97 has emerged as a potential therapeutic target. This review provides an overview of efforts towards the discovery of small molecule inhibitors of p97, offering a synopsis of efforts that parallel the excellent reviews that currently exist on p97 structure, function, and physiology. PMID- 25685912 TI - Novel orally active analgesic and anti-inflammatory cyclohexyl-N-acylhydrazone derivatives. AB - The N-acylhydrazone (NAH) moiety is considered a privileged structure, being present in many compounds with diverse pharmacological activities. Among the activities attributed to NAH derivatives anti-inflammatory and analgesic ones are recurrent. As part of a research program aiming at the design of new analgesic and anti-inflammatory lead-candidates, a series of cyclohexyl-N-acylhydrazones 10 26 were structurally designed from molecular modification on the prototype LASSBio-294, representing a new class of cycloalkyl analogues. Compounds 10-26 and their conformationally restricted analogue 9 were synthetized and evaluated as analgesic and anti-inflammatory agents in classical pharmacologic protocols. The cyclohexyl-N-acylhydrazones 10-26 and the cyclohexenyl analogue 9 showed great anti-inflammatory and/or analgesic activities, but compound 13 stood out as a new prototype to treat acute and chronic painful states due to its important analgesic activity in a neuropathic pain model. PMID- 25685913 TI - Selective C-C coupling reaction of dimethylphenol to tetramethyldiphenoquinone using molecular oxygen catalyzed by Cu complexes immobilized in nanospaces of structurally-ordered materials. AB - Two high-performance Cu catalysts were successfully developed by immobilization of Cu ions in the nanospaces of poly(propylene imine) (PPI) dendrimer and magadiite for the selective C-C coupling of 2,6-dimethylphenol (DMP) to 3,3',5,5' tetramethyldiphenoquinone (DPQ) with O2 as a green oxidant. The PPI dendrimer encapsulated Cu ions in the internal nanovoids to form adjacent Cu species, which exhibited significantly high catalytic activity for the regioselective coupling reaction of DMP compared to previously reported enzyme and metal complex catalysts. The magadiite-immobilized Cu complex acted as a selective heterogeneous catalyst for the oxidative C-C coupling of DMP to DPQ. This heterogeneous catalyst was recoverable from the reaction mixture by simple filtration, reusable without loss of efficiency, and applicable to a continuous flow reactor system. Detailed characterization using ultraviolet-visible (UV vis), Fourier transform infrared (FTIR), electronic spin resonance (ESR), and X ray absorption fine structure (XAFS) spectroscopies and the reaction mechanism investigation revealed that the high catalytic performances of these Cu catalysts were ascribed to the adjacent Cu species generated within the nanospaces of the PPI dendrimer and magadiite. PMID- 25685914 TI - Hope for decreasing socioeconomic disparities. PMID- 25685915 TI - The importance of soil archives for microbial ecology. PMID- 25685919 TI - Treatment With Multiple Blood Pressure Medications, Achieved Blood Pressure, and Mortality in Older Nursing Home Residents: The PARTAGE Study. AB - IMPORTANCE: Clinical evidence supports the beneficial effects of lowering blood pressure (BP) levels in community-living, robust, hypertensive individuals older than 80 years. However, observational studies in frail elderly patients have shown no or even an inverse relationship between BP and morbidity and mortality. OBJECTIVE: To assess all-cause mortality in institutionalized individuals older than 80 years according to systolic BP (SBP) levels and number of antihypertensive drugs. DESIGN, SETTING, AND PARTICIPANTS: This longitudinal study included elderly residents of nursing homes. The interaction between low (<130 mm Hg) SBP and the presence of combination antihypertensive treatment on 2 year all-cause mortality was analyzed. A total of 1127 women and men older than 80 years (mean, 87.6 years; 78.1% women) living in nursing homes in France and Italy were recruited, examined, and monitored for 2 years. Blood pressure was measured with assisted self-measurements in the nursing home during 3 consecutive days (mean, 18 measurements). Patients with an SBP less than 130 mm Hg who were receiving combination antihypertensive treatment were compared with all other participants. MAIN OUTCOMES AND MEASURES: All-cause mortality over a 2-year follow-up period. RESULTS: A significant interaction was found between low SBP and treatment with 2 or more BP-lowering agents, resulting in a higher risk of mortality (unadjusted hazard ratio [HR], 1.81; 95% CI, 1.36-2.41); adjusted HR, 1.78; 95% CI, 1.34-2.37; both P < .001) in patients with low SBP who were receiving multiple BP medicines compared with the other participants. Three sensitivity analyses confirmed the significant excess of risk: propensity score matched subsets (unadjusted HR, 1.97; 95% CI, 1.32-2.93; P < .001; adjusted HR, 2.05; 95% CI, 1.37-3.06; P < .001), adjustment for cardiovascular comorbidities (HR, 1.73; 95% CI, 1.29-2.32; P < .001), and exclusion of patients without a history of hypertension who were receiving BP-lowering agents (unadjusted HR, 1.82; 95% CI, 1.33-2.48; P < .001; adjusted HR, 1.76; 95% CI, 1.28-2.41; P < .001). CONCLUSIONS AND RELEVANCE: The findings of this study raise a cautionary note regarding the safety of using combination antihypertensive therapy in frail elderly patients with low SBP (<130 mm Hg). Dedicated, controlled interventional studies are warranted to assess the corresponding benefit to risk ratio in this growing population. PMID- 25685920 TI - Virulence of Trypanosoma congolense strains isolated from cattle and African buffaloes (Syncerus caffer) in KwaZulu-Natal, South Africa. AB - Trypanosoma congolense and Trypanosoma vivax are major species that infect cattle in north-eastern KwaZulu-Natal (KZN), South Africa. Of the two genetically distinct types of T. congolense, Savannah and Kilifi sub-groups, isolated from cattle and tsetse flies in KZN, the former is more prevalent and thought to be responsible for African animal trypanosomosis outbreaks in cattle. Furthermore, variation in pathogenicity within the Savannah sub-group is ascribed to strain differences and seems to be related to geographical locations. The objective of the present study was to compare the virulence of T. congolense strains isolated from African buffaloes (Syncerus caffer) inside Hluhluwe-iMfolozi Park, and from cattle on farms near wildlife parks (< 5 km), to isolates from cattle kept away (> 10 km) from parks. To obtain T. congolense isolates, blood of known parasitologically positive cattle or cattle symptomatically suspect with trypanosomosis, as well as isolates from buffaloes kept inside Hluhluwe-iMfolozi Park were passaged in inbred BALB/c mice. A total of 26 T. congolense isolates were obtained: 5 from buffaloes, 13 from cattle kept near parks and 8 from cattle distant from parks. Molecular characterisation revealed 80% and 20% of isolates to belong to T. congolense Savannah and Kilifi, respectively. To compare virulence, each isolate was inoculated into a group of six mice. No statistical differences were observed in the mean pre-patent period, maximum parasitaemia or drop in packed cell volume (PCV). Significant differences were found in days after infection for the drop in PCV, the patent period and the survival time. These differences were used to categorise the isolates as being of high, moderate or low virulence. Based on the virulence, 12 of 26 (46%) isolates were classified as highly virulent and 27% each as either of moderate or of low virulence. Whilst 11 of 12 high virulent strains were from buffaloes or cattle near the park, only 1 of 7 low virulent strains was from these animals. All the Kilifi T. congolense types were less virulent than the Savannah types. These results confirmed the higher virulence of T. congolense Savannah type compared to Kilifi type and indicated the prevalence of highly virulent strains to be higher in wildlife parks and in cattle near the parks than on farms further away. The geographical location of these strains in relation to the wildlife parks in the area was discussed. PMID- 25685921 TI - Respiratory infections: foreword. PMID- 25685922 TI - Respiratory infections: community-acquired pneumonia. AB - Pneumonia causes substantial morbidity and mortality. Older age, suppressed immune function, and certain drugs increase the risk of community-acquired pneumonia (CAP), whereas adequate dental care and high socioeconomic status decrease the risk. For patients without other significant cardiopulmonary disease, the diagnosis of pneumonia can be straightforward. Common symptoms include fever, chills, pleuritic chest pain, and a cough with mucopurulent sputum. Bacterial and viral infections are the most common etiologies. Fungal and parasitic etiologies are less common. Illness severity scores and new diagnostic methods, including procalcitonin, proadrenomedullin, and bacterial diagnostic testing, are being used increasingly for CAP diagnosis. Antibiotic selection and treatment duration for CAP have become more standardized to decrease rates of bacterial antibiotic resistance. Still, CAP causes significant expense in human life and cost expenditures worldwide. PMID- 25685923 TI - Respiratory infections: pulmonary tuberculosis. AB - Family physicians can prevent mortality and disability due to pulmonary tuberculosis (TB) by identifying high-risk patients. Recognition of symptoms (eg, cough for 3 weeks or longer) helps prevent overlooked diagnoses because results of tuberculin skin tests and interferon-gamma release assays are negative in up to 25% and 21%, respectively, of severe acute cases. The typical x-ray findings of cavities, infiltrates, and lymphadenopathy are minimal among immunosuppressed patients. Cases of active TB must be reported to local or state health departments within 24 hours of diagnosis. Sputum acid-fast bacillus tests provide results within hours and help quantify bacterial load but are not highly sensitive, and infection with nontuberculous mycobacteria can cause positive test results. Sputum cultures are adequately sensitive, identify mycobacterial species, and provide organisms for antibiotic susceptibility testing but require weeks for results. Molecular detection of Mycobacterium tuberculosis and of antibiotic-resistant mutations can expedite diagnosis and management of drug resistant TB. Management of active TB should include directly observed therapy. Standard 6-month therapy with rifampin, isoniazid, pyrazinamide, and ethambutol resolves infection in nearly all immunocompetent adults with pansensitive TB. Multidrug-resistant TB requires second-line antibiotics (eg, fluoroquinolones, linezolid) in individualized regimens lasting 2 years. Management of latent TB infection prevents progression to active TB disease, particularly if management is completed within 2 years of infection. PMID- 25685924 TI - Respiratory infections: fungal infections. AB - Fungal infections cause pneumonia but are less common than bacterial or viral etiologies; therefore, fungal infections often are diagnosed late and can be lethal in a small percentage of cases. Although traditionally thought to affect mostly individuals with impaired immunity, fungal infections also occur in immunocompetent individuals and can be severe, even in the latter group. Important advances in the diagnosis and management of fungal infections have occurred in the past decade. Obtaining a detailed history is critical because many fungal infections are associated with specific activities, geographic locations, and environmental exposures. Newer diagnostic methods such as galactomannan antigen testing, polymerase chain reaction, and breath testing are used increasingly in the diagnosis of fungal infections. Newer azole antibiotics also are available to manage these infections. PMID- 25685925 TI - Respiratory infections: respiratory infections in immigrants to the United States. AB - Immigration has brought millions of individuals into the United States over the past decade. The Centers for Disease Control and Prevention and the US Public Health Service are charged with ensuring that immigrants who enter do not pose a public health risk. Health examinations and immunization regimens are required for individuals wishing to live in the United States. Many immigrants and refugees are exposed to communicable diseases not routinely encountered in the United States These include helminthic infections, tuberculosis, malaria, and other infections. Zoonotic infections, such as influenza A, and novel coronavirus infections also are of increasing concern because of population mobility. PMID- 25685926 TI - Designing a risk communication strategy for health hazards posed by traditional slaughter of goats in Tshwane, South Africa. AB - In African societies, traditional slaughter is linked to celebrations like weddings or births, as well as funerals and ancestor veneration. Participants in traditional slaughter of goats are at risk of exposure to hazards during slaughter, food preparation and consumption of goat meat. For risk mitigation strategies to be implemented, identification of the population at risk is required. This study is based on the premise that the demographic profile of people involved in traditional slaughter of goats is important for risk communication. Both structured and informal interviews were recorded and analysed using a thematic analysis. A total of 105 people were interviewed at taxi ranks in Tshwane, Gauteng. Of these, 48 were women and 57 men. The median age of women and men was 40.6 years and 44.3 years, respectively. The majority of respondents (61.9%, n = 65) interviewed were from the Gauteng Province. Sixty percent (n = 63) of respondents had a secondary education, whilst less than 4.81% (n = 5) of respondents had no formal education. This study demonstrated that interviewing commuters at taxi ranks gave access to a cross section of gender, age, language and origin. It was found that both genders were involved in traditional slaughter of goats. Risk communication strategies should thus target women as well as men. Communication strategies to mitigate the risks of traditional slaughter of goats should take into consideration the dynamic nature of demographic and cultural norms. In light of the wide demographic profile of the respondents, it was concluded that it should be possible to use taxi ranks for successful dissemination of food safety and occupational health risk mitigation messages. PMID- 25685927 TI - The experience of cash transfers in alleviating childhood poverty in South Africa: mothers' experiences of the Child Support Grant. AB - Cash transfer (CT) programmes are increasingly being used as policy instruments to address child poverty and child health outcomes in developing countries. As the largest cash-transfer programme in Africa, the South African Child Support Grant (CSG) provides an important opportunity to further understand how a CT of its kind works in a developing country context. We explored the experiences and views of CSG recipients and non-recipients from four diverse settings in South Africa. Four major themes emerged from the data: barriers to accessing the CSG; how the CSG is utilised and the ways in which it makes a difference; the mechanisms for supplementing the CSG; and the impact of not receiving the grant. Findings show that administrative factors continue to be the greatest barrier to CSG receipt, pointing to the need for further improvements in managing queues, waiting times and coordination between departments for applicants trying to submit their applications. Many recipients, especially those where the grant was the only source of income, acknowledged the importance of the CSG, while also emphasising its inadequacy. To maximise their impact, CT programmes such as the CSG need to be fully funded and form part of a broader basket of poverty alleviation strategies. PMID- 25685928 TI - MicroRNA-31 Promotes Skin Wound Healing by Enhancing Keratinocyte Proliferation and Migration. AB - Wound healing is a basic biological process restoring the integrity of the skin. The role of microRNAs during this process remains largely unexplored. By using an in vivo human skin wound healing model, we show here that the expression of miR 31 is gradually upregulated in wound edge keratinocytes in the inflammatory (1 day after injury) through the proliferative phase (7 days after injury) in comparison with intact skin. In human primary keratinocytes, overexpression of miR-31 promoted cell proliferation and migration, whereas inhibition of miR-31 had the opposite effects. Moreover, we identified epithelial membrane protein 1 (EMP-1) as a direct target of miR-31 in keratinocytes. The expression of EMP-1 in the skin was negatively correlated with the level of miR-31 during wound healing. Silencing of EMP-1 mimicked the effects of overexpression of miR-31 on keratinocyte proliferation and migration, indicating that EMP-1 is a critical target mediating the functions of miR-31 in keratinocytes. Finally, we demonstrated that transforming growth factor-beta2, which is highly expressed in skin wounds, upregulated miR-31 expression in keratinocytes. Collectively, we identify miR-31 as a key regulator for promoting keratinocyte proliferation and migration during wound healing. PMID- 25685929 TI - Identification of BRAF 3'UTR Isoforms in Melanoma. PMID- 25685930 TI - Re: natural killer T cells are essential for the development of contact hypersensitivity in BALB/c mice. PMID- 25685931 TI - Keloid Pathogenesis: Potential Role of Cellular Fibronectin with the EDA Domain. PMID- 25685932 TI - Lived experiences of HIV community workers participating in a community empowerment programme. AB - BACKGROUND: Both non-governmental organisations and governmental organisations are very involved in the development and implementation of community empowerment programmes (CEPs). Because of various health issues within the community, 10 CEPs were launched in Ladysmith with a focus on addressing the particular needs of HIV affected and -infected members. Of the 10 programmes, however, only four were deemed sustainable after five years. OBJECTIVES: The researcher explored the lived experiences of HIV community workers participating in two CEPs in Ladysmith, KwaZulu-Natal in order to develop recommendations for CEPs. METHOD: Data were explored using a qualitative hermeneutic phenomenological approach. Ten participants who had been involved in HIV CEPs for more than six months were identified and individual interviews were held. RESULTS: Three themes emerged, namely, giving of yourself, maintaining sustainability and assisting the CEPs and community workers. Each of these themes also contained a number of subthemes. Exploring the lived experience of the community workers revealed that there are a number of ways in which to promote the sustainability of CEPs. CONCLUSION: The community should be involved in all aspects of the CEP and community workers must respect the community and their knowledge, experience and value systems. PMID- 25685933 TI - Slight pressure imbalances can affect accuracy and precision of dual inlet-based clumped isotope analysis. AB - It is well known that a subtle nonlinearity can occur during clumped isotope analysis of CO2 that - if remaining unaddressed - limits accuracy. The nonlinearity is induced by a negative background on the m/z 47 ion Faraday cup, whose magnitude is correlated with the intensity of the m/z 44 ion beam. The origin of the negative background remains unclear, but is possibly due to secondary electrons. Usually, CO2 gases of distinct bulk isotopic compositions are equilibrated at 1000 degrees C and measured along with the samples in order to be able to correct for this effect. Alternatively, measured m/z 47 beam intensities can be corrected for the contribution of secondary electrons after monitoring how the negative background on m/z 47 evolves with the intensity of the m/z 44 ion beam. The latter correction procedure seems to work well if the m/z 44 cup exhibits a wider slit width than the m/z 47 cup. Here we show that the negative m/z 47 background affects precision of dual inlet-based clumped isotope measurements of CO2 unless raw m/z 47 intensities are directly corrected for the contribution of secondary electrons. Moreover, inaccurate results can be obtained even if the heated gas approach is used to correct for the observed nonlinearity. The impact of the negative background on accuracy and precision arises from small imbalances in m/z 44 ion beam intensities between reference and sample CO2 measurements. It becomes the more significant the larger the relative contribution of secondary electrons to the m/z 47 signal is and the higher the flux rate of CO2 into the ion source is set. These problems can be overcome by correcting the measured m/z 47 ion beam intensities of sample and reference gas for the contributions deriving from secondary electrons after scaling these contributions to the intensities of the corresponding m/z 49 ion beams. Accuracy and precision of this correction are demonstrated by clumped isotope analysis of three internal carbonate standards. The proposed correction scheme can be easily applied if the slit width of the m/z 49 Faraday cup is bigger than that of the m/z 47 cup. PMID- 25685934 TI - Role of interfacial oxide in high-efficiency graphene-silicon Schottky barrier solar cells. AB - The advent of chemical vapor deposition (CVD) grown graphene has allowed researchers to investigate large area graphene/n-silicon Schottky barrier solar cells. Using chemically doped graphene, efficiencies of nearly 10% can be achieved for devices without antireflective coatings. However, many devices reported in past literature often exhibit a distinctive s-shaped kink in the measured I/V curves under illumination resulting in poor fill factor. This behavior is especially prevalent for devices with pristine (not chemically doped) graphene but can be seen in some cases for doped graphene as well. In this work, we show that the native oxide on the silicon presents a transport barrier for photogenerated holes and causes recombination current, which is responsible for causing the kink. We experimentally verify our hypothesis and propose a simple semiconductor physics model that qualitatively captures the effect. Furthermore, we offer an additional optimization to graphene/n-silicon devices: by choosing the optimal oxide thickness, we can increase the efficiency of our devices to 12.4% after chemical doping and to a new record of 15.6% after applying an antireflective coating. PMID- 25685935 TI - A key opinion leader interview with Prof D Santini: insight into cancer research. PMID- 25685937 TI - Controlling carbon-nanotube-phospholipid solubility by curvature-dependent self assembly. AB - Control of aqueous dispersion is central in the processing and usage of nanoscale hydrophobic objects. However, selecting dispersive agents based on the size and form of the hydrophobic object and the role of coating morphology in dispersion efficiency remain important open questions. Here, the effect of the substrate and the dispersing molecule curvature, as well as, the influence of dispersant concentration on the adsorption morphology are examined by molecular simulations of graphene and carbon nanotube (CNT) substrates with phospholipids of varying curvature as the dispersing agents. Lipid spontaneous curvature is increased from close to zero (effectively cylindrical lipid) to highly positive (effectively conical lipid) by studying double tailed dipalmitoylphosphadidylcholine (DPPC) and single tailed lysophosphadidylcholine (LPC) which differ in the number of acyl chains but have identical headgroup. We find that lipids are good dispersion agents for both planar and curved nanoparticles and induce a dispersive barrier nonsize selectively. Differences in dispersion efficiency arise from lipid headgroup density and their extension from the hydrophobic substrate in the adsorption morphology. We map the packing morphology contributing factors and report that the aggregate morphologies depend on the competition of interactions rising from (1) hydrophobicity driven maximization of lipid-substrate contacts and lipid self-adhesion, (2) tail bending energy cost, (3) preferential alignment along the graphitic substrate principal axes, and (4) lipid headgroup preferential packing. Curved substrates adjust the morphology by changing the balance between the interaction strengths. Jointly, the findings show substrate curvature and dimensions are a way to tune lipid adsorption to desired, self assembling patterns. Besides engineering dispersion efficiency, the findings could bear significance in designing materials with defined molecular scale, molecular coatings for orientation specific CNT assembly or lipid-based molecular masks and patterning on graphene. PMID- 25685938 TI - Copper-catalyzed regioselective trifluoromethylthiolation of pyrroles by trifluoromethanesulfonyl hypervalent iodonium ylide. AB - The copper-catalyzed trifluoromethylthiolation of pyrroles with a trifluoromethanesulfonyl hypervalent iodonium ylide under mild conditions has been achieved. A broad set of pyrroles could be transformed to the corresponding products in moderate to excellent yields. The reaction mechanism is hypothesized. PMID- 25685939 TI - A brief overview of the history of veterinary field services in South Africa. AB - The historical evolution of veterinary services in South Africa is closely linked to the colonial history of the past and the eventual political formation of the Union of South Africa in 1910, as well as the establishment of a fully democratic South Africa in 1994. The majority of the early pioneering veterinarians had close links to military activities and were originally mostly of British origin. The appointment of the first colonial chief veterinary officers occurred in the late 1800s. These appointments were dictated by the need to combat devastating animal diseases, such as rinderpest and African horse sickness, mainly because they affected draught oxen (used for travel) and horses (used in combat). Veterinary field services was established in 1962 as a separate functional entity within government services when M.C. Lambrechts became Director of Veterinary Services of South Africa. In the context of this article, veterinary field services refers to that sphere of veterinary service delivery conducted by government-appointed or seconded veterinarians applying disease control and prevention, as required by animal health legislation. Paging through the history of veterinary field services in South Africa confirms that the problems faced by the veterinary services of today were just as real during the times of our pioneers. The pioneers of veterinary services transformed unknown animal diseases into textbook descriptions still used today and also demonstrated the important link to, and use of, the observations made by farmers, as well as the need for continued basic and applied research on animal diseases. This article provided a brief overview of the evolution of veterinary field services and the important role played by pioneers over the last two centuries to make South Africa relatively free and safe from the most important trade-sensitive and economically important animal diseases. PMID- 25685940 TI - Congenital hypothyroidism and concurrent renal insufficiency in a kitten. AB - A 3-month-old male domestic short-hair kitten was presented with chronic constipation and disproportionate dwarfism. Radiographs of the long bones and spine revealed delayed epiphyseal ossification and epiphyseal dysgenesis. Diagnosis of congenital primary hypothyroidism was confirmed by low serum total thyroxine and high thyroid stimulating hormone concentrations. Appropriate supplementation of levothyroxine was instituted. The kitten subsequently developed mild renal azotaemia and renal proteinuria, possibly as a consequence of treatment or an unmasked congenital renal developmental abnormality. Early recognition, diagnosis and treatment are vital as alleviation of clinical signs may depend on the cat's age at the time of diagnosis. PMID- 25685941 TI - Melampodium leucanthum, a source of cytotoxic sesquiterpenes with antimitotic activities. AB - A new tricyclic sesquiterpene, named meleucanthin (1), was isolated from an extract of the leaves and branches of Melampodium leucanthum, along with four known germacranolide sesquiterpene lactones, leucanthin-A (2), leucanthin-B (3), melampodin-A acetate (4), and 3alpha-hydroxyenhydrin (5). The chemical structure of 1 was elucidated by analysis of 1D and 2D NMR and mass spectrometric data. All compounds exhibited antiproliferative and cytotoxic efficacy against PC-3 and DU 145 prostate cancer cells, as well as HeLa cervical cancer cells, with IC50 values ranging from 0.18 to 9 MUM. These compounds were effective in clonogenic assays and displayed high cellular persistence. They were also found to be capable of circumventing P-glycoprotein-mediated drug resistance. Mechanism of action studies showed that 4 caused an accumulation of cells in the G2/M phase of the cell cycle, and 2-5 caused the formation of abnormal mitotic spindles. These results suggest the cytotoxic effects of these germacranolides involve inhibition of mitotic spindle function, and it is likely that other mechanisms additionally contribute to cell death. These studies also demonstrate the possibility of isolating new, biologically active compounds from indigenous Texas plants. PMID- 25685942 TI - Tick-borne pathogens of potential zoonotic importance in the southern African Region. AB - The aim of this communication is to provide preliminary information on the tick borne pathogens of potential zoonotic importance present in southern Africa, mainly focusing on their geographical distribution and host range, and to identify research gaps. The following tick-borne zoonoses have been reported to occur in southern Africa based mainly on case reports: Crimean-Congo haemorrhagic fever caused by Crimean-Congo haemorrhagic fever virus; ehrlichiosis caused by Ehrlichia ruminantium, Ehrlichia canis and Anaplasma phagocytophilum; babesiosis caused by Babesia microti; relapsing fever caused by Borrelia duttonii and rickettsioses caused by Rickettsia africae, Rickettsia aeschlimannii and Rickettsia conorii. The epidemiological factors influencing their occurrence are briefly reviewed. PMID- 25685943 TI - Magnetofection Mediated Transient NANOG Overexpression Enhances Proliferation and Myogenic Differentiation of Human Hair Follicle Derived Mesenchymal Stem Cells. AB - We used magnetofection (MF) to achieve high transfection efficiency into human mesenchymal stem cells (MSCs). A custom-made magnet array, matching well-to-well to a 24-well plate, was generated and characterized. Theoretical predictions of magnetic force distribution within each well demonstrated that there was no magnetic field interference among magnets in adjacent wells. An optimized protocol for efficient gene delivery to human hair follicle derived MSCs (hHF MSCs) was established using an egfp-encoding plasmid, reaching approximately ~50% transfection efficiency without significant cytotoxicity. Then we applied the optimized MF protocol to express the pluripotency-associated transcription factor NANOG, which was previously shown to reverse the effects of organismal aging on MSC proliferation and myogenic differentiation capacity. Indeed, MF-mediated NANOG delivery increased proliferation and enhanced the differentiation of hHF MSCs into smooth muscle cells (SMCs). Collectively, our results show that MF can achieve high levels of gene delivery to MSCs and, therefore, may be employed to moderate or reverse the effects of cellular senescence or reprogram cells to the pluripotent state without permanent genetic modification. PMID- 25685944 TI - Hierarchy in gene expression is predictive of risk, progression, and outcome in adult acute myeloid leukemia. AB - Cancer progresses with a change in the structure of the gene network in normal cells. We define a measure of organizational hierarchy in gene networks of affected cells in adult acute myeloid leukemia (AML) patients. With a retrospective cohort analysis based on the gene expression profiles of 116 AML patients, we find that the likelihood of future cancer relapse and the level of clinical risk are directly correlated with the level of organization in the cancer related gene network. We also explore the variation of the level of organization in the gene network with cancer progression. We find that this variation is non-monotonic, which implies the fitness landscape in the evolution of AML cancer cells is non-trivial. We further find that the hierarchy in gene expression at the time of diagnosis may be a useful biomarker in AML prognosis. PMID- 25685945 TI - Impact of soyasaponin I on TLR2 and TLR4 induced inflammation in the MUTZ-3-cell model. AB - Previous studies have demonstrated that soyasaponin (SoSa) possesses anti inflammatory properties in lipopolysaccharide (LPS)-stimulated immune cells by influencing the immune sensing of toll-like receptor (TLR) 4. The aim of this study was to investigate the immune modulatory effect of SoSa I on TLR2- and TLR4 induced inflammation within the monocytic MUTZ-3-cell model. MUTZ-3 cells were stimulated with gram-negative (Escherichia coli) or gram-positive (Staphylococcus aureus) bacteria or bacterial pathogen-associated molecular patterns (PAMPs) such as LPS or peptidoglycans (PGN) alone or in combination with SoSa I. Cell morphology was characterized by raster scanning and light microscopy. Cytokine production (IL-1beta, IL-6, TNF-alpha, IP-10, RANTES and IL-8) was measured by cytometric bead array and the expression of surface markers was assessed by flow cytometry. MUTZ-3 cells revealed a cell maturation-like alteration in morphology and increased expression of CD80, CD86, TLR2 and TLR4 after stimulation with either gram-negative and gram-positive bacteria or bacterial PAMPs. The addition of SoSa I suppressed pro-inflammatory cytokine and chemokine secretions in a dose dependent manner regardless of TLR2 or TLR4 stimulation. Interestingly, E. coli- and S. aureus-induced inflammation was always inhibited better by SoSa I than that induced by LPS and PGN. Additionally, SoSa I reduced the expression of CD86 in PGN- or LPS-stimulated cells. This study demonstrated that the anti inflammatory capacity of SoSa I is based on influencing both monocytic TLR2 and TLR4 and that SoSa I inhibits more effectively whole bacteria compared to solely LPS or PGN what points to a broader role of SoSa I in the down-regulation of inflammation. PMID- 25685946 TI - Constraints in animal health service delivery and sustainable improvement alternatives in North Gondar, Ethiopia. AB - Poor livestock health services remain one of the main constraints to livestock production in many developing countries, including Ethiopia. A study was carried out in 11 districts of North Gondar, from December 2011 to September 2012, with the objective of identifying the existing status and constraints of animal health service delivery, and thus recommending possible alternatives for its sustainable improvement. Data were collected by using pre-tested questionnaires and focus group discussion. Findings revealed that 46.34% of the responding farmers had taken their animals to government veterinary clinics after initially trying treatments with local medication. More than 90.00% of the clinical cases were diagnosed solely on clinical signs or even history alone. The antibacterial drugs found in veterinary clinics were procaine penicillin (with or without streptomycin), oxytetracycline and sulphonamides, whilst albendazole, tetramisole and ivermectin were the only anthelmintics. A thermometer was the only clinical aid available in all clinics, whilst only nine (45.00%) clinics had a refrigerator. In the private sector, almost 95.00% were retail veterinary pharmacies and only 41.20% fulfilled the requirement criteria set. Professionals working in the government indicated the following problems: lack of incentives (70.00%), poor management and lack of awareness (60.00%) and inadequate budget (40.00%). For farmers, the most frequent problems were failure of private practitioners to adhere to ethical procedures (74.00%) and lack of knowledge of animal diseases and physical distance from the service centre (50.00%). Of all responding farmers, 58.54% preferred the government service, 21.14% liked both services equally and 20.33% preferred the private service. Farmers' indiscriminate use of drugs from the black market (23.00%) was also mentioned as a problem by private practitioners. Sustainable improvement of animal health service delivery needs increased awareness for all stakeholders and a well regulated private service in order to mitigate the constraints apparent in the government service. PMID- 25685947 TI - Analysis of Sequelae after Pediatric Phalangeal Fractures. AB - INTRODUCTION: The majority of pediatric phalangeal fractures yield excellent results following conservative or operative treatment. However, a certain subset of fractures is associated with long-term sequelae such as osteonecrosis, physeal growth arrest, malunion, and malposition. PATIENTS AND METHODS: This study summarizes all sequelae following phalangeal fractures treated within a 10-year period (2003-2012). The underlying fractures were analyzed and classified in fractures with extensive soft tissue involvement, fractures involving the joint and adjacent bony parts, neck fractures, fractures complicated by infection and sequelae after simple fractures following inadequate initial treatment. RESULTS: In total, 40 patients (27 males; 13 females) with a mean age of 6.2 years (range, 1-18 years) were treated for sequelae following fractures of the phalanges. Ten patients (6 males; 4 females) developed sequelae (limited range of motion, premature physeal closure) following fractures with extensive soft tissue damage. Thirteen patients presented with sequelae (mostly limited range of motion, premature physeal closure) following fractures involving the joint and adjacent bony parts of the phalanges. Transcondylar and subcondylar neck fractures leading to sequelae were seen in 10 patients. Sequelae consisted of limited range of motion in nine and malposition in six cases. In half of the patients, osteonecrosis (n = 5) and premature physeal closure (n = 5) complicated the clinical course. Three patients with open fractures and four patients with inadequate initial treatment presented with sequelae. CONCLUSION: Most sequelae of phalangeal fractures are consequences of fracture per se and are therefore fateful. However, the degree and severity of the long-term sequelae can be minimized by a correct and timely treatment. PMID- 25685948 TI - Hypoxic-ischemic encephalopathy: a review for the clinician. AB - IMPORTANCE: Hypoxic-ischemic encephalopathy (HIE) occurs in 1 to 8 per 1000 live births in developed countries. Historically, the clinician has had little to offer neonates with HIE other than systemic supportive care. Recently, the neuroprotective therapy of hypothermia has emerged as the standard of care, and other complementary therapies are rapidly transitioning from the basic science to clinical care. OBJECTIVE: To examine the pathophysiology of HIE and the state of the art for the clinical care of neonates with HIE. EVIDENCE REVIEW: We performed a literature review using the PubMed database. Results focused on reviews and articles published from January 1, 2004, through December 31, 2014. Articles published earlier than 2004 were included when appropriate for historical perspective. Our review emphasized evidence-based management practices for the clinician. FINDINGS: A total of 102 articles for critical review were selected based on their relevance to the incidence of HIE, pathophysiology, neuroimaging, placental pathology, biomarkers, current systemic supportive care, hypothermia, and emerging therapies for HIE and were reviewed by both of us. Seventy-five publications were selected for inclusion in this article based on their relevance to these topics. The publications highlight the emergence of serum-based biomarkers, placental pathology, and magnetic resonance imaging as useful tools to predict long-term outcomes. Hypothermia and systemic supportive care form the cornerstone of therapy for HIE. CONCLUSIONS AND RELEVANCE: The pathophysiology of HIE is now better understood, and treatment with hypothermia has become the foundation of therapy. Several neuroprotective agents offer promise when combined with hypothermia and are entering clinical trials. PMID- 25685949 TI - Morbillivirus infections: an introduction. AB - Research on morbillivirus infections has led to exciting developments in recent years. Global measles vaccination coverage has increased, resulting in a significant reduction in measles mortality. In 2011 rinderpest virus was declared globally eradicated - only the second virus to be eradicated by targeted vaccination. Identification of new cellular receptors and implementation of recombinant viruses expressing fluorescent proteins in a range of model systems have provided fundamental new insights into the pathogenesis of morbilliviruses, and their interactions with the host immune system. Nevertheless, both new and well-studied morbilliviruses are associated with significant disease in wildlife and domestic animals. This illustrates the need for robust surveillance and a strategic focus on barriers that restrict cross-species transmission. Recent and ongoing measles outbreaks also demonstrate that maintenance of high vaccination coverage for these highly infectious agents is critical. This introduction briefly summarizes the most important current research topics in this field. PMID- 25685950 TI - Announcing the 2015 viruses Young Investigator Prize and Graduate Student/Postdoctoral Fellow Travel awards. PMID- 25685951 TI - Photophysical and photochemical processes of excited singlet and triplet [3n]cyclophanes (N = 2-6) studied by emission measurements and steady-state and laser flash photolyses. AB - Photophysical and photochemical features of [3n]cyclophanes (3nCPs) (n = 2-6) in solution were investigated by emission and transient absorption measurements. The studied 3nCPs show excimer fluorescence without locally excited fluorescence whereas some of them emit excimer phosphorescence in rigid glass at 77 K. The probability of excimeric phosphorescence from transannular pi-electron systems was shown to strictly depend on the symmetric molecular structures. A feature of intersystem crossing from an excimeric fluorescence state to the excimeric triplet state was observed. Transient absorption spectra obtained upon laser flash photolysis of 3nCP revealed formation of the triplet excimer states. Triplet sensitization of 33CP using xanthone as the sensitizer demonstrated formation of triplet 33CP via triplet energy transfer whereas from the xanthone ketyl radical formation, it was inferred that triplet xanthone undergoes H atom abstraction from 32CP, providing a benzylic 32CP radical as the counter species. Based on kinetic and spectroscopic data obtained upon laser flash photolysis, differences in photochemical reactions of triplet xanthone between 32CP and 33CP were discussed. PMID- 25685952 TI - Drinking patterns and the association between socio-demographic factors and adolescents' alcohol use in three metropolises in China. AB - The current study was designed to investigate the drinking patterns and association between socio-demographic factors and adolescents' alcohol use among high school students from China's three metropolises, Beijing, Shanghai, and Guangzhou. Using a self-administered questionnaire, we conducted a cross sectional survey among 13,811 high school students from 136 schools between May and June 2013. A two-stage stratified sampling method was used for subject selection. The prevalence of lifetime drinking was 52.5%; in addition, 38.5% of the students were past-year drinkers, while 20.1% of them had consumed alcohol in the past 30 days. During the past year, 29.7% of the students reported that they drank once per month or less, and 22.0% of the students drank less than one standard drink (SD) per occasion. For the students who were not living with their mothers, as well as the students in higher socioeconomic status (SES), the adjusted odds of past and current drinking were significantly higher, compared with those who lived with both parents and low SES. Due to the high prevalence of alcohol consumption among junior and senior high school students in metropolises, attention should be paid by parents, school administrators, educational and public health agencies for making efforts collectively to reduce alcohol availability and drinking among adolescents. PMID- 25685953 TI - More than a pretty place: assessing the impact of environmental education on children's knowledge and attitudes about outdoor play in nature. AB - Our work assessed the influence of an urban environmental education program on children's attitudes toward outdoor play, as well as knowledge of neighborhood features that can facilitate this type of activity. The project team engaged 6 schools near the newest Urban Ecology Center location in Milwaukee, Wisconsin, USA, through a community-academic partnership entitled More Than a Pretty Place. Intervention classrooms participated in programming over the 2012-2013 academic year and pre and post surveys were implemented in classrooms. Data were analyzed using multilevel regression models. The intervention group reported reduced fears of outdoor play in nature and increased frequency of visits to the Urban Ecology Center. The proportion of students who acknowledged knowing of a place to play outside in nature increased significantly in both groups. Our findings indicate an important role for environmental education in addressing fears that may dissuade children from engaging in outdoor play in natural areas. PMID- 25685954 TI - Circadian rhythmicity of antioxidant markers in rats exposed to 1.8 GHz radiofrequency fields. AB - BACKGROUND: The potential health risks of exposure to Radiofrequency Fields (RF) emitted by mobile phones are currently of considerable public interest, such as the adverse effects on the circadian rhythmicities of biological systems. To determine whether circadian rhythms of the plasma antioxidants (Mel, GSH-Px and SOD) are affected by RF, we performed a study on male Sprague Dawley rats exposed to the 1.8 GHz RF. METHODS: All animals were divided into seven groups. The animals in six groups were exposed to 1.8 GHz RF (201.7 MUW/cm2 power density, 0.05653 W/kg specific absorption rate) at a specific period of the day (3, 7, 11, 15, 19 and 23 h GMT, respectively), for 2 h/day for 32 consecutive days. The rats in the seventh group were used as sham-exposed controls. At the end of last RF exposure, blood samples were collected from each rat every 4 h (total period of 24 h) and also at similar times from sham-exposed animals. The concentrations of three antioxidants (Mel, GSH-Px and SOD) were determined. The data in RF-exposed rats were compared with those in sham-exposed animals. RESULTS: circadian rhythms in the synthesis of Mel and antioxidant enzymes, GSH-Px and SOD, were shifted in RF-exposed rats compared to sham-exposed animals: the Mel, GSH-Px and SOD levels were significantly decreased when RF exposure was given at 23 and 3 h GMT. CONCLUSION: The overall results indicate that there may be adverse effects of RF exposure on antioxidant function, in terms of both the daily antioxidative levels, as well as the circadian rhythmicity. PMID- 25685955 TI - Addendum: shiue, I.; et Al. 2014 future Earth young scientists conference on integrated science and knowledge co-production for ecosystems and human well being. Int. J. Environ. Res. Public health 2014, 11, 11553-11558. AB - The authors would like to add the following affiliation for Peter Sogaard Jorgensen of paper [1]: 8 International Network of Next-Generation Ecologists, Universitetsparken 15, Building 3, Copenhagen 2100, Denmark[...]. PMID- 25685956 TI - pH-responsive iron manganese silicate nanoparticles as T1-T2* dual-modal imaging probes for tumor diagnosis. AB - Magnetic resonance imaging (MRI) probes can be concentrated in tumors through grafting targeting agents. However, the clinical application of such targeted MRI probes is largely limited because specific agents are only used to target specific characteristics of cancer cells. The development of the MRI probes that can be used regardless of tumor types or their developmental stages is highly appreciated. The acidic tumor microenvironments and acidic organelles (endosomes/lysosomes) in cancer cells are universal phenomena of solid tumors, and nanoparticles can also accumulate in tumor tissues by enhanced permeability and retention (EPR) effect. Here, we reported the synthesis of pH-responsive T1 T2* dual-modal contrast agents based on iron manganese silicate (FeMn(SiO4)) hollow nanospheres, which can release Mn(2+) ions in acidic environments, exhibiting excellent ability as agents for magnetic resonance and red fluorescence imaging. MRI for mouse models revealed that the nanoprobes could accumulate in tumors via EPR effect and then distinguish tumors from normal tissues with the synergistic effect of T1 and T2* signal only 10 min after intravenous injection. Fluorescence imaging demonstrated that the nanoprobes could be endocytosed into cancer cells and located at their lower pH compartments. Moreover, the hollow nanospheres showed no obvious toxicity and inflammation to the major organs of mice, which made them attractive diagnostic agents for different types of cancers. PMID- 25685957 TI - Unilateral forced nostril breathing and aphasia--exploring unilateral forced nostril breathing as an adjunct to aphasia treatment: a case series. AB - BACKGROUND AND PURPOSE: Unilateral forced nostril breathing (UFNB), a yogic pranayama technique, improves verbal and spatial cognition in healthy adults. The use of UFNB as an adjunct in aphasia recovery has not been explored. The current study investigated the use and potential benefit of combining UFNB with conventional speech-language therapy. METHODS: A multiple baseline single-subject AB design was conducted across three participants with stroke and aphasia. All participants practiced 40 minutes of UFNB daily at home, after instruction, and received conventional aphasia therapy. Speech and language skills were assessed before and after intervention, with individualized assessments throughout the period. Assessments included the Western Aphasia Battery-R (WAB-R) and the Communication Abilities of Daily Living-2 (CADL-2), as well as the Apraxia Battery for Adults if a diagnosis of apraxia was present. The Color Trails Test was performed and language samples collected for Correct Information Unit (CIU) and word productivity analyses. RESULTS: For the pre- and postassessments, visual inspection revealed an increase in CADL-2 scores for participants A2 and A3. In addition, A1 and A3 had a slight trend of increasing WAB-R aphasia quotients. Some change was observed for total number of CIUs and word productivity in two of the three participants. Attention did not markedly improve from baseline to treatment phase. CONCLUSION: This study suggests that UFNB combined with speech language therapy may benefit overall language production and functional communication. Further investigation on use of UFNB treatment alongside traditional speech-language therapy is warranted. PMID- 25685958 TI - Engagement in mindfulness practices by U.S. adults: sociodemographic barriers. AB - OBJECTIVE: To examine the effect of sociodemographic factors on mindfulness practices. METHODS: National Health Interview Survey Alternative Medicine Supplement data were used to examine sociodemographic predictors of engagement in meditation, yoga, tai chi, and qigong. RESULTS: Greater education was associated with mindfulness practices (odds ratio [OR], 4.02 [95% confidence interval [CI], 3.50-4.61]), men were half as likely as women to engage in any practice, and lower engagement was found among non-Hispanic blacks and Hispanics. CONCLUSION: Vulnerable population groups with worse health outcomes were less likely to engage in mindfulness practices. PMID- 25685959 TI - Injury-related predictors of symptom severity following sports-related concussion. AB - INTRODUCTION: Decisions regarding return to play after sports-related concussion partially revolve around athletes' self-reported symptoms. Given this emphasis on symptoms, it would be beneficial to be able to identify characteristics that could predict which athletes may be susceptible to developing an increase in postconcussion symptoms following head injury. The purpose of this study was to describe the symptoms that athletes endorse immediately following concussion and to determine what impact injury-related characteristics have on the development of postconcussion symptoms within the first week following concussion. METHOD: Participants included 54 collegiate athletes who sustained concussions and were referred to our concussion management program for postconcussion testing. The main outcome measures included the Post-Concussion Symptom Scale and an interview querying athletes' retrospective symptoms over time, starting immediately postinjury. RESULTS: Descriptive statistics revealed that the most common immediate symptoms following concussion include dizziness (endorsed by 83.6% of the sample), headache (65.5%), feeling in a fog (61.8%), and visual disturbance (60.0%). Logistic regression analyses indicated that retrograde and anterograde amnesia, as well as loss of consciousness, were not significantly predictive of postconcussion symptoms within one week following concussion (p > .05). However, the total symptom score assessed immediately postinjury, in addition to endorsing immediate headache symptoms following concussion, reliably predicted a higher level of symptom reporting in the first week following concussion (p < .05). Finally, receiver-operating characteristic (ROC) curve analysis, using 80% sensitivity to predict the high postconcussion symptom group, established cutoff scores of 7.5 for the immediate total symptom score and 0.5 for immediate headache. CONCLUSIONS: These findings demonstrate the importance of evaluating symptoms immediately following concussion. Athletes who endorse more immediate postconcussion symptoms, especially headache symptoms, may be at risk for greater and more severe postconcussion symptoms within the first week following concussion. The present findings have implications for the management and treatment of sports-related concussions. PMID- 25685960 TI - STEM-in-SEM high resolution imaging of gold nanoparticles and bivalve tissues in bioaccumulation experiments. AB - The methodology termed scanning transmission electron microscopy in scanning electron microscopy (STEM-in-SEM) has been used in this work to study the uptake of citrate stabilized gold nanoparticles (AuNPs) (average particle sizes of 23.5 +/- 4.0 nm) into tissue samples upon in vitro exposure of the dissected gills of the Ruditapes philippinarum marine bivalve to the nanoparticle suspensions. The STEM-in-SEM methodology has been optimized for achieving optimum resolution under SEM low voltage operating conditions (20-30 kV). Based on scanning microscope assessments and resolution testing (SMART), resolutions well below 10 nm were appropriately achieved by working at magnifications over 100k*, with experimental sample thickness between 300 and 200 nm. These relatively thick slices appear to be stable under the beam and help avoid NP displacement during cutting. We herein show that both localizing of the internalized nanoparticles and imaging of ultrastructural disturbances in gill tissues are strongly accessible due to the improved resolution, even at sample thicknesses higher than those normally employed in standard TEM techniques at higher voltages. Ultrastructural imaging of bio-nano features in bioaccumulation experiments have been demonstrated in this study. PMID- 25685961 TI - Adipose-derived mesenchymal stem cells reduce MMP-1 expression in UV-irradiated human dermal fibroblasts: therapeutic potential in skin wrinkling. AB - Adipose-derived mesenchymal stem cells (AdMSCs) have been reported to have therapeutic benefit in skin. The aim of this study was to examine the effects of AdMSCs in UV-irradiated human dermal fibroblasts (HDFs) for therapeutic potential in skin wrinkling. UV irradiation, a model naturally mimic skin wrinkle formation, is known to increase matrix metalloproteinase-1 (MMP-1), making MMP-1 a target for skin photoaging. Our findings identified that AdMSCs reduce MMP-1 level in UV-irradiated HDFs and increase type 1 procollagen in HDFs. A dose dependent increase in type 1 procollagen was confirmed by AdMSC-conditioned medium. Importantly, our current findings showing the effects of AdMSCs on the induction of MMP-1 in UV-radiated HDFs and the expression of collagen in HDFs can provide an evidence of relationship between MMP-1 and procollagen production for the protection against wrinkle formation. Collectively, AdMSCs may contribute to anti-wrinkle effects in skin but further experiments are needed to identify the mechanism. PMID- 25685962 TI - Multitoxin analysis of Aspergillus clavatus-infected feed samples implicated in two outbreaks of neuromycotoxicosis in cattle in South Africa. AB - Aspergillus clavatus intoxication is a highly fatal neuromycotoxicosis of ruminants, especially cattle. It is caused by the ingestion of infected sprouting grain and sorghum beer residue. Locomotor disturbances, tremors and paralysis are observed. Histologically, degeneration and necrosis of larger neurons in the medulla oblongata, the midbrain, the thalamus and the ventral horns of the spinal cord are observed. Although a range of mycotoxins such as patulin, cytochalasin E and pseurotin A have been isolated, there is limited information on which specific mycotoxin or group of mycotoxins are involved during outbreaks of intoxication in livestock. In the present study, two outbreaks of A. clavatus poisoning in cattle are briefly described. Feed samples were collected for fungal identification, and culture and multitoxin analysis. A range of fungal metabolites were detected, and the estimated concentrations (MUg/kg) are provided. Both the sprouting barley and brewer's grain were predominantly infected with A. clavatus and, to a lesser extent, Rhizopus arrhizus. The only common Aspergillus secondary metabolite present in all the samples was pseurotin A. Patulin and cytochalasin E were present in the sprouting barley samples, as well as the A. clavatus isolates cultured on malt extract agar for 2 weeks; however, neither of these mycotoxins could be detected in the brewer's grain sample. PMID- 25685963 TI - Efficiency indices and indicators of poor performance among emerging small-scale pig farmers in the Limpopo Province, South Africa. AB - Limpopo is a very important area for pig production in terms of animal populations and contributions to transboundary animal disease spread. Emerging small-scale pig farmers (ESSPF) are being encouraged to establish operations and spread in South Africa; however, for these farmers to perform optimally, they need to understand the basics of animal agriculture and contribute to enhancing biosecurity and efficient production systems. In the present study, the limitations to efficient production amongst ESSPF were evaluated and some improvements were suggested. It was found that the ESSPF are dominated by males and include a large percentage of older persons. A total of 26.54% of these farmers have post-matriculation qualifications. Undefined and indigenous breeds still dominate their animal genetics. The animal health technicians are the preferred channels by which farmers report diseases to the authorities (52.47%) and only one out of five (20.37%) will preferably report a disease situation direct to a veterinarian. These farmers do not vaccinate their stock, and knowledge of biosecurity is poor. Antimicrobials, especially tetracyclines, are abused. Animals that are slaughtered within the community or sold at local sale points, pension pay stations and auction markets are likely candidates for disease spread. It is recommended that the younger generations are retained and incentivised in animal agriculture. Improved training on management, health, biosecurity and better market access must be provided for the ESSPF, whilst efforts should made to consolidate these farmers into small cooperatives. The current government agricultural support system will need to be reworked to benefit the resource-poor farmers. Collaborative efforts in disease reporting and management among veterinarians, animal health technicians and extension officers will become necessary. Finally, the creation of a progressive quality grading system for ESSPF should be planned by the industry and this should be attached to a reward system that will encourage these farmers to target good farming practice. PMID- 25685965 TI - Re-envisioning paediatric nurse training in a re-engineered health care system. AB - BACKGROUND: South African's infant and child mortality rates remain high and at the current rate of decline will not meet the Millennium Development Goals of a two thirds decrease by 2015. At the latest available count, there were fewer than 1500 qualified paediatric nurses on the National South African Nursing Council register, with only about 100 nurses graduating with this qualification from South African nursing schools annually. It is not clear, however, if current paediatric nurse training programmes adequately equip nurses to make a real impact on reducing the under-5 mortality rate. In their 2011 interim report, the Ministerial Committee on Morbidity and Mortality in Children under 5 years recommended strengthening paediatric nurses' training as a strategy to reduce the under-5 mortality rate. METHOD: In response to the Committee on Morbidity and Mortality in Children recommendation, a colloquium was convened as a national forum for schools of nursing, departments of health, health care facilities, clinicians and regulatory bodies to advance children's nursing in South Africa. OBJECTIVES: The goals of the colloquium were to thoroughly investigate the situation in South Africa's paediatric nurse training, plot ways to strengthen and expand postgraduate paediatric programmes to meet priority child health needs, and to build relationships between the various schools and stakeholders. RESULTS: Outcomes included the clarification and strengthening of a 'stakeholder grid' in nurse training, recognition of the need for more active teaching and learning strategies in curricula linked to national child health priorities, as well as the need to develop and support clinical nursing practice in facilities. PMID- 25685964 TI - Valsartan Attenuates Atherosclerosis via Upregulating the Th2 Immune Response in Prolonged Angiotensin II-Treated ApoE(-/-) Mice. AB - Valsartan has a protective effect against hypertension and atherosclerosis in humans and experimental animal models. This study aimed to determine the effect of prolonged treatment with angiotensin II (Ang II) on atherosclerosis and the effect of valsartan on the activity of CD4(+) T lymphocyte subsets. The results showed that prolonged treatment (8 wks) with exogenous Ang II resulted in an increased atherosclerotic plaque size and a switch of stable-to-unstable plaque via modulating on CD4(+) T lymphocyte activity, including an increase in the T helper cell type 1 (Th1) and Th17 cells and a decrease in Th2 and regulatory T (Treg) cells. In contrast, valsartan treatment efficiently reversed the imbalance in CD4(+) T lymphocyte activity, ameliorated atherosclerosis and elicited a stable plaque phenotype in addition to controlling blood pressure. In addition, treatment with anti-interleukin (IL)-5 monoclonal antibodies weakened the antiatherosclerotic effects of valsartan without affecting blood pressure. PMID- 25685966 TI - Revascularization of immature, nonvital permanent tooth using platelet-rich fibrin in children. AB - The purpose of this paper was to present a new approach wherein revascularization of the immature, nonvital permanent tooth was performed using platelet-rich fibrin (PRF) as a novel scaffold material. This was performed after disinfection of the root canal space using triple antibiotic paste followed by placing a PRF membrane in the root canal. The patient was followed up regularly at three-, six , nine-, and 12-month intervals for review. After 12 months, clinical examination showed negative response to percussion and palpation tests but positive response to cold and electric pulp tests. Radiographic examination revealed continued thickening of the root dentinal walls, narrowing of root canal space, root lengthening, and closure of the root apex with normal periradicular architecture. However, more clinical research using large samples is necessary to prove it advantageous for regenerative endodontic therapy in children. PMID- 25685967 TI - The Affordable Care Act and health insurance exchanges: an opportunity to lead change. PMID- 25685968 TI - The Affordable Care Act and Health Insurance Exchanges: Advocacy Efforts for Children's Oral Health. AB - PURPOSE: To evaluate legislative differences in defining the Affordable Care Act's (ACA) pediatric dental benefit and the role of pediatric advocates across states with different health insurance Exchanges. METHODS: Data were collected through public record investigation and confidential health policy expert interviews conducted at the state and federal level. RESULTS: Oral health policy change by the pediatric dental profession requires advocating for the mandatory purchase of coverage through the Exchange, tax subsidy contribution toward pediatric dental benefits, and consistent regulatory insurance standards for financial solvency, network adequacy and provider reimbursement. CONCLUSIONS: The pediatric dental profession is uniquely positioned to lead change in oral health policy amidst health care reform through strengthening state-level formalized networks with organized dentistry and commercial insurance carriers. PMID- 25685969 TI - The Affordable Care Act and health insurance exchanges: effects on the pediatric dental benefit. AB - PURPOSE: To examine the relationship between state health insurance Exchange selection and pediatric dental benefit design, regulation and cost. METHODS: Medical and dental plans were analyzed across three types of state health insurance Exchanges: State-based (SB), State-partnered (SP), and Federally facilitated (FF). Cost-analysis was completed for 10,427 insurance plans, and health policy expert interviews were conducted. One-way ANOVA compared the cost sharing structure of stand-alone dental plans (SADP). T-test statistics compared differences in average total monthly pediatric premium costs. RESULTS: No causal relationships were identified between Exchange selection and the pediatric dental benefit's design, regulation or cost. Pediatric medical and dental coverage offered through the embedded plan design exhibited comparable average total monthly premium costs to aggregate cost estimates for the separately purchased SADP and traditional medical plan (P=0.11). Plan designs and regulatory policies demonstrated greater correlation between the SP and FF Exchanges, as compared to the SB Exchange. CONCLUSIONS: Parameters defining the pediatric dental benefit are complex and vary across states. Each state Exchange was subject to barriers in improving the quality of the pediatric dental benefit due to a lack of defined, standardized policy parameters and further legislative maturation is required. PMID- 25685970 TI - Comparison of Levels of Salivary Cytokines in Diabetic and Nondiabetic Puerto Rican Children: A Case-control Pilot Study. AB - PURPOSE: The oral health status of children with type 1 diabetes and its relationship to salivary cytokines have been researched in only one known study. The purpose of the present study was to evaluate the association between levels of salivary cytokines and gingival disease in diabetic and nondiabetic Puerto Rican children. METHODS: A matched case-control study with a convenience sample of 25 children with type 1 diabetes (cases) and 25 nondiabetic children (controls) were evaluated by a calibrated dentist for oral health indices. A five ml stimulated saliva sample was taken from each subject and analyzed to determine cytokine levels (IL-6, IL-17, IP-10, TNF-alpha, MMP-2, MMP-9, CRP). Descriptive statistics, chi-square tests, and t tests were used. RESULTS: Diabetic children are observed to have more plaque than control children (P=.007), more calculus (P=.06), and more bleeding on probing (P=.001). Only the level of the mediator IL 17 (P=.002) was higher in diabetic children than in nondiabetic children, but no significant differences were observed in the levels of other cytokines between the two groups. However, for each salivary mediator evaluated, diabetic children had higher levels of the respective mediator. CONCLUSION: Salivary cytokines levels were higher in diabetic type 1 children than in nondiabetic children. PMID- 25685971 TI - Oral health status of children with obstructive sleep apnea and snoring. AB - PURPOSE: The purpose of this study was to evaluate caries experience, oral hygiene, plaque deposition, and gingival health status of a group of Saudi children with obstructive sleep apnea and snoring (OSA). METHODS: The sample consisted of 30 OSA and snoring patients (three to eight years old) and 30 age- and gender-matched controls. Dental caries, oral hygiene, plaque deposition, and gingival health status were assessed. RESULTS: The prevalence of dental caries was 83 percent for the control group and 47 percent for the study group. More than one-third (37 percent) of the study group had good oral hygiene compared to only one case (three percent) in the control group. The mean plaque accumulation for the study group was (0.78+/-0.57) and (1.09+/-0.3) for the control group, while the mean gingival index score was (0.05+/-0.13) for the study group and (0.17+/-0.29) for the control group. CONCLUSIONS: Young children suffering from obstructive sleep apnea and snoring have different oral health status compared with nonobstructed control children. OSA subjects had less dental caries, plaque deposition, and gingival inflammation and better oral hygiene. PMID- 25685972 TI - The health belief model and determinants of oral hygiene practices and beliefs in preteen children: a pilot study. AB - PURPOSE: There is limited understanding of children's behavioral decisions for practicing good oral hygiene. The purpose of this study was to identify factors that may motivate children to practice good oral hygiene. METHODS: Guided by the Health Belief Model (HBM), eight focus groups of 42 American children (second through fifth graders) were interviewed concerning their histories with caries, perceived confidence in brushing, self-perceived susceptibility and vulnerability for caries and/or poor oral health, and perceived benefits and barriers to practicing oral hygiene. RESULTS: Most children equated good oral health as being central to their overall health; however, some viewed poor oral health as occurring only in the elderly while others believed poor oral health could begin at any age. Children cited esthetic appearance of teeth and the desire to please others by brushing without reminders as motivators of good oral hygiene. The greatest barriers to performing oral hygiene were a perceived lack of time and limited access to toothbrushes and dentifrice when away. CONCLUSIONS: To motivate children in this age range, emphasis should be placed on the positive aspects of maintaining good oral hygiene for its contribution to appearance and its implication for an overall healthy body and self-image. PMID- 25685973 TI - Chairside repair of preveneered primary molar stainless steel crowns: a pilot study. AB - PURPOSE: To evaluate the success of a direct chairside method for repair of esthetic facings in NuSmile(r) and Kinder Krowns(r) pediatric crowns. METHODS: A rapid direct chairside technique was developed for repair of fractured facings of preveneered primary molar crowns using the Co-Jet system to pretreat the exposed metal subsurface and composite resin (Herculite XRV). A total of 19 posterior crowns were included in the pilot sample. The loss of veneer was categorized as less than 50 percent and over 50 percent of the surface area. All clinical repairs were completed by one operator and evaluated by one examiner after three months. RESULTS: Clinically, all patients accepted the repair process achieved within 15 minutes. The repair was either fully intact (N=5) or completely lost (N=14) by three months. No crowns showed partially lost repairs. This protocol had a low success rate of 26 percent. The two successfully repaired Kinder Krowns(r) had the greatest occlusal surface area rebonded, exposing more fenestrations of the metal subsurface. CONCLUSIONS: Due to poor retention of the repaired composite, this protocol cannot be recommended routinely for in vivo repair of preveneered stainless steel crowns with fractured facings. It could be considered as an interim procedure in selected cases. PMID- 25685974 TI - Attitudes and preferences of parents about being present in the dental operatory. AB - PURPOSE: To determine if there was an association between the type of dental procedure being performed on children and parental desire to be present in the operatory. METHODS: Parents (N=339) whose children had dental appointments at a university pediatric dental clinic or affiliated practices in Southern Nevada completed a survey. Parents identified attitudes/preferences associated with five commonly conducted pediatric dental procedural scenarios. Data were analyzed using chi-square tests (P=.05). RESULTS: Most respondents (N=339) were female (N=248) and/or Hispanic (N=204), had a household income of less than $50,000 annually (N=251), and a high school education. The primary reason (78 percent) parents wanted to be present during their child's dental treatment was comfort. Most parents wanted to observe exams/X-rays (70 percent), sedation procedures (69 percent), fillings and crowns (66 percent), extractions (64 percent), and physical restraint (61 percent). Only 38 percent of parents would be content with the dentist unilaterally deciding about their presence in the operatory. CONCLUSIONS: Parents in this study expressed a preference to remain with their child during any dental treatment. Practitioners are encouraged to consider their presence customary and establish office policies and protocols that beneficially involve parents in the pediatric patient's care. PMID- 25685975 TI - Correlating parenting styles with child behavior and caries. AB - PURPOSE: This study evaluated the relationship between parenting style, sociodemographic data, caries status, and child's behavior during the first dental visit. METHODS: Parents/legal guardians of new patients aged three to six years presenting to Nationwide Children's Hospital dental clinic for an initial examination/hygiene appointment completed the Parenting Styles and Dimensions Questionnaire (PSDQ) to assess parenting style and a 15-question demographic survey. Blinded and calibrated expanded function dental auxiliaries or dental hygienists (EFDA/DH) performed a prophylaxis and assessed child behavior using the Frankl scale (inter-rater reliability was 92 percent). A blinded and calibrated dentist performed an oral examination. RESULTS: 132 parent/child dyads participated. Children with authoritative parents exhibited more positive behavior (P<.001) and less caries (P<.001) compared to children with authoritarian and permissive parents. Children attending daycare exhibited more positive behavior compared to children who did not (P<.001). Patients with private dental insurance exhibited more positive behavior (P>.04) and less caries (P>.024) compared to children with Medicaid or no dental insurance. CONCLUSIONS: Authoritative parenting and having private dental insurance were associated with less caries and better behavior during the first dental visit. Attending daycare was associated with better behavior during the first dental visit. PMID- 25685976 TI - Recurrent TMJ Dislocation Managed with Botulinum Toxin Type A Injections in a Pediatric Patient. AB - Chronic recurrent temporomandibular joint (TMJ) dislocation is an uncommon condition that is painful and distressing to patients and uniquely challenging for clinicians. Sustained TMJ dislocation is not amenable to manual reduction alone when the etiology is muscular in nature. The purpose of this report was to describe the case of a child presenting with recurring temporomandibular joint dislocation secondary to muscle hyperactivity of unknown etiology that was managed with injections of botulinum toxin type A into the inferior lateral pterygoid muscles. The use of this peripheral antispasmoic neurotoxin is a reasonable, safe, and conservative, palliative treatment option for pediatric patients suffering from chronic recurring TMJ dislocation. PMID- 25685977 TI - Tuberculosis of parotid gland: a rare clinical entity. AB - Tuberculosis (TB) can affect almost any organ of the body; however, TB of the salivary glands is a rare condition. The purpose of this paper was to report a case of a 14-year-old boy who presented with a painless swelling and discharging sinus in the parotid gland and cervical region on the left side. There was no clinical evidence of systemic signs and symptoms of active TB elsewhere in the body. The combination of clinical suspicion, a positive family history, and the cytological findings confirmed the diagnosis. The patient was successfully treated via antitubercular therapy for six months. This case report suggests that, although primary TB of the parotid gland is an unusual clinical presentation, it should be considered in the differential diagnosis of patients presenting with a parotid gland swelling. PMID- 25685978 TI - Advances in the understanding of the pathogenesis, progression and diagnosis of myxomatous mitral valve disease in dogs. AB - A number of key questions remain unanswered in the pathogenesis of myxomatous mitral valve disease (MMVD). As MMVD typically afflicts small-breed dogs, a genetic basis has been implied. In addition, the fact that not all dogs within a risk group develop MMVDis still unexplained. Research into the pathogenesis of MMVD typically falls under three categorical divisions, namely genetic factors, mechanical factors of the valve and systemic factors. Genetic studies have implicated certain loci in the pathogenesis of MMVD. Of particular interest is the insulin-like growth factor (IGF)-1 locus, as IGF-1 is also associated with growth. The mechanical structure and function of the mitral valve have also received much attention in recent years. What has emerged is the notion of a highly complex dynamic structure, which has an uneven distribution of stress and strain according to the flow of blood. Research efforts have also identified a number of systemic factors such as cytokines and signalling pathways that may contribute to the failure of the valve. Serotonin remains an area of interest in this field. Taken together, the amalgamation of research efforts in these three areas will go a long way towards resolving the understanding of this disease.Another area of focus in MMVD has been the development of clinical tests to diagnose the onset of congestive heart failure. To this end, echocardiographic indices and biochemical markers have been investigated. Echocardiographic indices such as left atrial to aortic ratio and the N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) have been identified as specific risk factors to predict progression. Advanced imaging studies such as cardiac magnetic resonance imaging have enabled investigators to determine the earliest remodelling changes that occur in MMVD. PMID- 25685979 TI - Bovine tuberculosis in Rwanda: Prevalence and economic impact evaluation by meat inspection at Societe des Abattoirs de Nyabugogo-Nyabugogo Abattoir, Kigali. AB - Despite the significant public health burden of bovine tuberculosis (bTB) in Rwanda, the prevalence of bTB is poorly documented. This study was conducted to estimate the prevalence of bTB in cattle using gross examination of granulomatous lesions, to identify mycobacteria species in suspected samples, and to evaluate the economic impact of meat condemnation based on bTB-like lesions in the meat industry in Rwanda. Routine meat inspection was conducted at Societe des Abattoirs de Nyabugogo (SABAN)-Nyabugogo Abattoir. Tissue samples including 31 lymph nodes, 3 lungs and 2 livers were obtained from cattle of different ages with gross tuberculous lesions. Mycobacterium bovis was identified using microscopy with Kinyoun staining and isolation of mycobacterial species in culture on Lowenstein-Jensen and Colestos media, further identified using biochemical tests. Our findings, based on culture and postmortem results, show that the prevalence of bTB is 0.5%(0.587*148/16753), with an overall gross tuberculous lesion prevalence of 0.9% (148/16753). The presence of lesions were higher in cattle aged 2 years and older (1.6% vs. 0.6%, p < 0.05) and higher in females than in males (1.4% vs. 0.6%, p < 0.05). Of the 36 samples tested, 26 (72.2%) were positive by microscopic examination with Kinyoun staining while M. bovis was culture-confirmed in 21 (58.7%) cases. Bovine tuberculosis caused condemnation of 1683.5 kg of meat, resulting in an estimated loss of $4810. Our findings indicate that the prevalence of bTB in Rwanda is significant, and that bTB is a major cause of meat condemnation requiring continued implementation of surveillance and control measures. Furthermore, the results from this study also show important variations in sensitivity of the different tests that were used to determine the prevalence of bTB in cattle in Rwanda. PMID- 25685980 TI - Specificity and detail in autobiographical memory: Same or different constructs? AB - Research on autobiographical memory has focused on whether memories are coded as specific (i.e., describe a single event that happened at a particular time and place). Although some theory and research suggests that the amount of detail in autobiographical memories reflects a similar underlying construct as memory specificity, past research has not investigated whether these variables converge. Therefore, the present study compared the proportion of specific memories and the amount of detail embedded in memory responses to cue words. Results demonstrated that memory detail and proportion of specific memories were not correlated with each other and showed different patterns of association with other conceptually relevant variables. When responses to neutral cue words were examined in multiple linear and logistic regression analyses, the proportion of specific memories uniquely predicted less depressive symptoms, low emotional avoidance, lower emotion reactivity, better executive control and lower rumination, whereas the amount of memory detail uniquely predicted the presence of depression diagnosis, as well as greater depressive symptoms, subjective stress, emotion reactivity and rumination. Findings suggest that the ability to retrieve specific memories and the tendency to retrieve detailed personal memories reflect different constructs that have different implications in the development of emotional distress. PMID- 25685981 TI - A model for determining baseline morphometrics of skeletal myofibres. AB - The minimum diameter method of morphometry (MDM) is used to measure and detect changes in myofibre diameters (FD). The MDM is used to identify pathology in skeletal muscle. In such studies, an assumption is made that the mean FD in a particular muscle in both limbs is essentially the same. This study explored this premise to determine the accuracy of MDM as a means of morphometric analysis. Muscle biopsies were obtained from the left (G1) and right (G2) tibialis anterior of four vervet monkeys and from the massaged left (G3) and untreated right (G4) tibialis anterior of four animals. Wax sections were prepared for MDM and FD was measured. Three specimens were re-measured on four occasions. The mean FD of each biopsy from G1 and G2 limbs were compared and the number of measurements necessary to produce a meaningful result determined. Repeated measurement showed a difference of < 3.0% in FD means between the first and three subsequent measurements. There was no significant difference of FD means between G1 and G2, whilst the difference between G3 and G4 was 11.2%. When > 175 FD were measured, the difference from the final mean was less than 2.0%. These data show that, (1) FD data derived from a muscle in an untreated limb can be used as a control for experiment mediated changes of FD in the other, (2) MDM is a reliable means of measuring FD and (3) 150-175 FD are needed to provide a dependable result. PMID- 25685982 TI - Modifying candle soot with FeP nanoparticles into high-performance and cost effective catalysts for the electrocatalytic hydrogen evolution reaction. AB - Developing inexpensive and highly efficient non-precious-metal electrocatalysts has been proposed as a promising alternative to platinum-based catalysts for the hydrogen evolution reaction (HER). Herein, we report novel FeP NPs supported on inexpensive and available candle soot (FeP-CS) derived from Fe3O4-CS hybrid precursors obtained after a phosphidation reaction. As HER electrocatalysts, the FeP-CS hybrids exhibit high electrocatalytic ability for HER with a Tafel slope of 58 mV dec(-1), a low onset overpotential of 38 mV, a large exchange current density of 2.2 * 10(-1) mA cm(-2) and an overpotential of 112 mV to obtain a current of 10 mA cm(-2). The present work shows significant advance in designing and developing non-precious-metal electrocatalysts for hydrogen evolution reaction. PMID- 25685983 TI - Dietary intake of trace elements by the population of Catalonia (Spain): results from a total diet study. AB - This study aimed to analyse the concentrations of Al, Ba, Bi, Cu, Cr, Ge, Mn, Mo, Ni, Sb, Se, Sr and Zn in food samples collected in 2008 in Catalonia (Spain). The dietary intake of these 13 trace elements was subsequently estimated by different age-gender groups of the population: children, adolescents, adults and seniors. In general terms, fish and shellfish, cereals, and pulses were the food groups showing the highest levels for most elements. Higher dietary intakes were associated with male groups (adolescents, adults and seniors). However, none exceeded the tolerable levels. When exposure was estimated based on body weight, children were the group with the highest dietary intake. Notwithstanding, only the weekly intake of Al by children exceeded the recommendations of the European Food Safety Authority (EFSA). It is a consequence of the higher intake of cereals in relation to their respective body weights. In addition to the periodical food surveillance of toxic metals (As, Cd, Hg and Pb), it is also important to determine the levels of other trace elements in order to ensure that the dietary exposure by the Catalan population is under control. PMID- 25685984 TI - Exploring volume, compressibility and hydration changes of folded proteins upon compression. AB - Understanding the physical basis of the structure, stability and function of proteins in solution, including extreme environmental conditions, requires knowledge of their temperature and pressure dependent volumetric properties. One physical-chemical property of proteins that is still little understood is their partial molar volume and its dependence on temperature and pressure. We used molecular dynamics simulations of aqueous solutions of a typical monomeric folded protein, staphylococcal nuclease (SNase), to study and analyze the pressure dependence of the apparent volume, Vapp, and its components by the Voronoi Delaunay method. We show that the strong decrease of Vapp with pressure (betaT = 0.95 * 10(-5) bar(-1), in very good agreement with the experimental value) is essentially due to the compression of the molecular volume, VM, ultimately, of its internal voids, V. Changes of the intrinsic volume (defined as the Voronoi volume of the molecule), the contribution of the solvent to the apparent volume, and of the contribution of the boundary voids between the protein and the solvent have also been studied and quantified in detail. The pressure dependences of the volumetric characteristics obtained are compared with the temperature dependent behavior of these quantities and with corresponding results for a natively unfolded polypeptide. PMID- 25685985 TI - Plant ferritin--a source of iron to prevent its deficiency. AB - Iron deficiency anemia affects a significant part of the human population. Due to the unique properties of plant ferritin, food enrichment with ferritin iron seems to be a promising strategy to prevent this malnutrition problem. This protein captures huge amounts of iron ions inside the apoferritin shell and isolates them from the environment. Thus, this iron form does not induce oxidative change in food and reduces the risk of gastric problems in consumers. Bioavailability of ferritin in human and animal studies is high and the mechanism of absorption via endocytosis has been confirmed in cultured cells. Legume seeds are a traditional source of plant ferritin. However, even if the percentage of ferritin iron in these seeds is high, its concentration is not sufficient for food fortification. Thus, edible plants have been biofortified in iron for many years. Plants overexpressing ferritin may find applications in the development of bioactive food. A crucial achievement would be to develop technologies warranting stability of ferritin in food and the digestive tract. PMID- 25685986 TI - Altered fetal skeletal muscle nutrient metabolism following an adverse in utero environment and the modulation of later life insulin sensitivity. AB - The importance of the in utero environment as a contributor to later life metabolic disease has been demonstrated in both human and animal studies. In this review, we consider how disruption of normal fetal growth may impact skeletal muscle metabolic development, ultimately leading to insulin resistance and decreased insulin sensitivity, a key precursor to later life metabolic disease. In cases of intrauterine growth restriction (IUGR) associated with hypoxia, where the fetus fails to reach its full growth potential, low birth weight (LBW) is often the outcome, and early in postnatal life, LBW individuals display modifications in the insulin-signaling pathway, a critical precursor to insulin resistance. In this review, we will present literature detailing the classical development of insulin resistance in IUGR, but also discuss how this impaired development, when challenged with a postnatal Western diet, may potentially contribute to the development of later life insulin resistance. Considering the important role of the skeletal muscle in insulin resistance pathogenesis, understanding the in utero programmed origins of skeletal muscle deficiencies in insulin sensitivity and how they may interact with an adverse postnatal environment, is an important step in highlighting potential therapeutic options for LBW offspring born of pregnancies characterized by placental insufficiency. PMID- 25685987 TI - Novel approaches to improve the intrinsic microbiological safety of powdered infant milk formula. AB - Human milk is recognised as the best form of nutrition for infants. However; in instances where breast-feeding is not possible, unsuitable or inadequate, infant milk formulae are used as breast milk substitutes. These formulae are designed to provide infants with optimum nutrition for normal growth and development and are available in either powdered or liquid forms. Powdered infant formula is widely used for convenience and economic reasons. However; current manufacturing processes are not capable of producing a sterile powdered infant formula. Due to their immature immune systems and permeable gastro-intestinal tracts, infants can be more susceptible to infection via foodborne pathogenic bacteria than other age groups. Consumption of powdered infant formula contaminated by pathogenic microbes can be a cause of serious illness. In this review paper, we discuss the current manufacturing practices present in the infant formula industry, the pathogens of greatest concern, Cronobacter and Salmonella and methods of improving the intrinsic safety of powdered infant formula via the addition of antimicrobials such as: bioactive peptides; organic acids; probiotics and prebiotics. PMID- 25685988 TI - Prevalence of anaemia and its associated factors in African children at one and three years residing in the Capricorn District of Limpopo Province, South Africa. AB - OBJECTIVE: The present study evaluated the prevalence of anaemia and its determinants in one- and three-year-old children from the Capricorn District of Limpopo Province, South Africa. METHODS: A prospective cohort study conducted in rural villages in the Capricorn District of Limpopo Province, South Africa. At birth, a cohort of 219 children was followed until they were one and three years of age. Data collected included the children's anthropometric measurements, blood for biochemical analysis (full blood count, ferritin, folate and vitamin B12) and socio-demographic status. RESULTS: At one year, anaemia (Hb < 11 g/dL) was present in 52% of the children, decreasing to 22% by the third year. Iron deficiency (ferritin < 12 ug/mL) was common in these children (39% and 33% at one year and three years, respectively) particularly in the presence of anaemia. Folate and vitamin B12 deficiencies (< 5 ng/mL and < 145 pg/mL, respectively) were common at one year, with the children accumulating enough vitamin B12 by three years; however, folate deficiency levels remained fairly constant between the two time points. CONCLUSION: There was a high prevalence of anaemia in the study participants at one year and three years of age. Factors that increased the risk of anaemia at three years were: a mother with only a primary school education, anaemia at one year, male gender, overweight, and combined overweight and stunting. Protective factors against anaemia were having a younger mother who served as the main caregiver. PMID- 25685989 TI - Transplanted Umbilical Cord Mesenchymal Stem Cells Modify the In Vivo Microenvironment Enhancing Angiogenesis and Leading to Bone Regeneration. AB - Umbilical cord mesenchymal stem cells (UC-MSCs) show properties similar to bone marrow mesenchymal stem cells (BM-MSCs), although controversial data exist regarding their osteogenic potential. We prepared clinical-grade UC-MSCs from Wharton's Jelly and we investigated if UC-MSCs could be used as substitutes for BM-MSCs in muscoloskeletal regeneration as a more readily available and functional source of MSCs. UC-MSCs were loaded onto scaffolds and implanted subcutaneously (ectopically) and in critical-sized calvarial defects (orthotopically) in mice. For live cell-tracking experiments, UC-MSCs were first transduced with the luciferase gene. Angiogenic properties of UC-MSCs were tested using the mouse metatarsal angiogenesis assay. Cell secretomes were screened for the presence of various cytokines using an array assay. Analysis of implanted scaffolds showed that UC-MSCs, contrary to BM-MSCs, remained detectable in the implants for 3 weeks at most and did not induce bone formation in an ectopic location. Instead, they induced a significant increase of blood vessel ingrowth. In agreement with these observations, UC-MSC-conditioned medium presented a distinct and stronger proinflammatory/chemotactic cytokine profile than BM-MSCs and a significantly enhanced angiogenic activity. When UC-MSCs were orthotopically transplanted in a calvarial defect, they promoted increased bone formation as well as BM-MSCs. However, at variance with BM-MSCs, the new bone was deposited through the activity of stimulated host cells, highlighting the importance of the microenvironment on determining cell commitment and response. Therefore, we propose, as therapy for bone lesions, the use of allogeneic UC-MSCs by not depositing bone matrix directly, but acting through the activation of endogenous repair mechanisms. PMID- 25685990 TI - The pain of low status: the relationship between subjective socio-economic status and analgesic prescriptions in a Scottish community sample. AB - There is a strong positive relationship between objective measures of socio economic status (OSS) and general health. However, there is an increasing interest in the relationship between health and subjective socio-economic status (SSS), which describes one's perceived rank in relation to the rest of the society, based on factors such as income, occupation and education. While the relationship between SSS and general health is well established, the relationship between SSS and pain has received little attention. Gathering both self-report questionnaire data and General Practitioner medical data from a large representative community sample in Scotland between 2012 and 2013 (N = 1824), we investigated the relationship between SSS and prescriptions for analgesic drugs. We found that higher levels of SSS significantly predicted lower odds of participants having been prescribed at least one analgesic drug in the previous six months. We obtained this result even after controlling for OSS-related variables (education, occupational status and geographical location) and demographic variables (age and gender). This suggests that, just like the relationship between SSS and general health, SSS has important effects on pain that go beyond the influence of OSS. PMID- 25685991 TI - Comparison of polymerase chain reaction and Warthin-Starry techniques to detect Leptospira spp. in kidneys of slaughtered cattle. AB - Leptospirosis is a worldwide zoonotic disease that is caused by Gram-negative spirochaetes, Leptospira species. Affected animals excrete the organism in the urine into the environment and act as a source of infection. Cattle are maintenance hosts for some serovars of leptospirosis and are important in the transmission of the infection to humans. At post mortem examination, affected cattle show white spots in their kidneys but these are not specific for leptospirosis. Sometimes it is necessary that leptospirosis be diagnosed in the carcass. Different direct methods, including polymerase chain reaction (PCR), Warthin-Starry silver stain (WS), immunofluorescence (IF) and immunohistochemistry (IHC) can be used in order to diagnose leptospirosis in the affected tissues, such as kidney. The main advantage of the WS technique is direct visualisation of the bacteria in the tissue samples. Silver staining is useful for retrospective studies on formalin-fixed and paraffin-embedded samples but little information is available on the sensitivity and specificity of the technique. The present study aimed to find a simple and inexpensive method that can be used in any laboratory and that also, if clinical samples are not available, can detect Leptospira in tissue samples post mortem. This study was performed on 19 paraffin-embedded kidneys of slaughtered cows that grossly had focal to multifocal white spots. Leptospirosis was confirmed in these samples with PCR based on the LipL32 gene. Out of 19 PCR positive kidneys, Leptospira was identified in 13 stained samples by WS. The kidneys revealed different grades of interstitial nephritis. No relationship was found between severity of lesions and presence of leptospires in the kidneys. The PCR results on the urine and blood were consistent with matching WS stained kidneys. Out of 13 kidneys that were positive with silver staining, 7 matching blood and 10 matching urine samples were confirmed positive for leptospirosis with PCR. In this study, the WS technique provided fewer positive results than PCR. This may be as a result of a low burden of Leptospira in the kidney, but the sensitivity of WS staining needs more investigation. PMID- 25685992 TI - Exploring nurse preceptors' perceptions of benefits and support of and commitment to the preceptor role in the Western Cape Province. AB - BACKGROUND: A preceptor is a specialised tutor who provides practical training to students in the practice setting. They are frequently used to orientate nursing students to prepare them for their duties as professional nurses. In the Western Cape Province professional nurses attend a training programme to prepare them for the role of preceptor. After completion of the training it is unclear how the trained nurse preceptors perceive their preparation for the role. The perceptions of preceptors may influence their commitment to their role. OBJECTIVE: The purpose of this study was to explore nurse preceptors' perceptions of benefits, support and commitment to the preceptor role. A conceptual framework guided the study which replicated previous studies that explored nurse preceptors' perceptions. METHOD: A quantitative approach utilising a descriptive correlational design was used in this study to address the research questions. A convenience sample was drawn from preceptors (n = 60) who had completed a preceptor training programme at the University of the Western Cape. Instrumentation for the study included the following scales: preceptors' perceptions of benefits and rewards, preceptors' perceptions of support, and commitment to the preceptor role. Data analysis was performed using SPSS 20.0. RESULTS: The findings indicate that nurse preceptors were committed to their role. CONCLUSION: The findings of this study are supported by Kanter's model of structural determinants of behaviour in organisations, since preceptors who see themselves as having access to opportunity and support are likely to be committed to their role. PMID- 25685993 TI - A facile method to fabricate functionally integrated devices for oil/water separation. AB - In this paper, we present a facile method for the fabrication of a functionally integrated device, which has the multi-functions of the oil-containment boom, oil sorption material, and water/oil-separating film, through a single immersion step in an ethanol solution of stearic acid. During the simple immersion process, the two dominant factors of superhydrophobicity, surface roughness and low-surface energy coatings, could be accomplished simultaneously. The as-prepared functionally integrated device with superhydrophobicity/superoleophilicity displayed a lower density than that of water, such that it could float on water and act as an oil-containment boom; an efficient oil-absorbing property, which was attributed to the capillary effect caused by micrometer-sized pore structures and could be used as oil-sorption materials; a high oil/water separating efficiency which was suitable for water/oil-separating film. In this way, the functions of oil collection, absorption, and water/oil separation are integrated into a single device, and these functions could work independently, reducing the cost in terms of energy consumption and being versatile for a wide range of applications. PMID- 25685994 TI - Reverse saphenous conduit flap in small animals: Clinical applications and outcomes. AB - Due to the lack of skin elasticity defects of the distal hind limb can be a challenge to close. This article assesses a well-described, but completely under used technique for closure of wounds on the distal tarsus. The technique was used with good success in six cases presenting to the Bryanston Veterinary Hospital with a wide range of underlying pathology ranging from trauma to neoplastic disease of the tarsus. All six cases were treated with a reverse saphenous conduit flap and two of them underwent radiation therapy with no adverse side effects. All cases showed excellent results with a very low degree of flap necrosis that never exceeded 15% of the total flap area. This skin flap provides an excellent treatment method that is reliable in closure of defects of the distal tarsus with few adverse effects. To the author's knowledge there has been only one previously published report on the clinical use of this type of skin flap, even though the flap is well described in most texts. PMID- 25685995 TI - Anthropometric and physical performance characteristics of top-elite, elite and non-elite youth female team handball players. AB - In order to maximise the potential for success, developing nations need to produce superior systems to identify and develop talent, which requires comprehensive and up-to-date values on elite players. This study examined the anthropometric and physical characteristics of youth female team handball players (16.07 +/- 1.30 years) in non-elite (n = 47), elite (n = 37) and top-elite players (n = 29). Anthropometric profiling included sum of eight skinfolds, body mass, stature, girths, breadths and somatotype. Performance tests included 20 m sprint, counter-movement jump, throwing velocity, repeated shuttle sprint and jump ability test, and Yo-Yo Intermittent Recovery Test Level 1. Youth top-elite players had greater body mass, lean mass, stature, limb girths and breadths than elite and non-elite players, while only stature and flexed arm were higher in elite compared to non-elite players (all P < 0.05). Sum of skinfolds and waist-to hip ratio were similar between groups (P > 0.05). Top-elite performed better in most performance tests compared to both elite and non-elite players (P < 0.05), although maximal and repeated 10 m sprints were similar between playing standards (P > 0.05). Elite outperformed non-elite players only in throwing velocity. The findings reveal that non-elite players compare unfavourably to top-elite international European players in many anthropometric and performance characteristics, and differ in a few characteristics compared to elite European club team players. This study is useful for emerging team handball nations in improving talent identification processes. PMID- 25685996 TI - Lived experiences of male intimate partners of female rape victims in Cape Town, South Africa. AB - BACKGROUND: Sexual violence in South Africa is a major public health and social problem. Sexual assault or rape is a traumatic event which disrupts not only the life of the female rape victim, but also that of her male intimate partner (MIP), irrespective of whether he witnessed or was informed of the incident. OBJECTIVES: The study aimed to explore the lived experiences of MIPs of female rape victims and the meaning of these experiences in the six months following the partner's rape. METHOD: We conducted a longitudinal hermeneutic phenomenological study. Nine purposively sampled adult MIPs were interviewed over a period of six months. The participants were in an intimate relationship with a female rape victim prior to and immediately after the rape; their partners had been treated at a specialised centre for victims of rape and sexual assault. Four interviews were conducted with each of the nine intimate partners of female rape victims: (1) within 14 days of, (2) a month after, (3) three months after, and (4) six months after the rape. RESULTS: Two major themes emerged: being-in-the-world as a secondary victim of rape, and living in multiple worlds, those of their female partners, family, friends, society, employers or colleagues, professionals and the justice system. The participant's familiar world became strange and even threatening, and his relationship with his partner became uncertain. CONCLUSION: Early supportive intervention for intimate partners of female rape victims is required to prevent on-going emotional trauma and alleviate the effects of chronic post-traumatic stress disorder and suffering at intra- and interpersonal levels. PMID- 25685997 TI - Evaluation of medicinal turpentine used for the prevention of bovine babesiosis in southern KwaZulu-Natal and the eastern Free State. AB - Medicinal turpentine has been used extensively in the eastern Free State and KwaZulu-Natal provinces of South Africa with reportedly excellent results. It is believed that it is able to prevent and treat babesiosis (redwater) in cattle. Redwater is an often-fatal disease in cattle and results in losses of large numbers every year in South Africa. This study was initiated in an attempt to investigate the validity of the use of the turpentine as a medicinal agent. Using a semi in vitro screening assay, Babesia caballi grown in primary equine erythrocytes was exposed to various concentrations of turpentine in comparison to diminazene and imidocarb. The turpentine had no parasiticidal effect following direct exposure. During the recovery phase, the previously exposed parasites appeared to grow more slowly than the controls. In comparison, diminazene and imidocarb were 100% effective in killing the parasites. In a subsequent tolerance study in adult cattle (n = 6) at 1x (2 mL), 3x and 5x the recommended dose, the product was non-toxic. Irritation was noted at the injection site with the higher dose. The only major finding on clinical pathology was a general increase in globulins, without a concurrent change in native babesia antibody titres. It was concluded that it is unlikely that medicinal turpentine is an effective treatment against babesiosis. PMID- 25685998 TI - Heat-shock protein 90 inhibitors: will they ever succeed as chemotherapeutics? PMID- 25685999 TI - Dynamical insights of Mnk2 kinase activation by phosphorylation to facilitate inhibitor discovery. AB - AIM: Mitogen-activated protein kinase-interacting kinases (Mnks) are emerging anticancer targets. Mnks feature unique structural features, enhancing their importance for selective inhibitor discovery. Nonetheless, the lack of structural details obstruct the development of selective Mnk inhibitors. RESULTS: We disclose the first complete structure model of the activated state of Mnk2. Using all-atom accelerated molecular dynamics, we also demonstrate that its activation by phosphorylation grants access to distinct activation loop conformations, steering the inactive-to-active conformational transformation. Then we propose the binding mode of CGP57380 to active Mnk2, and evaluate key interactions that could be critical for future Mnk-targeted inhibitors. CONCLUSION: Critical insights of the Mnk2 activation process are gained, while providing a platform for designing Mnk-targeted anticancer agents. PMID- 25686000 TI - Purine homo-N-nucleoside+coumarin hybrids as pleiotropic agents for the potential treatment of Alzheimer's disease. AB - AIM: Due to the complex nature of Alzheimer's disease, there is a renewed search for pleiotropic agents. RESULTS: Purine+coumarin hybrids have been synthesized and tested for the potential treatment of Alzheimer's disease. Hybrids 6, 4a-b, 14c and 14e inhibit significantly soybean lipoxygenase, whereas derivatives 14b, c and 20a present antioxidative/lipoxygenase inhibition activities. Cholinesterase (ChE) and monoamino oxidase (MAO) inhibition studies have been carried out. Hybrid 20a is the most potent ChE inhibitor, in the low micromolar range, and selective for hBuChE (IC50 = 4.65 +/- 0.23 MUM), whereas hybrid 14a is the most potent MAOI, in the low micromolar range, and selective for MAO-B (IC50 = 6.8 +/- 0.6 MUM). CONCLUSION: The preliminary experimental results point to two selective multitarget lead compounds 20a and 4b. PMID- 25686001 TI - Structural diversity and potency range distribution of scaffolds from compounds active against current pharmaceutical targets. AB - AIM: Large numbers of biologically active compounds are available from which scaffolds (core structures) can be isolated and compared focusing on structural, potency and promiscuity criteria. RESULTS: A computational analysis has been carried out to characterize all scaffolds and cyclic skeletons contained in currently available compounds from medicinal chemistry sources. Compounds active against hundreds of pharmaceutical targets were found to contain many structurally distinct scaffolds and cyclic skeletons. For given targets, these scaffolds often represent highly potent compounds. CONCLUSION: There is an abundance of scaffold diversity among specifically active compounds indicating that many pharmaceutically relevant proteins are highly permissive small molecular targets. These findings have several implications for drug discovery and design. PMID- 25686002 TI - Molecularly imprinted polymeric micro- and nano-particles for the targeted delivery of active molecules. AB - Molecular imprinting (MI) represents a strategy to introduce a 'molecular memory' in a polymeric system obtaining materials with specific recognition properties. MI particles can be used as drug delivery systems providing a targeted release and thus reducing the side effects. The introduction of molecular recognition properties on a polymeric drug carrier represents a challenge in the development of targeted delivery systems to increase their efficiency. This review will summarize the limited number of drug delivery MI particles described in the literature along with an overview of potential solutions for a larger exploitation of MI particles as targeted drug delivery carriers. Molecularly imprinted drug carriers can be considered interesting candidates to significantly improve the efficiency of a controlled drug treatment. PMID- 25686003 TI - Adipokines and their receptors: potential new targets in cardiovascular diseases. AB - Adipose tissue is an 'endocrine organ' that influences diverse physiological and pathological processes via adipokines secretion. Strong evidences suggest that epicardial and perivascular adipose tissue can directly regulate heart and vessels' structure and function. Indeed, in obesity there is a shift toward the secretion of adipokines that promote a pro-inflammatory status and contribute to obesity cardiomyopathy. The prospect of modulating adipokines and/or their receptors represents an attractive perspective to the treatment of cardiovascular diseases. In this paper, we described the most important actions of certain adipokines and their receptors that are capable of influencing cardiovascular physiology as well as their possible use as therapeutic targets. PMID- 25686004 TI - Photoaffinity labeling in target- and binding-site identification. AB - Photoaffinity labeling (PAL) using a chemical probe to covalently bind its target in response to activation by light has become a frequently used tool in drug discovery for identifying new drug targets and molecular interactions, and for probing the location and structure of binding sites. Methods to identify the specific target proteins of hit molecules from phenotypic screens are highly valuable in early drug discovery. In this review, we summarize the principles of PAL including probe design and experimental techniques for in vitro and live cell investigations. We emphasize the need to optimize and validate probes and highlight examples of the successful application of PAL across multiple disease areas. PMID- 25686005 TI - Research progress of indoleamine 2,3-dioxygenase inhibitors. AB - Indoleamine 2,3-dioxygenase (IDO, subsequently named IDO1) can degrade the level of essential amino acid tryptophan in mammals, and catalyze the initial and rate limiting step through the kynurenine pathway. Broad evidence implies that IDO is overexpressed in both tumor cells and antigen-presenting cells, facilitating the escape of malignant tumors from immune surveillance. In the past decades, the inhibition of IDO has been one of the most promising areas in cancer immunotherapy and many potential inhibitors of IDO have been designed, synthesized and evaluated, among which d-1-methyl-tryptophan and INCB24360 have advanced to clinical trial stage. This review aims to give an overview of the rationale for IDO as a therapeutic target as well as the research progress of IDO inhibitors. PMID- 25686006 TI - Progress toward JAK1-selective inhibitors. AB - The discovery of the JAK-STAT pathway was a landmark in cell biology. The identification of these pathways has changed the landscape of treatment of rheumatoid arthritis and other autoimmune diseases. The two first (unselective) JAK inhibitors have recently been approved by the US FDA for the treatment of myelofibrosis and rheumatoid arthritis and many other JAK inhibitors are currently in clinical development or at the discovery stage. Research groups have demonstrated the different roles of JAK member and the therapeutic potential of targeting them selectively. JAK1 plays a critical and potentially dominant role in the transduction of gammac cytokine (gammac = common gamma chain) and in IL-6 signaling. In this review, we will discuss the state-of-the-art research that evokes JAK1 selective inhibition. PMID- 25686007 TI - Photoremoval of protecting groups: mechanistic aspects of 1,3-dithiane conversion to a carbonyl group. AB - Photodeprotection of 1,3-dithianes in the presence of thiapyrylium was performed to return to the parent carbonyl compound, and the mechanism was studied by steady state photolysis, laser flash photolysis, and theoretical calculations. Electron transfer from dithianes to triplet sensitizers is extremely fast, and the decay of dithiane radical cations was not affected by the presence of water or oxygen as the consequence of a favorable unimolecular fragmentation pathway. Similar behaviors were observed for dithianes bearing electron-releasing or electron-withdrawing substituents on the aryl moiety, evidenced by C-S bond cleavage to form a distonic radical cation species. The lack of reaction under nitrogen atmosphere, requirement of oxygen for good conversion yields, inhibition of the photodeprotection process by the presence of p-benzoquinone, and absence of a labeled carbonyl final product when the reaction is performed in the presence of H2(18)O all suggest that the superoxide anion drives the deprotection reaction. Density functional theory computational studies on the reactions with water, molecular oxygen, and the superoxide radical anion support the experimental findings. PMID- 25686008 TI - tert-Butyl phenyl sulfoxide: a traceless sulfenate anion precatalyst. AB - tert-Butyl phenyl sulfoxide is employed as a traceless precatalyst for the generation of sulfenate anions under basic conditions and has been used to catalyze the coupling of benzyl halides to trans-stilbenes. The advantage of this precatalyst over previous precatalysts is that the byproduct generated on catalyst formation is a gas, facilitating product isolation in high purity. Using this second generation catalyst, a variety of trans-stilbenes were generated in 39-98% isolated yield. PMID- 25686009 TI - Phenolic metabolites of anthocyanins modulate mechanisms of endothelial function. AB - Anthocyanins are reported to have vascular bioactivity, however their mechanisms of action are largely unknown. Evidence suggests that anthocyanins modulate endothelial function, potentially by increasing nitric oxide (NO) synthesis, or enhancing NO bioavailability. This study compared the activity of cyanidin-3 glucoside, its degradation product protocatechuic acid, and phase II metabolite, vanillic acid. Production of NO and superoxide and expression of endothelial NO synthase (eNOS), NADPH oxidase (NOX), and heme oxygenase-1 (HO-1) were established in human vascular cell models. Nitric oxide levels were not modulated by the treatments, although eNOS was upregulated by cyanidin-3-glucoside, and superoxide production was decreased by both phenolic acids. Vanillic acid upregulated p22(phox) mRNA but did not alter NOX protein expression, although trends were observed for p47(phox) downregulation and HO-1 upregulation. Anthocyanin metabolites may therefore modulate vascular reactivity by inducing HO 1 and modulating NOX activity, resulting in reduced superoxide production and improved NO bioavailability. PMID- 25686010 TI - Tumor-targeted delivery of paclitaxel using low density lipoprotein-mimetic solid lipid nanoparticles. AB - Water-insoluble anticancer drugs, including paclitaxel, present severe clinical side effects when administered to patients, primarily associated with the toxicity of reagents used to solubilize the drugs. In efforts to develop alternative formulations of water-insoluble anticancer drugs suitable for intravenous administration, we developed biocompatible anticancer therapeutic solid lipid nanoparticles (SLNs), mimicking the structure and composition of natural particles, low-density lipoproteins (LDLs), for tumor-targeted delivery of paclitaxel. These therapeutic nanoparticles contained water-insoluble paclitaxel in the core with tumor-targeting ligand covalently conjugated on the polyethylene glycol (PEG)-modified surface (targeted PtSLNs). In preclinical human cancer xenograft mouse model studies, the paclitaxel-containing tumor targeting SLNs exhibited pronounced in vivo stability and enhanced biocompatibility. Furthermore, these SLNs had superior antitumor activity to in class nanoparticular therapeutics in clinical use (Taxol and Genexol-PM) and yielded long-term complete responses. The in vivo targeted antitumor activities of the SLN formulations in a mouse tumor model suggest that LDL-mimetic SLN formulations can be utilized as a biocompatible, tumor-targeting platform for the delivery of various anticancer therapeutics. PMID- 25686011 TI - Muscling in on the third dimension. AB - The development of a functional three-dimensional model of human skeletal muscle tissue could accelerate progress towards new and personalized treatments for skeletal muscle disorders. PMID- 25686012 TI - Atmospheric transport of persistent organic pollutants to and from the Arctic under present-day and future climate. AB - The long-term atmospheric cycling and fate of persistent organic pollutants under the influence of a changing climate is a concern. A GCM's realization of present day (1970-1999) and future (2070-2099) climate, the latter under a medium scenario of greenhouse gas emissions, is used to study meridional transports and their correlations with the Arctic and North Atlantic Oscillations (AO and NAO). Regions of import and export maxima into the Arctic are identified along the Arctic Circle. It is found that, under future climate conditions, the net export of PCB153 out of the Arctic will increase. The meridional net flux pattern of this substance is expected to become independent of AO and NAO. For DDT, a trend of decreasing net Arctic import will reverse to an increasing trend 100 years after peak emission, which is partly due to more frequent AO and NAO positive phases. It is concluded that the long-term accumulation trends in the Arctic of other persistent pollutants, including so-called emerging pollutants, are subject to the substances' specific behavior and fate in the environment and need to be studied specifically. PMID- 25686013 TI - Dissolution dynamic nuclear polarization of non-self-glassing agents: spectroscopy and relaxation of hyperpolarized [1-13C]acetate. AB - The intrinsic physicochemical properties of the sample formulation are the key factors for efficient hyperpolarization through dissolution dynamic nuclear polarization (dissolution-DNP). We provide a comprehensive characterization of the DNP process for Na-[1-(13)C]acetate selected as a model for non-self-glassing agents: the solid-state polarization dynamics of different formulations and the effect of the paramagnetic agent (trityl radical) on the pattern of polarization and the relaxation profile were extensively analyzed. We quantified the effects of the glassing agent and Gd(3+)-chelate on DNP performance. The results reported here describe the constraints of the acetate formulation useful for future studies in this field with non-self-glassing enriched molecules. PMID- 25686014 TI - Homogeneous nucleation of predominantly cubic ice confined in nanoporous alumina. AB - The nucleation mechanism of water can be precisely regulated by confinement within nanoporous alumina. We found a transition from heterogeneous nucleation of hexagonal ice (Ih) to homogeneous nucleation of predominantly cubic ice (Ic) with decreasing pore diameter. These results lead to a phase diagram of water under confinement. It contains a (stable) predominant Ic form, a form known to exist only in the upper atmosphere. Possible applications range from cryopreservation to construction materials like cement. PMID- 25686015 TI - Inkjet print microchannels based on a liquid template. AB - A simple method to fabricate microchannels is demonstrated based on an inkjet printing liquid template. The morphology of the liquid template can be well controlled by using ink with viscosity sensitive to temperature. The as-prepared Y-shape microchannel is used as a microfluidic reactor for an acylation fluorigenic reaction in a matrix of polydimethylsiloxane (PDMS). Arbitrary modification of the microchannels could be easily realized synchronously with the formation of the microchannels. By grafting polyethylene glycol (PEG) onto the internal surface, an anti-biosorption microchannel is obtained. The facile method will be significant for the fabrication of a microfluidic chip with functional modifications. PMID- 25686016 TI - The know, do, and quality gaps in international maternal and child health care interventions. PMID- 25686017 TI - Ambient benzotriazole ring opening through intermolecular radical addition to vinyltriazole. AB - Radical addition to vinyltriazole was developed as a new approach to achieve 1,2,3-triazole ring opening under mild conditions. Through reagent control, excellent chemoselectivity was achieved, giving either nitrile under basic conditions or quinoxaline under neutral conditions. Reactivities made this method an attractive new reaction mode. PMID- 25686018 TI - Bovine trypanosomosis and its fly vectors in three selected settlement areas of Hawa-Gelan district, western Ethiopia. AB - A cross-sectional study aimed at investigating the species diversity of fly vectors and estimating the prevalence of bovine trypanosomosis was carried out from October 2009 to May 2010 in selected settlement areas of the Hawa-Gelan district in the western Wollega zone of Ethiopia. Standard methods of sampling and identification were employed for both entomological and parasitological examination. Three species of the genus Glossina (Glossina pallidipes, Glossina morsitans submorsitans and Glossina fuscipes) and two genera of biting flies (Stomoxys and Tabanus) were caught and identified. The overall apparent density of Glossina species caught was 10.5 flies per trap per day, with a higher proportion of female flies (57.2%). Out of a total 389 cattle examined, 42 (10.8%; 95% CI: 7.89% - 14.3%) were found infected with trypanosomes. Three trypanosome species were detected in the study area, namely Trypanosoma congolense (54.8%), Trypanosoma brucei (23.8%) and Trypanosoma vivax (21.4%). The prevalence of trypanosomosis was found to be significantly (p < 0.05) higher in cattle with poor body condition. There was an association between mean packed cell volume (PCV) and the occurrence of parasitaemia (chi2 = 49.5, p < 0.05). About 95.2% of cattle that were positive for trypanosomes had a PCV less than the lower limit for cattle. Considering the current result, bovine trypanosomosis seems to be a serious constraint for agricultural activities in the settlement areas of the Hawa-Gelan district and seems to be associated with the presence of Glossina species. Therefore, application of control methods through community involvement to reduce the Glossina species infestation level is likely to increase animal productivity. PMID- 25686019 TI - Rough glass surface-mediated transition of micelle-to-vesicle in sodium dodecylbenzenesulfonate solutions. AB - In this paper, we report a micelle-to-vesicle transition in aqueous solution of the anionic single-tailed surfactant (STS) sodium dodecylbenzenesulfonate (SDBS), with the mediation of a rough glass surface (RGS) in the absence of cosurfactants or additives. This transition produced a mixed solution of vesicles and micelles. Interestingly, the obtained SDBS vesicles in the solution displayed good stability during a long-term storage (at least 6 months at room temperature), exposure to high temperature (80 degrees C for 2 h), and freeze-thawing (-20 or 196 degrees C for 2 h to approximately 25 degrees C) after the RGS was removed. Our results confirmed that SDBS could adsorb on the RGS to form bilayers, in which the molecular packing parameter of SDBS was in the range of 1/2-1. The bilayer adsorption and the roughness of the solid surface played an important role in the vesicle formation. In addition, we propose a possible mechanism for the RGS-mediated transition of micelle-to-vesicle in SDBS solutions: SDBS micelles and molecules adsorb on the RGS to form curved bilayers; the curved bilayers detach from the RGS, and then close to form vesicles. PMID- 25686020 TI - Tethered poly(2-isopropyl-2-oxazoline) chains: temperature effects on layer structure and interactions probed by AFM experiments and modeling. AB - Thermoresponsive polymer layers on silica surfaces have been obtained by utilizing electrostatically driven adsorption of a cationic-nonionic diblock copolymer. The cationic block provides strong anchoring to the surface for the nonionic block of poly(2-isopropyl-2-oxazoline), referred to as PIPOZ. The PIPOZ chain interacts favorably with water at low temperatures, but above 46 degrees C aqueous solutions of PIPOZ phase separate as water becomes a poor solvent for the polymer. We explore how a change in solvent condition affects interactions between such adsorbed layers and report temperature effects on both normal forces and friction forces. To gain further insight, we utilize self-consistent lattice mean-field theory to follow how changes in temperature affect the polymer segment density distributions and to calculate surface force curves. We find that with worsening of the solvent condition an attraction develops between the adsorbed PIPOZ layers, and this observation is in good agreement with predictions of the mean-field theory. The modeling also demonstrates that the segment density profile and the degree of chain interpenetration under a given load between two PIPOZ-coated surfaces rise significantly with increasing temperature. PMID- 25686021 TI - Highly stretchable and sensitive unidirectional strain sensor via laser carbonization. AB - In this paper, we present a simple and low-cost technique for fabricating highly stretchable (up to 100% strain) and sensitive (gauge factor of up to 20 000) strain sensors. Our technique is based on transfer and embedment of carbonized patterns created through selective laser pyrolization of thermoset polymers, such as polyimide, into elastomeric substrates (e.g., PDMS or Ecoflex). Embedded carbonized materials are composed of partially aligned graphene and carbon nanotube (CNT) particles and show a sharp directional anisotropy, which enables the fabrication of extremely robust, highly stretchable, and unidirectional strain sensors. Raman spectrum of pyrolized carbon regions reveal that under optimal laser settings, one can obtain highly porous carbon nano/microparticles with sheet resistances as low as 60 Omega/?. Using this technique, we fabricate an instrumented latex glove capable of measuring finger motion in real-time. PMID- 25686022 TI - Discovery and safety profiling of a potent preclinical candidate, (4-[4-[[(3R)-3 (hydroxycarbamoyl)-8-azaspiro[4.5]decan-3-yl]sulfonyl]phenoxy]-N-methylbenzamide) (CM-352), for the prevention and treatment of hemorrhage. AB - Discovery of potent and safe therapeutics that improve upon currently available antifibrinolytics, e.g., tranexamic acid (TXA, 1) and aprotinin, has been challenging. Matrix metalloproteinases (MMPs) participate in thrombus dissolution. Then we designed a novel series of optimized MMP inhibitors that went through phenotypic screening consisting of thromboelastometry and mouse tail bleeding. Our optimized lead compound, CM-352 (2), inhibited fibrinolysis in human whole blood functional assays and was more effective than the current standard of care, 1, in the tail-bleeding model using a 30 000 times lower dose. Moreover, 2 reduced blood loss during liver hepatectomy, while 1 and aprotinin had no effect. Molecule 2 displayed optimal pharmacokinetic and safety profiles with no evidence of thrombosis or coagulation impairment. This novel mechanism of action, targeting MMP, defines a new class of antihemorrhagic agents without interfering with normal hemostatic function. Furthermore, 2 represents a preclinical candidate for the acute treatment of bleeding. PMID- 25686023 TI - The role of the state in stock farming in rural areas: A case study of Hertzog, Eastern Cape, South Africa. AB - This study examined the role of the state in providing veterinary services to resource-poor stock farmers. Communal stock farmers in most rural areas have low incomes and generally poor access to commercial veterinary healthcare. The state veterinary services thus offer a means for stock farmers to maintain the health of their livestock and receive information on animal healthcare. Interviews and participant observation were used to collect data about animal healthcare practices in Hertzog, a village in the Eastern Cape Province of South Africa.The findings were that the state played an important role in animal healthcare and in the education of farmers. However, the lack of a skilled workforce was a constraint to effective service delivery, whilst veterinary educational institutions that disseminate information to the stock farmers were not utilised. It is thus important to fully utilise training centres to educate stock farmers and for more incentives to be given to state employees, so as to attract the necessary skilled personnel to improve service delivery. PMID- 25686024 TI - Idiopathic lymphoplasmacytic rhinitis in 33 dogs. AB - Idiopathic lymphoplasmacytic rhinitis (LPR) is recognised frequently in dogs with clinical signs typical of other chronic nasal diseases. The purpose of this study was to determine clinical signs, survey radiographic, rhinoscopic and histologic abnormalities and the response to therapy in dogs with LPR. It was a retrospective study of 33 client-owned animals of various breeds and ages that had been diagnosed with LPR. During the study period, a total of 110 dogs were diagnosed with nasal disease, of which 33 (30%) were diagnosed with idiopathic LPR. The median age was 9 years (range 2.3-17 years) and there were 15 female and 18 male dogs. The majority of dogs showed a mucoid nasal discharge, bilateral stertor and no overt radiographic changes. The most common finding on rhinos copy was hyperaemic nasal mucous membranes with mucoid material accumulation within the nasal cavity. In all 33 dogs bacterial culture yielded no pathogenic bacteria and fungal culture was negative. Histologically, all 33 dogs showed lymphoplasmacytic infiltration within the nasal mucosa. All 33 dogs were treated with systemic and topical corticosteroids for varying lengths of time and dosing intervals. Eleven dogs were treated with concurrent cyclosporine and three dogs underwent allergy testing followed by desensitisation therapy. The best response was seen in the dogs that underwent desensitisation therapy, followed by those treated with corticosteroids and cyclosporine. PMID- 25686025 TI - Detection of Alzheimer's disease amyloid-beta plaque deposition by deep brain impedance profiling. AB - OBJECTIVE: Alzheimer disease (AD) is the most common form of neurodegenerative disease in elderly people. Toxic brain amyloid-beta (Abeta) aggregates and ensuing cell death are believed to play a central role in the pathogenesis of the disease. In this study, we investigated if we could monitor the presence of these aggregates by performing in situ electrical impedance spectroscopy measurements in AD model mice brains. APPROACH: In this study, electrical impedance spectroscopy measurements were performed post-mortem in APPPS1 transgenic mice brains. This transgenic model is commonly used to study amyloidogenesis, a pathological hallmark of AD. We used flexible probes with embedded micrometric electrodes array to demonstrate the feasibility of detecting senile plaques composed of Abeta peptides by localized impedance measurements. MAIN RESULTS: We particularly focused on deep brain structures, such as the hippocampus. Ex vivo experiments using brains from young and old APPPS1 mice lead us to show that impedance measurements clearly correlate with the percentage of Abeta plaque load in the brain tissues. We could monitor the effects of aging in the AD APPPS1 mice model. SIGNIFICANCE: We demonstrated that a localized electrical impedance measurement constitutes a valuable technique to monitor the presence of Abeta plaques, which is complementary with existing imaging techniques. This method does not require prior Abeta staining, precluding the risk of variations in tissue uptake of dyes or tracers, and consequently ensuring reproducible data collection. PMID- 25686026 TI - JAMA patient page. Measles vaccination. PMID- 25686027 TI - Assessment of selected biochemical parameters and humoral immune response of Nile crocodiles (Crocodylus niloticus) experimentally infected with Trichinella zimbabwensis. AB - Fifteen crocodiles were randomly divided into three groups of five animals. They represented high-infection, medium-infection and low-infection groups of 642 larvae/kg, 414 larvae/kg and 134 larvae/kg bodyweight, respectively. The parameters assessed were blood glucose, creatine phosphokinase (CPK), lactate dehydrogenase (LDH), aspartate transaminase (AST) and alanine transaminase (ALT). The humoral immune response to Trichinella zimbabwensis infection was evaluated in all three groups by an indirect ELISA method. The results showed deviations from normal parameters of blood glucose, CPK, LDH, AST and ALT when compared with reported levels in uninfected reptiles. Contrary to studies involving mammals, hypoglycaemia was not observed in the infected groups in this study. Peak values of blood glucose were reached on post-infection (PI) Day 49, Day 42 and Day 35 in the high-infection, medium-infection and low-infection groups, respectively. Peak values of LDH and AST were observed on PI Day 56, Day 49 and Day 42 in the high infection, medium-infection and low-infection groups, respectively. Peak values of CPK were observed on Day 35 PI in all three groups. Peak ALT values were reached on Day 56 in the high-infection group and on Day 28 PI in both the medium infection and low-infection groups. No correlations between the biochemical parameters and infection intensity were observed. Peak antibody titres were reached on Day 49 PI in the medium-infection group, and on Day 42 PI in both the high-infection and low-infection groups. Infection intensity could not be correlated with the magnitude of the humoral immune response or time to sero conversion. Results from this study were in agreement with results reported in mammals infected with other Trichinella species and showed that antibody titres could not be detected indefinitely. PMID- 25686028 TI - Mitigating the dangers of opioids. PMID- 25686031 TI - Dietary exposure to organochlorine pesticide residues of the Hong Kong adult population from a total diet study. AB - Dietary exposure of the Hong Kong adult population to organochlorine pesticide (OCP) residues was estimated using a total diet study (TDS) approach. OCPs listed under the Stockholm Convention as persistent organic pollutants (POPs) including, aldrin, dieldrin, chlordane, chlordecone, dichlorodiphenyltricholroethane (DDT), endosulfan, endrin, heptachlor, hexachlorobenzene (HCB), alpha hexachlorocyclohexanes (HCH), beta-HCH, lindane, mirex, pentachlorobenzene and toxaphene, were studied. Out of 600 composite samples, 55% contained one or more OCP residues at detectable levels. The most commonly detected OCP was DDT (32% of all composite samples), followed by HCB (30%) and endosulfan (22%). The lower- and upper-bound mean exposure estimates of OCP residues ranged from 0% to 0.5% and were 0.1-8.4% of their respective health-based guidance values (HBGVs). The lower- and upper-bound 95th percentile exposure estimates ranged from 0% to 1.2% and were 0.1-13.6% of their respective HBGVs. This indicated that dietary exposures to the OCP residues analysed would be unlikely to pose unacceptable health risks to Hong Kong adults. PMID- 25686030 TI - Duration of menopausal vasomotor symptoms over the menopause transition. AB - IMPORTANCE: The expected duration of menopausal vasomotor symptoms (VMS) is important to women making decisions about possible treatments. OBJECTIVES: To determine total duration of frequent VMS (>= 6 days in the previous 2 weeks) (hereafter total VMS duration) during the menopausal transition, to quantify how long frequent VMS persist after the final menstrual period (FMP) (hereafter post FMP persistence), and to identify risk factors for longer total VMS duration and longer post-FMP persistence. DESIGN, SETTING, AND PARTICIPANTS: The Study of Women's Health Across the Nation (SWAN) is a multiracial/multiethnic observational study of the menopausal transition among 3302 women enrolled at 7 US sites. From February 1996 through April 2013, women completed a median of 13 visits. Analyses included 1449 women with frequent VMS. MAIN OUTCOMES AND MEASURES: Total VMS duration (in years) (hot flashes or night sweats) and post FMP persistence (in years) into postmenopause. RESULTS: The median total VMS duration was 7.4 years. Among 881 women who experienced an observable FMP, the median post-FMP persistence was 4.5 years. Women who were premenopausal or early perimenopausal when they first reported frequent VMS had the longest total VMS duration (median, >11.8 years) and post-FMP persistence (median, 9.4 years). Women who were postmenopausal at the onset of VMS had the shortest total VMS duration (median, 3.4 years). Compared with women of other racial/ethnic groups, African American women reported the longest total VMS duration (median, 10.1 years). Additional factors related to longer duration of VMS (total VMS duration or post-FMP persistence) were younger age, lower educational level, greater perceived stress and symptom sensitivity, and higher depressive symptoms and anxiety at first report of VMS. CONCLUSIONS AND RELEVANCE: Frequent VMS lasted more than 7 years during the menopausal transition for more than half of the women and persisted for 4.5 years after the FMP. Individual characteristics (eg, being premenopausal and having greater negative affective factors when first experiencing VMS) were related to longer-lasting VMS. Health care professionals should counsel women to expect that frequent VMS could last more than 7 years, and they may last longer for African American women. PMID- 25686032 TI - Investigation of the photochemical reactivity of soot particles derived from biofuels toward NO2. A kinetic and product study. AB - In the current study, the heterogeneous reaction of NO2 with soot and biosoot surfaces was investigated in the dark and under illumination relevant to atmospheric conditions (J(NO2) = 0.012 s(-1)). A flat-flame burner was used for preparation and collection of soot samples from premixed flames of liquid fuels. The biofuels were prepared by mixing 20% v/v of (i) 1-butanol (CH3(CH2)3OH), (ii) methyl octanoate (CH3(CH2)6COOCH3), (iii) anhydrous diethyl carbonate (C2H5O)2CO and (iv) 2,5 dimethyl furan (CH3)2C4H2O additive compounds in conventional kerosene fuel (JetA-1). Experiments were performed at 293 K using a low-pressure flow tube reactor (P = 9 Torr) coupled to a quadrupole mass spectrometer. The initial and steady-state uptake coefficients, gamma0 and gamma(ss), respectively, as well as the surface coverage, N(s), were measured under dry and humid conditions. Furthermore, the branching ratios of the gas-phase products NO (~80 100%) and HONO (<20%) were determined. Soot from JetA-1/2,5-dimethyl furan was the most reactive [gamma0 = (29.1 +/- 5.8) * 10(-6), gamma(ss)(dry) = (9.09 +/- 1.82) * 10(-7) and gamma(ss)(5.5%RH) = (14.0 +/- 2.8)(-7)] while soot from JetA 1/1-butanol [gamma0 = (2.72 +/- 0.544) * 10(-6), gamma(ss)(dry) = (4.57 +/- 0.914) * 10(-7), and gamma(ss)(5.5%RH) = (3.64 +/- 0.728) * 10(-7)] and JetA 1/diethyl carbonate [gamma0 = (2.99 +/- 0.598) * 10(-6), gamma(ss)(dry) = (3.99 +/- 0.798) * 10(-7), and gamma(ss)(5.5%RH) = (4.80 +/- 0.960) * 10(-7)] were less reactive. To correlate the chemical reactivity with the physicochemical properties of the soot samples, their chemical composition was analyzed employing Raman spectroscopy, NMR, and high-performance liquid chromatography. In addition, the Brunauer-Emmett-Teller adsorption isotherms and the particle size distributions were determined employing a Quantachrome Nova 2200e gas sorption analyzer. The analysis of the results showed that factors such as (i) soot mass collection rate, (ii) porosity of the particles formed, (iii) aromatic fraction, and (iv) pre-existence of nitro-containing species in soot samples (formed during the combustion process) can be used as indicators of soot reactivity with NO2. PMID- 25686033 TI - Multifunctional composites of chiral valine derivative Schiff base Cu(II) complexes and TiO2. AB - We have prepared four new Cu(II) complexes containing valine moieties with imidazole ligands at the fourth coordination sites and examined their photo induced reactions with TiO2 in order of understanding the reaction mechanisms. Under a nitrogen atmosphere, the intermolecular electron transfer reactions (essentially supramolecular interactions) of these systems, which resulted in the reduction of Cu(II) species to Cu(I) ones, occurred after UV light irradiation. In this study, we have investigated the conditions of the redox reactions in view of substituent effects of aldehyde moieties. The results of cyclic voltammetry (CV) on an rotating ring-disk electrode (RRDE) suggested that the substitution effects and redox potentials were correlated. Density functional theory (DFT) and time-dependent DFT (TD-DFT) calculations were also performed to simulate the UV Vis and circular dichroism (CD) spectra; the results revealed a reasonably good correlation between the substituent effects and the highest occupied molecular orbitals and the lowest unoccupied molecular orbitals (HOMO-LUMO) gaps associated with the most intense transition bands. In addition, we summarized the substitution effects of Cu(II) complexes for their corresponding UV light-induced reactions. PMID- 25686034 TI - Regulation of translation factor EEF1D gene function by alternative splicing. AB - Alternative splicing is an exquisite mechanism that allows one coding gene to have multiple functions. The alternative splicing machinery is necessary for proper development, differentiation and stress responses in a variety of organisms, and disruption of this machinery is often implicated in human diseases. Previously, we discovered a long form of eukaryotic elongation factor 1Bdelta (eEF1Bdelta; this long-form eEF1Bdelta results from alternative splicing of EEF1D transcripts and regulates the cellular stress response by transcriptional activation, not translational enhancement, of heat-shock responsive genes. In this review, we discuss the molecular function of EEF1D alternative splicing products and the estimated implication of human diseases. PMID- 25686035 TI - Isolation and cytotoxicity evaluation of the chemical constituents from Cephalantheropsis gracilis. AB - Cephalantheropsis gracilis afforded five new compounds: cephalanthrin-A (1), cephalanthrin-B (2), cephathrene-A (3), cephathrene-B (4), methyl 2 (aminocarbonyl) phenylcarbamate (5), and 52 known compounds. The structures of the new compounds were determined by spectroscopic analysis. Among the compounds isolated, tryptanthrin (6), phaitanthrin A (7), cephalinone D (19), and flavanthrin (30) showed significant cytotoxicity against MCF-7, NCI-H460, and SF 268 cell lines. PMID- 25686036 TI - Effect of porcine Akirin2 on skeletal myosin heavy chain isoform expression. AB - Akirin2 plays an important role in skeletal myogenesis. In this study, we found that porcine Akirin2 (pAkirin2) mRNA level was significantly higher in fast extensor digitorum longus (EDL) and longissimus lumborum (LL) muscles than in slow soleus (SOL) muscle of pigs. Overexpression of pAkirin2 increased the number of myosin heavy chain (MHC)-positive cells, indicating that pAkirin2 promoted myoblast differentiation. We also found that overexpression of pAkirin2 increased the mRNA expressions of MHCI and MHCIIa and decreased the mRNA expression of MHCIIb. Myocyte enhancer factor 2 (MEF2) and nuclear factor of activated T cells (NFAT) are the major downstream effectors of calcineurin. Here we also observed that the mRNA expressions of MEF2C and NFATc1 were notably elevated by pAkirin2 overexpression. Together, our data indicate that the role of pAkirin2 in modulating MHCI and MHCIIa expressions may be achieved through calcineurin/NFATc1 signaling pathway. PMID- 25686037 TI - Multiscale experimental and theoretical investigations of spin crossover Fe(II) complexes: examples of [Fe(phen)2(NCS)2] and [Fe(PM-BiA)2(NCS)2]. AB - For spin crossover (SCO) complexes, computation results are reported and confirmed with experiments at multiscale levels of the isolated molecule and extended solid on the one hand and theory on the other hand. The SCO phenomenon which characterizes organometallics based on divalent iron in an octahedral FeN6 like environment with high spin (HS) and low spin (LS) states involves the LS/HS switching at the cost of small energies provided by temperature, pressure or light, the latter connected with Light-Induced Excited Spin-State Trapping (LIESST) process. Characteristic infra red (IR) and Raman vibration frequencies are computed within density functional theory (DFT) framework. In [Fe(phen)2(NCS)2] a connection of selected frequencies is established with an ultra-fast light-induced LS -> HS photoswitching mechanism. In the extended solid, density of state DOS and electron localization function (ELF) are established for both LS and HS forms, leading to characterizion of the compound as an insulator in both spin states with larger gaps for LS configuration, while keeping molecular features in the solid. In [Fe(PM-BiA)2(NCS)2], by combining DFT and classical molecular dynamics, the properties and the domains of existence of the different phases are obtained by expressing the potential energy surfaces in a short range potential for Fe-N interactions. Applying such Fe-N potentials inserted in a classical force field and carrying out molecular dynamics (MD) in so-called "semi-classical MD" calculations, lead to the relative energies of HS/LS configurations of the crystal and to the assessment of the experimental (P, T) phase diagram. PMID- 25686038 TI - Biobanking in China. PMID- 25686039 TI - Turning point: biobanking in China and the future of translational research. PMID- 25686040 TI - Chinese biobanking initiatives. AB - Due to the requirement for comprehensive clinical research efforts in China, the importance of biobanking in modern clinical research is outlined in this overview. Hospitals, universities, and research institutes have been well organized as fundamental resources for Chinese biobanking initiatives and the resulting bio-sample collections. Here, a brief history and time line of development of biobanking in China will be introduced, as well as strategic designs for future biobanking development. PMID- 25686041 TI - Ethical management guidelines for the shanghai disease-based biobank network. AB - The Ethical Management Guidelines for the Shanghai Disease-Based Biobank Network are intended to safeguard the interests of all the participants, to standardize the construction, management, and resource sharing of the Shanghai Disease-based Biobank Network, to promote the development of medical research, and to improve public health and well-being. The guidelines contain seven chapters: General Principles; Informed Consent; Use of Bio-samples from Persons without the Capacity to Consent; Privacy and Confidentiality; Applications of Use of Biological Samples and Data; Intellectual Property and Resource Sharing; and Conflict of Interest. PMID- 25686042 TI - Biostorage and quality control for human peripheral blood leukocytes. AB - BACKGROUND: Peripheral blood leukocytes (PBLs) are the main source of DNA in blood samples. A common protocol is to store buffy coat specimens for future DNA isolation, and such samples may remain in frozen storage for years. However, the currently available methods to maintain buffy coat specimens can be optimized for better quality and cost efficiency. STUDY DESIGN AND METHODS: Seventeen donors (aged 24-34 years) were enrolled in this study. Initially, five centrifugal speeds were chosen to examine the distribution of PBLs in the cell layer; the buffy coat was then harvested to evaluate the cell quantity and viability after storing at 4 degrees C for various times. Finally, the buffy coat was isolated, snap frozen, and kept at -80 degrees C for 1 hour, 1 week, or 4 weeks until the DNA was extracted. Agarose gel electrophoresis and multiplex PCR were used to verify DNA integrity and amplifiability. RESULTS: There was a linear positive correlation between the amount of fresh PBLs and the DNA yield. At least 70% of PBLs were collected in the uppermost 40% of the cellular material when the centrifugal force was over 800 g compared to 400 g. Storing blood at 4 degrees C for no more than 24 hours did not have an effect on the amount of PBLs or their viability. In addition, the amount of extracted DNA was decreased in the frozen buffy coat that was stored for more than 7 days, though the DNA quality was acceptable. CONCLUSION: DNA should be extracted from fresh buffy coat samples as soon as possible after collection, especially for very important samples. Retaining the upper 40% of the cell pack of blood instead of whole blood could improve the storage efficiency of biobanking such samples. Our study provides a recommended option for blood collection and processing protocols in biobanking. PMID- 25686043 TI - Analysis of reproducibility and variability from a frozen sample aliquotter by metabolomics analysis. AB - PURPOSE: A novel frozen sample aliquotter, which consists of a drilling system in which a coring probe extracts multiple frozen cores from one frozen sample, was developed to avoid thawing and refreezing of samples. The aliquotter was tested to determine if it is suitable for metabolomics analyses in reproducibility and variability studies. METHOD: Twenty volunteers (10 males and 10 females) were enrolled in this study. Each of the volunteers' serum was aliquotted to one 1.8 mL tube and one 150 MUL tube (control). Then the serum was frozen at -80 degrees C for 2 weeks. Four frozen cores were taken from the perimeter of each of the 1.8 mL parent tubes by the aliquotter. The cores, the frozen serum remaining in the parent samples after extracting four frozen cores (Remainder), and control were analyzed using a gas chromatography time-of-flight mass spectrometry platform to test the reproducibility and variability of the samples in metabolomics analyses. RESULT: There were no significant differences between the Core, Remainder, and Control groups based on multivariate analysis of metabolomics analyses. In the reproducibility study, the average CV for the cores was 10.07%. In the variability study, the average changes ranged from 81.07% to 119.82% and 81.06% to 119.74% for Core and Remainder samples compared to Control, respectively. CONCLUSION: The frozen sample aliquotter technology can extract multiple consistently homogenous aliquots without thawing the parent sample, and the coring process with serum produces good samples for metabolomics analyses. PMID- 25686044 TI - Histological assessment of tumor tissue samples via the mirror image method. AB - Human tissue biorepositories have become key platforms for the acceleration of basic and translational biomedical research on cancer in China. The maintenance of sufficient amounts of tumor cells is critical for a wide variety of cancer studies. Ensuring the high quality of frozen stored tissue specimens is a crucial requirement. However, different tumor locations and various methods of tumor tissue removal can lead to variable numbers of tumor cells from banked tissue specimens. Thus, an effective method to assess the tumor cell content is essential for tissue samples in biobanks. In the present study, the mirror image method was used to evaluate the amount of tumor cells in stored tumor tissues of six common cancer types, including solid and hollow organ cancers. All tissues were stored in the Tianjin Medical University Cancer Institute and Hospital (TMUCIH). Histological assessment was performed by pathologists who conducted morphological diagnoses of tumor percentage on mirror image sections of frozen stored samples that were stained with hematoxylin and eosin (H&E). Results showed that the tumor percentage of solid organ cancers was higher than that of hollow organ cancers (chi(2)=17.11, p<0.0001). Among solid organ cancers, the highest tumor percentage was observed in renal tumor tissues, and likewise esophagus tumor tissues had the highest tumor content among hollow organ cancers (multiple tests, p<0.05). Three kinds of samples, which showed higher proportions of tumor content under 25%, were stomach, liver, and colorectal cancers, and the proportions were 15.0%, 10.9%, and 10.6%, respectively. Therefore, histological assessment based on the review of mirror-image H&E sections offers the most direct and objective judgment. The results can not only be applied to the tissue quality feedback process of biobanks, but also guide a wide variety of scientific studies. PMID- 25686045 TI - Methods of glioma sample processing for molecular diagnosis for the glioma tissue bank project. AB - Genome-wide sequencing in glioma samples provides comprehensive insights into oncogenesis and malignant transformation. Several distinct biomarkers have been proven to have clinical significance and are being widely applied in routine clinical practice. Standard sample processing lays the foundation for successful molecular testing. In this study, we found intraoperative neuronavigation ensured higher tumor purity during sample collection, and an automated device helped improve DNA quality and increased yields. These two technologies are beneficial for glioma tissue bank construction and provide for accurate molecular testing during routine clinical practice. PMID- 25686046 TI - Integrating clinical and biological information in a shanghai biobank: an introduction to the sample repository and information sharing platform project. AB - Biobanks are important resources and central tools for translational medicine, which brings scientific research outcomes to clinical practice. The key purpose of biobanking in translational medicine and other medical research is to provide biological samples that are integrated with clinical information. In 2008, the Shanghai Municipal Government launched the "Shanghai Tissue Bank" in an effort to promote research in translational medicine. Now a sharing service platform has been constructed to integrate clinical practice and biological information that can be used in diverse medical and pharmaceutical research studies. The platform collects two kinds of data: sample data and clinical data. The sample data are obtained from the hospital biobank management system, and mainly include the donors' age, gender, marital status, sample source, sample type, collection time, deposit time, and storage method. The clinical data are collected from the "Hospital-Link" system (a medical information sharing system that connects 23 tertiary hospitals in Shanghai). The main contents include donors' corresponding medication information, test reports, inspection reports, and hospital information. As of the end of September 2014, the project has a collection of 16,020 donors and 148,282 samples, which were obtained from 12 medical institutions, and automatically acquired donors' corresponding clinical data from the "Hospital-Link" system for 6830 occurrences. This project will contribute to scientific research at medical institutions in Shanghai, and will also support the development of the biopharmaceutical industry. In this article, we will describe the significance, the construction phases, the application prospects, and benefits of the sample repository and information sharing service platform. PMID- 25686047 TI - Establishment of a network-based intra-hospital virtual cancer biobank. AB - There is a growing interest in integrating biomaterial repositories into larger infrastructures in order to meet research demands. However, even for a single hospital or institute, where both population-based and multiple disease-based biobanks have existed for a long time, the integration of existing separate biobanks into a virtual cancer biobank is still challenging. The guidelines and procedures for biobanking are varied and not universally enforced or followed in separate biobanks. Within the last 2 years, we initiated a project to establish a centralized biobank facility in a common storage environment. Analyzing the challenges and interests of stakeholders for the biobanks, a working group comprised of representatives from the central and separate banks, ethic committees, and research administration offices reached an agreement to implement a central facility by following the ISBER best practices for biobanking, and including regular project reviews by the ethical and scientific boards. Furthermore, by implementing a modified minimum information system with biobank data sharing, a network based intra-hospital virtual cancer bank was established to facilitate sharing information of samples held by separate banks. Meanwhile, this virtual biobank network, which has integrated patient information from hospital health care systems, will gradually integrate follow-up information from the cancer registry office and data from epidemiology studies, providing controlled access for sample providers and resource users. In the future, this infrastructure designed for a single hospital may be helpful for building a broader virtual network for data and specimen exchanges. PMID- 25686048 TI - Evaluation of DNA/RNAshells for room temperature nucleic acids storage. AB - Traditional nucleic acids preservation methods rely on maintaining samples in cold environments, which are costly to operate and time sensitive. Recent work validated that using room temperature for the storage of nucleic acids is possible if the samples are completely protected from water and oxygen. Here, we conducted accelerated aging and real-time degradation studies to evaluate the new technology DNAshell and RNAshell, which preserves DNA and RNA at room temperature, including the DNA and RNA yield, purity, and integrity. DNA and RNA solutions are dried in the presence of stabilizers in stainless steel minicapsules, then redissolved after different time points of heating and storing at room temperature. Results show that DNAshell and RNAshell ensure the safe storage of nucleic acids at room temperature for long periods of time, and that the quality of these nucleic acids is suitable for common downstream analysis. PMID- 25686049 TI - Comparison of six different pretreatment methods for blood RNA extraction. AB - Human blood specimens serve as important research materials in the field of translational medicine research. The RNA extracted from blood, for example, represents the gene expression profiles of individuals or groups, and can be indicative of the pathological basis for human diseases. Meanwhile, the RNA quality may have severe impacts on the results of RNA studies. RNA is susceptible to many factors, such as the time of sample collection, transportation conditions, protectants, pretreatments, and extraction methods. In this study, six different pretreatment methods are evaluated for their effects on blood RNA extraction including the RNA yields and quality. Results show that most of these methods meet the basic requirements for RNA studies. While considering the simplicity of the procedure, the cost factor, and how to make full use of the samples, the proper method should be employed by researchers who have specific requirements for their research. PMID- 25686050 TI - Practical electronic information system and printed recording promote management accuracy in an early-stage small-scale non-automatic biobank. AB - It is particularly necessary for biomedical researchers to obtain applicable biosamples accurately and efficiently, especially from a biobank with multiple disease catalogs. To optimize the retrieval procedure, especially in the early stages of a non-automatic biobank, we developed a procedure that combined the electronic information system with a graphically designed printed recording system, which assisted in retrieving the samples quickly in a visualized way. In this procedure, we designed tables depending on the structure of equipment and registered the corresponding information in the tables layer by layer. Different samples from different types of diseases were first registered in the electronic system with the specific pre-allocation and barcodes. Then they were stored in the allocated position using their respective barcodes. In this way, the sample number and the location information in the electronic database were completely matched with the printed record. When the samples are needed, it is convenient to check the electronic information with the printed record. This procedure provides a convenient way to record the sample information during its lifecycle, and helps the administrator to double check information about the sample. The current solution offers an easy way for the transformation of a non-automatic biobank from the small-scale early-stage to the large-scale highly-automated level. PMID- 25686051 TI - The 2015 ISBER Annual Meeting & Exhibits in Phoenix, Arizona, USA: bridging the canyon-connecting biobank communities through innovations in global health, research and environmental preservation. PMID- 25686052 TI - Processing speed and working memory training in multiple sclerosis: a double blind randomized controlled pilot study. AB - Between 40-65% of multiple sclerosis patients experience cognitive deficits, with processing speed and working memory most commonly affected. This pilot study investigated the effect of computerized cognitive training focused on improving processing speed and working memory. Participants were randomized into either an active or a sham training group and engaged in six weeks of training. The active training group improved on a measure of processing speed and attention following cognitive training, and data trended toward significance on measures of other domains. Results provide preliminary evidence that cognitive training with multiple sclerosis patients may produce moderate improvement in select areas of cognitive functioning. PMID- 25686053 TI - Case reports and series: authenticate rare conditions. PMID- 25686054 TI - Evaluation of subjects with a moderate cup to disc ratio using optical coherence tomography and Heidelberg retina tomograph 3: impact of the disc area. AB - AIM: The aim was to evaluate subjects with a moderate cup to disc ratio using optical coherence tomograph (OCT) and Heidelberg retina tomograph (HRT) 3. SETTINGS AND DESIGN: We included 80 patients with early glaucoma and 80 nonglaucomatous subjects with moderate cup/disc ratio (range of 0.5-0.8) to this cross-sectional study. SUBJECTS AND METHODS: We compared results of color-coded algorithms of HRT 3 (Moorfields regression analysis [MRA] and Glaucoma probability score [GPS]) and OCT. All outputs are classified into three categories: Within normal limits (WNLs), borderline and outside normal limits (ONLs). Diagnostic accuracies of algorithms were determined using the highest sensitivity criteria. RESULTS: The sensitivities of global MRA, GPS and OCT were 0.75, 0.925 and 0.725, respectively, in average disc area group and 0.85, 1.0 and 0.425, respectively, in large disc area group. The specificities of global MRA, GPS and OCT were 0.55, 0.15 and 0.85, respectively, in average disc area group and 0.425, 0.025 and 0.80, respectively, in large disc area group. Area under receiver operating characteristic curve (AUROC) of global MRA, GPS and OCT were 0.667, 0.617 and 0.792, respectively, in average disc area group and 0.746, 0.576 and 0.627, respectively, in large disc area group. AUROC of global MRA and OCT combination in the average and large disc area groups were 0.828 and 0.825, respectively. CONCLUSIONS: In contrast to GPS and OCT algorithms, diagnostic performance of MRA algorithm increased in large disc area group. Combining MRA and OCT algorithms produced satisfactory diagnostic performance in subjects with an average and large disc area. PMID- 25686055 TI - Circulating levels of reactive oxygen species in patients with nonproliferative diabetic retinopathy and the influence of antioxidant supplementation: 6-month follow-up. AB - AIMS: The aim was to evaluate circulating levels of reactive oxygen species (ROS) and changes in central macular thickness (CMT) in patients with nonproliferative diabetic retinopathy (NPDR) after antioxidant supplementation. MATERIALS AND METHODS: A total of 68 patients (68 eyes) with NPDR were enrolled. Patients were randomly divided into two groups: Treated with antioxidant supplement (Group A) and untreated control group (Group B). Each tablet, for oral administration, containing pycnogenol 50 mg, Vitamin E 30 mg and coenzyme Q10 20 mg. CMT and free oxygen radical test (FORT) were analyzed at baseline (T0), 3 (T1) and 6 (T2) months in both groups. RESULTS: In Group A, FORT levels and CMT were significantly reduced over time (P < 0.001 for both). In Group B, FORT levels were increased (P < 0.001) and CMT did not vary significantly (P = 0.81) over 3 time points. CONCLUSIONS: This is the first study showing the reduction of ROS levels in patients with NPDR thanks to antioxidant therapy. Moreover, our findings have suggested also an influence on retinal thickness. PMID- 25686056 TI - Decreased keratocyte density and central corneal thickness in primary open-angle glaucoma patients undergoing treatment with topical prostaglandin analogues. AB - PURPOSE: To evaluate whether prostaglandin (PG) analogue use is associated with alterations in keratocyte density and central corneal thickness (CCT) in subjects with primary open-angle glaucoma (POAG). MATERIALS AND METHODS: Thirty-five POAG patients treated with PG analogues for >2 years and 35 control subjects without glaucoma were included in this cross-sectional study. All subjects were underwent CCT measurements using ultrasound pachymetry. Keratocyte densities of each stromal layer were determined by in vivo confocal microscopy. Student's t-test and Chi-square test were used for statistical evaluations. Correlations between keratocyte densities and CCT were analyzed using Pearson's correlation analysis. RESULTS: Keratocyte densities in each stromal layer were significantly lower in glaucoma patients receiving PG analogues as compared to those of controls (P < 0.001). The mean CCT was also lower in glaucoma patients (515.2 +/- 18.8 MU) than control subjects (549.6 +/- 21.1 MU, P < 0.001). A positive correlation between keratocyte densities in each stromal layer and CCT was observed in POAG patients. CONCLUSIONS: Long-term administration of topical PG analogues may adversely influence keratocyte densities and CCT. Further prospective studies are required clarify the relationship between PG analogues and their effects on the cornea. PMID- 25686057 TI - Socioeconomics of long-term glaucoma therapy in India. AB - PURPOSE: To determine the socioeconomic impact of long-term glaucoma therapy. MATERIALS AND METHODS: One hundred and fifty consecutive glaucoma patients on medical therapy, following up at our glaucoma service for at least 6 months were recruited. A questionnaire regarding monthly income, cost of glaucoma medications prescribed, availability of medications, travel time, time spent in review clinics, compliance, education status, medical insurance and systemic or local side-effects was administered. RESULTS: The patients seen at the tertiary government hospital had an average monthly income of Rs. 10,912/- (range: Rs. 500/- to Rs. 50,000/-) with approximately 56% of the patients having an income of less than Rs. 5000/month. The expenditure on anti-glaucoma medications ranged from 0.3% in high income group to 123% of their monthly gross income in low income group (P < 0.0001). The total expenditure including travel, stay, and loss of wages of patients and accompanying persons ranged from 1.6% in high income group to 137% of the monthly income in low income group (P < 0.0001). Mean time required for a glaucoma clinic visit was 15.66 h, (range: 6-96 h/month). About 2.7% experienced systemic side-effects and 21.3% had complaints of ocular adverse effects. About 90% of the patients were compliant. 92% were not covered by any insurance plan/government reimbursement for their treatment. CONCLUSIONS: Medical therapy for glaucoma is an economic burden to many patients and should be individualized, according to the socioeconomic status, availability of drugs and the required distance to travel to reach the specialist clinics. PMID- 25686058 TI - Short-term efficacy of intravitreal triamcinolone acetonide for macular edema secondary to retinal vein occlusion that is refractory to intravitreal bevacizumab. AB - AIMS: To evaluate the 1-month efficacy of intravitreal triamcinolone acetonide (TA) in treating macular edema secondary to retinal vein occlusion (RVO) that was refractory to intravitreal bevacizumab. MATERIALS AND METHODS: This retrospective, observational study included 23 eyes from 23 patients with macular edema secondary to RVO. Macular edema that did not respond to two or more consecutive intravitreal bevacizumab injections was treated with intravitreal TA. Central foveal thickness (CFT) and best-corrected visual acuity (BCVA) were compared before and one month after TA injection. RESULTS: Fifteen eyes were diagnosed with central RVO, and eight eyes were diagnosed with branch RVO. All patients were previously treated with 2.4 +/- 0.6 intravitreal bevacizumab injections. The TA injection was performed, on average, 5.8 +/- 1.4 weeks after the last bevacizumab injection. The CFT before TA injection was 516.6 +/- 112.4 MUm and significantly decreased to 402.3 +/- 159.7 MUm after TA therapy (P < 0.001). The logarithm of the minimal angle of resolution BCVA was 0.72 +/- 0.34 before TA therapy and was not significantly improved by the treatment (0.67 +/- 0.35, P = 0.119), despite a decrease in CFT. However, seven eyes (30.4%) had a BCVA gain of one or more lines. CONCLUSIONS: Intravitreal TA therapy was beneficial in some patients with macular edema secondary to RVO that was refractory to intravitreal bevacizumab therapy. This study suggests that intravitreal TA should be considered as a treatment option for refractory macular edema. PMID- 25686059 TI - Evaluation of corneal thickness alterations during menstrual cycle in productive age women. AB - PURPOSE: To determine the change in corneal thickness through different phases of menstrual cycle in women who are in their productive age. MATERIALS AND METHODS: Fifty healthy women with normal past medical history were enrolled in this prospective study. Central corneal thickness was measured with ultrasound pachymeter three times during a menstrual cycle: Beginning of the cycle (days 1 3), ovulation time, and at the end of cycle (days 27-32). We confirmed ovulation time with determining a peak in luteinizing hormone in urine. To avoid the diurnal variation of the corneal thickness which is well recognized, we checked all our subjects at 10 in the morning. RESULTS: In days 1 to 3 of menstruation, mean corneal thickness was 541.40 +/- 11.36 and 540.82 +/- 11.70 microns for left and right eyes respectively. At ovulation time the mean thickness changed to 556.50 +/- 7.11 and 555.98 +/- 7.26 microns for left and right eyes respectively, and at the end of the cycle, the corneal thickness turned in to 536.38 +/- 12.83 and 535.48 +/- 13.08 microns for left and right eyes respectively. The difference of corneal thickness was statistically significant relating to the different stages of menstrual cycle. CONCLUSION: The thickest cornea during the menstruation cycle is achieved at the ovulation time and the thinnest at the end of the cycle and this should be taken in to account whilst plan to do a corneal refractive surgery. PMID- 25686060 TI - Proliferative and inflammatory factors in the vitreous of patients with proliferative diabetic retinopathy. AB - PURPOSE: The purpose was to measure the concentrations of various cytokines and growth factors (including vascular endothelial growth factor [VEGF] and pigment epithelium-derived factor [PEDF]) in the vitreous of patients with proliferative diabetic retinopathy (PDR) and to investigate interaction between inflammatory and proliferative factors in the genesis of PDR. Materials and Methods : Vitreous samples from 32 eyes with PDR and 25 eyes without diabetes mellitus and signs of DR (control) were collected. Vitreous concentrations of VEGF, PEDF, monocyte chemotactic protein-1 (MCP-1), interleukin-4 (IL-4), IL-6, IL-8, IL-10, IL-17A, and secretory immunoglobulin A (sIgA) were simultaneously measured using enzyme linked immunoassay. Results : Vitreous levels of VEGF, PEDF, IL-17A, IL-6, IL-8, IL-4, and sIgA were significantly (Pi < 0.05) higher in eyes with PDR compared to control. The concentration of VEGF was more than 17-times higher than in control, and the concentration of PEDF was not changed oppositely and was also higher (1.45-times) compared to control, that may indicate disturbances of compensatory mechanisms in angiogenesis regulation in PDR. Significant (Pi < 0.05) positive correlations were observed between vitreous concentrations of VEGF and IL-17iota (r = 0.45), VEGF and IL-8 (r = 0.48), VEGF and IL-4 (r = 0.51), PEDF and IL 17iota (r = 0.48), PEDF and IL-8 (r = 0.59), MCP-1 and PEDF (r = 0.72), MCP-1 and IL-8 (r0 = 0.45), IL-4 and IL-17iota (r = 0.65), IL-4 and IL-8 (r = 0.71), IL-8 and IL-17iota (r = 0.59). CONCLUSIONS: Significantly raised levels of inflammatory and proliferative factors and numerous positive correlations between them may demonstrate a significant role of activation of vascular proliferation and local inflammation in the pathogenesis of PDR. PMID- 25686061 TI - The effect of intravitreal bevacizumab and transpupillary thermotherapy on choroidal metastases and literature review. AB - AIMS: To represent the effects of transpupillary thermotherapy (TTT) and intravitreal bevacizumab on choroidal metastases and review the literature. SETTINGS AND DESIGN: A retrospective, interventional, noncomparative case series. MATERIALS AND METHODS: A retrospective, interventional, noncomparative case series of five eyes in three patients with choroidal metastases was conducted. Fundus findings of choroidal metastases were divided into two types: Solitary or diffuse type. The size of the tumor was termed small (<10 mm diameter), medium (10-15 mm diameter) or large (>15 mm diameter). All eyes received one session of TTT followed by 3 weekly intravitreal bevacizumab injections as an adjuvant therapy. The parameters of treatment for TTT were 1.2-3 mm spot size, 150-300 mW, 60 s with the whole lesion covered confluently. The changes in preoperative and postoperative best-corrected visual acuity (BCVA) were recorded. Serial color fundus photography and optical coherent tomography were performed to measure the treatment efficacy. RESULTS: All eight choroidal metastases were solitary type. The size of six tumors was small, the size of one tumor was medium, and the size of one tumor was large. All five eyes of the three patients had improvement of BCVA after treatment. Fundus photos revealed tumor shrinkage and the mean shrinkage percentage was 61.27 +/- 21.71%. Optical coherence tomography revealed complete resolution of serous retinal detachment. There was no recurrence after 6 months follow-up. CONCLUSIONS: TTT combined with intravitreal bevacizumab injections brought about beneficial effects in reducing tumor size and improving vision in all five eyes of the three patients. Despite the retrospective nature of our study, the absence of control group and the size limitation that, of course, limit the statistical power, TTT combined with intravitreal bevacizumab seems to be efficient in providing another cost-reducing and time-saving treatment option for patients with choroidal metastases. The antineoplastic properties of bevacizumab make it a viable adjunctive therapy. Studies with more cases and a longer follow-up period are warranted. PMID- 25686062 TI - Converting a conventional wired-halogen illuminated indirect ophthalmoscope to a wireless-light emitting diode illuminated indirect ophthalmoscope in less than 1000/- rupees. AB - AIM: To report the "do it yourself" method of converting an existing wired halogen indirect ophthalmoscope (IO) to a wireless-light emitting diode (LED) IO and report the preferences of the patients and the ophthalmologists. SUBJECTS AND METHODS: In this prospective observational study, a conventional IO was converted to wireless-LED IO using easily available, affordable electrical components. Conventional and the converted IO were then used to perform photo-stress test and take the feedback of subjects and the ophthalmologists regarding its handling and illumination characteristics. RESULTS: The cost of conversion to wireless-LED was 815/- rupees. Twenty-nine subjects, mean age 34.3 [formula in text] 10 years with normal eyes were recruited in the study. Between the two illumination systems, there was no statistical difference in the magnitude of the visual acuity loss and the time to recovery of acuity and the bleached vision on photo-stress test, although the visual recovery was clinically faster with LED illumination. The heat sensation was more with halogen illumination than the LED (P = 0.009). The ophthalmologists rated wireless-LED IO higher than wired-halogen IO on the handling, examination comfort, patient's visual comfort and quality of the image. Twenty-two (81%) ophthalmologists wanted to change over to wireless-LED IO. CONCLUSIONS: Converting to wireless-LED IO is easy, cost-effective and preferred over a wired-halogen indirect ophthalmoscope. PMID- 25686063 TI - Current review and a simplified "five-point management algorithm" for keratoconus. AB - Keratoconus is a slowly progressive, noninflammatory ectatic corneal disease characterized by changes in corneal collagen structure and organization. Though the etiology remains unknown, novel techniques are continuously emerging for the diagnosis and management of the disease. Demographical parameters are known to affect the rate of progression of the disease. Common methods of vision correction for keratoconus range from spectacles and rigid gas-permeable contact lenses to other specialized lenses such as piggyback, Rose-K or Boston scleral lenses. Corneal collagen cross-linking is effective in stabilizing the progression of the disease. Intra-corneal ring segments can improve vision by flattening the cornea in patients with mild to moderate keratoconus. Topography guided custom ablation treatment betters the quality of vision by correcting the refractive error and improving the contact lens fit. In advanced keratoconus with corneal scarring, lamellar or full thickness penetrating keratoplasty will be the treatment of choice. With such a wide spectrum of alternatives available, it is necessary to choose the best possible treatment option for each patient. Based on a brief review of the literature and our own studies we have designed a five point management algorithm for the treatment of keratoconus. PMID- 25686064 TI - Bibliometric trends in ophthalmology 1997-2009. AB - AIMS: To track citation patterns in ophthalmic journals and contrast them with major medical and surgical journals from 1997 to 2009. In addition, we want to familiarize the ophthalmic community with bibliometrics indices. MATERIALS AND METHODS: Data retrieved from Institute for Scientific Information and related websites include 2-year journal impact factor JIF, 5-year impact, Eigenfactor score, H-factor, Article Influence score, and SCImago factor. RESULTS: JIF rose steadily around 10% annually in ophthalmic journals, and likewise for major medical and surgical journals. JIF correlated with recent bibliometric indicators like 5-year impact, H index, and SCImago factor but not with Eigenfactor. Ophthalmic journals publishing reviews, basic science, or large volume on broad range of topics ranked at the top for JIF, while subspecialty journals tended to have low JIF. JIF of subspecialty journal Retina rose from 0.740 (rank 23) in 2000 to 3.088 in 2007 (rank 6). CONCLUSIONS: JIF tends to rise annually by 10% in medical, surgical, and ophthalmic fields. Journals publishing reviews, basic science, or large volume on broad range of topics rank at the top for JIF. The rapid rise of JIF for Retina unlike other subspecialties that stayed status quo is multifactorial: Change in editorial policies (introduction of review articles and omission of case reports) and technological advances in the retinal field. PMID- 25686065 TI - Ocular pressure waveform reflects ventricular bigeminy and aortic insufficiency. AB - Ocular pulse amplitude (OPA) is defined as the difference between maximum and minimum intraocular pressure (IOP) during a cardiac cycle. Average values of OPA range from 1 to 4 mmHg. The purpose of this investigation is to determine the source of an irregular IOP waveform with elevated OPA in a 48-year-old male. Ocular pressure waveforms had an unusual shape consistent with early ventricular contraction. With a normal IOP, OPA was 9 mmHg, which is extraordinarily high. The subject was examined by a cardiologist and was determined to be in ventricular bigeminy. In addition, he had bounding carotid pulses and echocardiogram confirmed aortic insufficiency. After replacement of the aortic valve, the bigeminy resolved and the ocular pulse waveform became regular in appearance with an OPA of 1.6-2.0 mmHg. The ocular pressure waveform is a direct reflection of hemodynamics. Evaluating this waveform may provide an additional opportunity for screening subjects for cardiovascular anomalies and arrhythmias. PMID- 25686066 TI - Progressive hemifacial atrophy with ciliary body atrophy and ocular hypotony. AB - Progressive hemifacial atrophy (PHA) is a disease of unknown etiology affecting one-half of the face. Ocular involvement is uncommon. Atrophy of iris is rare, with only a few cases of partial atrophy being reported in the literature. We report a case of total atrophy of iris and ciliary body with associated ocular hypotony in a 16-year-old girl with PHA. We believe this is the first reported case of complete atrophy of iris and ciliary body in PHA. Ocular hypotony in PHA was thought to be due to intra-ocular inflammation. However in our case it appears to be secondary to severe atrophy of the ciliary body. PMID- 25686067 TI - To report a case of unilateral proliferative retinopathy following noncerebral malaria with Plasmodium falciparum in Southern India. AB - The retinopathy in association with malaria fever described so far includes retinal hemorrhages, vessel changes, retinal discoloration/whitening and papilledema. Malaria retinopathy has been mostly described in severe cases, associated with Plasmodium falciparum, correlating the patho-physiology of retinal and cerebral manifestations. We report an unusual case of proliferative retinopathy as a manifestation of malaria fever, caused by P. falciparum with no cerebral involvement. The patient had features of unilateral retinal vascular occlusion with proliferative changes and vitreous hemorrhage. To the best of our knowledge, such a case has never been reported so far in the literature. This report highlights the possible occurrence of severe proliferative changes associated with malaria fever, which if diagnosed early can prevent possible blindness. PMID- 25686068 TI - Epiretinal membrane removal in patients with Stargardt disease. AB - Epiretinal membranes (ERMs) in Stargardt disease have been known to undergo spontaneous separation in children. Results of surgical intervention in adult patients with Stargardt disease have rarely been reported. A retrospective review of results of surgical intervention for ERM causing visual impairment in two adult patients of Stargardt disease was carried out. Both patients developed ERM in one eye during their follow-up period with the resultant drop in their preexisting visual acuity. Postsurgery, restoration of foveal contour with some improvement in visual acuity was observed in both patients. No adverse effect of surgery was noted. PMID- 25686069 TI - Fundus imaging with a nasal endoscope. AB - Wide field fundus imaging is needed to diagnose, treat, and follow-up patients with retinal pathology. This is more applicable for pediatric patients as repeated evaluation is a challenge. The presently available imaging machines though provide high definition images, but carry the obvious disadvantages of either being costly or bulky or sometimes both, which limits its usage only to large centers. We hereby report a technique of fundus imaging using a nasal endoscope coupled with viscoelastic. A regular nasal endoscope with viscoelastic coupling was placed on the cornea to image the fundus of infants under general anesthesia. Wide angle fundus images of various fundus pathologies in infants could be obtained easily with readily available instruments and without the much financial investment for the institutes. PMID- 25686070 TI - Loop myopexy with true muscle transplantation for very large angle heavy eye syndrome patient. AB - A 42-year-old man presenting with complaints of squint for last 20 years. His visual acuity was 20/400 in right eye (RE) and 20/30 in left eye (LE) with glasses. His refraction was RE -16.75/-2.5 D cycl 180 and LE was -14.5/-1.5 D cycl 180. His axial length was 31.23 mm In RE and 29.72 mm in LE. On examination we found he had RE large esotropia with hypotropia measuring 130 pd base out and 40 pd base up in RE. A computerized tomography scan revealed that the superior rectus (SR) was shifted nasally, and lateral rectus (LR) was shifted inferiorly. A RE medial rectus (MR) recession and LR resection with muscle transplantation on the MR was done. A loop myopexy was done to correct the path of the LR and SR. The patient had only 18 pd eso and 20 pd hypo on follow-up after 3 months. Loop myopexy in conjunction with muscle transplantation is a safe and effective procedure for large angle esotropia associated with heavy eye syndrome. PMID- 25686071 TI - Bilateral optic neuropathy and intraretinal deposits after pars plana vitrectomy in amyloidosis. AB - Pathological examination of material from a nonextensive pars plana vitrectomy (PPV) in the right eye provided a diagnosis of nonfamilial amyloidosis in a 68 year-old woman, who presented with bilateral glass wool-like vitreous opacities. Genetic testing revealed a Tyr114Cys mutation in the transthyretin gene. Six months after PPV, perimetry showed intense constriction with a temporal island and central scotoma in the right eye. An extensive PPV was performed in the left eye. Spectral domain optical coherence tomography evidenced bilateral epimacular amyloid deposits and unreported reflective spots within the inner retina. One year later, visual acuity had decreased to 20/400 in the left eye, with mild vitreous opacity, pale cupped optic disc and inferior altitudinal field defect. Bilateral diurnal intraocular pressure, transiently increased after PPV, never exceeded 16 mmHg with medication. Our patient presented optic nerve blood supply impairment, due to amyloidosis, which caused optic atrophy. Epiretinal and intraretinal deposit detection could aid in diagnosing patients with suspected amyloidosis. PMID- 25686072 TI - Comment on Linezolid induced optic neuropathy. PMID- 25686073 TI - Comment on student-teacher research: a dilemma between power, ethics, and morality. PMID- 25686074 TI - Comment on Comparison of ocular response analyzer parameters in primary open angle glaucoma and exfoliative glaucoma patients. PMID- 25686075 TI - Comment on Repeat gas insufflation for successful closure of idiopathic macular hole following failed primary surgery. PMID- 25686076 TI - Primary cutaneous aggressive epidermotropic CD8 + T-cell lymphoma on upper eyelid. PMID- 25686077 TI - Vitamin D supplementation in antiphospholipid syndrome patients. PMID- 25686078 TI - Primary posterior capsulectomy with anterior vitrectomy in adult traumatic cataracts. PMID- 25686079 TI - Perceived risk factors and risk pathways of Rift Valley fever in cattle in Ijara district, Kenya. AB - Ijara district in Kenya was one of the hotspots of Rift Valley fever (RVF) during the 2006/2007 outbreak, which led to human and animal deaths causing major economic losses. The main constraint for the control and prevention of RVF is inadequate knowledge of the risk factors for its occurrence and maintenance. This study was aimed at understanding the perceived risk factors and risk pathways of RVF in cattle in Ijara to enable the development of improved community-based disease surveillance, prediction, control and prevention. A cross-sectional study was carried out from September 2012 to June 2013. Thirty-one key informant interviews were conducted with relevant stakeholders to determine the local pastoralists' understanding of risk factors and risk pathways of RVF in cattle in Ijara district. All the key informants perceived the presence of high numbers of mosquitoes and large numbers of cattle to be the most important risk factors contributing to the occurrence of RVF in cattle in Ijara. Key informants classified high rainfall as the most important (12/31) to an important (19/31) risk factor. The main risk pathways were infected mosquitoes that bite cattle whilst grazing and at watering points as well as close contact between domestic animals and wildlife. The likelihood of contamination of the environment as a result of poor handling of carcasses and aborted foetuses during RVF outbreaks was not considered an important pathway. There is therefore a need to conduct regular participatory community awareness sessions on handling of animal carcasses in terms of preparedness, prevention and control of any possible RVF epizootics. Additionally, monitoring of environmental conditions to detect enhanced rainfall and flooding should be prioritised for preparedness. PMID- 25686080 TI - A survey of feline leukaemia virus infection of domestic cats from selected areas in Harare, Zimbabwe. AB - A cross-sectional study was conducted to detect the feline leukaemia virus (FeLV) p27 antigen and to determine risk factors and the haematological changes associated with infection in domestic cats in Zimbabwe. Sera were collected for detection of the p27 antigen, urea, creatinine, alanine aminotransferase and gamma-glutamyl transferase levels, whilst whole blood was collected for haematology. FeLV p27 antigen was detected using a rapid enzyme-linked immunosorbent assay (ELISA) test kit. Data on risk factors were analysed using a logistic regression model. Of the 100 cats tested, 41% (95% CI: 31.19% - 50.81%) (41/100) were positive for the FeLV p27 antigen. Sex and health status of cats were not significantly (p > 0.05) associated with infection. Intact cats (OR = 9.73), those living in multicat housing (OR = 5.23) and cats that had access to outdoor life (OR = 35.5) were found to have higher odds of infection compared with neutered cats, those living in single-cat housing, and without access to outdoor life, respectively. Biochemistry and haematology revealed no specific changes. The results showed that FeLV infection was high in sampled cats, providing evidence of active infection. Thus, it would be prudent to introduce specific control measures for FeLV infection in Zimbabwe. PMID- 25686081 TI - Modulation of GluN3A expression in Huntington disease: a new n-methyl-D-aspartate receptor-based therapeutic approach? AB - Huntington disease (HD) is an inherited neurodegenerative disorder with no cure or effective palliative treatment. An ideal therapy would arrest pathogenesis at early stages before neuronal damage occurs. However, although the genetic mutation that causes HD is known, the molecular chain of events that leads from the mutation to disease is not well understood. Accumulating evidence suggests that synaptic dysregulation may be involved, and the earliest known deficit is hyperfunction of glutamate-type N-methyl-d-aspartate receptors (NMDARs) in the selectively vulnerable medium spiny neurons of the striatum. A previous study found that the mutant Htt protein interferes with downregulation of juvenile NMDAR subtypes that contain GluN3A subunits by sequestering the endocytic adaptor PACSIN1 and preventing their removal from the cell surface. Loss of PACSIN1 and consequent gain of GluN3A function reactivate a synapse pruning mechanism that is important during development but harmful when active at later stages. Suppressing the GluN3A reactivation corrected the NMDAR hyperfunction and prevented the full range of HD signs and symptoms in mouse models, encouraging efforts to develop GluN3A-selective antagonists and/or explore alternative therapeutic approaches to block GluN3A expression. PMID- 25686082 TI - Determination methods for the anticancer drug dicycloplatin, a supramolecule assembled through hydrogen bonding. AB - Dicycloplatin is a new generation supramolecular platinum-containing anti-cancer drug. Due to its structure, it is difficult to differentiate dicycloplatin from physical mixtures of carboplatin and cyclobutane dicarboxylate, and confounding results may arise during drug characterization. To solve this problem, this study aims to provide a reliable and reproducible standard for the determination of dicycloplatin. A simple method for dicycloplatin quality control has been developed using X-ray powder diffraction (XRPD) and high performance liquid chromatography (HPLC). XRPD allowed the control of impurities and dissociation of the dicycloplatin active ingredient to less than 1%, and HPLC allowed the monitoring and control of the relative molar ratio of carboplatin and cyclobutane dicarboxylate within the purity range. The study proved for the first time that the dicycloplatin supramolecule is substantially different from a physical mixture of carboplatin and cyclobutane dicarboxylate. PMID- 25686083 TI - The haematological profile of female bronze turkeys (Meleagris gallopavo) vaccinated with various commercial strains of Newcastle disease. AB - The effects of vaccination on avian blood parameters are poorly understood. The present study was designed to evaluate whether different strains (Ulster 2C, B1, live LaSota and inactivated LaSota) of Newcastle disease vaccines had an effect on the haematological profile of female turkeys. Seventy-five female turkeys were allocated to treatment groups according to vaccination strain. All the birds, except those in the control group, were vaccinated at 32 weeks of age and revaccinated at 40 and 48 weeks of age. Blood samples were obtained for haematological analyses and serum samples for the haemagglutination inhibition test. Haemoglobin concentration was significantly lower (p < 0.05) in vaccinated female turkeys than in the control birds 28 days after vaccination. Monocytes were significantly higher (p < 0.05) in 44-week-old female turkeys vaccinated with inactivated LaSota strain compared with the other groups. Turkeys vaccinated with the B1 strain showed significantly higher (p < 0.05) total white blood cell counts compared with the other groups vaccinated with various commercial strains of the Newcastle disease virus. In conclusion, female turkeys showed significant differences in haemoglobin concentrations, monocytes and white blood cell counts when vaccinated against Newcastle disease. PMID- 25686084 TI - Oesophagogastric intussusception associated with spirocercosis in a dog. AB - An oesophagogastric intussusception was diagnosed in an intact Bull Terrier female aged 2 years and 7 months with a concurrent Spirocerca lupi infection. The dog was presented collapsed with a history of inappetance and lethargy of one day's duration. Anaemia and melaena were present on clinical examination. Thoracic radiographs did not reveal any significant findings. Abdominal ultrasound was suspicious for gastric pathology or a possible foreign body. The final diagnosis of an oesophagogastric intussusception with an S. lupi nodule at the cardia was made on post-mortem. Oesophageal intussusceptions are rare in dogs and often fatal. Gastro-oesophageal intussusceptions usually present with obvious radiographic signs in the caudal thorax, unlike an oesophagogastric intussusception, where the pathologylies within the abdomen and may not be readily diagnosed. Although spirocercosis often presents with a caudal oesophageal mass, this may not be seen radiographically. In this case,the two conditions were present together but the thoracic radiographs were normal. PMID- 25686085 TI - Influence of cue word perceptual information on metamemory accuracy in judgement of learning. AB - Previous studies have suggested that perceptual information regarding to-be remembered words in the study phase affects the accuracy of judgement of learning (JOL). However, few have investigated whether the perceptual information in the JOL phase influences JOL accuracy. This study examined the influence of cue word perceptual information in the JOL phase on immediate and delayed JOL accuracy through changes in cue word font size. In Experiment 1, large-cue word pairs had significantly higher mean JOL magnitude than small-cue word pairs in immediate JOLs and higher relative accuracy than small-cue pairs in delayed JOLs, but font size had no influence on recall performance. Experiment 2 increased the JOL time, and mean JOL magnitude did not reliably differ for large-cue compared with small cue pairs in immediate JOLs. However, the influence on relative accuracy still existed in delayed JOLs. Experiment 3 increased the familiarity of small-cue words in the delayed JOL phase by adding a lexical decision task. The results indicated that cue word font size no longer affected relative accuracy in delayed JOLs. The three experiments in our study indicated that the perceptual information regarding cue words in the JOL phase affects immediate and delayed JOLs in different ways. PMID- 25686086 TI - Structural basis for bifunctional peptide recognition at human delta-opioid receptor. AB - Bifunctional MU- and delta-opioid receptor (OR) ligands are potential therapeutic alternatives, with diminished side effects, to alkaloid opiate analgesics. We solved the structure of human delta-OR bound to the bifunctional delta-OR antagonist and MU-OR agonist tetrapeptide H-Dmt-Tic-Phe-Phe-NH2 (DIPP-NH2) by serial femtosecond crystallography, revealing a cis-peptide bond between H-Dmt and Tic. The observed receptor-peptide interactions are critical for understanding of the pharmacological profiles of opioid peptides and for development of improved analgesics. PMID- 25686087 TI - A molecular chaperone breaks the catalytic cycle that generates toxic Abeta oligomers. AB - Alzheimer's disease is an increasingly prevalent neurodegenerative disorder whose pathogenesis has been associated with aggregation of the amyloid-beta peptide (Abeta42). Recent studies have revealed that once Abeta42 fibrils are generated, their surfaces effectively catalyze the formation of neurotoxic oligomers. Here we show that a molecular chaperone, a human Brichos domain, can specifically inhibit this catalytic cycle and limit human Abeta42 toxicity. We demonstrate in vitro that Brichos achieves this inhibition by binding to the surfaces of fibrils, thereby redirecting the aggregation reaction to a pathway that involves minimal formation of toxic oligomeric intermediates. We verify that this mechanism occurs in living mouse brain tissue by cytotoxicity and electrophysiology experiments. These results reveal that molecular chaperones can help maintain protein homeostasis by selectively suppressing critical microscopic steps within the complex reaction pathways responsible for the toxic effects of protein misfolding and aggregation. PMID- 25686088 TI - Structures of CYLD USP with Met1- or Lys63-linked diubiquitin reveal mechanisms for dual specificity. AB - The tumor suppressor CYLD belongs to a ubiquitin (Ub)-specific protease (USP) family and specifically cleaves Met1- and Lys63-linked polyubiquitin chains to suppress inflammatory signaling pathways. Here, we report crystal structures representing the catalytic states of zebrafish CYLD for Met1- and Lys63-linked Ub chains and two distinct precatalytic states for Met1-linked chains. In both catalytic states, the distal Ub is bound to CYLD in a similar manner, and the scissile bond is located close to the catalytic residue, whereas the proximal Ub is bound in a manner specific to Met1- or Lys63-linked chains. Further structure based mutagenesis experiments support the mechanism by which CYLD specifically cleaves both Met1- and Lys63-linked chains and provide insight into tumor associated mutations of CYLD. This study provides new structural insight into the mechanisms by which USP family deubiquitinating enzymes recognize and cleave Ub chains with specific linkage types. PMID- 25686089 TI - Crystal structure of a phosphorylation-coupled vitamin C transporter. AB - Bacteria use vitamin C (L-ascorbic acid) as a carbon source under anaerobic conditions. The phosphoenolpyruvate-dependent phosphotransferase system (PTS), comprising a transporter (UlaA), a IIB-like enzyme (UlaB) and a IIA-like enzyme (UlaC), is required for the anaerobic uptake of vitamin C and its phosphorylation to L-ascorbate 6-phosphate. Here, we present the crystal structures of vitamin C bound UlaA from Escherichia coli in two conformations at 1.65-A and 2.35-A resolution. UlaA forms a homodimer and exhibits a new fold. Each UlaA protomer consists of 11 transmembrane segments arranged into a 'V-motif' domain and a 'core' domain. The V motifs form the interface between the two protomers, and the core-domain residues coordinate vitamin C. The alternating access of the substrate from the opposite side of the cell membrane may be achieved through rigid-body rotation of the core relative to the V motif. PMID- 25686090 TI - Multidrug resistance transporters Snq2p and Pdr5p mediate caffeine efflux in Saccharomyces cerevisiae. AB - SNQ2 was identified as a caffeine-resistance gene by screening a genomic library of Saccharomyces cerevisiae in a multicopy vector YEp24. SNQ2 encodes an ATP binding cassette transporter and is highly homologous to PDR5. Multicopy of PDR5 also conferred resistance to caffeine, while its resistance was smaller than that of SNQ2. Residual caffeine contents were analyzed after transiently exposing cells to caffeine. The ratios of caffeine contents were 21.3 +/- 8.8% (YEp24 SNQ2) and 81.9 +/- 8.7% (YEp24-PDR5) relative to control (YEp24, 100%). In addition, multicopies of SNQ2 or PDR5 conferred resistance to rhodamine 6G (R6G), which was widely used as a substrate for transport assay. R6G was exported by both transporters, and their efflux activities were inhibited by caffeine with half-maximal inhibitory concentrations of 5.3 +/- 1.9 (YEp24-SNQ2) and 17.2 +/- 9.6 mM (YEp24-PDR5). These results demonstrate that Snq2p is a more functional transporter of caffeine than Pdr5p in yeast cells. PMID- 25686092 TI - Electrical spin injection and transport in semiconductor nanowires: challenges, progress and perspectives. AB - Spintronic devices are of fundamental interest for their nonvolatility and great potential for low-power electronics applications. The implementation of those devices usually favors materials with long spin lifetime and spin diffusion length. Recent spin transport studies on semiconductor nanowires have shown much longer spin lifetimes and spin diffusion lengths than those reported in bulk/thin films. In this paper, we have reviewed recent progress in the electrical spin injection and transport in semiconductor nanowires and drawn a comparison with that in bulk/thin films. In particular, the challenges and methods of making high quality ferromagnetic tunneling and Schottky contacts on semiconductor nanowires as well as thin films are discussed. Besides, commonly used methods for characterizing spin transport have been introduced, and their applicability in nanowire devices are discussed. Moreover, the effect of spin-orbit interaction strength and dimensionality on the spin relaxation and hence the spin lifetime are investigated. Finally, for further device applications, we have examined several proposals of spinFETs and provided a perspective of future studies on semiconductor spintronics. PMID- 25686091 TI - Animal models of chronic hepatitis delta virus infection host-virus immunologic interactions. AB - Hepatitis delta virus (HDV) is a defective RNA virus that has an absolute requirement for a virus belonging to the hepadnaviridae family like hepatitis B virus (HBV) for its replication and formation of new virions. HDV infection is usually associated with a worsening of HBV-induced liver pathogenesis, which leads to more frequent cirrhosis, increased risk of hepatocellular carcinoma (HCC), and fulminant hepatitis. Importantly, no selective therapies are available for HDV infection. The mainstay of treatment for HDV infection is pegylated interferon alpha; however, response rates to this therapy are poor. A better knowledge of HDV-host cell interaction will help with the identification of novel therapeutic targets, which are urgently needed. Animal models like hepadnavirus infected chimpanzees or the eastern woodchuck have been of great value for the characterization of HDV chronic infection. Recently, more practical animal models in which to perform a deeper study of host virus interactions and to evaluate new therapeutic strategies have been developed. Therefore, the main focus of this review is to discuss the current knowledge about HDV host interactions obtained from cell culture and animal models. PMID- 25686093 TI - The influence of environmental temperatures on farrowing rates and litter sizes in South African pig breeding units. AB - The reproductive performance of pigs is one of the main determinants of the profit farmers make from pig production. This study was undertaken to describe whether periods of high environmental temperature have an effect on the farrowing rate, litter sizes and number of stillbirths in commercial breeding units in South Africa. Data were collected weekly from four commercial breeding units with good records from December 2010 to August 2012. These data included the number of sows mated, number of sows farrowed and number of piglets born alive, as well as the number of stillbirths. Note was also taken of whether environmental temperature control mechanisms were employed. Temperature data from weather stations within 100 km of the breeding units were obtained from the South African Weather Service. In all breeding units a decrease in farrowing rate following mating during severe average temperatures (> 30 degrees C) when compared to the farrowing rate following mating during mild average temperatures (< 22 degrees C) was observed. When mating occurred at higher temperatures, the resultant litter size was marginally decreased in the breeding units that did not employ environmental temperature control, but was unaffected in the breeding units that did. In all four breeding units the trend was for the average number of piglets born alive to increase as the environmental temperature around the time of farrowing increased and the trend in three of the four breeding units was for the percentage of stillbirths per litter to decrease with increased temperature around the time of farrowing. The most significant observation in this study was the trend for farrowing rates to decrease following inseminations during times of high ambient temperatures (> 30 degrees C). Environmental temperature control did not negate this effect, but the breeding units employing the environmental temperature control did show higher average farrowing rates overall. PMID- 25686094 TI - Identity-level representations affect unfamiliar face matching performance in sequential but not simultaneous tasks. AB - According to cognitive and neurological models of the face-processing system, faces are represented at two levels of abstraction. First, image-based pictorial representations code a particular instance of a face and include information that is unrelated to identity-such as lighting, pose, and expression. Second, at a more abstract level, identity-specific representations combine information from various encounters with a single face. Here we tested whether identity-level representations mediate unfamiliar face matching performance. Across three experiments we manipulated identity attributions to pairs of target images and measured the effect on subsequent identification decisions. Participants were instructed that target images were either two photos of the same person (1ID condition) or photos of two different people (2ID condition). This manipulation consistently affected performance in sequential matching: 1ID instructions improved accuracy on "match" trials and caused participants to adopt a more liberal response bias than the 2ID condition. However, this manipulation did not affect performance in simultaneous matching. We conclude that identity-level representations, generated in working memory, influence the amount of variation tolerated between images, when making identity judgements in sequential face matching. PMID- 25686095 TI - Application of GFP imaging in cancer. AB - Multicolored proteins have allowed the color-coding of cancer cells growing in vivo and enabled the distinction of host from tumor with single-cell resolution. Non-invasive imaging with fluorescent proteins enabled the dynamics of metastatic cancer to be followed in real time in individual animals. Non-invasive imaging of cancer cells expressing fluorescent proteins has allowed the real-time determination of efficacy of candidate antitumor and antimetastatic agents in mouse models. The use of fluorescent proteins to differentially label cancer cells in the nucleus and cytoplasm can visualize the nuclear-cytoplasmic dynamics of cancer cells in vivo including: mitosis, apoptosis, cell-cycle position, and differential behavior of nucleus and cytoplasm that occurs during cancer-cell deformation and extravasation. Recent applications of the technology described here include linking fluorescent proteins with cell-cycle-specific proteins such that the cells change color from red to green as they transit from G1 to S phases. With the macro- and micro-imaging technologies described here, essentially any in vivo process can be imaged, giving rise to the new field of in vivo cell biology using fluorescent proteins. PMID- 25686096 TI - Involvement of hepatic stellate cell cytoglobin in acute hepatocyte damage through the regulation of CYP2E1-mediated xenobiotic metabolism. AB - Oxygen (O2) is required for cytochrome P450 (CYP)-dependent drug metabolism. Cytoglobin (CYGB) is a unique globin expressed exclusively in hepatic stellate cells (HSCs). However, its role in O2-dependent metabolism in neighboring hepatocytes remains unknown. This study provides evidence that CYGB in HSCs is involved in acetaminophen (N-acetyl-p-aminophenol; APAP)-induced hepatotoxicity. Serum alanine aminotransferase levels were higher in wild-type mice than in Cygb null mice. Wild-type mice exhibited more severe hepatocyte necrosis around the central vein area compared with Cygb-null mice, thus indicating that CYGB deficiency protects against APAP-induced liver damage. Although no difference in the hepatic expression of CYP2E1, a key enzyme involved in APAP toxicity, was observed between wild-type and Cygb-null mice, the serum levels of the APAP metabolites cysteinyl-APAP and N-acetyl-cysteinyl-APAP were decreased in Cygb null mice, suggesting reduced APAP metabolism in the livers of Cygb-null mice. In primary cultures, APAP-induced hepatocyte damage was increased by co-culturing with wild-type HSCs but not with Cygb-null HSCs. In addition, cell damage was markedly alleviated under low O2 condition (5% O2), suggesting the requirement of O2 for APAP toxicity. Carbon tetrachloride-induced liver injury (CYP2E1 dependent), but not lipopolysaccharide/D-galactosamine-induced injury (CYP2E1 independent), was similarly alleviated in Cygb-null mice. Considering the function of CYGB as O2 carrier, these results strongly support the hypothesis that HSCs are involved in the CYP2E1-mediated xenobiotic activation by augmenting O2 supply to hepatocytes. In conclusion, CYGB in HSCs contributes to the CYP mediated metabolism of xenobiotics in hepatocytes by supplying O2 for enzymatic oxidation. PMID- 25686098 TI - Corrigendum. AB - Van Driessche, K., Ducatelle, R., Chiers, K., Van Coster, R. and van der Kolk, J. H. (2015) Ultrastructural Mitochondrial Alterations in Equine Myopathies of Unknown Origin, Veterinary Quarterly, 35(01), pp. 3-9. http://dx.doi.org/10.1080/ 01652176.2015.983681 When the above article was first published online, J. H. van der Kolk's name was laid out in error as H. van der Kolk. This has now been corrected in both the print and online versions to J. H. van der Kolk. The authors apologise for this error. PMID- 25686097 TI - Antibiotic resistance from prehistoric to modern times. PMID- 25686099 TI - Initiation of a medical toxicology consult service at a tertiary care children's hospital. AB - Currently, only 10% of board-certified medical toxicologists are pediatricians. Yet over half of poison center calls involve children < 6 years, poisoning continues to be a common pediatric diagnosis and bedside toxicology consultation is not common at children's hospitals. In collaboration with executive staff from Department of Pediatrics and Emergency Medicine, regional poison center, and our toxicology fellowship, we established a toxicology consulting service at our tertiary-care children's hospital. There were 139 consultations, and the service generated 13 consultations in the first month; median of 11 consultations per month thereafter (range 8-16). The service increased pediatric cases seen by the fellowship program from 30 to 94. The transition to a consult service required a culture change. Historically, call center advice was the mainstay of consulting practice and the medical staff was not accustomed to the availability of bedside medical toxicology consultations. However, after promotion of the service and full attending and fellowship coverage, consultations increased. In collaboration with toxicologists from different departments, a consultation service can be rapidly established. The service filled a clinical need that was disproportionately utilized for high acuity patients, immediately utilized by the medical staff and provided a robust pediatric population for the toxicology fellowship. PMID- 25686100 TI - Pre-deployment preparation of military nurses of the South African National Defence Force for participation in peace support operations. AB - BACKGROUND: South Africa has dedicated itself to participate in peace support operations (PSOs). The concept of 'jointness', involving different arms of services, was adopted within the South African National Defence Force, thus involving nurses in PSOs. PROBLEM STATEMENT: Combat-readiness being a prerequisite for those involved in PSOs raised questions as to the readiness of forces to participate in these missions. There is a need for specific nursing care during PSOs, but the role and functions of nurses during such operations were not clearly defined; thus their preparation for these missions had very little scientific grounding. OBJECTIVES: These were to explore the pre-deployment preparation needs of military professional nurses during PSOs, and to describe the experience of these nurses whilst being deployed. METHOD: A quantitative exploratory, descriptive and contextual approach was used. Questionnaires were distributed to 99 professional nurses who had deployment experience, and 72 participated (73% response rate). Relevant peace mission concepts are the environment, jointness, behaviour and mission readiness, which served as the conceptual bases for the study. RESULTS: Findings indicated that the nurses were not fully informed of their responsibilities during deployment or the circumstances under which they would have to work and live. Their preparation is not fully integrated with that of the other armed forces, and deficiencies in their training and development were identified which negatively impact on their mission readiness. CONCLUSION: Recommendations were made in terms of human resource requirements, psychological training, better integration of jointness training, and content of training and development to ensure mission readiness of nurses. PMID- 25686101 TI - Evaluation of cross-protection of bluetongue virus serotype 4 with other serotypes in sheep. AB - Bluetongue (BT) is a non-contagious disease of sheep and other domestic and wild ruminants caused by the bluetongue virus (BTV). Currently 26 serotypes of the virus have been identified. In South Africa, 22 serotypes have been identified and BT is controlled mainly by annual vaccinations using a freeze-dried live attenuated polyvalent BTV vaccine. The vaccine is constituted of 15 BTV serotypes divided into three separate bottles and the aim is to develop a vaccine using fewer serotypes without compromising the immunity against the disease. This study is based on previously reported cross-neutralisation of specific BTV serotypes in in vitro studies. Bluetongue virus serotype 4 was selected for this trial and was tested for cross-protection against serotype 4 (control), 1 (unrelated serotype), 9, 10 and 11 in sheep using the serum neutralisation test. The purpose of the study was to determine possible cross-protection of different serotypes in sheep. Of those vaccinated with BTV-4 and challenged with BTV-1, which is not directly related to BTV-4, 20% were completely protected and 80% showed clinical signs, but the reaction was not as severe as amongst the unvaccinated animals. In the group challenged with BTV-10, some showed good protection and some became very sick. Those challenged with BTV-9 and BTV-11 had good protection. The results showed that BTV-4 does not only elicit a specific immune response but can also protect against other serotypes. PMID- 25686102 TI - Coenurus cerebralis cyst in the orbit of a ewe. AB - A 4-year-old Rahmani breed ewe was presented for surgery to the Veterinary Teaching Hospital, South Valley University, Egypt with enlargement and protrusion of the eye ball, blepharitis and congestion of the conjunctiva. On examination, a cyst 2.5 cm x 3.5 cm in diameter containing sandy fluid was detected in the perioptic nerve fat. Histopathological examination revealed that the epithelial lining of the conjunctiva was necrotic and severely infiltrated by neutrophils. The underlying connective tissue was oedematous, hyperaemic and severely infiltrated by neutrophils. Desquamation of the corneal epithelium was seen, together with oedema of the stroma. The tissue surrounding the cyst was compressed and the lacrimal glands revealed pressure atrophy. The muscular tissue was atrophied and infiltrated by fat cells. The cyst wall was lined with white scolices protruding from the inner wall. Based on the gross and histopathological characteristics of the cyst observed, the cyst was diagnosed as Coenurus cerebralis. This is the first report of orbital coenurosis in a sheep. PMID- 25686103 TI - Self-organized sheaf-like Fe3O4/C hierarchical microrods with superior lithium storage properties. AB - Functional nanomaterials with three-dimensional hierarchical structures are of high interest for many practical applications including lithium-ion batteries (LIBs). In this work, self-organized sheaf-like Fe3O4/C microrods constructed by porous nanowires have been synthesized by a facile solvothermal method combined with a subsequent annealing treatment. The morphology of the building blocks could be easily tuned by varying the synthesis parameters. When applied as an anode material for LIBs, these sheaf-like Fe3O4/C porous microrods manifest superior electrochemical lithium storage properties in terms of high reversible capacity, stable cycling capacity retention and good rate capability. PMID- 25686104 TI - Synthetic lethality by targeting EZH2 methyltransferase activity in ARID1A mutated cancers. AB - The gene encoding ARID1A, a chromatin remodeler, shows one of the highest mutation rates across many cancer types. Notably, ARID1A is mutated in over 50% of ovarian clear cell carcinomas, which currently have no effective therapy. To date, clinically applicable targeted cancer therapy based on ARID1A mutational status has not been described. Here we show that inhibition of the EZH2 methyltransferase acts in a synthetic lethal manner in ARID1A-mutated ovarian cancer cells and that ARID1A mutational status correlated with response to the EZH2 inhibitor. We identified PIK3IP1 as a direct target of ARID1A and EZH2 that is upregulated by EZH2 inhibition and contributed to the observed synthetic lethality by inhibiting PI3K-AKT signaling. Importantly, EZH2 inhibition caused regression of ARID1A-mutated ovarian tumors in vivo. To our knowledge, this is the first data set to demonstrate a synthetic lethality between ARID1A mutation and EZH2 inhibition. Our data indicate that pharmacological inhibition of EZH2 represents a novel treatment strategy for cancers involving ARID1A mutations. PMID- 25686105 TI - A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. AB - The NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome is a component of the inflammatory process, and its aberrant activation is pathogenic in inherited disorders such as cryopyrin-associated periodic syndrome (CAPS) and complex diseases such as multiple sclerosis, type 2 diabetes, Alzheimer's disease and atherosclerosis. We describe the development of MCC950, a potent, selective, small-molecule inhibitor of NLRP3. MCC950 blocked canonical and noncanonical NLRP3 activation at nanomolar concentrations. MCC950 specifically inhibited activation of NLRP3 but not the AIM2, NLRC4 or NLRP1 inflammasomes. MCC950 reduced interleukin-1beta (IL-1beta) production in vivo and attenuated the severity of experimental autoimmune encephalomyelitis (EAE), a disease model of multiple sclerosis. Furthermore, MCC950 treatment rescued neonatal lethality in a mouse model of CAPS and was active in ex vivo samples from individuals with Muckle-Wells syndrome. MCC950 is thus a potential therapeutic for NLRP3-associated syndromes, including autoinflammatory and autoimmune diseases, and a tool for further study of the NLRP3 inflammasome in human health and disease. PMID- 25686107 TI - Body composition assessment of English Premier League soccer players: a comparative DXA analysis of first team, U21 and U18 squads. AB - Professional soccer players from the first team (1st team, n = 27), under twenty one (U21, n = 21) and under eighteen (U18, n = 35) squads of an English Premier League soccer team were assessed for whole body and regional estimates of body composition using dual-energy X-ray absorptiometry (DXA). Per cent body fat was lower in 1st team (10.0 +/- 1.6) compared with both U21 (11.6 +/- 2.5, P = 0.02) and U18 (11.4 +/- 2.6, P = 0.01) players. However, this difference was not due to variations (P = 0.23) in fat mass between squads (7.8 +/- 1.6 v. 8.8 +/- 2.1 v. 8.2 +/- 2.4 kg, respectively) but rather the presence of more lean mass in 1st team (66.9 +/- 7.1 kg, P < 0.01) and U21 (64.6 +/- 6.5 kg, P = 0.02) compared with U18 (60.6 +/- 6.3 kg) players. Accordingly, fat mass index was not different (P = 0.138) between squads, whereas lean mass index was greater (P < 0.01) in 1st team players (20.0 +/- 1.1 kg . m(-2)) compared with U18 players (18.8 +/- 1.4 kg . m(-2)). Differences in lean mass were also reflective of higher lean tissue mass in all regions, for example, upper limbs/lower limbs and trunk. Data suggest that training and nutritional interventions for younger players should therefore be targeted to lean mass growth as opposed to body fat loss. PMID- 25686106 TI - The ketone metabolite beta-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. AB - The ketone bodies beta-hydroxybutyrate (BHB) and acetoacetate (AcAc) support mammalian survival during states of energy deficit by serving as alternative sources of ATP. BHB levels are elevated by starvation, caloric restriction, high intensity exercise, or the low-carbohydrate ketogenic diet. Prolonged fasting reduces inflammation; however, the impact that ketones and other alternative metabolic fuels produced during energy deficits have on the innate immune response is unknown. We report that BHB, but neither AcAc nor the structurally related short-chain fatty acids butyrate and acetate, suppresses activation of the NLRP3 inflammasome in response to urate crystals, ATP and lipotoxic fatty acids. BHB did not inhibit caspase-1 activation in response to pathogens that activate the NLR family, CARD domain containing 4 (NLRC4) or absent in melanoma 2 (AIM2) inflammasome and did not affect non-canonical caspase-11, inflammasome activation. Mechanistically, BHB inhibits the NLRP3 inflammasome by preventing K(+) efflux and reducing ASC oligomerization and speck formation. The inhibitory effects of BHB on NLRP3 are not dependent on chirality or starvation-regulated mechanisms like AMP-activated protein kinase (AMPK), reactive oxygen species (ROS), autophagy or glycolytic inhibition. BHB blocks the NLRP3 inflammasome without undergoing oxidation in the TCA cycle, and independently of uncoupling protein-2 (UCP2), sirtuin-2 (SIRT2), the G protein-coupled receptor GPR109A or hydrocaboxylic acid receptor 2 (HCAR2). BHB reduces NLRP3 inflammasome-mediated interleukin (IL)-1beta and IL-18 production in human monocytes. In vivo, BHB or a ketogenic diet attenuates caspase-1 activation and IL-1beta secretion in mouse models of NLRP3-mediated diseases such as Muckle-Wells syndrome, familial cold autoinflammatory syndrome and urate crystal-induced peritonitis. Our findings suggest that the anti-inflammatory effects of caloric restriction or ketogenic diets may be linked to BHB-mediated inhibition of the NLRP3 inflammasome. PMID- 25686108 TI - Impact of caring for people living with HIV on the psychosocial well-being of palliative caregivers. AB - Acquired immunodeficiency syndrome (AIDS) continues to be a serious public health issue, and it is often the caregivers who carry the brunt of the epidemic. Caregivers of people with AIDS face distinctive demands that could make them more prone to occupational stress, with serious consequences for their psychosocial well-being. The impact of caring for people living with HIV infection on the psychosocial well-being of palliative caregivers was investigated using in-depth interviews and questionnaires in 28 participants. The results indicated no burnout, but occupational stress was prevalent. Factors impacting negatively on well-being were stressors inherent in AIDS care, such as suffering and dying of the persons being cared for, work-related stressors such as heavy workload, lack of support and ineffective coping mechanisms. Positive aspects of caring such as job satisfaction, holistic palliative care, effective coping mechanisms and psychosocial support were identified. Recommendations to curb the negative effects of caregiving are provided. PMID- 25686109 TI - Circulating tumor DNA: new horizons for improving cancer treatment. PMID- 25686110 TI - Chemotherapy is getting 'smarter'. PMID- 25686111 TI - Systems oncology: toward the clinical application of cancer systems biology. PMID- 25686112 TI - Targeting triple-negative breast cancer and high-grade ovarian carcinoma: refining BRCAness beyond BRCA1/2 mutations? PMID- 25686113 TI - Intratumor heterogeneity: origins, clinical significance and optimal strategies for cancer treatment. PMID- 25686114 TI - Vemurafenib for the treatment of BRAF mutant metastatic melanoma. AB - Vemurafenib was the first selective BRAF inhibitor licensed in cancer. It is indicated for the treatment of patients affected by advanced melanoma with BRAF V600 mutation. It has shown successful results in terms of efficacy together with a favorable toxicity profile. Other compounds such as the BRAF inhibitor dabrafenib and the immunotherapeutic agent ipilimumab are also approved in the same group of patients. This article reviews the chemistry, pharmacokinetics, pharmacodynamics and clinical development of vemurafenib. Moreover, its efficacy and toxicity are compared with dabrafenib and ipilimumab. A number of trials with vemurafenib alone or in combination with other drugs are also analyzed. These trials will determine the role of vemurafenib in the treatment of BRAF mutant melanoma in forthcoming years. PMID- 25686115 TI - Histogram analysis of iodine maps from dual energy computed tomography for monitoring targeted therapy of melanoma patients. AB - AIM: Iodine quantification with dual energy computed tomography (DECT) enables quantitative assessment of contrast medium uptake. Our purpose was to investigate patterns of enhancement under BRAF inhibitor therapy by performing histogram analyses (HAs) of iodine maps. MATERIALS & METHODS: A total of 11 stage IV melanoma patients (32 metastases) underwent DECT at baseline and at least one follow up. Iodine uptake and HAs including maximum HU value (MAX), mean HU value (MEAN) and standard deviation (STD) was calculated. RESULTS: For BRAF-responders MEAN, MAX and STD decreased significantly (p < 0.05). Nonresponder showed increasing MAX and STD for six out of seven lesions, while MEAN and Iodine uptake decreased (four) and increased (three). CONCLUSION: HA based on DECT enables a quantitative and functional criterion and contributes to accurate response assessment for promising targeted therapies. PMID- 25686116 TI - Obesity, lymphadenectomy and survival outcomes in intermediate to high-risk, early-stage endometrial cancer patients. AB - AIM: Lymphadenectomy or lymph node dissection is a topic of controversy in endometrial cancer (EC) treatment. MATERIALS & METHODS: Associations between lymph node dissections and clinical factors were retrospectively examined in obese, endometrioid endometrial cancer patients with early-stage disease between 1995 and 2005. Overall, EC-specific and recurrence-free survival were also evaluated. RESULTS: Out of 192 patients, 61 (32%) did not have a lymph node examination, 55 (29%) had less than ten lymph nodes removed and 76 (39%) had >=10 removed. Lymph node dissection count was not significantly associated with overall, EC-specific or recurrence-free survival. CONCLUSION: Analysis revealed no significant associations between >=10 dissected lymph nodes and survival outcomes among obese, EC patients, which supports the need for additional investigation of the merit of lymphadenectomy among these patients. PMID- 25686117 TI - Randomized controlled trial on the skin toxicity of panitumumab in Japanese patients with metastatic colorectal cancer: HGCSG1001 study; J-STEPP. AB - AIM: We planned a randomized, open-label trial to evaluate differences between pre-emptive and reactive skin treatment for panitumumab (Pmab)-associated skin toxicities in Japanese patients with metastatic colorectal cancer. PATIENTS & METHODS: Patients receiving third-line Pmab-containing regimens were randomized to pre-emptive or reactive treatment. The primary end point was the cumulative incidence of >=grade 2 skin toxicities during 6 weeks. Retrospectively, a dermatologist reviewed skin toxicities, in a blinded manner. RESULTS: A total of 95 patients were enrolled (pre-emptive: 47, reactive: 48). The primary end point was achieved (21.3 and 62.5% [risk ratio: 0.34; p < 0.001], for pre-emptive and reactive treatment, respectively). A similar trend was observed in central review. CONCLUSION: Pre-emptive skin treatment could reduce the severity of Pmab associated skin toxicities in Japanese metastatic colorectal cancer patients. PMID- 25686118 TI - Prognostic role of KRAS, NRAS, BRAF and PIK3CA mutations in advanced colorectal cancer. AB - AIM: To explore the prognostic value of extended mutational profiling for metastatic colorectal cancer (mCRC). MATERIALS & METHODS: We retrospectively reviewed survival results of 194 mCRC patients that were assigned to four molecular subgroups: BRAF mutated; KRAS mutated codons 12-13 only; any of KRAS codons 61-146, PIK3CA or NRAS mutations and all wild-type. Point mutations were investigated by pyrosequencing. RESULTS: BRAF (5.2%) and KRAS 12-13 (31.9%) mutations were associated with poorer survival (HR 2.8 and 1.76, respectively). Presenting with right-sided colon cancer, not resected primary tumor, WBC >10 * 10(9)/l, receiving less chemotherapy or no bevacizumab were all associated with inferior outcome. The all-wild-type subgroup (39.2%) reported the longest survival. CONCLUSION: Extended mutational profile combined with clinical factors may impact on survival in mCRC. PMID- 25686119 TI - Shifting paradigms in the treatment of chronic lymphocytic leukemia. AB - The treatment of chronic lymphocytic leukemia (CLL) is evolving rapidly. Insight into the genetics and biology of the disease, including the importance of intracellular signaling pathways and interactions with the microenvironment has led to the development of rational targeted therapies which are having a major impact on the survival of patients with relapsed and high-risk disease. In addition, an exciting array of cellular therapies and immunotherapy options are in various stages of development. We review the current understanding of CLL genetics and biology, current treatment strategies in specific patient groups and opportunities for future treatment combinations which will bring the goal of cure or long-term disease control with minimal toxicity within reach for the majority of patients. PMID- 25686120 TI - Mutations in tyrosine kinase and tyrosine phosphatase and their relevance to the target therapy in hematologic malignancies. AB - Protein tyrosine kinases and protein tyrosine phosphatases play pivotal roles in regulation of cellular phosphorylation and signal transduction with opposite functions. Accumulating evidences have uncovered the relevance of genetic alterations in these two family members to hematologic malignancies. This review underlines progress in understanding the pathogenesis of these genetic alterations including mutations and aberrant expression and the evolving protein tyrosine kinases and protein tyrosine phosphatases targeted therapeutic strategies in hematologic neoplasms. PMID- 25686121 TI - The role of oncolytic virus immunotherapies to subvert cancer immune evasion. AB - ABSTRACT Despite huge economic and intellectual investments, developing effective cancer treatments continues to be an overarching challenge. Engineered oncolytic viruses (OVs) present self-amplifying immunotherapy platforms capable of preferential cytotoxicity to cancer cells and simultaneous activation of host anti-tumor immunity. In preclinical studies, OVs are showing potent therapeutic effects when used in combination with other immune therapy strategies. In the clinic, the immunotherapeutic effects of OVs are showing promising results. Here we review current strategies for engineering OVs, and present a perspective of future directions within a discussion of the current outcomes of combinatorial approaches with other cancer immunotherapy platforms. PMID- 25686122 TI - Gastrointestinal metastases from prostate cancer: a review of the literature. AB - The availability of active new drugs for the treatment of advanced castration resistant prostate cancer has significantly prolonged overall survival, thus changing the natural history of the disease and raising the likelihood of observing metastases in atypical sites. This review of the literature describes the frequency, clinical-pathological features and presenting symptoms of non liver gastrointestinal metastases (GIm) from prostate cancer. Its purpose is to increase clinical awareness of the increasing incidence of such GIm, contributing to the early detection, accurate diagnosis and, when feasible, appropriate management. PMID- 25686123 TI - Identifying locally advanced basal cell carcinoma eligible for treatment with vismodegib: an expert panel consensus. AB - Basal cell carcinoma (BCC) is the most common skin cancer worldwide. Most occur on the head and neck, where cosmetic and functional outcomes are critical. BCC can be locally destructive if not diagnosed early and treated appropriately. Surgery is the treatment of choice for the majority of high-risk lesions. Aggressive, recurrent or unresectable tumors can be difficult to manage. Until recently, no approved systemic therapy was available for locally advanced or metastatic BCC inappropriate for surgery or radiotherapy. Vismodegib provides a systemic treatment option. However, a consensus definition of advanced BCC is lacking. A multidisciplinary panel with expertise in oncology, dermatology, dermatologic surgery and radiation oncology proposes a consensus definition based on published evidence and clinical experience. PMID- 25686124 TI - A rare case of anal porocarcinoma treated by electrochemotherapy. PMID- 25686125 TI - Culicoides species abundance and potential over-wintering of African horse sickness virus in the Onderstepoort area, Gauteng, South Africa. AB - In South Africa, outbreaks of African horse sickness (AHS) occur in summer; no cases are reported in winter, from July to September. The AHS virus (AHSV) is transmitted almost exclusively by Culicoides midges (Diptera: Ceratopogonidae), of which Culicoides imicola is considered to be the most important vector. The over-wintering mechanism of AHSV is unknown. In this study, more than 500 000 Culicoides midges belonging to at least 26 species were collected in 88 light traps at weekly intervals between July 2010 and September 2011 near horses in the Onderstepoort area of South Africa. The dominant species was C. imicola. Despite relatively low temperatures and frost, at least 17 species, including C. imicola, were collected throughout winter (June-August). Although the mean number of midges per night fell from > 50 000 (March) to < 100 (July and August), no midge free periods were found. This study, using virus isolation on cell cultures and a reverse transcriptase polymerase chain reaction (RT-PCR) assay, confirmed low infection prevalence in field midges and that the detection of virus correlated to high numbers. Although no virus was detected during this winter period, continuous adult activity indicated that transmission can potentially occur. The absence of AHSV in the midges during winter can be ascribed to the relatively low numbers collected coupled to low infection prevalence, low virus replication rates and low virus titres in the potentially infected midges. Cases of AHS in susceptible animals are likely to start as soon as Culicoides populations reach a critical level. PMID- 25686126 TI - Jean-Antoine Villemin: ending an Alpine divide. PMID- 25686127 TI - Extra-pulmonary tuberculosis and Xpert(r) MTB/RIF: all about meta-analyses? PMID- 25686128 TI - To improve our tuberculosis burden estimates we need to learn from each other. PMID- 25686129 TI - On the virulence and specificity of tuberculosis. PMID- 25686130 TI - Jean-Antoine Villemin and the infectious nature of tuberculosis. PMID- 25686131 TI - Tuberculosis contact investigation in low- and middle-income countries: standardized definitions and indicators. AB - There is a need for better utilization of program data for global tuberculosis (TB) control. Significant information could be gained from data collected by TB programs that could supplement traditional sources of evidence and contribute to policy development. For this operational information to be useful, it must be collected in a uniform manner, using standardized definitions and approaches to evaluation. As an example of an approach to uniformity in generating useful program data, we present recommendations for the standardization of definitions and indicators for the investigation of contacts of persons with infectious TB in low- and middle-income countries. PMID- 25686132 TI - The complexities of Xpert(r) MTB/RIF interpretation. AB - The Xpert((r)) MTB/RIF assay has demonstrated robust capability for diagnosing tuberculosis (TB) and rifampin (RMP) resistance. Optimal use of Xpert in diverse settings will require knowledge of challenges when interpreting the results. We present three selected cases from the United States, a low-burden TB setting, to highlight important clinical scenarios encountered with Xpert testing: rapid RMP resistance detection in a patient with pre-extensively drug-resistant TB who immigrated from the Philippines, false-positive RMP resistance detection, and Mycobacterium tuberculosis detection in a culture-negative patient. These cases demonstrate that a low pre-test probability of TB or drug-resistant TB can complicate the interpretation of the Xpert assay. PMID- 25686133 TI - Appropriate use of the Xpert(r) MTB/RIF assay in suspected tuberculous meningitis. AB - We disagree with the recommendation by the World Health Organization to use Xpert((r)) MTB/RIF on cerebrospinal fluid for the initial diagnosis of tuberculous meningitis (TBM). TBM is a devastating disease requiring empirical treatment even when the probability of disease is low. We suggest that a useful TBM diagnostic test needs a negative predictive value (NPV) of ? 99% so that empirical treatment can be stopped safely. The NPV of Xpert is around 84%, making a negative test of limited value. While better tests are awaited, a composite score, possibly combining Xpert with clinical variables and with high NPV, should be constructed and validated prospectively. PMID- 25686134 TI - Diagnostic accuracy of the Xpert(r) MTB/RIF assay for extra-pulmonary tuberculosis: a meta-analysis. AB - BACKGROUND: Xpert((r)) MTB/RIF is a commercially available nucleic acid amplification test developed for the diagnosis of pulmonary tuberculosis (PTB). OBJECTIVE: To determine the diagnostic accuracy of Xpert for the detection of extra-pulmonary tuberculosis (EPTB). METHODS: We searched MEDLINE, EMBASE and Global Health databases from January 2010 to 15 August 2014 for studies of diagnostic performance in which Xpert was examined against culture for patients with clinically suspected EPTB. Bivariate random effects models were used to provide pooled estimates of diagnostic accuracy. RESULTS: Thirty-six studies were identified, with a pooled sensitivity and specificity of respectively 77% (95%CI 66-85) and 97% (95%CI 94-98). Substantial variations existed between study estimates of sensitivity (I(2) = 99%) and specificity (I(2) = 96%). Among site specific estimates for lymph, pleural fluid, cerebrospinal fluid, gastro intestinal and urinary samples, the pooled sensitivity was lower in pleural fluid (37%, 95%CI 26-50, meta-regression P < 0.001) and higher in lymph node samples (87%, 95%CI 75-95, meta-regression P = 0.03). CONCLUSION: Xpert has high specificity but limited sensitivity for the detection of EPTB. Although positive Xpert test results may be useful in rapidly identifying EPTB cases, negative test results provide less certainty for ruling out disease. PMID- 25686135 TI - The impact of Xpert(r) MTB/RIF depends on service coordination: experience in Burkina Faso. AB - Translating the potential of Xpert((r)) MTB/RIF into more effective tuberculosis (TB) care and control in low-income settings is challenged by operational issues. We report the experience in introducing this technology in Burkina Faso through a centralised approach. Xpert was successfully integrated into the diagnostic algorithm of multidrug-resistant TB cases. However, barriers to Xpert use for the diagnosis of TB in vulnerable populations, such as persons living with human immunodeficiency virus infection and children, were observed, mainly due to lack of coordination between services. Lessons learnt can be exploited to optimise the roll-out of this technology at country level. PMID- 25686136 TI - An approach to estimating tuberculosis incidence and case detection rate from routine notification data. AB - OBJECTIVE: To estimate tuberculosis (TB) incidence and case detection rate (CDR) using routine TB surveillance data only. METHODS: A mathematical model of the case detection process, representing competition between disease progression and case finding, is proposed. The model describes disease progression as a two-stage process (bacillary and non-bacillary TB), and so relates the proportion of bacillary TB cases on detection to the effectiveness of detection. Thus, given the annual numbers of newly detected TB cases stratified by bacillary status, the model estimates detection rates, incidence and CDR. Routine notification data from eight provinces in Russia, 2000-2011, were used for the study. RESULTS: Subnational level estimates of incidence and CDR were obtained. Incidence estimates varied by two-fold among the provinces; corrected CDR estimates varied by 1.5 times. The trend in the incidence estimates was similar to that in the World Health Organization estimates for the whole of Russia. The change in the trend in WHO CDR estimates in 2008-2009 was not supported by our estimates. CONCLUSION: The general approach that uses multistage models of disease progression and accordingly stratified notification data can be applied in various settings for the routine estimation of incidence and CDR. PMID- 25686137 TI - Six- vs. eight-month anti-tuberculosis regimen for pulmonary tuberculosis under programme conditions. AB - SETTING: One urban tertiary care and one rural secondary care hospital in Nigeria. OBJECTIVE: To compare the epidemiological characteristics and treatment outcomes of tuberculosis (TB) patients treated with an 8-month or 6-month anti tuberculosis regimen in a low-resource setting. DESIGN: Retrospective cohort study. RESULTS: A total of 928 newly diagnosed smear-positive TB patients were treated with either daily ethambutol (EMB), isoniazid (INH), rifampicin (RMP) and pyrazinamide (PZA) for 2 months followed by EMB and INH for 6 months (2RHZE/6EH), or the same intensive phase as the first regimen followed by 4 months of daily RMP and INH (2RHZE/4RH). The proportion of successful outcomes was 381/490 (77.8%) with 2RHZE/6EH and 373/438 (85.2%) with 2RHZE/4RH (P = 0.004). Defaulting was significantly more frequent in patients who received 2RHZE/6EH (14.3% vs. 5.5%; P < 0.001). Treatment failure was not significantly higher in patients who received 2RHZE/6EH (2.9% vs. 1.6%; P = 0.15). After adjusting for confounders, older age (adjusted odds ratio [aOR] 1.7), 2RHZE/6EH treatment (aOR 1.6) and male sex (aOR 1.5) independently predicted unsuccessful outcomes in human immunodeficiency virus negative TB patients. CONCLUSIONS: Newly diagnosed TB patients on 2RHZE/4RH have a higher treatment success rate than those treated with 2RHZE/6EH under programme conditions in a low-resource, high-burden setting. Current World Health Organization recommendations should be maintained. PMID- 25686138 TI - Vitamin D deficiency and risk of postpartum tuberculosis among HIV-infected breastfeeding mothers in India. AB - Some studies have associated low vitamin D levels with the risk of tuberculosis (TB), but its association in human immunodeficiency virus (HIV) infected mothers in a TB-endemic region has not been well studied. We conducted a nested 1:2 case control study among HIV-infected mothers in western India to evaluate the association between maternal vitamin D levels and the risk of postpartum TB. Vitamin D insufficiency, moderate deficiency and severe deficiency were observed in a high proportion of HIV-infected mothers, but were not associated with the risk of postpartum TB. PMID- 25686139 TI - Risk of cataract for people with tuberculosis: results from a population-based cohort study. AB - BACKGROUND: Tuberculosis (TB) is an infectious disease involving multiple organs, including the eyes. We examined the risk of cataract among patients with TB using population data. METHOD: Using data from the National Health Insurance (NHI) system of Taiwan, we established a TB cohort with 6994 patients newly diagnosed between 2000 and 2010. For each TB patient, four subjects without TB were randomly selected for the non-TB cohort, frequency matched by age, sex and diagnosis years. The incidence of cataract was measured by the end of 2011. The hazard ratio (HR) of cataract was estimated using Cox proportional hazards regression analysis. RESULTS: The overall incidence rate of cataract was 21% greater in the TB cohort than in the non-TB cohort (22.9 vs. 18.8/1000 person years, P < 0.001), with an adjusted HR (aHR) of 1.26 (95%CI 1.16-1.37). Cataract incidence increased with age, and was higher in men than women and much higher for those with comorbidity. The hazard of cataract was higher in the first 6 months after TB diagnosis. CONCLUSION: TB patients are at elevated risk of developing cataract. Although the incidence decreased with time, the aHR remains statistically significant through the follow-up years. PMID- 25686140 TI - Permanent employment or public assistance may increase tuberculosis survival among working-age patients in Japan. AB - OBJECTIVES: To measure the effect of employment and health insurance status on the survival of working age tuberculosis (TB) patients in Japan. METHODS: Retrospective cohort analysis of new smear-positive pulmonary TB patients aged 15 59 years registered in the Japanese national TB surveillance system between 2007 and 2010. We performed univariate and multivariate Cox proportional hazard model analysis. The survival curves for employment and health insurance status were calculated using Kaplan-Meier analysis. RESULTS: Of 9097 patients studied, 267 (2.9%) died of TB within 12 months. After adjustment with a multivariate model, employment and health insurance status were independently associated with increased risk of TB death: unemployment (HR 2.80, 95%CI 2.11-3.72), absence of insurance (HR 1.48, 95%CI 1.02-2.15). The analysis of survival curves indicated that those with public assistance had almost the same survival rate as insured patients in the unemployed group. Permanent workers (employed >30 days) had the highest survival rates, followed by casual workers (employed <30 days) and the unemployed in the insured group. CONCLUSION: Patients with permanent jobs had better survival rates than unemployed patients and casual workers. Despite being unemployed, receiving public assistance could improve survival. Health measures are required for the unemployed and casual workers. PMID- 25686141 TI - MTBDRplus results correlate with treatment outcome in previously treated tuberculosis patients. AB - BACKGROUND: Although MTBDRplus is validated for the detection of multidrug resistant tuberculosis (MDR-TB), its role in the assessment of treatment outcome is less clear. We evaluated the association of MTBDRplus results with treatment outcome in new and previously treated patients in an endemic setting in China and determined factors associated with poor treatment outcomes. METHODS: We prospectively enrolled 298 smear-positive pulmonary TB patients who received the World Health Organization recommended initial treatment regimen or retreatment regimen. MTBDRplus was compared with conventional drug susceptibility testing and DNA sequencing for the detection of MDR-TB. Treatment responses were monitored using sputum smear, culture and chest radiography. RESULTS: MTBDRplus successfully identified all MDR-TB and had good concordance with sequencing. MDR TB rates were low among new patients (4/187, 2.1%), but high in previously treated patients (12/28, 42.9%); 65.2% (15/23) of previously treated cases and 17.1% (27/158) of new cases were unsuccessfully treated (P < 0.001). Seven of eight (87.5%) previously treated MDR-TB patients failed the retreatment regimen. In addition to drug resistance, sputum smear positivity at week 8 and cavitation are associated with treatment failure. CONCLUSION: Not only did MTBDRplus correctly identify all MDR-TB cases, MTBDRplus results are also associated with treatment outcomes in previously treated patients. The retreatment regimen should no longer be used; treatment should be guided by molecular testing. PMID- 25686142 TI - A randomized trial comparing standard outcomes in two treatment models for substance users with tuberculosis. AB - SETTING: Chicago Department of Public Health (CDPH), TB Control Program. OBJECTIVES: To compare anti-tuberculosis treatment outcomes using two different types of directly observed therapy (DOT) outreach workers. METHODS: Substance users diagnosed with TB from October 1996 to July 2000 were randomized to DOT administered by either 1) CDPH personnel (standard arm) or 2) previous substance using human immunodeficiency virus/acquired immune-deficiency syndrome outreach workers (enhanced arm). Treatment completion was physician-determined, and adherence was estimated based on risk of missed DOT appointments. RESULTS: Of 94 patients, 46 were randomized to the standard and 48 to the enhanced arm. The standard arm had a significantly higher risk of non-completion of treatment (39% vs. 15%, RR 2.7, 95%CI 1.2-5.8), and a significantly higher risk of missing DOT appointments (RR 2.6, 95%CI 1.4-4.8). For both outcomes, housing instability was a significant predictor in multivariate analyses. CONCLUSIONS: TB treatment completion and adherence among substance users was improved by the enhanced intervention; the familiarity of enhanced-arm DOT workers with the patients' social norms due to their own previous substance use may have made them more effective. Successful DOT in hard-to-reach populations may require strategies that directly address the population's circumstances and utilize DOT workers who are intimately familiar with patients' life situations. PMID- 25686143 TI - Bioequivalence of fixed-dose combination RIN(r)-150 to each reference drug in loose combination. AB - BACKGROUND: RIN((r))-150 is a fixed-dose combination (FDC) tablet containing rifampicin (RMP, 150 mg) and isoniazid (INH, 75 mg) developed for the treatment of tuberculosis. SETTING: This study was conducted at a single center: the Pfizer Clinical Research Unit in Singapore. OBJECTIVE: To demonstrate bioequivalence of each drug component between RIN-150 and individual products in a loose combination. DESIGN: This was a randomized, open-label, single-dose, two-way crossover study. Subjects received single doses of RIN-150 or two individual reference products under fasting conditions in a crossover fashion, with at least 7 days washout between doses. The primary measures for comparison were peak plasma concentration (Cmax) and the area under plasma concentration-time curve (AUC). RESULTS: Of 28 subjects enrolled, 26 completed the study. The adjusted geometric mean ratios of Cmax and AUClast between the FDC and single-drug references and 90% confidence intervals were respectively 91.63% (90%CI 83.13 101.01) and 95.45% (90%CI 92.07-98.94) for RMP, and 107.58% (90%CI 96.07-120.47) and 103.45% (90%CI 99.33-107.75) for INH. Both formulations were generally well tolerated in this study. CONCLUSION: The RIN-150 FDC tablet formulation is bioequivalent to the two single-drug references for RMP and INH at equivalent doses. PMID- 25686144 TI - Concordance of Mycobacterium tuberculosis fluoroquinolone resistance testing: implications for treatment. AB - Fluoroquinolone (FQ) drug susceptibility testing (DST) is an important step in the design of effective treatment regimens for multidrug-resistant tuberculosis. Here we compare ciprofloxacin, ofloxacin and moxifloxacin (MFX) resistance results from 226 multidrug-resistant samples. The low level of concordance observed suggests that DST should be performed for the specific FQ planned for clinical use. The results also support the new World Health Organization recommendation for testing MFX at a critical concentration of 2.0 MUg/ml. PMID- 25686145 TI - Comparison of LTBI treatment regimens for patients receiving anti-tumour necrosis factor therapy. AB - SETTING: A tertiary referral centre in South Korea. OBJECTIVE: To compare the completion rates and adverse drug reactions of three latent tuberculous infection (LTBI) treatment regimens for patients receiving anti-tumour necrosis factor (anti-TNF) therapy. DESIGN: A total of 408 patients were diagnosed with LTBI before receiving anti-TNF therapy between December 2004 and December 2013. Nine months of isoniazid (9H), 4 months of rifampicin (4H) or 3 months of isoniazid/rifampicin (3HR) were prescribed. The results were analysed retrospectively. RESULTS: The mean age of the 408 study subjects was 44 years; 258 (63.2%) were male. The 9H, 4R and 3HR treatment regimens were given to respectively 61 (15.0%), 139 (34.1%) and 208 (51.0%) patients. A total of 362 (88.7%) patients completed the treatment. The treatment completion rate was highest in patients receiving 3HR (94.2%). Of the 408 patients, 54 (13.2%) had one or more adverse drug reactions; their frequency was similar in the three groups. CONCLUSIONS: In patients receiving anti-TNF therapy, 3HR seems to be the most acceptable treatment regimen for LTBI, given its high completion rate and acceptable rate of adverse drug reactions. PMID- 25686146 TI - The effect of exposure to wood smoke on outcomes of childhood pneumonia in Botswana. AB - SETTING: Tertiary hospital in Gaborone, Botswana. OBJECTIVE: To examine whether exposure to wood smoke worsens outcomes of childhood pneumonia. DESIGN: Prospective cohort study of children aged 1-23 months meeting clinical criteria for pneumonia. Household use of wood as a cooking fuel was assessed during a face to-face questionnaire with care givers. We estimated crude and adjusted risk ratios (RRs) and 95% confidence intervals (CIs) for treatment failure at 48 h by household use of wood as a cooking fuel. We assessed for effect modification by age (1-5 vs. 6-23 months) and malnutrition (none vs. moderate vs. severe). RESULTS: The median age of the 284 enrolled children was 5.9 months; 17% had moderate or severe malnutrition. Ninety-nine (35%) children failed treatment at 48 h and 17 (6%) died. In multivariable analyses, household use of wood as a cooking fuel increased the risk of treatment failure at 48 h (RR 1.44, 95%CI 1.09 1.92, P = 0.01). This association differed by child nutritional status (P = 0.02), with a detrimental effect observed only among children with no or moderate malnutrition. CONCLUSIONS: Exposure to wood smoke worsens outcomes for childhood pneumonia. Efforts to prevent exposure to smoke from unprocessed fuels may improve pneumonia outcomes among children. PMID- 25686147 TI - Bronchoscope insertion route and patient comfort during flexible bronchoscopy. AB - SETTING: Diagnostic flexible bronchoscopy performed in hospitalised and ambulatory patients in a tertiary care academic hospital in Monterrey, Mexico. OBJECTIVE: To determine the effect of the route of insertion of the bronchoscope (oral or nasal) on patient comfort, vocal cord visualisation, local anaesthetic and sedation requirements and possible complications. DESIGN: Prospective study carried out in patients aged ? 18 years with an indication for flexible bronchoscopy. The route of insertion was randomly assigned. Symptoms related to the procedure were evaluated using a questionnaire. RESULTS: Sixty-three patients were included: 32 in the oral insertion group and 31 in the nasal insertion group. There was no statistically significant difference in patient discomfort (1.91 +/- 2.95 vs. 2.39 +/- 3.56 points on a scale of 1 to 10, P = 0.74) or procedural complications (4 vs. 0 events, P = 0.12) between study groups. Oral insertion was associated with less time to vocal cord visualisation (25.5 +/- 156 s vs. 56 +/- 61 s, P < 0.01), lower requirement for lidocaine (15 +/- 7.50 vs. 16 +/- 4 ml, P = 0.01) and fewer insertion failures (0 vs. 6 cases, P < 0.01). CONCLUSIONS: With intravenous sedoanalgesia, route of insertion did not affect patient comfort. However, the oral route was associated with faster vocal cord visualisation, less use of lidocaine and no insertion failure. PMID- 25686148 TI - Two case reports of Castleman disease with pulmonary involvement. AB - Castleman disease (CD) is a rare reactive lymphoproliferative disorder, first identified in 1954. We recently had the opportunity to analyse the characteristics of two variations of CD with pulmonary involvement. Case 1 had localised retroperitoneal hyaline vascular type CD, while Case 2 was diagnosed as multicentric plasma cell type CD. Both patients had pulmonary symptoms and signs, including cough, dyspnoea, hypoxaemia and ventilatory dysfunction; however, they had different physiological manifestations of their pulmonary abnormalities. PMID- 25686149 TI - In reply to 'False-positive Xpert(r) MTB/RIF assays in previously treated patients'. PMID- 25686150 TI - Palladium catalyzed diaryl sulfoxide generation from aryl benzyl sulfoxides and aryl chlorides. AB - Diaryl sulfoxides are synthesized from aryl benzyl sulfoxides and aryl chlorides via three sequential catalytic cycles all promoted by a NiXantPhos-based palladium catalyst. The key step is S-arylation of a sulfenate anion. An air- and moisture-stable precatalyst derived from NiXantPhos efficiently facilitates the transformation. Various functional groups, including those with acidic protons, were tolerated. This method can also be extended to methyl and dibenzyl sulfoxides substrates. PMID- 25686151 TI - Evaluation of different parameters in the extraction of incurred pesticides and environmental contaminants in fish. AB - Sample processing is often ignored during analytical method development and validation, but accurate results for real samples depend on all aspects of the analytical process. Also, validation is often conducted using only spiked samples, but extraction yields may be lower in incurred samples. In this study, different variables in extraction for incurred pesticides and environmental contaminants in fish were investigated. Among 207 analytes screened using low pressure gas chromatography-tandem mass spectrometry, consisting of 150 pesticides, 15 polycyclic aromatic hydrocarbons (PAHs), 14 polychlorinated biphenyls (PCBs), 6 polybrominated diphenyl ethers (PBDEs), and 22 other flame retardants (FRs), 35 (16 pesticides, 9 PCBs, 5 PBDEs, and 5 PAHs) were identified for quantification in samples of salmon, croaker, and NIST Standard Reference Material 1947 (Lake Michigan Fish Tissue). Extraction efficiencies using different extraction devices (blending, vortexing, and vibrating) versus time, sample size, and sample/solvent ratio were determined. In comparison to blending results, use of a pulsed-vortexer for 1 min with 1/1 (g/mL) sample/acetonitrile ratio was generally sufficient to extract the incurred contaminants in the homogenized fish tissues. Conversely, extraction with a prototype vibration shaker often took 60 min to achieve 100% extraction efficiency. A main conclusion from this study is that accurate results for real samples can be obtained using batch extraction with a pulsed-vortexer in a simple and efficient method that achieves high sample throughput. PMID- 25686152 TI - Excited state dynamics of the isolated green fluorescent protein chromophore anion following UV excitation. AB - A combined frequency-, angle-, and time-resolved photoelectron spectroscopy study is used to unravel the excited state dynamics following UV excitation of the isolated anionic chromophore of the green fluorescent protein (GFP). The optically bright S3 state, which is populated for hv > 3.7 eV, is shown to decay predominantly by internal conversion to the S2 state that in turn autodetaches to the neutral ground state. For hv > 4.1 eV, a new and favorable autodetachment channel from the S2 state becomes available, which leads to the formation of the neutral in an excited state. The results indicate that the UV excited state dynamics of the GFP chromophore involve a number of strongly coupled excited states. PMID- 25686153 TI - Design, synthesis, and biological evaluation of novel matrix metalloproteinase inhibitors as potent antihemorrhagic agents: from hit identification to an optimized lead. AB - Growing evidence suggests that matrix metalloproteinases (MMP) are involved in thrombus dissolution; then, considering that new therapeutic strategies are required for controlling hemorrhage, we hypothesized that MMP inhibition may reduce bleeding by delaying fibrinolysis. Thus, we designed and synthesized a novel series of MMP inhibitors to identify potential candidates for acute treatment of bleeding. Structure-based and knowledge-based strategies were utilized to design this novel chemical series, alpha-spiropiperidine hydroxamates, of potent and soluble (>75 MUg/mL) pan-MMP inhibitors. The initial hit, 12, was progressed to an optimal lead 19d. Racemic 19d showed a remarkable in vitro phenotypic response and outstanding in vivo efficacy; in fact, the mouse bleeding time at 1 mg/kg was 0.85 min compared to 29.28 min using saline. In addition, 19d displayed an optimal ADME and safety profile (e.g., no thrombus formation). Its corresponding enantiomers were separated, leading to the preclinical candidate 5 (described in Drug Annotations series, J. Med. Chem. 2015, ). PMID- 25686154 TI - pTC Plasmids from Sulfolobus Species in the Geothermal Area of Tengchong, China: Genomic Conservation and Naturally-Occurring Variations as a Result of Transposition by Mobile Genetic Elements. AB - Plasmids occur frequently in Archaea. A novel plasmid (denoted pTC1) containing typical conjugation functions has been isolated from Sulfolobus tengchongensis RT8-4, a strain obtained from a hot spring in Tengchong, China, and characterized. The plasmid is a circular double-stranded DNA molecule of 20,417 bp. Among a total of 26 predicted pTC1 ORFs, 23 have homologues in other known Sulfolobus conjugative plasmids (CPs). pTC1 resembles other Sulfolobus CPs in genome architecture, and is most highly conserved in the genomic region encoding conjugation functions. However, attempts to demonstrate experimentally the capacity of the plasmid for conjugational transfer were unsuccessful. A survey revealed that pTC1 and its closely related plasmid variants were widespread in the geothermal area of Tengchong. Variations of the plasmids at the target sites for transposition by an insertion sequence (IS) and a miniature inverted-repeat transposable element (MITE) were readily detected. The IS was efficiently inserted into the pTC1 genome, and the inserted sequence was inactivated and degraded more frequently in an imprecise manner than in a precise manner. These results suggest that the host organism has evolved a strategy to maintain a balance between the insertion and elimination of mobile genetic elements to permit genomic plasticity while inhibiting their fast spreading. PMID- 25686155 TI - Being mindful of later-life sleep quality and its potential role in prevention. PMID- 25686156 TI - Fabrication of three-dimensional hierarchical nanostructures using template directed colloidal assembly. AB - Optical effects in template-directed colloidal assembly are explored to fabricate microscale patterns with integrated three-dimensional (3D) nanostructures. This method allows the patterning of periodic nanostructures in arbitrarily designed regions by controlling particle assembly and light illumination. Using both "bottom-up" and "top-down" methods, this approach enables low-cost fabrication of hierarchical devices. PMID- 25686157 TI - The role of the South African Veterinary Council, with special reference to the period 1982-2011. AB - The current South African Veterinary Council (SAVC) has a long and laborious history associated with the legislation responsible for its establishment. The forerunner of the SAVC, the South African Veterinary Board, was established in terms of the Veterinary Act 1933 (Act No. 16 of 1933), which was launched through Parliament as a private motion by Dr Hjalmar Reitz M.P. After several amendments, the Act was replaced with the Veterinary and Para-veterinary Professions Act 1982 (Act No. 19 of 1982), superseding the existing Board with the SAVC. One of the reasons for replacing this Act was to comply with Government policy for professional statutory bodies to become self-funding, with fees paid by registered professionals, and to constitute councils that were more representative of the profession. Apart from providing some background information, this article was virtually entirely confined to some historic aspects of the SAVC, using, as its basis, the main developments that occurred during the terms of office of its various presidents, serving from 1982 to 2011. The presidents concerned are: Prof. B.C. Jansen (28 March 1983 - 28 March 1986), Dr G.E. Frost (14 April 1986 - 31 March 1992), Prof. R.I. Coubrough (07 April 1992 - 21 March 1994), Dr P.C. Ardington (21 March 1994 - 31 March 1998), Prof H.M. Terblanche (31 March 1998 - 31 March 2004), Prof. S.S. van den Berg (01 April 2004 - 30 July 2007) and Dr R. Moerane (06 August 2007 - 31 July 2013). PMID- 25686158 TI - Topical non-steroidal anti-inflammatory agents for diabetic cystoid macular oedema. AB - BACKGROUND: Diabetic cystoid macular oedema (CMO) is a condition which involves fluid accumulation in the inner portion of the retina. It often follows changes in retinal blood vessels which enhance the fluid to come out of vessels. Although it may be asymptomatic, symptoms are primarily painless loss of central vision, often with the complaint of seeing black spots in front of the eye.It is reported that CMO may resolve spontaneously, or fluctuate for months, before causing loss of vision. If left untreated or undiagnosed, progression of CMO may lead to permanent visual loss.It has been noted that patients with diabetic retinopathy have elevated inflammatory markers, and therefore it is likely that inflammation aids in the progression of vascular disease in these patients. Several topical non-steroidal anti-inflammatory drugs (NSAIDs) such as ketorolac 0.5%, bromfenac 0.09%, and nepafenac 0.1%, have therefore also been used topically to treat chronic diabetic CMO. Hence this review was conducted to find out the effects of topical NSAIDs in diabetic CMO. OBJECTIVES: To assess the effects of topical non steroidal anti-inflammatory drugs (NSAIDs) for diabetic cystoid macular oedema (CMO). SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (2014, Issue 12), Ovid MEDLINE, Ovid MEDLINE In Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to January 2015), EMBASE (January 1980 to January 2015), Latin American and Caribbean Health Sciences Literature Database (LILACS) (January 1982 to January 2015), the ISRCTN registry (www.isrctn.com/editAdvancedSearch), ClinicalTrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 12 January 2015. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs investigating the effects of topically applied NSAIDs in the treatment of people with diabetic CMO aged 18 years of age or over. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial eligibility and screened all available titles and abstracts for inclusion. There were no discrepancies and we did not have to contact trial investigators for missing data. MAIN RESULTS: We did not identify any RCTs matching the inclusion criteria for this review. AUTHORS' CONCLUSIONS: The review did not identify any RCTs investigating the effects of topical NSAIDs in the treatment of diabetic CMO. Most of the studies identified through the electronic searches had been conducted to analyse the effect of topical NSAIDs for pseudophakic CMO.In the absence of high quality evidence, clinicians need to use their clinical judgement and other low level evidence, such as observational non-randomised trials, to decide whether to use topical NSAIDs in cases of diabetic CMO.More research is needed to better understand the cause of this condition and its pathophysiology. This systematic review has identified the need for well designed, adequately powered RCTs to assess possible beneficial and adverse effects of topical NSAIDs in people with diabetic CMO. Future trials should aim to include a large sample size with an adequate follow-up period of up to one year. PMID- 25686159 TI - A review of modern approaches to the hydrodynamic characterisation of polydisperse macromolecular systems in biotechnology. AB - This short review considers the range of modern techniques for the hydrodynamic characterisation of macromolecules - particularly large glycosylated systems used in the food, biopharma and healthcare industries. The range or polydispersity of molecular weights and conformations presents special challenges compared to proteins. The review is aimed, without going into any great theoretical or methodological depth, to help the Industrial Biotechnologist choose the appropriate methodology or combination of methodologies for providing the detail he/she needs for particular applications. PMID- 25686160 TI - Preparation of compact nanoparticle clusters from polyethylene glycol-coated gold nanoparticles by fine-tuning colloidal interactions. AB - Low-molecular weight polyethylene glycol (PEG) has a lower critical solution temperature well outside the boiling point of water at ambient pressure, but it can be reduced at high ionic strengths. We extend this concept to trigger the clustering of gold nanoparticles through the control of colloidal interactions. At high ionic strengths, low-molecular weight (<2000 Da) mPEG-SH-modified gold nanoparticles show clustering with an increase in the solution temperature. The clustering temperature decreases with an increasing ionic strength. The clustering is attributed to the delicate interplay between the high ionic strength and elevated temperature and is interpreted in terms of chain collapse of the surface-grafted PEG molecules. The chain collapse results in a change in the steric interaction term, whereas the high ionic strength eliminates the double-layer repulsion between the particles. The observations are backed by nanoparticle interaction model calculations. We found that the intermediate attractive potential on the order of a few kT allows the experimental fabrication of compact nanoparticle clusters in agreement with theoretical predictions. The approach presented here has the potential to be extended on the externally triggered preparation of nanoparticle clusters with different types of nanoparticles. PMID- 25686161 TI - IR-780 dye for near-infrared fluorescence imaging in prostate cancer. AB - BACKGROUND: The aim of this study was to investigate near-infrared fluorescence (NIRF) imaging as a novel imaging modality that allows for early detection of cancer and real-time monitoring to acquire related information. IR-780 iodide, a lipophilic dye, accumulates selectively in breast cancer cells and drug-resistant human lung cancer cells, with a peak emission at 780 nm that can be easily detected by the NIRF imaging system. The application of IR-780 for prostate cancer imaging was thoroughly investigated to further expand its clinical value. MATERIAL AND METHODS: The impact of IR-780 on the survival of prostate cancer cells PC-3 and LNCaP as well as normal prostate epithelial cells RWPE-1 was determined. Duration of IR-780 dye staining was optimized in PC-3 cells. The involvement of specific OATP1B3 inhibitor in the selective accumulation of IR-780 was investigated. IR-780 for prostate cancer imaging was carried out in athymic nude mouse models and, acute toxicity of IR-780 was evaluated. RESULTS: IR-780 incubation resulted in a dose-dependent inhibition to cell proliferation. Mean fluorescence intensity of prostate cancer cells peaked at 20-min IR-780 incubation. Specific uptake of IR-780 dye in prostate cancer cells was mainly through the function of OATP1B3. We also demonstrated that NIRF dye effectively identified the subcutaneous prostate cancer xenografts, subsequently confirmed by histological examination. There was no significant impact on the physical activity, weight, and tissue histology of BABL/C mice with 10-fold imaging dose of 1-month IR-780 dye administration. CONCLUSIONS: NIRF imaging using IR-780 dye is a feasible and practicable method for prostate cancer detection, with potential tumor-killing ability, although more investigations are needed before clinical translation. PMID- 25686162 TI - Environmental and nursing-staff factors contributing to aggressive and violent behaviour of patients in mental health facilities. AB - BACKGROUND: Aggressive and violent behaviour of inpatients in mental health facilities disrupts the therapeutic alliance and hampers treatment. OBJECTIVES: The aim of the study was to describe patients' perceptions of the possible environmental and staff factors that might contribute to their aggressive and violent behaviour after admission to a mental health facility; and to propose strategies to prevent and manage such behaviour. RESEARCH DESIGN: A qualitative, phenomenological study was utilised, in which purposefully sampled inpatients were interviewed over a six-month period. Inpatients were invited to participate if they had been admitted for at least seven days and were in touch with reality. METHOD: Forty inpatients in two mental health facilities in Cape Town participated in face-to-face, semi-structured interviews over a period of six months. Tesch's descriptive method of open coding formed the framework for the data analysis and presentation of the results. Trustworthiness was ensured in accordance with the principles of credibility, confirmability, transferability and dependability. RESULTS: Analysis of the data indicates two central categories in the factors contributing to patients' aggressive and violent behaviour, namely, environmental factors and the attitude and behaviour of staff. CONCLUSION: From the perspective of the inpatients included in this study, aggressive and violent episodes are common and require intervention. Specific strategies for preventing such behaviour are proposed and it is recommended that these strategies be incorporated into the in-service training programmes of the staff of mental health facilities. These strategies could prevent, or reduce, aggressive and violent behaviour in in-patient facilities. PMID- 25686163 TI - Pairing broadband noise with cortical stimulation induces extensive suppression of ascending sensory activity. AB - OBJECTIVE: The corticofugal system can alter coding along the ascending sensory pathway. Within the auditory system, electrical stimulation of the auditory cortex (AC) paired with a pure tone can cause egocentric shifts in the tuning of auditory neurons, making them more sensitive to the pure tone frequency. Since tinnitus has been linked with hyperactivity across auditory neurons, we sought to develop a new neuromodulation approach that could suppress a wide range of neurons rather than enhance specific frequency-tuned neurons. APPROACH: We performed experiments in the guinea pig to assess the effects of cortical stimulation paired with broadband noise (PN-Stim) on ascending auditory activity within the central nucleus of the inferior colliculus (CNIC), a widely studied region for AC stimulation paradigms. MAIN RESULTS: All eight stimulated AC subregions induced extensive suppression of activity across the CNIC that was not possible with noise stimulation alone. This suppression built up over time and remained after the PN-Stim paradigm. SIGNIFICANCE: We propose that the corticofugal system is designed to decrease the brain's input gain to irrelevant stimuli and PN-Stim is able to artificially amplify this effect to suppress neural firing across the auditory system. The PN-Stim concept may have potential for treating tinnitus and other neurological disorders. PMID- 25686164 TI - The clinical presentation of Fusobacterium-positive and streptococcal-positive pharyngitis in a university health clinic: a cross-sectional study. AB - BACKGROUND: Pharyngitis guidelines focus solely on group A beta-hemolytic streptococcal infection. European data suggest that in patients aged 15 to 30 years, Fusobacterium necrophorum causes at least 10% of cases of pharyngitis; however, few U.S. data exist. OBJECTIVE: To estimate the prevalence of F. necrophorum; Mycoplasma pneumoniae; and group A and C/G beta-hemolytic streptococcal pharyngitis and to determine whether F. necrophorum pharyngitis clinically resembles group A beta-hemolytic streptococcal pharyngitis. DESIGN: Cross-sectional. SETTING: University student health clinic. PATIENTS: 312 students aged 15 to 30 years presenting to a student health clinic with an acute sore throat and 180 asymptomatic students. MEASUREMENTS: Polymerase chain reaction testing from throat swabs to detect 4 species of bacteria and signs and symptoms used to calculate the Centor score. RESULTS: Fusobacterium necrophorum was detected in 20.5% of patients and 9.4% of asymptomatic students. Group A beta hemolytic streptococcus was detected in 10.3% of patients and 1.1% of asymptomatic students. Group C/G beta-hemolytic streptococcus was detected in 9.0% of patients and 3.9% of asymptomatic students. Mycoplasma pneumoniae was detected in 1.9% of patients and 0 asymptomatic students. Infection rates with F. necrophorum, group A streptococcus, and group C/G streptococcus increased with higher Centor scores (P < 0.001). LIMITATIONS: The study focused on a limited age group and took place at a single institution. Asymptomatic students-rather than seasonal control participants-and a convenience sample were used. CONCLUSION: Fusobacterium necrophorum-positive pharyngitis occurs more frequently than group A beta-hemolytic streptococcal-positive pharyngitis in a student population, and F. necrophorum-positive pharyngitis clinically resembles streptococcal pharyngitis. PRIMARY FUNDING SOURCE: University of Alabama at Birmingham and the Justin E. Rodgers Foundation. PMID- 25686165 TI - Single-component versus multicomponent dietary goals for the metabolic syndrome: a randomized trial. AB - BACKGROUND: Few studies have compared diets to determine whether a program focused on 1 dietary change results in collateral effects on other untargeted healthy diet components. OBJECTIVE: To evaluate a diet focused on increased fiber consumption versus the multicomponent American Heart Association (AHA) dietary guidelines. DESIGN: Randomized, controlled trial from June 2009 to January 2014. (ClinicalTrials.gov: NCT00911885). SETTING: Worcester, Massachusetts. PARTICIPANTS: 240 adults with the metabolic syndrome. INTERVENTION: Participants engaged in individual and group sessions. MEASUREMENTS: Primary outcome was weight change at 12 months. RESULTS: At 12 months, mean change in weight was -2.1 kg (95% CI, -2.9 to -1.3 kg) in the high-fiber diet group versus -2.7 kg (CI, 3.5 to -2.0 kg) in the AHA diet group. The mean between-group difference was 0.6 kg (CI, -0.5 to 1.7 kg). During the trial, 12 (9.9%) and 15 (12.6%) participants dropped out of the high-fiber and AHA diet groups, respectively (P = 0.55). Eight participants developed diabetes (hemoglobin A1c level >=6.5%) during the trial: 7 in the high-fiber diet group and 1 in the AHA diet group (P = 0.066). LIMITATIONS: Generalizability is unknown. Maintenance of weight loss after cessation of group sessions at 12 months was not assessed. Definitive conclusions cannot be made about dietary equivalence because the study was powered for superiority. CONCLUSION: The more complex AHA diet may result in up to 1.7 kg more weight loss; however, a simplified approach to weight reduction emphasizing only increased fiber intake may be a reasonable alternative for persons with difficulty adhering to more complicated diet regimens. PRIMARY FUNDING SOURCE: National Heart, Lung, and Blood Institute. PMID- 25686166 TI - Time-updated systolic blood pressure and the progression of chronic kidney disease: a cohort study. AB - BACKGROUND: Previous reports of the longitudinal association between achieved blood pressure (BP) and end-stage renal disease (ESRD) among patients with chronic kidney disease (CKD) have not incorporated time-updated BP with appropriate covariate adjustment. OBJECTIVE: To assess the association between baseline and time-updated systolic blood pressure (SBP) with CKD progression. DESIGN: Observational, prospective cohort study. (ClinicalTrials.gov: NCT00304148). SETTING: 7 U.S. clinical centers. PATIENTS: Patients in the Chronic Renal Insufficiency Cohort Study (n = 3708) followed for a median of 5.7 years (25th to 75th percentile, 4.6 to 6.7 years). MEASUREMENTS: The mean of 3 seated SBP measurements made up the visit-specific SBP. Time-updated SBP was the mean of that and all previous visits. Outcomes were ESRD and the composite end point of ESRD or halving of the estimated glomerular filtration rate. Analyses investigating baseline and time-updated SBP used Cox proportional hazards models and marginal structural models, respectively. RESULTS: Systolic blood pressure was 130 mm Hg or greater at all visits in 19.2% of patients. The hazard ratio for ESRD among patients with SBP of 130 to 139 mm Hg, compared with SBP less than 120 mm Hg, was 1.46 (95% CI, 1.13 to 1.88) using only baseline data and 2.37 (CI, 1.48 to 3.80) using time-updated data. Among patients with SBP of 140 mm Hg or greater, corresponding hazard ratios were 1.46 (CI, 1.18 to 1.88) and 3.37 (CI, 2.26 to 5.03) for models using only baseline data and those using time-updated data, respectively. LIMITATION: Blood pressure was measured once annually, and the cohort was not a random sample. CONCLUSION: Time-updated SBP greater than 130 mm Hg was more strongly associated with CKD progression than analyses based on baseline SBP. PRIMARY FUNDING SOURCE: National Institute of Diabetes and Digestive and Kidney Diseases. PMID- 25686167 TI - An analysis of calibration and discrimination among multiple cardiovascular risk scores in a modern multiethnic cohort. AB - BACKGROUND: Accurate risk assessment of atherosclerotic cardiovascular disease (ASCVD) is essential to effectively balance the risks and benefits of therapy for primary prevention. OBJECTIVE: To compare the calibration and discrimination of the new American Heart Association (AHA) and American College of Cardiology (ACC) ASCVD risk score with alternative risk scores and to explore preventive therapy as a cause of the reported risk overestimation using the AHA-ACC-ASCVD score. DESIGN: Prospective epidemiologic study of ASCVD. SETTING: MESA (Multi-Ethnic Study of Atherosclerosis), a community-based, sex-balanced, multiethnic cohort. PATIENTS: 4227 MESA participants aged 50 to 74 years and without diabetes at baseline. MEASUREMENTS: Observed and expected events for the AHA-ACC-ASCVD score were compared with 4 commonly used risk scores-and their respective end points-in MESA after a 10.2-year follow-up. RESULTS: The new AHA-ACC-ASCVD and 3 older Framingham-based risk scores overestimated cardiovascular events by 37% to 154% in men and 8% to 67% in women. Overestimation was noted throughout the continuum of risk. In contrast, the Reynolds Risk Score overestimated risk by 9% in men but underestimated risk by 21% in women. Aspirin, lipid-lowering or antihypertensive therapy, and interim revascularization did not explain the overestimation. LIMITATION: Comparability of MESA with target populations for primary prevention and possibility of missed events in MESA. CONCLUSION: Of the 5 risk scores, 4, including the new AHA-ACC-ASCVD score, showed overestimation of risk (25% to 115%) in a modern, multiethnic cohort without baseline clinical ASCVD. If validated, overestimation of ASCVD risk may have substantial implications for individual patients and the health care system. PRIMARY FUNDING SOURCE: National Heart, Lung, and Blood Institute. PMID- 25686168 TI - Innovations in data collection, management, and archiving for systematic reviews. AB - Data abstraction is a key step in conducting systematic reviews because data collected from study reports form the basis of appropriate conclusions. Recent methodological standards and expectations highlight several principles for data collection. To support implementation of these standards, this article provides a step-by-step tutorial for selecting data collection tools; constructing data collection forms; and abstracting, managing, and archiving data for systematic reviews. Examples are drawn from recent experience using the Systematic Review Data Repository for data collection and management. If it is done well, data collection for systematic reviews only needs to be done by 1 team and placed into a publicly accessible database for future use. Technological innovations, such as the Systematic Review Data Repository, will contribute to finding trustworthy answers for many health and health care questions. PMID- 25686169 TI - Celebrating the ACP centennial: from the Annals archive. PMID- 25686170 TI - Sore throat: avoid overcomplicating the uncomplicated. PMID- 25686171 TI - Comparing cardiovascular risk prediction scores. PMID- 25686172 TI - Corrections clinic. PMID- 25686173 TI - Albumin administration in patients with sepsis. PMID- 25686174 TI - Albumin administration in patients with sepsis--response. PMID- 25686175 TI - Rethinking the use of physicians as hired expert lecturers. PMID- 25686176 TI - Rethinking the use of physicians as hired expert lecturers. PMID- 25686177 TI - Rethinking the use of physicians as hired expert lecturers. PMID- 25686178 TI - Rethinking the use of physicians as hired expert lecturers--response. PMID- 25686179 TI - Metabolic acidosis in a patient with isopropyl alcohol intoxication: a case report. PMID- 25686183 TI - Summaries for patients. Weight loss with diets focused on 1 versus several dietary changes. PMID- 25686184 TI - Web Exclusives. The consult guys - twisted after surgery: what caused torsades? PMID- 25686185 TI - ACP Journal Club: the Ipswich Touch Test at home had 78% sensitivity and 94% specificity for detecting loss of foot sensation. PMID- 25686186 TI - ACP Journal Club: review: Xpert MTB/RIF assay detects extrapulmonary TB in lymph nodes and CSF, but not pleural fluid. PMID- 25686187 TI - ACP Journal Club: new use of atypical antipsychotics was linked to acute kidney injury and all-cause mortality at 90 days. PMID- 25686188 TI - ACP Journal Club: some antimicrobials increased admissions and ED visits for hypoglycemia in older users of glipizide or glyburide. PMID- 25686189 TI - ACP Journal Club: in HF, angiotensin-neprilysin inhibition reduced mortality and HF hospitalization compared with enalapril. PMID- 25686190 TI - ACP Journal Club: an elastic band exercise program improved fitness in older adults who use wheelchairs in nursing homes. PMID- 25686191 TI - ACP Journal Club: review: periprocedural high-dose statins reduce contrast induced acute kidney injury after coronary angiography. PMID- 25686192 TI - ACP Journal Club: after initial anticoagulation for a first unprovoked venous thromboembolism, aspirin reduced recurrence. PMID- 25686193 TI - ACP Journal Club: IIV3 reduced flu in HIV- pregnant women and infants, and in HIV+ pregnant women but not their infants. PMID- 25686194 TI - ACP Journal Club: review: oral antiviral drugs reduce clinical recurrence in recurrent genital herpes. PMID- 25686195 TI - ACP Journal Club: review: in knee and hip OA, opioids reduce pain and improve function but increase adverse events. PMID- 25686196 TI - ACP Journal Club: in obesity with type 2 diabetes, duodenal-jejunal bypass liners improved weight loss and HbA1c during treatment. PMID- 25686197 TI - Bovine trypanosomosis prevalence at the edge of Hluhluwe-iMfolozi Park, KwaZulu Natal, South Africa. AB - The northern KwaZulu-Natal (NKZN) region of South Africa is the southern limit of the African tsetse belt. Entomological information on Glossina brevipalpis and Glossina austeni was generated following the outbreak of trypanosomosis in cattle in 1990. However, these data have not been supported by parallel studies on epidemiology of the disease and therefore there has been no control policy in place. This study presented the first intensive investigations to address the epidemiology of trypanosomosis in NKZN. Tsetse abundance, trypanosome herd average prevalence (HAP), herd average anaemia (HAA) and herd average packed cell volume (HA-PCV) were investigated at three communal diptanks located at the edge of Hluhluwe-iMfolozi Park by monthly sampling from June 2006 - November 2007. Seasonal trypanosome surveys were conducted at seven other communal diptanks. Glossina brevipalpis prevalence was high at two of the diptanks, Mvutshini and Ekuphindisweni, but low at Ocilwane, whilst G. austeni was only collected from Mvutshini. This high and low tsetse challenge presented different disease scenarios. Cattle at Mvutshini and Ekuphindisweni had the highest HAP of 12.3% and 8.9% respectively, both significantly different (p = 0.001) from the HAP obtained from cattle at Ocilwane (2.9%). These two cattle herds also had the highest HAA, 27.7% and 33.4% respectively, whilst cattle at Ocilwane had the lowest, 11.1% (p = 0.001). Conversely, cattle at Ocilwane had the highest HA-PCV, ranging between 29.0% and 32.0%, whilst cattle at Mvutshini and Ekuphindisweni had the lowest HA-PCV (24.0% - 29.0%). By combining the data from the three diptanks (1318 observations), 62.0% of the infected cattle were found anaemic, compared to 20.0% in the uninfected group. Trypanosome seasonal surveys showed that cattle at all the seven diptanks were infected with trypanosomes; mean HAP, HAA and HA-PCV of 10.2%, 46.6% and 23.7%, respectively. This study generated information on the epidemiological factors related to the wide spread of trypanosome-infected cattle and tsetse flies. Trypanosomosis is a disease of economic importance impacting the livelihood of resource-poor farmers in NKZN. PMID- 25686198 TI - Ambient water and visible-light irradiation drive changes in graphene morphology, structure, surface chemistry, aggregation, and toxicity. AB - The environmental behaviors and risks associated with graphene have attracted considerable attention. However, the fundamental effects of ambient water and visible-light irradiation on the properties and toxicity of graphene remain unknown. This work revealed that hydration and irradiation result in the transformation of large-sheet graphene to long-ribbon graphene. The thickness of the treated graphene decreased, and oxides were formed through the generation of singlet oxygen. In addition, hydration and irradiation resulted in greater disorder in the graphene structure and in the expansion of the d-spacing of the structure due to the introduction of water molecules and modifications of the functional groups. Oxidative modifications with two-stage (fast and low) kinetics enhanced the number of negative surface charges on the graphene and enhanced graphene aggregation. The above property alterations reduced the nanotoxicity of graphene to algal cells by reducing the generation of reactive oxygen species, diminishing protein carbonylation and decreasing tail DNA. A comparative study using graphene oxide suggested that oxidative modifications could play an important role in inhibiting toxicological activity. This study provides a preliminary approach for understanding the environmental behaviors of graphene and avoids overestimating the risks of graphene in the natural environment. PMID- 25686199 TI - Ultrathin single-walled carbon nanotube network framed graphene hybrids. AB - Graphene and single-walled carbon nanotubes (SWNTs) have shown superior potential in electronics and optoelectronics because of their excellent thermal, mechanical, electronic, and optical properties. Here, a simple method is developed to synthesize ultrathin SWNT-graphene films through chemical vapor deposition. These novel two-dimensional hybrids show enhanced mechanical strength that allows them to float on water without polymer supporting layers. Characterizations by Raman spectroscopy and transmission electron microscopy indicate that SWNTs can interlace as a concrete backbone for the subsequent growth of monolayer graphene. Optical and electrical transport measurements further show that SWNT-graphene hybrids inherit high optical transparency and superior electrical conductivity from monolayer graphene. We also explore the local optoelectronic properties of SWNT-graphene hybrids through spatially resolved photocurrent microscopy and find that the interactions between SWNTs and graphene can induce a strong photocurrent response in the areas where SWNTs link different graphene domains together. These fundamental studies may open a door for engineering optoelectronic properties of SWNT-graphene hybrids by controlling the morphologies of the SWNT frames. PMID- 25686200 TI - Biodegradable stearylated peptide with internal disulfide bonds for efficient delivery of siRNA in vitro and in vivo. AB - RNA-based delivery system for cancer therapy remains a challenge. In this study, a stearyl-peptide (SHR) was synthesized using arginine, histidine, cysteine, and stearyl moieties. Further, the stearyl-peptides were cross-linked by disulfide bonds to obtain cross-linked polypeptides (SHRss) with different molecular weight (SHRss1, SHRss2, SHRss3, SHRss4). The SHRss could effectively condense small interfering RNA (siRNA) into polyplexes with a hydrodynamic size of 100-300 nm and zeta potential of 20-40 mV. Flow cytometry and confocal laser scanning microscope studies revealed high cellular uptake and rapid dissociation behavior of SHRss2/siRNA complexes. Long-lasting high concentration of siRNA in cytoplasm was observed even at 24 h after SHRss2/Cy3-siRNA transfection. Compared with SHR, the SHRss showed much improved siRNA interference efficiency targeting luciferase on Luc-Hela cells. Moreover, SHRss2 exhibited higher interference efficiency and slower decay rate on Luc-Hela cells than Lipofectamine 2000 and SHR. In addition, much weaker expression of red fluorescence protein was also observed on SHRss2/simCh-treated mCherry-HEK293 cells than Lipofectamine 2000 and SHR. The SHRss did not induce cytotoxicity at siRNA concentrations of 25-200 nM under transfection. The in vivo studies demonstrated the gene interference efficiency of SHRss2/siRNA complexes. Our studies indicated that the SHRss are promising and efficient nonviral vectors for siRNA delivery. PMID- 25686202 TI - Inferior olivary nucleus involvement in pediatric neurodegenerative disorders: does it play a role in neuroimaging pattern-recognition approach? AB - The diagnostic work up of neurometabolic/degenerative disorders is complex. In such context, identification of neuroradiological features suggestive of specific diagnoses is useful to prompt further diagnostic tests. Involvement of the inferior olivary nucleus (ION) has been reported in several pathologic conditions, either as a primary manifestation of disease or secondary to hypertrophic olivary degeneration (HOD). In this study, we analyzed a cohort of 95 children with different neurometabolic/degenerative diseases involving the brainstem and cerebellum, with the aim to evaluate whether ION involvement plays a role in a neuroimaging-based pattern-recognition approach. A total of 13 patients (13.7%) showed bilateral high-signal intensity and enlargement of the ION on T2-weighted images, while 16 (16.8%) had ION T2-hyperintensity without olivary nucleus enlargement. Our study demonstrates that ION involvement is not rare in children with neurometabolic/degenerative disorders. Two main neuroradiological patterns, that is, "T2-hyperintense signal" and "T2 hyperintense signal with enlargement" are found. These patterns can be related to different etiologies, and do not suggest specific diagnoses. Primary ION lesion can be characterized by olivary swelling, and the differentiation from typical secondary HOD may be difficult. PMID- 25686203 TI - Tuning the surface charge of 2D oxide nanosheets and the bulk-scale production of superlatticelike composites. AB - The surface charge of various anionic unilamellar nanosheets, such as graphene oxide (GO), Ti0.87O2(0.52-), and Ca2Nb3O10(-) nanosheets, has been successfully modified to be positive by interaction with polycations while maintaining a monodispersed state. A dilute anionic nanosheet suspension was slowly added dropwise into an aqueous solution of high molecular weight polycations, which attach on the surface of the anionic nanosheets via electrostatic interaction. Surface modification and transformation to positively charged nanosheets were confirmed by various characterizations including atomic force microscopy and zeta potential measurements. Because the sizes of the polycations used are much larger than the nanosheets, the polymer chains may run off the nanosheet edges and fold to the fronts of the nanosheets, which could be a reason for the continued dispersion of the modified nanosheets in the suspension. By slowly adding a suspension of polycation-modified nanosheets and pristine anionic nanosheet dropwise into water under suitable conditions, a superlatticelike heteroassembly can be readily produced. Characterizations including transmission electron microscopy and X-ray diffraction measurements provide evidence for the formation of the alternately stacked structures. This approach enables the combination of various pairs of anionic nanosheets with different functionalities, providing a new opportunity for the creation of unique bulk-scale functional materials and their applications. PMID- 25686204 TI - Assessment of the repellent effect of citronella and lemon eucalyptus oil against South African Culicoides species. AB - The use of insect repellents to reduce the attack rate of Culicoides species (Diptera:Ceratopogonidae) should form part of an integrated control programme to combat African horse sickness and other diseases transmitted by these blood feeding midges. In the present study the repellent effects of a commercially available mosquito repellent, a combination of citronella and lemon eucalyptus oils, on Culicoides midges was determined. The number of midges collected with two 220 V Onderstepoort traps fitted with 8 W 23 cm white light tubes and baited with peel-stick patches, each containing 40 mg of active ingredient, was compared with that of two unbaited traps. Two trials were conducted and in each trial the four traps were rotated in two replicates of a 4 x 4 randomised Latin square design. Although more midges were collected in the baited traps, the mean number in the baited and unbaited traps was not significantly different. This mosquito repellent did not influence either the species composition or the physiological groups of Culicoides imicola Kieffer. The higher mean numbers in the baited traps, although not statistically significant, may indicate that this mosquito repellent might even attract Culicoides midges under certain conditions. PMID- 25686205 TI - Magnetic and electric hotspots with silicon nanodimers. AB - The study of the resonant behavior of silicon nanostructures provides a new route for achieving efficient control of both electric and magnetic components of light. We demonstrate experimentally and numerically that enhancement of localized electric and magnetic fields can be achieved in a silicon nanodimer. For the first time, we experimentally observe hotspots of the magnetic field at visible wavelengths for light polarized across the nanodimer's primary axis, using near-field scanning optical microscopy. PMID- 25686206 TI - Multifunctional aptamer-silver conjugates as theragnostic agents for specific cancer cell therapy and fluorescence-enhanced cell imaging. AB - We fabricated a multifunctional theragnostic agent Ag-Sgc8-FAM for apoptosis based cancer therapy and fluorescence-enhanced cell imaging. For cancer therapy, aptamers Sgc8 and TDO5 acted as recognizing molecules to bind CCRF-CEM and Ramos cells specifically. It was found that aptamer-silver conjugates (Ag-Sgc8, Ag TDO5) could be internalized into cells by receptor-mediated endocytosis, inducing specific apoptosis of CCRF-CEM and Ramos cells. The apoptosis of cells depended on the concentration of aptamer-silver conjugates, as well as the incubation time between cells and aptamer-silver conjugates. The apoptotic effects on CCRF-CEM and Ramos cells were different. Annexin V/PI staining, AO/PI staining, MTT assays and ROS (reactive oxygen species) detection demonstrated the specific apoptosis of CCRF-CEM and Ramos cells. For fluorescence-enhanced cell imaging, Ag-Sgc8-FAM was prepared. Compared to Sgc8-FAM molecules, Ag-Sgc8-FAM was an excellent imaging agent as numerous Sgc8-FAM molecules were enriched on the surface of AgNPs for multiple binding with CCRF-CEM cells and signal amplification. Moreover, AgNPs could increase the fluorescence intensity of FAM by metal enhanced fluorescence (MEF) effect. Therefore, aptamer-silver conjugates can be potential theragnostic agents for inducing specific apoptosis of cells and achieving cells imaging in real time. PMID- 25686207 TI - Metal ion-assisted ring-opening of a quinazoline-based chemosensor: detection of copper(II) in aqueous media. AB - A quinazoline-based fluorescence chemosensor, 6-phenol-2-yl-(5,6 dihydrobenzimidazo[1,2-c])quinazoline (HL), for highly selective recognition of Cu(II) in aqueous media was synthesized. The detection limit was of the order of 10(-6) M. The crystal structures of the Cu(II) and Cd(II) complexes showed that HL changed to a Schiff base when it reacts with metal salts and that the metal ions coordinate with two nitrogen atoms and one hydroxyl oxygen atom from the Schiff base. The theoretical calculations at B3LYP-SCRF/6-31G(d) confirmed that it is the Cu(II) ion that assisted the ring-opening of the quinazoline derivative, forming a Cu(II) Schiff base complex during the detection. LMCT leads to the disappearance of fluorescence. A cell imaging study indicated that HL could be used to detect the intracellular Cu(2+) ion. PMID- 25686208 TI - Prescription opioid duration of action and the risk of unintentional overdose among patients receiving opioid therapy. AB - IMPORTANCE: The unprecedented increase in unintentional overdose events that has occurred in tandem with escalating sales of prescription opioids over the past 2 decades has raised concerns about whether the therapeutic use of opioids has contributed to increases in overdose injury. Few controlled studies have examined the extent to which ecologic measures of increases in opioid prescribing and overdose injuries reflect risk among patients prescribed opioids, let alone whether some opioid regimens are safer than others. OBJECTIVE: To examine whether the risk of unintentional overdose injury is associated with the duration of opioid action (ie, long-acting vs short-acting formulations). DESIGN, SETTING, AND PARTICIPANTS: A propensity score-adjusted cohort study was conducted using population-based health care utilization data from the Veterans Administration Healthcare System. The patients were veterans with chronic painful conditions who began therapy with opioid analgesics between January 1, 2000, and December 31, 2009. MAIN OUTCOMES AND MEASURES: Unintentional overdoses that are explicitly coded using International Classification of Disease, Ninth Revision codes as drug or medication poisonings of accidental intent (E850.x-860.x) or undetermined intent (E980.x or drug poisoning [960.x-980.x] without an accompanying external cause of injury code). RESULTS: A total of 319 unintentional overdose events were observed. Patients initiating therapy with long-acting opioids were more than twice as likely to overdose compared with persons initiating therapy with short acting opioids. After adjustment for age, sex, opioid dose, and other clinical characteristics, patients receiving long-acting opioids had a significantly higher rate of overdose injury than did those receiving short-acting opioids (hazard ratio [HR], 2.33; 95% CI, 1.26-4.32). The risk associated with long acting agents was particularly marked during the first 2 weeks after initiation of treatment (HR, 5.25; 1.88-14.72). CONCLUSIONS AND RELEVANCE: To our knowledge, the findings of the present study provide the first evidence that the risk of unintentional overdose injury is related to the prescribed opioid's duration of action. If replicated in other cohorts, our findings suggest that clinicians weighing the benefits and risks of initiating different opioid regimens should consider not only the daily dose prescribed but also the duration of opioid action, favoring short-acting agents whenever possible, especially during the first 2 weeks of therapy. PMID- 25686209 TI - Multiphase chemical kinetics of OH radical uptake by molecular organic markers of biomass burning aerosols: humidity and temperature dependence, surface reaction, and bulk diffusion. AB - Multiphase reactions of OH radicals are among the most important pathways of chemical aging of organic aerosols in the atmosphere. Reactive uptake of OH by organic compounds has been observed in a number of studies, but the kinetics of mass transport and chemical reaction are still not fully understood. Here we apply the kinetic multilayer model of gas-particle interactions (KM-GAP) to experimental data from OH exposure studies of levoglucosan and abietic acid, which serve as surrogates and molecular markers of biomass burning aerosol (BBA). The model accounts for gas-phase diffusion within a cylindrical coated-wall flow tube, reversible adsorption of OH, surface-bulk exchange, bulk diffusion, and chemical reactions at the surface and in the bulk of the condensed phase. The nonlinear dependence of OH uptake coefficients on reactant concentrations and time can be reproduced by KM-GAP. We find that the bulk diffusion coefficient of the organic molecules is approximately 10(-16) cm(2) s(-1), reflecting an amorphous semisolid state of the organic substrates. The OH uptake is governed by reaction at or near the surface and can be kinetically limited by surface-bulk exchange or bulk diffusion of the organic reactants. Estimates of the chemical half-life of levoglucosan in 200 nm particles in a biomass burning plume increase from 1 day at high relative humidity to 1 week under dry conditions. In BBA particles transported to the free troposphere, the chemical half-life of levoglucosan can exceed 1 month due to slow bulk diffusion in a glassy matrix at low temperature. PMID- 25686210 TI - gammadelta T Cell Immunotherapy-A Review. AB - Cancer immunotherapy utilizing Vgamma9Vdelta2 T cells has been developed over the past decade. A large number of clinical trials have been conducted on various types of solid tumors as well as hematological malignancies. Vgamma9Vdelta2 T cell-based immunotherapy can be classified into two categories based on the methods of activation and expansion of these cells. Although the in vivo expansion of Vgamma9Vdelta2 T cells by phosphoantigens or nitrogen-containing bisphosphonates (N-bis) has been translated to early-phase clinical trials, in which the safety of the treatment was confirmed, problems such as activation induced Vgamma9Vdelta2 T cell anergy and a decrease in the number of peripheral blood Vgamma9Vdelta2 T cells after infusion of these stimulants have not yet been solved. In addition, it is difficult to ex vivo expand Vgamma9Vdelta2 T cells from advanced cancer patients with decreased initial numbers of peripheral blood Vgamma9Vdelta2 T cells. In this article, we review the clinical studies and reports targeting Vgamma9Vdelta2 T cells and discuss the development and improvement of Vgamma9Vdelta2 T cell-based cancer immunotherapy. PMID- 25686211 TI - Hydroxymethyl radical self-recombination in high-temperature water. AB - The self-recombination reaction of (*)CH2OH radicals in neutral aqueous solution has been studied at temperatures up to 300 degrees C at a pressure of 220 bar using pulse radiolysis and transient absorption. (*)CH2OH species decay by second order kinetics independent of the applied dose, with a rate constant at 22 degrees C of 2k = 1.4 +/- 0.1 * 10(9) M(-1) s(-1). The recombination follows Arrhenius behavior with the activation energy (E(a)) 12.7 +/- 0.9 kJ/mol and pre exponential factor of 1.9 +/- 0.4 * 10(11) M(-1) s(-1). The overall recombination is significantly slower than the diffusion limit at elevated temperature, meaning that both disproportionation and dimerization channels have significant activation barriers. Ab initio calculations support the inference that the dimerization channel has no energy barrier, but has a large negative activation entropy barrier. The disproportionation channel (giving aqueous formaldehyde) almost certainly involves one or more specific water molecules to lower its activation energy relative to the gas phase. PMID- 25686212 TI - Effects of repetitive transcranial magnetic stimulation on motor symptoms in Parkinson disease: a systematic review and meta-analysis. AB - IMPORTANCE: Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive neuromodulation technique that has been closely examined as a possible treatment for Parkinson disease (PD). However, results evaluating the effectiveness of rTMS in PD are mixed, mostly owing to low statistical power or variety in individual rTMS protocols. OBJECTIVES: To determine the rTMS effects on motor dysfunction in patients with PD and to examine potential factors that modulate the rTMS effects. DATA SOURCES: Databases searched included PubMed, EMBASE, Web of Knowledge, Scopus, and the Cochrane Library from inception to June 30, 2014. STUDY SELECTION: Eligible studies included sham-controlled, randomized clinical trials of rTMS intervention for motor dysfunction in patients with PD. DATA EXTRACTION AND SYNTHESIS: Relevant measures were extracted independently by 2 investigators. Standardized mean differences (SMDs) were calculated with random-effects models. MAIN OUTCOMES AND MEASURES: Motor examination of the Unified Parkinson's Disease Rating Scale. RESULTS: Twenty studies with a total of 470 patients were included. Random-effects analysis revealed a pooled SMD of 0.46 (95% CI, 0.29-0.64), indicating an overall medium effect size favoring active rTMS over sham rTMS in the reduction of motor symptoms (P<.001). Subgroup analysis showed that the effect sizes estimated from high-frequency rTMS targeting the primary motor cortex (SMD, 0.77; 95% CI, 0.46-1.08; P<.001) and low-frequency rTMS applied over other frontal regions (SMD, 0.50; 95% CI, 0.13-0.87; P=.008) were significant. The effect sizes obtained from the other 2 combinations of rTMS frequency and rTMS site (ie, high-frequency rTMS at other frontal regions: SMD, 0.23; 95% CI, 0.02 to 0.48, and low primary motor cortex: SMD, 0.28; 95% CI, -0.23 to 0.78) were not significant. Meta-regression revealed that a greater number of pulses per session or across sessions is associated with larger rTMS effects. Using the Grading of Recommendations, Assessment, Development, and Evaluation criteria, we characterized the quality of evidence presented in this meta-analysis as moderate quality. CONCLUSIONS AND RELEVANCE: The pooled evidence suggests that rTMS improves motor symptoms for patients with PD. Combinations of rTMS site and frequency as well as the number of rTMS pulses are key modulators of rTMS effects. The findings of our meta-analysis may guide treatment decisions and inform future research. PMID- 25686213 TI - Lentivirus-mediated inhibition of tumour necrosis factor-alpha improves motor function associated with PRDX6 in spinal cord contusion rats. AB - The recovery of motor function in rats is inhibited following contusion spinal cord injury (cSCI). However, the mechanism of tumour necrosis factor alpha (TNF alpha) in motor function after cSCI associated with peroxiredoxin 6 (PRDX6) remains unknown. We randomly divided rats into four groups: sham, cSCI, vector and lentivirus mediating TNF-alpha RNA interference (TNF-alpha-RNAi-LV) group. The Basso, Beattie, Bresnahan (BBB) scale was used to evaluate motor function. Real-time quantitative PCR (qRT-PCR) and western blotting were used to detect the expression of TNF-alpha and PRDX6, which were located in neurons using immunohistochemistry (IHC) and immunofluorescence. Subsequently, lentiviral mediated TNF-alpha was used to determine the role of TNF-alphaand the relationship of PRDX6 and TNF-alpha in cSCI. After cSCI, the motor capability of hind limbs disappeared and was followed by recovery of function. IHC analysis indicated that TNF-alpha and PRDX6 were primarily located in spinal cord neurons. TNF-alpha interference significantly improved neural behaviour and increased expression of PRDX6. Our study suggests that inhibition of TNF-alpha can promote the recovery of motor function. The underlying mechanism of TNF-alpha-promoted motor function may be connected with the up-regulation of PRDX6. This provides a new strategy or target for the clinical treatment of SCI in future. PMID- 25686214 TI - First report of a mixed infection of Trichinella nelsoni and Trichinella T8 in a leopard (Panthera pardus) from the Greater Kruger National Park, South Africa. AB - At least three Trichinella species, namely Trichinella nelsoni, Trichinella britovi and Trichinella zimbabwensis, and one genotype (Trichinella T8), have been isolated from sylvatic carnivores on the African continent. With the exception of T. britovi, the other species are known to circulate in wildlife of the Kruger National Park (KNP), South Africa, and KNP neighbouring game reserves (collectively known as the greater KNP area). Lions (Panthera leo) and spotted hyenas (Crocuta crocuta) appear to be the most important reservoirs of T. nelsoni and Trichinella T8 in the KNP and surrounding areas. Interspecies predation between lions and hyenas has been implicated as a primary mode of maintaining the life cycles of these two Trichinella species. This is the first report of a mixed natural infection of T. nelsoni and Trichinella T8 in a leopard (Panthera pardus) from South Africa. Trichinella muscle larvae were identified to species level by multiplex polymerase chain reaction (PCR). Probable sources of infection, based on the known dietary preference and prey species' range of leopards, are also discussed. The described occurrence of Trichinella species in a leopard from the greater KNP area raises the question of possible sources of infection for this predator species. PMID- 25686215 TI - Injury prevention by medication among children with attention deficit/hyperactivity disorder: a case-only study. AB - IMPORTANCE: Children and adolescents with attention-deficit/hyperactivity disorder (ADHD) have an increased risk of injuries. Attention deficit/hyperactivity disorder is often treated with medication, but the evidence regarding prevention of injuries is inconclusive. OBJECTIVE: To determine via a case-only design whether the use of methylphenidate hydrochloride or atomoxetine hydrochloride reduces the risk of injuries among children and adolescents with ADHD. DESIGN, SETTING, AND PARTICIPANTS: We used the German Pharmacoepidemiological Research Database, which includes records from about 17 million insurees (approximately 20% of the population) from 4 statutory health insurance providers in Germany to identify children aged 3 to 17 years with new diagnoses of ADHD in 2005 and 2006. We identified 37,650 children with ADHD based on inpatient and outpatientdiagnostic codes (F90.0, F90.1, and F90.9) from the German modification of the International Statistical Classification of Diseases and Related Health Problems, 10th Revision. Among them, we identified those with an inpatient injury diagnosis during follow-up until 2009. A total of 2128 children with any injury diagnosis at hospitalization, 821 of whom had a brain injury diagnosis, were included in the analysis. We applied the self-controlled case series design to control for time-invariant characteristics of the patients and time trends in the exposure. EXPOSURES: Treatment with methylphenidate or atomoxetine based on prescription data. MAIN OUTCOMES AND MEASURES: Hospitalization because of any injury or brain injury according to the injury mortality diagnosis matrix. RESULTS: Incidence rate ratios for the periods with medication compared with nonmedicated periods were 0.87 (95% CI, 0.74-1.02) for hospitalization with any injuries and 0.66 (95% CI, 0.48-0.91) for brain injuries only in the full sample. These estimates remained stable in sensitivity analyses restricting the sample to a narrower age range or to patients with a single hospitalization. There was no indication that medication prescriptions are increased after hospitalizations. CONCLUSIONS AND RELEVANCE: No significant risk reduction for hospitalizations with injury diagnoses was observed during periods of ADHD medication, but there was a preventive effect on the risk of brain injuries (34% risk reduction). The effects were controlled for time-invariant characteristics of the patients by the study design. PMID- 25686216 TI - Canine multi-drug resistance-1 mutation prevalence: A South African perspective. AB - The multi-drug resistance (mdr-1) gene mutation is a phenomenon well known to current veterinary practitioners. The mutation causes a predisposition for, amongst other phenomena, macrocyclic lactone-induced neurotoxicosis in affected canines, a condition that can be fatal. Various herding dog breeds can be heterozygous or homozygous for the mutation, and prevalence differs only slightly in dog populations between geographical regions. This report provides prevalence data of the canine mdr-1 mutation in 306 South African dogs. PMID- 25686217 TI - Automatic enumeration of gold nanomaterials at the single-particle level. AB - In this study, we developed a highly sensitive automatic counting method for gold nanomaterials at the single particle level, which can serve as a general sensing platform based on counting of gold nanomaterials. This method substantially improved the sensitivity and accuracy for AuNP counting by adopting the color image processing based on the distinctive localized plasmonic light-scattering of gold nanomaterials. The 60-nm AuNPs, with concentrations down to 4 fM, can be detected with our method. As a universal counting approach for gold nanomaterials, such as gold nanospheres, nanorods, and aggregates from particles under detectable size, this quantification method should be versatile to a breadth of applications. PMID- 25686218 TI - Different types of theta rhythmicity are induced by social and fearful stimuli in a network associated with social memory. AB - Rhythmic activity in the theta range is thought to promote neuronal communication between brain regions. In this study, we performed chronic telemetric recordings in socially behaving rats to monitor electrophysiological activity in limbic brain regions linked to social behavior. Social encounters were associated with increased rhythmicity in the high theta range (7-10 Hz) that was proportional to the stimulus degree of novelty. This modulation of theta rhythmicity, which was specific for social stimuli, appeared to reflect a brain-state of social arousal. In contrast, the same network responded to a fearful stimulus by enhancement of rhythmicity in the low theta range (3-7 Hz). Moreover, theta rhythmicity showed different pattern of coherence between the distinct brain regions in response to social and fearful stimuli. We suggest that the two types of stimuli induce distinct arousal states that elicit different patterns of theta rhythmicity, which cause the same brain areas to communicate in different modes. PMID- 25686219 TI - Inhibition of mutant EGFR in lung cancer cells triggers SOX2-FOXO6-dependent survival pathways. AB - Treatment of EGFR-mutant lung cancer with erlotinib results in dramatic tumor regression but it is invariably followed by drug resistance. In characterizing early transcriptional changes following drug treatment of mutant EGFR-addicted cells, we identified the stem cell transcriptional regulator SOX2 as being rapidly and specifically induced, both in vitro and in vivo. Suppression of SOX2 sensitizes cells to erlotinib-mediated apoptosis, ultimately decreasing the emergence of acquired resistance, whereas its ectopic expression reduces drug induced cell death. We show that erlotinib relieves EGFR-dependent suppression of FOXO6, leading to its induction of SOX2, which in turn represses the pro apoptotic BH3-only genes BIM and BMF. Together, these observations point to a physiological feedback mechanism that attenuates oncogene addiction-mediated cell death associated with the withdrawal of growth factor signaling and may therefore contribute to the development of resistance. PMID- 25686220 TI - Haemangiosarcoma of the os penis in a dog: The most common neoplasm of the canine penis. AB - A castrated 9-year-old intact male boerboel cross-breed dog was presented with a month-long history of stranguria. On physical examination, a mass was noted at the caudal extremity of the os penis. Haematology, serum chemistry and urinalysis were all unremarkable. Abdominal and urethral ultrasound demonstrated an enlarged bladder and a dilated urethra, which was followed to the caudal extremity of the os penis. A hyperechoic, roughly spherical,vascularised mass was noted at the caudal os penis, which resulted in obstruction of the penile urethra. Radiographs demonstrated a soft tissue mass with osteolysis of the os penis. Cytology suggested an osteosarcoma. Treatment included amputation of the penis and adjuvant doxorubicin with carboplatin. Histopathology of the penis confirmed a haemangiosarcoma. The patient survived for 20 months. This is only the second published case report describing a penile haemangiosarcoma, and the first published report demonstrating the treatment and outcome of a case of haemangiosarcoma of the os penis. Based on published and unpublished reports, haemangiosarcoma appears to be the most common neoplasm of the canine penis. PMID- 25686221 TI - Colorimetric determination of fructose for the high-throughput microtiter plate assay of glucose isomerase. AB - A colorimetric method for the reducing monosaccharide determination is optimized for the assay of glucose isomerase, which converts glucose (Glc) to fructose (Fru). Test solution was mixed with 20-fold volume of the 50 mM Na2SiO3, 600 mM Na2MoO4, and 0.95 M HCl aqueous solution (pH 4.5), in which a yellow molybdosilicate species was formed. The mixture was kept at 70 degrees C for 30 min. Test solution containing 10 mM level Fru gave a remarkable blue reaction mixture, in which the Mo(VI) species was reduced by Fru to form a blue molybdosilicate species. The blueness increased with the Fru concentration. Glc cannot render the reaction mixture blue as strong as Fru. Thus, the colorimetric method can be used advantageously for the determination of 10 mM level Fru in the Glc isomerase reaction mixture, even in the presence of 100 mM level Glc, and has been applied successfully to the microtiter plate assay of the enzyme. PMID- 25686222 TI - Fusarium species isolated from Pennisetum clandestinum collected during outbreaks of kikuyu poisoning in cattle in South Africa. AB - Kikuyu poisoning occurs sporadically in South Africa. It is of major economic importance, as valuable dairy cows are often poisoned by it, and once affected, the mortality rate is high. Pennisetum clandestinum samples were collected during eight outbreaks of kikuyu poisoning in cattle in the Eastern Cape Province of South Africa from 2008 to 2010. The kikuyu grass samples were submitted specifically for the isolation and molecular identification of Fusarium species, as it was recently suggested that mycotoxins synthesised by Fusarium torulosum could be the cause of this intoxication. Ninety-four Fusarium isolates were retrieved from the grass samples, of which 72 were members of the Fusarium incarnatum/Fusarium equiseti species complex based on morphology and phylogenetic analyses of the translation elongation factor 1alpha sequence data. The South African isolates from kikuyu identified as members of the F. incarnatum/F. equiseti species complex grouped together in six separate clades. The other isolates were Fusarium culmorum (n = 3), Fusarium redolens (n = 4) and Fusarium oxysporum (n = 15). Although F. torulosum could not be isolated from P. clandestinum collected during kikuyu poisoning outbreaks in South Africa, the mycotoxicosis theory is still highly plausible. PMID- 25686243 TI - Fish oil ameliorates trimethylamine N-oxide-exacerbated glucose intolerance in high-fat diet-fed mice. AB - Trimethylamine N-oxide (TMAO), a component commonly present in seafood, has been found to have a harmful impact on glucose tolerance in high-fat diet (HFD)-fed mice. However, seafood also contains fish oil (FO), which has been shown to have beneficial effects on metabolism. Here, we investigated the effect of FO on TMAO induced impaired glucose tolerance in HFD-fed mice. Male C57BL/6 mice were randomly assigned to the high fat (HF), TMAO, and fish oil groups. The HF group was fed a diet containing 25% fat, the TMAO group was fed the HFD plus 0.2% TMAO, and the FO group was fed the HFD plus 0.2% TMAO and 2% fish oil for 12 weeks. After 10 weeks of feeding, oral glucose tolerance tests were performed. Dietary FO improved the fasting glucose level, the fasting insulin level, HOMA-IR value, QUICKI score and ameliorated TMAO-induced exacerbated impaired glucose tolerance in HFD-fed mice. These effects were associated with the expression of genes related to the insulin signalling pathway, glycogen synthesis, gluconeogenesis, and glucose transport in peripheral tissues. Dietary fish oil also decreased TMAO aggravated adipose tissue inflammation. Our results suggested that dietary FO ameliorated TMAO-induced impaired glucose tolerance, insulin signal transduction in peripheral tissue, and adipose tissue inflammation in HFD-fed mice. PMID- 25686244 TI - Illuminating the molecular mechanisms of tyrosine kinase inhibitor resistance for the FGFR1 gatekeeper mutation: the Achilles' heel of targeted therapy. AB - Human fibroblast growth factor receptors (FGFRs) 1-4 are a family of receptor tyrosine kinases that can serve as drivers of tumorigenesis. In particular, FGFR1 gene amplification has been implicated in squamous cell lung and breast cancers. Tyrosine kinase inhibitors (TKIs) targeting FGFR1, including AZD4547 and E3810 (Lucitanib), are currently in early phase clinical trials. Unfortunately, drug resistance limits the long-term success of TKIs, with mutations at the "gatekeeper" residue leading to tumor progression. Here we show the first structural and kinetic characterization of the FGFR1 gatekeeper mutation, V561M FGFR1. The V561M mutation confers a 38-fold increase in autophosphorylation achieved at least in part by a network of interacting residues forming a hydrophobic spine to stabilize the active conformation. Moreover, kinetic assays established that the V561M mutation confers significant resistance to E3810, while retaining affinity for AZD4547. Structural analyses of these TKIs with wild type (WT) and gatekeeper mutant forms of FGFR1 offer clues to developing inhibitors that maintain potency against gatekeeper mutations. We show that AZD4547 affinity is preserved by V561M FGFR1 due to a flexible linker that allows multiple inhibitor binding modes. This is the first example of a TKI binding in distinct conformations to WT and gatekeeper mutant forms of FGFR, highlighting adaptable regions in both the inhibitor and binding pocket crucial for drug design. Exploiting inhibitor flexibility to overcome drug resistance has been a successful strategy for combatting diseases such as AIDS and may be an important approach for designing inhibitors effective against kinase gatekeeper mutations. PMID- 25686245 TI - New era in gene therapy: end of the beginning. PMID- 25686247 TI - Lead toxicity induces autophagy to protect against cell death through mTORC1 pathway in cardiofibroblasts. AB - Heavy metals, such as lead (Pb(2+)), are usually accumulated in human bodies and impair human's health. Lead is a metal with many recognized adverse health side effects and yet the molecular processes underlying lead toxicity are still poorly understood. In the present study, we proposed to investigate the effects of lead toxicity in cultured cardiofibroblasts. After lead treatment, cultured cardiofibroblasts showed severe endoplasmic reticulum (ER) stress. However, the lead-treated cardiofibroblasts were not dramatically apoptotic. Further, we found that these cells determined to undergo autophagy through inhibiting mammalian target of rapamycin complex 1 (mTORC1) pathway. Moreover, inhibition of autophagy by 3-methyladenine (3-MA) may dramatically enhance lead toxicity in cardiofibroblasts and cause cell death. Our data establish that lead toxicity induces cell stress in cardiofibroblasts and protective autophagy is activated by inhibition of mTORC1 pathway. These findings describe a mechanism by which lead toxicity may promote the autophagy of cardiofibroblasts cells, which protects cells from cell stress. Our findings provide evidence that autophagy may help cells to survive under ER stress conditions in cardiofibroblasts and may set up an effective therapeutic strategy for heavy metal toxicity. PMID- 25686248 TI - Huntingtin functions as a scaffold for selective macroautophagy. AB - Selective macroautophagy is an important protective mechanism against diverse cellular stresses. In contrast to the well-characterized starvation-induced autophagy, the regulation of selective autophagy is largely unknown. Here, we demonstrate that Huntingtin, the Huntington disease gene product, functions as a scaffold protein for selective macroautophagy but it is dispensable for non selective macroautophagy. In Drosophila, Huntingtin genetically interacts with autophagy pathway components. In mammalian cells, Huntingtin physically interacts with the autophagy cargo receptor p62 to facilitate its association with the integral autophagosome component LC3 and with Lys-63-linked ubiquitin-modified substrates. Maximal activation of selective autophagy during stress is attained by the ability of Huntingtin to bind ULK1, a kinase that initiates autophagy, which releases ULK1 from negative regulation by mTOR. Our data uncover an important physiological function of Huntingtin and provide a missing link in the activation of selective macroautophagy in metazoans. PMID- 25686249 TI - ATG12-ATG3 interacts with Alix to promote basal autophagic flux and late endosome function. AB - The ubiquitin-like molecule ATG12 is required for the early steps of autophagy. Recently, we identified ATG3, the E2-like enzyme required for LC3 lipidation during autophagy, as an ATG12 conjugation target. Here, we demonstrate that cells lacking ATG12-ATG3 have impaired basal autophagic flux, accumulation of perinuclear late endosomes, and impaired endolysosomal trafficking. Furthermore, we identify an interaction between ATG12-ATG3 and the ESCRT-associated protein Alix (also known as PDCD6IP) and demonstrate that ATG12-ATG3 controls multiple Alix-dependent processes including late endosome distribution, exosome biogenesis and viral budding. Similar to ATG12-ATG3, Alix is functionally required for efficient basal, but not starvation-induced, autophagy. Overall, these results identify a link between the core autophagy and ESCRT machineries and uncover a role for ATG12-ATG3 in late endosome function that is distinct from the canonical role of either ATG in autophagosome formation. PMID- 25686252 TI - Seroprevalence of Rift Valley fever and lumpy skin disease in African buffalo (Syncerus caffer) in the Kruger National Park and Hluhluwe-iMfolozi Park, South Africa. AB - Rift Valley fever and lumpy skin disease are transboundary viral diseases endemic in Africa and some parts of the Middle East, but with increasing potential for global emergence. Wild ruminants, such as the African buffalo (Syncerus caffer), are thought to play a role in the epidemiology of these diseases. This study sought to expand the understanding of the role of buffalo in the maintenance of Rift Valley fever virus (RVFV) and lumpy skin disease virus (LSDV) by determining seroprevalence to these viruses during an inter-epidemic period. Buffaloes from the Kruger National Park (n = 138) and Hluhluwe-iMfolozi Park (n = 110) in South Africa were sampled and tested for immunoglobulin G (IgG) and neutralising antibodies against LSDV and RVFV using an indirect enzyme-linked immunosorbent assay (I-ELISA) and the serum neutralisation test (SNT). The I-ELISA for LSDV and RVFV detected IgG antibodies in 70 of 248 (28.2%) and 15 of 248 (6.1%) buffaloes, respectively. Using the SNT, LSDV and RVFV neutralising antibodies were found in 5 of 66 (7.6%) and 12 of 57 (21.1%), respectively, of samples tested. The RVFV I ELISA and SNT results correlated well with previously reported results. Of the 12 SNT RVFV-positive sera, three (25.0%) had very high SNT titres of 1:640. Neutralising antibody titres of more than 1:80 were found in 80.0% of the positive sera tested. The LSDV SNT results did not correlate with results obtained by the I-ELISA and neutralising antibody titres detected were low, with the highest (1:20) recorded in only two buffaloes, whilst 11 buffaloes (4.4%) had evidence of co-infection with both viruses. Results obtained in this study complement other reports suggesting a role for buffaloes in the epidemiology of these diseases during inter-epidemic periods. PMID- 25686253 TI - Enantioselective 6-endo bromoaminocyclization of 2,4-dienyl N-tosylcarbamates catalyzed by a chiral phosphine oxide-Sc(OTf)3 complex. A dramatic additive effect. AB - An effective enantioselective 6-endo bromoaminocyclization of 2,4-dienyl N tosylcarbamates catalyzed by a chiral phosphine oxide-Sc(OTf)3 complex is described. A wide variety of optically active 5-bromo-1,3-oxazinan-2-ones containing various functional groups can be obtained in 61-91% yields and 92-99% ees. An additive, such as NaCl, has been found to be crucial for the reaction process. PMID- 25686250 TI - Early steps in primary cilium assembly require EHD1/EHD3-dependent ciliary vesicle formation. AB - Membrane association with mother centriole (M-centriole) distal appendages is critical for ciliogenesis initiation. How the Rab GTPase Rab11-Rab8 cascade functions in early ciliary membrane assembly is unknown. Here, we show that the membrane shaping proteins EHD1 and EHD3, in association with the Rab11-Rab8 cascade, function in early ciliogenesis. EHD1 and EHD3 localize to preciliary membranes and the ciliary pocket. EHD-dependent membrane tubulation is essential for ciliary vesicle formation from smaller distal appendage vesicles (DAVs). Importantly, this step functions in M-centriole to basal body transformation and recruitment of transition zone proteins and IFT20. SNAP29, a SNARE membrane fusion regulator and EHD1-binding protein, is also required for DAV-mediated ciliary vesicle assembly. Interestingly, only after ciliary vesicle assembly is Rab8 activated for ciliary growth. Our studies uncover molecular mechanisms informing a previously uncharacterized ciliogenesis step, whereby EHD1 and EHD3 reorganize the M-centriole and associated DAVs before coordinated ciliary membrane and axoneme growth. PMID- 25686251 TI - Reduced adenosine-to-inosine miR-455-5p editing promotes melanoma growth and metastasis. AB - Although recent studies have shown that adenosine-to-inosine (A-to-I) RNA editing occurs in microRNAs (miRNAs), its effects on tumour growth and metastasis are not well understood. We present evidence of CREB-mediated low expression of ADAR1 in metastatic melanoma cell lines and tumour specimens. Re-expression of ADAR1 resulted in the suppression of melanoma growth and metastasis in vivo. Consequently, we identified three miRNAs undergoing A-to-I editing in the weakly metastatic melanoma but not in strongly metastatic cell lines. One of these miRNAs, miR-455-5p, has two A-to-I RNA-editing sites. The biological function of edited miR-455-5p is different from that of the unedited form, as it recognizes a different set of genes. Indeed, wild-type miR-455-5p promotes melanoma metastasis through inhibition of the tumour suppressor gene CPEB1. Moreover, wild-type miR 455 enhances melanoma growth and metastasis in vivo, whereas the edited form inhibits these features. These results demonstrate a previously unrecognized role for RNA editing in melanoma progression. PMID- 25686254 TI - Influence of non-preferred foot technical training in reducing lower limbs functional asymmetry among young football players. AB - The functional asymmetry of the lower limbs has been regarded as a relevant factor of the performance of football players. We purposed to ascertain whether a specific technical training programme for the non-preferred foot has implications in the increasing utilisation rate of the respective member during the game. Young football players (n = 71) were randomly divided into experimental group (N = 35; 14.37 +/- 1.94 years) and control group (N = 36; 14.50 +/- 1.81 years). The study was developed into three stages: first, assessment of the index utilisation of both limbs during the game; second, application of a technical training programme that includes the drilling of specific motor skills exclusively directed to the non-preferred foot; and third, assessment of the new rate of both limbs' utilisation after the predefined six months. The main findings were: (1) the use of the non-preferred foot increased significantly with the technical training programme in the experimental group and remained constant in the control group; (2) the use of the preferred foot decreased significantly in the experimental group and remained similar in control group. We concluded that a systematic and specific technical training for the non-preferred foot increases its use and reduces functional asymmetry in game situation, consequently improving the player's performance. PMID- 25686255 TI - Polymerase chain reaction-based discrimination of viable from non-viable Mycoplasma gallisepticum. AB - The present study was based on the reverse transcription polymerase chain reaction (RT-PCR) of the 16S ribosomal nucleic acid (rRNA) of Mycoplasma for detection of viable Mycoplasma gallisepticum. To determine the stability of M. gallisepticum 16S rRNA in vitro, three inactivation methods were used and the suspensions were stored at different temperatures. The 16S rRNA of M. gallisepticum was detected up to approximately 20-25 h at 37 degrees C, 22-25 h at 16 degrees C, and 23-27 h at 4 degrees C. The test, therefore, could detect viable or recently dead M. gallisepticum (< 20 h). The RT-PCR method was applied during an in vivo study of drug efficacy under experimental conditions, where commercial broiler-breeder eggs were inoculated with M. gallisepticum into the yolk. Hatched chicks that had been inoculated in ovo were treated with Macrolide 1. The method was then applied in a flock of day 0 chicks with naturally acquired vertical transmission of M. gallisepticum, treated with Macrolide 2. Swabs of the respiratory tract were obtained for PCR and RT-PCR evaluations to determine the viability of M. gallisepticum. This study proved that the combination of both PCR and RT-PCR enables detection and differentiation of viable from non-viable M. gallisepticum. PMID- 25686256 TI - Direct observation of the solvent effects on the low-lying npi* and pipi* excited triplet states of acetophenone derivatives in thermal equilibrium. AB - Low-lying excited triplet states of aromatic carbonyl compounds exhibit diverse photophysical and photochemical properties of fundamental importance. Despite tremendous effort in studying those triplet states, the effects of substituents and solvents on the energetics of the triplet manifold and on photoreactivity remain to be fully understood. We have recently studied the ordering of the low lying npi* and pipi* excited triplet states and its substituent dependence in acetophenone derivatives using nanosecond time-resolved near-IR (NIR) spectroscopy. Here we address the other important issue, the solvent effects, by directly observing the electronic bands in the NIR that originate from the lowest npi* and pipi* states of acetophenone derivatives in four solvents of different polarity (n-heptane, benzene, acetonitrile, and methanol). The two transient NIR bands decay synchronously in all the solvents, indicating that the lowest npi* and pipi* states are in thermal equilibrium irrespective of the solvent polarity studied here. We found that the pipi* band increases in intensity relative to the npi* band as solvent polarity increases. These results are compared with the photoreduction rate constant for the acetophenone derivatives in the solvents to which 2-propanol was added as a hydrogen-atom donor. Based on the present findings, we present a comprehensive, solvent- and substituent-dependent energy level diagram of the low-lying npi* and pipi* excited triplet states. PMID- 25686258 TI - Judging the reality of others' memories. AB - Interpersonal reality monitoring (IRM) refers to our ability to evaluate whether other people's memories reflect real or imagined events. The current work examined IRM and whether or not it can be affected by training and feedback. We found that people are better than chance and that the ability to accurately make this judgement can be improved or reduced with appropriate and inappropriate training, respectively. Understanding IRM has implications for applied psychologists interested in how people evaluate others' descriptions of past events (e.g., eyewitness testimony). PMID- 25686259 TI - The creation of a measurable contusion injury in skeletal muscle. AB - The effect that compressed air massage (CAM) has on skeletal muscle has been ascertained by the morphological and morphometric evaluation of healthy vervet monkey and rabbit skeletal muscle. How CAM may influence the process of healing following a contusion injury is not known. To determine how CAM or other physiotherapeutic modalities may influence healing, it is necessary to create a minor injury that is both reproducible and quantifiable at the termination of a pre-determined healing period. An earlier study described changes in the morphology of skeletal muscle following a reproducible contusion injury. This study extended that work in that it attempted to quantify the 'severity' of such an injury. A 201 g, elongated oval-shaped weight was dropped seven times through a 1 m tube onto the left vastus lateralis muscle of four New Zealand white rabbits. Biopsies were obtained 6 days after injury from the left healing juxta bone and sub-dermal muscle and uninjured (control) right vastus lateralis of each animal. The tissue was fixed in formal saline, embedded in wax, cut and stained with haematoxylin and phosphotungstic haematoxylin. The muscle was examined by light microscopy and quantification of the severity of injury made using a modified, 'in-house' morphological index and by the comparative morphometric measurement of the cross-sectioned epimysium and myofibres in injured and control muscle. The results showed that a single contusion causes multiple, quantifiable degrees of injury from skin to bone - observations of particular importance to others wishing to investigate contusion injury in human or animal models. PMID- 25686260 TI - Pathology of fatal lineage 1 and 2 West Nile virus infections in horses in South Africa. AB - Since 2007, West Nile virus (WNV) has been reported in South African horses, causing severe neurological signs. All cases were of lineage 2, except for one case that clustered with lineage 1 viruses. In the present study, gross and microscopic lesions of six South African lineage 2-infected horses and the one lineage 1 case are described. Diagnoses were confirmed by real-time reverse transcriptase polymerase chain reaction (RT-PCR) of central nervous system (CNS) tissue and one by RT-PCR of a brain virus isolate. The CNS of all cases was negative by RT-PCR or immunohistochemistry (IHC) for African horse sickness (AHS), equine encephalosis virus, equine herpes viruses 1 and 4, other zoonotic flaviviruses, alphaviruses, and shunivirus, and either by immunofluorescence or IHC for rabies. Gross visceral lesions were nonspecific but often mimicked those of AHS. The CNS histopathology of WNV lineage 2 cases resembled the nonsuppurative polioencephalomyelitis reported in the Northern Hemisphere lineage 1 and recent Hungarian lineage 2 cases. Occasional meningitis, focal spinal ventral horn poliomalacia, dorsal and lateral horn poliomyelitis, leucomyelitis, asymmetrical ventral motor spinal neuritis and frequent olfactory region involvement were also seen. Lineage 2 cases displayed marked variations in CNS lesion severity, type and distribution, and suggested various viral entry routes into the CNS, based on findings in experimental mice and hamsters. Lineage 1 lesions were comparable to the milder lineage 2 cases. West Nile virus IHC on CNS sections with marked lesions from all cases elicited only two antigen-positive cells in the olfactory cortex of one case. The presence in the CNS of T lymphocytes, B-lymphocytes, plasma cells and macrophage-monocytes was confirmed by cluster of differentiation (CD) 3, CD20, multiple myeloma oncogene 1 (MUM1) and macrophage (MAC) 387 IHC. PMID- 25686261 TI - Dirac mass generation from crystal symmetry breaking on the surfaces of topological crystalline insulators. AB - The tunability of topological surface states and controllable opening of the Dirac gap are of fundamental and practical interest in the field of topological materials. In the newly discovered topological crystalline insulators (TCIs), theory predicts that the Dirac node is protected by a crystalline symmetry and that the surface state electrons can acquire a mass if this symmetry is broken. Recent studies have detected signatures of a spontaneously generated Dirac gap in TCIs; however, the mechanism of mass formation remains elusive. In this work, we present scanning tunnelling microscopy (STM) measurements of the TCI Pb1-xSnxSe for a wide range of alloy compositions spanning the topological and non topological regimes. The STM topographies reveal a symmetry-breaking distortion on the surface, which imparts mass to the otherwise massless Dirac electrons-a mechanism analogous to the long sought-after Higgs mechanism in particle physics. Interestingly, the measured Dirac gap decreases on approaching the trivial phase, whereas the magnitude of the distortion remains nearly constant. Our data and calculations reveal that the penetration depth of Dirac surface states controls the magnitude of the Dirac mass. At the limit of the critical composition, the penetration depth is predicted to go to infinity, resulting in zero mass, consistent with our measurements. Finally, we discover the existence of surface states in the non-topological regime, which have the characteristics of gapped, double-branched Dirac fermions and could be exploited in realizing superconductivity in these materials. PMID- 25686262 TI - Topological insulators: Topology and structural distortions. PMID- 25686263 TI - Binding configurations and intramolecular strain in single-molecule devices. AB - The development of molecular-scale electronic devices has made considerable progress over the past decade, and single-molecule transistors, diodes and wires have all been demonstrated. Despite this remarkable progress, the agreement between theoretically predicted conductance values and those measured experimentally remains limited. One of the primary reasons for these discrepancies lies in the difficulty to experimentally determine the contact geometry and binding configuration of a single-molecule junction. In this Article, we apply a small-amplitude, high-frequency, sinusoidal mechanical signal to a series of single-molecule devices during junction formation and breakdown. By measuring the current response at this frequency, it is possible to determine the most probable binding and contact configurations for the molecular junction at room temperature in solution, and to obtain information about how an applied strain is distributed within the molecular junction. These results provide insight into the complex configuration of single-molecule devices, and are in excellent agreement with previous predictions from theoretical models. PMID- 25686264 TI - Dysprosium-doped cadmium oxide as a gateway material for mid-infrared plasmonics. AB - The interest in plasmonic technologies surrounds many emergent optoelectronic applications, such as plasmon lasers, transistors, sensors and information storage. Although plasmonic materials for ultraviolet-visible and near-infrared wavelengths have been found, the mid-infrared range remains a challenge to address: few known systems can achieve subwavelength optical confinement with low loss in this range. With a combination of experiments and ab initio modelling, here we demonstrate an extreme peak of electron mobility in Dy-doped CdO that is achieved through accurate 'defect equilibrium engineering'. In so doing, we create a tunable plasmon host that satisfies the criteria for mid-infrared spectrum plasmonics, and overcomes the losses seen in conventional plasmonic materials. In particular, extrinsic doping pins the CdO Fermi level above the conduction band minimum and it increases the formation energy of native oxygen vacancies, thus reducing their populations by several orders of magnitude. The substitutional lattice strain induced by Dy doping is sufficiently small, allowing mobility values around 500 cm(2) V(-1) s(-1) for carrier densities above 10(20) cm(-3). Our work shows that CdO:Dy is a model system for intrinsic and extrinsic manipulation of defects affecting electrical, optical and thermal properties, that oxide conductors are ideal candidates for plasmonic devices and that the defect engineering approach for property optimization is generally applicable to other conducting metal oxides. PMID- 25686265 TI - Molecular junctions: Single-molecule contacts exposed. PMID- 25686266 TI - Copper nanoparticle (CuNP) nanochain arrays with a reduced toxicity response: a biophysical and biochemical outlook on Vigna radiata. AB - Copper deficiency or toxicity in agricultural soil circumscribes a plant's growth and physiology, hampering photochemical and biochemical networks within the system. So far, copper sulfate (CS) has been used widely despite its toxic effect. To get around this long-standing problem, copper nanoparticles (CuNPs) have been synthesized, characterized, and tested on mung bean plants along with commercially available salt CS, to observe morphological abnormalities enforced if any. CuNPs enhanced photosynthetic activity by modulating fluorescence emission, photophosphorylation, electron transport chain (ETC), and carbon assimilatory pathway under controlled laboratory conditions, as revealed from biochemical and biophysical studies on treated isolated mung bean chloroplast. CuNPs at the recommended dose worked better than CS in plants in terms of basic morphology, pigment contents, and antioxidative activities. CuNPs showed elevated nitrogen assimilation compared to CS. At higher doses CS was found to be toxic to the plant system, whereas CuNP did not impart any toxicity to the system including morphological and/or physiological alterations. This newly synthesized polymer-encapsulated CuNPs can be utilized as nutritional amendment to balance the nutritional disparity enforced by copper imbalance. PMID- 25686267 TI - Stem cell mobilizers targeting chemokine receptor CXCR4: renoprotective application in acute kidney injury. AB - We have discovered a novel series of quinazoline-based CXCR4 antagonists. Of these, compound 19 mobilized CXCR4(+) cell types, including hematopoietic stem cells and endothelial progenitor cells, more efficiently than the marketed 1 (AMD3100) with subcutaneous administration at the same dose (6 mg/kg) in mice. This series of compounds thus provides a set of valuable tools to study diseases mediated by the CXCR4/SDF-1 axis, including myocardial infarction, ischemic stroke, and cancer metastasis. More importantly, treatment with compound 19 significantly lowered levels of blood urea nitrogen and serum creatinine in rats with renal ischemia-reperfusion injury, providing evidence for its therapeutic potential in preventing ischemic acute kidney injury. CXCR4 antagonists such as 19 might also be useful to increase circulating levels of adult stem cells, thereby exerting beneficial effects on damaged and/or inflamed tissues in diseases that currently are not treated by standard approaches. PMID- 25686268 TI - Global analysis of Salmonella alternative sigma factor E on protein translation. AB - The alternative sigma factor E (sigma(E)) is critical for response to extracytoplasmic stress in Salmonella. Extensive studies have been conducted on sigma(E)-regulated gene expression, particularly at the transcriptional level. Increasing evidence suggests however that sigma(E) may indirectly participate in post-transcriptional regulation. In this study, we conducted sample-matched global proteomic and transcriptomic analyses to determine the level of regulation mediated by sigma(E) in Salmonella. Samples were analyzed from wild-type and isogenic rpoE mutant Salmonella cultivated in three different conditions: nutrient-rich and conditions that mimic early and late intracellular infection. We found that 30% of the observed proteome was regulated by sigma(E) combining all three conditions. In different growth conditions, sigma(E) affected the expression of a broad spectrum of Salmonella proteins required for miscellaneous functions. Those involved in transport and binding, protein synthesis, and stress response were particularly highlighted. By comparing transcriptomic and proteomic data, we identified genes post-transcriptionally regulated by sigma(E) and found that post-transcriptional regulation was responsible for a majority of changes observed in the sigma(E)-regulated proteome. Further, comparison of transcriptomic and proteomic data from hfq mutant of Salmonella demonstrated that sigma(E)-mediated post-transcriptional regulation was partially dependent on the RNA-binding protein Hfq. PMID- 25686269 TI - Vasomotor symptom duration in midlife women--research overturns dogma. PMID- 25686270 TI - Ganoderma lucidum mushroom for the treatment of cardiovascular risk factors. AB - BACKGROUND: Ganoderma lucidum (also known as lingzhi or reishi) is a mushroom that has been consumed for its broad medicinal properties in Asia for over 2000 years. G lucidum is becoming increasingly popular in western countries as a complementary medicine for cardiovascular health. OBJECTIVES: To evaluate the effectiveness of G lucidum for the treatment of pharmacologically modifiable risk factors of cardiovascular disease in adults. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL Issue 6 of 12, 2014) on The Cochrane Library, MEDLINE (OVID, 1946 to June week 3 2014), EMBASE (OVID, 1980 to 2014 week 26), Science Direct (1823 to 2013), Current Controlled Trials (1990 to 2013), Australian New Zealand Clinical Trials Registry (2005 to 2013), Chinese Biomedical Literature Database (2007 to 2013), Chinese Medical Current Contents (2007 to 2013) and other databases. We checked reference lists of included studies, contacted content experts and handsearched The International Journal of Medicinal Mushrooms. We applied no language or publication restrictions. SELECTION CRITERIA: Randomised controlled trials and controlled clinical trials of G lucidum for the treatment of cardiovascular risk factors. Primary outcomes were blood glucose level, blood pressure and lipid profile. DATA COLLECTION AND ANALYSIS: Two authors independently selected trials, assessed risk of bias and cross checked data extraction and analysis. A third author arbitrated in the event of disagreement. MAIN RESULTS: Five trials with a total of 398 participants were eligible for inclusion. Of these, one study was published in Chinese and translated to English; one study was published but study authors provided the additional data used in this review; one study was unpublished and the study authors provided data; and two studies did not provide comparison group data suitable for statistical analyses. The three studies from which data were used for statistical analyses compared G lucidum (1.4 g to 3 g per day) to placebo over 12 to 16 weeks of intervention. Although inclusion criteria varied, all participants of these three studies had type 2 diabetes mellitus. Of the five included studies, risk of bias was low for one study and unclear for the remaining four.Results from two studies showed that G lucidum was not associated with statistically or clinically significant reduction in HbA1c (WMD -0.10%; 95% CI -1.05% to 0.85%; 130 participants), total cholesterol (WMD -0.07mmol/L; 95% CI -0.57 mmol/L to 0.42 mmol/L; 107 participants ), low-density lipoprotein cholesterol (WMD 0.02 mmol/L; 95% CI -0.41 mmol/L to 0.45 mmol/L; 107 participants), or body-mass index (WMD -0.32 kg/m(2); 95% CI -2.67 kg/m(2) to 2.03 kg/m(2;) 107 participants). All other analyses were from a single study of 84 participants. We found no improvement for fasting plasma glucose (WMD 0.30 mmol/L; 95% CI -0.95 mmol/L to 1.55 mmol/L). Measures of post-prandial blood glucose level found inconsistent results, being in favour of placebo for '2-hour post-prandial blood glucose' (WMD 0.7 mmol/L; 95% CI 0.29 mmol/L to 1.11 mmol/L) and in favour of G lucidum for 'plasma glucose under the curve at 4th hour' (WMD 49.4mg/dL/h; 95% CI -77.21 mg/dL/h to -21.59 mg/dL/h). As the Minimal Clinical Important Differences are unknown, the clinical significance of this effect is unclear. There were no statistically significant differences between groups for blood pressure or triglycerides. Participants who took G lucidum for four months were 1.67 times (RR 1.67 95% CI 0.86 to 3.24) more likely to experience an adverse event than those who took placebo but these were not serious side effects. AUTHORS' CONCLUSIONS: Evidence from a small number of randomised controlled trials does not support the use of G lucidum for treatment of cardiovascular risk factors in people with type 2 diabetes mellitus. Future research into the efficacy of G lucidum should be placebo-controlled and adhere to clinical trial reporting standards. PMID- 25686271 TI - Photoactive hybrid material based on pyrene functionalized PbS nanocrystals decorating CVD monolayer graphene. AB - A simple and facile solution-based procedure is implemented for decorating a large area, monolayer graphene film, grown by chemical vapor deposition, with size-tunable light absorbing colloidal PbS nanocrystals (NCs). The hybrid is obtained by exposing a large area graphene film to a solution of 1-pyrene butyric acid surface coated PbS NCs, obtained by a capping exchange procedure onto presynthesized organic-capped NCs. The results demonstrate that at the interface, multiple and cooperative pi-pi stacking interactions promoted by the pyrene ligand coordinating the NC surface lead to a successful anchoring of the nano objects on the graphene platform which concomitantly preserves its aromatic structure. Interligand interactions provide organization of the nano-objects in highly interconnected nanostructured multilayer coatings, where the NCs retain geometry and composition. The resulting hybrid exhibits a sheet resistance lower than that of bare graphene, which is explained in terms of electronic communication in the hybrid, due to the interconnection of the NC film and to a hole transfer from photoexcited PbS NCs to graphene, channelled at the interface by pyrene. Such a direct electron coupling makes the manufactured hybrid material an interesting component for optoelectronics, sensors and for optical communication and information technology. PMID- 25686272 TI - Conformational analysis of the oligosaccharides related to side chains of holothurian fucosylated chondroitin sulfates. AB - Anionic polysaccharides fucosylated chondroitin sulfates (FCS) from holothurian species were shown to affect various biological processes, such as metastasis, angiogenesis, clot formation, thrombosis, inflammation, and some others. To understand the mechanism of FCSs action, knowledge about their spatial arrangement is required. We have started the systematic synthesis, conformational analysis, and study of biological activity of the oligosaccharides related to various fragments of these types of natural polysaccharides. In this communication, five molecules representing distinct structural fragments of chondroitin sulfate have been studied by means of molecular modeling and NMR. These are three disaccharides and two trisaccharides containing fucose and glucuronic acid residues with one sulfate group per each fucose residue or without it. Long-range C-H coupling constants were used for the verification of the theoretical models. The presence of two conformers for both linkage types was revealed. For the Fuc-GlA linkage, the dominant conformer was the same as described previously in a literature as the molecular dynamics (MD) average in a dodechasaccharide FCS fragment representing the backbone chain of the polysaccharide including GalNAc residues. This shows that the studied oligosaccharides, in addition to larger ones, may be considered as reliable models for Quantitative Structure-Activity Relationship (QSAR) studies to reveal pharmacophore fragments of FCS. PMID- 25686273 TI - Design and synthesis of novel xyloketal derivatives and their protective activities against H2O2-induced HUVEC injury. AB - In this work, we designed and synthesized a series of amide derivatives (1-13), benzoxazine derivatives (16-28) and amino derivatives (29-30) from xyloketal B. All 28 new derivatives and seven known compounds (14, 15, 31-35) were evaluated for their protection against H2O2-induced HUVEC injury. 23 and 24 exhibited more potential protective activities than other derivatives; and the EC50 values of them and the leading compound 31 (xyloketal B) were 5.10, 3.59 and 15.97 MUM, respectively. Meanwhile, a comparative molecular similarity indices analysis (CoMSIA) was constructed to explain the structural activity relationship of these xyloketal derivatives. This 3D QSAR model from CoMSIA suggested that the derived model exhibited good predictive ability in the external test-set validation. Derivative 24 fit well with the COMSIA map, therefore it possessed the highest activity of all compounds. Compounds 23, 24 and 31 (xyloketal B) were further to examine in the JC-1 mitochondrial membrane potential (MMP) assay of HUVECs using flow cytometry (FCM). The result indicated that 23 and 24 significantly inhibited H2O2-induced decrease of the cell mitochondrial membrane potential (DeltaPsim) at 25 MUM. Collectively, the protective effects of xyloketals on H2O2-induced endothelial cells may be generated from oxidation action by restraining ROS and reducing the MMP. PMID- 25686274 TI - Trabectedin in soft tissue sarcomas. AB - Soft tissue sarcomas are a group of rare tumors derived from mesenchymal tissue, accounting for about 1% of adult cancers. There are over 60 different histological subtypes, each with their own unique biological behavior and response to systemic therapy. The outcome for patients with metastatic soft tissue sarcoma is poor with few available systemic treatment options. For decades, the mainstay of management has consisted of doxorubicin with or without ifosfamide. Trabectedin is a synthetic agent derived from the Caribbean tunicate, Ecteinascidia turbinata. This drug has a number of potential mechanisms of action, including binding the DNA minor groove, interfering with DNA repair pathways and the cell cycle, as well as interacting with transcription factors. Several phase II trials have shown that trabectedin has activity in anthracycline and alkylating agent-resistant soft tissue sarcoma and suggest use in the second- and third-line setting. More recently, trabectedin has shown similar progression free survival to doxorubicin in the first-line setting and significant activity in liposarcoma and leiomyosarcoma subtypes. Trabectedin has shown a favorable toxicity profile and has been approved in over 70 countries for the treatment of metastatic soft tissue sarcoma. This manuscript will review the development of trabectedin in soft tissue sarcomas. PMID- 25686276 TI - A novel and selective fluoride opening of aziridines by XtalFluor-E. synthesis of fluorinated diamino acid derivatives. AB - The selective introduction of fluorine onto the skeleton of an aminocyclopentane or cyclohexane carboxylate has been developed through a novel and efficient fluoride opening of an activated aziridine ring with XtalFluor-E. The reaction proceeded through a stereoselective aziridination of the olefinic bond of a bicyclic lactam and regioselective aziridine ring opening with difluorosulfiliminium tetrafluoroborate with the neighboring group assistance of the sulfonamide moiety to yield fluorinated diamino acid derivatives. The method based on the selective aziridine opening by fluoride has been generalized to afford access to mono- or bicyclic fluorinated substances. PMID- 25686275 TI - Selective blocking effects of 4,9-anhydrotetrodotoxin, purified from a crude mixture of tetrodotoxin analogues, on NaV1.6 channels and its chemical aspects. AB - Tetrodotoxin (TTX) is a potent neurotoxin found in a number of marine creatures including the pufferfish, where it is synthesized by bacteria and accumulated through the food chain. It is a potent and selective blocker of some types of voltage-gated Na+ channel (NaV channel). 4,9-Anhydrotetrodotoxin (4,9-anhydroTTX) was purified from a crude mixture of TTX analogues (such as TTX, 4-epiTTX, 6 epiTTX, 11-oxoTTX and 11-deoxyTTX) by the use of liquid chromatography fluorescence detection (LC-FLD) techniques. Recently, it has been reported that 4,9-anhydroTTX selectively blocks the activity of NaV1.6 channels with a blocking efficacy 40-160 times higher than that for other TTX-sensitive NaV1.x channel isoforms. However, little attention has been paid to the molecular properties of the alpha-subunit in NaV1.6 channels and the characteristics of binding of 4,9 anhydroTTX. From a functional point of view, it is important to determine the relative expression of NaV1.6 channels in a wide variety of tissues. The aim of this review is to discuss briefly current knowledge about the pharmacology of 4,9 anhydroTTX, and provide an analysis of the molecular structure of native NaV1.6 channels. In addition, chemical aspects of 4,9-anhydroTTX are briefly covered. PMID- 25686277 TI - The effects of midazolam and butorphanol, administered alone or combined, on the dose and quality of anaesthetic induction with alfaxalone in goats. AB - Goats are rarely anaesthetised; consequently, scant information is available on the efficacy of anaesthetic drugs in this species. Alfaxalone is a relatively new anaesthetic agent, of which the efficacy in goats has not yet been studied. In this study, the sedative and alfaxalone sparing effects of midazolam and butorphanol, administered alone or concomitantly, in goats were assessed. Eight clinically healthy goats, four does and four wethers, were enlisted in a randomised crossover manner to receive intramuscular sedative treatments consisting of saline 0.05 mL/kg, or midazolam 0.30 mg/kg, or butorphanol 0.10 mg/kg, or a combination of midazolam 0.30 mg/kg with butorphanol 0.10 mg/kg before intravenous induction of general anaesthesia with alfaxalone. Following induction, the goats were immediately intubated and the quality of anaesthesia and basic physiological cardiorespiratory and blood-gas parameters were assessed until the goats had recovered from anaesthesia. The degree of sedation, quality of induction and recovery were scored. When compared with saline (3.00 mg/kg), midazolam,administered alone or with butorphanol, caused a statistically significant increased level of sedation and a reduction in the amount of alfaxalone required for induction (2.00 mg/kg and 1.70 mg/kg, respectively). Butorphanol alone (2.30 mg/kg) did not cause significant changes in level of sedation or alfaxalone-induction dose. During induction and recovery, the goats were calm following all treatments, including the control group. Cardiorespiratory and blood-gas parameters were maintained within clinically acceptable limits. The present study showed that midazolam, administered alone or combined with butorphanol, produces a degree of sedation that significantly reduces the dose of alfaxalone required for induction of general anaesthesia in goats, without causing any major adverse cardiorespiratory effects. PMID- 25686278 TI - Exploration of knowledge of cervical cancer and cervical cancer screening amongst HIV-positive women. AB - BACKGROUND: Although preventable, cervical cancer, an AIDS-related disease, is the second most common cancer amongst South African women and the most common cancer amongst black women. OBJECTIVE: The objective of the study was to determine what women being treated for HIV and AIDS at a specific healthcare centre in Johannesburg knew about cervical cancer and cervical screening. METHOD: A survey design was used, with data gathered by means of a self-administered questionnaire. Convenience sampling selected 315 women to participate (n = 315). Descriptive statistics were used to analyse the data and chi-square testing found associations between categorical variables. RESULTS: The majority of respondents (78.7%; n = 248) indicated that they had heard of cervical cancer and 62.9% (n = 198) knew about the Pap smear, with nurses and doctors being the primary source of information. Of the women who knew about the Pap smear, less than one-third had had a smear done, the main reason being fear of the procedure. CONCLUSION: The study provided evidence that women attending the specific HIV clinic were more knowledgeable about cervical cancer and screening than those of unknown HIV status involved in previous studies. Knowledge was still at a low level, especially when their exceptionally high risk was taken into account. Once again it was found that having knowledge did not necessarily mean having had a Pap smear, which remains a huge challenge in the prevention of cervical cancer. PMID- 25686279 TI - Rapid molecular detection of invasive species in ballast and harbor water by integrating environmental DNA and light transmission spectroscopy. AB - Invasive species introduced via the ballast water of commercial ships cause enormous environmental and economic damage worldwide. Accurate monitoring for these often microscopic and morphologically indistinguishable species is challenging but critical for mitigating damages. We apply eDNA sampling, which involves the filtering and subsequent DNA extraction of microscopic bits of tissue suspended in water, to ballast and harbor water sampled during a commercial ship's 1400 km voyage through the North American Great Lakes. Using a lab-based gel electrophoresis assay and a rapid, field-ready light transmission spectroscopy (LTS) assay, we test for the presence of two invasive species: quagga (Dreissena bugensis) and zebra (D. polymorpha) mussels. Furthermore, we spiked a set of uninfested ballast and harbor samples with zebra mussel tissue to further test each assay's detection capabilities. In unmanipulated samples, zebra mussel was not detected, while quagga mussel was detected in all samples at a rate of 85% for the gel assay and 100% for the LTS assay. In the spiked experimental samples, both assays detected zebra mussel in 94% of spiked samples and 0% of negative controls. Overall, these results demonstrate that eDNA sampling is effective for monitoring ballast-mediated invasions and that LTS has the potential for rapid, field-based detection. PMID- 25686280 TI - Coprisamides A and B, new branched cyclic peptides from a gut bacterium of the dung beetle Copris tripartitus. AB - Coprisamides A and B (1 and 2) were isolated from a bacterium in the gut of the dung beetle Copris tripartitus. Spectroscopic analysis revealed that the planar structures of 1 and 2 are novel cyclic heptapeptides bearing unusual units, such as beta-methylaspartic acid and 2,3-diaminopropanoic acid branched to valine and 2-heptatrienyl cinnamic acid. Absolute configurations were established by chemical derivatization and chiroptical spectroscopy. The coprisamides displayed significant activity for induction of quinone reductase. PMID- 25686281 TI - Cobalt/polypyrrole nanocomposites with controllable electromagnetic properties. AB - In this work, cobalt/polypyrrole (Co/PPy) nanocomposites were prepared via an in situ oxidation polymerization of pyrrole in an aqueous dispersion of Co nanoparticles (NPs). The Co/PPy nanocomposites showed good electromagnetic properties because of the coexistence of magnetic loss and dielectric loss to electromagnetic waves. The electromagnetic wave absorbing bandwidth (reflection loss < -10 dB) for Co/PPy (30 wt% in a paraffin matrix) was located at 11.7-16.47 GHz with a thickness of 2 mm, and with a maximum reflection loss (around -33 dB) at 13.6 GHz. More interestingly, the electromagnetic wave absorbing properties of the nanocomposites can be easily controlled by tuning the ratio of the two components in the composites. This improved electromagnetic wave absorption may be attributed to the excellent electromagnetic match at the corresponding resonance peaks for dielectric and magnetic loss. These magnetic nanoparticles/conducting polymer nanocomposites are great potential candidates for use as electromagnetic wave absorbents due to their excellent properties such as wide absorbing frequency, strong absorption, good compatibility, low density and controllable absorbing properties. PMID- 25686282 TI - Carboxylic acid decorated self-assembled monolayer films: new acid synthesis chemistry and reaction chemistry including bridged diacyl peroxide preparation. AB - Interfacial chemical transformations are an important way to control the physical and chemical properties of surfaces. Organic molecules that self-assemble into monolayers are a proven, effective tool for surface modification, and the ability to do controlled chemical transformations on the exposed surface of the self assembled monolayer (SAM) adds significant diversity to this capability. Given the importance of carboxylic acid groups in applications ranging from controlling surface ionization to anchoring biological molecules, we have studied alternative ways to install acid groups on a surface and have probed the factors that control their chemistry. The work reported herein describes a new way to install carboxylic acid groups on surfaces and explores the intermolecular chemistry between acid groups on adjacent monolayer-forming molecules both on flat interfaces and on nanoparticles. It addresses the interplay of molecular flexibility and chain packing in controlling processes that bridge neighboring molecules. Finally, the creation of bridged diacyl peroxides from neighboring acid groups provides useful surface bound polymerization initiators that can effectively and conformally cover both flat surfaces and particles with ultrathin polymer films. PMID- 25686283 TI - The impact of alcohol on HIV prevention and treatment for South Africans in primary healthcare. AB - BACKGROUND: Antiretroviral treatment (ART) has substantially reduced morbidity and mortality for HIV patients. In South Africa, with the largest ART programme globally, attention is needed not only on the further expansion of ART coverage, but also on factors which undermine its effectiveness, such as alcohol use. OBJECTIVE: Given the decentralised approach of nurse-initiated and -sustained ART in the South African primary health sector, it is important to document key aspects of alcohol use to be conveyed to HIV-positive individuals and those at risk for HIV. METHOD: This study comprised a narrative review of relevant literature. RESULTS: Alcohol acts through both behavioural and physiological pathways to impact on the acquisition, further transmission and then progression of HIV disease. Besides links to risky sex, alcohol undermines the immune system, raising susceptibility to contracting and then countering HIV and other infections. There are important drug interactions between alcohol and ART, or therapies for opportunistic infections and other co-morbidities. Moreover, alcohol undermines adherence to the medication which is essential for effective ART. CONCLUSION: Primary healthcare clinic attendees need evidence-based information on the detrimental effects of alcohol consumption on HIV infection, which ensue throughout the clinical course of HIV. This spans the role of alcohol consumption as a risk factor for HIV infection, HIV replication in infected individuals, a person's response to HIV infection and HIV treatment. Primary healthcare workers, especially nurses and HIV counsellors, require training in order to screen for and provide appropriate interventions for HIV-positive patients, those on treatment and treatment-naive patients, who will benefit from reduced alcohol consumption or the cessation thereof. PMID- 25686284 TI - Variation characteristics of nitrogen concentrations through forest hydrologic subcycles in various forests across mainland China. AB - Increased anthropogenic nitrogen emissions and more severe environmental issues (e.g. air pollution, soil acidification, and plant nutrient imbalances) are striking forest ecosystems. Data on NH4+ and NO3- concentrations in throughfall and stemflow were collected to estimate variation characteristics of nitrogen concentrations through forest hydrological processes across China. A typical study was carried out in the three forest types in the Jinyun Mountain region of Chongqing, from May to October 2012. Nitrogen concentrations in throughfall and stemflow are higher than those in atmospheric precipitation. DIN concentrations in atmospheric precipitation, throughfall, and stemflow, across China and in the Jinyun Mountain region, were 2.18 and 1.51, 3.19 and 3.88, and 5.14 and 3.92 mg N L(-1), respectively. NH4+ concentration was higher than NO3- concentration, suggesting NH4+ is the dominant nitrogen component in China. Additionally, across China, a linear relationship existed between DIN and NH4+, and between DIN and NO3- in atmospheric precipitation. DIN concentrations in throughfall and stemflow changed with the observed changes in precipitation, and DIN concentrations in precipitation positively correlated with those in throughfall and in stemflow were also observed. Moreover, average DIN concentrations in throughfall and stemflow varied in different forest types, resulting from differences in forest canopy structures and tree species characteristics. In the Jinyun Mountain region, both throughfall and stemflow DIN concentrations were the highest in the mixed broadleaved/coniferous forest, followed by evergreen broadleaved forest, and the lowest in moso bamboo forest. Monthly variations of NH4+ and NO3- concentrations, in throughfall and stemflow, were observed in the Jinyun Mountain region. PMID- 25686285 TI - Symmetric bilateral transposition flap: a very versatile option in facial dermatological surgery. AB - AIM: Repair following excision of large tumours of the face can be problematic; primary closure may not be achievable and grafting or secondary intention healing carry the risk of necrosis and lengthy healing times. Flaps are usually associated with earlier healing and better cosmetic results, as the skin used for closure is similar to the tissue requiring repair. However, large wound sizes and difficulty in finding a suitable donor area means flaps can be complicated to perform. The aim of this paper was to identify a comparatively quick and simple alternative to standard repair techniques for the closure of large wound defects in critical anatomical areas, when the only realistic alternative would be grafting, offering both good cosmetic results and minimal risk of complications. RESULTS: We have developed a flap, modified from the classic, single lobe transposition flap. Two similar lobes placed symmetrically and perpendicularly to two opposite sides of the surgical wound are incised with fulcra centred on two opposite corners. The flaps are then rotated by approximately 80-90o into position side by side, sutured to the borders of the surgical wound and finally together with a longitudinal suture. The principle behind this flap is the split of the covering surface into 2 small units, rather than using a large single lobe, which, for large wounds, would make closure of the single donor area by first intention impossible. The split of the donor area in 2 smaller subunits makes it easier to close the two donor areas and allows a larger amount of tissue to be harvested. CONCLUSION: We have developed a twinned symmetric transposition flap to close large wounds on the face when the only realistic alternative would have been the use of grafting. It offers minimal distortion, and is both quick and simple to perform. The use of tissue similar to the original defect ensures good cosmetic results. Healing times were usually very rapid and complications limited to a very few cases of end flap necrosis. This technique is not applicable where donor areas fall in anatomic spots where harvesting of the lobes is impossible, e.g. when the wound is too close to the hair line and transposition of the lobes would cause the transfer of hairy skin to an area where the presence of hair is not desirable. PMID- 25686286 TI - To classify or to discern? That's the problem. PMID- 25686287 TI - Degos disease: report of a case and review of the literature. AB - We report the case of a 20-year-old woman with one-year history of asymptomatic pink papules on the abdomen, with central atrophy. Fever and symptoms suggesting involvement of other organs were absent. Histological examination revealed wedge shaped area of cutaneous ischemia extending into the deep dermis with superficial and deep perivascular lymphocytic infiltrate. On this basis, we diagnosed malignant atrophic papulosis. Laboratory tests and instrumental investigation did not reveal any systemic involvement. The rarity of this disease makes early diagnosis challenging, even if clinical and histological patterns of the skin lesions are peculiar. PMID- 25686288 TI - In vivo confocal microscopy for eyelids and ocular surface: a new horizon for dermatologists. PMID- 25686289 TI - Legionellosis and psoriasis in biologic era. PMID- 25686290 TI - Trichilemmal carcinoma of the lower eyelid in a oculocutaneous albino patient. PMID- 25686291 TI - Ionic liquids as plasticizers for polyelectrolyte complexes. AB - Uptake of salts by insoluble polyelectrolyte complexes (PECs) leads to plasticization, and here it is shown that ionic liquids (ILs) are more effective plasticizers than simple organic salts such as NaCl. The PEC uptake of IL cation was monitored by solution (1)H NMR, and the mechanical impacts of plasticization were tracked by dynamic mechanical analysis (DMA). PECs prepared with polystyrene sulfonate (PSS) and poly(diallyldimethylammonium chloride) (PDDA) under charge stoichiometric conditions were immersed in aqueous solutions of 1-butyl-3 methylimidazolium chloride [BMIM][Cl] to cause IL uptake, which could be controlled by the solution's IL concentration: higher concentration leads to higher uptake which leads to greater plasticization. The effectiveness of plasticization was assessed through the position and height of a DMA tan(delta) peak ascribed to a glassy-to-rubbery PEC transition. Consistent with greater PEC uptake, isothermal titration calorimetry demonstrated that solution binding by PSS of [BMIM](+) was much stronger than binding of Na(+). PMID- 25686292 TI - Synthesis of quinolinones with palladium-catalyzed oxidative annulation between acrylamides and arynes. AB - An unprecedented palladium-catalyzed oxidative annulation of acrylamides with benzyne precursors has been successfully developed. By using this mild "N-H activation/Heck reaction" method, a wide variety of quinolinones were conveniently prepared in one step with high efficiency. PMID- 25686293 TI - Word-level language modeling for P300 spellers based on discriminative graphical models. AB - OBJECTIVE: In this work we propose a probabilistic graphical model framework that uses language priors at the level of words as a mechanism to increase the performance of P300-based spellers. APPROACH: This paper is concerned with brain computer interfaces based on P300 spellers. Motivated by P300 spelling scenarios involving communication based on a limited vocabulary, we propose a probabilistic graphical model framework and an associated classification algorithm that uses learned statistical models of language at the level of words. Exploiting such high-level contextual information helps reduce the error rate of the speller. MAIN RESULTS: Our experimental results demonstrate that the proposed approach offers several advantages over existing methods. Most importantly, it increases the classification accuracy while reducing the number of times the letters need to be flashed, increasing the communication rate of the system. SIGNIFICANCE: The proposed approach models all the variables in the P300 speller in a unified framework and has the capability to correct errors in previous letters in a word, given the data for the current one. The structure of the model we propose allows the use of efficient inference algorithms, which in turn makes it possible to use this approach in real-time applications. PMID- 25686294 TI - Studies towards optimising the isolation of diplonine, a neurotoxin isolated from cultures of Stenocarpella maydis (Berk.) Sacc. AB - Diplonine, a mycotoxin that induces neurotoxic clinical signs in the guinea pig, resembling those occurring in cattle and sheep with diplodiosis, was isolated previously from a Stenocarpella maydisculture. Knowledge of the chemical properties of the toxin, which was characterised as a substituted beta cyclopropylamino acid, enabled amendments in the present study to the initial steps of the isolation procedure. Extraction with water and fractionation by cation exchange chromatography improved the efficiency of isolation, potentially allowing the preparation of larger amounts of the toxin. PMID- 25686295 TI - U(III)-CN versus U(IV)-NC coordination in tris(silylamide) complexes. AB - Treatment of the metallacycle [UN*2(N,C)] [N* = N(SiMe3)2; N,C = CH2SiMe2N(SiMe3)] with [HNEt3][BPh4], [HNEt3]Cl, and [pyH][OTf] (OTf = OSO2CF3) gave the cationic compound [UN*3][BPh4] (1) and the neutral complexes [UN*3X] [X = Cl (3), OTf (4)], respectively. The dinuclear complex [{UN*(MU-N,C)(MU-OTf)}2] (5) and its tetrahydrofuran (THF) adduct [{UN*(N,C)(THF)(MU-OTf)}2] (6) were obtained by thermal decomposition of 4. The successive addition of NEt4CN or KCN to 1 led to the formation of the cyanido-bridged dinuclear compound [(UN*3)2(MU CN)][BPh4] (7) and the mononuclear mono- and bis(cyanide) complexes [UN*3(CN)] (2) and [M][UN*3(CN)2] [M = NEt4 (8), K(THF)4 (9)], while crystals of [K(18-crown 6)][UN*3(CN)2] (10) were obtained by the oxidation of [K(18-crown-6)][UN*3(CN)] with pyridine N-oxide. The THF adduct of 1, [UN*3(THF)][BPh4], and complexes 2-7, 9 and 10 were characterized by their X-ray crystal structure. In contrast to their U(III) analogues [NMe4][UN*3(CN)] and [K(18-crown-6)]2[UN*3(CN)2] in which the CN anions are coordinated to the metal center via the C atom, complexes 2 and 9 exhibit the isocyanide U-NC coordination mode of the cyanide ligand. This U(III)/U(IV) differentiation has been analyzed using density functional theory calculations. The observed preferential coordinations are well explained considering the electronic structures of the different species and metal-ligand bonding energies. A comparison of the different quantum descriptors, i.e., bond orders, NPA/QTAIM data, and energy decomposition analysis, has allowed highlighting of the subtle balance between covalent, ionic, and steric factors that govern the U-CN/NC bonding. PMID- 25686296 TI - Efficient CO2 capture by functionalized graphene oxide nanosheets as fillers to fabricate multi-permselective mixed matrix membranes. AB - A novel multi-permselective mixed matrix membrane (MP-MMM) is developed by incorporating versatile fillers functionalized with ethylene oxide (EO) groups and an amine carrier into a polymer matrix. The as-prepared MP-MMMs can separate CO2 efficiently because of the simultaneous enhancement of diffusivity selectivity, solubility selectivity, and reactivity selectivity. To be specific, MP-MMMs were fabricated by incorporating polyethylene glycol- and polyethylenimine-functionalized graphene oxide nanosheets (PEG-PEI-GO) into a commercial low-cost Pebax matrix. The PEG-PEI-GO plays multiple roles in enhancing membrane performance. First, the high-aspect ratio GO nanosheets in a polymer matrix increase the length of the tortuous path of gas diffusion and generate a rigidified interface between the polymer matrix and fillers, enhancing the diffusivity selectivity. Second, PEG consisting of EO groups has excellent affinity for CO2 to enhance the solubility selectivity. Third, PEI with abundant primary, secondary, and tertiary amine groups reacts reversibly with CO2 to enhance reactivity selectivity. Thus, the as-prepared MP-MMMs exhibit excellent CO2 permeability and CO2/gas selectivity. The MP-MMM doped with 10 wt % PEG-PEI GO displays optimal gas separation performance with a CO2 permeability of 1330 Barrer, a CO2/CH4 selectivity of 45, and a CO2/N2 selectivity of 120, surpassing the upper bound lines of the Robeson study of 2008 (1 Barrer = 10(-10) cm(3) (STP) cm(-2) s(-1) cm(-1) Hg). PMID- 25686297 TI - Biomineralized matrices dominate soluble cues to direct osteogenic differentiation of human mesenchymal stem cells through adenosine signaling. AB - Stem cell differentiation is determined by a repertoire of signals from its microenvironment, which includes the extracellular matrix (ECM) and soluble cues. The ability of mesenchymal stem cells (MSCs), a common precursor for the skeletal system, to differentiate into osteoblasts and adipocytes in response to their local cues plays an important role in skeletal tissue regeneration and homeostasis. In this study, we investigated whether a bone-specific calcium phosphate (CaP) mineral environment could induce osteogenic differentiation of human MSCs, while inhibiting their adipogenic differentiation, in the presence of adipogenic-inducing medium. We also examined the mechanism through which the mineralized matrix suppresses adipogenesis of hMSCs to promote their osteogenic differentiation. Our results show that hMSCs cultured on mineralized matrices underwent osteogenic differentiation despite being cultured in the presence of adipogenic medium, which indicates the dominance of matrix-based cues of the mineralized matrix in directing osteogenic commitment of stem cells. Furthermore, the mineralized matrix-driven attenuation of adipogenesis was reversed with the inhibition of A2b adenosine receptor (A2bR), implicating a role of adenosine signaling in mineralized environment-mediated inhibition of adipogenesis. Such synthetic matrices with an intrinsic ability to direct differentiation of multipotent adult stem cells toward a targeted phenotype while inhibiting their differentiation into other lineages not only will be a powerful tool in delineating the role of complex microenvironmental cues on stem cell commitment but also will contribute to functional tissue engineering and their translational applications. PMID- 25686298 TI - Can We Really Predict Postoperative Acute Kidney Injury after Aortic Surgery? Diagnostic Accuracy of Risk Scores Using Gray Zone Approach. AB - Background Several risk scores have been developed to predict acute kidney injury (AKI) after cardiac surgery. We evaluated the accuracy of eight prediction models using the gray zone approach in patients who underwent aortic surgery. Patients and Methods We retrospectively applied the risk scores of Palomba, Wijeysundera, Mehta, Thakar, Brown, Aronson, Fortescue, and Rhamanian to 375 consecutive adult patients undergoing aortic surgery with cardiopulmonary bypass. The area under the receiver operating characteristic curve (AUC) and gray zone approach were used to evaluate the accuracy of the eight models for prediction of AKI, as defined by the RIFLE criteria. Results The incidence of AKI was 29% (109/375). The AUC for predicting AKI requiring dialysis ranged from 0.66 to 0.84, excluding the score described by Brown et al (0.50). The AUC for predicting the RIFLE criteria of risk and higher ranged from 0.57 to 0.68. The application of gray zone approach resulted in more than half of the patients falling in the gray zone: 275 patients (73%) for Palomba, 221 (59%) for Wijeysundera, 292 (78%) for Mehta, 311 (83%) for Thakar, 329 (88%) for Brown, 291 (78%) for Aronson, 205 (54%) for Fortescue, and 308 (82%) for Rhamanian. Conclusion More than half of the patients in our study sample were in the gray zone of eight scoring models for AKI prediction. The two cutoffs of the gray zone can be used when using risk models. A surgery-specific and more accurate prediction model with a smaller gray zone is required for patients undergoing aortic surgery. PMID- 25686299 TI - Comparison of Transcutaneous Electrical Nerve Stimulation and Paravertebral Block for Postthoracotomy Pain Relief. AB - BACKGROUND: Inadequate relief of postthoracotomy pain is a major reason of increased occurrence of postoperative complications. We aimed to investigate and compare the effects of transcutaneous electrical nerve stimulation (TENS) and paravertebral block (PVB) to relieve pain after thoracotomy procedures. MATERIALS AND METHODS: We studied 40 patients who underwent thoracotomy. Patients were randomly allocated to receive either PVB (group P, n = 20) or TENS (group T, n = 20) for postoperative pain. The electrodes of TENS were placed 2 cm under and 2 cm over the thoracotomy cut on both posterior and anterior sides. The surgeon inserted paravertebral catheters using direct vision at the end of the surgery. A patient-controlled analgesia (PCA) device was connected to all patients. Visual analog scales, patient demand, and consumption of tramadol were evaluated postoperatively. RESULTS: Mean visual analog scale (VAS) values were significantly lower in group P for all time points. The patients in group P needed lower amounts of opioid (tramadol) and the difference was statistically significant (258.4 +/- 13.52 mg vs. 314.4 +/- 8.65 mg, p = 0.005). In addition, the number of demand attempts recorded from the PCA device was significantly lower in group P (14.95 +/- 13.64 vs. 26.7 +/- 17.34, respectively and p < 0.001). CONCLUSION: TENS has beneficial effects for pain relief after thoracotomy, without any side effects; however, it cannot provide sufficient pain relief when compared with PVB. PMID- 25686300 TI - Biochemical and EPR-spectroscopic investigation into heterologously expressed vinyl chloride reductive dehalogenase (VcrA) from Dehalococcoides mccartyi strain VS. AB - Reductive dehalogenases play a critical role in the microbial detoxification of aquifers contaminated with chloroethenes and chlorethanes by catalyzing the reductive elimination of a halogen. We report here the first heterologous production of vinyl chloride reductase VcrA from Dehalococcoides mccartyi strain VS. Heterologously expressed VcrA was reconstituted to its active form by addition of hydroxocobalamin/adenosylcobalamin, Fe(3+), and sulfide in the presence of mercaptoethanol. The kinetic properties of reconstituted VcrA catalyzing vinyl chloride reduction with Ti(III)-citrate as reductant and methyl viologen as mediator were similar to those obtained previously for VcrA as isolated from D. mccartyi strain VS. VcrA was also found to catalyze a novel reaction, the environmentally important dihaloelimination of 1,2-dichloroethane to ethene. Electron paramagnetic resonance (EPR) spectroscopic studies with reconstituted VcrA in the presence of mercaptoethanol revealed the presence of Cob(II)alamin. Addition of Ti(III)-citrate resulted in the appearance of a new signal characteristic of a reduced [4Fe-4S] cluster and the disappearance of the Cob(II)alamin signal. UV-vis absorption spectroscopy of Ti(III)citrate-treated samples revealed the formation of two new absorption maxima characteristic of Cob(I)alamin. No evidence for the presence of a [3Fe-4S] cluster was found. We postulate that during the reaction cycle of VcrA, a reduced [4Fe-4S] cluster reduces Co(II) to Co(I) of the enzyme-bound cobalamin. Vinyl chloride reduction to ethene would be initiated when Cob(I)alamin transfers an electron to the substrate, generating a vinyl radical as a potential reaction intermediate. PMID- 25686301 TI - Prevalence of select vector-borne disease agents in owned dogs of Ghana. AB - Ticks, sera and ethylenediaminetetraacetic acid (EDTA) blood were collected from dogs evaluated at the Amakom Veterinary Clinic in Kumasi, Ghana. Sera were evaluated for Dirofilaria immitis antigen and antibodies against Borrelia burgdorferi, Anaplasma phagocytophilum and Ehrlichia canis. Conventional polymerase chain reaction assays designed to amplify the deoxyribonucleic acid (DNA) of Ehrlichia spp. or Anaplasma spp. or Neorickettsia spp. or Wolbachia spp., Babesia spp., Rickettsia spp., Hepatozoon spp., Bartonella spp. and the haemoplasmas were performed on DNA extracted from EDTA blood and all positive amplicons were sequenced. This small survey shows that the following vector-borne pathogens are present in urban Ghanian dogs: Ehrlichia canis, Hepatozoon canis,Dirofilaria immitis and Anaplasma platys. Bartonella henselae was isolated from ticks but not from the dogs. PMID- 25686302 TI - Heteroplasmon hybridization in stacked complementary plasmo-photonic crystals. AB - We constructed plasmo-photonic crystals in which efficient light-trapping, plasmonic resonances couple with photonic guided resonances of large density of states and high-quality factor. We have numerically and experimentally shown that heteroplasmon hybrid modes emerge in stacked complementary (SC) plasmo-photonic crystals. The resonant electromagnetic-field distributions evidence that the two hybrid modes originate from two different heteroplasmons, exhibiting a large energy splitting of 300 meV. We further revealed a series of plasmo-photonic modes in the SC crystals. PMID- 25686303 TI - Short Synthetic Terminators for Improved Heterologous Gene Expression in Yeast. AB - Terminators play an important role both in completing the transcription process and impacting mRNA half-life. As such, terminators are an important synthetic component considered in applications such as heterologous gene expression and metabolic engineering. Here, we describe a panel of short (35-70 bp) synthetic terminators that can be used for modulating gene expression in yeast. The best of these synthetic terminator resulted in 3.7-fold more fluorescent protein output and 4.4-fold increase in transcript level compared to that with the commonly used CYC1 terminator. These synthetic terminators offer several advantages over native sequences, including an easily synthesized short length, minimal sequence homology to native sequences, and similar or better performance characteristics than those of commonly used longer terminators. Furthermore, the synthetic terminators are highly functional in both Saccharomyces cerevisiae and an alternative yeast, Yarrowia lipolytica, demonstrating that these synthetic designs are transferrable between diverse yeast species. PMID- 25686305 TI - Combined radiocarbon and CO2 flux measurements used to determine in situ chlorinated solvent mineralization rate. AB - A series of combined measurements was made at the Naval Air Station North Island (NASNI) Installation Restoration Site 5, Unit 2 during July and August 2013. Combined measurements included CO2 respiration rate, CO2 radiocarbon content to estimate chlorinated hydrocarbon (CH) mineralization and a zone of influence (ZOI) model. CO2 was collected continuously over 2 two-week periods by recirculating monitoring well headspace gas through NaOH traps. A series of 12 wells in the main CH plume zone and a background well with no known historical contamination were sampled. The background well CO2 was used to determine radiocarbon content derived from respired natural organic matter. A two end member mixing model was then used to determine the amount of CH-derived carbon present in the CO2 collected from plume region wells. The ZOI model provided an estimate for the soil volume sampled at each well. CH mineralization rates were highest upgradient and at the plume fringe for areas of high historical contamination and ranged from 0.02 to 5.6 mg CH carbon per day. Using the ZOI model volume estimates, CH-carbon removal ranged from 0.2 to 32 mg CH-carbon m( 3) per day. Because the rate estimates were based on a limited sampling (temporally), they were not further extrapolated to long-term contaminant degradation estimates. However, if the site manager or regulators required them, estimates - subject to long-term variability uncertainties - could be made using volume and rate data determined over short timescales. A more comprehensive seasonal sampling is needed to constrain long-term remediation models for the entire impacted area and identify environmental conditions related to more rapid turnover times amongst the wells. PMID- 25686304 TI - Mindfulness meditation and improvement in sleep quality and daytime impairment among older adults with sleep disturbances: a randomized clinical trial. AB - IMPORTANCE: Sleep disturbances are most prevalent among older adults and often go untreated. Treatment options for sleep disturbances remain limited, and there is a need for community-accessible programs that can improve sleep. OBJECTIVE: To determine the efficacy of a mind-body medicine intervention, called mindfulness meditation, to promote sleep quality in older adults with moderate sleep disturbances. DESIGN, SETTING, AND PARTICIPANTS: Randomized clinical trial with 2 parallel groups conducted from January 1 to December 31, 2012, at a medical research center among an older adult sample (mean [SD] age, 66.3 [7.4] years) with moderate sleep disturbances (Pittsburgh Sleep Quality Index [PSQI] >5). INTERVENTIONS: A standardized mindful awareness practices (MAPs) intervention (n = 24) or a sleep hygiene education (SHE) intervention (n = 25) was randomized to participants, who received a 6-week intervention (2 hours per week) with assigned homework. MAIN OUTCOMES AND MEASURES: The study was powered to detect between group differences in moderate sleep disturbance measured via the PSQI at postintervention. Secondary outcomes pertained to sleep-related daytime impairment and included validated measures of insomnia symptoms, depression, anxiety, stress, and fatigue, as well as inflammatory signaling via nuclear factor (NF)-kappaB. RESULTS: Using an intent-to-treat analysis, participants in the MAPs group showed significant improvement relative to those in the SHE group on the PSQI. With the MAPs intervention, the mean (SD) PSQIs were 10.2 (1.7) at baseline and 7.4 (1.9) at postintervention. With the SHE intervention, the mean (SD) PSQIs were 10.2 (1.8) at baseline and 9.1 (2.0) at postintervention. The between-group mean difference was 1.8 (95% CI, 0.6-2.9), with an effect size of 0.89. The MAPs group showed significant improvement relative to the SHE group on secondary health outcomes of insomnia symptoms, depression symptoms, fatigue interference, and fatigue severity (P < .05 for all). Between-group differences were not observed for anxiety, stress, or NF-kappaB, although NF-kappaB concentrations significantly declined over time in both groups (P < .05). CONCLUSIONS AND RELEVANCE: The use of a community-accessible MAPs intervention resulted in improvements in sleep quality at immediate postintervention, which was superior to a highly structured SHE intervention. Formalized mindfulness based interventions have clinical importance by possibly serving to remediate sleep problems among older adults in the short term, and this effect appears to carry over into reducing sleep-related daytime impairment that has implications for quality of life. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01534338. PMID- 25686306 TI - Understanding the properties of inorganic benzenes based on pi-electron densities. AB - The properties of inorganic benzenes have been investigated by means of second order Moller-Plesset perturbation theory (MP2) calculations and quantum theory of atoms in molecules (QTAIM) studies. In this work, the sigma- and pi-electron densities were separated from the total electron densities, and it was therefore possible to evaluate the contributions of sigma and pi electrons to the chemical bonds and properties of inorganic benzenes. The following conclusions are given: (1) The pi-attractors' positions correlate to their respective atomic radii. With increasing atomic number in the same period, the attractor of pi-electron densities becomes closer to its respective nucleus. With increasing atomic number in the main group, the position of the pi attractor becomes farther from its respective nucleus. (2) The strength of the chemical bonds of the inorganic benzene rings is determined by sigma-electron densities, not pi-electron densities; their bonding character is mainly determined by the sigma-electron density; however, the role of the pi-electron density cannot be neglected. (3) For the inorganic benzenes studied, the electron localization function for pi (ELFpi) values are related to the differences of the electronegativity between the neighboring atoms of the inorganic benzene rings, Deltachi(X,Y). The smaller the difference of Deltachi(X,Y), the higher the value of ELFpi, resulting in more aromatic properties of the inorganic benzenes. PMID- 25686307 TI - Compressive SAR imaging with joint sparsity and local similarity exploitation. AB - Compressive sensing-based synthetic aperture radar (SAR) imaging has shown its superior capability in high-resolution image formation. However, most of those works focus on the scenes that can be sparsely represented in fixed spaces. When dealing with complicated scenes, these fixed spaces lack adaptivity in characterizing varied image contents. To solve this problem, a new compressive sensing-based radar imaging approach with adaptive sparse representation is proposed. Specifically, an autoregressive model is introduced to adaptively exploit the structural sparsity of an image. In addition, similarity among pixels is integrated into the autoregressive model to further promote the capability and thus an adaptive sparse representation facilitated by a weighted autoregressive model is derived. Since the weighted autoregressive model is inherently determined by the unknown image, we propose a joint optimization scheme by iterative SAR imaging and updating of the weighted autoregressive model to solve this problem. Eventually, experimental results demonstrated the validity and generality of the proposed approach. PMID- 25686308 TI - Wearable sensor-based rehabilitation exercise assessment for knee osteoarthritis. AB - Since the knee joint bears the full weight load of the human body and the highest pressure loads while providing flexible movement, it is the body part most vulnerable and susceptible to osteoarthritis. In exercise therapy, the early rehabilitation stages last for approximately six weeks, during which the patient works with the physical therapist several times each week. The patient is afterwards given instructions for continuing rehabilitation exercise by him/herself at home. This study develops a rehabilitation exercise assessment mechanism using three wearable sensors mounted on the chest, thigh and shank of the working leg in order to enable the patients with knee osteoarthritis to manage their own rehabilitation progress. In this work, time-domain, frequency domain features and angle information of the motion sensor signals are used to classify the exercise type and identify whether their postures are proper or not. Three types of rehabilitation exercise commonly prescribed to knee osteoarthritis patients are: Short-Arc Exercise, Straight Leg Raise, and Quadriceps Strengthening Mini-squats. After ten subjects performed the three kinds of rehabilitation activities, three validation techniques including 10-fold cross validation, within subject cross validation, and leave-one-subject cross validation are utilized to confirm the proposed mechanism. The overall recognition accuracy for exercise type classification is 97.29% and for exercise posture identification it is 88.26%. The experimental results demonstrate the feasibility of the proposed mechanism which can help patients perform rehabilitation movements and progress effectively. Moreover, the proposed mechanism is able to detect multiple errors at once, fulfilling the requirements for rehabilitation assessment. PMID- 25686309 TI - Sol-gel deposition of iridium oxide for biomedical micro-devices. AB - Flexible iridium oxide (IrOx)-based micro-electrodes were fabricated on flexible polyimide substrates using a sol-gel deposition process for utilization as integrated pseudo-reference electrodes for bio-electrochemical sensing applications. The fabrication method yields reliable miniature on-probe IrOx electrodes with long lifetime, high stability and repeatability. Such sensors can be used for long-term measurements. Various dimensions of sol-gel iridium oxide electrodes including 1 mm * 1 mm, 500 um * 500 um, and 100 um * 100 um were fabricated. Sensor longevity and pH dependence were investigated by immersing the electrodes in hydrochloric acid, fetal bovine serum (FBS), and sodium hydroxide solutions for 30 days. Less pH dependent responses, compared to IrOx electrodes fabricated by electrochemical deposition processes, were measured at 58.8 +/- 0.4 mV/pH, 53.8 +/- 1.3 mV/pH and 48 +/- 0.6 mV/pH, respectively. The on-probe IrOx pseudo-reference electrodes were utilized for dopamine sensing. The baseline responses of the sensors were higher than the one using an external Ag/AgCl reference electrode. Using IrOx reference electrodes integrated on the same probe with working electrodes eliminated the use of cytotoxic Ag/AgCl reference electrode without loss in sensitivity. This enables employing such sensors in long-term recording of concentrations of neurotransmitters in central nervous systems of animals and humans. PMID- 25686310 TI - Microbial biofilm as a smart material. AB - Microbial biofilm colonies will in many cases form a smart material capable of responding to external threats dependent on their size and internal state. The microbial community accordingly switches between passive, protective, or attack modes of action. In order to decide which strategy to employ, it is essential for the biofilm community to be able to sense its own size. The sensor designed to perform this task is termed a quorum sensor, since it only permits collective behaviour once a sufficiently large assembly of microbes have been established. The generic quorum sensor construct involves two genes, one coding for the production of a diffusible signal molecule and one coding for a regulator protein dedicated to sensing the signal molecules. A positive feedback in the signal molecule production sets a well-defined condition for switching into the collective mode. The activation of the regulator involves a slow dimerization, which allows low-pass filtering of the activation of the collective mode. Here, we review and combine the model components that form the basic quorum sensor in a number of Gram-negative bacteria, e.g., Pseudomonas aeruginosa. PMID- 25686311 TI - Ionizing radiation detectors based on Ge-doped optical fibers inserted in resonant cavities. AB - The measurement of ionizing radiation (IR) is a crucial issue in different areas of interest, from environmental safety and industrial monitoring to aerospace and medicine. Optical fiber sensors have recently proven good candidates as radiation dosimeters. Here we investigate the effect of IR on germanosilicate optical fibers. A piece of Ge-doped fiber enclosed between two fiber Bragg gratings (FBGs) is irradiated with gamma radiation generated by a 6 MV medical linear accelerator. With respect to other FBG-based IR dosimeters, here the sensor is only the bare fiber without any special internal structure. A near infrared laser is frequency locked to the cavity modes for high resolution measurement of radiation induced effects on the fiber optical parameters. In particular, we observe a variation of the fiber thermo-optic response with the radiation dose delivered, as expected from the interaction with Ge defect centers, and demonstrate a detection limit of 360 mGy. This method can have an impact in those contexts where low radiation doses have to be measured both in small volumes or over large areas, such as radiation therapy and radiation protection, while bare optical fibers are cheap and disposable. PMID- 25686312 TI - Differential wide temperature range CMOS interface circuit for capacitive MEMS pressure sensors. AB - We describe a Complementary Metal-Oxide Semiconductor (CMOS) differential interface circuit for capacitive Micro-Electro-Mechanical Systems (MEMS) pressure sensors that is functional over a wide temperature range between -55 degrees C and 225 degrees C. The circuit is implemented using IBM 0.13 MUm CMOS technology with 2.5 V power supply. A constant-gm biasing technique is used to mitigate performance degradation at high temperatures. The circuit offers the flexibility to interface with MEMS sensors with a wide range of the steady-state capacitance values from 0.5 pF to 10 pF. Simulation results show that the circuitry has excellent linearity and stability over the wide temperature range. Experimental results confirm that the temperature effects on the circuitry are small, with an overall linearity error around 2%. PMID- 25686313 TI - Simultaneous 2D strain sensing using polymer planar Bragg gratings. AB - We demonstrate the application of polymer planar Bragg gratings for multi-axial strain sensing and particularly highlight simultaneous 2D strain measurement. A polymer planar Bragg grating (PPBG) fabricated with a single writing step in bulk polymethylmethacrylate is used for measuring both tensile and compressive strain at various angles. It is shown that the sensitivity of the PPBG strongly depends on the angle between the optical waveguide into which the grating is inscribed and the direction along which the mechanical load is applied. Additionally, a 2D PPBG fabricated by writing two Bragg gratings angularly displaced from each other into a single polymer platelet is bonded to a stainless steel plate. The two reflected wavelengths exhibit different sensitivities while tested toward tensile and compressive strain. These characteristics make 2D PPBG suitable for measuring multi-axial tensile and compressive strain. PMID- 25686314 TI - An accurate link correlation estimator for improving wireless protocol performance. AB - Wireless link correlation has shown significant impact on the performance of various sensor network protocols. Many works have been devoted to exploiting link correlation for protocol improvements. However, the effectiveness of these designs heavily relies on the accuracy of link correlation measurement. In this paper, we investigate state-of-the-art link correlation measurement and analyze the limitations of existing works. We then propose a novel lightweight and accurate link correlation estimation (LACE) approach based on the reasoning of link correlation formation. LACE combines both long-term and short-term link behaviors for link correlation estimation. We implement LACE as a stand-alone interface in TinyOS and incorporate it into both routing and flooding protocols. Simulation and testbed results show that LACE: (1) achieves more accurate and lightweight link correlation measurements than the state-of-the-art work; and (2) greatly improves the performance of protocols exploiting link correlation. PMID- 25686315 TI - Development of an immunochromatographic strip for rapid detection of Pantoea stewartii subsp. stewartii. AB - A rapid, simple, sensitive, and specific immunochromatographic test strip was developed for the detection of Pantoea stewartii subsp. stewartii (Pss) in corn seed which was soaked overnight and then centrifuged for precipitate re-dissolved as samples. A pair of sensitive monoclonal antibodies for the immunochromatographic test strip was generated by mice immunization and cell fusion. Under optimized conditions, the lower detection limit of the strips for Pss was 1 * 10(5) cfu/mL both in 0.01 M phosphate buffer solution and corn seed samples, with no cross-reactivity with other common plant pathogens. The developed strip is useful and rapid for the detection of Pss in corn seed samples. PMID- 25686316 TI - An overview of distributed microgrid state estimation and control for smart grids. AB - Given the significant concerns regarding carbon emission from the fossil fuels, global warming and energy crisis, the renewable distributed energy resources (DERs) are going to be integrated in the smart grid. This grid can spread the intelligence of the energy distribution and control system from the central unit to the long-distance remote areas, thus enabling accurate state estimation (SE) and wide-area real-time monitoring of these intermittent energy sources. In contrast to the traditional methods of SE, this paper proposes a novel accuracy dependent Kalman filter (KF) based microgrid SE for the smart grid that uses typical communication systems. Then this article proposes a discrete-time linear quadratic regulation to control the state deviations of the microgrid incorporating multiple DERs. Therefore, integrating these two approaches with application to the smart grid forms a novel contributions in green energy and control research communities. Finally, the simulation results show that the proposed KF based microgrid SE and control algorithm provides an accurate SE and control compared with the existing method. PMID- 25686317 TI - Illumination-invariant and deformation-tolerant inner knuckle print recognition using portable devices. AB - We propose a novel biometric recognition method that identifies the inner knuckle print (IKP). It is robust enough to confront uncontrolled lighting conditions, pose variations and low imaging quality. Such robustness is crucial for its application on portable devices equipped with consumer-level cameras. We achieve this robustness by two means. First, we propose a novel feature extraction scheme that highlights the salient structure and suppresses incorrect and/or unwanted features. The extracted IKP features retain simple geometry and morphology and reduce the interference of illumination. Second, to counteract the deformation induced by different hand orientations, we propose a novel structure-context descriptor based on local statistics. To our best knowledge, we are the first to simultaneously consider the illumination invariance and deformation tolerance for appearance-based low-resolution hand biometrics. Settings in previous works are more restrictive. They made strong assumptions either about the illumination condition or the restrictive hand orientation. Extensive experiments demonstrate that our method outperforms the state-of-the-art methods in terms of recognition accuracy, especially under uncontrolled lighting conditions and the flexible hand orientation requirement. PMID- 25686318 TI - Driven molecular dynamics studies of the shared proton motion in the H5O2+.Ar cluster: the effect of argon tagging and deuteration on vibrational spectra. AB - We report IR spectra of H5O2(+) and H5O2(+).Ar and their deuterium isotopologues using ab initio molecular dynamics. The trajectories were propagated as microcanonical (NVE) ensembles at energies corresponding to temperatures 50 and 100 K. The potential energy surface is calculated on-the-fly at the MP2/aug-cc pVDZ level of theory. The calculations show that adding an argon atom to H5O2(+) introduces symmetry breaking in the Zundel core ion, causes blueshift in the shared proton vibration by about 200 cm(-1), and leads to the splitting of the OH stretch vibrations into four bands. Driven molecular dynamics (DMD) method is used to assign the spectrum by coupling the dipole moment to an external electric field oscillating at frequency omega. The broad feature at 1100 cm(-1) in the H5O2(+).Ar spectrum is ascribed to the large amplitude shared proton vibration coupled with torsion and wag modes. MD MP2 simulations predict the H/D redshift in the shared proton vibration and water bending vibration to be about 280 and 460 cm(-1), respectively, in good agreement with experimental observations. PMID- 25686319 TI - Primary familial brain calcification with known gene mutations: a systematic review and challenges of phenotypic characterization. AB - IMPORTANCE: In the past 2 years, 3 genes (SLC20A2, PDGFRB, and PDGFB) were identified as causative of primary familial brain calcification (PFBC), enabling genotype-specific phenotyping. OBJECTIVES: To provide a systematic literature review on the neuroimaging and clinical phenotype of genetically confirmed PFBC and summarize known pathophysiological mechanisms, to improve and harmonize future phenotype description and reporting by addressing data gaps, and to develop uniform definitions for clinical characterization. EVIDENCE REVIEW: We systematically searched the MEDLINE database among articles published from January 1, 2012, through May 31, 2014, for the 3 genes and selected 25 articles from all records (n=75) and from sources cited in the reference lists. Only genetically confirmed cases with individual clinical information were included, leaving 15 reports. Predefined categories for data extraction were different neurologic and psychiatric symptoms, imaging results, and age at onset (AAO). We also assessed availability of information to estimate possible bias. FINDINGS: We included a total of 179 cases, 162 of which belong to 25 families. Availability of information ranged from 96.6% for ethnicity to 24.4% for AAO. All cases had calcifications on comprehensive cranial computed tomography, most frequently located in the basal ganglia (70.6%), subcortical white matter (40.8%), cerebellum (34.1%), or thalamus (28.5%). Mean (SD) AAO was 27.9 (22.3) years, and the AAO was comparable across genes (P=.77). The most frequently described signs were movement disorders, such as parkinsonism (12%) and dystonia (19%). Penetrance of the imaging phenotype was 100% compared with only 61% of the clinical phenotype. We propose a novel definition of disease status by specifying PFBC into genetic, clinical, and imaging phenotypes. Pathophysiological pathways converge on impaired phosphorus homeostasis and integrity of the blood-brain barrier. CONCLUSIONS AND RELEVANCE: Especially in rare conditions, meta-analyses are the most suitable tool to extract reliable information on the natural course of a disease. For future analyses, we provide a minimal data set that can be used for systematic clinical and imaging data collection in PFBC and that will also improve informed counseling of patients. PMID- 25686320 TI - [Fifty years' retrospection of systemic study on salivary gland tumors]. AB - Salivary gland tumors are a group of the most common tumors in the oral and maxillofacial region with obvious characteristics of clinical, histopathologic, and therapeutic aspects. During the past 50 years, our research group performed a systemic study on salivary gland tumors including imaging diagnosis, fine needle aspiration cytology, FT-mid-IR fiber optics spectroscopy, histopathologic features and biological behaviour of the tumors, functional parotid surgery, and (125)I seed implant branchytherapy. More reasonable principles of management for various types of the tumors were put forward based on the histopathologic features of the tumors. The surgical techniques were modified and the postoperative complications were reduced obviously. Thus, the quality of life of the patients was improved greatly. PMID- 25686321 TI - [Activation of transient receptor potential vanilloid subtype 1 serves as a novel pathway to modulate secretion in submandibular gland]. AB - Our work focused on the studies on the expression and function of transient receptor potential vanilloid subtype 1 (TRPV1) in the submandibular gland. By using reverse transcription-polymerase chain reaction (RT-PCR), Western blotting, and immunofluorescence, our data demonstrated the expression and distribution characteristics of TRPV1 in rabbit and human submandibular glands, as well as rat submandibular gland cell line SMG-C6. Furthermore, the possible intracellular signal molecules involved in the TRPV1-modulated saliva secretion were explored. Activation of TRPV1 increased the intracellular Ca(2+) concentration, upregulated the expression of aquaporin 5 (AQP5), the main transporter that mediate water secretion through transcellular pathway, and led to AQP5 redistribution. Extracellular signal-regulated kinase 1/2 (ERK1/2) was involved in the TRPV1 regulated AQP5 content. Besides, TRPV1 activation also modulated the expression, distribution, and function of tight junction protein, and increased paracellular permeability. ERK1/2 and myosin light chain 2 (MLC2) were responsible for the regulation of TRPV1on tight junction properties. Taken together, our work suggested that TRPV1 was a potential target to promote saliva secretion, and activation of TRPV1 might provide a new and safe therapeutic strategy to ameliorate submandibular gland hypofunction. PMID- 25686322 TI - [Clinical and putative periodontal pathogens' features of different sites with probing depth reduction after non-surgical periodontal treatment of patients with aggressive periodontitis]. AB - OBJECTIVE: To evaluate the differences of clinical parameters and putative periodontal pathogens in sites of different probing depth (PD) reduction after non-surgical periodontal treatment in patients with aggressive periodontitis (AgP). METHODS: Clinical examinations including plaque index, probing depth (PD), attachment level (AL) and bleeding index (BI), and full-mouth periapical photographs were collected from 20 patients with AgP. All the patients received non-surgical periodontal treatment, including oral hygiene instruction, supra gingival scaling, subgingival scaling and root planing (SRP) and were followed up for 6 months post-therapy. Gingival crevicular fluids (GCF) were collected at 1 site in each quadrant before and at the end of 6 months post-therapy. Six kinds of putative periodontal pathogens and 6 kinds of short chain fatty acids (SCFAs) were detected in the GCF samples. RESULTS: The baseline clinical parameters of PD, AL and BI, the baseline concentration of succinic acid, acetic acid, propionic acid and butyric acid, and the prevalence of Treponema denticola were significantly higher in sites with PD reduction more than 2 mm sites compared with PD reduction no more than 2 mm sites [(7.7 +/- 1.2) mm vs. (5.1 +/- 1.8) mm, (6.3 +/- 1.9) mm vs. (4.5 +/- 2.2) mm, 3.8 +/- 0.4 vs. 3.3 +/- 0.8, 1.66 mmol/L vs. 1.10 mmol/L, 31.67 mmol/L vs.17.78 mmol/L, 3.31 mmol/L vs.1.95 mmol/L, 84.6% vs. 56.1%, P<0.05]. However, there were no significant differences in the clinical parameters, the 6 kinds of putative periodontal pathogen detection and SCFAs concentration between the 2 groups at the end of 6 months post-treatment. In sites with PD>5 mm at the end of 6 months post-therapy, all were found with red complex bacteria infection. CONCLUSION: The baseline clinical parameters are important factors in predicting PD reduction after non-surgical periodontal treatment in patients with AgP. In sites with deep pockets after non-surgical periodontal treatment, the active control of red complex bacteria is recommended. PMID- 25686323 TI - [Radiographic evaluation of ridge preservation after molar tooth extraction: a controlled clinical trial]. AB - OBJECTIVE: To compare the bone dimensional changes following tooth extraction alone with extraction plus ridge preservation (using deproteinized boving bone mineral Bio-Oss(r) and bioresorbable collagen mambrane Bio-Gide(r)) in periodontal compromised extraction sockets. METHODS: Eighteen molars of sixteen subjects requiring tooth extraction because of periodontal destruction were enrolled in this study. The subjects were assigned to the control group (extraction alone, EXT) or to the test group (ridge-preservation procedure with Bio-Oss(r) and Bio-Gide, RP). Parallel periapical X-rays and cone-beam computed tomography (CBCT) scans were taken immediately after tooth extraction alone or plus ridge-preservation (baseline) and 6 months later. The changes of horizontal ridge width and vertical ridge height were assessed. RESULTS: At the central buccal aspect, the ridge height increased 2.9 mm in RP group, and reduced 1.0 mm in EXT group. At the distal buccal aspect, the ridge height increased 1.45 mm in RP group, and reduced 1.45 mm in EXT group. The differences between the groups reached statistical significance (P<0.05). The mean ridge width increased at the 1 mm below the crest (the horizontal ridge width was measured with grafting material at three levels at 1 mm below the most coronal aspect of the crest,HW1), which amounted to 3.40 to 5.80 mm in RP group, and 1.45 to 2.90 mm in EXT group. The mean ridge increased at the 4 mm below the crest (the horizontal ridge width was measured with grafting material at three levels at 4 mm below the most coronal aspect of the crest,HW4), which amounted to 0.40 to 3.50 mm in RP group, and reduced 0.10 to increased 0.15 mm in EXT group. The test group and the control group were not significantly different (P>0.05). CONCLUSION: The ridge preservation approach using Bio-Oss(r) in combination with Bio-Gide(r) can significantly increase vertical ridge height and horizontal ridge width after tooth extraction compared with extraction alone in periodontal compromised molars. PMID- 25686324 TI - [Clinical effect of different sequences of debridement-antibiotic therapy in treatment of severe chronic periodontitis]. AB - OBJECTIVE: To evaluate the feasibility of full-mouth debridement (subgingival scaling and root planning, SRP) by 2 times within 1 week and compare the clinical effects of different sequences of debridement-antibiotic usage in patients with severe chronic periodontitis (CP). METHODS: A double-blinded, placebo-controlled, randomized clinical trial was conducted in 30 severe CP patients (14 males and 16 females, 40.5 +/- 8.4 years old on average from 35 to 60) receiving 3 different sequences of debridement-antibiotictherapy: Group A, antibiotic usage (metronidazole, MTZ, 0.2 g, tid, 7 d; amoxicillin, AMX 0.5 g, tid, 7 d) was started together with SRP (completed by 2 times in 7 d); Group B, antibiotic usage (MTZ 0.2 g, tid, 7 d; AMX 0.5 g, tid, 7 d) was started 1 d after SRP(completed by 2 times in 7 d); Group C, SRP alone[probing depth (PD), bleeding index (BI) and tooth mobility] was examined. The average full-mouth probing depth, the average full-mouth proximal probing depth (pPD), the percentage of sites with PD>5 mm (PD>5 mm%), the percentage of sites with proximal PD>5 mm (pPD>5 mm%), the average bleeding index (BI) and the percentage of sites with bleeding on probing (BOP%) were calculated. Clinical examinations were performed at baseline and 2 months post therapy. RESULTS: (1) Compared with baseline conditions, all the subjects showed clinical improvements in all the parameters evaluated 2 months post therapy, P<0.05. (2) Significant difference were observed in the average PD changes between Group A [(2.15 +/- 0.42) mm], Group B [(1.76 +/ 0.29) mm] and Group C [(1.57 +/- 0.33) mm], P<0.05. No significant difference was observed in the average PD changes between Group B and Group C, P=0.354. Significant differences were observed in the average pPD changes between Group A [(2.45 +/- 0.43)mm] and Group C[(1.90 +/- 0.48) mm], P<0.05. No significant difference was observed in BI and BOP% changes between Group A,Group B and Group C. CONCLUSION: For patients with severe chronic periodontitis, it is safe and feasible to receive full-mouth SRP by 2 times within 1 week. The short-term (2 months) advantages in PD changes are observed in patients receiving SRP and antibiotic usage at the same time comparing with patients using antibiotics after SRP or SRP alone. PMID- 25686325 TI - [Comparison of biological characteristics of human gingival junctional epithelial cells and oral epithelial cells]. AB - OBJECTIVE: To isolate P-cadherin positive and negative oral gingival epithelial cells, and to compare the biological characteristics with junctional epithelial cells. METHODS: Human oral gingival epithelial cells and junctional epithelial cells were cultured. P-cadherin positive and negative cells were isolated from oral gingival epithelial cells. The cellular adhesion, proliferation and migration were measured and compared. RESULTS: The P-cadherin positive cells accounted for 20% of oral gingival epithelial cells. Compared with juctional epithelial cells, P-cadherin positive oral gingival epithelial cells showed similar properties of adhesion and migration, and stronger proliferation ability (0.72 +/- 0.06 vs. 0.60 +/- 0.05, P<0.05). P-cadherin negative oral gingival epithelial cells showed weaker ability of adhesion (48% +/- 6% vs. 87% +/- 11%, P<0.05), proliferation (0.36 +/- 0.04 vs. 0.60 +/- 0.05, P<0.05) and migration (10.3 +/- 2.7 vs. 23.4 +/- 4.8, P<0.05). CONCLUSION: P-cadherin positive oral gingival epithelial cells showed some similar but different biological characteristics, compared with juctional epithelial cells, which suggested that during the process of transforming oral gingival epithelial cells into juctional epithelial cells, complex gene and protein changes were involved instead of simply cellular migration. PMID- 25686326 TI - [Determination of bone metabolic marker levels in perio-implant crevicular fluid and analysis of dental implants stability by resonance frequency in the early stage of healing]. AB - OBJECTIVE: To investigate the changes of osteoprotegerin (OPG) and receptor activator of nuclear factor kappa B ligand (RANKL) level in perio-implant crevicular fluid (PICF) and to monitor the development of the stability of Straumann(r) tissue-level implants by resonance frequency analysis (RFA) during the early phases of healing. METHODS: A total of 35 implants (length 10 mm) were placed. PICF samples were collected with filter paper strips at baseline, 1, 2, 3, 4, 6, 8, and 12 weeks post-surgery, respectively. The OPG, RANKL levels were determined by ELISA method. At the same time points, the implant stability quotient (ISQ) values were determined with OsstellTM mentor. RESULTS: During healing, PICF-OPG levels increased significantly 2 weeks after surgery when compared with the 4(th) -, 6(th) -, 8(th) - and 12(th) -week reevaluation (P<0.05). The OPG/RANKL ratio in PICF was significantly higher (P<0.05) than that in gingival crevicular fluid at 1 week post-surgery. ISQ slightly fluctuated within the first 4 weeks after installation. Following this, the ISQ values increased steadily for all the implants and up to 12 weeks. Significant differences were noted between the mean ISQ values at the 12th-week and other observation time points. CONCLUSION: The PICF-OPG levels may be effective in monitoring the process of osseointegration. All the ISQ values indicated the stability of Straumann(r) implants over a 12-week healing period. RFA is a reliable and effective assistant to monitor implant stability. PMID- 25686327 TI - [Spatiotemporal expression pattern of E-cadherin and P-cadherin during mouse tooth development]. AB - OBJECTIVE: To investigate the expression patterns of E-cadherin and P-cadherin in murine-tooth germs at early developmental stages. METHODS: Mandible samples of CD1 mice from embryonic day 12.5 to postnatal day 3.5 were collected. The expressions of E-cadherin and P-cadherin in murine mandibular first molar germs were detected by immunofluorescence and observed under confocal fluorescence microscope. HE staining was performed for tissue morphology. RESULTS: Both E cadherin and P-cadherin were widely expressed in the epithelial tissues through early developmental stages. The E-cadherin expression was increased in polarizing pre-ameloblasts, whereas the P-cadherin expression declined. The expression of the P-cadherin could be detected in epithelial tissues before bud stage, and expressed in mature ameloblasts at secretory stage. CONCLUSION: The E-cadherin and P-cadherin expressed in different spatiotemporal expression patterns, indicating their individual functions during tooth development. P-cadherin might function in the secretion and mineralization of enamel. PMID- 25686328 TI - [Ectopic osteogenesis of stromal cell-derived factor 1 combined with simvastatin loaded collagen scaffold in vivo]. AB - OBJECTIVE: To construct and evaluate a novel tissue-engineered bone composed of murine stromal cell-derived factor 1(mSDF-1), simvastatin (SIM) and collagen scaffold (Bio-Oss(r)), serving as a cell-homing approach for bone formation. METHODS: In the study, 32 ICR mice were randomly divided into 4 groups,each group including 8 mice. The drug-loaded collagen scaffolds were implanted subcutaneously onto the cranium of each mouse according to the groups: (1) 1:50 (volume ratio) dimethyl sulfoxide (DMSO)/phosphate-buffered saline (PBS) solution + collagen scaffold (blank control group); (2) 10-3 mol/L SIM solution + collagen scaffold (SIM group); (3) 200 mg/L mSDF-1 solution + collagen scaffold (mSDF-1 group); and (4) 10(r) mol/L SIM +200 mg/L mSDF-1 solution + collagen scaffold (SIM + mSDF-1 group). One week after implantation, the mice were treated by injecting the same drug solution mentioned above around the scaffold once a day for two days. The specimens were harvested 6 weeks after implantation and the bone formation was evaluated by soft X-ray analysis, HE staining and immunohistochemical staining. Angiogenesis of each group was checked by calculation of vessels in each tissue section. RESULTS: Six weeks after implantation, the collagen scaffolds were retrieved. The value of gray scale for the SIM+mSDF-1 group [(421 836.5 +/- 65 425.7)pixels] was significantly higher than that of the blank control group[(153 345.6 +/- 45 222.2) pixels, P<0.01], the SIM group [(158 119.2 +/- 100 284.2)pixels, P<0.01], and the mSDF-1 group[(255 529.5 +/- 152 142.4)pixels, P<0.05]; HE staining analysis revealed that significant bone formation was achieved in the SIM + mSDF-1 group; The immunohistochemical staining showed the existence of osteopontin and osteocalcin in the SIM + mSDF-1 group; There were more vessels in the SIM+mSDF-1 group[(46 +/ 8)vessels/mm2] than in the blank control group [(23 +/- 7) vessels/mm2, P<0.01], and the SIM group[(24 +/- 6) vessels/mm2, P<0.01]. CONCLUSION: The novel tissue engineered bone composed of mSDF-1, SIM and collagen scaffolds has the potential to form bone subcutaneously in vivo. It represents a novel method of in vivo bone re-generation without seed cell delivery. PMID- 25686329 TI - [Synergistic effects of lysozyme with EDTA-2Na on antibacterial activity]. AB - OBJECTIVE: To evaluate the synergistic antibacterial effects of lysozyme with ethylenediaminetetraacetic acid disodium salt (EDTA-2Na) on Enterococcus faecalis (E. faecalis) and Porphyromonas endodontalis (P. endodontalis). METHODS: E. faecalis and P. endodontalis were cultured and adjusted to 10(8) CFU/mL. Then 0.3, 0.5, 1, 2, 5, 10, 50, 100, 150 and 300 g/L of lysozyme were prepared with deionized water; and the lysozyme solutions were mixed with 0.5, 1.0, 2.0 g/L of EDTA-2Na, respectively. The bacteria and lysosome with/without EDTA-2Na interacted for 15 min, then water-soluble tetrazolium (WST) working solution was added and the activity of the bacteria was calculated by measuring optical densities at 450 nm and 630 nm with microplate spectrophotometer. RESULTS: Regarding the pure lysozyme from 0.5 g/L to 150 g/L, more E. faecalis and P. endodontalis were inhibited when the concentration of lysozyme was higher, especially for E. faecalis. There was synergistic effect of lysozyme with EDTA 2Na on antibacterial activity, which was related to the concentration of lysozyme. On E. faecalis, the antibacterial activity of lysozyme with EDTA-2Na was 1.2-3.7 folds than the pure lysozyme when the concentration of lysozyme was 0.5-50 g/L (P<0.05), and on P. endodontalis, the antibacterial activity of lysozyme with EDTA-2Na was 1.3-3.5 folds than the pure lysozyme when the concentration of lysozyme was 0.5-10 g/L (P<0.05). When the concentration of lysozyme was higher than 100 g/L, EDTA-2Na did not show synergistic effect on the antibacterial activity (P>0.05). CONCLUSION: For E. faecalis and P. endodontalis, a low concentration of lysozyme with EDTA-2Na showed significant synergistic antibacterial activity, while a high concentration of lysozyme with EDTA-2Na did not. PMID- 25686330 TI - [Study on prediction of involvement in facial nerve in the patients with parotid tumors by using facial electroneurography]. AB - OBJECTIVE: To investigate the possibility of predicting facial nerve involvement in the patients with parotid tumors using facial electroneurography (ENoG). METHODS: In the study, 53 patients with primary parotid tumors were included in the study, 28 were benign tumors and 25 were malignant. There was no significant difference of tumor locations and sizes between the two groups. House-Brackmann facial nerve function evaluation was grade I in all the patients who received examination of facial electroneurography, including stimulation strength, amplitude, and latent time bilaterally. The facial electroneurography results in the affected side were compared with the results of contralateral normal side, intraoperative appearance and postoperative histopathological diagnosis. The facial electroneurography results were analyzed by Wilcoxon signed rank test and receiver operator characteristic (ROC) curve. RESULTS: During the facial electroneurography examination, the mean stimulation strength in the patients with benign parotid tumor was 20.0 mA. There was significant decrease in the amplitude at the affected side compared with the normal side upon posterior auricular stimulation (P<0.05). But there was no significant difference in the latent time between the bilateral sides (P>0.05). However, in the patients with malignant parotid tumor, the mean stimulation strength was higher at 24.5 mA. There was significant decrease in the amplitude or even no response at the affected side compared to the normal side upon posterior auricular stimulation (P<0.05). No response was detected in the multiple branches of facial nerve of affected sides in 36.0% patients upon posterior auricular stimulation. The amplitude of branches III and IV was significantly lower at the affected side than that at the normal side upon anterior auricular stimulation (P<0.05). The area under the ROC curve for ENoG was 0.884. CONCLUSION: When the facial nerve was involved by the parotid tumors, the stimulation strength in the electroneurography was larger. There was significant difference in the amplitude and the latent time of the facial nerve between the affected side and the normal side upon the posterior auricular stimulation. The rate of absence of reaction wave was higher in the patients with malignant tumors. It was feasible to predict the facial nerve involvement by ENoG for the parotid gland tumor patients without clinical appearances of facial paralysis. PMID- 25686331 TI - [Study on interface compatibility and fracture resistance of polyglycidyl methacrylate pre-impregnated quartz fiber reinforced polymethyl methacrylate denture base resin]. AB - OBJECTIVE: To explore the reinforcement of polyglycidyl methacrylate (PGMA) pre impregnated quartz fiber mesh in denture base materials by investigation of interface compatibility and fracture resistance. METHODS: 1-layer, 2-layer, 3 layer PGMA pre-impregnated quartz fiber meshes, electrolyzed cobalt-chromium alloy mesh and cobalt-chromium alloy mesh conditioned by metal primer were integrated in polymethyl methacrylate (PMMA) resin by sandwich embedding method. Block samples of 5 groups were prepared (40 mm*15 mm*2 mm). Fracture resistance was determined in a 3-point bending test at 2 mm/min. Scanning electron microscope (SEM), micrographs were taken from the fractured surfaces to analyze the bonding interface compatibility. RESULTS: The group of 3-layer PGMA pre impregnated quartz fiber mesh presented the highest elastic modulus of 6 406 MPa and flexural strength of 227 MPa among the five groups, while the 1-layer and 2 layer expressed the similar elastic modulus and flexural strength to the pure PMMA group. The metal groups demonstrated better mechanical properties, while the metal surface conditioner played much better. The metal surface conditioner pre impregnated cobalt-chromium alloy and PGMA pre-impregnated quartz fiber mesh showed compatible interface with PMMA. CONCLUSION: The mechanical properties were improved by the increasing of the fiber by adding the more meshed. Although the benign interface did help the compatibility, the quantity of the fibers played an important role in the strength. PMID- 25686332 TI - [Comparison of soft and hard tissue stability between immediate implant and delayed implant in maxillary anterior region after loading 2 years]. AB - OBJECTIVE: To compare the peri-implant tissue stability between immediate implant and delayed implant in maxillary anterior region after loading 2 years. METHODS: In the study, 38 patients with single anterior tooth loss in the Second Clinical Division of Peking University School and Hospital of Stomatology from October 2010 to December 2011 were enrolled, and 43 implants were inserted. The gingival contour was induced using implant-supported temporary crowns prior to restoration till permanent prostheses delivered. The gingival papilla height, labial gingival margin level and peri-implant bone level were measured immediately after the permanent restoration and 2 years later. RESULTS: In the study, 16 patients were treated by immediate implant for 17 implants; 22 patients were treated by delayed implant for 26 implants. The implant stability quotient (ISQ) value of the 2 groups showed no significant difference before permanent restoration (P>0.05). In all the cases after loading 2 years, the average mesial gingival papilla height in the implant area of the immediate group and delayed group increased by (0.15 +/- 0.42) mm and (0.06 +/- 0.65) mm, respectively; the distal gingival papilla height increased by (0.06 +/- 0.50) mm and (0.02 +/- 0.57) mm respectively; while the labial gingival margin level shrinkages were (0.15 +/- 0.23) mm and (0.15 +/- 0.46) mm, respectively. The peri-implant bone losses in the mesial side were (0.67 +/- 0.35) mm and (0.6 9 +/- 0.49) mm, respectively, while in the distal side were (0.73 +/- 0.31) mm and (0.75 +/- 0.48) mm, respectively. All these indicators showed no significant difference between the 2 groups (P>0.05). CONCLUSION: Both the cases obtained optimizer results after loading 2 years, and the soft and hard tissues around the implant were very stable, which means that both the protocols can achieve reliable therapeutic effects. If we can handle the indications, immediate implant for anterior teeth shows similar efficacy with delayed implant in the short term. But immediate implant in terms of shortening the course of treatment is clearly superior to delayed implant. PMID- 25686333 TI - [Influence of attachment type on stress distribution of implant-supported removable partial dentures]. AB - OBJECTIVE: To compare influences of different retention attachments on stress among supporting structures. METHODS: By 3-dimensional laser scanner and reverse engineering computer aided design (CAD) software, a basic partially edentulous digital model with mandibular premolar and molar missing was established. Implant attachment and removable partial dentures (RPD) were added into the basic model to build three kinds of models: RPD only, RPD + implant + Locator attachment, and RPD + implant + Magfit attachment. Vertical and inclined loads were put on artificial teeth unilaterally. By means of 3-dimensional finite element analysis, the stress distribution and displacement of the main supportive structures were compared. RESULTS: A complete 3-dimensional finite element model was established, which contained tooth structure, and periodontal structures. The displacement of the denture was smaller in Locator (9.38 MUm vertically, 45.48 MUm obliquely) and Magfit models (9.54 MUm vertically, 39.45 MUm obliquely) compared with non implant RPD model (95.27 MUm vertically, 155.70 MUm obliquely). Compared with the two different attachments, cortical bone stress value was higher in Locator model (Locator model 10.850 MPa vertically, 43.760 MPa obliquely; Magfit model 7.100 MPa vertically, 19.260 MPa obliquely).The stress value of abutment periodontal ligamentin Magfit model (0.420 MPa vertically) was lower than that in Locator model (0.520 MPa vertically). CONCLUSION: The existence of implant could reduce maximum von Mises value of each supportive structure when Kennedy I partially edentulous mandible was restored. Comparing the structure of Magfit and Locator attachment, the contact of Magfit attachment was rigid, while Locator was resilient. Locator attachment could improve stability of the denture dramatically. Locator had stronger effect on defending horizontal movement of the denture. PMID- 25686334 TI - [Three-dimensional finite element analysis of one-piece computer aided design and computer aided manufacture involved zirconia post and core]. AB - OBJECTIVE: To analyze the biomechanics trait of one-piece computer aided design and computer aided manufacture (CAD/CAM) zirconia post and core by the Three dimensional finite element. METHODS: The Three-dimensional finite element models of three upper central incisors restored with one-piece CAD/CAM zirconia post and core (group 1), refabricated zirconia post and hot-pressed porcelain core (group 2), and cast gold alloy post and core (group 3) were built by geometry method respectively. 100 N vertical loading through the central incisor models long axis and 100 N loading along directing at an angle of 45 degrees with the models long axis were used to imitate the central incisor stress state in biting and mandible physiological protraction movement. RESULTS: Under vertical loading, the restored teeth without dentin ferrule, the maximum Von-Mises stress value of the tooth root in group 1 was the least(11.02 N), which was the largest (13.17 N)in group 2. The stress became weaker from the upper to the lower of the tooth root. The maximum Von-Mises stress value of the tooth root, post and core became smaller while the restored teeth with the 2.0 mm high dentin ferrule. Under directing at an angle of 45 degrees loading, without the design of dentin ferrule in the restored teeth, the maximum Von-Mises stress value of the post and core in group 1 was the greatest(20.45 N), while that stress of post and core in group 3 was the smallest(13.61 N). With 2.0 mm high dentin ferrule design in the restored teeth, the tooth root stress became weaker. The maximum Von-Mises stress value of the tooth root was the greatest (14.10 N) in group 3, but which was the lowest (13.38 N) in group 1. CONCLUSION: The results of the Three-dimensional finite element analysis infers that one-piece zirconia post and core restoration is more beneficial to disperse the bite force than the prefabricated zirconia post and the cast gold alloy post and core. The one-piece of zirconia post and core is good to protect the teeth and keep the restoration intact. PMID- 25686335 TI - [Precision of digital impressions with TRIOS under simulated intraoral impression taking conditions]. AB - OBJECTIVE: To evaluate the precision of digital impressions taken under simulated clinical impression taking conditions with TRIOS and to compare with the precision of extraoral digitalizations. METHODS: Six #14-#17 epoxy resin dentitions with extracted #16 tooth preparations embedded were made. For each artificial dentition, (1)a silicone rubber impression was taken with individual tray, poured with type IV plaster,and digitalized with 3Shape D700 model scanner for 10 times; (2) fastened to a dental simulator, 10 digital impressions for each were taken with 3Shape TRIOS intraoral scanner. To assess the precision, best-fit algorithm and 3D comparison were conducted between repeated scan models pairwise by Geomagic Qualify 12.0, exported as averaged errors (AE) and color-coded diagrams. Non-parametric analysis was performed to compare the precisions of digital impressions and model images. The color-coded diagrams were used to show the deviations distributions. RESULTS: The mean of AE for digital impressions was 7.058 281 MUm, which was greater than that of 4.092 363 MUm for the model images (P<0.05). However, the means and medians of AE for digital impressions were no more than 10 MUm, which meant that the consistency between the digital impressions was good. The deviations distribution was uniform in the model images,while nonuniform in the digital impressions with greater deviations lay mainly around the shoulders and interproximal surfaces. CONCLUSION: Digital impressions with TRIOS are of good precision and up to the clinical standard. Shoulders and interproximal surfaces scanning are more difficult. PMID- 25686336 TI - [Validation of subjective and objective evaluation methods for orthodontic treatment outcome]. AB - OBJECTIVE: To assess the correlations between objective measurements of 108 finished orthodontic cases and subjective assessments made by 69 orthodontic specialists, to explore the statistically significant measuring categories of cast and cephalogram and to validate the regression model. METHODS: A stratified random sample of 108 cases was drawn from the large sample of 2 383 patients who finished orthodontic treatment between July 2006 and August 2008 in six orthodontic treatment centers around China. For each patient, the post-treatment information sources evaluated in this study included standardized plaster study casts and a lateral cephalometric X-ray image. These information sources were evaluated both singly and in combination by a panel of 69 orthodontic specialists. The average subjective grading scores of 69 orthodontists were regarded as the gold standard. Six examiners used the peer assessment rating (PAR) index and American board of orthodontics-objective grading system (ABO-OGS) to measure all the study casts respectively and three other examiners measured all the lateral cephalometric X-ray images by using customized software. The objective measuring data were correlated with the gold standard. The correlations between the objective measurement and the subjective evaluation were assessed, the statistically significant measuring categories of cast and cephalogram were explored and the regression model was validated. RESULTS: The ABO-OGS scores of "occlusal relationship" correlated most strongly with the subjective scores of cast (r=0.655, P<0.01), and the secondarily correlated category with those were the PAR scores of "overjet" (r=0.525, P<0.01). The proclination of the lower incisors correlated most strongly with the subjective scores of cephalogram (r=0.446, P<0.01), and the secondarily correlated category with those was the protrusion of the lower lips (r=0.436, P<0.01). Nine components were predictive for the post-treatment model and lateral ephalometric film (Post-M+C) outcome: alignment (ABO-OGS), occlusal relationship (ABO-OGS), interproximal contact(ABO OGS), L1/NB degrees , overjet (PAR), SNB degrees , occlusal contacts (ABO-OGS), U1/SN2 degrees and centerline (PAR). These 9 components accounted for 72% of the variability in the average subjective grading scores. CONCLUSION: The objective regression model could replace the averaged opinion of Chinese orthodontic experts effectively, making objective assessment of orthodontic treatment outcome for Chinese patients. PMID- 25686337 TI - [Preliminary evaluation on 3-demension changes of facial soft tissue with structure light scanning technique before and after orthognathic surgery of Class III deformities]. AB - OBJECTIVE: To evaluate facial soft tissue 3-deminsion changes of skeletal Class III malocclusion patients after orthognathic surgery using structure light scanning technique. METHODS: Eight patients [3 males and 5 females, aged (27.08 +/- 4.42) years] with Class III dentoskeletal relationship who underwent a bimaxillary orthognathic surgical procedure involving advancement of the maxilla by Le Fort I osteotomy and mandibular setback by bilateral sagittal split ramus osteotomy (BSSO) and genioplasty to correct deformity were included. 3D facial images were obtained by structure light scanner for all the patients 2 weeks preoperatively and 6 months postoperatively. The facial soft tissue changes were evaluated in 3-dimension. The linear distances and angulation changes for facial soft tissue landmarks were analyzed. The soft tissue volumetric changes were assessed too. RESULTS: There were significant differences in the sagittal and vertical changes of soft tissue landmarks. The greatest amount of soft tissue change was close to lips. There were more volumetric changes in the chin than in the maxilla, and fewer in the forehead. CONCLUSION: After biomaxillary surgery, there were significant facial soft tissue differences mainly in the sagittal and vertical dimension for skeletal Class III patients. The structure light 3D scanning technique can be accurately used to estimate the soft tissue changes in patients who undergo orthognathic surgery. PMID- 25686338 TI - [Comparison of three surgical techniques for controlling nasal width after Le Fort I osteotomy]. AB - OBJECTIVE: To identify nasal width changes occurring after Le Fort I osteotomy and to compare prospectively the effect of three surgical techniques for controlling postoperative nasal width. METHODS: In the study, 79 patients (22 male and 57 female, mean age 23.2 +/- 3.4 years), who received Le Fort I osteotomy at Peking University Hospital of Stomatology from 2011 to 2014, were randomly divided into three groups. Group 1 was treated with traditional intraoral alar base cinch suture (ABCS); Group 2 with extraoral ABCS, and Group 3 with traditional ABCS plus an extra intraoral suture at points G.lat. All the patients had taken 3D photos using 3dMD camera before operation, and 3, and 6 months after operation. The nasal widths, which were indicated as distances between Sbal-Sbal, G.lat-G.lat and Al-Al, were measured by two examiners in the 3D photos three times with a time-interval of one week. SPSS 13.0 was used to do the statistic analysis. RESULTS: At the end of the postoperative 6 months, the nasal widths lessened as compared with the postoperative 3 months. No significant differences were found between the three groups 6 months after the operation. The degree of the postoperative nasal width widening had positive correlation with that of the intraoperative nasal width widening, and had negative correlation with the initial nasal width and the amount of post-suture narrowing. CONCLUSION: There is no difference between three suturing techniques for controlling nasal width widening after Le Fort I osteotomy. The postoperative nasal width-widening can't be totally avoided, and the alteration might last at least 6 months after the operation. For patients with narrow nasal width and need to move maxilla forward, more overcorrection of ABCS is needed to control the postoperative nasal base widening. PMID- 25686339 TI - [An investigation analysis of prophylactic application of antibiotics in ten types of oral and maxillofacial surgery]. AB - OBJECTIVE: To evaluate the prophylactic application of antibiotics in oral and maxillofacial surgery and to provide a scientific basis for its reasonable use. METHODS: The use of prophylactic antibiotics in the oral and maxillofacial surgery was conducted in our hospital from January 2011 to August 2013 based on a retrospective survey, and the conditions and affecting factors were analyzed. RESULTS: The utilization rates of prophylactic antibiotics were respectively 98.9%, 61.8%, and 24.6%, showing a downward trend. But the infection rate of surgical site did not significantly increase, and by Fisher's exact test, the difference was not significant (P>0.05). Surgical site infections (SSI) rates did not rise between using and not using prophylactic antibiotics (P>0.05). CONCLUSION: The use of prophylactic antibiotics is greatly influenced by the policy, and along with the decline in antibiotic usage, SSI have not increased significantly. PMID- 25686340 TI - [Three dimensional CT for measuring mandibles morphology in 54 normal Chinese adults]. AB - OBJECTIVE: To establish a method of morphologic measurement of the mandibles and obtain the average values of three dimensional morphologic measurements of the mandibles. METHODS: A method of morphologic measurement of the mandibles was established firstly. The three dimensional CT data of 54 normal adult skulls were measured by this method. The data were analyzed by SPSS 13.0 statistical software. RESULTS: In the study, 84 groups of mean values and standard deviations of the length, width, height, depth, thickness and angle of the mandibular contour in males and females were obtained. There were significant differences between the male and the female in the 66 of the 84 groups data, while the 16 of the 84 groups data had no significant differences and distributed symmetry on both sides of the mandibles. No correlation was found in the mandibular contour data in length, width, height and depth. CONCLUSION: The characteristics of adult mandibular contours are different between males and females, indicating that each individual has its own morphologic features. PMID- 25686341 TI - [Effects of different cavosurface margins on color matching of the resin composite]. AB - OBJECTIVE: To evaluate effects of color matching of different cavosurface margins on the resin composites in vitro. METHODS: Twenty extracted human premolars with an A2 shade buccal surface were used in this study. Rectangular shaped cavities (3.0 mm depth, 2.0 mm width, 2.0 mm length) were prepared in the center of the buccal surfaces. The gingival and occlusal cavosurface margins were prepared to be either shoulder or bevel; the other cavosurface margins remained vertical. Ten teeth were filled with Clearfil AP-X (AP), the other ten with Clearfil Majesty (MJ) and light cured. The color difference at the cavosurface margin area was measured using a spectrophotometer (CrystalEye) and evaluated by 3 observers subjectively. The data were statistically analyzed using repeated measures ANOVA and Chi-square test. RESULTS: When measured by CrystalEye, the color difference between the tooth and resin composite was reduced from the center of restoration to the cavosurface margin area. Both objective and subjective evaluations showed that for AP, the color difference at the cavosurface margin area had no statistical difference among 3 types of the margins; for MJ, the color difference at bevel margin area was significantly smaller than that at the vertical margin area. CONCLUSION: The resin composite restorations produced the color matching at marginal area. The color matching of resin composites with higher diffused light transmission property is more susceptible to the type of cavosurface margins. Preparing bevels may reduce the color difference between the restoration and tooth surface. PMID- 25686342 TI - [Microtensile strength of composite-composite bonding: an in vitro study]. AB - OBJECTIVE: To investigate the bonding strength of different resin composites. METHODS: Methacrylate-based resin APX and silorane-based resin composite P90 were chosen in this study, with their corresponding adhesives Clearfil SE Bond (SE) and Filtek P90 System Adhesive (SA). The specimens were divided into three groups: (1) bulk group, filling each block with the same composite, then curing; (2) direct filling group, curing and polishing one composite, then filling a new composite directly; (3) bonding group, after curing and polishing one composite, conditioning the surface with adhesives, then filling a new composite. Cut each resin blocks into 1 mm*1 mm*14 mm each piece, detecting the microtensile strength, and analyzing by One-Way ANOVA and LSD. RESULTS: (1) The microtensile strength of the bulk group was the highest. (2) In direct filling group, the microtensile strength of 4 subgroups showed no statistical significance with each other but lower than that of the bulk group. (3) In bonding group, the microtensile strength of repairing with APX was higher than that with P90. When repairing with same composite, the microtensile strength was higher if the resin type of substrates was same with restorations than that was different. The microtensile strength of adhesives SE was higher than that of SA. (4) The sorting of the microtensile strength: bulk>SE bonding APX>SA bonding APX>SE bonding P90=direct filling>SA bonding P90. CONCLUSION: Retention force is higher when substrates are repaired with Methacrylate-based resins and corresponding adhesives. Retention force is lower when repaired with silorane-based composites and corresponding adhesives. Types of the substrate composites show no influence on the bonding strength. PMID- 25686343 TI - [Comparison of the incidences of apical root cracks after canal preparation with two nickel-titanium rotary systems: an in vitro study]. AB - OBJECTIVE: To compare the incidences of root cracks after canal instrumentation with HyFlex CM system and the ProTaper Universal system. METHODS: Sixty mandibular incisors were mounted in resin blocks with simulated periodontal ligaments, and the apex was exposed. The control group of 20 teeth was not prepared, and the other 40 teeth were divided into 2 experimental groups (n=20). The 40 root canals of the experimental groups were instrumented using HyFlex CM and ProTaper Universal to the major apical foramen (AF). The horizontal sections 1 mm, 2 mm, and 3 mm from the apex were observed under an optical stereomicroscope at 25*magnification. The presence of cracks was noted. RESULTS: No cracks were found in the control teeth. Cracks were found in 1 of 20 (5%) teeth in HyFlex CM group, and 17 of 20 (85%) teeth in ProTaper Universal group. The difference between the two experimental groups was statistically significant (P<0.01). CONCLUSION: The HyFlex CM files caused fewer root cracks than the ProTaper Universal files during the root canal instrumentation. PMID- 25686344 TI - [Influence of the effect of general anaesthesia and restraint during dental treatment on dental anxiety and behavior in children]. AB - OBJECTIVE: To compare the level of dental anxiety and dental behavior between dental fear children with dental treatment under general anaesthesia (GA) and those under restraint. METHODS: The GA group included 31 dental fear children aged 4-6-year-old who received dental treatment under the GA. The restraint group included 31 dental fear children aged 4-6-year-old who received dental treatment under the restraint. Age, gender, parent's education level, decayed-missing filled-tooth (dmft) and face version of the Modified Child Dental Anxiety Scale (MCDASf) score before treatment were matched between the two groups. The Chinese version of MCDASf was used to evaluate the level of dental anxiety in each child before treatment, right after treatment and before examination at recall visit 2 3 weeks after treatment. And the Chinese version of Venham Clinical Anxiety and Cooperative Behavior Scale was used to evaluate children's dental behavior in each child before treatment and before examination at recall visit 2-3 weeks after treatment. RESULTS: The average scores of MCDASf in GA group right after treatment and before recall were lower than that before treatment. The difference was statistically significant (P<0.05). Furthermore, the average score of MCDASf before recall was lower than those after treatment, and the difference was statistically significant (P<0.05). The average scores of MCDASf in restraint group right after treatment and 2-3 weeks after treatment were higher than those before treatment, but the difference was not statistically significant (P>0.05). Children's dental behavior was significantly improved at recall visit in both groups (P<0.01). CONCLUSION: Dental fear could be reduced by treatment under GA. The children's dental behavior was improved after GA. Restraint did not result in the significant elevation of dental anxiety level, but dental behavior was improved after restraint during the short-term recall. PMID- 25686345 TI - [A retrospective study on pulpal tissue prognosis of avulsed permanent teeth in children]. AB - OBJECTIVE: To analyze the pulpal prognosis of replanted permanent teeth in children and to examine the associated factors. METHODS: The samples consisted of 67 children with 81 avulsed permanent teeth treated in Peking University Hospital of Stomatology from 2000 to 2012. Their clinical data of the replanted teeth were collected, and the follow-up period was no less than 12 months. The pulpal prognosis was classified as pulp necrosis and pulp non-necrosis. RESULTS: The replantation within 30 minutes after avulsion led to the most significant increase in pulpal healing (P<0.05). The dental pulp of 80% (4/5) young permanent teeth replanted within 30 minutes remained vital, while all the teeth replanted after 30 minutes developed pulp necrosis within 60 days after replantation. CONCLUSION: The extra-alveolar period significantly affects the prognosis of pulp in immature permanent teeth after replantation. When the extra-alveolar period is more than 30 minutes, the chance of pulp revascularization after replantation is very low, therefore pulp extirpation should be performed. PMID- 25686346 TI - [Change of airway anaphylatoxin C5a in patients with asthma]. AB - OBJECTIVE: To investigate the role of anaphylatoxin C5a in patients with asthma. METHODS: A prospective study was performed between September 2006 and February 2007. A total of 33 patients with acute exacerbation of asthma and 13 healthy subjects were recruited into the study. The patients with acute exacerbation of asthma were also studied when they returned to the remission state. Levels of lung function, levels of C5a in induced sputum and cell differential count in induced sputum were determined. RESULTS: The level of C5a in induced sputum was significantly higher in patients with acute exacerbation of asthma [0.85(0.68 2.13) MUg/L] than that in patients with stable asthma [0.45(0.26-0.88) MUg/L, Z= 2.193, P=0.013]; Sputum C5a levels in stable asthma patients were significantly higher than those in healthy controls [0.14(0.06-0.45) MUg/L, Z=-2.141, P=0.015]. The level of C5a in patients with severe exacerbation [2.21(1.27-9.0) MUg/L] was significantly higher than those in patients with mild exacerbation [0.34(0.17 0.63) MUg/L] and moderate exacerbation [0.85(0.55-1.67) MUg/L, chi2 = 12.330, P=0.001]. The level of C5a in induced sputum was positively correlated with the number of total cells count (r=0.797, P=0.004), neutrophils (r=0.504, P=0.032) and macrophages (r=0.424, P=0.036) in acute exacerbation of asthma. CONCLUSION: C5a levels in induced sputum could be identified as an important prognostic biomarker, which involved in asthma's pathogenesis. PMID- 25686347 TI - [Up-regulation of intrarenal renin-angiotensin system contributes to renal damage in high-salt induced hypertension rats]. AB - OBJECTIVE: To test the hypothesis that in a high-salt induced hypertension in normal rats, whether the changes of intrarenal renin-agiotensin system (RAS) play a critical role in renal damage and could be reflected by urinary angiotensinogen (AGT). METHODS: In the study, 27 normotensive male Wistar-Kyoto rats were divided into control group [0.3% (mass faction) NaCl in chow, n=9, NS], high-salt diet group [8% (mass faction) NaCl in chow, n=9, HS] and high-salt diet with Losartan group [8% (mass faction) NaCl in chow and 20 mg/(kg*d) Losartan in gavages, n=9, HS+L)], and were fed for six weeks. The blood pressure was monitored and urine samples were collected every 2 weeks. AGTs in plasma, kidney and urine were measured by ELISA kits. The renal cortex expression of mRNA and protein of AGT were measured by Real-time PCR and immunohistochemistry (IHC). The renin activity and ANG II were measured by radioimmunoassay (RIA) kits. RESULTS: Compared with NS, the systolic blood pressure (SBP) [(156 +/- 2) mmHg vs. (133 +/- 3) mmHg, P<0.05] increased significantly at the end of the 2nd week, and the urinary protein [(14.07 +/- 2.84) mg/24 h vs. (7.62 +/- 3.02) mg/24 h, P<0.05] increased significantly at the end of the 6th week in HS. Compared with HS, there was no significant difference in SBP (P>0.05) but the proteinuria [(9.69 +/- 2.73) mg/24 h vs. (14.07 +/- 2.84) mg/24 h, P<0.01] decreased significantly in HS+L. Compared with NS, there was no significant difference in the plasma renin activity, angiotensinogen and ANG II level in HS (P>0.05), but the renal cortex renin content [(8.72 +/- 1.98) ng/(mL * h) vs. (4.37 +/- 1.26) ng/(mL * h), P<0.05], AGT formation [(4.02 +/- 0.60) ng/mg vs. (2.59 +/- 0.42) ng/mg, P<0.01], ANG II level [(313.8 +/- 48.76) pmol/L vs. (188.9 +/- 46.95) pmol/L, P<0.05] were increased significantly in HS, and the urinary AGT and ANG II excretion rates increased significantly (P<0.05). Compared with HS, the plasma renin activity, angiotensinogen and ANG II level were significantly increased (P<0.05), but the renal cortex renin content, AGT formation, ANG II level significantly decreased (P<0.05), and the urinary AGT and ANG II excretion rates decreased significantly in HS+L (P<0.05). The urinary AGT excretion rates were positively correlated with the AGT level in the renal cortex (P<0.05). CONCLUSION: Up-regulation of intarenal RAS may contribute to renal damage in high-salt induced hypertension rats. Urinary AGT may reflect the status of intrarenal RAS. PMID- 25686348 TI - [Expression of apolipoprotein A-I in eight histological types of renal neoplasms]. AB - OBJECTIVE: To investigate the expression of apolipoprotein A-I(ApoA-I) in eight histological types of renal neoplasms and to explore a new biomarker for differential diagnosis. METHODS: The immunochemistry was used to detect the expression of ApoA-I in 23 cases of renal tumors, including clear cell carcinoma,papillary cell carcinoma, chromophobe cell carcinoma, oncocytoma,multilocular cystic carcinoma, renal pelvis invasive urothelial carcinoma,metanephric adenoma and collecting ducts carcinoma. Five cases of cancer-adjacent normal tissues were obtained from another five renal tumor patients and were chosen as control group. RESULTS: In the 23 cases of renal tumors, ApoA-I was expressed in 21 cases (positive rate was 91.3%). There were only two in five cases of normal tissues which expressed this protein (positive rate was 40.0%). A significant differentiation was observed between the two groups(Z=-2.829,P=0.003). In renal clear cell carcinoma (RCC), ApoA-I expression level was correlated with the grade and stage of tumor tissues. ApoA-I was stained much more stronger in RCC II-III than in RCC I (Z=-2.070,P=0.038).In various histological types of renal cancer, ApoA-I was all expressed to some degrees. CONCLUSION: ApoA-I can be chosen as a tumor biomarker to differentiate various histological types of renal neoplasms. PMID- 25686349 TI - [Complications of selective posterior rhizotomy for lower limb spasticity of cerebral palsy]. AB - OBJECTIVE: To investigate the complications of spastic cerebral palsy with selective posterior rhizotomy (SPR). METHODS: In the study, 2 593 patients who had undergone SPR from January 2000 to September 2012 were followed-up for at least one year. The complications were classified. RESULTS: Peri-operative complications: pulmonary system complications including bronchial spasm (5 cases, 0.19%) and aspiration pneumonia (4 cases, 0.15%); digestive system complications including abdominal bloating (145 cases, 5.6%) and colic (80 cases, 3.1%); urinary system complications including temporary bladder dysfunction (54 cases, 2.1%) and urinary tract infection (6 cases, 0.23%); peripheral nervous system complications including lower extremity weakness (327 cases, 12.6%) and lower extremity sensory disturbances (140 cases, 5.4%); central nervous system complications including headache (112 cases, 4.3%) and epileptic seizures (4 cases, 0.15%). None spinal or intracranial infection, intraspinal hematoma or intracranial hemorrhage were identified. General surgery complications including back pain (1 382 cases, 53.3%), delay wound healing caused by infection (5 cases, 0.19%) and cerebrospinal fluid leakage (8 cases, 0.31%). Long-term follow-up complications including lower limb decreased exercise capacity (incidence: 7.33%) and lower extremity sensory disturbance (incidence: 5.59%). Urination occurred in only one case and defecation function disturbance with no sexual dysfunction was identified. The incidences of scoliosis, thoracic kyphosis, spondylolisthesis and long-term back pain were 7.23% (31/429), 4.2% (18/429), 10.49% (45/429) and 9.72% respectively. CONCLUSION: SPR is one of the effective and safe surgical treatments for spastic cerebral palsy. Valid methods should be applied to reduce the incidence of postoperative complications, such as choosing the appropriate patients, meticulously operating in the surgery, assistance of electrophysiological guidance, reinforcing perioperative management and regular rehabilitation training after operation. PMID- 25686350 TI - [Surgical treatment and prognostic analysis of osteosarcoma in adults older than 40 years]. AB - OBJECTIVE: To determine the prognostic factors of primary osteosarcoma in adults. METHODS: This is a review of 54 patients older than 40 years (24 men and 30 women) who were treated between 1998 and 2011 at the authors' institution. Demographic information and follow-up data were obtained and statistically analyzed. RESULTS: Tumors involved the limbs in 30 patients (55.5%) and axial skeleton in 17 patients (31.5%), and arose from soft tissue in 7 patients (13%). And 6 patients (11.1%) had synchronous metastasis. According to our review, tumors were treated surgically in 52 patients (96.3%). Local recurrence was documented in 14 patients (26.9%). Metastasis after diagnosis appeared in 21 patients (38.9%). In the 52 patients who received the surgical treatment, the 5 year disease-free survival and overall survival rates were 43.7% and 50.4%, respectively. CONCLUSION: Adult patients with primary osteosarcoma had a poor clinical outcome. Inadequate surgical margins, more tumors in the axial location due to high recurrence rates, metastatic disease at presentation, and large tumor volumes were associated with significantly lower survival rates. Aggressive multi agent treatment regimens might improve survival. PMID- 25686351 TI - [Comparison of tubeless-percutaneous nephrolithotomy and ureteroscopic lithotripsy in treatment of upper-ureteral calculi sized >= 1.5 cm]. AB - OBJECTIVE: To compare the efficacy and safety of tubeless percutaneous nephrolithotomy (tubeless-PCNL) and ureteroscopic lithotripsy (URL) in treatment of impacted upper-ureteral calculi >= 1.5 cm in size. METHODS: Patients with ureteral stones sized >= 1.5 cm and lodged above the fourth lumbar vertebra who were treated between September 2009 and July 2013 in Peking University People's Hospital were retrospectively analyzed. In the study, 182 patients underwent tubeless-PCNL or URL treatment respectively, and the operation success rates were compared. The duration of operation, intraoperative blood loss(average hemoglobin decrease), complications, mean hospital stay and residual stone rates were also compared. RESULTS: Fifty-four patients underwent tubeless-PCNL treatment,the average stone size was (1.9 +/- 0.4) cm,nephrostomy tubes were placed in two patients,and the operation success rate was 96.3%(52/54). In the rest of the 52 patients,and the mean operation time was (30.1 +/- 14.8) minutes with an average postoperative hemoglobin decrease of (10.2 +/- 6.1) g/L, and the mean hospital stay was (3.0 +/- 1.4) days. Only one of the patients had residual fragments (2%). The main complications included minor perirenal hematoma in 1 patient, fever in 2 patients,elevated blood WBC in 11 patients,and analgesics requirement in 3 patients. In the study, 128 patients were treated with URL,the average stone size was (1.7 +/- 0.3) cm. 19 procedures failed,and 10 patients were converted to PCNL,extracorporeal shock wave lithotripsy was executed subsequently after double J stent placement in 5 patients,and migration of calculi or stone fragments happened in 4 patients. The mean operative time was (51.3 +/- 25.5) minutes for the remaining 109 patients with a hemoglobin reduction of (5.2 +/- 7.2) g/L. The mean hospital stay was (2.9 +/- 1.3) days, and residual stones were found in 13 of the 109 patients (11.9%). The main complications included fever in 3 patients, elevated blood WBC in 42 patients, analgesics requirement in 13 patients because of pain in the urethra or flank. The size of the stones between the two group didn't show significant difference,but the success rate of the tubeless-PCNL procedure was significantly higher. Except that hemoglobin decrease was slightly higher in the tubeless-PCNL group,the mean operative time, the rate of residual stones and rate of complications of the tubeless-PCNL group were lower significantly. CONCLUSION: Treating stones above 4th lumbar vertebra larger than 1.5 cm were challenging. It is difficult to treat these stones with URL because of a high probability to fail, but on the contrary, tubeless-PCNL was more likely to be performed successfully. For surgeons experienced with the PCNL technology, treating stones >= 1.5 cm with tubeless-PCNL procedure may turn out to be more efficient and with a higher operation success rate, and the risk of complications was lower without lengthening the postoperative hospital stay. PMID- 25686352 TI - [Diagnostic value of fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography in fever of unknown origin]. AB - OBJECTIVE: To evaluate the diagnostic value of fluorine-18 fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) in fever of unknown origin (FUO) in a Chinese hospital. METHODS: The records of 51 patients with FUO (32 men and 19 women; mean age 54 years with a range between 3 and 81 years) were analyzed retrospectively. All the patients were examined by 18F-FDG PET/CT scan and the results were compared with the final diagnosis which was established by additional procedures including pathology, laboratory examination, and clinical follow-up for more than 3 months. The t test was used for statistical analysis. RESULTS: A final diagnosis was established for 48 patients, including 32 patients with infectious diseases, 9 with malignancies, and 7 with non-infectious inflammatory diseases. By FDG PET scan alone, the rates of true positive, false positive, false negative, and true negative were 52.9%, 27.5%, 17.6%, and 2.0%, respectively. By FDG PET/CT scan, the rates of true positive, false positive, false negative, and true negative were 70.6%, 27.5%, 2.0%, and 0, respectively. 18F-PET/CT had a sensitivity of 97.3% (36/37), specificity of 0 (0/14), and accuracy of 70.6% (36/51) in FUO, especially a high sensitivity and accuracy of 100% (9/9) in the diagnosis of malignant tumor. Moreover, the maximum standardized uptake value (SUVmax) in tumor was significant higher than that in infection (3.7 +/- 2.7 vs. 7.7 +/- 3.5, P=0.001, t=3.6), which implied that SUVmax might be useful in differential diagnosis in FUO. CONCLUSION: FDG PET/CT is a valuable imaging tool for the identification and location of the potential lesion in FUO and is helpful for the etiological diagnosis, especially in the diagnosis of malignant lesions. PMID- 25686353 TI - [Morphological typing of the middle cerebral artery M1 segment by magnetic resonance angiography]. AB - OBJECTIVE: To study the morphology of middle cerebral artery (MCA) M1 segment. METHODS: We selected the MRA data of 794 MCA (400 of the left side and 394 of the right side) from January 1, 2011 to June 30, 2011 consecutively and analyzed the morphology of the MCA M1 segment in axial, anteroposterior and lateral view, measured the length of the M1 segment, and analyzed the similarity of the left and right side M1 segment morphology. RESULTS: In axial, anteroposterior and lateral view, the MCA M1 segment showed C-shape > L-shape > S-shape. In axial view, it was about 373 (47%) M1 segment performance for the C-shape, of which 340 (42.8%) M1 segments showed bowing to the dorsal side, only 33 (4.2%) M1 segments showed bowing to the ventral side. In anteroposterior view, it was about 322 (40.6%) M1 segments of the performance of the C-shape, of which 262(33.0%) M1 segments showed a bowing to the superior, 60 (7.6%) showed bowing to the inferior. The similarity of the left and right MCA M1 segments was 27.2% (114/419) in axial view and 42.7% (179/419) in anteroposterior view. It was more similar in anteroposterior view than in axial view. Along with the increase of age, in the axial view, L-shape converted to C-shape very obviously, but only mildly elevated in S-shape. In anteroposterior view, the L-shape converted to the C-shape or S-shape along with the increase of age. CONCLUSION: The different morphology of MCA M1 segment in axial and anteroposterior view may be involved in the development of intracranial atherosclerosis. PMID- 25686354 TI - [Evaluation of the rapid trehalose test for the identification of the Candida glabrata]. AB - OBJECTIVE: To explore a rapid and cost-effective method for identification of Candida glabrata through the comparison of two different methods, using molecular methods of sequencing as gold standard. METHODS: From our clinic, 200 strains of suspected Candida glabrata were collected during the last 3 years and selected after incubation in CHROMagar Candida medium for 48 h. By comparing the results of the CHROMagar Candida medium, the identification of the rapid trehalose test for different kinds of strains were analyzed under incubation in the tubes for 3 h, 6 h, and 24 h at 37 degrees C and 42 degrees C, respectively. All the strains were identified to species level by methods of sequencing. The optimal time and temperature of the trehalose test for the identification of Candida glabrata were assessed. Two different methods, CHROMagar Candida medium and the rapid trehalose test, in identification of Candida glabrata were compared. RESULTS: In all the 200 strains, Candida glabrata ferment trehalose with 3 h incubation under 42 degrees C were the optimal time and temperature for fermenting trehalose. The accuracy, sensitivity, and specificity of the rapid trehalose test were 99.00% (198/200), 98.66% (147/149) and 100.00% (51/51). The accuracy rate of CHROMagar Candida medium was 79.50% (159/200), the sensitivity and specificity were only 89.93% (134/149) and 49.02% (25/51), however, compared with the domestic current popular methods, the rapid trehalose test had better time efficiency ratio. CONCLUSION: The evaluation results suggest that the rapid trehalose test has advantages in terms of operational convenience and low cost, and the results can be obtained in 3 h. Therefore, it has application value in clinical laboratory. PMID- 25686355 TI - [Influence of feeding patterns on the development of teeth, dentition and jaw in children]. AB - Breastfeeding has been recognized as the most natural and nutritious way of feeding babies. Besides the nutritional, immunological and emotional benefits, breastfeeding promotes a healthy stomatognathic system. First of all, the nutrients and minerals in maternal milk are easy to be absorbed by the infants, which contributes to the mineralization of the teeth, and suppress the propagation of bacteria on the teeth. Though the jury is still out on whether breastfeeding can prevent Early Childhood Caries (ECC), it is definite that we should pay attention to feeding at night and the oral hygiene of the babies. Secondly, the method of feeding is closely bound up with the development of dentition and jaw. Breast- and bottle-feeding involve different orofacial muscles, which possibly have different effects on the harmonic growth of maxilla and dental arches. Meanwhile, breathing, swallowing and mastication should be developing in harmony, and differences exist in the learning of the coordinated movement between breast feeding and bottle feeding children. Bottle feeding had been proved to be closely related with the non-nutritive sucking habits which can cause malocclusion. At last, it should be pointed out that breast feeding should be the only feeding source in the first 6 months of life, then supplementary foods should be added. And prolonged bottle feeding should be avoided. We can see that breast feeding is definitely good for the infants, but the reality is not optimistic in our country. PMID- 25686356 TI - Dynamic upper respiratory abnormalities in Thoroughbred racehorses in South Africa. AB - Upper airway endoscopy at rest has been the diagnostic method of choice for equine upper respiratory tract (URT) conditions. Development of high-speed treadmill endoscopy improved the sensitivity of URT endoscopy by allowing observation of the horse's nasopharynx and larynx during exercise. However, treadmill exercise may not always accurately represent the horse's normal exercise as track surface, rider, tack and environmental variables are altered. Recently, the development of dynamic overground endoscopy (DOE) has addressed some of these shortcomings. A retrospective study was undertaken to describe the URT abnormalities detected during DOE in racehorses presenting with poor performance and/or abnormal respiratory noise. Patient records of Thoroughbred racehorses undergoing DOE from November 2011 to August 2012 were reviewed. Data collected included signalment, primary complaint, distance exercised, maximum speed and dynamic airway abnormalities detected. Fifty-two horses underwent DOE for investigation of poor performance and/or abnormal respiratory noise. The main abnormalities detected included axial deviation of the aryepiglottic folds (40%), vocal cord collapse (35%), abnormal arytenoid function (33%) and dorsal displacement of the soft palate (25%). A total of 40 horses were diagnosed with one or more abnormalities of the URT (77%). Fifteen horses (29%) had a single abnormality and 25 horses (48%) had multiple abnormalities. This study showed that DOE is a useful technique for investigating dynamic disorders of the URT in racehorses in South Africa. The total number and type of dynamic pathological conditions were comparable with those identified in similar populations in other geographical locations. PMID- 25686357 TI - The know-do gap in quality of health care for childhood diarrhea and pneumonia in rural India. AB - IMPORTANCE: In rural India, as in many developing countries, childhood mortality remains high and the quality of health care available is low. Improving care in such settings, where most health care practitioners do not have formal training, requires an assessment of the practitioners' knowledge of appropriate care and the actual care delivered (the know-do gap). OBJECTIVE: To assess the knowledge of local health care practitioners and the quality of care provided by them for childhood diarrhea and pneumonia in rural Bihar, India. DESIGN, SETTING, AND PARTICIPANTS: We conducted an observational, cross-sectional study of the knowledge and practice of 340 health care practitioners concerning the diagnosis and treatment of childhood diarrhea and pneumonia in Bihar, India, from June 29 through September 8, 2012. We used data from vignette interviews and unannounced standardized patients (SPs). MAIN OUTCOMES AND MEASURES: For SPs and vignettes, practitioner performance was measured using the numbers of key diagnostic questions asked and examinations conducted. The know-do gap was calculated by comparing fractions of practitioners asking key diagnostic questions on each method. Multivariable regressions examined the relation among diagnostic performance, prescription of potentially harmful treatments, and the practitioners' characteristics. We also examined correct treatment recommended by practitioners with both methods. RESULTS: Practitioners asked a mean of 2.9 diagnostic questions and suggested a mean of 0.3 examinations in the diarrhea vignette; mean numbers were 1.4 and 0.8, respectively, for the pneumonia vignette. Although oral rehydration salts, the correct treatment for diarrhea, are commonly available, only 3.5% of practitioners offered them in the diarrhea vignette. With SPs, no practitioner offered the correct treatment for diarrhea, and 13.0% of practitioners offered the correct treatment for pneumonia. Diarrhea treatment has a large know-do gap; practitioners asked diagnostic questions more frequently in vignettes than for SPs. Although only 20.9% of practitioners prescribed treatments that were potentially harmful in the diarrhea vignettes, 71.9% offered them to SPs (P < .001). Unqualified practitioners were more likely to prescribe potentially harmful treatments for diarrhea (adjusted odds ratio, 5.11 [95% CI, 1.24-21.13]). Higher knowledge scores were associated with better performance for treating diarrhea but not pneumonia. CONCLUSIONS AND RELEVANCE: Practitioners performed poorly with vignettes and SPs, with large know-do gaps, especially for childhood diarrhea. Efforts to improve health care for major causes of childhood mortality should emphasize strategies that encourage pediatric health care practitioners to diagnose and manage these conditions correctly through better monitoring and incentives in addition to practitioner training initiatives. PMID- 25686358 TI - Bovine trypanosome species prevalence and farmers' trypanosomiasis control methods in south-western Uganda. AB - A cross-sectional study was conducted in Mbarara district, south-western Uganda in May 2012 to determine the burden of African animal trypanosomosis (AAT) in the semi-intensive dairy production systems where pyrethroid acaricides are frequently used in the control of tick-borne diseases (TBDs). A total of 295 cattle blood samples were taken and analysed using a single pair of primers previously designed to amplify internal transcribed spacer (ITS1) of trypanosome ribosomal deoxyribonucleic acid (rDNA). A structured questionnaire was administered to 55 participating livestock farmers to generate data on acaricide and trypanocidal drug usage. The overall prevalence of trypanosome species was 2.4% (95% CI; 1.0% - 4.8%); Trypanosoma vivax was the most predominant species (2.0%; 95% CI; 0.7% - 4.4%). A single mixed infection of T. vivax and Trypanosoma brucei s.l. was detected. All the participating farmers used acaricides for tsetse and TBD control; 89.1% of the acaricides used were pyrethroids. About half of the farmers used trypanocidal drugs, mainly diminazene formulations (Berenil(r)). Low prevalence of trypanosomes in examined samples is most likely related to the frequent use of pyrethroid insecticides, trypanocides and restricted grazing (paddocking and tethering). These rigorous management practices are geared towards optimising production of exotic dairy breeds kept in this region that are highly susceptible to TBDs and AAT. PMID- 25686359 TI - Determination of quinolones and fluoroquinolones, tetracyclines and sulfonamides in bovine, swine and poultry liver using LC-MS/MS. AB - Antibacterials are widely used in veterinary medicine. Residues of these drugs can remain in food of animal origin, including bovine liver. This paper describes a fast and simple analytical method for the determination of quinolones and fluoroquinolones, tetracyclines and sulfonamides in bovine liver samples. Deuterated enrofloxacin, sulfapyridine and demeclocycline were used as internal standards. The homogenised liver samples were extracted with acidified acetonitrile. Steps of non-solid-phase extraction (SPE) clean-up and concentration were used in the presented method. The final extracts were analysed by sensitive and selective detection of all components in a single run using LC MS/MS. Acceptable recoveries between 66% and 110% were obtained. Good linearity (r(2)) above 0.96, considering three different days, for all drugs was achieved in concentrations ranging from 0.0 to 2.0 * the maximum residue limit (MRL). Intraday precision with coefficient of variation (CV%) (n = 6) lower than 14.7% and inter-day precision lower than 18.8% in agreement with European Commission Decision 2002/657/EC were obtained in concentrations ranging from 0.5 to 1.5 MRL. Accuracy was between 86% and 110%. Limits of detection and quantitation, as well as decision limit (CCalpha) and detection capability (CCbeta), were also evaluated. PMID- 25686360 TI - A Retrospective Evaluation of 192 Implants Placed in Augmented Bone: Long-Term Follow-Up Study. AB - The purpose of the present study was to assess the cumulative survival rate (CSR) of 192 implants placed in association with guided bone regeneration (GBR) procedures to evaluate the long-term predictability of this technique. Moreover, the Kaplan Meier survival analysis was applied to the data in order to evaluate predictors of implant failures, including the source of the graft, the type of membrane, and the timing of implant placement. The CSR of the sample was 95.6% over a mean follow-up period of 78 months (range, 1-175 months). Considering the source of graft, a 95.0%, 93.3%, and 97.7% CSR was obtained for demineralized bovine bone mineral (DBBM), autologous, and 1:1 ratio mixture of autologous and DBBM grafts,, respectively. The CSR referred to bioabsorbable membranes was 96.5%, whereas 94.6% was the CSR reported for nonresorbable membranes. The CSR of simultaneous surgeries was 96.8%, whereas staged surgeries showed a CSR of 94.5%. According to the data, implants placed in conjunction with GBR procedures presented a satisfying survival rate even in the long term. All the procedures performed with different bone grafts and type of membranes guaranteed optimal results both in one- and two-stage approaches. No statistically significant differences could be detected among the groups; indeed, the use of DBBM associated with resorbable membranes may be suggested to reduce patients' morbidity and treatment time. Therefore, the dental implants placed in association with bone regenerative procedures presented safe and predictable long term clinical results. PMID- 25686361 TI - Antiallergic activity of rosmarinic acid esters is modulated by hydrophobicity, and bulkiness of alkyl side chain. AB - Methyl, propyl and hexyl esters of rosmarinic, caffeic and p-coumaric acids were tested for antiallergic activity, and rosmarinic acid propyl ester exhibited the greatest beta-hexosaminidase release suppression (IC50, 23.7 MUM). Quadratic correlations between pIC50 and cLogP (r(2) = 0.94, 0.98, and 1.00, respectively) were observed in each acid ester series. The antiallergic activity is modulated by hydrophobicity, and alkyl chain bulkiness. PMID- 25686362 TI - Evolution of antimicrobial resistance of Salmonella enteritidis (1972-2005). AB - With the extensive use of antibiotics in livestock production, surveillance revealed an increase in Salmonella resistance to the commonly used antimicrobials in veterinary and public health. This serious threat to health care is further exacerbated by the limited epidemiological information about the common zoonotic agent, Salmonella enteritidis, required to determine antibiotic therapy. The aim was to characterise the antimicrobial resistance patterns of S. enteritidis isolates across different timelines (1972-2005) with accompanying genetic changes being investigated. Thirty-seven stored S. enteritidis isolates were collected from the Central Veterinary Laboratory, Harare, with antimicrobial susceptibility determined against eight antibiotics. Plasmids were isolated to analyse any genetic variation. An overall significant increase in resistance (p < 0.05) to nalidixic acid (0% - 10%), ampicillin (14.3% - 50%), tetracycline (14.3% - 30%) and erythromycin (71.4% - 100%) was observed across the timeline. However, the highest rates of susceptibility were maintained for gentamicin, sulphamethoxazole trimethoprim, kanamycin and chloramphenicol. We report an increase in multidrug resistance (MDR) of 14.2% - 50% with an increase in resistotypes and plasmid profiles across the timeline. Eleven plasmid profiles were obtained in the 37 isolates studied with a minority of isolates (21.6%, 8/37) harbouring a 54 kb plasmid, commonly serovar-specific. A concerning increase in antimicrobial resistance to commonly administered drugs was observed across the timeline. The surge in MDR is of great concern and implies the need for consistent antimicrobial stewardship. No correlation was observed between the plasmid and antibiotic profiles. PMID- 25686363 TI - Eukaryotic LYR Proteins Interact with Mitochondrial Protein Complexes. AB - In eukaryotic cells, mitochondria host ancient essential bioenergetic and biosynthetic pathways. LYR (leucine/tyrosine/arginine) motif proteins (LYRMs) of the Complex1_LYR-like superfamily interact with protein complexes of bacterial origin. Many LYR proteins function as extra subunits (LYRM3 and LYRM6) or novel assembly factors (LYRM7, LYRM8, ACN9 and FMC1) of the oxidative phosphorylation (OXPHOS) core complexes. Structural insights into complex I accessory subunits LYRM6 and LYRM3 have been provided by analyses of EM and X-ray structures of complex I from bovine and the yeast Yarrowia lipolytica, respectively. Combined structural and biochemical studies revealed that LYRM6 resides at the matrix arm close to the ubiquinone reduction site. For LYRM3, a position at the distal proton-pumping membrane arm facing the matrix space is suggested. Both LYRMs are supposed to anchor an acyl-carrier protein (ACPM) independently to complex I. The function of this duplicated protein interaction of ACPM with respiratory complex I is still unknown. Analysis of protein-protein interaction screens, genetic analyses and predicted multi-domain LYRMs offer further clues on an interaction network and adaptor-like function of LYR proteins in mitochondria. PMID- 25686364 TI - Triboelectric effect as a new strategy for sealing and controlling the flow in paper-based devices. AB - We reported here for the first time that triboelectric charges on PET sheets can be used to seal and control the flow rate in paper-based devices. The proposed method exhibits simplicity and low cost, provides reversible sealing and minimizes the effect of sample evaporation. PMID- 25686365 TI - An Improved Index of Image Quality for Task-based Performance of CT Iterative Reconstruction across Three Commercial Implementations. AB - PURPOSE: To develop and validate a metric of computed tomographic (CT) image quality that incorporates the noise texture and resolution properties of an image. MATERIALS AND METHODS: Images of the American College of Radiology CT quality assurance phantom were acquired by using three commercial CT systems at seven dose levels with filtered back projection (FBP) and iterative reconstruction (IR). Image quality was characterized by the contrast-to-noise ratio (CNR) and a detectability index (d') that incorporated noise texture and spatial resolution. The measured CNR and d' were compared with a corresponding observer study by using the Spearman rank correlation coefficient to determine how well each metric reflects the ability of an observer to detect subtle lesions. Statistical significance of the correlation between each metric and observer performance was determined by using a Student t distribution; P values less than .05 indicated a significant correlation. Additionally, each metric was used to estimate the dose reduction potential of IR algorithms while maintaining image quality. RESULTS: Across all dose levels, scanner models, and reconstruction algorithms, the d' correlated strongly with observer performance in the corresponding observer study (rho = 0.95; P < .001), whereas the CNR correlated weakly with observer performance (rho = 0.31; P = .21). Furthermore, the d' showed that the dose-reduction capabilities differed between clinical implementations (range, 12%-35%) and were less than those predicted from the CNR (range, 50%-54%). CONCLUSION: The strong correlation between the observer performance and the d' indicates that the d' is superior to the CNR for the evaluation of CT image quality. Moreover, the results of this study indicate that the d' improves less than the CNR with the use of IR, which indicates less potential for IR dose reduction than previously thought. PMID- 25686366 TI - Establishing the Lysine-rich Protein CEST Reporter Gene as a CEST MR Imaging Detector for Oncolytic Virotherapy. AB - PURPOSE: To (a) evaluate whether the lysine-rich protein (LRP) magnetic resonance (MR) imaging reporter gene can be engineered into G47Delta, a herpes simplex derived oncolytic virus that is currently being tested in clinical trials, without disrupting its therapeutic effectiveness and (b) establish the ability of chemical exchange saturation transfer (CEST) MR imaging to demonstrate G47Delta LRP. MATERIALS AND METHODS: The institutional subcommittee for research animal care approved all in vivo procedures. Oncolytic herpes simplex virus G47Delta, which carried the LRP gene, was constructed and tested for its capacity to replicate in cancer cells and express LRP in vitro. The LRP gene was detected through CEST imaging of lysates derived from cells infected with G47Delta-LRP or the control G47Delta-empty virus. G47Delta-LRP was then tested for its therapeutic effectiveness and detection with CEST MR imaging in vivo. Images of rat gliomas were acquired before and 8-10 hours after injection of G47Delta-LRP (n = 7) or G47Delta-empty virus (n = 6). Group comparisons were analyzed with a paired t test. RESULTS: No significant differences were observed in viral replication or therapeutic effectiveness between G47Delta-LRP and G47Delta-empty virus. An increase in CEST image contrast was observed in cell lysates (mean +/- standard deviation, 0.52% +/- 0.06; P = .01) and in tumors (1.1% +/- 0.3, P = .02) after infection with G47Delta-LRP but not G47Delta-empty viruses. No histopathologic differences were observed between tumors infected with G47Delta LRP and G47Delta-empty virus. CONCLUSION: This study has demonstrated the ability of CEST MR imaging to show G47Delta-LRP at acute stages of viral infection. The introduction of the LRP transgene had no effect on the viral replication or therapeutic effectiveness. This can aid in development of the LRP gene as a reporter for the real-time detection of viral spread. Online supplemental material is available for this article. PMID- 25686367 TI - Effect of Evidence-based Clinical Decision Support on the Use and Yield of CT Pulmonary Angiographic Imaging in Hospitalized Patients. AB - PURPOSE: To determine the effect of clinical decision support (CDS) on the use and yield of inpatient computed tomographic (CT) pulmonary angiography for acute pulmonary embolism (PE). MATERIALS AND METHODS: This HIPAA-compliant, institutional review board-approved study with waiver of informed consent included all adults admitted to a 793-bed teaching hospital from April 1, 2007, to June 30, 2012. The CDS intervention, implemented after a baseline observation period, informed providers who placed an order for CT pulmonary angiographic imaging about the pretest probability of the study based on a validated decision rule. Use of CT pulmonary angiographic and admission data from administrative databases was obtained for this study. By using a validated natural language processing algorithm on radiology reports, each CT pulmonary angiographic examination was classified as positive or negative for acute PE. Primary outcome measure was monthly use of CT pulmonary angiography per 1000 admissions. Secondary outcome was CT pulmonary angiography yield (percentage of CT pulmonary angiographic examinations that were positive for acute PE). Linear trend analysis was used to assess for effect and trend differences in use and yield of CT pulmonary angiographic imaging before and after CDS. RESULTS: In 272 374 admissions over the study period, 5287 patients underwent 5892 CT pulmonary angiographic examinations. A 12.3% decrease in monthly use of CT pulmonary angiography (26.0 to 22.8 CT pulmonary angiographic examinations per 1000 admissions before and after CDS, respectively; P = .008) observed 1 month after CDS implementation was sustained over the ensuing 32-month period. There was a nonsignificant 16.3% increase in monthly yield of CT pulmonary angiography or percentage of CT pulmonary angiographic examinations positive for acute PE after CDS (P = .65). CONCLUSION: Implementation of evidence-based CDS for inpatients was associated with a 12.3% immediate and sustained decrease in use of CT pulmonary angiographic examinations in the evaluation of inpatients for acute PE. for this article. PMID- 25686368 TI - Trapping of intermediates with substrate analog HBOCoA in the polymerizations catalyzed by class III polyhydroxybutyrate (PHB) synthase from Allochromatium vinosum. AB - Polyhydroxybutyrate (PHB) synthases (PhaCs) catalyze the formation of biodegradable PHB polymers that are considered as an ideal alternative to petroleum-based plastics. To provide strong evidence for the preferred mechanistic model involving covalent and noncovalent intermediates, a substrate analog HBOCoA was synthesized chemoenzymatically. Substitution of sulfur in the native substrate HBCoA with an oxygen in HBOCoA enabled detection of (HB)nOCoA (n = 2-6) intermediates when the polymerization was catalyzed by wild-type (wt )PhaECAv at 5.84 h(-1). This extremely slow rate is due to thermodynamically unfavorable steps that involve the formation of enzyme-bound PHB species (thioesters) from corresponding CoA oxoesters. Synthesized standards (HB)nOCoA (n = 2-3) were found to undergo both reacylation and hydrolysis catalyzed by the synthase. Distribution of the hydrolysis products highlights the importance of the penultimate ester group as previously suggested. Importantly, the reaction between primed synthase [(3)H]-sT-PhaECAv and HBOCoA yielded [(3)H]-sTet-O-CoA at a rate constant faster than 17.4 s(-1), which represents the first example that a substrate analog undergoes PHB chain elongation at a rate close to that of the native substrate (65.0 s(-1)). Therefore, for the first time with a wt-synthase, strong evidence was obtained to support our favored PHB chain elongation model. PMID- 25686369 TI - Effects of education and word reading on cognitive scores in a community-based sample of Spanish elders with diverse socioeconomic status. AB - INTRODUCTION: The influence of education and oral word-reading ability on cognitive performance was examined in a sample of 1510 nondemented elders differing in socioeconomic status (SES) from three Spanish communities. METHOD: All individuals were enrolled in the Neurological Disorders in Central Spain, a population-based epidemiological study in central Spain. They completed a detailed demographic survey and a short standardized neuropsychological battery assessing psychomotor speed, attention, language, and memory. The Word Accentuation Test (WAT) was used as measure of oral reading ability. The influence of education and oral reading on cognitive performance was determined by multiple linear regression models, first controlling for demographics (age and sex), and subsequently for the WAT score and education. The contribution of socioeconomic conditions was addressed by stratifying the sample into groups of high and low SES. RESULTS: The WAT showed a significant independent effect on cognitive scores, generally greater than that predicted by demographics. The higher predictive power of oral word reading on cognitive scores compared to education was consistent across the three communities. Although the variance explained by WAT was very similar in areas with diverse SES (low vs. high), WAT scores accounted for slightly more variance in naming and memory tasks in low SES areas. In contrast, the variance explained by WAT was higher for verbal fluency and the Trail-Making Test in areas with high SES. CONCLUSION: Oral word-reading ability predicts cognitive performance better than years of education across individuals with different SES. The influence of WAT may be modulated by SES and cognitive task properties. PMID- 25686370 TI - Novel directions in neoadjuvant therapy for pancreas adenocarcinoma. AB - Surgical resection of pancreatic carcinoma has long represented the only viable option for a potential cure of pancreas cancer. The use of adjuvant chemotherapy post-resection has been established in treating micro metastases and prolonging disease-free survival. However, studies of neoadjuvant therapy have not come to any definitive conclusion regarding the overall efficacy of such treatment, despite the theoretical benefits. In this review, we examine the historical precedent as well as the current state of affairs regarding neoadjuvant therapy in resectable and borderline resectable pancreatic adenocarcinoma. In addition, we review the definitions for resectable and borderline resectable disease and highlight key areas of clinical investigation in the field and summarize the major ongoing neoadjuvant studies focused on resectable pancreatic adenocarcinoma. PMID- 25686371 TI - Dispensability of zinc and the putative zinc-binding domain in bacterial glutamyl tRNA synthetase. AB - The putative zinc-binding domain (pZBD) in Escherichia coli glutamyl-tRNA synthetase (GluRS) is known to correctly position the tRNA acceptor arm and modulate the amino acid-binding site. However, its functional role in other bacterial species is not clear since many bacterial GluRSs lack a zinc-binding motif in the pZBD. From experimental studies on pZBD-swapped E. coli GluRS, with Thermosynechoccus elongatus GluRS, Burkholderia thailandensis GluRS and E. coli glutamyl-queuosine-tRNA(Asp) synthetase (Glu-Q-RS), we show that E. coli GluRS, containing the zinc-free pZBD of B. thailandensis, is as functional as the zinc bound wild-type E. coli GluRS, whereas the other constructs, all zinc-bound, show impaired function. A pZBD-tinkered version of E. coli GluRS that still retained Zn-binding capacity, also showed reduced activity. This suggests that zinc is not essential for the pZBD to be functional. From extensive structural and sequence analyses from whole genome database of bacterial GluRS, we further show that in addition to many bacterial GluRS lacking a zinc-binding motif, the pZBD is actually deleted in some bacteria, all containing either glutaminyl-tRNA synthetase (GlnRS) or a second copy of GluRS (GluRS2). Correlation between the absence of pZBD and the occurrence of glutamine amidotransferase CAB (GatCAB) in the genome suggests that the primordial role of the pZBD was to facilitate transamidation of misacylated Glu-tRNA(Gln) via interaction with GatCAB, whereas its role in tRNA(Glu) interaction may be a consequence of the presence of pZBD. PMID- 25686372 TI - Compounds targeting disulfide bond forming enzyme DsbB of Gram-negative bacteria. AB - In bacteria, disulfide bonds confer stability on many proteins exported to the cell envelope or beyond. These proteins include numerous bacterial virulence factors, and thus bacterial enzymes that promote disulfide bond formation represent targets for compounds inhibiting bacterial virulence. Here, we describe a new target- and cell-based screening methodology for identifying compounds that inhibit the disulfide bond-forming enzymes Escherichia coli DsbB (EcDsbB) or Mycobacterium tuberculosis VKOR (MtbVKOR), which can replace EcDsbB, although the two are not homologs. Initial screening of 51,487 compounds yielded six specifically inhibiting EcDsbB. These compounds share a structural motif and do not inhibit MtbVKOR. A medicinal chemistry approach led us to select related compounds, some of which are much more effective DsbB inhibitors than those found in the screen. These compounds inhibit purified DsbB and prevent anaerobic growth of E. coli. Furthermore, these compounds inhibit all but one of the DsbBs of nine other Gram-negative pathogenic bacteria tested. PMID- 25686374 TI - The importance of loop length on the stability of i-motif structures. AB - Using UV and srCD spectroscopy it is found that loop length within the i-motif structure is important for both thermal and pH stability, but in contrast to previous statements, it is the shorter loops that exhibit the highest stability. PMID- 25686373 TI - Arginine-rhamnosylation as new strategy to activate translation elongation factor P. AB - Ribosome stalling at polyproline stretches is common and fundamental. In bacteria, translation elongation factor P (EF-P) rescues such stalled ribosomes, but only when it is post-translationally activated. In Escherichia coli, activation of EF-P is achieved by (R)-beta-lysinylation and hydroxylation of a conserved lysine. Here we have unveiled a markedly different modification strategy in which a conserved arginine of EF-P is rhamnosylated by a glycosyltransferase (EarP) using dTDP-L-rhamnose as a substrate. This is to our knowledge the first report of N-linked protein glycosylation on arginine in bacteria and the first example in which a glycosylated side chain of a translation elongation factor is essential for function. Arginine-rhamnosylation of EF-P also occurs in clinically relevant bacteria such as Pseudomonas aeruginosa. We demonstrate that the modification is needed to develop pathogenicity, making EarP and dTDP-L-rhamnose-biosynthesizing enzymes ideal targets for antibiotic development. PMID- 25686375 TI - Enterococcal-related vertebral osteoarthritis in South African broiler breeders: A case report. AB - Infections in broilers and broiler breeders by Enterococcus cecorum, causing clinical disease, have increasingly been described in various countries in the Northern Hemisphere over the past decade. This case report describes an outbreak of enterococcal-associated vertebral osteoarthritis (EVOA) in male broiler breeders in several flocks in South Africa. Male birds aged 4 and 9 weeks displayed the common presentation of lameness, paresis or complete paralysis. Autopsies of culled birds revealed masses on caudal thoracic vertebrae T5-T7, with vertebral osteomyelitis and spondylitis. Microbiological assays identified E. cecorum cultured from spondylitic lesions. Affected flocks were treated with amoxycillin at 25 mg/kg in the drinking water for 5 days, resulting in decreased numbers of lame birds and culls. The origin and pathogenesis of EVOA are poorly understood, which limits prevention to environmental factors that may inhibit systemic access by the enteric bacteria. Skeletal growth trends of male birds are thought to increase their susceptibility to bacterial colonisation at sites of skeletal strain, resulting in abscesses and lesions. Evidence points to the emergence of E. cecorum strains with increased pathogenicity; this highlights the need for greater understanding of the origins, treatment and prevention of EVOA to minimise its economic impact on poultry operations. PMID- 25686376 TI - Perception of spin and the interception of curved football trajectories. AB - Using plain white and chequered footballs, we evaluated observers' sensitivity to rotation direction and the effects of ball texture on interceptive behaviour. Experiment 1 demonstrated that the maximal distance at which observers (n = 8) could perceive the direction of ball rotation decreased when rotation frequency increased from 5 to 11 Hz. Detection threshold distances were nevertheless always larger for the chequered (decreasing from 47 to 28 m) than for the white (decreasing from 15 to 11 m) ball. In Experiment 2, participants (n = 7) moved laterally along a goal line to intercept the two balls launched with or without +/-4.3 Hz sidespin from a 30-m distance. The chequered ball gave rise to shorter movement initiation times when trajectories curved outward (+/-6 m arrival positions) or did not curve (+/-2 m arrival positions). Inward curving trajectories, arriving at the same +/-2 m distances from the participants as the non-curving trajectories, evoked initial movements in the wrong direction for both ball types, but the amplitude and duration of these reversal movements were attenuated for the chequered ball. We conclude that the early detection of rotation permitted by the chequered ball allowed modulation of interception behaviour without changing its qualitative characteristics. PMID- 25686377 TI - The nonlinear viscoelasticity of hyaluronic acid and its role in joint lubrication. AB - Hyaluronic acid solutions have been widely studied due to their relevance to the rheological behavior of synovial fluid and joint lubrication. Ambulatory joint motion is typically large oscillatory deflections; therefore, large amplitude oscillatory shear strain experiments are used to examine the relevant non-linear viscoelastic properties of these solutions. Using the sequence of physical processes method to analyze data provides time dependent viscoelastic moduli, which exhibit a clear physiologically relevant behavior to hyaluronic acids non linear viscoelasticity. In particular, it is seen that during peak strain/acceleration, the time dependent elastic modulus peaks and the loss modulus is at a minimum. The hyaluronic acid can provide an immediate elastic response to sudden forces, acting like a shock absorber during sudden changes in direction of motion or maximum deflection. However, during peak rate, the elastic modulus is at a minimum and the loss modulus is at a maximum, which provides greater efficacy to hydrodynamic shear lubrication. PMID- 25686378 TI - Prevalence and effect of oxytetracycline on congenital fetlock knuckling in neonatal dairy calves. AB - Musculoskeletal system deformities were observed in 24 (34.3%) of 70 neonatal dairy calves that presented with different congenital abnormalities. Among them, 19 calves (27.1%), the majority of which were crossbred Jersey calves of either gender with mean (+/- s.e.) body weight 22.00 kg +/- 1.17 kg and aged 7.11 +/- 1.16 days, were presented for treatment of congenital knuckling. Five of the knuckling calves had additional concurrent congenital conditions and were excluded from the present study. All of the remaining 14 calves showing moderate, bilateral fetlock knuckling had a wooden or polyvinyl chloride (PVC) splint applied to the palmar or plantar aspect of the affected limbs. All of the animals received a dose of the analgesic tolfenamic acid intramuscularly, and were randomly allocated to two equal groups. Calves of Group I additionally received oxytetracycline (20 mg/kg intravenous daily for 3 days). The condition resolved satisfactorily in 83.3% and 80.0% calves from the two groups, respectively. The left and right fetlock angle (mean +/- SE) reduced significantly (p <= 0.01) from 50.57 degrees +/- 4.20 degrees to 4.00 degrees +/- 2.27 degrees and 48.71 degrees +/- 2.37 degrees to 5.33 degrees +/- 3.03 degrees , respectively in animals of Group I. In Group II calves, the angles showed reduction from 50.86 degrees +/- 2.94 degrees to 4.20 degrees +/- 2.75 degrees and from 48.71 degrees +/- 3.14 degrees to 6.80 degrees +/- 3.34 degrees , respectively. From the present study, it was concluded that bilateral moderate fetlock knuckling in the neonatal dairy calves can be managed satisfactorily with early application of splints. Supplementary use of oxytetracycline at repeated doses of low toxicity had only a marginally beneficial effect. PMID- 25686379 TI - Ionic clusters vs shear viscosity in aqueous amino acid ionic liquids. AB - Aqueous solutions of amino acid ionic liquids (AAILs) are of high importance for applications in protein synthesis and solubilization, enzymatic reactions, templates for synthetic study, etc. This work employs molecular dynamics simulations using our own force field to investigate shear viscosity and cluster compositions of three 1-ethyl-3-methylimidazolium (emim) amino acid salts: [emim][ala], [emim][met], and [emim][trp] solutions (2, 5, 10, 20, and 30 mol %) in water at 310 K. We, for the first time, establish simple correlations between cluster composition, on one side, and viscosity, on another side. We argue that knowledge about any of these properties alone is enough to derive insights regarding the missed properties, using the reported correlations. The numerical observations and qualitative correlations are discussed in the context of the chemical structure of the amino acid anions, [ala], [met], and [trp]. The reported results will enhance progress in the efficient design and applications of AAILs and their solutions. PMID- 25686380 TI - Enhanced oxygen reduction activity and solid oxide fuel cell performance with a nanoparticles-loaded cathode. AB - Reluctant oxygen-reduction-reaction (ORR) activity has been a long-standing challenge limiting cell performance for solid oxide fuel cells (SOFCs) in both centralized and distributed power applications. We report here that this challenge has been tackled with coloading of (La,Sr)MnO3 (LSM) and Y2O3 stabilized zirconia (YSZ) nanoparticles within a porous YSZ framework. This design dramatically improves ORR activity, enhances fuel cell output (200-300% power improvement), and enables superior stability (no observed degradation within 500 h of operation) from 600 to 800 degrees C. The improved performance is attributed to the intimate contacts between nanoparticulate YSZ and LSM particles in the three-phase boundaries in the cathode. PMID- 25686381 TI - Blissfully unaware: Anosognosia and anosodiaphoria after acquired brain injury. AB - Historically, anosognosia referred to under-report of striking symptoms of acquired brain injury (e.g., hemiplegia) with debilitating functional consequences and was linked with anosodiaphoria, an emotional reaction of indifference. It was later extended to include under-report of all manner of symptoms of acquired brain injury by the patient compared to clinicians, family members, or functional performance. Anosognosia is related to time since onset of brain injury but not consistently to demographic variables, lesion location (except that it is more common after unilateral right than left hemispheric injury), or specific neuropsychological test scores. This review considers all manifestations of anosognosia as a unitary phenomenon with differing clinical characteristics dictated by variability in linked cognitive impairments. It is concluded that anosognosia has three chief contributing factors: (1) procedural: measurement differences across studies in terms of symptom selection and the designation of a "gold standard" of patient symptomatology; (2) psychological: a tendency towards positive self-evaluation and the avoidance of adverse information, that also occurs in neurologically intact individuals; and (3) neuropathological: an increased likelihood of error recognition failure from disconnections that disrupt feedback between injured brain regions governing specific behaviours (symptoms) and anterior cingulate/insular cortex. Anosodiaphoria is considered as an associated symptom, resulting from the same psychological and neuropathological factors. PMID- 25686382 TI - Serological detection of infection with canine distemper virus, canine parvovirus and canine adenovirus in communal dogs from Zimbabwe. AB - Domestic dogs are common amongst communities in sub-Saharan Africa and may serve as important reservoirs for infectious agents that may cause diseases in wildlife. Two agents of concern are canine parvovirus (CPV) and canine distemper virus (CDV), which may infect and cause disease in large carnivore species such as African wild dogs and African lions, respectively. The impact of domestic dogs and their diseases on wildlife conservation is increasing in Zimbabwe, necessitating thorough assessment and implementation of control measures. In this study, domestic dogs in north-western Zimbabwe were evaluated for antibodies to CDV, CPV, and canine adenovirus (CAV). These dogs were communal and had no vaccination history. Two hundred and twenty-five blood samples were collected and tested using a commercial enzyme-linked immunosorbent assay (ELISA) for antibodies to CPV, CDV, and CAV. Of these dogs, 75 (34%) had detectable antibodies to CDV, whilst 191 (84%) had antibodies to CPV. Antibodies to canine adenovirus were present in 28 (13%) dogs. Canine parvovirus had high prevalence in all six geographic areas tested. These results indicate that CPV is circulating widely amongst domestic dogs in the region. In addition, CDV is present at high levels. Both pathogens can infect wildlife species. Efforts for conservation of large carnivores in Zimbabwe must address the role of domestic dogs in disease transmission. PMID- 25686383 TI - Willingness to participate in mammography screening: a randomized controlled questionnaire study of responses to two patient information leaflets with different factual content. AB - BACKGROUND: From 2010 onward, a new leaflet about mammography screening for breast cancer, more informative than the preceding version, has been sent to women in Germany aged 50 to 69 with the invitation to undergo screening. The purpose of this study was to determine the effect of different informational content on the decision whether or not to be screened. METHODS: In a randomized and blinded design, 792 women aged 48 to 49 were sent either the old or the new leaflet. Questionnaires were sent together with the leaflets in order to assess the following: willingness to undergo mammography screening, knowledge, decisional confidence, personal experiences of breast cancer, and demographic data. RESULTS: 370 (46.7%) of the questionnaires were returned, and 353 were evaluable. The two groups did not differ significantly in their willingness to be screened: 81.5% (95% confidence interval [CI] 75.8%-87.2%) versus 88.6% (95% CI 83.9%-91.3%, p = 0.060). A post-hoc analysis showed that women who reported having had personal experience of breast cancer (18.7%) were more willing to be screened if they were given the new leaflet, rather than the old one (interaction p = 0.014). The two groups did not differ in their knowledge about screening (p = 0.260). Women who received the old leaflet reported a higher decisional confidence (p = 0.017). The most commonly mentioned factors affecting the decision were experience of breast cancer in relatives and close acquaintances (26.5% of mentions) and a doctor's recommendation (48.2%). Leaflets (3.6%) and all other factors played only a secondary role. CONCLUSION: The greater or lesser informativeness of the leaflet affected neither the participants' knowledge of mammography screening nor their willingness to undergo it. The leaflet was not seen as an aid to decision-making. The best way to assure an informed decision about screening may be for the patient to discuss the matter personally with a qualified professional. PMID- 25686384 TI - Critical comments necessary. PMID- 25686385 TI - In reply. PMID- 25686386 TI - Questionable statement. PMID- 25686387 TI - In reply. PMID- 25686388 TI - The pathophysiology, diagnosis, and treatment of dry eye disease. AB - BACKGROUND: Dry eye disease (DED) is common; its prevalence around the world varies from 5% to 34%. Its putative pathogenetic mechanisms include hyperosmolarity of the tear film and inflammation of the ocular surface and lacrimal gland. Dry eye is clinically subdivided into two subtypes: one with decreased tear secretion (aqueous-deficient DED), and one with increased tear evaporation (hyperevaporative DED). METHODS: This review is based on pertinent publications retrieved by a selective PubMed search and on the authors' own clinical and scientific experience. RESULTS: The diagnostic evaluation of dry eye disease should include a detailed patient history, thorough split-lamp examination, and additional tests as indicated. Few randomized controlled therapeutic trials for dry eye have been published to date. Artificial tears of various kinds are recommended if the symptoms are mild. Lid hygiene is helpful in the treatment of hyperevaporative dry eye, while collagen or silicon plugs can be used for partial occlusion of the efferent lacrimal ducts to treat severe hyposecretory dry eye. The benefit of long-term topical anti-inflammatory treatment of moderate or severe dry eye disease with corticosteroids or cyclosporine A eye drops has been documented in clinical trials on a high evidence level. Orally administered tetraycycline derivatives and omega-3 or omega-6 fatty acids are also used. CONCLUSION: The treatment of dry eye has evolved from tear substitution alone to a rationally based therapeutic algorithm. Current research focuses on pathophysiology, new diagnostic techniques, and novel therapies including secretagogues, topical androgens, and new anti- inflammatory drugs. PMID- 25686389 TI - Improved data analysis for the MinION nanopore sequencer. AB - Speed, single-base sensitivity and long read lengths make nanopores a promising technology for high-throughput sequencing. We evaluated and optimized the performance of the MinION nanopore sequencer using M13 genomic DNA and used expectation maximization to obtain robust maximum-likelihood estimates for insertion, deletion and substitution error rates (4.9%, 7.8% and 5.1%, respectively). Over 99% of high-quality 2D MinION reads mapped to the reference at a mean identity of 85%. We present a single-nucleotide-variant detection tool that uses maximum-likelihood parameter estimates and marginalization over many possible read alignments to achieve precision and recall of up to 99%. By pairing our high-confidence alignment strategy with long MinION reads, we resolved the copy number for a cancer-testis gene family (CT47) within an unresolved region of human chromosome Xq24. PMID- 25686390 TI - Ultrastructurally smooth thick partitioning and volume stitching for large-scale connectomics. AB - Focused-ion-beam scanning electron microscopy (FIB-SEM) has become an essential tool for studying neural tissue at resolutions below 10 nm * 10 nm * 10 nm, producing data sets optimized for automatic connectome tracing. We present a technical advance, ultrathick sectioning, which reliably subdivides embedded tissue samples into chunks (20 MUm thick) optimally sized and mounted for efficient, parallel FIB-SEM imaging. These chunks are imaged separately and then 'volume stitched' back together, producing a final three-dimensional data set suitable for connectome tracing. PMID- 25686391 TI - Computational polypharmacology analysis of the heat shock protein 90 interactome. AB - The design of a single drug molecule that is able to simultaneously and specifically interact with multiple biological targets is gaining major consideration in drug discovery. However, the rational design of drugs with a desired polypharmacology profile is still a challenging task, especially when these targets are distantly related or unrelated. In this work, we present a computational approach aimed at the identification of suitable target combinations for multitarget drug design within an ensemble of biologically relevant proteins. The target selection relies on the analysis of activity annotations present in molecular databases and on ligand-based virtual screening. A few target combinations were also inspected with structure-based methods to demonstrate that the identified dual-activity compounds are able to bind target combinations characterized by remote binding site similarities. Our approach was applied to the heat shock protein 90 (Hsp90) interactome, which contains several targets of key importance in cancer. Promising target combinations were identified, providing a basis for the computational design of compounds with dual activity. The approach may be used on any ensemble of proteins of interest for which known inhibitors are available. PMID- 25686392 TI - Myxochelins target human 5-lipoxygenase. AB - Extracts of the predatory myxobacterium Pyxidicoccus fallax HKI 727 showed antiproliferative effects on leukemic K-562 cells. Bioactivity-guided fractionation led to the isolation of the bis-catechol myxochelin A and two new congeners. The biosynthetic origin of myxochelins C and D was confirmed by feeding studies with isotopically labeled precursors. Pharmacological testing revealed human 5-lipoxygenase (5-LO) as a molecular target of the myxochelins. In particular, myxochelin A efficiently inhibited 5-LO activity with an IC50 of 1.9 MUM and reduced the proliferation of K-562 cells at similar concentrations. PMID- 25686393 TI - Monitoring newly synthesized proteins over the adult life span of Caenorhabditis elegans. AB - Little is known regarding how the synthesis and degradation of individual proteins change during the life of an organism. Such knowledge is vital to understanding the aging process. To fill this knowledge gap, we monitored newly synthesized proteins on a proteome scale in Caenorhabditis elegans over time during adulthood using a stable-isotope labeling by amino acids in cell culture (SILAC)-based label-chase approach. For most proteins, the rate of appearance of newly synthesized protein was high during the first 5 days of adulthood, slowed down between the fifth and the 11th days, and then increased again after the 11th day. However, the magnitude of appearance rate differed significantly from protein to protein. For example, the appearance of newly synthesized protein was fast for proteins involved in embryonic development, transcription regulation, and lipid binding/transport, with >70% of these proteins newly synthesized by day 5 of adulthood, whereas it was slow for proteins involved in cellular assembly and motility, such as actin and myosin, with <70% of these proteins newly synthesized even on day 16. The late-life increase of newly synthesized protein was especially high for ribosomal proteins and ATP synthases. We also investigated the effect of RNAi-mediated knockdown of the rpl-9 (ribosomal protein), atp-3 (ATP synthase), and ril-1 (RNAi-induced longevity-1) genes and found that inhibiting the expression of atp-3 and ril-1 beginning in late adulthood is still effective to extend the life span of C. elegans. PMID- 25686394 TI - Patterns of use and cost for inappropriate radioactive iodine treatment for thyroid cancer in the United States: use and misuse. PMID- 25686395 TI - Lymph node metastasis and pattern of recurrence in clinically early stage endometrial cancer with positive lymphovascular space invasion. AB - OBJECTIVE: To investigate the rate, predictors of lymph node metastasis (LNM) and pattern of recurrence in clinically early stage endometrial cancer (EC) with positive lymphovascular space invasion (LVSI). METHODS: Women with clinically early stage EC and positive LVSI 2005 to 2012 were identified. Kaplan-Meier curves and logistic regression models were used. RESULTS: One hundred forty-eight women were identified. Of them, 25.7% had LNM (21.7% pelvic LNM, 18.5% para aortic LNM). Among patients with LNM who had both pelvic and para-aortic lymphadenectomy, isolated pelvic, para-aortic and both LNM were noted in 51.4%, 17.1%, and 31.4% respectively. Age and depth of myometrial invasion were significant predictors of LNM in LVSI positive EC. Node positive patients had high recurrence rate (47% vs. 11.8%, p<0.05) especially distant (60.9% vs. 7.9%, p<0.001) and para-aortic (13.2% vs. 1.8%, p=0.017) recurrences compared to node negative EC. LNM was associated with lower progression-free survival (p=0.002) but not overall survival (p=0.73). CONCLUSION: EC with positive LVSI is associated with high risk of LNM. LNM is associated with high recurrence rate especially distant and para-aortic recurrences. Adjuvant treatments should target prevention of recurrences in these areas. PMID- 25686396 TI - Quality of life and sexuality comparison between sexually active ovarian cancer survivors and healthy women. AB - OBJECTIVE: compare quality of life (QoL) and sexual functioning between sexually active ovarian cancer survivors and healthy women. METHODS: A cross-sectional study was performed in 103 successfully treated ovarian cancer survivors and 220 healthy women. All women had engaged in sexual activity within the previous 3 months, and ovarian cancer survivors were under surveillance after primary treatment without evidence of disease. QoL and sexual functioning were assessed using three questionnaires; the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30), Ovarian Cancer Module (EORTC QLQ-OV28), and the Female Sexual Function Index (FSFI). Propensity score matching was used to adjust covariates between the ovarian cancer survivor and healthy women groups. In total, 73 ovarian cancer survivors and 73 healthy women were compared. RESULTS: Poorer social functioning (mean, 82.4 vs. 90.9; p=0.010) and more financial difficulties (mean, 16.4 vs. 7.8; p=0.019) were observed among ovarian cancer survivors than among healthy women. Sexuality, both in terms of desire, arousal, lubrication, orgasm, satisfaction, and pain and in terms of interest in sex, sexual activity, and enjoyment of sex (EORTC QLQ-OV28) were similar between the groups. However, vaginal dryness was more problematic in ovarian cancer survivors, with borderline statistical significance (p=0.081). CONCLUSION: Sexuality was not impaired in ovarian cancer survivors who were without evidence of disease after primary treatment and having sexual activities, compared with healthy women, whereas social functioning and financial status did deteriorate. Prospective cohort studies are needed. PMID- 25686397 TI - Efficacy and tolerability of paclitaxel, ifosfamide, and cisplatin as a neoadjuvant chemotherapy in locally advanced cervical carcinoma. AB - OBJECTIVE: To evaluate the efficacy and tolerability of a neoadjuvant paclitaxel, ifosfamide, and cisplatin chemotherapy in patients with locally advanced cervical carcinoma. METHODS: Patients with histologically confirmed locally advanced cervical carcinoma, aged >=18 years, were treated with intravenous ifosfamide 5,000 mg/m2 and mesna 5,000 mg/m2, on day 1; intravenous paclitaxel 175 mg/m2 and cisplatin 75 mg/m2, on day 2; every 3 weeks for three cycles. Following chemotherapy, operable patients underwent radical hysterectomy and pelvic lymphadenectomy, and, if necessary, adjuvant radiotherapy. RESULTS: One hundred fifty-two patients with median age 53 years (range, 24 to 79 years), FIGO stage IIB in 126 (89%), were treated with chemotherapy for median 3 cycles (range, 1 to 3). Treatment was delayed or withdrawn in 23 patients (15%). One hundred thirty nine patients (91%) underwent surgery. Postchemotherapy pathological complete response rate was 18% (25 patients). Postoperative radiotherapy was administered in 100 patients (72%). The 5-year overall survival and progression-free survival were 87.3% (95% confidence interval [CI], 84.5 to 90.3) and 76.4% (95% CI, 73.5 to 79.5), respectively. CONCLUSION: Neoadjuvant paclitaxel, ifosfamide, and cisplatin chemotherapy was feasible and effective in the treatment of locally advanced cervical carcinoma patients with older age and more advanced disease stage than reported in previous studies. Hematological and renal toxicity could be carefully prevented. PMID- 25686398 TI - Prognostic impact of lymphadenectomy in uterine clear cell carcinoma. AB - OBJECTIVE: The aim of this study was to estimate the survival impact of lymphadenectomy in patients diagnosed with uterine clear cell cancer (UCCC). METHODS: Patients with a diagnosis of UCCC were identified from Surveillance, Epidemiology, and End Results (SEER) program from 1988 to 2007. Only surgically treated patients were included. Statistical analysis using Student t-test, Kaplan Meier survival methods, and Cox proportional hazard regression were performed. RESULTS: One thousand three hundred eighty-five patients met the inclusion criteria; 955 patients (68.9%) underwent lymphadenectomy. Older patients (>=65) were less likely to undergo lymphadenectomy compared with their younger cohorts (64.3% vs. 75.9%, p<0.001). The prevalence of nodal metastasis was 24.8%. Out of 724 women who had disease clinically confined to the uterus and underwent lymphadenectomy, 123 (17%) were found to have nodal metastasis. Lymphadenectomy was associated with improved survival. Patients who underwent lymphadenectomy were 39% (hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.52 to 0.72; p<0.001) less likely to die than patient who did not have the procedure. Moreover, more extensive lymphadenectomy correlated positively with survival. Compared to patients with 0 nodes removed, patients with more extensive lymphadenectomy (1 to 10 and >10 nodes removed) were 32% (HR, 0.68; 95% CI, 0.56 to 0.83; p<0.001) and 47% (HR, 0.53; 95% CI, 0.43 to 0.65; p<0.001) less likely to die, respectively. CONCLUSION: The extent of lymphadenectomy is associated with an improved survival of patients diagnosed with UCCC. PMID- 25686399 TI - High-dose oral tegafur-uracil maintenance therapy in patients with uterine cervical cancer. AB - OBJECTIVE: The aim of this study was to determine the efficacy and toxicity of oral administration of tegafur-uracil (UFT) at a high dose, 600 mg/day, based on the tegafur dose, against uterine cervical cancer. METHODS: This study consisted of a retrospective analysis. From April 1986 to March 1997, 309 patients with uterine cervical cancer were registered. Oral UFT was administered to 162 patients for maintenance therapy after an initial treatment (the UFT group). The other 147 patients were not treated with UFT (the control group). The survival rate was calculated for both groups and statistically analyzed using the log-rank test. Adverse events were compared between the UFT and control groups. RESULTS: In the UFT group, 103 patients (63.6%) received UFT for >=90 days. The drug dose was 600 mg/day for 137 patients (84.6%) and 300 to 400 mg/day for the remainder. The overall survival rate was significantly higher in the UFT group than in the control group (p<0.05). The prognosis was particularly favorable in stage III cases, in cases of squamous cell carcinoma, and in cases that were treated by radiotherapy. The most frequent side effects were nausea/vomiting (12.2%), appetite loss (10.1%), and leukopenia/neutropenia (5.8%). CONCLUSION: High-dose oral UFT maintenance treatment prolonged the disease-free survival and overall survival of patients with uterine cervical cancer, particularly of those with advanced disease. PMID- 25686400 TI - Cell microenvironment-controlled antitumor drug releasing-nanomicelles for GLUT1 targeting hepatocellular carcinoma therapy. AB - In clinical therapy, the poor prognosis of hepatocellular carcinoma (HCC) is mainly attributed to the failure of chemotherapeutical agents to accumulate in tumor as well as their serious systemic toxicity. In this work, we developed actively tumor-targeting trilayer micelles with microenvironment-sensitive cross links as a novel nanocarrier for HCC therapy. These micelles comprised biodegradable PEG-pLys-pPhe polymers, in which pLys could react with a disulfide containing agent to form redox-responsive cross-links. In vitro drug release and pharmacokinetics studies showed that these cross-links were stable in physiological condition whereas cleaved once internalized into cells due to the high level of glutathione, resulting in facilitated intracellular doxorubicin release. In addition, dehydroascorbic acid (DHAA) was decorated on the surface of micelles for specific recognition of tumor cells via GLUT1, a member of glucose transporter family overexpressed on hepatocarcinoma cells. Moreover, DHAA exhibited a "one-way" continuous accumulation within tumor cells. Cellular uptake and in vivo imaging studies proved that these micelles had remarkable targeting property toward hepatocarcinoma cells and tumor. Enhanced anti-HCC efficacy of the micelles was also confirmed both in vitro and in vivo. Therefore, this micellar system may be a potential platform of chemotherapeutics delivery for HCC therapy. PMID- 25686401 TI - Synthesis of oxazolines from amides via palladium-catalyzed functionalization of unactivated C(sp(3))-H bond. AB - A complementary method that enables the expeditious synthesis of oxazolines from amides via Pd-catalyzed C(sp(3))-H functionalization has been described. Preliminary studies indicate that the reaction might go through a chlorination/nucleophilic cyclization sequence, and the high efficiency of this sequence is enhanced by the in situ cyclative capture of the chlorinated intermediate. The resulting oxazolines can be further converted into the corresponding beta-amino alcohols without chromatography. PMID- 25686402 TI - Epineurial repair of an iatrogenic facial nerve neurotmesis after total ear canal ablation and lateral bulla osteotomy in a dog with concurrent cranio-mandibular osteopathy. AB - A 7-year-old male entire West Highland white terrier was referred to the Small Animal Hospital at the University of Glasgow for bilateral, chronic, medically unresponsive otitis media and externa. A history of cranio-mandibular osteopathy was also reported. Bilateral total ear canal ablation and lateral bulla osteotomy was performed with the aid of a pneumatic burr. Extensive bone proliferation was present bilaterally originating from the caudal mandibular ramus and tympanic bulla which incorporated the horizontal canal on each side. The right facial nerve was identified leaving the stylomastoid foramen and running in a cranial direction through a 1.5 cm diameter cuff of bone surrounding the horizontal canal and external acoustic meatus. Despite careful dissection, a facial nerve neurotmesis ensued which required microsurgical epineurial repair. Neurologic examination performed 12 h post-operatively revealed abnormalities consistent with right facial nerve paralysis. At 3 months, the facial nerve function was found to have improved significantly and was assessed to be normal four months after surgery. To the authors' knowledge, this clinical communication described the first reported clinical case where unilateral facial nerve paralysis resulting from iatrogenic facial nerve neurotmesis was successfully treated by microsurgical epineurial repair. PMID- 25686403 TI - Patients' experiences of being nursed by student nurses at a teaching hospital. AB - BACKGROUND: Teaching hospitals are medical institutes at which most nursing education institutions provide their students with practical nursing experience. Although the focus of care is the patient, attention is sometimes focused more on the nursing students rather than on the patients who are undergoing care at the hands of both the nursing professionals and students. However, proper nursing care should also take into account the experiences of patients during the care process in the health facility. OBJECTIVES: The study had three objectives: to describe the experiences of patients nursed by student nurses in a teaching hospital in the Western Cape; to identify patterns in the experiences of patients receiving patient care from student nurses; and to analyse aspects of the experiences that may need further attention for the training of student nurses. METHOD: A descriptive phenomenological approach was used to explore the experiences of patients nursed by student nurses. Participant selection took place purposively from different wards of the identified teaching hospital, and thematic saturation was achieved at 10 participants. The data were collected through in-depth interviews and analysed using thematic content analysis. RESULTS: Three main themes were discovered after data analysis: methods of identification of student nurses by patients; positive perceptions of student nurses by patients; and negative perceptions of student nurses by patients. CONCLUSION: The findings will inform the clinical supervisors and educational institutions of aspects of the nursing training of student nurses that need improvement and those that require enforcement. PMID- 25686405 TI - Pinpoint-fluorinated phenacenes: new synthesis and solubility enhancement strategies. AB - The Pd(II)-catalyzed cyclizations of 2,2-difluorovinylated biaryls, following a Friedel-Crafts-type mechanism, provide a new route to pinpoint-fluorinated phenacenes. The single fluorine substituent stabilized the synthesized fluoropicenes (fluoro[5]phenacenes) toward aerial oxidation and contributed to their solubility in organic solvents. For example, 6- and 13-fluoropicenes were 25- and 15-fold more soluble in THF than nonfluorinated picene. X-ray crystal structure analysis revealed that the fluorine substituent did not alter molecular planarity. PMID- 25686404 TI - Assessing polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans in air across Latin American countries using polyurethane foam disk passive air samplers. AB - A passive air sampling network has been established to investigate polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) at Global Atmospheric Passive Sampling (GAPS) sites and six additional sites in the Group of Latin American and Caribbean Countries (GRULAC) region. The air sampling network covers background, agricultural, rural, and urban sites. Samples have been collected over four consecutive periods of 6 months, which started in January 2011 [period 1 (January to June 2011), period 2 (July to December 2011), period 3 (January to June 2012), and period 4 (July 2012 to January 2013)]. Results show that (i) the GAPS passive samplers (PUF disk type) and analytical methodology are adequate for measuring PCDD/F burdens in air and (ii) PCDD/F concentrations in air across the GRULAC region are widely variable by almost 2 orders of magnitude. The highest concentrations in air of Sigma4 8PCDD/Fs were found at the urban site Sao Luis (Brazil, UR) (i.e., 2560 fg/m3) followed by the sites in Sao Paulo (Brazil, UR), Mendoza (Argentina, RU), and Sonora (Mexico, AG) with values of 1690, 1660, and 1610 fg/m3, respectively. Very low concentrations of PCDD/Fs in air were observed at the background site Tapanti (Costa Rica, BA), 10.8 fg/m3. This variability is attributed to differences in site characteristics and potential local/regional sources as well as meteorological influences. The measurements of PCDD/Fs in air agree well with model-predicted concentrations performed using the Global EMEP Multimedia Modeling System (GLEMOS) and emission scenario constructed on the basis of the UNEP Stockholm Convention inventory of dioxin and furan emissions. PMID- 25686406 TI - A manual and an automatic TERS based virus discrimination. AB - Rapid techniques for virus identification are more relevant today than ever. Conventional virus detection and identification strategies generally rest upon various microbiological methods and genomic approaches, which are not suited for the analysis of single virus particles. In contrast, the highly sensitive spectroscopic technique tip-enhanced Raman spectroscopy (TERS) allows the characterisation of biological nano-structures like virions on a single-particle level. In this study, the feasibility of TERS in combination with chemometrics to discriminate two pathogenic viruses, Varicella-zoster virus (VZV) and Porcine teschovirus (PTV), was investigated. In a first step, chemometric methods transformed the spectral data in such a way that a rapid visual discrimination of the two examined viruses was enabled. In a further step, these methods were utilised to perform an automatic quality rating of the measured spectra. Spectra that passed this test were eventually used to calculate a classification model, through which a successful discrimination of the two viral species based on TERS spectra of single virus particles was also realised with a classification accuracy of 91%. PMID- 25686408 TI - Rhodium-catalyzed dehydrogenative coupling of phenylheteroarenes with alkynes or alkenes. AB - Benzo-fused tri- to heptacyclic heteroarenes were effectively constructed by the rhodium-catalyzed dehydrogenative coupling of phenylheteroarenes with alkynes. Using alkenes as coupling partners, dehydrogenative alkenylation took place selectively on the phenyl moiety of phenylheteroarenes. Several experiments with deuterium-labeled substrates indicated that double C-H bond cleavages take place even in the reaction with alkenes. PMID- 25686407 TI - Photoactive fluoropolymer surfaces that release sensitizer drug molecules. AB - We describe a physical-organic study of two fluoropolymers bearing a photoreleasable PEGylated photosensitizer that generates (1)O2((1)Deltag) [chlorin e6 methoxy tri(ethylene glycol) triester]. The surfaces are Teflon/poly(vinyl alcohol) (PVA) nanocomposite and fluorinated silica. The relative efficiency of these surfaces to photorelease the PEGylated sensitizer [shown previously to be phototoxic to ovarian cancer cells (Kimani, S. et al. J. Org. Chem 2012, 77, 10638)] was slightly higher for the nanocomposite. In the presence of red light and O2, (1)O2 is formed, which cleaves an ethene linkage to liberate the sensitizer in 68-92% yield. The fluoropolymers were designed to deal with multiple problems. Namely, their success relied not only on high O2 solubility and drug repellency but also on the C-F bonds, which physically quench little (1)O2, for singlet oxygen's productive use away from the surface. The results obtained here indicate that Teflon-like surfaces have potential uses in delivering sensitizer and singlet oxygen for applications in tissue repair and photodynamic therapy (PDT). PMID- 25686409 TI - Orthodontics: a themed issue. PMID- 25686410 TI - Gross miscarriage of justice. PMID- 25686411 TI - Anaesthesia: over prescription. PMID- 25686412 TI - Selective literature use. PMID- 25686413 TI - Dental education: blow a little harder. PMID- 25686415 TI - BDA museum: dentures: necessity or vanity? PMID- 25686416 TI - Standardised cigarette packaging to be fast-tracked. PMID- 25686417 TI - Glasgow dentists treat children in Palestine. PMID- 25686418 TI - Greater measures needed to tackle tooth decay. PMID- 25686420 TI - An orthodontic registrar's life: spinning many plates. PMID- 25686422 TI - World Oral Health Day focuses on a smile for life. PMID- 25686424 TI - Recent research. PMID- 25686425 TI - Who needs orthodontic treatment? Who gets it? And who wants it? AB - As the health and expectations of the UK population improve, demand for orthodontic treatment is increasing. This article will examine who actually needs orthodontic treatment and who is currently receiving it, while also providing an opinion on the the risks versus benefits in providing demand-led treatment. PMID- 25686426 TI - Myths and realities in orthodontics. AB - Comprehensive orthodontic treatment typically comprises an initial phase of alignment over a period of four to six months, followed by vertical, transverse and antero-posterior corrections, space closure, finishing and detailing to enhance dental and facial aesthetics and function. Each course of treatment involves a series of decisions and alternatives relating to objectives, appliance design and treatment mechanics. In recent years there has been increasing interest in short-term approaches to treatment with more limited objectives and the avoidance of phases traditionally considered integral to successful treatment. In this review the veracity of accepted truths in orthodontics are discussed; specifically, the importance of initial molar relationship, final incisor relationship, the merits of orthodontic extractions, anticipated treatment times, the value of modern fixed appliance systems, the importance of torque expression and the relative merits of bonded retainers and inter-proximal reduction are considered. PMID- 25686427 TI - Adults seeking orthodontic treatment: expectations, periodontal and TMD issues. AB - The growth in adult orthodontics presents new challenges to both the general dental practitioner and the orthodontist. Although many of the main objectives of orthodontic treatment are similar for adults, young adults and children, adult patients frequently bring significant challenges in several areas not often seen in the younger patient group. In areas such as planning realistic treatment outcomes, it is paramount that the patient's expectations are identified, respected and managed where appropriate. The adult patient's dental health often dictates deviation from the ideal treatment plan and periodontal problems are a common example. Based on current evidence, this paper presents an overview of some of the difficulties in the management of these issues, as well as highlighting developments with regard to pain conditions and their relevance to orthodontic treatment and its effects on temporomandibular joint disorders (TMD) management. PMID- 25686428 TI - Retention in orthodontics. AB - Retention is necessary following orthodontic treatment to prevent relapse of the final occlusal outcome. Relapse can occur as a result of forces from the periodontal fibres around the teeth which tend to pull the teeth back towards their pre-treatment positions, and also from deflecting occlusal contacts if the final occlusion is less than ideal. Age changes, in the form of ongoing dentofacial growth, as well as changes in the surrounding soft tissues, can also affect the stability of the orthodontic outcome. It is therefore essential that orthodontists, patients and their general dental practitioners understand the importance of wearing retainers after orthodontic treatment. This article will update the reader on the different types of removable and fixed retainers, including their indications, duration of wear, and how they should be managed in order to minimise any unwanted effects on oral health and orthodontic outcomes. The key roles that the general dental practitioner can play in supporting their patients wearing orthodontic retainers are also emphasised. PMID- 25686429 TI - The use of functional appliances in contemporary orthodontic practice. AB - Functional appliances have been used for over 100 years in orthodontics to correct Class II malocclusion. During this time numerous different systems have been developed often accompanied by claims of modification and enhancement of growth. Recent clinical evidence has questioned whether they really have a lasting influence on facial growth, their skeletal effects appearing to be short term. However, despite these findings, the clinical effectiveness of these appliances is acknowledged and they can be very useful in the correction of sagittal arch discrepancies. This article will discuss the clinical use of functional appliances, the underlying evidence for their use and their limitations. PMID- 25686430 TI - Craniofacial malformations and the orthodontist. AB - This review article presents an overview of craniofacial malformations and the role of the orthodontist in their management. The first part of this article focuses on cleft lip and palate, followed by more complex deformities including craniosynostosis and craniofacial microsomia. The main features of these anomalies are discussed as well as the clinical problems seen in this group of patients. The emphasis is on the role of the orthodontist in the multi disciplinary management of these cases. PMID- 25686431 TI - The multidisciplinary management of hypodontia: a team approach. AB - Hypodontia is a frequently encountered condition within general dental practice. Its successful management involves the interplay of a number of clinicians. The general dental practitioner plays a key role in the management of patients. The aim of this short article is to outline some of the principles of the multidisciplinary management of hypodontia with an emphasis on orthodontic treatment. PMID- 25686432 TI - The developing occlusion of children and young people in general practice: when to watch and when to refer. AB - This paper discusses the assessment of the developing occlusions of children and adolescents in the general practice setting; that is, reviewing the potential of interceptive orthodontics. In particular we will illustrate the management of these individuals with case examples. We have also provided a handy pull-out guide with this issue of the Journal which can be used in the GDP's surgery for quick reference. PMID- 25686433 TI - A discerning approach to simple aesthetic orthodontics. AB - There is currently considerable interest from general dental practitioners (GDPs) in the use of simple orthodontics to treat adult malocclusions. There is controversy in this, particularly in relation to 'quick fixes', simple orthodontics and 'straight teeth in six months' as opposed to more conventional treatment where the whole malocclusion is treated. This article will present a case for the use of simple aesthetic adult orthodontics in a measured and planned way. It will discuss the processes, planning and the importance of consent. It will also highlight how digital technology is used to preview, consent and execute an aesthetic result. Many of the recent systems emerging, have been as a result of the demand and supply of cosmetic dentistry. This, to a degree, has not helped since the implication of a 'quick-fix' is associated with this field. There has also been discussion on what the limits of GDP orthodontics should be. There is variability in how GDPs approach orthodontics, their experience, skill and ability to treat to an acceptable standard. Short courses may be one way of delivering orthodontic training but some of these courses are not regulated and the amount of internal mentoring is variable. This article highlights some of the systems in use, and potential upsides and downsides of this approach. PMID- 25686434 TI - Orthognathic correction of dento-facial discrepancies. AB - Orthognathic treatment is a process which involves orthodontics and maxillofacial surgery and is used to treat those dento-facial discrepancies which are outside the scope of conventional orthodontic treatment, for example severe Class II or Class III problems, anterior open bites and facial asymmetries. Patients who present with these severe problems may encounter a wide range of different problems ranging from functional problems (for example, difficulties biting and chewing) to self-consciousness in a wide range of work and social situations. This paper discusses the possible indications for orthognathic treatment and looks at the risks and benefits of treatment. The treatment pathway is also described. PMID- 25686439 TI - Summary of: advances in orthodontic anchorage with the use of mini-implant techniques. AB - Orthodontic mini-implants (OMIs) represent a new form of anchorage provision and appear to provide a variety of benefits for both anchorage-demanding and complex orthodontic cases. This paper reports the latest perspectives on OMIs in terms of the emerging clinical evidence base coupled with their varied clinical applications. PMID- 25686440 TI - A viewpoint on the current status of UK orthodontic education and the challenges for the future. AB - In this paper we will provide our personal viewpoint on the current provision of orthodontic education and discuss the need for further developments. This will include training relevant to the following: (i) student dentists, (ii) specialists, and (iii) general practitioners: particularly those who wish to develop an interest in orthodontics. We will attempt to take into account the many changes in methods of delivery of care, the changing demands of the public for high quality treatment and the influence of the curricula produced by the General Dental Council (GDC). PMID- 25686442 TI - 'Who does what' in the orthodontic workforce. AB - The contraction of the economy in the United Kingdom and constraints on the National Health Service (NHS) together with new opportunities for the delivery of orthodontic treatment has resulted in an increasing number of dental personnel across the different registrant groups. This article focuses on the changes that have taken place in the orthodontic workforce over the past decade. Although others help deliver orthodontic services such as material suppliers, treatment coordinators and those involved in marketing, this article will restrict itself to informing the reader specifically about which dental registrants are doing what at the clinical interface. How health professionals have developed their skills to undertake the role they play within the team and possible threats arising because of these changes are also discussed. PMID- 25686441 TI - What is the value of orthodontic treatment? AB - Orthodontic treatment is as popular as ever. Orthodontists frequently have long lists of people wanting treatment and the cost to the NHS in England was L258m in 2010-2011 (approximately 10% of the NHS annual spend on dentistry). It is important that clinicians and healthcare commissioners constantly question the contribution of interventions towards improving the health of the population. In this article, the authors outline some of the evidence for and against the claims that people with a malocclusion are at a disadvantage compared with those without a malocclusion and that orthodontic treatment has significant health benefits. The authors would like to point out that this is not a comprehensive and systematic review of the entire scientific literature. Rather the evidence is presented in order to stimulate discussion and debate. PMID- 25686443 TI - An introduction to dento-legal issues and risks in orthodontics. AB - Orthodontic treatment is not without risk. This article aims to look at some of the dento-legal issues surrounding orthodontic treatment, the risks to both the clinician and the patient, and how some of these risks can be mitigated. PMID- 25686460 TI - Advances in orthodontic anchorage with the use of mini-implant techniques. AB - Orthodontic mini-implants (OMIs) represent a new form of anchorage provision and appear to provide a variety of benefits for both anchorage-demanding and complex orthodontic cases. This paper reports the latest perspectives on OMIs in terms of the emerging clinical evidence base coupled with their varied clinical applications. PMID- 25686461 TI - [Career perspectives of hospital health workers after maternity and paternity leave: survey and observational study in Germany]. AB - OBJECTIVE: A term of maternity and paternity (parental) leave becomes frequent on the career paths of medical personnel. Hospitals are highly competitive environments. The question employees universally face is how such a leave will alter their personal work situation and prospects upon return. DESIGN AND PARTICIPANTS: We questioned 709 leave-takers and 88 department heads of a German university hospital (2009-12; full data sets: n = 406 and n = 63) about their experiences. This data was validated by epidemiology data extraction and expert interviews, also in a Swiss and in a Norwegian institution. RESULTS: Parental leave elicited high emotionality (score: 4.0 +/- 2 out of 5). Superiors' appraisal of employees' parental leave was more positive than negative (p < 0.001, mean + 0.8 +/- 0.9 on a bipolar Likert scale (BLS) from - 2 to + 2). However, the annual labor turnover in leave takers doubled to 39 %; 51 % of leave takers experienced significant task profile changes. 58 % of doctors thought about changing their employer and 17 % of leave-taking executives lost status after return. Employees' "power" and "influence" dropped significantly (p < 0.05; determined on BLS) whereas the "professional workload" increased (p < 0.001). Consequently, after return career perspectives (measured on a bipolar visual analogue scale from - 5 to + 5) were perceived significantly more negative than positive (p < 0.0001, mean: - 1.3 +/- 2), especially by high-commitment staff (i. e. female executives, mean: - 2.1 +/- 2, pDelta < 0.05 vs. others). These perceptions significantly influenced future choices concerning further terms of leave. The Swiss and Norwegian comparators appeared to have more liberal substitution and part-time schemes than the German institution. DISCUSSION: A competitive hospital environment can effectively demote leave-taking medical employees in their jobs. Despite sufficient financial arrangements high commitment staff will only take parental leave of adequate length when an institutional framework protects their status. Data support four requirements: 1. Formal recognition of the leave taker's status pre-leave. 2. Establishment of a written ("claimable") return policy. 3. Substitution scheme for each individual, preferably by a locum. 4. Redirection of funds to facilitate part-time work schemes temporarily after return. PMID- 25686462 TI - Multiple-stimuli responsive bioelectrocatalysis based on reduced graphene oxide/poly(N-isopropylacrylamide) composite films and its application in the fabrication of logic gates. AB - In the present work, reduced graphene oxide (rGO)/poly(N-isopropylacrylamide) (PNIPAA) composite films were electrodeposited onto the surface of Au electrodes in a fast and one-step manner from an aqueous mixture of a graphene oxide (GO) dispersion and N-isopropylacrylamide (NIPAA) monomer solutions. Reflection absorption infrared (IR) and Raman spectroscopies were employed to characterize the successful construction of the rGO/PNIPAA composite films. The rGO/PNIPAA composite films exhibited reversible potential-, pH-, temperature-, and sulfate sensitive cyclic voltammetric (CV) on-off behavior to the electroactive probe ferrocenedicarboxylic acid (Fc(COOH)2). For instance, after the composite films were treated at -0.7 V for 7 min, the CV responses of Fc(COOH)2 at the rGO/PNIPAA electrodes were quite large at pH 8.0, exhibiting the on state. However, after the films were treated at 0 V for 30 min, the CV peak currents became much smaller, demonstrating the off state. The mechanism of the multiple-stimuli switchable behaviors for the system was investigated not only by electrochemical methods but also by scanning electron microscopy and X-ray photoelectron spectroscopy. The potential-responsive behavior for this system was mainly attributed to the transformation between rGO and GO in the films at different potentials. The film system was further used to realize multiple-stimuli responsive bioelectrocatalysis of glucose catalyzed by the enzyme of glucose oxidase and mediated by the electroactive probe of Fc(COOH)2 in solution. On the basis of this, a four-input enabled OR (EnOR) logic gate network was established. PMID- 25686463 TI - Anomalous stiffening and ion-induced coil-helix transition of carrageenans under monovalent salt conditions. AB - The macromolecular conformations of anionic polysaccharides with decreasing linear charge densities-lambda, iota, and kappa carrageenan-, at varying NaCl concentrations, are studied by single-chain statistical analysis of high resolution atomic force microscopy (AFM) images. Lambda remains in the random coil conformation, whereas iota and kappa undergo ion-induced coil-helix transitions, with a 2-3-fold increase in chain rigidity. At low ionic strengths, I, the polymer chains sequester Na+, leading to a greater flexibility, and beyond a critical I to the formation of an intramolecular single helix. The persistence length exhibits a sublinear dependence on the Debye screening length, kappa-1, L(p)(e) ~ kappa(-y) (with 0 < y < 1), deviating from the classical polyelectrolyte behavior expressed by Odijk-Skolnick-Fixman or Barrat-Joanny models. Above a certain I, the L(p) shows an upturn, resulting in polymer stiffening and nonmonotonic behavior. This phenomenon is inferred from specific ion-polymer interactions and/or nonlinear electrostatic physics involving ion-ion correlations. PMID- 25686465 TI - Thromboelastography (TEG) and rotational thromboelastometry (ROTEM) for trauma induced coagulopathy in adult trauma patients with bleeding. AB - BACKGROUND: Trauma-induced coagulopathy (TIC) is a disorder of the blood clotting process that occurs soon after trauma injury. A diagnosis of TIC on admission is associated with increased mortality rates, increased burdens of transfusion, greater risks of complications and longer stays in critical care. Current diagnostic testing follows local hospital processes and normally involves conventional coagulation tests including prothrombin time ratio/international normalized ratio (PTr/INR), activated partial prothrombin time and full blood count. In some centres, thromboelastography (TEG) and rotational thromboelastometry (ROTEM) are standard tests, but in the UK they are more commonly used in research settings. OBJECTIVES: The objective was to determine the diagnostic accuracy of thromboelastography (TEG) and rotational thromboelastometry (ROTEM) for TIC in adult trauma patients with bleeding, using a reference standard of prothrombin time ratio and/or the international normalized ratio. SEARCH METHODS: We ran the search on 4 March 2013. Searches ran from 1970 to current. We searched The Cochrane Library, MEDLINE (OvidSP), EMBASE Classic and EMBASE, eleven other databases, the web, and clinical trials registers. The Cochrane Injuries Group's specialised register was not searched for this review as it does not contain diagnostic test accuracy studies. We also screened reference lists, conducted forward citation searches and contacted authors. SELECTION CRITERIA: We included all cross-sectional studies investigating the diagnostic test accuracy of TEG and ROTEM in patients with clinically suspected TIC, as well as case-control studies. Participants were adult trauma patients in both military and civilian settings. TIC was defined as a PTr/INR reading of 1.2 or greater, or 1.5 or greater. DATA COLLECTION AND ANALYSIS: We piloted and performed all review stages in duplicate, including quality assessment using the QUADAS-2 tool, adhering to guidance in the Cochrane Handbook for Diagnostic Test Accuracy Reviews. We analysed sensitivity and specificity of included studies narratively as there were insufficient studies to perform a meta-analysis. MAIN RESULTS: Three studies were included in the final analysis. All three studies used ROTEM as the test of global haemostatic function, and none of the studies used TEG. Tissue factor-activated assay EXTEM clot amplitude (CA) was the focus of the accuracy measurements in blood samples taken near to the point of admission. These CAs were not taken at a uniform time after the start of the coagulopathic trace; the time varied from five minutes, to ten minutes and fifteen minutes. The three included studies were conducted in the UK, France and Afghanistan in both civilian and military trauma settings. In two studies, median Injury Severity Scores were 12, inter-quartile range (IQR) 4 to 24; and 22, IQR 12 to 34; and in one study the median New Injury Severity Score was 34, IQR 17 to 43.There were insufficient included studies examining each of the three ROTEM CAs at 5, 10 and 15 minutes to make meta-analysis and investigation of heterogeneity valid. The results of the included studies are thus reported narratively and illustrated by a forest plot and results plotted on the receiver operating characteristic (ROC) plane.For CA5 the accuracy results were sensitivity 70% (95% CI 47% to 87%) and specificity 86% (95% CI 82% to 90%) for one study, and sensitivity 96% (95% CI 88% to 100%) and specificity 58% (95% CI 44% to 72%) for the other.For CA10 the accuracy results were sensitivity 100% (95% CI 94% to 100%) and specificity 70% (95% CI 56% to 82%).For CA15 the accuracy results were sensitivity 88% (95% CI 69% to 97%) and specificity 100% (95% CI 94% to 100%).No uninterpretable ROTEM study results were mentioned in any of the included studies.Risk of bias and concerns around applicability of findings was low across all studies for the patient and flow and timing domains. However, risk of bias and concerns around applicability of findings for the index test domain was either high or unclear, and the risk of bias for the reference standard domain was high. This raised concerns around the interpretation of the sensitivity and specificity results of the included studies, which may be misleading. AUTHORS' CONCLUSIONS: We found no evidence on the accuracy of TEG and very little evidence on the accuracy of ROTEM. The value of accuracy estimates are considerably undermined by the small number of included studies, and concerns about risk of bias relating to the index test and the reference standard. We are unable to offer advice on the use of global measures of haemostatic function for trauma based on the evidence on test accuracy identified in this systematic review. This evidence strongly suggests that at present these tests should only be used for research. We consider more thoroughly what this research could be in the Discussion section. PMID- 25686466 TI - Validation of an ELISA for the concurrent detection of total antibodies (IgM and IgG) to Rift Valley fever virus. AB - Rift Valley fever virus (RVFV) infects humans and livestock, causing haemorrhaging and abortions in animals. Three major RVF epizootics have occurred in South Africa since the 1950s and the outbreak in 2010 had a mortality rate of 10.7% in humans. Accurate and early detection is therefore essential for management of this zoonotic disease. Enzyme-linked immunosorbent assays (ELISAs) have been developed for the detection of either IgM or IgG antibodies to RVFV in animal sera. In this study, data are presented on the validation of a double antigen ELISA for the simultaneous detection of both classes of antibodies to RVFV ina single test. ELISA plates were coated with a recombinant nucleoprotein. The nucleoprotein,conjugated to horseradish peroxidase, was used as the detecting reagent. A total of 534 sera from sheep and cattle were used in the validation. The sheep sera were collected during a RVF pathogenesis study at the Agricultural Research Council (ARC) - Onderstepoort Veterinary Institute and the cattle sera were collected during an outbreak of RVF in 2008 at the ARC -Animal Production Institute in Irene, Pretoria. The ELISA had a diagnostic sensitivity of 98.4% and a specificity of 100% when compared to a commercial cELISA. This convenient and fast assay is suitable for use in serological surveys or monitoring immune responses in vaccinated animals. PMID- 25686467 TI - Polychlorinated biphenyls (PCBs) inhibit hepcidin expression through an estrogen like effect associated with disordered systemic iron homeostasis. AB - Polychlorinated biphenyls (PCBs), with 209 congeners, are a large family of persistent organic pollutants. PCBs elicit a wide range of toxicities, such as neurotoxicity, hepatoxicity, oncogenicity, and endocrine-disrupting effects. However, an understanding of the potential disruption of systematic iron metabolism by PCBs is still limited. To maintain iron homeostasis, the hepcidin ferroportin (FPN) axis is critically important, and hepcidin is the central governor in guiding dietary iron absorption and iron egress from macrophages. Hepcidin is secreted by hepatocytes and binds to FPN to promote its degradation. Dysregulation of hepcidin gives rise to disordered iron homeostasis, associated with diverse diseases including anemia and beta-thalassemia. Our previous study demonstrated that there is an estrogen response element (ERE) within the promoter of hepcidin gene and that its expression is regulated by estrogen. In the current study, we demonstrated that both PCB153 and PCB126 greatly suppress hepcidin expression in HepG2 cells, with a greater repression occurring in cells upon PCB126 treatment. Further studies uncovered that both PCB153 and PCB126 harbor estrogenic activity and that the estrogenic activity of PCB126 was stronger than that of PCB153 in HepG2 cells. Mechanistic investigation revealed that PCBs suppress hepcidin transcription through a functional ERE within the hepcidin promoter, analogous to the action of 17beta-estradiol. Moreover, hepatic hepcidin was downregulated in wild-type mice upon PCB126 administration, coupled with elevated serum iron content as well as reduced hepatic and splenic iron mass. These changes were not replicated in hepcidin-deficient mice upon PCB administration. Additionally, hepatocytes were observed with severe accumulation of lipid droplets in the livers of mice challenged with PCB126, irrespective of the presence of hepcidin. To summarize, our results have deciphered a suppressive role of PCBs in restraining the expression of hepcidin through mimicking estrogenic activity and revealed a novel property of PCBs in disrupting systemic iron metabolism. This study also unearthed a PCB-mediated connection linking estrogen-like activity, iron effects, and lipid homeostasis. PMID- 25686468 TI - Patient-centered medical home implementation and use of preventive services: the role of practice socioeconomic context. AB - IMPORTANCE: The patient-centered medical home (PCMH) model of primary care is being implemented in a wide variety of socioeconomic contexts, yet there has been little research on whether its effects differ by context. Clinical preventive service use, including cancer screening, is an important outcome to assess the effectiveness of the PCMH within and across socioeconomic contexts. OBJECTIVE: To determine whether the relationship between the PCMH and cancer screening is conditional on the socioeconomic context in which a primary care physician practice operates. DESIGN, SETTING, AND PARTICIPANTS: A longitudinal study spanning July 1, 2009, through June 30, 2012, using data from the Blue Cross Blue Shield of Michigan Physician Group Incentive Program was conducted. Michigan nonpediatric primary care physician practices that participated in the Physician Group Incentive Program (5452 practice-years) were included. Sample size and outlier exclusion criteria were applied to each outcome. We examined the interaction between practices' PCMH implementation scores and their socioeconomic context. The implementation of a PCMH was self-reported by the practice's affiliated physician organizations and was measured as a continuous score ranging from 0 to 1. Socioeconomic context was calculated using a market-based approach based on zip code characteristics of the practice's patients and by combining multiple measures using principal components analysis. MAIN OUTCOMES AND MEASURES: Breast, cervical, and colorectal cancer screening rates for practices' Blue Cross Blue Shield of Michigan patients. RESULTS: The implementation of a PCMH was associated with higher breast, cervical, and colorectal cancer screening rates across most market socioeconomic contexts. In multivariable models, the PCMH was associated with a higher rate of screening for breast cancer (5.4%; 95% CI, 1.5% to 9.3%), cervical cancer (4.2%; 95% CI, 1.4% to 6.9%), and colorectal cancer (7.0%; 95% CI, 3.6% to 10.5%) in the lowest socioeconomic group but nonsignificant differences in screening for breast cancer (2.6%; 95% CI, -0.1% to 5.3%) and cervical cancer (-0.5%; 95% CI, -2.7% to 1.7%) and a higher rate of colorectal cancer (4.5%; 95% CI, 1.8% to 7.3%) screening in the highest socioeconomic group. Because PCMH implementation was associated with larger increases in screening in lower socioeconomic practice settings, models suggest reduced disparities in screening rates across these contexts. For example, the model-predicted disparity in breast cancer screening rates between the highest and lowest socioeconomic contexts was 6% (77.9% vs 72.2%) among practices with no PCMH implementation and 3% (80.3% vs. 77.0%) among practices with full PCMH implementation. CONCLUSIONS AND RELEVANCE: In our study, the PCMH model was associated with improved cancer screening rates across contexts but may be especially relevant for practices in lower socioeconomic areas. PMID- 25686469 TI - Gut feedback mechanisms and food intake: a physiological approach to slow carbohydrate bioavailability. AB - Glycemic carbohydrates in foods are an important macronutrient providing the biological fuel of glucose for a variety of physiological processes. A classification of glycemic carbohydrates into rapidly digestible carbohydrate (RDC) and slowly digestible carbohydrate (SDC) has been used to specify their nutritional quality related to glucose homeostasis that is essential to normal functioning of the brain and critical to life. Although there have been many studies and reviews on slowly digestible starch (SDS) and SDC, the mechanisms of their slow digestion and absorption were mostly investigated from the material side without considering the physiological processes of their in vivo digestion, absorption, and most importantly interactions with other food components and the gastrointestinal tract. In this article, the physiological processes modulating the bioavailability of carbohydrates, specifically the rate and extent of their digestion and absorption as well as the related locations, in a whole food context, will be discussed by focusing on the activities of the gastrointestinal tract including glycolytic enzymes and glucose release, sugar sensing, gut hormones, and neurohormonal negative feedback mechanisms. It is hoped that a deep understanding of these physiological processes will facilitate the development of innovative dietary approaches to achieve desired carbohydrate or glucose bioavailability for improved health. PMID- 25686470 TI - Dynamics of ground state absorption spectra in donor-acceptor pairs with ultrafast charge recombination. AB - A theoretical approach to simulation of the transient spectra in molecular systems with ultrafast photoinduced nonradiative electronic transitions is developed. The evolution of the excited and ground state populations as well as the nonradiative transitions between them are calculated in the framework of the stochastic multichannel point-transition model involving the reorganization of the medium and the intramolecular high frequency vibrational modes. Simulations of transient spectra of donor-acceptor pairs excited in the charge-transfer band that are accompanied by ultrafast charge recombination into the ground state demonstrate a possibility of positive band appearance in the transient absorption spectrum caused by those systems in the ground state, which returned there from the excited state. The region of the parameters of the donor-acceptor systems where a positive ground state absorption signal can be observed is discussed. A qualitative comparison of the simulated transient spectra with the experimental data on betaine-30 is presented. PMID- 25686471 TI - Free energy map for the co-oligomerization of formaldehyde and ammonia. AB - Density functional theory calculations, including Poisson-Boltzmann implicit solvent and free energy corrections, are applied to construct a free energy map of formaldehyde and ammonia co-oligomerization in aqueous solution at pH 7. The stepwise route to forming hexamethylenetetramine (HMTA), the one clearly identified major product in a complex mixture, involves a series of addition reactions of formaldehyde and ammonia coupled with dehydration and cyclization reactions at key steps in the pathway. The free energy map also allows us to propose the possible identity of some major peaks observed by mass spectroscopy in the reaction mixture being the result of stable species not along the pathway to HMTA, in particular those formed by intramolecular condensation of hydroxyl groups to form six-membered rings with ether linkages. Our study complements a baseline free energy map previously worked out for the self-oligomerization of formaldehyde in solution at pH 7 using the same computational protocol and published in this journal (J. Phys. Chem. A 2013, 117, 12658). PMID- 25686472 TI - Measurement of carotid plaque burden. PMID- 25686473 TI - Predictors of community therapists' use of therapy techniques in a large public mental health system. AB - IMPORTANCE: Few studies have examined the effects of individual and organizational characteristics on the use of evidence-based practices in mental health care. Improved understanding of these factors could guide future implementation efforts to ensure effective adoption, implementation, and sustainment of evidence-based practices. OBJECTIVE: To estimate the relative contribution of individual and organizational factors on therapist self-reported use of cognitive-behavioral, family, and psychodynamic therapy techniques within the context of a large-scale effort to increase use of evidence-based practices in an urban public mental health system serving youth and families. DESIGN, SETTING, AND PARTICIPANTS: In this observational, cross-sectional study of 23 organizations, data were collected from March 1 through July 25, 2013. We used purposive sampling to recruit the 29 largest child-serving agencies, which together serve approximately 80% of youth receiving publically funded mental health care. The final sample included 19 agencies with 23 sites, 130 therapists, 36 supervisors, and 22 executive administrators. MAIN OUTCOMES AND MEASURES: Therapist self-reported use of cognitive-behavioral, family, and psychodynamic therapy techniques, as measured by the Therapist Procedures Checklist-Family Revised. RESULTS: Individual factors accounted for the following percentages of the overall variation: cognitive-behavioral therapy techniques, 16%; family therapy techniques, 7%; and psychodynamic therapy techniques, 20%. Organizational factors accounted for the following percentages of the overall variation: cognitive-behavioral therapy techniques, 23%; family therapy techniques, 19%; and psychodynamic therapy techniques, 7%. Older therapists and therapists with more open attitudes were more likely to endorse use of cognitive-behavioral therapy techniques, as were those in organizations that had spent fewer years participating in evidence-based practice initiatives, had more resistant cultures, and had more functional climates. Women were more likely to endorse use of family therapy techniques, as were those in organizations employing more fee for-service staff and with more stressful climates. Therapists with more divergent attitudes and less knowledge about evidence-based practices were more likely to use psychodynamic therapy techniques. CONCLUSIONS AND RELEVANCE: This study suggests that individual and organizational factors are important in explaining therapist behavior and use of evidence-based practices, but the relative importance varies by therapeutic technique. PMID- 25686474 TI - Dietary exposure to benzoates (E210-E213), parabens (E214-E219), nitrites (E249 E250), nitrates (E251-E252), BHA (E320), BHT (E321) and aspartame (E951) in children less than 3 years old in France. AB - This study aimed to estimate the exposure to seven additives (benzoates, parabens, nitrites, nitrates, BHA, BHT and aspartame) in children aged less than 3 years old in France. A conservative approach, combining individual consumption data with maximum permitted levels, was carried out for all the additives. More refined estimates using occurrence data obtained from products' labels (collected by the French Observatory of Food Quality) were conducted for those additives that exceeded the acceptable daily intake (ADI). Information on additives' occurrence was obtained from the food labels. When the ADI was still exceeded, the exposure estimate was further refined using measured concentration data, if available. When using the maximum permitted level (MPL), the ADI was exceeded for benzoates (1.94 mg kg(-1) bw day(-1)), nitrites (0.09 mg kg(-1) bw day(-1)) and BHA (0.39 mg kg(-1) bw day(-1)) in 25%, 54% and 20% of the entire study population respectively. The main food contributors identified with this approach were current foods as these additives are not authorised in specific infant food: vegetable soups and broths for both benzoates and BHA, delicatessen and meat for nitrites. The exposure estimate was significantly reduced when using occurrence data, but in the upper-bound scenario the ADI was still exceeded significantly by the age group 13-36 months for benzoates (2%) and BHA (1%), and by the age group 7-12 months (16%) and 13-36 months (58%) for nitrites. Measured concentration data were available exclusively for nitrites and the results obtained using these data showed that the nitrites' intake was below the ADI for all the population considered in this study. These results suggest that refinement of exposure, based on the assessment of food levels, is needed to estimate the exposure of children to BHA and benzoates for which the risk of exceeding the ADI cannot be excluded when using occurrence data. PMID- 25686475 TI - Gastrointestinal Parasites of Ecuadorian Mantled Howler Monkeys (Alouatta palliata aequatorialis) Based on Fecal Analysis. AB - An analysis of gastrointestinal parasites of Ecuadorian mantled howler monkeys, Alouatta palliata aequatorialis, was conducted based on examination of fecal smears, flotations, and sedimentations. At least 1 type of parasite was detected in 97% of the 96 fecal samples screened across 19 howler monkey groups using these techniques. Samples averaged 3.6 parasite species per individual (+/-1.4 SD). Parasites included species representing genera of 2 apicomplexans: Cyclospora sp. (18% of individual samples) and Isospora sp. (3%); 6 other protozoa: Balantidium sp. (9%), Blastocystis sp. (60%), Chilomastix sp. (4%), Dientamoeba sp. (3%), Entamoeba species (56%), Iodamoeba sp. (5%); 4 nematodes: Enterobius sp. (3%), Capillaria sp. (78%), Strongyloides spp. (88%) which included 2 morphotypes, Trypanoxyuris sp. (12%); and the platyhelminth Controrchis sp. (15%). A statistically significant positive correlation was found between group size and each of 3 different estimators of parasite species richness adjusted for sampling effort (ICE: r(2) = 0.24, P = 0.05; Chao2: r(2) = 0.25, P = 0.05, and Jackknife: r(2) = 0.31, P = 0.03). Two significant associations between co-infecting parasites were identified. Based on the prevalence data, individuals infected with Balantidium sp. were more likely to also be infected with Isospora sp. (chi(2) = 6.02, P = 0.01), while individuals harboring Chilomastix sp. were less likely to have Capillaria sp. present (chi(2) = 4.03, P = 0.04). PMID- 25686477 TI - Vernon B. Mountcastle 1918-2015. PMID- 25686476 TI - Proton radiobiology. AB - In addition to the physical advantages (Bragg peak), the use of charged particles in cancer therapy can be associated with distinct biological effects compared to X-rays. While heavy ions (densely ionizing radiation) are known to have an energy and charge-dependent increased Relative Biological Effectiveness (RBE), protons should not be very different from sparsely ionizing photons. A slightly increased biological effectiveness is taken into account in proton treatment planning by assuming a fixed RBE of 1.1 for the whole radiation field. However, data emerging from recent studies suggest that, for several end points of clinical relevance, the biological response is differentially modulated by protons compared to photons. In parallel, research in the field of medical physics highlighted how variations in RBE that are currently neglected might actually result in deposition of significant doses in healthy organs. This seems to be relevant in particular for normal tissues in the entrance region and for organs at risk close behind the tumor. All these aspects will be considered and discussed in this review, highlighting how a re-discussion of the role of a variable RBE in proton therapy might be well-timed. PMID- 25686478 TI - Microwave-driven coherent operation of a semiconductor quantum dot charge qubit. AB - An intuitive realization of a qubit is an electron charge at two well-defined positions of a double quantum dot. This qubit is simple and has the potential for high-speed operation because of its strong coupling to electric fields. However, charge noise also couples strongly to this qubit, resulting in rapid dephasing at all but one special operating point called the 'sweet spot'. In previous studies d.c. voltage pulses have been used to manipulate semiconductor charge qubits but did not achieve high-fidelity control, because d.c. gating requires excursions away from the sweet spot. Here, by using resonant a.c. microwave driving we achieve fast (greater than gigahertz) and universal single qubit rotations of a semiconductor charge qubit. The Z-axis rotations of the qubit are well protected at the sweet spot, and we demonstrate the same protection for rotations about arbitrary axes in the X-Y plane of the qubit Bloch sphere. We characterize the qubit operation using two tomographic approaches: standard process tomography and gate set tomography. Both methods consistently yield process fidelities greater than 86% with respect to a universal set of unitary single-qubit operations. PMID- 25686479 TI - Improving the organization of palliative care: identification of barriers and facilitators in five European countries. AB - BACKGROUND: Interventions to improve palliative care encounter challenges beyond the usual implementation problems because of palliative care's complex and changing character. In this study, we explored barriers and facilitators faced by health-care professionals in five European countries (England, Germany, Italy, Norway and the Netherlands) with regard to improving the organization of their palliative care service. METHODS: Semi-structured individual and focus group interviews were conducted with purposefully selected health-care professionals. The constant comparative method was used to analyse the data. RESULTS: Professionals working in hospitals, hospices, nursing homes and primary care facilities who provide palliative care to adult patients were interviewed (n =40) or participated in ten focus group interviews (n =59). Barriers and facilitators were inductively grouped into 16 categories and arranged into five themes: innovation, individual professional level, group dynamics, organizational context and local political-economic context. Although the barriers and facilitators identified differed in scope, context, strength and provenance, they were shared by professionals from different European countries. CONCLUSION: This study identified barriers and facilitators to organizational change in palliative care. Some of these barriers and facilitators were experienced by professionals in almost all countries and are therefore prerequisites to change. Understanding the barriers to and facilitators of change will help tailor organizational improvements to the needs of individuals and organizations. PMID- 25686480 TI - Glycemic control and use of A1c in primary care patients with type 2 diabetes mellitus. AB - AIMS: To evaluate the degree of glycemic control and its relationship with disease characteristics and antidiabetic treatment in patients with type 2 diabetes mellitus (DM), as well as the frequency of A1c use. METHODS: For this purpose, an observational, cross-sectorial, and multicenter study was performed. A total of 443 patients were monitored in 17 Spanish primary healthcare centers. Demographic and clinical variables were recorded from the clinical history of patients. RESULTS: Mean age was 68.9+/-12.0 years. Time of evolution of DM was 9.2+/-6.4 years. Mean A1c was 7.38+/-1.34% and 45% of patients achieved A1c <7%. There was a no significant relationship between the degree of control and time of evolution of DM. In 16% of patients no A1c determination was performed in the previous twelve months. In those patients in whom A1c was determined, 95% received pharmacologic treatment, and 31% insulin therapy. 66% of patients on monotherapy attained A1C <7%, compared with 39% and 23% of those receiving double and triple-oral therapy, respectively (p<0.001). Only 21% of patients on insulin therapy achieved A1c <7%. The worst-controlled patients were those receiving oral antidiabetic agents and insulin (24% had A1c levels >=9%). CONCLUSIONS: A large proportion of patients are poorly controlled. Poor control increases according to complexity of treatment. A1c is underdetermined in many patients, likely related to clinical inertia. PMID- 25686481 TI - Validation of methylation markers for diagnosis of oral cavity cancer. AB - PURPOSE: Activation of proto-oncogenes and inactivation of tumour suppressor genes are the major genetic alterations involved in carcinogenesis. The increase in methylation at the promoter region of a tumour suppressor gene can lead to gene inactivation, selecting cells with proliferative advantage. Thus, promoter hypermethylation is considered a marker in a variety of malignant tumours, including oral cavity. EXPERIMENTAL DESIGN: The methylation pattern of eight genes was evaluated in 40 oral cavity squamous cell carcinomas (OSCCs) and 40 saliva samples from healthy individuals by Q-MSP. Different combinations of genes were also assessed in order to identify gene panels that could better distinguish between OSCC and saliva samples. RESULTS: CCNA1, DAPK, DCC and TIMP3 methylation were highly specific for being found in the OSCC samples. Moreover, the combination of these genes improved detection when compared with single markers, reaching values of 92.5% for sensitivity and specificity (when using the panel CCNA1, DCC, TIMP3). Moreover, DAPK, DCC and TIMP3 were hypermethylated in nearly 90% of clinically T1 and T2 cases. CONCLUSION: The pursuing of this panel of hypermethylated genes is an important tool for the detection of individuals with OSCC. Moreover, the identification of these markers in early stages of OSCC shows the feasibility of using the panel on saliva as possible biomarkers for early diagnosis. The lack of association between the methylation status of these genes and clinical characteristics shows that they are able to distinguish OSCC cases irrespective of social and clinical factors (gender, age, human papillomavirus (HPV) status, clinical stage, vascular embolisation and perineural invasion). PMID- 25686482 TI - Stereotactic body radiation therapy for lung metastases from soft tissue sarcoma. AB - PURPOSE: To appraise the role of stereotactic body radiation therapy (SBRT) in patients with lung metastasis from primary soft tissue sarcoma. METHODS: Twenty eight patients (51 lesions) were analysed. All patients were in good performance status (1-2 eastern cooperative oncology group (ECOG)), unsuitable for surgical resection, with controlled primary tumour and the number of lung metastases was ?4. In a risk adaptive scheme, the dose prescription was: 30Gy/1fr, 60Gy/3fr, 60Gy/8fr and 48Gy/4fr. Treatments were performed with Volumetric Modulated Arc Therapy. Clinical outcome was evaluated by thoracic and abdominal computed tomography (CT) scan before SBRT and than every 3months. Toxicity was evaluated with Common Terminology Criteria for Adverse Events (CTCAE) scale version 4.0. RESULTS: Leiomyosarcoma (36%) and synovial sarcoma (25%) were the most common histologies. Five patients (18%) initially presented with pulmonary metastasis, whereas 23 (82%) developed them at a median time of 51months (range 11-311months) from the initial diagnosis. The median follow-up time from initial diagnosis was 65months (5-139months) and from SBRT was 21months (2-80months). No severe toxicity (grades III-IV) was recorded and no patients required hospitalisation. The actuarial 5-years local control rate (from SBRT treatment) was 96%. Overall survival at 2 and 5years was 96.2% and 60.5%, respectively. At last follow-up 15 patients (54%) were alive. All other died because of distant progression. CONCLUSIONS: SBRT provides excellent local control of pulmonary metastasis from soft tissue sarcoma (STS) and may improve survival in selected patients. SBRT should be considered for all patients with pulmonary metastasis (PM) and evaluated in a multidisciplinary team. PMID- 25686483 TI - Fruit and vegetable consumption in the former Soviet Union: the role of individual- and community-level factors. AB - OBJECTIVE: To explain patterns of fruit and vegetable consumption in nine former Soviet Union countries by exploring the influence of a range of individual- and community-level determinants. DESIGN: Cross-sectional nationally representative surveys and area profiles were undertaken in 2010 in nine countries of the former Soviet Union as part of the Health in Times of Transition (HITT) study. Individual- and area-level determinants were analysed, taking into account potential confounding at the individual and area level. SETTING: Armenia, Azerbaijan, Belarus, Georgia, Kazakhstan, Kyrgyzstan, Moldova, Russia and Ukraine. SUBJECTS: Adult survey respondents (n 17 998) aged 18-95 years. RESULTS: Being male, increasing age, lack of education and lack of financial resources were associated with lower probability of consuming adequate amounts of fruit or vegetables. Daily fruit or vegetable consumption was positively correlated with the number of shops selling fruit and vegetables (for women) and with the number of convenience stores (for men). Billboard advertising of snacks and sweet drinks was negatively related to daily fruit or vegetable consumption, although the reverse was true for billboards advertising soft drinks. Men living near a fast food outlet had a lower probability of fruit or vegetable consumption, while the opposite was true for the number of local food restaurants. CONCLUSIONS: Overall fruit and vegetable consumption in the former Soviet Union is inadequate, particularly among lower socio-economic groups. Both individual- and community level factors play a role in explaining inadequate nutrition and thus provide potential entry points for policy interventions, while the nuanced influence of community factors informs the agenda for future research. PMID- 25686484 TI - [Withholding and withdrawal of treatments at the acute phase of severe stroke: can we go until withdrawing artificial nutrition and hydration?]. PMID- 25686485 TI - [Address from the president, January 15th 2015]. PMID- 25686486 TI - Dual self-healing abilities of composite gels consisting of polymer-brush afforded particles and an azobenzene-doped liquid crystal. AB - We prepared the composite gels from polymer-brush-afforded silica particles (P SiPs) and an azobenzene-doped liquid crystal, and investigated their inner structure, dynamic viscoelastic properties, thermo- and photoresponsive properties, and self-healing behaviors. It was found that the composite gels had a sponge-like inner structure formed with P-SiPs and exhibited good elastic property and shape recoverability. The surface dents made on the composite gel could be repaired spontaneously at room temperature. Moreover, the composite gel exhibited a gel-sol transition induced by the trans-cis photoisomerization of the azo dye, and the transition could be used as a mending mechanism for surface cracks. Consequently, we successfully developed a material exhibiting two types of self-healing abilities simultaneously: (1) spontaneous repair of surface dents by means of the excellent elasticity of the composite gel and (2) light-assisted mending of surface cracks by photoinduced gel-sol transition. PMID- 25686487 TI - Open flower fluoroimmunoassay: a general method to make fluorescent protein-based immunosensor probes. AB - Fluorescence-based probes, especially those that utilize Forster resonance energy transfer (FRET) between fluorescent protein (FP) variants, are widely used to monitor various biological phenomena, most often detecting its ligand-induced conformational change through the receptor domain. While antibody provides a fertile resource of a specific receptor for various biomolecules, its potential has not been fully exploited. An exception is a pair of donor FP-fused VH and acceptor FP-fused VL fragments, which has been proven useful when their association increases in the presence of antigen (open sandwich fluoroimmunoassay, OS-FIA). However, probes for larger proteins such as serum albumin (SA) were difficult to produce, since the interaction between VH and VL of these antibodies is barely affected by the bound antigen. Here, we propose a novel strategy, called open flower fluoroimmunoassay (OF-FIA), using a probe composed of a donor-fused VH and an acceptor-fused VL linked by a disulfide bond between VH and VL (CyPet/YPet-dsFv). The probe gave high FRET efficiency due to the dimerization propensity of the FP pair, while the efficiency got lower as SA concentration increased, probably due to dimer disruption. The constructed probe could detect clinically relevant range of SA, showing its potential as a diagnostic reagent. PMID- 25686488 TI - A two-dimensional coupled flow-mass transport model based on an improved unstructured finite volume algorithm. AB - A two-dimensional coupled water quality model is developed for modeling the flow mass transport in shallow water. To simulate shallow flows on complex topography with wetting and drying, an unstructured grid, well-balanced, finite volume algorithm is proposed for numerical resolution of a modified formulation of two dimensional shallow water equations. The slope-limited linear reconstruction method is used to achieve second-order accuracy in space. The algorithm adopts a HLLC-based integrated solver to compute the flow and mass transport fluxes simultaneously, and uses Hancock's predictor-corrector scheme for efficient time stepping as well as second-order temporal accuracy. The continuity and momentum equations are updated in both wet and dry cells. A new hybrid method, which can preserve the well-balanced property of the algorithm for simulations involving flooding and recession, is proposed for bed slope terms approximation. The effectiveness and robustness of the proposed algorithm are validated by the reasonable good agreement between numerical and reference results of several benchmark test cases. Results show that the proposed coupled flow-mass transport model can simulate complex flows and mass transport in shallow water. PMID- 25686489 TI - Public perception of an ecological rehabilitation project in inland river basins in northern China: Success or failure. AB - The need for environmental protection challenges societies to deal with difficult problems because strategies designed by scientists to protect the environment often create negative effects on impoverished local residents. We investigated the effects of China's national and regional policies related to environmental protection and rehabilitation projects in inland river basins, by studying the effect of projects in the Heihe and Shiyang river basins, in northwest China. Interviews and surveys were conducted at 30 sites in the lower reaches of these two arid basins, an area that has experienced severe ecological degradation. The survey results show the ecological rehabilitation projects adversely affected the livelihoods of 70.35% of foresters, 64.89% of farmers and 62.24% of herders in the Minqing region in the lower Shiyang River Basin; also, the projects negatively affected 51.9% of residents in the Ejin Qi in the lower Heihe River Basin. This caused 16.33% of foresters, 39.90% of farmers and 45.32% of herders in the Minqing region to not support the project and 37.5% of residents in the Ejin Qi region said they will deforest and graze again after the project ends. The negative impacts of the policies connected to the projects cause these attitudes. The projects prohibit felling and grazing and require residents to give up groundwater mining; this results in a great amount of uncompensated economic loss to them. Extensive survey data document the concerns of local residents, concerns that are supported by the calculation of actual incomes. In addition, the surveys results show poorer interviewees believe the projects greatly affected their livelihoods. While citizens in this region support environment protection work, the poor require considerable assistance if one expects them to support this type of work. Governmental assistance can greatly improve their living conditions, and hence encourage them to participate in and support the implementation of the projects within and outside the districts where they live. PMID- 25686490 TI - Pseudomonas aeruginosa pyocyanin induces neutrophil death via mitochondrial reactive oxygen species and mitochondrial acid sphingomyelinase. AB - AIMS: Pulmonary infections with Pseudomonas aeruginosa are a serious clinical problem and are often lethal. Because many strains of P. aeruginosa are resistant to antibiotics, therapeutic options are limited. Neutrophils play an important role in the host's early acute defense against pulmonary P. aeruginosa. Therefore, it is important to define the mechanisms by which P. aeruginosa interacts with host cells, particularly neutrophils. RESULTS: Here, we report that pyocyanin, a membrane-permeable pigment and toxin released by P. aeruginosa, induces the death of wild-type neutrophils; its interaction with the mitochondrial respiratory chain results in the release of reactive oxygen species (ROS), the activation of mitochondrial acid sphingomyelinase, the formation of mitochondrial ceramide, and the release of cytochrome c from mitochondria. A genetic deficiency in acid sphingomyelinase prevents both the activation of this pathway and pyocyanin-induced neutrophil death. This reduced death, on the other hand, is associated with an increase in the release of interleukin-8 from pyocyanin-activated acid sphingomyelinase-deficient neutrophils but not from wild type cells. INNOVATION: These studies identified the mechanisms by which pyocyanin induces the release of mitochondrial ROS and by which ROS induce neutrophil death via mitochondrial acid sphingomyelinase. CONCLUSION: These findings demonstrate a novel mechanism of pyocyanin-induced death of neutrophils and show how this apoptosis balances innate immune reactions. PMID- 25686491 TI - TNF alpha inhibits myogenic differentiation of C2C12 cells through NF-kappaB activation and impairment of IGF-1 signaling pathway. AB - Cachexia or muscle wasting is a common condition that occurs in many chronic diseases. The wasting conditions are characterized by increased levels of TNF alpha which was also known as cachectin in the past. But how TNF-alpha exerts its cachetic effects remains controversial. To clarify this issue, we investigated the impact of TNF-alpha on C2C12 cell myogenic differentiation. Our results demonstrate that myotube formation was completely inhibited by TNF-alpha when added to differentiating C2C12 myoblasts. The inhibitory effect of TNF-alpha on differentiation was accompanied by activation of NF-kappaB and down regulation of myogenin and Akt. Importantly, TNF-alpha's effect on differentiation was abolished when IGF-1 was added to the culture. IGF-1 treatment also inhibited NF kappaB reporter activity and restored Akt levels. Our data suggest that TNF-alpha inhibits myogenic differentiation through NF-kappaB activation and impairment of IGF-1 signaling pathway. The reversal of TNF-alpha induced inhibition of myogenesis by IGF-1 may have significant therapeutic potential. PMID- 25686492 TI - Channel characteristics of VDAC-3 from Arabidopsis thaliana. AB - Four different isoforms of the Voltage-Dependent Anion Channel (VDAC) have been identified in Arabidopsis plant cells. The electrophysiological characteristics of several VDAC channels from animal as well as plant cells are well documented, but those of this model plant are unknown. One isoform, AtVDAC-3 was obtained either directly by cell-free synthesis or produced in Escherichia coli, as inclusion bodies, and re-natured. An electrophysiological study of the purified proteins in planar lipid bilayers showed that both methods yielded proteins with similar channel activity. The characteristics of AtVDAC-3 are that of a bona fide VDAC-like channel. PMID- 25686493 TI - NLRP3 inflammasome expression is driven by NF-kappaB in cultured hepatocytes. AB - The inflammasomes are cytoplasmic multiprotein complexes that are responsible for activation of inflammatory reactions. In principle, there are four individual inflammasome branches (NLRP1, NLRP3, NLRC4/NALP4, and AIM2) that mediate the cleavage and activation of Caspase-1 and IL-1beta that in turn lead to a complex network of cellular reactions initiating local and systemic inflammatory reactions. We have recently shown that NLRP3 expression is virtually absent in primary cultured hepatocytes and that in vitro the stimulation of hepatocytes with lipopolysaccharides results in strong activation of NLRP3 expression. We here demonstrate that this activation can be blocked by the NF-kappaB activation inhibitor QNZ or by infection with an adenoviral expression vector constitutively expressing a superrepressor of NF-kappaB. We show that QNZ blocks NF-kappaB dependent expression of TNF-alpha, IL-1beta and NLRP3. Likewise, the superrepressor of NF-kappaB prevents expression of NLRP3 and significantly reduces expression of inflammatory marker genes in liver cells. In a primary murine hepatoma cells, the concomitant depletion of NEMO and Caspase-8 resulted in a significant suppression of NLRP3 expression after Lipopolysaccharide challenge. Moreover, we demonstrate that a 1.3-kbp fragment located in close proximity of the most upstream transcriptional start site of the human NLRP3 gene that harbours one putative octamer NF-kappaB binding site renders LPS sensitivity in reporter gene assay. We conclude that NF-kappaB signalling is a necessary prerequisite for proper activation of the NLRP3 inflammasome in primary hepatocytes. PMID- 25686494 TI - Coordinated regulation by two VPS9 domain-containing guanine nucleotide exchange factors in small GTPase Rab5 signaling pathways in fission yeast. AB - The small GTPase Rab5 is reported to regulate various cellular functions, such as vesicular transport and endocytosis. VPS9 domain-containing proteins are thought to activate Rab5(s) by their guanine-nucleotide exchange activities. Numerous VPS9 proteins have been identified and are structurally conserved from yeast to mammalian cells. However, the functional relationships among VPS9 proteins in cells remain unclear. Only one Rab5 and two VPS9 proteins were identified in the Schizosaccharomyces pombe genome. Here, we examined the cellular function of two VPS9 proteins and the relationship between these proteins in cellular functions. Vps901-GFP and Vps902-GFP exhibited dotted signals in vegetative and differentiated cells. vps901 deletion mutant (Deltavps901) cells exhibited a phenotype deficient in the mating process and responses to high concentrations of ions, such as calcium and metals, and Deltavps901Deltavps902 double mutant cells exhibited round cell shapes similar to ypt5-909 (Rab5 mutant allele) cells. Deletion of both vps901 and vps902 genes completely abolished the mating process and responses to various stresses. A lack of vacuole formation and aberrant inner cell membrane structures were also observed in Deltavps901Deltavps902 cells by electron microscopy. These data strongly suggest that Vps901 and Vps902 are cooperatively involved in the regulation of cellular functions, such as cell morphology, sexual development, response to ion stresses, and vacuole formation, via Rab5 signaling pathways in fission yeast cells. PMID- 25686495 TI - Baicalin and baicalein inhibit transforming growth factor-beta1-mediated epithelial-mesenchymal transition in human breast epithelial cells. AB - Since the epithelial-mesenchymal transition (EMT) is involved in many crucial functions of cancer cells, we set out to identify a natural compound capable of inhibiting EMT processes. TGF-beta1 treatment induces EMT among normal mammary epithelial cells (MCF10A cells), as reflected by characteristic morphological changes into the fibroblastic phenotype, reduced expression of E-cadherin. Interestingly, butanol extracts of Scutellaria baicalensis Georgi significantly reduced the TGF-beta1-mediated EMT of MCF10A cells. Further analysis revealed that baicalin and baicalein, the major flavones of these butanol extracts, inhibited TGF-beta1-mediated EMT by reducing the expression level of the EMT related transcription factor, Slug via the NF-kappaB pathway, and subsequently increased migration in MCF10A cells. Finally, both compounds reduced the TGF beta1-mediated EMT, anchorage-independent growth and cell migration of human breast cancer cells (MDA-MB-231 cells). Taken together, these results suggest that baicalin and baicalein of Scutellaria baicalensis Georgi may suppress the EMT of breast epithelial cells and the tumorigenic activity of breast cancer cells. Thus, these compounds could have potential as therapeutic or supplementary agents for the treatment of breast cancer. PMID- 25686496 TI - miR-1271 promotes non-small-cell lung cancer cell proliferation and invasion via targeting HOXA5. AB - MicroRNAs (miRNAs) are short, non-coding RNAs (~ 22 nt) that play important roles in the pathogenesis of human diseases by negatively regulating numerous target genes at posttranscriptional level. However, the role of microRNAs in lung cancer, particularly non-small-cell lung cancer (NSCLC), has remained elusive. In this study, two microRNAs, miR-1271 and miR-628, and their predicted target genes were identified differentially expressed in NSCLC by analyzing the miRNA and mRNA expression data from NSCLC tissues and their matching normal controls. miR-1271 and its target gene HOXA5 were selected for further investigation. CCK-8 proliferation assay showed that the cell proliferation was promoted by miR-1271 in NSCLC cells, while miR-1271 inhibitor could significantly inhibited the proliferation of NSCLC cells. Interestingly, migration and invasion assay indicated that overexpression of miR-1271 could significantly promoted the migration and invasion of NSCLC cells, whereas miR-1271 inhibitor could inhibited both cell migration and invasion of NSCLC cells. Western blot showed that miR 1271 suppressed the protein level of HOXA5, and luciferase assays confirmed that miR-1271 directly bound to the 3'untranslated region of HOXA5. This study indicated indicate that miR-1271 regulates NSCLC cell proliferation and invasion, via the down-regulation of HOXA5. Thus, miR-1271 may represent a potential therapeutic target for NSCLC intervention. PMID- 25686497 TI - Oregonin reduces lipid accumulation and proinflammatory responses in primary human macrophages. AB - Inflammation in the vascular wall is important for the development of atherosclerosis. We have previously shown that inflammatory macrophages are more abundant in human atherosclerotic lesions than in healthy arteries. Activated macrophages produce reactive oxygen species (ROS) that promote local inflammation in atherosclerotic lesions. Here, we investigated the role of oregonin, a diarylheptanoid, on proinflammatory responses in primary human macrophages and found that oregonin decreased cellular lipid accumulation and proinflammatory cytokine secretion. We also found that oregonin decreased ROS production in macrophages. Additionally, we observed that treatment of lipopolysaccharide exposed macrophages with oregonin significantly induced the expression of antioxidant-related genes, including Heme oxygenase-1 and NADPH dehydrogenase quinone 1. In summary, we have shown that oregonin reduces lipid accumulation, inflammation and ROS production in primary human macrophages, indicating that oregonin has anti-inflammatory bioactivities. PMID- 25686498 TI - Rab25 upregulation correlates with the proliferation, migration, and invasion of renal cell carcinoma. AB - Renal cell carcinoma (RCC) is a common urological cancer with a poor prognosis. A recent cohort study revealed that the median survival of RCC patients was only 1.5 years and that <10% of the patients in the study survived up to 5 years. In tumor development, Rab GTPase are known to play potential roles such as regulation of cell proliferation, migration, invasion, communication, and drug resistance in multiple tumors. However, the correlation between Rabs expression and the occurrence, development, and metastasis of RCC remains unclear. In this study, we analyzed the transcriptional levels of 52 Rab GTPases in RCC patients. Our results showed that high levels of Rab25 expression were significantly correlated with RCC invasion classification (P < 0.01), lymph-node metastasis (P < 0.001), and pathological stage (P < 0.01). Conversely, in 786-O and A-498 cells, knocking down Rab25 protein expression inhibited cell proliferation, migration, and invasion. Our results also demonstrated that Rab25 is a target gene of let-7d, and further suggested that Rab25 upregulation in RCC is due to diminished expression of let-7d. These findings indicate that Rab25 might be a novel candidate molecule involved in RCC development, thus identifying a potential biological therapeutic target for RCC. PMID- 25686499 TI - Compensatory hyperinsulinemia in high-fat diet-induced obese mice is associated with enhanced insulin translation in islets. AB - A high-fat diet (HF) is associated with obesity, insulin resistance, and hyperglycemia. Animal studies have shown compensatory mechanisms in pancreatic beta-cells after high fat load, such as increased pancreatic beta-cell mass, enhanced insulin secretion, and exocytosis. However, the effects of high fat intake on insulin synthesis are obscure. Here, we investigated whether insulin synthesis was altered in correlation with an HF diet, for the purpose of obtaining further understanding of the compensatory mechanisms in pancreatic beta cells. Mice fed an HF diet are obese, insulin resistant, hyperinsulinemic, and glucose intolerant. In islets of mice fed an HF diet, more storage of insulin was identified. We analyzed insulin translation in mouse islets, as well as in INS-1 cells, using non-radioisotope chemicals. We found that insulin translational levels were significantly increased in islets of mice fed an HF diet to meet systemic demand, without altering its transcriptional levels. Our data showed that not only increased pancreatic beta-cell mass and insulin secretion but also elevated insulin translation is the major compensatory mechanism of pancreatic beta-cells. PMID- 25686500 TI - The oncoprotein HBXIP promotes migration of breast cancer cells via GCN5-mediated microtubule acetylation. AB - We have documented that the oncoprotein hepatitis B X-interacting protein (HBXIP) is able to promote migration of breast cancer cells. A subset of acetylated microtubules that accumulates in the cell leading edge is necessary for cell polarization and directional migration. In this study, we explored the hypothesis that HBXIP contributes to migration of breast cancer cells by supporting microtubule acetylation in breast cancer cells. We found that HBXIP could induce acetylated microtubules accumulating into the leading protrusion in wound-induced directional migration in breast cancer cells by immunofluorescence staining analysis. Interestingly, HBXIP was able to increase the acetylation of alpha tubulin in the cells by immunofluorescence staining and Western blot analysis. Furthermore, we observed that acetyltransferase GCN5 was involved in the event that HBXIP induced increase of acetylated microtubules and their expansion in protrusions in breast cancer cells by Western blot analysis and immunofluorescence staining. Moreover, GCN5 was required for the HBXIP-enhanced migration of breast cancer cells by wound healing assay. Thus, we conclude that HBXIP promotes the migration of breast cancer cells through modulating microtubule acetylation mediated by GCN5. Therapeutically, HBXIP may serve as a novel target in breast cancer. PMID- 25686501 TI - The activation of peroxisome proliferator-activated receptor gamma is regulated by Kruppel-like transcription factors 6 & 9 under steatotic conditions. AB - Liver steatosis is characterised by lipid droplet deposition in hepatocytes that can leads to an inflammatory and fibrotic phenotype. Peroxisome proliferator activated receptors (PPARs) play key roles in energetic homeostasis by regulating lipid metabolism in hepatic tissue. In adipose tissue PPARgamma regulates the adipocyte differentiation by promoting the expression of lipid-associated genes. Within the liver PPARgamma is up-regulated under steatotic conditions; however, which transcription factors participate in its expression is not completely understood. Kruppel-like transcription factors (KLFs) regulate various cellular mechanisms, such as cell proliferation and differentiation. KLFs are key components of adipogenesis by regulating the expression of PPARgamma and other proteins such as the C-terminal enhancer binding protein (C/EBP). Here, we demonstrate that the transcript levels of Klf6, Klf9 and Ppargamma are increased in response to a steatotic insult in vitro. Chromatin immunoprecipitation (ChIp) experiments showed that klf6 and klf9 are actively recruited to the Ppargamma promoter region under these conditions. Accordingly, the loss-of-function experiments reduced cytoplasmic triglyceride accumulation. Here, we demonstrated that KLF6 and KLF9 proteins directly regulate PPARgamma expression under steatotic conditions. PMID- 25686502 TI - Bovine leukemia virus nucleocapsid protein is an efficient nucleic acid chaperone. AB - Nucleocapsid proteins (NCs) direct the rearrangement of nucleic acids to form the most thermodynamically stable structure, and facilitate many steps throughout the life cycle of retroviruses. NCs bind strongly to nucleic acids (NAs) and promote NA aggregation by virtue of their cationic nature; they also destabilize the NA duplex via highly structured zinc-binding motifs. Thus, they are considered to be NA chaperones. While most retroviral NCs are structurally similar, differences are observed both within and between retroviral genera. In this work, we compare the NA binding and chaperone activity of bovine leukemia virus (BLV) NC to that of two other retroviral NCs: human immunodeficiency virus type 1 (HIV-1) NC, which is structurally similar to BLV NC but from a different retrovirus genus, and human T-cell leukemia virus type 1 (HTLV-1) NC, which possesses several key structural differences from BLV NC but is from the same genus. Our data show that BLV and HIV-1 NCs bind to NAs with stronger affinity in relation to HTLV-1 NC, and that they also accelerate the annealing of complementary stem-loop structures to a greater extent. Analysis of kinetic parameters derived from the annealing data suggests that while all three NCs stimulate annealing by a two-step mechanism as previously reported, the relative contributions of each step to the overall annealing equilibrium are conserved between BLV and HIV-1 NCs but are different for HTLV-1 NC. It is concluded that while BLV and HTLV-1 belong to the same genus of retroviruses, processes that rely on NC may not be directly comparable. PMID- 25686503 TI - Berberine improves endothelial function by inhibiting endoplasmic reticulum stress in the carotid arteries of spontaneously hypertensive rats. AB - Activation of endoplasmic reticulum (ER) stress in endothelial cells leads to increased oxidative stress and often results in cell death, which has been implicated in hypertension. The present study investigated the effects of berberine, a botanical alkaloid purified from Coptidis rhizoma, on ER stress in spontaneously hypertensive rats (SHRs) and the underling mechanism. Isolated carotid arteries from normotensive WKYs and SHRs were suspended in myograph for isometric force measurement. Protein phosphorylations and expressions were determined by Western blotting. Reactive oxygen species (ROS) level was measured by DHE staining. SHR carotid arteries exhibited exaggerated acetylcholine triggered endothelium-dependent contractions (EDCs) and elevated ROS accumulation compared with WKY arteries. Moreover, Western blot analysis revealed the reduced AMPK phosphorylation, increased eIF2alpha phosphorylation, and elevated levels of ATF3, ATF6, XBP1 and COX-2 in SHR carotid arteries while these pathological alterations were reversed by 12 h-incubation with berberine. Furthermore, AMPK inhibitor compound C or dominant negative AMPK adenovirus inhibited the effects of berberine on above-mentioned marker proteins and EDCs. More importantly, ROS scavengers, tempol and tiron plus DETCA, or ER stress inhibitors, 4-PBA and TUCDA normalized the elevated levels of ROS and COX-2 expression, and attenuated EDCs in SHR arteries. Taken together, the present results suggest that berberine reduces EDCs likely through activating AMPK, thus inhibiting ER stress and subsequently scavenging ROS leading to COX-2 down-regulation in SHR carotid arteries. The present study thus provides additional insights into the vascular beneficial effects of berberine in hypertension. PMID- 25686504 TI - Serum NSE level and disability progression in multiple sclerosis. AB - BACKGROUND: Previous studies suggested that serum neuron specific enolase (NSE) may be a biomarker associated with progression in MS. METHODS: We measured serum NSE levels in 385 patients with multiple sclerosis (MS) (264 with relapsing remitting (RR) MS, 86 with secondary progressive (SP) MS, and 35 with primary progressive (PP) MS), and compared levels between disease courses, between users and non-users of immunomodulatory treatment, and between patients with worsening or stable disability at one year follow-up (available in 161 patients). We also investigated the correlation between serum NSE and Expanded Disability Status Scale (EDSS) and MS Severity Score (MSSS) scores in the whole cohort and in subgroups, and built a multiple linear regression model to assess the influence of predictor variables on serum NSE. RESULTS: Age was the only independent predictor of serum NSE levels in the multiple linear regression model. In the subgroup of patients with PPMS, there was a moderate correlation between serum NSE and increasing MSSS (Pearson's r 0.35, p=0.04) and EDSS (Spearman's rho 0.37, p=0.03) scores. CONCLUSION: Our data do not support the use of serum NSE as a prognostic biomarker in RRMS or SPMS. The correlations of serum NSE with EDSS and MSSS in the PPMS subgroup are interesting, but based on a small sample size and require replication in other cohorts. PMID- 25686505 TI - Patterns of dietary behaviours identified by latent class analysis are associated with chronic uninvestigated dyspepsia. AB - To our knowledge, no study has assessed the relationships between patterns of dietary behaviours, identified by latent class analysis (LCA), and chronic uninvestigated dyspepsia (CUD). The present study was conducted to determine the association between the patterns of dietary behaviours, identified by LCA, and CUD in a large sample of adults. In a cross-sectional study conducted on 4763 Iranian adults, we assessed the patterns of dietary behaviours in four domains, including 'meal patterns', 'eating rate', 'intra-meal fluid intake' and 'meal-to sleep interval', as identified by LCA, using a pre-tested comprehensive questionnaire. Patients with CUD were identified using the Rome III diagnostic criteria. CUD was prevalent in 15.2 % (95 % CI 14.4, 16.2 %; n 723) of patients. Early satiation occurred in 6.3 % (n 302) of patients, bothersome postprandial fullness in 8.0 % (n 384) of patients and epigastric pain in 7.8 % (n 371) of patients. We defined two distinct classes of meal patterns: 'regular' and 'irregular'. For eating rates, three classes were defined: 'moderate', 'moderate to-slow' and 'moderate-to-fast'. Participants were identified as ingesting fluid with meals in two major classes: 'moderate intra-meal drinking' and 'high intra meal drinking'. In terms of the interval between meals and sleeping, two distinct classes were identified: 'short meal-to-sleep interval' and 'long meal-to-sleep interval'. After controlling for potential confounders, the 'irregular meal pattern' was significantly associated with a greater odds of CUD (OR 1.42, 95 % CI 1.12, 1.78) compared with a 'regular meal pattern'. Individuals with a 'moderate-to-fast eating rate' were more likely to have CUD compared with those who had a 'moderate eating rate' (OR 1.42, 95 % CI 1.15, 1.75). Patterns of the 'meal-to-sleep interval' and 'intra-meal fluid intake' were not significantly associated with CUD. In conclusion, the 'irregular meal pattern' and the 'moderate-to-fast eating rate' were significantly associated with a greater odds of CUD. Further prospective investigations are warranted to confirm this association. PMID- 25686506 TI - Sleep, Hansen's disease and the immune system--a not so harmonic triad. AB - Hansen's disease is one of the oldest skin diseases in the world characterized by a spectrum of clinical manifestations that are associated with stigmatization and poor quality of life. It is also considered a model disease for investigating the human immune system because of its association with immune reactions, which are thought to be a reflection of the host's immunological response, promoting intense cellular activity or humoral secretion. This relationship between the cellular and microbial components of skin and their regulation by local immune responses may be modulated by a currently neglected behavior: sleep. Recent studies have demonstrated that sleep deprivation may aggravate the progression of chronic dermatological diseases, which in turn can lead to a non-restorative sleep pattern. Indeed, sleep is essential for immune and skin integrity. Thus, we propose here a hypothesis linking Hansen's disease, sleep and immunity in a bidirectional relationship. Hansen's disease patients may demonstrate a worse sleep quality than the general population through the modulation of immunological environment; and sleep restriction, a hallmark of modern society, being a possible predictor of the disease progression. PMID- 25686507 TI - Type D personality, suboptimal health behaviors and emotional distress in adults with diabetes: results from Diabetes MILES-The Netherlands. AB - AIMS: Type D personality - defined as high negative affectivity (NA) and high social inhibition (SI) - has been associated with adverse cardiovascular prognosis. We explored the differential associations of Type D personality and its constituent components with health behaviors, emotional distress and standard biomedical risk factors as potential risk mechanisms in adults with diabetes. METHODS: 3314 Dutch adults with self-reported type 1 or 2 diabetes completed an online survey, including the DS14 Type D Scale. AN(C)OVAs and X(2) tests were used to compare participants scoring (i) low on NA and SI; (ii) high on SI only; (iii) high on NA only; (iv) high on NA and SI (Type D). RESULTS: Participants with Type D personality (29%) were less likely to follow a healthy diet or to consult healthcare professionals in case of problems with diabetes management than those scoring high on neither or only one component. They also reported more barriers surrounding medication use, diabetes-specific social anxiety, loneliness and symptoms of depression and anxiety. There were no differences in standard biomedical risk factors (body mass index, blood pressure, cholesterol, HbA1c). After adjustment for demographics, clinical characteristics, NA, and SI in multivariable logistic regression analyses, Type D personality was independently associated with 2 to 3-fold increased odds of suboptimal health behaviors and over 15-fold increased odds of general emotional distress. CONCLUSIONS: Type D personality was not related to standard biomedical risk factors, but was associated with unhealthy behaviors and negative emotions that are likely to have adverse impact on adults with diabetes. PMID- 25686508 TI - Trends in the prescription of antidiabetic medications from 2009 to 2012 in a general practice of Southern Italy: a population-based study. AB - OBJECTIVE: To assess the prescribing pattern of antidiabetic drugs (AD) in a general practice of Southern Italy from 2009 to 2012, with focus on behaviour prescribing changes. METHODS: This retrospective, drug utilization study was conducted using administrative databases of the Local Health Unit of Caserta (Southern Italy) including about 1 million citizens. The standardized prevalence of AD use was calculated within each study year. A sample cohort of 78,789 subjects with at least one prescription of AD was identified during the study period. RESULTS: There was an overall increase of the proportion of the patients treated with monotherapy, which was significant for insulin monotherapy (from 11.2 to 14.6%, p<0.001). The proportion of patients treated with metformin remained stable (from 68.3% to 67.8%, p=0.076), while those receiving sulfonylurea dropped from 18.4% to 12.5% (p<0.001); GLP-1 analogues and DPP-4 inhibitors showed the greatest increase (from 1.2% to 6.6%, p<0.001). In the whole sample of 25,148 new AD users, metformin was the most commonly prescribed drug in monotherapy (41.9%), while insulin ranked second (13.3%). CONCLUSION: This study shows a rising trend of AD monotherapy, with sulfonylureas and incretins showing the more negative and positive trend, respectively. PMID- 25686509 TI - Prediction of heart failure in patients with type 2 diabetes mellitus- a systematic review and meta-analysis. AB - BACKGROUND: Heart failure (HF) is a major cause of mortality and disability in type 2 diabetes mellitus (T2DM). This study sought to improve the assessment of HF risk in patients with T2DM-a step that would be critical for effective HF screening. METHODS: A systematic literature search was performed on electronic databases including MEDLINE and EMBASE, using MeSH terms 'heart failure', 'risk factor', 'T2DM', 'cardiac dysfunction', 'stage B heart failure', 'incident heart failure', 'risk assessment', 'risk impact', 'risk score', 'predictor', 'prediction' and related free text terms. The search was limited to human studies in full-length publications in English language journal from 1946 to 2014. Univariable and multivariable relative risk (RR) and hazard ratio (HR) were obtained from each study. RESULTS: Twenty-one studies (n=1111,569, including 507,637 subjects with T2DM) were included in this analysis with a follow-up ranging from 1 to 12 years. Associations between incident HF and risk variables described in >=3 studies were reported. This association was greatest for insulin use (HR 2.48; 1.24-4.99), HbA1c 7.0-8.0% (2.41; 1.62-3.59), 5 years increase in age (1.47; 1.25-1.73), fasting glucose (1.28; 1.10-1.51 per standard deviation) and HbA1c (1.18; 1.14-1.23 each 1% increase). After adjustment for confounders, there were strong associations with coronary artery disease (1.77; 1.31, 2.39), HbA1c >= 10% (1.66; 1.45-1.89), insulin use (1.43; 1.14-1.79), HbA1c 9.0-10.0% (1.31; 1.14-1.50), fasting glucose (1.27; 1.10-1.47 per standard deviation) and 5 years increase in age (1.26; 1.13-1.40). CONCLUSION: Among patients with T2DM, five common clinical variables are associated with significantly increased risk of incident HF. PMID- 25686510 TI - Correction to "A crystal structure of an oligoproline PPII-helix, at last". PMID- 25686511 TI - Transversus abdominis muscle release for repair of complex incisional hernias in kidney transplant recipients. AB - BACKGROUND: Incisional hernias in kidney transplant recipients (KTRs) can be complex because of adjacent bony structures, proximity of the allograft/transplant ureter, and context of immunosuppression. We hypothesized that our novel posterior component separation with transversus abdominis muscle release (TAR) and retromuscular mesh reinforcement offers a safe and durable repair. METHODS: KTRs with incisional hernias repaired using the aforementioned technique were identified within our prospective database (2007 to 2013) and analyzed. RESULTS: Eleven patients were identified (median age 49 years, body mass index 32). The median hernia size was 30 cm(2) (range 88 to 1,040 cm(2)) and 8 of the 11 patients were recurrent. Intraoperative morbidity consisted of one transplant ureter injury repaired primarily over a stent. Postoperative morbidity consisted of 2 superficial surgical site infections that resolved and 1 readmission for a blood transfusion. There were no instances of mesh infection, explantation, graft loss, or graft dysfunction. With a median follow-up of 12 months (range 3 to 69), 1 (9%) lateral recurrence has been documented. CONCLUSIONS: For complex incisional hernias in KTRs, TAR is associated with low perioperative morbidity and durable repair. PMID- 25686512 TI - Faculty evaluations of resident medical knowledge: can they be used to predict American Board of Surgery In-Training Examination performance? AB - BACKGROUND: The American Board of Surgery In-Training Examination (ABSITE) offers annual assessment of resident medical knowledge. We sought to determine if ongoing end-of-rotation evaluations by faculty of residents' medical knowledge correlate with ABSITE performance. METHODS: Retrospective cross-sectional study was conducted over 3 years at 2 institutions. Faculty rated residents' clinical knowledge as part of a global summative evaluation. The intraclass correlation coefficient and convergent validity between faculty evaluations and ABSITE performance were assessed. RESULTS: A total of 1,562 faculty evaluations were completed for about 147 residents. There was poor agreement among faculty for each resident, with intraclass correlation coefficients of less than 0.2. Spearman's correlation coefficient was calculated for evaluations and ABSITE scores and were found to be weakly correlative at one institution and not correlated at all at the other. Finally, evaluations across quartiles of resident ABSITE scores were examined and show no correlation. CONCLUSION: Faculty evaluations of resident medical knowledge correlate poorly with resident ABSITE performance, and should not be used as an ongoing predictive tool. PMID- 25686513 TI - Face validity of a Wii U video game for training basic laparoscopic skills. AB - BACKGROUND: Although the positive effects of playing video games on basic laparoscopic skills have been studied for several years, no games are actually used in surgical training. This article discusses the face validity of the first video game and custom-made hardware, which takes advantage of these effects. METHODS: Participants were recruited at the Chirurgendagen 2013 and the Society of American Gastrointestinal and Endoscopic Surgeons 2014 annual meeting. In total, 72 laparoscopic surgeons completed a demo of the game and filled in a questionnaire. RESULTS: On a 1-to-10 scale, the mean score for hardware realism was 7.2 and the mean score for usefulness as a training tool was 8.4. Participants did not mind the fact that the workspace does not look like an abdominal cavity, but do have some trouble with the absence of tactile feedback. CONCLUSION: We obtained face validity for both the hardware and the usefulness of Underground, a video game made for training basic laparoscopic skills. PMID- 25686514 TI - Lower extremity arterial reconstruction in obese patients. AB - BACKGROUND: Previous reports have noted that obese patients undergoing lower extremity arterial reconstruction have higher complication rates compared with nonobese patients. We evaluated the effect of obesity on outcomes following open infrainguinal arterial reconstruction on a national level. METHODS: A query of the American College of Surgeons' National Surgical Quality Improvement Program Database was conducted to identify all adult patients who underwent open infrainguinal lower extremity arterial reconstruction from 2005 to 2009. Postoperative outcomes were analyzed in different body mass index groups. RESULTS: Obese and morbidly obese patients had a higher risk of wound infection when compared with normal weight patients (odds ratios 2.1 and 2.7, P < .05). Obese patients had a lower mortality when compared with normal weight patients (odds ratio .83, P < .05). CONCLUSIONS: Obesity was associated with an increase in wound infection after open lower extremity arterial reconstruction. Obesity, but not morbid obesity, was associated with decreased mortality. PMID- 25686515 TI - Amplified recruitment pressure of biofouling organisms in commercial salmon farms: potential causes and implications for farm management. AB - The development of biofouling on finfish aquaculture farms presents challenges for the industry, but the factors underlying nuisance growths are still not well understood. Artificial settlement surfaces were used to examine two possible explanations for high rates of biofouling in Norwegian salmon farms: (1) increased propagule release during net cleaning operations, resulting in elevated recruitment rates; and (2) potential reservoir effects of farm surfaces. The presence of salmon farms was associated with consistently and substantially (up to 49-fold) elevated recruitment rates. Temporal patterns of recruitment were not driven by net cleaning. Resident populations of biofouling organisms were encountered on all submerged farm surfaces. Calculations indicate that a resident population of the hydroid Ectopleura larynx, a major biofouling species, could release between 0.3 * 10(9) and 4.7 * 10(9) larvae per farm annually. Such resident populations could form propagule reservoirs and be one explanation for the elevated recruitment pressure at salmon farms. PMID- 25686516 TI - Health care worker attitudes and identified barriers to patient sleep in the medical intensive care unit. AB - OBJECTIVE: To identify barriers to sleep for intensive care unit (ICU) patients. DESIGN: A qualitative study using semi-structured interviews. SUBJECTS: Nurses and physicians who had experience working the night shift. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Multiple environmental barriers to sleep in the ICU were identified when participants were directly asked about factors affecting sleep. Responses highlighted healthcare system-based barriers related to hospital/ICU policy and workflow. Implicit barriers to sleep were found when participants responded to open-ended questions. These included attitudinal barriers such as the uncertainty about the significance of sleep, the tension between providing protocol-driven ICU care and allowing uninterrupted patient sleep, and lack of consensus regarding interventions to promote sleep. CONCLUSIONS: This qualitative study suggests that health care worker attitudes, methods of sleep promotion, hospital institutional policies and workflow may contribute to sleep disruption in the ICU. These barriers provide additional targets for intervention in studies designed to improve sleep in the ICU. PMID- 25686517 TI - Ventilator-associated events prevention, learning lessons from the past: A systematic review. AB - BACKGROUND: Preventing Ventilator-associated events (VAE) is a major challenge. Strictly monitoring for ventilator-associated pneumonia (VAP) is not sufficient to ensure positive outcomes. Therefore, the surveillance definition was updated and a change to the broader VAE was advocated. OBJECTIVE: This paper summarizes the scientific efforts assessing VAP preventive bundles and the recent transition in surveillance methods. METHODS: We conducted a systematic review to identify lessons from past clinical studies assessing VAP prevention bundles. We then performed a thorough literature review on the recent VAE surveillance algorithm, highlighting its advantages and limitations. CONCLUSION: VAP prevention bundles have historically proven their efficacy and the introduction of the new VAE definition aimed at refining and objectivizing surveillance methods. Randomized controlled trials remain vital to determine the effect of VAE prevention on patient outcomes. We recommend expanding beyond limited VAP prevention strategies towards VAE prevention bundles. PMID- 25686518 TI - Potential biomarkers for early diagnosis of acute aortic dissection. AB - OBJECTIVE: The purpose of this study was to identify biological markers for early diagnosis of acute aortic dissection (AAD). METHODS: 76 patients presented to the emergency room with acute chest pain within 6 h of occurrence were recruited for this study, and AAD diagnosed by aortic CTA. Biomarkers were measured by ELISA. ROC curve and Pearson correlation analysis were used to evaluate the sensitivity and specificity to diagnosis of AAD. RESULTS: The serum levels of alpha-SMA, smMHC, sELAF, PC1 and D-dimer were significantly higher in AAD patients than in other groups (P < 0.05). Significant correlations between smMHC, sELAF, PC1, and D-dimer level were observed in AAD. Any combination of two markers showed good sensitivity (94.29%) and specificity (85.37%). CONCLUSION: smMHC, sELAF, PC1, or D-dimer alone is a biomarker for early diagnosis of AAD, but the combination of these markers has significantly higher diagnostic value. PMID- 25686519 TI - Removal of amoxicillin and cefuroxime axetil by advanced membranes technology, activated carbon and micelle-clay complex. AB - Two antibacterials, amoxicillin trihydrate and cefuroxime axetil spiked into wastewater were completely removed by sequential wastewater treatment plant's membranes, which included activated sludge, ultrafiltration (hollow fibre and spiral wound membranes with 100 and 20 kDa cut-offs), activated carbon column and reverse osmosis. Adsorption isotherms in synthetic water which employed activated carbon and micelle-clay complex (octadecyltrimethylammonium-montmorillonite) as adsorbents fitted the Langmuir equation. Qmax of 100 and 90.9 mg g(-1), and K values of 0.158 and 0.229 L mg(-1) were obtained for amoxicillin trihydrate using activated carbon and micelle-clay complex, respectively. Filtration of antibacterials in the ppm range, which yielded variable degrees of removal depending on the volumes passed and flow rates, was simulated and capacities for the ppb range were estimated. Stability study in pure water and wastewater revealed that amoxicillin was totally stable for one month when kept at 37 degrees C, whereas cefuroxime axetil underwent slow hydrolysis to cefuroxime. PMID- 25686520 TI - Drug-eluting stent thrombosis in the treatment of chronic total coronary occlusions: incidence, presentation and related factors. Data from the CIBELES trial. AB - INTRODUCTION AND OBJECTIVES: The aim of this study was to analyze the incidence of drug-eluting stent thrombosis (sirolimus or everolimus) in patients with chronic total coronary occlusions (CTO) and to determine its clinical implications and related factors. METHODS: Data from the 12-month follow-up of the 207 patients included in the CIBELES trial with CTO were analyzed. RESULTS: Stent thrombosis occurred in three patients, two definite and one probable (overall thrombosis rate: 1.4%). However, there were no cases of death or Q-wave myocardial infarction. In univariate analysis, patients with a higher incidence of stent thrombosis were those in whom the target vessel was the left anterior descending, who had single-vessel disease, were assigned to treatment with sirolimus-eluting stents, and those with smaller minimum luminal diameter immediately after the procedure. In multivariate analysis, the only independent predictor of stent thrombosis was minimal luminal diameter immediately after the procedure. CONCLUSIONS: The rate of drug-eluting stent thrombosis in patients with CTO is relatively low (1.4%). The only independent predictor of stent thrombosis in this context was minimal luminal diameter after the procedure and the clinical presentation was in all cases relatively benign. PMID- 25686521 TI - Corpus callosum abnormalities in medication-naive adult patients with obsessive compulsive disorder. AB - Emerging evidence demonstrates widespread abnormalities involving white matter (WM) tracts connecting different cortical regions in obsessive-compulsive disorder (OCD). The corpus callosum (CC), the largest inter-hemispheric tract connecting the association cortices, has been shown to be affected in OCD. This study examines CC abnormalities in a large sample of medication-naive OCD patients in comparison to matched healthy controls (HCs). We examined the mid sagittal area of the CC in medication-naive OCD patients (n=49) in comparison with age-, sex-, and handedness-matched HCs (n=38). Witelson's method was used to measure the sub-regions of the CC - namely, the genu, body, isthmus and splenium with good inter-rater reliability. The area of the body of the CC and total CC area were significantly larger in OCD patients than in HCs after controlling for age, sex and intracranial area. The Yale-Brown Obsessive-Compulsive Scale (Y BOCS) compulsion score had a significant negative correlation with the areas of the isthmus and splenium of the CC in addition to the total CC area. The region specific differences in the body of the CC and the region-specific association of severity score with posterior regions of the CC might be indicative of the involvement of additional areas like the dorsolateral prefrontal cortex, posterior parietal areas, occipital and association cortices in OCD that extend beyond the conventional orbito-fronto-striatal circuitry that is often posited to be involved in OCD. PMID- 25686522 TI - Detection of early changes in the parahippocampal and posterior cingulum bundles during mild cognitive impairment by using high-resolution multi-parametric diffusion tensor imaging. AB - We aimed to determine alterations occurring in the parahippocampal cingulum bundle (PhC) and posterior cingulum bundle (PoC) in patients with mild cognitive impairment (MCI) through analysis of high-resolution multi-parametric diffusion tensor imaging (DTI). Participants comprised 41 patients with MCI (21 AD converters [MCI-C] and 20 non-converters [MCI-NC]), 20 patients with Alzheimer's disease (AD), and 26 healthy elderly subjects who underwent prospective examination with high-resolution DTI. An atlas-based regions-of-interest (ROIs) method calculated fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (DA), and radial diffusivity (DR) in the PhC and PoC. For the PhC, FA values showed significant decreases, and MD and DR values showed significantly increases, in the MCI-C and AD groups compared with the healthy controls, although the MCI-C and MCI-NC groups did not differ significantly in these metrics. Conversely, none of the diffusion metrics for the PoC showed a significant difference among the MCI groups and the control groups, although there were significant differences between the AD group and control groups. High resolution multi-parametric DTI analysis was able to detect substantial changes in diffusion anisotropy and diffusivity in the PhC of patients with MCI who were destined to convert to AD. PMID- 25686523 TI - Impramine, fluoxetine and clozapine differently affected reactivity to positive and negative stimuli in a model of motivational anhedonia in rats. AB - Anhedonia is a relevant symptom in depression and schizophrenia. Chronic stress exposure induces in rats escape deficit, disrupts the dopaminergic response to palatable food and the competence to acquire sucrose self-administration (SA), thus configuring a possible model of motivational anhedonia. Repeated lithium administration reverts stress effects and brings back to control values the breaking point (BP) score, a measure of reward motivation. In this study, we tested on this model two antidepressants, imipramine and fluoxetine, and two antipsychotics, haloperidol and clozapine. The dopaminergic response to sucrose consumption was studied in non food-deprived rats in terms of dopamine D1 receptor signaling in the nucleus accumbens shell (NAcS). More specifically, we studied the modifications in dopamine and cAMP-regulated phosphoprotein of Mr 32,000 (DARPP-32) phosphorylation pattern following sucrose consumption. Fluoxetine reverted the escape deficit and showed no effects on dopaminergic response and sucrose SA. Imipramine reverted sucrose SA and dopamine response deficit in half of the rats and the escape deficit in all animals. Haloperidol did not affect stress-induced deficits. Clozapine-treated rats recovered the dopaminergic response to sucrose consumption and the competence to acquire sucrose SA, although they still showed the escape deficit, thus confirming that motivation toward reward may be dissociated from that to punishment escape. These results indicate that imipramine or fluoxetine are not endowed with a rapid onset antianhedonic effect. On the other hand, clozapine treatment showed a motivational antianhedonic activity similar to that observed after lithium treatment. PMID- 25686524 TI - P2X7 receptor-mediated analgesia in cancer-induced bone pain. AB - Pain is a common and debilitating complication for cancer patients significantly compromising their quality of life. Cancer-induced bone pain involves a complex interplay of molecular events, including mechanisms observed in inflammatory and neuropathic pain states, but also changes unique for cancer-induced bone pain. The P2X7 receptor (P2X7R) is involved in a variety of cellular functions and has been linked to both inflammatory and neuropathic pain. Here we study the analgesic potential of P2X7R antagonism in a rat model of cancer-induced bone pain. In cancer-bearing animals, the P2X7R antagonist A839977 attenuated dorsal horn neuronal responses in a modality and intensity-specific way. Spinal application of 0.4-mg/kg and 1.2-mg/kg A839977 significantly reduced the evoked responses to high-intensity mechanical and thermal stimulation, whereas no effect was seen in response to low-intensity or electrical stimulation. In contrast, A839977 had no effect on the tested parameters in naive or sham animals. In awake animals, 40-mg/kg A839977 (i.p.) significantly reduced both early- and late-stage pain behavior. In contrast, no effect was observed in sham or vehicle-treated animals. The results suggest that the P2X7R is involved in the mechanisms of cancer-induced bone pain, and that P2X7R antagonism might be a useful analgesic target. No effect was observed in sham or naive animals, indicating that the P2X7R-mediated effect is state-dependent, and might therefore be an advantageous target compared to traditional analgesics. PMID- 25686525 TI - Electrophysiological characterization of spinal neurons in different models of diabetes type 1- and type 2-induced neuropathy in rats. AB - Diabetic polyneuropathy (DPN) is a devastating complication of diabetes. The underlying pathogenesis of DPN is still elusive and an effective treatment devoid of side effects presents a challenge. There is evidence that in type-1 and -2 diabetes, metabolic and morphological changes lead to peripheral nerve damage and altered central nociceptive transmission, which may contribute to neuropathic pain symptoms. We characterized the electrophysiological response properties of spinal wide dynamic range (WDR) neurons in three diabetic models. The streptozotocin (STZ) model was used as a drug-induced model of type-1 diabetes, and the BioBreeding/Worcester (BB/Wor) and Zucker diabetic fatty (ZDF) rat models were used for genetic DPN models. Data were compared to the respective control group (BB/Wor diabetic-resistant, Zucker lean (ZL) and saline-injected Wistar rat). Response properties of WDR neurons to mechanical stimulation and spontaneous activity were assessed. We found abnormal response properties of spinal WDR neurons in all diabetic rats but not controls. Profound differences between models were observed. In BB/Wor diabetic rats evoked responses were increased, while in ZDF rats spontaneous activity was increased and in STZ rats mainly after discharges were increased. The abnormal response properties of neurons might indicate differential pathological, diabetes-induced, changes in spinal neuronal transmission. This study shows for the first time that specific electrophysiological response properties are characteristic for certain models of DPN and that these might reflect the diverse and complex symptomatology of DPN in the clinic. PMID- 25686526 TI - Local knockdown of the NaV1.6 sodium channel reduces pain behaviors, sensory neuron excitability, and sympathetic sprouting in rat models of neuropathic pain. AB - In the spinal nerve ligation (SNL) model of neuropathic pain, as in other pain models, abnormal spontaneous activity of myelinated sensory neurons occurs early and is essential for establishing pain behaviors and other pathologies. Sympathetic sprouting into the dorsal root ganglion (DRG) is observed after SNL, and sympathectomy reduces pain behavior. Sprouting and spontaneous activity may be mutually reinforcing: blocking neuronal activity reduces sympathetic sprouting, and sympathetic spouts functionally increase spontaneous activity in vitro. However, most studies in this field have used nonspecific methods to block spontaneous activity, methods that also block evoked and normal activity. In this study, we injected small inhibitory (si) RNA directed against the NaV1.6 sodium channel isoform into the DRG before SNL. This isoform can mediate high-frequency repetitive firing, like that seen in spontaneously active neurons. Local knockdown of NaV1.6 markedly reduced mechanical pain behaviors induced by SNL, reduced sympathetic sprouting into the ligated sensory ganglion, and blocked abnormal spontaneous activity and other measures of hyperexcitability in myelinated neurons in the ligated sensory ganglion. Immunohistochemical experiments showed that sympathetic sprouting preferentially targeted NaV1.6 positive neurons. Under these experimental conditions, NaV1.6 knockdown did not prevent or strongly alter single evoked action potentials, unlike previous less specific methods used to block spontaneous activity. NaV1.6 knockdown also reduced pain behaviors in another pain model, chronic constriction of the sciatic nerve, provided the model was modified so that the lesion site was relatively close to the siRNA-injected lumbar DRGs. The results highlight the relative importance of abnormal spontaneous activity in establishing both pain behaviors and sympathetic sprouting, and suggest that the NaV1.6 isoform may have value as a therapeutic target. PMID- 25686527 TI - Theoretical Analysis of the Effect of Temperature on Current Delivery to the Brain During tDCS. AB - BACKGROUND: Transcranial direct current simulation (tDCS) is a non-invasive neuromodulation technique that has become increasingly popular as a potential therapeutic method for a variety of brain disorders. Since the treatment outcome may depend on the current density delivered to the brain cortical region, a significant challenge is to control the current dose reaching the cortical region. OBJECTIVE AND METHODS: This study aims to investigate the effect of temperature on current delivery to the brain. We devised a method for modulating the amount of current delivered to the brain by changing the temperature of the scalp. We developed analytical and numerical models that describe the relationship between temperature and electrical properties of the scalp based on the following mechanisms: ion mobility and blood perfusion in scalp. RESULTS AND CONCLUSIONS: The current delivery to brain was investigated by changing the temperature between two electrodes that are attached to the surface of the scalp, within a tolerable physiological range. Results show that by increasing the temperature between two electrodes, a higher portion of current is shunted via the scalp and the proportion of the current that penetrates the scalp and skull into brain is decreased. On the other hand, cooling the area between two electrodes on the scalp increases the current delivery to the cortical region of the brain. Our results show that cooling the scalp during tDCS can be considered as a possible way to effectively control the current delivery to the brain and increase the efficacy of tDCS. PMID- 25686528 TI - Validating a Sham Condition for Use in High Definition Transcranial Direct Current Stimulation. AB - High Definition Transcranial Direct Current Stimulation (HD-tDCS) offers improved focality for targeting specific brain areas to modulate neural excitability, compared to conventional tDCS. HD-tDCS is associated with increased scalp sensation during stimulation, potentially rendering conventional tDCS sham methods ineffective due to lack of blinding. Here we report validation data on a novel method for modeling the sham condition in HD-tDCS studies. Thirty-one participants completed sensation ratings during 20 min of continuous active versus sham stimulation. Over half of the participants reported feeling the stimulation for the duration of the experiment. There were no statistically significant differences in sensation ratings between sham and active stimulation. Further, participants were unable to guess above chance level when they received sham stimulation. PMID- 25686529 TI - Giant cell arteritis occurring during psoriatic arthritis treated by adalimumab. PMID- 25686530 TI - Transitions in pressure collapsed clathrate hydrates. AB - Type II clathrate hydrates (CHs), or ice clathrates, are inclusion compounds in which a hydrogen-bonded cage-like structure of H2O accommodates molecules of suitable size, known as "guest molecules". CHs have similar local geometrical arrangements of the hydrogen-bonded water network as ice and both are known to collapse to amorphous states on isothermal pressurization at temperatures below about 140 K. Moreover, the collapsed CH states undergo a glass, or glass-like, transition at 140 K on heating at 1 GPa, which is identical to that of collapsed ice, or high density amorphous ice. Here we use thermal conductivity and dielectric measurements to study the transition behavior of two type II CHs with tetrahydrofuran and 1,3 dioxolane, respectively, as guest molecules. After their collapsed states have been heated to well above the glass transition at 1 GPa, we find transitions corresponding to the high to low density amorphous ice transition of ice with only slightly shifted temperature-pressure (T-p) coordinates compared to those of pure water. Thus, collapsed CHs show the same transition behaviors as cold water, which provide the basis for the model that explains the unusual temperature and pressure behaviors of water's properties in terms of two distinct types of liquid water. Collapsed CHs are, however, more stable than collapsed ice and can therefore be studied in a wider T-p interval. The results suggest sluggish homogenizing and phase separation processes, which affect the transition behaviors of collapsed CHs. PMID- 25686531 TI - Novel multifunctional nanofibers based on thermoplastic polyurethane and ionic liquid: towards antibacterial, anti-electrostatic and hydrophilic nonwovens by electrospinning. AB - Novel antibacterial, anti-electrostatic, and hydrophilic nanofibers based on a blend containing thermoplastic polyurethane (TPU) and a room-temperature ionic liquid (IL), 1-butyl-3-methylimidazolium hexafluorophosphate [BMIM][PF6], were fabricated by electrospinning. We investigated the effect of the IL on the morphology and the physical properties of the TPU nanofibers. Nanofibers with a 'bead-on-string' morphology were obtained by electrospinning from a neat TPU solution. The incorporation of the IL, at levels as low as 1 wt%, largely suppressed the formation of beads during electrospinning, and homogeneous nanofibers were obtained. The as-spun TPU/IL composite nanofibers showed significant activity against both Escherichia coli (E coli) and Staphylococcus aureus (S. aureus), with antibacterial activities of more than four and three, respectively. This means that the antibacterial efficiencies of TPU/IL composite nanofibers toward E coli and S. aureus are 99.99% and 99.9%, respectively. Moreover, nonwoven fabrics derived from the electrospun TPU/IL composite nanofibers exhibit better stretchability, elasticity, and higher electrical conductivity compared to those made using neat TPU without an IL. Additionally, the incorporation of the IL leads to a hydrophilic surface for the TPU/IL composite nanofibers compared to hydrophobic neat TPU nanofibers. These multifunctional nanofibers with excellent antibacterial, anti-electrostatic, and mechanical properties and improved hydrophilicity are promising candidates for biomedical and wastewater treatment applications. PMID- 25686532 TI - Insight into spin transport in oxide heterostructures from interface-resolved magnetic mapping. AB - At interfaces between complex oxides, electronic, orbital and magnetic reconstructions may produce states of matter absent from the materials involved, offering novel possibilities for electronic and spintronic devices. Here we show that magnetic reconstruction has a strong influence on the interfacial spin selectivity, a key parameter controlling spin transport in magnetic tunnel junctions. In epitaxial heterostructures combining layers of antiferromagnetic LaFeO(3) (LFO) and ferromagnetic La(0.7)Sr(0.3)MnO(3) (LSMO), we find that a net magnetic moment is induced in the first few unit planes of LFO near the interface with LSMO. Using X-ray photoemission electron microscopy, we show that the ferromagnetic domain structure of the manganite electrodes is imprinted into the antiferromagnetic tunnel barrier, endowing it with spin selectivity. Finally, we find that the spin arrangement resulting from coexisting ferromagnetic and antiferromagnetic interactions strongly influences the tunnel magnetoresistance of LSMO/LFO/LSMO junctions through competing spin-polarization and spin-filtering effects. PMID- 25686533 TI - Dependence of fibroblast infiltration in tumor stroma on type IV collagen initiated integrin signal through induction of platelet-derived growth factor. AB - Cancer-associated fibroblasts play a crucial role in accelerating tumor progression, but there is a knowledge gap regarding the chemotactic signal activated in a tumor microenvironment. In this study, the expression of type IV collagen was knocked down using a lentiviral-mediated short hairpin RNA strategy. Although there was no obvious effect on cell growth in vitro, silencing the Col4 alpha1 gene decreased the tumorigenicity of B16F10 in C57BL/6 mice, which was accompanied by a reduction in the infiltration of alpha-smooth muscle actin positive (alpha-SMA+) fibroblasts. Silencing the Col4-alpha1 gene or disrupting integrin engagement by blocking the antibody reduced the expression of platelet derived growth factor A (PDGF-A), a potent chemotactic factor for fibroblasts. Furthermore, ectopic expression of the autoclustering integrin mutant significantly stimulated PDGF-A expression in murine B16F10 and human U118MG and Huh7 cells. PDGF-A-specific sh-RNA and neutralizing anti-PDGF-A antibody effectively inhibited the transwell migration of fibroblasts. Adding recombinant PDGF-A back to shCol cell-conditioned media restored the fibroblast-attraction ability indicating that PDGF-A is a major chemotactic factor for fibroblasts in the current study model. The integrin-associated PDGF-A production correlated with the activation of Src and ERK. High type IV collagen staining intensity colocalized with elevated PDGF-A expression was observed in tumor tissues obtained from hepatoma and glioma patients. The integrin signal pathway was activated by collagen engagement through Src and ERK, leading to enhanced PDGF-A production, which serves as a key regulator of fibroblast recruitment. PMID- 25686534 TI - Defective insulin signaling and mitochondrial dynamics in diabetic cardiomyopathy. AB - Diabetic cardiomyopathy (DCM) is a common consequence of longstanding type 2 diabetes mellitus (T2DM) and encompasses structural, morphological, functional, and metabolic abnormalities in the heart. Myocardial energy metabolism depends on mitochondria, which must generate sufficient ATP to meet the high energy demands of the myocardium. Dysfunctional mitochondria are involved in the pathophysiology of diabetic heart disease. A large body of evidence implicates myocardial insulin resistance in the pathogenesis of DCM. Recent studies show that insulin signaling influences myocardial energy metabolism by impacting cardiomyocyte mitochondrial dynamics and function under physiological conditions. However, comprehensive understanding of molecular mechanisms linking insulin signaling and changes in the architecture of the mitochondrial network in diabetic cardiomyopathy is lacking. This review summarizes our current understanding of how defective insulin signaling impacts cardiac function in diabetic cardiomyopathy and discusses the potential role of mitochondrial dynamics. PMID- 25686536 TI - The power of power: electrokinetic control of PAH interactions with exfoliated graphite. AB - Exfoliated graphite (EG) exhibits exceptional sorption capacity for petroleum and dissolved hydrocarbons owing to its highly hydrophobic surface and wide pore size distribution. The high price of preparing EG, however, restricts its application. Methods which increase the rate or extent of sorption to EG even further are thus longed for. Here, we assess the effects of weak direct current (DC) fields on the sorption of the polycyclic aromatic hydrocarbon phenanthrene (PHE) to EG. DC applied to an ionic solution in a solid matrix invokes electroosmotic flow (EOF), i.e., the surface charge-induced movement of the solution. EG was exposed to weak DC fields in the presence of dissolved PHE to test if EOF increases transport of PHE to poorly accessible sorption sites. DC fields increased PHE sorption rates in EG sevenfold and reduced the desorption rate of sorbed PHE by >99%. EOF thus appeared to be highly effective in translocating PHE into pores, which contribute most of the sorption sites, but are difficult to access in the absence of EOF by molecular diffusion only. The observed 'power of power' may be used to kinetically regulate the interaction of sorbates with EG or other porous sorbents in environmental (bio-) technology. PMID- 25686535 TI - Advanced paramagnetic resonance spectroscopies of iron-sulfur proteins: Electron nuclear double resonance (ENDOR) and electron spin echo envelope modulation (ESEEM). AB - The advanced electron paramagnetic resonance (EPR) techniques, electron nuclear double resonance (ENDOR) and electron spin echo envelope modulation (ESEEM) spectroscopies, provide unique insights into the structure, coordination chemistry, and biochemical mechanism of nature's widely distributed iron-sulfur cluster (FeS) proteins. This review describes the ENDOR and ESEEM techniques and then provides a series of case studies on their application to a wide variety of FeS proteins including ferredoxins, nitrogenase, and radical SAM enzymes. This article is part of a Special Issue entitled: Fe/S proteins: Analysis, structure, function, biogenesis and diseases. PMID- 25686537 TI - Ultra-fast and energy-efficient sintering of ceramics by electric current concentration. AB - Electric current activated/assisted sintering (ECAS) techniques, such as electrical discharge sintering (EDS) or resistive sintering (RS), have been intensively investigated for longer than 50 years. In this work, a novel system including an electrically insulated graphite die for Spark Plasma Sintering (SPS) is described, which allows the sintering of any refractory ceramic material in less than 1 minute starting from room temperature with heating rates higher than 2000 degrees C/min and an energy consumption up to 100 times lower than with SPS. The system alternates or combines direct resistive sintering (DRS) and indirect resistive sintering (IRS). Electrical insulation of the die has been achieved through the insertion of a film made of alumina fibers between the graphite die and the graphite punches, which are protected from the alumina fiber film by a graphite foil. This system localized the electric current directly through the sample (conductive materials) as in DRS and EDS, or through the thin graphite foil (non-conductive materials) as in IRS, and is the first system capable of being used under EDS or RS conditions independently combining current concentration/localization phenomena. PMID- 25686538 TI - A randomized controlled trial of an online self-management program for adults with arthritis pain. AB - The objective of this RCT was to assess the efficacy of an online pain self management program with adults who had a self-reported doctor diagnosis of arthritis pain (N = 228). Participants were recruited via flyers and online postings then randomized to the experimental condition or the wait-list control condition. Individuals in the experimental condition reported significantly (1) increased arthritis self-efficacy and (2) reduced pain catastrophizing from baseline to follow up compared to those in the control condition. High user engagement (>204.5 min on the website) was also significantly associated with improved self-management outcomes. These findings suggest that use of an online self-management program may positively impact self-efficacy and catastrophizing among adults with arthritis pain at 6 month follow up. Nonsignificant findings for hypothesized variables such as pain intensity and health behaviors are also discussed. Future longitudinal research is needed to assess if cognitive changes associated with participation in an online self-management program leads to reduced pain. PMID- 25686539 TI - Aminolysis of ezetimibe. AB - The aminolysis of ezetimibe (1) and the structurally similar (3R*,4S*)-(4 fluorophenyl)-4-(4-hydroxyphenyl)-3-methylazetidin-2-one (4a) giving the corresponding beta-aminoamides 2a-d and 5a-c was studied spectrophotometrically under pseudo-first order conditions in aqueous butylamine, 3-methoxypropylamine, 2-methoxyethylamine and 2-hydroxyethylamine buffer solutions at 39 degrees C. It was found that the reaction mechanism involves uncatalyzed nucleophilic attack of an amine on the azetidinone carbonyl group as the rate-limiting step. On the basis of the Bronsted beta(Nuc) value (0.58 and 0.55 respectively) an early transition state was proposed in which the extent of C-N(amine) bond formation is low and the C-N(lactam) bond remains almost intact. It was also found that the presence of the phenolic group has a crucial role in the aminolysis because the analogous O-methyl derivative 4b does not react with amines at all. This observation would explain the fact that aminolysis of ezetimibe was not observed in human serum albumins where faster glucuronidation which blocks the phenolic hydroxide group occurs. PMID- 25686541 TI - Robot-assisted radical cystectomy: extracorporeal vs intracorporeal urinary diversion. PMID- 25686540 TI - CYP epoxygenase 2J2 prevents cardiac fibrosis by suppression of transmission of pro-inflammation from cardiomyocytes to macrophages. AB - Cytochrome P450 epoxygenase (CYP450)-derived epoxyeicosatrienoic acids (EETs) are important regulators of cardiac remodeling; but the underlying mechanism remains unclear. The present study aimed to elucidate how EETs regulated cardiac fibrosis in response to isoprenaline (Iso) or angiotensin (Ang) II. Cardiac-specific human CYP2J2 transgenic mice (Tr) and wild-type (WT) C57BL/6 littermates were infused with Iso- or Ang II. Two weeks after infusion, Tr mice showed more alleviative cardiac fibrosis and inflammation compared with WT mice. In vitro, we found Iso or Ang II induced nuclear transfer of NF-kappaB p65 and inflammatory cytokines expression in cardiomyocytes. Furthermore, inflammation response emerged in macrophages cultured in cardiomyocytes-conditioned medium. When pretreatment with 14,15-EET in cardiomyocytes, the inflammatory response was markedly suppressed and the transmission of inflammation from cardiomyocytes to macrophages was reduced. In conclusion, CYP2J2 and EETs prevent cardiac fibrosis and cardiac dysfunction by suppressing transmission of pro-inflammation from cardiomyocytes to macrophages in heart, suggesting that elevation of EETs level could be a potential strategy to prevent cardiac fibrosis. PMID- 25686542 TI - Radionuclide and Fluorescence Imaging of Clear Cell Renal Cell Carcinoma Using Dual Labeled Anti-Carbonic Anhydrase IX Antibody G250. AB - PURPOSE: Tumor targeted optical imaging using antibodies labeled with near infrared fluorophores is a sensitive imaging modality that might be used during surgery to assure complete removal of malignant tissue. We evaluated the feasibility of dual modality imaging and image guided surgery with the dual labeled anti-carbonic anhydrase IX antibody preparation (111)In-DTPA-G250 IRDye800CW in mice with intraperitoneal clear cell renal cell carcinoma. MATERIALS AND METHODS: BALB/c nu/nu mice with intraperitoneal SK-RC-52 lesions received 10 MUg DTPA-G250-IRDye800CW labeled with 15 MBq (111)In or 10 MUg of the dual labeled irrelevant control antibody NUH-82 (20 mice each). To evaluate when tumors could be detected, 4 mice per group were imaged weekly during 5 weeks with single photon emission computerized tomography/computerized tomography and the fluorescence imaging followed by ex vivo biodistribution studies. RESULTS: As early as 1 week after tumor cell inoculation single photon emission computerized tomography and fluorescence images showed clear delineation of intraperitoneal clear cell renal cell carcinoma with good concordance between single photon emission computerized tomography/computerized tomography and fluorescence images. The high and specific accumulation of the dual labeled antibody conjugate in tumors was confirmed in the biodistribution studies. Maximum tumor uptake was observed 1 week after inoculation (mean +/- SD 58.5% +/- 18.7% vs 5.6% +/- 2.3% injected dose per gm for DTPA-G250-IRDye800CW vs NUH-82, respectively). High tumor uptake was also observed at other time points. CONCLUSIONS: This study demonstrates the feasibility of dual modality imaging with dual labeled antibody (111)In-DTPA-G250-IRDye800CW in a clear cell renal cell carcinoma model. Results indicate that preoperative and intraoperative detection of carbonic anhydrase IX expressing tumors, positive resection margins and metastasis might be feasible with this approach. PMID- 25686543 TI - Intermediate-Term Risk of Prostate Cancer is Directly Related to Baseline Prostate Specific Antigen: Implications for Reducing the Burden of Prostate Specific Antigen Screening. AB - PURPOSE: Prostate specific antigen screening is controversial, as a large number of men must be screened annually to achieve a benefit. We sought to determine whether baseline prostate specific antigen could reliably predict subsequent risk of prostate cancer and risk of consequential prostate cancer. MATERIALS AND METHODS: A multiethnic cohort of 2,923 prostate cancer-free men was recruited between 2000 and 2012, and followed for a median of 7.5 years. Baseline prostate specific antigen was stratified into 6 strata and relative hazards of prostate cancer detection for each prostate specific antigen stratum were estimated, adjusting for ethnicity, family history and age. RESULTS: During followup 289 patients were diagnosed with prostate cancer. Men with baseline prostate specific antigen in the lowest stratum (0.1 to 1.0 ng/ml) were at greatly reduced risk for prostate cancer during followup. This half of the cohort with prostate specific antigen 1.0 ng/ml or less were at 3.4% (95% CI 2.1, 4.5) 10-year risk of prostate cancer and 90% of the cancers were low risk. By comparison the other half were at 15% to 39% risk of cancer detection with a 39% risk in the highest stratum (3 to 10 ng/ml). CONCLUSIONS: Optimal prostate specific antigen screening frequency for men with a prostate specific antigen level of 0.1 to 1.0 ng/ml may be up to every 10 years. This approach has the potential to dramatically reduce the cost of screening, decreasing over detection of inconsequential tumors, while maintaining detection of tumors for which treatment has been proven to reduce prostate cancer mortality. PMID- 25686544 TI - The effect of temperature and heating rate on char properties obtained from solar pyrolysis of beech wood. AB - Char samples were produced from pyrolysis in a lab-scale solar reactor. The pyrolysis of beech wood was carried out at temperatures ranging from 600 to 2000 degrees C, with heating rates from 5 to 450 degrees C/s. CHNS, scanning electron microscopy analysis, X-ray diffractometry, Brunauer-Emmett-Teller adsorption were employed to investigate the effect of temperature and heating rate on char composition and structure. The results indicated that char structure was more and more ordered with temperature increase and heating rate decrease (higher than 50 degrees C/s). The surface area and pore volume firstly increased with temperature and reached maximum at 1200 degrees C then reduced significantly at 2000 degrees C. Besides, they firstly increased with heating rate and then decreased slightly at heating rate of 450 degrees C/s when final temperature was no lower than 1200 degrees C. Char reactivity measured by TGA analysis was found to correlate with the evolution of char surface area and pore volume with temperature and heating rate. PMID- 25686545 TI - Pyrolysis behaviors of four lignin polymers isolated from the same pine wood. AB - Four lignin polymers, alkali lignin (AL), klason lignin (KL), organosolv lignin (OL), and milled wood lignin (MWL), were isolated from the same pine wood. Structural characterization by FTIR and (13)C NMR indicated that the four lignins have different structural features. Their pyrolysis behaviors were analyzed by TG FTIR and Py-GC/MS. Thermally unstable ether bonds and side branches were well preserved in AL and MWL, but were broken in OL and KL. Pyrolysis of AL and KL produce more phenols at low temperature by the breakage of ether bonds. AL and KL show lower activation energies in the main degradation stage, quantified by a distribution activation energy model with two linearly combined Gaussian functions. The evolution behaviors of typical gaseous products, CH4, CO2, and CO, were analyzed, and insights about the correlation between chemical structure and pyrolysis behavior were obtained. PMID- 25686546 TI - Integration of Shiitake cultivation and solid-state anaerobic digestion for utilization of woody biomass. AB - Pretreatment technologies that can not only reduce the recalcitrance of woody biomass but also achieve a high benefit-cost ratio are desirable for bioenergy production from woody biomass. In this study, an integrated process was proposed and conducted by pretreating woodchips via Shiitake cultivation for improved methane yield during solid-state anaerobic digestion (SS-AD), and simultaneously producing mushrooms as a high-value co-product. Shiitake cultivation using woodchips as the main substrate ingredient obtained mushroom yields comparable to those using a commercial substrate. Enzymatic digestibility and cumulative methane yields (133-160 L kg(-1)VS during 62 days of SS-AD) of pretreated substrates (spent mushroom substrate) were at least 1.5 times as high as those of untreated woodchips. Compared to a sole SS-AD process, the integrated Shiitake cultivation/SS-AD process increased methane production and solid waste reduction per kilogram of woodchips by about 1.5 and 8 times, respectively. PMID- 25686547 TI - A green route to fabricate MoS2 nanosheets in water-ethanol-CO2. AB - We show that bulk MoS2 can be efficiently exfoliated into ultrathin nanosheets in supercritical CO2 with ethanol as cosolvent. Moreover, such tailored MoS2 nanostructures, when they are directly used as labels for bioimaging, show excellent imaging effects with strong fluorescence and nontoxicity. PMID- 25686548 TI - Quality of life of Chinese urologists: a cross-sectional study using WHOQOL-BREF. AB - OBJECTIVES: In recent years, Chinese hospital settings are under violent threats. The exact status of quality of life of Chinese doctors under these disastrous situations remains obscure. The aim of this study was to assess the quality of life of Chinese urologists and analyse its potential affecting factors. DESIGN: Cross-sectional survey. SETTING: Beijing, China. PARTICIPANTS: Overall, 1000 participants from more than 30 areas of China, who participated in the 20th National Urology Conference in Beijing in 2013, were surveyed. The brief version of the World Health Organization Quality of Life (WHOQOL-BREF) Chinese version was used to assess the quality of life among these urologists. The relationship between quality of life and the affecting factors was analysed. RESULTS: Of the 1000 questionnaires, 856 were completed and returned, and 708 questionnaires were valid for analysis. Approximately 46% of the respondents came from provincial capitals, 54.2% of them felt stress from medical environment, while 76.0% felt stress from research work, and 85.3% from promotion. Cronbach's alpha coefficient of the instrument was 0.825, Kaiser-Meyer-Olkin measure was 0.841, and P value of Bartlett's sphericity was <0.001. The results of binary logistic regression indicated gender, work years, and medical environment as potential affecting factors of quality of life only influenced one domain. In contrast, research work and promotion influenced three domains of the WHOQOL-BREF. CONCLUSIONS: The study indicated that the WHOQOL-BREF may be a reliable and valid tool to assess quality of life of Chinese urologists. In China it is true that the deteriorative medical environment negatively affects medical practice according to previous studies, and policies are recommended to improve the situation. Nevertheless, we should not be too pessimistic about it, as in today's context research work and promotion may be the most extensive and significant affecting factors on doctors' quality of life. PMID- 25686549 TI - Erratum to: What gets noticed: how barrier and facilitator perceptions relate to the adoption and implementation of innovative mental health practices. PMID- 25686550 TI - Open Dialogue and its Relevance to the NHS: Opinions of NHS Staff and Service Users. AB - Open Dialogue is a model of mental health services that originated in Finland and has since, been taken up in trial teams worldwide. As this is a relatively unknown approach in the UK, it is important to tentatively explore perspectives of NHS staff and service-users. Sixty-one Open Dialogue conference attendees, both staff and service-users, were recruited for this study. A feedback questionnaire was administered to determine the extent to which they believed the key tenets of Open Dialogue were important to service user care, and the extent to which they existed within current NHS services. Analysis of data demonstrated a strong consensus on the importance of the key principles of Open Dialogue for mental health care and also moderate disagreement that these principles exist within current NHS service provision. The Open Dialogue principles may offer a useful framework in order to develop services in a clinically meaningful way. PMID- 25686551 TI - An efficient approach to gem-difluorocyclopropylstannanes via highly regio- and stereoselective hydrostannylation of gem-difluorocyclopropenes and their unique ring-opening reaction to afford beta-fluoroallylic alcohols. AB - Treatment of various gem-difluorocyclopropenes with 1.2 equiv. of n-Bu3SnH in the presence of 20 mol% of Et3B at 80 degrees C for 4 h led to the quantitative formation of the hydrostannylated products in a highly regio- and trans-selective manner. Additionally, the prepared trans-gem-difluorocyclopropylstannanes were treated with 1.5 equiv. of MeLi in THF at -78 degrees C for 5 min, followed by quenching the reaction with various agents, such as H2O, alcohols, carboxylic acids, and tosylamide, to give the corresponding beta-fluoroallylic alcohols, ethers, esters, and amides respectively with exclusive Z selectivity in acceptable yields. PMID- 25686552 TI - Haematological and serum biochemical responses of rabbit does to crude Moringa oleifera leaf extract at gestation and lactation. AB - As the plant Moringa oleifera is used in herbal medicines for animals, an experiment was carried out to assess the effects of crude M. oleifera leaf extract (CMOLE) on the blood profile of rabbit does during gestation and lactation. Twenty-four mature does (mean weight 2200 g) housed individually were assigned to four treatments in a completely randomised design. The animals in treatments 2, 3 and 4 were orally given 100, 200 and 300 mL/L CMOLE, respectively, at 2.5 mL/kg body weight at 48 h intervals for 9 weeks. The control animals (treatment 1) were given with water only. All the does were mated with untreated bucks 2 weeks into the experiment. Blood samples were collected at 3rd trimester (day 25 of gestation) and 2nd week of lactation. During gestation, levels of erythrocytes, leukocytes, haematocrit, haemoglobin, lymphocytes, monocytes and eosinophils were not significantly different among the treatments. However, animals on treatment 2 had the highest platelets (148.8 * 10(9)/L), not significantly different from those on treatments 3 (141.5 * 10(9)/L) and 4 (135.0 * 10(9)/L), but higher (p < 0.05) than the control (126.6 * 10(9)/L). Haematological parameters during lactation were not significantly different among the treatments. Of the serum biochemical variables examined during gestation, only urea was higher (p < 0.05) in control rabbits than those administered with 300 mL/L CMOLE. In lactation, only cholesterol was significantly (p < 0.05) reduced with an increase in CMOLE concentration. This suggests that Moringa has a hypocholesterolemic effect and is safe for use up to 300 mL/L for both nutritional and medicinal purposes. PMID- 25686553 TI - Cassava peel as a replacement for corn in the diet of lactating cows. AB - The aim of this study was to evaluate the effect of the replacement of corn with cassava peel in the diets of dairy cows. Eight Holstein cows were used. The experimental treatments consisted of four replacement levels of corn with cassava peel (0, 33, 66, and 100 %). The replacement of corn with cassava peel linearly decreased the intake and digestibility of dry matter and organic matter, but did not alter the intake of neutral detergent fiber and crude protein. In addition, there was a linear decrease in milk production. The milk components (g/kg) of fat, protein, lactose, and total solids were not altered. Although cassava peel decreased intake, digestibility, and milk production, the replacement of corn with cassava peel may be advantageous in locations close to the starch industry. PMID- 25686554 TI - Effect of protein level and urea in concentrate mixture on feed intake and rumen fermentation in swamp buffaloes fed rice straw-based diet. AB - Four rumen-fistulated Thai native swamp buffaloes were randomly assigned according to a 2 * 2 factorial arrangement in a 4 * 4 Latin square design to assess the effect of protein (CP) level and urea (U) source in concentrate diet on feed utilization and rumen ecology. The treatments were as follows: concentrate containing CP at 120 g/kg (soybean meal, SBM) (T1), 160 g/kg (SBM) (T2), 120 g/kg (U) (T3), and 160 g/kg (U) (T4), respectively. All buffaloes were fed concentrate at 10 g/kg of body weight, and rice straw was offered ad libitum. Feed intake and digestibilities of CP, neutral detergent fiber, and acid detergent fiber increased (P < 0.05) in treatments with higher level of CP especially with U source (P < 0.05). In contrast, CP level and source in concentrate did not affect on ruminal pH and temperature (P > 0.05), while concentration of ruminal ammonia (N), blood urea (U), volatile fatty acids profile, microorganism populations, and variable bacterial growth increased in buffaloes consumed concentrate containing CP at 160 g/kg (T2 and T4; P < 0.05). Fecal and urinary N excretions decreased in buffaloes consumed concentrate containing higher CP level especially with U source while purine derivatives increased which resulted in a higher N balance as compared to lower CP level and SBM source treatments (P < 0.05). In summary, higher CP level in concentrate improved feed intake, nutrient digestibility, purine derivatives, and rumen ecology, and U had shown better result than SBM. Concentrate mixtures containing 16 g/kg CP with U 40 g/kg could improved nutrients utilization with no adverse effects for swamp buffaloes fed on rice straw. PMID- 25686555 TI - Oxidation of the GaAs semiconductor at the Al2O3/GaAs junction. AB - Atomic-scale understanding and processing of the oxidation of III-V compound semiconductor surfaces are essential for developing materials for various devices (e.g., transistors, solar cells, and light emitting diodes). The oxidation induced defect-rich phases at the interfaces of oxide/III-V junctions significantly affect the electrical performance of devices. In this study, a method to control the GaAs oxidation and interfacial defect density at the prototypical Al2O3/GaAs junction grown via atomic layer deposition (ALD) is demonstrated. Namely, pre-oxidation of GaAs(100) with an In-induced c(8 * 2) surface reconstruction, leading to a crystalline c(4 * 2)-O interface oxide before ALD of Al2O3, decreases band-gap defect density at the Al2O3/GaAs interface. Concomitantly, X-ray photoelectron spectroscopy (XPS) from these Al2O3/GaAs interfaces shows that the high oxidation state of Ga (Ga2O3 type) decreases, and the corresponding In2O3 type phase forms when employing the c(4 * 2)-O interface layer. Detailed synchrotron-radiation XPS of the counterpart c(4 * 2)-O oxide of InAs(100) has been utilized to elucidate the atomic structure of the useful c(4 * 2)-O interface layer and its oxidation process. The spectral analysis reveals that three different oxygen sites, five oxidation-induced group III atomic sites with core-level shifts between -0.2 eV and +1.0 eV, and hardly any oxygen-induced changes at the As sites form during the oxidation. These results, discussed within the current atomic model of the c(4 * 2)-O interface, provide insight into the atomic structures of oxide/III-V interfaces and a way to control the semiconductor oxidation. PMID- 25686556 TI - Oral anticoagulant therapy and bleeding events with vitamin K antagonists in patients with atrial fibrillation in a Hungarian county hospital. AB - BACKGROUND: Vitamin K antagonists, despite their tight therapeutic spectrum and the fear of bleeding complications, were long the most important drugs used in anticoagulant therapy. The aim of this study was to evaluate the quality of anticoagulant therapy and its relation with bleedings in everyday clinical practice. MATERIAL AND METHODS: We analyzed the data of 272 patients with non valvular atrial fibrillation treated in our county hospital using retrospective data collection of the last 1008+/-384 days. The INR (International Normalized Ratio) values and the time in therapeutic range (TTR) were analyzed. We asked patients about bleeding complications and searched the medical records. RESULTS: The TTR proved to be 64% and there was no statistically significant difference between that of 252 (92.7%) patients taking acenocoumarol and 20 (7.3%) on warfarin. Analyzing various factors leading to TTR under 70%, we found that none of them have a significant impact. Significantly more bleeding events occurred in the first 3 months after the initiation of anticoagulant therapy and in patients with TTR under 70%, but the latter was not significant after adjustment for factors influencing bleeding (OR 1.607, CI 0.571-4.522, p=0.392). CONCLUSIONS: Although the present study's TTR values were similar to those found in the warfarin branch of various large-scale international trials and in real-life settings, further improvement of vitamin K antagonist therapy are necessary. As the possibilities for this are limited, we believe that the new type anticoagulant agents have a place in everyday clinical practice. PMID- 25686557 TI - A tissue-engineered therapeutic device inhibits tumor growth in vitro and in vivo. AB - Bone metastasis is one of the leading causes of death in breast cancer patients. The current treatment is performed as a palliative therapy and the adverse side effects can compromise the patients' quality of life. In order to both effectively treat bone metastasis and avoid the limitation of current strategies, we have invented a drug eluting scaffold with clay matrix release doxorubicin (DESCLAYMR_DOX) to mechanically support the structure after resecting the metastatic tissue while also releasing the anticancer drug doxorubicin which supplements growth inhibition and elimination of the remaining tumor cells. We have previously demonstrated that this device has the capacity to regenerate the bone and provide sustained release of the anticancer drug in vitro. In this study, we focus on the ability of the device to inhibit cancer cell growth in vitro as well as in vivo. Drug-release kinetics was investigated and the cell viability test showed that the tumor inhibitory effect is sustained for up to 4weeks in vitro. Subcutaneous implantation of DESCLAYMR_DOX in athymic mice resulted in significant growth inhibition of human tumor xenografts of breast origin and decelerated multi-organ metastasis formation. Fluorescence images, visualizing doxorubicin, showed a sustained drug release from the DESCLAYMR device in vivo. Furthermore, local use of DESCLAYMR_DOX implantation reduced the incidence of doxorubicin's cardio-toxicity. These results suggest that DESCLAYMR_DOX can be used in reconstructive surgery to support the structure after bone tumor resection and facilitate a sustained release of anticancer drugs in order to prevent tumor recurrence. PMID- 25686558 TI - Highly elastic and suturable electrospun poly(glycerol sebacate) fibrous scaffolds. AB - Poly(glycerol sebacate) (PGS) is a thermally-crosslinked elastomer suitable for tissue regeneration due to its elasticity, degradability, and pro-regenerative inflammatory response. Pores in PGS scaffolds are typically introduced by porogen leaching, which compromises strength. Methods for producing fibrous PGS scaffolds are very limited. Electrospinning is the most widely used method for laboratory scale production of fibrous scaffolds. Electrospinning PGS by itself is challenging, necessitating a carrier polymer which can affect material properties if not removed. We report a simple electrospinning method to produce distinct PGS fibers while maintaining the desired mechanical and cytocompatibility properties of thermally crosslinked PGS. Fibrous PGS demonstrated 5 times higher tensile strength and increased suture retention compared to porous PGS foams. Additionally, similar modulus and elastic recovery were observed. A final advantage of fibrous PGS sheets is the ability to create multi-laminate constructs due to fiber bonding that occurs during thermal crosslinking. Taken together, these highly elastic fibrous PGS scaffolds will enable new approaches in tissue engineering and regenerative medicine. PMID- 25686559 TI - Preparation and testing of quaternized chitosan nanoparticles as gene delivery vehicles. AB - The aim of this study was to synthesize a chitosan (CS) derivative, a quaternary ammonium salt crystal called N-2-hydroxypropyl trimethyl ammonium chloride chitosan (HACC), and test a series of HACC and pEGFP-DNA complexes at different weight ratios for their efficiency of gene delivery into human cells. CS was modified with cationic etherifying agent to obtain the CS derivative. Fourier transform infrared spectra were recorded on KBr pellets with a spectrometer. (1)H nuclear magnetic resonance (NMR) spectra of HACC were obtained using a spectrometer. HACC was subsequently used to prepare HACC/DNA complexes at different weight ratios by coacervation method. The resulting particle size and surface charge were assessed by laser light scattering using a zeta potential analyzer. The HACC/DNA complex formation and DNA protection in the nanoparticle complex was investigated by gel mobility shift assay and DNase I protection assay, respectively. The cytotoxicity of HACC and HACC/DNA nanoparticles was evaluated by MTT assay using (mesenchymal stem cell) MSC lines. The nanoscale structure of the particles was obtained by transmission electron microscope (TEM). The FTIR spectrum of HACC showed the characteristic quaternary ammonium group absorption band at 1475 cm(-1), which indicated the presence of quaternary ammonium group. The successful synthesis of HACC was also confirmed by (1)H NMR spectrum. HACC showed good solubility in water and was electropositive. HACC efficiently packed and protected pEGFP-DNA at a weight ratio of 10. With increased weight ratios, the surface charge of the composite particle increased from negative to positive, the average particle size increased, and HACC nanoparticle had a higher carrying efficiency. The nanoparticles released DNA in two distinct phases, and 55 % was released within the first 20 h of solubilization. The nanoparticles under TEM showed circular or oval shapes. The particles exhibited no cytotoxicity against human cells. No significant difference in gene delivery efficiency was detected between HACC/pEGFP-GDNF and liposome/pEGFP-GDNF complexes (33.8 vs. 34 %, P = 0.363). In this study, HACC was successfully synthesized, and HACC/DNA complex assembled efficiently. HACC showed strong DNA binding affinity and high protection of DNA and was non-cytotoxic to human cells. The particles had appropriate nanostructure, mean diameter, and DNA release time. The results suggest that HACC nanoparticles are a novel tool for efficient and safe gene delivery. PMID- 25686560 TI - Improvement of zinc bioaccumulation and biomass yield in the mycelia and fruiting bodies of Pleurotus florida cultured on liquid media. AB - The effect of different concentrations of zinc on the bioaccumulation of zinc and biomass yield in both mycelium and fruiting body of Pleurotus florida cultivated in liquid medium was studied. The results showed that the optimum yield of mycelia (11.33 +/- 0.44 g/L) and fruiting bodies (7.70 +/- 0.19 g/L) dry biomass was obtained in a liquid medium containing 100 mg/L of zinc. At a zinc concentration of 200 mg/L, the highest concentration of zinc in the mycelia and fruiting bodies reached 1.869 +/- 0.115 and 0.151 +/- 0.008 mg/g dry weight, respectively. The addition of zinc to the culture media significantly reduced zinc bioaccumulation factor in mycelia (from 24.64 +/- 0.52 to 3.35 +/- 0.24) and fruiting bodies (from 36.71 +/- 0.30 to 0.49 +/- 0.02) dry weight. Our findings indicated that the ability of zinc bioaccumulation in the mycelia is much higher than in the fruiting bodies. The fundamental information obtained in this study will be useful for the improvement of zinc bioaccumulation and biomass yield in mycelia and fruiting bodies of P. florida cultivated in liquid media to obtain maximum zinc-enriched biomass. PMID- 25686561 TI - Asarones from Acorus calamus in combination with azoles and amphotericin B: a novel synergistic combination to compete against human pathogenic Candida species in vitro. AB - The increase in drug resistance to current antifungal drugs brings enormous challenges to the management of Candida infection. Therefore, there is a continuous need for the discovery of new antimicrobial agents that are effective against Candida infections especially from natural source especially from medical plants. The present investigation describes the synergistic anticandidal activity of two asarones (infinity and beta) purified from Acorus calamus in combination with three clinically used antifungal drugs (fluconazole, clotrimazole, and amphotericin B). The synergistic anticandidal activities of asarones and drugs were assessed using the checkerboard microdilution and time-kill assays. The results of the present study showed that the combined effects of asarones and drugs principally recorded substantial synergistic activity (fractional inhibitory concentration index (FICI) <0.5). Time-kill study by combination of the minimal inhibitory concentration (MIC) of asarones and drugs (1:1) recorded that the growth of the Candida species was significantly arrested between 0 and 2 h and almost completely attenuated between 2 and 6 h of treatment. These findings have potential implications in adjourning the development of resistance as the anticandidal activity is achieved with lower concentrations of asarones and drugs. The combination of asarones and drugs also significantly inhibit the biofilm formation by Candida species, and this would also help to fight against drug resistance because biofilms formed by Candida species are ubiquitous in nature and are characterized by their recalcitrance toward antimicrobial treatment. The in vitro synergistic activity of asarones and drugs against pathogenic Candida species is reported here for the first time. PMID- 25686562 TI - When your best friend turns on you; the impact of bad Propofol. PMID- 25686563 TI - Caudal bupivacaine and morphine provides effective postoperative analgesia but does not prevent hemodynamic response to pneumoperitoneum for major laparoscopic surgeries in children. AB - The use of a caudal block in laparoscopic surgery in children is limited to minor procedures like inguinal hernia repair, and intravenous opioids remain the analgesic modality of choice in major laparoscopic surgery. However, a caudal block is frequently performed at our institute even for laparoscopic surgery. Therefore, we planned to evaluate the analgesic efficacy of caudal bupivacaine and morphine in major laparoscopic surgery as compared to intravenous opioids. Our hypothesis was that a single-shot caudal block would increase the duration of analgesia and minimize the hemodynamic response to pneumoperitoneum. After institutional ethics committee clearance, data were collected for 65 ASA I-II children aged 6 months to 12 years who underwent laparoscopic surgery in the last 14 months. Demographic, surgical, and perioperative anesthetic and analgesic data were noted and analyzed. Twenty-four children received a caudal block with 0.25 % bupivacaine (1-1.25 ml/kg) with morphine (30-50 mcg/kg). In the caudal group, the time to first analgesic request was increased (165 vs. 45 min; p = 0.00) and tachycardia response to port site incision was less observed (33 vs. 63 % children; p = 0.019). Hemodynamic response to pneumoperitoneum was equal in both of the groups. Single-shot caudal injection of local anesthetic with morphine reduces port site skin incision response and increases the duration of postoperative analgesia but fails to prevent hemodynamic response to pneumoperitoneum. PMID- 25686564 TI - Transient global amnesia after stellate ganglion block. PMID- 25686565 TI - Resveratrol improves high-fat diet induced insulin resistance by rebalancing subsarcolemmal mitochondrial oxidation and antioxidantion. AB - Although resveratrol (RES) is thought to be a key regulator of insulin sensitivity in rodents, the exact mechanism underlying this effect remains unclear. Therefore, we sought to investigate how RES affects skeletal muscle oxidative and antioxidant levels of subsarcolemmal (SS) and intermyofibrillar (IMF) mitochondrial populations in high-fat diet (HFD)-induced insulin resistance (IR) rats. Systemic and skeletal muscle insulin sensitivity together with expressions of several genes related to mitochondrial biogenesis and skeletal muscle SIRT1, SIRT3 protein levels were studied in rats fed a normal diet, a HFD, and a HFD with intervention of RES for 8 weeks. Oxidative stress levels and antioxidant enzyme activities were assessed in SS and IMF mitochondria. HFD fed rats exhibited obvious systemic and skeletal muscle IR as well as decreased SIRT1 and SIRT3 expressions, mitochondrial DNA (mtDNA), and mitochondrial biogenesis (p < 0.05). Both SS and IMF mitochondria demonstrated elevated reactive oxygen species (ROS) and malondialdehyde (MDA) levels. In addition, SS mitochondrial antioxidant enzyme activities were significantly lower, while IMF mitochondrial antioxidant enzyme activities were higher (p < 0.05). By contrast, RES treatment protected rats against diet induced IR, increased SIRT1 and SIRT3 expressions, mtDNA, and mitochondrial biogenesis (p < 0.05). Moreover, the activities of SS and IMF mitochondrial antioxidant enzymes were increased, which reverted the increased SS mitochondrial oxidative stress levels (p < 0.05). This study suggests that RES ameliorates insulin sensitivity consistent with improved SIRT3 expressions and rebalance between SS mitochondrial oxidative stress and antioxidant competence in HFD rats. PMID- 25686566 TI - Effects of adipocyte-secreted factors on decidualized endometrial cells: modulation of endometrial receptivity in vitro. AB - Obesity is defined as an excessive accumulation of adipose tissue that may lead to health complications. Mounting evidence indicates that obesity has a negative impact on fertility. Yet, the link between adipose tissue biology and infertility remains unclear. We aimed to investigate the communication between the adipose tissue and the reproductive system and the importance of this cross talk for the development of a receptive endometrium. To that end, we generated an in vitro model with endometrial and adipocyte cell lines. Sexual hormones, progesterone and estradiol, were used to decidualize endometrial cells and sensitize adipocytes. Decidualization produced a simultaneous increase of adipokine receptors in endometrial cells paralleling changes in their receptivity status. Furthermore, sensitization of 3T3-L1 adipocytes increased mRNA levels of leptin and resistin and decreased the expression of adiponectin and chemerin levels. This was accompanied by increased isoproterenol-induced lipolysis and reduced insulin-stimulated glucose uptake. Lastly, conditioned culture medium of those sensitized adipocytes was used to feed endometrial cells. This treatment resulted in (i) upregulation of genes previously identified as positive regulators of endometrial receptivity, such as leukemia inhibitory factor and glutathione peroxidase 3, and (ii) downregulation of interleukin-15 and mucin1, both genes negatively related with endometrial receptivity. Our results indicate that the endocrine communication between adipose tissue and the reproductive system is bidirectional and stress the importance of the adipose tissue to modulate the reproductive fitness. PMID- 25686570 TI - Prevention: Intensive exercise associated with reduced risk of diabetic nephropathy in patients with type 1 diabetes mellitus. PMID- 25686569 TI - HIV-associated nephropathies: epidemiology, pathology, mechanisms and treatment. AB - HIV is a highly adaptive, rapidly evolving virus, which is associated with renal diseases including collapsing glomerulopathy-the classic histomorphological form of HIV-associated nephropathy. Other nephropathies related to viral factors include HIV-immune-complex kidney disease and thrombotic microangiopathy. The distribution of HIV-associated kidney diseases has changed over time and continues to vary across geographic regions worldwide. The reasons for this diversity are complex and include a critical role of APOL1 variants and possibly other genetic factors, disparities in access to effective antiviral therapies, and likely other factors that we do not yet fully understand. The mechanisms responsible for HIVAN, including HIV infection of podocytes and tubular epithelial cells, the molecules responsible for HIV entry, and diverse mechanisms of cell injury, have been the focus of much study. Although combined antiretroviral therapy is effective at preventing and reversing HIVAN, focal segmental glomerulosclerosis, arterionephrosclerosis and diabetic nephropathy are increasingly common in individuals who have received such therapy for many years. These diseases are associated with metabolic syndrome, obesity and premature ageing. Future directions for HIV-related kidney disease will involve regular screening for drug nephrotoxicity and incipient renal disease, as well as further research into the mechanisms by which chronic inflammation can lead to glomerular disease. PMID- 25686571 TI - Immunology: Clonal deletion contributes to allograft tolerance. PMID- 25686574 TI - Trends in the HIV Epidemic Among African American Men Who Have Sex with Men, San Francisco, 2004-2011. AB - African American men who have sex with men have been disproportionately affected by the HIV epidemic in the United States and remain to this day one of the groups with highest HIV prevalence and incidence. Our goal was to clarify the current state of HIV risk, sexual behaviors, and structural/network-network level factors that affect black MSM's population risk of HIV, enabling the formulation of targeted and up-to-date public health messages/campaigns directed at this vulnerable population. Our approach maximized the use of local data through a process of synthesis and triangulation of multiple independent and overlapping sources of information that are sometimes separately published and often not examined side-by-side. Among African American MSM, we observed stable HIV incidence despite increases in reported individual risk behavior and STDs. An increasing proportion of African American MSM are reporting HIV testing in the past 6 months and seroadaptive behaviors, which may play a role in this observed decline in HIV among MSM in San Francisco, California. Our analysis suggests that currently the HIV epidemic is stable among African American MSM in San Francisco. However, we suggest that the observed stability is due to factors prohibiting expansion of new infections rather than decreasing risks for HIV infection among African American MSM. PMID- 25686575 TI - Use of quetiapine in children and adolescents. AB - The atypical antipsychotic quetiapine has been used in different psychotic and non-psychotic disorders in children and adolescents in randomized clinical trials, open-label studies and chart reviews. Most of these studies suggest that quetiapine may be a promising agent with a potential for use in young patients. The aim of this paper is to critically review available literature on quetiapine in the treatment of children and adolescents with a variety of psychiatric disorders, including psychotic disorders, bipolar disorders (manic and depressive episodes), conduct disorder, autism spectrum disorder, Tourette's syndrome and personality disorders. Furthermore, we report on possible neurochemical pathways involved during treatment with quetiapine, and discuss some issues that are clinically relevant in daily practice, such as titration strategies, safety and tolerability, and monitoring possible side effects. Controlled studies support the short-term efficacy for treating psychosis, mania, and aggression within certain diagnostic categories. However, although quetiapine seems well tolerated in various pediatric populations during acute and intermediate treatments, and hyper-prolactinemia and extra-pyramidal side effects are consistently low among studies, weight gain and alterations in lipid profile need to be closely monitored. Furthermore, the distal benefit/risk ratio during long-term treatment remains to be determined. PMID- 25686576 TI - Ambipolar organic field-effect transistors based on solution-processed single crystal microwires of a quinoidal oligothiophene derivative. AB - A simple and versatile solution-processing method based on molecular self assembly is used to fabricate organic single crystal microwires of a low bandgap quinoidal oligothiophene derivative. Individual single crystal microwire transistors present well-balanced ambipolar behaviour with hole and electron mobilities as high as 0.4 and 0.5 cm(2) V(-1) s(-1), respectively. PMID- 25686577 TI - Magnetic resonance imaging findings in patients presenting with (sub)acute cerebellar ataxia. AB - INTRODUCTION: Acute or subacute cerebellar inflammation is mainly caused by postinfectious, toxic, neoplastic, vascular, or idiopathic processes and can result in cerebellar ataxia. Previous magnetic resonance (MR) studies in single patients who developed acute or subacute ataxia showed varying imaging features. METHODS: Eighteen patients presenting with acute and subacute onset of ataxia were included in this study. Cases of chronic-progressive/hereditary and noncerebellar causes (ischemia, multiple sclerosis lesions, metastasis, bleedings) were excluded. MR imaging findings were then matched with the clinical history of the patient. RESULTS: An underlying etiology for ataxic symptoms were found in 14/18 patients (postinfectious/infectious, paraneoplastic, autoimmune, drug-induced). In two of five patients without MR imaging findings and three of eight patients with minimal imaging features (cerebellar atrophy, slight signal alterations, and small areas of restricted diffusion), adverse clinical outcomes were documented. Of the five patients with prominent MR findings (cerebellar swelling, contrast enhancement, or broad signal abnormalities), two were lost to follow-up and two showed long-term sequelae. CONCLUSION: No correlation was found between the presence of initial MRI findings in subacute or acute ataxia patients and their long-term clinical outcome. MR imaging was more flagrantly positive in cases due to encephalitis. PMID- 25686578 TI - A general design rule to manipulate photocarrier transport path in solar cells and its realization by the plasmonic-electrical effect. AB - It is well known that transport paths of photocarriers (electrons and holes) before collected by electrodes strongly affect bulk recombination and thus electrical properties of solar cells, including open-circuit voltage and fill factor. For boosting device performance, a general design rule, tailored to arbitrary electron to hole mobility ratio, is proposed to decide the transport paths of photocarriers. Due to a unique ability to localize and concentrate light, plasmonics is explored to manipulate photocarrier transport through spatially redistributing light absorption at the active layer of devices. Without changing the active materials, we conceive a plasmonic-electrical concept, which tunes electrical properties of solar cells via the plasmon-modified optical field distribution, to realize the design rule. Incorporating spectrally and spatially configurable metallic nanostructures, thin-film solar cells are theoretically modelled and experimentally fabricated to validate the design rule and verify the plasmonic-tunable electrical properties. The general design rule, together with the plasmonic-electrical effect, contributes to the evolution of emerging photovoltaics. PMID- 25686580 TI - Improved nitrogen use efficiency in transgenic sugarcane: phenotypic assessment in a pot trial under low nitrogen conditions. AB - KEY MESSAGE: Sugarcane lines transformed with an alanine aminotransferase gene demonstrated an improved nitrogen use efficiency compared with untransformed controls in a pot trial under low nitrogen conditions. PMID- 25686579 TI - Plasma membrane H(+)-ATPase is involved in methyl jasmonate-induced root hair formation in lettuce (Lactuca sativa L.) seedlings. AB - KEY MESSAGE: Our results show that methyl jasmonate induces plasma membrane H (+) -ATPase activity and subsequently influences the apoplastic pH of trichoblasts to maintain a cell wall pH environment appropriate for root hair development. Root hairs, which arise from root epidermal cells, are tubular structures that increase the efficiency of water absorption and nutrient uptake. Plant hormones are critical regulators of root hair development. In this study, we investigated the regulatory role of the plasma membrane (PM) H(+)-ATPase in methyl jasmonate (MeJA)-induced root hair formation. We found that MeJA had a pronounced effect on the promotion of root hair formation in lettuce seedlings, but that this effect was blocked by the PM H(+)-ATPase inhibitor vanadate. Furthermore, MeJA treatment increased PM H(+)-ATPase activity in parallel with H(+) efflux from the root tips of lettuce seedlings and rhizosphere acidification. Our results also showed that MeJA-induced root hair formation was accompanied by hydrogen peroxide accumulation. The apoplastic acidification acted in concert with reactive oxygen species to modulate root hair formation. Our results suggest that the effect of MeJA on root hair formation is mediated by modulation of PM H(+)-ATPase activity. PMID- 25686590 TI - Molecular design, synthesis and biological research of novel pyridyl acridones as potent DNA-binding and apoptosis-inducing agents. AB - A series of novel pyridyl acridone derivatives comprised of a pseudo-five-cyclic system to extend the pi-conjugated acridone chromophore, were designed and synthesized as potent DNA binding antitumor compounds. Most synthesized compounds displayed good activity against human leukemia K562 cells in MTT tests, with compound 6d exhibiting the highest activity with IC50 value at 0.46 MUM. Moreover, 6d showed potent activities against solid tumor cell lines (0.16-3.79 MUM). Several experimental studies demonstrated that the antitumor mode of action of compound 6d involves DNA intercalation, topoisomerase I inhibition, and apoptosis induction through the mitochondrial pathway. In summary, compound 6d represents a novel and promising lead structure for the development of new potent anticancer DNA-binding agents. PMID- 25686591 TI - 5'-(N-aminoacyl)-sulfonamido-5'-deoxyadenosine: attempts for a stable alternative for aminoacyl-sulfamoyl adenosines as aaRS inhibitors. AB - Synthesis of aminoacyl-sulfamoyl adenosines (aaSAs) and their peptidyl conjugates as aminoacyl tRNA synthetase (aaRS) inhibitors remains problematic due to the low yield of the aminoacylation and the subsequent conjugation reaction causing concomitant formation of a cyclic adenosine derivative. In an effort to reduce this undesirable side reaction, we aimed to prepare the corresponding aminoacyl sulfonamide (aaSoA) analogues as more stable alternatives for aaSA derivatives. Deletion of the 5'-oxygen in aaSA analogues should render the C-5' less electrophilic and therefore improve the stability of the aminoacyl sulfamate analogues. We therefore synthesized six sulfonamides and compared their activity against the respective aaSA analogues. However, except for the aspartyl derivative, the new compounds are not able to inhibit the corresponding aaRS. Possible reasons for this loss of activity are discussed by modeling and comparison of the newly synthesized aaSoA derivatives with their parent aaSA analogues. PMID- 25686592 TI - Xanthone analogues as potent modulators of intestinal P-glycoprotein. AB - Intestinal P-glycoprotein (P-gp) is a limiting step for oral absorption of drugs. Therefore, P-gp inhibitors have been studied as enhancers of oral absorption of drugs that are P-gp substrates. We investigated the in vitro and in vivo P-gp inhibitory activity of synthesized xanthone analogues. With 3-(3-chloro-2 hydroxypropoxy)-1-hydroxy-9H-thioxanthen-9-one, compound 13, accumulation of daunomycin (DNM) increased 707% and efflux of DNM decreased 66% compared to DNM alone. Relative bioavailability (RB) of paclitaxel (PTX, 25 mg/kg) increased 2.5 fold after oral administration with 13 (5 mg/kg). In a xenograft animal model, oral administration of PTX (40 mg/kg) with 13 (10 mg/kg) significantly inhibited tumour growth and was more effective than intravenously administered PTX (10 mg/kg) alone. Therefore, the synthesized xanthone analogue 13 might have therapeutic benefits for oral absorption of P-gp substrate anticancer drugs. PMID- 25686593 TI - Synthesis, QSAR and anticandidal evaluation of 1,2,3-triazoles derived from naturally bioactive scaffolds. AB - In the present study, we used eight natural precursors (1a-h) with most of them having promising antimicrobial activities and synthesised their novel 1,2,3 triazole derivatives (3a-h). In the reaction sequences, the precursor compounds (1a-h) were converted to their respective alkyne (2a-h) followed by addition of benzyl azide freshly prepared by the reaction of benzyl bromide with sodium azide using [3 + 2] azide-alkyne cycloaddition strategy. Structural elucidation of all the triazole derivatives was done using FT-IR, (1)H, (13)C NMR, mass and elemental analysis techniques. The single crystal X-ray diffraction for 3d was also recorded. The result of in vitro anticandidal activity performed against three different strains of Candida showed that compound 3e was found superior/comparable to fluconazole (FLC) with IC50 values of 0.044 MUg/mL against Candida albicans (ATCC 90028), 12.022 MUg/mL against Candida glabrata (ATCC 90030), and 3.60 MUg/mL against Candida tropicalis (ATCC 750). Moreover, at their IC50 values, compounds 3e and 3h showed <5% hemolysis which indicates the non toxic behaviour of these inhibitors. Cytotoxicity assay was also performed on VERO cell line and all the derivatives were found non-toxic up to the concentration of 10.0 MUg/mL. The in silico technique of 3D-QSAR was applied to establish structure activity relationship of the synthesized compounds. The results reveal the molecular fragments that play an essential role in improving the anticandidal activity. PMID- 25686594 TI - Structure-based modification of 3-/4-aminoacetophenones giving a profound change of activity on tyrosinase: from potent activators to highly efficient inhibitors. AB - In this study, we developed 3-/4-aminoacetophenones and their structure-based 3 /4-aminophenylethylidenethiosemicarbazide derivatives, respectively, as novel tyrosinase activators and inhibitors. Notably, all the obtained thiosemicarbazones displayed more potent tyrosinase inhibitory activities than kojic acid. Especially, compound 7k was found to be the most active tyrosinase inhibitor with IC50 value of 0.291 MUM. The structure-activity relationships (SARs) analysis showed that: (1) the amine group was absolutely necessarily for determining the tyrosinase activation activity; (2) the introduction of thiosemicarbazide group played a very vital role in transforming tyrosinase activators into tyrosinase inhibitors; (3) the phenylethylenethiosemicarbazide moiety was crucial for determining the tyrosinase inhibitory activity; (4) the type of acyl group had no obvious effect on the inhibitory activity; (5) the position of amide substituent on the phenyl ring influenced the tyrosinase inhibitory potency. Moreover, the inhibition mechanism and inhibition kinetics study revealed that compound 7k was reversible and non-competitive inhibitor, and compound 8h was reversible and competitive-uncompetitive mixed-II type inhibitor. PMID- 25686595 TI - Indications for apheresis as an ultima ratio treatment of refractory hyperlipidemias. AB - Lipid apheresis is at present well established in routine treatment of diverse hyperlipoproteinemias refractory to conventional dietary and medical regimens, especially in countries with high medical and socioeconomic standards. Severe familial hypercholesterolemia with atherosclerotic vessel disease involving the coronary arteries is the most frequent indication for lipid apheresis as well as homozygous familial hypercholesterolemia before the development of cardiovascular complications.In hyperlipoproteinemia (a) with progressive vessel disease, lipid apheresis is regularly accepted in Germany. The indication of apheresis in Refsum's disease and the chylomicronemia syndrome is described. PMID- 25686596 TI - Animal models for cutaneous vaccine delivery. AB - Main challenges in skin vaccination are overcoming the stratum corneum (SC) barrier and targeting the antigen presenting cells (APC) in the epidermis and the dermis. For this purpose many delivery techniques are being developed. In vivo immunogenicity and safety studies in animals are mandatory before moving to clinical trials. However, the results obtained in animals may or may not be predictive for humans. Knowledge about differences and similarities in skin architecture and immunology within a species and between species is crucial. In this review, we discuss variables, including skin morphology, skin barrier function, mechanical properties, site of application and immunology, which should be taken into account when designing animal studies for vaccination via the skin in order to support the translation to clinical trial outcomes. PMID- 25686597 TI - Investigation and correlation of drug polymer miscibility and molecular interactions by various approaches for the preparation of amorphous solid dispersions. AB - Curcumin (CUR) was used as a poorly soluble drug whereas polyvinyl pyrrolidone K90 (PVP), Eudragit EPO (EPO), hydroxypropyl methylcellulose E5 (HPMC) and polyethylene glycol 8000 (PEG) were used as hydrophilic polymers. CUR polymer miscibility was evaluated by solubility parameter, melting point depression and glass transition temperature (Tg) measurements. Molecular interactions between CUR and polymers were determined by Fourier-transform infrared spectroscopy (FTIR) and Raman. Amorphous solid dispersions were prepared with CUR-polymer ratio of 70:30 (w/w) by solvent evaporation technique and were evaluated for dissolution enhancement using USP II method. Physical states of solid dispersions were characterized by X-ray diffraction (XRD) whereas thermal behaviors were investigated using modulated differential scanning calorimetry (MDSC). CUR-EPO system showed good miscibility through all the approaches, whereas immiscibility was found in other CUR-polymer systems. CUR-EPO and CUR-HPMC systems showed significant molecular interactions whereas CUR-PVP and CUR-PEG showed no molecular interactions. All solid dispersions showed significant dissolution enhancement with CUR-EPO showing highest dissolution rate during first 1h whereas CUR-HPMC was effective in maintaining high CUR concentrations for 6h. The study highlights the importance of investigating and correlating drug polymer miscibility and molecular interactions by various approaches for successful formulation of amorphous solid dispersions. PMID- 25686598 TI - [The utilization of brain plasticity by cochlear implants : Molecular and cellular changes due to electrical intracochlear stimulation]. AB - BACKGROUND AND OBJECTIVES: During pre- and postnatal development, a high level of growth-associated protein 43 (Gap43) is expressed in the brain. This neuron specific protein is expressed in somata, axons, and growth cones and plays a key role in neurite outgrowth and synaptogenesis. With maturation of the brain, Gap43 is down-regulated by most neurons, except in brain areas such as the hippocampal CA3 region or the binaural auditory regions lateral superior olive (LSO) and central inferior colliculus (CIC). This study investigated how changes in sensory activity levels and patterns can modulate the adult plasticity response. METHODS: To study the effect of sensory activity on adult Gap43 expression, mRNA and protein levels were determined in LSO and CIC of hearing-experienced rats, unilaterally and bilaterally deafened rats, or rats unilaterally stimulated by a cochlear implant (CI). RESULTS: Unilateral hearing loss of an adult auditory system causes asymmetrical expression of Gap43 mRNA between ipsi- and contralateral LSOs or CICs of the brain stem. While the mRNA level rose on the contralateral side of the LSO, CIC neurons increased their gap43 transcription ipsilaterally compared to the control level (p<0.001). Compensation of the lost sensory input by way of CI stimulation resulted in a bilaterally symmetric but increased gap43 transcription. CONCLUSIONS: Our data indicate that Gap43 is not only a marker for neuronal growth and synaptogenesis, but also reflects modified patterns of synaptic activities on auditory neurons. Thus, unilateral deafness directly results in an asymmetrical adaptation of the gap43 transcription between both sides of the auditory brain stem. This can be prevented by simple-patterned stimulation of the auditory nerve via a CI. PMID- 25686599 TI - [Medical examination: Preparation for ENT specialisation : Part 18]. PMID- 25686600 TI - Isotopic evidence for biological nitrogen fixation by molybdenum-nitrogenase from 3.2 Gyr. AB - Nitrogen is an essential nutrient for all organisms that must have been available since the origin of life. Abiotic processes including hydrothermal reduction, photochemical reactions, or lightning discharge could have converted atmospheric N2 into assimilable NH4(+), HCN, or NOx species, collectively termed fixed nitrogen. But these sources may have been small on the early Earth, severely limiting the size of the primordial biosphere. The evolution of the nitrogen fixing enzyme nitrogenase, which reduces atmospheric N2 to organic NH4(+), thus represented a major breakthrough in the radiation of life, but its timing is uncertain. Here we present nitrogen isotope ratios with a mean of 0.0 +/- 1.20/00 from marine and fluvial sedimentary rocks of prehnite-pumpellyite to greenschist metamorphic grade between 3.2 and 2.75 billion years ago. These data cannot readily be explained by abiotic processes and therefore suggest biological nitrogen fixation, most probably using molybdenum-based nitrogenase as opposed to other variants that impart significant negative fractionations. Our data place a minimum age constraint of 3.2 billion years on the origin of biological nitrogen fixation and suggest that molybdenum was bioavailable in the mid-Archaean ocean long before the Great Oxidation Event. PMID- 25686601 TI - An extremely high-altitude plume seen at Mars' morning terminator. AB - The Martian limb (that is, the observed 'edge' of the planet) represents a unique window into the complex atmospheric phenomena occurring there. Clouds of ice crystals (CO2 ice or H2O ice) have been observed numerous times by spacecraft and ground-based telescopes, showing that clouds are typically layered and always confined below an altitude of 100 kilometres; suspended dust has also been detected at altitudes up to 60 kilometres during major dust storms. Highly concentrated and localized patches of auroral emission controlled by magnetic field anomalies in the crust have been observed at an altitude of 130 kilometres. Here we report the occurrence in March and April 2012 of two bright, extremely high-altitude plumes at the Martian terminator (the day-night boundary) at 200 to 250 kilometres or more above the surface, and thus well into the ionosphere and the exosphere. They were spotted at a longitude of about 195 degrees west, a latitude of about -45 degrees (at Terra Cimmeria), extended about 500 to 1,000 kilometres in both the north-south and east-west directions, and lasted for about 10 days. The features exhibited day-to-day variability, and were seen at the morning terminator but not at the evening limb, which indicates rapid evolution in less than 10 hours and a cyclic behaviour. We used photometric measurements to explore two possible scenarios and investigate their nature. For particles reflecting solar radiation, clouds of CO2-ice or H2O-ice particles with an effective radius of 0.1 micrometres are favoured over dust. Alternatively, the plume could arise from auroral emission, of a brightness more than 1,000 times that of the Earth's aurora, over a region with a strong magnetic anomaly where aurorae have previously been detected. Importantly, both explanations defy our current understanding of Mars' upper atmosphere. PMID- 25686602 TI - Stem cells: Chasing blood. PMID- 25686603 TI - Axitinib effectively inhibits BCR-ABL1(T315I) with a distinct binding conformation. AB - The BCR-ABL1 fusion gene is a driver oncogene in chronic myeloid leukaemia and 30 50% of cases of adult acute lymphoblastic leukaemia. Introduction of ABL1 kinase inhibitors (for example, imatinib) has markedly improved patient survival, but acquired drug resistance remains a challenge. Point mutations in the ABL1 kinase domain weaken inhibitor binding and represent the most common clinical resistance mechanism. The BCR-ABL1 kinase domain gatekeeper mutation Thr315Ile (T315I) confers resistance to all approved ABL1 inhibitors except ponatinib, which has toxicity limitations. Here we combine comprehensive drug sensitivity and resistance profiling of patient cells ex vivo with structural analysis to establish the VEGFR tyrosine kinase inhibitor axitinib as a selective and effective inhibitor for T315I-mutant BCR-ABL1-driven leukaemia. Axitinib potently inhibited BCR-ABL1(T315I), at both biochemical and cellular levels, by binding to the active form of ABL1(T315I) in a mutation-selective binding mode. These findings suggest that the T315I mutation shifts the conformational equilibrium of the kinase in favour of an active (DFG-in) A-loop conformation, which has more optimal binding interactions with axitinib. Treatment of a T315I chronic myeloid leukaemia patient with axitinib resulted in a rapid reduction of T315I-positive cells from bone marrow. Taken together, our findings demonstrate an unexpected opportunity to repurpose axitinib, an anti-angiogenic drug approved for renal cancer, as an inhibitor for ABL1 gatekeeper mutant drug-resistant leukaemia patients. This study shows that wild-type proteins do not always sample the conformations available to disease-relevant mutant proteins and that comprehensive drug testing of patient-derived cells can identify unpredictable, clinically significant drug-repositioning opportunities. PMID- 25686604 TI - ATG14 promotes membrane tethering and fusion of autophagosomes to endolysosomes. AB - Autophagy, an important catabolic pathway implicated in a broad spectrum of human diseases, begins by forming double membrane autophagosomes that engulf cytosolic cargo and ends by fusing autophagosomes with lysosomes for degradation. Membrane fusion activity is required for early biogenesis of autophagosomes and late degradation in lysosomes. However, the key regulatory mechanisms of autophagic membrane tethering and fusion remain largely unknown. Here we report that ATG14 (also known as beclin-1-associated autophagy-related key regulator (Barkor) or ATG14L), an essential autophagy-specific regulator of the class III phosphatidylinositol 3-kinase complex, promotes membrane tethering of protein free liposomes, and enhances hemifusion and full fusion of proteoliposomes reconstituted with the target (t)-SNAREs (soluble N-ethylmaleimide-sensitive factor attachment protein receptors) syntaxin 17 (STX17) and SNAP29, and the vesicle (v)-SNARE VAMP8 (vesicle-associated membrane protein 8). ATG14 binds to the SNARE core domain of STX17 through its coiled-coil domain, and stabilizes the STX17-SNAP29 binary t-SNARE complex on autophagosomes. The STX17 binding, membrane tethering and fusion-enhancing activities of ATG14 require its homo oligomerization by cysteine repeats. In ATG14 homo-oligomerization-defective cells, autophagosomes still efficiently form but their fusion with endolysosomes is blocked. Recombinant ATG14 homo-oligomerization mutants also completely lose their ability to promote membrane tethering and to enhance SNARE-mediated fusion in vitro. Taken together, our data suggest an autophagy-specific membrane fusion mechanism in which oligomeric ATG14 directly binds to STX17-SNAP29 binary t-SNARE complex on autophagosomes and primes it for VAMP8 interaction to promote autophagosome-endolysosome fusion. PMID- 25686605 TI - Fundamental properties of unperturbed haematopoiesis from stem cells in vivo. AB - Haematopoietic stem cells (HSCs) are widely studied by HSC transplantation into immune- and blood-cell-depleted recipients. Single HSCs can rebuild the system after transplantation. Chromosomal marking, viral integration and barcoding of transplanted HSCs suggest that very low numbers of HSCs perpetuate a continuous stream of differentiating cells. However, the numbers of productive HSCs during normal haematopoiesis, and the flux of differentiating progeny remain unknown. Here we devise a mouse model allowing inducible genetic labelling of the most primitive Tie2(+) HSCs in bone marrow, and quantify label progression along haematopoietic development by limiting dilution analysis and data-driven modelling. During maintenance of the haematopoietic system, at least 30% or ~5,000 HSCs are productive in the adult mouse after label induction. However, the time to approach equilibrium between labelled HSCs and their progeny is surprisingly long, a time scale that would exceed the mouse's life. Indeed, we find that adult haematopoiesis is largely sustained by previously designated 'short-term' stem cells downstream of HSCs that nearly fully self-renew, and receive rare but polyclonal HSC input. By contrast, in fetal and early postnatal life, HSCs are rapidly used to establish the immune and blood system. In the adult mouse, 5-fluoruracil-induced leukopenia enhances the output of HSCs and of downstream compartments, thus accelerating haematopoietic flux. Label tracing also identifies a strong lineage bias in adult mice, with several-hundred-fold larger myeloid than lymphoid output, which is only marginally accentuated with age. Finally, we show that transplantation imposes severe constraints on HSC engraftment, consistent with the previously observed oligoclonal HSC activity under these conditions. Thus, we uncover fundamental differences between the normal maintenance of the haematopoietic system, its regulation by challenge, and its re-establishment after transplantation. HSC fate mapping and its linked modelling provide a quantitative framework for studying in situ the regulation of haematopoiesis in health and disease. PMID- 25686606 TI - Vertically transmitted faecal IgA levels determine extra-chromosomal phenotypic variation. AB - The proliferation of genetically modified mouse models has exposed phenotypic variation between investigators and institutions that has been challenging to control. In many cases, the microbiota is the presumed cause of the variation. Current solutions to account for phenotypic variability include littermate and maternal controls or defined microbial consortia in gnotobiotic mice. In conventionally raised mice, the microbiome is transmitted from the dam. Here we show that microbially driven dichotomous faecal immunoglobulin-A (IgA) levels in wild-type mice within the same facility mimic the effects of chromosomal mutations. We observe in multiple facilities that vertically transmissible bacteria in IgA-low mice dominantly lower faecal IgA levels in IgA-high mice after co-housing or faecal transplantation. In response to injury, IgA-low mice show increased damage that is transferable by faecal transplantation and driven by faecal IgA differences. We find that bacteria from IgA-low mice degrade the secretory component of secretory IgA as well as IgA itself. These data indicate that phenotypic comparisons between mice must take into account the non chromosomal hereditary variation between different breeders. We propose faecal IgA as one marker of microbial variability and conclude that co-housing and/or faecal transplantation enables analysis of progeny from different dams. PMID- 25686607 TI - Super-enhancers delineate disease-associated regulatory nodes in T cells. AB - Enhancers regulate spatiotemporal gene expression and impart cell-specific transcriptional outputs that drive cell identity. Super-enhancers (SEs), also known as stretch-enhancers, are a subset of enhancers especially important for genes associated with cell identity and genetic risk of disease. CD4(+) T cells are critical for host defence and autoimmunity. Here we analysed maps of mouse T cell SEs as a non-biased means of identifying key regulatory nodes involved in cell specification. We found that cytokines and cytokine receptors were the dominant class of genes exhibiting SE architecture in T cells. Nonetheless, the locus encoding Bach2, a key negative regulator of effector differentiation, emerged as the most prominent T-cell SE, revealing a network in which SE associated genes critical for T-cell biology are repressed by BACH2. Disease associated single-nucleotide polymorphisms for immune-mediated disorders, including rheumatoid arthritis, were highly enriched for T-cell SEs versus typical enhancers or SEs in other cell lineages. Intriguingly, treatment of T cells with the Janus kinase (JAK) inhibitor tofacitinib disproportionately altered the expression of rheumatoid arthritis risk genes with SE structures. Together, these results indicate that genes with SE architecture in T cells encompass a variety of cytokines and cytokine receptors but are controlled by a 'guardian' transcription factor, itself endowed with an SE. Thus, enumeration of SEs allows the unbiased determination of key regulatory nodes in T cells, which are preferentially modulated by pharmacological intervention. PMID- 25686608 TI - The double-degenerate, super-Chandrasekhar nucleus of the planetary nebula Henize 2-428. AB - The planetary nebula stage is the ultimate fate of stars with masses one to eight times that of the Sun (M(?)). The origin of their complex morphologies is poorly understood, although several mechanisms involving binary interaction have been proposed. In close binary systems, the orbital separation is short enough for the primary star to overfill its Roche lobe as the star expands during the asymptotic giant branch phase. The excess gas eventually forms a common envelope surrounding both stars. Drag forces then result in the envelope being ejected into a bipolar planetary nebula whose equator is coincident with the orbital plane of the system. Systems in which both stars have ejected their envelopes and are evolving towards the white dwarf stage are said to be double degenerate. Here we report that Henize 2-428 has a double-degenerate core with a combined mass of ~1.76M(?), which is above the Chandrasekhar limit (the maximum mass of a stable white dwarf) of 1.4M(?). This, together with its short orbital period (4.2 hours), suggests that the system should merge in 700 million years, triggering a type Ia supernova event. This supports the hypothesis of the double-degenerate, super-Chandrasekhar evolutionary pathway for the formation of type Ia supernovae. PMID- 25686609 TI - Evolution of Darwin's finches and their beaks revealed by genome sequencing. AB - Darwin's finches, inhabiting the Galapagos archipelago and Cocos Island, constitute an iconic model for studies of speciation and adaptive evolution. Here we report the results of whole-genome re-sequencing of 120 individuals representing all of the Darwin's finch species and two close relatives. Phylogenetic analysis reveals important discrepancies with the phenotype-based taxonomy. We find extensive evidence for interspecific gene flow throughout the radiation. Hybridization has given rise to species of mixed ancestry. A 240 kilobase haplotype encompassing the ALX1 gene that encodes a transcription factor affecting craniofacial development is strongly associated with beak shape diversity across Darwin's finch species as well as within the medium ground finch (Geospiza fortis), a species that has undergone rapid evolution of beak shape in response to environmental changes. The ALX1 haplotype has contributed to diversification of beak shapes among the Darwin's finches and, thereby, to an expanded utilization of food resources. PMID- 25686610 TI - X-domain of peptide synthetases recruits oxygenases crucial for glycopeptide biosynthesis. AB - Non-ribosomal peptide synthetase (NRPS) mega-enzyme complexes are modular assembly lines that are involved in the biosynthesis of numerous peptide metabolites independently of the ribosome. The multiple interactions between catalytic domains within the NRPS machinery are further complemented by additional interactions with external enzymes, particularly focused on the final peptide maturation process. An important class of NRPS metabolites that require extensive external modification of the NRPS-bound peptide are the glycopeptide antibiotics (GPAs), which include vancomycin and teicoplanin. These clinically relevant peptide antibiotics undergo cytochrome P450-catalysed oxidative crosslinking of aromatic side chains to achieve their final, active conformation. However, the mechanism underlying the recruitment of the cytochrome P450 oxygenases to the NRPS-bound peptide was previously unknown. Here we show, through in vitro studies, that the X-domain, a conserved domain of unknown function present in the final module of all GPA NRPS machineries, is responsible for the recruitment of oxygenases to the NRPS-bound peptide to perform the essential side-chain crosslinking. X-ray crystallography shows that the X-domain is structurally related to condensation domains, but that its amino acid substitutions render it catalytically inactive. We found that the X-domain recruits cytochrome P450 oxygenases to the NRPS and determined the interface by solving the structure of a P450-X-domain complex. Additionally, we demonstrated that the modification of peptide precursors by oxygenases in vitro--in particular the installation of the second crosslink in GPA biosynthesis--occurs only in the presence of the X-domain. Our results indicate that the presentation of peptidyl carrier protein (PCP)-bound substrates for oxidation in GPA biosynthesis requires the presence of the NRPS X-domain to ensure conversion of the precursor peptide into a mature aglycone, and that the carrier protein domain alone is not always sufficient to generate a competent substrate for external cytochrome P450 oxygenases. PMID- 25686612 TI - Structural basis of CpG and inhibitory DNA recognition by Toll-like receptor 9. AB - Innate immunity serves as the first line of defence against invading pathogens such as bacteria and viruses. Toll-like receptors (TLRs) are examples of innate immune receptors, which sense specific molecular patterns from pathogens and activate immune responses. TLR9 recognizes bacterial and viral DNA containing the cytosine-phosphate-guanine (CpG) dideoxynucleotide motif. The molecular basis by which CpG-containing DNA (CpG-DNA) elicits immunostimulatory activity via TLR9 remains to be elucidated. Here we show the crystal structures of three forms of TLR9: unliganded, bound to agonistic CpG-DNA, and bound to inhibitory DNA (iDNA). Agonistic-CpG-DNA-bound TLR9 formed a symmetric TLR9-CpG-DNA complex with 2:2 stoichiometry, whereas iDNA-bound TLR9 was a monomer. CpG-DNA was recognized by both protomers in the dimer, in particular by the amino-terminal fragment (LRRNT LRR10) from one protomer and the carboxy-terminal fragment (LRR20-LRR22) from the other. The iDNA, which formed a stem-loop structure suitable for binding by intramolecular base pairing, bound to the concave surface from LRR2-LRR10. This structure serves as an important basis for improving our understanding of the functional mechanisms of TLR9. PMID- 25686613 TI - Primary familial brain calcification: update on molecular genetics. AB - Primary familial brain calcification is a neuropsychiatric disorder with calcium deposits in the brain, especially in basal ganglia, cerebellum and subcortical white matter. The disease is characterized by a clinical heterogeneity, with a various combination of symptoms that include movement disorders and psychiatric disturbances; asymptomatic patients have been also reported. To date, three causative genes have been found: SLC20A2, PDGFRB and PDGFB. SLC20A2 gene codes for the 'sodium-dependent phosphate transporter 2' (PiT-2), a cell membrane transporters of inorganic phosphate, involved in Pi uptake by cells and maintenance of Pi body levels. Over 40 pathogenic variants of SLC20A2 have been reported, affecting the regulation of Pi homeostasis. It was hypothesized that SLC20A2 mutations cause brain calcification most likely through haploinsufficiency. PDGFRB encodes for the platelet-derived growth factor receptor-beta (PDGFRbeta), a cell-surface tyrosine-kinase (RTK) receptor that regulates cell proliferation, migration, survival and differentiation. PDGFB encodes for the 'platelet-derived growth factor beta' (PDGFbeta), the ligand of PDGFRbeta. The loss of function of PDGFRbeta and PDGFbeta could lead to the impairment of the pericytes function and blood brain barrier integrity, causing vascular and perivascular calcium accumulation. SLC20A2 accounts for about 40 % of familial form and 14 % of sporadic cases, while PDGFRB and PDGFB mutations are likely rare. However, approximately 50 % of patients are not genetically defined and there should be at least another causative gene. PMID- 25686614 TI - Paraneoplastic cerebellar degeneration with anti-CV2/CRMP5 antibodies and prostate adenocarcinoma. PMID- 25686615 TI - Static stretch affects neural stem cell differentiation in an extracellular matrix-dependent manner. AB - Neural stem and progenitor cell (NSPC) fate is strongly influenced by mechanotransduction as modulation of substrate stiffness affects lineage choice. Other types of mechanical stimuli, such as stretch (tensile strain), occur during CNS development and trauma, but their consequences for NSPC differentiation have not been reported. We delivered a 10% static equibiaxial stretch to NSPCs and examined effects on differentiation. We found static stretch specifically impacts NSPC differentiation into oligodendrocytes, but not neurons or astrocytes, and this effect is dependent on particular extracellular matrix (ECM)-integrin linkages. Generation of oligodendrocytes from NSPCs was reduced on laminin, an outcome likely mediated by the alpha6 laminin-binding integrin, whereas similar effects were not observed for NSPCs on fibronectin. Our data demonstrate a direct role for tensile strain in dictating the lineage choice of NSPCs and indicate the dependence of this phenomenon on specific substrate materials, which should be taken into account for the design of biomaterials for NSPC transplantation. PMID- 25686616 TI - Silybum marianum: Beyond Hepatoprotection. AB - Silybum marianum is a medicinal plant that has long been used as hepatoprotective remedy. It has been used for the treatment of numerous liver disorders characterized by functional impairment or degenerative necrosis. Its hepatoprotective activity is unique and acts in different ways, including antioxidant and anti-inflammatory activities, cell permeability regulator and membrane stabilizer, stimulation of liver regeneration and inhibition of deposition in collagen fibers, which may lead to cirrhosis. Most of documented data with Silybum marianum are about liver disorders; however, recently several beneficial properties on a wide variety of other disorders such as renal protection, hypolipidemic and anti-atherosclerosis activities, cardiovascular protection, prevention of insulin resistance, especially in cirrhotic patients, cancer, and Alzheimer prevention. It is also used as a food remedy. This review article aims to present different aspects of Silybum marianum, especially the data in recently published articles about its effects on different diseases, apart from presenting the aspects of its hepatoprotection. PMID- 25686617 TI - Analysis of Edg-Like LPA Receptor-Ligand Interactions. AB - The phospholipid derivative lysophosphatidic acid (LPA) serves as a signalling molecule through the activation of LPA receptors, which belong to the G-protein coupled receptors. From a pharmacological point of view, the ('EDG-like') LPA1-3 receptors have attracted much attention, therefore we have also been focusing in our study on these subtypes. The LPA1receptors are widely expressed in the human body; interestingly, LPA1 might have a role in the pathomechanism of obesity. In order to recognize key structural features of the molecular interactions of human LPA1with its agonists, we built up the 3D structure of the LPA1 through homology modeling. Next, LPA1 agonists and antagonists were docked into the model. The mode of binding and the interactions between ligands and key amino acids (R3.28 and Q3.29) were consistent with mutagenesis assays and previously published models, indicating that this model is able to discriminate high-affinity compounds and may be useful for the development of novel agonists of LPA1. Homology models were also constructed for LPA2 and LPA3. All available agonists with published EC50 values, antagonists with IC50 values and compounds with Ki values for either of LPA1, LPA2 or LPA3 were collected from the ChEMBL database and were docked into the corresponding model.Ourmodels for the LPA1-3 receptors can discriminate high-affinity compounds identified in silico HTS studies and may be useful for the development of novel agonistsof LPA receptors. With a better understanding of the differences between LPA1-3 receptors new, selective agonists and antagonist could be designed, which could be used in the therapy of various diseases with a better side-effect profile. PMID- 25686618 TI - The administration of pertussis vaccine to pregnant women was associated with a small increased risk of chorioamnionitis, but not an increased risk of hypertensive disorders or preterm birth. PMID- 25686619 TI - Breakfast skipping and the risk of type 2 diabetes: a meta-analysis of observational studies. AB - OBJECTIVE: Breakfast skipping has been reported to be associated with type 2 diabetes (T2D), but the results are inconsistent. No meta-analyses have applied quantitative techniques to compute summary risk estimates. The present study aimed to conduct a meta-analysis of observational studies summarizing the evidence on the association between breakfast skipping and the risk of T2D. DESIGN: Systematic review and meta-analysis. SETTING: Relevant studies were identified by a search of PubMed, Embase, Web of Science, China National Knowledge Infrastructure (CNKI) and SINOMED up to 9 August 2014. We also reviewed reference lists from retrieved articles. We included studies that reported risk estimates (including relative risks, odds ratios and hazard ratios) with 95% confidence intervals for the association between breakfast skipping and the risk of T2D. SUBJECTS: Eight studies involving 106,935 participants and 7419 patients with T2D were included in the meta-analysis. RESULTS: A pooled adjusted relative risk for the association between exposure to breakfast skipping and T2D risk was 1.21 (95% CI 1.12, 1.31; P=0.984; I2 =0.0%) in cohort studies and the pooled OR was 1.15 (95% CI, 1.05, 1.24; P=0.770; I2 =0.0%) in cross-sectional studies. Visual inspection of a funnel plot and Begg's test indicated no evidence of publication bias. CONCLUSIONS: Breakfast skipping is associated with a significantly increased risk of T2D. Regular breakfast consumption is potentially important for the prevention of T2D. PMID- 25686620 TI - The rise and fall of gluten! AB - Mankind has existed for 2.5 million years but only in the last 10,000 years have we been exposed to wheat. Wheat was first cultivated in the Fertile Crescent (South Western Asia) with a farming expansion that lasted from about 9000BC to 4000BC. Thus it could be considered that wheat (and gluten) is a novel introduction to man's diet! Prior to 1939 the rationing system had already been devised. This led to an imperative to try to increase agricultural production. Thus it was agreed in 1941 that there was a need to establish a Nutrition Society. The very roots of the society were geared towards necessarily increasing the production of wheat. This goal was achieved and by the end of the 20th century, global wheat output had expanded 5-fold. Perhaps as a result the epidemiology of coeliac disease (CD) or gluten sensitive enteropathy has changed. CD is a state of heightened immunological responsiveness to ingested gluten in genetically susceptible individuals. CD now affects 1 % or more of all adults, for which the treatment is a strict lifelong gluten-free diet. However, there is a growing body of evidence to show that a far greater proportion of individuals without coeliac disease are taking a gluten-free diet of their own volition. This clinical entity has been termed non-coeliac gluten sensitivity (NCGS), although the condition is fraught with complexities due to overlap with other gluten-based constituents that can also trigger similar clinical symptoms. This review will explore the relationship between gluten, the rising prevalence of modern coeliac disease, and the new entity of NCGS along with its associated uncertainties. PMID- 25686621 TI - How Schwann Cells Sort Axons: New Concepts. AB - Peripheral nerves contain large myelinated and small unmyelinated (Remak) fibers that perform different functions. The choice to myelinate or not is dictated to Schwann cells by the axon itself, based on the amount of neuregulin I-type III exposed on its membrane. Peripheral axons are more important in determining the final myelination fate than central axons, and the implications for this difference in Schwann cells and oligodendrocytes are discussed. Interestingly, this choice is reversible during pathology, accounting for the remarkable plasticity of Schwann cells, and contributing to the regenerative potential of the peripheral nervous system. Radial sorting is the process by which Schwann cells choose larger axons to myelinate during development. This crucial morphogenetic step is a prerequisite for myelination and for differentiation of Remak fibers, and is arrested in human diseases due to mutations in genes coding for extracellular matrix and linkage molecules. In this review we will summarize progresses made in the last years by a flurry of reverse genetic experiments in mice and fish. This work revealed novel molecules that control radial sorting, and contributed unexpected ideas to our understanding of the cellular and molecular mechanisms that control radial sorting of axons. PMID- 25686622 TI - Genetic and Developmental Perspective of Language Abnormality in Autism and Schizophrenia: One Disease Occurring at Different Ages in Humans? AB - Language and communication through it are two of the defining features of normally developed human beings. However, both these functions are often impaired in autism and schizophrenia. In the former disorder, the problem usually emerges in early childhood (~2 years old) and typically includes a lack of communication. In the latter condition, the language problems usually occur in adolescence and adulthood and presents as disorganized speech. What are the fundamental mechanisms underlying these two disorders? Is there a shared genetic basis? Are the traditional beliefs about them true? Are there any common strategies for their prevention and management? To answer these questions, we searched PubMed by using autism, schizophrenia, gene, and language abnormality as keywords, and we reconsidered the basic concepts about these two diseases or syndromes. We found many functional genes, for example, FOXP2, COMT, GABRB3, and DISC1, are actually implicated in both of them. After observing the symptoms, genetic correlates, and temporal progression of these two disorders as well as their relationships more carefully, we now infer that the occurrence of these two diseases is likely developmentally regulated via interaction between the genome and the environment. Furthermore, we propose a unified view of autism and schizophrenia: a single age dependently occurred disease that is newly named as Systemic Integral Disorder: if occurring in children before age 2, it is called autism; if in adolescence or a later age, it is called schizophrenia. PMID- 25686624 TI - Eyes on crowding: crowding is preserved when responding by eye and similarly affects identity and position accuracy. AB - Peripheral vision guides recognition and selection of targets for eye movements. Crowding-a decline in recognition performance that occurs when a potential target is surrounded by other, similar, objects-influences peripheral object recognition. A recent model study suggests that crowding may be due to increased uncertainty about both the identity and the location of peripheral target objects, but very few studies have assessed these properties in tandem. Eye tracking can integrally provide information on both the perceived identity and the position of a target and therefore could become an important approach in crowding studies. However, recent reports suggest that around the moment of saccade preparation crowding may be significantly modified. If these effects were to generalize to regular crowding tasks, it would complicate the interpretation of results obtained with eye tracking and the comparison to results obtained using manual responses. For this reason, we first assessed whether the manner by which participants responded-manually or by eye-affected their performance. We found that neither recognition performance nor response time was affected by the response type. Hence, we conclude that crowding magnitude was preserved when observers responded by eye. In our main experiment, observers made eye movements to the location of a tilted Gabor target while we varied flanker tilt to manipulate target-flanker similarity. The results indicate that this similarly affected the accuracy of peripheral recognition and saccadic target localization. Our results inform about the importance of both location and identity uncertainty in crowding. PMID- 25686623 TI - Broad bandwidth of perceptual learning in second-order contrast modulation detection. AB - Comparing characteristics of learning in first- and second-order systems might inform us about different neural plasticity in the two systems. In the current study, we aim to determine the properties of perceptual learning in second-order contrast modulation detection in normal adults. We trained nine observers to detect second-order gratings at an envelope modulation spatial frequency of 8 cycles/ degrees with their nondominant eyes. We found that, although training generated the largest improvements around the trained frequency, contrast sensitivity over a broad range of spatial frequencies also improved, with a 4.09 octave bandwidth of perceptual learning, exhibiting specificity to the trained spatial frequency as well as a relatively large degree of generalization. The improvements in the modulation sensitivity function (MSF) were not significantly different between the trained and untrained eyes. Furthermore, training did not significantly change subjects' ability in detecting first-order gratings. Our results suggest that perceptual learning in second-order detection might occur at the postchannel level in binocular neurons, possibly through reducing the internal noise of the visual system. PMID- 25686625 TI - Romancing the boundary: client masculinities in the Chinese sex industry. AB - This paper draws on 24 in-depth interviews and 2 focus-group discussions conducted since 2012 with Hong Kong heterosexual men who buy sex in order to examine men's level of physical and emotional engagement with sex workers under two dominant sexual scripts in contemporary Hong Kong. Torn between companionate sexuality, with its companionate model of relationships, and recreational sexuality, with its promiscuous model of sexual pleasure, Hong Kong male clients seek to satisfy their sexual and affective needs through commercial sexual relationships. The term (meaning 'chicken worm', connoting a 'McSex' form of masculinity) refers to those men who seek impersonal sexual release with as many women as they wish, while the term (meaning 'sunken boat' and connoting a 'Titanic' form of masculinity) refers to those men who seek an intense level of emotional intimacy with sex workers. Between these two contrasting types, the majority of respondents fall into a form of 'bounded' masculinity characteristic of men who emphasise control and balance by seeking emotionally responsive women in a time-bound romance. By comparing clients' variations in the level of physical and emotional engagement with sex workers, this paper seeks to understand individual differences in client types and offers a new understanding of Chinese male sexuality and relationship formation, and the corresponding health risks (e.g., sexual, emotional) associated with each type. PMID- 25686626 TI - The Role of PB1 Domain Proteins in Endothelial Cell Dysfunction and Disease. AB - SIGNIFICANCE: There are a limited number of proteins containing the Phox-Bem1 (PB1) protein interaction domain, and almost all of them play some role in endothelial cell (EC) function, health, and homeostasis. RECENT ADVANCES: Most of these proteins have been shown to physically interact through PB1-PB1 binding and, as such, are linked together to form complexes that are responsive to hemodynamic force. These complexes range from redox regulation to inflammation to autophagy and back, and they employ multiple feedback mechanisms that are reliant on PB1 domain proteins. CRITICAL ISSUES: Pathologic roles for PB1 domain containing proteins have been demonstrated in multiple diseases, including vascular disease, cancer, liver disease, and myriad other concerns. Findings cited in this review show that dimerization of PB1 proteins exerts novel effects on EC function that may be important in multiple cardiovascular diseases, including atherosclerosis, thrombosis, inflammation, and hypertension. FUTURE DIRECTIONS: As mechanistic understanding of the component pathways (redox regulation, cell polarity, inflammation, atheroprotection, and autophagy) is continually increasing, the larger picture of how these pathways interact with one another is evolving rapidly. We can now evaluate the PB1 domain proteins as a family in the context of multiple phenotypic readouts in EC function as well as evaluate them as drug targets against disease. PMID- 25686627 TI - The performance of a biological aerated filter loaded with a novel non-sintered fly-ash ceramsite as pretreatment for dual membrane processes. AB - This work focused on wastewater reclamation of secondary treated ethylene chemical plant effluent, which contained high conductivity and high organic concentration. To reduce the cost and improve operation stability, a biological aerated filter-ultrafiltration-reverse osmosis (BAF-UF-RO) process was proposed. The feasibility and effectiveness of BAF loaded with a novel non-sintered fly-ash ceramsite (NSFC) as a pretreatment method of a dual membrane system were investigated in detail. The results showed that the CODCr, turbidity, NH3-N and the silt density index (SDI) in the effluent from the BAF were reduced to 24.2 mg/L, 12.17 NTU, 0.42 mg/L and 7.52, respectively, and most of the organic compounds were biodegraded. The BAF-UF-RO process was stable with a recovery rate of 75%, and the desalination rate was up to about 97.5%. Compared with the UF-RO process, the operating pressure and backwash frequency decreased from 1.12-1.26 Mpa and 3 times/d to 0.94-0.98 Mpa and 2 times/d, respectively. After continuous operation for four months, there appeared to be no need for chemical cleaning of the RO membrane. Moreover, the analysis results of X-ray photoelectron spectroscopy and Fourier transform infrared spectroscopy proved that there was only slight membrane fouling, which was mainly colloidal blocking caused by refractory organic compound. PMID- 25686628 TI - A new anthraquinone from Morinda elliptica Ridl. AB - A new anthraquinone, morinquinone, together with 18 known anthraquinones were isolated from the stems of Morinda elliptica Ridl. Their structures were elucidated on the basis of spectroscopic data. They each showed weak inhibitory activity against a susceptible strain of Staphylococcus aureus and a methicillin resistant S. aureus. Damnacanthal was effective against Microsporum gypseum (MIC 1 MUg/mL). Lucidin was active against Entamoeba histolytica (MIC 31.25 MUg/mL) and Giardia intestinalis (MIC 7.8 MUg/mL). PMID- 25686629 TI - Formation of ripples in atomically thin MoS2 and local strain engineering of electrostatic properties. AB - Ripple is a common deformation in two-dimensional materials due to localized strain, which is expected to greatly influence the physical properties. The effects of the ripple deformation in the MoS2 layer on their physics, however, are rarely addressed experimentally. We here grow atomically thin MoS2 nanostructures by employing a vapor phase deposition method without any catalyst and observed the ripples in MoS2 nanostructures. The MoS2 ripples exhibit quasi periodical ripple structures in the MoS2 surface. The heights of the ripples vary from several angstroms to tens of nanometers and the wavelength is in the range of several hundred nanometers. The growth mechanism of rippled MoS2 nanostructures is elucidated. We have also simultaneously investigated the electrostatic properties of MoS2 ripples by using Kelvin probe force microscopy, which shows inhomogeneous surface potential and charge distributions for MoS2 ripple nanostructures with different local strains. PMID- 25686630 TI - Exercise pathophysiology and sildenafil effects in chronic thromboembolic pulmonary hypertension. AB - OBJECTIVES: Symptoms in patients with chronic thromboembolic pulmonary hypertension (CTEPH) predominantly occur during exercise, while haemodynamic assessment is generally performed at rest. We hypothesised that exercise imaging of RV function would better explain exercise limitation and the acute effects of pulmonary vasodilator administration than resting measurements. METHODS: Fourteen patients with CTEPH and seven healthy control subjects underwent cardiopulmonary testing to determine peak exercise oxygen consumption (VO2peak) and ventilatory equivalent for carbon dioxide (VE/VCO2) at the anaerobic threshold. Subsequently, cardiac MRI was performed at rest and during supine bicycle exercise with simultaneous invasive measurement of mean pulmonary arterial pressure (mPAP) before and after sildenafil. RESULTS: During exercise, patients with CTEPH had a greater increase in the ratio of mPAP relative to cardiac output (CO) than controls (6.7 (5.1-8.7) vs 0.94 (0.86-1.8) mm Hg/L/min; p < 0.001). Stroke volume index (SVi) and RVEF increased during exercise in controls, but not in patients with CTEPH (interaction p < 0.001). Sildenafil decreased the mPAP/CO slope and increased SVi and RVEF in patients with CTEPH (p < 0.05) but not in controls. In patients with CTEPH, RVEF reserve correlated moderately with VO2peak (r = 0.60; p = 0.030) and VE/VCO2 (r = -0.67; p = 0.012). By contrast, neither VO2peak nor VE/VCO2 correlated with resting RVEF. CONCLUSIONS: Exercise measures of RV function explain much of the variance in the exercise capacity of patients with CTEPH while resting measures do not. Sildenafil increases SVi during exercise in patients with CTEPH, but not in healthy subjects. PMID- 25686631 TI - Investigation of patients presenting with chest pain. PMID- 25686632 TI - Evaluation of the association of sleep apnea-related systemic inflammation with CRP, ESR, and neutrophil-to-lymphocyte ratio. AB - BACKGROUND: Obstructive sleep apnea syndrome (OSAS) is characterized by cyclic episodes of hypoxemia and reoxygenation. It has been suggested that OSAS is associated with chronic inflammation within the microvasculature. This low-grade inflammation may play a role in the pathophysiology of OSAS-related comorbidities. Evaluation of the inflammatory markers may predict the degree of the systemic inflammation and this may be a prognostic factor for future adverse events such as cardiovascular risks. Proinflammatory cytokines have been extensively studied in sleep-disordered breathing. Neutrophil-to-lymphocyte ratio is a recently described indicator of systemic inflammation, but it has not been studied in OSAS patients. In this study we aimed to evaluate the easily measurable parameters of systemic inflammation in these patients. We conducted this study to examine the association among OSAS and C- reactive protein, erythrocyte sedimentation rate, and neutrophil-to-lymphocyte ratio. MATERIAL AND METHODS: OSAS patients who underwent overnight polysomnography were studied retrospectively. They were divided into 4 groups: control, mild, moderate, and severe OSAS patients. Blood test results and inflammatory markers were compared between the groups. One-way ANOVA and Kruskall-Wallis H test were used for statistical analysis. RESULTS: A total of 147 patients were included in the study. No differences in evaluated inflammatory markers were observed among the 4 groups. CONCLUSIONS: Evaluation of the OSAS-related systemic inflammation is not likely to be possible by CRP, ESR, or neutrophil-to-lymphocyte ratio measurements. These markers do not seem to be associated with the degree of the upper airway obstruction. PMID- 25686633 TI - Two colors of light are needed to break bonds and release small molecules from the surface of SiO2-Au core-shell nanoparticles. AB - The photothermal effect is not able to break bonds and release small molecules from the surface of SiO2-Au core-shell nanoparticles unless the nanosystem is first exposed to visible light. Only after this light triggers the ring-opening reaction of dithienylethene chromophores attached to the surface of the nanoparticles can the heat generated by the NIR light induce reverse Diels-Alder reactions. PMID- 25686634 TI - Unpolarized and polarized Raman spectroscopy of nylon-6 polymorphs: a quantum chemical approach. AB - Exploiting the very recent potentialities of state-of-the-art quantum chemical simulations of crystalline solids, unpolarized Raman spectra of alpha and gamma polymorphs of Nylon-6 obtained through periodic density functional theory calculations are presented for the first time. The computed spectra are compared with the experimental spectra reported in the literature and allow a detailed interpretation to be proposed of the patterns observed, identifying unambiguous Raman marker bands of the different phases. The calculations of single crystal directional intensities gave the further possibility to predict the polarization properties of the Raman spectra of these polymorphs: considering in particular the alpha phase, polarized Raman spectra have been computed and showed a very good agreement with measurements previously reported for uniaxially oriented samples. PMID- 25686635 TI - Folding RaCe: a robust method for predicting changes in protein folding rates upon point mutations. AB - MOTIVATION: Protein engineering methods are commonly employed to decipher the folding mechanism of proteins and enzymes. However, such experiments are exceedingly time and resource intensive. It would therefore be advantageous to develop a simple computational tool to predict changes in folding rates upon mutations. Such a method should be able to rapidly provide the sequence position and chemical nature to modulate through mutation, to effect a particular change in rate. This can be of importance in protein folding, function or mechanistic studies. RESULTS: We have developed a robust knowledge-based methodology to predict the changes in folding rates upon mutations formulated from amino and acid properties using multiple linear regression approach. We benchmarked this method against an experimental database of 790 point mutations from 26 two-state proteins. Mutants were first classified according to secondary structure, accessible surface area and position along the primary sequence. Three prime amino acid features eliciting the best relationship with folding rates change were then shortlisted for each class along with an optimized window length. We obtained a self-consistent mean absolute error of 0.36 s(-1) and a mean Pearson correlation coefficient (PCC) of 0.81. Jack-knife test resulted in a MAE of 0.42 s(-1) and a PCC of 0.73. Moreover, our method highlights the importance of outlier(s) detection and studying their implications in the folding mechanism. AVAILABILITY AND IMPLEMENTATION: A web server 'Folding RaCe' has been developed and is available at http://www.iitm.ac.in/bioinfo/proteinfolding/foldingrace.html. CONTACT: gromiha@iitm.ac.in SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25686636 TI - Characterizing spatial distributions of astrocytes in the mammalian retina. AB - MOTIVATION: In addition to being involved in retinal vascular growth, astrocytes play an important role in diseases and injuries, such as glaucomatous neuro degeneration and retinal detachment. Studying astrocytes, their morphological cell characteristics and their spatial relationships to the surrounding vasculature in the retina may elucidate their role in these conditions. RESULTS: Our results show that in normal healthy retinas, the distribution of observed astrocyte cells does not follow a uniform distribution. The cells are significantly more densely packed around the blood vessels than a uniform distribution would predict. We also show that compared with the distribution of all cells, large cells are more dense in the vicinity of veins and toward the optic nerve head whereas smaller cells are often more dense in the vicinity of arteries. We hypothesize that since veinal astrocytes are known to transport toxic metabolic waste away from neurons they may be more critical than arterial astrocytes and therefore require larger cell bodies to process waste more efficiently. AVAILABILITY AND IMPLEMENTATION: A 1/8th size down-sampled version of the seven retinal image mosaics described in this article can be found on BISQUE (Kvilekval et al., 2010) at http://bisque.ece.ucsb.edu/client_service/view?resource=http://bisque.ece.ucsb.ed /data_service/dataset/6566968. PMID- 25686637 TI - TarPred: a web application for predicting therapeutic and side effect targets of chemical compounds. AB - MOTIVATION: Discovering the relevant therapeutic targets for drug-like molecules, or their unintended 'off-targets' that predict adverse drug reactions, is a daunting task by experimental approaches alone. There is thus a high demand to develop computational methods capable of detecting these potential interacting targets efficiently. RESULTS: As biologically annotated chemical data are becoming increasingly available, it becomes feasible to explore such existing knowledge to identify potential ligand-target interactions. Here, we introduce an online implementation of a recently published computational model for target prediction, TarPred, based on a reference library containing 533 individual targets with 179 807 active ligands. TarPred accepts interactive graphical input or input in the chemical file format of SMILES. Given a query compound structure, it provides the top ranked 30 interacting targets. For each of them, TarPred not only shows the structures of three most similar ligands that are known to interact with the target but also highlights the disease indications associated with the target. This information is useful for understanding the mechanisms of action and toxicities of active compounds and can provide drug repositioning opportunities. AVAILABILITY AND IMPLEMENTATION: TarPred is available at: http://www.dddc.ac.cn/tarpred. PMID- 25686638 TI - RAPTR-SV: a hybrid method for the detection of structural variants. AB - MOTIVATION: Identification of structural variants (SVs) in sequence data results in a large number of false positive calls using existing software, which overburdens subsequent validation. RESULTS: Simulations using RAPTR-SV and other, similar algorithms for SV detection revealed that RAPTR-SV had superior sensitivity and precision, as it recovered 66.4% of simulated tandem duplications with a precision of 99.2%. When compared with calls made by Delly and LUMPY on available datasets from the 1000 genomes project, RAPTR-SV showed superior sensitivity for tandem duplications, as it identified 2-fold more duplications than Delly, while making ~85% fewer duplication predictions. AVAILABILITY AND IMPLEMENTATION: RAPTR-SV is written in Java and uses new features in the collections framework in the latest release of the Java version 8 language specifications. A compiled version of the software, instructions for usage and test results files are available on the GitHub repository page: https://github.com/njdbickhart/RAPTR-SV. CONTACT: derek.bickhart@ars.usda.gov. PMID- 25686639 TI - Evidence of nutrition transition in Southern Africa. AB - Nutrition transition is characterised by shift to highly refined diets high in fat, salt and caloric sweeteners and low in fibre in rapidly growing economies. Dietary shifts occur almost concurrently with demographic and epidemiologic shifts, urbanisation and industrialisation and together contribute to increased prevalence of nutrition related (NR)-non-communicable disease (NCR). The emergence of nutrition transition in Southern Africa countries (SAC) was examined using anthropometric, NCD prevalence, and food consumption data. The findings reveal growing prevalence of overweight and obesity (OWOB) across SAC, with national prevalence estimated between 30 and 60 % in all but two SAC. Overweight prevalence in excess of 60 % has been reported in some sub-population groups. Hypertension prevalence of at least 30 % has also been reported. Further, the prevalence of OWOB and hypertension in many SAC exceeds that of HIV and is often at par with stunting in children. NCD are equally serious public health problems as stunting and HIV. Collectively, NR-NCD explain 20-31 % of mortality for Botswana, South Africa, Swaziland, Mozambique and Zambia. At least 72 % of adults in SAC have fewer servings of fruit and vegetable servings daily than recommended. Additionally, adults in SAC do poorly in physical activity; 31-75 % do not exercise regularly. Not surprisingly, 15-40 % of adults in SAC have at least three risk factors of CVD. SAC are grappling with NR-NCD which threaten to surpass infectious diseases burden. SAC are at various levels in interventions for moving their populations to stage 5, but there is room for much improvement. PMID- 25686640 TI - A systematic review on empowerment for healthy nutrition in health promotion. AB - OBJECTIVE: The present review aimed to identify and synthesize studies that used an empowerment approach within the field of healthy nutrition. DESIGN: A systematic review was conducted. Studies were identified by database searching (PubMed, PsycINFO, Web of Science and Psyndex). Searching, selecting and reporting were done according to the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) Statement. SETTING: Health promotion including the subject of healthy nutrition. SUBJECTS: Individuals from non clinical populations. RESULTS: A total of 1226 studies were screened for eligibility, eight studies were finally included. Three studies used the empowerment approach within a qualitative research paradigm and five studies within (quasi-) experimental intervention studies. Heterogeneity in settings, samples and evaluation methods was high. Most studies referred to the key message of empowerment, i.e. taking control over one's own life. However, the ways in which this key message was implemented in the interventions differed considerably. CONCLUSIONS: The number of studies included was very low. Furthermore, most studies had some limitations in terms of reporting how the empowerment approach was actually applied. The empowerment approach still seems to be unfamiliar within the field of healthy nutrition. PMID- 25686641 TI - Managing a Multisite Academic-Private Radiology Practice Reading Environment: Impact of IT Downtimes on Enterprise Efficiency. AB - PURPOSE: The aim of this study was to assess whether the complex radiology IT infrastructures needed for large, geographically diversified, radiology practices are inherently stable with respect to system downtimes, and to characterize the nature of the downtimes to better understand their impact on radiology department workflow. METHODS: All radiology IT unplanned downtimes over a 12-month period in a hybrid academic-private practice that performs all interpretations in-house (no commercial "nighthawk" services) for approximately 900,000 studies per year, originating at 6 hospitals, 10 outpatient imaging centers, and multiple low volume off-hours sites, were logged and characterized using 5 downtime metrics: duration, etiology, failure type, extent, and severity. RESULTS: In 12 consecutive months, 117 unplanned downtimes occurred with the following characteristics: duration: median time = 3.5 hours with 34% <1.5 hours and 30% >12 hours; etiology: 87% were due to software malfunctions, and 13% to hardware malfunctions; failure type: 88% were transient component failures, 12% were complete component failures; extent: all sites experienced downtimes, but downtimes were always localized to a subset of sites, and no system-wide downtimes occurred; severity (impact on radiologist workflow): 47% had minimal impact, 50% moderate impact, and 3% severe impact. CONCLUSIONS: In the complex radiology IT system that was studied, downtimes were common; they were usually a result of transient software malfunctions; the geographic extent was always localized rather than system wide; and most often, the impacts on radiologist workflow were modest. PMID- 25686642 TI - The risks of innovation in health care. AB - Innovation in health care creates risks that are unevenly distributed. An evolutionary analogy using species to represent business models helps categorize innovation experiments and their risks. This classification reveals two qualitative categories: early and late diversification experiments. Early diversification has prolific innovations with high risk because they encounter a "decimation" stage, during which most experiments disappear. Participants face high risk. The few decimation survivors can be sustaining or disruptive according to Christensen's criteria. Survivors enter late diversification, during which they again expand, but within a design range limited to variations of the previous surviving designs. Late diversifications carry lower risk. The exception is when disruptive survivors "diversify," which amplifies their disruption. Health care and radiology will experience both early and late diversifications, often simultaneously. Although oversimplifying Christensen's concepts, early diversifications are likely to deliver disruptive innovation, whereas late diversifications tend to produce sustaining innovations. Current health care consolidation is a manifestation of late diversification. Early diversifications will appear outside traditional care models and physical health care sites, as well as with new science such as molecular diagnostics. They warrant attention because decimation survivors will present both disruptive and sustaining opportunities to radiology. Radiology must participate in late diversification by incorporating sustaining innovations to its value chain. Given the likelihood of disruptive survivors, radiology should seriously consider disrupting itself rather than waiting for others to do so. Disruption entails significant modifications of its value chain, hence, its business model, for which lessons may become available from the pharmaceutical industry's current simultaneous experience with early and late diversifications. PMID- 25686643 TI - Goblet cell appendiceal tumors--management dilemmas and long-term outcomes. AB - BACKGROUND: Appendiceal Goblet cell tumors (GCTs) are clinically more aggressive, and have a worse outcome than midgut neuroendocrine tumors (mNETs). Guidelines for management of GCTs are limited. METHODS: A retrospective case-study analysis was performed in patients with a diagnosis of GCT, confirmed on histological review. Patients were evaluated clinically, biochemically, and radiologically. RESULTS: 48 patients were identified (TNM stage I-II: 27, stage III: 15, stage IV: 6). Median follow-up was 44 months and was complete in all patients. 68.8% presented with acute appendicitis. 44/48 patients had initial appendectomy, followed by prophylactic right hemicolectomy in 41. 10/48 patients had recurrent disease [median time to recurrence 28 months (range 4-159)]. Of those, 9 received systemic chemotherapy (FOLFOX/FOLFIRI), which was also given in 5/48 patients with disseminated disease at diagnosis. Partial response, stable disease and disease progression was noted in 22%, 22% and 56%, respectively. Adjuvant chemotherapy was also administered in 9/48 patients with stage III disease after right hemicolectomy, however in 3/9 the disease recurred. Median progression/disease-free-survival was 44 months (range 3-159) and overall 5-year survival rate was 41.6%. CONCLUSIONS: The clinical behaviour of GCTs is more similar to colorectal adenocarcinomas than to NETs. A prophylactic right hemicolectomy is recommended to reduce the risk of recurrence. Systemic chemotherapy, using colorectal adenocarcinoma regimens, is indicated for advanced or recurrent disease and has encouraging results. Prospective studies are needed to define the role of adjuvant chemotherapy and the optimal chemotherapy regimen. PMID- 25686645 TI - Co-existence of JAK2 V617F and CALR mutations in primary myelofibrosis. PMID- 25686644 TI - Two courses of four weekly infusions of rituximab with or without interferon alpha2a: final results from a randomized phase III study in symptomatic indolent B-cell lymphomas. AB - Patients with advanced CD20 + indolent lymphoma, requiring therapy, were randomized to rituximab (four weekly infusions of 375 mg/m(2)) or to rituximab combined with 5 weeks of interferon-alpha2a (IFN-alpha2a) (3-4.5 MIU daily) as priming. Responding patients were eligible for a second cycle with the same allocated treatment. In total, 156 patients were randomized to rituximab and 157 to rituximab + IFN-alpha2a. In the intention-to treat (ITT) population, 244 patients (78%) responded to cycle 1. After a second cycle the complete remission/complete remission unconfirmed (CR/CRu) rate was 41% with the combination versus 24% with monotherapy (p = 0.005). The median time to treatment failure (primary endpoint) in ITT patients was 28 vs. 21.5 months, respectively (p = 0.302). After a long median follow-up (61 months), 33% (42% of patients responding to cycle 1) were still failure-free with an overall survival rate of 88% and with no difference between the treatment groups. The trial was registered at ClinicalTrials.gov Identifier: NCT01609010. PMID- 25686646 TI - A unique presentation of unilateral pleural effusion in a patient with a high grade plasma cell neoplasm. PMID- 25686647 TI - Impact of transplant eligibility and availability of a human leukocyte antigen identical matched related donor on outcome of older patients with acute lymphoblastic leukemia. AB - The role of allogeneic hematopoietic cell transplant (allo-HCT) in elderly patients with acute lymphoblastic leukemia (ALL) is unclear. We conducted a prospective study including 110 homogeneously treated patients with ALL aged 50 70 years. Their outcomes were analyzed by intention-to-treat on a donor-versus-no donor basis. Fifty-five patients (50%) underwent human leukocyte antigen (HLA) typing and were considered potential allo-HCT candidates, although only 25 (23%) eventually received an allo-HCT. Among potential allo-HCT candidates, patients with (n = 28) and without (n = 27) an HLA-identical sibling showed similar leukemia-free survival, overall survival (OS) and relapse risk, and the only variable associated with a better outcome was achievement of first complete remission (CR1) after induction therapy. Among the 25 patients who actually received an allo-HCT, the 4-year non-relapse mortality and OS were 42% (95% confidence interval 31-53%) and 37% (95% confidence interval 27-47%), respectively. In conclusion, having an HLA-identical sibling donor was not associated with a better outcome in patients with ALL aged 50-70 years. PMID- 25686648 TI - Prognostic role of peripheral blood lymphocyte/monocyte ratio at diagnosis in diffuse large B-cell lymphoma: a meta-analysis. AB - To evaluate the prognostic value of the absolute lymphocyte count/absolute monocyte count ratio (ALC/AMC ratio) at diagnosis in diffuse large B-cell lymphoma (DLBCL), we performed a meta-analysis of published studies that provided survival information with reference to the ALC/AMC ratio at diagnosis. Nine studies covering a total of 4198 subjects were included in this analysis. The summary hazard ratios of low ALC/AMC ratio for overall survival were 2.00 (p = 0.000) in the population that received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) and 1.12 (p = 0.479) in the population that received CHOP. The corresponding ratios for event-free survival and progression free survival were 1.93 (p = 0.000) and 2.31 (p = 0.000) in the population that received R-CHOP. These results may justify risk-adapted therapeutic strategies for patients with DLBCL treated with R-CHOP to account for the ALC/AMC ratio at diagnosis. PMID- 25686649 TI - Two new eudesmane-type glucopyranosides from the fruits of Daucus carota L. AB - Two new eudesmane-type glucopyranosides have been isolated from the fruits of Daucus carota L. On the basis of their spectroscopic and chemical evidence, the new compounds were elucidated as daucucarotol-10-O-beta-D-glucopyranoside (1) and decahydro-7-[(2-O-beta-D-glucopyranosyl)-isopropyl]-1beta,4aalpha-dimethyl (1alpha,4alpha,8abeta)-naphthalenetriol (2). Compounds 1 and 2 showed moderate antitumour activity against human ECA-109 and gave IC50 values of 23.22 and 26.76 MUM, respectively. PMID- 25686650 TI - Pulmonary oil micro-embolism (POME) syndrome: a review and summary of a large case series. AB - The use of steroid compounds formulated in oil for depot injection can be associated with acute pulmonary reactions characterized primarily by cough, but sometimes with other associated symptoms. The pathophysiology of these reactions remains unclear, although they are reported in the literature as 'POMEs' or pulmonary oil micro-embolism events. We report on a large case series and propose a case definition for these events. These events can raise significant concern even though they are often self-limited. It is hoped that clinicians will recognize these events more readily and be able to inform patients better, and that future reports and assessments can benefit from our proposed case definition. PMID- 25686651 TI - Critical analysis of common canister programs: a review of cross-functional considerations and health system economics. AB - Respiratory inhalers constitute a large percentage of hospital pharmacy expenditures. Metered-dose inhaler (MDI) canisters usually contain enough medication to last 2 to 4 weeks, while the average hospital stay for acute hospitalizations of respiratory illnesses is only 4-5 days. Hospital pharmacies are often unable to operationalize relabeling of inhalers at discharge to meet regulatory requirements. This dilemma produces drug wastage. The common canister (CC) approach is a method some hospitals implemented in an effort to minimize the costs associated with this issue. The CC program uses a shared inhaler, an individual one-way valve holding chamber, and a cleaning protocol. This approach has been the subject of considerable controversy. Proponents of the CC approach reported considerable cost savings to their institutions. Opponents of the CC approach are not convinced the benefits outweigh even a minimal risk of cross contamination since adherence to protocols for hand washing and disinfection of the MDI device cannot be guaranteed to be 100% (pathogens from contaminated devices can enter the respiratory tract through inhalation). Other cost containment strategies, such as unit dose nebulizers, may be useful to realize similar reductions in pharmacy drug costs while minimizing the risks of nosocomial infections and their associated medical costs. The CC strategy may be appropriate for some hospital pharmacies that face budget constraints, but a full evaluation of the risks, benefits, and potential costs should guide those who make hospital policy decisions. PMID- 25686652 TI - [Implementation of the COBAS Taqman HIV-1 Test, v1.0 for vertical transmission diagnosis]. AB - Vertical transmission is the main route of HIV infection in childhood. Because of the persistence of maternal HIV antibodies, virologic assays that directly detect HIV are required to diagnose HIV infection in infants younger than 18 months of age. The sensitivity of HIV RNA/DNA assays increases as the child becomes older. These tests have specificity values greater than 95%. The aim of this study was to evaluate the performance of the COBAS Taqman HIV-1 Test, v1.0 assay (Roche) and its concordance with a Multiplex Nested-PCR. Of 341 samples processed, 15 were positive and 326 negative by both methods. Sensitivity and specificity overall values for the viral load assay were 88.2% and 100%, respectively. Our results indicate that the COBAS Taqman assay evaluated could be used as an alternative method to diagnose HIV congenital infection. PMID- 25686653 TI - An atypical caseof Churg-Strauss syndrome. PMID- 25686654 TI - Immediate single-stage reconstruction of complex frontofaciobasal injuries: Part II. AB - OBJECTIVES: The purpose of this prospective study was to identify selection criteria for immediate single-stage reconstruction in patients with severe complex craniofacial trauma to improve their functional outcome and reduce complications. PATIENTS AND METHODS: In this series, 24 new patients (16 men and 8 women) were added to our previous group (26 patients) with an age range from 10 to 55 years with mean of 26 years and Glasgow Coma Scale scores of 5-13; all patients had a combined single-stage repair of their complex craniofacial injuries within 6 h of their admission. We added some modifications to our standard technique using three-dimensional computed tomography, intracranial pressure monitoring, and support of dural repair/graft using dural patch and glue. The esthetic facial outcome was evaluated by an independent plastic assessor based on objective scale criteria. This series was carried out in Prince Salman Military Hospital between November 2010 and September 2013. RESULTS: Early neurosurgical outcome was considered good in 22/24 patients (92%), moderate in one patient (4%), and poor in the last one (4%). At late evaluation, 20 cases (83%) regained their consciousness without any cognitive deficit. One patient (4%) remained in neurovegetative status. Early esthetic outcome was considered to be excellent in 18/24 patients (75%), good in 3 patients (12.5%), deemed fair in 2 patients (8%), and labeled poor in only 1 patient (4%). At late evaluation, the patient labeled fair had improved to good with topical scar management and the patient deemed poor had improved to fair with two successive plastic procedures. Complications included a cerebrospinal fluid leak in 2 patients (8%), one was managed conservatively and the second was treated surgically with intra- and extradural grafting. CONCLUSION: In complex frontofaciobasal injuries, successful facial repair depends on immediate and definitive reconstruction. However, improved neurological outcomes in these patients depend on judicious selection of the appropriate candidates from severely head-injured patients. PMID- 25686656 TI - Critical tracheal stenosis caused by mediastinal lipomatosis: Long-term efficacy of airway stenting. PMID- 25686657 TI - Diffusion-weighted magnetic resonance imaging in preoperative assessment of non small cell lung cancer. AB - BACKGROUND: Diffusion-weighted magnetic resonance imaging (DWI) frequently shows heterogeneity of signal intensity (SI) in non-small cell lung cancer (NSCLC). The purpose of our study was to examine the association of SI and DWI patterns with histology, tumor invasiveness, lymph node metastasis, and (18)F fluorodeoxyglucose positron emission tomography (FDG-PET) uptake in NSCLC. METHODS: One hundred forty-five patients with NSCLC underwent preoperative DWI and FDG-PET. DWI patterns were visually classified as homogenous (HOM) (n = 81) or heterogeneous (HET) (n = 64). The former was further classified as faint (faint-HOM) (n = 27) or dark (dark-HOM) (n = 54) according to a cutoff value of SI. Associations of SI and DWI patterns with tumor histology, lymphatic or vascular invasion, pleural invasion, lymph node metastasis, and FDG uptake were evaluated. RESULTS: All faint-HOM tumors were well-differentiated adenocarcinoma, whereas dark-HOM and HET tumors were less-differentiated adenocarcinoma or non adenocarcinoma. Although the dark areas in HET tumors showed a dense aggregation of tumor cells, their faint areas showed abundant fibrovascular stroma or necrosis, or a well-differentiated part of adenocarcinoma. Tumor size and the frequencies of lymphatic or vascular invasion, pleural invasion, and nodal metastasis were highest in HET tumors, followed by dark-HOM and faint-HOM (P = .1 P < .001) tumors. Sixty-five tumors having at least 1 of the invasions or metastasis showed significantly higher SI than the 81 tumors without (P < .001). HET tumors had the highest FDG uptake, followed by dark-HOM and faint-HOM tumors; differences between the groups were significant (P < .01 to P < .001). CONCLUSIONS: The SI and heterogeneity of DWI reflect the histologic heterogeneity, tumor aggressiveness, and FDG-PET uptake in NSCLC. PMID- 25686658 TI - Effects of salinity on performance and microbial community structure of an anoxic aerobic sequencing batch reactor. AB - The effects of salinity on the performance and microbial community structure of activated sludge were investigated in an anoxic-aerobic sequencing batch reactor (SBR). The removal efficiencies of chemical oxygen demand (COD) and [Formula: see text]-N decreased as the influent salinity increased from 0.5% to 6%. The specific oxygen utilization rate of activated sludge increased from 22.47 to 43.16 mg O2 g(-1) mixed liquid suspended solids (MLSS) h(-1) with the increase in salinity from 0.5% to 4% and subsequently decreased to 18.3 mg O2 g(-1) MLSS h( 1) at 6% salinity. The specific ammonium oxidation rate (SAOR) and specific nitrite oxidation rate (SNOR) decreased slowly at 0.5-1% salinity and then decreased rapidly with the increase in salinity from 1% to 6%. The SNOR diminished at a faster rate than the SAOR with the increase in salinity from 0.5% to 6%. The specific nitrate reduction rate (SNRR) decreased with the increase in salinity, whereas the SNRR was higher than the sum of SAOR and SNOR at 0.5-6% salinity. The denaturing gradient gel electrophoresis profiles revealed obvious changes in microbial community structure at different salinities. Some microbes were capable of tolerating up to 6% salinity in the SBR, such as Planomonospora sphaerica, Nitrosomonas sp. Is32, and Denitromonas sp. D2-1. PMID- 25686659 TI - Human antimicrobial peptide LL-37 induces glial-mediated neuroinflammation. AB - LL-37 is the sole cathelicidin-derived antimicrobial peptide found in humans. It becomes active upon C-terminal cleavage of its inactive precursor hCAP18. In addition to antimicrobial action, it also functions as an innate immune system stimulant in many tissues of the body. Here we report that hCAP18 and LL-37 are expressed in all organs of the human body that were studied with the highest basic levels being expressed in the GI tract and the brain. Its expression and functional role in the central nerve system (CNS) has not previously been reported. We found increased expression of LL-37 in IFNgamma-stimulated human astrocytes and their surrogate U373 cells, as well as in LPS/IFNgamma-stimulated human microglia and their surrogate monocyte-derived THP-1 cells. We found that treatment of microglia, astrocytes, THP-1 cells and U373 cells with LL-37 induced secretion of the inflammatory cytokines IL-1beta and IL-6; the chemokines IL-8 and CCL-2, and other materials toxic to human neuroblastoma SH-SY5Y cells. The mechanism of LL-37 stimulation involves activation of intracellular proinflammatory pathways involving phospho-P38 MAP kinase and phospho-NFkappaB proteins. We blocked the inflammatory stimulant action of LL-37 by removing it with an anti-LL-37 antibody. The inflammatory effect was also prevented by treatment with inhibitors of PKC, PI3K and MEK-1/2 as well as with the intracellular Ca(2+)-chelator, BAPTA-AM. This indicates involvement of these intracellular pathways. Our data suggest that LL-37, in addition to its established roles, may play a role in the chronic neuroinflammation which is observed in neurodegenerative diseases such as Alzheimer's and Parkinson's disease. PMID- 25686660 TI - Identifying the mechanisms of drug release from amorphous solid dispersions using MRI and ATR-FTIR spectroscopic imaging. AB - The dissolution mechanism of a poorly aqueous soluble drug from amorphous solid dispersions was investigated using a combination of two imaging methods: attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopic imaging and magnetic resonance imaging (MRI). The rates of elementary processes such as water penetration, polymer swelling, growth and erosion of gel layer, and the diffusion, release and in some cases precipitation of drug were evaluated by image analysis. The results from the imaging methods were compared with drug release profiles obtained by classical dissolution tests. The study was conducted using three polymeric excipients (soluplus, polyvinylpyrrolidone - PVP K30, hydroxypropylmethyl cellulose - HPMC 100M) alone and in combination with a poorly soluble drug, aprepitant. The imaging methods were complementary: ATR-FTIR imaging enabled a qualitative observation of all three components during the dissolution experiments, water, polymer and drug, including identifying structural changes from the amorphous form of drug to the crystalline form. The comparison of quantitative MRI data with drug release profiles enabled the different processes during dissolution to be established and the rate-limiting step to be identified, which - for the drug-polymer combinations investigated in this work - was the drug diffusion through the gel layer rather than water penetration into the tablet. PMID- 25686661 TI - Effects of nitrogen addition on soil microbes and their implications for soil C emission in the Gurbantunggut Desert, center of the Eurasian Continent. AB - Nitrogen (N) deposition can influence carbon cycling of terrestrial ecosystems. However, a general recognition of how soil microorganisms respond to increasing N deposition is not yet reached. We explored soil microbial responses to two levels of N addition (2.5 and 5 gN m(-2) yr(-1)) in interplant soil and beneath shrubs of Haloxylon ammodendron and their consequences to soil respiration in the Gurbantunggut Desert, northwestern China from 2011 to 2013. Microbial biomass and respiration were significantly higher beneath H. ammodendron than in interplant soil. The responses of microbial biomass carbon (MBC) and microbial respiration (MR) showed opposite responses to N addition in interplant and beneath H. ammodendron. N addition slightly increased MBC and MR in interplant soil and decreased them beneath H. ammodendron, with a significant inhibition only in 2012. N addition had no impacts on the total microbial physiological activity, but N addition decreased the labile carbon substrate utilization beneath H. ammodendron when N addition level was high. Phospholipid fatty acid (PLFA) analysis showed that N addition did not alter the soil microbial community structure as evidenced by the similar ratios of fungal to bacterial PLFAs and gram-negative to gram-positive bacterial PLFAs. Microbial biomass and respiration showed close correlations with soil water content and dissolved carbon, and they were independent of soil inorganic nitrogen across three years. Our study suggests that N addition effects on soil microorganisms and carbon emission are dependent on the respiratory substrates and water availability in the desert ecosystem. PMID- 25686662 TI - Developing a statewide electronic public health care coordination tracking system. PMID- 25686663 TI - Detergent sclerosants are deactivated and consumed by circulating blood cells. AB - OBJECTIVE: To investigate the deactivating effects of circulating blood cells on the lytic activity of detergent sclerosants. METHODS: Samples of whole blood (WB), platelet-rich plasma (PRP), and isolated leukocytes were incubated with various concentrations of sodium tetradecyl sulfate (STS) or polidocanol (POL) and added to human umbilical vein endothelial cells (HUVECs), which were then counted using a fluorescent plate reader. Full blood counting was performed using a hematology analyzer. Platelet lysis and microparticle formation was assessed using lactadherin binding in flow cytometry. RESULTS: Detergent sclerosant activity was decreased in WB when compared with plasma and saline controls. The sclerosant lytic activity on endothelial cells was increased 23-fold for STS and 59-fold for POL in saline controls compared with WB. At high concentrations, sclerosants lysed erythrocytes, leukocytes, and platelets. Platelets were more sensitive to the lytic activity of sclerosants than other cell types. Neutrophils were the most susceptible of all leukocytes to the lytic activity of sclerosants. The presence of erythrocytes and leukocytes in samples decreased the lytic activity of sclerosants. Sclerosants at all concentrations induced erythrocyte derived microparticle formation. CONCLUSIONS: Detergent sclerosants are consumed and deactivated by circulating blood cells. This deactivating effect is above and beyond the neutralizing effects of plasma proteins and contributes to the overall neutralizing effect of blood. Different blood cell types exhibited varying levels of vulnerability to the lytic activity of sclerosants with platelets being the most and erythrocytes the least vulnerable (platelets > leukocytes > erythrocytes). PMID- 25686664 TI - [Reconstruction of the medial nasal canthus using a single-stage paramedian forehead flap]. PMID- 25686665 TI - [Pilomatricomas of the scrotum]. PMID- 25686666 TI - [Pseudomonilethrix: more an artifact than a disease]. PMID- 25686667 TI - Functional roles of tumor necrosis factor-alpha and interleukin 1-Beta in hypoxia and reoxygenation. AB - BACKGROUND: Intercellular signaling plays an important role in the development of lung ischemia-reperfusion injury. However, the role of specific mediators remains poorly characterized. Alveolar macrophages (AM) produce soluble mediators early in reperfusion, which modulate the responses of endothelial and epithelial cells to oxidative stress. There is a burst of proinflammatory cytokine production in a variety of cells; however, interleukin 1-beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) localize to the AM. We hypothesized that these cytokines account for the costimulatory effects that AM exert on endothelial and epithelial cells. METHODS: Activated AM media was placed on cultured rat type 2 pneumocytes and pulmonary artery endothelial cells, which were then subjected to hypoxia and reoxygenation. To assess the contributions of IL-1beta and TNF-alpha, the cells were treated with control media or media that had been depleted of IL-1beta or TNF-alpha. To deplete specific cytokines, activated media was passed through a column with immobilized IL-1beta or TNF-alpha antibodies. Nuclear translocation of transcription factors, mitogen-activated protein kinase activation, and cytokine and chemokine production were assessed. RESULTS: Depletion of IL-1beta or TNF-alpha effectively eliminated the ability of AM media to enhance the response of endothelial and epithelial cells to oxidative stress. There were significant reductions in monocyte chemotactic protein 1 and cytokine-induced neutrophil chemoattractant (CINC) production (p < 0.05) at 4 hours of reperfusion. Additionally there was decreased nuclear translocation of nuclear factor-kappa B, and extracellular signal-regulated kinase phosphorylation. CONCLUSIONS: Interleukin 1-beta and TNF-alpha are critical mediators in the intercellular communication pathways that allow the AM to enhance the response of surrounding cells to oxidative stress. PMID- 25686668 TI - Improved long-term survival for diabetic patients with surgical versus interventional revascularization. AB - BACKGROUND: Diabetes is increasing at an alarming rate, affecting nearly 8% of the population. Previous studies have demonstrated a potential benefit for surgical over interventional revascularization in diabetics. However, randomized clinical trials comparing coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) many not accurately reflect current clinical practice. We therefore undertook a prospective registry of coronary revascularization (CR) in diabetic patients with CABG, on-pump and off-pump, and PCI with bare-metal and drug-eluting stents to determine long-term clinical outcomes. METHODS: All patients undergoing isolated CR in 8 community hospitals were enrolled. Follow-up was obtained after 5 to 8 years; all mortalities were checked against the Social Security Death Index. The ST-elevation myocardial infarction and salvage patients were excluded. Propensity matching was used to account for differences between PCI and CABG groups. Survival curves were derived using Kaplan-Meier methods, whereas hazard ratios and cumulative hazards were calculated using the Cox proportional hazard model. RESULTS: Of the 3,156 patients in the registry, there were 1,082 diabetics; 334 CABG and 748 PCI. Due to the differences in baseline characteristics between the 2 groups, propensity score matching was used to achieve clinically comparable groups of 240 patients each. In matched patient groups mortality was more common in the PCI group with an odds ratio (OR) of 0.60 (95% confidence interval [CI] 0.39% to 0.93%; p = 0.023). Similarly, occurrence of any major cardiac adverse event (MACE) (mortality, non-fatal myocardial infarction, or revascularization) was more frequent in the PCI group with an OR of 0.57 (95% CI 0.31% to 0.70%, p < 0.001). Kaplan-Meier event-free survival of matched groups was significantly improved in the CABG versus PCI group (p = 0.001). CONCLUSIONS: In the current era of on-pump and off-pump CABG surgery and bare-metal and drug-eluting stents, this registry which unselectively records all non-ST elevation myocardial infarction patients undergoing coronary revascularization, diabetic patients benefit from improved long-term survival and reduced MACE with CABG versus PCI. These findings corroborate recent evidence from prospective randomized trials and thus provide clinically relevant validation of their broad applicability to diabetics with extensive coronary artery disease in need of revascularization. PMID- 25686669 TI - Prolonged effect of postoperative infectious complications on survival after cardiac surgery. AB - BACKGROUND: Whether patients having infections after cardiac surgery are at a survival disadvantage after hospital discharge is unclear. Our objectives were (1) to identify characteristics of such patients and (2) to determine whether this complication is associated with increased mortality beyond hospital discharge. METHODS: In all, 30,414 patients were discharged after isolated coronary artery bypass grafting, valve, ascending aorta repair, or combined procedures from January 2000 to January 2011. Surgical site infection, septicemia, pneumonia, and urinary tract infection occurred in 1,868 patients (6.1%). Propensity matching was used to account for differences in perioperative characteristics and postoperative in-hospital events between these patients and those not having postoperative infections, to give 1,593 propensity-matched pairs. Time-related mortality and instantaneous risk were compared. RESULTS: Surgical site infection occurred in 122 patients (0.40%), sternal wound infection in 263 (0.86%), septicemia in 656 (2.2%), urinary tract infection in 853 (2.8%), and pneumonia in 513 (1.7%). Infections were associated with older age, female sex, larger body mass index, and multiple comorbidities. Among 1,593 propensity matched pairs, postdischarge survival at 6 months and at 1, 5, and 10 years, respectively, was 89%, 86%, 67%, and 45% for patients without infections, and 86%, 83%, 63%, and 43% (p = 0.008) for patients with infections. Survival differences resulted from a higher, but gradually declining, early instantaneous risk during the first year after surgery. Elevated risk was of shorter duration for surgical site infections than for other infections. CONCLUSIONS: Postoperative infection is associated with a high-risk patient profile, and risk of death is elevated early after hospital discharge. Reasons for this prolonged effect are unclear. PMID- 25686670 TI - Propensity adjusted analysis of open and endovascular thoracic aortic repair for chronic type B dissection: a twenty-year evaluation. AB - BACKGROUND: Optimal treatment of chronic type B aortic dissection (CBAD), whether open (open descending aortic repair, OAR) or endovascular (thoracic endovascular aortic repair, TEVAR), is controversial, suggesting a comparative analysis is warranted. METHODS: One hundred twenty-two of 1,049 patients (1993 to 2013) undergoing descending aortic repair required intervention for CBAD 29.2 +/- 34.9 months after the initial acute event and formed the study cohort (mean age 59.7 years). Those with degenerated residual type A dissection were excluded (n = 65). Eighty-eight had extent IIIB CBAD; 11 had intramural hematoma. Indications for surgery included aneurysmal degeneration (n = 105), rupture (n = 8), acute or chronic dissection (n = 8), and extension of dissection (n = 1). Open strategy included descending (n = 71) and thoracoabdominal repair (n = 19), with hypothermic circulatory arrest used in 70 patients. The TEVAR was performed with (n = 2) or without (n = 30) visceral debranching. A treatment strategy propensity score incorporating time since initial acute event, CBAD extent, year of intervention, age, and selected comorbidities was constructed for multivariable analysis. RESULTS: Early outcome included the following: 30-day mortality 4% (n = 5); stroke 2% (n = 2); permanent paraplegia 3% (n = 4); renal failure requiring dialysis 7% (n = 8, 5 temporary and 3 permanent); and tracheostomy 3% (n = 4). Visceral aorta intervention (odds ratio [OR] 3.5, p = 0.026) and maximum aortic diameter (OR 1.1, p = 0.001) but not treatment type (p = 0.64) independently predicted an early composite outcome comprised of these variables. Ten-year survival was 56.2%. Baseline creatinine (hazard ratio [HR] 1.7, p < 0.001) and peripheral vascular disease (HR 2.5, p = 0.021), but not treatment type (p = 0.225) predicted late mortality. Ten-year freedom from aortic rupture or need for reintervention was 78.3%. Treatment efficacy was improved after OAR (3-year freedom 96.7% vs TEVAR 87.5%, p = 0.026), and this was confirmed after Cox regression (TEVAR, HR 4.6, p = 0.046). CONCLUSIONS: Intervention for CBAD can be performed with excellent results, either by an open or endovascular approach. The higher rate of treatment failure after TEVAR warrants modification of current device design or endovascular approach before broad application of this treatment strategy. PMID- 25686671 TI - Postnatal lung function in congenital cystic adenomatoid malformation of the lung. AB - BACKGROUND: Management of prenatally diagnosed but postnatal asymptomatic pulmonary lesions remains controversial. The aim of this study was to investigate the effect of congenital cystic adenomatoid malformation of the lung (CCAM) on postnatal lung function tests (LFT) and to elucidate whether LFTs help identify infants who would benefit from early surgery. METHODS: The LFTs were performed in 26 CCAM infants at a median (interquartile range) postmenstrual age of 42.4 (39.6 to 44.0) weeks and compared with LFT from 30 healthy controls. The LFT included the measurement of tidal breathing, functional residual capacity by body plethysmography, respiratory mechanics (respiratory compliance), and respiratory resistance by occlusion test and blood gas analysis. RESULTS: The CCAM infants showed a restrictive ventilation disorder with increased respiratory rates (p = 0.006) and marginally decreased tidal volumes (p = 0.043). Furthermore, respiratory compliance was significantly reduced as compared with controls (p < 0.001). No statistically significant differences were seen in the respiratory resistance, functional residual capacity, and capillary blood gases. Particularly in CCAM infants who had surgery in the first 2 years of life, a marked reduction of respiratory compliance (p < 0.001) was seen preoperatively. CONCLUSIONS: Congenital cystic adenomatoid malformation can cause restrictive ventilation disorders, which can be detected and monitored by postnatal LFT. Thus, LFT represents an additional tool to support the decision for or against surgical intervention. PMID- 25686672 TI - Optimization of dual slot antenna using floating metallic sleeve for microwave ablation. AB - Backward heating reduction is vital in power distribution optimization in microwave thermal ablation. In this study, we optimized dual slot antenna to yield reduction in backward heating pattern along the antenna shaft with the application of floating metallic sleeve. Finite element methods were used to generate the electromagnetic (EM) field and thermal distribution in liver tissue. The position of the sleeve from the tip of the probe (z = 0 mm) was varied within the range 14 <= z <= 22 mm while sleeve length was varied within 16 <= z <= 48 mm at 2 mm interval using operating frequency of 2.45 GHz. The best optimized design has reflection coefficient of -20.87 dB and axial ratio of 0.41 when the sleeve position was at 17 mm and sleeve length was 18 mm. Experimental validation shows that inclusion of a floating metallic sleeve on dual slot antenna for hepatic microwave ablation averagely increased ablation diameter and aspect ratio by 17.8% and 33.9% respectively and decreased ablation length by 11.2%. Reduction in backward heating and increase in power deposition into liver tissue could be achieved by using this antenna to provide greater efficiency and localization of specific absorption rate in delivering microwave energy for hepatic ablation. PMID- 25686673 TI - A mathematical model approach quantifying patients' response to changes in mechanical ventilation: evaluation in volume support. AB - This paper presents a mathematical model-approach to describe and quantify patient-response to changes in ventilator support. The approach accounts for changes in metabolism (VO2, VCO2) and serial dead space (VD), and integrates six physiological models of: pulmonary gas-exchange; acid-base chemistry of blood, and cerebrospinal fluid; chemoreflex respiratory-drive; ventilation; and degree of patients' respiratory muscle-response. The approach was evaluated with data from 12 patients on volume support ventilation mode. The models were tuned to baseline measurements of respiratory gases, ventilation, arterial acid-base status, and metabolism. Clinical measurements and model simulated values were compared at five ventilator support levels. The models were shown to adequately describe data in all patients (chi(2), p > 0.2) accounting for changes in VCO2, VD and inadequate respiratory muscle-response. F-ratio tests showed that this approach provides a significantly better (p < 0.001) description of measured data than: (a) a similar model omitting the degree of respiratory muscle-response; and (b) a model of constant alveolar ventilation. The approach may help predict patients' response to changes in ventilator support at the bedside. PMID- 25686674 TI - The pathological role and prognostic impact of miR-181 in acute myeloid leukemia. AB - In addition to genetic abnormalities, such as chromosomal translocations and somatic mutations that have been widely acknowledged in the leukemogenesis of acute myeloid leukemia (AML), epigenetic modifications also play a vital role in this process. MicroRNA (miRNA) regulation is emerging as a new layer of epigenetic regulation besides DNA methylation and histone modifications. Among the miRNAs first identified to be specifically expressed in hematopoietic cells, the miR-181 family has been implicated in regulating the differentiation of B cells, T cells, and natural killer cells during normal hematopoiesis, and has been linked tightly to the pathogenesis and prognosis of AML. Accumulating evidence indicates that miR-181 acts as a tumor suppressor in the pathogenesis of AML and exhibits a significant impact on the survival of patients with AML. Herein, we review the role of miR-181 as a diagnostic marker and prognostic predictor in AML, and discuss the potential use of miR-181 as a therapeutic target for AML. PMID- 25686675 TI - Sensorimotor function of the cervical spine in healthy volunteers. AB - BACKGROUND: Sensorimotor mechanisms are important for controlling head motion. However, relatively little is known about sensorimotor function in the cervical spine. This study investigated how age, gender and variations in the test conditions affect measures of position sense, movement sense and reflex activation in cervical muscles. METHODS: Forty healthy volunteers (19M/21F, aged 19-59 years) participated. Position sense was assessed by determining repositioning errors in upright and flexed neck postures during tests performed in 25%, 50% and 75% cervical flexion. Movement sense was assessed by detecting thresholds to passive flexion and extension at velocities between 1 and 25 degrees s(-1). Reflexes were assessed by determining the latency and amplitude of reflex activation in trapezius and sternocleidomastoid muscles. Reliability was evaluated from intraclass correlation coefficients. FINDINGS: Mean repositioning errors ranged from 1.5 degrees to 2.6 degrees , were greater in flexed than upright postures (P=0.006) and in people aged over 25 years (P=0.05). Time to detect head motion decreased with increasing velocity (P<0.001) and was lower during flexion than extension movements (P=0.002). Reflexes demonstrated shorter latency (P<0.001) and greater amplitude (P=0.009) in trapezius compared to sternocleidomastoid, and became slower and weaker with age. None of the measures were influenced by gender. Reliability was good for movement sense measures, but was influenced by the test conditions when assessing position sense. INTERPRETATION: Increased repositioning errors and slower reflexes in older subjects suggest that sensorimotor function in the cervical spine becomes impaired with age. In position sense tests, reliability was influenced by the test conditions with mid-range flexion movements, performed in standing, providing the most reliable measurements. PMID- 25686676 TI - Increasing pullout strength of suture anchors in osteoporotic bone using augmentation--a cadaver study. AB - BACKGROUND: Rotator cuff tears are of increasing clinical impact in the physically active elderly patients. Recent research revealed, that a high percentage of these patients present with significant loss of bone mineral density at the insertion site of the rotator cuff, thereby compromising suture anchorage for operative repair. We therefore hypothesized that augmentation of suture anchors improves biomechanical properties in low bone quality. METHODS: 28 osteoporotic humeral heads were included in this biomechanical study. Bone quality at the anchor insertion sites (group 1: posterior-medial; group 2: anterior-lateral) within the greater tuberosity was analyzed using HR-pQCT (voxel size: 82MUm). Anchor positions of identical quality were then randomized to either conventional screw anchorage or polymethylmethacrylat augmented screw anchorage. All anchors were cyclically ramp-loaded until pullout. FINDINGS: Pullout strength accounted for 226N in group I for conventional anchorage and for 332N in augmented technique. In group 2 (anterior-lateral) the pullout strength was 209N (conventional) and 304N (augmented). Pull-out strength of augmented screw anchors was significantly higher in both groups (p<0.05). INTERPRETATION: Compared to conventional insertion techniques, the cement augmentation technique increases the pullout strength of suture anchors in low bone quality significantly. Cement augmentation could therefore be a helpful tool for improved suture anchor stability, especially in locations of low bone quality. PMID- 25686677 TI - Increased carotid intima-media thickness is not associated with T-cell activation nor with cytomegalovirus in HIV-infected never-smoker patients. AB - OBJECTIVES: Increased risk of cardiovascular disease in patients infected with HIV has been attributed to immune activation, inflammation, and immunosenescence, all of which are linked to chronic immune activation by viral infections, particularly cytomegalovirus (CMV). Our aim is to evaluate the impact of these atherogenic markers in HIV-infected patients who never smoked. DESIGN: Exposure matched, cross-sectional study. METHODS: In 59 HIV-infected individuals [n = 30 undergoing >=4 years of antiretroviral therapy (ART); n = 29 never treated with ART] and 30 age-matched HIV-negative controls, we measured the level of activation and senescence, as well as the frequency of CMV-specific T cells, on peripheral blood mononuclear cells, while examining their association with carotid intima-media thickness. Partial correlations were adjusted for age, systolic blood pressure, and nadir CD4 cell count. RESULTS: The previously described roles of T-cell activation, CMV, and immunosenescence in the atherosclerotic risk of HIV-infected patients, as assessed by carotid intima media thickness, were not apparent in our cohort of particularly 'healthy' HIV infected never-smokers. CONCLUSION: In HIV-infected individuals at low cardiovascular disease risk, our data show that the increased risk of carotid atherosclerosis is not associated with immunological markers described to be associated with HIV disease progression. PMID- 25686678 TI - Early viral suppression improves neurocognitive outcomes in HIV-infected children. AB - OBJECTIVE: To estimate the association of age of viral suppression and central nervous system penetration effectiveness (CPE) score with neurocognitive functioning among school-age children with perinatally acquired HIV infection (PHIV+). DESIGN: We analyzed data from two US-based multisite prospective cohort studies. METHODS: Multivariable general linear regression models were used to evaluate associations of age at viral suppression and CPE scores (of initial antiretroviral therapy regimen and weighted average) with the Wechsler Intelligence Scale for Children, Third or Fourth Edition neurocognitive assessments [Full-Scale Intelligence Quotient (FSIQ); Performance IQ/Perceptual Reasoning Index (PIQ/PRI); and Verbal IQ/Verbal Comprehension Index (VIQ/VCI)], adjusted for demographic and clinical covariates. Sensitivity analyses were stratified by birth cohort (before versus after 1996). RESULTS: A total of 396 PHIV+ children were included. Estimated differences in mean FSIQ (comparing virally suppressed versus unsuppressed children) by each age cutoff were 3.7, 2.2, 3.2, 4.4, and 3.9 points at ages 1, 2, 3, 4, and 5, respectively. For PIQ/PRI, estimated mean differences were 3.7, 2.4, 2.2, 4.6, and 4.5 at ages 1 through 5, respectively. In both cases, these differences were significant only at the age 4 and 5 thresholds. After stratifying by birth cohort, the association between age at suppression and cognitive function persisted only among those born after 1996. Age at viral suppression was not associated with VIQ/VCI; CPE score was not associated with FSIQ, verbal comprehension, or perceptual reasoning indices. CONCLUSION: Virologic suppression during infancy or early childhood is associated with improved neurocognitive outcomes in school-aged PHIV+ children. In contrast, CPE scores showed no association with neurocognitive outcomes. PMID- 25686679 TI - HAART slows progression to anal cancer in HIV-infected MSM. AB - OBJECTIVE: Antiretrovirals do not prevent anal intraepithelial neoplasia. However, the influence of antiretrovirals in the natural history of invasive anal cancer is less clear. The objective is to investigate the impact of antiretrovirals in the time to the development of anal cancer in HIV-positive MSM. DESIGN: A retrospective analysis of cases of anal cancer in a cohort of HIV positive MSM receiving antiretrovirals between 1988 and 2008. METHODS: Time from first CD4 cell count or HIV RNA viral load test to anal cancer diagnosis was analysed using Cox regression and Kaplan-Meier curves. Anal cancer cases treated in the era prior to HAART (<1996) were compared with those treated later (1996 2008). RESULTS: Anal cancer cases (n = 37) were compared with a cohort of 1654 HIV-positive MSM on antiretrovirals. Antiretrovirals were started in the pre HAART era by 70% of cancer cases, and median CD4 cell count nadir was 70 cells/MUl (10-130). Time to development of anal cancer was shorter for cases treated during the pre-HAART era [adjusted hazard ratio (AHR) 3.04, 95% confidence interval (95% CI) 1.48-6.24, P = 0.002], with a CD4 cell count nadir less than 100 cells/MUl (AHR 2.21, 95% CI 1.06-4.62, P = 0.035) and longer duration of CD4 cell count less than 100 cells/MUl (AHR 1.33, 95% CI 1.11-1.58, P = 0.002). CONCLUSION: Results show that severe immunosuppression and starting therapy pre-HAART are associated with an increased risk of anal cancer. HIV positive MSM initiating antiretrovirals during the HAART era (1996-2008) had a longer time to the development of anal cancer than those treated pre-HAART. Our results suggest that early use of HAART may delay progression to anal cancer. PMID- 25686680 TI - Statin therapy decreases N-terminal pro-B-type natriuretic peptide in HIV: randomized placebo-controlled trial. AB - OBJECTIVE: HIV-infected participants are at a higher risk for cardiovascular disease (CVD). N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a significant predictor of CVD in the general population and is associated with mortality in HIV. DESIGN AND METHODS: The 96-week Stopping Atherosclerosis and Treating Unhealthy Bone with Rosuvastatin in HIV (SATURN-HIV) trial randomized 147 patients on stable antiretroviral therapy with low-density lipoprotein cholesterol level lower than 130 mg/dl and without overt heart failure to 10 mg daily rosuvastatin or placebo. We measured NT-proBNP levels by enzyme-linked immunosorbent assay (ELISA). Baseline and changes in NT-proBNP were compared between groups. Spearman correlation was used to explore relationships between baseline NT-proBNP, inflammation, and CVD risk markers. Multivariable analyses were conducted to assess associations with NT-proBNP levels. RESULTS: Median age was 46 years, 80% were men, 69% were African American, and 46% were on protease inhibitors. At baseline, median (Q1, Q3) NT-proBNP was higher in the rosuvastatin group than placebo [41 (20, 66.5) versus 25 pg/ml (11, 56), P = 0.012)]. Baseline NT-proBNP correlated with bulb and common carotid artery intima-media thickness, coronary calcium score, interleukin 6, and cystatin C. After 96 weeks, median NT proBNP decreased significantly in the rosuvastatin group versus placebo (-1.50 versus +4.50 pg/ml, P = 0.041). Within the rosuvastatin group, changes in NT proBNP were negatively correlated with changes in insulin resistance and total limb fat. CONCLUSION: Rosuvastatin reduces plasma NT-proBNP in HIV-infected participants on antiretroviral therapy. NT-proBNP correlated with several measures of CVD risk, independent of inflammation markers. PMID- 25686681 TI - Antiretroviral therapy reduces neurodegeneration in HIV infection. AB - OBJECTIVE: To determine the effect of virally suppressive antiretroviral therapy (ART) on cortical neurodegeneration and associated neurocognitive impairment. DESIGN: Retrospective, postmortem observational study. METHODS: Clinical neuropsychological and postmortem neuropathology data were analyzed in 90 HIV infected volunteers from the general community who had never undergone ART (n = 7, 'naive') or who had undergone ART and whose plasma viral load was detectable (n = 64 'unsuppressed') or undetectable (n = 19, 'suppressed') at the last clinical visit before death. Individuals were predominately men (74/90, 82%) with a mean age of 44.7 years (SD 9.8). Cortical neurodegeneration was quantified by measuring microtubule-associated protein (MAP2) and synaptophysin (SYP) density in midfrontal cortex tissue sections. RESULTS: The suppressed group had higher SYP density than the naive group (P = 0.007) and higher MAP2 density than the unsuppressed group (P = 0.04). The suppressed group had lower odds of HIV associated neurocognitive disorders than naive [odds ratio (OR) 0.07, P = 0.03]. Higher SYP was associated with lower likelihood of HIV-associated neurocognitive disorders in univariable (OR 0.8, P = 0.03) and multivariable models after controlling for ART and brain HIV p24 protein levels (OR 0.72, P = 0.01). CONCLUSION: We conclude that virally suppressive ART protects against cortical neurodegeneration. Further, we find evidence supporting the causal chain from treatment-mediated peripheral and central nervous system viral load suppression to reduced neurodegeneration and improved neurocognitive outcomes. PMID- 25686682 TI - Modelling the HIV epidemic among MSM in the United Kingdom: quantifying the contributions to HIV transmission to better inform prevention initiatives. AB - OBJECTIVES: HIV is a major public health problem among MSM in the United Kingdom with around 2400 new infections annually. We quantified the contribution of biological and behavioural factors. DESIGN: Modelling study. METHODS: A partnership-based model of HIV transmission among UK MSM aged 15-64 years was developed and calibrated to time series HIV prevalence. The calibration was validated using multiple surveillance datasets. Population-attributable fractions were used to estimate the contribution of behavioural and biological factors to HIV transmission over the period 2001-2002, 2014-2015, and 2019-2020. RESULTS: The contribution of most biological and behavioural factors was relatively constant over time, with the key group sustaining HIV transmission being higher sexual activity MSM aged below 35 years living with undiagnosed HIV. The effect of primary HIV infection was relatively small with 2014-2015 population attributable fraction of 10% (3-28%) in comparison with other subsequent asymptomatic stages. Diagnosed men who were not on antiretroviral therapy (ART) currently contributed 26% (14-39%) of net infections, whereas ART-treated MSM accounted for 17% (10-24%). A considerable number of new infections are also likely to occur within long-term relationships. CONCLUSION: The majority of the new HIV infections among MSM in the United Kingdom during 2001-2020 is expected to be accounted for by a small group of younger and highly sexually active individuals, living with undiagnosed HIV in the asymptomatic stage. Bringing this group into HIV/AIDS care by improving testing uptake is a vital step for preventing onward transmission and will determine the success of using ART as prevention. PMID- 25686683 TI - Tuberculosis incidence after 36 months' isoniazid prophylaxis in HIV-infected adults in Botswana: a posttrial observational analysis. AB - OBJECTIVE: Thirty-six months of isoniazid preventive therapy (36IPT) was superior to 6 months of IPT (6IPT) in preventing tuberculosis (TB) among HIV-infected adults in Botswana. We assessed the posttrial durability of this benefit. DESIGN: A 36-month double-blind placebo controlled trial (1 : 1 randomization) with recruitment between November 2004 and July 2006 and observation until June 2011. METHODS: One thousand, nine hundred and ninety-five participants were followed in eight public health clinics. Twenty-four percent had a tuberculin skin test >=5 mm (TST-positive). A minimum CD4 lymphocyte count was not required for enrolment. Antiretroviral therapy (ART) was provided in accordance with Botswana guidelines; 72% of participants retained by June 2011 had initiated ART. Multivariable analysis using Cox regression analysis included treatment arm, TST status, ART as a time-dependent variable and CD4 cell count at baseline and updated at 36 months. RESULTS: In the posttrial period, 2.13 and 2.14 per 100 person-years accumulated, whereas 0.93 and 1.13% TB incidence rates were observed in the 36IPT and 6IPT arms, respectively (P = 0.52). The crude hazard ratio of TB during the trial and posttrial was 0.57 [95% confidence intervals (CI) 0.33, 0.99] and 0.82 (95% CI 0.46, 1.49), and when restricted to TST-positive participants was 0.26 (95% CI 0.08, 0.80) and 0.40 (95% CI 0.15, 1.08), respectively. Multivariable analysis showed that ART use was associated with reduced death (adjusted hazard ratio 0.36, 95% CI 0.17-0.75) but not TB (0.92, 95% CI 0.55-1.53) in the posttrial period. CONCLUSION: The benefit of 36IPT for TB prevention declined posttrial in this cohort. Adjunctive measures are warranted to prevent TB among HIV-infected persons receiving long-term ART in TB-endemic settings. PMID- 25686684 TI - Incomplete adherence among treatment-experienced adults on antiretroviral therapy in Tanzania, Uganda and Zambia. AB - OBJECTIVES: To characterize antiretroviral therapy (ART) adherence across different programmes and examine the relationship between individual and programme characteristics and incomplete adherence among ART clients in sub Saharan Africa. DESIGN: A cross-sectional study. METHODS: Systematically selected ART clients (>=18 years; on ART >=6 months) attending 18 facilities in three countries (250 clients/facility) were interviewed. Client self-reports (3-day, 30 day, Case Index >=48 consecutive hours of missed ART), healthcare provider estimates and the pharmacy medication possession ratio (MPR) were used to estimate ART adherence. Participants from two facilities per country underwent HIV RNA testing. Optimal adherence measures were selected on the basis of degree of association with concurrent HIV RNA dichotomized at less than or greater/equal to 1000 copies/ml. Multivariate regression analysis, adjusted for site-level clustering, assessed associations between incomplete adherence and individual and programme factors. RESULTS: A total of 4489 participants were included, of whom 1498 underwent HIV RNA testing. Nonadherence ranged from 3.2% missing at least 48 consecutive hours to 40.1% having an MPR of less than 90%. The percentage with HIV RNA at least 1000 copies/ml ranged from 7.2 to 17.2% across study sites (mean = 9.9%). Having at least 48 consecutive hours of missed ART was the adherence measure most strongly related to virologic failure. Factors significantly related to incomplete adherence included visiting a traditional healer, screening positive for alcohol abuse, experiencing more HIV symptoms, having an ART regimen without nevirapine and greater levels of internalized stigma. CONCLUSION: Results support more in-depth investigations of the role of traditional healers, and the development of interventions to address alcohol abuse and internalized stigma among treatment-experienced adult ART patients. PMID- 25686686 TI - Seven years of chronic hepatitis C virus infection in an HIV-infected man without detectable antibodies. PMID- 25686685 TI - Impact of low-level viremia on clinical and virological outcomes in treated HIV-1 infected patients. AB - BACKGROUND: The goal of antiretroviral therapy (ART) is to reduce HIV-related morbidity and mortality by suppressing HIV replication. The prognostic value of persistent low-level viremia (LLV), particularly for clinical outcomes, is unknown. OBJECTIVE: Assess the association of different levels of LLV with virological failure, AIDS event, and death among HIV-infected patients receiving combination ART. METHODS: We analyzed data from 18 cohorts in Europe and North America, contributing to the ART Cohort Collaboration. Eligible patients achieved viral load below 50 copies/ml within 3-9 months after ART initiation. LLV50-199 was defined as two consecutive viral loads between 50 and 199 copies/ml and LLV200-499 as two consecutive viral loads between 50 and 499 copies/ml, with at least one between 200 and 499 copies/ml. We used Cox models to estimate the association of LLV with virological failure (two consecutive viral loads at least 500 copies/ml or one viral load at least 500 copies/ml, followed by a modification of ART) and AIDS event/death. RESULTS: Among 17 902 patients, 624 (3.5%) experienced LLV50-199 and 482 (2.7%) LLV200-499. Median follow-up was 2.3 and 3.1 years for virological and clinical outcomes, respectively. There were 1903 virological failure, 532 AIDS events and 480 deaths. LLV200-499 was strongly associated with virological failure [adjusted hazard ratio (aHR) 3.97, 95% confidence interval (CI) 3.05-5.17]. LLV50-199 was weakly associated with virological failure (aHR 1.38, 95% CI 0.96-2.00). LLV50-199 and LLV200-499 were not associated with AIDS event/death (aHR 1.13, 95% CI 0.81-1.68; and aHR 0.95, 95% CI 0.62-1.48, [corrected] respectively). CONCLUSION: LLV200-499 was strongly associated with virological failure, but not with AIDS event/death. Our results support the US guidelines, which define virological failure as a confirmed viral load above 200 copies/ml. PMID- 25686687 TI - Acute pancreatitis associated with dolutegravir and lamivudine/abacavir administration. PMID- 25686688 TI - Changes in kidney function in patients with suppressed HIV RNA who substitute their protease inhibitor with atazanavir/ritonavir. PMID- 25686689 TI - An NMR crystallography study of the hemihydrate of 2', 3'-O isopropylidineguanosine. AB - An NMR crystallography study of the hemihydrate of 2', 3'-O isopropylidineguanosine (Gace) is presented, together with powder X-ray diffraction and thermogravimetric analysis. (1)H double-quantum and (14)N-(1)H HMQC spectra recorded at 850MHz and 75kHz MAS (using a JEOL 1mm probe) are presented together with a (1)H-(13)C refocused INEPT spectrum recorded at 500MHz and 12.5kHz MAS using eDUMBO-122(1)H homonuclear decoupling. NMR chemical shieldings are calculated using the GIPAW (gauge-including projector augmented wave) method; good two-dimensional agreement between calculation and experiment is observed for (13)C and (1)H chemical shifts for directly bonded CH and CH3 peaks. There are two Gace molecules in the asymmetric unit cell: differences in specific (1)H chemical shifts are rationalised in terms of the strength of CH-pi and intermolecular hydrogen bonding interactions. PMID- 25686690 TI - Differential gene expression analysis of benzo(a)pyrene toxicity in the clam, Ruditapes philippinarum. AB - Polycyclic aromatic hydrocarbons (PAHs) are known for their carcinogenic, teratogenic and mutagenic properties. Benzo(a)pyrene (BaP) possesses the greatest carcinogenic potential among the various PAHs. In this study, digital gene expression (DGE) was performed to investigate the digestive gland transcriptome profile of the clam Ruditapes philippinarum exposed to BaP. A total of 10,508,312 and 11,414,297 clean reads were generated respectively, from control and BaP exposure DGE libraries. One hundred and forty-five differentially expressed genes were detected after comparing two libraries with 58 up-regulated and 87 down regulated genes. GO annotation and KEGG pathway analyses were performed on all genes to understand their biological functions and processes. The results showed that numerous enriched differentially expressed genes are related to growth and development, antioxidant metabolism, apoptosis and detoxification metabolism. Quantitative real-time PCR was performed to verify the expressed genes of DGE. Our results provide evidences that RNA-seq is a powerful tool for toxicology and capable of generating novel and valuable information at the transcriptome level for characterizing deleterious effects caused by BaP. PMID- 25686691 TI - Matrix metalloproteinases in destructive lung disease. AB - Matrix metalloproteinases (MMPs) play essential physiologic roles in numerous processes ranging from development to wound repair. Unfortunately, given the broad substrate specificity of the MMP family as a whole, aberrant degradation of extracellular matrix proteins can result in destructive disease. Emphysema, the result of destroyed lung elastin and collagen matrix, is the prototypical example of such a destructive process. More recent data has highlighted that MMPs play much more elaborate physiologic and pathophysiologic roles than simple matrix protein cleavage. Key pathophysiological roles for MMPs in emphysema will be discussed herein. PMID- 25686692 TI - Differential characteristics of primary infection and re-infection can cause backward bifurcation in HCV transmission dynamics. AB - Backward bifurcation, a phenomenon typically characterized by the co-existence of multiple stable equilibria when the associated reproduction number of the model is less than unity, has been observed in numerous disease transmission models. This study establishes, for the first time, the presence of this phenomenon in the transmission dynamics of hepatitis C virus (HCV) within an IDU population. It is shown that the phenomenon does not exist under four scenarios, namely (i) in the absence of re-infection, (ii) in the absence of differential characteristics of HCV infection (with respect to infectivity, progression, treatment and recovery) between re-infected individuals and primary-infected individuals, (iii) when re-infected and treated individuals do not transmit HCV infection and (iv) when the average infectivity-adjusted duration of re-infection is less than that of primary infection. This study identifies, using sensitivity analysis, five parameters of the model that have the most influence on the disease transmission dynamics, namely: effective contact rate, progression rate from acute to chronic infection, recovery rate from acute infection, natural death rate and the relative infectiousness of chronically-infected individuals. Numerical simulations of the model show that the re-infection of recovered individuals has marginal effect on the HCV burden (as measured in terms of the cumulative incidence and the prevalence of the disease) in the IDU community. Furthermore, treatment of infected IDUs, even for small rate (such as 4%), offers significant impact on curtailing HCV spread in the community. PMID- 25686693 TI - A Nagumo-type model for competing populations with nonlocal coupling. AB - We consider a model of two competing species with nonlocal competition for resources. The net birthrate is cubic, so that the model allows simulation of the Allee effect, whereby extinction is stable and intermediate populations promote growth, while saturation occurs via cubic competition terms. The model includes both interspecies and intraspecies nonlocal competition which enters via convolution integrals with a specified asymmetric competition kernel function. We introduce two parameters, delta, describing the extent of the coupling, with delta = 0 corresponding to local coupling, and alpha, describing the extent of the asymmetry, with alpha = 0 corresponding to symmetric nonlocal interactions. We consider the case where the local model admits a stable coexistence (populations of both species positive) equilibrium solution. We perform a linear stability analysis and show that this solution can be destabilized by sufficient nonlocality, i.e., when delta increases beyond a critical value. We then consider nonlinear patterns, far from the stability boundary. We show that nonlinear patterns consist of arrays of islands, regions of nonzero population, separated by deadzones, where the populations are essentially extinct, (with the array propagating in the case alpha ? 0). The predominant effect of the cubic model is that the islands for the two species are disjoint, so that each species lives in the deadzone of the other species. In addition, some patterns involve both hospitable and inhospitable deadzones, so that islands form in only some of the deadzones. PMID- 25686694 TI - Global stability of an infection-age structured HIV-1 model linking within-host and between-host dynamics. AB - Although much evidence shows the inseparable interaction between the within-host progression of HIV-1 infection and the transmission of the disease at the population level, few models coupling the within-host and between-host dynamics have been developed. In this paper, we adopt the nested approach, viewing the transmission rate at each stage (primary, chronic, and AIDS stage) of HIV-1 infection as a saturated function of the viral load, to formulate an infection age structured epidemic model. We explicitly link the individual and the host population scale, and derive the basic reproduction number R0 for the coupled system. To analyze the model and perform a detailed global dynamics analysis, two Lyapunov functionals are constructed to prove the global asymptotical stability of the disease-free and endemic equilibria. Theoretical results indicate that R0 provides a threshold value determining whether or not the disease dies out. Numerical simulations are presented to quantitatively investigate the influence of the within-host viral dynamics on between-host transmission dynamics. The results suggest that increasing the effectiveness of inhibitors can decrease the basic reproduction number, but can also increase the overall infected population because of a lower disease-induced mortality rate and a longer lifespan of HIV infected individuals. PMID- 25686695 TI - Microbial diagnosis of bloodstream infection: towards molecular diagnosis directly from blood. AB - When a bloodstream infection (BSI) is suspected, most of the laboratory results biochemical and haematologic-are available within the first hours after hospital admission of the patient. This is not the case for diagnostic microbiology, which generally takes a longer time because blood culture, which is to date the reference standard for the documentation of the BSI microbial agents, relies on bacterial or fungal growth. The microbial diagnosis of BSI directly from blood has been proposed to speed the determination of the etiological agent but was limited by the very low number of circulating microbes during these paucibacterial infections. Thanks to recent advances in molecular biology, including the improvement of nucleic acid extraction and amplification, several PCR-based methods for the diagnosis of BSI directly from whole blood have emerged. In the present review, we discuss the advantages and limitations of these new molecular approaches, which at best complement the culture-based diagnosis of BSI. PMID- 25686697 TI - Step behaviour and autonomic nervous system activity in multiparous dairy cows during milking in a herringbone milking system. AB - Behavioural and cardiac responses of multiparous dairy cows (n=24) during milking in a 2*4 stall herringbone milking system were evaluated in this study. Heart rate (HR), parasympathetic tone index (high frequency component, HF) of heart rate variability and sympathovagal balance indicator LF/HF ratio (the ratio of the low frequency (LF) and the HF component) were analysed. Measurement periods were established as follows: (1) standing calm (baseline), (2) udder preparation, (3) milking, (4) waiting after milking in the milking stall and (5) in the night (2 h after milking). Step behaviour was recorded and calculated per minute for the three phases of the milking process (udder preparation, milking and waiting after milking). HR was higher during udder preparation and milking compared with baseline (P=0.03, 0.027, respectively). HF was significantly lower than baseline levels during waiting in the milking stall after milking (P=0.009), however, during udder preparation, milking and 2 h after milking did not differ from baseline (P>0.05, in either case). LF/HF during the three phases of the milking process differed neither from baseline levels nor from each other. Steps occurred more often during waiting after milking than during udder preparation (P=0.042) or during milking (23; P=0.017). Our results suggest that the milking procedure itself was not stressful for these animals. After milking (following the removal of the last teat cup and before leaving the milking stall), both decreased parasympathetic tone (lower HF) and increased stepping rate indicated a sensitive period for animals during this phase. PMID- 25686696 TI - Current preventive strategies and management of Epstein-Barr virus-related post transplant lymphoproliferative disease in solid organ transplantation in Europe. Results of the ESGICH Questionnaire-based Cross-sectional Survey. AB - There is limited clinical evidence on the utility of the monitoring of Epstein Barr virus (EBV) DNAemia in the pre-emptive management of post-transplant lymphoproliferative disease (PTLD) in solid organ transplant (SOT) recipients. We investigated current preventive measures against EBV-related PTLD through a web based questionnaire sent to 669 SOT programmes in 35 European countries. This study was performed on behalf of the ESGICH study group from the European Society of Clinical Microbiology and Infectious Diseases. A total of 71 SOT programmes from 15 European countries participated in the study. EBV serostatus of the recipient is routinely obtained in 69/71 centres (97%) and 64 (90%) have access to EBV DNAemia assays. EBV monitoring is routinely used in 85.9% of the programmes and 77.4% reported performing pre-emptive treatment for patients with significant EBV DNAemia levels. Pre-emptive treatment for EBV DNAemia included reduction of immunosuppression in 50.9%, switch to mammalian target of rapamycin inhibitors in 30.9%, and use of rituximab in 14.5% of programmes. Imaging by whole-body 18-fluoro-deoxyglucose positron emission tomography (FDG-PET) is used in 60.9% of centres to rule out PTLD and complemented computer tomography is used in 50%. In 10.9% of centres, FDG-PET is included in the first-line diagnostic workup in patients with high-risk EBV DNAemia. Despite the lack of definitive evidence, EBV load measurements are frequently used in Europe to guide diagnostic workup and pre-emptive reduction of immunosuppression. We need prospective and controlled studies to define the impact of EBV monitoring in reducing the risk of PTLD in SOT recipients. PMID- 25686698 TI - Cytotoxicity of phenothiazine derivatives associated with mitochondrial dysfunction: a structure-activity investigation. AB - Phenothiazine derivatives are neuroleptic drugs used in the treatment of schizophrenia and anxiety. Several side effects are described for these drugs, including hepatotoxicity, which may be related to their cytotoxic activity. Working with isolated rat liver mitochondria, we previously showed that phenothiazine derivatives induced the mitochondrial permeability transition associated with cytochrome c release. Since the mitochondrial permeabilization process plays a central role in cell death, the aim of this work was to evaluate the effects of five phenothiazine derivatives (chlorpromazine, fluphenazine, thioridazine, trifluoperazine, and triflupromazine) on the viability of hepatoma tissue culture (HTC) cells to establish the structural requirements for cytotoxicity. All phenothiazine derivatives decreased the viability of the HTC cells in a concentration-dependent manner and exhibited different cytotoxic potencies. The EC50 values ranged from 45 to 125 MUM, with the piperidinic derivative thioridazine displaying the most cytotoxicity, followed by the piperazinic and aliphatic derivatives. The addition of the phenothiazine derivatives to cell suspensions resulted in significant morphological changes and plasma membrane permeabilization. Octanol/water partition studies revealed that these drugs partitioned preferentially to the apolar phase, even at low pH values (<=4.5). Also, structural and electronic properties were calculated employing density functional theory. Interestingly, the phenothiazine derivatives promoted an immediate dissipation of the mitochondrial transmembrane potential in HTC cells, and the EC50 values were closely correlated with those obtained in cell viability assays, as well as the EC50 for swelling in isolated mitochondria. These results significantly contribute to improving our understanding of the specific structural requirements of the phenothiazine derivatives to induce cell death and suggest the involvement of the mitochondrial permeability transition in phenothiazine-induced cytotoxicity in HTC cells. PMID- 25686699 TI - LncRNA Dum interacts with Dnmts to regulate Dppa2 expression during myogenic differentiation and muscle regeneration. AB - Emerging studies document the roles of long non-coding RNAs (LncRNAs) in regulating gene expression at chromatin level but relatively less is known how they regulate DNA methylation. Here we identify an lncRNA, Dum (developmental pluripotency-associated 2 (Dppa2) Upstream binding Muscle lncRNA) in skeletal myoblast cells. The expression of Dum is dynamically regulated during myogenesis in vitro and in vivo. It is also transcriptionally induced by MyoD binding upon myoblast differentiation. Functional analyses show that it promotes myoblast differentiation and damage-induced muscle regeneration. Mechanistically, Dum was found to silence its neighboring gene, Dppa2, in cis through recruiting Dnmt1, Dnmt3a and Dnmt3b. Furthermore, intrachromosomal looping between Dum locus and Dppa2 promoter is necessary for Dum/Dppa2 interaction. Collectively, we have identified a novel lncRNA that interacts with Dnmts to regulate myogenesis. PMID- 25686700 TI - Involvement of an extracellular fungus laccase in the flavonoid metabolism in Citrus fruits inoculated with Alternaria alternata. AB - Fungi of the genus Alternaria are responsible for substantial pre-harvest losses in Citrus. In this study a degradative metabolism of flavonoids (flavanones, flavones and polymethoxyflavones) was observed when 'Fortune' mandarin, Citrus limon and Citrus paradisi, fruits were inoculated with Alternaria alternata, a pre-harvest pathogenic fungus. Associated to this flavonic metabolism the de novo synthesis of the phytoalexin scoparone was detected. This metabolism of flavonoids is caused by an extracellular fungus laccase. The kinetic characterisation of this enzyme revealed that the activity was induced by Citrus flavonoids and was dependent on flavonoid concentrations. The enzyme exhibited a Km of 1.9 mM using ABTS as substrate with an optimum pH of 3.5 in citrate buffer 100 mM. The enzyme is active between 15 and 45 degrees C, the optimum temperature being around 35 degrees C, although 50% of the initial activity is lost after 45 min at 35 degrees C. The A. alternata laccase was inhibited by 0.5 mM l-cysteine and by caffeic acid. Study of the substrate specificity of this enzyme revealed that Citrus flavonoids are substrates of A. alternata laccase. These results suggest that the laccase enzyme could be involved in the pathogenesis of A. alternata in Citrus. PMID- 25686701 TI - Expression of an exogenous 1-aminocyclopropane-1-carboxylate deaminase gene in psychrotolerant bacteria modulates ethylene metabolism and cold induced genes in tomato under chilling stress. AB - The role of stress induced ethylene under low temperature stress has been controversial and hitherto remains unclear. In the present study, 1 aminocyclopropane-1-carboxylate deaminase (ACCD) gene, acdS expressing mutant strains were generated from ACCD negative psychrotolerant bacterial strains Flavobacterium sp. OR306 and Pseudomonas frederiksbergensis OS211, isolated from agricultural soil during late winter. After transformation with plasmid pRKACC which contained the acdS gene, both the strains were able to exhibit ACCD activity in vitro. The effect of this ACCD under chilling stress with regards to ethylene was studied in tomato plants inoculated with both acdS expressing and wild type bacteria. On exposing the plants to one week of chilling treatment at 12/10 degrees C, it was found that stress ethylene, ACC accumulation and ACO activity which are markers of ethylene stress, were significantly reduced in plants inoculated with the acdS gene transformed mutants. In case of plants inoculated with strain OS211-acdS, ethylene emission, ACC accumulation and ACO activity was significantly reduced by 52%, 75.9% and 23.2% respectively compared to uninoculated control plants. Moreover, expression of cold induced LeCBF1 and LeCBF3 genes showed that these genes were significantly induced by the acdS transformed mutants in addition to reduced expression of ethylene-responsive transcription factor 13 (ETF-13) and ACO genes. Induced expression of LeCBF1 and LeCBF3 in plants inoculated with acdS expressing mutants compared to wild type strains show that physiologically evolved stress ethylene and its transcription factors play a role in regulation of cold induced genes as reported earlier in the literature. PMID- 25686702 TI - Transcription factors and anthocyanin genes related to low-temperature tolerance in rd29A:RdreB1BI transgenic strawberry. AB - Dehydration-responsive element-binding (DREB) transcription factors play critical roles in plant stress responses and signal transduction. To further understand how DREB regulates genes expression to promote cold-hardiness, Illumina/Solexa sequencing technology was used to compare the transcriptomes of non-transgenic and rd29A:RdreB1BI transgenic strawberry plants exposed to low temperatures. Approximately 3.5 million sequence tags were obtained from non-transgenic (NT) and transgenic (T) strawberry untreated (C) or low-temperature treated (LT) leaf samples. Over 1000 genes were differentially expressed between the NT-C and T-C plants, and also the NT-C and NT-LT, as well as the T-C and T-LT plants. Analysis of the genes up-regulated following low-temperature treatment revealed that the majority are linked to metabolism, biosynthesis, transcription and signal transduction. Uniquely up-regulated transcription factors as well as anthocyanin biosynthetic pathway genes are discussed. Accumulation of anthocyanin in the stolon and the base of the petiole differed between non-treated NT and T plants, and this correlated with gene expression patterns. The differentially expressed genes that encode transcription factors and anthocyanin enzymes may contribute to the cold hardiness of RdreB1BI transgenic strawberry. The transcriptome data provide a valuable resource for further studies of strawberry growth and development and DREB-mediated gene regulation under low-temperature stress. PMID- 25686703 TI - Anti-metastatic effect of deoxyelephantopin from Elephantopus scaber in A549 lung cancer cells in vitro. AB - In this study, we focused on the in vitro anti-metastatic effects of deoxyelephantopin (DOE), a sesquiterpene lactone from Elephantopus scaber on lung cancer A549 cells. DOE significantly decreased the metastatic potential of A549 cells as demonstrated by transwell invasion and migration assay. DOE inhibited the expression of matrix metalloproteinase-2 (MMP-2), MMP-9, urokinase-type plasminogen activator and urokinase-type plasminogen activator receptor at transcript level. Tissue inhibitors of metalloproteinase-2 (TIMP-2) mRNA levels was up-regulated in A549 tumour cells without any change in TIMP-1 expression after DOE treatment. DOE inhibited the protein levels of p-ERK1/2 and p-Akt in A549 cells but it activated p-JNK, p-p38 protein expression. NF-kappaB and IkappaBalpha expressions were down-regulated in DOE-treated cells. All these results demonstrated that DOE has shown anti-metastatic activity against A549 tumour cells. PMID- 25686704 TI - The third term. PMID- 25686705 TI - Xanthogranulomatous inflammation of terminal ileum: report of a case with small bowel involvement. AB - Xanthogranulomatous inflammation is a rare pathological condition most frequently detected in the kidney and gallbladder. Reported herein is a case of xanthogranulomatous inflammation in a 51-year-old male presenting as a mass forming lesion in the terminal ileum with mucosal ulceration. Diagnostic laparoscopy followed by ileocecectomy was performed due to intra-operative suspicion of carcinoma of appendix. This is a report of the condition involving the terminal ileum with mucosal ulceration and full-thickness involvement of bowel wall which are uncommon features of xanthogranulomatous inflammation in previously reported lower gastro-intestinal tract lesions. PMID- 25686706 TI - Magnetic resonance imaging features of vascular leiomyoma of the ankle. AB - Vascular leiomyoma is a benign soft tissue tumour with a predilection for middle aged women. It is most often seen in the extremities, particularly in the lower leg. The typical lesion is a small, slow-growing subcutaneous nodule. These tumours are often unexpected or preoperatively confused with other soft tissue tumours including low-grade sarcomas, leading to wide surgical excision. This may partly be due to the relatively few studies delineating the characteristic imaging features of this entity. Here, the imaging findings of a case of vascular leiomyoma in the ankle are presented. Literature review of the magnetic resonance imaging findings of published reports and series of vascular leiomyomas of the extremities is also performed. PMID- 25686707 TI - Synthetic fibre granuloma of the conjunctiva. AB - Synthetic fibre granuloma of the conjunctiva, sometimes known as 'teddy bear granuloma', results from granulomatous foreign body reaction of the conjunctiva to synthetic fibres. It is often an incidental finding, most commonly found in children, is unilateral, and occurs in the lower eyelid. We present here, what we believe is the first reported case of synthetic fibre conjunctival granuloma in Hong Kong, together with a review of the condition. An awareness of this clinical entity allows early and accurate diagnosis and early treatment. PMID- 25686708 TI - From observation to aetiology: a case report of a twin fetus-in-fetu and a revisit of the known rarity. AB - A baby girl presented with an antenatal diagnosis of a retroperitoneal tumour. Postnatal imaging suggested that this mass contained two fetiform structures with spine and long bone formation. This teratomatous mass was completely excised at 3 weeks of age. Histology was consistent with twin fetuses-in-fetu, revealing two fetiform masses each with an umbilical cord connecting to a common placenta-like mass. Despite a difference in the weight of the twin fetuses-in-fetu, the level of organogenesis was identical and corresponded to fetuses of 10 weeks of gestation. Each mass had four limbs, intact skin, rib cage, intestines, anus, ambiguous genitalia, primitive brain tissue and a spine with ganglion cells in the cord. Although considered a mature teratoma in the current World Health Organization classification, the theory of formation from multiple pregnancies has been commonly implied in more recent literature. The true aetiology of this rare condition remains unclear. PMID- 25686709 TI - Double-chambered right ventricle: a commonly overlooked diagnosis. PMID- 25686710 TI - Inflammatory myoglandular polyps of the rectum. PMID- 25686711 TI - Targeting cancer stem cells in breast cancer: potential anticancer properties of 6-shogaol and pterostilbene. AB - Breast cancer stem cells (BCSCs) constitute a small fraction of the primary tumor that can self-renew and become a drug-resistant cell population, thus limiting the treatment effects of chemotherapeutic drugs. The present study evaluated the cytotoxic effects of five phytochemicals including 6-gingerol (6-G), 6-shogaol (6 S), 5-hydroxy-3,6,7,8,3',4'-hexamethoxyflavone (5-HF), nobiletin (NOL), and pterostilbene (PTE) on MCF-7 breast cancer cells and BCSCs. The results showed that 6-G, 6-S, and PTE selectively killed BCSCs and had high sensitivity for BCSCs isolated from MCF-7 cells that expressed the surface antigen CD44(+)/CD24( ). 6-S and PTE induced cell necrosis phenomena such as membrane injury and bleb formation in BCSCs and inhibited mammosphere formation. In addition, 6-S and PTE increased the sensitivity of isolated BCSCs to chemotherapeutic drugs and significantly increased the anticancer activity of paclitaxel. Analysis of the underlying mechanism showed that 6-S and PTE decreased the expression of the surface antigen CD44 on BCSCs and promoted beta-catenin phosphorylation through the inhibition of hedgehog/Akt/GSK3beta signaling, thus decreasing the protein expression of downstream c-Myc and cyclin D1 and reducing BCSC stemness. PMID- 25686712 TI - Silver sulfide nanoparticles (Ag2S-NPs) are taken up by plants and are phytotoxic. AB - Silver nanoparticles (NPs) are used in more consumer products than any other nanomaterial and their release into the environment is unavoidable. Of primary concern is the wastewater stream in which most silver NPs are transformed to silver sulfide NPs (Ag2S-NPs) before being applied to agricultural soils within biosolids. While Ag2S-NPs are assumed to be biologically inert, nothing is known of their effects on terrestrial plants. The phytotoxicity of Ag and its accumulation was examined in short-term (24 h) and longer-term (2-week) solution culture experiments with cowpea (Vigna unguiculata L. Walp.) and wheat (Triticum aestivum L.) exposed to Ag2S-NPs (0-20 mg Ag L(-1)), metallic Ag-NPs (0-1.6 mg Ag L(-1)), or ionic Ag (AgNO3; 0-0.086 mg Ag L(-1)). Although not inducing any effects during 24-h exposure, Ag2S-NPs reduced growth by up to 52% over a 2-week period. This toxicity did not result from their dissolution and release of toxic Ag(+) in the rooting medium, with soluble Ag concentrations remaining below 0.001 mg Ag L(-1). Rather, Ag accumulated as Ag2S in the root and shoot tissues when plants were exposed to Ag2S-NPs, consistent with their direct uptake. Importantly, this differed from the form of Ag present in tissues of plants exposed to AgNO3. For the first time, our findings have shown that Ag2S-NPs exert toxic effects through their direct accumulation in terrestrial plant tissues. These findings need to be considered to ensure high yield of food crops, and to avoid increasing Ag in the food chain. PMID- 25686713 TI - Long-term prevalence of NIRF-labeled magnetic nanoparticles for the diagnostic and intraoperative imaging of inflammation. AB - Inflammation is a very common disease worldwide. In severe cases, surgery is often the method of choice. Today, there is a general need for the implementation of image-based guidance methodologies for reliable target resection. We investigated new near infrared fluorescence (NIRF)-nanoparticles (NPs) as a simple but effective bimodal magnetic resonance imaging (MRI) and optical contrast agent for diagnosis and intraoperative imaging of inflammation. Physicochemical analysis revealed that these NPs were highly fluorescent with similar characteristics like unlabeled NPs (hydrodynamic diameter about 130 nm and zeta potential about -10 mV). NP-uptake and NIR-dye labeling was biocompatible to macrophages (no impact on cellular ATP and reactive oxygen species production). These cells could successfully be tracked with MRI and NIRF optical imaging. I.v. injection of fluorescent NPs into mice led to highly specific T2-weighted signal of edema due to uptake by phagocytic cells and subsequent migration to the site of inflammation. NIRF signals of the edema region were well detectable for up to 4 weeks, underlining the potential of the NPs for systematic planning and flexible time scheduling in intraoperative applications. NPs were degraded over a time period of 12 weeks, which was not altered due to inflammation. Redistribution of iron might be primarily due to inflammation and not to the presence of NPs per se in a concentration suitable for imaging. Our findings highlight the potential of the NPs to be used as a suitable tool for pre- and intraoperative imaging of inflammation. PMID- 25686714 TI - Identification of five Shiga toxin-producing Escherichia coli genes by Luminex microbead-based suspension array. AB - To rapidly identify the presence of potentially virulent O157:H7 and non-O157 Shiga toxin-producing Escherichia coli (STEC), a PCR-based Luminex suspension assay was developed to detect the genes coding for four virulence factors (stx1, stx2, eae, and ehxA) plus the O157:H7-specific +93 uidA single nucleotide polymorphism. PMID- 25686715 TI - [Exploration of renal glomerular function: estimation of glomerular filtration rate]. AB - In addition to direct measurement methods of glomerular filtration rate, there are many formulas whose purpose is to estimate glomerular filtration rate from endogenous markers, of which the most used is serum creatinine. The latest recommendations the French health agency Haute Autorite de sante (HAS) unambiguously endorse the use of the CKD-EPI equation. The assessment of glomerular filtration rate from this equation however remains approximate in many situations where the plasma creatinine concentration poorly reflects the glomerular filtration rate. In these situations, plasma cystatin C could potentially be a more reliable alternative to endogenous plasma creatinine marker, especially since a reference standard for the determination of serum cystatin C concentration has recently been developed. Use of serum cystatin C concentration in clinical practice begins to be mentioned, but still needs to be fully validated. PMID- 25686716 TI - Biological potential of microalgae in China for biorefinery-based production of biofuels and high value compounds. AB - Microalgae abundance and diversity in China shows promise for identifying suitable strains for developing algal biorefinery. Numerous strains of microalgae have already been assessed as feedstocks for bioethanol and biodiesel production, but commercial scale algal biofuel production is yet to be demonstrated, most likely due to huge energy costs associated with algae cultivation, harvesting and processing. Biorefining, integrated processes for the conversion of biomass into a variety of products, can improve the prospects of microalgal biofuels by combining them with the production of high value co-products. Numerous microalgal strains in China have been identified as producers of various high value by products with wide application in the medicine, food, and cosmetics industries. This paper reviews microalgae resources in China and their potential in producing liquid biofuels (bioethanol and biodiesel) and high value products in an integrated biorefinery approach. Implementation of a 'high value product first' principle should make the integrated process of fuels and chemicals production economically feasible and will ensure that public and private interest in the development of microalgal biotechnology is maintained. PMID- 25686717 TI - Cambial meristematic cells: a platform for the production of plant natural products. AB - Plant cell culture constitutes a sustainable, controllable and environmentally friendly tool to produce natural products for the pharmaceutical, cosmetic and industrial biotechnology industries. However, there are significant obstacles to the commercial synthesis of high value chemicals from plant culture including low yields, performance instability, slow plant cell growth, industrial scale-up and downstream processing. Cambial meristematic cells constitute a platform to ameliorate many of these potential problems enabling the commercial production of high value chemicals. PMID- 25686718 TI - Nickel and platinum group metal nanoparticle production by Desulfovibrio alaskensis G20. AB - Desulfovibrio alaskensis G20 is an anaerobic sulfate reducing bacteria. While Desulfovibrio species have previously been shown to reduce palladium and platinum to the zero-state, forming nanoparticles in the process; there have been no reports that D. alaskensis is able to form these nanoparticles. Metal nanoparticles have properties that make them ideal for use in many industrial and medical applications, such as their size and shape giving them higher catalytic activity than the bulk form of the same metal. Nanoparticles of the platinum group metals in particular are highly sought after for their catalytic ability and herein we report the formation of both palladium and platinum nanoparticles by D. alaskensis and the biotransformation of solvated nickel ions to nanoparticle form. PMID- 25686719 TI - Surfactants modify the torsion properties of proteins: a single molecule study. AB - Surfactants are widely used in diagnostic assays to prevent protein aggregation and non-specific adsorption at surfaces. Here, a single molecule magnetic torque tweezers study is reported, aiming to quantify surfactant-induced changes in the torsional flexibility of a protein model system: protein-G-immunoglobulin G (IgG) attached to a glass surface. The influences of Sodium Dodecyl Sulphate (SDS) and Polysorbate 20 (Tween 20) on the protein pair have been investigated. The proteins were exposed to the surfactants at concentrations relative to the Critical Micelle Concentration (CMC), namely 0.1* CMC, 1* CMC and 10* CMC. Both surfactants increase the torsional flexibility of the protein-G-IgG complex. Tween 20 is most effective at increasing the torsional flexibility of the complex at the surface while SDS is more effective at dissociating the protein bonds. Tweezer data on the IgG-IgG protein pair show no influence of Tween 20 on the torsional flexibility. Furthermore, temperature dependent near-UV and far-UV Circular Dichroism (CD) data at 10* CMC show that Tween 20 does not significantly alter the secondary and tertiary structure of both protein-G and IgG while SDS does. These results provide evidence that both the mechanical properties of the protein structure and the interaction between proteins can alter the torsional rigidity measured with magnetic torque tweezers. This study shows for the first time the ability to use magnetic torque tweezers as a probe for surfactant induced changes in proteins at a single molecule level. PMID- 25686720 TI - Ara h 1 protein-antibody dissociation study: evidence for binding inhomogeneities on a molecular scale. AB - The characterization of biomolecular interactions is essential when designing novel biosensors, since the interaction between the bioreceptor and the ligand determines important biosensing parameters such as sensitivity and selectivity. In this paper we study the interaction of the trimeric Ara h 1 protein with a monoclonal anti-Ara h 1 antibody by means of magnetic force-induced dissociation. The proteins were bound to magnetic particles and polystyrene surfaces by EDC/NHS reaction chemistry and by physisorption, respectively. Two different molecular configurations have been investigated, with either the Ara h 1 protein on the particles or the Ara h 1 protein on the polystyrene surface. A model with a Gaussian distribution of energy barriers for dissociation gives an adequate description for the measured multi-exponential decays. We hypothesize that distributions of molecular orientations as well as experimentally induced variations may underlay the observed distributions. The two molecular configurations show a different peak value of the energy distribution. Similarly, SPR experiments for two distinct configurations (either Ara h 1 protein on the surface, or anti-Ara h 1 antibody on the surface) also show clear differences in dissociation behavior. We hypothesize that the multivalency of the involved molecules leads to different modes of binding. The results of this work highlight the importance of molecular inhomogeneities when studying the interaction processes of biomolecular complexes. PMID- 25686721 TI - Encapsulated Lactococcus lactis with enhanced gastrointestinal survival for the development of folate enriched functional foods. AB - Two lactic acid bacteria (LAB) isolated from cow's milk were identified as Lactococcus lactis strains and designated as L. lactis CM22 and L. lactis CM28. They were immobilised by co-encapsulation using alginate and mannitol and by hybrid entrapment with skim milk, glycerol, CaCO3 and alginate. The encapsulated cells survived better in simulated gastrointestinal conditions compared to the free cells. The percentage survival of probiotics encapsulated by hybrid entrapment method was 62.74% for L. lactis CM22 and 68% for L. lactis CM28. Studies to check their efficacy in fermentative fortification of skim milk and ice cream revealed an enhancement in folate level. PMID- 25686722 TI - Dark fermentative bioconversion of glycerol to hydrogen by Bacillus thuringiensis. AB - Biodiesel manufacturing units discharge effluents rich in glycerol. The need is to convert crude glycerol (CG) into useful products such as hydrogen (H2). Under batch culture, Bacillusthuringiensis EGU45 adapted on pure glycerol (PG, 2% v/v) resulted in an H2 yield of 0.646 mol/mol glycerol consumed on minimal media (250 mL) supplemented with 1% ammonium nitrate at 37 degrees C over 4 days. Here, H2 constituted 67% of the total biogas. Under continuous culture, at 2 days of hydraulic retention time, B. thuringiensis immobilized on ligno-cellulosic materials (banana leaves - BL, 10% v/v) resulted in a H2 yield of 0.386 mol/mol PG consumed. On CG, the maximal H2 yield of 0.393 mol/mol feed consumed was recorded. In brief, B. thuringiensis could transform CG, on limited resources - minimal medium with sodium nitrate, by immobilizing them on cheap and easily available biowaste, which makes it a suitable candidate for H2 production on a large scale. PMID- 25686723 TI - Cloning and expression of gamma carbonic anhydrase from Serratia sp. ISTD04 for sequestration of carbon dioxide and formation of calcite. AB - Bacterial strains isolated from marble mines rock and enriched in the chemostat culture with different concentrations of sodium bicarbonate. The enriched consortium had six bacterial isolates. One of bacterium isolate showed carbonic anhydrase (CA) activity by catalyzing the reversible hydration reaction of carbon dioxide to bicarbonate. The bacterium was identified as Serratia sp. by 16S rRNA sequence analysis. The carbonic anhydrase gene from Serratia sp. was found to be homologous with gamma carbonic anhydrase. The carbonic anhydrase gene was cloned in PET21b(+) and expressed it in recombinant Escherichia coli BL21 (DE3) with His tag at the C-terminus. The recombinant protein was purified efficiently by using one-step nickel affinity chromatography. Expected size of carbonic anhydrase was approximately 29 kDa in SDS-PAGE gel. Recombinant carbonic anhydrase enzyme was used for biomineralization-based conversion of atmospheric CO2 into valuable calcite minerals. The calcification was confirmed by using XRD, FTIR, EDX and SEM analysis. PMID- 25686724 TI - Malathion-induced testicular toxicity is associated with spermatogenic apoptosis and alterations in testicular enzymes and hormone levels in male Wistar rats. AB - Malathion has a broad range of toxicities while its reproductive effects have not been fully elucidated. In this study, we treated animals with malathion by gavage at doses of 0, 33.75, 54, and 108 mg/kg for 60 days and evaluated the alterations in histology, biochemistry and serology. Malathion caused the reduction in the sperm counts and motility. The reduced body and testis weights were coupled with mild to severe degenerative changes in seminiferous tubules. We found malathion at 54 mg/kg increased spermatogenic apoptosis rate which was confirmed by changes in protein expression of Bax and Bcl-2. The activities of testicular enzymes including ACP, LDH and gamma-GT were significantly altered with the reduced level of reproductive hormones such as LH, FSH and T. These results indicate that malathion can elicit deleterious effects on reproductive system of rats. The abnormal levels of hormones and apoptotic proteins induced by malathion may play important roles. PMID- 25686725 TI - Development of docetaxel nanocapsules for improving in vitro cytotoxicity and cellular uptake in MCF-7 cells. AB - The aim of this study was to fabricate docetaxel loaded nanocapsules (DTX-NCs) with a high payload using Layer-by-Layer (LbL) technique by successive coating with alternate layers of oppositely charged polyelectrolytes. Developed nanocapsules (NCs) were characterized in terms of morphology, particle size distribution, zeta potential (zeta-potential), entrapment efficiency and in vitro release. The morphological characteristics of the NCs were assessed using transmission electron microscopy (TEM) that revealed coating of polyelectrolytes around the surface of particles. The developed NCs successfully attained a submicron particle size while the zeta-potential of optimized NCs alternated between (+) 34.64 +/- 1.5 mV to (-) 33.25 +/- 2.1 mV with each coating step. The non-hemolytic potential of the NCs indicated the suitability of the developed formulation for intravenous administration. A comparative study indicated that the cytotoxicity of positively charged NCs (F4) was significant higher (p < 0.05) rather than negative charged NCs (F3), plain drug (DTX) and marketed preparation (Taxotere(r)) when evaluated in vitro on MCF-7 cells. Furthermore, cell uptake studies evidenced a higher uptake of positive NCs (>=1.2 fold) in comparison to negative NCs. In conclusion, formulated NCs are an ideal vehicle for passive targeting of drugs to tumor cells that may result in improved efficacy and reduced toxicity of encapsulated drug moiety. PMID- 25686726 TI - Phospholipid complex as an approach for bioavailability enhancement of echinacoside. AB - CONTEXT: Echinacoside (ECH) has been shown to possess a multitude of pharmacological activities, however, oral administered ECH failed to fulfill its therapeutic potential due to poor absorption and low bioavailability. Thus, there is a pressing need to develop a new oral dosage form to enhance its intestinal absorption and improve bioavailability. OBJECTIVE: The aim of this study was to formulate ECH into phospholipid complex (phytosome, PHY) to enhance intestinal absorption and oral bioavailability of ECH in vivo. METHODS: The PHY was prepared by a solvent evaporation method and was characterized by differential scanning calorimetry (DSC) and infrared spectroscopy (IR), and then the physicochemical properties, intestinal absorption and bioavailability of the PHY were investigated. RESULTS: Compared with the physical mixture (MIX) or ECH alone, the n-octanol/water partition coefficient (P) determination results showed that the lipophilicity of ECH was significantly enhanced by formation of PHY. Accordingly, the intestinal absorption rate (Ka) was improved to 2.82-fold and the effective permeability coefficient (Peff) increased to 3.39-fold. The concentrations of ECH in rat plasma at different times after oral administration of PHY were determined by HPLC. Pharmacokinetic parameters of the PHY in rats were Tmax = 1.500 h, Cmax = 3.170 mg/mL, AUC0-infinity = 9.375 mg/L h and AUC0-24 = 7.712 mg/L h, respectively. CONCLUSIONS: Compared with ECH alone or the MIX group, the relative bioavailability of ECH was increased significantly after formulation into PHY (p < 0.05). This might be mainly due to an improvement of the absorption of PHY. PMID- 25686727 TI - Possibility of wine dating using the natural Pb-210 radioactive isotope. AB - To control the authenticity of an old wine without opening the bottle, we developed a few years ago a method based on the measurement of the (137)Cs activity. However, for recent vintages, the (137)Cs activity drops to far too low values (most of the time less than 10 mBq/L for a 10-year-old wine) for this method to perform correctly. In this paper we examine the possibility to date wines using the natural radio-element (210)Pb which has a 22-year period. This new method we propose implies the opening of the bottle and the follow-on destruction of the wine itself, which means that it can only be used for investigating non-expensive bottles or wine lots where there are multiple bottles of the same provenance. Uncertainties on the resulting (210)Pb radioactivity values are large, up to more than 50%, mainly due to local atmospheric variations, which prevents us to carry out precise dating. However it can be used to discriminate between an old wine (pre-1952) and a young wine (past-1990), an information that cannot be obtained with the other techniques based on other isotopes ((137)Cs, (14)C or tritium). PMID- 25686728 TI - Simultaneous submicrometric 3D imaging of the micro-vascular network and the neuronal system in a mouse spinal cord. AB - Faults in vascular (VN) and neuronal networks of spinal cord are responsible for serious neurodegenerative pathologies. Because of inadequate investigation tools, the lacking knowledge of the complete fine structure of VN and neuronal system represents a crucial problem. Conventional 2D imaging yields incomplete spatial coverage leading to possible data misinterpretation, whereas standard 3D computed tomography imaging achieves insufficient resolution and contrast. We show that X ray high-resolution phase-contrast tomography allows the simultaneous visualization of three-dimensional VN and neuronal systems of ex-vivo mouse spinal cord at scales spanning from millimeters to hundreds of nanometers, with nor contrast agent nor sectioning and neither destructive sample-preparation. We image both the 3D distribution of micro-capillary network and the micrometric nerve fibers, axon-bundles and neuron soma. Our approach is very suitable for pre clinical investigation of neurodegenerative pathologies and spinal-cord-injuries, in particular to resolve the entangled relationship between VN and neuronal system. PMID- 25686729 TI - Azithromycin use in patients with cystic fibrosis. AB - Rational antimicrobial administration is still considered to be the most effective therapeutic approach in cystic fibrosis (CF), and long-term treatment with azithromycin (Az) is included in the current guidelines for CF patients aged >= 6 years. Az has microbiological, immunomodulatory and anti-inflammatory properties that can reduce some of the biological problems that are among the causes of the progressive lung damage associated with CF. Moreover, although it is not active against Pseudomonas aeruginosa (the most important bacterial pathogen responsible for infectious exacerbations), it can be efficiently used in the case of P. aeruginosa infections because sub-inhibitory concentrations can reduce their pathogenic role by interfering with some bacterial activities and increasing their susceptibility to antibiotics. Az also has anti-viral activity that limits the risk of the bacterial pulmonary exacerbations that frequently occur after apparently mild viral infections. The available data seem to indicate that it is effective during its first year of administration, but the impact of longer treatment is debated. Other still undefined aspects of the use of Az include the possible emergence of antibiotic resistance in the other bacterial pathogens that usually colonise CF patients, the real incidence of adverse events and the drug's potential interference with other routine therapies. PMID- 25686730 TI - Predicting Clostridium difficile infection in diabetic patients and the effect of metformin therapy: a retrospective, case-control study. AB - Data on risk factors for Clostridium difficile infection (CDI) in diabetic patients are scarce. Recently, it has been shown that metformin increases the Bacteroidetes/Firmicutes ratio; therefore, it may yield a protective effect against CDI. We aimed to assess risk factors for CDI in diabetic patients beyond antibiotic treatment, and to determine the impact of metformin therapy on the development of CDI in these patients. In this retrospective, case-control study, all consecutive CDI diabetic patients, from January 2009 to December 2013, were included and compared to consecutive diabetic patients without CDI, hospitalized during the same period and in the same departments. Of 7,670 patients tested for C. difficile toxins, 486 were diabetics. Of them, 150 (30.8 %) were positive for C. difficile toxins and 336 (69.1 %) were negative. On multivariate analysis, metformin treatment was associated with a significant reduction in CDI [odds ratio (OR) = 0.58; 95 % confidence interval (CI), 0.37-0.93; p = 0.023], while heart failure was associated with significantly higher rates of CDI (OR = 1.654; 95 % CI, 1.007-2.716; p = 0.047), together with poor functional status, previous hospitalization, and abdominal surgery. Our findings suggest that, in diabetic patients, in addition to the well-recognized risk factors, heart failure is an additional risk factor for CDI, while metformin treatment seems to have a protective effect against the development of CDI. The exact mechanisms underlying this protective effect remain to be fully understood. PMID- 25686731 TI - Bothrops pauloensis snake venom toxins: the search for new therapeutic models. AB - Snake venoms constitute a mixture of bioactive components that are involved not only in envenomation pathophysiology but also in the development of new drugs to treat many diseases. Different enzymatic and non-enzymatic proteins, such as phospholipases A2, hyaluronidases, L-amino acid oxidases, metalloproteinases, serine proteinases, lectins and disintegrins have been isolated and their functional and structural properties described in the literature. Many of these studies have also explored their medicinal potential focusing mainly on anticancer, antithrombotic and microbicide therapies. Bothrops pauloensis is a species found in Brazil, whose venom has been the focus of our studies in order to explore the biochemical and functional characteristics of their components. In this review, we have presented the main results of years of research on different toxins from B. pauloensis emphasizing their therapeutic potential. Studies concerning snake venom toxins to search for new therapeutic models open perspectives for new drug discovery. PMID- 25686732 TI - Hypotensive peptides from snake venoms: structure, function and mechanism. AB - Snake venoms have evolved over millions of years, and some toxins have evolved to specifically target various sites in the cardiovascular system of prey animals, producing prey hypotension. So far, a number of specific hypotensive peptides have been identified from different snake venoms. These snake hypotensive peptides are divided into five classes: bradykinin potentiating peptides, natriuretic peptides, sarafotoxins, Phospholipases A2 and L-type Ca(2+) channel blockers. They differ widely in their structure, mechanism and points of action. Each class has many different isoforms with similar structures but different hypotensive activities. In the last decade, research efforts on snake hypotensive peptides have produced great advance in their understanding and applications in designing antihypertensive agents. In addition, several new classes of hypotensive peptides have been found from snake venoms. This review attempts to provide an overview of the current understanding of the structure, function and mechanism of snake hypotensive peptides. PMID- 25686733 TI - Antiproliferative activity of cobra venom cytotoxins. AB - Cytotoxins (or cardiotoxins, CTs) are small rigid membrane-active proteins of the three-finger toxin (TFT) family. They comprise about 60 amino acid residues, stabilized by four disulphide bridges. CTs, the most abundant proteins in cobra venom are able to kill cancer cells in a dose and time-dependent manner. The present review summarizes the current data on the molecular pathways of cancer cell death, induced by CTs. A relationship between structural characteristics of CTs and mechanism of their antiproliferative activity is reviewed as well. The CT molecules are rigid and their structure does not change significantly, when they interact with their molecular targets. This rigidity facilitates identification of molecular entities, responsible for antiproliferative activity of the toxins. We demonstrate that consideration of a net electrostatic charge and recently introduced HTL (Hydrophobicity of the Tips of the Loops) score allows distinguishing between the two mechanisms of cell death. The first is related to membrane destabilization by the toxins. The second involves their capture inside the cells, followed by interrogation into signal cascades mediated by the proteins, essential for cell life. Via addressing to antibacterial activity of CTs, which is supposed to arise from the plasma membrane damage, we demonstrate that, if membrane deterioration is involved in malignant cell death, the toxic activity of CTs correlates with their HTL scores and net electrostatic charge. We assume the relationship found may be used for rational design of antiproliferative compounds. PMID- 25686734 TI - Research strategies for pain in lumbar radiculopathy focusing on acid-sensing ion channels and their toxins. AB - In lumbar radiculopathy, the dorsal root or dorsal root ganglia (DRG) are compressed or affected by herniated discs or degenerative spinal canal stenosis. The disease is multi-factorial and involves almost all types of pain, such as ischemic, inflammatory, mechanical, and neuropathic pain. Acid-sensing ion channels (ASICs) activated by extracellular acidosis play an important role in pain generation, and the effects of ASICs are widespread in lumbar radiculopathy. ASICs may be involved in the disc degeneration process, which results in disc herniation and, therefore, the compression of the dorsal roots or DRG. ASIC3 is involved in inflammatory pain and ischemic pain, and, likely, mechanical pain. ASIC1a and ASIC3 may have an important effect on control of the vascular tone of the radicular artery. In the central nervous system, ASIC1a modulates the central sensitization of the spinal dorsal horn. Thus, toxins targeting ASICs, because of their specificity, may help elucidate the roles of ASICs in lumbar radiculopathy and could be developed as novel analgesic agents. PMID- 25686735 TI - Organic toxins as tools to understand ion channel mechanisms and structure. AB - Ion channels constitute a varied class of membrane proteins with pivotal roles in cellular physiology and that are fundamental for neuronal signaling, hormone secretion and muscle contractility. Hence, it is not unanticipated that toxins from diverse organisms have evolved to modulate the activity of ion channels. For instance, animals such as cone snails, scorpions, spiders and snakes use toxins to immobilize and capture their prey by affecting ion channel function. This is a beautiful example of an evolutionary process that has led to the development of an injection apparatus from predators and to the existence of toxins with high affinity and specificity for a given target. Toxins have been used in the field of ion channel biophysics for several decades to gain insight into the gating mechanisms and the structure of ion channels. Through the use of these peptides, much has been learned about the ion conduction pathways, voltage-sensing mechanisms, pore sizes, kinetics, inactivation processes, etc. This review examines an assortment of toxins that have been used to study different ion channels and describes some key findings about the structure-function relationships in these proteins through the details of the toxin-ion channel interactions. PMID- 25686736 TI - Biological toxins and medicinal chemistry: research and therapeutic tools. PMID- 25686737 TI - High efficiency silicon nanowire/organic hybrid solar cells with two-step surface treatment. AB - A simple two-step surface treatment process is proposed to boost the efficiency of silicon nanowire/PEDOT:PSS hybrid solar cells. The Si nanowires (SiNWs) are first subjected to a low temperature ozone treatment to form a surface sacrificial oxide, followed by a HF etching process to partially remove the oxide. TEM investigation demonstrates that a clean SiNW surface is achieved after the treatment, in contrast to untreated SiNWs that have Ag nanoparticles left on the surface from the metal-catalyzed etching process that is used to form the SiNWs. The cleaner SiNW surface achieved and the thin layer of residual SiO2 on the SiNWs have been found to improve the performance of the hybrid solar cells. Overall, the surface recombination of the hybrid SiNW solar cells is greatly suppressed, resulting in a remarkably improved open circuit voltage of 0.58 V. The power conversion efficiency has also increased from about 10% to 12.4%. The two-step surface treatment method is promising in enhancing the photovoltaic performance of the hybrid silicon solar cells, and can also be applied to other silicon nanostructure based solar cells. PMID- 25686738 TI - Action of the Hsp70 chaperone system observed with single proteins. AB - In Escherichia coli, the binding of non-native protein substrates to the Hsp70 chaperone DnaK is mediated by the co-chaperone DnaJ. DnaJ accelerates ATP hydrolysis on DnaK, by closing the peptide-binding cleft of DnaK. GrpE catalysed nucleotide exchange and ATP re-binding then lead to substrate release from DnaK, allowing folding. Here we refold immunoglobulin 27 (I27) to better understand how DnaJ-DnaK-GrpE chaperones cooperate. When DnaJ is present, I27 is less likely to misfold and more likely to fold, whereas the unfolded state remains unaffected. Thus, the 'holdase' DnaJ shows foldase behaviour. Misfolding of I27 is fully abrogated when DnaJ cooperates with DnaK, which stabilizes the unfolded state and increases the probability of folding. Addition of GrpE shifts the unfolded fraction of I27 to pre-chaperone levels. These insights reveal synergistic mechanisms within the evolutionary highly conserved Hsp70 system that prevent substrates from misfolding and promote their productive transition to the native state. PMID- 25686739 TI - Nationwide renal biopsy data in Lithuania 1994-2012. AB - BACKGROUND: Our aim was to evaluate the incidence of biopsy-proven kidney diseases in Lithuania and to compare their changes in three different time intervals. All Lithuanian kidney biopsies were performed in the National Center of Pathology, enabling analysis at the national level. METHODS: The native kidney biopsy data were reviewed, and incidence of renal disorders and patient demographics were compared during three time intervals: 1994-1999, 2000-2006, and 2007-2012. RESULTS: A total of 5,368 kidney biopsies were performed, including 3,640 native kidney and 1,728 kidney transplant biopsies; 59.5% (2,165) of the native kidney biopsies were classified as primary glomerulopathies. The most common entity was IgA nephropathy (737; 34.0%), followed by focal segmental glomerulosclerosis (285; 13.2%) and membranoproliferative glomerulonephritis (256; 11.8%). Prominent decrease in incidence of membranoproliferative glomerulonephritis (16.8 to 8.7% from the first to third time interval) and increase in (mainly, pauci-immune) crescentic glomerulonephritis (6.2 to 15.3%) were noted over the study period. In a subgroup of 427 pediatric native kidney biopsies, IgAN accounted for 24.9% of biopsies. The incidence of MCNS increased dramatically from the first to third time interval (6.3 to 25.4%), while the number of MPGN increased in the second time interval (from 7.2 to 8.9%) but decreased in the third one (to 4.4%). CONCLUSIONS: Decrease in relative incidence of membranoproliferative glomerulonephritis, most likely, reflects improvement in socioeconomic conditions, while relative increase in crescentic glomerulonephritis is interpreted as improved diagnostics of the disease. PMID- 25686740 TI - Therapeutic effects and associated adverse events of first-line treatments of advanced renal cell carcinoma (RCC): a meta-analysis. AB - PURPOSE: To compare the therapeutic effects and adverse events (AE) of current first-line treatments of advanced RCC, including sorafenib, sunitinib, temsirolimus, and the combination of bevacizumab and IFN-alpha. METHODS: We performed a meta-analysis of randomized controlled trials of the effectiveness of the five treatments among patients with advanced RCC. The data of progressive disease, objective response rate (ORR), disease control rate (DCR), grade 3/4 AE, progression-free survival (PFS), and overall survival (OS) were extracted to assess therapeutic effects, toxicity, and prognosis, respectively. RESULTS: Two studies that assessed the combination of bevacizumab with IFN alpha (n = 1381), one sunitinib (n = 750), one sorafenib (n = 189) and one temsirolimus (n = 416) were included. Sorafenib, sunitinib, temsirolimus (R = 0.35, 95% confidence interval [CI] 0.26-0.48, P < 0.01), and the combination of bevacizumab with IFN (R = 0.64, 95% CI 0.42-0.99, P = 0.04) were more effective in controlling tumor progression than IFN. Sorafenib, sunitinib, and temsirolimus do not own advantage in ORR compared with IFN (R = 2.06, 95% CI 0.53-7.95, P = 0.30), but combination of bevacizumab with IFN showed better results in ORR than IFN (R = 2.56, 95% CI 1.91-3.42, P < 0.01). Sorafenib, sunitinib, temsirolimus (R = 2.90, 95% CI 2.23 3.78, P < 0.01), and combination of bevacizumab with IFN (R = 2.14, 95% CI 1.65 2.78, P < 0.01) were more effective than IFN in DCR. Sorafenib, sunitinib, and temsirolimus had similar rate of grade 3/4 AE as IFN (R = 1.21, 95% CI 0.96-1.51, P = 0.10). Combined use of bevacizumab and IFN is associated with higher frequency of the AE (R = 2.09, 95% CI 1.66-2.63, P < 0.01). Sorafenib and sunitinib had similar median PFS (R = 0.67, 95% CI 0.42-1.08, P = 0.10); temsirolimus had longer median OS (R = 0.82, 95% CI 0.67-1.00, P = 0.049) as IFN. Combined use of bevacizumab and IFN had longer median PFS (R = 0.68, 95% CI 0.60 0.76, P < 0.01) and OS (R = 0.86, 95% CI 0.76-0.97, P = 0.01) than IFN. CONCLUSION: Sorafenib, sunitinib, temsirolimus, and the combination of bevacizumab with IFN are more effective in stabilizing disease. Combined use of bevacizumab and IFN is better than sorafenib, sunitinib, and temsirolimus in ORR, PFS, and OS, but associated with higher level of AE. PMID- 25686741 TI - Antisense Long Noncoding RNA HIF1A-AS2 Is Upregulated in Gastric Cancer and Associated with Poor Prognosis. AB - BACKGROUND: Long noncoding RNAs (lncRNAs) have been recently shown to play important regulatory roles in fundamental biological processes, and many of them are deregulated in several human cancers. LncRNA hypoxia-inducible factor 1alpha antisense RNA-2 (HIF1A-AS2) is overexpressed in nonpapillary clear-cell renal carcinomas and involved in cancer progression. AIM: This study was to evaluate the expression of HIF1A-AS2 in gastric cancer (GC) and further explore its biological function in GC cells. MATERIALS AND METHODS: Quantitative real-time polymerase chain reaction was used to detect the expression level of HIF1A-AS2 in GC tissues. The correlation of its expression with clinicopathological features was analyzed. Area under receiver operating characteristic curve (ROC(AUC)) was constructed to evaluate the diagnostic value of HIF1A-AS2. Besides, tumor cell proliferation was assessed following knockdown of HIF1A-AS2, by MTT and colony formation assay in vitro, and tumor formation assay in a nude mouse model in vivo. RESULTS: The expression of HIF1A-AS2 was upregulated in GC tumorous tissues compared with the adjacent normal tissues (P < 0.001). Its overexpression was correlated with TNM stages (P = 0.008), tumor invasion (P = 0.016), lymph node metastasis (P = 0.042), and poor prognosis (P = 0.001). In addition, ROC(AUC) of HIF1A-AS2 was up to 0.673 (95 % CI 0.596-0.744, P < 0.001). Moreover, knockdown of HIF1A-AS2 expression by siRNA could inhibit cell proliferation in vitro and tumorigenesis in vivo. CONCLUSIONS: HIF1A-AS2 is overexpressed in GC and may play a pivotal role in tumor cell proliferation. It can be used as a potential diagnostic and prognostic biomarker for GC. PMID- 25686742 TI - Prevalence of Insulin Resistance in Subjects with Nonalcoholic Fatty Liver Disease and Its Predictors in a Chinese Population. AB - OBJECTIVE: Insulin resistance (IR) is a key factor involved in the development and progression of nonalcoholic fatty liver disease (NAFLD). However, the prevalence of IR in NAFLD patients and its risk factors have been rarely reported, especially in China. This prospective study was undertaken to clarify these issues in the Chinese population. METHODS: A total of 600 NAFLD patients and 300 age- and sex-matched healthy controls were recruited between January 1, 2011, and December 31, 2013. Demographic information and clinical characteristics were collected, and the presence of IR was evaluated using the homeostasis model. Uni- and multivariate analyses were conducted, and receiver operating characteristic (ROC) curves were generated to identify IR predictors. RESULTS: NAFLD patients had a much higher prevalence of IR than healthy controls (37.8 vs. 2.3 %, P < 0.001). The rates of elevated alanine transferase (ALT) and aspartate transferase (AST) levels were much higher in NAFLD patients with IR than those without (53.7 vs. 41.6 % and 28.6 vs. 18.2 %, respectively, P < 0.001). Uni- and multivariate analyses revealed that female sex, general obesity, abdominal obesity, and hypertension were independent predictors for IR. The area under the ROC curve for fasting plasma insulin (FPI) detecting IR was 0.93 (P < 0.001), and the optimal cutoff was 11.3 MUU/ml (sensitivity = 0.86, specificity = 0.92). CONCLUSION: Chinese NAFLD patients are susceptible to IR. Female sex, general and abdominal obesity, and hypertension were independent predictors for IR in NAFLD patients. FPI is an optimal predictor for IR. PMID- 25686743 TI - Are endoclips best approach to cannulate an ampulla hidden in the duodenal diverticulum? PMID- 25686744 TI - Bregs in Chronic HBV: Is It Time for Bragging Rights? PMID- 25686745 TI - MicroRNA-370 Attenuates Hepatic Fibrogenesis by Targeting Smoothened. AB - BACKGROUND AND AIMS: Recent research shows that abnormal expression of microRNA plays an important role in the process of hepatic fibrosis . miR-370 has been reported to be involved in liver function and is suppressed during hepatic carcinogenesis. The aim of this study was to investigate the role of miR-370 in hepatic fibrosis. METHODS: The expression levels of miR-370 in rat fibrotic livers and activated hepatic stellate cells (HSCs) were evaluated by quantitative real-time PCR. The effect of miR-370 on the activation of HSCs was analyzed by flow cytometric analyses, real-time PCR and Western blot. Adenovirus carrying miR 370 was injected through the tail vein to access the effect of miR-370 on hepatic fibrosis induced by CCl4 in rats. The downstream targets of miR-370 were predicted by the Target Scan database and verified by luciferase assays, real time PCR and Western blot in HSCs and were further confirmed by immunohistochemistry in vivo. RESULTS: Real-time PCR showed that miR-370 expression was significantly reduced in rat fibrotic livers and TGFbeta1 stimulated HSCs. Overexpression of miR-370 inhibited the proliferation of HSC-T6 cells via inducing cell apoptosis and suppressed the activation of HSCs. Upregulation of miR-370 obviously attenuated the CCl4-induced liver fibrosis in rats. miR-370 was directly bound to the 3'UTR of Smoothened (SMO) and suppressed the expression of SMO in HSCs and fibrotic livers. CONCLUSIONS: Our study demonstrated that miR-370 plays an inhibitory role in hepatic fibrogenesis by targeting SMO. Restoration of miR-370 may have beneficial effects on the treatment of liver fibrosis. PMID- 25686746 TI - Sodium Butyrate Reduces Organ Injuries in Mice with Severe Acute Pancreatitis Through Inhibiting HMGB1 Expression. AB - OBJECTIVE: The present study was designed to evaluate the effect of sodium butyrate on pancreas damage and to investigate the role of high-mobility group box-1 (HMGB1) and nuclear factor-kappaB (NF-kappaB) in the development of severe acute pancreatitis (SAP) in a mouse model. METHODS: The SAP model was established by intraperitoneal injection of two doses of 20 % L-2 arginine (200 mg/g). Female Sprague-Dawley mice were randomly allocated into three groups (n = 48/group): the control, untreated SAP, and sodium butyrate-treated SAP groups. The animals were euthanized at 0, 12, 24, and 48 h after the establishment of the SAP. Histopathology of the pancreas was performed, and the NF-kappaB levels were determined by immunohistochemistry. The serum levels of tumor necrosis factor (TNFalpha), interleukin-6 (IL-6), and HMGB1 were measured by ELISA. The HMGB1 mRNA levels were determined by qRT-PCR. RESULTS: The sodium butyrate-treated SAP animals showed significantly improved pancreas histopathology and lower serum amylase levels than the untreated SAP animals. In the SAP group, the mRNA levels of HMGB1 were remarkably increased at the 12 h, peaked at 24 h, and remained at a high level up to 48 h after L-2 arginine injection. The levels of TNFalpha and IL 6 were decreased at 48 h. Treatment with sodium butyrate reduced the pathological lesions, the serum levels of HMGB1, TNFalpha, and IL-6, the HMGB1 mRNA levels, and NF-kappaB activity. CONCLUSION: Sodium butyrate inhibits the NF-kappaB activation and reduces pancreas injury in SAP through the modulation of HMGB1 and other inflammatory cytokine responses. PMID- 25686747 TI - Lead and mercury in fall migrant golden eagles from western North America. AB - Lead exposure from ingestion of bullet fragments is a serious environmental hazard to eagles. We determined blood lead levels (BLL) in 178 golden eagles (Aquila chrysaetos) captured during fall migration along a major North American flyway. These eagles spent the breeding season distributed over a large range and are the best currently available representation of free flying golden eagles on the continent. We found 58 % of these eagles containing increased BLL > 0.1 mg/L; 10 % were clinically lead poisoned with BLL > 0.6 mg/L; and 4 % were lethally exposed with BLL > 1.2 mg/L. No statistical difference in BLL existed between golden and bald eagles (Haliaeetus leucocephalus). Golden eagles captured on carrion had higher BLL than those captured using live bait suggesting differences in feeding habits among individuals. Median BLL increased with age class. We propose a conceptual model for the long-term increase in BLL after ingestion of lead particles. The mean blood mercury level in golden eagles was 0.023 mg/L. We evaluate a field test for BLL that is based on anodic stripping voltammetry. This cost-effective and immediate method correlated well with results from inductively coupled plasma-mass spectrometry, although results needed to be corrected for each calibration of the test kit. PMID- 25686748 TI - Histone demethylase KDM5A is regulated by its reader domain through a positive feedback mechanism. AB - The retinoblastoma binding protein KDM5A removes methyl marks from lysine 4 of histone H3 (H3K4). Misregulation of KDM5A contributes to the pathogenesis of lung and gastric cancers. In addition to its catalytic jumonji C domain, KDM5A contains three PHD reader domains, commonly recognized as chromatin recruitment modules. It is unknown whether any of these domains in KDM5A have functions beyond recruitment and whether they regulate the catalytic activity of the demethylase. Here using biochemical and nuclear magnetic resonance (NMR)-based structural studies, we show that the PHD1 preferentially recognizes unmethylated H3K4 histone tail, product of KDM5A-mediated demethylation of tri-methylated H3K4 (H3K4me3). Binding of unmodified H3 peptide to the PHD1 stimulates catalytic domain-mediated removal of methyl marks from H3K4me3 peptide and nucleosome substrates. This positive-feedback mechanism--enabled by the functional coupling between a reader and a catalytic domain in KDM5A--suggests a model for the spread of demethylation on chromatin. PMID- 25686749 TI - Information transfer by exosomes: A new frontier in hematologic malignancies. AB - Exosomes are small (30-150 mm) vesicles secreted by all cell types and present in all body fluids. They are emerging as vehicles for delivery of membrane-tethered signaling molecules and membrane enclosed genes to target cells. Exosome-mediated information transfer allows for crosstalk of cells within the hematopoietic system and for interactions between hematopoietic cells and local or distant tissue cells. Exosomes carry physiological signals essential for health and participate in pathological processes, including malignant transformation. In hematologic malignancies, exosomes reprogram the bone marrow microenvironment, creating a niche for abnormal cells and favoring their expansion. The molecular and genetic mechanisms exosomes utilize to shuttle information between cells are currently being examined as are the potential roles exosomes play as biomarkers of disease or future therapeutic targets. PMID- 25686750 TI - Auditory nerve synapses persist in ventral cochlear nucleus long after loss of acoustic input in mice with early-onset progressive hearing loss. AB - Perceptual performance in persons with hearing loss, especially those using devices to restore hearing, is not fully predicted by traditional audiometric measurements designed to evaluate the status of peripheral function. The integrity of auditory brainstem synapses may vary with different forms of hearing loss, and differential effects on the auditory nerve-brain interface may have particularly profound consequences for the transfer of sound from ear to brain. Loss of auditory nerve synapses in ventral cochlear nucleus (VCN) has been reported after acoustic trauma, ablation of the organ of Corti, and administration of ototoxic compounds. The effects of gradually acquired forms deafness on these synapses are less well understood. We investigated VCN gross morphology and auditory nerve synapse integrity in DBA/2J mice with early-onset progressive sensorineural hearing loss. Hearing status was confirmed using auditory brainstem response audiometry and acoustic startle responses. We found no change in VCN volume, number of macroneurons, or number of VGLUT1-positive auditory nerve terminals between young adult and older, deaf DBA/2J. Cell-type specific analysis revealed no difference in the number of VGLUT1 puncta contacting bushy and multipolar cell body profiles, but the terminals were smaller in deaf DBA/2J mice. Transmission electron microscopy confirmed the presence of numerous healthy, vesicle-filled auditory nerve synapses in older, deaf DBA/2J mice. The present results suggest that synapses can be preserved over a relatively long time-course in gradually acquired deafness. Elucidating the mechanisms supporting survival of central auditory nerve synapses in models of acquired deafness may reveal new opportunities for therapeutic intervention. PMID- 25686751 TI - Unveiling the dependence of glass transitions on mixing thermodynamics in miscible systems. AB - The dependence of the glass transition in mixtures on mixing thermodynamics is examined by focusing on enthalpy of mixing, DeltaHmix with the change in sign (positive vs. negative) and magnitude (small vs. large). The effects of positive and negative DeltaHmix are demonstrated based on two isomeric systems of o- vs. m methoxymethylbenzene (MMB) and o- vs. m-dibromobenzene (DBB) with comparably small absolute DeltaHmix. Two opposite composition dependences of the glass transition temperature, Tg, are observed with the MMB mixtures showing a distinct negative deviation from the ideal mixing rule and the DBB mixtures having a marginally positive deviation. The system of 1, 2- propanediamine (12PDA) vs. propylene glycol (PG) with large and negative DeltaHmix is compared with the systems of small DeltaHmix, and a considerably positive Tg shift is seen. Models involving the properties of pure components such as Tg, glass transition heat capacity increment, DeltaCp, and density, rho, do not interpret the observed Tg shifts in the systems. In contrast, a linear correlation is revealed between DeltaHmix and maximum Tg shifts. PMID- 25686752 TI - Complement evasion by Bordetella pertussis: implications for improving current vaccines. AB - Bordetella pertussis causes whooping cough or pertussis, a highly contagious disease of the respiratory tract. Despite high vaccination coverage, reported cases of pertussis are rising worldwide and it has become clear that the current vaccines must be improved. In addition to the well-known protective role of antibodies and T cells during B. pertussis infection, innate immune responses such as the complement system play an essential role in B. pertussis killing. In order to evade this complement activation and colonize the human host, B. pertussis expresses several molecules that inhibit complement activation. Interestingly, one of the known complement evasion proteins, autotransporter Vag8, is highly expressed in the recently emerged B. pertussis isolates. Here, we describe the current knowledge on how B. pertussis evades complement-mediated killing. In addition, we compare this to complement evasion strategies used by other bacterial species. Finally, we discuss the consequences of complement evasion by B. pertussis on adaptive immunity and how identification of the bacterial molecules and the mechanisms involved in complement evasion might help improve pertussis vaccines. PMID- 25686753 TI - Diverse phenotypic consequences of mutations affecting the C-terminus of FLNA. AB - Filamin A, the filamentous protein encoded by the X-linked gene FLNA, cross-links cytoskeletal actin into three-dimensional networks, facilitating its role as a signalling scaffold and a mechanosensor of extrinsic shear forces. Central to these functions is the ability of FLNA to form V-shaped homodimers through its C terminal located filamin repeat 24. Additionally, many proteins that interact with FLNA have a binding site that includes the C-terminus of the protein. Here, a cohort of patients with mutations affecting this region of the protein is studied, with particular emphasis on the phenotype of male hemizygotes. Seven unrelated families are reported, with five exhibiting a typical female presentation of periventricular heterotopia (PH), a neuronal migration disorder typically caused by loss-of-function mutations in FLNA. One male presents with widespread PH consistent with previous male phenotypes attributable to hypomorphic mutations in FLNA. In stark contrast, two brothers are described with a mild PH presentation, due to a missense mutation (p.Gly2593Glu) inserting a large negatively charged amino acid into the hydrophobic dimerisation interface of FLNA. Co-immunoprecipitation, in vitro cross-linking studies and gel filtration chromatography all demonstrated that homodimerisation of isolated FLNA repeat 24 is abolished by this p.Gly2593Glu substitution but that extended FLNA(Gly2593Glu) repeat 16-24 constructs exhibit dimerisation. These observations imply that other interactions apart from those mediated by the canonical repeat 24 dimerisation interface contribute to FLNA homodimerisation and that mutations affecting this region of the protein can have broad phenotypic effects. KEY MESSAGES: * Mutations in the X-linked gene FLNA cause a spectrum of syndromes. * Genotype-phenotype correlations are emerging but still remain unclear. * C-term mutations can confer male lethality, survival or connective tissue defects. * Mutations leading to the latter affect filamin dimerisation. * This deficit is compensated for by remotely acting domains elsewhere in FLNA. PMID- 25686755 TI - Stroke: Risk assessment to prevent recurrence after mild stroke or TIA. PMID- 25686754 TI - The role of inflammation in perinatal brain injury. AB - Inflammation is increasingly recognized as being a critical contributor to both normal development and injury outcome in the immature brain. The focus of this Review is to highlight important differences in innate and adaptive immunity in immature versus adult brain, which support the notion that the consequences of inflammation will be entirely different depending on context and stage of CNS development. Perinatal brain injury can result from neonatal encephalopathy and perinatal arterial ischaemic stroke, usually at term, but also in preterm infants. Inflammation occurs before, during and after brain injury at term, and modulates vulnerability to and development of brain injury. Preterm birth, on the other hand, is often a result of exposure to inflammation at a very early developmental phase, which affects the brain not only during fetal life, but also over a protracted period of postnatal life in a neonatal intensive care setting, influencing critical phases of myelination and cortical plasticity. Neuroinflammation during the perinatal period can increase the risk of neurological and neuropsychiatric disease throughout childhood and adulthood, and is, therefore, of concern to the broader group of physicians who care for these individuals. PMID- 25686756 TI - Dementia: type 2 diabetes has a slow and insidious effect on cognition. PMID- 25686757 TI - Age-related hearing impairment-a risk factor and frailty marker for dementia and AD. AB - Age-related hearing impairment (ARHI, also known as presbycusis) is potentially a reversible risk factor for dementia and Alzheimer disease (AD). Social isolation, loneliness, poor verbal communication, and cognitive reserve depletion might causally link ARHI with cognitive impairment. ARHI is an important frailty marker, and several factors related to physical frailty could be associated with cognitive impairment. Such factors include inflammatory markers and vascular factors, which might also directly contribute to ARHI. Randomized controlled trials of potential interventions, and larger population-based studies, could facilitate further understanding of the interplay between cognitive impairment, ARHI and frailty in older age. Deficits in both peripheral hearing and central auditory processing (CAP) can contribute to ARHI. Impairments in peripheral hearing and CAP have been linked to accelerated cognitive decline, incident cognitive impairment and AD; moreover, CAP dysfunction is common in mild cognitive impairment (MCI) and AD. Assessment of CAP dysfunction in people with ARHI might, therefore, aid identification of older individuals with increased risk of MCI and AD. PMID- 25686758 TI - Multiple sclerosis-a quiet revolution. AB - Multiple sclerosis (MS) has been thought to be a complex and indecipherable disease, and poorly understood with regards to aetiology. Here, we suggest an emphatically positive view of progress over several decades in the understanding and treatment of MS, particularly focusing on advances made within the past 20 years. As with virtually all complex disorders, MS is caused by the interaction of genetic and environmental factors. In recent years, formidable biochemical, bioinformatic, epidemiological and neuroimaging tools have been brought to bear on research into the causes of MS. While susceptibility to the disease is now relatively well accounted for, disease course is not and remains a salient challenge. In the therapeutic realm, numerous agents have become available, reflecting the fact that the disease can be attacked successfully at many levels and using varied strategies. Tailoring therapies to individuals, risk mitigation and selection of first-line as compared with second-line medications remain to be completed. In our view, the MS landscape has been comprehensively and irreversibly transformed by this progress. Here we focus on MS therapeutics-the most meaningful outcome of research efforts. PMID- 25686759 TI - Infectious disease: neurological disease in children linked to enterovirus D68. PMID- 25686761 TI - Specific light-up bioprobes based on AIEgen conjugates. AB - Driven by the high demand for sensitive and specific tools for optical sensing and imaging, bioprobes with various working mechanisms and advanced functionalities are flourishing at an incredible speed. Conventional fluorescent probes suffer from the notorious effect of aggregation-caused quenching that imposes limitation on their labelling efficiency or concentration to achieve desired sensitivity. The recently emerged fluorogens with an aggregation-induced emission (AIE) feature offer a timely remedy to tackle the challenge. Utilizing the unique properties of AIE fluorogens (AIEgens), specific light-up probes have been constructed through functionalization with recognition elements, showing advantages such as low background interference, a high signal to noise ratio and superior photostability with activatable therapeutic effects. In this tutorial review, we summarize the recent progress in the development of specific AIEgen based light-up bioprobes. Through illustration of their operation mechanisms and application examples, we hope to provide guidelines for the design of more advanced AIE sensing and imaging platforms with high selectivity, great sensitivity and wide adaptability to a broad range of biomedical applications. PMID- 25686760 TI - White matter hyperintensities, cognitive impairment and dementia: an update. AB - White matter hyperintensities (WMHs) in the brain are the consequence of cerebral small vessel disease, and can easily be detected on MRI. Over the past three decades, research has shown that the presence and extent of white matter hyperintense signals on MRI are important for clinical outcome, in terms of cognitive and functional impairment. Large, longitudinal population-based and hospital-based studies have confirmed a dose-dependent relationship between WMHs and clinical outcome, and have demonstrated a causal link between large confluent WMHs and dementia and disability. Adequate differential diagnostic assessment and management is of the utmost importance in any patient, but most notably those with incipient cognitive impairment. Novel imaging techniques such as diffusion tensor imaging might reveal subtle damage before it is visible on standard MRI. Even in Alzheimer disease, which is thought to be primarily caused by amyloid, vascular pathology, such as small vessel disease, may be of greater importance than amyloid itself in terms of influencing the disease course, especially in older individuals. Modification of risk factors for small vessel disease could be an important therapeutic goal, although evidence for effective interventions is still lacking. Here, we provide a timely Review on WMHs, including their relationship with cognitive decline and dementia. PMID- 25686763 TI - Mutation in the type II collagen gene (COL2A1) as a cause of early osteoarthritis and juvenile idiopathic arthritis-A pseudorheumatoid arthritis variant. PMID- 25686762 TI - Clinical validity: Combinatorial pharmacogenomics predicts antidepressant responses and healthcare utilizations better than single gene phenotypes. AB - In four previous studies, a combinatorial multigene pharmacogenomic test (GeneSight) predicted those patients whose antidepressant treatment for major depressive disorder resulted in poorer efficacy and increased health-care resource utilizations. Here, we extended the analysis of clinical validity to the combined data from these studies. We also compared the outcome predictions of the combinatorial use of allelic variations in genes for four cytochrome P450 (CYP) enzymes (CYP2D6, CYP2C19, CYP2C9 and CYP1A2), the serotonin transporter (SLC6A4) and serotonin 2A receptor (HTR2A) with the outcome predictions for the very same subjects using traditional, single-gene analysis. Depression scores were measured at baseline and 8-10 weeks later for the 119 fully blinded subjects who received treatment as usual (TAU) with antidepressant standard of care, without the benefit of pharmacogenomic medication guidance. For another 96 TAU subjects, health-care utilizations were recorded in a 1-year, retrospective chart review. All subjects were genotyped after the clinical study period, and phenotype subgroups were created among those who had been prescribed a GeneSight panel medication that is a substrate for either CYP enzyme or serotonin effector protein. On the basis of medications prescribed for each subject at baseline, the combinatorial pharmacogenomic (CPGxTM) GeneSight method categorized each subject into either a green ('use as directed'), yellow ('use with caution') or red category ('use with increased caution and with more frequent monitoring') phenotype, whereas the single-gene method categorized the same subjects with the traditional phenotype (for example, poor, intermediate, extensive or ultrarapid CYP metabolizer). The GeneSight combinatorial categorization approach discriminated and predicted poorer outcomes for red category patients prescribed medications metabolized by CYP2D6, CYP2C19 and CYP1A2 (P=0.0034, P=0.04 and P=0.03, respectively), whereas the single-gene phenotypes failed to discriminate patient outcomes. The GeneSight CPGx process also discriminated health-care utilization and disability claims for these same three CYP-defined medication subgroups. The CYP2C19 phenotype was the only single-gene approach to predict health-care outcomes. Multigenic combinatorial testing discriminates and predicts the poorer antidepressant outcomes and greater health-care utilizations by depressed subjects better than do phenotypes derived from single genes. This clinical validity is likely to contribute to the clinical utility reported for combinatorial pharmacogenomic decision support. PMID- 25686764 TI - Regiospecific synthesis of neuroprotective 1,4-benzoxazine derivatives through a tandem oxidation-Diels-Alder reaction. AB - The tandem oxidation-inverse electron demand Diels-Alder reaction of o aminophenol derivatives and enamines has been accomplished at room temperature using a stoichiometric amount of manganese dioxide as the oxidant to furnish highly substituted 1,4-benzoxazine cycloadducts with complete regiochemical control. Because of its efficiency in introducing diverse elements in both cycloaddition partners, this one-pot process should allow the assembly of libraries of biologically relevant 1,4-benzoxazine derivatives. In this respect, the 3,3-diphenyl-substituted-1,4-benzoxazine derivative 3n was found to be a potent neuroprotective agent in an animal model of excitotoxic lesions in newborn mice. PMID- 25686765 TI - Cadmium Accumulation and Metallothionein Response in the Freshwater Bivalve Corbicula fluminea Under Hydrodynamic Conditions. AB - Freshwater bivalves such as Corbicula fluminea (Muller) are useful biomonitors for cadmium pollution because they absorb heavy metals and accumulate them in their tissues. We exposed C. fluminea in the laboratory to natural and cadmium (Cd)-spiked sediments below flowing water in order to evaluate the organisms' Cd accumulation and metallothionein (MT) response under hydrodynamic conditions. The accumulation of Cd and the induction of MT in C. fluminea were determined at 0, 1, 3, 6, 10, 16, and 23 days. Hydrodynamic conditions, represented by a water flow rate of 14 or 3.2 cm/s, increased Cd accumulation in the visceral mass, gill, foot, and mantle of C. fluminea in the first 3 or 6 days in the natural sediment. Cd concentrations in the C. fluminea tissues kept increasing over time in the three treatments, and significant differences were observed in Cd accumulation after 6 (visceral mass), 10 (foot) and 16 (gill and mantle) days among the three groups. The MT concentrations were barely affected by hydrodynamic conditions and were significantly linearly related to the Cd concentration in the visceral mass in the natural sediment and binomially related to it in the Cd-spiked sediment. Hydrodynamic conditions enhanced the accumulation of Cd in the soft tissues of C. fluminea, especially in the Cd spiked sediment, but stronger hydrodynamic forces did not increase Cd accumulation. MT may be considered an indicator for Cd accumulation in C. fluminea under hydrodynamic conditions, but only when the Cd concentrations in the tissue remain below the toxic threshold values. PMID- 25686766 TI - Magnesium Supplementation Prevents and Reverses Experimentally Induced Movement Disturbances in Rats: Biochemical and Behavioral Parameters. AB - Reserpine administration results in a predictable animal model of orofacial dyskinesia (OD) that has been largely used to access movement disturbances related to extrapyramidal oxidative damage. Here, OD was acutely induced by reserpine (two doses of 0.7 mg/kg subcutaneous (s.c.)), every other day for 3 days), which was administered after (experiment 1) and before (experiment 2) magnesium (Mg) supplementation (40 mg/kg/mL, peroral (p.o.)). In experiment 1, Mg was administered for 28 days before reserpine treatment, while in experiment 2, it was initiated 24 h after the last reserpine administration and was maintained for 10 consecutive days. Experiment 1 (prevention) showed that Mg supplementation was able to prevent reserpine-induced OD and catalepsy development. Mg was also able to prevent reactive species (RS) generation, thus preventing increase of protein carbonyl (PC) levels in both cortex and substantia nigra, but not in striatum. Experiment 2 (reversion) showed that Mg was able to decrease OD and catalepsy at all times assessed. In addition, Mg was able to decrease RS generation, with lower levels of PC in both cortex and striatum, but not in substantia nigra. These outcomes indicate that Mg is an important metal that should be present in the diet, since its intake is able to prevent and minimize the development of movement disorders closely related to oxidative damage in the extrapyramidal brain areas, such as OD. PMID- 25686767 TI - Developing a simplified finite element model of a car seat with occupant for predicting vibration transmissibility in the vertical direction. AB - The transmissibility of seat depends on the dynamics of both the seat and the human body, and shows how the amplification and attenuation of vibration varies with the frequency of vibration. A systematic methodology was developed for finite element (FE) modelling of the dynamic interaction between a seat and the human body and predicting the transmissibility of a seat. A seat model was developed to improve computational efficiency before models of the seat pan and backrest were calibrated separately using load-deflection and dynamic stiffness measurements, joined to form the complete seat model, and integrated with the model of a manikin for further calibration. The calibrated seat model was combined with a human body model to predict the transmissibility of the seat. By combining a calibrated seat model with a calibrated human body model, and defining appropriate contacts between the two models, the vibration transmissibility with a seat-occupant system can be predicted. PRACTITIONER SUMMARY: FE models are capable of reflecting complex dynamic characteristics of a seat-body system. A methodology for using FE methods to model a seat-body system to predict seat transmissibility has been demonstrated. The method can be developed to explore how seating dynamics interact with human biodynamics. PMID- 25686768 TI - Time course of left ventricular reverse remodeling in response to pharmacotherapy: clinical implication for heart failure prognosis in patients with idiopathic dilated cardiomyopathy. AB - The present study aimed to identify the clinical significance of differences in detection timings of left ventricular reverse remodeling (LVRR) on heart failure (HF) prognosis in patients with idiopathic dilated cardiomyopathy (IDCM). We investigated 207 patients with IDCM who underwent pharmacotherapeutic treatment. LVRR was defined as improvements in both LV ejection fraction >=10 % and indexed LV end-diastolic dimension (LVEDDi) >=10 %. Patients were stratified into 3 groups by LVRR timing: patients with LVRR <24 months (Early LVRR), those with LVRR >=24 months (Delayed LVRR), and those without LVRR during the entire follow up period (No LVRR). The major endpoint was first detection of composite event including readmission for decompensated HF, major ventricular arrhythmias, or all cause mortality. LVRR was recognized in 108 patients (52 %): Early LVRR in 83 (40 %), Delayed LVRR in 25 (12 %), and No LVRR in 99 (48 %). The survival rate for the major endpoint was significantly higher for Delayed LVRR than for No LVRR (P = 0.001); there was no significant difference between Early and Delayed LVRR. Among patients without LVRR <24 months (Delayed + No LVRR), receiver operating characteristic curve analysis showed that the area under the curve for improvement in LVEDDi during the first 6 months for predicting subsequent LVRR (Delayed LVRR) [0.822 (95 % confidence interval, 0.740-0.916; P = 0.038)] was greater than that for improvement in LVEF. In conclusion, LVRR was a favorable prognostic indicator in patients with IDCM irrespective of its detection timing. Reduced LVEDDi during the first 6 months was predictive for subsequent LVRR in the later phase. PMID- 25686769 TI - A case of tremor in Klinefelter syndrome worsened by testosterone administration. PMID- 25686770 TI - Highly selective detection of Cr(VI) in water matrix by a simple 1,8 naphthalimide-based turn-on fluorescent sensor. AB - 4-Bis-(2-hydroxyethyl)amino-N-n-butyl-1,8-naphthalimide was developed into a turn on fluorescent sensor for Cr(VI). In the mixture of N,N-dimethylformamide and deionized water (1:9, v/v), the sensor could highly selectively distinguish CrO4(2-) from Cr(3+), Na(+), K(+), Mg(2+), Ca(2+), Mn(2+), Fe(2+), Fe(3+), Co(2+), Ni(2+), Cu(2+), Zn(2+), Cd(2+), Hg(2+), Pb(2+), NO(3-), SO4(2-), PO4(3-), IO3(-), ClO(-) and Cl(-) by a 6-fold fluorescence enhancement. The working concentration of CrO4(2-) was from 0 to 90 MUM with a detection limit of 3.6 * 10(-7) mol/L. The detection could be carried out in water matrix and within a wide pH range (approximately from 2 to 12), and a large number of environmentally and biologically relevant ions including Cr(3+) showed no significant interferences with the detection. The sensing mechanism was explored by reversibility and LC/MS analysis, as well as Job's plot experiment, and the results suggested that the recognition was based on the oxidation of the primary alcohol in the structure of the sensor by the Cr(VI) sources. PMID- 25686771 TI - Cycloalkyl-aminomethylrhodamines: pH dependent photophysical properties tuned by cycloalkane ring size. AB - A series of fluorescent pH probes based on the spiro-cyclic rhodamine core, aminomethylrhodamines (AMR), was synthesized and the effect of cycloalkane ring size on the acid/base properties of the AMR system was explored. The study involved a series of rhodamine 6G (cAMR6G) and rhodamine B (cAMR) pH probes with cycloalkane ring sizes from C-3 to C-6 on the spiro-cyclic amino group. It is known that the pKa value of cycloalkylamines can be tuned by different ring sizes in accordance with the Baeyer ring strain theory. Smaller ring amines have lower pKa value, i.e., they are less basic, such that the relative order in cycloalkylamine basicity is: cyclohexyl > cyclopentyl > cyclobutyl > cyclopropyl. Herein, it was found that the pKa values of the cAMR and cAMR6G systems can also be predicted by Baeyer ring strain theory. The pKa values for the cAMR6G series were shown to be higher than the cAMR series by a value of approximately 1. PMID- 25686772 TI - Nanospherical silica as luminescent markers obtained by sol-gel. AB - Hybrid nanosilicas constitute a broad study field. They find application as catalysts, pigments, drug delivery systems, and biomaterials, among others, and it is possible to obtain them via the sol-gel methodology. Lanthanide ions present special properties like light emission. Their incorporation into a silica matrix can enhance their luminescent properties, which enables their application as luminescent markers. This work reports on (i) the preparation of luminescent spherical hybrid silica nanoparticles by the hydrolytic sol-gel methodology, (ii) doping of the resulting matrix with the europium(III) ion or its complex with 1,10-phenanthroline, and (iii) characterization of the final powders by scanning electron microscopy, infrared spectroscopy, X-ray diffraction, and europium(III) ion photoluminescence. The synthesized materials consisted of hybrid, amorphous, polydispersed nonspherical silicas with average size of 180 nm. Photoluminescence confirmed incorporation of the europium(III) ion and its complex into the silica matrix-the ligand-metal charge transfer band emerged in the excitation spectra. The emission spectra presented the bands corresponding to the transition of the excited state (5)D0 level to (7)FJ (J = 0, 1, 2, 3 and 4). The main emission occurred in the red region; the lifetime was long. These characteristics indicated that the prepared nanospherical hybrid silicas could act as luminescent markers. PMID- 25686773 TI - Intracranial aneurysm rupture during flow diverter stent placement: successful treatment with stent-in-stent combination. PMID- 25686774 TI - Routine postoperative upper gastrointestinal fluoroscopy after laparoscopic sleeve gastrectomy: Is there still a utility? AB - PURPOSE: To assess the performance of routine esophagogastric transit studies (OGT) performed between day 2 (D2) and day 4 (D4) following sleeve gastrectomy for the diagnosis of gastric fistula. PATIENTS AND METHODS: Single center study including 736 patients undergoing surgery for sleeve gastrectomy including 32 of whom developed gastric fistula. Seven hundred and twenty OGT on D2 and 86 abdominal and pelvic CT scans were performed to investigate for a fistula and whether or not a blood collection was present. Sensitivity, specificity, positive and negative predictive values, Youden index (YI) and dosimetry were calculated for both investigations. RESULTS: The sensitivity and specificity of OGT for the diagnosis of fistula were 7% and 98% respectively with a PPV of 18%, an NPV of 96% and YI of 0.06. The mean DSP was 5500MUGy.m(2). Sensitivity, specificity, positive and negative predictive values and Youden index for CT were 55%, 100%, 100%, 81%, 0.55, respectively for the presence of a fistula; and 96%, 86%, 78%, 98%, 0.83 for the presence of a non-blood collection and; 100%, 86%, 78%, 100%, 0.86 for the presence of a non-blood collection and/or fistula. The mean DLP was 3700 mGy.cm. CONCLUSION: Because of its very poor sensitivity for the diagnosis of gastric fistula, the OGT on D2 needs to be reconsidered. CT performed on clinical suspicion appears to be a better diagnostic tool. PMID- 25686775 TI - CT pulmonary angiogram with 60% dose reduction: Influence of iterative reconstructions on image quality. AB - GOALS: To compare the quality of low-dose CT images with sinogram affirmed iterative reconstruction (SAFIRE), and full-dose CT with filtered back projection reconstructions (FBP). MATERIALS AND METHODS: Fifty pulmonary CT performed by a dual-source technique (120kVp; 110mAs) with (a) the same energy in both tubes, and (b) the distribution of reference mAs with 40% in tube A (44mAs) and 60% in tube B (66mAs). Each acquisition allowed reconstruction of: (a) full-dose images (with both tubes) with FBP reconstructions (group 1); and (b) low-dose images (from tube A) reconstructed with SAFIRE (group 2). RESULTS: Group 2 images presented: (a) a significant objective reduction in noise measured in the trachea on mediastinal (16.04+/-5.66 vs 17.66+/-5.84) (P=0.0284) and pulmonary (29.77+/ 6.79 vs 37.96+/-9.03) (P<0.0001) images; (b) a similar subjective perception of noise and overall image quality (P=1), which was considered to be excellent in 66% (33/50) of the cases, with no influence on the detection of elementary pulmonary lesions of infiltration (98.4%; 95% CI=[96.9%-99.9%]). CONCLUSION: Despite a 60% reduction in radiation dose, the image quality with iterative reconstruction is objectively better and subjectively similar to full-dose FBP images. PMID- 25686776 TI - Clinical efficacy of transcatheter embolization of visceral artery pseudoaneurysms using N-butyl cyanoacrylate (NBCA). AB - PURPOSE: Transcatheter endovascular embolization within a reasonable time before rupture or deterioration of a patient's general condition is an important procedure for managing visceral pseudoaneurysms. N-butyl 2-cyanoacrylate (NBCA, enbucrilate) is an embolic material used in the blockade of visceral pseudoaneurysms. This study evaluated the clinical efficacy of transcatheter embolization of visceral artery pseudoaneurysms using NBCA. PATIENTS AND METHODS: Between June 2004 and February 2014, 13 patients (9 males and 4 females; age range, 26-80years; mean, 57.9years) with 14 pseudoaneurysms were treated by transcatheter embolization using NBCA. NBCA was mixed with iodized oil at a 1:3 ratio to control its polymerization time and to render it radiopaque. Pseudoaneurysms were located on the gastroduodenal artery (n=1), pancreaticoduodenal artery (n=2), dorsal pancreatic artery (n=1), proximal jejunal artery (n=1), colic artery (n=1), splenic artery (n=3), renal artery (n=4; two in one patient), and hepatic artery (n=1). RESULTS: All patients recovered immediately following the embolization procedure, and two patients showed minor complications that required only medical observation. CONCLUSIONS: Transcatheter embolization using NBCA for the treatment of visceral pseudoaneurysms is a safe, effective, and low-cost treatment method with a high success rate. PMID- 25686777 TI - Violence prevention and municipal licensing of indoor sex work venues in the Greater Vancouver Area: narratives of migrant sex workers, managers and business owners. AB - Using a socio-ecological, structural determinants framework, this study assesses the impact of municipal licensing policies and related policing practices across the Greater Vancouver Area (Canada) on the risk of violence within indoor sex work venues. Qualitative interviews were conducted with 46 migrant/immigrant sex workers, managers and owners of licensed indoor sex work establishments and micro brothels. Findings indicate that policing practices and licensing requirements increase sex workers' risk of violence and conflict with clients and result in heightened stress, an inability to rely on police support, lost income and the displacement of sex workers to more hidden informal work venues. Prohibitive licensing and policing practices prevent sex workers, managers and owners from adopting safer workplace measures and exacerbate health and safety risks for sex workers. This study provides critical evidence of the negative public health implications of prohibitive municipal licensing in the context of a criminalised and enforcement-based approach to sex work. Workplace safety recommendations include the decriminalisation of sex work and the elimination of disproportionately high fees for licences, criminal record restrictions, door lock restrictions, employee registration requirements and the use of police as licensing inspectors. PMID- 25686778 TI - A lower neutrophil to lymphocyte ratio is closely associated with catarrhal appendicitis versus severe appendicitis. AB - PURPOSE: Catarrhal appendicitis (CA) could be treated effectively with antibiotics in some patients because of the milder inflammation associated with this form of appendicitis. Although several trials have compared surgery with antibiotic therapy for acute appendicitis (AA), the indications for antibiotic therapy remain controversial. METHODS: The subjects of this study were 342 patients who underwent appendectomy at our hospital between January, 2000 and March, 2013. The patients were divided into two groups based on the severity of their appendicitis: Group A comprised patients with severe appendicitis and Group B comprised patients with CA. Statistical analyses were performed to assess the clinical features associated with CA. RESULTS: Multivariate analysis of the eight clinical features correlated with CA according to univariate analysis revealed that the neutrophil to lymphocyte ratio (NLR) (<5/>5), age (<38/>38 years), fever (<38/>38 degrees C), white blood cell count (<11.5/>11.5 * 103/mm3) and serum level of C-reactive protein (<110/>110 mg/L) were significantly associated with CA. The NLR (<5/>5) (OR 0.421; 95 % CI 0.218-0.811; P = 0.010) was the most useful predictor of CA, because the area under the ROC curve of NLR was the lowest of all these features. CONCLUSION: The preoperative NLR in patients undergoing appendectomy is closely associated with CA. PMID- 25686779 TI - Erratum to: Advantages of FDG-PET/CT over CT alone in the preoperative assessment of lymph node metastasis in patients with esophageal cancer. PMID- 25686780 TI - Antinociceptive activity of extracts and secondary metabolites from wild growing and micropropagated plants of Renealmia alpinia. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Renealmia alpinia is native to the American continent and can be found from Mexico to Brazil, and in the Caribbean islands. It is known as "matandrea" in Colombia, and it has been commonly used in traditional medicine to treat painful diseases and ailments. Based on its traditional uses, it is of interest to evaluate the pharmacologic effects of this plant and its secondary metabolites. MATERIALS AND METHODS: Methanol and aqueous extracts of wild and micropropagated R. alpinia (leaves) were obtained and chemically compared by High Performance Thin Layer Chromatography (HPTLC). The antinociceptive activity of these extracts was examined using an in vivo assay (Siegmund test). Additionally, the dichloromethane extract of R. alpinia was fractionated and pure compounds were isolated by chromatographic methods. The structure elucidation of isolated compounds was performed by NMR experiments and spectroscopic techniques and comparison with the literature data. Purified compounds were evaluated for their in vitro binding affinity for opioids and cannabinoids receptors. RESULTS: The dichloromethane extract of the plant's aerial part afforded sinostrobin (1), naringenin 7,4'-dimethyl ether (2), 2',6' dihydroxy-4'-methoxychalcone (3), 4-methoxy-6-(2-phenylethenyl)-2H-pyran-2-one (4), naringenin 7-methyl ether (5) and 3,5-heptanediol, 1,7-diphenyl (6), which were isolated using chromatographic methods. Their chemical structures were established by physical and spectroscopic techniques. The antinociceptive effects observed in mice by extracts of wild and micropropagated plants were similar. The compounds isolated from R. alpinia do not show affinity to opioid or cannabinoid receptors. CONCLUSION: Aqueous and methanol extracts of R. alpinia provide antinociceptive and analgesic effects in an in vivo model. These results contribute additional insight as to why this plant is traditionally used for pain management. Also, this is the first comprehensive report of a phytochemical study of R. alpinia. PMID- 25686781 TI - Effect of bajijiasu isolated from Morinda officinalis F. C. how on sexual function in male mice and its antioxidant protection of human sperm. AB - ETHNOPHARMACOLOGICAL RELEVANCE: In recent years, the physiological aspects of human fertility have been seriously influenced by the interactions of genetic and environmental factors. Almost one in 20 males has been affected by male infertility, providing a great challenge and an opportunity to use natural compounds as alternatives to chemical drugs with comprehensive adverse effects. However, ample evidences are scanty to support the physiological mechanisms of natural compounds used to treat male infertility. In traditional Chinese medicine, Morinda officinalis F. C. How is widely used as a herb that invigorates the kidneys and supports yang, the original energy in the human body, to resist diseases and in treating male infertility. In this study, we evaluated whether bajijiasu isolated from the roots of M. officinalis F.C. How is a potential agent for the treatment of male infertility. MATERIALS AND METHOD: In this study, both normal and kidney-yang-deficient mice were administered bajijiasu orally at different concentrations. To determine the pharmacological mechanism of bajijiasu, we observed the sexual behavior and genital organ coefficients, determined their serum hormone levels, analyzed their sperm quality parameters, and examined histopathological sections from them. We also used enzymatic assays to determine the effects of bajijiasu on superoxide dismutase, glutathione peroxidase, and malondialdehyde. Confocal micro-Raman spectroscopy was used to investigate the changes in the DNA of H2O2-damaged human sperm after treatment with bajijiasu in vitro. RESULTS: Our results showed that bajijiasu enhanced the sexual behavior of both normal and kidney-yang-deficient mice. It also markedly increased the testosterone concentrations, reduced the levels of cortisol, improved the quality of the sperm, and counteracted the histopathological impairment induced by hydroxyurea in the kidney-yang-deficient mice. The enzymatic assay and Raman spectra showed that bajijiasu protects the DNA of sperm from damage by H2O2. CONCLUSION: Bajijiasu is a potential androgen-like drug that modulates hormone levels to some extent without producing reproductive-organ lesions, enhances the sexual function of male mice, and protects the DNA of human sperm from H2O2 damage. Thus, bajijiasu is an active ingredient of M. officinalis F.C. How that improves the human reproductive capacity. PMID- 25686782 TI - No Superiority of High-Flexion vs Standard Total Knee Arthroplasty: An Update Meta-Analysis of Randomized Controlled Trials. AB - This meta-analysis was performed using a Cochrane systematic review approach to examine published data with an aim to clarify whether standard or high flexion prostheses increase the range of knee motion and clinical outcomes. 1778 patients from 17 randomized controlled trials were identified. No significant differences in the range of motion, weight-bearing flexion and hip functions scores were found between treatment groups. We also found no significant differences in complications with regard to revision, component loosening, deep infection, anterior knee pain, stiffness, post-operative bone fracture and post-operative patella clunk syndrome, but the high flexion prostheses group had a higher incidence of deep venous thrombosis. The results do not support the proposition that high flexion knee prostheses provide substantial clinical advantages over standard knee prostheses. PMID- 25686783 TI - The Cumulative Risk of Re-dislocation After Revision THA Performed for Instability Increases Close to 35% at 15years. AB - A retrospective analysis was conducted on 539 hips undergoing revision total hip arthroplasty done for instability to report the cumulative risk and factors associated with re-dislocation and re-revision. The cumulative risk of re dislocation and re-revision for all cause was 34.5% and 45.9% at 15 years, respectively. Multiple variable analyses revealed history of 2 or more previous surgeries, use of head size less than 36 mm, and cup retention to be risk factors for re-dislocation and re-revision. The use of a constrained liner was protective against re-dislocation but was not associated with a lower re-revision rate. Understanding the risk factors associated with re-dislocation or re-revision may help with perioperative decision making in order to decrease the high failure rate seen in this study. PMID- 25686784 TI - Perioperative management strategies to improve outcomes and reduce cost during an episode of care. AB - Total joint arthroplasty is a successful procedure with measurable and clear outcomes that have historically required a complex array of resources to deliver. The resulting expense burden has placed this procedure at the center of many payment reform efforts, including bundled payments. The orthopedic surgeon, through his orders and known preferences, determines the resource consumption during an episode of care. Strategies to better optimize the medical and social determinants of care prior to surgery can pay off in improved outcomes at reduced cost. Physician leadership is critical to altering the culture and achieving the desired results. PMID- 25686785 TI - Diagnosis of Periprosthetic Joint Infection: The Role of Nuclear Medicine May Be Overestimated. AB - Although the International Consensus Meeting on Periprosthetic Joint Infection's definition of periprosthetic joint infection (PJI) does not include nuclear imaging as part of the diagnostic criteria, many contemporary nuclear imaging studies are reporting exceptional results in PJI diagnosis. We conducted a systematic review of studies published from 2004 to 2012 reporting the accuracy of nuclear imaging for diagnosis of PJI, utilizing a specially designed tool (QUADAS-2) for critical appraisal and investigation of bias. Our results revealed high risk of bias as well as high levels of concern regarding the clinical applicability of these tests in a majority of the studies. On the basis of our findings, we recommend that the use of nuclear imaging for diagnosis of PJI be limited to a few select cases. PMID- 25686786 TI - Functional Results of the ROCC(r) Mobile Bearing Knee. 602 Cases at Midterm Follow-Up (5 to 14 Years). AB - We report midterm results of a prospective continuous cohort of ROCC(r) Total Knee Arthroplasties (TKA). Between 2001 and 2008, all primary TKA patients (n=500) received 602 ROCC saddle-shaped rotating platform TKAs. Mean follow-up was 7.5 years (5-13) (>10 years in 123 knees). 82 patients (93 knees) died; 20 patients (21 knees) were lost to follow-up. Active flexion improved from 119 degrees (10 degrees -150 degrees ) to 127 degrees (90 degrees -155 degrees ) and Knee Society knee score from 39+/-11 to 94+/-9. Two knees were reoperated for aseptic loosening: Kaplan-Meier 14-year survivorship with aseptic loosening as end-point was 99.4% (95% CI, 99.8-100). UCLA mean score increased from 3.8/10 at baseline to 7.3/10 at last FU, 91% recovering pre-disease activity, and 27% with UCLA score >=8/10. ROCC TKA demonstrated solid midterm survivorship without activity-related complications. LEVEL OF EVIDENCE: Therapeutic, Level IV. PMID- 25686787 TI - Comparison of Quality Oncology Practice Initiative (QOPI) Measure Adherence Between Oncology Fellows, Advanced Practice Providers, and Attending Physicians. AB - Quality improvement measures are uniformly applied to all oncology providers, regardless of their roles. Little is known about differences in adherence to these measures between oncology fellows, advance practice providers (APP), and attending physicians. We investigated conformance across Quality Oncology Practice Initiative (QOPI) measures for oncology fellows, advance practice providers, and attending physicians at the Durham Veterans Affairs Medical Center (DVAMC). Using data collected from the Spring 2012 and 2013 QOPI cycles, we abstracted charts of patients and separated them based on their primary provider. Descriptive statistics and the chi-square test were calculated for each QOPI measure between fellows, advanced practice providers (APPs), and attending physicians. A total of 169 patients were reviewed. Of these, 31 patients had a fellow, 39 had an APP, and 99 had an attending as their primary oncology provider. Fellows and attending physicians performed similarly on 90 of 94 QOPI metrics. High-performing metrics included several core QOPI measures including documenting consent for chemotherapy, recommending adjuvant chemotherapy when appropriate, and prescribing serotonin antagonists when prescribing emetogenic chemotherapies. Low-performing metrics included documentation of treatment summary and taking action to address problems with emotional well-being by the second office visit. Attendings documented the plan for oral chemotherapy more often (92 vs. 63%, P=0.049). However, after the chart audit, we found that fellows actually documented the plan for oral chemotherapy 88% of the time (p=0.73). APPs and attendings performed similarly on 88 of 90 QOPI measures. The quality of oncology care tends to be similar between attendings and fellows overall; some of the significant differences do not remain significant after a second manual chart review, highlighting that the use of manual data collection for QOPI analysis is an imperfect system, and there may be significant inter observer variability. PMID- 25686788 TI - Abstracts of the Irish Society of Gastroenterology Winter Meeting, November 22 23, 2013, Killarney, Co. Kerry, Ireland. PMID- 25686789 TI - Influence of copper surfaces on biofilm formation by Legionella pneumophila in potable water. AB - Legionella pneumophila is a waterborne pathogen that can cause Legionnaires' disease, a fatal pneumonia, or Pontiac fever, a mild form of disease. Copper is an antimicrobial material used for thousands of years. Its incorporation in several surface materials to control the transmission of pathogens has been gaining importance in the past decade. In this work, the ability of copper to control the survival of L. pneumophila in biofilms was studied. For that, the incorporation of L. pneumophila in polymicrobial drinking water biofilms formed on copper, PVC and PEX, and L. pneumophila mono-species biofilms formed on copper and uPVC were studied by comparing cultivable and total numbers (quantified by peptide nucleic acid (PNA) hybridisation). L. pneumophila was never recovered by culture from heterotrophic biofilms; however, PNA-positive numbers were slightly higher in biofilms formed on copper (5.9 * 10(5) cells cm(-2)) than on PVC (2.8 * 10(5) cells cm(-2)) and PEX (1.7 * 10(5) cells cm(-2)). L. pneumophila mono species biofilms grown on copper gave 6.9 * 10(5) cells cm(-2) for PNA-positive cells and 4.8 * 10(5) CFU cm(-2) for cultivable numbers, showing that copper is not directly effective in killing L. pneumophila. Therefore previous published studies showing inactivation of L. pneumophila by copper surfaces in potable water polymicrobial species biofilms must be carefully interpreted. PMID- 25686790 TI - Administering the cost of death: organisational perspectives on workers' compensation and common law claims following traumatic death at work in Australia. AB - Quite apart from its devastating human and psychological effects, the death of a worker can have significant, life-changing effects on their families. For many affected families, workers' compensation entitlements represent the primary financial safeguard. Where the worker was self-employed, the family will generally be excluded from this remedy and have to take the more problematic option of claiming damages at common law. Despite the centrality of workers' compensation, little attention has been given to how effectively workers' compensation agencies address the needs of bereaved families or the views of other organisations involved, such as safety inspectors, unions, employers and victim advocates. Based on interviews with forty eight organisational representatives in five Australian states, this study examines how workers' compensation regimes deal with work-related death from the perspective of those organisations involved directly or indirectly in the process. The study highlighted a number of problems, including the exclusion of self-employed workers and dealing with 'mixed families'. PMID- 25686791 TI - The DSM-5 Limited Prosocial Emotions subtype of Conduct Disorder in incarcerated male and female juvenile delinquents. AB - The aim of the present study was to analyze the relevance of the DSM-5's Conduct Disorder new Limited Prosocial Emotions (CD LPE) specifier in incarcerated juvenile delinquents. A sample of 201 males and 98 females from the Juvenile Detention Centers managed by the Portuguese Ministry of Justice diagnosed with Conduct Disorder (CD) was used. Results showed that male juvenile delinquents with the CD LPE specifier scored higher on callous-unemotional traits (CU), general psychopathic traits, psychopathy taxon membership, self-reported delinquency, and crime seriousness, and lower on prosocial behavior and social desirability, while female juvenile delinquents with the CD LPE specifier scored higher on callous-unemotional traits (CU) and general psychopathic traits, and lower on prosocial behavior. Significant associations for both genders were found between the CD LPE specifier and age of crime onset and first problems with the law. PMID- 25686792 TI - Characterization and immobilization of trypsin on tannic acid modified Fe3O4 nanoparticles. AB - Fe3O4 nanoparticles (NPs) were synthesized by co-precipitating Fe2+ and Fe3+ in an ammonia solution. Fe3O4 NPs functionalized with tannic acid were prepared. After functionalization process, trypsin enzyme was immobilized on these Fe3O4 NPs. The influence of pH, temperature, thermal stability, storage time stability and reusability on non-covalent immobilization was studied. The properties of Fe3O4 and its modified forms were examined by scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), thermal gravimetric analysis (TGA), UV-vis spectrometer (UV) and X-ray diffraction (XRD), magnetization and zeta potential measurements. The immobilized enzyme was slightly more stable than the free enzyme at 45 degrees C. According to the results, the activity of immobilized trypsin was preserved 55% at 45 degrees C after 2 h and 90% after 120 days storage. In addition, the activity of the immobilized trypsin was preserved 40% of its initial activity after eight times of successive reuse. PMID- 25686793 TI - Quaternary ammonium poly(diethylaminoethyl methacrylate) possessing antimicrobial activity. AB - Quaternary ammonium (QA) methacrylate monomers and polymers were synthesized from a N-alkylation of N,N-diethylaminoethyl methacrylate (DEAEM) monomer. Linear copolymers, and for the first time reported crosslinked nanoparticles (NPs), based QA-PDEAEM were prepared by radical polymerization of the quaternized QA DEAEM monomers with either methyl methacrylate (MMA) or a divinyl monomer. QA PDEAEM NPs of 50-70 nm were embedded in polyethylene vinyl acetate coating. QA polymers with N-C8 and N-C18 alkyl chains and copolymers with methyl methacrylate were prepared at different molar ratios and examined for their antimicrobial effectiveness. These coatings exhibited strong antibacterial activity against four representative Gram-positive and Gram-negative bacteria. PMID- 25686794 TI - Interaction of transglutaminase with adsorbed and spread films of beta-casein and k-casein. AB - Enzymes can be used to enable a specific and controlled approach for structural modifications of protein networks in food technology. Enzymatically induced cross links between proteins in the continuous phase and/or at interfaces result in better stabilisation and enhanced material properties in foams and emulsions. In this work the interfacial properties of beta-casein and k-casein films were investigated with a special focus on the mechanism of transglutaminase (TG) induced cross-linking at the air/water interface. The surface rheology results showed that for the enhanced interfacial strength the order and timing of TG addition matters: TG reaction was most effective when the enzyme was applied during adsorption of proteins to the interface. Differences observed between enzymatic cross-linking of beta-casein and k-casein at the air/water interface verified the importance of molecular structure and close packing for formation of an elastic protein network. PMID- 25686795 TI - Molecular characterization and transcriptome analysis of orange head Chinese cabbage (Brassica rapa L. ssp. pekinensis). AB - MAIN CONCLUSION: The orange head phenotype of Br - or resulted from a large insertion in carotenoid isomerase (BrCRTISO) . Comparative transcriptome analysis revealed that the mutation affected the expression of abundant transcription factor genes. A new orange trait-specific marker was developed for marker assisted breeding. Orange head leaves are a desirable quality trait for Chinese cabbage. Our previous fine mapping identified BrCRTISO as the Br-or candidate gene for the orange Chinese cabbage mutant. Here, we examined the BrCRTISO gene from white and orange head Chinese cabbage. While BrCRTISO from the white control plant was able to complement the Arabidopsis Atcrtiso mutant phenotype, Brcrtiso with a large insertion from the orange head Chinese cabbage failed to rescue the Arabidopsis mutant phenotype. The results show that Brcrtiso was non-functional, concomitant with the accumulation of prolycopene in Br-or to yield orange head. Comparative transcriptome analysis by RNA-seq identified 372 differentially expressed genes between the control and Br-or mutant using two near-isogenic lines with white and orange inner leaves. The mutation in BrCRTISO specifically affected many genes in the functional groups involved in RNA, protein, transport, and signaling. Particularly, expressions of many transcription factor genes were dramatically altered in Br-or, suggesting a potential role of BrCRTISO or carotenoid metabolites in affecting transcription. A novel co-dominant gene specific marker was developed that co-segregated with orange color phenotype and would be useful for marker-assisted selection with enhanced selection efficiency. Our study provides new insights into understanding of the molecular basis of Br or in mediating head leaf color and depicts a global view of the effect of BrCRTISO on cellular processes in plant. It also provides a molecular tool to accelerate breeding new Chinese cabbage cultivars with unique health quality and visual appearance. PMID- 25686796 TI - The influence of performance-based payment on childhood immunisation coverage. AB - BACKGROUND: Pay-for-performance, also called the quality system (QS) in Estonia, was implemented in 2006 and one indicator for achievement is the childhood immunisation coverage rate. The WHO vaccination coverage in Europe for diphtheria, tetanus and pertussis, and measles in children aged around one year old should meet or exceed 90 per cent. METHODS: The study was conducted using a database from the Estonian Health Insurance Fund. The study compared childhood immunisation coverage rates of all Estonian family physicians in two groups, joined and not joined to the quality system during the observation period 2006 2012. Immunisation coverage was calculated as the percentage of persons in the target age group who received a vaccine dose by a given age. The target level of immunisations in Estonia is set at 90 per cent and higher. RESULTS: Immunisation coverage rates of family doctors (FD) in Estonia showed significant differences between two groups of doctors: joined to the quality system and not joined. Doctors joined to the quality system met the 90 per cent vaccination criterion more frequently compared to doctors not joined to the quality system. Doctors not joined to the quality system were below the 90 per cent vaccination criterion in all vaccinations listed in the Estonian State Immunisation Schedule. CONCLUSION: Pay-for-performance as a financial incentive encourages higher levels of childhood immunisations. PMID- 25686797 TI - Structure-tunable Janus fibers fabricated using spinnerets with varying port angles. AB - The preparation of Janus fibers using a new side-by-side electrospinning process is reported. By manipulating the angle between the two ports of the spinneret emitting the working fluids, Janus nanofibers with tunable structures in terms of width, interfacial area and also volume of each side can be easily fabricated. PMID- 25686798 TI - Reduction of kynurenic acid to quinolinic acid ratio in both the depressed and remitted phases of major depressive disorder. AB - Low-grade inflammation is characteristic of a subgroup of currently depressed patients with major depressive disorder (dMDD). It may lead to the activation of the kynurenine-metabolic pathway and the increased synthesis of potentially neurotoxic metabolites such as 3-hydroxykynurenine (3HK) and quinolinic acid (QA), relative to kynurenic acid (KynA). Nevertheless, few studies have examined whether abnormalities in this pathway are present in remitted patients with MDD (rMDD). Here we compared the serum concentrations of kynurenine metabolites, measured using high performance liquid chromatography with tandem mass spectrometry, across 49 unmedicated subjects meeting DSM-IV-TR criteria for MDD, 21 unmedicated subjects meeting DSM-IV-TR criteria for rMDD, and 58 healthy controls (HCs). There was no significant group difference in the concentrations of the individual kynurenine metabolites, however both the dMDD group and the rMDD group showed a reduction in KynA/QA, compared with the HCs. Further, there was an inverse correlation between KynA/QA and anhedonia in the dMDD group, while in the rMDD group, there was a negative correlation between lifetime number of depressive episodes and KynA/QA as well as a positive correlation between the number of months in remission and KynA/QA. Our results raise the possibility that a persistent abnormality exists within the kynurenine metabolic pathway in MDD that conceivably may worsen with additional depressive episodes. The question of whether persistent abnormalities in kynurenine metabolism predispose to depression and/or relapse in remitted individuals remains unresolved. PMID- 25686799 TI - The Challenges and Opportunities Associated with Reimbursement for Obesity Pharmacotherapy in the USA. AB - Obesity has become a serious public health problem that has stimulated primordial and primary prevention efforts, and a triad of management options (lifestyle, pharmacotherapy, and surgical interventions). A growing body of evidence supports the need for a multi-pronged, clinic-based approach that leverages the synergy between pharmaceutical and lifestyle modification. Recent US policy changes namely, the passage of the Patient Protection and Affordable Care Act coupled with recognition of obesity as a disease by the American Medical Association suggest that financial incentives and attitudes towards obesity management are changing. This paradigm shift has implications for current and future obesity pharmacotherapy. However, barriers to pharmacotherapy utilization include patient and physician perceptions of modest efficacy, historical safety issues, regulatory obstacles, and lack of reimbursement. The shifting attitudes and challenges associated not only with a multi-payer system, but also the lack of clearly defined cross-payer reimbursement strategies, prompted a survey to determine coverage for obesity treatment. Participants indicated that federal/state mandates and growth of quality-driven healthcare initiatives will eventually drive wider pharmacotherapy reimbursement within 1-5 years. There are signs that federal/state programs are already moving towards reimbursement by improving quality measures to track obesity outcomes and reduce costs. Future research on clinical and economic outcomes of combination weight-management programs coupled with innovative approaches (e.g., eHealth) in the real-world setting that demonstrate value to patients, healthcare providers, payers, and employers will help reshape obesity management by reducing barriers and broadening reimbursement coverage for anti-obesity pharmacotherapy. PMID- 25686800 TI - LC3 overexpression reduces Abeta neurotoxicity through increasing alpha7nAchR expression and autophagic activity in neurons and mice. AB - Autophagy is an intracellular degradation pathway with dynamic interactions for eliminating damaged organelles and protein aggregates by lysosomal digestion. The EGFP-conjugated microtubule-associated protein 1 light chain 3 (EGFP-LC3) serves to monitor autophagic process. Extracellular beta-amyloid peptide accumulation is reported as a major cause in Alzheimer's disease (AD) pathogenesis; large numbers of autophagic vacuoles accumulate in patients' brains. We previously demonstrated that extracellular Abeta (eAbeta) induces strong autophagic response and alpha7nAChR acts as a carrier to bind with eAbeta; which further inhibits Abeta induced neurotoxicity via autophagic degradation. In the present study, we overexpressed LC3 in both neuroblastoma cells (SH-SY5Y/pEGFP-LC3) and mice (TgEGFP-LC3) to assess the effect of LC3 overexpression on Abeta neurotoxicity. SH-SY5Y/pEGFP-LC3 cells and primary cortical neuron cultures derived from E17 (embryonic day 17) TgEGFP-LC3 mice showed not only better resistance against Abeta neurotoxicity but also higher alpha7nAChR expression and autophagic activity than control. Administration of alpha-bungarotoxin (alpha-BTX) to block alpha7nAChR antagonized the neuroprotective action of SH-SY5Y/pECGF-LC3 cells, suggesting that eAbeta binding with alpha7nAChR is an important step in Abeta detoxification. LC3 overexpression thus exerts neuroprotection through increasing alpha7nAChR expression for eAbeta binding and further enhancing autophagic activity for Abeta clearance in vitro and in vivo. PMID- 25686801 TI - The effectiveness of psychoeducational family intervention for patients with schizophrenia in a 14-year follow-up study in a Chinese rural area. AB - BACKGROUND: It is unclear if the impact of psychoeducational family intervention for patients with schizophrenia can be sustained over 10 years. In this study, we explored the 14-year effect of psychoeducational family intervention for patients with schizophrenia in a Chinese rural area. METHOD: The data from a cluster randomized control trial (CRCT) study of psychoeducational family intervention in a 14-year follow-up was analyzed. All patients with schizophrenia (n = 326) who participated in the CRCT drawn from six townships in Xinjin County of Chengdu in 1994, of whom 238 (73.0%) who were still alive, and their informants were followed up in 2008. The Patients Follow-up Scale, the Positive and Negative Syndrome Scale (PANSS) and the Global Assessment of Functioning were used in the follow-up study. RESULTS: There were no significant differences of marital status, mean scores of PANSS positive symptoms, negative symptoms, general mental health, and total scores among the psychoeducational family intervention, medication, and control groups in 2008. The psychoeducational family intervention group had a significantly higher rate of antipsychotic medication and a higher level of work ability than other two groups. The control group had a significantly higher rate of never-treated (26.0%) than psychoeducational family intervention group (6.5%). CONCLUSION: Psychoeducational family intervention might be still effective in the 14-year follow-up, especially in patients' treatment adherence/compliance and social functioning. Psychoeducational family intervention might be more effective in places where family members frequently participated in patients' care and had a lower level of knowledge on mental illness. Family intervention should be considered when making mental health policy and planning mental health services. PMID- 25686802 TI - Epoxide hydrolase activities and epoxy fatty acids in the mosquito Culex quinquefasciatus. AB - Culex mosquitoes have emerged as important model organisms for mosquito biology, and are disease vectors for multiple mosquito-borne pathogens, including West Nile virus. We characterized epoxide hydrolase activities in the mosquito Culex quinquefasciatus, which suggested multiple forms of epoxide hydrolases were present. We found EH activities on epoxy eicosatrienoic acids (EETs). EETs and other eicosanoids are well-established lipid signaling molecules in vertebrates. We showed EETs can be synthesized in vitro from arachidonic acids by mosquito lysate, and EETs were also detected in vivo both in larvae and adult mosquitoes by LC-MS/MS. The EH activities on EETs can be induced by blood feeding, and the highest activity was observed in the midgut of female mosquitoes. The enzyme activities on EETs can be inhibited by urea-based inhibitors designed for mammalian soluble epoxide hydrolases (sEH). The sEH inhibitors have been shown to play diverse biological roles in mammalian systems, and they can be useful tools to study the function of EETs in mosquitoes. Besides juvenile hormone metabolism and detoxification, insect epoxide hydrolases may also play a role in regulating lipid signaling molecules, such as EETs and other epoxy fatty acids, synthesized in vivo or obtained from blood feeding by female mosquitoes. PMID- 25686803 TI - Spatial function in adolescents and young adults with congenital adrenal hyperplasia: clinical phenotype and implications for the androgen hypothesis. AB - Females with the classic form of congenital adrenal hyperplasia (CAH) due to 21 hydroxylase deficiency are said to perform better than unaffected female controls on tests of mental rotation or other visuospatial abilities, but findings are conflicting. We studied 31 adolescents and young adults with CAH and 19 unaffected sibling controls, who were given standardized spatial tests and tests of other sexually differentiated cognitive functions (verbal fluency, perceptual speed). The possible role of CAH subtype (salt-wasting or simple-virilizing) was evaluated. Only females with the more severe, salt-wasting form of CAH, but not females with the simple-virilizing form, performed significantly better than sex matched sibling controls on measures of mental rotation. Subtype differences were not significant for verbal fluency or perceptual speed. Severity of prenatal genital virilization, but not postnatal age when medication was started, predicted accuracy on the Mental Rotations Test. Results are consistent with the possibility of an organizational effect of androgens in the central nervous system that impacts the development of spatial abilities. Implications for the timing of the hypothetical critical period are discussed. PMID- 25686804 TI - Maternal cortisol during pregnancy is related to infant cardiac vagal control. AB - BACKGROUND: Prenatal exposure to maternal psychological distress and glucocorticoids result in neurobiological adaptations within the fetus that increase risk for developing exaggerated emotional, behavioral, and stress responses to novelty and challenges in childhood. The current study investigated the influence of maternal depressed mood and cortisol during pregnancy on infant cardiac vagal control (CVC) to standardized laboratory challenge tasks. METHODS: The sample comprised 194 women and their infants. Maternal reports of depressed mood and salivary cortisol were assessed at 14 and 32 weeks gestational age. Linear regression was used to examine associations between maternal measures during early and late pregnancy, and infant CVC indexed via respiratory sinus arrhythmia (RSA) at rest and in response to laboratory tasks designed to elicit frustration when infants were 6 months of age. It was hypothesized that maternal depressed mood and cortisol would be associated with lower basal RSA and smaller decreases in RSA from baseline to challenge. RESULTS: A significant decrease in infant RSA from baseline to frustration tasks indicated that laboratory tasks elicited a reliable decrease in RSA from baseline to frustration among infants which is characterized by reduction in vagal efferent activity on the heart in response to challenge. Higher maternal cortisol, but not depressed mood, was associated with lower basal RSA and greater decrease in RSA from baseline to frustration. Associations between maternal cortisol and infant basal RSA were observed for both early and late pregnancy whereas the associations between prenatal cortisol and decrease in RSA from baseline to frustration were observed for early, but not late, pregnancy. CONCLUSIONS: Maternal cortisol during pregnancy was associated with infant CVC at 6-months of age. Such influences may have enduring impacts on the child and important implications for the development of physical and mental health outcomes. PMID- 25686805 TI - Mineralocorticoid receptor haplotypes sex-dependently moderate depression susceptibility following childhood maltreatment. AB - The MR is an important regulator of the hypothalamic-pituitary-adrenal (HPA) axis and a prime target for corticosteroids. There is increasing evidence from both clinical and preclinical studies that the MR has different effects on behavior and mood in males and females. To investigate the hypothesis that the MR sex dependently influences the relation between childhood maltreatment and depression, we investigated three common and functional MR haplotypes (GA, CA, and CG haplotype, based on rs5522 and rs2070951) in a population-based cohort (N = 665) and an independent clinical cohort from the Netherlands Study of Depression and Anxiety (NESDA) (N = 1639). The CA haplotype sex-dependently moderated the relation between childhood maltreatment and depressive symptoms both in the population-based sample (sex * maltreatment * haplotype: beta = 4.07, P = 0.029) and in the clinical sample (sex * maltreatment * haplotype, beta = -2.40, P = 0.011). Specifically, female individuals in the population-based sample were protected (beta = -4.58, P = 2.0 e(-5)), whereas males in the clinical sample were at increased risk (beta = 2.54, P = 0.0022). In line with these results, female GA haplotype carriers displayed increased vulnerability in the population-based sample (beta = 4.58, P = 7.5 e(-5)) whereas male CG-carriers showed increased resilience in the clinical sample (beta = -2.71, P = 0.016). Consistently, we found a decreased lifetime MDD risk for male GA haplotype carriers following childhood maltreatment but an increased risk for male CA haplotype carriers in the clinical sample. In both samples, sex-dependent effects were observed for GA-GA diplotype carriers. In summary, sex plays an important role in determining whether functional genetic variation in MR is beneficial or detrimental, with an apparent female advantage for the CA haplotype but male advantage for the GA and CG haplotype. These sex-dependent effects of MR on depression susceptibility following childhood maltreatment are relevant in light of the increased prevalence of mood disorders in women and point to a sex specific role of MR in the etiology of depression following childhood maltreatment. PMID- 25686806 TI - Regional differences in birth size: a comparison between the Helsinki Birth Cohort Study and contemporaneous births on the Aland Islands. AB - The Aland Islands were recently ranked as Finland's healthiest region with lower prevalence of several non-communicable diseases compared with the national mean. We have compared birth characteristics of 1697 individuals born on the Aland Islands between 1937 and 1944 with contemporaneous data from the Helsinki Birth Cohort Study (HBCS; n=11,808). This is a first step towards a potential future analysis of Alandic health from a life-course perspective. Mean birth weight and length were calculated for both cohorts. Birth weight was entered into a multiple linear regression model with sex, maternal age, marital status and birth year as predictors. Mean birth weight in the Aland cohort was 3499 g, 87 g (95% CI 62; 111) higher compared with the HBCS. Sex and maternal marital status were the strongest predictors of birth weight. More detailed studies are needed to explore the potential effects of this difference in average birth weight between cohorts. PMID- 25686807 TI - First report of Babesia divergens infection in an HIV patient. AB - Human babesiosis is a zoonosis primarily transmitted through Ixodes ticks and alternatively by routes such as blood transfusions from asymptomatic donors. We report the first case of human babesiosis caused by Babesia divergens in a patient with HIV. This study also focuses on elucidating the possible transmission route of infection in this patient, who received numerous blood transfusions but showed patent symptoms only after splenectomy. A battery of detection tools along with a novel Western-Blot Assay and Enzyme Linked Immunosorbent Assay using the major surface protein of B. divergens (Bd37) as a target were used to evaluate the presence of B. divergens or antibodies against the parasite in samples from the patient and the blood donors involved in this case. A retrospective study of the humoral status against the parasite revealed B. divergens IgG antibodies in one of the implicated donors, but also showed that the patient had been already exposed to the parasite before any transfusion. Thus, this analysis of natural and transfusion transmission routes suggests a pre existing subclinical babesiosis in the patient. PMID- 25686808 TI - Checkpoint inhibitors for cancer immunotherapy. Multiple checkpoints on the long road towards cancer immunotherapy. PMID- 25686809 TI - Serving persons with severe mental illness in primary care-based medical homes. AB - OBJECTIVE: Primary care-based medical homes are rapidly disseminating through populations with chronic illnesses. Little is known about how these models affect the patterns of care for persons with severe mental illness who typically receive much of their care from mental health specialists. This study examined whether enrollment in a primary care medical home alters the patterns of care for Medicaid enrollees with severe mental illness. METHODS: The authors conducted a retrospective secondary data analysis of medication adherence, outpatient and emergency department visits, and screening services used by adult Medicaid enrollees with diagnoses of schizophrenia (N=7,228), bipolar disorder (N=13,406), or major depression (N=45,000) as recorded in North Carolina Medicaid claims from 2004-2007. Participants not enrolled in a medical home (control group) were matched by propensity score to medical home participants on the basis of demographic characteristics and comorbidities. Those dually enrolled in Medicare were excluded. RESULTS: Results indicate that medical home enrollees had greater use of both primary and specialty mental health care, better medication adherence, and reduced use of the emergency department. Better rates of preventive lipid and cancer screening were found only for persons with major depression. CONCLUSIONS: Enrollment in a medical home was associated with substantial changes in patterns of care among persons with severe mental illness. These changes were associated with only a modest set of incentives, suggesting that medical homes can have large multiplier effects in primary care of persons with severe mental illness. PMID- 25686810 TI - Impact of patients' psychiatric hospitalization on caregivers: a systematic review. AB - OBJECTIVE: A systematic literature review was conducted to assess the impact of patients' psychiatric hospitalizations on caregivers. METHODS: A systematic search of the Web of Knowledge, PsycINFO, and MEDLINE (PubMed) was conducted for peer-reviewed articles published in English before August 31, 2013. Qualitative, quantitative, and mixed-methods studies were included if they focused on the outcomes of caregivers of either adult or youth patients and presented data collected directly from caregivers of patients who had been psychiatrically hospitalized. RESULTS: Twenty-nine articles met the inclusion criteria. The review found that caregivers are heterogeneous in their reaction to patients' psychiatric hospitalization; however, many report distress. Many caregivers have reported experiencing stigma, disruptions in daily life, worse general medical health, economic strain, and changes in relationships after hospitalization. Negative reactions to the hospitalization may decrease over time, but distress can remain elevated compared with the general population. Nonetheless, many caregivers have also reported experiencing positive changes as a result of the hospitalization. The reaction of caregivers may be influenced by the severity of the patient's psychiatric problems as well as the caregiver's demographic characteristics and style of coping. CONCLUSIONS: Caregivers experience a range of reactions to psychiatric hospitalizations. Providing caregivers with psychoeducation about their possible reaction to hospitalization and teaching them coping techniques may improve clinical outcomes for patients. Future research is needed to understand the heterogeneity in caregivers' reactions to patients' psychiatric hospitalization. PMID- 25686811 TI - Cost-effectiveness of on-site versus off-site collaborative care for depression in rural FQHCs. AB - OBJECTIVE: Collaborative care for depression in primary care settings is effective and cost-effective. However, there is minimal evidence to support the choice of on-site versus off-site models. This study examined the cost effectiveness of on-site practice-based collaborative care (PBCC) versus off-site telemedicine-based collaborative care (TBCC) for depression in federally qualified health centers (FQHCs). METHODS: In a multisite, randomized, pragmatic comparative cost-effectiveness trial, 19,285 patients were screened for depression, 2,863 (14.8%) screened positive, and 364 were enrolled. Telephone interview data were collected at baseline and at six, 12, and 18 months. Base case analysis used Arkansas FQHC health care costs, and secondary analysis used national cost estimates. Effectiveness measures were depression-free days and quality-adjusted life years (QALYs) derived from depression-free days, the 12 Item Short-Form Survey, and the Quality of Well-Being (QWB) Scale. Nonparametric bootstrap with replacement methods were used to generate an empirical joint distribution of incremental costs and QALYs and acceptability curves. RESULTS: The TBCC intervention resulted in more depression-free days and QALYs but at a greater cost than the PBCC intervention. The disease-specific (depression-free day) and generic (QALY) incremental cost-effectiveness ratios (ICERs) were below their respective ICER thresholds for implementation, suggesting that the TBCC intervention was more cost effective than the PBCC intervention. CONCLUSIONS: These results support the cost-effectiveness of TBCC in medically underserved primary care settings. Information about whether to insource (make) or outsource (buy) depression care management is important, given the current interest in patient-centered medical homes, value-based purchasing, and bundled payments for depression care. PMID- 25686812 TI - Barriers to serving clients with co-occurring disorders in a transformed mental health system. AB - OBJECTIVE: The publication of the President's New Freedom Commission Report in 2003 led to hope and anticipation that system transformation would address barriers that have impeded the delivery of integrated services for clients with co-occurring mental health and substance use disorders. Have problems been resolved? This study analyzed providers' perspectives on serving clients with co occurring disorders in a large mental health system that has undergone transformation. METHODS: Six focus groups were conducted with providers at specialty mental health treatment organizations that received funding to transform services. Using content analysis, the authors identified major themes of the focus group discussions. RESULTS: Participants reported several barriers within the mental health system and challenges associated with collaborating with specialty substance abuse treatment providers that impede the delivery of integrated care. CONCLUSIONS: In spite of efforts to improve co-occurring disorder service delivery in a transformed mental health system, barriers that have historically impeded integrated treatment persist. PMID- 25686813 TI - Life changes among homeless persons with mental illness: a longitudinal study of housing first and usual treatment. AB - OBJECTIVE: This study compared the life changes of homeless people with mental illness participating in Housing First or treatment as usual and examined factors related to various changes. METHODS: Semistructured narrative interviews were conducted with 219 participants in five Canadian cities at baseline; 197 were interviewed again at 18 months after random assignment to Housing First (N=119) or treatment as usual (N=78). Interviews were coded across 13 life domains, and each participant was categorized as reporting positive, mixed-neutral, or negative changes. Housing First and treatment as usual participants were compared with respect to change patterns. Thematic analysis was used to examine factors related to various changes. RESULTS: The percentage of participants in Housing First reporting positive changes was more than double that for participants in treatment as usual, and treatment as usual participants were four times more likely than Housing First participants to report negative changes. Factors related to positive changes included having stable good-quality housing, increased control over substance use, positive relationships and social support, and valued social roles. Factors related to negative changes included precarious housing, negative social contacts, isolation, heavy substance use, and hopelessness. Factors related to mixed-neutral changes were similar to those for participants reporting negative changes but were less intense. CONCLUSIONS: Housing First with intensive support was related to more positive changes among homeless adults with mental illness across five Canadian cities. Those with poor housing or support, more common in treatment as usual, continued to struggle. These findings are relevant for services and social change to benefit this population. PMID- 25686814 TI - Prospective study of violence risk reduction by a mental health court. AB - OBJECTIVE: Although many mental health courts (MHCs) have been established to reduce criminal justice involvement of persons with mental disorders, research has not kept pace with the widespread implementation of these courts. Whereas early MHCs were restricted to persons charged with nonviolent misdemeanors, many MHCs now accept persons with more serious charges for whom ameliorating risk of violence is a greater concern. This study evaluated the relationship between MHC participation and risk of violence by using a prospective design. It was hypothesized that MHC participation would decrease the risk of violence during a one year follow-up compared with a matched comparison group. METHODS: The sample included 169 jail detainees with a mental disorder who either entered an MHC (N=88) or received treatment as usual (N=81). Seventy-two percent had been charged with felonies. Participants were interviewed at baseline and during a one year follow up, and their arrest records were reviewed. Propensity-adjusted logistic regression evaluated the relationship between MHC participation and risk of violence, controlling for potential confounders such as history of violence, demographic characteristics, baseline treatment motivation, and time at risk in the community. RESULTS: MHC participation was associated with reduction in risk of violence (odds ratio=.39). During follow-up, 25% of the MHC group perpetrated violence, compared with 42% of the treatment-as-usual group. CONCLUSIONS: MHC participation can reduce the risk of violence among justice-involved persons with mental disorders. The findings support the conclusion that the MHC model can be extended beyond persons charged with nonviolent misdemeanors in a way that enhances public safety. PMID- 25686815 TI - Multilevel predictors of clinic adoption of state-supported trainings in children's services. AB - OBJECTIVE: Characteristics associated with participation in training in evidence informed business and clinical practices by 346 outpatient mental health clinics licensed to treat youths in New York State were examined. METHODS: Clinic characteristics extracted from state administrative data were used as proxies for variables that have been linked with adoption of innovation (extraorganizational factors, agency factors, clinic provider-level profiles, and clinic client-level profiles). Multiple logistic regression models were used to assess the independent effects of theoretical variables on the clinics' participation in state-supported business and clinical trainings between September 2011 and August 2013 and on the intensity of participation (low or high). Interaction effects between clinic characteristics and outcomes were explored. RESULTS: Clinic characteristics were predictive of any participation in trainings but were less useful in predicting intensity of participation. Clinics affiliated with larger (adjusted odds ratio [AOR]=.65, p<.01), more efficient agencies (AOR=.62, p<.05) and clinics that outsourced more clinical services (AOR=.60, p<.001) had lower odds of participating in any business-practice trainings. Participation in business trainings was associated with interaction effects between agency affiliation (hospital or community) and clinical staff capacity. Clinics with more full-time-equivalent clinical staff (AOR=1.52, p<.01) and a higher proportion of clients under age 18 (AOR=1.90, p<.001) had higher odds of participating in any clinical trainings. Participating clinics with larger proportions of youth clients had greater odds of being high adopters of clinical trainings (odds ratio=1.54, p<.01). CONCLUSIONS: Clinic characteristics associated with uptake of business and clinical training could be used to target state technical assistance efforts. PMID- 25686816 TI - Supporting safe driving practices among consumers of mental health services: guidelines for assessment. AB - Driving is often omitted or ignored during assessment and ongoing work with consumers of mental health services. This Open Forum describes guidelines to help providers of psychiatric services to support safe driving practices among consumers. The guidelines were developed over seven years with contributions from a wide range of stakeholders. They include key principles for conducting screening and initial assessment, obtaining a detailed driving history, and performing risk assessment. The guidelines include information about process (how to assess) and content (what information to seek) of driving assessment. Because driving is regulated by local jurisdictions and national legislation, the guidelines provide a general framework for addressing questions about driving practices among consumers of mental health services. They are intended to complement, rather than replace, existing guidelines, by providing a focus on the occupation of driving. In so doing, they provide principled information to embed driving assessment and intervention as part of psychiatric services. PMID- 25686817 TI - Do the effects of antistigma programs persist over time? Findings from a meta analysis. AB - OBJECTIVES: A previous analysis showed the positive impact of education and contact with persons with lived experience on public stigma toward mental illness, with contact yielding significantly greater effect sizes than education. This study reported a further analysis of those data that examined effects of education and contact at follow-up. METHODS: The literature (before October 2010) was searched and coded for studies that examined strategies for changing public stigma. RESULTS: The search found 72 articles, and 19 contained follow-up data. The effect size for overall impact was significantly different from zero for education, but a similar effect size was not significantly different from zero for contact because a small number of contact-intervention studies included follow-up. Effect sizes for attitudinal change were significantly different from zero for education and contact, but the effect size for contact was significantly greater. CONCLUSIONS: Future research designs need to include strategies for follow-up assessments. PMID- 25686818 TI - The new, confusing CPT codes: tips for documenting and billing to get paid what you deserve. AB - As of January 1, 2013, psychiatrists should be billing for services by using Evaluation and Management Current Procedural Terminology (CPT) codes for any encounter related to medical services. Because detailed information about these CPT codes became available only toward the end of 2012, clinicians had little time to be trained in their use, resulting in widespread confusion about when and how to use these codes for reimbursement. The authors describe strategies that psychiatrists can use to ensure appropriate reimbursement for patient care, such as how to code the initial psychiatric evaluation, acute or chronic conditions, medical decision-making complexity, psychotherapy, counseling, coordination of care, and crisis care. The authors suggest use of templates, with checklists, during patient examinations to facilitate documentation. PMID- 25686819 TI - Smoking cessation services and smoke-free policies at substance abuse treatment facilities: national survey results. AB - OBJECTIVE: The high prevalence of cigarette smoking among substance-abusing patients has raised concern. This study assessed the prevalence of and factors related to smoking cessation services and smoke-free policies in substance abuse treatment facilities in the United States. METHODS: Facility-level data were obtained from the 2012 National Survey of Substance Abuse Treatment Services (N=13,094). Multivariate logistic regressions were used to examine institutional- and state-level factors associated with use of smoking cessation services and smoking bans. RESULTS: Of all facilities, 46.8% offered behavioral counseling or pharmacotherapy services for smoking cessation, and 35.2% banned smoking on the property. Programs were more likely to offer smoking cessation services and to ban smoking if they had the following characteristics: they offered inpatient services, accepted government insurance, were licensed by state mental health departments, or were located in metropolitan areas, states with comprehensive smoke-free laws, or states where >30% of substance abuse treatment facilities were smoke free. Public programs were more likely than private for-profit organizations to offer smoking cessation services and to ban smoking. Providing a greater number of services was positively associated with delivery of smoking cessation services but negatively associated with smoking bans. Larger programs were more likely to provide smoking cessation services but less likely to ban smoking. CONCLUSIONS: Institutional characteristics and state environments influenced provision of smoking cessation services and smoke-free policies at substance abuse treatment facilities. These factors could be used to design comprehensive programs for dissemination of smoking cessation treatment and promotion of smoking bans at these facilities. PMID- 25686820 TI - Protective effect of C. sativa leaf extract against UV mediated-DNA damage in a human keratinocyte cell line. AB - Toxic effects of ultraviolet (UV) radiation on skin include protein and lipid oxidation, and DNA damage. The latter is known to play a major role in photocarcinogenesis and photoaging. Many plant extracts and natural compounds are emerging as photoprotective agents. Castanea sativa leaf extract is able to scavenge several reactive species that have been associated to UV-induced oxidative stress. The aim of this work was to analyze the protective effect of C. sativa extract (ECS) at different concentrations (0.001, 0.01, 0.05 and 0.1 MUg/mL) against the UV mediated-DNA damage in a human keratinocyte cell line (HaCaT). For this purpose, the cytokinesis-block micronucleus assay was used. Elucidation of the protective mechanism was undertaken regarding UV absorption, influence on (1)O2 mediated effects or NRF2 activation. ECS presented a concentration-dependent protective effect against UV-mediated DNA damage in HaCaT cells. The maximum protection afforded (66.4%) was achieved with the concentration of 0.1 MUg/mL. This effect was found to be related to a direct antioxidant effect (involving (1)O2) rather than activation of the endogenous antioxidant response coordinated by NRF2. Electrochemical studies showed that the good antioxidant capacity of the ECS can be ascribed to the presence of a pool of different phenolic antioxidants. No genotoxic or phototoxic effects were observed after incubation of HaCaT cells with ECS (up to 0.1 MUg/mL). Taken together these results reinforce the putative application of this plant extract in the prevention/minimization of UV deleterious effects on skin. PMID- 25686821 TI - SKI2162, an inhibitor of the TGF-beta type I receptor (ALK5), inhibits radiation induced fibrosis in mice. AB - Here we demonstrated that SKI2162, a small-molecule inhibitor of the TGF-beta type I receptor (ALK5), prevented radiation-induced fibrosis (RIF) in mice. SKI2162 inhibited phosphorylation of Smad and induction of RIF-related genes in vitro. In RIF a mouse model, SKI2162 reduced late skin reactions and leg contracture without jeopardizing the acute skin reaction. Irradiation of mouse tissue increased COL1A2 mRNA levels, and topical administration of SKI2162 significantly inhibited this effect. Thus, these findings support that SKI2162 has potential value as novel RIF-protective agent, and could be candidate for clinical trials. PMID- 25686822 TI - Targeting EGF-receptor(s) - STAT1 axis attenuates tumor growth and metastasis through downregulation of MUC4 mucin in human pancreatic cancer. AB - Transmembrane proteins MUC4, EGFR and HER2 are shown to be critical in invasion and metastasis of pancreatic cancer. Besides, we and others have demonstrated de novo expression of MUC4 in ~70-90% of pancreatic cancer patients and its stabilizing effects on HER2 downstream signaling in pancreatic cancer. Here, we found that use of canertinib or afatinib resulted in reduction of MUC4 and abrogation of in vitro and in vivo oncogenic functions of MUC4 in pancreatic cancer cells. Notably, silencing of EGFR family member in pancreatic cancer cells decreased MUC4 expression through reduced phospho-STAT1. Furthermore, canertinib and afatinib treatment also inhibited proliferation, migration and survival of pancreatic cancer cells by attenuation of signaling events including pERK1/2 (T202/Y204), cyclin D1, cyclin A, pFAK (Y925) and pAKT (Ser473). Using in vivo bioluminescent imaging, we demonstrated that canertinib treatment significantly reduced tumor burden (P=0.0164) and metastasis to various organs. Further, reduced expression of MUC4 and EGFR family members were confirmed in xenografts. Our results for the first time demonstrated the targeting of EGFR family members along with MUC4 by using pan-EGFR inhibitors. In conclusion, our studies will enhance the translational acquaintance of pan-EGFR inhibitors for combinational therapies to combat against lethal pancreatic cancer. PMID- 25686823 TI - SNAI2/Slug gene is silenced in prostate cancer and regulates neuroendocrine differentiation, metastasis-suppressor and pluripotency gene expression. AB - Prostate Cancer (PCa)-related deaths are mostly due to metastasization of poorly differentiated adenocarcinomas often endowed with neuroendocrine differentiation (NED) areas.The SNAI2/Slug gene is a major regulator of cell migration and tumor metastasization. We here assessed its biological significance in NED, and metastatic potential of PCa.SNAI2 expression was down-regulated in most PCa epithelia, in association with gene promoter methylation, except for cell clusters forming: a. the expansion/invasion front of high-grade PCa, b. NED areas, or c. lymph node metastasis.Knockdown of SNAI2 in PC3 cells down-regulated the expression of neural-tissue-associated adhesion molecules, Neural-Cadherin, Neural-Cadherin-2, Neuronal-Cell-Adhesion-Molecule, and of the NED marker Neuron Specific Enolase, whereas it abolished Chromogranin-A expression. The metastasis suppressor genes, Nm23-H1 and KISS1, were up-regulated, while the pluripotency genes SOX2, NOTCH1, CD44v6, WWTR1/TAZ and YAP1 were dramatically down-regulated. Over-expression of SNAI2 in DU145 cells substantiated its ability to regulate metastasis-suppressor, NED and pluripotency genes. In PCa and lymph node metastasis, expression of SOX2 and NOTCH1 was highly related to that of SNAI2.In conclusion, I. SNAI2 silencing in PCa may turn-off the expression of NED markers and pluripotency genes, while turning-on that of specific metastasis-suppressors, II. SNAI2 expression in selected PCa cells, by regulating their self-renewal, NED and metastatic potential, endows them with highly malignant properties. SNAI2 may thus constitute a key target for modern approaches to PCa progression. PMID- 25686824 TI - RACK1 is a candidate gene associated with the prognosis of patients with early stage non-small cell lung cancer. AB - BACKGROUND: This study was conducted to identify genetic polymorphisms associated with the prognosis of patients with early stage NSCLC. MATERIALS AND METHODS: We genotyped 1,969 potentially functional single nucleotide polymorphisms (SNPs) of 1,151 genes involved in carcinogenesis in 166 NSCLC patients who underwent curative surgery, using the Affymetrix custom-made GeneChip. A replication study was performed in an independent cohort of 626 patients. RESULTS: Fifty six SNPs which were associated with both overall survival (OS) and disease-free survival (DFS) with log-rank P values < 0.05 in discovery set were selected for validation. Among those, five SNPs (RACK1 rs1279736C>A and rs3756585T>G, C3 rs2287845T>C, PCAF rs17006625A>G, and PCM1 rs17691523C>G) were found to be significantly associated with survival in the same direction as the discovery set. In combined analysis, the rs1279736C>A and rs3756585T>G were most significantly associated with OS and DFS in multivariate analysis (P for OS = 4 * 10-5 and 7 * 10-5, respectively; and P for DFS = 0.003, both; under codominant model). In vitro promoter assay and electrophoretic mobility shift assay revealed that the rs3756585 T-to-G change increased promoter activity and transcription factor binding of RACK1. CONCLUSIONS: We identified five SNPs, especially RACK1 rs3756585T>G, as markers for prognosis of patients with surgically resected NSCLC. PMID- 25686825 TI - NF-kappaB signaling mediates acquired resistance after PARP inhibition. AB - PARP inhibitors are a class of promising anti-cancer drugs, with proven activity in BRCA mutant cancers. However, as with other targeted agents, treatment with PARP inhibitors generates acquired resistance within these tumors. The mechanism of this acquired resistance is poorly understood. We established cell lines that are resistant to PARP inhibitor by continuous treatment with the drug, and then used RNA sequencing to compare gene expression. Pathway analysis on the RNA sequencing data indicates that NF-kappaB signaling is preferentially up-regulated in PARP inhibitor-resistant cells, and that knockdown of core components in NF kappaB signaling reverses the sensitivity to PARP inhibitor in resistant cells. Of therapeutic relevance, we show that PARP inhibitor-resistant cells are sensitive to an NF-kappaB inhibitor in comparison to their parental controls. Malignancies with up-regulation of NF-kappaB are sensitive to bortezomib, a proteasome inhibitor that is currently used in the clinic. We also show that treatment with bortezomib results in cell death in the PARP inhibitor-resistant cells, but not in parental cells. Therefore we propose that up-regulation of NF kappaB signaling is a key mechanism underlying acquired resistance to PARP inhibition, and that NF-kappaB inhibition, or bortezomib are potentially effective anti-cancer agents after the acquisition of resistance to PARP inhibitors. PMID- 25686826 TI - Novel long non-coding RNAs are specific diagnostic and prognostic markers for prostate cancer. AB - Current prostate cancer (PCa) biomarkers such as PSA are not optimal in distinguishing cancer from benign prostate diseases and predicting disease outcome. To discover additional biomarkers, we investigated PCa-specific expression of novel unannotated transcripts. Using the unique probe design of Affymetrix Human Exon Arrays, we identified 334 candidates (EPCATs), of which 15 were validated by RT-PCR. Combined into a diagnostic panel, 11 EPCATs classified 80% of PCa samples correctly, while maintaining 100% specificity. High specificity was confirmed by in situ hybridization for EPCAT4R966 and EPCAT2F176 (SChLAP1) on extensive tissue microarrays. Besides being diagnostic, EPCAT2F176 and EPCAT4R966 showed significant association with pT-stage and were present in PIN lesions. We also found EPCAT2F176 and EPCAT2R709 to be associated with development of metastases and PCa-related death, and EPCAT2F176 to be enriched in lymph node metastases. Functional significance of expression of 9 EPCATs was investigated by siRNA transfection, revealing that knockdown of 5 different EPCATs impaired growth of LNCaP and 22RV1 PCa cells. Only the minority of EPCATs appear to be controlled by androgen receptor or ERG. Although the underlying transcriptional regulation is not fully understood, the novel PCa-associated transcripts are new diagnostic and prognostic markers with functional relevance to prostate cancer growth. PMID- 25686827 TI - Carbonic anhydrase XII is a new therapeutic target to overcome chemoresistance in cancer cells. AB - Multidrug resistance (MDR) in cancer cells is a challenging phenomenon often associated with P-glycoprotein (Pgp) surface expression. Finding new ways to bypass Pgp-mediated MDR still remains a daunting challenge towards the successful treatment of malignant neoplasms such as colorectal cancer.We applied the Cell Surface Capture technology to chemosensitive and chemoresistant human colon cancer to explore the cell surface proteome of Pgp-expressing cells in a discovery-driven fashion. Comparative quantitative analysis of identified cell surface glycoproteins revealed carbonic anhydrase type XII (CAXII) to be up regulated on the surface of chemoresistant cells, similarly to Pgp. In cellular models showing an acquired MDR phenotype due to the selective pressure of chemotherapy, the progressive increase of the transcription factor hypoxia inducible factor-1 alpha was paralleled by the simultaneous up-regulation of Pgp and CAXII. CAXII and Pgp physically interacted at the cell surface. CAXII silencing or pharmacological inhibition with acetazolamide decreased the ATPase activity of Pgp by altering the optimal pH at which Pgp operated and promoted chemosensitization to Pgp substrates in MDR cells.We propose CAXII as a new secondary marker of the MDR phenotype that influences Pgp activity directly and can be used as a pharmacological target for MDR research and potential treatment. PMID- 25686828 TI - Shed syndecan-2 enhances tumorigenic activities of colon cancer cells. AB - Because earlier studies showed the cell surface heparan sulfate proteoglycan, syndecan-2, sheds from colon cancer cells in culture, the functional roles of shed syndecan-2 were assessed. A non-cleavable mutant of syndecan-2 in which the Asn148-Leu149 residues were replaced with Asn148-Ile149, had decreased shedding, less cancer-associated activities of syndecan-2 in vitro, and less syndecan-2 mediated metastasis of mouse melanoma cells in vivo, suggesting the importance of shedding on syndecan-2-mediated pro-tumorigenic functions. Indeed, shed syndecan 2 from cancer-conditioned media and recombinant shed syndecan-2 enhanced cancer associated activities, and depletion of shed syndecan-2 abolished these effects. Similarly, shed syndecan-2 was detected from sera of patients from advanced carcinoma (625.9 ng/ml) and promoted cancer-associated activities. Furthermore, a series of syndecan-2 deletion mutants showed that the tumorigenic activity of shed syndecan-2 resided in the C-terminus of the extracellular domain and a shed syndecan-2 synthetic peptide (16 residues) was sufficient to establish subcutaneous primary growth of HT29 colon cancer cells, pulmonary metastases (B16F10 cells), and primary intrasplenic tumor growth and liver metastases (4T1 cells). Taken together, these results demonstrate that shed syndecan-2 directly enhances colon cancer progression and may be a promising therapeutic target for controlling colon cancer development. PMID- 25686829 TI - Role of microRNA221 in regulating normal mammary epithelial hierarchy and breast cancer stem-like cells. AB - Increasing evidence suggests that lineage specific subpopulations and stem-like cells exist in normal and malignant breast tissues. Epigenetic mechanisms maintaining this hierarchical homeostasis remain to be investigated. In this study, we found the level of microRNA221 (miR-221) was higher in stem-like and myoepithelial cells than in luminal cells isolated from normal and malignant breast tissue. In normal breast cells, over-expression of miR-221 generated more myoepithelial cells whereas knock-down of miR-221 increased luminal cells. Over expression of miR-221 stimulated stem-like cells in luminal type of cancer and the miR-221 level was correlated with clinical outcome in breast cancer patients. Epithelial-mesenchymal transition (EMT) was induced by overexpression of miR-221 in normal and breast cancer cells. The EMT related gene ATXN1 was found to be a miR-221 target gene regulating breast cell hierarchy. In conclusion, we propose that miR-221 contributes to lineage homeostasis of normal and malignant breast epithelium. PMID- 25686830 TI - p22phox confers resistance to cisplatin, by blocking its entry into the nucleus. AB - Cisplatin (CDDP) is a potent chemotherapeutic agent but resistance to the drug remains a major challenge in cancer treatment. To evaluate the efficacy of CDDP in oral squamous cell carcinoma (OSCC), we found that p22phox was highly expressed in CDDP-resistant OSCC specimens. Knockdown of p22phox sensitized OSCC cell lines to CDDP (P < 0.05). Stable overexpression of p22phox augmented CDDP resistance, as evidenced by the significantly higher IC50 values. This cytoprotective effect was attributed to the abrogation of CDDP-induced apoptosis. Akt phosphorylation was increased in p22phox stable lines. However, blocking PI3K/Akt pathway only partially restored CDDP-induced apoptosis. In addition, the overexpressed p22phox in OSCC cells exhibited cytoplasmic localization with enhanced perinuclear expression, consistent with the localization pattern in OSCC specimens. Remarkably, CDDP entry into the nucleus was severely impaired in p22phox-overexpressing cells (P < 0.001), and cytoplasmically accumulated CDDP was co-localized with overexpressed p22phox. This was supported by decreased CDDP DNA adduct formation and delayed chk1-p53 signaling activation. Together, overexpression of p22phox sequestered CDDP and caused defective CDDP entry into the nucleus, significantly attenuating CDDP-induced apoptosis. Such diminished apoptosis was further abolished by p22phox-activating PI3K/Akt pathway. Our work has suggested a novel biomarker and insight into the mechanism of CDDP resistance. PMID- 25686831 TI - Morphine promotes cancer stem cell properties, contributing to chemoresistance in breast cancer. AB - Morphine is an opioid analgesic drug commonly used for pain relief in cancer patients. Here, we report that morphine enhances the mammosphere forming capacity and increases the expression of stemness-related transcription factors Oct4, Sox2 and Nanog. Treatment with morphine leads to enrichment of a side population fraction in MCF-7 cells and the CD44+/CD24(-/low) population in BT549 cells. Consistently, morphine activates Wnt/beta-catenin signaling to induce epithelial to mesenchymal transition and promotes metastasis. Moreover, morphine decreases the sensitivity of traditional anti-cancer drugs in breast cancer cells. Nalmefene, an antagonist of morphine, reverses morphine-induced cancer stem cell properties and chemoresistance in breast cancer. In addition, nalmefene abolishes morphine enhancing tumorigenesis in a NOD/SCID mouse model. In conclusion, our findings demonstrate that morphine contributes to chemoresistance via expanding the population of cancer stem cells and promotes tumor growth, thereby revealing a novel role of morphine and providing some new guides in clinical use of morphine. PMID- 25686832 TI - Zfra activates memory Hyal-2+ CD3- CD19- spleen cells to block cancer growth, stemness, and metastasis in vivo. AB - Zfra is a 31-amino-acid zinc finger-like protein, which participates in the tumor necrosis factor signaling. Here, we determined that when nude mice and BALB/c mice were pre-injected with nanogram levels of a synthetic Zfra1-31 or truncated Zfra4-10 peptide via tail veins, these mice became resistant to the growth, metastasis and stemness of melanoma cells, and many malignant cancer cells. The synthetic peptides underwent self-polymerization in phosphate-buffered saline. Alteration of the Ser8 phosphorylation site to Gly8 abolished Zfra aggregation and its-mediated cancer suppression in vivo. Injected Zfra peptide autofluoresced due to polymerization and was trapped mainly in the spleen. Transfer of Zfra stimulated spleen cells to naive mice conferred resistance to cancer growth. Zfra binding cells, designated Hyal-2+ CD3- CD19- Z cells, are approximately 25-30% in the normal spleen, but are significantly downregulated (near 0-3%) in tumor growing mice. Zfra prevented the loss of Z cells caused by tumors. In vitro stimulation or education of naive spleen cells with Zfra allowed generation of activated Z cells to confer a memory anticancer response in naive or cancer growing mice. In particular, Z cells are abundant in nude and NOD-SCID mice, and can be readily activated by Zfra to mount against cancer growth. PMID- 25686833 TI - Vacuolar ATPase 'a2' isoform exhibits distinct cell surface accumulation and modulates matrix metalloproteinase activity in ovarian cancer. AB - Tumor associated vacuolar H+-ATPases (V-ATPases) are multi-subunit proton pumps that acidify tumor microenvironment, thereby promoting tumor invasion. Subunit 'a' of its V0 domain is the major pH sensing unit that additionally controls sub cellular targeting of V-ATPase and exists in four different isoforms. Our study reports an elevated expression of the V-ATPase-V0a2 isoform in ovarian cancer(OVCA) tissues and cell lines(A2780, SKOV-3 and TOV-112D). Among all V0'a' isoforms, V0a2 exhibited abundant expression on OVCA cell surface while normal ovarian epithelia did not. Sub-cellular distribution of V-ATPase-V0a2 confirmed its localization on plasma-membrane, where it was also co-associated with cortactin, an F-actin stabilizing protein at leading edges of cancer cells. Additionally, V0a2 was also localized in early and late endosomal compartments that are sites for modulations of several signaling pathways in cancer. Targeted inhibition of V-ATPase-V0a2 suppressed matrix metalloproteinase activity(MMP-9 & MMP-2) in OVCA cells. In conclusion, V-ATPase-V0a2 isoform is abundantly expressed on ovarian tumor cell surface in association with invasion assembly related proteins and plays critical role in tumor invasion by modulating the activity of matrix-degrading proteases. This study highlights for the first time, the importance of V-ATPase-V0a2 isoform as a distinct biomarker and possible therapeutic target for treatment of ovarian carcinoma. PMID- 25686834 TI - miR-34a induces cellular senescence via modulation of telomerase activity in human hepatocellular carcinoma by targeting FoxM1/c-Myc pathway. AB - Increasing evidence suggests that miRNAs can act as either tumor suppressors or oncogenes in carcinogenesis. In the present study, we identified the role of miR 34a in regulating telomerase activity, with subsequent effect on cellular senescence and viability. We found the higher expression of miR-34a was significantly correlated with the advanced clinicopathologic parameters in hepatocellular carcinoma. Furthermore, tumor tissues of 75 HCC patients demonstrated an inverse correlation between the miR-34a level and telomere indices (telomere length and telomerase activity). Transient introduction of miR 34a into HCC cell lines inhibited the telomerase activity and telomere length, which induced senescence-like phenotypes and affected cellular viability. We discovered that miR-34a potently targeted c-Myc and FoxM1, both of which were involved in the activation of telomerase reverse transcriptase (hTERT) transcription, essential for the sustaining activity of telomerase to avoid senescence. Taken together, our results demonstrate that miR-34a functions as a potent tumor suppressor through the modulation of telomere pathway in cellular senescence. PMID- 25686835 TI - Small non-coding RNA deregulation in endometrial carcinogenesis. AB - Small non-coding RNAs (sncRNAs) represent a heterogeneous group of <200nt-long transcripts comprising microRNAs, PIWI-interacting RNAs (piRNAs) and small nucleolar-RNAs (snoRNAs) involved in physiological and pathological processes such as carcinogenesis and tumor progression. Aberrant sncRNA expression in cancer has been associated with specific clinical phenotypes, grading, staging, metastases development and resistance to therapy.Aim of the present work is to study the role of sncRNAs in endometrial carcinogenesis. Changes in sncRNA expression were identified by high-throughput genomic analysis of paired normal, hyperplastic and cancerous endometrial tissues obtained by endometrial biopsies (n = 10). Using smallRNA sequencing and microarrays we identified significant differences in sncRNA expression pattern between normal, hyperplastic and neoplastic endometrium. This led to the definition of a sncRNA signature (129 microRNAs, 2 of which not previously described, 10 piRNAs and 3 snoRNAs) of neoplastic transformation. Functional bioinformatics analysis identified as downstream targets multiple signaling pathways potentially involved in the hyperplastic and neoplastic tissue responses, including Wnt/beta-catenin, and ERK/MAPK and TGF-beta-Signaling.Considering the regulatory role of sncRNAs, this newly identified sncRNA signature is likely to reflect the events leading to endometrial cancer, which can be exploited to dissect the carcinogenic process including novel biomarkers for early and non-invasive diagnosis of these tumors. PMID- 25686836 TI - Hepatocellular carcinoma in a large medical center of China over a 10-year period: evolving therapeutic option and improving survival. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is among the most common and lethal cancers worldwide, especially in China. METHODS: We retrospectively analyzed data from patients who were diagnosed and treated HCC between 2002 and 2011 in a large hospital in northwest China and compared the data between periods 2002-2006 (P1) and 2007-2011 (P2). RESULTS: 2045 patients were included in analysis. The HCC stages at diagnosis according to the Barcelona clinic liver cancer staging system had no significant change. Treatment options of liver transplantation, transcatheter arterial chemoembolization and other therapy decreased while percutaneous local ablation and supportive care increased from P1 to P2. Options of surgical resection and systematic therapy had no significant change. Patient survival rates at 1, 3 and 5 years significantly improved from P1 to P2. The treatments with increasing option trend had a higher magnitude of survival increase and vise versa. CONCLUSION: Over the last 10 years, the patient survival had a significant increase which was mainly a result of the optimal therapeutic selections according to disease stages in this center. However, the proportion of patients diagnosed at early stages of HCC remained low and did not increase, a result calling for implementing surveillance system for at risk patients. PMID- 25686837 TI - CtBP2 is an independent prognostic marker that promotes GLI1 induced epithelial mesenchymal transition in hepatocellular carcinoma. AB - C-terminal binding protein 2 (CtBP2) is a transcriptional co-repressor that promotes cancer cell migration and invasion by inhibiting multiple tumor suppressor genes that contribute to cell mobility and adhesion. In this investigation, we showed thatCtBP2 expression was increased significantly in HCC tissues when compared to matched normal adjacent liver tissues. We also showed that CtBP2 expression is associated with worse HCC patient prognosis after liver resection. CtBP2 over-expression induced epithelial-mesenchymal transition (EMT) in Huh7 cells and, correspondingly, silencing CtBP2 suppressed EMT in MHCC97H cells. ChIP assays revealed that GLI1 increased CtBP2 transcription by directly binding its promoter. Furthermore, interaction of CtBP2 and Snail Family Zinc Finger 1 (SNAI1), both of which were found to be positively regulated by GLI1, was confirmed by Co-IP assay. SNAI1 knockdown revealed that SNAI1 was essential for CtBP2 induction of the EMT phenotype of HCC cells, and CtBP2 knockdown reversed GLI1-SNAI1 driven EMT in Huh7 cells. Finally, in vivo experiments demonstrated that enhanced CtBP2expression promoted HCC xenograft growth and induced EMT. In conclusion, CtBP2 may serve as a prognostic marker for post liver resection HCC and may play a role during GLI1-driven EMT as a transcriptional co repressor of SNAI1. PMID- 25686838 TI - 14q32-encoded microRNAs mediate an oligometastatic phenotype. AB - Oligometastasis is a clinically distinct subset of metastasis characterized by a limited number of metastases potentially curable with localized therapies. We analyzed pathways targeted by microRNAs over-expressed in clinical oligometastasis samples and identified suppression of cellular adhesion, invasion, and motility pathways in association with the oligometastatic phenotype. We identified miR-127-5p, miR-544a, and miR-655-3p encoded in the 14q32 microRNA cluster as co-regulators of multiple metastatic pathways through repression of shared target genes. These microRNAs suppressed cellular adhesion and invasion and inhibited metastasis development in an animal model of breast cancer lung colonization. Target genes, including TGFBR2 and ROCK2, were key mediators of these effects. Understanding the role of microRNAs expressed in oligometastases may lead to improved identification of and interventions for patients with curable metastatic disease, as well as an improved understanding of the molecular basis of this unique clinical entity. PMID- 25686839 TI - Protease nexin 1 induces apoptosis of prostate tumor cells through inhibition of X-chromosome-linked inhibitor of apoptosis protein. AB - Protease nexin 1 (PN1) is an endogenous serine protease inhibitor (SERPIN), expressed at high levels in the prostate, and capable of inhibiting the proliferation of prostate cancer cells. We previously showed that PN1-uPA complexes inhibited Sonic Hedgehog (SHH) signalling through engagement of the LRP receptor. Here, we describe an alternative anti-proliferative mechanism through which PN1 expression leads to apoptosis. In prostate cancer cells, increased expression of PN1 led to substantial reduction of XIAP levels and apoptosis mediated through the uPAR, but not the LRP receptor. The alterations in XIAP were effected in two ways 1) via alteration in the NF-kappaB pathway, a pathway known to signal XIAP transcription and 2) by promoting XIAP instability. The AKT pathway is known to phosphorylate XIAP at serine 87 leading to protein stability and PN1 expression is shown to interfere with this process. As a result of both mechanisms, programmed cell death is substantially increased. Consistent with these observations, reduced PN1 protein correlated with elevated p65/XIAP expression and with higher Gleason scores in human prostate tissue arrays. Thus, PN1 expression appears to differentially down-regulate distinct oncogenic pathways depending upon the cell surface receptor engaged by its complexes and demonstrates a novel molecular mechanism by which the protein can promote tumor cell apoptosis. PMID- 25686840 TI - Pseudogene INTS6P1 regulates its cognate gene INTS6 through competitive binding of miR-17-5p in hepatocellular carcinoma. AB - The complex regulation of tumor suppressive gene and its pseudogenes play key roles in the pathogenesis of hepatocellular cancer (HCC). However, the roles played by pseudogenes in the pathogenesis of HCC are still incompletely elucidated. This study identifies the putative tumor suppressor INTS6 and its pseudogene INTS6P1 in HCC through the whole genome microarray expression. Furthermore, the functional studies - include growth curves, cell death, migration assays and in vivo studies - verify the tumor suppressive roles of INTS6 and INTS6P1 in HCC. Finally, the mechanistic experiments indicate that INTS6 and INTS6P1 are reciprocally regulated through competition for oncomiR-17 5p. Taken together, these findings demonstrate INTS6P1 and INTS6 exert the tumor suppressive roles through competing for oncomiR-17-5p. Our investigation of this regulatory circuit reveals novel insights into the underlying mechanisms of hepatocarcinogenesis. PMID- 25686841 TI - Experimental Traumatic Brain Injury Induces Bone Loss in Rats. AB - Few studies have investigated the influence of traumatic brain injury (TBI) on bone homeostasis; however, pathophysiological mechanisms involved in TBI have potential to be detrimental to bone. The current study assessed the effect of experimental TBI in rats on the quantity and quality of two different weight bearing bones, the femur and humerus. Rats were randomly assigned into either sham or lateral fluid percussion injury (FPI) groups. Open-field testing to assess locomotion was conducted at 1, 4, and 12 weeks post-injury, with the rats killed at 1 and 12 weeks post-injury. Bones were analyzed using peripheral quantitative computed tomography (pQCT), histomorphometric analysis, and three point bending. pQCT analysis revealed that at 1 and 12 weeks post-injury, the distal metaphyseal region of femora from FPI rats had reduced cortical content (10% decrease at 1 week, 8% decrease at 12 weeks; p < 0.01) and cortical thickness (10% decrease at 1 week, 11% decrease at 12 weeks p < 0.001). There was also a 23% reduction in trabecular bone volume ratio at 1 week post-injury and a 27% reduction at 12 weeks post-injury in FPI rats compared to sham (p < 0.001). There were no differences in bone quantity and mechanical properties of the femoral midshaft between sham and TBI animals. There were no differences in locomotor outcomes, which suggested that post-TBI changes in bone were not attributed to immobility. Taken together, these findings indicate that this rat model of TBI was detrimental to bone and suggests a link between TBI and altered bone remodeling. PMID- 25686842 TI - Predictors of favorable growth patterns during the obesity epidemic among US school children. AB - OBJECTIVE: To report the prevalence of favorable growth patterns, including healthy weight maintenance (HWM) and return to healthy weight (RHW) among US school-age children. METHODS: A longitudinal analysis of childhood growth patterns from the Early Childhood Longitudinal Study-Kindergarten Cohort was completed (n = 9416). The primary outcome included describing the prevalence of HWM/RHW patterns using consecutive child growth data from kindergarten to fifth grades. Multivariate logistic regression was used to explore predictors of HWM/RHW. Incidence of RHW is calculated by grade level. RESULTS: Seventy percent (n = 6617) of children enter kindergarten at a healthy weight and approximately 70% maintained a healthy weight through fifth grade. Among overweight/obese kindergartners, only 17.1% outgrew their weight risk (RHW) by fifth grade. CONCLUSIONS: Fewer than 1 in 5 at-risk children outgrow their weight risk during school-age yet a majority of healthy weight children can maintain healthy weight during a critical growth period. Future work should explore additional socioecologic factors associated with favorable growth. PMID- 25686843 TI - An online system shows promise for the early detection of osteoporosis in Asian women. PMID- 25686844 TI - Pioneers in pediatric psychology: environments shape behavior. PMID- 25686845 TI - Critical appraisal of alternative irritation models: three decades of testing ophthalmic pharmaceuticals. AB - BACKGROUND: Testing ocular tolerability of ocular pharmaceuticals is an essential regulatory requirement. The current approved reference model (gold standard) for ocular irritation testing is the Draize test. However this method is subjective and involves using live animals, hence the need to develop alternative in vitro and ex vivo testing strategies. SOURCE OF DATA: Pubmed, Science Direct, Scopus, Google Scholar, Medline, Current Content, Web of Science and validation reports from international regulatory bodies; The Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) and European Centre for the Validation of Alternative Methods (ECVAM) were searched for in vitro alternatives. AREA OF AGREEMENT: Whilst no single in vitro test can effectively replace the Draize eye irritation test, regulatory bodies and cosmetic/pharmaceutical industries agree that there is a need for in vitro alternatives with validated endpoints to evaluate pharmaceutical ingredients and finished eye products. AREA OF CONTROVERSY: There is no single in vitro test / assay that can predict the ocular irritation potential of mild to moderate test substances. AREA TIMELY FOR DEVELOPING RESEARCH: This review provides a critical appraisal of the selected in vitro and ex vivo ocular toxicity models recommended by international regulatory bodies. These include cytotoxicity methods, biochemical systems and ex vivo assays. The latter are approved by ECVAM as in vitro alternatives for the well-known Draize test. Hen's egg test-chorioallantoic membrane and the isolated rabbit eye test are also accepted by regulatory agencies in France, Germany, the Netherlands and the UK. A combination of ex vivo assays along with histological examination of excised bovine cornea can predict the conjunctival and corneal tolerability and cover a wider range of ocular pharmaceutical substances. PMID- 25686846 TI - Smoke-free policies in New Zealand public tertiary education institutions. AB - The Framework Convention on Tobacco Control mandates the creation of smoke-free environments to protect non-smokers from second-hand smoke and reduce demand for tobacco. We aimed to examine the extent and nature of smoke-free campus policies at tertiary education institutions throughout New Zealand, and examine the policy development process. Stage one comprised an audit and content analysis of smoke free policies. In stage two, semi-structured telephone interviews were conducted to investigate the process of developing and implementing policies. Qualitative content analysis was undertaken on interview notes. Policies were identified for most institutions (n = 26/29), though varied widely in nature. Only nine mandated 100% smoke-free campuses without exceptions and few prohibited the sale of tobacco on campus, or connections with the tobacco industry. During interviews (n = 22/29), cited barriers to developing a 100% smoke-free policy included enforcement challenges and anticipated opposition from staff and students. However, participants from institutions with 100% smoke-free policies reported having encountered few challenges. Varying levels of compliance with 100% smoke free policies were reported yet, overall, these policies were viewed as being effective. Smoke-free campus policies could be strengthened to better reflect a completely tobacco-free organization. Other institutions and workplaces could use these findings to develop 100% smoke-free policies. PMID- 25686847 TI - The brain as a working syncytium and memory as a continuum in a hyper timespace: Oscillations lead to a new model. AB - The aim of this study is threefold: (1) we propose a new framework describing the neurophysiologic functioning and cognitive processing of neural populations, and we extend the neuron doctrine to the physiology of neural assemblies. (2) The extension from neurons to neural populations implies that the brain, with its connectivity, should be considered a working syncytium, which extends Brodmann mapping to the CLAIR model, which includes oscillatory components and their connectivity. (3) In such a working syncytium, a new description of "memory" is needed in the broad time-space continuum, which embraces all memory states. This will be called "hypermemory." PMID- 25686848 TI - Rapid isolation and purification of phorbol esters from Jatropha curcas by high speed countercurrent chromatography. AB - In this work, a high-speed countercurrent chromatography (HSCCC) method was established for the preparation of phorbol esters (PEs) from Jatropha curcas. n Hexane-ethyl acetate-methanol-water (1.5:1.5:1.2:0.5, v/v) was selected as the optimum two-phase solvent system to separate and purify jatropha factor C1 (JC1) with a purity of 85.2%, as determined by HPLC, and to obtain a mixture containing four or five PEs. Subsequently, continuous semipreparative HPLC was applied to further purify JC1 (99.8% as determined by HPLC). In addition, UPLC-PDA and UPLC MS were established and successfully used to evaluate the isolated JC1 and PE rich crude extract. The purity of JC1 was only 87.8% by UPLC-UV. A peak (a compound highly similar to JC1) was indentified as the isomer of JC1 by comparing the characteristic UV absorption and MS spectra. Meanwhile, this strategy was also applied to analyze the PE-rich crude extract from J. curcas. It is interesting that there may be more than 15 PEs according to the same quasi molecular ion peaks, highly similar sequence-specific fragment ions, and similar UV absorption spectrum. PMID- 25686849 TI - Syncope: diagnosis and management. Foreword. PMID- 25686850 TI - Syncope: diagnosis and management. AB - Syncope is defined as transient loss of consciousness due to global cerebral hypoperfusion. It is characterized by having a relatively rapid onset, brief duration with spontaneous and full recovery. The major challenge in the evaluation of patients with syncope is that most patients are asymptomatic at the time of their presentation. A thorough history and physical examination including orthostatic assessment are crucial for making the diagnosis. After initial evaluation, short-term risk assessment should be performed to determine the need for admission. If the short-term risk is high, inpatient evaluation is needed. If the short-term risk is low, outpatient evaluation is recommended. In patients with suspected cardiac syncope, monitoring is indicated until a diagnosis is made. In patients with suspected reflex syncope or orthostatic hypotension, outpatient evaluation with tilt-table testing is appropriate. Syncope units have been shown to improve the rate of diagnosis while reducing cost and thus are highly recommended. PMID- 25686851 TI - Novel thiazole-thiophene conjugates as adenosine receptor antagonists: synthesis, biological evaluation and docking studies. AB - Here we report novel thiazole-thiophene conjugates as adenosine receptor antagonists. All the molecules were evaluated for their binding affinity for adenosine receptors. Most of the molecules were found to interact with the A1, A2A and A3 adenosine receptor subtypes with good affinity values. The most potent and selective compound 8n showed an A3Ki value of 0.33MUM with selectivity ratios of >90 versus the A1 and >30 versus the A2 subtypes. For compound 8n docking studies into the binding site of the A3 adenosine receptor are provided to visualize its binding mode. PMID- 25686852 TI - Synthesis and biological evaluation of novel pyrrolidine acid analogs as potent dual PPARalpha/gamma agonists. AB - The design, synthesis and structure-activity relationships of a novel series of 3,4-disubstituted pyrrolidine acid analogs as PPAR ligands is outlined. In both the 1,3- and 1,4-oxybenzyl pyrrolidine acid series, the preferred stereochemistry was shown to be the cis-3R,4S isomer, as exemplified by the potent dual PPARalpha/gamma agonists 3k and 4i. The N-4-trifluoromethyl-pyrimidinyl pyrrolidine acid analog 4i was efficacious in lowering fasting glucose and triglyceride levels in diabetic db/db mice. PMID- 25686853 TI - Biotransformation of xenobiotics in the human colon and rectum and its association with colorectal cancer. AB - In humans, the liver is generally considered to be the major organ contributing to drug metabolism, but studies during the last years have suggested an important role of the extra-hepatic drug metabolism. The gastrointestinal tract (GI-tract) is the major path of entry for a wide variety of compounds including food, and orally administered drugs, but also compounds - with neither nutrient nor other functional value - such as carcinogens. These compounds are metabolized by a large number of enzymes, including the cytochrome P450 (CYP), the glutathione S transferase (GST) family, the uridine 5'-diphospho- glucuronosyltransferase (UDP glucuronosyltransferase - UGT) superfamily, alcohol-metabolizing enzymes, sulfotransferases, etc. These enzymes can either inactivate carcinogens or, in some cases, generate reactive species with higher reactivity compared to the original compound. Most data in this field of research originate from animal or in vitro studies, wherein human studies are limited. Here, we review the human studies, in particular the studies on the phenotypic expression of these enzymes in the colon and rectum to get an impression of the actual enzyme levels in this primary organ of exposure. The aim of this review is to give a summary of currently available data on the relation between the CYP, the GST and the UGT biotransformation system and colorectal cancer obtained from clinical and epidemiological studies in humans. PMID- 25686854 TI - Analysis of essential oils from Voacanga africana seeds at different hydrodistillation extraction stages: chemical composition, antioxidant activity and antimicrobial activity. AB - In this study, essential oils from Voacanga africana seeds at different extraction stages were investigated. In the chemical composition analysis, 27 compounds representing 86.69-95.03% of the total essential oils were identified and quantified. The main constituents in essential oils were terpenoids, alcohols and fatty acids accounting for 15.03-24.36%, 21.57-34.43% and 33.06-57.37%, respectively. Moreover, the analysis also revealed that essential oils from different extraction stages possessed different chemical compositions. In the antioxidant evaluation, all analysed oils showed similar antioxidant behaviours, and the concentrations of essential oils providing 50% inhibition of DPPH scavenging activity (IC50) were about 25 mg/mL. In the antimicrobial experiments, essential oils from different extraction stages exhibited different antimicrobial activities. The antimicrobial activity of oils was affected by extraction stages. By controlling extraction stages, it is promising to obtain essential oils with desired antimicrobial activities. PMID- 25686855 TI - Abnormal immune regulation in children with irritable bowel syndrome. PMID- 25686856 TI - Association of ABO blood types with the risk of in-stent restenosis. AB - OBJECTIVES: To investigate the prevalence of in-stent restenosis (ISR) in patients with various ABO blood types. METHODS: Clinical information from 150 patients with a confirmed diagnosis of ISR and 150 patients with a diagnosis of patent coronary stents in the secondary angiography was collected. Comprehensive demographic and laboratory data, including ABO and Rhesus blood groups, as well as comorbid conditions and vessel and stent characteristics, were recorded for each patient. The association of ABO blood groups with the risk of ISR before and after controlling for coronary risk factors was determined. Categorical data were analyzed with the Chi-square test and numerical values were analyzed with t tests. Binary logistic regression models were constructed to compare type A and non-A for the frequency of risk factors. RESULTS: A total of 392 stents were implanted in 300 patients. Two hundred and fourteen stents (54.6%) were patent and 178 stents (45.4%) were stenosed. Blood group A was significantly more common in the ISR group (43.3% vs. 28.7%, p=0.03). However, the frequencies of other blood types, as well as Rh antigen, were similar between the two groups. Triglyceride and low-density lipoproteins were the only significantly different variables (221 +/- 198 mg/dL vs. 138 +/- 76 mg/dL, p<0.001 and 108 +/- 36 mg/dL vs. 96 +/- 73 mg/dL, p=0.04, in type-A vs. non-A, respectively). After matching for coronary risk factors, there was no difference between A blood type patients and their controls. CONCLUSION: ISR is significantly more prevalent in individuals with the type A blood group. However, this higher association is most likely due to higher atherogenic conditions in patients within this population. PMID- 25686857 TI - Effects of sevoflurane vs. propofol on mitochondrial functional activity after ischemia-reperfusion injury and the influence on clinical parameters in patients undergoing CABG surgery with cardiopulmonary bypass. AB - The aim of the study was to evaluate the effects of sevoflurane and propofol on the activity of mitochondrial function related to ischemia-reperfusion injury, myocardial damage biomarkers release and clinical parameters in the postoperative period. Seventy-two patients scheduled for elective coronary artery bypass graft surgery with cardiopulmonary bypass were randomized into two groups: 36 patients received sevoflurane during anesthesia (Group S) and 36 patients received propofol (Group P). To investigate the functional activity of mitochondria, we used skinned fibers prepared from biopsies of right atrial tissue before cardioplegia and after the aorta cross-clamp removal (within 10-15 minutes after reperfusion). Patients' clinical data (length of stay in ICU, hemodynamic parameters, duration of mechanical ventilation (MV) and the amount of lactate and troponin I in the blood serum) were evaluated postoperatively. The results showed that, before cardioplegia and after reperfusion, there was no significant difference in the mitochondrial routine and State 3 respiration rates between the groups. The effect of cytochrome c was higher in Group P. Troponin I concentration at the 12(th) hour after the surgery was 2.2 +/- 0.8 ng/mL in Group S and 3.5 +/- 1.1 ng/mL in Group P (p<0.001). There were no significant differences in the duration of mechanical ventilation, hemodynamic parameters and length of stay in the ICU between the groups. We conclude that sevoflurane slightly protects the mitochondrial outer membrane from ischemia-reperfusion injury and the loss of cytochrome c, yet has the similar effect on clinical parameters in the postoperative period when compared to propofol. PMID- 25686858 TI - Old And New Oral Anticoagulants In Management Of Atrial Fibrillation: A Double Edged Sword For Women. AB - Atrial fibrillation (AF), one of the most prevalent supra-ventricular arrhythmia in adults, is related to a substantial increase in the risk of thromboembolic events requiring tailored preventive strategy. In AF, antithrombotic therapy should be individualized according to a careful decisionmaking process, taking in account the likely concomitant presence of risk factors for stroke and bleeding. Anticoagulation management is particularly challenging in women with AF, to the extent that female sex is incorporated in commonly used stratification schemes for both thromboembolic and bleeding risk evaluation. Nevertheless, gender- based differences on the efficacy and safety of either "old" (i.e. vitamin K antagonist) or "new" oral anticoagulants (i.e. direct thrombin inhibitors and activated factor X inhibitors) are not conclusive and not always reported. This review aims to analyse the literature on sex differences in AF anticoagulation management. We focus on safety data, bleeding complications and specific haemostatic mechanisms currently under investigation, which could account for observed disparities among sexes. Moreover, details on sex difference in response to anticoagulant treatment will be discussed. Comparing old and new antithrombotics, a need clearly emerges for differentiated and integrated strategies for the treatment of AF in female patients. PMID- 25686859 TI - The Spanish biology/disease initiative within the human proteome project: Application to rheumatic diseases. AB - The Spanish Chromosome 16 consortium is integrated in the global initiative Human Proteome Project, which aims to develop an entire map of the proteins encoded following a gene-centric strategy (C-HPP) in order to make progress in the understanding of human biology in health and disease (B/D-HPP). Chromosome 16 contains many genes encoding proteins involved in the development of a broad range of diseases, which have a significant impact on the health care system. The Spanish HPP consortium has developed a B/D platform with five programs focused on selected medical areas: cancer, obesity, cardiovascular, infectious and rheumatic diseases. Each of these areas has a clinical leader associated to a proteomic investigator with the responsibility to get a comprehensive understanding of the proteins encoded by Chromosome 16 genes. Proteomics strategies have enabled great advances in the area of rheumatic diseases, particularly in osteoarthritis, with studies performed on joint cells, tissues and fluids. BIOLOGICAL SIGNIFICANCE: In this manuscript we describe how the Spanish HPP-16 consortium has developed a B/D platform with five programs focused on selected medical areas: cancer, obesity, cardiovascular, infectious and rheumatic diseases. Each of these areas has a clinical leader associated to a proteomic investigator with the responsibility to get a comprehensive understanding of the proteins encoded by Chromosome 16 genes. We show how the Proteomic strategy has enabled great advances in the area of rheumatic diseases, particularly in osteoarthritis, with studies performed on joint cells, tissues and fluids. This article is part of a Special Issue entitled: HUPO 2014. PMID- 25686860 TI - Properties of spray pyrolised ZnO:Sn thin films and their antibacterial activity. AB - Tin doped zinc oxide (ZnO:Sn) thin films were deposited onto glass substrates by the spray pyrolysis technique with the substrate temperature 400 degrees C. The structural, optical, photoluminescence (PL) properties and morphological studies were investigated for the films deposited with various doping concentration (0, 2, 4, 6 and 8 at.%) of tin. The XRD results had shown that the films were polycrystalline ZnO with hexagonal wurtzite type structure and the crystallites in the films were oriented along (002) direction. Surface morphology of the films obtained by scanning electron microscope (SEM) exhibited the change in morphology with doping concentration and porous nature for the film with 6 at.% of tin. Atomic force microscopy (AFM) revealed nanometer sized particles with decreased surface roughness for Sn doping. Optical analysis exhibited the band gap value of 2.8 eV for ZnO:Sn (6 at.%) which was lower than the band gap value for undoped ZnO film (3.2 eV). The resistivity of 6 at.% of Sn doped film was 1.28*10(2) Omega cm with increase in the hall mobility and carrier concentration. The ZnO and Sn doped ZnO thin films exhibited antibacterial activity against Staphylococcus aureus. PMID- 25686861 TI - Spectroscopic and biological studies of new mononuclear metal complexes of a bidentate NN and NO hydrazone-oxime ligand derived from egonol. AB - A novel ligand, vicinal dioxime ligand (egonol-hydrazone glyoxime) (LH2) was synthesized and characterized using (1)H NMR, (13)C NMR, MS, AAS, infrared spectroscopy, and magnetic susceptibility measurements. Mononuclear nickel (II), copper (II) and cobalt (II) complexes with a metal:ligand ratio of 1:2 for LH2 were also synthesized. Zn(II) forms complex [Zn(LH)Cl2] with a metal to ligand ratio of 1:1. IR spectrum shows that the ligand act in a bidentate manner and coordinates N4 donor groups of the ligands to Ni(II), Cu(II), Co(II) and Zn(II) ions. The detection of H-bonding (OH?O) in the [M(LH)2] metal complexes by IR spectra supported the square-planar MN4 coordination of Ni(II), Cu(II) and Co(II) complexes. The antimicrobial activities of compounds LH2 and their Ni(II), Cu(II), Co(II) and Zn(II) complexes were evaluated using the disc diffusion method against 16 bacteria and 5 yeasts. The minimal inhibitory concentrations (MICs) against all the bacteria and yeasts were also determined. Among the attempted test compounds, it is showed that all the compounds (L, LH2, [Ni(LH)2], [Cu(LH)2], [Co(LH)2(H2O)2], [Zn(LH)Cl2]) were effective against used test microorganisms. PMID- 25686862 TI - The clinical reasoning processes of extended scope physiotherapists assessing patients with low back pain. AB - INTRODUCTION: Employing allied health professionals in extended scope roles has developed relatively recently in health-care. Within physiotherapy, the extended role has provided clinicians with autonomy to use knowledge and clinical acumen to request investigations such as Magnetic Resonance Imaging (MRI) and X-ray as part of the diagnostic process, a practice beyond the traditional scope of physiotherapy. In these advancing roles, little is written about the clinical reasoning processes that clinicians use in managing patients with musculoskeletal pain and knowledge of these processes would advance training for new recruits to this arena. STUDY: This qualitative study has explored the processes by which extended scope physiotherapists (ESPs) clinically reason their decisions regarding patients reporting low back pain in a musculoskeletal outpatient setting. The study used a multiple case study design informed by grounded theory methodology, using focus groups (involving ESPs and non-ESPs/musculoskeletal physiotherapists) and semi-structured interviews with a think-aloud method (ESPs only) to investigate these processes. CONCLUSIONS: The themes identified include: prior thinking; patient interaction; formal testing; time; safety and accountability; external and internal factors; and gut-feeling (which challenges current physiotherapy models of reasoning). Extended scope physiotherapists reported experiencing greater stress due to higher levels of perceived accountability, safety requirements and internal drivers for competence than non ESPs. Further research is indicated to explore the role of gut-feeling in musculoskeletal physiotherapy clinical reasoning. PMID- 25686863 TI - Large-scale synthesis of palladium concave nanocubes with high-index facets for sustainable enhanced catalytic performance. AB - The catalytic activity of palladium (Pd) nanostructures highly relies on their size and morphology, especially enclosed with high-index facets, which provide more active sites so as to enhance their catalytic performance comparing with their low-index facet counterparts. Herein, Pd concave nanocubes enclosed with {730} facets by a one-pot scalable liquid method, with various high-index facets are synthesized via tuning reduction kinetics. Due to their high-index facets, the Pd concave nanocubes exhibit much higher electrocatalytic activity and stability for methanol oxidation than the Pd nanocubes enclosed by {100} facets and commercial Pd/C. Furthermore, we scale up synthesis of Pd concave nanocubes by expanding the volume of all species to fifty times with high-yield production. PMID- 25686864 TI - Obesity-hypertension and its relation to other diseases in dogs. AB - Obesity is a chronic disease in which adipose tissue accumulates in such a way that it affects the health of the patient and is associated with a myriad of alterations such as systemic hypertension (HTN). The mechanisms by which obesity causes HTN are complex and involve several organic mechanisms. The objective of this study was to determine the correlation between obesity to HTN in dogs in accordance with recent international protocols (systolic blood pressure >160 mmHg) relating to age, genre, gonadal status, breed and other diseases commonly associated with HTN. A total of 244 dogs were studied, 105 non-obese controls and 139 in the obese group. For both groups, healthy and a variety of diseased dogs were observed; the correlations between pathologies and obesity were studied, paying special attention to diseases whose pathophysiologies could lead to HTN. We conclude that obesity is not a risk factor for dogs to develop HTN, and that HTN present in these patients was related to comorbidities such as chronic kidney disease, cardiopathies and endocrinopathies. PMID- 25686865 TI - The influence of enrofloxacin, florfenicol, ceftiofur and E. coli LPS interaction on T and B cells subset in chicks. AB - This study aimed to investigate the influence of enrofloxacin, florfenicol, ceftiofur and E. coli LPS interaction on T and B subsets in thymus and spleen of newly-hatched chicks. A 126, 1-day-old chicks were administered enrofloxacin, florfenicol or ceftiofur in recommended doses according to the currently treatment schedule advises. E .coli LPS was given intravenously once at the dose of 200 MUg kg(-1) BW on the 2nd day of experiment (d. e.). On the 6th and the 14th d. e. thymus and spleens were subjected to flow cytometry investigation.The most significant changes were demonstrated in spleen. The antibiotics administration decreased the percentage of B and T cells subset. Moreover, this suppressive effect was enhanced by E. coli LPS administration. On the 6th d. e. the percentage of CD3(+)TCRgammadelta(-), CD3(+)TCRgammadelta(+), CD4(+)CD8(-), CD4(-)CD8(+) decreased significantly after ceftiofur and LPS treatment. A lower percentage of CD3(+)TCRgammadelta(-), CD4(-)CD8(+) and CD3(+)TCRgammadelta(+) was observed in enrofloxacine and LPS treated group. The decrease percentage of CD3(+)TCRgammadelta(+)cells and Bu-1(+) was found after florfenicol and LPS treatment. On the 14th d. e. a decreased percentage of CD4(+)CD8(-) and increased percentage of CD4(-)CD8(+) cells was shown in ceftiofur or enrofloxacine and LPS treated groups. In addition decreased percentage of CD3(+)TCRgammadelta(+) was found in all antibiotic and LPS treated groups.In this study, it was shown that enrofloxacine, florfenicol, ceftiofur treatment may change the proportions among lymphocytes subset and might have an impact on the immune response to bacterial endotoxins in chicks. PMID- 25686866 TI - Self-assembly of linear [Mn(II)2Mn(III)] units with end-on azido bridges: the construction of a ferromagnetic chain using ST = 7 high-spin trimers. AB - The controlled organization of high-spin complexes into 1D coordination polymers is a challenge in molecular magnetism. In this work, we report a ferromagnetic Mn trimer Mn3(HL)2(CH3OH)6(Br)4.Br.(CH3OH)2 1 (H2L = 2-[(9H-fluoren-9 yl)amino]propane-1,3-diol) with the ground spin state of ST = 7 that can be assembled into a one-dimensional coordination chain [Mn3(HL)2(CH3OH)2(Br)4(N3)(H2O).CH3OH]infinity 2 using azido bridging ligands. Interestingly, the ferromagnetic nature of 1 is well retained in 2. However, due to the negligible magnetic anisotropy in 1, both 1 and 2 do not show slow relaxation of magnetization, which indicates that during the process of molecular assembly not only the intratrimer magnetic interaction but also the magnetic anisotropy of the trimer can be reserved. PMID- 25686867 TI - A preliminary assessment of polychlorinated biphenyls and polybrominated diphenyl ethers in deep-sea sediments from the Indian Ocean. AB - Ten surface sediments were collected from the open Indian Ocean at depths below 4000 m in 2011, for the analysis of polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs). The concentrations of Sigma32 PCBs, Sigma7 PBDEs, and BDE-209 were 120-514, 49-152, and 7-133 pg/g, respectively. These concentrations are close to the lowest values recorded in the global marine environment. The PCBs had a relatively uniform composition, and were dominated by low chlorinated congeners. The concentrations of di-, tri-, and tetra-PCBs were strongly correlated with the total organic carbon (TOC), suggesting the dissolved PCBs were derived from the atmosphere via diffusive air-water exchange, and absorbed by phytoplankton. A high proportion of BDE209 was only detected in the sediment of the low fan of the Ganga River. There were weak correlations between low brominated BDEs and TOC, implying the degradation of BDE209 is a possible source of lower-brominated BDEs in deep-sea sediments. PMID- 25686868 TI - Radiation-Induced Bystander Effects in A549 Cells Exposed to 6 MV X-rays. AB - The aim of the study is to explore the bystander effects in A549 cells that have been exposed to 6MV X-ray. Control group, irradiated group, irradiated conditioned medium (ICM)-received group, and fresh medium group were designed in this study. A549 cells in the logarithmic growth phase were irradiated with 6MV X ray at 0, 0.5, 1, 1.5, and 2. In ICM-received group, post-irradiation A549 cells were cultured for 3 h and were transferred into non-irradiated A549 cells for further cultivation. Clone forming test was applied to detect the survival fraction of cells. Annexin V-FITC/PI double-staining assay was used to detect the apoptosis of A549 cells 24, 48, 72, and 96 h after 2-Gy 6MV X-ray irradiation, and the curves of apoptosis were drawn. The changes in the cell cycles 4, 48, 72, and 96 h after 2-Gy 6MV X-ray irradiation were detected using PI staining flow cytometry. With the increase of irradiation dose, the survival fraction of A549 cells after the application of 0.5 Gy irradiation was decreasing continuously. In comparison to the control group, the apoptosis rate of the ICM-received group was increased in a time-dependent pattern, with the highest apoptosis rate observed at 72 h (p < 0.05). Cell count in G2/M stages was obviously increased compared with that of the control group (p < 0.05), with the highest count observed at 72 h, after which G2/M stage arrest was diminished. ICM can cause apparent A549 cell damage, indicating that 6MV X-ray irradiation can induce bystander effect on A549 cells, which reaches a peak at 72 h. PMID- 25686869 TI - Neurocutaneous melanocytosis, hemimegalencephaly and large ovarian cyst in a newborn. AB - We report a case of a newborn girl with neurocutaneous melanocytosis, hemimegalencephaly and a large ovarian cyst. She also had melanocyte deposition in the filum terminale. The ultrasound and the magnetic resonance imaging findings are discussed. PMID- 25686870 TI - Bone involvement by Sporothrix schenckii in an immunocompetent child. AB - Sporotrichosis in children is rare, and its osteoarticular form is very unusual. Disseminated forms are described mostly in immunocompromised patients. We report a case of a 5-year-old immunocompetent boy with multiple suppurated cutaneous lesions that progressed to polyarthritis of the hands and feet. Radiographic imaging demonstrated multifocal lytic lesions. Sporotrichosis was diagnosed through biopsy and culture. This article describes the radiographic appearance of a rare manifestation of this disease. In areas of high prevalence, the diagnosis of sporotrichosis should be taken into account, even in immunocompetent patients, when dactylitis with lytic lesions is present. PMID- 25686871 TI - Evidence of a specialized feeding niche in a Late Triassic ray-finned fish: evolution of multidenticulate teeth and benthic scraping in ?Hemicalypterus. AB - Fishes have evolved to exploit multiple ecological niches. Extant fishes in both marine (e.g., rabbitfishes, surgeonfishes) and freshwater systems (e.g., haplochromine cichlids, characiforms) have evolved specialized, scoop-like, multidenticulate teeth for benthic scraping, feeding primarily on algae. Here, I report evidence of the oldest example of specialized multidenticulate dentition in a ray-finned fish, ?Hemicalypterus weiri, from the Upper Triassic Chinle Formation of southeastern Utah (~210-205 Ma), USA. ?H. weiri is a lower actinopterygian species that is phylogenetically remote from modern fishes, and has evolved specialized teeth that converge with those of several living teleost fishes (e.g., characiforms, cichlids, acanthurids, siganids), with a likely function of these teeth being to scrape algae off a rock substrate. This finding contradicts previously held notions that fishes with multicuspid, scoop-like dentition were restricted to teleosts, and indicates that ray-finned fishes were diversifying into different trophic niches and exploring different modes of feeding earlier in their history than previously thought, fundamentally altering our perceptions of the ecological roles of fishes during the Mesozoic. PMID- 25686872 TI - Greater curvature myotomy is a safe and effective modified technique in per-oral endoscopic myotomy (with videos). AB - BACKGROUND: Per-oral endoscopic myotomy (POEM) for achalasia with esophagocardiomyotomy in the lesser curvature (LC myotomy) is now established and accepted widely. However, in some cases LC myotomy is precluded by previous procedures, such as Heller myotomy, or by other anatomic considerations that obscure the normal dissection planes. It may also be difficult to identify the esophagogastric junction (EGJ), which can result in an incomplete gastric myotomy and poor rates of symptom relief. On the other hand, the angle of His is always located in the greater curvature of the stomach and serves as a consistent, definite landmark of the gastric side. OBJECTIVE: To evaluate esophagocardiomyotomy in the greater curvature (GC myotomy) as an alternative POEM technique in cases where a prior LC myotomy or supervening anatomic constraints make identification of the EGJ technically challenging. DESIGN: Prospective. SETTING: Single-center study. PATIENTS: Twenty-one achalasia patients who received POEM with GC myotomy. INTERVENTIONS: POEM. MAIN OUTCOME MEASUREMENTS: Efficacy and safety of GC myotomy measured in terms of reduction in lower esophageal sphincter (LES) pressures, improvement in Eckardt scores, and development of intraoperative or postoperative adverse events. RESULTS: Identification of the EGJ was achieved in all cases, resulting in a mean gastric myotomy length of 2.6+/-1.1 cm. Mean LES pressure and Eckardt symptom scores decreased significantly (21.2+/-7.3 vs 10.5+/-2.7 mm Hg, 5 [2-8] vs 1 [0-5], respectively) (P<.01). Endoscopic evidence of gastroesophageal reflux was identified in 52% of patients (11/21) postmyotomy; however, only 9.5% (2/11) were symptomatic, and these patients were successfully controlled with proton pump inhibitors. No severe adverse events were encountered. LIMITATIONS: Single center. CONCLUSIONS: GC myotomy is a promising, safe modification of the POEM technique and may be especially useful in cases of redo POEM, POEM post-Heller myotomy, or when the EGJ is difficult to recognize because of supervening anatomic constraints. PMID- 25686873 TI - Endoscopic resection of gastritis cystica profunda: preliminary experience with 34 patients from a single center in China. PMID- 25686874 TI - Factors associated with post-ERCP pancreatitis and the effect of pancreatic duct stenting in a pediatric population. AB - BACKGROUND: Risk factors for the development of post-ERCP pancreatitis (PEP) have not been identified in the pediatric population. It remains unclear what constitutes appropriate prophylaxis in this patient population. OBJECTIVES: To assess the prevalence and severity of PEP in the pediatric population and identify factors associated with developing PEP and to evaluate the effect of prophylactic pancreatic duct stenting in high-risk patients. DESIGN: Retrospective analysis of an ERCP database at a single large pediatric center. SETTING: Academic center. PATIENTS: A total of 432 ERCPs performed on 313 patients younger than 19 years of age from January 2004 to October 2013. INTERVENTION: ERCP for any indication. MAIN OUTCOME MEASUREMENTS: Rates and severity of PEP, preprocedural and procedural risk factors for the development of PEP, and the effect of pancreatic stents on preventing PEP in high-risk patients. RESULTS: PEP occurred after 47 procedures (prevalence, 10.9%). Thirty-four cases were mild, 9 were moderate, and 4 were severe. There was no mortality. On multiple logistic analysis, pancreatic duct injection (P<.0001; odds ratio 30.8; 95% confidence interval [CI], 9.1-103.9) and pancreatic sphincterotomy (P<.01; OR 3.8; 95% CI, 1.6-9.8) were positively associated with PEP. A history of chronic pancreatitis was negatively associated with PEP (P<.05; OR 0.37; 95% CI, 0.15 0.93). On subset analysis, placing a prophylactic pancreatic stent was associated with significantly increased rates of PEP in patients with pancreatic duct injection compared with those who had no attempt at stent placement (P<.01). Two patients with severe pancreatitis had prophylactic pancreatic stents in place. LIMITATIONS: Retrospective investigation. CONCLUSIONS: In the pediatric population, pancreatic duct injection and pancreatic sphincterotomy are associated with significantly increased rates of PEP, whereas a history of chronic pancreatitis is negatively associated. Prophylactic pancreatic stenting is associated with higher rates of PEP in high-risk patients and does not eliminate severe PEP. PMID- 25686875 TI - Assessment and documentation of women's labour pain: A cross-sectional study in Swedish delivery wards. AB - BACKGROUND: A woman's pain during labour plays a dominant role in childbirth. The midwife's role is to assess the degree of pain experienced during labour. When professionals respond to labour pain with acknowledgement and understanding, the woman's sense of control and empowerment is increased, which could contribute to a positive experience of childbirth. The aim of this study is to describe how labour pain in Swedish delivery wards is assessed and documented. METHODS: This quantitative descriptive study was designed as a national survey performed through telephone interviews with the representatives of 34 delivery wards in Sweden. RESULTS AND CONCLUSION: The majority of the participating delivery wards assessed and documented women's labour pain, but in an unstructured manner. The wards differed in how the assessments and documentation were performed. In addition, almost all the delivery wards that participated in the survey lacked guidelines for the assessment and documentation of the degree of pain during labour. The findings also showed that the issue of labour pain was sometimes discussed in the delivery wards, but not in a structured or consistent way. PMID- 25686876 TI - Midwives' experiences of caring for women with female genital mutilation: Insights and ways forward for practice in Australia. AB - BACKGROUND: Female genital mutilation (FGM) has serious health consequences, including adverse obstetric outcomes and significant physical, sexual and psychosocial complications for girls and women. Migration to Australia of women with FGM from high-prevalence countries requires relevant expertise to provide women and girls with FGM with specialised health care. Midwives, as the primary providers of women during pregnancy and childbirth, are critical to the provision of this high quality care. AIM: To provide insight into midwives' views of, and experiences working with, women affected by FGM. METHODS: A descriptive qualitative study was undertaken using focus group discussions with midwives from four purposively selected antenatal clinics and birthing units in three hospitals in urban New South Wales. The transcripts were analysed thematically. FINDINGS: Midwives demonstrated knowledge and recalled skills in caring for women with FGM. However, many lacked confidence in these areas. Participants expressed fear and a lack of experience caring for women with FGM. Midwives described practice issues, including the development of rapport with women, working with interpreters, misunderstandings about the culture of women, inexperience with associated clinical procedures and a lack of knowledge about FGM types and data collection. CONCLUSION: Midwives require education, training and supportive supervision to improve their skills and confidence when caring for women with FGM. Community outreach through improved antenatal and postnatal home visitation can improve the continuity of care provided to women with FGM. PMID- 25686877 TI - Trends and oscillations in the Indian summer monsoon rainfall over the last two millennia. AB - Observations show that summer rainfall over large parts of South Asia has declined over the past five to six decades. It remains unclear, however, whether this trend is due to natural variability or increased anthropogenic aerosol loading over South Asia. Here we use stable oxygen isotopes in speleothems from northern India to reconstruct variations in Indian monsoon rainfall over the last two millennia. We find that within the long-term context of our record, the current drying trend is not outside the envelope of monsoon's oscillatory variability, albeit at the lower edge of this variance. Furthermore, the magnitude of multi-decadal oscillatory variability in monsoon rainfall inferred from our proxy record is comparable to model estimates of anthropogenic-forced trends of mean monsoon rainfall in the 21st century under various emission scenarios. Our results suggest that anthropogenic-forced changes in monsoon rainfall will remain difficult to detect against a backdrop of large natural variability. PMID- 25686878 TI - Injection of Peptide nanogels preserves postinfarct diastolic function and prolongs efficacy of cell therapy in pigs. AB - Accumulating evidence suggests that the benefits of cell therapy for cardiac repair are modest and transient due to progressive harmful cardiac remodeling as well as loss of transplanted cells. We previously demonstrated that injection of peptide nanofibers (NFs) reduces ventricular remodeling and facilitates cell retention at 1 month after acute myocardial infarction (MI) in pigs. However, it remains unclear whether these benefits still persist as the material is being degraded. In this study, 2 mL of placebo or NFs, with or without 1*10(8) mononuclear cells (MNCs), was injected into the pig myocardium after MI (n>=5 in each group), and cardiac function was assessed by echocardiography, including myocardial deformation analyses and catheterization at 3 months post-MI. Our results reveal that MNC-only injection slightly improved cardiac systolic function at 1 month post-MI, but this benefit was lost at later time points (ejection fraction: 42.0+/-2.3 in MI+normal saline [NS] and 43.5+/-1.1 in MI+MNCs). In contrast, NF-only injection resulted in improved cardiac diastolic function and reduced pathological remodeling at 3 months post-MI. Furthermore, combined injection of MNCs/NFs provided a greater and longer term cardiac performance (52.1+/-1.2 in MI+MNCs/NFs, p<0.001 versus MI+NS and MI+MNCs) and 11.3-fold transplanted cell retention. We also found that about 30% NFs remained at 3 months after injection; however, endogenous myofibroblasts were recruited to the NF-injected microenvironment to replace the degraded NFs and preserved cardiac dimensions and mechanics. In conclusion, we demonstrated that injection of NFs contributes to preservation of ventricular mechanical integrity and sustains MNC efficacy at 3 months postinjection. PMID- 25686879 TI - Shotgun analysis of plasma fibrin clot-bound proteins in patients with acute myocardial infarction. AB - INTRODUCTION: The presence and amount of the proteins within a plasma clot may influence clot properties, like susceptibility to fibrinolysis, however, the clot proteome has not yet been extensively described. The aim of the study was to investigate the protein composition of clots of four patients with acute myocardial infarction (AMI) in two time points: in the acute ischemic phase and two months later during the standard therapy. MATERIALS AND METHODS: Shotgun proteomic method (2DLC-MS/MS) was used to investigate time-dependent protein composition changes of clots prepared ex vivo from citrated plasma of the peripheral blood of patients with AMI. RESULTS: Proteomic analysis revealed a total number of 62 proteins identified in all 8 samples grouping into several distinct functional clusters (e.g. cholesterol transporter activity, immunoglobulin binding and peptidase regulatory activity). The protein signatures of clots differed significantly depending on time after ACS, showing 30% greater variability in protein composition of the clots prepared in the plasma two months after the onset of AMI. Several proteins potentially involved in clot formation and resolution showed an interesting pattern of changes over time. CONCLUSION: We provided the first qualitative analysis of proteomes of fibrin clots generated ex vivo in plasma taken from patients with AMI showing differences between clots generated in the acute ischemic phase and those prepared two months later. It might be hypothesized that differences involving proteins of potential influence on within-clot fibrinolysis and clot stability may partially explain time dependent changes in the clots structure and firmness in patients with AMI. PMID- 25686880 TI - Ultrastructure and composition of thrombi in coronary and peripheral artery disease: correlations with clinical and laboratory findings. AB - INTRODUCTION: Fibrin structure and cellular composition of thrombi profoundly affect the clinical outcomes in ischemic coronary and peripheral artery disease. Our study addressed the interrelations of structural features of thrombi and routinely measured laboratory parameters. MATERIALS AND METHODS: Thrombi removed by thromboaspiration following acute myocardial infarction (n=101) or thrombendarterectomy of peripheral arteries (n=50) were processed by scanning electron microscopy and immunostaining for fibrin and platelet antigen GPIIb/IIIa to determine fibrin fibre diameter and relative occupancy by fibrin and cells. Correlations between the structural characteristics and selected clinical parameters (age, sex, vascular localization, blood cell counts, ECG findings, antiplatelet medication, accompanying diseases, smoking) were assessed. RESULTS: We observed significant differences in mean fibre diameter (122 vs. 135 nm), fibrin content (70.5% vs. 83.9%), fluorescent fibrin/platelet coverage ratio (0.18 vs. 1.06) between coronary and peripheral thrombi. Coronary thrombi from smokers contained more fibrin than non-smokers (78.1% vs. 62.2% mean occupancy). In the initial 24 h, fibrin content of coronary thrombi decreased with time, whereas in peripheral thrombi platelet content increased in the first 7 days. In coronaries, higher platelet content and smaller vessel diameter were associated with thinner fibrin fibres, whereas hematocrit higher than 0.35 correlated with larger intrathrombotic platelet occupancy. Smoking and dyslipidaemia strengthened the dependence of clot platelet content on systemic platelet count (the adjusted determination coefficient increased from 0.33 to 0.43 and 0.65, respectively). CONCLUSION: Easily accessible clinical parameters could be identified as significant determinants of ultrastructure and composition of coronary and peripheral thrombi. PMID- 25686881 TI - Primitive macrophages control HSPC mobilization and definitive haematopoiesis. AB - In vertebrates, haematopoietic stem/progenitor cells (HSPCs) first emerge in the aorta-gonad-mesonephros (AGM) before colonizing transitory and subsequently definitive haematopoietic organs allowing haematopoiesis throughout adult life. Here we identify an unexpected primitive macrophage population accumulated in the dorsal mesenteric mesoderm surrounding the dorsal aorta of the human embryo and study its function in the transparent zebrafish embryo. Our study reveals dynamic interactions occurring between the HSPCs and primitive macrophages in the AGM. Specific chemical and inducible genetic depletion of macrophages or inhibition of matrix metalloproteinases (Mmps) leads to an accumulation of HSPCs in the AGM and a decrease in the colonization of haematopoietic organs. Finally, in vivo zymography demonstrates the function of primitive macrophages in extracellular matrix degradation, which allows HSPC migration through the AGM stroma, their intravasation, leading to the colonization of haematopoietic organs and the establishment of definitive haematopoiesis. PMID- 25686882 TI - Survival rate and breeding outputs in a high Arctic seabird exposed to legacy persistent organic pollutants and mercury. AB - Chronic exposure to pollutants may represent a threat for wildlife. We tested whether adult survival rate, breeding probability and breeding success the year of sampling and the following year were affected by blood levels of mercury or persistent organic pollutants in Svalbard black-legged kittiwake Rissa tridactyla, by using capture-mark-recapture models over a five-year period. Survival rate was negatively linked to HCB levels in females, to chlordane mixture and oxychlordane, tended to decrease with increasing PCBs or DDE levels, but was unrelated to mercury. Breeding probability decreased with increasing mercury levels during the sampling year and with increasing CHL or HCB levels during the following year, especially in males observed as breeders. Surprisingly, the probability of raising two chicks increased with increasing HCB levels. Although levels of these legacy pollutants are expected to decline, they represent a potential threat for adult survival rate and breeding probability, possibly affecting kittiwake population dynamics. PMID- 25686883 TI - Size-dependent distribution and inhalation cancer risk of particle-bound polycyclic aromatic hydrocarbons at a typical e-waste recycling and an urban site. AB - Atmospheric particle size distribution of polycyclic aromatic hydrocarbons (PAHs) in a typical e-waste recycling zone and an urban site (Guangzhou) in southern China featured a unimodal peak in 0.56-1.8 MUm for 4-6 ring PAHs but no obvious peak for 2-3 ring PAHs at both sites. The atmospheric deposition fluxes of PAHs were estimated at 5.4 +/- 2.3 MUg m(-2) d(-1) in the e-waste recycling zone and 3.1 +/- 0.6 MUg m(-2) d(-1) in Guangzhou. In addition, dry and wet deposition fluxes of PAHs were dominated by coarse (Dp > 1.8 MUm) and fine particles (Dp < 1.8 MUm), respectively. Fine particles predominated the deposition of PAHs in the lung. The results estimated by incremental inhalation cancer risk suggested that particle-bound PAHs posed serious threat to human health within the e-waste recycling zone and Guangzhou. PMID- 25686884 TI - Health risk assessment of various metal(loid)s via multiple exposure pathways on children living near a typical lead-acid battery plant, China. AB - Manufacture of lead-acid batteries is of widespread interest because of its emissions of heavy metals and metalloids into environment, harming environmental quality and consequently causing detrimental effects on human health. In this study, exposure pathways and health risks of children to heavy metal(loid)s (Pb, Cd, As, etc) were investigated based on field sampling and questionnaire. Pb was one of the most abundant elements in children's blood, with an elevated blood lead level of 12.45 MUg dL(-1). Soil/dust and food were heavily polluted by targeted metal(loid)s. Food ingestion accounted for more than 80% of the total exposure for most metal(loid)s. The non-cancer risks to children were 3-10 times higher than the acceptable level of 1, while the cancer risks were 5-200 times higher than the maximum acceptable level of 1.0 * 10(-4). The study emphasized the significance of effective environmental management, particularly to ensure food security near battery facilities. PMID- 25686885 TI - Temporal-spatial distributions and ecological risks of perfluoroalkyl acids (PFAAs) in the surface water from the fifth-largest freshwater lake in China (Lake Chaohu). AB - To investigate the residues, compositions, distributions and potential ecological risks of perfluoroalkyl acids (PFAAs), water samples were collected seasonally between August 2011 and November 2012 from 20 sites in Lake Chaohu and its tributary rivers. The mean concentration of total PFAAs (TPFAAs) was 14.46 +/- 6.84 ng/L. PFOA was the predominant contaminant (8.62 +/- 4.40 ng/L), followed by PFBA (2.04 +/- 1.16 ng/L) and PFHxA (1.23 +/- 1.50 ng/L). The TPFAAs concentrations peaked in August 2012 in each area, except for the western river. The opposite spatial trends were found for PFOA and PFOS in both the lake and river areas. Except for PFOS and PFUdA, the levels of TPFAAs and PFAAs were significantly related to the composition of fluorescent dissolved organic matter (FDOM) but not related to total DOM expressed by dissolved organic carbon (DOC). The risk of PFOS determined by a species sensitivity distribution model was notably above that of PFOA. PMID- 25686886 TI - The effects of rice canopy on the air-soil exchange of polycyclic aromatic hydrocarbons and organochlorine pesticides using paired passive air samplers. AB - The rice canopy in paddy fields can influence the air-soil exchange of organic chemicals. We used paired passive air samplers to assess the exchange of polycyclic aromatic hydrocarbons (PAHs) and organochlorine pesticides (OCPs) in a paddy field, South China. Levels of OCPs and light PAHs were generally higher under the canopy than above it. We found that the rice canopy can physically obstruct the evaporation of most OCPs and light PAHs, and can also act as a barrier to the gaseous deposition of p,p'-DDT and heavy PAHs. Paddy fields can behave as a secondary source of OCPs and light PAHs. The homolog patterns of these two types of chemical varied slightly between the air below and above the rice canopy, implying contributions of different sources. Paired passive air samplers can be used effectively to assess the in situ air-soil exchange of PAHs and OCPs in subtropical paddy fields. PMID- 25686887 TI - Does size matter? Minimally invasive approach in pediatric neurosurgery--a review of 125 minimally invasive surgeries in children: clinical history and operative results. AB - OBJECTIVE: Surgery is an integral component and typically the first line of therapy for children with central nervous system tumors. Conventional aims of neurosurgery including tumor removal, management of hydrocephalus, and diagnostic sampling have been radically modified with innovative technologies such as navigational guidance, functional mapping, endoscopic surgery, second-look surgery, and physiologic imaging. The aim of the study was to investigate our operative results using minimally invasive technique in children. METHODS: Clinical features, surgical technique and results, length of hospital stay, and complications were reviewed retrospectively. Pre- and early postoperative MRI was evaluated for degree of surgical resection. Correlation of tumor localization, lengths of hospital stay as well as surgical techniques and clinical outcome with follow-up was investigated. RESULTS: One hundred ten patients underwent 125 tumor resections using minimally invasive approaches (image- and functional guided tailored keyhole approaches for supratentorial, retrosigmoidal, and suboccipital keyhole approaches for infratentorial lesions). Most tumors were located supratentorial (62.4 %). In 29.6 % of the cases, the surgery was performed endoscope-assisted or endoscope-controlled; neuronavigation was used in 45.6 % and ultrasound in 24 % of the cases. Astrocytomas were diagnosed in 26.4 % of cases, ependymomas in 9.6 %, and medulloblastomas in 14.4 %. Gross total resection was achieved in 60.8 %. The most common complication was CSF fistula (n = 9), and the occurrence was significantly higher in younger children (p = 0.0001) and infratentorial located tumors (p = 0.02). Surgery for posterior fossa lesions was associated with a longer hospital stay (p = 0.02) compared to surgery of supratentorial lesions. Mean follow-up was 29.7 months (range 0.3-79.1 months), and most of the children recovered during the further course of the follow-up (symptoms better or idem in 74.4 %). CONCLUSION: In conclusion, our study shows that it is possible to achieve surgical results in the pediatric population applying minimal invasive techniques comparable to those described in the literature. PMID- 25686888 TI - Surgical treatment for cervicomedullary compression among infants with achondroplasia. AB - PURPOSE: Achondroplasia is the most common form of dwarfism. Respiratory failure is responsible for most deaths among these children and is often related to cervicomedullary compression (CMC). We present our experience with early cervicomedullary decompression in infants with achondroplasia. METHODS: Data was retrospectively collected for infants with achondroplasia who underwent CMC decompression between 1998 and 2013. Data included presurgical and postsurgical neurological examinations, MRI scans, and sleep study results. RESULTS: Ten infants were included. Ages at surgery were 4 to 23 months (12.5 +/- 6.88 months). All infants displayed neurological findings prior to surgery, although often subtle. All infants underwent a foramen magnum opening with a wide C1 laminectomy. Following surgery, seven patients (70 %) demonstrated improved neurological status, and one displayed neurological deterioration. Seven patients demonstrated improved sleep quality 1 year after surgery. These patients had a good or improved neurological status following surgery. Preoperative radiological findings included abnormal hyperintense T2 changes in all children (improved following surgery in six children), brainstem distortion in four children (improved in all), and diminished cerebrospinal fluid (CSF) spaces at the level of the foramen magnum in eight children (improved in seven). One child with extensive preoperative T2 changes accompanied by neurological and respiratory decline, deteriorated following surgery, and remains chronically ventilated. CONCLUSIONS: Infants with achondroplasia are prone to neurological and respiratory symptoms. We believe that early diagnosis and early surgery for decompression of the foramen magnum and C1 lamina can alleviate respiratory symptoms, improve neurological status, and perhaps prevent sudden infant death in this population. PMID- 25686889 TI - Genetic hearing impairment. AB - INTRODUCTION: Three out of 1000 newborns are affected by a hearing loss, one of these being profound congenital deafness, whereas in the population of children treated in the intensive care unit, the incidence is 1:50. The purpose of this paper is to show in which genetic diseases and syndromes that hearing impairment can occur. DISCUSSION: A large number of pathological conditions, (genetic, infectious, and metabolic) can manifest themselves in a conductive or sensorineural hearing loss. Nonsyndromic autosomal recessive hearing loss is found in 56 % of cases, syndromic recessive in 30 %, nonsyndromic autosomal dominant in 12 %, and nonsyndromic related to the X chromosome and mitochondrial in 2 % of the cases. CONCLUSION: To make a diagnosis, the knowledge of clinical features of genetic syndromes is of paramount importance. Complete evaluation includes pediatric examination, bone and soft tissue radiological visualization, i.e., computed tomography and nuclear magnetic resonance, and finally genetic tests in cases where a hereditary disorder is suspected or identified. PMID- 25686890 TI - Cerebral Rosai-Dorfman disease. AB - BACKGROUND: Sinus histiocytosis (Rosai-Dorfman disease) with massive lymphadenopathy is a rare nonneoplastic and nonlangerhans cell proliferation disorder of the histiocytes. Extranodal location with or without lymphadenopathy occurs in about 40 % of the cases. Intracranial location is rare in children often mimicking meningiomas. The parasphenoidal region is more frequently involved though intraxial or intraventricular locations were described as well. Rarely, the surgical treatment allows the complete excision of the lesion; however, in symptomatic cases, partial resections of the tumor allow to counteract its mass effect. Long survivals are possible, even without radiotherapy or chemotherapy, due to the frequent spontaneous benign evolution of the lesions. CASE REPORT: A 2-year-10-month-old girl presented with high fever and vomiting. One year ago, she had a period of muscular weakness in both legs that recovered completely. MRI of the brain revealed an axial enhancing lesion with ventricular spreading mainly to the left occipital horn and bilateral frontal periventricular infiltration. After steroid therapy, all the symptoms recovered. Partial removal of the occipital intraventricular lesion was performed and the diagnosis of Rosai-Dorfman disease was established and confirmed by the reference center. At the latest follow-up (16 months), the girl is without any neurological symptoms and without any treatment. PMID- 25686891 TI - Pontine Rosai-Dorfman disease in a child. AB - INTRODUCTION: Rosai-Dorfman Disease (RDD) is a benign histiocytic disorder that commonly presents with massive lymphadenopathy. Central nervous system (CNS) involvement is only 5%; isolated CNS involvement is much rarer. The patient presented here has been diagnosed with isolated pontine RDD. CASE REPORT: A 5 year-old child was admitted to the hospital with the history of double vision and ptosis of the left eye. Magnetic resonance imaging revealed presence of a mass at the pontomesencephalic junction. Subtotal tumor excision was performed. Microscopic examination of the lesion showed histologic features consistent with RDD. The patient was followed up without medication, with a small residue. CONCLUSION: RDD is rare in childhood, and isolated CNS involvement is also quite rare. The tumor is located in pons in our case. The treatment of choice is gross total resection. Even total excision is not possible, follow up without medication may be an option because of the indolent and self-limited course of the disease. PMID- 25686892 TI - Morphological brain lesions of pediatric cerebellar tumor survivors correlate with inferior neurocognitive function but do not affect health-related quality of life. AB - PURPOSE: We aimed to determine whether extent of morphological brain injury in pediatric cerebellar tumor survivors correlates with neurocognitive function and health-related quality of life (HrQoL). METHODS: Seventeen cerebellar pilocytic astrocytoma (cPA) and 17 medulloblastoma (MB) survivors were examined for HrQoL, intelligence using the German version of the WISC-III, attention, working memory, and visual motor coordination. MRI scans were analyzed for extent of posterior fossa brain tissue loss. RESULTS: We found significant correlations between amount and extent morphological brain lesions of pediatric cerebellar tumor survivors and several cognitive impairments including intelligence and attention in both patient groups. These were in total more pronounced in MB patients when compared to cPA patients. Still, function loss and brain lesions detected on conventional MRI did not influence HrQoL. CONCLUSIONS: These findings support the notion that long-term neurocognitive deficits of pediatric posterior fossa tumor survivors significantly correlate with brain tissue damage. The cerebellum plays a role in regulating higher-order functions. On the contrary, the extent brain injury is not detected by HrQoL assessment. PMID- 25686893 TI - Evidence-based interventions to reduce shunt infections: a systematic review. AB - PURPOSE: Cerebrospinal fluid shunt infection is associated with patient morbidity and high cost. We conducted a systematic review of the current evidence of comprehensive surgical protocols or individual interventions designed to reduce shunt infection incidence. METHODS: A systematic review using PubMed and SCOPUS identified studies evaluating the effect of a particular intervention on shunt infection risk. Systemic prophylactic antibiotic or antibiotic-impregnated shunt efficacy studies were excluded. A total of 7429 articles were screened and 23 articles were included. RESULTS: Eight studies evaluated the effect of comprehensive surgical protocols. Shunt infection was reduced in all studies (absolute risk reduction 2.2-12.3 %). Level of evidence was low (level 4 in seven studies) due to the use of historical controls. Compliance ranged from 24.6 to 74.5 %. Surgical scrub with antiseptic foam and omission of a 5 % chlorhexidine gluconate preoperative hair wash were both associated with increased shunt infection. Twelve studies evaluated the effect of a single intervention. Only antibiotic-impregnated suture, a no-shave policy, and double gloving with glove change prior to shunt handling, were associated with a significant reduction in shunt infection. In a hospital with high methicillin-resistant staphylococcus aureus (MRSA) prevalence, a randomized controlled trial found that perioperative vancomycin rather than cefazolin significantly reduced shunt infection rates. CONCLUSION: Despite wide variation in compliance rates, the implementation of comprehensive surgical protocols reduced shunt infection in all published studies. Antibiotic-impregnated suture, a no-shave policy, double gloving with glove change prior to device manipulation, and 5 % chlorhexidine hair wash were associated with significant reductions in shunt infection. PMID- 25686894 TI - Morphology of the foramen magnum in syndromic and non-syndromic brachycephaly. AB - PURPOSE: The shape and size of the foramen magnum (FM) can be altered in craniosynostoses. However, few studies have investigated these changes. In this paper, we investigate the morphology of the foramen magnum in syndromic and non syndromic brachycephaly. METHODS: Surface area, anteroposterior (AP) diameter, and transverse diameters of the FM were measured on high-resolution CT scans in children with Crouzon (25), Pfeiffer (21), Apert (26), Saethre-Chotzen (7) syndromes, and isolated bicoronal synostosis (9) and compared to an age-matched control group (30). RESULTS: A significantly smaller FM surface area was observed in Crouzon (6.3 +/- 1.7 cm(2)) and Pfeiffer (6.4 +/- 2.3 cm(2)) syndromes as compared to the control group (7.4 +/- 1.3 cm(2), p = 0.006 and p = .017, respectively). In comparison to the control group, no statistically significant alteration in FM surface area was noted in patients with Apert, Saethre-Chotzen, or isolated bicoronal synostosis (p = 0.37, p = 0.71, p = 0.40 respectively). The transverse diameter of FM was significantly smaller in Crouzon, Pfeiffer, and Apert syndromes compared to the control group (p = 0.005, p = 0.002, p = 0.03 respectively). In Saethre-Chotzen and isolated bicoronal synostosis, no difference in transverse diameter was demonstrated. Among all groups, only Crouzon syndrome showed reduced anteroposterior diameter as compared to controls (p = 0.005). In Pfeiffer and Apert syndromes, there was elongation of the shape of the FM with a relatively narrowed width as demonstrated in a significantly increased AP to transverse diameter ratio (p = 0.002 and p = 0.019, respectively). DISCUSSION AND CONCLUSIONS: The FM shape and area is significantly altered in fibroblast growth factor receptor (FGFR)-related brachycephaly syndromes (Crouzon, Pfeiffer, and Apert), whereas in patients with Saethre Chotzen syndrome (TWIST-1 mutation) and isolated non-syndromic bicoronal synostosis, the shape and mean FM area was not statistically different from that of normals. This study brings to light the important role of FGFRs on FM growth and shape. TWIST-1 mutation (Saethre-Chotzen syndrome) does not appear to have an important effect in shaping the FM. PMID- 25686895 TI - Physical model from 3D ultrasound and magnetic resonance imaging scan data reconstruction of lumbosacral myelomeningocele in a fetus with Chiari II malformation. AB - Rapid prototyping is becoming a fast-growing and valuable technique for physical models in case of congenital anomalies. Manufacturing models are generally built from three-dimensional (3D) ultrasound, computed tomography, and fetal magnetic resonance imaging (MRI) scan data. Physical prototype has demonstrated to be clinically of value in case of complex fetal malformations and may improve antenatal management especially in cases of craniosynostosis, orofacial clefts, and giant epignathus. In addition, it may enhance parental bonding in visually impaired parents and have didactic value in teaching program. Hereby, the first 3D physical model from 3D ultrasound and MRI scan data reconstruction of lumbosacral myelomeningocele in a third trimester fetus affected by Chiari II malformation is reported. PMID- 25686896 TI - Beckwith-Wiedemann syndrome and Chiari I malformation--a case-based review of central nervous system involvement in hemihypertrophy syndromes. AB - BACKGROUND: Beckwith-Wiedemann syndrome (BWS) is an unusual complex of abnormalities that includes mainly omphalocele, macroglossia, gigantism, visceromegaly, and neonatal hypoglycemia. Type I Chiari malformation, on the other hand, is defined as ectopia of the cerebellar tonsils below the plane of the foramen magnum. Only one case of association of BWS with Chiari I malformation has been previously reported in the literature. DISCUSSION: Several conditions involving congenital hemihypertrophy have been previously reported in association with Type I Chiari malformation. The pathophysiological mechanism for most of these associations is thought to be quite complex and still remains unclear. However, the presence of tonsillar herniation in BWS has been explained by Tubbs and Oakes in the only one existing case report of BWS with Type I Chiari malformation in the literature, to be due to associated hemihypertrophy of the skull base. We additionally suggest that cerebellar hypertrophy may also contribute to the tonsillar herniation and fourth ventricular outlet obstruction. ILLUSTRATIVE CASE: We now report our recent experience on this association following a review of the literature on association of other hemihypertrophy syndromes with the central nervous system anomalies. CONCLUSION: We believe that a common pathogenesis of Type I Chiari malformation occurs in conditions of hemihypertrophy including BWS, probably secondary to dysmorphology involving the posterior cranial fossa, and is not just an associated finding. PMID- 25686897 TI - De novo AVM formation. PMID- 25686898 TI - Transient lesion in the splenium of the corpus callosum due to rotavirus infection. AB - Transient signal changes in magnetic resonance imaging (MRI) of the splenium of the corpus callosum (SCC) can result from many different reasons, including encephalitis and encephalopathy caused by infection, seizures, metabolic disorders and asphyxia. We report a case of a 6-year-old Polish girl with rotavirus infection demonstrating a reversible SCC lesion on diffusion-weighted MRI images. She presented six episodes of generalized tonic seizures with mild acute gastroenteritis. Stool test for rotavirus antigen was positive. At the time of admission imaging showed the hyperintense region in T2-weighted and fluid attenuated inversion-recovery MRI, a well-defined lesion in the splenium of the corpus callosum with restricted diffusion in diffusion-weighted MRI and no enhancement in post contrast T1-weighted imaging. Her first EEG showed slow brain activity in the posterior occipitotemporal portion, consisting mainly of theta waves with a frequency of 4.5-5.5 Hz and amplitude of 40 uV. The lesion had completely disappeared on follow-up MRI 10 days later. The patient recovered fully without any sequelae. PMID- 25686899 TI - Meningeal relationships to the spinal nerves and rootlets: a gross, histological, and radiological study with application to intradural extramedullary spinal tumors. AB - INTRODUCTION: Juxtapositional tumors of the spinal nerve roots have been noted to not only interact with the roots at various vertebral levels, but also differ among patients. Therefore, the aim of the current study was to elucidate the potential for variation among the relationships of the meningeal layers at different nerve levels. METHODS: In 20 unembalmed adult cadavers and five fetal specimens, the spinal nerve roots from the cervical, thoracic, and lumbar regions were harvested with their associated meningeal layers and subjected to microdissection, histological analysis, or radiological imaging using 9.4-T MRI. RESULTS: As the nerve rootlets passed from the cord, they received their root sheath covering from the pia. After crossing the subarachnoid space to reach the apertures in the dura, they received two additional looser sheaths, an outer from the dura and an inner from the arachnoid. The pia mater always ended proximal to the arachnoid, and the pia and arachnoid layers extended more distally along the roots with caudal descent. Although the dorsal and ventral roots generally exited through separate dural openings, a single dural opening was also observed, often in the lower spinal regions. Thin intradural septations almost always separated the dorsal and ventral rootlets. The left and right sides frequently differed within individuals. CONCLUSIONS: On the basis of our study, variations of the meninges surrounding the spinal nerve roots are common, but themes do exist. Such data support surgical observations of the different interactions between tumors in these regions with surrounding neural tissues. PMID- 25686900 TI - Basic cerebrospinal fluid flow patterns in ventricular catheters prototypes. AB - OBJECT: A previous study by computational fluid dynamics (CFD) of the three dimensional (3-D) flow in ventricular catheters (VC) disclosed that most of the total fluid mass flows through the catheter's most proximal holes in commercially available VC. The aim of the present study is to investigate basic flow patterns in VC prototypes. METHODS: The general procedure for the development of a CFD model calls for transforming the physical dimensions of the system to be studied into a virtual wire-frame model which provides the coordinates for the virtual space of a CFD mesh, in this case, a VC. The incompressible Navier-Stokes equations, a system of strongly coupled, nonlinear, partial differential conservation equations governing the motion of the flow field, are then solved numerically. New designs of VC, e.g., with novel hole configurations, can then be readily modeled, and the corresponding flow pattern computed in an automated way. Specially modified VCs were used for benchmark experimental testing. RESULTS: Three distinct types of flow pattern in prototype models of VC were obtained by varying specific parameters of the catheter design, like the number of holes in the drainage segments and the distance between them. Specifically, we show how to equalize and reverse the flow pattern through the different VC drainage segments by choosing appropriate parameters. CONCLUSIONS: The flow pattern in prototype catheters is determined by the number of holes, the hole diameter, the ratio hole/segment, and the distance between hole segments. The application of basic design principles of VC may help to develop new catheters with better flow circulation, thus reducing the possibility of becoming occluded. PMID- 25686901 TI - Improved one-pot multienzyme (OPME) systems for synthesizing UDP-uronic acids and glucuronides. AB - Arabidopsis thaliana glucuronokinase (AtGlcAK) was cloned and shown to be able to use various uronic acids as substrates to produce the corresponding uronic acid-1 phosphates. AtGlcAK or Bifidobacterium infantis galactokinase (BiGalK) was used with a UDP-sugar pyrophosphorylase, an inorganic pyrophosphatase, with or without a glycosyltransferase for highly efficient synthesis of UDP-uronic acids and glucuronides. These improved cost-effective one-pot multienzyme (OPME) systems avoid the use of nicotinamide adenine dinucleotide (NAD(+))-cofactor in dehydrogenase-dependent UDP-glucuronic acid production processes and can be broadly applied for synthesizing various glucuronic acid-containing molecules. PMID- 25686902 TI - Microfabricated infuse-withdraw micropump component for an integrated inner-ear drug-delivery platform. AB - One of the major challenges in treatment of auditory disorders is that many therapeutic compounds are toxic when delivered systemically. Local intracochlear delivery methods are becoming critical in emerging treatments and in drug discovery. Direct infusion via cochleostomy, in particular, is attractive from a pharmacokinetics standpoint, as there is potential for the kinetics of delivery to be well-controlled. Direct infusion is compatible with a large number of drug types, including large, complex molecules such as proteins and unstable molecules such as siRNA. In addition, hair-cell regeneration therapy will likely require long-term delivery of a timed series of agents. This presents unknown risks associated with increasing the volume of fluid within the cochlea and mechanical damage caused during delivery. There are three key requirements for an intracochlear drug delivery system: (1) a high degree of miniaturization (2) a method for pumping precise and small volumes of fluid into the cochlea in a highly controlled manner, and (3) a method for removing excess fluid from the limited cochlear fluid space. To that end, our group is developing a head-mounted microfluidics-based system for long-term intracochlear drug delivery. We utilize guinea pig animal models for development and demonstration of the device. Central to the system is an infuse-withdraw micropump component that, unlike previous micropump-based systems, has fully integrated drug and fluid storage compartments. Here we characterize the infuse-withdraw capabilities of our micropump, and show experimental results that demonstrate direct drug infusion via cochleostomy in animal models. We utilized DNQX, a glutamate receptor antagonist that suppresses CAPs, as a test drug. We monitored the frequency dependent changes in auditory nerve CAPs during drug infusion, and observed CAP suppression consistent with the expected drug transport path based on the geometry and tonotopic organization of the cochlea. PMID- 25686903 TI - 3D printing of soft lithography mold for rapid production of polydimethylsiloxane based microfluidic devices for cell stimulation with concentration gradients. AB - Three-dimensional (3D) printing is advantageous over conventional technologies for the fabrication of sophisticated structures such as 3D micro-channels for future applications in tissue engineering and drug screening. We aimed to apply this technology to cell-based assays using polydimethylsiloxane (PDMS), the most commonly used material for fabrication of micro-channels used for cell culture experiments. Useful properties of PDMS include biocompatibility, gas permeability and transparency. We developed a simple and robust protocol to generate PDMS based devices using a soft lithography mold produced by 3D printing. 3D chemical gradients were then generated to stimulate cells confined to a micro-channel. We demonstrate that concentration gradients of growth factors, important regulators of cell/tissue functions in vivo, influence the survival and growth of human embryonic stem cells. Thus, this approach for generation of 3D concentration gradients could have strong implications for tissue engineering and drug screening. PMID- 25686904 TI - Effects of tanshinones from Salvia miltiorrhiza on CYP2C19 activity in human liver microsomes: enzyme kinetic and molecular docking studies. AB - OBJECTIVES: This study aimed to investigate the effects of five tanshinones, the lipophilic components from Danshen (Salvia miltiorrhiza), on CYP2C19 activity in pooled human liver microsomes (HLMs). METHODS: The effects of tanshinones on CYP2C19 activity were compared by enzyme inhibition study using omeprazole 5 hydroxylation in pooled HLMs. The inhibition constant (Ki) values and inhibition modes of effective tanshinones were evaluated by enzyme kinetic study. Molecular docking analysis was used to simulate the binding conformations of tanshinones to the active cavity of human CYP2C19. RESULTS: Dihydrotanshinone and miltirone showed potent inhibitory effects on CYP2C19 activity in a concentration-dependent manner. Tanshinone I showed weaker inhibitory effect, whereas tanshinone IIA and cryptotanshinone had no inhibitory effect. Further enzyme kinetic study showed that the inhibition by dihydrotanshinone and miltirone was a mixed type. The effects of tanshinones were also confirmed by a molecular docking study. Besides, the ethanol extract of Danshen also showed a mixed type of inhibition, whereas the water extract had no inhibitory effect. CONCLUSIONS: The current findings demonstrate the inhibition of CYP2C19 activity by the ethanol extract of Danshen and its components tanshinones, implicating the potential herb-drug interactions between Danshen and therapeutic agents metabolized by CYP2C19 in clinical practice. PMID- 25686905 TI - Acquisition of doxorubicin resistance facilitates migrating and invasive potentials of gastric cancer MKN45 cells through up-regulating aldo-keto reductase 1B10. AB - Continuous exposure to doxorubicin (DOX) accelerates hyposensitivity to the drug elicited lethality of gastric cells, with increased risks of the recurrence and serious cardiovascular side effects. However, the detailed mechanisms underlying the reduction of DOX sensitivity remain unclear. In this study, we generated a DOX-resistant variant upon continuously treating human gastric cancer MKN45 cells with incremental concentrations of the drug, and investigated whether the gain of DOX resistance influences gene expression of four aldo-keto reductases (AKRs: 1B10, 1C1, 1C2 and 1C3). RT-PCR analysis revealed that among the enzymes AKR1B10 is most highly up-regulated during the chemoresistance induction. The up regulation of AKR1B10 was confirmed by analyses of Western blotting and enzyme activity. The DOX sensitivity of MKN45 cells was reduced and elevated by overexpression and inhibition of AKR1B10, respectively. Compared to the parental MKN45 cells, the DOX-resistant cells had higher migrating and invasive abilities, which were significantly suppressed by addition of AKR1B10 inhibitors. Zymographic and real-time PCR analyses also revealed significant increases in secretion and expression of matrix metalloproteinase (MMP) 2 associated with DOX resistance. Moreover, the overexpression of AKR1B10 in the parental cells remarkably facilitated malignant progression (elevation of migrating and invasive potentials) and MMP2 secretion, which were lowered by the AKR1B10 inhibitors. These results suggest that AKR1B10 is a DOX-resistance gene in the gastric cancer cells, and is responsible for elevating the migrating and invasive potentials of the cells through induction of MMP2. PMID- 25686906 TI - Burkitt lymphoma research in East Africa: highlights from the 9(th) African organization for research and training in cancer conference held in Durban, South Africa in 2013. AB - A one-day workshop on Burkitt lymphoma (BL) was held at the 9(th) African Organization for Research and Training in Cancer (AORTIC) conference in 2013 in Durban, South Africa. The workshop featured 15 plenary talks by delegates representing 13 institutions that either fund or implement research on BL targeting AORTIC delegates primarily interested in pediatric oncology. The main outcomes of the meeting were improved sharing of knowledge and experience about ongoing epidemiologic BL research, BL treatment in different settings, the role of cancer registries in cancer research, and opportunities for African scientists to publish in scientific journals. The idea of forming a consortium of BL to improve coordination, information sharing, accelerate discovery, dissemination, and translation of knowledge and to build capacity, while reducing redundant efforts was discussed. Here, we summarize the presentations and discussions from the workshop. PMID- 25686907 TI - Late-onset toxic anterior segment syndrome. AB - We describe 6 cases that developed intraocular inflammation between 42 days and 137 days after implantation of an acrylic foldable intraocular lens (IOL) (ISert model 251) and failed to respond to antibiotic treatment. One eye required a vitrectomy and IOL removal, 2 eyes required irrigation of the capsule, and 5 eyes required systemic administration of steroids. The healing process took 30 to 108 days after onset. Simultaneous with our cases was an epidemic outbreak of sterile anterior segment inflammation with the same characteristics associated with the same IOL. The clinical features indicated late-onset toxic anterior segment syndrome. Analysis of the outbreak strongly suggested that toxicity of the aluminum used in the IOL production process was the cause. This contamination risk exists even with modern manufacturing technology. FINANCIAL DISCLOSURE: Mr. Shibuya is an employee of Hoya Corporation Medical Division. No other author has a financial or proprietary interest in any material or method mentioned. PMID- 25686908 TI - Electron microscopic evaluation of a gold glaucoma micro shunt after explantation. AB - We present a case of an explanted gold glaucoma micro shunt (GMS Plus) and the subsequent light and electron microscopic analyses. The shunt was implanted in a patient with medically refractive glaucoma. The intraocular pressure (IOP) was stable at 12 mm Hg 6 months postoperatively but spiked to 26 mm Hg 6 months later; membranous growth was visible on the implant gonioscopically. A second gold micro shunt was placed 2 years after the first. The IOP was 7 mm Hg 1 week postoperatively but increased to 23 mm Hg 3 weeks later; similar membranous growth was visible on this implant. One of the shunts was explanted, and light and scanning electron microscopic analyses revealed encapsulation around the shunt exterior and connective tissue invasion of the microstructure. This represents the first electron microscopic analysis of an explanted gold glaucoma micro shunt and the first unequivocal images of the fibrotic pseudo-capsule traversing its microchannels and fenestrations. FINANCIAL DISCLOSURE: Dr. Ahmed is a consultant to and has received research grants from Solx, Inc. No other author has a financial or proprietary interest in any material or method mentioned. PMID- 25686909 TI - Geochemistry of tin (Sn) in Chinese coals. AB - Based on 1625 data collected from the published literature, the geochemistry of tin (Sn) in Chinese coals, including the abundance, distribution, modes of occurrence, genetic types and combustion behavior, was discussed to make a better understanding. Our statistic showed the average Sn of Chinese coal was 3.38 mg/kg, almost two times higher than the world. Among all the samples collected, Guangxi coals occupied an extremely high Sn enrichment (10.46 mg/kg), making sharp contrast to Xinjiang coals (0.49 mg/kg). Two modes of occurrence of Sn in Chinese coals were found, including sulfide-bounded Sn and clay-bounded Sn. In some coalfields, such as Liupanshui, Huayingshan and Haerwusu, a response between REEs distribution and Sn content was found which may caused by the transportation of Sn including clay minerals between coal seams. According to the responses reflecting on REEs patterns of each coalfield, several genetic types of Sn in coalfields were discussed. The enrichment of Sn in Guangxi coals probably caused by Sn-rich source rocks and multiple-stage hydrothermal fluids. The enriched Sn in western Guizhou coals was probably caused by volcanic ashes and sulfide-fixing mechanism. The depletion of Sn in Shengli coalfield, Inner Mongolia, may attribute to hardly terrigenous input and fluids erosion. As a relative easily volatilized element, the Sn-containing combustion by-products tended to be absorbed on the fine particles of fly ash. In 2012, the emission flux of Sn by Chinese coal combustion was estimated to be 0.90 * 10(9) g. PMID- 25686910 TI - Gender differences in socio-demographic, clinical characteristics and psychiatric diagnosis in/of suicide attempters in a Mexican population. AB - OBJECTIVE: The aim of the present study was to analyse demographic and clinical characteristics, as well as psychiatric diagnoses to identify gender differences in patients with attempted suicide in a Mexican population. METHODS: Between September 2010 and September 2012, 140 suicide attempts were documented in the Department of Psychiatry at the General Hospital of Comalcalco (Hospital General de Comalcalco in Spanish) in Tabasco, Mexico. Diagnoses were established using the DSM-IV questionnaire in which Axis I and II were considered. The Suicide Intent Scale was also applied. RESULTS: In our sample, 63.6% were females and 36.4% males. With regard to socio-demographic characteristics, the predominant marital status in males was single, and in females married (chi2=5.93, df=2, p=0.05). In occupation the male group was mainly unemployed and housewife in females (chi2=55.51, df=4, p<0.001). Male subjects were more likely to consume alcohol (chi2=20.40, df=1, p<=0.001), cannabis (chi2=16.62, df=1, p<=0.001) or tobacco. The prevalence of psychiatric diagnosis was significantly different because, the male group was mainly diagnosed with substance-related disorders, whereas female participants showed a prevalence of stress-related disorders (chi2=34.17, gl=4, p=0.0001). CONCLUSION: Our results provide evidence that the characteristics of suicide attempt are different by gender in the Mexican population. Interventions are necessary for the development of prevention strategies that may lead to a reduction in suicidal behaviour. These preventive activities should consider the occupation for the female group and consumption of alcohol, cannabis or tobacco in the male group. PMID- 25686911 TI - Palladium-catalyzed direct arylation of phenols with aryl iodides. AB - An efficient protocol of palladium-catalyzed direct para-arylation of unfunctionalized phenols with aryl iodides under mild conditions was reported. A variety of substrates were applied in this reaction with yields up to 87%. PMID- 25686912 TI - EEG-NIRS based assessment of neurovascular coupling during anodal transcranial direct current stimulation--a stroke case series. AB - A method for electroencephalography (EEG) - near-infrared spectroscopy (NIRS) based assessment of neurovascular coupling (NVC) during anodal transcranial direct current stimulation (tDCS). Anodal tDCS modulates cortical neural activity leading to a hemodynamic response, which was used to identify impaired NVC functionality. In this study, the hemodynamic response was estimated with NIRS. NIRS recorded changes in oxy-hemoglobin (HbO2) and deoxy-hemoglobin (Hb) concentrations during anodal tDCS-induced activation of the cortical region located under the electrode and in-between the light sources and detectors. Anodal tDCS-induced alterations in the underlying neuronal current generators were also captured with EEG. Then, a method for the assessment of NVC underlying the site of anodal tDCS was proposed that leverages the Hilbert-Huang Transform. The case series including four chronic (>6 months) ischemic stroke survivors (3 males, 1 female from age 31 to 76) showed non-stationary effects of anodal tDCS on EEG that correlated with the HbO2 response. Here, the initial dip in HbO2 at the beginning of anodal tDCS corresponded with an increase in the log-transformed mean-power of EEG within 0.5Hz-11.25Hz frequency band. The cross-correlation coefficient changed signs but was comparable across subjects during and after anodal tDCS. The log-transformed mean-power of EEG lagged HbO2 response during tDCS but then led post-tDCS. This case series demonstrated changes in the degree of neurovascular coupling to a 0.526 A/m(2) square-pulse (0-30 s) of anodal tDCS. The initial dip in HbO2 needs to be carefully investigated in a larger cohort, for example in patients with small vessel disease. PMID- 25686913 TI - Towards a smart non-invasive fluid loss measurement system. AB - In this article, a smart wireless sensing non-invasive system for estimating the amount of fluid loss, a person experiences while physical activity is presented. The system measures three external body parameters, Heart Rate, Galvanic Skin Response (GSR, or skin conductance), and Skin Temperature. These three parameters are entered into an empirically derived formula along with the user's body mass index, and estimation for the amount of fluid lost is determined. The core benefit of the developed system is the affluence usage in combining with smart home monitoring systems to care elderly people in ambient assisted living environments as well in automobiles to monitor the body parameters of a motorist. PMID- 25686914 TI - A novel microwave sensor to detect specific biomarkers in human cerebrospinal fluid and their relationship to cellular ischemia during thoracoabdominal aortic aneurysm repair. AB - Thoraco-abdominal aneurysms (TAAA) represents a particularly lethal vascular disease that without surgical repair carries a dismal prognosis. However, there is an inherent risk from surgical repair of spinal cord ischaemia that can result in paraplegia. One method of reducing this risk is cerebrospinal fluid (CSF) drainage. We believe that the CSF contains clinically significant biomarkers that can indicate impending spinal cord ischaemia. This work therefore presents a novel measurement method for proteins, namely albumin, as a precursor to further work in this area. The work uses an interdigitated electrode (IDE) sensor and shows that it is capable of detecting various concentrations of albumin (from 0 to 100 g/L) with a high degree of repeatability at 200 MHz (R(2) = 0.991) and 4 GHz (R(2) = 0.975). PMID- 25686915 TI - The influence of low-level laser therapy with alendronate irrigation on healing of bone defects in rats. AB - The aim of this study was to investigate the effects of alendronate (Aln) irrigation with low-level laser therapy (LLLT) on the healing of bone defects in rats. Sixty Wistar rats weighing 250 to 300 g were randomly divided into three groups of 20 animals each: (1) control group, (2) Aln group, and (3) Aln with LLLT group. The distal epiphysis of all rats was perforated with a surgical bone drill. Twenty rats served as control. The bone defects of 40 rats received local alendronate sodium trihydrate irrigation (1 mg/ml) at the time of surgery. LLLT was applied to the bone defects of 20 rats immediately after Aln irrigation, and repeated on days 2, 4, 6, and 8 with a total dose of 10 J/cm(2) (2 J/cm(2) * 5). Continuous wave of GaAlAs laser (808 nm) was used with a power density of 0.1 W/cm(2). Laser energy was applied for 20 s (0.1 W * 20 s/1 cm(2)) per session. Control group, Aln group, and Aln with LLLT group rats were sacrificed at days 10 and 20 to compare the bone healing of each group histologically. There were significant differences between the three groups regarding union, substantia spongiosa, cortex formation, and in sum of histologic scores on days 10 and 20 (P < 0.0001). Our findings demonstrated that Aln has a more positive effect with LLLT on bone healing in rats. It was concluded that combining LLLT (808 nm laser at 10 J/cm(2)) with Aln irrigation has a beneficial effect in bone repair. It was demonstrated experimentally that Aln irrigation during the surgery had a significant effect to enhance bone formation, and LLLT significantly potentiated the osseous healing effects of Aln on bone defects. This administration method is able to minimize the dose of Aln in order to avoid both systemic and local adverse effects as well as the local injection times during the bone healing process. PMID- 25686916 TI - PEDF counteracts DL-alpha-aminoadipate toxicity and rescues gliotoxic damages in RPE-free chicken retinal explants. AB - Gliotoxic responses complicate human eye diseases, the causes of which often remain obscure. Here, we activated Muller cells (MCs) by the gliotoxin DL-alpha aminoadipate (AAA) and assayed possible protective effects by pigment epithelium derived factor (PEDF) in RPE-free retinal explants of the E6 chick embryo. These models are suited to analyze gliotoxic reactions in vitro, since the avian retina contains only Muller cells (MCs) as glial components, and the RPE-free explants are devoid of a major PEDF source. ChAT- and AChE-immunohistochemistry (IHC) revealed that AAA treatment disrupted the differentiation of cholinergic amacrine cells in the inner plexiform layer. At the applied concentration of 1 mM AAA, apoptosis of MCs was slightly increased, as shown by TUNEL and caspase-3 activity assays. Concomitantly, cell-free gaps emerged in the middle of the retina, where MCs were swollen and amassed glutamine synthetase (shown by GS and Vimentin IHC). AAA treatment strongly activated MCs, as shown by GFAP IHC, and by an increase of stress-related catalase activity. Remarkably, nearly all effects of AAA on MCs were effectively counter-balanced by 50 ng/ml PEDF co-treatment, as also shown by RT-PCR. These findings suggest that supplementation with PEDF can protect the retina against gliotoxic attacks. Further studies should establish whether PEDF similarly protects a gliotoxic human retina. PMID- 25686917 TI - Strongly anisotropic in-plane thermal transport in single-layer black phosphorene. AB - Using first principles calculations, we predict the thermal conductivity of the two-dimensional materials black phosphorene and blue phosphorene. Black phosphorene has an unprecedented thermal conductivity anisotropy ratio of three, with predicted values of 110 W/m-K and 36 W/m-K along its armchair and zigzag directions at a temperature of 300 K. For blue phosphorene, which is isotropic with a zigzag structure, the predicted value is 78 W/m-K. The two allotropes show strikingly different thermal conductivity accumulation, with phonons of mean free paths between 10 nm and 1 MUm dominating in black phosphorene, while a much narrower band of mean free paths (50-200 nm) dominate in blue phosphorene. Black phosphorene shows intriguing potential for strain-tuning of its thermal conductivity tensor. PMID- 25686918 TI - Set-shifting as a component process of goal-directed problem-solving. AB - In two experiments, we compared secondary task interference on Tower of London performance resulting from three different secondary tasks. The secondary tasks were designed to tap three different executive functions, namely set-shifting, memory monitoring and updating, and response inhibition. Previous work using individual differences methodology suggests that, all other things being equal, the response inhibition or memory tasks should result in the greatest interference. However, this was not found to be the case. Rather, in both experiments the set-shifting task resulted in significantly more interference on Tower of London performance than either of the other secondary tasks. Subsequent analyses suggest that the degree of interference could not be attributed to differences in secondary task difficulty. Results are interpreted in the light of related work which suggests that solving problems with non-transparent goal/subgoal structure requires flexible shifting between subgoals-a process that is held to be impaired by concurrent performance of a set-shifting task. PMID- 25686919 TI - Higher impact energy in traumatic brain injury interferes with noncovalent and covalent bonds resulting in cytotoxic brain tissue edema as measured with computational simulation. AB - BACKGROUND: Cytotoxic brain tissue edema is a complicated secondary consequence of ischemic injury following cerebral diseases such as traumatic brain injury and stroke. To some extent the pathophysiological mechanisms are known, but far from completely. In this study, a hypothesis is proposed in which protein unfolding and perturbation of nucleotide structures participate in the development of cytotoxic edema following traumatic brain injury (TBI). METHODS: An advanced computational simulation model of the human head was used to simulate TBI. The consequences of kinetic energy transfer following an external dynamic impact were analyzed including the intracranial pressure (ICP), strain level, and their potential influences on the noncovalent and covalent bonds in folded protein structures. RESULTS: The result shows that although most of the transferred kinetic energy is absorbed in the skin and three bone layers, there is a substantial amount of energy reaching the gray and white matter. The kinetic energy from an external dynamic impact has the theoretical potential to interfere not only with noncovalent but also covalent bonds when high enough. The induced mechanical strain and pressure may further interfere with the proteins, which accumulate water molecules into the interior of the hydrophobic structures of unfolded proteins. Simultaneously, the noncovalent energy-rich bonds in nucleotide adenosine-triphosphates may be perturbed as well. CONCLUSIONS: Based on the analysis of the numerical simulation data, the kinetic energy from an external dynamic impact has the theoretical potential to interfere not only with noncovalent, but also with covalent bonds when high enough. The subsequent attraction of increased water molecules into the unfolded protein structures and disruption of adenosine-triphosphate bonds could to some extent explain the etiology to cytotoxic edema. PMID- 25686920 TI - Hydrothermal treatment for TiN as abrasion resistant dental implant coating and its fibroblast response. AB - Dental implant made of pure titanium (Ti) is prone to scratch and abrasion during routine oral hygiene procedures. This results an increase in surface roughness and therefore, facilitates the adhesion of bacteria. In severe cases, this could lead to peri-implantitis. To overcome this problem, surface modification of Ti is necessary to improve its abrasion resistance. Besides, a strong implant-gingiva interface should also be guaranteed to prevent the adhesion of bacteria. In this study, titanium nitride (TiN) coating was first prepared with gas nitriding to increase surface hardness of pure the substrate. Then, the TiN was hydrothermally treated in CaCl2 solution in order to improve its soft tissue biocompatibility. The effect of hydrothermal treatment temperature on surface properties of TiN was investigated and its biocompatibility was assessed in vitro using NIH3T3 fibroblast cell. It was determined that 120 degrees C was the critical temperature for the hydrothermal treatment condition. Treatment below 120 degrees C could incorporate Ca into TiN surface, oxidize TiN surface partially and then improve the wettability while preserving its morphology and hardness. Fibroblast cell attachment and proliferation were improved and cell spreading was enhanced on hydrothermally treated specimens compared with untreated ones. Improved wettability, Ca incorporation and negative surface due to interstitial N were believed to be the main reasons. Hydrothermal treatment is expected to make TiN a promising dental implant coating with excellent abrasion resistance and good soft tissue affinity. PMID- 25686921 TI - Characterization of the aspects of osteoprogenitor cell interactions with physical tetracalcium phosphate anchorage on titanium implant surfaces. AB - Well-designed implants are used not only to modify the geometry of the implant but also to change the chemical properties of its surfaces. The present study aims to assess the biofunctional effects of tetracalcium phosphate (TTCP) particles as a physical anchor on the implant surface derived through sandblasting. The characteristics of the surface, cell viability, and alkaline phosphatase (ALP) activity toward osteoprogenitor cells (D1) were obtained. D1 cells were cultured on a plain surface that underwent sandblasting and acid etching (SLA) (control SLA group) and on different SLA surfaces with different anchoring TTCP rates (new test groups, M and H). The mean anchoring rates were 57% (M) and 74% (H), and the anchored thickness was estimated to range from 12.6MUm to 18.3MUm. Compared with the control SLA surface on Ti substrate, the new test groups with different TTCP anchoring rates (M and H) failed to improve cell proliferation significantly but had a well-differentiated D1 cell phenotype that enhanced ALP expression in the early stage of cell cultures, specifically, at day 7. Results suggest that the SLA surface with anchored TTCP can accelerate progenitor bone cell mineralization. This study shows the potential clinical application of the constructed geometry in TTCP anchorage on Ti for dental implant surface modification. PMID- 25686922 TI - Local administration of calcitriol positively influences bone remodeling and maturation during restoration of mandibular bone defects in rats. AB - The aim of this study was to investigate the influence of calcitriol on osteoinduction following local administration into mandibular bone defects. Calcitriol-loaded absorbable collagen membrane scaffolds were prepared using the polydopamine coating method and characterized by scanning electron microscopy. Composite scaffolds were implanted into rat mandibular bone defects in the following groups: no graft material (control), bare collagen membrane (CM group), collagen membrane bearing polydopamine coating (DOP/CM group), and collagen membrane bearing polydopamine coating absorbed with calcitriol (CAL/DOP/CM group). At 1, 2, 4 and 8weeks post-surgery, the osteogenic potential of calcitriol was examined by histological and immunohistochemical methods. Following in vivo implantation, calcitriol-loaded composite scaffolds underwent rapid degradation with pronounced replacement by new bone and induced reunion of the bone marrow cavity. Calcitriol showed strong potential in inhibiting osteoclastogenesis and promotion of osteogenic differentiation at weeks 1, and 2. Furthermore, statistical analysis revealed that the newly formed bone volume in the CAL/DOP/CM group was significantly higher than other groups at weeks 1, and 2. At weeks 4, and 8, the CAL/DOP/CM group showed more mineralized bone and uniform collagen structure. These data suggest that local administration of calcitriol is promising in promoting osteogenesis and mineralization for restoration of mandibular bone defects. PMID- 25686923 TI - Development of an imprinted polymeric sensor with dual sensing property for trace level estimation of zinc and arginine. AB - Using virtuousness of multi-template imprinting and selectivity of single template imprinting, for the first time, we have prepared an imprinted polymer matrix that can detect two target analyte viz., Zn(2+) and arginine in single motif. For the preparation of imprinted polymer network, a new monomer {2 acrylamido-4-(methylthio)butanoic acid} was synthesized, which gives a biocompatible polymer network. Herein, the synthesized imprinted polymer mixed with multi-walled carbon nanotubes was immobilized onto the surface of platinum electrode to develop an electrochemical sensor for quantitative recognition of Zn(2+) and arginine using differential pulse voltammetry. Cyclic voltammetry, electrochemical impedance spectroscopy, and chronocoulometric analysis were also performed to study the kinetics of zinc-arginine complex. Under the optimal conditions the linear range of the calibration curve for Zn(2+) and arginine was 0.04-310.0ngmL(-1) and 0.04-235.0ngmL(-1), with the detection limit of 18.0 and 15.0pgmL(-1). The sensor has been successfully applied to the determination of Zn(2+) and arginine in water, food, and pharmaceutical samples and achieved high sensitivity and selectivity. PMID- 25686924 TI - Electrochemical deoxyribonucleic acid biosensor based on electrodeposited graphene and nickel oxide nanoparticle modified electrode for the detection of salmonella enteritidis gene sequence. AB - In this paper a new electrochemical DNA biosensor was prepared by using graphene (GR) and nickel oxide (NiO) nanocomposite modified carbon ionic liquid electrode (CILE) as the substrate electrode. GR and NiO nanoparticles were electrodeposited on the CILE surface step-by-step to get the nanocomposite. Due to the strong affinity of NiO with phosphate groups of ssDNA, oligonucleotide probe with a terminal 5'-phosphate group could be attached on the surface of NiO/GR/CILE, which could further hybridize with the target ssDNA sequence. Methylene blue (MB) was used as the electrochemical indicator for monitoring the hybridization reaction. Under the optimal conditions the reduction peak current of MB was proportional to the concentration of salmonella enteritidis gene sequence in the range from 1.0*10(-13) to 1.0*10(-6)molL(-1) with a detection limit as 3.12*10( 14)molL(-1). This electrochemical DNA sensor exhibited good discrimination ability to one-base and three-base mismatched ssDNA sequences, and the polymerase chain reaction amplification product of salmonella enteritidis gene sequences were further detected with satisfactory results. PMID- 25686925 TI - Electrospinning thermoplastic polyurethane/graphene oxide scaffolds for small diameter vascular graft applications. AB - Fabrication of small diameter vascular grafts plays an important role in vascular tissue engineering. In this study, thermoplastic polyurethane (TPU)/graphene oxide (GO) scaffolds were fabricated via electrospinning at different GO contents as potential candidates for small diameter vascular grafts. In terms of mechanical and surface properties, the tensile strength, Young's modulus, and hydrophilicity of the scaffolds increased with an increase of GO content while plasma treatment dramatically improved the scaffold hydrophilicity. Mouse fibroblast (3T3) and human umbilical vein endothelial cells (HUVECs) were cultured on the scaffolds separately to study their biocompatibility and potential to be used as vascular grafts. It was found that cell viability for both types of cells, fibroblast proliferation, and HUVEC attachment were the highest at a 0.5wt.% GO loading whereas oxygen plasma treatment also enhanced HUVEC viability and attachment significantly. In addition, the suture retention strength and burst pressure of tubular TPU/GO scaffolds containing 0.5wt.% GO were found to meet the requirements of human blood vessels, and endothelial cells were able to attach to the inner surface of the tubular scaffolds. Platelet adhesion tests using mice blood indicated that vascular scaffolds containing 0.5% GO had low platelet adhesion and activation. Therefore, the electrospun TPU/GO tubular scaffolds have the potential to be used in vascular tissue engineering. PMID- 25686926 TI - Porous hydrophilic core/hydrophobic shell nanoparticles for particle size and drug release control. AB - Polymeric nanoparticle has been developed for drug delivery during the past decades. However, the size of hydrophilic nanoparticles would increase in the aqueous environment due to water absorption, and then influence the in vivo biodistribution and drug release behavior. In the present study, the metronidazole-loaded porous Eudragit(r) RS (ERS)/poly(methyl methacrylate) (PMMA) core/shell nanoparticles were prepared by coaxial electrospray. Compared to the hydrophilic ERS nanoparticles, the porous hydrophilic core/hydrophobic shell nanoparticles displayed a slower drug release, and the release rate can be adjusted to change the surface area and particle size. In addition, the porous core/shell nanoparticles could maintain a stable particle size distribution in simulated body fluid for 8h, which can be attributed to the bioinert nature of PMMA coating. And porous core/shell nanoparticles showed slight in vitro cytotoxicity and good cellular internalization property. The results demonstrated that the prepared porous hydrophilic core/hydrophobic shell nanoparticles is a potential candidate for delivering drugs, which can also be used as a platform and further modified into targeted drug delivery systems for clinical application. PMID- 25686927 TI - In situ sonochemical synthesis of ZnO particles embedded in a thermoplastic matrix for biomedical applications. AB - Zinc oxide particles were synthesized and dispersed in situ in a polystyrene (PS) matrix using ultrasound. PS ultrasonic degradation was investigated at different polymer concentrations in organic solvent in contact with aqueous media prior to the particle synthesis. Decrease in weight-average molecular weight (Mw) was strongly dependent on polymer concentration in organic solvent and sonication time: degradation occurred less at higher polymer concentration, yet increased with longer times of more than 30min. The ZnO particles with a 800nm flower-like morphology were dispersed in the polystyrene matrix in situ; the composite presented both a lower average molecular weight (Mw) and lower number average molecular weight Mn when compared to pristine polystyrene, however thermal degradation temperature and Young's modulus were similar to the pristine polystyrene. The composite prepared in situ presented lower particle aggregation in comparison with ZnO commercially dispersed with ultrasound under the same conditions. Antibacterial activity of the ZnO/PS coating was tested against Escherichia coli (Gram-negative bacteria; DMS No. 10290) by evaluating bacterial growth inhibition after 20h on contact with the film surface. The results indicated that bacterial growth was inhibited in the medium in contact with the composite prepared in situ compared to the film of composite prepared by mixing and the pristine PS. This study showed the potential use of ZnO/PS composite prepared in situ as antibacterial coatings. PMID- 25686928 TI - Piperazine and its carboxylic acid derivatives-functionalized mesoporous silica as nanocarriers for gemcitabine: adsorption and release study. AB - Piperazine-functionalized SBA-15 nanorods were synthesized by post grafting method with methyldimethoxysilylpropylpiperazine (MDSP). The carboxylic acid derivatives of piperazine-functionalized SBA-15 nanorods were obtained using two different kinds of precursors (bromoacetic acid and succinic anhydride). The prepared materials were used as nanocarriers for the anticancer drug (gemcitabine). The obtained samples were characterized by SAXS, N2 adsorption desorption, SEM, TEM, DLS, thermogravimetric analysis, FTIR, Raman and UV spectroscopies. The adsorption and release properties of all samples were investigated. In vitro study included cell toxicity. It was found that the surface functionalization increases the interaction between the carrier and gemcitabine and results in the loading enhancement of the drug. In addition, the adsorption of gemcitabine on the modified mesoporous matrix depends on the type of the introduced functional groups. The carboxylic acid-modified samples have higher loading content, due to the strong interaction with gemcitabine. The maximum content of deposited drug in the modified SBA-15 nanorods is close to 36wt.% that it is related to PC2-SBA-15 sample which obtained using succinic anhydride. The obtained results reveal that the surface functionalization leads toward a significant decrease of the drug release rate without any appreciable cytotoxicity. No significant differences are observed among the drug release rate from the modified samples. PMID- 25686929 TI - Real time, in situ observation of the photocatalytic inactivation of Saccharomyces cerevisiae cells. AB - An in situ microscopy technique was developed to observe in real time the photocatalytic inactivation process of Saccharomyces cerevisiae (S. cerevisiae) cells by palladium-modified nitrogen-doped titanium oxide (TiON/PdO) under visible light illumination. The technique was based on building a photocatalytic micro-reactor on the sample stage of a fluorescence/phase contrast microscopy capable of simultaneously providing the optical excitation to activate the photocatalyst in the micro-reactor and the illumination to acquire phase contrast images of the cells undergoing the photocatalytic inactivation process. Using TiON/PdO as an example, the technique revealed for the first time the vacuolar activities inside S. cerevisiae cells subjected to a visible light photocatalytic inactivation. The vacuoles responded to the photocatalytic attack by the first expansion of the vacuolar volume and then contraction, before the vacuole disappeared and the cell structure collapsed. Consistent with the aggregate behavior observed from the cell culture experiments, the transition in the vacuolar volume provided clear evidence that photocatalytic disinfection of S. cerevisiae cells started with an initiation period in which cells struggled to offset the photocatalytic damage and moved rapidly after the photocatalytic damage overwhelmed the defense mechanisms of the cells against oxidative attack. PMID- 25686930 TI - A facile method for synthesizing water-soluble and superior sustained release anti-HIV prodrug SCs-d4T. AB - To efficiently deliver stavudine (d4T) for AIDS therapy, chitosan-stavudine conjugate (Cs-d4T) was synthesized. However, its poor water-solubility limited its clinical application. In this study, a sulphonated chitosan-stavudine conjugate (SCs-d4T) was synthesized with a mild SO3.Py complex sulphonation strategy. Chemical characteristics and morphology of Cs-d4T and SCs-d4T were performed by NMR, XRD, FTIR, ICP-AES and SEM. SCs-d4T demonstrated satisfactory solubility (106-bold of Cs-d4T solubility), good anti-HIV activity (6-fold of d4T anti-HIV activity), and well sustained release ability. The major release product O-isopropyl-5'-H-phosphonate of d4T (d4T-P-H) showed higher anti-HIV activity than d4T. For further evaluating the influence of linker and sulphonation strategy on anti-HIV activity, chitosan grafted with d4T by succinyl linker (Cs sd4T) and SCs-d4T sulphonated by oleum were also prepared. The result showed that the O-isopropyl monophosphate linker of Cs-d4T and SO3.Py complex sulphonation strategy revealed higher anti-HIV activity than succinyl linker of Cs-sd4T and oleum sulphonation strategy, respectively. PMID- 25686931 TI - Microstructures, mechanical and corrosion properties and biocompatibility of as extruded Mg-Mn-Zn-Nd alloys for biomedical applications. AB - Extruded Mg-1Mn-2Zn-xNd alloys (x=0.5, 1.0, 1.5 mass %) have been developed for their potential use as biomaterials. The extrusion on the alloys was performed at temperature of 623K with an extrusion ratio of 14.7 under an average extrusion speed of 4mm/s. The microstructure, mechanical property, corrosion behavior and biocompatibility of the extruded Mg-Mn-Zn-Nd alloys have been investigated in this study. The microstructure was examined using X-ray diffraction analysis and optical microscopy. The mechanical properties were determined from uniaxial tensile and compressive tests. The corrosion behavior was investigated using electrochemical measurement. The biocompatibility was evaluated using osteoblast like SaOS2 cells. The experimental results indicate that all extruded Mg-1Mn-2Zn xNd alloys are composed of both alpha phase of Mg and a compound of Mg7Zn3 with very fine microstructures, and show good ductility and much higher mechanical strength than that of cast pure Mg and natural bone. The tensile strength and elongation of the extruded alloys increase with an increase in neodymium content. Their compressive strength does not change significantly with an increase in neodymium content. The extruded alloys show good biocompatibility and much higher corrosion resistance than that of cast pure Mg. The extruded Mg-1Mn-2Zn-1.0Nd alloy shows a great potential for biomedical applications due to the combination of enhanced mechanical properties, high corrosion resistance and good biocompatibility. PMID- 25686932 TI - Correction of some mechanical characteristics of human dentin under compression considering the shape effect. AB - The paper is aimed to determine the true compression strength and Poisson's ratio of human dentin. The origin of the shape effect in dentin under compression is discussed, too. It was shown that the shape effect is mainly caused by the friction between the surface of the sample and the compression plates. Ratio d/h=4 is the optimal proportion between the diagonal of compression surface and the height of dentin sample for compression testing. Inhomogeneous deformation takes place in the sample with a low aspect ratio whereas lateral deformation is suppressed in the sample with a high aspect ratio. There is significant difference between the conventional compression strength and the true compression strength. True compression strength of human dentin is 432+/-16MPa, the Young's modulus is 4.04+/-0.12GPa and Poisson's ratio of human dentin is 0.14+/-0.04. PMID- 25686933 TI - Calcium phosphate bone cements for local vancomycin delivery. AB - Among calcium phosphate biomaterials, calcium phosphate bone cements (CPCs) have attracted increased attention because of their ability of self-setting in vivo and injectability, opening the new opportunities for minimally invasive surgical procedures. However, any surgical procedure carries potential inflammation and bone infection risks, which could be prevented combining CPC with anti inflammatory drugs, thus overcoming the disadvantages of systemic antibiotic therapy and controlling the initial burst and total release of active ingredient. Within the current study alpha-tricalcium phosphate based CPCs were prepared and it was found that decreasing the solid to liquid phase ratio from 1.89g/ml to 1.23g/ml, initial burst release of vancomycin within the first 24h increased from 40.0+/-2.1% up to 57.8+/-1.2% and intrinsic properties of CPC were changed. CPC modification with vancomycin loaded poly(lactic acid) (PLA) microcapsules decreased the initial burst release of drug down to 7.7+/-0.6%, while only 30.4+/ 1.3% of drug was transferred into the dissolution medium within 43days, compared to pure vancomycin loaded CPC, where 100% drug release was observed already after 12days. During the current research a new approach was found in order to increase the drug bioavailability. Modification of CPC with novel PLA/vancomycin microcapsules loaded and coated with nanosized hydroxyapatite resulted in 85.3+/ 3.1% of vancomycin release within 43days. PMID- 25686934 TI - Mesoporous materials as multifunctional tools in biosciences: principles and applications. AB - Research on mesoporous materials for biomedical and biological applications has experienced an outstanding increase during recent years. This review with ca. 420 references provides an overview of mesoporous structures covering synthesis and bioapplications. Various methods of mesoporous material preparation and modification are discussed as controlled synthesis of these molecular sieves has great impact on their properties and applications. In the area of bioapplications, mesoporous materials offer the potential for drug delivery, bioimaging, regenerative medicine, optical and electrochemical biosensing, enzyme immobilization, biomolecule sorption and separation and many others. We also discuss the cytotoxicity aspects of mesoporous structures being of crucial importance for successful application of these novel tools in the biomedical field. Future prospects of mesoporous materials have been also briefly discussed. We believe that the present review will serve as a comprehensive guide for scientists in the area of biosciences giving the background in regard to mesoporous materials. PMID- 25686935 TI - Titanium implants with modified surfaces: meta-analysis of in vivo osteointegration. AB - Titanium-based implants are widely used in modern clinical practice, but their "optimal" properties in terms of porosity and topology, roughness and hydrophilic parameters are being a subject of intensive discussions. Recent in vitro results have shown a possibility to optimize the surface of an implant with maximal repelling of bacteria (Staphylococcus aureus, Staphylococcus epidermidis) and improvement in human osteogenic and endothelial cell adhesion, proliferation and differentiation. In this work, these different grades titanium implants were tested in vivo using the same analytical methodology. In addition to material parameters, key histomorphometrical parameters such a regeneration area, bone adaptation area and bone-to-implant contact were determined after 2 and 4weeks of implantation in rabbit animal model. Porous implants have more clear differences than non-porous ones, with the best optimum values obtained on hydrothermally treated electrophoretically deposited titanium. These in vivo data correlate well with the optimal prediction made by in vitro tests. PMID- 25686936 TI - Bioactivity of coatings formed on Ti-13Nb-13Zr alloy using plasma electrolytic oxidation. AB - In this work, we investigated the bioactivity of anodic oxide coatings on Ti-13Nb 13Zr alloy by plasma electrolytic oxidation (PEO) in solutions containing Ca and P. The bioactive properties of the films were determined by immersion in simulated body fluid (SBF), and their biocompatibility was examined using adult human bone marrow derived mesenchymal stem cells (hBMSCs). The oxide layers were characterised based on their surface morphology (SEM, AFM, profilometry) as well as on their chemical and phase compositions (EDX, XRF, XRD, XPS). We report that anodic oxidation of Ti-13Nb-13Zr led to the development of relatively thick anodic oxide films that were enriched in Ca and P in the form of phosphate compounds. Furthermore, the treatment generated rough surfaces with a significant amount of open pores. The surfaces were essentially amorphous, with small amounts of crystalline phases (anatase and rutile) being observed, depending on the PEO process parameters. SBF soaking led to the precipitation of small crystals after one week of experiment. During culturing of hBMSCs on the bioactive Ti-13Nb-13Zr surfaces the differentiation of human mesenchymal stem cells toward osteoblasts was promoted, which indicated a potential of the modified materials to improve implant osseointegration. PMID- 25686937 TI - Pore architecture and cell viability on freeze dried 3D recombinant human collagen-peptide (RHC)-chitosan scaffolds. AB - Pore architecture of 3D scaffolds used in tissue engineering plays a critical role in the maintenance of cell survival, proliferation and further promotion of tissue regeneration. We investigated the pore size and structure, porosity, swelling as well as cell viability of a series of recombinant human collagen peptide-chitosan (RHCC) scaffolds fabricated by lyophilization. In this paper, freezing regime containing a final temperature of freezing (Tf) and cooling rates was applied to obtain scaffolds with pore size ranging from 100MUm to 120MUm. Other protocols of RHC/chitosan suspension concentration and ratio modification were studied to produce more homogenous and appropriate structural scaffolds. The mean pore size decreased along with the decline of Tf at a slow cooling rate of 0.7 degrees C/min; a more rapid cooling rate under 5 degrees C/min resulted to a smaller pore size and more homogenous microstructure. High concentration could reduce pore size and lead to thick well of scaffold, while improved the ratio of RHC, lamellar and fiber structure coexisted with cellular pores. Human umbilical vein endothelial cells (HUVECs) were seeded on these manufactured scaffolds, the cell viability represented a negative correlation to the pore size. This study provides an alternative method to fabricate 3D RHC-chitosan scaffolds with appropriate pores for potential tissue engineering. PMID- 25686938 TI - Microbial-assisted synthesis and evaluation the cytotoxic effect of tellurium nanorods. AB - The present study was designed to isolate bacterial strain capable of tellurium nanorods' (Te NRs) production followed by purification and evaluation of the cytotoxic effect of Te NRs. Among 25 environmental samples collected for screening of Te NR-producer bacterial strains one bacterial colony (isolated from hot spring and identified as Pseudomonas pseudoalcaligenes strain Te) was selected and applied for biosynthesis of Te NRs. Thereafter, an organic-aqueous partitioning system was applied for the purification of the biogenic Te NRs and the purified Te NRs were characterized using transmission electron microscopy (TEM), scanning electron microscopy (SEM), energy dispersive X-ray (EDX), X-ray diffraction spectroscopy (XRD), UV-visible spectroscopy, and Fourier transform infrared spectroscopy (FTIR) techniques. The cytotoxic effect of biologically synthesized Te NRs and potassium tellurite on four cell lines of MCF-7, HT1080, HepG2 and A549 was then determined using the MTT assay method. The obtained results revealed lower toxicity for the rod-shaped biogenic tellurium nanostructures (~22nm diameter by 185nm length) compared to K2TeO3. PMID- 25686939 TI - Mechanical behaviour of cp-magnesium with duplex hydroxyapatite and PEO coatings. AB - Hydroxyapatite-magnesia coatings were formed on cp-magnesium by plasma electrolytic oxidation (PEO) followed by cathodic electrodeposition (CED). The static tensile and cyclic fatigue performance of the coated samples were investigated. The cracking behaviour of the coatings during the tensile tests was studied by fracture analysis. The effects of the surface treatment on the fatigue performance of the magnesium substrate were addressed. Tensile strength of cp-Mg was not significantly affected, whereas the fatigue performance was improved by the PEO+CED coatings in the low-cycle region, possibly due to compressive residual stress induced to the metal substrate by the surface treatment. However, reduced fatigue strength was observed in the high-cycle region, which might be attributed to the defects at the coating/substrate interface produced during the surface modification. The in vitro corrosion reduced the fatigue strength in both the low- and high-cycle regions. Finally, the applicability of surface engineered magnesium for biomedical applications was demonstrated from the mechanical standpoint. PMID- 25686940 TI - Silver doped titanium oxide-PDMS hybrid coating inhibits Staphylococcus aureus and Staphylococcus epidermidis growth on PEEK. AB - Bacterial infection remains one of the most serious issues affecting the successful installation and retention of orthopedic implants. Many bacteria develop resistance to current antibiotics, which complicates or prevents traditional antibiotic-dependent eradication therapy. In this study, a hybrid coating of titanium dioxide and polydimethylsiloxane (PDMS) was synthesized to regulate the release of silver. The coatings were benefited from the antimicrobial activity of silver ion, the biocompatibility of titanium dioxide, and the flexibility of the polymer. Three studied silver doped coatings with different titanium dioxide-PDMS ratios effectively inhibited the attachment and growth of Staphylococcus aureus and Staphylococcus epidermidis in a dose dependent manner. The coatings were successfully applied on the discs of polyether ether ketone (PEEK), a common spinal implant material and antibacterial property of these coatings was assessed via Kirby Bauer assay. More importantly, these selected coatings completely inhibited biofilm formation. The release study demonstrated that the release rate of silver from the coating depended on doping levels and also the ratios of titanium dioxide and PDMS. This result is crucial for designing coatings with desired silver release rate on PEEK materials for antimicrobial applications. PMID- 25686941 TI - Bone cement based on vancomycin loaded mesoporous silica nanoparticle and calcium sulfate composites. AB - A novel bone cement pellet, with sustained release of vancomycin (VAN), was prepared by mixing VAN loaded mesoporous silica nanoparticle (MSN) and calcium sulfate alpha-hemihydrate (CS) together. To improve the VAN loading ability, MSN was functionalized with aminopropyltriethoxysilane (APS) to give APS-MSN. The VAN loading content and entrapment efficiency of APS-MSN could reach up to 45.91+/ 0.81% and 84.88+/-1.52%, respectively, much higher than those of MSN, which were only 3.91% and 4.07%, respectively. The nitrogen adsorption-desorption measurement results demonstrated that most of the VAN were in the pores of APS MSN. The CS/VAN@APS-MSN composite pellet showed a strongly drug sustained release effect in comparison with CS control pellet. The in vitro cell assays demonstrated that CS/APS-MSN composite was highly biocompatible and suitable to use as bone cement. Furthermore, CS/VAN@APS-MSN pellet showed no pyrogenic effect and meet the clinical requirements on hemolytic reaction. These results imply that CS/VAN@APS-MSN was an ideal candidate to replace CS bone cement in the treatment of open fractures. PMID- 25686942 TI - Analysis of long- and short-range contribution to adhesion work in cardiac fibroblasts: an atomic force microscopy study. AB - Atomic force microscopy (AFM) for single-cell force spectroscopy (SCFS) and Poisson statistic were used to analyze the detachment work recorded during the removal of gold-covered microspheres from cardiac fibroblasts. The effect of Cytochalasin D, a disruptor of the actin cytoskeleton, on cell adhesion was also tested. The adhesion work was assessed using a Poisson analysis also derived from single-cell force spectroscopy retracting curves. The use of Poisson analysis to get adhesion work from AFM curves is quite a novel method, and in this case, proved to be effective to study the short-range and long-range contributions to the adhesion work. This method avoids the difficult identification of minor peaks in the AFM retracting curves by creating what can be considered an average adhesion work. Even though the effect of actin depolymerisation is well documented, its use revealed that control cardiac fibroblasts (CT) exhibit a work of adhesion at least 5 times higher than that of the Cytochalasin treated cells. However, our results indicate that in both cells short-range and long-range contributions to the adhesion work are nearly equal and the same heterogeneity index describes both cells. Therefore, we infer that the different adhesion behaviors might be explained by the presence of fewer membrane adhesion molecules available at the AFM tip-cell interface under circumstances where the actin cytoskeleton has been disrupted. PMID- 25686943 TI - Effect of different calcium phosphate scaffold ratios on odontogenic differentiation of human dental pulp cells. AB - Calcium phosphate (CaP) scaffolds have been widely and successfully used with osteoblast cells for bone tissue regeneration. However, it is necessary to investigate the effects of these scaffolds on odontoblast cells' proliferation and differentiation for dentin tissue regeneration. In this study, three different hydroxyapatite (HA) to beta tricalcium phosphate (beta-TCP) ratios of biphasic calcium phosphate (BCP) scaffolds, BCP20, BCP50, and BCP80, with a mean pore size of 300MUm and 65% porosity were prepared from phosphoric acid (H2PO4) and calcium carbonate (CaCO3) sintered at 1000 degrees C for 2h. The extracts of these scaffolds were assessed with regard to cell viability and differentiation of odontoblasts. The high alkalinity, more calcium, and phosphate ions released that were exhibited by BCP20 decreased the viability of human dental pulp cells (HDPCs) as compared to BCP50 and BCP80. However, the cells cultured with BCP20 extract expressed high alkaline phosphatase activity and high expression level of bone sialoprotein (BSP), dental matrix protein-1 (DMP-1), and dentin sialophosphoprotein (DSPP) genes as compared to that cultured with BCP50 and BCP80 extracts. The results highlighted the effect of different scaffold ratios on the cell microenvironment and demonstrated that BCP20 scaffold can support HDPC differentiation for dentin tissue regeneration. PMID- 25686944 TI - Stable poly(St-co-BA) nanoemulsion polymerization for high performance antibacterial coatings in the presence of dioctyldimethylammonium chloride. AB - In this study, a stable antibacterial poly(styrene-co-butyl acrylate) (poly(St-co BA)) nano-latex was prepared in the presence of a dioctyldimethylammonium chloride (D821)-CTAB mixed surfactant and a novel bis-unsaturated Gemini comonomer (i.e., alpha,omega-hexanediyl bis(dimethyl methacrylamidopropyl ammonium bromide) (GMAP-6-MAP)) using a feasible and mild semicontinuous technology. The effects of the emulsifiers and GMAP-6-MAP on the properties and antibacterial activities of poly(St-co-BA) coatings were systematically investigated. The results indicate that an optimal monodispersed stable nanoemulsion was obtained with Dw=58.24nm and PDI=0.026, the emulsifier amount was 3.75% (D821/CTAB=4:1), and the GMAP-6-MAP amount was 1.5%. CTAB improved the stabilities and antibacterial activities of the poly(St-co-BA) nanoemulsions. The incorporation of GMAP-6-MAP into poly(St-co-BA) can enhance the antibacterial activity, improve the thermal stability of latex films, as well as the consistency among the chain segments, and decrease the roughness of latex films. This nanoemulsion exhibits effective antibacterial activity with MBCs of 2MUg.mL( 1) against Staphylococcus aureus and 16MUg.mL(-1) against Escherichia coli. The sterilization rates of the optimized latex film reached 100% against S. aureus and 98.74% against E. coli, which indicated that this latex film could be utilized as an outstanding antibacterial coating. PMID- 25686945 TI - An investigation into mechanical strength of exoskeleton of hydrothermal vent shrimp (Rimicaris exoculata) and shallow water shrimp (Pandalus platyceros) at elevated temperatures. AB - This investigation reports a comparison of the exoskeleton mechanical strength of deep sea shrimp species Rimicaris exoculata and shallow water shrimp species Pandalus platyceros at temperatures ranging from 25 degrees C to 80 degrees C using nanoindentation experiments. Scanning Electron Microscopy (SEM) observations suggest that both shrimp exoskeletons have the Bouligand structure. Differences in the structural arrangement and chemical composition of both shrimps are highlighted by SEM and EDX (Energy Dispersive X-ray) analyses. The variation in the elastic moduli with temperature is found to be correlated with the measured compositional differences. The reduced modulus of R. exoculata is 8.26+/-0.89GPa at 25 degrees C that reduces to 7.61+/-0.65GPa at 80 degrees C. The corresponding decrease in the reduced modulus of P. platyceros is from 27.38+/-2.3GPa at 25 degrees C to 24.58+/-1.71GPa at 80 degrees C. The decrease in reduced moduli as a function of temperature is found to be dependent on the extent of calcium based minerals in exoskeleton of both types of shrimp exoskeletons. PMID- 25686946 TI - Cellulose acetate/hydroxyapatite/chitosan coatings for improved corrosion resistance and bioactivity. AB - Cellulose acetate (CA) nanofibers were deposited on stainless steel plates by electrospinning technique. The composite of hydroxyapatite (HAP) nanoparticles and chitosan (CHI) was coated subsequently by dip-coating. The structure and morphology of the obtained coatings were investigated by Fourier transform infrared spectroscopy and scanning electron microscopy. The stability of the coatings in physiological environment was studied using electrochemical polarization and impedance spectroscopy. The CA nanofibers were embedded in the HAP/CHI coating and the resulted composite film was densely packed and uniform on the substrate. The in vitro biomineralization study of the coated samples immersed in simulated body fluid (SBF) confirmed the formation ability of bone like apatite layer on the surface of HAP-containing coatings. Furthermore, the coatings could provide corrosion resistance to the stainless steel substrate in SBF. The electrochemical results suggested that the incorporation of CA nanofibers could improve the corrosion resistance of the HAP/CHI coating. Thus, biocompatible CA/HAP/CHI coated metallic implants could be very useful in the long-term stability of the biomedical applications. PMID- 25686947 TI - Arrayed three-dimensional structures designed to induce and maintain a cell pattern by a topographical effect on cell behavior. AB - We investigated the ability of the microscale topography of a three-dimensional (3-D) structure arrayed on the surface of a substrate to induce and maintain a cell pattern by controlling cell behavior. Arrayed 3-D structures having different topographical characteristics, i.e., geometry and dimension, were fabricated on the surface of glass substrates by masked sand blasting. Each 3-D structure was designed to have a unit composed of a planar island for cell growth and surrounding grooves exhibiting cell repellency. The principle of the cell repellency is based on the topographical control of cell attachment, spreading, growth, and differentiation by utilizing the spatially restricted microenvironment of the grooves. Grooves with a width of less than approximately 116MUm and a depth of approximately 108MUm formed narrow V-shapes with a dihedral angle of less than approximately 44.4 degrees . Cell culture experiments using osteoblast-like cells demonstrated that these narrow V-shaped grooves had sufficient cell repellency to form and maintain a cell pattern on the surface for at least 14days. From the present study, arrayed 3-D structures designed to have narrow V-shaped grooves with optimal topographical characteristics for cell repellency are promising for the formation of stable cell patterns for creating novel cell microarray platforms without using conventional protein/cell-repellent chemicals. PMID- 25686948 TI - Thermogel-mediated sustained drug delivery for in situ malignancy chemotherapy. AB - In the past few decades, the in situ sustained drug delivery platforms present fascinating potential in sentinel chemotherapy of various solid tumors. In this work, doxorubicin (DOX), a model antitumor drug, was loaded into the thermogel of poly(lactide-co-glycolide)-block-poly(ethylene glycol)-block-poly(lactide-co glycolide). The moderate mechanical property of DOX-loaded hydrogel was confirmed by rheological test. In vitro degradation revealed the good biodegradability of thermogel. The DOX-loaded hydrogel exhibited the sustained release profiles up to 30days without and even with elastase. The improved in vivo tumor inhibition and reduced side-effects were observed in the DOX-incorporated hydrogel group compared with those in free DOX group. The excellent in vivo results were further confirmed by the histopathological evaluation or terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay. The thermogel with great prospect may be used as an ideal controlled drug delivery platform for the designated and long-term antitumor chemotherapy. PMID- 25686949 TI - Repressive effects of oat extracts on intracellular lipid-droplet formation in adipocytes and a three-dimensional subcutaneous adipose tissue model. AB - We assessed the repression of lipid-droplet formation in mouse mesenchymal stromal preadipocytes OP9 by specified oat extracts (Hatomugi, Coix lacryma-jobi var. ma-yuen) named "SPH" which were proteolytically and glucosyl-transferredly prepared from finely-milled oat whole-grain. Stimulation of OP9 preadipocytes with insulin-containing serum-replacement promoted differentiation to adipocytes, concurrently with an increase in the intracellular lipid droplets by 51.5%, which were repressed by SPH-bulk or SPH-water-extract at 840ppm, to 33.5% or 46.9%, respectively, but not by SPH-ethanol-extract at the same dose, showing the hydrophilic property of the anti-adipogenetic ingredients. The intracellular lipid droplets were scanty for intact preadipocytes, small-sized but abundant for the SPH-unadministered adipocytes, and large-sized but few for SPH-bulk administered adipocytes being coexistent with many lipid-droplet-lacking viable cells, suggesting "the all-or-none rule" for lipid-droplet generation in cell-to cell. Hydrogen-peroxide-induced cell death in human epidermal keratinocytes HaCaT was prevented by SPH-bulk at 100 or 150ppm by 5.6-8.1%, being consistent with higher viabilities of SPH-bulk-administered OP9 cells, together with repressions of both cell shrinkage and cell detachment from the culture substratum. In three dimensional subcutaneous adipose tissue models reconstructed with HaCaT keratinocytes and OP9-preadipocytes, lipid droplets were accumulated in dermal OP9-cell-parts, and repressed to 43.5% by SPH-bulk at 840ppm concurrently with marked diminishment of huge aggregates of lipid droplets. Thus SPH-bulk suppresses adipogenesis-associated lipid-droplet accumulation during differentiation of OP9 preadipocytes together with lowered cytotoxicity to either HaCaT keratinocytes or the preadipocytes. PMID- 25686950 TI - Biological safety evaluation of the modified urinary catheter. AB - The purpose of this study was to evaluate in vitro safety of the novel tosufloxacin (TOS)-treated catheters with the prolonged antimicrobial activity. The test samples of silicone latex catheter were prepared by the immobilization of TOS on chitosan (CHIT)-coated catheter by means of covalent bonds and non covalent interactions. Each step of the modification process of catheter surface was observed using ATR-Fourier transform infrared spectroscopy. In vitro cytotoxicity of the modified and unmodified catheters was assessed by direct and indirect tests in accordance with ISO standards using green monkey kidney (GMK) cell line. The MTT, lactate dehydrogenase activity (LDH), WST-8, Sulforhodamine B (SRB) test results and microscopic observation clearly indicated that unmodified silicone latex catheters decrease cell metabolic activity, act as a cytotoxic agent causing cell lysis and induce cell death through necrotic or apoptotic process. We suggest that chitosan coat with TOS immobilized limits leaching of harmful agents from silicone latex material, which significantly enhances survivability of GMK cells and therefore is quite a good protection against the cytotoxic effect of this material. PMID- 25686951 TI - Effect of CNT on collagen fiber structure, stiffness assembly kinetics and stem cell differentiation. AB - Collagen is a native one-dimensional nanomaterial. Carbon nanotube (CNT) was found to interface with biological materials and show promising applications in creating reinforced scaffolds for tissue engineering and regenerative medicine. In this study, we examined the unique role of CNT in collagen fiber structure, mechanical strength and assembly kinetics. The results imply that CNT interacts with collagen at the molecular level. It relaxes the helical coil of collagen fibrils and has the effect of flattening the fibers leading to the elongation of D-period, the characteristic banding feature of collagen fibers. The surface charge of oxidized CNT leads to enhanced local ionic strength during collagen fibrillogenesis, accounting for the slower kinetics of collagen-CNT (COL-CNT) fiber assembly and the formation of thicker fibers. Due to the rigidity of CNT, the addition of CNT increases the fiber stiffness significantly. When applied as a matrix for human decidua parietalis placental stem cells (hdpPSCs) differentiation, COL-CNT was found to support fast and efficient neural differentiation ascribed to the elongated D-period. These results highlight the superiority of CNT to modulate collagen fiber assembly at the molecular level. The study also exemplifies the use of CNT to enhance the functionality of collagen for biological and biomedical applications. PMID- 25686952 TI - A simple approach for producing highly efficient DNA carriers with reduced toxicity based on modified polyallylamine. AB - Nowadays gene delivery is a topic in many research studies. Non-viral vectors have many advantages over viral vectors in terms of safety, immunogenicity and gene carrying capacity but they suffer from low transfection efficiency and high toxicity. In this study, polyallylamine (PAA), the cationic polymer, has been modified with hydrophobic branches to increase the transfection efficiency of the polymer. Polyallylamine with molecular weights of 15 and 65kDa was selected and grafted with butyl, hexyl and decyl acrylate at percentages of 10, 30 and 50. The ability of the modified polymer to condense DNA was examined by ethidium bromide test. The complex of modified polymer and DNA (polyplex) was characterized for size, zeta potential, transfection efficiency and cytotoxicity in Neuro2A cell lines. The results of ethidium bromide test showed that grafting of PAA decreased its ability for DNA condensation but vectors could still condense DNA at moderate and high carrier to DNA ratios. Most of polyplexes had particle size between 150 and 250nm. The prepared vectors mainly showed positive zeta potential but carriers composed of PAA with high percentage of grafting had negative zeta potential. The best transfection activity was observed in vectors with hexyl acrylate chain. Grafting of polymer reduced its cytotoxicity especially at percentages of 30 and 50. The vectors based of PAA 15kDa had better transfection efficiency than the vectors made of PAA 65kDa. In conclusion, results of the present study indicated that grafting PAA 15kDa with high percentages of hexyl acrylate can help to prepare vectors with better transfection efficiency and less cytotoxicity. PMID- 25686953 TI - Graphene-gold nanoparticle composite: application as a good scaffold for construction of glucose oxidase biosensor. AB - In the present work we report a facile method for fabrication of glucose oxidase immobilized on the partially reduced graphene-gold nanocomposite (PRGO-AuNPs/GOx) as a novel biosensor for determination of glucose concentration. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) were used to study the morphology of PRGO and PRGO-AuNPs. Also, fast Fourier transformation infrared spectroscopy (FTIR) and UV-Vis spectroscopy were used to confirm formation of graphene and graphene-gold composite. Then, the electrochemical behavior of PRGO-AuNPs/GOx modified electrode was studied by cyclic voltammetry (CV). Our electrochemical studies, especially chronoamperometry (CA), showed that the PRGO-AuNPs/GOx modified electrode has excellent electrocatalytic activity towards the glucose. The limit of detection and sensitivity towards glucose were estimated as 0.06MUM and 15.04mAmM(-1), respectively. PMID- 25686954 TI - Degradation behaviour of LAE442-based plate-screw-systems in an in vitro bone model. AB - The use of absorbable implant materials for fixation after bone fracture helps to avoid a second surgery for implant removal and the risks and costs involved. Magnesium (Mg) is well known as a potential metallic material for degradable implants. The aim of the present in vitro study was to evaluate if degradable LAE442-based magnesium plate-screw-systems are suitable candidates for osteosynthesis implants in load-bearing bones. The corrosion behaviour was tested concerning the influence of different surface treatments, coatings and screw torques. Steel plates and screws of the same size served as control. Plates without special treatment screwed on up to a specified torque of 15cNm or 7cNm, NaOH treated plates (15cNm), magnesium fluoride coated plates (15cNm) and steel plates as control (15cNm) were examined in pH-buffered, temperature-controlled SBF solution for two weeks. The experimental results indicate that the LAE442 plates and screws coated with magnesium fluoride revealed a lower hydrogen evolution in SBF solution as well as a lower weight loss and volume decrease in MU-computed tomography (MUCT). The nanoindentation and SEM/EDX measurements at several plate areas showed no significant differences. Summarized, the different screw torques did not affect the corrosion behaviour differently. Also the NaOH treatment seemed to have no essential influence on the degradation kinetics. The plates coated with magnesium fluoride showed a decreased corrosion rate. Hence, it is recommended to consider this coating for the next in vivo study. PMID- 25686955 TI - Antibacterial activity of silver nanoparticles synthesized from serine. AB - Silver nanoparticles (Ag NPs) were synthesized by a simple microwave irradiation method using polyvinyl pyrrolidone (PVP) as a capping agent and serine as a reducing agent. UV-Visible spectra were used to confirm the formation of Ag NPs by observing the surface plasmon resonance (SPR) band at 443nm. The emission spectrum of Ag NPs showed an emission band at 484nm. In the presence of microwave radiation, serine acts as a reducing agent, which was confirmed by Fourier transformed infrared (FT-IR) spectrum. High-resolution transmission electron microscopy (HR-TEM) and high-resolution scanning electron microscopy (HR-SEM) were used to investigate the morphology of the synthesized sample. These images showed the sphere-like morphology. The elemental composition of the sample was determined by the energy dispersive X-ray analysis (EDX). Selected area electron diffraction (SAED) was used to find the crystalline nature of the Ag NPs. The electrochemical behavior of the synthesized Ag NPs was analyzed by the cyclic voltammetry (CV). Antibacterial experiments showed that the prepared Ag NPs showed relatively similar antibacterial activities, when compared with AgNO3 against Gram-positive and Gram-negative bacteria. PMID- 25686956 TI - The physicochemical/biological properties of porous tantalum and the potential surface modification techniques to improve its clinical application in dental implantology. AB - More rapid restoration and more rigid functionality have been pursued for decades in the field of dental implantology. Under such motivation, porous tantalum has been recently introduced to design a novel type of dental implant. Porous tantalum bears interconnected porous structure with pore size ranging from 300 to 600MUm and a porosity of 75-85%. Its elastic modulus (1.3-10GPa) more closely approximates that of natural cortical (12-18GPa) and cancellous bone (0.1-0.5GPa) in comparison with the most commonly used dental materials, such as titanium and titanium alloy (106-115GPa). Porous tantalum is highly corrosion-resistant and biocompatible. It can significantly enhance the proliferation and differentiation of primary osteoblasts derived from elderly people than titanium. Porous tantalum can allow bone ingrowth and establish not only osseointegration but also osseoincorporation, which will significantly enhance the secondary stability of implants in bone tissue. In this review, we summarize the physicochemical, mechanical and biological properties of porous tantalum. We further discuss the performance of current tantalum dental implants and present the methodologies of surface modifications in order to improve their biological performance. PMID- 25686957 TI - Methotrexatum intercalated layered double hydroxides: statistical design, mechanism explore and bioassay study. AB - A series of methotrexatum intercalated layered double hydroxide (MTX/LDH for short) hybrids have been synthesized by a mechanochemical-hydrothermal method, the statistical experiments are planned and conducted to find out the critical factor influencing the physicochemical properties. Four variables, i.e., addition of NaOH solution, grinding duration, hydrothermal temperature and time, are chosen to play as the examined factors in the orthogonal design. Furthermore, three respective levels, i.e., high, medium and low levels, are conducted in the design. The resulting hybrids are then characterized by X-ray diffraction (XRD) patterns, transmission electron microscope (TEM) graphs and Zeta potentials. XRD diffractions indicate that MTX anions have been successfully intercalated into LDH interlayers and the amount of NaOH solution can change the gallery height greatly. The information from TEM graphs and Zeta potentials state that the increase of alkali solution gives rise to regular morphology and the increase of Zeta potentials. As a result of the statistical analysis, addition of alkali solution is the major factor affecting the morphology and drug-loading capacity. At last, the mechanism of particle growth is explored emphatically, and the anticancer efficacy of some MTX/LDH hybrids is estimated by MTT assay on A549 cells as well. PMID- 25686958 TI - Bio-mimetic mineralization potential of collagen hydrolysate obtained from chromium tanned leather waste. AB - Hydroxyapatite (HA) ceramics serve as an alternative to autogenous-free bone grafting by virtue of their excellent biocompatibility. However, chemically synthesized HA lacks the strong load-bearing capacity as required by bone. The bio-mimetic growth of HA crystals on collagen surface provides a feasible solution for synthesizing bone substitutes with the desired properties. This study deals with the utilization of the collagen hydrolysate recovered from leather waste as a substrate for promoting HA crystal growth. Bio-mimetic growth of HA was induced by subjecting the hydrolysate to various mineralization conditions. Parameters that would have a direct effect on crystal growth were varied to determine the optimal conditions necessary. Maximum mineralization was achieved with a combination of 10mM of CaCl2, 5mM of Na2HPO4, 100mM of NaCl and 0.575% glutaraldehyde at a pH of 7.4. The metal-protein interactions leading to formation of HA were identified through Fourier-transform infrared (FTIR) spectroscopy and x-ray diffraction (XRD) studies. The crystal dimensions were determined to be in the nanoscale range by atomic force microscopy (AFM) and scanning electron microscopy (SEM). The size and crystallinity of bio-mimetically grown HA indicate that hydrolysate from leather waste can be used as an ideal alternative substrate for bone growth. PMID- 25686959 TI - Co-delivery of docetaxel and Poloxamer 235 by PLGA-TPGS nanoparticles for breast cancer treatment. AB - Multidrug resistance (MDR) is a major hurdle to the success of cancer chemotherapy. Poloxamers have been shown to reverse MDR by inhibiting the P glycoprotein (P-gp) pump. The objective of this research is to test the feasibility of docetaxel-loaded PLGA-TPGS/Poloxamer 235 nanoparticles to overcome MDR in docetaxel-resistant human breast cancer cell line. Docetaxel-loaded nanoparticles were prepared by a modified nanoprecipitation method using PLGA TPGS and PLGA-TPGS/Poloxamer 235 mixture, respectively. The PLGA-TPGS/Poloxamer 235 nanoparticles were of spherical shape and have a rough and porous surface. The docetaxel-loaded PLGA-TPGS/Poloxamer 235 porous nanoparticles which had an average size of around 180nm with a narrow size distribution were stable, showing almost no change in particle size and surface charge during the 3-month storage period. The in vitro drug release profile of both nanoparticle formulations showed a biphasic release pattern. There was an increased level of uptake of PLGA TPGS/Poloxamer 235 porous nanoparticles (PPNPs) in docetaxel-resistant human breast cancer cell line, MCF-7/TXT, in comparison with PLGA-TPGS nanoparticles (PTNPs). The PLGA-TPGS/Poloxamer 235 porous nanoparticles produced significantly higher level of toxicity than both of PLGA-TPGS nanoparticle formulation and Taxotere(r) both in vitro and in vivo, indicating docetaxel-loaded PLGA TPGS/Poloxamer 235 porous nanoparticles have significant potential for the treatment of breast cancer. PMID- 25686960 TI - Development of polymer wicks for the fabrication of bio-medical sensors. AB - Polymer based wicking structures were fabricated by sintering powders of polycarbonate (PC), ultra-high molecular weight polyethylene and polyamide 12, aiming at selecting a suitable material for an innovative electroencephalography (EEG) bio-electrode. Preliminary experiments showed that PC based wicks displayed the best mechanical properties, therefore more detailed studies were carried out with PC to evaluate the influence of powder granulometry and processing parameters (pressure, temperature and time) on the mechanical properties, porosity, mean pore radius and permeability of the wicks. It was concluded that the mechanical properties are significantly enhanced by increasing the processing time and pressure, although at the expense of a significant decrease of porosity and mean pore diameter (and thus permeability), particularly for the highest applied pressures (74kPa). However, a good compromise between porosity/permeability and mechanical properties could be obtained by sintering PC powders of particle sizes below 500MUm at 165 degrees C for 5min, upon an applied pressure of 56kPa. Moreover, PC proved to be chemically stable in contact with an EEG common used disinfectant. Thus, wicking structures with appropriate properties for the fabrication of reusable bio-electrodes could be fabricated from the sintering of PC powders. PMID- 25686961 TI - Rapid coating of AZ31 magnesium alloy with calcium deficient hydroxyapatite using microwave energy. AB - Due to their unique biodegradability, magnesium alloys have been recognized as suitable metallic implant materials for degradable bone implants and bioresorbable cardiovascular stents. However, the extremely high degradation rate of magnesium alloys in physiological environment has restricted its practical application. This paper reports the use of a novel microwave assisted coating technology to improve the in vitro corrosion resistance and biocompatibility of Mg alloy AZ31. Results indicate that a dense calcium deficient hydroxyapatite (CDHA) layer was uniformly coated on a AZ31 substrate in less than 10min. Weight loss measurement and SEM were used to evaluate corrosion behaviors in vitro of coated samples and of non-coated samples. It was seen that CDHA coatings remarkably reduced the mass loss of AZ31 alloy after 7days of immersion in SBF. In addition, the prompt precipitation of bone-like apatite layer on the sample surface during immersion demonstrated a good bioactivity of the CDHA coatings. Proliferation of osteoblast cells was promoted in 5days of incubation, which indicated that the CDHA coatings could improve the cytocompatibility of the AZ31 alloy. All the results suggest that the CDHA coatings, serving as a protective layer, can enhance the corrosion resistance and biological response of magnesium alloys. Furthermore, this microwave assisted coating technology could be a promising method for rapid surface modification of biomedical materials. PMID- 25686962 TI - Green synthesis and characterization of silver nanoparticles using Lantana camara leaf extract. AB - In this work, we have investigated on Lantana camara mediated silver nanoparticles (AgNPs) with different leaf extract (LE) quantity for the evaluation of efficient bactericidal activity. The AgNPs were prepared by simple, capable, eco-friendly and biosynthesis method using L. camara LE. This method allowed the synthesis of crystalline nanoparticles, which was confirmed by X-ray diffraction (XRD) and selected area electron diffraction (SAED) patterns. The X ray photoelectron spectroscopy (XPS) analysis confirmed the formation of metallic silver and elucidates the surface state composition of AgNPs. UV-vis spectra of AgNPs and visual perception of brownish yellow color from colorless reaction mixture confirmed the AgNP formation. Involvement of functional groups of L. camara leaf extract in the reduction and capping process of nanoparticles was well displayed in Fourier transform infrared spectroscopy (FTIR). Decrement of particle size with an increment of leaf extract volume was evident in AFM, TEM images and also through a blue shift in the UV-vis spectra. The rate of formation and size of AgNPs were dependent on LE quantity. Meanwhile, these AgNPs exhibited effective antibacterial activity with the decrement of particle size against all tested bacterial cultures. PMID- 25686963 TI - Surface energy of bovine dentin and enamel by means of inverse gas chromatography. AB - Adhesion between tooth tissues and dental fillings depends on the surface energy of both connected materials. Bond strength can be determined directly or indirectly as a work of adhesion on the basis of values of surface energy of these materials. Inverse gas chromatography (IGC) is one of the methods of surface energy examination. In this study the values of total surface energy components of wet and dry teeth fragments (enamel, crown dentin and root dentin) were determined with the use of inverse gas chromatography. Inverse gas chromatography has never been used for investigation of surface energy of natural tooth tissues. Different storage conditions were examined - wet and dry. Different values of surface energy are observed according to the type of tooth tissue (dentin or enamel), occurring place (crown or root) and storage conditions (dry or wet). The effect of tissue type and occurring place was the greatest, while storage conditions were of secondary importance. Surface energy depends on composition of tissue, its surface area and the presence of pores. PMID- 25686964 TI - Patterned substrates fabricated by a controlled freezing approach and biocompatibility evaluation by stem cells. AB - Patterned substrates have been widely used in the studies investigating how to regulate cell growth and alignment. Such substrates may be fabricated by various techniques such as photolithography, soft lithography and microcontact printing. We report here a facile approach to fabricate aligned and grid surface patterns by a controlled freezing approach and further investigate their biocompatibility. The fabrication has been demonstrated with polymers (hydrophilic & hydrophobic), nanoparticles (organic & inorganic), or mixtures of these components. For the aligned surface patterns, the spacings between the patterned ridges can be tuned by varying the freezing rates. The biocompatibility of the substrates is evaluated by WST-8 viability tests with cell counting kit-8 (CCK-8) and by culturing with mouse mesenchymal stem cells (mMSCs). Three surface-patterned substrates (PLGA, PLGA nanospheres with chitosan, and silica colloids) are evaluated in more details to show that the mMSCs can grow alongside the aligned ridges while the cells grow randomly when plain glass slides are used as control. Further observations show that PLGA substrates undergo degradation, and are thus unsuitable for cell culture over the longer term. On the other hand, the PLGA chitosan substrate and silica substrate were stable and could maintain mMSC alignment throughout the culture period. PMID- 25686965 TI - Feasibility study of the production of biomedical Ti-6Al-4V alloy by powder metallurgy. AB - Titanium and its alloys are characterized by an exceptional combination of properties like high strength, good corrosion resistance and biocompatibility which makes them suitable materials for biomedical prosthesis and devices. The wrought Ti-6Al-4V alloy is generally favored in comparison to other metallic biomaterials due to its relatively low elastic modulus and it has been long used to obtain products for biomedical applications. In this work an alternative route to fabricate biomedical implants made out of the Ti-6Al-4V alloy is investigated. Specifically, the feasibility of the conventional powder metallurgy route of cold uniaxial pressing and sintering is addressed by considering two types of powders (i.e. blended elemental and prealloyed). The characterization of physical properties, chemical analysis, mechanical behavior and microstructural analysis is carried out in-depth and the properties are correlated among them. On the base of the results found, the produced alloys are promising materials for biomedical applications as well as cheaper surgical devices and tools. PMID- 25686966 TI - Synthesis of cerium oxide nanoparticles using Gloriosa superba L. leaf extract and their structural, optical and antibacterial properties. AB - CeO2 nanoparticles (NPs) were green synthesized using Gloriosa superba L. leaf extract. The synthesized nanoparticles retained the cubic structure, which was confirmed by X-ray diffraction studies. The oxidation states of the elements (C (1s), O (1s) and Ce (3d)) were confirmed by XPS studies. TEM images showed that the NPs possessed spherical shape and particle size of 5nm. The Ce-O stretching bands were observed at 451cm(-1) and 457cm(-1) from the FT-IR and Raman spectra respectively. The band gap of the CeO2 NPs was estimated as 3.78eV from the UV visible spectrum. From the photoluminescence measurements, the broad emission composed of eight different bands were found. The antibacterial studies performed against a set of bacterial strains showed that Gram positive (G+) bacteria were relatively more susceptible to the NPs than Gram negative (G-) bacteria. The toxicological behavior of CeO2 NPs was found due to the synthesized NPs with uneven ridges and oxygen defects in CeO2 NPs. PMID- 25686967 TI - Solid phase extraction of Cd(II) and Pb(II) ions based on a novel functionalized Fe3O4@ SiO2 core-shell nanoparticles with the aid of multivariate optimization methodology. AB - This work describes novel Fe3O4@SiO2 core-shell nanoparticles functionalized with phenyl isothiocyanate and its application in the preconcentration of Cd(II) and Pb(II) ions. The parameters affecting the preconcentration procedure were optimized by a Box-Behnken design through response surface methodology. Three variables (extraction time, magnetic sorbent amount, and pH value) were selected as the main factors affecting the sorption step, while four variables (type, volume and concentration of the eluent; and elution time) were selected as effective factors of elution step in the optimization study. Following the sorption and elution, the ions were quantified by FAAS. The limits of detection were 0.05 and 0.9ngmL(-1) for Cd(II) and Pb(II) ions, respectively. The relative standard deviations were less than 6.4%. The sorption capacity (in mg g(-1)) of this new sorbent is 179 for Cd(II) and 156 for Pb(II). Finally, this nanocomposite was successfully applied to the rapid extraction of trace quantities of heavy metal ions from fish, sediment, soil, and water samples and satisfactory results were obtained. PMID- 25686968 TI - Study on microstructure and properties of extruded Mg-2Nd-0.2Zn alloy as potential biodegradable implant material. AB - Mg-2Nd-0.2Zn (NZ20) alloy was prepared for the application as biodegradable implant material in this study. The effects of the extrusion process on microstructure, mechanical and corrosion properties of the alloy were investigated. The as-cast alloy was composed of alpha-Mg matrix and Mg12Nd eutectic compound. The solution treatment could lead to the Mg12Nd phase dissolution and the grain coarsening. The alloy (E1) preheated at 380 degrees C for 1h and extruded at 390 degrees C presents fine grains with amounts of tiny Mg12Nd particles uniformly dispersed throughout the boundaries and the interior of the grains. The alloy (E2) preheated at 480 degrees C for 1h and extruded at 500 degrees C exhibits relatively larger grains with few nano-scale Mg12Nd phase particles dispersed. The alloy of E1, compared with E2, showed relatively lower corrosion rate, higher yield strength and slightly lower elongation. PMID- 25686969 TI - Hydrothermal treatment of titanium alloys for the enhancement of osteoconductivity. AB - The surface wettability of implants is a crucial factor in their osteoconductivity because it influences the adsorption of cell-attached proteins onto the surface. In this study, a single-step hydrothermal surface treatment using distilled water at a temperature of 180 degrees C for 3h was applied to titanium (Ti) and its alloys (Ti-6Al-4V, Ti-6Al-7Nb, Ti-29Nb-13Ta-4.6Zr, Ti-13Cr 1Fe-3Al; mass%) and compared with as-polished Ti implants and with implants produced by anodizing Ti in 0.1M of H3PO4 with applied voltages from 0V to 150V at a scanning rate of 0.1Vs(-1). The surface-treated samples were stored in a five time phosphate buffered saline (*5 PBS(-)) solution to prevent increasing the water contact angle (WCA) with time. The surface characteristics were evaluated using scanning electron microscopy, X-ray diffraction, X-ray photoelectron spectroscopy, Auger electron spectroscopy, surface roughness, and contact angle measurement using a 2MUL droplet of distilled water. The relationship between WCA and osteoconductivity at various surface modifications was examined using in vivo tests. The results showed that a superhydrophilic surface with a WCA<=10 degrees and a high osteoconductivity (RB-I) of up to 50% in the cortical bone part, about four times higher than the as-polished Ti and Ti alloys, were provided by the combination of the hydrothermal surface treatment and storage in *5 of PBS(-). PMID- 25686970 TI - Surface modification of biodegradable porous Mg bone scaffold using polycaprolactone/bioactive glass composite. AB - A reduction in the degradation rate of magnesium (Mg) and its alloys is in high demand to enable these materials to be used in orthopedic applications. For this purpose, in this paper, a biocompatible polymeric layer reinforced with a bioactive ceramic made of polycaprolactone (PCL) and bioactive glass (BG) was applied on the surface of Mg scaffolds using dip-coating technique under low vacuum. The results indicated that the PCL-BG coated Mg scaffolds exhibited noticeably enhanced bioactivity compared to the uncoated scaffold. Moreover, the mechanical integrity of the Mg scaffolds was improved using the PCL-BG coating on the surface. The stable barrier property of the coatings effectively delayed the degradation activity of Mg scaffold substrates. Moreover, the coatings induced the formation of apatite layer on their surface after immersion in the SBF, which can enhance the biological bone in-growth and block the microcracks and pore channels in the coatings, thus prolonging their protective effect. Furthermore, it was shown that a three times increase in the concentration of PCL-BG noticeably improved the characteristics of scaffolds including their degradation resistance and mechanical stability. Since bioactivity, degradation resistance and mechanical integrity of a bone substitute are the key factors for repairing and healing fractured bones, we suggest that PCL-BG is a suitable coating material for surface modification of Mg scaffolds. PMID- 25686971 TI - A new approach for decreasing the detection limit for a ketamine(I) ion-selective electrode. AB - Our endeavors of lowering the detection limit for a ketamine(I) ion-selective electrode were described. The paper stresses the electrode which showed best results for determination of ketamine ion. The present electrode incorporates ketamine-phosphomolybdate (KT-PM) as ion-exchanger combined with the lipophilic anionic additive (Na-TPB) dissolved in dibutyl phthalate (DBP) as a plasticizer. The characteristics of the electrode were elaborately measured and its performance was tested in various samples and urine. It has favorable features as it provides measurements of the potential with a near-Nernstian slope of 56.6+/ 0.3mV/decade over the concentration range of 1.5*10(-6)-1.0*10(-2)M over the pH range 3.0-6.8 in a short response time (7s). Importantly, it has a low detection limit of 1.2*10(-7)M and its life-span is 22days. Moreover, it displayed notable selectivity for ketamine ion over other species such as inorganic and organic cations and different excipients which may be present in pharmaceutical preparations. The sensor was applied for determination of KT ions in urine and pharmaceutical preparations using potentiometric determination, standard addition and the calibration curve methods. The standard deviation computed on the results indicated excellent repeatability of the measurements. Overall, it showed satisfactory results with excellent percentage recovery comparable to and sometimes better than those obtained by other routine methods for the assay. PMID- 25686972 TI - Wear mapping of CoCrMo alloy in simulated bio-tribocorrosion conditions of a hip prosthesis bearing in calf serum solution. AB - Wear maps were developed following a series of micro-abrasion-corrosion testing during idealised hip contact conditions for a CoCrMo alloy in a foetal calf serum solution. The main aim of the study was to characterise wear-corrosion or bio tribocorrosion regimes of the alloy over a range of applied loads and applied potentials. The transitioning micro-abrasion-corrosion mechanisms, synergisms and wastage behaviours in the presence of additional abrasive particles were identified and mapped. Wear maps in earlier work show the wear-corrosion transitions of CoCrMo alloy in the absence of abrasive particles for similar conditions; the wear maps developed in this work were compared. Mapping the micro abrasion-corrosion regimes indicated that proteins present in foetal calf serum solution, resulting in development of a graphitic tribo-layer, may play a critical role in enhancing or protecting against tribo-corrosive degradation. PMID- 25686973 TI - Incorporation of poly(ethylene glycol) grafted cellulose nanocrystals in poly(lactic acid) electrospun nanocomposite fibers as potential scaffolds for bone tissue engineering. AB - Poly(ethylene glycol) (PEG)-grafted cellulose nanocrystals (CNCs) were successfully synthesized and incorporated into poly(lactic acid) (PLA) as a reinforcing filler to produce nanocomposite scaffolds consisting of CNC-g-PEG and PLA using an electrospinning technique. Morphological, thermal, mechanical, and wettability properties as well as preliminary biocompatibility using human mesenchymal stem cells (hMSCs) of PLA/CNC and PLA/CNC-g-PEG nanocomposite scaffolds were characterized and compared. The average diameter of the electrospun nanofibers decreased with increased filler loading level, due to the increased conductivity of the electrospun solutions. DSC results showed that both the glass transition temperature and cold crystallization temperature decreased progressively with higher CNC-g-PEG loading level, suggesting that improved interfacial adhesion between CNCs and PLA was achieved by grafting PEG onto the CNCs. Wettability of the electrospun nanofibers was not affected with the addition of CNCs or CNC-g-PEG and indicating that the fillers tended to stay inside of the fiber matrix under electrical field. The tensile strength of the composite fiber mats was effectively improved by the addition of up to 5% CNC-g PEG up to 5wt.%. In addition, the cell culture results showed that PLA/CNC-g-PEG composite nanofibers exhibited improved biocompatibility to hMSCs, which revealed the potential application of this nanocomposite as the scaffolds in bone tissue engineering. PMID- 25686974 TI - Biocompatibility and drug release behavior of scaffolds prepared by coaxial electrospinning of poly(butylene succinate) and polyethylene glycol. AB - Scaffolds constituted by electrospun microfibers of poly(ethylene glycol) (PEG) and poly(butylene succinate) (PBS) were studied. Specifically, coaxial microfibers having different core-shell distributions and compositions were considered as well as uniaxial micro/nanofibers prepared from mixtures of both polymers. Processing conditions were optimized for all geometries and compositions and resulting morphologies (i.e. diameter and surface texture) characterized by scanning electron microscopy. Chemical composition, molecular interactions and thermal properties were evaluated by FTIR, NMR, XPS and differential scanning calorimetry. The PEG component of electrospun fibers could be solubilized by immersion of scaffolds in aqueous medium, giving rise to high porosity and hydrophobic samples. Nevertheless, a small amount of PEG was retained in the PBS matrix, suggesting some degree of mixing. Solubilization was slightly dependent on fiber structure; specifically, the distribution of PEG in the core or shell of coaxial fibers led to higher or lower retention levels, respectively. Scaffolds could be effectively loaded with hydrophobic drugs having antibacterial and anticarcinogenic activities like triclosan and curcumin, respectively. Their release was highly dependent on their chemical structure and medium composition. Thus, low and high release rates were observed in phosphate buffer saline (SS) and SS/ethanol (30:70 v/v), respectively. Slight differences in the release of triclosan were found depending on fiber distribution and composition. Antibacterial activity and biocompatibility were evaluated for both loaded and unloaded scaffolds. PMID- 25686975 TI - Click modification of helical amylose by poly(l-lysine) dendrons for non-viral gene delivery. AB - Although amylose as a naturally-occurring helical polysaccharide has been widely used for biomedical applications, few studies have dealt with its chemical modification for non-viral gene delivery. In this work, the click modification of amylose by poly(l-lysine) dendrons was carried out and then characterized by Fourier transform infrared spectroscopy, wide-angle X-ray diffraction and elemental analyses. Such a modified polysaccharide exhibited excellent ability to condense plasmid pMSCV-GFP-PARK2 into compact and spherical nanoparticles. Moreover, it displayed much lower cytotoxicity when compared to branched polyethylenimine (bPEI, 25kDa), a commercially available gene vector. Similar to bPEI, it had a dose-dependent gene transfection activity in human embryonic kidney 293T cells, as observed by confocal laser scanning microscopy and flow cytometry. At each optimized N/P ratio, the percentage of transfected cells by this modified polysaccharide was found to be comparable to that by bPEI. Western blot and cell apoptosis analyses confirmed its effectiveness for the delivery of plasmid pMSCV-GFP-PARK2 to 293T cells. PMID- 25686976 TI - A zeolite modified carbon paste electrode as useful sensor for voltammetric determination of acetaminophen. AB - The voltammetric behavior of a carbon paste electrode modified with Co(II) exchanged zeolite A (Co(II)-A/ZMCPE) for determination of acetaminophen was studied. The proposed electrode showed a diffusion controlled reaction with the electron transfer rate constant (Ks) of 0.44s(-1) and charge transfer coefficient of 0.73 in the absence of acetaminophen. A linear voltammetric response was obtained in the range of 0.1 to 190MUmolL(-1) of acetaminophen [r(2)=0.9979, r=0.9989 (n=10)] with a detection limit of 0.04MUmolL(-1). The method was successfully applied to the analysis of acetaminophen in some drugs. PMID- 25686977 TI - Tunable release of clavam from clavam stabilized gold nanoparticles--design, characterization and antimicrobial study. AB - A facile one-step approach is developed to synthesize highly stable (up to 6months) gold nanoparticles (GNPs) using Clavam, pharmaceutical form of amoxicillin which contains a mixture of amoxicillin and potassium salt of clavulanic acid, at room temperature (25-30 degrees C). The clavam stabilized GNPs are characterized using various techniques including UV-Visible, FT-IR spectrophotometry and transmission electron microscopy (TEM). Tunable release of clavam from clavam stabilized GNPs is demonstrated using intracellular concentrations of glutathione (GSH). The process is monitored using an UV-Vis spectroscopy and the amount of clavam released in terms of amoxicillin concentration is quantitatively estimated using reverse phase high performance liquid chromatographic (RP-HPLC) technique. In vitro study reveals that the clavam released from GNPs' surface was found to show a significant enhancement in antibacterial activity against Escherichia coli and the cause of enhancement is addressed. PMID- 25686978 TI - Thermoforming techniques for manufacturing porous scaffolds for application in 3D cell cultivation. AB - Within the scientific community, there is an increasing demand to apply advanced cell cultivation substrates with increased physiological functionalities for studying spatially defined cellular interactions. Porous polymeric scaffolds are utilized for mimicking an organ-like structure or engineering complex tissues and have become a key element for three-dimensional (3D) cell cultivation in the meantime. As a consequence, efficient 3D scaffold fabrication methods play an important role in modern biotechnology. Here, we present a novel thermoforming procedure for manufacturing porous 3D scaffolds from permeable materials. We address the issue of precise thermoforming of porous polymer foils by using multilayer polymer thermoforming technology. This technology offers a new method for structuring porous polymer foils that are otherwise available for non-porous polymers only. We successfully manufactured 3D scaffolds from solvent casted and phase separated polylactic acid (PLA) foils and investigated their biocompatibility and basic cellular performance. The HepG2 cell culture in PLA scaffold has shown enhanced albumin secretion rate in comparison to a previously reported polycarbonate based scaffold with similar geometry. PMID- 25686979 TI - Investigation on the microstructure, mechanical property and corrosion behavior of the selective laser melted CoCrW alloy for dental application. AB - In this study, an experimental investigation on fabricating Ni-free CoCrW alloys by selective laser melting (SLM) for dental application was conducted in terms of microstructure, hardness, mechanical property, electrochemical behavior, and metal release; and line and island scanning strategy were applied to determine whether these strategies are able to obtain expected CoCrW parts. The XRD revealed that the gamma-phase and epsilon-phase coexisted in the as-SLM CoCrW alloys; The OM and SEM images showed that the microstructure of CoCrW alloys appeared square-like pattern with the fine cellular dendrites at the borders; tensile test suggested that the difference of mechanical properties of line- and island-formed specimens was very small; whilst the outcomes from the electrochemical and metal release tests indicated that the island-formed alloys showed slightly better corrosion resistance than line-formed ones in PBS and Hanks solutions. Considering that the mechanical properties and corrosion resistance of line-formed and island-formed specimens meet the standards of ISO 22674:2006 and EN ISO 10271, CoCrW dental alloys can be successfully fabricated by line and island scanning strategies in the SLM process. PMID- 25686980 TI - Surface controlled calcium phosphate formation on three-dimensional bacterial cellulose-based nanofibers. AB - Studies on the early calcium phosphate (Ca-P) formation on nanosized substrates may allow us to understand the biomineralization mechanisms at the molecular level. In this work, in situ formation of Ca-P minerals on bacterial cellulose (BC)-based nanofibers was investigated, for the first time, using the X-ray absorption near-edge structure (XANES) spectroscopy. In addition, the influence of the surface coating of nanofibers on the formation of Ca-P minerals was determined. Combined with XRD analysis, XANES results revealed that the nascent precursor was ACP (amorphous calcium phosphate) which was converted to TCP (beta tricalcium phosphate), then OCP (octacalcium phosphate), and finally to HAP (hydroxyapatite) when phosphorylated BC nanofibers were the templates. However, the formation of nascent precursor and its transformation process varied depending on the nature of the coating material on nanofibrous templates. These results provide new insights into basic mechanisms of mineralization and can lead to the development of novel bioinspired nanostructured materials. PMID- 25686981 TI - Silver release and antimicrobial properties of PMMA films doped with silver ions, nano-particles and complexes. AB - Materials prepared on the base of bioactive silver compounds have become more and more popular due to low microbial resistance to silver. In the present work, the efficiency of polymethylmethacrylate (PMMA) thin films doped with silver ions, nanoparticles and silver-imidazole polymer complex was studied by a combination of AAS, XPS and AFM techniques. The biological activities of the proposed materials were discussed in view of the rate of silver releasing from the polymer matrix. Concentrations of Ag active form were estimated by its ability to interact with l-cysteine using electronic circular dichroism spectroscopy. Rates of the released silver were compared with the biological activity in dependence on the form of embedded silver. Antimicrobial properties of doped polymer films were studied using two bacterial strains: Staphylococcus epidermidis and Escherichia coli. It was found that PMMA films doped with Ag(+) had greater activity than those doped with nanoparticles and silver-imidazole polymeric complexes. However, the antimicrobial efficiency of Ag(+) doped films was only short-term. Contrary, the antimicrobial activity of silver-imidazole/PMMA films increased in time of sample soaking. PMID- 25686982 TI - Development and evaluation of elastomeric hollow fiber membranes as small diameter vascular graft substitutes. AB - Engineering of small diameter (<6mm) vascular grafts (SDVGs) for clinical use remains a significant challenge. Here, elastomeric polyester urethane (PEU)-based hollow fiber membranes (HFMs) are presented as an SDVG candidate to target the limitations of current technologies and improve tissue engineering designs. HFMs are fabricated by a simple phase inversion method. HFM dimensions are tailored through adjustments to fabrication parameters. The walls of HFMs are highly porous. The HFMs are very elastic, with moduli ranging from 1-4MPa, strengths from 1-5MPa, and max strains from 300-500%. Permeability of the HFMs varies from 0.5-3.5*10(-6)cm/s, while burst pressure varies from 25 to 35psi. The suture retention forces of HFMs are in the range of 0.8 to 1.2N. These properties match those of blood vessels. A slow degradation profile is observed for all HFMs, with 71 to 78% of the original mass remaining after 8weeks, providing a suitable profile for potential cellular incorporation and tissue replacement. Both human endothelial cells and human mesenchymal stem cells proliferate well in the presence of HFMs up to 7days. These results demonstrate a promising customizable PEU HFMs for small diameter vascular repair and tissue engineering applications. PMID- 25686983 TI - Influence of barium substitution on bioactivity, thermal and physico-mechanical properties of bioactive glass. AB - Barium with low concentration in the glasses acts as a muscle stimulant and is found in human teeth. We have made a primary study by substituting barium in the bioactive glass. The chemical composition containing (46.1-X) SiO2--24.3 Na2O 26.9 CaO-2.6 P2O5, where X=0, 0.4, 0.8, 1.2 and 1.6mol% of BaO was chosen and melted in an electric furnace at 1400+/-5 degrees C. The glasses were characterized to determine their use in biomedical applications. The nucleation and crystallization regimes were determined by DTA and the controlled crystallization was carried out by suitable heat treatment. The crystalline phase formed was identified by using XRD technique. Bioactivity of these glasses was assessed by immersion in simulated body fluid (SBF) for various time periods. The formation of hydroxy carbonate apatite (HCA) layer was identified by FTIR spectrometry, scanning electron microscope (SEM) and XRD which showed the presence of HCA as the main phase in all tested bioactive glass samples. Flexural strength and densities of bioactive glasses have been measured and found to increase with increasing the barium content. The human blood compatibility of the samples was evaluated and found to be pertinent. PMID- 25686984 TI - Cytotoxicity evaluation of biodegradable Zn-3Mg alloy toward normal human osteoblast cells. AB - The recent proposal of using Zn-based alloys for biodegradable implants was not supported with sufficient toxicity data. This work, for the first time, presents a thorough cytotoxicity evaluation of Zn-3Mg alloy for biodegradable bone implants. Normal human osteoblast cells were exposed to the alloy's extract and three main cell-material interaction parameters: cell health, functionality and inflammatory response, were evaluated. Results showed that at the concentration of 0.75mg/ml alloy extract, cell viability was reduced by ~50% through an induction of apoptosis at day 1; however, cells were able to recover at days 3 and 7. Cytoskeletal changes were observed but without any significant DNA damage. The downregulation of alkaline phosphatase protein levels did not significantly affect the mineralization process of the cells. Significant differences of cyclooxygenase-2 and prostaglandin E2 inflammatory biomarkers were noticed, but not interleukin 1-beta, indicating that the cells underwent a healing process after exposure to the alloy. Detailed analysis on the cell-material interaction is further discussed in this paper. PMID- 25686985 TI - Titania nanotubes from weak organic acid electrolyte: fabrication, characterization and oxide film properties. AB - In this study, TiO2 nanotubes were fabricated using anodic oxidation in fluoride containing weak organic acid for different durations (0.5h, 1h, 2h and 3h). Scanning electron microscope (SEM) micrographs reveal that the morphology of titanium oxide varies with anodization time. Raman spectroscopy and X-ray diffraction (XRD) results indicate that the as-formed oxide nanotubes were amorphous in nature, yet transform into crystalline phases (anatase and rutile) upon annealing at 600 degrees C. Wettability measurements show that both as formed and annealed nanotubes exhibited hydrophilic behavior. The electrochemical behavior was ascertained by DC polarization and AC electrochemical impedance spectroscopy (EIS) measurements in 0.9% NaCl solution. The results suggest that the annealed nanotubes showed higher impedance (10(5)-10(6)Omegacm(2)) and lower passive current density (10(-7)Acm(-2)) than the as-formed nanotubes. In addition, we investigated the influence of post heat treatment on the semiconducting properties of the oxides by capacitance measurements. In vitro bioactivity test in simulated body fluid (SBF) showed that precipitation of Ca/P is easier in crystallized nanotubes than the amorphous structure. Our study uses a simple strategy to prepare nano-structured titania films and hints the feasibility of tailoring the oxide properties by thermal treatment, producing surfaces with better bioactivity. PMID- 25686986 TI - A sensitive glucose biosensor based on Ag@C core-shell matrix. AB - Nano-Ag particles were coated with colloidal carbon (Ag@C) to improve its biocompatibility and chemical stability for the preparation of biosensor. The core-shell structure was evidenced by transmission electron microscope (TEM) and the Fourier transfer infrared (FTIR) spectra revealed that the carbon shell is rich of function groups such as -OH and -COOH. The as-prepared Ag@C core-shell structure can offer favorable microenvironment for immobilizing glucose oxidase and the direct electrochemistry process of glucose oxidase (GOD) at Ag@C modified glassy carbon electrode (GCE) was realized. The modified electrode exhibited good response to glucose. Under optimum experimental conditions the biosensor linearly responded to glucose concentration in the range of 0.05-2.5mM, with a detection limit of 0.02mM (S/N=3). The apparent Michaelis-Menten constant (KM(app)) of the biosensor is calculated to be 1.7mM, suggesting high enzymatic activity and affinity toward glucose. In addition, the GOD-Ag@C/Nafion/GCE shows good reproducibility and long-term stability. These results suggested that core-shell structured Ag@C is an ideal matrix for the immobilization of the redox enzymes and further the construction of the sensitive enzyme biosensor. PMID- 25686987 TI - Probing the role of scaffold dimensionality and media composition on matrix production and phenotype of fibroblasts. AB - Porous sponges, hydrogels, and micro/nanofibrous matrix are most commonly used three dimensional (3D) biomaterials in tissue engineering; however, reciprocal interaction between internal dimensionality of biomaterials and fibroblasts remains largely unexplored. Such studies would have potential to generate valuable insights about wound healing, tissue morphogenesis and homeostasis. To the best of our knowledge this is the first study to evaluate functionality of porous collagen matrix and collagen gels for in vitro culture of fibroblasts while investigating the role of culture media composition in modulating morphology, phenotype, extracellular matrix (ECM)-related gene expression and protein synthesis by fibroblasts. Encapsulation of fibroblasts in collagen gel was found to be more effective for ECM production compared to scaffold-based culture, as evidenced by enhanced collagen type I, elastin, lysyl oxidase, aggrecan gene expression. High glucose media induced spindle like morphology of typical in vivo fibroblasts and enhanced collagen production compared to other media. This variation in biosynthesis in different glucose concentrations was possibly due to endogenous activation of TGF-beta or by an increase in ATP consuming anabolic pathways in high glucose concentration. PMID- 25686988 TI - Microfabrication of gelatin-polycaprolactone composites for customized drug delivery. AB - Dynamic properties of water molecules present in the vicinity of protein are sensitive to its local conformational motions. Water mobility at the protein surface/interfaces is affected by its polar and charged groups, which are capable of anchoring water molecules through H-bonds. Differential scanning calorimetry, ATR-FTIR spectroscopy and circular dichroic analysis have been employed to substantiate the changes in hydration of gelatin, interacting with polycaprolactone. Enthalpy of denaturation and decrease in melting temperature indicate alteration in water-bridges around gelatin. In vitro drug release studies substantiate the influence of hydration on its release kinetics. These studies would aid in exploration of potential drug carrier. PMID- 25686989 TI - Anti-biofilm and cytotoxicity activity of impregnated dressings with silver nanoparticles. AB - Infections arising from bacterial adhesion and colonization on chronic wounds are a significant healthcare problem. Silver nanoparticles (AgNPs) impregnated in dressing have attracted a great deal of attention as a potential solution. The goal of the present study was to evaluate the anti-biofilm activities of AgNPs impregnated in commercial dressings against Pseudomonas aeruginosa, bacteria isolated of chronic wounds from a hospital patient. The antimicrobial activity of AgNPs was tested within biofilms generated under slow fluid shear conditions using a standard bioreactor. A 2-log reduction in the number of colony-forming units of P. aeruginosa was recorded in the reactor on exposure to dressing impregnated with 250ppm of AgNPs, diameter 9.3+/-1.1nm, and also showed compatibility to mammalian cells (human fibroblasts). Our study suggests that the use of dressings with AgNPs may either prevent or reduce microbial growth in the wound environment, and reducing wound bioburden may improve wound-healing outcomes. PMID- 25686990 TI - Mechanical and thermal property characterization of poly-l-lactide (PLLA) scaffold developed using pressure-controllable green foaming technology. AB - Poly-l-lactide (PLLA) is one of the most promising biological materials used for tissue engineering scaffolds (TES) because of their excellent biodegradability and tenability. Here, microcellular PLLA foams were fabricated by pressure controllable green foaming technology. Scanning electron microscopy (SEM), dynamic mechanical analysis (DMA), differential scanning calorimetry (DSC), wide angle X-ray diffraction measurement (WAXRD), thermogravimetric (TG) analysis, reflection-Fourier transform infrared (FTIR) analysis, enzymatic degradation study and MTT assay were used to analyze the scaffolds' morphologies, structures and crystallinities, mechanical and biodegradation properties, as well as their cytotoxicity. The results showed that PLLA foams with pore sizes from 8 to 103MUm diameters were produced when the saturation pressure decreased from 7.0 to 4.0MPa. Through a combination of StepScan DSC (SSDSC) and WAXRD approaches, it was observed in PLLA foams that the crystallinity, highly-oriented metastable state and rigid amorphous phase increased with the increasing foaming pressure. It was also found that both the glass transition temperature and apparent enthalpy of PLLA significantly increased after the foaming process, which suggested that the changes of microcellular structure could provide PLLA scaffolds better thermal stability and elasticity. Moreover, MTT assessments suggested that the smaller pore size should benefit cell attachment and growth in the scaffold. The results of current work will give us better understanding of the mechanisms involved in structure and property changes of PLLA at the molecular level, which enables more possibilities for the design of PLLA scaffold to satisfy various requirements in biomedical and green chemical applications. PMID- 25686991 TI - High porous titanium scaffolds showed higher compatibility than lower porous beta tricalcium phosphate scaffolds for regulating human osteoblast and osteoclast differentiation. AB - We compared osteoblast and osteoclast differentiation when using beta-tricalcium phosphate (betaTCP) and titanium scaffolds by investigating human mesenchymal stem cells (hMSCs) and osteoclast progenitor cell activities. hMSCs were cultured for 7, 14, and 21days on titanium scaffolds with 60%, 73%, and 87% porosity and on betaTCP scaffolds with 60% and 75% porosity. Human osteoclast progenitor cells were cultured with osteoblast for 14 and 21days on 87% titanium and 75% betaTCP scaffolds. Viable cell numbers with 60% and 73% titanium were higher than with 87% titanium and betaTCP scaffolds (P<0.05). An 87% titanium scaffold resulted in the highest osteocalcin production with calcification on day 14 (P<0.01) in titanium scaffolds. All titanium scaffolds resulted in higher osteocalcin production on days 7 and 14 compared to betaTCP scaffolds (P<0.01). Osteoblasts cultured on 87% titanium scaffolds suppressed osteoclast differentiation on day 7 but enhanced osteoclast differentiation on day 14 compared to 75% betaTCP scaffolds (P<0.01). These findings concluded that high porosity titanium scaffolds could enhance progression of hMSC/osteoblast differentiation and regulated osteoclast differentiation cooperating with osteoblast differentiation for calcification as compared with lower porous betaTCP. PMID- 25686992 TI - Fabrication and characterization of poly-(epsilon)-caprolactone and bioactive glass composites for tissue engineering applications. AB - Much work has focused on developing synthetic materials that have tailored degradation profiles and physical properties that may prove useful in developing biomaterials for tissue engineering applications. In the present study, three different composite sheets consisting of biodegradable poly-epsilon-caprolactone (PCL) and varying types of bioactive glass were investigated. The three composites were composed of 50wt.% PCL and (1) 50wt.% 13-93 B3 borate glass particles, (2) 50wt.% 45S5 silicate glass particles, or (3) a blend of 25wt.% 13 93 B3 and 25wt.% 45S5 glass particles. Degradation profiles determined for each composite showed the composite that contained only 13-93 B3 borate glass had a higher degradation rate compared to the composite containing only 45S5 silicate glass. Uniaxial tensile tests were performed on the composites to determine the effect of adding glass to the polymer on mechanical properties. The peak stress of all of the composites was lower than that of PCL alone, but 100% PCL had a higher stiffness when pre-reacted in cell media for 6weeks, whereas composite sheets did not. Finally, to determine whether the composite sheets would maintain neuronal growth, dorsal root ganglia isolated from embryonic chicks were cultured on composite sheets, and neurite outgrowth was measured. The bioactive glass particles added to the composites showed no negative effects on neurite extension, and neurite extension increased on PCL:45S5 PCL:13-93 B3 when pre reacted in media for 24h. This work shows that composite sheets of PCL and bioactive glass particles provide a flexible biomaterial for neural tissue engineering applications. PMID- 25686993 TI - A bisphenol A sensor based on novel self-assembly of zinc phthalocyanine tetrasulfonic acid-functionalized graphene nanocomposites. AB - In this work, a novel zinc phthalocyanine tetrasulfonic acid (ZnTsPc) functionalized graphene nanocomposites (f-GN) was synthesized by a simple and efficient electrostatic self-assembly method, where the positive charged GN decorated by (3-aminopropyl) triethoxysilane (APTES) was self-assemblied with ZnTsPc, a two dimensional (2-D) molecules. It not only enhanced its stability for the hybrid structure, but also avoided the reaggregation of ZnTsPc or f-GN themselves. Based on layered ZnTsPc/f-GN nanocomposites modified glassy carbon electrode, a rapid and sensitive sensor was developed for the determination of bisphenol A (BPA). Under the optimal conditions, the oxidation peak current increased linearly with the concentration of BPA in the range of 5.0*10(-8) to 4.0*10(-6)M with correlation coefficient 0.998 and limits of detection 2.0*10( 8)M. Due to high absorption nature for BPA and electron deficiency on ZnTsPc/f GN, it presented the unique electron pathway arising from pi-pi stackable interaction during redox process for detecting BPA. The sensor exhibited remarkable long-term stability, good anti-interference and excellent electrocatalytic activity towards BPA detection. PMID- 25686994 TI - Preparation of gelatin based porous biocomposite for bone tissue engineering and evaluation of gamma irradiation effect on its properties. AB - Biodegradable porous hybrid polymer composites were prepared by using gelatin as base polymer matrix, beta-tricalcium phosphate (TCP) and calcium sulfate (CS) as cementing materials, chitosan as an antimicrobial agent, and glutaraldehyde and polyethylene glycol (PEG) as crosslinkers at different mass ratios. Thereafter, the composites were subjected to gamma-radiation sterilization. The structure and properties of these composite scaffolds were characterized by Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), mechanical properties testing (compressive, bending, tensile and impact), thermogravimetry/differential thermal analysis (TG/DTA), and physical stability test in simulated body fluid (SBF). We found that TCP rich composites showed enhanced mechanical properties among all the crosslinked composites. gamma Radiation sterilization triggered further cross linking in polymer matrix resulting a decrease in pore size of the composites and an increase in pore wall thickness with improved mechanical and thermal properties. The chemically crosslinked composite with 40% TCP followed by gamma-radiation sterilization showed the smallest pore size distribution with a mean pore diameter of 159.22MUm, which falls in the range of 100-350MUm - known to be suitable for osteoconduction. Considering its improved mechanical and thermal properties along with osteoconduction ability without cytotoxicity, we propose this biocomposite as a viable candidate for bone tissue engineering. PMID- 25686995 TI - Characterization of nickel-doped biphasic calcium phosphate/graphene nanoplatelet composites for biomedical application. AB - The effect of the addition of an ionic dopant to calcium phosphates for biomedical applications requires specific research due to the essential roles played in such processes. In the present study, the mechanical and biological properties of Ni-doped hydroxyapatite (HA) and Ni-doped HA mixed with graphene nanoplatelets (GNPs) were evaluated. Ni (3wt.% and 6wt.%)-doped HA was synthesized using a continuous precipitation method and calcined at 900 degrees C for 1h. The GNP (0.5-2wt.%)-reinforced 6% Ni-doped HA (Ni6) composite was prepared using rotary ball milling for 15h. The sintering process was performed using hot isostatic pressing at processing conditions of 1150 degrees C and 160MPa with a 1-h holding time. The results indicated that the phase compositions and structural features of the products were noticeably affected by the Ni and GNPs. The mechanical properties of Ni6 and 1.5Ni6 were increased by 55% and 75% in hardness, 59% and 163% in fracture toughness and 120% and 85% in elastic modulus compared with monolithic HA, respectively. The in-vitro biological behavior was investigated using h-FOB osteoblast cells in 1, 3 and 5days of culture. Based on the osteoblast results, the cytotoxicity of the products was indeed affected by the Ni doping. In addition, the effect of GNPs on the growth and proliferation of osteoblast cells was investigated in Ni6 composites containing different ratios of GNPs, where 1.5wt.% was the optimum value. PMID- 25686996 TI - The effect of NaOH concentration on the steam-hydrothermally treated bioactive microarc oxidation coatings containing Ca, P, Si and Na on pure Ti surface. AB - The microarc oxidation (MAO) coating covered pure Ti plates are steam hydrothermally treated in autoclaves containing NaOH solutions with different concentrations of 0, 0.001, 0.01, 0.1 and 1mol.L(-1). Due to the composition of Ti, O, Ca, P, Si and Na elements in the MAO coating, anatase and hydroxyapatite (HA) crystals are generated from the previously amorphous MAO coating after the steam-hydrothermal treatment. Meanwhile, it is noticed that the amount of HA crystals increases but showing a decline trend in aspect ratio in morphologies with the increasing of NaOH concentration. Interestingly, the steam hydrothermally treated MAO coatings exhibit better bonding strength with Ti substrate (up to 43.8+/-1.1MPa) than that of the untreated one (20.1+/-3.1MPa). In addition, benefiting from the corrosive attack of the dissolved NaOH in water vapor on the MAO coating, Ti-OH is also formed on the steam-hydrothermally treated MAO coating surface, which can trigger apatite nucleation. Thus, the steam-hydrothermally treated MAO coatings exhibit good apatite-inducing ability. PMID- 25686997 TI - A novel simple one-step air jet spinning approach for deposition of poly(vinyl acetate)/hydroxyapatite composite nanofibers on Ti implants. AB - A biocompatible coating consists of a poly(vinyl acetate)/hydroxyapatite (PVAc/HA) composite nanofiber mat was applied to NaOH-treated titanium metal by means of a novel, facile and efficient air jet spinning (AJS) approach. Results showed that HA nanoparticles (NPs) strongly embedded onto the AJS single fiber surface resulting in a strong chemical interfacial bonding between the two phases due to the difference in kinetic energies. It was proven that AJS membrane coatings can provide significant improvement in the corrosion resistance of titanium substrate. Interestingly, the biocompatibility using MC3T3-E1 osteoblast to the PVAc/HA fiber composite layer coated on Ti was significantly higher than pure titanium-substrates. PMID- 25686998 TI - A potent inhibition of oxidative stress induced gene expression in neural cells by sustained ferulic acid release from chitosan based hydrogel. AB - Traumatic brain injury (TBI) is an extremely cataclysmic neurological disorder and the inhibition of oxidative stress following TBI could effectively protect the brain from further impairments. An injectable thermosensitive chitosan/gelatin/beta-Glycerol phosphate (C/G/GP) hydrogel for the controlled release of the phenolic antioxidant ferulic acid (FA) to inhibit the neurological oxidative stress was demonstrated. The C/G/GP hydrogel ensures an excellent clinical expediency with a gelation temperature of 32.6 degrees C and gelation time of 75.58s. In-vitro cytotoxicity assays of C/G/GP hydrogel and FA have revealed an excellent biocompatibility with the Neuro-2a cells. 500MUM of FA was considered to be an effective concentration to reduce the oxidative stress in Neuro-2a cells. TUNEL staining images evidenced that the H2O2 induced DNA fragmentation was comprehensively controlled after FA treatment. The mRNA gene expression profiles markedly authenticate the neuroprotectivity of FA by down regulating ROS, inflammatory and apoptosis related markers. The outcomes of this study suggest that, C/G/GP hydrogel carrying ferulic acid could effectively protect further secondary traumatic brain injury associated impairments. PMID- 25686999 TI - In vitro evaluation of alginate/halloysite nanotube composite scaffolds for tissue engineering. AB - In this study, a series of alginate/halloysite nanotube (HNTs) composite scaffolds were prepared by solution-mixing and freeze-drying method. HNTs are incorporated into alginate to improve both the mechanical and cell-attachment properties of the scaffolds. The interfacial interactions between alginate and HNTs were confirmed by the atomic force microscope (AFM), transmission electron microscope (TEM) and FTIR spectroscopy. The mechanical, morphological, and physico-chemical properties of the composite scaffolds were investigated. The composite scaffolds exhibit significant enhancement in compressive strength and compressive modulus compared with pure alginate scaffold both in dry and wet states. A well-interconnected porous structure with size in the range of 100 200MUm and over 96% porosity is found in the composite scaffolds. X-ray diffraction (XRD) result shows that HNTs are uniformly dispersed and partly oriented in the composite scaffolds. The incorporation of HNTs leads to increase in the scaffold density and decrease in the water swelling ratio of alginate. HNTs improve the stability of alginate scaffolds against enzymatic degradation in PBS solution. Thermogravimetrica analysis (TGA) shows that HNTs can improve the thermal stability of the alginate. The mouse fibroblast cells display better attachment to the alginate/HNT composite than those to the pure alginate, suggesting the good cytocompatibility of the composite scaffolds. Alginate/HNT composite scaffolds exhibit great potential for applications in tissue engineering. PMID- 25687000 TI - Bone-like hydroxyapatite precipitated from 10*SBF-like solution by microwave irradiation. AB - Microwave-assisted methods have been frequently used in many processes owing to their numerous advantages such as performing fast, efficient and homogenous processes and reducing side reactions. In view of these benefits, in this study it was purposed to produce bone-like hydroxyapatite (HA) by inducing biomimetic process with microwave-irradiation. This is why, concentrated body fluid (SBF) i.e. 10*SBF-like solution was used and it was precipitated in different microwave powers i.e. 90W, 360W, 600W, and 1200W and in different exposure times. For comparison, precipitation process was also carried out at room temperature for 6h and at 80 degrees C for 1h. The obtained HA structures were characterized by appropriate instrumental techniques. As a result, microwave-induced precipitation at 600W for 9 times 30s was determined as the optimum condition for the production of HA which has similar properties to the cortical bone. At this condition, B-type HA with 9.22% (wt.) carbonate content, 1.61 Ca/P molar ratio and amorphous structure was obtained easily, rapidly and efficiently. So, this is the first time microwave technology has been used to precipitate HA from SBF solution. PMID- 25687001 TI - Mechanical response of collagen molecule under hydrostatic compression. AB - Proteins like collagen are the basic building blocks of various body tissues (soft and hard). Collagen molecules find their presence in the skeletal system of the body where they bear mechanical loads from different directions, either individually or along with hydroxy-apatite crystals. Therefore, it is very important to understand the mechanical behavior of the collagen molecule which is subjected to multi-axial state of loading. The estimation of strains of collagen molecule along different directions resulting from the changes in hydrostatic pressure magnitude, can provide us new insights into its mechanical behavior. In the present work, full atomistic simulations have been used to study global (volumetric) as well as local (along different directions) mechanical properties of the hydrated collagen molecule which is subjected to different hydrostatic pressure magnitudes. To estimate the local mechanical properties, the strains of collagen molecule along its longitudinal and transverse directions have been acquired at different hydrostatic pressure magnitudes. In spite of non homogeneous distribution of atoms within the collagen molecule, the calculated values of local mechanical properties have been found to carry the same order of magnitude along the longitudinal and transverse directions. It has been demonstrated that the values of global mechanical properties like compressibility, bulk modulus, etc. as well as local mechanical properties like linear compressibility, linear elastic modulus, etc. are functions of magnitudes of applied hydrostatic pressures. The mechanical characteristics of collagen molecule based on the atomistic model have also been compared with that of the continuum model in the present work. The comparison showed up orthotropic material behavior for the collagen molecule. The information on collagen molecule provided in the present study can be very helpful in designing the future bio materials. PMID- 25687002 TI - Compressive evaluation of homogeneous and graded epoxy-glass particulate composites. AB - The propagation of stress waves in epoxy-glass particulate composites and graded materials was studied experimentally. Materials tested in this study consisted of an epoxy matrix with various concentrations of spherical glass particles having a mean diameter of 42MUm. Plate impact experiments were performed using a gas gun. Embedded within the specimens were manganin stress gauges used to record propagating compressive longitudinal stress waves through the material. High strain rate experiments using a Split Hopkinson Pressure Bar (SHPB) apparatus were also performed to evaluate the dynamic strength of the specimens, while quasi-static compression tests were undertaken to characterize their quasi-static behavior. Ultrasonic wave speed measurements were carried-out in order to obtain additional material properties and characterize the gradation in functionally graded materials (FGM). It was found that low volume fractions of particles are detrimental to the performance of the material under impact loading, while concentrations in the range of about 30 to 45% by volume exhibit characteristics of higher degrees of scattering. This suggests that materials in this latter range would be more effective in the thwarting of destructive shock waves than the homogeneous matrix material. Impact testing of FGM specimens suggests that impact loading on the stiff (high volume fraction) face results in much higher levels of scattering. Therefore, such materials would be effective for use in light weight armor or as shielding materials due to their effective attenuation of mechanical impulses. PMID- 25687003 TI - Titania nanotube arrays as interfaces for neural prostheses. AB - Neural prostheses have become ever more acceptable treatments for many different types of neurological damage and disease. Here we investigate the use of two different morphologies of titania nanotube arrays as interfaces to advance the longevity and effectiveness of these prostheses. The nanotube arrays were characterized for their nanotopography, crystallinity, conductivity, wettability, surface mechanical properties and adsorption of key proteins: fibrinogen, albumin and laminin. The loosely packed nanotube arrays fabricated using a diethylene glycol based electrolyte, contained a higher presence of the anatase crystal phase and were subsequently more conductive. These arrays yielded surfaces with higher wettability and lower modulus than the densely packed nanotube arrays fabricated using water based electrolyte. Further the adhesion, proliferation and differentiation of the C17.2 neural stem cell line was investigated on the nanotube arrays. The proliferation ratio of the cells as well as the level of neuronal differentiation was seen to increase on the loosely packed arrays. The results indicate that loosely packed nanotube arrays similar to the ones produced here with a DEG based electrolyte, may provide a favorable template for growth and maintenance of C17.2 neural stem cell line. PMID- 25687004 TI - Calcium phosphate coated Keratin-PCL scaffolds for potential bone tissue regeneration. AB - The incorporation of hydroxyapatite (HA) nanoparticles within or on the surface of electrospun polymeric scaffolds is a popular approach for bone tissue engineering. However, the fabrication of osteoconductive composite scaffolds via benign processing conditions still remains a major challenge to date. In this work, a new method was developed to achieve a uniform coating of calcium phosphate (CaP) onto electrospun keratin-polycaprolactone composites (Keratin PCL). Keratin within PCL was crosslinked to decrease its solubility, before coating of CaP. A homogeneous coating was achieved within a short time frame (~10min) by immersing the scaffolds into Ca(2+) and (PO4)(3-) solutions separately. Results showed that the incorporation of keratin into PCL scaffolds not only provided nucleation sites for Ca(2+) adsorption and subsequent homogeneous CaP surface deposition, but also facilitated cell-matrix interactions. An improvement in the mechanical strength of the resultant composite scaffold, as compared to other conventional coating methods, was also observed. This approach of developing a biocompatible bone tissue engineering scaffold would be adopted for further in vitro osteogenic differentiation studies in the future. PMID- 25687005 TI - Investigation into the electromechanical properties of dielectric elastomers subjected to pre-stressing. AB - Dielectric elastomers (DEs) are being exploited for biological applications such as artificial blood pumps, biomimetic grippers and biomimetic robots. Generally, polyacrylate and silicone rubber (SR) are the most widely used materials for fabricating DEs in terms of mixing with other polymers or compounding them with highly dielectric particles. Furthermore, pre-stretch offers an effective approach to increasing actuated strain and dielectric strength and eliminating 'pull-in' instability. In the work described here, a comparison in electromechanical properties was made between SR/10% barium titanate (BaTiO3) and commercial VHB 4910. Trends in these dielectric parameters are shown graphically for variation in pre-stretch ratio (lambdapre). It was found that permittivity of SR/10% BaTiO3 was independent of frequency, whereas permittivity was frequency independent due to the polarization of polymer chains. The maximum deformation and the coupling efficiency for SR/10% BaTiO3 can be achieved at a pre-stretch ratio between 1.6 and 1.9. For VHB 4910, they can be obtained in the pre-stretch ratio range from 2.6 to 3.0. A maximum energy density of 0.05MJ/m(3) was achieved by SR/10% BaTiO3 (lambdapre=1.6) and VHB 4910 (lambdapre=3.4). The findings provide an insight into critical pre-stretch ratios required for a range of applications of DEs based on silicone and the commercially available polyacrylate VHB 4910. PMID- 25687006 TI - Surface characterization and cytotoxicity response of biodegradable magnesium alloys. AB - Magnesium alloys have raised an immense amount of interest to many researchers because of their evolution as a new kind of third generation materials. Due to their biocompatibility, density, and mechanical properties, magnesium alloys are frequently reported as prospective biodegradable implant materials. Moreover, magnesium alloys experience a natural phenomenon to biodegrade in aqueous solutions due to its corrosion activity, which is excellent for orthopedic and cardiovascular applications. However, a major concern with such alloys is fast and non-uniform corrosion degradation. Controlling the degradation rate in the physiological environment determines the success of biodegradable implants. In this investigation, three different grades of magnesium alloys: AZ31B, AZ91E and ZK60A were studied for their corrosion resistance and biocompatibility. Scanning electron microscopy, energy dispersive spectroscopy, atomic force microscopy and contact angle meter are used to study surface morphology, chemistry, roughness and wettability, respectively. Additionally, the cytotoxicity of the leached metal ions was evaluated by using a tetrazolium based bio-assay, MTS. PMID- 25687007 TI - Fabrication of an electrochemical sensor based on carbon nanotubes modified with gold nanoparticles for determination of valrubicin as a chemotherapy drug: valrubicin-DNA interaction. AB - In this study, an electrochemical sensor was fabricated based on gold nanoparticles/ ethylenediamine/ multi-wall carbon-nanotubes modified gold electrode (AuNPs/en/MWCNTs/AuE) for determination of valrubicin in biological samples. Valrubicin was effectively accumulated on the surface of AuNPs/en/MWCNTs/AuE and produced a pair of redox peaks at around 0.662 and 0.578V (vs. Ag/AgCl) in citrate buffer (pH4.0). The electrochemical parameters including pH, buffer, ionic strength, scan rate and size of AuNPs have been optimized. There was a good linear correlation between cathodic peak current and concentration of valrubicin in the range of 0.5 to 80.0MUmolL(-1) with the detection limit of 0.018MUmolL(-1) in citrate buffer (pH4.0) and 0.1molL(-1) KCl. Finally, the constructed sensor was successfully applied for determination of valrubicin in human urine and blood serum. In further studies, the different sequences of single stranded DNA probes have been immobilized on the surface of AuNPs decorated on MWCNTs to study the interaction of oligonucleotides with valrubicin. PMID- 25687008 TI - Biomimetic hybrid nanofibrous substrates for mesenchymal stem cells differentiation into osteogenic cells. AB - Mimicking native extracellular matrix with electrospun porous bio-composite nanofibrous scaffolds has huge potential in bone tissue regeneration. The aim of this study is to fabricate porous poly(l-lactic acid)-co-poly-(epsilon caprolactone)/silk fibroin/ascorbic acid/tetracycline hydrochloride (PLACL/SF/AA/TC) and nanohydroxyapatite (n-HA) was deposited by calcium-phosphate dipping method for bone tissue engineering (BTE). Fabricated nanofibrous scaffolds were characterized for fiber morphology, hydrophilicity, porosity, mechanical test and chemical properties by FT-IR and EDX analysis. The results showed that the fiber diameter and pore size of scaffolds observed around 228+/ 62-320+/-22nm and 1.5-6.9MUm respectively. Resulting nanofibrous scaffolds are highly porous (87-94%) with ultimate tensile strength observed in the range of 1.51-4.86MPa and also showed better hydrophilic properties after addition of AA, TC and n-HA. Human mesenchymal stem cells (MSCs) cultured on these bio-composite nanofibrous scaffolds and stimulated to osteogenic differentiation in the presence of AA/TC/n-HA for BTE. The cell proliferation and biomaterial interactions were studied using MTS assay, SEM and CMFDA dye exclusion methods. Osteogenic differentiation of MSCs was proven by using alkaline phosphatase activity, mineralization and double immunofluorescence staining of both CD90 and osteocalcin. The observed results suggested that the fabricated PLACL/SF/AA/TC/n HA biocomposite hybrid nanofibrous scaffolds have good potential for the differentiation of MSCs into osteogenesis for bone tissue engineering. PMID- 25687009 TI - Potentiometric biosensor for determination of urea in milk using immobilized Arthrobacter creatinolyticus urease. AB - The extracellular urease from Arthrobacter creatinolyticus was partially purified by ammonium sulfate precipitation and immobilized on PAN [poly(acrylonitrile methylmethacrylate-sodium vinylsulfonate)] membrane. The urease immobilized PAN membrane exhibited an activity of 97.92U/cm(2) under the optimum conditions of 1.0% enzyme concentration, 15% glutaraldehyde, 24h immobilization time and temperature of 4 degrees C. The changes in surface morphology of the membrane after immobilization were studied by SEM and ATR-FTIR analysis. Immobilized membrane was associated with potentiometric electrode for calibration of biosensor and the results showed a linear response for wide range of urea concentration from 1 to 100mM. The immobilized urease had good storage stability for a period of 70days at 4 degrees C and could be effectively reused for 13cycles. Urease immobilized membrane was also employed in analysis of urea spiked milk samples. PMID- 25687010 TI - Characterization of particle morphology of biochanin A molecularly imprinted polymers and their properties as a potential sorbent for solid-phase extraction. AB - Molecularly imprinted polymers (MIPs) with biochanin A as a template were obtained using a bulk polymerization with non-covalent imprinting approach. The polymers were prepared in acetonitrile as porogen, using ethylene glycol dimethacrylate (EDMA) as cross-linking agent. The synthesis, with an application of 1',1'-azobis(cyclohexanecarbonitrile) (ACHN) as an initiator, has been performed thermally. During the synthesis process the effect of different functional monomers such as methacrylic acid (MAA), acrylamide (AA) and 4 vinylpyridine (4-VP) was investigated. The application of nitrogen sorption porosimetry, scanning electron microscopy (SEM), and Fourier transform infrared spectroscopy (FTIR) permitted the characterization and evaluation of synthesized polymers. The adsorption capacity of obtained MIPs was checked by using the binding testing. All synthesized polymers were evaluated as solid-phase extraction (SPE) sorbents for isolation and preconcentration of biochanin A and its analogues, daidzein and genistein. The MIPs exhibited higher affinity for biochanin A over competitive compounds. PMID- 25687011 TI - Bioprocess intensification of antibiotic production by Streptomyces coelicolor A3(2) in micro-porous culture. AB - A novel functionalized micro-porous matrix was developed with well-controlled physicochemical proprieties such as pore size and surface chemistry. The matrix was used as a solid support in the growth of "Streptomyces coelicolor" A3(2) to enhance the production of antibiotics. The results shown support a higher production of prodigiosin and actinorhodin with overall production increase of 2 5 and 6-17, respectively, compared to conventional submerged liquid culture, offering a potential improvement in volumetric productivity. Scanning Electron Microscopy was used to evaluate pore size as well as bacterial adhesion, penetration, proliferation and migration within the micro-porous matrix. PMID- 25687012 TI - Mimicking the quasi-random assembly of protein fibers in the dermis by freeze drying method. AB - Freeze-drying is extensively used for fabrication of porous materials in tissue engineering and biomedical applications, due to its versatility and use of no toxic solvent. However, it has some significant drawbacks. Conventional freeze drying technique leads to the production of heterogeneous porous structures with side orientated columnar pores. As the top and bottom surfaces of the sample are not in contact with similar environments, different rates of heat transfer in the surfaces and the temperature gradient across the sample establish the preferential direction of heat transfer. To achieve a scaffold with a desirable microstructure for skin tissue engineering, freeze-drying method was modified by controlling the rate of cooling and regulation of heat transfer across the sample during the freezing step. It could create a homogeneous porous structure with more equiaxed non-oriented pores. Freezing the polymeric solution in the aluminum mold enhanced pore interconnectivity relative to the polystyrene mold. Recrystallization process was discussed how to influence the mean pore size of the scaffold when the final freezing temperature varied. Higher final freezing temperature can easily provide the energy required for the recrystallization process, which lead to enlarged ice crystals and resulting pores. PMID- 25687013 TI - Converted marine coral hydroxyapatite implants with growth factors: in vivo bone regeneration. AB - Herein we report rabbit model in vivo bone regeneration of hydrothermally converted coralline hydroxyapatite (HCCHAp) scaffolds without (group I) and with growth factors namely insulin like growth factor-1 (IGF-1) (group II) and bone morphogenetic protein-2 (BMP-2) (group III). All HCCHAp scaffolds have been characterized for phase purity and morphology before implantation. Calcined marine coral was hydrothermally converted using a mineralizer/catalyst to phase pure HAp retaining original pore structure and geometry. After sintering at 1250 degrees C, the HCCHAp found to have ~87% crystallinity, 70-75% porosity and 2+/ 0.5MPa compressive strength. In vitro growth factor release study at day 28 revealed 77 and 98% release for IGF-1 and BMP-2, respectively. The IGF-1 release was more sustained than BMP-2. In vivo bone healing of different groups was compared using chronological radiology, histological evaluations, scanning electron microscopy and fluorochrome labeling up to 90days of implantation. In vivo studies showed substantial reduction in radiolucent zone and decreased radiodensity of implants in group II followed by group III and group I. These observations clearly suggest in-growth of osseous tissue, initiation of bone healing and complete union between implants and natural bone in group II implants. A statistical score sheet based on histological observations showed an excellent osseous tissue formation in group II and group III scaffolds and moderate bone regeneration in group I scaffolds. PMID- 25687014 TI - Single step natural poly(tannic acid) particle preparation as multitalented biomaterial. AB - In this study, we report the preparation of poly(tannic acid) (p(TA)) particles by crosslinking with glycerol diglycidyl ether (GDE) and trimethylolpropane triglycidyl ether (TMPGDE). The p(TA) particles are negatively charged as obtained by the zeta potential measurements, -27mV. P(TA) particles are found to be an effective antioxidant material as 170mgL(-1) of p(TA) particle demonstrated the antioxidant equivalency of 82.5+/-7.2mgL(-1) of gallic acid (GA), used as standard in Folin-Ciocalteau (FC) method. Additionally, TA and p(TA) particles have a strong antimicrobial effect against Escherichia coli ATCC 8739, Staphylococcus aureus ATCC 6538, and Bacillus subtilis ATCC 6633. Furthermore, p(TA) particles were used as drug delivery materials by using model drugs such as TA itself, and GA in the release studies in PBS at pH7.4 at 37.5 degrees C, and found that p(TA) particles can release 80.8 and 87.4% of the loaded TA and GA, respectively. Interestingly, p(TA) maintained its fluorescent property upon crosslinking of TA units. It is further demonstrated that p(TA) particles are as effective as cisplatin (a cancer drug) against A549 cancerous cells that both showed about 36 and 34% cell viability, respectively whereas linear TA showed 66% cell viability at 37.5MUgmL(-1) concentration. Above this concentration p(TA) and cisplatin showed almost the same toxicity against A549 cancerous cells. Additionally, p(TA) particles are found to be much more biocompatible against L929 Fibroblast cells, about 84% cell viability in comparison to linear TA with about 53% at 75MUgmL(-1) concentration. PMID- 25687015 TI - 3-Dimensional cell-laden nano-hydroxyapatite/protein hydrogels for bone regeneration applications. AB - The ability to encapsulate cells in three-dimensional (3D) protein-based hydrogels is potentially of benefit for tissue engineering and regenerative medicine. However, as a result of their poor mechanical strength, protein-based hydrogels have traditionally been considered for soft tissue engineering only. Hence, in this study we tried to render these hydrogels suitable for hard tissue regeneration, simply by incorporation of bioactive nano-hydroxyapatite (HAp) into a photocrosslinkable gelatin hydrogel. Different cell types were also encapsulated in three dimensions in the resulting composites to prepare cell laden constructs. According to the results, HAp significantly improves the stiffness of gelatin hydrogels, while it maintains their structural integrity and swelling ratio. It was also found that while the bare hydrogel (control) was completely inert in terms of bioactivity, a homogeneous 3D mineralization occurs throughout the nanocomposites after incubation in simulated body fluid. Moreover, encapsulated cells readily elongated, proliferated, and formed a 3D interconnected network with neighboring cells in the nanocomposite, showing the suitability of the nano-HAp/protein hydrogels for cellular growth in 3D. Therefore, the hydrogel nanocomposites developed in this study may be promising candidates for preparing cell-laden tissue-like structures with enhanced stiffness and increased osteoconductivity to induce bone formation in vivo. PMID- 25687016 TI - Porous chitosan-supported metal tetra(4-carboxyphenyl)porphyrin as a practical model for the hydrophobic pocket/cavity of cytochrome P-450 enzyme. AB - The objective of this study was to investigate porous chitosan-supported metal tetra(4-carboxyphenyl)porphyrin [Me TCPP/p-CTS] as a practical model for the structure and function of the hydrophobic pocket cavity in cytochrome P-450 enzyme. Porous and non-porous chitosan-supported Me TCPPs [Me TCPP/p- and nonp CTS] were prepared by a similar procedure, characterized using various techniques, and then used as catalysts for the aerobic oxidation of cyclohexane. The Me TCPP/p-CTS, which contained many cavities, showed higher catalytic activity than the Me TCPP/nonp-CTS. The catalytic activities of Mn TCPP/p-CTS and Fe TCPP/p-CTS were 12.4% and 24.4% greater than those of Mn TCPP/nonp-CTS and Fe TCPP/nonp-CTS, respectively. These differences in catalytic activity were mainly influenced by the characteristics and numbers of cavities (or pores) contained in the supported catalysts. PMID- 25687017 TI - RETRACTED: Effects of high-energy electro-pulsing treatment on microstructure, mechanical properties and corrosion behavior of Ti-6Al-4V alloy. AB - This article has been retracted: please see Elsevier Policy on Article Withdrawal Withdrawal (https://www.elsevier.com/about/our-business/policies/article withdrawal).This article has been retracted at the request of This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy).This article has been retracted at the request of the Editor.Figure 5 duplicates figure 8 of the article that had already appeared in Materials Characterization 98 (2014) 147-161, http://dx.doi.org/10.1016/j.matchar.2014.10.026, figure 12 of the paper that had appeared in Applied Physics A 117 (2014) 2251-2264, http://dx.doi.org/10.1007/s00339-014-8655-1, as well as panels from figure 12 of the article that had appeared in the Journal of Alloys and Compounds 616 (2014) 173-183, http://dx.doi.org/10.1016/j.jallcom.2014.07.143.Figure 6 duplicates figure 9 of the article that had already appeared in Materials Characterization 98 (2014) 147-161, http://dx.doi.org/10.1016/j.matchar.2014.10.026 and figure 13 of the article that had appeared in the Journal of Alloys and Compounds 616 (2014) 173-183, http://dx.doi.org/10.1016/j.jallcom.2014.07.143.Figure 7 duplicates figure 10 of the article that had already appeared in Surface & Coatings Technology 258 (2014) 467-484, http://dx.doi.org/10.1016/j.surfcoat.2014.08.052.One of the conditions of submission of a paper for publication is that authors declare explicitly that their work is original and has not appeared in a publication elsewhere. Re-use of any data should be appropriately cited. As such this article represents an abuse of the scientific publishing system. The scientific community takes a very strong view on this matter and apologies are offered to readers of the journal that this was not detected during the submission process.Journal records indicate that confirmation of the submission and publication of the article was sent to the first author's email address, in addition to an email that used the corresponding author's name (guoyitangforwork@163.com).The corresponding author and the first author wish to mention that the co-author Zion T.H. Tse was not involved in the preparation and handling of this article. He was not informed about the publication and he did not grant the use of his name and affiliation in the publication.Prof. S. Petter Lyngstadaas, Dr. Hanna Tiainen and Dr. Sebastian Geissler from University of Oslo are acknowledged for the considerable effort put into collecting the evidence and reporting this case of multiple publication. PMID- 25687018 TI - Design and construction of new potentiometric sensors for determination of Al3+ ion based on (Z)-2-(2-methyl benzylidene)-1-(2,4-dinitrophenyl) hydrazine. AB - (Z)-2-(2-methyl benzylidene)-1-(2,4-dinitrophenyl) hydrazine (L) was used as an active component of PVC membrane electrode (PME), coated graphite electrode (CGE) and coated silver wire electrode (CWE) for sensing Al(3+) ion. The electrodes exhibited linear Nernstian responses to Al(3+) ion in the concentration range of 1.0*10(-6) to 1.0*10(-1)M (for PME, LOD=8.8*10(-7)M), 5.5*10(-7) to 2.0*10(-1)M (for CWE, LOD=3.3*10(-7)M) and 1.5*10(-7) to 1.0*10(-1)M (for CGE, LOD=9.2*10( 8)M). The best performances were observed with the membranes having the composition of L:PVC:NPOE:NaTPB in the ratio of 5:35:57:3 (w/w; mg). The electrodes have a response time of 6s and an applicable pH range of 3.5-9.1. The sensors have a lifetime of about 15weeks and exhibited excellent selectivity over a number of mono-, bi-, and tri-valent cations including alkali, alkaline earth metal, heavy and transition metal ions. Analytical utility of the proposed sensor has been further tested by using it as an indicator electrode in the potentiometric titration of Al(3+) with EDTA. The electrode was also successfully applied for the determination of Al(3+) ion in real and pharmaceutical samples. PMID- 25687019 TI - Medication knowledge to be improved in participants in community universities in Taiwan: Outcome of a nationwide community university program. AB - BACKGROUND/PURPOSE: To assess knowledge improvement by the participants in a pharmacist-facilitated national community education program over a 4-month semester and to identify the educational needs of adults related to medications. METHODS: This was a single-group, pre- and post-program comparative study. From February 2005 to February 2006, 1983 community residents participating in the education program implemented at 57 community universities nationwide were included. A questionnaire consisting of 50 true/false questions was administered before and after the program to assess the participants' medication knowledge. Paired t test was used to analyze the pre- and post-program differences and generalized linear mixed models were applied to examine the demographic variables that might influence the background knowledge and outcome after adjusting for school effects. RESULTS: A total of 848 participants (42.8%) completed the pre-to post questionnaire. Baseline medication knowledge was positively correlated with participants' education level and negatively correlated with age. Significant improvement (11.3%, p < 0.001) in medication knowledge was evident at the end of the program. The age and education level were significant determinants in the improvement of the pre-to-post program test score. The specific areas that required improvement most in the knowledge of the participants were: instructions on refill prescriptions, proper storage of medication, the health insurance system, drug use in special populations, and over-the-counter drugs. CONCLUSION: This national program improved participants' medication knowledge over a 4-month period. Patient counseling focusing more on the knowledge deficiency identified in this study during patient care is recommended. PMID- 25687020 TI - Enantioselective synthesis of planar-chiral benzosiloloferrocenes by Rh-catalyzed intramolecular C-H silylation. AB - The first synthesis of planar-chiral benzosiloloferrocenes was achieved by the intramolecular reaction of 2-(dimethylhydrosilyl)arylferrocenes. The enantioselective cross dehydrogenative coupling of an sp(2) C-H bond of ferrocene with a Si-H bond proceeded efficiently with the use of a Rh-chiral diene catalyst. PMID- 25687021 TI - Anti-inflammatory effect of resveratrol in old mice liver. AB - Inflammation is a hallmark of aging. Caloric restriction and resveratrol (RSV) have shown important effects on prevention of oxidative stress and inflammation. Here, we investigate the progression of proinflammatory markers in liver during aging and the effect of RSV on inflammation markers in the liver of old male C57BL/6J mice. Young (2 months), mature (12 months) and old (18 months) mice were fed during 6 months with RSV. Levels of IL-1beta, IL-6, IL-10, IL-17 and TNF alpha were evaluated by ELISA in mice liver. Levels of pro-inflammatory cytokines, IL-1beta, IL-6, IL-17 and TNF-alpha and also their respective mRNA increased in the liver from old mice. However, RSV decreased these levels in the case of IL-1beta and TNF-alpha but only in old mice showing no effect on young and mature animals. This reduction was also found at the mRNA level. Levels of mRNA of the components of NALP-3 inflammasome, ASC, CASP-1, NALP-1 and NALP-3, also showed an age-dependent increase that was reversed by RSV. Furthermore, cyclooxygenase 2 levels, a marker of proinflammatory innate immune activity, were also upregulated in aged liver and reversed again by RSV. In conclusion, our study confirms that aging is accompanied by an increase in the proinflammatory pattern in the liver and that RSV reduces this pattern in old mice liver. PMID- 25687022 TI - Identification of fipronil metabolites by time-of-flight mass spectrometry for application in a human exposure study. AB - Fipronil is a phenylpyrazole insecticide commonly used in residential and agricultural applications. To understand more about the potential risks for human exposure associated with fipronil, urine and serum from dosed Long Evans adult rats (5 and 10mg/kg bw) were analyzed to identify metabolites as potential biomarkers for use in human biomonitoring studies. Urine from treated rats was found to contain seven unique metabolites, two of which had not been previously reported-M4 and M7 which were putatively identified as a nitroso compound and an imine, respectively. Fipronil sulfone was confirmed to be the primary metabolite in rat serum. The fipronil metabolites identified in the respective matrices were then evaluated in matched human urine (n=84) and serum (n=96) samples from volunteers with no known pesticide exposures. Although no fipronil or metabolites were detected in human urine, fipronil sulfone was present in the serum of approximately 25% of the individuals at concentrations ranging from 0.1 to 4ng/mL. These results indicate that many fipronil metabolites are produced following exposures in rats and that fipronil sulfone is a useful biomarker in human serum. Furthermore, human exposure to fipronil may occur regularly and require more extensive characterization. PMID- 25687023 TI - Initial in vivo experience of pig artery patch transplantation in baboons using mutant MHC (CIITA-DN) pigs. AB - BACKGROUND: In the pig-to-nonimmunosuppressed baboon artery patch model, a graft from an alpha1,3-galactosyltransferase gene-knockout pig transgenic for human CD46 (GTKO/CD46) induces a significant adaptive immune response (elicited anti pig antibody response, increase in T cell proliferation on MLR, cellular infiltration of the graft), which is effectively prevented by anti-CD154mAb-based therapy. METHODS: As anti-CD154mAb is currently not clinically applicable, we evaluated whether it could be replaced by CD28/B7 pathway blockade or by blockade of both pathways (using belatacept + anti-CD40mAb [2C10R4]). We further investigated whether a patch from a GTKO/CD46 pig with a mutant human MHC class II transactivator (CIITA-DN) gene would allow reduction in the immunosuppressive therapy administered. RESULTS: When grafts from GTKO/CD46 pigs were transplanted with blockade of both pathways, a minimal or insignificant adaptive response was documented. When a GTKO/CD46/CIITA-DN graft was transplanted, but no immunosuppressive therapy was administered, a marked adaptive response was documented. In the presence of CD28/B7 pathway blockade (abatacept or belatacept), there was a weak adaptive response that was diminished when compared with that to a GTKO/CD46 graft. Blockade of both pathways prevented an adaptive response. CONCLUSION: Although expression of the mutant MHC CIITA-DN gene was associated with a reduced adaptive immune response when immunosuppressive therapy was inadequate, when blockade of both the CD40/CD154 and CD28/B7 pathways was present, the response even to a GTKO/CD46 graft was suppressed. This was confirmed after GTKO/CD46 heart transplantation in baboons. PMID- 25687024 TI - Outcomes after Intravitreal Bevacizumab versus Laser Photocoagulation for Retinopathy of Prematurity: A 5-Year Retrospective Analysis. AB - PURPOSE: To determine the relative effectiveness, major complications, and refractive errors associated with intravitreal bevacizumab (IVB) versus panretinal photocoagulation (PRP) to treat type 1 retinopathy of prematurity (ROP). DESIGN: Retrospective case series. PARTICIPANTS: Consecutive infants with type 1 ROP who received either IVB or PRP and had at least 6 months of follow-up. METHODS: The data from infants treated with either IVB or PRP for type 1 ROP between 2008 and 2012 were recorded from 2 medical centers in Atlanta, Georgia. MAIN OUTCOME MEASURES: Recurrence rate, complication rate, and refractive error. RESULTS: A total of 54 eyes (28 patients) with type 1 ROP were evaluated: 22 eyes (11 patients) received IVB, and 32 eyes (17 patients) received PRP. Among the 22 eyes treated with IVB, 16 eyes had zone I ROP and 6 eyes had posterior zone II ROP. The number of zone I and II ROP eyes treated with PRP were 5 and 27, respectively. Mean gestational age, birth weight, postmenstrual age at initial treatment, and follow-up period for the infants receiving IVB were 24.2 weeks, 668.1 g, 35.1 weeks, and 21.7 weeks, respectively, and for the infants receiving PRP, these were 24.8 weeks, 701.4 g, 36.1 weeks, and 34.5 weeks, respectively. Retinopathy of prematurity recurred in 3 (14%) of 22 IVB-treated eyes and in 1 (3%) of 32 PRP-treated eyes. Neither retinal detachment nor macular ectopia developed in any of the IVB-treated eyes. In PRP-treated eyes, retinal detachment developed in only 1 eye and macular ectopia developed in 5 eyes. Mean spherical equivalent and postgestational age at the last refraction for IVB-treated eyes were -2.4 diopters (D) and 22.4 months, respectively, and for PRP-treated eyes, these were -5.3 D and 37.1 months, respectively. Mean spherical equivalent for zone I ROP eyes treated with IVB and PRP were -3.7 D and -10.1 D, respectively, and for zone II ROP eyes, these were 0.6 D and -4.7 D, respectively. CONCLUSIONS: Both IVB and PRP are effective treatment options for type 1 ROP with low complication rates. IVB was associated with less myopia than PRP, although longer follow-up was available for PRP. PMID- 25687025 TI - Early subclinical macular edema in eyes with uveal melanoma: association with future cystoid macular edema. AB - PURPOSE: To determine the frequency of early subclinical macular edema in eyes with uveal melanoma and its association with future cystoid macular edema (CME). DESIGN: Retrospective cohort study. PARTICIPANTS: A total of 306 patients with uveal melanoma; 260 patients had follow-up of 1 or more years after plaque radiotherapy (follow-up cohort). METHODS: Review of medical records and spectral domain optical coherence tomography (OCT) images. MAIN OUTCOME MEASURES: Frequency of early subclinical macular edema (increased central macular thickness of >10 MUm without cystoid changes before or at 4 months after plaque radiotherapy); rate of future CME. RESULTS: At baseline, 164 patients (54%) had subclinical macular edema in the involved eye. On multivariate analysis, factors associated with subclinical macular edema at baseline were increasing tumor diameter (P = 0.001), increasing tumor thickness (P = 0.010), and subretinal fluid (P = 0.001). Of 260 patients in the follow-up cohort, 105 (40%) developed CME during a median follow-up of 31 months (mean, 34; range, 12-70 months). Eyes with subclinical macular edema at baseline (and at 4 months after plaque radiotherapy) had a significantly higher rate of future CME (n = 66; 50%) compared with eyes without subclinical macular edema at baseline (n = 39; 30%) (P = 0.005; hazard ratio, 1.77; 95% confidence interval, 1.19-2.64). On multivariate analysis, the factors associated with future development of CME included female gender (P = 0.004), increasing tumor thickness (P < 0.001), decreasing tumor distance to foveola (P = 0.002), hemorrhage over tumor (P = 0.017), and increased CMT of >10% at baseline in the involved eyes compared with the opposite eyes (P = 0.012). CONCLUSIONS: Subclinical macular edema is common in eyes with uveal melanoma before and at 4 months after plaque radiotherapy and is associated with initial larger tumor size. Eyes with early subclinical macular edema are at significantly higher risk for future CME. These findings suggest that tumor related factors, most likely mediated through proinflammatory cytokines, may play an important role in development of post-radiation CME. PMID- 25687026 TI - Aqueous Levels of Angiopoietin-like 4 and Semaphorin 3E Correlate with Nonperfusion Area and Macular Volume in Diabetic Retinopathy. AB - OBJECTIVE: To investigate the aqueous levels of angiopoietin-like 4 (ANGPTL4), semaphorin 3E (Sema3E), and vascular endothelial growth factor (VEGF) in patients with diabetic retinopathy and to ascertain their association with diabetic retinopathy phenotypes. DESIGN: Prospective, nonrandomized, comparative case series. PARTICIPANTS: Of all 104 consecutive patients (104 eyes) who had intravitreal anti-VEGF injections from April 2012 through April 2013 for diabetic macular edema (DME), 51 had severe nonproliferative diabetic retinopathy (NPDR) and 53 had proliferative diabetic retinopathy (PDR). The controls were 54 consecutive nondiabetic patients who had undergone cataract surgery (54 eyes) during the same period. METHODS: The ANGPTL4, Sema3E, and VEGF levels in aqueous humor samples obtained before intravitreal injections were measured by enzyme linked immunosorbent assay. Capillary nonperfusion area (NPA) was calculated from encircled angiography using the 7 standard field images described in the Early Treatment Diabetic Retinopathy Study protocol. Total macular volume (TMV) was measured by spectral-domain optical coherence tomography. MAIN OUTCOME MEASURES: Aqueous ANGPTL4, Sema3E, and VEGF levels in severe NPDR, PDR, and control groups and their correlations with each other, NPA, and TMV. RESULTS: The severe NPDR and PDR groups had higher aqueous levels of ANGPTL4 and VEGF than the control group (all P < 0.001). The PDR group had higher ANGPTL4 and VEGF levels than the severe NPDR group (both P < 0.001). The aqueous ANGPTL4 levels of all diabetic retinopathy patients correlated positively with NPA (r = 0.820, P = 0.003) and TMV (r = 0.824, P < 0.001). The control group had higher aqueous Sema3E levels than the NPDR and PDR groups (both P < 0.001). Aqueous Sema3E levels correlated negatively with VEGF levels in all subjects (r = -0.57, P = 0.025). CONCLUSIONS: The ANGPTL4 may be a candidate target in DME treatment and a biomarker of ischemic-induced retinopathy, including diabetic retinopathy. PMID- 25687027 TI - Sarcoidosis in the national veteran population: association of ocular inflammation and mortality. AB - PURPOSE: To describe the distribution of ocular sarcoidosis in the veteran population and to determine the association between ocular disease and all-cause mortality. DESIGN: Retrospective review. METHODS: The Veterans Health Administration National Patient Care Database information on medical diagnoses, date of diagnosis, age, race, gender, and Veterans Administration medical center station number for site-specific calculations for fiscal years 2010 through 2012 was collected. Mortality data were obtained from the Beneficiary Identification Records Locator Subsystem. The patient cohort was identified with a primary diagnosis of sarcoidosis using International Classification of Disease, ninth edition, code of 135 in outpatient treatment files for the study period. The sarcoidosis patients were divided into those with uveitis or orbital inflammation (defined as ocular inflammation for this study) and those without uveitis or orbital inflammation. Survival analysis was performed using the Cox proportional hazard method. MAIN OUTCOME MEASURE: Association between ocular inflammation and 1-year mortality. RESULTS: Of 15 130 subjects with sarcoidosis, 3364 (22.2%) were evaluated in an eye clinic within a Veterans Administration Medical Center. Most patients were diagnosed with anterior uveitis (n = 1013; 80.7% of ocular inflammation), and the least common diagnosis was orbital granuloma (n = 28; 2.2% of ocular inflammation). Male gender was protective to the development of uveitis (estimate, 0.76; 95% confidence interval, 0.65-0.88; P = 0.0005). The overall 1 year all-cause mortality for all patients with a diagnosis of sarcoidosis was 2.0%. Ocular inflammation was associated with a decrease in 1-year all-cause mortality (simple model: hazard ratio, 0.36; P = 0.0015; complex model: hazard ratio, 0.35; P = 0.013). CONCLUSIONS: Veterans with ocular inflammation had significantly lower 1-year all-cause mortality than those without documented ocular inflammation. The reason for this finding remains to be established. PMID- 25687028 TI - Focal Choroidal Excavation in Multifocal Choroiditis and Punctate Inner Choroidopathy. PMID- 25687029 TI - Relationships among Socioeconomic Status, Dietary Intake, and Stress in Breastfeeding Women. AB - BACKGROUND: As breastfeeding duration increases, it is important to understand diets of breastfeeding women and other factors salient to maternal/offspring health, including stress. It is important to further consider sociodemographic factors, given their associations with nutritional deficiencies and perceived stress. OBJECTIVE: We cross-sectionally compared breastfeeding women's dietary intakes from a food frequency questionnaire (assessing from pregnancy through 3 months postpartum) with Estimated Average Requirements (EARs). We hypothesized that dietary intake was related to sociodemographic variables and parenting stress. DESIGN: We examined a cohort of predominately breastfeeding women. Food frequency questionnaire results were compared with EARs, the Parenting Stress Index: Short Form, and a demographic questionnaire. PARTICIPANTS/SETTING: Participants included 101 women (of 289 recruited) who breastfed singleton, full term infants for the first 3 months while using <28 oz formula/wk. The study included community recruitment in rural Oklahoma from 2008 to 2012. STATISTICAL ANALYSES: Mean and standard deviation or frequencies were reported. One-sample t tests compared EARs with mean dietary intakes over the past 12 months. Pearson correlations and one-way analyses of variance explored relationships among dietary, sociodemographic, and stress variables. RESULTS: Twenty-two percent of women did not meet EAR minimum energy recommendations and >40% did not meet protein recommendations. Despite widespread supplement use, some consumed less than the EAR for vitamin E (35%), calcium (22%), and vitamin C (19%). Carbohydrate consumption was positively related to the difficult child scale (r=0.19; P=0.05). Dietary riboflavin (r=-0.19; P=0.05) and vitamin D intake (r= 0.19; P=0.05) were negatively related to the parent-child dysfunction scale. CONCLUSIONS: Despite efforts to enhance education and counseling regarding adequate perinatal nutrition-related practices, even well-educated women may not meet EARs. This poor dietary intake may be associated with parenting stress and have potential long-term implications for child health. PMID- 25687031 TI - A disconnection account of subjective empathy impairments in diffuse low-grade glioma patients. AB - Human empathic experience is a multifaceted psychological construct which arises from functional integration of multiple neural networks. Despite accumulating knowledge about the cortical circuitry of empathy, almost nothing is known about the connectivity that may be concerned in conveying empathy-related neural information. To bridge this gap in knowledge, we studied dispositional empathy in a large-sized cohort of 107 patients who had undergone surgery for a diffuse low grade glioma. The self-report questionnaire used enabled us to obtain a global measure of subjective empathy but also, importantly, to assess the two main components of empathy (cognitive and emotional). Data were processed by combining voxelwise and tractwise lesion-symptom analyses. Several major findings emerged from our analyses. First of all, topological voxelwise analyses were inconclusive. Conversely, tractwise multiple regression analyses, including all major associative white matter pathways as potential predictors, yielded to significant models explaining substantial part of the behavioural variance. Among the main results, we found that disconnection of the left cingulum bundle was a strong predictor of a low cognitive empathy (p<0.0005 Bonferroni-corrected). Similarly, we found that disconnection of the right uncinate fasciculus and the right inferior fronto-occipital fasciculus predicted, respectively, a low (p<0.05 Bonferroni-corrected) and a high (p<0.05 Bonferroni-corrected) subjective empathy. Finally, although we failed to relate emotional empathy to disruption of a specific tract, correlation analyses indicated a positive association between this component of empathy and the volumes of residual lesion infiltration in the right hemisphere (p<0.01). Taken as a whole, these findings provide key fundamental insights into the anatomical connectivity of empathy. They may help to better understand the pathophysiology of empathy impairments in pathological conditions characterized by abnormalities of long-range anatomical connectivity, such as autism spectrum disorders, schizophrenia and fronto-temporal dementia. PMID- 25687030 TI - Quality of communication in the ICU and surrogate's understanding of prognosis. AB - OBJECTIVE: Although misperceptions about prognosis by surrogates in ICUs are common and influence treatment decisions, there is no validated, practical way to measure the effectiveness of prognostic communication. Surrogates' subjective ratings of quality of communication have been used in other domains as markers of effectiveness of communication. We sought to determine whether surrogates' subjective ratings of the quality of prognostic communication predict accurate expectation about prognosis by surrogates. DESIGN: We performed a cross-sectional cohort study. Surrogates rated the quality of prognostic communication by survey. Physicians and surrogates gave their percentage estimate of patient survival on ICU day 3 on a 0-100 probability scale. We defined discordance about prognosis as a difference in the physician's and surrogate's estimates of greater than or equal to +/-20%. We used multilevel logistic regression modeling to account for clustering under physicians and patients and adjust for confounders. SETTING: Medical-surgical, trauma, cardiac, and neurologic ICUs of five U.S. academic medical centers located in California, Pennsylvania, Washington, North Carolina, and Massachusetts. PATIENTS: Two hundred seventy-five patients with acute respiratory distress syndrome at high risk of death or severe functional impairment, their 546 surrogate decision makers, and their 150 physicians. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: There was no predictive utility of surrogates' ratings of the quality of communication about prognosis to identify inaccurate expectations about prognosis (odds ratio, 1.04 +/- 0.07; p = 0.54). Surrogates' subjective ratings of the quality of communication about prognosis were high, as assessed with a variety of questions. Discordant prognostic estimates were present in 63.5% (95% CI, 59.0-67.9) of physician surrogate pairs. CONCLUSIONS: Although most surrogates rate the quality of prognostic communication high, inaccurate expectations about prognosis are common among surrogates. Surrogates' ratings of the quality of prognostic communication do not reliably predict an accurate expectation about prognosis. PMID- 25687032 TI - The overlapping relationship between emotion perception and theory of mind. AB - Socio-cognitive skills are crucial for successful interpersonal interactions. Two particularly important socio-cognitive processes are emotion perception (EP) and theory of mind (ToM), but agreement is lacking on terminology and conceptual links between these constructs. Here we seek to clarify the relationship between the two at multiple levels, from concept to neuroanatomy. EP is often regarded as a low-level perceptual process necessary to decode affective cues, while ToM is usually seen as a higher-level cognitive process involving mental state deduction. In information processing models, EP tends to precede ToM. At the neuroanatomical level, lesion study data suggest that EP and ToM are both right hemisphere based, but there is also evidence that ToM requires temporal-cingulate networks, whereas EP requires partially separable regions linked to distinct emotions. Common regions identified in fMRI studies of EP and ToM have included medial prefrontal cortex and temporal lobe areas, but differences emerge depending on the perceptual, cognitive and emotional demands of the EP and ToM tasks. For the future, clarity of definition of EP and ToM will be paramount to produce distinct task manipulations and inform models of socio-cognitive processing. PMID- 25687033 TI - Non-destructive determination of fat content in green hams using ultrasound and X rays. AB - This work addresses the use of ultrasound (US) and medical dual energy X-ray absorptiometry methods to predict the fat content in green pork hams. Ultrasonic velocity (upsilon) and X-ray absorption were measured in 78 green hams. An increase in the fat content involved an increase in upsilon and a decrease in the X-ray attenuation measured at 2 degrees C. Models developed to predict the fat content from the ultrasonic velocity or X-ray parameters provided errors of 2.97% and 4.65%, respectively. The combination of both US and X-ray technologies did not improve prediction accuracy. These models allowed green hams to be classified into three levels of fatness, with 88.5% and 65.4% of the hams correctly classified when using models based on ultrasonic and X-ray parameters, respectively. Therefore, US and X-rays emerge as useful quality control technologies with which to estimate the fat content in green pork hams. PMID- 25687034 TI - Deficits in information transfer between hospital-based and primary-care physicians, the case of kidney disease: a cross-sectional study. AB - BACKGROUND: Late recognition plays an important role in prognosis associated with kidney disease; thus, information transfer at hospital discharge regarding kidney disease is crucial. Whether it is notified in patients' hospital discharge summary (HDS) is presently largely unknown. STUDY DESIGN: Cross-sectional. SETTING AND PARTICIPANTS: The prevalence of kidney dysfunction [estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m(2)] and its reporting to primary-care physicians from 26 units [11 surgery, 11 medical, 4 intensive care units (ICUs)] of a university hospital were analyzed in 14,000 hospitalizations. PREDICTOR: eGFR. OUTCOME: Notification of kidney dysfunction in HDS. MEASUREMENTS: GFR was estimated from serum creatinine using the Modification of Diet in Renal Disease formula. RESULTS: Kidney dysfunction was frequent (27.2 %) but infrequently notified in the main-body of the HDS (overall 25.3 %, medical 25 %, surgical 16.3 %, ICU 48.4 %) even when severe (eGFR 15-29.9 ml/min/1.73 m(2) was notified in 68.8, 38.5, and 79.8 % of HDSs in medical, surgical and ICUs, respectively). Notification in the HDS conclusion was rare (overall 11.4 %, medical 9.8 %, surgical 8.4 %, ICU 27.5 %). Reporting remained low when eGFR remained abnormal at discharge (medical 35.8 %, surgical 22.5 %, ICU 62.2 %) but was worse for acute kidney injury (16.0, 17.1, and 37.7 %, respectively). The optimal eGFR cut-off for reporting was 39 ml/min/1.73 m(2). Longer durations of hospitalization, greater numbers of creatinine measurements and of abnormal eGFR were associated with notification, regardless of the type of unit. LIMITATIONS: Lack of data to define acute or chronic kidney injury with precision. CONCLUSIONS: Kidney dysfunction is frequent in hospitalized patients but is usually not notified, even when severe or still present at discharge, suggesting that it is not considered important to disclose to primary-care physicians. This lack of information may decrease physicians' awareness, and may affect continuity of care in patients with kidney dysfunction. PMID- 25687035 TI - Inhibition of RAC1-GEF DOCK3 by miR-512-3p contributes to suppression of metastasis in non-small cell lung cancer. AB - MicroRNAs are a class of small non-coding RNAs regulating gene expression. In this study, we demonstrated that retinoic acid (RA) treatment increases the expression of miR-512-3p. Overexpression of miR-512-3p inhibited cell adhesion, migration, and invasion in non-small cell lung cancer (NSCLC) cell lines A549 and H1299. miR-512-3p inhibitor partially reversed these effects in H1299 cells stably expressing miR-512. We identified DOCK3, a RAC1-GEF (guanine nucleotide exchange factor), as a target gene of miR-512-3p. Overexpression of miR-512-3p led to the decrease of DOCK3 protein but not its mRNA. Knockdown of DOCK3 resulted in similar effects on adhesion, migration, and invasion as observed of miR-512-3p overexpression. Active RAC1 pull-down assay indicated that overexpression of miR-512-3p could decrease the activity of RAC1 with a higher efficiency than that of DOCK3 knockdown. Furthermore, expression of miR-512-3p was suppressed in most NSCLC patient tumor samples compared to its paired normal controls, suggesting that miR-512-3p might play a crucial role in lung cancer development. In conclusion, our results supported that miR-512-3p could inhibit tumor cell adhesion, migration, and invasion by regulating the RAC1 activity via DOCK3 in NSCLC A549 and H1299 cell lines. PMID- 25687036 TI - [Clonal evolution in leukemia]. AB - The theory of evolution of tumor cell population has been established for nearly 40 years. It was widely accepted for research and clinical anti-tumor treatment. Recently, it was suggested that cancer stem cells are the unit of evolution. Considering recent advances on genesis of tumor and leukemia with ecological and evolutionary views, this article reviews origin and evolution of leukemia stem cells. Over the last few years, clinical and experimental data suggest there are two paths for the origin of leukemia stem cells: from a transformed hematopoietic stem cell or progenitor. The mechanisms of leukemia stem cell formation and clonal evolution were elucidated. Sub-clonal mutations and clonal architectures in leukemia were studied and a mosaic evolution pattern is described. Random evolution or non-inherited mutations of leukemia cells would accelerate the progression of malignant disease. Finally, the mosaic or network mechanism for leukemogenesis is also discussed. PMID- 25687037 TI - [Clinical significance of CASP8AP2 gene methylation in childhood acute lymphoblastic leukemia]. AB - OBJECTIVE: To study the methylation level in the promoter of caspase 8 associated protein 2 (CASP8AP2) gene between samples at diagnosis and in complete remission, and to investigate its relationship with clinical features and prognosis in children with acute lymphoblastic leukemia (ALL). METHODS: Diagnostic DNA samples from 109 newly diagnosed children with ALL admitted from August 2007 to March 2010, and 94 ALL children in CR (complete remission) among them were collected. Bisulfite modification and MethyLight method established by our research team were used to determine the methylation level of the two key CpG sites (at -1189 and -1176) of the promoter of CASP8AP2 gene. RESULTS: The average methylation level of the two CpG sites in newly diagnosted samples was higher than that in CR samples (71.1% +/- 1.7% vs 64.2% +/- 21.2%) (P = 0.008). Analysis with receiver operating characteristic (ROC) curve showed that the area under curve was 0.687 (P = 0.024), indicating that the methylation level of the two CpG sites was able to predict relapse efficiently to some extent, 76.9% was chosed as a cutoff value to divide the patients into high methylation group (49 patients) and low methylation group (60 patients). The incidence of relapse in high methylation group was higher than that in low methylation group (20.4% vs 6.7%) (P = 0.044), five year relapse free survival in high methylation group was also lower than that in low methylation group (Log rank, P = 0.033). Furthermore, high methylation at new diagnosis were correlated with high level of minimal residual disease (MRD) before consolidation therapy (P = 0.011). In the 34 children with MRD >= 10(-4) at the end of induction remission, the relapse rate of high methylation patients was significantly higher than that of low methylation patients (8/16 vs 3/18)(P = 0.038). CONCLUSION: The abnormal hypermethylation of the two CpG sites (at -1189 and -1176) of the promoter of the CASP8AP2 gene is possibly associated with leukemogenesis in childhood ALL. The treatment outcome is more poor in patients with hypermethylation than that in patients with low methylation. The combination of the methylation level of the two CpG sites and MRD level at the end induction remission is able to predict relapse more effectively. PMID- 25687038 TI - [Construction of SIRT1 promoter expression vector and its activity analysis as well as influence of AML1-ETO on transcriptional regulation of SIRT1 gene]. AB - OBJECTIVE: This study was aimed to analyze the expression and regulation mechanism of SIRT1 in AML1-ETO positive leukemia to find the core promoter. METHODS: The real-time RT-PCR was used to detect the expression of SIRT1 in AML1 ETO positive leukemia cell line and clinical samples of leukemia patients, a SIRT1 promoter-luciferase reporter vector was constructed and the promoter activity was evaluated in the 293T cell line. A series of possible core promoter fragments of the SIRT1 5'-untranslated region were amplified by PCR, the PCR products were cloned into XhoI/HindIII-digested pGL3-Basic reporter vector, the poly-cationic compound SuperFect reporter vector complexes were transfected into 293T cells.The dual-luciferase Reporter Assay System was used to quantitate the reporter vector luciferase activity. RESULTS: The six kinds of promoter fragment of SIRT1 gene were successfully constructed and cloned into the pGL3-Basic reporter vector, which was authenticated by XhoI/HindIII co-digestion and DNA sequencing. The luciferase activity of the promoter construct was significantly higher than that of the pGL3-Basic promoter in 293T cells. The luciferase report gene assay was also used to detect the regulation of AML1-ETO on the transcription activity of SIRT1 promoter. The results showed that the expression level of SIRT1 increased with the increase mens of AML1-ETO, the promoter of SIRT1 could be bound by AML1-ETO. CONCLUSION: The SIRT1 promoter-luciferase reporter vector is successfully constructed, the transfection system used in this study can effectively transfer gene in 293T cells. The SIRT1 core promoter possesses higher activity in 293T cells and can promote significantly expression of luciferase reporter gene in 293T cells. The transcription regulation of AML1 ETO on SIRT1 is carried out via promoting its promoter activity. PMID- 25687039 TI - [Expression of HIF-1alpha in primary acute myeloid leukemia cells and its relationship with prognosis]. AB - OBJECTIVE: This study was aimed to detect the expression of HIF-1alpha in acute myeloid leukemia (AML) except acute promyelocyte leukemia (APL) and investigate the relationship of its expression levels with clinical parameters and prognosis. METHODS: The primary AML cells were collected from peripheral blood of 53 newly diagnosed AML patients by using CD3 negative sorting. The expression of HIF 1alpha was measured by real-time fluorescent quantitative PCR (FQ-PCR) , and the relationship between expression level of HIF-1alpha and clinical parameters (age, sex, WBC count, clinical typing, prognosis) was analysed according to relative expression level. Furthermore, Western blot was used to detect the protein level of HIF-1alpha in AML patients with or without extramedullary infiltration. RESULTS: The expression level of HIF-1alpha did not correlate with age, sex, WBC count, Hb level, Plt count and the percentage of blast. There was no significant difference of HIF-1alpha expression between different AML subtype based on FAB. The higher level of HIF-1alpha was found in AML patients who did not get complete remission after one or two courses of chemotherapy, however, the difference was not statistically significant. The relapse rate was higher in AML patients with the higher expression of HIF-1alpha. In addition, the higher level of HIF-1alpha mRNA and protein were found in bone marrow of AML patients with extramedullary infiltration (P < 0.01). The negative correlation between HIF-1alpha and PTEN was observed (r = -0.48, P = 0.001). CONCLUSIONS: Overexpression of HIF-1alpha are closely related with extramedullary infiltration and prognosis of acute myeloid leukemia, and may be used as an early indicator of extramedullary infiltration and prognosis. PMID- 25687040 TI - [Expression and clinical significance of PDCD5 in patients with acute myeloid leukemia]. AB - OBJECTIVE: This study was aimed to investigate the roles of PDCD5 (programmed cell death 5) in pathogenesis of acute myeloid leukemia (AML) and the relevance of PDCD5 with the clinical characteristics and prognosis of patients by testing the PDCD5 expression in adult AML patients. METHODS: The mRNA and intracellular protein levels of PDCD5 from 36 newly diagnosed AML patients were analyzed by real-time fluorescence quantitative polymerase chain reaction (RQ-PCR) and flow cytometry (FCM), respectively. The correlation of mRNA levels and intracellular protein levels of PDCD5 with the clinical characteristics and survival time of patients were analyzed. RESULTS: The intracellular protein expression levels of PDCD5 in AML patients were significantly higher than those in normal controls (P < 0.05). The PDCD5 mRNA levels were not significantly different between patients and controls (P > 0.05). The mRNA and protein levels of PDCD5 did not significantly correlate with sex, age, WBC count, FAB subtype, extramedullary infiltration, WT1 gene, NPM1 gene mutation and the patients response to induction therapy. The patients with positive FLT3/ITD mutation displayed higher protein levels of PDCD5 as compared with negative FLT3/ITD mutation patients (P < 0.05). CONCLUSION: The intracellular protein of PDCD5 significantly increased in AML patients. However, the increased PDCD5 does not exert the pro-apoptotic effects on AML cells. The patients with positive FLT3/ITD mutation show higher protein levels of PDCD5. PMID- 25687041 TI - [MicroRNA-10a expression in FAB different subtype of acute myeloid leukemia and its relationship with drug resistance]. AB - OBJECTIVE: This study was to investigate the expression of miR-10a in the different FAB subtype of acute myeloid leukemia (AML) and its relationship with drug resistance. METHODS: Forty de novo patients with AML, 16 patients with non malignant hematologic disease and three AML cell lines HL-60, U937 and HL-60/ADR were enrolled in this study, the MiR-10a expression in bone marrow mononuclear cells of above-mentioned patients and 3 AML cell lines was detected by TaqMan RT PCR. The correlation of miR-10a with clinicopathological factors of AML patients was analyzed. RESULTS: The miR-10a expression level in HL-60 cell line was higher than that in U937 cell line (P = 0.039). And its expression level in de novo AML patients was higher than that in patients with non-malignant hematologic disease (P < 0.01). FAB-AML-M3 patients exhibited higher expression of miR-10a than that in M1, M2 and M4 (P < 0.05); HL-60/ADR cell line showed higher miR-10a expression than that in HL-60 cell line (P < 0.01) . Except M3, the patients without CR (non CR) after the first cycle of chemotherapy showed a higher level of miR-10a as compared with CR patients (P < 0.01). CONCLUSION: The high expression of miR-10a may be closely related to over-proliferation of promyelocyte and drug resistance of acute myeloid leukemia cells, except M3. PMID- 25687042 TI - [Expression and clinical significance of LIMD-1 gene in adult patients with acute leukemia]. AB - OBJECTIVE: The reduced expression or expression deletion of LIM domain-containing protein 1(LIMD1) gene associates with the occurrence of various solid tumors, while its role in adult acute leukemia (AL) has been rarely reported, this study was to detect LIMD1 expression in adult patients with AL and to evaluate its correlation with the different clinical and laboratorial data. METHODS: The expression levels of LIMD1 were determined by real-time quantitative PCR (RT qPCR), LIMD1 transcripts were measured by using a relative quantification with GAPDH as a housekeeping gene, and the relationship between its expression levels and clinical parameters (sex, age, subtype, leukocyte count, leukemic blasts) was investigated by statistical analysis. RESULTS: The LIMD1 expression was reduced in de novo AL patients as compared with normal controls and complete remission patients(P < 0.01). In univariate analysis, LIMD1 associated with age and leukocyte count (P = 0.011, 0.035 respectively). LIMD1 decreased along with increasing age and leukocyte count in de novo AL patients, the LIMD1 expression levels in de novo AL patients with age >= 60 years old were lower than that in group of patients <60 years, and which were significantly lower in the leukocyte count >= 100*10(9)/L compared to leukocyte count < 100*10(9)/L. there was no statistically significant association between LIMD1 expression and sex, subtype, and leukemic blasts of patients. CONCLUSIONS: The LIMD1 gene may be involved in the pathogenesis and progression of adult AL, and may be used as an indicator of prognosis evaluation. PMID- 25687043 TI - [Relationship between BH3 mimetic S1 and expression of BCL-2 family members in acute myeloid leukemia]. AB - OBJECTIVE: This study was to investigate the molecular biomarkers of apoptosis induced by BH3 mimetic S1 in human primary AML cells. METHODS: Mononuclear cells were isolated from 27 newly diagnosed AML samples. Apoptosis was analyzed by flow cytometry. IC(50) value of S1 on these samples was determined by XTT assay. The expression level of BCL-2 family members and phosphorylated BCL-2 were assessed by Western blot with subsequent semi-quantitatively densitometric analysis. XTT assay was performed to determine the cell viability of the combined use of S1 and MEK/ERK inhibitor PD98059. The interactions between BCL-2 and pro-apoptosis proteins were tested by co-immunoprecipitation. RESULTS: The flow-cytometry detection showed that S1 induced the apoptosis of primary AML cells. Based on the responses, 27 primary samples could be classified into three groups: (1) a sensitive group (12 of 27 cases) with IC(50)<14 umol/L, (2) an intermediate group (8 of 27 cases) with IC(50) of 14-30 umol/L and (3) a resistant group (7 of 27 cases) with IC(50)>30 umol/L. The ratio of pBCL-2/(BCL-2+MCL-1) showed a good linear correlation with the IC(50) values. (R(2) = 0.71, P < 0.0001). PD98059 suppressed BCL-2 phosphorylation. When PD98059 suppressed BCL-2 phosphorylation, the apoptotic rate of drug-resistant cells induced by S1 increased from 9.8% to 64.5% (combination index, CI = 0.4), accompanied by more dissociation of BCL-2 heterodimers. CONCLUSION: The combination of S1 with PD98059 decrease pBCL-2 level of AML patients and inhibits of the anti-apoptotic function of BCL-2 through enhancing the dissociation of BCL-2 heterodimers. PMID- 25687044 TI - [mRNA Expressions of T-bet, GATA-3, ROR gammat and Foxp3 in peripheral blood of patients with chronic lymphocytic leukemia in different stages]. AB - OBJECTIVE: This study was to investigate the mRNA expression of T-bet, GATA-3, ROR gammat and Foxp3 mRNA in peripheral blood of patients with chronic lymphocytic leukemia (CLL) in different stages and explore their potential role in the pathogenesis and clinical diagnosis. METHODS: A total of 46 newly diagnosed and untreated patients with CLL was chosen as patient group, including 16 patients in the stage of Binet A, 15 in the stage of Binet B, and 15 in the stage of Binet C; 20 healthy persons were selected as controls. The quantitative fluorescence PCR was adopted to detect the mRNA expression of T-bet, GATA-3, RORgammat and Foxp3 in peripheral blood mononuclear cell (PBMNC). RESULTS: (1) The expression of T-bet mRNA in patient group was lower than that in normal controls (P < 0.05), while the mRNA expression of GATA-3 mRNA, ROR gammat, Foxp3 in CLL patients group were higher than that in normal controls (P < 0.05), and the ratio of T-bet/GATA-3 and RORgammat/Foxp3 in CLL in patient group were lower than that in normal controls(P < 0.05); (2) The later the stage, the higher the mRNA expression of GATA-3 and Foxp3. The mRNA expression of GATA-3 in stage Binet B and stage Binet C of CLL patients were higher than that in stage Binet A (P < 0.05),and the mRNA expression of Foxp3 in stage Binet C was higher than that in stage of Binet A and Binet B (P < 0.05); the later the stage, the lower the ratio of T-bet/GATA-3 and RORgammat/Foxp3. The ratio of T-bet/GATA-3 in stage of Binet A CLL patients was higher than that in stage Binet C (P < 0.05) and the ratio of RORgammat/Foxp3 in stage of Binet A and stage of Binet B were higher than that in stage Binet C (P < 0.05). CONCLUSION: This study found in the level of transcription factors in CLL patients that with the process of disease, the balance shifts from Th1/Th2 and Th17/Treg to Th17 and Treg, and Treg cell may play a critical immunosuppressive role in the development of CLL. PMID- 25687045 TI - [Establishment of the human acute promyelocytic leukemia pathological model in the SCID beige mice by using NB4 cell line]. AB - OBJECTIVE: This study was to establish a stable, effective and reproducible human acute promyelocytic leukemia model in severe combined immunodeficient (SCID) mice by using NB4 cell line, and to investigate the disease course character and biological behaviors. METHODS: Three-five-week-old SCID beige mice were divided randomly into two groups: experimental and control group. SCID mice of experimental group were transplanted by tail vein (iv) injection of 5*10(6) NB4 cells. The WBC cell count and the positive rate of promyelocytes in peripheral blood were dynamically monitored by using smears. Morphological examination and histopathological assay were employed to confirm NB4 cell infiltration in organs (liver, spleen, lung, kidney and brain). The expression level of PML-RARalpha fusion protein was detected by Western blot. RESULTS: Within two weeks there was no significant difference in peripheral blood WBC count between two groups (P > 0.05), meanwhile, NB4 cells were not found. At the day 21 and 28 after inoculation, the peripheral blood white blood cell count of experimental group reached to (4.79 +/- 1.13)*10(9)/L and (7.62 +/- 2.24)*10(9)/L respectively, which were significantly higher than that in control group (P < 0.05); simultaneously, the positive rates of promyelocytes on smears were (2.14 +/- 0.63)% and (6.6 +/- 2.76)%, respectively. Morphological observation showed single or multiple tumor lumps at day 21 after inoculation; HE staining of tissue biopsies demonstrated a large number of promyelocyte in the liver, spleen, lung, kidney and brain tissue. Cell immunofluorescence results showed that the CD33 expression of bone marrow cells in mice of experimental group was strongly positive (P < 0.05). Western blot confirmed that the PML-RARalpha fusion protein was expressed variously in liver, kidney and brain tissue. CONCLUSIONS: The human acute promyelocytic leukemia SCID mouse model is succesfully established by tail vein injection of NB4 cells. This model can mimic the characters of involved bone marrow and diffuse growth of cells. This model is a useful tool to explore the pathogenic mechanism and experimental treatment of human leukemia. PMID- 25687046 TI - [Analysis of the key factors in SCID mouse-human leukemia model]. AB - OBJECTIVE: This study was to explore the key factors in leukemia model through the analysis of mouse with bad life state in the modeling process of leukemia so as to provide the theoretical reference for improving the success rate of modeling. METHODS: At 1 week after inoculation of leukemia cells into SCID mice, the life status and peripheral hemogram of SCID mice were tested, the bone marrow smears, splean biopsy and spleen index of mice were examined after dissecting mormal and agoned/died mice during modoling, and the examined results were compared. RESULTS: As compared with control mice, the life status of experimental mice was poor; the blood smear test showed juvenile cells, slightly more white blood cells with irregular shape and partial rupture, the lymphocytes and band cells obviously increased, the neutrophile granulocytes showed nuclear left shift; the bone marrow smears showed larger cell volume, smaller mulcoplasm, abnormal morphology of cells and cell nuclei and serious cell rapture; the spleen examination showed that the spleen diplayed enlargement and hyperemia to varying degree, the spleen index obviously increase, the spleen interstitial expansion, cell disordered arragement and irregular cell shope were observed, however there was no infiltration of leukemia cells in control and experimental mice. CONCLUSION: The mouse age, pathway of inoculating the leukemia cells, sterile condition in breading and avoiding the rejection and inflammatory response in modeling process are the key foctors influencing the modeling success. PMID- 25687047 TI - [Analysis of tumor lysis syndrome in 380 cases of acute leukemia]. AB - OBJECTIVE: This studay was aimed to explore the incidence and risk factors of tumor lysis syndrome (TLS) in patients with acute leukemia. METHODS: A tatol of 380 patients who were newly diagnosed as acute leukemia and received combination chemotherapy were retrospectively analyzed. The TLS was diagnosed according to criteria of Cario and Bioshop, the risk factors were evaluated on basis of examination results. RESULTS: The tumor lysis syndrome occurred in 20.8% (79/380) of patients, out of them the clinical TLS was 0.5% (2/380), laboratorial TLS was 20.3% (77/380). The unvariate analysis showed that male, high WBC count, hepatomegaly, splenomegaly, lympha-denoctasis, elevated AST, high creatinine, high uric acid level, high serum lactate dehydrogenase (LDH) level, or renal insufficiency were independent risk factors for TLS. CONCLUSION: The TLS is a clinically common complication in patients with leukemia, especially during induction chemotherapy, therefore, for AL patients with high risk factors the TLS should be closely monitored, prevented and given better therapy. PMID- 25687048 TI - [Clinical efficacy of switching to 2nd generation of tyrosine kinase inhibitor on CML patients at poor responses to imatinib]. AB - OBJECTIVE: This study was to investigate the timing and clinical efficacy of switching to the 2nd generation of tyrosine kinase inhibitor (TKI) for CML patients at poor response to imatinib (dissatifed efficacy or intolerance). METHODS: The therapeatic efficacy and side reaction of switched 2nd TKI in patients with newly diagnsed CML-CP who poorly responded to imatinib were observed, anong them 3 cases were intolerant, 6 cases did not acquire satisfied efficacy. RESULTS: After switching to 2nd generation TKI, 3 patients with intolerance achieved complete cytogenetic remission (CCyR) in 3 months, and major molecular remission (MMR) in 3-6 months. All of them achieved optimal efficacy according to European Leukemia Network (ELN), but the pleural effusion appeared in 1 case after use of 2nd generation of TKI for 3 months, and the dadatinib was stoped temporally, and the curative efficacy still was maintained. Among 6 cases with poor efficacy by treatment with imatinib, 2 cases with BCR/ABL mutation progressed after switching 2nd generation of TKI, out of them 1 case with poor tolerance progeressed to the accelerated phase, but was cured by haploidentical allogeneic hematopoictic stem cell transplantation, 1 case progressed to blastic crisis and died of serious infection; the another 4 cases achieved MMR in 3-12 months after using 2nd generation of TKI, and maintained CMR for 12-36 months. CONCLUSION: CML-CP patients without the optimal response to imatinib should be treated by switching to 2nd generation of TKI as soon as possible, and thereby patients may acquired satisfactory therapentic efficacy. PMID- 25687049 TI - [Effect of quercetin on doxorubicin-induced expression of MDR1 gene in HL-60 cells]. AB - OBJECTIVE: Leukemia cells can acquire a multidrug resistant (MDR) phenotype in response to a wide variety of chemotherapeutic agents including doxorubicin (Dox). In addition to the constitutive expression in the leukemia prior to chemotherapy, a complex phenotype of pleiotropic resistance is presented in the residual or recurrent leukemia. Recent studies showed Dox-induced coexpression of COX2 and MDR1 genes in human leukaemia cells, and whether Dox-induced MDR1 up regulation in acute leukaemia cells is dependent on COX2-transcriptional activity and thus might be overcome or prevented with COX2-promotor inhibitor quercetin interfering with COX2 expression and activity. This study was purposed to investigate the impacts of quercetin on Dox-induced mRNA expression of MDR1 and COX2 genes in HL-60 leukemia cells. METHODS: The MDR1 and COX2 mRNA expression in HL-60 cells was detected by RT-PCR; the prostaglandin E2 (PGE2) release was measured by ELISA; the cytotoxicity of Dox was determined by MTT test. RESULTS: The incubation of HL-60 cells with Dox not only up-regulated MDR1 mRNA, but also COX2 mRNA expression, and after co-incubation with quercetin or celecoxib, Dox induced overexpression of MDR1 and COX2 mRNA were reduced by quercetin, not by celecoxib, whereas PGE2 release was significantly decreased with subsequent enhancement of Dox cytotoxic efficacy by both of them. CONCLUSIONS: Dox-induced MDR1 up-regulation may be dependent on COX2-transcriptional activity, not PGE2, suggesting that the existence of causal link between COX2 and MDR1 expression induced by Dox, and modulation of COX2 transcriptional expression by quercetin would not only sensitize leukemia cells to Dox, but also prevent the acquisition of MDR during chemotherapy. PMID- 25687050 TI - [Mechanisms of sorafenib induced NB4 cell apoptosis]. AB - OBJECTIVE: To investigate the effects of sorafenib on human acute promyelocytic leukemia cell NB4 and its mechanism. METHODS: The human acute promyelocytic leukemia cell NB4 was treated with different concentrations (0, 1.5, 3, 6 and 12 umol/L) of sorafenib, the proliferation inhibitory rate of NB4 cells was assayed by MTT, the apoptosis of NB4 was determined with flow-cytomatry after treatment; after extraction of total protein, the Western blot was performed to determine the expressions of apoptosis-relatived molecules Caspase-3, Caspase-8 and MCL-1. The mRNA expressions of Caspase-3, Caspase-8 and MCL-1 were determined by RT-PCR. RESULTS: As compared with the control group, the proliferation of NB4 significantly decreased after treatment with different concentrations of sorafenib. The sorafenib significantly induced the apopotosis of NB4 cells in time- and dose-dependent manners. Furthermore, sorafenib treatment resulted in the obvious increase of the Caspase-3 and Caspase-8 protein and mRNA expressions, and down-regulated the MCL-1 protein and mRNA expressions in NB4 cells. CONCLUSION: Sorafenib can inhibit proliferation and induce apopotosis of human acute promyelocytic leukemia cell NB4 through the expression of Caspase-3 and Caspase-8, and down-regulation of the expression of MCL-1. PMID- 25687051 TI - [Apoptosis of retinoic acid-resistant APL NB4-R1 cells induced by As4S4 and its molecular mechanism]. AB - OBJECTIVE: This study was to investigate the apoptosis-inducing effect of As(4)S(4) on the retinoic acid-resistant acute promyelocytic leukemia (APL) NB4 R1 cells and its potential mechanisms. METHODS: The leukemia cell line NB4-R1 was cultured in vitro and divided into control group and treatment group. The apoptosis rate and cell cycle were detected by flow cytometry. The apoptotic DNA fragments were analyzed by agarose gel electrophoresis. The changes of BCL-2, BAX and Caspase-3 were determined by Western blot. RESULTS: After NB4-R1 cells were treated with As(4)S(4)(25 umol/L) for 0 h, 24 h, 48 h, the percentage of early apoptotic cells was obviously raised from 0% to 24.49% and 47.41%, the percentage of late apoptotic cells were elevated from 0.08% to 14.72% and 20.70%. Compared with control group, the DNA degradation revealed a characteristic DNA ladder during agarose gel electrophoresis after treatment for 24 h. The drug significantly induced an accumulation of the S phase cell population from 31.85% of the untreated cells to 42.53% and 55.12% treated with the different time whereas the NB4-R1 cells in G0/G1 phase decreased from 57.30% to 37.56% and 28.51%. As(4)S(4) could decrease the expression of BCL-2 and increase the level of BAX. Pro-caspase-3 could be cleaved into small active fragments under the apoptotic stimulation. CONCLUSION: As(4)S(4) can efficiently induce NB4-R1 cell apoptosis, which may be related with the down-regulation of BCL-2 and the up regulation of BAX, as well as the activation of Caspase-3. PMID- 25687052 TI - [Clinical resarch of decitabine combined with modified CAG regimen for treatment of relapsed or refractory acute myeloid leukemia]. AB - OBJECTIVE: This study was to investigate the therapeutic effectiveness and side effect of decitabine combined with modified CAG regimen for relapse or refractory patients with acute myeloid leukemia. METHODS: Ten patients suffered from relapsed or refractory acute myeloid leukemia from January 2013 to July 2013 were analyzed retrospectively, and the clinical characteristics, therapeutic effectiveness, side effect were observed. Among 10 patients 7 patients were males and 3 patients were females, the ratio of male to female was 7:3, median age was 45 (17-61) years. RESULTS: After treatment by using decitabine combined with modified CAG regimen, 7 patients achived complete remission, 1 patient achived partial remission, 2 patient did not achieve remission, the overall remission rate was 80% (8/10), the median time of white blood cell count recovery was 18.5 (5-28) days, median time of platelet level recovery was 19 (12-29) days. The main side effects of treatment were myelosuppression. There was no new lung infection in all cases, one case died of exacerbation of primary lung infection after therapy. CONCLUTION: The treatment of decitabine combined with modified CAG regimen for relapsed and refractory AML shows high response rate, low side effects, so it worthy to further clinical study. PMID- 25687053 TI - [Effect of has-miR-150 on proliferation and apoptosis of Jurkat cells and its mechanism]. AB - OBJECTIVE: This study was to investigate the effect of has-miR-150 on the proliferation and apoptosis in human acute T lymphocytic leukemia (T-ALL) cell line Jurkat, and explore its mechanism. METHODS: Lentivirus-has-miR-150 was constructed and transfected to Jurkat cells. The expression of miR-150 was detected by real time PCR; the cell proliferation and apoptosis were detected by CCK-8 method and Annexin V/7-AAD labeling, respectively; the cell-related protein expressions of phosphatidylinositol-3-kinase(PI3K)/serine/ threonine kinase (Akt) signaling pathway were detected by Western blot. RESULTS: The expression of miR 150 in infected Jurkat cells was significantly upregulated by constructing lentivirus-has-miR-150. Compared to negative control (transfected with empty vector lentivirus), the cell proliferation after LV-miR-150 transfection was significantly inhibited and cell apoptosis was remarkably induced. Phosphorylation levels of P13K/Akt/NF-kappaB signaling pathway protein p-Akt and p-p65 decreased,whereas no obvious change was found in the expression of Akt. CONCLUSION: miR-150 may be a putative oncoprotein in T-ALL cells. Overexpression of miR-150 has noticeable effects on the proliferation inhibition and apoptosis induction of Jurkat cells, which may be mediated by the negative regulation of PI3K/Akt /NF-kappaB signaling pathway. PMID- 25687054 TI - [Elderly chronic lymphocytic leukemia combined with invasive aspergillosis infection in one case]. AB - OBJECTIVE: This study was aimed to investigate the morphological, immunophenotype, cytogenetic characteristics, clinical and therapy features in one elderly patient with chronic lymphocytic leukemia (CLL) combined with invasive aspergillose infection(IAI). METHODS: The morphological features of bone marrow cells from patient were observed by light microscope, the immunophenotype were detected by flow cytometry, the cytogenetic characteristics were assayed by conventional chromosomal analysis and fluorescence in situ hybridization (FISH). RESULTS: at onset of disease, the patient was diagnosed as B-CLL, Rai stage is II. He was treated with a course of RF(fludarabine 50 mg*5, rituximab 600 mg*5) chemotherapy, and achived complete remission (CR) lasting for five years, then the patient was treated with multiple courses of chemotherapy and maintained at a steady state of disease. After the last chemotherapy, this patient developed a fever, his temperature fluctuated at 37.2-38.7 degrees C, the lung CT showed the presence of massive shadow, repeated 1-3-beta-D-glucan test was positive,and he was considered as invasive aspergillosis infection, voriconazole was intravenously injected him for 2 months, his lung CT showed better efficacy. However, the leukemia continued progress, his hemogram was extremely low, invasive aspergillosis infection relapsed,voriconazole treatment was poor effect,ultimately this patient died of the rapid progress of leukemia and multiple organ invasive aspergillosis. Autopsy showed chronic lymphocytic leukemia with multiple metastases and multiple organ invasive aspergillosis. CONCLUSION: invasive aspergillosis is a serious complication for CLL patients,once occurs, the prognosis is poor,so early diagnosis and prophylactic antifungal therapy may reduce fungal infection complication. PMID- 25687055 TI - [Effect of arsenic trioxide on differentiation induction of chronic myeloid leukemia k562 cells and its potential mechanism]. AB - OBJECTIVE: This study was to explore the effect of arsenic trioxide (ATO; As(2)O(3)) on differentiation of chronic myeloid leukemia K562 cells and its potential mechanism. METHODS: ATO with different concentration (0.1, 0.5, 1.0, 2.0, 5.0 umol/L) were used to treat K562 cells, and MTT assay was used to detect the growth level of K562 cells; Benzidine staining was applied to measure the change of hemoglobin content; flow cytometry (FCM) was conducted to detect the expression of CD41 and GPA on K562 cells; RT-PCR and Western blot were used to measure the mRNA expression of BTG1 and TAL1 and the protein expression of BTG1 and TAL1, respectively. RESULTS: ATO significantly inhibited the growth of K562 with dose- and time- dependent manners by benzidine staining, the positive rate of K562 cells induced by ATO reached to 17.63% +/- 1.18%, which was significantly higher than that of control (2.87% +/- 0.63%) (P < 0.01), and GPA, as the specific marker of erythroid cell differentiation, achieved 68.46% +/- 3.67%, while it in control was 3.39% +/- 0.84% (P < 0.01), besides, the CD41 expression of megakaryocyte increased but not so obvious as GPA. Meanwhile, the differentiation-related transcriptional factors TAL1 and BTG1 mRNA and the corresponding proteins were expressed more highly. CONCLUSION: ATO can induce the differentiation of K562 cells into erythroid cells and megakaryocyte, which is associated with up-regulation of the related transcription factors TAL1 and BTG1. PMID- 25687056 TI - [Clinical characteristics and prognosis of 20 cases of primary central nervous system lymphoma]. AB - OBJECTIVE: This study was to investigate the clinical and pathological characteristics, curative effect and prognosis of primary central nervous system lymphoma (PCNSL). METHODS: The clinical and pathological features, diagnosis and treatment, curative efficacy and survival rate of 20 cases of primary central nervous system lymphoma were retrospectivaly analyzed. RESULTS: The indicated that the clinical manifestations included headache, paralysis, seizures, dizziness and mental acuity, etc. There were 7 cases with single focus of lesion, 13 cases with multiple foci of lesions. The pathologic examimation showed 1 case of peripheral T-cell lymphoma and 19 cases of diffuse large B cell lymphoma, they all were from non-germinal center. Out of 20 cases, 11 cases with Ki-67>75%,6 cases with Ki-67 50%-75%, 2 cases with Ki-67 25%-50% and 1 case with Ki-67 10%. Therapeutic evaluation were as follows: 10 cases with CR, 2 cases with PR, 6 cases with PD in 18 patients recieved treatment. The use of ritusimab in treatment or no use and number of lesion foci in cranium were related to survival time (P < 0.05) . The survival time in group with Ki-67(+)<75% was longer than that in group with Ki-67(+)>75% (P = 0.042). Age and CSF-TP level were related to curative effect (P < 0.05) . CONCLUTION: There is no specific clinical manifestation. The physical examination and imageological diagnosis of PCNSL, as well as pathological biopsy are necessary for diagnose of PCNSL. The factors for poor prognosis include age > 60 years, CSF-TP > 600 mg/L, multiple lesions and Ki 67(+)>75%. PCNSL has high malignancy and poor prognosis. The chemotherapy based on high dose of MTX (among which MTX combined with rituximab) and HSCT after CR are the best treatment regimen for DLBCL. PMID- 25687057 TI - [Analysis of bortezomib treatment efficacy and adverse reactions for patients with follicular lymphoma]. AB - OBJECTIVE: This study was aimed to investigate the therapeutic efficacy and safety of bortezomib in the treatment of follicular lymphoma patients. METHODS: According to treatment methods, the 56 follicular lymphoma patients were divided into 2 groups: CHOP group (26 cases) and bortezomib group (30 cases). The patients in CHOP group received the CHOP chemotherapy regimens (cyclophosphamide+ epirubicin+vincristine+prednisolone), the patients in bortezomib group received bortezomib based on CHOP. The clinical curative effect and adverse reaction between the two groups were compared. RESULTS: The short-term efficacy of bortezomib group showed significantly better than that in CHOP group (P < 0.05), the total efficiency in bortezomib group (80%) was significantly higher than that in CHOP group (53.85%) (P < 0.05). The progression free survival of the patients in the bortezomib group was statistically longer than that in the CHOP group (10 months vs 6 months) (P = 0.013). There was no significant differences in the overall survival mediam survival time between these two groups (10 months vs 11 months)(P = 0.107). The occurrence of adverse reactions in the two groups was no significant different (P > 0.05). CONCLUSION: Bortezomib combined with CHOP chemotherapy can obviously prolong the progression free survival of patients, and improve the total efficiency without increase of adverse reaction. The benefit to overall survival needs to further extend follow-up observation. PMID- 25687058 TI - [Clinical efficacy of radiotherapy and chemotherapy combined with surgical treatment for the patients with primay mediastinal B-cell lymphoma]. AB - OBJECTIVE: This study was to investigate the clinical efficacy of radiotherapy and chemotherapy combined with surgical treatment for treatment of patients with primay mediastinal B-cell lymphoma. METHODS: A total of 62 patients with primay mediastinal B-cell lymphoma was selected, out of them 26 patients received radiotherapy and che-motherapy were selected as A group, other 36 patients received radiotherapy and chemotherapy combined with surgical treatment and were selected as B group. Clinical efficacy were observed and compared after treatment. RESULTS: In A group 5 patients achieved complete remission (CR), 5 patients achieved partial remission (PR), the total remission rate of A group was 27.8%; in B grouop, 13 patients achieved complete remission (CR), 10 patients achieved PR, the total remission rate of B group was 63.9%. The average survival time of patients in B group was 57.244 months, and the average survival time of patients in A group was 55.541 months, the former was higher than latter. The 5 years survical rate of patients in A group was 57.7%, and the 5 years survival rate of patients in B group was 80.6%, the latter was significantly higher than former. CONCLUSIONS: Radiotherapy and chemotherapy combined with surgical treatment for patients with primay media-stinal B-cell lymphoma has been confirmed to be effective, and may be used in clinic. PMID- 25687059 TI - [Application of 18F-FDG PET/CT images in the newly diagnosed extranodal NK/T cell lymphoma]. AB - OBJECTIVE: This study was to explore the use value of (18)F-FDG PET/CT in patients with extranodal NK/T cell lymphoma (ENKTL). METHODS: Both PET/CT and CT images were retrospectively analyzed in 43 newly diagnosed patients with ENKTL, and the anatomical position, extent of foci, subtypes, staging and therapeutic regimen determined by both these 2 imaging methods were compared, and relationship between the maximum standard uptake value (SUV(max)) and subtypes, different staging and constitutional symptoms were evaluated. RESULTS: The top four anatomical positions involved were nose (76.74%), pharynx nasalis (41.86%), Waldeyer's ring (30.23%) and paranasal sinus (27.91%), respectively according to the results of the PET/CT examination, and (18)F-FDG uptake was not found in four patients in the region of upper aerodigestive tract. The PET/CT staging was significantly correlated with constitutional symptoms (P < 0.01). The mean SUV(max) of 43 patients was 13.65 +/- 6.35, and the SUV(max) of advanced stages (III/IV) was higher than that of early stage (I/II). Different staging results were found in 21 patients between PET/CT and CT images, 14 patients out of them had direct influence on the treatment plan. Staging of 8 cases was changed from early stage judged by CT image into advaneed stage judged by PET/CT, and radiotherapy regimen of 6 cases at early stage were altered because of the application of PET/CT. CONCLUSION: The location and scope of foci in ENKTL patients can be displayed more accurately by PET/CT, the PET/CT is more accurate and reliable than traditional CT image, and has considerable value in determining the treatment plan, and it should be applied in clinical practice widely. PMID- 25687060 TI - [Effects of nuclear factor of kappa B decoy oligodeoxynucleotides on murine with multiple myeloma]. AB - OBJECTIVE: The present study was to evaluate the effects of nuclear factor of kappa B decoy oligodeoxynucleotides on murine multiple myeloma models. METHODS: The severe combined immunodeficient mice were injected subcutaneously with RPMI 8226 myeloma cells. When tumors became measurable, the mice were divided into 2 treatment groups who respectively received 5 ug/g or 10 ug/g liposome-NF-kappaB decoy ODN compounds, and one control group was selected; the control group received 10 ug/g liposome-NF-kappaB mutant decoy ODN compounds, twice per week for 4 weeks. The mice were killed when they died or the tumor diameter became >2 cm. RESULTS: The liposome-NF-kappaB decoy ODN could efficiently suppress NF kappaB DNA binding activity and inhibited the expression of IL-6. As compared with the control group, the two liposome-NF-kappaB decoy ODN-treated groups showed more remarkably survival time and smaller tumor volume. CONCLUSION: In vivo transfection of NF-kappaB decoy ODN may provide a new therapeutic strategy for multiple myeloma. PMID- 25687061 TI - [Analysis of cell morphology and immunophenotypic characteristics in 47 cases of multiple myeloma]. AB - OBJECTIVE: This study was to investigate the cell morphology and cell immune phenotypic characteristics in patients with multiple myeloma (MM). METHODS: The flow cytometry with multiparametric direct immunofluorescence technique, and CD45/SSC and CD38(+)(+)/CD138(+) gating were used to measure cell markers CD138, CD38, CD56, CD117, CD3, CD13, CD33, CD19, CD7, CD20, CD22, CD34, CD28 in 47 MM patients. At the same time the morphology examination of bone marrow cells was performed. RESULTS: The suspicious myeloma cell ratio in MM patients was 9.42% 74.25% detected by flow cytometry, moreover, the myeloma cell ratio detected by morphology examination was 11.0%-80.6%, there was a good correlation between the two detection methods (r(2) = 0.54, P < 0.001). The ratio of antigen positive expression was as follows: 74.46% for CD138, 100% for CD38, 57.44% for CD56, 40.42% for CD117, 6.38% for CD13, 19.15% for CD33, 8.51% for CD20, 27.66% for CD28, 2.12% for CD22, 4.25% for CD34, 0% for CD3, 0% for CD19, 0% for CD7. CONCLUSIONS: CD45/SSC and CD38(+)/CD138(+) gating technique can accurately gate multiple myeloma cell sets which need analysis, the majority of myeloma cells expreses CD138, CD38, CD56 antigens. The immunophenotypic analysis combined with the cell morphology examination more contribute to the diagnosis and differential diagnosis of multiple myeloma. PMID- 25687062 TI - [Hypercoagulable state in patients with multiple myeloma]. AB - OBJECTIVE: This study was to detect the plasma thrombomodulin (TM), D-dimer and fibrinogen in patients with multiple myeloma (MM) and to analyze their relationship with morbid state, and also to investigate the relationship of the expression of coagulation factor with the ratio of myeloma cells. METHODS: ELISA was used to detect the TM level in 45 cases of MM at different stages. The plasma level of D-dimer and fibrinogen was detected by STA automatic coagulation analyser. RESULTS: The level of plasma TM in newly diagnosed patients was higer than that in normal control group and in platform stage group (P < 0.01; P < 0.05). There were significant differences between relapsed or refractory group and normal control group or those reached platform stage group (P < 0.05). Meanwhile, the level of plasma TM in the group of thalidomide combined with chemotherapy was higer than that in newly diagnosed patients (P < 0.05). The level of plasma D-dimer and fibrinogen of MM patients was higher than that in normal controls (P < 0.01;P < 0.05). The expression of D-Dimer in relapsed or refractory group reached the maximum. Also, the level of plasma D-Dimer in group of thalidomide combined chemotherapy was higer than in newly diagnosed patients (P < 0.05). The expression of coagulation factor did not correlate with the ratio of myeloma cells. CONCLUSIONS: Level of plasma TM, D-Dimer and fibrinogen of MM patients is higher than that in control group. The level of plasma TM and D-Dimer can be elevated when thalidomide used, which indirectly suggested the tendency for thrombosis in MM patients. PMID- 25687063 TI - [Expression of autophagy related gene BECLIN-1 and number of autophagic vacuoles in bone marrow mononuclear cells from 40 myelodysplastic syndromes patients and their significance]. AB - OBJECTIVE: The purpose of this study was to detect the expression level of autophagy related gene BECLIN-1 and the number of autophagic vacuoles in bone marrow mononuclear cells (BMMNC) from myelodysplastic syndrome(MDS) patients and to explore their difference in different stage of MDS and relationship between their difference and disease characteristics. METHODS: The BMMNC from 9 normal controls, 19 cases of low-risk MDS, 14 cases of high-risk MDS and 7 cases of MDS transformed AML were collected. The expression level of BECLIN-1 was detected by real time PCR (RT-PCR) and the amount of autophagic vacuoles was counted by transmission electron microscopy. RESULTS: The expression level of BECLIN-1 in BMMNC from patients with low-risk group was obviously higher than that in BMMNC from normal controls; the expression level of BECLIN-1 in BMMNC from patients of hgh risk group was higher than that in BMMNC of normal group, but there was no statistical significance (P > 0.05); the expression level of BECLIN-1 in BMMNC from patients with MDS-transformed AML group was significanly lower than that in BMMNC of normal group (P < 0.05). Transinission electron microscopy showed that the amount of autophagic vacuoles in BMMNC from patients with low-risk and high risk MDS groups was more than that in normal control, but there was no stetistcal significance (P > 0.05), while the amount of autopuagic vecuoles in BMMNC from patients of MDS-transformed AML group was significantly less (P < 0.05). CONCLUSIONS: The expression of BECLIN-1 and the number of autophagic vacuoles in BMMNC from patients with MDS progression and patients with MDS-transformed AML are gradually declining. The autophagy may be associated with disease progression. PMID- 25687064 TI - [Prognostic significance of morbidly hematopoietic characteristics in 69 patients with myelodysplastic syndrome]. AB - OBJECTIVE: This study was to investigate the influence of morbidly hematopoietic characteristics on the prognosis of patients with myelodysplastic syndrome (MDS). METHODS: A total of 69 cases of MDS were analyzed retrospectively on ralatienship between sex, age, MDS types, WBC count, hemoglobin (Hb) level, platelet (Plt) count at diagnosis, morbidly cytologic features of bone marrow and survival time of MDS patients. RESULTS: The median survival time of 69 cases of MDS was 29.90 months. The patients of different sexes and Plt level at diagnosis did not display statistically significant difference in median survival time (P > 0.05); the patients with different ages, WBC count and Hb level showed statistically significant difference in median survival time (P < 0.05); the median survival time of patients with different MDS types was significant different (P < 0.01); the MDS patients with myeloid lineage containing nuclear plasma development imbalance, micronuclei, abnormal mitotic figures, with erythroid lineage containing megaloblastic degeneration, cell size disparity, nuclcar budding and muclear fragmentation, and with megakaryocyte lineage containing micromegaryocytes, excessive muclear leaves, displayed significant difference in median survival time (P < 0.05). The MDS patients with ALIP positive, fibrosis in bone marrow blopsy showed significant difference in median survival time. CONCLUSION: The age, MDS types, Hb level and WBC count at diagnosis are indicators influencing the prognosis. The unbalanced development of muclear plasma, micronuclei, abnormal mitotic figures in myeloid morbid hematopoiesis, the megaloblastic degeneration, cell size disperity, muclear budding, nuclear fragmentation in erythroid morbid hematopoiesis, the micro-megakaryocytes, excessive nuclear leaves in megakaryocytic morbid hematopoiesis, and existance of ALIP posstive and fibrosis in bone marrow biopsy indicate important values for evaluation of MDS prognosis. PMID- 25687065 TI - [Diagnostic value of hepcidin in elderly patients with iron deficiency anemia and anemia of chronic disease]. AB - OBJECTIVE: This study was to evaluate the differential diagnostic value of serum Hepcidin in elderly patients with iron deficiency anemia (IDA)and anemia of chronic disease (ACD). METHODS: The group of IDA consisted of 28 elderly patients, and the group of ACD consisted of 21 elderly patients, the control group included 25 healthy elderly people. Hepcidin was measured by ELISA; WBC,RBC counts were assayed by haematology analyzer; the serum ferritin level was measured by using radioimmunoassay; C-reaction protein(CRP) and serum iron levels were assayed by a biochemical analyzer. RESULTS: Hepcidin level between the three groups was significantly different (P < 0.01); serum ferritin,WBC and CRP levels in ACD patients were significantly higher than that in IDA patients (P < 0.01); according to the receivers operating characteristic (ROC) curve, the best threshold in diagnosis of IDA was 93.31 ug/L with the sensitivity of 88% and the specificity of 89%; the best threshold diagnosis of ACD was 130.05 ug/L with the sensitivity of 72% and the specificity of 96%. CONCLUSIONS: serum Hepcidin has a certain value in the differential diagnosis of IDA and ACD in elderly patients. PMID- 25687066 TI - [Single center comparative analysis of hematopoietic cell transplantation from alternated donor in patients with hematologic malignancies]. AB - OBJECTIVE: One of the truly revolutionary advances in hematopoietic cell transplantation (HCT) is the increasingly successful use of alternative donors, as only 1/4 of patients who require an allogeneic hematopoietic cell transplant will have a HLA-matched sibling donor. Thereby, three alternative graft sources: umbilical cord blood (UCB), haploidentical (hi) related donor and mismatched unrelated donor hematopoietic cell transplantation (MMUDT) are available. This study was purposed to compare the characteristics of umbilical cord blood transplantation(UCBT), haplaidentical (hi) related donor hematopoieetic cell transplantation(hi-HSCT) and MMUDT. METHODS: The clinical date of 93 patients with hematologic malignancies who received UCBT (n = 22), hi-HSCT (n = 42) and MMUDT (n = 29), and the days of hematopoietic reconstration and engraftment, rate of acute graft-versus-host disease (GVHD), relapse rate, and overall survival (OS) were analysed. RESULTS: The median days of hematopoietic reconstitution (WBC>1.0*10(9)) among UCBT recipients were significantly longer than those among hi-HSCT/MMUDT recipients, (19 in UCBT, 12 in hi-HSCT and 12 in MMUDT)(P < 0.001), whereas the median days of full engraftment (STR >95%) among hi-HSCT recipients were longer than those among UCBT/MMUDT recipients (26 in hi-HSCT, 15 in UCBT and 20 in MMUDT, P = 0.028), the implant failure rate of UCBT recipients was higher than others (26% in UCBT, 5% in hi-HSCT, 3% in MUUDT)(P < 0.05). Multivarite analysis demonstrated no apparent differences in the rate of aGVHD (50% in UCBT,57.1% in hi-HSCT and 72.4% in MMUDT) (P = 0.498), and the rate of III-VI aGVHD also was no significant defference (27.3% in UCBT, 28.6% in hi-HSCT and 17.2% in MMUDT)(P = 0.543), the rate of chronic GVHD of UCBT recipients was lowered (19.0% in UCBT, 45.5% in hi-HSCT, 58.3% in MMUDT, P = 0.026). Overall survival at 2 years was 79.9% in UCBT, 80.9% in hi-HSCT and 88.0% in MUUDT (P = 0.097), and the TRM in 100 days was 23.8% in UCBT, 20.0% in hi-HSCT and 11.1% in MMUDT (P = 0.245) respectively. CONCLUSIONS: The UCBT is characterised by lowest rate of cGVHD, but its hematopoietic recostruction is slow; the hi-HSCT has more alternative donors for using in clinic and can achieve post-transplant adoptive cellular immunotherapy, but its TRM has been found to be higher; the first important problem for MMUDT is to decrease the higher incidence of aGVHD and cGVHD. PMID- 25687067 TI - [Hematopoietic reconstitution after transplantation of uncontrolled-rate cryopreservation autologous peripheral blood hematopoietic stem cells using -80 degrees C mechanical freezer]. AB - OBJECTIVE: This study was to identify the efficacy of -80 degrees C cryopreservated peripheral blood hemato-poietic stem cell (PBHSC) transplantation for hematopoietic reanstitution in patients. METHODS: The efficacy of 104 patients underwent autologous peripheral blood hematopoietic stem cell transplantation using uncontrolled-rate freezing and storage at -80 degrees C was evaluated. RESULTS: This cryopreservation method could effectively cryopreserve peripheral blood stem cells. Out of 104 patients only 2 patients died, other patients got hematologic reconstition satisfactorily, the median engrafement times of neutrophils and platelet were 12 and 14 days respectively, the activity of cells after rehabilitation was 94%, the mean recovery rates of CD34(+) cells and mononuclear cells (MNC) were 86% and 80.3% respectively. There were no significant influences on engrafement time in sex, chemotherapy circles and radiotherapy. The engrafement of leukocytes associated with amount of CD34(+) cells. CONCLUSION: This simple uncontrolled-rate freezing PBHSC at -80 degrees C is safe, effective and economic, and can meet clinical needs. As compared with the classical cryopreservation, there were no significant differences in hematopoietic reconstitution. Therefore, this method worth to popularize and apply in clinic. PMID- 25687068 TI - [Analysis of prognosis in acute myeloid leukemia treated with allogeneic hematopoietic stem cell transplantation]. AB - OBJECTIVE: The study was to investigate the prognosis factors in acute myeloid leukemia (AML) patients treated with allogeneic hematopoietic stem cell transplantation (allo-HSCT). METHODS: The clinical information of 60 patients in our hospital was retrospectively analyzed and the prognosis factors of survival and relapse were explored by COX's proportional hazard model. RESULTS: The elderly (HR = 4.530, P = 0.012), cGVHD (HR = 0.023, P = 0.003) and infection fungal disease (IFD) (HR = 4.019, P = 0.017) were influence factors for 2 year cumulative overall survival (OS). Response status (high risk vs low risk: HR = 3.465, P = 0.028), preconditioning regimens (TBI/Cy vs Bu/Cy: HR = 0.071, P = 0.012; FB vs Bu/Cy: HR = 7.547, P = 0.025) and cGVHD (HR = 0.088, P = 0.004) were influence factors for 2 year cumulative relapse rate (RR). cGVHD (P = 0.017) and IFD (P = 0.000) had an effect on OS after 2 years since allo-HSCT. CONCLUSION: Age, response status, preconditioning regimens, cGVHD and IFD are closely associated with the prognosis of AML patients treated with allo-HSCT, and different patients need the individualized treatment. PMID- 25687069 TI - [Clinical analysis of acute heart failure's risk factor for chronic myelogenous leukemia patient during the early stage of allogeneic hematopoietic stem cell transplantation]. AB - OBJECTIVE: The study was to analyze the acute heart failure's risk factors and clinical characteristics for the patient with chronic myelogenous leukemia (CML) during the early stage (within 100 d) of allogeneic hematopoietic stem cell transplantation (allo-HSCT). METHODS: A total of 106 cases of CML received allo HSCT were retrospectively studied in Nanfang Hospital from May 2003 to May 2013. On the basis of existence or absence of acute heart failure during early stage of allo-HSCT (100 d), the patients were divided into heart failure (15 cases) and control group (91 cases). Using Logistic univariate analysis, Fisher' exact test and Pearson X(2) test, the acute heart failure's risk factors and clinical characteristics of both groups were analyzed. RESULTS: The median occurrence time of acute heart failure was 3 d (1 d before transplantation to 84 d after transplantation). Logistic univariate analysis indicated that the imatinib treatment history and time, and the prophylaxis regimens for GVHD with anti thymocyte globulin (ATG) were all the poor prognostic factors for acute heart failure. Incidence of hepatic veno-occlusive disease (HVOD), bacterial infection and adverse prognostic events including death in the heart failure group patients were statistically higher than that in control group (P < 0.05). CONCLUSION: Acute heart failure mostly happened in the early stage after allo-HSCT, imatinib treatment and GVHD prophylaxis regimens with ATG are the poor prognostic factors for acute heart failure. The patients of heart failure group seem to have higher incidence of hepatic veno-occlusive disease (HVOD), bacterial infection and deaths. PMID- 25687070 TI - [Effects of catalase on the engraftment of human hematopoietic stem cells in NOD/SCID mice]. AB - OBJECTIVE: To investigate the effect of catalase (CAT) on engraftment of human hematopoietic stem cells (HSC) by co-transplanting umbilical cord-derived mesenchymal stem cells (UC-MSC) with over-expressed CAT and human HSC into NOD/SCID mice. METHODS: The UC-MSC cultured in vitro were transfected by the retrovirus containing green fluorescent protein (GFP) and GFP-CAT genes respectively. MSC-GFP and MSC-GFP-CAT cell lines were sorted by flow cytometry. Co-culture and co-transplant experiments were performed to detect the effects of CAT on expansion and engraftment of human HSC. RESULTS: The percentage of GFP(+) cells were approximately 97.6% and 96.8% after sorting. The mRNA expression of CAT in MSC-GFP-CAT was 23.9-fold higher than that in UC-MSC. The activity of CAT in UC-MSC, MSC-GFP, MSC-GFP-CAT cells were 19.5, 20.3 and 74.1 Unit respectively. There was no significant differences in the percentage of CD34(+) cells between 3 groups in co-culture experiment. And the percentage of human CD45(+) cells in NOD/SCID mice were (3.22 +/- 3.1)%, (4.26 +/- 3.56)% and (7.37 +/- 4.51)% respectively. CONCLUSION: MSC-GFP-CAT significantly improves the engraftment of human HSC in NOD/SCID mice, whereas co-culture with the MSC-GFP-CAT can not promote the expansion of HSC in vitro. PMID- 25687071 TI - [Change and clinical significance of peripheral blood T-lymphocyte functional subsets in acute graft-versus-host disease]. AB - OBJECTIVE: This study was aimed to detect the change of T-lymphocyte functional subsets marked by CCR7 and CD45RA in the aGVHD within 100 days after allo-HSCT and to explore its clinical significance. METHODS: The peripheral blood of 42 patients after allo-HSCT was collected every two weeks since hematopoietic reconstitution. The expression of CD3, CD4, CD8, CCR7 and CD45RA-marked T lymphocytes was detected by flow cytometry, the relationship between their expression and the prognosis of aGVHD was analyzed. RESULTS: The percentage and the absolute count of CCR7(+) T lymphocyte were significantly reduced in aGVHD. The percentage of T(naive), T(CM), T(EM) and the absolute count of T(naive), T(EM), TTD were sharply reduced in aGVHD, moreover has changed correspondingly with outcome of aGVHD. The percentage of CD3, CD4, CD8-marked T-lymphocyte subsets did not significantly changed. CONCLUSION: T-lymphocyte functional subsets marked by CCR7 and CD45RA are a valuable indicator to monitor early immune reconstruction for patients with the aGVHD after allo-HSCT. PMID- 25687072 TI - [Expansion and function of MHC restricted killer T cells derived from umbilical cord blood]. AB - OBJECTIVE: This study was to expand the cytotoxic T lymphocytes (CTL) through inducing the differentiation of umbilical blood monomuclear cells (UBMNC) by using various combination of cytokines, and to investigate the functions of expanded CTL. METHODS: The MNC were isolated by ficoll density gradient centrifugation. Then, the PHA-P, IFN-gamma combined with IL-2, IL-15 and other cytokines were used for induction and expansion of the cord blood-derived CTL. The biological function of CTL was examined by phenotype analysis, cytotoxic tests and real-time fluorescence quantitative PCR. RESULTS: After expansion for 15 days, the cell number increased by 1522% +/- 137%. The content of CD3(-)CD8(-) cells in uncultured cord blood MNC was 95%, and the CD3(+)CD8(+) CTL cells reached 82.77% in cultured cord blood MNC after expansion for 15 days. The expanded CTL cell showed the cytotoxic activity against K562 and HeLa cell line. The killing rate of MNC was 61.88 +/- 1.08%. After expansion, the killing rate could reach to 90% with the average value of 90.33 +/- 2.02%. The expanded CTL cells highly expressed some key cytokines, such as granzyme A, granzyme B, GM CSF, granulysin, IFN-gamma, TGF-beta, TNF-alpha and perforin. Compared with the control group, the expression of IFN-gamma and TGF-beta significantly increased (P < 0.05), and the other factors dramatically increased (P < 0.01). CONCLUSION: The cord blood-derived CTL can be expanded by different combinations of cytokines. These protocols may provide alternative choices for CTL cell expansion in tumor adoptive immunotherapy. PMID- 25687073 TI - [Slowly-adhered primary bone marrow mesenchymal stem cells may exhibit more potent immuno-regulatory activity]. AB - OBJECTIVE: This study was to investigate the relationship between the adherent ability of freshly isolated MSCs with their inhibitory effect on lymphocyte activation. METHODS: Human bone marrow mononucleated cells were maintained in culture for 48 hours, the attached and the non-attached cells were then cultured separately and the adherent cells were collected and passaged. Cellular surface markers were analyzed with flow cytometry. Alkaline phosphatase activity and the intracellular lipid droplets were measured by histological staining, the in vitro osteogenesis and adipogenesis were identified. One-way mixed lymphocyte reaction was used to evaluate the suppressive activity of the adherent cells on lymphocyte proliferation, the prostaglandin E2 level in supernatant of cultured cells was detected by ELISA. RESULTS: Some cells attached to the plastic after the bone marrow mononucleated cells were allowed to adhere for 48 hours. The slowly attached cells were fibroblast-like in morphology, homogenously positive for CD44 and CD73 and negative for CD31 and CD45. They could be coaxed into osteoblasts and adipoblasts under the standard inductive conditions. These cells were able to inhibit lymphocyte proliferation in mixed lymphocyte reaction and their effect was more potent than those from the adherent cells appeared within 48 hours. The concentration of prostaglandin E-2 in the supernatants of the slowly-adhered cells was significantly higher than that in the MSCs cultured with the traditional method (90.8 +/- 10.37 ng/ml vs 70.2 +/- 8.98 ng/ml) (P < 0.01). CONCLUSIONS: The MSCs exist in the marrow mononucleated cells after adherent culture for 48 hours, and the MSCs may exhibit more potently inhibitory activity on lymphocyte activation. PMID- 25687074 TI - [Effect of umbilical cord blood mesenchymal stem cells on peripheral blood lymphocyte subsets]. AB - OBJECTIVE: This study was aimed to investigate the effect of mesenchymal stem cells (MSCs) on subsets and cytokine secretion of T lymphocytes. METHODS: Umbilical cord blood-derived mesenchymal stem cells (UCBMSCs) were isolated by density gradient and were cultared by amplifying culture. The subsets and cytokine secretion of T lymphocytes were detected by flow cytomety after being co cultured with UCBMSC. RESULTS: The proliferation of lymphocytes was inhibited. CD4(+)T cell subsets were increased, CD8(+)T cell subsets decreased when co cultured with UCBMSC; Th1 and Tc1 level significantly reduced, while Th2 and Tc2 level slightly increased. CONCLUSION: The UCBMSC can inhibit the proliferation of lymphocytes, especially CD8(+)T cell subsets. In addition, UCBMSCs can reduce Th1 and Tc1 cells, and increase Th2 and Tc2 cells. UCBMSC may have the clinical application potential for preventing and remedying GVHD. PMID- 25687075 TI - [Genotype analysis and telomere length measure in patients with dyskeratosis congenita]. AB - OBJECTIVE: To analysze genotype and measure telomere length in two Chinese patients with dyskeratosis congenita(DC). METHODS: The peripleral blood DNA was extracted in two patients characterized by mucocutaneous abnormalities (abnormal nails, lacy reticulated skin pigmentation, and oral leukoplakia), bone marrow failure, DC genes were amplified by polymerase chain reaction (PCR), including DKC1, TERT, TERC, TINF2, NOP10, NHP2, then DNA sequencing was performed for abnormal exons. Lymphocyte telomere length was measured by flow cytometry fluorescence in situ hybridization(Flow-FISH). RESULTS: Abnormal peaks were found in exon 6 of TINF2 gene of the two patients and a 811C->T transition in TINF2 gene in one patient. DNA sequencing showed a 848C->A transition in TINF2 gene in another patient. Relative telomere length was remarkable less than that of normal children with same age. CONCLUSIONS: Physician should think about DC if the young patients with mucocutaneous abnormalities and marrow failure. Early detection of related genes and measurernant of tolomere length may contribute to avoid misdiagnosis. TINF2 c.811C->T (Q271X) and TINF2 c.848C->A (P283H) exist in the two patients, it is reported in China for the first time. PMID- 25687076 TI - [Effect of leukoreduction on tumor-associated cytokine accumutation in supernatant of stored packed red cells and its effect on tumor cell proliferation in vitro]. AB - OBJECTIVE: This study was to investigate whether prestorage leukoreduction could decrease the accumulative concentration of tumor-associated cytokines in supernatant of stored packed red blood cells (pRBC) and to study the effect of prestorage leukoreduction on proliferation of HepG2 tumor cells by in vitro. The leukoreduced (LR) and non-leukoreduced (NLR) pRBC were equally obtained from one donation and were stored under 2 degrees C-6 degrees C. The supernatants of pRBC in these two group were performed by centrifugation with 1 006*g for 10 min at day 0 and 35 d. The enzyme-linked immunosorbent assay (ELISA) was used to detect the expression of normal T cells and secretory factor (RANTES/CCL5), as well as the accumulative concentrations of tumor-necrosis factor (TNF-alpha), platelet derived growth factor (PDGF), vascular endothelial growth factor (VEGF) and monocyte chemotactic protein-1 (MCP-1) in pRBC supernantant of above-mentioned two groups. After HepG2 cells was cultured with the supernatant of NLR-pRBC and LR-pRBC at the end of day 35 together for 48 hours, the methyl thiazolil tetracolium (MTT) method was used to measure the proliferation of tumor cells in vitro. RESULTS: The accumulative concentration of 5 cytokines in supernatants of above menthioned two groups increased in different degrees along with the prolongation of storage time,that is, the accumulative concentrations of 5 cytokines at 35 d were higher than that at day 0, in which the change of VEGF accumu-lative concentration showed statistical significance, its accumulative concentration in NLR group at day 35 elevated to 549.61 +/- 299.43 pg/ml, and was higher than that in LR group (95.46 +/- 110.87 pg/ml) (P < 0.05). The experiment of HepG2 cell proliferation indicated that the supernatant of LR pRBC group produced less proliferation of tumor cells with OD value 0.40 (95% CI, 0.38-0.42) than that of NLR pRBC group with OD value 0.49 (95% CI, 0.43-0.55) (P < 0.05). CONCLUSION: The prestorage leukoreduction has been confirmed to decrease the accumulative level of cytokines, particalarly decrease the accumulative level of VEGF, moreover, it may be a factor for inhibiting the proliferation of tumor cells in vitro. PMID- 25687077 TI - [Influence of "dosage effect" on unexpected antibody identification]. AB - OBJECTIVE: This study was to investigate the influence of "dosage effect" on unexpected antibody identification and explore its condition, scope and regularity. METHODS: A total of 40 blood recipient samples containing definite unexpected antibodies were selected by column agglutination technology, then AB fresh plasma was used to dilute the samples to obtain different concentrate liquid. After selecting panel cells which show positive with corresponding unexpected antibody in the serum, "single dosage" antigens were distinguished from "double dosage" ones, and then the antigen-antibody reactions were observed between "single dosage" panel cells and respective diluted recipient samples (by column agglutination technology). It's believable that the highest concentration which retains a negative result was choose to evaluate the agglutination strength between "double dosage" panel cells and diluted unexpected antibody, and to observe the difference happened at different "dosage" antigens with unexpressed antibody. RESULTS: Among 40 diluted recipient samples detected by column agglutination technology, the "dosage effect" appeared in 31 diluted samples. There were 30 samples in which the unexpected antibody agglutinated "double dosage" antigens <= 2+, while "single dosage" antigens negative. It appeared in another 1 diluted sample, in which the unexpected antibody agglutinated "double dosage" antigens 3+. There were 9 diluted samples in which the unexpected antibody agglutinated panel cells showing negative results (strength was between 1+-3+ before dilution). CONCLUSIONS: When the unexpected antibodies in Rh, MNS, Kidd, Duffy agglutinated "double dosage" antigens <= 2+ (by column agglutination technology) , "single dosage" antibody reaction maybe weaken, even be negative, and it may cause the "dosage effect" to interfere the unexpected antibody identification. The "dosage effect" appears in Rh, MNS, Kidd, Duffy blood system usually. PMID- 25687078 TI - [Investigation and analysis of blood transfusion in 1 766 hospitalized trauma patients]. AB - OBJECTIVE: The study was to understand the incidence of traumatic coagulopathy and the clinical blood transfusion in hospitalized trauma patients so as to provide a reference for guiding scientific component transfusion in trauma or surgical patients. METHODS: By using a software "clinical transfusion database" developed by our department, 1 766 trauma cases who suffered traumatic injury and required hospital admission between 2001 and 2012 were retrieved, and out of them 1 211 patients were given transfusion, and the transfusion-related indicators of the patients such as coagulation, hemoglobin levels before transfusion, trauma situation, massive blood transfusion and total blood transfusion were retrospectively analyzed. According total volume of blood usage during hospitalization,1 211 cases with transfusion were divided into three groups: low volume transfusion group ( <= 5 U, n = 471), moderate volume transfusion group (5 10 U, n = 449) and high volume transfusion group (>10 U, n = 291), then the difference of indicators among the 3 groups was compared, and the risk factors of high volume transfusion were analyzed. RESULTS: There were 33 cases of coagulopathy and 52 cases of massive transfusion in trauma patients with transfusion. The transfusion rate of trauma patients was about 68.6%. There was no association between the total amount of blood transfusion and surgical grade or whether surgery. The most patients were transfused using two components (plasma and red blood cell), the ratio of plasma to RBC transfused in patients with coagulopathy was approximately 1.0. In high volume transfusion group, there were more younger and male patients with more serious injury, their infection and death were significantly higher than that in other two groups (P < 0.01). CONCLUSION: There were approximately 69% of hospitalized trauma patients require transfusion, the patients in high volume transfusion group have two populations such as middle-aged and young men who was vulnerable to severe trauma mainly caused by accident injury or fall injury and older women who was vulnerable to osteoporotic hip fractures mainly caused by fall injuries. The coagulation disorders in the patients with trauma coagulopathy should be corrected by transfusion with high ratios of plasma to RBC. Massive transfusion (OR = 95.22), hemorrhagic shock (OR = 17.2), trauma coagulopathy (OR = 4.52) are risk factors of high volume transfusion > 10 U, and massive transfusion also is a risk factor of trauma coagulopathy (OR = 16.257). The routine dynamic monitoring of coagulation should be performed for trauma or surgical patients to guide the clinical transfusion scientifically. PMID- 25687079 TI - [Expression of CD71 on cell proliferation in hematologic malignancy and its correlation with Ki-67]. AB - OBJECTIVE: This study was to explore the expression of CD71, as a proliferation indicator, on cell proliferaration in hematologic malignancy and its correlation with Ki-67, so as to assess the feasibility of CD71 instead of Ki-67 for assaying cell proliferation by flow cytometry (FCM). METHODS: (1) Compared with mature B lymphoctyes during stationary phase in peripheral blood from healthy people, the cell cycle and the expression of CD71 and Ki-67 of cell lines from patients with leukemia and lymphoma were examined, the correlation among CD71, S-phase cell fraction (SPF) and Ki-67 were analyzed; (2) Compared with mature B lymphoctyes in bone marrow from non-hematologic disease patients, the expression and correlation of CD71 and Ki-67 of all kinds of leukemic cells and myeloma cells from bone marrow were analyzed by using Ki-67/CD71/CD45/CD123, Ki-67/CD71/CD45/CD20 or Ki 67/CD71/CD45/CD138. RESULTS: (1) in respect to the expression rate of CD71 on tumor cell lines, the expression rate of CD71 on HL-60 cells was (99.77 +/- 0.064)%, the expression rate of CD71 on NB4 cells was (99.23 +/- 0.12)%, the expression rate on THP-1 cells was (98.90 +/- 0.30)% and the expression rate on K562 cells was (97.03 +/- 0.15)% in myelogenous leukemia cell lines, the expression rate of CD71 on Raji cells was (99.35 +/- 0.21)% and the expression rate on Mino cell was (96.95 +/- 0.42)% in lymphoma cell lines, which were also obviously higher than that on cells of the control group (P < 0.05); (2) in respect to the expression rate of CD71 on tumor cells in bone marrow, the expression rate of CD71 on poorly differentiated AML(M1 and M2) cells was (51.50 +/- 19.31)%, the expression rate of CD71 on acute promyelocytic leukemia (AML-M3) cells was (35.71 +/- 14.02) %, the expression rate of CD71 on acute monocytic leukemia (AML-M5) cells was (30.54 +/- 14.38)%, the expression rate of CD71 on acute T lymphoblastic leukemia cells was (68.40 +/- 20.83)%, the expression rate of CD71 on acute B lymphoblastic leukemia was (39.67 +/- 18.27)%, the expression rate of CD71 on multiple myeloma (MM) cells was (55.49 +/- 18.15%), the expression rate of CD71 on chronic lymphocytic leukemia(CLL) was (1.32 +/- 0.33%), which were also higher than that on cells in the control group(P < 0.05) except for CLL cells (P > 0.05); (3) CD71 had a positive linear corrlation with SPF in cell lines (r = 0.914, P < 0.05), and also had a positive linear corrlation with Ki-67 in cell lines and carcinoma cells from bone marrow (r = 0.894,r = 0.904, P < 0.05). CONCLUSION: The CD71 can take the place of Ki-67 as an indicator of cell proliferation activity of hematologic malignancies and the determination CD71 by FCM is simpler and better than that of Ki-67 in respest of methodology. PMID- 25687080 TI - [Research progress on multiple myeloma immunophenotyping and minimal residual disease detected by flow cytometry]. AB - Multiple myeloma (MM) is a haematological malignancy characterized by the accumulation of monoclonal plasma cells in the bone marrow and remained incurable. Flow cytometry has been widely used in the detection of immunophenotype and minimal residual disease, diagnosis, monitoring and prognosis of MM. Normal plasma cells and malignant plasma cells can be distinguished according to different cell surface antigen expression. The clinical significane of many immune markes has been elucidated. However, the clinical significance of some phenotype remains controversial, the detection scheme and gating strategy are not unified. This review discusses the recent research progress on detection of MM immunophenotype and minimal residual disease by flow cytovetry. PMID- 25687081 TI - [Progress of research on clarithromycin for treatment of multiple myeloma]. AB - Clarithromycin is a 14-membered ring macrolide antibiotics that is widely used in the treatment of infectious disease. Several clinical investigations showed that clarithromycin was highly efficient for multiple myeloma in improving response rate and survival when used in combination with the conventional chemotherapy since 1997. This finding highlights the importance of clarithromycin on the treatment of multiple myeloma. It offers a new regimen for the relapsed/refractory multiple myeloma patients, and provids a new thought for the treatment of multiple myeloma. However, its related mechanism is still unclear, and more investigations are needed. This review summerizes the recent research progress of clarithromycin for treatment of multiple myeloma and its potential mechanisms. PMID- 25687082 TI - [Latest advances on the maintenance therapy of multiple myeloma]. AB - Multiple myeloma (MM) is an uncurable disease. Chemotherapy with standard dose or autologous stem cell transplantation (auto-HSCT) after chemotherapy with high dose is able to induce remission, but relapse still exists. For this reason the ultimate goal of MM treatment is to improve relapse free survival (RFS) and progression free survival (PFS) efficiently. Recently, maintenance therapy made substantial progress in improving progression-free survival and overall survival (OS) of patients with multiple myeloma, especially thalidomide, lenalidomide and bortezomib used in clinic. Here, the latest advances of clinical researches on maintenance therapy of MM are summarized briefly in this review. PMID- 25687083 TI - [Research progress on 18F-FDG PET/CT in evaluating prognosis of patient with diffuse large B cell lymphoma]. AB - Diffuse large B cell lymphoma (DLBCL) is one of the most common pathological type of non Hodgkin's lymphoma in adult, with a high mortality and a variety of prognostic factors. (18)F-FDG PET/CT, a functional imaging modality used for staging and monitoring response of a variety of human neoplasia to treatment, has a higher sensitivity and specificity than conventional anatomical imaging. Patinets taking (18)F-FDG PET/CT scanning for DLBCL before treatment and after complete standard treatment of DLBCL patients not only contributes to the clinical accurate staging, but also has a certain value in evaluating the prognosis of DLBCL patients and monitoring of recurrence. However, the value of interim PET/CT for evaluation of prognosis remains controversial. Therefore, this review focuses on the research progress of (18)F-FDG PET/CT for evaluating prognosis of patient with DLBCL, including baseline, interim and post-treatment (18)F-FDG PET/CT. PMID- 25687084 TI - [Recent advances of studies on abnormal HOX gene in myelodysplastic syndromes and its molecular mechanisms]. AB - HOX gene encodes a group of homeodomain transcription factors which are highly conserved. The caudal-type homeobox (CDX) , ten-eleven translocation (TET) genes and polycomb group (PcG) , trithorax group (TrxG) proteins act as upstream regulators of HOX genes that manipulate the targeted gene expression through genetic and epigenetic mechanisms. The abnormal expression of HOX genes and their fusions contribute to myelodysplastic syndromes (MDS) pathogenesis. Aberrant DNA methylation and NUP98-HOX translocation serve as molecular mediators of dysfunction in MDS which can be used for the evaluation of biology and therapy. This article provides an overview of recent advances of studies on HOX gene and its abnormal molecular mechanisms, as well as potential correlation with MDS. PMID- 25687085 TI - [Progress of gene therapy for hemophilia]. AB - Hemophilia is a hereditary hemorrhagic disease induced by synthesis reducing of clotting factors or functional defect because of genetic mutations, Its treatment methods include traditional replacement therapy and new types of gene therapy. Replacement therapy is to reduce the bleeding complication and prevent the loss of function through the infusion exogenous recombinant coagulation factor, and gene therapy is to import the gene that exogenous code clotting factor into the patients' body by gene transfer technology, and express the treatment level of clotting factors to achieve the purpose of the permanent cure hemophilia. The various factors which affecting effects of the hemophilia's gene therapy include carrier factors, target cell factors, the timing of treatment, immune response caused by carrier. This review summarizes briefly the research progress of the factors affecting the gene therapy for hemophilia. PMID- 25687086 TI - [Myeloproliferative neoplasms and endothelial progenitor cells]. AB - JAK2V617F is a novel oncogene involved in myeloproliferative neoplasms (MPN) and closely related to its vascular complications. Recent researches found the vascular endothelial injury in patients with MPN. It is increasingly being recognized that endothelial cells and endothelial progenitor cells (EPC) play an important role in MPN. Here, the pathogenesis of the EPC JAK2V617F mutation and peripheral blood EPC counts in patients with MPN or with vascular complications are reviewed. PMID- 25687087 TI - [Correlation between IgG subtypes and hematological diseases]. AB - IgG is the main immunoglobulin, brings the immunolgic effects in body. The human IgG can be divided into four kinds; IgG1, IgG2, IgG3, IgG4, respectively. The structures of IgG1, IgG2, IgG3, IgG4 are different, therefore, their functions are also different. The defects, increase or imbalance of the IgG subtypes in autoimmune diseases, infectious diseases, cancer and other diseases are indicators of the immune response. IgG1, IgG2, IgG3 and IgG4 also play a different important roles in the disease progress. The analysis of IgG subtypes is beneficial to study the etiology, pathogenesis and prognosis of above menthioned deseases. This review briefly summarizes the characteristics of IgG subtypes in thrombotic thrombocytopenic purpura, autoimmune hemolytic anemia, hemophilia, lymphoma and leukemia. PMID- 25687088 TI - [Research progress of myeloproliferative neoplasms]. AB - The classic BCR-ABL negative myeloproliferative neoplasm (MPN) comprise polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). These three disorders are characterized by stem cell-derived clonal myeloproliferation and presence of somatic mutations. The WHO diagnostic criteria for the classic BCR-ABL negative MPN has been revised in the 2008 edition by incorporating new information about their molecular pathogenesis. Robust prognostic system for PMF has already done, and those for PV and ET are under discussion. Treatment with novel drugs is promising, and allo-stem cell transplantation (allo-ASCT) is the only curative treatment for myelofibrosis, however, the patient selection and management before transplant have been discussed for a long time. PMID- 25687089 TI - [Establishing aplastic anemia animal model based on different pathogenesis]. AB - Aplastic anemia(AA) is a disease,including congenital AA and acquired AA, characterized by an extremely hypocellular marrow and peripheral blood pancytopenia due to bone marrow failure. Congenital AA is a autosomal recessive disease due to gene mutation. Persently, acquired AA is recognized as a disease caused by destruction of hematopoietic stem cells, defective marrow microenvironment and aberrant T cellular-immunity. In order to further study its pathogenesis and to choose effective therapeutic target, it has important clinical significance to establish correspondent animal model based on different pathogenesis. This article summarizes the congenital AA amimal models including Fanc A(-/-) mouse, Fanc C(-/-) mouse, Fanc G(-/-) mouse, Fanc D1(-/-)/Fanc 2(-/-) mouse, Fanc D2(-/-) mouse and other gene deficiency mouse AA models, and the acguired AA models resulting from the hematopoietic stem cell decrease, hematopoietic microenvironment injury, immune mediation and combination of hematopoietic stem cell dicrease with immune mediation. PMID- 25687090 TI - [Latest advances of research on autophagy and leukemia treatment]. AB - Autophagy, as a conservative self-degradative approach of eukaryotic cells, plays an important role in cellular growth, proliferation,differentiation, death and keeping intracellular steady state. On one hand, autophagy can protect tumor cells to keep survival; on the other hand, autophagy can lead to apoptosis of leukemia cells. The double-edged impacts of autophagy make it to be the hotspot for research on mechanism and treatment of leukemia. This article reviews the diverse effects of autophagy in different leukemia cell lines, as well as its corresponding mechanism resulting in drug resistance, so as to provide theoretic guide for direct rational application of drugs according to their various mechnisms. PMID- 25687091 TI - A Systems Biology Perspective on the Molecular Mechanisms Underlying the Therapeutic Effects of Buyang Huanwu Decoction on Ischemic Stroke. AB - Ischemic stroke is the leading cause of adult disability worldwide. The outcome is worse in older patients, especially in terms of disability. Buyang Huanwu decoction (BHD), a famous traditional Chinese medicine formula, has been used extensively in the treatment of ischemic stroke for centuries. However, its pharmacological mechanisms have not been fully elucidated. In this study, 82 putative targets for 411 composite compounds contained in BHD were predicted on the basis of our previously developed target prediction system. On the basis of large-scale molecular docking, more than 80% compound-putative target pairs had medium to strong binding efficiency. The pharmacological networks of BHD were built according to relationships among herbs, putative targets, and known therapeutic targets for ischemic stroke, and 121 major nodes were identified by calculating three topological features-degree, node betweenness, and closeness. Importantly, the pathway enrichment analysis identified several signaling pathways involved with major putative targets of BHD, such as the calcium signaling pathway, vascular smooth muscle contraction, and nucleotide-binding oligomerization domain (NOD)-like receptor signaling pathway, which have not hitherto been reported. These data are expected to help find new therapeutic effects of BHD and optimize clinical use of this formula. Collectively, our study developed a comprehensive systems approach integrating drug target prediction and network and functional analyses to reveal the relationships of the herbs in BHD with their putative targets, and for the first time with ischemic stroke-related pathway systems. This is a pilot study based on bioinformatics analysis; thus, further experimental studies are required to validate our findings. PMID- 25687093 TI - Mesenchymal stem cell growth behavior on micro/nano hierarchical surfaces of titanium substrates. AB - Surface topography of an orthopedic implant plays an essential role in the regulation of bone formation with surrounding bone tissue. To investigate the effects of surface topography of titanium (Ti) substrates on cellular behavior of mesenchymal stem cells (MSCs), a series of micro/nano hierarchical structures were fabricated onto micro-structured titanium (Micro-Ti) substrates via a sol gel method with spin-coat technique. Scanning electron microscopy (SEM), surface profiler, X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS) and water contact angle measurement were employed to certify the successful fabrication of micro/nano hierarchical structures with the presence of various nano-sized TiO2 grains (20 nm, 40 nm and 80 nm, respectively) onto micro structured surfaces. The formation mechanism of the micro/nano hierarchical structures was proposed. Moreover, the effects of those hierarchical structures on the growth behavior of MSCs were evaluated both on cellular and molecular levels in vitro. The results confirmed that micro/nano hierarchical structures with large grains (80 nm) greatly promoted the proliferation and differentiation of MSCs comparing with other small grains (20 nm and 40 nm). The study provides an alternative for the fabrication of hierarchically structured Ti implants for potential orthopedic application. PMID- 25687094 TI - Investigating the role of surface micro/nano structure in cell adhesion behavior of superhydrophobic polypropylene/nanosilica surfaces. AB - The main aim of the current study was to investigate the effects of different topographical features on the biological performance of polypropylene (PP)/silica coatings. To this end, a novel method including combined use of nanoparticles and non-solvent was used for preparation of superhydrophobic PP coatings. The proposed method led to a much more homogeneous appearance with a better adhesion to the glass substrate. Moreover, a notable reduction was observed in the required contents of nanoparticles (100-20 wt% with respect to the polymer) and non-solvent (35.5-9 vol%) for achieving superhydrophobicity. Surface composition and morphology of the coatings were also investigated via X-ray photoelectron spectroscopy and scanning electron microscopy. Based on both qualitative and quantitative evaluations, it was found that the superhydrophobic coatings with only nano-scale roughness strongly prevented adhesion and proliferation of 4T1 mouse mammary tumor cells as compared to the superhydrophobic surfaces with micro scale structure. Such results demonstrate that the cell behavior could be controlled onto the polymer and nanocomposite-based surfaces via tuning the surface micro/nano structure. PMID- 25687095 TI - Developing an ultra non-fouling SU-8 and PDMS hybrid microfluidic device by poly(amidoamine) engraftment. AB - A new strategy to prepare an ultra non-fouling SU-8/poly(dimethylsiloxane) (PDMS) hybrid microfluidic system is presented. We report a simple method to bond both SU-8 and PDMS surfaces to prepare the hybrid microfluidic device and then simultaneously modify both SU-8 and PDMS surfaces using poly(amidoamine) (PAMAM), a highly hydrophilic dendrimer to enhance non-fouling properties of the hybrid microfluidic channel. Water contact angle, atomic force microscopy (AFM) and X ray photoelectron spectroscopy (XPS) are used to characterize and confirm surface modifications. Finally the non-fouling performance of the resulting microfluidic system is tested using both microbeads and Escherichia coli O157:H7 bacterial cells. We demonstrate that the obtained hybrid microfluidic system shows a significant microbead adsorption suppression of 99.7%, an ultra non-fouling performance that has not been reported in the literature before; in addition, 95% bacteria surface adsorption suppression is also obtained. Considering the significantly improved non-fouling performance and the ease of preparing the hybrid microfluidic system, we anticipate that this strategy will find wide applications in biosensing and detection. PMID- 25687096 TI - Synthesis and characterization of modified carrageenan microparticles for the removal of pharmaceuticals from aqueous solutions. AB - In the present study, carrageenan microparticles were synthesized using spray drying method and used as biosorbents for the removal of pharmaceutical compounds. The cross-linking reaction of iota-carrageenan (iCAR) and kappa carrageenan (kCAR) with glutaraldehyde (GLA) at different concentrations (2.5% or 5% (w/w), mass of GLA per mass of CAR) was studied (iCAR/GLA2.5, iCAR/GLA5, kCAR/GLA2.5, kCAR/GLA5). The physicochemical properties of the novel cross-linked polymers were investigated by scanning electron microscopy (SEM), X-ray diffraction (XRD) and Fourier transform infrared spectroscopy (FT-IR). Swelling studies were in accordance with the polymer properties, showing the lowest swelling degree (19%) by using the iCAR/GLA5 microparticles. The optimal kCAR/GLA5 microparticles were successfully employed for the removal of Metoprolol (MTPL) from aqueous samples. The adsorption capacity of the adsorbents was investigated using a batch adsorption procedure and the kinetics and thermodynamics of the adsorption process were further investigated. It was found that the adsorption isotherms agree well with the Langmuir-Freundlich model. The maximum adsorption capacity (Qm) was achieved in pH 6, whereas an increase of Qm was observed increasing the temperature (from 109 at 20 degrees C to 178 mg/g at 40 degrees C). Kinetic studies showed that the adsorption process on iCAR/GLA5 microparticles followed pseudo-second-order rate mechanism. Finally, a new phenomenological model of the adsorption process was proposed in order to extract information on the relevant sub-processes. PMID- 25687097 TI - Self-assembling systems based on quaternized derivatives of 1,4 diazabicyclo[2.2.2]octane in nutrient broth as antimicrobial agents and carriers for hydrophobic drugs. AB - Aggregation properties of mono (mono-CS) and dicationic (di-CS) surfactants, namely quaternised derivatives of 1,4-diazabicyclo[2.2.2]octane (DABCO), have been evaluated in water and in nutrient broths of different pH, i.e. in Hottinger broth (rN=7.2) and Sabouraud dextrose broth (rN=5.6). Aggregation capacity of surfactants was shown to be responsible for the solubilization properties of a complex composed of a hydrophobic probe (Sudan I) and a selected drug (quercetin), contributing to the antimicrobial activity of this surfactant system. The effect of N-methyl-d-glucamine (NmDg) additive on the antimicrobial activity of mono-CS, and its aggregation and solubilization parameters, has also been evaluated. A substantial decrease in critical micelle concentration (CMC) of cationic surfactants in nutrient broths (up to 60 times) has been reported. Twofold dilution of monocationic surfactant by NmDg slightly changed the CMC of surfactant; however, it provided a remarkable increase in solubilization capacity (~by 4 times) and decrease in its toxicity. The data anticipate the potential use of DABCO quaternized derivatives as innovative non-toxic delivery systems for hydrophobic drugs. PMID- 25687098 TI - Green synthesis of curcumin conjugated nanosilver for the applications in nucleic acid sensing and anti-bacterial activity. AB - Silver nanoparticles (Ag NPs) are often synthesized by chemical and physical methods. Natural and non-toxic molecules are recently being replaced for nanoparticles preparation. In this paper we have used curcumin, which interacts with Ag+ and subsequently synthesizes silver nanoparticles. Further continuation of the reaction often makes aggregation and forms dark brown/black silver oxide. Presence of glycerol in the reaction mixture gives mono-disperse curcumin conjugated Ag NPs, which can be made stable by capping with polyvinylpyrolidone (PVP). XRD data confirm that curcumin conjugated Ag NPs are crystalline in nature with a mean crystalline size of 13.27 nm. The Ag NPs are spherical and in the range of 10-50 nm though their hydrodynamic radius is found to be higher, ~294 nm, due to polyvinylpyrolidone capping and aggregation of nanoparticles in solution. The production of curcumin conjugated Ag NPs follows first order kinetics and the effect of curcumin concentration during formation of Ag NPs indicates a linear enhancement in the production of Ag NPs with an increase in concentration of curcumin. These curcumin conjugated silver nanoparticles show anti-bacterial activity and can successfully determine nucleic acid (DNA and RNA) in the concentration range 100-1000 ng/mL with a linear regression coefficient >0.997 using Resonance Rayleigh Scattering spectra. PMID- 25687099 TI - Near infrared (NIR) laser mediated surface activation of graphene oxide nanoflakes for efficient antibacterial, antifungal and wound healing treatment. AB - Photothermal treatment of graphene oxide (GO) for antibacterial, antifungal and controlling the wound infection treatment using near infrared laser (NIR, Nd-YAG (lambda=1064 nm) were reported. Various pathogenic bacteria (Pseudomonas aeruginosa, Staphylococcus aureus) and fungi (Saccharomyces cerevisiae and Candida utilis) were investigated. The cytotoxicity was measured using the proteomic analysis by matrix assisted laser desorption/ionization mass spectrometry (MALDI-MS), optical density (OD600), standard microdilution procedures, transmission electron microscopy (TEM) and epifluorescence microscopy. The laser mediated the surface activation of GO offer high efficiency for antifungal and antibacterial. Wide broad cells with various instruments approved that graphene oxide is promising material for nanomedicine in the near future. PMID- 25687100 TI - Effects of orally applied Fes p1-displaying L. plantarum WCFS1 on Fes p1 induced allergy in mice. AB - Group I grass pollen allergens are major contributors to grass pollen-related seasonal allergic rhinitis, and as such a primary target for allergen specific immunotherapy. In this study the potential therapeutic role of oral application of Lactobacillus plantarum WCFS1, directing cell wall attachment of the recombinant Fes p1 allergen, from Festuca pratensis was tested in a mouse model of Fes p1 allergy. For surface expression of Fes p1 allergen in L. plantarum WCFS1 pSIP system with inducible expression was used. Balb/c mice were sensitized with Fes p1 protein in alum and subsequently received live recombinant L. plantarum orally. Antibody levels (IgE, total IgG, IgG1, IgG2a, and IgA) were determined by ELISA. Differential eosinophil count in peripheral blood was performed. Reduced peripheral blood eosinophilia and increased serum IgG2A levels was detected in both groups which received live L. plantarum orally. Specific serum IgA levels were increased only in mice treated with the recombinant bacteria. Oral application of L. plantarum WCFS1 has a beneficial therapeutic effect in a mouse model of Fes p1 allergy. Cell surface expression of Fes p1 allergen potentiates this phenomenon in an allergen specific way. PMID- 25687101 TI - Potential and limitations of microscopy and Raman spectroscopy for live-cell analysis of 3D cell cultures. AB - Today highly complex 3D cell culture formats that closely mimic the in vivo situation are increasingly available. Despite their wide use, the development of analytical methods and tools that can work within the depth of 3D-tissue constructs lags behind. In order to get the most information from a 3D cell sample, adequate and reliable assays are required. However, the majority of tools and methods used today have been originally designed for 2D cell cultures and translation to a 3D environment is in general not trivial. Ideally, an analytical method should be non-invasive and allow for repeated observation of living cells in order to detect dynamic changes in individual cells within the 3D cell culture. Although well-established laser confocal microscopy can be used for these purposes, this technique has serious limitations including penetration depth and availability. Focusing on two relevant analytical methods for live-cell monitoring, we discuss the current challenges of analyzing living 3D samples: microscopy, which is the most widely used technology to observe and examine cell cultures, has been successfully adapted for 3D samples by recording of so-called "z-stacks". However the required equipment is generally very expensive and therefore access is often limited. Consequently alternative and less advanced approaches are often applied that cannot capture the full structural complexity of a 3D sample. Similarly, image analysis tools for quantification of microscopic images range from highly specialized and costly to simplified and inexpensive. Depending on the actual sample composition and scientific question the best approach needs to be assessed individually. Another more recently introduced technology for non-invasive cell analysis is Raman micro-spectroscopy. It enables label-free identification of cellular metabolic changes with high sensitivity and has already been successful applied to 2D and 3D cell cultures. However, its future significance for cell analysis will strongly depend on the availability of application oriented and user-friendly systems including specific tools for easy analysis and interpretation of spectral data focusing on biological relevant information. PMID- 25687102 TI - Complete genome sequence of Streptomyces vietnamensis GIMV4.0001 T, a genetically manipulable producer of the benzoisochromanequinone antibiotic granaticin. AB - We report the complete genome sequence of Streptomyces vietnamensis GIMV4.0001(T), a new and genetically manipulable producer of the benzoisochromanequinone antibiotic granaticin, whose unique sugar attachment pattern in structure has drawn much attention among chemical and biochemical researchers. The genome of S. vietnamensis GIMV4.0001(T) consists of one linear chromosome (8,867,142 bp, 72.09% G+C content) and one linear megaplasmid named pSVL1 (286,635 bp, 69.04% G+C content), encoding a total of 7356 protein coding genes. Twenty-nine gene clusters for secondary metabolites were predicted on the chromosome. PMID- 25687103 TI - Engineering of global regulator cAMP receptor protein (CRP) in Escherichia coli for improved lycopene production. AB - Transcriptional engineering has received significant attention for improving strains by modulating the behavior of transcription factors, which could be used to reprogram a series of gene transcriptions and enable multiple simultaneous modifications at the genomic level. In this study, engineering of the cAMP receptor protein (CRP) was explored with the aim of subtly balancing entire pathway networks and potentially improving lycopene production without significant genetic intervention in other pathways. Amino acid mutations were introduced to CRP by error-prone PCR, and three variants (mcrp26, mcrp159 and mcrp424) with increased lycopene productivity were screened. Combinations of three point mutations were then created via site-directed mutagenesis. The best mutant gene (mcrp26) was integrated into the genome of E. coli BW25113-BIE to replace the wild-type crp gene (MT-1), which resulted in a higher lycopene production (18.49mg/g DCW) compared to the original strain (WT). The mutant strain MT-1 was further investigated in a 10-L bench-top fermentor with a lycopene yield of 128mg/l at 20h, approximately 25% higher than WT. DNA microarray analyses showed that 396 genes (229 up-regulated and 167 down regulated) were differentially expressed in the mutant MT-1 compared to WT. Finally, the introduction of the mutant crp gene (mcrp26) increased beta-carotene production in E. coli. This is the first report of improving the phenotype for metabolite overproduction in E. coli using a CRP engineering strategy. PMID- 25687104 TI - Expression of enzymes for the usage in food and feed industry with Pichia pastoris. AB - The methylotrophic yeast Pichia pastoris is an established protein expression host for the production of industrial enzymes. This yeast can be grown to very high cell densities and produces high titers of recombinant protein, which can be expressed intercellularly or be secreted to the fermentation medium. P. pastoris offers some advantages over other established expression systems especially in protein maturation. In food and feed production many enzymatically catalyzed processes are reported and the demand for new enzymes grows continuously. For instance the unique catalytic properties of enzymes are used to improve resource efficiency, maintain quality, functionalize food, and to prevent off-flavors. This review aims to provide an overview on recent developments in heterologous production of enzymes with P. pastoris and their application within the food sector. PMID- 25687105 TI - Current knowledge on biodegradable microspheres in drug delivery. AB - INTRODUCTION: Biodegradable microspheres have gained popularity for delivering a wide variety of molecules via various routes. These types of products have been prepared using various natural and synthetic biodegradable polymers through suitable techniques for desired delivery of various challenging molecules. Selection of biodegradable polymers and technique play a key role in desired drug delivery. AREAS COVERED: This review describes an overview of the fundamental knowledge and status of biodegradable microspheres in effective delivery of various molecules via desired routes with consideration of outlines of various compendial and non-compendial biodegradable polymers, formulation techniques and release mechanism of microspheres, patents and commercial biodegradable microspheres. EXPERT OPINION: There are various advantages of using biodegradable polymers including promise of development with different types of molecules. Biocompatibility, low dosage and reduced side effects are some reasons why usage biodegradable microspheres have gained in popularity. Selection of biodegradable polymers and formulation techniques to create microspheres is the biggest challenge in research. In the near future, biodegradable microspheres will become the eco-friendly product for drug delivery of various genes, hormones, proteins and peptides at specific site of body for desired periods of time. PMID- 25687106 TI - Digital mammography screening in Germany: Impact of age and histological subtype on program sensitivity. AB - INTRODUCTION: Program sensitivity (PS), i.e., the ratio of screen-detected cancers divided by the sum of screen-detected plus interval cancers, is a major outcome in population-based mammography screening programs (MSP). This study evaluated PS within the digital MSP in Germany focussing on the impact of age and histological subtype. METHODS: Data of 838,579 first-time participants aged 50-69 years who were screened in 2005-2008 were linked with cancer registry data from Germany's most populous state, North Rhine-Westphalia. Invasive breast cancers and ductal carcinomas in situ (DCIS) were detected either at screening or during the 24 month post-screening interval. PS was evaluated with respect to age at screening, in-situ or invasive cancer and histological characteristics. RESULTS: In total, 6767 cancers were detected at screening and 1884 cancers were diagnosed during the post-screening interval. The overall PS amounted to 78.2% and increased from 72.1% at age 50-54 years to 82.4% at age 65-69 years (p for trend <0.0001). PS was higher for non-lobular (79.1%) than lobular carcinomas (72.1%, p < 0.0001). The highest PS was observed in DCIS across all ages (>90%), while PS was lowest among participants aged 50-54 years with invasive breast cancer (67.7%), particularly among those with lobular subtype (62.8%). Interval cancers showed generally more advanced tumour stages. CONCLUSIONS: While overall PS was high, differences across subgroups indicated that youngest screening participants are at higher risk of interval cancer. Age-adapted recall and assessment strategies in younger participants may need to be considered to improve PS in younger women. PMID- 25687107 TI - Two new chalcones from Shuteria sinensis. AB - Two new chalcones, 2',3,4,4'-tetrahydroxy-2-prenylchalcone (1) and 3-methoxy 2',4,4'-trihydroxy-2-prenylchalcone (2), together with two known compounds, munsericin (3) and 3,4-dihydroxylonchocarpin (4), were isolated from the ethanol extract of the whole plant of Shuteria sinensis. Their structures were identified by spectroscopic analysis methods, such as 1D and 2D NMR, along with HR-MS data. Glucose metabolism activity of four compounds was tested, compounds 3 and 4 showed effect on the glucose consumption of insulin-resistant HepG2 cells. PMID- 25687108 TI - Decrease in serine protease HtrA1 expression correlates with grade and recurrence in meningiomas. AB - PURPOSE: HtrA1 is a serine protease which was shown to be down-regulated in a variety of human cancers. It is considered to be a tumor suppressor and suggested as a prognostic marker and a therapeutic candidate. In order to investigate any possible implication of HtrA1 in meningioma we studied 100 cases. MATERIAL/METHODS: We used immunohistochemistry to determine HtrA1 expression in tumor tissue. Expression levels were evaluated with respect to tumor grade and recurrence. RESULTS: Our data revealed a strong association between decrease in HtrA1 expression and increase in meningioma grade (p=0.005). Most importantly, patients with higher HtrA1 expression had a lower rate of recurrence (p<0.001). CONCLUSIONS: According to our results HtrA1 appeared as an immunohistochemical marker to predict behaviour of the meningioma, mainly the recurrence. Although the exact mechanisms of HtrA1 are still largely unknown, we think that further in vivo and in vitro studies explaining the molecular targets of HtrA1 would have a great importance with regard to its role as a therapeutic agent for meningioma. PMID- 25687109 TI - EUROASPIRE IV: A European Society of Cardiology survey on the lifestyle, risk factor and therapeutic management of coronary patients from 24 European countries. AB - AIMS: To determine whether the Joint European Societies guidelines on cardiovascular prevention are being followed in everyday clinical practice of secondary prevention and to describe the lifestyle, risk factor and therapeutic management of coronary patients across Europe. METHODS AND RESULTS: EUROASPIRE IV was a cross-sectional study undertaken at 78 centres from 24 European countries. Patients <80 years with coronary disease who had coronary artery bypass graft, percutaneous coronary intervention or an acute coronary syndrome were identified from hospital records and interviewed and examined >= 6 months later. A total of 16,426 medical records were reviewed and 7998 patients (24.4% females) interviewed. At interview, 16.0% of patients smoked cigarettes, and 48.6% of those smoking at the time of the event were persistent smokers. Little or no physical activity was reported by 59.9%; 37.6% were obese (BMI >= 30 kg/m(2)) and 58.2% centrally obese (waist circumference >= 102 cm in men or >=88 cm in women); 42.7% had blood pressure >= 140/90 mmHg (>=140/80 in people with diabetes); 80.5% had low-density lipoprotein cholesterol >= 1.8 mmol/l and 26.8% reported having diabetes. Cardioprotective medication was: anti-platelets 93.8%; beta-blockers 82.6%; angiotensin-converting enzyme inhibitors/angiotensin receptor blockers 75.1%; and statins 85.7%. Of the patients 50.7% were advised to participate in a cardiac rehabilitation programme and 81.3% of those advised attended at least one half of the sessions. CONCLUSION: A large majority of coronary patients do not achieve the guideline standards for secondary prevention with high prevalences of persistent smoking, unhealthy diets, physical inactivity and consequently most patients are overweight or obese with a high prevalence of diabetes. Risk factor control is inadequate despite high reported use of medications and there are large variations in secondary prevention practice between centres. Less than one half of the coronary patients access cardiac prevention and rehabilitation programmes. All coronary and vascular patients require a modern preventive cardiology programme, appropriately adapted to medical and cultural settings in each country, to achieve healthier lifestyles, better risk factor control and adherence with cardioprotective medications. PMID- 25687110 TI - Use of Platelet-Rich Plasma in Intra-Articular Knee Injections for Osteoarthritis: A Systematic Review. AB - OBJECTIVE: To systematically analyze the literature on the use of platelet-rich plasma (PRP) for intra-articular injections of the knee and its efficacy in the treatment of knee osteoarthritis (OA). DESIGN: Systematic literature reviews were conducted in PubMed, Embase, and CINAHL (ie, Cumulative Index to Nursing and Allied Health Literature) on October 30, 2013, using the keywords "platelet-rich plasma" and "knee" and "osteoarthritis." Inclusion criteria included (1) studies with human subjects, (2) prospective clinical studies (including either clinical trials or observational studies), and (3) full-text articles published in English. Exclusion criteria were: (1) animal studies; (2) retrospective studies; (3) patients with previous surgical intervention with total knee arthroplasty or reconstruction of the anterior cruciate ligaments; and (4) articles not published in English RESULTS: A total of 319 abstracts and titles were reviewed (60 from PubMed, 250 from Embase, and 9 from CINAHL). A total of 8 relevant journal articles were identified, all of which were published between 2010 and 2013. One half of the studies were prospective observational studies that included only PRP treatment; the rest were prospective comparative studies including both PRP and controls-2 were randomized controlled trials. Of the 4 comparative studies, 3 compared PRP with hyaluronic acid, which was considered as a commonly used effective treatment for knee OA; the other one used saline injection (ie, placebo) as the control. Although most of the analyses suffered from small sample size and was thus inconclusive, the findings consistently indicated that PRP might have better outcomes in patients with a lesser degree of degeneration and in younger patients. CONCLUSION: PRP intra-articular injections of the knee may be an effective alternative treatment for knee OA. However, current studies are at best inconclusive regarding the efficacy of the PRP treatment. A large, multicenter randomized trial study is needed to further assess the efficacy of PRP treatment for patients with knee OA. PMID- 25687112 TI - San Francisco train commuters may have been exposed to measles. PMID- 25687111 TI - Determinants of Effective Caregiver Communication After Adolescent Traumatic Brain Injury. AB - OBJECTIVE: To characterize the effects of caregiver mental health and coping strategies on interactions with an injured adolescent acutely after traumatic brain injury (TBI). DESIGN: Multi-site, cross-sectional study. SETTING: Outpatient setting of 3 tertiary pediatric hospitals and 2 tertiary general medical centers. PARTICIPANTS: Adolescents (N = 125) aged 12-17 years, 1-6 months after being hospitalized with complicated mild to severe TBI. METHODS: Data were collected as part of a multi-site clinical trial of family problem-solving therapy after TBI. Multiple regression analyses were used to examine the relationship of caregiver and environmental characteristics to the dimensions of effective communication, warmth, and negativity during caregiver-adolescent problem-solving discussions. MAIN OUTCOMES MEASURES: Adolescent and caregiver interactions, as measured by the Iowa Family Interaction Rating Scales. RESULTS: Caregivers who utilized problem-focused coping strategies were rated as having higher levels of effective communication (P < .01), as were those with higher socioeconomic status (P < .01). Problem-focused coping style and higher socioeconomic status were also associated lower levels of negative interactions (P < .01 and P < .05, respectively). Female gender of the adolescent and fewer children in the home were associated with increased parental warmth during the interaction (P < .01 and P < .05, respectively). Neither adolescent TBI severity nor caregiver depression significantly influenced caregiver-teen interactions. CONCLUSIONS: Problem-focused coping strategies are associated with higher levels of effective communication and lower levels of caregiver negativity during the initial months after adolescent TBI, suggesting that effective caregiver coping may facilitate better caregiver-adolescent interactions after TBI. PMID- 25687113 TI - Effect of previous history of cancer on survival of patients with a second cancer of the head and neck. AB - OBJECTIVE: To provide head and neck squamous cell carcinoma (HNSCC) survival estimates with respect to patient previous history of cancer. MATERIALS AND METHODS: Data from ten French population-based cancer registries were used to establish a cohort of all male patients presenting with a HNSCC diagnosed between 1989 and 2004. Vital status was updated until December 31, 2007. The 5-year overall and net survival estimates were assessed using the Kaplan-Meier and Pohar Perme estimators, respectively. Multivariate Cox regression models were used to assess the effect of cancer history adjusted for age and year of HNSCC diagnosis. RESULTS: Among the cases of HNSCC, 5553 were localized in the oral cavity, 3646 in the oropharynx, 3793 in the hypopharynx and 4550 in the larynx. From 11.0% to 16.8% of patients presented with a previous history of cancer according to HNSCC. Overall and net survival were closely tied to the presence, or not, of a previous cancer. For example, for carcinoma of the oral cavity, the five-year overall survival was 14.0%, 5.9% and 36.7% in case of previous lung cancer, oesophagus cancer or no cancer history, respectively. Multivariate analyses showed that previous history of cancer was a prognosis factor independent of age and year of diagnosis (p<.001). CONCLUSION: Previous history of cancer is strongly associated with survival among HNSCC patients. Survival estimates based on patients' previous history of cancer will enable clinicians to assess more precisely the prognosis of their patients with respect to this major comorbid condition. PMID- 25687114 TI - In vivo localization studies in the stramenopile alga Nannochloropsis oceanica. AB - The tiny eustigmatophyte Nannochloropsis sp. recently emerged as a promising model organism for biotechnology as it possesses a considerably high cellular oil content interesting for biodiesel production. Furthermore, the alga was shown to be genetically well accessible providing powerful tools for biotechnological engineering as well as basic research. Nannochloropsis sp. can be transformed very efficiently taking advantage of homologous recombination, however, so far it remained unclear whether these organisms are also suitable model systems for in vivo protein localization studies due to their small cell size. Here we present, to our knowledge, the first protein localization studies based on the expression of chimeric fluorescent fusion proteins in the genus Nannochloropsis using N. oceanica CCMP1779 as a model organism. Besides expressing a cytosolic green fluorescent protein (GFP), the reporter could be directed into subcellular structures such as the mitochondria, the endoplasmic reticulum and secretory pathway as well as the complex plastid including the periplastidal compartment and the stroma via fusion of specific N-terminal targeting sequences. These results expand the potential of N. oceanica as a model system in biotechnology as well as cellular biology for which now an almost complete molecular tool set exists. PMID- 25687116 TI - A new photoactive Ru(II)tris(2,2'-bipyridine) templated Zn(II) benzene-1,4 dicarboxylate metal organic framework: structure and photophysical properties. AB - It has now been demonstrated that Ru(ii)tris(2,2'-bipyridine) (RuBpy) can be utilized to template the formation of new metal organic framework (MOF) materials containing crystallographically resolved RuBpy clusters with unique photophysical properties. Two such materials, RWLC-1 and RWLC-2, have now been reported from our laboratory and are composed of RuBpy encapsulated in MOFs composed of Zn(ii) ions and 1,3,5-tris(4-carboxyphenyl)benzene ligands (C. L. Whittington, L. Wojtas and R. W. Larsen, Inorg. Chem., 2014, 53, 160-166). Here, a third RuBpy templated photoactive MOF is described (RWLC-3) that is derived from the reaction between Zn(ii) ions and 1,4-dicarboxybenzene in the presence of RuBpy. Single Crystal X ray diffraction studies determined the position of RuBpy cations within the crystal lattice. The RWLC-3 structure is described as a 2-fold interpenetrated pillared honeycomb network (bnb) containing crystallographically resolved RuBpy clusters. The two bnb networks are weakly interconnected. The encapsulated RuBpy exhibits two emission decay lifetimes (tau-fast = 120 ns, tau-slow = 453 ns) and a bathochromic shift in the steady state emission spectrum relative to RuBpy in ethanol. PMID- 25687117 TI - Interdependence of pyrene interactions and tetramolecular G4-DNA assembly. AB - Controlling the arrangement of organic chromophores in supramolecular architectures is of primary importance for the development of novel functional molecules. Insertion of a twisted intercalating nucleic acid (TINA) moiety, containing phenylethynylpyren-1-yl derivatives, into a G-rich DNA sequence alters G-quadruplex folding, resulting in supramolecular structures with defined pyrene arrangements. Based on CD, NMR and ESI-mass-spectra, as well as TINA excited dimer (excimer) fluorescence emission we propose that insertion of the TINA monomer in the middle of a dTG4T sequence (i.e. dTGGXGGT, where X is TINA) converts a parallel tetramolecular G-quadruplex into an assembly composed of two identical antiparallel G-quadruplex subunits stacked via TINA-TINA interface. Kinetic analysis showed that TINA-TINA association controls complex formation in the presence of Na(+) but barely competes with guanine-mediated association in K(+) or in the sequence with the longer G-run (dTGGGXGGGT). These results demonstrate new perspectives in the design of molecular entities that can kinetically control G-quadruplex formation and show how tetramolecular G quadruplexes can be used as a tuneable scaffold to control the arrangement of organic chromophores. PMID- 25687118 TI - Expansion of CAG triplet repeats by human DNA polymerases lambda and beta in vitro, is regulated by flap endonuclease 1 and DNA ligase 1. AB - Huntington's disease (HD) is a neurological genetic disorder caused by the expansion of the CAG trinucleotide repeats (TNR) in the N-terminal region of coding sequence of the Huntingtin's (HTT) gene. This results in the addition of a poly-glutamine tract within the Huntingtin protein, resulting in its pathological form. The mechanism by which TRN expansion takes place is not yet fully understood. We have recently shown that DNA polymerase (Pol) beta can promote the microhomology-mediated end joining and triplet expansion of a substrate mimicking a double strand break in the TNR region of the HTT gene. Here we show that TNR expansion is dependent on the structure of the DNA substrate, as well as on the two essential Pol beta co-factors: flap endonuclease 1 (Fen1) and DNA ligase 1 (Lig1). We found that Fen1 significantly stimulated TNR expansion by Pol beta, but not by the related enzyme Pol lambda, and subsequent ligation of the DNA products by Lig1. Interestingly, the deletion of N-terminal domains of Pol lambda, resulted in an enzyme which displayed properties more similar to Pol beta, suggesting a possible evolutionary mechanism. These results may suggest a novel mechanism for somatic TNR expansion in HD. PMID- 25687119 TI - Cloning, Characterization and Anti-Inflammatory Properties of Bothrops jararaca Snake Antithrombin. AB - Antithrombin inhibits blood coagulation through the interaction with serine proteases in both intrinsic and extrinsic pathways. In addition, antithrombin also shows anti-inflammatory properties, which are independent of its effects on coagulation. This work shows for the first time the cloning and sequencing of antithrombin from a snake species. This predicted protein is composed by 430 amino acids and presents about 64.5% sequence identity to human antithrombin. Biacore experiments revealed that the binding affinity of Bothrops jararaca snake antithrombin to heparin was ~30 times higher than that of human antithrombin. Furthermore, Bothrops jararaca antithrombin is more effective in preventing acute inflammation induced by carrageenan when compared to human antithrombin. Hence, the results showed herein suggest that Bothrops jararaca antithrombin can play a key role in the control of acute inflammation and that this molecule might be used as a pharmacological tool and as a prototype for drug development. PMID- 25687120 TI - On-chip fabrication of high performance nanostructured ZnO UV detectors. AB - Developing rationally controlled bottom-up device fabrication processes is essential for the achievement of high performance optimal devices. We report a controlled, seedless and site-selective hydrothermal technique to fabricate high performance nanostructured ZnO UV-detectors directly on-chip. We demonstrate that by controlling the nanowire growth process, via tuning the experimental parameters such as the concentration of reactants and the growth time, and by introducing a refresh of the growth solution, the device structure efficiency can be enhanced to significantly improve its performance. The on-chip fabricated bridging nanosyringe ultraviolet detector demonstrates improved sensitivity (~10(5)), nanowatts detectability, and ultrafast response-time (90 ms) and recovery-time (210 ms). The improvement in response-time and recovery-time is attributed to the unique nanowire-nanowire junction barrier dominated resistance and the direct contact between ZnO and Au electrodes. Furthermore, the enhanced sensitivity and nanowatts detectability of the bridging nanosyringe device are due to the reduction in dimensionality and ultrahigh surface-to-volume ratio. This work paves the way toward low cost, large scale, low temperature, seedless and site-selective fabrication of high performance ZnO nanowire sensors on flexible and transparent substrates. PMID- 25687122 TI - Characterization and complete genome sequence analysis of Staphylococcus aureus bacteriophage JS01. AB - Staphylococcus aureus is a primary pathogen that causes bovine mastitis resulting in serious economic losses and herd management problems in dairy cows. A novel bacteriophage, JS01, specifically infecting bovine S. aureus, was isolated from milk of mastitis-affected cattle. TEM observation showed that it belonged to the family Siphovirus. The JS01 strain demonstrated a broad host range. The prediction result of PHACTS suggested that the JS01 strain was temperate phage. The JS01 genome is 43,458 bp long, with a GC content of 33.32% and no tRNAs. Annotation and functional analysis of the predicted ORFs revealed six functional groups: structure and morphology, DNA replication and regulation, packaging, lysogeny, lysis, and pathogenicity. Comparative analysis between JS01, S. aureus MSSA476, and S. aureus prophage PVL was also performed. The characterization and genomic analysis of JS01 provide a better understanding of S. aureus-targeting bacteriophages and useful information for the development of phage-based biocontrol agents against S. aureus. PMID- 25687121 TI - Toll-Like Receptor Pathways in Autoimmune Diseases. AB - Autoimmune diseases are a family of chronic systemic inflammatory disorders, characterized by the dysregulation of the immune system which finally results in the break of tolerance to self-antigen. Several studies suggest that Toll-like receptors (TLRs) play an essential role in the pathogenesis of autoimmune diseases. TLRs belong to the family of pattern recognition receptors (PRRs) that recognize a wide range of pathogen-associated molecular patterns (PAMPs). TLRs are type I transmembrane proteins and located on various cellular membranes. Two main groups have been classified based on their location; the extracelluar group referred to the ones located on the plasma membrane while the intracellular group all located in endosomal compartments responsible for the recognition of nucleic acids. They are released by the host cells and trigger various intracellular pathways which results in the production of proinflammatory cytokines, chemokines, as well as the expression of co-stimulatory molecules to protect against invading microorganisms. In particular, TLR pathway-associated proteins, such as IRAK, TRAF, and SOCS, are often dysregulated in this group of diseases. TLR-associated gene expression profile analysis together with single nucleotide polymorphism (SNP) assessment could be important to explain the pathomechanism driving autoimmune diseases. In this review, we summarize recent findings on TLR pathway regulation in various autoimmune diseases, including Sjogren's syndrome (SS), systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), systemic sclerosis (SSc), and psoriasis. PMID- 25687123 TI - Isolation and characterization of two mitoviruses and a putative alphapartitivirus from Fusarium spp. AB - The filamentous fungus Fusarium spp. includes several important plant pathogens. We attempted to reveal presence of double-stranded (ds) RNAs in the genus. Thirty seven Fusarium spp. at the MAFF collection were analyzed. In the strains of Fusarium coeruleum, Fusarium globosum and Fusarium solani f. sp. pisi, single dsRNA bands were detected. The strains of F. coeruleum and F. solani f. sp. pisi cause potato dry rot and mulberry twig blight, respectively. Sequence analyses revealed that dsRNAs in F. coeruleum and F. globosum consisted of 2423 and 2414 bp, respectively. Using the fungal mitochondrial translation table, the positive strands of these cDNAs were found to contain single open reading frames with the potential to encode a protein of putative 757 and 717 amino acids (molecular mass 88.5 and 84.0 kDa, respectively), similar to RNA-dependent RNA polymerases of members of the genus Mitovirus. These dsRNAs in F. coeruleum and F. globosum were assigned to the genus Mitovirus (family Narnaviridae), and these two mitoviruses were designated as Fusarium coeruleum mitovirus 1 and Fusarium globosum mitovirus 1. On the other hand, a positive strand of cDNA (1950 bp) from dsRNA in F. solani f. sp. pisi contained an ORF potentially encoding a putative RdRp of 608 amino acids (72.0 kDa). The putative RdRp was shown to be related to those of members of the genus of Alphapartitivirus (family Partitiviridae). We coined the name Fusarium solani partitivirus 2 for dsRNA in F. solani f. sp. pisi. PMID- 25687124 TI - The triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio as a predictor of beta-cell function in African American women. AB - BACKGROUND: The TG/HDL-C ratio is used as a marker of insulin resistance (IR) in Caucasians. However, there are conflicting data on TG/HDL-C ratio as a predictor of IR in African Americans. Compared to Caucasians, African Americans have lower TG levels and increased insulin levels despite a greater risk for diabetes. We hypothesized that the TG/HDL-C ratio is predictive of IR and/or beta-cell function in African American (AA) women. METHODS: Non-diabetic AA women (n = 41) with a BMI > 25 kg/m(2) underwent frequently sampled intravenous glucose tolerance test (FSIGTT). Insulin sensitivity (SI) and the acute insulin response to glucose (AIRg) were measured using minimal model and beta-cell function was determined by disposition index (DI = S I*AIRg). IR was defined as the lowest tertile of SI (<1.8 * 10(-4)min(-1)/MUU/ml) and inadequate beta cell compensation was defined as the lowest tertile of DI (< 900). Data were analyzed using logistic regression models and area under the receiver operating characteristic curve (AUC-ROC). An AUC-ROC > 0.70 was defined as significant discrimination. RESULTS: The mean (+/- SD) age was 38.5 +/- 11.3 years, with BMI of 33.5 +/- 6.7 kg/m(2) and fasting glucose of 86.5 +/- 10.5 mg/dL. The AUC-ROC for the prediction of DI < 900 was 0.74 indicating that a higher TG/HDL-C ratio was associated with decreased DI. However, the AUC-ROC for prediction of IR or low AIRg (<335 MUU/ml) was not significant. CONCLUSION: This study confirmed that the TG/HDL-C ratio is a poor predictor of IR in AA women. However, we did show an inverse association between the TG/HDL-C ratio and beta-cell function, suggesting that this simple tool may effectively identify AA women at risk for DM2. PMID- 25687125 TI - Resource Type and Availability Regulate Fungal Communities Along Arable Soil Profiles. AB - Soil fungi play an essential role in the decomposition of plant-derived organic material entering soils. The quality and quantity of organic compounds vary seasonally as well as with soil depth. To elucidate how these resources affect fungal communities in an arable soil, a field experiment was set up with two plant species, maize and wheat. Resource availability was experimentally manipulated by maize litter input on one half of these maize and wheat plots after harvest in autumn. Fungal biomass was determined by ergosterol quantification, and community structure was investigated by fungal automated ribosomal intergenic spacer analysis (F-ARISA). An annual cycle was assessed across a depth gradient, distinguishing three soil habitats: the plough layer, rooted soil below the plough layer, and deeper root-free soil. Fungal communities appeared highly dynamic and varied according to soil depth and plant resources. In the plough layer, the availability of litter played a dominant role in shaping fungal communities, whereas in the rooted layer below, community structure and biomass mainly differed between plant species. This plant effect was also extended into the root-free soil at a depth of 70 cm. In winter, the availability of litter also affected fungal communities in deeper soil layers, suggesting vertical transport processes under fallow conditions. These distinct resource effects indicate diverse ecological niches along the soil profile, comprising specific fungal metacommunities. The recorded responses to both living plants and litter point to a central role of fungi in connecting primary production and decomposition within the plant-soil system. PMID- 25687126 TI - The Microbiome of Pinus muricata Ectomycorrhizae: Community Assemblages, Fungal Species Effects, and Burkholderia as Important Bacteria in Multipartnered Symbioses. AB - Bacteria have been observed to grow with fungi, and those that associate with ectomycorrhizal fungi have often been thought of as symbionts that may either increase or decrease ectomycorrhizal formation rate or provide other unaccounted benefits. To explore this symbiosis from a community ecology perspective, we sampled ectomycorrhizal root tips over a 3-year period and used 454 pyrosequencing to identify the bacteria that live inside the ectomycorrhizal root tips. The results showed that fungal community composition within the same soil core and fungal taxonomic identity had a stronger effect on bacterial community composition than sample year or site. Members of the Burkholderiales and Rhizobiales were most highly represented, reflecting many previous reports of these bacteria in association with fungi. The repeated occurrences of these two bacterial orders suggest that they may be symbiotic with their fungal hosts, although the nature of such mechanisms, be it symbiotic diazotrophy or otherwise, remains to be thoroughly tested. PMID- 25687127 TI - Moth outbreaks alter root-associated fungal communities in subarctic mountain birch forests. AB - Climate change has important implications on the abundance and range of insect pests in forest ecosystems. We studied responses of root-associated fungal communities to defoliation of mountain birch hosts by a massive geometrid moth outbreak through 454 pyrosequencing of tagged amplicons of the ITS2 rDNA region. We compared fungal diversity and community composition at three levels of moth defoliation (intact control, full defoliation in one season, full defoliation in two or more seasons), replicated in three localities. Defoliation caused dramatic shifts in functional and taxonomic community composition of root-associated fungi. Differentially defoliated mountain birch roots harbored distinct fungal communities, which correlated with increasing soil nutrients and decreasing amount of host trees with green foliar mass. Ectomycorrhizal fungi (EMF) abundance and richness declined by 70-80 % with increasing defoliation intensity, while saprotrophic and endophytic fungi seemed to benefit from defoliation. Moth herbivory also reduced dominance of Basidiomycota in the roots due to loss of basidiomycete EMF and increases in functionally unknown Ascomycota. Our results demonstrate the top-down control of belowground fungal communities by aboveground herbivory and suggest a marked reduction in the carbon flow from plants to soil fungi following defoliation. These results are among the first to provide evidence on cascading effects of natural herbivory on tree root-associated fungi at an ecosystem scale. PMID- 25687128 TI - Fine mapping of a major quantitative trait locus, qLG-9, that controls seed longevity in rice (Oryza sativa L.). AB - KEY MESSAGE: We fine-mapped a quantitative trait locus, qLG - 9, for seed longevity detected between Japonica-type and Indica-type cultivars. qLG - 9 was mapped in a 30-kb interval of the Nipponbare genome sequence. A quantitative trait locus, qLG-9, for seed longevity in rice has previously been detected on chromosome 9 by using backcross inbred lines derived from a cross between Japonica-type (Nipponbare) and Indica-type (Kasalath) cultivars. In the present study, the chromosomal location of qLG-9 was precisely determined by fine-scale mapping. Firstly, allelic difference in qLG-9 was verified by QTL analysis of an F2 population derived from a cross between Nipponbare and NKSL-1, in which a segment of Kasalath chromosome 9 was substituted in Nipponbare genetic background. Then, we selected F2 plants in which recombination had occurred near qLG-9 and performed F3 progeny testing on these plants to determine the genotype classes of qLG-9. Eventually, qLG-9 was mapped in a 30-kb interval (defined by two markers, CAPSb and CHPa12) of the Nipponbare genome sequence. This allowed us to nominate positional candidate genes of qLG-9. Additionally, we developed near isogenic lines (NIL) for qLG-9 by marker-assisted selection. qLG-9 NIL showed significantly higher seed longevity than isogenic control of Nipponbare. These results will facilitate cloning of the gene(s) underlying qLG-9 as well as marker assisted transfer of desirable genes for seed longevity improvement in rice. PMID- 25687129 TI - Genetic control of plant height in European winter wheat cultivars. AB - KEY MESSAGE: Plant height variation in European winter wheat cultivars is mainly controlled by the Rht - D1 and Rht - B1 semi-dwarfing genes, but also by other medium- or small-effect QTL and potentially epistatic QTL enabling fine adjustments of plant height. Plant height is an important goal in wheat (Triticum aestivum L.) breeding as it affects crop performance and thus yield and quality. The aim of this study was to investigate the genetic control of plant height in European winter wheat cultivars. To this end, a panel of 410 winter wheat varieties from across Europe was evaluated for plant height in multi-location field trials and genotyped for the candidate loci Rht-B1, Rht-D1, Rht8, Ppd-B1 copy number variation and Ppd-D1 as well as by a genotyping-by-sequencing approach yielding 23,371 markers with known map position. We found that Rht-D1 and Rht-B1 had the largest effects on plant height in this cultivar collection explaining 40.9 and 15.5% of the genotypic variance, respectively, while Ppd-D1 and Rht8 accounted for 3.0 and 2.0% of the variance, respectively. A genome-wide scan for marker-trait associations yielded two additional medium-effect QTL located on chromosomes 6A and 5B explaining 11.0 and 5.7% of the genotypic variance after the effects of the candidate loci were accounted for. In addition, we identified several small-effect QTL as well as epistatic QTL contributing to the genetic architecture of plant height. Taken together, our results show that the two Rht-1 semi-dwarfing genes are the major sources of variation in European winter wheat cultivars and that other small- or medium-effect QTL and potentially epistatic QTL enable fine adjustments in plant height. PMID- 25687131 TI - Mobile phone use and willingness to pay for SMS for diabetes in Bangladesh. AB - BACKGROUND: Mobile phone SMS is increasingly used as a means of communication between patients and their healthcare providers in many countries of the world. We investigated mobile phone use and factors associated with willingness-to-pay (WTP) for diabetes SMS among patients with type 2 diabetes in Bangladesh. METHODS: As part of a randomized controlled study, in 515 patients with type 2 diabetes, socioeconomic status, mobile phone use, WTP for diabetes SMS, anthropometry and HbA1c were measured. Multivariate regression was used to identify factors associated with WTP. RESULTS: The median (interquartile range [IQR]) of WTP for diabetes SMS was 20 (45) Bangladesh Taka (BDT) (1 BDT = 0.013 US$). WTP was significantly higher for males [OR 2.4, 95% CI (1.0-5.7)], patients with household income >50 000 BDT [4.6 (1.1-20.4)] and those with primary education [5.6 (1.2-26.6)] and secondary and higher education [5.2 (1.4-19.6)]. CONCLUSIONS: The high proportion of mobile phone use and WTP for diabetes SMS are encouraging as possible strategy to use such technologies and deserve further evaluation. PMID- 25687130 TI - Multilayered Nanoparticles for Gene Delivery Used to Reprogram Human Foreskin Fibroblasts to Neurospheres. AB - Polycationic nanocomplexes are a robust means for achieving nucleic acid condensation and efficient intracellular gene deliveries. To enhance delivery, a multilayered nanoparticle consisting of a core of electrostatically bound elements was used. These included a histone-mimetic peptides, poly-l-arginine and poly-d-glutamic acid was coated with silicate before surface functionalization with poly-l-arginine. Transfection efficiencies and duration of expression were similar when using green fluorescent protein (GFP) plasmid DNA (pDNA) or GFP mRNA. These nanoparticles demonstrated significantly higher (>100%) and significantly longer (15 vs. 4 days) transfection efficiencies in comparison to a commercial transfection agent (Lipofectamine 2000). Reprogramming of human foreskin fibroblasts using mRNA to the Sox2 transcription factor resulted in three-fold higher neurosphere formation in comparison to the commercial reagent. These results demonstrate the potential of these nanoparticles as ideal vectors for gene delivery. PMID- 25687132 TI - Towards improving service delivery in screening and intervention services in community pharmacies: a case study of an alcohol IBA service. AB - BACKGROUND: Previous studies have demonstrated positive outcomes from a range of pharmacy public health services, but barriers to delivery remain. This paper explores the processes of delivering an alcohol screening and intervention service, with a view to improving service delivery. METHODS: A mixed-methods, multi-perspective approach was used, comprising in-pharmacy observations and recording of service provision, follow-up interviews with service users and interactive feedback sessions with service providers. RESULTS: Observations and recordings indicate that staff missed opportunities to offer the service and that both availability and delivery of the service were inconsistent, partly owing to unavailability of trained staff and service restrictions. Most service users gave positive accounts of the service and considered pharmacies to be appropriate places for this service. Respondents also described positive impacts, ranging from thinking more about alcohol consumption generally to substantial reductions in consumption. Key facilitators to service provision included building staff confidence and service champions. Barriers included commissioning issues and staff perception of alcohol as a sensitive topic. CONCLUSIONS: Findings support expansion of pharmacies' role in delivering public health services and highlight benefits of providing feedback to pharmacy staff on their service provision as a possible avenue for service improvement. PMID- 25687133 TI - Comparison of fusion rates between rod-based laminar claw hook and posterior cervical screw constructs in Type II odontoid fractures. AB - BACKGROUND: This study was aimed (i) to compare the fusion rates of rod-based laminar claw hook constructs to that of posterior C1/C2 screw constructs in odontoid fractures, and (ii) to evaluate any complications associated with claw hook/rod constructs. To our knowledge, no study in contemporary literature has presented the effects of using modern rod-based laminar claw hooks for treating odontoid fractures. Unlike laminar clamps from the 1980s, contemporary laminar hook-rod instrumentation systems provide better immobilisation of the cervical spine and allows for building reliable frame-like constructs similar to cervical screw-rod systems. METHODS: A retrospective review of a series of 167 consecutive odontoid fractures from a single-institution was conducted. 30 cases from the series were treated using posterior atlantoaxial fusion, 12 using C1/C2 posterior screws (control group), and 18 with rod-based laminar claw hooks (study group). Hooks were mounted bilaterally in a claw manner on each individual lamina and were rigidly fixed to perpendicular rods with a transverse connector whenever feasible. The minimum follow-up period was one year. Bony union was determined using computed tomography (CT) scan, while stability at the fusion site was assessed using dynamic radiograms. RESULTS: The study group had an overall fusion rate of 89% (non-geriatric 93% while geriatric subgroup 75%) with a 100% stability rate at the fusion site in all cases. In the control group fusion rate was 100%. There were no major complications in both control and study groups. Four minor complications, three in the control and one in the study group, were noted in 3 patients. CONCLUSION: Preliminary results of this study suggest that laminar claw hook-rod systems are useful alternatives to posterior screw techniques. Moreover, the fusion rate in non-geriatric patients is comparable to that of posterior screws. Importantly, they are devoid of the disadvantages and complications posed by screw constructs. Further studies are necessary to confirm these promising results. PMID- 25687134 TI - Macroscopic rotation of photon polarization induced by a single spin. AB - Entangling a single spin to the polarization of a single incoming photon, generated by an external source, would open new paradigms in quantum optics such as delayed-photon entanglement, deterministic logic gates or fault-tolerant quantum computing. These perspectives rely on the possibility that a single spin induces a macroscopic rotation of a photon polarization. Such polarization rotations induced by single spins were recently observed, yet limited to a few 10(-3) degrees due to poor spin-photon coupling. Here we report the enhancement by three orders of magnitude of the spin-photon interaction, using a cavity quantum electrodynamics device. A single hole spin in a semiconductor quantum dot is deterministically coupled to a micropillar cavity. The cavity-enhanced coupling between the incoming photons and the solid-state spin results in a polarization rotation by +/- 6 degrees when the spin is optically initialized in the up or down state. These results open the way towards a spin-based quantum network. PMID- 25687135 TI - Emergence of coherence in the charge-density wave state of 2H-NbSe2. AB - A charge-density wave (CDW) state has a broken symmetry described by a complex order parameter with an amplitude and a phase. The conventional view, based on clean, weak-coupling systems, is that a finite amplitude and long-range phase coherence set in simultaneously at the CDW transition temperature T(cdw). Here we investigate, using photoemission, X-ray scattering and scanning tunnelling microscopy, the canonical CDW compound 2H-NbSe2 intercalated with Mn and Co, and show that the conventional view is untenable. We find that, either at high temperature or at large intercalation, CDW order becomes short-ranged with a well defined amplitude, which has impacts on the electronic dispersion, giving rise to an energy gap. The phase transition at T(cdw) marks the onset of long-range order with global phase coherence, leading to sharp electronic excitations. Our observations emphasize the importance of phase fluctuations in strongly coupled CDW systems and provide insights into the significance of phase incoherence in 'pseudogap' states. PMID- 25687136 TI - N-doped microporous carbons derived from direct carbonization of K+ exchanged meta-aminophenol-formaldehyde resin for superior CO2 sorption. AB - N-doped microporous carbons with uniform ultramicropores (~0.50 nm) are facilely prepared by direct carbonization of K(+) exchanged meta-aminophenol-formaldehyde resin. These materials give an unprecedented CO2 uptake of 1.67 mmol g(-1) at 25 degrees C and 0.15 bar and superior CO2-over-N2 selectivity (50 : 1). PMID- 25687137 TI - NH2-truncated human tau induces deregulated mitophagy in neurons by aberrant recruitment of Parkin and UCHL-1: implications in Alzheimer's disease. AB - Disarrangement in functions and quality control of mitochondria at synapses are early events in Alzheimer's disease (AD) pathobiology. We reported that a 20-22 kDa NH2-tau fragment mapping between 26 and 230 amino acids of the longest human tau isoform (aka NH2htau): (i) is detectable in cellular and animal AD models, as well in synaptic mitochondria and cerebrospinal fluids (CSF) from human AD subjects; (ii) is neurotoxic in primary hippocampal neurons; (iii) compromises the mitochondrial biology both directly, by inhibiting the ANT-1-dependent ADP/ATP exchange, and indirectly, by impairing their selective autophagic clearance (mitophagy). Here, we show that the extensive Parkin-dependent turnover of mitochondria occurring in NH2htau-expressing post-mitotic neurons plays a pro death role and that UCHL-1, the cytosolic Ubiquitin-C-terminal hydrolase L1 which directs the physiological remodeling of synapses by controlling ubiquitin homeostasis, critically contributes to mitochondrial and synaptic failure in this in vitro AD model. Pharmacological or genetic suppression of improper mitophagy, either by inhibition of mitochondrial targeting to autophagosomes or by shRNA mediated silencing of Parkin or UCHL-1 gene expression, restores synaptic and mitochondrial content providing partial but significant protection against the NH2htau-induced neuronal death. Moreover, in mitochondria from human AD synapses, the endogenous NH2htau is stably associated with Parkin and with UCHL-1. Taken together, our studies show a causative link between the excessive mitochondrial turnover and the NH2htau-induced in vitro neuronal death, suggesting that pathogenetic tau truncation may contribute to synaptic deterioration in AD by aberrant recruitment of Parkin and UCHL-1 to mitochondria making them more prone to detrimental autophagic clearance. PMID- 25687138 TI - Role of Foxl2 in uterine maturation and function. AB - Foxl2 codes for a forkhead/HNF3 transcription factor essential for follicular maturation and maintenance of ovarian identity. FOXL2 mutations are associated with Blepharophimosis, Ptosis and Epicanthus inversus Syndrome (BPES) characterized by eyelid malformations (types I and II) and premature ovarian insufficiency (type I). We show that Foxl2 is not only expressed by the ovary, but also by other components of the mouse female reproductive tract, including the uterus, the cervix and the oviduct. In the uterus, Foxl2 expression is first observed in the neonatal mesenchyme and, during uterine maturation, persists in the stroma and in the deep inner myometrial layer (IML). In the adult, Foxl2 is expressed in the differentiated stromal layer, but no longer in the myometrium. Conditional deletion of Foxl2 in the postnatal (PN) uterus using Progesterone Receptor-cre (Pgr(cre/+)) mice results in infertility. During PN uterine maturation Pgr(cre/+); Foxl2(flox/flox) mice present a severely reduced thickness of the stroma layer and an hypertrophic, disorganized IML. In adult Pgr(cre/+); Foxl2(flox/flox) mice a supplementary muscular layer is present at the stroma/myometrium border and vascular smooth muscle cells fail to form a coherent layer around uterine arteries. Wnt signalling pathways play a central role in uterine maturation; in Pgr(cre/+); Foxl2(flox/flox) mice, Wnt genes are deregulated suggesting that Foxl2 acts through these signals. In humans, thickening of the IML (also called "junctional zone") is associated with reduced fertility, endometriosis and adenomyosis. Our data suggest that Foxl2 has a crucial role in PN uterine maturation and could help to understand sub-fertility predisposition in women. PMID- 25687139 TI - Improved nutrition delivery and nutrition status in critically ill children with heart disease. AB - BACKGROUND: This initiative sought to improve nutrition delivery in critically ill children with heart disease admitted to the cardiac ICU (CICU) and neonates undergoing stage 1 palliation (S1P) for single-ventricle physiology through interdisciplinary team interventions. Specific goals were increased caloric and protein delivery for all patients and a more nourished state for infants with single ventricles at the time of discharge. METHODS: We developed a nutrition flow sheet in the electronic health record to track whether daily nutrition goals were met. Interventions included nurses reporting daily whether caloric and protein goals were met, mandatory involvement of feeding specialists, and introduction of an enteral nutrition guideline. For infants undergoing S1P, weight-for-age z score (as an indicator for assessing malnutrition) was calculated at admission and discharge. RESULTS: The percentage of patient days per month when daily caloric goals were met increased from 50.1% to 60.7%, and protein goals met increased from 51.6% to 72.7%. Hospital length of stay, need for ventilation, and mortality did not differ. Patients undergoing S1P demonstrated a statistically significant improvement in weight-for-age z score compared with the preintervention group (P = .003). Thirteen S1P patients were discharged undernourished in the preintervention group; 5 were severely undernourished. In the intervention group, 4 patients were discharged undernourished, and none were severely undernourished. CONCLUSIONS: This initiative resulted in improved nutrition delivery for a heterogeneous population of cardiac patients in the CICU as well as significant improvements in weight gain and nourishment status at discharge in infants undergoing S1P. PMID- 25687141 TI - The continuing challenge of outcome disparities in children with diabetes. PMID- 25687142 TI - The great sleep recession: changes in sleep duration among US adolescents, 1991 2012. AB - BACKGROUND: Average nightly sleep times precipitously decline from childhood through adolescence. There is increasing concern that historical shifts also occur in overall adolescent sleep time. METHODS: Data were drawn from Monitoring the Future, a yearly, nationally representative cross-sectional survey of adolescents in the United States from 1991 to 2012 (N = 272 077) representing birth cohorts from 1973 to 2000. Adolescents were asked how often they get >=7 hours of sleep and how often they get less sleep than they should. Age-period cohort models were estimated. RESULTS: Adolescent sleep generally declined over 20 years; the largest change occurred between 1991-1995 and 1996-2000. Age-period cohort analyses indicate adolescent sleep is best described across demographic subgroups by an age effect, with sleep decreasing across adolescence, and a period effect, indicating that sleep is consistently decreasing, especially in the late 1990s and early 2000s. There was also a cohort effect among some subgroups, including male subjects, white subjects, and those in urban areas, with the earliest cohorts obtaining more sleep. Girls were less likely to report getting >=7 hours of sleep compared with boys, as were racial/ethnic minorities, students living in urban areas, and those of low socioeconomic status (SES). However, racial/ethnic minorities and adolescents of low SES were more likely to self-report adequate sleep, compared with white subjects and those of higher SES. CONCLUSIONS: Declines in self-reported adolescent sleep across the last 20 years are concerning. Mismatch between perceptions of adequate sleep and actual reported sleep times for racial/ethnic minorities and adolescents of low SES are additionally concerning and suggest that health education and literacy approaches may be warranted. PMID- 25687143 TI - Moisture damage and asthma: a birth cohort study. AB - BACKGROUND: Excess moisture and visible mold are associated with increased risk of asthma. Only a few studies have performed detailed home visits to characterize the extent and location of moisture damage and mold growth. METHODS: Structured home inspections were performed in a birth cohort study when the children were 5 months old (on average). Children (N = 398) were followed up to the age of 6 years. Specific immunoglobulin E concentrations were determined at 6 years. RESULTS: Moisture damage and mold at an early age in the child's main living areas (but not in bathrooms or other interior spaces) were associated with the risk of developing physician-diagnosed asthma ever, persistent asthma, and respiratory symptoms during the first 6 years. Associations with asthma ever were strongest for moisture damage with visible mold in the child's bedroom (adjusted odds ratio: 4.82 [95% confidence interval: 1.29-18.02]) and in the living room (adjusted odds ratio: 7.51 [95% confidence interval: 1.49-37.83]). Associations with asthma ever were stronger in the earlier part of the follow-up and among atopic children. No consistent associations were found between moisture damage with or without visible mold and atopic sensitization. CONCLUSIONS: Moisture damage and mold in early infancy in the child's main living areas were associated with asthma development. Atopic children may be more susceptible to the effects of moisture damage and mold. PMID- 25687144 TI - Prevalence of Duchenne and Becker muscular dystrophies in the United States. AB - OBJECTIVE: To estimate prevalence of childhood-onset Duchenne and Becker muscular dystrophies (DBMD) in 6 sites in the United States by race/ethnicity and phenotype (Duchenne muscular dystrophy [DMD] or Becker muscular dystrophy [BMD]). METHODS: In 2002, the Centers for Disease Control and Prevention established the Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STARnet) to conduct longitudinal, population-based surveillance and research of DBMD in the United States. Six sites conducted active, multiple-source case finding and record abstraction to identify MD STARnet cases born January 1982 to December 2011. We used cross-sectional analyses to estimate prevalence of DBMD per 10 000 boys, ages 5 to 9 years, for 4 quinquennia (1991-1995, 1996-2000, 2001-2005, and 2006-2010) and prevalence per 10 000 male individuals, ages 5 to 24 years, in 2010. Prevalence was also estimated by race/ethnicity and phenotype. RESULTS: Overall, 649 cases resided in an MD STARnet site during >=1 quinquennia. Prevalence estimates per 10 000 boys, ages 5 to 9 years, were 1.93, 2.05, 2.04, and 1.51, respectively, for 1991-1995, 1996-2000, 2001-2005, and 2006-2010. Prevalence tended to be higher for Hispanic individuals than non-Hispanic white or black individuals, and higher for DMD than BMD. In 2010, prevalence of DBMD was 1.38 per 10 000 male individuals, ages 5 to 24 years. CONCLUSIONS: We present population-based prevalence estimates for DBMD in 6 US sites. Prevalence differed by race/ethnicity, suggesting potential cultural and socioeconomic influences in the diagnosis of DBMD. Prevalence also was higher for DMD than BMD. Continued longitudinal surveillance will permit us to examine racial/ethnic and socioeconomic differences in treatment and outcomes for MD STARnet cases. PMID- 25687145 TI - Azithromycin in early infancy and pyloric stenosis. AB - BACKGROUND AND OBJECTIVE: Use of oral erythromycin in infants is associated with infantile hypertrophic pyloric stenosis (IHPS). The risk with azithromycin remains unknown. We evaluated the association between exposure to oral azithromycin and erythromycin and subsequent development of IHPS. METHODS: A retrospective cohort study of children born between 2001 and 2012 was performed utilizing the military health system database. Infants prescribed either oral erythromycin or azithromycin as outpatients in the first 90 days of life were evaluated for development of IHPS. Specific diagnostic and procedural codes were used to identify cases of IHPS. RESULTS: A total of 2466 of 1 074 236 children in the study period developed IHPS. Azithromycin exposure in the first 14 days of life demonstrated an increased risk of IHPS (adjusted odds ratio [aOR], 8.26; 95% confidence interval [CI], 2.62-26.0); exposure between 15 and 42 days had an aOR of 2.98 (95% CI, 1.24-7.20). An association between erythromycin and IHPS was also confirmed. Exposure to erythromycin in the first 14 days of life had an aOR of 13.3 (95% CI, 6.80-25.9), and 15 to 42 days of life, aOR 4.10 (95% CI, 1.69 9.91). There was no association with either macrolide between 43 and 90 days of life. CONCLUSIONS: Ingestion of oral azithromycin and erythromycin places young infants at increased risk of developing IHPS. This association is strongest if the exposure occurred in the first 2 weeks of life, but persists although to a lesser degree in children between 2 and 6 weeks of age. PMID- 25687140 TI - Racial-ethnic disparities in management and outcomes among children with type 1 diabetes. AB - BACKGROUND AND OBJECTIVES: Previous research has documented racial/ethnic disparities in diabetes treatments and outcomes. It remains controversial whether these disparities result from differences in socioeconomic status (SES) or other factors. We examined racial/ethnic disparities in therapeutic modalities and diabetes outcomes among the large number of pediatric participants in the T1D Exchange Clinic Registry. METHODS: The cohort included 10 704 participants aged <18 years with type 1 diabetes for >=1 year (48% female; mean age: 11.9 +/- 3.6 years; diabetes duration: 5.2 +/- 3.5 years). Diabetes management and clinical outcomes were compared among 8841 non-Hispanic white (white) (83%), 697 non Hispanic black (black) (7%), and 1166 Hispanic (11%) participants. The population included 214 high-income black and Hispanic families. RESULTS: Insulin pump use was higher in white participants than in black or Hispanic participants (61% vs 26% and 39%, respectively) after adjusting for gender, age, diabetes duration, and SES (P < .001). Mean hemoglobin A1c was higher (adjusted P < .001) in black participants than in white or Hispanic participants (9.6%, 8.4%, and 8.7%). More black participants experienced diabetic ketoacidosis and severe hypoglycemic events in the previous year than white or Hispanic participants (both, P < .001). There were no significant differences in hemoglobin A1c, diabetic ketoacidosis, or severe hypoglycemia between white and Hispanic participants after adjustment for SES. CONCLUSIONS: Even after SES adjustment, marked disparities in insulin treatment method and treatment outcomes existed between black versus Hispanic and white children within this large pediatric cohort. Barriers to insulin pump use and optimal glycemic control beyond SES should be explored in all ethnic groups. PMID- 25687146 TI - Changing policy and practice in the control of pediatric schistosomiasis. AB - Schistosomiasis is a chronic disease that affects ~200 million people. The extended health impact of the disease has been estimated to exceed that of malaria or tuberculosis and to be nearer to that of HIV/AIDS. Within endemic areas, children carry the heaviest burden of infection. Infection/disease is controlled by the treatment of infected subjects with the anthelminthic drug praziquantel. Global initiatives from Partners of Parasite Control, including the World Health Organization (WHO), advocate regular school-based deworming strategies to reduce the development of severe morbidity, promote school-child health and development, and improve the cognitive potential of children. Until recently, preschool-aged children were excluded from schistosome treatment, creating a health inequity in affected populations. In 2010, the WHO updated their recommendations for the treatment of schistosomiasis in preschool-aged children (ie, children aged <=5 years). This change was the culmination of several decades of research on schistosome epidemiology, immunology, and pathology in this age group. The recent development of a pediatric formulation of praziquantel (soon to enter clinical trials) should advance control efforts in preschool-aged children, with the goal of including these children in preventative chemotherapy (as currently occurs for soil-transmitted helminths). This review discusses the research work supporting the WHO revision of recommendations for treating preschool-aged children, as well as current barriers and knowledge gaps in pediatric schistosomiasis control. PMID- 25687147 TI - Sucrose and warmth for analgesia in healthy newborns: an RCT. AB - BACKGROUND AND OBJECTIVE: Increasing data suggest that neonatal pain has long term consequences. Nonpharmacologic techniques (sucrose taste, pacifier suckling, breastfeeding) are effective and now widely used to combat minor neonatal pain. This study examined the analgesic effect of sucrose combined with radiant warmth compared with the taste of sucrose alone during a painful procedure in healthy full-term newborns. METHODS: A randomized, controlled trial included 29 healthy, full-term newborns born at the University of Chicago Hospital. Both groups of infants were given 1.0 mL of 25% sucrose solution 2 minutes before the vaccination, and 1 group additionally was given radiant warmth from an infant warmer before the vaccination. We assessed pain by comparing differences in cry, grimace, heart rate variability (ie, respiratory sinus arrhythmia), and heart rate between the groups. RESULTS: The sucrose plus warmer group cried and grimaced for 50% less time after the vaccination than the sucrose alone group (P < .05, respectively). The sucrose plus warmer group had lower heart rate and heart rate variability (ie, respiratory sinus arrhythmia) responses compared with the sucrose alone group (P < .01), reflecting a greater ability to physiologically regulate in response to the painful vaccination. CONCLUSIONS: The combination of sucrose and radiant warmth is an effective analgesic in newborns and reduces pain better than sucrose alone. The ready availability of this practical nonpharmacologic technique has the potential to reduce the burden of newborn pain. PMID- 25687148 TI - Institutional protocol to manage consanguinity detected by genetic testing in pregnancy in a minor. AB - Single-nucleotide polymorphism arrays and other types of genetic tests have the potential to detect first-degree consanguinity and uncover parental rape in cases of minor teenage pregnancy. We present 2 cases in which genetic testing identified parental rape of a minor teenager. In case 1, single-nucleotide polymorphism array in a patient with multiple developmental abnormalities demonstrated multiple long stretches of homozygosity, revealing parental rape of a teenage mother. In case 2, a vague maternal sexual assault history and diagnosis of Pompe disease by direct gene sequencing identified parental rape of a minor. Given the medical, legal, and ethical implications of such revelations, a protocol was developed at our institution to manage consanguinity identified via genetic testing. PMID- 25687149 TI - BMI curves for preterm infants. AB - BACKGROUND AND OBJECTIVES: Preterm infants experience disproportionate growth failure postnatally and may be large weight for length despite being small weight for age by hospital discharge. The objective of this study was to create and validate intrauterine weight-for-length growth curves using the contemporary, large, racially diverse US birth parameters sample used to create the Olsen weight-, length-, and head-circumference-for-age curves. METHODS: Data from 391 681 US infants (Pediatrix Medical Group) born at 22 to 42 weeks' gestational age (born in 1998-2006) included birth weight, length, and head circumference, estimated gestational age, and gender. Separate subsamples were used to create and validate curves. Established methods were used to determine the weight-for length ratio that was most highly correlated with weight and uncorrelated with length. Final smoothed percentile curves (3rd to 97th) were created by the Lambda Mu Sigma (LMS) method. The validation sample was used to confirm results. RESULTS: The final sample included 254 454 singleton infants (57.2% male) who survived to discharge. BMI was the best overall weight-for-length ratio for both genders and a majority of gestational ages. Gender-specific BMI-for-age curves were created (n = 127 446) and successfully validated (n = 126 988). Mean z scores for the validation sample were ~0 (~1 SD). CONCLUSIONS: BMI was different across gender and gestational age. We provide a set of validated reference curves (gender-specific) to track changes in BMI for prematurely born infants cared for in the NICU for use with weight-, length-, and head-circumference-for-age intrauterine growth curves. PMID- 25687150 TI - The clinical and policy implications of new measures of premature infant growth. PMID- 25687151 TI - Medical journals and free speech. PMID- 25687152 TI - A school-based sleep education program for adolescents: a cluster randomized trial. AB - OBJECTIVES: To evaluate the effectiveness of a multilevel and multimodal school based education program. METHODS: A cluster randomized controlled trial with 14 secondary schools in Hong Kong and a total of 3713 students (intervention: 1545 vs control: 2168; 40.2% boys; mean age +/- SD: 14.72 +/- 1.53 years) were included in the final analysis. The intervention included a town hall seminar, small class workshops, a slogan competition, a brochure, and an educational Web site. Their parents and teachers were offered sleep education seminars. The control schools did not receive any sleep program. Data were collected before and 5 weeks after the intervention. RESULTS: The students in the intervention group had significantly improved sleep knowledge compared with the control group (mean difference: 3.64 [95% confidence interval (CI): 3.21 to 4.07]; Cohen's d = 0.51) as measured by using a sleep knowledge questionnaire. Weekday sleep duration was reduced in both groups, and the significant difference in weekday sleep duration was lost in the intention-to-treat analysis (mean difference: 0:01 [95% CI: -0:00 to 0:04]). In addition, the intervention group had a lower incidence of consuming caffeine-containing energy drinks (adjusted odds ratio: 0.46 [95% CI: 0.22 to 0.99]) and had better behavioral (mean difference: -0.56 [95% CI: -1.02 to 0.10]; Cohen's d = 0.13) and mental health (mean difference: -0.30 [95% CI: -0.15 to -0.46]; Cohen's d = 0.11) outcomes. CONCLUSIONS: A school-based sleep education program was effective in enhancing sleep knowledge and improving behavioral and mental health, but it had no significant impact on sleep duration or pattern among adolescents. PMID- 25687153 TI - Personal, dyadic, and contextual resilience in parents experiencing homelessness. AB - Adopting a developmental psychopathology (DP) perspective, the present study systematically reviewed the quantitative literature on positive functioning and outcomes in parents experiencing homelessness. Studies were identified from PubMed, PsycInfo, and Web of Science using an exhaustive list of key terms. Of 3443 total studies screened, 219 were inspected, 176 were excluded, and 43 were included. Included studies fell into three outcome categories: the ability to function well personally (cope effectively, meet basic family needs, experience reduced psychopathology); dyadically (demonstrate positive parenting practices and promote child adjustment); and contextually (exit episodes of homelessness and avoid shelter re-entry). Results also reflected personal, dyadic, and contextual independent variables associated with each positive outcome category. Many parents experiencing homelessness display positive outcomes, and many factors support positive functioning. Future research should replicate these findings and examine multilevel parental functioning to help bridge the gap between the DP theoretical perspective and the quantitative evidence for parental resilience as a process. PMID- 25687154 TI - Treatment options for lactic acidosis and metabolic crisis in children with mitochondrial disease. AB - The mitochondrial pyruvate oxidation route is a tightly regulated process, which is essential for aerobic cellular energy production. Disruption of this pathway may lead to severe neurometabolic disorders with onset in early childhood. A frequent finding in these patients is acute and chronic lactic acidemia, which is caused by increased conversion of pyruvate via the enzyme lactate dehydrogenase. Under stable clinical conditions, this process may remain well compensated and does not require specific therapy. However, especially in situations with altered energy demands, such as febrile infections or longer periods of fasting, children with mitochondrial disorders have a high risk of metabolic decompensation with exacerbation of hyperlactatemia and severe metabolic acidosis. Unfortunately, no controlled studies regarding therapy of this critical condition are available and clinical outcome is often unfavorable. Therefore, the aim of this review was to formulate expert-based suggestions for treatment of these patients, including dietary recommendations, buffering strategies and specific drug therapy. However, it is important to keep in mind that a specific therapy for the underlying metabolic cause in children with mitochondrial diseases is usually not available and symptomatic therapy especially of severe lactic acidosis has its ethical limitations. PMID- 25687156 TI - The impact of disease severity, age and surgical approach on the outcome of acute appendicitis in children. AB - PURPOSE: Although a national guideline has been implemented, the optimal approach for appendectomy in children remains subject of debate in the Netherlands. Opponents of laparoscopy raise their concerns regarding its use in complex appendicitis as it is reported to be associated with an increased incidence of intra-abdominal abscesses. The aim of this study was to evaluate the outcome of surgical approaches in both simple and complex appendicitis in paediatric patients. METHODS: A 10-year retrospective cohort study was performed (2001-2010) in paediatric patients treated for suspected acute appendicitis. Patients were divided into either simple or complex appendicitis and into different age groups. Primary outcome parameters were complication rate (intra-abdominal abscess (IAA), superficial surgical site infection (SSI) and readmission) and hospital stay. RESULTS: In total, 878 patients have been treated (median age 12, range 0-17 years). Two-thirds of the patients younger than 6 years had complex appendicitis, compared to one quarter in the group aged 13-18. In the complex appendicitis group, LA was associated with more IAA and early readmissions. In the simple appendicitis group, the complication rate was comparable between the two approaches. Significantly more IAAs were seen after LA in the youngest age group. CONCLUSION: This study demonstrates the unfavourable outcome of LA in the youngest age group and in patients with complex appendicitis. Therefore, we advise to treat these patients with an open approach. PMID- 25687157 TI - Autophagy is involved in the initiation and progression of Graves' orbitopathy. AB - BACKGROUND: Differentiation of orbital fibroblasts into mature adipocytes and subsequent accumulation of adipose tissue has been shown in the progression of Graves' orbitopathy (GO). Autophagy is involved in adipogenesis, but little is known about the role of autophagy in the initiation and progression of GO. The aim of this study is to investigate the role of autophagy in the pathogenesis of GO. METHODS: Orbital adipose/connective tissue explants from patients with GO and from normal subjects, as well as isolated orbital fibroblasts, were analyzed. Adipogenesis was induced using differentiating medium with or without hydrogen peroxide, and autophagy was manipulated using bafilomycin A1 and Atg5-targeted short hairpin RNA (shRNA). Autophagosomes were identified by electron microscopy. Expression of autophagy-related genes and adipogenesis-related transcription factors were analyzed by real time reverse transcription-polymerase chain reaction and/or Western blot analysis. Lipid droplet accumulation was examined by Oil Red O staining. RESULTS: Autophagic vacuoles were more abundant in GO cells than in non-GO cells (p<0.05). Expression of autophagy-related genes was significantly higher in GO tissues and cells than in their non-GO counterparts, respectively. Interleukin-1beta increased LC3-II, p62, and Atg7 protein in GO cells. Autophagosome accumulation was shown at day 4 of adipogenesis and decreased by day 10, along with lipid droplet formation. Expression of LC3 and p62 proteins increased within 48 hours of differentiation and diminished gradually from day 4 to 10. Bafilomycin A1 treatment and Atg5 knockdown by shRNA inhibited lipid droplet accumulation and suppressed expression of adipogenic markers. CONCLUSIONS: Autophagy was increased in GO tissue and cells compared to non-GO tissue and cells, suggesting that autophagy plays a role in GO pathogenesis. Autophagy manipulation may be a therapeutic target for GO. PMID- 25687155 TI - Peroxisome-mitochondria interplay and disease. AB - Peroxisomes and mitochondria are ubiquitous, highly dynamic organelles with an oxidative type of metabolism in eukaryotic cells. Over the years, substantial evidence has been provided that peroxisomes and mitochondria exhibit a close functional interplay which impacts on human health and development. The so-called "peroxisome-mitochondria connection" includes metabolic cooperation in the degradation of fatty acids, a redox-sensitive relationship, an overlap in key components of the membrane fission machineries and cooperation in anti-viral signalling and defence. Furthermore, combined peroxisome-mitochondria disorders with defects in organelle division have been revealed. In this review, we present the latest progress in the emerging field of peroxisomal and mitochondrial interplay in mammals with a particular emphasis on cooperative fatty acid beta oxidation, redox interplay, organelle dynamics, cooperation in anti-viral signalling and the resulting implications for disease. PMID- 25687158 TI - Novel trophic cascades: apex predators enable coexistence. AB - Novel assemblages of native and introduced species characterize a growing proportion of ecosystems worldwide. Some introduced species have contributed to extinctions, even extinction waves, spurring widespread efforts to eradicate or control them. We propose that trophic cascade theory offers insights into why introduced species sometimes become harmful, but in other cases stably coexist with natives and offer net benefits. Large predators commonly limit populations of potentially irruptive prey and mesopredators, both native and introduced. This top-down force influences a wide range of ecosystem processes that often enhance biodiversity. We argue that many species, regardless of their origin or priors, are allies for the retention and restoration of biodiversity in top-down regulated ecosystems. PMID- 25687159 TI - Energetics and behavior: unrequited needs and new directions. AB - The number of studies investigating links between among-individual differences in metabolic rate (MR) and behavior has grown dramatically in the past several years. A major and often untested assumption of these studies is that the selected measure of MR is a valid proxy for energetic constraints. We argue that without explicitly testing this assumption, observed patterns between MR and behavior are uninterpretable. We provide guidelines for evaluating how a given measure of MR relates to constraints on the acquisition or expenditure of energy. The approach we advocate will allow researchers to develop and test a priori predictions relating energy metabolism and behavior. We conclude by highlighting several exciting directions for future work in this rapidly growing field. PMID- 25687160 TI - Oculomotor apraxia in Gaucher disease. PMID- 25687161 TI - Determination of cortisol and cortisone in human mother's milk. PMID- 25687162 TI - A head-to-head comparison of homocysteine and cystatin C as pre-procedure predictors for contrast-induced nephropathy in patients undergoing coronary computed tomography angiography. AB - BACKGROUND: Homocysteine is a potential predictor for contrast-induced nephropathy (CIN). We aimed to compare homocysteine with cystatin C as pre procedure predictors for CIN in patients undergoing coronary computed tomography angiography (CCTA). METHODS: A total of 580 consecutive patients were enrolled. Concentrations of plasma homocysteine and serum cystatin C were measured before CCTA. CIN is defined as an elevation of creatinine by >= 25% or >= 0.5mg/dl from baseline within 48h. Receiver operating characteristic curves, Pearson correlation coefficients and logistic regression analysis were used to evaluate the efficiency of potential predictors. RESULTS: Fifty-seven (9.83%) patients developed CIN. Concentrations of homocysteine (19.35 +/- 4.32 MUmol/l vs. 13.42 +/- 3.96 MUmol/l, p<0.001) and cystatin C (1.20 +/- 0.21 mg/dl vs. 0.99 +/- 0.15 mg/dl, p<0.001) increased significantly in CIN subjects. CIN was predicted by homocysteine (AUC 0.829, p<0.001) and cystatin C (AUC 0.774, p<0.001), while creatinine was not predictive. Both homocysteine and cystatin C had positive correlation with DeltaCreatinine48h-0 (p<0.001) and negative correlation with DeltaeGFR48h-0 (p<0.001). Regression analysis confirmed that increased baseline homocysteine [OR: 1.262 (1.123, 2.554), p<0.001] and cystatin C [OR: 1.565 (1.380, 1.775), p<0.001] were independent predictors for CIN. CONCLUSIONS: Homocysteine, with similar predictive value compared to cystatin C, was an independent biomarker for predicting CIN before CCTA examination. PMID- 25687163 TI - First observation of N-acetyl leucine and N-acetyl isoleucine in diabetic patient hair and quantitative analysis by UPLC-ESI-MS/MS. AB - BACKGROUND: Type 2 diabetes patients (DP) have significantly higher plasma levels of valine, leucine, isoleucine and alanine than the controls. Specific amino acids may acutely and chronically regulate insulin secretion from the pancreatic beta-cells. We recently identified a metabolic signature of N-acetyl leucine (Ac Leu) that strongly predicts diabetes development in mice hair. The Ac-Leu appears to be a potential biomarker candidate related to diabetes. However, the determination of Ac-Leu in human hair has not been reported. We measured the Ac Leu, and its structure is similar to N-acetyl isoleucine (Ac-Ile) in human hair by ultra-performance liquid chromatography (UPLC) with electrospray ionization tandem mass spectrometry (ESI-MS/MS). The developed method was applied to the determination of Ac-Leu and Ac-Ile in the hair of healthy volunteers (HV) and DP. METHODS: Ac-Leu, Ac-Ile and N-acetyl norleucine (Ac-Nle, IS) were extracted from human hair samples by a micropulverized extraction procedure, then separated on a C18 column by isocratic elution of acetonitrile-0.1% formic acid in water:0.1% formic acid (14:86, vol./vol.). MRM using the fragmentation transitions of m/z 174.1->86.1 in the positive ESI mode was performed to quantify the N-acetyl leucine, N-acetyl isoleucine and IS. RESULTS: Ac-Leu, Ac-Ile and Ac-Nle in the human hair samples were completely separated by isocratic elution of a 5.0 min duration wash program using a reversed-phase column, and sensitively detected by LC-MS/MS in the ESI(+) MRM mode. The amounts of Ac-Leu and Ac-Ile in the hairs of HV and DP were determined. When comparing the concentrations between DP and those from HV, a statistically significant correlation was observed for the Ac-Leu (p<0.001) and Ac-Ile (p<0.01). CONCLUSIONS: The proposed method is useful for the determination of Ac-Leu and Ac-Ile in the hairs of DP and HV. Human hair may serve as a noninvasive biosample for the diagnosis of diabetes. PMID- 25687164 TI - Increasing fat content from 20 to 45 wt% in a complex diet induces lower endotoxemia in parallel with an increased number of intestinal goblet cells in mice. AB - The impacts of high-fat diets (HFDs) on the onset of metabolic endotoxemia and low-grade inflammation are well established in rodent models. However, the dose effect of dietary lipid intakes on these parameters is not known. We hypothesized that increasing dietary lipid amounts could be linked to parallel increases of endotoxemia, low-grade inflammation, and metabolic and intestinal alterations. Six-week-old male C57BL/6J mice were fed a low-fat diet (LFD, 2.6 wt% of lipids), a moderate HFD (mHFD, 22 wt% of lipids), or a very HFD (vHFD, 45 wt% of lipids) formulated mainly using chow ingredients and milk fat. After 12 weeks, white adipose tissues, liver, intestine, distal colon contents, and plasma were collected. Only vHFD mice significantly increased body weight and fat mass vs LFD mice. This was associated with increases of plasma concentrations of triglycerides, leptin and adiponectin, and liver lipids. No such differences were observed between LFD and mHFD mice. However, mHFD developed metabolic endotoxemia and inflammation, unlike vHFD mice. In turn, vHFD mice showed more goblet cells in all intestine segments vs both other groups and a decrease of Bacteroides Prevotella in their microbiota vs LFD mice. Finally, mHFD mice colon exhibited a decrease in lactobacilli and in the levels of occludin phosphorylation. Altogether, using complex HFD, no associations were observed between dietary lipid amounts and the magnitude of endotoxemia, inflammation, and physiological alterations developed. These results reveal the impact of the diet composition on intestinal goblet cells and mucus coat, bringing new insights about further consequences on HFD-induced metabolic disorders. PMID- 25687165 TI - Quantification of rHVT-F genome load in feather follicles by specific real-time qPCR as an indicator of NDV-specific humoral immunity induced by day-old vaccination in SPF chickens. AB - The purpose of this study was to look for a reliable molecular method for confirmation of uptake of recombinant turkey herpesvirus vaccine against Newcastle disease (rHVT-F) and for use as a valuable prediction tool of Newcastle disease virus (NDV)-specific immune response in chickens deprived of maternally derived antibody (MDA). A quantitative real-time polymerase chain reaction (real time qPCR) specific to rHVT-F was developed. The method was applied to various tissue samples taken from specific pathogen free (SPF) chickens experimentally inoculated at day-old with one dose of rHVT-F vaccine over a 6-week period. Among the tested tissues, the rHVT-F vaccine was detected predominantly in the bursa of Fabricius (BF) and the lung for the first week, followed by a progressive decline from 9 days onwards. Then, an increase of genome load was observed in the feather follicles (FF) with a peak at 2 weeks, rising to a level almost 10(3)-fold greater than in the other tissues. Importantly, the rHVT-F genome load in FF appeared to be strongly correlated to the humoral immunity specific to NDV as evaluated by haemagglutination inhibition (HI) test and NDV-specific IgG, IgM and IgA ELISAs. This is the first report of quantification of rHVT-F vaccine in FF and its correlation with the induction of ND-specific immune response in chickens with no MDA. Our data indicate that the application of this real-time qPCR assay on FF samples taken from chickens in the field may be used to confirm rHVT-F vaccine administration and uptake with the important added benefit of offering a non-disruptive sampling procedure. PMID- 25687166 TI - Predictors of appendicitis on computed tomography among cases with borderline appendix size. AB - Confident diagnosis of appendicitis when the appendix is borderline (6 to 7 mm) in size can be challenging. This retrospective study assessed computed tomography (CT) findings that are most predictive of appendicitis when the appendix is borderline in diameter. Three radiologists conducted separate, blind retrospective reviews of 105 contrast-enhanced CTs with borderline appendices. Presence or absence of appendicitis was confirmed by chart review of clinical or surgical outcomes. Logistic regression was used to determine the odds ratio (OR) and the receiver operating characteristic for CT features predictive of appendicitis. Absence of intraluminal air (OR = 5.11, p < 0.001), wall hyperemia (OR = 3.92, p = 0.002), wall thickening (OR = 29.7, p < 0.001), and fat stranding (OR = 3.85, p = 0.003) were significant findings in univariate logistic regression. Using a multivariate model, we found that the absence of intraluminal air (OR = 6.04, p = 0.002) and wall thickening (OR = 24.6, p < 0.001) remained statistically significant and were unaffected by adjustment for gender and pediatric age. The area under the curve was significantly greater for the multivariate model than the initial, clinical CT impressions (p = 0.024). The combination of wall thickening and absence of intraluminal air was 92.6 % (95 % CI 75.7-99.1) sensitive and 82.4 % (95 % CI 65.5-93.2) specific for appendicitis. Wall thickening and the absence of intraluminal air are prominent predictors of appendicitis and, if present together, these features may aid in identifying appendicitis on CT when the appendix is borderline in size. PMID- 25687167 TI - Preterm and postterm birth in immigrant- and Swedish-born parents: a population register-based study. AB - Ethnic minorities/immigrant groups tend to have increased risk for preterm birth. Less is known about this risk in diverse immigrant groups, couples of mixed ethnic-origin and in relation to duration of residence. Data from the Swedish Medical Birth Register on 1,028,303 mothers who gave birth to 1,766,026 singleton live born infants (1982-2002), was linked to the Education and Total Population Registers. Immigrant parents were identified by country of birth. Risk of early preterm, late preterm and postterm birth was analyzed using multinomial logistic regression. Polish, Yugoslavian, Iranian, South Asian, East Asian and Sub-Saharan African parents, Swedish mothers who had children with non-Swedish fathers, and parents from two different immigrant groups had higher risk of early preterm birth [adjusted relative risk (RR) (95% CI) 1.76 (1.24-2.50), 1.57 (1.31-1.87), 1.67 (1.30-2.14), 1.52 (1.07-2.16), 1.51 (1.08-2.10), 2.03 (1.32-3.12), 1.56 (1.45-1.67), and 1.55 (1.35-1.77) respectively] compared to Swedish-born parents. South Asian, Sub-Saharan African, and East Asian immigrants had a higher risk of late preterm birth compared to Swedish-born parents. North African and Middle Eastern, Somali, and Ethiopian/Eritrean groups had increased risk of postterm birth [adjusted RR 1.31 (1.16-1.47), 2.57 (2.31-2.86), 1.85 (1.67-2.04) respectively]. Adjustment for covariates did not substantially change associations. Immigrant mothers resident <3 years had higher risk for early preterm and postterm birth compared to residents >10 years [adjusted RR 1.46 (1.24-1.71) and 1.16 (1.11-1.23) respectively]. In addition to higher risk of preterm birth in select immigrant groups, some immigrant groups are also at higher risk of postterm birth. Shorter duration of residence is associated with higher risk of non-term deliveries. PMID- 25687168 TI - Limitations of individual causal models, causal graphs, and ignorability assumptions, as illustrated by random confounding and design unfaithfulness. AB - We describe how ordinary interpretations of causal models and causal graphs fail to capture important distinctions among ignorable allocation mechanisms for subject selection or allocation. We illustrate these limitations in the case of random confounding and designs that prevent such confounding. In many experimental designs individual treatment allocations are dependent, and explicit population models are needed to show this dependency. In particular, certain designs impose unfaithful covariate-treatment distributions to prevent random confounding, yet ordinary causal graphs cannot discriminate between these unconfounded designs and confounded studies. Causal models for populations are better suited for displaying these phenomena than are individual-level models, because they allow representation of allocation dependencies as well as outcome dependencies across individuals. Nonetheless, even with this extension, ordinary graphical models still fail to capture distinctions between hypothetical superpopulations (sampling distributions) and observed populations (actual distributions), although potential-outcome models can be adapted to show these distinctions and their consequences. PMID- 25687169 TI - Toll-like receptor-2 deficiency induces schizophrenia-like behaviors in mice. AB - Dysregulation of the immune system contributes to the pathogenesis of neuropsychiatric disorders including schizophrenia. Here, we demonstrated that toll-like receptor (TLR)-2, a family of pattern-recognition receptors, is involved in the pathogenesis of schizophrenia-like symptoms. Psychotic symptoms such as hyperlocomotion, anxiolytic-like behaviors, prepulse inhibition deficits, social withdrawal, and cognitive impairments were observed in TLR-2 knock-out (KO) mice. Ventricle enlargement, a hallmark of schizophrenia, was also observed in TLR-2 KO mouse brains. Levels of p-Akt and p-GSK-3alpha/beta were markedly higher in the brain of TLR-2 KO than wild-type (WT) mice. Antipsychotic drugs such as haloperidol or clozapine reversed behavioral and biochemical alterations in TLR-2 KO mice. Furthermore, p-Akt and p-GSK-3alpha/beta were decreased by treatment with a TLR-2 ligand, lipoteichoic acid, in WT mice. Thus, our data suggest that the dysregulation of the innate immune system by a TLR-2 deficiency may contribute to the development and/or pathophysiology of schizophrenia-like behaviors via Akt-GSK-3alpha/beta signaling. PMID- 25687170 TI - Seroprevalence and associated risk factors of Toxoplasma gondii infection in psychiatric patients: a case-control study in eastern China. AB - In recent years, the effect of Toxoplasma gondii infection on the cerebrum and neuropsychiatric patients has been increasingly highlighted. However, there is limited information about the epidemiology of T. gondii infection in psychiatric patients in Shandong province, eastern China. Therefore, through a case-control study, 445 patients hospitalized for diacrisis or treatment in Weihai, eastern China, and 445 control subjects from the general population of the same region matched by gender, age, and residence were examined with enzyme-linked immunoassays for the presence of IgG and IgM antibodies to T. gondii and associated sociodemographic and behavioural characteristics in a population of psychiatric patients. Seroprevalence of IgG antibodies to T. gondii in psychiatric patients (77/445, 17.30%) was significantly higher than in control subjects (55/445, 12.36%) (P = 0.038). Fourteen (3.15%) psychiatric patients and 10 (2.25%) control subjects had IgM antibodies to T. gondii (P = 0.408). Multivariate analysis using logic regression showed that T. gondii infection was associated with cats at home and consumption of raw/undercooked meat in psychiatric patients. Considering that most psychiatric patients usually have lower cognitive functioning and additional transmission routes related to their inappropriate behaviours that could enhance the risk of infection, psychiatric patients should be considered as a specific group of T. gondii infection. PMID- 25687171 TI - Assessing the risks and benefits of step-down asthma care: a case-based approach. AB - Guidelines have called for pharmacologic stepped care to improve asthma treatment. Therapeutic options which have been approved provide physicians and their patients alternatives for stepping up asthma treatment to achieve control. However, few studies have been performed to identify and characterize procedures for optimal stepping-down treatment in patients with asthma. The resulting uncertainty as well as a lack of prioritization for asthma reassessment once control has been maintained has led to a lack of well-defined procedures for stepping down asthma treatment. However, recent studies provide guidance regarding the risks of stepping down asthma medications. This review uses case based examples to demonstrate how health care providers may engage patients in discussions regarding guideline recommendations to promote individualized asthma care. PMID- 25687172 TI - Use of chloroacetate esterase staining for the histological diagnosis of prosthetic joint infection. AB - A heavy neutrophil polymorph infiltrate [>5 per high-power field (HPF) after examination of at least 5 HPF by Musculoskeletal Infection Society (MSIS) criteria] is characteristically seen in peri-implant tissues of infected prosthetic hip and knee joints. We determined whether chloroacetate esterase (CAE) staining facilitated the identification of neutrophil polymorphs in peri implant tissues in cases of hip and knee arthroplasty infection and reassessed MSIS criteria in the light of our findings. Frozen and paraffin sections of peri prosthetic tissues of 76 cases of failed hip and knee arthroplasties classified as septic or aseptic loosening microbiologically were analysed histologically by both haematoxylin-eosin and CAE staining. The extent of the neutrophil polymorph infiltrate was determined semiquantitatively and correlated with the microbiological and clinical diagnosis. CAE staining facilitated identification of neutrophil polymorphs in arthroplasty tissues. All cases of aseptic loosening contained fewer than two neutrophil polymorphs per HPF. CAE staining showed that in some cases of septic loosening, fewer than five neutrophil polymorphs per HPF (on average) are present in peri-prosthetic tissues. The histological criterion of more than two neutrophil polymorphs per HPF showed increased sensitivity and accuracy for the diagnosis of septic loosening. CAE is a useful stain that facilitates the identification of neutrophil polymorphs in both frozen and paraffin sections of peri-implant tissues. CAE staining shows that some microbiologically confirmed cases of septic loosening contain relatively few neutrophil polymorphs, indicating that the MSIS histological criterion of more than five neutrophil polymorphs per HPF is too high an index figure for the diagnosis of all cases of hip and knee arthroplasty infection. PMID- 25687173 TI - A transformation process and mechanism between the alpha-conformation and beta conformation of conjugated polymer PFO in precursor solution. AB - In this work, the solvent field and temperature are used to explore the mutual transformation dynamic process and mechanism between the alpha-conformation and beta-conformation in poly(9,9-dioctylfluorene) (PFO) precursor solution. The conformational transformation of the PFO chain is researched by UV-vis absorption spectra and the proportions of the beta-conformation are quantitatively calculated. The corresponding variation trend of the aggregation structure is researched using a static and dynamic light scattering (SLS/DLS) method. It is found that the mutual transformation processes between the alpha-conformation and beta-conformation are reversible in essence. Especially in the transformation processes, the complicated relationship between the beta-conformation and the aggregation structure is understood, that is the aggregation structure promotes formation of the beta-conformation under solvent field, then the conformational transformation of the beta-conformation promotes the dissociation of the aggregation structure under temperature. The above results give an insight into the beta-conformation and the aggregation structure of PFO in theory. Furthermore, under the temperature, we find that both two transformation steps have good linear correlations, which indicates that using temperature can be considered as a good method to accurately control the proportion of beta conformation in actual applications, and it will help us to get the desired proportion of the beta-conformation in PFO precursor solution so as to make the charge carrier mobility of optoelectronic films increased and device performance better. PMID- 25687174 TI - Preoperative Versus Postoperative Radiotherapy in Extremity Soft Tissue Sarcoma: A Changing Trend Towards Preoperative Radiotherapy in the UK. PMID- 25687175 TI - Stereotactic body radiotherapy for spinal and bone metastases. AB - Stereotactic body radiotherapy (SBRT) can deliver high radiation doses to small volumes with very tight margins, which has significant advantages when treating tumours close to the spinal cord or at sites of retreatment. When treating spinal tumours, meticulous quality control is essential with effective immobilisation, as dose gradients at the edge of the spinal cord will be steep and excessive movements can be catastrophic. A range of dose-fractionation schedules have been used from single doses of 15-24 Gy to fractionated schedules delivering 15-35 Gy in three to five fractions. Indications include solitary or up to three vertebral metastases and primary tumours, in particular chordomas or bone sarcomas. Pain relief from metastatic disease is seen in over 80%, with similar rates of objective local control. Local control can be achieved in primary tumours of the spine in up to 95% and similar response rates are seen in non-spinal bone metastases. Toxicity rates are low, even in series that have delivered re irradiation with myelopathy in <1%, although later vertebral fracture may occur. Further prospective studies are required to formally evaluate patient selection and optimal dose and fractionation alongside an evaluation of cost-effectiveness. PMID- 25687176 TI - Connective tissue diseases: SLE classification: plus ca change, plus c'est la meme chose. AB - The sensitivity of the long-awaited SLICC classification criteria for systemic lupus erythematosus (SLE) has now been examined in a cross-sectional observational study. Will the new criteria enable advances in the management of SLE? PMID- 25687178 TI - Inflammation: New classification criteria for autoinflammatory periodic fevers. PMID- 25687177 TI - Rheumatoid arthritis therapy reappraisal: strategies, opportunities and challenges. AB - Rheumatoid arthritis (RA) is considered a chronic disease that cannot be cured. Biologic agents have enabled good therapeutic successes; however, the response to biologic therapy depends on treatment history and, especially, disease duration. In general, the more drug-experienced the patients, the lower the response rates, although this limitation can be overcome by promptly adjusting or switching treatment in a treat-to-target approach. Another challenge is the question of how long therapy should be continued once the treatment target, which should be remission or at least a state of low disease activity, has been reached. The data available suggest that, in most patients with established disease, cessation of biologic therapy will be followed by disease flares, whereas a reduction of dose or an increase in the interval between doses enables maintenance of treatment success. Induction therapy very early in the disease course followed by withdrawal of the biologic agent might also be a feasible approach to attain sustained good outcomes, but currently available data are not strong enough to allow for such a conclusion to be reached. Taken together, this underscores the importance of research into the cause(s) of RA so that curative therapies can be developed. PMID- 25687179 TI - Epigenetics: Demethylation of IFN-regulated genes in SLE neutrophils. PMID- 25687180 TI - Religious Dissociation and Economic Appraisal in Brazil. AB - Research on the association between religion and health often neglects to provide an explicit theoretical mechanism of influence between faith and well-being. This research posits that dissociative behaviors, such as glossolalia, may provide a biological pathway that influences both physiological and psychological health. This paper argues that religious dissociation acts as a moderator between economic stressors and psychobiological appraisal. Brazil, with its economic inequality and preponderance of religious dissociative rituals, provides an ideal context to examine religious dissociation as a moderator of stress. Utilizing data from a cross section of Brazilian faiths, this paper examines: (1) Whether individuals with low socioeconomic status preferentially participate and experience religious dissociative states and (2) whether dissociative states are correlated with greater psychological appraisal of status. PMID- 25687181 TI - Contributing and Terminating Factors of a Large RSV Outbreak in an Adult Hematology and Transplant Unit. AB - BACKGROUND: In January 2012, an increase of respiratory syncytial virus (RSV) infections on an adult hematology and transplant unit in a German university hospital was detected. We investigated the outbreak to assess its timing and extent and to identify risk factors for transmission. METHODS: We tested and typed patient samples pro- and retrospectively for RSV. We conducted a cohort and a case-control study. A confirmed outbreak case had laboratory-diagnosed, nosocomially-acquired RSV infection. Possible outbreak cases had pneumonia but were not laboratory-confirmed. RESULTS: Of 53 outbreak cases, 36 (68%) were confirmed and 17 (32%) possible. Retrospective testing and chart review dated the beginning of the outbreak to November 2011. Patients with community-acquired RSV infection were identified when the community epidemic began in January 2012. In multivariable analysis (controlling for contact with medical personnel, hygiene behaviour and age) patients with active social behaviour were more at risk for RSV infection (odds ratio 23.8, 95% confidence interval, 1.3 to 434.9; p-value, 0.03). Confirmed outbreak cases were more likely than controls to have been accomodated together with a confirmed or possible case before their onset of illness (OR 9.3, 95%CI: 2.1-85.1; p<0.001). Control measures, including isolation of every patient in the unit, initiated until the end of January terminated the outbreak. CONCLUSIONS: Epidemiological investigations revealed co-accomodation with a case-patient and active social behaviour as likely risk factors for RSV infection. Awareness of and vigorous testing for respiratory viruses in immunosuppressed hospitalised patients is necessary to timely detect cases with outbreak potential. Isolation of patients with respiratory infectious illnesses is crucial to prevent the continuation or occurrence of outbreaks. PMID- 25687182 TI - USP2 promotes cell migration and invasion in triple negative breast cancer cell lines. AB - Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer that is often associated with a poor prognosis. The aim of our study was to identify biomarkers predictive of TNBC progression. Primary TNBC breast tissue samples including four with metastasis and six without metastasis were subjected to Affymetrix GeneChip(r) analysis (human genome U133). Ubiquitin-specific protease 2 (USP2) was identified as an upregulated gene in the metastatic group, and its expression was analyzed by immunohistochemistry in 121 primary breast cancers, 13 paired normal tissues, and 13 paired metastatic lesions. Survival analysis was performed using the log-rank test and Cox regression hazard model. Matrigel migration and invasion assays in USP2-silenced and USP2-overexpressed breast cancer cell lines were used to investigate the mechanisms of USP2 in vitro. Positive immunostaining for USP2 was detected in breast tumors and was correlated with estrogen receptor (ER) and progesterone receptor (PR) statuses and TNBC subtype. USP2 was overexpressed in distant metastatic lesions compared with primary breast cancers. Survival analyses demonstrated that positive USP2 is a poor prognostic factor for disease-free survival. Silencing of USP2 expression decreased migration and invasion in LM2-4175 and SCP46 cells in association with the downregulation of matrix metalloproteinase-2 (MMP2) expression, whereas overexpression of USP2 in MDA-MB-468 and MDA-MB-231 cells enhanced migration and invasion and upregulated the expression of MMP2. The present study showed that USP2 expression is associated with TNBC cell line's invasiveness and poor survival of breast cancer patients and may serve as a prognostic biomarker and therapeutic target for TNBC. PMID- 25687183 TI - MicroRNA-21 promotes cell proliferation in human hepatocellular carcinoma partly by targeting HEPN1. AB - It has been reported that miR-21 is upregulated in hepatocellular carcinoma (HCC), and overexpressed miR-21 plays a key role in promoting cell cycle progression, reducing cell death and favoring angiogenesis and invasion. Overexpression of hepatocellular carcinoma, downregulated 1 (HEPN1) exhibits an antiproliferative effect on HepG2 cells, suggesting that silencing of HEPN1 may contribute to carcinogenesis of hepatocytes. In silico analysis revealed that HEPN1 may be a potential target of miR-21. Using quantitative reverse transcription PCR and Western blot, we found that HEPN1 was strikingly downregulated in both mRNA (fold change was 33.5, P < 0.0001) and protein levels in human HCC tumor tissues, in comparison with the adjacent non-tumor tissues. More importantly, the expression level of HEPN1 was inversely correlated with the expression of miR-21 in HCC (R (2) = 0.442, P < 0.0001). The combination between the 3' untranslated region (UTR) of HEPN1 with miR-21 was experimentally verified by a miRNA luciferase reporter approach. The suppressed cell proliferation upon stimulation of miR-21 inhibitor could be partially abolished by knocking down HEPN1, so inhibition of miR-21 expression in HCC cells profoundly suppressed cell proliferation partially by upregulating HEPN1 expression. Taken together, the current study suggested an underlying mechanism that miR-21 directly target HEPN1 and inhibit its expression during the carcinogenesis of HCC. HEPN1 may thus be a candidate as a therapeutic target for patients with HCC. PMID- 25687184 TI - Genome-wide association pathway analysis to identify candidate single nucleotide polymorphisms and molecular pathways for gastric adenocarcinoma. AB - To demonstrate candidate single nucleotide polymorphisms that might affect susceptibility to gastric adenocarcinoma as well as their potential mechanisms and pathway hypotheses, we performed a genome-wide association study dataset of gastric adenocarcinoma. Our study included 472,342 single nucleotide polymorphisms from 2766 cases of gastric cardia adenocarcinoma cases and 11,013 subjects from north central China as control groups. The identify candidate causal SNPs and pathways (ICSNPathway) analysis was employed to identify 13 candidate single nucleotide polymorphisms, nine genes, and 15 pathways. The top three candidate SNPs were rs3765524 (-log10(p) = 8.556), rs2274223 (-log10(p) = 8.633), and rs2076472 (-log10(p) = 3.205). The strongest mechanism involved the modulation of rs4745 and rs12904, thereby affecting their regulatory roles in ephrin receptor binding (p = 0.001; FDR = 0.005). The second strongest hypothetical biological mechanism was that rs932972 and rs1052177 alters the regulatory role of the glycolysis pathway (p < 0.001; FDR = 0.013). The most significant pathway was the regulation of the ephrin receptor binding pathway, which involved EFNA1, TIAM1, EFNA5, EFNB2, and EFNB3. PMID- 25687185 TI - An NMR study on the 6,6'-(2-(diethylamino)ethylazanediyl)bis(methylene)bis(5 hydroxy-2-hydroxymethyl-4H-pyran-4-one) interaction with Al(III) and Zn(II) ions. AB - Here we report about the complex formation among an amine-bearing bis-kojic acid, 6,6'-(2-(diethylamino)ethylazanediyl)bis(methylene)bis(5-hydroxy-2-hydroxymethyl 4H-pyran-4-one) and two metal ions, the trivalent hard and not essential metal ion Al(III) and the borderline and essential divalent metal ion Zn(II). We carried out a thorough NMR study in order to reach the indispensable structural information on the behavior of these complexes in solution. A combination of 1D, 2D total correlation spectroscopy, heteronuclear single quantum coherence spectroscopy, nuclear Overhauser enhancement spectroscopy and rotating-frame Overhauser effect spectroscopy experiments was used to assign the signals of both free and metal-bound ligand at different pH values. Our results highlighted the different coordination behaviors of the ligand towards the different metal ions, depending on their hard or borderline character. The trivalent metal ion, Al(III), mainly forms dinuclear helicate complexes of M2L3 stoichiometry, and the coordination only involves both hydroxypyrone (O,O)-donor atoms. NMR data are in agreement with the presence of a rigid and symmetric structure of L9-Al(III) complexes up to physiological pH. On the contrary, with the divalent metal ion, NMR data showed the coexistence of several species in solution though Zn(II) forms complexes of ML stoichiometry at physiological pH, where the metal coordination involves the nitrogen atoms of both the linker and the side-chain amine groups together with the oxygen atoms of phenolate groups. The in solution study will be of interest for providing an insight on the ligand bioavailability and on its behavior in the chelation treatments. PMID- 25687186 TI - Diffusional kurtosis imaging in hydrocephalus. AB - PURPOSE: Diffusional kurtosis imaging is an advanced diffusion magnetic resonance imaging method that yields, in addition to conventional diffusion information, non-Gaussian diffusion effects, which may allow a more comprehensive characterization of tissue microstructure. The purpose of this study is to use diffusional kurtosis to assess white matter integrity in patients with hydrocephalus and to determine whether changes in kurtosis correlate with the severity of hydrocephalus and leukoaraiosis (LA), a commonly seen comorbidity in hydrocephalus. METHODS: 26 patients with imaging evidence of hydrocephalus and 26 age- and sex- matched subjects with normal ventricular size were retrospectively analyzed. Standard diffusion tensor imaging and diffusional kurtosis metrics were compared between the two groups. Correlation between kurtosis and severity of hydrocephalus and presence and severity of LA was determined. RESULTS: Hydrocephalus patients relative to controls demonstrated statistically significant decrease in all kurtosis metrics in most brain regions studied. The severity of hydrocephalus was associated with greater decrease in kurtosis in the corpus callosum. There was more LA in the hydrocephalus group, and severity of LA was associated with decrease in kurtosis. After controlling for the degree of LA, kurtosis was still decreased in hydrocephalus relative to the controls. CONCLUSION: Diffusional kurtosis imaging detects microstructural changes in the white matter of patients with hydrocephalus. Our results suggest that hydrocephalus plays a role in altering white matter integrity. PMID- 25687187 TI - Prostate cancer discrimination in the peripheral zone with a reduced field-of view T(2)-mapping MRI sequence. AB - OBJECTIVES: To evaluate the performance of T2 mapping in discriminating prostate cancer from normal prostate tissue in the peripheral zone using a practical reduced field-of-view MRI sequence requiring less than 3 minutes of scan time. MATERIALS AND METHODS: Thirty-six patients with biopsy-proven peripheral zone prostate cancer without prior treatment underwent routine multiparametric MRI at 3.0T with an endorectal coil. An Inner-Volume Carr-Purcell-Meiboom-Gill imaging sequence that required 2.8 minutes to obtain data for quantitative T2 mapping covering the entire prostate gland was added to the routine multiparametric protocol. Suspected cancer (SC) and suspected healthy (SH) tissue in the peripheral zone were identified in consensus by three radiologists and were correlated with available biopsy results. Differences in mean T2 values in SC and SH regions-of-interest (ROIs) were tested for significance using unpaired Student's two-tailed t-test. The area under the receiver operating characteristic curve was used to assess the optimal threshold T2 value for cancer discrimination. RESULTS: ROI analyses revealed significantly (p<0.0001) shorter T2 values in SC (85.4+/-12.3ms) compared to SH (169.6+/-38.7ms). An estimated T2 threshold of 99ms yielded a sensitivity of 92% and a specificity of 97% for prostate cancer discrimination. CONCLUSIONS: Quantitative values derived from this clinically practical T2-mapping sequence allow high precision discrimination between healthy and cancerous peripheral zone in the prostate. PMID- 25687188 TI - Biomarkers of intergenerational risk for depression: a review of mechanisms in longitudinal high-risk (LHR) studies. AB - BACKGROUND: Longitudinal research is critical for understanding the biological mechanisms underlying the development of depression. Researchers recruit high risk cohorts to understand how risk is transmitted from one generation to the next. Biological measurements have been incorporated into these longitudinal high risk (LHR) studies in order to illuminate mechanistic pathways. METHODS: To frame our review, we first present heritability estimates along the gene-by-environment continuum as a foundation. We then offer a Biomarkers of Intergenerational Risk for Depression (BIRD) model to describe the multiple hits individuals at risk receive and to allow for greater focus on the interactive effects of markers. BIRD allows for the known multifinality of pathways towards depression and considers the context (i.e., environment) in which these mechanisms emerge. Next, we review the extant LHR cohort studies that have assessed central nervous system (electroencephalography (EEG), neuroimaging), endocrine (hypothalamic-pituitary adrenal axis (HPA)/cortisol), autonomic (startle, heart rate), genetic, sleep, and birth characteristics. RESULTS: Results to date, in conjunction with the proposed model, point towards several pathways of discovery in understanding mechanisms, providing clear direction for future research examining potential endophenotypes. LIMITATIONS: Our review is based on relatively narrow inclusion and exclusion criteria. As such, many interesting studies were excluded, but this weakness is offset by strengths such as the increased reliability of findings. CONCLUSIONS: Blanket prevention programs are inefficient and plagued by low effect sizes due to low rates of actual conversion to disorder. The inclusion of biomarkers of risk may lead to enhanced program efficiency by targeting those at greatest risk. PMID- 25687189 TI - Are the visual transients from microsaccades helpful? Measuring the influences of small saccades on contrast sensitivity. AB - Like all saccades, microsaccades cause both spatial and temporal changes in the input to the retina. In space, recent studies have shown that these small shifts precisely relocate a narrow (smaller than the foveola) high-acuity retinal locus on the stimulus. However, it has long been questioned whether the temporal modulations resulting from microsaccades are also beneficial for vision. To address this question, we combined spectral analysis of the visual input to the retina with measurements of contrast sensitivity in humans. Estimation of how different types of eye movements redistribute the power of an otherwise stationary stimulus shows that small saccades contribute more temporal power than ocular drift in the low-frequency range, suggesting a specific role for these movements in the encoding of low spatial frequencies. However, an influence on contrast sensitivity was only found for saccades with amplitudes larger than 30'. Contrast thresholds remained highly similar in the presence and absence of smaller saccades. Furthermore, saccades of all amplitudes, including microsaccades, were strongly suppressed during exposure to the stimulus. These findings do not support an important function of the visual transients caused by microsaccades. PMID- 25687190 TI - Computational analysis of RNA structures with chemical probing data. AB - RNAs play various roles, not only as the genetic codes to synthesize proteins, but also as the direct participants of biological functions determined by their underlying high-order structures. Although many computational methods have been proposed for analyzing RNA structures, their accuracy and efficiency are limited, especially when applied to the large RNAs and the genome-wide data sets. Recently, advances in parallel sequencing and high-throughput chemical probing technologies have prompted the development of numerous new algorithms, which can incorporate the auxiliary structural information obtained from those experiments. Their potential has been revealed by the secondary structure prediction of ribosomal RNAs and the genome-wide ncRNA function annotation. In this review, the existing probing-directed computational methods for RNA secondary and tertiary structure analysis are discussed. PMID- 25687191 TI - Isolation of a 1,4-diketone intermediate in oxidative dimerization of 2 hydroxyanthracene and its conversion to oxahelicene. AB - Oxidation of 2-hydroxy-9,10-dialkynylanthracenes resulted in highly regioselective dimerization to furnish metastable dearomatized 1,4-diketones rather than stable aromatic diols. The 1,4-diketones were converted to oxahelicenes, which exhibited strong fluorescence both in solution and solid state as well as chiroptical properties. PMID- 25687192 TI - Baseline factors associated with treatment response in patients infected with hepatitis C virus 1b by stratification of IL28B polymorphisms. AB - Although the single-nucleotide polymorphism (SNP) rs12979860 in the IL28B gene is a better predictor of sustained virological response to treatment of chronic hepatitis C (CHC) than other baseline factors, some CHC patients with the favorable C allele cannot achieve a sustained virological response when treated with peginterferon plus ribavirin. The aim of this study was to examine baseline factors as predictors of rapid virological response (RVR) and complete early virological response (cEVR) to peginterferon alfa-2a plus ribavirin treatment in Chinese CHC patients with hepatitis C virus (HCV) genotype 1b, with emphasis on the difference between the rs129860 CC and CT/TT genotypes. A total of 337 treatment-naive patients participated in this study. All patients were treated with peginterferon alfa-2a plus ribavirin at standard dosage. Serum samples from all patients were collected at baseline, week 4, and week 12 for testing of laboratory parameters, and IL28B genotypes were determined. Multivariate analysis showed that among rs12979860 CC genotype patients, glucose level and aspartate amino transferase (AST) activity were inversely associated with RVR, while abnormal platelet count and allergy inversely associated with cEVR. Among rs12979860 CT genotype patients, age below 40 years and short infection duration were associated with RVR, while age below 40 years, short infection duration, high body mass index (BMI), and no history of allergies were associated with cEVR. The baseline factors associated with the response to CHC treatment may depend on the IL28B genotype. Refinement of the baseline predictors based on IL28B genotypes may be useful for management of HCV infection. PMID- 25687193 TI - Erratum to: Th1/Th2 Cell Differentiation and Molecular Signals. PMID- 25687194 TI - Pigmented lesions on the mucosa: a wide range of diagnoses. PMID- 25687195 TI - The effect of calibration and detector temperature on the reconstructed cone beam computed tomography image quality: a study for the workflow of the iCAT Classic equipment. AB - OBJECTIVE: The image quality of the reconstructed dental cone beam computed tomography (CBCT) acquisition is strongly dependent on the characteristics of the applied detector. Some flat panel detector (FPD) types require a warming-up period (WUP) to achieve a steady-state temperature; and some of them, those that have a cesium iodide detector, may require a calibration process (CP) after each WUP. STUDY DESIGN: Quality-assurance phantom was used for the evaluation of image quality, including spatial accuracy and density response with and without WUP and CP using iCAT Classic equipment. RESULTS: The correlation between the measured gray values and the multidetector computed tomography (MDCT) values deviated slightly from linearity (defined by the 45-degree line). There was no detectable difference in the spatial accuracy of the four different scanning modes. CONCLUSIONS: Although the WUP is important to reach the required steady-state temperature, the CP has a greater effect on the image quality. PMID- 25687196 TI - Health-related quality of life after surgical treatment of mandibular fracture. AB - OBJECTIVES: We evaluated health-related quality of life (HRQoL) before and after surgical treatment of mandibular fracture and assessed patients' perceptions of the esthetic and functional outcomes of surgery. STUDY DESIGN: We established a prospective study of adult patients who were to undergo open reduction and rigid fixation of mandibular fracture. Of the patients, 49 met the inclusion criteria, and of these, 45 agreed to participate. HRQoL was measured with the generic 15 dimensional (15-D) instrument, and patients' satisfaction was assessed with an additional questionnaire. RESULTS: The average preoperative 15-D score among patients (0.891) was significantly lower than that in the general population (0.964) (P < .01). Patients were worse off on 9 of the 15 dimensions of HRQoL; however, at 3 months following surgery, all dimensions had improved to the level observed in the general population. CONCLUSIONS: HRQoL is significantly reduced after mandibular trauma but improves in a few months after surgery. Sensory disturbance is the most significant disadvantage of the surgery. PMID- 25687197 TI - Direct and CBCT dentogingival tissue thickness measurements. PMID- 25687198 TI - Regulatory T cells ameliorate acetaminophen-induced immune-mediated liver injury. AB - The contribution of innate immune cells to acetaminophen (APAP)-induced liver injury has been extensively investigated. However, the roles of T cell populations among adaptive immune cells in APAP-induced liver injury remain to be elucidated. Herein, we found that distinct CD4(+) T cell subsets but not CD8(+) T cells modulated APAP-induced liver injury in mice. After APAP challenge, more CD62L(low)CD44(hi)CD4(+) T cells appeared in the liver, accompanied by increased IFN-gamma. The removal of CD4(+) T cells by either antibody depletion or genetic deficiency markedly compromised pro-inflammatory cytokine levels and ameliorated liver injury. Meanwhile, we also found that the frequency and absolute number of Treg cells also increased. Treg cell depletion increased hepatic CD62L(low)CD44(hi)CD4(+) T cells, augmented pro-inflammatory cytokines, and exacerbated liver injury, while adoptive transfer of Treg cells ameliorated APAP induced liver injury. Furthermore, the recruitment of Treg cells into the liver through specific expression of CXCL10 in the liver could ameliorate APAP-induced liver injury. Our investigation suggests that Th1 and Treg subsets are involved in regulating APAP-induced liver injury. Thus, modulating the Th1/Treg balance may be an effective strategy to prevent and/or treat APAP-induced liver injury. PMID- 25687199 TI - Telocinobufagin enhances the Th1 immune response and protects against Salmonella typhimurium infection. AB - Ideal potential vaccine adjuvants to stimulate a Th1 immune response are urgently needed to control intracellular infections in clinical applications. Telocinobufagin (TBG), an active component of Venenum bufonis, exhibits immunomodulatory activity. Therefore, we investigated whether TBG enhances the Th1 immune response to ovalbumin (OVA) and formalin-inactivated Salmonella typhimurium (FIST) in mice. TBG augmented serum OVA- and FIST-specific IgG and IgG2a and the production of IFNgamma by antigen-restimulated splenocytes. TBG also dramatically enhanced splenocyte proliferative responses to concanavalin A, lipopolysaccharide, and OVA and substantially increased T-bet mRNA levels and the CD3(+)/CD3(+)CD4(+)/CD3(+)CD8(+) phenotype in splenocytes from OVA-immunized mice. In in vivo protection studies, TBG significantly decreased the bacterial burdens in the spleen and prolonged the survival time of FIST-immunized mice challenged with live S. typhimurium. In vivo neutralization of IFNgamma with anti IFNgamma mAbs led to a significant reduction in FIST-specific IgG2a and IFNgamma levels and in anti-Salmonella effect in TBG/FIST-immunized mice. In conclusion, these results suggest that TBG enhances a Th1 immune response to control intracellular infections. PMID- 25687200 TI - The association between the ACTN3 R577X polymorphism and noncontact acute ankle sprains. AB - Ankle sprains are one of the most severe musculoskeletal soft tissue injuries during physical activity. Although many risk factors have been offered, it is unclear why some individuals develop noncontact ankle sprains when participating in comparable levels of physical exertion under identical environmental conditions and others do not. The ACTN3 gene that encodes the alpha-actinin-3 protein, which is, only expressed in the Z line of fast glycolytic muscle fibres was found to associate with power/strength performance. The aim of this study was therefore to investigate whether the ACTN3 gene polymorphism is associated with noncontact acute ankle sprains. One hundred and forty-two participants with clinically diagnosed noncontact acute ankle sprains as well as 280 physically active controls participants without any history of ankle sprains were included in this case-control genetic association study. The RR genotype (odds ratio (OR) = 0.56; 95% confidence interval (CI), 0.32-0.65, P = 0.011) and R allele (OR = 0.64; 95% CI, 0.37-0.68, P = 0.002) of the ACTN3 were significantly low represented in the acute ankle sprains group compared with the control group. The ACTN3 R577X is associated with acute ankle sprains in Chinese participants in this study. This is the first study to suggest that an individual with a RR genotype is at a decreased risk of acute ankle sprains. PMID- 25687201 TI - Paroxysmal nonepileptic motor phenomena in newborn. AB - INTRODUCTION: Understanding the pathophysiological meaning of paroxysmal nonepileptic motor phenomena in newborns represents a challenge for the clinicians of the Neonatal Intensive Care Unit. METHODS: This paper provides an extensive review of the most frequent paroxysmal nonepileptic motor phenomena in newborns, in order to improve the knowledge about this sub-topic of the neonatal pathology and to guide the diagnostic-therapeutic approach. RESULTS: The correct identification of an epileptic form, among different motor phenomena, which may clinically mimic seizures, is essential for a correct management, avoiding overtreatment. However, it is likewise important to know and to be able to identify other rare neurological conditions, such as hyperekplexia, spinal muscular atrophy, acute bilirubin encephalopathy, that could make a first appearance with paroxysmal motor manifestations, needing specific diagnostic work up and treatment. CONCLUSIONS: These clinical events should not be underestimated because, even if many times they are physiological and age-related, sometimes they could be the visible signs of an underlying epileptic or nonepileptic neurological disease. PMID- 25687202 TI - Characteristic MRI features of chronic inflammatory demyelinating polyradiculoneuropathy. AB - We present characteristic magnetic resonance imaging (MRI) features in a pediatric female patient with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Muscle weakness developed at 8 years old and fluctuated during the clinical course over 7 years. Electrophysiological studies showed a demyelination pattern with moderately delayed nerve conduction velocity, as well as dispersion phenomenon. MRI showed marked changes in thickening of the spinal nerve roots and their peripheral nerves in the lumber and brachial plexuses, as well as in the bilateral trigeminal nerves. It is suggested that these MRI features are characteristic and strongly supportive of the diagnosis of CIDP with a prolonged clinical course. PMID- 25687203 TI - Incidence, management, and course of cancer in patients with inflammatory bowel disease. AB - BACKGROUND AND AIMS: Patients with inflammatory bowel disease [IBD] are at increased risk for developing some types of neoplasia. Our aims were to determin the risk for cancer in patients with IBD and to describe the relationship with immunosuppressive therapies and clinical management after tumor diagnosis. METHODS: Retrospective, multicenter, observational, 5-year follow-up, cohort study. Relative risk [RR] of cancer in the IBD cohort and the background population, therapeutic strategies, and cancer evolution were analyzed. RESULTS: A total of 145 cancers were diagnosed in 133 of 9100 patients with IBD (global cumulative incidence 1.6% vs 2.4% in local population; RR = 0.67; 95% confidence interval [CI]: 0.57-0.78). Patients with IBD had a significantly increased RR of non-melanoma skin cancer [RR = 3.85; 2.53-5.80] and small bowel cancer [RR = 3.70; 1.23-11.13]. After cancer diagnosis, IBD treatment was maintained in 13 of 27 [48.1%] patients on thiopurines, in 2 of 3 on methotrexate [66.6%], none on anti-TNF-alpha monotherapy [n = 6] and 4 of 12 [33.3%] patients on combined therapy. Rate of death and cancer remission during follow-up did not differ [p > 0.05] between patients who maintained the treatment compared with patients who withdrew [5% vs 8% and 95% vs 74%, respectively]. An association between thiopurines [p = 0.20] or anti-TNF-alpha drugs [p = 0.77] and cancer was not found. CONCLUSIONS: Patients with IBD have an increased risk for non-melanoma skin cancer and small bowel cancer. Immunosuppresive therapy is not related to a higher overall risk for cancer or worse tumor evolution in patients who maintain these drugs after cancer diagnosis. PMID- 25687204 TI - Value-based health care for inflammatory bowel diseases. AB - Increasing healthcare costs worldwide put the current healthcare systems under pressure. Although many efforts have aimed to contain costs in medicine, only a few have achieved substantial changes. Inflammatory bowel diseases rank among the most costly of chronic diseases, and physicians nowadays are increasingly engaged in health economics discussions. Value-based health care [VBHC] has gained a lot of attention recently, and is thought to be the way forward to contain costs while maintaining quality. The key concept behind VBHC is to improve achieved outcomes per encountered costs, and evaluate performance accordingly. Four main components need to be in place for the system to be effective: [1] accurate measurement of health outcomes and costs; [2] reporting of these outcomes and benchmarking against other providers; [3] identification of areas in need of improvement based on these data and adjusting the care delivery processes accordingly; and [4] rewarding high-performing participants. In this article we will explore the key components of VBHC, we will review available evidence focussing on inflammatory bowel diseases, and we will present our own experience as a guide for other providers. PMID- 25687205 TI - Fecal microbiota transplantation for recurrent C. difficile infection in a patient with chronic refractory ulcerative colitis. PMID- 25687206 TI - Introducing vedolizumab to clinical practice: who, when, and how? AB - Vedolizumab (VDZ), a humanized monoclonal antibody that selectively targets alpha4beta7 integrin, is approved for use in inflammatory bowel disease (IBD). Here we review the evidence for the safety and efficacy of VDZ in IBD, in order to identify patients likely to benefit from therapy and to integrate VDZ into clinical practice. A bibliographic search was performed of the online databases MEDLINE, EMBASE, PubMed, and the Cochrane Library, using the key words 'inflammatory bowel diseases' OR 'ulcerative colitis' OR 'Crohn's disease' AND 'vedolizumab' OR 'MLN0002' OR 'integrin alpha4beta7' OR 'anti-integrin'. Eight nine articles were returned using the primary search. Eight randomized controlled trials, one Cochrane review, and two network meta-analyses were identified. VDZ is well tolerated with a low rate of adverse events (similar to placebo), and is associated with minimal systemic immunosuppression. VDZ is effective for induction and maintenance of remission in outpatients with moderate to severe ulcerative colitis (UC) or Crohn's disease (CD) who have failed conventional and anti-tumor necrosis factor (anti-TNF) therapy. VDZ is also a first-line alternative to anti-TNF therapy in UC. The efficacy of VDZ is best assessed at, or beyond, 10 weeks of therapy. The safety, tolerability, and efficacy profile of VDZ place it as a new therapy in IBD, though further trials directly comparing VDZ with other biological agents as well as pragmatic studies to evaluate cost effectiveness are necessary. PMID- 25687207 TI - The culprit in obscure gastrointestinal bleeding: intestinal cavernous haemangioma in a patient with ulcerative colitis. PMID- 25687208 TI - Vulval Crohn's disease: a clinical study of 22 patients. AB - Vulval Crohn's disease [VCD] is a challenging condition that can occur without gastrointestinal Crohn's disease [GCD]. We reviewed the clinical features and effects of therapy in a cohort of 22 patients with VCD to determine whether the presence of GCD affected the clinical presentation and treatment response. Of these, 64% had GCD and 65% of these presented with GCD prior to VCD. Fissuring, ulceration, and scarring were more common in those with VCD alone. Potent and ultra-potent topical steroids showed benefit in most patients. There was no clear evidence of sustained remission with metronidazole. Azathioprine was the most commonly used oral immunosuppressive agent, with an efficacy of 57%. Patients with both VCD and GCD had a better clinical response compared with those with VCD alone [70% and 25%, respectively]. Infliximab and adalimumab were effective in 56% and 71% of patients, respectively. Excision of redundant tissue was helpful in four patients. The absence of GCD may delay the diagnosis in women who present with vulval symptoms alone. The more active clinical features in those with VCD alone may represent a more aggressive condition, or the severity of the cutaneous disease may have been reduced by immunosuppression taken for GCD. Several patients obtained sustained remission in their GCD with anti-tumor necrosis factor alpha [anti-TNFalpha] agents while the VCD remained active. PMID- 25687210 TI - Be honest and help me prepare for the future: What people with interstitial lung disease want from education in pulmonary rehabilitation. AB - Pulmonary rehabilitation (PR) is recommended for people with interstitial lung disease (ILD); however, the educational content of PR was not designed for this group. This study explored the perspectives of patients and ILD clinicians regarding the educational content of PR for ILD. A qualitative study using individual semi-structured interviews was undertaken. Transcripts were coded independently by two investigators and themes established by consensus. Participants were 18 people with ILD (9 idiopathic pulmonary fibrosis, diffusing capacity for carbon monoxide 54 (20)% predicted) and 14 clinicians from 5 countries and 5 disciplines. Major themes from patient interviews were the importance of knowing what the future might bring and the need for honesty from clinicians. Most were happy to attend standard PR education sessions but wanted ILD-specific content. Patients wanted information about end-of-life planning and most were happy to discuss it in a group. Among clinicians, there was no consensus regarding whether prognosis should be discussed in PR. Most clinicians supported discussion of advanced care planning, however, some thought it should not be discussed in a group. We conclude that people with ILD have specific educational needs that may not be met in the current PR format. Patients and clinicians have some discordant views about programme content. PMID- 25687209 TI - An update on Acanthamoeba keratitis: diagnosis, pathogenesis and treatment. AB - Free-living amoebae of the genus Acanthamoeba are causal agents of a severe sight threatening infection of the cornea known as Acanthamoeba keratitis. Moreover, the number of reported cases worldwide is increasing year after year, mostly in contact lens wearers, although cases have also been reported in non-contact lens wearers. Interestingly, Acanthamoeba keratitis has remained significant, despite our advances in antimicrobial chemotherapy and supportive care. In part, this is due to an incomplete understanding of the pathogenesis and pathophysiology of the disease, diagnostic delays and problems associated with chemotherapeutic interventions. In view of the devastating nature of this disease, here we present our current understanding of Acanthamoeba keratitis and molecular mechanisms associated with the disease, as well as virulence traits of Acanthamoeba that may be potential targets for improved diagnosis, therapeutic interventions and/or for the development of preventative measures. Novel molecular approaches such as proteomics, RNAi and a consensus in the diagnostic approaches for a suspected case of Acanthamoeba keratitis are proposed and reviewed based on data which have been compiled after years of working on this amoebic organism using many different techniques and listening to many experts in this field at conferences, workshops and international meetings. Altogether, this review may serve as the milestone for developing an effective solution for the prevention, control and treatment of Acanthamoeba infections. PMID- 25687211 TI - The chemical space project. AB - One of the simplest questions that can be asked about molecular diversity is how many organic molecules are possible in total? To answer this question, my research group has computationally enumerated all possible organic molecules up to a certain size to gain an unbiased insight into the entire chemical space. Our latest database, GDB-17, contains 166.4 billion molecules of up to 17 atoms of C, N, O, S, and halogens, by far the largest small molecule database reported to date. Molecules allowed by valency rules but unstable or nonsynthesizable due to strained topologies or reactive functional groups were not considered, which reduced the enumeration by at least 10 orders of magnitude and was essential to arrive at a manageable database size. Despite these restrictions, GDB-17 is highly relevant with respect to known molecules. Beyond enumeration, understanding and exploiting GDBs (generated databases) led us to develop methods for virtual screening and visualization of very large databases in the form of a "periodic system of molecules" comprising six different fingerprint spaces, with web-browsers for nearest neighbor searches, and the MQN- and SMIfp-Mapplet application for exploring color-coded principal component maps of GDB and other large databases. Proof-of-concept applications of GDB for drug discovery were realized by combining virtual screening with chemical synthesis and activity testing for neurotransmitter receptor and transporter ligands. One surprising lesson from using GDB for drug analog searches is the incredible depth of chemical space, that is, the fact that millions of very close analogs of any molecule can be readily identified by nearest-neighbor searches in the MQN-space of the various GDBs. The chemical space project has opened an unprecedented door on chemical diversity. Ongoing and yet unmet challenges concern enumerating molecules beyond 17 atoms and synthesizing GDB molecules with innovative scaffolds and pharmacophores. PMID- 25687212 TI - Histone deacetylases: structural determinants of inhibitor selectivity. AB - Histone deacetylases (HDACs) are epigenetic targets with an important role in cancer, neurodegeneration, inflammation, and metabolic disorders. Although clinically effective HDAC inhibitors have been developed, the design of inhibitors with the desired isoform(s) selectivity remains a challenge. Selective inhibitors could help clarify the function of each isoform, and provide therapeutic agents having potentially fewer adverse effects. Crystal structures of several HDACs have been reported, enabling structure-based drug design and providing important information to understand enzyme function. Here, we provide a comprehensive review of the structural information available on HDACs, discussing both conserved and isoform-specific structural and mechanistic features. We focus on distinctive aspects that help rationalize inhibitor selectivity, and provide structure-based recommendations for achieving the desired selectivity. PMID- 25687213 TI - Chemical composition and antioxidant activity of essential oil from aerial parts of Teucrium flavum L. subsp. flavum growing spontaneously in Tunisia. AB - The objectives of this study were to chemically characterise and evaluate the antioxidant potential of the essential oil from Teucrium flavum L. subsp. flavum growing spontaneously in Tunisia. The volatile oil was extracted by hydrodistillation of the aerial parts in a Clevenger type apparatus. Forty constituents were identified via GC and GC-MS analysis. beta-caryophyllene (32.5%) and alpha-humulene (17.8%) were the most abundant components. The evaluation of free radical scavenging activity using stable DPPH free radical showed that the volatile oil exhibits a moderate antioxidant activity and reduces DPPH to 50% at EC50 value of 1230 MUg mL(-1). PMID- 25687214 TI - The brome mosaic virus 3' untranslated sequence regulates RNA replication, recombination, and virion assembly. AB - The 3' untranslated region in each of the three genomic RNAs of Brome mosaic virus (BMV) is highly homologous and contains a sequence that folds into a tRNA like structure (TLS). Experiments performed over the past four decades revealed that the BMV 3' TLS regulates many important steps in BMV infection. This review summarizes in vitro and in vivo studies of the roles of the BMV 3' TLS functioning as a minus-strand promoter, in RNA recombination, and to nucleate virion assembly. PMID- 25687215 TI - Combined Occurrence of Autosomal Dominant Aniridia and Autosomal Recessive Albinism in Several Members of a Family. AB - PURPOSE: To characterize clinical and genetic aspects of a family with a unique combination of two hereditary blinding eye diseases. METHODS: Comprehensive eye examination of proband and family members. Molecular analyses of the TYR and PAX6 genes. RESULTS: A young couple, both legally blind, requested genetic counselling regarding their ocular condition. The female was previously diagnosed with oculocutaneous albinism (OCA1A) and her spouse was diagnosed with Peters anomaly. A comprehensive clinical examination revealed that the female had OCA1A combined with signs of another ocular disease, showing some similarity to aniridia. A complete ocular examination of her family members revealed that her brother also suffered from the same combined phenotype, her father had typical OCA1A signs, and her mother and sister had aniridia-like phenotype, without clinical diagnosis until the time of presentation. Molecular analysis identified two compound heterozygous TYR mutations known to cause OCAIA and cosegregate with oculocutaneous albinism. In addition, we identified a novel heterozygous PAX6 mutation confirming the atypical aniridia phenotype. CONCLUSIONS: We report here a unique and rare clinical phenotype that is explained by the segregation of two severe inherited eye diseases. The clinical and genetic analysis in this family allowed them to receive accurate genetic counseling. PMID- 25687216 TI - Whole Exome Sequencing Identifies an Adult-Onset Case of Methylmalonic Aciduria and Homocystinuria Type C (cblC) with Non-Syndromic Bull's Eye Maculopathy. AB - BACKGROUND: Methylmalonic aciduria and homocystinuria type C (cblC), a disorder of vitamin B12 (cobalamin) metabolism caused by mutations in the MMACHC gene, presents with many systemic symptoms, including neurological, cognitive, psychiatric, and thromboembolic events. Retinal phenotypes, including maculopathy, pigmentary retinopathy, and optic atrophy are common in early onset form of the disease but are rare in adult onset forms. MATERIALS AND METHODS: An adult Hispanic female presented with decreased central vision, bilateral pericentral ring scotomas and bull's eye-appearing macular lesions at 28 years of age. Her medical history was otherwise unremarkable except for iron deficiency anemia and both urinary tract and kidney infections. Screening of the ABCA4 gene, mutations in which frequently cause bull's eye maculopathy, was negative. Subsequently, analysis with whole exome sequencing was performed. RESULTS: Whole exome sequencing discovered compound heterozygous mutations in MMACHC, c.G482A:p.Arg161Gln and c.270_271insA:p.Arg91Lysfs*14, which segregated with the disease in the family. The genetic diagnosis was confirmed by biochemical laboratory testing, showing highly elevated urine methylmalonic acid/creatinine and homocysteine levels, and suggesting disease management with hydroxycobalamin injections and carnitine supplementation. CONCLUSIONS: In summary, a unique case of an adult patient with bull's eye macular lesions and no clinically relevant systemic symptoms was diagnosed with cblC by genetic screening and follow-up biochemical laboratory tests. PMID- 25687217 TI - Analysis of BAP1 Germline Gene Mutation in Young Uveal Melanoma Patients. AB - BACKGROUND: To evaluate the prevalence of BAP1 germline mutations in a series of young patients with uveal melanoma (UM), diagnosed before age 30. MATERIALS AND METHODS: The study was carried out on 14 young uveal melanoma patients (average age 21.4 years, range 3 months to 29 years). Germline DNA was extracted from peripheral blood. BAP1 sequencing was carried out using direct sequencing of all exons and adjacent intronic sequences. We also tested for germline mutations in additional melanoma-associated candidate genes CDKN2A and CDK4 (exon 4). RESULTS: We identified one patient with a pathogenic mutation (c. 1717delC, p.L573fs*3) in BAP1. This patient was diagnosed with UM at age 18 years and had a family history of a father with UM and a paternal grandfather with cancer of unknown origin. One additional patient had an intronic variant of uncertain significance (c.123-48T > G) in BAP1 while the remaining 12 patients had no alteration. None of the patients had CDKN2A or CDK4 (Exon 4) mutations. Family history was positive for a number of additional malignancies in this series, in particular for cutaneous melanoma, prostate, breast and colon cancers. There were no families with a history of mesothelioma or renal cell carcinoma. CONCLUSIONS: This study suggests that a small subset of patients with early onset UM has germline mutation in BAP1. While young patients with UM should be screened for germline BAP1 mutations, our results suggest that there is a need to identify other candidate genes which are responsible for UM in young patients. PMID- 25687218 TI - Effect of local A-site strain on dipole stability in A6GaNb9O30 (A = Ba, Sr, Ca) tetragonal tungsten bronze relaxor dielectrics. AB - A series of isovalently A-site substituted relaxor dielectric tetragonal tungsten bronzes of general formula Ba(6-x-y)Sr(x)Ca(y)GaNb(9)O(30) were investigated. The long-range (average) crystal structure as determined by conventional diffraction techniques varies monotonically according to Vegard's law. The dielectric properties, however, do not display a similar, simple "average size" dependence and instead show a dependence on the statistical size variance, i.e. size mismatch, of the A-cation. The difficulties in Vogel-Fulcher analysis of relative permittivity and the complementary approach of using dielectric loss data fitted to Jonscher's empirical universal dielectric relaxation model is discussed. PMID- 25687219 TI - Use of neuraminidase inhibitors in primary health care during pandemic and seasonal influenza between 2009 and 2013. AB - BACKGROUND: In a context of controversy about influenza antiviral treatments, this study assessed primary health-care physicians' prescription of neuraminidase inhibitors (NIs) in France during pandemic and seasonal influenza between 2009 and 2013. METHODS: This observational study, using data recorded in three national databases, estimated the rate of NI prescription among influenza-like illness (ILI) patients seen in GP and paediatrician consultations, and determined factors associated with this prescription according to a multivariate analysis. NI delivery by pharmacists was also evaluated. RESULTS: Rates of NI prescription were estimated to be 61.1% among ILI patients with a severe influenza risk factor seen in GP consultation during the A(H1N1)pdm2009 pandemic versus an average rate of 25.9% during the three following seasonal influenza epidemics. Factors associated with NI prescription were a chronic disease in patients under 65 years (OR 14.85; 95% CI 13.00, 16.97) and in those aged 65 and older (OR 7.54; 5.86, 9.70), an age >=65 years in patients without chronic disease (OR 1.35; 1.04, 1.74), a pregnancy (OR 10.63; 7.67, 15.76), obesity (OR 4.67; 3.50, 6.22) and a consultation during the pandemic A(H1N1)pdm2009 (OR 3.19; 2.93, 3.48). The number of antiviral treatments delivered by pharmacists during the A(H1N1)pdm2009 pandemic was 835 per 100,000 inhabitants, and an average of 275 per 100,000 inhabitants during the three following seasonal influenza epidemics. CONCLUSIONS: Although physicians seem to follow the recommended indications for NIs in primary health-care practice, this study confirms the low rate of NI prescription to ILI patients with a severe influenza risk factor, especially during seasonal epidemics. PMID- 25687220 TI - CD36 AA genotype is associated with decreased lipid taste perception in young obese, but not lean, children. AB - BACKGROUND/OBJECTIVE: Obesity is an alarming threat for all age groups, including children. Fat overconsumption is one of the factors that directly influences this pathology. Recent studies have suggested that a common variant in the CD36 gene, that is, single-nucleotide polymorphism (SNP) rs1761667-A allele, that reduces CD36 expression, associates with high oral fat detection thresholds in some obese subjects. The objective was to assess fatty acid sensitivity in relation to CD36 SNP in young lean and obese children. SUBJECTS/METHODS: We studied lingual detection thresholds for emulsions, containing oleic acid, in Algerian children (n=116, age=8+/-0.5 years) who were divided into two groups: obese (n=57; body mass index (BMI) z-score=2.513+/-0.490) and lean children (n=59; BMI z-score= 0.138+/-0.601) by alternative-forced choice method. To correlate the lipid taste perception thresholds with CD36 SNP, the children were genotyped for A/G SNP rs1761667 in 5'UTR region of CD36 by using PCR and restriction fragment length polymorphism. RESULTS: We noticed significantly higher CD36 A-allele frequency (P=0.036) in young obese children compared with leans. CD36 A-allele was associated with higher lipid taste perception thresholds than G-allele in obese children, but not in lean controls. Moreover, waist circumference was positively correlated with reduced fat taste sensitivity in these children. CONCLUSIONS: CD36 SNP A-allele, being present both in young lean and in obese children, is associated with high threshold for fatty acid taste sensitivity only in obese children. PMID- 25687221 TI - Calcium supplements controversy in osteoporosis: a physiological mechanism supporting cardiovascular adverse effects. AB - Recently, administration of calcium supplements for the prevention and treatment of osteoporosis has become a highly controversial issue. The findings of epidemiological studies are not necessarily supportive of the practice and are also open to different interpretations. In this article, we attempt to broaden the discussion and provide evidence that calcium supplementation may fail to compensate for renal calcium loss, and also that the resultant increased calcium load in the circulation could lead to extraskeletal deposition, including in the coronary arteries. PMID- 25687222 TI - A room-temperature protocol to access isoquinolines through Ag(I) catalysed annulation of o-(1-alkynyl)arylaldehydes and ketones with NH4OAc: elaboration to berberine and palmatine. AB - An efficient and mild protocol for the direct construction of aryl- and alkyl substituted isoquinolines has been realized through silver nitrate catalyzed aromatic annulation of o-(1-alkynyl)arylaldehydes and ketones with ammonium acetate. The salient feature of this methodology is that this annulation could be effected at room temperature leading to a wide range of isoquinoline derivatives in good to excellent yields. Additionally, this approach has been employed to the synthesis of biologically important isoquinoline alkaloids such as berberine and palmatine. PMID- 25687223 TI - Examination of thermal unfolding and aggregation profiles of a series of developable therapeutic monoclonal antibodies. AB - Screening for pharmaceutically viable stability from measurements of thermally induced protein unfolding and short-term accelerated stress underpins much molecule design, selection, and formulation in the pharmaceutical biotechnology industry. However, the interrelationships among intrinsic protein conformational stability, thermal denaturation, and pharmaceutical stability are complex. There are few publications in which predictions from thermal unfolding-based screening methods are examined together with pharmaceutically relevant long-term storage stability performance. We have studied eight developable therapeutic IgG molecules under solution conditions optimized for large-scale commercial production and delivery. Thermal unfolding profiles were characterized by differential scanning calorimetry (DSC) and intrinsic fluorescence recorded simultaneously with static light scattering (SLS). These molecules exhibit a variety of thermal unfolding profiles under common reference buffer conditions and under individually optimized formulation conditions. Aggregation profiles by SE-HPLC and bioactivity upon long-term storage at 5, 25, and 40 degrees C establish that IgG molecules possessing a relatively wide range of conformational stabilities and thermal unfolding profiles can be formulated to achieve pharmaceutically stable drug products. Our data suggest that a formulation design strategy that increases the thermal unfolding temperature of the Fab transition may be a better general approach to improving pharmaceutical storage stability than one focused on increasing Tonset or Tm of the first unfolding transition. PMID- 25687224 TI - The decrease in silicon concentration of the connective tissues with age in rats is a marker of connective tissue turnover. AB - Silicon may be important for bone and connective tissue health. Higher concentrations of silicon are suggested to be associated with bone and the connective tissues, compared with the non-connective soft tissues. Moreover, in connective tissues it has been suggested that silicon levels may decrease with age based upon analyses of human aorta. These claims, however, have not been tested under controlled conditions. Here connective and non-connective tissues were collected and analysed for silicon levels from female Sprague-Dawley rats of different ages (namely, 3, 5, 8, 12, 26 and 43 weeks; n=8-10 per age group), all maintained on the same feed source and drinking water, and kept in the same environment from weaning to adulthood. Tissues (696 samples) were digested in nitric acid and analysed by inductively coupled plasma optical emission spectrometry for total silicon content. Fasting serum samples were also collected, diluted and analysed for silicon. Higher concentrations of silicon (up to 50-fold) were found associated with bone and the connective tissues compared with the non-connective tissues. Although total silicon content increased with age in all tissues, the highest connective tissue silicon concentrations (up to 9.98 MUg/g wet weight) were found in young weanling rats, decreasing thereafter with age (by 2-6 fold). Fasting serum silicon concentrations reflected the pattern of connective tissue silicon concentrations and, both measures, when compared to collagen data from a prior experiment in Sprague-Dawley rats, mirrored type I collagen turnover with age. Our findings confirm the link between silicon and connective tissues and would imply that young growing rats have proportionally higher requirements for dietary silicon than mature adults, for bone and connective tissue development, although this was not formally investigated here. However, estimation of total body silicon content suggested that actual Si requirements may be substantially lower than previously estimated which could explain why absolute silicon deficiency is difficult to achieve but, when it is achieved in young growing animals, it results in stunted growth and abnormal development of bone and other connective tissues. PMID- 25687225 TI - Semiquinone oscillations as a tool for investigating the ubiquinone binding to photosynthetic reaction centers. AB - Semiquinone oscillations induced by light pulses in the presence of exogenous electron donors are a valuable source of information on the kinetics and thermodynamics of ubiquinone chemistry relevant to the QB site of the photosynthetic reaction center (RC). In previous attempts to achieve the quantitative interpretation of data, the ubiquinone concentration was considered constant during the experiment since it was much bigger than that of RC. In this work, we extended existing models to low ubiquinone concentrations revealing several hidden processes taking place during the ubiquinone photoreduction and enabling the evaluation of the ubiquinone binding constant K Q at the QB site. The proposed approach provides for the first time the evaluation of K Q without any preliminary treatment of ubiquinone extraction from the binding site, thereby better preserving its native structure. PMID- 25687226 TI - Cell penetrating peptides as a therapeutic strategy in chronic lymphocytic leukemia. AB - PP2A is a serine/threonine phosphatase critical to a number of physiological and developmental processes. In this manuscript, we show that a peptide, specifically blocking the caspase- 9/PP2A interaction, DPT-C9h, induces apoptosis in primary tumour B cells isolated from peripheral blood mononuclear cells or bone marrow of chronic lymphocytic leukemia (CLL) patients, but not on B cells obtained from healthy donors (HD). Moreover, in both CLL patients and HD, DPT-C9h does not induce apoptosis on T- and NKcells and monocytes. Our results strongly suggest that DPT-C9h peptide has tumour specificity and that caspase-9/PP2Ac interaction constitutes a novel therapeutic approach for the treatment in CLL patients. PMID- 25687227 TI - Properties of an alkali-thermo stable xylanase from Geobacillus thermodenitrificans A333 and applicability in xylooligosaccharides generation. AB - An extracellular thermo-alkali-stable and cellulase-free xylanase from Geobacillus thermodenitrificans A333 was purified to homogeneity by ion exchange and size exclusion chromatography. Its molecular mass was 44 kDa as estimated in native and denaturing conditions by gel filtration and SDS-PAGE analysis, respectively. The xylanase (GtXyn) exhibited maximum activity at 70 degrees C and pH 7.5. It was stable over broad ranges of temperature and pH retaining 88 % of activity at 60 degrees C and up to 97 % in the pH range 7.5-10.0 after 24 h. Moreover, the enzyme was active up to 3.0 M sodium chloride concentration, exhibiting at that value 70 % residual activity after 1 h. The presence of other metal ions did not affect the activity with the sole exceptions of K(+) that showed a stimulating effect, and Fe(2+), Co(2+) and Hg(2+), which inhibited the enzyme. The xylanase was activated by non-ionic surfactants and was stable in organic solvents remaining fully active over 24 h of incubation in 40 % ethanol at 25 degrees C. Furthermore, the enzyme was resistant to most of the neutral and alkaline proteases tested. The enzyme was active only on xylan, showing no marked preference towards xylans from different origins. The hydrolysis of beechwood xylan and agriculture-based biomass materials yielded xylooligosaccharides with a polymerization degree ranging from 2 to 6 units and xylobiose and xylotriose as main products. These properties indicate G. thermodenitrificans A333 xylanase as a promising candidate for several biotechnological applications, such as xylooligosaccharides preparation. PMID- 25687229 TI - Effects of hazardous pollutants on the walls of Valence Aqueduct (Istanbul) by Raman spectroscopy, SEM-EDX and Geographical Information System. AB - This study involves Raman spectroscopic (176-2900cm(-1)), SEM-EDX and Geographical Information System studies of the pollutants on the walls of Valence Aqueduct (Bozdogan Kemeri), Istanbul, Turkey. Raman spectroscopy is a useful analytical method in characterization of painting materials and corrosion products. Especially, when it is not possible to take the samples from the place they exist, handheld Raman spectrometers play an important role to identify the materials in these samples. Furthermore, more information could be gathered when it is combined with SEM-EDX studies. On the other hand, regarding the cultural heritage, it is crucial to determine precise coordinates of the historical peninsula and the samples which have been exposed to pollutants, by Geographical Information Systems in order to study them and take precautions for the future. Handheld Raman spectrometer (NanoRam by B&WTek) allows recording of acceptable and good quality spectra of a large majority of minerals outdoors. Raman spectra of minerals and pollutants in this study were obtained using 785nm laser excitation source. Observed Raman bands are found at correct wavenumber positions within +/-3cm(-1) compared to reference values in the literature. Taking into account the resolution of the spectrometer (9cm(-1)), the results are still reliable and applicable on such systems. Areas of potential applications of these instruments include all kind of common geoscience work outdoors. PMID- 25687228 TI - Functional variants regulating LGALS1 (Galectin 1) expression affect human susceptibility to influenza A(H7N9). AB - The fatality of avian influenza A(H7N9) infection in humans was over 30%. To identify human genetic susceptibility to A(H7N9) infection, we performed a genome wide association study (GWAS) involving 102 A(H7N9) patients and 106 heavily exposed healthy poultry workers, a sample size critically restricted by the small number of human A(H7N9) cases. To tackle the stringent significance cutoff of GWAS, we utilized an artificial imputation program SnipSnip to improve the association signals. In single-SNP analysis, one of the top SNPs was rs13057866 of LGALS1. The artificial imputation (AI) identified three non-genotyped causal variants, which can be represented by three anchor/partner SNP pairs rs13057866/rs9622682 (AI P = 1.81 * 10(-7)), rs4820294/rs2899292 (2.13 * 10(-7)) and rs62236673/rs2899292 (4.25 * 10(-7)) respectively. Haplotype analysis of rs4820294 and rs2899292 could simulate the signal of a causal variant. The rs4820294/rs2899292 haplotype GG, in association with protection from A(H7N9) infection (OR = 0.26, P = 5.92 * 10(-7)) correlated to significantly higher levels of LGALS1 mRNA (P = 0.050) and protein expression (P = 0.025) in lymphoblast cell lines. Additionally, rs4820294 was mapped as an eQTL in human primary monocytes and lung tissues. In conclusion, functional variants of LGALS1 causing the expression variations are contributable to the differential susceptibility to influenza A(H7N9). PMID- 25687230 TI - Too much technology. PMID- 25687231 TI - PTSD and depression symptoms are associated with binge eating among US Iraq and Afghanistan veterans. AB - OBJECTIVE: US Iraq and Afghanistan Veterans with post-traumatic stress disorder (PTSD) and depression are at increased risk for obesity. Understanding the contribution of health behaviors to this relationship will enhance efforts to prevent and reduce obesity. Therefore, we examined the association of PTSD and depression symptoms with binge eating, a risk factor for obesity, among Iraq/Afghanistan Veterans. METHOD: Iraq/Afghanistan Veterans were assessed at intake to the VA Puget Sound Healthcare System-Seattle post-deployment clinic (May 2004-January 2007). The Patient Health Questionnaire was used to measure depression and binge eating symptoms, and the PTSD Checklist-Military Version assessed PTSD symptoms. RESULTS: The majority of the sample (N=332) was male (91.5%) and Caucasian (72.6%), with an average age of 31.1 (SD=8.5) years; 16.3% met depression screening criteria, 37.8% met PTSD screening criteria, and 8.4% met binge eating screening criteria. In adjusted models, those meeting depression (odds ratio (OR)=7.53; 95% CI=2.69, 21.04; p<.001) and PTSD (OR=3.37; 95% CI=1.34, 8.46; p=.01) screening criteria were more likely to meet binge eating screening criteria. Continuous measures of PTSD and depression symptom severity were also associated with meeting binge eating screening criteria (ps<.05). CONCLUSION: PTSD and depression are common conditions among Iraq/Afghanistan Veterans. In the present study, PTSD and depression symptoms were associated with meeting binge eating screening criteria, identifying a possible pathway by which psychiatric conditions lead to disproportionate burden of overweight and obesity in this Veteran cohort. Tailored dietary behavior interventions may be needed for Iraq/Afghanistan Veterans with co-morbid obesity and psychiatric conditions. PMID- 25687232 TI - The role of sensation seeking and motivations for eating in female and male adolescents who binge eat. AB - OBJECTIVES: Although different personality traits have been associated with the onset and maintenance of binge eating, the role of sensation seeking is still not well documented. The aim of the present study was to investigate the role of sensation seeking and motivations for eating in male and female adolescents who binge eat. METHODS: 336 adolescents (196 boys and 140 girls, mean age 17.48) completed a survey composed of Binge Eating Scale, Motivation for Eating Scale, and Brief Sensation Seeking Scale. RESULTS: Our results showed that for female adolescents, binge eating was significantly correlated with age, body mass index (BMI), Environmental and Emotional Eating. Hierarchical multiple regression analysis indicated that BMI was a significant positive predictor of binge eating; Emotional and Physical Eating accounted for 34% of the variance. For male adolescents, binge eating was significantly correlated with age, BMI, Boredom susceptibility, Experience seeking, environmental, Social and Emotional Eating. The most significant variables that contribute to binge symptoms, were age and BMI (that accounted for 16% of the variance), Experience seeking and Boredom susceptibility (11%) and emotional eating (18%). CONCLUSIONS: Our results provided support for emotional motivations as significant triggers for binge eating behavior in both male and female adolescents. Although two sensation seeking dimensions were significant predictors of binge eating in males, sensation seeking was not associated to binge eating in the female subsample. PMID- 25687233 TI - Course and outcome of schizophrenia in asian countries: review of research in the past three decades. AB - Considerable variation has been observed in the course and outcome of schizophrenia. With regard to epidemiology of schizophrenia, papers from different Asian countries have reported findings which are in contrast with literature from the western countries. In this background we undertook a narrative review of literature regarding course and outcome of schizophrenia in Asian countries. We conducted Medline search for English-language papers on long term course and outcome of schizophrenia conducted in Asia in the past 3 decades. We also reviewed data pertaining to Asian countries from the World Health Organization's International Study of Schizophrenia (ISoS). In addition to ISoS, we retrieved 14 reports from 9 Asian countries. While ISoS used comparable methodology across the countries, non-ISoS studies differed substantially in their aims, sampling, follow-up rates and assessment tools used for studying the course and outcome. Overall, the percentage of patients who experienced clinical and functional outcome in the Asian countries were largely comparable to those in the western studies. We observed significant variations in the long-term outcome and mortality in schizophrenia even among the Asian countries. In conclusion, there is substantial variation in the long-term course and outcome and mortality across different Asian countries. The reason for this remains unexplored. Cross national studies exploring biological and cultural explanations for this variation may provide clues, which may have heuristic, translational and public health significance. PMID- 25687234 TI - Analysis of peri-islet CD45-positive leucocytic infiltrates in long-standing type 1 diabetic patients. AB - AIMS/HYPOTHESIS: The role of peri-islet CD45-positive leucocytes, as one component of insulitis, in beta cell death during human type 1 diabetes remains unclear. We undertook a case study, comparing and quantifying leucocytes in the peri- and intra-islet areas in insulin-positive and -negative islets, to assess whether peri-islet leucocytes are pathogenic to beta cells during type 1 diabetes. METHODS: Pancreatic sections from 12 diabetic patients (0.25-12 years of disease) and 13 non-diabetic individuals with and without autoantibodies were triple-immunostained for islet leucocytes, insulin and glucagon cells. Islets were graded for insulitis, enumerated and mapped for the spatial distribution of leucocytes in peri- and intra-islet areas in relation to insulin- and glucagon immunopositive cells. RESULTS: In the non-diabetic autoantibody-negative group, the percentage of islets with insulitis was either absent or <1% in five out of eight cases and ranged from 1.3% to 19.4% in three cases. In the five non diabetic autoantibody-positive cases, it varied from 1.5% to 16.9%. In the diabetic group, it was <1% in one case and 1.1-26.9% in 11 cases, with insulitis being absent in 68% of insulin-positive islets. Peri-islet leucocytes were more numerous than intra-islet leucocytes in islets with insulin positivity. Increasing numbers of exocrine leucocytes in non-diabetic autoantibody-positive and diabetic donors were also present. CONCLUSIONS/INTERPRETATION: The prominence of peri-islet leucocytes in insulin-positive islets in most long-standing diabetic individuals suggests that they may be pathogenic to residual beta cells. Increasing numbers of leucocytes in the exocrine region may also participate in the pathogenesis of type 1 diabetes. PMID- 25687235 TI - Role of the receptor for advanced glycation endproducts (RAGE) in retinal vasodegenerative pathology during diabetes in mice. AB - AIMS/HYPOTHESIS: The receptor for AGEs (RAGE) is linked to proinflammatory pathology in a range of tissues. The objective of this study was to assess the potential modulatory role of RAGE in diabetic retinopathy. METHODS: Diabetes was induced in wild-type (WT) and Rage (-/-) mice (also known as Ager (-/-) mice) using streptozotocin while non-diabetic control mice received saline. For all groups, blood glucose, HbA1c and retinal levels of methylglyoxal (MG) were evaluated up to 24 weeks post diabetes induction. After mice were killed, retinal glia and microglial activation, vasopermeability, leucostasis and degenerative microvasculature changes were determined. RESULTS: Retinal expression of RAGE in WT diabetic mice was increased after 12 weeks (p < 0.01) but not after 24 weeks. Rage (-/-) mice showed comparable diabetes but accumulated less MG and this corresponded to enhanced activity of the MG-detoxifying enzyme glyoxalase I in their retina when compared with WT mice. Diabetic Rage (-/-) mice showed significantly less vasopermeability, leucostasis and microglial activation (p < 0.05-0.001). Rage (-/-) mice were also protected against diabetes-related retinal acellular capillary formation (p < 0.001) but not against pericyte loss. CONCLUSIONS/INTERPRETATION: Rage (-/-) in diabetic mice is protective against many retinopathic lesions, especially those related to innate immune responses. Inhibition of RAGE could be a therapeutic option to prevent diabetic retinopathy. PMID- 25687236 TI - Safety of teriflunomide for the management of relapsing-remitting multiple sclerosis. AB - INTRODUCTION: Teriflunomide is a new oral disease-modifying drug (DMD), recently approved for the first-line treatment of relapsing multiple sclerosis (MS). Since MS is a chronic disease, which often necessitates long-term treatment, data not only on efficacy but also on long-term safety, including pregnancy-related issues, are very important. AREAS COVERED: In this review article, we outline the key preclinical and clinical data on teriflunomide with a focus on its safety profile. We summarize adverse events observed in the Phase II and III clinical trials and the safety data from the long-term extension phases as well as the > 15-year post-marketing experience with the parent drug, leflunomide. We also consider the evidence regarding immune competence and potential fetal risks of the drug. EXPERT OPINION: Teriflunomide has the advantage of a convenient once daily oral administration scheme and a large body of evidence suggesting a manageable safety profile (clinical development program with > 6800 patient-years of exposure and post-marketing experience with leflunomide). Further post marketing data, especially regarding pregnancy outcomes and risks of infections, will help to define the exact place of teriflunomide in the treatment of MS in the future, especially compared with the other oral DMDs. PMID- 25687237 TI - Mutation within the hinge region of the transcription factor Nr2f2 attenuates salt-sensitive hypertension. AB - Genome-wide association studies (GWAS) have prioritized a transcription factor, nuclear receptor 2 family 2 (NR2F2), as being associated with essential hypertension in humans. Here we provide evidence that validates this association and indicates that Nr2f2 is a genetic determinant of blood pressure (BP). Using the zinc-finger nuclease technology, the generation of a targeted Nr2f2-edited rat model is reported. The resulting gene-edited rats have a 15 bp deletion in exon 2 leading to a five-amino-acid deletion in the hinge region of the mutant Nr2f2 protein. Both systolic and diastolic blood pressures of the Nr2f2(mutant) rats are significantly lower than controls. Because the hinge region of Nr2f2 is required for interaction with Friend of Gata2 (Fog2), protein-protein interaction is examined. Interaction of Nr2f2(mutant) protein with Fog2 is greater than that with the wild-type Nr2f2, indicating that the extent of interaction between these two transcription factors critically influences BP. PMID- 25687238 TI - Incidence of eclampsia with HELLP syndrome and associated mortality in Latin America. AB - OBJECTIVE: To describe the maternal outcome among women with eclampsia with and without HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count). METHODS: A cross-sectional study of women with eclampsia was undertaken in 14 maternity units in Latin America between January 1 and December 31, 2012. Outcomes were compared between women with and without concomitant HELLP syndrome. Logistic regression analysis was performed to identify independent risk factors of maternal mortality. RESULTS: There were 196 eclampsia cases among 115 038 deliveries; 142 (72.4%) women had eclampsia alone and 54 (27.6%) women had concomitant HELLP syndrome. Severe systolic hypertension (>=160 mm Hg), severe diastolic hypertension (>=110 mm Hg), and hypertensive encephalopathy were significantly more common among women with HELLP than among those with eclampsia alone (P=0.01 for all). There were 8 (4.1%) maternal deaths, all in the group with HELLP syndrome, and 18 (9.1%) perinatal deaths. In a multivariate regression model, maternal mortality was significantly associated with low platelet count and severe systolic hypertension (P<0.05). CONCLUSION: Eclampsia with HELLP syndrome is a dangerous complication associated with pregnancy. Low platelet count secondary to HELLP syndrome and severe systolic hypertension were independently associated with maternal mortality from eclampsia. PMID- 25687239 TI - Use of complementary medical therapies by Israeli patients undergoing in vitro fertilization. AB - OBJECTIVE: To evaluate the prevalence and characteristics of complementary medical therapy (CMT) use among Israeli couples undergoing in vitro fertilization (IVF). METHODS: In a cross-sectional study, men and women undergoing treatment at four IVF units in Israel were invited to complete an anonymous questionnaire between May 2010 and December 2011. Patients were considered users of CMT if they reported that either partner used at least one type of CMT for treating infertility. Stepwise backward logistic regression was used to assess the independent effects of variables on CMT utilization. RESULTS: Of 511 patients approached, 400 (78.1%) completed the survey and 159 (39.8%) indicated that CMT for infertility was used by one or both partners. Higher CMT use was significantly associated with the treating hospital, post high-school education, more than three previous IVF trials, being employed, and using psychosocial support (all P<0.05). Most users (75/129; 58.1%) did not notify the IVF clinic medical staff about concurrent use of CMT. CONCLUSION: Use of CMTs was widely reported by Israeli patients undergoing IVF, particularly those with higher education, and those undergoing repeated IVF trials and receiving psychosocial support. IVF staff ought to be aware of the widespread utilization of CMTs because the impact of these therapies on IVF outcomes is inconclusive. PMID- 25687240 TI - An antibody-graphene oxide nanoribbon conjugate as a surface enhanced laser desorption/ionization probe with high sensitivity and selectivity. AB - Graphene oxide nanoribbons (GONRs) were covalently functionalized with an antibody using polyethylene glycol (PEG) as a linker to produce a novel probe for surface enhanced laser desorption/ionization mass spectrometry (SELDI MS). This probe provides a highly sensitive and selective platform for enrichment and MS detection of small molecules in complex media. PMID- 25687241 TI - Strong interactive growth behaviours in solution-phase synthesis of three dimensional metal oxide nanostructures. AB - Wet-chemical synthesis is a promising alternative to the conventional vapour phase method owing to its advantages in commercial-scale production at low cost. Studies on nanocrystallization in solution have suggested that growth rate is commonly affected by the size and density of surrounding crystals. However, systematic investigation on the mutual interaction among neighbouring crystals is still lacking. Here we report on strong interactive growth behaviours observed during anisotropic growth of zinc oxide hexagonal nanorods arrays. In particular, we found multiple growth regimes demonstrating that the diameter of the rod is dependent on its height. Local interactions among the growing rods result in cases where height is irrelevant to the diameter, increased with increasing diameter or inversely proportional to the diameter. These phenomena originate from material diffusion and the size-dependent Gibbs-Thomson effect that are universally applicable to a variety of material systems, thereby providing bottom up strategies for diverse three-dimensional nanofabrication. PMID- 25687242 TI - What is a good life? Selecting capabilities to assess women's quality of life in rural Malawi. AB - There is growing interest in using Sen's Capability Approach to assess quality of life and to evaluate social policies. This paper describes the formative stages of developing a quality of life measure: the selection of the relevant capabilities. This measure is intended to provide a more comprehensive outcome measure for the evaluation of complex interventions such as Maimwana womens' groups, a community based participatory intervention to improve maternal health in rural Malawi. Fifteen focus group discussions with 129 women were conducted to explore relevant concepts of quality of life in rural Malawi. Data collection started in October 2009. Findings were elicited based on framework analysis. The findings portray a complex and highly nuanced perception that women in rural Malawi have of their life and wellbeing. Quality of life was described using a variety of dimensions that are highly interconnected. Quality of life emerges to be not only shaped by the realisation of basic material needs such as being sufficiently nourished and adequately sheltered, but is also highly dependent on complex feelings, relations and social norms. The full exposition of wellbeing with its domains was organised into a framework constituting six different spheres of wellbeing: physical strength, inner wellbeing, household wellbeing, community relations, economic security and happiness. Despite the list being developed in a specific context and for a specific group of people, the similarities with lists developed in other contexts, with different methods and for different purposes, are considerable. This suggests that there are a number of core aspects of wellbeing considered a minimum requirement for a life of human dignity, that should be included in any attempt to assess quality of life and human development across populations. PMID- 25687243 TI - The role of neighborhood characteristics in racial/ethnic disparities in type 2 diabetes: results from the Boston Area Community Health (BACH) Survey. AB - Racial/ethnic disparities in the prevalence of type 2 diabetes mellitus (T2DM) are well documented and until recently, research has focused almost exclusively on individual-based determinants as potential contributors to these disparities (health behaviors, biological/genetic factors, and individual-level socio demographics). Research on the role of neighborhood characteristics in relation to racial/ethnic disparities in T2DM is very limited. Therefore, the aim of this research is to identify and estimate the contribution of specific aspects of neighborhoods that may be associated with racial/ethnic disparities in T2DM. Data from the Boston Area Community Health III Survey (N = 2764) was used in this study, which is a community-based random-sample survey of adults in Boston, Massachusetts from three racial/ethnic groups (Black, Hispanic, and White). We applied two-level random intercepts logistic regression to assess the associations between race/ethnicity, neighborhood characteristics (census tract socioeconomic status, racial composition, property and violent crime, open space, geographic proximity to grocery stores, convenience stores, and fast food, and neighborhood disorder) and prevalent T2DM (fasting glucose > 125 mg/dL, HbA1c >= 6.5%, or self-report of a T2DM diagnosis). Black and Hispanic participants had 2.89 times and 1.48 times the odds of T2DM as White participants, respectively. Multilevel models indicated a significant between-neighborhood variance estimate of 0.943, providing evidence of neighborhood variation. Individual demographics (race/ethnicity, age and gender) explained 22.3% of the neighborhood variability in T2DM. The addition of neighborhood-level variables to the model had very little effect on the magnitude of the racial/ethnic disparities and on the between-neighborhood variability. For example, census tract poverty explained less than 1% and 6% of the excess odds of T2DM among Blacks and Hispanics and only 1.8% of the neighborhood variance in T2DM. While the findings of this study overall suggest that neighborhood factors are not a major contributor to racial/ethnic disparities in T2DM, further research is needed including data from other geographic locations. PMID- 25687244 TI - Review of genotoxicity biomonitoring studies of glyphosate-based formulations. AB - Abstract Human and environmental genotoxicity biomonitoring studies involving exposure to glyphosate-based formulations (GBFs) were reviewed to complement an earlier review of experimental genotoxicity studies of glyphosate and GBFs. The environmental and most of the human biomonitoring studies were not informative because there was either a very low frequency of GBF exposure or exposure to a large number of pesticides without analysis of specific pesticide effects. One pesticide sprayer biomonitoring study indicated there was not a statistically significant relationship between frequency of GBF exposure reported for the last spraying season and oxidative DNA damage. There were three studies of human populations in regions of GBF aerial spraying. One study found increases for the cytokinesis-block micronucleus endpoint but these increases did not show statistically significant associations with self-reported spray exposure and were not consistent with application rates. A second study found increases for the blood cell comet endpoint at high exposures causing toxicity. However, a follow up to this study 2 years after spraying did not indicate chromosomal effects. The results of the biomonitoring studies do not contradict an earlier conclusion derived from experimental genotoxicity studies that typical GBFs do not appear to present significant genotoxic risk under normal conditions of human or environmental exposures. PMID- 25687245 TI - Assessment of health risks resulting from early-life exposures: Are current chemical toxicity testing protocols and risk assessment methods adequate? AB - Abstract Over the last couple of decades, the awareness of the potential health impacts associated with early-life exposures has increased. Global regulatory approaches to chemical risk assessment are intended to be protective for the diverse human population including all life stages. However, questions persist as to whether the current testing approaches and risk assessment methodologies are adequately protective for infants and children. Here, we review physiological and developmental differences that may result in differential sensitivity associated with early-life exposures. It is clear that sensitivity to chemical exposures during early-life can be similar, higher, or lower than that of adults, and can change quickly within a short developmental timeframe. Moreover, age-related exposure differences provide an important consideration for overall susceptibility. Differential sensitivity associated with a life stage can reflect the toxicokinetic handling of a xenobiotic exposure, the toxicodynamic response, or both. Each of these is illustrated with chemical-specific examples. The adequacy of current testing protocols, proposed new tools, and risk assessment methods for systemic noncancer endpoints are reviewed in light of the potential for differential risk to infants and young children. PMID- 25687246 TI - Recurrence-free survival, but not surgical therapy per se, determines 583 patients' long-term satisfaction following primary pilonidal sinus surgery. AB - PURPOSE: With pilonidal sinus disease (PSD) incidence increasing and patients freely choosing their surgeon, patients' interest issues have been brought forward estimating patient satisfaction following pilonidal sinus surgery. The influence of wound healing time and long-term recurrence rate on patient satisfaction in primary PSD surgery has not been investigated yet. METHODS: Five hundred eighty-three patients (German military cohort) were interviewed, compiling wound healing time, aesthetic satisfaction, long-term recurrence-free survival and patient satisfaction having undergone primary open (PO) treatment, marsupialization (MARS) or primary midline closure (PMC) treatment. Recurrence rate was determined by Kaplan-Meier calculation following up to 20 years after primary PSD surgery. RESULTS: Patient satisfaction ranking from 1 to 10 (10 = max. satisfied) showed an average satisfaction of 8.2 (range 0-10; 95% confidence interval (CI) 7891-8250). In-hospital stay time was significantly longer in primary open (PO) and marsupialization (MARS) group as compared to primary midline closure (PMC; p < 0.0001, Kruskal-Wallis test). Satisfaction was comparable between treatment groups, and was neither linked to in-hospital stay time nor to longer outpatient wound care period or total treatment time. Recurrence-free survival, as seen in the PO and PMC treatment group, revealed a highly significant difference for all patients. Improvement in MARS patients with versus without recurrence was low, as satisfaction with primary treatment was lower as the other groups. CONCLUSIONS: Neither choice of surgical treatment nor treatment duration within hospital or after hospital influences patient satisfaction, as long as recurrence-free survival can be provided. Marsupialization was ranked lower in both groups (with or without recurrence), and should be abandoned, as patients are significantly less satisfied with either results, independent of recurrence. PMID- 25687247 TI - History of colorectal surgery: A comprehensive historical review from the ancient Egyptians to the surgical robot. AB - BACKGROUND: Colorectal surgery has its roots in the early civilisations and its development followed a complex pathway never disjoined from the social and cultural environment where it took place. METHOD: The most relevant historical sources have been evaluated. RESULTS: A comprehensive review of the history of colorectal surgery is presented, from the ancient Egyptian culture to the modern achievements. The development of surgery of colon, rectum and anus is reported with particular reference to the social environment and history; as the development of colorectal surgery parallels the occurrence of human historical events, the study of the former cannot be disjoined from the latter. CONCLUSION: Study and knowledge of the history of medicine--and, in particular, of colorectal surgery for those interested in this particular subject--is a privileged way to understand who we are nowadays and where we come from. PMID- 25687248 TI - Rapid bedside tests for diagnosis, management, and prevention of nosocomial influenza. AB - Like other respiratory viruses, influenza is responsible for devastating nosocomial epidemics in nursing homes as well as in conventional wards and emergency departments. Patients, healthcare workers, and visitors may be the source of nosocomial influenza. Despite their limited sensitivity, rapid diagnostic tests for influenza can be of real value; they enable early introduction of measures to prevent spread and early specific antiviral treatment of cases. However, these tests cannot detect oseltamivir resistance, susceptibility testing being carried out only in specialist laboratories. Although resistance is rare, it can emerge during treatment, especially of very young children or immunocompromised patients. In the latter, the shedding of resistant influenza virus can last several weeks. Sporadic instances of nosocomial transmission among immunocompromised patients have been reported. The limitations of bedside tests for influenza make them unsuitable for use as stand alone diagnostic tools. However, their limitations do not preclude their use for detection and subsequent management of nosocomial influenza, for which they are rapid, easy, and cost-effective. Recent developments in these tests look promising, offering prospects of increased sensitivity, increased specificity, and screening for antiviral susceptibility. PMID- 25687249 TI - Surveillance and management of ventriculitis following neurosurgery. AB - Ventriculitis is an important complication following neurosurgery and is often associated with the use of an external ventricular drain (EVD). The incidence varies from <5% to 20%, partly due to variations in the definitions used for diagnosis. Staphylococci are the most important causes but the isolation of coagulase-negative staphylococci from a cerebrospinal fluid (CSF) sample needs to be interpreted with caution as it may represent contamination. Risk factors for ventriculitis include advanced age, the duration of EVD placement, the number of manipulations and the presence of intraventricular haemorrhage. Prevention strategies increasingly focus on the implementation of a care bundle that includes aseptic technique at the time of insertion and during any manipulations, skin preparation, prophylactic antibiotics, and appropriate dressings at the site of the EVD. The use of EVDs impregnated with antimicrobial agents is increasing but, whereas some studies show that these are effective, it is not clear whether they provide added benefit when there is compliance with other measures. Antimicrobial treatment is challenging as many widely used agents do not penetrate into the CSF and causative bacteria are increasingly multidrug resistant. Often a combination of high-dose intravenous and intraventricular agents is required, especially for Gram-negative infections. Large trials in this area are challenging to conduct; therefore, to better inform preventive strategies and to optimize management of this important condition, ongoing national surveillance and pooling of data on treatment approaches and outcomes are needed. PMID- 25687250 TI - 'Driven to distraction' and driving for excellence in ward round practice. PMID- 25687251 TI - Analysis of the ghrelin receptor-independent vascular actions of ulimorelin. AB - Ulimorelin (TZP101) is a ghrelin receptor agonist that stimulates intestinal motility, but also reduces blood pressure in rodents and humans and dilates blood vessels. It has been proposed as a treatment for intestinal motility disorders. Here we investigated the mechanisms through which ulimorelin affects vascular diameter. Actions of ulimorelin on wall tension of rodent arteries were investigated and compared with other ghrelin receptor agonists. Saphenous, mesenteric and basilar arteries were obtained from Sprague-Dawley rats (male, 8 weeks) and saphenous arteries were obtained from wild type or ghrelin receptor null mice. These were mounted in myography chambers to record artery wall tension. Ulimorelin (0.03-30uM) inhibited phenylephrine-induced contractions of rat saphenous (IC50=0.6uM; Imax=66+/-5%; n=3-6) and mesenteric arteries (IC50=5uM, Imax=113+/-16%; n=3-4), but not those contracted by U46619, ET-1 or 60mM [K(+)]. Relaxation of phenylephrine-constricted arteries was not observed with ghrelin receptor agonists TZP102, capromorelin or AZP-531. In rat saphenous and basilar arteries, ulimorelin (10-100uM) and TZP102 (10-100uM) constricted arteries (EC50=9.9uM; Emax=50+/-7% and EC50=8uM; Emax=99+/-16% respectively), an effect not attenuated by the ghrelin receptor antagonist YIL 781 3uM or mimicked by capromorelin or AZP-531. In mesenteric arteries, ulimorelin, 1-10uM, caused a surmountable rightward shift in the response to phenylephrine (0.01-1000uM; pA2=5.7; n=3-4). Ulimorelin had similar actions in mouse saphenous artery from both wild type and ghrelin receptor null mice. We conclude that ulimorelin causes vasorelaxation through competitive antagonist action at alpha1-adrenoceptors and a constrictor action not mediated via the ghrelin receptor. PMID- 25687252 TI - Pharmacological activation of PPAR gamma ameliorates vascular endothelial insulin resistance via a non-canonical PPAR gamma-dependent nuclear factor-kappa B trans repression pathway. AB - Vascular endothelial insulin resistance (IR) is a critically initial factor in cardiocerebrovascular events resulted from diabetes and is becoming a worldwide public health issue. Thiazolidinediones (TZDs) are clinical insulin-sensitizers acting through a canonical peroxisome proliferator-activated receptor gamma (PPARgamma)-dependent insulin trans-activation pathway. However, it remains elusive whether there are other mechanisms. In current study, we investigated whether TZDs improve endothelial IR induced by high glucose concentration or hyperglycemia via a non-canonical PPARgamma-dependent nuclear factor-kappa B (NF kappaB) trans-repression pathway. Our results showed that pre-treatment with TZDs dramatically decrease the susceptibility of endothelial cell to IR, while post treatment notably improve the endothelial IR both in vitro and in vivo. Moreover, TZDs substantially increase the levels of endothelial nitric oxide synthase (eNOS) and inhibitory kappaB alpha (IkappaBalpha), whereas decrease those of the phosphorylated inhibitory kappaB kinase alpha/beta (phosphor-IKKalpha/beta) and the cytokines including tumor necrosis factor alpha (TNFalpha), interleukin-6 (IL 6), soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cellular adhesion molecule-1 (sVCAM-1), suggesting that TZDs act indeed through a PPARgamma-dependent NF-kappaB trans-repression pathway. These findings highlighted a non-canonical mechanism for TZDs to ameliorate endothelial IR which might provide a potential strategy to prevent and treat the diabetic vascular complications clinically. PMID- 25687253 TI - Minimally invasive endoscopic surgery for treatment of spontaneous intracerebral haematomas. AB - Spontaneous intracerebral haemorrhage (ICH) is a devastating disease with a mortality rate of more than 40 % and a high morbidity rate with 10-15 % of survivors remaining fully dependent [11]. The role of surgical treatment of ICH remains a matter of controversy and ongoing investigation. Advances in neurosurgical techniques such as endoscopy and neuronavigation have been established in various fields of neurosurgery. Results of reported case series have suggested that some patients with ICH may benefit from haematoma evacuation through minimally invasive endoscopic procedures. In this article, we focus on the pathophysiologic rationales behind minimally invasive haematoma evacuation through endoscopic surgery and provide an overview of technical developments and reported patient series. In addition, the modalities of the surgical procedure at the authors' institution are described. Controlled clinical trials are needed to evaluate the full potential and limitations of this promising technique. PMID- 25687254 TI - Rapid spread of Clostridium difficile NAP1/027/ST1 in Chile confirms the emergence of the epidemic strain in Latin America. AB - Clostridium difficile infection has gained importance in recent years as a result of the rapid spread of epidemic strains, including hypervirulent strains. This study reports the molecular epidemiology of C. difficile obtained from hospitalized patients in Chile. Seven hundred and nineteen isolates of toxigenic C. difficile from 45 hospitals across the country were characterized through toxin profile, pulsed-field gel electrophoresis (PFGE), and sequencing of the tcdC gene. In addition, polymerase chain reaction (PCR) ribotyping and multilocus sequence typing (MLST) were performed on a subset of selected strains. PFGE typing of 719 isolates of C. difficile produced 60 PFGE patterns (subtypes). Subtype 1 was predominant (79% of isolates) and related to the hypervirulent strain (NAP1). Subtype 1 showed 73% relatedness with nine other subtypes, which had a similar tcdC deletion. Subtype 1 corresponded to ribotype 027 and ST1. This report shows the wide dissemination of the hypervirulent strain NAP1/027/ST1 in Chile. PMID- 25687255 TI - Design and fabrication of far ultraviolet filters based on pi-multilayer technology in high-k materials. AB - Application of pi-multilayer technology is extended to high extinction coefficient materials, which is introduced into metal-dielectric filter design. Metal materials often have high extinction coefficients in far ultraviolet (FUV) region, so optical thickness of metal materials should be smaller than that of the dielectric material. A broadband FUV filter of 9-layer non-periodic Al/MgF2 multilayer was successfully designed and fabricated and it shows high reflectance in 140-180 nm, suppressed reflectance in 120-137 nm and 181-220 nm. PMID- 25687256 TI - The influence of hypothermia on the management of traumatic cardiac arrest. AB - Post-traumatic hypothermia often occurs as a direct consequence of haemorrhage and shock. Environmental exposure in austere environments may also contribute to its pathogenesis. In those casualties that present in cardiac arrest following injury, coexisting hypothermia may be the primary cause of the arrest, or a marker of the severity of shock. A case of a 25-year-old combat casualty is presented, illustrating some of the technical challenges faced by clinicians while resuscitating hypothermic trauma patients in cardiac arrest. PMID- 25687257 TI - Sudden onset hemiplegia at high altitude. AB - Travel to high altitude and the incumbent exposure to hypobaric hypoxia leads to a prothrombotic state. This may increase the likelihood of thromboembolic events, including stroke, in otherwise healthy individuals. While there have been sporadic anecdotal reports of 'stroke-like' syndromes at high altitude for over 100 years, there are surprisingly few detailed reports supported by imaging.This report describes a case of posterior circulation infarct thought to be due to a paradoxical embolus through a patent foramen ovale. The relationship between high altitude physiology, increased incidence of thromboembolism and the significance of patent foramen are discussed in the report. PMID- 25687258 TI - The role of testosterone therapy in cardiovascular mortality: culprit or innocent bystander? AB - Testosterone therapy is recommended for men with symptomatic androgen deficiency and unequivocally low testosterone levels. Although the prevalence of hypogonadism seems relatively constant, studies of prescribing patterns in both the United States and the United Kingdom show a dramatic increase in testosterone prescription in recent years, possibly due to increased marketing and inappropriate therapy. Concurrent with this, there has been growing concern regarding the potential adverse effects of testosterone therapy, particularly its cardiovascular risks. In this review, we present our current understanding of the implications of testosterone deficiency, as well as the conflicting evidence surrounding the cardiovascular effects of testosterone replacement therapy. Although there is a lack of adequate data, based on the current evidence, we conclude that testosterone therapy can be safely considered in men with appropriately diagnosed clinical androgen deficiency and increased cardiovascular risk after a thorough discussion of potential risks and with guideline recommended safety monitoring. PMID- 25687259 TI - Numerical simulations of heavily polluted fine-grained sediment remobilization using 1D, 1D+, and 2D channel schematization. AB - This article used various hydrodynamic and sediment transport models to analyze the potential and the limits of different channel schematizations. The main aim was to select and evaluate the most suitable simulation method for fine-grained sediment remobilization assessment. Three types of channel schematization were selected to study the flow potential for remobilizing fine-grained sediment in artificially modified channels. Schematization with a 1D cross-sectional horizontal plan, a 1D+ approach, splitting the riverbed into different functional zones, and full 2D mesh, adopted in MIKE by the DHI modeling suite, was applied to the study. For the case study, a 55-km stretch of the Bilina River, in the Czech Republic, Central Europe, which has been heavily polluted by the chemical and coal mining industry since the mid-twentieth century, was selected. Long-term exposure to direct emissions of toxic pollutants including heavy metals and persistent organic pollutants (POPs) resulted in deposits of pollutants in fine grained sediments in the riverbed. Simulations, based on three hydrodynamic model schematizations, proved that for events not exceeding the extent of the riverbed profile, the 1D schematization can provide comparable results to a 2D model. The 1D+ schematization can improve accuracy while keeping the benefits of high-speed simulation and low requirements of input DEM data, but the method's suitability is limited by the channel properties. PMID- 25687260 TI - Young, active and well-connected: adult-born neurons in the zebra finch are activated during singing. AB - Neuronal replacement in the pallial song control nucleus HVC of adult zebra finches constitutes an interesting case of homeostatic plasticity; in spite of continuous addition and attrition of neurons in ensembles that code song elements, adult song remains remarkably invariant. New neurons migrate into HVC and later synapse with their target, arcopallial song nucleus RA (HVCRA). New HVCRA neurons respond to auditory stimuli (in anaesthetised animals), but whether and when they become functionally active during singing is unknown. We studied this, using 5-bromo-2'-deoxyuridine to birth-date neurons, combined with immunohistochemical detection of immediate-early gene (IEG) expression and retrograde tracer injections into RA to track connectivity. Interestingly, singing was followed by IEG expression in a substantial fraction of new neurons that were not retrogradely labelled from RA, suggesting a possible role in HVC intrinsic network function. As new HVC neurons matured, the proportion of HVCRA neurons that expressed IEGs after singing increased significantly. Since it was previously shown that singing induces IEG expression in HVC also in deaf birds and that hearing song does not induce IEG expression in HVC, our data provide the first direct evidence that new HVC neurons are engaged in song motor behaviour. PMID- 25687261 TI - Cytoarchitecture of the human lateral occipital cortex: mapping of two extrastriate areas hOc4la and hOc4lp. AB - The microstructural correlates of the functional segregation of the human lateral occipital cortex are largely unknown. Therefore, we analyzed the cytoarchitecture of this region in ten human post-mortem brains using an observer-independent and statistically testable parcellation method to define the position and extent of areas in the lateral occipital cortex. Two new cytoarchitectonic areas were found: an anterior area hOc4la and a posterior area hOc4lp. hOc4la was located behind the anterior occipital sulcus in rostral and ventral portions of this region where it occupies the anterior third of the middle and inferior lateral occipital gyri. hOc4lp was found in caudal and dorsal portions of this region where it extends along the superior and middle lateral occipital gyri. The cytoarchitectonic areas were registered to 3D reconstructions of the corresponding brains, which were subsequently spatially normalized to the Montreal Neurological Institute reference space. Continuous probabilistic maps of both areas based on the analysis of ten brains were generated to characterize their inter-subject variability in location and size. The maps of hOc4la and hOc4lp were then used as seeds for meta-analytic connectivity modeling and quantitative functional decoding to identify their co-activation patterns and assignment to functional domains. Convergent evidence from their location, topography, size, functional domains and connectivity indicates that hOc4la and hOc4lp are the potential anatomical correlates of the functionally defined lateral occipital areas LO-1 and LO-2. PMID- 25687262 TI - Acute kidney injury and mortality in the elderly: add atypical antipsychotics to the list. PMID- 25687263 TI - Associated liver and multivisceral resections: should we extend the frontiers of resectability? AB - Combined liver and multivisceral resections (CLMVRs) are rare procedures that demand extensive surgical skills. Few reports have discussed the benefit of these complex procedures and their indications are poorly defined. The aim of the present study is to present short- and long-term results of CLMVRs in primary and metastatic malignancies, including a risk analysis for perioperative morbidity and mortality. A review of our prospective surgical database between November 2007 and August 2013 identified 21 patients who had undergone CLMVRs. Preoperative radiologic evaluation and laboratory data, intraoperative results, hospital outcomes, and long-term follow-up were analyzed. CLMVRs were performed due to metastatic disease from different sites in 17 patients, and due to direct local invasion of the liver in the remaining 4 cases. Major hepatectomy was performed in 7 cases. Morbidity was 57% and 90-day postoperative mortality was 9%. Gender and resection of more than 4 organs were found as statistically significant risk factors to develop major complications. Five of 7 patients with 4 or more organs resected presented major complications including mortality (p = 0.026). The overall 1- and 3-year survival rates were 57 and 24%, respectively. Patients undergoing CLMVRs experience acceptable postoperative morbidity and mortality rates. Surgery should be performed only in carefully selected patients, considering their preoperative comorbidities, and in high-volume centers. PMID- 25687264 TI - Clarifying the associations between age at menarche and adolescent emotional and behavioral problems. AB - Better understanding risk factors for the development of adolescent emotional and behavioral problems can help with intervention and prevention efforts. Previous studies have found that an early menarcheal age predicts several adolescent problems, including depressive symptoms, delinquency, and early age at first intercourse. Few studies, nevertheless, have explicitly tested (a) whether the associations with menarcheal age vary across racial/ethnic groups or (b) whether the sources of the associations are within-families (i.e., consistent with a direct, causal link) or only between-families (i.e., due to selection or confounding factors). The current study analyzed data from a nationally representative US Sample of females (N = 5,637). We examined whether race/ethnicity moderated the associations between early menarche and several adolescent problems by using multiple-group analyses and we examined the degree to which genetic and environmental factors shared by family members account for the associations by comparing sisters and cousins with differing menarcheal ages. Menarcheal age predicted subsequent depressive symptoms, delinquency, and early age at first intercourse in the population. The magnitudes of the associations were similar across all racial/ethnic groups for all outcomes. The within-family associations (i.e., when comparing siblings and cousins with different menarcheal age) were large and statistically significant when predicting early intercourse, but not the other outcomes. The findings suggest that selection or confounding factors account for the associations between menarcheal age and subsequent depressive symptoms and delinquency, whereas the independent association between menarcheal age and early age at first intercourse is consistent with a direct, causal effect. PMID- 25687265 TI - An Investigation of Short-Term Longitudinal Associations Between Social Anxiety and Victimization and Perpetration of Traditional Bullying and Cyberbullying. AB - Previous research has suggested that social anxiety is associated with victimization and perpetration of (cyber)bullying. The direction and causality of this relationship has not yet been empirically supported for both traditional and cyberbullying involvement. This study examined short-term longitudinal associations between feelings of social anxiety and involvement in traditional bullying and cyberbullying among 2128 adolescents aged 10-17 (56.6 % girls). A cross-lagged panel analysis provided evidence for the contribution of social anxiety to later victimization of bullying, both on- and off-line. The possibility of a reciprocal relationship was also examined, although it was not supported. Furthermore, longitudinal bidirectional relationships between social anxiety and the perpetration of bullying were investigated. Only one significant longitudinal association was found: the perpetration of traditional bullying predicted subsequent higher levels of social anxiety. The implications of these findings are discussed. PMID- 25687266 TI - Pathogenesis, diagnosis, and management of ulcerative proctitis, chronic radiation proctopathy, and diversion proctitis. AB - Chronic proctitis refers to persistent or relapsing inflammation of the rectum, which results from a wide range of etiologies with various pathogenic mechanisms. The patients may share similar clinical presentations. Ulcerative proctitis, chronic radiation proctitis or proctopathy, and diversion proctitis are the 3 most common forms of chronic proctitis. Although the diagnosis of these disease entities may be straightforward in the most instances based on the clinical history, endoscopic, and histologic features, differential diagnosis may sometimes become problematic, especially when their etiologies and the disease processes overlap. The treatment for the 3 forms of chronic proctitis is different, which may shed some lights on their pathogenetic pathway. This article provides an overview of the latest data on the clinical features, etiologies, diagnosis, and management of ulcerative proctitis, chronic radiation proctopathy, and diversion proctitis. PMID- 25687267 TI - Prostate cancer: AR targeting--it all makes sense. PMID- 25687268 TI - Prostate cancer: MRI/TRUS fusion outperforms standard and combined biopsy approaches. PMID- 25687269 TI - Prostate cancer: Hypofractionation not associated with reduced toxicity. PMID- 25687270 TI - High-density lipoprotein particle concentration and subclinical atherosclerosis of the carotid arteries in Japanese men. AB - OBJECTIVE: The association of high-density lipoprotein particle (HDL-P) with atherosclerosis may be stronger than that of HDL-cholesterol (HDL-C) and independent of conventional cardiovascular risk factors. Whether associations persist in populations at low risk of coronary heart disease (CHD) remains unclear. This study examines the associations of HDL-P and HDL-C with carotid intima-media thickness (cIMT) and plaque counts among Japanese men, who characteristically have higher HDL-C levels and a lower CHD burden than those in men of Western populations. METHODS: We cross-sectionally examined a community based sample of 870 Japanese men aged 40-79 years, free of known clinical cardiovascular disease (CVD) and not on lipid-lowering medication. Participants were randomly selected among Japanese living in Kusatsu City in Shiga, Japan. RESULTS: Both HDL-P and HDL-C were inversely and independently associated with cIMT in models adjusted for conventional CHD risk factors, including low-density lipoprotein cholesterol (LDL-C) and diabetes. HDL-P maintained an association with cIMT after further adjustment for HDL-C (P < 0.01), whereas the association of HDL-C with cIMT was noticeably absent after inclusion of HDL-P in the model. In plaque counts of the carotid arteries, HDL-P was significantly associated with a reduction in plaque count, whereas HDL-C was not. CONCLUSION: HDL-P, in comparison to HDL-C, is more strongly associated with measures of carotid atherosclerosis in a cross-sectional study of Japanese men. Findings demonstrate that, HDL-P is a strong correlate of subclinical atherosclerosis even in a population at low risk for CHD. PMID- 25687271 TI - Incremental value of a genetic risk score for the prediction of new vascular events in patients with clinically manifest vascular disease. AB - BACKGROUND: Several genetic markers are related to incidence of cardiovascular events. We evaluated whether a genetic risk score (GRS) based on 30 single nucleotide-polymorphisms associated with coronary artery disease (CAD) can improve prediction of 10-year risk of new cardiovascular events in patients with clinical manifest vascular disease. METHODS: In 5742 patients with symptomatic vascular disease enrolled in the SMART study, we developed Cox regression models based on the SMART Risk Score (SRS) and based on the SRS plus the GRS in all patients, in patients with a history of acute arterial thrombotic events and in patients with a history of more stable atherosclerosis and without CAD. The discriminatory ability was expressed by the c-statistic. Model calibration was evaluated by calibration plots. The incremental value of adding the GRS was assessed by net reclassification index (NRI) and decision curve analysis. RESULTS: During a median follow-up of 6.5 years (IQR4.0-9.5), the composite outcome of myocardial infarction, stroke, or vascular death occurred in 933 patients. Hazard ratios of GRS ranging from 0.86 to 1.35 were observed. The discriminatory capacity of the SRS for prediction of 10-year risk of cardiovascular events was fairly good (c-statistic 0.70, 95%CI 0.68-0.72), similar to the model based on the SRS plus the GRS. Calibration of the models based on SRS and SRS plus GRS was adequate. No increase in c-statistics, categorical NRIs and decision curves was observed when adding the GRS. The continuous NRI improved only in patients with stable atherosclerosis (0.14, 95%CI 0.03-0.25), increasing further excluding patients with a history of CAD (0.21, 95%CI 0.06-0.36). CONCLUSIONS: In patients with symptomatic vascular disease, a GRS did not improve risk prediction of 10-year risk of cardiovascular events beyond clinical characteristics. The GRS might improve risk prediction of first vascular events in the subgroup of patients with a history of stable atherosclerosis. PMID- 25687272 TI - A score including ADAM17 substrates correlates to recurring cardiovascular event in subjects with atherosclerosis. AB - OBJECTIVE: Atherosclerosis disease is a leading cause for mortality and morbidity. The narrowing/rupture of a vulnerable atherosclerotic plaque is accountable for acute cardiovascular events. However, despite of an intensive research, a reliable clinical method which may disclose a vulnerable patient is still unavailable. APPROACH AND RESULTS: We tested the association of ADAM17 (A Disintegrin and Metallo Protease Domain 17) circulating substrates (sICAM-1, sVCAM-1, sIL6R and sTNFR1) with a second major cardiovascular events [MACEs] (cardiovascular death, peripheral artery surgeries, non-fatal myocardial infarction and non-fatal stroke) in 298 patients belonging to the Vascular Diabetes (AVD) study. To evaluate ADAM17 activity we create ADAM17 score through a RECPAM model. Finally we tested the discrimination ability and the reclassification of clinical models. At follow-up (mean 47 months, range 1-118 months), 55 MACEs occurred (14 nonfatal MI, 14 nonfatal strokes, 17 peripheral artery procedures and 10 cardiovascular deaths) (incidence = 7.8% person-years). An increased risk for incident events was observed among the high ADAM17 score individuals both in univariable (HR 19.20, 95% CI 15.82-63.36, p < 0.001) and multivariable analysis (HR 3.42, 95% CI 1.55-7.54, p < 0.001). Finally we found that ADAM17 score significantly increases the prediction accuracy of the Framingham Recurring-Coronary-Heart-Disease-Score, with a significant improvement in discrimination (integrated discrimination improvement = 9%, p = 0.012) and correctly reclassifying 10% of events and 41% of non-events resulting in a cNRI = 0.51 (p = 0.005). CONCLUSION: We demonstrated a positive role of ADAM17 activity to predicting CV events. We think that an approach that targets strategies beyond classic cardiovascular risk factors control is necessary in individuals with an established vascular atherosclerosis. PMID- 25687273 TI - A research agenda for humanitarian health ethics. AB - This paper maps key research questions for humanitarian health ethics: the ethical dimensions of healthcare provision and public health activities during international responses to situations of humanitarian crisis. Development of this research agenda was initiated at the Humanitarian Health Ethics Forum (HHE Forum) convened in Hamilton, Canada in November 2012. The HHE Forum identified priority avenues for advancing policy and practice for ethics in humanitarian health action. The main topic areas examined were: experiences and perceptions of humanitarian health ethics; training and professional development initiatives for humanitarian health ethics; ethics support for humanitarian health workers; impact of policies and project structures on humanitarian health ethics; and theoretical frameworks and ethics lenses. Key research questions for each topic area are presented, as well as proposed strategies for advancing this research agenda. Pursuing the research agenda will help strengthen the ethical foundations of humanitarian health action. PMID- 25687274 TI - Glycoside phosphorylases: structure, catalytic properties and biotechnological potential. AB - Glycoside phosphorylases (GPs) are the enzymes that reversibly phosphorolytically process glycosidic bond in sucrose (6'-phosphate), alpha-1,4-glucan and maltodextrins, alpha-glucobioses, alpha-1,3-oligoglucan, beta-glucobioses and beta-glucodextrins, chitobiose, beta-galactosides and beta-mannosides, and transfer non-reducing end terminal glycosyl residue to inorganic phosphate. They are modular enzymes that form biologically active homooligomers. From a mechanistic as well as structural point of view, they are similar to glycoside hydrolases or glycosyltransferases. Regardless the stereochemical outcome of the phosphorylase-catalyzed reaction (inversion or retention) the phosphorolytic cleavage of glycosidic bond is reversible, therefore glycosyl phosphates may efficiently be used for oligosaccharide synthesis. Although majority of GPs show very high substrate and positional selectivity, they might be employed for a green, inexpensive and often one-pot conversion of one sugar (cheap) to another one (expensive). This fascinating capability is due to the fact that pathways of several GPs share the same glycosyl phosphate, i.e. a product of one phosphorylase is simultaneously consumed as a substrate by another one, or even the same enzyme in a second step if the phosphorylase possesses a relaxed acceptor specificity. In some cases glycosyl phosphates may be interconverted using other auxiliary carbohydrate-active enzymes, achieving for example galactoside synthesis from gluco-configured sugar donors, thus widening synthetic potential of these biocatalysts. In comparison with common hydrolysis, the energy of glycosidic bond is not annihilated during phosphorolysis. This energetic aspect of the reactions catalyzed by GPs and their physiological role is discussed in relation to often concurrently occurring glycoside hydrolases. PMID- 25687275 TI - Enzymatic reactors for biodiesel synthesis: Present status and future prospects. AB - Lipases are being extensively researched for the production of biodiesel as a "silver bullet" in order to avoid the drawbacks of the traditional alkaline transesterification. In this review, we analyzed the main factors involved in the enzymatic synthesis of biodiesel, focusing in the choice of the immobilization protocol, and the parameters involved in the choice and configuration of the reactors. An extensive discussion is presented about the advantages and disadvantages of each type of reactor and their mode of operation. The current scenario of the market for enzymatic biodiesel and some future prospects and necessary developments are also briefly presented. PMID- 25687276 TI - Recent advances in topical delivery of proteins and peptides mediated by soft matter nanocarriers. AB - Proteins and peptides are increasingly important therapeutics for the treatment of severe and complex diseases like cancer or autoimmune diseases due to their high specificity and potency. Their unique structure and labile physicochemical properties, however, require special attention in the production and formulation process as well as during administration. Aside from conventional systemic injections, the topical application of proteins and peptides is an appealing alternative due to its non-invasive nature and thus high acceptance by patients. For this approach, soft matter nanocarriers are interesting delivery systems which offer beneficial properties such as high biocompatibility, easiness of modifications, as well as targeted drug delivery and release. This review aims to highlight and discuss technological developments in the field of soft matter nanocarriers for the delivery of proteins and peptides via the skin, the eye, the nose, and the lung, and to provide insights in advantages, limitations, and practicability of recent advances. PMID- 25687277 TI - Biocatalysis and biotransformation in Brazil: An overview. AB - This review presents the recent research in biocatalysis and biotransformation in Brazil. Several substrates were biotransformed by fungi, bacteria and plants. Biocatalytic deracemization of secondary alcohols, oxidation of sulfides, sp(3) CH hydroxylation and epoxidation of alkenes were described. Chemo-enzymatic resolution of racemic alcohols and amines were carried out with lipases using several substrates containing heteroatoms such as silicon, boron, selenium and tellurium. Biotransformation of nitriles by marine fungi, hydrolysis of epoxides by microorganisms of Brazilian origin and biooxidation of natural products were described. Enzymatic reactions under microwave irradiation, continuous flow, and enzymatic assays using fluorescent probes were reported. PMID- 25687278 TI - Biocatalysts for the formation of three- to six-membered carbo- and heterocycles. AB - During the last decade, the number of different types of enzymes applicable for organic synthesis as biocatalysts has significantly increased. Consequently, the spectrum of reactions has significantly expanded also for cyclisations. This review highlights heterologously expressable biocatalysts transforming non natural substrates for the formation of three- to six-membered carbo- and heterocycles, excluding terpene cyclases as well as SAM-dependent enzymes. The review focuses on the non-natural substrate scope and the mechanism of the selected enzymes. PMID- 25687279 TI - Depressive mixed states: A reappraisal of Koukopoulos' criteria. AB - BACKGROUND: Mixed states have been a fundamental part of Kraepelin's conceptualization of the manic-depressive illness. However, after Kraepelin, the study of mixed states was not of great interest, until the publication of the RDC criteria (1978) and then the DSM-III edition (1980), where criteria for mixed manic states were operationalized. The most notable victims of DSM nosology were depressive mixed states, in particular depression with flight of ideas and excited (agitated) depression. METHODS: We briefly review the clinical work of Athanasios Koukopoulos on depressive mixed states (in particular agitated depression) pointing out the diagnostic and therapeutic contributions, especially in the lights of Koukopoulos' first description of depressive mixed syndrome in 1992. RESULTS: The mixed depressive syndrome is not a transitory state but a state of long duration, which may last weeks or several months. The clinical picture is characterized by dysphoric mood, emotional lability, psychic and/or motor agitation, talkativeness, crowded and/or racing thoughts, rumination, initial or middle insomnia. Impulsive suicidal attempts may be frequent. The family observes incessant complaints, irritability, occasional verbal outbursts, occasional physical aggression, and occasional hypersexuality. Treatment with antipsychotics and ECT is very effective; antidepressants can worsen the clinical picture. LIMITATIONS: Selective but not systematic review of the literature on depressive mixed states. Relatively little research data is currently available for validation of the criteria proposed by Koukopoulos. CONCLUSIONS: Koukopoulos' proposal of mixed depression, besides its diagnostic implications, clearly identifying it as manifestations of bipolar disorder, allows for better clinical characterization of cases and improves treatment decisions. PMID- 25687280 TI - Pregnancy anxiety: A systematic review of current scales. AB - BACKGROUND: Depression in pregnancy is a serious health issue; however, anxiety in pregnancy, with a reported higher prevalence, may also be a serious issue. Anxiety symptoms in pregnancy can relate to several anxiety types, such as general anxiety, anxiety disorders, and pregnancy-related anxiety (PrA), anxiety characterised by pregnancy specific fears and worries. Awareness of these distinctions however, is not always widespread. Both general anxiety and PrA are associated with maternal negative outcomes (e.g. increased nausea) however; PrA is more often associated with negative outcomes for the child (e.g. preterm birth). Furthermore, PrA is potentially a risk factor for postnatal depression with assessment of PrA potentially affording important intervention opportunities. Currently several different instruments are used for PrA however their psychometric properties are unclear. To our knowledge a review of current instruments and their psychometric properties is lacking, this paper aims to fill that gap. METHODS: Studies, which assessed PrA, published between 1983 and 2013 in peer-reviewed journals, were identified. RESULTS: Sixty studies were identified after applying inclusion/exclusion criteria, and classified as: pregnancy-related anxiety specific, scales for other constructs, sub scales of another instrument and general anxiety scales. Each scale's strengths and limitations were discussed. LIMITATIONS: Our findings may be limited by restricting our review to peer-reviewed journals. This was done however as we sought to identify scales with good psychometric properties. CONCLUSIONS: Currently no scales are available for pregnancy-related anxiety with sound theoretical and psychometric properties. Clinically the need for such a scale is highlighted by the potential intervention opportunities this may afford. Future research should be directed towards the development of such a scale. PMID- 25687281 TI - Circulating precursors of human CD1c+ and CD141+ dendritic cells. AB - Two subsets of conventional dendritic cells (cDCs) with distinct cell surface markers and functions exist in mouse and human. The two subsets of cDCs are specialized antigen-presenting cells that initiate T cell immunity and tolerance. In the mouse, a migratory cDC precursor (pre-CDC) originates from defined progenitors in the bone marrow (BM). Small numbers of short-lived pre-CDCs travel through the blood and replace cDCs in the peripheral organs, maintaining homeostasis of the highly dynamic cDC pool. However, the identity and distribution of the immediate precursor to human cDCs has not been defined. Using a tissue culture system that supports the development of human DCs, we identify a migratory precursor (hpre-CDC) that exists in human cord blood, BM, blood, and peripheral lymphoid organs. hpre-CDCs differ from premonocytes that are restricted to the BM. In contrast to earlier progenitors with greater developmental potential, the hpre-CDC is restricted to producing CD1c(+) and CD141(+) Clec9a(+) cDCs. Studies in human volunteers demonstrate that hpre-CDCs are a dynamic population that increases in response to levels of circulating Flt3L. PMID- 25687282 TI - Coupling of T cell receptor specificity to natural killer T cell development by bivalent histone H3 methylation. AB - The fidelity of T cell immunity depends greatly on coupling T cell receptor signaling with specific T cell effector functions. Here, we describe a chromatin based mechanism that enables integration of TCR specificity into definite T cell lineage commitment. Using natural killer T cells (iNKT cell) as a model of a T cell subset that differentiates in response to specific TCR signaling, we identified a key role of histone H3 lysine 27 trimethylation (H3K27me3) in coupling iNKT cell TCR specificity with the generation of iNKT cells. We found that the Zbtb16/PLZF gene promoter that drives iNKT cell differentiation possesses a bivalent chromatin state characterized by the simultaneous presence of negative and positive H3K27me3 and H3K4me3 modifications. Depletion of H3K27me3 at the Zbtb16/PLZF promoter leads to uncoupling of iNKT cell development from TCR specificity and is associated with accumulation of iNKT-like CD4(+) cells that express a non-iNKT cell specific T cell repertoire. In turn, stabilization of H3K27me3 leads to a drastic reduction of the iNKT cell population. Our data suggest that H3K27me3 levels at the bivalent Zbtb16/PLZF gene define a threshold enabling precise coupling of TCR specificity to lineage commitment. PMID- 25687284 TI - Unsolved problems in biology--The state of current thinking. AB - Many outstanding problems have been solved in biology and medicine for which scientists have been awarded prestigious prizes including the Nobel Prize, Lasker Award and Breakthrough Prizes in life sciences. These have been the fruits of years of basic research. From time to time, publications have appeared listing "unsolved" problems in biology. In this article, I ask the question whether it is possible to have such a list, if not a unique one, at least one that is analogous to the Millennium Prize in mathematics. My approach to finding an answer to this question was to gather views of leading biologists. I have also included my own views. Analysis of all the responses received over several years has convinced me that it is difficult, but not impossible, to have such a prize. Biology is complex and very interdisciplinary these days at times involving large numbers of teams, unlike mathematics, where Andrew Wiles spent seven years in complete isolation and secrecy solving Fermat's last theorem. Such an approach is simply not possible in biology. Still I would like to suggest that a similar prize can be established by a panel of distinguished scientists. It would be awarded to those who solved one of the listed problems in biology that warrant a verifiable solution. Despite many different opinions, I found that there is some commonality in the responses I received - I go on to discuss what these are and how they may impact future thinking. PMID- 25687283 TI - Restricted dendritic cell and monocyte progenitors in human cord blood and bone marrow. AB - In mice, two restricted dendritic cell (DC) progenitors, macrophage/dendritic progenitors (MDPs) and common dendritic progenitors (CDPs), demonstrate increasing commitment to the DC lineage, as they sequentially lose granulocyte and monocyte potential, respectively. Identifying these progenitors has enabled us to understand the role of DCs and monocytes in immunity and tolerance in mice. In humans, however, restricted monocyte and DC progenitors remain unknown. Progress in studying human DC development has been hampered by lack of an in vitro culture system that recapitulates in vivo DC hematopoiesis. Here we report a culture system that supports development of CD34(+) hematopoietic stem cell progenitors into the three major human DC subsets, monocytes, granulocytes, and NK and B cells. Using this culture system, we defined the pathway for human DC development and revealed the sequential origin of human DCs from increasingly restricted progenitors: a human granulocyte-monocyte-DC progenitor (hGMDP) that develops into a human monocyte-dendritic progenitor (hMDP), which in turn develops into monocytes, and a human CDP (hCDP) that is restricted to produce the three major DC subsets. The phenotype of the DC progenitors partially overlaps with granulocyte-macrophage progenitors (GMPs). These progenitors reside in human cord blood and bone marrow but not in the blood or lymphoid tissues. PMID- 25687285 TI - One-pot refolding of core histones from bacterial inclusion bodies allows rapid reconstitution of histone octamer. AB - We report an optimized method to purify and reconstitute histone octamer, which utilizes high expression of histones in inclusion bodies but eliminates the time consuming steps of individual histone purification. In the newly modified protocol, Xenopus laevis H2A, H2B, H3, and H4 are expressed individually into inclusion bodies of bacteria, which are subsequently mixed together and denatured in 8M guanidine hydrochloride. Histones are refolded and reconstituted into soluble octamer by dialysis against 2M NaCl, and metal-affinity purified through an N-terminal polyhistidine-tag added on the H2A. After cleavage of the polyhistidine-tag, histone octamer is further purified by size exclusion chromatography. We show that the nucleosomes reconstituted using the purified histone octamer above are fully functional. They serve as effective substrates for the histone methyltransferases DOT1L and MLL1. Small angle X-ray scattering further confirms that the reconstituted nucleosomes have correct structural integration of histone octamer and DNA as observed in the X-ray crystal structure. Our new protocol enables rapid reconstitution of histone octamer with an optimal yield. We expect this simplified approach to facilitate research using recombinant nucleosomes in vitro. PMID- 25687286 TI - On winning the "lottery": psychological preparation for football penalty shoot outs. AB - The outcome of penalty shoot-outs is often referred to as a "lottery", suggesting that luck, rather than the skill level of the player, predetermines outcome success. Throughout this article, we hope to show why such attitudes towards physical and psychological preparation can increase anxiety, diminish perceptions of control and negatively affect the behaviour and subsequent performance of penalty takers. From the synthesis of this evidence, we provide task-specific recommendations that are structured around the dynamic nature of emotions that players are likely to experience during each phase of the shoot-out and which can be implemented or adapted to suit the individual needs of the player. These recommendations are designed to provide a framework to help applied professionals to optimise the psychological preparation for this scenario with the overall aim of helping players to (re)gain control of this situation. PMID- 25687287 TI - Water-mediated long-range interactions between the internal vibrations of remote proteins. AB - It is generally acknowledged that the mobility of protein atoms and the mobility of water molecules in the solvation layer are connected. In this article, we answer the question whether a similar interdependence exists between the motions of atoms of proteins separated by the hydration layers of variable thickness. The system consisted of a kinesin catalytic domain and a tubulin dimer. It was studied using molecular dynamics simulations. The analyzed atoms were located at the two distant protein surfaces that were facing each other. We demonstrated that the low-frequency (ca. 2 THz and less) collective movements of these two separate sets of atoms are to some extent interdependent. Based on this finding, it can be inferred that the low frequency large-scale internal motions of these proteins are also partially interdependent. The water-mediated protein-protein interactions, which are responsible for this interdependence, have a relatively long range of at least 2 nm at room temperature. PMID- 25687288 TI - Incidence of suspected perioperative anaphylaxis: A multicenter snapshot study. PMID- 25687289 TI - Systemic mastocytosis presenting as IgE-mediated food-induced anaphylaxis: A report of two cases. PMID- 25687291 TI - Digging for biosynthetic dark matter. AB - An analysis of bacterial communities in soil samples from around the world reveals unexplored diversity in biosynthetic enzymes. PMID- 25687290 TI - Proteasome regulates transcription-favoring histone methylation, acetylation and ubiquitination in long-term synaptic plasticity. AB - Histone modifications, such as lysine methylation, acetylation and ubiquitination, are epigenetic tags that shape the chromatin landscape and regulate transcription required for synaptic plasticity and memory. Here, we show that transcription-promoting histone H3 trimethylated at lysine 4 (H3K4me3), histone H3 acetylated at lysine 9 and 14 (H3K9/14ac), and histone H2B monoubiquitinated at lysine 120 (H2BK120ub) are enhanced after the induction of long-lasting chemically-induced long-term potentiation (cLTP) in the murine hippocampus. While H3K4me3 and H3K9/14ac were transiently upregulated, H2BK120ub levels oscillated after cLTP induction. In addition, we present results showing that blocking the proteasome, a molecular complex specialized for targeted protein degradation, inhibited the upregulation of these epigenetic tags after cLTP. Thus, our study provides the initial steps toward understanding the role of the proteasome in regulating histone modifications critical for synaptic plasticity. PMID- 25687292 TI - Posterior fossa syndrome in a patient with an ornithine transcarbamylase deficiency. AB - The posterior fossa syndrome (PFS) is a well-known clinical entity and mainly occurs in children. Ornithine transcarbamylase deficiency (OTC) is the most common urea cycle disorder, which occurs in an estimated 1 per 50.000 live births in Japan. Symptoms are mostly due to hyperammonemia and include nausea, vomiting, lethargia and even convulsions and coma. Common neurological symptoms at presentation of a hyperammonemia are a decreased level of consciousness, abnormal motor function or seizures. In this case we describe a girl with late onset OCT deficiency presenting with transient mutism and subsequent dysarthria, ataxia and behavioural changes. This is an exceptional report of a not yet described neurologic syndrome in OTC. SYNOPSIS: Neurologic symptoms in ornithine transcarbamylase deficiency do not only occur during an episode of hyperammonemia and may present as a transient neurologic symptoms compatible with the posterior fossa syndrome. PMID- 25687293 TI - Preliminary noise reduction efforts in a medical intensive care unit. AB - Noise is a significant contributor to sleep disruption in the intensive care unit (ICU) that may result in increased patient morbidity such as delirium and prolonged length of stay in ICU. We conducted a pre-post intervention study in a 24-bed tertiary care academic medical ICU to reduce the mean noise levels. Baseline dosimeter recordings of ICU noise levels demonstrated a mean noise level of 54.2 A-weighted decibels (dBA) and peak noise levels of 109.9 dBA, well above the Environmental Protection Agency's recommended levels. There were 1735 episodes of "defects" (maximum noise levels > 60 dBA). Following implementation of multipronged interventions, although the mean noise levels did not change significantly between pre- and post-intervention (54.2 vs 53.8 dBA; p = 0.96), there was a significant reduction in the number of "defects" post-intervention (1735 vs 1289, p <= 0.000), and the providers felt that the patients were sleeping longer in the ICU post-intervention. PMID- 25687294 TI - Light and auxin responsive cytochrome P450s from Withania somnifera Dunal: cloning, expression and molecular modelling of two pairs of homologue genes with differential regulation. AB - Cytochrome P450s (CYPs) catalyse a wide variety of oxygenation/hydroxylation reactions that facilitate diverse metabolic functions in plants. Specific CYP families are essential for the biosynthesis of species-specialized metabolites. Therefore, we investigated the role of different CYPs related to secondary metabolism in Withania somnifera, a medicinally important plant of the Indian subcontinent. In this study, complete complementary DNAs (cDNAs) of four different CYP genes were isolated and christened as WSCYP93Id, WSCYP93Sm, WSCYP734B and WSCYP734R. These cDNAs encoded polypeptides comprising of 498, 496, 522 and 550 amino acid residues with their deduced molecular mass of 56.7, 56.9, 59.4 and 62.2 kDa, respectively. Phylogenetic study and molecular modelling analysis of the four cloned WSCYPs revealed their categorization into two CYP families (CYP83B1 and CYP734A1) belonging to CYP71 and CYP72 clans, respectively. BLASTp searches showed similarity of 75 and 56 %, respectively, between the two CYP members of CYP83B1 and CYP734A1 with major variances exhibited in their N terminal regions. The two pairs of homologues exhibited differential expression profiles in the leaf tissues of selected chemotypes of W. somnifera as well as in response to treatments such as methyl jasmonate, wounding, light and auxin. Light and auxin regulated two pairs of WSCYP homologues in a developing seedling in an interesting differential manner. Their lesser resemblance and homology with other CYP sequences suggested these genes to be more specialized and distinct ones. The results on chemotype-specific expression patterns of the four genes strongly suggested their key/specialized involvement of the CYPs in the biosynthesis of chemotype-specific metabolites, though their further biochemical characterization would reveal the specificity in more detail. It is revealed that WSCYP93Id and WSCYP93Sm may be broadly involved in the oxygenation reactions in the plant and, thereby, control various pathways involving such metabolic reactions in the plant. As a representative experimental validation of this notion, WSCYP93Id was heterologouly expressed in Escherichia coli and catalytic capabilities of the recombinant WSCYP93Id protein were evaluated using withanolides as substrates. Optimized assays with some major withanolides (withanone, withaferin A and withanolide A) involving spectrophotometric as well as high-pressure liquid chromatography (HPLC)-based evaluation (product detection) of the reactions showed conversion of withaferin A to a hydroxylated product. The genes belonging to other CYP group are possibly involved in some specialised synthesis such as that of brassinosteroids. PMID- 25687295 TI - Operative photo assimilation associated proteome modulations are critical for iron-dependent cadmium tolerance in Oryza sativa L. AB - Iron-dependent Cd tolerance in Oryza sativa L. cv 7029 had been explored. Photo assimilatory process such as photosynthesis and nitrogen fixation found to be functional in the presence of excess Fe during Cd stress. Cd-inducible Fe deficiency demonstrated with upregulation of iron uptake gene families such as OsIRT and OsYSL was attributed as foremost reason for retardation of photo assimilation in the course of Cd treatment. Upholding of photo assimilation during Fe supplement was associated with proteome modulations. Monitoring of proteome responses in leaf and root revealed proteins imperative for alleviation of Cd stress. Specifically, proteins that take part in photosynthesis, glucose metabolism, nitrogen fixation, and abiotic stress tolerance played key role in Fe dependent Cd detoxification. It is concluded that Fe supply help to operate photo assimilation which enable favorable proteome responses of Cd stress tolerance. PMID- 25687296 TI - Isolation and molecular characterization of a novel WIN1/SHN1 ethylene-responsive transcription factor TdSHN1 from durum wheat (Triticum turgidum. L. subsp. durum). AB - Over the last decade, APETALA2/Ethylene Responsive Factor (AP2/ERF) proteins have become the subject of intensive research activity due to their involvement in a variety of biological processes. This research led to the identification of AP2/ERF genes in many species; however, little is known about these genes in durum wheat, one of the most important cereal crops in the world. In this study, a new member of the AP2/ERF transcription factor family, designated TdSHN1, was isolated from durum wheat using thermal asymetric interlaced PCR (TAIL-PCR) method. Protein sequence analysis showed that TdSHN1 contained an AP2/ERF domain of 63 amino acids and a putative nuclear localization signal (NLS). Phylogenetic analysis showed that TdSHN1 belongs to a group Va protein in the ERF subfamily which contains the Arabidopsis ERF proteins (SHN1, SHN2, and SHN3). Expression of TdSHN1 was strongly induced by salt, drought, abscisic acid (ABA), and cold. In planta, TdSHN1 protein was able to activate the transcription of GUS reporter gene driven by the GCC box and DRE element sequences. In addition, TdSHN1 was targeted to the nucleus when transiently expressed in tobacco epidermal cells. In transgenic yeast, overexpression of TdSHN1 increased tolerance to multiple abiotic stresses. Taken together, the results showed that TdSHN1 encodes an abiotic stress-inducible, transcription factor which confers abiotic stress tolerance in yeast. TdSHN1 is therefore a promising candidate for improvement of biotic and abiotic stress tolerance in wheat as well as other crops. PMID- 25687297 TI - Using Oct4:MerCreMer Lineage Tracing to Monitor Endogenous Oct4 Expression During the Reprogramming of Fibroblasts into Induced Pluripotent Stem Cells (iPSCs). AB - The reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) using a combination of defined transcription factors has become one of the most widely used techniques in stem cell biology. A critical, early event in iPSC reprogramming is the induction of the endogenous transcription factor network that maintains pluripotency in iPSCs. Here we describe using a transgenic, conditional Oct4-Cre construct to investigate the spatial and temporal induction of endogenous Oct4 expression during the reprogramming of mouse fibroblasts into iPS cells. PMID- 25687298 TI - Generation and Characterization of Rat iPSCs. AB - The laboratory rat (Rattus norvegicus) is now on the leading edge used as a laboratory model system to study pharmacology, toxicology, immunology, nutrition, behavior, and numerous other topics. Therefore, generation of rat induced pluripotent stem cells (iPSCs) through somatic cells reprogramming is a powerful tool for establishing in vitro disease model, development of new protocols for treatment of different diseases, and creating transgenic rat models. Here, we describe a simple adopted protocol for establishing rat iPSCs from different types of somatic cells including rat primary ear fibroblast (PEF) and primary bone marrow cells (BMC). PMID- 25687299 TI - Enhancing Induced Pluripotent Stem Cell Generation by MicroRNA. AB - Somatic reprogramming to generate induced pluripotent stem cells, or iPSC, is a powerful tool in developmental biology, disease modeling, and regenerative medicine. microRNAs have been shown to regulate many key pathways in iPSC induction. Here we describe a microRNA mimic enhanced somatic reprogramming process starting from mouse embryonic fibroblast isolation to iPSC induction to colony derivation and characterization. PMID- 25687300 TI - Generation of Human Induced Pluripotent Stem Cells from Peripheral Blood Mononuclear Cells Using Sendai Virus. AB - This protocol describes the efficient isolation of peripheral blood mononuclear cells from circulating blood via density gradient centrifugation and subsequent generation of integration-free human induced pluripotent stem cells. Peripheral blood mononuclear cells are cultured for 9 days to allow expansion of the erythroblast population. The erythroblasts are then used to derive human induced pluripotent stem cells using Sendai viral vectors, each expressing one of the four reprogramming factors Oct4, Sox2, Klf4, and c-Myc. PMID- 25687301 TI - Induced Pluripotent Stem (iPS) Cell Culture Methods and Induction of Differentiation into Endothelial Cells. AB - The study of stem cell behavior and differentiation in a developmental context is complex, time-consuming, and expensive, and for this reason, cell culture remains a method of choice for developmental and regenerative biology and mechanistic studies. Similar to ES cells, iPS cells have the ability to differentiate into endothelial cells (ECs), and the route for differentiation appears to mimic the developmental process that occurs during the formation of an embryo. Traditional EC induction methods from embryonic stem (ES) cells rely mostly on the formation of embryoid body (EB), which employs feeder or feeder-free conditions in the presence or absence of supporting cells. Similar to ES cells, iPS cells can be cultured in feeder layer or feeder-free conditions. Here, we describe the iPS cell culture methods and induction differentiation of these cells into ECs. We use anti-mouse Flk1 and anti-mouse VE-cadherin to isolate and characterize mouse ECs, because these antibodies are commercially available and their use has been described in the literature, including by our group. The ECs produced by this method have been used by our laboratory, and we have demonstrated their in vivo potential. We also discuss how iPS cells differ in their ability to differentiate into endothelial cells in culture. PMID- 25687302 TI - Neurofilament Light Chain Determination from Peripheral Blood Samples. AB - The loss of neurological function is closely related to axonal damage. Neurofilament subunits are concentrated in neurons and axons and have emerged as promising biomarkers for neurodegeneration. Electrochemiluminescence (ECL) based assays are known to be of superior sensitivity and require less sample volume than conventional ELISAs. Here, we describe a highly sensitive ECL based immunoassay for quantification of neurofilament light chain (NfL) in blood and CSF. PMID- 25687303 TI - Epidemiological, clinical and laboratory features of murine typhus in central Tunisia. AB - OBJECTIVE: Murine typhus is an endemic zoonosis. It is difficult to diagnose because of its non-specific clinical manifestations. Our objective was to describe the epidemiological, clinical, laboratory, and treatment features of murine typhus. METHODS: We conducted a retrospective study of 73 adult patients hospitalized for murine typhus from 2006 to 2011. The diagnosis was confirmed by a single titer of IgM>=128 or by seroconversion to typhus group antigen identified by indirect fluorescent assay. RESULTS: The mean age of patients was 33.1 years (range, 13-68 years). Thirty-eight patients (52%) lived in rural or suburban areas; neither fleabites nor exposure to rats were reported. The most common clinical symptoms were: fever, headache, and myalgia. A maculopapular and non-confluent rash was observed in 47 patients (64.4%). No inoculation eschar was observed in any patient. Eight patients presented with interstitial pneumonia and two with lymphocytic meningitis. The diagnosis was confirmed by indirect fluorescence assay in every case. A single titer of IgM >= 128 was found in 62 (84.9%) cases. The other 11 cases were diagnosed by seroconversion. All patients were given antibiotics. Tetracyclines were prescribed in 57 cases (78%). The two patients presenting with meningitis were treated with fluoroquinolone. The outcome was favorable for all patients and no relapse was observed. CONCLUSION: The features of murine typhus are non-specific. The definitive diagnosis is based on serologic testing by indirect fluorescent assay. Cyclins were the most prescribed antibiotics. PMID- 25687304 TI - The active site of yeast phosphatidylinositol synthase Pis1 is facing the cytosol. AB - Five yeast enzymes synthesizing various glycerophospholipids belong to the CDP alcohol phosphatidyltransferase (CAPT) superfamily. They only share the so-called CAPT motif, which forms the active site of all these enzymes. Bioinformatic tools predict the CAPT motif of phosphatidylinositol synthase Pis1 as either ER luminal or cytosolic. To investigate the membrane topology of Pis1, unique cysteine residues were introduced into either native or a Cys-free form of Pis1 and their accessibility to the small, membrane permeating alkylating reagent N ethylmaleimide (NEM) and mass tagged, non-permeating maleimides, in the presence and absence of non-denaturing detergents, was monitored. The results clearly point to a cytosolic location of the CAPT motif. Pis1 is highly sensitive to non denaturing detergent, and low concentrations (0.05%) of dodecylmaltoside change the accessibility of single substituted Cys in the active site of an otherwise cysteine free version of Pis1. Slightly higher detergent concentrations inactivate the enzyme. Removal of the ER retrieval sequence from (wt) Pis1 enhances its activity, again suggesting an influence of the lipid environment. The central 84% of the Pis1 sequence can be aligned and fitted onto the 6 transmembrane helices of two recently crystallized archaeal members of the CAPT family. Results delineate the accessibility of different parts of Pis1 in their natural context and allow to critically evaluate the performance of different cysteine accessibility methods. Overall the results show that cytosolically made inositol and CDP-diacylglycerol can access the active site of the yeast PI synthase Pis1 from the cytosolic side and that Pis1 structure is strongly affected by mild detergents. PMID- 25687305 TI - Changes afoot! PMID- 25687306 TI - Ultrasound-guided delivery of microRNA loaded nanoparticles into cancer. AB - Ultrasound induced microbubble cavitation can cause enhanced permeability across natural barriers of tumors such as vessel walls or cellular membranes, allowing for enhanced therapeutic delivery into the target tissues. While enhanced delivery of small (<1nm) molecules has been shown at acoustic pressures below 1MPa both in vitro and in vivo, the delivery efficiency of larger (>100nm) therapeutic carriers into cancer remains unclear and may require a higher pressure for sufficient delivery. Enhanced delivery of larger therapeutic carriers such as FDA approved pegylated poly(lactic-co-glycolic acid) nanoparticles (PLGA-PEG-NP) has significant clinical value because these nanoparticles have been shown to protect encapsulated drugs from degradation in the blood circulation and allow for slow and prolonged release of encapsulated drugs at the target location. In this study, various acoustic parameters were investigated to facilitate the successful delivery of two nanocarriers, a fluorescent semiconducting polymer model drug nanoparticle as well as PLGA-PEG-NP into human colon cancer xenografts in mice. We first measured the cavitation dose produced by various acoustic parameters (pressure, pulse length, and pulse repetition frequency) and microbubble concentration in a tissue mimicking phantom. Next, in vivo studies were performed to evaluate the penetration depth of nanocarriers using various acoustic pressures, ranging between 1.7 and 6.9MPa. Finally, a therapeutic microRNA, miR-122, was loaded into PLGA-PEG-NP and the amount of delivered miR-122 was assessed using quantitative RT-PCR. Our results show that acoustic pressures had the strongest effect on cavitation. An increase of the pressure from 0.8 to 6.9MPa resulted in a nearly 50-fold increase in cavitation in phantom experiments. In vivo, as the pressures increased from 1.7 to 6.9MPa, the amount of nanoparticles deposited in cancer xenografts was increased from 4- to 14-fold, and the median penetration depth of extravasated nanoparticles was increased from 1.3-fold to 3-fold, compared to control conditions without ultrasound, as examined on 3D confocal microscopy. When delivering miR-122 loaded PLGA-PEG-NP using optimal acoustic settings with minimum tissue damage, miR-122 delivery into tumors with ultrasound and microbubbles was 7.9-fold higher compared to treatment without ultrasound. This study demonstrates that ultrasound induced microbubble cavitation can be a useful tool for delivery of therapeutic miR loaded nanocarriers into cancer in vivo. PMID- 25687307 TI - Determination of polymeric micelles' structural characteristics, and effect of the characteristics on pharmacokinetic behaviors. AB - We evaluated structural factors characterizing PEG-b-P(Asp-Bzl) micelles including core size, aggregation number (Nagg), and core surface PEG density by means of small-angle X-ray scattering (SAXS), field flow fractionation with multi angle light scattering (FFF-MALS) analysis, and DLS. Furthermore, we evaluated the stability of PEG-b-P(Asp-Bzl) micelles by means of GPC. This paper reports the correlation between the evaluated micelles' structural factors and the micelles' behaviors including the micelles' in vivo pharmacokinetic behaviors. One micelle PEG(12)-b-P(Asp-Bzl) (PEG=12,000) exhibited a high core surface density (~0.99 chain/nm(2)). In these circumstances, PEG(12)-b-P(Asp-Bzl) micelles exhibited a highly stretched PEG brush form. However, the evaluated core surface PEG densities could not fully explain the micelles' in vivo pharmacokinetic behaviors. In contrast, GPC will become a strong tool for predicting PEG(12)-b-P(Asp-Bzl) micelles' in vivo behaviors, as well as the micelles' in vitro behaviors. The stability results correlated strongly with the area-under-the-curve (AUC) values of PEG-b-P(Asp-Bzl) micelles' in vivo pharmacokinetics. Finally, we evaluated PEG(12)-b-P(Asp-Bzl) micelles' most effective structural factor for determining the micelles' behaviors, and the micelles' outermost shell surface's PEG density (DOS, PEG) correlated with the micelles' behaviors. We revealed that the evaluated DOS, PEG is the most important factor for understanding PEG(12)-b-P(Asp-Bzl) micelles' behaviors. PMID- 25687308 TI - Selective targeting of alveolar type II respiratory epithelial cells by anti surfactant protein-C antibody-conjugated lipoplexes. AB - Alveolar type II (ATII) respiratory epithelial cells are essential to normal lung function. They may be also central to the pathogenesis of diseases such as acute lung injury, pulmonary fibrosis, and pulmonary adenocarcinoma. Hence, ATII cells are important therapeutic targets. However, effective ATII cell-specific drug delivery in vivo requires carriers of an appropriate size, which can cross the hydrophobic alveolar surfactant film and polar aqueous layer overlying ATII cells, and be taken up without inducing ATII cell dysfunction, pulmonary inflammation, lung damage, or excessive systemic spread and side-effects. We have developed lipoplexes as a versatile nanoparticle carrier system for drug/RNA delivery. To optimize their pulmonary localization and ATII cell specificity, lipoplexes were conjugated to an antibody directed against the ATII cell-specific antigen surfactant protein-C (SP-C) then administered to C57BL/6 mice via the nares. Intranasally-administered, anti-SP-C-conjugated lipoplexes targeted mouse ATII cells with >70% specificity in vivo, were retained within ATII cells for at least 48h, and did not accumulate at significant levels in other lung cell types or viscera. 48h after treatment with anti-SP-C-conjugated lipoplexes containing the test microRNA miR-486, expression of mature miR-486 was approximately 4-fold higher in ATII cells than whole lung by qRT-PCR, and was undetectable in other viscera. Lipoplexes induced no weight loss, hypoxemia, lung dysfunction, pulmonary edema, or pulmonary inflammation over a 6-day period. These findings indicate that ATII cell-targeted lipoplexes exhibit all the desired characteristics of an effective drug delivery system for the treatment of pulmonary diseases that result primarily from ATII cell dysfunction. PMID- 25687309 TI - Surgical technique for optimal outcomes: Part I. Cutting tissue: incising, excising, and undermining. AB - Sound surgical technique is necessary to achieve excellent surgical outcomes. Despite the fact that dermatologists perform more office-based cutaneous surgery than any other specialty, few dermatologists have opportunities for practical instruction to improve surgical technique after residency and fellowship. This 2 part continuing medical education article will address key principles of surgical technique at each step of cutaneous reconstruction. Part I reviews incising, excising, and undermining. Objective quality control questions are proposed to provide a framework for self-assessment and continuous quality improvement. PMID- 25687310 TI - Surgical technique for optimal outcomes: Part II. Repairing tissue: suturing. AB - Sound surgical technique is necessary to achieve excellent surgical outcomes. Despite the fact that dermatologists perform more office-based cutaneous surgery than any other specialty, few dermatologists have opportunities for practical instruction to improve surgical technique after residency and fellowship. This 2 part continuing medical education article will address key principles of surgical technique at each step of cutaneous reconstruction. Part II reviews the placement of deep and superficial sutures. Objective quality control questions are proposed to provide a framework for self-assessment and continuous quality improvement. PMID- 25687311 TI - Attitudes, knowledge, and practices regarding sun safety among third to fifth graders from Chicago-area schools. PMID- 25687312 TI - Teledermatology as pedagogy: diagnostic and management concordance between resident and attending dermatologists. PMID- 25687313 TI - Assessing frequency and quality of US dermatologist sunscreen recommendations to their patients. PMID- 25687314 TI - Treatment of superficial basal cell carcinoma and squamous cell carcinoma in situ on the trunk and extremities with ablative fractional laser-assisted delivery of topical fluorouracil. PMID- 25687315 TI - The role of skin trauma (isotopic and isomorphic) in the distribution of morphea. PMID- 25687320 TI - The "pinch and slide" suture technique. PMID- 25687321 TI - Bilateral mucosal rotation flap for repair of lower lip defect. PMID- 25687322 TI - Rotation flap with an inferior Z-plasty for the reconstruction of alar defects. PMID- 25687323 TI - Cutaneous pseudolymphoma: a rare side effect of cyclosporine. PMID- 25687324 TI - Chronic obstructive pulmonary disease exacerbation: A single-center perspective on hospital readmissions. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is the third most common cause in the United States of hospital readmission within 30 days of discharge. Readmissions, which are attributed to poor quality of care, are costly. We examined the factors associated with 30-day readmission in patients hospitalized with acute exacerbation of COPD. Our hypothesis was that early readmissions among patients with COPD are related to patient factors rather than system or provider factors. METHODS: We performed a retrospective chart review of all patients discharged from our facility from June 2010 to May 2011 with a primary discharge diagnosis of COPD. Detailed patient characteristics were obtained from the electronic medical record. Patients were followed for 30 days post-discharge date. We examined the differences in baseline characteristics of patients readmitted within 30 days and those not readmitted. RESULTS: A total of 160 patients were admitted for 192 hospitalizations during the study period; 31 patients (19.4%) were readmitted within 30 days. Patients who were readmitted did not differ from those who were not readmitted of the following factors: baseline medication use, length of stay, and outpatient follow-up postdischarge. Readmitted patients were more likely to be black, to have coronary artery disease, to have a history of alcohol abuse, and to be on supplemental oxygen. Multivariate analysis showed a 2.17 odds of 30-day readmission (95% CI, 1.16 4.09) in patients with alcohol abuse, and 2.52 (95% CI, 1.18-5.38) in those on supplemental oxygen. CONCLUSION: In our study population, 19.4% of acute exacerbation COPD patients were readmitted within 30 days. Patient factors (such as alcohol abuse and advanced disease) were associated with 30-day readmission. PMID- 25687325 TI - The concept of mixed organic ligands in metal-organic frameworks: design, tuning and functions. AB - The research on metal-organic frameworks (MOFs) has been developing at an extraordinary pace in its two decades of existence, as judged by the exponential growth of novel structures and the constant expansion of its applicability and research scope. A major part of the research and its success are due to the vital role of the concept of mixed organic ligands in the design, tuning and functions. This perspective, therefore, reviews the recent advances in MOFs based on this concept, which is generally based on employing a small polydentate ligand (here labelled as "nodal ligand") to form either clusters, rods or layers, which are then connected by a second ditopic linker ligand to form the framework. The structures of the materials can be grouped into the following three categories: layer-spacer (usually known as pillared-layer), rod-spacer, and cluster-spacer based MOFs. Depending on the size and geometry of the spacer ligands, interpenetrations of frameworks are occasionally found. These MOFs show a wide range of properties such as (a) crystal-to-crystal transformations upon solvent modifications, post-synthetic metal exchange or ligand reactions, (b) gas sorption, solvent selectivity and purification, (c) specific catalysis, (d) optical properties including colour change, luminescence, non-linear optic, (e) short- and long range magnetic ordering, metamagnetism and reversible ground state modifications and (f) drug and iodine carriers with controlled release. In the following, we will highlight the importance of the above concept in the design, tuning, and functions of a selection of existing MOFs having mixed organic ligands and their associated structures and properties. The results obtained so far using this concept look very promising for fine-tuning the pore size and shape for selective adsorption and specificity in catalytic reactions, which appears to be one way to propel the advances in the application and commercialization of MOFs. PMID- 25687326 TI - High-resolution AFM in liquid: what about the tip? AB - Atomic Force Microscopy relies on a nanoscale tip to image and probe samples, often down to the sub-nanometre level. The measurement process depends on the precise geometry and chemical nature of the tip apex, and is therefore difficult to control. In the current issue of Nanotechnology, Akrami and co-workers show that, for measurements in aqueous solutions and on flat samples, the presence of stable hydration sites at the tip apex is key to achieving high-resolution images. These sites can be created on commercial tips using a simple preparation strategy that prevents build-up of interfering contaminants. The findings by Akrami et al also suggest a possible way forward to control the influence of the tip on high-resolution measurements. PMID- 25687327 TI - MIR137 Regulates Starvation-Induced Autophagy by Targeting ATG7. AB - Autophagy is a cellular catabolic mechanism in response to stress conditions and has been implicated in the progression and chemoresistance of various cancers. Human microR-137 (MIR137) is involved in neuronal maturation and neurogenesis, while little is known about its role in cancer. In this study, we showed that starvation increased the formation of autophagic marker microtubule-associated protein 1 light chain 3 (LC3) without significant change of MIR137 level in U87 cells. In addition, overexpression of MIR137 decreased LC3 expression and inhibited the degradation of the autophagy receptor sequestosome 1(SQSTM1/p62), while the MIR137 antagomirs showed the opposite effect on these autophagic markers. Moreover, MIR137 overexpression decreased, while its antagomirs increased the expression of autophagy-related 7(ATG7) mRNA and protein. MIR137 mediated inhibition of autophagy was prevented by ATG7. Finally, MIR137 promoted the sensitivity of U87 cells to adriamycin, an anticancer drug. Taken together, our study demonstrated that MIR137 attenuated starvation-induced autophagy by regulating the expression of ATG7. PMID- 25687328 TI - Pcdh11x Negatively Regulates Dendritic Branching. AB - Proper formation of neuronal dendritic branching is crucial for correct brain function. The number and distribution of receptive synaptic contacts are defined by the size and shape of dendritic arbors. Our previous research found that protocadherin 11 X-linked protein (Pcdh11x) is predominantly expressed in neurons and has an influence on dendritic branching. In this study, gain-of-function and loss-of-function experiments revealed that Pcdh11x acts as a negative regulator of dendritic branching in cultured cortical neurons derived from embryonic day 16 mice. Overexpression of wild-type Pcdh11x (Pcdh11x-GFP) reduced dendritic complexity, whereas knockdown of Pcdh11x increased dendritic branching. It was further demonstrated that Pcdh11x activates PI3K/AKT signaling to negatively regulate dendritic branching. PMID- 25687329 TI - Role of Astrocytes in Leptin Signaling. AB - To test the hypothesis that astrocytic leptin signaling induces an overall potentiation of the neuronal response to leptin, we generated a new line of astrocyte-specific leptin receptor knockout (ALKO-Delta1) mice in which no leptin receptor is expressed in astrocytes. Corresponding to cell-specific Cre recombinase expression in hypothalamic astrocytes but not neurons, this new strain of ALKO mice had attenuated pSTAT3 signaling in the arcuate nucleus of the hypothalamus 30 min after intracerebroventricular delivery of leptin. In response to high-fat diet for 2 months, the ALKO mice showed a greater increase of percent fat and blood leptin concentration. This coincided with a mild reactive gliosis in the hypothalamus. Overall, the absence of leptin receptors in astrocytes attenuated hypothalamic pSTAT3 signaling, induced a mild reactive morphology, and promoted the development of diet-induced obesity. We conclude that leptin signaling in astrocytes is essential for the homeostasis of neuroendocrine regulation in obesity. PMID- 25687330 TI - Escitalopram Ameliorates Forskolin-Induced Tau Hyperphosphorylation in HEK239/tau441 Cells. AB - To investigate the effect of escitalopram (a widely used and highly efficacious antidepressant from the SSRI class) on tau hyperphosphorylation, HEK293/tau441 cells were pretreated with 4 MUM of forskolin for 2 h. Then we treated the cells with different doses of escitalopram (0, 5, 10, 20, 40, 80 MUM) for 22 h. We measured the phosphorylation level of tau by Western blotting. It was shown that escitalopram could protect tau from hyperphosphorylation induced by pharmacological activation of protein kinase A (PKA) at a dose of 20, 40, and 80 MUM in vitro. Interestingly, the same dose of escitalopram could also increase the level of serine-9-phosphorylated GSK-3beta (inactive form) and the phosphorylation level of Akt at Ser473 (active form) with no significant change in the level of total GSK-3beta and Akt. Unexpectedly, 5-hydroxytryptamine 1A receptor (5-HT1A) agonist 8-OH-DPAT did not decrease forskolin-induced tau hyperphosphorylation. Our results suggest that escitalopram can ameliorate forskolin-induced tau hyperphosphorylation, which is not through the typical 5 HT1A pathway, and Akt/GSK-3beta signaling pathway is involved. These findings may support an effective role of antidepressants in the prevention of dementia associated with depression in patients. PMID- 25687332 TI - In-depth analysis of drivers' merging behavior and rear-end crash risks in work zone merging areas. AB - This study investigates the drivers' merging behavior and the rear-end crash risk in work zone merging areas during the entire merging implementation period from the time of starting a merging maneuver to that of completing the maneuver. With the merging traffic data from a work zone site in Singapore, a mixed probit model is developed to describe the merging behavior, and two surrogate safety measures including the time to collision (TTC) and deceleration rate to avoid the crash (DRAC) are adopted to compute the rear-end crash risk between the merging vehicle and its neighboring vehicles. Results show that the merging vehicle has a bigger probability of completing a merging maneuver quickly under one of the following situations: (i) the merging vehicle moves relatively fast; (ii) the merging lead vehicle is a heavy vehicle; and (iii) there is a sizable gap in the adjacent through lane. Results indicate that the rear-end crash risk does not monotonically increase as the merging vehicle speed increases. The merging vehicle's rear-end crash risk is also affected by the vehicle type. There is a biggest increment of rear-end crash risk if the merging lead vehicle belongs to a heavy vehicle. Although the reduced remaining distance to work zone could urge the merging vehicle to complete a merging maneuver quickly, it might lead to an increased rear-end crash risk. Interestingly, it is found that the rear-end crash risk could be generally increased over the elapsed time after the merging maneuver being triggered. PMID- 25687331 TI - Protein networks and activation of lymphocytes. AB - The signal transduction pathways initiated by lymphocyte activation play a critical role in regulating host immunity. High-resolution mass spectrometry has accelerated the investigation of these complex and dynamic pathways by enabling the qualitative and quantitative investigation of thousands of proteins and phosphoproteins simultaneously. In addition, the unbiased and wide-scale identification of protein-protein interaction networks and protein kinase substrates in lymphocyte signaling pathways can be achieved by mass spectrometry based approaches. Critically, the integration of these discovery-driven strategies with single-cell analysis using mass cytometry can facilitate the understanding of complex signaling phenotypes in distinct immunophenotypes. PMID- 25687333 TI - Gait propulsion in patients with facioscapulohumeral muscular dystrophy and ankle plantarflexor weakness. AB - Facioscapulohumeral muscular dystrophy is a slowly progressive hereditary disorder resulting in fatty infiltration of eventually most skeletal muscles. Weakness of trunk and leg muscles causes problems with postural balance and gait, and is associated with an increased fall risk. Although drop foot and related tripping are common problems in FSHD, gait impairments are poorly documented. The effect of ankle plantarflexor involvement on gait propulsion has never been addressed. In addition to ankle plantarflexion, gait propulsion is generated through hip flexion and hip extension. Compensatory shifts between these propulsion sources occur when specific muscles are affected. Such a shift may be expected in patients with FSHD since the calves may show early fatty infiltration, whereas iliopsoas and gluteus maximus muscles are often spared for a longer time. In the current study, magnetic resonance imaging was used to assess the percentage of unaffected calf, iliopsoas and gluteus maximus muscles. Joint powers were analyzed in 10 patients with FSHD at comfortable and maximum walking speed to determine the contribution of ankle plantarflexor, hip flexor and hip extensor power to propulsion. Associations between muscle morphology, power generation and gait speed were assessed. Based on multivariate regression analysis, ankle plantarflexor power was the only factor that uniquely contributed to the explained variance of comfortable (R(2)=80%) and maximum (R(2)=86%) walking speed. Although the iliopsoas muscles were largely unaffected, they appeared to be sub-maximally recruited. This submaximal recruitment may be related to poor trunk stability, resulting in a disproportionate effect of calf muscle affliction on gait speed in patients with FSHD. PMID- 25687334 TI - Temporal responses of human endothelial and smooth muscle cells exposed to uniaxial cyclic tensile strain. AB - The physiology of vascular cells depends on stimulating mechanical forces caused by pulsatile flow. Thus, mechano-transduction processes and responses of primary human endothelial cells (ECs) and smooth muscle cells (SMCs) have been studied to reveal cell-type specific differences which may contribute to vascular tissue integrity. Here, we investigate the dynamic reorientation response of ECs and SMCs cultured on elastic membranes over a range of stretch frequencies from 0.01 to 1 Hz. ECs and SMCs show different cell shape adaptation responses (reorientation) dependent on the frequency. ECs reveal a specific threshold frequency (0.01 Hz) below which no responses is detectable while the threshold frequency for SMCs could not be determined and is speculated to be above 1 Hz. Interestingly, the reorganization of the actin cytoskeleton and focal adhesions system, as well as changes in the focal adhesion area, can be observed for both cell types and is dependent on the frequency. RhoA and Rac1 activities are increased for ECs but not for SMCs upon application of a uniaxial cyclic tensile strain. Analysis of membrane protrusions revealed that the spatial protrusion activity of ECs and SMCs is independent of the application of a uniaxial cyclic tensile strain of 1 Hz while the total number of protrusions is increased for ECs only. Our study indicates differences in the reorientation response and the reaction times of the two cell types in dependence of the stretching frequency, with matching data for actin cytoskeleton, focal adhesion realignment, RhoA/Rac1 activities, and membrane protrusion activity. These are promising results which may allow cell-type specific activation of vascular cells by frequency-selective mechanical stretching. This specific activation of different vascular cell types might be helpful in improving strategies in regenerative medicine. PMID- 25687335 TI - Bariatric surgery from the pioneer phase to evidence-based medicine: why hasn't this transition become reality in daily practice? PMID- 25687336 TI - C-N bond formation between alcohols and amines using an iron cyclopentadienone catalyst. AB - An iron-tetraphenylcyclopentadienone tricarbonyl complex is demonstrated to act as a precursor of a catalyst for the formation of C-N bonds through a "hydrogen borrowing" reaction between amines and alcohols. PMID- 25687337 TI - MHC class II variation in a rare and ecological specialist mouse lemur reveals lower allelic richness and contrasting selection patterns compared to a generalist and widespread sympatric congener. AB - The polymorphism of immunogenes of the major histocompatibility complex (MHC) is thought to influence the functional plasticity of immune responses and, consequently, the fitness of populations facing heterogeneous pathogenic pressures. Here, we evaluated MHC variation (allelic richness and divergence) and patterns of selection acting on the two highly polymorphic MHC class II loci (DRB and DQB) in the endangered primate Madame Berthe's mouse lemur (Microcebus berthae). Using 454 pyrosequencing, we examined MHC variation in a total of 100 individuals sampled over 9 years in Kirindy Forest, Western Madagascar, and compared our findings with data obtained previously for its sympatric congener, the grey mouse lemur (Microcebus murinus). These species exhibit a contrasting ecology and demography that were expected to affect MHC variation and molecular signatures of selection. We found a lower allelic richness concordant with its low population density, but a similar level of allelic divergence and signals of historical selection in the rare feeding specialist M. berthae compared to the widespread generalist M. murinus. These findings suggest that demographic factors may exert a stronger influence than pathogen-driven selection on current levels of allelic richness in M. berthae. Despite a high sequence similarity between the two congeners, contrasting selection patterns detected at DQB suggest its potential functional divergence. This study represents a first step toward unravelling factors influencing the adaptive divergence of MHC genes between closely related but ecologically differentiated sympatric lemurs and opens new questions regarding potential functional discrepancy that would explain contrasting selection patterns detected at DQB. PMID- 25687338 TI - Impact of Sox9 dosage and Hes1-mediated Notch signaling in controlling the plasticity of adult pancreatic duct cells in mice. AB - In the adult pancreas, there has been a long-standing dispute as to whether stem/precursor populations that retain plasticity to differentiate into endocrine or acinar cell types exist in ducts. We previously reported that adult Sox9 expressing duct cells are sufficiently plastic to supply new acinar cells in Sox9 IRES-CreERT2 knock-in mice. In the present study, using Sox9-IRES-CreERT2 knock in mice as a model, we aimed to analyze how plasticity is controlled in adult ducts. Adult duct cells in these mice express less Sox9 than do wild-type mice but Hes1 equally. Acinar cell differentiation was accelerated by Hes1 inactivation, but suppressed by NICD induction in adult Sox9-expressing cells. Quantitative analyses showed that Sox9 expression increased with the induction of NICD but did not change with Hes1 inactivation, suggesting that Notch regulates Hes1 and Sox9 in parallel. Taken together, these findings suggest that Hes1 mediated Notch activity determines the plasticity of adult pancreatic duct cells and that there may exist a dosage requirement of Sox9 for keeping the duct cell identity in the adult pancreas. In contrast to the extended capability of acinar cell differentiation by Hes1 inactivation, we obtained no evidence of islet neogenesis from Hes1-depleted duct cells in physiological or PDL-induced injured conditions. PMID- 25687339 TI - Forensic DNA phenotyping in criminal investigations and criminal courts: assessing and mitigating the dilemmas inherent in the science. AB - Forensic DNA Phenotyping ("FDP"), estimating the externally visible characteristics ("EVCs") of the source of human DNA left at a crime scene, is evolving from science fiction toward science fact. FDP can already identify a source's gender with 100% accuracy, and likely hair color, iris color, adult height, and a number of other EVCs with accuracy rates approaching 70%. Patent applications have been filed for approaches to generating 3D likenesses of DNA sources based on the DNA alone. Nonetheless, criminal investigators, particularly in the United States, have been reticent to apply FDP in their casework. The reticence is likely related to a number of perceived and real dilemmas associated with FDP: is FDP racial profiling, should we test unknown and unseen physical conditions, does testing for behavioral characteristics impermissibly violate the source's privacy, ought testing be permitted for samples from known sources or DNA databases, and should FDP be limited to use in investigations only or is FDP appropriate for use in a criminal court. As this article explains, although those dilemmas are substantive, they are not insurmountable, and can be quite easily managed with appropriate regulation and protocols. As FDP continues to develop, there will be less need for criminal investigators to shy away from FDP. Cold cases, missing persons, and victims in crimes without other evidence will one day soon all be well served by FDP. PMID- 25687340 TI - Genes, blame and loss of control: is there a place in criminal law for a 'genetic defense'? AB - In 2002, Caspi and colleagues proposed that a specific gene by environment (GxE) interaction is related to antisocial tendencies. Since then, a substantial body of literature has examined the potential implications of such a correlation for the criminal justice system, and in particular, for the attribution of responsibility and blame that lies at the core of that system. It is probably accurate to say that the majority position among criminal theorists is that evidence of such a nature does not undermine or seriously challenge existing notions of responsibility, and could not constitute a full defense to a criminal charge - although it may have a role to play in sentencing. Less consideration, however, has been given to the role such evidence may play in so-called 'partial defenses' - those like diminished responsibility (DR), which serve not to exculpate the defendant entirely, but rather, to mitigate his responsibility for the criminal act. This paper aims to assess the most important feature of the Caspi Sudy - the low variant gene for the production of Monoamine Oxidase Acid A gene (MAOA-L) - and its possible role in a defense of DR. We argue that, following the approach of common law jurisdictions to analogous situations, there is no principled reason to exclude evidence of MAOA-L as a basis of DR. PMID- 25687341 TI - Preliminary perspectives on DNA collection in anti-human trafficking efforts. AB - Forensic DNA methodologies have potential applications in the investigation of human trafficking cases. DNA and relationship testing may be useful for confirmation of biological relationship claims in immigration, identification of trafficked individuals who are missing persons, and family reunification of displaced individuals after mass disasters and conflicts. As these applications rely on the collection of DNA from non-criminals and potentially vulnerable individuals, questions arise as to how to address the ethical challenges of collection, security, and privacy of collected samples and DNA profiles. We administered a survey targeted to victims' advocates to gain preliminary understanding of perspectives regarding human trafficking definitions, DNA and sex workers, and perceived trust of authorities potentially involved in DNA collection. We asked respondents to consider the use of DNA for investigating adoption fraud, sex trafficking, and post-conflict child soldier cases. We found some key differences in perspectives on defining what qualifies as "trafficking." When we varied terminology between "sex worker" and "sex trafficking victim" we detected differences in perception on which authorities can be trusted. Respondents were supportive of the hypothetical models proposed to collect DNA. Most were favorable of DNA specimens being controlled by an authority outside of law enforcement. Participants voiced concerns focused on privacy, misuse of DNA samples and data, unintentional harms, data security, and infrastructure. These preliminary data indicate that while there is perceived value in programs to use DNA for investigating cases of human trafficking, these programs may need to consider levels of trust in authorities as their logistics are developed and implemented. PMID- 25687342 TI - The Study of HFE Genotypes and Its Expression Effect on Iron Status of Iranian Haemochromatosis, Iron Deficiency Anemia Patients, Iron-Taker and Non Iron-Taker Controls. AB - The role of HFE gene mutations or its expression in regulation of iron metabolism of hereditary haemochromatosis (HH) patients is remained controversial. Therefore here the correlation between two common HFE genotype (p.C282Y, p.H63D) and HFE gene expression with iron status in HH, iron deficiency anemia (IDA) and healthy Iranian participants was studied. For this purpose genotype determination was done by polymerase chain reaction--restriction fragment length polymorphism (PCR RFLP). Real-Time PCR was applied for evaluation of HFE gene expression. Biochemical parameters and iron consumption were also assessed. Homozygote p.H63D mutation was seen in all HH patients and p.C282Y was not observed in any member of the population. A significant correlation was observed between serum ferritin (SF) level and gender or age of HH patients. p.H63D homozygote was seen to be able to significantly increase SF and transferrin saturation (TS) level without affecting on liver function. Our results also showed that iron consumption affects on TS level increasing. HFE gene expression level of IDA patients was significantly higher than other groups. Also the HFE gene expression was negatively correlated with TS. Finally, the main result of our study showed that loss of HFE function in HH is not derived from its gene expression inhibition and much higher HFE gene expression might lead to IDA. However we propose repeating of the study for more approval of our finding. PMID- 25687343 TI - The mirror neuron analogy: implications for rehabilitation neuroscience: comment on "Grasping synergies: a motor-control approach to the mirror neuron mechanism" by A. D'Ausilio et al. PMID- 25687345 TI - Accidental contamination of a German town's drinking water with sodium hydroxide. AB - Case report of a very serious drinking water incident putting up to 50,000 inhabitants of a town near Bonn in North Rhine-Westphalia, Germany at risk. A concentrated solution of highly alkaline water by sodium hydroxide was accidentally washed into the town's drinking water at a pumping station and increased the pH-value of the water to 12. Residents who came into contact with the contaminated water immediately had a toxic reaction. The incident was detected by complaints from customers and after that was stopped within several hours. The pipes were flushed and the customers were warned not to use the water till the all clear. After this immediate management there was an investigation and the cause of the incident was detected as an accidental release of accumulated sodium hydroxide (NaOH) solution. The lack of a network alarm system and the automatic cut-off mechanisms as deficiencies in the design of the station were rectified by the water company immediately after the incident. PMID- 25687344 TI - Integrated primary care for patients with mental and physical multimorbidity: cluster randomised controlled trial of collaborative care for patients with depression comorbid with diabetes or cardiovascular disease. AB - OBJECTIVE: To test the effectiveness of an integrated collaborative care model for people with depression and long term physical conditions. DESIGN: Cluster randomised controlled trial. SETTING: 36 general practices in the north west of England. PARTICIPANTS: 387 patients with a record of diabetes or heart disease, or both, who had depressive symptoms (>= 10 on patient health questionaire-9 (PHQ 9)) for at least two weeks. Mean age was 58.5 (SD 11.7). Participants reported a mean of 6.2 (SD 3.0) long term conditions other than diabetes or heart disease; 240 (62%) were men; 360 (90%) completed the trial. INTERVENTIONS: Collaborative care included patient preference for behavioural activation, cognitive restructuring, graded exposure, and/or lifestyle advice, management of drug treatment, and prevention of relapse. Up to eight sessions of psychological treatment were delivered by specially trained psychological wellbeing practitioners employed by Improving Access to Psychological Therapy services in the English National Health Service; integration of care was enhanced by two treatment sessions delivered jointly with the practice nurse. Usual care was standard clinical practice provided by general practitioners and practice nurses. MAIN OUTCOME MEASURES: The primary outcome was reduction in symptoms of depression on the self reported symptom checklist-13 depression scale (SCL-D13) at four months after baseline assessment. Secondary outcomes included anxiety symptoms (generalised anxiety disorder 7), self management (health education impact questionnaire), disability (Sheehan disability scale), and global quality of life (WHOQOL-BREF). RESULTS: 19 general practices were randomised to collaborative care and 20 to usual care; three practices withdrew from the trial before patients were recruited. 191 patients were recruited from practices allocated to collaborative care, and 196 from practices allocated to usual care. After adjustment for baseline depression score, mean depressive scores were 0.23 SCL-D13 points lower (95% confidence interval -0.41 to -0.05) in the collaborative care arm, equal to an adjusted standardised effect size of 0.30. Patients in the intervention arm also reported being better self managers, rated their care as more patient centred, and were more satisfied with their care. There were no significant differences between groups in quality of life, disease specific quality of life, self efficacy, disability, and social support. CONCLUSIONS: Collaborative care that incorporates brief low intensity psychological therapy delivered in partnership with practice nurses in primary care can reduce depression and improve self management of chronic disease in people with mental and physical multimorbidity. The size of the treatment effects were modest and were less than the prespecified effect but were achieved in a trial run in routine settings with a deprived population with high levels of mental and physical multimorbidity. TRIAL REGISTRATION: ISRCTN80309252. PMID- 25687346 TI - Multilocus sequence analysis of the genus Citrobacter and description of Citrobacter pasteurii sp. nov. AB - Strains originating from various sources and classified as members of the genus Citrobacter within the family Enterobacteriaceae were characterized by sequencing internal portions of genes rpoB, fusA, pyrG and leuS, 16S rRNA gene sequencing, average nucleotide identity (ANI) of genomic sequences and biochemical tests. Phylogenetic analysis based on the four housekeeping genes showed that the 11 species of the genus Citrobacter with validly published names are well demarcated. Strains CIP 55.13(T) and CIP 55.9 formed a distinct branch associated with Citrobacter youngae. The ANI between CIP 55.9 and CIP 55.13(T) was 99.19%, whereas it was 94.75% between CIP 55.13(T) and strain CIP 105016(T) of the species C. youngae, the most closely related species. Biochemical characteristics consolidated the fact that the two isolates represent a separate species, for which the name Citrobacter pasteurii sp. nov. is proposed. The type strain is CIP 55.13(T) ( =DSM 28879(T) =Na 1a(T)). PMID- 25687347 TI - Puniceibacterium sediminis sp. nov., from intertidal sediment. AB - The Gram-stain-negative, rod-shaped bacterial strain designated RU-1-R-18(T) was isolated from intertidal sediment on Sakhalin Island in Russia. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain RU-1-R-18(T) was related to the genus Puniceibacterium and shared highest sequence similarities with the type strain Puniceibacterium antarcticum KACC 16875(T) (97.9%). The predominant cellular fatty acid was C(18:1)omega7c. The polar lipid profile contained diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine, one unidentified aminophospholipid and seven unidentified polar lipids. The genomic DNA G+C content of strain RU-1-R-18(T) was 59.1 mol%. Combined data from phenotypic, phylogenetic and DNA-DNA relatedness studies demonstrated that strain RU-1-R-18(T) represents a novel species of the genus Puniceibacterium , for which the name Puniceibacterium sediminis sp. nov. is proposed (type strain RU-1-R-18(T) =LMG 28384(T) =DSM 29052(T)). PMID- 25687348 TI - Micromonospora costi sp. nov., isolated from a leaf of Costus speciosus. AB - An endophytic actinobacterial strain, CS1-12(T), was isolated from a leaf of Costus speciosus. Single spores were observed directly on the substrate mycelia. The cell-wall peptidoglycan of this strain exhibited meso-diaminopimelic acid and 3-OH-meso-diaminopimelic acid. Arabinose, glucose, ribose, xylose and rhamnose were detected as whole-cell sugars. The diagnostic phospholipids of this strain were phosphatidylethanolamine, diphosphatidylglycerol, phosphatidylglycerol, phosphatidylinositol and phosphatidylinositol mannosides. The predominant menaquinones were MK-10(H6), MK-10(H8), MK-9(H4) and MK-10(H4). The main components of the cellular fatty acids (>10%) were iso-C15 : 0, anteiso-C17 : 0, iso-C16 : 0 and anteiso-C15 : 0. The G+C content of the genomic DNA was 72.8 mol%. 16S rRNA gene sequence analysis data showed that strain CS1-12(T) should be classified in the genus Micromonospora and that it is closely related to Micromonospora fulviviridis DSM 43906(T) (99.3%). The physiological, biochemical and chemotaxonomic properties, including the DNA-DNA hybridization results, indicated that strain CS1-12(T) could be judged a novel species of the genus Micromonospora , for which the name Micromonospora costi sp. nov. is proposed. The type strain is CS1-12(T) ( =BCC 58124(T) =NBRC 109518(T)). PMID- 25687349 TI - Streptomyces albiflavescens sp. nov., an actinomycete isolated from soil. AB - Two actinobacterial strains, m20(T) and z8, were isolated from soil taken from rainforest areas/tropic forest region, Yunnan Province, south-west China. The 16S rRNA gene sequence similarities and DNA-DNA relatedness values between strains m20(T) and z8 were 100 and 88.2%, respectively, which indicated that these two strains should be classified as the same species. The taxonomic position of the strains was determined by a polyphasic approach. Morphological and chemotaxonomic features of the strains were consistent with those of the genus Streptomyces . A phylogenetic tree based on 16S rRNA gene sequences showed that strains m20(T) and z8 formed an evolutionary branch within the genus Streptomyces and shared relatively high 16S rRNA gene sequence similarity values with other members of this genus, including 'Streptomyces siamensis' NBRC 108799 (98.95%), Streptomyces graminilatus NBRC 108882(T) (98.25%), Streptomyces seoulensis NBRC 16668(T) (98.11%), Streptomyces peucetius ATCC 29050(T) (98.11%) and Streptomyces hygroscopicus subsp. ossamyceticus ATCC 15420(T) (98.11%). DNA-DNA relatedness values between strain m20(T) and the five above-mentioned strains were 56.3, 55.1, 52.8, 50.1 and 48.4%, respectively. On the basis of phenotypic, genotypic and phylogenetic properties, strains m20(T) and z8 could be distinguished from phylogenetically related members of the genus Streptomyces . The isolates thus merit species status within the genus Streptomyces , for which the name http://dx.doi.org/10.1601/nm.6817 Streptomyces albiflavescens sp. nov. is proposed. The type strain is m20(T) ( =CGMCC 4.7111(T) =KCTC 29196(T)). Strain z8 ( =CGMCC 4.7112=KCTC 29197) is a reference strain. PMID- 25687350 TI - Botulinum toxin A complex exploits intestinal M cells to enter the host and exert neurotoxicity. AB - To cause food-borne botulism, botulinum neurotoxin (BoNT) in the gastrointestinal lumen must traverse the intestinal epithelial barrier. However, the mechanism by which BoNT crosses the intestinal epithelial barrier remains unclear. BoNTs are produced along with one or more non-toxic components, with which they form progenitor toxin complexes (PTCs). Here we show that serotype A1 L-PTC, which has high oral toxicity and makes the predominant contribution to causing illness, breaches the intestinal epithelial barrier from microfold (M) cells via an interaction between haemagglutinin (HA), one of the non-toxic components, and glycoprotein 2 (GP2). HA strongly binds to GP2 expressed on M cells, which do not have thick mucus layers. Susceptibility to orally administered L-PTC is dramatically reduced in M-cell-depleted mice and GP2-deficient (Gp2(-/-)) mice. Our finding provides the basis for the development of novel antitoxin therapeutics and delivery systems for oral biologics. PMID- 25687351 TI - Cardiac computed tomography in patients with acute chest pain. AB - The efficient and reliable evaluation of patients with acute chest pain is one of the most challenging tasks in the emergency department. Coronary computed tomography (CT) angiography may play a major role, since it permits ruling out coronary artery disease with high accuracy if performed with expertise in properly selected and prepared patients. Several randomized trials have established early cardiac CT as a viable safe and potentially more efficient alternative to functional testing in the evaluation of acute chest pain. Ongoing investigations explore whether advanced anatomic and functional assessments such as high-risk coronary plaque, resting myocardial perfusion, and left ventricular function, or the simulation of the fractional coronary flow reserve will add information to the anatomic assessment for stenosis, which would allow expanding the benefits of cardiac CT from triage to treatment decisions. Especially, the combination of high-sensitive troponins and coronary computed tomography angiography may play a valuable role in future strategies for the management of patients presenting with acute chest pain. PMID- 25687352 TI - Edoxaban vs. warfarin in vitamin K antagonist experienced and naive patients with atrial fibrillation?. AB - AIMS: Edoxaban is an oral, once-daily factor Xa inhibitor that is non-inferior to well-managed warfarin in patients with atrial fibrillation (AF) for the prevention of stroke and systemic embolic events (SEEs). We examined the efficacy and safety of edoxaban vs. warfarin in patients who were vitamin K antagonist (VKA) naive or experienced. METHODS AND RESULTS: ENGAGE AF-TIMI 48 randomized 21 105 patients with AF at moderate-to-high risk of stroke to once-daily edoxaban vs. warfarin. Subjects were followed for a median of 2.8 years. The primary efficacy endpoint was stroke or SEE. As a pre-specified subgroup, we analysed outcomes for those with or without prior VKA experience (>60 consecutive days). Higher-dose edoxaban significantly reduced the risk of stroke or SEE in patients who were VKA naive [hazard ratio (HR) 0.71, 95% confidence interval (CI) 0.56 0.90] and was similar to warfarin in the VKA experienced (HR 1.01, 95% CI 0.82 1.24; P interaction = 0.028). Lower-dose edoxaban was similar to warfarin for stroke or SEE prevention in patients who were VKA naive (HR 0.92, 95% CI 0.73 1.15), but was inferior to warfarin in those who were VKA experienced (HR 1.31, 95% 1.08-1.60; P interaction = 0.019). Both higher-dose and lower-dose edoxaban regimens significantly reduced the risk of major bleeding regardless of prior VKA experience (P interaction = 0.90 and 0.71, respectively). CONCLUSION: In patients with AF, edoxaban appeared to demonstrate greater efficacy compared with warfarin in patients who were VKA naive than VKA experienced. Edoxaban significantly reduced major bleeding compared with warfarin regardless of prior VKA exposure. PMID- 25687354 TI - Diversified syntheses of multifunctionalized thiazole derivatives via regioselective and programmed C-H activation. AB - The sequential construction of diversified multifunctionalized thiazole derivatives through Pd-catalyzed regioselective C-H alkenylation has been accomplished. This versatile approach provides the diversified thiazole derivatives featuring orthogonal substitution patterns at the C-2, C-4 and C-5 positions from mono-substituted (2- or 4-substituted) thiazole derivatives or even more challenging simple thiazole. PMID- 25687355 TI - Safety and effectiveness of enzalutamide in men with metastatic, castration resistant prostate cancer. AB - INTRODUCTION: Enzalutamide (MDV3100) is a second-generation androgen receptor antagonist that improves survival in metastatic, castration-resistant prostate cancer (mCRPC). Alternatives include chemotherapy, radiation, immunotherapy and abiraterone. AREAS COVERED: The Phase I/II study showed early evidence of efficacy and determined that fatigue is the dose-limiting toxicity. Two randomized, placebo-controlled trials have demonstrated superiority of enzalutamide 160 mg by mouth daily over placebo in terms of overall survival, radiographic progression-free survival as well as a broad range of secondary and exploratory end points in men who had received previous chemotherapy (AFFIRM) and in those who were chemotherapy naive (PREVAIL). Common side effects include fatigue, arthralgias and constipation. A post hoc analysis from AFFIRM found that enzalutamide is safe and effective in men aged >= 75 years. The Phase I/II studies as well as AFFIRM and PREVAIL are described in this review. EXPERT OPINION: Enzalutamide extends overall and progression-free survival and is associated with robust response rates and quality of life benefits in men with mCRPC. Enzalutamide has not been proven to be effective in biochemically relapsed disease or in castration-sensitive prostate cancer. It should not be used in men at high risk for seizure, and patients should be counseled about the increased risk of falls. PMID- 25687353 TI - Efficacy and safety of alirocumab in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia on maximally tolerated doses of statins: the ODYSSEY COMBO II randomized controlled trial. AB - AIMS: To compare the efficacy [low-density lipoprotein cholesterol (LDL-C) lowering] and safety of alirocumab, a fully human monoclonal antibody to proprotein convertase subtilisin/kexin 9, compared with ezetimibe, as add-on therapy to maximally tolerated statin therapy in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia. METHODS AND RESULTS: COMBO II is a double-blind, double-dummy, active-controlled, parallel-group, 104 week study of alirocumab vs. ezetimibe. Patients (n = 720) with high cardiovascular risk and elevated LDL-C despite maximal doses of statins were enrolled (August 2012-May 2013). This pre-specified analysis was conducted after the last patient completed 52 weeks. Patients were randomized to subcutaneous alirocumab 75 mg every 2 weeks (plus oral placebo) or oral ezetimibe 10 mg daily (plus subcutaneous placebo) on a background of statin therapy. At Week 24, mean +/- SE reductions in LDL-C from baseline were 50.6 +/- 1.4% for alirocumab vs. 20.7 +/- 1.9% for ezetimibe (difference 29.8 +/- 2.3%; P < 0.0001); 77.0% of alirocumab and 45.6% of ezetimibe patients achieved LDL-C <1.8 mmol/L (P < 0.0001). Mean achieved LDL-C at Week 24 was 1.3 +/- 0.04 mmol/L with alirocumab and 2.1 +/- 0.05 mmol/L with ezetimibe, and were maintained to Week 52. Alirocumab was generally well tolerated, with no evidence of an excess of treatment-emergent adverse events. CONCLUSION: In patients at high cardiovascular risk with inadequately controlled LDL-C, alirocumab achieved significantly greater reductions in LDL-C compared with ezetimibe, with a similar safety profile. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01644188. PMID- 25687356 TI - Sirolimus and trastuzumab combination therapy for HER2-positive metastatic breast cancer after progression on prior trastuzumab therapy. AB - Constitutive activation of the PI3K/Akt/mTOR pathway has been suggested as a mechanism of resistance to trastuzumab therapy. This phase II trial was designed to evaluate the safety and clinical activity of daily oral sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, in combination with trastuzumab in HER2 positive metastatic breast cancer following disease progression on prior trastuzumab therapy. Sirolimus 6 mg oral daily dose was administered with a standard dose and schedule of trastuzumab weekly or every 3 weeks. Pharmacodynamic studies included Western blot analysis of S6K1, phosphoS6K1, and mTOR in peripheral mononuclear cells, circulating tumor cells (CTC), and endothelial cells (CEC). Eleven patients were evaluable for safety; and nine were evaluable for response assessment. Subsequent enrollment was stopped due to slow accrual. Study treatment-related grade 3 toxicity included pneumonitis, myelosuppression (leukopenia/anemia), and dermatologic reactions (mucositis, nail changes and rash), with no grade 4 events. One patient received eight cycles (58 weeks) and achieved a partial response. Five patients treated for a total of 101 weeks (median 12 weeks, range 8-47 weeks) achieved stable disease as best response. Overall response rate was 1/9 (11 %) and clinical benefit rate was 4/9 (44 %). There was no statistically significant correlation between response and post-treatment change in levels of the mTOR pathway biomarkers, CTCs, HER2 CTCs, or CECs. Sirolimus 6 mg administered daily with trastuzumab appears to be well tolerated in patients with metastatic HER2-positive breast cancer following disease progression on prior trastuzumab therapy, with evidence of disease activity. mTOR inhibition may overcome resistance to trastuzumab in some HER2 positive tumors. PMID- 25687357 TI - Comparison of two methods of documenting urinary and central venous catheters at an academic medical center. AB - Accurate documentation of the use of invasive devices, such as urinary and central line catheters, is important to track potential catheter-associated infections. Real-time identification of device infections allows practitioners to initiate timely apparent-cause analyses, therefore allowing rapid improvement of practice. For this reason, it was crucial to ensure our institution's mechanism to capture possible catheter-associated infections is validated after the adoption of a new electronic medical record system. PMID- 25687358 TI - Prevalence and risk factors for methicillin-resistant Staphylococcus aureus in an HIV-positive cohort. AB - BACKGROUND: Persons living with HIV (PLWH) are disproportionately burdened with methicillin-resistant Staphylococcus aureus (MRSA). Our objective was to evaluate prevalence and risks for MRSA colonization in PLWH. METHODS: Adults were recruited from Johns Hopkins University AIDS Service in Baltimore, Maryland. A risk questionnaire and specimen collection from anatomic sites with culture susceptibility and genotyping were completed. Generalized estimating equation modeling identified MRSA colonization risk factors. RESULTS: Of 500 participants, most were black (69%), on antiretroviral therapy (ART) (87%), with undetectable viral loads (73.4%). Median CD4 count was 487 cells/mm(3) (interquartile range, 316-676.5 cells/mm(3)). MRSA prevalence was 15.4%, predominantly from the nares (59.7%). Forty percent were nares negative but were colonized elsewhere. Lower odds for colonization were associated with recent sexual activity (adjusted odds ratio [AOR] = 0.84, P < .001) and ART (AOR = 0.85, P = .011). Increased odds were associated with lower income (<$25,000 vs >$75,000; AOR = 2.68, P < .001), recent hospitalization (AOR = 1.54, P < .001), incarceration (AOR = 1.55, P < .001), use of street drugs (AOR = 1.43, P < .001), and skin abscess (AOR = 1.19, P < .001). CONCLUSIONS: Even with high MRSA prevalence, the proportion identified through nares surveillance alone was low, indicating the importance of screening multiple anatomic sites. Associations were not found with same-sex coupling or black race. MRSA prevention might be a benefit of ART in PLWH. PMID- 25687359 TI - Impact of polymerase chain reaction testing on Clostridium difficile infection rates in an acute health care facility. AB - Two rapid methods of Clostridium difficile infection (CDI) diagnosis were compared between June 2012 and March 2013: a GeneXpert (Cepheid, Sunnyvale, Calif) polymerase chain reaction (PCR) test and an enzyme immunoassay (EIA). The influence of these methods on the detection of hospital-acquired CDI and identification of CDI outbreaks was evaluated. We tested 1,592 stool samples for C difficile. The GeneXpert PCR test identified 211 positive samples (68 determined to be hospital-acquired infection), whereas EIA identified 105 positive samples (36 determined to be hospital-acquired infection). The GeneXpert PCR method in contrast to the EIA method increased the detection rates of nosocomial CDI cases and contributed to the declaration of CDI outbreaks. PMID- 25687360 TI - Formaldehyde concentration in discharge from land based aquaculture facilities in Atlantic Canada. AB - Formaldehyde is used in freshwater aquaculture facilities in the Maritimes region of Canada to prevent external parasites and is discharged without treatment to freshwater receiving environments. In this study, formaldehyde was measured at effluent outfalls and 100 m downstream of four land based aquaculture facilities at various post-treatment time intervals. Concentrations of formaldehyde ranged from 0.2 to 7.1 mg/L. Based on Environment Canada's environmental no effect value, all of the samples show a potential risk to aquatic life. Furthermore, based on a chronic aquatic life water quality criterion of 1.61 mg/L all but two of the samples had concentrations considered to be toxic to aquatic life. An acute water quality criteria was only exceeded once in all of the environmental measurements of formaldehyde. These results lead us to hypothesize that the discharge of formaldehyde from land-based facilities may cause adverse chronic impacts. PMID- 25687361 TI - Methylene blue for burn-induced vasoplegia: case report and review of literature. AB - We report the use of a single dose of methylene blue in a patient with burn induced vasoplegia refractory to fluids, vasopressors, and steroids. Administration of methylene blue allowed for cessation of epinephrine infusion within 2 hours of administration, and reduction in excessive fluid resuscitation. The patient's clinical course continued for 2 months and was complicated by severe acute respiratory distress syndrome, pneumonia, septic shock, poor skin graft adherence, renal failure requiring continuous renal replacement therapy, cutaneous mucormycosis, and ultimately, withdrawal of care and death. Despite the eventual outcome, this is the longest reported survival following methylene blue administration for vasoplegia secondary to burn injury. PMID- 25687362 TI - The emerging role of tissue plasminogen activator in the management of severe frostbite. AB - This article presents a small case series demonstrating clinical success with thrombolytic agents for severe frostbite injury to the lower extremities. The authors report three patients with severe frostbite injuries to their distal lower extremities who were managed with urgent interventional radiology and intra arterial tissue plasminogen activator infusion according to a prespecified protocol. Limbs and digits were successfully salvaged and patients returned to normal activity within 2 weeks. Although further studies are needed, results of this study support a new approach in the management of frostbite: from conservative management and observation to urgent interventional radiology and possible tissue plasminogen activator infusion. A protocol for the management of such injuries is presented. PMID- 25687363 TI - In vitro analysis of scaffold-free prevascularized microtissue spheroids containing human dental pulp cells and endothelial cells. AB - INTRODUCTION: Scaffolds often fail to mimic essential functions of the physiologic extracellular matrix (ECM) that regulates cell-cell communication in tissue microenvironments. The development of scaffold-free microtissues containing stem cell-derived ECM may serve as a successful alternative to the use of artificial scaffolds. The current study aimed to fabricate 3-dimensional microtissue spheroids of dental pulp cells (DPCs) prevascularized by human umbilical vein endothelial cells (HUVECs) and to characterize these scaffold-free spheroids for the in vitro formation of pulplike tissue constructs. METHODS: Three-dimensional microtissue spheroids of DPC alone and DPC-HUVEC co-cultures were fabricated using agarose micro-molds. Cellular organization within the spheroids and cell viability (live/dead assay) were assessed at days 1, 7, and 14. Microtissue spheroids were allowed to self-assemble into macrotissues, induced for odontogenic differentiation (21 days), and examined for expression levels of osteo/odontogenic markers: alkaline phosphatase, bone sialoprotein and RUNX2 (Real-time PCR), mineralization (von-Kossa), and prevascularisation (immunohistochemistry for CD31). RESULTS: The DPC microtissue microenvironment supported HUVEC survival and capillary network formation in the absence of a scaffolding material and external angiogenic stimulation. Immunohistochemical staining for CD31 showed the capillary network formed by HUVECs did sustain-for a prolonged period-even after the microtissues transformed into a macrotissue. Induced, prevascularized macrotissues showed enhanced differentiation capacity compared with DPC alone macrotissues, as shown by higher osteo/odontogenic gene expression levels and mineralization. CONCLUSIONS: These findings provide insight into the complex intercellular cross talk occurring between DPCs and HUVECs in the context of angiogenesis and pulp regeneration and highlight the significance of developing a favorable 3-dimensional microenvironment that can, in turn, contribute toward successful pulp regeneration strategies. PMID- 25687364 TI - Clinical outcomes for teeth treated with electrospun poly(epsilon-caprolactone) fiber meshes/mineral trioxide aggregate direct pulp capping. AB - INTRODUCTION: Mineral trioxide aggregate (MTA) is a biocompatible material for direct pulp capping. This study was designed to compare the clinical outcomes of pulp-exposed teeth treated with either poly(epsilon-caprolactone) fiber mesh (PCL FM) as a barrier for MTA (so-called PCL-FM/MTA) or MTA direct pulp capping. METHODS: Sixty human vital teeth were evenly divided into 4 groups (n = 15 in each group). Teeth in groups 1 and 3 had pulp exposure <1 mm in diameter, whereas teeth in groups 2 and 4 had pulp exposure of 1-1.5 mm in diameter. Teeth in groups 1 and 2 were treated with PCL-FM/MTA direct pulp capping, and those in groups 3 and 4 were treated with MTA direct pulp capping. RESULTS: Teeth treated with PCL-FM/MTA direct pulp capping needed a significantly shorter mean duration for dentin bridge formation than teeth treated with MTA direct pulp capping. Moreover, teeth with pulp exposure <1.0 mm in diameter needed a significantly shorter mean duration for dentin bridge formation than teeth with pulp exposure of 1-1.5 mm in diameter after either PCL-FM/MTA or MTA direct pulp capping treatment. In addition, teeth treated with PCL-FM/MTA direct pulp capping formed an approximately 3-fold thicker dentin bridge than teeth treated with MTA direct pulp capping 8 weeks or 3 months later. Furthermore, none of the teeth treated with PCL-FM/MTA direct pulp capping showed tooth discoloration after treatment for 3 months. CONCLUSIONS: PCL-FM/MTA is a better combination material than MTA alone for direct pulp capping of human permanent teeth. PMID- 25687365 TI - Advanced heart failure due to cancer therapy. AB - Certain chemotherapeutic agents and mediastinal irradiation can be cardiotoxic and place cancer survivors at risk for developing advanced heart failure (HF). Anthracyclines are the prototypical agents associated with left ventricular (LV) dysfunction. Newer agents including trastuzumab and certain tyrosine kinase inhibitors such as sunitinib can also cause cardiomyopathy. Cancer survivors with advanced HF refractory to standard medical management should be considered for advanced therapies, including mechanical circulatory support (MCS) and transplantation. While overall outcomes after MCS and transplantation are similar in cancer survivors compared to other etiologies of HF, patients with radiation induced restrictive cardiomyopathy have a significantly worse prognosis after transplantation. The increased need for right ventricular (RV) support after MCS in cancer survivors necessitates a careful evaluation for pre-operative RV dysfunction. Special consideration must also be given to the risk for recurrent malignancy, neurocognitive dysfunction, and increased psychological needs in this patient population. PMID- 25687366 TI - Acute coronary syndrome in young women under 55 years of age: clinical characteristics, treatment, and outcomes. AB - BACKGROUND: Young women with acute coronary syndrome (ACS) may represent a high risk group, but little is known about specific age and sex differences in clinical characteristics, treatment, outcomes, and trends over time. METHODS: Data from 3237 men and women admitted with an ACS event from 1999 to 2006 were analyzed. Patients were grouped by sex and age less than 55 years. Demographics, presentation, treatment, and outcomes at 6 months were analyzed. Primary outcomes included mortality, recurrent myocardial infarction, rehospitalization, and stroke at 6 months. Secondary analyses assessed risk factors, management, and trends over time. RESULTS: Women under 55 years represented 8% of the entire cohort, and 26% of patients under age 55 years. Compared to older women, young women were more likely to be smokers (51 vs. 14%, p < 0.001) and obese (44 vs. 34%, p = 0.006). Young women had more diabetes and hypertension than young men. Mortality was lowest among young women and did not change over time. Young women received less treatment with aspirin, beta blockers, lipid-lowering agents, and ACE inhibitors, and underwent less coronary angiography and stenting than young men (44 vs. 59%, p < 0.001). Rehospitalization was higher among young women than young men (37 vs. 27%, p < 0.001), with no change over time. CONCLUSIONS: Modifiable risk factors such as smoking, obesity, diabetes, and hypertension should be addressed in young women. Following ACS, young women received fewer evidence-based medications, were treated less invasively, and had higher readmission rates within 6 months compared to young men. PMID- 25687367 TI - Inflammation-induced endothelial cell-derived extracellular vesicles modulate the cellular status of pericytes. AB - Emerging lines of evidence have shown that extracellular vesicles (EVs) mediate cell-to-cell communication by exporting encapsulated materials, such as microRNAs (miRNAs), to target cells. Endothelial cell-derived EVs (E-EVs) are upregulated in circulating blood in different pathological conditions; however, the characteristics and the role of these E-EVs are not yet well understood. In vitro studies were conducted to determine the role of inflammation-induced E-EVs in the cell-to-cell communication between vascular endothelial cells and pericytes/vSMCs. Stimulation with inflammatory cytokines and endotoxin immediately induced release of shedding type E-EVs from the vascular endothelial cells, and flow cytometry showed that the induction was dose dependent. MiRNA array analyses revealed that group of miRNAs were specifically increased in the inflammation-induced E-EVs. E-EVs added to the culture media of cerebrovascular pericytes were incorporated into the cells. The E-EV-supplemented cells showed highly induced mRNA and protein expression of VEGF-B, which was assumed to be a downstream target of the miRNA that was increased within the E-EVs after inflammatory stimulation. The results suggest that E-EVs mediate inflammation induced endothelial cell-pericyte/vSMC communication, and the miRNAs encapsulated within the E-EVs may play a role in regulating target cell function. E-EVs may be new therapeutic targets for the treatment of inflammatory diseases. PMID- 25687368 TI - Prognostic value of paradoxical low-gradient severe aortic stenosis in Japan: Japanese Multicenter Aortic Stenosis Study, Retrospective (JUST-R) Registry. AB - BACKGROUND: Whether the prognosis of paradoxical low-gradient severe aortic stenosis (PLG-SAS), especially due to paradoxical low-flow low-gradient SAS (PLFLG-SAS), is malignant in any specific ethnicity, including Japanese, remains unclear. METHODS: We retrospectively enrolled 385 consecutive Japanese patients (age, 76+/-8 years; 148 men) with moderate AS [MAS: 0.6<=indexed aortic valve area (iAVA)<0.85cm(2)/m(2)] or SAS (iAVA <0.6cm(2)/m(2)) with preserved left ventricular ejection fraction (>=50%). SAS patients were divided into PLG-SAS and high-gradient (HG)-SAS according to the transvalvular mean gradient (40mmHg). PLG SAS was categorized into 2 groups: normal-flow (NF) LG-SAS [stroke volume index (SVi) >=35mL/m(2)] and PLFLG-SAS (SVi <35mL/m(2)). Endpoints were all-cause death and major adverse cardio-cerebrovascular events (MACE). RESULTS: During a median follow-up of 15 months, 31 patients died and 48 suffered MACE. All-cause death and MACE rates in PLG-SAS and PLFLG-SAS were significantly lower than those in HG SAS and similar to those in MAS. On multivariate analysis, neither PLG-SAS nor PLFLG-SAS were independent determinants for all-cause death compared with MAS [MAS as reference, PLG-SAS: hazard ratio (HR) 0.47, p=0.32; PLFLG-SAS: HR 0.01, p=0.20; HG-SAS: HR 3.37, 95% confidence interval 1.24-9.74, p=0.02]. CONCLUSIONS: In Japanese patients, the prognoses of PLG-SAS and PLFLG-SAS were better than that of HG-SAS and similar to that of MAS, being better than that in Western populations. PMID- 25687369 TI - Simultaneous bilateral total knee arthroplasty in severe hemophilia: a retrospective cost-effectiveness analysis. AB - INTRODUCTION: Simultaneous bilateral total knee arthroplasty (TKA) is proposed in the general population as an alternative to staged bilateral TKA and has the advantage of reducing costs with equivalent complication rates. The aim of this study was to evaluate the cost-effectiveness of this alternative in a population of patients with severe hemophilia. HYPOTHESIS: Simultaneous bilateral TKA is less expensive than staged bilateral TKA. MATERIALS AND METHODS: We performed a retrospective case control study in patients with severe hemophilia A to compare the direct costs of coagulation factors, the length of hospital stay and sick leave as well as the clinical outcome (KKS) of simultaneous bilateral TKA (group 1; G1: 5 patients) and staged bilateral TKA (group 2; G2: 12 patients). RESULTS: The mean cost of coagulation factors was 65,880 ? in G1 and 139,000 ? in G2 (P<0.001). The length of the hospital stay (24 days vs 44 cumulative days, respectively) and sick leave (105 days vs 183 cumulative days, respectively) was significantly reduced in G1. There was no significant difference in clinical outcome at the final follow-up. One patient in G2 had a late knee infection. DISCUSSION: Simultaneous bilateral TKA in severe hemophilia is associated with lower costs than staged bilateral TKA with equivalent clinical results. LEVEL OF EVIDENCE: Level 3, case control study. PMID- 25687370 TI - AT1 Angiotensin receptors-vascular and renal epithelial pathways for blood pressure regulation. AB - Angiotensin type 1 (AT1) receptors are key effector elements of the renin angiotensin system, mediating virtually all of the classical physiological actions of angiotensin II. Pharmacological blockade of the AT1 receptor effectively lowers blood pressure in a substantial proportion of patients with hypertension, indicating the pivotal role of these receptors in human hypertension. AT1 receptors are expressed in many different organ systems where they have myriad cellular actions. However, several lines of evidence have suggested that direct actions of AT1 receptors in kidney have a major role in regulation of blood pressure and in the pathogenesis of hypertension. Here we review recent studies suggesting that renal epithelium and vasculature may be key cellular targets, where AT1 receptor activation has powerful physiological impact. We will also examine novel regulatory mechanisms by peptides associated with the C-terminus of the AT1 receptor. PMID- 25687371 TI - Early recurrence of migrainous infarction. PMID- 25687372 TI - The antinociceptive effect of stimulating the retrosplenial cortex in the rat tail-flick test but not in the formalin test involves the rostral anterior cingulate cortex. AB - The stimulation of the retrosplenial cortex (RSC) is antinociceptive in the rat tail-flick and formalin tests. The rat RSC is caudal to and send projections to the ipsilateral anterior cingulate cortex (ACC), which is also involved in pain processing. This study demonstrated that pre-treating the rostral (rACC), but not the caudal ACC with CoCl2 (1mM), or the rACC ablation increased the duration of the antinociceptive effect evoked by a 15-s period of electrical stimulation (AC, 60Hz, 20MUA) of the RSC in the rat tail-flick. Injecting the GABA-A antagonist bicuculline (50ng/0.25MUL), but not the GABA-B antagonist phaclofen (300ng/0.25MUL) into the rACC also increased the duration of the stimulation induced antinociception from the RSC. In contrast, the effects of rACC stimulation persisted after the injection of CoCl2 (1mM) into the RSC. The injection of CoCl2 into the rACC did not change the nociceptive behavior of rats during phase 1 of the formalin response but reduced licking response duration during phase 2. This effect was similar in sham or stimulated animals at the RSC. We conclude that the antinociceptive effect of stimulating the RSC in the rat tail-flick test is modulated by the rACC involving GABA-A receptors in this cortex. In contrast, the antinociceptive effect of stimulating the RSC in the formalin test does not involve the rACC. PMID- 25687373 TI - Nicotine withdrawal in selectively bred high and low nicotine preferring rat lines. AB - BACKGROUND: We have generated high- and low-nicotine preferring (high-NP, low-NP) rat lines using voluntary oral nicotine intake as the selection criterion. After nine generations, the estimated realized heritability for high intake was 0.26. The aim of the current study is to compare how nicotine withdrawal varies between these two lines. This new analysis would help elucidate if nicotine withdrawal and intake share common genetic mechanisms. METHODS: After exposing male and female Sprague Dawley rats (F8 generation) to six weeks of nicotine exposure, nicotine was withdrawn. Somatic signs of withdrawal, locomotor activity, and weight were measured at 16 and 40h. One week after withdrawal, resumption of nicotine intake was determined. RESULTS: The High-NP line had higher nicotine intake before and after withdrawal than the Low-NP line. High-NP rats were more active than Low-NP rats, and locomotor activity decreased during withdrawal; this decrease was more pronounced in the High-NP line. High-NP rats gained more weight during withdrawal than Low-NP rats. Escape attempts decreased during withdrawal in all groups, but overall females demonstrated more escape attempts than males. The other somatic signs of withdrawal were higher during withdrawal compared to baseline and more pronounced in females. CONCLUSIONS: Selection for nicotine preference affected nicotine intake, locomotion and weight, suggesting the heritability of these traits. However, despite differences in nicotine preference and intake, high-NP and low-NP rats showed similar withdrawal responses: escape attempts decreased and somatic signs increased. Withdrawal responses of females were more pronounced than males suggesting sex differences in the negative affect induced by nicotine withdrawal. The major finding of this novel analysis is showing that nicotine preference does not predict withdrawal symptoms. This finding, together with sex differences observed during withdrawal, may contribute to a better understanding of nicotine dependence and have translational value in developing more effective strategies for smoking cessation. PMID- 25687374 TI - Differential and additive suppressive effects of 5-HT3 (palonosetron)- and NK1 (netupitant)-receptor antagonists on cisplatin-induced vomiting and ERK1/2, PKA and PKC activation. AB - To better understand the anti-emetic profile of the 5-HT3 (palonosetron)- and the tachykinin NK1 (netupitant) -receptor antagonists, either alone or in combination, we evaluated the effects of palonosetron and/or netupitant pretreatment on cisplatin-evoked vomiting and changes in the phosphorylation of brainstem kinases such as the extracellular signal-regulated protein kinases 1 and 2 (ERK1/2), protein kinase C alpha/beta (PKCalpha/beta), and protein kinase A (PKA) in the least shrew. Our results demonstrate that cisplatin (10mg/kg, i.p.) causes emesis in the least shrew over 40h with respective peak early- and delayed phases occurring at 1 - 2 and 32 - 34h post-injection. During the early phase (0 16h post cisplatin), palonosetron (0.1mg/kg, s.c.) significantly protected shrews from vomiting with a near complete suppression of vomit frequency. Palonosetron also significantly protected shrews from vomiting during the delayed phase (27 - 40h post cisplatin), but the reduction in mean vomit frequency failed to achieve significance. On the other hand, netupitant (5mg/kg, i.p.) totally abolished vomiting during the delayed phase, and tended to suppress the mean vomit frequency during the acute phase. The combined treatment protected shrews almost completely from vomiting during both phases. Brainstem pERK1/2 levels were significantly elevated at all time-points except at 40h post-cisplatin administration. PKA phosphorylation tended to be elevated throughout the delayed phase, but a significant increase only occurred at 33h. Brainstem pPKCalpha/beta levels were enhanced during acute-phase with a significant elevation at 2h. Palonosetron, netupitant or their combination had no effect on elevated pERK1/2 levels during acute phase, but the combination reversed ERK1/2 phosphorylation at 33h post-cisplatin treatment. In addition, only the combined regimen prevented the cisplatin-induced PKCalpha/beta phosphorylation observed at the acute phase. On the other hand, palonosetron and netupitant, either alone or in combination, were effective in reducing the induced elevated pPKA levels during the delayed phase. These effects on cisplatin-related emetic signals downstream of 5-HT3- and NK1-receptors help us to better understand the intracellular basis of cisplatin induced vomiting. PMID- 25687375 TI - The treatment combination of vitamins E and C and astaxanthin prevents high-fat diet induced memory deficits in rats. AB - Cognitive function is impaired by imbalanced diet consumption. High-fat diet (HFD) induces oxidative stress and metabolic disorders, which results in neuronal damage and interferes with synaptic transmission and neurogenesis; hence, a decline in learning and memory. Antioxidants are believed to have positive effects on cognitive function. The objective of this study was to determine the relation between the chronic consumption of a HFD and antioxidants on passive avoidance learning (PAL) in male rats. Wistar rats were randomly assigned into the following five groups (N=6-8): Control group-consumed an ordinary diet; HFD group-received high-fat diets only; ANO group-received HFD plus antioxidants (vitamins C and E and astaxanthin (ASX)); RHFD group-received the restricted HFD (30% less than the HFD group); and RANO group-received restricted HFD plus antioxidants (30% less than the ANO group). Following 6months of controlled dietary condition as mentioned above, in each experimental group, the PAL was assessed using shuttle box apparatus. Our results showed that HFD caused a decrease in step through latency in the retention test (STLr) and increased the time spent in the dark compartment in the retention test (TDC) when compared to the control group. Antioxidant supplementation caused an increase in STLr and decrease in TDC when compared to the control group. Furthermore, RHFD and RANO had no significant effect on STLr and TDC compared with the control group. According to our results, HFD impairs PAL and the combination of vitamins C and E and astaxanthin improves PAL deficits in the HFD group. PMID- 25687376 TI - Assessment of a novel, full-thickness incisional biopsy model to restage rectal tumours after neoadjuvant chemoradiotherapy: results of an ex vivo pilot study. AB - BACKGROUND: There is currently no reliable means to restage rectal cancers after neoadjuvant chemoradiation. Recent histological evidence shows that the epicentre for residual cancer cells is focussed directly underneath any residual mucosal abnormality (RMA). This proof-of-concept study aimed to determine the utility of a novel, minimally invasive method of incisional biopsy as a restaging tool. A secondary aim was to compare its performance to clinical response assessment. METHODS: After surgical resection, 0.5 * 0.5 cm, full-thickness incisional biopsy was performed in 15 rectal cancers. Of these, 13 had RMA and 2 had mucosal cCR but a palpable intramural abnormality. In all patients, a full-thickness incisional biopsy was taken through the centre of these areas. The ypT stage of the incisional biopsy and the final total specimen were compared. Complete mucosal clinical response was deemed to have occurred when either no residual tumour or only a flat mucosal scar remained. RESULTS: Incisional biopsy correctly identified all patients that had been downstaged to ypT0; however, it also falsely identified 5 of 10 patients (50%) with yp residual disease as ypT0. Overall performance of incisional biopsy to detect residual cancer was 50% sensitivity, 100 % specificity, 100% PPV, and 50% NPV with an accuracy of 66%. A complete mucosal clinical response occurred in only one of five patients downstaged to ypT0 (20% sensitive). It also occurred in one patient, which was ultimately staged as ypT3. CONCLUSION: This prospective data demonstrates that incisional biopsy is not suitable as a stand-alone method to restage rectal cancer after CRT. Alternate or complementary means of restaging are needed. PMID- 25687377 TI - Assessing traumatic experiences in screening for PTSD in substance use disorder patients: what is the gain in addition to PTSD symptoms? AB - Traumatic experiences have been linked with substance use disorders (SUD) and may be an important factor in the perpetuation of SUD, even in the absence of posttraumatic stress disorder (PTSD) symptoms. The purpose of the current study was to examine the relationship between childhood trauma and substance use severity in 192 SUD inpatients. Childhood trauma was assessed using the Traumatic Experiences Checklist (TEC). With variables derived from this measure in addition to PTSD symptoms, two regression models were created with alcohol use or drug use severity as dependent variables. Alcohol severity was explained by PTSD symptoms as well as the age of trauma. Drug severity was explained solely by PTSD symptoms. The clinical value of assessing childhood trauma in determining the addiction severity appears to be limited in comparison with PTSD symptoms. PMID- 25687378 TI - CO oxidation catalyzed by neutral and anionic Cu20 clusters: relationship between charge and activity. AB - Reactions of CO and O2 on neutral and anionic Cu20 clusters have been investigated by spin-polarized density functional theory. Three reaction mechanisms of CO oxidation are explored: reactions with atomic oxygen (dissociated O2) as well as reactions with molecular oxygen, including Langmuir Hinshelwood (LH) and Eley-Rideal (ER) mechanisms. The adsorption energies, reaction pathways, and reaction barriers for CO oxidation are calculated systematically. The anionic Cu20(-) cluster can adsorb CO and O2 more strongly than the neutral counterpart due to the superatomic shell closing of 20 valence electrons which leaves one electron above the band gap. The activation of O2 molecule upon adsorption is crucial to determine the rate of CO oxidation. The CO oxidation proceeds efficiently on both Cu20 and Cu20(-) clusters, when O2 is pre adsorbed dissociatively. The ER mechanism has a lower reaction barrier than the LH mechanism on the neutral Cu20. In general, CO oxidation occurs more readily on the anionic Cu20(-) (effective reaction barriers 0.1-0.3 eV) than on the neutral Cu20 cluster (0.3-0.5 eV). Moreover, Cu20(-) exhibits enhanced binding for CO2. From the analysis of the reverse direction of CO oxidation, it is observed that the transition of CO2 to CO + O can occur on the Cu20(-) cluster, which demonstrates that Cu clusters may serve as good catalyst for CO2 chemistry. PMID- 25687379 TI - Prognostic value of ABO blood group in patients with renal cell carcinoma: single institution results from a large cohort. AB - OBJECTIVES: To evaluate the association between ABO blood group and prognosis in patients with renal cell carcinoma (RCC) undergoing surgery. MATERIALS AND METHODS: A review of the nephrectomy database of the Asan Medical Center identified 3,172 consecutive patients who underwent nephrectomy for RCC between 1997 and 2012. Patients were followed up for a median 60.2 months (interquartile range 33-102 months). Recurrence-free (RFS), cancer-specific (CSS), and overall survival (OS) were calculated by the Kaplan-Meier method and compared using the log-rank test. A Cox proportional hazards regression model was used to estimate the prognostic significance of each variable. RESULTS: Of these 3,172 patients, 915 (28.8 %), 1,057 (33.7 %), 860 (26.7 %) and 340 (10.8 %) were blood types O, A, B, and AB, respectively. ABO blood group was not associated with age, sex, operation method, American Society of Anesthesiologists physical status classification, histologic subtype, or pathological TNM stage. The 5-year OS rates in patients with blood types O, A, B, and AB were 86.0, 86.8, 86.6, and 88.6 %, respectively, and the 10-year OS rates were 78.7, 78.6, 79.1, and 76.9 %, respectively (P = 0.990). ABO blood group was not significantly associated with RFS (P = 0.921) or CSS (P = 0.808). Univariable and multivariable analyses showed that ABO blood group was not a significant prognostic factor of RFS, CSS, or OS. CONCLUSIONS: Our study found that ABO blood group is not associated with survival outcomes and is not a prognostic factor in patients who underwent surgery for RCC. PMID- 25687380 TI - Early detection of colorectal cancer: from conventional methods to novel biomarkers. AB - PURPOSE: Colorectal cancer (CRC) is one of the major health problems worldwide and is often diagnosed at late stage. There is growing body of evidence in early detection of this disease with novel screening modalities to reduce compliance and increase specificity of available methods. The aim of current review is to give an overview on currently available screening methods (e.g., fecal occult blood testing (FOBT), flexible sigmoidoscopy, and colonoscopy), with their own merits and disadvantages, and new genetic/epigenetic/protein markers, as novel screening modalities. RESULT: There are several serum and fecal biomarkers that can predict CRC and polyps. Overall sensitivities for detection by fecal DNA markers ranged from 53 to 87%, while a panel of serum protein markers provides a sensitivity/specificity up to 85% for CRC. In particular, DNA methylation markers (e.g., SEPT9, SFRP2, and ALX4), circulating microRNAs (e.g., microRNA21), SNPs in microRNAs binding site (e.g., rs4596 located within a target region of the predicted miR-518a-5p and miR-527), protein markers (e.g., carcinoembryonic antigen, N-methyltransferase), or microsatellites instability in tumors with deficient mismatch repair of some genes are among the most interesting and promising biomarkers. CONCLUSION: Increasing evidence supports the use of combined fecal and serum biomarkers with sigmoidoscopy and colonoscopy screening in order to maximize the benefits and reduce the number of false-positive tests and patients undergoing invasive methods, which in turn could overcome the limitations of the current screening methods for early detection of CRC and adenomas. PMID- 25687381 TI - Hypoxia-induced nitric oxide release by luminal cells stimulates proliferation and uPA secretion of myoepithelial cells in a bicellular murine mammary tumor. AB - INTRODUCTION: LM38 murine mammary adenocarcinoma model is formed by LM38-LP (myoepithelial and luminal), LM38-HP (luminal) and LM38-D2 (myoepithelial) cell lines. In a previous work, we had shown that LM38-HP and LM38-D2 cell lines are less malignant than the bicellular LM38-LP cell line. PURPOSE: To study the role of nitric oxide (NO) as one of the mediators of functional interactions between malignant luminal and myoepithelial cells. METHODS AND RESULTS: Using immunohistochemistry, in vivo iNOS expression was only detected in the luminal cells of bicellular LM38-LP and most cells of LM38-HP tumors. In cobalt-induced pseudohypoxia, LM38-LP and LM38-HP cell lines significantly increased HIF-1alpha and iNOS expression (Western blotting) and therefore NO production (Griess method). This increase was inhibited by the iNOS inhibitor 1400 W. On the other side, NO was not detectable in LM38-D2 cells either in basal or in pseudohypoxia. In addition, pseudohypoxia increased urokinase-type plasminogen activator (uPA) secretion by LM38-LP and LM38-HP cells and migration in the LM38-LP cell line, without modulating these properties in LM38-D2 cells (radial caseinolysis). The NO donor DETA/NONOate (500 MUM) was able to increase uPA secretion and in vitro growth of LM38-D2. In agreement, 1400 W prevented in vivo growth of the myoepithelial LM38-D2 cells. CONCLUSIONS: Hypoxia leads to an enhanced NO production by the luminal component, through HIF-1alpha and iNOS, which can stimulate myoepithelial cell proliferation and uPA secretion. In these new conditions, myoepithelial cells might act as an invasive forefront generating gaps that could help luminal cells to escape from the primary tumor. PMID- 25687382 TI - Long-term prognosis of idiopathic nephrotic syndrome in children. AB - BACKGROUND: To investigate the demographic, clinical and laboratory data of the children with idiopathic nephrotic syndrome (INS), and to determine prognostic factors that affect the clinical outcome of the patients. METHODS: Medical charts of 372 patients diagnosed to have INS and followed up at least 5 years between January 1990 and December 2008 were evaluated, respectively. After initial demographic, clinical and laboratory findings of the patients were documented, therapeutic protocols, prognosis and prognostic factors were investigated. RESULTS: 299 of the patients (80.4%) were steroid responsive and 73 (19.6%) were not. Focal segmental glomerulosclerosis (FSGS) was observed in 57%, minimal change disease (MCD) in 20.6% and diffuse mesengial proliferation in 21.9% renal biopsy materials. Steroid sensitivity was higher in patients with MCD and under the age of five years. Resistance to steroids was higher in children with FSGS. Complete remission was achieved in 96% of patients who were sensitive to steroids and in 46.6% who were resistant. 15% of patients who were steroid resistant developed chronic kidney disease (CKD). CONCLUSION: Intercurrent infections and response to steroid therapy are the most important factors affecting the prognosis of the disease. PMID- 25687383 TI - Urokinase can reduce heparin dose in patients with hypercoagulable states during hemodialysis. AB - Heparin is routinely administered at high doses during hemodialysis to patients with hypercoagulable states. This study aimed to evaluate the safety and efficacy of low-dose heparin in combination with urokinase in this patient population. The presence of a hypercoagulable state was confirmed by thromboelastography. Doses of heparin and urokinase were adjusted based on activated partial thromboplastin time (APTT). Clotting in the extracorporeal circuit was evaluated by a semi quantitative index. Prothrombin time (PT) and APTT were measured before, during and after dialysis. Kt/V(urea) was used to assess the efficacy of dialysis. D dimer levels were measured 2 h after the start of hemodialysis. Hemodialysis data with heparin administered alone prior to dialysis were used as control in the present study. With urokinase treatment, the initial dose of heparin was reduced by 45.0 +/- 11.4% during hemodialysis and the maintenance dose by 46.8 +/- 12.8% compared with heparin alone. No side effects due to urokinase were observed. Bleeding events were rare. Post-dialysis PT (12.99 +/- 1.41 vs. 15.22 +/- 3.12 s, p = 0.02) and APTT (97.75 +/- 43.62 vs. 140.16 +/- 30.12 s, p = 0.002) with urokinase plus heparin were significantly shorter than with heparin alone. Finally, during dialysis, D-dimer levels were significantly higher with heparin alone (0.21 +/- 0.11 mg/L) than with heparin and urokinase (0.169 +/- 0.122 mg/L, p = 0.017). In conclusion, urokinase significantly reduced the dose of heparin required during hemodialysis without any side effects in patients with hypercoagulable states during hemodialysis. PMID- 25687384 TI - Plasma endothelin-1 level, measured glomerular filtration rate and effective renal plasma flow in diabetic nephropathy. AB - BACKGROUND: Endothelin-1 (ET-1) is potent vasoconstrictor peptide which is able to contribute to the functional and structural renal changes. The aim of this study was to investigate the relationship between plasma concentration of ET-1 and indices of renal function in patients with diabetic nephropathy. METHODS: We measured plasma ET-1 levels in 99 patients with type 2 diabetes, divided into two groups according to the values of their glomerular filtration rate (GFR): group I (GFR >= 60 mL/min/1.73 m(2); n = 50), group II (GFR >= 60 mL/min/1.73 m(2), n = 49), and the control group (n = 30) with clinically healthy subjects who were matched by age and sex. GFR and effective renal plasma flow (ERPF) were measured by the radioisotopic clearance. Other renal function parameters, such as serum concentrations of cystatin C, urea, creatinine, uric acid, 24-h albuminuria and proteinuria were additionally measured. RESULTS: There were significant differences in plasma concentration of ET-1 among groups I, II and the control group (1.45 vs. 2.40 vs. 0.80 pg/mL, p < 0.001). The correlation between ET-1 and mGFR (r = -0.52, p < 0.001), ERPF (r = -0.42, p < 0.001), albuminuria and proteinuria (r = 0.36, p < 0.001; r = 0.48, p < 0.001) and cystatin C (r = 0.42, p < 0.001) was significant. In multiple regression analyses, only plasma concentration of ET-1 (p < 0.001) and duration of hypertension (p < 0.05) were independently and significantly associated with mGFR. CONCLUSION: A higher plasma concentration of ET-1 is independently associated with a decreased value of GFR in patients with diabetic nephropathy. PMID- 25687385 TI - The effect of dexmedetomidine against oxidative and tubular damage induced by renal ischemia reperfusion in rats. AB - Dexmedetomidine (dex) is a potent, highly selective and specific alpha2 adrenoreceptor agonist. This experimental study was designed to investigate protective and therapeutic effect of two different doses of dex, on kidney damage induced by ischemia-reperfusion (I/R) in rats. Male Sprague-Dawley rats were divided into four groups, each including 10 animals: control group, ischemia reperfusion (I/R) group; treated groups with 10 MUg/kg of dex and 100 MUg/kg of dex. After removing right kidney of the rats, the left kidney has performed ischemia during 40 min and reperfusion in the following 3 h. The histopathological findings, and also tissue superoxide dismutase (SOD) and catalase (CAT) enzyme activity, malondialdehyde (MDA), glutathione (GSH), serum blood urea nitrogen (BUN), creatinine (Cre) and tumor necrosis factor-alpha (TNF alpha) levels were determined. In the I/R group, compared to the control group, levels of BUN, Cre and kidney tissue MDA have increased significantly, SOD, CAT enzyme activity and glutathione levels have decreased significantly. In the dex10 group, compared to the I/R group, levels of Cre and TNF-alpha have decreased significantly, while the SOD activity has increased significantly. In the dex100 group, compared to the I/R group, levels of BUN, Cre have decreased significantly, while the SOD activity has increased significantly. In the I/R group, there was also extensive tubular necrosis, glomerular damage in the histological evaluation. Dex ameliorated these histological damages in different amounts in two treatment groups. In this study, the protective effects of dex against renal I/R injury have been evaluated by two different amount of doses. PMID- 25687386 TI - The relationship between brain-derived neurotrophic factor levels, oxidative and nitrosative stress and depressive symptoms: a study on peritoneal dialysis. AB - BACKGROUND: Depression is one of the most commonly encountered psychiatric problems in peritoneal dialysis (PD) patients. Our aim was to investigate the associations between oxidative and nitrosative stress (O&NS) and brain-derived neurotrophic factor (BDNF) in PD patients with elevated depressive symptoms (EDS). METHODS: Eighty-three patients with PD and 84 healthy controls were enrolled in this study. In PD patients, two subgroups were formed: 28 with and 55 without EDS. EDS were defined as a Beck Depression Inventory (BDI) score >=17 in patients. Serum malondialdehyde (MDA) erythrocyte, glutathione (GSH) levels measured spectrophotometrically. Serum superoxide dismutase (SOD) activity, nitric oxide (NO) and BDNF levels were determined by ELISA. RESULTS: While MDA and NO levels were higher, levels of SOD, GSH and BDNF were lower in PD patients compared to controls (p < 0.001). The patients with EDS had higher levels of MDA and lower levels of BDNF as compared to those without EDS (p < 0.005). In linear regression analysis, the BDNF levels were dependently associated with SOD levels in PD patients (B: 0.274, p: 0.043). In addition, while a negative correlation existed between BDI scores with BDNF levels (r = -0.312, p = 0.004), a positive correlation was present between BDI scores and MDA levels (r = 0.320, p = 0.005) in PD patients. CONCLUSION: Our results suggest the presence of high O&NS and low antioxidant capacity accompanied with decreased levels of BDNF in PD patients, especially those with EDS were deeper. These may represent the risk factors for cellular injury and might reveal part of the mechanism causing the depressive state in PD patients. PMID- 25687387 TI - Attachment style predict compliance, quality of life and renal function in adult patients after kidney transplant: preliminary results. AB - AIM: Aim of this study was to evaluate the association between attachment style, compliance, quality of life and renal function in adult patients after kidney transplantation. METHODS: A total of 43 adult patients who received a kidney transplant more than 3 months before were enrolled and were asked to complete two Self-Report questionnaires: Attachment Style Questionnaire (ASQ-40) and Short Form Health Survey (SF-36). Also compliance was measured using appropriate questions. RESULTS: Linear regression analysis showed associations between the confidence in relationships (ASQ-40) and compliance [beta = -0.37; B = -0.02; t(41) = -2.51; p = 0.02]; aspects of anxious attachment style (ASQ-40) and creatinine levels [beta = 0.3; B = 0.13; t(41) = 2.03; p = 0.04]; aspects of avoidant attachment style (ASQ-40) and compliance [beta = -0.37; B = -3.15; t(41) = -2.35; p = 0.02]. Patients who exhibited avoidant attachment had a significantly better perception of their own general health than patients with anxious [F(2,37) = 6.8; p < 0.05] or secure attachment; however, they had a worse perception regarding role limitations due to emotional problems, compared to patients with anxious attachment [F(2,37) = 6.4; p < 0.05]. DISCUSSION: The results of this study suggest that the evaluation of the attachment style in adult kidney transplant patients can contribute to plan a goal-directed psychological support program for these patients, in order to increase their compliance. The association between aspects of anxious attachment style and creatinine level needs more investigations. PMID- 25687388 TI - Laparoscopic-assisted percutaneous nephrolithotomy in malrotated and ectopic pelvic kidneys: calyceal or direct pelvic access? PMID- 25687389 TI - Inhibition of retinoic acid synthesis disrupts spermatogenesis and fecundity in zebrafish. AB - Timing of germ cell entry into meiosis is sexually dimorphic in mammals. However it was recently shown that germ cells initiate meiosis at the same time in male and female zebrafish. Retinoic acid (RA) has been shown to be critical for mammalian spermatogenesis. Inhibition of RA synthesis by WIN 18,446 has been reported to inhibit spermatogenesis in a wide variety of animals including humans and was once used as a contraceptive in humans. In this study we explored the role of RA in zebrafish spermatogenesis. In silico analysis with Internal coordinate mechanics docking software showed that WIN 18,446 can bind to the rat, human and zebrafish Aldh1a2 catalytic domain with equivalent potency. RA exposure resulted in up-regulation of the RA metabolizing enzyme genes cyp26a1, cyp26b1 and cyp26c1 in vitro and in vivo. Exposure to WIN 18,446 resulted in down regulation of Aldh1a2, cyp26a1 and cyp26b1 in vivo. WIN 18,446 was effective in disrupting spermatogenesis and fecundity in zebrafish but the reduction in sperm count and fecundity was only observed when zebrafish were maintained on a strict Artemia nauplii diet which is known to contain low levels of vitamin A. This study shows that RA is involved in spermatogenesis as well as oocyte development in zebrafish. As the zebrafish Aldh1a2 structure and function is similar to the mammalian counterpart, Aldh1a2 inhibitor screening using zebrafish as a model system may be beneficial in the discovery and development of new and safe contraceptives for humans. PMID- 25687390 TI - Improving operating room schedules. AB - Operating rooms (ORs) in US hospitals are costly to staff, generate about 70 % of a hospital's revenues, and operate at a staffed-capacity utilization of 60-70 %. Many hospitals allocate blocks of OR time to individual or groups of surgeons as guaranteed allocation, who book surgeries one at a time in their blocks. The booking procedure frequently results in unused time between surgeries. Realizing that this presents an opportunity to improve OR utilization, hospitals manually reschedule surgery start times one or two days before each day of surgical operations. The purpose of rescheduling is to decrease OR staffing costs, which are determined by the number of concurrently staffed ORs. We formulate the rescheduling problem as a variant of the bin-packing problem with interrelated items, which are the surgeries performed by the same surgeon. We develop a lower bound (LB) construction algorithm and prove that the LB is at least (2/3) of the optimal staffing cost. A key feature of our approach is that we allow hospitals to have two shift lengths. Our analytical results form the basis of a branch-and bound algorithm, which we test on data obtained from three hospitals. Experiments show that rescheduling saves significant staffing costs. PMID- 25687391 TI - The Eisenmenger malformation: a morphologic study. AB - We studied 11 autopsied cases of the Eisenmenger malformation, comparing the findings with 11 hearts with intact ventricular septal structures, and nine hearts having perimembranous ventricular septal defects in the absence of aortic overriding. We found variable lengths for the subpulmonary infundibulum in the hearts with Eisenmenger defects. It was well developed in three hearts, of intermediate length in seven, and very short in one of the specimens. The muscular outlet septum was also of variable length compared with the free standing subpulmonary infundibular sleeve. Except for one, all hearts had fibrous continuity between the aortic and tricuspid valvar leaflets, such that the ventricular septal defect was then perimembranous. In the remaining case, there was a completely subaortic muscular infundibulum, with the ventricular septal defect showing only muscular borders. The medial papillary muscle was absent in the majority of cases, but was well formed in three hearts, all with relatively short muscular outlet septums. We identified mild, intermediate, and severe degrees of rightward rotation of the aortic valve, and these findings correlated with the extent of aortic valvar overriding. In nine of the 11 hearts, the ventriculo-arterial connections were concordant, but there was double-outlet from the right ventricle in the other two specimens. Based on our anatomic and morphometric observations, we conclude that the hearts we have defined as having Eisenmenger defects show marked individual variation in their specific phenotypic anatomy. PMID- 25687392 TI - Characterization and expression analysis of Toll-like receptor 2 gene in large yellow croaker, Larimichthys crocea. AB - Toll-like receptor 2 (TLR2) plays an important role in innate immune responses. Here we describe the isolation and characterization of the full-length cDNA sequence of toll-like receptor 2 in large yellow croaker Larimichthys crocea (LcTLR2). The LcTLR2 cDNA contains a 5'-terminal untranslated region (5'-UTR) of 135 bp, an open reading frame (ORF) of 2478 bp encoding a polypeptide of 825 amino acid residues and a 3'-UTR of 50 bp. Subcellular localization analysis suggested that the LcTLR2-pEGFP was mainly expressed in cytoplasm. Quantitative real-time reverse transcription PCR (qRT-PCR) analysis revealed a broad expression of LcTLR2 in most examined tissues, with the most predominant expression in blood, followed by spleen, and the weakest expression in stomach. The expression levels of LcTLR2 after injection with Vibrio parahaemolyticus, Lipopolysaccharides (LPS) and poly inosinic:cytidylic (polyI:C) were investigated in spleen, head-kidney and liver. Our results showed that LcTLR2 transcripts increased significantly after all the three immune challenges (p < 0.05). However, compared with polyI:C and LPS, higher expression levels of LcTLR2 were induced in all examined tissues after V. parahaemolyticus stimulation. In addition, the expression levels of LcTLR2 after flagellin, polyI:C, peptidoglycan (PGN) and LPS challenge in LCK were investigated, our findings showed that high LcTLR2 transcripts were induced after flagellin and PGN stimulation, suggesting that LcTLR2 might play a vital role in fish defense against bacterial infection. Furthermore, compared with LPS, flagellin and peptidoglycan might play an important role in LcTLR2 induction in large yellow croaker. PMID- 25687393 TI - Systemic and mucosal immune response of rainbow trout to immunization with an attenuated Flavobacterium psychrophilum vaccine strain by different routes. AB - Teleosts possess three immunoglobulin (Ig) heavy chain isotypes viz., IgM, IgT and IgD and all three isotypes are reported in rainbow trout. The expression of these Ig isotypes in response to different immunization routes was investigated and results provide a better understanding of the role these Igs in different tissues. Rainbow trout (Oncorhynchus mykiss) were immunized with an attenuated Flavobacterium psychrophilum strain, 259-93-B.17 grown under iron limiting conditions, by intraperitoneal, anal intubation and immersion routes. Serum, gill mucus, skin mucus and intestinal mucus samples were collected at 0, 3, 7, 14, 28, 42 and 56 days post immunization by sacrificing four fish from each treatment group and the unimmunized control group, and the IgM levels were estimated by an enzyme linked immunosorbent assay (ELISA). In addition, blood, gill, skin and intestinal tissue samples were collected for Ig gene expression studies. The secretory IgM, IgD and IgT gene expression levels in these tissues were estimated by reverse transcription quantitative real time PCR (RT-qPCR). Levels of IgM in serum, gill and skin mucus increased significantly by 28 days after immunization in the intraperitoneally immunized group, while no significant increase in IgM level was observed in fish groups immunized by other routes. Secretory IgD and IgT expression levels were significantly upregulated in gills of fish immunized by the immersion route. Similarly, secretory IgT and IgD were upregulated in intestines of fish immunized by anal intubation route. The results confirm mucosal association of IgT and suggest that IgD may also be specialized in mucosal immunity and contribute to immediate protection to the fish at mucosal surfaces. PMID- 25687394 TI - Immunotoxic effects of perfluorooctane sulfonate and di(2-ethylhexyl) phthalate on the marine fish Oryzias melastigma. AB - Perfluorooctane sulfonate (PFOS) and di(2-ethylhexyl) phthalate (DEHP) have both been reported to induce adverse effects including immunotoxicity. Despite the widespread presence of these two chemicals in estuaries and seawater, their health effects on marine fish have received little attention. Oryzias melastigma is a potential marine fish model for immunological studies. In the present study, immune-related genes in O. melastigma were enriched at the transcriptome level. Three-month-old fish were exposed to PFOS and DEHP (single or combined) for one week. The liver index-hepatosomatic index (HSI) of the fish was higher in the PFOS-exposed group and combined group than in the control group. This result indicates that PFOS might lead to liver toxicity. The mRNA level of interleukin-1 beta (IL1beta) was upregulated after exposure. For catalase (CAT), glutathione peroxidase (GPx) and cluster of differentiation 3 (CD3), single exposure did not affect mRNA levels, but the combined exposure did significantly alter the expression of these genes. In all, our study provides a useful reference for immunotoxicological studies with O. melastigma; it also highlights the importance of assessing the combined effects of pollutant mixtures when determining the risk to aquatic organisms. PMID- 25687395 TI - Healthcare Coordination and Transition for Individuals with Genetic Conditions. AB - This study aimed to examine insurance coverage, use of the healthcare system, satisfaction with care, transition from pediatric to adult healthcare services, and social and emotional support for individuals with genetic conditions. In June 2013, the National Genetics Education and Consumer Network surveyed US individuals with genetic conditions about their healthcare experiences. Chi square statistics were used to compare use of the healthcare system, satisfaction, social and emotional support of children (0-17 years) and adults (18 + years) with genetic conditions. There were 1895 valid responses (53.0 % individuals with genetic conditions, 47.0 % parents of these individuals). The findings suggest several potential areas to impact the quality of care received by this population. The majority of respondents reported that they had: (1) more than one health professional they considered to be their personal doctor or nurse (70.5 % children; 57.8 % adults); (2) providers that listened carefully to their needs always or most of the time (82.2 % children; 83.5 % adults); and (3) providers that usually or always involved them as partners in their care (78.4 % children; 66.6 % adults). However, several significant differences around care and support received between children versus adults and areas of need were reported. Most persons surveyed received care from a system of providers that was self- or parent- coordinated and lacked sufficient social and emotional support. Data from this study will inform practice and identifies further research needed to improve care provided to individuals with genetic conditions who require a combination of specialty and primary care. PMID- 25687396 TI - [Achilles tendon xanthoma imaging on ultrasound and magnetic resonance imaging]. AB - The Achilles tendon xanthoma is a rare disease and has a high association with primary hyperlipidemia. An early diagnosis is essential to start treatment and change the disease course. Imaging exams can enhance diagnosis. This study reports the case of a 60-year-old man having painless nodules on his elbows and Achilles tendons without typical gout crisis, followed in the microcrystalline disease clinic of Unifesp for diagnostic workup. Laboratory tests obtained showed dyslipidemia. The ultrasound (US) showed a diffuse Achilles tendon thickening with hypoechoic areas. Magnetic resonance imaging (MRI) showed a diffuse tendon thickening with intermediate signal areas, and a reticulate pattern within. Imaging studies showed relevant aspects to diagnose a xanthoma, thus helping in the differential diagnosis. PMID- 25687397 TI - Influence of climacteric on sexual dysfunctions in women with rheumatic diseases. PMID- 25687398 TI - Thymidylate synthase genetic polymorphism and plasma total homocysteine level in a group of Turkish patients with rheumatoid arthritis: relationship with disease activity and methotrexate toxicity. AB - BACKGROUND: The polymorphism of thymidylate synthase (TS) gene and homocysteine are reported to have a relationship to methotrexate (MTX) metabolism, with conflicting results. The aim of this study was to determine homocysteine levels and the frequency of TS gene triple repeat (TS3R) and double repeat (TS2R) polymorphisms in a group of Turkish RA patients and evaluate its association with MTX toxicity and disease activity. METHODS: Sixty-four patients with RA and 31 control subjects with a mean age of 48.7 +/- 12.5 and 46.2 +/- 13.4 years, were enrolled to the study. Demographic characteristics were obtained and number of patients with MTX-related adverse affects, were recorded in the patient group. The homocysteine levels and TS2R/TS3R polymorphisms of the TS gene were analyzed and the distribution of genotypes according to MTX toxicity and disease activity, were determined. RESULTS: The demographic properties were similar between the patient and control subjects. Folic acid supplementation with a mean dose of 5mg folic acid/week, was present in all patients. Thirty-six of the 64 patients showed adverse effects to MTX treatment. The frequency of TS2R and TS3R polymorphisms were found to be similar in the patient and control groups. TS2R and TS3R gene polymorphisms were found to be similar in patients with and without MTX-related adverse events. The mean homocysteine level was also similar in patients with and without TS gene polymorphism, but was found to be higher (12.45MUmol/L vs 10.7MUmol/L) in patients with MTX-related side effects than in patients without side effects. The mean level of homocysteine was correlated with levels of ESR in the patient group. CONCLUSIONS: In conclusion, homocysteine levels might effect the disease activity and toxicity of MTX but 2R and 3R polymorphisms in the TS gene, were not related with MTX-related toxicity in RA patients receiving folate supplementation. Further studies are needed to illuminate the polymorphisms in other enzymes that might be responsible from the MTX toxicity in patients suffering from RA. PMID- 25687399 TI - Misfit accommodation mechanism at the heterointerface between diamond and cubic boron nitride. AB - Diamond and cubic boron nitride (c-BN) are the top two hardest materials on the Earth. Clarifying how the two seemingly incompressible materials can actually join represents one of the most challenging issues in materials science. Here we apply the temperature gradient method to grow the c-BN single crystals on diamond and report a successful epitaxial growth. By transmission electron microscopy, we reveal a novel misfit accommodation mechanism for a {111} diamond/c-BN heterointerface, that is, lattice misfit can be accommodated by continuous stacking fault networks, which are connected by periodically arranged hexagonal dislocation loops. The loops are found to comprise six 60 degrees Shockley partial dislocations. Atomically, the carbon in diamond bonds directly to boron in c-BN at the interface, which electronically induces a two-dimensional electron gas and a quasi-1D electrical conductivity. Our findings point to the existence of a novel misfit accommodation mechanism associated with the superhard materials. PMID- 25687400 TI - Core-shell superparamagnetic Fe3O4@beta-CD composites for host-guest adsorption of polychlorinated biphenyls (PCBs). AB - The effective recognition and enrichment of trace polychlorinated biphenyls (PCBs) in the environment are currently challenging issues due to human health concerns. In this paper, a surface absorptive layer coating superparamagnetic Fe3O4 nanoparticles for PCBs enrichment were prepared. This protocol involved the synthesis of Fe3O4 particles through a solvothermal reaction and the covering of a silica layer bonded beta-cyclodextrin (beta-CD) over Fe3O4 via a sol-gel process to construct core-shell Fe3O4@beta-CD composites. beta-CD was linked covalently to Fe3O4 nanoparticles to generate the binding sites, enhancing the stability of Fe3O4 nanoparticles in water. Meanwhile, superparamagnetic Fe3O4 core could be rapidly separated from matrix to simplify time-consuming washing extraction. The adsorption capacity of Fe3O4@beta-CD composites to PCB28 and PCB52 in aqueous solutions was investigated. To estimate the theoretical binding site number of Fe3O4@beta-CD, the obtained binding data were replotted according to Scatchard equation. The host-guest interaction between beta-CD and PCBs were further examined with density functional theory (DFT) calculations. It provides theoretical evidence of beta-CD as host molecule has a higher binding amount towards PCB-28 than PCB-52 on the basis of their optimized geometries and calculated complexation energies. The nanomaterial reported herein is an ideal candidate for various applications, including the recognition and removal of environmentally deleterious substances. PMID- 25687402 TI - Towards explaining the health impacts of residential energy efficiency interventions - A realist review. Part 1: Pathways. AB - This paper is Part 1 of a realist review that tries to explain the impacts of residential energy efficiency interventions (REEIs) on householder health. According to recent systematic reviews residential energy efficiency interventions may benefit health. It is argued that home energy improvement are complex interventions and that a better understanding of the latent mechanisms and contextual issues that may shape the outcome of interventions is needed for effective intervention design. This realist review synthesises the results of 28 energy efficiency improvement programmes. This first part provides a review of the explanatory factors of the three key pathways, namely warmth in the home, affordability of fuel and psycho-social factors, and the pitfall of inadequate indoor air quality. The review revealed that REEIs improved winter warmth and lowered relative humidity with benefits for cardiovascular and respiratory health. In addition, residential energy efficiency improvements consolidated the meaning of the home as a safe haven, strengthened the householder's perceived autonomy and enhanced social status. Although satisfaction with the home proved to be an important explanation for positive mental health outcomes, financial considerations seemed to have played a secondary role. Evidence for negative impacts was rare but the risk should not be dismissed. Comprehensive refurbishments were not necessarily more effective than thermal retrofits or upgrades. A common protocol for the quantitative and qualitative evaluation of interventions would facilitate the synthesis of future studies. Householder and contextual influences are addressed in Part 2. PMID- 25687401 TI - A review of rectal toxicity following permanent low dose-rate prostate brachytherapy and the potential value of biodegradable rectal spacers. AB - Permanent radioactive seed implantation provides highly effective treatment for prostate cancer that typically includes multidisciplinary collaboration between urologists and radiation oncologists. Low dose-rate (LDR) prostate brachytherapy offers excellent tumor control rates and has equivalent rates of rectal toxicity when compared with external beam radiotherapy. Owing to its proximity to the anterior rectal wall, a small portion of the rectum is often exposed to high doses of ionizing radiation from this procedure. Although rare, some patients develop transfusion-dependent rectal bleeding, ulcers or fistulas. These complications occasionally require permanent colostomy and thus can significantly impact a patient's quality of life. Aside from proper technique, a promising strategy has emerged that can help avoid these complications. By injecting biodegradable materials behind Denonviller's fascia, brachytherpists can increase the distance between the rectum and the radioactive sources to significantly decrease the rectal dose. This review summarizes the progress in this area and its applicability for use in combination with permanent LDR brachytherapy. PMID- 25687405 TI - Stem cell transplantation reverses chemotherapy-induced cognitive dysfunction. AB - The frequent use of chemotherapy to combat a range of malignancies can elicit severe cognitive dysfunction often referred to as "chemobrain," a condition that can persist long after the cessation of treatment in as many as 75% of survivors. Although cognitive health is a critical determinant of therapeutic outcome, chemobrain remains an unmet medical need that adversely affects quality of life in pediatric and adult cancer survivors. Using a rodent model of chemobrain, we showed that chronic cyclophosphamide treatment induced significant performance based decrements on behavioral tasks designed to interrogate hippocampal and cortical function. Intrahippocampal transplantation of human neural stem cells resolved all cognitive impairments when animals were tested 1 month after the cessation of chemotherapy. In transplanted animals, grafted cells survived (8%) and differentiated along neuronal and astroglial lineages, where improved cognition was associated with reduced neuroinflammation and enhanced host dendritic arborization. Stem cell transplantation significantly reduced the number of activated microglia after cyclophosphamide treatment in the brain. Granule and pyramidal cell neurons within the dentate gyrus and CA1 subfields of the hippocampus exhibited significant reductions in dendritic complexity, spine density, and immature and mature spine types following chemotherapy, adverse effects that were eradicated by stem cell transplantation. Our findings provide the first evidence that cranial transplantation of stem cells can reverse the deleterious effects of chemobrain, through a trophic support mechanism involving the attenuation of neuroinflammation and the preservation host neuronal architecture. PMID- 25687406 TI - Suppressing TGFbeta signaling in regenerating epithelia in an inflammatory microenvironment is sufficient to cause invasive intestinal cancer. AB - Genetic alterations in the TGFbeta signaling pathway in combination with oncogenic alterations lead to cancer development in the intestines. However, the mechanisms of TGFbeta signaling suppression in malignant progression of intestinal tumors have not yet been fully understood. We have examined Apc(Delta716) Tgfbr2(DeltaIEC) compound mutant mice that carry mutations in Apc and Tgfbr2 genes in the intestinal epithelial cells. We found inflammatory microenvironment only in the invasive intestinal adenocarcinomas but not in noninvasive benign polyps of the same mice. We thus treated simple Tgfbr2(DeltaIEC) mice with dextran sodium sulfate (DSS) that causes ulcerative colitis. Importantly, these Tgfbr2(DeltaIEC) mice developed invasive colon cancer associated with chronic inflammation. We also found that TGFbeta signaling is suppressed in human colitis-associated colon cancer cells. In the mouse invasive tumors, macrophages infiltrated and expressed MT1-MMP, causing MMP2 activation. These results suggest that inflammatory microenvironment contributes to submucosal invasion of TGFbeta signaling-repressed epithelial cells through activation of MMP2. We further found that regeneration was impaired in Tgfbr2(DeltaIEC) mice for intestinal mucosa damaged by DSS treatment or X-ray irradiation, resulting in the expansion of undifferentiated epithelial cell population. Moreover, organoids of intestinal epithelial cells cultured from irradiated Tgfbr2(DeltaIEC) mice formed "long crypts" in Matrigel, suggesting acquisition of an invasive phenotype into the extracellular matrix. These results, taken together, indicate that a simple genetic alteration in the TGFbeta signaling pathway in the inflamed and regenerating intestinal mucosa can cause invasive intestinal tumors. Such a mechanism may play a role in the colon carcinogenesis associated with inflammatory bowel disease in humans. PMID- 25687407 TI - Impact of childlessness on life and attitudes towards continuation of medically assisted reproduction and/or adoption. AB - Infertility and fertility treatment have the potential to impact and disrupt a couple's overall life. In order to study the associations between the impact of childlessness on one's life, and men and women's attitudes towards fertility treatment continuation and/or adoption, we analysed data from a one-year follow up questionnaire in a prospective, longitudinal cohort study of consecutive couples initiating fertility treatment in Denmark. The study comprised 302 couples with no children at baseline and no joint children at one-year follow-up. In total, 71.9% of women and 72.5% of men reported that they wished to continue fertility treatment, while 20.2% of women and 19.2% of men reported that they wished to pursue adoption. The attitudes of nearly 8 in 10 couples were congruent towards further fertility treatments, while nearly 7 in 10 couples were congruent in their attitudes to pursuing adoption. Significantly more men who reported a lower impact of childlessness on their daily life wished to continue fertility treatment, compared with those reporting that childlessness had a greater impact on their life. Among women, significantly more were undecided about whether or not to pursue adoption when reporting a greater impact of childlessness on social life, compared with those reporting a lower impact of their childlessness. PMID- 25687408 TI - Occupational risk factors and frequency of sex chromosome disomy. AB - Possible reproductive toxicants such as occupational factors may affect the normal disjunction of chromosomes during meiosis, thereby altering the number of chromosomes in sperm nuclei. The purpose of the present analysis was to determine whether exposure to occupational factors existing in a contemporary work setting affected sperm aneuploidy. The study population consisted of 212 men who attended the infertility clinic for diagnostic purposes. The men either had a normal semen concentration of 20-300 million/ml or slight oligozoospermia (semen concentration of 15-20 million/ml) ( WHO 1999 ). All participants were interviewed and provided a semen sample. Sperm aneuploidy was assessed using multicolor FISH. After adjustment for potential confounders, positive associations were found between disomy XY18, 18, and sex chromosome disomy and exposure to mechanical vibrations (p = 0.03, p = 0.04, p = 0.03, respectively). In addition, sitting for more than 6 h at work increased X and Y disomy (p = 0.03, p = 0.04, respectively). To the best of our knowledge, this is the first study to show a significant effect of occupational factors on sperm aneuploidy. As such, the results need to be confirmed in larger studies. PMID- 25687409 TI - Mesoporous titania-vertical nanorod films with interfacial engineering for high performance dye-sensitized solar cells. AB - Working electrode (WE) fabrication offers significant challenges in terms of achieving high-efficiency dye-sensitized solar cells (DSCs). We have combined the beneficial effects of vertical nanorods grown on conducting glass substrate for charge transport and mesoporous particles for dye loading and have achieved a high photoconversion efficiency of (eta) > 11% with an internal quantum efficiency of ~93% in electrode films of thickness ~7 +/- 0.5 MUm. Controlling the interface between the vertical nanorods and the mesoporous film is a crucial step in attaining high eta. We identify three parameters, viz., large surface area of nanoparticles, increased light scattering of the nanorod-nanoparticle layer, and superior charge transport of nanorods, that simultaneously contribute to the improved photovoltaic performance of the WE developed. PMID- 25687411 TI - KLF5 regulates infection- and inflammation-induced pro-labour mediators in human myometrium. AB - The transcription factor Kruppel-like factor 5 (KLF5) has been shown to associate with nuclear factor kappa B (NFkappaB) to regulate genes involved in inflammation. However, there are no studies on the expression and regulation of KLF5 in the processes of human labour and delivery. Thus, the aims of this study were to determine the effect of i) human labour on KLF5 expression in both foetal membranes and myometrium; ii) the pro-inflammatory cytokine interleukin 1 beta (IL1beta), bacterial product flagellin and the viral dsRNA analogue poly(I:C) on KLF5 expression and iii) KLF5 knockdown by siRNA in human myometrial primary cells on pro-inflammatory and pro-labour mediators. In foetal membranes, there was no effect of term or preterm labour on KLF5 expression. In myometrium, the term labour was associated with an increase in nuclear KLF5 protein expression. Moreover, KLF5 expression was also increased in myometrial cells treated with IL1beta, flagellin or poly(IC), likely factors contributing to preterm birth. KLF5 silencing in myometrial cells significantly decreased IL1beta-induced cytokine expression (IL6 and IL8 mRNA expression and release), COX2 mRNA expression, and subsequent release of prostaglandins PGE2 and PGF2 alpha. KLF5 silencing also significantly reduced flagellin- and poly(I:C)-induced IL6 and IL8 mRNA expression. Lastly, IL1beta-, flagellin- and poly(I:C)-stimulated NFkappaB transcriptional activity was significantly suppressed in KLF5-knockout myometrial cells. In conclusion, this study describes novel data in which KLF5 is increased in labouring myometrium, and KLF5 silencing decreased inflammation- and infection induced pro-labour mediators. PMID- 25687410 TI - Estrogen promotes luteolysis by redistributing prostaglandin F2alpha receptors within primate luteal cells. AB - Prostaglandin F2alpha (PGF2alpha) has been proposed as a functional luteolysin in primates. However, administration of PGF2alpha or prostaglandin synthesis inhibitors in vivo both initiate luteolysis. These contradictory findings may reflect changes in PGF2alpha receptors (PTGFRs) or responsiveness to PGF2alpha at a critical point during the life span of the corpus luteum. The current study addressed this question using ovarian cells and tissues from female cynomolgus monkeys and luteinizing granulosa cells from healthy women undergoing follicle aspiration. PTGFRs were present in the cytoplasm of monkey granulosa cells, while PTGFRs were localized in the perinuclear region of large, granulosa-derived monkey luteal cells by mid-late luteal phase. A PTGFR agonist decreased progesterone production in luteal cells obtained at mid-late and late luteal phases, but did not decrease progesterone production by granulosa cells or luteal cells from younger corpora lutea. These findings are consistent with a role for perinuclear PTGFRs in functional luteolysis. This concept was explored using human luteinizing granulosa cells maintained in vitro as a model for luteal cell differentiation. In these cells, PTGFRs relocated from the cytoplasm to the perinuclear area in an estrogen- and estrogen receptor-dependent manner. Similar to our findings with monkey luteal cells, human luteinizing granulosa cells with perinuclear PTGFRs responded to a PTGFR agonist with decreased progesterone production. These data support the concept that PTGFR stimulation promotes functional luteolysis only when PTGFRs are located in the perinuclear region. Estrogen receptor-mediated relocation of PTGFRs within luteal cells may be a necessary step in the initiation of luteolysis in primates. PMID- 25687412 TI - Basic fibroblast growth factor promotes macaque follicle development in vitro. AB - Fertility preservation is an important type of frontier scientific research in the field of reproductive health. The culture of ovarian cortices to i) initiate primordial follicle growth and ii) procure developing follicles for later oocyte maturation is a promising fertility preservation strategy, especially for older women or cancer patients. At present, this goal remains largely unsubstantiated in primates because of the difficulty in attaining relatively large follicles via ovarian cortex culture. To overcome this hurdle, we cultured macaque monkey ovarian cortices with FSH, kit ligand (KL), basic fibroblast growth factor (bFGF), and/or epidermal growth factor (EGF). The various factors and factor combinations promoted primordial follicle development to different extents. Notably, both bFF (bFGF, 100 ng/ml and FSH, 50 ng/ml) and KF (KL, 100 ng/ml and FSH, 50 ng/ml) contributed to the activation of primordial follicles at day 12 (D12) of culture, whereas at D18, the proportions of developing follicles were significantly higher in the bFF and KF groups relative to the other treatment groups, particularly in the bFF group. Estradiol and progesterone production were also highest in the bFF group, and primary follicle diameters were the largest. Up until D24, the bFF group still exhibited the highest proportion of developing follicles. In conclusion, the bFGF-FSH combination promotes nonhuman primate primordial follicle development in vitro, with the optimal experimental window within 18 days. These results provide evidence for the future success of human ovarian cortex culture and the eventual acquisition of mature human follicles or oocytes for fertility restoration. PMID- 25687414 TI - Comparison of surgical treatment with direct repair versus conservative treatment in young patients with spondylolysis: a prospective, comparative, clinical trial. AB - BACKGROUND CONTEXT: Although direct repair (DR) with screw fixation at the pars defect is a common surgical treatment for lumbar spondylolysis, it is unknown whether DR leads to better outcomes for young patients with spondylolysis than traditional nonsurgical treatment. PURPOSE: The purpose of the study was to investigate whether DR was associated with better outcomes for lumbar spondylolysis in young patients than traditional conservative treatment. STUDY DESIGN: This is a prospective cohort study. PATIENT SAMPLE: Of 1,784 patients with low back pain in the reference period, 149 young patients with spondylolysis who followed up for at least 1 year were enrolled in the study. OUTCOME MEASURES: The primary outcome was pain intensity at the lower back measured with a Visual Analog Scale. Secondary outcomes included the functional outcome as measured with the Oswestry disability index (ODI) and the 12-item short-form health survey (SF 12) consisting of the physical component summary (PCS) and mental component summary (MCS) scores, the radiologic outcome as measured with lumbar spine radiographs and computed tomography scans, and complications of treatment. METHODS: This was a prospective comparative study between two groups of patients who were treated with either conservative treatment or surgery for lumbar spondylolysis. Enrolled patients self-selected their own treatment and were allocated to either the traditional care group with conservative treatment (87 patients) or the surgery group (62 patients). All patients were followed up for at least 1 year. RESULTS: Pain intensity at the lower back did not differ significantly between groups at the final follow-up. Likewise, the ODI and SF-12 (PCS and MCS) scores did not differ significantly between groups (p=.13, .71, and .68, respectively). The change in the gap distance of the pars defect at the final follow-up was significantly different between groups (traditional care group: +0.8+/-0.4 mm; surgery group: -0.7+/-0.5; p=.01). The union rate at 1 year after surgical treatment was 52% (32/61). The rate of complications was significantly higher in the surgery group (31%) than the traditional care group (20%) (p=.02). CONCLUSIONS: Conservative treatment for young patients with spondylolysis may produce similar clinical outcomes and fewer complications over 12-month follow-up than surgical treatment with DR. PMID- 25687413 TI - Effects of the Social Environment and Stress on Glucocorticoid Receptor Gene Methylation: A Systematic Review. AB - The early-life social environment can induce stable changes that influence neurodevelopment and mental health. Research focused on early-life adversity revealed that early-life experiences have a persistent impact on gene expression and behavior through epigenetic mechanisms. The hypothalamus-pituitary-adrenal axis is sensitive to changes in the early-life environment that associate with DNA methylation of a neuron-specific exon 17 promoter of the glucocorticoid receptor (GR) (Nr3c1). Since initial findings were published in 2004, numerous reports have investigated GR gene methylation in relationship to early-life experience, parental stress, and psychopathology. We conducted a systematic review of this growing literature, which identified 40 articles (13 animal and 27 human studies) published since 2004. The majority of these examined the GR exon variant 1F in humans or the GR17 in rats, and 89% of human studies and 70% of animal studies of early-life adversity reported increased methylation at this exon variant. All the studies investigating exon 1F/17 methylation in conditions of parental stress (one animal study and seven human studies) also reported increased methylation. Studies examining psychosocial stress and psychopathology had less consistent results, with 67% of animal studies reporting increased exon 17 methylation and 17% of human studies reporting increased exon 1F methylation. We found great consistency among studies investigating early-life adversity and the effect of parental stress, even if the precise phenotype and measures of social environment adversity varied among studies. These results are encouraging and warrant further investigation to better understand correlates and characteristics of these associations. PMID- 25687415 TI - Incidence, associated factors, and survival in metastatic spinal cord compression secondary to lung cancer. AB - BACKGROUND CONTEXT: Bone metastasis (BM) occurs frequently in patients with lung cancer (LC). The most affected are the bones of the spine, increasing the risk of developing metastatic spinal cord compression (MSCC). Although MSCC is one of the most disabling complications, few studies have reported relevant results related to its frequency and prognosis among patients with LC. PURPOSE: The purpose of this study was to determine the incidence and associated factors of the development of MSCC after BM with LC and its prognosis. STUDY DESIGN/SETTING: This is a cohort study. PATIENT SAMPLE: A cohort of 112 patients with BM because of LC, whose treatment was performed exclusively at the National Cancer Institute, was analyzed. OUTCOME MEASURES: Study outcome measures included incidence of MSCC, factors associated with MSCC, and survival analysis. METHODS: A cohort study was performed involving patients with BM because of LC diagnosed between 2007 and 2011. Clinical and sociodemographic data were extracted from the physical and electronic medical records because of initial diagnosis (up until December 2013). The association between the independent variables and the outcomes was performed by using crude and adjusted odds ratios (ORs), assuming 95% confidence intervals (CIs). For the exploratory evaluation between the independent variables and the time until the outcomes, Kaplan-Meier survival analysis was conducted. To identify if the differences between the curves were statistically significant, a log-tank test was calculated. A Cox multiple regression model, using the forward stepwise method, was applied, aiming to estimate the factors associated with time to death in the different exposure groups. RESULTS: Of the 112 patients with BM, 31 (27.7%) developed MSCC. The univariate analysis showed that patients with three or more involved vertebrae revealed a 6.1 times greater risk of developing MSCC, compared with those with up to two metastatic vertebrae involved (OR: 6.1, 95% CI: 2.5-15.1, p<.001). Among the patients who developed MSCC, the median survival time was 4.4 months (95% CI: 1.5-7.3) and 4.7 months (95% CI: 3.5-5.9) in the patients without MSCC, not being a statistically significant difference (p=.19). After the occurrence of the MSCC, the median survival time was 2.8 months (95% CI: 1.4-4.1). CONCLUSIONS: In this study, a high incidence of MSCC was observed in patients with BM. The study suggests that patients with three or more involved vertebrae per metastasis are more likely to develop MSCC. No alteration in the overall survival time was noticed among the patients with or without MSCC. PMID- 25687416 TI - Dosimetric characterization of INTRABEAM(r) miniature accelerator flat and surface applicators for dermatologic applications. AB - PURPOSE: This study aims at characterizing the dosimetric behavior of an INTRABEAM((r)) miniature accelerator equipped with flat and surface applicators, converting the spherical dose distribution into a flat one. METHODS: Dosimetric characterization was carried out in two steps. Firstly characterization was made in standard conditions for dermatologic applications, which is with the applicator directly on contact with the skin. Secondly, characterization was made in more clinical conditions, such as obliquities and heterogeneities. RESULTS: Behaviors of flat and surface applicators are different. Dose distribution for surface applicators is uniform at surface, whereas for flat applicator the maximum homogeneity is shown at a particular depth in water. Some results are different from previously published studies due to differences in the X-ray source design. The study showed that in the absence of a perfect contact between the applicator and the skin of the patient, there is a dose distribution spread on the edge of the irradiation field where the contact is not made. Dose loss due to lack of backscatter radiations is significant. By contrast, influence of a denser material behind the measurement point has no significant influence on the dose at this point. Thickness of tissue treated with flat and surface applicators is only a few millimeters, depending on the applicator's size, making these applicators ideal for superficial lesions, compared to high energy electrons and iridium brachytherapy. CONCLUSIONS: The INTRABEAM((r)) miniature accelerator equipped with surface applicators is a reliable way of treating superficial cutaneous malignancies. PMID- 25687417 TI - Monte Carlo modeling of the Siemens Optifocus multileaf collimator. AB - We have developed a new component module for the BEAMnrc software package, called SMLC, which models the tongue-and-groove structure of the Siemens Optifocus multileaf collimator. The ultimate goal is to perform accurate Monte Carlo simulations of the IMRT treatments carried out with Optifocus. SMLC has been validated by direct geometry checks and by comparing quantitatively the results of simulations performed with it and with the component module VARMLC. Measurements and Monte Carlo simulations of absorbed dose distributions of radiation fields sensitive to the tongue-and-groove effect have been performed to tune the free parameters of SMLC. The measurements cannot be accurately reproduced with VARMLC. Finally, simulations of a typical IMRT field showed that SMLC improves the agreement with experimental measurements with respect to VARMLC in clinically relevant cases. PACS NUMBER: 87.55. K. PMID- 25687418 TI - Multifunctional cell-culture platform for aligned cell sheet monitoring, transfer printing, and therapy. AB - While several functional platforms for cell culturing have been proposed for cell sheet engineering, a soft integrated system enabling in vitro physiological monitoring of aligned cells prior to their in vivo applications in tissue regeneration has not been reported. Here, we present a multifunctional, soft cell culture platform equipped with ultrathin stretchable nanomembrane sensors and graphene-nanoribbon cell aligners, whose system modulus is matched with target tissues. This multifunctional platform is capable of aligning plated cells and in situ monitoring of cellular physiological characteristics during proliferation and differentiation. In addition, it is successfully applied as an in vitro muscle-on-a-chip testing platform. Finally, a simple but high-yield transfer printing mechanism is proposed to deliver cell sheets for scaffold-free, localized cell therapy in vivo. The muscle-mimicking stiffness of the platform allows the high-yield transfer printing of multiple cell sheets and results in successful therapies in diseased animal models. Expansion of current results to stem cells will provide unique opportunities for emerging classes of tissue engineering and cell therapy technologies. PMID- 25687419 TI - Round robin test for odour testing of migration waters. AB - For a round robin test for EN 1420-1 (Odour assessment for organic materials in contact with drinking water) with 14 contributing laboratories from 10 European countries segments of a plastic pipe were sent to the laboratories which performed a migration test and an odour analysis of the migration waters (water that had contact with the organic material) according to the procedure described in the standard from 1999. In addition reference substances (Methyl tert-butyl ether, 1-butanol and hexanal) were investigated for their suitability to qualify the panels and the individual panellists. Methyl tert-butyl ether (MtBE) and 1 butanol proved to be suitable for this purpose, whereas hexanal showed a wide distribution of the individual odour threshold concentrations. Both possible testing options (unforced and forced choice) were performed and gave similar results. However, with respect to the qualification of the panellists and the data analysis the unforced choice procedure showed advantages. As human olfactory perception is used for the analysis, the reproducibility and the comparability between laboratories is of particular concern. For the pipe material the TON results of the different laboratories were in a range of +/-1.5 dilutions based on a dilution factor of 2. This might be improved by taking the individual sensitivities of the panellists into account more strongly. Appropriate measures for the improvement of the test method appear to be the use of the proposed reference substances for the training of the panellists as well as the auditing and the selection of the panellists. The results of this round robin test are used in the revision process of the standard. PMID- 25687420 TI - Removal of bacterial contaminants and antibiotic resistance genes by conventional wastewater treatment processes in Saudi Arabia: Is the treated wastewater safe to reuse for agricultural irrigation? AB - This study aims to assess the removal efficiency of microbial contaminants in a local wastewater treatment plant over the duration of one year, and to assess the microbial risk associated with reusing treated wastewater in agricultural irrigation. The treatment process achieved 3.5 logs removal of heterotrophic bacteria and up to 3.5 logs removal of fecal coliforms. The final chlorinated effluent had 1.8 * 10(2) MPN/100 mL of fecal coliforms and fulfils the required quality for restricted irrigation. 16S rRNA gene-based high-throughput sequencing showed that several genera associated with opportunistic pathogens (e.g. Acinetobacter, Aeromonas, Arcobacter, Legionella, Mycobacterium, Neisseria, Pseudomonas and Streptococcus) were detected at relative abundance ranging from 0.014 to 21 % of the total microbial community in the influent. Among them, Pseudomonas spp. had the highest approximated cell number in the influent but decreased to less than 30 cells/100 mL in both types of effluent. A culture-based approach further revealed that Pseudomonas aeruginosa was mainly found in the influent and non-chlorinated effluent but was replaced by other Pseudomonas spp. in the chlorinated effluent. Aeromonas hydrophila could still be recovered in the chlorinated effluent. Quantitative microbial risk assessment (QMRA) determined that only chlorinated effluent should be permitted for use in agricultural irrigation as it achieved an acceptable annual microbial risk lower than 10(-4) arising from both P. aeruginosa and A. hydrophila. However, the proportion of bacterial isolates resistant to 6 types of antibiotics increased from 3.8% in the influent to 6.9% in the chlorinated effluent. Examples of these antibiotic resistant isolates in the chlorinated effluent include Enterococcus and Enterobacter spp. Besides the presence of antibiotic-resistant bacterial isolates, tetracycline resistance genes tetO, tetQ, tetW, tetH, tetZ were also present at an average 2.5 * 10(2), 1.6 * 10(2), 4.4 * 10(2), 1.6 * 10(1) and 5.5 * 10(3) copies per mL of chlorinated effluent. Our study highlighted that potential risks associated with the reuse of treated wastewater arise not only from conventional fecal indicators or known pathogens, but also from antibiotic resistant bacteria and genes. PMID- 25687421 TI - Polysiloxane layers created by sol-gel and photochemistry: ideal surfaces for rapid, low-cost and high-strength bonding of epoxy components to polydimethylsiloxane. AB - In this article we introduce and compare three techniques for low-cost and rapid bonding of stereolithographically structured epoxy components to polydimethylsiloxane (PDMS). In short, we first create a polysiloxane layer on the epoxy surface via silane surface coupling and polymerization. Afterwards, the modified epoxy surface can be bonded to a PDMS component at room temperature using a handheld corona discharger, which is a commonly used low-cost technique for bonding two PDMS components. Using these methods bonds of desirable strength can be generated within half an hour. Depending on the epoxy resin, we found it necessary to modify the silanization procedure. Therefore, we provide a total of three different silanization techniques that allow bonding of a wide variety of stereolithographically structurable epoxy resins. The first technique is a UV light induced silanization process which couples a silane that contains an epoxy ring ((3-glycidoxypropyl)trimethoxysilane (GPTMS)). For surfaces that cannot be modified with this silane we use dimethoxydimethylsilane (DMDMS). This silane can either be coupled to the surface by a sol-gel process or UV-light induced polymerisation. The sol-gel process which is a heat induced surface modification technique results in high bond strengths. Because of the heat which triggers the sol-gel process, this technique is limited to epoxy polymers with high glass transition temperatures. For the majority of stereolithographically structured epoxy resins which typically have glass transition temperatures of around 60 degrees C the light-induced bonding technique is preferable. For all three techniques we performed DIN EN-conform tensile testing demonstrating maximum bond strengths of up to 350 kPa which is comparable with bond strengths reported for PDMS-to-PDMS bonds. For all bond methods, long-term stability as well as hydrolytic stability was assessed. PMID- 25687422 TI - Mega2: validated data-reformatting for linkage and association analyses. AB - BACKGROUND: In a typical study of the genetics of a complex human disease, many different analysis programs are used, to test for linkage and association. This requires extensive and careful data reformatting, as many of these analysis programs use differing input formats. Writing scripts to facilitate this can be tedious, time-consuming, and error-prone. To address these issues, the open source Mega2 data reformatting program provides validated and tested data conversions from several commonly-used input formats to many output formats. RESULTS: Mega2, the Manipulation Environment for Genetic Analysis, facilitates the creation of analysis-ready datasets from data gathered as part of a genetic study. It transparently allows users to process genetic data for family-based or case/control studies accurately and efficiently. In addition to data validation checks, Mega2 provides analysis setup capabilities for a broad choice of commonly used genetic analysis programs. First released in 2000, Mega2 has recently been significantly improved in a number of ways. We have rewritten it in C++ and have reduced its memory requirements. Mega2 now can read input files in LINKAGE, PLINK, and VCF/BCF formats, as well as its own specialized annotated format. It supports conversion to many commonly-used formats including SOLAR, PLINK, Merlin, Mendel, SimWalk2, Cranefoot, IQLS, FBAT, MORGAN, BEAGLE, Eigenstrat, Structure, and PLINK/SEQ. When controlled by a batch file, Mega2 can be used non interactively in data reformatting pipelines. Support for genetic data from several other species besides humans has been added. CONCLUSIONS: By providing tested and validated data reformatting, Mega2 facilitates more accurate and extensive analyses of genetic data, avoiding the need to write, debug, and maintain one's own custom data reformatting scripts. Mega2 is freely available at https://watson.hgen.pitt.edu/register/. PMID- 25687423 TI - Novel topical formulation for ischemic chronic wounds. Technological design, quality control and safety evaluation. AB - Ulceration of the foot in diabetes is common and disabling, and frequently leads to amputation of the leg. The pathogenesis of foot ulceration is complex, clinical presentation variable and management requires early expert assessment. Despite treatment, ulcers readily become chronic wounds. Chronic wounds are those that remain in a chronic inflammatory state failing a normal healing process patterns. This is partially caused by inefficient eradication of opportunistic pathogens like Pseudomonas aeruginosa. We propose its control or eradication will promote wound healing. Lactobacillus plantarum cultures supernatants (LAPS) shows antipathogenic and pro-healing properties. The main objective was to design two pharmaceutical dosage forms by using LAPS as active pharmaceutical ingredient and to perform its quality control, in vitro activity conservation tests and human trials (safety evaluation). Both selected formulations reach the technological quality expected for 120 days, shows adequate occlusive characteristics and proper adhesion to human skin. From the in vitro release assays were found that LAPS shows adequate release from matrix and maintain its antimicrobial and anti biofilm activity. First human trials were developed and neither edema nor erythema on healthy skin voluntaries was found. We conclude that C80 and C100 are adequate for their use in future clinical trials to demonstrate a comprehensive therapeutic effectiveness in ischemic chronic wounds. PMID- 25687424 TI - YAP in tumorigenesis: Friend or foe? PMID- 25687425 TI - The TM6SF2 rs58542926 T allele is significantly associated with non-alcoholic fatty liver disease in Chinese. PMID- 25687426 TI - Reply to: "Interferon regulatory factor 9 plays a dual function in health and disease". PMID- 25687428 TI - Reference values for digital X-ray radiogrammetry parameters in children and adolescents in comparison to estimates in patients with distal radius fractures. AB - The first objective of this study was to determine normative digital X-ray radiogrammetry (DXR) values, based on original digital images, in a pediatric population (aged 6-18 years). The second aim was to compare these reference data with patients suffering from distal radius fractures, whereas both cohorts originated from the same geographical region and were evaluated using the same technical parameters as well as inclusion and exclusion criteria. DXR-BMD and DXR MCI of the metacarpal bones II-IV were assessed on standardized digital hand radiographs, without printing or scanning procedures. DXR parameters were estimated separately by gender and among six age groups; values in the fracture group were compared to age- and gender-matched normative data using Student's t tests and Z scores. In the reference cohort (150 boys, 138 girls), gender differences were found in bone mineral density (DXR-BMD), with higher values for girls from 11 to 14 years and for boys from 15 to 18 years (p < 0.05). Girls had higher normative metacarpal index (DXR-MCI) values than boys, with significant differences at 11-14 years (p < 0.05). In the case-control investigation, the fracture group (95 boys, 69 girls) presented lower DXR-BMD at 15-18 years in boys and 13-16 years in girls vs. the reference cohort (p < 0.05); DXR-MCI was lower at 11-18 years in boys and 11-16 years in girls (p < 0.05). Mean Z scores in the fracture group for DXR-BMD were -0.42 (boys) and -0.46 (girls), and for DXR-MCI were -0.51 (boys) and -0.53 (girls). These findings indicate that the fully digital DXR technique can be accurately applied in pediatric populations >= 6 years of age. The lower DXR-BMD and DXR-MCI values in the fracture group suggest promising early identification of individuals with increased fracture risk, without the need for additional radiation exposure, enabling the initiation of prevention strategies to possibly reduce the incidence of osteoporosis later in life. PMID- 25687429 TI - Fact or fiction? Examining a role for N-methyl-D-aspartate receptor autoantibodies in psychiatric illness. PMID- 25687430 TI - Deconstructing N-methyl-d-aspartate glutamate receptor contributions to cortical circuit functions to construct better hypotheses about the pathophysiology of schizophrenia. PMID- 25687431 TI - Combining data across methodologies and continents to test a mechanistic hypothesis: setting up the future. PMID- 25687432 TI - Neuroprotection of Sevoflurane Against Ischemia/Reperfusion-Induced Brain Injury Through Inhibiting JNK3/Caspase-3 by Enhancing Akt Signaling Pathway. AB - In this study, we investigated the neuroprotective effect of sevoflurane against ischemic brain injury and its underlying molecular mechanisms. Transient global brain ischemia was induced by 4-vessel occlusion in adult male Sprague-Dawley rats. The rats were pretreated with sevoflurane alone or sevoflurane combined with LY294002/wortmannin (selective inhibitor of PI3K) before ischemia. Cresyl violet staining was used to examine the survival of hippocampal CA1 pyramidal neurons. Immunoblotting and immunoprecipitation were performed to measure the phosphorylation of Akt1, PRAS40, ASK1, and JNK3 and the expression of cleaved caspase-3. The results demonstrated that a moderate dose of sevoflurane inhalation of 2% for 2 h had significant neuroprotective effects against ischemia/reperfusion induced hippocampal neuron death. Sevoflurane significantly increased Akt and PRAS40 phosphorylation and decreased the phosphorylation of ASK1 at 6 h after reperfusion and the phosphorylation of JNK3 at 3 days after reperfusion following 15 min of transient global brain ischemia. Conversely, LY294002 and wortmannin significantly inhibited the effects of sevoflurane. Taken together, the results suggest that sevoflurane could suppress ischemic brain injury by downregulating the activation of the ASK1/JNK3 cascade via increasing the phosphorylation of Akt1 during ischemia/reperfusion. PMID- 25687433 TI - Prognostic Significance of Hyperglycemia in Patients with Brain Tumors: a Meta Analysis. AB - Hyperglycemia has been associated with poor outcomes of patients with various diseases. There were several studies published to assess the association between hyperglycemia and prognosis of patients with brain tumors, but no consistent conclusion was available. We therefore performed a meta-analysis of available studies to evaluate the prognostic role of hyperglycemia in brain tumors. Several common databases were searched for eligible studies on the association between hyperglycemia and survival of patients with brain tumors. Two investigators used a set of predefined inclusion criteria to assess eligible studies independently. The pooled hazard ratios (HRs) with 95% confidence intervals (95% CIs) were used to assess the prognostic role of hyperglycemia. Finally, seven studies with a total of 2168 patients with brain tumors were included into the meta-analysis. Meta-analysis of total seven studies showed that hyperglycemia was significantly associated with shorter overall survival of brain tumors (HR = 2.04, 95% CI 1.51 2.76, P < 0.001). Meta-analysis of studies focusing on hyperglycemia showed that hyperglycemia was still significantly associated with shorter overall survival of brain tumors (HR = 1.82, 95% CI 1.29-2.59, P = 0.001). Meta-analysis of three studies on diabetes showed that diabetes was significantly associated with shorter overall survival of brain tumors (HR = 2.09, 95% CI 1.22-3.57, P = 0.007). Meta-regression analysis showed that there was no obvious difference in the roles of between hyperglycemia caused by glucocorticoids and hyperglycemia from diabetes (P = 0.25). Thus, hyperglycemia has an obvious prognostic significance in patients with brain tumors, and hyperglycemia is significantly associated with shorter overall survival of brain tumors. PMID- 25687434 TI - Featured Article: Hypoxia-inducible factor-1alpha dependent nuclear entry of factor inhibiting HIF-1. AB - The regulation of hypoxia-inducible factor-1 (HIF-1) transcriptional activity in the nucleus is related to factor inhibiting HIF-1 (FIH-1). FIH-1 hydrolyzes asparagine at the C-terminal of HIF-1alpha, preventing the interaction between HIF-1alpha and its associated cofactors, and leading to suppressed activation of HIF-1. FIH-1 is a cytosolic protein and its entry to the nucleus has to be coordinated with HIF-1alpha. The present study was undertaken to examine the correlation between HIF-1alpha and FIH-1 in their nuclear entry. Human umbilical vein endothelial cells were treated with dimethyloxalylglycine at a final concentration of 100 uM for 4 h, resulting in an accumulation of HIF-1alpha and an increase of FIH-1 in the nucleus as determined by Western blot analysis. Pretreatment of the cells with copper (Cu) chelator tetraethylenepentamine at 50 uM in cultures for 24 h reduced both HIF-1alpha protein levels and the HIF-1alpha entry to the nucleus, along with decreased FIH-1 protein levels in the nucleus but no changes in the total FIH-1 protein levels in the cells. These effects were prevented by simultaneous addition of 50 uM CuSO4 with tetraethylenepentamine. Gene-silencing of HIF-1alpha significantly inhibited FIH-1 entry to the nucleus, but did not affect the total protein levels of FIH-1 in the cells. This work demonstrates that the nuclear entry of FIH-1 depends on HIF-1alpha. Cu deficiency caused a decrease of HIF-1alpha, leading to suppression of FIH-1 entry to the nucleus. PMID- 25687435 TI - The role of the cerebral ganglia in the venom-induced behavioral manipulation of cockroaches stung by the parasitoid jewel wasp. AB - The jewel wasp stings cockroaches and injects venom into their cerebral ganglia, namely the subesophageal ganglion (SOG) and supraesophageal ganglion (SupOG). The venom induces a long-term hypokinetic state, during which the stung cockroach shows little or no spontaneous walking. It was shown that venom injection to the SOG reduces neuronal activity, thereby suggesting a similar effect of venom injection in the SupOG. Paradoxically, SupOG-ablated cockroaches show increased spontaneous walking in comparison with control. Yet most of the venom in the SupOG of cockroaches is primarily concentrated in and around the central complex (CX). Thus the venom could chiefly decrease activity in the CX to contribute to the hypokinetic state. Our first aim was to resolve this discrepancy by using a combination of behavioral and neuropharmacological tools. Our results show that the CX is necessary for the initiation of spontaneous walking, and that focal injection of procaine to the CX is sufficient to induce the decrease in spontaneous walking. Furthermore, it was shown that artificial venom injection to the SOG decreases walking. Hence our second aim was to test the interactions between the SupOG and SOG in the venom-induced behavioral manipulation. We show that, in the absence of the inhibitory control of the SupOG on walking initiation, injection of venom in the SOG alone by the wasp is sufficient to induce the hypokinetic state. To summarize, we show that venom injection to either the SOG or the CX of the SupOG is, by itself, sufficient to decrease walking. PMID- 25687436 TI - Octopus arm movements under constrained conditions: adaptation, modification and plasticity of motor primitives. AB - The motor control of the eight highly flexible arms of the common octopus (Octopus vulgaris) has been the focus of several recent studies. Our study is the first to manage to introduce a physical constraint to an octopus arm and investigate the adaptability of stereotypical bend propagation in reaching movements and the pseudo-limb articulation during fetching. Subjects (N=6) were placed inside a transparent Perspex box with a hole at the center that allowed the insertion of a single arm. Animals had to reach out through the hole toward a target, to retrieve a food reward and fetch it. All subjects successfully adjusted their movements to the constraint without an adaptation phase. During reaching tasks, the animals showed two movement strategies: stereotypical bend propagation reachings, which were established at the hole of the Perspex box and variant waving-like movements that showed no bend propagations. During fetching movements, no complete pseudo-joint fetching was observed outside the box and subjects pulled their arms through the hole in a pull-in like movement. Our findings show that there is some flexibility in the octopus motor system to adapt to a novel situation. However, at present, it seems that these changes are more an effect of random choices between different alternative motor programs, without showing clear learning effects in the choice between the alternatives. Interestingly, animals were able to adapt the fetching movements to the physical constraint, or as an alternative explanation, they could switch the motor primitive fetching to a different motor primitive 'arm pulling'. PMID- 25687437 TI - Social dominance and reproductive differentiation mediated by dopaminergic signaling in a queenless ant. AB - In social Hymenoptera with no morphological caste, a dominant female becomes an egg layer, whereas subordinates become sterile helpers. The physiological mechanism that links dominance rank and fecundity is an essential part of the emergence of sterile females, which reflects the primitive phase of eusociality. Recent studies suggest that brain biogenic amines are correlated with the ranks in dominance hierarchy. However, the actual causality between aminergic systems and phenotype (i.e. fecundity and aggressiveness) is largely unknown due to the pleiotropic functions of amines (e.g. age-dependent polyethism) and the scarcity of manipulation experiments. To clarify the causality among dominance ranks, amine levels and phenotypes, we examined the dynamics of the aminergic system during the ontogeny of dominance hierarchy in the queenless ant Diacamma sp., which undergoes rapid physiological differentiation based on dominance interactions. Brain dopamine levels differed between dominants and subordinates at day 7 after eclosion, although they did not differ at day 1, reflecting fecundity but not aggressiveness. Topical applications of dopamine to the subordinate workers induced oocyte growth but did not induce aggressiveness, suggesting the gonadotropic effect of dopamine. Additionally, dopamine receptor transcripts (dopr1 and dopr2) were elevated in the gaster fat body of dominant females, suggesting that the fat body is a potential target of neurohormonal dopamine. Based on this evidence, we suggest that brain dopamine levels are elevated in dominants as a result of hierarchy formation, and differences in dopamine levels cause the reproductive differentiation, probably via stimulation of the fat body. PMID- 25687438 TI - Comparison of actigraphy immobility rules with polysomnographic sleep onset latency in children and adolescents. AB - PURPOSE: While actigraphy has gained popularity in pediatric sleep research, questions remain about the validity of actigraphy as an estimate of sleep-wake patterns. In particular, there is little consistency in the field in terms of scoring rules used to determine sleep onset latency. The purpose of this study was to evaluate different criteria of immobility as a measure of sleep onset latency in children and adolescents. METHODS: Ninety-five youth (ages 3-17 years, 46 % male) wore both the Ambulatory Monitoring Inc. Motionlogger Sleep Watch (AMI) and the Philips Respironics Mini-Mitter Actiwatch-2 (PRMM) during overnight polysomnography in a pediatric sleep lab. We examined different sleep onset latency scoring rules (3, 5, 10, 15, and 20 min of immobility) using different algorithms (Sadeh and Cole-Kripke) and sensitivity settings (low, medium, high) for the devices. Comparisons were also made across age groups (preschoolers, school-aged, adolescents) and sleep disordered breathing status (no obstructive sleep apnea [OSA], mild OSA, clinically significant OSA). RESULTS: For the AMI device, shorter scoring rules performed best for children and longer scoring rules were better for adolescents, with shorter scoring rules best across sleep disordered breathing groups. For the PRMM device, medium to longer scoring rules performed best across age and sleep disordered breathing groups. CONCLUSIONS: Researchers are encouraged to determine the scoring rule that best fits their population of interest. Future studies are needed with larger samples of children and adolescents to further validate actigraphic immobility as a proxy for sleep onset latency. PMID- 25687439 TI - The Prevention and Treatment of Delirium in Elderly Patients Following Hip Fracture Surgery. AB - Osteoporotic hip fracture needs a specific approach and treatment, since elderly patients are at high risk for adverse outcomes after surgery. In particular, delirium often occurs in the peri-operative period, and it is associated with death, hospital-acquired complications, persistent cognitive impairments, poor functional recovery after surgery and increased healthcare costs. The pre operative assessment of the risk factors for delirium improves the preventive measures. The delirium diagnostic tools should be included in the standard of orthogeriatric cure for hip fracture. Given the increasing complexity of the clinical pictures, we present a review of the available treatment options for delirium in patients with hip fracture. The metabolic pre-operative disorders and the management of co-morbid diseases are specific targets of treatment in order to optimize the outcomes after surgery. In particular, elderly patients with Alzheimer's disease are highly vulnerable to hip fracture and delirium, and they are severely frail with reduced physiologic reserves. An integrated approach combining environmental and pharmacological strategies is useful in the delirium treatment, with a close collaboration between the orthopedic and geriatric team. PMID- 25687441 TI - Margaret McCartney: Female genital mutilation: a wise doctor and a foolish prosecution. PMID- 25687442 TI - Surgical treatment of giant cell tumor of the cervicothoracic spine with combined anterior and posterior approaches. AB - Generally, giant cell tumors are rare and their localization in the spine is even more so. They are locally aggressive leading to spine instability and neurologic deficits. Radical excision is highly advocated. A role of radiotherapy in these tumors is controversial. We report the case of a giant cell tumor localized in D1 and D2 on a 39-year-old patient, presented with interscapular back pain, paraparesis grade 3/5 and sphincter dysfunction. Thoracic spine computed tomogarphy and magnetic resonance imaging showed a vertebral body tumor in D1 and D2, compressing the spinal cord at the same level. The patient initially underwent decompressive laminectomy of affected levels and stabilized with laminar hooks and rods. Second surgery performed through an anterior approach whereby tumor excision together with corpectomy of D1 and D2 carried out, autograft was placed and plate applied. Three weeks postoperatively, the patient's neurologic deficit recovered fully and back pain subsided. PMID- 25687443 TI - Vesicocutaneous fistula treatment by using omental flap interposition. AB - A fistula is defined as an abnormal association of two or more epithelial lining. Therefore, vesicocutaneous fistula (VCF) represents an extra anatomic communication between the bladder wall and the external surface of the skin. The most common cause is iatrogenic; however, numerous factors may play a role in the formation of VCFs. When a VCF is identified, it should be treated properly due to its bothersome complaints and social effects. Nonetheless, no certain consensus has been achieved, yet. In this case, we report the feasibility and efficacy of omental flap interposition during VCF repair. PMID- 25687444 TI - A case of abdominal trauma. AB - Multiple injuries resulting from the use of nail guns have been described in the literature; however, to date there has been no report of a nail gun injury to the abdomen. We describe the case of a 30-year-old male tradesperson who suffered a penetrating nail gun injury to the epigastrium, resulting in multiple injuries to the bowel and an inferior vena caval injury with massive haemorrhage. This case demonstrates the wide range of injuries capable of being inflicted by a single penetrating injury, and emphasizes the need for proper training and safety measures in the use of nail guns. PMID- 25687445 TI - An unusual case of pulmonary embolism. AB - Pulmonary embolism carries a significant morbidity and mortality. Metastatic choriocarcinoma presenting as pulmonary embolism is a rare event. Here, we report a case of a 25-year-lady with a history of worsening shortness of breath for 4 months who was treated as a case of pneumonia and tuberculosis. Owing to the worsening condition, she had a contrast enhanced computed tomography (CECT) chest done and was diagnosed to have pulmonary embolism. She underwent pulmonary embolectomy. The histopathological examination of the embolus revealed it to be metastatic choriocarcinoma. She showed a good response to chemotherapy. Metastatic choriocarcinoma should be considered as a differential diagnosis in females presenting with pulmonary embolism. PMID- 25687446 TI - Revealing backward rescattering photoelectron interference of molecules in strong infrared laser fields. AB - Photoelectrons ionized from atoms and molecules in a strong laser field are either emitted directly or rescattered by the nucleus, both of which can serve as efficiently useful tools for molecular orbital imaging. We measure the photoelectron angular distributions of molecules (N2, O2 and CO2) ionized by infrared laser pulses (1320 nm, 0.2 ~ 1 * 10(14) W/cm(2)) from multiphoton to tunneling regime and observe an enhancement of interference stripes in the tunneling regime. Using a semiclassical rescattering model with implementing the interference effect, we show that the enhancement arises from the sub-laser-cycle holographic interference of the contributions of the back-rescattering and the non-rescattering electron trajectory. It is shown that the low-energy backscattering photoelectron interference patterns have encoded the structural information of the molecular initial orbitals and attosecond time-resolved dynamics of photoelectron, opening new paths in high-resolution imaging of sub Angstrom and sub-femtosecond structural dynamics in molecules. PMID- 25687447 TI - Genome sequence and genome mining of a marine-derived antifungal bacterium Streptomyces sp. M10. AB - A marine-derived actinobacteria Streptomyces sp. M10 was identified as a prolific antifungal compounds producer and shared a 99.02 % 16S ribosomal RNA (rRNA) sequence similarity with that of Streptomyces marokkonensis Ap1(T), which can produce polyene macrolides. To further evaluate its biosynthetic potential, the 7,207,169 bp Streptomyces sp. M10 linear chromosome was sequenced and mined for identifiable secondary metabolite-associated gene clusters. A total of 20 secondary metabolite-associated gene clusters were deduced, including three polyketide synthases (PKSs), four non-ribosomal peptide synthetases (NRPSs), four hybrid NRPS-PKSs, three NRPS-independent siderophores, and two lantibiotic and four terpene biosynthetic gene clusters. One of the type I PKS gene cluster, pks1, shared a 85 % nucleotide similarity with candicidin/FR008 gene cluster, indicating the capacity of this organism to produce polyene macrolides. This assumption was verified by a scale-up culturing of Streptomyces sp. M10 on A1 agar plates, which lead to the isolation of two polyene families PF1 and PF2, with characteristic UV adsorption at 269, 278, and 290 nm (PF1) and 363, 386, and 408 nm (PF2), respectively. Compound 9-04 was further purified from PF1, and its chemical structure was partially elucidated to be a typical polyene macrolide by NMR and UV spectrum. This study affirmatively identified Streptomyces sp. M10 as a source of polyene metabolites and highlighted genome mining of interested organism as a powerful tool for natural product discovery. PMID- 25687448 TI - Improvement of atopic dermatitis-like skin lesions by IL-4 inhibition of P14 protein isolated from Lactobacillus casei in NC/Nga mice. AB - Atopic dermatitis (AD) is a chronic inflammatory skin disease, with a complex etiology encompassing immunologic responses. AD is frequently associated with elevated serum immunoglobulin (Ig) E levels and is exacerbated by a variety of environmental factors, which contribute to its pathogenesis. However, the etiology of AD remains unknown. Recently, reports have documented the role of lactic acid bacteria (LAB) in the treatment and prevention of AD in humans and mice. The LAB, Lactobacillus casei (LC), is frequently used in the treatment of AD. To identify the active component of LC, we screened fractions obtained from the ion exchange chromatography of LC extracts. Using this approach, we identified the candidate protein, P14. We examined whether the P14 protein has anti-atopic properties, using both in vitro and in vivo models. Our results showed that the P14 protein selectively downregulated serum IgE and interleukin-4 cytokine levels, as well as the AD index and scratching score in AD-like NC/Nga mice. In addition, histological examination was also effective in mice. These results suggest that the P14 protein has potential therapeutic effects and that it may also serve as an effective immunomodulatory agent for treating patients with AD. PMID- 25687449 TI - [(125)I]Iodo-ASEM, a specific in vivo radioligand for alpha7-nAChR. AB - [(125)I]Iodo-ASEM, a new radioligand with high affinity and selectivity for alpha7-nAChRs (K(i) = 0.5 nM; alpha7/alpha4beta2 = 3414), has been synthesized in radiochemical yield of 33 +/- 6% from the corresponding di-butyltriazene derivative and at high specific radioactivity (1600Ci/mmol; 59.2 MBq/MUmol). [(125)I]Iodo-ASEM readily entered the brains of normal CD-1 mice and specifically and selectively labeled cerebral alpha7-nAChRs. [(125)I]iodo-ASEM is a new useful tool for studying alpha7-nAChR. PMID- 25687450 TI - Stability and in vivo behavior of Rh[16aneS4-diol]211 at complex: a potential precursor for astatine radiopharmaceuticals. AB - INTRODUCTION: The heavy halogen (211)At is of great interest for targeted radiotherapy because it decays by the emission of short-range, high-energy alpha particles. However, many astatine compounds that have been synthesized are unstable in vivo, providing motivation for seeking other (211)At labeling strategies. One relatively unexplored approach is to utilize prosthetic groups based on astatinated rhodium (III) complex stabilized with a tetrathioether macrocyclic ligand - Rh[16aneS(4)-diol](211)At. The purpose of the current study was to evaluate the in vitro and in vivo stability of this complex in comparison to its iodine analog - Rh[16aneS(4)-diol](131)I. METHODS: Rh[16aneS(4) diol](211)At and Rh[16aneS(4)-diol](131)I complexes were synthesized and purified by HPLC. The stability of both complexes was evaluated in vitro by incubation in phosphate-buffered saline (PBS) and human serum at different temperatures. The in vivo behavior of the two radiohalogenated complexes was assessed by a paired label biodistribution study in normal Balb/c mice. RESULTS: Both complexes were synthesized in high yield and purity. Almost no degradation was observed for Rh[16aneS(4)-diol](131)I in PBS over a 72 h incubation. The astatinated analog exhibited good stability in PBS over 14 h. A slow decline in the percentage of intact complex was observed for both tracers in human serum. In the biodistribution study, retention of (211)At in most tissues was higher than that of (131)I at all time points, especially in spleen and lungs. Renal clearance of Rh[16aneS(4)-diol](211)At and Rh[16aneS(4)-diol](131)I predominated, with 84.1 +/ 2.3% and 94.6 +/- 0.9% of injected dose excreted via the urine at 4 h. CONCLUSIONS: The Rh[16aneS(4)-diol](211)At complex might be useful for constructing prosthetic groups for the astatination of biomolecules and further studies are planned to evaluate this possibility. PMID- 25687451 TI - Gene expression-based classifications of fibroadenomas and phyllodes tumours of the breast. AB - Fibroepithelial tumors (FTs) of the breast are a heterogeneous group of lesions ranging from fibroadenomas (FAD) to phyllodes tumors (PT) (benign, borderline, malignant). Further understanding of their molecular features and classification might be of clinical value. In this study, we analysed the expression of 105 breast cancer-related genes, including the 50 genes of the PAM50 intrinsic subtype predictor and 12 genes of the Claudin-low subtype predictor, in a panel of 75 FTs (34 FADs, 5 juvenile FADs, 20 benign PTs, 5 borderline PTs and 11 malignant PTs) with clinical follow-up. In addition, we compared the expression profiles of FTs with those of 14 normal breast tissues and 49 primary invasive ductal carcinomas (IDCs). Our results revealed that the levels of expression of all breast cancer-related genes can discriminate the various groups of FTs, together with normal breast tissues and IDCs (False Discovery Rate < 5%). Among FTs, the levels expression of proliferation-related genes (e.g. CCNB1 and MKI67) and mesenchymal/epithelial-related (e.g. CLDN3 and EPCAM) genes were found to be most discriminative. As expected, FADs showed the highest and lowest expression of epithelial- and proliferation-related genes, respectively, whereas malignant PTs showed the opposite expression pattern. Interestingly, the overall profile of benign PTs was found more similar to FADs and normal breast tissues than the rest of tumours, including juvenile FADs. Within the dataset of IDCs and normal breast tissues, the vast majority of FADs, juvenile FADs, benign PTs and borderline PTs were identified as Normal-like by intrinsic breast cancer subtyping, whereas 7 (63.6%) and 3 (27.3%) malignant PTs were identified as Claudin-low and Basal like, respectively. Finally, we observed that the previously described PAM50 risk of relapse prognostic score better predicted outcome in FTs than the morphological classification, even within PTs-only. Our results suggest that classification of FTs using gene expression-based data is feasible and might provide clinically useful biological and prognostic information. PMID- 25687452 TI - Trifluoromethylthiolation of allylsilanes and silyl enol ethers with trifluoromethanesulfonyl hypervalent iodonium ylide under copper catalysis. AB - Electrophilic trifluoromethylthiolation of allylsilanes and silyl enol ethers with trifluoromethanesulfonyl hypervalent iodonium ylide has been conducted. In the presence of a catalytic amount of CuF2, the reaction proceeded in modest to high yields under mild conditions. PMID- 25687453 TI - Prevalence, clinical characteristics and outcomes of high-risk patients treated for severe aortic stenosis prior to and after transcatheter aortic valve implantation availability. AB - OBJECTIVES: Transcatheter aortic valve implantation (TAVI) has emerged as an effective treatment for high-risk patients with severe aortic stenosis (AS). The aim of our study was to compare the prevalence, characteristics and outcomes of high-risk patients treated prior to and after the availability of TAVI in our high-volume surgical institution. METHODS: Among 879 consecutive patients treated 2 years before ('pre-TAVI era') and after ('modern era') the availability of TAVI in our institution, 83 patients were at high risk [defined by logistic European System for Cardiac Operative Risk Evaluation (EuroSCORE) >20%]. RESULTS: Among all patients treated for severe AS, the prevalence of high-risk patients was higher in the modern era (12.7 vs 4.9%, P < 0.0001). In the modern era, high-risk patients were treated by TAVI in 89% of cases. Despite similar logistic EuroSCORE (34.9 vs 34%, P = 0.96), the clinical characteristics of these patients have evolved: high-risk patients in the modern era were older (85.3 +/- 5.9 vs 78.5 +/ 6.5 years, P = 0.0005) and presented more frequently with New York Heart Association class III-IV (92.3 vs 61.1%, P = 0.003), while high-risk patients treated by surgical aortic valve replacement in the pre-TAVI era presented more frequently with a critical preoperative status (33.3 vs 7.7%, P = 0.01), lower left ventricular ejection fraction (41 +/- 14 vs 49 +/- 15%, P = 0.05) and a history of recent myocardial infarction (27.8 vs 6.1%, P = 0.02). The overall 1 year survival was not different for high-risk patients treated in the pre-TAVI era or in the modern era (61 +/- 11 vs 68 +/- 6%, P = 0.52). CONCLUSIONS: The availability of TAVI has increased the prevalence of high-risk patients treated for severe AS and changed the clinical features of this kind of patients who were rarely surgically treated before. The 1-year survival was similar between pre TAVI and modern eras. PMID- 25687454 TI - A new approach to determine the results of minimally invasive pulmonary vein isolation using a continuous loop monitor: preliminary results. AB - OBJECTIVES: Surgical ablation is a well-known treatment for atrial fibrillation (AF); however, little is known about the absolute success rate. The aim of this study is to compare the absolute pre- and postoperative incidence of AF after minimally invasive surgical ablation for paroxysmal AF. METHODS: Twenty consecutive patients (mean age 55 +/- 8; 55% male) received a continuous loop monitor (CLM) 4 weeks prior to a minimally invasive pulmonary vein isolation (MIPVI). The mean preoperative AF burden was compared with the mean AF burden during follow-up. Follow-up was achieved for a period of 12 months. RESULTS: Seventeen patients underwent an MIPVI successfully. Two patients did not reach the threshold for surgery. In 1 patient, surgery was discontinued because of a perioperative bleeding due to adhesions after a previous percutaneous AF ablation. Mean AF burden preoperatively was 66%. After 12 months, there was an absolute reduction in AF burden of 65% (95% CI 42-88, P < 0.001) and 12 of 15 patients in follow-up (80%) were free of AF without antiarrhythmic drugs (AADs). CONCLUSIONS: The use of a CLM in the follow-up of surgical ablation is a very accurate way to confirm absolute surgical results. Furthermore, with the use of a CLM, preoperative evaluation can be done more accurately, and the surgical procedure can be adjusted to the patients' needs. PMID- 25687455 TI - Overcoming solubility limits in overloaded gradient hydrophobic interaction chromatography. AB - The impact of the solubility limits on the performance of gradient protein chromatography has been studied. As a case study elution of model protein, i.e., lysozyme, on hydrophobic interaction media has been selected. A dependence of the protein solubility and crystallization kinetics on the content of cosmotropic salt in the mobile phase has been determined. Moreover, adsorption properties of the protein versus the mobile phase composition have been quantified. A model of chromatographic column dynamics has been developed which incorporated the mass transport kinetics accompanying both adsorption and crystallization processes. The model was used to study the influence of operating parameters such as flowrate and concentration loading on the solubility pattern inside the column and the separation performance. The analysis performed indicated existence of supersaturation regions for which, due to slow kinetics of crystallization, chromatographic process could be performed under conditions of strong concentration overloading while avoiding undesirable effects of flow blockage in chromatographic systems. PMID- 25687456 TI - New method for the analysis of lipophilic marine biotoxins in fresh and canned bivalves by liquid chromatography coupled to high resolution mass spectrometry: a quick, easy, cheap, efficient, rugged, safe approach. AB - A new method for the analysis of lipophilic marine biotoxins (okadaic acid, dinophysistoxins, azaspiracids, pectenotoxins, yessotoxins, spirolids) in fresh and canned bivalves has been developed. A QuEChERS methodology is applied; i.e. the analytes are extracted with acetonitrile and clean-up of the extracts is performed by dispersive solid phase extraction with C18. The extracts are analyzed by ultra-high performance liquid chromatography coupled to a hybrid quadrupole-Orbitrap mass spectrometer, operating in tandem mass spectrometry mode, with resolution set at 70,000 (m/z 200, FWHM). Separation of the analytes, which takes about 10min, is carried out in gradient elution mode with a BEH C18 column and mobile phases based on 6.7mM ammonia aqueous solution and acetonitrile mixtures. For each analyte the molecular ion and 1 or 2 product ions are acquired, with a mass accuracy better than 5ppm. The quantification is performed using surrogate matrix matched standards, with eprinomectin as internal standard. The high-throughput method, which has been successfully validated, fulfills the requirements of European Union legislation, and has been implemented as a routine method in a public health laboratory. PMID- 25687457 TI - Direct separation of the diastereomers of phosphatidylcholine hydroperoxide bearing 13-hydroperoxy-9Z,11E-octadecadienoic acid using chiral stationary phase high-performance liquid chromatography. AB - Increasing evidence suggests that phospholipid peroxidation plays important roles in the pathogenesis of various diseases, such as atherosclerosis. With regard to the biochemical processes that initiate phospholipid peroxidation in vivo, enzymatic conversion of phosphatidylcholine to phosphatidylcholine hydroperoxide (PCOOH) by lipoxygenase (LOX) may play a crucial role. This will become clear if we can analyze PCOOH bearing hydroperoxy fatty acids with S-stereoconfiguration. In this study, we therefore attempted such an analysis. Initially, we used LOX, linoleic acid and Lyso phosphatidylcholine, and synthesized PCOOH bearing 13S hydroperoxy-9Z,11E-octadecadienoic acid (13(S)-9Z,11E-HPODE). PCOOH bearing racemic 13-9Z,11E-HPODE was also prepared. We used liquid chromatography equipped with CHIRALPAK OP (+) (poly (o-pyridyl diphenylmethacrylate) coated on silica), a UV detector and a quadrupole-time-of-flight mass spectrometer, and achieved diastereomer separation of PCOOH stereoisomers with excellent resolution and peak shape. This is the first study reporting the diastereomer separation of PCOOH. The present method will be beneficial in developing a better understanding of the biochemical processes that initiate oxidative stress (PCOOH formation) in vivo, which may lead to further elucidation of the involvement of PCOOH in the development of diseases. In addition to clinical applications, the present method may also be effective in the evaluation of enzymatic oxidative food deterioration. PMID- 25687458 TI - Exploring the enantioseparation of amino-naphthol analogues by supercritical fluid chromatography. AB - The direct separation of the enantiomers of 1-(alpha-aminoarylmethyl)-2-naphthol, 1-(alpha-aminoalkyl)-2-naphthol, 2-(alpha-aminoarylmethyl)-1-naphthol analogues and 2-(1-amino-2-methylpropyl)-1-naphthol) was investigated in supercritical fluid chromatography. Five commercially available chiral stationary phases based on immobilized polysaccharide chiral selectors (Chiralpak IA, IB, IC, ID and IE) were evaluated. Chiralpak IB was by far the most efficient to achieve the separation of these racemates and was further selected for optimization of elution conditions. The effects of column temperature (varying between 5 and 45 degrees C) and co-solvent added to carbon dioxide (methanol, ethanol, isopropanol and dichloromethane) were investigated. A particular attention was paid to mobile phase additives. Several of them, acids, bases or salts (namely water, formic acid, acetic acid, trifluoroacetic acid, diethylamine, diethanolamine, triethylamine, triethanolamine, dimethylethanolamine, ammonia and ammonium acetate), were tested in order to improve peak shapes while maintaining selectivity. With the help of other achiral naphthol derivatives, the additive effects were examined. PMID- 25687459 TI - How might epigenetic dysregulation in early embryonic life contribute to autism spectrum disorder? PMID- 25687461 TI - Epigenetic reprogramming and blood development. PMID- 25687460 TI - Isoform-selective histone deacetylase inhibitors: the trend and promise of disease treatment. PMID- 25687462 TI - Candidate gene methylation studies are at high risk of erroneous conclusions. PMID- 25687463 TI - A study in familial hypercholesterolemia suggests reduced methylomic plasticity in men with coronary artery disease. AB - AIM: To assess whether DNA methylation is associated with coronary artery disease (CAD). MATERIALS & METHODS: An epigenome-wide analysis has been performed on leucocytes from familial hypercholesterolemic (FH) men with (n = 6) or without CAD (n = 6). The results were replicated in an extended sample of FH men (n = 61) and in non-FH men (n = 100) for two of the top differentially methylated loci. RESULTS: FH men with CAD had significantly more hypomethylated and hypermethylated loci and showed less DNA methylation level variability compared with men without CAD (p < 0.001). Moreover, COL14A1 and MMP9 DNA methylation levels were associated with CAD, age of onset of CAD or CAD risk factors. CONCLUSION: These results suggest that epigenome-wide changes are associated with CAD occurrence in men. PMID- 25687464 TI - Aberrations in DNA methylation are detectable during remission of acute lymphoblastic leukemia and predict patient outcome. AB - AIM: Aberrant DNA methylation patterns are a hallmark of cancer, although the extent to which they underlie cancer development is unknown. In this study, we aimed to determine whether acute lymphoblastic leukemia (ALL) patients in clinical remission retained abnormal DNA methylation patters and whether these were associated with patient outcome. MATERIALS & METHODS: We investigated CpG island methylation of genes known to exhibit hypermethylation in leukemia using quantitative pyrosequencing analysis. RESULTS: Although methylation levels were reduced in remission samples, they remained significantly higher than those seen in healthy controls. This retained methylation was not related to low levels of residual leukemia cells still present at remission. Methylation levels were also stable (or increased) during continuous remission and significantly correlated with long-term survival in adult ALL patients. CONCLUSION: This study determined that abnormalities in DNA methylation are retained during ALL remission and may represent a novel prognostic marker for adult ALL patients. PMID- 25687465 TI - Improved tagmentation-based whole-genome bisulfite sequencing for input DNA from less than 100 mammalian cells. AB - AIM: To develop a whole-genome methylation sequencing method that fulfills the needs for studies using ultra-low-input DNA. MATERIALS & METHODS: The tagmentation-based whole-genome bisulfite sequencing (T-WGBS) technology is modified, enabling stable library construction with complexity from minimally 0.5 ng of initial genomic DNA, which equals less than 100 mammalian cells. RESULTS: We thoroughly assessed the performance of this T-WGBS method by sequencing the methylomes of a rice strain and pre-implantation embryos of rhesus monkey and compare to traditional WGBS approach, thereby demonstrating the efficacy of this new approach. CONCLUSION: This new approach is highly attractive for the complete methylome analysis of very few cells, for example, mammalian pre-implantation embryos, or tiny human biopsy specimens. PMID- 25687466 TI - High-throughput screening to identify inhibitors of lysine demethylases. AB - Lysine demethylases (KDMs) are epigenetic regulators whose dysfunction is implicated in the pathology of many human diseases including various types of cancer, inflammation and X-linked intellectual disability. Particular demethylases have been identified as promising therapeutic targets, and tremendous efforts are being devoted toward developing suitable small-molecule inhibitors for clinical and research use. Several High-throughput screening strategies have been developed to screen for small-molecule inhibitors of KDMs, each with advantages and disadvantages in terms of time, cost, effort, reliability and sensitivity. In this Special Report, we review and evaluate the High-throughput screening methods utilized for discovery of novel small-molecule KDM inhibitors. PMID- 25687467 TI - DNA methylation in psychosis: insights into etiology and treatment. AB - Evidence for involvement of DNA methylation in psychosis forms the focus of this perspective. Of interest are results from two independent sets of experiments including rats treated with antipsychotic drugs and monozygotic twins discordant for schizophrenia. The results show that DNA methylation is increased in rats treated with antipsychotic drugs, reflecting the global effect of the drugs. Some of these changes are also seen in affected schizophrenic twins that were treated with antipsychotics. The genes and pathways identified in the unrelated experiments are relevant to neurodevelopment and psychiatric disorders. The common cause is hypothesized to be aberrations resulting from medication use. However, this needs to be established by future studies that address the origin of methylation changes in psychosis. PMID- 25687468 TI - Polycomb group protein-mediated histone modifications during cell differentiation. AB - Polycomb group (PcG) proteins play an important role in the regulation of gene expression, especially genes encoding lineage-specific factors. Perturbations in PcG protein expression may trigger an unexpected developmental pathway, resulting in birth defects and developmental disabilities. Two Polycomb repressive complexes, PRC1 and PRC2, have been identified and are related with diverse cellular processes through histone modifications. Many developmental genes are trimethylated at histone H3 lysine 27 (H3K27me3) mediated by PRC2, which provides a binding site for PRC1. These processes contribute to chromatin compaction and transcriptional repression. In this review, we discuss about the complex formation of PcG proteins, the mechanism through which they are recruited to target sites and their functional roles in cell differentiation. PMID- 25687469 TI - Lifestyle, pregnancy and epigenetic effects. AB - Rapidly growing evidences link maternal lifestyle and prenatal factors with serious health consequences and diseases later in life. Extensive epidemiological studies have identified a number of factors such as diet, stress, gestational diabetes, exposure to tobacco and alcohol during gestation as influencing normal fetal development. In light of recent discoveries, epigenetic mechanisms such as alteration of DNA methylation, chromatin modifications and modulation of gene expression during gestation are believed to possibly account for various types of plasticity such as neural tube defects, autism spectrum disorder, congenital heart defects, oral clefts, allergies and cancer. The purpose of this article is to review a number of published studies to fill the gap in our understanding of how maternal lifestyle and intrauterine environment influence molecular modifications in the offspring, with an emphasis on epigenetic alterations. To support these associations, we highlighted laboratory studies of rodents and epidemiological studies of human based on sampling population cohorts. PMID- 25687470 TI - Histone deacetylase 6 in health and disease. AB - Histone deacetylase (HDAC)6 is a member of the class IIb HDAC family. This enzyme is zinc-dependent and mainly localized in the cytoplasm. HDAC6 is a unique isoenzyme with two functional catalytic domains and specific physiological roles. Indeed, HDAC6 deacetylates various substrates including alpha-tubulin and HSP90alpha, and is involved in protein trafficking and degradation, cell shape and migration. Consequently, deregulation of HDAC6 activity was associated to a variety of diseases including cancer, neurodegenerative diseases and pathological autoimmune response. Therefore, HDAC6 represents an interesting potential therapeutic target. In this review, we discuss structural features of this histone deacetylase, regulation of its expression and activity, biological functions, implication in human disease initiation and progression. Finally will describe novel and selective HDAC6 inhibitors. PMID- 25687471 TI - Nasal epithelial cells: a tool to study DNA methylation in airway diseases. AB - A number of chronic airway diseases are characterized by high inflammation and unbalanced activation of the immune response, which lead to tissue damage and progressive reduction of the pulmonary function. Because they are exposed to various environmental stimuli, lung cells are prone to epigenomic changes. Many genes responsible for the immune response and inflammation are tightly regulated by DNA methylation, which suggests that alteration of the epigenome in lung cells may have a considerable impact on the penetrance and/or the severity of airway diseases. A major hurdle in clinical epigenomic studies is to gather appropriate biospecimens. Herein, we show that nasal epithelial cells are suitable to analyze DNA methylation in human diseases primarily affecting the lower airway tract. PMID- 25687472 TI - Trans-mitochondrial coordination of cristae at regulated membrane junctions. AB - Reminiscent of bacterial quorum sensing, mammalian mitochondria participate in inter-organelle communication. However, physical structures that enhance or enable interactions between mitochondria have not been defined. Here we report that adjacent mitochondria exhibit coordination of inner mitochondrial membrane cristae at inter-mitochondrial junctions (IMJs). These electron-dense structures are conserved across species, resistant to genetic disruption of cristae organization, dynamically modulated by mitochondrial bioenergetics, independent of known inter-mitochondrial tethering proteins mitofusins and rapidly induced by the stable rapprochement of organelles via inducible synthetic linker technology. At the associated junctions, the cristae of adjacent mitochondria form parallel arrays perpendicular to the IMJ, consistent with a role in electrochemical coupling. These IMJs and associated cristae arrays may provide the structural basis to enhance the propagation of intracellular bioenergetic and apoptotic waves through mitochondrial networks within cells. PMID- 25687473 TI - Hybrid copolymer-phospholipid vesicles: phase separation resembling mixed phospholipid lamellae, but with mechanical stability and control. AB - Vesicles whose bilayer membranes contain phospholipids mixed with co-polymers or surfactants comprise new hybrid materials having potential applications in drug delivery, sensors, and biomaterials. Here we describe a model polymer phospholipid hybrid membrane system exhibiting strong similarities to binary phospholipid mixtures, but with more robust membrane mechanics. A lamella-forming graft copolymer, PDMS-co-PEO (polydimethylsiloxane-co-polyethylene oxide) was blended with a high melting temperature phospholipid, DPPC (1,2-dipalmitoyl-sn glycero-3-phosphocholine), over a broad compositional range. The resulting giant hybrid unilamellar vesicles were compared qualitatively and quantitatively to analogous mixed phospholipid membranes in which a low melting temperature phospholipid, DOPC (1,2-dioleoyl-sn-glycero-3-phosphocholine), was blended with DPPC. The mechanical properties of the hybrid vesicles, even when phase separated, were robust with high lysis stresses and strains approaching those of the pure copolymer vesicles. The temperature-composition phase diagram of the hybrid vesicles closely resembled that of the mixed phospholipids; with only slightly greater nonidealities in the hybrid compared with DOPC/DPPC mixed membranes. In both systems, it was demonstrated that tension could be used to manipulate DPPC solidification into domains of patchy or striped morphologies that exhibited different tracer incorporation. The patch and stripe-shaped domains are thought to be different solid DPPC polymorphys: ripple and tilt (or gel). This work demonstrates that in mixed-phospholipid bilayers where a high melting phospholipid solidifies on cooling, the lower-melting phospholipid may be substituted by an appropriate copolymer to improve mechanical properties while retaining the underlying membrane physics. PMID- 25687474 TI - Modulation by licofelone and celecoxib of experimentally induced cancer and preneoplastic lesions in mice exposed to cigarette smoke. AB - Chronic inflammation plays a crucial role in cigarette smoke-related carcinogenesis. Accordingly, anti-inflammatory agents, such as nonsteroidal anti inflammatory drugs (NSAIDs), provide a rational strategy in cancer chemoprevention. We assayed celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, and licofelone, an inhibitor of COX-1, COX-2, and 5- lipoxygenase (5 LOX), for the ability to modulate carcinogenesis in neonatal mice exposed to mainstream cigarette smoke (MCS) for 4 months and thereafter kept in filtered air for 3.5 months. A preliminary toxicity study and a chemoprevention study involved the use of 591 Swiss H mice. Exposure to MCS caused a variety of pulmonary emphysema, alveolar and bronchial epithelial hyperplasias, proliferation of blood vessels, microadenomas, adenomas and malignant tumors, as well as kidney tubular and urinary bladder papillary epithelial hyperplasias. Celecoxib (1600 mg/kg diet) and even better licofelone (960 mg/kg diet) were able to significantly attenuate the MCS-induced alterations of inflammatory nature, including pulmonary emphysema, alveolar epithelial hyperplasias and microadenomas and urinary tract hyperplastic lesions when given to mice according to a protocol that mimics an intervention in current smokers. Moreover, celecoxib attenuated the yield of lung adenomas and both NSAIDs showed some involvement in lowering the progression to cancer in the lung. Celecoxib exhibited some protective effects even when given according to a protocol involving its administration after discontinuation of exposure to MCS. However, both agents and especially celecoxib showed some hepatotoxicity and affected survival and body weight gain of mice when administered to MCS-exposed mice in the long term. PMID- 25687475 TI - Prevalence of obstructive sleep apnea detected by the Berlin Questionnaire in patients with nocturia attending a urogynecology unit. AB - INTRODUCTION AND HYPOTHESIS: Nocturia has been associated with several chronic conditions including obstructive sleep apnea (OSA). The pathophysiological link between nocturia and OSA has been well delineated, but the prevalence of this condition in patients with nocturia is unknown. The aim of this study was to determine the prevalence of sleep apnea in patients with nocturia compared with patients without nocturia in a group of women referred to a urogynecology unit. METHODS: After ethics approval, a cross-sectional case control study including 81 cases and 79 controls was conducted. The sample size of 72 patients was required for each arm to detect a 23 % difference in the prevalence of OSA with a 95 % confident interval (CI) and statistical power of 80 %. All patients completed the Nocturia, Nocturia Enuresis and Sleep Interruption Questionnaire (NNES-Q) and the Berlin OSA Questionnaire. The NNES-Q was used to define cases and controls. The Berlin Questionnaire was used to classify patients as being at a high or a low risk of having OSA. Univariate analysis was first performed, followed by logistic regression to assess the association between nocturia and OSA, as well as other possible variables associated with nocturia. RESULTS: Fifty of the cases (61.7 %) were classified as being at a high risk of having OSA compared with only 19 (24.1 %) in the control group (OR 2.9, 95 % CI 1.29-6.52, p = 0.01). Other variables found to be statistically significant by logistic regression were high BMI, overactive bladder, and low bladder capacity (<300 cc). CONCLUSION: Patients with nocturia showed a significantly higher risk of having OSA. Patients with nocturia should be screened for OSA. PMID- 25687476 TI - Supramolecular hydrogels as drug delivery systems. AB - Drug delivery from a hydrogel carrier implanted under the kidney capsule is an innovative way to induce kidney tissue regeneration and/or prevent kidney inflammation or fibrosis. We report here on the development of supramolecular hydrogels for this application. Chain-extended hydrogelators containing hydrogen bonding units in the main chain, and bifunctional hydrogelators end functionalized with hydrogen bonding moieties, were made. The influence of these hydrogels on the renal cortex when implanted under the kidney capsule was studied. The overall tissue response to these hydrogels was found to be mild, and minimal damage to the cortex was observed, using the infiltration of macrophages, formation of myofibroblasts, and the deposition of collagen III as relevant read out parameters. Differences in tissue response to these hydrogels could be related to the different physico-chemical properties of the three hydrogels. PMID- 25687477 TI - Enhanced thermal stability and pH behavior of glucose oxidase on electrostatic interaction with polyethylenimine. AB - Electrostatic interactions, mediated by ionic-exchange, between polyethylenimine (PEI) and glucose oxidase (GOx) were used to form GOx-PEI macro-complex, which were evaluated for pH and thermal stability of GOx. Under the experimental conditions, the complex had a dominant GOx presence on its surface and a hydrodynamic diameter of 205 +/- 16 nm. Activity was evaluated from 40 to 75 degrees C, and at pH from 2 to 12. GOx activity in complex was maintained up to 70 degrees C and it was lost at 75 degrees C. In contrast, free GOx showed a maximum activity at 50 degrees C, which was completely lost at 70 degrees C. This difference, observed by fluorescence analysis, was associated with the compact unfolded structure of GOx in the complex. This GOx stability was not observed under pH variations, and complex formation was only possible at pH >= 5 where enzymatic activity was diminished by the presence of PEI. PMID- 25687478 TI - Isolation and characterization of exopolysaccharide from Leuconostoc lactis KC117496 isolated from idli batter. AB - Diverse exopolysaccharide (EPS)-producing isolates were isolated from an Indian acidic fermented food (Idli) based on the colony morphology. One of the EPS producing microflora (Leuconostoc lactis KC117496) was selected for further characterization using FT-IR, HPTLC, AFM, SEM, TGA and XRD analysis. FT-IR spectroscopy revealed the alpha-d-glucose nature of the EPS. HPTLC analysis confirmed the presence of only glucose monomers, indicating the glucan nature of EPS. NMR spectra revealed the presence of 95% alpha-(1->6) and 5% branching alpha (1->3) linkages. The SEM and AFM showed smooth surfaces and compact structure. TGA results showed higher degradation temperature of 272.01 degrees C. XRD analysis proved the 33.4% crystalline nature of the EPS. Water solubility index and water-holding capacity of EPS are 14.2+/-0.208% and 117+/-7.5%. All the above characteristics of the EPS produced by L. lactis showed that the EPS is of a good quality polysaccharide with potential applications in the food industry. PMID- 25687479 TI - Gynecologic follow up of 129 women on dialysis and after kidney transplantation: a retrospective cohort study. AB - OBJECTIVE: To describe the gynecologic issues and follow-up in our referral center of women on dialysis and after kidney transplantation. STUDY DESIGN: This retrospective cohort study included 129 dialysed women among whom 102 had had transplants. Data on menstrual pattern, pregnancies, contraception, and cervical cytology were retrieved from patients' files. RESULTS: The follow-up started at age 41.6+/-14.2 years and lasted for 9.5+/-10.2 years. Of the women, 78.7% had regular menses before dialysis, decreasing to 30.6% on dialysis (p<0.001), when 43.1% were amenorrheic (p<0.001). After transplantation, more patients had regular menstruation and fewer were amenorrheic (respectively 57.1% and 23.1%, p<0.001). On dialysis and after transplantation, 25% and 30.5% of patients suffered from metrorrhagia (compared to 17.1% before, p<0.01). Concerning pregnancies, rates of spontaneous abortions (33.3%, p=0.01), intrauterine growth retardation (28.5%, p<0.001) and prematurity (23.8%, p=0.008) were significantly higher after transplantation than before dialysis. Prescriptions for the combined contraceptive pill and intrauterine device decreased whereas chlormadinone acetate was widely used: it treated metrorrhagia and relieved mastodynia in 80% and 12% of the cases. Smear tests showed more inflammation (33% vs 0.8%, p<0.05), condylomas (13.6% vs 3.1%, p=0.005) and intraepithelial neoplasias (12.6% vs 2.3%, p=0.003) among patients after renal graft than before dialysis. CONCLUSION: Women on dialysis and after kidney transplantation suffered more from irregular menses and metrorrhagia which was improved by chlormadinone acetate. We noted high rates of obstetrical complications and abnormal smear tests. Consequently, this population must have close follow-up to identify and treat gynecologic issues. PMID- 25687480 TI - Obscure etiology, unusual disparity: the epidemiology of testicular cancer in New Zealand. AB - PURPOSE: Testicular cancer (TC) remains perplexing, both in terms of what causes the disease and why certain populations are at greater risk of developing it. In New Zealand, an unusual ethnic disparity exists, whereby the indigenous Maori population suffer the highest rates of disease. In this study, we further describe the epidemiology of TC in the New Zealand context. METHODS: Eligible patients diagnosed with TC between 2000 and 2011 (n = 1,800) were determined from the NZ Cancer Registry and linked to mortality data. Census data were used to estimate population incidence of TC and tumor sub-type by ethnic group. Kaplan Meier and Cox regression analyses were used to compare survival between ethnic groups. RESULTS: Maori males aged 15-44 were 80% more likely to be diagnosed with TC compared to European/Other males [age-standardized relative risk (RR) 1.80, 95% CI 1.58-2.05]. By contrast, disease burden was comparatively low among Pacific and Asian populations. Maori had a greater incidence of both seminoma (RR 1.88, 95% CI 1.52-2.22) and non-seminoma (RR 1.67, 95% CI 1.35-2.07) germ cell tumors than the European/Other population, reducing the likelihood that our observed disparity is driven by differential propensity to one given sub-type among Maori. Maori had poorer survival outcomes [cancer-specific adjusted hazard ratio (HR) 2.29, 95% CI 1.14-4.59] than the European/Other population. CONCLUSIONS: Understanding the drivers of New Zealand's unusual incidence disparities--particularly between Maori and Pacific--could further our understanding of the key exposures involved in TC etiology. PMID- 25687481 TI - Soy isoflavone intake and bone mineral density in breast cancer survivors. AB - PURPOSE: Low bone mineral density (BMD) is common among breast cancer survivors due to acute estrogen deprivation. Soy food is a rich source of phytoestrogens, namely isoflavones, known to have both estrogenic and anti-estrogenic effects. The objective of the study was to assess the association between soy consumption and BMD in breast cancer survivors, which has not previously been evaluated. METHODS: Forearm BMD was evaluated using dual-energy X-ray absorptiometry at 60 months post-diagnosis for 1,587 participants of the Shanghai Breast Cancer Survival Study. Soy intakes collected at 6, 18, and 36 months post-diagnosis were averaged, and the association with BMD, osteopenia, and osteoporosis was evaluated using linear and logistic regression. RESULTS: The mean (standard deviation) intake of isoflavones was 48.1 (28.0) mg/day. Soy intake was inversely associated with BMD and positively associated with osteoporosis. Compared with the lowest quartile, the highest quartile of soy isoflavone intake, >= 62.64 mg/day, was associated with a reduction of BMD by 1.95% [95% confidence interval (CI) -3.54, -0.36%] and an increased odds ratio of 1.69 for osteoporosis (95% CI 1.09, 2.61). The inverse association was predominantly seen among women who recently entered menopause (<= 5 years). CONCLUSION: In contrast to observations from general populations, high soy intake (>= 62.64 mg of soy isoflavone/day) was associated with lower proximal forearm BMD among breast cancer survivors, particularly during the early years of menopause. Our finding needs to be replicated, particularly in studies with more comprehensive bone density evaluation. PMID- 25687482 TI - Informed Consent Examined Within the Context of Culturally Congruent Care: An Interprofessional Perspective. AB - The process of obtaining informed consent for diverse patients poses many challenges for health care professionals as they try to balance ethical, legal, and accreditation requirements of the country within which they practice with the culture care needs of diverse consumers. Culturally competent health care organizations create a governance infrastructure that promotes equity and supports the delivery of culturally appropriate health care services that are responsive to diverse patients. The purpose of this article is to examine the concept of informed consent within the context of culturally congruent care to Saudi patients and families in an American hospital setting. The need for the provision of culturally congruent care that respects the contextual rights and dignity of patients and families while, at the same time, recognizing the legal, ethical, and moral codes of the health professions and requirements of federal, state, and regulatory agencies within the United States will be explored. PMID- 25687483 TI - Pattern changes in step count accumulation and peak cadence due to a physical activity intervention. AB - OBJECTIVES: The purpose was to determine if a 12-week weight loss intervention with a physical activity (PA) component would lead to changes in steps/day, step count accumulation patterns, and peak cadence. DESIGN: Randomized clinical trial. METHODS: Overall, 121 overweight/obese White and African-American adults (ages 35 64yrs) were randomized to a diet education plus PA education and behavior change intervention group (DE+PA) or diet education and behavior change group (DE). The DE+PA intervention was designed to increase steps/day, and steps at moderate-to vigorous intensity. The Actigraph GT3X+ accelerometer was used to measure steps accumulated in different cadence bands (1-19, 20-39, 40-59, 60-79, 80-99, 100 119, 120+ steps/min), and peak 1-min, 30-min and 60-min cadence. Pre- to post intervention changes in steps/day, step count within each cadence band, and peak cadences were compared within groups using paired sample t-test and between groups after adjustment for baseline values of the same variable using ANCOVA. RESULTS: Ninety participants had valid data (44 in the DE+PA group). Change in steps/day was not significantly different between the groups. However, participants in the DE+PA group accumulated significantly more steps at post intervention in the 80-99, 100-119, and 120+ cadence bands, all p<0.02. The DE+PA group increased step counts accumulated within the 100-119 (463+/-1092 vs 56+/ 546 step counts; p=0.01) and 120+ (390+/-999 vs 34+/-321 step counts; p=0.03) cadence bands, as well as peak 60-min cadence when compared to the DE group. CONCLUSIONS: Non-significant changes in steps/day following a PA intervention may mask changes in steps accumulated at moderate-to-vigorous intensity cadences. PMID- 25687485 TI - New BMA campaign calls on politicians to stop using NHS to score points. PMID- 25687484 TI - Facilitatory and inhibitory effects of Kinesio tape: Fact or fad? AB - OBJECTIVES: Kinesio tape (KT) is a commonly used intervention in sports. It claims to be able to alter the muscle activity, in terms of both facilitation and inhibition, by certain application methods. This study compared the neuromuscular activity of the wrist extensor muscles and maximal grip strength with facilitatory, inhibitory KT, and tapeless condition in healthy adults who were ignorant about KT. Potential placebo effects were eliminated by deception. DESIGN: Randomized deceptive trial. METHODS: 33 participants performed maximal grip assessment in a randomly assigned order of three taping conditions: true facilitatory KT, inhibitory KT, and no tape. The participants were blindfolded during the evaluation. Under the pretense of applying a series of adhesive muscle sensors, KT was applied to their wrist extensor muscles of the dominant forearm in the first two conditions. Within-subject comparisons of normalized root mean square of the wrist extensors electromyographic activity and maximal grip strength were conducted across three taping conditions. RESULTS: 31 out of 33 enlisted participants were confirmed to be ignorant about KT. No significant differences were found in the maximum grip strength (p=0.394), electromyographic activity (p=0.276), and self-perceived performance (p=0.825) between facilitatory KT, inhibitory KT, and tapeless conditions. CONCLUSIONS: Neither facilitatory nor inhibitory effects were observed between different application techniques of KT in healthy participants. Clinically, alternative method should be used for muscle activity modulation. PMID- 25687486 TI - Effect of methoxychlor on Ca2+ homeostasis and apoptosis in HA59T human hepatoma cells. AB - Methoxychlor, an organochlorine pesticide, is thought to be an endocrine disrupter that affects Ca2+ homeostasis and cell viability in different cell models. This study explored the action of methoxychlor on cytosolic free Ca2+ concentrations ([Ca2+]i) and apoptosis in HA59T human hepatoma cells. Fura-2, a Ca2+-sensitive fluorescent dye, was applied to measure [Ca2+]i. Methoxychlor at concentrations of 0.1-1 MUM caused a [Ca2+]i rise in a concentration-dependent manner. Removal of external Ca2+ abolished methoxychlor's effect. Methoxychlor induced Ca2+ influx was confirmed by Mn2+-induced quench of fura-2 fluorescence. Methoxychlor-induced Ca2+ entry was inhibited by nifedipine, econazole, SK&F96365, and protein kinase C modulators. Methoxychlor killed cells at concentrations of 10-130 MUM in a concentration-dependent fashion. Chelation of cytosolic Ca2+ with 1,2-bis(2-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid/AM (BAPTA/AM) did not prevent methoxychlor's cytotoxicity. Methoxychlor (10 and 50 MUM) induced apoptosis concentration-dependently as determined by using Annexin V/propidium iodide staining. Together, in HA59T cells, methoxychlor induced a [Ca2+]i rise by inducing Ca2+ entry via protein kinase C-sensitive Ca2+-permeable channels, without causing Ca2+ release from stores. Methoxychlor also induced apoptosis that was independent of [Ca2+]i rises. PMID- 25687487 TI - Modulation of soleus H-reflex during shortening and lengthening muscle actions in young and older adults. AB - The H-reflex is dependently modulated during isometric and anisometric muscle actions. However, the manner of the H-reflex modulation during dynamic muscle movements in relation to ageing is less stated in the literature. This study was designed to investigate the effects of ageing on soleus (SOL) H-reflex modulation during dynamic muscle actions. Twenty young (24 +/- 4 years of age) and 20 older adults (73 +/- 5 years of age) voluntarily participated in the study. The SOL H reflex was measured during passive and active shortening and lengthening muscle actions in a sitting position. The older group showed a lower ratio of the maximal amplitude of H-reflex to M-wave (SOL Hmax/Mmax) during the passive lengthening than that during the passive shortening (shortening: 0.40 +/- 0.22 vs. lengthening: 0.15 +/- 0.10, P < 0.05), whereas the SOL Hmax/Mmax ratio of the young group was significantly higher during the shortening than that during the lengthening contractions at maximal effort (shortening: 0.51 +/- 0.26 vs. lengthening: 0.37 +/- 0.18, P < 0.05). These results suggested different modulations of group Ia afferent inputs to the SOL motoneurons during passive and active dynamic muscle actions between young and older adults. PMID- 25687488 TI - Effects of light-dark cycle on hippocampal iNOS expression and CREB activation in rats. AB - Nitric oxide (NO) is one of the most important interneural signaling molecules mediating hippocampal functions for learning and memory. The diurnal expression of neuronal NO synthase (nNOS) has been well studied. However, the temporal profile and underlying mechanisms of inducible NOS (iNOS) expression in a normal photoperiod or in altered light-dark cycles remain unclear. We examined the temporal profile of iNOS expression in adult male Sprague-Dawley rats maintained in a 12h-light/ 12h-dark photoperiod (12L/12D), which were pre-synchronized for 7 days before the experiment. The protein and mRNA levels of iNOS in the cortex and hippocampus were measured to examine the photic influences on iNOS expression. The results showed rhythmically changes of the levels of iNOS mRNA and protein in the hippocampus, but not in the cerebral cortex. The iNOS mRNA levels peaked at Zeitgeber time (ZT) 6 and ZT22, and the protein levels peaked at ZT8 and ZT18. Notably, the peaks in iNOS mRNA and protein levels in the 12L/12D group were 10 to 12 h apart, and the rhythmic pattern was absent in the 24-h period of the darkness group. In addition, the level of the phosphorylated cAMP response element binding protein (phospho-CREB) was the highest at ZT18, prior to a peak in iNOS mRNA expression at ZT22. A phospho-CREB-iNOS signaling pathway was further confirmed by the interaction of phospho-CREB and the iNOS DNA in histone complexes isolated by chromatin immunoprecipitation at ZT18. In conclusion, the photoperiod affects the diurnal expression of iNOS and activation of CREB in the hippocampus, which provide clues for the possible impact of circadian changes in hippocampal functions. PMID- 25687489 TI - Establishment of a DsRed-monomer-harboring ICR transgenic mouse model and effects of the transgene on tissue development. AB - DsRed-monomer is an enhanced red fluorescent protein that may serve as a marker for studies in biotechnology and cell biology. Since the ICR mouse strain is a widely utilized outbred strain for oncology, toxicology, vaccine development and for aging studies, the objective of this study was to produce a DsRed-monomer transgenic mouse by means of pronuclear micro-injection of a vector driven by the cytomegalovirus (CMV) enhancer/chicken beta-actin promoter. Four transgenic mice were successfully produced, one of which expressed the DsRed-monomer protein in every tissue, although at varying levels. High expression levels were observed in the heart, pancreas and muscle. Moreover, amniotic fluid-derived progenitor cells, which also expressed the DsRed-monomer protein, could be collected from the DsRed-monomer- harboring ICR mice. As compared to wild-type mice, a few biochemical and histological dissimilarities were found in the DsRed-monomer transgenic mice, including the presence of intra-cytoplasmic eosinophilic threadlike materials in the acinar cells. Taken together, transgenic mice stably expressing DsRed-monomer can be produced using pronuclear micro-injection; however, expression of the DsRed-monomer gene or its insertion position may lead to minor influences. PMID- 25687490 TI - Anti-apoptosis effects on hearts of SHSST cyclodextrin complex in a carbon tetrachloride-induced cirrhotic cardiomyopathy rat model. AB - Cirrhotic cardiomyopathy (CCM) is a common cardiac dysfunction in patients waiting for orthotopic liver transplantation (OLT). Carbon tetrachloride (CCl4) intraperitoneal (IP) injection has been reported as successful in a cirrhosis induced CCM model. In this work, we used the same assay for CCM induction using CCl4 (0.2 mg/kg) IP injection twice per day for 14 days during the cardiac protection drugs treatment process. The cardiac protection drugs were silymarin (100 mg/kg/day), baicalein (30 mg/kg/day), San Huang Shel Shin Tang (SHSST, 30 mg/kg/day) and beta-cyclodextrin modified SHSST (SHSSTc, 30 mg/kg/day and 300 mg/kg/day). After 4 weeks of treatment, the SHSSTc cardiac protection effects were determined through activation of the IGF1R cell survival pathway and inhibition of Fas-FADD death domain induced-apoptosis. SHSSTc cardiac protection was enhanced through beta-cyclodextrin modification, which increased bio availability, and displayed stronger protective effects than silymarin and baicalein, both of which are well-known liver protection drugs. Thus, SHSSTc might provide the best therapeutic benefit in CCM treatment. PMID- 25687491 TI - Dopaminergic facilitation of GABAergic transmission in layer III of rat medial entorhinal cortex. AB - The medial entorhinal cortex (MEC) receives a dense dopaminergic innervation and expresses dopamine receptors. However, little is known about the effect of dopamine on GABAergic transmission in this region of the brain. In this study, we recorded GABAA receptor-mediated spontaneous inhibitory postsynaptic currents (sIPSCs) and miniature inhibitory postsynaptic currents (mIPSCs) by using whole cell patch-clamp technique. Application of dopamine at 10 MUM and 100 MUM significantly increased the frequency and amplitude of sIPSCs. This effect of dopamine is primarily mediated by acting at D1-like dopamine receptors, but not D2-like and alpha1 adrenergic receptors, since dopamine-induced increased in frequency and amplitude of the sIPSCs was completely blocked by D1-like, but not D2-like or alpha1 adrenergic, receptor antagonist. However, application of dopamine did not affect the frequency and amplitude of the mIPSCs, implying that the effect of dopamine on the GABAergic transmission is action potential dependent. Together, these findings reveal an indirect mechanism by which activation of D1-like receptors could inhibit the excitability of layer III pyramidal neurons in the MEC. PMID- 25687492 TI - Protective effects of Ocimum gratissimum polyphenol extract on carbon tetrachloride-induced liver fibrosis in rats. AB - Ocimum gratissimum found in tropical regions is a traditional herb commonly which prevents free radical damage and protects liver from oxidative stress and fibrosis. Ocimum gratissimum polyphenol extract (OGPE) was purified by resin tube to 33.24% polyphenol and 8.2% flavonoid, which were three-fold higher compared with the pre-purification concentrations. The abstract was used to determine if the antioxidant components in the O. gratissimum extract (OGE) were responsible for protective effects on liver fibrosis. High-performance liquid chromatography analysis revealed that the content levels of catechin, caffeic acid and epicatechin in OGPE also increased three-fold. Male Wistar rats were administered with carbon tetrachloride (CCl4) and varying amounts of OGPE doses [0-12 mg/kg body weight (BW)] or OGE dose (40 mg/kg BW) for 8 weeks. Results showed that OGPE at 12 mg/kg BW, similar to OGE at 40 mg/kg BW, maintained the liver weight, significantly ameliorated CCl4-induced steatosis, and mitigated other pathological changes. OGPE (12 mg/kg BW) also maintained the levels of serum alanine aminotransferase and aspartate aminotransferase, as well as the levels of malondialdehyde, catalase and alpha-smooth muscle actin in liver tissues from CCl4-induced changes. These findings suggest that antioxidant components in OGPE were the major factors that prevented liver fibrosis. Moreover, higher polyphenol concentrations were necessary for higher effectiveness. PMID- 25687493 TI - Contribution of double strand break repair gene XRCC3 genotypes to nasopharyngeal carcinoma risk in Taiwan. AB - The DNA double strand break repair protein XRCC3 plays a central role in removing double strand breaks from the genome and defects in cellular repair capacity is closely related to human cancer initiation. Therefore, we aimed to investigate the contribution of XRCC3 genotypes to individual nasopharyngeal carcinoma (NPC) susceptibility. In this hospital-based population research, the genotyping and analyzing of XRCC3 rs1799794, rs45603942, rs861530, rs3212057, rs1799796, rs861539, rs28903081 in a large Taiwanese population was performed. Totally, 176 NPC patients and 880 age- and gender-matched healthy controls were genotyped and analyzed by PCR-RFLP method. The results showed that there was a differential distribution among NPC and control subjects in the genotypic (P = 0.000488) and allelic (P = 0.0002) frequencies of XRCC3 rs861539. As for the gene-environment interaction, we have firstly provided evidence showing that there is an obvious joint effect of XRCC3 rs861539 CT and TT genotypes with individual smoking habits on increased NPC risk. In conclusion, the T allele of XRCC3 rs861539, interacts with smoking habit in increasing NPC risk, may be an early detection marker for NPC. PMID- 25687494 TI - Tonic modulation of nociceptive behavior and allodynia by cannabinoid receptors in formalin test in rats. AB - Cannabinoids produce anti-nociceptive and anti-hyperalgesic effects in acute, inflammatory and neuropathic pain models. The current study investigated the role of cannabinoid (CB1 and CB2) receptors in modulating formalin-induced nociceptive behavior and mechanical allodynia in the rat. Rats received subcutaneous plantar injections of 5% formalin in the hind paws. Licking, biting and paw flinching nociceptive behaviors were measured 0-60 min after formalin injection. Allodynia was measured at 3 and 6 h, and 1, 3, 5 and 7 days post-injection using the mechanical paw withdrawal threshold. Animals in the experimental group were given i.p. injections of CB1 and CB2 receptor antagonists AM281 and AM630 at a dose of 1 mg/kg concomitant with formalin, and then twice daily for the following 7 days. AM281 and AM630 enhanced nociceptive behaviors, and attenuated the bilateral mechanical paw withdrawal threshold, compared with the vehicle. The results indicate that CB1 and CB2 receptors mediate a tonically inhibitory action on formalin-induced inflammatory pain, especially long-term allodynia, in bilateral hind paws. PMID- 25687495 TI - Watching polymers grow: real time monitoring of polymerizations via an on-line ESI-MS/microreactor coupling. AB - A technique for the continuous on-line monitoring of polymerization processes by electrospray ionization mass spectrometry (ESI-MS) is presented via coupling with a commercial microreactor system. The potential is demonstrated by monitoring polymerizations in real time under synthesis conditions. Furthermore, a single acrylate monomer insertion into a oligo-RAFT agent, as used in the synthesis of monodisperse sequence controlled materials, was optimized by on-line screening of reaction conditions. PMID- 25687496 TI - The effect of modifying dietary LA and ALA intakes on omega-3 long chain polyunsaturated fatty acid (n-3 LCPUFA) status in human adults: a systematic review and commentary. AB - This paper presents a systematic review of human studies investigating the effect of altering dietary omega-3 polyunsaturated fatty acid (n-3 PUFA) alpha-linolenic acid (ALA) and omega-6 polyunsaturated fatty acid (n-6 PUFA) linoleic acid (LA) intakes on n-3 long-chain polyunsaturated fatty acid (LCPUFA) status in adult humans. The results suggest that it is possible to increase n-3 LCPUFA status by reducing LA and/or increasing ALA intake in humans, although decreasing LA intake to below 2.5%E may be required to specifically increase levels of the n-3 LCPUFA docosahexaenoic acid (DHA). The majority of studies in this area to date have been relatively poor in quality, which limits the ability to draw robust conclusions, and we present a series of recommendations to improve the quality of future studies in fatty acid nutrition in humans. PMID- 25687497 TI - Schistosome infection-derived Hepatic Stellate Cells are cellular source of prostaglandin D2: role in TGF-beta-stimulated VEGF production. AB - Hepatic Stellate Cells (HSCs) play a crucial role in pathogenesis of liver inflammation and fibrosis. During chronic liver injury, HSCs lose vitamin A and transform into myofibroblastic cells. In schistosomal granulomas, these activated HSCs are called GR-HSCs. Schistosomal-triggered hepatic fibrogenesis has TGF-beta as the most potent fibrogenic stimulus, that also controls gene expression of the angiogenic molecule VEGF in HSCs. COX-dependent production of prostaglandins (PGs) also play role in angiogenic processes. Besides angiogenic roles, prostanoids control immunomodulation of Schistosoma mansoni infection. Specifically, schistosoma-derived PGD2 has emerged as a key parasite regulator of immune defense evasion, while no role is still established to host PGD2. Therefore, the aim of this work is to investigate the ability of GR-HSCs to synthesize COX-derived PGD2 and a potential role of this prostanoid in VEGF production by GR-HSCs in vitro. Here, we confirmed that GR-HSCs express COX-2, which displayed perinuclear localization. While unstimulated GR-HSCs produce basal levels of PGD2, TGF-beta stimulation besides increasing COX2- mRNA levels, enhanced synthesis/secretion of PGD2 in GR-HSCs supernatant. Moreover, GR-HSCs derived PGD2 mediate VEGF production by TGF-beta-stimulated GR-HSCs, since the pre-treatment with HQL-79, an inhibitor of hematopoietic PGD synthase inhibited both PGD2 synthesis and VEGF secretion by TGF-beta-stimulated GR-HSCs. All together, our findings show an autocrine/paracrine activity of GR-HSCs-derived PGD2 on TGF-beta-induced VEGF production by GR-HSCs, unveiling a role for PGD2 as important regulator of HSCs activation in hepatic granulomas from schistosome infected mice. PMID- 25687498 TI - Changes in serum alanine aminotransferase levels in telbivudine versus lamivudine treatment for chronic hepatitis B: a meta-analysis. AB - OBJECTIVE: A meta-analysis to compare the efficacy and safety of telbivudine (TBV) and lamivudine (LAM) in patients with chronic hepatitis B (CHB), assessed via changes in serum alanine aminotransferase (ALT) levels. METHOD: The electronic literature databases PubMed(r), Embase(r), Web of Science, Cochrane Library, CISCOM, CINAHL, Google Scholar, China BioMedicine and China National Knowledge Infrastructure were searched for relevant studies. The effect of TBV and LAM treatment on serum ALT was assessed using standard mean differences (SMDs) and 95% confidence intervals (CI). RESULTS: The meta-analysis included six studies (TBV n = 202; LAM, n = 208). Post-treatment ALT levels were significantly lower than pretreatment values for both TBV and LAM (TBV: SMD = 3.00, 95%CI 1.91, 4.09; LAM: SMD = 2.33, 95%CI 1.58, 3.07). Post-treatment ALT was significantly lower after treatment with TBV than LAM (SMD = 0.58, 95%CI 0.21, 0.94). CONCLUSION: Both LAM and TBV are effective in normalizing ALT levels in patients with CHB, but TBV may be a better choice due to its lower rates of drug resistance. PMID- 25687499 TI - Septal myectomy for hypertrophic obstructive cardiomyopathy in Friedreich's ataxia. AB - Hypertrophic cardiomyopathy associated with Friedreich's ataxia is progressive, and there are few, if any, effective treatments available at present. This case report describes a Friedreich's ataxia patient who had a septal myectomy for the management of hypertrophic cardiomyopathy with improved symptoms over a 7-year period. This suggests that septal myectomy may be a viable option to relieve symptoms and interrupt progression of heart disease in appropriately selected Friedreich's ataxia patients. PMID- 25687500 TI - Lipodystrophic diabetes mellitus: a lesson for other forms of diabetes? AB - Lipodystrophies are a genetically heterogeneous group of disorders characterized by loss of subcutaneous adipose tissue and metabolic dysfunction, including insulin resistance, increased levels of free fatty acids, abnormal adipocytokine secretion, and ectopic fat deposition, which are also observed in patients with visceral obesity and/or type 2 diabetes mellitus. Pathophysiological, biochemical, and genetic studies suggest that impairment in multiple adipose tissue functions, including adipocyte maturation, lipid storage, formation and/or maintenance of the lipid droplet, membrane composition, DNA repair efficiency, and insulin signaling, results in severe metabolic and endocrine consequences, ultimately leading to specific lipodystrophic phenotypes. In this review, recent evidences on the causes and metabolic processes of lipodystrophies will be presented, proposing a disease model that could be potentially informative for better understanding of common metabolic diseases in humans, including obesity, metabolic syndrome, and type 2 diabetes. PMID- 25687501 TI - Tau silencing by siRNA in the P301S mouse model of tauopathy. AB - Suppression of tau protein expression has been shown to improve behavioral deficits in mouse models of tauopathies, offering an attractive therapeutic approach. Experimentally this had been achieved by switching off the promoters controlling the transgenic human tau gene (MAPT), which is not possible in human patients. The aim of the present study was therefore to evaluate the effectiveness of small interfering RNAs (siRNAs) and their cerebral delivery to suppress human tau expression in vivo, which might be a therapeutic option for human tauopathies. We used primary cortical neurons of transgenic mice expressing P301S-mutated human tau and Lund human mesencephalic (LUHMES) cells to validate the suppressive effect of siRNA in vitro. For measuring the effect in vivo, we stereotactically injected siRNA into the brains of P301S mice to reveal the suppression of tau by immunochemistry (AT180, MC1, and CP13 antibodies). We found that the AccellTM SMART pool siRNA against MAPT can effectively suppress tau expression in vitro and in vivo without a specific delivery agent. The siRNA showed a moderate distribution in the hippocampus of mice after single injection. NeuN, GFAP, Iba-1, MHC II immunoreactivities and the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay showed neither signs of neurotoxicity or neuroinflammation nor apoptosis when MAPT siRNA is present in the hippocampus. Our data suggest that siRNA against MAPT can serve as a potential tool for gene therapy in tauopathies. PMID- 25687502 TI - Codon swapping of zinc finger nucleases confers expression in primary cells and in vivo from a single lentiviral vector. AB - BACKGROUND: Zinc finger nucleases (ZFNs) are promising tools for genome editing for biotechnological as well as therapeutic purposes. Delivery remains a major issue impeding targeted genome modification. Lentiviral vectors are highly efficient for delivering transgenes into cell lines, primary cells and into organs, such as the liver. However, the reverse transcription of lentiviral vectors leads to recombination of homologous sequences, as found between and within ZFN monomers. METHODS: We used a codon swapping strategy to both drastically disrupt sequence identity between ZFN monomers and to reduce sequence repeats within a monomer sequence. We constructed lentiviral vectors encoding codon-swapped ZFNs or unmodified ZFNs from a single mRNA transcript. Cell lines, primary hepatocytes and newborn rats were used to evaluate the efficacy of integrative-competent (ICLV) and integrative-deficient (IDLV) lentiviral vectors to deliver ZFNs into target cells. RESULTS: We reduced total identity between ZFN monomers from 90.9% to 61.4% and showed that a single ICLV allowed efficient expression of functional ZFNs targeting the rat UGT1A1 gene after codon-swapping, leading to much higher ZFN activity in cell lines (up to 7-fold increase compared to unmodified ZFNs and 60% activity in C6 cells), as compared to plasmid transfection or a single ICLV encoding unmodified ZFN monomers. Off-target analysis located several active sites for the 5-finger UGT1A1-ZFNs. Furthermore, we reported for the first time successful ZFN-induced targeted DNA double-strand breaks in primary cells (hepatocytes) and in vivo (liver) after delivery of a single IDLV encoding two ZFNs. CONCLUSION: These results demonstrate that a codon swapping approach allowed a single lentiviral vector to efficiently express ZFNs and should stimulate the use of this viral platform for ZFN-mediated genome editing of primary cells, for both ex vivo or in vivo applications. PMID- 25687503 TI - Reversal of bone cancer pain by HSV-1-mediated silencing of CNTF in an afferent area of the spinal cord associated with AKT-ERK signal inhibition. AB - Pain induced by bone metastases has a strong impact on the quality of life of patients with cancer, but current therapies for bone cancer pain cannot attain a satisfactory therapeutic goal because of various adverse reactions. Currently, advanced monitoring is required to clarify pathogenic mechanisms, so as to develop more effective treatments. We constructed herpes simplex virus carrying small interference RNA for CNTF (HSV-siCNTF) and established cancer-induced bone cancer pain models with intra-tibial injection of MRMT-1 cells. At different time points after treatment, sensory function indicated by thermal hyperalgesia and mechanical allodynia was measured. The mechanism underlying sensory function regulated by CNTF was also determined. There was apparent mechanical and thermal hyperalgesia in rats injected with bone cancer cells. Bone destruction was detected in the area of tibia injected with tumor cells by the plain radiography. MRMT-1 cells and the increased number of osteoclasts were found in tibia sections stained with hematoxylin and eosin. Intrathecal injection of morphine or HSV siCNTF significantly reduced the mechanical allodynia and thermal hyperalgesia, which was accompanied by astrocyte hypertrophy. The number of nerve fibers positive for substance P (SP) and calcitonin gene related peptide (CGRP) was significantly decreased, which was consistent with the decrease of CNTF, ERK/pERK, AKT/pAKT and c-fos expression. These results demonstrate that the HSV siCNTF gene therapy appears beneficial for the treatment of pain induced by bone cancer via blocking the AKT-ERK signaling pathway. Our data suggest that CNTF interference may be considered a new target to develop an effective management for bone cancer pain. PMID- 25687504 TI - Influences of weather on Ixodes scapularis nymphal densities at long-term study sites in Connecticut. AB - Tick species worldwide are implicated in transmission of pathogens that cause mild to severe diseases in humans and livestock. Although tick population densities are often highly correlated with tick-borne disease rates, we currently know little about which factors underlie annual changes in those tick population densities. We used a 25-year dataset of Ixodes scapularis drag-sampling surveys at two locations in CT, USA, to investigate the relationship between average nymphal density from mid-May to mid-August and monthly, lagged regional weather variables. The dataset was randomly split into two data subsets, one for hypothesis development and one for hypothesis testing. Nymphal density showed the strongest association with the Standardized Precipitation Index for January of the same year that density data were collected in the analysis based on the hypothesis development data subset. This association was positive; nymphal tick density increased with regional winter precipitation. Nymphal density was positively associated with this same weather variable in the hypothesis testing data subset. Weather conditions during the coldest months of the year may serve as a bottleneck to tick populations, thereby functioning as an important correlate of not only annual blacklegged tick nymphal densities the following summer, but also entomological risk associated with tick-borne pathogens transmitted by this species. PMID- 25687505 TI - Erratum to: PGRMC1 contributes to doxorubicin-induced chemoresistance in MES-SA uterine sarcoma. PMID- 25687507 TI - Prmt5: a guardian of the germline protects future generations. PMID- 25687506 TI - Pathological implications of cadherin zonation in mouse liver. AB - Both acute and chronic liver diseases are associated with ample re-modeling of the liver parenchyma leading to functional impairment, which is thus obviously the cause or the consequence of the disruption of the epithelial integrity. It was, therefore, the aim of this study to investigate the distribution of the adherens junction components E- and N-cadherin, which are important determinants of tissue cohesion. E-cadherin was expressed in periportal but not in perivenous hepatocytes. In contrast, N-cadherin was more enriched towards the perivenous hepatocytes. In agreement, beta-catenin, which links both cadherins via alpha catenin to the actin cytoskeleton, was expressed ubiquitously. This zonal expression of cadherins was preserved in acute liver injury after treatment with acetaminophen or partial hepatectomy, but disrupted in chronic liver damage like in non-alcoholic steatohepatitis (NASH) or alpha1-antitrypsin deficiency. Hepatocyte proliferation during acetaminophen-induced liver damage was predominant at the boundary between the damaged perivenous and the intact periportal parenchyma indicating a minor contribution of periportal hepatocytes to liver regeneration. In NASH livers, an oval cell reaction was observed pointing to massive tissue damage coinciding with the gross impairment of hepatocyte proliferation. In the liver parenchyma, metabolic functions are distributed heterogeneously. For example, the expression of phosphoenolpyruvate carboxykinase and E-cadherin overlapped in periportal hepatocytes. Thus, during liver regeneration after acute damage, the intact periportal parenchyma might sustain essential metabolic support like glucose supply or ammonia detoxification. However, disruption of epithelial integrity during chronic challenges may increase susceptibility to metabolic liver diseases such as NASH or vice versa. This might suggest the regulatory integration of tissue cohesion and metabolic functions in the liver. PMID- 25687508 TI - Using chemo-drugs or irradiation to break immune tolerance and facilitate immunotherapy in solid cancer. AB - The immunity is dual host-protective and tumor-promoting in cancer development and progression. Many immune suppressive cells and cytokines in microenvironment can prevent cytotoxic T lymphocytes (CTL) and natural killer cells (NK) from killing tumor cells. Chemotherapy drugs and irradiation have been reported helpful in breaking immune tolerance and creating microenvironment for adoptive cell therapy. Low-dose cyclophosphamide or gemcitabine therapy can selectively deplete T regulatory cells (Treg). Paclitaxel can alter cytokine network at the tumor site, and 5-fluorouracil shows a pronounced effect on myeloid-derived suppressor cells (MDSC) depletion. Local tumor irradiation and total body irradiation (TBI) can also affect tumor microenvironment and facilitate immunotherapy. In this review, we summarize the particular effects of these agents and methods on immunomodulation, as well as their potential values in immunotherapy. The combination with immunotherapy represents a novel therapeutic strategy. PMID- 25687509 TI - All the Tested Human Somatic Cells Express Both Oct4A and Its Pseudogenes but Express Oct4A at Much Lower Levels Compared with Its Pseudogenes and Human Embryonic Stem Cells. AB - Oct4 pseudogenes and isoforms seriously confuse the detection of the pluripotency associated Oct4A expression in somatic cells, which in many cases was not accurately determined. This confusion has recently been discussed, but the wrong conclusions have continuously been made. Most studies failed to detect the expression of Oct4 pseudogenes and isoforms in somatic cells but detected only Oct4A, for which the detection signals incorrectly came from its pseudogenes and isoforms. Some studies detected the expression of only Oct4 pseudogenes in somatic cells but failed to detect Oct4A. The other studies failed to detect the expression of any Oct4 genes. Oct4A is more homologous to its pseudogenes than its isoforms, and it is much more difficult to distinguish Oct4A from its pseudogenes, so this study focused on them. In this study, the strict experimental procedures were followed. Three pairs of Oct4A-specific polymerase chain reaction (PCR) primers were carefully designed and tested by sequencing reverse transcription-polymerase chain reaction (RT-PCR) clones, which showed that only one of them was truly specific to Oct4A. RT-PCR was also performed with the primers amplifying both Oct4A and its pseudogenes, and several hundreds of PCR clones from each cell type were sequenced to reliably distinguish the low abundant Oct4A from its high-abundant pseudogenes. Western blot, immunocytochemistry, and flow cytometric analyses were performed with three Oct4 antibodies to confirm the results of Oct4 mRNA expression. This study undoubtedly made the correct conclusions about Oct4 expression in human somatic cells and showed that all the tested human somatic cells expressed both Oct4A and its pseudogenes but expressed Oct4A at much lower levels compared with its pseudogenes. PMID- 25687510 TI - Robotic Stereotactic Body Radiation Therapy in Patients With Recurrent or Metastatic Abdominopelvic Tumors: A Single Institute Experience. AB - BACKGROUND: The aim of this study was to evaluate the efficacy and toxicity of robotic CyberKnife (Accuray Incorporated, Sunnyvale, California)-based stereotactic body radiation therapy (SBRT) in patients with recurrent or metastatic abdominopelvic tumors. METHODS AND MATERIALS: A total of 69 patients treated between May 2008 and January 2011 were evaluated retrospectively. Indication for SBRT was persistent disease in 3 (4%) patients, local recurrence in 29 (42%) patients, regional recurrence in 13 (19%) patients, and oligometastatic disease in 24 (35%) patients. Forty-two (61%) patients were previously irradiated to the same region and 27 (39%) patients were treated for the first time. The median age was 59 years (range, 24-86 years). There were 31 (45%) male and 38 (55%) female patients. The median total dose was 30 Gy (range, 15-60 Gy) delivered with a median 3 fractions (range, 2-5 fractions). The tumor response to treatment was assessed by computed tomography, magnetic resonance imaging, or positron emission tomography. RESULTS: At the 12-month (range, 2-44 months) median follow-up, local control was 65% and median overall survival (OS) was 20 months. A larger gross tumor volume (>= 67 cm(3)) was significantly correlated with worse 1-year OS (81% vs 48%, P = .03). The patients with local recurrence occurring <11 months had a significantly shorter 1-year local control rate than patients with >= 11 months (31% vs 91%, P < .001). Grade 3-4 acute and late toxicities were seen in 7% and 15% of patients, respectively. The patients with previous radiotherapy history had significantly higher rate of acute toxicity (19% vs 0%, P = .019). Late toxicity was significantly higher in pelvic tumors than in abdominal tumors (3% vs 28%, P = .004). CONCLUSION: The SBRT seems to be feasible and resulted in good treatment outcomes in patients with recurrent or metastatic abdominopelvic tumors. PMID- 25687511 TI - Ethnicity and rehabilitation outcomes: the Needs Assessment Checklist. AB - STUDY DESIGN: Retrospective cohort study with matched samples. OBJECTIVES: To investigate whether significant differences in rehabilitation outcomes exist between different ethnic groups, using the Needs Assessment Checklist (NAC). SETTINGS: Tertiary care, spinal cord injury rehabilitation unit (National Spinal Injuries Centre), Stoke Mandeville Hospital, UK. METHODS: Rehabilitation outcomes and demographic information were obtained from the NAC. Data on 461 individuals were included in the study. Analysis of variance was employed to investigate differences in rehabilitation outcomes between various ethnic groups, across both the whole cohort and matched samples. RESULTS: Significant differences were evident across the different rehabilitation domains when ethnicity was examined, in particular within the domains of physical healthcare and psychological well being. Within the unmatched data set, significant differences were found to exist in 3 of the 10 rehabilitation domains, and with the matched data set within 4 of the 10 domains. The results indicated that the cohort as a whole made significant improvements from the first to the second NAC within all rehabilitation domains. CONCLUSION: Results indicate that ethnicity may have an impact on rehabilitation outcomes for individuals with spinal cord injury. Further investigation is needed to explore the nature of this relationship, and the future role of targeted interventions focusing on improving rehabilitation outcomes within the domains of physical and psychological care, in particular for individuals from different ethnic backgrounds. PMID- 25687512 TI - Relationships between wheeling parameters and wheelchair skills in adults and children with SCI. AB - STUDY DESIGN: Cross-sectional. OBJECTIVES: To determine the relationships between (1) wheeling parameters using the SmartWheel Clinical Protocol (SCP) and wheelchair skills (wheelchair skills test 4.1 (WST)) and (2) push effectiveness (m per push) and the WST, among individuals with spinal cord injury. SETTING: Biomechanics Laboratory, Canada. METHODS: Sixteen adults and eight children participated in this study. Multiple regression analyses were used to determine significant SCP predictors (that is, weight-normalised peak force, speed, push frequency and mechanical effectiveness) of WST score. To determine relationships between push effectiveness and WST scores, Pearson's correlations were calculated. RESULTS: SCP-TILE: speed and mechanical effectiveness explained 36% of the variance in the WST score. SCP-RAMP and SCP-CARPET: speed explained 58% and 37% of the variance in the WST score, respectively. Push effectiveness was significantly correlated with the WST score on all three surfaces (tile, ramp and carpet). CONCLUSION: Wheeling speed was a significant predictor of the WST score for all surfaces tested. Regression analyses demonstrated that SCP-RAMP had the strongest relationship with WST score. Therefore, when time is restricted, the SCP-RAMP may be the most predictive test and speed may be the most useful variable to evaluate. However, the authors do not believe that one single variable should ever replace a full assessment of skills. PMID- 25687513 TI - The effect of functional electrical stimulation cycling on late functional improvement in patients with chronic incomplete spinal cord injury. AB - STUDY DESIGN: Prospective single-arm study. OBJECTIVES: To investigate the effect of functional electrical stimulation (FES) cycling on late functional recovery, spasticity, gait parameters and oxygen consumption during walking in patients with chronic incomplete spinal cord injury (SCI). SETTING: Turkish Armed Forces Rehabilitation Center, Ankara, Turkey. METHODS: Ten patients with chronic (duration of more than 2 years) incomplete SCI who could ambulate at least 10 m independently or with the assistance of a cane or walker, but no hip-knee-ankle foot orthosis. The subjects underwent 1-h FES cycling sessions three times a week for 16 weeks. Outcome measures including the total motor score, the Functional Independence Measure (FIM) score, the Modified Ashworth Scale for knee spasticity, temporal spatial gait parameters and oxygen consumption rate during walking were assessed at baseline, 3 and 6 months after the baseline. RESULTS: There were statistically significant improvements in total motor scores, the FIM scores and spasticity level at the 6-month follow-up (P<0.01). The changes in gait parameters reached no significant level (P>0.05). Oxygen consumption rate of the patients showed significant reduction at only 6 months compared with baseline (P<0.01). CONCLUSION: The results suggest that FES cycling may provide some functional improvements in the late period of SCI. SPONSORSHIP: The study was supported by The Scientific and Technological Research Council of Turkey (TUBITAK). PMID- 25687514 TI - The effectiveness of inpatients rehabilitation for spinal cord patients in Siriraj hospital. AB - STUDY DESIGN: Retrospective study. OBJECTIVES: To study the effectiveness of inpatient rehabilitation in spinal cord injury (SCI) patients. SETTING: Rehabilitation Medicine Department, Faculty of Medicine Siriraj Hospital. SUBJECTS: SCI patients admitted from 2006 to 2010. METHODS: Medical records of SCI patients including baseline characteristic, functional score using Barthel index (BI), length of stay (LOS) and complications were reviewed. The effectiveness and efficiency were calculated by difference of BI admission and BI discharge (DeltaBI) and DeltaBI/LOS, respectively. The factors associated with the effectiveness were then determined by multivariate linear regression analysis. RESULTS: There were 201 admissions with complete data. There were 164 (81.6%) admissions that had objective for intensive rehabilitation. The average LOS was 39.8 days (s.d.=23.6). BI score was significantly increased after inpatient rehabilitation with the effectiveness of 13.0 (s.d.=15.2) and BI efficiency of 0.37 score per day (s.d.=0.47). SCI patients admitted for intensive rehabilitation goal had significantly better BI effectiveness and efficiency compared with other objective group. Only the objective of admission for intensive rehabilitation, the shorter duration of onset before admission, lower BI score on admission and absence of comorbidity were found to associate with the change of BI score. CONCLUSION: Inpatient rehabilitation is considered as important part for improving SCI patients' functional abilities. The shorter duration between SCI and rehabilitation, a lower BI score on admission, the absence of comorbidity and the ability to undertake an intensive rehabilitation program were positively associated with the effectiveness of rehabilitation. These factors should be taken care during inpatient rehabilitation program. PMID- 25687515 TI - Does locomotor training improve pulmonary function in patients with spinal cord injury? AB - OBJECTIVES: The aim of this study was to compare the effects of a locomotor training (LT) combined rehabilitation program with a rehabilitation-only program on pulmonary function in spinal cord injury (SCI) patients by investigating spirometric analyses of the patients. SETTING: Rehabilitation center in Ankara, Turkey. METHODS: Fifty-two patients (40 male, 12 female) with SCI enrolled in the study. The subjects were divided into two groups: the first group (group A) received both LT and a rehabilitation program and the second group (group B) received only the rehabilitation program for 4 weeks. The LT program was prescribed as three 30-min sessions per week. Pulmonary function was evaluated spirometrically in both groups before and after the rehabilitation program. RESULTS: The spirometric values of the SCI patients, including forced vital capacity, forced expiratory volume in 1 second, forced expiratory flow rate and vital capacity (VC) and VC%, increased significantly with LT in the first group (all P<0.05). Maximum voluntary ventilation values increased significantly in both groups (both P<0.05). CONCLUSION: These findings suggest that LT is effective for improving pulmonary function in SCI patients. We also highlight the useful effects of LT, which are likely the result of erect posture, gait and neuroplastic changes that prevent potential complications in SCI patients. PMID- 25687516 TI - Access to surgical upper extremity care for people with tetraplegia: an international perspective. AB - STUDY DESIGN: Survey. OBJECTIVES: To determine whether upper extremity reconstruction in patients with tetraplegia is underutilized internationally and, if so, what are the barriers to care. SETTING: International-attendees of a meeting in Paris, France. METHODS: One hundred and seventy attendees at the Tetrahand meeting in Paris in 2010 were sent a 13-question survey to determine the access and utilization of upper limb reconstruction in tetraplegic patients in their practice. RESULTS: Respondents ranged the globe including North America, South America, Europe, Asia and Australia. Fifty-nine percent of respondents had been practicing for more than 10 years. Sixty-four percent of respondents felt that at least 25% of people with tetraplegia would be candidates for surgery. Yet the majority of respondents found that <15% of potential patients underwent upper extremity reconstruction. Throughout the world direct patient referral was the main avenue of surgeons meeting patients with peer networking a distant second. Designated as the top three barriers to this care were lack of knowledge of surgical options by patients, lack of desire for surgery and poor referral patterns to appropriate upper extremity surgeons. CONCLUSION: The results of this survey, of a worldwide audience, indicate that many of the same barriers to care exist regardless of the patient's address. This was a preliminary opinion survey and thus the results are subjective. However, these results provide a roadmap to improving access to care by improving patient education and interdisciplinary physician communication. PMID- 25687517 TI - Beliefs relating to recurrence of heterotopic ossification following excision in patients with spinal cord injury: a review. AB - STUDY DESIGN: Review of the literature. OBJECTIVES: It is widely believed that the timing of surgery and the size of the initial Neurological Heterotopic Ossification (NHO) affect the recurrence risk of NHO after SCI. A large number of studies were published in the 80s and the 90s, mostly of poor quality despite the fact that they were carried out by experienced surgical teams. The aim of this study was to suggest recommendations relating to the timing of excision of heterotopic ossification after SCI following the analysis of a recent review of the literature. SETTING: France. METHODS: A systematic literature search was performed in the PubMed Embase from January 2002 until June 2014 using the MESH headings 'spinal cord injury', 'paraplegia', 'heterotopic ossification' and 'surgery'. Results were compared with results from epidemiological studies based on the BANKHO database (patients who underwent surgery for troublesome HO after central neurological system (CNS) lesions in our center (357 patients, 539 surgeries)). RESULTS: Few studies were found in the literature, results were sometimes contradictory and practices heterogeneous. Results from the BANKHO database showed that troublesome recurrence of NHO was not associated with 'early' surgery (before 6 months), and no association was found between recurrence and the size of the NHO around the joint (Brooker status). CONCLUSION: We suggest that surgical excision of the NHO should be carried out when it begins to be troublesome, as soon as comorbid factors are under control and the HO is sufficiently constituted for excision. PMID- 25687518 TI - The influence of question design on the response to self-assessment in www.elearnSCI.org: a submodule pilot study. AB - STUDY DESIGN: This is an interventional training session. OBJECTIVE: The objective of this study was to investigate the difference in response to self assessment questions in the original and an adjusted version for a submodule of www.elearnSCI.org for student nurses. SETTING: The study was conducted in a teaching hospital affiliated to Peking University, China. METHODS: In all, 28 student nurses divided into two groups (groups A and B; 14 in each) received a print-out of a Chinese translation of the slides from the 'Maintaining skin integrity following spinal cord injury' submodule in www.elearnSCI.org for self study. Both groups were then tested using the 10 self-assessment multiple-choice questions (MCQs) related to the same submodule. Group A used the original questions, whereas group B received an adjusted questionnaire. RESULTS: The responses to four conventional single-answer MCQs were nearly all correct in both groups. However, in three questions, group A, with the option 'All of the above', had a higher number of correct answers than group B, with multiple-answer MCQs. In addition, in another three questions, group A, using the original multiple answer MCQs, had fewer correct answers than group B, where it was only necessary to tick a single incorrect answer. CONCLUSION: Variations in design influence the response to questions. The use of conventional single-answer MCQs should be reconsidered, as they only examine the recall of isolated knowledge facts. The 'All of the above' option should be avoided because it would increase the number of correct answers arrived at by guessing. When using multiple-answer MCQs, it is recommended that the questions asked should be in accordance with the content within the www.elearnSCI.org. PMID- 25687519 TI - Synergistic behaviour of ZnO nanoparticles and gemini surfactants on the dynamic and equilibrium oil/water interfacial tension. AB - In this work the effect of ZnO nanoparticles on the interfacial behaviour of gemini surfactants (12-3-12 and 14-3-14) at the oil/water interface was investigated. Equilibrium and dynamic interfacial tension in the absence and presence of ZnO was measured and compared. The results show that the synergistic interactions between the surfactants and nanoparticles decrease the interfacial tension beyond that observed for each component, alone. Modelling of dynamic data with two different models indicates that the mechanism of surfactant migration (with and without ZnO) is mixed diffusion-kinetic-control. The Gibbs free energy of micellization and the Gibbs free energy of adsorption in the absence and presence of ZnO were calculated and compared. Finally the effect of addition of ZnO nanoparticles on emulsion stability was also examined. PMID- 25687520 TI - A sustainable slashing industry using biodegradable sizes from modified soy protein to replace petro-based poly(vinyl alcohol). AB - Biodegradable sizing agents from triethanolamine (TEA) modified soy protein could substitute poly(vinyl alcohol)(PVA) sizes for high-speed weaving of polyester and polyester/cotton yarns to substantially decrease environmental pollution and impel sustainability of textile industry. Nonbiodegradable PVA sizes are widely used and mainly contribute to high chemical oxygen demand (COD) in textile effluents. It has not been possible to effectively degrade, reuse or replace PVA sizes so far. Soy protein with good biodegradability showed potential as warp sizes in our previous studies. However, soy protein sizes lacked film flexibility and adhesion for required high-speed weaving. Additives with multiple hydroxyl groups, nonlinear molecule, and electric charge could physically modify secondary structure of soy protein and lead to about 23.6% and 43.3% improvement in size adhesion and ability of hair coverage comparing to unmodified soy protein. Industrial weaving results showed TEA-soy protein had relative weaving efficiency 3% and 10% higher than PVA and chemically modified starch sizes on polyester/cotton fabrics, and had relative weaving efficiency similar to PVA on polyester fabrics, although with 3- 6% lower add-on. In addition, TEA-soy sizes had a BOD5/COD ratio of 0.44, much higher than 0.03 for PVA, indicating that TEA soy sizes were easily biodegradable in activated sludge. PMID- 25687521 TI - Genetic variability of Taenia saginata inferred from mitochondrial DNA sequences. AB - Taenia saginata is an important tapeworm, infecting humans in many parts of the world. The present study was undertaken to identify inter- and intraspecific variation of T. saginata isolated from cattle in different parts of Iran using two mitochondrial CO1 and 12S rRNA genes. Up to 105 bovine specimens of T. saginata were collected from 20 slaughterhouses in three provinces of Iran. DNA were extracted from the metacestode Cysticercus bovis. After PCR amplification, sequencing of CO1 and 12S rRNA genes were carried out and two phylogenetic analyses of the sequence data were generated by Bayesian inference on CO1 and 12S rRNA sequences. Sequence analyses of CO1 and 12S rRNA genes showed 11 and 29 representative profiles respectively. The level of pairwise nucleotide variation between individual haplotypes of CO1 gene was 0.3-2.4% while the overall nucleotide variation among all 11 haplotypes was 4.6%. For 12S rRNA sequence data, level of pairwise nucleotide variation was 0.2-2.5% and the overall nucleotide variation was determined as 5.8% among 29 haplotypes of 12S rRNA gene. Considerable genetic diversity was found in both mitochondrial genes particularly in 12S rRNA gene. PMID- 25687522 TI - Inducible nitric oxide synthase response and associated cytokine gene expression in the spleen of mice infected with Clonorchis sinensis. AB - Clonorchis sinensis is a food-borne parasite that induces a permanent increase of nitrosation in the body upon infection. The spleen is an important secondary lymphoid organ for the regulation of immune responses locally and in the whole body. However, the functions and mechanisms of the spleen in nitric oxide (NO) responses after C. sinensis infection remain unknown. In this study, BALB/c mice were infected with 20, 40, and 80 C. sinensis metacercariae to simulate mild, moderate, and severe infections, respectively. We examined the expression of inducible nitric oxide synthase (iNOS) in the spleen and the relevant cytokine transcription in splenocytes from the mice infected with different amounts of metacercariae. The iNOS of the mice infected with 80 metacercariae was expressed in the spleen as early as 10 days post-infection (dpi) and gradually increased until 90 dpi. The iNOS expression in the mice infected with 40 metacercariae was detected only at 45 and 90 dpi, but not in the mice infected with 20 metacercariae. The level of interferon (IFN)-gamma messenger RNA (mRNA) transcription in splenocytes significantly increased at 10 and 20 dpi (P < 0.05) in response to mild/moderate infection but gradually decreased to normal levels after 45 dpi. The level of IL-12p35 mRNA transcription did not change at 10 and 20 dpi but significantly decreased after 45 dpi under moderate/severe infection (P < 0.05/0.01/0.001). The level of IL-18 mRNA transcription significantly increased at 10 dpi (P < 0.05/0.01) but significantly decreased after 20 dpi (P < 0.05/0.01/0.001). These results suggest that spleen is an important organ for iNOS/NO responses, which correspond to the severity of C. sinensis infection, but cannot be attributed to the expression of the Th1 cytokines. PMID- 25687523 TI - Occurrence of Cryptosporidium and Giardia in recycled waters used for irrigation and first description of Cryptosporidium parvum and C. muris in Greece. AB - Here, we present the first time findings regarding the occurrence of Cryptosporidium and Giardia in sewage waters and the first molecular characterization of Cryptosporidium species in Greece. Biological treatment plants from three regions in Greece have been investigated. The detection of Cryptosporidium oocysts was by modified Ziehl-Neelsen acid fast (MZN-AF) and by immunofluorescence microscopy (IFT) for Cryptosporidium and Giardia (oo)cysts, whereas nested PCR based on the SSU rDNA assay was used for molecular detection of Cryptosporidium followed by sequencing for the genetic characterization of the species. In total, 73 samples (37 raw sewage samples and 38 of treated water samples) were collected and analyzed. Of the 73 water samples, 4 samples were Cryptosporidium-positive by IFT and staining, 12 samples were Cryptosporidium positive by nested PCR; 9 samples were Giardia-positive by IFT. We showed that Cryptosporidium cysts are found both in the input and the discharge of the biological treatment plants. Molecular characterization of Cryptosporidium based on the small subunit ribosomal DNA gene resulted in the determination of Cryptosporidium parvum and Cryptosporidium muris Greek isolates. This is the first report of Cryptosporidium and Giardia occurrence in wastewaters and the first molecular identification of Cryptosporidium species in Greek environments. As the treated water is used for irrigation, or it is discharged into the sea, our findings indicate that biological treatment facilities constitute a possible risk for public health because the related species are prevalent in humans; the results invite for further epidemiological investigations to evaluate the real public health risk in Greece. PMID- 25687524 TI - Light and scanning electron microscopical examination of the third stage larva of Physocephalus dromedarii (Nematoda: Spirocercidae)--an abomasal nematode of the one humped camel (Camelus dromedarius). AB - The life cycle of Physocephalus dromedarii was studied under experimental conditions. Larvae obtained from naturally infected Scarabaeus cristatus and Aphodius sp. (Coleoptera: Scarabaeidae) were measured and examined in light and scanning electron microscopy and used to infect a dromedary as final host as well as chicken, mice and a toad as possible paratenic hosts. Larvae with the same morphology and similar measurements were found in naturally infected reptiles (Trapelus flavimaculatus, Eryx jayakari, Cerastes gasperettii). Body length of examined larvae varied between 1450 and 1700 MUm. Dorsal, ventral and lateral lips, peg-like papillae and amphideal pits are located on the cephalic cone. There are two asymmetrical cervical deirids, long simple lateral wings and a knob like posterior end covered with minute spines. In the camel, patency is reached within 12 weeks after infection while larvae in paratenic hosts migrate into the wall of the alimentary tract and become dormant. PMID- 25687525 TI - Pearsonema plica (Capillaria plica) infection and associated urinary bladder pathology in red foxes (Vulpes vulpes) from Bosnia and Herzegovina. AB - Pearsonema plica is a widely distributed nematode parasite that occurs in the urinary tract of various domestic and wild carnivores. The aim of this study was to investigate the occurrence and geographical distribution of P. plica and associated urinary bladder pathology in 112 red foxes (70 males, 42 females; 87 adults >1 year, 25 juveniles <1 year) from six different geographical regions in Bosnia and Herzegovina. The urinary bladders of the red foxes were subjected to gross examination and histopathology. Urine content (n = 40) and mucosal smears (n = 71) of the urinary bladders were examined microscopically for the presence of P. plica. Overall, adults and eggs of P. plica were detected in 65 (58.0 %; 95% CI 48.9-67.2%) of the foxes. Out of the positive foxes, 42 were males (64.6%) and 23 females (35.3%). According to age, 49 adults (75.3%) and 16 juveniles (24.6%) were positive. There were no statistically significant differences in the infection prevalence between the geographical regions (p = 0.701), sex (p = 0.693), or age (p = 0.646) of the host. Also, no significant differences in the prevalence of parasites in urine content (48.7%; 20/41) and mucosal smears (63.3%; 45/71) were observed (p = 0.165). Eosinophilic cystitis characterized with mild to severe infiltrates of eosinophils in the propria of the bladder mucosa accompanied by hyperemia and edema was observed in 36 examined foxes, 24 of which were P. plica positive. Parasites attached and embedded into the mucosa and free in the lumen were recorded in both cystitis positive and negative foxes. Beside clear numerical differences, the influence of P. plica infection on the occurrence of cystitis was not significant (p = 0.309). The results of this study give the first insight into the distribution of P. plica infection among the red fox population in Bosnia and Herzegovina. Observed microscopic changes may contribute toward a better understanding of pathology caused by this widely distributed parasite in free-ranging red foxes. PMID- 25687526 TI - Copromicroscopic and molecular investigations on intestinal parasites in kenneled dogs. AB - Intestinal parasites are common in dogs worldwide, and their importance has recently increased for a renewed awareness on the public health relevance that some of them have. In this study, the prevalence of helminths and protozoa was evaluated by microscopy in 318 canine faecal samples collected from eight rescue shelters in the North-eastern Italy; 285 of them were also submitted to the molecular characterization of Giardia duodenalis and Cryptosporidium spp. isolates. An analysis was performed to evaluate the prevalence rates in relation to canine individual data, shelter provenance and anthelmintic treatments. Overall, 52.5% (167/318) of faecal samples were positive for at least one parasite. Trichuris vulpis showed the highest overall prevalence rate (29.2%), followed by G. duodenalis (15.1%), Toxocara canis (9.7%), ancylostomatids (8.2%) and Cystoisospora (5.7%). The prevalence of G. duodenalis, evaluated by real-time PCR, was 57.9% (165/285), and 79 isolates were characterized by nested PCR on the beta-giardin gene. The assemblages found were mainly the host-specific genotypes C and D, while only one assemblage was identified as the human-specific genotype B1. Isolates of Cryptosporidium spp., recorded in 3/285 (1.1%) stool samples, were Cryptosporidium parvum based on the characterization of the Cryptosporidium oocyst wall protein (COWP) gene. Although the results describe a relatively limited risk of dog-originating zoonoses, there is the need to improve the quality of shelter practices towards better health managements for safe pet adoption campaigns and a minimization of the environmental faecal pollution with canine intestinal parasites. PMID- 25687527 TI - A fast Resazurin-based live viability assay is equivalent to the MTT-test in the KeratinoSens assay. AB - The KeratinoSensTM assay was the first cell-based in vitro test in the skin sensitisation adverse outcome pathway to be endorsed by an ECVAM statement. It includes a cell viability assessment, which serves two purposes: It forms part of the prediction model to exclude false-positive irritants and cytotoxicity provides some information on sensitizer potency of chemicals, which can feed into a multivariate potency model. In the KeratinoSensTM protocol, Nrf2-dependent luciferase induction and the MTT-viability assay are performed in parallel plates. Resazurin-based viability assays do not require cell lysis and are compatible with luciferase measurements in the same cells. Here, we performed detailed comparison of the tetrazolium-based MTT assay and the PrestoBlue(r) assay on 35 reference chemicals tested in the full KeratinoSensTM protocol. Log transformed IC50 and IC30 values measured with both methods correlate with an R(2) of 0.97 and 0.95. A single chemical showed divergent results and analysis by four different viability assays indicated the PrestoBlue(r) read-out to be correct. The new more rapid and resource efficient approach has clear advantages: Dose-response curves show lower variability and the two endpoints are measured on the same cells. This approach is a valid addition to or replacement of the MTT readout in the KeratinoSensTM assay and it is recommended as a general tool for luciferase-based reporter assays. PMID- 25687528 TI - Identification of di-2-ethylhexyl terephthalate (DEHTP) metabolites using human liver microsomes for biomonitoring applications. AB - Di-2-ethylhexyl terephthalate (DEHTP), a structural isomer of the plasticizer di 2-ethylhexyl phthalate (DEHP), is used in food packaging and medical devices, among other applications, and is a potential replacement for DEHP and other ortho phthalate plasticizers. Identifying sensitive and specific biomarkers of DEHTP is necessary to assess humans' background exposure to DEHTP. Using mass spectrometry, we investigated the metabolism of DEHTP by human liver microsomes to identify in vitro DEHTP metabolites. We unequivocally identified terephthalic acid (TPA) and mono-2-ethylhydroxyhexyl terephthalate (MEHHTP), using authentic standards, and tentatively identified mono-2-ethylhexyl terephthalate (MEHTP) and two other oxidative metabolites of DEHTP: mono-2-ethyloxohexyl terephthalate (MEOHTP), and mono-2-ethyl-5-carboxypentyl terephthalate (MECPTP) from their mass spectrometry fragmentation patterns. We also evaluated the formation of in vitro metabolites of DEHP. DEHTP and DEHP produced similar metabolites, but their metabolite profiles differed considerably. DEHTP metabolized to form TPA, a metabolite of several terephthalates, as the major in vitro metabolite, followed by MEHTP, MEHHTP, MEOHTP and MECPTP. MEHTP, MEHHTP, MEOHTP and MECPTP, which are specific metabolites of DEHTP, may be suitable biomarkers for assessing exposure to DEHTP. Nonetheless, data on the urinary excretion fraction and temporal stability of these metabolites, among other considerations, are needed to demonstrate their utility as exposure biomarkers. PMID- 25687529 TI - Orthostatic hypotension, orthostatic intolerance and frailty: The Irish Longitudinal Study on Aging-TILDA. AB - Because frailty may represent impaired response to physiological stress we explored the associations between frailty and orthostatic hypotension (OH), and orthostatic intolerance (OI). This study was based on a cross-sectional analysis of 5692 community dwelling adults aged 50 years and older included in wave 1 of the Irish Longitudinal Study on Aging. Frailty was assessed using both the phenotypic (FP) and frailty index (FI) models. OH was defined as a drop of >=20 mmHg in systolic blood pressure or a drop of >=10 mmHg diastolic pressure on standing from a seated position. OI was defined as reporting feeling dizzy, light headed or unsteady during this test. 346 (6.1%) participants had OH and 381 (6.7%) participants had OI. The prevalence OH in frail participants was 8.9%, compared to 5% in robust. Similarly the prevalence of OI was 14.3% in frail and 5.7% in robust participants. After adjustment for age and gender, OH was not significantly related to the FP (OR=1.10 95% CI=0.67, 1.81). Conversely OI was (OR=1.80 95% CI=1.13, 2.87), even after adjustment for age, gender, cardiovascular factors and mental health. In fully adjusted models OI remained related to slowness and low muscle strength and to higher FI scores. These data suggest OI symptoms in older adults may reflect various important underlying health deficits, indicative of increasing levels of frailty. Further assessment of frailty in patients experiencing OI is a potential opportunity for early intervention to delay functional decline. PMID- 25687530 TI - Effects of self-care behaviors on medical utilization of the elderly with chronic diseases - A representative sample study. AB - BACKGROUND: Research indicates that self-care affects lifestyle and health behaviors; however, little is known about whether or not self-care affects medical utilization. OBJECTIVES: Exploring the effects on self-care behaviors to medical utilizations by elderly with chronic conditions. METHOD: Data from the Taiwanese National Survey of Health and Living Status of Older Adults and the National Health Insurance claim databases in 2007 were used. Indicators of self care were disease management behavior and self-care confidence of the elderly. We considered hospital admissions, emergency room services, and avoidable hospitalizations as representing utilization of medical services. RESULTS: In total, 2531 cases were recruited. After controlling for demographic factors and health status, a logistic regression showed that higher self-care confidence and beginning an exercise program decreased avoidable hospitalizations. Furthermore, beginning an exercise program decreased hospital admissions and also decreased utilization of emergency services. DISCUSSION: Self-care behavior and confidence decreased avoidable hospitalization, hospital admission and emergency services. More research is needed to identify the interaction between self-care literacy, self-care behavior and health services that may clarify the effective means and provide appropriate intervention programs. PMID- 25687531 TI - Grey matter volume differences in non-affective psychosis and the effects of age of onset on grey matter volumes: A voxelwise study. AB - Previous evidence indicates that structural brain alterations are already present in the early phases of psychosis. In this study we aim to investigate the relationships among the different diagnoses in the spectrum of non-affective psychosis. A hundred-and-one first-episode psychosis patients (FEP) and 69 healthy volunteers, matched for age, gender, handedness and educational level were analyzed by structural MRI and high-dimensional voxel-based morphometry as implemented in SPM8 software. We obtained three main results: (1) FEP patients showed reduction of grey matter volume (GMV) in the frontal, temporal and occipital lobes, left insula and cerebellum. (2) Age of disease onset was an important factor revealing a gradual decrease of GMV (healthy controls>late onset>intermediate onset>early onset) in the frontal, temporal and occipital lobes, insula and cerebellum. (3) A gradual reduction of GMV related to diagnosis spectrum in the frontal, temporal, parietal and occipital lobes of schizophrenia patients being the most affected. These results suggest that an earlier onset of psychosis is linked to an earlier disease-related disruption of structural brain development, which may be most pronounced in schizophrenia compared to other psychoses. PMID- 25687532 TI - Royleanumioside--a new phytotoxic triterpenoid from Teucrium royleanum. AB - Royleanumioside (1), a new lupane type triterpenoid, was secluded from the CHCl3 soluble fraction of Teucrium royleanum. The structure of royleanumioside (1) was ascertained by spectral studies including 1D and 2D NMR spectroscopy and by the assessment with the reported data in literature. This new identified compound 1 was further tested for its phytotoxic activity against lettuce seedlings. Interestingly royleanumioside (1) had shown moderate phytotoxic activity. PMID- 25687533 TI - Long-term Efficacy and Safety of Enzalutamide Monotherapy in Hormone-naive Prostate Cancer: 1- and 2-Year Open-label Follow-up Results. AB - BACKGROUND: Enzalutamide is an androgen receptor inhibitor with a demonstrated overall survival benefit in metastatic castration-resistant prostate cancer. A phase 2 study of enzalutamide monotherapy in patients with hormone-naive prostate cancer (HNPC) showed a high response rate for the prespecified primary endpoint (ie, prostate-specific antigen [PSA] response at week 25), regardless of metastases at baseline, and favorable tolerability. OBJECTIVE: To determine the long-term efficacy and safety of enzalutamide monotherapy at 1 and 2 yr. DESIGN, SETTING, AND PARTICIPANTS: Open-label, single-arm study in patients with HNPC and noncastrate testosterone (>=230 ng/dl). INTERVENTION: Oral enzalutamide 160mg/d until disease progression or unacceptable toxicity. OUTCOME MEASUREMENTS AND ANALYSIS: PSA response (>=80% decline from baseline) assessed at 1 yr (49 wk) and 2 yr (97 wk). RESULTS AND LIMITATIONS: The median (range) age was 73 (48-86) yr and 26 patients (39%) presented with metastases at study entry. Of 67 patients enrolled, 45 (67%) remained on enzalutamide at week 97. For patients remaining on therapy, the PSA response rate at week 97 was 100% (95% confidence interval 92 100%). Of 26 patients with metastases at baseline, 13 (50%) had a complete and four (15.4%) had a partial response as best overall tumor response up to 97 wk on treatment. There was overall maintenance of total-body bone mineral density (BMD) and moderate changes in lean and fat body mass at 49 and 97 wk. The most common adverse events were gynecomastia, nipple pain, fatigue, and hot flushes. The study limitations include lack of a control group and of endocrine, glycemic, and lipid data at 97 wk. CONCLUSIONS: Long-term enzalutamide monotherapy in men with noncastrate HNPC is associated with large sustained reductions in PSA, signals indicating a favorable tumor response, and favorable safety/tolerability profile, with relatively small negative effects on total-body BMD. PATIENT SUMMARY: In this long-term follow-up of the efficacy and safety of enzalutamide monotherapy in patients with hormone-naive prostate cancer, enzalutamide maintained long-term reductions in prostate-specific antigen, with a minimal impact on total-body bone mineral density. TRIAL REGISTRATION: NCT01302041. PMID- 25687534 TI - The predictive value of 18F-FDG PET/CT for assessing pathological response and survival in locally advanced rectal cancer after neoadjuvant radiochemotherapy. AB - PURPOSE: To evaluate whether metabolic changes in the primary tumour during and after preoperative radiochemotherapy (RCT) can predict the histopathological response in patients with locally advanced rectal cancer as well as disease-free survival (DFS) and overall survival (OS). METHODS: Consecutive patients with cT2 4 N0-2 rectal adenocarcinoma were included. (18)F-FDG PET/CT was performed at baseline, at the end of the second week of RCT (early PET/CT) and before surgery (late PET/CT). The PET/CT results were compared with histopathological data (ypT0 N0 vs. ypT1-4 N0-2 as well as TRG1 vs.TRG2-5) and survival. RESULTS: The study included 126 patients. Among 124 patients in whom TNM classification was available, 28 (22.6 %) were ypT0 N0, and among all 126 patients, 31 (24.6 %) were TRG1. The areas under the curve of the early response index (RI) for identifying non-complete pathological response (non-cPR) were 0.74 (95 % CI 0.61 - 0.87) for ypT1-4 N0-2 patients and 0.75 (95 % CI 0.62 - 0.88) for TRG2-5 patients. The optimal cut-off for differentiating patients with non-cPR and cPR was found to be a reduction of 61.2 % (83.1 % sensitivity and 65 % specificity in ypT1-4 N0-2 patients; 85.4 % sensitivity and 65.2 % specificity in TRG2-5 patients). The optimal cut-off for late RI could not be found. The qualitative analysis of images obtained after RCT demonstrated 81.5 % sensitivity and 61.3 % specificity in predicting TRG2-5. After a median follow-up of 68 months, the low number of patients with local/distant recurrence or who had died did not allow the value of PET/CT for predicting DFS and OS to be calculated. CONCLUSION: The early assessment of response to RCT by (18)F-FDG PET/CT can predict non-cPR allowing practical modification of preoperative treatment. Conversely, late RI is not sufficiently accurate for guiding the decision as to whether local excision or even observation is appropriate in an individual patient. Qualitative analysis of late PET/CT images is also not sensitive enough alone to rule out the presence of residual disease. PMID- 25687535 TI - Highlights lecture EANM 2014: "Gimme gimme gimme those nuclear Super Troupers". AB - The EANM Congress 2014 took place in Gothenburg, Sweden, from 18 to 22 October under the presidency of Prof. Wim Oyen, chair of the EANM Scientific Committee. Prof. Peter Gjertsson chaired the Local Organizing Committee, according to the standardized EANM congress structure. The meeting was a highlight for the multidisciplinary community that forms the heart and soul of nuclear medicine; attendance was exceptionally high. In total almost 5,300 participants came to Gothenburg, and 1,397 colleagues participated via the EANM LIVE sessions ( http://eanmlive.eanm.org/index.php ). Participants from all continents were presented with an excellent programme consisting of symposia, scientific and featured sessions, CME sessions, and plenary lectures. These lectures were devoted to nuclear medicine therapy, hybrid imaging and molecular life sciences. Two tracks were included in the main programme, clustering multi-committee involvement: the 5th International Symposium on Targeted Radionuclide-therapy and Dosimetry (ISTARD) and the first Molecules to Man (M2M) track, an initiative of the EANM Committees for Translational Molecular Imaging, Radiopharmacy and Drug Development. The industry made a substantial contribution to the success of the congress demonstrating the latest technology and innovations in the field. During the closing Highlights Lecture, a selection of the best-rated abstracts was presented including diverse areas of nuclear medicine: physics and instrumentation, radiopharmacy, preclinical imaging, oncology (with a focus on the clinical application of newly developed tracers) and radionuclide therapy, cardiology and neurosciences. This Highlights Lecture could only be a brief summary of the large amount of data presented and discussed during the meeting, which can be found in much greater detail in the congress proceedings book, published as Volume 41, Supplement 2 of the European Journal of Nuclear Medicine and Molecular Imaging in October 2014. PMID- 25687536 TI - Ursodeoxycholic acid versus phenobarbital pretreatment prior to hepatobiliary scintigraphy in neonatal cholestasis: is it time for shifting gears towards a practice change? PMID- 25687537 TI - Heritability of catastrophizing: the biopsychosocial model in action. PMID- 25687538 TI - What is special about the vulvar vestibule? PMID- 25687539 TI - GABAergic modulation in central sensitization in humans: a randomized placebo controlled pharmacokinetic-pharmacodynamic study comparing clobazam with clonazepam in healthy volunteers. AB - Positive allosteric modulators of GABAA receptors (GAMs) acting at specific subtypes of GABAA receptors effectively restore compromised spinal pain control in rodents. Studies addressing a similar antihyperalgesic effect in humans are sparse and are hampered by sedative effects of nonselective GAMs available for use in humans. We present results from a randomized controlled double-blind crossover study in 25 healthy volunteers, which addressed potential antihyperalgesic actions of clobazam (CBZ) and clonazepam (CLN) at mildly sedating equianticonvulsive doses. Clobazam was chosen because of its relatively low sedative properties and CLN because of its use in neuropathic pain. Tolterodine (TLT) was used as an active placebo. The primary outcome parameter was a change in the area of cutaneous UVB irradiation-induced secondary hyperalgesia (ASH), which was monitored for 8 hours after drug application. Sedative effects were assessed in parallel to antihyperalgesia. Compared with TLT, recovery from hyperalgesia was significantly faster in the CBZ and CLN groups (P = 0.009). At the time point of maximum effect, the rate of recovery from hyperalgesia was accelerated by CBZ and CLN, relative to placebo by 15.7% (95% confidence interval [CI] 0.8-30.5), P = 0.040, and 28.6% (95% CI 4.5-52.6), P = 0.022, respectively. Active compounds induced stronger sedation than placebo, but these differences disappeared 8 hours after drug application. We demonstrate here that GAMs effectively reduce central sensitization in healthy volunteers. These results provide proof-of-principle evidence supporting efficacy of GAMs as antihyperalgesic agents in humans and should stimulate further research on compounds with improved subtype specificity. PMID- 25687540 TI - Pattern of neuropathic pain induced by topical capsaicin application in healthy subjects. AB - Human experimental pain models are widely used to study drug effects under controlled conditions, but they require further optimization to better reflect clinical pain conditions. To this end, we measured experimentally induced pain in 110 (46 men) healthy volunteers. The quantitative sensory testing (QST) battery (German Research Network on Neuropathic Pain) was applied on untreated ("control") and topical capsaicin-hypersensitized ("test") skin. Z-transformed QST-parameter values obtained at the test site were compared with corresponding values published from 1236 patients with neuropathic pain using Bayesian statistics. Subjects were clustered for the resemblance of their QST pattern to neuropathic pain. Although QST parameter values from the untreated site agreed with reference values, several QST parameters acquired at the test site treated with topical capsaicin deviated from normal. These deviations resembled in 0 to 7 parameters of the QST pattern observed in patients with neuropathic pain. Higher degrees (50%-60%) of resemblance to neuropathic QST pattern were obtained in 18% of the subjects. Inclusion in the respective clusters was predictable at a cross validated accuracy of 86.9% by a classification and regression tree comprising 3 QST parameters (mechanical pain sensitivity, wind-up ratio, and z-transformed thermal sensory limen) from the control sites. Thus, we found that topical capsaicin partly induced the desired clinical pattern of neuropathic pain in a preselectable subgroup of healthy subjects to a degree that fuels expectations that experimental pain models can be optimized toward mimicking clinical pain. The subjects, therefore, qualify for enrollment in analgesic drug studies that use highly selected cohorts to enhance predictivity for clinical analgesia. PMID- 25687541 TI - Peripheral NLCR4 inflammasome participates in the genesis of acute inflammatory pain. AB - Inflammatory hyperalgesia is a complex process that depends on the sensitization of primary nociceptive neurons triggered by proinflammatory mediators, such as interleukin 1beta (IL-1beta). Recently, the peripheral activation of caspase-1 (previously known as IL-1beta-converting enzyme) was implicated in the induction of acute inflammatory pain by promoting the processing of IL-1beta from its precursor form, pro-IL-1beta. Caspase-1 activation in several systems requires the assembly of an intracellular molecular platform called an inflammasome. Inflammasomes consist of 1 nucleotide-binding oligomerization domain-like receptor (NLR), the adapter molecule apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC), and caspase-1. NLRP3 and NLRC4 inflammasomes are well described. However, the identity of the inflammasome that is involved in the peripheral activation of caspase-1 that accounts for acute inflammatory hyperalgesia has not been described. The present findings demonstrated that mice deficient in NLRC4 or ASC, but not in NLRP3, present reduced mechanical and thermal acute inflammatory hyperalgesia induced by carrageenan. The reduced hyperalgesia was accompanied by significant impairments in the levels of mature forms of IL-1beta (p17) and caspase-1 (p20) compared to wild-type mice at the inflammatory site. Therefore, these results identified the inflammasome components NLRC4 and ASC as the molecular platform involved in the peripheral activation of caspase-1 and IL-1beta maturation, which are responsible for the induction of acute inflammatory pain. In conclusion, our study provides new therapeutic targets for the control of acute inflammatory pain. PMID- 25687542 TI - Acid-sensing ion channels detect moderate acidifications to induce ocular pain. AB - Sensory nerve fibers innervating the ocular anterior surface detect external stimuli producing innocuous and painful sensations. Protons are among the first mediators released by damaged cells during inflammation, tissue injury, or other chronic ophthalmic conditions. We studied whether acid-sensing ion channels (ASICs) are expressed in corneal sensory neurons and their roles in the response to moderate acidifications of the ocular surface and in pathologies producing ocular surface inflammation. Moderate acidic pH (6.6) activated ASIC-like currents in corneal sensory neurons, which were blocked by ASIC1- or ASIC3 specific toxins. Acidic pH depolarizes corneal sensory neurons to fire action potentials, an effect blocked by the ASIC3 inhibitor APETx2. 2-Guanidino-4 methylquinazoline, an ASIC3 agonist, activated a population of corneal polymodal sensory nerve fibers and significantly increased the blinking and tearing rate. The nocifensive behaviors produced by application of either a moderate acidic stimulus or ophthalmic drugs formulated in acidic solution were abolished by ASIC blockers. In a model of allergic keratoconjunctivitis, nocifensive behavior was greatly reduced by ASIC3 blockade, presumably by reducing nociceptor sensitization during the inflammatory process. Our results show that, in addition to the established role of TRPV1, ASICs play a significant role in the detection of acidic insults at the ocular surface. The identification of ASICs in corneal neurons and their alterations during different diseases is critical for the understanding of sensory ocular pathophysiology. They are likely to mediate some of the discomfort sensations accompanying several ophthalmic formulations and may represent novel targets for the development of new therapeutics for ocular pathologies. PMID- 25687543 TI - Exercise therapy normalizes BDNF upregulation and glial hyperactivity in a mouse model of neuropathic pain. AB - Treatment of neuropathic pain is a clinical challenge likely because of the time dependent changes in many neurotransmitter systems, growth factors, ionic channels, membrane receptors, transcription factors, and recruitment of different cell types. Conversely, an increasing number of reports have shown the ability of extended and regular physical exercise in alleviating neuropathic pain throughout a wide range of mechanisms. In this study, we investigate the effect of swim exercise on molecules associated with initiation and maintenance of nerve injury induced neuropathic pain. BALB/c mice were submitted to partial ligation of the sciatic nerve followed by a 5-week aerobic exercise program. Physical training reversed mechanical hypersensitivity, which lasted for an additional 4 weeks after exercise interruption. Swim exercise normalized nerve injury-induced nerve growth factor, and brain-derived neurotrophic factor (BDNF) enhanced expression in the dorsal root ganglion, but had no effect on the glial-derived neurotrophic factor. However, only BDNF remained at low levels after exercise interruption. In addition, exercise training significantly reduced the phosphorylation status of PLCgamma-1, but not CREB, in the spinal cord dorsal horn in response to nerve injury. Finally, prolonged swim exercise reversed astrocyte and microglia hyperactivity in the dorsal horn after nerve lesion, which remained normalized after training cessation. Together, these results demonstrate that exercise therapy induces long-lasting analgesia through various mechanisms associated with the onset and advanced stages of neuropathy. Moreover, the data support further studies to clarify whether appropriate exercise intensity, volume, and duration can also cause long-lasting pain relief in patients with neuropathic pain. PMID- 25687544 TI - Distinct roles of the DmNav and DSC1 channels in the action of DDT and pyrethroids. AB - Voltage-gated sodium channels (Nav channels) are critical for electrical signaling in the nervous system and are the primary targets of the insecticides DDT and pyrethroids. In Drosophila melanogaster, besides the canonical Nav channel, Para (also called DmNav), there is a sodium channel-like cation channel called DSC1 (Drosophila sodium channel 1). Temperature-sensitive paralytic mutations in DmNav (para(ts)) confer resistance to DDT and pyrethroids, whereas DSC1 knockout flies exhibit enhanced sensitivity to pyrethroids. To further define the roles and interaction of DmNav and DSC1 channels in DDT and pyrethroid neurotoxicology, we generated a DmNav/DSC1 double mutant line by introducing a para(ts1) allele (carrying the I265N mutation) into a DSC1 knockout line. We confirmed that the I265N mutation reduced the sensitivity to two pyrethroids, permethrin and deltamethrin of a DmNav variant expressed in Xenopus oocytes. Computer modeling predicts that the I265N mutation confers pyrethroid resistance by allosterically altering the second pyrethroid receptor site on the DmNav channel. Furthermore, we found that I265N-mediated pyrethroid resistance in para(ts1) mutant flies was almost completely abolished in para(ts1);DSC1(-/-) double mutant flies. Unexpectedly, however, the DSC1 knockout flies were less sensitive to DDT, compared to the control flies (w(1118A)), and the para(ts1);DSC1(-/-) double mutant flies were even more resistant to DDT compared to the DSC1 knockout or para(ts1) mutant. Our findings revealed distinct roles of the DmNav and DSC1 channels in the neurotoxicology of DDT vs. pyrethroids and implicate the exciting possibility of using DSC1 channel blockers or modifiers in the management of pyrethroid resistance. PMID- 25687545 TI - Maternal folic acid supplementation and the risk of congenital heart defects in offspring: a meta-analysis of epidemiological observational studies. AB - Epidemiological studies have reported conflicting results regarding the association between maternal folic acid supplementation and the risk of congenital heart defects (CHDs). However, a meta-analysis of the association between maternal folic acid supplementation and CHDs in offspring has not been conducted. We searched the MEDLINE and EMBASE databases for articles cataloged between their inceptions and October 10, 2014 and identified relevant published studies that assessed the association between maternal folate supplementation and the risk of CHDs. Study-specific relative risk estimates were pooled using random effects or fixed-effects models. Out of the 1,606 articles found in our initial literature searches, a total of 1 randomized controlled trial, 1 cohort study, and 16 case-control studies were included in our final meta-analysis. The overall results of this meta-analysis provide evidence that maternal folate supplementation is associated with a significantly decreased risk of CHDs (RR = 0.72, 95% CI: 0.63-0.82). Statistically significant heterogeneity was detected (Q = 82.48, P < 0.001, I(2) = 79.4%). We conducted stratified and meta-regression analyses to identify the origin of the heterogeneity among the studies, and a Galbraith plot was generated to graphically assess the sources of heterogeneity. This meta-analysis provides a robust estimate of the positive association between maternal folate supplementation and a decreased risk of CHDs. PMID- 25687546 TI - Non-excitatory electrical stimulation attenuates myocardial infarction via homeostasis of calcitonin gene-related peptide in myocardium. AB - Electrical stimulation has been shown protection of brain, retina, optic nerves and pancreatic beta-cells but the effect on cardio-protection is still unknown. Calcitonin gene-related peptide (CGRP) participates in the pathology of injury and protection of myocardium but whether or not electrical stimulation modulates endogenous CGRP is not clear. Male Sprague-Dawley rats were divided into 4 groups: (1) control group, without any treatment. (2) I/R group, animals were subjected to 30 min of myocardial ischemia followed by 60 min reperfusion. (3) NES+I/R group, non-excitatory electrical stimulation (NES) was commenced from 15 min before coronary artery occlusion till the end of reperfusion. (4) I/R+CGRP8 37 group, animals were given with CGRP8-37 (an antagonist of CGRP receptor, 10( 7) mol/L, 0.3 ml, i.v.) at 5 min before reperfusion without any electrical stimulation. The hemodynamics and electrocardiogram were monitored and recorded. Infarct size and troponin I were examined and CGRP expression in the myocardium and serum was analyzed. It was found that the infarct size and TnI were significantly reduced in NES+I/R group, by 45% and 58% respectively, accompanied by an obvious fall back of CGRP in myocardium, compared to I/R group (all p<0.05). Treatment with CGRP8-37 resulted in the same protection on myocardium as NES did. No significant difference in hemodynamics or ventricular tachycardia was detected among the groups (all p>0.05). It can be concluded that NES reduced the infarction size after acute myocardial ischemia and reperfusion, for which the underlying mechanism may be associated with modulation of endogenous CGRP in myocardium. PMID- 25687547 TI - Functional assembly of 260-kDa oligomers required for mosquito-larvicidal activity of the Bacillus thuringiensis Cry4Ba toxin. AB - Oligomerization has been shown to contribute to the toxicity of Bacillus thuringiensis Cry toxins. Mutations have been made in the Cry4Ba toxin and resulted in toxic to non-toxic mutants toward Aedes aegypti larvae. In this study, Cry4Ba wild type and mutants were analyzed for oligomer formation in vitro, biochemical properties and their relationships with larvicidal activity. In vitro, the Cry4Ba forms two-main types of the oligomers including (1) the 260 kDa and larger oligomers, which assembled in the carbonate buffer, pH 10.0 and completely dissociated by heating at 90 degrees C and (2) 190-kDa oligomer, which was induced by heat, sodium-salt and detergent addition. Polar and charge residues in the toxin domain I and II may contribute to formation of the 260-kDa oligomers. A single Cys-525 in domain III was replaced with serine resulting in the C525S mutant, which exhibited a 50% reduction in larvicidal activity compared to the Cry4Ba wild-type. The mutant exhibited partial loss in larger oligomer of the 260kDa and total loss of 190-kDa oligomer. The results revealed an important role of the Cys-525 in intermolecular disulfide formation of larger oligomer as well as the 190-kDa oligomer. Despite of their formations in the receptor free condition, the 260-kDa and larger oligomers were found to strongly correspond to Cry4Ba toxicity suggesting their functional roles in the A. aegypti larvae. Also, possible roles of the 260-kDa and larger oligomers have been proposed in this report. PMID- 25687548 TI - Understanding Societies from Inside the Organisms. Leo Pardi's Work on Social Dominance in Polistes Wasps (1937-1952). AB - Leo Pardi (1915-1990) was the initiator of ethological research in Italy. During more than 50 years of active scientific career, he gave groundbreaking contributions to the understanding of social life in insects, especially in Polistes wasps, an important model organism in sociobiology. In the 1940s, Pardi showed that Polistes societies are organized in a linear social hierarchy that relies on reproductive dominance and on the physiological and developmental mechanisms that regulate it, i.e. on the status of ovarian development of single wasps. Pardi's work set the stage for further research on the regulatory mechanisms governing social life in primitively eusocial organisms both in wasps and in other insect species. This article reconstructs Pardi's investigative pathway between 1937 and 1952 in the context of European ethology and American animal sociology. This reconstruction focuses on the development of Pardi's physiological approach and presents a new perspective on the interacting development of these two fields at the origins of our current understanding of animal social behavior. PMID- 25687549 TI - Sibling composition, executive function, and children's thinking about mental diversity. AB - Prior investigations of relations between sibling composition and theory of mind have focused almost exclusively on false belief understanding in children 6 years of age and younger. The current work expands previous research by examining whether sibling composition predicts 4- to 11-year-olds' (N=192) more advanced mental state reasoning on interpretive theory of mind tasks. Even when controlling for age and executive function, children with a greater number of older siblings or with more same-sex siblings demonstrated stronger knowledge in both their predictions and explanations that people with different past experiences can have diverse interpretations of ambiguous stimuli. These data provide some of the first documentation of sibling constellations that predict individual differences in theory of mind during middle childhood. PMID- 25687550 TI - Overexpression of GRK6 rescues L-DOPA-induced signaling abnormalities in the dopamine-depleted striatum of hemiparkinsonian rats. AB - l-DOPA therapy in Parkinson's disease often results in side effects such as l DOPA-induced dyskinesia (LID). Our previous studies demonstrated that defective desensitization of dopamine receptors caused by decreased expression of G protein coupled receptor kinases (GRKs) plays a role. Overexpression of GRK6, the isoform regulating dopamine receptors, in parkinsonian rats and monkeys alleviated LID and reduced LID-associated changes in gene expression. Here we show that 2-fold lentivirus-mediated overexpression of GRK6 in the dopamine-depleted striatum in rats unilaterally lesioned with 6-hydroxydopamine ameliorated supersensitive ERK response to l-DOPA challenge caused by loss of dopamine. A somewhat stronger effect of GRK6 was observed in drug-naive than in chronically l-DOPA-treated animals. GRK6 reduced the responsiveness of p38 MAP kinase to l-DOPA challenge rendered supersensitive by dopamine depletion. The JNK MAP kinase was unaffected by loss of dopamine, chronic or acute l-DOPA, or GRK6. Overexpressed GRK6 suppressed enhanced activity of Akt in the lesioned striatum by reducing elevated phosphorylation at its major activating residue Thr(308). Finally, GRK6 reduced accumulation of DeltaFosB in the lesioned striatum, the effect that paralleled a decrease in locomotor sensitization to l-DOPA in GRK6-expressing rats. The results suggest that elevated GRK6 facilitate desensitization of DA receptors, thereby normalizing of the activity of multiple signaling pathways implicated in LID. Thus, improving the regulation of dopamine receptor function via the desensitization mechanism could be an effective way of managing LID. PMID- 25687551 TI - Daily acute intermittent hypoxia elicits functional recovery of diaphragm and inspiratory intercostal muscle activity after acute cervical spinal injury. AB - A major cause of mortality after spinal cord injury is respiratory failure. In normal rats, acute intermittent hypoxia (AIH) induces respiratory motor plasticity, expressed as diaphragm (Dia) and second external intercostal (T2 EIC) long-term facilitation (LTF). Dia (not T2 EIC) LTF is enhanced by systemic adenosine 2A (A2A) receptor inhibition in normal rats. We investigated the respective contributions of Dia and T2 EIC to daily AIH-induced functional recovery of breathing capacity with/without A2A receptor antagonist (KW6002, i.p.) following C2 hemisection (C2HS). Rats received daily AIH (dAIH: 10, 5-min episodes, 10.5% O2; 5-min normoxic intervals; 7 successive days beginning 7days post-C2HS) or daily normoxia (dNx) with/without KW6002, followed by weekly (reminder) presentations for 8weeks. Ventilation and EMGs from bilateral diaphragm and T2 EIC muscles were measured with room air breathing (21% O2) and maximum chemoreceptor stimulation ( MCS: 7% CO2, 10.5% O2). dAIH increased tidal volume (VT) in C2HS rats breathing room air (dAIH+vehicle: 0.47+/-0.02, dNx+vehicle: 0.40+/-0.01ml/100g; p<0.05) and MCS (dAIH+vehicle: 0.83+/-0.01, dNx+vehicle: 0.73+/-0.01ml/100g; p<0.001); KW6002 had no significant effect. dAIH enhanced contralateral (uninjured) diaphragm EMG activity, an effect attenuated by KW6002, during room air breathing and MCS (p<0.05). Although dAIH enhanced contralateral T2 EIC EMG activity during room air breathing, KW6002 had no effect. dAIH had no statistically significant effects on diaphragm or T2 EIC EMG activity ipsilateral to injury. Thus, two weeks post-C2HS: 1) dAIH enhances breathing capacity by effects on contralateral diaphragm and T2 EIC activity; and 2) dAIH-induced recovery is A2A dependent in diaphragm, but not T2 EIC. Daily AIH may be a useful in promoting functional recovery of breathing capacity after cervical spinal injury, but A2A receptor antagonists (e.g. caffeine) may undermine its effectiveness shortly after injury. PMID- 25687552 TI - Experimental optic neuritis induced by the microinjection of lipopolysaccharide into the optic nerve. AB - Optic neuritis (ON) is a condition involving primary inflammation, demyelination, and axonal injury in the optic nerve which leads to retinal ganglion cell (RGC) loss, and visual dysfunction. We investigated the ability of a single microinjection of bacterial lipopolysaccharide (LPS) directly into the optic nerve to induce functional and structural alterations compatible with ON. For this purpose, optic nerves from male Wistar rats remained intact or were injected with vehicle or LPS. The effect of LPS was evaluated at several time points post injection in terms of: i) visual pathway and retinal function (visual evoked potentials (VEPs) and electroretinograms, (ERGs), respectively), ii) anterograde transport from the retina to its projection areas, iii) consensual pupil light reflex (PLR), iv) optic nerve histology, v) microglia/macrophage reactivity (by Iba-1- and ED1-immunostaining), vi) astrocyte reactivity (by glial fibrillary acid protein-immunostaining), vii) axon number (by toluidine blue staining), vii) demyelination (by myelin basic protein immunoreactivity and luxol fast blue staining), viii) optic nerve ultrastructure, and ix) RGC number (by Brn3a immunoreactivity). LPS induced a significant and persistent decrease in VEP amplitude and PLR, without changes in the ERG. In addition, LPS induced a deficit in anterograde transport, and an early inflammatory response consisting in an increased cellularity, and Iba-1 and ED1-immunoreactivity in the optic nerve, which were followed by changes in axonal density, astrocytosis, demyelination, and axon and RGC loss. These results suggest that the microinjection of LPS into the optic nerve may serve as a new experimental model of primary ON. PMID- 25687553 TI - Determinants of reaching drug-free remission in patients with early rheumatoid or undifferentiated arthritis after one year of remission-steered treatment. AB - OBJECTIVE: The aim of this study was to assess whether baseline characteristics in patients with undifferentiated arthritis or early RA affect the possibility of achieving drug-free remission after 1 year (DFR1 year) of early remission induction therapy. METHODS: We included 375 patients participating in the IMPROVED study who achieved remission (DAS < 1.6) after 4 months (early remission) and were by protocol able to achieve DFR1 year. Having started with MTX plus prednisone, patients tapered prednisone to zero; after 8 months, those still in remission tapered MTX to zero, while those not in remission restarted prednisone. Characteristics of patients achieving and not achieving DFR1 year were compared. Logistic regression was performed to identify predictors of DFR1 year. RESULTS: After 1 year, 119 patients (32%) were in DFR. Presence of RF, fulfilling the 2010 criteria for RA, and a low tender joint count were associated with achieving DFR1 year, whereas presence of ACPA was not. None of the baseline characteristics was independently associated with DFR1 year. DFR1 year was sustained for 4 months in 65% of the patients. ACPA-positive patients less often had sustained DFR than ACPA-negative patients (58% vs 80%, P = 0.013). CONCLUSION: After 1 year of remission-steered treatment, 32% of the patients who had achieved early remission after 4 months were able to taper medication and achieved DFR. Neither the presence of ACPA nor any other baseline characteristics were independently associated with achieving DFR1 year, but in ACPA-positive patients DFR was less often sustained. PMID- 25687554 TI - Evaluation of submarine atmospheres: effects of carbon monoxide, carbon dioxide and oxygen on general toxicology, neurobehavioral performance, reproduction and development in rats. II. Ninety-day study. AB - Carbon monoxide (CO), carbon dioxide (CO2) and low-level oxygen (O2) (hypoxia) are submarine atmosphere components of highest concern because of a lack of toxicological data available to address the potential effects from long-duration, combined exposures on female reproductive and developmental health. In this study, subchronic toxicity of mixed atmospheres of these three submarine air components was evaluated in rats. Male and female rats were exposed via inhalation to clean air (0.4 ppm CO; 0.13% CO2; 20.6% O2) (control), a low-dose (5.0 ppm CO; 0.41% CO2; 17.1% O2), a mid-dose (13.9 ppm CO; 1.19 or 1.20% CO2; 16.1% O2) and a high-dose (89.9 ppm CO; 2.5% CO2; 15.0% O2) gas mixture for 23 h per day for 70 d premating and a 14-d mating period. Impregnated dams continued exposure to gestation day 19. Adverse reproductive effects were not identified in exposed parents (P0) or first (F1) and second generation (F2) offspring during mating, gestation or parturition. No adverse changes to the estrous cycle or in reproductive hormone concentrations were identified. The exposure-related effects were reduced weight gains and adaptive up-regulation of erythropoiesis in male rats from the high-dose group. No adverse, dose-related health effects on clinical data or physiological data were observed. Neurobehavioral tests identified no apparent developmental deficits at the tested levels of exposure. In summary, subchronic exposures to the submarine atmosphere gases did not affect the ability of the exposed rats or their offspring to reproduce and did not appear to have any significant adverse health effects. PMID- 25687555 TI - A new form of communication between rheumatology and primary care: The virtual consultation. AB - In recent years, the prevalence of rheumatic diseases has increased. The virtual consultation of rheumatology could help to avoid unnecessary visits and attend those who need an early visit. The virtual consultation is associated with telemedicine and telecommunication. The objective of this study is to describe the characteristics of all virtual consultations performed in the Rheumatology Service during a one year period. More than a 50% were resolved without giving the patients an appointment. With virtual consultation we have achieved: 1) a closer contact with primary care, 2) rapid resolution of doubts about rheumatic disease in patients, 3) improvement of training in rheumatic disorders and 4) prioritizing those patients requiring early assessment by a rheumatologist. PMID- 25687556 TI - High-resolution crystal structure of Z-DNA in complex with Cr(3+) cations. AB - This work is part of our project aimed at characterizing metal-binding properties of left-handed Z-DNA helices. The three Cr(3+) cations found in the asymmetric unit of the d(CGCGCG)2-Cr(3+) crystal structure do not form direct coordination bonds with atoms of the Z-DNA molecule. Instead, the hydrated Cr(3+) ions are engaged in outer-sphere interactions with phosphate groups and O6 and N7 guanine atoms of the DNA. The Cr(3+)(1) and Cr(3+)(2) ions have disordered coordination spheres occupied by six water molecules each. These partial-occupancy chromium cations are 2.354(15) A apart and are bridged by three water molecules from their hydration spheres. The Cr(3+)(3) cation has distorted square pyramidal geometry. In addition to the high degree of disorder of the DNA backbone, alternate conformations are also observed for the deoxyribose and base moieties of the G2 nucleotide. Our work illuminates the question of conformational flexibility of Z DNA and its interaction mode with transition-metal cations. PMID- 25687557 TI - Dynamics of an initially spherical bubble rising in quiescent liquid. AB - The beauty and complexity of the shapes and dynamics of bubbles rising in liquid have fascinated scientists for centuries. Here we perform simulations on an initially spherical bubble starting from rest. We report that the dynamics is fully three-dimensional, and provide a broad canvas of behaviour patterns. Our phase plot in the Galilei-Eotvos plane shows five distinct regimes with sharply defined boundaries. Two symmetry-loss regimes are found: one with minor asymmetry restricted to a flapping skirt; and another with marked shape evolution. A perfect correlation between large shape asymmetry and path instability is established. In regimes corresponding to peripheral breakup and toroid formation, the dynamics is unsteady. A new kind of breakup, into a bulb-shaped bubble and a few satellite drops is found at low Morton numbers. The findings are of fundamental and practical relevance. It is hoped that experimenters will be motivated to check our predictions. PMID- 25687558 TI - ROCK and Rho: Promising therapeutic targets to ameliorate pulmonary fibrosis. AB - This commentary highlights the article by Sisson et al, which establishes the importance of the myocardin-related transcription factor/serum response factor signaling pathway as a therapeutic target in the management of fibrotic lung disease. PMID- 25687559 TI - New insights about miRNAs in cystic fibrosis. AB - The molecular basis of cystic fibrosis (CF) is a mutation-related defect in the epithelial-cell chloride channel called CF transmembrane conductance regulator (CFTR). This defect alters chloride ion transport and impairs water transport across the cell membrane. Marked clinical heterogeneity occurs even among patients carrying the same mutation in the CFTR gene. Recent studies suggest that such heterogeneity could be related to epigenetic factors and/or miRNAs, which are small noncoding RNAs that modulate the expression of various proteins via post-transcriptional inhibition of gene expression. In the respiratory system, it has been shown that the dysregulation of miRNAs could participate in and lead to pathogenicity in several diseases. In CF airways, recent studies have proposed that miRNAs may modulate disease progression by affecting the production of either CFTR or various proteins that are dysregulated in the CF lung. Herein, we provide an overview of studies showing how miRNAs may modulate CF pathology and the efforts to develop miRNA-based treatments and/or to consider miRNAs as biomarkers. The identification of miRNAs involved in CF disease progression opens up new avenues toward treatments targeting selected clinical components of CF, independently from the CFTR mutation. PMID- 25687560 TI - Preliminary evaluation of a self-directed video-based 1-2-3 Magic parenting program: a randomized controlled trial. AB - The current study examined the effectiveness of a self-directed video-based format of the 1-2-3 Magic parenting program in reducing dysfunctional parenting and child problem behaviors. Eighty-four parents of children aged 2-10 were randomly assigned to either the intervention group (n = 43) or the waitlist control group (n = 41). Participants in the intervention group reported significantly less problem behaviors for their children, and significantly less dysfunctional parenting, at post-intervention when compared to the control group. The results were maintained at 6-month follow-up. There was no significant change on measures of parental adjustment for either group. The current results provide preliminary support for the conclusion that the video-based self-directed format of the 1-2-3 Magic parenting program is suitable as an entry-level intervention in a multi-level intervention model and is suitable for inclusion in a population approach to parenting program delivery. PMID- 25687561 TI - A urinary metabolomics study of rats after the exposure to acrylamide by ultra performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry. AB - Acrylamide (ACR) is known to induce neurotoxicity in humans and occupational exposure to ACR has an effect on human health. Since some animal experiments indicate the metabolic change caused by the ACR based on the metabolomics, increasing concern is the change of metabolite profiles by the low-dose ACR. In the present study, a low-dose of ACR (18 mg kg(-1)) was administered to male Wistar rats for 40 days. Ultra performance liquid chromatography/time of flight mass spectrometry (UPLC-Q-TOF MS) was used to examine urine samples from ACR dosed and control animals. Multiple statistical analyses with principal component analysis (PCA) were used to investigate metabolite profile changes in urine samples, and to screen for potential neurotoxicity biomarkers. PCA showed differences between the ACR-dosed and control groups 20 days after the start of dosing; a bigger separation between the two groups was seen after dosing for 40 days. Levels of 4-guanidinobutanoic acid and 2-oxoarginine were significantly higher in urine from the ACR-dosed group than in urine from the control group after 10 days (p < 0.05). Receiver operator characteristic (ROC) curve analysis suggested that 4-guanidinobutanoic acid and 2-oxoarginine were the major metabolites. Our results suggest that high levels of 4-guanidinobutanoic acid and 2-oxoarginine may be related to ACR neurotoxicity. These metabolites could, therefore, act as sensitive biomarkers for ACR exposure and be useful for investigating toxic mechanisms. They may also provide a scientific foundation for assessing the effects of chronic low-dose ACR exposure on human health. PMID- 25687562 TI - The risk of infant and fetal death by each additional week of expectant management in intrahepatic cholestasis of pregnancy by gestational age. AB - OBJECTIVE: The objective of the study was to characterize the risk of infant and fetal death by each additional week of expectant management vs immediate delivery in pregnancies complicated by cholestasis. STUDY DESIGN: This was a retrospective cohort study of 1,604,386 singleton, nonanomalous pregnancies of women between 34 and 40 weeks' gestation with and without intrahepatic cholestasis of pregnancy (ICP) in the state of California during the years of 2005-2008. International Classification of Diseases, 9th version, codes and linked hospital discharge and vital statistics data were utilized. For each week of gestation, the following outcomes were assessed: the risk of stillbirth, the risk of delivery (represented by the risk of infant death at a given week of gestation), and the composite risk of expectant management for 1 additional week. Composite risk combines the risk of stillbirth at this gestational age week plus the risk of infant death if delivered at the subsequent week of gestation. RESULTS: Among women with ICP, the mortality risk of delivery is lower than the risk of expectant management at 36 weeks' gestation (4.7 vs 19.2 per 10,000). The risk of expectant management remains higher than delivery and continues to rise by week of gestation beyond 36 weeks. The risk of expectant management in women with ICP reaches a nadir at 35 weeks (9.1 per 10,000; 95% confidence interval, 1.4-16.9) and rises at 36 weeks (19.2 per 10,000; 95% confidence interval, 7.6-30.8). CONCLUSION: Among women with ICP, delivery at 36 weeks' gestation would reduce the perinatal mortality risk as compared with expectant management. For later diagnoses, this would also be true at gestational ages beyond 36 weeks. Timing of delivery must take into account both the reduction in stillbirth risk balanced with the morbidities associated with preterm delivery. PMID- 25687563 TI - Fetal DNA methylation of autism spectrum disorders candidate genes: association with spontaneous preterm birth. AB - OBJECTIVE: Autism spectrum disorder (ASD) is associated with preterm birth (PTB), although the reason underlying this relationship is still unclear. Our objective was to examine DNA methylation patterns of 4 ASD candidate genes in human fetal membranes from spontaneous PTB and uncomplicated term birth. STUDY DESIGN: A literature search for genes that have been implicated in ASD yielded 14 candidate genes (OXTR, SHANK3, BCL2, RORA, EN2, RELN, MECP2, AUTS2, NLGN3, NRXN1, SLC6A4, UBE3A, GABA, AFF2) that were epigenetically modified in relation to ASD. DNA methylation in fetal leukocyte DNA in 4 of these genes (OXTR, SHANK3, BCL2, and RORA) was associated with PTB in a previous study. This study evaluated DNA methylation, transcription (reverse transcription polymerase chain reaction), and translation patterns (immunostaining and Western blot) in fetal membrane from term labor (n = 14), term not in labor (TNIL; n = 29), and spontaneous preterm birth (PTB; n = 27). Statistical analysis was performed with analysis of variance; a probability value of < .05 was significant. RESULTS: Higher methylation of the OXTR promoter was seen in fetal membranes from PTB, compared with term labor or TNIL. No other gene showed any methylation differences among groups. Expression of OXTR was not different among groups, but the 70 kDa OXTR protein was seen only in PTB, and immunostaining was more intense in PTB amniocytes than term labor or TNIL. CONCLUSION: Among the 4 genes that were studied, fetal membranes from PTB demonstrate differences in OXTR methylation and regulation and expression, which suggest that epigenetic alteration of this gene in fetal membrane may likely be indicating an in utero programing of this gene and serve as a surrogate in a subset of PTB. The usefulness of OXTR hypermethylation as a surrogate for a link to ASD should be further evaluated in longitudinal and in vitro studies. PMID- 25687565 TI - Pregnancy complications in women with rare tumor suppressor syndromes affecting central and peripheral nervous system. PMID- 25687564 TI - The phenotype of spontaneous preterm birth: application of a clinical phenotyping tool. AB - OBJECTIVE: Spontaneous preterm birth (SPTB) is a complex condition that is likely a final common pathway with multiple possible causes. We hypothesized that a comprehensive classification system appropriately could group women with similar STPB causes and could provide an explanation, at least in part, for the disparities in SPTB that are associated with race and gestational age at delivery. STUDY DESIGN: This was a planned analysis of a multicenter, prospective study of singleton SPTBs. Women with SPTB at <34 weeks' gestation were included. We defined 9 potential SPTB phenotypes based on clinical data: infection/inflammation, maternal stress, decidual hemorrhage, uterine distention, cervical insufficiency, placental dysfunction, premature rupture of the membranes, maternal comorbidities, and familial factors. Each woman's condition was evaluated for each phenotype. Delivery gestational age was compared between those with and without each phenotype. Phenotype profiles were also compared between women with very early (20.0-27.9 weeks' gestation) SPTB vs those with early SPTB (28.0-34.0 weeks' gestation) and between African American and white women. Statistical analysis was by t test and chi(2) test, as appropriate. RESULTS: The phenotyping tool was applied to 1025 women with SPTBs who delivered at a mean 30.0 +/- 3.2 (SD) weeks' gestation. Of these, 800 women (78%) had >=2 phenotypes. Only 43 women (4.2%) had no phenotypes. The 281 women with early SPTBs were more likely to have infection/inflammation, decidual hemorrhage, and cervical insufficiency phenotypes (all P <= .001). African American women had more maternal stress and cervical insufficiency but less decidual hemorrhage and placental dysfunction compared with white women (all P < .05). Gestational age at delivery decreased as the number of phenotypes that were present increased. CONCLUSION: Precise SPTB phenotyping classifies women with SPTBs and identifies specific differences between very early and early SPTB and between African American and white women. PMID- 25687567 TI - Mitochondrial DNA sequence variation is largely conserved at birth with rare de novo mutations in neonates. AB - OBJECTIVE: Mitochondrial DNA (mtDNA) encodes the proteins of the electron transfer chain to produce adenosine triphosphate through oxidative phosphorylation, and is essential to sustain life. mtDNA is unique from the nuclear genome in so much as it is solely maternally inherited (non-mendelian patterning), and shows a relatively high rate of mutation due to the absence of error checking capacity. While it is generally assumed that most new mutations accumulate through the process of heteroplasmy, it is unknown whether mutations initiated in the mother are inherited, occur in utero, or occur and accumulate early in life. The purpose of this study is to examine the maternally heritable and de novo mutation rate in the fetal mtDNA through high-fidelity sequencing from a large population-based cohort. STUDY DESIGN: Samples were obtained from 90 matched maternal (blood) and fetal (placental) pairs. In addition, a smaller cohort (n = 5) of maternal (blood), fetal (placental), and neonatal (cord blood) trios were subjected to DNA extraction and shotgun sequencing. The whole genome was sequenced on the Illumina HiSeq platform (Illumina Inc., San Diego, CA), and haplogroups and mtDNA variants were identified through mapping to reference mitochondrial genomes (NC_012920). RESULTS: We observed 665 single nucleotide polymorphisms and 82 insertions-deletions variants identified in the cohort at large. We achieved high sequencing depth of the mtDNA to an average depth of 65X (range, 20-171X) coverage. The proportions of haplogroups identified in the cohort are consistent with the patient's self-identified ethnicity (>90% Hispanic), and all maternal-fetal pairs mapped to the identical haplogroup. Only variants from samples with average depth >20X and allele frequency >1% were included for further analysis. While the majority of the maternal-fetal pairs (>90%) demonstrated identical variants at the single nucleotide level, we observed rare mitochondrial single nucleotide polymorphism discordance between maternal and fetal mitochondrial genomes. CONCLUSION: In this first in-depth sequencing analysis of mtDNA from maternal-fetal pairs at the time of birth, a low rate of de novo mutations appears in the fetal mitochondrial genome. This implies that these mutations likely arise from the maternal heteroplasmic pool (eg, in the oocyte), and accumulate later in the offspring's life. These findings have key implications for both the occurrence and screening for mitochondrial disorders. PMID- 25687566 TI - Detection of microbial invasion of the amniotic cavity by analysis of cervicovaginal proteins in women with preterm labor and intact membranes. AB - OBJECTIVE: Microbial invasion of the amniotic cavity (MIAC) is common in early preterm labor and is associated with maternal and neonatal infectious morbidity. MIAC is usually occult and is reliably detected only with amniocentesis. We sought to develop a noninvasive test to predict MIAC based on protein biomarkers in cervicovaginal fluid (CVF) in a cohort of women with preterm labor (phase 1) and to validate the test in an independent cohort (phase 2). STUDY DESIGN: This was a prospective study of women with preterm labor who had amniocentesis to screen for MIAC. MIAC was defined by positive culture and/or 16S ribosomal DNA results. Nine candidate CVF proteins were analyzed by enzyme-linked immunosorbent assay. Logistic regression was used to identify combinations of up to 3 proteins that could accurately classify the phase 1 cohort (N = 108) into those with or without MIAC. The best models, selected by area under the curve (AUC) of the receiver operating characteristic curve in phase 1, included various combinations of interleukin (IL)-6, chemokine (C-X-C motif) ligand 1 (CXCL1), alpha fetoprotein, and insulin-like growth factor binding protein-1. Model performance was then tested in the phase 2 cohort (N = 306). RESULTS: MIAC was present in 15% of cases in phase 1 and 9% in phase 2. A 3-marker CVF model using IL-6 plus CXCL1 plus insulin-like growth factor binding protein-1 had AUC 0.87 in phase 1 and 0.78 in phase 2. Two-marker models using IL-6 plus CXCL1 or alpha fetoprotein plus CXCL1 performed similarly in phase 2 (AUC 0.78 and 0.75, respectively), but were not superior to CVF IL-6 alone (AUC 0.80). A cutoff value of CVF IL-6 >=463 pg/mL (which had 81% sensitivity in phase 1) predicted MIAC in phase 2 with sensitivity 79%, specificity 78%, positive predictive value 38%, and negative predictive value 97%. CONCLUSION: High levels of IL-6 in CVF are strongly associated with MIAC. If developed into a bedside test or rapid laboratory assay, cervicovaginal IL-6 might be useful in selecting patients in whom the probability of MIAC is high enough to warrant amniocentesis or transfer to a higher level of care. Such a test might also guide selection of potential subjects for treatment trials. PMID- 25687568 TI - Impact of probiotics in women with gestational diabetes mellitus on metabolic health: a randomized controlled trial. AB - OBJECTIVE: Probiotics are live microorganisms that may confer health benefits on the host. Recent trials of probiotic use among healthy pregnant women demonstrate potential for improved glycemic control. The aim of this study was to investigate the effects of a probiotic capsule intervention on maternal metabolic parameters and pregnancy outcome among women with gestational diabetes. STUDY DESIGN: This double-blind placebo-controlled randomized trial recruited pregnant women with a new diagnosis of gestational diabetes or impaired glucose tolerance following a 3 hour 100-g glucose tolerance test. Women were randomized to a daily probiotic (Lactobacillus salivarius UCC118) or placebo capsule from diagnosis until delivery. Fasting blood samples were collected at baseline and 4-6 weeks after capsule commencement for analysis of glucose, insulin, c-peptide, and lipids. The primary outcome was difference in fasting glucose postintervention, first analyzed on an intention-to-treat basis and followed by per-protocol analysis that excluded women commenced on pharmacological therapy (insulin or metformin). Secondary outcomes were changes in insulin, c-peptide, homeostasis model assessment and lipids, requirement for pharmacological therapy, and neonatal anthropometry. RESULTS: Of 149 women recruited and randomized, there were no differences between the probiotic and placebo groups in postintervention fasting glucose (4.65 +/- 0.49 vs 4.65 +/- 0.53 mmol/L; P = 373), requirement for pharmacological therapy (17% vs 14%; P = .643), or birthweight (3.57 +/- 0.64 vs 3.60 +/- 0.57 kg; P = .845). Among 100 women managed with diet and exercise alone, fasting plasma glucose decreased significantly within both the probiotic (4.76 +/- 0.45 to 4.57 +/- 0.42 mmol/L; P < .001) and placebo (4.85 +/- 0.58 to 4.58 +/- 0.45 mmol/L; P < .001) groups, but the levels between groups did not differ (P = .316). The late gestation-related rise in total and low-density lipoprotein (LDL) cholesterol was attenuated in the probiotic vs the placebo group (+0.27 +/- 0.48 vs +0.50 +/- 0.52 mmol/L total cholesterol, P = .031; +0.08 +/- 0.51 vs +0.31 +/- 0.45 mmol/L LDL cholesterol, P = .011). No differences were noted between groups in other metabolic parameters or pregnancy outcome. CONCLUSION: A probiotic capsule intervention among women with abnormal glucose tolerance had no impact on glycemic control. The observed attenuation of the normal pregnancy-induced rise in total and LDL cholesterol following probiotic treatment requires further investigation, particularly in this obstetric group at risk of future metabolic syndrome. PMID- 25687569 TI - Audit of pediatric transfusion practices: a commentary. PMID- 25687570 TI - Quantitative protein topography analysis and high-resolution structure prediction using hydroxyl radical labeling and tandem-ion mass spectrometry (MS). AB - Hydroxyl radical footprinting based MS for protein structure assessment has the goal of understanding ligand induced conformational changes and macromolecular interactions, for example, protein tertiary and quaternary structure, but the structural resolution provided by typical peptide-level quantification is limiting. In this work, we present experimental strategies using tandem-MS fragmentation to increase the spatial resolution of the technique to the single residue level to provide a high precision tool for molecular biophysics research. Overall, in this study we demonstrated an eightfold increase in structural resolution compared with peptide level assessments. In addition, to provide a quantitative analysis of residue based solvent accessibility and protein topography as a basis for high-resolution structure prediction; we illustrate strategies of data transformation using the relative reactivity of side chains as a normalization strategy and predict side-chain surface area from the footprinting data. We tested the methods by examination of Ca(+2)-calmodulin showing highly significant correlations between surface area and side-chain contact predictions for individual side chains and the crystal structure. Tandem ion based hydroxyl radical footprinting-MS provides quantitative high-resolution protein topology information in solution that can fill existing gaps in structure determination for large proteins and macromolecular complexes. PMID- 25687572 TI - US panel proposes new name and diagnostic criteria for chronic fatigue syndrome. PMID- 25687571 TI - The last enzyme of the de novo purine synthesis pathway 5-aminoimidazole-4 carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase (ATIC) plays a central role in insulin signaling and the Golgi/endosomes protein network. AB - Insulin is internalized with its cognate receptor into the endosomal apparatus rapidly after binding to hepatocytes. We performed a bioinformatic screen of Golgi/endosome hepatic protein fractions and found that ATIC, which is a rate limiting enzyme in the de novo purine biosynthesis pathway, and PTPLAD1 are associated with insulin receptor (IR) internalization. The IR interactome (IRGEN) connects ATIC to AMPK within the Golgi/endosome protein network (GEN). Forty-five percent of the IR Golgi/endosome protein network have common heritable variants associated with type 2 diabetes, including ATIC and AMPK. We show that PTPLAD1 and AMPK are rapidly compartmentalized within the plasma membrane (PM) and Golgi/endosome fractions after insulin stimulation and that ATIC later accumulates in the Golgi/endosome fraction. Using an in vitro reconstitution system and siRNA-mediated partial knockdown of ATIC and PTPLAD1 in HEK293 cells, we show that both ATIC and PTPLAD1 affect IR tyrosine phosphorylation and endocytosis. We further show that insulin stimulation and ATIC knockdown readily increase the level of AMPK-Thr172 phosphorylation in IR complexes. We observed that IR internalization was markedly decreased after AMPKalpha2 knockdown, and treatment with the ATIC substrate AICAR, which is an allosteric activator of AMPK, increased IR endocytosis in cultured cells and in the liver. These results suggest the presence of a signaling mechanism that senses adenylate synthesis, ATP levels, and IR activation states and that acts in regulating IR autophosphorylation and endocytosis. PMID- 25687573 TI - [Disseminated cutaneous larva migrans infestation]. PMID- 25687574 TI - Erratum: Conserved and host-specific features of influenza virion architecture. PMID- 25687575 TI - Predicting pulmonary hypertension with standard computed tomography pulmonary angiography. AB - The most common feature of pulmonary hypertension (PH) on computed tomography pulmonary angiography (CTPA) is an increased diameter-ratio of the pulmonary artery to the ascending aorta (PA/AAAX). The aim of this study was to investigate whether combining PA/AAAX measurements with ventricular measurements improves the predictive value of CTPA for precapillary PH. Three predicting models were analysed using baseline CTPA scans of 51 treatment naive precapillary PH patients and 25 non-PH controls: model 1: PA/AAAX only; model 2: PA/AAAX combined with the ratio of the right ventricular and left ventricular diameter measured on the axial view (RV/LVAX); model 3: PA/AAAX combined with the RV/LV-ratio measured on a four chamber view (RV/LV4CH). Prediction models were compared using multivariable binary logistic regression, ROC analyses and decision curve analyses (DCA). Multivariable binary logistic regression showed an improvement of the predictive value of model 2 (-2LL = 26.48) and 3 (-2LL = 21.03) compared to model 1 (-2LL = 21.03). ROC analyses showed significantly higher AUCs of model 2 and 3 compared to model 1 (p = 0.011 and p = 0.007, respectively). DCA showed an increased clinical benefit of model 2 and 3 compared to model 1. The predictive value of model 2 and 3 were almost equal. We found an optimal cut-off value for the RV/LV-ratio for predicting precapillary PH of RV/LV >= 1.20. The predictive value of CTPA for precapillary PH improves when ventricular and pulmonary artery measurements are combined. A PA/AAAX >= 1 or a RV/LVAX >= 1.20 needs further diagnostic evaluation to rule out or confirm the diagnosis. PMID- 25687576 TI - Simulating long-term occupational exposure to decabrominated diphenyl ether using C57BL/6 mice: biodistribution and pathology. AB - Decabrominated biphenyl ether (BDE-209) is a fully brominated diphenyl ether compound used widely as an additive brominated flame retardant in a variety of consumer products. In recent years, BDE-209 has been reported to be abundant and persistent in the environment, and comparatively high burdens have been found in occupational environmental compartments and exposed individuals. In the present study, an animal model for simulating long-term occupational exposure to BDE-209 was set up. Female C57BL/6 mice (n=10) were intragastrically administered BDE-209 at a dose of 800 mg kg(-1) bw at 2-d intervals for 2 years with an internal blood level of approximately 200 ng mL(-1), which was comparable to the high level of BDE-209 detected in the occupational population, and the biodistribution and biological effects were evaluated systematically. The results showed that large amounts of the chemical accumulated in most tissues, and the preferential organs were the ovary and uterus, liver and lung. Decreased survival was observed in the exposed mice. The subsequent pathological analysis revealed hepatomegaly in the exposed mice, accompanied by obvious histopathological changes in the liver, lung, brain, spleen, kidney and ovary. No neoplastic lesions were observed in this lifetime exposure study. Although the number of experimental mice was limited, our observations offer a comprehensive understanding of the chronic toxicology of BDE-209 after continuous high-dose exposure. PMID- 25687577 TI - Lessons from the 2004 Asian tsunami: Nature, prevalence and determinants of prolonged grief disorder among tsunami survivors in South Indian coastal villages. AB - BACKGROUND: Prolonged grief disorder (PGD), previously called complicated grief, is associated with significant distress and long-term disability, and it may complicate assessments for post-traumatic stress disorder (PTSD) after traumatic events. METHODS: In order to distinguish PGD from PTSD, we conducted a cross sectional survey among tsunami survivors in five tsunami-affected coastal villages in India, 9 months after the Asian tsunami. RESULTS: Prevalence of PGD among 643 tsunami survivors was 14.2% (95% confidence interval (CI): 11.5%-16.9%) and among the 351 bereaved survivors was 25.9% (95% CI: 21.3%-30.5%). Spousal bereavement, extensive damage to homes, fewer years of education, and absence of tsunami-related physical injury differentiated those with PGD, after adjusting for potential confounders (p < .05). These factors were distinct from the factors associated with post-traumatic stress symptoms (PTSS) among these survivors. Scores on the avoidance, hyper-arousal and intrusion subscales of the Impact of Events Scale-Revised were significantly lower in those with PGD alone than in those with PTSS or with both disorders. CONCLUSION: Our findings support the validity of PGD in a non-Western post-disaster community and its distinctness from PTSD. They have important public health implications in planning responses to natural disasters and for future revisions of diagnostic classifications. PMID- 25687579 TI - Encapsulation of hydrophobic allergens into nanoparticles improves the in vitro immunological diagnosis of allergic contact dermatitis. AB - The diagnosis of allergic contact dermatitis (ACD) relies on in vivo patch testing. In vitro immunological assays based on the characterization of circulating allergen-specific memory T cells represent a promising alternative to patch testing. However, their development is hampered by the technical challenge of assessing hydrophobic allergens in serum-based assays. In this study, we show that the encapsulation of fragrance mix 1 (FMI, a mixture of 8 hydrophobic allergens) into poly-epsilon-caprolactone nanoparticle (NP) vectors: (1) dramatically increases the solubilization of allergens in conventional cell culture media and (2) allows for a robust in vitro reactivation of allergen specific T cells in large numbers of fragrance allergic patients. Therefore, the encapsulation of hydrophobic allergens into NP vectors opens new avenues to improve the in vitro immunobiological diagnosis of ACD. FROM THE CLINICAL EDITOR: Allergic Contact Dermatitis (ACD) is a delayed-type hypersensivity reaction prevalent in many individuals. Currently, skin patch testing has been the mainstay for diagnosis clinically. In this study, the authors described an improvement to in vitro immunological assays measuring circulating allergen specific memory T cells, using nanoparticle vectors. The positive data might provide an exciting alternative to current practice of patch-testing. PMID- 25687580 TI - Dynamics of a liquid film of arbitrary thickness perturbed by a nano-object. AB - We provide a theoretical description of the dynamics of a liquid film perturbed by a nano-object. Our analysis is based on the general dispersion relation for surface perturbations which is valid for films of arbitrary thickness. In the case of thin liquid films the lubrication approximation is retrieved. The relevant time scales are derived and related to the characteristic length scales present in the system. We show that the multi length-scale character of the interfacial deformation is reflected in a wide range of the time scales describing the dynamics of the liquid film. In the case of relaxation under the action of a time-independent perturbation the analytical approximations to the interface evolution are obtained in several time regimes. The case of a general time-dependent perturbation is studied within the point-force approximation which allows determination of the universal aspects of liquid film dynamics. This method is also used to describe the response of the liquid film to a periodic perturbation which simulates the dynamic mode of the tip of an atomic force microscope. It is shown that proper consideration of the thickness of the film leads to results which significantly differ from those obtained within the lubrication approximation even for relatively thin films. PMID- 25687581 TI - Molecular epidemiology of infectious bursal disease virus in Zambia. AB - Nucleotide sequences of the VP2 hypervariable region (VP2-HVR) of 10 infectious bursal disease viruses detected in indigenous and exotic chickens in Zambia from 2004 to 2005 were determined. Phylogenetic analysis showed that the viruses diverged into two genotypes and belonged to the African very virulent types (VV1 and VV2). In the phylogenetic tree, strains in one genotype clustered in a distinct group and were closely related to some strains isolated in western Africa (VV1), with nucleotide similarities of 95.7%- 96.5%. Strains in the other genotype were clustered within the eastern African VV type (VV2), with nucleotide similarities of 97.3%- 98.5%. Both genotypes were distributed in the southern parts of Zambia and had a unique conserved amino acid substitution at 300 (E->A) in addition to the putative virulence marker at positions 222(A), 242(I), 256(I), 294(I) and 299(S). These findings represent the first documentation of the existence of the African VV-IBDV variants in both indigenous and exotic chickens in Zambia. PMID- 25687582 TI - [Encephalopathy syndrome: A serius clinical case]. PMID- 25687583 TI - Molecular Docking Studies of Some Novel Antidepressant 5-Substituted Phenyl-3 (Thiophen-2-yl)-4, 5-Dihydro-1h-Pyrazole-1-Carboxamides Against Monoamine Oxidase Isoforms. AB - Previously we have reported 5-substituted phenyl-3-(thiophen-2-yl)-4, 5-dihydro 1hpyrazole- 1-carboxamides as a novel class of antidepressants. The aim of the current study is to proposing the reason for such biological activities of the molecules by using molecular docking studies using AutoDock4.2. Using molecular docking studies, we propose that most of the antidepressant molecules showed good binding affinity towards MAO-A than MAO-B which is an effective target for the treatment of depression. The R and S form of thiophene based pyrazolines carboxamides showed a binding energy and inhibition constant between 7.93 to 8.76 and 1.54 to 0.38 MUM toward MAO-A and -6.39 to -8.51 and 20.84 to 0.57 MUM toward MAO-B respectively. PMID- 25687584 TI - Optimization of supercritical fluid extraction and HPLC identification of wedelolactone from Wedelia calendulacea by orthogonal array design. AB - The purpose of this work is to provide a complete study of the influence of operational parameters of the supercritical carbon dioxide assisted extraction (SC CO2E) on yield of wedelolactone from Wedelia calendulacea Less., and to find an optimal combination of factors that maximize the wedelolactone yield. In order to determine the optimal combination of the four factors viz. operating pressure, temperature, modifier concentration and extraction time, a Taguchi experimental design approach was used: four variables (three levels) in L9 orthogonal array. Wedelolactone content was determined using validated HPLC methodology. Optimum extraction conditions were found to be as follows: extraction pressure, 25 MPa; temperature, 40 degrees C; modifier concentration, 10% and extraction time, 90 min. Optimum extraction conditions demonstrated wedelolactone yield of 8.01 +/- 0.34 mg/100 g W. calendulacea Less. Pressure, temperature and time showed significant (p < 0.05) effect on the wedelolactone yield. The supercritical carbon dioxide extraction showed higher selectivity than the conventional Soxhlet assisted extraction method. PMID- 25687585 TI - Drug-induced cellular death dynamics monitored by a highly sensitive organic electrochemical system. AB - We propose and demonstrate a sensitive diagnostic device based on an Organic Electrochemical Transistor (OECT) for direct in-vitro monitoring cell death. The system efficiently monitors cell death dynamics, being able to detect signals related to specific death mechanisms, namely necrosis or early/late apoptosis, demonstrating a reproducible correlation between the OECT electrical response and the trends of standard cell death assays. The innovative design of the Twell-OECT system has been modeled to better correlate electrical signals with cell death dynamics. To qualify the device, we used a human lung adenocarcinoma cell line (A549) that was cultivated on the micro-porous membrane of a Transwell (Twell) support, and exposed to the anticancer drug doxorubicin. Time-dependent and dose dependent dynamics of A549 cells exposed to doxorubicin are evaluated by monitoring cell death upon exposure to a range of doses and times that fully covers the protocols used in cancer treatment. The demonstrated ability to directly monitor cell stress and death dynamics upon drug exposure using simple electronic devices and, possibly, achieving selectivity to different cell dynamics is of great interest for several application fields, including toxicology, pharmacology, and therapeutics. PMID- 25687586 TI - Structural basis for PPARgamma transactivation by endocrine-disrupting organotin compounds. AB - Organotin compounds such as triphenyltin (TPT) and tributyltin (TBT) act as endocrine disruptors through the peroxisome proliferator-activated receptor gamma (PPARgamma) signaling pathway. We recently found that TPT is a particularly strong agonist of PPARgamma. To elucidate the mechanism underlying organotin dependent PPARgamma activation, we here analyzed the interactions of PPARgamma ligand-binding domain (LBD) with TPT and TBT by using X-ray crystallography and mass spectroscopy in conjunction with cell-based activity assays. Crystal structures of PPARgamma-LBD/TBT and PPARgamma-LBD/TPT complexes were determined at 1.95 A and 1.89 A, respectively. Specific binding of organotins is achieved through non-covalent ionic interactions between the sulfur atom of Cys285 and the tin atom. Comparisons of the determined structures suggest that the strong activity of TPT arises through interactions with helix 12 of LBD primarily via pi pi interactions. Our findings elucidate the structural basis of PPARgamma activation by TPT. PMID- 25687587 TI - A cluster of invasive listeriosis in Brescia, Italy. PMID- 25687588 TI - Hospital use of systemic antifungal drugs: a multi-center surveillance update from Germany. AB - BACKGROUND: The consumption of antifungal agents increased over the last decade, resulting in the development of resistant organisms and causing a significant pharmaco economic burden. Antifungal drugs are widely used for the treatment of systemic fungal infections and high-risk patients, especially with severe hematological or oncological conditions. Up to date, there are no reliable and systematically reported data on the consumption of antifungal substances on a nationwide level available. The presented study gives an update to the previously published multicenter study investigating antifungal consumption in different settings from five university hospital centers in Germany from 2001 to 2003. METHODS: Consumption data for systemic antifungal drugs were obtained through the hospital pharmacies for 2001-2003 and 2008-2011 regarding the medical and surgical services of five university hospital centers in Germany (A-E). Drug use densities were calculated as yearly RDDs/100 patient days. These calculations were performed for the surgical and medical services, and independently for surgical and medical ICUs, as well as for the hematology-oncology services. RESULTS: We report an increased utilization of systemic antifungal drugs in both study periods. The mean drug use density (mean value of all 5 hospitals) in the medical services increased by 24% between 2001 and 2003. In 2011, this value was 37% above the level from 2001 (12.4 RDD/100 patient days in 2001, 15.4 RDD/100 patient days in 2003, 17.0 RDD/100 patient days in 2011). The 4-year average drug use density (2008-2011) of medical services ranged between 11.6 RDD/100 patient days (hospital E) and 23.8 RDD/100 patient days (hospital A). Drug use densities were in medical intensive care units 29.4 RDD/100 patient days and hematology oncology services 49.9 RDD/100 patient days. CONCLUSIONS: Despite the variability of the prescribing patterns between the tertiary hospitals, the presented pharmaco-epidemiological data are a cornerstone for the initiation and implementation of effective antifungal stewardship programmes and might serve as important benchmarking information for other hospitals with similar structures and baseline settings. PMID- 25687589 TI - Mussel-inspired synthesis of boron nitride nanosheet-supported gold nanoparticles and their application for catalytic reduction of 4-nitrophenol. AB - Gold nanoparticle (AuNP)-decorated boron nitride nanosheet (BNNS) was successfully prepared through the simultaneous reduction of Au(3+) ions and the growth of AuNPs on polydopamine (PDA)-grafted BNNS. Both BNNS-AuNP and PDA-BNNS are successfully synthesized in an aqueous buffer solution (pH 8.5) in the absence of any chemical reducing agent and organic reaction, which is therefore environmentally friendly and highly beneficial for the mass production of green catalysts from 2D nanomaterials. BNNS-AuNP showed remarkable dispersion stability in aqueous media and revealed high catalytic efficiency for the reduction of nitrophenol as (4-NP) into 4-aminophenol (4-AP) within 8 min in water. The 2D structural feature of BNNS-AuNP also enables isolation and recycling of catalyst from 4-AP through the ultracentrifugation, which shows the retention of more than 60% of catalytic activity of BNNS-AuNP after five repetitions of the of recycling steps. PMID- 25687590 TI - Long-term EEG in children. AB - Long-term video-EEG corresponds to a recording ranging from 1 to 24 h or even longer. It is indicated in the following situations: diagnosis of epileptic syndromes or unclassified epilepsy, pre-surgical evaluation for drug-resistant epilepsy, follow-up of epilepsy or in cases of paroxysmal symptoms whose etiology remains uncertain. There are some specificities related to paediatric care: a dedicated pediatric unit; continuous monitoring covering at least a full 24-hour period, especially in the context of pre-surgical evaluation; the requirement of presence by the parents, technician or nurse; and stronger attachment of electrodes (cup electrodes), the number of which is adapted to the age of the child. The chosen duration of the monitoring also depends on the frequency of seizures or paroxysmal events. The polygraphy must be adapted to the type and topography of movements. It is essential to have at least an electrocardiography (ECG) channel, respiratory sensor and electromyography (EMG) on both deltoids. There is no age limit for performing long-term video-EEG even in newborns and infants; nevertheless because of scalp fragility, strict surveillance of the baby's skin condition is required. In the specific context of pre-surgical evaluation, long-term video-EEG must record all types of seizures observed in the child. This monitoring is essential in order to develop hypotheses regarding the seizure onset zone, based on electroclinical correlations, which should be adapted to the child's age and the psychomotor development. PMID- 25687591 TI - EEG guidelines in the diagnosis of brain death. AB - In France, for the determination and diagnostic validation of brain death the law requires either two EEG recordings separated by a 4-hour observation period, both showing electrocerebral inactivity; or cerebral angiography examination. Since EEG is available in most hospitals and clinics, it is often used in this indication, at the patient's bedside, especially in the context of organ donation. However, very precise methodology must be followed. The last French guidelines date back to 1989, before the development of digital EEG recording. We present the new guidelines from the Societe de Neurophysiologie Clinique de Langue Francaise. Electrocerebral inactivity may be confirmed when a 30-minute good quality EEG recording shows complete electrocerebral silence, defined as no cerebral activity greater than 2 uV, having first ruled out the possible influence of sedative drugs, metabolic disorders or hypothermia. In the presence of sedative drugs, CT brain angiography will be the gold standard test for this diagnosis. In the newborn, the utmost caution is indicated since electrocerebral inactivity can be observed in the absence of cerebral death. In the infant, the criterion for the observation period to be respected between both EEG recordings needs to be more clearly refined. PMID- 25687592 TI - Hybridized electromagnetic-triboelectric nanogenerator for scavenging biomechanical energy for sustainably powering wearable electronics. AB - We report a hybridized electromagnetic-triboelectric nanogenerator for highly efficient scavenging of biomechanical energy to sustainably power wearable electronics by human walking. Based on the effective conjunction of triboelectrification and electromagnetic induction, the hybridized nanogenerator, with dimensions of 5 cm * 5 cm * 2.5 cm and a light weight of 60 g, integrates a triboelectric nanogenerator (TENG) that can deliver a peak output power of 4.9 mW under a loading resistance of 6 MOmega and an electromagnetic generator (EMG) that can deliver a peak output power of 3.5 mW under a loading resistance of 2 kOmega. The hybridized nanogenerator exhibits a good stability for the output performance and a much better charging performance than that of an individual energy-harvesting unit (TENG or EMG). Furthermore, the hybridized nanogenerator integrated in a commercial shoe has been utilized to harvest biomechanical energy induced by human walking to directly light up tens of light-emitting diodes in the shoe and sustainably power a smart pedometer for reading the data of a walking step, distance, and energy consumption. A wireless pedometer driven by the hybrid nanogenerator can work well to send the walking data to an iPhone under the distance of 25 m. This work pushes forward a significant step toward energy harvesting from human walking and its potential applications in sustainably powering wearable electronics. PMID- 25687593 TI - Genetic risk for Alzheimer's disease alters the five-year trajectory of semantic memory activation in cognitively intact elders. AB - Healthy aging is associated with cognitive declines typically accompanied by increased task-related brain activity in comparison to younger counterparts. The Scaffolding Theory of Aging and Cognition (STAC) (Park and Reuter-Lorenz, 2009; Reuter-Lorenz and Park, 2014) posits that compensatory brain processes are responsible for maintaining normal cognitive performance in older adults, despite accumulation of aging-related neural damage. Cross-sectional studies indicate that cognitively intact elders at genetic risk for Alzheimer's disease (AD) demonstrate patterns of increased brain activity compared to low risk elders, suggesting that compensation represents an early response to AD-associated pathology. Whether this compensatory response persists or declines with the onset of cognitive impairment can only be addressed using a longitudinal design. The current prospective, 5-year longitudinal study examined brain activation in APOE epsilon4 carriers (N=24) and non-carriers (N=21). All participants, ages 65-85 and cognitively intact at study entry, underwent task-activated fMRI, structural MRI, and neuropsychological assessments at baseline, 18, and 57 months. fMRI activation was measured in response to a semantic memory task requiring participants to discriminate famous from non-famous names. Results indicated that the trajectory of change in brain activation while performing this semantic memory task differed between APOE epsilon4 carriers and non-carriers. The APOE epsilon4 group exhibited greater activation than the Low Risk group at baseline, but they subsequently showed a progressive decline in activation during the follow-up periods with corresponding emergence of episodic memory loss and hippocampal atrophy. In contrast, the non-carriers demonstrated a gradual increase in activation over the 5-year period. Our results are consistent with the STAC model by demonstrating that compensation varies with the severity of underlying neural damage and can be exhausted with the onset of cognitive symptoms and increased structural brain pathology. Our fMRI results could not be attributed to changes in task performance, group differences in cerebral perfusion, or regional cortical atrophy. PMID- 25687594 TI - Affected connectivity organization of the reward system structure in obesity. AB - With the prevalence of obesity rapidly increasing worldwide, understanding the processes leading to excessive eating behavior becomes increasingly important. Considering the widely recognized crucial role of reward processes in food intake, we examined the white matter wiring and integrity of the anatomical reward network in obesity. Anatomical wiring of the reward network was reconstructed derived from diffusion weighted imaging in 31 obese participants and 32 normal-weight participants. Network wiring was compared in terms of the white matter volume as well as in terms of white matter microstructure, revealing lower number of streamlines and lower fiber integrity within the reward network in obese subjects. Specifically, the orbitofrontal cortex and striatum nuclei including accumbens, caudate and putamen showed lower strength and network clustering in the obesity group as compared to healthy controls. Our results provide evidence for obesity-related disruptions of global and local anatomical connectivity of the reward circuitry in regions that are key in the reinforcing mechanisms of eating-behavior processes. PMID- 25687595 TI - Frontal P3 event-related potential is related to brain glutamine/glutamate ratio measured in vivo. AB - BACKGROUND: The auditory P3 event-related potential (ERP) is thought to index cognitive processing relevant to attention and working memory processes. Drug challenge studies suggest that glutamate neurotransmission plays an important role in modulating P3 ERP. However, while direct links between glutamate activity and P3 ERP response in humans are suspected, mechanistic details remain largely unknown. We investigated here the relationships between P3 ERP and indices of glutamatergic processing measured in vivo with proton magnetic resonance spectroscopy ((1)H MRS). We hypothesized that a higher index of glutamatergic processing (glutamine/glutamate ratio; abbreviated Gln/Glu) in the anterior cingulate (ACC) and in the parietal-occipital (POC) cortices would associate with larger frontal P3a and parietal P3b amplitudes, respectively. METHODS: Frontal P3a (Fz) and parietal P3b (Pz) were collected from 32 healthy participants who performed an auditory oddball task. Resting glutamate (Glu), glutamine (Gln), and Gln/Glu (an index of glutamatergic processing) measures were obtained on a 4T MR scanner using J-resolved MR spectroscopy. Linear regression and partial correlations were used for statistical analysis. RESULTS: Significant positive correlations were found between frontal P3a amplitude and ACC Gln/Glu ratio (partial R=0.57; P=0.001) and between frontal P3a amplitude and ACC Gln concentration (partial R=0.43; P=0.02). Relationships between parietal P3b and the glutamate indices in the POC were not significant. CONCLUSIONS: These results indicate a specific connection between an index of glutamate neurotransmitter function in ACC and frontal P3 ERP, providing a novel insight into the neurochemistry underlying scalp recorded EEG response. Abnormalities in glutamate neurotransmission have been observed in schizophrenia and other psychiatric conditions and may underlie illness related deficits of P3 ERP. PMID- 25687596 TI - fMRI identifies chronotype-specific brain activation associated with attention to motion--why we need to know when subjects go to bed. AB - Human cognition relies on attentional capacities which, among others, are influenced by factors like tiredness or mood. Based on their inherent preferences in sleep and wakefulness, individuals can be classified as specific "chronotypes". The present study investigated how early, intermediate and late chronotypes (EC, IC, LC) differ neurally on an attention-to-motion task. Twelve EC, 18 IC and 17 LC were included into the study. While undergoing functional magnetic resonance imaging (fMRI) scans, subjects looked at vertical bars in an attention-to-motion task. In the STATIONARY condition, subjects focused on a central fixation cross. During Fix-MOVING and Attend-MOVING, bars were moving horizontally. Only during the Attend-MOVING, subjects were required to attend to changes in the velocity of bars and indicate those by button presses. A two-way repeated measures ANOVA probed group by attentional load effects. The dorsolateral prefrontal cortex (DLPFC), insula and anterior cingulate cortex showed group by attention specific activations. Specifically, EC and LC presented attenuated DLPFC activation under high attentional load (Attend-MOVING), while EC showed less anterior insula activation than IC. LC compared to IC exhibited attenuation of superior parietal cortex. Our study reveals that individual sleep preferences are associated with characteristic brain activation in areas crucial for attention and bodily awareness. These results imply that considering sleep preferences in neuroimaging studies is crucial when administering cognitive tasks. Our study also has socio-economic implications. Task performance in non optimal times of the day (e.g. shift workers), may result in cognitive impairments leading to e.g. increased error rates and slower reaction times. PMID- 25687597 TI - Modelling aerobic stabilization of domestic and industrial sludge using a multi component biomass model. AB - The objective of the study was to investigate the achievable limits of aerobic sludge stabilization applied on waste-activated sludge generated in domestic, tannery, and pharmaceutical wastewater treatment plants. Stabilization study involved monitoring of conventional parameters and model evaluation of oxygen uptake rate and particulate components of waste sludge. Multi-component biomass approach was adopted based on death-regeneration mechanism. The results showed that sludge stabilization efficiency ranged between 25% and 30%, which was closely related to the fate of different particulate fractions of biomass, that is, viable biomass, hydrolysable particulates, and microbial metabolic products. Model calibration exercises yield in rate coefficient ranges of 0.18-0.32/day for biomass decay and 0.60-0.65/day for hydrolysis of non-biomass components. Degradation rates of particulate metabolic products were estimated as 0.035, 0.04, and 0.01/day for domestic, tannery, and pharmaceutical sludge, respectively. Relatively low degradation rates compared to conventional biological treatment processes confirmed reduced microbial activity in the course of aerobic stabilization. PMID- 25687598 TI - A modified simple triage and rapid treatment algorithm from the New York City (USA) Fire Department. AB - INTRODUCTION: The objective of this study was to determine if modification of the Simple Triage and Rapid Treatment (START) system by the addition of an Orange category, intermediate between the most critically injured (Red) and the non critical, non-ambulatory injured (Yellow), would reduce over- and under-triage rates in a simulated mass-casualty incident (MCI) exercise. METHODS: A computer simulation exercise of identical presentations of an MCI scenario involving a 2 train collision, with 28 case scenarios, was provided for triaging to two groups: the Fire Department of the City of New York (FDNY; n=1,347) using modified START, and the Emergency Medical Services (EMS) providers from the Eagles 2012 EMS conference (Lafayette, Louisiana USA; n=110) using unmodified START. Percent correct by triage category was calculated for each group. Performance was then compared between the two EMS groups on the five cases where Orange was the correct answer under the modified START system. RESULTS: Overall, FDNY-EMS providers correctly triaged 91.2% of cases using FDNY-START whereas non-FDNY Eagles providers correctly triaged 87.1% of cases using unmodified START. In analysis of the five Orange cases (chest pain or dyspnea without obvious trauma), FDNY-EMS performed significantly better using FDNY-START, correctly triaging 86.3% of cases (over-triage 1.5%; under-triage 12.2%), whereas the non-FDNY Eagles group using unmodified START correctly triaged 81.5% of cases (over-triage 17.3%; under-triage 1.3%), a difference of 4.9% (95% CI, 1.5-8.2). CONCLUSIONS: The FDNY-START system may allow providers to prioritize casualties using an intermediate category (Orange) more properly aligned to meet patient needs, and as such, may reduce the rates of over-triage compared with START. The FDNY-START system decreases the variability in patient sorting while maintaining high field utility without needing computer assistance or extensive retraining. Comparison of triage algorithms at actual MCIs is needed; however, initial feedback is promising, suggesting that FDNY-START can improve triage with minimal additional training and cost. PMID- 25687599 TI - The conundrum of arterial stiffness, elevated blood pressure, and aging. AB - Isolated systolic hypertension is a major health burden that is expanding with the aging of our population. There is evidence that central arterial stiffness contributes to the rise in systolic blood pressure (SBP); at the same time, central arterial stiffening is accelerated in patients with increased SBP. This bidirectional relationship created a controversy in the field on whether arterial stiffness leads to hypertension or vice versa. Given the profound interdependency of arterial stiffness and blood pressure, this question seems intrinsically challenging, or probably naive. The aorta's function of dampening the pulsatile flow generated by the left ventricle is optimal within a physiological range of distending pressure that secures the required distal flow, keeps the aorta in an optimal mechanical conformation, and minimizes cardiac work. This homeostasis is disturbed by age-associated, minute alterations in aortic hemodynamic and mechanical properties that induce short- and long-term alterations in each other. Hence, it is impossible to detect an "initial insult" at an epidemiological level. Earlier manifestations of these alterations are observed in young adulthood with a sharp decline in aortic strain and distensibility accompanied by an increase in diastolic blood pressure. Subsequently, aortic mechanical reserve is exhausted, and aortic remodeling with wall stiffening and dilatation ensue. These two phenomena affect pulse pressure in opposite directions and different magnitudes. With early remodeling, there is an increase in pulse pressure, due to the dominance of arterial wall stiffness, which in turn accelerates aortic wall stiffness and dilation. With advanced remodeling, which appears to be greater in men, the effect of diameter becomes more pronounced and partially offsets the effect of wall stiffness leading to plateauing in pulse pressure in men and slower increase in pulse pressure (PP) than that of wall stiffness in women. The complex nature of the hemodynamic changes with aging makes the "one-size-fits all" approach suboptimal and urges for therapies that address the vascular profile that underlies a given blood pressure, rather than the blood pressure values themselves. PMID- 25687600 TI - Effects of terpenes on fluidity and lipid extraction in phospholipid membranes. AB - Electron paramagnetic resonance (EPR) spectroscopy was used in a detailed study of the interactions of several terpenes with DPPC membranes. EPR spectra of a spin-label lipid allowed the identification of two well-resolved spectral components at temperatures below and above the main phase transition of the lipid bilayer. Terpenes caused only slight mobility increases in each of these spectral components; however, they substantially increased the population of the more mobile component. In addition, the terpenes reduced the temperature of the main phase transition by more than 8 degrees C and caused the extraction of the spin labeled lipid. Nerolidol, which had the highest octanol-water partition coefficient, generated the highest amount of spin label extraction. Acting as spacers, terpenes should cause major reorganization in cell membranes, leading to an increase in the overall molecular dynamics of the membrane. At higher concentrations, terpenes may cause lipid extraction and thus leakage of the cytoplasmic content. PMID- 25687601 TI - Measuring frailty using self-report and test-based health measures. AB - BACKGROUND: previously, frailty indices were constructed using mostly subjective health measures. The reporting error in this type of measure can have implications on the robustness of frailty findings. OBJECTIVE: to examine whether frailty assessment differs when we construct frailty indices using solely self reported or test-based health measures. DESIGN: secondary analysis of data from The Irish LongituDinal study on Ageing (TILDA). SUBJECTS AND METHODS: 4,961 Irish residents (mean age: 61.9 +/- 8.4; 54.2% women) over the age of 50 years who underwent a health assessment were included in this analysis. We constructed three frailty indices using 33 self-reported health measures (SRFI), 33 test based health measures (TBFI) and all 66 measures combined (CFI). The 2-year follow-up outcomes examined were all-cause mortality, disability, hospitalisation and falls. RESULTS: all three indices had a right-skewed distribution, an upper limit to frailty, a non-linear increase with age, and had a dose-response relationship with adverse outcomes. Levels of frailty were lower when self reported items were used (SRFI: 0.12 +/- 0.09; TBFI: 0.17 +/- 0.15; CFI: 0.14 +/- 0.13). Men had slightly higher frailty index scores than women when test-based measures were used (men: 0.17 +/- 0.09; women: 0.16 +/- 0.10). CFI had the strongest prediction for risk of adverse outcomes (ROC: 0.64-0.81), and age was not a significant predictor when it was included in the regression model. CONCLUSIONS: except for sex differences, characteristics of frailty are similar regardless of whether self-reported or test-based measures are used exclusively to construct a frailty index. Where available, self-reported and test-based measures should be combined when trying to identify levels of frailty. PMID- 25687602 TI - Use of the MMRI-R prognostic tool for older patients discharged to nursing homes from hospital: a prospective cohort study. AB - BACKGROUND: the Minimum Dataset Mortality Risk Index-Revised (MMRI-R) is a prognostic score predicting 6-month mortality in US nursing homes. It has not been validated in the UK nor at the hospital-nursing home interface. METHODS: prospective cohort study of consecutive patients discharged from hospital or intermediate care to nursing homes from January 2012 to January 2014. MMRI-R scoring was done prior to discharge and subsequent deaths were ascertained. Calibration plots, receiver operative characteristic curves with area under the curve (AUC) and an optimal cutpoint were obtained. Kaplan-Meier curves were plotted with scores stratified by the cutpoint. RESULTS: a total of 183 patients were followed up for a median of 230 days. Median age was 87 years and 55.7% were female. Median MMRI-R score was 55. By the end of follow-up, 99 patients (54.1%) were dead. The Hosmer-Lemeshow test showed P-values of 0.4406 for 3-month and 0.8904 for 6-month mortality. The AUC was 0.70 (95% CI: 0.622-0.777) for 3-month death prediction and 0.723 (95% CI: 0.649-0.797) for death at 6 months. Of patients with MMRI-R scores >48 (the cutpoint), 43.6% were dead at 3 months and 53.6% by 6 months. The corresponding figures for scores <48 were 9.6 and 16.4% (P < 0.001, log-rank test). CONCLUSION: the MMRI-R can be used at the acute hospital/nursing home interface, and can help predict 3-month and 6-month mortality. The finding of an MMRI-R score of >=48 should trigger end-of-life discussions. PMID- 25687603 TI - Iridoid glucosides in the endemic Picconia azorica (Oleaceae). AB - In our continued investigation of plants from the family Oleaceae we have now investigated Picconia azorica endemic to the Azores. Like most species within the family it contains the oleoside-based secoiridoid glucosides ligstroside and oleuropein as the main compounds and in addition verbascoside and echinacoside. As with the previously investigated Picconia excelsa, it also contained the carbocyclic iridoid glucosides involved in the biosynthetic pathway to the oleoside derivatives. However, while P. excelsa contained loganin esterified with some monoterpenoid acids, P. azorica contains similar esters of 7-epi-loganic acid named Picconioside A and B. In addition were found the two 7-O-E/Z-cinnamoyl esters of 7-epi-loganic acid named Picconioside C and D. PMID- 25687604 TI - Cytotoxic indole alkaloids from Tabernaemontana officinalis. AB - Continued interest in cytotoxic alkaloids resulted in the isolation of 37 alkaloids including 29 known monoterpenoid indole alkaloids from the aerial parts of Tabernaemontana officinalis. Of the remaining 8 alkaloids, six were bisindole alkaloids named taberdivarines A-F (1-6) and the two were monomers named taberdivarines G and H (7-8). Alkaloids 1 and 2 are voaphylline-vobasinyl type bisindole alkaloids, a structural type previously unknown, while 3-6 exhibited cytotoxicity against three human cancer cell lines HeLa, MCF-7, and SW480 with IC50 values ranging from 1.42 to 11.35 MUM. PMID- 25687605 TI - Long-term persistence of seeded grass species: an unwanted side effect of ecological restoration. AB - Spoil heaps are the visible footprint of hydropower production, particularly in vulnerable alpine environments. Speeding up vegetation development by seeding commercial grass species has been a common restoration practice for the last 50 years, but we lack information on whether seeded species decline and allow native plant cover to develop. We visually estimated cover of native vascular plants and five seeded grass species (Agrostis capillaris, Festuca ovina, Festuca rubra, Schedonorus pratensis and Phleum pratense) on eight spoil heaps at different elevations (boreal-alpine zone) in western Norway. Spoil heap vegetation was censused twice (9-20 and 24-36 years after spoil heap construction); the undisturbed surrounding vegetation was also censused on the second occasion. Total cover on the spoil heaps showed some increase, but remained far below that in surrounding areas. Cover of seeded grass species in the surroundings was low (but not negligible), indicating suboptimal establishment ability. Seeded species usually covered less than 20 % of the spoil heaps, and only F. rubra, F. ovina and A. capillaris contributed substantially. Proportional cover indicated better initial establishment by seeded species, but their cover decreased between the censuses on all but the highest located spoil heap. The persistence of seeded grass species is problematic, and despite the decrease in proportional cover, they are likely to persist for decades on spoil heaps, posing a risk of invasion of surrounding areas. We therefore recommend replacing the practice of seeding with more appropriate restoration measures. PMID- 25687606 TI - Game theory and fuzzy programming approaches for bi-objective optimization of reservoir watershed management: a case study in Namazgah reservoir. AB - In this study, game theory and fuzzy programming approaches were used to balance economic and environmental impacts in the Namazgah reservoir, Turkey. The main goals identified were to maximize economic benefits of land use and to protect water quality of reservoir and land resources. Total phosphorous load (kg ha(-1) year(-1)) and economic income (USD ha(-1) year(-1)) from land use were determined as environmental value and economic value, respectively. The surface area of existing land use types, which are grouped under 10 headings according to the investigations on the watershed area, and the constraint values for the watershed were calculated using aerial photos, master plans, and basin slope map. The results of fuzzy programming approach were found to be very close to the results of the game theory model. It was concluded that the amount of fertilizer used in the current situation presents a danger to the reservoir and, therefore, unnecessary fertilizer use should be prevented. Additionally, nuts, fruit, and vegetable cultivation, instead of wheat and corn cultivation, was found to be more suitable due to their high economic income and low total phosphorus (TP) load. Apart from agricultural activities, livestock farming should also be considered in the area as a second source of income. It is believed that the results obtained in this study will help decision makers to identify possible problems of the watershed. PMID- 25687607 TI - Response of the microbial community to seasonal groundwater level fluctuations in petroleum hydrocarbon-contaminated groundwater. AB - The effects of seasonal groundwater level fluctuations on the contamination characteristics of total petroleum hydrocarbons (TPH) in soils, groundwater, and the microbial community were investigated at a typical petrochemical site in northern China. The measurements of groundwater and soil at different depths showed that significant TPH residue was present in the soil in this study area, especially in the vicinity of the pollution source, where TPH concentrations were up to 2600 mg kg(-1). The TPH concentration in the groundwater fluctuated seasonally, and the maximum variation was 0.8 mg L(-1). The highest TPH concentrations were detected in the silty clay layer and lied in the groundwater level fluctuation zones. The groundwater could reach previously contaminated areas in the soil, leading to higher groundwater TPH concentrations as TPH leaches into the groundwater. The coincident variation of the electron acceptors and TPH concentration with groundwater-table fluctuations affected the microbial communities in groundwater. The microbial community structure was significantly different between the wet and dry seasons. The canonical correspondence analysis (CCA) results showed that in the wet season, TPH, NO3(-), Fe(2+), TMn, S(2-), and HCO3(-) were the major factors correlating the microbial community. A significant increase in abundance of operational taxonomic unit J1 (97% similar to Dechloromonas aromatica sp.) was also observed in wet season conditions, indicating an intense denitrifying activity in the wet season environment. In the dry season, due to weak groundwater level fluctuations and low temperature of groundwater, the microbial activity was weak. But iron and sulfate-reducing were also detected in dry season at this site. As a whole, groundwater-table fluctuations would affect the distribution, transport, and biodegradation of the contaminants. These results may be valuable for the control and remediation of soil and groundwater pollution at this site and in other petrochemical contaminated areas. Furthermore, they are probably helpful for reducing health risks to the general public from contaminated groundwater. PMID- 25687608 TI - Role of hydrological conditions on organic phosphorus forms and their availability in sediments from Poyang Lake, China. AB - Biogeochemical cycling of internal bioavailable organic phosphorus (OP) is an important source for algal bloom after exogenous P inputs are controlled. Biogeochemical cycling may be affected by hydrological processes and the water cycle and eventually result in water quality deterioration and accelerated lake eutrophication. Poyang Lake is the largest freshwater lake in China. The hydrological condition of the lake has significantly changed since 2003, thereby causing a continuous decline in water level. In this study, sediments were obtained from different elevations and different hydrological conditions in Poyang Lake. The sediments were subjected to sequential extraction and enzymatic hydrolysis to determine the transformation of OP into various chemical forms, their bioavailability, and the exchange between the sediments and overlying water. Results suggested that the descending water level caused by the changes in hydrological conditions was one of the major factors affecting OP dynamics. Long exposure of sediments resulted in high OP content and increased availability. The increased OP content in exposed sediments was primarily derived from H2O-Po and NaOH-EDTA-Po. Moreover, the increased OP availability in exposed sediments was mainly attributed to the increasing amount of orthophosphate caused by processes governing sediment exposure, promotion of OP release, and transformation of chemical forms from nonlabile to labile. Sediment exposure time and area have considerably expanded since 2003; hence, the amounts of OP and orthophosphate in the sediments have increased by as much as 600 and 120 tons in the lake every year, respectively. Although the increase in orthophosphate only accounted for 6% of the external total phosphorus, the local region may exhibit higher risk for OP release from the sediments, thereby accelerating quality deterioration. Therefore, maintaining reasonable hydrological conditions is important to protect Poyang Lake water. PMID- 25687609 TI - Sorption of halogenated phenols and pharmaceuticals to biochar: affecting factors and mechanisms. AB - The feasibility of using biochar as a sorbent to remove nine halogenated phenols (2,4-dichlorophenol, 2,4-dibromophenol, 2,4-difluorophenol, 2-chlorophenol, 4 chlorophenol, 2-bromophenol, 4-bromophenol, 2-fluorophenol, and 4-fluorophenol) and two pharmaceuticals (triclosan and ibuprofen) from water was examined through a series of batch experiments. Types of biochar, synthesized using various biomasses including fallen leaves, rice straw, corn stalk, used coffee grounds, and biosolids, were evaluated. Compared to granular activated carbon (GAC), most of the biochar samples did not effectively remove halogenated phenols or pharmaceuticals from water. The increase in pH and deprotonation of phenols in biochar systems may be responsible for its ineffectiveness at this task. When pH was maintained at 4 or 7, the sorption capacity of biochar was markedly increased. Considering maximum sorption capacity and properties of sorbents and sorbates, it appears that the sorption capacity of biochar for halogenated phenols is related to the surface area and carbon content of the biochar and the hydrophobicity of halogenated phenols. In the cases of triclosan and ibuprofen, the sorptive capacities of GAC, graphite, and biochars were also significantly affected by pH, according to the point of zero charge (PZC) of sorbents and deprotonation of the pharmaceuticals. Pyrolysis temperature did not affect the sorption capacity of halogenated phenols or pharmaceuticals. Based on the experimental observations, some biochars are good candidates for removal of halogenated phenols, triclosan, and ibuprofen from water and soil. PMID- 25687610 TI - Nonstationary porosity evolution in mixing zone in coastal carbonate aquifer using an alternative modeling approach. AB - In the last few decades, hydrogeochemical problems have benefited from the strong interest in numerical modeling. One of the most recognized hydrogeochemical problems is the dissolution of the calcite in the mixing zone below limestone coastal aquifer. In many works, this problem has been modeled using a coupling algorithm between a density-dependent flow model and a geochemical model. A related difficulty is that, because of the high nonlinearity of the coupled set of equations, high computational effort is needed. During calcite dissolution, an increase in permeability can be identified, which can induce an increase in the penetration of the seawater into the aquifer. The majority of the previous studies used a fully coupled reactive transport model in order to model such problem. Romanov and Dreybrodt (J Hydrol 329:661-673, 2006) have used an alternative approach to quantify the porosity evolution in mixing zone below coastal carbonate aquifer at steady state. This approach is based on the analytic solution presented by Phillips (1991) in his book Flow and Reactions in Permeable Rock, which shows that it is possible to decouple the complex set of equation. This equation is proportional to the square of the salinity gradient, which can be calculated using a density driven flow code and to the reaction rate that can be calculated using a geochemical code. In this work, this equation is used in nonstationary step-by-step regime. At each time step, the quantity of the dissolved calcite is quantified, the change of porosity is calculated, and the permeability is updated. The reaction rate, which is the second derivate of the calcium equilibrium concentration in the equation, is calculated using the PHREEQC code (Parkhurst and Apello 1999). This result is used in GEODENS (Bouhlila 1999; Bouhlila and Laabidi 2008) to calculate change of the porosity after calculating the salinity gradient. For the next time step, the same protocol is used but using the updated porosity and permeability distributions. PMID- 25687611 TI - Dynamic of bacterial communities attached to lightened phytodetritus. AB - The effects of singlet oxygen ((1)O2) transfer to bacteria attached on phytodetritus were investigated under laboratory-controlled conditions. For this purpose, a nonaxenic culture of Emiliania huxleyi in late stationary phase was studied for bacterial viability. Our results indicated that only 9 +/- 3% of attached bacteria were alive compared to 46 +/- 23% for free bacteria in the E. huxleyi culture. Apparently, under conditions of low irradiance (36 W m(-2)), during the culture, the cumulative dose received (22,000 kJ m(-2)) was sufficiently important to induce an efficient (1)O2 transfer to attached bacteria during the senescence of E. huxleyi cells. At this stage, attached bacteria appeared to be dominated by pigmented bacteria (Maribacter, Roseobacter, Roseovarius), which should resist to (1)O2 stress probably due to their high contents of carotenoids. After subsequent irradiation of the culture until fully photodegradation of chlorophyll, DGGE analyses showed that the diversity of bacteria attached to E. huxleyi cells is modified by light. Photooxidative alterations of bacteria were confirmed by the increasing amounts of cis-vaccenic photoproducts (bacterial marker) per bacteria observed during irradiation time. Interestingly, preliminary chemotaxis experiments showed that Shewanella oneidensis considered here as a model of motile bacteria was attracted by phytodetritus producing or not (1)O2. This lack of repulsive effects could explain the high mortality rate of bacteria measured on E. huxleyi cells. PMID- 25687612 TI - Cysteine-beta-cyclodextrin enhanced phytoremediation of soil co-contaminated with phenanthrene and lead. AB - It is necessary to find an effective soil remediation technology for the simultaneous removal of hydrophobic organic contaminants and heavy metals from contaminated soils. In this work, a novel cysteine-beta-cyclodextrin (CCD) was synthesized by the reaction of beta-cyclodextrin with cysteine, and the structure of CCD was confirmed by (1)H-NMR, (13)C-NMR, FT-IR spectroscopy and elemental analysis. Pot-culture experiments were conducted to investigate the effects of CCD on the phytoremediation of soil co-contaminated with phenanthrene and lead. The results showed that CCD can enhance the phytoremediation of soil co contaminated with phenanthrene and lead. When CCD was added to the co contaminated soil, the concentrations of phenanthrene and Pb in roots and shoots of ryegrass (Lolium perenne L.) significantly increased, the presence of CCD is beneficial to the accumulation of phenanthrene and Pb in ryegrass, and the residual concentrations of phenanthrene and Pb in soils significantly decreased. Under the co-contamination of 500 mg Pb kg(-1) and 50 mg PHE kg(-1), the bioconcentration factor of phenanthrene and Pb in the presence of CCD was increased by 1.43-fold and 4.47-fold, respectively. After CCD was added to the contaminated soils, the residual concentration of phenanthrene and Pb in unplanted soil was decreased by 18 and 25%, respectively. However, for the planted soil, the residual concentration of phenanthrene and Pb was decreased by 48 and 56%, respectively. CCD may improve the bioavailability of phenanthrene and Pb in co-contaminated soil; CCD enhanced phytoremediation technology may be a good alternative for the removal of hydrophobic organic contaminants and heavy metals from contaminated soils. PMID- 25687613 TI - Ultrastructural changes, increased oxidative stress, inflammation, and altered cardiac hypertrophic gene expressions in heart tissues of rats exposed to incense smoke. AB - Incense smoke exposure has recently been linked to cardiovascular disease risk, heart rate variability, and endothelial dysfunction. To test the possible underlying mechanisms, oxidative stress, and inflammatory markers, gene expressions of cardiac hypertrophic and xenobiotic-metabolizing enzymes and ultrastructural changes were measured, respectively, using standard, ELISA-based, real-time PCR, and transmission electron microscope procedures in heart tissues of Wistar rats after chronically exposing to Arabian incense. Malondialdehyde, tumor necrosis alpha (TNF)-alpha, and IL-4 levels were significantly increased, while catalase and glutathione levels were significantly declined in incense smoke-exposed rats. Incense smoke exposure also resulted in a significant increase in atrial natriuretic peptide, brain natriuretic peptide, beta-myosin heavy chain, CYP1A1 and CYP1A2 messenger RNAs (mRNAs). Rats exposed to incense smoke displayed marked ultrastructural changes in heart muscle with distinct cardiac hypertrophy, which correlated with the augmented hypertrophic gene expression as well as markers of cardiac damage including creatine kinase myocardial bound (CK-MB) and lactate dehydrogenase (LDH). Increased oxidative stress, inflammation, altered cardiac hypertrophic gene expression, tissue damage, and architectural changes in the heart may collectively contribute to increased cardiovascular disease risk in individuals exposed to incense smoke. Increased gene expressions of CYP1A1 and CYP1A2 may be instrumental in the incense smoke-induced oxidative stress and inflammation. Thus, incense smoke can be considered as a potential environmental pollutant and its long-term exposure may negatively impact human health. PMID- 25687614 TI - Conserved hydrogen bonding in tetrahydrocarbazolone derivatives: influence of solution-state assembly on crystal form nucleation. AB - Two tetrahydocarbazolone derivatives were found to show multiple unsolvated crystal forms. A persistent dimer motif was detected in solution by FTIR spectroscopy that is maintained in the kinetic crystal forms. Rationally introduced steric bulk induces the formation of a more stable catemeric form. PMID- 25687615 TI - [Catheter ablation of persistent atrial fibrillation : pulmonary vein isolation, ablation of fractionated electrograms, stepwise approach or rotor ablation?]. AB - Catheter ablation is an established treatment option for patients with atrial fibrillation (AF). In paroxysmal AF ablation, pulmonary vein isolation alone is a well-defined procedural endpoint, leading to success rates of up to 80% with multiple procedures over 5 years of follow-up. The success rate in persistent AF ablation is significantly more limited. This is partly due to the rudimentary understanding of the substrate maintaining persistent AF. Three main pathophysiological concepts for this arrhythmia exist: the multiple wavelet hypothesis, the concept of focal triggers, mainly located in the pulmonary veins and the rotor hypothesis. However, the targets and endpoints of persistent AF ablation are ill-defined and there is no consensus on the optimal ablation strategy in these patients. Based on these concepts, several ablation approaches for persistent AF have emerged: pulmonary vein isolation, the stepwise approach (i.e. pulmonary vein isolation, ablation of fractionated electrograms and linear ablation), magnetic resonance imaging (MRI) and rotor-based approaches. Currently, persistent AF ablation is a second-line therapy option to restore and maintain sinus rhythm. Several factors, such as the presence of structural heart disease, duration of persistent AF and dilatation and possibly also the degree of fibrosis of the left atrium should influence the decision to perform persistent AF ablation. PMID- 25687616 TI - 18-carbon polyunsaturated fatty acids ameliorate palmitate-induced inflammation and insulin resistance in mouse C2C12 myotubes. AB - Skeletal muscle is a major site of insulin action. Intramuscular lipid accumulation results in inflammation, which has a strong correlation with skeletal muscle insulin resistance (IR). The aim of this study was to explore the effects of linoleic acid, alpha-linolenic acid, and gamma-linolenic acid (GLA), 18-carbon polyunsaturated fatty acids (PUFAs), on palmitic acid (PA)-induced inflammatory responses and IR in C2C12 myotubes. Our data demonstrated that these three test 18-carbon PUFAs can inhibit PA-induced interleukin-6 and tumor necrosis factor-alpha messenger RNA (mRNA) expression and IR as evidenced by increases in phosphorylated AKT and the 160-kD AKT substrate, mRNA and plasma membrane protein expression of glucose transporter 4, and glucose uptake. Moreover, the 18-carbon PUFAs blocked the effects of PA on activation of mitogen activated protein kinases (MAPKs), protein kinase C-theta (PKC-theta), AMP activated protein kinase (AMPK) and nuclear factor-kappaB (NF-kappaB). Of note, supplementation with GLA-rich borage oil decreased proinflammatory cytokine production and hindered the activation of MAPKs, PKC-theta and NF-kappaB in the skeletal muscles of diabetic mice. The 18-carbon PUFAs did not reverse PA-induced inflammation or IR in C2C12 myotubes transfected with a constitutively active mutant IkappaB kinase-beta plasmid, which suggests the importance of the inhibition of NF-kappaB activation by the 18-carbon PUFAs. Moreover, blockade of AMPK activation by short hairpin RNA annulled the inhibitory effects of the 18 carbon PUFAs on PA-induced IR but not inflammation. Our findings suggest that the 18-carbon PUFAs may be useful in the management of PA-induced inflammation and IR in myotubes. PMID- 25687617 TI - Internet-purchased ibogaine toxicity confirmed with serum, urine, and product content levels. AB - Ibogaine, a psychotropic indole alkaloid, is gaining popularity among medical subcultures for its purported anti addictive properties. Its use has been associated with altered mental status, ataxia, gastrointestinal distress, ventricular arrhythmias, and sudden and unexplained deaths.Its pharmacokinetics in toxic states is not well understood. Case report:A 33-year-old man overdosed on ibogaine in an attempt to quit his use of heroin. He developed altered state of consciousness, tremor, ataxia,nausea, vomiting, and transient QT interval prolongation, which all remitted as he cleared the substance. Ibogaine was confirmed in his urine and serum with a peak serum concentration of 377 ng/mL. Nonlinear elimination kinetics and a formula match to its active metabolite noriobgaine were observed as well. CONCLUSION: This case presents the unique description of serial serum concentrations as well as urine and product-confirmed ibogaine toxicity with transient toxin-related QT interval prolongation. PMID- 25687618 TI - Effect of regular marijuana smoking on platelet function. PMID- 25687619 TI - Patient preferences regarding medical decision making in the emergency care setting: a pilot-study. PMID- 25687620 TI - Combination of mean platelet volume and the CURB-65 score better predicts 28-day mortality in patients with community-acquired pneumonia. AB - OBJECTIVE: This study aims to investigate whether mean platelet volume (MPV) is correlated with the CURB-65 (Confusion, Urea, Respiratory rate, Blood pressure, >65 years of age) score, and whether a combination of the CURB-65 score with MPV could better predict the 28-day mortality in patients with community-acquired pneumonia (CAP). METHODS: This prospective, observational, single-center, and cross-sectional study was conducted at emergency department (ED) between September 1, 2013, and July 31, 2014. All patients underwent follow-up evaluations 28 days after admission. The end point was defined as all-cause mortality. RESULTS: A total of 174 patients (mean age, 66.7 +/- 15.8 years; 66.1% men) with CAP were enrolled in this study. All-cause mortality at the 28-day follow-up evaluation was 16.1%. A significant and inverse correlation between MPV and CURB-65 score was found (R = -.58, P < .001). We determined that the optimal MPV cutoff for predicting 28-day mortality at the time of ED admission was 8.55 fL, with a 75.0% sensitivity and a 75.3% specificity. For the prediction of 28 day mortality, the area under the receiver operating characteristic curve was 0.819 (95% confidence interval [CI], 0.740-0.898; P < .001) when the CURB-65 score was used alone, whereas it increased to 0.895 (95% CI, 0.819-0.936; P < .001) with the addition of MPV to the score. CONCLUSIONS: Mean platelet volume level is valuable for predicting mortality and the severity of disease among patients with CAP at ED admission. Furthermore, a combination of CURB-65 score and MPV can enhance the predictive accuracy of 28-day mortality. PMID- 25687621 TI - Mid-infrared laser filaments in the atmosphere. AB - Filamentation of ultrashort laser pulses in the atmosphere offers unique opportunities for long-range transmission of high-power laser radiation and standoff detection. With the critical power of self-focusing scaling as the laser wavelength squared, the quest for longer-wavelength drivers, which would radically increase the peak power and, hence, the laser energy in a single filament, has been ongoing over two decades, during which time the available laser sources limited filamentation experiments in the atmosphere to the near infrared and visible ranges. Here, we demonstrate filamentation of ultrashort mid infrared pulses in the atmosphere for the first time. We show that, with the spectrum of a femtosecond laser driver centered at 3.9 MUm, right at the edge of the atmospheric transmission window, radiation energies above 20 mJ and peak powers in excess of 200 GW can be transmitted through the atmosphere in a single filament. Our studies reveal unique properties of mid-infrared filaments, where the generation of powerful mid-infrared supercontinuum is accompanied by unusual scenarios of optical harmonic generation, giving rise to remarkably broad radiation spectra, stretching from the visible to the mid-infrared. PMID- 25687622 TI - Understanding ferroelectricity in layered perovskites: new ideas and insights from theory and experiments. AB - ABO(3) perovskites have fascinated solid-state chemists and physicists for decades because they display a seemingly inexhaustible variety of chemical and physical properties. However, despite the diversity of properties found among perovskites, very few of these materials are ferroelectric, or even polar, in bulk. In this Perspective, we highlight recent theoretical and experimental studies that have shown how a combination of non-polar structural distortions, commonly tilts or rotations of the BO(6) octahedra, can give rise to polar structures or ferroelectricity in several families of layered perovskites. We discuss the crystal chemical origin of the polarization in each of these families - which emerges through a so-called 'trilinear coupling' or 'hybrid improper' mechanism - and emphasize areas in which further theoretical and experimental investigation is needed. We also consider how this mechanism may provide a generic route for designing not only new ferroelectrics, but also materials with various other multifunctionalities, such as magnetoelectrics and electric field controllable metal-insulator transitions. PMID- 25687623 TI - Particular aspects of proctology for anoperineal lesions in Crohn's disease. AB - All practitioners caring for patients with Crohn's disease (CD) must know all the various aspects of anoperineal lesions in this singular entity. Suppuration in CD does not follow the classic routes and spaces of diffusion and is often associated with endolumenal lesions that can evolve on their own. Abscesses and fistulas require specific medico-surgical management where seton drainage, staged operative and sphincter-sparing procedures have a dominant place. The variability of associated lesions and the particularly individualized efficacy of drugs call for case-by-case management, thus, making standardization and comparisons difficult. Recent therapeutic progress has led to modifications of the minimally invasive management policies practiced in the last decades. PMID- 25687624 TI - Single-port Colectomy VS Multi-port Laparoscopic Colectomy. Systematic Review and Meta-analysis of More Than 2800 Procedures. AB - OBJECTIVE: Multiport laparoscopic surgery in colon pathology has been demonstrated as a safe and effective technique. Interest in reducing aggressiveness has led to other procedures being described, such as SILS. The aim of this meta-analysis is to evaluate feasibility and security of SILS technique in colonic surgery. MATERIAL AND METHODS: A meta-analysis of twenty 7 observational studies and one prospective randomized trial has been conducted by the use of random-effects models. RESULTS: A total amount of 2870 procedures was analyzed: 1119 SILS and 1751 MLC. We did not find statistically significant differences between SILS and MLC in age (WMD 0.28 [-1.13, 1.68]; P=.70), BMI (WMD -0.63 [-1.34, 0.08]; P=.08), ASA score (WMD -0.02 [-0.08, 0.04]; P=.51), length of incision (WMD -1.90 [-3.95, 0.14]; P=.07), operating time (WMD -2.69 (-18.33, 12.95]; P=.74), complications (OR=0.89 [0.69, 1.15]; P=.37), conversion to laparotomy (OR=0.59 [0.33, 1.04]; P=.07), mortality (OR=0.91 [0.36, 2.34]; P=.85) or number of lymph nodes harvested (WMD 0.13 [-2.52, 2.78]; P=.92). The blood loss was significantly lower in the SILS group (WMD -42.68 [-76.79, -8.57]; P=.01) and the length of hospital stay was also significantly lower in the SILS group (WMD -0.73 [-1.18, -0.28]; P=.001). CONCLUSION: Single-port laparoscopic colectomy is a safe and effective technique with additional subtle benefits compared to multiport laparoscopic colectomy. However, further prospective randomized studies are needed before single-port colectomy can be considered an alternative to multiport laparoscopic surgery of the colon. PMID- 25687625 TI - Genome-wide analysis and expression of the calcium-dependent protein kinase gene family in cucumber. AB - Calcium-dependent protein kinases (CDPKs) are multi-functional proteins that combine calcium-binding and signaling capabilities within a single gene product. Current studies have shown that the CDPKs regulate numerous growth and developmental processes and biotic and abiotic stress responses. Nonetheless, knowledge concerning the specific expression patterns and evolutionary history of the CDPK family in cucumber (Cucumis sativus L.) remains very limited. We, therefore, investigated the phylogenetic relationships and expression profiles of the 19 CDPK genes identified in the cucumber genome sequence, resolving them into four subfamilies based on a phylogenetic tree and gene structures. Tissue specific expression profiles suggest that cucumber CDPK genes are involved in cucumber tissue development. An expression analysis based on qRT-PCR indicated that cucumber CDPK genes are extensively involved in abscisic acid, salt, cold, drought, heat, and waterlogging responses, possibly by different mechanisms. The fates of two paralogs after divergence were also investigated, suggesting subfunctionalization and neofunctionalization during evolution. These observations lay an important foundation for functional and evolutionary analyses of the CDPK gene family in cucurbitaceae species. PMID- 25687626 TI - Genome-wide identification, classification and functional analyses of the bHLH transcription factor family in the pig, Sus scrofa. AB - The basic helix-loop-helix (bHLH) transcription factors are one of the largest families of gene regulatory proteins and play crucial roles in genetic, developmental and physiological processes in eukaryotes. Here, we conducted a survey of the Sus scrofa genome and identified 109 putative bHLH transcription factor members belonging to super-groups A, B, C, D, E, and F, respectively, while four members were orphan genes. We identified 6 most significantly enriched KEGG pathways and 116 most significant GO annotation categories. Further comprehensive surveys in human genome and other 12 medical databases identified 72 significantly enriched biological pathways with these 113 pig bHLH transcription factors. From the functional protein association network analysis 93 hub proteins were identified and 55 hub proteins created a tight network or a functional module within their protein families. Especially, there were 20 hub proteins found highly connected in the functional interaction network. The present study deepens our understanding and provided insights into the evolution and functional aspects of animal bHLH proteins and should serve as a solid foundation for further for analyses of specific bHLH transcription factors in the pig and other mammals. PMID- 25687627 TI - A retrospective clinical and epidemiological study on feline coronavirus (FCoV) in cats in Istanbul, Turkey. AB - The presence of antibodies to feline coronavirus (FCoV) and feline immunodeficiency virus (FIV), together with feline leukemia virus (FeLV) antigen was investigated in 169 ill household and stray cats attending a veterinary surgery in Istanbul in 2009-14. The estimated FCoV and FIV seroprevalence (95% confidence intervals) were 37% (30-45%) and 11% (6-16%), respectively and FeLV prevalence was 1% (0-3%). FCoV seroprevalence increased until 2 years of age, was highest in 2014 and among household cats living with other cats and with outdoor access, and was lower in FIV seropositive compared to seronegative cats. Symptoms typically associated with wet feline infectious peritonitis (FIP) including ascites, abdominal distention or pleural effusion, coupled in many cases with non antibiotic responsive fever, were observed in 19% (32/169) of cats, and 75% (24/32) of these cats were FCoV seropositive. FCoV seropositivity was also associated with a high white blood cell count, high plasma globulin, low plasma albumin and low blood urea nitrogen. The percentage of FCoV seropositive and seronegative cats that died in spite of supportive veterinary treatment was 33% (21/63) and 12% (13/106), respectively. These results indicate that FCoV is widespread and has a severe clinical impact in cats from Istanbul. Moreover, the incidence of FCoV infections could be rising, and in the absence of effective vaccination cat owners need to be made aware of ways to minimize the spread of this virus. PMID- 25687628 TI - Effects of cementation surface modifications on fracture resistance of zirconia. AB - OBJECTIVES: To examine the effects of glass infiltration (GI) and alumina coating (AC) on the indentation flexural load and four-point bending strength of monolithic zirconia. METHODS: Plate-shaped (12 mm * 12 mm * 1.0 mm or 1.5 or 2.0 mm) and bar-shaped (4 mm * 3 mm * 25 mm) monolithic zirconia specimens were fabricated. In addition to monolithic zirconia (group Z), zirconia monoliths were glass-infiltrated or alumina-coated on their tensile surfaces to form groups ZGI and ZAC, respectively. They were also glass-infiltrated on their upper surfaces, and glass-infiltrated or alumina-coated on their lower (tensile) surfaces to make groups ZGI2 and ZAC2, respectively. For comparison, porcelain-veneered zirconia (group PVZ) and monolithic lithium disilicate glass-ceramic (group LiDi) specimens were also fabricated. The plate-shaped specimens were cemented onto a restorative composite base for Hertzian indentation using a tungsten carbide spherical indenter with a radius of 3.2mm. Critical loads for indentation flexural fracture at the zirconia cementation surface were measured. Strengths of bar-shaped specimens were evaluated in four-point bending. RESULTS: Glass infiltration on zirconia tensile surfaces increased indentation flexural loads by 32% in Hertzian contact and flexural strength by 24% in four-point bending. Alumina coating showed no significant effect on resistance to flexural damage of zirconia. Monolithic zirconia outperformed porcelain-veneered zirconia and monolithic lithium disilicate glass-ceramics in terms of both indentation flexural load and flexural strength. SIGNIFICANCE: While both alumina coating and glass infiltration can be used to effectively modify the cementation surface of zirconia, glass infiltration can further increase the flexural fracture resistance of zirconia. PMID- 25687629 TI - The epidemiology of inflammatory bowel disease. AB - BACKGROUND AND AIMS: The inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis (UC), are chronic relapsing disorders of unknown aetiology. The aim of this review is to present the latest epidemiology data on occurrence, disease course, risk for surgery, as well as mortality and cancer risks. MATERIAL AND METHODS: Gold standard epidemiology data on the disease course and prognosis of patients with inflammatory bowel disease (IBD) are based on unselected population-based cohort studies. RESULTS: The incidence of ulcerative colitis (UC) and Crohn's disease (CD) has increased overall in Europe from 6.0 per 100,000 person-years in UC and 1.0 per 100,000 person-years in CD in 1962 to 9.8 per 100,000 person-years and 6.3 per 100,000 person-years in 2010, respectively. The highest incidence of IBD is found on the Faroe Islands. Overall, surgery rates have been declining over the last decades, partly due to aggressive medical therapy. Among IBD patients, mortality risk is increased by up to 50% in CD when compared to the background population, but this is not the case for UC. In CD, 25 - 50% deaths are disease-specific deaths, e.g. malnutrition, postoperative complications and intestinal cancer. In UC, disease-specific causes of deaths include colorectal cancer (CRC), and surgical and postoperative complications. The risk of CRC and small bowel cancer is increased two- to eightfold among IBD patients. Various subgroups carry increased risk of malignancy, e.g. those with persistent inflammation, long-standing disease, extensive disease, young age at diagnosis, family history of CRC and co-existing primary sclerosing cholangitis. The risk of extra-intestinal cancers, including lymphoproliferative disorders (LD) and intra- and extrahepatic cholangio carcinoma, is significantly higher among IBD patients. CONCLUSION: In recent years, self-management and patient empowerment, combined with evolving eHealth solutions, has utilized epidemiological knowledge on disease patterns and has been improving compliance and the timing of adjusting therapies, thus optimizing efficacy by individualizing medication in the community setting. PMID- 25687630 TI - Budd-Chiari syndrome: a prospective analysis of hepatic vein obstruction on ultrasonography, multidetector-row computed tomography and MR imaging. AB - PURPOSE: The goal of this study was to prospectively describe the imaging presentation of hepatic vein (HV) obstruction in patients with Budd-Chiari syndrome (BCS) on duplex and color Doppler ultrasonography (DCD-US), multidetector-row computed tomography (MDCT) and magnetic resonance imaging (MRI). MATERIALS AND METHODS: A total of 176 patients with primary BCS (mean age, 33 years; 101 women) were prospectively included. BCS diagnosis was made by direct visualization of HV and/or upper portion of the inferior vena cava (IVC) obstruction on DCD-US and/or MDCT and/or MRI. Location (right, middle, and left HV), type (thrombus, stenosis, or both), and age (recent vs. long-standing) of HV obstruction were described on each imaging examination. RESULTS: HV obstruction was a constant (100%) finding and associated with IVC abnormalities in 51/176 (28.98%) patients. Obstruction of the three HVs was present in 158/176 (89.77%) patients. The prevalences of right, middle, and left HV thrombus were 151/169 (89.35%), 146/169 (86.39%), and 111/169 (65.68%), respectively. Long-standing HV thrombus was observed in more than 92% of patients on the three imaging methods. Agreement between DCD-US, MDCT, and MRI was perfect in the identification of long standing HV thrombus (kappa = 0.9); this agreement was slight to moderate in revealing the type of HV abnormality (i.e., fibrotic cord and non-visible HV). CONCLUSION: Our results indicate that BCS is a chronic and insidious disease, more often discovered at an advanced stage. These results should warrant further evaluation of screening strategies in patients with risk factors for BCS to identify the disease at an early stage. PMID- 25687631 TI - Direct MRI-guided biopsy of the prostate: use of post-biopsy needle track imaging to confirm targeting. AB - PURPOSE: To report the observation that in-plane post-biopsy T2-weighted MRI often demonstrates the needle track as a transient visible linear tissue distortion during direct MRI-guided biopsy. MATERIALS AND METHODS: We retrospectively identified 11 prostatic lesions in 9 men that underwent direct MRI-guided biopsy and in which post-biopsy images were obtained in the plane of the biopsy needle. RESULTS: In 9 of 11 targets, a post-biopsy needle track was visible as a linear tissue distortion on in-plane T2-weighted images obtained at a mean interval of 6 min (range 3-15). In these nine cases, the needle track traversed the intended target, and the biopsy was positive for malignancy in six. Biopsy was positive in one of two cases where the needle track was not visible. In five targets, one or more delayed series were obtained after a mean interval of 21 min (range 8-33), showing the track was no longer visible (n = 3) or was of progressively decreased conspicuity (n = 2). CONCLUSION: Accurate targeting during direct MRI-guided biopsy of the prostate can be confirmed by obtaining post-biopsy in-plane images, since the needle track is usually visible as a transient linear tissue distortion. PMID- 25687632 TI - Purification and properties of recombinant Brassica napus diacylglycerol acyltransferase 1. AB - Diacylglycerol acyltransferase 1 (DGAT1) catalyzes the final step in the acyl-CoA dependent triacylglycerol biosynthesis. Although the first DGAT1 gene was identified many years ago and the encoded enzyme catalyzes a key step in lipid biosynthesis, no detailed structure-function information is available on the enzyme due to difficulties associated with its purification. This study describes the purification of recombinant Brassica napus DGAT1 (BnaC.DGAT1.a) in active form through solubilization in n-dodecyl-beta-D-maltopyranoside, cobalt affinity chromatography, and size-exclusion chromatography. Different BnaC.DGAT1.a oligomers in detergent micelles were resolved during the size-exclusion process. BnaC.DGAT1.a was purified 126-fold over the solubilized fraction and exhibited a specific activity of 26 nmol TAG/min/mg protein. The purified enzyme exhibited substrate preference for alpha-linolenoyl-CoA>oleoyl-CoA=palmitoyl-CoA>linoleoyl CoA>stearoyl-CoA. PMID- 25687633 TI - Array tomography for the detection of non-dilated, injured axons in traumatic brain injury. AB - BACKGROUND: Axonal injury is a key feature of several types of brain trauma and neurological disease. However, in mice and humans, many axons are less than 500 nm in diameter which is at or below the resolution of most conventional light microscopic imaging methods. In moderate to severe forms of axon injury, damaged axons become dilated and therefore readily detectible by light microscopy. However, in more subtle forms of injury, the damaged axons may remain undilated and therefore difficult to detect. NEW METHOD: Here we present a method for adapting array tomography for the identification and quantification of injured axons. In this technique, ultrathin (~70 nm) plastic sections of tissue are prepared, labeled with axon injury-relevant antibodies and imaged using conventional epifluorescence. RESULTS: To demonstrate the use of array-tomography based methods, we determined that mice that received two closed-skull concussive traumatic brain injury impacts had significantly increased numbers of non-dilated axons that were immunoreactive for non-phosphorylated neurofilament (SMI-32; a marker of axonal injury), compared to sham mice (1682+/-628 versus 339+/-52 per mm(2), p=0.004, one-tailed Mann-Whitney U test). Tubulin loss was not evident (p=0.2063, one-tailed Mann-Whitney U test). Furthermore, mice that were subjected to more severe injury had a loss of tubulin in addition to both dilated and non dilated SMI-32 immunoreactive axons indicating that this technique is suitable for the analysis of various injury conditions. COMPARISON WITH EXISTING METHOD: With array tomography we could detect similar overall numbers of axons as electron microscopy, but accurate diameter measurements were limited to those with diameters >200 nm. Importantly, array tomography had greater sensitivity for detecting small non-dilated injured axons compared with conventional immunohistochemistry. CONCLUSION: Imaging of individual axons and quantification of subtle axonal injury is possible using this array tomography method. This method may be most useful for the assessment of concussive injuries and other pathologies in which injured axons are not typically dilated. The ability to process moderately large volumes of tissue, label multiple proteins of interest, and automate analysis support array tomography as a useful alternative to electron microscopy. PMID- 25687634 TI - Sensitivity of fNIRS measurement to head motion: an applied use of smartphones in the lab. AB - BACKGROUND: Powerful computing capabilities in small, easy to use hand-held devices have made smart technologies such as smartphones and tablets ubiquitous in today's society. The capabilities of these devices provide scientists with many tools that can be used to improve the scientific method. METHOD: Here, we demonstrate how smartphones may be used to quantify the sensitivity of functional near-infrared spectroscopy (fNIRS) signal to head motion. By attaching a smartphone to participants' heads during the fNIRS scan, we were able to capture data describing the degree of head motion. RESULTS: Our results demonstrate that data recorded from an off-the-shelf smartphone accelerometer may be used to identify correlations between head-movement and fNIRS signal change. Furthermore, our results identify correlations between the magnitudes of head-movement and signal artifact, as well as a relationship between the direction of head movement and the location of the resulting signal noise. CONCLUSIONS: These data provide a valuable proof-of-concept for the use of off-the-shelf smart technologies in neuroimaging applications. PMID- 25687635 TI - Premature pubarche in children with Pompe disease. AB - Pompe disease (PD), or glycogen storage disease type II, results from deficiency of acid alpha-glucosidase. Patients with infantile-onset PD die by early childhood if untreated. Patient survival has improved with enzyme replacement therapy. We report a case series of 8 patients with infantile-onset PD on enzyme replacement therapy with premature pubarche. PMID- 25687636 TI - Prejudiced interactions: implicit racial bias reduces predictive simulation during joint action with an out-group avatar. AB - During social interactions people automatically apply stereotypes in order to rapidly categorize others. Racial differences are among the most powerful cues that drive these categorizations and modulate our emotional and cognitive reactivity to others. We investigated whether implicit racial bias may also shape hand kinematics during the execution of realistic joint actions with virtual in- and out-group partners. Caucasian participants were required to perform synchronous imitative or complementary reach-to-grasp movements with avatars that had different skin color (white and black) but showed identical action kinematics. Results demonstrate that stronger visuo-motor interference (indexed here as hand kinematics differences between complementary and imitative actions) emerged: i) when participants were required to predict the partner's action goal in order to on-line adapt their own movements accordingly; ii) during interactions with the in-group partner, indicating the partner's racial membership modulates interactive behaviors. Importantly, the in-group/out-group effect positively correlated with the implicit racial bias of each participant. Thus visuo-motor interference during joint action, likely reflecting predictive embodied simulation of the partner's movements, is affected by cultural inter individual differences. PMID- 25687637 TI - Pyrroloquinoline Quinone Slows Down the Progression of Osteoarthritis by Inhibiting Nitric Oxide Production and Metalloproteinase Synthesis. AB - Osteoarthritis (OA) is the most common arthritis and also one of the major causes of joint pain in elderly people. The aim of this study was to investigate the effects of pyrroloquinoline quinone (PQQ) on degenerated-related changes in osteoarthritis (OA). SW1353 cells were stimulated with IL-1beta to establish the chondrocyte injury model in vitro. PQQ was administrated into SW1353 cultures 1 h before IL-1beta treatment. Amounts of MMP-1, MMP-13, P65, IkappaBalpha, ERK, p ERK, P38, and p-P38 were measured via western blot. The production of NO was determined by Griess reaction assay and reflected by the iNOS level. Meniscal ligamentous injury (MLI) was performed on 8-week-old rats to establish the OA rat model. PQQ was injected intraperitoneally 3 days before MLI and consecutively until harvest, and the arthritis cartilage degeneration level was assessed. The expressions of MMP-1 and MMP-13 were significantly downregulated after PQQ treatment compared with that in IL-1beta alone group. NO production and iNOS expression were decreased by PQQ treatment compared with control group. Amounts of nucleus P65 were upregulated in SW1353 after stimulated with IL-1beta, while PQQ significantly inhibited the translocation. In rat OA model, treatment with PQQ markedly decelerated the degeneration of articular cartilage. These findings suggested that PQQ could inhibit OA-related catabolic proteins MMPs expression, NO production, and thus, slow down the articular cartilage degeneration and OA progression. Owing to its beneficial effects, PQQ is expected to be a novel pharmacological application in OA clinical prevention and treatment in the near future. PMID- 25687638 TI - Celecoxib Combined with Diacerein Effectively Alleviates Osteoarthritis in Rats via Regulating JNK and p38MAPK Signaling Pathways. AB - Osteoarthritis (OA) has long been a difficult to overcome joint disease for medical workers. However, there is still a lack of effective treatments for OA. In the present study, we aimed to evaluate the treatment effect of celecoxib (CLX) combined with diacerein (DC) on OA and delineate the underlying molecular mechanism. The OA model was established by using rats, and OA rats were treated with either CLX alone, DC alone, and CLX combined with DC. The results showed that, as compared with a single treatment of CLX or DC, CLX combined with DC markedly attenuated OA and inhibited the levels of inflammatory mediators interleukin-1beta and nitric oxide, improved bone cartilage metabolism, and suppressed chondrocyte apoptosis. Most importantly, CLX combined with DC significantly inactivated the c-Jun N-terminal kinases (JNK) signaling pathway by the inhibition of MEKK1 and MKK7, as detected by Western blot analysis. Furthermore, the protein expression of downstream genes of JNK, including activating-transcription factor (Atf-2), matrix metalloproteinase-13 (MMP-13), and cyclooxygenase (COX-2), were also significantly inhibited by CLX combined with DC as compared with single treatments. Furthermore, CLX combined with DC also effectively inhibits p38 mitogen-activated protein kinase and nuclear factor kappaB signaling pathways. Taken together, our study suggests that CLX combined with DC has satisfactory treatment effects on OA via a stronger inhibitory effect on inflammatory signaling pathway. PMID- 25687639 TI - The Neuroprotective Effect of Glycyrrhizic Acid on an Experimental Model of Focal Cerebral Ischemia in Rats. AB - Cerebral ischemia is still one of the most important topics in neurosciences. Our study aimed to investigate the neuroprotective and anti-oxidant effects of glycyrrhizic acid on focal cerebral ischemia in rats. Twenty-four rats were divided equally into three groups. A middle cerebral artery occlusion model was performed in this study where sham and glycyrrhizic acid were administered intraperitoneally following middle cerebral artery occlusion. Group I was evaluated as control. Malondialdehyde (MDA), superoxide dismutase (SOD), and nuclear respiratory factor-1 (NRF1) levels were analyzed biochemically on the right cerebral hemisphere, while ischemic histopathological studies were completed to investigate the anti-oxidant status. Biochemical results showed that SOD and NRF1 levels were significantly increased in the glycyrrhizic acid group compared with the sham group while MDA levels were significantly decreased. On histopathological examination, cerebral edema, vacuolization, degeneration, and destruction of neurons were decreased in the glycyrrhizic acid group compared with the sham group. Cerebral ischemia was attenuated by glycyrrhizic acid administration. These observations indicate that glycyrrhizic acid may have potential as a therapeutic agent in cerebral ischemia by preventing oxidative stress. PMID- 25687640 TI - Macrophage-Microglia Networks Drive M1 Microglia Polarization After Mycobacterium Infection. AB - Central nervous system tuberculosis (CNS-TB) is caused by infection with Mycobacterium tuberculosis (Mtb). The inflammatory response following CNS-TB involves the activation of resident microglia and the infiltration of macrophages. However, it has not been clarified whether microglia can be polarized into the classically activated proinflammatory M1 phenotype or the alternatively activated anti-inflammatory M2 phenotype after Mtb infection. In this study, we found that BV2 treated with conditioned media from cultures of macrophages infected with Mycobacterium marinum (Mm) induced the expression of M1 phenotypic genes including iNOS, TNF-alpha, IL-1beta, IL-6, CCL2, and CXCL10 but reduced that of M2 phenotypic genes such as Arginase 1, Ym1, and CD163. These results suggest that polarization of microglia is partly mediated through macrophage-microglia interactions as a priming signal. Overall, these results provide new insights into the modulatory mechanisms of microglial polarization, thereby possibly facilitating the development of new therapies for CNS-TB infection via the regulation of microglial polarization through signalling derived from macrophages infected with mycobacteria. PMID- 25687641 TI - Triptolide Protects Against Ischemic Stroke in Rats. AB - Inflammatory response plays an important role in the pathogenesis of ischemic stroke and anti-inflammatory agents may provide a choice of treatment. Triptolide is reported to be anti-inflammatory. In this study, we investigated the effects of triptolide on cultured neuronal cell line in vitro and experimental ischemic stroke in vivo. Oxygen-glucose deprivation (OGD) and tumor necrosis factor-alpha (TNF-alpha) stimulated SH-SY5Y cells were incubated with triptolide. In vivo, rats were subjected to middle cerebral artery occlusion (MCAO) for 1 h, followed by reperfusion for 23 h. Results of this study showed that triptolide treatment reduced the OGD-induced cytotoxicity and apoptosis and blocked TNF-alpha-induced activation of NF-kappaB and p38MAPK in SH-SY5Y cells. Intraperitoneal injection of triptolide showed significant neuroprotective actions in stroke rats. Triptolide attenuated neurological deficit, brain infarct volume, and brain water content, and inhibited activation of NF-kappaB and p38MAPK. These data show that triptolide protects rats against ischemic cerebral injury via inhibiting NF kappaB and p38MAPK signaling pathways. PMID- 25687642 TI - Inhibitory Effect of Orientin on Secretory Group IIA Phospholipase A2. AB - It is well known that the expression level of secretory group IIA phospholipase A2 (sPLA2-IIA) is elevated in inflammatory diseases and lipopolysaccharide (LPS) upregulates the expression of sPLA2-IIA in human umbilical vein endothelial cells (HUVECs). Orientin, a C-glycosyl flavonoid, is known to have anxiolytic, anti oxidative, and anti-inflammatory activity. Here, orientin was examined for its effects on the expression and activity of sPLA2-IIA in HUVECs and mouse. Prior treatment of cells or mouse with orientin inhibited LPS-induced expression and activity of sPLA2-IIA. And orientin suppressed the activation of cytosolic phospholipase A2 (cPLA2) and extracellular signal-regulated kinase (ERK) 1/2 by LPS. Therefore, these results suggest that orientin may inhibit LPS-mediated expression of sPLA2-IIA by suppression of cPLA2 and ERK 1/2. PMID- 25687643 TI - Synergy of chemotherapy and immunotherapy revealed by a genome-scale analysis of murine tuberculosis. AB - OBJECTIVES: Although TB immunotherapy improves the results of conventional drug treatment, the effects of combining chemotherapy and immunotherapy have never been systematically evaluated. We used a comprehensive lung transcriptome analysis to directly compare the activity of combined chemotherapy and immunotherapy with that of single treatments in a mouse model of TB. METHODS: Mycobacterium tuberculosis-infected mice in the chronic phase of the disease (day 30) received: (i) isoniazid and rifampicin (drugs) daily for 30 days; (ii) DNA immunotherapy (DNA), consisting of four 100 MUg injections at 10 day intervals; (iii) both therapies (DNA + drugs); or (iv) saline. The effects were evaluated 10 days after the end of treatment (day 70 post-infection). RESULTS: In all groups a systemic reduction in the load of bacilli was observed, bacilli became undetectable in the drugs and DNA + drugs groups, but the whole lung transcriptome analysis showed 867 genes exclusively modulated by the DNA + drugs combination. Gene enrichment analysis indicated that DNA + drugs treatment provided synergistic effects, including the down-regulation of proinflammatory cytokines and mediators of fibrosis, as confirmed by real-time PCR, ELISA, histopathology and hydroxyproline assay. CONCLUSIONS: Our results provide a molecular basis for the advantages of TB treatment using combined chemotherapy and DNA immunotherapy and demonstrate the synergistic effects obtained with this strategy. PMID- 25687644 TI - CTX-M-27- and CTX-M-14-producing, ciprofloxacin-resistant Escherichia coli of the H30 subclonal group within ST131 drive a Japanese regional ESBL epidemic. AB - OBJECTIVES: The global increase in ESBL-producing Escherichia coli is associated with the ST131 clonal group, especially its CTX-M-15-producing H30Rx subset. To understand the rapid spread of ESBL-producing E. coli in Japan, we investigated the molecular epidemiology and ESBL-associated genetic environments of Japanese ST131 isolates. METHODS: Between 2001 and 2012, 1079 ESBL-producing E. coli isolates were collected at 10 Japanese acute-care hospitals. ESBL types, ST131 status, fimH allele, H30Rx-defining sequences and ESBL-associated genetic environments were defined using PCR and sequencing. Subclonal groups were defined based on fimH allele and H30Rx status. RESULTS: Overall, 461 (43%) of the 1079 ESBL-producing E. coli isolates represented ST131. According to fimH-based subclonal typing, the ST131 isolates included 398 fimH allele 30 (H30) isolates, 49 H41 isolates, 10 H22 isolates and 4 other fimH-type isolates. The 398 H30 isolates included 396 ciprofloxacin-resistant H30R isolates, of which 64 (16%) represented the H30Rx subset. Between 2001 and 2007, the CTX-M-14-producing H30R subgroup predominated, accounting for 46% of ST131 isolates, whereas the CTX-M-27 producing H30R and CTX-M-15-producing H30Rx subgroups were rarely detected. In contrast, from 2008 onward the latter two subgroups rose to dominance, accounting for 45% and 24% of ST131 isolates, respectively, versus only 15% for the (formerly dominant) CTX-M-14-producing H30R subgroup. The emergent CTX-M-27-H30R subgroup frequently had an IS26-DeltaISEcp1-blaCTX-M-27-DeltaIS903D-IS26-like structure, whereas the older CTX-M-14-H30R subgroup frequently had an ISEcp1 blaCTX-M-14-IS903D-like structure. CONCLUSIONS: This Japanese regional ESBL producing E. coli epidemic is closely associated with newly identified CTX-M-27- and CTX-M-14-producing ST131 H30R subclonal groups and with mobile elements IS26, ISEcp1 and IS903D. PMID- 25687645 TI - Unveiling pseudospin and angular momentum in photonic graphene. AB - Pseudospin, an additional degree of freedom inherent in graphene, plays a key role in understanding many fundamental phenomena such as the anomalous quantum Hall effect, electron chirality and Klein paradox. Unlike the electron spin, the pseudospin was traditionally considered as an unmeasurable quantity, immune to Stern-Gerlach-type experiments. Recently, however, it has been suggested that graphene pseudospin is a real angular momentum that might manifest itself as an observable quantity, but so far direct tests of such a momentum remained unfruitful. Here, by selective excitation of two sublattices of an artificial photonic graphene, we demonstrate pseudospin-mediated vortex generation and topological charge flipping in otherwise uniform optical beams with Bloch momentum traversing through the Dirac points. Corroborated by numerical solutions of the linear massless Dirac-Weyl equation, we show that pseudospin can turn into orbital angular momentum completely, thus upholding the belief that pseudospin is not merely for theoretical elegance but rather physically measurable. PMID- 25687646 TI - Corneal neovascularization and contemporary antiangiogenic therapeutics. AB - Corneal neovascularization (NV), the excessive ingrowth of blood vessels from conjunctiva into the cornea, is a common sequela of disease insult that can lead to visual impairment. Clinically, topical steroid, argon laser photocoagulation, and subconjunctival injection of bevacizumab have been used to treat corneal NV. Sometimes, the therapies are ineffective, especially when the vessels are large. Large vessels are difficult to occlude and easily recanalized. Scientists and physicians are now dedicated to overcoming this problem. In this article, we briefly introduce the pathogenesis of corneal NV, and then highlight the existing animal models used in corneal NV research-the alkali-induced model and the suture induced model. Most of all, we review the potential therapeutic targets (i.e., vascular endothelial growth factor and platelet-derived growth factor) and their corresponding inhibitors, as well as the immunosuppressants that have been discovered in recent years by corneal NV studies. PMID- 25687647 TI - (1)H, (13)C and (15)N backbone and side-chain resonance assignment of the LAM RRM1 N-terminal module of La protein from Dictyostelium discoideum. AB - The N-terminal half of La protein consists of two concatenated motifs: La motif (LAM) and the N-terminal RNA recognition motif (RRM1) both of which are responsible for poly(U) RNA binding. Here, we present the backbone and side-chain assignments of the (1)H, (13)C and (15)N resonances of the 191-residue LAM-RRM1 region of the La protein from the lower eukaryote Dictyostelium discoideum and its secondary structure prediction. PMID- 25687648 TI - Chemistry of carotenoid neutral radicals. AB - Proton loss from the carotenoid radical cations (Car(+)) to form neutral radicals (#Car) was investigated by numerous electrochemical, EPR, ENDOR and DFT studies described herein. The radical cation and neutral radicals were formed in solution electrochemically and stabilized on solid silica-alumina and MCM-41 matrices. Carotenoid neutral radicals were recently identified in Arabidopsis thaliana plant and photosystem II samples. Deprotonation at the terminal ends of a zeaxanthin radical cation could provide a secondary photoprotection pathway which involves quenching excited state chlorophyll by the long-lived zeaxanthin neutral radicals formed. PMID- 25687649 TI - Characterization of the transcriptional activation domains of human TEF3-1 (transcription enhancer factor 3 isoform 1). AB - TEF3-1 (transcription enhancer factor 3 isoform 1) is a human transcriptional factor, which has a N-terminal TEA/ATTS domain supposedly for DNA binding and C terminal PRD and STY domains for transcriptional activation. Taking advantage of the efficient reporter design of yeast two-hybrid system, we characterized the TEF3-1 domains in activating gene expression. Previously study usually mentioned that the C-terminal domain of TEF3-1 has the transcriptional activity, however, our data shows that the peptides TEF3-11-66 and TEF3-1197-434 functioned as two independent activation domains, suggesting that N-terminal domain of TEF3-1 also has transcriptional activation capacity. Additionally, more deletions of amino acids 197-434 showed that only the peptides TEF3-1197-265 contained the minimum sequences for the C-terminal transcriptional activation domain. The protein structure is predicted to contain a helix-turn-helix structure in TEF3-11-66 and four beta sheets in TEF3-1197-265. Finally, after the truncated fragments of TEF3 1 were expressed in HUVEC cells, the whole TEF3-1 and the two activation domains could increase F-actin stress fiber, cell proliferation, migration and targeted gene expression. Further analysis and characterization of the activation domains in TEF3-1 may broaden our understanding of the gene involved in angiogenesis and other pathological processes. PMID- 25687650 TI - Ab initio water pair potential with flexible monomers. AB - A potential energy surface for the water dimer with explicit dependence on monomer coordinates is presented. The surface was fitted to a set of previously published interaction energies computed on a grid of over a quarter million points in the 12-dimensional configurational space using symmetry-adapted perturbation theory and coupled-cluster methods. The present fit removes small errors in published fits, and its accuracy is critically evaluated. The minimum and saddle-point structures of the potential surface were found to be very close to predictions from direct ab initio optimizations. The computed second virial coefficients agreed well with experimental values. At low temperatures, the effects of monomer flexibility in the virial coefficients were found to be much smaller than the quantum effects. PMID- 25687651 TI - [Flexible ureteroscope damages. Evaluation of university hospital service equipment]. AB - OBJECTIVE: To evaluate predictors of flexible ureterorenoscopes breakage and damage of their optical beam. MATERIALS AND METHODS: Retrospective survey, single center on 393 interventions with 4 flexible ureterorenoscopes between January 2009 and March 2013. We analyzed factors linked to patient, pathology and surgical technique. RESULTS: We identified 21 major accidents, a breakage rate of 5.34% and 76 pixels losses in the maintenance of endoscopes and 10 during the procedure. The only statistically significant predictor of loss was the cumulative duration of operating time since the last repair (P=0.04, OR=1.001 [1 1001]). For lesions of the optical beam between the procedures, parameters appearing as significant were the ureterorenoscope model (P=0.01, OR=2.558, 95% CI [1229-5326]), the use of instruments by the working channel: the laser (P=0.02, OR=2.06, 95% CI [1109-3827]), or the use of endoluminal graspers (P=0.007, OR=0.467, 95% CI [0269-0809]). Intraoperatively, the number of open or laparoscopic surgery (P=0.007, OR=3.105, 95% CI [1364-7068]), duration of intervention (P=0.01, OR=1.023, 95% CI [1.006-1041]) and the cumulative duration of intervention (P=0.003, OR=1.001, 95% CI [1-1002]) appeared to be statistically significant. CONCLUSION: The only predictor of loss of equipment under repair was the cumulative duration of operation time. It has not been demonstrated any difference between ureterorenoscopes. It was during the endoscopes disinfection that the majority of optical beam lesions take place. PMID- 25687652 TI - Outcomes of gamma knife radiosurgery, bi-modality & tri-modality treatment regimens for patients with one or multiple brain metastases: the Columbia University Medical Center experience. AB - Optimal treatment of brain metastases (BMs) is debatable. However, surgery or gamma knife radiosurgery (GKRS) improves survival when combined with whole brain radiotherapy (WBRT) versus WBRT alone. We retrospectively reviewed an institutional database of patients treated with GKRS for BMs from 1998 to 2013 to explore effects of single or multi-modality therapies on survival. There were 528 patients with median age 62 years. Histologies included 257 lung, 102 breast, 62 melanoma, 40 renal cell, 29 gastrointestinal, and 38 other primary cancers. Treatments included: 206 GKRS alone, 111 GKRS plus WBRT, 109 GKRS plus neurosurgical resection (NSG), and 102 all three modalities. Median overall survival (mOS) was 16.6 months. mOS among patients with one versus multiple metastasis was 17.2 versus 16.0 months respectively (p = 0.825). For patients with one BM, mOS following GKRS alone, GKRS plus WBRT, GKRS plus NSG, and all three modalities was 9.0, 19.1, 25.5, and 25.0 months, respectively, and for patients with multiple BMs, mOS was 8.6, 20.4, 20.7, 24.5 months for the respective groups. Among all patients, multivariate analysis confirmed that tri modality group had the longest survival (HR 0.467; 95 % CI 0.350-0.623; p < 0.001) compared to GKRS alone; however, this was not significantly different than bi-modality approaches. Uncontrolled primary extra-CNS disease, age and KPS were also independent predictors of survival. Patients treated with GKRS plus NSG, GKRS plus WBRT, or all three modalities had improved OS versus GKRS alone. In our analysis, resection and GKRS allowed avoidance of WBRT without shortening survival. PMID- 25687653 TI - Different biological risk factors in young poor-prognosis and elderly patients with diffuse large B-cell lymphoma. AB - Prognostically relevant risk factors in patients with diffuse large B-cell lymphoma (DLBCL) have predominantly been evaluated in elderly populations. We tested whether previously described risk factors are also valid in younger, poor prognosis DLBCL patients. Paraffin-embedded samples from 112 patients with de novo DLBCL, enrolled in the R-MegaCHOEP trial of the German High Grade Non Hodgkin Lymphoma Study Group (DSHNHL) were investigated using immunohistochemistry (MYC, FOXP1, LMO2, GCET1, CD5, CD10, BCL2, BCL6, IRF4/MUM1) and fluorescence in situ hybridization (MYC, BCL2, BCL6). MYC, BCL2 and BCL6 breaks occurred in 14, 21 and 31%, respectively. In the majority of cases, MYC was simultaneously rearranged with BCL2 and/or BCL6. The adverse impact of MYC rearrangements was confirmed, but the sole presence of BCL2 breaks emerged as a novel prognostic marker associated with inferior overall survival (OS) (P=0.002). Combined overexpression of MYC and BCL2 showed only limited association with inferior OS. All immunohistochemical cell of origin classifiers applied failed to predict survival time. DLBCL tumors with significant proportion of immunoblastic and/or immunoblastic-plasmacytoid cells had inferior OS, independently from from BCL2 break. Younger, poor-prognosis DLBCL patients, therefore, display different biological risk factors compared with an elderly population, with BCL2 translocations emerging as a powerful negative prognostic marker. PMID- 25687654 TI - Japanese orthopaedic association back pain evaluation questionnaire (JOABPEQ) as an outcome measure for patients with low back pain: reference values in healthy volunteers. AB - BACKGROUND: In 2007, the Japanese orthopaedic association back pain evaluation questionnaire (JOABPEQ) was established to overcome the limitations of the original JOA scoring system developed in 1986. Although this new self administered questionnaire is a more accurate outcome measure for evaluating patients with low back pain, physicians were unable to as certain the exact status of a patient at a single time point because of a lack of reference values. This study aimed to establish the reference values of JOABPEQ in different age and gender groups using data obtained from healthy volunteers. METHODS: This study was conducted in 21 university hospitals and affiliated hospitals from October 2012 to July 2013. The JOABPEQ includes 25 questions that yield five domains to evaluate individuals with low back pain from five different perspectives. A total of 1,456 healthy volunteers (719 men, 737 women; age range, 20-89 years) answered the questionnaire. The differences in scores according to age and gender were examined by non-parametric tests. RESULTS: The JOABPEQ scores significantly decreased with age in the domains of lumbar spine dysfunction, gait disturbance, and social life dysfunction. In these three domains, the median scores approached the 100 possible points in individuals aged 20-70 for both genders. However, the median scores for lumbar spine dysfunction and social life dysfunction decreased to 83.0 and 65.0-78.0 points, respectively, in individuals in their 80 s and 70-80 s, respectively; and the scores for gait disturbance decreased to 93.0 and 71.0 points for males and females in their 80 s. Overall, the median scores for pain-related and psychological disorders were 100 and 60.0 72.0 points, respectively. CONCLUSION: The reference values for JOABPEQ according to age and gender were established herein. Patients with low back pain should be evaluated with this new self-administered questionnaire taking these reference values into account. PMID- 25687655 TI - The relationship between the lesion-to-ankle articular length ratio and clinical outcomes after bone marrow stimulation for small osteochondral lesions of the talus. AB - PURPOSE: The purpose of this study was to determine the relationship between the defect-to-ankle articular length ratio and clinical outcomes after arthroscopic bone marrow stimulation. METHODS: Seventeen male and 24 female patients (mean age 36.0 years, height 160.7 cm, weight 62.5 kg, body mass index 24.0) with an osteochondral lesion of the talus were treated with arthroscopic bone marrow stimulation and assessed using the Japanese Society for Surgery of the Foot (JSSF) ankle-hindfoot scale, Berndt and Harty scales and clinical outcome criteria. The lengths of the tibial and talar articular surfaces were defined from the anterior tip to posterior tip of the articular cartilage on sagittal magnetic resonance imaging scans. The size of the defect area was defined and determined for each patient on magnetic resonance images using coronal length, sagittal length, and area. The relationship between clinical outcome and sagittal tibia ratio (sagittal length of defect/length of tibia articular cartilage) and sagittal talus ratio (sagittal length of defect/length of talus articular cartilage) were assessed. RESULTS: The mean lesion length was 11 mm (range 6-14 mm), lesion size was 67 mm(2) (range 19-134 mm(2)), sagittal tibia ratio was 0.42 (range 0.21-0.75), and sagittal talus ratio was 0.32 (range 0.16-0.58). The mean JSSF scale improved from 74 (range 18-90) to 89 (range 67-100) postoperatively. Lesion area was not associated with the JSSF scale (r = -0.10, P = 0.52). Talus articular length (r = 0.64, P < 0.0001) and tibia articular length (r = 0.64, P < 0.0001) were correlated with patient height. The sagittal talus ratio and sagittal tibia ratio were not associated with the JSSF scale (r = -0.10, P = 0.55; r = -0.02, P = 0.90). CONCLUSION: Arthroscopic bone marrow stimulation provides good clinical outcomes in small osteochondral lesions of the talus (<15 mm). For small lesions, the lesion size is not a prognostic factor. LEVEL OF EVIDENCE: IV: Retrospective Case Series. PMID- 25687656 TI - A comparison of lateral release rates in fixed- versus mobile-bearing total knee arthroplasty. AB - BACKGROUND: With increasing functional demands of patients undergoing total knee arthroplasty, mobile-bearing (MB) implants were developed in an attempt to increase the functional outcome of such patients. In theory, with MB implants, the self-alignment should reduce the rate of lateral release of the patella, which is usually performed to optimise patellofemoral mechanics. This study reports on the lateral release rates for the P.F.C. Sigma(r) MB posterior stabilised total knee replacement (TKR) implant compared with its fixed-bearing (FB) equivalent. MATERIALS AND METHODS: A total of 352 patients undergoing TKR were randomly allocated to receive either MB (176 knees) or FB (176 knees) posterior-stabilised TKR. Further sub-randomisation into patellar resurfacing or retention was performed for both designs. The need for lateral patellar release was assessed during surgery using a 'no thumb technique', and after releasing the tourniquet if indicated. RESULTS: The lateral release rate was the same for FB (10 %) and MB implants (10 %) (p = 0.9). However, patellar resurfacing resulted in lower lateral release rates when compared to patellar retention (6 vs 14 %; p = 0.0179) especially in MB implants (3 %). CONCLUSIONS: It has been previously reported that alterations to the design of the P.F.C. system with a more anatomical trochlea in the femoral component improved patellar tracking. The addition of a rotating platform tibial component to the P.F.C. Sigma system has, on its own, had no impact on the lateral release rate in this study. Optimising patellar geometry by patellar resurfacing appears more important than tibial bearing design. Although MB implants appear to reduce the need for lateral release in the P.F.C. Sigma Rotating Platform, this only occurs when the patellar geometry has been optimised with patellar resurfacing. LEVEL OF EVIDENCE: Level 2. PMID- 25687657 TI - Modulation of the IGF system and proliferation in human endometrial stromal cells by metformin: a dose-dependent effect. AB - PURPOSE: To assess the metformin effect on endometrial stromal cell decidualization, proliferation, gene and protein expression of IGFBPs, IGFs and their receptors. METHODS: Human endometrial stromal cells (hESCs) were cultured from endometrial biopsies of 11 women undergoing surgery for benign reasons. hESCs were decidualized with and without metformin in increasing doses. Supernatant and cells were harvested after decidualization for 12-14 days, followed by real-time PCR of IGFBP 1-6, IGF I, IGF II and their receptors. Prolactin, and IGFBP-1, -3, and -6 were additionally analyzed in supernatant by ELISA. Proliferation of hESCs and decidualization of hESCs were assessed under the influence of metformin. Data were analyzed using the paired t test with p < 0.05 considered significant. RESULTS: While lower concentrations of metformin (10(-4), 10(-5 )M) did not influence the decidualization and proliferation capacity of hESCs, higher concentrations (10(-3), 10(-2 )M metformin) significantly (p < 0.05) diminished decidualization, as well as stromal cell proliferation in a dose-dependent manner. Higher concentrations of metformin lead to a significant (p < 0.05) dose-dependent attenuation of the progesterone effect with regard to IGFBP-1, -3, -5, -6, as well as IGF I receptor, while it did not change the expression of IGFBP-2 and -4, IGF I and II and the IGF II receptor. This was confirmed on the protein level for IGFBP-1, -3, and -6. CONCLUSION: We were able to demonstrate for the first time a dose-dependent local effect of metformin within hESCs. Metformin might therefore influence locally the endometrial proliferation and maturation, and could open up new treatment options for gynecological diseases by vaginal application of metformin. PMID- 25687658 TI - Methods employed to overcome difficult embryo transfer during assisted reproduction treatment. AB - PURPOSE: Multiple steps, at both scientific and clinical level, are involved in assisted reproduction technology (ART). Optimization of each of these steps contributes to maximize the success of ART. Embryo transfer is one of the vital steps in ART. An easy embryo transfer increases the success of ART. Adequate training is required to undertake embryo transfer, but anatomical difficulties in completing this procedure alter the success of treatment. Difficult embryo transfer is challenging for clinicians but has an overwhelming negative impact on patients. Difficult embryo transfer may cause cervical or endometrial trauma with uterine contractions which can lead to unsuccessful implantation and poor outcome after ART. METHODS: Literature review of published material looking at all interventions that were employed to overcome difficult embryo transfers during ART. RESULTS: We identified 5 methods (17 studies) were employed to overcome difficult embryo transfer which are: Hysteroscopic methods in 4 studies (2 case reports, 2 case series). Malecot catheters after hysteroscopic evaluation were used in 2 studies (1 case report, 1 case series). Dilators including hygroscopic dilators were used in 2 studies (1 case report, 1 case series) and mechanical dilators were used in 3 studies (2 case series, 1 RCT-patients 367). Intrafollopian transfer was reported in 1 case report. Transmyometrial embryo transfers were reported in 5 studies (2 case reports, 2 case series, 1 RCT). CONCLUSION: There were only two randomized controlled studies (RCTs) identified in the review. All other were either case series or case reports. We found that there was no uniform classification or grading of difficulty of embryo transfer in the literature. A grading system has been suggested in this review. We recommend that there should be a consensus guideline formulated for interventions to overcome difficult embryo transfer. A large multicenter randomized controlled study is required to compare different methods for women with difficult embryo transfer. PMID- 25687659 TI - "Empiric" inositol supplementation in normal-weight non insulin resistant women with polycystic ovarian disease: from the absence of benefit to the potential adverse effects. PMID- 25687660 TI - Authors' reply to: "Empiric" inositol supplementation in normal-weight non insulin resistant women with polycystic ovarian disease: from the absence of benefit to the potential adverse effects. PMID- 25687661 TI - ATM protein kinase signaling, type 2 diabetes and cardiovascular disease. AB - The ataxia-telangiectasia mutated (ATM) protein kinase is well known to play a significant role in the response to double stranded DNA breaks in the nucleus. Recently, it has become apparent that ATM is also involved in a large number of cytoplasmic processes and responses, some of which may contribute to metabolic and cardiovascular complications when disrupted. Due to its involvement in these processes, therapeutic activation of ATM could potentially be a novel approach for the prevention or treatment of cardiovascular disease. However, relatively little is currently known about the cardiovascular role of ATM. In this review, we highlight studies that have shed some light on the role of ATM in the cardiovascular context, namely in oxidative stress, atherosclerosis and metabolism, insulin resistance and cardiac remodeling. PMID- 25687662 TI - A Randomized, Placebo-Controlled, Active-Reference, Double-Blind, Flexible-Dose Study of the Efficacy of Vortioxetine on Cognitive Function in Major Depressive Disorder. AB - This multicenter, randomized, double-blind, placebo-controlled, active-referenced (duloxetine 60 mg), parallel-group study evaluated the short-term efficacy and safety of vortioxetine (10-20 mg) on cognitive function in adults (aged 18-65 years) diagnosed with major depressive disorder (MDD) who self-reported cognitive dysfunction. Efficacy was evaluated using ANCOVA for the change from baseline to week 8 in the digit symbol substitution test (DSST)-number of correct symbols as the prespecified primary end point. The patient-reported perceived deficits questionnaire (PDQ) and physician-assessed clinical global impression (CGI) were analyzed in a prespecified hierarchical testing sequence as key secondary end points. Additional predefined end points included the objective performance-based University of San Diego performance-based skills assessment (UPSA) (ANCOVA) to measure functionality, MADRS (MMRM) to assess efficacy in depression, and a prespecified multiple regression analysis (path analysis) to calculate direct vs indirect effects of vortioxetine on cognitive function. Safety and tolerability were assessed at all visits. Vortioxetine was statistically superior to placebo on the DSST (P < 0.05), PDQ (P < 0.01), CGI-I (P < 0.001), MADRS (P < 0.05), and UPSA (P < 0.001). Path analysis indicated that vortioxetine's cognitive benefit was primarily a direct treatment effect rather than due to alleviation of depressive symptoms. Duloxetine was not significantly different from placebo on the DSST or UPSA, but was superior to placebo on the PDQ, CGI-I, and MADRS. Common adverse events (incidence ? 5%) for vortioxetine were nausea, headache, and diarrhea. In this study of MDD adults who self-reported cognitive dysfunction, vortioxetine significantly improved cognitive function, depression, and functionality and was generally well tolerated. PMID- 25687663 TI - Self-controlled practice benefits motor learning in older adults. AB - Providing learners with the chance to choose over certain aspects of practice has been consistently shown to facilitate the acquisition of motor skills in several populations. However, studies investigating the effects of providing autonomy support during the learning process of older adults remain scarce. The objective of the present study was to investigate the effects of self-controlled amount of practice on the learning of a sequential motor task in older adults. Participants in the self-control group were able to choose when to stop practicing a speed cup stacking task, while the number of practice trials for a yoked group was pre determined, mirroring the self-control group. The opportunity to choose when stop practicing facilitated motor performance and learning compared to the yoked condition. The findings suggest that letting older adult learners choose the amount of practice, supporting their autonomy needs, has a positive influence on motor learning. PMID- 25687664 TI - Advanced age brings a greater reliance on visual feedback to maintain balance during walking. AB - We implemented a virtual reality system to quantify differences in the use of visual feedback to maintain balance during walking between healthy young (n=12, mean age: 24 years) and healthy old (n=11, 71 years) adults. Subjects walked on a treadmill while watching a speed-matched, virtual hallway with and without mediolateral visual perturbations. A motion capture system tracked center of mass (CoM) motion and foot kinematics. Spectral analysis, detrended fluctuation analysis, and local divergence exponents quantified old and young adults' dynamic response to visual perturbations. Old and young adults walked normally with comparable CoM spectral characteristics, lateral step placement temporal persistence, and local divergence exponents. Perturbed visual flow induced significantly larger changes in mediolateral CoM motion in old vs. young adults. Moreover, visual perturbations disrupted the control of lateral step placement and compromised local dynamic stability more significantly in old than young adults. Advanced age induces a greater reliance on visual feedback to maintain balance during waking, an effect that may compensate for degradations in somatosensation. Our findings are relevant to the early diagnosis of sensory induced balance impairments and also point to the potential use of virtual reality to evaluate sensory rehabilitation and balance training programs for old adults. PMID- 25687665 TI - Personality traits and individual differences predict threat-induced changes in postural control. AB - This study explored whether specific personality traits and individual differences could predict changes in postural control when presented with a height-induced postural threat. Eighty-two healthy young adults completed questionnaires to assess trait anxiety, trait movement reinvestment (conscious motor processing, movement self-consciousness), physical risk-taking, and previous experience with height-related activities. Tests of static (quiet standing) and anticipatory (rise to toes) postural control were completed under low and high postural threat conditions. Personality traits and individual differences significantly predicted height-induced changes in static, but not anticipatory postural control. Individuals less prone to taking physical risks were more likely to lean further away from the platform edge and sway at higher frequencies and smaller amplitudes. Individuals more prone to conscious motor processing were more likely to lean further away from the platform edge and sway at larger amplitudes. Individuals more self-conscious about their movement appearance were more likely to sway at smaller amplitudes. Evidence is also provided that relationships between physical risk-taking and changes in static postural control are mediated through changes in fear of falling and physiological arousal. Results from this study may have indirect implications for balance assessment and treatment; however, further work exploring these factors in patient populations is necessary. PMID- 25687666 TI - Experimental protocol of a randomized controlled clinical trial investigating exercise, subclinical atherosclerosis, and walking mobility in persons with multiple sclerosis. AB - BACKGROUND: This randomized controlled trial (RCT) will investigate the effects of a home-based aerobic exercise training regimen (i.e., cycle ergometry) on subclinical atherosclerosis and walking mobility in persons with multiple sclerosis (MS) and minimal disability. METHODS/DESIGN: This RCT will recruit 54 men and women who have an Expanded Disability Status Scale characteristic of the 1st stage of MS (i.e., 0-4.0) to participate in a 3 month exercise or stretching intervention, with assessments of subclinical atherosclerosis and walking mobility conducted at baseline, week 6 (midpoint), and week 12 (conclusion) of the program. The exercise intervention will consist of 3 days/week of cycling, with a gradual increase of duration followed by an increase in intensity across the 3 month period. The attention-control condition will incorporate stretching activities and will require the same contact time commitment as the exercise condition. Both study groups will participate in weekly video chat sessions with study personnel in order to monitor and track program adherence. Primary outcomes will consist of assessments of vascular structure and function, as well as several walking tasks. Additional outcomes will include questionnaires, cardiorespiratory fitness assessment, and a 1-week free-living physical activity assessment. DISCUSSION: This investigation will increase understanding of the role of aerobic exercise as part of a treatment plan for managing subclinical atherosclerosis and improving walking mobility persons in the 1st stage of MS. Overall, this study design has the potential to lead to effective aerobic exercise intervention strategies for this population and improve program adherence. PMID- 25687668 TI - Gulp and think of your waistline. PMID- 25687667 TI - Design and methods for "Commit to Get Fit" - a pilot study of a school-based mindfulness intervention to promote healthy diet and physical activity among adolescents. AB - INTRODUCTION: Cardiovascular prevention is more effective if started early in life, but available interventions to promote healthy lifestyle habits among youth have been ineffective. Impulsivity in particular has proven to be an important barrier to the adoption of healthy behaviors in youth. Observational evidence suggests that mindfulness interventions may reduce impulsivity and improve diet and physical activity. We hypothesize that mindfulness training in adjunct to traditional health education will improve dietary habits and physical activity among teenagers by reducing impulsive behavior and improving planning skills. METHODS/DESIGN: The Commit to Get Fit study is a pilot cluster randomized controlled trial examining the feasibility, acceptability and preliminary efficacy of school-based mindfulness training in adjunct to traditional health education for promotion of a healthy diet and physical activity among adolescents. Two schools in central Massachusetts (30 students per school) will be randomized to receive mindfulness training plus standard health education (HE M) or an attention-control intervention plus standard health education (HE-AC). Assessments will be conducted at baseline, intervention completion (2 months), and 8 months. Primary outcomes are feasibility and acceptability. Secondary outcomes include physical activity, diet, impulsivity, mood, body mass index, and quality of life. CONCLUSIONS: This study will provide important information about feasibility and preliminary estimates of efficacy of a school-delivered mindfulness and health education intervention to promote healthy dietary and physical activity behaviors among adolescents. Our findings will provide important insights about the possible mechanisms by which mindfulness training may contribute to behavioral change and inform future research in this important area. PMID- 25687669 TI - A refined 2010-based VOC emission inventory and its improvement on modeling regional ozone in the Pearl River Delta Region, China. AB - Accurate and gridded VOC emission inventories are important for improving regional air quality model performance. In this study, a four-level VOC emission source categorization system was proposed. A 2010-based gridded Pearl River Delta (PRD) regional VOC emission inventory was developed with more comprehensive source coverage, latest emission factors, and updated activity data. The total anthropogenic VOC emission was estimated to be about 117.4 * 10(4)t, in which on road mobile source shared the largest contribution, followed by industrial solvent use and industrial processes sources. Among the industrial solvent use source, furniture manufacturing and shoemaking were major VOC emission contributors. The spatial surrogates of VOC emission were updated for major VOC sources such as industrial sectors and gas stations. Subsector-based temporal characteristics were investigated and their temporal variations were characterized. The impacts of updated VOC emission estimates and spatial surrogates were evaluated by modeling O3 concentration in the PRD region in the July and October of 2010, respectively. The results indicated that both updated emission estimates and spatial allocations can effectively reduce model bias on O3 simulation. Further efforts should be made on the refinement of source classification, comprehensive collection of activity data, and spatial-temporal surrogates in order to reduce uncertainty in emission inventory and improve model performance. PMID- 25687670 TI - A multi-scale health impact assessment of air pollution over the 21st century. AB - BACKGROUND: Ozone and PM2.5 are current risk factors for premature death all over the globe. In coming decades, substantial improvements in public health may be achieved by reducing air pollution. To better understand the potential of emissions policies, studies are needed that assess possible future health impacts under alternative assumptions about future emissions and climate across multiple spatial scales. METHOD: We used consistent climate-air-quality-health modeling framework across three geographical scales (World, Europe and Ile-de-France) to assess future (2030-2050) health impacts of ozone and PM2.5 under two emissions scenarios (Current Legislation Emissions, CLE, and Maximum Feasible Reductions, MFR). RESULTS: Consistently across the scales, we found more reductions in deaths under MFR scenario compared to CLE. 1.5 [95% CI: 0.4, 2.4] million CV deaths could be delayed each year in 2030 compared to 2010 under MFR scenario, 84% of which would occur in Asia, especially in China. In Europe, the benefits under MFR scenario (219000 CV deaths) are noticeably larger than those under CLE (109,000 CV deaths). In Ile-de-France, under MFR more than 2830 annual CV deaths associated with PM2.5 changes could be delayed in 2050 compared to 2010. In Paris, ozone-related respiratory mortality should increase under both scenarios. CONCLUSION: Multi-scale HIAs can illustrate the difference in direct consequences of costly mitigation policies and provide results that may help decision-makers choose between different policy alternatives at different scales. PMID- 25687671 TI - Modeling the transport behavior of 16 emerging organic contaminants during soil aquifer treatment. AB - In this study, four one-dimensional flow and transport models based on the data of a field scale experiment in Greece were constructed to investigate the transport behavior of sixteen organic trace pollutants during soil aquifer treatment. At the site, tap water and treated wastewater were intermittently infiltrated into a porous aquifer via a small pilot pond. Electrical conductivity data was used to calibrate the non-reactive transport models. Transport and attenuation of the organic trace pollutants were simulated assuming 1st order degradation and linear adsorption. Sorption was found to be largely insignificant at this site for the compounds under investigation. In contrast, flow path averaged first order degradation rate constants were mostly higher compared to the literature and lay between 0.036 d(-1) for clofibric acid and 0.9 d(-1) for ibuprofen, presumably owing to the high temperatures and a well adapted microbial community originating from the wastewater treatment process. The study highlights the necessity to obtain intrinsic attenuation parameters at each site, as findings cannot easily be transferred from one site to another. PMID- 25687672 TI - Enantioselective stable isotope analysis (ESIA) - a new concept to evaluate the environmental fate of chiral organic contaminants. AB - Since 2011, the enantiospecific stable carbon isotope analysis (ESIA) has emerged as an innovative technique to assess the environmental fate of chiral emerging compounds by combining in one experimental technique both compound specific isotope analysis (CSIA) and enantioselective analysis. To date, the ESIA was applied for four classes of compounds: alpha-hexachlorocyclohexane (alpha-HCH), polar herbicides (phenoxy acids), synthetic polycyclic musk galaxolide (HHCB), and phenoxyalkanoic methyl herbicides. From an analytical point of view there are factors that are hindering the application of ESIA methods for the field samples: (i.e. amounts of target analyte, matrix effects, GC resolution) and overcoming these factors is challenging. While ESIA was shown as a mature technique for the first three abovementioned class of compounds, no isotope analysis of individual enantiomers could be performed for phenoxyalkanoic methyl herbicides. With respect to field studies, one study showed that ESIA might be a promising tool to distinguish between biotic and abiotic transformation pathways of chiral organic contaminants and even to differentiate between their aerobic and anaerobic biotransformation pathways. The development of ESIA methods for new chiral emerging contaminants in combination with development of multi-element isotope analysis will contribute to a better characterization of transformation pathways of chiral organic contaminants. PMID- 25687673 TI - Programming macro-materials from DNA-directed self-assembly. AB - DNA is a powerful tool that can be attached to nano- and micro-objects and direct the self-assembly through base pairing. Since the strategy of DNA programmable nanoparticle self-assembly was first introduced in 1996, it has remained challenging to use DNA to make powerful diagnostic tools and to make designed materials with novel properties and highly ordered crystal structures. In this review, we summarize recent experimental and theoretical developments of DNA programmable self-assembly into three-dimensional (3D) materials. Various types of aggregates and 3D crystal structures obtained from an experimental DNA-driven assembly are introduced. Furthermore, theoretical calculations and simulations for DNA-mediated assembly systems are described and we highlight some typical theoretical models for Monte Carlo and Molecular Dynamics simulations. PMID- 25687674 TI - Adding justice to the clinical and public health ethics arguments for mandatory seasonal influenza immunisation for healthcare workers. AB - Ethical considerations from both the clinical and public health perspectives have been used to examine whether it is ethically permissible to mandate the seasonal influenza vaccine for healthcare workers (HCWs). Both frameworks have resulted in arguments for and against the requirement. Neither perspective resolves the question fully. By adding components of justice to the argument, I seek to provide a more fulsome ethical defence for requiring seasonal influenza immunisation for HCWs. Two critical components of a just society support requiring vaccination: fairness of opportunity and the obligation to follow democratically formulated rules. The fairness of opportunity is informed by Rawls' two principles of justice. The obligation to follow democratically formulated rules allows us to focus simultaneously on freedom, plurality and solidarity. Justice requires equitable participation in and benefit from cooperative schemes to gain or profit socially as individuals and as a community. And to be just, HCW immunisation exemptions should be limited to medical contraindications only. In addition to the HCWs fiduciary duty to do what is best for the patient and the public health duty to protect the community with effective and minimally intrusive interventions, HCWs are members of a just society in which all members have an obligation to participate equitably in order to partake in the benefits of membership. PMID- 25687675 TI - Ghrelin gene expression in rats with ethanol-induced gastric ulcers: a role of melatonin. AB - OBJECTIVES: The aim of the present work was to reveal the mechanisms of melatonin treatment on ethanol-induced gastric mucosal lesions in rats, including its role in the induction of ghrelin biosynthesis. METHODS: Sixty male Wistar rats were divided into 3 groups (20 in each group): a) control group, b) ulcer group (100% ethanol was given intragastrically (i.g.) in a dose of 1 ml/100 g of body weight), and 3) melatonin-treated group, which received a single dose (25 mg/kg) of melatonin (Biovea) i.g. 30 min before ulcer induction with ethanol. Reduced glutathione (GSH) and malondialdehyde (MDA) were measured in tissues and ghrelin levels determined in the serum. RNA isolation and RT-PCR expression of ghrelin were performed. Both macroscopic and microscopic examinations of gastric mucosa were done in all groups. RESULTS: Significant decrease in ghrelin levels and mRNA expression and reduced levels of GSH were observed in ulcer group of rats in comparison with controls. All parameters studied were significantly increased after treatment with melatonin in comparison with ulcer bearing group of rats. On the other hand, the tissue levels of MDA were significantly increased in ulcer group of rats in comparison with controls and significantly decreased after melatonin treatment in comparison with the ulcer group of rats. Histological examinations revealed severe mucosal lesions induced by ethanol which were significantly improved by melatonin administration. CONCLUSIONS: The present data indicate that melatonin may have a potential impact in the treatment of peptic ulcer not only via its known antioxidant effect but also via induction of the ghrelin biosynthesis, as it was documented by significant increase in ghrelin mRNA expression. PMID- 25687676 TI - Low vitamin D intake is associated with increase in cardiovascular risk factors in obese adolescents. AB - OBJECTIVES: This study aimed to investigate the effect of vitamin D on cardiovascular risk in obese adolescents. METHODS: Thirty (16 females/14 males) post-puberty obese adolescents (15-19 years) were involved and measurements of inflammatory biomarkers, body composition, visceral fat, and vitamin D (serum and intake) were performed. The adolescents were submitted to a long-term interdisciplinary therapy with physical exercise, nutritional, psychological, and clinical interventions. RESULTS: Negative correlations between vitamin D intake with plasminogen activator inhibitor-1 (PAI-1) (r=-0.69; p=0.01) and vascular cell adhesion molecule (VCAM-1) (r=-0.82; p=0.001) were found in the population analyzed. Improvement in PAI-1, VCAM-1, body composition, and visceral fat, were observed. CONCLUSIONS: We showed that low vitamin D intake is associated with an increase in the cardiovascular risk factors in obese adolescents. PMID- 25687677 TI - Serum pyroglutamyl aminopeptidase activity: a promising novel biomarker candidate for liver cirrhosis. AB - OBJECTIVE: As a reflect of tissue damage, serum aminopeptidases have been proposed as biomarkers of various diseases. In order to search new serologic markers for liver cirrhosis we conducted a preliminary study in which we analyzed a broad range of aminopeptidase activities in serum of controls and patients diagnosed with pancreatitis, hepatitis, and liver cirrhosis without distinction among the etiological type or the degree of severity of each condition. METHODS: Alanyl-, arginyl-, glutamyl-, cystinyl- pyroglutamyl-, and aspartyl aminopeptidase activities were analyzed fluorometrically, using aminoacyl-beta naphthylamides as substrates. In addition, various parameters, such as alanine transaminase, aspartate transaminase, alkaline phosphatase, total bilirubin, direct bilirubin, and gamma glutamyl transpeptidase were assayed as routine laboratory test for liver function. RESULTS: Compared with control group, alanyl- and arginyl-aminopeptidase activities increased nonspecifically in pancreatitis, hepatitis and liver cirrhosis, glutamyl- and cystinyl-aminopeptidases did not differ between groups and pyroglutamyl-aminopeptidase demonstrated that while pancreatitis and hepatitis did not differ between them and with controls, this activity decreased selectively in liver cirrhosis compared with all the rest of groups (p<0.001 vs. control and p<0.01 vs. pancreatitis and hepatitis). Aspartyl aminopeptidase also decreased significantly (p<0.05) in liver cirrhosis compared with controls. Routine parameters for liver function test increased, as expected, in the three pathologies analyzed. CONCLUSIONS: Despite the heterogeneous composition of the three patient groups, the specific reduction of the levels of pyroglutamyl-aminopeptidase activity in serum of liver cirrhosis patients might be considered as a potential candidate to be included in a combination of markers for the diagnosis of this disease. PMID- 25687678 TI - Global pollution by organochlorinated endocrine disruptors - possible challenge for mankind at the onset of millennium. AB - Author of this review submits a comprehensive report of his long-lasting research regarding the global pollution by endocrine disruptors (EDs), EDs and diabetes and obesity, EDs and the thyroid in highly polluted Slovakia, Ah-receptor: the central pivot responsible for such global "EDs disaster", EDs and immune system, EDs and testosterone, EDs in mothers and newborns, EDs and human genome, and EDs at the beginning of the millennium. PMID- 25687679 TI - Organization of the expanded cumulus-extracellular matrix in preovulatory follicles: a role for inter-alpha-trypsin inhibitor. AB - It has been shown that following endogenous gonadotropin surge, oocyte-cumulus complexes (OCC) synthesize hyaluronan (HA) in a process called cumulus expansion. During this process, HA associates with proteins and proteoglycans to form the expanded HA-rich oocyte-cumulus extracellular matrix (ECM), where the heavy chains of the serum derived inter-alpha-trypsin inhibitor family (IalphaI) bind covalently to HA. No study has been performed on the occurrence and regulation of this process during oocyte maturation in species other than mouse and pig, although, the heavy chains (of IalphaI)-HA complex was purified from human amniotic membrane. The present review pointing out that: 1/ formation of expanded HA-rich oocyte-cumulus ECM is dependent on the presence of IalphaI molecules, 2/ the heavy chains of IalphaI molecules identified in the serum are covalently linked to HA during cumulus expansion in mouse and pig, 3/ the family of IalphaI molecules can freely cross the blood-follicle barrier, and the follicular fluid collected at any stage of folliculogenesis can be successfully used instead of serum to form expanded cumulus ECM in pig, and 4/ proteins of the IalphaI family can affect reproductive process by modulating the expression of a large number of cellular genes during a preovulatory period. Finally, this review provides clear evidence that IalphaI family members present in the serum or follicular fluid become responsible for cumulus expansion, as without these proteins, expanded cumulus HA-rich ECM is not formed and HA is released into medium. PMID- 25687680 TI - Differential diagnosis of flaccid paralysis in paediatric medicine. PMID- 25687681 TI - The challenge of on-tissue digestion for MALDI MSI- a comparison of different protocols to improve imaging experiments. AB - Mass spectrometry imaging (MSI) has become a powerful and successful tool in the context of biomarker detection especially in recent years. This emerging technique is based on the combination of histological information of a tissue and its corresponding spatial resolved mass spectrometric information. The identification of differentially expressed protein peaks between samples is still the method's bottleneck. Therefore, peptide MSI compared to protein MSI is closer to the final goal of identification since peptides are easier to measure than proteins. Nevertheless, the processing of peptide imaging samples is challenging due to experimental complexity. To address this issue, a method development study for peptide MSI using cryoconserved and formalin-fixed paraffin-embedded (FFPE) rat brain tissue is provided. Different digestion times, matrices, and proteases were tested to define an optimal workflow for peptide MSI. All practical experiments were done in triplicates and analyzed by the SCiLS Lab software, using structures derived from myelin basic protein (MBP) peaks, principal component analysis (PCA) and probabilistic latent semantic analysis (pLSA) to rate the experiments' quality. Blinded experimental evaluation in case of defining countable structures in the datasets was performed by three individuals. Such an extensive method development for peptide matrix-assisted laser desorption/ionization (MALDI) imaging experiments has not been performed so far, and the resulting problems and consequences were analyzed and discussed. PMID- 25687682 TI - ToF-SIMS observation for evaluating the interaction between amyloid beta and lipid membranes. AB - The adsorption behaviour of amyloid beta (Abeta), thought to be a key peptide for understanding Alzheimer's disease, was investigated by means of time-of-flight secondary ion mass spectrometry (ToF-SIMS). Abeta aggregates depending on the lipid membrane condition though it has not been fully understood yet. In this study, Abeta samples on different lipid membranes, 1,2-dipalmitoyl-sn-glycero-3 phosphocholine (DPPC), 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and 1,2 dioleoyl-sn-glycero-3-phosphocholine (DOPC), were observed with ToF-SIMS and the complex ToF-SIMS data of the Abeta samples was interpreted using data analysis techniques such as principal component analysis (PCA), gentle-SIMS (G-SIMS) and g ogram. DOPC and DMPC are liquid crystal at room temperature, while DPPC is gel at room temperature. As primary ion beams, Bi3(+) and Ar cluster ion beams were used and the effect of an Ar cluster ion for evaluating biomolecules was also studied. The secondary ion images of the peptide fragment ions indicated by G-SIMS and g ogram were consistent with the PCA results. It is suggested that Abeta is adsorbed homogeneously on the liquid-crystalline-phase lipid membranes, while it aggregates along the lipid on the gel-phase lipid membrane. Moreover, in the results using the Ar cluster, the influence of contamination was reduced. PMID- 25687683 TI - Nitric oxide synthase in innate and adaptive immunity: an update. AB - Thirty years after the discovery of its production by activated macrophages, our appreciation of the diverse roles of nitric oxide (NO) continues to grow. Recent findings have not only expanded our understanding of the mechanisms controlling the expression of NO synthases (NOS) in innate and adaptive immune cells, but have also revealed new functions and modes of action of NO in the control and escape of infectious pathogens, in T and B cell differentiation, and in tumor defense. I discuss these findings, in the context of a comprehensive overview of the various sources and multiple reaction partners of NO, and of the regulation of NOS2 by micromilieu factors, antisense RNAs, and 'unexpected' cytokines. PMID- 25687684 TI - The molecular basis for functional plasticity in type I interferon signaling. AB - Type I interferons (IFNs) are best known for their role in innate immunity, but they are also involved in other functions including immunomodulation, restricting proliferation, cancer surveillance, and the regulation of the adaptive immune response. All these responses are mediated through the interaction with a single cell surface receptor, albeit at different ligand and receptor concentrations, ligand subtypes, and time of activation. Here we review the functional plasticity of IFN signaling from a quantitative perspective, showing how variations in different ingredients of the system lead to differential IFN responses and how cells tune the system to maximize efficiency while minimizing detrimental effects. We present a basic model wherein the integrated action of different feedback mechanisms can provide sufficient temporal control to differentially drive cellular decisions. PMID- 25687685 TI - Retracted: A Role for PPAR gamma in the Regulation of Cytokines in Immune Cells and Cancer. AB - [This retracts the article DOI: 10.1155/2008/961753.]. PMID- 25687686 TI - Activatable nanoprobes for biomolecular detection. AB - Precise detection of pathologically relevant biomolecules could provide essential information on important intercellular, cellular, and subcellular events for accurate disease diagnosis and staging, thus leading to appropriate treatment recommendation. Activatable nanoprobes are nanoscale objects that can be turned on through specific reactions or interactions with biomolecules of interest, and afford some advantageous properties for improved detection of biomolecules both in vitro and in vivo. In this brief review, we highlight several recent examples in the development of activatable nanoprobes for biomolecule detection. PMID- 25687687 TI - Application of IL-36 receptor antagonist weakens CCL20 expression and impairs recovery in the late phase of murine acetaminophen-induced liver injury. AB - Overdosing of the analgesic acetaminophen (APAP, paracetamol) is a major cause of acute liver injury. Whereas toxicity is initiated by hepatocyte necrosis, course of disease is regulated by mechanisms of innate immunity having the potential to serve in complex manner pathogenic or pro-regenerative functions. Interleukin (IL)-36gamma has been identified as novel IL-1-like cytokine produced by and targeting epithelial (-like) tissues. Herein, we investigated IL-36gamma in acute liver disease focusing on murine APAP-induced hepatotoxicity. Enhanced expression of hepatic IL-36gamma and its prime downstream chemokine target CCL20 was detected upon liver injury. CCL20 expression coincided with the later regeneration phase of intoxication. Primary murine hepatocytes and human Huh7 hepatocellular carcinoma cells indeed displayed enhanced IL-36gamma expression when exposed to inflammatory cytokines. Administration of IL-36 receptor antagonist (IL-36Ra) decreased hepatic CCL20 in APAP-treated mice. Unexpectedly, IL-36Ra likewise increased late phase hepatic injury as detected by augmented serum alanine aminotransferase activity and histological necrosis which suggests disturbed tissue recovery upon IL-36 blockage. Finally, we demonstrate induction of IL-36gamma in inflamed livers of endotoxemic mice. Observations presented introduce IL-36gamma as novel parameter in acute liver injury which may contribute to the decision between unleashed tissue damage and initiation of liver regeneration during late APAP toxicity. PMID- 25687688 TI - Cutaneous leishmaniasis: recent developments in diagnosis and management. AB - This review focuses on recent developments in the diagnosis, treatment, management, and strategies for the prevention and control of cutaneous leishmaniasis (CL) caused by both Old and New World Leishmania species. CL is caused by the vector-borne protozoan parasite Leishmania and is transmitted via infected female sandflies. The disease is endemic in more than 98 countries and an estimated 350 million people are at risk. The overall prevalence is 12 million cases and the annual incidence is 2-2.5 million. The World Health Organization considers CL a severely neglected disease and a category 1 emerging and uncontrolled disease. The management of CL differs from region to region and is primarily based on local experience-based evidence. Most CL patients can be treated with topical treatments, but some Leishmania species can cause mucocutaneous involvement requiring a systemic therapeutic approach. Moreover, Leishmania species can vary in their sensitivity to available therapeutic options. This makes species determination critical for the choice of treatment and the clinical outcome of CL. Identification of the infecting parasite used to be laborious, but now the Leishmania species can be identified relatively easy with new DNA techniques that enable a more rational therapy choice. Current treatment guidelines for CL are based on poorly designed and reported trials. There is a lack of evidence for potentially beneficial treatments, a desperate need for large well-conducted studies, and standardization of future trials. Moreover, intensified research programs to improve vector control, diagnostics, and the therapeutic arsenal to contain further incidence and morbidity are needed. PMID- 25687689 TI - Efficacy of prophylactic minocycline treatment for skin toxicities induced by erlotinib plus gemcitabine in patients with advanced pancreatic cancer: a retrospective study. AB - BACKGROUND: Erlotinib has been reported as being associated with a high incidence of skin toxicities such as acneiform rash, paronychia, and xerosis. OBJECTIVE: The aim of this study was to evaluate the efficacy of prophylactic minocycline treatment for the skin toxicities induced by erlotinib as compared with deferred minocycline treatment in patients with pancreatic cancer treated with erlotinib plus gemcitabine. METHODS: A total of 96 patients were studied retrospectively, of whom 44 received prophylactic minocycline between August 2012 and June 2013 and 52 received deferred minocycline treatment between August 2011 and July 2012 at the National Cancer Center Hospital East, Kashiwa, Japan. In the prophylactic minocycline group, 200 mg/day oral minocycline was prophylactically administered during the treatment period. RESULTS: The incidence rate of acneiform rash and xerosis of any grade during the first 6 weeks of treatment was significantly reduced in the prophylactic minocycline group compared with the deferred minocycline treatment group (47.7 vs. 80.8%, p<0.001; 2.3 vs. 19.2%, p=0.01). Multivariate analysis identified prophylactic minocycline as a significant independent factor associated with the incidence of acneiform rash and xerosis of any severity (odds ratio [OR] 0.16, 95% confidence interval [CI] 0.06-0.46, p<0.001; OR 0.11, 95% CI 0.01-0.90, p=0.04). CONCLUSION: Prophylactic minocycline appears to be useful for the management of erlotinib-related acneiform rash and xerosis during chemotherapy in patients with advanced pancreatic cancer. PMID- 25687690 TI - Risk of sudden sensorineural hearing loss in patients with psoriasis: a retrospective cohort study. AB - SIGNIFICANCE: Psoriasis, a common immune-mediated disease, affects approximately 2% of the population worldwide. Sudden sensorineural hearing loss (SSNHL) might be a manifestation of systemic vascular involvement in autoimmune disease. However, to the best of our knowledge, there is no systematic English-language examination of the risk of SSNHL in patients with psoriasis. OBJECTIVES: We tested the hypothesis that psoriasis is a risk factor for developing SSNHL. METHODS: Using Taiwan's National Health Insurance Research Database, we conducted a retrospective cohort study to compare patients diagnosed with psoriasis from January 1, 2001 through December 31, 2006 (n=28,817) with gender-, age-, and comorbidities-matched controls (n=28,817). We followed each patient until the end of 2011 and evaluated the incidence of SSNHL for at least 6 years after the initial psoriasis diagnosis. RESULTS: The incidence of SSNHL was 1.51 times higher in the psoriasis cohort than in the control cohort (7.12 vs 4.73 per 10,000 person-years). Using Cox proportional hazard regressions, the adjusted hazard ratio (AHR) was 1.51 (95% confidence interval [CI] 1.18-1.93). Comorbid hypertension was an independent risk factor for SSNHL (AHR 1.49; 95% CI 1.05 2.13). However, the incidence rate ratios (IRRs) for each comorbidity subgroup in the psoriasis and control cohorts were not significantly different. CONCLUSIONS AND RELEVANCE: Psoriasis was significantly associated with a higher risk of developing SSNHL. We suggest that physicians advise patients with psoriasis to seek medical attention if they have hearing impairments, because they may also have a higher risk of developing SSNHL. PMID- 25687691 TI - Low defect concentration few-layer graphene using a two-step electrochemical exfoliation. AB - Low defect concentration few-layer graphene (FLG) sheets were fabricated by a two step electrochemical intercalation exfoliation, including a graphite foil pretreatment in sodium hydroxide solution and a subsequent further exfoliation in sulfuric acid solution. During the process, the pretreatment results in the expansion of the graphite foil and in turn facilitates the final exfoliation in sulfuric acid solution. The results show that the I(D)/I(G) of the obtained FLG sheets is as low as 0.29 while maintaining relatively high yield, more than 56%. In addition, the oxygen content in the FLG sheets is 8.32% with the C/O ratio of 11.02. PMID- 25687692 TI - Touchscreen tasks in mice to demonstrate differences between hippocampal and striatal functions. AB - In mammals, hippocampal and striatal regions are engaged in separable cognitive processes usually assessed through species-specific paradigms. To reconcile cognitive testing among species, translational advantages of the touchscreen based automated method have been recently promoted. However, it remains undetermined whether similar neural substrates would be involved in such behavioral tasks both in humans and rodents. To address this question, the effects of hippocampal or dorso-striatal fiber-sparing lesions were first assessed in mice through a battery of tasks (experiment A) comprising the acquisition of two touchscreen paradigms, the Paired Associates Learning (dPAL) and Visuo-Motor Conditional Learning (VMCL) tasks, and a more classical T-maze alternation task. Additionally, we sought to determine whether post-acquisition hippocampal lesions would alter memory retrieval in the dPAL task (experiment B). Pre-training lesions of dorsal striatum caused major impairments in all paradigms. In contrast, pre-training hippocampal lesions disrupted the performance of animals trained in the T-maze assay, but spared the acquisition in touchscreen tasks. Nonetheless, post-training hippocampal lesions severely impacted the recall of the previously learned dPAL task. Altogether, our data show that, after having demonstrated their potential in genetically modified mice, touchscreens also reveal perfectly adapted to taxing functional implications of brain structures in mice by means of lesion approaches. Unlike its human counterpart requiring an intact hippocampus, the acquisition of the dPAL task requires the integrity of the dorsal striatum in mice. The hippocampus only later intervenes, when acquired information needs to be retrieved. Touchscreen assays may therefore be suited to study striatal- or hippocampal dependent forms of learnings in mice. PMID- 25687693 TI - Two waves of proteasome-dependent protein degradation in the hippocampus are required for recognition memory consolidation. AB - Healthy neuronal function and synaptic modification require a concert of synthesis and degradation of proteins. Increasing evidence indicates that protein turnover mediated by proteasome activity is involved in long-term synaptic plasticity and memory. However, its role in different phases of memory remains debated, and previous studies have not examined the possible requirement of protein degradation in recognition memory. Here, we show that the proteasome inhibitor, lactacystin (LAC), infused into the CA1 area of the hippocampus at two specific time points during consolidation, impairs 24-retention of memory for object recognition in rats. Administration of LAC after retrieval did not affect retention. These findings provide the first evidence for a requirement of proteasome activity in recognition memory, indicate that protein degradation in the hippocampus is necessary during selective time windows of memory consolidation, and further our understanding of the role of protein turnover in memory formation. PMID- 25687694 TI - Development of a postgraduate interventional cardiac nursing curriculum. AB - Interventional cardiology practices have advanced immensely in the last two decades, but the educational preparation of the workforce in cardiac catheter laboratories has not seen commensurate changes. Although on-the-job training has sufficed in the past, recognition of this workforce as a specialty practice domain now demands specialist educational preparation. The aim of this paper is to present the development of an interventional cardiac nursing curriculum nested within a Master of Nursing Practice in Australia. International and national health educational principles, teaching and learning theories and professional frameworks and philosophies are foundational to the program designed for interventional cardiac specialist nurses. These broader health, educational and professional underpinnings will be described to illustrate their application to the program's theoretical and clinical components. Situating interventional cardiac nursing within a Master's degree program at University provides nurses with the opportunities to develop high level critical thinking and problem solving knowledge and skills. PMID- 25687695 TI - Treatment of urban river contaminated sediment with ex situ advanced oxidation processes: technical feasibility, environmental discharges and cost-performance analysis. AB - The technical feasibility, environmental discharges and cost-performance of urban river contaminated sediment treatment with ex situ advanced oxidation processes were evaluated for the purpose of achieving an ideal treatment goal (for marine disposal) and a cost-performance treatment goal (for beneficially reusing as a filling material). Sediment samples were collected from a river located in southern China. To achieve the ideal treatment goal, sequential treatments (Fenton's reaction+activated persulphate oxidation) were carried out. One-step Fenton's reaction was applied to achieve the cost-performance treatment goal. The resulting effluent was treated and discharged, and sludge generated in wastewater treatment was characterized. The resources input throughout the treatment processes were recorded for cost estimation. After the treatment designed for achieving the ideal treatment goal, most pollutants fulfilled the treatment goal except Pb, Cd, Hg and Ag, probably because these four metals were present mainly in stable fractions of the sediment. The cost-performance treatment goal was achieved in view of low pollutant contents in the toxicity characteristic leaching procedure leachate of treated sediment. The cost for achieving the cost performance treatment goal is much less than that for achieving the ideal treatment goal. The major cost difference is attributed to chemical cost. Stringent sediment treatment goals based on existing standards would lead to massive chemical use, complex treatment and hence huge cost. A simpler treatment with fewer chemicals is adequate for sediment beneficially reused as a filling material, and is economically more advantageous than handling sediment for marine disposal. PMID- 25687696 TI - Development and psychometric evaluation of a scale to measure impaired self awareness of hyper- and hypokinetic movements in Parkinson's disease. AB - OBJECTIVE: Patients with Parkinson's disease (PD) can show impaired self awareness of motor deficits (ISAm). We developed a new scale that measures ISAm severity of hyper- and hypokinetic movements in PD during medication on state and defined its psychometric criteria. METHOD: Included were 104 right-handed, non depressed, non-demented patients. Concerning ISAm, 38 motor symptoms were assessed using seven tasks, which were performed and self-rated concerning presence of deficit (yes/no) by all patients. The whole procedure was videotaped. Motor symptoms were then evaluated by two independent experts, blinded for patient's ratings, concerning presence, awareness of deficit, and severity. Exploratory principal component analysis (promax rotation) was applied to reduce items. Principal axis factoring was conducted to extract factors. Reliability was examined regarding internal consistency, split-half reliability, and interrater reliability. Validity was verified by applying two additional measures of ISAm. RESULTS: Of the initial 38 symptoms, 15 remained, assessed in five motor tasks and merged to a total severity score. Factor analysis resulted in a four factor solution (dyskinesia, resting tremor right hand, resting tremor left hand, bradykinesia). For all subscales and the total score, measures of reliability (values 0.64-0.89) and validity (effect sizes>0.3) were satisfactory. Descriptive results showed that 66% of patients had signs of ISAm (median 2, range 0-15), with ISAm being most distinct for dyskinesia. CONCLUSIONS: We provide the first validation of a test for ISAm in PD. Using this instrument, future studies can further analyze the pathophysiology of ISAm, the psychosocial sequelae, therapeutic strategies and compliance with therapy. PMID- 25687697 TI - Parkinson's disease and sleep/wake disturbances. AB - Sleep disturbances are a common non-motor feature in patients with Parkinson's disease (PD). Early diagnosis and appropriate management are imperative for enhancing patient quality of life. Sleep disturbances can be caused by multiple factors in addition to age-related changes in sleep, such as nocturnal motor symptoms (rigidity, resting tremor, akinesia, tardive dyskinesia, and the "wearing off" phenomenon), non-motor symptoms (pain, hallucination, and psychosis), nocturia, and medication. Disease-related pathology involving the brainstem and changes in the neurotransmitter systems (norepinephrine, serotonin, and acetylcholine) responsible for regulating sleep structure and the sleep/wake cycle play a role in emerging excessive daytime sleepiness and sleep disturbances. Additionally, screening for sleep apnea syndrome, rapid eye movement sleep behavior disorder, and restless legs syndrome is clinically important. Questionnaire-based assessment utilizing the PD Sleep Scale-2 is useful for screening PD-related nocturnal symptoms. In this review, we focus on the current understanding and management of sleep disturbances in PD. PMID- 25687698 TI - Neuroimaging insights into insomnia. AB - Insomnia is one of the most prevalent health complaints afflicting approximately 10% of the population in Western industrialized countries at a clinical level. Despite the proposition that both biological and psychological factors play a role in the experience of insomnia, the field continues to puzzle over so-called "discrepancies" between objective and subjective measurements of sleep and daytime functioning. The promise of neuroimaging is to uncover physiological processes that may readily explain patient reports. However, while there has been an explosion in the number of studies investigating the neural correlates of insomnia with neuroimaging technologies, there appears to be little consistency in findings across studies. We suggest a number of methodological reasons which may, at least partially, explain variability in findings across neuroimaging studies in insomnia. PMID- 25687699 TI - Vascular risk factors and Alzheimer's disease pathogenesis: are conventional pharmacological approaches protective for cognitive decline progression? AB - Alzheimer's disease (AD) is the most common cause of dementia, accounting for more than half of cases with cognitive impairment. With numbers of patients expected to rise sharply over the following years in parallel with the ageing of population, there is intense clinical interest in discovering modifiable risk factors that may contribute to the increasing prevalence of AD. Accumulating data from in vitro and epidemiological studies have highlighted the vascular component of AD and raised hope that treatment of vascular risk factors could eventually lead to primary prevention of AD. Among all the possible pathologic processes that have been tested for an association with AD, diabetes, hypertension and dyslipidemia are the most prominent. Here, we will briefly review the data highlighting a potential correlation of these diseases with AD. Then, we will present observational studies and clinical trials that assessed the impact of their respective approved medical therapies on AD incidence. We conclude by providing clinical information for the physician on potentially effective and non effective medical treatments. Further research is ongoing and time will show whether AD will cease to be considered a pure, non-preventable neurodegenerative process or whether vascular risk factor management may also result in primary AD prevention. PMID- 25687700 TI - Interferon-gamma-induced neurotoxicity of human astrocytes. AB - Activated astrocytes, which can also be referred to as reactive astrocytes or astrogliosis, have been identified in affected regions of common neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and multiple sclerosis. Activated astrocytes may be beneficial, promoting neuronal survival due to their production of growth factors and neurotrophins. Activated astrocytes can also be detrimental to neighboring neurons in neuroinflammatory processes. Astrocytes exposed to certain inflammatory stimulants in vitro have been shown to release potentially neurotoxic molecules, including inflammatory cytokines, glutamate, nitric oxide and reactive oxygen species. It has recently been shown that adult human astrocytes stimulated with interferon-gamma, a common inflammatory cytokine evidently present in neuropathological brains, exert potent neurotoxicity in vitro. This interferon- gamma-induced astrocytic neurotoxicity is mediated by the activation of the Janus kinase-signal transducer and activator of transcription (STAT) 3 pathway in the astrocytes, and involves intracellular phosphorylation of STAT3 at tyrosine-705 residue. Therefore, control of STAT3 activation in human astrocytes may be a promising new therapeutic strategy for a broad spectrum of neurodegenerative and neuroinflammatory disorders where activated astrocytes may contribute to the pathology. PMID- 25687701 TI - Not just the brain: methamphetamine disrupts blood-spinal cord barrier and induces acute glial activation and structural damage of spinal cord cells. AB - Acute methamphetamine (METH) intoxication induces metabolic brain activation as well as multiple physiological and behavioral responses that could result in life threatening health complications. Previously, we showed that METH (9 mg/kg) used in freely moving rats induces robust leakage of blood-brain barrier, acute glial activation, vasogenic edema, and structural abnormalities of brain cells. These changes were tightly correlated with drug-induced brain hyperthermia and were greatly potentiated when METH was used at warm ambient temperatures (29 degrees C), inducing more robust and prolonged hyperthermia. Extending this line of research, here we show that METH also strongly increases the permeability of the blood-spinal cord barrier as evidenced by entry of Evans blue and albumin immunoreactivity in T9-12 segments of the spinal cord. Similar to the blood-brain barrier, leakage of bloodspinal cord barrier was associated with acute glial activation, alterations of ionic homeostasis, water tissue accumulation (edema), and structural abnormalities of spinal cord cells. Similar to that in the brain, all neurochemical alterations correlated tightly with drug-induced elevations in brain temperature and they were enhanced when the drug was used at 29 degrees C and brain hyperthermia reached pathological levels (>40 degrees C). We discuss common features and differences in neural responses between the brain and spinal cord, two inseparable parts of the central nervous system affected by METH exposure. PMID- 25687702 TI - Strategies to alleviate poverty and grassland degradation in Inner Mongolia: intensification vs production efficiency of livestock systems. AB - Semi-nomadic pastoralism was replaced by sedentary pastoralism in Inner Mongolia during the 1960's in response to changes in land use policy and increasing human population. Large increases in numbers of livestock and pastoralist households (11- and 9-fold, respectively) during the past 60 yrs have variously degraded the majority of grasslands in Inner Mongolia (78 M ha) and jeopardize the livelihoods of 24 M human inhabitants. A prevailing strategy for alleviating poverty and grassland degradation emphasizes intensification of livestock production systems to maintain both pastoral livelihoods and large livestock numbers. We consider this strategy unsustainable because maximization of livestock revenue incurs high supplemental feed costs, marginalizes net household income, and promotes larger flock sizes to create a positive feedback loop driving grassland degradation. We offer an alternative strategy that increases both livestock production efficiency and net pastoral income by marketing high quality animal products to an increasing affluent Chinese economy while simultaneously reducing livestock impacts on grasslands. We further caution that this strategy be designed and assessed within a social-ecological framework capable of coordinating market expansion for livestock products, sustainable livestock carrying capacities, modified pastoral perceptions of success, and incentives for ecosystem services to interrupt the positive feedback loop that exists between subsistence pastoralism and grassland degradation in Inner Mongolia. PMID- 25687703 TI - The bronze kidney: membranous glomerulonephritis associated with iron overload. AB - A 55-year-old man with a history of diabetes mellitus, hypertension and hypercholesterolaemia developed increasing peripheral oedema over the course of several months. He was found to have nephrotic range proteinuria (15.7 g/24 h). His renal ultrasound scan was normal and the autoimmune screen was negative. His renal biopsy demonstrated evidence of membranous glomerulonephritis and increased iron deposition. At this juncture, a serum ferritin was checked which showed an initial value 933 ug/L with transferrin saturation at 96.6%. A subsequent liver biopsy also showed evidence of iron overload but without fibrotic changes. Genetic studies including C282Y HFE, ferroportin and DMT1 studies were also negative. He was subsequently treated with interval venesection which was associated with significant symptomatic and biochemical evidence of improvement in oedema and proteinuria. PMID- 25687704 TI - Teary eyes due to 21 pence? AB - A woman in her late 70s with chronic bilateral epiphora under ophthalmology review was referred to our department for dacryocystorhinostomy after punctoplasty and detection of nasolacrimal duct obstruction. A CT scan of the paranasal sinuses for preoperative planning revealed complete opacification of the right maxillary, anterior ethmoid, frontal and sphenoid sinuses, left septal deviation and an incidental finding of foreign bodies in the right anterior nasal airspace. She proceeded with functional endoscopic sinus surgery (FESS) and removal of foreign bodies. To our surprise, a partially eroded 20 pence and 1 penny coin were found and removed from her right nasal airway. There was no history given about foreign bodies in her nose. Her symptoms improved postoperatively. PMID- 25687705 TI - Proximal fibular stress fractures in children and adolescents, what should we rely on? Lessons learned from a case. AB - Fibula fractures are the third most common stress fractures in children and adolescents. The triad of localised periosteal reaction, endosteal thickening and radiolucent cortical lines, localised in the distal third of the fibula along with a typical clinical history is in most cases sufficient to establish the diagnosis. Proximal fibula stress lesions are a very rare finding, with few reports in the literature. Stress fractures in this location demand careful investigation before a definitive diagnosis can be made. In the presence of non specific MRI findings, stress fracture should be a diagnosis of exclusion. The authors report a case referred to their department by a sports medicine physician with a suspicion of stress fracture of the proximal fibula without characteristic imaging findings, which was ultimately confirmed as a stress lesion only by biopsy. PMID- 25687706 TI - An unusual association of Menetrier's disease with a gastric bezoar. AB - Menetrier's disease is a rare protein-losing hypertrophic gastroenteropathy. While it still remains a medical curiosity, infection with Cytomegalovirus and Helicobacter pylori, and hormonal, congenital, dietary and neurogenic factors have been postulated as causative factors. We describe a case of a 14-year boy who presented with epigastric discomfort, vomiting, inability to gain weight and pedal oedema. Investigations revealed hypoproteinaemia without proteinuria and elevated faecal alpha-1-antitrypsin levels suggestive of protein-losing enteropathy. Imaging and endoscopic features demonstrated cerebriform gastric folds indicative of Menetrier's disease. Infective, hormonal and neurogenic causes were ruled out in our patient. Surprisingly, the patient had a history of pica and an associated large gastric bezoar, which was ultimately removed surgically. An association of Menetrier's disease with a bezoar has been reported only once previously. We thus add to the existing literature and highlight the plausible role of a bezoar as a causative factor in the pathogenesis of Menetrier's disease due to its irritant nature. PMID- 25687707 TI - Traumatic intradiploic epidermoid cyst manifest as scalp papule. AB - A posterior fossa intradiploic epidermoid cyst was removed from the calvarium of an otherwise healthy 34-year-old woman after work up for dizziness and blurry vision. The patient admitted to a history of a firm papule that occurred occasionally after a trauma sustained to the region years prior. The authors propose that trauma and cutaneous stigmata are potential associations with intradiploic epidermoid cysts. PMID- 25687708 TI - Hyperdense basilar artery sign. PMID- 25687709 TI - Preventing sight loss in older people. A qualitative study exploring barriers to the uptake of regular sight tests of older people living in socially deprived communities in South Wales. AB - OBJECTIVES: This paper describes research findings that try to understand some of the reasons that prevent older people in deprived communities in South Wales from accessing NHS funded sight tests and leads to a discussion of suitable interventions that seek to improve access to primary eye care services and prevent avoidable sight loss. STUDY DESIGN: Data were collected from eight focus groups (n = 63) of mixed gender and ages (60-80+ years), of white origin living in deprived communities in South Wales. Individuals were recruited for the focus groups by extensively publicizing the project, with a range of health and older people's community services and groups such as sheltered housing complexes, stroke support groups and coffee morning groups. The study included people who attended optometry services and people not engaged with services. A purposive sampling technique summarizes the sampling approach taken, an approach which the team utilized to recruit 'information rich' cases, namely individuals, groups and organizations that provided the greatest insight into the research question. METHODS: Focus groups were recorded and transcribed verbatim. Data underwent thematic content analysis and subsequent interpretations were corroborated by expert advisors and a project steering group. RESULTS: Cost was perceived as a significant barrier to accessing sight tests, particularly in relation to purchasing glasses. Other barriers included the perceived pressure to buy glasses associated with visits to the optometrists; poor understanding of the purpose of a sight test in a health prevention context and acceptance of deteriorating sight loss due to the ageing process. CONCLUSION: Areas of improvement for the delivery of preventative eye health services to older people are identified, as are areas for reflection on the part of those who work within the eye health industry. PMID- 25687710 TI - Physical activity among older people with sight loss: a qualitative research study to inform policy and practice. AB - OBJECTIVES: To investigate the ways in which participation in physical activity is prevented or facilitated among older people with acquired sight loss later in life. STUDY DESIGN: Qualitative research. METHODS: Interviews were conducted with 48 visually impaired adults age 60+ years, recruited from a range of settings including local sight loss organisations and via talking newspaper advertisements. Visual impairment was defined by self-report. Data was analysed using a thematic analysis. This research represents a first step toward the development of empirically based practical suggestions for decision-makers and health professionals in terms of supporting - when required - visually impaired older adults participation in physical activity. RESULTS: Six themes were identified that captured why physical activity was prevented or facilitated: disabling environments; organisational opportunities; transport; lack of information; confidence, fear and personal safety; and exercise as medicine. CONCLUSIONS: Recommendations for policy change need to be focused at the societal level. This includes developing more accessible and inclusive environments and providing meaningful information about physical activity to older adults with a visual impairment, and visual impairment in older age to physical activity providers. PMID- 25687711 TI - Area deprivation and age related macular degeneration in the EPIC-Norfolk Eye Study. AB - OBJECTIVES: To investigate the relationship between area deprivation, individual socio-economic status (SES) and age related macular degeneration (AMD). STUDY DESIGN: Cross sectional study nested within a longitudinal cohort study. METHODS: Data were collected in the EPIC-Norfolk Eye Study by trained nurses, using standardized protocols and lifestyle questionnaires. The English Index of multiple deprivation 2010 (IMD) was derived from participants' postcodes. AMD was identified from standardized grading of fundus photographs. Logistic regression was used to examine associations between IMD, SES and AMD. RESULTS: 5344 pairs (62.0% of total 8623) of fundus photographs were of sufficient quality for grading of AMD. Of 5182 participants with complete data, AMD was identified in 653 participants (12.60%, 95%CI = 11.7-13.5%). Multivariable logistic regression showed that people living in the most affluent 5% of areas had nearly half the odds of AMD compared to those living in comparatively more deprived areas (OR = 0.56, 95% CI = 0.36-0.89, P = 0.02), after adjusting for age, sex, education, social class and smoking. CONCLUSIONS: The authors found that living in the most affluent areas exerted a protective effect on AMD, independently of education and social class. Further investigation into underlying mechanisms will inform potential interventions to reduce health inequalities relating to AMD. PMID- 25687712 TI - The potential and electric field in the cochlear outer hair cell membrane. AB - Outer hair cell electromechanics, critically important to mammalian active hearing, is driven by the cell membrane potential. The membrane protein prestin is a crucial component of the active outer hair cell's motor. The focus of the paper is the analysis of the local membrane potential and electric field resulting from the interaction of electric charges involved. Here the relevant charges are the ions inside and outside the cell, lipid bilayer charges, and prestin-associated charges (mobile-transferred by the protein under the action of the applied field, and stationary-relatively unmoved by the field). The electric potentials across and along the membrane are computed for the case of an applied DC-field. The local amplitudes and phases of the potential under different frequencies are analyzed for the case of a DC + AC-field. We found that the effect of the system of charges alters the electric potential and internal field, which deviate significantly from their traditional linear and constant distributions. Under DC + AC conditions, the strong frequency dependence of the prestin mobile charge has a relatively small effect on the amplitude and phase of the resulting potential. The obtained results can help in a better understanding and experimental verification of the mechanism of prestin performance. PMID- 25687713 TI - [Patients' preferences in the medicamentous treatment of diabetes mellitus type 2: A systematic classification and meta-comparison of patient preference studies]. AB - OBJECTIVE: Diabetes Mellitus is one of the most expensive common diseases. Because of the great socio-economic importance of this indication, it seems necessary to consider the expectations and needs of all patients with regard to treatment characteristics. To evaluate patient preferences stated-preference methods are increasingly used. The aim was to analyze and compare the available evidence from patient preference studies regarding the treatment characteristics and to display which target criteria in the medicinal treatment of diabetes mellitus type 2 are most important from the patients view. METHODS: A literature review in PubMed was conducted to identify stated preference studies in the indication of diabetes and show which properties of a treatment are relevant to the patient's benefit. By means of level difference calculation and a subsequent normalization uniform weights for the attributes of the studies were determined. Based on a final ranking the key criteria according to their value proposition from the perspective of affected populations are demonstrated. RESULTS: N = 13 studies could be included in the analysis. By calculating the level difference and performing a normalization it was possible to obtain a uniform representation of all attributes of N = 7 studies. The preference studies show that the control of blood sugar, side effects (such as hypoglycemia, nausea and stomach discomfort or weight changes), long-term complications and the mode of administration represent the most common patient-relevant outcomes in diabetes therapy. In five of the 13 DCE studies the blood glucose control achieved the highest ranking within the relative importance score in the treatment of diabetes mellitus. In two studies, the side effects hypoglycemia and weight changes occupied the first rank. Furthermore, in two other studies, the side effects of nausea/upset stomach and in one study the type of application determined as the primary outcome measure. CONCLUSIONS: The use of stated preference methods in health economics aims to reflect the benefit assessments of therapy features from patient's or expert perspective. So far it is unclear how this evidence is documented in benefit assessment of medical interventions and how the findings will be made available to decision-makers. Based on the findings of this review the evidence of patient preferences in diabetes treatment is synthesized. The results show the relative importance based on a derived ranking score of the used patient-relevant endpoints. The ranking allows the comparison of the results of the identified preference studies. PMID- 25687714 TI - Factors associated with dual use of tobacco and electronic cigarettes: A case control study. AB - BACKGROUND: Many electronic cigarette (EC) users reduce cigarette consumption without completely quitting. It is important to assess the characteristics and experiences of these users, commonly called "dual users", in comparison with EC users who have completely substituted smoking (non-smoking vapers). METHODS: A questionnaire was uploaded in an online survey tool. EC users were invited to participate irrespective of their current smoking status. Dual users were matched for age and gender with non-smoking vapers. RESULTS: From 19,441 participants, 3682 were dual users. After random 1:1 matching with non-smoking vapers (all of whom were former smokers), 3530 participants in each group were compared. Dual users had longer smoking history, lower daily cigarette consumption and similar cigarette dependence compared to non-smoking vapers. Their daily consumption was reduced after initiation of EC use from 20 to 4 cigarettes per day. Most of them were using ECs daily, however, more were occasional EC users compared to non smoking vapers. Use of advanced (third generation) devices and daily liquid consumption was lower in dual users compared to non-smoking vapers. The most important reason for initiating EC use was to reduce smoking and exposure of family members to smoke for both groups, but higher scores were given to "avoid smoking ban in public places" by dual users compared to non-smoking vapers. The strongest predictors of being dual user from multivariate analysis were: higher risk perception for ECs (OR=2.27, 95% CI=1.40-3.68), use of first-generation EC devices (OR=1.98, 95% CI=1.47-2.66), use of prefilled cartomizers (OR=1.94, 95% CI=1.23-3.06) and occasional use of ECs (OR=1.62, 95% CI=1.21-2.17). CONCLUSIONS: The results of this case-control study indicate that higher risk perceptions about, and less frequent use of, ECs was associated with dual use of ECs and tobacco cigarettes. Since this is a cross-sectional survey, which explores association but not causation, longitudinal studies are warranted to further explore the reasons for dual use. PMID- 25687715 TI - Biological augmentation and tissue engineering approaches in meniscus surgery. AB - PURPOSE: The purpose of this review was to evaluate the role of biological augmentation and tissue engineering strategies in meniscus surgery. Although clinical (human), preclinical (animal), and in vitro tissue engineering studies are included here, we have placed additional focus on addressing preclinical and clinical studies reported during the 5-year period used in this review in a systematic fashion while also providing a summary review of some important in vitro tissue engineering findings in the field over the past decade. METHODS: A search was performed on PubMed for original works published from 2009 to March 31, 2014 using the term "meniscus" with all the following terms: "scaffolds," "constructs," "cells," "growth factors," "implant," "tissue engineering," and "regenerative medicine." Inclusion criteria were the following: English-language articles and original clinical, preclinical (in vivo), and in vitro studies of tissue engineering and regenerative medicine application in knee meniscus lesions published from 2009 to March 31, 2014. RESULTS: Three clinical studies and 18 preclinical studies were identified along with 68 tissue engineering in vitro studies. These reports show the increasing promise of biological augmentation and tissue engineering strategies in meniscus surgery. The role of stem cell and growth factor therapy appears to be particularly useful. A review of in vitro tissue engineering studies found a large number of scaffold types to be of promise for meniscus replacement. Limitations include a relatively low number of clinical or preclinical in vivo studies, in addition to the fact there is as yet no report in the literature of a tissue-engineered meniscus construct used clinically. Neither does the literature provide clarity on the optimal meniscus scaffold type or biological augmentation with which meniscus repair or replacement would be best addressed in the future. There is increasing focus on the role of mechanobiology and biomechanical and biochemical cues in this process, however, and it is hoped that this may lead to improvements in this strategy. CONCLUSIONS: There appears to be significant potential for biological augmentation and tissue engineering strategies in meniscus surgery to enhance options for repair and replacement. However, there are still relatively few clinical studies being reported in this regard. There is a strong need for improved translational activities and infrastructure to link the large amounts of in vitro and preclinical biological and tissue engineering data to clinical application. LEVEL OF EVIDENCE: Level IV, systematic review of Level I-IV studies. PMID- 25687716 TI - Thermodynamic stability and structure of cuprous chloride surfaces: a DFT investigation. AB - Density functional theory together with ab initio atomistic thermodynamics has been utilized to study the structures and stabilities of the low index CuCl surfaces. It is shown that the Cl-terminated structures are more stable than the Cu-terminated configurations, and that the defective CuCl(110)-Cu structure is more stable than the stoichiometric CuCl(110) surface. The equilibrium shape of a cuprous chloride nanostructure terminated by low-index CuCl surfaces has also been predicted using a Wulff construction. It was found that the (110) facets dominate at low chlorine concentration. As the chlorine concentration is increased, however, the contributions of the (100) and (111) facets to the Wulff construction also increase giving the crystal a semi-prism shape. At high chlorine concentration, and close to the rich limit, the (111) facets were found to be the only contributors to the Wulff construction, resulting in prismatic nanocrystals. PMID- 25687718 TI - Treatment of complex atherosclerotic femoropopliteal artery disease with a self expanding interwoven nitinol stent: Midterm results. AB - OBJECTIVE: To examine the efficacy and durability of an interwoven self-expanding nitinol stent for the treatment of superficial femoral and popliteal arteries. METHOD: Consecutive patients with severely diseased superficial femoral and popliteal arteries who received SUPERA(r) stents were retrospectively identified. The patients were followed for 12 months by Doppler ultrasound examinations, stent roentgenograms, and estimation of Rutherford-Becker class and ankle brachial index. RESULTS: From July 2012 to May 2014, 42 limbs in 36 patients (mean age, 61.5 +/- 7.5 years; 75% male) were treated with angioplasty and primary stenting. Total occlusions were present in 14 limbs, and 63.8% had either moderate or severe calcification. The mean (+/-SD) lesion length was 105 mm (+/ 28). Primary patency was 91.4% at 6 months and 85.7% at 12 months. The ankle brachial index increased from 0.57 +/- 0.19 preoperative to 0.91 +/- 0.12 postoperative. There was no procedural or device-related morbidity or mortality after revascularization and only one major amputation was observed on follow-up. CONCLUSIONS: Our experience shows that, Supera stents are safe and effective in our cohort of patients, with acceptable patency rates. There were no stent fractures so far even with stenting of the femoropopliteal segments. Stent design provides a viable option for high-grade obstructive disease in the femoropopliteal artery. PMID- 25687717 TI - Insights into the role of substrates on the interaction between cytochrome b5 and cytochrome P450 2B4 by NMR. AB - Mammalian cytochrome b5 (cyt b5) is a membrane-bound protein capable of donating an electron to cytochrome P450 (P450) in the P450 catalytic cycle. The interaction between cyt b5 and P450 has been reported to be affected by the substrates of P450; however, the mechanism of substrate modulation on the cyt b5 P450 complex formation is still unknown. In this study, the complexes between full-length rabbit cyt b5 and full-length substrate-free/substrate-bound cytochrome P450 2B4 (CYP2B4) are investigated using NMR techniques. Our findings reveal that the population of complexes is ionic strength dependent, implying the importance of electrostatic interactions in the complex formation process. The observation that the cyt b5-substrate-bound CYP2B4 complex shows a weaker dependence on ionic strength than the cyt b5-substrate-free CYP2B4 complex suggests the presence of a larger fraction of steoreospecific complexes when CYP2B4 is substrate-bound. These results suggest that a CYP2B4 substrate likely promotes specific interactions between cyt b5 and CYP2B4. Residues D65, V66, T70, D71 and A72 are found to be involved in specific interactions between the two proteins due to their weak response to ionic strength change. These findings provide insights into the mechanism underlying substrate modulation on the cyt b5 P450 complexation process. PMID- 25687719 TI - Epileptiform activity during induction of anesthesia with sevoflurane prior to elective carotid endarterectomy. AB - The optimal anesthetic technique for carotid endarterectomy is still controversial. For general anesthesia, various induction agents have been used. We present two patients with asymptomatic high-grade carotid stenosis where induction with sevoflurane resulted in epileptiform discharges seen on perioperative electroencephalogram monitoring without adverse clinical sequelae. The occurrence of epileptogenic electroencephalogram during sevoflurane anesthesia has been widely described despite its popular use in pediatric anesthesia. This phenomenon, however, has not been previously described during electroencephalogram monitoring in carotid surgery. The authors suggest that induction anesthesia with sevoflurane should be avoided in this patient population especially where routine electroencephalogram monitoring is not performed. PMID- 25687720 TI - Analysis of risk factors and diseases associated with atherosclerosis in the progression of carotid artery stenosis. AB - OBJECTIVE: The objective of this study was to analyze the roles of demographic, clinical, and laboratory factors on the progression of atherosclerotic stenosis in carotid bifurcation. It was based on prospective information from records entered on a specific application form for follow-up outpatients at a tertiary university service. METHODS: Consecutive symptomatic and asymptomatic patients (n = 210) who had undergone more than one carotid duplex scan but no surgical intervention were selected for the analysis. The patients were divided into two groups: patients whose duplex scans did not show bilateral progression of carotid stenosis and patients with carotid stenosis progression of <50%, 50%-69%, or >70%. Clinical and demographic parameters were compared between groups. RESULTS: Group II levels of plasma urea (51.6 +/- 27.8 mg/dl) and fibrinogen (493.2 +/- 113.3 mg/dl) were higher than the Group I levels (43.0 +/- 14.9 mg/dl and 441.3 +/- 106.7 mg/dl, respectively) with statistical significance (p urea = 0.013 and p fibrinogen = 0.018). Paradoxically, the mean body mass index was higher in Group I (26.4 +/- 4.6 kg/m(2)) than in Group II (24.6 +/- 3.9 kg/m(2); p = 0.02). CONCLUSIONS: Traditional risk factors for the development of atherosclerosis in a carotid bifurcation are important but not unique. Metabolic and inflammatory factors can contribute to disease progression. PMID- 25687721 TI - Anatomic and procedural determinants of fluoroscopy time during elective endovascular aortic aneurysm repair. AB - OBJECTIVE: To identify both the procedural and anatomic factors which determine duration of fluoroscopy during elective endovascular aortic aneurysm repair (EVAR). METHODS: We retrospectively analyzed our prospectively maintained EVAR database for the relationship between fluoroscopy time and both procedural (type of graft, configuration, number of components, surgeon) and anatomic factors reflective of aneurysm complexity (15 variables). RESULTS: A total of 128 patients underwent elective EVAR with a mean fluoroscopy time of 5.7 +/- 3.4 min. The type of grafts used consisted of 41 (32%) Zenith, 85 (66.4%) Endurant and 2 (1.6%) Anaconda, with 105 (82%) being bifurcated and 23 (18%) being aorto-uni iliac (AUI) in configuration. Both the surgeon performing the procedure (p = 0.001) and graft configuration (bifurcated vs. AUI, p = 0.03) were found to be predictive of fluoroscopy time; while procedural and anatomic variables were not. CONCLUSIONS: The surgeon's efficiency in the use of fluoroscopy during EVAR is the most important determinant of total fluoroscopy time. Anatomic complexity, make of device, and number of components inserted have minimal impact on duration of fluoroscopy. An endovascular surgeon's ability to curtail fluoroscopy duration is the key component in minimizing radiation exposure to both the surgical team and the patient. PMID- 25687722 TI - Associations of cadmium, bisphenol A and polychlorinated biphenyl co-exposure in utero with placental gene expression and neonatal outcomes. AB - In utero co-exposure to endocrine disrupting compounds can perturb fetal development. However, the effect of co-exposure on pivotal regulatory genes has seldom been investigated. We explored the effects of in utero co-exposure to cadmium (Cd), bisphenol A (BPA) and polychlorinated biphenyls (PCBs) on master regulator genes. We recruited 284 healthy pregnant women, of whom 262 provided both cord blood and placenta samples, and 200 had all measurements taken. Placental Cd, cord blood BPA and total PCBs in the exposed group were higher than a reference group. KISS1 expression level in placental tissue was threefold higher in the exposed group than in the reference, and was positively associated with all toxicants. Leptin and leptin receptor expression were also significantly higher, but were only associated with BPA. From our findings, we conclude that lower birth weight is correlated with Cd and PCBs, and may result from the increased KISS1 mRNA expression. PMID- 25687723 TI - Epigenetic dimension of oxygen radical injury in spermatogonial epithelial cells. AB - The present work reports a direct role of mitochondrial oxidative stress induced aberrant chromatin regulation, as a central phenomenon, to perturbed genomic integrity in the testicular milieu. Oxygen-radical injury following N succinimidyl N-methylcarbamate treatment in mouse spermatogonial epithelial (GC-1 spg) cells induced functional derailment of mitochondrial machinery. Mitophagy resulted in marked inhibition of mitochondrial respiration and reduced mtDNA copy number. Impaired cell cycle progression along with altered H3K9me1, H4K20me3, H3, AcH3 and uH2A histone modifications were observed in the treated cells. Dense heterochromatin foci and aberrant expression of HP1alpha in nuclei of treated cells implied onset of senescence associated secretory phenotype mediated through nuclear accumulation of NF-kappaB. Neoplastic nature of daughter clones, emerged from senescent mother phenotypes was confirmed by cytogenetic instability, aberrant let-7a and let-7b miRNA expression and anchorage independent growth. Together, our results provide the first insights of redox-dependent epigenomic imbalance in spermatogonia, a previously unknown molecular paradigm. PMID- 25687724 TI - Study of the concordance between p16 immunohistochemistry and HPV-PCR genotyping for the viral diagnosis of oropharyngeal squamous cell carcinoma. AB - OBJECTIVE: The diagnosis of HPV-related oropharyngeal cancer in clinical practice is based on p16 immunohistochemistry and PCR detection of viral DNA (HPV-PCR). The primary objective of this study was to evaluate the concordance between these 2 diagnostic tests. The secondary objective was to study the clinical characteristics of these patients. MATERIALS AND METHODS: This single-centre prospective study was conducted between February 2010 and July 2012. Immunohistochemical analysis of p16 and HPV-PCR were performed on tumour biopsies. Concordance was evaluated according to Cohen's kappa coefficient and was interpreted according to the Landis and Koch scale. The patients' clinical data were analysed as a function of the diagnostic test results. RESULTS: Seventy one patients were included in this study. The prevalence of HPV was 43.7% according to p16 and 31% according to HPV-PCR. The concordance study revealed a kappa coefficient of 0.615. A tumour of the tonsil or base of the tongue was detected in 100% of p16+/HPV-PCR+ cases. Smoking and alcohol abuse were significantly less frequent among HPV+ patients regardless of the method of detection. These patients were older and presented tumours with a lower grade of histological differentiation. CONCLUSION: p16 immunohistochemistry or HPV-PCR used alone appear to be insufficient. These results confirm the high prevalence of HPV-related oropharyngeal squamous cell carcinoma (OSCC) and the previously reported specific clinical and histological features, apart from age. It appears essential for future clinical trials to be stratified according to smoking and tumour HPV status, defined by means of reliable virological tests targeting E6/E7 mRNA and no longer a simple positive response to the p16 marker, as is frequently the case at the present time. New tests suitable for use in routine practice therefore need to be developed. PMID- 25687725 TI - Deferitazole, a new orally active iron chelator. AB - Following a systematic search of desferrithiocin analogs, a polyether derivative, deferitazole (formerly FBS0701), has entered into phase 1 and 2 clinical trials with promising biological properties. However, until now, detailed physicochemical properties of this chelator have not been reported. The compound displays a high affinity and selectivity for iron(III) as demonstrated by the log beta2 = 33.39 +/- 0.03 and the pFe(3+) value of 22.3. Two equilibrating isomeric forms of the iron(III) complex exist under biological conditions. Deferitazole also binds the trivalent metals Al(III) and La(III) with high affinity; log beta2 values, 26.68 and 21.55 respectively. The affinity of deferitazole for divalent cations is somewhat lower, with the exception of Cu(II) which possesses a log beta2 value of 25.5; deferitazole scavenges iron from labile sources such as citrate and albumin with efficiencies comparable with those of other therapeutic iron chelators, including deferasirox, deferiprone and desferrioxamine. The Fe(III)(deferitazole)2 is stable under physiological conditions and does not redox cycle. The high affinity of deferitazole for iron(III) renders it unlikely that this chelator will lead to the redistribution of iron and consequently deferitazole shows considerable promise as a therapeutic iron(III) chelator. PMID- 25687727 TI - Carbon-ion radiotherapy for locally advanced primary or postoperative recurrent epithelial carcinoma of the lacrimal gland. AB - PURPOSE: To evaluate the applicability of carbon ion beams for the treatment of carcinoma of the lacrimal gland with regard to normal tissue morbidity and local tumor control. METHODS AND MATERIALS: Between April 2002 and January 2011, 21 patients with locally advanced primary epithelial carcinoma of the lacrimal gland were enrolled in a Phase I/II clinical trial of carbon-ion radiotherapy (CIRT) at the National Institute of Radiological Sciences. Acute radiation toxicity was the primary endpoint of this dose-escalation study and the late toxicity, local control, and overall survival were additionally evaluated as secondary endpoints. Of the 21 subjects enrolled, all patients were followed for more than 6 months and analyzed. RESULTS: The radiation dose was increased from the initial dose of 48.0Gy equivalents (GyE)/12 fractions at 10% increments up to 52.8GyE. Of the 21 patients, five received a total dose of 48.0GyE, and 16 received a total dose of 52.8GyE. No patient developed grade 3 or higher skin toxicity. As late ocular/visual toxicity, three patients had grade 3 retinopathy and seven patients lost their vision. Among the 10 patients treated until May 2005, five patients had local recurrence, three of whom had marginal recurrence. Therefore, the margin for the CTV (clinical target volume) was set to a range according to the orbital exenteration since June 2005. After the application of the extended margin, no local recurrence has been observed. The three-year overall survival and local control rates were 82.2% and 79.0%, respectively. CONCLUSION: CIRT can be applied for primary epithelial carcinoma of the lacrimal gland, with a borderline acceptable morbidity and sufficient antitumor effect when an extended margin is adopted. PMID- 25687726 TI - Obesity and genomics: role of technology in unraveling the complex genetic architecture of obesity. AB - Obesity is a complex and multifactorial disease that occurs as a result of the interaction between "obesogenic" environmental factors and genetic components. Although the genetic component of obesity is clear from the heritability studies, the genetic basis remains largely elusive. Successes have been achieved in identifying the causal genes for monogenic obesity using animal models and linkage studies, but these approaches are not fruitful for polygenic obesity. The developments of genome-wide association approach have brought breakthrough discovery of genetic variants for polygenic obesity where tens of new susceptibility loci were identified. However, the common SNPs only accounted for a proportion of heritability. The arrival of NGS technologies and completion of 1000 Genomes Project have brought other new methods to dissect the genetic architecture of obesity, for example, the use of exome genotyping arrays and deep sequencing of candidate loci identified from GWAS to study rare variants. In this review, we summarize and discuss the developments of these genetic approaches in human obesity. PMID- 25687728 TI - Identification of small molecule inhibitors of cisplatin-induced hair cell death: results of a 10,000 compound screen in the zebrafish lateral line. AB - HYPOTHESIS: The zebrafish lateral line can be used to identify small molecules that protect against cisplatin-induced hair cell death. BACKGROUND: Cisplatin is a commonly used chemotherapeutic agent, which causes hearing loss by damaging hair cells of the inner ear. There are currently no FDA-approved pharmacologic strategies for preventing this side effect. The zebrafish lateral line has been used successfully in the past to study hair cell death and protection. METHODS: In this study, we used the zebrafish lateral line to screen a library of 10,000 small molecules for protection against cisplatin-induced hair cell death. Dose response relationships for identified protectants were determined by quantifying hair cell protection. The effect of each protectant on uptake of a fluorescent cisplatin analog was also quantified. RESULTS: From this screen, we identified 2 compounds exhibiting dose-dependent protection: cisplatin hair cell protectant 1 and 2 (CHCP1 and 2). CHCP1 reduced the uptake of a fluorescent cisplatin analog, suggesting its protective effects may be due to decreased cisplatin uptake. CHCP2 did not affect uptake, which suggests an intracellular mechanism of action. Evaluation of analogs of CHCP2 revealed 3 additional compounds that significantly reduced cisplatin-induced hair cell death, although none exceed the effectiveness or potency of the parent compound. CONCLUSION: The zebrafish lateral line was used to identify 2 small molecules that protected against cisplatin-induced hair cell death. PMID- 25687729 TI - Cochlear implantation in late-implanted prelingually deafened adults: changes in quality of life. PMID- 25687730 TI - Hepatitis C. AB - Hepatitis C virus (HCV) infection is a major health problem worldwide. The effects of chronic infection include cirrhosis, end-stage liver disease, and hepatocellular carcinoma. As a result of shared routes of transmission, co infection with HIV is a substantial problem, and individuals infected with both viruses have poorer outcomes than do peers infected with one virus. No effective vaccine exists, although persistent HCV infection is potentially curable. The standard of care has been subcutaneous interferon alfa and oral ribavirin for 24 72 weeks. This treatment results in a sustained virological response in around 50% of individuals, and is complicated by clinically significant adverse events. In the past 10 years, advances in HCV cell culture have enabled an improved understanding of HCV virology, which has led to development of many new direct acting antiviral drugs that target key components of virus replication. These direct-acting drugs allow for simplified and shortened treatments for HCV that can be given as oral regimens with increased tolerability and efficacy than interferon and ribavirin. Remaining obstacles include access to appropriate care and treatment, and development of a vaccine. PMID- 25687732 TI - Categorizing identity from facial motion. AB - Advances in marker-less motion capture technology now allow the accurate replication of facial motion and deformation in computer-generated imagery (CGI). A forced-choice discrimination paradigm using such CGI facial animations showed that human observers can categorize identity solely from facial motion cues. Animations were generated from motion captures acquired during natural speech, thus eliciting both rigid (head rotations and translations) and nonrigid (expressional changes) motion. To limit interferences from individual differences in facial form, all animations shared the same appearance. Observers were required to discriminate between different videos of facial motion and between the facial motions of different people. Performance was compared to the control condition of orientation-inverted facial motion. The results show that observers are able to make accurate discriminations of identity in the absence of all cues except facial motion. A clear inversion effect in both tasks provided consistency with previous studies, supporting the configural view of human face perception. The accuracy of this motion capture technology thus allowed stimuli to be generated that closely resembled real moving faces. Future studies may wish to implement such methodology when studying human face perception. PMID- 25687731 TI - Oxidative stress causes imbalance of renal renin angiotensin system (RAS) components and hypertension in obese Zucker rats. AB - BACKGROUND: Oxidative stress plays an important role in the pathogenesis of hypertension, especially in obesity-related hypertension. The natriuretic and antinatriuretic components of the renal renin angiotensin system (RAS) maintain sodium homeostasis and blood pressure. Here, we test the hypothesis that increased oxidative stress leads to the imbalance of RAS components and hypertension in obese Zucker rats. METHODS AND RESULTS: Lean and obese rats received vehicle or tempol, a superoxide dismutase mimetic in the drinking water for 4 weeks. Compared with vehicle-treated lean rats, vehicle-treated obese rats exhibited higher blood pressure and increased renal oxidative stress, accompanied by increased diuretic and natriuretic responses to AT1R antagonist (Candesartan) and AT2R agonist (CGP-42112A) and reduced diuretic and natriuretic response to MasR agonist (Ang-[1 to 7]). Moreover, obese rats had higher ACE, AT1R and AT2R, lower ACE2 and MasR expressions in the kidney. All of the above-mentioned abnormalities were reversed to some degree by tempol treatment. In primary cultures of renal proximal tubular (RPT) cells from lean and obese rats, tempol treatment also increased AT2R, ACE2, and MasR expressions but decreased AT1R and ACE expressions in obese rats. CONCLUSIONS: Taken together, our study indicated that the imbalance of renal RAS components was associated with increased oxidative stress in obese rats. Furthermore, antioxidant treatment with tempol reversed the imbalance of renal RAS components and led to diuresis and natriuresis, which, at least in part, explains the blood pressure-lowering effect of antioxidant supplementation in obesity-related hypertension. PMID- 25687733 TI - Holography and coherent diffraction with low-energy electrons: A route towards structural biology at the single molecule level. AB - The current state of the art in structural biology is led by NMR, X-ray crystallography and TEM investigations. These powerful tools however all rely on averaging over a large ensemble of molecules. Here, we present an alternative concept aiming at structural analysis at the single molecule level. We show that by combining electron holography and coherent diffraction imaging estimations concerning the phase of the scattered wave become needless as the phase information is extracted from the data directly and unambiguously. Performed with low-energy electrons the resolution of this lens-less microscope is just limited by the De Broglie wavelength of the electron wave and the numerical aperture, given by detector geometry. In imaging freestanding graphene, a resolution of 2A has been achieved revealing the 660.000 unit cells of the graphene sheet from a single data set. Once applied to individual biomolecules the method shall ultimately allow for non-destructive imaging and imports the potential to distinguish between different conformations of proteins with atomic resolution. PMID- 25687734 TI - Screening for celiac disease in Danish adults. AB - OBJECTIVE: The prevalence of celiac disease (CD) as recorded in the Danish National Patient Registry is ~50/100,000 persons. This is much lower than the reported prevalence of CD in other Nordic countries and underdiagnosis is suspected. Our aim was to estimate the prevalence of CD in a population-based study of Danish adults. METHODS: A total of 2297 adults aged 24-76 years living in the southwestern part of Copenhagen were screened for CD by immunoglobulin (Ig)A and IgG antibodies to transglutaminases and deamidated gliadin. IgA/IgG positive participants were invited to a clinical evaluation, including biopsies, by a gastroenterologist. RESULTS: Of the invited 56 participants, 40 underwent a full clinical evaluation and 8 persons were diagnosed with CD; 2 of the 16 persons, who did not complete the clinical evaluation, were considered by experts to have probable CD. None of the above 56 participants had a known history of CD or a recorded diagnosis of CD in National Patient Registry. By combining cases of biopsy-proven CD (n = 8), probable CD (n = 2), and registry-recorded CD (n = 1), the prevalence of CD was estimated to be 479/100,000 (11/2297) persons (95% CI: 197-761). CONCLUSION: In this general adult population, the prevalence of CD as estimated by screening and clinical evaluation was 10 times higher than the registry-based prevalence of CD. Of 11 participants diagnosed with CD in our screening study, 10 were unaware of the diagnosis prior to the study. Thus, our study suggests that CD is markedly underdiagnosed in Danish adults. PMID- 25687735 TI - Temperament and character dimensions assessed in general population, in individuals with psychoactive substance dependence and in young male conscripts. AB - BACKGROUND: In this work we consider Cloninger's psychobiological model, which measures two dimensions of personality: character and temperament. Temperament refers to the biological basis of personality and its characteristics, while character refers to an individual's attitudes towards own self, towards humanity and as part of the universe. METHODS: The Temperament and Character Inventory Revised-140 (TCI-R-140) was administered to 3 divergent samples: a general population sample, a sample of male conscripts and a sample of individuals attending a substance abuse rehabilitation programme. Score differences among the three samples were assessed controlling for age and gender and reliability coefficients are reported. The latent structure was studied in all samples, using exploratory and confirmatory factor analysis methods (EFA and CFA respectively). RESULTS: The proposed structure was partially replicated via EFA. CFA however indicated less than satisfactory fit, as in previously reported results. To improve the fit, the path diagram was augmented to account for multiple factor complexity, as suggested by the EFA results in all samples. While retaining the original seven-factor structure, the augmented model provided adequate fit. The consistency of the inventory was satisfactory in all samples. Evidence for the construct validity was found in relation to aggression. CONCLUSIONS: This is the first study to conclude in adequate fit, after allowing for the indicators to load on more than one factor within each dimension. While cross-national differences apply, our results were similar (when comparable) with previously reported ones in the literature. PMID- 25687736 TI - Intra-adrenal murine TH-MYCN neuroblastoma tumors grow more aggressive and exhibit a distinct tumor microenvironment relative to their subcutaneous equivalents. AB - In around half of the patients with neuroblastoma (NBL), the primary tumor is located in one of the adrenal glands. We have previously reported on a transplantable TH-MYCN model of subcutaneous (SC) growing NBL in C57Bl/6 mice for immunological studies. In this report, we describe an orthotopic TH-MYCN transplantable model where the tumor cells were injected intra-adrenally (IA) by microsurgery. Strikingly, 9464D cells grew out much faster in IA tumors compared to the subcutis. Tumors were infiltrated by equal numbers of lymphocytes and myeloid cells. Within the myeloid cell population, however, tumor-infiltrating macrophages were more abundant in IA tumors compared to SC tumors and expressed lower levels of MHC class II, indicative of a more immunosuppressive phenotype. Using 9464D cells stably expressing firefly luciferase, enhanced IA tumor growth could be confirmed using bioluminescence. Collectively, these data show that the orthotopic IA localization of TH-MYCN cells impacts the NBL tumor microenvironment, resulting in a more stringent NBL model to study novel immunotherapeutic approaches for NBL. PMID- 25687737 TI - Is there any relationship between polymorphism of Heat Shock Protein 70 genes and Pemphigus foliaceus? AB - The human Heat Shock Proteins (HSP70) family plays a key role in up-regulating stress responses. Some studies reported possible associations of single nucleotide polymorphisms in the HSP70 genes with some autoimmune diseases. However, whether HSP70 polymorphisms represent a risk factor for pemphigus foliaceus (PF) is still unkown. We analyzed by PCR-RFLP polymorphisms of HSP70 genes HSA1A, HSPA1B and HSPA1L in 80 Tunisian patients with PF, 160 matched healthy controls and 147 related healthy subjects. There were significant differences between PF patients and controls in the allelic (pc=5.91*10(-12), pc=1.14*10(-5) and pc=0.0089, respectively) and homozygous genotypic frequencies of HSPA1L>T, HSPA1A>C and HSPA1B>G (p=2.617*10(-12), p=1.017*10(-5) and p=0.0058, respectively). Haplotype analysis showed significant differences between PF patients and controls: the CCA, CGA, CCG and CGG haplotypes were significantly over-represented in controls whereas the TCG haplotype was significantly over represented in patients. However, the significant LD found between the HSP70 and the HLA class II susceptibility alleles together with the multivariant regression analysis data between the two loci could argue against a direct role of the HSP70 polymorphism in the occurrence of PF. PMID- 25687738 TI - Prediction of pediatric unipolar depression using multiple neuromorphometric measurements: a pattern classification approach. AB - BACKGROUND: Diagnosis of pediatric neuropsychiatric disorders such as unipolar depression is largely based on clinical judgment - without objective biomarkers to guide diagnostic process and subsequent therapeutic interventions. Neuroimaging studies have previously reported average group-level neuroanatomical differences between patients with pediatric unipolar depression and healthy controls. In the present study, we investigated the utility of multiple neuromorphometric indices in distinguishing pediatric unipolar depression patients from healthy controls at an individual subject level. METHODS: We acquired structural T1-weighted scans from 25 pediatric unipolar depression patients and 26 demographically matched healthy controls. Multiple neuromorphometric indices such as cortical thickness, volume, and cortical folding patterns were obtained. A support vector machine pattern classification model was 'trained' to distinguish individual subjects with pediatric unipolar depression from healthy controls based on multiple neuromorphometric indices and model predictive validity (sensitivity and specificity) calculated. RESULTS: The model correctly identified 40 out of 51 subjects translating to 78.4% accuracy, 76.0% sensitivity and 80.8% specificity, chi-square p-value = 0.000049. Volumetric and cortical folding abnormalities in the right thalamus and right temporal pole respectively were most central in distinguishing individual patients with pediatric unipolar depression from healthy controls. CONCLUSIONS: These findings provide evidence that a support vector machine pattern classification model using multiple neuromorphometric indices may qualify as diagnostic marker for pediatric unipolar depression. In addition, our results identified the most relevant neuromorphometric features in distinguishing PUD patients from healthy controls. PMID- 25687739 TI - Anxiety sensitivity as a mechanism for gender discrepancies in anxiety and mood symptoms. AB - Despite the well-established gender differences in the prevalence of anxiety and depressive disorders, there is a dearth of research looking at sex-linked, variable risk factors that could serve as appropriate intervention targets to ameliorate these discrepancies. One such potential variable risk factor is anxiety sensitivity (AS), or a fear of anxiety related sensations. Studies have established elevated AS in women compared to men, and that AS prospectively predicts the development of anxiety and depressive symptoms. Additionally, research has demonstrated some specificity with regard to the lower-order AS dimensions (physical, cognitive, and social concerns) in relation to symptoms of anxiety and depression. The purpose of the current study was to examine whether overall AS, as well as lower-order AS dimensions, statistically mediate the relations between gender and anxiety and depressive symptoms in a sample of individuals with elevated AS presenting for an AS intervention. Data for the current study were collected from participants (N = 106) at baseline prior to randomization to treatment condition. Results revealed that overall AS statistically mediated the relations between gender and symptoms of anxiety and depression. Significant statistical mediation was also found for AS physical and social concerns for anxiety symptoms, and AS cognitive concerns for depressive symptoms. These results suggest the possible importance of AS in the gender discrepancies in anxiety and depression. Future research should examine whether an AS intervention can help ameliorate this prevalence gap. PMID- 25687740 TI - Neuropeptide discovery in the Araneae (Arthropoda, Chelicerata, Arachnida): elucidation of true spider peptidomes using that of the Western black widow as a reference. AB - The public deposition of large transcriptome shotgun assembly (TSA) datasets for the Araneae (true spiders) provides a resource for determining the structures of the native neuropeptides present in members of this chelicerate order. Here, the Araneae TSA data were mined for putative peptide-encoding transcripts using the recently deduced neuropeptide precursors from the Western black widow Latrodectus hesperus as query templates. Neuropeptide-encoding transcripts from five spiders, Latrodectus tredecimguttatus, Stegodyphus mimosarum, Stegodyphus lineatus, Stegodyphus tentoriicola and Acanthoscurria geniculata, were identified, including ones encoding members of the allatostatin A, allatostatin B, allatostatin C, allatotropin, CAPA/periviscerokinin/pyrokinin, crustacean cardioactive peptide, crustacean hyperglycemic hormone/ion transport peptide, diuretic hormone 31, diuretic hormone 44, eclosion hormone, FMRFamide-like peptide (FLP), GSEFLamide, insulin-like peptide, orcokinin, proctolin, short neuropeptide F, SIFamide, sulfakinin and tachykinin-related peptide (TRP) families. A total of 156 distinct peptides were predicted from the precursor proteins deduced from the S. mimosarum transcripts, with 65, 26, 21 and 12 peptides predicted from those deduced from the A. geniculata, L. tredecimguttatus, S. lineatus and S. tentoriicola sequences, respectively. Among the peptides identified were variant isoforms of FLP, orcokinin and TRP, peptides whose structures are similar to ones previously identified from L. hesperus. The prediction of these atypical peptides from multiple spiders suggests that they may be broadly conserved within the Araneae rather than being species-specific variants. Taken collectively, the data described here greatly expand the number of known Araneae neuropeptides, providing a foundation for future functional studies of peptidergic signaling in this important Chelicerate order. PMID- 25687741 TI - Characterization of the teneurin C-terminal associated peptide (TCAP) in the vase tunicate, Ciona intestinalis: A novel peptide system associated with energy metabolism and reproduction. AB - The vase tunicate, Ciona intestinalis, is a protochordate and is considered a sister lineage to the chordates. The recent sequencing of its genome has made this species a particularly important model to understand the genetic basis of vertebrate evolution. However, C. intestinalis is also a highly invasive species along the Atlantic coast of North America and other regions of the world which have caused considerable economic stress due to its biofouling actions and, in particular, negative impacts on the mussel- and oyster-based aquaculture industry. Despite this background, little is known about C. intestinalis physiology. The teneurin C-terminal associated peptides (TCAP) are a family of highly conserved peptide hormones found in most metazoans. Moreover, these peptides have been implicated in the inhibition of stress and stimulation of feeding-based metabolism. We have, therefore, identified this peptide using an in silico approach and characterized its immunological expression in tissues using a mouse polyclonal antiserum. These data indicate that its primary structure is more similar to invertebrate TCAPs relative to vertebrate TCAPs. Immunological expression indicates that it is highly expressed in the digestive tract and gonads consistent with findings in vertebrates. Synthetic mouse TCAP-1 administered into the brachial basket significantly increases the incidence of non-stress contractile behaviors. These findings support the hypothesis that TCAP is a bioactive peptide in C. intestinalis. Thus, C. intestinalis and tunicates in general may offer a simple model to investigate peptide interaction while providing information on how to control this invasive species. PMID- 25687742 TI - Uncoupling clutch size, prolactin, and luteinizing hormone using experimental egg removal. AB - Clutch size is a key avian fitness and life history trait. A physiological model for clutch size determination (CSD), involving an anti-gonadal effect of prolactin (PRL) via suppression of luteinizing hormone (LH), was proposed over 20 years ago, but has received scant experimental attention since. The few studies looking at a PRL-based mechanistic hypothesis for CSD have been equivocal, but recent experiments utilizing a pharmacological agent to manipulate PRL in the zebra finch (Taeniopygia guttata) found no support for a role of this hormone in clutch size determination. Here, we take a complementary approach by manipulating clutch size through egg removal, examining co-variation in PRL and LH between two breeding attempts, as well as through experimentally-extended laying. Clutch size increased for egg removal females, but not controls, but this was not correlated with changes in PRL or LH. There were also no differences in PRL between egg removal females and controls, nor did PRL levels during early, mid- or late laying of supra-normal clutches predict clutch size. By uncoupling PRL, LH and clutch size in our study, several key predictions of the PRL-based mechanistic model for CSD were not supported. However, a positive correlation between PRL levels late in laying and days relative to the last egg (clutch completion) provides an alternative explanation for the equivocal results surrounding the conventional PRL-based physiological model for CSD. We suggest that females coordinate PRL-mediated incubation onset with clutch completion to minimize hatching asynchrony and sibling hierarchy, a behavior that is amplified in females laying larger clutches. PMID- 25687743 TI - No difference in small bowel microbiota between patients with irritable bowel syndrome and healthy controls. AB - Several studies have indicated that colonic microbiota may exhibit important differences between patients with irritable bowel syndrome (IBS) and healthy controls. Less is known about the microbiota of the small bowel. We used massive parallel sequencing to explore the composition of small bowel mucosa-associated microbiota in patients with IBS and healthy controls. We analysed capsule biopsies from the jejunum of 35 patients (26 females) with IBS aged 18-(36)-57 years and 16 healthy volunteers (11 females) aged 20-(32)-48 years. Sequences were analysed based on taxonomic classification. The phyla with the highest total abundance across all samples were: Firmicutes (43%), Proteobacteria (23%), Bacteroidetes (15%), Actinobacteria (9.3%) and Fusobacteria (7.0%). The most abundant genera were: Streptococcus (19%), Veillonella (13%), Prevotella (12%), Rothia (6.4%), Haemophilus (5.7%), Actinobacillus (5.5%), Escherichia (4.6%) and Fusobacterium (4.3%). We found no difference among major phyla or genera between patients with IBS and controls. We identified a cluster of samples in the small bowel microbiota dominated by Prevotella, which may represent a common enterotype of the upper small intestine. The remaining samples formed a gradient, dominated by Streptococcus at one end and Escherichia at the other. PMID- 25687744 TI - Interatrial septum puncture in an atypical scenario. PMID- 25687745 TI - How adequate are the current methods of lead extraction? A review of the efficiency and safety of transvenous lead extraction methods. AB - Currently several extraction tools are available in order to allow safe and successful transvenous lead extraction (TLE) of pacemaker and ICD leads; however, no directives exist to guide physicians in their choice of extraction tools and approaches. To aim of the current review is to provide an overview of the success and complication rates of different extraction methods and tools available. A comprehensive search of all published literature was conducted in the databases of PubMed, Embase, Web of Science, and Central. Included papers were original articles describing a specific method of TLE and the corresponding success rates of at least 50 patients. Fifty-three studies were included; the majority (56%) utilized 2 (1-4) different venous extraction approaches (subclavian and femoral), the median number of extraction tools used was 3 (1-6). A stepwise approach was utilized in the majority of the studies, starting with simple traction which resulted in successful TLE in 7-85% of the leads. When applicable the procedure was continued with non-powered tools resulting in a successful extraction of 34 87% leads. Subsequently, powered tools were applied whereby success rates further increased to 74-100%. The final step in TLE was usually utilized by femoral snare leading to an overall TLE success rate of 96-100%. The median procedure-related mortality and major complication described were, respectively, 0% (0-3%) and 1% (0-7%) per patient. In conclusion, a stepwise extraction approach can result in a clinical successful TLE in up to 100% of the leads with a relatively low risk of procedure-related mortality and complications. PMID- 25687746 TI - Clinical course and prognostic relevance of antitachycardia pacing-terminated ventricular tachyarrhythmias in implantable cardioverter-defibrillator patients. AB - AIMS: In patients with an implantable cardioverter-defibrillator (ICD), ICD shocks due to ventricular tachycardia (VT) or ventricular fibrillation (VF) have been associated with an increased mortality. It is not known whether patients with antitachycardia pacing (ATP)-terminated VT/VF episodes have a similar worse outcome. The aim of this study was to evaluate the clinical course and prognostic impact of ATP-terminated episodes on mortality in ICD patients. METHODS AND RESULTS: A total of 1398 consecutive patients of the prospective single-centre ICD-registry Ludwigshafen who underwent an ICD implantation between 1992 and 2008 for primary or secondary prevention of sudden cardiac death were analysed. Patients treated with ATP were compared with patients with appropriate ICD shocks or patients without any appropriate ATP or ICD shock. During the median follow-up time of 6 years, 749 (54%) patients experienced 17 827 episodes of VT or VF which were terminated by ATP in 74% and by shock in 26% of patients. In approximately half (n = 321/749) of those patients with VT/VF, the first episode was terminated by ATP. In a multivariate analysis adjusted for different baseline confounding parameters, the occurrence of first ATP therapy was associated with a higher mortality rate [hazard ratio (HR) 2.60, 95% confidence interval (CI) 2.02-3.35]. When excluding all patients with appropriate ICD shocks first ATP therapy remained associated with a worse prognosis (HR 1.92, 95% CI 1.38-2.67). CONCLUSIONS: In ICD patients, about three-fourths of ventricular arrhythmias are terminated by ATP. The occurrence of ATP-terminated episode is associated with an increased mortality rate. PMID- 25687747 TI - Early pulmonary vein reconnection as a predictor of left atrial ablation outcomes for paroxysmal atrial fibrillation. AB - AIM: The objective of the study was to investigate whether early pulmonary vein reconnection (PVR) is a predictor of late arrhythmia recurrence after a single ablation procedure for paroxysmal atrial fibrillation (AF). Further ablation was delivered to patients with acute PVR to test whether this strategy could reduce recurrences. METHODS AND RESULTS: One hundred and forty-four consecutive patients with symptomatic, drug-refractory paroxysmal AF, undergoing pulmonary vein isolation (PVI), were assigned to the 'PVR30 test' group, where PVR was monitored for 30 min after initial PVI and further ablation was applied if needed, and compared with a control group of 128 patients, where the procedure was terminated after initial successful isolation. During a mean follow-up of 17.7 months, sinus rhythm was maintained in 101 patients in the 'PVR30 test' group (70.1%) vs. 78 in the control group (60.9%) (P = 0.13). Among patients with acute PVR and reablation after 30 min, the recurrence rate was 45.3 vs. 39.1% in the control group (P = 0.47). Multivariable logistic regression analysis showed that PVR was independently associated with AF recurrence (adjusted hazard ratio 4.7, 95% confidence interval 1.8-12.2), along with left atrial diameter (adjusted hazard ratio 1.3/mm of higher diameter, 95% confidence interval 1.2-1.4). CONCLUSION: In patients with paroxysmal AF undergoing a single ablation procedure, PVR 30 min after the initial PVI is associated with late AF recurrence. However, the strategy of 30 min waiting and reablating does not appear to be superior to immediate termination of the procedure after initial PVI. PMID- 25687748 TI - A randomized prospective mechanistic cardiac magnetic resonance study correlating catheter stability, late gadolinium enhancement and 3 year clinical outcomes in robotically assisted vs. standard catheter ablation. AB - AIMS: To prospectively compare cardiac magnetic resonance late gadolinium enhancement (LGE) findings created by standard vs. robotically assisted catheter ablation lesions and correlate these with clinical outcomes. METHODS AND RESULTS: Forty paroxysmal atrial fibrillation patients (mean age 54 +/- 13.8 years) undergoing first left atrial ablation were randomized to either robotic-assisted navigation (Hansen Sensei((r)) X) or standard navigation. Pre-procedural, acute (24 h post-procedure) and late (beyond 3 months) scans were performed with LGE and T2W imaging sequences and percentage circumferential enhancement around the pulmonary vein (PV) antra were quantified. Baseline pre-procedural enhancements were similar in both groups. On acute imaging, mean % encirclements by LGE and T2W signal were 72% and 80% in the robotic group vs. 60% (P = 0.002) and 76%(P = 0.45) for standard ablation. On late imaging, the T2W signal resolved to baseline in both groups. Late gadolinium enhancement remained the predominant signal with 56% encirclement in the robotic group vs. 45% in the standard group (P = 0.04). At 6 months follow-up, arrhythmia-free patients had an almost similar mean LGE encirclement (robotic 64%, standard 60%, P = 0.45) but in recurrences, LGE was higher in the robotic group (43% vs. 30%, P = 0.001). At mean 3 years follow-up, 1.3 procedures were performed in the robotic group compared with 1.9 (P < 0.001) in the standard to achieve a success rate of 80% vs. 75%. CONCLUSION: Robotically assisted ablation results in greater LGE around the PV antrum. Effective lesions created through improved catheter stability and contact force during initial treatment may have a role in reducing subsequent re-do procedures. PMID- 25687749 TI - Magnetic resonance imaging in patients with a subcutaneous implantable cardioverter-defibrillator. AB - AIMS: Our aim was to evaluate the potential for safely imaging patients with a new type of implantable cardioverter-defibrillator called the subcutaneous implantable cardioverter-defibrillator (S-ICD) in a 1.5 T magnetic resonance imaging (MRI) scanner. With the increasing number of patients with cardiac implantable devices who are indicated for MRI, there is a growing need for establishing MRI compatibility of cardiac implantable devices. METHODS AND RESULTS: Patients with implanted S-ICD systems underwent one or more types of anatomical MRI scans. The S-ICD was programmed off and patients were monitored throughout the imaging procedure. Device function was evaluated pre- and post scan. Patients were asked to report immediately any pain, torqueing movement, or heating sensation in the area of the pocket or electrode. Fifteen patients underwent a total of 22 examinations at 1.5 T. Scans included brain, spine, knee, and heart. Two patients were re-scanned due to complaints of heating over the can during lumbar scans, which was caused by a thermistor probe placed on the skin to measure skin temperature. All the remaining scans occurred without incident. No evidence of device malfunction was observed. CONCLUSION: This study is the first to domonstrate the feasibility of exposing S-ICD patients to MRI using the scanning and monitoring protocol described. More data are required to support S ICD as a MRI conditional device. PMID- 25687750 TI - Corticosteroids for parasitic eosinophilic meningitis. AB - BACKGROUND: Angiostrongylus cantonensis (A. cantonensis) is the major cause of infectious eosinophilic meningitis. Dead larvae of this parasite cause inflammation and exacerbate symptoms of meningitis. Corticosteroids are drugs used to reduce the inflammation caused by this parasite. OBJECTIVES: To assess the efficacy and safety of corticosteroids for the treatment of eosinophilic meningitis. SEARCH METHODS: We searched CENTRAL (2014, Issue 11), MEDLINE (1950 to November Week 3, 2014), EMBASE (1974 to December 2014), Scopus (1960 to December 2014), Web of Science (1955 to December 2014), LILACS (1982 to December 2014) and CINAHL (1981 to December 2014). SELECTION CRITERIA: Randomised controlled trials (RCTs) of corticosteroids versus placebo for eosinophilic meningitis. DATA COLLECTION AND ANALYSIS: Two review authors (SiT, SaT) independently collected and extracted study data. We graded the methodological quality of the RCTs. We identified and analysed outcomes and adverse effects. MAIN RESULTS: We did not identifiy any new trials for inclusion or exclusion in this 2014 update. One study involving 110 participants (55 participants in each group) met our inclusion criteria. The corticosteroid (prednisolone) showed a benefit in shortening the median time to resolution of headaches (five days in the treatment group versus 13 days in the control group, P value < 0.0001). Corticosteroids were also associated with smaller numbers of participants who still had headaches after a two-week course of treatment (9.1% versus 45.5%, P value < 0.0001). The number of patients who needed repeat lumbar puncture was also smaller in the treatment group (12.7% versus 40%, P value = 0.002). There was a reduction in the median time of analgesic use in participants receiving corticosteroids (10.5 versus 25.0, P value = 0.038). There were no reported adverse effects from prednisolone in the treatment group. AUTHORS' CONCLUSIONS: Corticosteroids significantly help relieve headache in patients with eosinophilic meningitis, who have a pain score of four or more on a visual analogue scale. However, there is only one RCT supporting this benefit and this trial did not clearly mention allocation concealment and stratification. Therefore, we agreed to grade our included study as a moderate quality trial. Future well-designed RCTs are necessary. PMID- 25687751 TI - Pharmaceutical aspects of anti-inflammatory TNF-blocking drugs. AB - Tumor necrosis factor (TNF) is a key regulator of inflammatory processes in several immune-mediated inflammatory diseases such as rheumatoid arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, psoriasis and psoriatic arthritis. Inactivating TNF has been found to be a plausible approach in treating these conditions. Two major strategies have been adopted by scientists to inactivate TNF: one is to use monoclonal antibodies (mAbs) that bind to TNF, and the other is to use fusion proteins that bind to TNF, both inactivate TNF and help to prevent TNF-mediated inflammatory processes. Monoclonal antibodies (mAbs) are biological products that selectively bind to specific antigen molecules, and fusion proteins are soluble receptors that bind to TNF. These types of drugs are generally known as biologics and there has been an explosion in the development and testing of biologics since the 1994 US approval and launch of abciximab, a mAb that binds to GPIIb/IIIa on platelets. Anti-TNF drugs that are currently approved by FDA for treating inflammatory conditions include adalimumab, certolizumab pegol, golimumab, infliximab and etanercept. Since these agents are complex protein molecules, the pharmacodynamics and pharmacokinetics of these drugs are different from small molecule anti-inflammatory agents. This review focuses on the pharmaceutical aspects of these drugs such as mechanism of action, adverse effects, pharmacokinetics and drug interactions. An effort was also taken to compare the pharmacodynamics and pharmacokinetic properties of these drugs, with the available data at this time. PMID- 25687752 TI - Immortalization and characterization of human dental mesenchymal cells. AB - OBJECTIVES: Due to the rarity of human embryonic samples and limited proliferating capability of primary human dental mesenchymal cells, it is valuable to create an immortalized human dental mesenchymal cell line for studying dental mesenchymal cell differentiation and signalling pathways during dentinogenesis in humans. METHODS: In this study, dental mesenchymal cells from human molar tooth germs at 19-week gestation were isolated and immortalized with pSV40. Single cell colonies were then selected by 96-well plate dilution. The immortalized cell line was characterized using immunofluorescent microscopy, RT PCR and Western blot for the expression of SV40 large T antigen and five genes specific for the mesenchymal stage during tooth development. The differentiation and mineralization activities of the immortalized and primary cells were compared using adipogenic and calcifying induction. RESULTS: The immortalized dental mesenchymal cell line displayed a higher proliferation rate, expressed several tooth-specific markers including Msx1, Pax9, Lhx6, Barx1, and Runx2, and maintained the ability to differentiate and form mineralized nodules. CONCLUSIONS: Our results demonstrated that the immortalized human mesenchymal cell line retained the characteristics similar to primary human dental mesenchymal cells and can be used for studying the mechanisms of human dental mesenchymal cell differentiation and signalling pathways involved in human odontogenesis. PMID- 25687753 TI - Essential need for research in hepatitis C. PMID- 25687754 TI - The polymeric mucin Muc5ac is required for allergic airway hyperreactivity. AB - In asthma, airflow obstruction is thought to result primarily from inflammation triggered airway smooth muscle (ASM) contraction. However, anti-inflammatory and smooth muscle-relaxing treatments are often temporary or ineffective. Overproduction of the mucin MUC5AC is an additional disease feature that, while strongly associated pathologically, is poorly understood functionally. Here we show that Muc5ac is a central effector of allergic inflammation that is required for airway hyperreactivity (AHR) to methacholine (MCh). In mice bred on two well characterized strain backgrounds (C57BL/6 and BALB/c) and exposed to two separate allergic stimuli (ovalbumin and Aspergillus extract), genetic removal of Muc5ac abolishes AHR. Residual MCh responses are identical to unchallenged controls, and although inflammation remains intact, heterogeneous mucous occlusion decreases by 74%. Thus, whereas inflammatory effects on ASM alone are insufficient for AHR, Muc5ac-mediated plugging is an essential mechanism. Inhibiting MUC5AC may be effective for treating asthma and other lung diseases where it is also overproduced. PMID- 25687755 TI - Protein kinase calpha regulates the expression of complement receptor Ig in human monocyte-derived macrophages. AB - The complement receptor Ig (CRIg) is selectively expressed by macrophages. This receptor not only promotes the rapid phagocytosis of bacteria by macrophages but also has anti-inflammatory and immunosuppressive functions. Previous findings have suggested that protein kinase C (PKC) may be involved in the regulation of CRIg expression in human macrophages. We have now examined the role of PKCalpha in CRIg expression in human monocyte-derived macrophages (MDM). Macrophages nucleofected with plasmid containing short hairpin RNA against PKCalpha showed markedly reduced expression of PKCalpha, but normal PKCzeta expression, by Western blotting analysis, and vice versa. PKCalpha-deficient MDM showed increased expression of CRIg mRNA and protein (both the long and short form), an increase in phagocytosis of complement-opsonized Candida albicans, and decreased production of TNF-alpha and IL-6. TNF-alpha caused a marked decrease in CRIg expression, and addition of anti-TNF mAb to the TNF-alpha-producing MDMs increased CRIg expression. PKCalpha-deficient macrophages also showed significantly less bacterial LPS-induced downregulation of CRIg. In contrast, cells deficient in PKCalpha showed decreased expression of CR type 3 (CR3) and decreased production of TNF-alpha and IL-6 in response to LPS. MDM developed under conditions that increased expression of CRIg over CR3 showed significantly reduced production of TNF-alpha in response to opsonized C. albicans. The findings indicate that PKCalpha promotes the downregulation of CRIg and upregulation of CR3 expression and TNF-alpha and IL-6 production, a mechanism that may promote inflammation. PMID- 25687756 TI - SHIP1 intrinsically regulates NK cell signaling and education, resulting in tolerance of an MHC class I-mismatched bone marrow graft in mice. AB - NK cells are an important component of host immune defense against malignancy and infection. NK cells are educated by MHC class I ligands to ensure self-tolerance while also promoting lytic competency against altered self and damaged self targets. However, the intracellular molecular events that culminate in tolerance and functional competency of educated NK cells remain undefined. Mice with germline deficiency in SHIP1 were shown to have a defective NK cell compartment. However, SHIP1 is expressed in all hematopoietic lineages, and consequently several hematolymphoid phenotypes have already been identified in certain cell types that are the result of SHIP1 deficiency in cells in separate and distinct lineages, that is, cell-extrinsic phenotypes. Thus, it was previously impossible to determine the NK cell-intrinsic role of SHIP1. In the present study, through the creation of an NK cell-specific deletion mouse model of SHIP1, we show that SHIP1 plays a profound NK lineage-intrinsic role in NK cell homeostasis, development, education, and cytokine production. Moreover, we show SHIP1 expression by NK cells is required for in vivo-mismatched bone marrow allograft rejection as well as for NK memory responses to hapten. PMID- 25687757 TI - Differential roles for Bim and Nur77 in thymocyte clonal deletion induced by ubiquitous self-antigen. AB - Negative selection, primarily mediated through clonal deletion of self-reactive thymocytes, is critical for establishing self-tolerance and preventing autoimmunity. Recent studies suggest that the molecular mechanisms of negative selection differ depending on the thymic compartment and developmental stage at which thymocytes are deleted. Using the physiological HY(cd4) TCR transgenic model of negative selection against ubiquitous self-antigen, we previously found that one of the principal mediators implicated in clonal deletion, Bim, is required for caspase-3 activation but is ultimately dispensable for negative selection. On the basis of these data, we hypothesized that Nur77, another molecule thought to be a key mediator of clonal deletion, could be responsible for Bim-independent deletion. Despite comparable Nur77 induction in thymocytes during negative selection, Bim deficiency resulted in an accumulation of high affinity-signaled thymocytes as well as impairment in caspase-mediated and caspase-independent cell death. Although these data suggested that Bim may be required for Nur77-mediated cell death, we found that transgenic Nur77 expression was sufficient to induce apoptosis independently of Bim. However, transgenic Nur77-induced apoptosis was significantly inhibited in the context of TCR signaling, suggesting that endogenous Nur77 could be similarly regulated during negative selection. Although Nur77 deficiency alone did not alter positive or negative selection, combined deficiency in Bim and Nur77 impaired clonal deletion efficiency and significantly increased positive selection efficiency. Collectively, these data shed light on the different roles for Bim and Nur77 during ubiquitous Ag-mediated clonal deletion and highlight potential differences from their reported roles in tissue-restricted Ag-mediated clonal deletion. PMID- 25687758 TI - PRL-3 mediates the protein maturation of ULBP2 by regulating the tyrosine phosphorylation of HSP60. AB - Many malignant cells release the NKG2D ligand ULBP2 from their cell surface to evade immunosurveillance by NK cells and CD8 T cells. Although the shedding mechanism remains unclear, various inhibitors of matrix metalloproteinases have been shown to efficiently block the release of soluble ULBP2. The clinical use of these inhibitors, however, is limited because of adverse side effects. Using high throughput screening technique, we identified a specific inhibitor of phosphatase of regenerating liver 3 (PRL-3) that could reduce the level of soluble ULBP2 in the culture supernatant of various cancer cell lines. Inhibition or gene knockdown of PRL-3 did not reduce ULBP2 shedding, but rather suppressed posttranslational maturation of ULBP2, resulting in intracellular retention of immature ULBP2. We then found that ULBP2 was constitutively associated with heat shock protein HSP60. Complete maturation of ULBP2 required tyrosine phosphorylation of HSP60 which was mediated by PRL-3. PMID- 25687759 TI - Transient blockade of delta-like Notch ligands prevents allograft rejection mediated by cellular and humoral mechanisms in a mouse model of heart transplantation. AB - Rejection remains a major clinical challenge limiting allograft survival after solid organ transplantation. Both cellular and humoral immunity contribute to this complication, with increased recognition of Ab-mediated damage during acute and chronic rejection. Using a mouse model of MHC-mismatched heart transplantation, we report markedly protective effects of Notch inhibition, dampening both T cell and Ab-driven rejection. T cell-specific pan-Notch blockade prolonged heart allograft survival and decreased IFN-gamma and IL-4 production by alloreactive T cells, especially when combined with depletion of recipient CD8(+) T cells. These effects were associated with decreased infiltration by conventional T cells and an increased proportion of regulatory T cells in the graft. Transient administration of neutralizing Abs specific for delta-like (Dll)1/4 Notch ligands in the peritransplant period led to prolonged acceptance of allogeneic hearts, with superior outcome over Notch inhibition only in T cells. Systemic Dll1/4 inhibition decreased T cell cytokines and graft infiltration, germinal center B cell and plasmablast numbers, as well as production of donor-specific alloantibodies and complement deposition in the transplanted hearts. Dll1 or Dll4 inhibition alone provided partial protection. Thus, pathogenic signals delivered by Dll1/4 Notch ligands early after transplantation promote organ rejection through several complementary mechanisms. Transient interruption of these signals represents an attractive new therapeutic strategy to enhance long-term allograft survival. PMID- 25687760 TI - Histone lysine methyltransferase Ezh1 promotes TLR-triggered inflammatory cytokine production by suppressing Tollip. AB - Histone modifications play critical roles in the regulation of gene expression; however, their roles in the regulation of the innate response remain to be fully investigated. Using transcriptome analysis of mouse immature dendritic cells (DCs) and LPS-induced mature DCs, we identified that Ezh1 was the most upregulated histone methyltransferase during DC maturation. In this study, we investigated the role of Ezh1 in regulating the innate immune response. We found that silencing of Ezh1 significantly suppressed TLR-triggered production of cytokines, including IL-6, TNF-alpha, and IFN-beta, in DCs and macrophages. Accordingly, TLR-activated signaling pathways were impaired in Ezh1-silenced macrophages. By transcriptome analysis of Ezh1-silenced macrophages, we found that Toll-interacting protein (Tollip), one well-known negative regulator of TLR signaling, was upregulated. Silencing of Tollip rescued TLR-triggered cytokine production in Ezh1-silenced macrophages. The SET domain of Ezh1 is essential for its enhancing effect on the TLR-triggered innate immune response and downstream signaling, indicating that Ezh1 promotes a TLR-triggered innate response through its lysine methyltransferase activity. Finally, Ezh1 was found to suppress the transcription of Tollip by directly targeting the proximal promoter of tollip and maintaining the high level of trimethylation of histone H3 lysine 27 there. Therefore, Ezh1 promotes TLR-triggered inflammatory cytokine production by suppressing the TLR negative regulator Tollip, contributing to full activation of the innate immune response against invading pathogens. PMID- 25687761 TI - Small angle X-ray scattering analysis of Cu(2+)-induced oligomers of the Alzheimer's amyloid beta peptide. AB - Research into causes of Alzheimer's disease and its treatment has produced a tantalising array of hypotheses about the role of transition metal dyshomeostasis, many of them on the interaction of these metals with the neurotoxic amyloid-beta peptide (Abeta). Here, we have used small angle X-ray scattering (SAXS) to study the effect of the molar ratio, Cu(2+)/Abeta, on the early three-dimensional structures of the Abeta1-40 and Cu(2+)/Abeta1-42 peptides in solution. We found that at molar ratios of 0.5 copper to peptide Abeta1-40 aggregated, while Abeta1-42 adopted a relatively monodisperse cylindrical shape, and at a ratio of 1.5 copper to peptide Abeta1-40 adopted a monodisperse cylindrical shape, while Abeta1-42 adopted the shape of an ellipsoid of rotation. We also found, via in-line rapid mixing SAXS analysis, that both peptides in the absence of copper were monodisperse at very short timeframes (<2 s). Kratky plots of these scattering profiles indicated that immediately after mixing both were intrinsically disordered. Ensemble optimisation modelling reflected this, indicating a wide range of structural conformers. These data reflect the ensembles from which the Cu(2+)-promoted oligomers were derived. Our results are discussed in the light of other studies that have shown that the Cu(2+)/Abeta has a marked effect on fibril and oligomer formation by this peptide, with a higher ratio favouring the formation of cytotoxic non-amyloid oligomers. Our results are relatively consistent with previous two-dimensional studies of the conformations of these Cu(2+)-induced entities, made on a much longer time-scale than SAXS, by transmission electron microscopy and atomic force microscopy, which showed that a range of oligomeric species are formed. We propose that SAXS carried out on a modern synchrotron beamline enables studies on initial events in disordered protein folding on physiologically-relevant time-scales, and will likely provide great insight into the initiating processes of the Abeta misfolding, oligomerisation and amyloid formation. PMID- 25687762 TI - Characterization of N2O emission and associated bacterial communities from the gut of wood-feeding termite Nasutitermes voeltzkowi. AB - Xylophagous termites rely on nitrogen deficient foodstuff with a low C/N ratio. Most research work has focused on nitrogen fixation in termites highlighting important inflow and assimilation of atmospheric nitrogen into their bodies fundamentally geared up by their intestinal microbial symbionts. Most of termite body nitrogen is of atmospheric origin, and microbially aided nitrification is the principal source of this nitrogen acquisition, but contrarily, the information regarding potent denitrification process is very scarce and poorly known, although the termite gut is considered to carry all favorable criteria necessary for microbial denitrification. Therefore, in this study, it is hypothesized that whether nitrification and denitrification processes coexist in intestinal milieu of xylophagous termites or not, and if yes, then is there any link between the denitrification product, i.e., N2O and nitrogen content of the food substrate, and moreover where these bacterial communities are found along the length of termite gut. To answer these questions, we measured in vivo N2O emission by Nasutitermes voeltzkowi (Nasutitermitinae) maintained on different substrates with varying C/N ratio, and also, molecular techniques were applied to study the diversity (DGGE) and density (qPCR) of bacterial communities in anterior and posterior gut portions. Rersults revealed that xylophagous termites emit feeble amount of N2O and molecular studies confirmed this finding by illustrating the presence of an ample density of N2O-reductase (nosZ) gene in the intestinal tract of these termites. Furthermore, intestinal bacterial communities of these termites were found more dense and diverse in posterior than anterior portion of the gut. PMID- 25687763 TI - Invited commentary on comparison of robotics, functional electrical stimulation, and motor learning methods for treatment of persistent upper extremity dysfunction after stroke: a randomized controlled trial. AB - In this issue of Archives of Physical Medicine and Rehabilitation, Jessica McCabe and colleagues report findings from their methodologically sound, dose-matched clinical trial in 39 patients beyond 6 months poststroke. In this phase II trial, the effects of 60 treatment sessions, each involving 3.5 hours of intensive practice plus either 1.5 hours of functional electrical stimulation (FES) or a shoulder-arm robotic therapy, were compared with 5 hours of intensive daily practice alone. Although no significant between-group differences were found on the primary outcome measure of Arm Motor Ability Test and the secondary outcome measure of Fugl-Meyer Arm motor score, 10% to 15% within-group therapeutic gains were on the Arm Motor Ability Test and Fugl-Meyer Arm. These gains are clinically meaningful for patients with stroke. However, the underlying mechanisms that drive these improvements remain poorly understood. The approximately $1000 cost reduction per patient calculated for the use of motor learning (ML) methods alone or combined with FES, compared with the combination of ML and shoulder-arm robotics, further emphasizes the need for cost considerations when making clinical decisions about selecting the most appropriate therapy for the upper paretic limb in patients with chronic stroke. PMID- 25687764 TI - Attachment of Water and Alcohol Molecules onto Water and Alcohol Clusters. AB - Absolute attachment cross sections of single molecules M (M = water, ethanol, or methanol) onto positively charged mass-selected clusters XnH(+) (X = water, ethanol, or methanol) were measured for cluster sizes ranging from tens to hundreds of molecules and center-of-mass collision energies varying from 0.1 to ~1 eV. The attachment cross sections, which converge as expected toward geometrical cross sections at large cluster sizes, are systematically and noticeably lower than geometrical cross sections at small sizes. Attachment cross sections depend barely on the nature of the reactants. Homogeneous attachment reactions XnH(+) + X -> Xn+1H(+) can be accounted for by a dynamical collisional model, in which the intermolecular interactions between the target cluster and the impinging molecule can be neglected. Dynamical arguments account satisfactorily for size and energy dependences of attachment cross sections and also for their variation from one element to another. It is thus suggested that either the attachment probabilities are likely to be more governed by the capacity of clusters to absorb collision energy rather than by cluster/molecule intermolecular interactions, or it indicates that the strength of these interactions does not differ noticeably among the hydrogen-bonded systems investigated. However, for inhomogeneous reactions of the form XnH(+) + Y -> XnYH(+) (X, Y = water, ethanol, methanol), although the global size dependences are qualitatively reproduced, the variations of attachment cross sections with the nature on the impinging molecule are not satisfactorily accounted for within the simple empirical model proposed for homogeneous reactions. PMID- 25687765 TI - Structure based virtual screening to identify selective phosphodiesterase 4B inhibitors. AB - Phosphodiesterase 4 (PDE4), is a hydrolytic enzyme, is proposed as a promising target in asthma and chronic obstructive pulmonary disease. PDE4B selective inhibitors are desirable to reduce the dose limiting adverse effect associated with non-selective PDE4B inhibitors. To achieve this goal, ligand based pharmacophore modeling and molecular docking approach is employed. Pharmacophore hypotheses for PDE4B and PDE4D are generated using HypoGen algorithm. The best PDE4B pharmacophore hypothesis (Hypo1_PDE4B) consist of one hydrogen-bond acceptor and two ring aromatic features, whereas PDE4D pharmacophore hypothesis (Hypo1_PDE4D) consist of one hydrogen-bond acceptor, one hydrophobic aliphatic, and two ring aromatic features. The validated pharmacophore hypotheses are used in virtual screening to identify selective PDE4B inhibitors. The hits were screened for their estimated activity, FitValue, and quantitative estimation of drug likeness. After molecular docking analysis, ten hits were purchased for in vitro analysis. Out of these, six hits have shown potent and selective inhibitory activity against PDE4B with IC50 values ranging from 2 to 378nM. PMID- 25687766 TI - A cluster of person-to-person transmission cases caused by SFTS virus in Penglai, China. AB - An emerging infectious disease, severe fever with thrombocytopenia syndrome (SFTS), was identified to be associated with a novel SFTS virus (SFTSV). Transmission of the disease among humans has been described, but clinical impact factors and transmission mechanisms still need further study. An outbreak of person-to-person transmission of SFTS in a cluster of nine patients that occurred in an SFTS endemic area, Penglai County, Shandong province, China, was investigated. We found that the onset date of all eight secondary SFTS patients ranged from 7 to 13 days after exposure to the corpse of the index patient, and clinical incubation time was mostly focused on 9-10 days (n = 6). The two dead patients, including the index patient and one secondary infected patient, presented unusually high levels of viral load (6 * 10(8-9) copies/mL), low levels of platelets count (<55 * 10(9)/L), and significant increase of alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, and creatine kinase values in the second week, and died on day 10 or 11 after disease onset. Genetic sequencing revealed 100% homology among virus strains isolated from the index patient and five secondary patients. Risk factors assessment of the person to-person transmission revealed that the major exposure factor was blood contact without personal protection equipment. Information from this study provided solid references of SFTS incubation time, clinical and laboratory parameters related to SFTS severity and outcome, and biosafety issues for preventing person-to-person transmission or nosocomial infection of SFTSV. PMID- 25687767 TI - Combined oral supplementation of fish oil and quercetin enhances neuroprotection in a chronic rotenone rat model: relevance to Parkinson's disease. AB - While the neuromodulatory efficacy of n-3 polyunsaturated fatty acids present in fish and fish oil (FO) are well known, some evidence in animal models suggests that chronic consumption of FO supplements may predispose the brain to lipid peroxidation. In view of this, recent approaches envisage the use of dietary antioxidants as adjuncts with FO to obtain a better clinical outcome in neurological disorders. In furtherance of our previous work, in the present study, we examined whether enrichment of FO with quercetin (Q) would enhance the neuroprotective outcome employing a chronic rotenone (ROT) model of neurotoxicity in rats. Growing male rats supplemented either with FO (2 mL/kg bw) or Q (25 mg/kg bw) or FO + Q for 28 days were administered with ROT (0.5 mg/kg bw, 21 days). Monitoring the behavioral phenotype by a battery of tests, terminally, oxidative response in brain regions, mitochondrial dysfunctions and striatal dopamine levels were determined. While both FO and Q offered varying degree of protection, the FO + Q combination offered a higher degree of protection. FO + Q combination significantly attenuated behavioral impairments, restored the ROT induced oxidative markers, depleted dopamine levels in striatum and reduced mitochondrial dysfunction. These salient findings besides corroborating with our previous data suggest that enrichment of FO with Q indeed offers a higher degree of neuroprotection under chronic exposure to a model neurotoxin such as ROT. Hence, we propose that a combination of FO with known antioxidants such as quercetin is more likely to provide a superior therapeutic advantage in the prevention/treatment of oxidative stress-mediated neurodegenerative conditions such as Parkinson's disease. PMID- 25687768 TI - The association between temporomandibular disorders and joint hypermobility syndrome: a nationwide population-based study. AB - OBJECTIVES: This study aims to investigate the risk factors of temporomandibular disorders (TMDs), including disc or non-disc-related disorders, and joint hypermobility syndrome (JHS) retrospectively and to analyze the factors by estimating the magnitude of the association between the two conditions using a nationwide population-based dataset. MATERIALS AND METHODS: A total of 975,788 eligible patients' de-identified data were obtained from a representative database composed of one million of Taiwan's population since 2004 to 2008. All associated factors, such as gender, age, facial trauma, and psychosis, which correlated with TMDs and JHS were examined. Multiple logistic regression modeling adjusted for confounding variables to determine the odds ratio of variables that made an important contribution to TMDs and JHS. RESULTS: For all TMDs patients, only 1.47% patients had disc-related disorders. For all JHS patients, only 3.85% patients are diagnosed with concomitant TMDs. Statistically significant association was observed between joint hypermobility and TMDs. Furthermore, the prevalence of JHS patients shows significant difference within TMD subgroups, in which 9.52% of JHS patients have disc disorders and 90.48% of JHS patients do not. All associated factors, such as gender, age, JHS, facial trauma, and psychosis, had a significant impact on the TMDs. Interestingly, patients with TMJ articular disc disorders are 6.7 times more likely to be diagnosed with JHS compared to patients without disc-related disorders. CONCLUSIONS: Our results confirm that there is a significant positive association between TMDs and JHS, highlighting that patients with disc-related TMDs are more likely to experience JHS than patients with TMDs without disc disorders. CLINICAL RELEVANCE: Individuals with TMD associated with JHS should be carefully evaluated by inter disciplinary specialists as these factors may eventually have impact on the prognosis of TMDs and JHS. PMID- 25687769 TI - Effects of strain artefacts arising from a pre-defined callus domain in models of bone healing mechanobiology. AB - Iterative computational models have been used to investigate the regulation of bone fracture healing by local mechanical conditions. Although their predictions replicate some mechanical responses and histological features, they do not typically reproduce the predominantly radial hard callus growth pattern observed in larger mammals. We hypothesised that this discrepancy results from an artefact of the models' initial geometry. Using axisymmetric finite element models, we demonstrated that pre-defining a field of soft tissue in which callus may develop introduces high deviatoric strains in the periosteal region adjacent to the fracture. These bone-inhibiting strains are not present when the initial soft tissue is confined to a thin periosteal layer. As observed in previous healing models, tissue differentiation algorithms regulated by deviatoric strain predicted hard callus forming remotely and growing towards the fracture. While dilatational strain regulation allowed early bone formation closer to the fracture, hard callus still formed initially over a broad area, rather than expanding over time. Modelling callus growth from a thin periosteal layer successfully predicted the initiation of hard callus growth close to the fracture site. However, these models were still susceptible to elevated deviatoric strains in the soft tissues at the edge of the hard callus. Our study highlights the importance of the initial soft tissue geometry used for finite element models of fracture healing. If this cannot be defined accurately, alternative mechanisms for the prediction of early callus development should be investigated. PMID- 25687770 TI - Impact of environmental air pollutants on disease control in asmathic patients. AB - PURPOSE: Asthmatics are adversely affected by the presence of air pollutants, the concentrations of which can nowadays be measured. However, the utility of this information in clinical practice has not been defined in a group of asthmatics in stable condition. Our objective was to determine what impact the level of air pollutants had on the control of their asthma and the degree of airway inflammation. METHODS: We performed a cross-sectional study of adult asthmatics in stable condition. From the regional environmental authority, we obtained the concentrations of ambient nitric oxide (NO2), ozone (O3), suspended particulate matter up to 10 micrometers in diameter (PM10) and sulphur dioxide (SO2) at fixed geographical points. Disease control was assessed using asthma control test (ACT) scores, and airway inflammation using fraction of exhaled nitric oxide (FeNO) values. Correlation and linear regression studies were performed using ACT scores as the dependent variable. RESULTS: The study included 99 asthmatics, aged 39 years (SD 8), 55% women. Mean ACT value was 17.2 (SD 6.5), and FeNO 33.7 (SD 16). Of the pollutants studied, only NO2 was correlated with ACT scores (CC = 0.45, p < 0.001). We found no relationship between pollutants and airway inflammation. Multivariate analysis showed that ACT score was predicted by ambient air NO2 concentration and, to a lesser extent, mean FeNO. CONCLUSIONS: Information on the concentration of ambient NO2 in our environment can help the clinician to interpret the evolution of asthmatic patients. PMID- 25687771 TI - A retrospective study on annual evaluation of radiation processing for frozen bone allografts complying to quality system requirements. AB - Bone allografts have been used widely to fill up essential void in orthopaedic surgeries. The benefit of using allografts to replace and reconstruct musculoskeletal injuries, fractures or disease has obtained overwhelming acceptance from orthopaedic surgeons worldwide. However, bacterial infection and disease transmission through bone allograft transplantation have always been a significant issue. Sterilization by radiation is an effective method to eliminate unwanted microorganisms thus assist in preventing life threatening allograft associated infections. Femoral heads procured from living donors and long bones (femur and tibia) procured from cadaveric donors were sterilized at 25 kGy in compliance with international standard ISO 11137. According to quality requirements, all records of bone banking were evaluated annually. This retrospective study was carried out on annual evaluation of radiation records from 1998 until 2012. The minimum doses absorbed by the bones were ranging from 25.3 to 38.2 kGy while the absorbed maximum doses were from 25.4 to 42.3 kGy. All the bones supplied by our UMMC Bone Bank were sterile at the required minimum dose of 25 kGy. Our analysis on dose variation showed that the dose uniformity ratios in 37 irradiated boxes of 31 radiation batches were in the range of 1.003 1.251, which indicated the doses were well distributed. PMID- 25687772 TI - Lithium in the treatment of bipolar disorder: pharmacology and pharmacogenetics. AB - After decades of research, the mechanism of action of lithium in preventing recurrences of bipolar disorder remains only partially understood. Lithium research is complicated by the absence of suitable animal models of bipolar disorder and by having to rely on in vitro studies of peripheral tissues. A number of distinct hypotheses emerged over the years, but none has been conclusively supported or rejected. The common theme emerging from pharmacological and genetic studies is that lithium affects multiple steps in cellular signaling, usually enhancing basal and inhibiting stimulated activities. Some of the key nodes of these regulatory networks include GSK3 (glycogen synthase kinase 3), CREB (cAMP response element-binding protein) and Na(+)-K(+) ATPase. Genetic and pharmacogenetic studies are starting to generate promising findings, but remain limited by small sample sizes. As full responders to lithium seem to represent a unique clinical population, there is inherent value and need for studies of lithium responders. Such studies will be an opportunity to uncover specific effects of lithium in those individuals who clearly benefit from the treatment. PMID- 25687774 TI - Daytime spikes in dopaminergic activity drive rapid mood-cycling in mice. PMID- 25687773 TI - Genetic overlap between Alzheimer's disease and Parkinson's disease at the MAPT locus. AB - We investigated the genetic overlap between Alzheimer's disease (AD) and Parkinson's disease (PD). Using summary statistics (P-values) from large recent genome-wide association studies (GWAS) (total n=89 904 individuals), we sought to identify single nucleotide polymorphisms (SNPs) associating with both AD and PD. We found and replicated association of both AD and PD with the A allele of rs393152 within the extended MAPT region on chromosome 17 (meta analysis P-value across five independent AD cohorts=1.65 * 10(-7)). In independent datasets, we found a dose-dependent effect of the A allele of rs393152 on intra-cerebral MAPT transcript levels and volume loss within the entorhinal cortex and hippocampus. Our findings identify the tau-associated MAPT locus as a site of genetic overlap between AD and PD, and extending prior work, we show that the MAPT region increases risk of Alzheimer's neurodegeneration. PMID- 25687775 TI - Optogenetic activation of intracellular adenosine A2A receptor signaling in the hippocampus is sufficient to trigger CREB phosphorylation and impair memory. AB - Human and animal studies have converged to suggest that caffeine consumption prevents memory deficits in aging and Alzheimer's disease through the antagonism of adenosine A2A receptors (A2ARs). To test if A2AR activation in the hippocampus is actually sufficient to impair memory function and to begin elucidating the intracellular pathways operated by A2AR, we have developed a chimeric rhodopsin A2AR protein (optoA2AR), which retains the extracellular and transmembrane domains of rhodopsin (conferring light responsiveness and eliminating adenosine binding pockets) fused to the intracellular loop of A2AR to confer specific A2AR signaling. The specificity of the optoA2AR signaling was confirmed by light induced selective enhancement of cAMP and phospho-mitogen-activated protein kinase (p-MAPK) (but not cGMP) levels in human embryonic kidney 293 (HEK293) cells, which was abolished by a point mutation at the C terminal of A2AR. Supporting its physiological relevance, optoA2AR activation and the A2AR agonist CGS21680 produced similar activation of cAMP and p-MAPK signaling in HEK293 cells, of p-MAPK in the nucleus accumbens and of c-Fos/phosphorylated-CREB (p CREB) in the hippocampus, and similarly enhanced long-term potentiation in the hippocampus. Remarkably, optoA2AR activation triggered a preferential p-CREB signaling in the hippocampus and impaired spatial memory performance, while optoA2AR activation in the nucleus accumbens triggered MAPK signaling and modulated locomotor activity. This shows that the recruitment of intracellular A2AR signaling in the hippocampus is sufficient to trigger memory dysfunction. Furthermore, the demonstration that the biased A2AR signaling and functions depend on intracellular A2AR loops prompts the possibility of targeting the intracellular A2AR-interacting partners to selectively control different neuropsychiatric behaviors. PMID- 25687776 TI - Hypertension: Tight control of hypertension is safe in pregnant women. PMID- 25687777 TI - Coronary artery disease: Interventional narrowing of the coronary sinus in refractory angina. PMID- 25687778 TI - Hypertension: Cost-effectiveness of 2014 guidelines. PMID- 25687779 TI - Prehypertension--prevalence, health risks, and management strategies. AB - Prehypertension (blood pressure 120-139/80-89 mmHg) affects ~25-50% of adults worldwide, and increases the risk of incident hypertension. The relative risk of incident hypertension declines by ~20% with intensive lifestyle intervention, and by 34-66% with single antihypertensive medications. To prevent one case of incident hypertension in adults with prehypertension and a 50% 5-year risk of hypertension, 10 individuals would need to receive intensive lifestyle intervention, and four to six patients would need to be treated with antihypertensive medication. The relative risk of incident cardiovascular disease (CVD) is greater with 'stage 2' (130-139/85-89 mmHg) than 'stage 1' (120-129/80 84 mmHg) prehypertension; only stage 2 prehypertension increases cardiovascular mortality. Among individuals with prehypertension, the 10-year absolute CVD risk for middle-aged adults without diabetes mellitus or CVD is ~10%, and ~40% for middle-aged and older individuals with either or both comorbidities. Antihypertensive medications reduce the relative risk of CVD and death by ~15% in secondary-prevention studies of prehypertension. Data on primary prevention of CVD with pharmacotherapy in prehypertension are lacking. Risk-stratified, patient centred, comparative-effectiveness research is needed in prehypertension to inform an acceptable, safe, and effective balance of lifestyle and medication interventions to prevent incident hypertension and CVD. PMID- 25687780 TI - External Iliac Vein Aneurysm. PMID- 25687781 TI - Editor's perspectives - February 2015. PMID- 25687782 TI - Farmers value on-farm ecosystem services as important, but what are the impediments to participation in PES schemes? AB - Optimal participation in market-based instruments such as PES (payment for ecosystem services) schemes is a necessary precondition for achieving large scale cost-effective conservation goals from agricultural landscapes. However farmers' willingness to participate in voluntary conservation programmes is influenced by psychological, financial and social factors and these need to be assessed on a case-by-case basis. In this research farmers' values towards on-farm ecosystem services, motivations and perceived impediments to participation in conservation programmes are identified in two local land services regions in Australia using surveys. Results indicated that irrespective of demographics such as age, gender, years farmed, area owned and annual gross farm income, farmers valued ecosystem services important for future sustainability. Non-financial motivations had significant associations with farmer's perceptions regarding attitudes and values towards the environment and participation in conservation-related programmes. Farmer factors such as lack of awareness and unavailability of adequate information were correlated with non-participation in conservation-based programmes. In the current political context, government uncertainty regarding schemes especially around carbon sequestration and reduction was the most frequently cited impediment that could deter participation. Future research that explores willingness of farmers towards participation in various types of PES programmes developed around carbon reduction, water quality provision and biodiversity conservation, and, duration of the contract and payment levels that are attractive to the farmers will provide insights for developing farmer friendly PES schemes in the region. PMID- 25687783 TI - Characterizing heavy metal build-up on urban road surfaces: implication for stormwater reuse. AB - Stormwater reuse is increasingly popular in the worldwide. In terms of urban road stormwater, it commonly contains toxic pollutants such as heavy metals, which could undermine the reuse safety. The research study investigated heavy metal build-up characteristics on urban roads in a typical megacity of South China. The research outcomes show the high variability in heavy metal build-up loads among different urban road sites. The degree of traffic congestion and road surface roughness was found to exert a more significant influence on heavy metal build-up rather than traffic volume. Due to relatively higher heavy metal loads, stormwater from roads with more congested traffic conditions or rougher surfaces might be suitable for low-water-quality required activities while the stormwater from by-pass road sections could be appropriate for relatively high-water-quality required purposes since the stormwater could be relatively less polluted. Based on the research outcomes, a decision-making process for heavy metals based urban road stormwater reuse was proposed. The new finding highlights the importance to undertaking a "fit-for-purpose" road stormwater reuse strategy. Additionally, the research results can also contribute to enhancing stormwater reuse safety. PMID- 25687784 TI - Semiflexible polymer brushes and the brush-mushroom crossover. AB - Semiflexible polymers end-grafted to a repulsive planar substrate under good solvent conditions are studied by scaling arguments, computer simulations, and self-consistent field theory. Varying the chain length N, persistence length lp, and grafting density sigmag, the chain linear dimensions and distribution functions of all monomers and of the free chain ends are studied. Particular attention is paid to the limit of very small sigmag, where the grafted chains behave as "mushrooms" no longer interacting with each other. Unlike a flexible mushroom, which has a self-similar structure from the size (a) of an effective monomer up to the mushroom height (h/a ? N(v), nu ~ 3/5), a semiflexible mushroom (like a free semiflexible chain) exhibits three different scaling regimes, h/a ? N for contour length L = Na < lp, a Gaussian regime, h/a ? (Llp)(1/2)/a for lp ? L ? R* ? (lp(2)/a), and a regime controlled by excluded volume, h/a ? (lp/a)(1/5)N(nu). The semiflexible brush is predicted to scale as h/a ? (lpasigmag)(1/3)N in the excluded volume regime, and h/a ? (lpa(3)sigma(2))(1/4)N in the Gaussian regime. Since in the volume taken by a semiflexible mushroom excluded-volume interactions are much weaker in comparison to a flexible mushroom, there occurs an additional regime where semiflexible mushrooms overlap without significant chain stretching. Moreover, since the size of a semiflexible mushroom is much larger than the size of a flexible mushroom with the same N, the crossover from mushroom to brush behavior is predicted to take place at much smaller densities than for fully flexible chains. The numerical results, however, confirm the scaling predictions only qualitatively; for chain lengths that are relevant for experiments, often intermediate effective exponents are observed due to extended crossovers. PMID- 25687785 TI - Association of VNTR polymorphisms in DRD4, 5-HTT and DAT1 genes with obesity. AB - OBJECTIVE: To investigate the association between VNTR polymorphisms of DRD4, DAT1 and 5-HTT genes and obesity. MATERIAL AND METHODS: Peripheral blood samples of 234 obese (BMI >= 30) and 148 healthy individuals (BMI <= 25) were objected to PCR to detect the VNTR of the 2nd intron of 5-HTT, 3rd exon of DRD4 and 3'UTR of DAT1 genes. RESULTS: The association between obesity and genotype distributions of 5-HTT, DAT1 and DRD4 genes and between obesity and distributions of allele frequencies were tested by Chi Square (chi(2)) test and were not found statistically significant. BMI values for genotype of obese and morbidly obese (BMI > 40) individuals were analyzed by Kruskal-Wallis and not found statistically significant differences between BMI values for the most frequent genotypes of 5-HTT, DAT1 and DRD4 genes. CONCLUSIONS: As a conclusion, there was no association between 5-HTT, DAT1 and DRD4 genes VNTR polymorphisms and obesity. PMID- 25687786 TI - [Keloid scars: a case series study]. AB - Keloids scars are a pathological way of wound healing of the human skin. They are responsible for an unsightly and functional discomfort, and recurrence is common after surgery. There are specific treatments in order to lower this risk. They can be hard to distinguish from an hypertrophic scar on clinical and histological examination. Moreover, mixed forms exist, combining keloid and hypertrophic features. We retrospectively reviewed 52 patients who underwent surgery for keloid scars. On 54 scars, histological examination found 38 keloids, 8 hypertrophic, 7 mixed scars and 2 neither keloid nor hypertrophic. Mean age was 30 years. Sex ratio was 1.2 women per 1 man. Most frequent locations were ear (44.4%), thorax (33.3%), and shoulder (7.4%). In all cases, disease duration exceeded one year. Histology help to make the definitive diagnosis of keloid, hypertrophic and mixed scar, confirmed by trichrome or orcein staining and alpha smooth muscle actin immunostaining. PMID- 25687787 TI - Emerging impact of skeletal muscle in health and disease. PMID- 25687788 TI - Propagation capacity of bacterial contaminants in platelet concentrates using a luciferase reporter system. AB - INTRODUCTION: Currently the use of molecular tools and techniques of Genetic Engineering in the study of microbial behavior in blood components has replaced the employment of classical methods of microbiology. This work focuses on the use of a novel lux reporter system for monitoring the contaminating propagation capacity of bacteria present in platelet concentrates under standard storage conditions in the blood bank. METHODS: A miniTn5 promotor probe carrying the lux operon from Photorhabdus luminiscens (pUTminiTn5luxCDABEKm2) was used to construct four bacterial bioluminescent mutants: Escherichia coli, Salmonella typhi, Proteus mirabilis and Pseudomonas aeruginosa. Luminescent mutants were used for contamination tests with 20 CFU in platelet concentrates bags and were stored under standard storage conditions in the blood bank (100 rpm at 22 degrees C). The measurements of luminous activity and optical density were used to monitor bacterial proliferation during 7 days (168 h). RESULTS: During the exponential growth phase (log) of bacterial strains, a lineal correlation between luminous activity vs biomass was observed (R(2) = 0.985, 0.976, 0.981) for E. coli::Tn5luxCDABEKm2, P. mirabilis::Tn5luxCDABEKm2 and P. auriginosa::Tn5luxCDABEKm2, respectively. The above indicates that metabolic activity (production of ATP) is directly related to biomass in this phase of microbial growth. While conducting experiments, the inability to propagate S. typhi::Tn5luxCDABEKm2 was detected. We can speculate that platelet concentrates contain specific components that prevent the propagation of S. typhi. CONCLUSION: The use of luxCDABE system for the quantification of luminous activity is a rapid and sensitive alternative to study the propagation and auto-sterilization of bacterial contaminants in platelet concentrates. PMID- 25687789 TI - Delay-induced patterns in a two-dimensional lattice of coupled oscillators. AB - We show how a variety of stable spatio-temporal periodic patterns can be created in 2D-lattices of coupled oscillators with non-homogeneous coupling delays. The results are illustrated using the FitzHugh-Nagumo coupled neurons as well as coupled limit cycle (Stuart-Landau) oscillators. A "hybrid dispersion relation" is introduced, which describes the stability of the patterns in spatially extended systems with large time-delay. PMID- 25687790 TI - Pattern formation during early floral development. AB - Flowers are central to sexual reproduction in plants. The study of floral development proved tremendously successful in obtaining key insight into processes, such as fate determination, pattern formation, and growth regulation. Recent advances relate to the complex mechanisms underlying the crosstalk between phytohormone signaling, cell and tissue mechanics, and regulatory gene networks that positions floral buds at the apex and directs floral specification, initiation and outgrowth. Furthermore, progress has been made in elucidating the intercellular communication and temporal coordination necessary to organize the behavior of the various functional subdomains within the young flower. PMID- 25687791 TI - Drug safety meta-analysis: promises and pitfalls. AB - Meta-analysis has increasingly been used to identify adverse effects of drugs and vaccines, but the results have often been controversial. In one respect, meta analysis is an especially appropriate tool in these settings. Efficacy studies are often too small to reliably assess risks that become important when a medication is in widespread use, so meta-analysis, which is a statistically efficient way to pool evidence from similar studies, seems like a natural approach. But, as the examples in this paper illustrate, different syntheses can come to qualitatively different conclusions, and the results of any one analysis are usually not as precise as they seem to be. There are three reasons for this: the adverse events of interest are rare, standard meta-analysis methods may not be appropriate for the clinical and methodological heterogeneity that is common in these studies, and adverse effects are not always completely or consistently reported. To address these problems, analysts should explore heterogeneity and use random-effects or more complex statistical methods, and use multiple statistical models to see how dependent the results are to the choice of models. PMID- 25687792 TI - Using VigiBase to Identify Substandard Medicines: Detection Capacity and Key Prerequisites. AB - BACKGROUND: Substandard medicines, whether the result of intentional manipulation or lack of compliance with good manufacturing practice (GMP) or good distribution practice (GDP), pose a significant potential threat to patient safety. Spontaneous adverse drug reaction reporting systems can contribute to identification of quality problems that cause unwanted and/or harmful effects, and to identification of clusters of lack of efficacy. In 2011, the Uppsala Monitoring Centre (UMC) constructed a novel algorithm to identify reporting patterns suggestive of substandard medicines in spontaneous reporting, and applied it to VigiBase((r)), the World Health Organization's global individual case safety report database. The algorithm identified some historical clusters related to substandard products, which were later able to be confirmed in the literature or by contact with national centres (NCs). As relevant and detailed information is often lacking in the VigiBase reports but might be available at the reporting NC, further evaluation of the algorithm was undertaken with involvement from NCs. OBJECTIVE: To evaluate the effectiveness of an algorithm that identifies clusters of potentially substandard medicines, when these are assessed directly at the NC concerned. METHODS: The algorithm identifies countries and time periods with disproportionately high reporting of product inadequacy. NCs with at least 20 clusters were eligible to participate in the study, and six NCs-those in the Republic of Korea, Malaysia, Singapore, South Africa, the UK and the USA-were selected, taking into account the geographical spread and prevalence of recent clusters. The clusters were systematically assessed at the NCs, following a standardized protocol, and then compiled centrally at the UMC. The clusters were classified as 'confirmed', 'potential' or 'unlikely' substandard products; or as 'confirmed not substandard' when confirmed by an investigation; or as 'indecisive' when the information available did not allow a sound assessment even at the NC. RESULTS: The assessment of a total of 147 clusters resulted in 8 confirmed, 12 potential and 51 unlikely substandard products, and a further 19 clusters were confirmed as not substandard. Reflecting the difficulty of evaluating suspected substandard products retrospectively when additional information from the primary reporter, as well as samples, are no longer available, 57 clusters were classified as indecisive. CONCLUSION: While application of the algorithm to VigiBase allowed identification of some substandard medicines, some key prerequisites have been identified that need to be fulfilled at the national level for the algorithm to be useful in practice. Such key factors are fast handling and transfer of incoming reports into VigiBase, detailed information on the product and its distribution channels, the possibility of contacting primary reporters for further information, availability of samples of suspected products and laboratory capacity to analyse suspected products. PMID- 25687794 TI - Erratum: Anatomic features of the neck as predictive markers of difficult direct laryngoscopy in men and women: A prospective study: Erratum. AB - [This corrects the article on p. 176 in vol. 58, PMID: 24963183.]. PMID- 25687793 TI - Tailoring the diameter and density of self-catalyzed GaAs nanowires on silicon. AB - Nanowire diameter has a dramatic effect on the absorption cross-section in the optical domain. The maximum absorption is reached for ideal nanowire morphology within a solar cell device. As a consequence, understanding how to tailor the nanowire diameter and density is extremely important for high-efficient nanowire based solar cells. In this work, we investigate mastering the diameter and density of self-catalyzed GaAs nanowires on Si(111) substrates by growth conditions using the self-assembly of Ga droplets. We introduce a new paradigm of the characteristic nucleation time controlled by group III flux and temperature that determine diameter and length distributions of GaAs nanowires. This insight into the growth mechanism is then used to grow nanowire forests with a completely tailored diameter-density distribution. We also show how the reflectivity of nanowire arrays can be minimized in this way. In general, this work opens new possibilities for the cost-effective and controlled fabrication of the ensembles of self-catalyzed III-V nanowires for different applications, in particular in next-generation photovoltaic devices. PMID- 25687795 TI - Impact of conditioning regimen on outcomes for patients with lymphoma undergoing high-dose therapy with autologous hematopoietic cell transplantation. AB - There are limited data to guide the choice of high-dose therapy (HDT) regimen before autologous hematopoietic cell transplantation (AHCT) for patients with Hodgkin (HL) and non-Hodgkin lymphoma (NHL). We studied 4917 patients (NHL, n = 3905; HL, n = 1012) who underwent AHCT from 1995 to 2008 using the most common HDT platforms: carmustine (BCNU), etoposide, cytarabine, and melphalan (BEAM) (n = 1730); cyclophosphamide, BCNU, and etoposide (CBV) (n = 1853); busulfan and cyclophosphamide (BuCy) (n = 789); and total body irradiation (TBI)-containing treatment (n = 545). CBV was divided into CBV(high) and CBV(low) based on BCNU dose. We analyzed the impact of regimen on development of idiopathic pulmonary syndrome (IPS), transplantation-related mortality (TRM), and progression-free and overall survival. The 1-year incidence of IPS was 3% to 6% and was highest in recipients of CBV(high) (hazard ratio [HR], 1.9) and TBI (HR, 2.0) compared with BEAM. One-year TRM was 4% to 8%, respectively, and was similar between regimens. Among patients with NHL, there was a significant interaction between histology, HDT regimen, and outcome. Compared with BEAM, CBV(low) (HR, .63) was associated with lower mortality in follicular lymphoma (P < .001), and CBV(high) (HR, 1.44) was associated with higher mortality in diffuse large B cell lymphoma (P = .001). For patients with HL, CBV(high) (HR, 1.54), CBV(low) (HR, 1.53), BuCy (HR, 1.77), and TBI (HR, 3.39) were associated with higher mortality compared with BEAM (P < .001). The impact of specific AHCT regimen on post-transplantation survival is different depending on histology; therefore, further studies are required to define the best regimen for specific diseases. PMID- 25687797 TI - Cord Blood Banking in the Arab World: Current Status and Future Developments. AB - Umbilical cord blood transplants are now used to treat numerous types of immune- and blood-related disorders and genetic diseases. Cord blood (CB) banks play an important role in these transplants by processing and storing CB units. In addition to their therapeutic potential, these banks raise ethical and regulatory questions, especially in emerging markets in the Arab world. In this article, the authors review CB banking in five countries in the region, Jordan, Saudi Arabia, Egypt, Qatar, and the United Arab Emirates, selected for their different CB banking policies and initiatives. In assessing these case studies, the authors present regional trends and issues, including religious perspectives, policies, and demographic risk factors. This research suggests strong incentives for increasing the number of CB units that are collected from and available to Arab populations. In addition, the deficit in knowledge concerning public opinion and awareness in the region should be addressed to ensure educated decision-making. PMID- 25687796 TI - Intensified Mycophenolate Mofetil Dosing and Higher Mycophenolic Acid Trough Levels Reduce Severe Acute Graft-versus-Host Disease after Double-Unit Cord Blood Transplantation. AB - Although mycophenolate mofetil (MMF) has replaced corticosteroids as immunosuppression in cord blood transplantation (CBT), optimal MMF dosing has yet to be established. We intensified MMF dosing from every 12 to every 8 hours to augment graft-versus-host disease (GVHD) prophylaxis in double-unit cord blood transplantation (dCBT) and evaluated outcomes according to the total daily MMF dose/kg in 174 dCBT recipients (median age, 39 years; range, 1 to 71) who underwent transplantation for hematologic malignancies. Recipients of an MMF dose <= the median (36 mg/kg/day) had an increased day 100 grade III and IV acute GVHD (aGVHD) incidence compared with patients who received >36 mg/kg/day (24% versus 8%, P = .008). Recipients of <= the median dose who had highly HLA allele (1 to 3 of 6) mismatched dominant units had the highest day 100 grade III and IV aGVHD incidence of 37% (P = .009). This finding was confirmed in multivariate analysis (P = .053). In 83 patients evaluated for mycophenolic acid (MPA) troughs, those with a mean week 1 and 2 trough < .5 MUg/mL had an increased day 100 grade III and IV aGVHD of 26% versus 9% (P = .063), and those who received a low total daily MMF dose and had a low mean week 1 and 2 MPA trough had a 40% incidence (P = .008). Higher MMF dosing or MPA troughs had no impact on engraftment after myeloablation. This analysis supports intensified MMF dosing in milligram per kilogram per day and MPA trough level monitoring early after transplantation in dCBT recipients. PMID- 25687798 TI - Predictive value of bronchiolitis obliterans syndrome stage 0p in chronic graft versus-host disease of the lung. AB - Bronchiolitis obliterans syndrome (BOS) is a significant post-transplant complication with low survival. BOS stage 0p (BOS 0p) is a parameter detected on pulmonary function tests (PFTs) after lung transplantation to identify patients at risk to develop BOS. We performed a retrospective study on 442 patients who underwent allogeneic stem cell transplant from 2007 to 2011 to evaluate whether development of BOS 0p is a risk factor in this population for BOS. Patients who met criteria for BOS 0p were significantly more likely to develop BOS (hazard ratio [HR], 3.22; P < .001). BOS 0p was significantly associated with a history of lung disease pretransplant (HR, 2.48; P = .001) and chronic graft-versus-host disease (GVHD) outside the lung post-transplant (HR, 23; P < .001). Finally, BOS 0p criteria were adequately sensitive in predicting BOS (85%), with a high negative predictive value (98%). Our findings suggest a routine PFT screening strategy with the intent of detecting BOS 0p, especially among patients with prior lung disease and who developed chronic GVHD, could suitably identify an at risk population for the development of BOS. PMID- 25687799 TI - Endogenous and exogenous estrogens during embryonic development affect timing of hatch and growth in the American alligator (Alligator mississippiensis). AB - Prenatal exposure to estrogenic endocrine disrupting chemicals (EDCs) can affect length of gestation and body mass and size of offspring. However, the dose, timing, and duration of exposure as well as sex and strain of the experimental animals determine the direction and magnitude of these effects. In this study, we examined the effects of a one-time embryonic exposure to either 17 beta-estradiol (E2) or bisphenol A (BPA) on rate of development and growth in American alligators (Alligator mississippiensis). Our results indicate that BPA and E2 treated alligators hatched approximately 1.4 days earlier than vehicle-treated (control) alligators, suggesting that estrogenic chemicals hasten hatching in these animals. We assessed growth rates, growth allometry, and body condition for 21 weeks after hatching and found that BPA-treated alligators grew more quickly shortly after hatching but more slowly thereafter compared to control alligators. Conversely, E2-treated alligators grew more slowly shortly after hatching but more quickly thereafter compared to control alligators. As a result of differences in growth rate, BPA-treated alligators were heavier, longer, and fatter than control alligators at age 5 weeks but were similar in size and leaner than control alligators at age 21 weeks. Biochemical analytes were examined at the end of the 21-week study to assess overall metabolic condition. We found that E2-treated alligators had significantly higher circulating plasma concentrations of cholesterol and triglycerides than control alligators while BPA-treated alligators had blood profiles comparable to control alligators. Our results provide important insights into the effects of exogenous estrogens on morphology and metabolism in an oviparous, semi-aquatic reptile. PMID- 25687800 TI - A simple method for measuring porcine circovirus 2 whole virion particles and standardizing vaccine formulation. AB - Porcine Circovirus 2 (PCV2) is involved in porcine circovirus-associated disease, that causes great economic losses to the livestock industry worldwide. Vaccination against PCV2 proved to be very effective in reducing disease occurrence and it is currently performed on a large scale. Starting from a previous model concerning Foot-and Mouth Disease Virus antigens, we developed a rapid and simple method to quantify PCV2 whole virion particles in inactivated vaccines. This procedure, based on sucrose gradient analysis and fluorometric evaluation of viral genomic content, allows for a better standardization of the antigen payload in vaccine batches. It also provides a valid indication of virion integrity. Most important, such a method can be applied to whole virion vaccines regardless of the production procedures, thus enabling meaningful comparisons on a common basis. In a future batch consistency approach to PCV2 vaccine manufacture, our procedure represents a valuable tool to improve in-process controls and to guarantee conformity of the final product with passmarks for approval. This might have important repercussions in terms of reduced usage of animals for vaccine batch release, in the framework of the current 3Rs policy. PMID- 25687801 TI - Mineralization of hetero bi-functional reactive dye in aqueous solution by Fenton and photo-Fenton reactions. AB - This study focused on the advanced oxidation of the hetero bi-functional reactive dye Sumifix Supra Yellow 3RF (CI Reactive Yellow 145) using dark Fenton and photo Fenton conditions in a lab-scale experiment. A 2(3) factorial design was used to evaluate the effects of the three key factors: temperature, Fe(II) and H2O2 concentrations, for a dye concentration of 250 mg L(-1) with chemical oxygen demand (COD) of 172 mg L(-1) O2 at pH=3. The response function was the COD reduction. This methodology lets us find the effects and interactions of the studied variables and their roles in the efficiency of the treatment process. In the optimization, the correlation coefficients for the model (R2) were 0.948 and 0.965 for Fenton and photo-Fenton treatments, respectively. Under optimized reaction conditions: pH=3, temperature=298 K, [H2O2]=11.765 mM and [Fe(II)]=1.075 mM; 60 min of treatment resulted in a 79% and 92.2% decrease in COD, for the dye taken as the model organic compound, after Fenton and photo-Fenton treatments, respectively. PMID- 25687802 TI - Determination and pharmacokinetic study of two triterpenoid saponins in rat plasma after oral administration of the extract of Aralia elata leaves by UHPLC ESI-MS/MS. AB - Aralia elata (Miq.) Seems (A. elata) grow in Northeast China and the total saponins of A. elata is used to auxiliary treatment for the acute hepatitis, chronic hepatitis and the transaminase on the high side. Aralia-saponinV and Aralia-saponinVI are the major bioactive saponins in A. elata leaves. A selective and sensitive UHPLC-MS/MS method was developed and validated for the determination and pharmacokinetic study of Aralia-saponinV and Aralia-saponinVI indwelling the extract in rat plasma in this article. The sample pretreatment involved a one-step extraction of 0.2mL plasma with methanol. Shengmaxinside C was used as internal standard (I.S.). The separation was carried out on an Agilent SB-C18 column (1.8MUm, 50mm*2.1mm) at 30 degrees C with a mobile phase of acetonitrile-5mM ammonium acetate (90:10, v/v) at a flow rate of 0.2mL/min. The detection was performed on a triple quadrupole tandem mass spectrometer by multiple reaction monitoring (MRM) mode via electrospray ionization (ESI) source operating in the negative ionization mode. The optimized mass transition ion pairs (m/z) monitored for Aralia-saponinV, Aralia-saponinVI and I.S. were 1103.2/941.2, 1119.2/957.0 and 707.0/647.1, respectively. The current UHPLC-MS/MS assay method was validated for linearity, intra-day and inter-day precisions, accuracy, extraction recovery and stability, and it was suitable for the pharmacokinetic studies of the two saponins after oral administration of extract of A. elata leaves. The lower limits of quantification were 5.70ng/mL for Aralia saponinV and 6.15ng/mL for Aralia-saponinVI. Intra-day and inter-day precisions were less than 7.4% and the accuracy range was from 1.19% to 8.60%. The mean extraction recoveries of analytes and I.S. from rat plasma were all more than 89.5%. This paper described a simple, sensitive and validated UHPLC-MS/MS method for simultaneous determination of Aralia-saponinV and Aralia-saponinVI in rat plasma after oral administration of the extract of A. elata leaves, and investigated on their pharmacokinetic studies as well. PMID- 25687803 TI - Quantitation of pilsicainide in microscale samples of human biological fluids using liquid chromatography-tandem mass spectrometry. AB - This paper describes a sensitive, reliable method to determine pilsicainide (PLC) levels in microscale sample volumes of human biological fluids using liquid chromatography-tandem mass spectrometry (LC-MS/MS) with electrospray ionization (ESI). PLC and quinidine as an internal standard were extracted with diethylether from 0.1mL of alkalinized biological fluids. The extract was injected into an analytical column (l-column 2 ODS, 75mm*2.1mm i.d.). The mobile phase for separation consisted of 5mM ammonium acetate (pH 4.5)/methanol (4:1, v/v) and was delivered at a flow rate of 0.2mL/min. The drift voltage was 100V. The sampling aperture was heated at 120 degrees C and the shield temperature was 260 degrees C. The ion transitions used to monitor analytes were m/z 273->m/z 110 for PLC and m/z 325->m/z 79 for quinidine. The total time for chromatographic separation was less than 8min. The validated concentration ranges of this method for PLC were 5 2000ng/mL in plasma, 5-500ng/mL in ultrafiltered plasma solution, and 25 2000ng/mL in urine. Mean recoveries of PLC in plasma, ultrafiltered plasma solution, and urine were 93.2-99.7%, 91.4-100.6%, and 93.9-104.7%, respectively. Intra- and interday coefficients of variation for PLC were less than 6.0% and 4.3% in plasma, 6.1% and 3.7% in ultrafiltered plasma solution, and 5.4% and 2.5% in urine at the above concentration ranges, respectively. The lower limit of quantification for PLC in plasma, ultrafiltered plasma solution, and urine were 5ng/mL, 5ng/mL, and 25ng/mL, respectively. This method can be applied to pharmacokinetic study and therapeutic drug monitoring in special populations such as neonates, infants, and the elderly by making effective use of residual samples used for general clinical laboratory testing. PMID- 25687804 TI - Method validation and application of a liquid chromatography-tandem mass spectrometry method for drugs of abuse testing in exhaled breath. AB - A mass spectrometric method for drugs of abuse testing in exhaled breath employing a sampling device collecting aerosol particles was developed and applied in routine use. Analytes covered were amphetamine, methamphetamine, 6 acetylmorphine, morphine, cocaine, benzoylecgonine, diazepam, oxazepam and tetrahydrocannabinol. The method involved eluting drugs from the collection filter with methanol, quantification using deuterated analogs as internal standards, reversed phase chromatography with gradient elution, positive electrospray ionization and monitoring of two product ions per analyte in selected reaction monitoring mode. The measuring range was 6.0-1000pg/filter. The intra- and inter-assay imprecision expressed as the coefficient of variation was less than 7%. Influence from matrix was noted for most compounds but was compensated for the use of co-eluting internal standards. The LLOQ was 6.0pg/filter with intra-assay CV <5% and accuracy within 99-102% for all analytes. No chromatographic interference was observed in 20 negative control samples. The LC-MS/MS method was successfully applied for measuring drugs in unknown samples collected for the purpose of drug testing. Among the 1096 analyzed samples analytical findings were made in breath in 39 cases (3.6%). Most frequently found substances were the following: amphetamine (25 cases) methamphetamine (10 cases), THC (8 cases), cocaine (4 cases), benzoylecgonine (2 cases) and diazepam (2 cases). In conclusion, a fully validated and robust screening method suitable for the routine measurement of drugs of abuse in exhaled breath with a simple procedure for specimen collection and sample preparation was successfully developed. PMID- 25687805 TI - The role of transoral robotic surgery in the management of oropharyngeal squamous cell carcinoma: a current review. AB - The incidence of oropharyngeal squamous cell carcinoma (OPSCC) is increasing in the USA despite a decline in traditional risk factors. This trend is attributed to human papillomavirus (HPV)-associated malignancies and is particularly notable in a younger patient demographic with fewer comorbid diseases and longer life expectancies. Therefore, both oncologic and functional outcomes are important to consider when managing OPSCC in the modern era. The historical management of OPSCC was typically surgical, but traditional open approaches resulted in significant morbidity. As the paradigm shifted, organ-preserving treatment regimens, namely, radiotherapy (RT) and chemoradiation (CRT), replaced surgery as the primary treatment modality. However, these treatment strategies are not without risk of significant sequelae and functional impairment. Transoral robotic surgery (TORS) is a minimally invasive surgical approach that offers surgical access to the oropharynx without the morbidity of open procedures while achieving excellent oncologic and functional outcomes. The appropriate application of this new technology is still being investigated but the current literature supports TORS as a viable option in the management of OPSCC. PMID- 25687806 TI - Surgical salvage of recurrent nasopharyngeal carcinoma. AB - Nasopharyngeal carcinoma is a unique tumour which is endemic in southern China including Hong Kong. Whilst the treatment results for the primary cancer has been encouraging, management of recurrent tumours has been challenging. Compared to other surgical approaches, the maxillary swing operation provides wide access to the bilateral nasopharynx and the ipsilateral parapharyngeal space, allowing resection of tumours with adequate margins. Among the 312 patients who had received salvage nasopharyngectomy via the maxillary swing approach, the chance of achieving microscopically clear resection margins was 79.5 %. The overall local recurrence rate after surgery was 13.1 %. Multivariate analysis showed that resection margin status, synchronous nodal recurrence and cavernous sinus invasion were independent prognostic factors for overall survival. For small tumours located in the posterior wall, endoscopic resection, or more recently, the transoral robotic (TORS)-assisted approach, can be performed. Every effort should be made to ensure microscopic clearance of disease as well as to minimize the potential complications of surgery that may adversely affect the subsequent quality of life. PMID- 25687807 TI - Long-term experience with (laterally) extended endopelvic resection (LEER) in relapsed pelvic malignancies. AB - Gynecologic cancers recurring in the pelvis are generally advanced in malignant progression limiting curative treatment approaches. The cancer field theory links cancer progression to reversed morphogenesis and allows the exact anatomical delineation of the cancer field, i.e., the tissue compartment of potential tumor infiltration related to the tumor's ontogenetic stage. Cancer surgery is redefined with the resection of ontogenetic stage-related cancer fields instead of the mere removal of the malignant tumor with an uninvolved tissue margin. Most gynecologic pelvic malignancies recurring in the pelvis represent ontogenetic stages 3 and 4. (Laterally) extended endopelvic resection ((L)EER) has been designed to resect the cancer fields of gynecologic tumors in these advanced ontogenetic stages. This paper reports long-term experience with (L)EER for relapsed pelvic malignancies strongly supporting the cancer field theory and the principle and practice of cancer field resection. PMID- 25687808 TI - Agricultural conversion of floodplain ecosystems: implications for groundwater quality. AB - With current trends of converting grasslands to row crop agriculture in vulnerable areas, there is a critical need to evaluate the effects of land use on groundwater quality in large river floodplain systems. In this study, groundwater hydrology and nutrient dynamics associated with three land cover types (grassland, floodplain forest and cropland) were assessed at the Cedar River floodplain in southeastern Iowa. The cropland site consisted of newly-converted grassland, done specifically for our study. Our objectives were to evaluate spatial and temporal variations in groundwater hydrology and quality, and quantify changes in groundwater quality following land conversion from grassland to row crop in a floodplain. We installed five shallow and one deep monitoring wells in each of the three land cover types and recorded water levels and quality over a three year period. Crop rotations included soybeans in year 1, corn in year 2 and fallow with cover crops during year 3 due to river flooding. Water table levels behaved nearly identically among the sites but during the second and third years of our study, NO3-N concentrations in shallow floodplain groundwater beneath the cropped site increased from 0.5 mg/l to more than 25 mg/l (maximum of 70 mg/l). The increase in concentration was primarily associated with application of liquid N during June of the second year (corn rotation), although site flooding may have exacerbated NO3-N leaching. Geophysical investigation revealed differences in ground conductivity among the land cover sites that related significantly to variations in groundwater quality. Study results provide much needed information on the effects of different land covers on floodplain groundwater and point to challenges ahead for meeting nutrient reduction goals if row crop land use expands into floodplains. PMID- 25687809 TI - Corporate environmentalism and environmental innovation. AB - Several papers have explored the effect of tighter environmental standards on environmental innovation. While mandatory regulation remains the central tenet of US environmental policy, the regulatory landscape has changed since the early 1990s with the increased recourse by federal and state agencies to corporate environmentalism--voluntary pollution prevention (P2) by firms--to achieve environmental improvements. We therefore estimate the effects of voluntary P2 activities on the patenting of environmental technologies by a sample of manufacturing firms. With our panel data of 352 firms over the 1991-2000 period, we adopt an instrumental variable Poisson framework to account for the count nature of patents and the endogeneity of the P2 adoption decision. Our results indicate that the adoption of voluntary P2 activities in the manufacturing sector has led to a statistically and economically significant increase in the number of environmental patents, suggesting that corporate environmentalism can act as a catalyst for investments in cleaner technologies. Our findings are internationally relevant given the increasing ubiquity of corporate environmentalism in both developed and developing economies. PMID- 25687810 TI - International governance structures for health-care waste management: a systematic review of scientific literature. AB - Significant differences exist in the management of health-care waste management, globally. This is particularly so between low, middle and high-income countries. A systematic review of scientific literature on global healthcare waste management spanning the period 2000 - current was undertaken, in order to identify key policies, practices, challenges and best practice. The findings were analysed considering the Gross National Income and the Human Development Index of each country. Effective regulation and operative definitions of waste categories are key-factors requiring improvement at the national level. The economic conditions in the country are an important factor, especially regarding treatment and disposal. Areas for improvement (e.g. the need for improved governance structures, the development of regional clusters, as well as sharps waste segregation) are suggested. PMID- 25687811 TI - Can ruptured abdominal aortic aneurysm be accurately diagnosed as the cause of death without postmortem computed tomography when autopsies cannot be performed? AB - PURPOSE: This study aimed to conduct a multicentre retrospective review of cases to clarify how many ruptured abdominal aortic aneurysms (RAAAs) as the cause of death could be diagnosed without post-mortem computed tomography (PMCT) when autopsies cannot be performed. METHODS: We collected consecutive PMCT data from January 2002 to December 2009 from three institutes where PMCT examinations are performed on a routine basis for deceased patients with unknown causes of death. A total of 19 cases were identified where PMCT revealed RAAAs. Ante-mortem clinical presentations, post-mortem external examinations, and peri-mortem ultrasonography findings were assessed for their diagnostic accuracy. RESULTS: The correct diagnosis based on the classic triad of shock, acute abdominal pain, and pulsatile abdominal mass was made in only one of 19 (5.3%) patients. Shock, acute abdominal pain, and abdominal swelling were found in five of 19 (26%) patients. Shock and acute abdominal pain or abdominal swelling were found in two of 19 (10%) patients. Ten of 19 (53%) patients only had shock. Peri-mortem ultrasonography was performed in seven of 19 patients; one was diagnosed with RAAA (14%). No patients had pre-mortem CT examinations. CONCLUSIONS: Post-mortem diagnosis of RAAA is difficult to make based on ante-mortem clinical presentation, post-mortem external examinations, or peri-mortem ultrasonography. PMCT is recommended for diagnosing RAAA as the cause of death if pre-mortem CT examinations are not carried out when autopsies cannot be performed. PMID- 25687812 TI - Cross-language differences of articulation rate and its transfer into Japanese as a second language. AB - Recently, the articulation rate has been attracting attention in forensic speech investigation as an acoustic feature that varies across speakers, dialects, and languages. The present study investigates how cross-language differences in the articulation rate are transferred into Japanese as a second language. Participants were speakers of Japanese, Chinese, Korean, and Thai. They were recorded while they read a passage in their native language and in Japanese. Local and global articulation rates were calculated based on the number of syllables as well as the number of morae for Japanese speech. When we compared the articulation rate of the native languages, Japanese was the fastest, then Korean, Chinese, and Thai in that order. Also, a significant positive correlation was observed between the articulation rate of the native language and that of the second language. A gender difference was found in the articulation rate of some languages, with males speaking faster than females. The effect of age was limited to Thai speakers only. Accent discrimination and identification experiments were conducted and the results revealed that native and non-native accents could be correctly discriminated just by the articulation rate. PMID- 25687813 TI - [Prefabrication of heart valves]. AB - BACKGROUND: Commonly used heart valve prostheses have specific drawbacks and limitations. OBJECTIVES AND METHODS: Optimization of conventional methods and techniques for heart valve replacement by application of tissue engineering principles. RESULTS AND CONCLUSIONS: Recent studies have impressively shown that allogeneic decellularized matrices have the potential to overcome limitations of conventional prostheses and to provide all the characteristics of an ideal graft for heart valve replacement. PMID- 25687814 TI - [Intraoperative complications of the lower gastrointestinal tract : Prevention, recognition and therapy]. AB - Every surgical intervention is associated with the risk of intraoperative complications. These occur in approximately 2-12% of patients but significantly influence the postoperative outcome, overall complication and mortality rates. This article presents the treatment of typical intraoperative complications during surgery of the lower gastrointestinal tract with a focus on the prevention and identification of risk factors. Especially changes in the regular anatomy caused by previous surgery, inflammation, tumors and emergency situations carry the risk of iatrogenic injuries to the bowels, spleen, ureter and blood vessels. These risk factors must be considered when choosing a surgical procedure, a surgical approach or an appropriate surgeon. The early detection of complications with a definitive restoration is the essential step for a successful treatment without long-term sequelae. Every delay in therapy is associated with an increased morbidity and mortality and should be avoided. PMID- 25687815 TI - Antibodies to Leptospira interrogans in goats and risk factors of the disease in Santa Catarina (West side), Brazil. AB - Leptospirosis is an infectious disease caused by the bacterium Leptospira spp. In goats, the productive impact of leptospirosis is not well known and totally unknown in Santa Catarina (SC), Brazil. This study aimed to investigate leptospirosis seroprevalence and its risk factors in goats in the west side of SC. A total of 654 blood samples were analyzed using the microscopic agglutination technique and 35.47% (232) of the animals were seropositives. Except for serogroup Autumnalis, positive samples for all other serogroups were found as follows: Sejroe (Hardjo, Wolffi), Grippotyphosa (Grippotyphosa), Canicola (Canicola), Icterohaemorrhagiae (Icterohaemorrhagiae, Copenhageni), Australis (Australis, Bratislava) and Pomona (Pomona). The contact among sheep and goats, and the addition of concentrate as food supplement were found to be risk factors for leptospirosis. Based on these results, we conclude that there is a high occurrence of anti-Leptospira antibodies in goats in the Western part of Santa Catarina State. PMID- 25687816 TI - Anthelmintic activity of Ocimum sanctum leaf extract against ovine gastrointestinal nematodes in India. AB - Leaves of Ocimum sanctum have been traditionally used for various ethno veterinary practices as well as medicinal purpose. In vitro ovicidal and larvicidal potential of crude aqueous and hydro-alcoholic extracts of the bulb of O. sanctum was investigated. Alkaloids, carbohydrates, steroids and tannins were identified in phytochemical analyses. The various blood parameters coupled marker enzymes and antioxidant status were also evaluated during in vivo trial. Aqueous extract showed better EC50 and EC99 values in comparison with methanolic extract in egg hatch assay and larval development test, respectively. However, in the larval paralysis test, both aqueous and methanolic extracts showed almost similar efficacy. A 77.64% reduction in fecal egg output was observed on day 14. No deleterious ill effect was found in any of the hematological and biochemical parameters suggesting that the plant could be safer for use in sheep. PMID- 25687817 TI - Ulcer disease prophylaxis in koi carp by bath immersion with chicken egg yolk containing anti-Aeromonas salmonicida IgY. AB - Ulcer disease, caused by atypical Aeromonas salmonicida, is a serious concern in ornamental koi carp, because it induces skin ulceration, disfiguring ornamental fish and causing economic loses. The present study aimed to establish a novel prophylaxis with chicken egg yolk immunoglobulin, IgY, against ulcer disease and to assess its feasibility in the ornamental fish industry. Addition of egg yolk powder containing anti-A. salmonicida IgY to rearing water provided significant protection against an A. salmonicida bath infection, whereas administration of non-specific IgY did not. Consecutive immersion of fish into rearing water containing specific IgY completely prevented ulcer disease resulting from cohabitation infection, indicating that this prophylaxis could prevent infection from such type of contact. Thus, passive immunization induced by immersing fish into aquarium water containing specific IgY is a prospective prophylaxis against diseases caused by pathogens that invade the skin and gills. PMID- 25687818 TI - Intra-patient variability in tacrolimus exposure: causes, consequences for clinical management. AB - Tacrolimus (Tac) is widely used for the prevention of rejection after solid organ transplantation. Finding the optimal balance between effective Tac concentrations and toxicity is a challenge and requires therapeutic drug monitoring. In addition to the well-known inter-patient variability, the clinical use of Tac is also complicated by considerable intra-patient variability (IPV) in Tac exposure. Tac IPV is defined as the amount of fluctuation of whole-blood concentrations over a certain period of time during which the Tac dose remains unchanged. A high IPV in Tac exposure has recently been recognized as a strong risk factor for acute rejection and poor long-term kidney transplantation outcome. In addition to non adherence, several other factors determine the magnitude of the IPV in Tac exposure. Quantification of IPV is easy and can be easily incorporated into everyday clinical practice as a tool for optimizing transplantation outcomes. PMID- 25687819 TI - [Lung hernia provoked by a cough fit]. AB - Lung hernias are rare and their pathogenesis is few described. They are defined as the protrusion of lung parenchyma through the chest wall: intercostal space, inter-costo-clavicular, supra-clavicular or diaphragmatic hiatus. Lung hernias are classically divided into congenital and acquired hernias. Those are usually post-traumatic or post-surgical but can be provoked by cough. Clinical diagnosis is often evident but is confirmed by chest radiograph and especially computed tomography. Major risks are lung incarceration and necrosis but also ventilatory distress due to paradoxical respiration, in case of large defect. Treatment is first and foremost surgical but debated and should consider the localization, the size, the length of evolution and the possible infectious context. We report the case of a right basi-thoracic lung hernia induced by a cough fit, in a patient with chronic bronchitis. PMID- 25687820 TI - [Lung cancer surgery and cirrhosis]. AB - INTRODUCTION: Lung cancer is the leading cause of death by cancer and cirrhosis is the fourteenth, all causes included. Surgery increases postoperative risks in cirrhotic patients. Our purpose was to analyze this point in lung cancer surgery. METHODS: We collected, among 7162 patients, the data concerning those operated for lung cancer (n=6105) and compared patients with hepatic disease (n=448) to those presenting other medical disorder (n=2587). We analyzed cirrhotic patients' characteristics (n=49). RESULTS: Five-year survival of patients with hepatic disease was lower (n=5657/6105): 35.3% versus 43.8% for patients with no hepatic disease, P=0.0021. Survival of cirrhotic patients was not statistically different from the one of patients with other hepatic disorder, but none survived beyond 10 years (0% versus 26.4%). Surgery in cirrhotic patients consisted in one explorative thoracotomy, three wedges resections, two segmentectomies, 33 lobectomies and 10 pneumonectomies. Postoperative mortality (8.2%; 4/49) was not different for patients without hepatic disease (4.2%; 239/5657) (P=0.32), as well as the rate of complications (40.8%; 20/49 and 24.8%; 1404/5657, P=0.11). Only one postoperative death was associated to a hepatic failure. Multivariate analysis pointed age, histological subtype of the tumour and stage of disease as independent prognosis factors. CONCLUSION: When cirrhosis is well compensated, surgical resection of lung cancer can be performed with acceptable postoperative morbidity and satisfactory rates of survival. Progressive potential of this disease is worse after five years. PMID- 25687821 TI - [Immunotherapy in non-small cell lung cancer: inhibition of PD1/PDL1 pathway]. AB - Despite recent advances in targeted therapy of non-small cell lung cancer (NSCLC), many patients do not benefit from these therapies. Inhibition of PD1/PDL1 is an interesting therapeutic target which restores the immune system against tumor cells. PD1 is located on lymphocytes and PDL1 on the antigen presenting cells. PD1 and PDL1 are co-inhibition molecules and their interaction results in immune tolerance against tumor cells. Anti-PD1 and anti-PDL1 antibodies have been developed to restore immune system in solid cancer including NSCLC. In phase I, studies assessing nivolumab, an anti-PD1 antibody, objective responses were observed in 13 to 18% of NSCLC patients failing previous treatment. The data obtained with anti-PDL1 antibodies is similar with objective responses ranging from 6 to 22%. The encouraging results of phase I/II studies must be confirmed in ongoing phase III studies. Anti-PD1 and anti-PDL1 antibodies exposed to new adverse events including auto-immune diseases whose support is not codified. Questions about treatment duration and criteria evaluation are not resolved. These treatments pave the way for immunomodulation in NSCLC treatment. PMID- 25687822 TI - [Mucoepidermoid tracheo-bronchial tumors in adulthood. A series of 22 cases]. AB - INTRODUCTION: Mucoepidermoid tumours (TME) are rare tumours arising from the submucosal glands of the tracheobronchial tree. The majority of these tumours develop in a benign fashion but some of them are malignant. The latter can be easily mistaken for adenosquamous carcinomas. PATIENTS AND METHOD: We have reviewed 22 patients suffering from TME observed over a period of 25 years. Two arose from the trachea and 20 from the cartilaginous bronchi; 12 of these tumours had macroscopic and histological criteria of low-grade malignancy, 4 had macroscopic and 6 macroscopic and microscopic criteria of high grade malignancy. RESULTS: Prognosis of the latter was very poor and no survival observed after 6 years follow-up, a behavior similar to that observed in non-small cell lung carcinomas and adenosquamous carcinomas. CONCLUSION: The best treatment of these orphan tumours remains surgery. PMID- 25687823 TI - Subpicosecond surface dynamics in genomic DNA from in vitro-grown plant species: a SERS assessment. AB - In this work the surface-enhanced Raman total half band widths of seven genomic DNAs from leaves of chrysanthemum (Dendranthema grandiflora Ramat.), common sundew (Drosera rotundifolia L.), edelweiss (Leontopodium alpinum Cass), Epilobium hirsutum L., Hypericum richeri ssp. transsilvanicum (Celak) Ciocarlan, rose (Rosa x hybrida L.) and redwood (Sequoia sempervirens D. Don. Endl.) have been measured. We have shown that surface-enhanced Raman spectroscopy (SERS) can be used to study the fast subpicosecond dynamics of DNA in the proximity of a metallic surface. The dependencies of the total half band widths and the global relaxation times, on the DNA molecular subgroup structure and on the type of genomic DNA, are reported. In our study, the full widths at half-maximum (FWHMs) for the SERS bands of genomic DNAs from different leaf tissues are typically in the wavenumber range from 15 to 55 cm(-1). Besides, it can be observed that molecular relaxation processes studied in this work have a global relaxation time smaller than 0.71 ps and larger than 0.19 ps. A comparison between different ranges of FT-Raman and SERS band parameters, respectively, corresponding to DNA extracted from leaf tissues is given. It is shown that the interaction between DNA and a metallic surface has the potential to lead to a shortening of the global relaxation times, as compared with molecular dynamics in solution. We have found that the surface dynamics of molecular subgroups in plant DNA is, in some cases, about two times faster than the solution dynamics of nucleic acids. This can be rationalized in a qualitative manner by invoking the complex landscape of the interaction energy between the molecule and the silver surface. PMID- 25687824 TI - Neuroinflammation and Abeta accumulation linked to systemic inflammation are decreased by genetic PKR down-regulation. AB - Alzheimer's disease (AD) is a neurodegenerative disorder, marked by senile plaques composed of amyloid-beta (Abeta) peptide, neurofibrillary tangles, neuronal loss and neuroinflammation. Previous works have suggested that systemic inflammation could contribute to neuroinflammation and enhanced Abeta cerebral concentrations. The molecular pathways leading to these events are not fully understood. PKR is a pro-apoptotic kinase that can trigger inflammation and accumulates in the brain and cerebrospinal fluid of AD patients. The goal of the present study was to assess if LPS-induced neuroinflammation and Abeta production could be altered by genetic PKR down regulation. The results show that, in the hippocampus of LPS-injected wild type mice, neuroinflammation, cytokine release and Abeta production are significantly increased and not in LPS-treated PKR knock out mice. In addition BACE1 and activated STAT3 levels, a putative transcriptional regulator of BACE1, were not found increased in the brain of PKR knock-out mice as observed in wild type mice. Using PET imaging, the decrease of hippocampal metabolism induced by systemic LPS was not observed in LPS-treated PKR knock-out mice. Altogether, these findings demonstrate that PKR plays a major role in brain changes induced by LPS and could be a valid target to modulate neuroinflammation and Abeta production. PMID- 25687825 TI - Loss of Nrf2 in bone marrow-derived macrophages impairs antigen-driven CD8(+) T cell function by limiting GSH and Cys availability. AB - NF-E2-related factor 2 (Nrf2), known to protect against reactive oxygen species, has recently been reported to resolve acute inflammatory responses in activated macrophages. Consequently, disruption of Nrf2 promotes a proinflammatory macrophage phenotype. In the current study, we addressed the impact of this macrophage phenotype on CD8(+) T cell activation by using an antigen-driven coculture model consisting of Nrf2(-/-) and Nrf2(+/+) bone marrow-derived macrophages (BMDMPhi) and transgenic OT-1 CD8(+) T cells. OT-1 CD8(+) T cells encode a T cell receptor that specifically recognizes MHC class I-presented ovalbumin OVA(257-264) peptide, thereby causing a downstream T cell activation. Interestingly, coculture of OVA(257-264)-pulsed Nrf2(-/-) BMDMPhi with transgenic OT-1 CD8(+) T cells attenuated CD8(+) T cell activation, proliferation, and cytotoxic function. Since the provision of low-molecular-weight thiols such as glutathione (GSH) or cysteine (Cys) by macrophages limits antigen-driven CD8(+) T cell activation, we quantified the amounts of intracellular and extracellular GSH and Cys in both cocultures. Indeed, GSH levels were strongly decreased in Nrf2(-/ ) cocultures compared to wild-type counterparts. Supplementation of thiols in Nrf2(-/-) cocultures via addition of glutathione ester, N-acetylcysteine, beta mercaptoethanol, or cysteine itself restored T cell proliferation as well as cytotoxicity by increasing intracellular GSH. Mechanistically, we identified two potential Nrf2-regulated genes involved in thiol synthesis in BMDMPhi: the cystine transporter subunit xCT and the modulatory subunit of the GSH synthesizing enzyme gamma-GCS (GCLM). Pharmacological inhibition of gamma-GCS dependent GSH synthesis as well as knockdown of the cystine antiporter xCT in Nrf2(+/+) BMDMPhi mimicked the effect of Nrf2(-/-) BMDMPhi on CD8(+) T cell function. Our findings demonstrate that reduced levels of GCLM as well as xCT in Nrf2(-/-) BMDMPhi limit GSH availability, thereby inhibiting antigen-induced CD8(+) T cell function. PMID- 25687826 TI - Modeling course-based undergraduate research experiences: an agenda for future research and evaluation. AB - Course-based undergraduate research experiences (CUREs) are being championed as scalable ways of involving undergraduates in science research. Studies of CUREs have shown that participating students achieve many of the same outcomes as students who complete research internships. However, CUREs vary widely in their design and implementation, and aspects of CUREs that are necessary and sufficient to achieve desired student outcomes have not been elucidated. To guide future research aimed at understanding the causal mechanisms underlying CURE efficacy, we used a systems approach to generate pathway models representing hypotheses of how CURE outcomes are achieved. We started by reviewing studies of CUREs and research internships to generate a comprehensive set of outcomes of research experiences, determining the level of evidence supporting each outcome. We then used this body of research and drew from learning theory to hypothesize connections between what students do during CUREs and the outcomes that have the best empirical support. We offer these models as hypotheses for the CURE community to test, revise, elaborate, or refute. We also cite instruments that are ready to use in CURE assessment and note gaps for which instruments need to be developed. PMID- 25687827 TI - Clinical significance of patterns of incidental thyroid uptake at (18)F-FDG PET/CT. AB - Incidental uptake of 2-[(18)F]-fluoro-2-deoxy-d-glucose ((18)F-FDG) in the thyroid gland is not uncommonly encountered in day-to-day practice of oncological (18)F-FDG positron-emission tomography/computed tomography (PET/CT). These are often felt to be "nuisance lesions" by referring clinicians and radiologists alike. However, recognition of the importance of different patterns of FDG uptake in the thyroid gland and knowledge of the possible underlying aetiologies are crucial in ensuring that patients are managed appropriately in the clinical context of their primary diagnosis, as the underlying pathological condition may be clinically important in a significant minority of such cases. This review describes the various patterns of (18)F-FDG uptake within the thyroid and discusses the clinical significance and possible impact on patient management. Incidental low-grade homogeneous diffuse increased thyroid (18)F-FDG uptake is usually seen in the patients with chronic thyroiditis, Grave's disease, and hypothyroidism. Thyroid function tests and antibody profiling are advised in these patients. Incidental focal (18)F-FDG thyroid uptake should raise the possibility of underlying malignancy. Ultrasound with or without fine-needle aspiration cytology is usually recommended for the evaluation of these lesions. Heterogeneous uptake with prominent focal uptake in the thyroid should be further evaluated to exclude malignancy. PMID- 25687828 TI - Reversible energy-transfer switching on a DNA scaffold. AB - We show that FRET between Pacific Blue (PB) and Alexa488 (A488) covalently attached to a DNA scaffold can be reversibly controlled by photochromic switching of a spiropyran derivative. With the spiropyran in the closed spiro isomeric form, FRET occurs freely between PB and A488. UV-induced isomerization to the open merocyanine form shuts down the FRET process by efficient quenching of the PB excited state. The process is reversed by exposure to visible light, triggering the isomerization to the spiro isomer. PMID- 25687829 TI - Cycloaddition reactions of (C6F5)2BN3 with dialkyl acetylenedicarboxylates. AB - The 1,3-dipolar cycloaddition reactions of the electron deficient boron azide, (C6F5)2BN3 (1) with the electron-poor acetylenes RO2CC=CCO2R (R = Me, Et) afforded the new mono- and bis-1,2,3-triazole derivatives and . PMID- 25687830 TI - Contrasting growth responses of dominant peatland plants to warming and vegetation composition. AB - There is growing recognition that changes in vegetation composition can strongly influence peatland carbon cycling, with potential feedbacks to future climate. Nevertheless, despite accelerated climate and vegetation change in this ecosystem, the growth responses of peatland plant species to combined warming and vegetation change are unknown. Here, we used a field warming and vegetation removal experiment to test the hypothesis that dominant species from the three plant functional types present (dwarf-shrubs: Calluna vulgaris; graminoids: Eriophorum vaginatum; bryophytes: Sphagnum capillifolium) contrast in their growth responses to warming and the presence or absence of other plant functional types. Warming was accomplished using open top chambers, which raised air temperature by approximately 0.35 degrees C, and we measured air and soil microclimate as potential mechanisms through which both experimental factors could influence growth. We found that only Calluna growth increased with experimental warming (by 20%), whereas the presence of dwarf-shrubs and bryophytes increased growth of Sphagnum (46%) and Eriophorum (20%), respectively. Sphagnum growth was also negatively related to soil temperature, which was lower when dwarf-shrubs were present. Dwarf-shrubs may therefore promote Sphagnum growth by cooling the peat surface. Conversely, the effect of bryophyte presence on Eriophorum growth was not related to any change in microclimate, suggesting other factors play a role. In conclusion, our findings reveal contrasting abiotic and biotic controls over dominant peatland plant growth, suggesting that community composition and carbon cycling could be modified by simultaneous climate and vegetation change. PMID- 25687831 TI - Changes in the apparent survival of a tropical bird in response to the El Nino Southern Oscillation in mature and young forest in Costa Rica. AB - The effects of habitat alteration and climatic instability have resulted in the loss of bird populations throughout the globe. Tropical birds in particular may be sensitive to climate and habitat change because of their niche specialization, often sedentary nature, and unique life-cycle phenologies. Despite the potential influence of habitat and climatic interactions on tropical birds, we lack comparisons of avian demographics from variably aged forests subject to different climatic phenomena. Here, we measured relationships between forest type and climatic perturbations on White-collared Manakin (Manacus candei), a frugivorous tropical bird, by using 12 years of capture data in young and mature forests in northeastern Costa Rica. We used Cormack-Jolly-Seber models and an analysis of deviance to contrast the influence of the El Nino Southern Oscillation (ENSO) on manakin survival. We found that ENSO had little effect on manakin survival in mature forests. Conversely, in young forests, ENSO explained 79% of the variation where dry El Nino events negatively influenced manikin survival. We believe mature forest mitigated negative effects of dry El Nino periods and can serve as refugia for some species by buffering birds from climatic instability. Our results represent the first published documentation that ENSO influences the survival of a resident Neotropic landbird. PMID- 25687832 TI - Eye movements during the handwriting of words: Individually and within sentences. AB - Handwriting, a complex motor process involves the coordination of both the upper limb and visual system. The gaze behavior that occurs during the handwriting process is an area that has been little studied. This study investigated the eye movements of adults during writing and reading tasks. Eye and handwriting movements were recorded for six different words over three different tasks. The results compared reading and handwriting the same words, a between condition comparison and a comparison between the two handwriting tasks. Compared to reading, participants produced more fixations during handwriting tasks and the average fixation durations were longer. When reading fixations were found to be mostly around the center of word, whereas fixations when writing appear to be made for each letter in a written word and were located around the base of letters and flowed in a left to right direction. Between the two writing tasks more fixations were made when words were written individually compared to within sentences, yet fixation durations were no different. Correlation of the number of fixations made to kinematic variables revealed that horizontal size and road length held a strong correlation with the number of fixations made by participants. PMID- 25687833 TI - Increased likelihood of post-polycythemia vera myelofibrosis in Ph-negative MPN patients with chromosome 12 abnormalities. AB - Chromosome 12 (Chr12) abnormalities have been described for individual patients with Philadelphia chromosome-negative myeloproliferative neoplasms (Ph-neg MPN), however the frequency, characteristics, and outcomes of such patients as a whole have not been investigated. We reviewed a database of 1787 consecutive Ph-neg MPN patients seen at our institution and determined that 2% of Ph-neg MPN patients harbored an alteration involving Chr12 by cytogenetic evaluation. Retrospective chart review revealed that patients with Chr12 abnormalities had a higher likelihood of having myelofibrosis (MF) compared to patients without a Chr12 abnormality, and were more likely to have post-polycythemia vera MF. The most common alterations in Chr12 in MF patients involved 12q13, 12q15, 12q24, and trisomy 12, and >40% of Chr12 Ph-neg MPN patients had cytogenetic evolution. Chr12 abnormalities did not significantly correlate with JAK2 status, progression to acute myeloid leukemia, or survival, however patients with 12q24 abnormalities trended toward poorer outcomes. PMID- 25687834 TI - Human acellular dermal matrix allograft: A randomized, controlled human trial for the long-term evaluation of patients with extensive burns. AB - The potential of acellular dermal matrix (ADM) to improve cosmetic and functional outcomes has been demonstrated; however, there have been few clinical comparative studies assessing the long-term morphological, histological and functional changes after ADM placement. This study was designed to retrospectively evaluate the long-term outcomes of the cograft acellular dermal matrix with autologous thin split-thickness skin for the coverage of wounds in extensively burned patients. Thirty burn patients treated with a composite graft of ADM with autologous split-thickness skin from January 2007 to December 2009 were enrolled in this study. Another group of thirty patients who received only an autogenous split-thickness skin implant served as the control. Our study revealed that the collagen in the dermis treated with ADM were ordered, and the proportion of collagen III/I was much higher in the control group than in the ADM group. The basement membrane was prominent and continuous. Meanwhile, the VBSS (Vancouver Burn Skin Score) was used to evaluate skin quality, which shows a significant differences between the two group (P<0.001). Then the functional level was evaluated by the BI (Barthel Index), and the ADM group was much better than the control group (P=0.005). Based on these results, we concluded that the composite graft of ADM with autologous thin split-thickness skin was suitable for repairing the defects in functional areas after a burn. This technique might facilitate wound management with acceptable esthetic outcomes, good functional recovery and less scar hyperplasia at the donor site. PMID- 25687835 TI - Feet sunk in molten aluminium: The burn and its prevention. AB - Nowadays, despite improvements in safety rules and inspections in the metal industry, foundry workers are not free from burn accidents. Injuries caused by molten metals include burns secondary to molten iron, aluminium, zinc, copper, brass, bronze, manganese, lead and steel. Molten aluminium is one of the most common causative agents of burns (60%); however, only a few publications exist concerning injuries from molten aluminium. The main mechanisms of lesion from molten aluminium include direct contact of the molten metal with the skin or through safety apparel, or when the metal splash burns through the pants and rolls downward along the leg. Herein, we report three cases of deep dermal burns after 'soaking' the foot in liquid aluminium and its evolutive features. This paper aims to show our experience in the management of burns due to molten aluminium. We describe the current management principles and the key features of injury prevention. PMID- 25687836 TI - Randomized controlled trial of three burns dressings for partial thickness burns in children. AB - BACKGROUND: This study compared the effects of three silver dressing combinations on small to medium size acute partial thickness burns in children, focusing on re epithelialization time, pain and distress during dressing changes. METHOD: Children (0-15 years) with clean, <= 10% total body surface area (TBSA) partial thickness burns who met the inclusion criteria were included in the study. Children received either (1) ActicoatTM; (2) ActicoatTM with MepitelTM; or (3) Mepilex AgTM dressings. Measures of burn re-epithelialization, pain, and distress were recorded at dressing changes every 3-5 days until full re-epithelialization occurred. RESULTS: One hundred and three children were recruited with 96 children included for analysis. No infections were detected for the course of the study. When adjusted for burn depth, ActicoatTM significantly increased the expected days to full re-epithelialization by 40% (IRR = 1.40; 95% CI: 1.14-1.73, p < 0.01) and ActicoatTM with MepitelTM significantly increased the expected days to full re-epithelialization by 33% (IRR = 1.33; 95% CI: 1.08-1.63, p <= 0.01) when compared to Mepilex AgTM. Expected FLACC scores in the Mepilex AgTM group were 32% lower at dressing removal (p = 0.01) and 37% lower at new dressing application (p = 0.04); and scores in the ActicoatTM with MepitelTM group were 23% lower at dressing removal (p = 0.04) and 40% lower at new dressing application (p < 0.01), in comparison to the ActicoatTM group. Expected Visual Analog Scale-Pain (VAS-P) scores were 25% lower in the Mepilex AgTM group at dressing removal (p = 0.04) and 34% lower in the ActicoatTM with MepitelTM group (p = 0.02) at new dressing application in comparison to the ActicoatTM group. There was no significant difference between the Mepilex AgTM and the ActicoatTM with MepitelTM groups at all timepoints and with any pain measure. CONCLUSION: Mepilex AgTM is an effective silver dressing, in terms of accelerated wound re epithelialization time (compared to ActicoatTM and ActicoatTM with MepitelTM) and decreased pain during dressing changes (compared to ActicoatTM), for clean, < 10% TBSA partial thickness burns in children. PMID- 25687837 TI - Transfer time to a specialist burn service and influence on burn mortality in Australia and New Zealand: A multi-centre, hospital based retrospective cohort study. AB - BACKGROUND: In Australia and New Zealand (ANZ), health care is provided for ~26 million people dispersed across the eight million square kilometres of the two countries. Providing optimal care prior to and during transfer across such vast distances is challenging. Lengthening the time taken to definitive burn care has a negative impact on burn outcome. The aims of this study were to determine if transfer time and admission pathway influenced burn mortality and to identify the factors predicting burn mortality in ANZ. METHOD: The study included all adult burn patient admission data from 15 of 17 burn services submitted to the Australian and New Zealand Burn Association bi-national registry (2010-2012). Multivariate logistic regression analyses were conducted to address the study aims. RESULTS: Of the 2892 patients, 69 (2.4%) died following burn. Time to admission and direct admission to a burn centre did not independently influence burn mortality except when patients with inhalation injury took >16 h to transfer to definitive care. The risk of death was increased 5.7 times in the presence of inhalation injury. Burn size and age amplified the risk of death while gender did not. CONCLUSION: In ANZ, pre-hospital transport systems and peripheral hospital stabilisation were not associated with an increased risk of death due to burn except when inhalation injury was present. The results of this study indicate that burn patients with inhalation injury should be stabilised and transferred to a burn service within 16 h of burn. PMID- 25687838 TI - Potentiation of neurite outgrowth by brexpiprazole, a novel serotonin-dopamine activity modulator: a role for serotonin 5-HT1A and 5-HT2A receptors. AB - Brexpiprazole, a novel atypical antipsychotic drug, is currently being tested in clinical trials for treatment of psychiatric disorders, such as schizophrenia and major depressive disorder. The drug is known to act through a combination of partial agonistic activity at 5-hydroxytryptamine (5-HT)1A, and dopamine D2 receptors, and antagonistic activity at 5-HT2A receptors. Accumulating evidence suggests that antipsychotic drugs act by promoting neurite outgrowth. In this study, we examined whether brexpiprazole affected neurite outgrowth in cell culture. We found that brexpiprazole significantly potentiated nerve growth factor (NGF)-induced neurite outgrowth in PC12 cells, in a concentration dependent manner. The selective 5-HT1A receptor antagonist, WAY-100,635, was able to block the effects of brexpiprazole on neurite outgrowth, unlike the selective dopamine D2 receptor antagonist, raclopride. Furthermore, the selective 5-HT2A receptor antagonist M100907, but not DOI (5-HT2A receptor agonist), significantly potentiated NGF-induced neurite outgrowth. Moreover, xestospongin C and 2 aminoethoxydiphenyl borate (2-APB), both specific inhibitors of inositol 1,4,5 triphosphate (IP3) receptors, significantly blocked the effects of brexpiprazole. These findings suggest that brexpiprazole-induced neurite outgrowth is mediated through 5-HT1A and 5-HT2A receptors, and subsequent Ca(2+) signaling via IP3 receptors. PMID- 25687839 TI - Modified ESHAP regimen for relapsed/refractory T cell lymphoma: a retrospective analysis. AB - Peripheral T cell lymphomas account for approximately 10 % of all the non-Hodgkin lymphomas and are characterized by an aggressive clinical course and poor treatment outcome. In contrast to the improvement in the treatment of B cell lymphomas, there is no established standard chemotherapy regimen for relapsed/refractory T cell lymphomas. Our institute introduced modified ESHAP (mESHAP) regimen to reduce renal toxicity of standard ESHAP therapy, in which cisplatin was switched to carboplatin. We retrospectively analyzed the efficacy of mESHAP against relapsed/refractory T cell lymphomas. Twenty-two patients with relapsed/refractory T cell lymphomas were treated with mESHAP regimen at the University of Tokyo Hospital between January 2001 and December 2012. The median age was 59 years (range, 36-77). The diagnosis comprised peripheral T cell lymphoma, not otherwise specified (n = 10), angioimmunoblastic T cell lymphoma (AITL; n = 9), mycosis fungoides (n = 1), and anaplastic lymphoma kinase (ALK) negative anaplastic large cell lymphoma (n = 2). The median follow-up period was 9.5 months (range, 2.5-62.3). Complete remission (CR) was achieved in four patients (18 %) and partial remission (PR) in three patients (14 %). The median overall survival (OS) and progression-free survival (PFS) were 11.0 and 2.5 months, respectively. Leukopenia was the most frequent side effect and renal impairment was rare. According to a multivariate analysis, better OS and PFS were recorded in patients without bone marrow invasion (OS, hazard ratio (HR) 0.13, p = 0.0079; PFS, HR 0.13, p = 0.0044) or those with AITL (OS, HR 0.21, p = 0.021; PFS, HR 0.15, p = 0.0043). Although overall outcomes of mESHAP for relapsed/refractory T cell lymphomas were not excellent, this regimen remains one of the possible candidates for those with AITL histology or without bone marrow invasion. PMID- 25687840 TI - Diffuse thyroid 18F-FDG uptake after R-CHOP therapy predicts favorable outcome in patients with DLBCL. AB - Therapy-induced autoimmunity may mediate the destruction of cancer cells. Previous studies have demonstrated that presence of autoimmune thyroid disorder is associated with favorable outcome in patients with solid cancer. Patients with diffuse large B cell lymphoma (DLBCL) who achieved complete response on positron emission tomography/computed tomography (PET/CT) after rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy were enrolled in this study. The patients with and without diffuse thyroid uptake (DTU) were classified by PET/CT. A total of 270 patients were enrolled in this study. DTU related to autoimmune thyroiditis was present in 61 patients. The median time to DTU detection was 5.7 months (range, 0-21.3 months). High International Prognostic Index (IPI) score (progression-free survival [PFS], p = 0.001; overall survival [OS], p = 0.008), bulky mass >=10 cm (PFS, p = 0.001; OS, p = 0.001), bone marrow involvement (PFS, p < 0.001; OS, p = 0.001), and DTU after R-CHOP therapy (PFS, p < 0.001; OS, p = 0.001) were significantly associated with PFS and OS. High IPI score (PFS, p = 0.003; OS, p = 0.014), BM involvement (PFS, p = 0.009; OS, p = 0.039), and DTU after R-CHOP therapy (PFS, p = 0.002; OS, p = 0.002) were independently associated with PFS and OS. DTU after R-CHOP therapy independently predicted favorable outcomes in patients with DLBCL. PMID- 25687841 TI - Double somatic mosaic mutations in TET2 and DNMT3A--origin of peripheral T cell lymphoma in a case. PMID- 25687842 TI - Treatment outcome of patients with advanced stage natural killer/T-cell lymphoma: elucidating the effects of asparaginase and postchemotherapeutic radiotherapy. AB - The prognosis of advanced stage natural killer/T-cell lymphoma (NKTCL) remains relatively disappointing, and the optimal treatment strategy for this disease has yet to be discovered. Seventy-three patients with Ann Arbor stage III or IV NKTCL were retrospectively reviewed. The treatment efficacies of asparaginase containing and asparaginase-absent chemotherapy regimens were compared, and the effects of postchemotherapeutic radiotherapy were explored. The overall response rate (ORR) of the asparaginase-containing regimens was marginally higher than that of the asparaginase-absent regimens (56.5 vs 32.6 %, P = 0.057). However, no significant difference was observed in 2-year overall survival (OS) (38.3 vs 22.7 %, P = 0.418) or 2-year progression-free survival (PFS) (25.4 vs 14.9 %, P = 0.134) between the asparaginase-containing and asparaginase-absent groups. Postchemotherapeutic radiotherapy was associated with a significantly prolonged survival (2-year OS 57.5 vs 14.5 %, P < 0.001; 2-year PFS 46.3 vs 8.4 %, P < 0.001) and was an independent predictor of both OS and PFS. Radiotherapy significantly improved the prognosis among the patients who exhibited complete or partial remission after initial chemotherapy (2-year OS 81.5 vs 40.2 %, P = 0.002; 2-year PFS 65.6 vs 23.4 %, P = 0.008) but failed to provide a significant survival advantage among those who experienced stable or progressive disease after initial chemotherapy. In conclusion, the use of asparaginase did not significantly improve survival for the treatment of patients with stage III/IV NKTCL. Postchemotherapeutic radiotherapy provided additional prognostic benefits to patients who responded well to the initial chemotherapy, which requires further validation in future prospective studies using larger sample sizes. PMID- 25687843 TI - Sex differences in the stress response in SD rats. AB - Sex differences play an important role in depression, the basis of which is an excessive stress response. We aimed at revealing the neurobiological sex differences in the same study in acute- and chronically-stressed rats. Female Sprague-Dawley (SD) rats were randomly divided into 6 groups: chronic unpredictable mild stress (CUMS), acute foot shock (FS) and controls, animals in all 3 groups were sacrificed in proestrus or diestrus. Male SD rats were randomly divided into 3 groups: CUMS, FS and controls. Comparisons were made of behavioral changes in CUMS and control rats, plasma levels of corticosterone (CORT), testosterone (T) and estradiol (E2), and of the hypothalamic mRNA-expression of stress-related molecules, i.e. estrogen receptor alpha and beta, androgen receptor, aromatase, mineralocorticoid receptor, glucocorticoid receptor, corticotropin-releasing hormone, arginine vasopressin and oxytocin. CUMS resulted in disordered estrus cycles, more behavioral and hypothalamic stress-related molecules changes and a stronger CORT response in female rats compared with male rats. Female rats also showed decreased E2 and T levels after FS and CUMS, while male FS rats showed increased E2 and male CUMS rats showed decreased T levels. Stress affects the behavioral, endocrine and the molecular response of the stress systems in the hypothalamus of SD rats in a clear sexual dimorphic way, which has parallels in human data on stress and depression. PMID- 25687844 TI - Tipepidine increases dopamine level in the nucleus accumbens without methamphetamine-like behavioral sensitization. AB - We previously reported that the novel antidepressant-like effect of tipepidine may be produced at least partly through the activation of mesolimbic dopamine neurons via inhibition of G protein-coupled inwardly rectifying potassium channels. In this study, we investigated whether tipepidine increases dopamine levels in the nucleus accumbens (NAc) in rats using an in vivo microdialysis technique. We further assessed whether tipepidine at antidepressant-like effective doses induces behavioral- and cross-sensitization of locomotor activity in rats using the open field test. We found that acute administration of tipepidine increased dopamine levels in the NAc in freely moving rats without increasing locomotor activity. Tipepidine at antidepressant-like effective doses (20 and 40 mg/kg, i.p.) did not cause behavioral sensitization in rats. Furthermore, cross-sensitization between tipepidine and methamphetamine was not observed in rats. These results further support our working hypothesis that tipepidine may produce a novel antidepressant-like effect through activation of ventral tegmental area-NAc dopaminergic neurons whose mechanisms differ from those contributing to the reinforcing effects of addictive drugs. PMID- 25687845 TI - Anxiolytic-like effects of restraint during the dark cycle in adolescent mice. AB - Stress during developmental stage may cause psychological morbidities, and then the studies on stress are important in adolescent rodents. Restraint is used as a common stressor in rodents and the effects of restraint during the light cycle have been studied, but those of restraint during the dark cycle have not. The present study examined the effects of restraint during the light and dark cycles on anxiety behaviors in adolescent mice. Restraint for 3h during either the light or dark cycle impaired memory function in the fear conditioning test, but did not affect locomotor activity. In the elevated plus-maze test, restraint during the dark cycle reduced anxiety-like behaviors in mice. Repeated exposure to a 3-h period dark cycle restraint for 2 weeks had a similar anxiolytic-like effect. In contrast, restraint for 3h during the light cycle produced anxiety behavior in adolescent, but not adult, mice. The light cycle stress increased plasma corticosterone levels, and elevated c-Fos expression in the prefrontal cortex, paraventricular hypothalamic nucleus, basolateral amygdala and dentate gyrus, and enhanced serotonin turnover in the hippocampus and striatum, while the dark cycle stress did not. There was no difference in the stress-mediated reduction in pentobarbital-induced sleeping time between dark and light cycle restraint. These findings suggest that the anxiolytic effect of dark cycle restraint is mediated by corticosterone, serotonin or gamma-aminobutyric acid-independent mechanisms, although the anxiogenic effect of light cycle restraint is associated with changes in plasma corticosterone levels and serotonin turnover in specific brain regions. PMID- 25687846 TI - Effects of Phoenixin-14 on anxiolytic-like behavior in mice. AB - Phoenixin is an amidated neuropeptide, which is widely distributed in brain and periphery regions and is known for its key role in reproduction. Phoenixin-14 (PNX-14), one of the endogenous active isoforms, was reported to regulate pituitary gonadotrophin secretion by increasing the expression of the GnRH receptor mRNA. Studies showed that GnRH could regulate brain responses to anxiety. However, the role of PNX-14 in anxiety was largely unclear. Here, we investigated that the effects of PNX-14 in anxiety-related behavior in adult mice via the open field and elevated plus maze. PNX-14 was administered intracerebroventricularly (i.c.v.) in different doses (5, 10, 25 and 50 nmol), and dose-dependently induced anxiolytic effects. Then this anxiolytic action was presented after PNX-14 injected into the anterior hypothalamic area (AHA), while PNX-14 infused into the amygdala did not exert anxiolytic effects. GnRH receptor antagonist (Cetrorelix) could significantly antagonize the anxiolytic effects of PNX-14, while Atosiban, a competitive vasopressin/oxytocin receptor antagonist could not. Moreover, PNX-14 could significantly lower the core temperature and Cetrorelix could block this effect of PNX-14. Additionally, the AHA infusion of PNX-14 (5 nmol) increased the expression level of the GnRH mRNA in the hypothalamus and plasma concentrations of GnRH. Similarly, i.c.v. injection of PNX-20 also reduced the core temperature and exerted anxiolytic effects. Taken together, centrally injected PNX-14 generates anxiolytic effects in mice, via the activation of the AHA GnRH system. PMID- 25687847 TI - HPV-Related Retroperitoneal Squamous Cell Carcinoma of Unknown Primary: A Case Report. AB - A 56-year-old female was referred to our hospital due to a mass measuring 5 cm in size in the left pelvic cavity, which was found incidentally during a health examination by ultrasonography. Exploratory laparotomy was performed and the mass was located at the left retroperitoneal parametrium without invasion of the uterus and ovary. The pathology report confirmed squamous cell carcinoma. Even after further studies, we did not find any other primary lesion. Human papillomavirus (HPV) DNA chip test (HPV 9G DNA Membrane Kit, Biometrixtechnology Inc.) showed that the surgical specimen was positive for HPV 18. She received adjuvant chemotherapy and would receive radiation therapy for the possibility of occult gynecologic cancer. Retroperitoneal squamous cell carcinoma of unknown primary is extremely rare and little is known about it. It is reported that HPV may be associated with the disease. Hence, the result of HPV test could have an impact on finding a suspicious primary lesion and treatment modality in this case. PMID- 25687848 TI - Results of a Phase II Study to Evaluate the Efficacy of Docetaxel and Carboplatin in Metastatic Malignant Melanoma Patients Who Failed First-Line Therapy Containing Dacarbazine. AB - PURPOSE: There is no standard second-line regimen for malignant melanoma patients with disease progression after first-line chemotherapy, and platinum-alkylating agents combined with paclitaxel have shown modest efficacy. MATERIALS AND METHODS: We conducted a phase II, open-label, single-arm study to test the efficacy of docetaxel combined with carboplatin for malignant melanoma patients who failed previous treatment with dacarbazine. Intravenous docetaxel (35 mg/m(2) on days 1 and 8 of each cycle) and carboplatin (area under the curve 3 on days 1 and 8 of each cycle) was administered every 21 days. Primary end point was objective response rate (ORR). RESULTS: Thirty patients were enrolled in the study, and the median follow-up duration was 19.8 months. Among 25 per-protocol patients, there were three responders (1 with complete response and 2 with partial response) and 17 stable disease patients (ORR, 12.0%). Among the per protocol population, the median progression-free survival (PFS) was 4.3 months and the median overall survival (OS) was 9.6 months. Uveal melanoma patients (n=9) showed the best prognosis compared to other subtypes (median PFS, 7.6 months; OS, 9.9 months). The most common grade 3 or 4 adverse event was neutropenia (n=15, 50.0%). CONCLUSION: Docetaxel combined with carboplatin showed association with an acceptable safety profile and overall efficacy for patients with malignant melanoma who had progressed on chemotherapy containing dacarbazine. PMID- 25687849 TI - Role of Radiotherapy in the Multimodal Treatment of Ewing Sarcoma Family Tumors. AB - PURPOSE: The aim of this study was to evaluate the role of radiotherapy (RT) in the management of Ewing sarcoma family tumors (ESFT). MATERIALS AND METHODS: Retrospective analysiswas performed on 91 patientswith localized ESFT treated from 1988 to 2012. Primary tumor size was >= 8 cm in 33 patients. Surgery, RT, and combined surgery with RT were applied in 37, 15, and 33 patients, respectively. RESULTS: Median follow-up was 43.8 months. Forty-three patients (47.3%) showed recurrence or progressive disease. Twelve patients (13.2%) showed local failure after initial treatment. Thirty-nine patients (42.9%) experienced distant metastases. The 5-year overall survival (OS), progression-free survival, and local control (LC) were 60.5%, 58.2%, and 85.1%, respectively. According to treatment, 5-year LCwas 64.8% with RT and 90.2% with combined surgery and RT (p=0.052). Prognostic factors for OS were tumor size (>= 8 cm, p < 0.001) and surgical resection (p < 0.001). In large tumors (>= 8 cm), combined surgery and RT produced better LC compared to RT (p=0.033). However, in smaller tumors (< 8 cm), RT without surgery resulted in a similar LC rate as RT with surgery (p=0.374). CONCLUSION: RT used for patients with unfavorable risk factors resulted in worse outcome than for patientswho received surgery. Smallertumors could be controlled locallywith chemotherapy and RT. For large tumors, combined surgery and RT is needed. Proper selection of local treatment modality, RT, surgery, or both is crucial in the management of ESFT. PMID- 25687850 TI - Pemetrexed Singlet Versus Nonpemetrexed-Based Platinum Doublet as Second-Line Chemotherapy after First-Line Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor Failure in Non-small Cell Lung Cancer Patients with EGFR Mutations. AB - PURPOSE: Platinum-based doublet chemotherapy is the treatment of choice for patients with non-small cell lung cancer (NSCLC); however, the role of a platinum based doublet as second-line therapy after failure of an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) for NSCLC patients has not yet been elucidated. The purpose of this study was to compare the clinical efficacy of pemetrexed versus a platinum-based doublet as second-line therapy after failure of EGFR TKI used as first-line therapy for NSCLC patients with EGFR mutations. MATERIALS AND METHODS: We designed a multicenter retrospective cohort study of 314 NSCLC patients with EGFR mutations who received an EGFR TKI as first line palliative chemotherapy. Our analysis included 83 patients who failed EGFR TKI therapy and received second-line cytotoxic chemotherapy. RESULTS: Forty-six patients were treated using a platinum-based doublet and 37 patients were treated using singlet pemetrexed. The overall response rates of patients receiving a platinum-based doublet and patients receiving pemetrexed were17.4% and 32.4%, respectively (p=0.111). The median progression-free survival (PFS) of patients receiving pemetrexed was significantly longer than that of patients receiving a platinum-based doublet (4.2 months vs. 2.7 months, respectively; p=0.008). The hazard ratio was 0.54 (95% confidence interval, 0.34 to 0.86; p=0.009). CONCLUSION: Our retrospective analysis found that second-line pemetrexed singlet therapy provided significantly prolonged PFS compared to second-line platinum based doublet chemotherapy for NSCLC patients with EGFR mutations who failed first-line EGFR TKI. Conduct of prospective studies for confirmation of our results is warranted. PMID- 25687851 TI - Cancer Treatment near the End-of-Life Becomes More Aggressive: Changes in Trend during 10 Years at a Single Institute. AB - PURPOSE: The purpose of this study was to investigate and compare cancer treatment near the end-of-life (EOL) over a 10-year period. MATERIALS AND METHODS: Patients with advanced solid cancer at Seoul National University Hospital who received palliative chemotherapy and had died were enrolled. We categorized the consecutive patients according to two time periods: 2002 (n=57) and 2012 (n=206). Aggressiveness of cancer treatment near the EOL was evaluated. RESULTS: The median patient age was 62, and 65.4% of patients (n=172) were male. Time from the last chemotherapy to death (TCD) was found to have been significantly shortened, from 66.0 days to 34.0 days during 10 years (p < 0.001); 17% of patients received molecular targeted agents as the last chemotherapy regimen in 2012. The proportion of patients who received intensive care unit care within the last month increased from 1.8% in 2002 to 19.9% in 2012 (p < 0.001), and emergency room visits within the last month also increased from 22.8% to 74.8% (p < 0.001). Although hospice referral increased from 9.1% to 37.4% (p < 0.001), timing of referral was delayed from median 53 days to 8 days before death (p=0.004). Use of targeted agents as the last chemotherapy for over-two-regimen users was associated with shortened TCD (hazard ratio, 2.564; p=0.002). CONCLUSION: Cancer treatment near the EOL became more aggressive over 10 years. PMID- 25687852 TI - Gastroenteropancreatic Neuroendocrine Tumors with Liver Metastases in Korea: A Clinicopathological Analysis of 72 Cases in a Single Institute. AB - PURPOSE: Management of gastroenteropancreatic (GEP) neuroendocrine tumors with liver metastases (NETLM) presents many clinical challenges. Assessment of the extent of disease and primary tumor site is crucial for management. In this study, we investigated the primary tumor sites and prognostic factors in GEP NETLM among Korean patients. MATERIALS AND METHODS: We reviewed the medical records of 72 Korean patients diagnosed with GEP NETLM between January 1999 and May 2013, focusing on their clinical and pathologic characteristics. RESULTS: The most frequently encountered primary tumor sites were the pancreas (n=25, 35%), stomach (n=8, 11%), gall bladder (n=4, 6%) and rectum (n=3, 4%). Twenty-five patients (35%) had occult primary tumor. Twelve patients (17%) had histological grade G1 tumors, 30 patients (42%) had G2 tumors, and 30 patients (42%) had G3 tumors. The mean follow-up period after histological confirmation of hepatic metastases was 11.30+/-2.44 months for G3 tumors, 19.67+/-4.09 months for G2 tumors, and 30.67+/-6.51 months for G1 tumors. Multivariate analyses revealed that an unknown primary tumor site (p=0.001) and higher histological grade (p < 0.001) were independent prognostic indicators for shorter overall survival (OS). Most long-term survivors (OS > 24 months) had received antitumor treatment. CONCLUSION: The primary tumor site most frequently associated with GEP NETLM was the pancreas. Unknown primary tumor and higher histological grade were independent prognostic indicators for shorter OS. Patients identified as being at a risk of shorter OS should be followed up closely. PMID- 25687853 TI - Simultaneous Detection of Disseminated and Circulating Tumor Cells in Primary Breast Cancer Patients. AB - PURPOSE: Disseminated tumor cells (DTCs) from bone marrow (BM) are a surrogate of minimal residual disease (MRD) in primary breast cancer (PBC) patients and associated with an adverse prognosis. However, BM sampling is an invasive procedure. Although there is growing evidence that circulating tumor cells (CTCs) from the blood are also suitable for monitoring MRD, data on the simultaneous detection of DTCs and CTCs are limited. MATERIALS AND METHODS: We determined the presence of DTCs using immunocytochemistry and the pan-cytokeratin antibody A45 B/B3. CTCs were determined simultaneously using a reverse transcription polymerase chain reaction-based assay (AdnaTest Breast Cancer) and CellSearch (at least one CTC per 7.5 mL blood). We compared the detection of DTCs and CTCs and evaluated their impact on disease-free and overall survival. RESULTS: Of 585 patients, 131 (22%) were positive for DTCs; 19 of 202 (9%) and 18 of 383 (5%) patients were positive for CTCs, as shown by AdnaTest and CellSearch, respectively. No significant association was observed between DTCs and CTCs (p=0.248 and p=0.146 as shown by AdnaTest and CellSearch, respectively). The presence of DTCs (p=0.046) and the presence of CTCs as shown by CellSearch (p=0.007) were predictive of disease-free survival. CONCLUSION: Our data confirm the prognostic relevance of DTCs and CTCs in patients with PBC. As we found no significant relationship between DTCs and CTCs, prospective trials should include their simultaneous detection. Within those trials, the question of whether or not DTCs and CTCs are independent subpopulations of malignant cell clones should be determined by molecular characterization. PMID- 25687854 TI - Palliative Radiotherapy in the Presence of Well-Controlled Metastatic Disease after Initial Chemotherapy May Prolong Survival in Patients with Metastatic Esophageal and Gastric Cancer. AB - PURPOSE: We report the outcomes of patients treated with palliative radiotherapy (pRT) to the primary tumour in the context of well-controlled metastatic disease after initial chemotherapy. MATERIALS AND METHODS: Clinical records of 132 patients with metastatic esophago-gastric (OG) cancer treated with palliative chemotherapy (pCT) between January 2009 and June 2013 were reviewed. Ninetyseven patients had responding or stable disease after 3 months of chemotherapy, of whom 53 patients received pRT to the primary tumour after initial chemotherapy in the presence of well-controlled metastatic disease (group A, pCT-RT). The remaining 44 patients were treated with pCT alone (group B, pCT). Treatment-related outcomes were assessed in above groups including time to local progression (TTLP), progression-free and overall survival. RESULTS: The median overall survival for patients treated with pRT after initial chemotherapy (group A) was 23.3 months (95% confidence interval [CI], 17.70 to 28.89 months) and significantly higher than the 14 months (95% CI, 10.91 to 17.08 months) in patients treated with pCT alone (group B) (p < 0.001). The use of pCT-RT was an independent predictor of OS in multivariate analysis. Local recurrence was observed in 12/53 of patients (23%) in group A compared to 16/44 (36%) in group B. The median TTLP was significantly higher in patients after pCT-RT at 17.3 months (5.23 months to 44.50 months) compared to 8.3 months (range, 4.10 to 25.23 months) in patients treated with pCT alone (p=0.006). CONCLUSION: The possibility of pRT influencing systemic disease in advanced OG cancer has not been reported, and results from the present study present strong arguments for investigation of this therapeutic strategy in a randomized trial. PMID- 25687855 TI - ATAD2 as a Poor Prognostic Marker for Hepatocellular Carcinoma after Curative Resection. AB - PURPOSE: Cancer cells frequently express genes that are specifically or preferentially expressed in male germ cells under normal conditions. The ATPase family AAA domain-containing 2 (ATAD2) is one such and works as an important cofactor for MYC-dependent transcription. In hepatocellular carcinoma (HCC), ATAD2 has been identified as a candidate driver gene located within the amplified 8q24 locus. However, the prognostic significance of ATAD2 protein expression in HCC remains uncertain. MATERIALS AND METHODS: We investigated ATAD2 protein expression by immunohistochemistry in tumor tissue from 182 HCC patients who underwent curative resection. Associations of ATAD2 expression with clinicopathologic variables or prognosis of HCC patients were analyzed. RESULTS: ATAD2 expression was observed in 119 (65.4%) of the 182 HCCs and tended to be independent predictor of early recurrence (p=0.059). ATAD2 expression showed an unfavorable influence on recurrence-free survival (RFS) (p < 0.001). Subgroup analysis among patients with tumor size <= 5.0 cm (n=109), patients at Barcelona Clinic Liver Cancer stage 0 or A (n=92), and patients with alpha-fetoprotein <= 20 ng/mL (n=61), the ATAD2-positive groups unfavorably influenced RFS (p=0.008, p=0.009, and p=0.013, respectively). In addition, ATAD2 expression was an independent predictor of shorter RFS (p=0.002). ATAD2 expression showed an unfavorable influence on disease-specific survival (p=0.001), but was not an independent predictor of shorter disease-specific survival (p=0.109). CONCLUSION: ATAD2 protein expression may be a potential predictor of RFS in HCC patients after curative resection and ATAD2 may have prognostic value in patients with early stage HCC or normal serum alpha-fetoprotein level. PMID- 25687856 TI - Interstitial Lung Change in Pre-radiation Therapy Computed Tomography Is a Risk Factor for Severe Radiation Pneumonitis. AB - PURPOSE: We examined clinical and dosimetric factors as predictors of symptomatic radiation pneumonitis (RP) in lung cancer patients and evaluated the relationship between interstitial lung changes in the pre-radiotherapy (RT) computed tomography (CT) and symptomatic RP. MATERIALS AND METHODS: Medical records and dose volume histogram data of 60 lung cancer patients from August 2005 to July 2006 were analyzed. All patients were treated with three dimensional (3D) conformal RT of median 56.9 Gy. We assessed the association of symptomatic RP with clinical and dosimetric factors. RESULTS: With a median follow-up of 15.5 months (range, 6.1 to 40.9 months), Radiation Therapy Oncology Group grade >= 2 RP was observed in 14 patients (23.3%). Five patients (8.3%) died from RP. The interstitial changes in the pre-RT chest CT, mean lung dose (MLD), and V30 significantly predicted RP in multivariable analysis (p=0.009, p < 0.001, and p < 0.001, respectively). MLD, V20, V30, and normal tissue complication probability normal tissue complication probability (NTCP) were associated with the RP grade but less so for grade 5 RP. The risk of RP grade >= 2, >= 3, or >= 4 was higher in the patients with interstitial lung change (grade 2, 15.6% to 46.7%, p=0.03; grade 3, 4.4% to 40%, p=0.002; grade 4, 4.4% to 33.3%, p=0.008). Four of the grade 5 RP patients had diffuse interstitial change in pre-RT CT and received chemoradiotherapy. CONCLUSION: Our study identified diffuse interstitial disease as a significant clinical risk for RP, particularly fatal RP. We showed the usefulness of MLD, V20, V30, and NTCP in predicting the incidence and severity of RP. PMID- 25687857 TI - Setup Error and Effectiveness of Weekly Image-Guided Radiation Therapy of TomoDirect for Early Breast Cancer. AB - PURPOSE: This study investigated setup error and effectiveness of weekly image guided radiotherapy (IGRT) of TomoDirect for early breast cancer. MATERIALS AND METHODS: One hundred and fifty-one breasts of 147 consecutive patients who underwent breast conserving surgery followed by whole breast irradiation using TomoDirect in 2012 and 2013 were evaluated. All patients received weekly IGRT. The weekly setup errors from simulation to each treatment in reference to chest wall and surgical clips were measured. Random, systemic, and 3-dimensional setup errors were assessed. Extensive setup error was defined as 5 mm above the margin in any directions. RESULTS: All mean errors were within 3 mm of all directions. The mean angle of gantry shifts was 0.6 degrees . The mean value of absolute 3 dimensional setup error was 4.67 mm. In multivariate analysis, breast size (odds ratio, 2.82; 95% confidence interval, 1.00 to 7.90) was a significant factor for extensive error. The largest significant deviation of setup error was observed in the first week of radiotherapy (p < 0.001) and the deviations gradually decreased with time. The deviation of setup error was 5.68 mm in the first week and within 5 mm after the second week. CONCLUSION: In this study, there was a significant association between breast size and significant setup error in breast cancer patients who received TomoDirect. The largest deviation occurred in the first week of treatment. Therefore, patients with large breasts should be closely observed on every fraction and fastidious attention is required in the first fraction of IGRT. PMID- 25687858 TI - Role of Chemotherapy in Stage II Nasopharyngeal Carcinoma Treated with Curative Radiotherapy. AB - PURPOSE: To define the role of neoadjuvant and concurrent chemotherapy in stage II nasopharyngeal carcinoma, we compared the treatment outcomes of patients treated with curative radiotherapy with or without chemotherapy. MATERIALS AND METHODS: From 2004 to 2011, 138 patients with American Joint Committee on Cancer (AJCC) 2002 stage II nasopharyngeal carcinoma were treated with curative radiotherapy in 12 hospitals in South Korea. Treatment methods included radiotherapy alone in 34 patients, neoadjuvant chemotherapy followed by radiotherapy alone in seven, concurrent chemoradiotherapy in 80, and neoadjuvant chemotherapy followed by concurrent chemoradiotherapy in 17. Adjuvant chemotherapy was used in 42 patients. Total radiation dose ranged from 64 Gy to 74.2 Gy (median, 70 Gy). RESULTS: Median follow-up was 48 months (range, 7 to 97 months) for all patients. At the last follow-up, 13 patients had died and 32 had experienced treatment failure; locoregional failure occurred in 14, distant failure in 16, and both in two. Five-year locoregional relapse-free survival, distant metastasis-free survival, progression-free survival, and overall survival were 86.2%, 85.5%, 74.4%, and 88.2%, respectively. Multivariate analyses showed that the significant prognostic factors were concurrent chemotherapy and N stage for locoregional relapse-free survival, concurrent chemotherapy for progression free survival, and age and N stage for overall survival. Neither neoadjuvant nor concurrent chemotherapy improved distant metastasis-free survival. CONCLUSION: Concurrent chemotherapy significantly improved 5-year locoregional relapse-free survival and progression-free survival in stage II nasopharyngeal carcinoma. However, neoadjuvant chemotherapy failed to improve either. PMID- 25687859 TI - Long-Term Outcome of Definitive Radiotherapy for Early Glottic Cancer: Prognostic Factors and Patterns of Local Failure. AB - PURPOSE: This study evaluates the long-term results of definitive radiotherapy (RT) for early glottic cancer. Clinical and treatment factors related to local control and patterns of failure are analyzed. MATERIALS AND METHODS: We retrospectively reviewed 222 patients with T1-2N0 squamous cell carcinoma of the glottic larynx treated with definitive RT from 1981 to 2010. None of the patients received elective nodal RT or combined chemotherapy. The median total RT dose was 66 Gy. The daily fraction size was < 2.5 Gy in 69% and 2.5 Gy in 31% of patients. The RT field extended from the hyoid bone to the cricoid cartilage. RESULTS: The median age was 60 years, and 155 patients (70%) had T1 disease. The 5-year rates of local recurrence-free survival (LRFS) and ultimate LRFS with voice preservation were 87.8% and 90.3%, respectively. T2 (hazard ratio [HR], 2.30; 95% confidence interval [CI], 1.08 to 4.94) and anterior commissural involvement (HR, 3.37; 95% CI, 1.62 to 7.02) were significant prognostic factors for LRFS. In 34 patients with local recurrence, tumors recurred in the ipsilateral vocal cord in 28 patients. There were no contralateral vocal cord recurrences. Most acute complications included grade 1-2 dysphagia and/or hoarseness. There was no grade 3 or greater chronic toxicity. CONCLUSION: Definitive RT achieved a high cure rate, voice preservation, and tolerable toxicity in early glottic cancer. T2 stage and anterior commissural involvement were prognostic factors for local control. Further optimization of the RT method is needed to reduce the risk of ipsilateral tumor recurrence. PMID- 25687860 TI - The Economic Burden of Breast Cancer in Korea from 2007-2010. AB - PURPOSE: This study estimates the socioeconomic cost and burden for breast cancer patients in Korea between 2007 and 2010. MATERIALS AND METHODS: This study used a prevalence-based approach to estimate the cost of breast cancer. Breast cancer patients were defined as those who were hospitalized or have visited an outpatient clinic during the period from 2007 to 2010. The socioeconomic costs of breast cancer were subdivided into two costs: direct and indirect. RESULTS: From 2007 to 2010, the prevalence of treated breast cancer increased from 7.9% to 20.4%. The total socioeconomic costs incurred by breast cancer increased by approximately 40.7% from US $668.49 million in 2007 to US $940.75 million in 2010. The direct medical care costs for 2010 were 1.4 times greater (US $399.22 million) than for 2007 (US $278.71 million). The direct non-medical costs rose from US $50.69 million in 2007 to US $75.83 million in 2010, a 49.6% increase. Regarding the economic burden of breast cancer, the total indirect costs were US $339.09 million in 2007 and increased by 37.3% to US $465.70 million in 2010. In the sensitivity analysis, with the annual discount rate for each year ranging from 0%-5%, the costs increased 1.1-1.2 times. CONCLUSION: Due to the growing incidence of breast cancer, the annual prevalence and related costs are increasing. We must strive to reduce the socioeconomic burden of breast cancer through preventive measures and early screening. PMID- 25687861 TI - A Case Report of Partial Nephrectomy of Mucinous Cystadenocarcinoma in Kidney and Its Literature Review. AB - Mucinous cystadenocarcinoma (MC) of the kidney is a rare epithelial tumor originating from the renal pelvic urothelium and few study cases have been reported. Because of the rarity of these tumors and their unknown histogenesis, its diagnosis is difficult until surgical exploration. We report here on a 55 year-old man referred to the urology department from the hepatology department because of a cystic renal mass measuring approximately 5 cm in size, which was detected incidentally under ultrasonography during the routine examination of liver. The renal mass was finally diagnosed as MC originating from kidney after partial nephrectomy and the patient still showed no evidence of recurrence until 12 months postoperatively. This is the first report on a case of renal MC in a patient who underwent partial nephrectomy. The aim of this report is to present our unusual case of MC and also review the previous literature on the pathological and radiological aspects of MC of kidney. PMID- 25687862 TI - Expression of PEG10 Is Associated with Poor Survival and Tumor Recurrence in Hepatocellular Carcinoma. AB - PURPOSE: Paternally expressed gene 10 (PEG10), first identified as an imprinted gene, is paternally expressed and maternally silenced. In hepatocellular carcinoma (HCC), PEG10 has been identified as a potential target gene located within the amplified 7q21 locus. The purpose of this study was to investigate the expression of PEG10 protein in HCC and evaluate its prognostic significance. MATERIALS AND METHODS: PEG10 protein expression was examined by immunohistochemistry in tumor tissues from 218 HCC patients undergoing curative resection. Furthermore, the relationships between PEG10 expression and clinicopathologic features or postoperative survival of HCC patients were evaluated. The median follow-up period was 119.8 months for survivors. RESULTS: PEG10 expression was observed in 148 of the 218 HCCs (67.9%) and was significantly correlated with younger age, female, higher Edmondson grade, microvascular invasion, intrahepatic metastasis, higher American Joint Committee on Cancer T-stage, and higher alpha-fetoprotein level. PEG10 expression was an independent predictor of early recurrence (p=0.013), and it showed an unfavorable influence on recurrence-free survival (p < 0.001). A subgroup analysis showed that among patients with alpha-fetoprotein <= 20 ng/mL (80 patients), the PEG10 positive group also showed an unfavorable influence on recurrence-free survival (p=0.002). Moreover, a multivariate survival analysis identified PEG10 as an independent predictor of shorter recurrence-free survival (p=0.005). PEG10 expression showed an unfavorable influence on overall survival (p=0.007) but was not an independent predictor of shorter overall survival (p=0.128). CONCLUSION: PEG10 protein could be a potential biomarker predicting early recurrence and recurrence-free survival in HCC patients after curative resection, even in those with normal serum alpha-fetoprotein levels. PMID- 25687863 TI - Detecting Metastatic Bladder Cancer Using (18)F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography. AB - PURPOSE: The purpose of this study was to retrospectively investigate the contribution of (18)F-fluorodeoxyglucose-positron emission tomography/computed tomography ((18)F-FDG-PET/CT) to detection of metastatic bladder cancer. MATERIALS AND METHODS: The present study included 79 patients (69 men and 10 women) undergoing (18)F-FDG-PET/CT upon suspicion of metastatic bladder cancer between July 2007 and April 2013. The mean age was 66.1 years with a standard deviation of 10.7 years (range, 21 to 85 years). Patients were required to fast for 6 hours prior to scanning, and whole-body PET scanning from the skull base to the upper thighs was performed approximately 1 hour after intravenous injection of 555 MBq of (18)F-FDG. Whole body CT scanning was performed in the cranio caudal direction. FDG-PET images were reconstructed using CT data for attenuation correction. Suspicious recurrent or metastatic lesions were confirmed by histopathology or clinical follow-up. RESULTS: The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of (18)F-FDG PET/CT were 89%, 78%, 90%, 75%, and 86%, respectively. CONCLUSION: (18)F-FDG PET/CT can detect metastases with high sensitivity and positive predictive values in patients with metastatic bladder carcinoma. PMID- 25687864 TI - Definitive Bimodality Concurrent Chemoradiotherapy in Patients with Inoperable N2 positive Stage IIIA Non-small Cell Lung Cancer. AB - PURPOSE: This study was conducted to evaluate the treatment outcomes following definitive bimodality concurrent chemoradiotherapy (CCRT) in patients with inoperable N2-positive stage IIIA (N2-IIIA) non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: From May 1997 to December 2012, 65 out of 633 patients with N2-IIIA NSCLC received bimodality therapy. The treatment modality was selected during/after neoadjuvant CCRT in 21 patients or primarily at diagnosis in 44 through a multidisciplinary consensus meeting. The median age was 65 years (range, 36 to 76 years). Sixty patients (92.3%) had clinically evident N2 disease, while 22 (33.8%) had multi-station N2 involvement. The median radiation therapy dose was 66 Gy in 33 fractions, while the dose was elevated to 72 Gy in 13 patients who had a treatment break due to delayed decision regarding resectability. The most frequent chemotherapy regimen was weekly paclitaxel or docetaxel plus cisplatin or carboplatin (54, 83.1%). RESULTS: During the median follow-up of 18.8 months (range, 1.6 to 173.1 months), 34 patients (52.3%) experienced disease progression, with distant metastasis being the most common first treatment failure pattern (23, 34.8%). The median and 2-year rates of progression-free survival were 18.8 months and 45.9%, respectively. The median and 2-year rates of overall survival were 28.6 months and 50.1%, respectively. CONCLUSION: Definitive bimodality therapy in patients with N2-IIIA NSCLC demonstrated favorable outcomes, while trimodality therapy could be considered for candidates for less than pneumonectomy. PMID- 25687865 TI - Effect of Radiation Therapy Techniques on Outcome in N3-positive IIIB Non-small Cell Lung Cancer Treated with Concurrent Chemoradiotherapy. AB - PURPOSE: This study was conducted to evaluate clinical outcomes following definitive concurrent chemoradiotherapy (CCRT) for patients with N3-positive stage IIIB (N3-IIIB) non-small cell lung cancer (NSCLC), with a focus on radiation therapy (RT) techniques. MATERIALS AND METHODS: From May 2010 to November 2012, 77 patients with N3-IIIB NSCLC received definitive CCRT (median, 66 Gy). RT techniques were selected individually based on estimated lung toxicity, with 3-dimensional conformal RT (3D-CRT) and intensity-modulated RT (IMRT) delivered to 48 (62.3%) and 29 (37.7%) patients, respectively. Weekly docetaxel/paclitaxel plus cisplatin (67, 87.0%) was the most common concurrent chemotherapy regimen. RESULTS: The median age and clinical target volume (CTV) were 60 years and 288.0 cm(3), respectively. Patients receiving IMRT had greater disease extent in terms of supraclavicular lymph node (SCN) involvement and CTV >= 300 cm(3). The median follow-up time was 21.7 months. Fortyfive patients (58.4%) experienced disease progression, most frequently distant metastasis (39, 50.6%). In-field locoregional control, progression-free survival (PFS), and overall survival (OS) rates at 2 years were 87.9%, 38.7%, and 75.2%, respectively. Although locoregional control was similar between RT techniques, patients receiving IMRT had worse PFS and OS, and SCN metastases from the lower lobe primary tumor and CTV >= 300 cm(3)were associated with worse OS. The incidence and severity of toxicities did not differ significantly between RT techniques. CONCLUSION: IMRT could lead to similar locoregional control and toxicity, while encompassing a greater disease extent than 3D-CRT. The decision to apply IMRT should be made carefully after considering oncologic outcomes associated with greater disease extent and cost. PMID- 25687866 TI - Oncologists' Experience with Patients with Second Primary Cancer and the Attitudes toward Second Primary Cancer Screening: A Nationwide Survey. AB - PURPOSE: Screening for second primary cancer (SPC) is one of the key components to survivorship care. We aim to evaluate the oncologists' experience with SPCs and assess the current practice, perceived barriers, and recommendations related to SPC screening. MATERIALS AND METHODS: A nationwide survey was conducted with a representative sample of 496 Korean oncologists. A questionnaire based on the findings from our previous qualitative study was administered. RESULTS: More than three-fourths of oncologists (76.3%), who participated in the study, had experience with SPC patients. Over half of them (51.9%) stated that it was an embarrassing experience. While the current management practice for SPC varies, most oncologists (80.2%) agreed on the necessity in proactively providing information on SPC screening. A short consultation time (52.3%), lack of guidelines and evidence on SPC screening (47.7%), and patients' lack of knowledge about SPCs (45.1%) or SPC screening (41.4%) were most frequently reported as barriers to providing appropriate care for managing SPC. Oncologists recommended the development of specific screening programs or guidelines in accordance to the type of primary cancer (65.9%), the development of an internal system for SPC screening within the hospital (59.7%) or systematic connection with the national cancer screening program (44.3%), and education of oncologists (41.4%) as well as patients (48.9%) regarding SPC screening. CONCLUSION: Many oncologists reported the occurrence of SPC as an embarrassing experience. Given the variations in current practice and the lack of consensus, further studies are warranted to develop the optimal clinical strategy to provide SPC screening for cancer survivors. PMID- 25687867 TI - Phase I Study of Axitinib in Combination with Cisplatin and Capecitabine in Patients with Previously Untreated Advanced Gastric Cancer. AB - PURPOSE: This phase I trial evaluated the question of whether the standard starting dose of axitinib could be administered in combination with therapeutic doses of cisplatin/capecitabine in patients with previously untreated advanced gastric cancer, and assessed overall safety, pharmacokinetics, and preliminary antitumor activity of this combination. MATERIALS AND METHODS: Patients in dose level (DL) 1 received axitinib 5 mg twice a day (days 1 to 21) with cisplatin 80 mg/m(2) (day 1) and capecitabine 1,000 mg/m(2) twice a day (days 1 to 14) in 21 day cycles. Maximum tolerated dose (MTD) was the highest dose at which <= 30% of the first 12 patients experienced a dose-limiting toxicity (DLT) during cycle 1. Ten additional patients were enrolled and treated at the MTD in order to obtain additional safety and pharmacokinetic data. RESULTS: Three DLTs occurred during cycle 1 in three (25%) of the first 12 patients: ruptured abdominal aortic aneurysm, acute renal failure, and > 5 consecutive days of missed axitinib due to thrombocytopenia. DL1 was established as the MTD, since higher DL cohorts were not planned. Common grade 3/4 non-hematologic adverse events in 22 patients treated at DL1 included hypertension (36.4%) and decreased appetite and stomatitis (18.2% each). Cisplatin/capecitabine slightly increased axitinib exposure; axitinib decreased capecitabine and 5-fluorouracil exposure. Eight patients (36.4%) each had partial response or stable disease. Median response duration was 9.1 months; median progression-free survival was 3.8 months. CONCLUSION: In patients with advanced gastric cancer, standard doses of axitinib plus therapeutic doses of cisplatin and capecitabine could be administered in combination. Adverse events were manageable. PMID- 25687868 TI - Long-term Outcome of Chondrosarcoma: A Single Institutional Experience. AB - PURPOSE: The prognostic factors of chondrosarcoma remain uncertain as only a few large studies with long-term follow-up have been reported. The aim of this study was to analyze oncological outcomes and prognostic factors. MATERIALS AND METHODS: A retrospective review of oncological outcomes and prognostic factors was performed on 125 consecutive chondrosarcoma patients who underwent surgery at our institution. RESULTS: Overall survival was 91.6%+/-2.5%, 84.1%+/-3.8%, and 84.1%+/-3.8% at 5, 10, and 15 years respectively. Among the histological types, dedifferentiated type showed the worst survival (p < 0.001). As for conventional type chondrosarcoma, histologic grade and anatomical location predicted outcome, with high-grade with axial location having the worst outcome (p < 0.001). In contrast, low-grade chondrosarcoma of appendicular skeleton could be treated safely by intralesional curettage. CONCLUSION: Histological type was significantly associated with the outcome of chondrosarcoma. For the conventional type, histologic grade and anatomical location predicted outcome, with high-grade with axial location having the worst outcome. PMID- 25687869 TI - Population-based Incidence and Survival for Primary Central Nervous System Lymphoma in Korea, 1999-2009. AB - PURPOSE: Primary central nervous system lymphoma (PCNSL) is an uncommon brain tumor accounting for 2%-5% of all primary brain tumors. Few population-based analyses of survival for patients with PCNSL have been conducted, particularly in Asian countries. MATERIALS AND METHODS: Using the Korea National Cancer Incidence Database, 1,062 cases of PCNSL newly diagnosed from 1999 to 2009 were analyzed. The crude rate, age-standardized rate (ASR), and annual percent change were calculated. To estimate the observed survival, we restricted the data to between 1999 and 2007 and followed the cases until December 2010. The overall survival was estimated using the Kaplan-Meier method, and piecewise Poisson regression model. RESULTS: The ASR for PCNSL between 1999 and 2009 was 0.17 per 100,000, and the annual percent change from 1999 to 2009 was 8.8% (p < 0.001). The ASR of males was higher than that of females, and the older groups (60s or over) showed the largest increase in incidence rates. For all ages, the five-year survival from PCNSL was 29.9% between 1999 and 2007. Survival from PCNSL is known to show strong association with age at diagnosis. CONCLUSION: These results are similar to those of previous studies. Our findings may be helpful to clinicians and patients in determining long-term prognoses for PCNSL. PMID- 25687870 TI - Overexpression of Plasminogen Activator Inhibitor-1 in Advanced Gastric Cancer with Aggressive Lymph Node Metastasis. AB - PURPOSE: The purpose of this study is to investigate differentially expressed genes using DNA microarray between advanced gastric cancer (AGC) with aggressive lymph node (LN) metastasis and that with a more advanced tumor stage but without LN metastasis. MATERIALS AND METHODS: Five sample pairs of gastric cancer tissue and normal gastric mucosa were taken from three patients with T3N3 stage (highN) and two with T4N0 stage (lowN). Data from triplicate DNA microarray experiments were analyzed, and candidate genes were identified using a volcano plot that showed >= 2-fold differential expression and were significant by Welch's t test (p < 0.05) between highN and lowN. Those selected genes were validated independently by reverse-transcriptase-polymerase chain reaction (RT-PCR) using five AGC patients, and tissue-microarray (TMA) comprising 47 AGC patients. RESULTS: CFTR, LAMC2, SERPINE2, F2R, MMP7, FN1, TIMP1, plasminogen activator inhibitor-1 (PAI-1), ITGB8, SDS, and TMPRSS4 were commonly up-regulated over 2 fold in highN. REG3A, CD24, ITLN1, and WBP5 were commonly down-regulated over 2 fold in lowN. Among these genes, overexpression of PAI-1 was validated by RT-PCR, and TMA showed 16.7% (7/42) PAI-1 expression in T3N3, but none (0/5) in T4N0 (p=0.393). CONCLUSION: DNA microarray analysis and validation by RT-PCR and TMA showed that overexpression of PAI-1 is related to aggressive LN metastasis in AGC. PMID- 25687871 TI - GRP78 Protein Expression as Prognostic Values in Neoadjuvant Chemoradiotherapy and Laparoscopic Surgery for Locally Advanced Rectal Cancer. AB - PURPOSE: We investigated the relationships between biomarkers related to endoplasmic reticulum stress proteins (glucose-regulated protein of molecular mass 78 [GRP78] and Cripto-1 [teratocarcinoma-derived growth factor 1 protein]), pathologic response, and prognosis in locally advanced rectal cancer. MATERIALS AND METHODS: All clinical stage II and III rectal cancer patients received 50.4 Gy over 5.5 weeks, plus 5-fluorouracil (400 mg/m(2)/day) and leucovorin (20 mg/m(2)/day) bolus on days 1 to 5 and 29 to 33, and surgery was performed at 7 to 10 weeks after completion of all therapies. Expression of GRP78 and Cripto-1 proteins was determined by immunohistochemistry and was assessed in 101 patients with rectal cancer treated with neoadjuvant chemoradiotherapy (CRT). RESULTS: High expression of GRP78 and Cripto-1 proteins was observed in 86 patients (85.1%) and 49 patients (48.5%), respectively. Low expression of GRP78 protein was associated with a significantly high rate of down staging (80.0% vs. 52.3%, respectively; p=0.046) and a significantly low rate of recurrence (0% vs. 33.7%, respectively; p=0.008) compared with high expression of GRP78 protein. Mean recurrence-free survival according to GRP78 expression could not be estimated because the low expression group did not develop recurrence events but showed a significant correlation with time to recurrence, based on the log rank method (p=0.007). GRP78 also showed correlation with overall survival, based on the log rank method (p=0.045). CONCLUSION: GRP78 expression is a predictive and prognostic factor for down staging, recurrence, and survival in rectal cancer patients treated with 5-fluorouracil and leucovorin neoadjuvant CRT. PMID- 25687872 TI - Identification of EGFR Mutations by Immunohistochemistry with EGFR Mutation Specific Antibodies in Biopsy and Resection Specimens from Pulmonary Adenocarcinoma. AB - PURPOSE: Mutation-specific antibodies have recently been developed for identification of epidermal growth factor receptor (EGFR) mutations by immunohistochemistry (IHC). This study was designed to investigate whether the type of specimen (biopsy vs. resection) would make a difference in determining mutation status by IHC, and to evaluate whether biopsies are suitable for detection of mutant EGFR protein. MATERIALS AND METHODS: IHC was performed using mutation-specific antibodies for E746-A750 deletion (DEL) and L858R point mutation (L858R) in biopsies and tissue microarrays of resected tumors from 154 patients with pulmonary adenocarcinoma. Results were then compared with DNA sequencing data. RESULTS: Molecular-based assays detected EGFR mutations in 62 patients (40.3%), including 14 (9.1%) with DEL, and 31 (20.1%) with L858R. IHC with two mutation-specific antibodies showed a homogeneous staining pattern, and correctly identified EGFR mutation status in 89% (137/154). Overall (biopsy/resection) sensitivity, specificity, positive predictive value, and negative predictive value were 75.6% (78.3%/72.7%), 94.5% (90.9%/96.3%), 85% (78.3%/88.9%), and 90.4% (90.9%/89.7%), respectively. CONCLUSION: Our data showed that IHC using EGFR mutation-specific antibodies is useful for detection of EGFR mutations with high specificity and good sensitivity not only for resection specimens but also for biopsy materials. Therefore, IHC using EGFR mutation specific antibodies may preclude a second biopsy procedure to obtain additional tissues for identification of EGFR mutations by molecular assays in biopsies from advanced cancer, particularly when tumor cells in the samples are limited. PMID- 25687873 TI - Can Serum be Used for Analyzing the KRAS Mutation Status in Patients with Advanced Colorectal Cancer? AB - PURPOSE: KRAS mutations have been used widely as prognostic or predictive marker in patients with advanced colorectal cancer (CRC). However, it may be difficult to obtain a tumor tissue for analyzing the status of KRAS mutation in large proportion of patients with advanced disease. MATERIALS AND METHODS: We obtained pairs of tumor and serum samples from 65 patients with advanced CRC, between March 2008 and July 2011. KRAS mutation status from the tumor samples was analyzed by genomic polymerase chain reaction and direct sequence, and KRAS mutation status from the serum samples was determined by a genomic polymerase chain reaction-restriction fragment length polymorphism assay. RESULTS: KRAS mutations were detected in the serum samples of 26 patients and in the tumor samples of 31 patients. KRAS mutation status in the serum and tumor samples was consistent in 44 of the 65 pairs (67.7%). There was a significant correlation between the mutations detected in the serum sample and the mutations detected in the matched tumor sample (correlation index, 0.35; p < 0.004). Twenty-two of the 57 patients (38.5%) received anti-epidermal growth factor receptor therapy as any line therapy. There was no significant difference in the overall survival (OS) in accordance to the status of KRAS mutations in both the serum and tumor samples (p > 0.05). In a multivariate analysis, liver metastasis and no cytoreductive operation were independent prognostic factors for decreased OS. CONCLUSION: The serum sample might alternatively be used when it is difficult to obtain tumor tissues for analyzing the status of KRAS mutation in patients with advanced CRC. PMID- 25687874 TI - Optimal Interval for Repeated Gastric Cancer Screening in Normal-Risk Healthy Korean Adults: A Retrospective Cohort Study. AB - PURPOSE: This retrospective cohort study was conducted to estimate the optimal interval for gastric cancer screening in Korean adults with initial negative screening results. MATERIALS AND METHODS: This study consisted of voluntary Korean screenees aged 40 to 69 years who underwent subsequent screening gastroscopies after testing negative in the baseline screening performed between January 2007 and December 2011. A new case was defined as the presence of gastric cancer cells in biopsy specimens obtained upon gastroscopy. The follow-up periods were calculated during the months between the date of baseline screening gastroscopy and positive findings upon subsequent screenings, stratified by sex and age group. The mean sojourn time (MST) for determining the screening interval was estimated using the prevalence/incidence ratio. RESULTS: Of the 293,520 voluntary screenees for the gastric cancer screening program, 91,850 (31.29%) underwent subsequent screening gastroscopies between January 2007 and December 2011. The MSTs in men and women were 21.67 months (95% confidence intervals [CI], 17.64 to 26.88 months) and 15.14 months (95% CI, 9.44 to 25.85 months), respectively. CONCLUSION: These findings suggest that the optimal interval for subsequent gastric screening in both men and women is 24 months, supporting the 2 year interval recommended by the nationwide gastric cancer screening program. PMID- 25687875 TI - Incidence and Treatment Pattern of Extremity Soft Tissue Sarcoma in Korea, 2009 2011: A Nationwide Study Based on the Health Insurance Review and Assessment Service Database. AB - PURPOSE: We conducted a nationwide study to assess the incidence and treatment patterns of extremity soft tissue sarcoma (STS) in South Korea. MATERIALS AND METHODS: The nationwide incidence and treatment patterns of extremity STS were assessed using two nationwide databases, the Korea National Cancer Incidence (KNCI) database and the Health Insurance Review and Assessment Service (HIRA) database. RESULTS: A total of 1,236 patients were newly diagnosed with extremity STS during the 3-year study period, from 2009 to 2011. The annual incidence of extremity STS in the Korean population was approximately 0.9 per 100,000 people with a male bias that increased with age and was especially pronounced amongst individuals aged > 80 years. Approximately 7% of patients did not receive any treatment, and surgical excision was performed for 85% of those who were treated. CONCLUSION: This is the first nationwide study of the incidence and treatment patterns of extremity STS in Korea using two national databases (KNCI and HIRA), which include the entire Korean population. The results of this study may be useful for future planning and management of STS, at the national level. PMID- 25687876 TI - A Novel, Potent, Small Molecule AKT Inhibitor Exhibits Efficacy against Lung Cancer Cells In Vitro. AB - PURPOSE: Anomalies of Akt regulation, including overexpression in lung cancer, impart resistance to conventional chemotherapy and radiation, thereby implicating this kinase as a therapeutic intervention point. A novel scaffold of Akt inhibitors was developed through virtual screening of chemical databases available at Birla Institute of Technology and Science, Pilani, Hyderabad, based on docking studies using Maestro. A benzothienopyrimidine derivative (BIA-6) was identified as a potential lead molecule that inhibited Akt1 enzyme activity with an IC50 of 256 nM. MATERIALS AND METHODS: BIA-6 was tested for in vitro Akt1 inhibition using a fluorescence resonance energy transfer kit. Anti-proliferative activity was tested in NCI-H460, A549, NCI-H1975, and NCI-H2170 cell lines. The effect of the compound on p-Akt (S(473)) was estimated. RESULTS: BIA-6 allosterically caused a dose dependent reduction of growth of cell lines with a half maximal growth inhibition (GI50) range of 0.49 MUM to 6.6 MUM. Cell cycle analysis indicated that BIA-6 caused a G1 phase arrest at < 100 nM but led to apoptosis at higher doses. BIA-6 also exhibited synergism with standard chemotherapeutic agents. CONCLUSION: BIA-6 is a novel, allosteric Akt inhibitor with potent anti-cancer activity in lung cancer cell lines, that effectively blocks the phosphoinositide-3 kinase/Akt pathway with a high margin selectivity towards normal cells. PMID- 25687877 TI - Dynamic quantification of antigen molecules with flow cytometry. AB - Traditional methods for estimating the number of expressed molecules, based on the detection of target antigens bound with fluorescently labeled antibodies, assume that the antigen-antibody reaction reaches equilibrium. A calibration procedure is used to convert the intensity of the fluorescence signal to the number of target molecules. Along with the different limitations of every calibration system, this substantially limits the applicability of the traditional approaches especially in the case of low affinity antibodies. We address this problem here with studies in which we demonstrate a new approach to the antigen molecule quantification problem. Instead of using a static calibration system, we analyzed mean fluorescence values over time by flow cytometry during antibody-antigen binding. Experimental data obtained with an LSRII cytometer were fitted by a diffusion-reaction mathematical model using the Levenberg-Marquardt nonlinear least squares curve-fitting algorithm in order to obtain the number of target antigen molecules per cell. Results were compared with the Quanti-BRITE calibration system. We conclude that, instead of using experiment-specific calibration, the value of the binding rate constant for each particular antibody-antigen reaction can be used to quantify antigen molecules with flow cytometry. The radius of CD8 antibody molecule binding site was found, that allows recalculating the binding rate constant for other conditions (different sizes of reagent molecules, fluorescent label, medium viscosity and temperature). This approach is independent of specially prepared calibration beads, antibody reagents and the specific dye and can be applied to both low and high affinity antibodies, under both saturating and non-saturating binding conditions. The method was demonstrated on a human blood sample dataset investigating CD8alpha antigen on T cells in stable binding conditions. PMID- 25687878 TI - Galvanic Vestibular Stimulation: a new model of placebo-induced nausea. AB - OBJECTIVE: Traditional rotation-based models of placebo nausea are limited because they do not have vehicle settings and are tied to their context. The present study introduces a new model for examining placebo-induced nausea in the laboratory that overcomes these limitations, namely, Galvanic Vestibular Stimulation (GVS). GVS stimulates the vestibular system to cause nausea through sensory mismatch with visual cues and importantly has a non-nauseating placebo setting. Using this, we tested whether conditioning could elicit placebo nausea when participants were later exposed to placebo stimulation as well as whether this placebo nausea was generalised across contexts--something that is extremely difficult to test with rotation-based models of placebo nausea. METHODS: Thirty healthy undergraduate students were randomised to receive either placebo GVS (controls) or active GVS during training (Context-Consistent and Context-Change). On test, all groups received placebo GVS. The controls and Context-Consistent groups were tested in the same context as training, whereas the Context-Change group was tested in a new context. RESULTS: Participants conditioned with nausea during training had significantly higher nausea symptom ratings after placebo stimulation on test than those given no conditioning. This placebo-induced nausea also generalised to a novel test context with no differences observed between the Context-Change and Context-Consistent groups. CONCLUSION: GVS provides a new model of placebo-induced nausea that overcomes limitations to traditional rotation-based paradigms. Future studies should use this device to explore the effect of instructions and conditioning on the development of placebo nausea and to assess the efficacy of conditioning-based interventions for clinical use. PMID- 25687879 TI - Arterial Stiffness: A Novel Risk Factor for Kidney Injury Progression? AB - Arterial stiffness is typical feature of vascular remodeling in chronic kidney disease (CKD). Increased arterial stiffness raises flow and pressure pulsatility and is considered the principle pathogenic mechanism of isolated systolic hypertension, left ventricular hypertrophy, and congestive heart failure. Apart from the impact of arterial stiffness on left ventricular afterload, downstream transmission of pressure pulsatility to the level of microcirculation is suggested to promote injury of other susceptible organs. This may be of particular importance for kidney injury progression, since passive renal perfusion along with low resistance and input impedance in renal microvessels make kidneys particularly vulnerable to the damaging effect of systemic pulsatile pressure. Recent studies have provided evidence that arterial stiffness culminates in elevated pulsatility and resistance in renal microvasculature, promoting structural damage of small intra-renal arterioles. Further, prospective observational studies have shown that reduced aortic compliance is closely associated with the annual rate of renal function decline and represents independent predictor of kidney injury progression to end-stage renal disease among patients with CKD. This article provides insights into the cross-talk between macrocirculation and renal microcirculation and summarizes the currently available clinical evidence linking increased arterial stiffness with kidney disease progression. PMID- 25687880 TI - MDR1 siRNA loaded hyaluronic acid-based CD44 targeted nanoparticle systems circumvent paclitaxel resistance in ovarian cancer. AB - Development of multidrug resistance (MDR) is an almost universal phenomenon in patients with ovarian cancer, and this severely limits the ultimate success of chemotherapy in the clinic. Overexpression of the MDR1 gene and corresponding P glycoprotein (Pgp) is one of the best known MDR mechanisms. MDR1 siRNA based strategies were proposed to circumvent MDR, however, systemic, safe, and effective targeted delivery is still a major challenge. Cluster of differentiation 44 (CD44) targeted hyaluronic acid (HA) based nanoparticle has been shown to successfully deliver chemotherapy agents or siRNAs into tumor cells. The goal of this study is to evaluate the ability of HA-PEI/HA-PEG to deliver MDR1 siRNA and the efficacy of the combination of HA-PEI/HA-PEG/MDR1 siRNA with paclitaxel to suppress growth of ovarian cancer. We observed that HA PEI/HA-PEG nanoparticles can efficiently deliver MDR1 siRNA into MDR ovarian cancer cells, resulting in down-regulation of MDR1 and Pgp expression. Administration of HA-PEI/HA-PEG/MDR1 siRNA nanoparticles followed by paclitaxel treatment induced a significant inhibitory effect on the tumor growth, decreased Pgp expression and increased apoptosis in MDR ovarian cancer mice model. Our findings suggest that CD44 targeted HA-PEI/HA-PEG/MDR1 siRNA nanoparticles can serve as a therapeutic tool with great potentials to circumvent MDR in ovarian cancer. PMID- 25687882 TI - Role of carcinogenesis related mechanisms in cataractogenesis and its implications for ionizing radiation cataractogenesis. AB - Ionizing radiation is a proven human carcinogen and cataractogen. The crystalline lens of the eye is among the most radiosensitive tissues in the body. A clouding of the normally transparent lens (i.e., cataract) is very common. Conversely, the lens continues to grow throughout life without developing tumors, suggesting that the lens possesses strong anti-carcinogenesis mechanisms. There is mounting evidence that mutations of oncogenes, tumor suppressor genes, DNA repair genes involved in base excision repair, nucleotide excision repair, and DNA double strand break repair, and genes involved in intercellular interactions (e.g., via connexin gap junctions), and inflammation affect cataract development. Associations of these factors with cancer have long been recognized, highlighting that cataractogenesis shares some common mechanisms with carcinogenesis. This paper briefly overviews the current knowledge on the potential involvement of tumor related factors, DNA repair factors, intercellular interactions and inflammation in spontaneous cataractogenesis, and discusses its implications for cataractogenesis induced by targeted and nontargeted effects of ionizing irradiation. PMID- 25687883 TI - Metabolic tumor burden is associated with major oncogenomic alterations and serum tumor markers in patients with resected pancreatic cancer. AB - Pancreatic cancer is an aggressive and lethal disease with an overall 5-year survival rate of only 5%. Studies have demonstrated the ability of (18)F fludrodeoxyglucose ((18)F-FDG) positron emission tomography/computed tomography (PET/CT) to measure the metabolic tumor burden in patients with various tumors, including pancreatic cancer. In a previous study, we investigated the predictive significance of the metabolic tumor burden in terms of the metabolic tumor volume (MTV) and total lesion glycolysis (TLG). In this study, we analyzed the correlation between metabolic tumor burden and the status of the KRAS, TP53, CDKN2A/p16, and SMAD4/DPC4 genes. Our results showed that the metabolic tumor burden was associated with oncogenomic alterations that reflected the abnormal expression of carbohydrate metabolic enzymes (GLUT1, ALDOA and FBP1). We also identified a linear correlation between serum tumor markers and the metabolic tumor burden. To estimate the metabolic tumor burden when (18)F-FDG PET/CT is not available, we used the linear regression models to establish equations for MTV and TLG using CA19-9 and CA125 as independent variables. Our results suggest that the metabolic tumor burden, as evaluated by (18)F-FDG PET/CT or estimated by serum tumor markers, may be suitable for monitoring treatment response and disease progression of pancreatic cancer. Further research is needed to better understand why pancreatic cancer patients with abnormal expressions of TP53, CDKN2A/p16, and SMAD4/DPC4 get high metabolic tumor burden. PMID- 25687884 TI - ROMO1 regulates RedOx states and serves as an inducer of NF-kappaB-driven EMT factors in Fanconi anemia. AB - Fanconi anemia (FA) is a rare genetic disorder associated with a bone-marrow failure, genome instability, hypersensitivity to DNA crosslinking agents and a predisposition to cancer. Mutations have been documented in 16 FA genes that participate in the FA-BRCA DNA repair pathway, a fundamental pathway in the development of the disease and the presentation of its symptoms. Besides the well established role of FA genes in DNA damage and repair pathways, recent reports have revealed an overproduction of epithelial to mesenchymal transition (EMT) factors via a NF-kappaB-dependent mechanism that results in the proliferation of neighboring tumor cells and FA cells have also been shown to possess damaged mitochondria, accompanied by altered RedOx pathways. This study has focused on reactive oxygen species Modulator-1 (ROMO1), an oncomarker and mitochondrial membrane protein, which is known to be associated with cancer growth and in the modulation of RedOx states in some cancer models. Here, we reveal the role of ROMO1 and demonstrate its link in regulating RedOx states and in the activation of NF-kappaB-dependent EMT factors in FA. PMID- 25687885 TI - CXCL8, overexpressed in colorectal cancer, enhances the resistance of colorectal cancer cells to anoikis. AB - Anoikis is a form of apoptosis which occurs when anchorage-dependent cells either show loss of adhesion or inappropriate adhesion. Only a few cancer cells that detach from the primary site of the tumor acquire the ability to resist anoikis and form metastasis. The mechanism underlying the resistance of colorectal cancer (CRC) cells to anoikis remains unclear. Interleukin-8 (alternatively known as CXCL8) is associated with CRC angiogenesis and progression. Here, we found that a high abundance of CXCL8 or TOPK strongly correlated with poor overall and disease free survival of 186 patients with CRC. A combination of high CXCL8 and high TOPK expressions had the worst prognosis. We showed that CXCL8 expression was negatively correlated with anoikis in CRC cells. CXCL8 treatment enhanced the resistance of CRC cells to apoptosis, which was accompanied by the increase of TOPK, and the activation of AKT and ERK. Moreover, we demonstrated that the inhibition of either ERK or AKT by specific chemical inhibitors attenuated the CXCL8-mediated resistance to anoikis. Treatment with AKT inhibitor abolished the effects of CXCL8 on TOPK expression, suggesting that TOPK was downstream of AKT in the process of anoikis. Taken together, we demonstrated that CXCL8 is strongly implicated in the resistance of CRC cells to anoikis, and that the AKT, TOPK and ERK pathway may be a potential therapeutic target for CRC. PMID- 25687886 TI - Epigenetic modifications as regulatory elements of autophagy in cancer. AB - Epigenetic modifications have been considered as hallmarks of cancer and play an important role in tumor initiation and development. Epigenetic mechanisms, including DNA methylation, histone modifications, and microRNAs, may regulate cell cycle and apoptosis, as well as macroautophagy (hereafter referred to as autophagy). Autophagy, as a crucial cellular homeostatic mechanism, performs a dual role, having pro-survival or pro-death properties. A variety of signaling pathways including epigenetic control have been implicated in the upregulation or downregulation of autophagy. However, the role of epigenetic regulation in autophagy is still less well acknowledged. Recent studies have linked epigenetic control to the autophagic process. Some epigenetic modifiers are also involved in the regulation of autophagy and potentiate the efficacy of traditional therapeutics. Thus, understanding the novel functions of epigenetic control in autophagy may allow us to develop potential therapeutic approaches for cancer treatment. PMID- 25687887 TI - Visualization of molecular fluorescence point spread functions via remote excitation switching fluorescence microscopy. AB - The enhancement of molecular absorption, emission and scattering processes by coupling to surface plasmon polaritons on metallic nanoparticles is a key issue in plasmonics for applications in (bio)chemical sensing, light harvesting and photocatalysis. Nevertheless, the point spread functions for single-molecule emission near metallic nanoparticles remain difficult to characterize due to fluorophore photodegradation, background emission and scattering from the plasmonic structure. Here we overcome this problem by exciting fluorophores remotely using plasmons propagating along metallic nanowires. The experiments reveal a complex array of single-molecule fluorescence point spread functions that depend not only on nanowire dimensions but also on the position and orientation of the molecular transition dipole. This work has consequences for both single-molecule regime-sensing and super-resolution imaging involving metallic nanoparticles and opens the possibilities for fast size sorting of metallic nanoparticles, and for predicting molecular orientation and binding position on metallic nanoparticles via far-field optical imaging. PMID- 25687888 TI - Ivabradine in combination with Beta-blockers in patients with chronic stable angina after percutaneous coronary intervention. AB - INTRODUCTION: The anti-anginal efficacy of ivabradine is well established. We describe a post hoc analysis in the ADDITIONS database to investigate effectiveness and tolerability of ivabradine in combination with beta-blocker in patients with angina who have had a percutaneous coronary intervention (PCI). METHODS: ADDITIONS was a non-interventional, multicenter prospective study including 2,330 patients with stable angina. In addition to beta-blocker, patients were treated with ivabradine in approved dosages for 4 months. We divided the population according to whether they had previously had a PCI or not, and explored the effect of ivabradine on heart rate, number of weekly angina attacks, frequency of nitrate consumption, as well as quality of life (QoL) and tolerability. RESULTS: Data were available for 2,319 patients, of whom 51.4% had previously had a PCI. There was no difference in the effect of ivabradine on mean heart rate between patients with a previous PCI [64.4 +/- 7.6 beats per minute (bpm)] than those without (66.8 +/- 8.5 bpm) at 4 months (both P < 0.0001). Similarly, the number of angina attacks decreased from 1.9 +/- 2.4 to 0.5 +/- 1.5 per week in patients with a previous PCI and 1.5 +/- 2.0 to 0.3 +/- 1.0 per week in patients without a previous PCI (both P < 0.0001). The frequency of nitrate consumption fell from 2.7 +/- 3.7 to 1.0 +/- 1.9 per week and 1.8 +/- 2.8 to 0.6 +/- 1.5 per week (both P < 0.0001) in patients with and without a previous PCI, respectively. There was no difference in the improvements in Canadian Cardiovascular Society class of angina, QoL, and physicians' assessment of effectiveness and tolerability between patients with a previous PCI and those without. CONCLUSION: Ivabradine is an effective and well-tolerated anti-anginal treatment in patients with stable angina after PCI. Ivabradine reduced the frequency of weekly angina attacks and nitrate consumption, led to an improvement in Canadian Cardiovascular Society class and a substantial improvement in the QoL of stable angina patients. PMID- 25687889 TI - A single pre-operative antibiotic dose is as effective as continued antibiotic prophylaxis in implant-based breast reconstruction: A matched cohort study. AB - PURPOSE: Infections following implant-based breast reconstruction can lead to devastating consequences. There is currently no consensus on the need for post operative antibiotics in preventing immediate infection. This study compared two different methods of infection prevention in this group of patients. METHOD: A retrospective matched cohort study was performed on consecutive women undergoing implant-based breast reconstruction at University Health Network, Toronto (November 2008-December 2012). All patients received a single pre-operative intravenous antibiotic dose. Group A received minimal interventions and Group B underwent maximal prophylactic measures. Patient (age, smoking, diabetes, co morbidities), oncologic and procedural variables (timing and laterality) were collected. Univariate and multivariate logistic regression were performed to compare outcomes between the two groups. RESULTS: Two hundred and eight patients underwent 647 implant procedures. After matching the two treatment groups by BMI, 94 patients in each treatment group yielding a total of 605 implant procedures were selected for analysis. The two groups were comparable in terms of patient and disease variables. Post-operative wound infection was similar in Group A (n = 11, 12%) compared with Group B (n = 9, 10%; p = 0.8). Univariate analysis revealed only pre-operative radiotherapy to be associated with the development of infection (0.004). Controlling for the effect of radiotherapy, multivariate analysis demonstrated that there was no statistically significant difference between the two methods for infection prevention. CONCLUSIONS: Our findings suggest that a single pre-operative dose of intravenous antibiotics is equally as effective as continued antibiotic prophylaxis in preventing immediate infection in patients undergoing implant-based breast reconstructions. PMID- 25687890 TI - Extended vulvar immediate reconstruction using the bilateral transverse pedicled DIEP flap. PMID- 25687891 TI - Tuning the dielectric properties of metallic-nanoparticle/elastomer composites by strain. AB - Tunable metal/dielectric composites are promising candidates for a large number of potential applications in electronics, sensor technologies and optical devices. Here we systematically investigate the dielectric properties of Ag nanoparticles embedded in the highly flexible elastomer poly-dimethylsiloxane (PDMS). As tuning parameter we use uniaxial and biaxial strain applied to the composite. We demonstrate that both static variations of the filling factor and applied strain lead to the same behavior, i.e., the filling factor of the composite can be tuned by application of strain. In this way the effective static permittivity epsiloneff of the composite can be varied over a very large range. Once the Poisson's ratio of the composite is known, the strain dependent dielectric constant can be accurately described by effective medium theory without any additional free fit parameter up to metal filling factors close to the percolation threshold. It is demonstrated that, starting above the percolation threshold in the metallic phase, applying strain provides the possibility to cross the percolation threshold into the insulating region. The change of regime from conductive phase down to insulating follows the description given by percolation theory and can be actively controlled. PMID- 25687892 TI - Toward an understanding of the function of Chlamydiales in plastid endosymbiosis. AB - Plastid endosymbiosis defines a process through which a fully evolved cyanobacterial ancestor has transmitted to a eukaryotic phagotroph the hundreds of genes required to perform oxygenic photosynthesis, together with the membrane structures, and cellular compartment associated with this process. In this review, we will summarize the evidence pointing to an active role of Chlamydiales in metabolic integration of free living cyanobacteria, within the cytosol of the last common plant ancestor. PMID- 25687893 TI - Biogenesis of light harvesting proteins. AB - The LHC family includes nuclear-encoded, integral thylakoid membrane proteins, most of which coordinate chlorophyll and xanthophyll chromophores. By assembling with the core complexes of both photosystems, LHCs form a flexible peripheral moiety for enhancing light-harvesting cross-section, regulating its efficiency and providing protection against photo-oxidative stress. Upon its first appearance, LHC proteins underwent evolutionary diversification into a large protein family with a complex genetic redundancy. Such differentiation appears as a crucial event in the adaptation of photosynthetic organisms to changing environmental conditions and land colonization. The structure of photosystems, including nuclear- and chloroplast-encoded subunits, presented the cell with a number of challenges for the control of the light harvesting function. Indeed, LHC-encoding messages are translated in the cytosol, and pre-proteins imported into the chloroplast, processed to their mature size and targeted to the thylakoids where are assembled with chromophores. Thus, a tight coordination between nuclear and plastid gene expression, in response to environmental stimuli, is required to adjust LHC composition during photoacclimation. In recent years, remarkable progress has been achieved in elucidating structure, function and regulatory pathways involving LHCs; however, a number of molecular details still await elucidation. In this review, we will provide an overview on the current knowledge on LHC biogenesis, ranging from organization of pigment-protein complexes to the modulation of gene expression, import and targeting to the photosynthetic membranes, and regulation of LHC assembly and turnover. Genes controlling these events are potential candidate for biotechnological applications aimed at optimizing light use efficiency of photosynthetic organisms. This article is part of a Special Issue entitled: Chloroplast biogenesis. PMID- 25687894 TI - Diverse mechanisms for photoprotection in photosynthesis. Dynamic regulation of photosystem II excitation in response to rapid environmental change. AB - Photosystem II (PSII) of photosynthesis catalyzes one of the most challenging reactions in nature, the light driven oxidation of water and release of molecular oxygen. PSII couples the sequential four step oxidation of water and two step reduction of plastoquinone to single photon photochemistry with charge accumulation centers on both its electron donor and acceptor sides. Photon capture, excitation energy transfer, and trapping occur on a much faster time scale than the subsequent electron transfer and charge accumulation steps. A balance between excitation of PSII and the use of the absorbed energy to drive electron transport is essential. If the absorption of light energy increases and/or the sink capacity for photosynthetically derived electrons decreases, potentially deleterious side reactions may occur, including the production of reactive oxygen species. In response, a myriad of fast (second to minutes timescale) and reversible photoprotective mechanisms are observed to regulate PSII excitation when the environment changes more quickly than can be acclimated to by gene expression. This review compares the diverse photoprotective mechanisms that are used to dissipate (quench) PSII excitation within the antenna systems of higher land plants, green algae, diatoms, and cyanobacteria. The molecular bases of how PSII excitation pressure is sensed by the antenna system and how the antenna then reconfigures itself from a light harvesting to an energy dissipative mode are discussed. PMID- 25687895 TI - Calcium-dependent regulation of photosynthesis. AB - The understanding of calcium as a second messenger in plants has been growing intensively over the last decades. Recently, attention has been drawn to the organelles, especially the chloroplast but focused on the stromal Ca2+ transients in response to environmental stresses. Herein we will expand this view and discuss the role of Ca2+ in photosynthesis. Moreover we address of how Ca2+ is delivered to chloroplast stroma and thylakoids. Thereby, new light is shed on the regulation of photosynthetic electron flow and light-dependent metabolism by the interplay of Ca2+, thylakoid acidification and redox status. This article is part of a Special Issue entitled: Chloroplast biogenesis. PMID- 25687896 TI - Skeletal muscle mitochondria of NDUFS4-/- mice display normal maximal pyruvate oxidation and ATP production. AB - Mitochondrial ATP production is mediated by the oxidative phosphorylation (OXPHOS) system, which consists of four multi-subunit complexes (CI-CIV) and the FoF1-ATP synthase (CV). Mitochondrial disorders including Leigh Syndrome often involve CI dysfunction, the pathophysiological consequences of which still remain incompletely understood. Here we combined experimental and computational strategies to gain mechanistic insight into the energy metabolism of isolated skeletal muscle mitochondria from 5-week-old wild-type (WT) and CI-deficient NDUFS4-/- (KO) mice. Enzyme activity measurements in KO mitochondria revealed a reduction of 79% in maximal CI activity (Vmax), which was paralleled by 45-72% increase in Vmax of CII, CIII, CIV and citrate synthase. Mathematical modeling of mitochondrial metabolism predicted that these Vmax changes do not affect the maximal rates of pyruvate (PYR) oxidation and ATP production in KO mitochondria. This prediction was empirically confirmed by flux measurements. In silico analysis further predicted that CI deficiency altered the concentration of intermediate metabolites, modestly increased mitochondrial NADH/NAD+ ratio and stimulated the lower half of the TCA cycle, including CII. Several of the predicted changes were previously observed in experimental models of CI deficiency. Interestingly, model predictions further suggested that CI deficiency only has major metabolic consequences when its activity decreases below 90% of normal levels, compatible with a biochemical threshold effect. Taken together, our results suggest that mouse skeletal muscle mitochondria possess a substantial CI overcapacity, which minimizes the effects of CI dysfunction on mitochondrial metabolism in this otherwise early fatal mouse model. PMID- 25687897 TI - A nomogram to estimate the HbA1c response to different DPP-4 inhibitors in type 2 diabetes: a systematic review and meta-analysis of 98 trials with 24 163 patients. AB - OBJECTIVES: To develop a nomogram for estimating the glycated haemoglobin (HbA1c) response to different dipeptidyl peptidase-4 (DPP-4) inhibitors in type 2 diabetes. DESIGN: A systematic review and meta-analysis of randomised controlled trials (RCTs) of DPP-4 inhibitors (vildagliptin, sitagliptin, saxagliptin, linagliptin and alogliptin) on HbA1c were conducted. Electronic searches were carried out up to December 2013. Trials were included if they were carried out on participants with type 2 diabetes, lasted at least 12 weeks, included at least 30 participants and had a final assessment of HbA1c. A random effect model was used to pool data. A nomogram was used to represent results of the metaregression model. PARTICIPANTS: Adults with type 2 diabetes. INTERVENTIONS: Any DPP-4 inhibitor (vildagliptin, sitagliptin, saxagliptin, linagliptin or alogliptin). OUTCOME MEASURES: The HbA1c response to each DPP-4 inhibitor within 1 year of therapy. RESULTS: We screened 928 citations and reviewed 98 articles reporting 98 RCTs with 100 arms in 24 163 participants. There were 26 arms with vildagliptin, 37 with sitagliptin, 13 with saxagliptin, 13 with linagliptin and 11 with alogliptin. For all 100 arms, the mean baseline HbA1c value was 8.05% (64 mmol/mol); the decrease of HbA1c from baseline was -0.77% (95% CI -0.82 to 0.72%), with high heterogeneity (I(2)=96%). Multivariable metaregression model that included baseline HbA1c, type of DPP-4 inhibitor and fasting glucose explained 58% of variance between studies, with no significant interaction between them. Other factors, including age, previous diabetes drugs and duration of treatment added low predictive power (<1%). The nomogram estimates the absolute HbA1c reduction from baseline using the type of DPP-4 inhibitor, baseline values of HbA1c and fasting glucose. CONCLUSIONS: Baseline HbA1c level and fasting glucose explain most of the variance in HbA1c change in response to DPP-4 inhibitors: each increase of 1.0% units HbA1c provides a 0.4-0.5% units greater fall. PMID- 25687898 TI - Dynamics of resilience in forced migration: a 1-year follow-up study of longitudinal associations with mental health in a conflict-affected, ethnic Muslim population. AB - OBJECTIVE: The concept of 'resilience' is of increasing interest in studies of mental health in populations facing adversity. However, lack of longitudinal data on the dynamics of resilience and non-usage of resilience-specific measurements have prevented a better understanding of resilience-mental health interactions. Hence, the present study was conducted to investigate the stability of levels of resilience and its associations with sociodemographic and mental health exposures in a conflict-affected internal-migrant population in Sri Lanka. DESIGN: A prospective follow-up study of 1 year. SETTING: Puttalam district of North Western province in postconflict Sri Lanka (baseline in 2011, follow-up in 2012). PARTICIPANTS: An ethnic Muslim population internally displaced 20 years ago (in 1990) from Northern Sri Lanka, aged 18 or above and currently in the process of return migration. MEASURES: It was hypothesised that levels of resilience would be associated with mental health outcomes. Resilience was measured on both occasions using the 14-item Resilience Scale (RS-14), social support by the Multidimensional Social Support Scale and Lubben Social Network Scale and common mental disorders by the Patient Health Questionnaire (PHQ). RESULTS: Of 450 participants interviewed at baseline in 2011, 338 (75.1%) were re-interviewed in 2012 after a 1-year follow-up. The mean resilience scores measured by RS-14 were 80.2 (95% CI 78.6 to 81.9) at baseline and 84.9 (83.5 to 86.3) at follow-up. At both time points, lower resilience was independently associated with food insecurity, lower social support availability and social isolation. At both time points, there were significant associations with common mental disorders (CMDs) in unadjusted analyses, but they only showed independence at baseline. The CMD prevalence, maintenance and incidence at follow-up was 8.3%, 28.2% and 2.2%, respectively. CONCLUSIONS: In this displaced population facing a potential reduction in adversity, resilience was more strongly and robustly associated with economic and social factors than with the presence of mental disorder. PMID- 25687899 TI - A survey-based cross-sectional study of doctors' expectations and experiences of non-technical skills for Out of Hours work. AB - OBJECTIVES: The skill set required for junior doctors to work efficiently and safely Out of Hours (OoH) in hospitals has not been established. This is despite the OoH period representing 75% of the year and it being the time of highest mortality. We set out to explore the expectations of medical students and experiences of junior doctors of the non-technical skills needed to work OoH. DESIGN: Survey-based cross-sectional study informed by focus groups. SETTING: Online survey with participants from five large teaching hospitals across the UK. PARTICIPANTS: 300 Medical Students and Doctors OUTCOME MEASURE: Participants ranked the importance of non-technical skills, as identified by literature review and focus groups, needed for OoH care. RESULTS: The focus groups revealed a total of eight non-technical skills deemed to be important. In the survey 'Task Prioritisation' (mean rank 1.617) was consistently identified as the most important non-technical skill. Stage of training affected the ranking of skills, with significant differences for 'Communication with Senior Doctors', 'Dealing with Clinical Isolation', 'Task Prioritisation' and 'Communication with Patients'. Importantly, there was a significant discrepancy between the medical student expectations and experiences of doctors undertaking work. CONCLUSIONS: Our findings suggest that medical staff particularly value task prioritisation skills; however, these are not routinely taught in medical schools. The discrepancy between expectations of students and experience of doctors reinforces the idea that there is a gap in training. Doctors of different grades place different importance on specific non-technical skills with implications for postgraduate training. There is a pressing need for medical schools and deaneries to review non-technical training to include more than communication skills. PMID- 25687900 TI - The Men's Safer Sex (MenSS) trial: protocol for a pilot randomised controlled trial of an interactive digital intervention to increase condom use in men. AB - INTRODUCTION: Sexually transmitted infections (STI) are a major public health problem. Condoms provide effective protection but there are many barriers to use. Face-to-face health promotion interventions are resource-intensive and show mixed results. Interactive digital interventions may provide a suitable alternative, allowing private access to personally tailored behaviour change support. We have developed an interactive digital intervention (the Men's Safer Sex (MenSS) website) which aims to increase condom use in men. We describe the protocol for a pilot trial to assess the feasibility of a full-scale randomised controlled trial of the MenSS website in addition to usual sexual health clinical care. METHODS AND ANALYSIS: PARTICIPANTS: Men aged 16 or over who report female sexual partners and recent unprotected sex or suspected acute STI. PARTICIPANTS (N=166) will be enrolled using a tablet computer in clinic waiting rooms. All trial procedures will be online, that is, eligibility checks; study consent; trial registration; automated random allocation; and data submission. At baseline and at 3, 6 and 12 months, an online questionnaire will assess condom use, self reported STI diagnoses, and mediators of condom use (eg, knowledge, intention). Reminders will be by email and mobile phone. The primary outcome is condom use, measured at 3 months. STI rates will be recorded from sexual health clinic medical records at 12 months. The feasibility of a cost-effectiveness analysis will be assessed, to calculate incremental cost per STI prevented (Chlamydia or Gonorrhoea), from the NHS perspective. ETHICS AND DISSEMINATION: Ethical approval: City and East NHS Research Ethics Committee (reference number 13 LO 1801). Findings will be made available through publication in peer-reviewed journals, and to participants and members of the public via Twitter and from the University College London eHealth Unit website. Raw data will be made available on request. TRIAL REGISTRATION NUMBER: Current Controlled Trials. ISRCTN18649610. Registered 15 October 2013 http://www.controlled-trials.com/ISRCTN18649610. PMID- 25687901 TI - Comparing kidney outcomes in type 2 diabetes treated with different sulphonylureas in real-life clinical practice. AB - AIM: Although several sulphonylureas are widely used in type 2 diabetes (T2D), their differential impacts on long-term major kidney outcomes remain unclear. This study aimed to investigate the effects of the two most commonly prescribed sulphonylureas, glimepiride and gliclazide, on kidney outcomes in patients with T2D. METHODS: A total of 4486 patients treated with either glimepiride or gliclazide for more than 2 years were followed for up to 5.5 years (median: 4.7 years). A propensity score based on baseline characteristics was used to match 1427 patients treated with glimepiride with 1427 gliclazide-treated patients; incidences of end-stage renal disease (ESRD) and sustained doubling of creatinine to>132.6 MUmol/L (1.5mg/dL) were also compared. RESULTS: In the matched cohort with 12,122 person-years of follow-up, there was no significant difference between groups in risk of ESRD [hazard ratio (HR): 0.57, 95% confidence interval (CI): 0.29-1.12] or doubling of creatinine (HR: 0.74, 95% CI: 0.44-1.26), although there was a trend towards higher risks in the glimepiride group. Subgroup analyses showed that, compared with glimepiride, gliclazide was associated with a lower risk of doubling of creatinine in patients with preserved renal function (glomerular filtration rate >= 60 mL/min/1.73 m(2), HR: 0.21, 95% CI: 0.04-0.99) and good glycaemic control (HbA1c < 7%, HR: 0.35, 95% CI: 0.14 0.86), and in older subjects (>= 62 years, HR: 0.52, 95% CI: 0.27-0.99). CONCLUSION: In a real-life setting, there was no significant difference in clinical outcomes of kidney disease for patients treated with glimepiride vs gliclazide. However, gliclazide appeared to protect against renal complication progression in certain populations. PMID- 25687902 TI - Pharmacists as immunizers: a survey of community pharmacists' willingness to administer adult immunizations. AB - BACKGROUND: Adult immunization rates worldwide fall below desired targets. Pharmacists are highly accessible healthcare providers with the potential to increase immunization rates among adults by administering vaccines in their practice setting. OBJECTIVE: To determine the attitudes of community-based Canadian pharmacists with respect to expanding their scope of practice to include administration of immunizations. METHOD: An internet-based survey was emailed to community pharmacists across Canada. The survey was piloted through focus groups for qualitative feedback, tested for content validity, and test-retest reliability prior to dissemination. RESULTS: There were 495 responses to the survey. The majority (88 %) agreed that pharmacists as immunizers would increase public access, improve rates (84 %), and be acceptable to the public (72 %). However, only 68 % agreed that pharmacists should be permitted to immunize. The majority of respondents (90 %) agreed that certification in vaccine administration should be required for pharmacists to administer vaccines. Pharmacists identified education, reimbursement, and negative interactions with other providers as barriers to pharmacists administering vaccines. CONCLUSION: Canadian pharmacists are willing to expand their scope of practice to include immunization. However, implementation requires professional development and certification in vaccine administration. PMID- 25687903 TI - Theoretical study of stereoselectivity of the [1 + 2] cycloaddition reaction between (1S,3R,8S)-2,2-dichloro-3,7,7,10-tetramethyltricyclo[6,4,0,0(1.3)]dodec-9 ene and dibromocarbene using density functional theory (DFT) B3LYP/6-31G*(d). AB - In this work we used density functional theory (DFT) B3LYP/6-31G*(d) to study the stoichiometric reaction between the product (1S,3R,8S)-2,2-dichloro-3,7,7,10 tetramethyltricyclo[6,4,0,0(1.3)]dodec-9-ene (referred to here as P1) and dibromocarbene. We have shown that P1 behaves as a nucleophile, while dibromocarbene behaves as an electrophile; that the chemical potential of dibromocarbene is superior to that of P1 in absolute terms; and that P1 reacts with an equivalent quantity of dibromocarbene to produce two products: (1S,3R,8R,9S,11R)-10,10-dibromo-2,2-dichloro-3,7,7,11 tetramethyltetracyclo[6,5,0,0(1.3),0(9.11)] tridecane (referred to here as P2) and (1S,3R,8R,9R,11S)-10,10-dibromo-2,2-dichloro-3,7,7,11 tetramethyltetracyclo[6,5,0,0(1.3),0(9.11)] tridecane (referred to here as P3). P2 and P3 are formed at the alpha and beta sides, respectively, of the C2 = C3 double bond of P1. This reaction is exothermic, stereoselective and chemospecific, and is controlled by charge transfer. Regioselectivity of the reaction was interpreted using the Lee-Yang-Parr functional. PMID- 25687904 TI - New insights into steric and electronic effects in a series of phosphine ligands from the perspective of local quantum similarity using the Fukui function. AB - The field of molecular quantum similarity (MQS) was introduced by Carbo-Dorca 30 years ago. MQS currently suffers from numerous bottlenecks, for example when studying similarities in chemical reactivity, because there is no clear guidance on the best methodology to follow. For this reason, we have revisited this topic here. Today's search tools and methodologies have made an important contribution to studying steric and electronic effects in phosphine ligands (PR3). In this contribution, we propose a hybrid methodology joining (MQS) and chemical reactivity. Additionally, a chemical reactivity study using global and local reactivity descriptors was performed in the context of density functional theory (DFT). Phosphines are sigma-donor and pi-acceptor ligands, therefore reactivity descriptors allow us quantify the retrodonor process in terms of quantum similarity (QS). In this regard, new ways to characterize steric and electronic effects in phosphine ligands and their chemical bonds are presented in the QS context. PMID- 25687906 TI - Habituation-Like Decrease of Acetylcholine-Induced Inward Current in Helix Command Neurons: Role of Microtubule Motor Proteins. AB - The role of kinesin and dynein microtubule-associated molecular motors in the cellular mechanism of depression of acetylcholine-induced inward chloride current (ACh-current) was examined in command neurons of land snails (Helix lucorum) in response to repeated applications of ACh to neuronal soma. This pharmacological stimulation imitated the protocol of tactile stimulation evoking behavioural habituation of the defensive reaction. In this system, a dynein inhibitor (erythro-9-(2-hydroxy-3-nonyl)adenine, 50 uM) decreased the ACh-current depression rate. Kinesin Eg5 inhibitors (Eg5 inhibitor III, 10 uM and Eg5 inhibitor V, trans-24, 15 uM) reduced the degree of current depression, and Eg5 inhibitor V also reduced the initial rate of depression. The results of electrophysiological experiments in combination with mathematical modelling provided evidence of the participation of dyneins and kinesin Eg5 proteins in the radial transport of acetylcholine receptors in command neurons of H. lucorum in the cellular analogue of habituation. Furthermore, these results suggest that the reciprocal interaction between dynein and kinesin proteins located on the same vesicle can lead to reverse their usual direction of transport (dyneins-in exocytosis and kinesin Eg5-in endocytosis). PMID- 25687905 TI - Multiple system atrophy: the application of genetics in understanding etiology. AB - Classically defined phenotypically by a triad of cerebellar ataxia, parkinsonism, and autonomic dysfunction in conjunction with pyramidal signs, multiple system atrophy (MSA) is a rare and progressive neurodegenerative disease affecting an estimated 3-4 per every 100,000 individuals among adults 50-99 years of age. With a pathological hallmark of alpha-synuclein-immunoreactive glial cytoplasmic inclusions (GCIs; Papp-Lantos inclusions), MSA patients exhibit marked neurodegenerative changes in the striatonigral and/or olivopontocerebellar structures of the brain. As a member of the alpha-synucleinopathy family, which is defined by its well-demarcated alpha-synuclein-immunoreactive inclusions and aggregation, MSA's clinical presentation exhibits several overlapping features with other members including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Given the extensive fund of knowledge regarding the genetic etiology of PD revealed within the past several years, a genetic investigation of MSA is warranted. While a current genome-wide association study is underway for MSA to further clarify the role of associated genetic loci and single-nucleotide polymorphisms, several cases have presented solid preliminary evidence of a genetic etiology. Naturally, genes and variants manifesting known associations with PD (and other phenotypically similar neurodegenerative disorders), including SNCA and MAPT, have been comprehensively investigated in MSA patient cohorts. More recently variants in COQ2 have been linked to MSA in the Japanese population although this finding awaits replication. Nonetheless, significant positive associations with subsequent independent replication studies have been scarce. With very limited information regarding genetic mutations or alterations in gene dosage as a cause of MSA, the search for novel risk genes, which may be in the form of common variants or rare variants, is the logical nexus for MSA research. We believe that the application of next generation genetic methods to MSA will provide valuable insight into the underlying causes of this disease, and will be central to the identification of etiologic-based therapies. PMID- 25687907 TI - Targeted therapies: DNA polymerase theta-a new target for synthetic lethality? PMID- 25687909 TI - Targeted therapies: Drug addiction revealed in BRAF and MEK inhibitor-resistant melanoma cells. PMID- 25687908 TI - Can oncology recapitulate paleontology? Lessons from species extinctions. AB - Although we can treat cancers with cytotoxic chemotherapies, target them with molecules that inhibit oncogenic drivers, and induce substantial cell death with radiation, local and metastatic tumours recur, resulting in extensive morbidity and mortality. Indeed, driving a tumour to extinction is difficult. Geographically dispersed species of organisms are perhaps equally resistant to extinction, but >99.9% of species that have ever existed on this planet have become extinct. By contrast, we are nowhere near that level of success in cancer therapy. The phenomena are broadly analogous--in both cases, a genetically diverse population mutates and evolves through natural selection. The goal of cancer therapy is to cause cancer cell population extinction, or at least to limit any further increase in population size, to prevent the tumour burden from overwhelming the patient. However, despite available treatments, complete responses are rare, and partial responses are limited in duration. Many patients eventually relapse with tumours that evolve from cells that survive therapy. Similarly, species are remarkably resilient to environmental change. Paleontology can show us the conditions that lead to extinction and the characteristics of species that make them resistant to extinction. These lessons could be translated to improve cancer therapy and prognosis. PMID- 25687910 TI - Biomarkers: exceptional responders-discovering predictive biomarkers. PMID- 25687911 TI - Gynaecological cancer: Survival benefit and quality of life. PMID- 25687912 TI - Toll-like receptor 1 and 10 polymorphisms, Helicobacter pylori susceptibility and risk of gastric lesions in a high-risk Chinese population. AB - Genetic polymorphisms of Toll-like receptor (TLR) 1 and 10 may influence Helicobacter pylori (H. pylori) susceptibility. To evaluate associations between TLR1 and 10 polymorphisms, H. pylori infection, and precancerous gastric lesions, a population-based study was conducted in a high-risk Chinese population. Three single-nucleotide polymorphisms, TLR1 rs4833095, TLR10 rs10004195, and TLR10 rs4129009 were genotyped by TaqMan SNP genotyping assay in 2553 participants with diverse gastric lesions. The status of H. pylori infection was determined by (13)C-urea breath test. TLR1 rs4833095 T and TLR10 rs10004195 T alleles were the minor alleles and showed in linkage disequilibrium (D'=0.98, r(2)=0.73) in the Chinese population. A decreased risk of H. pylori infection was observed in subjects with TLR1 rs4833095 CT genotype [adjusted odds ratio (OR)=0.80; 95% confidence interval (CI): 0.66-0.96] or T allele (OR=0.82; 95%CI: 0.69-0.99). Moreover, subjects carrying TLR1 rs4833095 TT genotype were associated with reduced risks of chronic atrophic gastritis (CAG, OR=0.66; 95%CI: 0.45-0.97) and intestinal metaplasia (IM, OR=0.57; 95%CI: 0.36-0.90). The risk of CAG was also decreased in subjects carrying TLR10 rs10004195 T allele (OR=0.75; 95%CI: 0.57 0.99). Furthermore, haplotype analysis indicated that haplotype TT of rs4833095 and rs10004195 had a protective effect on H. pylori infection (OR=0.83; 95%CI: 0.72-0.96) or precancerous gastric lesions (OR=0.78; 95%CI: 0.64-0.96 for CAG, and OR=0.74; 95%CI: 0.57-0.96 for IM). These findings suggest that TLR1 rs4833095 and TLR10 rs10004195 may play crucial roles in H. pylori susceptibility and gastric pathogenesis. PMID- 25687913 TI - Geographical segregation of Cryptosporidium parvum multilocus genotypes in Europe. AB - Cryptosporidium parvum is a common enteric protozoan pathogen of humans and livestock. Multilocus genotyping based on simple sequence repeat polymorphisms has been used extensively to identify transmission cycles and to investigate the structure of C. parvum populations and of the related pathogen Cryptosporidiumhominis. Using such methods, the zoonotic transmission of C. parvum has been shown to be epidemiologically important. Because different genetic markers have been used in different surveys, the comparison of Cryptosporidium genotypes across different laboratories is often not feasible. Therefore, few comparisons of Cryptosporidium populations across wide geographical areas have been published and our understanding of the epidemiology of cryptosporidiosis is fragmented. Here we report on the genotypic analysis of a large collection of 692 C. parvum isolates originating primarily from cattle and other ruminants from Italy, Ireland and Scotland. Because the same genotypic markers were used in these surveys, it was possible to merge the data. We found significant geographical segregation and a correlation between genetic and geographic distance, consistent with a model of isolation by distance. The presence of strong LD and positive IA(S) values in the combined MLG dataset suggest departure from panmixia, with different population structures of the parasite prevailing in each country. PMID- 25687914 TI - Just dip it: online coupling of "Dip-it" polymer monolith microextraction with plasma assisted laser desorption ionization mass spectrometry. AB - A polymer monolith microextraction (PMME) procedure coupled to plasma assisted laser desorption ionization mass spectrometry (PMME-PALDI-MS) was developed for rapid and organic solvent-free trace analysis. The extraction device used a "Dip it" sampler coated with a MWNT incorporated monolith, and the analytes adsorbed on monoliths were effectively desorbed by laser, improving detection sensitivity. PMID- 25687915 TI - Post-closure care of engineered municipal solid waste landfills. AB - Post-closure care is divided into perpetual care (PPC) and long-term care (LTC). Guidelines for post-closure care and associated costs are important for engineered municipal solid waste (MSW) landfills. In many states in the USA, landfill owners are required to set aside funds for 30-40 years of LTC. Currently there are no guidelines for PPC, which is also required. We undertook a pilot study, using two landfills (note: average landfill capacity 2.5 million MT MSW waste) in Wisconsin, to establish an approach for estimating the LTC period using field data and PPC funding need. Statistical analysis of time versus concentration data of selected leachate parameters showed that the concentration of most parameters is expected to be at or below the preventive action limit of groundwater and leachate volume will be very low, within 40 years of the LTC period. The gas extraction system may need to be continued for more than 100 years. Due to lack of data no conclusion could be made regarding adequacy of the LTC period for the groundwater monitoring system. The final cover must be maintained for perpetuity. The pilot study shows that although technology is available, the financial liability of maintaining a 'Dry Tomb' design for landfills is significantly higher than commonly perceived. The paper will help landfill professionals to estimate realistic post-closure funding and to develop field-based policies for LTC and PPC of engineered MSW landfills. PMID- 25687916 TI - Anaerobic digestion of bio-waste: A mini-review focusing on territorial and environmental aspects. AB - Scientific and industrial experiences, together with economical and policies changes of last 30 years, bring anaerobic digestion among the most environmental friendly and economically advantageous technologies for organic waste treatment and management in Europe. In this short review, the role of anaerobic digestion of organic wastes is discussed, considering the opportunity of a territorial friendly approach, without barriers, where different organic wastes are co treated. This objective can be achieved through two proposed strategies: one is the anaerobic digestion applied as a service for the agricultural and farming sector; the other as a service for citizen (biowaste, diapers and wastewater treatment integration). The union of these two strategies is an environmental- and territorial-friendly process that aims to produce renewable energy and fertiliser material, with a low greenhouse gas emission and nutrients recovery. The advantage of forthcoming application of anaerobic digestion of organic wastes, even for added value bioproducts production and new energy carriers, are finally discussed. Among several advantages of anaerobic digestion, the role of the environmental controller was evaluated, considering the ability of minimising the impacts exploiting the biochemical equilibrium and sensitivity as a quality assurance for digestate. PMID- 25687917 TI - Enabling safe dry cake disposal of bauxite residue by deliquoring and washing with a membrane filter press. AB - Dry cake disposal is the preferred technique for the disposal of bauxite residue, when considering environmental issues together with possible future utilisation of the solids. In order to perform dry cake disposal in an economical way, the deliquoring of the residue must be carried out efficiently, and it is also important to wash the obtained solids well to minimise the amount of soluble soda within the solids. The study presented in this article aims at detecting the most important variables influencing the deliquoring and washing of bauxite residue, performed with a horizontal membrane filter press and by determining the optimal washing conditions. The results obtained from pilot-scale experiments are evaluated by considering the properties of the solids, for instance, the residual alkali and aluminium content, as well as the consumption of wash liquid. Two different cake washing techniques, namely classic washing and channel washing, are also used and their performances compared. The results show that cake washing can be performed successfully in a horizontal membrane filter press, and significant improvements in the recovery of alkali and aluminium can be achieved compared with pressure filtration carried out without washing, or especially compared with the more traditionally used vacuum filtration. PMID- 25687918 TI - The role and utility of measuring red blood cell methotrexate polyglutamate concentrations in inflammatory arthropathies--a systematic review. AB - PURPOSE: Evidence regarding the relationship between red blood cell methotrexate polyglutamate concentration and response to treatment and adverse drug reactions in patients using methotrexate for inflammatory arthropathies is complex and in some respects appears conflicting. Accordingly, we undertook a systematic analysis of available evidence to determine the clinical utility of dosing methotrexate to a target red blood cell methotrexate polyglutamate concentration. METHODS: A systematic literature review was conducted to identify all studies that had reported an association between red blood cell methotrexate polyglutamate concentration and disease activity or adverse drug reactions in users of methotrexate for the treatment of rheumatoid arthritis, juvenile idiopathic arthritis or psoriatic arthritis. RESULTS: No randomised controlled trials were identified. Thirteen studies (ten in patients with rheumatoid arthritis and three in patients with juvenile idiopathic arthritis) were identified. All studies evaluated an association between red blood cell methotrexate polyglutamate concentration and response to treatment, and eight evaluated an association with toxicity. Eight studies identified lower disease activity with at least one higher red blood cell methotrexate polyglutamate concentration, although there was at least moderate potential for bias in all of these studies. Relatively large increases in concentration appeared to be required to produce a meaningful reduction in disease activity. Only one study identified an association between red blood cell methotrexate polyglutamate concentration and methotrexate-induced side effects, although studies were likely underpowered to detect this type of association. CONCLUSIONS: The manner in which data were presented in the included studies had many limitations that hampered its conclusive assessment, but red blood cell methotrexate polyglutamate concentrations appear to be a potentially useful guide to treatment in patients with inflammatory arthropathies, but the specific polyglutamate that should be monitored and how monitoring could be integrated into treat-to-target approaches should be clarified before it can be routinely implemented. PMID- 25687919 TI - Building global nurse capacity through relationships, education, and collaboration. PMID- 25687920 TI - Shape-modification of patterned nanoparticles by an ion beam treatment. AB - This paper evaluated a practical approach to the fabrication of arrays of non spherical nanoparticles by colloidal etching without a mask involving exposure to a low energy ion beam. A spherical nanoparticle array was transferred using a soft nanolithography technique, which is a simple and effective pattern transfer method for nanostructures on the surface of thin adhesive polymers on a planar substrate, after placing the spherical nanoparticles on a patterned PDMS [poly(dimethysiloxane)] stamp produced from a patterned Si wafer. The resulting non-spherical nanoparticle array was driven from a spherical nanoparticle array shape-modified by ion beam irradiation. A well-arrayed layer of cone-like-shapes were produced using a head-on ion beam for different exposure times. Also, a variety of mushroom-like-shapes depending on the exposure angle were produced on a substrate with a well-arranged spherical nanoparticle array. This technique has potential applications in nanophotonics, field emission displays (FEDs) and microfluid. PMID- 25687921 TI - Helicobacter pylori FKBP-type PPIase promotes gastric epithelial cell proliferation and anchorage-independent growth through activation of ERK-mediated mitogenic signaling pathway. AB - Though Helicobacter pylori (H. pylori) has been classified as class I carcinogen, key virulence factor(s) generated by H. pylori that causes gastric cancer remains to be fully determined. Here, we show that deletion of peptidyl-prolyl cis-trans isomerase (PPIase) prevented H. pylori from stimulating human gastric epithelial cell (AGS) proliferation. Consistent with this observation, ectopic expression of H. pylori PPIase promoted AGS cell proliferation and anchorage-independent growth. To gain insight into the biochemical mechanism of PPIase-induced effect, early signal events involved in mitogenic signaling pathways were evaluated. Expression of H. pylori PPIase caused an increase in basal as well as EGF stimulated phosphorylation of ERK and EGF receptor at Tyr1086. Treatment with MEK inhibitor completely blocked PPIase-induced cell proliferation. Our results suggest that H. pylori PPIase has the potential to activate mitogenic signaling pathway and to promote transformation of gastric epithelial cells. H. pylori PPIase may represent a novel target for therapeutic management of gastric cancer patients. PMID- 25687922 TI - Temporal expression of the staphylococcal enterotoxin D gene under NaCl stress conditions. AB - Staphylococcus aureus is one of the most osmotolerant food-borne pathogens. While its growth is repressed by competing bacteria, the organism exhibits a growth advantage at increased salt concentrations. Staphylococcal enterotoxin D leads to vomiting and diarrhea upon ingestion. To date, the effect of NaCl on both sed expression and its regulatory control are unclear. We determined the impact of NaCl stress on sed expression and the influence of agr, sarA and sigB on sed expression under NaCl stress. The temporal expression of sed in LB and LB with 4.5% NaCl was compared, as well as sed expression of wild-type (wt) strains and isogenic Deltaagr, DeltasarA and DeltasigB mutants. In general, NaCl stress led to decreased sed expression. However, one strain exhibited a trend towards increased sed expression under NaCl stress. No significant effect of agr on sed expression was detected and only one DeltasigB mutant showed a significant decrease in sed expression in the early stationary phase under NaCl stress. One DeltasarA mutant showed decreased sed expression in the early stationary and another increased sed expression in the stationary growth phase under NaCl stress. These findings suggest high strain-specific variation in sed expression and its regulation under NaCl stress. PMID- 25687923 TI - Aspartate inhibits Staphylococcus aureus biofilm formation. AB - Biofilm formation renders Staphylococcus aureus highly resistant to conventional antibiotics and host defenses. Four D-amino acids (D-Leu, D-Met, D-Trp and D-Tyr) have been reported to be able to inhibit biofilm formation and disassemble established S. aureus biofilms. We report here for the first time that both D- and L-isoforms of aspartate (Asp) inhibited S. aureus biofilm formation on tissue culture plates. Similar biofilm inhibition effects were also observed against other staphylococcal strains, including S. saprophyticus, S. equorum, S. chromogenes and S. haemolyticus. It was found that Asp at high concentrations (>10 mM) inhibited the growth of planktonic N315 cells, but at subinhibitory concentrations decreased the cellular metabolic activity without influencing cell growth. The decreased cellular metabolic activity might be the reason for the production of less protein and DNA in the matrix of the biofilms formed in the presence of Asp. However, varied inhibition efficacies of Asp were observed for biofilms formed by clinical staphylococcal isolates. There might be mechanisms other than decreasing the metabolic activity, e.g. the biofilm phenotypes, affecting biofilm formation in the presence of Asp. PMID- 25687924 TI - Correction. AB - [This corrects the article DOI: 10.1136/lupus-2014-000061.]. PMID- 25687925 TI - The course of neuropsychiatric symptoms in dementia: a 3-year longitudinal study. AB - OBJECTIVES: Patients with dementia experience a wide range of neuropsychiatric symptoms. These symptoms often cause considerable distress to patients and caregivers, and often contribute to institutionalization. The current study examined the prevalence and course of neuropsychiatric symptoms in a large sample of patients with dementia attending memory clinics. DESIGN: Three-year nonprescriptive, observational study examining relationships between predictors and outcome variables in patients with dementia. SETTING: Nine memory clinics around Australia. PARTICIPANTS: Of 970 patients recruited, 779 patients had dementia at baseline. MEASUREMENTS: Over 3 years, patients were rated on 6 occasions on the 12-item Neuropsychiatric Inventory and measures of cognition, dementia severity, function, and medication use. Analyses focused on the 514 patients with dementia who completed the Neuropsychiatric Inventory on 4 or more occasions. RESULTS: Overall levels of neuropsychiatric symptoms increased over the 3 years. In particular, delusions, hallucinations, agitation, anxiety, apathy, disinhibition, irritability, and aberrant motor behavior increased over the 3 years. Depression, euphoria, night time behavior, and appetite did not significantly increase over this period. Severity of dementia, male sex, and frontotemporal dementia were associated with greater levels of neuropsychiatric symptoms at baseline. Dementia with Lewy bodies was associated with more hallucinations and less appetite disturbances, and Alzheimer's disease was associated with lower levels of neuropsychiatric symptoms than other types of dementia at baseline. CONCLUSIONS: The findings confirm that different symptoms have different trajectories and that baseline characteristics of patients, including sex and dementia type, predict the subsequent course of symptoms. The findings also highlight the association between dementia severity and neuropsychiatric symptoms, indicating the need to control for this variable when examining their longitudinal trajectories. PMID- 25687926 TI - Markers of Impaired Decision Making in Nursing Home Residents: Assessment by Nursing Home Staff in a Population-Based Study. AB - INTRODUCTION: Many nursing home residents have cognitive impairment that affects their decision making. In order to identify potential markers of impaired decision making, we investigated the association between a range of nursing home resident characteristics and impaired decision making in a population-based sample. METHODS: Participants were 13,013 residents in the 2004 National Nursing Home Survey. We used logistic regression to determine the association between resident characteristics (ie, gender, age, race, mood, recent pain, falls, fractures, or hospitalizations, length of stay, number of activities of daily living (ADL) requiring help, and diagnoses of dementia, anxiety disorders, and depression) and impaired (vs independent) decision making. RESULTS: After controlling for depression and anxiety diagnoses, as well as gender, age, race, and recent hospitalization or pain, characteristics associated with impaired decision making included depressed, sad, or anxious mood ["mild" odds ratio (OR) = 1.39, 95% confidence interval (CI) = 1.23-1.58; "severe" OR = 2.69, 95% CI = 2.27-3.20); diagnosed dementia or living on a dementia hall (OR = 5.07, 95% CI = 4.52-5.67); number of ADL requiring assistance (with 5 ADL, OR = 10.69, 95% CI = 6.82-16.75); length of nursing home stay [101-365 days (OR = 1.60, 95% CI = 1.36 1.89); 366 days-2 years (OR = 1.60, 95% CI = 1.34-1.90); >2 years (OR = 2.25, 95% CI = 1.92-2.63)]; and history of falls or fractures in the last 6 months (OR = 1.19, 95% CI = 1.07-1.32)]. Residents reporting pain in the last week were less likely to have impaired decision making (OR = 0.58, 95% CI = 0.52-0.66). CONCLUSIONS: We found several independent markers of impaired decision making in nursing home residents, including depressed, sad, or anxious mood (independent of depression or anxiety diagnosis); dementia; and greater need for ADL assistance. Some of these factors, in particular mood, are modifiable and addressing them may help improve decision making. These markers should be explored further to help identify residents with impaired decision making. PMID- 25687927 TI - Effects of a home-based physical rehabilitation program on physical disability after hip fracture: a randomized controlled trial. AB - OBJECTIVE: Fewer than half of the patients with hip fracture will regain the prefracture level of physical functioning. This secondary analysis of a randomized controlled trial investigated the effects of a multicomponent home based rehabilitation program (ProMo) on physical disability after hip fracture. DESIGN: Randomized, controlled, parallel-group trial. SETTING: Rehabilitation in participants' homes; measurements in university-based laboratory and local hospital. PARTICIPANTS: Population-based clinical sample of community-dwelling people older than 60 years (n = 81) operated for hip fracture were randomized into intervention and control groups. INTERVENTION: The year-long intervention aimed at restoring mobility. It included evaluation and modification of environmental hazards, guidance for safe walking, pain management, home exercise, physical activity counseling, and standard care. MEASUREMENTS: Physical disability was assessed by a questionnaire at baseline, and 3, 6, and 12 months thereafter. Sum scores were computed for basic (ADLs) and instrumental activities of daily living (IADLs). A higher score indicated more difficulty. GEE models were constructed to analyze the effect of the intervention. RESULTS: In the intention-to-treat analysis, no intervention effect was observed for sum scores. For the single disability items, borderline significant positive effects were observed for preparing food and handling medication (interaction P = .061 and P = .061, respectively). In the per-protocol analysis, the mean differences between groups were -0.4 points (SE 0.5), -1.7 (0.7), and -1.2 (0.7) at 3, 6, and 12 months for ADLs and -1.0 (1.2), -3.2 (1.5), and -2.5 (1.4) for IADLs, correspondingly. CONCLUSION: The current analyses suggest that home-based rehabilitation may reduce disability among older people after hip fracture. The present results need to be confirmed in a study with larger sample size. Potentially a more task-oriented rehabilitation approach might gain more benefits. Current Controlled Trials (ISRCTN53680197). PMID- 25687928 TI - Telehealth can bridge the gap for rural, disabled, and elderly patients. PMID- 25687929 TI - Eating Alone as Social Disengagement is Strongly Associated With Depressive Symptoms in Japanese Community-Dwelling Older Adults. AB - OBJECTIVES: Depression in later life poses a grave challenge for the aging countries. The reported key risk factors include social disengagement, but the lack of social companionship during mealtimes, namely eating alone, has not been examined extensively, especially in relation to living arrangement. Past studies on changes along geriatric trajectories in the association between social engagement and depression also remain inadequate. This study aims to examine the association between social engagement and depressive symptoms with a particular focus on eating alone and how the association changes along the aging and mental frailty trajectories. DESIGN: A cross-sectional study. SETTING: Kashiwa-city, Chiba-prefecture in Japan. PARTICIPANTS: A total of 1856 community-dwelling older adults. MEASUREMENTS: The 15-item Geriatric Depression Scale was used to measure depressive symptoms. The indicators used to assess social engagement included eating alone, living arrangement, reciprocity of social support, social participation, social stressors and social ties. RESULTS: Social engagement was significantly associated with depressive symptoms. Those who live with their families yet eat alone were found to be at particular risk (odds ratio = 5.02, 95% confidence interval 2.5-9.9 for young-old; odds ratio = 2.41, 95% confidence interval 1.2-4.8 for old-old). Younger and less mentally frail populations showed stronger associations. CONCLUSIONS: Eating alone was a key risk factor for depressive symptoms in community-dwelling older adults. The living arrangement in which they eat alone is important in identifying those with the greatest risk. Mental health management for older adults requires comprehensive assessment of their social relations that takes into account their companionship during mealtimes. Social preventive measures need to involve early interventions in order to augment their effectiveness against mental frailty. PMID- 25687930 TI - Relationships, expertise, incentives, and governance: supporting care home residents' access to health care. An interview study from England. AB - OBJECTIVES: To explore what commissioners of care, regulators, providers, and care home residents in England identify as the key mechanisms or components of different service delivery models that support the provision of National Health Service (NHS) provision to independent care homes. METHODS: Qualitative, semistructured interviews with a purposive sample of people with direct experience of commissioning, providing, and regulating health care provision in care homes and care home residents. Data from interviews were augmented by a secondary analysis of previous interviews with care home residents on their personal experience of and priorities for access to health care. Analysis was framed by the assumptions of realist evaluation and drew on the constant comparative method to identify key themes about what is required to achieve quality health care provision to care homes and resident health. RESULTS: Participants identified 3 overlapping approaches to the provision of NHS that they believed supported access to health care for older people in care homes: (1) Investment in relational working that fostered continuity and shared learning between visiting NHS staff and care home staff, (2) the provision of age appropriate clinical services, and (3) governance arrangements that used contractual and financial incentives to specify a minimum service that care homes should receive. CONCLUSION: The 3 approaches, and how they were typified as working, provide a rich picture of the stakeholder perspectives and the underlying assumptions about how service delivery models should work with care homes. The findings inform how evidence on effective working in care homes will be interrogated to identify how different approaches, or specifically key elements of those approaches, achieve different health-related outcomes in different situations for residents and associated health and social care organizations. PMID- 25687932 TI - Positional cloning in Cryptococcus neoformans and its application for identification and cloning of the gene encoding methylenetetrahydrofolate reductase. AB - Cryptococcus neoformans, a basidiomycetous human pathogenic yeast, has been widely used in research fields in medical mycology as well as basic biology. Gene cloning or identification of the gene responsible for a mutation of interest is a key step for functional analysis of a particular gene. The availability therefore, of the multiple methods for cloning is desirable. In this study, we proposed a method for a mapping-based gene identification/cloning (positional cloning) method in C. neoformans. To this end, we constructed a series of tester strains, one of whose chromosomes was labeled with the URA5 gene. A heterozygous diploid constructed by crossing one of the tester strains to a mutant strain of interest loses a chromosome(s) spontaneously, which is the basis for assigning a recessive mutant gene to a particular chromosome in the mitotic mapping method. Once the gene of interest is mapped to one of the 14 chromosomes, classical genetic crosses can then be performed to determine its more precise location. The positional information thus obtained can then be used to significantly narrow down candidate genes by referring to the Cryptococcus genome database. Each candidate gene is then examined whether it would complement the mutation. We successfully applied this method to identify CNA07390 encoding methylenetetrahydrofolate reductase as the gene responsible for a methionine requiring mutant in our mutant collection. PMID- 25687931 TI - Kexin-like endoprotease KexB is required for N-glycan processing, morphogenesis and virulence in Aspergillus fumigatus. AB - Kexin-like proteins belong to the subtilisin-like family of the proteinases that cleave secretory proproteins to their active forms. Several fungal kexin-like proteins have been investigated. The mutants lacking of kexin-like protein display strong phenotypes such as cell wall defect, abnormal polarity, and, in case of Candida albicans, diminished virulence. However, only several proteins have been confirmed as the substrates of kexin-like proteases in these fungal species. It still remains unclear how kexin-like proteins contribute to the morphogenesis in these fungal species. In this study, a kexB-null mutant of the human opportunistic fungal pathogen Aspergillus fumigatus was constructed and analyzed. The DeltakexB mutant showed retarded growth, temperature-sensitive cell wall defect, reduced conidia formation, and abnormal polarity. Biochemical analyses revealed that deletion of the kexB gene resulted in impaired N-glycan processing, activation of the MpkA-dependent cell wall integrity signaling pathway, and ER-stress. Results from in vivo assays demonstrated that the mutant exhibited an attenuated virulence in immunecompromised mice. Based on our results, the kexin-like endoprotease KexB was involved in the N-glycan processing, which provides a novel insight to understand how kexin-like protein affects the cell-wall modifying enzymes and therefore morphogenesis in fungi. PMID- 25687933 TI - Fluorescence Assisted Selection of Transformants (FAST): Using flow cytometry to select fungal transformants. AB - The availability of drug resistance markers for fungal transformation is often a limiting factor in both fungal genetics research and industrial applications. We describe a new technique using flow cytometry to select fungal transformants using well-known fluorescent proteins as markers for transformation. This new technique, Fluorescence-Assisted Selection of Transformants (FAST), was used for a transformation of Fusarium oxysporum with GFP as a marker targeted at a specific site on chromosome 14. The resulting strain was then transformed again with a gene replacement construct containing both RFP and a gene for drug resistance as markers. By directly comparing FAST with drug resistance selection we show that both methods yield comparable numbers of gene deletion mutants. PMID- 25687935 TI - Structure based approaches for targeting non-coding RNAs with small molecules. AB - The increasing appreciation of the central role of non-coding RNAs (miRNAs and long non-coding RNAs) in chronic and degenerative human disease makes them attractive therapeutic targets. This would not be unprecedented: the bacterial ribosomal RNA is a mainstay for antibacterial treatment, while the conservation and functional importance of viral RNA regulatory elements has long suggested they would constitute attractive targets for new antivirals. Oligonucleotide based chemistry has obvious appeals but also considerable pharmacological limitations that are yet to be addressed satisfactorily. Recent studies identifying small molecules targeting non-coding RNAs may provide an alternative approach to oligonucleotide methods. Here we review recent work investigating new structural and chemical principles for targeting RNA with small molecules. PMID- 25687934 TI - Genetic structure and parasitization-related ability divergence of a nematode fungal pathogen Hirsutella minnesotensis following founder effect in China. AB - The fungal parasitoid, Hirsutella minnesotensis, is a dominant parasitoid of the soybean cyst nematode, which is a destruction pest of soybean crops. We investigated population structure and parasitism pattern in samples of H. minnesotensis in China to reveal the spreading pattern of this fungal species and the underlying mechanism generating the parasitization-related ability variability in Chinese population. In cross-inoculation experiments using different combinations of H. minnesotensis and soybean cyst nematode samples from China, most H. minnesotensis isolates fitted the criterion for "local versus foreign" parasitism profile, exhibiting local adaptation pattern to the SCN host. However, the genetic analysis of the single nucleotide polymorphisms with clone corrected samples based on ten DNA fragments in 56 isolates of H. minnesotensis from China revealed that the Chinese H. minnesotensis population was a clonal lineage that underwent a founder event. The results demonstrated that the Chinese H. minnesotensis population had generated parasitization-related ability diversity after a founder event through individual variation or phenotypic plasticity other than local adaptation. The rapid divergence of parasitization related abilities with simple genetic structure in Chinese H. minnesotensis population indicates a fundamental potential for the establishment of invasive fungal species, which is a prerequisite for biological control agents. PMID- 25687936 TI - The immunological contribution to heterotopic ossification disorders. AB - The formation of bone outside the endogenous skeleton is a significant clinical event, rendering affected individuals with immobility and a diminished quality of life. This bone, termed heterotopic ossification (HO), can appear in patients following invasive surgeries and traumatic injuries, as well as progressively manifest in several congenital disorders. A unifying feature of both genetic and nongenetic episodes of HO is immune system involvement at the early stages of disease. Activation of the immune system sets the stage for the downstream anabolic events that eventually result in ectopic bone formation, rendering the immune system a particularly appealing site of early therapeutic intervention for optimal management of disease. In this review, we will discuss the immunological contributions to HO disorders, with specific focus on contributing cell types, signaling pathways, relevant in vivo animal models, and potential therapeutic targets. PMID- 25687937 TI - Sexualizing reality television: associations with trait and state self objectification. AB - Two studies combining cross-sectional and daily experience methods tested whether watching sexualizing reality television is associated with self-objectification in women. In Study 1, an online survey of 495 undergraduate women, we demonstrated that watching sexualizing reality television was associated with higher levels of trait self-objectification. In Study 2, an online daily experience study of 94 undergraduate women, we extended the results from Study 1 by focusing on state self-objectification and showed that changes in daily exposure to sexualizing reality television correspond to fluctuations in the importance participants attached to appearance, but were unrelated to the importance attached to body-competence. The results of these two studies with multiple methods provide support for the influence of exposure to sexualizing reality television to the development of an objectified self-concept but also underline differences in how exposure to sexualizing reality television relates to trait and state self-objectification. PMID- 25687938 TI - Erratum to: congenital pericardial defect: a case of right pericardial partial absence with normal parietal pleura. PMID- 25687939 TI - Prediction of upper limb recovery in the acute phase of cerebrovascular disease: evaluation of "functional hand" using the manual function test. AB - BACKGROUND: Prediction of upper limb function recovery in the acute phase of cerebrovascular disease can help clarify goal setting in rehabilitation and subsequently shorten hospital stay. The present study aimed to develop regression equations that can be used to predict the Manual Function Test (MFT) score 3 weeks after onset and to determine the optimal cutoff MFT score for the identification of "Functional Hand." METHODS: In all, 190 patients with cerebrovascular disease were included in this study. The baseline survey performed within 1 week after onset assessed sociodemographic profiles, medical profiles, and acute symptoms. MFT was performed to determine the cutoff score to indicate Functional Hand. We used stepwise multiple regression analysis to establish the prediction equations with the best fit for the MFT score 3 weeks after onset. In addition, the sensitivity and specificity of the MFT as an indicator of Functional Hand with cutoff values were determined. RESULTS: The multiple regression analysis showed that the following factors had a significant influence on the MFT: Brunnstrom recovery stage, cognitive function, range of motion, age, and sensation. The area under the curve was .93 for the MFT score as an indicator of Functional Hand. The cutoff MFT score to identify Functional Hand was 22/21 points, with a sensitivity and specificity of 91.1% and 82.1%, respectively. CONCLUSIONS: Our findings helped develop regression equations that can be used to predict the MFT score 3 weeks after onset of cerebrovascular disease by evaluating factors reportedly associated with upper limb function recovery. PMID- 25687940 TI - [Difficult airway by tonsillar and anterior vertebral osteophyte tumor]. PMID- 25687941 TI - [Innominate artery dolichoectasia identified during ultrasound assessment prior to percutaneous tracheostomy]. PMID- 25687942 TI - Patent foramen ovale diagnosed with echocardiographic checking of the positioning of a central venous catheter. PMID- 25687943 TI - [Foreign body in airway after assisted Frova guide intubation]. PMID- 25687944 TI - [Management of difficult airway with inhalation induction in a patient with Lennox-Gastaut syndrome and neck injury]. AB - Lennox-Gastaut syndrome is a childhood epileptic encephalopathy, and is characterized by frequent and difficult to treat seizures associated with mental retardation. The case is presented of a 21 year-old male with Lennox-Gastaut syndrome, with bilateral cervical facet joint dislocation fracture at C6-C7 and spinal canal compression as a result of a fall during a seizure. In this case the management of the difficult airway expected in an awake and uncooperative patient, with cervical spinal cord injury is described. An airway management strategy was proposed, that allowed a rapid and safe airway control with the best possible tolerance and maintaining the neck immobilised, so as not to increase neurological injury. Within this strategy, plan A was defined as inhalation induction with sevoflurane to maintain spontaneous breathing and tracheal intubation with Airtraq(r). We believe that the Airtraq(r) video laryngoscope with inhalational induction with sevoflurane is a valid and effective alternative in the management of expected difficult airway. PMID- 25687945 TI - [Prevention of occupational solar UV radiation-induced epithelial skin cancer]. AB - Malignancies of the skin, with an incidence of more than 200,000 newly registered cases/year, are the most frequently notified malignances in Germany. In Europe, squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) account for about 30 cases/100,000 persons and 50-100 cases/100,000 persons, respectively. Ultraviolet (UV) exposure is the main risk factor to induce these cancers. Increased incidence rates were shown for persons having red/blonde hair as well as light eye colour, acquire sun burns easily, hardly tan and develop freckles. The majority of the malignancies and precursor lesions are acquired by UV exposure in leisure time. However, in highly occupationally UV-exposed outdoor workers, UV monitoring revealed that exposure levels are 2-3 times higher compared to the general population. Occupations likely to be highly exposed are farmers, forestry workers, gardeners, landscapers, fishermen and seafarers, construction workers, builders, tin smiths, sport teachers, mountain guides, etc. Recent metaanalyses showed that occupational UV exposure is a relevant and independent risk factor for SCC and to a lesser extent also for BCC. To prevent occupationally caused malignancies of the skin a significant reduction of occupationally acquired UV dosages in outdoor workers is mandatory. Relevant factors influencing the cumulative sun exposure in outdoor workers are the amount of UV exposure, the specific tasks to be performed in the sun as well as the UV protection habits of the workers. Besides adequate behavior, textile protection by headgear and clothing as well as the regular use of sunscreens and sun glasses are important. PMID- 25687947 TI - The genetic basis for variation in olfactory behavior in Drosophila melanogaster. AB - The genetic underpinnings that contribute to variation in olfactory perception are not fully understood. To explore the genetic basis of variation in olfactory perception, we measured behavioral responses to 14 chemically diverse naturally occurring odorants in 260400 flies from 186 lines of the Drosophila melanogaster Genetic Reference Panel, a population of inbred wild-derived lines with sequenced genomes. We observed variation in olfactory behavior for all odorants. Low to moderate broad-sense heritabilities and the large number of tests for genotype olfactory phenotype association performed precluded any individual variant from reaching formal significance. However, the top variants (nominal P < 5*10(-5)) were highly enriched for genes involved in nervous system development and function, as expected for a behavioral trait. Further, pathway enrichment analyses showed that genes tagged by the top variants included components of networks centered on cyclic guanosine monophosphate and inositol triphosphate signaling, growth factor signaling, Rho signaling, axon guidance, and regulation of neural connectivity. Functional validation with RNAi and mutations showed that 15 out of 17 genes tested indeed affect olfactory behavior. Our results show that in addition to chemoreceptors, variation in olfactory perception depends on polymorphisms that can result in subtle variations in synaptic connectivity within the nervous system. PMID- 25687948 TI - Recovery of ammonia from swine manure using gas-permeable membranes: effect of waste strength and pH. AB - Nitrogen recovery from swine manure was investigated using gas-permeable membranes. The process involved a continuous recirculation of an acidic solution through a gas-permeable membrane submerged in manure. Ammonia from manure was concentrated in the acidic solution increasing its pH, while pH decreased in manure. In the first set of experiments, nitrogen recovery efficiency was evaluated with no pH adjustment of manure; whereas in the second, manure with three different ammonia (NH3) concentrations (from 1070 to 2290 mg/L) was used adjusting their pH to 9 whenever pH decreased below 7.7. With no pH adjustment, NH3 recovery from manure was 55%, while NH3 recovery averaged 81% when pH of manure was adjusted. This work showed that as waste strength and available NH3 content increased in manure, more N was captured by the membrane. These results suggested that the gas-permeable membranes are a useful technology for NH3 recovery from manure, reducing environmental pollution whilst converting NH3 into a valuable ammonium (NH4(+)) salt fertilizer. PMID- 25687949 TI - The reactions of N-methylformamide and N,N-dimethylformamide with OH and their photo-oxidation under atmospheric conditions: experimental and theoretical studies. AB - The reactions of OH radicals with CH3NHCHO (N-methylformamide, MF) and (CH3)2NCHO (N,N-dimethylformamide, DMF) have been studied by experimental and computational methods. Rate coefficients were determined as a function of temperature (T = 260 295 K) and pressure (P = 30-600 mbar) by the flash photolysis/laser-induced fluorescence technique. OH radicals were produced by laser flash photolysis of 2,4-pentanedione or tert-butyl hydroperoxide under pseudo-first order conditions in an excess of the corresponding amide. The rate coefficients obtained show negative temperature dependences that can be parameterized as follows: kOH+MF = (1.3 +/- 0.4) * 10(-12) exp(3.7 kJ mol(-1)/(RT)) cm(3) s(-1) and kOH+DMF = (5.5 +/- 1.7) * 10(-13) exp(6.6 kJ mol(-1)/(RT)) cm(3) s(-1). The rate coefficient kOH+MF shows very weak positive pressure dependence whereas kOH+DMF was found to be independent of pressure. The Arrhenius equations given, within their uncertainty, are valid for the entire pressure range of our experiments. Furthermore, MF and DMF smog-chamber photo-oxidation experiments were monitored by proton-transfer-reaction time-of-flight mass spectrometry. Atmospheric MF photo-oxidation results in 65% CH3NCO (methylisocyanate), 16% (CHO)2NH, and NOx dependent amounts of CH2[double bond, length as m-dash]NH and CH3NHNO2 as primary products, while DMF photo-oxidation results in around 35% CH3N(CHO)2 as primary product and 65% meta-stable (CH3)2NC(O)OONO2 degrading to NOx-dependent amounts of CH3N[double bond, length as m-dash]CH2 (N-methylmethanimine), (CH3)2NNO (N nitroso dimethylamine) and (CH3)2NNO2 (N-nitro dimethylamine). The potential for nitramine formation in MF photo-oxidation is comparable to that of methylamine whereas the potential to form nitrosamine and nitramine in DMF photo-oxidation is larger than for dimethylamine. Quantum chemistry supported atmospheric degradation mechanisms for MF and DMF are presented. Rate coefficients and initial branching ratios calculated with statistical rate theory based on molecular data from quantum chemical calculations at the CCSD(T*)-F12a/aug-cc pVTZ//MP2/aug-cc-pVTZ level of theory show satisfactory agreement with the experimental results. It turned out that adjustment of calculated threshold energies by 0.2 to 8.8 kJ mol(-1) lead to agreement between experimental and predicted results. PMID- 25687950 TI - Human papillomavirus 16 infection as a potential risk factor for prostate cancer: an adaptive meta-analysis. AB - OBJECTIVES: Although an expert review published in 2013 concluded that an association between human papillomavirus (HPV) infection and prostate cancer (PCa) risk had not yet been firmly established, a 2011 systematic review of 14 articles revealed an increased prevalence of HPV-16 DNA in PCa tissues. Another meta-analysis of the related articles is needed to evaluate the potential link between HPV infection and PCa risk. METHODS: A snowballing search strategy was applied to the previously cited articles in the above-mentioned expert review and systematic review. Additional articles selected for this meta-analysis should fulfill all following inclusion criteria: (a) evaluation of detected HPV-16 DNA in tissue samples and the PCa risk and (b) report of the HPV-16 prevalence in both cancer and control tissues. Estimated summary odds ratios (sOR) with 95% confidence intervals (CI) were calculated using fixed effect or random-effect models. RESULTS: Hand searching identified 16 new articles. The sOR of the total 30 articles indicated a significant HPV-16 infection-related increase in the PCa risk (sOR, 1.851; 95% CI, 1.353 to 2.532, I(2)=37.82%). CONCLUSIONS: These facts provide additional supportive evidence for a causal role of HPV-16 infection in prostate carcinogenesis. As the PCa incidence rates have increased rapidly in Asian countries, including Korea, during the last several decades, further studies of HPV-related PCa carcinogenesis may be necessary. PMID- 25687951 TI - Stomach cancer incidence rates among Americans, Asian Americans and Native Asians from 1988 to 2011. AB - Stomach cancer is the second most common cancer in Eastern Asia, accounting for approximately 50% of all new cases of stomach cancer worldwide. Our objective was to compare the stomach cancer incidence rates of Asian Americans in Los Angeles with those of native Asians to assess the etiology of stomach cancer from 1988 to 2011. To examine these differences, Asian Americans (Korean, Japanese, Chinese, and Filipino Americans living in Los Angeles, California, USA) and native Asians (from Korea, Japan, China, and the Philippines) were selected for this study. Using the Cancer Incidence in Five Continents database, stomach cancer incidence rates were examined. Data from the National Cancer Registry of Korea were used for native Koreans. Between native countries, the incidence rates in Japan, China, the Philippines, and the US declined over time, but the incidence in Korea has remained constant. The incidences among Asian immigrants were lower than those among native Asians. The incidence rates of males were approximately 2 times higher than those among females in Asian countries were. The effect of immigration on stomach cancer incidence suggests that lifestyle factors are a significant determinant of stomach cancer risk. However, the incidence in Korea remains the highest of these countries. PMID- 25687952 TI - Predictors of human immunodeficiency virus and tuberculosis co-infection. PMID- 25687953 TI - Reversible monolayer-to-crystalline phase transition in amphiphilic silsesquioxane at the air-water interface. AB - We report on the counter intuitive reversible crystallisation of two-dimensional monolayer of Trisilanolisobutyl Polyhedral Oligomeric SilSesquioxane (TBPOSS) on water surface using synchrotron x-ray scattering measurements. Amphiphilic TBPOSS form rugged monolayers and Grazing Incidence X-ray Scattering (GIXS) measurements reveal that the in-plane inter-particle correlation peaks, characteristic of two dimensional system, observed before transition is replaced by intense localized spots after transition. The measured x-ray scattering data of the non-equilibrium crystalline phase on the air-water interface could be explained with a model that assumes periodic stacking of the TBPOSS dimers. These crystalline stacking relaxes upon decompression and the TBPOSS layer retains its initial monolayer state. The existence of these crystals in compressed phase is confirmed by atomic force microscopy measurements by lifting the materials on a solid substrate. PMID- 25687954 TI - Involvement of orphan nuclear receptor COUP-TFII in cadherin-6 and cadherin-11 regulation: implications in development and cancer. AB - Changes in cadherin expression are instrumental both in embryonic development and disease, underlining the importance of understanding how cadherin expression is controlled. Kidney development is characterized by a mesenchymal-epithelial transition underlain by a cadherin-11 to cadherin-6 switch, the regulation mechanisms of which are presently unexplained. Using transfection and RNA interference we demonstrate that COUP-TFII (NR2F2) induces down-regulation of cadherin-6 and up-regulation of cadherin-11 in cultured cell lines. Double immunolabeling of mouse embryos provides indirect evidence that COUP-TFII negatively controls the cadherin-11 to cadherin-6 switch underlying the kidney developmental mesenchymal-epithelial transition. Furthermore, we found high expression of COUP-TFII in some gastric and oesophageal adenocarcinomas, correlating with abnormal cadherin-11 expression and suggesting reactivation of embryonic pathways linked to COUP-TFII in these tumors. Altogether, our data shed new light upon the role of COUP-TFII in development and in cancer. PMID- 25687955 TI - Difficult conversations: a national course for neurosurgery residents in physician-patient communication. AB - OBJECTIVE: To describe the design, content, implementation, and evaluation of a national curriculum for teaching practical skills in empathic communication to residents in neurosurgery. DESIGN: Based on needs assessed through a national survey of neurosurgery program directors, videotaped scenarios using standardized patients illustrating good and bad communication skills were developed. Presurveys and postsurveys were conducted querying participants on their level of competence and the specific behaviors they would attempt to change following participation. A subgroup of residents was evaluated before and after the training based on videotaped role-play exercises. SETTING: A pilot study was conducted at the authors' institution and later implemented at National Neurosurgery Boot Camps. PARTICIPANTS: A total of 14 Duke graduate medical education neurosurgery residents agreed to participate in the pilot study. From across the country, 93 residents (representing 59 institutions) participated in the communication training as part of the Neurosurgery Boot camps, 11 of whom volunteered to participate in a role-playing session before and after the formal teaching session. RESULTS: Most of the neurosurgery program directors responding to the survey indicated that an interactive online communication-training module would be of value (77%). A total of 93 residents participated in communication training as part of the Neurosurgery Boot Camps. Approximately half of the residents reported having no formal physician-patient communication training. Presurvey and postsurvey results showed significant improvement in several of the communication scenarios. Those who participated in role-play showed significant improvement in "asking open-ended questions," "listening," "fire warning shot," "allowing patient to absorb," and "explaining in clear language." CONCLUSIONS: Neurosurgeons frequently participate in difficult conversations. Both residents and faculty note that exposure to this content is suboptimal. A hybrid approach to teaching communication skills is well received and enhances graduate medical education training of surgical subspecialists. PMID- 25687956 TI - Proficiency performance benchmarks for removal of simulated brain tumors using a virtual reality simulator NeuroTouch. AB - OBJECTIVE: Assessment of neurosurgical technical skills involved in the resection of cerebral tumors in operative environments is complex. Educators emphasize the need to develop and use objective and meaningful assessment tools that are reliable and valid for assessing trainees' progress in acquiring surgical skills. The purpose of this study was to develop proficiency performance benchmarks for a newly proposed set of objective measures (metrics) of neurosurgical technical skills performance during simulated brain tumor resection using a new virtual reality simulator (NeuroTouch). DESIGN: Each participant performed the resection of 18 simulated brain tumors of different complexity using the NeuroTouch platform. Surgical performance was computed using Tier 1 and Tier 2 metrics derived from NeuroTouch simulator data consisting of (1) safety metrics, including (a) volume of surrounding simulated normal brain tissue removed, (b) sum of forces utilized, and (c) maximum force applied during tumor resection; (2) quality of operation metric, which involved the percentage of tumor removed; and (3) efficiency metrics, including (a) instrument total tip path lengths and (b) frequency of pedal activation. SETTING: All studies were conducted in the Neurosurgical Simulation Research Centre, Montreal Neurological Institute and Hospital, McGill University, Montreal, Canada. PARTICIPANTS: A total of 33 participants were recruited, including 17 experts (board-certified neurosurgeons) and 16 novices (7 senior and 9 junior neurosurgery residents). RESULTS: The results demonstrated that "expert" neurosurgeons resected less surrounding simulated normal brain tissue and less tumor tissue than residents. These data are consistent with the concept that "experts" focused more on safety of the surgical procedure compared with novices. By analyzing experts' neurosurgical technical skills performance on these different metrics, we were able to establish benchmarks for goal proficiency performance training of neurosurgery residents. CONCLUSION: This study furthers our understanding of expert neurosurgical performance during the resection of simulated virtual reality tumors and provides neurosurgical trainees with predefined proficiency performance benchmarks designed to maximize the learning of specific surgical technical skills. PMID- 25687957 TI - Conventional Laparoscopic vs Robotic Training: Which is Better for Naive Users? A Randomized Prospective Crossover Study. AB - OBJECTIVE: Robotic training (RT) using the da Vinci skills simulator and conventional training (CT) using a laparoscopic "training box" are both used to augment operative skills in minimally invasive surgery. The current study tests the hypothesis that skill acquisition is more rapid using RT than using CT among naive learners. DESIGN AND PARTICIPANTS: A total of 40 subjects without laparoscopic or robotic surgical experience were enrolled and randomized to begin with either RT or CT. Then, 2 specific RT tasks were reproduced for CT and repeated 5 times each with RT and CT. Time and quality indicators were measured quantitatively. A crossover technique was used to control for in-study experience bias. RESULTS: The tasks "pick and place jacks" (PP) and "thread the rings" (TR) were achieved faster with RT than with CT despite crossover (p < 0.0001). An RT favoring difference was observed in speed for both tasks when changing modality. Percentage improvement with increasing trials was similar for RT and CT: RT completion time averaged 39 seconds and 211 seconds (PP and TR, respectively), compared with 65 seconds and 362 seconds when using CT (p < 0.0001); final improvement averaged 26% and 46% for RT (PP and TR, respectively) vs 31% and 47% for CT (p was 0.76 for PP and 0.20 for TR). Within the PP task, RT times averaged 41 seconds without previous CT experience vs 35 seconds with previous CT experience (p = 0.20); CT times averaged 61 seconds without and 69 seconds with previous RT experience (p = 0.48). Comparable times for the TR task were 212 seconds vs 216 seconds (p = 0.66) and 388 seconds vs 334 seconds (p = 0.17). Both instrument collisions and excessive force occurred more commonly for RT than for CT within the TR task (p < 0.0001). CONCLUSIONS: Speeds were faster overall with RT than with CT, but the percentage of speed improvement with trials was similar, suggesting similar learning curves, with minimal transfer effect appreciated. PMID- 25687958 TI - The effect of an evidence-based medicine curriculum on breast cancer knowledge and satisfaction of surgical residents. AB - OBJECTIVE: The current study was performed to determine if evidence-based medicine (EBM) curriculum would affect education of surgical residents. DESIGN: A 5-year prospective study was designed to determine if EBM curriculum could improve residents' satisfaction and understanding of breast cancer management during a breast surgical oncology rotation. During the first 2 years, 45 journal articles were used. During the subsequent 3 years, journal articles were not used. The proportion of patients seen in clinic was collected as an objective measure of the "effort" made by the resident. The final assessment was a 120 question examination. SETTING: Maricopa Medical Center, Phoenix, AZ. Safety net institution with General Surgery residency program. PARTICIPANTS: Postgraduate year 2 general surgery residents. RESULTS: Over 5 years, 30 postgraduate year 2 residents were involved. Univariate analysis showed that female sex (p = 0.04), residents with peer-reviewed publications (p = 0.03), younger age (p = 0.04), American Board of Surgery in-service training examination score (p = 0.01), and clinical effort (p < 0.01) were associated with higher scores. Although residents taught using the journal articles scored 7 points higher on the final examination, this was not significant (p = 0.10). Multivariate analysis showed that American Board of Surgery in-service training examination score and clinic efficiency remained statistically significant. Residents who were taught using the EBM curriculum had significantly higher satisfaction (4.4 vs 3.5, p = 0.001) compared with those who did not go through the EBM curriculum. CONCLUSIONS: The current study demonstrates that an EBM curriculum significantly improved resident satisfaction with the rotation. The EBM curriculum may improve residents' breast cancer knowledge. The most important predictor of resident performance was the effort of resident. PMID- 25687959 TI - Principles for a surgical career: lessons from the Normandy beaches. PMID- 25687960 TI - Design and experimental evaluation of an anti-leak feeding tube. AB - BACKGROUND: Enteral feeding via gastrostomy or jejunostomy tube is often required to adequately treat patients with cancer, gastrointestinal disorders, and cerebral vascular accident. Although sufficient to provide adequate caloric intake, the present design of a gastrostomy tube is inadequate. Leakage of gastric contents onto the skin is commonplace prompting emergency department visits and skin damage that requires costly nonoperative and operative intervention. We introduce a new gastrostomy tube design and prototype that inhibits leakage by using an adjustable external retaining member, which compresses against the feeding tube shaft thereby preventing dynamic friction. METHODS: A conventional external retaining member of a 22 French gastrostomy tube was tested against a novel compression-fitting external retaining member. Each gastrostomy tube was clamped to a scale and the external retaining member moved to slide along the tubing at a constant rate, and the applied frictional force was recorded. Thirty repetitions were performed. RESULTS: The experimental prototype generated *2.5-3 the frictional force preventing tube excursion. Mean (standard deviation) forces were 18 (3) versus 46 (4) ounces (n = 10, P = 2.57E 13) and 15 (4) versus 48 (4) ounces (n = 10, P = 1.90E-13) for conventional and experimental designs, respectively. Simulated in situ environment mean forces were 19 (3) versus 39 (3) ounces (n = 10, P = 3.30E-11) for conventional and experimental designs, respectively. CONCLUSIONS: The experimental design created an increased static frictional force that inhibited the movement of the external retaining member against the gastrostomy tube. Clinical implementation is the next step to evaluate for reduced feeding tube morbidity and healthcare expenses by preventing leakage of gastric contents. PMID- 25687961 TI - Peritoneal lavage using chlorhexidine gluconate at the end of colon surgery reduces postoperative intra-abdominal infection in mice. AB - BACKGROUND: The use of peritoneal lavage with antiseptic solutions after bowel surgery remains controversial. This study compared peritoneal lavage using chlorhexidine gluconate at low concentrations and normal saline in mice with cecal ligation and perforation. METHODS: A total of 180 mice were randomized to six groups. Groups A, B, and C received one-time intraperitoneal injections of normal saline, chlorhexidine gluconate 0.05%, and chlorhexidine gluconate 0.025%, respectively. Groups D, E, and F were all subject to cecal ligation and perforation, then underwent partial cecectomy and peritoneal lavage with normal saline only, chlorhexidine gluconate 0.05% followed by normal saline, and chlorhexidine gluconate 0.025% followed by normal saline, respectively. Animals were followed postoperatively then sacrificed and examined at necropsy for occurrence of intra-abdominal abscesses, adhesions, or other pathology. RESULTS: A total of 48 mice (26.7%) developed postoperative intra-abdominal abscesses. Group E mice that had chlorhexidine gluconate 0.05% lavage had significantly lower incidence of postoperative intra-abdominal abscesses compared with that of group D mice that had saline lavage only (P = 0.0113). There was no significant difference in occurrence of macroscopic adhesions among mice groups that had or did not have surgery. (P = 1 and P = 0.3728). Microscopic peritoneal fibrosis occurred significantly more among group E mice that had chlorhexidine gluconate 0.05% lavage compared with group D mice that had saline lavage only (P = <0.005). There was no significant difference in postoperative mortality between surgical groups (P = 0.8714). CONCLUSIONS: Chlorhexidine gluconate 0.05% peritoneal lavage after partial colectomy (cecectomy) in mice reduces postoperative intra-abdominal infection without significant macroscopic adhesion formation. PMID- 25687962 TI - Myogenesis in the genomics era. AB - Skeletal myogenesis is the process of formation of the muscles that enable movement and breathing. Muscles form after the fate determination and differentiation of precursor cells. Being an extraordinarily complex process, myogenesis is regulated at multiple levels, and transcriptional regulation naturally plays a big part in the making of muscle. A significant part of what we know today of the transcriptional regulatory networks overseeing myogenesis comes from large-scale functional genomics studies. The objective of this review is to provide an overview of the various genomics techniques that have been employed over the years to understand myogenic regulation, to give a sense of the degree of understanding they have provided us up to now, and to highlight the next challenges to be overcome. PMID- 25687963 TI - The PRE-Derived NMR Model of the 38.8-kDa Tri-Domain IsdH Protein from Staphylococcus aureus Suggests That It Adaptively Recognizes Human Hemoglobin. AB - Staphylococcus aureus is a medically important bacterial pathogen that, during infections, acquires iron from human hemoglobin (Hb). It uses two closely related iron-regulated surface determinant (Isd) proteins to capture and extract the oxidized form of heme (hemin) from Hb, IsdH and IsdB. Both receptors rapidly extract hemin using a conserved tri-domain unit consisting of two NEAT (near iron transporter) domains connected by a helical linker domain. To gain insight into the mechanism of extraction, we used NMR to investigate the structure and dynamics of the 38.8-kDa tri-domain IsdH protein (IsdH(N2N3), A326-D660 with a Y642A mutation that prevents hemin binding). The structure was modeled using long range paramagnetic relaxation enhancement (PRE) distance restraints, dihedral angle, small-angle X-ray scattering, residual dipolar coupling and inter-domain NOE nuclear Overhauser effect data. The receptor adopts an extended conformation wherein the linker and N3 domains pack against each other via a hydrophobic interface. In contrast, the N2 domain contacts the linker domain via a hydrophilic interface and, based on NMR relaxation data, undergoes inter-domain motions enabling it to reorient with respect to the body of the protein. Ensemble calculations were used to estimate the range of N2 domain positions compatible with the PRE data. A comparison of the Hb-free and Hb-bound forms reveals that Hb binding alters the positioning of the N2 domain. We propose that binding occurs through a combination of conformational selection and induced-fit mechanisms that may promote hemin release from Hb by altering the position of its F helix. PMID- 25687964 TI - Roles of intramolecular and intermolecular interactions in functional regulation of the Hsp70 J-protein co-chaperone Sis1. AB - Unlike other Hsp70 molecular chaperones, those of the eukaryotic cytosol have four residues, EEVD, at their C-termini. EEVD(Hsp70) binds adaptor proteins of the Hsp90 chaperone system and mitochondrial membrane preprotein receptors, thereby facilitating processing of Hsp70-bound clients through protein folding and translocation pathways. Among J-protein co-chaperones functioning in these pathways, Sis1 is unique, as it also binds the EEVD(Hsp70) motif. However, little is known about the role of the Sis1:EEVD(Hsp70) interaction. We found that deletion of EEVD(Hsp70) abolished the ability of Sis1, but not the ubiquitous J protein Ydj1, to partner with Hsp70 in in vitro protein refolding. Sis1 co chaperone activity with Hsp70?EEVD was restored upon substitution of a glutamic acid of the J-domain. Structural analysis revealed that this key glutamic acid, which is not present in Ydj1, forms a salt bridge with an arginine of the immediately adjacent glycine-rich region. Thus, restoration of Sis1 in vitro activity suggests that intramolecular interactions between the J-domain and glycine-rich region control co-chaperone activity, which is optimal only when Sis1 interacts with the EEVD(Hsp70) motif. However, we found that disruption of the Sis1:EEVD(Hsp70) interaction enhances the ability of Sis1 to substitute for Ydj1 in vivo. Our results are consistent with the idea that interaction of Sis1 with EEVD(Hsp70) minimizes transfer of Sis1-bound clients to Hsp70s that are primed for client transfer to folding and translocation pathways by their preassociation with EEVD binding adaptor proteins. These interactions may be one means by which cells triage Ydj1- and Sis1-bound clients to productive and quality control pathways, respectively. PMID- 25687965 TI - In and out of home care decisions: The influence of confirmation bias in developing decision supportive reasoning. AB - The aims of this study were to identify the themes Social Workers regard as important in supporting decisions to remove children from, or return them to, the care of their parents. To further elicit underlying hypotheses that are discernible in interpretation of evidence. A case study, comprising a two-part vignette with a questionnaire, recorded demographic information, child welfare attitudes and risk assessments, using scales derived from standardised instruments, was completed by 202 Social Workers in Northern Ireland. There were two manipulated variables, mother's attitude to removal and child's attitude to reunification 2 years later. In this paper we use data derived from respondents' qualitative comments explaining their reasoning for in and out of home care decisions. Some 60.9% of respondent's chose the parental care option at part one, with 94% choosing to have the child remain in foster care at part two. The manipulated variables were found to have no significant statistical effect. However, three underlying hypotheses were found to underpin decisions; (a) child rescue, (b) kinship defence and (c) a hedged position on calculation of risk subject to further assessment. Reasoning strategies utilised by social workers to support their decision making suggest that they tend to selectively interpret information either positively or negatively to support pre-existing underlying hypotheses. This finding is in keeping with the literature on 'confirmation bias.' The research further draws attention to the need to incorporate open questions in quantitative studies, to help guard against surface reading of data, which often does not 'speak for itself.' PMID- 25687967 TI - Instrumented Assessment of Oral Motor Function in Healthy Subjects and People with Systemic Sclerosis. AB - The aim of the present study was to provide quantitative data of oral function in healthy subjects (HSs), validity of measurements and estimation of measurement bias, as well as quantify oral impairment in persons with scleroderma (SSc). 151 HSs and 12 subjects with SSc were recruited and assessed using instrumented tools, measuring maximal mouth opening; lip strength; and tongue strength, protrusion, retraction, and endurance. Twenty HSs were also retested 3-5 weeks later in order to assess the test-retest reliability of the measurements. Intraclass correlation coefficients proved to be satisfactory (>0.8) for both inter-rater and test-retest reliabilities of all measurements except for tongue retraction. In the HS group, maximal mouth opening and tongue and lips strength values were larger (P < 0.05) for males than females, while no significant differences were found for other variables. Older subjects had statistically significantly lower tongue retraction values and tongue endurance values than younger subjects. The SSc group showed a statistically significant decrease (P < 0.05) in almost all the measurements. Assessment procedures proved to be valid and reliable. Gender and height were predictors of mouth opening, lip and tongue strength, while age correlates with tongue retraction and endurance. Measurements highlighted the strong impact of SSc on oral functions and in particular on tongue protrusion, tongue strength, and endurance. PMID- 25687968 TI - Electrophysiological Evaluation of Dysphagia in the Mild or Moderate Patients with Multiple Sclerosis: A Concept of Subclinical Dysphagia. AB - Swallowing mechanism and neurogenic dysphagia in MS have been rarely studied by electromyographical (EMG) methods. This study aims to evaluate the presence of subclinical dysphagia in patients with mild multiple sclerosis (MS) using electrophysiological methods. A prospective study of 51 patients with relapsing remitting multiple sclerosis and 18 age-matched healthy adults was investigated. We used electromyography to measure the activity of the submental muscles during swallowing. Electrophysiological recordings of patients were obtained during relapse, after relapse, and at any time in remission period. Clinical dysphagia was found in 12% of MS patients, while electrophysiological swallowing abnormalities were encountered in 33% of patients. Subclinical dysphagia was determined in 35% of patients during an MS relapse, in 20% of patients after a relapse, and in 25% of all 51 patients in the remission period based on EMG findings. Duration of swallowing signal of submental muscles in all MS patients was found to be longer than in normal subjects (p = 0.001). During swallowing of 50 ml of sequential water, the compensatory respiratory cycles occurred more often in MS patients than normal subjects, especially during a relapse (p = 0.005). This is the first study investigating swallowing abnormalities and subclinical dysphagia from the electrophysiological aspect in MS patients with mild disability. The electrophysiological tests described in this study are useful to uncover subclinical dysphagia since they have the advantage of being rapid, easy to apply, non-invasive, and without risk for the patients. PMID- 25687969 TI - A solution-processed molybdenum oxide treated silver nanowire network: a highly conductive transparent conducting electrode with superior mechanical and hole injection properties. AB - We demonstrate the fabrication of solution-processed MoOx-treated (s-MoOx) silver nanowire (AgNW) transparent conductive electrodes (TCEs) utilizing low temperature (sub-100 degrees C) processes. The s-MoOx aggregates around the AgNW and forms gauze-like MoOx thin films between the mesh, which can effectively lower the sheet resistance by more than two orders of magnitude. Notably, these s MoOx-treated AgNW TCEs exhibit a combination of several promising characteristics, such as a high and broad transmittance across a wavelength range of 400 to 1000 nm, transmission of up to 96.8%, a low sheet resistance of 29.8 ohm sq(-1), a low haze value of 0.90%, better mechanical properties against bending and adhesion tests, and preferable gap states for efficient hole injection in optoelectronic applications. By utilizing these s-MoOx-treated AgNW TCEs as the anode in ITO-free organic light emitting diodes, promising performance of 29.2 lm W(-1) and 10.3% external quantum efficiency are demonstrated. The versatile, multi-functional s-MoOx treatment presented here paves the way for the use of low-temperature, solution-processed MoOx as both a nanowire linker and a hole injection interfacial layer for future flexible optoelectronic devices. PMID- 25687970 TI - Controlling the spins angular momentum in ferromagnets with sequences of picosecond acoustic pulses. AB - Controlling the angular momentum of spins with very short external perturbations is a key issue in modern magnetism. For example it allows manipulating the magnetization for recording purposes or for inducing high frequency spin torque oscillations. Towards that purpose it is essential to modify and control the angular momentum of the magnetization which precesses around the resultant effective magnetic field. That can be achieved with very short external magnetic field pulses or using intrinsically coupled magnetic structures, resulting in a transfer of spin torque. Here we show that using picosecond acoustic pulses is a versatile and efficient way of controlling the spin angular momentum in ferromagnets. Two or three acoustic pulses, generated by femtosecond laser pulses, allow suppressing or enhancing the magnetic precession at any arbitrary time by precisely controlling the delays and amplitudes of the optical pulses. A formal analogy with a two dimensional pendulum allows us explaining the complex trajectory of the magnetic vector perturbed by the acoustic pulses. PMID- 25687971 TI - Na,K-ATPase structure/function relationships probed by the denaturant urea. AB - Urea interacts with the Na,K-ATPase, leading to reversible as well as irreversible inhibition of the hydrolytic activity. The enzyme purified from shark rectal glands is more sensitive to urea than Na,K-ATPase purified from pig kidney. An immediate and reversible inhibition under steady-state conditions of hydrolytic activity at 37 degrees C is demonstrated for the three reactions studied: the overall Na,K-ATPase activity, the Na-ATPase activity observed in the absence of K+ as well as the K+-dependent phosphatase reaction (K-pNPPase) seen in the absence of Na+. Half-maximal inhibition is seen with about 1M urea for shark enzyme and about 2M urea for pig enzyme. In the presence of substrates there is also an irreversible inhibition in addition to the reversible process, and we show that ATP protects against the irreversible inhibition for both the Na,K-ATPase and Na-ATPase reaction, whereas the substrate paranitrophenylphosphate leads to a slight increase in the rate of irreversible inhibition of the K-pNPPase. The rate of the irreversible inactivation in the absence of substrates is much more rapid for shark enzyme than for pig enzyme. The larger number of potentially urea-sensitive hydrogen bonds in shark enzyme compared to pig enzyme suggests that interference with the extensive hydrogen bonding network might account for the higher urea sensitivity of shark enzyme. The reversible inactivation is interpreted in terms of domain interactions and domain accessibilities using as templates the available crystal structures of Na,K-ATPase. It is suggested that a few interdomain hydrogen bonds are those mainly affected by urea during reversible inactivation. PMID- 25687972 TI - Hydroxytyrosol and tyrosol esters partitioning into, location within, and effect on DOPC liposome bilayer behavior. AB - The phenols hydroxytyrosol and tyrosol made abundantly available through olive oil processing were enzymatically transesterified into effective lipophilic antioxidants with cuphea oil. The hydroxytyrosyl and tyrosyl esters made from cuphea oil were assessed for their ability to partition into, locate within and effect the bilayer behavior of 1,2-dioloeoylphosphatidylcholine liposomes and compared to their counterparts made from decanoic acid. Partitioning into liposomes was on the same scale for both hydroxytyrosyl derivatives and both tyrosyl derivatives. All were found to locate nearly at the same depth within the bilayer. Each was found to affect bilayer behavior in a distinct manner. PMID- 25687973 TI - Interaction of a peptide derived from C-terminus of human TRPA1 channel with model membranes mimicking the inner leaflet of the plasma membrane. AB - The transient receptor potential ankyrin 1 channel (TRPA1) belongs to the TRP cation channel superfamily that responds to a panoply of stimuli such as changes in temperature, calcium levels, reactive oxygen and nitrogen species and lipid mediators among others. The TRP superfamily has been implicated in diverse pathological states including neurodegenerative disorders, kidney diseases, inflammation, pain and cancer. The intracellular C-terminus is an important regulator of TRP channel activity. Studies with this and other TRP superfamily members have shown that the C-terminus association with lipid bilayer alters channel sensitivity and activation, especially interactions occurring through basic residues. Nevertheless, it is not yet clear how this process takes place and which regions in the C-terminus would be responsible for such membrane recognition. With that in mind, herein the first putative membrane interacting region of the C-terminus of human TRPA1, (corresponding to a 29 residue peptide, IAEVQKHASLKRIAMQVELHTSLEKKLPL) named H1 due to its potential helical character was chosen for studies of membrane interaction. The affinity of H1 to lipid membranes, H1 structural changes occurring upon this interaction as well as effects of this interaction in lipid organization and integrity were investigated using a biophysical approach. Lipid models systems composed of zwitterionic and anionic lipids, namely those present in the lipid membrane inner leaflet, where H1 is prone to interact, where used. The study reveals a strong interaction and affinity of H1 as well as peptide structuration especially with membranes containing anionic lipids. Moreover, the interactions and peptide structure adoption are headgroup specific. PMID- 25687974 TI - A refined atomic scale model of the Saccharomyces cerevisiae K+-translocation protein Trk1p combined with experimental evidence confirms the role of selectivity filter glycines and other key residues. AB - Potassium ion (K+) uptake in yeast is mediated mainly by the Trk1/2 proteins that enable cells to survive on external K+ concentration as low as a few MUM. Fungal Trks are related to prokaryotic TRK and Ktr and plant HKT K+ transport systems. Overall sequence similarity is very low, thus requiring experimental verification of homology models. Here a refined structural model of the Saccharomyces cerevisiae Trk1 is presented that was obtained by combining homology modeling, molecular dynamics simulation and experimental verification through functional analysis of mutants. Structural models and experimental results showed that glycines within the selectivity filter, conserved among the K-channel/transporter family, are not only important for protein function, but are also required for correct folding/membrane targeting. A conserved aspartic acid in the PA helix (D79) and a lysine in the M2D helix (K1147) were proposed earlier to interact. Our results suggested individual roles of these residues in folding, structural integrity and function. While mutations of D79 completely abolished protein folding, mutations at position 1147 were tolerated to some extent. Intriguingly, a secondary interaction of D79 with R76 could enhance folding/stability of Trk1 and enable a fraction of Trk1[K1147A] to fold. The part of the ion permeation path containing the selectivity filter is shaped similar to that of ion channels. However below the selectivity filter it is obstructed or regulated by a proline containing loop. The presented model could provide the structural basis for addressing the long standing question if Trk1 is a passive or active ion translocation system. PMID- 25687975 TI - Secretory vesicle cholesterol: Correlating lipid domain organization and Ca2+ triggered fusion. AB - Membrane organization has received substantial research interest since the degree of ordering in membrane regions is relevant in many biological processes. Here we relate the impact of varying cholesterol concentrations on native secretory vesicle fusion and the lateral domain organization of membrane extracts from these vesicles. Membranes of isolated cortical secretory vesicles were either depleted of cholesterol, had cholesterol loaded to excess of native levels, or were depleted of cholesterol but subsequently reloaded to restore native cholesterol levels. Lipid analyses confirmed cholesterol was the only species significantly altered by these treatments. Treated vesicles were characterized for their ability to undergo fusion. Cholesterol depletion resulted in a decrease of Ca2+ sensitivity and the extent of fusion, while cholesterol loading had no effect on fusion parameters. Membrane extracts were characterized in terms of lipid packing by surface pressure-area isotherms whereas the lateral membrane organization was analyzed by Brewster angle microscopy. While no differences in the isotherms were observed, imaging revealed drastic differences in domain size, shape and frequency between the various conditions. Cholesterol depletion induced larger but fewer domains, suggesting that domain coalescence into larger structures may disrupt the native temporal-spatial organization of the fusion machinery and thus inhibit vesicle docking, priming, and fusion. In contrast, adding excess cholesterol, or rescuing with exogenous cholesterol after sterol depletion, resulted in more but smaller domains. Therefore, cholesterol is an important membrane organizer in the process of Ca2+ triggered vesicular fusion, which can be related to specific physical effects on native membrane substructure. PMID- 25687976 TI - Contribution of acidic extracellular microenvironment of cancer-colonized bone to bone pain. AB - Solid and hematologic cancer colonized bone produces a number of pathologies. One of the most common complications is bone pain. Cancer-associated bone pain (CABP) is a major cause of increased morbidity and diminishes the quality of life and affects survival. Current treatments do not satisfactorily control CABP and can elicit adverse effects. Thus, new therapeutic interventions are needed to manage CABP. However, the mechanisms responsible for CABP are poorly understood. The observation that specific osteoclast inhibitors can reduce CABP in patients indicates a critical role of osteoclasts in the pathophysiology of CABP. Osteoclasts create an acidic extracellular microenvironment by secretion of protons via vacuolar proton pumps during bone resorption. In addition, bone colonized cancer cells also release protons and lactate via plasma membrane pH regulators to avoid intracellular acidification resulting from increased aerobic glycolysis known as the Warburg effect. Since acidosis is algogenic for sensory neurons and bone is densely innervated by sensory neurons that express acid sensing nociceptors, the acidic bone microenvironments can evoke CABP. Understanding of the mechanism by which the acidic extracellular microenvironment is created in cancer-colonized bone and the expression and function of the acid sensing nociceptors are regulated should facilitate the development of novel approaches for management of CABP. Here, the contribution of the acidic microenvironment created in cancer-colonized bone to elicitation of CABP and potential therapeutic implications of blocking the development and recognition of acidic microenvironment will be described. This article is part of a Special Issue entitled: Membrane channels and transporters in cancers. PMID- 25687977 TI - The Influences of Whole Brain Radiotherapy on Social Cognition and Association with Hippocampal and Frontal Dosimetry. AB - The influence of brain radiotherapy on neurocognition is a major concern. Social cognition is a mental process in the meaning of social interaction and the recognition of facial emotion is a domain of social cognition. Thus, we aimed to investigate the early effect of whole brain radiotherapy on facial emotion recognition ability. Thirteen patients with various brain tumors in the study. Beck depression and anxiety inventory and the facial emotion recognition test by using a set of photographs were performed at the beginning and post radiotherapy. The severity of depression (16.40 +/- 12.16 vs 04.00 +/- 02.38 points) and anxiety (14.47 +/- 11.96 vs 04.54 +/- 03.30 points) were significantly higher in patients. The only significance according to facial emotion recognition rate between initial phase of patients and healthy controls was identifying neutral facial em otion (p = 0.002). The patients after brain radiotherapy had significantly better rate of recognizing fear facial emotions (p = 0.039). This study is the first that investigated the effects of cranial irradiation on facial emotion recognition ability and compares this ability with healthy controls. Interestingly, in the early phase the patients seem to be improved in fear facial emotion after brain radiotherapy without sparing cognition specific regions as hippocampus and frontal regions. PMID- 25687978 TI - Open-irrigated laser catheter ablation: influence of catheter-tissue contact force on lesion formation. AB - PURPOSE: Catheter-tissue contact force (CF) is a major determinant for radiofrequency (RF) ablation lesion size and quality. We sought to test the influence of catheter CF on lesion formation by using an open-irrigated electrode laser mapping and ablation (ELMA) catheter. METHODS: With the ELMA catheter in a stable vertical position, continuous wave 1064 nm laser impacts at 15 W (9.5 W/mm(2)), 30 s (285 J/mm(2)), irrigation flow 30 mL/min, were aimed at the endocardial surface of bovine myocardium in heparinized stagnant blood (ACT >350 s) at room temperature (18 degrees C). Lesions were produced with CFs of 100 g, 10 g, in contact but without pressure, with the catheter tip 2.0 mm, and 5.0 mm away (n = 10, each). Lesions were evaluated morphometrically and were compared by the unpaired t tests. RESULTS: There were no significant differences between volumes of lesions achieved with catheter-tissue CF of 100 g, 10 g, and in contact without pressure: 297 +/- 56.0 vs. 300 +/- 39 vs. 320 +/- 24, respectively (p > 0.05). However, volumes of lesions produced at a distance of 2 mm (95 +/- 14 mm(3)) were significantly smaller (p < 0.0001), whereas at a distance of 5.0 mm, no lesions were produced. No steam-pop with crater or thrombus formation occurred. CONCLUSIONS: By using an open-irrigated ELMA catheter, catheter-tissue CF is not a determinant for laser ablation lesion size and quality. Maximum sizes of lesions can be achieved with the catheter in intimate endocardial contact without pressure. However, lesions can be produced also at a catheter-tissue distance of 2.0 mm. Noticeably, there is no thrombus formation during laser application with the free floating ELMA catheter in the stagnant blood. PMID- 25687979 TI - Comparison of pharmacological treatment alone versus treatment combined with cardiac resynchronization therapy in patients over 75 years. AB - BACKGROUND: The role of cardiac resynchronization therapy (CRT) in patients aged >=75 years is not well established. METHODS: We identified 607 patients aged >=75 years with left ventricular ejection fraction (LVEF) of <=35 %, of whom 78 met the guidelines for indication of CRT. Based on the decision of the patients or attending cardiologists, 34 patients received a CRT defibrillator (CRT-D). RESULTS: The age of patients with a CRT indication was 80 +/- 4 years, and 73 % were males. As compared with patients on medical therapy, CRT-D patients were younger (79 +/- 3 vs. 83 +/- 4, P < 0.001), had lower LVEF (23 +/- 7 vs. 27 +/- 7 %, P = 0.008) and higher rate of decompensated heart failure episodes (77 vs. 55 %, P = 0.04), were more frequently New York Heart Association (NYHA) class III-IV (53 vs. 25 %, P = 0.01), and were more likely to be on beta-blockers (88 vs. 66 %, P = 0.023), anticoagulants (61 vs. 32 % P = 0.02), and anti-aldosterone drugs (82 vs. 50 %, P = 0.003). After a median follow-up of 26 months, seven patients in the CRT-D group (21 %) and 20 non-CRT patients (46 %) died (hazard ratio (HR) 0.16 [95 % confidence interval (CI) 0.06-0.46]). The end point of mortality or hospitalization was not reduced because of a similar rate of hospitalizations for heart failure of CRT-D patients. Four CRT-D patients (12 %) had received appropriate device therapy, and one had been inappropriately discharged. During follow-up, 44 % of CRT-D patients improved their LVEF by >40 %. CONCLUSION: CRT-D is potentially of benefit in terms of mortality in our population; this effect persists after correction for use of beta-blockers. In patients >=75 years, CRT indications should be similar to those accepted for younger subjects. PMID- 25687980 TI - Erratum to: impact of hybrid procedure on P wave duration for atrial fibrillation ablation. PMID- 25687981 TI - Psychosocial stress at work and cardiovascular diseases: an overview of systematic reviews. AB - PURPOSE: Based on information reported in systematic reviews (SRevs), this study aimed to find out whether psychosocial stress at work leads to cardiovascular (CV) morbidity and mortality. METHODS: A systematic search in PubMed and EMBASE (until 2014) used a string based on PICOS components. A manual search was followed. Applying the predefined criteria, two reviewers independently screened the titles, abstracts, selected full texts, and validated their quality. Discrepancies were resolved by discussion between reviewers. Studies of low quality were excluded. Contents of enrolled SRevs were extracted by one reviewer; a second reviewer evaluated their accurateness. RESULTS: The search resulted in 462 records. Six SRevs based on 81 studies (total population: ~1,468,670) fulfilled the inclusion criteria, four of "very good" (++) and two of "good" (+) quality. Excluded records were filed, and reasons for exclusion were documented in all cases. Different stress models were used to measure the work-related stress; the "demand-control model" was most commonly used. The two enrolled meta analysis confirmed a modest (1.32, 95 % CI 1.09-1.59; Virtanen et al. 2013) to moderate evidence (1.45, 95 % CI 1.15-1.84; Kivimaki et al. 2006), predominantly among men, for the association between psychosocial stress at work and CV outcomes. Due to lacking information, it was not possible to give evidence on the dose-response relationship. CONCLUSIONS: Same to a SRev, an overview of SRev is used to summarize literature and identify areas in which research is needed. This overview can be used to: (a) Disseminate an up-to-date information on work related stress as a risk factors for CV morbidity and mortality to government, health care providers, workers, and other stakeholders; (b) Encourage governments to better regulate the working conditions and consider work-related psychosocial stress as a hazardous factor that leads to CV diseases or mortality; and (c) Analyze gaps in the literature and provide a summary of research needs. PMID- 25687982 TI - The current role of systemic chemotherapy in the primary treatment of head and neck cancer. AB - The treatment of patients with locoregionally advanced squamous cell carcinoma of the head and neck (HNSCC) is still evolving into the perfect combination of the different multidisciplinary approaches. Induction chemotherapy (ICT) prior to planned definitive local therapy is widely used in this patient population for over 30 years but it is still unclear how to incorporate ICT into multimodality treatment the best. It appears to have a role in selected clinical situations especially for those patients with high risk for distant metastasis. However, since ICT protocols in different studies varies a lot, a comparative and consistent statement of benefits is difficult. We show the recent developments including randomized trials comparing radiochemotherapy (RCT) and ICT followed by definitive RCT here. This review summarizes how ICT has developed over the years, provides critical remarks of recent developments, and discusses how clinical trials including ICT should be conducted in the future. PMID- 25687983 TI - Organ damage in patients with incomplete lupus syndromes: from a Chinese academic center. AB - With this study, we provide insight into the clinical characteristics, laboratory characteristics, and organ damage associated with incomplete lupus syndromes (ILE) and search for predictors of organ damage in ILE. A retrospective chart review was performed on 77 hospitalized patients with ILE. The control patient group comprised 2104 systemic lupus erythematosus (SLE) patients who were entered into the Chinese SLE Treatment and Research group (CSTAR). The Systemic Lupus International Collaborating Clinics (SLICC)/ACR Damage Index (SDI) was used to classify damage features. Based on their SDI score, ILE patients were divided into SDI > 0 and SDI = 0 groups. The percentages of anti-SSA-seropositive (54.5 %) and anti-RNP-seropositive (24.7 %) patients with ILE were higher than those found among the SLE patients from CSTAR (p < 0.001). The mean SDI score was 0.66 (range 0-2), and a damage score greater than 0 was present in 41 (53.3 %) patients. The most prevalent damage category was pulmonary damage, present in 17 (22.1 %) patients. Peripheral vascular damage occurred in individuals who were significantly older than those who had musculoskeletal damage (p = 0.031). The subgroup with SDI > 0 had a higher mean age (36.8 +/- 2.04 years) than those with SDI = 0 (30.8 +/- 2.08 years; p = 0.044). The mean SLEDAI score in the SDI > 0 patient group (8.2 +/- 0.74) was higher than that of the SDI = 0 group (4.8 +/- 0.54; p = 0.001). ILE patients may include a subset that is likely to experience progressive organ damage. Organ damage was more common in patients of older age and with high SLEDAI scores. PMID- 25687984 TI - Mesenteric vasculitis in children with systemic lupus erythematosus. AB - Lupus mesenteric vasculitis (LMV) is a severe and potentially fatal complication of systemic lupus erythematosus (SLE). Although LMV is always a consideration in adolescents and adult patients with SLE, who present with acute abdominal pain, diagnosis and management remain a great challenge. We describe the cases of five patients age 14 to 21 years old diagnosed with LMV. All five patients had active SLE and typical clinical presentation suspicious of LMV. Abdominal CT was the preferred imaging modality and was useful in four patients. Corticosteroids were the mainstay of treatment for all five patients. All five patients survived and complete remission of symptoms was achieved in four out of five patients with the addition of cyclophosphamide and in one out of five with rituximab. A review of the literature was performed including a systemic review of the case reports and case series published in the English literature over the last 20 years. PMID- 25687985 TI - Sociodemographic factors associated with functional disability in outpatients with rheumatoid arthritis in Southwest China. AB - With the rising number of patients with rheumatoid arthritis (RA), there is a limited understanding about sociodemographic factors that influence functional disability in Chinese patients. In order to provide more targeted interventions to improve health-related quality of life (HRQoL) for patients with RA, we conducted a cross-sectional study to investigate the level and influencing factors of functional disability. Convenient samples were collected in outpatients with RA from a rheumatological center in southwest China from September to December 2013. Data were collected by printed questionnaires, and functional disability was measured by the Health Assessment Questionnaire Disability Index (HAQ-DI). The results showed that 58.48 % of 607 outpatients had functional disability. Patients from rural residents, with lower household income and lower education level, were significantly associated with worse functional disability. Multivariate regression findings showed that pain, age, disease duration, total cost for treatment, and frequency of hospitalization were positively associated with functional disability. Meanwhile, subjective and available social support was the protective predictors for functional disability. The results suggested that systematic intervention and therapies should be provided as early as possible. Patients and health care providers should promote the awareness of the importance of accessible health education in early intervention of RA. Besides, pain management and social support are encouraged to postpone the process of disability of patients and improve the HRQoL. Lastly, but not least, prevention and intervention of RA should be incorporated into public health education. PMID- 25687986 TI - Circulating tumor cell detection using a parallel flow micro-aperture chip system. AB - We report on-chip isolation and detection of circulating tumor cells (CTCs) from blood samples using a system that integrates a microchip with immunomagnetics, high-throughput fluidics and size-based filtration. CTCs in a sample are targeted via their surface antigens using magnetic beads functionalized with antibodies. The mixture is then run through a fluidic chamber that contains a micro fabricated chip with arrays of 8 MUm diameter apertures. The fluid runs parallel to the microchip while a magnetic field is generated underneath to draw the beads and cells bound to them toward the chip surface for detection of CTCs that are larger than the apertures and clear out free beads and other smaller particles bound to them. The parallel flow configuration allows high volumetric flow rates, which reduces nonspecific binding to the chip surface and enables multiple circulations of the sample fluid through the system in a short period of time. In this study we first present models of the magnetic and fluidic forces in the system using a finite element method. We then verify the simulation results experimentally to determine an optimal flow rate. Next, we characterize the system by detecting cancer cell lines spiked into healthy human blood and show that on average 89% of the spiked MCF-7 breast cancer cells were detected. We finally demonstrate detection of CTCs in 49 out of 50 blood samples obtained from non-small cell lung cancer (NSCLC) patients and pancreatic cancer (PANC) patients. The number of CTCs detected ranges from 2 to 122 per 8 mL s of blood. We also demonstrate a statistically significant difference between the CTC counts of NSCLC patients who have received therapy and those who have not. PMID- 25687987 TI - Presence of Human and Animal Viruses in Surface Waters in Vojvodina Province of Serbia. AB - For the first time in Serbia, a small surveillance study was conducted in order to estimate the presence and frequency of occurrence of selected human [adenoviruses (HAdV), noroviruses, (NoV GI, NoV GII) and hepatitis A virus (HAV)], animal [porcine adenovirus (PAdV) and bovine polyomavirus (BPyV)] and zoonotic [hepatitis E virus (HEV)] viruses in selected surface waters. In total, 60 surface water samples were collected in two sampling occasions at 30 locations, with each sampling time being separated by 1-5 months. In addition, six sewage effluent samples were collected at one sampling site per each of the three tested town sewage systems, in two sampling occasions with 2 months intervals, before their discharge into the surface waters. The most prevalent virus found was HAdV which was detected in 43.33 % samples. NoV GII was found in 40 % samples. NoV GI was found in 10 % samples, and PAdV, BPyV and HEV were detected in 5 (8.33 %), 4 (6.67 %) and 2 (3.33 %) samples, respectively. HAV was not found in any of analysed surface waters or urban sewage samples. The obtained results confirm the presence of pathogenic enteric viruses of both human and animal origin in surface waters in Serbia indicating the existence of diverse contamination sources. PMID- 25687988 TI - Hepatitis B virus reactivation and hepatitis in gastrointestinal cancer patients after chemotherapy. AB - PURPOSE: The objectives of this study were to investigate the incidences of hepatitis B virus (HBV) reactivation and hepatitis in gastrointestinal cancer patients with positive hepatitis B surface antigen (HBsAg) after chemotherapy and assess the effect of antiviral therapy on preventing HBV reactivation and hepatitis. METHODS: The medical records of gastric or colorectal cancer patients with positive HBsAg undergoing chemotherapy in West China Hospital were reviewed from January 2009 to August 2014. RESULTS: One hundred and fifty-six patients were included. Seventy-six patients had no records of the baseline HBV DNA copy (bHDC) and received no antiviral therapy. Of 80 patients with known bHDCs, 39 patients received antiviral therapy. The incidence of HBV reactivation was 14.6% in the non-antiviral group with known bHDCs (n = 41), compared with 0% in the antiviral group (P = 0.039). Compared with 12.8% in the antiviral group (P = 0.034), 29.9% of patients suffered from hepatitis in the total non-antiviral group (n = 117). More patients with moderate/severe hepatitis were seen in the non-antiviral group (P = 0.027). Non-antiviral therapy was the only risk factor for hepatitis in multivariate analysis (HR 3.195, 95% CI 1.117-10.989; P = 0.043). CONCLUSIONS: HBV reactivation and hepatitis occurred in a significant proportion of gastrointestinal cancer patients with positive HBsAg who received chemotherapy. Antiviral therapy could reduce the incidences of HBV reactivation and hepatitis. PMID- 25687989 TI - A pharmacokinetic binding model for bevacizumab and VEGF165 in colorectal cancer patients. AB - PURPOSE: To characterize the population pharmacokinetics of bevacizumab, its binding properties to VEGF165 and the effect of demographic data and VEGF-A polymorphisms on the interplay between bevacizumab serum pharmacokinetics and VEGF165 serum concentrations in patients with colorectal cancer stage IV. METHODS: Bevacizumab and VEGF165 data were collected from 19 adult patients with metastatic colorectal cancer enrolled in an observational clinical study. Bevacizumab was administered with one of the following combinations: 5 FU/Leucovorin/Irinotecan, 5-FU/Leucovorin/Oxaliplatin, Capecitabine/Irinotecan at doses ranging from 5 to 10 mg/kg every 2 or 3 weeks. Data analysis was performed using nonlinear mixed-effects modeling implemented in NONMEM 7.3. RESULTS: A target-mediated drug disposition model adequately described bevacizumab concentration changes over time and its binding characteristics to VEGF165. The estimated clearance of bevacizumab was 0.18 L/day, the free VEGF165 levels at baseline were 212 ng/L, and the elimination rate constant of free VEGF165 was 0.401 day(-1). Body weight was allometrically included in all PK parameters. CONCLUSION: The final model adequately described the pre- and post-dose concentrations of total bevacizumab and free VEGF165 in patients with colorectal cancer. Model parameters were consistent with those previously reported for patients with solid tumors. Correlations between the binding affinity of bevacizumab and the VEGF-2578C/A and VEGF-634G/C polymorphisms were noticed. PMID- 25687990 TI - Phase I trial of oral S-1 combined with hepatic arterial infusion of gemcitabine in unresectable biliary tract cancer. AB - PURPOSE: S-1 and gemcitabine (GS) combination therapy is a promising treatment for advanced biliary tract cancer (BTC). However, systemic administration of GS is associated with a high rate of grade 3 and 4 neutropenia. Hepatic arterial infusion (HAI) of gemcitabine may overcome this problem. We conducted a prospective phase 1 trial to determine the maximum tolerated dose (MTD) of S-1 and rates of dose-limiting toxicities (DLTs) associated with HAI of gemcitabine in patients with unresectable BTC. METHODS: BTC patients were treated with 21-day cycles of HAI of gemcitabine (1000 mg/m(2) on days 1 and 8) and oral S-1 (60, 70, or 80 mg/m(2) on days 1-14) until disease progression occurred. RESULTS: Fifteen patients were enrolled in the study. Grade 3 and 4 neutropenia occurred in five of 15 (33%) patients. Among six patients who were treated with 60 mg/m(2) S-1, one developed grade 4 neutropenia. DLTs (grade 4 neutropenia and bladder infection) occurred in two of six patients who were treated with 70 mg/m(2) S-1. Two of the three patients who were treated with 80 mg/m(2) S-1 experienced DLTs (grade 4 leukopenia and neutropenia and grade 3 febrile neutropenia). Thus, 80 mg/m(2) was defined as the MTD of S-1. CONCLUSION: The MTD of oral S-1 in GS therapy is 80 mg/m(2). Furthermore, HAI of gemcitabine may reduce the rate of grade 3 and 4 neutropenia in BTC patients receiving GS therapy. PMID- 25687991 TI - Bandgap tunability at single-layer molybdenum disulphide grain boundaries. AB - Two-dimensional transition metal dichalcogenides have emerged as a new class of semiconductor materials with novel electronic and optical properties of interest to future nanoelectronics technology. Single-layer molybdenum disulphide, which represents a prototype two-dimensional transition metal dichalcogenide, has an electronic bandgap that increases with decreasing layer thickness. Using high resolution scanning tunnelling microscopy and spectroscopy, we measure the apparent quasiparticle energy gap to be 2.40 +/- 0.05 eV for single-layer, 2.10 +/- 0.05 eV for bilayer and 1.75 +/- 0.05 eV for trilayer molybdenum disulphide, which were directly grown on a graphite substrate by chemical vapour deposition method. More interestingly, we report an unexpected bandgap tunability (as large as 0.85 +/- 0.05 eV) with distance from the grain boundary in single-layer molybdenum disulphide, which also depends on the grain misorientation angle. This work opens up new possibilities for flexible electronic and optoelectronic devices with tunable bandgaps that utilize both the control of two-dimensional layer thickness and the grain boundary engineering. PMID- 25687992 TI - Obesity. Unravelling the neural networks that drive different eating behaviours. PMID- 25687998 TI - Surgery. Papillary thyroid cancer--how aggressive should surgery be? PMID- 25687993 TI - Adenosine signalling in diabetes mellitus--pathophysiology and therapeutic considerations. AB - Adenosine is a key extracellular signalling molecule that regulates several aspects of tissue function by activating four G-protein-coupled receptors, A1, A2A, A2B and A1 adenosine receptors. Accumulating evidence highlights a critical role for the adenosine system in the regulation of glucose homeostasis and the pathophysiology of type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). Although adenosine signalling is known to affect insulin secretion, new data indicate that adenosine signalling also contributes to the regulation of beta-cell homeostasis and activity by controlling the proliferation and regeneration of these cells as well as the survival of beta cells in inflammatory microenvironments. Furthermore, adenosine is emerging as a major regulator of insulin responsiveness by controlling insulin signalling in adipose tissue, muscle and liver; adenosine also indirectly mediates effects on inflammatory and/or immune cells in these tissues. This Review critically discusses the role of the adenosine-adenosine receptor system in regulating both the onset and progression of T1DM and T2DM, and the potential of pharmacological manipulation of the adenosinergic system as an approach to manage T1DM, T2DM and their associated complications. PMID- 25688000 TI - Combination immunotherapies for type 1 diabetes mellitus. AB - Immunotherapies for type 1 diabetes mellitus (T1DM) have been the focus of intense basic and clinical research over the past few decades. Restoring beta cell function is the ultimate goal of intervention trials that target the immune system in T1DM. In an attempt to achieve this aim, different combination therapies have been proposed over the past few years that are based on treatments tackling the various mechanisms involved in the destruction of beta cells. The results of clinical trials have not matched expectations based on the positive results from preclinical studies. The heterogeneity of T1DM might explain the negative results obtained, but previous trials have not addressed this issue. However, novel promising combination therapies are being developed, including those that couple immunomodulators with drugs that stimulate beta-cell regeneration in order to restore normoglycaemia. This strategy is an encouraging one to pursue the goal of finding a cure for T1DM. This Review summarizes the available data about combination immunotherapies in T1DM, particularly addressing their clinical importance. The available data supporting the use of registered drugs, such as proton pump inhibitors and incretin-based agents, that have been shown to induce beta-cell regeneration will also be discussed. PMID- 25687999 TI - Diabetes mellitus--advances and challenges in human beta-cell proliferation. AB - The treatment of diabetes mellitus represents one of the greatest medical challenges of our era. Diabetes results from a deficiency or functional impairment of insulin-producing beta cells, alone or in combination with insulin resistance. It logically follows that the replacement or regeneration of beta cells should reverse the progression of diabetes and, indeed, this seems to be the case in humans and rodents. This concept has prompted attempts in many laboratories to create new human beta cells using stem-cell strategies to transdifferentiate or reprogramme non-beta cells into beta cells or to discover small molecules or other compounds that can induce proliferation of human beta cells. This latter approach has shown promise, but has also proven particularly challenging to implement. In this Review, we discuss the physiology of normal human beta-cell replication, the molecular mechanisms that regulate the cell cycle in human beta cells, the upstream intracellular signalling pathways that connect them to cell surface receptors on beta cells, the epigenetic mechanisms that control human beta-cell proliferation and unbiased approaches for discovering novel molecules that can drive human beta-cell proliferation. Finally, we discuss the potential and challenges of implementing strategies that replace or regenerate beta cells. PMID- 25688001 TI - IgA vasculitis (Henoch-Shonlein purpura) in adults: Diagnostic and therapeutic aspects. AB - Immunoglobulin A (IgA) vasculitis, formerly called Henoch-Schonlein purpura, is an immune complex vasculitis affecting small vessels with dominant IgA deposits. Clinical manifestations mainly involve cutaneous purpura, arthralgias and/or arthritis, acute enteritis and glomerulonephritis. IgA vasculitis is more common among children than adults, with more severe disease in adults. Gastrointestinal and renal involvements represent the principal causes of morbidity and mortality in adults. Factors associated with long-term end-stage renal disease (ESRD) include baseline renal function impairment and baseline proteinuria >1 or 1.5 g/day, and on renal biopsy degree of interstitial fibrosis, sclerotic glomeruli and fibrinoid necrosis. Management of IgA vasculitis in adults is rendered difficult for clinicians because of the absence of correlation between initial presentation and long-term renal outcome, and the possible occurrence of spontaneous remission in patients with severe presentation or, in contrast, possible evolution to ESRD in patients with mild symptoms. Treatment is often symptomatic because disease course is usually benign. Treatment of severe involvement, including severe gastrointestinal complications or proliferative glomerulonephritis, remains controversial, with no evidence that corticosteroids or immunosuppressive agents improved long-term outcome. Prospective, randomized, controlled trials are thus needed to analyze the benefit-risk ratio of such treatments. PMID- 25688002 TI - Visible light induced radical cyclization of o-iodophenylacrylamides: a concise synthesis of indolin-2-one. AB - A [Ir(ppy)2(dtb-bpy)]PF6-catalyzed intramolecular radical cyclization of o iodophenylacrylamides affording indolin-2-ones in moderate to excellent yields via 5-exo-trig radical cyclization under visible light is presented. This method provides new access to the synthesis of indolin-2-ones under mild reaction conditions. PMID- 25688003 TI - Levels and profiles of chlorinated and brominated contaminants in Southern Hemisphere humpback whales, Megaptera novaeangliae. AB - The study documents the levels and profiles of selected contaminants [polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs), polybrominated diphenyl ethers (PBDEs) and methoxylated PBDEs (MeO-PBDEs)] in blubber biopsy samples collected from humpback whales (Megaptera novaeangliae) in Antarctic Peninsula waters. In addition, we investigated year-to-year and sex related differences in the bioaccumulation patterns. Except for hexachlorobenzene (HCB), whose concentrations were in the same range as those found in whales from the Northern Hemisphere, levels of all other compounds were lower in Southern Hemisphere whales compared to literature data on animals from the Arctic and subarctic region. The mean contribution to the sum of all anthropogenic organohalogen compounds (SigmaOHC) decreased in the following order SigmaPCBs (44%)>HCB (31%)>SigmaDDXs (13%)>SigmaCHLs (4.6%)>SigmaHCHs (4.4%)>SigmaPBDEs (0.9%). The predominant compounds within each chemical class were: PCBs 153, 149, 101 and 138; p,p'-DDE; gamma-HCH; trans-nonachlor; PBDEs 99 and 47. The most dominant MeO-PBDE congener was 6-MeO-BDE 47. As samples were collected during three consecutive summer seasons, year-to-year trends could be assessed indicating a significant decrease from 2000 to 2003 for SigmaCHL levels. Higher SigmaPBDE concentrations and higher values of the SigmaPBDE / SigmaMeO-PBDE ratio, as well as higher ratios between the two MeO-BDEs (2'-MeO-BDE 68/6-MeO-BDE 47) were found in females compared to males. Higher SigmaMeO-PBDE concentrations and higher values of the ratios between the lower chlorinated and the higher chlorinated PCBs were found in males than in females. In addition, five out of six significant differences found through discriminant function analysis were gender-related. The literature reports both feeding in mid- to low-latitudes and sex-related differences in migration patterns for humpback whales from the Southern Hemisphere, indicating that the hypothesis of dietary differences between males and females cannot be excluded. Nevertheless, additional studies are required for further investigation of this hypothesis. PMID- 25688004 TI - Evidence for dose-additive effects of a type II pyrethroid mixture. In vitro assessment. AB - Despite the widespread use of pyrethroid insecticides that led to common exposure in the population, few studies have been conducted to quantitatively assess dose additive effects of pyrethroids using a funcional measure involved in the common toxic mode of action. The aim of this study was to evaluate the potency and efficacy of 6 Type II pyretroids (alpha-cypermethrin, cyfluthrin, lambda cyhalothrin, deltamethrin, cyphenothrin and esfenvalerate) to evoke induction of both nitric oxide and lipid peroxides levels measured as malondialdehyde in three in vitro models (SH-SY5Y, HepG2 and Caco-2 human cells) as well as to test the hypothesis of dose additivity for mixtures of these same 6 pyrethroids. Concentration-responses for 6 pyrethroids were determined as well as the response to mixtures of all 6 pyrethroids. Additivity was tested assuming a dose-additive model. The human neuroblastoma SH-SY5Y cell line was the most sensitive in vitro model. The rank order of potency for cell SH-SY5Y viability MTT assay was deltamethrin>cyphenothrin>lambda-cyhalothrin>cyfluthrin>esfenvalerate>alpha cypermethrin. When 6 pyrethroids were present in the mixture at an equitoxic mixing ratio, the action on nitric oxide (NO) and lipid peroxides measured as malondialdehyde (MDA) production was consistent with a dose-additive model. The results of the present study are consistent with previous reports of additivity of pyrethroids in vivo e in vitro. PMID- 25688005 TI - Re-description and assessment of the taxonomic status of Saguinus fuscicollis cruzlimai Hershkovitz, 1966 (Primates, Callitrichinae). AB - Cruz Lima's saddle-back tamarin Saguinus fuscicollis cruzlimai Hershkovitz, 1966, was described from a painting by Eladio da Cruz Lima in his book Mammals of Amazonia, Vol. 1, Primates (1945). The painting was of four saddle-back tamarins from the upper Rio Purus, one of them distinct and the inspiration for Hershkovitz to describe it as a new subspecies. Its exact provenance was unknown, however, and the specimen was lost. Surveys in the Purus National Forest in 2011 resulted in sightings of this tamarin along the north bank of the Rio Inauini, a left-bank tributary of the middle Purus, and also on the left bank of the Purus, north and south of the Rio Inauini. It is possible that it extends north as far as the Rio Pauini, and that S. f. primitivus Hershkovitz, 1977, occurs north of the Pauini as far the Rio Tapaua, both also left-bank tributaries of the Purus. Morphometric and molecular genetic analyses and the coloration of the pelage indicate that this tamarin differs from its neighbors sufficiently to be considered a full species. In his doctoral dissertation [2010, Taxonomy, Phylogeny and Distribution of Tamarins (Genus Saguinus Hoffmannsegg, 1807) Georg August Universitat, Gottingen], C. Matauschek found that saddle-back and black mantle tamarins diverged from the tamarin lineage around 9.2 million years ago; time enough to warrant their classification in a distinct genus. Leontocebus Wagner, 1840, is the first name available. In this article we re-describe Cruz Lima's saddle-back tamarin. We propose a neotype with a precise locality, and make it a full species in the genus Leontocebus. PMID- 25688006 TI - The differential loading of two barley CENH3 variants into distinct centromeric substructures is cell type- and development-specific. AB - The organization of centromeric chromatin of diploid barley (Hordeum vulgare) encoding two (alpha and beta) CENH3 variants was analysed by super-resolution microscopy. Antibody staining revealed that both CENH3 variants are organized in distinct but intermingled subdomains in interphase, mitotic and meiotic centromeres. Artificially extended chromatin fibres illustrate that these subdomains are formed by polynucleosome clusters. Thus, a CENH3 variant-specific loading followed by the arrangement into specific intermingling subdomains forming the centromere region appears. The CENH3 composition and transcription vary among different tissues. In young embryos, most interphase centromeres are composed of both CENH3 variants, while in meristematic root cells, a high number of nuclei contain betaCENH3 mainly dispersed within the nucleoplasm. A similar distribution and no preferential arrangement of the two CENH3 variants in relationship to the spindle poles suggest that both homologs meet the same function in metaphase cells. PMID- 25688007 TI - Discriminative fluorescence sensing of biothiols in vitro and in living cells. AB - Simultaneous discriminative sensing of biothiols in vitro and in living cells has remained challenging. Herein, we report a new sulfonamide-based self-quenched fluorescent probe 1 for this purpose with high sensitivity and good selectivity. Treatment of 1 with cysteine (Cys), homocysteine (Hcy), or glutathione (GSH) yields aminoluciferin, 2-cyano-6-aminobenzothiazole homocysteine (CBTHcy), or 2 cyano-6-aminobenzothiazole (CBT), turning "on" the fluorescence at wavelengths of 522, 517, or 490 nm, respectively. Kinetic study indicated that 1 reacts with Cys faster than with Hcy or GSH. With these unique properties of 1, we applied 1 for highly sensitive sensing of Cys, Hcy, and GSH among other 19 natural amino acids (AAs) with good selectivity. Confocal fluorescence microscopic imaging of 1 treated HepG2 cells at two channels (522 +/- 8 and 490 +/- 8 nm), together with quantitative analysis, indicated that the "turn-on" fluorescence was induced by intracellular Cys-dominating condensation and reduction of 1 but not by intracellular GSH-dominating reduction of 1. This suggests that 1 could be applied for discriminative sensing of intracellular Cys from the abundant GSH. Further development of 1 might bring about an efficient tool for probing cellular functions that relate to biothiols. PMID- 25688008 TI - Generalized Hypertrichosis Due to Topical Minoxidil. PMID- 25688009 TI - Effect of u18666a on beta-glucosidase, sphingomyelinase, and beta-galactosidase activities in astrocytes of young rats. AB - Niemann-Pick type C disease (NPC) is a neurodegenerative genetic disorder caused by accumulation of lipids, especially cholesterol, in the perinuclear space. U18666A is a cholesterol transport-inhibiting agent, being used to mimic NPC, mainly in fibroblasts. The objective of this study was to observe the effect of the drug U18666A, which causes the accumulation of cholesterol in the cytoplasm of astrocytes from newborn rats, on some lysosomal hydrolase activities. Filipin staining and fluorescence microscopy, through CellM software, were used for visualization and quantification of cholesterol. The dose of U18666A that provided the greatest accumulation of cholesterol was that of 0.25 ug/mL in incubation for 48 h. Primary rat astrocytes incubated with the drug (NPC) showed a significantly higher amount of cholesterol than those without U18666A (controls). The measurement of activity of enzymes sphingomyelinase and beta glucosidase in astrocytes of rats with NPC was significantly lower than that of control astrocytes, which is consistent with the disease in humans. The activity of the enzyme beta-galactosidase showed no significant difference between both groups. We concluded that U18666A appears to be an excellent intracellular cholesterol transport-inhibiting agent affecting some metabolic pathways in astrocytes of young rats, which mimics NPC in these animals. Just like the change in the activity of lysosomal enzymes has been demonstrated, other biochemical parameters of the cell can be tested with this animal model, thus contributing to a better understanding of the disease. PMID- 25688010 TI - Inhibition of Kv1.3 Channels in Human Jurkat T Cells by Xanthohumol and Isoxanthohumol. AB - Using whole-cell patch-clamp technique, we investigated influence of selected compounds from groups of prenylated chalcones and flavonoids: xanthohumol and isoxanthohumol on the activity of Kv1.3 channels in human leukemic Jurkat T cells. Obtained results provide evidence that both examined compounds were inhibitors of Kv1.3 channels in these cells. The inhibitory effects occurred in a concentration-dependent manner. The estimated value of the half-blocking concentration (EC50) was about 3 MUM for xanthohumol and about 7.8 MUM for isoxanthohumol. The inhibition of Kv1.3 channels by examined compounds was not complete. Upon an application of the compounds at the maximal concentrations equal to 30 MUM, the activity of Kv1.3 channels was inhibited to about 0.13 of the control value. The inhibitory effect was reversible. The application of xanthohumol and isoxanthohumol did not change the currents' activation and inactivation rate. These results may confirm our earlier hypothesis that the presence of a prenyl group in a molecule is a factor that facilitates the inhibition of Kv1.3 channels by compounds from the groups of flavonoids and chalcones. The inhibition of Kv1.3 channels might be involved in antiproliferative and proapoptotic effects of the compounds observed in cancer cell lines expressing these channels. PMID- 25688011 TI - Two-component energy spectrum of cuprates in the pseudogap phase and its evolution with temperature and at charge ordering. AB - In the search for mechanisms of high-temperature superconductivity it is critical to know the electronic spectrum in the pseudogap phase from which superconductivity evolves. The lack of angle-resolved photoemission data for every cuprate family precludes an agreement as to its structure, doping and temperature dependence and the role of charge ordering. Here we show that, in the entire Fermi-liquid-like regime that is ubiquitous in underdoped cuprates, the spectrum consists of holes on the Fermi arcs and an electronic pocket. We argue that experiments on the Hall coefficient identify the latter as a permanent feature at doped hole concentration x > 0.08-0.10, in contrast to the idea of the Fermi surface reconstruction via charge ordering. The longstanding issue of the origin of the negative Hall coefficient in YBCO and Hg1201 at low temperature is resolved: the electronic contribution prevails as mobility of the latter (evaluated by the Dingle temperature) becomes temperature independent, while the mobility of holes scattered by the short-wavelength charge density waves decreases. PMID- 25688013 TI - Climate change and vector-borne diseases: what are the implications for public health research and policy? AB - Vector-borne diseases continue to contribute significantly to the global burden of disease, and cause epidemics that disrupt health security and cause wider socioeconomic impacts around the world. All are sensitive in different ways to weather and climate conditions, so that the ongoing trends of increasing temperature and more variable weather threaten to undermine recent global progress against these diseases. Here, we review the current state of the global public health effort to address this challenge, and outline related initiatives by the World Health Organization (WHO) and its partners. Much of the debate to date has centred on attribution of past changes in disease rates to climate change, and the use of scenario-based models to project future changes in risk for specific diseases. While these can give useful indications, the unavoidable uncertainty in such analyses, and contingency on other socioeconomic and public health determinants in the past or future, limit their utility as decision support tools. For operational health agencies, the most pressing need is the strengthening of current disease control efforts to bring down current disease rates and manage short-term climate risks, which will, in turn, increase resilience to long-term climate change. The WHO and partner agencies are working through a range of programmes to (i) ensure political support and financial investment in preventive and curative interventions to bring down current disease burdens; (ii) promote a comprehensive approach to climate risk management; (iii) support applied research, through definition of global and regional research agendas, and targeted research initiatives on priority diseases and population groups. PMID- 25688012 TI - Climate, environmental and socio-economic change: weighing up the balance in vector-borne disease transmission. AB - Arguably one of the most important effects of climate change is the potential impact on human health. While this is likely to take many forms, the implications for future transmission of vector-borne diseases (VBDs), given their ongoing contribution to global disease burden, are both extremely important and highly uncertain. In part, this is owing not only to data limitations and methodological challenges when integrating climate-driven VBD models and climate change projections, but also, perhaps most crucially, to the multitude of epidemiological, ecological and socio-economic factors that drive VBD transmission, and this complexity has generated considerable debate over the past 10-15 years. In this review, we seek to elucidate current knowledge around this topic, identify key themes and uncertainties, evaluate ongoing challenges and open research questions and, crucially, offer some solutions for the field. Although many of these challenges are ubiquitous across multiple VBDs, more specific issues also arise in different vector-pathogen systems. PMID- 25688014 TI - Evolution in action: climate change, biodiversity dynamics and emerging infectious disease. AB - Climatological variation and ecological perturbation have been pervasive drivers of faunal assembly, structure and diversification for parasites and pathogens through recurrent events of geographical and host colonization at varying spatial and temporal scales of Earth history. Episodic shifts in climate and environmental settings, in conjunction with ecological mechanisms and host switching, are often critical determinants of parasite diversification, a view counter to more than a century of coevolutionary thinking about the nature of complex host-parasite assemblages. Parasites are resource specialists with restricted host ranges, yet shifts onto relatively unrelated hosts are common during phylogenetic diversification of parasite lineages and directly observable in real time. The emerging Stockholm Paradigm resolves this paradox: Ecological Fitting (EF)--phenotypic flexibility and phylogenetic conservatism in traits related to resource use, most notably host preference--provides many opportunities for rapid host switching in changing environments, without the evolution of novel host-utilization capabilities. Host shifts via EF fuel the expansion phase of the Oscillation Hypothesis of host range and speciation and, more generally, the generation of novel combinations of interacting species within the Geographic Mosaic Theory of Coevolution. In synergy, an environmental dynamic of Taxon Pulses establishes an episodic context for host and geographical colonization. PMID- 25688015 TI - Present and future projections of habitat suitability of the Asian tiger mosquito, a vector of viral pathogens, from global climate simulation. AB - Climate change can influence the transmission of vector-borne diseases (VBDs) through altering the habitat suitability of insect vectors. Here we present global climate model simulations and evaluate the associated uncertainties in view of the main meteorological factors that may affect the distribution of the Asian tiger mosquito (Aedes albopictus), which can transmit pathogens that cause chikungunya, dengue fever, yellow fever and various encephalitides. Using a general circulation model at 50 km horizontal resolution to simulate mosquito survival variables including temperature, precipitation and relative humidity, we present both global and regional projections of the habitat suitability up to the middle of the twenty-first century. The model resolution of 50 km allows evaluation against previous projections for Europe and provides a basis for comparative analyses with other regions. Model uncertainties and performance are addressed in light of the recent CMIP5 ensemble climate model simulations for the RCP8.5 concentration pathway and using meteorological re-analysis data (ERA Interim/ECMWF) for the recent past. Uncertainty ranges associated with the thresholds of meteorological variables that may affect the distribution of Ae. albopictus are diagnosed using fuzzy-logic methodology, notably to assess the influence of selected meteorological criteria and combinations of criteria that influence mosquito habitat suitability. From the climate projections for 2050, and adopting a habitat suitability index larger than 70%, we estimate that approximately 2.4 billion individuals in a land area of nearly 20 million km(2) will potentially be exposed to Ae. albopictus. The synthesis of fuzzy-logic based on mosquito biology and climate change analysis provides new insights into the regional and global spreading of VBDs to support disease control and policy making. PMID- 25688016 TI - Accelerated phenology of blacklegged ticks under climate warming. AB - The phenology of tick emergence has important implications for the transmission of tick-borne pathogens. A long lag between the emergence of tick nymphs in spring and larvae in summer should increase transmission of persistent pathogens by allowing infected nymphs to inoculate the population of naive hosts that can subsequently transmit the pathogen to larvae to complete the transmission cycle. In contrast, greater synchrony between nymphs and larvae should facilitate transmission of pathogens that do not produce long-lasting infections in hosts. Here, we use 19 years of data on blacklegged ticks attached to small-mammal hosts to quantify the relationship between climate warming and tick phenology. Warmer years through May and August were associated with a nearly three-week advance in the phenology of nymphal and larval ticks relative to colder years, with little evidence of increased synchrony. Warmer Octobers were associated with fewer larvae feeding concurrently with nymphs during the following spring. Projected warming by the 2050s is expected to advance the timing of average nymph and larva activity by 8-11 and 10-14 days, respectively. If these trends continue, climate warming should maintain or increase transmission of persistent pathogens, while it might inhibit pathogens that do not produce long-lasting infections. PMID- 25688017 TI - Climate influences on the cost-effectiveness of vector-based interventions against malaria in elimination scenarios. AB - Despite the dependence of mosquito population dynamics on environmental conditions, the associated impact of climate and climate change on present and future malaria remains an area of ongoing debate and uncertainty. Here, we develop a novel integration of mosquito, transmission and economic modelling to assess whether the cost-effectiveness of indoor residual spraying (IRS) and long lasting insecticidal nets (LLINs) against Plasmodium falciparum transmission by Anopheles gambiae s.s. mosquitoes depends on climatic conditions in low endemicity scenarios. We find that although temperature and rainfall affect the cost-effectiveness of IRS and/or LLIN scale-up, whether this is sufficient to influence policy depends on local endemicity, existing interventions, host immune response to infection and the emergence rate of insecticide resistance. For the scenarios considered, IRS is found to be more cost-effective than LLINs for the same level of scale-up, and both are more cost-effective at lower mean precipitation and higher variability in precipitation and temperature. We also find that the dependence of peak transmission on mean temperature translates into optimal temperatures for vector-based intervention cost-effectiveness. Further cost-effectiveness analysis that accounts for country-specific epidemiological and environmental heterogeneities is required to assess optimal intervention scale-up for elimination and better understand future transmission trends under climate change. PMID- 25688018 TI - Potential effects of warmer worms and vectors on onchocerciasis transmission in West Africa. AB - Development times of eggs, larvae and pupae of vectors of onchocerciasis (Simulium spp.) and of Onchocerca volvulus larvae within the adult females of the vectors decrease with increasing temperature. At and above 25 degrees C, the parasite could reach its infective stage in less than 7 days when vectors could transmit after only two gonotrophic cycles. After incorporating exponential functions for vector development into a novel blackfly population model, it was predicted that fly numbers in Liberia and Ghana would peak at air temperatures of 29 degrees C and 34 degrees C, about 3 degrees C and 7 degrees C above current monthly averages, respectively; parous rates of forest flies (Liberia) would peak at 29 degrees C and of savannah flies (Ghana) at 30 degrees C. Small temperature increases (less than 2 degrees C) might lead to changes in geographical distributions of different vector taxa. When the new model was linked to an existing framework for the population dynamics of onchocerciasis in humans and vectors, transmission rates and worm loads were projected to increase with temperature to at least 33 degrees C. By contrast, analyses of field data on forest flies in Liberia and savannah flies in Ghana, in relation to regional climate change predictions, suggested, on the basis of simple regressions, that 13-41% decreases in fly numbers would be expected between the present and before 2040. Further research is needed to reconcile these conflicting conclusions. PMID- 25688019 TI - The impact of climate change on the geographical distribution of two vectors of Chagas disease: implications for the force of infection. AB - Chagas disease, caused by the parasite Trypanosoma cruzi, is the most important vector-borne disease in Latin America. The vectors are insects belonging to the Triatominae (Hemiptera, Reduviidae), and are widely distributed in the Americas. Here, we assess the implications of climatic projections for 2050 on the geographical footprint of two of the main Chagas disease vectors: Rhodnius prolixus (tropical species) and Triatoma infestans (temperate species). We estimated the epidemiological implications of current to future transitions in the climatic niche in terms of changes in the force of infection (FOI) on the rural population of two countries: Venezuela (tropical) and Argentina (temperate). The climatic projections for 2050 showed heterogeneous impact on the climatic niches of both vector species, with a decreasing trend of suitability of areas that are currently at high-to-moderate transmission risk. Consequently, climatic projections affected differently the FOI for Chagas disease in Venezuela and Argentina. Despite the heterogeneous results, our main conclusions point out a decreasing trend in the number of new cases of Tr. cruzi human infections per year between current and future conditions using a climatic niche approach. PMID- 25688020 TI - Climate change impacts on West Nile virus transmission in a global context. AB - West Nile virus (WNV), the most widely distributed virus of the encephalitic flaviviruses, is a vector-borne pathogen of global importance. The transmission cycle exists in rural and urban areas where the virus infects birds, humans, horses and other mammals. Multiple factors impact the transmission and distribution of WNV, related to the dynamics and interactions between pathogen, vector, vertebrate hosts and environment. Hence, among other drivers, weather conditions have direct and indirect influences on vector competence (the ability to acquire, maintain and transmit the virus), on the vector population dynamic and on the virus replication rate within the mosquito, which are mostly weather dependent. The importance of climatic factors (temperature, precipitation, relative humidity and winds) as drivers in WNV epidemiology is increasing under conditions of climate change. Indeed, recent changes in climatic conditions, particularly increased ambient temperature and fluctuations in rainfall amounts, contributed to the maintenance (endemization process) of WNV in various locations in southern Europe, western Asia, the eastern Mediterranean, the Canadian Prairies, parts of the USA and Australia. As predictions show that the current trends are expected to continue, for better preparedness, any assessment of future transmission of WNV should take into consideration the impacts of climate change. PMID- 25688021 TI - Dengue: recent past and future threats. AB - This article explores four key questions about statistical models developed to describe the recent past and future of vector-borne diseases, with special emphasis on dengue: (1) How many variables should be used to make predictions about the future of vector-borne diseases? (2) Is the spatial resolution of a climate dataset an important determinant of model accuracy? (3) Does inclusion of the future distributions of vectors affect predictions of the futures of the diseases they transmit? (4) Which are the key predictor variables involved in determining the distributions of vector-borne diseases in the present and future? Examples are given of dengue models using one, five or 10 meteorological variables and at spatial resolutions of from one-sixth to two degrees. Model accuracy is improved with a greater number of descriptor variables, but is surprisingly unaffected by the spatial resolution of the data. Dengue models with a reduced set of climate variables derived from the HadCM3 global circulation model predictions for the 1980s are improved when risk maps for dengue's two main vectors (Aedes aegypti and Aedes albopictus) are also included as predictor variables; disease and vector models are projected into the future using the global circulation model predictions for the 2020s, 2040s and 2080s. The Garthwaite-Koch corr-max transformation is presented as a novel way of showing the relative contribution of each of the input predictor variables to the map predictions. PMID- 25688022 TI - Climate change and Ixodes tick-borne diseases of humans. AB - The evidence that climate warming is changing the distribution of Ixodes ticks and the pathogens they transmit is reviewed and evaluated. The primary approaches are either phenomenological, which typically assume that climate alone limits current and future distributions, or mechanistic, asking which tick-demographic parameters are affected by specific abiotic conditions. Both approaches have promise but are severely limited when applied separately. For instance, phenomenological approaches (e.g. climate envelope models) often select abiotic variables arbitrarily and produce results that can be hard to interpret biologically. On the other hand, although laboratory studies demonstrate strict temperature and humidity thresholds for tick survival, these limits rarely apply to field situations. Similarly, no studies address the influence of abiotic conditions on more than a few life stages, transitions or demographic processes, preventing comprehensive assessments. Nevertheless, despite their divergent approaches, both mechanistic and phenomenological models suggest dramatic range expansions of Ixodes ticks and tick-borne disease as the climate warms. The predicted distributions, however, vary strongly with the models' assumptions, which are rarely tested against reasonable alternatives. These inconsistencies, limited data about key tick-demographic and climatic processes and only limited incorporation of non-climatic processes have weakened the application of this rich area of research to public health policy or actions. We urge further investigation of the influence of climate on vertebrate hosts and tick-borne pathogen dynamics. In addition, testing model assumptions and mechanisms in a range of natural contexts and comparing their relative importance as competing models in a rigorous statistical framework will significantly advance our understanding of how climate change will alter the distribution, dynamics and risk of tick-borne disease. PMID- 25688023 TI - Climate change influences on global distributions of dengue and chikungunya virus vectors. AB - Numerous recent studies have illuminated global distributions of human cases of dengue and other mosquito-transmitted diseases, yet the potential distributions of key vector species have not been incorporated integrally into those mapping efforts. Projections onto future conditions to illuminate potential distributional shifts in coming decades are similarly lacking, at least outside Europe. This study examined the global potential distributions of Aedes aegypti and Aedes albopictus in relation to climatic variation worldwide to develop ecological niche models that, in turn, allowed anticipation of possible changes in distributional patterns into the future. Results indicated complex global rearrangements of potential distributional areas, which--given the impressive dispersal abilities of these two species--are likely to translate into actual distributional shifts. This exercise also signalled a crucial priority: digitization and sharing of existing distributional data so that models of this sort can be developed more rigorously, as present availability of such data is fragmentary and woefully incomplete. PMID- 25688024 TI - Evidence that implicit assumptions of 'no evolution' of disease vectors in changing environments can be violated on a rapid timescale. AB - Projected impacts of climate change on vector-borne disease dynamics must consider many variables relevant to hosts, vectors and pathogens, including how altered environmental characteristics might affect the spatial distributions of vector species. However, many predictive models for vector distributions consider their habitat requirements to be fixed over relevant time-scales, when they may actually be capable of rapid evolutionary change and even adaptation. We examine the genetic signature of a spatial expansion by an invasive vector into locations with novel temperature conditions compared to its native range as a proxy for how existing vector populations may respond to temporally changing habitat. Specifically, we compare invasions into different climate ranges and characterize the importance of selection from the invaded habitat. We demonstrate that vector species can exhibit evolutionary responses (altered allelic frequencies) to a temperature gradient in as little as 7-10 years even in the presence of high gene flow, and further, that this response varies depending on the strength of selection. We interpret these findings in the context of climate change predictions for vector populations and emphasize the importance of incorporating vector evolution into models of future vector-borne disease dynamics. PMID- 25688025 TI - Climate change and vector-borne diseases of humans. PMID- 25688026 TI - Analysis of phosphoinositide-binding properties and subcellular localization of GFP-fusion proteins. AB - Specific protein-phosphoinositide (PI) interactions are known to play a key role in the targeting of proteins to specific cellular membranes. Investigation of these interactions would be greatly facilitated if GFP-fusion proteins expressed in mammalian cells and used for their subcellular localization could also be employed for in vitro lipid binding. In this study, we found that lysates of cells overexpressing GFP-fusion proteins could be used for in vitro protein-PI binding assays. We applied this approach to examine the PI-binding properties of Aplysia Sec7 protein (ApSec7) and its isoform ApSec7(VPKIS), in which a VPKIS sequence is inserted into the PH domain of ApSec7. EGFP-ApSec7 but not EGFP ApSec7(VPKIS) did specifically bind to PI(3,4,5)P3 in an in vitro lipid-coated bead assay. Overexpression of EGFP-ApSec7 but not EGFP-ApSec7(VPKIS) did induce neurite outgrowth in Aplysia sensory neurons. Structure modeling analysis revealed that the inserted VPKIS caused misfolding around the PI(3,4,5)P3-binding pocket of ApSec7 and disturbed the binding of PI(3,4,5)P3 to the pleckstrin homology (PH) domain. Our data indicate that plasma membrane localization of EGFP ApSec7 via the interaction between its PH domain and PI(3,4,5)P3 might play a key role in neurite outgrowth in Aplysia. PMID- 25688027 TI - Magnetic-field-enabled resolution enhancement in super-resolution imaging. AB - A novel strategy for modulating the photophysics of organic dyes in super resolution fluorescence imaging using an external magnetic field was reported. The magnetic field induced increase in fluorescence intensity, localization number of probe molecules, and the number of photons emitted per molecule as compared to those acquired without a magnetic field were experimentally confirmed. Improved dSTORM localization precision and imaging resolution were consequently achieved. PMID- 25688028 TI - Connecting Past with Present: A Mixed-Methods Science Ethics Course and its Evaluation. AB - We present a graduate science ethics course that connects cases from the historical record to present realities and practices in the areas of social responsibility, authorship, and human/animal experimentation. This content is delivered with mixed methods, including films, debates, blogging, and practicum; even the instructional team is mixed, including a historian of science and a research scientist. What really unites all of the course's components is the experiential aspect: from acting in historical debates to participating in the current scientific enterprise. The course aims to change the students' culture into one deeply devoted to the science ethics cause. To measure the sought after cultural change, we developed and validated a relevant questionnaire. Results of this questionnaire from students who took the course, demonstrate that the course had the intended effect on them. Furthermore, results of this questionnaire from controls indicate the need for cultural change in that cohort. All these quantitative results are reinforced by qualitative outcomes. PMID- 25688029 TI - Transversely isotropic material characterization of the human anterior longitudinal ligament. AB - The present work represents the first study to report transversely isotropic material parameters for the human anterior longitudinal ligament (ALL) in the thoraco-lumbar spine. Force-deformation data from multi-axial testing was collected from 30 cadaveric spine test specimens using an anisotropic quarter punch test technique. The experimental data was fit to a commonly used anisotropic soft tissue material model using an FEA system identification technique. The material model correlated well with the experimental response (R(2)>=0.98). The constitutive parameter values, as well as the nonlinear anisotropic stress-strain response of the ALL specimens are reported to facilitate application to biomechanical models (including finite element models) of the spine. PMID- 25688030 TI - Biocompatibility evaluation of a thermoplastic rubber for wireless telemetric intracranial pressure sensor coating. AB - This study investigated the biocompatibility of the experimental thermoplastic rubber Arbomatrix(TM) that will be used as the protective coating on a novel intracranial pressure (ICP) sensor silicon chip. Arbomatrix(TM) was benchmarked against biocompatible commercial silicone rubber shunt tubing in the brain via a rat model with 60-day implant duration. A bare silicon chip was also implanted. The results showed similar cellular distribution in the brain-implant boundary and surrounding tissues. Quantitative analysis of neuron and glia density did not show significant difference between implants. Through histological and immunohistochemical evaluation we conclude that Arbomatrix(TM) is well tolerated by the brain. Due to its exceptional barrier properties Arbomatrix(TM) has already been shown to be an excellent protective coating for new ICP monitoring chip. PMID- 25688031 TI - Influence of the stem fixation scenario on load transfer in a hip resurfacing arthroplasty with a biomimetic stem. AB - Finite element (FE) analysis is a widely used tool for extensive preclinical testing of orthopaedic implants such as hip resurfacing femoral components, including evaluation of different stem fixation scenarios (cementation vs osseointegration, etc.). Most FE models use surface-to-surface contact elements to model the load-bearing interfaces that connect bone, cement and implant and neglect the mechanical effects of phenomena such as residual stresses from bone cement curing. The objective of the current study is to evaluate and quantify the effect of different stem fixation scenarios and related phenomena such as residual stresses from bone cement curing. Four models of a previously clinically available implant (Durom) were used to model different stem fixation scenarios of a new biomimetic stem: a cemented stem, a frictional stem, a partially and completely bonded stem, with and without residual stresses from bone cement curing. For the frictional stem, stem-bone micromotions were increased from 0% to 61% of the available surface subjected to micromotions between 10 and 40MUm with the inclusion of residual stresses from bone cement curing. Bonding the stem, even partially, increased stress in the implant at the stem-head junction. Complete bonding of the stem decreased bone strain at step tip, at the cost of increased strain shielding when compared with the frictional stem and partially bonded stem. The increase of micromotions and changes in bone strain highlighted the influence of interfacial conditions on load transfer, and the need for a better modeling method, one capable of assessing the effect of phenomena such as interdigitation and residual stresses from bone cement curing. PMID- 25688032 TI - Clinical characteristics and prognosis factors analysis for post-operative ptosis of sphenocavernous meningiomas: a single institution study. AB - OBJECTIVE: Complete and safe resection of sphenocavernous (SC) meningiomas is difficult and also a great challenge for neurosurgeons. The goal of our study was to report the surgical results and complications for these patients treated at our institution as well as trying to find the factors resulted in ptosis after the operation. MATERIALS AND METHODS: Forty-nine consecutive SC meningiomas cases that underwent surgery between April 1997 and December 2012 were reviewed. The clinical courses of all patients were recorded. Prognosis factors of post operative ptosis were evaluated. RESULTS: There were 38 female and 11 male patients. Mean duration of symptoms was 20.9 months. Visual deficit (34.7%) and headache (22.4%) were the most common presenting symptoms. Mean maximum diameter of the tumors on MRI was 5.1 cm. Subtotal resection was achieved in 51.0% of patients. Follow-up data were available for 39 patients, with a mean follow-up of 73.7 months, and four patients died during follow-up period. Of the 35 living patients, 22 (62.9%) lived a normal life. Univariate analyses showed that factors associated with post-operative ptosis included female patient, with primary operation and the cavernous extension in Category 3 of Hirsch' grading, while multivariate regression analyses showed that only the cavernous extension in Category 3 of Hirsch' grading was independently associated with post-operative ptosis. CONCLUSIONS: Our experience suggests that the most common complication after the SC meningioma surgery is ocular cranial nerve dysfunction, and the only significance factor relative to post-operative ptosis is the level of extension to the cavernous. PMID- 25688033 TI - Coherent anti-Stokes Raman scattering and two photon excited fluorescence for neurosurgery. AB - OBJECTIVE: There is no established method for in vivo imaging during biopsy and surgery of the brain, which is capable to generate competitive images in terms of resolution and contrast comparable with histopathological staining. METHODS: Coherent anti-Stokes Raman scattering (CARS) and two photon excited fluorescence (TPEF) microscopy are non-invasive all optical imaging techniques that are capable of high resolution, label-free, real-time, nondestructive examination of living cells and tissues. They provide image contrast based on the molecular composition of the specimen which allows the study of large tissue areas of frozen tissue sections ex vivo. RESULTS: Here, preliminary data on 55 lesions of the central nervous system are presented. The generated images very nicely demonstrate cytological and architectural features required for pathological tumor typing and grading. Furthermore, information on the molecular content of a probe is provided. The tool will be implemented into a biopsy needle or endoscope in the near future for in vivo studies. CONCLUSION: With this promising multimodal imaging approach the neurosurgeon might directly see blood vessels to minimize the risk for biopsy associated hemorrhages. The attending neuropathologist might directly identify the tumor and guide the selection of representative specimens for further studies. Thus, collection of non representative material could be avoided and the risk to injure eloquent brain tissue minimized. PMID- 25688034 TI - Association between physical fitness, quality of life, and depression in stage II III colorectal cancer survivors. AB - PURPOSE: The impact of cancer on quality of life and depression is an important issue. The purpose of this study was to identify the impact of physical fitness on quality of life and depression in stage II-III colorectal cancer survivors. METHODS: Participants in the current study included 122 stage II-III colorectal cancer survivors (57 females; 56.67 +/- 9.16 years of age and 55 males; 54.69 +/- 9.78 years of age). Fitness was assessed using the 6-min walk test, chair stand test, and push-up test. Quality of life and depression were measured using the Functional Assessment of Cancer Therapy-Colorectal (FACT-C) scale and a 9-item patient health questionnaire interview, respectively. RESULTS: There was a significant association between physical fitness and quality of life and depression in colorectal cancer survivors. The 6-min walk test results were associated with FACT-C total (r = 0.298, p < 0.05), physical well-being (r = 0.230, p < 0.05), functional well-being (r = 0.234, p < 0.05), colorectal cancer concern (r = 0.229, p < 0.05), and depression (r = -0.228, p < 0.05), and the chair stand test results were associated with functional well-being (r = 0.231, p < 0.05), colorectal cancer concern (r = 0.242, p < 0.05), and depression (r = 0.227, p < 0.05) even after controlling for all potentially confounding variables. A multiple regression analysis indicated that the 6-min walk was a significant predictor of health-related quality of life, and participants in the lowest tertile of the 6-min walk test results had lower quality of life and greater depression than those in the highest tertile. CONCLUSION: Improving and maintaining physical fitness are important for quality of life and depression in stage II-III colorectal cancer survivors. PMID- 25688035 TI - Rutile TiO2 mesocrystals/reduced graphene oxide with high-rate and long-term performance for lithium-ion batteries. AB - An in situ hydrothermal route is developed for fabricating rutile TiO2 mesocrystals/reduced graphene oxide nanosheets (TGR) hybrids in the presence of dodecylbenzenesulphonic acid (ADBS). These rutile TiO2 mesocrystals with a Wulff shape are composed of ultra-tiny rod-like subunits with the same oriented direction and closely wrapped by the nanosheets of reduced graphene oxide (RGO). It is found that ADBS played a key role for the formation of mesocrystals during the self-assembly process, which pillared the graphene oxide (GO) nanosheets and involved the aggregation of the mesocrystal subunits. Furthermore, the TGR hybrids are used as an anode material and exhibited a large capacity over 150 mA h g(-1) at 20 C after 1000 cycles, and high rate capability up to 40 C. These high performance characteristics may be due to the intrinsic characteristics of rutile TiO2 mesocrystals constructed from ultra-tiny subunits and hybridized with super conductive RGO nanosheets. PMID- 25688036 TI - Chromatin compaction under mixed salt conditions: opposite effects of sodium and potassium ions on nucleosome array folding. AB - It is well known that chromatin structure is highly sensitive to the ionic environment. However, the combined effects of a physiologically relevant mixed ionic environment of K(+), Mg(2+) and Na(+), which are the main cations of the cell cytoplasm, has not been systematically investigated. We studied folding and self-association (aggregation) of recombinant 12-mer nucleosome arrays with 177 bp DNA repeat length in solutions of mixtures of K(+) and Mg(2+) or Na(+) and Mg(2+). In the presence of Mg(2+), the addition of sodium ions promotes folding of array into 30-nm fibres, whereas in mixtures of K(+) and Mg(2+), potassium ions abrogate folding. We found that self-association of nucleosome arrays in mixed salt solutions is synergistically promoted by Mg(2+) and monovalent ions, with sodium being slightly more efficient than potassium in amplifying the self association. The results highlight the importance of a mixed ionic environment for the compaction of chromatin under physiological conditions and demonstrate the complicated nature of the various factors that determine and regulate chromatin compaction in vivo. PMID- 25688037 TI - High-Performance Liquid Chromatographic Analysis of Sarcosine as a Fluorescent Levofloxacin Derivative. AB - Sarcosine, N-methyl glycine, could be used as a biomarker for the diagnosis of prostate cancer. It exists in biosamples at low levels; therefore, sensitive methods are necessary for its detection. In this study, we developed a sensitive and selective method for the analysis of sarcosine, based on derivatizing sarcosine with a fluorescent reagent levofloxacin acyl chloride. The resulting derivative is highly responsive to a fluorimetric detector (lambdaex = 290 nm, lambdaem = 460 nm). The sarcosine derivative can be separated from its molecular isomers (alpha-l-alanine, alpha-d-alanine and beta-alanine) on a hexyl-phenyl column by gradient elution using sodium acetate buffer (pH 3.8; 50 mM) and tetrahydrofuran as the mobile phase. The method showed a determination range of sarcosine in water over 44.5-1780.0 ng/mL (0.5-20.0 uM) and the limit of detection at 8.9 ng/mL (0.1 uM) (S/N = 3 with 20 uL injected). Intra- and inter day precision (as % relative standard deviation) and accuracy (as % relative error) were all below 4.8%. Application of the method to the analysis of sarcosine in human urine proved feasible. PMID- 25688038 TI - The effect of mirabegron on patient-related outcomes in patients with overactive bladder: the results of post hoc correlation and responder analyses using pooled data from three randomized Phase III trials. AB - PURPOSE: To understand how improvements in the symptoms of overactive bladder (OAB) seen with the beta3-adrenoceptor agonist mirabegron 50 mg, correlate with patient experience as measured by validated and standard patient-reported outcomes (PROs), and to identify whether there is overall directional consistency in the responsiveness of PROs to treatment effect. METHODS: In a post hoc analysis of pooled data from three randomized, double-blind, placebo-controlled, 12-week Phase III trials of mirabegron 50 mg once daily, responder rates for incontinence frequency (>=50 % reduction in incontinence episodes/24 h from baseline to final visit), micturition frequency (<=8 micturitions/24 h at final visit), and PROs [minimally important differences in patient perception of bladder condition (PPBC) and subsets of the overactive bladder questionnaire (OAB q) measuring total health-related quality of life (HRQoL), and symptom bother] were evaluated individually and in combination. RESULTS: Mirabegron 50 mg demonstrated greater improvement from baseline to final visit than placebo for each of the responder analyses, whether for individual objective and subjective outcomes or combinations thereof. These improvements versus placebo were statistically significant for all double and triple responder analyses and for all single responder analyses except PPBC. PRO measurements showed directional consistency and significant correlations, and there were also significant correlations between objective and subjective measures of efficacy. CONCLUSIONS: The improvements in objective measures seen with mirabegron 50 mg translate into a meaningful clinical benefit as evident by the directional consistency seen in HRQoL measures of benefit. PMID- 25688039 TI - Psychometric properties of the Chalder Fatigue Scale revisited: an exploratory structural equation modeling approach. AB - OBJECTIVE: Previous validation studies of the Chalder Fatigue Scale (CFS) suffer methodological shortcomings. The present study aimed to re-evaluate its psychometric properties using exploratory structural equation modeling (ESEM). METHODS: A Chinese sample of 1259 community-dwelling residents completed the 11 item Chinese CFS and a variety of health measures (anxiety, depression, exhaustion, sleep disturbance, and quality of life). In addition to traditional confirmatory factor analysis, ESEM was performed to assess the fit of two- and three-factor models using robust maximum likelihood estimation and oblique geomin rotation. Convergent validity of the CFS was examined via associations with five covariates (gender, age, exercise, perceived health, and life event) and the health measures in the ESEM model. RESULTS: The ESEM models displayed a superior fit to confirmatory factor models. The three-factor ESEM model showed a satisfactory model fit to the data but not for the two-factor model. The three factors were physical fatigue (three items, alpha = .800), low energy (four items, alpha = .821), and mental fatigue (four items, alpha = .861). The factors exhibited convergent validity with the model covariates and health measures. CONCLUSION: The results demonstrate the satisfactory reliability and convergent validity for the three-factor structure of the CFS as a valid measure of fatigue symptoms in the general population. Future psychometric studies could adopt the ESEM approach as a practical alternative to traditional confirmatory factor analysis. PMID- 25688040 TI - Differences in metabolic and inflammatory responses in lower and upper body high intensity intermittent exercise. AB - PURPOSE: The purpose of this study was to compare the effect of upper and lower body high-intensity intermittent exercise (HIIE) on immunometabolism profile. METHODS: Seven male judo athletes completed two experimental sessions separated by at least 48 h. The athletes completed four bouts of the upper and lower body Wingate tests separated by 3-min recovery periods. The blood samples were collected at rest and immediately after the fourth bout of lower and upper body Wingate tests. Serum was analysed for IL-1ra (Interleukin-1 Receptor Antagonist), interleukins (IL-1) IL-2, IL-4, IL-6, IL-10, TNF-alpha (tumor necrosis factor alpha), cortisol, glucose, and NEFA (non-ester fatty acid). Peak power (maximum power attained during the 30 s test), mean power were calculated. In addition, after 1 and 2.5-min of each Wingate bout, blood samples from the ear lobe were collected for lactate analysis. RESULTS: Our data demonstrated that lower body HIIE promoted a greater metabolic rate (values pre- vs. post-Wingate, for lactate: 1.02 +/- 0.16 vs. 14.44 +/- 1.08 mmol/L; for glucose: 112.5 +/- 16.7 vs. 147.9 +/- 23.5 mg/dL) and resulted in higher mechanical (mean power: 621 +/- 46 vs. 427 +/- 40 W, peak power: 794 +/- 61 vs. 602 +/- 109 W) performance compared to the upper body HIIE (lactate: 0.85 +/- 0.18 vs. 12.69 +/- 0.74 mmol/L; for glucose: 115.3 +/- 20.4 vs. 123.7 +/- 28.6 mg/dL; mean power: 480 +/- 46 vs. 341 +/- 45 W; and peak power: 672 +/- 83 vs. 501 +/- 120 W), but NEFA showed a similar response to both conditions, with increased IL-10 levels. CONCLUSIONS: In conclusion, our results demonstrated that despite the higher performance in lower body HIIE, the inflammatory response did not differ between exercise modalities. PMID- 25688041 TI - Hyperventilation-induced respiratory alkalosis falls short of countering fatigue during repeated maximal isokinetic contractions. AB - PURPOSE: Hyperventilation, implemented during recovery of repeated maximal sprints, has been shown to attenuate performance decrement. This study evaluated the effects of hyperventilation, using strength exercises, on muscle torque output and EMG amplitude. METHODS: Fifteen power-trained athletes underwent maximal isokinetic knee extensions consisting of 12 repetitions * 8 sets at 60 degrees /s and 25 repetitions * 8 sets at 300 degrees /s. The inter-set interval was 40 s for both speeds. For the control condition, subjects breathed spontaneously during the interval period. For the hyperventilation condition, subjects hyperventilated for 30 s before each exercise set (50 breaths/min, PETCO2: 20-25 mmHg). EMG was recorded from the vastus medialis and lateralis muscles to calculate the mean amplitude for each contraction. RESULTS: Hyperventilation increased blood pH by 0.065-0.081 and lowered PCO2 by 8.3-10.3 mmHg from the control values (P < 0.001). Peak torque declined with repetition and set numbers for both speeds (P < 0.001), but the declining patterns were similar between conditions. A significant, but small enhancement in peak torque was observed with hyperventilation at 60 degrees /s during the initial repetition phase of the first (P = 0.032) and fourth sets (P = 0.040). EMG amplitude also declined with set number (P < 0.001) for both speeds and muscles, which was, however, not attenuated by hyperventilation. CONCLUSION: Despite a minor ergogenic effect in peak torque at 60 degrees /s, hyperventilation was not effective in attenuating the decrement in torque output at 300 degrees /s and decrement in EMG amplitude at both speeds during repeated sets of maximal isokinetic knee extensions. PMID- 25688042 TI - Come dine with me: food-associated social signalling in wild bottlenose dolphins (Tursiops truncatus). AB - Food-related signalling is widespread in the animal kingdom with some food associated vocalizations considered functionally referential. Food calls can, however, vary greatly in the type of information they convey. Thus, there are a multitude of purposes for which food calls are used, including social recruitment, caller spacing, the indication of type, quantity, quality, divisibility of food, the caller's hunger level and even as tools to manipulate prey behaviour. Yet little work has focused on the social aspect of food calling in animals. We investigated the association of social signals in wild bottlenose dolphins with foraging behaviour where context-specific food-associated calls are commonly produced. Our data showed that specific social signals were significantly correlated with food call production and these calls rarely occurred in the absence of food calls. We suggest that animals are sharing additional information on the food patch itself with their social affiliates. PMID- 25688043 TI - Phosphoribulokinase from Chlamydomonas reinhardtii: a Benson-Calvin cycle enzyme enslaved to its cysteine residues. AB - Phosphoribulokinase (PRK) in the green alga Chlamydomonas reinhardtii is a finely regulated and well-studied enzyme of the Benson-Calvin cycle. PRK can form a complex with glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and the small chloroplast protein CP12. This study aimed to determine the molecular determinants on PRK involved in the complex and the mechanism of action of a recently described novel regulation of PRK that involves glutathionylation. A combination of mass spectrometry, mutagenesis and activity analyses showed that Cys16, besides its role as the binding site of ATP, was also the site for S glutathionylation. Previous kinetic analysis of the C55S mutant showed that in the oxidized inactive form of PRK, this residue formed a disulfide bridge with the Cys16 residue. This is the only bridge reported for PRK in the literature. Our data show for the first time that a disulfide bridge between Cys243 and Cys249 on PRK is required to form the PRK-GAPDH-CP12 complex. These results uncover a new mechanism for the PRK-GAPDH-CP12 formation involving a thiol disulfide exchange reaction with CP12 and identify Cys16 of PRK as a target of glutathionylation acting against oxidative stress. Although Cys16 is the key residue involved in binding ATP and acting as a defense against oxidative damage, the formation of the algal ternary complex requires the formation of another disulfide bridge on PRK involving Cys243 and Cys249. PMID- 25688044 TI - Radiosurgery for the treatment of dominant hemisphere periventricular heterotopia and intractable epilepsy in a series of three patients. AB - Periventricular heterotopia (PVH) is a neuronal migration disorder characterized by masses of gray matter located along the lateral ventricles that commonly cause epilepsy. The benefit of surgical resection of the PVH has been demonstrated in case reports to date; however, the location of the PVH in the paratrigonal region of the lateral ventricles can present significant surgical challenges. Noninvasive modalities of ablating this epileptogenic focus must therefore be considered. We present a small series of three patients who underwent stereotactic radiosurgery (SRS) for inoperable unilateral dominant hemisphere PVHs in order to illustrate the potential benefits and risks of this treatment modality. A total dose of 37.5-65 Gy resulted in seizure freedom for at least 14 months at the time of their last follow-up, even in patients harboring a second independent epileptic focus. Whether intracranial electrode recording truly offers added value is therefore uncertain. The two patients who received higher radiation doses suffered from symptomatic radiation necrosis and associated cerebral edema, requiring further medical intervention, and persistent monocular visual loss in one patient. While a longer interval prior to re-treatment may have been attempted, neither patient demonstrated radiographic findings typically associated with seizure remission. Refractory epilepsy due to PVH may be successfully treated with radiation therapy; but further work is needed to define the optimal dosing parameters in order to lower toxicity to normal tissue. PMID- 25688045 TI - Two foreign language automatisms in complex partial seizures. AB - Ictal speech manifestations with or without loss of consciousness can frequently occur in TLE in which sometimes the patient may remain responsive, even in conjunction with automatisms. Foreign language ictal speech automatism (FLISA) is a rare ictal sign in temporal lobe epilepsy arising from the non-dominant hemisphere. While our literature review revealed no report of CPSs with two foreign language ictal speech automatisms, we here represented a rare case of a Turkish woman with TLE experiencing two foreign language ictal speech automatisms. PMID- 25688046 TI - Myoclonic status epilepticus in six patients without epilepsy. AB - Myoclonic status epilepticus (MSE) is defined as prolonged period of myoclonic jerks that are correlated with epileptiform discharges on EEG. We here describe clinical features and video-EEG records of six adult patients with MSE who did not have a prior diagnosis of epilepsy. In four out of six patients, MSE was precipitated by drugs. Two out of four patients had chronic renal disease and received beta lactam group antibiotics. Two other patients, who described chronic pain, developed MSE while taking pregabalin. One patient who had dementia and family history of juvenile myoclonic epilepsy (JME) developed MSE one month after quetiapine was introduced. Another patient, who had a recent ischemic stroke, developed MSE due to an unknown reason. In these last two patients, an immediate triggering factor was not evident. Myoclonic status epilepticus ceased in five out of six patients after withdrawal of the drugs and/or intravenous antiepileptic treatment. Myoclonic status epilepticus is a rare event in patients without epilepsy. A correct diagnosis and prompt drug discontinuation may reverse this severe and life-threatening condition. PMID- 25688047 TI - Pathological laughter associated with paroxysmal kinesigenic dyskinesia: A rare presentation of acute disseminated encephalomyelitis. AB - A 13-year-old boy presented with recurrent episodes of sudden brief posturing of the right upper and lower limbs accompanied by transient inability to speak and a tendency to smile which would sometimes break into laughter. Awareness was retained during the attack, and there was no associated emotional abnormality. The events were precipitated by walking and occurred several times in a day. The laughter was pathological in nature, and the abnormal posturing was akin to 'paroxysmal kinesigenic dyskinesia' (PKD). 'Pathological laughter or crying' is defined as an involuntary, inappropriate, unmotivated laughter, crying or both, without any associated mood change. It can occur as a result of cerebral lesions like tumors, trauma, vascular insults, multiple sclerosis and/or degenerative disorders. It can also be a component of gelastic epilepsy which is characterized by stereotyped recurrences, presence of interictal and ictal epileptiform discharges and absence of external precipitants. In our patient, however, there was no ictal or interictal EEG correlate. Paroxysmal kinesigenic dyskinesia is characterized by intermittent, involuntary movements triggered by kinesigenic stimuli and is usually familial but can also be secondary to metabolic and structural brain disorders. Magnetic Resonance Imaging (MRI), in our case, revealed multiple T2 and FLAIR hyperintense, non-enhancing lesions in the periaqueductal gray matter, pontine and midbrain tegmentum, bilateral thalami and left lentiform nucleus suggesting a diagnosis of 'acute disseminated encephalomyelitis', in which this unique combination of pathological laughter and PKD has not been described so far. Magnetic Resonance Spectroscopy (MRS) confirmed a demyelinating pathology, and the patient responded well to steroids. PMID- 25688048 TI - Post-ictal, lateralized hyperkinetic motor behavior. AB - Recognition of a transient, focal neurologic dysfunction after a seizure is important when evaluating patients with idiopathic epilepsy. Todd's palsy, a transient focal weakness after a seizure, is a highly accurate clinical sign indicative of a contralateral, cerebral epileptic focus. In contrast, a transient, lateralized hyperkinetic motor behavior from a contralateral, hemispheric ictal focus has not been emphasized as a localizing clinical sign. The following case demonstrates that transient hyperkinetic behavior occurs as a post-ictal phenomenon and may have a localizing value, as in Todd's palsy. PMID- 25688049 TI - Low-dose lacosamide-induced atrial fibrillation: Case analysis with literature review. AB - Lacosamide (LCM) is a novel antiepileptic drug (AED) approved by the FDA for adjunctive treatment of partial epilepsy with and without secondary generalization. Lacosamide dose-dependent dysrhythmias (PR-interval prolongation, AV block, and atrial fibrillation/flutter) have been reported. This case represents the first instance of LCM-induced atrial fibrillation following a low loading dose (200 mg). Risk factors for atrial fibrillation are addressed and discussed in the context of this case. Full cardiac history is recommended prior to patients being initiated on LCM. Cardiac monitoring may be required for at risk patients on LCM. Clinicians need to be cognizant of this potential adverse effect. PMID- 25688050 TI - Ventricular tachycardia associated with lacosamide co-medication in drug resistant epilepsy. AB - We report a case of sustained ventricular tachycardia following the initiation of lacosamide as adjunctive epilepsy treatment. A 49-year-old male with intractable frontal lobe seizures experienced severe ventricular tachycardia following the addition of 400 mg lacosamide to his existing regimen of carbamazepine, lamotrigine, clonazepam, and valproate. The tachycardia occurred during a cardiac stress test; stress tests prior to initiation of lacosamide were normal. Conduction defects, including QRS prolongation, persisted during hospitalization until lacosamide was discontinued. The patient had no prior history of cardiac arrhythmia but did possess cardiac risk factors, including hypertension, hypercholesterolemia, and low heart rate variability. This case represents one part of a growing body of literature suggesting a link between arrhythmia and use of lacosamide, which enhances slow inactivation of sodium channels in both the brain and the heart. We believe further study may be necessary to assess the safety of lacosamide in epilepsy patients with cardiac risk factors. PMID- 25688051 TI - Surgical outcome in neocortical resections of type IIId focal cortical dysplasia with accompanying medial temporal pathology. AB - Focal cortical dysplasia (FCD) type IIId is a newly proposed type associated with early-life brain insults. Such patients are often considered unsuitable for resective epilepsy surgery, given the usually wide extent of the lesion and the poor correlation of MRI to the epileptogenic pathology. Two patients with intractable epilepsy, early-life ischemic/traumatic injury and MRI findings of extensive unilateral cystic-gliotic and ipsilateral medial temporal sclerotic malformative lesions were subjected to presurgical evaluation revealing well localized neocortical ictal onsets. They underwent tailored neocortical resections sparing medial temporal areas and achieved Engel class I postsurgical outcomes. Histopathology was consistent with type IIId focal cortical dysplasia. Successful outcomes with tailored resections may be achieved in cases with this subtype of focal cortical dysplasia, in the presence of converging and well localized semiological, EEG and functional imaging data, even on a background of complex and extensive MRI abnormalities. Medial temporal pathology, although often present in this setting, is not necessarily the site of ictal onsets, and its resection may not be always mandatory for a favorable outcome. PMID- 25688052 TI - Software for enhanced video capsule endoscopy: challenges for essential progress. AB - Video capsule endoscopy (VCE) has revolutionized the diagnostic work-up in the field of small bowel diseases. Furthermore, VCE has the potential to become the leading screening technique for the entire gastrointestinal tract. Computational methods that can be implemented in software can enhance the diagnostic yield of VCE both in terms of efficiency and diagnostic accuracy. Since the appearance of the first capsule endoscope in clinical practice in 2001, information technology (IT) research groups have proposed a variety of such methods, including algorithms for detecting haemorrhage and lesions, reducing the reviewing time, localizing the capsule or lesion, assessing intestinal motility, enhancing the video quality and managing the data. Even though research is prolific (as measured by publication activity), the progress made during the past 5 years can only be considered as marginal with respect to clinically significant outcomes. One thing is clear-parallel pathways of medical and IT scientists exist, each publishing in their own area, but where do these research pathways meet? Could the proposed IT plans have any clinical effect and do clinicians really understand the limitations of VCE software? In this Review, we present an in depth critical analysis that aims to inspire and align the agendas of the two scientific groups. PMID- 25688053 TI - IBS: Mast cells cause nerves to sprout in patients with IBS. PMID- 25688054 TI - Colorectal cancer. Combining drug therapies to improve treatment efficacy in metastatic colorectal cancer. PMID- 25688055 TI - Gut microbiota. Microbiota organization--a key to understanding CRC development. AB - The gut microbiota has an important role in colorectal cancer (CRC). Dejea and colleagues have demonstrated that particular bacterial biofilms are associated with proximal CRC, correlating with changes in tissue biology associated with oncogenesis. These findings provide a fresh perspective on the microbiota in cancer: microbial organization might provide critical insight into understanding CRC development. PMID- 25688056 TI - Hepatitis: HBV vaccine--the first vaccine to prevent cancer. PMID- 25688057 TI - Surgical outcomes of inflammatory glaucoma: a comparison of trabeculectomy and glaucoma-drainage-device implantation. AB - PURPOSE: Our aim was to compare surgical outcomes of trabeculectomy and nonvalved glaucoma-drainage-device (GDD) implantation in eyes with chronic inflammatory glaucoma and uncontrolled intraocular pressure (IOP). METHODS: A retrospective chart review was conducted on patients with glaucomatous optic neuropathy, chronic anterior or posterior segment inflammation, and >=6 months postoperative follow-up. All eyes underwent trabeculectomy with either antifibrotic therapy or implantation of a Baerveldt GDD (Abbott Laboratories Inc., Abbott Park, IL, USA). Failure was defined as IOP >21 mmHg, <20 % reduction below baseline or IOP <5 mmHg on two consecutive follow-up visits after 3 months, reoperation for glaucoma, or loss of light-perception vision. Statistical methods consisted of Student's t tests, chi(2) test, and Kaplan-Meier time to failure analysis. RESULTS: Nineteen trabeculectomies of 42 patients were followed for a mean of 31 +/- 23 and 23 GDD eyes for a mean of 39 +/- 19 months (P = 0.22). At last follow up, mean IOP (11.83 +/- 4.59 and 13.15 +/- 6.11 mmHg, P = 0.45) and number of glaucoma medications (1.28 +/- 1.56 and 1.26 +/- 1.25, P = 0.97) were similar between the trabeculectomy and GDD groups. The frequency and types of postoperative complications in both groups were similar. The cumulative probability of failure after 5 years of follow-up was significantly greater in trabeculectomy eyes (62 %) compared with GDD eyes (25 %) (P = 0.006). CONCLUSIONS: Nonvalved tube-shunt surgery was more likely to maintain IOP control and avoid reoperation than trabeculectomy with antifibrotic therapy in eyes with chronic inflammatory glaucoma. PMID- 25688058 TI - Radiofrequency ablation is a valid treatment option for lung metastases: experience in 566 patients with 1037 metastases. AB - BACKGROUND: Minimal invasive methods are needed as an alternative to surgery for treatment of lung metastases. PATIENTS AND METHODS: The prospective database of two cancer centers including all consecutive patients treated with radiofrequency ablation (RFA) for lung metastasis over 8 years was reviewed. RFA was carried out under general anesthesia, with computed tomography guidance using a 15-gauge multitined expandable electrodes RF needle. RESULTS: Five hundred sixty-six patients including 290 men (51%), 62.7 +/- 13.2 years old with primary tumor to the colon (34%), rectum (18%), kidney (12%), soft tissue (9%) and miscellaneous (27%) received 642 RFA for 1037 lung metastases. Fifty-three percent of patients had 1 metastasis, 25% had 2, 14% had 3, 5% had 4 and 4% had 5-8. Metastases were unilateral (75%), or bilateral (25%). The median diameter [extremes] of metastases was 15 mm (4-70). Twenty-two percent of patients had extrapulmonary disease amenable to local therapy including 49 liver, 16 bone and 60 miscellaneous metastases. Median follow-up was 35.5 months. Median overall survival (OS) was 62 months. Four-year local efficacy was 89%. Four-year lung disease control rate was 44.1%, with patient retreated safely up to four times. Primary origin, disease-free interval, size and number of metastases were associated with OS in multivariate analysis. Progression at RFA site was associated with poor OS [P = 0.011, hazard ratio (HR): 1.69 (95% confidence interval 1.13-2.54)]. In the 293 colorectal cancer metastases, size >2 cm (HR = 2.10, P = 0.0027) and a number of metastases >=3 (HR = 1.86, P = 0.011) remained significantly associated with OS. A prognostic score made of three groups based on the four above-mentioned prognostic factors demonstrated 3-year OS rates of respectively 82.2%, 69.5% and 53.6% (log-rank test, P <= 0.0001) among the three groups in the overall population, and of 81.3%, 72.8% and 57.9% (log-rank test, P = 0.005) in the colorectal cancer patients. CONCLUSION: Radiofrequency is an option for treatment of small size lung metastases, namely the ones below 2-3 cm. PMID- 25688059 TI - Randomized phase II-III study of bevacizumab in combination with chemotherapy in previously untreated extensive small-cell lung cancer: results from the IFCT-0802 trial?. AB - BACKGROUND: This randomized phase II-III trial sought to evaluate the efficacy and safety of adding bevacizumab (Bev) following induction chemotherapy (CT) in extensive small-cell lung cancer (SCLC). PATIENTS AND METHODS: Enrolled SCLC patients received two induction cycles of CT. Responders were randomly assigned 1:1 to receive four additional cycles of CT alone or CT plus Bev (7.5 mg/kg), followed by single-agent Bev until progression or unacceptable toxicity. The primary end point was the percentage of patients for whom disease remained controlled (still in response) at the fourth cycle. RESULTS: In total, 147 patients were enrolled. Partial response was observed in 103 patients, 74 of whom were eligible for Bev and randomly assigned to the CT alone group (n = 37) or the CT plus Bev group (n = 37). Response assessment at the end of the fourth cycle showed that disease control did not differ between the two groups (89.2% versus 91.9% of patients remaining responders in CT alone versus CT plus Bev, respectively; Fisher's exact test: P = 1.00). Progression-free survival (PFS) since randomization did not significantly differ, with a median PFS of 5.5 months [95% confidence interval (CI) 4.9% to 6.0%] versus 5.3 months (95% CI 4.8% to 5.8%) in the CT alone and CT plus Bev groups, respectively [hazard ratio (HR) for CT alone: 1.1; 95% CI 0.7% to 1.7%; unadjusted P = 0.82]. Grade >=2 hypertension and grade >=3 thrombotic events were observed in 40% and 11% of patients, respectively, in the CT plus Bev group. Serum vascular endothelial growth factor (VEGF) and soluble VEGF receptor titrations failed to identify predictive biomarkers. CONCLUSION: Administering 7.5 mg/kg Bev after induction did not improve outcome in extensive SCLC patients. PMID- 25688061 TI - Sensitivity and fading of pMOS dosemeters irradiated with X-ray radiation doses from 1 to 100 cGy. AB - In this paper, the results of pMOS dosemeters sensitivity to X-ray radiation and 28-d fading at room temperature are presented. Two types of dosemeters were used, which differ in gate oxide layer thickness. The sensitivity of pMOS dosemeters with gate oxide layer thickness of 1 um was followed in the dose intervals of 1 to 10 cGy and 10 to 100 cGy, whereas that of 400 nm was in the interval of 10 to 100 cGy. The sensitivity was characterised by the threshold voltage shift, which was determined as a function of absorbed radiation dose and time after irradiation. Linear dependence between threshold voltage shift and absorbed radiation dose was established, as well as that considerable fading occurs during the first few days after irradiation. The mechanisms responsible for threshold voltage shift during irradiation and latter annealing have been also discussed. PMID- 25688060 TI - mTOR: a potential therapeutic target in osteoarthritis? AB - Osteoarthritis (OA) is a chronic degenerative joint disease characterized by the progressive loss of articular cartilage, remodeling of the subchondral bone, and synovial inflammation. Mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase that controls critical cellular processes such as growth, proliferation, and protein synthesis. Recent studies suggest that mTOR plays a vital role in cartilage growth and development and in altering the articular cartilage homeostasis as well as contributing to the process of cartilage degeneration associated with OA. Both pharmacological inhibition and genetic deletion of mTOR have been shown to reduce the severity of OA in preclinical mouse models. In this review article, we discuss the roles of mTOR in cartilage development, in maintaining articular cartilage homeostasis, and its potential as an OA therapeutic target. PMID- 25688062 TI - Patient radiation doses in various fluoroscopically guided orthopaedic procedures. AB - All orthopaedic fluoroscopic procedures performed using C-arm guidance were monitored for 1 y. The type of procedure, fluoroscopy time (T), kerma-area product (KAP) values and number of radiographs (F) were recorded. The two most often performed techniques were as follows: intramedullary nailing (IMN) of intertrochanteric/peritrochanteric (IP) fractures (101 cases, 49.3 %) and antergrade IMN of femur or tibia shaft (TS) fractures (28 cases, 13.7 %). For the remaining procedures, none accounted for >5 %, categorised as 'various' (76 cases, 37 %). Large variations in T, KAP and F were observed. For IMN of IP fractures, antergrade IMN of femur and TS fractures and for various procedures, respectively, median values were T--2.1, 2.2 and 0.6 min, KAP--6.3, 6.3 and 0.6 Gy cm(-2) and F--21, 2.2 and 6.7. The patient doses during fluoroscopically guided procedures are relatively low compared with other interventional procedures. PMID- 25688063 TI - The draft genome sequence of Xanthomonas species strain Nyagatare, isolated from diseased bean in Rwanda. AB - We announce the genome sequence for Xanthomonas species strain Nyagatare, isolated from beans showing unusual disease symptoms in Rwanda. This strain represents the first sequenced genome belonging to an as-yet undescribed Xanthomonas species known as species-level clade 1. It has at least 100 kb of genomic sequence that shows little or no sequence similarity to other xanthomonads, including a unique lipopolysaccharide synthesis gene cluster. At least one genomic region appears to have been acquired from relatives of Agrobacterium or Rhizobium species. The genome encodes homologues of only three known type-three secretion system effectors: AvrBs2, XopF1 and AvrXv4. Availability of the genome sequence will facilitate development of molecular tools for detection and diagnostics for this newly discovered pathogen of beans and facilitate epidemiological investigations of a potential causal link between this pathogen and the disease outbreak. PMID- 25688064 TI - A GntR-type transcriptional repressor controls sialic acid utilization in Bifidobacterium breve UCC2003. AB - Bifidobacterium breve strains are numerically prevalent among the gut microbiota of healthy, breast-fed infants. The metabolism of sialic acid, a ubiquitous monosaccharide in the infant and adult gut, by B. breve UCC2003 is dependent on a large gene cluster, designated the nan/nag cluster. This study describes the transcriptional regulation of the nan/nag cluster and thus sialic acid metabolism in B. breve UCC2003. Insertion mutagenesis and transcriptome analysis revealed that the nan/nag cluster is regulated by a GntR family transcriptional repressor, designated NanR. Crude cell extract of Escherichia coli EC101 in which the nanR gene had been cloned and overexpressed was shown to bind to two promoter regions within this cluster, each of which containing an imperfect inverted repeat that is believed to act as the NanR operator sequence. Formation of the DNA-NanR complex is prevented in the presence of sialic acid, which we had previously shown to induce transcription of this gene cluster. PMID- 25688065 TI - Examination of the cell sensitizing gene orf43 of ICE R391 suggests a role in ICE transfer enhancement to recipient cells. AB - SXT/R391 family of ICEs have been found to express an unusual function that enhances bacterial cell death post-UV irradiation. Previous analysis of ICE R391 found four core SXT/R391 ICE genes to be involved-orf96, orf90, orf91 and orf43. These genes functioned as part of a UV-inducible pathway, where upon exposure to UV, the levels of the Orf43 protein, a TraV homolog which we propose naming TraV(R391), were upregulated, resulting in increased cell sensitization. Here, we examined the effect of orf43 overexpression and found it led to host cell permeabilization. The inducing agent for orf43, UV irradiation, is also known to increase the ICE R391 extrachromosomal form and apparent conjugative transfer rate. We demonstrated, via conjugative transfer deficient mutants, that orf43 overexpression alone restored a small level of ICE R391 transfer to recipient cells via an unknown mechanism other than conjugation. TraV homologs have been reported to function in conjugative transfer. However, TraV(R391) is the first homolog to cause UV-associated cell sensitization. TraV(R391) when overexpressed must contain a unique adaptation or function which results in cell lysis and decreased survival. A hypothesis for retaining such a detrimental effect may be in its role of enhancing ICE survival upon cell damage. PMID- 25688066 TI - Small transcriptome analysis indicates that the enzyme RppH influences both the quality and quantity of sRNAs in Neisseria gonorrhoeae. AB - Prokaryotic mRNA turnover can be initiated by the removal of pyrophosphate from the 5' end of a transcript using the RNA pyrophosphohydrolase enzyme RppH. Following the initial dephosphorylation step, RNaseE then degrades the message into small oligonucleotide segments. This study assessed the small RNA transcriptome of Neisseria gonorrhoeae strain MS11 in two genetic backgrounds; using wild type cells as well as cells carrying a rppH insertional mutation. It was found that the presence of the RppH enzyme affected both the quantity and length of small RNAs (sRNAs) in various chromosomal locations and involved sense transcripts (seRNAs), transcripts originating from the opposite strand (asRNAs) as well as inter-genic-derived RNAs (IGRs). In comparing the two transcriptomes, we found that not all small RNAs were expressed in both genetic backgrounds, suggesting that RppH apparently targets only a subset of transcripts. Overall, this study shows that small RNAs can be detected from the majority of genes within the chromosome, as well as from inter-genic regions, and that more sRNA transcripts are detected in the absence of the RppH enzyme. PMID- 25688067 TI - Growth and survival of the fish pathogenic bacterium, Flavobacterium columnare, in tilapia mucus and porcine gastric mucin. AB - Flavobacterium columnare, an economically important Gram-negative bacterium of freshwater farmed fish, colonizes the skin and gills in the initial steps of pathogenesis. The surface of fish is coated with mucus made up of high molecular weight glycoproteins. Limited studies have described the ability of bacterial pathogens to grow in fish mucus. Our objective was to determine if F. columnare isolates could grow and survive in formulated water (FW) containing autoclaved tilapia mucus or porcine gastric mucin. We demonstrated the ability of F. columnare genomovars I, II, II-B and III to replicate (2-3 logs) and survive (21 to >100 days) in FW containing tilapia mucus. In a second experiment, genomovar I and II isolates were found to replicate in FW containing tilapia mucus or porcine mucin but not in FW only. From a practical standpoint, fish handling and/or hauling results in stress that leads to mucus sloughing often with subsequent F. columnare infection. Flavobacterium columnare utilizes fish mucus as a nutrient source, and studies are underway to determine if growth in mucus or mucin results in differential protein expression and/or increased virulence of F. columnare towards fish. PMID- 25688068 TI - Presence of calcium-binding motifs in PilY1 homologs correlates with Ca-mediated twitching motility and evolutionary history across diverse bacteria. AB - Twitching motility, involving type IV pili, is essential for host colonization and virulence of many pathogenic bacteria. Studies of PilY1, a tip-associated type IV pili protein, indicate that PilY1 functions as a switch between pilus extension and retraction, resulting in twitching motility. Recent work detected a calcium-binding motif in PilY1 of some animal bacterial pathogens and demonstrated that binding of calcium to PilY1 with this motif regulates twitching. Though studies of PilY1 in non-animal pathogens are limited, our group demonstrated that twitching motility in the plant pathogen Xylella fastidiosa, which contains three PilY1 homologs, is increased by calcium supplementation. A study was conducted to investigate the phylogenetic relationship between multiple PilY1 homologs, the presence of calcium-binding motifs therein, and calcium mediated twitching motility across diverse bacteria. Strains analyzed contained one to three PilY1 homologs, but phylogenetic analyses indicated that PilY1 homologs containing the calcium-binding motif Dx[DN]xDGxxD are phylogenetically divergent from other PilY1 homologs. Plant-associated bacteria included in these analyses were then examined for a calcium-mediated twitching response. Results indicate that bacteria must have at least one PilY1 homolog containing the Dx[DN]xDGxxD motif to display a calcium-mediated increase in twitching motility, which likely reflects an adaption to environmental calcium concentrations. PMID- 25688069 TI - Specific genetic features of Campylobacter jejuni strain G1 revealed by genome sequencing. AB - This report describes a draft genome sequence of Campylobacter jejuni strain G1. The strain contains no plasmids, despite being resistant to tetracycline (Tet). Comparison of the genome of this strain with that of a reference strain NCTC 11168 (Tet sensitive) revealed the presence of a candidate gene that may be responsible for antibiotic resistance, as well as the genes involved in the synthesis of ganglioside-mimicking molecules responsible for the development of a neurodegenerative disorder, Guillain-Barre syndrome. PMID- 25688070 TI - Emergency Department Management of Pediatric Unprovoked Seizures and Status Epilepticus in the State of Illinois. AB - The purpose of this survey and record review was to characterize emergency department management of unprovoked seizures and status epilepticus in children in Illinois. The survey was sent to 119 participating emergency departments in the Emergency Medical Services for Children program; responses were received from 103 (88% response rate). Only 44% of the emergency departments had a documented protocol for seizure management. Only 12% of emergency departments had child neurology consultation available at all times. Record review showed that 58% of patients were discharged home, 26% were transferred to another institution, and 10% were admitted to a non-intensive care unit setting. Ninety percent of patients were treated with anticonvulsants. Seizure education was provided by the primary emergency department nurse (97%) and the treating physician (79%). This project demonstrated strengths and weaknesses in the current management of pediatric seizure patients in Illinois emergency departments. PMID- 25688071 TI - Challenges in Determining the Role of Rest and Exercise in the Management of Mild Traumatic Brain Injury. AB - Current consensus guidelines recommending physical and cognitive rest until a patient is asymptomatic after a sports concussion (ie, a mild traumatic brain injury) are being called into question, particularly for patients who are slower to recover and in light of preclinical and clinical research demonstrating that exercise aids neurorehabilitation. The pathophysiological response to mild traumatic brain injury includes a complex neurometabolic cascade of events resulting in a neurologic energy deficit. It has been proposed that this energy deficit leads to a period of vulnerability during which the brain is at risk for additional injury, explains why early postconcussive symptoms are exacerbated by cognitive and physical exertion, and is used to rationalize absolute rest until all symptoms have resolved. However, at some point, rest might no longer be beneficial and exercise might need to be introduced. At both extremes, excessive exertion and prolonged avoidance of exercise (physical and mental) have negative consequences. Individuals who have experienced a concussion need guidance for avoidance of triggers of severe symptoms and a plan for graduated exercise to promote recovery as well as optimal functioning (physical, educational, and social) during the postconcussion period. PMID- 25688072 TI - Fears in the General Population: More Frequent in Females and Associated With the Serotonin Transporter Promoter Polymorphism and Perceived Relationship With Mothers. AB - This study aimed to examine the structure of fears of youth, and its associations with gender, genetic variation of the serotonin transporter (5-HTTLPR), and perceived maternal acceptance/rejection and control, in a population representative sample. Participants were 453 adolescents and 540 young adults. Fears were assessed by a 18-item Fear Questionnaire, and perceived maternal relationships by the Mother Acceptance-Rejection/Control Questionnaire. A structured psychiatric interview was used to assess current and lifetime psychiatric disorders in participants from the older cohort. A principal component analyses indicated 2 components, named Fear/Phobia and Panic/Despair. Females expressed higher level of fears and symptoms of despair regardless of the serotonin transporter genotype. The 5-HTTLPR genotype nevertheless played a role in the association between fears and perceived relationships: in S/S-genotype, more Fear/Phobia was reported by the participants who perceived greater maternal acceptance in combination with strict maternal control, and had a history of psychiatric disorder. PMID- 25688074 TI - Premature senescence of T-cell subsets in axial spondyloarthritis. AB - OBJECTIVE: To investigate the possible occurrence of early thymic failure and premature senescence of naive and memory T-cells in patients with axial spondyloarthritis (aSpA). METHODS: Prospective, cross-sectional study of consecutive patients with aSpA (n=51), rheumatoid arthritis (RA, n=51) and healthy controls (HCs, n=50). Demographic, clinical and laboratory parameters were collected in all patients and we isolated naive (CD45RA(+)) and memory (CD45RO(+)) CD4(+) and CD8(+) T-cell subsets by MACS technology. T-cell receptor rearrangement excision circle (TREC) and telomere length were measured by real time PCR. We used TRECs as a surrogate for thymus function and telomere length as an indicator of cellular senescence. Telomerase activity was analysed with the Telomeric Repeat Amplification Protocols. RESULTS: We observed a premature decline of thymic output in patients with aSpA and patients with RA compared with HCs as indicated by a reduction of TREC levels in naive T-cells (aSpA: age adjusted regression coefficient (regcoeff) for CD4(+)CD45RA(+) T-cells -2.566, p=0.023; RA regcoeff=-2.844, p=0.008). Telomere length of all CD4(+) and CD8(+) T cell subsets was reduced in young patients with aSpA compared with HCs, whereas data for patients with RA were comparable with HCs. Telomerase activity was inversely correlated with telomere length in HCs (correlation coefficient (corcoeff)=-0.532, p<0.001) but not in patients with aSpA (corcoeff=-0.056, p=0.697) and RA (corcoeff=-0.003, p=0.982). CONCLUSIONS: Our data indicate an age inappropriate shrinkage of thymic output, an inappropriate shortening of telomeres in young patients with aSpA and an impaired telomerase enzyme in patients with aSpA and RA. PMID- 25688073 TI - Digital ulcers predict a worse disease course in patients with systemic sclerosis. AB - OBJECTIVE: Systemic sclerosis (SSc) is a systemic autoimmune disease with high morbidity and significant mortality. There is a great need of predictors that would allow risk stratification of patients with SSc and ultimately initiation of treatment early enough to ensure optimal clinical results. In this study, we evaluated whether a history of digital ulcers (HDU) at presentation may be a predictor of vascular outcomes and of overall clinical worsening and death in patients with SSc. METHODS: Patients from the EULAR Scleroderma Trials and Research (EUSTAR) database, satisfying at inclusion the 1980 American College of Rheumatology classification criteria for SSc, who had a follow-up of at least 3 years since baseline or who have died, were included in the analysis. HDU at presentation as a predictor of disease worsening or death was evaluated by Cox proportional hazards regression analysis. RESULTS: 3196 patients matched the inclusion criteria (male sex 13.2%, 33.4% diffuse subset). At presentation, 1092/3196 patients had an HDU (34.1%). In multivariable analysis adjusting for age, gender and all parameters considered potentially significant, HDU was predictive for the presence of active digital ulcers (DUs) at prospective visits (HR (95% CI)): 2.41 (1.91 to 3.03), p<0.001, for an elevated systolic pulmonary arterial pressure on heart ultrasound (US-PAPs):1.36 (1.03 to 1.80), p=0.032, for any cardiovascular event (new DUs, elevated US-PAPs or LV failure): 3.56 (2.26 to 5.62), p<0.001, and for death (1.53 (1.16 to 2.02), p=0.003). CONCLUSIONS: In patients with SSc, HDU at presentation predicts the occurrence of DUs at follow up and is associated with cardiovascular worsening and decreased survival. PMID- 25688075 TI - Erratum. PMID- 25688076 TI - Comparing language outcomes in monolingual and bilingual stroke patients. AB - Post-stroke prognoses are usually inductive, generalizing trends learned from one group of patients, whose outcomes are known, to make predictions for new patients. Research into the recovery of language function is almost exclusively focused on monolingual stroke patients, but bilingualism is the norm in many parts of the world. If bilingual language recruits qualitatively different networks in the brain, prognostic models developed for monolinguals might not generalize well to bilingual stroke patients. Here, we sought to establish how applicable post-stroke prognostic models, trained with monolingual patient data, are to bilingual stroke patients who had been ordinarily resident in the UK for many years. We used an algorithm to extract binary lesion images for each stroke patient, and assessed their language with a standard tool. We used feature selection and cross-validation to find 'good' prognostic models for each of 22 different language skills, using monolingual data only (174 patients; 112 males and 62 females; age at stroke: mean = 53.0 years, standard deviation = 12.2 years, range = 17.2-80.1 years; time post-stroke: mean = 55.6 months, standard deviation = 62.6 months, range = 3.1-431.9 months), then made predictions for both monolinguals and bilinguals (33 patients; 18 males and 15 females; age at stroke: mean = 49.0 years, standard deviation = 13.2 years, range = 23.1-77.0 years; time post-stroke: mean = 49.2 months, standard deviation = 55.8 months, range = 3.9-219.9 months) separately, after training with monolingual data only. We measured group differences by comparing prediction error distributions, and used a Bayesian test to search for group differences in terms of lesion-deficit associations in the brain. Our models distinguish better outcomes from worse outcomes equally well within each group, but tended to be over-optimistic when predicting bilingual language outcomes: our bilingual patients tended to have poorer language skills than expected, based on trends learned from monolingual data alone, and this was significant (P < 0.05, corrected for multiple comparisons) in 13/22 language tasks. Both patient groups appeared to be sensitive to damage in the same sets of regions, though the bilinguals were more sensitive than the monolinguals. media-1vid1 10.1093/brain/awv020_video_abstract awv020_video_abstract. PMID- 25688077 TI - Cerebrospinal fluid leakage and headache after lumbar puncture: a prospective non invasive imaging study. AB - The spatial distribution and clinical correlation of cerebrospinal fluid leakage after lumbar puncture have not been determined. Adult in-patients receiving diagnostic lumbar punctures were recruited prospectively. Whole-spine heavily T2 weighted magnetic resonance myelography was carried out to characterize post lumbar puncture spinal cerebrospinal fluid leakages. Maximum rostral migration was defined as the distance between the most rostral spinal segment with cerebrospinal fluid leakage and the level of lumbar puncture. Eighty patients (51 female/29 male, mean age 49.4 +/- 13.3 years) completed the study, including 23 (28.8%) with post-dural puncture headache. Overall, 63.6% of periradicular leaks and 46.9% of epidural collections were within three vertebral segments of the level of lumbar puncture (T12-S1). Post-dural puncture headache was associated with more extensive and more rostral distributions of periradicular leaks (length 3.0 +/- 2.5 versus 0.9 +/- 1.9 segments, P = 0.001; maximum rostral migration 4.3 +/- 4.7 versus 0.8 +/- 1.7 segments, P = 0.002) and epidural collections (length 5.3 +/- 6.1 versus 1.0 +/- 2.1 segments, P = 0.003; maximum rostral migration 4.7 +/- 6.7 versus 0.9 +/- 2.4 segments, P = 0.015). In conclusion, post-dural puncture headache was associated with more extensive and more rostral distributions of periradicular leaks and epidural collections. Further, visualization of periradicular leaks was not restricted to the level of dural defect, although two-thirds remained within the neighbouring segments. PMID- 25688078 TI - Chitinase 3-like 1: prognostic biomarker in clinically isolated syndromes. AB - Chitinase 3-like 1 (CHI3L1) has been proposed as a biomarker associated with the conversion to clinically definite multiple sclerosis in patients with clinically isolated syndromes, based on the finding of increased cerebrospinal fluid CHI3L1 levels in clinically isolated syndrome patients who later converted to multiple sclerosis compared to those who remained as clinically isolated syndrome. Here, we aimed to validate CHI3L1 as a prognostic biomarker in a large cohort of patients with clinically isolated syndrome. This is a longitudinal cohort study of clinically isolated syndrome patients with clinical, magnetic resonance imaging, and cerebrospinal fluid data prospectively acquired. A total of 813 cerebrospinal fluid samples from patients with clinically isolated syndrome were recruited from 15 European multiple sclerosis centres. Cerebrospinal fluid CHI3L1 levels were measured by enzyme-linked immunosorbent assay. Multivariable Cox regression models were used to investigate the association between cerebrospinal fluid CHI3L1 levels and time to conversion to multiple sclerosis and time to reach Expanded Disability Status Scale 3.0. CHI3L1 levels were higher in patients who converted to clinically definite multiple sclerosis compared to patients who continued as clinically isolated syndrome (P = 8.1 * 10(-11)). In the Cox regression analysis, CHI3L1 levels were a risk factor for conversion to multiple sclerosis (hazard ratio = 1.7; P = 1.1 * 10(-5) using Poser criteria; hazard ratio = 1.6; P = 3.7 * 10(-6) for McDonald criteria) independent of other covariates such as brain magnetic resonance imaging abnormalities and presence of cerebrospinal fluid oligoclonal bands, and were the only significant independent risk factor associated with the development of disability (hazard ratio = 3.8; P = 2.5 * 10(-8)). High CHI3L1 levels were associated with shorter time to multiple sclerosis (P = 3.2 * 10(-9) using Poser criteria; P = 5.6 * 10(-11) for McDonald criteria) and more rapid development of disability (P = 1.8 * 10(-10)). These findings validate cerebrospinal fluid CHI3L1 as a biomarker associated with the conversion to multiple sclerosis and development of disability and reinforce the prognostic role of CHI3L1 in patients with clinically isolated syndrome. We propose that determining cerebrospinal fluid chitinase 3-like 1 levels at the time of a clinically isolated syndrome event will help identify those patients with worse disease prognosis. PMID- 25688079 TI - Venular degeneration leads to vascular dysfunction in a transgenic model of Alzheimer's disease. AB - Most patients with Alzheimer's disease exhibit accumulation of amyloid-beta peptide on leptomeningeal and cortical arterioles, or cerebral amyloid angiopathy, which is associated with impaired vascular reactivity and accelerated cognitive decline. Despite widespread recognition of the significance of vascular dysfunction in Alzheimer's disease aetiology and progression, much uncertainty still surrounds the mechanism underlying Alzheimer's disease vascular injury. Studies to date have focused on amyloid-beta-induced damage to capillaries and plaque-associated arterioles, without examining effects across the entire vascular bed. In the present study, we investigated the structural and functional impairment of the feeding arteriolar versus draining venular vessels in a transgenic murine Alzheimer's disease model, with a particular focus on the mural cell populations that dictate these vessels' contractility. Although amyloid-beta deposition was restricted to arterioles, we found that vascular impairment extended to the venules, which showed significant depletion of their mural cell coverage by the mid-stage of Alzheimer's disease pathophysiology. These structural abnormalities were accompanied by an abolishment of the normal vascular network flow response to hypercapnia: this functional impairment was so severe as to result in hypercapnia-induced flow decreases in the arterioles. Further pharmacological depletion of mural cells using SU6668, a platelet-derived growth factor receptor-beta antagonist, resulted in profound structural abnormalities of the cortical microvasculature, including vessel coiling and short-range looping, increased tortuosity of the venules but not of the arterioles, increased amyloid-beta deposition on the arterioles, and further alterations of the microvascular network cerebral blood flow response to hypercapnia. Together, this work shows hitherto unrecognized structural alterations in penetrating venules, demonstrates their functional significance and sheds light on the complexity of the relationship between vascular network structure and function in Alzheimer's disease. PMID- 25688080 TI - Post-mortem assessment of hypoperfusion of cerebral cortex in Alzheimer's disease and vascular dementia. AB - Perfusion is reduced in the cerebral neocortex in Alzheimer's disease. We have explored some of the mechanisms, by measurement of perfusion-sensitive and disease-related proteins in post-mortem tissue from Alzheimer's disease, vascular dementia and age-matched control brains. To distinguish physiological from pathological reduction in perfusion (i.e. reduction exceeding the decline in metabolic demand), we measured the concentration of vascular endothelial growth factor (VEGF), a protein induced under conditions of tissue hypoxia through the actions of hypoxia-inducible factors, and the myelin associated glycoprotein to proteolipid protein 1 (MAG:PLP1) ratio, which declines in chronically hypoperfused brain tissue. To evaluate possible mechanisms of hypoperfusion, we also measured the levels of amyloid-beta40, amyloid-beta42, von Willebrand factor (VWF; a measure of microvascular density) and the potent vasoconstrictor endothelin 1 (EDN1); we assayed the activity of angiotensin I converting enzyme (ACE), which catalyses the production of another potent vasoconstrictor, angiotensin II; and we scored the severity of arteriolosclerotic small vessel disease and cerebral amyloid angiopathy, and determined the Braak tangle stage. VEGF was markedly increased in frontal and parahippocampal cortex in Alzheimer's disease but only slightly and not significantly in vascular dementia. In frontal cortex the MAG:PLP1 ratio was significantly reduced in Alzheimer's disease and even more so in vascular dementia. VEGF but not MAG:PLP1 increased with Alzheimer's disease severity, as measured by Braak tangle stage, and correlated with amyloid-beta42 and amyloid-beta42: amyloid-beta40 but not amyloid-beta40. Although MAG:PLP1 tended to be lowest in cortex from patients with severe small vessel disease or cerebral amyloid angiopathy, neither VEGF nor MAG:PLP1 correlated significantly with the severity of structural vascular pathology (small vessel disease, cerebral amyloid angiopathy or VWF). However, MAG:PLP1 showed a significant negative correlation with the level of EDN1, which we previously showed to be elevated in the cerebral cortex Alzheimer's disease. These finding are in contrast with the previously demonstrated reduction in EDN1, and positive correlation with MAG:PLP1, in the hypoperfused white matter in Alzheimer's disease. The decline in MAG:PLP1 strongly suggests pathological hypoperfusion of the frontal cortex in Alzheimer's disease. Although severe small vessel disease or cerebral amyloid angiopathy may contribute in some cases, abnormal vascular contractility mediated by EDN1 is likely to be a more important overall contributor. Both amyloid-beta accumulation and hypoperfusion are likely to cause the upregulation of VEGF. PMID- 25688081 TI - Rapidly progressive Alzheimer's disease features distinct structures of amyloid beta. AB - Genetic and environmental factors that increase the risk of late-onset Alzheimer disease are now well recognized but the cause of variable progression rates and phenotypes of sporadic Alzheimer's disease is largely unknown. We aimed to investigate the relationship between diverse structural assemblies of amyloid beta and rates of clinical decline in Alzheimer's disease. Using novel biophysical methods, we analysed levels, particle size, and conformational characteristics of amyloid-beta in the posterior cingulate cortex, hippocampus and cerebellum of 48 cases of Alzheimer's disease with distinctly different disease durations, and correlated the data with APOE gene polymorphism. In both hippocampus and posterior cingulate cortex we identified an extensive array of distinct amyloid-beta42 particles that differ in size, display of N-terminal and C-terminal domains, and conformational stability. In contrast, amyloid-beta40 present at low levels did not form a major particle with discernible size, and both N-terminal and C- terminal domains were largely exposed. Rapidly progressive Alzheimer's disease that is associated with a low frequency of APOE e4 allele demonstrates considerably expanded conformational heterogeneity of amyloid beta42, with higher levels of distinctly structured amyloid-beta42 particles composed of 30-100 monomers, and fewer particles composed of < 30 monomers. The link between rapid clinical decline and levels of amyloid-beta42 with distinct structural characteristics suggests that different conformers may play an important role in the pathogenesis of distinct Alzheimer's disease phenotypes. These findings indicate that Alzheimer's disease exhibits a wide spectrum of amyloid-beta42 structural states and imply the existence of prion-like conformational strains. PMID- 25688082 TI - Therapy-induced brain reorganization patterns in aphasia. AB - Both hemispheres are engaged in recovery from word production deficits in aphasia. Lexical therapy has been shown to induce brain reorganization even in patients with chronic aphasia. However, the interplay of factors influencing reorganization patterns still remains unresolved. We were especially interested in the relation between lesion site, therapy-induced recovery, and beneficial reorganization patterns. Thus, we applied intensive lexical therapy, which was evaluated with functional magnetic resonance imaging, to 14 chronic patients with aphasic word retrieval deficits. In a group study, we aimed to illuminate brain reorganization of the naming network in comparison with healthy controls. Moreover, we intended to analyse the data with joint independent component analysis to relate lesion sites to therapy-induced brain reorganization, and to correlate resulting components with therapy gain. As a result, we found peri lesional and contralateral activations basically overlapping with premorbid naming networks observed in healthy subjects. Reduced activation patterns for patients compared to controls before training comprised damaged left hemisphere language areas, right precentral and superior temporal gyrus, as well as left caudate and anterior cingulate cortex. There were decreasing activations of bilateral visuo-cognitive, articulatory, attention, and language areas due to therapy, with stronger decreases for patients in right middle temporal gyrus/superior temporal sulcus, bilateral precuneus as well as left anterior cingulate cortex and caudate. The joint independent component analysis revealed three components indexing lesion subtypes that were associated with patient specific recovery patterns. Activation decreases (i) of an extended frontal lesion disconnecting language pathways occurred in left inferior frontal gyrus; (ii) of a small frontal lesion were found in bilateral inferior frontal gyrus; and (iii) of a large temporo-parietal lesion occurred in bilateral inferior frontal gyrus and contralateral superior temporal gyrus. All components revealed increases in prefrontal areas. One component was negatively correlated with therapy gain. Therapy was associated exclusively with activation decreases, which could mainly be attributed to higher processing efficiency within the naming network. In our joint independent component analysis, all three lesion patterns disclosed involved deactivation of left inferior frontal gyrus. Moreover, we found evidence for increased demands on control processes. As expected, we saw partly differential reorganization profiles depending on lesion patterns. There was no compensatory deactivation for the large left inferior frontal lesion, with its less advantageous outcome probably being related to its disconnection from crucial language processing pathways. PMID- 25688084 TI - Grasshopper (Orthoptera: Acrididae) community composition in the rangeland of the northern slopes of The Qilian Mountains in northwestern China. AB - In order to describe grasshopper (Orthoptera: Acrididae) species composition, diversity, abundance, and density of four rangelands types, we compared the grasshopper community composition and dynamics in the rangeland of the northern slopes of the Qilian Mountains. In total, 55 grasshopper species were collected from 2007 to 2009, representing three families and six subfamilies. The subfamily Oedipodinae was dominant, followed by Gomphocerinae and Catantopinae. Species abundance varied among rangeland types (RTs). The greatest abundance of grasshoppers was found in mountain rangeland, while the lowest abundance of grasshoppers was caught in alpine shrublands. Three species (Chorthippus cf. brunneus (Thunberg) (Acrididae), Chorthippus Dubius (Zubovski), and Gomphocerus licenti (Chang) were broadly distributed in the four RTs and constituted 7.5% of all grasshoppers collected. Ch. dubius was very abundant in desert rangeland and alpine shrubland. Bryodema dolichoptera Yin et Feng Eremippus qilianshanensis Lian and Zheng, and Filchnerella qilianshanensis Xi and Zheng (Pamphagidae) were endemic to the region of the Qilian Mountains. Species similarity between RTs ranged from 17.8 to 51.6 based on the Renkonen index. Similarly, the Sorensen index indicated a wide separation in species composition among RTs. The abundance of the eight most common species showed obvious differences among RTs and years. On average, mountain rangeland had the highest density values in 2007 and 2008, and alpine shrubland supported the smallest density. The densities in desert and mountain rangeland in 2007 were significantly higher than in 2008, while alpine rangeland and shrublands did not present obvious differences among years. PMID- 25688083 TI - Early behavioural changes in familial Alzheimer's disease in the Dominantly Inherited Alzheimer Network. AB - Prior studies indicate psychiatric symptoms such as depression, apathy and anxiety are risk factors for or prodromal symptoms of incipient Alzheimer's disease. The study of persons at 50% risk for inheriting autosomal dominant Alzheimer's disease mutations allows characterization of these symptoms before progressive decline in a population destined to develop illness. We sought to characterize early behavioural features in carriers of autosomal dominant Alzheimer's disease mutations. Two hundred and sixty-one persons unaware of their mutation status enrolled in the Dominantly Inherited Alzheimer Network, a study of persons with or at-risk for autosomal dominant Alzheimer's disease, were evaluated with the Neuropsychiatric Inventory-Questionnaire, the 15-item Geriatric Depression Scale and the Clinical Dementia Rating Scale (CDR). Ninety seven asymptomatic (CDR = 0), 25 mildly symptomatic (CDR = 0.5), and 33 overtly affected (CDR > 0.5) autosomal dominant Alzheimer's disease mutation carriers were compared to 106 non-carriers with regard to frequency of behavioural symptoms on the Neuropsychiatric Inventory-Questionnaire and severity of depressive symptoms on the Geriatric Depression Scale using generalized linear regression models with appropriate distributions and link functions. Results from the adjusted analyses indicated that depressive symptoms on the Neuropsychiatric Inventory-Questionnaire were less common in cognitively asymptomatic mutation carriers than in non-carriers (5% versus 17%, P = 0.014) and the odds of experiencing at least one behavioural sign in cognitively asymptomatic mutation carriers was lower than in non-carriers (odds ratio = 0.50, 95% confidence interval: 0.26-0.98, P = 0.042). Depression (56% versus 17%, P = 0.0003), apathy (40% versus 4%, P < 0.0001), disinhibition (16% versus 2%, P = 0.009), irritability (48% versus 9%, P = 0.0001), sleep changes (28% versus 7%, P = 0.003), and agitation (24% versus 6%, P = 0.008) were more common and the degree of self-rated depression more severe (mean Geriatric Depression Scale score of 2.8 versus 1.4, P = 0.006) in mildly symptomatic mutation carriers relative to non-carriers. Anxiety, appetite changes, delusions, and repetitive motor activity were additionally more common in overtly impaired mutation carriers. Similar to studies of late-onset Alzheimer's disease, we demonstrated increased rates of depression, apathy, and other behavioural symptoms in the mildly symptomatic, prodromal phase of autosomal dominant Alzheimer's disease that increased with disease severity. We did not identify any increased psychopathology in mutation carriers over non-carriers during the presymptomatic stage, suggesting these symptoms result when a threshold of neurodegeneration is reached rather than as life-long qualities. Unexpectedly, we found lower rates of depressive symptoms in cognitively asymptomatic mutation carriers. PMID- 25688085 TI - Chemical composition, antifeedant, repellent, and toxicity activities of the rhizomes of galangal, Alpinia galanga against Asian subterranean termites, Coptotermes gestroi and Coptotermes curvignathus (Isoptera: Rhinotermitidae). AB - Dual choice bioassays were used to evaluate the antifeedant property of essential oil and methanolic extract of Alpinia galanga (L.) (locally known as lengkuas) against two species of termites, Coptotermes gestroi (Wasmann) and Coptotermes curvignathus (Holmgren) (Isoptera: Rhinotermitidae). A 4-cm-diameter paper disc treated with A. galanga essential oil and another treated with either methanol or hexane as control were placed in a petri dish with 10 termites. Mean consumption of paper discs (miligram) treated with 2,000 ppm of essential oil by C. gestroi was 3.30 +/- 0.24 mg and by C. curvignathus was 3.32 +/- 0.24 mg. A. galanga essential oil showed significant difference in antifeedant effect, 2,000 ppm of A. galanga essential oil was considered to be the optimum concentration that gave maximum antifeedant effect. The essential oil composition was determined using gas chromatography-mass spectrometry. The major component of the essential oil was 1,8-cineol (61.9%). Antifeedant bioassay using 500 ppm of 1,8-cineol showed significant reduction in paper consumption by both termite species. Thus, the bioactive agent in A. galangal essential oil causing antifeeding activity was identified as 1,8-cineol. Repellent activity shows that 250 ppm of 1,8-cineol caused 50.00 +/- 4.47% repellency for C. gestroi, whereas for C. curvignathus 750 ppm of 1,8-cineol was needed to cause similar repellent activity (56.67 +/- 3.33%). C. curvignathus is more susceptible compare to C. gestroi in Contact Toxicity study, the lethal dose (LD50) of C. curvignathus was 945 mg/kg, whereas LD50 value for C. gestroi was 1,102 mg/kg. Hence 1,8-cineol may be developed as an alternative control against termite in sustainable agriculture practices. PMID- 25688086 TI - Differences in antennal sensillae of male and female peach fruit flies in relation to hosts. AB - Antennal sensillae of male and female peach fruit flies, Bactrocera zonata (Saunders) (Diptera: Tephritidae), obtained from three different host fruit species (guava, Psidium guajava L. (Myrtales: Myrtaceae); peach, Prunus persica (L.) Stokes (Rosales: Rosaceae); and orange, Citrus sinensis (L.) Osbeck (Sapindales: Rutaceae)), were studied with scanning electron microscopy. This study was carried out to describe the different types of sensillae present on the three antennal segments (scape, pedicel, and flagellum or funiculus) of both sexes of B. zonata on different host fruit. The antennal segments of females tended to be larger than those of males feeding on peach and guava fruit. On orange, both sexes were similar (no significant differences were found). The first two antennal segments, scape and pedicel, are reinforced by some bristles and have different types of sensillae, including trichoid I, II, S; basiconic II; and sensilla chaetica in different numbers on different host fruit species. Numerous microtrichia, as well as trichoid (I, II), basiconic (I), clavate, and coeloconic (I, II) sensillae were observed on the funiculus with a great variation in number and length. As a result of feeding on different hosts, differences were found between sexes and some plasticity in size, number, distribution, and position of some sensillae, including trichoid, basiconic, chaetica, and clavate on the antennae of the female B. zonata. These sensillae were significantly larger in females. Also, some morphological and morphemetric differences have been found according to their feeding on different host fruit. PMID- 25688087 TI - Expression profiles of the heat shock protein 70 gene in response to heat stress in Agrotis c-nigrum (Lepidoptera: Noctuidae). AB - Heat shock proteins (HSPs) are molecular chaperones, and their overexpression enhances the survivability and stress tolerance of the cell. To understand the characteristics of HSP70 in Agrotis c-nigrum Linnaeus larvae, the coding sequence of this protein was cloned, and the effect of heat stress on transcription and protein properties was assessed. The obtained cDNA sequence of HSP70 was 2,213 bp, which contained an ORF of 1,965 bp and encoded 654 amino acid residues. Isolated HSP70 cDNA demonstrated more than 80% identity with the sequences of other known insect HSP70s. Next, HSP70 was expressed in Escherichia coli BL21 (DE3) cells and identified using SDS-PAGE and western blotting analyses. In addition, anti-HSP70-specific antisera were prepared using a recombinant HSP70 protein, and the results showed that this antisera was very specific to AcHSP70. Real-time quantitative polymerase chain reaction detected the relative transcription of the HSP70 gene in larvae and the transcription of A. c-nigrum in response to high temperatures. Induction of HSP70 was up-regulated to peak expression at 36 degrees C. PMID- 25688088 TI - The effects of colony structure and resource abundance on food dispersal in Tapinoma sessile (Hymenoptera: Formicidae). AB - The odorous house ant, Tapinoma sessile (Say) (Hymenoptera: Formicidae), exhibits a high degree of variation in colony spatial structure which may have direct and indirect effects on foraging. Protein marking and mark-release-recapture techniques were utilized to examine the effect of colony spatial structure on food dispersal. Sucrose water spiked with rabbit IgG protein was presented to colonies with varying spatial configurations in laboratory and field experiments. In monodomous lab colonies, the rate and extent of food dispersal was rapid due to a decrease in foraging area. In polydomous colonies, food dispersal was slower because conspecifics were forced to forage and share food over longer distances. However, over time, food was present in all extremities of the colony. Experiments conducted in the field produced similar results, with nests in close proximity to food yielding higher percentages of workers scoring positive for the marker. However, the percentage of workers possessing the marker decreased over time. Results from this study provide experimental data on mechanisms of food dispersal in monodomous and polydomous colonies of ants, and may be important for increasing the efficacy of management strategies against T. sessile and other pest ant species. PMID- 25688089 TI - Implementing a spinosad-based local bait station to control Bactrocera cucurbitae (Diptera: Tephritidae) in high rainfall areas of Reunion Island. AB - Three species of fruit flies cause serious damage to cucurbit crops on Reunion Island: Bactrocera cucurbitae (Diptera: Tephritidae) (Coquillett 1899), Dacus ciliatus (Loew 1901), and Dacus demmerezi (Bezzi 1917). To control them, a program of agroecological management of cucurbit flies has been implemented based on the application of Syneis-appat, especially spot sprays on corn borders. However, the high rainfall on Reunion Island limits the long-term efficiency of the bait; in addition, this method cannot be used for large chayote trellises, because corn borders cannot be planted around them. The aim of this study was to design a bait station adapted to prevailing conditions on Reunion Island. An 'umbrella trap' tested in Taiwan was used as a reference to compare its efficacy with our local bait station. Experiments were conducted in field cages on B. cucurbitae to test different characteristics of bait stations and to construct one using local materials. Results were validated in the field. The attractiveness of the bait station was related mainly to the color of the external surface, yellow being the most attractive color. The efficacy of the bait station with respect to fly mortality was found to be linked to the accessibility of the bait, and direct application of Syneis-appat on the bait station was found to be the most efficient. In the field, B. cucurbitae were more attracted to the local bait station than to the umbrella trap, while the two other fly species displayed equal attraction to both trap types. Our local bait station is a useful alternative to spot sprays of Syneis-appat and is now included in a local pest management program and is well accepted by farmers. PMID- 25688090 TI - Comparative feeding performance and digestive physiology of Helicoverpa armigera (Lepidoptera: Noctuidae) larvae-fed 11 corn hybrids. AB - This study aimed to evaluate the feeding responses and digestive proteolytic and amylolytic activity of Helicoverpa armigera (Hubner) on 11 corn (Zea mays L.) hybrids at 25 +/- 1 degrees C, 65 +/- 5% relative humidity (RH), and a photoperiod of 16:8 (L:D) h. The fourth- and fifth-instar larvae fed on hybrid K47*K19 had the highest weight of food consumption and those reared on hybrid KSC705 had the lowest value of food consumption. The highest weight gain of the larvae was observed when H. armigera were fed hybrid KLM78*MO17 and lowest when they were fed hybrids K36 * MO17, KSC705, and K35 * K36. Pupal weight of H. armigera was heaviest when larvae were fed hybrid K47*K19 and lightest when they were fed hybrid KSC705. The highest proteolytic activity of the fourth-instar larvae was observed when they were fed hybrid KSC705, and the lowest activity was observed when they were fed hybrid K47*A67. Fifth-instar larvae that fed on hybrid K47*K19 showed the highest proteolytic activity. Fourth-instar larvae that fed on hybrid K36*MO17 showed the highest amylase activity. The fifth-instar larvae fed on hybrid K47*A67 showed the maximum amylase activity and those reared on the K48*K18 showed the minimum activity. Our results indicated that K36 * MO17, KSC705, and K48 * K18 were the most unsuitable hybrids for feeding H. armigera. PMID- 25688091 TI - The mitochondrial quality control protein Yme1 is necessary to prevent defective mitophagy in a yeast model of Barth syndrome. AB - The Saccharomyces cerevisiae TAZ1 gene is an orthologue of human TAZ; both encode the protein tafazzin. Tafazzin is a transacylase that transfers acyl chains with unsaturated fatty acids from phospholipids to monolysocardiolipin to generate cardiolipin with unsaturated fatty acids. Mutations in human TAZ cause Barth syndrome, a fatal childhood cardiomyopathy biochemically characterized by reduced cardiolipin mass and increased monolysocardiolipin levels. To uncover cellular processes that require tafazzin to maintain cell health, we performed a synthetic genetic array screen using taz1Delta yeast cells to identify genes whose deletion aggravated its fitness. The synthetic genetic array screen uncovered several mitochondrial cellular processes that require tafazzin. Focusing on the i-AAA protease Yme1, a mitochondrial quality control protein that degrades misfolded proteins, we determined that in cells lacking both Yme1 and Taz1 function, there were substantive mitochondrial ultrastructural defects, ineffective superoxide scavenging, and a severe defect in mitophagy. We identify an important role for the mitochondrial protease Yme1 in the ability of cells that lack tafazzin function to maintain mitochondrial structural integrity and mitochondrial quality control and to undergo mitophagy. PMID- 25688092 TI - Sulfide oxidation by a noncanonical pathway in red blood cells generates thiosulfate and polysulfides. AB - A cardioprotectant at low concentrations, H2S is a toxin at high concentrations and inhibits cytochrome c oxidase. A conundrum in H2S homeostasis is its fate in red blood cells (RBCs), which produce H2S but lack the canonical mitochondrial sulfide oxidation pathway for its clearance. The sheer abundance of RBCs in circulation enhances the metabolic significance of their clearance strategy for H2S, necessary to avoid systemic toxicity. In this study, we demonstrate that H2S generation by RBCs is catalyzed by mercaptopyruvate sulfurtransferase. Furthermore, we have discovered the locus of sulfide oxidation in RBCs and describe a new role for an old protein, hemoglobin, which in the ferric or methemoglobin state binds H2S and oxidizes it to a mixture of thiosulfate and hydropolysulfides. Our study reveals a previously undescribed route for the biogenesis of hydropolysulfides, which are increasingly considered important for H2S-based signaling, but their origin in mammalian cells is unknown. An NADPH/flavoprotein oxidoreductase system restores polysulfide-carrying hemoglobin derivatives to ferrous hemoglobin, thus completing the methemoglobin-dependent sulfide oxidation cycle. Methemoglobin-dependent sulfide oxidation in mammals is complex and has similarities to chemistry reported for the dissolution of iron oxides in sulfidic waters and during bioleaching of metal sulfides. The catalytic oxidation of H2S by hemoglobin explains how RBCs maintain low steady-state H2S levels in circulation, and suggests that additional hemeproteins might be involved in sulfide homeostasis in other tissues. PMID- 25688094 TI - In situ SEM observation of the Si negative electrode reaction in an ionic-liquid based lithium-ion secondary battery. AB - By exploiting characteristics such as negligible vapour pressure and ion conductive nature of an ionic liquid (IL), we established an in situ scanning electron microscope (SEM) method to observe the electrode reaction in the IL based Li-ion secondary battery (LIB). When 1-ethyl-3-methylimidazolium bis(fluorosulfonyl)amide ([C2mim][FSA]) with lithium bis(trifluoromethanesulfonyl)amide (Li[TFSA]) was used as the electrolyte, the Si negative electrode exhibited a clear morphology change during the charge process, without any solid electrolyte interphase (SEI) layer formation, while in the discharge process, the appearance was slightly changed, suggesting that a morphology change is irreversible in the charge-discharge process. On the other hand, the use of 1-ethyl-3-methylimidazolium bis(trifluoromethanesulfonyl)amide ([C2mim][TFSA]) with Li[TFSA] did not induce a change in the Si negative electrode. It is interesting to note this distinct contrast, which could be attributed to SEI layer formation from the electrochemical breakdown of [C2mim](+) at the Si negative electrode|separator interface in the [C2mim][TFSA] based LIB. This in situ SEM observation technique could reveal the effect of the IL species electron-microscopically on the Si negative electrode reaction. PMID- 25688093 TI - Phosphorylation of targeting protein for Xenopus kinesin-like protein 2 (TPX2) at threonine 72 in spindle assembly. AB - The human ortholog of the targeting protein for Xenopus kinesin-like protein 2 (TPX2) is a cytoskeletal protein that plays a major role in spindle assembly and is required for mitosis. During spindle morphogenesis, TPX2 cooperates with Aurora A kinase and Eg5 kinesin to regulate microtubule organization. TPX2 displays over 40 putative phosphorylation sites identified from various high throughput proteomic screenings. In this study, we characterize the phosphorylation of threonine 72 (Thr(72)) in human TPX2, a residue highly conserved across species. We find that Cdk1/2 phosphorylate TPX2 in vitro and in vivo. Using homemade antibodies specific for TPX2 phosphorylated at Thr(72), we show that this phosphorylation is cell cycle-dependent and peaks at M phase. Endogenous TPX2 phosphorylated at Thr(72) does not associate with the mitotic spindle. Furthermore, ectopic GFP-TPX2 T72A preferentially concentrates on the spindle, whereas GFP-TPX2 WT distributes to both spindle and cytosol. The T72A mutant also increases the proportion of cells with multipolar spindles phenotype. This effect is associated with increased Aurora A activity and abnormally elongated spindles, indicative of higher Eg5 activity. In summary, we propose that phosphorylation of Thr(72) regulates TPX2 localization and impacts spindle assembly via Aurora A and Eg5. PMID- 25688095 TI - A speaker's gesture style can affect language comprehension: ERP evidence from gesture-speech integration. AB - In face-to-face communication, speech is typically enriched by gestures. Clearly, not all people gesture in the same way, and the present study explores whether such individual differences in gesture style are taken into account during the perception of gestures that accompany speech. Participants were presented with one speaker that gestured in a straightforward way and another that also produced self-touch movements. Adding trials with such grooming movements makes the gesture information a much weaker cue compared with the gestures of the non grooming speaker. The Electroencephalogram was recorded as participants watched videos of the individual speakers. Event-related potentials elicited by the speech signal revealed that adding grooming movements attenuated the impact of gesture for this particular speaker. Thus, these data suggest that there is sensitivity to the personal communication style of a speaker and that affects the extent to which gesture and speech are integrated during language comprehension. PMID- 25688096 TI - Amygdala reactivity to negative stimuli is influenced by oral contraceptive use. AB - The amygdala is a highly interconnected region of the brain that is critically important to emotional processing and affective networks. Previous studies have shown that the response of the amygdala to emotionally arousing stimuli can be modulated by sex hormones. Because oral contraceptive pills dramatically lower circulating sex hormone levels with potent analogs of those hormones, we performed a functional magnetic resonance imaging experiment to measure amygdala reactivity in response to emotional stimuli in women using oral contraceptives, and compared their amygdala reactivity with that of naturally cycling women. Here, we show that women who use oral contraceptive pills have significantly decreased bilateral amygdala reactivity in response to negatively valenced, emotionally arousing stimuli compared with naturally cycling women. We suggest that by modulating amygdala reactivity, oral contraceptive pills may influence behaviors that have previously been shown to be amygdala dependent-in particular, emotional memory. PMID- 25688097 TI - Decoding covert motivations of free riding and cooperation from multi-feature pattern analysis of EEG signals. AB - Cooperation and free riding are among the most frequently observed behaviors in human social decision-making. In social interactions, the effects of strategic decision processes have been consistently reported in iterative cooperation decisions. However, the neural activity immediately after new information is presented, the time at which strategy learning potentially starts has not yet been investigated with high temporal resolution. Here, we implemented an iterative, binary public goods game that simulates cooperation/free riding behavior. We applied the multi-feature pattern analysis method by using a support vector machine and the unique combinatorial performance measure, and identified neural features from the single-trial, event-related spectral perturbation at the result-presentation of the current round that predict participants' decisions to cooperate or free ride in the subsequent round. We found that neural oscillations in centroparietal and temporal regions showed the highest predictive power through 10-fold cross-validation; these predicted the participants' next decisions, which were independent of the neural responses during their own preceding choices. We suggest that the spatial distribution and time-frequency information of the selected features represent covert motivations to free ride or cooperate in the next round and are separately processed in parallel with information regarding the preceding results. PMID- 25688098 TI - Health system strategies supporting transition to adult care. AB - BACKGROUND: The transition from paediatric to adult care is associated with poor clinical outcomes, increased costs and low patient and family satisfaction. However, little is known about health system strategies to streamline and safeguard care for youth transitioning to adult services. Moreover, the needs of children and youth are often excluded from broader health system reform discussions, leaving this population especially vulnerable to system 'disintegration'. OBJECTIVES: (1) To explore the international policy profile of paediatric-to-adult care transitions, and (2) to document policy objectives, initiatives and outcomes for jurisdictions publicly committed to addressing transition issues. METHODS: An international policy scoping review of all publicly available government documents detailing transition-related strategies was completed using a web-based search. Our analysis included a comparable cohort of nine wealthy Organisation for Economic Co-operation and Development (OECD) jurisdictions with Beveridge-style healthcare systems (deemed those most likely to benefit from system-level transition strategies). RESULTS: Few jurisdictions address transition of care issues in either health or broader social policy documents. While many jurisdictions refer to standardised practice guidelines, a few report the intention to use powerful policy levers (including physician remuneration and non-physician investments) to facilitate the uptake of best practice. Most jurisdictions do not address the policy infrastructure required to support successful transitions, and rigorous evaluations of transition strategies are rare. CONCLUSIONS: Despite the well-documented risks and costs associated with a poor transition from paediatric to adult care, little policy attention has been paid to this issue. We recommend that healthcare providers engage health system planners in the design and evaluation of system-level, policy-sensitive transition strategies. PMID- 25688099 TI - Male infants with hypospadias and/or cryptorchidism show a lower 2D/4D digit ratio than normal boys. AB - BACKGROUND: In humans the ratio of the index finger to the ring finger is sexually dimorphic, with the mean ratio being larger in women than in men. It has been suggested that this difference is related to prenatal androgen exposure. This has been further demonstrated in children with congenital adrenal hyperplasia. Normal development of the male external genitalia is linked to androgen-mediated events during gestation. We therefore wanted to determine if the 2D:4D digit ratio was normal in boys with cryptorchidism or hypospadias. METHODS: We prospectively enrolled all prepubertal patients seen in the outpatient clinic for cryptorchidism or hypospadias between September and December 2012. We then compared their 2D:4D digit ratio with two control groups made up of normal boys and normal girls. Interobserver and intraobserver variability was evaluated. RESULTS: We included 57 boys with hypospadias and/or cryptorchidism, 79 boys without genital abnormalities and 25 girls without genital abnormalities. The mean 2D:4D ratio for both hands was significantly different between the three groups, with the digit ratio for boys with genital anomalies being lower than for normal boys and normal girls (p<0.0001). CONCLUSIONS: It appears that boys with genital abnormalities (cryptorchidism and/or hypospadias) have a lower 2D:4D digit ratio than boys without genital anomalies. PMID- 25688100 TI - Impact of anaesthetic technique on survival in colon cancer: a review of the literature. AB - An oncological surgical resection is the mainstay of treatment for potentially curable colon cancer. At the time of surgery, a large fraction of patients do harbour-although not visibly-minimal residual disease at the time of surgery. The immunosuppression that accompanies surgery may have an effect on disease recurrence and survival. Regional or neuraxial anaesthetic techniques like epidural anaesthesia may suppress immune function less than opioid analgesia, by reducing stress response and significantly reducing exposure to opioids. Consistent with this hypothesis, regional anaesthetic techniques have been associated with lower recurrence rates in breast cancer and prostate cancer. Results for colon cancer, however, are contradictory. In this review of the literature we describe all studies addressing the association of the use of epidural anaesthesia and survival in colon cancer surgery. PMID- 25688101 TI - An unusual cause of acute anemia in an immunosuppressed patient. AB - Gastrointestinal mucormycosis is an uncommon, invasive, opportunistic fungal infection with a high mortality rate, seen more commonly in immunocompromised patients. This lethal infection has a wide range of presentations, from colonization of peptic ulcers to infiltrative disease and eventually vascular invasion. Here we present a case of upper gastrointestinal bleeding in an immunocompromised patient, which was proved to be secondary to gastric involvement by mucormycosis. PMID- 25688102 TI - Histopathological study using computer database of 10 000 consecutive gastric specimens: (1) benign conditions. AB - Using a computer database, the author investigated the histopathology of 10 000 consecutive gastric specimens, taken in the last 12 years (2002-2013) at the pathology laboratory of a Japanese hospital. Re-observation of the already examined histological sections was done when the histological diagnosis and findings on the computer data base were not very obvious. The gastric specimens were identified as 8579 benign conditions and 1421 malignant lesions. The 8579 benign conditions were comprised almost normal stomach in 74 cases (0.9%), chronic gastritis in 4374 (51.0%), benign gastric peptic ulcer in 2195 (25.6%), foveolar hyperplastic polyp in 1004 (11.7%), fundic gland polyp in 421 (4.9%), adenoma in 487 (5.6%), heterotopic pancreas in 9 (0.1%), pancreatic acinar metaplasia (PAM) in 8 (0.1%), and amyloidosis in 7 (0.1%). Chronic gastritis showed lymphocytic infiltration and frequently showed erosions and intestinal metaplasia. Gastric peptic ulcer showed exudate, necrosis, active inflammation, and regenerative atypia of the epithelium. Foveolar hyperplastic polyp revealed 23 malignant changes and frequently showed dysplastic glands and intestinal metaplasia. Fundic gland polyp demonstrated cystic dilations of fundic gland ducts. Gastric adenoma showed adenomatous proliferation in the superficial mucosa and cystic dilation of the epithelium under the adenoma. Heterotopic pancreas was located in the submucosa and consisted of acinar cells, ducts, and occasionally islets. PAM was a tiny lesion in the mucosa and consisted of only pancreatic acinar cells. Amyloidosis was primary amyloidosis with positive reaction with Congo-red stain. PMID- 25688103 TI - Unique ATPase site architecture triggers cis-mediated synchronized ATP binding in heptameric AAA+-ATPase domain of flagellar regulatory protein FlrC. AB - Bacterial enhancer-binding proteins (bEBPs) oligomerize through AAA(+) domains and use ATP hydrolysis-driven energy to isomerize the RNA polymerase-sigma(54) complex during transcriptional initiation. Here, we describe the first structure of the central AAA(+) domain of the flagellar regulatory protein FlrC (FlrC(C)), a bEBP that controls flagellar synthesis in Vibrio cholerae. Our results showed that FlrC(C) forms heptamer both in nucleotide (Nt)-free and -bound states without ATP-dependent subunit remodeling. Unlike the bEBPs such as NtrC1 or PspF, a novel cis-mediated "all or none" ATP binding occurs in the heptameric FlrC(C), because constriction at the ATPase site, caused by loop L3 and helix alpha7, restricts the proximity of the trans-protomer required for Nt binding. A unique "closed to open" movement of Walker A, assisted by trans-acting "Glu switch" Glu 286, facilitates ATP binding and hydrolysis. Fluorescence quenching and ATPase assays on FlrC(C) and mutants revealed that although Arg-349 of sensor II, positioned by trans-acting Glu-286 and Tyr-290, acts as a key residue to bind and hydrolyze ATP, Arg-319 of alpha7 anchors ribose and controls the rate of ATP hydrolysis by retarding the expulsion of ADP. Heptameric state of FlrC(C) is restored in solution even with the transition state mimicking ADP.AlF3. Structural results and pulldown assays indicated that L3 renders an in-built geometry to L1 and L2 causing sigma(54)-FlrC(C) interaction independent of Nt binding. Collectively, our results underscore a novel mechanism of ATP binding and sigma(54) interaction that strives to understand the transcriptional mechanism of the bEBPs, which probably interact directly with the RNA polymerase sigma(54) complex without DNA looping. PMID- 25688104 TI - SU2C phase Ib study of paclitaxel and MK-2206 in advanced solid tumors and metastatic breast cancer. AB - BACKGROUND: There is preclinical synergism between taxanes and MK-2206. We aim to determine the maximum tolerated dose, safety, and activity of combining MK-2206 and paclitaxel in metastatic cancer. METHODS: Patients received weekly doses of paclitaxel at 80mg/m2 on day 1, followed by MK-2206 orally on day 2 escalated at 90mg, 135mg, and 200mg. Treatment continued until progression, excessive toxicity, or patient request. Blood and tissue were collected for pharmacokinetic and pharmacodynamics markers. A cycle consisted of three weeks of therapy. Dose limiting toxicity (DLT) was defined as unacceptable toxicity during the first cycle. All statistical tests were two-sided. RESULTS: Twenty-two patients were treated, nine in dose escalation and 13 in dose expansion. Median age was 55 years. Median number of cycles was four. Dose escalation was completed with no DLT. CTCAE Grade 3 or higher adverse events were fatigue (n = 2), rash (n = 2), hyperglycemia (n = 1), and neutropenia (n = 7). Four patients in the expansion phase required MK-2206 dose reduction. Phase II recommended dose was established as paclitaxel 80mg/m2 weekly on day 1, and MK-2206 135mg weekly on day 2. Paclitaxel systemic exposure was similar in the presence or absence of MK-2206. Plasma MK-2206 concentrations were similar to data from previous phase I monotherapy. There was a statistically significant decrease in expression of pAKT S473 (P = .01) and pAKT T308 (P = .002) after therapy. PI3K/AKT/mTOR downregulation in tumor tissues and circulating markers did not correlate with tumor response or clinical benefit. There were five objective responses, and nine patients had stable disease. CONCLUSION: MK-2206 was well tolerated with paclitaxel. Preliminary antitumor activity was documented. PMID- 25688105 TI - Urogenital Chlamydia trachomatis strain types, defined by high-resolution multilocus sequence typing, in relation to ethnicity and urogenital symptoms among a young screening population in Amsterdam, The Netherlands. AB - INTRODUCTION: Previous studies found conflicting results regarding associations between urogenital Chlamydia trachomatis infections and ethnicity or urogenital symptoms among at-risk populations using either ompA-based genotyping or high resolution multilocus sequence typing (MLST). This study applied high-resolution MLST on samples of individuals from a selected young urban screening population to assess the relationship of C. trachomatis strain types with ethnicity and self reported urogenital symptoms. Demographic and sexual risk behaviour characteristics of the identified clusters were also analysed. METHODS: We selected C. trachomatis-positive samples from the Dutch Chlamydia Screening Implementation study among young individuals in Amsterdam, the Netherlands. All samples were typed using high-resolution MLST. Clusters were assigned using minimum spanning tree analysis and were combined with epidemiological data of the participants. RESULTS: We obtained full MLST data for C. trachomatis-positive samples from 439 participants and detected nine ompA genovars. MLST analysis identified 175 sequence types and six large clusters; in one cluster, participants with Surinamese/Antillean ethnicity were over-represented (58.8%) and this cluster predominantly consisted of genovar I. In addition, we found one cluster with an over-representation of participants with Dutch ethnicity (90.0%) and which solely consisted of genovar G. No association was observed between C. trachomatis clusters and urogenital symptoms. CONCLUSIONS: We found an association between urogenital C. trachomatis clusters and ethnicity among young screening participants in Amsterdam, the Netherlands. However, no association was found between C. trachomatis clusters and self-reported urogenital symptoms. PMID- 25688106 TI - Extreme Aesthetic Surgery. PMID- 25688107 TI - Environmental selection pressures related to iron utilization are involved in the loss of the flavodoxin gene from the plant genome. AB - Oxidative stress and iron limitation represent the grim side of life in an oxygen rich atmosphere. The versatile electron transfer shuttle ferredoxin, an iron sulfur protein, is particularly sensitive to these hardships, and its downregulation under adverse conditions severely compromises survival of phototrophs. Replacement of ferredoxin by a stress-resistant isofunctional carrier, flavin-containing flavodoxin, is a widespread strategy employed by photosynthetic microorganisms to overcome environmental adversities. The flavodoxin gene was lost in the course of plant evolution, but its reintroduction in transgenic plants confers increased tolerance to environmental stress and iron starvation, raising the question as to why a genetic asset with obvious adaptive value was not kept by natural selection. Phylogenetic analyses reveal that the evolutionary history of flavodoxin is intricate, with several horizontal gene transfer events between distant organisms, including Eukarya, Bacteria, and Archaea. The flavodoxin gene is unevenly distributed in most algal lineages, with flavodoxin-containing species being overrepresented in iron-limited regions and scarce or absent in iron-rich environments. Evaluation of cyanobacterial genomic and metagenomic data yielded essentially the same results, indicating that there was little selection pressure to retain flavodoxin in iron-rich coastal/freshwater phototrophs. Our results show a highly dynamic evolution pattern of flavodoxin tightly connected to the bioavailability of iron. Evidence presented here also indicates that the high concentration of iron in coastal and freshwater habitats may have facilitated the loss of flavodoxin in the freshwater ancestor of modern plants during the transition of photosynthetic organisms from the open oceans to the firm land. PMID- 25688108 TI - Molecular evolution of cytochrome bd oxidases across proteobacterial genomes. AB - This work is aimed to resolve the complex molecular evolution of cytochrome bd ubiquinol oxidase, a nearly ubiquitous bacterial enzyme that is involved in redox balance and bioenergetics. Previous studies have created an unclear picture of bd oxidases phylogenesis without considering the existence of diverse types of bd oxidases. Integrated approaches of genomic and protein analysis focused on proteobacteria have generated a molecular classification of diverse types of bd oxidases, which produces a new scenario for interpreting their evolution. A duplication of the original gene cluster of bd oxidase might have occurred in the ancestors of extant alpha-proteobacteria of the Rhodospirillales order, such as Acidocella, from which the bd-I type of the oxidase might have diffused to other proteobacterial lineages. In contrast, the Cyanide-Insensitive Oxidase type may have differentiated into recognizable subtypes after another gene cluster duplication. These subtypes are widespread in the genomes of alpha-, beta-, and gamma-proteobacteria, with occasional instances of lateral gene transfer. In resolving the evolutionary pattern of proteobacterial bd oxidases, this work sheds new light on the basal taxa of alpha-proteobacteria from which the gamma proteobacterial lineage probably emerged. PMID- 25688109 TI - Les Entretiens Jacques Cartier Symposium 4--targeted cancer therapies: stakes and prospects for patients. PMID- 25688111 TI - Arginine methyltransferases as novel therapeutic targets for breast cancer. AB - Breast cancer is the most commonly diagnosed female cancer in the world. Though therapeutic treatments are available to treat breast cancer and in some instances are successful, the occurrence of unsuccessful treatment, or the rate of tumour recurrence, still remains strikingly high. Therefore, novel therapeutic treatment targets need to be discovered and tested. The protein arginine methyltransferases (PRMTs) are a family of enzymes that catalyse arginine methylation and are implicated in a myriad of cellular pathways including transcription, DNA repair, RNA metabolism, signal transduction, protein-protein interactions and subcellular localisation. In breast cancer, the expression levels and enzymatic activity of a number of PRMTs is dysregulated; significantly altering the regulation of many cellular pathways that are implicated in breast cancer development and progression. Here, we review the current knowledge on PRMTs in breast cancer and provide a rationale for how PRMTs may provide novel therapeutic targets for the treatment of breast cancer. PMID- 25688110 TI - The expanding role of mTOR in cancer cell growth and proliferation. AB - The mechanistic/mammalian target of rapamycin (mTOR) is a conserved protein kinase that controls several anabolic processes required for cell growth and proliferation. As such, mTOR has been implicated in an increasing number of pathological conditions, including cancer, obesity, type 2 diabetes and neurodegeneration. As part of the mTOR complex 1 (mTORC1), mTOR regulates cell growth by promoting the biosynthesis of proteins, lipids and nucleic acids. Several mTORC1 substrates have been shown to regulate protein synthesis, including the eukaryotic initiation factor 4E (eIF4E)-binding proteins (4E-BPs) and the ribosomal S6 kinases (S6Ks) 1 and 2. In this work, we focus on the signalling pathways that lie both upstream and downstream of mTORC1, as well as their relevance to human pathologies. We further discuss pharmacological approaches that target mTOR and their applications for the treatment of cancer. PMID- 25688112 TI - The shortest path is not the one you know: application of biological network resources in precision oncology research. AB - Several decades of molecular biology research have delivered a wealth of detailed descriptions of molecular interactions in normal and tumour cells. This knowledge has been functionally organised and assembled into dedicated biological pathway resources that serve as an invaluable tool, not only for structuring the information about molecular interactions but also for making it available for biological, clinical and computational studies. With the advent of high throughput molecular profiling of tumours, close to complete molecular catalogues of mutations, gene expression and epigenetic modifications are available and require adequate interpretation. Taking into account the information about biological signalling machinery in cells may help to better interpret molecular profiles of tumours. Making sense out of these descriptions requires biological pathway resources for functional interpretation of the data. In this review, we describe the available biological pathway resources, their characteristics in terms of construction mode, focus, aims and paradigms of biological knowledge representation. We present a new resource that is focused on cancer-related signalling, the Atlas of Cancer Signalling Networks. We briefly discuss current approaches for data integration, visualisation and analysis, using biological networks, such as pathway scoring, guilt-by-association and network propagation. Finally, we illustrate with several examples the added value of data interpretation in the context of biological networks and demonstrate that it may help in analysis of high-throughput data like mutation, gene expression or small interfering RNA screening and can guide in patients stratification. Finally, we discuss perspectives for improving precision medicine using biological network resources and tools. Taking into account the information about biological signalling machinery in cells may help to better interpret molecular patterns of tumours and enable to put precision oncology into general clinical practice. PMID- 25688113 TI - Paradigm shift in oncology: targeting the immune system rather than cancer cells. AB - The clinical benefits obtained with rituximab in the treatment of CD20(+) B-cell malignancies and of imatinib in the treatment of Phi(+) leukaemias have opened a new era in oncology, transforming the concepts of tumour-targeted therapies and personalised medicine into reality. Since then, many tumour-targeted monoclonal antibodies and tyrosine kinase inhibitors have been approved for the treatment of cancers. Compared to conventional chemotherapies, these new drugs have more specificity against cancer cells and less systemic toxicities. However, like conventional chemotherapies, they often provide limited therapeutic benefits with short-lasting tumour responses as the vast majority of cancers become resistant to these drugs over time. Therefore, tumour-targeted therapies are an incremental innovation as compared to historical chemotherapies. Recently, a paradigm shift has been brought to the clinic with drugs targeting immune cells rather than cancer cells with the aim of stimulating the anti-tumour immune response of patients against their own cancer. Immunomodulatory drugs such as anti-CTLA4 and anti-PD-1 have generated long-lasting tumour responses when used as single agent in patients with refractory/relapsing cancers such as metastatic melanomas, renal cell carcinoma or non-small-cell lung carcinoma. These new immune-targeted therapies are therefore a disruptive innovation in cancer treatment: they demonstrate that long-lasting clinical benefits could be obtained by targeting molecules involved in the immune tolerance of cancer cells rather than by targeting oncogenic drivers or antigens expressed by cancer cells. PMID- 25688114 TI - Therogenetics: transferring GWAS technology to the clinic. AB - Molecular characteristics of breast tumours have been used for the last decades to guide clinicians in treating this devastating disease. More recent information has led to further refinement of molecular characteristics of breast tumours, and subsequent indications for specific treatments. However, evidence exists that factors independent of the primary tumour type, potentially germline genetics, may influence progression to metastasis. In this review, we expose some of this evidence, and propose tools needed to overcome current limitations to the identification of specific germline variants that influence risk of metastases in breast cancer patients. PMID- 25688115 TI - Pretreatment FDG-PET metrics in stage III non-small cell lung cancer: ACRIN 6668/RTOG 0235. AB - BACKGROUND: ACRIN 6668/RTOG 0235 evaluated the prognostic value of positron emission tomography with (18)F-fluorodeoxyglucose (FDG-PET) uptake before and after definitive, concurrent, platinum-based chemoradiotherapy for locally advanced non-small cell lung cancer (NSCLC). In this secondary analysis, we evaluate volumetric pretreatment PET measures as predictors of clinical outcomes. METHODS: Patients with stage III NSCLC underwent FDG-PET prior to treatment. A commercially available gradient-based segmentation tool was used to contour all visible hypermetabolic lesions on each scan. For each patient, the maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total glycolytic activity (TGA) for all contoured lesions were recorded. Cox proportional hazards regression models were used to evaluate clinical variables and PET metrics as predictors of overall survival (OS) and locoregional control (LRC). Time-dependent covariables were added to the models when necessary to address nonproportional hazards. All statistical tests were two-sided. RESULTS: Complete data were available for 214 patients in the OS analysis and 189 subjects in the LRC analysis. In multivariable analysis incorporating clinical and imaging data available prior to treatment, MTV was an independent predictor of OS (HR = 1.04 per 10 cm(3) increase, 95% CI = 1.03 to 1.06, P < .001). High MTV was also associated with increased risk of locoregional failure at baseline (HR = 1.16 per 10 cm(3) increase, 95% CI = 1.08 to 1.23, P < .001) and at six months (HR = 1.05 per 10 cm(3) increase, 95% CI = 1.02 to 1.07, P < .001) but not at 12 months or later time points. CONCLUSION: Pretreatment MTV is a predictor of clinical outcomes for NSCLC patients treated with chemoradiotherapy. Quantitative PET measures may serve as stratification factors in clinical trials for this patient population and may help guide novel trial designs. PMID- 25688116 TI - Leveraging biospecimen resources for discovery or validation of markers for early cancer detection. AB - Validation of early detection cancer biomarkers has proven to be disappointing when initial promising claims have often not been reproducible in diagnostic samples or did not extend to prediagnostic samples. The previously reported lack of rigorous internal validity (systematic differences between compared groups) and external validity (lack of generalizability beyond compared groups) may be effectively addressed by utilizing blood specimens and data collected within well conducted cohort studies. Cohort studies with prediagnostic specimens (eg, blood specimens collected prior to development of clinical symptoms) and clinical data have recently been used to assess the validity of some early detection biomarkers. With this background, the Division of Cancer Control and Population Sciences (DCCPS) and the Division of Cancer Prevention (DCP) of the National Cancer Institute (NCI) held a joint workshop in August 2013. The goal was to advance early detection cancer research by considering how the infrastructure of cohort studies that already exist or are being developed might be leveraged to include appropriate blood specimens, including prediagnostic specimens, ideally collected at periodic intervals, along with clinical data about symptom status and cancer diagnosis. Three overarching recommendations emerged from the discussions: 1) facilitate sharing of existing specimens and data, 2) encourage collaboration among scientists developing biomarkers and those conducting observational cohort studies or managing healthcare systems with cohorts followed over time, and 3) conduct pilot projects that identify and address key logistic and feasibility issues regarding how appropriate specimens and clinical data might be collected at reasonable effort and cost within existing or future cohorts. PMID- 25688117 TI - Procalcitonin as an Early Predictor of Contrast-Induced Acute Kidney Injury in Patients With Acute Coronary Syndromes Who Underwent Percutaneous Coronary Intervention. AB - Contrast-induced acute kidney injury (CI-AKI) is a major issue after percutaneous coronary intervention (PCI), especially in the setting of acute coronary syndrome (ACS). Contrast-induced acute kidney injury is associated with increased mortality and morbidity. Inflammation plays an important role in the pathophysiology of CI-AKI. Procalcitonin (PCT) is introduced as a new marker of inflammation. We sought to examine whether admission PCT levels predict the development of CI-AKI. Patients (n = 814) were divided into 2 groups, namely, CI AKI (-) and CI-AKI (+). An increase in serum creatinine of >=0.5 mg/dL from baseline within 48 to 72 hours of contrast exposure was defined as CI-AKI. Contrast-induced acute kidney injury occurred in 96 (11.8%) patients. The PCT levels were significantly higher in patients with CI-AKI than in those without, 0.11 (0.056-0.495) vs 0.04 (0.02-0.078) ug/L; P < .001. After multivariable analysis, PCT remained a significant independent predictor of CI-AKI (odds ratio 2.544; 95% CI [1.207-5.347]; P = .014) as well as age, women, white blood cell, hemoglobin, glomerular filtration rate, creatine kinase myocarial band, and SYNTAX score. In conclusion, serum PCT levels are independently associated with a risk of CI-AKI in patients with ACS who underwent urgent PCI. PMID- 25688118 TI - Dexamethasone downregulates caveolin-1 causing muscle atrophy via inhibited insulin signaling. AB - Glucocorticoids play a major role in the development of muscle atrophy in various medical conditions, such as cancer, burn injury, and sepsis, by inhibiting insulin signaling. In this study, we report a new pathway in which glucocorticoids reduce the levels of upstream insulin signaling components by downregulating the transcription of the gene encoding caveolin-1 (CAV1), a scaffolding protein present in the caveolar membrane. Treatment with the glucocorticoid dexamethasone (DEX) decreased CAV1 protein and Cav1 mRNA expression, with a concomitant reduction in insulin receptor alpha (IRalpha) and IR substrate 1 (IRS1) levels in C2C12 myotubes. On the basis of the results of promoter analysis using deletion mutants and site-directed mutagenesis a negative glucocorticoid-response element in the regulatory region of the Cav1 gene was identified, confirming that Cav1 is a glucocorticoid-target gene. Cav1 knockdown using siRNA decreased the protein levels of IRalpha and IRS1, and overexpression of Cav1 prevented the DEX-induced decrease in IRalpha and IRS1 proteins, demonstrating a causal role of Cav1 in the inhibition of insulin signaling. Moreover, injection of adenovirus expressing Cav1 into the gastrocnemius muscle of mice prevented DEX-induced atrophy. These results indicate that CAV1 is a critical regulator of muscle homeostasis, linking glucocorticoid signaling to the insulin signaling pathway, thereby providing a novel target for the prevention of glucocorticoid-induced muscle atrophy. PMID- 25688119 TI - Alisertib is active as single agent in recurrent atypical teratoid rhabdoid tumors in 4 children. AB - BACKGROUND: Aurora Kinase A (AURKA) encodes a protein that regulates the formation and stability of the mitotic spindle and is highly active in atypical teratoid rhabdoid tumors (ATRT) through loss of the INI1 tumor suppressor gene. Alisertib (MLN8237) inhibits AURKA in vitro and in vivo. Given the strong preclinical data supporting the use of alisertib for ATRT patients, we sought and obtained permission to use alisertib in single patient treatment plans for 4 recurrent pediatric ATRT patients. METHODS: Patients with recurrent or progressive ATRT received alisertib 80 mg/m(2) by mouth once daily for 7 days of a 21-day treatment cycle. Disease evaluation (MRI of brain and spine and lumbar puncture) was done after 2 cycles of alisertib and every 2-3 cycles thereafter for as long as the patients remained free from tumor progression. RESULTS: Four patients with median age of 2.5 years (range, 1.39-4.87 y) at diagnosis received alisertib 80 mg/m(2) by mouth once daily for 7 days of a 21-day treatment cycle, and all 4 patients had disease stabilization and/or regression after 3 cycles of alisertib therapy. Two patients continued to have stable disease regression for 1 and 2 years, respectively, on therapy. CONCLUSIONS: Single-agent alisertib produced marked and durable regression in disease burden, as detected by brain and spine MRI and by evaluation of spinal fluid cytology. Alisertib has moderate but manageable toxicities, and its chronic administration appears feasible in this pediatric population. These novel data support the incorporation of alisertib in future therapeutic trials for children with ATRT. PMID- 25688120 TI - Variation over time and interdependence between disease progression and death among patients with glioblastoma on RTOG 0525. AB - BACKGROUND: We assessed the longitudinal hazard characteristics for death and progression in patients with glioblastoma, evaluated the impact of prognostic factors and treatment on the hazard within different time intervals to determine if effects are time varying, and quantified the influence of progression on survival. METHODS: Among patients randomized to Radiation Therapy Oncology Group trial 0525, which compared dose-dense with standard-dose temozolomide, we estimated the hazards of death and treatment failure (death or progression) over time and their interdependence. RESULTS: The peak hazard of death was reached at around 16 months with a slow decline after that; the hazard of progression/death reached a peak at around 6 months and decreased dramatically thereafter. The survival advantages for patients with MGMT gene promoter methylation and recursive partitioning analysis class III were substantial in the first 2 years, but lessened thereafter. The progression-free survival benefit of dose-dense over standard-dose temozolomide occurred in the first 6 months (hazard ratio: 0.70; 95% CI: 0.58-0.86; P < .001), although it diminished thereafter. After adjusting for recursive partitioning analysis class and MGMT methylation status, the hazard ratio of death for patients who had progressed over nonprogressors was 6.59 (95% CI: 5.15-8.43; P < .001). CONCLUSION: After the peak hazard of death, a consistently high hazard remains, but it is lower than in the peak period. The progression hazard peak is earlier, and then hazard consistently declines. The rate of dying after disease progression is about 6.59 times the rate for nonprogressors, suggesting that progression-free survival may be a relevant clinical endpoint. PMID- 25688121 TI - The clinical meaning of obsessive-compulsive symptoms in bipolar disorder and schizophrenia. PMID- 25688122 TI - Bradycardia and reduced exercise capacity associated with chronic normotherpaeutic lithium therapy. PMID- 25688123 TI - Cyclical suicidal ideation following natalizumab infusion for multiple sclerosis. PMID- 25688124 TI - Personality characteristics in childhood and outcomes in adulthood: findings from a 30 year longitudinal study. AB - OBJECTIVE: Personality has been associated with a variety of outcomes in adulthood. Most of the literature related to mental state disorder and personality is cross sectional. METHODS: Data from more than 900 participants of the Christchurch Health and Development Study (CHDS) were examined. Extroversion and neuroticism were measured at 14 years old and social outcomes at age 30. The presence of mental state disorder between 18-30 years old was identified. Multiple potential confounders in childhood were included in the analysis. RESULTS: Neuroticism at fourteen was significantly correlated with multiple environmental exposures whereas extroversion had relatively few associations. Regression analysis found that neuroticism at 14 predicted depression, anxiety, suicidality and overall mental health problems at 30 as well as poor self-esteem but not relationship quality or wellbeing. Extroversion at 14 predicted alcohol and drug dependence and overall mental health problems, but also predicted improved social wellbeing, self-esteem and relationship quality at 30. CONCLUSIONS: In this analysis extroversion interacts with significantly fewer environmental factors than neuroticism in predicting adult outcomes. Neuroticism at 14 years predicts poorer mental health outcomes in adulthood. Extroversion in childhood may be a protective factor in the development of mental disorder other than alcohol use disorders. Extroverted adolescents have more positive social outcomes at 30 years. PMID- 25688129 TI - Hesitancies in saying 'No'. AB - OBJECTIVE: This paper aims to explore why staff, agencies and families, might be reluctant to use 'no' as a therapeutic manoeuvre. CONCLUSION: Various factors contribute to this hesitancy and when understood and acknowledged, may serve to return the clinician to the task at hand. PMID- 25688130 TI - Surveying clinician perceptions of risk assessment and management practices in mental health service provision. AB - OBJECTIVES: This study aimed to survey multidisciplinary mental health staff on their perceptions of risk assessment and management practices in a local health district in Sydney. METHODS: The research team developed the risk assessment and management survey (RAMS) which was distributed to staff across the district from November 2013 to January 2014. RESULTS: A total of 340 RAMS were distributed and 164 were returned (48% response rate). There was considerable agreement that risk assessment and management is essential to maintaining safety and delivering good mental health care, and respondents reported high levels of confidence in their judgement when carrying out such practices. Respondents identified organisational pressure in relation to risk assessment and management but also felt supported. However, 65% of respondents considered that there 'is good evidence that risk assessment and management practices are effective in reducing risk in mental health care', when this is not the case. CONCLUSION: The confidence that clinicians placed in risk assessment and management practices (despite an absence of evidence) is disconcerting. Given the dominance of risk assessment and management, health services mandating such practices have a duty to inform employees of the current evidence base for this approach in reducing risk. PMID- 25688131 TI - Thoru Pederson: Spotting novel roles for the nucleolus. PMID- 25688132 TI - In praise of other model organisms. AB - The early cell biological literature is the resting place of false starts and lost opportunities. Though replete with multiple studies of diverse organisms, a few of which served as foundations for several fields, most were not pursued, abandoned largely for technical reasons that are no longer limiting. The time has come to revisit the old literature and to resurrect the organisms that are buried there, both to uncover new mechanisms and to marvel at the richness of the cellular world. PMID- 25688133 TI - The F-BAR Cdc15 promotes contractile ring formation through the direct recruitment of the formin Cdc12. AB - In Schizosaccharomyces pombe, cytokinesis requires the assembly and constriction of an actomyosin-based contractile ring (CR). Nucleation of F-actin for the CR requires a single formin, Cdc12, that localizes to the cell middle at mitotic onset. Although genetic requirements for formin Cdc12 recruitment have been determined, the molecular mechanisms dictating its targeting to the medial cortex during cytokinesis are unknown. In this paper, we define a short motif within the N terminus of Cdc12 that binds directly to the F-BAR domain of the scaffolding protein Cdc15. Mutations preventing the Cdc12-Cdc15 interaction resulted in reduced Cdc12, F-actin, and actin-binding proteins at the CR, which in turn led to a delay in CR formation and sensitivity to other perturbations of CR assembly. We conclude that Cdc15 contributes to CR formation and cytokinesis via formin Cdc12 recruitment, defining a novel cytokinetic function for an F-BAR domain. PMID- 25688134 TI - Two Polo-like kinase 4 binding domains in Asterless perform distinct roles in regulating kinase stability. AB - Plk4 (Polo-like kinase 4) and its binding partner Asterless (Asl) are essential, conserved centriole assembly factors that induce centriole amplification when overexpressed. Previous studies found that Asl acts as a scaffolding protein; its N terminus binds Plk4's tandem Polo box cassette (PB1-PB2) and targets Plk4 to centrioles to initiate centriole duplication. However, how Asl overexpression drives centriole amplification is unknown. In this paper, we investigated the Asl Plk4 interaction in Drosophila melanogaster cells. Surprisingly, the N-terminal region of Asl is not required for centriole duplication, but a previously unidentified Plk4-binding domain in the C terminus is required. Mechanistic analyses of the different Asl regions revealed that they act uniquely during the cell cycle: the Asl N terminus promotes Plk4 homodimerization and autophosphorylation during interphase, whereas the Asl C terminus stabilizes Plk4 during mitosis. Therefore, Asl affects Plk4 in multiple ways to regulate centriole duplication. Asl not only targets Plk4 to centrioles but also modulates Plk4 stability and activity, explaining the ability of overexpressed Asl to drive centriole amplification. PMID- 25688135 TI - Telomeres and centromeres have interchangeable roles in promoting meiotic spindle formation. AB - Telomeres and centromeres have traditionally been considered to perform distinct roles. During meiotic prophase, in a conserved chromosomal configuration called the bouquet, telomeres gather to the nuclear membrane (NM), often near centrosomes. We found previously that upon disruption of the fission yeast bouquet, centrosomes failed to insert into the NM at meiosis I and nucleate bipolar spindles. Hence, the trans-NM association of telomeres with centrosomes during prophase is crucial for efficient spindle formation. Nonetheless, in approximately half of bouquet-deficient meiocytes, spindles form properly. Here, we show that bouquet-deficient cells can successfully undergo meiosis using centromere-centrosome contact instead of telomere-centrosome contact to generate spindle formation. Accordingly, forced association between centromeres and centrosomes fully rescued the spindle defects incurred by bouquet disruption. Telomeres and centromeres both stimulate focal accumulation of the SUN domain protein Sad1 beneath the centrosome, suggesting a molecular underpinning for their shared spindle-generating ability. Our observations demonstrate an unanticipated level of interchangeability between the two most prominent chromosomal landmarks. PMID- 25688136 TI - Mitofusin 2 is required to maintain mitochondrial coenzyme Q levels. AB - Mitochondria form a dynamic network within the cell as a result of balanced fusion and fission. Despite the established role of mitofusins (MFN1 and MFN2) in mitochondrial fusion, only MFN2 has been associated with metabolic and neurodegenerative diseases, which suggests that MFN2 is needed to maintain mitochondrial energy metabolism. The molecular basis for the mitochondrial dysfunction encountered in the absence of MFN2 is not understood. Here we show that loss of MFN2 leads to impaired mitochondrial respiration and reduced ATP production, and that this defective oxidative phosphorylation process unexpectedly originates from a depletion of the mitochondrial coenzyme Q pool. Our study unravels an unexpected and novel role for MFN2 in maintenance of the terpenoid biosynthesis pathway, which is necessary for mitochondrial coenzyme Q biosynthesis. The reduced respiratory chain function in cells lacking MFN2 can be partially rescued by coenzyme Q10 supplementation, which suggests a possible therapeutic strategy for patients with diseases caused by mutations in the Mfn2 gene. PMID- 25688137 TI - Gene of the month: PIK3CA. AB - PIK3CA encodes the p110alpha catalytic subunit of phosphatidylinositol 3-kinase (PI3K) which through its role in the PI3K/Akt pathway is important for the regulation of important cellular functions such as proliferation, metabolism and protein synthesis, angiogenesis and apoptosis. Mutations in PIK3CA are known to be involved in a wide range of human cancers and mutant PIK3CA is thought to act as an oncogene. The specific PIK3CA inhibitor, NVP-BYL719, has displayed promising results in cancer therapy and is currently under clinical trials. Furthermore, PI3K regulates autophagy, a cellular process that recycles proteins and organelles through lysosomal degradation and has recently been recognised as an attractive therapeutic target due to its pro- and anti-cancer properties. Several studies have attempted to investigate the effects of combining the inhibition of both PI3K and autophagy in cancer therapy, and an in vivo model has demonstrated that the combined use of a concomitant PI3K and autophagy inhibitor induced apoptosis in glioma cells. PMID- 25688138 TI - Clinical utility of anti-Xa monitoring and differential sensitivity of prothrombin time assays: an illustrated case report. PMID- 25688140 TI - What's in it for me? The meaning of involvement in a self-advocacy group for six people with intellectual disabilities. AB - BACKGROUND: This article explores the experiences of six people with intellectual disabilities in the context of a self-advocacy group, identifying the benefits and difficulties of being part of the group. MATERIALS AND METHODS: Six adults with intellectual disabilities were interviewed about their experiences. Each individual took part in two individual and two group interviews. The transcripts were analysed using thematic analysis. RESULTS: Analysis revealed four themes, namely, being part of the group, self-esteem, self-determination and empowerment. CONCLUSION: Being part of the group is central to the experience of self-esteem, self-development and empowerment. Responses allow the exploration of the interrelationship between individual, group and community. Consideration is given to models of disability and the evidence base in relation to personal and political outcomes of self-advocacy. Links are made with developing a sense of self, self-determination, interpersonal learning and building resilience. Implications for practice are discussed. PMID- 25688141 TI - Photo quiz. A 32-year-old man with HIV and chronic diarrhea. PMID- 25688143 TI - Safety of ventricular tachycardia ablation in clinical practice: findings from 9699 hospital discharge records. AB - BACKGROUND: Outcomes of ventricular tachycardia (VT) ablation have been described in clinical trials and single-center studies. We assessed the safety of VT ablation in clinical practice. METHODS AND RESULTS: Using administrative hospitalization data between 1994 and 2011, we identified hospitalizations with primary diagnosis of VT (International Classification of Diseases-9 Clinical Modification code: 427.1) and cardiac ablation (International Classification of Diseases-9 Clinical Modification code: 37.34). We quantified in-hospital adverse events (AEs), including death, stroke, intracerebral hemorrhage, pericardial complications, hematoma or hemorrhage, blood transfusion, or cardiogenic shock. Secondary outcomes included major AEs (stroke, tamponade, or death) and death. Multivariable mixed effects models identified patient and hospital characteristics associated with AEs. Of 9699 hospitalizations with VT ablations (age, 56.5 +/- 17.6; 60.1% men), AEs were reported in 825 (8.5%), major AEs in 295 (3.0%), and death in 110 (1.1%). Heart failure had the strongest association with death (odds ratio, 5.52; 95% confidence interval, 2.97-10.3) and major AE (odds ratio, 2.99; 95% confidence interval, 2.15-4.16). Anemia (odds ratio, 4.84; 95% confidence interval, 3.79-6.19) and unscheduled admission (odds ratio, 1.64; 95% confidence interval, 1.37-1.97) were associated with AEs. During the study period, incidence of AEs increased from 9.2% to 12.8% as did the burden of AE risk factors (0.034 patient/y; P < 0.001). Hospital volume > 25 cases/y was associated with fewer AEs compared with lower volume centers (6.4% versus 8.8%; P = 0.008). CONCLUSIONS: VT ablation-associated AE rates in clinical practice are similar to those reported in the literature. Over time rates have increased as have the number of AE risk factors per patient. Ablations done electively and at hospitals with higher procedural volume are associated with lower incidence of AEs. PMID- 25688144 TI - Microdomain switch of cGMP-regulated phosphodiesterases leads to ANP-induced augmentation of beta-adrenoceptor-stimulated contractility in early cardiac hypertrophy. AB - RATIONALE: Cyclic nucleotides are second messengers that regulate cardiomyocyte function through compartmentalized signaling in discrete subcellular microdomains. However, the role of different microdomains and their changes in cardiac disease are not well understood. OBJECTIVE: To directly visualize alterations in beta-adrenergic receptor-associated cAMP and cGMP microdomain signaling in early cardiac disease. METHODS AND RESULTS: Unexpectedly, measurements of cell shortening revealed augmented beta-adrenergic receptor stimulated cardiomyocyte contractility by atrial natriuretic peptide/cGMP signaling in early cardiac hypertrophy after transverse aortic constriction, which was in sharp contrast to well-documented beta-adrenergic and natriuretic peptide signaling desensitization during chronic disease. Real-time cAMP analysis in beta1- and beta2-adrenergic receptor-associated membrane microdomains using a novel membrane-targeted Forster resonance energy transfer-based biosensor transgenically expressed in mice revealed that this unexpected atrial natriuretic peptide effect is brought about by spatial redistribution of cGMP-sensitive phosphodiesterases 2 and 3 between both receptor compartments. Functionally, this led to a significant shift in cGMP/cAMP cross-talk and, in particular, to cGMP driven augmentation of contractility in vitro and in vivo. CONCLUSIONS: Redistribution of cGMP-regulated phosphodiesterases and functional reorganization of receptor-associated microdomains occurs in early cardiac hypertrophy, affects cGMP-mediated contractility, and might represent a previously not recognized therapeutically relevant compensatory mechanism to sustain normal heart function. PMID- 25688145 TI - Performance metrics as drivers of quality: getting to second gear. PMID- 25688146 TI - Doing the right things and doing them the right way: association between hospital guideline adherence, dosing safety, and outcomes among patients with acute coronary syndrome. AB - BACKGROUND: Performance metrics currently focus on the measurement of the application of guideline-indicated medications without considering the appropriate dosing of these drugs. METHODS AND RESULTS: We studied 39 291 patients from the Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the ACC/AHA Guidelines (CRUSADE) registry with non-ST-segment elevation acute coronary syndromes. We evaluated hospital variability in the composite use of American College of Cardiology/American Heart Association guideline-recommended therapies (adherence) and the proportion of treated patients with the recommended dose of heparins or a glycoprotein IIb/IIIa antagonist (safety), and its association with risk-adjusted in-hospital mortality and bleeding. The rates of composite guideline adherence (median, 85%; 25th, 75th percentile, 82, 88) and antithrombotic dosing safety (median, 53%; 25th, 75th percentile, 45%, 60%) varied among hospitals. Correlation between hospital composite adherence and safety metrics was significant but low (r=0.16, P=0.008). Risk-adjusted in-hospital mortality was inversely related to both guideline adherence (odds ratio-10% increment, 0.80; 95% confidence interval, 0.67-0.94) and safety metrics (odds ratio-10% increment, 0.90; 95% confidence interval, 0.83-0.98). Safety was inversely related to major bleeding (adjusted odds ratio-10% increment, 0.93; 95% confidence interval, 0.87 0.98). In comparison with hospitals with low adherence and safety (<=median performance) metrics, those with mixed performance metrics (high adherence and low safety, low adherence and high safety) had intermediate risk-adjusted mortality rates, whereas hospitals with above-average performance on both metrics (>median performance) had a trend for lowest risk adjusted mortality rates (odds ratio 0.83; 95% confidence interval, 0.68-1.01). Hospitals with high safety had lower bleeding rates in comparison to those with low safety. CONCLUSIONS: Guideline adherence and dosing safety appeared to provide independent and complementary information on hospital bleeding and mortality, supporting the need for broader metrics of quality that should include measures of both guideline based care and safety. PMID- 25688147 TI - Physical activity: can there be too much of a good thing? PMID- 25688148 TI - Frequent physical activity may not reduce vascular disease risk as much as moderate activity: large prospective study of women in the United Kingdom. AB - BACKGROUND: Although physical activity has generally been associated with reduced risk of vascular disease, there is limited evidence about the effects of the frequency and duration of various activities on the incidence of particular types of vascular disease. METHODS AND RESULTS: In 1998, on average, 1.1 million women without prior vascular disease reported their frequency of physical activity and many other personal characteristics. Three years later, they were asked about hours spent walking, cycling, gardening, and housework each week. Women were followed by record linkage to National Health Service cause-specific hospital admissions and death records. Cox regression was used to calculate adjusted relative risks for first vascular events in relation to physical activity. During an average of 9 years follow-up, 49,113 women had a first coronary heart disease event, 17,822 had a first cerebrovascular event, and 14,550 had a first venous thromboembolic event. In comparison with inactive women, those reporting moderate activity had significantly lower risks of all 3 conditions (P<0.001 for each). However, women reporting strenuous physical activity daily had higher risks of coronary heart disease (P=0.002), cerebrovascular disease (P<0.001), and venous thromboembolic events (P<0.001) than those reporting doing such activity 2 to 3 times per week. Risks did not differ between hemorrhagic and ischemic stroke, or between venous thromboembolic events with or without pulmonary embolism. CONCLUSIONS: Moderate physical activity is associated with a lower risk of coronary heart disease, venous thromboembolic event, and cerebrovascular disease than inactivity. However, among active women, there is little to suggest progressive reductions in risk of vascular diseases with increasing frequency of activity. PMID- 25688149 TI - Primary aortic sarcoma: a rare but critical cause of stroke. PMID- 25688150 TI - MRI of toxic leukoencephalopathy syndrome associated with methylenedioxymethamphetamine. PMID- 25688151 TI - The global burden of neurologic diseases. PMID- 25688152 TI - High-dose methotrexate with or without rituximab in newly diagnosed primary CNS lymphoma. PMID- 25688153 TI - Clinical reasoning: transient cervical cord swelling in monomelic amyotrophy. PMID- 25688154 TI - Pearls & Oy-sters: fragile X tremor/ataxia syndrome: a diagnostic dilemma. PMID- 25688155 TI - Residency training: bilateral facial nerve palsies after a suicide attempt by hanging. PMID- 25688156 TI - Clinical reasoning: a 51-year-old woman with acute foot drop. PMID- 25688157 TI - Molecular Changes Associated with Acquired Resistance to Crizotinib in ROS1 Rearranged Non-Small Cell Lung Cancer. AB - PURPOSE: Although ROS1-rearranged non-small cell lung cancer (NSCLC) is sensitive to crizotinib, development of resistance is inevitable. Here, we identified molecular alterations in crizotinib-resistant tumors from two NSCLC patients with the CD74-ROS1 rearrangement, and in HCC78 cells harboring SLC34A2-ROS1 that showed resistance to crizotinib (HCC78CR cells). EXPERIMENTAL DESIGN: ROS1 kinase domain mutations were examined in fresh tumor tissues from two NSCLC patients and HCC78CR1-3 cells by direct sequencing. Ba/F3 cells expressing ROS1 secondary mutations were constructed to evaluate resistance to crizotinib. An upregulated pathway was identified using phospho-receptor tyrosine kinase array, EGFR signaling antibody array, and RNA sequencing (RNA-seq). Cell proliferation and ROS1 downstream signaling pathways were compared between HCC78 and HCC78CR1-3 cells. RESULTS: The ROS1 G2032R mutation was identified in crizotinib-resistant tumors from one patient. Furthermore, HCC78CR1 and CR2 cells harbored a novel ROS1 L2155S mutation (73.3% and 76.2%, respectively). ROS1 G2032R and L2155S mutations conferred resistance to crizotinib in Ba/F3 cells. Evidence of epithelial-to-mesenchymal transition with downregulated E-cadherin and upregulated vimentin was observed in HCC78CR1-2 cells and in the other patient. RNA-seq and EGFR signaling antibody array revealed that the EGFR pathway was significantly upregulated in HCC78CR3 versus HCC78 cells. Cells with the ROS1 mutation and upregulated EGFR were sensitive to foretinib, an inhibitor of c-MET, VEGFR2, and ROS1 and irreversible EGFR tyrosine kinase inhibitors plus crizotinib, respectively. CONCLUSIONS: Molecular changes associated with acquired crizotinib resistance in ROS1-rearranged NSCLC are heterogeneous, including ROS1 tyrosine kinase mutations, EGFR activation, and epithelial-to-mesenchymal transition. PMID- 25688158 TI - Selective Inhibition of HDAC1 and HDAC2 as a Potential Therapeutic Option for B ALL. AB - PURPOSE: Histone deacetylase inhibitors (HDACi) have recently emerged as efficacious therapies that target epigenetic mechanisms in hematologic malignancies. One such hematologic malignancy, B-cell acute lymphoblastic leukemia (B-ALL), may be highly dependent on epigenetic regulation for leukemia development and maintenance, and thus sensitive to small-molecule inhibitors that target epigenetic mechanisms. EXPERIMENTAL DESIGN: A panel of B-ALL cell lines was tested for sensitivity to HDACi with varying isoform sensitivity. Isoform specific shRNAs were used as further validation of HDACs as relevant therapeutic targets in B-ALL. Mouse xenografts of B-cell malignancy-derived cell lines and a pediatric B-ALL were used to demonstrate pharmacologic efficacy. RESULTS: Nonselective HDAC inhibitors were cytotoxic to a panel of B-ALL cell lines as well as to xenografted human leukemia patient samples. Assessment of isoform specific HDACi indicated that targeting HDAC1-3 with class I HDAC-specific inhibitors was sufficient to inhibit growth of B-ALL cell lines. Furthermore, shRNA-mediated knockdown of HDAC1 or HDAC2 resulted in growth inhibition in these cells. We then assessed a compound that specifically inhibits only HDAC1 and HDAC2. This compound suppressed growth and induced apoptosis in B-ALL cell lines in vitro and in vivo, whereas it was far less effective against other B-cell derived malignancies. CONCLUSIONS: Here, we show that HDAC inhibitors are a potential therapeutic option for B-ALL, and that a more specific inhibitor of HDAC1 and HDAC2 could be therapeutically useful for patients with B-ALL. PMID- 25688159 TI - Targeted T-cell Therapy in Stage IV Breast Cancer: A Phase I Clinical Trial. AB - PURPOSE: This study reports a phase I immunotherapy trial in 23 women with metastatic breast cancer consisting of eight infusions of anti-CD3 * anti-HER2 bispecific antibody (HER2Bi) armed anti-CD3-activated T cells (ATC) in combination with low-dose IL-2 and granulocyte-macrophage colony-stimulating factor to determine safety, maximum tolerated dose (MTD), technical feasibility, T-cell trafficking, immune responses, time to progression, and overall survival (OS). EXPERIMENTAL DESIGN: ATC were expanded from leukapheresis product using IL2 and anti-CD3 monoclonal antibody and armed with HER2Bi. In 3+3 dose escalation design, groups of 3 patients received 5, 10, 20, or 40 * 10(9) armed ATC (aATC) per infusion. RESULTS: There were no dose-limiting toxicities and the MTD was not defined. It was technically feasible to grow 160 * 10(9) ATC from a single leukapheresis. aATC persisted in the blood for weeks and trafficked to tumors. Infusions of aATC induced anti-breast cancer responses and increases in immunokines. At 14.5 weeks after enrollment, 13 of 22 (59.1%) evaluable patients had stable disease and 9 of 22 (40.9%) had progressive disease. The median OS was 36.2 months for all patients, 57.4 months for HER2 3+ patients, and 27.4 months for HER2 0-2+ patients. CONCLUSIONS: Targeting HER2(+) and HER2(-) tumors with aATC infusions induced antitumor responses, increases in Th1 cytokines, and IL12 serum levels that suggest that aATC infusions vaccinated patients against their own tumors. These results provide a strong rationale for conducting phase II trials. PMID- 25688160 TI - Orchestration and Prognostic Significance of Immune Checkpoints in the Microenvironment of Primary and Metastatic Renal Cell Cancer. AB - PURPOSE: Clear cell renal cell carcinoma (ccRCC) has shown durable responses to checkpoint blockade therapies. However, important gaps persist in the understanding of its immune microenvironment. This study aims to investigate the expression and prognostic significance of immune checkpoints in primary and metastatic ccRCC, in relation with mature dendritic cells (DC) and T-cell densities. EXPERIMENTAL DESIGN: We investigated the infiltration and the localization of CD8(+) T cells and mature DC, and the expression of immune checkpoints (PD-1, LAG-3, PD-L1, and PD-L2) in relation with prognosis, in 135 primary ccRCC tumors and 51 ccRCC lung metastases. RNA expression data for 496 primary ccRCC samples were used as confirmatory cohort. RESULTS: We identify two groups of tumors with extensive CD8(+) T-cell infiltrates. One group, characterized by high expression of immune checkpoints in the absence of fully functional mature DC, is associated with increased risk of disease progression. The second group, characterized by low expression of immune checkpoints and localization of mature DC in peritumoral immune aggregates (tertiary lymphoid structures), is associated with good prognosis. CONCLUSIONS: The expression of the immune checkpoints and the localization of DC in the tumor microenvironment modulate the clinical impact of CD8(+) T cells in ccRCC. PMID- 25688161 TI - Correction. PMID- 25688162 TI - Review of the British Thoracic Society Winter Meeting 2014, 3-5 December, London, UK. AB - The British Thoracic Society Winter Meeting 2014 is reviewed in this article. This annual scientific meeting attracted its largest number of delegates ever and over 3 days in December up-to-date respiratory research was presented and current thinking in respiratory science and clinical academia was discussed. This article reviews a number of symposia and selected abstract presentations from the meeting. PMID- 25688165 TI - Health, healthcare access, and use of traditional versus modern medicine in remote Peruvian Amazon communities: a descriptive study of knowledge, attitudes, and practices. AB - There is an urgent need for healthcare research, funding, and infrastructure in the Peruvian Amazon. We performed a descriptive study of health, health knowledge and practice, and healthcare access of 13 remote communities of the Manati and Amazon Rivers in northeastern Peru. Eighty-five adults attending a medical boat service were interviewed to collect data on socioeconomic position, health, diagnosed illnesses, pain, healthcare access, and traditional versus modern medicine use. In this setting, poverty and gender inequality were prevalent, and healthcare access was limited by long distances to the health post and long waiting times. There was a high burden of reported pain (mainly head and musculoskeletal) and chronic non-communicable diseases, such as hypertension (19%). Nearly all participants felt that they did not completely understand their diagnosed illnesses and wanted to know more. Participants preferred modern over traditional medicine, predominantly because of mistrust or lack of belief in traditional medicine. Our findings provide novel evidence concerning transitional health beliefs, hidden pain, and chronic non-communicable disease prevalence in marginalized communities of the Peruvian Amazon. Healthcare provision was limited by a breach between health education, knowledge, and access. Additional participatory research with similar rural populations is required to inform regional healthcare policy and decision-making. PMID- 25688166 TI - Sociocultural and economic dimensions of Rift Valley fever. AB - Health researchers have advocated for a cross-disciplinary approach to the study and prevention of infectious zoonotic diseases, such as Rift Valley Fever. It is believed that this approach can help bring out the social determinants and effects of the zoonotic diseases for the design of appropriate interventions and public health policy. A comprehensive literature review using a systematic search strategy was undertaken to explore the sociocultural and economic factors that influence the transmission and spread of Rift Valley Fever. Although the findings reveal a paucity of social research on Rift Valley Fever, they suggest that livestock sacrificial rituals, food preparation and consumption practices, gender roles, and inadequate resource base for public institutions are the key factors that influence the transmission. It is concluded that there is need for cross disciplinary studies to increase the understanding of Rift Valley Fever and facilitate appropriate and timely response and mitigation measures. PMID- 25688172 TI - Should all stationary objects move when hit? Developments in infants' causal and statistical expectations about collision events. AB - Four experiments examined 8- and 9-month-old infants' expectations about collision events. The infants saw test events in which a small cylinder rolled down a ramp and hit one of several different boxes. These boxes varied in width and height and always remained stationary when hit. The results revealed two separate developments. The first involved infants' knowledge of the variables relevant to collision events. At 8 months, the infants expected all of the boxes to move when hit, regardless of their sizes; at 9 months, the infants began to take into account the size of the boxes to predict whether they should move when hit. The second development concerned infants' ability to generate explanations for outcomes that violated their collision knowledge. At both ages, upon observing that a box with a salient vertical dimension did not move when hit, the infants apparently concluded that the box must be one of those objects we term pillars-vertical objects that are attached at one or both ends to adjacent surfaces. At 8 months, the infants considered any vertical box as a potential pillar; at 9 months, the infants considered only boxes that were both vertical and narrow as potential pillars. The development of infants' knowledge about collision events is thus one that is complex and protracted and weaves together many separate developments. PMID- 25688173 TI - Fetal Cocaine Exposure: Neurologic Effects and Sensory-Motor Delays. AB - Research on animal models demonstrates that fetal cocaine exposure results in neurologic deficits in memory and learning. Although drug effects on human infants are difficult to separate from other environmental influences of a drug using lifestyle, studies suggest that infants exposed to cocaine in utero have reduced growth, delays in sensory-motor development, attentional deficits, and depressed responsivity to social stimulation. Standard interventions to promote behavioral state regulation in affected infants may be helpful when parents are capable of participating. PMID- 25688174 TI - Next generation sequencing to determine the cystic fibrosis mutation spectrum in Palestinian population. AB - An extensive molecular analysis of the CF transmembrane regulator (CFTR) gene was performed to establish the CFTR mutation spectrum and frequencies in the Palestinian population, which can be considered as an understudied population. We used a targeted Next Generation Sequencing approach to sequence the entire coding region and the adjacent sequences of the CFTR gene combined with MLPA analysis of 60 unrelated CF patients. Eighteen different CF-causing mutations, including one previously undescribed mutation p.(Gly1265Arg), were identified. The overall detection rate is up to 67%, and when we consider only CF patients with sweat chloride concentrations >70 mEq/L, we even have a pickup rate of 92%. Whereas p.(Phe508del) is the most frequent allele (35% of the positive cases), 3 other mutations c.2988+1Kbdel8.6Kb, c.1393-1G>A, and p.(Gly85Glu) showed frequencies higher than 5% and a total of 9 mutations account for 84% of the mutations. This limited spectrum of CF mutations is in agreement with the homozygous ethnic origin of the Palestinian population. The relative large portion of patients without a mutation is most likely due to clinical misdiagnosis. Our results will be important in the development of an adequate molecular diagnostic test for CF in Palestine. PMID- 25688175 TI - Human leucocyte antigen-G (HLA-G) and its murine functional homolog Qa2 in the Trypanosoma cruzi Infection. AB - Genetic susceptibility factors, parasite strain, and an adequate modulation of the immune system seem to be crucial for disease progression after Trypanosoma cruzi infection. HLA-G and its murine functional homolog Qa2 have well-recognized immunomodulatory properties. We evaluated the HLA-G 3' untranslated region (3'UTR) polymorphic sites (associated with mRNA stability and target for microRNA binding) and HLA-G tissue expression (heart, colon, and esophagus) in patients presenting Chagas disease, stratified according to the major clinical variants. Further, we investigated the transcriptional levels of Qa2 and other pro- and anti-inflammatory genes in affected mouse tissues during T. cruzi experimental acute and early chronic infection induced by the CL strain. Chagas disease patients exhibited differential HLA-G 3'UTR susceptibility allele/genotype/haplotype patterns, according to the major clinical variant (digestive/cardiac/mixed/indeterminate). HLA-G constitutive expression on cardiac muscle and colonic cells was decreased in Chagasic tissues; however, no difference was observed for Chagasic and non-Chagasic esophagus tissues. The transcriptional levels of Qa2 and other anti and proinflammatory (CTLA-4, PDCD1, IL-10, INF-gamma, and NOS-2) genes were induced only during the acute T. cruzi infection in BALB/c and C57BL/6 mice. We present several lines of evidence indicating the role of immunomodulatory genes and molecules in human and experimental T. cruzi infection. PMID- 25688176 TI - Genetic deletion of soluble epoxide hydrolase attenuates inflammation and fibrosis in experimental obstructive nephropathy. AB - Soluble epoxide hydrolase (sEH) is abundantly expressed in kidney and plays a potent role in regulating inflammatory response in inflammatory diseases. However, the role of sEH in progression of chronic kidney diseases such as obstructive nephropathy is still elusive. In current study, wild-type (WT) and sEH deficient (sEH (-/-)) mice were subjected to the unilateral ureteral obstruction (UUO) surgery and the kidney injury was evaluated by histological examination, western blotting, and ELISA. The protein level of sEH in kidney was increased in UUO-treated mice group compared to nonobstructed group. Additionally, UUO-induced hydronephrosis, renal tubular injury, inflammation, and fibrosis were ameliorated in sEH (-/-) mice with the exception of glomerulosclerosis. Moreover, sEH (-/-) mice with UUO showed lower levels of inflammation-related and fibrosis-related protein such as monocyte chemoattractant protein-1, macrophage inflammatory protein-2, interleukin-1beta (IL-1beta), IL-6, inducible nitric oxide synthase, collagen 1A1, and alpha-actin. The levels of superoxide anion radical and hydrogen peroxide as well as NADPH oxidase activity were also decreased in UUO kidneys of sEH (-/-) mice compared to that observed in WT mice. Collectively, our findings suggest that sEH plays an important role in the pathogenesis of experimental obstructive nephropathy and may be a therapeutic target for the treatment of obstructive nephropathy-related diseases. PMID- 25688177 TI - Supplementation with red palm oil increases beta-carotene and vitamin A blood levels in patients with cystic fibrosis. AB - Patients with cystic fibrosis (CF) show decreased plasma concentrations of antioxidants due to malabsorption of lipid soluble vitamins and consumption by chronic pulmonary inflammation. beta-Carotene is a major source of retinol and therefore is of particular significance in CF. The aim of this study was to investigate the effect of daily intake of red palm oil (RPO) containing high amounts of beta-carotene on the antioxidant levels in CF patients. Sixteen subjects were recruited and instructed to enrich their food with 2 to 3 tablespoons of RPO (~1.5 mg of beta-carotene) daily over 8 weeks. Carotenoids, retinol, and alpha-tocopherol were measured in plasma at baseline and after intervention. In addition beta-carotene, lycopene, alpha-tocopherol, and vitamin C were measured in buccal mucosa cells (BMC) to determine the influence of RPO on antioxidant tissue levels. Eleven subjects completed the study properly. Plasma beta-carotene, retinol, and alpha-carotene of these patients increased, but plasma concentrations of other carotenoids and alpha-tocopherol as well as concentrations of beta-carotene, lycopene, alpha-tocopherol, and vitamin C in BMC remained unchanged. Since RPO on a daily basis did not show negative side effects the data suggest that RPO may be used to elevate plasma beta-carotene in CF. PMID- 25688178 TI - Recombinant cyclodextrinase from Thermococcus kodakarensis KOD1: expression, purification, and enzymatic characterization. AB - A gene encoding a cyclodextrinase from Thermococcus kodakarensis KOD1 (CDase-Tk) was identified and characterized. The gene encodes a protein of 656 amino acid residues with a molecular mass of 76.4 kDa harboring four conserved regions found in all members of the alpha-amylase family. A recombinant form of the enzyme was purified by ion-exchange chromatography, and its catalytic properties were examined. The enzyme was active in a broad range of pH conditions (pHs 4.0-10.0), with an optimal pH of 7.5 and a temperature optimum of 65 degrees C. The purified enzyme preferred to hydrolyze beta-cyclodextrin (CD) but not alpha- or gamma-CD, soluble starch, or pullulan. The final product from beta-CD was glucose. The V max and K m values were 3.13 +/- 0.47 U mg(-1) and 2.94 +/- 0.16 mg mL(-1) for beta-CD. The unique characteristics of CDase-Tk with a low catalytic temperature and substrate specificity are discussed, and the starch utilization pathway in a broad range of temperatures is also proposed. PMID- 25688179 TI - Assays of different aspects of haemostasis - what do they measure? AB - Haemostasis is a complex process affected by many factors including both cellular and plasma components. It is a multistep process starting with platelet adhesion to damaged endothelium and ending in clot fibrinolysis. There are several methods available to study different aspects of haemostasis including adhesion, aggregation, coagulation and fibrinolysis. This review describes the different methods, what aspects of haemostasis they measure and their limitations. Methods discussed include methods to study adhesion (e.g. PFA-100, cone and platelet(let) analyzer and perfusion chambers) and aggregation (e.g. Multiplate, VerifyNow and Plateletworks). Furthermore the principles behind viscoelastic haemostatic assays are presented as well as methods that can analyse aspects of haemostasis in plasma or platelet-rich-plasma samples (thrombin generation, overall haemostasis potential and Thrombodynamics Analyzer). PMID- 25688180 TI - Time-resolved insight into the photosensitized generation of singlet oxygen in endoperoxides. AB - A synergistic approach combining high-level multiconfigurational static calculations and full-dimensional ab initio surface hopping dynamics has been employed to gain insight into the photochemistry of endoperoxides. Electronic excitation of endoperoxides triggers two competing pathways, cycloreversion and O O homolysis, that result in the generation of singlet oxygen and oxygen diradical rearrangement products. Our results reveal that cycloreversion or the rupture of the two C-O bonds occurs via an asynchronous mechanism that can lead to the population of a ground-state intermediate showing a single C-O bond. Furthermore, singlet oxygen is directly generated in its most stable excited electronic state 1Deltag. The triplet states do not intervene in this mechanism, as opposed to the O-O homolysis where the exchange of population between the singlet and triplet manifolds is remarkable. In line with recent experiments performed on the larger anthracene-9,10-endoperoxide, upon excitation to the spectroscopic pipi* electronic states, the primary photoreactive pathway that governs deactivation of endoperoxides is O-O homolysis with a quantum yield of 65%. PMID- 25688181 TI - Deciphering solution scattering data with experimentally guided molecular dynamics simulations. AB - Time-resolved X-ray solution scattering is an increasingly popular method to measure conformational changes in proteins. Extracting structural information from the resulting difference X-ray scattering data is a daunting task. We present a method in which the limited but precious information encoded in such scattering curves is combined with the chemical knowledge of molecular force fields. The molecule of interest is then refined toward experimental data using molecular dynamics simulation. Therefore, the energy landscape is biased toward conformations that agree with experimental data. We describe and verify the method, and we provide an implementation in GROMACS. PMID- 25688183 TI - Neural competition via lateral inhibition between decision processes and not a STOP signal accounts for the antisaccade performance in healthy and schizophrenia subjects. PMID- 25688182 TI - Perceptual factors contribute more than acoustical factors to sound localization abilities with virtual sources. AB - Human sound localization abilities rely on binaural and spectral cues. Spectral cues arise from interactions between the sound wave and the listener's body (head related transfer function, HRTF). Large individual differences were reported in localization abilities, even in young normal-hearing adults. Several studies have attempted to determine whether localization abilities depend mostly on acoustical cues or on perceptual processes involved in the analysis of these cues. These studies have yielded inconsistent findings, which could result from methodological issues. In this study, we measured sound localization performance with normal and modified acoustical cues (i.e., with individual and non individual HRTFs, respectively) in 20 naive listeners. Test conditions were chosen to address most methodological issues from past studies. Procedural training was provided prior to sound localization tests. The results showed no direct relationship between behavioral results and an acoustical metrics (spectral-shape prominence of individual HRTFs). Despite uncertainties due to technical issues with the normalization of the HRTFs, large acoustical differences between individual and non-individual HRTFs appeared to be needed to produce behavioral effects. A subset of 15 listeners then trained in the sound localization task with individual HRTFs. Training included either visual correct answer feedback (for the test group) or no feedback (for the control group), and was assumed to elicit perceptual learning for the test group only. Few listeners from the control group, but most listeners from the test group, showed significant training-induced learning. For the test group, learning was related to pre-training performance (i.e., the poorer the pre-training performance, the greater the learning amount) and was retained after 1 month. The results are interpreted as being in favor of a larger contribution of perceptual factors than of acoustical factors to sound localization abilities with virtual sources. PMID- 25688184 TI - Ultradian oscillation in expression of four melatonin receptor subtype genes in the pineal gland of the grass puffer, a semilunar-synchronized spawner, under constant darkness. AB - Melatonin receptor gene expression as well as melatonin synthesis and secretion activities were examined in the pineal gland of the grass puffer, which exhibits unique lunar/tidal cycle-synchronized mass spawing: spawning occurs before high tide on the day of spring tide during spawing season. Melatonin synthesizing activity was assessed by the abundance of arylalkylamine N-acetyltransferase 2 (AANAT2) mRNA. The amount of aanat2 mRNA was low during light phase and initiated to increase after the light was turned off. The secretion of melatonin from primary pineal organ culture was stimulated after the light was turned off and ceased immediately after the light was turned on. The expression levels of four melatonin receptor subtype genes (mel 1a 1.4, mel 1a 1.7, mel1b, and mel1c) showed synchronous variations, and the levels tended to be high during the dark phase under light/dark conditions. These results suggest that the action of melatonin on the pineal gland is highly dependent on light and photoperiod, possibly with stronger action during night time. Under constant darkness, the expression of four melatonin receptor subtype genes showed unique ultradian oscillations with the period of 14.0-15.4 h, suggesting the presence of a circatidal oscillator in the pineal gland. The present results indicate that melatonin may serve local chronobiological functions in the pineal gland. These cyclic expressions of melatonin receptor genes in the pineal gland may be important in the control of the lunar/tidal cycle-synchronized mass spawning in the grass puffer. PMID- 25688185 TI - Control of cortical neuronal migration by glutamate and GABA. AB - Neuronal migration in the cortex is controlled by the paracrine action of the classical neurotransmitters glutamate and GABA. Glutamate controls radial migration of pyramidal neurons by acting primarily on NMDA receptors and regulates tangential migration of inhibitory interneurons by activating non-NMDA and NMDA receptors. GABA, acting on ionotropic GABAA-rho and GABAA receptors, has a dichotomic action on radially migrating neurons by acting as a GO signal in lower layers and as a STOP signal in upper cortical plate (CP), respectively. Metabotropic GABAB receptors promote radial migration into the CP and tangential migration of interneurons. Besides GABA, the endogenous GABAergic agonist taurine is a relevant agonist controlling radial migration. To a smaller extent glycine receptor activation can also influence radial and tangential migration. Activation of glutamate and GABA receptors causes increases in intracellular Ca(2+) transients, which promote neuronal migration by acting on the cytoskeleton. Pharmacological or genetic manipulation of glutamate or GABA receptors during early corticogenesis induce heterotopic cell clusters in upper layers and loss of cortical lamination, i.e., neuronal migration disorders which can be associated with neurological or neuropsychiatric diseases. The pivotal role of NMDA and ionotropic GABA receptors in cortical neuronal migration is of major clinical relevance, since a number of drugs acting on these receptors (e.g., anti-epileptics, anesthetics, alcohol) may disturb the normal migration pattern when present during early corticogenesis. PMID- 25688186 TI - Super-resolution microscopy of the synaptic active zone. AB - Brain function relies on accurate information transfer at chemical synapses. At the presynaptic active zone (AZ) a variety of specialized proteins are assembled to complex architectures, which set the basis for speed, precision and plasticity of synaptic transmission. Calcium channels are pivotal for the initiation of excitation-secretion coupling and, correspondingly, capture a central position at the AZ. Combining quantitative functional studies with modeling approaches has provided predictions of channel properties, numbers and even positions on the nanometer scale. However, elucidating the nanoscopic organization of the surrounding protein network requires direct ultrastructural access. Without this information, knowledge of molecular synaptic structure-function relationships remains incomplete. Recently, super-resolution microscopy (SRM) techniques have begun to enter the neurosciences. These approaches combine high spatial resolution with the molecular specificity of fluorescence microscopy. Here, we discuss how SRM can be used to obtain information on the organization of AZ proteins. PMID- 25688188 TI - Audiovisual emotional processing and neurocognitive functioning in patients with depression. AB - Alterations in the processing of emotional stimuli (e.g., facial expressions, prosody, music) have repeatedly been reported in patients with major depression. Such impairments may result from the likewise prevalent executive deficits in these patients. However, studies investigating this relationship are rare. Moreover, most studies to date have only assessed impairments in unimodal emotional processing, whereas in real life, emotions are primarily conveyed through more than just one sensory channel. The current study therefore aimed at investigating multi-modal emotional processing in patients with depression and to assess the relationship between emotional and neurocognitive impairments. Fourty one patients suffering from major depression and 41 never-depressed healthy controls participated in an audiovisual (faces-sounds) emotional integration paradigm as well as a neurocognitive test battery. Our results showed that depressed patients were specifically impaired in the processing of positive auditory stimuli as they rated faces significantly more fearful when presented with happy than with neutral sounds. Such an effect was absent in controls. Findings in emotional processing in patients did not correlate with Beck's depression inventory score. Furthermore, neurocognitive findings revealed significant group differences for two of the tests. The effects found in audiovisual emotional processing, however, did not correlate with performance in the neurocognitive tests. In summary, our results underline the diversity of impairments going along with depression and indicate that deficits found for unimodal emotional processing cannot trivially be generalized to deficits in a multi-modal setting. The mechanisms of impairments therefore might be far more complex than previously thought. Our findings furthermore contradict the assumption that emotional processing deficits in major depression are associated with impaired attention or inhibitory functioning. PMID- 25688187 TI - Long-latency reflexes account for limb biomechanics through several supraspinal pathways. AB - Accurate control of body posture is enforced by a multitude of corrective actions operating over a range of time scales. The earliest correction is the short latency reflex (SLR) which occurs between 20-45 ms following a sudden displacement of the limb and is generated entirely by spinal circuits. In contrast, voluntary reactions are generated by a highly distributed network but at a significantly longer delay after stimulus onset (greater than 100 ms). Between these two epochs is the long-latency reflex (LLR) (around 50-100 ms) which acts more rapidly than voluntary reactions but shares some supraspinal pathways and functional capabilities. In particular, the LLR accounts for the arm's biomechanical properties rather than only responding to local muscle stretch like the SLR. This paper will review how the LLR accounts for the arm's biomechanical properties and the supraspinal pathways supporting this ability. Relevant experimental paradigms include clinical studies, non-invasive brain stimulation, neural recordings in monkeys, and human behavioral studies. The sum of this effort indicates that primary motor cortex and reticular formation (RF) contribute to the LLR either by generating or scaling its structured response appropriate for the arm's biomechanics whereas the cerebellum scales the magnitude of the feedback response. Additional putative pathways are discussed as well as potential research lines. PMID- 25688189 TI - Off the beaten track: the molecular structure of long-term memory: three novel hypotheses-electrical, chemical and anatomical (allosteric). PMID- 25688190 TI - Evidence for a functional subdivision of Premotor Ear-Eye Field (Area 8B). AB - The Supplementary Eye Field (SEF) and the Frontal Eye Field (FEF) have been described as participating in gaze shift control. Recent evidence suggests, however, that other areas of the dorsomedial prefrontal cortex also influence gaze shift. Herein, we have investigated electrically evoked ear- and eye movements from the Premotor Ear-Eye Field, or PEEF (area 8B) of macaque monkeys. We stimulated PEEF during spontaneous condition (outside the task performance) and during the execution of a visual fixation task (VFT). In the first case, we functionally identified two regions within the PEEF: a core and a belt. In the core region, stimulation elicited forward ear movements; regarding the evoked eye movements, in some penetrations, stimulation elicited contraversive fixed-vectors with a mean amplitude of 5.14 degrees ; while in other penetrations, we observed prevalently contralateral goal-directed eye movements having end-points that fell within 15 degrees in respect to the primary eye position. On the contrary, in the belt region, stimulation elicited backward ear movements; regarding the eye movements, in some penetrations stimulation elicited prevalently contralateral goal-directed eye movements having end-points that fell within 15 degrees in respect to the primary eye position, while in the lateral edge of the investigated region, stimulation elicited contralateral goal-directed eye movements having end-points that fell beyond 15 degrees in respect to the primary eye position. Stimulation during VFT either did not elicit eye movements or evoked saccades of only a few degrees. Finally, even though no head rotation movements were observed during the stimulation period, we viewed a relationship between the duration of stimulation and the neck forces exerted by the monkey's head. We propose an updated vision of the PEEF composed of two functional regions, core and belt, which may be involved in integrating auditory and visual information important to the programming of gaze orienting movements. PMID- 25688191 TI - Investigation of gene effects and epistatic interactions between Akt1 and neuregulin 1 in the regulation of behavioral phenotypes and social functions in genetic mouse models of schizophrenia. AB - Accumulating evidence from human genetic studies has suggested several functional candidate genes that might contribute to susceptibility to schizophrenia, including AKT1 and neuregulin 1 (NRG1). Recent findings also revealed that NRG1 stimulates the PI3-kinase/AKT signaling pathway, which might be involved in the functional outcomes of some schizophrenic patients. The aim of this study was to evaluate the effect of Akt1-deficiency and Nrg1-deficiency alone or in combination in the regulation of behavioral phenotypes, cognition, and social functions using genetically modified mice as a model. Male Akt1 (+/-), Nrg1 (+/ ), and double mutant mice were bred and compared with their wild-type (WT) littermate controls. In Experiment 1, general physical examination revealed that all mutant mice displayed a normal profile of body weight during development and a normal brain activity with microPET scan. In Experiment 2, no significant genotypic differences were found in our basic behavioral phenotyping, including locomotion, anxiety-like behavior, and sensorimotor gating function. However, both Nrg1 (+/-) and double mutant mice exhibited impaired episodic-like memory. Double mutant mice also had impaired sociability. In Experiment 3, a synergistic epistasis between Akt1 and Nrg1 was further confirmed in double mutant mice in that they had impaired social interaction compared to the other 3 groups, especially encountering with a novel male or an ovariectomized female. Double mutant and Nrg1 (+/-) mice also emitted fewer female urine-induced ultrasonic vocalization calls. Collectively, our results indicate that double deficiency of Akt1 and Nrg1 can result in the impairment of social cognitive functions, which might be pertinent to the pathogenesis of schizophrenia-related social cognition. PMID- 25688192 TI - Functional connectivity changes during a working memory task in rat via NMF analysis. AB - Working memory (WM) is necessary in higher cognition. The brain as a complex network is formed by interconnections among neurons. Connectivity results in neural dynamics to support cognition. The first aim is to investigate connectivity dynamics in medial prefrontal cortex (mPFC) networks during WM. As brain neural activity is sparse, the second aim is to find the intrinsic connectivity property in a feature space. Using multi-channel electrode recording techniques, spikes were simultaneously obtained from mPFC of rats that performed a Y-maze WM task. Continuous time series converted from spikes were embedded in a low-dimensional space by non-negative matrix factorization (NMF). mPFC network in original space was constructed by measuring connections among neurons. And the same network in NMF space was constructed by computing connectivity values between the extracted NMF components. Causal density (Cd) and global efficiency (E) were estimated to present the network property. The results showed that Cd and E significantly peaked in the interval right before the maze choice point in correct trials. However, the increase did not emerge in error trials. Additionally, Cd and E in two spaces displayed similar trends in correct trials. The difference was that the measures in NMF space were significantly greater than those in original space. Our findings indicated that the anticipatory changes in mPFC networks may have an effect on future WM behavioral choices. Moreover, the NMF analysis achieves a better characterization for a brain network. PMID- 25688193 TI - FRIEND Engine Framework: a real time neurofeedback client-server system for neuroimaging studies. AB - In this methods article, we present a new implementation of a recently reported FSL-integrated neurofeedback tool, the standalone version of "Functional Real time Interactive Endogenous Neuromodulation and Decoding" (FRIEND). We will refer to this new implementation as the FRIEND Engine Framework. The framework comprises a client-server cross-platform solution for real time fMRI and fMRI/EEG neurofeedback studies, enabling flexible customization or integration of graphical interfaces, devices, and data processing. This implementation allows a fast setup of novel plug-ins and frontends, which can be shared with the user community at large. The FRIEND Engine Framework is freely distributed for non commercial, research purposes. PMID- 25688194 TI - Spatially specific vs. unspecific disruption of visual orientation perception using chronometric pre-stimulus TMS. AB - Transcranial magnetic stimulation (TMS) over occipital cortex can impair visual processing. Such "TMS masking" has repeatedly been shown at several stimulus onset asynchronies (SOAs), with TMS pulses generally applied after the onset of a visual stimulus. Following increased interest in the neuronal state-dependency of visual processing, we recently explored the efficacy of TMS at "negative SOAs", when no visual processing can yet occur. We could reveal pre-stimulus TMS disruption, with results moreover hinting at two separate mechanisms in occipital cortex biasing subsequent orientation perception. Here we extended this work, including a chronometric design to map the temporal dynamics of spatially specific and unspecific mechanisms of state-dependent visual processing, while moreover controlling for TMS-induced pupil covering. TMS pulses applied 60-40 ms prior to a visual stimulus decreased orientation processing independent of stimulus location, while a local suppressive effect was found for TMS applied 30 10 ms pre-stimulus. These results contribute to our understanding of spatiotemporal mechanisms in occipital cortex underlying the state-dependency of visual processing, providing a basis for future work to link pre-stimulus TMS suppression effects to other known visual biasing mechanisms. PMID- 25688195 TI - Different forms of decision-making involve changes in the synaptic strength of the thalamic, hippocampal, and amygdalar afferents to the medial prefrontal cortex. AB - Decision-making and other cognitive processes are assumed to take place in the prefrontal cortex. In particular, the medial prefrontal cortex (mPFC) is identified in rodents by its dense connectivity with the mediodorsal (MD) thalamus, and because of its inputs from other sites, such as hippocampus and amygdala (Amyg). The aim of this study was to find a putative relationship between the behavior of mice during the performance of decision-making tasks that involve penalties as a consequence of induced actions, and the strength of field postsynaptic potentials (fPSPs) evoked in the prefrontal cortex from its thalamic, hippocampal, and amygdalar afferents. Mice were chronically implanted with stimulating electrodes in the MD thalamus, the hippocampal CA1 area, or the basolateral amygdala (BLA), and with recording electrodes in the prelimbic/infralimbic area of the prefrontal cortex. Additional stimulating electrodes aimed at evoking negative reinforcements were implanted on the trigeminal nerve. FPSPs evoked at the mPFC from the three selected projecting areas during the food/shock decision-making task decreased in amplitude with shock intensity and animals' avoidance of the reward. FPSPs collected during the operant task also decreased in amplitude (but that evoked by amygdalar stimulation) when lever presses were associated with a trigeminal shock. Results showed a general decrease in the strength of these potentials when animals inhibited their natural or learned appetitive behaviors, suggesting an inhibition of the prefrontal cortex in these conflicting situations. PMID- 25688196 TI - Sadness is unique: neural processing of emotions in speech prosody in musicians and non-musicians. AB - Musical training has been shown to have positive effects on several aspects of speech processing, however, the effects of musical training on the neural processing of speech prosody conveying distinct emotions are yet to be better understood. We used functional magnetic resonance imaging (fMRI) to investigate whether the neural responses to speech prosody conveying happiness, sadness, and fear differ between musicians and non-musicians. Differences in processing of emotional speech prosody between the two groups were only observed when sadness was expressed. Musicians showed increased activation in the middle frontal gyrus, the anterior medial prefrontal cortex, the posterior cingulate cortex and the retrosplenial cortex. Our results suggest an increased sensitivity of emotional processing in musicians with respect to sadness expressed in speech, possibly reflecting empathic processes. PMID- 25688197 TI - Introduction to the special research topic on the neurobiology of emotion cognition interactions. PMID- 25688198 TI - A theory of attentional modulations of the supratemporal generation of the auditory mismatch negativity (MMN). PMID- 25688199 TI - Spatial coding of ordinal information in short- and long-term memory. AB - The processing of numerical information induces a spatial response bias: Faster responses to small numbers with the left hand and faster responses to large numbers with the right hand. Most theories agree that long-term representations underlie this so called SNARC effect (Spatial Numerical Association of Response Codes; Dehaene et al., 1993). However, a spatial response bias was also observed with the activation of temporary position-space associations in working memory (ordinal position effect; van Dijck and Fias, 2011). Items belonging to the beginning of a memorized sequence are responded to faster with the left hand side while items at the end of the sequence are responded to faster with the right hand side. The theoretical possibility was put forward that the SNARC effect is an instance of the ordinal position effect, with the empirical consequence that the SNARC effect and the ordinal position effect cannot be observed simultaneously. In two experiments we falsify this claim by demonstrating that the SNARC effect and the ordinal position effect are not mutually exclusive. Consequently, this suggests that the SNARC effect and the ordinal position effect result from the activation of different representations. We conclude that spatial response biases can result from the activation of both pre-existing positions in long-term memory and from temporary space associations in working memory at the same time. PMID- 25688200 TI - Cortical responses to salient nociceptive and not nociceptive stimuli in vegetative and minimal conscious state. AB - AIMS: Questions regarding perception of pain in non-communicating patients and the management of pain continue to raise controversy both at a clinical and ethical level. The aim of this study was to examine the cortical response to salient visual, acoustic, somatosensory electric non-nociceptive and nociceptive laser stimuli and their correlation with the clinical evaluation. METHODS: Five Vegetative State (VS), 4 Minimally Conscious State (MCS) patients and 11 age- and sex-matched controls were examined. Evoked responses were obtained by 64 scalp electrodes, while delivering auditory, visual, non-noxious electrical and noxious laser stimulation, which were randomly presented every 10 s. Laser, somatosensory, auditory and visual evoked responses were identified as a negative positive (N2-P2) vertex complex in the 500 ms post-stimulus time. We used Nociception Coma Scale-Revised (NCS-R) and Coma Recovery Scale (CRS-R) for clinical evaluation of pain perception and consciousness impairment. RESULTS: The laser evoked potentials (LEPs) were recognizable in all cases. Only one MCS patient showed a reliable cortical response to all the employed stimulus modalities. One VS patient did not present cortical responses to any other stimulus modality. In the remaining participants, auditory, visual and electrical related potentials were inconstantly present. Significant N2 and P2 latency prolongation occurred in both VS and MCS patients. The presence of a reliable cortical response to auditory, visual and electric stimuli was able to correctly classify VS and MCS patients with 90% accuracy. Laser P2 and N2 amplitudes were not correlated with the CRS-R and NCS-R scores, while auditory and electric related potentials amplitude were associated with the motor response to pain and consciousness recovery. DISCUSSION: pain arousal may be a primary function also in vegetative state patients while the relevance of other stimulus modalities may indicate the degree of cognitive and motor behavior recovery. This underlines the importance of considering the potential experience of pain also in patients in vegetative state and to appropriately assess a possible treatment also in those patients. PMID- 25688201 TI - Forward models and passive psychotic symptoms. PMID- 25688202 TI - Gaussian mixture models and semantic gating improve reconstructions from human brain activity. AB - Better acquisition protocols and analysis techniques are making it possible to use fMRI to obtain highly detailed visualizations of brain processes. In particular we focus on the reconstruction of natural images from BOLD responses in visual cortex. We expand our linear Gaussian framework for percept decoding with Gaussian mixture models to better represent the prior distribution of natural images. Reconstruction of such images then boils down to probabilistic inference in a hybrid Bayesian network. In our set-up, different mixture components correspond to different character categories. Our framework can automatically infer higher-order semantic categories from lower-level brain areas. Furthermore, the framework can gate semantic information from higher-order brain areas to enforce the correct category during reconstruction. When categorical information is not available, we show that automatically learned clusters in the data give a similar improvement in reconstruction. The hybrid Bayesian network leads to highly accurate reconstructions in both supervised and unsupervised settings. PMID- 25688203 TI - Adaptation of short-term plasticity parameters via error-driven learning may explain the correlation between activity-dependent synaptic properties, connectivity motifs and target specificity. AB - The anatomical connectivity among neurons has been experimentally found to be largely non-random across brain areas. This means that certain connectivity motifs occur at a higher frequency than would be expected by chance. Of particular interest, short-term synaptic plasticity properties were found to colocalize with specific motifs: an over-expression of bidirectional motifs has been found in neuronal pairs where short-term facilitation dominates synaptic transmission among the neurons, whereas an over-expression of unidirectional motifs has been observed in neuronal pairs where short-term depression dominates. In previous work we found that, given a network with fixed short-term properties, the interaction between short- and long-term plasticity of synaptic transmission is sufficient for the emergence of specific motifs. Here, we introduce an error driven learning mechanism for short-term plasticity that may explain how such observed correspondences develop from randomly initialized dynamic synapses. By allowing synapses to change their properties, neurons are able to adapt their own activity depending on an error signal. This results in more rich dynamics and also, provided that the learning mechanism is target-specific, leads to specialized groups of synapses projecting onto functionally different targets, qualitatively replicating the experimental results of Wang and collaborators. PMID- 25688204 TI - The mapping of eccentricity and meridional angle onto orthogonal axes in the primary visual cortex: an activity-dependent developmental model. AB - Primate vision research has shown that in the retinotopic map of the primary visual cortex, eccentricity and meridional angle are mapped onto two orthogonal axes: whereas the eccentricity is mapped onto the nasotemporal axis, the meridional angle is mapped onto the dorsoventral axis. Theoretically such a map has been approximated by a complex log map. Neural models with correlational learning have explained the development of other visual maps like orientation maps and ocular-dominance maps. In this paper it is demonstrated that activity based mechanisms can drive a self-organizing map (SOM) into such a configuration that dilations and rotations of a particular image (in this case a rectangular bar) are mapped onto orthogonal axes. We further demonstrate using the Laterally Interconnected Synergetically Self Organizing Map (LISSOM) model, with an appropriate boundary and realistic initial conditions, that a retinotopic map which maps eccentricity and meridional angle to the horizontal and vertical axes respectively can be developed. This developed map bears a strong resemblance to the complex log map. We also simulated lesion studies which indicate that the lateral excitatory connections play a crucial role in development of the retinotopic map. PMID- 25688205 TI - Application of Parallel Factor Analysis (PARAFAC) to electrophysiological data. AB - The identification of important features in multi-electrode recordings requires the decomposition of data in order to disclose relevant features and to offer a clear graphical representation. This can be a demanding task. Parallel Factor Analysis (PARAFAC; Hitchcock, 1927; Carrol and Chang, 1970; Harshman, 1970) is a method to decompose multi-dimensional arrays in order to focus on the features of interest, and provides a distinct illustration of the results. We applied PARAFAC to analyse spatio-temporal patterns in the functional connectivity between neurons, as revealed in their spike trains recorded in cat primary visual cortex (area 18). During these recordings we reversibly deactivated feedback connections from higher visual areas in the pMS (posterior middle suprasylvian) cortex in order to study the impact of these top-down signals. Cross correlation was computed for every possible pair of the 16 electrodes in the electrode array. PARAFAC was then used to reveal the effects of time, stimulus, and deactivation condition on the correlation patterns. Our results show that PARAFAC is able to reliably extract changes in correlation strength for different experimental conditions and display the relevant features. Thus, PARAFAC proves to be well suited for the use in the context of electrophysiological (action potential) recordings. PMID- 25688206 TI - Targeting cholesterol homeostasis to fight hearing loss: a new perspective. AB - Sensorineural hearing loss (SNHL) is a major pathology of the inner ear that affects nearly 600 million people worldwide. Despite intensive researches, this major health problem remains without satisfactory solutions. The pathophysiological mechanisms involved in SNHL include oxidative stress, excitotoxicity, inflammation, and ischemia, resulting in synaptic loss, axonal degeneration, and apoptosis of spiral ganglion neurons. The mechanisms associated with SNHL are shared with other neurodegenerative disorders. Cholesterol homeostasis is central to numerous pathologies including neurodegenerative diseases and cholesterol regulates major processes involved in neurons survival and function. The role of cholesterol homeostasis in the physiopathology of inner ear is largely unexplored. In this review, we discuss the findings concerning cholesterol homeostasis in neurodegenerative diseases and whether it should be translated into potential therapeutic strategies for the treatment of SNHL. PMID- 25688207 TI - Absence of a significant pharmacokinetic interaction between atorvastatin and fenofibrate: a randomized, crossover, study of a fixed-dose formulation in healthy Mexican subjects. AB - Several clinical trials have substantiated the efficacy of the co-administration of statins like atorvastatin (ATO) and fibrates. Without information currently available about the interaction between the two drugs, a pharmacokinetic study was conducted to investigate the effect when both drugs were co-administered. The purpose of this study was to investigate the pharmacokinetic profile of tablets containing ATO 20 mg, or the combination of ATO 20 mg with fenofibrate (FNO) 160 mg administered to healthy Mexican volunteers. This was a randomized, two-period, two-sequence, crossover study; 36 eligible subjects aged between 20-50 years were included. Blood samples were collected up to 96 h after dosing, and pharmacokinetic parameters were obtained by non-compartmental analysis. Adverse events were evaluated based on subject interviews and physical examinations. Area under the concentration-time curve (AUC) and maximum plasma drug concentration (Cmax) were measured for ATO as the reference and ATO and FNO as the test product for bioequivalence design. The estimation computed (90% confidence intervals) for ATO and FNO combination versus ATO for Cmax, AUC0-t and AUC0-infinity, were 102,09, 125,95, and 120,97%, respectively. These results suggest that ATO and FNO have no relevant clinical-pharmacokinetic drug interaction. PMID- 25688208 TI - Structural determinants for binding to angiotensin converting enzyme 2 (ACE2) and angiotensin receptors 1 and 2. AB - Angiotensin converting enzyme 2 (ACE2) is a zinc carboxypeptidase involved in the renin-angiotensin system (RAS) and inactivates the potent vasopressive peptide angiotensin II (Ang II) by removing the C-terminal phenylalanine residue to yield Ang1-7. This conversion inactivates the vasoconstrictive action of Ang II and yields a peptide that acts as a vasodilatory molecule at the Mas receptor and potentially other receptors. Given the growing complexity of RAS and level of cross-talk between ligands and their corresponding enzymes and receptors, the design of molecules with selectivity for the major RAS binding partners to control cardiovascular tone is an on-going challenge. In previous studies we used single beta-amino acid substitutions to modulate the structure of Ang II and its selectivity for ACE2, AT1R, and angiotensin type 2 (AT2R) receptor. We showed that modification at the C-terminus of Ang II generally resulted in more pronounced changes to secondary structure and ligand binding, and here, we further explore this region for the potential to modulate ligand specificity. In this study, (1) a library of 47 peptides derived from the C-terminal tetrapeptide sequence (-IHPF) of Ang II was synthesized and assessed for ACE2 binding, (2) the terminal group requirements for high affinity ACE2 binding were explored by and N and C-terminal modification, (3) high affinity ACE2 binding chimeric AngII analogs were then synthesized and assessed, (4) the structure of the full-length Ang II analogs were assessed by circular dichroism, and (5) the Ang II analogs were assessed for AT1R/AT2R selectivity by cell-based assays. Studies on the C terminus of Ang II demonstrated varied specificity at different residue positions for ACE2 binding and four Ang II chimeric peptides were identified as selective ligands for the AT2 receptor. Overall, these results provide insight into the residue and structural requirements for ACE2 binding and angiotensin receptor selectivity. PMID- 25688209 TI - Clinical application of kampo medicine (rikkunshito) for common and/or intractable symptoms of the gastrointestinal tract. AB - Gastroenterological reflux disease and functional dyspepsia are usually treatable using Western medical practices. Nonetheless, some cases present with intractable symptoms that are not amenable to these therapies. Treatment with kampo, a traditional Japanese medicine, recently has been proposed as an alternative therapy for use in combination with the Western practices. In general, traditional Japanese medicines have been used empirically for intractable symptoms correctively designated as "general malaises." Accumulating lines of evidence, including basic and clinical researches, have demonstrate detailed mechanisms where traditional Japanese medicines exert pharmacological action to improve symptoms. Therefore, traditional Japanese medicines have been gaining use by various medical doctors as the specific modes of pharmacological action are recognized. This review covers both the pharmacological functions and the clinical efficacies of rikkunshito for use in treating disorders of the gastrointestinal tract. PMID- 25688210 TI - Macropinocytosis in phagocytes: regulation of MHC class-II-restricted antigen presentation in dendritic cells. AB - Dendritic cells (DCs) are outstanding antigen presenting cells (APCs) due to their robust ability to internalize extracellular antigens using endocytic processes such as receptor-mediated endocytosis, phagocytosis, and macropinocytosis. Macropinocytosis mediates the non-specific uptake of soluble antigens and occurs in DCs constitutively. Macropinocytosis plays a key role in DC-mediated antigen presentation to T cells against pathogens and the efficiency of macropinocytosis in antigen capture is regulated during the process of DC maturation. Here, we review the methods to study macropinocytosis, describe our current knowledge of the regulatory mechanisms of antigen uptake via macropinocytosis and the intracellular trafficking route followed by macropinocytosed antigens, and discuss the significance of macropinocytosis for DC function. PMID- 25688211 TI - Brown adipose tissue activity as a target for the treatment of obesity/insulin resistance. AB - Presence of brown adipose tissue (BAT), characterized by the expression of the thermogenic uncoupling protein 1 (UCP1), has recently been described in adult humans. UCP1 is expressed in classical brown adipocytes, as well as in "beige cells" in white adipose tissue (WAT). The thermogenic activity of BAT is mainly controlled by the sympathetic nervous system. Endocrine factors, such as fibroblast growth factor 21 (FGF21) and bone morphogenic protein factor-9 (BMP 9), predominantly produced in the liver, were shown to lead to activation of BAT thermogenesis, as well as to "browning" of WAT. This was also observed in response to irisin, a hormone secreted by skeletal muscles. Different approaches were used to delineate the impact of UCP1 on insulin sensitivity. When studied under thermoneutral conditions, UCP1 knockout mice exhibited markedly increased metabolic efficiency due to impaired thermogenesis. The impact of UCP1 deletion on insulin sensitivity in these mice was not reported. Conversely, several studies in both rodents and humans have shown that BAT activation (by cold exposure, beta3-agonist treatment, transplantation and others) improves glucose tolerance and insulin sensitivity. Interestingly, similar results were obtained by adipose tissue-specific overexpression of PR-domain-containing 16 (PRDM16) or BMP4 in mice. The mediators of such beneficial effects seem to include FGF21, interleukin-6, BMP8B and prostaglandin D2 synthase. Interestingly, some of these molecules can be secreted by BAT itself, indicating the occurrence of autocrine effects. Stimulation of BAT activity and/or recruitment of UCP1-positive cells are therefore relevant targets for the treatment of obesity/type 2 diabetes in humans. PMID- 25688212 TI - Differential signaling during macropinocytosis in response to M-CSF and PMA in macrophages. AB - The cellular movements that construct a macropinosome have a corresponding sequence of chemical transitions in the cup-shaped region of plasma membrane that becomes the macropinosome. To determine the relative positions of type I phosphatidylinositol 3-kinase (PI3K) and phospholipase C (PLC) in this pathway, we analyzed macropinocytosis in macrophages stimulated by the growth factor macrophage-colony-stimulating factor (M-CSF) and by the diacylglycerol (DAG) analog phorbol 12-myristate 13-acetate (PMA). In cells stimulated with M-CSF, microscopic imaging of fluorescent probes for intracellular lipids indicated that the PI3K product phosphatidylinositol (3,4,5)-trisphosphate (PIP3) appeared in cups just prior to DAG. We then tested the hypothesis that PMA and DAG function after PI3K and prior to Ras and protein kinase C (PKC) during macropinosome formation in macrophages. Although the PI3K target Akt was activated by M-CSF, the Akt inhibitor MK-2206 did not inhibit macropinocytosis. The phospholipase C (PLC) inhibitor U73122 blocked macropinocytosis by M-CSF but not PMA. Macropinocytosis in response to M-CSF and PMA was inhibited by the Ras inhibitor farnesyl thiosalicylate (FTS), by the PKC inhibitor Calphostin C and by the broad specificity inhibitor rottlerin. These studies support a model in which M-CSF stimulates PI3K in macropinocytic cups, and the resulting increase in PIP3 activates PLC, which in turn generates DAG necessary for activation of PKC, Ras and the late stages of macropinosome closure. PMID- 25688213 TI - Regulation of Ca(2+) transient by PP2A in normal and failing heart. AB - Calcium transient in cardiomyocytes is regulated by multiple protein kinases and phosphatases. PP2A is a major protein phosphatase in the heart modulating Ca(2+) handling through an array of ion channels, antiporters and pumps, etc. The assembly, localization/translocation, and substrate specificity of PP2A are controlled by different post-translational mechanisms, which in turn are linked to the activities of upstream signaling molecules. Abnormal PP2A expression and activities are associated with defective response to beta-adrenergic stimulation and are indication and causal factors in arrhythmia and heart failure. PMID- 25688214 TI - Chronic intermittent hypoxia increases rat sternohyoid muscle NADPH oxidase expression with attendant modest oxidative stress. AB - Chronic intermittent hypoxia (CIH) causes upper airway muscle dysfunction. We hypothesized that the superoxide generating NADPH oxidase (NOX) is upregulated in CIH-exposed muscle causing oxidative stress. Adult male Wistar rats were exposed to intermittent hypoxia (5% O2 at the nadir for 90 s followed by 210 s of normoxia), for 8 h per day for 14 days. The effect of CIH exposure on the expression of NOX subunits, total myosin and 4-hydroxynonenal (4-HNE) protein adducts in sternohyoid muscle was determined by western blotting and densitometry. Sternohyoid protein free thiol and carbonyl group contents were determined by 1D electrophoresis using specific fluorophore probes. Aconitase and glutathione reductase activities were measured as indices of oxidative stress. HIF-1alpha content and key oxidative and glycolytic enzyme activities were determined. Contractile properties of sternohyoid muscle were determined ex vivo in the absence and presence of apocynin (putative NOX inhibitor). We observed an increase in NOX 2 and p47 phox expression in CIH-exposed sternohyoid muscle with decreased aconitase and glutathione reductase activities. There was no evidence, however, of increased lipid peroxidation or protein oxidation in CIH-exposed muscle. CIH exposure did not affect sternohyoid HIF-1alpha content or aldolase, lactate dehydrogenase, or glyceraldehyde-3-phosphate dehydrogenase activities. Citrate synthase activity was also unaffected by CIH exposure. Apocynin significantly increased sternohyoid force and power. We conclude that CIH exposure upregulates NOX expression in rat sternohyoid muscle with concomitant modest oxidative stress but it does not result in a HIF-1alpha-dependent increase in glycolytic enzyme activity. Constitutive NOX activity decreases sternohyoid force and power. Our results implicate NOX-dependent reactive oxygen species in CIH-induced upper airway muscle dysfunction which likely relates to redox modulation of key regulatory proteins in excitation-contraction coupling. PMID- 25688215 TI - To center or not to center? Investigating inertia with a multilevel autoregressive model. AB - Whether level 1 predictors should be centered per cluster has received considerable attention in the multilevel literature. While most agree that there is no one preferred approach, it has also been argued that cluster mean centering is desirable when the within-cluster slope and the between-cluster slope are expected to deviate, and the main interest is in the within-cluster slope. However, we show in a series of simulations that if one has a multilevel autoregressive model in which the level 1 predictor is the lagged outcome variable (i.e., the outcome variable at the previous occasion), cluster mean centering will in general lead to a downward bias in the parameter estimate of the within-cluster slope (i.e., the autoregressive relationship). This is particularly relevant if the main question is whether there is on average an autoregressive effect. Nonetheless, we show that if the main interest is in estimating the effect of a level 2 predictor on the autoregressive parameter (i.e., a cross-level interaction), cluster mean centering should be preferred over other forms of centering. Hence, researchers should be clear on what is considered the main goal of their study, and base their choice of centering method on this when using a multilevel autoregressive model. PMID- 25688216 TI - The case for social evaluation in preverbal infants: gazing toward one's goal drives infants' preferences for Helpers over Hinderers in the hill paradigm. AB - In a 2007 empirical report, Hamlin, Wynn, and Bloom provided the first evidence that preverbal infants at 6 and at 10 months of age evaluate others on the basis of their helpful and unhelpful actions toward unknown third parties. In their "hill paradigm," a Climber puppet tried but failed to climb a steep hill, and was alternately bumped up the hill by the Helper and bumped down the hill by the Hinderer. After being habituated to these events, both 10- and 6-month-olds selectively reached for the Helper over the Hinderer. In response, Scarf et al. (2012b) provided evidence that rather than reflecting an early developing capacity for social evaluation, infants' choices in Hamlin et al. (2007) reflected low-level perceptual preferences whereby infants are drawn to any character who is associated with the Climber bouncing. The current studies represent an attempt to adjudicate between the social and perceptual accounts of infants' preferences for Helpers over Hinderers in the hill paradigm, by pitting a perceptual cue (e.g., bouncing) against a social cue (e.g., whether or not the Climber gazes toward his goal). Infants' patterns of preference across two experiments support the social account. PMID- 25688217 TI - Two routes to actorhood: lexicalized potency to act and identification of the actor role. AB - The inference of causality is a crucial cognitive ability and language processing is no exception: recent research suggests that, across different languages, the human language comprehension system attempts to identify the primary causer of the state of affairs described (the "actor") quickly and unambiguously (Bornkessel-Schlesewsky and Schlesewsky, 2009). This identification can take place verb-independently based on certain prominence cues (e.g., case, word order, animacy). Here, we present two experiments demonstrating that actor potential is also encoded at the level of individual nouns (a king is a better actor than a beggar). Experiment 1 collected ratings for 180 German nouns on 12 scales defined by adjective oppositions and deemed relevant for actorhood potential. By means of structural equation modeling, an actor potential (ACT) value was calculated for each noun. Experiment 2, an event-related potential study, embedded nouns from Experiment 1 in verb-final sentences, in which they were either actors or non-actors. N400 amplitude increased with decreasing ACT values and this modulation was larger for highly frequent nouns and for actor versus non-actor nouns. We argue that potency to act is lexically encoded for individual nouns and, since it modulates the N400 even for non-actor participants, it should be viewed as a property that modulates ease of lexical access (akin, for example, to lexical frequency). We conclude that two separate dimensions of actorhood computation are crucial to language comprehension: an experience-based, lexically encoded (bottom-up) representation of actorhood potential, and a prominence-based, computational mechanism for calculating goodness-of-fit to the actor role in a particular (top-down) sentence context. PMID- 25688218 TI - The impact of perception and presence on emotional reactions: a review of research in virtual reality. AB - Virtual reality (VR) has made its way into mainstream psychological research in the last two decades. This technology, with its unique ability to simulate complex, real situations and contexts, offers researchers unprecedented opportunities to investigate human behavior in well controlled designs in the laboratory. One important application of VR is the investigation of pathological processes in mental disorders, especially anxiety disorders. Research on the processes underlying threat perception, fear, and exposure therapy has shed light on more general aspects of the relation between perception and emotion. Being by its nature virtual, i.e., simulation of reality, VR strongly relies on the adequate selection of specific perceptual cues to activate emotions. Emotional experiences in turn are related to presence, another important concept in VR, which describes the user's sense of being in a VR environment. This paper summarizes current research into perception of fear cues, emotion, and presence, aiming at the identification of the most relevant aspects of emotional experience in VR and their mutual relations. A special focus lies on a series of recent experiments designed to test the relative contribution of perception and conceptual information on fear in VR. This strand of research capitalizes on the dissociation between perception (bottom-up input) and conceptual information (top down input) that is possible in VR. Further, we review the factors that have so far been recognized to influence presence, with emotions (e.g., fear) being the most relevant in the context of clinical psychology. Recent research has highlighted the mutual influence of presence and fear in VR, but has also traced the limits of our current understanding of this relationship. In this paper, the crucial role of perception on eliciting emotional reactions is highlighted, and the role of arousal as a basic dimension of emotional experience is discussed. An interoceptive attribution model of presence is suggested as a first step toward an integrative framework for emotion research in VR. Gaps in the current literature and future directions are outlined. PMID- 25688219 TI - An experimental study of gender and cultural differences in hue preference. AB - This paper investigates the influence of both gender and culture on color preference. Inspection of previous studies of color preference reveals that many of these studies have poor control over the colors that are shown-the chromatic co-ordinates of colors are either not noted or the illuminant that colors are shown under is not controlled. This means that conclusions about color preference are made using subjective terms for hue with little knowledge about the precise colors that were shown. However, recently, a new quantitative approach to investigating color preference has been proposed, where there is no need to summarize color preference using subjective terms for hue (Hurlbert and Ling, 2007; Ling and Hurlbert, 2007). This approach aims to quantitatively summarize hue preference in terms of weights on the two channels or "cardinal axes" underlying color vision. Here I further extend Hurlbert and Ling's (2007) approach to investigating color preference, by replicating their study but with Arabic and English participants, and to answer several questions: First, are there cultural differences in the shape of the overall preference curve for English and Arabic participants? Second, are there gender differences in the shape of the overall preference curve for English and Arabic participants? Thirty eight British and 71 Saudi Arabian (Arabic) participants were compared. Results revealed that Arabic and English preference curves were found to differ, yet there was greater similarity for Arabic and English males than Arabic and English females. There was also a sex difference that was present for both Arabic and English participants. The male curve is fairly similar for both samples: peak preference is in the blue-green region, and a preference minimum is in the red pink/purple region. For Arabic females the preference peak appears to be in the red-pink region, whilst for English females it is shifted toward purple/blue green. PMID- 25688220 TI - Ego depletion interferes with rule-defined category learning but not non-rule defined category learning. AB - Considerable research on category learning has suggested that many cognitive and environmental factors can have a differential effect on the learning of rule defined (RD) categories as opposed to the learning of non-rule-defined (NRD) categories. Prior research has also suggested that ego depletion can temporarily reduce the capacity for executive functioning and cognitive flexibility. The present study examined whether temporarily reducing participants' executive functioning via a resource depletion manipulation would differentially impact RD and NRD category learning. Participants were either asked to write a story with no restrictions (the control condition), or without using two common letters (the ego depletion condition). Participants were then asked to learn either a set of RD categories or a set of NRD categories. Resource depleted participants performed more poorly than controls on the RD task, but did not differ from controls on the NRD task, suggesting that self regulatory resources are required for successful RD category learning. These results lend support to multiple systems theories and clarify the role of self-regulatory resources within this theory. PMID- 25688221 TI - Prison brain? Executive dysfunction in prisoners. AB - A better understanding of the functioning of the brain, particularly executive functions, of the prison population could aid in reducing crime rates through the reduction of recidivism rates. Indeed, reoffending appears to be related to executive dysfunction and it is known that executive functions are crucial for self-regulation. In the current paper, studies to executive functions in regular adult prisoners compared to non-offender controls were reviewed. Seven studies were found. Specific executive functions were found to be impaired in the general prison population, i.e., attention and set-shifting, as well as in separate subgroups of violent (i.e., set-shifting and working memory) and non-violent offenders (i.e., inhibition, working memory and problem solving). We conclude that the limited number of studies is remarkable, considering the high impact of this population on society and elaborate on the implications of these specific impairments that were found. Further empirical research is suggested, measuring executive functioning within subjects over time for a group of detainees as well as a control group. PMID- 25688222 TI - Mindfulness meditation and explicit and implicit indicators of personality and self-concept changes. AB - The scientific interest on mindfulness meditation (MM) has significantly increased in the last two decades probably because of the positive health effects that this practice exerts in a great variety of clinical and non-clinical conditions. Despite attention regulation, emotional regulation, and body awareness have been argued to be critical mechanisms through which MM improves well-being, much less is known on the effects of this practice on personality. Here we review the current state of knowledge about the role of MM in promoting changes in practitioners' personality profiles and self-concepts. We first focus on studies that investigated the relations between mindfulness and personality using well-known self-report inventories such as the Five-Factor model of personality traits and the Temperament and Character Inventory. Second, based on the intrinsic limitations of these explicit personality measures, we review a key set of results showing effects of MM on implicit, as well as explicit, self representations. Although the research on MM and personality is still in its infancy, it appears that this form of meditative practice may notably shape individuals' personality and self-concept toward more healthy profiles. PMID- 25688223 TI - Observing end-state comfort favorable actions does not modulate action plan recall. AB - A large corpus of work demonstrates that observing other people's actions activates corresponding motor representations in the observer by running an internal simulation of the observed action. Recent evidence suggests that recalled action plans reflect a plan of how the observer would execute that action (based on the specific motor representation) rather than a plan of the actually observed action (based on the visual representation). This study examined whether people would recall an action plan based on a visual representation if the observed movement is biomechanically favorable for their own subsequent action. Participants performed an object manipulation task alongside a confederate. In the intra-individual task, the participant (or confederate) transported a plunger from an outer platform of fixed height to a center target platform located at different heights (home-to-target move), and then the same person transported the plunger back to the outer platform (target back-to-home move). In the inter-individual task, the sequence was split between the two persons such that the participant (or confederate) performed the home-to target move and the other person performed the target-back-to-home move. Importantly, the confederate always grasped the plunger at the same height. This grasp height was designated such that if participants would copy the action (i.e., grasp the object at the same height) it would place the participant's arm in a comfortable position at the end of the target-back-to-home move (i.e., end state comfort). Results show that participants' grasp height was inversely related to center target height and similar regardless of direction (home-to target vs. target-back-to-home move) and task (intra- vs. inter-individual). In addition, during the inter-individual task, participant's target-back-to-home grasp height was correlated with their own, but not with the confederate's grasp height during the home-to-target moves. These findings provide evidence that observing actions that are biomechanically favorable for subsequent action execution does not influence action plan recall processes. PMID- 25688224 TI - Category learning in a dynamic world. PMID- 25688225 TI - Pronunciation difficulty, temporal regularity, and the speech-to-song illusion. AB - The speech-to-song illusion (Deutsch et al., 2011) tracks the perceptual transformation from speech to song across repetitions of a brief spoken utterance. Because it involves no change in the stimulus itself, but a dramatic change in its perceived affiliation to speech or to music, it presents a unique opportunity to comparatively investigate the processing of language and music. In this study, native English-speaking participants were presented with brief spoken utterances that were subsequently repeated ten times. The utterances were drawn either from languages that are relatively difficult for a native English speaker to pronounce, or languages that are relatively easy for a native English speaker to pronounce. Moreover, the repetition could occur at regular or irregular temporal intervals. Participants rated the utterances before and after the repetitions on a 5-point Likert-like scale ranging from "sounds exactly like speech" to "sounds exactly like singing." The difference in ratings before and after was taken as a measure of the strength of the speech-to-song illusion in each case. The speech-to-song illusion occurred regardless of whether the repetitions were spaced at regular temporal intervals or not; however, it occurred more readily if the utterance was spoken in a language difficult for a native English speaker to pronounce. Speech circuitry seemed more liable to capture native and easy-to-pronounce languages, and more reluctant to relinquish them to perceived song across repetitions. PMID- 25688226 TI - The comparative science of "self-control": what are we talking about? PMID- 25688227 TI - Synesthesia and release phenomena in sensory and motor grounding. Cases of disinhibited embodiment? PMID- 25688228 TI - Student polling software: where cognitive psychology meets educational practice? PMID- 25688229 TI - Body in mind. PMID- 25688230 TI - Auditory reafferences: the influence of real-time feedback on movement control. AB - Auditory reafferences are real-time auditory products created by a person's own movements. Whereas the interdependency of action and perception is generally well studied, the auditory feedback channel and the influence of perceptual processes during movement execution remain largely unconsidered. We argue that movements have a rhythmic character that is closely connected to sound, making it possible to manipulate auditory reafferences online to understand their role in motor control. We examined if step sounds, occurring as a by-product of running, have an influence on the performance of a complex movement task. Twenty participants completed a hurdling task in three auditory feedback conditions: a control condition with normal auditory feedback, a white noise condition in which sound was masked, and a delayed auditory feedback condition. Overall time and kinematic data were collected. Results show that delayed auditory feedback led to a significantly slower overall time and changed kinematic parameters. Our findings complement previous investigations in a natural movement situation with non artificial auditory cues. Our results support the existing theoretical understanding of action-perception coupling and hold potential for applied work, where naturally occurring movement sounds can be implemented in the motor learning processes. PMID- 25688232 TI - Improvement of skeletal fragility by teriparatide in adult osteoporosis patients: a novel mechanostat-based hypothesis for bone quality. PMID- 25688231 TI - Control of adipocyte differentiation in different fat depots; implications for pathophysiology or therapy. AB - Adipocyte differentiation and its impact on restriction or expansion of particular adipose tissue depots have physiological and pathophysiological significance in view of the different functions of these depots. Brown or "beige" fat [brown adipose tissue (BAT)] expansion can enhance thermogenesis, lipid oxidation, insulin sensitivity, and glucose tolerance; conversely expanded visceral fat [visceral white adipose tissue (VAT)] is associated with insulin resistance, low grade inflammation, dyslipidemia, and cardiometabolic risk. The largest depot, subcutaneous white fat [subcutaneous white adipose tissue (SAT)], has important beneficial characteristics including storage of lipid "out of harms way" and secretion of adipokines, especially leptin and adiponectin, with positive metabolic effects including lipid oxidation, energy utilization, enhanced insulin action, and an anti-inflammatory role. The absence of these functions in lipodystrophies leads to major metabolic disturbances. An ability to expand white adipose tissue adipocyte differentiation would seem an important defense mechanism against the detrimental effects of energy excess and limit harmful accumulation of lipid in "ectopic" sites, such as liver and muscle. Adipocyte differentiation involves a transcriptional cascade with PPARgamma being most important in SAT but less so in VAT, with increased angiogenesis also critical. The transcription factor, Islet1, is fairly specific to VAT and in vitro inhibits adipocyte differentiation. The physiological importance of Islet1 requires further study. Basic control of differentiation is similar in BAT but important differences include the effect of PGC-1alpha on mitochondrial biosynthesis and upregulation of UCP1; also PRDM16 plays a pivotal role in expression of the BAT phenotype. Modulation of the capacity or function of these different adipose tissue depots, by altering adipocyte differentiation or other means, holds promise for interventions that can be helpful in human disease, particularly cardiometabolic disorders associated with the world wide explosion of obesity. PMID- 25688233 TI - Chloramphenicol and tetracycline decrease motility and increase invasion and attachment gene expression in specific isolates of multidrug-resistant Salmonella enterica serovar Typhimurium. AB - Salmonella enterica serovar Typhimurium is one of the most common serovars isolated from humans and livestock, and over 35% of these isolates are resistant to three or more antibiotics. Multidrug-resistant (MDR) Salmonella is a public health concern as it is associated with increased morbidity in patients compared to antibiotic sensitive strains, though it is unknown how the antibiotic resistant isolates lead to a more severe infection. Cellular invasion is temporally regulated in Salmonella and normally occurs during late-log and stationary growth. However, our previous work determined that a 30 min exposure to a sub-inhibitory concentration of tetracycline can induce the full invasion phenotype during early-log growth in certain MDR S. Typhimurium isolates. The current study examined whether sub-inhibitory concentrations of other antibiotics could also induce the invasiveness in the same set of isolates. Ampicillin and streptomycin had no effect on invasion, but certain concentrations of chloramphenicol were found to induce invasion in a subset of isolates. Two of the isolates induced by chloramphenicol were also inducible by tetracycline. RNA-seq analyses demonstrated that chloramphenicol and tetracycline both down-regulated motility gene expression, while up-regulating genes associated with attachment, invasion, and intracellular survival. Eleven fimbrial operons were up-regulated, which is notable as only three fimbrial operons were thought to be inducible in culture; six of these up-regulated operons have been reported to play a role in Salmonella persistence in mice. Overall, these data show that the normal progression of the genetic pathways that regulate invasion can be expedited to occur within 30 min due to antibiotic exposure. This altered invasion process due to antibiotics may play a role in the increased intensity and duration of infection observed in patients with MDR Salmonella. PMID- 25688234 TI - Replicating phages in the epidermal mucosa of the eel (Anguilla anguilla). AB - In this work, we used the eel (Anguilla anguilla) as an animal model to test the hypothesis of Barr et al. (2013a,b) about the putative role of the epidermal mucosa as a phage enrichment layer. To this end, we analyzed the microbial content of the skin mucus of wild and farmed eels by using a metagenomic approach. We found a great abundance of replicating phage genomes (concatemers) in all the samples. They were assembled in four complete genomes of three Myovirus and one Podovirus. We also found evidences that PhiKZ and Podovirus phages could be part of the resident microbiota associated to the eel mucosal surface and persist on them over the time. Moreover, the viral abundance estimated by epiflorescent counts and by metagenomic recruitment from eel mucosa was higher than that of the surrounding water. Taken together, our results support the hypothesis that claims a possible role of phages in the animal mucus as agents controlling bacterial populations, including pathogenic species, providing a kind of innate immunity. PMID- 25688235 TI - The length of a lantibiotic hinge region has profound influence on antimicrobial activity and host specificity. AB - Lantibiotics are ribosomally synthesized (methyl)lanthionine containing peptides which can efficiently inhibit the growth of Gram-positive bacteria. As lantibiotics kill bacteria efficiently and resistance to them is difficult to be obtained, they have the potential to be used in many applications, e.g., in pharmaceutical industry or food industry. Nisin can inhibit the growth of Gram positive bacteria by binding to lipid II and by making pores in their membrane. The C-terminal part of nisin is known to play an important role during translocation over the membrane and forming pore complexes. However, as the thickness of bacterial membranes varies between different species and environmental conditions, this property could have an influence on the pore forming activity of nisin. To investigate this, the so-called "hinge region" of nisin (residues NMK) was engineered to vary from one to six amino acid residues and specific activity against different indicators was compared. Antimicrobial activity in liquid culture assays showed that wild type nisin is most active, while truncation of the hinge region dramatically reduced the activity of the peptide. However, one or two amino acids extensions showed only slightly reduced activity against most indicator strains. Notably, some variants (+2, +1, -1, -2) exhibited higher antimicrobial activity than nisin in agar well diffusion assays against Lactococcus lactis MG1363, Listeria monocytogenes, Enterococcus faecalis VE14089, Bacillus sporothermodurans IC4 and Bacillus cereus 4153 at certain temperatures. PMID- 25688237 TI - Evident bacterial community changes but only slight degradation when polluted with pyrene in a red soil. AB - Understanding the potential for Polycyclic aromatic hydrocarbons (PAH) degradation by indigenous microbiota and the influence of PAHs on native microbial communities is of great importance for bioremediation and ecological evaluation. Various studies have focused on the bacterial communities in the environment where obvious PAH degradation was observed, little is known about the microbiota in the soil where poor degradation was observed. Soil microcosms were constructed with a red soil by supplementation with a high-molecular-weight PAH (pyrene) at three dosages (5, 30, and 70 mg ? kg(-1)). Real-time PCR was used to evaluate the changes in bacterial abundance and pyrene dioxygenase gene (nidA) quantity. Illumina sequencing was used to investigate changes in diversity, structure, and composition of bacterial communities. After 42 days of incubation, no evident degradation was observed. The poor degradation ability was associated with the stability or significant decrease of abundance of the nidA gene. Although the abundance of the bacterial 16S rRNA gene was not affected by pyrene, the bacterial richness and diversity were decreased with increasing dosage of pyrene and the community structure was changed. Phylotypes affected by pyrene were comprehensively surveyed: (1) at the high taxonomic level, seven of the abundant phyla/classes (relative abundance >1.0%) including Chloroflexi, AD3, WPS 2, GAL5, Alphaproteobacteria, Actinobacteria, and Deltaproteobacteria and one rare phylum Crenarchaeota were significantly decreased by at least one dosage of pyrene, while three phyla/classes (Acidobacteria, Betaproteobacteria, and Gammaproteobacteria) were significantly increased; and (2) at the lower taxonomic level, the relative abundances of twelve orders were significantly depressed, whereas those of nine orders were significantly increased. This work enhanced our understanding of the biodegradation potential of pyrene in red soil and the effect of pyrene on soil ecosystems at the microbial community level. PMID- 25688236 TI - The immunoproteasome and viral infection: a complex regulator of inflammation. AB - During viral infection, proper regulation of immune responses is necessary to ensure successful viral clearance with minimal host tissue damage. Proteasomes play a crucial role in the generation of antigenic peptides for presentation on MHC class I molecules, and thus activation of CD8 T cells, as well as activation of the NF-kappaB pathway. A specialized type of proteasome called the immunoproteasome is constitutively expressed in hematopoietic cells and induced in non-immune cells during viral infection by interferon signaling. The immunoproteasome regulates CD8 T cell responses to many viral epitopes during infection. Accumulating evidence suggests that the immunoproteasome may also contribute to regulation of proinflammatory cytokine production, activation of the NF-kappaB pathway, and management of oxidative stress. Many viruses have mechanisms of interfering with immunoproteasome function, including prevention of transcriptional upregulation of immunoproteasome components as well as direct interaction of viral proteins with immunoproteasome subunits. A better understanding of the role of the immunoproteasome in different cell types, tissues, and hosts has the potential to improve vaccine design and facilitate the development of effective treatment strategies for viral infections. PMID- 25688238 TI - Resuscitation of the rare biosphere contributes to pulses of ecosystem activity. AB - Dormancy is a life history trait that may have important implications for linking microbial communities to the functioning of natural and managed ecosystems. Rapid changes in environmental cues may resuscitate dormant bacteria and create pulses of ecosystem activity. In this study, we used heavy-water (H(18) 2O) stable isotope probing (SIP) to identify fast-growing bacteria that were associated with pulses of trace gasses (CO2, CH4, and N2O) from different ecosystems [agricultural site, grassland, deciduous forest, and coniferous forest (CF)] following a soil-rewetting event. Irrespective of ecosystem type, a large fraction (69-74%) of the bacteria that responded to rewetting were below detection limits in the dry soils. Based on the recovery of sequences, in just a few days, hundreds of rare taxa increased in abundance and in some cases became dominant members of the rewetted communities, especially bacteria belonging to the Sphingomonadaceae, Comamonadaceae, and Oxalobacteraceae. Resuscitation led to dynamic shifts in the rank abundance of taxa that caused previously rare bacteria to comprise nearly 60% of the sequences that were recovered in rewetted communities. This rapid turnover of the bacterial community corresponded with a 5 20-fold increase in the net production of CO2 and up to a 150% reduction in the net production of CH4 from rewetted soils. Results from our study demonstrate that the rare biosphere may account for a large and dynamic fraction of a community that is important for the maintenance of bacterial biodiversity. Moreover, our findings suggest that the resuscitation of rare taxa from seed banks contribute to ecosystem functioning. PMID- 25688239 TI - Prevalence and antimicrobial susceptibility of Vibrio parahaemolyticus isolated from retail shrimps in Malaysia. AB - Vibrio parahaemolyticus is a marine and estuarine bacterium that has been the leading cause of foodborne outbreaks which leads to a significant threat to human health worldwide. Consumption of seafood contaminated with V. parahaemolyticus causes acute gastroenteritis in individuals. The bacterium poses two main virulence factor including the thermostable direct hemolysin (tdh) which is a pore-forming protein that contributes to the invasiveness of the bacterium in humans and TDH-related hemolysin (trh), which plays a similar role as tdh in the disease pathogenesis. This study aimed to investigate the antimicrobial resistance V. parahaemolyticus strains in shrimps purchased from wetmarkets and supermarkets. The toxR-based PCR assay indicated that a total of 57.8% (185/320) isolates were positive for V. parahaemolyticus. Only 10% (19/185) toxR-positive isolate exhibit the trh gene and none of the isolates were tested positive for tdh. The MAR index was measured for 14 common antimicrobial agents. The results indicated 98% of the isolates were highly susceptible to imipenem, ampicillin sulbactam (96%), chloramphenicol (95%), trimethoprim-sulfamethoxazole (93%), gentamicin (85%), levofloxacin (83%), and tetracycline (82%). The chloramphenicol (catA2) and kanamycin (aphA-3) resistance genes were detected in the resistant V. parahaemolyticus isolates. Our results demonstrate that shrimps are contaminated with V. parahaemolyticus, some of which carry the trh-gene thus being potential to cause food borne illness. The occurrence of multidrug resistance strains in the environment could be an indication of excessive usage of antibiotics in agriculture and aquaculture fields. PMID- 25688240 TI - Regulation of Interferon-Stimulated Gene BST2 by a lncRNA Transcribed from a Shared Bidirectional Promoter. AB - Recent genome-wide studies have revealed the presence of thousands of long non protein-coding RNAs (lncRNAs), some of which may play critical roles in the cell. We have previously shown that a large number of lncRNAs show differential expression in response to interferon (IFN)alpha stimulation in primary human cells. Here, we show that a subset of IFN-induced lncRNAs are positioned in proximity of protein-coding IFN-stimulated genes (ISGs). The majority of gene pairs originated from bidirectional promoters and showed positively correlated expression. We focused our analysis on a pair consisting of the known protein coding ISG, BST2, and an un-studied putative lncRNA originating from the promoter region of BST2 in a divergent orientation. We showed that this transcript was a multi-exonic, polyadenylated long RNA that lacked protein-coding capacity. BST2 and the lncRNA were both induced in response to IFNalpha in diverse cell types. The induction of both genes was mediated through the JAK-STAT pathway, suggesting that IFN-stimulated response elements within the shared promoter activated the transcription of both genes. RNAi-mediated knock-down of the lncRNA resulted in down-regulation of BST2, and we could show that this down-regulation occurred at the level of transcription. Forced overexpression of this lncRNA, which we named BST2 IFN-Stimulated Positive Regulator (BISPR), resulted in up-regulation of BST2, indicating that the regulation of expression of BST2 by BISPR is mediated through interactions involving BISPR RNA itself, rather than the impact of its transcription from an adjacent locus. Importantly, upon IFN stimulation, transcriptional activation of BISPR preceded the induction of BST2, suggesting that expression of BISPR facilitated the initiation of transcription in its paired protein-coding gene. The lncRNA-mediated transcriptional regulation described in this study may help govern the expression of additional protein coding RNAs involved in IFN response and other cellular processes. PMID- 25688241 TI - gammadelta T Cells in HIV Disease: Past, Present, and Future. AB - Human immunodeficiency virus (HIV) type 1 dysregulates gammadelta T cells as part of an immune evasion mechanism. Nearly three decades of research defined the effects of HIV on gammadelta T cells and how this impacts disease. With highly effective antiretroviral therapy providing virus suppression and longer survival, we expected a return to normal for gammadelta T cells. This is not the case. Even in patients with CD4 T cell reconstitution, normal gammadelta T cell levels and function are not recovered. The durable damage to Vdelta2 T cells is paralleled by defects in NK, CD8 T cells, and dendritic cells. Whether these consequences of HIV stem from similar or distinct mechanisms are not known and effective means for recovering the full range of cellular immunity have not been discovered. These unanswered questions receive too little attention in the overall program of efforts to cure HIV this disease. Approved drugs capable of increasing Vdelta2 T cell function are being tested in clinical trials for cancer and hold promise for restoring normal function in patients with HIV disease. The impetus for conducting clinical trials will come from understanding the significance of gammadelta T cells in HIV disease and what might be gained from targeted immunotherapy. This review traces the history and current progress of AIDS related research on gammadelta T cells. We emphasize the damage to gammadelta T cells that persists despite effective virus suppression. These chronic immune deficits may be linked to the comorbidities of AIDS (cancer, cardiovascular disease, metabolic disease, and others) and will hinder efforts to eradicate HIV by cytotoxic T or NK cell killing. Here, we focus on one subset of T cells that may be critical in the pathogenesis of HIV and an attractive target for new immune-based therapies. PMID- 25688242 TI - Urinary extracellular vesicles as source of biomarkers in kidney diseases. AB - Most cells physiologically release vesicles as way of intercellular communication. The so-called Extracellular Vesicles (EVs) include exosomes, ectosomes, and apoptotic bodies, which basically differ in their composition and subcellular origin. Specifically, EVs found in urine reflect the state of the urinary system, from podocytes to renal-tubular cells, thus making them an excellent source of samples for the study of kidney physiology and pathology. Several groups have focused on defining biomarkers of kidney-related disorders, from graft rejection to metabolic syndromes. So far, the lack of a standard protocol for EVs isolation precludes the possibility of a proper comparison among the different biomarkers proposed in the literature, stressing the need for validation of these biomarkers not only in larger cohorts of patients but also considering the different methods for EVs isolation. In this review, we aim to gather the current knowledge about EVs-related biomarkers in kidney diseases, with a special emphasis in the methods used to date for EVs enrichment, and discussing the need for more specific protocols of EV isolation in clinical practice. PMID- 25688244 TI - Do antimicrobial peptides and complement collaborate in the intestinal mucosa? AB - It is well understood that multiple antimicrobial peptides (AMPs) are constitutively deployed by the epithelium to bolster the innate defenses along the entire length of the intestines. In addition to this constitutive/homeostatic production, AMPs may be inducible and levels changed during disease. In contrast to this level of knowledge on AMP sources and roles in the intestines, our understanding of the complement cascade in the healthy and diseased intestines is rudimentary. Epithelial cells make many complement proteins and there is compelling evidence that complement becomes activated in the lumen. With the common goal of defending the host against microbes, the opportunities for cross talk between these two processes is great, both in terms of actions on the target microbes but also on regulating the synthesis and secretion of the alternate family of molecules. This possibility is beginning to become apparent with the finding that colonic epithelial cells possess anaphylatoxin receptors. There still remains much to be learned about the possible points of collaboration between AMPs and complement, for example, whether there is reciprocal control over expression in the intestinal mucosa in homeostasis and restoring the balance following infection and inflammation. PMID- 25688243 TI - Chemokine receptor-specific antibodies in cancer immunotherapy: achievements and challenges. AB - The 1990s brought a burst of information regarding the structure, expression pattern, and role in leukocyte migration and adhesion of chemokines and their receptors. At that time, the FDA approved the first therapeutic antibodies for cancer treatment. A few years later, it was reported that the chemokine receptors CXCR4 and CCR7 were involved on directing metastases to liver, lung, bone marrow, or lymph nodes, and the over-expression of CCR4, CCR6, and CCR9 by certain tumors. The possibility of inhibiting the interaction of chemokine receptors present on the surface of tumor cells with their ligands emerged as a new therapeutic approach. Therefore, many research groups and companies began to develop small molecule antagonists and specific antibodies, aiming to neutralize signaling from these receptors. Despite great expectations, so far, only one anti chemokine receptor antibody has been approved for its clinical use, mogamulizumab, an anti-CCR4 antibody, granted in Japan to treat refractory adult T-cell leukemia and lymphoma. Here, we review the main achievements obtained with anti-chemokine receptor antibodies for cancer immunotherapy, including discovery and clinical studies, proposed mechanisms of action, and therapeutic applications. PMID- 25688245 TI - Turning 21: Induction of miR-21 as a Key Switch in the Inflammatory Response. AB - miR-21 is one of the most highly expressed members of the small non-coding microRNA family in many mammalian cell types. Its expression is further enhanced in many diseased states including solid tumors, cardiac injury, and inflamed tissue. While the induction of miR-21 by inflammatory stimuli cells has been well documented in both hematopoietic cells of the immune system (particularly monocytes/macrophages but also dendritic and T-cells) and non-hematopoietic tumorigenic cells, the exact functional outcome of this elevated miR-21 is less obvious. Recent studies have confirmed a key role for miR-21 in the resolution of inflammation and in negatively regulating the pro-inflammatory response induced by many of the same stimuli that trigger miR-21 induction itself. In particular, miR-21 has emerged as a key mediator of the anti-inflammatory response in macrophages. This suggests that miR-21 inhibition in leukocytes will promote inflammation and may enhance current therapies for defective immune responses such as cancer, mycobacterial vaccines, or Th2-associated allergic inflammation. At the same time, miR-21 has been shown to promote inflammatory mediators in non hematopoietic cells resulting in neoplastic transformation. This review will focus on functional studies of miR-21 during inflammation, which is complicated by the numerous molecular targets and processes that have emerged as miR-21 sensitive. It may be that the exact functional outcome of miR-21 is determined by multiple features including the cell type affected, the inducing signal, the transcriptomic profile of the cell, which ultimately affect the availability and ability to engage different target mRNAs and bring about its unique responses. Reviewing this data may illustrate that RNA-based oligonucleotide therapies for different diseases based upon miR-21 may have to target the unique and operative miRNA:mRNA interactions' functionally active in disease. PMID- 25688246 TI - gammadelta T Lymphocytes in the Diagnosis of Human T Cell Receptor Immunodeficiencies. PMID- 25688247 TI - Exploring the importance of sulfate transporters and ATP sulphurylases for selenium hyperaccumulation-a comparison of Stanleya pinnata and Brassica juncea (Brassicaceae). AB - Selenium (Se) hyperaccumulation, the capacity of some species to concentrate Se to levels upwards of 0.1% of dry weight, is an intriguing phenomenon that is only partially understood. Questions that remain to be answered are: do hyperaccumulators have one or more Se-specific transporters? How are these regulated by Se and sulfur (S)? In this study, hyperaccumulator Stanleya pinnata was compared with related non-hyperaccumulator Brassica juncea with respect to S dependent selenate uptake and translocation, as well as for the expression levels of three sulfate/selenate transporters (Sultr) and three ATP sulphurylases (APS). Selenium accumulation went down ~10-fold with increasing sulfate supply in B. juncea, while S. pinnata only had a 2-3-fold difference in Se uptake between the highest (5 mM) and lowest sulfate (0 mM) treatments. The Se/S ratio was generally higher in the hyperaccumulator than the non-hyperaccumulator, and while tissue Se/S ratio in B. juncea largely reflected the ratio in the growth medium, S. pinnata enriched itself up to 5-fold with Se relative to S. The transcript levels of Sultr1;2 and 2;1 and APS1, 2, and 4 were generally much higher in S. pinnata than B. juncea, and the species showed differential transcript responses to S and Se supply. These results indicate that S. pinnata has at least one transporter with significant selenate specificity over sulfate. Also, the hyperaccumulator has elevated expression levels of several sulfate/selenate transporters and APS enzymes, which likely contribute to the Se hyperaccumulation and hypertolerance phenotype. PMID- 25688248 TI - Development and Characterization of Somatic Hybrids of Ulva reticulata Forsskal (*) Monostroma oxyspermum (Kutz.)Doty. AB - Ulvophycean species with diverse trait characteristics provide an opportunity to create novel allelic recombinant variants. The present study reports the development of seaweed variants with improved agronomic traits through protoplast fusion between Monostroma oxyspermum (Kutz.) Doty and Ulva reticulata Forsskal. A total of 12 putative hybrids were screened based on the variations in morphology and total DNA content over the fusion partners. DNA-fingerprinting by inter simple sequence repeat (ISSR) and amplified fragment length polymorphism (AFLP) analysis confirmed genomic introgression in the hybrids. The DNA fingerprint revealed sharing of parental alleles in regenerated hybrids and a few alleles that were unique to hybrids. The epigenetic variations in hybrids estimated in terms of DNA methylation polymorphism also revealed sharing of methylation loci with both the fusion partners. The functional trait analysis for growth showed a hybrid with heterotic trait (DGR% = 36.7 +/- 1.55%) over the fusion partners U. reticulata (33.2 +/- 2.6%) and M. oxyspermum (17.8 +/- 1.77%), while others were superior to the mid-parental value (25.2 +/- 2.2%) (p < 0.05). The fatty acid (FA) analysis of hybrids showed notable variations over fusion partners. Most hybrids showed increased polyunsaturated FAs (PUFAs) compared to saturated FAs (SFAs) and mainly includes the nutritionally important linoleic acid, alpha linolenic acid, oleic acid, stearidonic acid, and docosahexaenoic acid. The other differences observed include superior cellulose content and antioxidative potential in hybrids over fusion partners. The hybrid varieties with superior traits developed in this study unequivocally demonstrate the significance of protoplast fusion technique in developing improved varients of macroalgae. PMID- 25688249 TI - When plants produce not enough or at all: metabolic engineering of flavonoids in microbial hosts. AB - As a result of the discovery that flavonoids are directly or indirectly connected to health, flavonoid metabolism and its fascinating molecules that are natural products in plants, have attracted the attention of both the industry and researchers involved in plant science, nutrition, bio/chemistry, chemical bioengineering, pharmacy, medicine, etc. Subsequently, in the past few years, flavonoids became a top story in the pharmaceutical industry, which is continually seeking novel ways to produce safe and efficient drugs. Microbial cell cultures can act as workhorse bio-factories by offering their metabolic machinery for the purpose of optimizing the conditions and increasing the productivity of a selective flavonoid. Furthermore, metabolic engineering methodology is used to reinforce what nature does best by correcting the inadequacies and dead-ends of a metabolic pathway. Combinatorial biosynthesis techniques led to the discovery of novel ways of producing natural and even unnatural plant flavonoids, while, in addition, metabolic engineering provided the industry with the opportunity to invest in synthetic biology in order to overcome the currently existing restricted diversification and productivity issues in synthetic chemistry protocols. In this review, is presented an update on the rationalized approaches to the production of natural or unnatural flavonoids through biotechnology, analyzing the significance of combinatorial biosynthesis of agricultural/pharmaceutical compounds produced in heterologous organisms. Also mentioned are strategies and achievements that have so far thrived in the area of synthetic biology, with an emphasis on metabolic engineering targeting the cellular optimization of microorganisms and plants that produce flavonoids, while stressing the advances in flux dynamic control and optimization. Finally, the involvement of the rapidly increasing numbers of assembled genomes that contribute to the gene- or pathway-mining in order to identify the gene(s) responsible for producing species-specific secondary metabolites is also considered herein. PMID- 25688250 TI - The absence of protein Y4yS affects negatively the abundance of T3SS Mesorhizobium loti secretin, RhcC2, in bacterial membranes. AB - Mesorhizobium loti MAFF303099 has a functional type III secretion system (T3SS) that is involved in the determination of nodulation competitiveness on Lotus. The M. loti T3SS cluster contains gene y4yS (mlr8765) that codes for a protein of unknown function (Y4yS). A mutation in the y4yS gene favors the M. loti symbiotic competitive ability on Lotus tenuis cv. Esmeralda and affects negatively the secretion of proteins through T3SS. Here we localize Y4yS in the bacterial membrane using a translational reporter peptide fusion. In silico analysis indicated that this protein presents a tetratricopeptide repeat (TPR) domain, a signal peptide and a canonical lipobox LGCC in the N-terminal sequence. These features that are shared with proteins required for the formation of the secretin complex in type IV secretion systems and in the Tad system, together with its localization, suggest that the y4yS-encoded protein is required for the formation of the M. loti T3SS secretin (RhcC2) complex. Remarkably, analysis of RhcC2 in the wild-type and M. loti y4yS mutant strains indicated that the absence of Y4yS affects negatively the accumulation of normal levels of RhcC2 in the membrane. PMID- 25688251 TI - Facile high-throughput forward chemical genetic screening by in situ monitoring of glucuronidase-based reporter gene expression in Arabidopsis thaliana. AB - The use of biologically active small molecules to perturb biological functions holds enormous potential for investigating complex signaling networks. However, in contrast to animal systems, the search for and application of chemical tools for basic discovery in the plant sciences, generally referred to as "chemical genetics," has only recently gained momentum. In addition to cultured cells, the well-characterized, small-sized model plant Arabidopsis thaliana is suitable for cultivation in microplates, which allows employing diverse cell- or phenotype based chemical screens. In such screens, a chemical's bioactivity is typically assessed either through scoring its impact on morphological traits or quantifying molecular attributes such as enzyme or reporter activities. Here, we describe a facile forward chemical screening methodology for intact Arabidopsis seedlings harboring the beta-glucuronidase (GUS) reporter by directly quantifying GUS activity in situ with 4-methylumbelliferyl-beta-D-glucuronide (4-MUG) as substrate. The quantitative nature of this screening assay has an obvious advantage over the also convenient histochemical GUS staining method, as it allows application of statistical procedures and unbiased hit selection based on threshold values as well as distinction between compounds with strong or weak bioactivity. At the same time, the in situ bioassay is very convenient requiring less effort and time for sample handling in comparison to the conventional quantitative in vitro GUS assay using 4-MUG, as validated with several Arabidopsis lines harboring different GUS reporter constructs. To demonstrate that the developed assays is particularly suitable for large-scale screening projects, we performed a pilot screen for chemical activators or inhibitors of salicylic acid-mediated defense signaling using the Arabidopsis PR1p::GUS line. Importantly, the screening methodology provided here can be adopted for any inducible GUS reporter line. PMID- 25688252 TI - To grow old: regulatory role of ethylene and jasmonic acid in senescence. AB - Senescence, the final stage in the development of an organ or whole plant, is a genetically programmed process controlled by developmental and environmental signals. Age-related signals underlie the onset of senescence in specific organs (leaf, flower, and fruit) as well as the whole plant (monocarpic senescence). Rudimentary to most senescence processes is the plant hormone ethylene, a small gaseous molecule critical to diverse processes throughout the life of the plant. The role of ethylene in senescence was discovered almost 100 years ago, but the molecular mechanisms by which ethylene regulates senescence have been deciphered more recently primarily through genetic and molecular studies in Arabidopsis. Jasmonic acid (JA), another plant hormone, is emerging as a key player in the control of senescence. The regulatory network of ethylene and JA involves the integration of transcription factors, microRNAs, and other hormones. In this review, we summarize the current understanding of ethylene's role in senescence, and discuss the interplay of ethylene with JA in the regulation of senescence. PMID- 25688253 TI - Time to dig deep into the plant proteome: a hunt for low-abundance proteins. PMID- 25688255 TI - Toward a more physiologically and evolutionarily relevant definition of metal hyperaccumulation in plants. PMID- 25688254 TI - To die or not to die? Lessons from lesion mimic mutants. AB - Programmed cell death (PCD) is a ubiquitous genetically regulated process consisting in an activation of finely controlled signaling pathways that lead to cellular suicide. Although some aspects of PCD control appear evolutionary conserved between plants, animals and fungi, the extent of conservation remains controversial. Over the last decades, identification and characterization of several lesion mimic mutants (LMM) has been a powerful tool in the quest to unravel PCD pathways in plants. Thanks to progress in molecular genetics, mutations causing the phenotype of a large number of LMM and their related suppressors were mapped, and the identification of the mutated genes shed light on major pathways in the onset of plant PCD such as (i) the involvements of chloroplasts and light energy, (ii) the roles of sphingolipids and fatty acids, (iii) a signal perception at the plasma membrane that requires efficient membrane trafficking, (iv) secondary messengers such as ion fluxes and ROS and (v) the control of gene expression as the last integrator of the signaling pathways. PMID- 25688256 TI - MRM-DIFF: data processing strategy for differential analysis in large scale MRM based lipidomics studies. AB - Based on theoretically calculated comprehensive lipid libraries, in lipidomics as many as 1000 multiple reaction monitoring (MRM) transitions can be monitored for each single run. On the other hand, lipid analysis from each MRM chromatogram requires tremendous manual efforts to identify and quantify lipid species. Isotopic peaks differing by up to a few atomic masses further complicate analysis. To accelerate the identification and quantification process we developed novel software, MRM-DIFF, for the differential analysis of large-scale MRM assays. It supports a correlation optimized warping (COW) algorithm to align MRM chromatograms and utilizes quality control (QC) sample datasets to automatically adjust the alignment parameters. Moreover, user-defined reference libraries that include the molecular formula, retention time, and MRM transition can be used to identify target lipids and to correct peak abundances by considering isotopic peaks. Here, we demonstrate the software pipeline and introduce key points for MRM-based lipidomics research to reduce the mis identification and overestimation of lipid profiles. The MRM-DIFF program, example data set and the tutorials are downloadable at the "Standalone software" section of the PRIMe (Platform for RIKEN Metabolomics, http://prime.psc.riken.jp/) database website. PMID- 25688257 TI - Global DNA cytosine methylation as an evolving trait: phylogenetic signal and correlated evolution with genome size in angiosperms. AB - DNA cytosine methylation is a widespread epigenetic mechanism in eukaryotes, and plant genomes commonly are densely methylated. Genomic methylation can be associated with functional consequences such as mutational events, genomic instability or altered gene expression, but little is known on interspecific variation in global cytosine methylation in plants. In this paper, we compare global cytosine methylation estimates obtained by HPLC and use a phylogenetically informed analytical approach to test for significance of evolutionary signatures of this trait across 54 angiosperm species in 25 families. We evaluate whether interspecific variation in global cytosine methylation is statistically related to phylogenetic distance and also whether it is evolutionarily correlated with genome size (C-value). Global cytosine methylation varied widely between species, ranging between 5.3% (Arabidopsis) and 39.2% (Narcissus). Differences between species were related to their evolutionary trajectories, as denoted by the strong phylogenetic signal underlying interspecific variation. Global cytosine methylation and genome size were evolutionarily correlated, as revealed by the significant relationship between the corresponding phylogenetically independent contrasts. On average, a ten-fold increase in genome size entailed an increase of about 10% in global cytosine methylation. Results show that global cytosine methylation is an evolving trait in angiosperms whose evolutionary trajectory is significantly linked to changes in genome size, and suggest that the evolutionary implications of epigenetic mechanisms are likely to vary between plant lineages. PMID- 25688258 TI - Assessment of autozygosity in Nellore cows (Bos indicus) through high-density SNP genotypes. AB - The use of relatively low numbers of sires in cattle breeding programs, particularly on those for carcass and weight traits in Nellore beef cattle (Bos indicus) in Brazil, has always raised concerns about inbreeding, which affects conservation of genetic resources and sustainability of this breed. Here, we investigated the distribution of autozygosity levels based on runs of homozygosity (ROH) in a sample of 1,278 Nellore cows, genotyped for over 777,000 SNPs. We found ROH segments larger than 10 Mb in over 70% of the samples, representing signatures most likely related to the recent massive use of few sires. However, the average genome coverage by ROH (>1 Mb) was lower than previously reported for other cattle breeds (4.58%). In spite of 99.98% of the SNPs being included within a ROH in at least one individual, only 19.37% of the markers were encompassed by common ROH, suggesting that the ongoing selection for weight, carcass and reproductive traits in this population is too recent to have produced selection signatures in the form of ROH. Three short-range highly prevalent ROH autosomal hotspots (occurring in over 50% of the samples) were observed, indicating candidate regions most likely under selection since before the foundation of Brazilian Nellore cattle. The putative signatures of selection on chromosomes 4, 7, and 12 may be involved in resistance to infectious diseases and fertility, and should be subject of future investigation. PMID- 25688259 TI - Genetics of kidney disease and related cardiometabolic phenotypes in Zuni Indians: the Zuni Kidney Project. AB - The objective of this study is to identify genetic factors associated with chronic kidney disease (CKD) and related cardiometabolic phenotypes among participants of the Genetics of Kidney Disease in Zuni Indians study. The study was conducted as a community-based participatory research project in the Zuni Indians, a small endogamous tribe in rural New Mexico. We recruited 998 members from 28 extended multigenerational families, ascertained through probands with CKD who had at least one sibling with CKD. We used the Illumina Infinium Human1M Duo version 3.0 BeadChips to type 1.1 million single nucleotide polymorphisms (SNPs). Prevalence estimates for CKD, hyperuricemia, diabetes, and hypertension were 24%, 30%, 17% and 34%, respectively. We found a significant (p < 1.58 * 10( 7)) association for a SNP in a novel gene for serum creatinine (PTPLAD2). We replicated significant associations for genes with serum uric acid (SLC2A9), triglyceride levels (APOA1, BUD13, ZNF259), and total cholesterol (PVRL2). We found novel suggestive associations (p < 1.58 * 10(-6)) for SNPs in genes with systolic (OLFML2B), and diastolic blood pressure (NFIA). We identified a series of genes associated with CKD and related cardiometabolic phenotypes among Zuni Indians, a population with a high prevalence of kidney disease. Illuminating genetic variations that modulate the risk for these disorders may ultimately provide a basis for novel preventive strategies and therapeutic interventions. PMID- 25688260 TI - Werner Syndrome-specific induced pluripotent stem cells: recovery of telomere function by reprogramming. AB - Werner syndrome (WS) is a rare human autosomal recessive premature aging disorder characterized by early onset of aging-associated diseases, chromosomal instability, and cancer predisposition. The function of the DNA helicase encoded by WRN, the gene responsible for WS, has been studied extensively. WRN helicase is involved in the maintenance of chromosome integrity through DNA replication, repair, and recombination by interacting with a variety of proteins associated with DNA repair and telomere maintenance. The accelerated aging associated with WS is reportedly caused by telomere dysfunction, and the underlying mechanism of the disease is yet to be elucidated. Although it was reported that the life expectancy for patients with WS has improved over the last two decades, definitive therapy for these patients has not seen much development. Severe symptoms of the disease, such as leg ulcers, cause a significant decline in the quality of life in patients with WS. Therefore, the establishment of new therapeutic strategies for the disease is of utmost importance. Induced pluripotent stem cells (iPSCs) can be established by the introduction of several pluripotency genes, including Oct3/4, Sox2, Klf4, and c-myc into differentiated cells. iPSCs have the potential to differentiate into a variety of cell types that constitute the human body, and possess infinite proliferative capacity. Recent studies have reported the generation of iPSCs from the cells of patients with WS, and they have concluded that reprogramming represses premature senescence phenotypes in these cells. In this review, we summarize the findings of WS patient-specific iPSCs (WS iPSCs) and focus on the roles of telomere and telomerase in the maintenance of these cells. Finally, we discuss the potential use of WS iPSCs for clinical applications. PMID- 25688261 TI - The role of GSK3beta in the development of the central nervous system. AB - Glycogen synthase kinase 3beta (GSK3beta) is a multifunctional serine/threonine kinase. It is particularly abundant in the developing central nervous system (CNS). Since GSK3beta has diverse substrates ranging from metabolic/signaling proteins and structural proteins to transcription factors, it is involved in many developmental events in the immature brain, such as neurogenesis, neuronal migration, differentiation and survival. The activity of GSK3beta is developmentally regulated and is affected by various environmental/cellular insults, such as deprivation of nutrients/trophic factors, oxidative stress and endoplasmic reticulum stress. Abnormalities in GSK3beta activity may disrupt CNS development. Therefore, GSK3beta is a critical signaling protein that regulates brain development. It may also determine neuronal susceptibility to damages caused by various environmental insults. PMID- 25688262 TI - Awareness and uptake of family screening in patients diagnosed with colorectal cancer at a young age. AB - Background. One-fifth of people who develop colorectal cancer (CRC) have a first degree relative (FDR) also affected. There is a large disparity in guidelines for screening of relatives of patients with CRC. Herein we address awareness and uptake of family screening amongst patients diagnosed with CRC under age 60 and compare guidelines for screening. Study Design. Patients under age 60 who received surgical management for CRC between June 2009 and May 2012 were identified using pathology records and theatre logbooks. A telephone questionnaire was carried out to investigate family history and screening uptake among FDRs. Results. Of 317 patients surgically managed for CRC over the study period, 65 were under age 60 at diagnosis (8 deceased). The mean age was 51 (30 59). 66% had node positive disease. 25% had a family history of colorectal cancer in a FDR. While American and Canadian guidelines identified 100% of these patients as requiring screening, British guidelines advocated screening for only 40%. Of 324 FDRs, only 40.9% had been screened as a result of patient's diagnosis. Conclusions. Uptake of screening in FDRs of young patients with CRC is low. Increased education and uniformity of guidelines may improve screening uptake in this high-risk population. PMID- 25688263 TI - Vascular endothelial injury and apoptosis in rats with severe acute pancreatitis. AB - We explored mechanisms of vascular endothelial injury that lead to systemic multiple organ failure by detecting the soluble endothelial protein C receptor (sEPCR), von Willebrand factor (vWF), serum nitric oxide (NO), and tumor necrosis factor alpha (TNF-alpha) and Bcl-2 mRNA and Bax mRNA expression in a severe acute pancreatitis (SAP) rat model. Compared to controls, the levels of TNF-alpha, vWF, and sEPCR were significantly increased in the experimental group at 12 hours and 24 hours and the NO level was significantly decreased. After 12 hours, the aortic endothelial apoptosis index and Bax mRNA expression in aortic endothelial cells had increased in the experimental group, but Bcl-2 mRNA levels had decreased. All these changes appeared at both 12 h and 24 hours. The results indicated that vascular endothelial injury and apoptosis markers were elevated in SAP. Endothelial injury and increased apoptosis in the experimental group were related to the increased expression of TNF-alpha. PMID- 25688264 TI - Immunohistochemical expression of dual-specificity protein phosphatase 4 in patients with colorectal adenocarcinoma. AB - The role of dual-specificity protein phosphatase 4 (DUSP4) appears to vary with the type of malignant tumors and is still controversial. The purpose of our study was to clarify the exact role of DUSP4 expression in colorectal adenocarcinoma. We constructed tissue microarrays and investigated DUSP4 expression by immunohistochemistry. DUSP4 was more frequently expressed in adenocarcinomas and lymph node/distant metastases compared to that in normal colorectal tissues and tubular adenomas (P < 0.001). Mean DUSP4 expression score was significantly higher in malignant tumors than in benign lesions (P < 0.001). DUSP4 expression was significantly correlated with older age (P = 0.017), male gender (P = 0.036), larger tumor size (P = 0.014), nonmucinous tumor type (P = 0.023), and higher T stage (P = 0.040). Kaplan-Meier survival curves revealed a significant effect of DUSP4 expression on both overall survival and disease-free survival in AJCC stage I (P = 0.008 and P = 0.003, resp., log-rank test) and male gender (P = 0.017 and P = 0.049, resp., log-rank test). DUSP4 protein is frequently upregulated in colorectal adenocarcinoma and may play an important role in carcinogenesis and cancer progression and may be a marker of adverse prognosis. PMID- 25688265 TI - Potential risk factors for the onset of complex regional pain syndrome type 1: a systematic literature review. AB - Anaesthetists in the acute and chronic pain teams are often involved in treating Complex Regional Pain Syndromes. Current literature about the risk factors for the onset of Complex Regional Pain Syndrome Type 1 (CRPS 1) remains sparse. This syndrome has a low prevalence, a highly variable presentation, and no gold standard for diagnosis. In the research setting, the pathogenesis of the syndrome continues to be elusive. There is a growing body of literature that addresses efficacy of a wide range of interventions as well as the likely mechanisms that contribute to the onset of CRPS 1. The objective for this systematic search of the literature focuses on determining the potential risk factors for the onset of CRPS 1. Eligible articles were analysed, dated 1996 to April 2014, and potential risk factors for the onset of CRPS 1 were identified from 10 prospective and 6 retrospective studies. Potential risk factors for the onset of CRPS 1 were found to include being female, particularly postmenopausal female, ankle dislocation or intra-articular fracture, immobilisation, and a report of higher than usual levels of pain in the early phases of trauma. It is not possible to draw definite conclusions as this evidence is heterogeneous and of mixed quality, relevance, and weighting strength against bias and has not been confirmed across multiple trials or in homogenous studies. PMID- 25688266 TI - Higher Performance of DSSC with Dyes from Cladophora sp. as Mixed Cosensitizer through Synergistic Effect. AB - Chlorophyll and xanthophyll dyes extracted from a single source of filamentous freshwater green algae (Cladophora sp.) were used to sensitize dye sensitized solar cells and their performances were investigated. A more positive interaction is expected as the derived dyes come from a single natural source because they work mutually in nature. Cell sensitized with mixed chlorophyll and xanthophyll showed synergistic activity with improved cell performance of 1.5- to 2-fold higher than that sensitized with any individual dye. The effect of temperature and the stability of these dyes were also investigated. Xanthophyll dye was found to be more stable compared to chlorophyll that is attributed in the ability of xanthophyll to dissipate extra energy via reversible structural changes. Mixing the dyes resulted to an increase in effective electron life time and reduced the process of electron recombination during solar cell operation, hence exhibiting a synergistic effect. PMID- 25688267 TI - Increased susceptibility to ethylmercury-induced mitochondrial dysfunction in a subset of autism lymphoblastoid cell lines. AB - The association of autism spectrum disorders with oxidative stress, redox imbalance, and mitochondrial dysfunction has become increasingly recognized. In this study, extracellular flux analysis was used to compare mitochondrial respiration in lymphoblastoid cell lines (LCLs) from individuals with autism and unaffected controls exposed to ethylmercury, an environmental toxin known to deplete glutathione and induce oxidative stress and mitochondrial dysfunction. We also tested whether pretreating the autism LCLs with N-acetyl cysteine (NAC) to increase glutathione concentrations conferred protection from ethylmercury. Examination of 16 autism/control LCL pairs revealed that a subgroup (31%) of autism LCLs exhibited a greater reduction in ATP-linked respiration, maximal respiratory capacity, and reserve capacity when exposed to ethylmercury, compared to control LCLs. These respiratory parameters were significantly elevated at baseline in the ethylmercury-sensitive autism subgroup as compared to control LCLs. NAC pretreatment of the sensitive subgroup reduced (normalized) baseline respiratory parameters and blunted the exaggerated ethylmercury-induced reserve capacity depletion. These findings suggest that the epidemiological link between environmental mercury exposure and an increased risk of developing autism may be mediated through mitochondrial dysfunction and support the notion that a subset of individuals with autism may be vulnerable to environmental influences with detrimental effects on development through mitochondrial dysfunction. PMID- 25688268 TI - Survival Outcomes and Tumor IMP3 Expression in Patients with Sarcomatoid Metastatic Renal Cell Carcinoma. AB - Metastatic renal cell carcinoma with sarcomatoid histology (SmRCC) is associated with poor survival. No data is available from randomized trials on the efficacy of vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) inhibitors in SmRCC. We identified SmRCC patients from a single institutional database. To identify predictive and prognostic biomarkers, immunohistochemistry (IHC) analysis was performed on the tumor samples for downstream targets of VEGF and mTOR pathways. Survival outcomes were stratified by IHC analysis, extent of sarcomatoid component, Memorial Sloan-Kettering Cancer Center (MSKCC), and Heng risk criteria. Twenty-seven patients with SmRCC were included. First line therapy included targeted therapy (n = 19), immunotherapy (n = 4), cytotoxic chemotherapy (n = 1), and no treatment (n = 3). Median OS was 8.2 months (95% CI 3.8-14.2 months). Median survival in months, based on MSKCC and Heng risk groups, was favorable 89.3 versus 84.5, intermediate 9.5 versus 12.7, and poor 3.9 versus 5.1. None of the IHC markers predicted outcomes of treatment with VEGF or mTOR inhibitors. Only tumor IMP3 expression was associated with inferior OS, although not statistically significant (IMP3 negative 14.2 versus IMP3 positive 4.9 months; HR 0.46, 95% CI 0.16-1.21; P = 0.12). The study was limited by small sample size. PMID- 25688269 TI - Acute obstructive suppurative pancreatic ductitis in an asymptomatic patient. AB - Acute obstructive suppurative pancreatic ductitis (AOSPD), defined as suppuration from the pancreatic duct without associated pseudocyst, abscess, or necrosis, is a rare complication of chronic pancreatitis. We present the first case of AOSPD in an asymptomatic patient with a polymicrobial infection and review the literature on this rare clinical entity. PMID- 25688270 TI - Fatal retroperitoneal bleeding caused by neurofibromatosis: a case report and review of the literature. AB - A young female was brought into the emergency department with pulseless electrical activity (PEA) after local resection of neurofibromateous lesions. Chest ultrasonography was normal. Abdominal ultrasonography was not performed. After successful resuscitation a total body CT-scan was performed to rule out potential bleeding sources. However, haemodynamic instability reoccurred and the scan had to be aborted at the thoracoabdominal level. No thoracic abnormalities were found. Resuscitation was reinitiated and abdominal ultrasonography was performed, showing a large amount of abdominal fluid. A progressive fall in haemoglobin was noted. Emergency laparotomy was performed, revealing a large retroperitoneal haematoma. Despite ligation and packing, bleeding continued. Postoperative angiography showed active bleeding from a branch of the left internal iliac artery, which could be successfully coiled. Unfortunately, the patient died five days later due to irreversible brain damage. Revision of an MRI scan made one year earlier showed a 10 cm large retroperitoneal neurofibromatous lesion exactly at the location of the current bleeding. This case shows that patients with neurofibromatosis might develop spontaneous life-threatening bleeding from retroperitoneal located lesions. Furthermore, it points out the necessity of focused assessment with ultrasonography of the abdomen in all patients with PEA of unknown origin. PMID- 25688271 TI - Giant polypoid tumor expressing on the pyloric ring. AB - A 66-year-old Japanese man was referred to our hospital because of suspected duodenal cancer. Upper gastric endoscopy revealed a giant polypoid-type tumor that extended from the duodenum bulb to the pyloric ring. A computed tomography scan revealed a slightly enhanced lobular tumor protruding into the duodenum bulb. Positron emission tomography showed an accumulation of (18)F fluorodeoxyglucose in the area extending from the antrum of the stomach to the duodenum bulb. Since an endoscopic ultrasound test suggested that the tumor might invade the muscular tunic, indications of endoscopic mucosal resection were not favored, and the tumor was curatively removed via distal gastrectomy. The histopathologic diagnosis was papillary adenocarcinoma, and the invasion depth was the mucosal layer without vascular invasion, which was different from the preoperative diagnosis. Our case suggests the difficulties in precise diagnosis of the invasion depth of the giant polypoid cancer. PMID- 25688272 TI - Human adult stem cells maintain a constant phenotype profile irrespective of their origin, Basal media, and long term cultures. AB - The study aims to identify the phenotypic marker expressions of different human adult stem cells derived from, namely, bone marrow, subcutaneous fat, and omentum fat, cultured in different media, namely, DMEM-Low Glucose, Alpha-MEM, DMEM-F12 and DMEM-KO and under long term culture conditions (>P20). We characterized immunophenotype by using various hematopoietic, mesenchymal, endothelial markers, and cell adhesion molecules in the long term cultures (Passages-P1, P3, P5, P9, P12, P15, and P20.) Interestingly, data revealed similar marker expression profiles irrespective of source, basal media, and extensive culturing. This demonstrates that all adult stem cell sources mentioned in this study share similar phenotypic marker and all media seem appropriate for culturing these sources. However, a disparity was observed in the markers such as CD49d, CD54, CD117, CD29, and CD106, thereby warranting further research on these markers. Besides the aforesaid objective, it is understood from the study that immunophenotyping acts as a valuable tool to identify inherent property of each cell, thereby leading to a valuable cell based therapy. PMID- 25688273 TI - Multiple myeloma patients at various cytogenetic risks benefit differently from autologous stem cell transplantation as a consolidation therapy. AB - Aim. To evaluate whether patients with multiple myeloma at various risks can still benefit the same from autologous stem cell transplantation consolidation in the era of novel agents. We retrospectively analyzed 67 consecutive myeloma patients receiving autologous stem cell transplantation after bortezomib and/or thalidomide based inductions. Totally 17 high-risk, 24 intermediate-risk, and 26 low-risk patients were enrolled, based on fluorescence in situ hybridization and ISS stage. Meanwhile, another 67 risk-, response depth-, and age-matched patients not proceeding to autologous stem cell transplantation were chosen as controls. Our preliminary data indicated that, in the high-risk subgroup, progression-free survival and overall survival were both significantly prolonged after autologous stem cell transplantation (P < 0.001 and P = 0.015) while, in the intermediate risk subgroup, neither progression-free survival nor overall survival was prolonged significantly after autologous stem cell transplantation (P > 0.05), and in the low-risk subgroup, only progression-free survival was extended significantly (P = 0.012) after autologous stem cell transplantation. Multiple variables analysis further indicated that autologous stem cell transplantation and risk stratification were two independent prognostic factors for overall survival. Our results indicated that myeloma patients at different risks all benefit from autologous stem cell transplantation consolidation even in the era of novel agents. PMID- 25688274 TI - Comparison of selected metals content in Cambodian striped snakehead fish (Channa striata) using solar drying system and open sun drying. AB - The content of 12 elements in Cambodian dried striped snakehead fish was determined using inductively coupled plasma mass spectrometry. The present study compares the level of the trace toxic metals and nutritional trace elements in the fish processed using solar drying system (SDS) and open sun drying (OSD). The skin of SDS fish has lower level of As, Pb, and Cd compared to the OSD sample. As such, the flesh of the fish accumulated higher amount of toxic metals during OSD compared to SDS. However, arsenic was detected in both samples within the safe limit. The nutritional elements (Fe, Mn, Mg, Se, Mo, Cu, Ni, and Cr) were higher in the skin sample SDS fish compared to OSD fish. These beneficial metals were not accumulated in the flesh sample SDS fish demonstrating lower level compared to drying under conventional system. The reddish coloration of the SDS fish was due to the presence of high Cu content in both the skin and flesh samples which possibly account for no mold formation 5 days after packaging. As conclusion, drying of Cambodian C. striata using solar-assisted system has proven higher content of the nutritious elements compared to using the conventional system despite only slight difference in the toxic metals level between the two systems. PMID- 25688275 TI - Translational research in complementary and alternative medicine 2014. PMID- 25688276 TI - Sitting tai chi improves the balance control and muscle strength of community dwelling persons with spinal cord injuries: a pilot study. AB - Objective. To investigate the effects of sitting Tai Chi on muscle strength, balance control, and quality of life (QOL) among survivors with spinal cord injuries (SCI). Methods. Eleven SCI survivors participated in the sitting Tai Chi training (90 minutes/session, 2 times/week for 12 weeks) and eight SCI survivors acted as controls. Dynamic sitting balance was evaluated using limits of stability test and a sequential weight shifting test in sitting. Handgrip strength was also tested using a hand-held dynamometer. QOL was measured using the World Health Organization's Quality of Life Scale. Results. Tai Chi practitioners achieved significant improvements in their reaction time (P = 0.042); maximum excursion (P = 0.016); and directional control (P = 0.025) in the limits of stability test after training. In the sequential weight shifting test, they significantly improved their total time to sequentially hit the 12 targets (P = 0.035). Significant improvement in handgrip strength was also found among the Tai Chi practitioners (P = 0.049). However, no significant within and between group differences were found in the QOL outcomes (P > 0.05). Conclusions. Twelve weeks of sitting Tai Chi training could improve the dynamic sitting balance and handgrip strength, but not QOL, of the SCI survivors. PMID- 25688277 TI - Effectiveness of moxibustion treatment in quality of life in patients with knee osteoarthritis: a randomized, double-blinded, placebo-controlled trial. AB - Objective. To observe the effects of traditional Chinese moxibustion, compared with sham moxibustion, on the quality of life (QOL) in patients with chronic knee osteoarthritis (KOA). Methods. This is a randomized double-blinded, placebo controlled trial. 150 patients with KOA were randomly allocated to either a true moxibustion treatment (n = 77) or a sham moxibustion treatment (n = 73) three times a week for six weeks. The QOL of patients was evaluated with SF-36 at baseline and 3, 6, and 12 weeks after baseline. Results. 136 patients were available for analysis. Participants in the true moxibustion group experienced statistically significantly greater improvement in GH (general health) scores than the sham group at week 6 (P = 0.015) and week 12 (P = 0.029). Participants in the true moxibustion group experienced statistically significantly greater improvement in VT (vitality) scores than the sham group at week 12 (P = 0.042). No significant adverse effects were found during the trial. Conclusion. A 6-week moxibustion treatment seems to improve general health and vitality, which are associated with physical and mental quality of life, in patients with KOA up to 12 weeks, relative to credible sham moxibustion. This trial is registered with Clinicaltrials.gov ISRCTN68475405. PMID- 25688278 TI - Evaluation of Antibacterial and Antifungal Properties of Alchornea laxiflora (Benth.) Pax. & Hoffman. AB - Alchornea laxiflora leaf extract was tested against a range of microorganisms using standard microbiological methods for antimicrobial activities. The extract inhibited the growth of all the bacterial and 15 fungal isolates tested. The zones of inhibition exhibited against the test bacteria ranged between 12 mm and 24 mm and between 11 mm and 24 mm for the extract and the antibiotic streptomycin, respectively. The zones of inhibition observed against the fungal isolates by the extract ranged between 12 mm and 23 mm. The minimum inhibitory concentrations (MICs) and the minimum bactericidal concentrations (MBCs) exhibited by the extract against test bacteria ranged between 0.78 mg/mL-25 mg/mL and 1.56 mg/mL-25 mg/mL, respectively, while the MICs and minimum fungicidal concentrations (MFCs) values for the test fungi ranged between 8.75 mg/mL-35.00 mg/mL and 8.75 mg/mL-35.00 mg/L, respectively. The preliminary phytochemical screening of the extract revealed the presence of alkaloids, tannins, flavonoids, saponins, and reducing sugars as major phytoconstituents in the extract. A. laxiflora leaf extract is a potent source of antibacterial and antifungal compounds; further studies on the extract are ongoing in our laboratories to elucidate the probable mechanism(s) of action on bacteria and fungi found to be susceptible to the extract. PMID- 25688279 TI - Effect of Rat Medicated Serum Containing Zuo Gui Wan and/or You Gui Wan on the Differentiation of Stem Cells Derived from Human First Trimester Umbilical Cord into Oocyte-Like Cells In Vitro. AB - Zuo Gui Wan (ZGW) and You Gui Wan (YGW) are two classic formulas used in clinical treatment of infertility in traditional Chinese medicine (TCM). However, the actions of the formulas remain to be proven at the cellular and molecular levels. In this study, we investigate whether the two formulas have any effect on germ cell formation and differentiation by culturing rat medicated serums containing YGW or ZGW with stem cells derived from human first trimester umbilical cord. Our results showed that while the normal rat serums had no significant effects, the rat medicated serums had significant effects on the differentiation of the stem cells into oocyte-like cells (OLCs) based on (1) cell morphological changes that resembled purative cumulus-oocyte complexes (COCs); (2) expressions of specific markers that were indicative of germ cell formation and oocyte development; and (3) estradiol production by the COC-like cells. Furthermore, ZGW medicated serums exhibited more obvious effects on specific gene expressions of germ cells, whereas YGW medicated serums showed stronger effects on estradiol production. Accordingly, our study provides evidence demonstrating for the first time that one of molecular and cellular actions of YGW or ZGW in treating human reproductive dysfunctions may be through an enhancement of neooogenesis. PMID- 25688280 TI - The effects of tai chi in centrally obese adults with depression symptoms. AB - This study examined the effects of Tai Chi, a low-impact mind-body movement therapy, on severity of depression, anxiety, and stress symptoms in centrally obese people with elevated depression symptoms. In total, 213 participants were randomized to a 24-week Tai Chi intervention program or a wait-list control group. Assessments were conducted at baseline and 12 and 24 weeks. Outcomes were severity of depression, anxiety, and stress symptoms, leg strength, central obesity, and other measures of metabolic symptom. There were statistically significant between-group differences in favor of the Tai Chi group in depression (mean difference = -5.6 units, P < 0.001), anxiety (-2.3 units, P < 0.01), and stress (-3.6 units, P < 0.001) symptom scores and leg strength (1.1 units, P < 0.001) at 12 weeks. These changes were further improved or maintained in the Tai Chi group relative to the control group during the second 12 weeks of follow-up. Tai Chi appears to be beneficial for reducing severity of depression, anxiety, and stress and leg strength in centrally obese people with depression symptoms. More studies with longer follow-up are needed to confirm the findings. This trial is registered with ACTRN12613000010796. PMID- 25688281 TI - The Protective Effect of Lacidipine on Myocardial Remodeling Is Mediated by the Suppression in Expression of GPR78 and CHOP in Rats. AB - Lacidipine (LAC) is now widely used for the treatment of hypertension and further can prevent cardiac hypertrophy and remodeling. However, the underlying mechanism has not been fully understood. In this study, we examined the protective effects of LAC on cardiac remodeling in spontaneously hypertensive rats (SHR) and investigated the possible mechanism. Four weeks after administration of the designated drugs, blood pressure, left ventricular mass index (LVMI), and rterial pressure (MAP) were measured. The endoplasmic reticulum stress (ERS) parameters such as GRP78 and CHOP expressions in cardiomyocytes were also detected by immunohistochemistry. Results showed that the MAP in 0.36 and 0.72 mg/kg LAC groups was markedly lowered compared with that of the SHR control group (P < 0.01 or P < 0.05). Moreover, 0.72 mg/kg LAC could also significantly decrease the LVMI (P < 0.05). Simultaneously, the results of immunohistochemistry demonstrated that the expression of GRP78 and CHOP was significantly decreased by 0.72 mg/kg LAC (P < 0.05), respectively. Our present study suggested that LAC could lower blood pressure and could prevent left ventricular hypertrophy accompanied by inhibiting expression of GRP78 and CHOP in ERS. PMID- 25688282 TI - Prognostic influence of witness/victim experiences and PTSD-specific symptoms on working and educational capacity: a comparison between two groups of individuals post-trauma. AB - BACKGROUND: Trauma exposure depends of the type of trauma and can result in the development of posttraumatic stress disorder (PTSD). The type of traumatization (such as Holocaust experiences and other sources of trauma) and specific symptoms of PTSD have influences on the outcome, and specific symptoms of PTSD influence personal and professional outcomes. Another factor is the role of the victim in their traumatization. Some patients are actively traumatized through being victims of torture, while others are passively traumatized by witnessing the traumatization of others. METHODS: We compared two groups of victim/witness trauma sufferers (PTSD vs. Holocaust-experience PTSD (HE-PTSD)) with regard to PTSD symptoms, educational and working capacity, and functional outcome parameters. RESULTS: HE-PTSD survivors with victim/witness trauma experience showed substantially more specific PTSD symptoms and higher symptom-specific intensities but had high social function and education levels. The intensity and type of intrusive memories and sociodemographic factors do not seem to have a prognostic influence on working or educational outcomes. CONCLUSIONS: Identifying the combined victim/witness experience seems to play an important prognostic role in the assessment of PTSD victims. Further studies should consider these findings within other specific traumatization groups. PMID- 25688283 TI - A rapid and sensitive method for determination of carotenoids in plant tissues by high performance liquid chromatography. AB - BACKGROUND: The dietary carotenoids serve as precursor for vitamin A and prevent several chronic-degenerative diseases. The carotenoid profiling is necessary to understand their importance on human health. However, the available high performance liquid chromatography (HPLC) methods to resolve the major carotenoids require longer analysis times and do not adequately resolve the violaxanthin and neoxanthin. RESULTS: A fast and sensitive HPLC method was developed using a C30 column at 20 degrees C with a gradient consisting of methanol, methyl-tert-butyl ether and water. A total of 15 major carotenoids, including 14 all-trans forms and one cis form were resolved within 20 min. The method also distinctly resolved violaxanthin and neoxanthin present in green tissues. Additionally this method also resolved geometrical isomers of the carotenoids. CONCLUSION: The HPLC coupled with C30 column efficiently resolved fifteen carotenoids and their isomers in shorter runtime of 20 min. Application of this method to diverse matrices such as tomato fruits and leaves, Arabidopsis leaves and green pepper fruits showed the versatility and robustness of the method. The method would be useful for high throughput analysis of large number of samples. PMID- 25688284 TI - Robust and accurate anomaly detection in ECG artifacts using time series motif discovery. AB - Electrocardiogram (ECG) anomaly detection is an important technique for detecting dissimilar heartbeats which helps identify abnormal ECGs before the diagnosis process. Currently available ECG anomaly detection methods, ranging from academic research to commercial ECG machines, still suffer from a high false alarm rate because these methods are not able to differentiate ECG artifacts from real ECG signal, especially, in ECG artifacts that are similar to ECG signals in terms of shape and/or frequency. The problem leads to high vigilance for physicians and misinterpretation risk for nonspecialists. Therefore, this work proposes a novel anomaly detection technique that is highly robust and accurate in the presence of ECG artifacts which can effectively reduce the false alarm rate. Expert knowledge from cardiologists and motif discovery technique is utilized in our design. In addition, every step of the algorithm conforms to the interpretation of cardiologists. Our method can be utilized to both single-lead ECGs and multilead ECGs. Our experiment results on real ECG datasets are interpreted and evaluated by cardiologists. Our proposed algorithm can mostly achieve 100% of accuracy on detection (AoD), sensitivity, specificity, and positive predictive value with 0% false alarm rate. The results demonstrate that our proposed method is highly accurate and robust to artifacts, compared with competitive anomaly detection methods. PMID- 25688285 TI - Autoradiography imaging in targeted alpha therapy with Timepix detector. AB - There is a lack of data related to activity uptake and particle track distribution in targeted alpha therapy. These data are required to estimate the absorbed dose on a cellular level as alpha particles have a limited range and traverse only a few cells. Tracking of individual alpha particles is possible using the Timepix semiconductor radiation detector. We investigated the feasibility of imaging alpha particle emissions in tumour sections from mice treated with Thorium-227 (using APOMAB), with and without prior chemotherapy and Timepix detector. Additionally, the sensitivity of the Timepix detector to monitor variations in tumour uptake based on the necrotic tissue volume was also studied. Compartmental analysis model was used, based on the obtained imaging data, to assess the Th-227 uptake. Results show that alpha particle, photon, electron, and muon tracks were detected and resolved by Timepix detector. The current study demonstrated that individual alpha particle emissions, resulting from targeted alpha therapy, can be visualised and quantified using Timepix detector. Furthermore, the variations in the uptake based on the tumour necrotic volume have been observed with four times higher uptake for tumours pretreated with chemotherapy than for those without chemotherapy. PMID- 25688286 TI - Computation of nonlinear parameters of heart rhythm using short time ECG segments. AB - We propose the method to compute the nonlinear parameters of heart rhythm (correlation dimension D2 and correlation entropy K2) using 5-minute ECG recordings preferred for screening of population. Conversion of RR intervals' time series into continuous function x(t) allows getting the new time series with different sampling rate dt. It has been shown that for all dt (250, 200, 125, and 100 ms) the cross-plots of D2 and K2 against embedding dimension m for phase space reconstruction start to level off at m = 9. The sample size N at different sampling rates varied from 1200 at dt = 250 ms to 3000 at dt = 100 ms. Along with, the D2 and K2 means were not statistically different; that is, the sampling rate did not influence the results. We tested the feasibility of the method in two models: nonlinear heart rhythm dynamics in different states of autonomous nervous system and age-related characteristics of nonlinear parameters. According to the acquired data, the heart rhythm is more complex in childhood and adolescence with more influential parasympathetic influence against the background of elevated activity of sympathetic autonomous nervous system. PMID- 25688287 TI - Theoretical Analysis of Dynamic Processes for Interacting Molecular Motors. AB - Biological transport is supported by collective dynamics of enzymatic molecules that are called motor proteins or molecular motors. Experiments suggest that motor proteins interact locally via short-range potentials. We investigate the fundamental role of these interactions by analyzing a new class of totally asymmetric exclusion processes where interactions are accounted for in a thermodynamically consistent fashion. It allows us to connect explicitly microscopic features of motor proteins with their collective dynamic properties. Theoretical analysis that combines various mean-field calculations and computer simulations suggests that dynamic properties of molecular motors strongly depend on interactions, and correlations are stronger for interacting motor proteins. Surprisingly, it is found that there is an optimal strength of interactions (weak repulsion) that leads to a maximal particle flux. It is also argued that molecular motors transport is more sensitive to attractive interactions. Applications of these results for kinesin motor proteins are discussed. PMID- 25688288 TI - Simultaneous improvement in production of microalgal biodiesel and high-value alpha-linolenic acid by a single regulator acetylcholine. AB - BACKGROUND: Photoautotrophic microalgae are a promising avenue for sustained biodiesel production, but are compromised by low yields of biomass and lipids at present. We are developing a chemical approach to improve microalgal accumulation of feedstock lipids as well as high-value alpha-linolenic acid which in turn might provide a driving force for biodiesel production. RESULTS: We demonstrate the effectiveness of the small bioactive molecule "acetylcholine" on accumulation of biomass, total lipids, and alpha-linolenic acid in Chlorella sorokiniana. The effectiveness exists in different species of Chlorella. Moreover, the precursor and analogs of acetylcholine display increased effectiveness at higher applied doses, with maximal increases by 126, 80, and 60% over controls for biomass, total lipids, and alpha-linolenic acid, respectively. Production of calculated biodiesel was also improved by the precursor and analogs of acetylcholine. The biodiesel quality affected by changes in microalgal fatty acid composition was addressed. CONCLUSION: The chemical approach described here could improve the lipid yield and biodiesel production of photoautotrophic microalgae if combined with current genetic approaches. PMID- 25688289 TI - Study of liquid-phase molecular packing interactions and morphology of fatty acid methyl esters (biodiesel). AB - BACKGROUND: (1)H low field nuclear magnetic resonance (LF-NMR) relaxometry has been suggested as a tool to distinguish between different molecular ensembles in complex systems with differential segmental or whole molecular motion and/or different morphologies. In biodiesel applications the molecular structure versus liquid-phase packing morphologies of fatty acid methyl esters (FAMEs) influences physico-chemical characteristics of the fuel, including flow properties, operability during cold weather, blending, and more. Still, their liquid morphological structures have scarcely been studied. It was therefore the objective of this work to explore the potential of this technology for characterizing the molecular organization of FAMEs in the liquid phase. This was accomplished by using a combination of supporting advanced technologies. RESULTS: We show that pure oleic acid (OA) and methyl oleate (MO) standards exhibited both similarities and differences in the (1)H LF-NMR relaxation times (T2s) and peak areas, for a range of temperatures. Based on X-ray measurements, both molecules were found to possess a liquid crystal-like order, although a larger fluidity was found for MO, because as the temperature is increased, MO molecules separate both longitudinally and transversely from one another. In addition, both molecules exhibited a preferred direction of diffusion based on the apparent hydrodynamic radius. The close molecular packing arrangement and interactions were found to affect the translational and segmental motions of the molecules, as a result of dimerization of the head group in OA as opposed to weaker polar interactions in MO. CONCLUSIONS: A comprehensive model for the liquid crystal-like arrangement of FAMEs in the liquid phase is suggested. The differences in translational and segmental motions of the molecules were rationalized by the differences in the (1)H LF-NMR T2 distributions of OA and MO, which was further supported by (13)C high field (HF)-NMR spectra and (1)H HF-NMR relaxation. The proposed assignment allows for material characterization based on parameters that contribute to properties in applications such as biodiesel fuels. PMID- 25688290 TI - Comparative metagenomics of biogas-producing microbial communities from production-scale biogas plants operating under wet or dry fermentation conditions. AB - BACKGROUND: Decomposition of biomass for biogas production can be practiced under wet and dry fermentation conditions. In contrast to the dry fermentation technology, wet fermentation is characterized by a high liquid content and a relatively low total solid content. In this study, the composition and functional potential of a biogas-producing microbial community in an agricultural biogas reactor operating under wet fermentation conditions was analyzed by a metagenomic approach applying 454-pyrosequencing. The obtained metagenomic dataset and corresponding 16S rRNA gene amplicon sequences were compared to the previously sequenced comparable metagenome from a dry fermentation process, meeting explicitly identical boundary conditions regarding sample and community DNA preparation, sequencing technology, processing of sequence reads and data analyses by bioinformatics tools. RESULTS: High-throughput metagenome sequencing of community DNA from the wet fermentation process applying the pyrosequencing approach resulted in 1,532,780 reads, with an average read length of 397 bp, accounting for approximately 594 million bases of sequence information in total. Taxonomic comparison of the communities from wet and dry fermentation revealed similar microbial profiles with Bacteria being the predominant superkingdom, while the superkingdom Archaea was less abundant. In both biogas plants, the bacterial phyla Firmicutes, Bacteroidetes, Spirochaetes and Proteobacteria were identified with descending frequencies. Within the archaeal superkingdom, the phylum Euryarchaeota was most abundant with the dominant class Methanomicrobia. Functional profiles of the communities revealed that environmental gene tags representing methanogenesis enzymes were present in both biogas plants in comparable frequencies. 16S rRNA gene amplicon high-throughput sequencing disclosed differences in the sub-communities comprising methanogenic Archaea between both processes. Fragment recruitments of metagenomic reads to the reference genome of the archaeon Methanoculleus bourgensis MS2(T) revealed that dominant methanogens within the dry fermentation process were highly related to the reference. CONCLUSIONS: Although process parameters, substrates and technology differ between the wet and dry biogas fermentations analyzed in this study, community profiles are very similar at least at higher taxonomic ranks, illustrating that core community taxa perform key functions in biomass decomposition and methane synthesis. Regarding methanogenesis, Archaea highly related to the type strain M. bourgensis MS2(T) dominate the dry fermentation process, suggesting the adaptation of members belonging to this species to specific fermentation process parameters. PMID- 25688291 TI - Impact of two ionic liquids, 1-ethyl-3-methylimidazolium acetate and 1-ethyl-3 methylimidazolium methylphosphonate, on Saccharomyces cerevisiae: metabolic, physiologic, and morphological investigations. AB - BACKGROUND: Ionic liquids (ILs) are considered as suitable candidates for lignocellulosic biomass pretreatment prior enzymatic saccharification and, obviously, for second-generation bioethanol production. However, several reports showed toxic or inhibitory effects of residual ILs on microorganisms, plants, and animal cells which could affect a subsequent enzymatic saccharification and fermentation process. RESULTS: In this context, the impact of two hydrophilic imidazolium-based ILs already used in lignocellulosic biomass pretreatment was investigated: 1-ethyl-3-methylimidazolium acetate [Emim][OAc] and 1-ethyl-3 methylimidazolium methylphosphonate [Emim][MeO(H)PO2]. Their effects were assessed on the model yeast for ethanolic fermentation, Saccharomyces cerevisiae, grown in a culture medium containing glucose as carbon source and various IL concentrations. Classical fermentation parameters were followed: growth, glucose consumption and ethanol production, and two original factors: the respiratory status with the oxygen transfer rate (OTR) and carbon dioxide transfer rate (CTR) of yeasts which were monitored online by respiratory activity monitoring systems (RAMOS). In addition, yeast morphology was characterized by environmental scanning electron microscope (ESEM). The addition of ILs to the growth medium inhibited the OTR and switched the metabolism from respiration (conversion of glucose into biomass) to fermentation (conversion of glucose to ethanol). This behavior could be observed at low IL concentrations (<=5% IL) while above there is no significant growth or ethanol production. The presence of IL in the growth medium also induced changes of yeast morphology, which exhibited wrinkled, softened, and holed shapes. Both ILs showed the same effects, but [Emim][MeO(H)PO2] was more biocompatible than [Emim][OAc] and could be better tolerated by S. cerevisiae. CONCLUSIONS: These two imidazolium-derived ILs were appropriate candidates for useful pretreatment of lignocellulosic biomass in the context of second-generation bioethanol production. This fundamental study provides additional information about the toxic effects of ILs. Indeed, the investigations highlighted the better tolerance by S. cerevisiae of [Emim][MeO(H)PO2] than [Emim][OAc]. PMID- 25688292 TI - Copy number variation and brain structure: lessons learned from chromosome 16p11.2. AB - Recent work has linked specific genetic variation found in human populations to risk for developing neuropsychiatric diseases. How that risk is mediated through molecular-, cellular- and systems-level mechanisms now becomes the central question in this field. Two recent papers studying high-penetrance copy number variation at chromosome 16p11.2 find large changes in brain structure, refining hypotheses about the regions of the brain that are affected and implicating specific neurodevelopmental processes in these changes. PMID- 25688293 TI - Growth of an Ultrathin Zirconia Film on Pt3Zr Examined by High-Resolution X-ray Photoelectron Spectroscopy, Temperature-Programmed Desorption, Scanning Tunneling Microscopy, and Density Functional Theory. AB - Ultrathin (~3 A) zirconium oxide films were grown on a single-crystalline Pt3Zr(0001) substrate by oxidation in 1 * 10-7 mbar of O2 at 673 K, followed by annealing at temperatures up to 1023 K. The ZrO2 films are intended to serve as model supports for reforming catalysts and fuel cell anodes. The atomic and electronic structure and composition of the ZrO2 films were determined by synchrotron-based high-resolution X-ray photoelectron spectroscopy (HR-XPS) (including depth profiling), low-energy electron diffraction (LEED), scanning tunneling microscopy (STM), and density functional theory (DFT) calculations. Oxidation mainly leads to ultrathin trilayer (O-Zr-O) films on the alloy; only a small area fraction (10-15%) is covered by ZrO2 clusters (thickness ~0.5-10 nm). The amount of clusters decreases with increasing annealing temperature. Temperature-programmed desorption (TPD) of CO was utilized to confirm complete coverage of the Pt3Zr substrate by ZrO2, that is, formation of a closed oxide overlayer. Experiments and DFT calculations show that the core level shifts of Zr in the trilayer ZrO2 films are between those of metallic Zr and thick (bulklike) ZrO2. Therefore, the assignment of such XPS core level shifts to substoichiometric ZrO x is not necessarily correct, because these XPS signals may equally well arise from ultrathin ZrO2 films or metal/ZrO2 interfaces. Furthermore, our results indicate that the common approach of calculating core level shifts by DFT including final-state effects should be taken with care for thicker insulating films, clusters, and bulk insulators. PMID- 25688294 TI - Xanthine oxidoreductase reference values in platelet-poor plasma and platelets in healthy volunteers. AB - INTRODUCTION: Xanthine oxidoreductase (XOR) is an enzyme belonging to the class of hydroxylases. XOR is stated, inter alia, in the kidneys, liver, and small intestine as well as in leukocytes and platelets and endothelial cells of capillaries. Its main role is to participate in the conversion of hypoxanthine to xanthine and the uric acid. It occurs in two isoforms: dehydrogenase (XD) and oxidase (XO), which is considered one of the sources of reactive oxygen species. Aim of the Study. Determination of reference values of xanthine oxidoreductase activity in PPP and platelets. MATERIALS AND METHODS: Study group consisted of 70 healthy volunteers. The isoform activities of xanthine oxidoreductase were determined by kinetic spectrophotometry. RESULTS: A statistically significant difference between the activity of the XOR in PPP and platelets (P < 0.001). The highest activity of XO was found in both PPP and blood platelets. Significant differences between the activity of the various isoforms in PPP (P = 0.0032) and platelets (P < 0.001) were also found. CONCLUSIONS: The healthy volunteers showed the highest activity XO (prooxidant) and the lowest XD (antioxidant), which indicates a slight oxidative stress and confirmed physiological effects of XOR. PMID- 25688295 TI - Management of Adverse Events During the Treatment of Chronic Hepatitis C Infection. PMID- 25688296 TI - Sol-Generating Chemical Vapor into Liquid (SG-CViL) Deposition- A Facile Method for Encapsulation of Diverse Cell Types in Silica Matrices. AB - In nature, cells perform a variety of complex functions such as sensing, catalysis, and energy conversion which hold great potential for biotechnological device construction. However, cellular sensitivity to ex-vivo environments necessitates development of bio-nano interfaces which allow integration of cells into devices and maintain their desired functionality. In order to develop such an interface, the use of a novel Sol Generating Chemical Vapor into Liquid (SG CViL) deposition process for whole cell encapsulation in silica was explored. In SG-CViL, the high vapor pressure of tetramethyl orthosilicate (TMOS) is utilized to deliver silica into an aqueous medium, creating a silica sol. Cells are then mixed with the resulting silica sol, facilitating encapsulation of cells in silica while minimizing cell contact with the cytotoxic products of silica generating reactions (i.e. methanol), and reduce exposure of cells to compressive stresses induced from silica condensation reactions. Using SG-CVIL, Saccharomyces cerevisiae (S. cerevisiae) engineered with an inducible beta galactosidase system were encapsulated in silica solids and remained both viable and responsive 29 days post encapsulation. By tuning SG-CViL parameters thin layer silica deposition on mammalian HeLa and U87 human cancer cells was also achieved. The ability to encapsulate various cell types in either a multi cell (S. cerevisiae) or a thin layer (HeLa and U87 cells) fashion shows the promise of SG-CViL as an encapsulation strategy for generating cell-silica constructs with diverse functions for incorporation into devices for sensing, bioelectronics, biocatalysis, and biofuel applications. PMID- 25688297 TI - Prevalence of ovine haemonchosis in wukro, ethiopia. AB - Background. Haemonchosis caused by Haemonchus contortus is a predominant, highly pathogenic, and economically important disease of sheep and goats. Objective. Assessing the prevalence of Haemonchus parasite and its associated risk factors in sheep slaughtered at different restaurants of Wukro. Methods. Cross-sectional study using random sampling from November 2013 to April 2014 in a total of 384 sheep was conducted and SPSS version 20 software using descriptive statistics was used for data analysis and P < 0.05 was considered significant. Result. The overall prevalence of Haemonchus contortus was 40.9% (n = 157). The prevalence in medium body condition 27.3% (n = 105) varies significantly from that of good body condition 13.5% (n = 52) (P < 0.05). Moreover, there was significant variation (P < 0.05) in the prevalence in young and adult sheep with rates of 21.9% (n = 84) and 19% (n = 73), respectively. At the same time, there is significant variation (P < 0.05) in male and female sheep with prevalence of 29.7% (n = 114) and 11.2% (n = 43), respectively. The prevalence of 25.3% (n = 97) in sheep that originated from Negash compared to Wukro and Agulae showed no significant variation (P > 0.05). Conclusion. The current finding revealed that significant numbers of sheep were affected by the parasites. Hence strategic deworming with good husbandry practice should be implemented. PMID- 25688298 TI - Early results of slanted recession of the lateral rectus muscle for intermittent exotropia with convergence insufficiency. AB - The aim of this study was to evaluate the efficacy of slanted recession of the lateral rectus muscle for intermittent exotropia with convergence insufficiency. This prospective study included 31 patients who underwent slanted lateral rectus recession for intermittent exotropia with convergence insufficiency between June 2010 and June 2012. Following parameters were recorded and analyzed: patient sex, age, preoperative and postoperative near and distance ocular alignment, and changes in stereopsis. The mean age of the patients was 9.2 years. The preoperative mean deviation angle was 32.4 PD at distance and 43.4 PD at near. After 6 months, slanted lateral rectus recession reduced the deviation angles to 2 PD at distance and 3.4 PD at near. In addition, the mean difference between distance and near deviation angles was significantly reduced from 11 PD to 1.4 PD at 6 months postoperatively. Slanted lateral rectus recession for intermittent exotropia with convergence insufficiency in children successfully reduced the distance and near exodeviations and the near-distance difference without increasing the risk of long-term postoperative esotropia or diplopia. PMID- 25688299 TI - Alterations induced by bangerter filters on the visual field: a frequency doubling technology and standard automated perimetry study. AB - Purpose. To investigate the effects of Bangerter filters on the visual field in healthy and in amblyopic patients. Materials and Methods. Fifteen normal adults and fifteen anisometropic amblyopia patients were analysed with standard automated perimetry (SAP) and frequency doubling technology (FDT) at baseline and with filters 0.8 and 0.1. Results. With 0.1 filter in SAP there was an increase of MD compared with controls (-10.24 +/- 1.09 dB) in either the amblyopic (-11.34 +/- 2.06 dB; P < 0.050) or sound eyes (-11.34 +/- 1.66 dB; P < 0.030). With filters 0.8 the PSD was increased in the amblyopic eyes (2.09 +/- 0.70 dB; P < 0.007) and in the sound eyes (1.92 +/- 0.29 dB; P < 0.004) compared with controls. The FDT-PSD values in the control group were increased with the interposition of the filters compared to baseline (0.8; P < 0.0004 and 0.1; P < 0.0010). We did not find significant differences of the baseline PSD between amblyopic eyes (3.80 +/- 2.21 dB) and the sound eyes (4.33 +/- 1.31 dB) and when comparing the filters 0.8 (4.55 +/- 1.50 versus 4.53 +/- 1.76 dB) and 0.1 (4.66 +/- 1.80 versus 5.10 +/- 2.04 dB). Conclusions. The use of Bangerter filters leads to a reduction of the functionality of the magno- and parvocellular pathway. PMID- 25688300 TI - Long-Range PCR Amplification of DNA by DNA Polymerase III Holoenzyme from Thermus thermophilus. AB - DNA replication in bacteria is accomplished by a multicomponent replicase, the DNA polymerase III holoenzyme (pol III HE). The three essential components of the pol III HE are the alpha polymerase, the beta sliding clamp processivity factor, and the DnaX clamp-loader complex. We report here the assembly of the functional holoenzyme from Thermus thermophilus (Tth), an extreme thermophile. The minimal holoenzyme capable of DNA synthesis consists of alpha, beta and DnaX (tau and gamma), delta and delta' components of the clamp-loader complex. The proteins were each cloned and expressed in a native form. Each component of the system was purified extensively. The minimum holoenzyme from these five purified subunits reassembled is sufficient for rapid and processive DNA synthesis. In an isolated form the alpha polymerase was found to be unstable at temperatures above 65 degrees C. We were able to increase the thermostability of the pol III HE to 98 degrees C by addition and optimization of various buffers and cosolvents. In the optimized buffer system we show that a replicative polymerase apparatus, Tth pol III HE, is capable of rapid amplification of regions of DNA up to 15,000 base pairs in PCR reactions. PMID- 25688301 TI - Long-Term Consequences of Hepatitis C Viral Clearance on the CD4 (+) T Cell Lymphocyte Course in HIV/HCV Coinfected Patients. AB - The long-term impact of pegylated-interferon plus ribavirin treatment outcome on CD4 T cell course in patients coinfected with human immunodeficiency virus and hepatitis C virus is largely unclear in the literature. The aim of this study was to investigate the impact of HCV-RNA clearance by standard anti-HCV therapy on long-term CD4 cells recovery in HIV/HCV patients on successful combined antiretroviral therapy. We retrospectively enrolled HIV/HCV-coinfected patients on HIV medications and treated for hepatitis C. CD4 + T cell counts were registered at baseline and after hepatitis C therapy. Multiple linear regression analysis was performed to identify independent predictors of CD4 + T cell change following the anti-HCV treatment outcome. Of the 116 patients enrolled, 54 (46.6%) reached a sustained virological response. During a follow-up of 24 months, the SVR group showed a mean annual increase in CD4 + T cell from baseline of 84 cells/ll at 1 year and of a further 38 cells/ll within the second year (P = 0.01, 0.001, resp.). An insignificant mean increase of 77 cells/ll occurred in the non-SVR group within month 24 (P = 0.06). Variables associated with greater CD4 gains were higher nadir, lower preinterferon CD4 counts, and lower body mass index (BMI). PMID- 25688302 TI - Percutaneous vertebral augmentation with polyethylene mesh and allograft bone for traumatic thoracolumbar fractures. AB - Purpose. In cases of traumatic thoracolumbar fractures, percutaneous vertebral augmentation can be used in addition to posterior stabilisation. The use of an augmentation technique with a bone-filled polyethylene mesh as a stand-alone treatment for traumatic vertebral fractures has not yet been investigated. Methods. In this retrospective study, 17 patients with acute type A3.1 fractures of the thoracic or lumbar spine underwent stand-alone augmentation with mesh and allograft bone and were followed up for one year using pain scales and sagittal endplate angles. Results. From before surgery to 12 months after surgery, pain and physical function improved significantly, as indicated by an improvement in the median VAS score and in the median pain and work scale scores. From before to immediately after surgery, all patients showed a significant improvement in mean mono- and bisegmental kyphoses. During the one-year period, there was a significant loss of correction. Conclusions. Based on this data a stand-alone approach with vertebral augmentation with polyethylene mesh and allograft bone is not a suitable therapy option for incomplete burst fractures for a young patient collective. PMID- 25688303 TI - Acute compartment syndrome in orthopedics: causes, diagnosis, and management. AB - Almost all orthopaedic surgeons come across acute compartment syndrome (ACS) in their clinical practice. Diagnosis of ACS mostly relies on clinical findings. If the diagnosis is missed and left untreated, it can lead to serious consequences which can endanger limb and life of the patient and also risk the clinician to face lawsuits. This review article highlights the characteristic features of ACS which will help an orthopaedic surgeon to understand the pathophysiology, natural history, high risk patients, diagnosis, and surgical management of the condition. PMID- 25688304 TI - Effects of yoga on utero-fetal-placental circulation in high-risk pregnancy: a randomized controlled trial. AB - Introduction. Impaired placentation and inadequate trophoblast invasion have been associated with the etiology of many pregnancy complications and have been correlated with the first trimester uterine artery resistance. Previous studies have shown the benefits of yoga in improving pregnancy outcomes and those of yogic visualization in revitalizing the human tissues. Methods. 59 high-risk pregnant women were randomized into yoga (n = 27) and control (n = 32) groups. The yoga group received standard care plus yoga sessions (1 hour/day, 3 times/week), from 12th to 28th week of gestation. The control group received standard care plus conventional antenatal exercises (walking). Measurements were assessed at 12th, 20th, and 28th weeks of gestation. Results. RM-ANOVA showed significantly higher values in the yoga group (28th week) for biparietal diameter (P = 0.001), head circumference (P = 0.002), femur length (P = 0.005), and estimated fetal weight (P = 0.019). The resistance index in the right uterine artery (P = 0.01), umbilical artery (P = 0.011), and fetal middle cerebral artery (P = 0.048) showed significantly lower impedance in the yoga group. Conclusion. The results of this first randomized study of yoga in high-risk pregnancy suggest that guided yogic practices and visualization can improve the intrauterine fetal growth and the utero-fetal-placental circulation. PMID- 25688305 TI - Odorant receptors signaling instructs the development and plasticity of the glomerular map. AB - The olfactory system provides a great opportunity to explore the mechanisms that underlie the formation and function of neural circuits because of the simplicity of its structure. Olfactory sensory neurons (OSNs) located in the peripheral olfactory epithelium (OE) take part in the initial formation and function of glomeruli in the olfactory bulb (OB) inside the central nervous system. Glomeruli are key in the process of transduction of olfactory information, as they constitute a map in the OB that sorts the different types of odorant inputs. This odorant categorization allows proper olfactory perception, and it is achieved through the anatomical organization and function of the different glomerular circuits. Once formed, glomeruli keep the capacity to undergo diverse plasticity processes, which is unique among the different neural circuits of the central nervous system. In this context, through the expression and function of the odorant receptors (ORs), OSNs perform two of the most important roles in the olfactory system: transducing odorant information to the nervous system and initiating the development of the glomerular map to organize olfactory information. This review addresses essential information that has emerged in recent years about the molecular basis of these processes. PMID- 25688306 TI - Cardiac Tamponade following Mitral Valve Replacement for Active Infective Endocarditis with Ring Abscess. AB - Periannular extension and abscess formation are rare but deadly complications of infective endocarditis (IE) with high mortality. Multimodality cardiac imaging, invasive and noninvasive, is needed to accurately define the extent of the disease. Debridement, reconstruction, and valve replacement, often performed in an emergent setting, remain the treatment of choice. Here we present a case of severe IE in a 29-year-old intravenous drug user who after undergoing debridement of the abscess, annular reconstruction, and mitral valve replacement (MVR) presented with recurrence of shortness of breath and pedal edema. Transthoracic echocardiogram (TTE) showed a 6.2 * 5.5 cm cavity, posterior to and communicating with the left ventricle through a 3 cm wide fistulous opening, in proximity of the reconstructed mitral annulus. The patient underwent a redo MVR with patch closure of the fistulous opening, with good clinical outcome. This case highlights the classic TTE findings and the necessity for close follow-up in the perioperative period in patients undergoing surgery for periannular extension of infection. A cardiac magnetic resonance imaging can be considered, preoperatively, in such cases to identify the extent of myocardial involvement and surgical planning. PMID- 25688307 TI - Papillary Tumor of the Pineal Region: MR Signal Intensity Correlated to Histopathology. AB - Tumors of the pineal region are rare and can be challenging to differentiate by imaging. Papillary tumor of the pineal region (PTPR) was recently recognized as a neoplasm in the World Health Organization (WHO) 2007 classification, arising from specialized ependymocytes in the subcommissural organ, which is located in the pineal region. It is a rare histological type of pineal tumor with only a few cases reported. Here, we describe a case of histologically confirmed PTPR in a 17 year-old man who presented with a headache. A literature review was performed to clarify the clinical, radiological, and pathological features of PTPR. Pineal neoplasms do not have pathognomonic imaging findings; however, we discuss T1 hyperintensity, which is a key for imaging diagnosis according to recent reports. In particular, if the hyperintensity in T1 is not due to fat, calcification, melanin, or hemorrhage in a mass of the posterior commissure or pineal region, the diagnosis of a PTPR may be suggested, as observed in this case. PMID- 25688308 TI - Occipital neuralgia after hair transplantation and its treatment. AB - While undergoing full thickness tissue harvest from the posterior scalp, a 72 year-old man experienced immediate severe pain in the right occiput and was unable to complete the procedure. The pain was constant "sharp" and "shocking" with numbness in the distribution of the lesser occipital nerve, exacerbated by physical activity, and local anesthetic blocks provided temporary complete relief. After numerous treatments over several years, including oral analgesics, botulinum toxin injections, and acupuncture, proved ineffective, pulsed radiofrequency neuromodulation provided greater than 80% relief for 5 months. PMID- 25688309 TI - Intraosseous lipomatous meningioma. AB - A 49-year-old man with intermittent headaches and right sided parietal lump was found to have an intraosseous right parietal lesion on computed tomography (CT) and magnetic resonance imaging (MRI). A stereotactic craniectomy and excision of the lesion were performed with histopathology confirming features consistent with primary lipomatous meningioma with intraosseous extension. Lipomatous meningiomas are very uncommon subtype of meningiomas, with ongoing discussions as to their true pathogenesis. To our knowledge this case represents the first reported case of a lipomatous meningioma with predominant intraosseous extension. PMID- 25688310 TI - Massive Cerebral Gas Embolism under Discectomy due to Hydrogen Peroxide Irrigation. AB - Massive cerebral and spinal gas embolism occurs rarely as a complication of discectomy. We report a 54-year-old female who had undergone a discectomy (L3/4 and L4/5) under epidural anesthesia in a local hospital developed multiple massive gas embolisms. At closure, surgeons irrigated the incision wound with hydrogen peroxide. Soon after the irrigation, the patient suddenly developed tachycardia, hypotension, and rapid oxygen desaturation. Subsequently, patient progressed into unconsciousness and right hemianopsia quadriplegia. Computed tomography (CT) scan showed multiple hypointensity spots around the brain due to cerebral gas embolism, which indicated the pneumoencephalos. The likely mechanism was the absorption of hydrogen peroxide into blood. When the amount of oxygen evolved exceeded its maximal blood solubility, venous embolization occurred. Though the patient was treated with supportive treatments and hyperbaric oxygen, she did not get full recovery and was left with severe long-term cerebral injury. PMID- 25688311 TI - Delayed Interval Delivery following Early Loss of the Leading Twin. AB - This was a case of a nulliparous woman with reduced chance of conception following unilateral salpingectomy and years of infertility. She eventually conceived following ovulation induction resulting in twin pregnancy. She had miscarriage that led to loss of one of the twins at 17 weeks of gestational age. The pregnancy was however continued for 116 days following meticulous management with eventual delivery of a live female baby with good outcome. PMID- 25688312 TI - Intrapartum intrauterine fetal demise with normal umbilical cord blood gas values at birth. AB - A case is presented in which a fetus was delivered by cesarean section for failure to progress and a "nonreassuring heart rate tracing" in which the Apgar scores were unexpectedly 0 at 1, 5, and 10 minutes. Resuscitation was unsuccessful after 30 minutes. The venous cord gas was normal and the arterial blood gas was not consistent with intrapartum asphyxia. At the time of surgery, the placenta appeared grossly normal. The autopsy was entirely normal. This case raises questions about our understanding of intrauterine fetal demise and suggests an approach to future research. PMID- 25688313 TI - Hemangiopericytoma of the breast: a case report and a review of the literature. AB - Introduction. Sarcomas of the breast are rare and hemangiopericytoma (HPC) of the breast is even rarer. Case Report. We report a case of a 43-year-old woman who presented with a 4 cm mass in her right breast. Her family history was positive for breast cancer. A fine needle aspiration indicated a malignant vascular tumor. An excision biopsy and frozen section analysis confirmed the presence of an encapsulated mesenchymal tumor. Its morphology and immunohistochemical marker profile were characteristic for a malignant hemangiopericytoma. Thus, she underwent a tumor excision without an axilla sampling. Approximately one year after the surgery the patient is well without local recurrence or metastasis disease to be observed. We also reviewed the literature and discuss the treatment options, characteristics, and immunophenotype of HPC. Conclusions. The accurate diagnosis of HPC depends on the appropriate histological and immunohistochemical examination. Surgical resection is the treatment of choice and due to scarcity of cases and unpredictable biological behavior of these tumors long term follow-up may be warranted. PMID- 25688314 TI - Primary angiosarcoma of urinary bladder: 13th reported patient. AB - Angiosarcoma of the urinary bladder is an extremely rare and poorly characterized tumor. We are presenting the 13th reported patient who was an 89-year-old man initially presented with massive hematuria. His past medical history included external-beam radiation for prostate cancer 12 years ago. His PSA was 0.26 ng/dL. His CT-Urography demonstrated a highly vascular mass originating from the bladder base. The mass was partially resected, transurethrally. The pathology was consistent with primary angiosarcoma of the urinary bladder. Bone scan and CT-U showed metastasis to spine. The patient was treated with palliative radiotherapy for back pain due to metastasis, and he refused chemotherapy. The patient died 3 months after his initial diagnosis. PMID- 25688315 TI - Arthroscopic-assisted treatment of a reversed hill-sachs lesion: description of a new technique using cerament. AB - Purpose. Impaction fractures of the anterior aspect of the humeral head, the reversed Hill-Sachs lesion, are common in posterior shoulder dislocation. We present a new technique to address these lesions arthroscopic-assisted with the use of a bone substitute. Methods. We report the case of a 45-year-old male with a reversed Hill-Sachs lesion after posterior shoulder dislocation. Initially a glenohumeral arthroscopy is performed to address concomitant intra-articular injuries. Guided by the k-wire a cannulated sizer was inserted for reduction of the fracture under arthroscopic visualization. For reduction of the impacted part of the humeral head the subcortical defect was filled with an injectable bone substitute (Cerament) to prevent secondary dislocation. Results. X-ray at follow up 6 months after the index procedure documents the bony remodeling of the bone substitute. At that time the patient was pain-free (VAS 0) and satisfied with the outcome (Constant score: 78, Rand-36 score: 84, Rowe score: 81) with a good ROM. Conclusions. In conclusion, arthroscopic-assisted reconstruction of reversed Hill Sachs lesions with an injectable bone substitute is feasible and may provide patients with all the benefits of an anatomic reconstruction with decreased risks related to open surgery. PMID- 25688316 TI - A case of chondrosarcoma arising in the temporomandibular joint. AB - Chondrosarcoma is a malignant tumor originating in cartilaginous cells. And there are only few reports of the case of chondrosarcoma in temporomandibular joint. We discuss a case of chondrosarcoma in temporomandibular joint in a 28-year-old man. Tumor was in contact with the dura, but en bloc resection was performed. After surgical resection of the tumor, face defect was reconstructed by rectus abdominis-free flap. And there is no recurrence after ten years from the resection. PMID- 25688317 TI - Liver Transplant in a Patient under Methylphenidate Therapy: A Case Report and Review of the Literature. AB - Background. Methylphenidate (MPH) is widely used in treating children with attention-deficit-hyperactivity disorder. Hepatotoxicity is a rare phenomenon; only few cases are described with no liver failure. Case. We report on the case of a 12-year-old boy who received MPH for attention-deficit-hyperactivity disorder. Two months later the patient presented with signs and symptoms of hepatitis and MPH was discontinued, showing progressive worsening and developing liver failure and a liver transplantation was required. Other causes of liver failure were ruled out and the liver biopsy was suggestive of drug toxicity. Discussion. One rare adverse reaction of MPH is hepatotoxicity. The review of the literature shows few cases of liver injury attributed to MPH; all of them recovered after withdrawing the treatment. The probable mechanism of liver injury was MPH direct toxicity to hepatocytes. In order to establish the diagnosis of MPH-induced liver injury, we used CIOMS/RUCAM scale that led to an assessment of "possible" relationship. This report provides the first published case of acute MPH-induced liver failure with successful hepatic transplantation. Conclusions. It is important to know that hepatotoxicity can occur in patients with MPH treatment and monitoring the liver's function is highly recommended. PMID- 25688318 TI - Psychogenic polydipsia: the result, or cause of, deteriorating psychotic symptoms? A case report of the consequences of water intoxication. AB - Water intoxication is a rare condition characterised by overconsumption of water. It can occur in athletes engaging in endurance sports, users of MDMA (ecstasy), and patients receiving total parenteral nutrition. This case outlines water intoxication in a patient with psychogenic polydipsia. When the kidney's capacity to compensate for exaggerated water intake is exceeded, hypotonic hyperhydration results. Consequences can involve headaches, behavioural changes, muscular weakness, twitching, vomiting, confusion, irritability, drowsiness, and seizures. Cerebral oedema can lead to brain damage and eventual death. In this case, psychogenic polydipsia led to significant hyponatraemia, cerebral oedema, and tonic-clonic seizures. Differential diagnoses for hyponatraemia are outlined. The aetiology of psychogenic polydipsia is uncertain, but postulated hypotheses are explored. Psychogenic polydipsia occurs in up 20% of psychiatric patients and this case serves to remind us to be cognizant of water overconsumption. PMID- 25688319 TI - Hamman's Syndrome: A Rare Cause of Chest Pain in a Postpartum Patient. AB - Hamman's syndrome is a rare condition represented by spontaneous pneumomediastinum and subcutaneous emphysema. Excessive Valsalva maneuver during vaginal delivery and excessive retching, coughing, and straining are frequently reported causes. The incidence of Hamman's syndrome is believed to be 1 in 100,000 deliveries. The pathophysiology of this condition is rupture of alveoli and seepage of air through bronchovascular connective tissue. Diffusion of air to subcutaneous tissues results in subcutaneous emphysema. In most cases, it is a benign condition and resolves spontaneously. In life-threatening cases, a cardiac tamponade can ensue. Chest X-ray is a useful early diagnostic technique. We report a case of a twenty-four-year-old female who was diagnosed with Hamman's syndrome after prolonged, exhaustive labor. PMID- 25688320 TI - The rare cuboid-navicular coalition presenting as chronic foot pain. AB - Tarsal coalitions are relatively rare diagnoses affecting adolescent patients that typically present with progressive foot pain. Cuboid-navicular coalition, a type of tarsal coalition, is extremely rare with less than 10 reported cases to date. Most prevailing theories reported have described this specific type of coalition as asymptomatic except at specific moments of stress and exercise. The purpose in presenting this case is to demonstrate that cuboid-navicular coalition can be associated with chronic unremitting pain, as in our patient. We present a case of cuboid-navicular fibrocartilaginous coalition in an adolescent patient presenting with chronic foot pain. Furthermore, from an imaging standpoint, radiographic findings are often subtle and radiologists cannot rely on indirect signs such as talar beak in clinching the diagnosis of cuboid-navicular coalition. Instead, abnormal articulation between the cuboid and navicular must be sought. PMID- 25688321 TI - Radiographic and MR Imaging Findings of the Spine after Bisphosphonate Treatment, in a Child with Idiopathic Juvenile Osteoporosis. AB - Bisphosphonates are employed with increasing frequency in various pediatric disorders, mainly associated with osteoporosis. After cessation of bisphosphonate treatment in children, skeletal radiologic changes have been documented including dense metaphyseal lines of the long bones and "bone in bone" appearance of the vertebrae. However, the evolution of these radiographic changes has not been fully explored. We describe the MR imaging appearance of the spine that, to our knowledge, has not been previously addressed in a child with idiopathic juvenile osteoporosis who had received bisphosphonates and emphasize the evolution of the radiographic findings of the spine and pelvis over a four-year period. PMID- 25688322 TI - Motor vehicle collision patient with simultaneous duodenal transection and thoracic aorta injury: a case report and review of the literature. AB - Blunt polytrauma can present complex management decisions. Here we report the case of a 31-year-old male involved in a high speed motor vehicle collision resulting in both duodenal and thoracic aorta injury that was managed collaboratively between the trauma, vascular, and cardiothoracic surgical teams. The patient went on to a full recovery. We also review the management of such injuries which has evolved over the past two decades resulting in less morbidity and mortality. PMID- 25688323 TI - Aneurysmal Rupture of a Mesodiverticular Band to a Meckel's Diverticulum. AB - Aneurysmal rupture of a mesodiverticular band has not previously been reported in the clinical literature. We are reporting a case of hemoperitoneum in a 51-year old male after an aneurysmal rupture of a mesodiverticular band. This case demonstrates that in rare instances, a rupture of the mesodiverticular band leading to Meckel's diverticulum can lead to significant hemoperitoneum. This is usually caused by a traumatic injury but in our case was apparently caused by an aneurysm of the mesodiverticular artery. Patients with known Meckel's diverticula should be aware of the possibility of rupture, as should clinicians treating those with a history of this usually benign congenital abnormality. Rapid surgical intervention is necessary to repair the source of bleeding, as massive blood loss was encountered in this case. PMID- 25688324 TI - Voluminous omental inflammatory myofibroblastic tumor in an elderly man: a case report and literature review. AB - Inflammatory myofibroblastic tumor (IMT) is a rare neoplasm of intermediate biologic potential, with uncertain etiology. This tumor occurs primarily in the lung, but the tumor may affect any organ system. A 75-year-old male was evaluated for voluminous palpable high abdominal mass with continuous and moderately abdominal pain, associated with abdominal distension for the last two months. Abdominal computed tomography showed a large (32 * 29 * 15 cm) heterogeneously enhanced mass with well-defined margins. At surgery, the mass originated from the greater omentum was completely excised. Histologically the tumor was a mesenchymal neoplasm in smooth muscle differentiation and was characterized by spindle-cell proliferation with lymphocytes, plasma cells, and rare eosinophils. Immunohistochemically, the tumor cells were positive for vimentin and smooth muscle actin and negative for anaplastic lymphoma kinase. Complete surgical resection of IMTs remains the mainstay of treatment associated with a low rate of recurrence. Final diagnosis should be based on histopathological and immunohistochemical findings. Appropriate awareness should be exercised by surgeons to abdominal IMTs in combination with constitutional symptoms, abnormal hematologic findings, and radiological definition, to avoid misdiagnosed. PMID- 25688325 TI - Torsion of undescended third testis, as rare cause of painful inguinal mass. AB - Twenty years old young was referred to our department due to painful inguinal mass. The mass was diagnosed as torsion of third testis which was treated by orchiectomy. Polyorchidism is a rare entity with increased risk for malignancy and torsion. PMID- 25688326 TI - Identification of Changing Lower Limb Neuromuscular Activation in Parkinson's Disease during Treadmill Gait with and without Levodopa Using a Nonlinear Analysis Index. AB - Analysis of electromyographic (EMG) data is a cornerstone of research related to motor control in Parkinson's disease. Nonlinear EMG analysis tools have shown to be valuable, but analysis is often complex and interpretation of the data may be difficult. A previously introduced algorithm (SYNERGOS) that provides a single index value based on simultaneous multiple muscle activations (MMA) has been shown to be effective in detecting changes in EMG activation due to modifications of walking speeds in healthy adults. In this study, we investigated if SYNERGOS detects MMA changes associated with both different walking speeds and levodopa intake. Nine male Parkinsonian patients walked on a treadmill with increasing speed while on or off medication. We collected EMG data and computed SYNERGOS indices and employed a restricted maximum likelihood linear mixed model to the values. SYNERGOS was sensitive to neuromuscular modifications due to both alterations of gait speed and intake of levodopa. We believe that the current experiment provides evidence for the potential value of SYNERGOS as a nonlinear tool in clinical settings, by providing a single value index of MMA. This could help clinicians to evaluate the efficacy of interventions and treatments in Parkinson's disease in a simple manner. PMID- 25688327 TI - Thyroid cytopathology reporting by the bethesda system: a two-year prospective study in an academic institution. AB - Background. The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) has attempted to standardize reporting and cytological criteria in aspiration smears. Aims. The objective of this study was to analyze the thyroid cytology smears by TBSRTC, to determine the distribution of diagnostic categories and subcategories, to analyze cytological features, and to correlate the cytopathology with histopathology, wherever surgery was done. Materials and Methods. This was a prospective study of 225 fine needle aspirations (FNA) of thyroid nodules. All fine needle aspiration cytology (FNAC) diagnoses were classified according to the features given in the monograph of TBSRTC into nondiagnostic/unsatisfactory (ND/UNS), benign, atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS), follicular neoplasm/suspicious of a follicular neoplasm (FN/SFN), suspicious for malignancy (SFM), and malignant. Cytohistological correlation was done, when surgical material was available. Results. The distribution of various categories from 225 evaluated thyroid nodules was as follows: 7.2% ND/UNS, 80.0% benign, 4.9% AUS/FLUS, 2.2% FN, 3.5% SFM, and 2.2% malignant. Sensitivity, specificity, positive predictive value, and negative predictive value were calculated. Conclusions. TBSRTC is an excellent reporting system for thyroid FNA. It also provides clear management guidelines to clinicians to go for follow-up FNA or surgery and also the extent of surgery. PMID- 25688328 TI - Elephant (Elephas maximus) Health and Management in Asia: Variations in Veterinary Perspectives. AB - There is a need to identify strategic investments in Asian elephant (Elephas maximus) health that will yield maximal benefits for overall elephant health and conservation. As an exploratory first step, a survey was administered to veterinarians from Asian elephant range countries at a workshop and via email to help prioritize health-related concerns that will mostly benefit elephants. Responses were received from 45 veterinarians from eight countries that had a range of experience with captive and wild elephants. The occurrence of medical conditions and responses to treatment varied among responses. However, injuries, parasitism, and gastrointestinal disease were reported as the most common syndromes responsible for elephant morbidity, whereas injury and infectious disease not due to parasitism were the most commonly reported sources of elephant mortality. Substandard nutrition, water quality and quantity deficiencies, and inadequate or absent shelter were among the factors listed as barriers to optimal elephant health. While this survey's results do not support definitive conclusions, they can be used to identify where and how subsequent investigations should be directed. Rigorous assessment of the relative costs and benefits of available options is required to ensure that investments in individual and population health yield the maximal benefits for elephants. PMID- 25688330 TI - A Joint Modeling Approach for Right Censored High Dimensional Multivariate Longitudinal Data. AB - Analysis of multivariate longitudinal data becomes complicated when the outcomes are of high dimension and informative right censoring is prevailing. Here, we propose a likelihood based approach for high dimensional outcomes wherein we jointly model the censoring process along with the slopes of the multivariate outcomes in the same likelihood function. We utilized pseudo likelihood function to generate parameter estimates for the population slopes and Empirical Bayes estimates for the individual slopes. The proposed approach was applied to jointly model longitudinal measures of blood urea nitrogen, plasma creatinine, and estimated glomerular filtration rate which are key markers of kidney function in a cohort of renal transplant patients followed from kidney transplant to kidney failure. Feasibility of the proposed joint model for high dimensional multivariate outcomes was successfully demonstrated and its performance was compared to that of a pairwise bivariate model. Our simulation study results suggested that there was a significant reduction in bias and mean squared errors associated with the joint model compared to the pairwise bivariate model. PMID- 25688329 TI - Sleep and Women's Health. AB - Sex differences in sleep begin at a very early age and women report poorer sleep quality and have higher risk for insomnia than do men. Sleep may be affected by variation in reproductive hormones, stress, depression, aging, life/role transitions, and other factors. The menstrual cycle is associated with changes in circadian rhythms and sleep architecture. Menstruating women (even without significant menstrual-related complaints) often report poorer sleep quality and greater sleep disturbance during the premenstrual week compared to other times of her menstrual cycle. In addition to these sleep disturbances, women with severe premenstrual syndrome often report more disturbing dreams, sleepiness, fatigue, decreased alertness and concentration during the premenstrual phase. Sleep disturbances are also commonly reported during pregnancy and increase in frequency and duration as the pregnancy progresses. The precipitous decline in hormones and unpredictable sleep patterns of the newborn contribute to and/or exacerbate poor sleep and daytime sleepiness during the early postpartum period. Insomnia is also among the most common health complaints that are reported by perimenopausal women. Women are particularly vulnerable to developing insomnia disorder during these times of reproductive hormonal change. In this review, we present a discussion on the most relevant and recent publications on sleep across the woman's lifespan, including changes in sleep related to menstruation, pregnancy, postpartum, and the menopausal transition. Treatment for sleep disturbances and insomnia disorder and special considerations for treating women will also be discussed. PMID- 25688331 TI - The "S" Allele of the Serotonin Transporter Is Not Associated with Major Depression in a Sample OF Veterans. AB - The results of some studies suggest that the serotonin transporter-linked polymorphic region (5-HTTLPR) short (S) allele, relative to the long (L) allele, is associated with risk for Major Depressive Disorder (MDD), and thus serves as a biomarker for MDD, while results from other studies do not support that conclusion. Persons with an S allele demonstrate a 2- to 2.5 fold decrease in serotonin transcription rate compared to the L-allele, which may increase their risk for MDD. Differences in study populations may help explain the differences in findings between those meta-analyses. To date, there have been no published reports which have addressed the possible association between the S allele and MDD among military veterans. This manuscript describes a first study to assess the possible association of the S allele with MDD among a study population of veterans in treatment for a substance use disorder. We hypothesized that the S allele would be associated with MDD in our study sample. Subjects signing informed consent were 101 Veterans recruited from VA behavioral health and substance use treatment clinics in the VA Pittsburgh Healthcare System, and 91 of those subjects were genotyped for 5-HTTLPR polymorphisms. The study sample from whom genetic material was collected included 82 males and 9 females, of whom 53 were white, 38 were black, and one was "other". Fifty-four members of the study sample (59%) met DSM-IV criteria for an MDD on the SCID. Forty-five of the subjects demonstrated one or two S alleles, while 46 did not do so. The presence of the S allele of the serotonin transporter was not found to be significantly associated with the diagnosis of major depressive disorder in our sample (Chi square=0.1.63, df=1, p=0.199). That finding, in combination with other recent negative findings from other researchers involving non-veterans, raises questions regarding the clinical utility of utilizing genetics tests involving the assessment of the alleles of the serotonin transporter as a possible biomarker for MDD. PMID- 25688332 TI - Biological characterization of preclinical Bioluminescent Osteosarcoma Orthotopic Mouse (BOOM) model: A multi-modality approach. AB - Osteosarcoma (OS) is a bone malignancy that affects children and adolescents. It is a highly aggressive tumor and typically metastasizes to lungs. Despite aggressive chemotherapy and surgical treatments, the current 5 year survival rate is 60-70%. Clinically relevant models are needed to understand OS pathobiology, metastatic progression from bones to lungs, and ultimately, to develop more efficacious treatment strategies and improve survival rates in OS patients with metastasis. The main goal of this study was to develop and characterize an in vivo OS model that will allow non-invasive tracking of tumor progression in real time, and aid in studying OS pathobiology, and screening of potential therapeutic agents against OS. In this study, we have used a multi-modality approach using bioluminescent imaging, electron microscopy, micro-computed tomography, and histopathology to develop and characterize a preclinical Bioluminescent Osteosarcoma Orthotopic Mouse (BOOM) model, using 143B human OS cell line. The results of this study clearly demonstrate that the BOOM model represents the clinical disease as evidenced by a spectrum of changes associated with tumor establishment, progression and metastasis, and detection of known OS biomarkers in the primary and metastatic tumor tissue. Key novel findings of this study include: (a) multimodality approach for extensive characterization of the BOOM model using 143B human OS cell line; (b) evidence of renal metastasis in OS orthotopic model using 143B cells; (c) evidence of Runx2 expression in the metastatic lung tissue; and (d) evidence of the presence of extracellular membrane vesicles and myofibroblasts in the BOOM model. PMID- 25688333 TI - Current Therapeutic Advances Targeting EGFR and EGFRvIII in Glioblastoma. AB - Epidermal growth factor receptor (EGFR) and EGFRvIII analysis is of current interest in glioblastoma - the most common malignant primary CNS tumor, because of new EGFRvIII vaccine trials underway. EGFR activation in glioblastoma promotes cellular proliferation via activation of MAPK and PI3K-Akt pathways, and EGFRvIII is the most common variant, leading to constitutively active EGFR. This review explains EGFR and EGFRvIII signaling in GBM; describes targeted therapy approaches to date including tyrosine kinase inhibitor, antibody-based therapies, vaccines and pre-clinical RNA-based therapies, and discusses the difficulties encountered with these approaches including pathway redundancy and intratumoral heterogeneity. PMID- 25688334 TI - Mechanisms of Translocation of ER Chaperones to the Cell Surface and Immunomodulatory Roles in Cancer and Autoimmunity. AB - Endoplasmic reticulum (ER) chaperones (e.g., calreticulin, heat shock proteins, and isomerases) perform a multitude of functions within the ER. However, many of these chaperones can translocate to the cytosol and eventually the surface of cells, particularly during ER stress induced by e.g., drugs, UV irradiation, and microbial stimuli. Once on the cell surface or in the extracellular space, the ER chaperones can take on immunogenic characteristics, as mostly described in the context of cancer, appearing as damage-associated molecular patterns recognized by the immune system. How ER chaperones relocate to the cell surface and interact with other intracellular proteins appears to influence whether a tumor cell is targeted for cell death. The relocation of ER proteins to the cell surface can be exploited to target cancer cells for elimination by immune mechanism. Here we evaluate the evidence for the different mechanisms of ER protein translocation and binding to the cell surface and how ER protein translocation can act as a signal for cancer cells to undergo killing by immunogenic cell death and other cell death pathways. The release of chaperones can also exacerbate underlying autoimmune conditions, such as rheumatoid arthritis and multiple sclerosis, and the immunomodulatory role of extracellular chaperones as potential cancer immunotherapies requires cautious monitoring, particularly in cancer patients with underlying autoimmune disease. PMID- 25688335 TI - Immunotherapeutic advancements for glioblastoma. AB - Immunotherapy seeks to improve the body's immune response to a tumor. Currently, the principal mechanisms employed are: (1) to improve an aspect of the immune response (e.g., T cell activation) and (2) to encourage the targeting of particular antigens. The latter is typically achieved by exposing the immune system to the antigen in question, in vivo, or in vitro followed by re introduction of the primed cells to the body. The clinical relevance of these approaches has already been demonstrated for solid tumors such as melanoma and prostate cancer. The central nervous system was previously thought to be immune privileged. However, we know now that the immune system is highly active in the brain and interacts with brain tumors. Thus, harnessing and exploiting this interaction represents an important approach for treating malignant brain tumors. We present a summary of progress in this area, focusing particularly on immune checkpoint inhibition, vaccines, and T cell engineering. PMID- 25688336 TI - Hemocytes from Pediculus humanus humanus are hosts for human bacterial pathogens. AB - Pediculus humanus humanus is an human ectoparasite which represents a serious public health threat because it is vector for pathogenic bacteria. It is important to understand and identify where bacteria reside in human body lice to define new strategies to counterstroke the capacity of vectorization of the bacterial pathogens by body lice. It is known that phagocytes from vertebrates can be hosts or reservoirs for several microbes. Therefore, we wondered if Pediculus humanus humanus phagocytes could hide pathogens. In this study, we characterized the phagocytes from Pediculus humanus humanus and evaluated their contribution as hosts for human pathogens such as Rickettsia prowazekii, Bartonella Quintana, and Acinetobacter baumannii. PMID- 25688337 TI - Salmonella-how a metabolic generalist adopts an intracellular lifestyle during infection. AB - The human-pathogenic bacterium Salmonella enterica adjusts and adapts to different environments while attempting colonization. In the course of infection nutrient availabilities change drastically. New techniques, "-omics" data and subsequent integration by systems biology improve our understanding of these changes. We review changes in metabolism focusing on amino acid and carbohydrate metabolism. Furthermore, the adaptation process is associated with the activation of genes of the Salmonella pathogenicity islands (SPIs). Anti-infective strategies have to take these insights into account and include metabolic and other strategies. Salmonella infections will remain a challenge for infection biology. PMID- 25688338 TI - Wavelength-Filter Based Spectral Calibrated Wave number - Linearization in 1.3 mm Spectral Domain Optical Coherence. AB - In this study, we demonstrate the enhanced spectral calibration method for 1.3 MUm spectral-domain optical coherence tomography (SD-OCT). The calibration method using wavelength-filter simplifies the SD-OCT system, and also the axial resolution and the entire speed of the OCT system can be dramatically improved as well. An externally connected wavelength-filter is utilized to obtain the information of the wavenumber and the pixel position. During the calibration process the wavelength-filter is placed after a broadband source by connecting through an optical circulator. The filtered spectrum with a narrow line width of 0.5 nm is detected by using a line-scan camera. The method does not require a filter or a software recalibration algorithm for imaging as it simply resamples the OCT signal from the detector array without employing rescaling or interpolation methods. One of the main drawbacks of SD-OCT is the broadened point spread functions (PSFs) with increasing imaging depth can be compensated by increasing the wavenumber-linearization order. The sensitivity of our system was measured at 99.8 dB at an imaging depth of 2.1 mm compared with the uncompensated case. PMID- 25688339 TI - A comparative study of mesenchymal stem cell transplantation with its paracrine effect on control of hyperglycemia in type 1 diabetic rats. AB - BACKGROUND: Many studies suggested mesenchymal stem cells (MSCs) transplantation as a new approach to control hyperglycemia in type 1 diabetes mellitus through differentiation mechanism. In contrary others believed that therapeutic properties of MSCs is depends on paracrine mechanisms even if they were not engrafted. This study aimed to compare these two approaches in control of hyperglycemia in STZ-induced diabetic rats. METHODS: Animals were divided into five groups: normal; diabetic control; diabetic received MSCs; diabetic received supernatant of MSCs; diabetic received co-administration of MSCs with supernatant. Blood glucose, insulin levels and body weight of animals were monitored during experiment. Immunohistochemical and immunofluorescence analysis were performed to monitor functionality and migration of labeled-MSCs to pancreas. RESULTS: First administration of MSCs within the first 3 weeks could not reduce blood glucose, but second administration significantly reduced blood glucose after week four compared to diabetic controls. Daily injection of supernatant could not reduce blood glucose as efficient as MSCs. Interestingly; Co-administration of MSCs with supernatant significantly reduced blood glucose more than other treated groups. Insulin levels and body weight were significantly increased in MSCs + supernatant-treated animals compared to other groups. Immunohistological analysis showed an increase in number and size of islets per section respectively in supernatant, MSCs and MSCs + supernatant-treated groups. CONCLUSION: Present study exhibited that repeated-injection of MSCs reduced blood glucose and increased serum insulin levels in recipient rats. Injection of supernatant could not reverse hyperglycemia as efficient as MSCs. Interestingly; co-administration of MSCs with supernatant could reverse hyperglycemia more than either group alone. PMID- 25688340 TI - The impact of family intactness on family functioning, parental control, and parent-child relational qualities in a chinese context. AB - The current study investigated the differences between intact and non-intact families in family processes, including systematic family functioning, parental behavioral control, parental psychological control, and parent-child relational qualities. The participants were 3,328 Secondary One students, with a mean age of 12.59 years, recruited from 28 secondary schools in Hong Kong. Four validated scales were used to assess family processes. Results showed that adolescents in non-intact families perceived relatively poorer family functioning, lower level of paternal and maternal behavioral control, lower level of paternal psychological control, and poorer parent-child relational qualities than did adolescents in intact families. This generally indicated that family processes were poorer in non-intact families, compared with those in intact families. The theoretical and practical implications of the findings were discussed. PMID- 25688341 TI - Novel TTC37 Mutations in a Patient with Immunodeficiency without Diarrhea: Extending the Phenotype of Trichohepatoenteric Syndrome. AB - Unbiased genetic diagnosis has increasingly associated seemingly unrelated somatic and immunological phenotypes. We report a male infant who presented within the first year of life with physical growth impairment, feeding difficulties, hyperemesis without diarrhea, and abnormal hair findings suggestive of trichorrhexis nodosa. With advancing age, moderate global developmental delay, susceptibility to frequent viral illnesses, otitis media, and purulent conjunctivitis were identified. Because of the repeated infections, an immunological evaluation was pursued and identified impaired antibody memory responses following pneumococcal vaccine administration. Immunoglobulin replacement therapy and nutritional support were employed as mainstays of therapy. The child is now aged 12 years and still without diarrhea. Whole exome sequencing identified compound heterozygous mutations in the TTC37 gene, a known cause of the trichohepatoenteric syndrome (THES). This case extends the known phenotype of THES and defines a potential subset for inclusion as an immune overlap syndrome. PMID- 25688342 TI - Mechanisms Involved in the Association between Periodontitis and Complications in Pregnancy. AB - The association between periodontitis and some of the problems with pregnancy such as premature delivery, low weight at birth, and preeclampsia (PE) has been suggested. Nevertheless, epidemiological data have shown contradictory data, mainly due to differences in clinical parameters of periodontitis assessment. Furthermore, differences in microbial composition and immune response between aggressive and chronic periodontitis are not addressed by these epidemiological studies. We aimed to review the current data on the association between some of these problems with pregnancy and periodontitis, and the mechanisms underlying this association. Shifts in the microbial composition of the subgingival biofilm may occur during pregnancy, leading to a potentially more hazardous microbial community. Pregnancy is characterized by physiological immune tolerance. However, the infection leads to a shift in maternal immune response to a pathogenic pro inflammatory response, with production of inflammatory cytokines and toxic products. In women with periodontitis, the infected periodontal tissues may act as reservoirs of bacteria and their products that can disseminate to the fetus placenta unit. In severe periodontitis patients, the infection agents and their products are able to activate inflammatory signaling pathways locally and in extra-oral sites, including the placenta-fetal unit, which may not only induce preterm labor but also lead to PE and restrict intrauterine growth. Despite these evidences, the effectiveness of periodontal treatment in preventing gestational complications was still not established since it may be influenced by several factors such as severity of disease, composition of microbial community, treatment strategy, and period of treatment throughout pregnancy. This lack of scientific evidence does not exclude the need to control infection and inflammation in periodontitis patients during pregnancy, and treatment protocols should be validated. PMID- 25688343 TI - Health care providers and human trafficking: what do they know, what do they need to know? Findings from the middle East, the Caribbean, and central america. AB - BACKGROUND: Human trafficking is a crime that commonly results in acute and chronic physical and psychological harm. To foster more informed health sector responses to human trafficking, training sessions for health care providers were developed and pilot-tested in the Middle East, Central America, and the Caribbean. This study presents the results of an investigation into what health care providers knew and needed to know about human trafficking as part of that training program. METHODS: Participants attended one of seven two-day training courses in Antigua and Barbuda, Belize, Costa Rica, Egypt, El Salvador, Guyana, and Jordan. We assessed participants' knowledge about human trafficking and opinions about appropriate responses in trafficking cases via questionnaires pre training, and considered participant feedback about the training post-training. RESULTS: 178 participants attended the trainings. Pre-training questionnaires were completed by 165 participants (93%) and post-training questionnaires by 156 participants (88%). Pre-training knowledge about health and human trafficking appeared generally high for topics such as the international nature of trafficking and the likelihood of poor mental health outcomes among survivors. However, many participants had misconceptions about the characteristics of trafficked persons and a provider's role in responding to cases of trafficking. The most valued training components included the "Role of the Health Provider," "Basic Definitions and Concepts," and "Health Consequences of Trafficking." DISCUSSION: Training health care providers on caring for trafficked persons has the potential to improve practitioners' knowledge about human trafficking and its health consequences, and to increase safe practices when responding in cases of trafficking. This study provides lessons for the design of training programs on human trafficking that aim to help health care providers identify and refer victims, and provide care for survivors. PMID- 25688344 TI - Factors Associated with Underweight among Children of Former-Kamaiyas in Nepal. AB - BACKGROUND: Bonded labor was a tradition in Nepal since the 16th century. In 2002, the Government of Nepal freed Kamaiyas and gave the newly freed individuals support for basic living. Many children of former-Kamaiyas live below subsistence level and are vulnerable to undernutrition. The aim of this study was to identify the factors associated with underweight among the children of former-Kamaiyas. METHODS: We conducted the community based cross-sectional study from June to December, 2012. Face-to-face interviews were conducted using semi-structured questionnaires with randomly selected mothers of 280 children under 5 years of age from former-Kamaiya families residing in Banke district. We also measured the weight and height of the children. Undernutrition was defined according to the World Health Organization child growth standards. Factors associated with underweight were examined using a Chi-square test followed by multiple logistic regression. RESULTS: Out of 280 children, 116 (41.4%) were underweight (<=2 SD weight-for-age), 156 (55.7%) were stunted (<=2 SD height-for-age), and 52 (18.6%) were wasted (<=2 SD weight-for-height). Females were more likely to be underweight than males [adjusted odds ratio (aOR) = 1.696, 95% confidence interval (CI) = 1.026-2.804]. Children were less likely to be underweight if they were having daily bath (aOR = 0.532; 95% CI = 0.314-0.899) or if their mothers were >=24 years of age (aOR = 0.440; 95% CI = 0.266-0.727). CONCLUSION: The proportion of underweight, stunting, and wasting was more than the national average among the children of former-Kamaiyas. Female children were more likely to be underweight whereas children who were being bathed daily and with mothers whose age was >=24 years were less likely to be underweight. PMID- 25688345 TI - Optimizing care and outcomes for people with type 2 diabetes - lessons from a translational research program on insulin initiation in general practice. AB - BACKGROUND: Clinical inertia, failure to intensify treatment according to evidence-based guidelines, leads to prolonged, avoidable hyperglycemia in people with type 2 diabetes (T2D). This is a challenge for General Practice and Primary Care, where most people with T2D receive most of their care. Sustained, integrated translational research programs are needed to embed effective treatments in routine practice, yet many challenges exist for developing such programs. OBJECTIVES: To explore challenges and facilitators to implementing a translational research program focused on insulin initiation and titration among people with T2D in general practice and to identify key factors important to support and sustain such translation research in primary care. Operationalizing a program of translational work in primary care: We describe a series of studies on insulin initiation and titration in general practice including theory and qualitative work (Phase 1), a small feasibility and acceptability pilot (Phase 2), a large scale pilot (Phase 3), and a pragmatic cluster randomized trial currently under way (Phase 4). We used mixed methods to explore practice level implementation issues, and reflective investigator discussions to explore broader research program sustainability. Challenges for translational research in primary care: Key facilitators and barriers at practice and research program levels, include: Appropriate funding structures to secure long-term capacity building and people support; Building and maintaining linkages between communities of practice, primary and secondary/tertiary care researchers, institutions, and industry partners; Strategies for engagement and support for practitioners and participants. CONCLUSION: Building effective and sustainable translational research programs are critical for developing evidence-based policy that drives improved outcomes at a population level. Diverse sources of funding that support extensive and sustained trans-mural collaboration as well as engagement with practitioners, patients, and policymakers in the field are crucial. PMID- 25688347 TI - Scene-Motion Thresholds Correlate with Angular Head Motions for Immersive Virtual Environments. AB - To better understand motion perception in immersive virtual environments, we conducted a user study to quantify perception of scene motion as subjects yawed their heads. We measured psychometric functions of scene-velocity thresholds for different head motions and then extracted 75% thresholds, creating scene-velocity thresholds as functions of three measures of head motion: 1) Angular Range, 2) Peak Angular Velocity, 3) and Peak Angular Acceleration. We also measured scene velocity thresholds for four phases of head motion: 1) the Start of the head turn, 2) the Center of the head turn, 3) the End of the head turn, 4) and All of the head turn. Scene-velocity thresholds increased as head motion increased for all tested conditions. PMID- 25688346 TI - Complement system in dermatological diseases - fire under the skin. AB - The complement system plays a key role in several dermatological diseases. Overactivation, deficiency, or abnormality of the control proteins are often related to a skin disease. Autoimmune mechanisms with autoantibodies and a cytotoxic effect of the complement membrane attack complex on epidermal or vascular cells can cause direct tissue damage and inflammation, e.g., in systemic lupus erythematosus (SLE), phospholipid antibody syndrome, and bullous skin diseases like pemphigoid. By evading complement attack, some microbes like Borrelia spirochetes and staphylococci can persist in the skin and cause prolonged symptoms. In this review, we present the most important skin diseases connected to abnormalities in the function of the complement system. Drugs having an effect on the complement system are also briefly described. On one hand, drugs with free hydroxyl on amino groups (e.g., hydralazine, procainamide) could interact with C4A, C4B, or C3 and cause an SLE-like disease. On the other hand, progress in studies on complement has led to novel anti-complement drugs (recombinant C1-inhibitor and anti-C5 antibody, eculizumab) that could alleviate symptoms in diseases associated with excessive complement activation. The main theme of the manuscript is to show how relevant the complement system is as an immune effector system in contributing to tissue injury and inflammation in a broad range of skin disorders. PMID- 25688348 TI - On the mathematical analysis of Ebola hemorrhagic fever: deathly infection disease in West African countries. AB - For a given West African country, we constructed a model describing the spread of the deathly disease called Ebola hemorrhagic fever. The model was first constructed using the classical derivative and then converted to the generalized version using the beta-derivative. We studied in detail the endemic equilibrium points and provided the Eigen values associated using the Jacobian method. We furthered our investigation by solving the model numerically using an iteration method. The simulations were done in terms of time and beta. The study showed that, for small portion of infected individuals, the whole country could die out in a very short period of time in case there is not good prevention. PMID- 25688349 TI - Bone cement solidifiliation influence the limb alignment and gap balance during TKA. AB - INTRODUCTION: Mechanical alignment deviation after total knee arthroplasty is a major reason for early loosening of the prosthesis. Achieving optimum cement penetration during fixation of the femoral and tibial component is an essential step in performing a successful total knee arthroplasty. Bone cement is used to solidify the bone and prosthesis. Thickness imbalance of bone cement leads to the deviation of mechanical alignment. To estimate the influence of bone cement, a retrospective study was conducted. MATERIALS AND METHODS: A total of 36 subjects were studied. All the TKA were performed following the standard surgical protocol for navigated surgery by medial approach with general anaesthesia. Prostheses were fixed by bone cement. RESULTS: We compared the mechanical axis, flexion/extension, and gap balance before and after cementation. All the factors were different compared with those before and after cementation. Internal rotation was reached with statistical significance (P=0.03). CONCLUSION: Bone cement can influence the mechanical axis, flexion/extension, and gap balance. It also can prompt us to make a change when poor knee kinematics were detected before cementation. PMID- 25688350 TI - Dragging human mesenchymal stem cells with the aid of supramolecular assemblies of single-walled carbon nanotubes, molecular magnets, and peptides in a magnetic field. AB - Human adipose-derived stem cells (hASCs) are an attractive cell source for therapeutic applicability in diverse fields for the repair and regeneration of damaged or malfunctioning tissues and organs. There is a growing number of cell therapies using stem cells due to their characteristics of modulation of immune system and reduction of acute rejection. So a challenge in stem cells therapy is the delivery of cells to the organ of interest, a specific site. The aim of this paper was to investigate the effects of a supramolecular assembly composed of single-walled carbon nanotubes (SWCNT), molecular magnets (lawsone-Co phenanthroline), and a synthetic peptide (FWYANHYWFHNAFWYANHYWFHNA) in the hASCs cultures. The hASCs were isolated, characterized, expanded, and cultured with the SWCNT supramolecular assembly (SWCNT-MA). The assembly developed did not impair the cell characteristics, viability, or proliferation. During growth, the cells were strongly attached to the assembly and they could be dragged by an applied magnetic field of less than 0.3 T. These assemblies were narrower than their related allotropic forms, that is, multiwalled carbon nanotubes, and they could therefore be used to guide cells through thin blood capillaries within the human body. This strategy seems to be useful as noninvasive and nontoxic stem cells delivery/guidance and tracking during cell therapy. PMID- 25688351 TI - The preventive effect of oxytocin to Cisplatin-induced neurotoxicity: an experimental rat model. AB - Peripheral neurotoxicity is a frequent dose-limiting side effect of the chemotherapeutic agent cisplatin. This study was conducted to investigate the preventive effect of oxytocin (OT) on cisplatin-induced neurotoxicity in rats. Forty-four adult female rats were included in the study. Thirty-six rats were administered intraperitoneally (i.p.) single dose cisplatin 10 mg/kg and divided in to 3 groups. The first group (n=12) received saline i.p., whereas the second group (n=12) and the third group (n=12) were injected with 80 ug/kg and 160 ug/kg OT, respectively, for 10 days. The remaining 8 rats served as the control group. Electromyography (EMG) studies were recorded and blood samples were collected for the measurement of plasma lipid peroxidation (malondialdehyde; MDA), tumor necrosis factor (TNF)-alpha, and glutathione (GSH) levels. EMG findings revealed that compound muscle action potential amplitude was significantly decreased and distal latency was prolonged in the nontreated cisplatin-injected rats compared with the control group (P<0.005). Also, nontreated cisplatin-injected rats showed significantly higher TNF-alpha and MDA levels and lower GSH level than control group. The administration of OT significantly ameliorated the EMG alterations, suppressed oxidative stress and inflammatory parameters, and increased antioxidative capacity. We suggest that oxytocin may have beneficial effects against cisplatin-induced neurotoxicity. PMID- 25688352 TI - Genetic association between methylenetetrahydrofolate reductase gene polymorphism and risk of osteonecrosis of the femoral head. AB - BACKGROUND: Methylenetetrahydrofolate reductase (MTHFR) SNP rs1801133 has been frequently investigated in recent years. Relevant candidate gene association studies with this SNP and osteonecrosis of the femoral head (ONFH) reported conflicting results. Meta-analysis provides a method to combine these data and to determine the association in a larger sample size. METHOD: We conducted a systematic search to identify possible studies. Four pooled ORs (odds ratios, T versus C, TT versus CC, TT/CT versus CC, and TT versus CT/CC), along with 95% confidence interval (CI), were calculated to evaluate the association between SNP rs1801133 and ONFH susceptibility. Both fixed effects model and random effects model were used. FINDINGS: We eventually included twelve studies in this analysis, with results showing no overall association between ONFH susceptibility and SNP rs1801133 (T versus C: OR=1.15, 95% CI=0.97-1.38; TT versus CC: OR=1.15, 95% CI=0.91-1.46; TT/CT versus CC: OR=1.09, 95% CI=0.95-1.25; and TT versus CT/CC: OR=1.16, 95% CI=0.93-1.45). When stratified based on ethnicity, the results were still not significant. CONCLUSION: Our findings are generally supportive of no association between MTHFR SNP rs1801133 and the etiology of ONFH. PMID- 25688353 TI - Bone regeneration of hydroxyapatite/alumina bilayered scaffold with 3 mm passage like medullary canal in canine tibia model. AB - The aim of this study was to evaluate the bone regeneration of hydroxyapatite (HA)/alumina bilayered scaffold with a 3 mm passage-like medullary canal in a beagle tibia model. A porous HA/alumina scaffold was fabricated using a polymeric template-coating technique. HA/alumina scaffold dimensions were 10 mm in outer diameter, 20 mm in length, and with either a 3 mm passage or no passage. A 20 mm segmental defect was induced using an oscillating saw through the diaphysis of the beagle tibia. The defects of six beagles were filled with HA/alumina bilayered scaffolds with a 3 mm passage or without. The segmental defect was fixated using one bone plate and six screws. Bone regeneration within the HA/alumina scaffolds was observed at eight weeks after implantation. The evaluation of bone regeneration within the scaffolds after implantation in a beagle tibia was performed using radiography, computerized tomography (CT), micro CT, and fluorescence microscopy. New bone successfully formed in the tibia defects treated with 3 mm passage HA/alumina scaffolds compared to without passage HA/alumina scaffolds. It was concluded that the HA/alumina bilayered scaffold with 3 mm passage-like medullary canal was instrumental in inducing host scaffold engraftment of the defect as well as distributing the newly formed bone throughout the scaffold at 8 weeks after implantation. PMID- 25688354 TI - CD8+ T-cells count in acute myocardial infarction in HIV disease in a predominantly male cohort. AB - Human Immunodeficiency Virus- (HIV-) infected persons have a higher risk for acute myocardial infarction (AMI) than HIV-uninfected persons. Earlier studies suggest that HIV viral load, CD4+ T-cell count, and antiretroviral therapy are associated with cardiovascular disease (CVD) risk. Whether CD8+ T-cell count is associated with CVD risk is not clear. We investigated the association between CD8+ T-cell count and incident AMI in a cohort of 73,398 people (of which 97.3% were men) enrolled in the U.S. Veterans Aging Cohort Study-Virtual Cohort (VACS VC). Compared to uninfected people, HIV-infected people with high baseline CD8+ T cell counts (>1065 cells/mm3) had increased AMI risk (adjusted HR=1.82, P<0.001, 95% CI: 1.46 to 2.28). There was evidence that the effect of CD8+ T-cell tertiles on AMI risk differed by CD4+ T-cell level: compared to uninfected people, HIV infected people with CD4+ T-cell counts>=200 cells/mm3 had increased AMI risk with high CD8+ T-cell count, while those with CD4+ T-cell counts<200 cells/mm3 had increased AMI risk with low CD8+ T-cell count. CD8+ T-cell counts may add additional AMI risk stratification information beyond that provided by CD4+ T cell counts alone. PMID- 25688356 TI - Complete nucleotide sequence analysis of the norovirus GII.4 Sydney variant in South Korea. AB - Norovirus is the primary cause of acute gastroenteritis in individuals of all ages. In Australia, a new strain of norovirus (GII.4) was identified in March 2012, and this strain has spread rapidly around the world. In August 2012, this new GII.4 strain was identified in patients in South Korea. Therefore, to examine the characteristics of the epidemic norovirus GII.4 2012 variant in South Korea, we conducted KM272334 full-length genomic analysis. The genome of the gg-12-08-04 strain consisted of 7,558 bp and contained three open reading frame (ORF) composites throughout the whole genome: ORF1 (5,100 bp), ORF2 (1,623 bp), and ORF3 (807 bp). Phylogenetic analyses showed that gg-12-08-04 belonged to the GII.4 Sydney 2012 variant, sharing 98.92% nucleotide similarity with this variant strain. According to SimPlot analysis, the gg-12-08-04 strain was a recombinant strain with breakpoint at the ORF1/2 junction between Osaka 2007 and Apeldoorn 2008 strains. This study is the first report of the complete sequence of the GII.4 Sydney 2012 strain in South Korea. Therefore, this may represent the standard sequence of the norovirus GII.4 2012 variant in South Korea and could therefore be useful for the development of norovirus vaccines. PMID- 25688357 TI - A prospective randomized controlled trial of AJG522 versus standard PEG+E as bowel preparation for colonoscopy. AB - Polyethylene glycol- (PEG-) based bowel preparations for colonoscopies are often poorly tolerated due to the large volumes of fluid intake required. We compared low-volume "modified" PEG + ascorbic acid (AJG522) with standard PEG with electrolytes (PEG+E) in addition to a stimulant laxative and an agent to improve bowel function for the bowel cleansing before colonoscopy to evaluate its efficacy, safety, and acceptability. Outpatients scheduled to undergo colonoscopy were randomized to receive either AJG522 or PEG+E. Bowel cleansing conditions were assessed via macroscopic fecal findings by blinded and independent investigators. A survey of the patients' feedback regarding the preparation was conducted by questionnaire. Successful cleansing was achieved in all cases, except for 4 cases in the PEG+E group, at 3 hours after taking the preparation. The fecal properties were significantly clearer in the AJG522 group than in the PEG+E group at 2 hours after taking each preparation (P=0.013). Although the total liquid volume of the bowel preparation was not reduced, the AJG522 preparation could significantly reduce the required volume of the preparation (P<0.0001). Moreover, the patients in the AJG522 group had better acceptability (P=0.010). There were no significant differences in the safety profiles between groups (UMIN000013892). PMID- 25688355 TI - Primary retinal cultures as a tool for modeling diabetic retinopathy: an overview. AB - Experimental models of diabetic retinopathy (DR) have had a crucial role in the comprehension of the pathophysiology of the disease and the identification of new therapeutic strategies. Most of these studies have been conducted in vivo, in animal models. However, a significant contribution has also been provided by studies on retinal cultures, especially regarding the effects of the potentially toxic components of the diabetic milieu on retinal cell homeostasis, the characterization of the mechanisms on the basis of retinal damage, and the identification of potentially protective molecules. In this review, we highlight the contribution given by primary retinal cultures to the study of DR, focusing on early neuroglial impairment. We also speculate on possible themes into which studies based on retinal cell cultures could provide deeper insight. PMID- 25688358 TI - The correlation between miRNA and lymph node metastasis in gastric cancer. AB - Lymph node metastasis (LNM) in gastric cancer is associated with higher rate of cancer recurrence and poor prognosis. As a result, a reliable biomarker for the prediction of LNM is important and would be valuable in the clinical practice. MiRNA microarray revealed that ten miRNAs were expressed significantly different among patients with or without LNM. A total of 46 gastric cancer patients were enrolled and divided into two groups (23 in each group) according to the presence or absence of LNM. RT-PCR of these 10 miRNAs was investigated and compared between the two groups. MiR-1207-5p was significantly upregulated in gastric cancer patients without LNM compared with those with LNM. Patients with upregulated miR-1207-5p had less scirrhous stromal reaction, less lymphovascular invasion, and earlier pathological T category, N category, and TNM stage, compared with those with downregulated or unchanged miR-1207-5p. Multivariate analysis showed that stromal reaction type, lymphovascular invasion, pathological T category and TNM stage, and expression of miR-1207-5p were independent risk factors of LNM. MiR-1207-5p could serve as a useful biomarker in the prediction of LNM in gastric cancer. PMID- 25688359 TI - Self-medication practices among parents in Italy. AB - The aims of this cross-sectional survey were to document the prevalence, the determinants, and the reasons of oral medication use without the prescription of a physician among a random sample of 672 parents of students attending randomly selected public schools in Italy. A total of 69.2% practiced self-medication at least once. The odds of having performed a self-medication were higher in females, in younger population, and in those who have had a health problem in the preceding year and were lower in respondents with a middle or lower school level of education. Among those reporting experience of self-medication, 53.4% have practiced at least once in the last year and this was more likely for those who have had a health problem. Nonsteroidal anti-inflammatory drugs were more frequently used without a prescription in the last year. Two-thirds inappropriately self-medicated in the last year at least once. Of those who did not report a self-medication, 13.1% were willing to practice it. Females were more willing and those with a secondary school level of education less willing to practice self-medication. The frequency of oral self-medication was quite high and in most cases inappropriate with a potential impact on the health status and educative programs are needed. PMID- 25688360 TI - Monitoring the modifications of the vitreous humor metabolite profile after death: an animal model. AB - We applied a metabolomic approach to monitor the modifications occurring in goat vitreous humor (VH) metabolite composition at different times (0, 6, 12, 18, and 24 hours) after death. The (1)H-NMR analysis of the VH samples was performed for the simultaneous determination of several metabolites (i.e., the metabolite profile) representative of the VH status at different times. Spectral data were analyzed by Principal Component Analysis (PCA) and by Orthogonal Projection to Latent Structures (OPLS) regression technique. PCA and OPLS suggested that different spectral regions were involved in time-related changes. The major time related compositional changes, here detected, were the increase of lactate, hypoxanthine, alanine, total glutathione, choline/phosphocholine, creatine, and myo-inositol and the decrease of glucose and 3-hydroxybutyrate. We attempted a speculative interpretation of the biological mechanisms underlying these changes. These results show that multivariate statistical approach, based on (1)H NMR metabolite profiling, is a powerful tool for detecting ongoing differences in VH composition and may be applied to investigate several physiological and pathological conditions. PMID- 25688362 TI - Zeaxanthin inhibits hypoxia-induced VEGF secretion by RPE cells through decreased protein levels of hypoxia-inducible factors-1alpha. AB - Hypoxia is the most important stimulus leading to upregulation of VEGF in the retina and this is caused by accumulation of hypoxia-inducible factors-1alpha (HIF-1alpha) protein. The effects of zeaxanthin, a natural phytochemical, on the VEGF and HIF-1alpha expression in the primary culture of human retinal pigment epithelial (RPE) cells were studied. An in vitro RPE cell hypoxia model was established by placing cells under 1% oxygen pressure or by adding cobalt chloride (CoCl2) to the culture medium. RPE cells and conditioned media were collected from cultures treated with and without zeaxanthin under normoxic and hypoxic conditions. VEGF and HIF-1alpha protein and RNA levels were measured by ELISA kits and RT-PCR, respectively. Hypoxia caused a significant increase of VEGF expression and accumulation of HIF-1alpha in RPE cells. Zeaxanthin at 50-150 MUM significantly inhibited the expression of VEGF and accumulation of HIF-1alpha protein caused by hypoxia but did not affect expression of VEGF and HIF-1alpha under normoxic conditions. This is the first report on the effect of zeaxanthin on VEGF and HIF-1alpha levels in cultured RPE cells and suggests that zeaxanthin may have potential value in the prevention and treatment of various retinal diseases associated with vascular leakage and neovascularization. PMID- 25688363 TI - Dependence of thyroid sonographic markers of malignancy and its influence on the diagnostic value of sonographic findings. AB - INTRODUCTION: Thyroid nodules constitute frequent medical condition. Ultrasonographic (US) examination remains the basis in the diagnostics of nodular goiter and selection of the suspected ones requiring fine-needle aspiration biopsy (FNAB). The aim of this study was to evaluate if the features so far considered to be US malignancy markers are dependent or independent variables and to check if these data are clinically relevant. MATERIALS AND METHODS: Patients with diagnosed thyroid nodular goiter admitted for thyroidectomy, irrespectively of the indications for surgery, were involved. The following parameters were assessed: echogenicity, the presence of calcifications, presence of halo, shape, margins, structure (solid, partially or pure cystic), and elasticity of the nodules (assessed quantitatively). RESULTS: 122 consecutive patients with 393 thyroid nodules were included. There were significant associations between halo absence and irregular borders, micro- and macrocalcifications, taller-than-wide feature and macrocalcifications, irregular margins and macrocalcifications, and also decreased elasticity of nodules and several attributes (partially cystic character, micro- and macrocalcifications). CONCLUSIONS: Not only diagnostic value of particular sonographic features but also data about cooccurrence and associations between them are clinically relevant. Although most of these features turned out to be independent, omitting significant association can lead to incorrect assessment of the risk of malignancy. PMID- 25688361 TI - Dietary factors in the etiology of Parkinson's disease. AB - Parkinson's disease (PD) is the second most common neurodegenerative disorder. The majority of cases do not arise from purely genetic factors, implicating an important role of environmental factors in disease pathogenesis. Well-established environmental toxins important in PD include pesticides, herbicides, and heavy metals. However, many toxicants linked to PD and used in animal models are rarely encountered. In this context, other factors such as dietary components may represent daily exposures and have gained attention as disease modifiers. Several in vitro, in vivo, and human epidemiological studies have found a variety of dietary factors that modify PD risk. Here, we critically review findings on association between dietary factors, including vitamins, flavonoids, calorie intake, caffeine, alcohol, and metals consumed via food and fatty acids and PD. We have also discussed key data on heterocyclic amines that are produced in high temperature cooked meat, which is a new emerging field in the assessment of dietary factors in neurological diseases. While more research is clearly needed, significant evidence exists that specific dietary factors can modify PD risk. PMID- 25688364 TI - Salivary desmoglein enzyme-linked immunosorbent assay for diagnosis of pemphigus vulgaris: a noninvasive alternative test to serum assessment. AB - BACKGROUND: Serum desmoglein enzyme-linked immunosorbent assay (ELISA) is used for the diagnosis and monitoring of pemphigus diseases. OBJECTIVES: To compare the diagnostic accuracy of salivary antidesmoglein (Dsg) 1 and 3 ELISA in the diagnosis of pemphigus vulgaris (PV) patients with that of serum desmogleins ELISA. METHODS: Eighty-six untreated PV patients and 180 age- and sex-matched PV free controls were recruited in this case-control study. PV was diagnosed based on clinical, histopathological, and direct immunofluorescence findings. After processing, serum and salivary anti-Dsg 1 and 3 were measured by the ELISA method using Euroimmun kit (Lubeck, Germany). RESULTS: Using the cut-off point of 20 relative units (RU)/mL, the serum anti-Dsg 1 and 3 ELISA were positive in 62 (72.1%) and 83 (96.5%) patients, respectively, and the salivary anti-Dsg 1 and 3 ELISA were positive in 31 (36.1%) and 63 (73.3%) patients, respectively. The specificity of salivary anti-Dsg 1 and anti-Dsg 3 were both 98.9%. Optimal cut off values of 7.7 and 13.4 RU/mL were determined for the salivary anti-Dsg 1 and anti-Dsg 3 ELISA, respectively. CONCLUSION: Salivary anti-Dsg 1 and 3 ELISA with high specificities (98.9%) could be suggested as safe and noninvasive methods for the diagnosis of PV when obtaining a blood sample is difficult. PMID- 25688365 TI - Serum miR-224 reflects stage of hepatocellular carcinoma and predicts survival. AB - BACKGROUND: In our previous study, we conducted a systematic screening of miRNA to identify potential serum biomarkers for predicting venous metastasis and survival in patients with hepatocellular carcinoma (HCC). miR-224 was one of the differentially expressed miRNAs. This study aimed to confirm whether serum miR 224 level is associated with the presence of venous metastasis and survival. METHODS: TaqMan miRNA probe was used to perform qRT-PCR assays to evaluate the expression of serum miR-224 in a cohort of 182 HCC patients. RESULTS: Patients with high miR-224 serum level showed poor survival compared to that with low miR 224 serum level (HR 1.985; 95% CI, 1.08, 3.65, P=0.027). The serum miR-224 levels were significantly higher in the BCLC stage C patients compared with the stage B patients (P=0.005). In further analysis, significant difference of serum miR-224 expression level was observed when patients grouped by the status of PVTT but not the status of extra-liver metastasis (P=0.013 and P=0.091). Serum levels of miR 224 showed significant relation with parameters of liver damage and serum AFP. CONCLUSION: Serum miR-224 might be BCLC stage dependent. It can reflect the status of tumor and liver damage. It was an independent predictor for the survival of HCC patients. PMID- 25688367 TI - Identification of potential transcriptomic markers in developing ankylosing spondylitis: a meta-analysis of gene expression profiles. AB - The goal of this study was to identify potential transcriptomic markers in developing ankylosing spondylitis by a meta-analysis of multiple public microarray datasets. Using the INMEX (integrative meta-analysis of expression data) program, we performed the meta-analysis to identify consistently differentially expressed (DE) genes in ankylosing spondylitis and further performed functional interpretation (gene ontology analysis and pathway analysis) of the DE genes identified in the meta-analysis. Three microarray datasets (26 cases and 29 controls in total) were collected for meta-analysis. 905 consistently DE genes were identified in ankylosing spondylitis, among which 482 genes were upregulated and 423 genes were downregulated. The upregulated gene with the smallest combined rank product (RP) was GNG11 (combined RP=299.64). The downregulated gene with the smallest combined RP was S100P (combined RP=335.94). In the gene ontology (GO) analysis, the most significantly enriched GO term was "immune system process" (P=3.46*10(-26)). The most significant pathway identified in the pathway analysis was antigen processing and presentation (P=8.40*10(-5)). The consistently DE genes in ankylosing spondylitis and biological pathways associated with those DE genes identified provide valuable information for studying the pathophysiology of ankylosing spondylitis. PMID- 25688366 TI - Structure-function based molecular relationships in Ewing's sarcoma. AB - Ewing's Sarcoma Oncogene (ews) on chromosome 22q12 is encoding a ubiquitously expressed RNA-binding protein (EWS) with unknown function that is target of tumor specific chromosomal translocations in Ewing's sarcoma family of tumors. A model of transcription complex was proposed in which the heterodimer Rpb4/7 binds to EAD, connecting it to Core RNA Pol II. The DNA-binding domain, provided by EFP, is bound to the promoter. Rpb4/7 binds RNA, stabilizing the transcription complex. The complex Rpb4/7 can stabilize the preinitiation complexes by converting the conformation of RNA Pol II. EWS may change its conformation, so that NTD becomes accessible. Two different mechanisms of interaction between EWS and RNA Pol II are proposed: (I) an intermolecular EWS-EWS interaction between two molecules, pushing conformation from "closed" to "open" state, or (II) an intramolecular interaction inside the molecule of EWS, pushing conformation of the molecule from "closed" to "open" state. The modified forms of EWS may interact with Pol II subunits hsRpb5 and hsRpb7. The EWS and EFPs binding partners are described schematically in a model, an attempt to link the transcription with the splicing. The proposed model helps to understand the functional molecular interactions in cancer, to find new partners and ways to treat cancer. PMID- 25688368 TI - Alleviation of kainic acid-induced brain barrier dysfunction by 4-o methylhonokiol in in vitro and in vivo models. AB - This experiment was designed to investigate whether 4-O-methylhonokiol (MH), a principal ingredient of Magnolia (M.) officinalis bark, alleviated acute intraperitoneal (i.p.) kainic acid- (KA-) induced brain blood barrier dysfunction (BBBD) via pathological examination and cytological analyses of the brain tissues of mice. KA (10-30 mg/kg) time- and dose-dependently increased the water content of brain tissues and induced edema and encephalopathy. However, pretreatment with MH (5 and 20 mg/kg, i.p.) significantly reduced the water content of the brain compared to that observed in the KA control group. Furthermore, MH significantly and dose-dependently reversed the remarkable variations in evan's blue dye (EBD) staining and malondialdehyde (MDA) levels that were induced by KA (10 mg/kg, i.p.). MH also decreased the elevated seizure scores that were induced by KA (10 mg/kg, i.p.) in mice in a manner similar to scavengers such as DMTU and trolox. Additionally, MH significantly scavenged intracellular ROS and Ca2+ within hippocampal cells. The tight junction seals mediated by claudin (Cld-5) were also found to be modulated by MH. MH efficiently reduced 1,1-diphenyl-2-picrylhydrazyl (DPPH) (IC50, 52.4 mM) and *OH with an electron spin resonance (ESR) signal rate constant of 4*10(9) M(-1).S(-1), which is close to the reactivity of the vitamin E analog trolox. Taken together, these results suggest that MH may enhance radical scavenging in lipid and hydrophobic environments, which may be important for the physiological activity of the barrier. PMID- 25688369 TI - Icariin intervenes in cardiac inflammaging through upregulation of SIRT6 enzyme activity and inhibition of the NF-kappa B pathway. AB - The aim of the study was to investigate the effect of icariin (ICA) on cardiac aging through its effects on the SIRT6 enzyme and on the NF-kappaB pathway. Investigating the effect of ICA on the enzymatic activity of histone deacetylase SIRT6 revealed a concentration of 10(-8) mol/L ICA had a maximum activating effect on histone deacetylase SIRT6 enzymatic activity. Western analysis showed that ICA upregulated SIRT6 protein expression and downregulated NF-kappaB (p65) protein expression in animal tissues and cell models. ICA upregulated the expression of SIRT6 and had an inhibitory effect on NF-kappaB inflammatory signaling pathways as shown by decreasing mRNA levels of the NF-kappaB downstream target genes TNF-alpha, ICAM-1, IL-2, and IL-6. Those effects were mediated directly or indirectly by SIRT6. We provided evidence that inflammaging may involve a novel link between the effects of ICA on SIRT6 (a regulator of aging) and NF-kappaB (a regulator of inflammation). PMID- 25688370 TI - Lentiviral-mediated silencing of farnesyl pyrophosphate synthase through RNA interference in mice. AB - Farnesyl pyrophosphate synthase (FPPS) plays a vital role in the mevalonate pathway and has been shown to be involved in hypertrophy and cardiovascular diseases. Lentivirus-mediated RNA interference (RNAi) to knock down a gene of interest has become a promising new tool for the establishment of transgenic animals. The interfering fragment, named pLVT202, was chosen from cardiomyocytes tested in vitro and was microinjected into the perivitelline space of zygotes from C57BL/6J mice via a lentivirus vehicle; 20 were identified as carrying copies of the transgene using the polymerase chain reaction (PCR). Real-time PCR and western blotting analysis showed that FPPS was downregulated in multiple tissues in the transgenic mice. The transgenic mouse model provides a novel means of studying the gene function of FPPS. PMID- 25688371 TI - A hybrid IMRT/VMAT technique for the treatment of nasopharyngeal cancer. AB - Hybrid IMRT/VMAT technique which combined intensity modulated radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT) was developed for the treatment of nasopharyngeal cancer (NPC). Two-full-arc VMAT (2ARC-VMAT), 9-field IMRT (9F IMRT), and Hybrid IMRT/VMAT plans for NPC were compared in terms of the dosimetric quality, sparing of organs at risk (OARs), and delivery efficiency. The Hybrid IMRT/VMAT technique can improve the target dose homogeneity and conformity compared with 9F-IMRT and 2ARC-VMAT. It can reduce the dose delivered to the TMJ, mandible, temporal lobe, and unspecified tissue with fewer MUs compared with 9F-IMRT and dose delivered to parotids, brainstem, and spinal cord compared with 2ARC-VMAT technique. The mean delivery time of Hybrid plans was shorter than that of 9F-IMRT plans (408 s versus 812 s; P=0.00) and longer than that of 2ARC-VMAT plans (408 s versus 179 s; P=0.00). Hybrid IMRT/VMAT technique could be a viable radiotherapy technique with better plan quality. PMID- 25688372 TI - Serum/plasma microRNAs as biomarkers for HBV-related hepatocellular carcinoma in China. AB - MicroRNAs (miRNAs) are a group of small RNAs with a fundamental role in the regulation of gene expression. These RNAs have been shown to participate in various cellular and physiological processes, including cellular development, apoptosis, proliferation, and differentiation. Aberrant expression of several miRNAs was found to be involved in a large variety of neoplasms, including hepatocellular carcinoma (HCC). Previous studies have shown the existence of a large amount of stable miRNAs in human serum/plasma, which laid the foundation for studying the role of serum/plasma miRNAs in the diagnosis and prognosis of HCC. Here, we review the recent progress in research on serum miRNAs as biomarkers for HCC in Chinese patients. PMID- 25688373 TI - Effects of glucagon-like peptide-1 receptor agonists on weight loss in patients with type 2 diabetes: a systematic review and network meta-analysis. AB - To evaluate the effectiveness of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) on weight reduction in patients with Type 2 diabetes mellitus (Type 2 DM), a network meta-analysis was conducted. MEDLINE, EMBASE, Cochrane Library, and ClinicalTrials.gov were searched from 1950 to October 2013. Randomized controlled trials (RCTs) involving GLP-1 RAs were included if they provided information on body weight. A total of 51 RCTs were included and 17521 participants were enrolled. The mean duration of 51 RCTs was 31 weeks. Exenatide 10 MUg twice daily (EX10BID) reduced weight compared with exenatide 5 MUg twice daily (EX5BID), liraglutide 0.6 mg once daily (LIR0.6QD), liraglutide-1.2 mg once daily (LIR1.2QD), and placebo treatment, with mean differences of -1.07 kg (95% CI: 2.41, -0.02), -2.38 kg (95% CI: -3.71, -1.06), -1.62 kg (95% CI: -2.79, -0.43), and -1.92 kg (95% CI: -2.61, -1.24), respectively. Reductions of weight treated with liraglutide-1.8 mg once daily (LIR1.8QD) reach statistical significance ( 1.43 kg (95% CI: -2.73, -0.15)) versus LIR1.2QD and (-0.98 kg (95% CI: -1.94, 0.02)) versus placebo. Network meta-analysis found that EX10BID, LIR1.8QD, and EX2QW obtained a higher proportion of patients with weight loss than other traditional hypoglycemic agents. Our results suggest GLP-1 RAs are promising candidates for weight control in comparison with traditional hypoglycemic drugs, and EX10BID, LIR1.8QD, and EX2QW rank the top three drugs. PMID- 25688374 TI - Determining predictors of early response to exenatide in patients with type 2 diabetes mellitus. AB - Exenatide is a GLP-1 analogue used in the management of T2DM yet within a subset of patients fails due to adverse side effects or from failure to attain the end goal. This retrospective observational study aimed to determine whether we could predict response to exenatide in patients with T2DM. 112 patients on exenatide were included with patient age, gender, duration of T2DM, medications alongside exenatide and weight, BMI, and HbA1c at baseline and 3 and 6 months of exenatide use being recorded. 63 responded with 11 mmol/mol reduction from baseline HbA1c after six months and 49 did not respond to exenatide. HbA1c solely differed significantly between cohorts at baseline, 3 months, and 6 months (P < 0.05). Regression analyses identified a negative linear relationship with higher baseline HbA1c correlating to greater reductions in HbA1c by 6 months (P < 0.0001). HbA1c was the sole predictor of exenatide response with higher baseline HbA1c increasing the odds of response by 5% (P = 0.004). Patients with HbA1c reductions >=15-20% by 3 months were more likely to be responders by 6 months (P = 0.033). Our study identified that baseline HbA1c acted as the sole predictor of exenatide response and that response may be determined after 3 months of exenatide administration. PMID- 25688375 TI - Surgical treatment of primary intracardiac myxoma: 20-year experience in "Shahid Modarres Hospital"--a tertiary university hospital--Tehran, Iran. AB - Although cardiac tumors are not common they may vary in terms of race and surgical approach in different countries. METHOD: Patients data of 20 years was collected and evaluated in the "Shahid Modarres Hospital"--a tertiary university hospital--Tehran, Iran. RESULTS: 42 patients with cardiac myxoma (all cases in 20 years) were included in study, 17 males and 25 females, age difference: 13 to 76 years (mean 50.6). Most of patients were in functional classes I, II. 35 patients complained of dyspnea and 3 patients had embolic events. 97.6% of tumors were primary (41 patients) and one tumor was recurrent (2.4%), 85.7% of tumors (36 cases) were located in LA, and 88.1% of tumors (37 cases) were pediculated. 40 patients (95%) had one tumor. In 22 patients (52.3%) after tumor resection septal defects were repaired primarily while in 18 patients (42.8%) the defects were repaired with pericardial patch and In one patient, tumor resected without any septal defect. Mean tumor size was about 5.22 cm (range of 2.2 to 8.2 cm). Postoperatively, 33 patients discharged from hospital without any complication. DISCUSSION: The research reveals that patients' age and gender were similar to that of other studies in other countries while tumor's incidence seems to be higher. 3 patients were diagnosed after remote embolic event and one patient was diagnosed after MI reflecting relatively high tumor complications and late diagnosis. CONCLUSION: In our study mean time from diagnosis to operation was too long. The patients had more preoperative embolic events and complication. However, size of myxoma and location of that was as same as its rate in the other literature. As recommendation we suggested that in all patients with vague chest pain or remote embolic events cardiac myxomas should be ruled out. PMID- 25688376 TI - Colonization and diversity of AM fungi by morphological analysis on medicinal plants in southeast China. AB - The arbuscular mycorrhizal (AM) fungal distributions in the rhizosphere of 20 medicinal plants species in Zhangzhou, southeast China, were studied. The results showed 66 species of 8 genera of AM fungi were identified, of which 38 belonged to Glomus, 12 to Acaulospora, 9 to Scutellospora, 2 to Gigaspora, 2 to Funneliformis, 1 to Septoglomus, 1 to Rhizophagus, and 1 to Archaeospora. Glomus was the dominant genera and G. melanosporum, Acaulospora scrobiculata, G. etunicatum, Funneliformis mosseae, and G. rubiforme were the prevalent species. The highest colonization (100%) was recorded in Desmodium pulchellum (L.) Benth. while the lowest (8.0%) was in Acorus tatarinowii Schott. The AM fungi spore density ranged from 270 to 2860 per 100 g soil (average 1005), and the species richness ranged from 3 to 14 (average 9.7) per soil sample. Shannon-Wiener index ranged from 0.52 to 2 (average 1.45). In the present study, the colonization had a highly negative correlation with available K and electrical conductivity. Species richness correlated positively with electrical conductivity and organic matter. Shannon-Wiener index had a highly significant negative correlation with pH. This study provides a valuable germplasm and theoretical basis for AM fungal biotechnology on medicinal standardization planting. PMID- 25688377 TI - Heavy metal stress and some mechanisms of plant defense response. AB - Unprecedented bioaccumulation and biomagnification of heavy metals (HMs) in the environment have become a dilemma for all living organisms including plants. HMs at toxic levels have the capability to interact with several vital cellular biomolecules such as nuclear proteins and DNA, leading to excessive augmentation of reactive oxygen species (ROS). This would inflict serious morphological, metabolic, and physiological anomalies in plants ranging from chlorosis of shoot to lipid peroxidation and protein degradation. In response, plants are equipped with a repertoire of mechanisms to counteract heavy metal (HM) toxicity. The key elements of these are chelating metals by forming phytochelatins (PCs) or metallothioneins (MTs) metal complex at the intra- and intercellular level, which is followed by the removal of HM ions from sensitive sites or vacuolar sequestration of ligand-metal complex. Nonenzymatically synthesized compounds such as proline (Pro) are able to strengthen metal-detoxification capacity of intracellular antioxidant enzymes. Another important additive component of plant defense system is symbiotic association with arbuscular mycorrhizal (AM) fungi. AM can effectively immobilize HMs and reduce their uptake by host plants via binding metal ions to hyphal cell wall and excreting several extracellular biomolecules. Additionally, AM fungi can enhance activities of antioxidant defense machinery of plants. PMID- 25688378 TI - Hesitant fuzzy soft sets with application in multicriteria group decision making problems. AB - Soft sets have been regarded as a useful mathematical tool to deal with uncertainty. In recent years, many scholars have shown an intense interest in soft sets and extended standard soft sets to intuitionistic fuzzy soft sets, interval-valued fuzzy soft sets, and generalized fuzzy soft sets. In this paper, hesitant fuzzy soft sets are defined by combining fuzzy soft sets with hesitant fuzzy sets. And some operations on hesitant fuzzy soft sets based on Archimedean t-norm and Archimedean t-conorm are defined. Besides, four aggregation operations, such as the HFSWA, HFSWG, GHFSWA, and GHFSWG operators, are given. Based on these operators, a multicriteria group decision making approach with hesitant fuzzy soft sets is also proposed. To demonstrate its accuracy and applicability, this approach is finally employed to calculate a numerical example. PMID- 25688380 TI - Relation of the cyclotomic equation with the harmonic and derived series. AB - We associate some (old) convergent series related to definite integrals with the cyclotomic equation x (m) - 1 = 0, for several natural numbers m; for example, for m = 3, x(3) - 1 = (x - 1)(1 + x + x (2)) leads to ?(1)0 dx(1/(1 +x + x2)) = pi/(3?3) = (1 - 1/2) + (1/4 - 1/5) + (1/7 - 1/8) + ... . In some cases, we express the results in terms of the Dirichlet characters. Generalizations for arbitrary m are well defined but do imply integrals and/or series summations rather involved. PMID- 25688379 TI - A novel method of early diagnosis of Alzheimer's disease based on EEG signals. AB - Studies have reported that electroencephalogram signals in Alzheimer's disease patients usually have less synchronization than those of healthy subjects. Changes in electroencephalogram signals start at early stage but, clinically, these changes are not easily detected. To detect this perturbation, three neural synchrony measurement techniques: phase synchrony, magnitude squared coherence, and cross correlation are applied to three different databases of mild Alzheimer's disease patients and healthy subjects. We have compared the right and left temporal lobes of the brain with the rest of the brain areas (frontal, central, and occipital) as temporal regions are relatively the first ones to be affected by Alzheimer's disease. Moreover, electroencephalogram signals are further classified into five different frequency bands (delta, theta, alpha beta, and gamma) because each frequency band has its own physiological significance in terms of signal evaluation. A new approach using principal component analysis before applying neural synchrony measurement techniques has been presented and compared with Average technique. The simulation results indicated that applying principal component analysis before synchrony measurement techniques shows significantly better results as compared to the lateral one. At the end, all the aforementioned techniques are assessed by a statistical test (Mann-Whitney U test) to compare the results. PMID- 25688381 TI - Elevation of Cardiac Troponins in Prolonged Status Epilepticus: A Retrospective Chart Analysis. AB - INTRODUCTION: To determine the clinical significance of elevation of Troponin-I [cTn-I] during prolonged status epilepticus [pSE] SE is known to be accompanied by an increase in sympathetic outflow. Elevation of cTn-I has been linked to myocardial stress. We hypothesize that in patients with risk factors for coronary artery disease[CAD], pSE may lead to myocardial stress and an elevation of cTn-I. METHODS: This is a retrospective study of patients over the age of 18 years who were presented to Virginia Commonwealth University with SE between 2005 and 2010. Data was evaluated using the 30-minute definition for SE and 30 day mortality. Risk factors for CAD and cTn-I levels within the first 24 hours of diagnosis of pSE were analyzed. KEY FINDINGS: There were a total of 435 patients with a confirmed diagnosis of pSE, of which 266 had cTn-I concentrations reported. Statistical analysis showed a significant association between CAD risk factors and cTn-I elevation (chi2 =12.87, p-value <0.01), with Crude Odds Ratio of 4.7. In patients with a CAD risk factor, an elevation of cTn-I is associated with a significantly increased risk of mortality, with an Odds ratio of 8.0, (chi2 =40, [95% CI 4.1-15.9] p-value < 0.01). Mortality was higher in those with an elevation of cTn-I [54.65%] as opposed to those who did not have an elevation [15.08%], irrespective of CAD risk factors. OR=6.7, (chi2 =45, [95% CI=3.7-12.2] p-value < 0.01). CONCLUSIONS: In patients with pSE values, elevated cTn-I values are seen four to five time more often in those with CAD risk factors, as opposed to those without the risks. An elevation of cTn-I in this subgroup of patients with CAD risk factors was associated with an eight to nine fold increase in their 30 day mortality as compared to patients with pSE, who did not have an elevation of cTn-I. PMID- 25688382 TI - Cabozantinib Loaded DSPE-PEG2000 Micelles as Delivery System: Formulation, Characterization and Cytotoxicity Evaluation. AB - Cabozantinib, a potent pan-tyrosine kinase inhibitor, has been reported to provide enhanced antitumor efficacy by simultaneously inhibiting both MET and VEGF pathways, which are critical to tumor angiogenesis, survival and migration. It's very poor water solubility prevents its administration by the intravenous route, which may be important in patients unable to take the drug orally. In this study, we developed an efficient PEG-lipid-based polymeric micelle formulation with enhanced drug solubility and stability for cabozantinib delivery. DSPE PEG2000 micelles encapsulating cabozantinib were prepared by a thin-film rehydration method followed by a lyophilization process to generate the dry dosage form. The average hydrodynamic diameter of freshly prepared micelles was 11 nm with a narrow size distribution, and the dry micelle cake could be fully reconstituted by rehydration. Approximately 75% of the drug was encapsulated into the lyophilized cake, and a sustained drug release profile was observed in simulated normal physiological release medium. Compared with the free cabozantinib solution, the drug-loaded micelles displayed significantly enhanced intracellular accumulation and cytotoxicity in human glioblastoma cancer cells and non-small lung cancer cells. These results suggest that the micellar formulation of cabozantinib may serve as a promising nanocarrier in anticancer treatments. PMID- 25688383 TI - Preparing a New Generation of Clinicians for the Era of Big Data. AB - As medicine becomes increasingly complex and financially constrained, it will be the responsibility of every clinician to understand and participate in the enterprise of extracting lessons learned from digitally captured patient care. PMID- 25688384 TI - Micropatterned, clickable culture substrates enable in situ spatiotemporal control of human PSC-derived neural tissue morphology. AB - We describe a modular culture platform that enables spatiotemporal control of the morphology of 2D neural tissues derived from human pluripotent stem cells (hPSCs) by simply adding clickable peptides to the media. It should be widely applicable for elucidating how spatiotemporal changes in morphology and substrate biochemistry regulate tissue morphogenesis. PMID- 25688385 TI - Rhenium-catalysed dehydrogenative borylation of primary and secondary C(sp3)-H bonds adjacent to a nitrogen atom. AB - Rhenium-catalysed C(sp(3))-H bond borylation in the absence of any oxidant, hydrogen acceptor, or external ligand, with the generation of H2 as the sole byproduct is described. The transformation, which represents a rare example of rhenium-catalysed C(sp(3))-H bond functionalisation, features high atom efficiency and simple reaction conditions. PMID- 25688386 TI - Loading of mesoporous titania films by CH3NH3PbI3 perovskite, single step vs. sequential deposition. AB - Infiltration of mesoporous TiO2 scaffolds by CH3NH3PbI3 is more complete when using sequential compared to single step deposition processing and avoids formation of disordered capping layers affording greatly improved performance of perovskite based photovoltaics. PMID- 25688387 TI - Proceedings of Metabolism 2014--alterations of metabolic pathways as therapeutic targets, January 29-31, 2014, Esch-sur-Alzette, Luxembourg. PMID- 25688388 TI - Proceedings of The 15th International Meeting on the Biology and Pathogenicity of Free-Living Amoebae (FLAM 2013), July 2013, Vienna, Austria. PMID- 25688389 TI - Proceedings of the Ninth International Symposium on Biological Monitoring in Occupational and Environmental Health (ISBM-9) , 9-11 September, 2013, Manchester, UK. PMID- 25688390 TI - Proceedings and Abstracts of the 7th International Conference on Thrombosis and Hemostasis Issues in Cancer, May 9-11, 2014, Bergamo, Italy. PMID- 25688391 TI - Proceedings of the 3rd International Congress on Analytical Proteomics (ICAP), July 28-31, 2013, Sao Pedro, Brazil. PMID- 25688392 TI - Proceedings of IMmune-related Pathologies: Understanding Leukocyte Signaling and Emerging Therapies- Impulse 2013, September 2013, Matrahaza, Hungary. PMID- 25688393 TI - Re: Gulabi D, Cecen GS, Bekler HI, Saglam F and Tanju N. A study of 60 patients with percutaneous trigger finger releases: clinical and ultrasonographic findings. J Hand Surg Eur. 2014, 39: 699-703. PMID- 25688394 TI - Proceedings of the 12th International Plant Virus Epidemiology Symposium, 28 January-1 February 2013, Arusha, Tanzania. PMID- 25688395 TI - Shouldn't we care about the biology of benign tumours? AB - While focusing on malignant tumours seems medically reasonable, from a biological perspective, benign and malignant tumours provide complementary and perhaps equally relevant perspectives on the mechanisms of tumour invasion and metastasis. However, the biology of benign neoplasms is rarely studied. PMID- 25688396 TI - Proceedings of the No oxygen-still vigorous: 8th International Symposium on Anaerobic Microbiology (ISAM 8), June 12-15, 2013, Innsbruck, Austria. PMID- 25688397 TI - Proceedings of the 9th International Conference on HFRS, HPS and hantaviruses,June 5-7, 2013, Beijing, China. PMID- 25688398 TI - Reply. PMID- 25688400 TI - Special issue as tribute to John D Biggers. PMID- 25688399 TI - Reply: To PMID 24401738. PMID- 25688401 TI - Proceedings of the XIIIth International Congress of Pediatric Laboratory Medicine, June 20-22, 2014, Istanbul, Turkey. PMID- 25688402 TI - Mining the genomes of exceptional responders. AB - The National Cancer Institute of the United States recently announced a major new initiative in understanding the genomes or, more broadly, the molecular phenotypes of exceptional responders. What can we expect to learn from exceptional responders? What are the potential benefits, and how do we approach studying them? PMID- 25688403 TI - Does everyone develop covert cancer? AB - Around one in three individuals, if they live long enough, will have a confirmed clinical diagnosis of overt cancer, and there is increasing evidence that many of us - I contend all of us - develop covert cancer. PMID- 25688404 TI - NUT midline carcinoma. AB - NUT midline carcinoma, a squamous cell carcinoma, is one of the most aggressive human cancers, and there is a desperate need for effective therapies for patients with this disease. Will the new bromodomain and extra terminal (BET) inhibitors prove to be one such treatment for this rare and enigmatic cancer? PMID- 25688405 TI - Revisiting tissue specificity of germline cancer predisposing mutations. AB - Heritable germline mutations in major cancer genes generally lead to a restricted pattern of tissue-specific malignancies, yet many of the same mutations frequently occur somatically in a broad range of spontaneous neoplasms affecting different organs. Might this reflect a difference in tumorigenesis in children and adults? PMID- 25688406 TI - Metaplastic breast carcinoma: more than a special type. AB - Metaplastic breast carcinoma (MBC) is a special histological type of invasive breast cancer. MBC is a descriptive and operational term for a heterogeneous collection of tumours with distinct histologies, clinical behaviours and potentially responses to therapy. PMID- 25688407 TI - The "evidence" is in! It does get better! PMID- 25688408 TI - Satoru Sumitsuji MD FACC. PMID- 25688409 TI - A batteryless cardiac pacemaker based on the automatic wristwatch. PMID- 25688410 TI - Research excellence on diabetes and cardiovascular disease rewarded. PMID- 25688411 TI - The heritable effects of nanotoxicity. AB - The widespread entry of nanomaterials into manifold life fields posed serious concerns on environmental health and safety issues. Potential adverse effects of nanoparticles (NPs) are continuously faced using in vitro cell systems and by mean of cell and molecular biology tools, several mechanisms have been found beyond their toxicity. The evaluation of the in vivo possible consequences derived from exposure of living organisms to NPs is instead more complex but compulsory in view of their application for diagnosis or therapeutic purposes. Here the effects of NP-induced genetic alteration on the progeny of treated animals will be treated, considering selected species from invertebrate and vertebrates as examples of transgenerational transmission of NP toxicity. The effects on reproductive capability, fertility and embryogenesis observed in different animal species upon treatment with different materials will provide an overview of the current knowledge on the heritable feature of nanotoxicity. PMID- 25688412 TI - 'Knowing is not enough; we must apply. Willing is not enough; we must do.'. PMID- 25688413 TI - States leverage telepsychiatry solutions to ease ED crowding, accelerate care. AB - Many states are having success turning to telepsychiatry-based solutions to connect mental health patients with needed care while also decompressing crowded EDs. Just one year into a statewide telepsychiatry initiative in North Carolina (NC-STeP), administrators say the approach has saved as much as $7 million, and hospital demand for the service is higher than anticipated. In Texas, mental health emergency centers (MHEC) that use telepsychiatry to connect patients in rural areas with needed psychiatric care are freeing up EDs to focus on medical care. In just 11 months, 91 North Carolina hospitals have at least started the process to engage in NC-STeP. Much of the savings from NC-STeP come from involuntary commitment orders being overturned as a result of the telepsychiatry consults, reducing the need for expensive inpatient care. Implementing NC-STeP has involved multiple hurdles including credentialing difficulties and technical/firewall challenges. The Texas model provides 24/7 availability of psychiatrists via telemedicine through a network of MHECs. In-person staff at the MHECs perform basic screening tests and blood draws so that medical clearance can be achieved without the need for an ED visit in most cases. Funding for the MHECs comes from the state, hospitals in the region, and local governmental authorities that reap savings or benefits from the initiative. PMID- 25688414 TI - Carolinas HealthCare system gets jump on potential for telepsychiatry. PMID- 25688415 TI - Use screening tools, partnerships to improve identification, care of victims of IPV. AB - While accrediting organizations require hospitals to put protocols in place to deal with intimate partner violence (IPV), research shows that the problem is often left uncovered in women who present for care in busy EDs. One study suggests that as much as 72% of women with a history of IPV are not identified when they visit the ED for medical issues. Experts are hopeful that recent publicity about IPV will heighten awareness and improve screening for the problem. Experts say providers are often reluctant to ask questions about IPV, either because they are unsure of how to respond or they lack ready access to resources for referral. When screening for IPV, it is important to ask behavior specific questions so that there is no room for misinterpretation. To bolster the emergency response to incidents of IPV, hospitals need to seek out and nurture relationships with community organizations that can serve as referral sources to victims. Experts say providers need to consider the possibility of traumatic brain injury in women who present with head and/or facial injuries. PMID- 25688416 TI - Study: Education, training on proper splint technique needed in EDs, urgent care centers. AB - A new study suggests that most of the splints applied in EDs and urgent care settings on pediatric patients with potential fractures are being placed improperly, leading to the potential for complications such as excessive swelling, blistering and other skin problems, and improper mobilization of the fracture. Researchers at the University of Maryland say this points to a need for better education and training of frontline practitioners on splinting techniques. Investigators plan to create and disseminate educational materials on correct splinting techniques for display in EDs and urgent care facilities. A second study is planned to evaluate the impact of these interventions. In a sample of 275 patients who were initially seen in community hospital EDs and urgent care facilities in Maryland and then later evaluated by pediatric orthopedic specialists, researchers found that the splints on more than 90% of the potential fracture cases were placed incorrectly. The most common problem that researchers identified with splints was the elastic bandage was placed directly on the skin; this occurred in 77% of cases. In 59% of the cases, the joint was not immobilized correctly, and in 52% of cases the splint was not the right size. PMID- 25688417 TI - Glimpses of God's grace. PMID- 25688419 TI - Proceedings of the Annual Meeting of the American Electrophoresis Society (AES), November 3rd - 8th, 2013, San Francisco, CA. PMID- 25688418 TI - Proceedings of the XVII International Plant Nutrition Colloquium (IPNC), August 19-22, 2013, Istanbul, Turkey. PMID- 25688420 TI - Abstracts of he International Research Congress on Integrative Medicine and Health (IRCIMH), May 13-16, 2014, Miami, Florida. PMID- 25688421 TI - Experimental demonstration of the benefits of somatic fusion and the consequences for allorecognition. AB - Allorecognition, the ability to distinguish "self" from "nonself" based on allelic differences at allorecognition loci, is common in all domains of life. Allorecognition restricts the opportunities for social parasitism, and is therefore crucial for the evolution of cooperation. However, the maintenance of allorecognition diversity provides a paradox. If allorecognition is costly relative to cooperation, common alleles will be favored. Thus, the cost of allorecognition may reduce the genetic variation upon which allorecognition crucially relies, a prediction now known as "Crozier's paradox." We establish the relative costs of allorecognition, and their consequences for the short-term evolution of recognition labels theoretically predicted by Crozier. We use fusion among colonies of the fungus Neurospora crassa, regulated by highly variable allorecognition genes, as an experimental model system. We demonstrate that fusion among colonies is mutually beneficial, relative to absence of fusion upon allorecognition. This benefit is due not only to absence of mutual antagonism, which occurs upon allorecognition, but also to an increase in colony size per se. We then experimentally demonstrate that the benefit of fusion selects against allorecognition diversity, as predicted by Crozier. We discuss what maintains allorecognition diversity. PMID- 25688422 TI - Sustained NIK-mediated antiviral signalling confers broad-spectrum tolerance to begomoviruses in cultivated plants. AB - Begomovirus-associated epidemics currently threaten tomato production worldwide due to the emergence of highly pathogenic virus species and the proliferation of a whitefly B biotype vector that is adapted to tomato. To generate an efficient defence against begomovirus, we modulated the activity of the immune defence receptor nuclear shuttle protein (NSP)-interacting kinase (NIK) in tomato plants; NIK is a virulence target of the begomovirus NSP during infection. Mutation of T474 within the kinase activation loop promoted the constitutive activation of NIK-mediated defences, resulting in the down-regulation of translation-related genes and the suppression of global translation. Consistent with these findings, transgenic lines harbouring an activating mutation (T474D) were tolerant to the tomato-infecting begomoviruses ToYSV and ToSRV. This phenotype was associated with reduced loading of coat protein viral mRNA in actively translating polysomes, lower infection efficiency and reduced accumulation of viral DNA in systemic leaves. Our results also add some relevant insights into the mechanism underlying the NIK-mediated defence. We observed that the mock-inoculated T474D overexpressing lines showed a constitutively infected wild-type transcriptome, indicating that the activation of the NIK-mediated signalling pathway triggers a typical response to begomovirus infection. In addition, the gain-of-function mutant T474D could sustain an activated NIK-mediated antiviral response in the absence of the virus, further confirming that phosphorylation of Thr-474 is the crucial event that leads to the activation of the kinase. PMID- 25688423 TI - New approaches to uncertainty analysis for use in aggregate and cumulative risk assessment of pesticides. AB - Risk assessments for human exposures to plant protection products (PPPs) have traditionally focussed on single routes of exposure and single compounds. Extensions to estimate aggregate (multi-source) and cumulative (multi-compound) exposure from PPPs present many new challenges and additional uncertainties that should be addressed as part of risk analysis and decision-making. A general approach is outlined for identifying and classifying the relevant uncertainties and variabilities. The implementation of uncertainty analysis within the MCRA software, developed as part of the EU-funded ACROPOLIS project to address some of these uncertainties, is demonstrated. An example is presented for dietary and non dietary exposures to the triazole class of compounds. This demonstrates the chaining of models, linking variability and uncertainty generated from an external model for bystander exposure with variability and uncertainty in MCRA dietary exposure assessments. A new method is also presented for combining pesticide usage survey information with limited residue monitoring data, to address non-detect uncertainty. The results show that incorporating usage information reduces uncertainty in parameters of the residue distribution but that in this case quantifying uncertainty is not a priority, at least for UK grown crops. A general discussion of alternative approaches to treat uncertainty, either quantitatively or qualitatively, is included. PMID- 25688424 TI - Apathy in schizophrenia as a deficit in the generation of options for action. AB - Negative symptoms are a core feature of schizophrenia and have been grouped into 2 factors: a motivational factor, which we refer to as apathy, and a diminished expression factor. Recent studies have shown that apathy is closely linked to functional outcome. However, knowledge about its mechanisms and its relation to decision-making is limited. In the current study, we examined whether apathy in schizophrenia is associated with predecisional deficits, that is, deficits in the generation of options for action. We applied verbal protocol analysis to investigate the quantity of options generated in ill-structured real world scenarios in 30 patients with schizophrenia or schizoaffective disorder and 21 healthy control participants. Patients generated significantly fewer options than control participants and clinical apathy ratings correlated negatively with the quantity of generated options. We show that the association between measures of psychopathology and option generation is most pronounced in regard to apathy symptoms and that it is only partially mediated by deficits in verbal fluency. This study provides empirical support for dysfunctional option generation as a possible mechanism for apathy in schizophrenia. Our data emphasize the potential importance of predecisional stages in the development and persistence of apathy symptoms in neuropsychiatric disorders and might also inform the development of novel treatment options in the realm of cognitive remediation. PMID- 25688425 TI - "Psychophysiologic reactivity, subjective distress, and their associations with PTSD diagnosis": Correction to Pineles et al. (2013). AB - Reports an error in "Psychophysiologic reactivity, subjective distress, and their associations with PTSD diagnosis" by Suzanne L. Pineles, Michael K. Suvak, Gabrielle I. Liverant, Kristin Gregor, Blair E. Wisco, Roger K. Pitman and Scott P. Orr (Journal of Abnormal Psychology, 2013[Aug], Vol 122[3], 635-644). In Table 1 the sample of participants included in Orr et al.'s (1998) paper was incorrectly described as 100% male, rather than 100% female. PMID- 25688426 TI - Affect regulation and purging: An ecological momentary assessment study in purging disorder. AB - Research suggests that affect may play an important role in the propensity to purge among women with purging disorder (PD). However, prior work has been constrained to cross-sectional or laboratory designs, which impact temporal interpretations and ecological validity. This study examined negative affect (NA) and positive affect (PA) in triggering and maintaining purging in PD using ecological momentary assessment. Women with PD (N = 24) made multiple daily ratings of affect and behavior for 2 weeks. Multilevel models examined associations between affect and purging at different levels of analysis, including a novel analytic approach to address the specificity of changes in affect relative to purging behavior by comparing trajectories of change on purge versus nonpurge days. For trajectories of affect over time, NA increased before purging and decreased following purging on purge days; however, only the decrease in NA following purging was significantly different from the trajectory of NA on nonpurge days. Conversely, PA failed to increase before purging on purge days compared with a matched time-point on nonpurge days. These findings suggest unique roles of PA in triggering and NA in maintaining purging in PD and support models in which purging functions to regulate affect. For comparisons of ratings before and after purging, NA increased and PA decreased after purging, highlighting how different analytic strategies produce different findings requiring integration into affect regulation models. These data provide insight into why women with PD purge after consuming normal amounts of food, a crucial first step for developing effective interventions. PMID- 25688427 TI - Stress sensitivity and stress sensitization in psychopathology: an introduction to the special section. AB - The goal of this special section is to examine the mechanisms of enhanced sensitivity and sensitization to stress as they influence the etiology and pathophysiology of psychopathology. The 12 articles in the section focus on some of the most crucial and unanswered questions regarding the underlying mechanisms and functional consequences of stress sensitivity and stress sensitization in psychopathology. They address the constructs of stress sensitivity and stress sensitization using state-of-the-art, and often novel, methodologies. The special section also focuses on an important terminological distinction between two related but distinct stress mechanisms that are often conflated. Individuals who are sensitive to stress possess this characteristic as a putative trait that develops through genetically mediated transactional relations between temperamental characteristics and the early contextual environment. In contrast, individuals who are sensitized to stress become so over time through repeated exposure to external, as well as endogenous, stressors. Enhanced stress sensitivity and sensitization have been included in conceptual models of psychopathology. Yet, the specific mechanisms by which these stress processes impact the onset and course of psychiatric disorders are not fully understood. These articles focus on several mechanistic accounts of stress sensitivity and sensitization. PMID- 25688428 TI - Kindling of life stress in bipolar disorder: comparison of sensitization and autonomy models. AB - Research on life stress in bipolar disorder largely fails to account for the possibility of a dynamic relationship between psychosocial stress and episode initiation. The kindling hypothesis (Post, 1992) states that over the course of recurrent affective disorders, there is a weakening temporal relationship between major life stress and episode initiation that could reflect either a progressive sensitization or progressive autonomy to life stress. The present study involved a comprehensive and precise examination of the kindling hypothesis in 102 participants with bipolar II disorder that allowed for a direct comparison of sensitization and autonomy models. Polarity-specific tests were conducted across the continuum of event severity with respect to impact and frequency of life events. Hypotheses were polarity- and event-valence specific and were based on the stress sensitization model. Results were only partially consistent with the sensitization model: Individuals with more prior mood episodes had an increased frequency of minor negative events before depression and of minor positive events before hypomania. However, the number of past episodes did not moderate relationships between life events and time until prospective onset of mood episodes. These results are more consistent with a sensitization than an autonomy model, but several predictions of the sensitization model were not supported. Methodological strengths, limitations, and implications are discussed regarding putative changes in stress reactivity that may occur with repeated exposure to mood episodes in bipolar II disorder. PMID- 25688429 TI - Rumination predicts heightened responding to stressful life events in major depressive disorder and generalized anxiety disorder. AB - Although studies have documented heightened stress sensitivity in major depressive disorder (MDD) and generalized anxiety disorder (GAD), the mechanisms involved are poorly understood. One possible mechanism is the tendency to ruminate in response to stress. We used ecological momentary assessment to study ruminative thoughts after stressful events in 145 adults with MDD, GAD, comorbid MDD-GAD, or no psychopathology. Diagnosed individuals reported more event-related rumination than controls, even after adjusting for event stressfulness. Rumination was equally common in MDD and GAD and was especially severe among comorbid cases. More rumination immediately after the event predicted poorer affect, more maladaptive behavior, and more MDD and GAD symptoms at the next signal, even when pre-event levels of these variables were controlled. Rumination mediated, but did not moderate, the association of stress with affect and with symptoms. Stress-related rumination was more deleterious for diagnosed than healthy individuals, more intense for more severe clinical cases, and more persistent for cases with a greater temperamental vulnerability for emotional disorders. These results implicate rumination as a mechanism of stress sensitivity and suggest pathways through which it may maintain depression and anxiety in everyday life. PMID- 25688430 TI - Psychotic reactivity to daily life stress and the dopamine system: a study combining experience sampling and [18F]fallypride positron emission tomography. AB - Stressful life events increase the risk for psychosis, and the subjective experience of stress related to daily life activities drives moment-to-moment variation in psychotic intensity. Positron emission tomography (PET) studies suggest that dopaminergic (DAergic) activity mediates the behavioral response to an experimental stressor. However, it is not known how alterations in this DAergic stress response relate to the subjective experience of stress in real life situations assessed in momentary assessment studies. This study combined [18F]fallypride PET with an Experience Sampling ambulatory assessment approach to examine the association between the prefrontal DAergic response to experimentally induced stress and real life psychotic reactivity to the subjective experience of stress in daily life. Healthy first-degree relatives of individuals with a psychotic disorder (N = 14) and healthy controls (N = 11) participated in (a) a psychosocial [18F]fallypride PET stress paradigm and (b) an experience sampling study, using a structured diary approach. Mixed multilevel random intercept models revealed that stress-induced [18F]fallypride displacement, indicative of DAergic activity, in ventromedial prefrontal cortex (VMPFC) was associated with psychotic reactivity to daily life stress in the entire sample. Lower levels of [18F]fallypride displacement to stress predicted increased psychotic reactivity to daily life stress. This study combined PET neuroimaging with real life behavioral assessments in the investigation of psychotic symptoms; we showed decreased [18F]fallypride displacement to stress in VMPFC to be associated with increased psychotic reactivity to daily life stress. The preliminary evidence in this study demonstrates that it is possible to acquire a grasp on how brain function is associated with contextualized experience, which has relevance for neuroimaging studies in general. PMID- 25688431 TI - A two-factor model of relapse/recurrence vulnerability in unipolar depression. AB - The substantial health burden associated with major depressive disorder (MDD) is a product of both its high prevalence and the significant risk of relapse, recurrence, and chronicity. Establishing recurrence vulnerability factors (VFs) could improve the long-term management of MDD by identifying the need for further intervention in seemingly recovered patients. We present a model of sensitization in depression vulnerability, with an emphasis on the integration of behavioral and neural systems accounts. Evidence suggests that VFs fall into 2 categories: dysphoric attention and dysphoric elaboration. Dysphoric attention is driven by fixation on negative life events, and is characterized behaviorally by reduced executive control, and neurally by elevated activity in the brain's salience network. Dysphoric elaboration is driven by rumination that promotes overgeneral self- and contextual appraisals, and is characterized behaviorally by dysfunctional attitudes, and neurally by elevated connectivity within normally distinct prefrontal brain networks. Although few prospective VF studies exist from which to catalogue a definitive neurobehavioral account, extant data support the value of the proposed 2-factor model. Measuring the continued presence of these 2 VFs during recovery may more accurately identify remitted patients who would benefit from targeted prophylactic intervention. PMID- 25688432 TI - Cortisol reactivity to stress among youth: stability over time and genetic variants for stress sensitivity. AB - Stress sensitivity may be one process that can explain why some genetically at risk individuals are more susceptible to some types of stress-reactive psychopathologies. Dysregulation of the limbic-hypothalamic-pituitary-adrenal (LHPA) axis, including cortisol reactivity to challenge, represents a key aspect of stress sensitivity. However, the degree of stability over time among youth, especially differential stability as a function of particular genetic variants, has not been investigated. A general community sample of children and adolescents (mean age = 11.4; 56% girls) provided a DNA sample and completed 2 separate laboratory stress challenges, across an 18-month follow-up (N = 224 at Time 1; N = 194 at Time 2), with repeated measures of salivary cortisol. Results showed that test-retest stability for several indices of cortisol reactivity across the laboratory challenge visits were significant and of moderate magnitude for the whole sample. Moreover, gene variants of several biologically plausible systems relevant for stress sensitivity (especially 5-HTTLPR and CRHR1) demonstrated differential stability of cortisol reactivity over 18-months, such that carriers of genotypes conferring enhanced environmental susceptibility exhibited greater stability of cortisol levels over time for some LHPA axis indices. Findings suggest that LHPA axis dysregulation may exhibit some trait-like aspects underlying stress sensitivity in youth, especially for those who carry genes related to greater genetic susceptibility to environmental stress. PMID- 25688433 TI - Child anxiety symptoms related to longitudinal cortisol trajectories and acute stress responses: evidence of developmental stress sensitization. AB - Cross-sectional research suggests that individuals at risk for internalizing disorders show differential activation levels and/or dynamics of stress-sensitive physiological systems, possibly reflecting a process of stress sensitization. However, there is little longitudinal research to clarify how the development of these systems over time relates to activation during acute stress, and how aspects of such activation map onto internalizing symptoms. We investigated children's (n = 107) diurnal hypothalamic-pituitary-adrenal activity via salivary cortisol (morning and evening levels) across 29 assessments spanning 6+ years, and related longitudinal patterns to acute stress responses at the end of this period (age 9-10). Associations with child psychiatric symptoms at age 10 were also examined to determine internalizing risk profiles. Increasing morning cortisol levels across assessments predicted less of a cortisol decline following interpersonal stress at age 9, and higher cortisol levels during performance stress at age 10. These same profiles of high and/or sustained cortisol elevation during psychosocial stress were associated with child anxiety symptoms. Results suggest developmental sensitization to stress-reflected in rising morning cortisol and eventual hyperactivation during acute stress exposure-may distinguish children at risk for internalizing disorders. PMID- 25688434 TI - Correction to Keane et al. (2013). AB - In the article, "Reduced Depth Inversion Illusions in Schizophrenia Are State Specific and Occur for Multiple Object Types and Viewing Conditions" by Brian P. Keane, Steven M. Silverstein, Yushi Wang, and Thomas V. Papathomas (Journal of Abnormal Psychology, 2014, Vol. 122, No. 2, pp. 506-512. doi: 10.1037/a0032110), the supplemental videos were not included in the original supplemental materials. All versions of the article have been corrected. PMID- 25688435 TI - A developmentally informed perspective on the relation between stress and psychopathology: when the problem with stress is that there is not enough. AB - A common tenet of several prominent theories of stress and psychopathology (e.g., stress exposure) is that experiencing high rates of life stressors is associated with greater risk for negative mental health outcomes. Although there has been substantial empirical support for this position, another possibility that has received considerably less attention to date is that early life stressors may share a curvilinear rather than monotonic relation with psychological well-being. In what has been termed the "steeling effect," "stress inoculation," and "antifragility," exposure to moderate stressors early in life may confer resilience to potential detrimental effects of later stressors. An interesting implication of this model is that low levels of early life stressors, relative to normatively moderate rates, may be associated with greater sensitivity to future stressors. The present article reviews preliminary evidence consistent with this possibility, drawing on behavioral and neurobiological studies in animal models, and the more modest literature on neurocognitive, psychological, and psychophysiological functioning in humans. Limitations of the clinical literature and possible directions for future research are discussed, including naturalistic longitudinal studies with clinical outcomes, and for research examining moderators and mechanisms, across multiple levels of analysis (e.g., cognitive, immunological, and neurobiological). PMID- 25688436 TI - Threat sensitivity in bipolar disorder. AB - Life stress is a major predictor of the course of bipolar disorder. Few studies have used laboratory paradigms to examine stress reactivity in bipolar disorder, and none have assessed autonomic reactivity to laboratory stressors. In the present investigation we sought to address this gap in the literature. Participants, 27 diagnosed with bipolar I disorder and 24 controls with no history of mood disorder, were asked to complete a complex working memory task presented as "a test of general intelligence." Self-reported emotions were assessed at baseline and after participants were given task instructions; autonomic physiology was assessed at baseline and continuously during the stressor task. Compared to controls, individuals with bipolar disorder reported greater increases in pretask anxiety from baseline and showed greater cardiovascular threat reactivity during the task. Group differences in cardiovascular threat reactivity were significantly correlated with comorbid anxiety in the bipolar group. Our results suggest that a multimethod approach to assessing stress reactivity-including the use of physiological parameters that differentiate between maladaptive and adaptive profiles of stress responding-can yield valuable information regarding stress sensitivity and its associations with negative affectivity in bipolar disorder. (PsycINFO Database Record (c) 2015 APA, all rights reserved). PMID- 25688437 TI - Stress sensitivity and stress generation in social anxiety disorder: a temporal process approach. AB - Dominant theoretical models of social anxiety disorder (SAD) suggest that people who suffer from function-impairing social fears are likely to react more strongly to social stressors. Researchers have examined the reactivity of people with SAD to stressful laboratory tasks, but there is little knowledge about how stress affects their daily lives. We asked 79 adults from the community, 40 diagnosed with SAD and 39 matched healthy controls, to self-monitor their social interactions, social events, and emotional experiences over 2 weeks using electronic diaries. These data allowed us to examine associations of social events and emotional well-being both within-day and from one day to the next. Using hierarchical linear modeling, we found all participants to report increases in negative affect and decreases in positive affect and self-esteem on days when they experienced more stressful social events. However, people with SAD displayed greater stress sensitivity, particularly in negative emotion reactions to stressful social events, compared to healthy controls. Groups also differed in how previous days' events influenced sensitivity to current days' events. Moreover, we found evidence of stress generation in that the SAD group reported more frequent interpersonal stress, though temporal analyses did not suggest greater likelihood of social stress on days following intense negative emotions. Our findings support the role of heightened social stress sensitivity in SAD, highlighting rigidity in reactions and occurrence of stressful experiences from one day to the next. These findings also shed light on theoretical models of emotions and self-esteem in SAD and present important clinical implications. PMID- 25688438 TI - Heightened reward learning under stress in generalized anxiety disorder: a predictor of depression resistance? AB - Stress-induced anhedonia is associated with depression vulnerability (Bogdan & Pizzagalli, 2006). We investigated stress-induced deficits in reward learning in a depression-vulnerable group with analogue generalized anxiety disorder (GAD, n = 34), and never-depressed healthy controls (n = 41). Utilizing a computerized signal detection task, reward learning was assessed under stressor and neutral conditions. Controls displayed intact reward learning in the neutral condition, and the expected stress-induced blunting. The GAD group as a whole also showed intact reward learning in the neutral condition. When GAD subjects were analyzed as a function of prior depression history, never-depressed GAD subjects showed heightened reward learning in the stressor condition. Better reward learning under stress among GAD subjects predicted lower depression symptoms 1 month later. Robust reward learning under stress may indicate depression resistance among anxious individuals. PMID- 25688439 TI - Anticipation of smoking sufficiently dampens stress reactivity in nicotine deprived smokers. AB - Most smokers attempting to quit will relapse, even when using evidence-based cessation treatment. This illustrates the need for better understanding of the relapse process to thereby improve cessation treatments. Although the impact of stress sensitivity on relapse is clear, little research has precisely examined stress reactivity in addicted individuals. Further, most research on relapse focuses on affect surrounding self-administration, and does not address potentially important preconsumption processes such as anticipation of use. We examined the effects of anticipation and actual smoking on stress reactivity in 34 deprived smokers withdrawn for 24 hr and 37 nondeprived smokers, with 37 nonsmoker controls. Using a cued shock stressor task, we measured stress reactivity via startle potentiation and self-reported anxiety. After completing the task once, smokers anticipated smoking a cigarette resting in front of them while they completed the task a second time. Smokers then smoked before completing the task a third and final time. Nonsmokers anticipated and drank water as a control. Anticipation of smoking significantly attenuated both startle potentiation and self-reported anxiety to shock cues for deprived smokers relative to nondeprived smokers. Smokers' stress reactivity was not reduced by smoking beyond the prior effect of anticipation. These results suggest that anticipation, rather than actual drug consumption, may drive the primary reinforcing effect of reduced stress reactivity in smoking. Future research is needed to understand this effect of anticipation on drug use and to determine whether anticipation would make an effective intervention target for addiction and other psychopathology that exhibits increased stress sensitivity. PMID- 25688440 TI - Harsh parenting, parasympathetic activity, and development of delinquency and substance use. AB - Stress response systems are thought to play an important role in the development of psychopathology. In addition, family stress may have a significant influence on the development of stress response systems. One potential avenue of change is through alterations to thresholds for the activation of stress responses: Decreased threshold for responding may mark increased stress sensitivity. Our first aim was to evaluate the interaction between thresholds for parasympathetic nervous system (PNS) responding, operationalized as resting respiratory sinus arrhythmia (RSA), and harsh parenting in the prediction of development of delinquency and adolescent substance use (resting RSA as a biomarker of risk). The second aim was to evaluate if resting RSA changes over time as a function of harsh parenting and stress reactivity indexed by RSA withdrawal (altered threshold for stress responding). Our third aim was to evaluate the moderating role of sex in these relations. We used longitudinal data from 251 children ages 8-16 years. Mother-reports of child delinquency and RSA were acquired at all ages. Adolescents self-reported substance use at age 16 years. Family stress was assessed with child-reported harsh parenting. Controlling for marital conflict and change over time in harsh parenting, lower resting RSA predicted increases in delinquency and increased likelihood of drug use in contexts of harsh parenting, especially for boys. Harsh parenting was associated with declining resting RSA for children who exhibited greater RSA withdrawal to stress. Findings support resting PNS activity as a moderator of developmental risk that can be altered over time. PMID- 25688441 TI - Stress sensitivity in psychopathology: mechanisms and consequences. AB - The special section on "Stress Sensitivity in Psychopathology: Mechanisms and Consequences" presents an array of articles and results across samples of children, adolescents, and adults that are at once exciting for the field and challenging. The articles highlight an empirically and conceptually important topic in psychopathology- the role of stress. For many years, this topic was mainly a focus of depression research but has now widened to include relevance to a variety of forms of psychological disorders, as shown in this special section. In addition to the applications to many different disorders, our field of psychopathology is enriched by highlighting the remarkable range of naturalistic and experimental paradigms for studying stress processes in humans, and to learn about diverse conceptual models. The authors of the articles in this special section have given us much food for thought in their innovative studies, and their work provides fruitful guides for next steps. It is to be hoped that such work points to future integrative and collaborative studies, across levels of analyses, methods, and samples that will further elaborate on the associations between stress and psychopathology, as well as the mechanisms that have relevance to the advancement of knowledge of disorders and their treatment. PMID- 25688443 TI - The role of macroaggregated albumin lung perfusion scan in hepatopulmonary syndrome: are we ready to draw conclusions? PMID- 25688446 TI - Tuberculosis reactivation in hepatocellular carcinoma: association with transarterial chemoembolization. AB - Transarterial chemoembolization (TACE) is an important therapeutic option for patients with hepatocellular carcinoma (HCC). We discuss five patients with HCC and tuberculosis (TB) reactivation following TACE. Screening patients for latent TB infection at diagnosis of cirrhosis or HCC should be considered because of the immunosuppression inherent in both the diseases and their treatments. PMID- 25688444 TI - Preparation, characterization, and biochemical activities of N-(2 Carboxyethyl)chitosan from squid pens. AB - Chitosan was prepared by alkaline N-deacetylation of beta-chitin from squid pens, and N-carboxyethylated derivatives (N-CECS) with different degrees of substitution (DS) were synthesized. The carboxyethylation of the polysaccharide was identified by Fourier transform infrared, (1)H and (13)C nuclear magnetic resonance (NMR), and X-ray diffraction analyses. The DS of the derivatives was calculated by (1)H NMR and elemental analysis. All three N-CECS samples showed good water solubility at pH > 6.5. The antioxidant properties and bile acid binding capacity of the derivatives were studied in vitro. The highest bile acid binding capacity of all N-CECS reached 36.9 mg/g, which was 2.6-fold higher than that of chitosan. N-CECS showed a stronger scavenging effect on 2,2'-azinobis(3 ethylbenzothiazoline-6-sulfonic acid) radical ability, and EC50 values were below 2 mg/mL. The scavenging ability of N-CECS against superoxide radicals correlated well with the DS and concentration of N-CECS. These results indicated that N carboxyethylation is a possible approach to prepare chitosan derivatives with desirable in vitro biochemical properties. PMID- 25688447 TI - Potential role of serum BAFF as a biomarker in HIV infection. AB - We evaluated the potential role of serum B-cell activating factor (BAFF) as a biomarker in HIV infection and analyzed the relationship between BAFF concentration and the immunophenotypic activation status of T-cells. We tested the hypothesis that higher serum BAFF concentrations are associated with risk for development of AIDS in HIV positive individuals. Forty-one HIV patients (CDC category A 17, category B 24) were evaluated retrospectively. Serum BAFF concentrations were assessed using a commercial enzyme-linked immunosorbent assay. Cox regression was used to estimate the probability for development of AIDS. Patients with higher BAFF concentrations (> 2100 pg/mL) were at greater risk of developing AIDS (relative hazard 5.69; p = 0.0033). BAFF levels were independently associated with risk of AIDS after adjustment by clinical risk factors. Serum BAFF was correlated with activated T-cell subsets and with neopterin levels. BAFF is a good candidate for further evaluation as a nonspecific surrogate marker in HIV infection. PMID- 25688448 TI - Isolation of non-tuberculous mycobacteria among tuberculosis patients during a 5 year period in Croatia. PMID- 25688449 TI - Influence of oxygenation on chromium redox reactions with manganese sulfide (MnS(s)). AB - Manganese sulfide (MnS(s)) minerals exist in sulfidic environments and can have unique reactive abilities because of sulfide, which is a known reductant, and Mn, the oxyhydroxides of which are known oxidants. This study elucidated the role of MnS(s) in controlling Cr speciation with implications on its fate and toxicity in the natural environment, specifically sulfidic sediments that undergo biogeochemical changes due to sediment resuspension during dredging, bioturbation, and flood events. In continuously mixed batch reaction experiments, aqueous CrVI reduction under anaerobic conditions occurred primarily on the surface of MnS(s) displaying a biphasic behavior- the initial rapid removal of CrVI from solution was followed by a slow decline due to surface passivation by reaction products, mainly sorbed or precipitated CrIII. The reaction progress increased with MnS(s) surface area loading but decreased on increasing CrVI concentration and pH, suggesting that surface site regeneration through product desorption was the rate-controlling mechanism. Below circum-neutral pH, higher solubility of MnS(s) resulted in additional CrVI reduction by reduced sulfur species in solution, whereas increased CrIII solubility lowered surface passivation allowing for more reactive sites to participate in the reaction. Aeration of MnS(s) at pH>=7 caused the formation of a heterogeneous MnIII(hydr)oxide that was composed of hausmanite and manganite. CrVI reoccurrence was observed on aeration of CrVI-spiked MnS(s) from the oxidation of product CrIII. The reoccurrence at pH>=7 was attributed to the oxidation of product CrIII by MnIII(hydr)oxide, whereas the reoccurrence at pH<7 was hypothesized from the oxidation of product CrIII by intermediate aqueous MnIII and/or sulfur species. Just as with Cr, MnS(s) may play an important role in speciation, fate, and transport of other environmental contaminants. PMID- 25688450 TI - Stigma, sex work, and substance use: a comparative analysis. AB - Stigma is a widely used concept in social science research and an extensive literature claims that stigmatisation contributes to numerous negative health outcomes. However, few studies compare groups that vary in the extent to which they are stigmatised and even fewer studies examine stigma's independent and mediating effects. This article addresses these gaps in a comparative study of perceived stigma and drug use among three low-income feminised service occupations: sex work, food and alcoholic beverage serving, and barbering and hairstyling. An analysis of longitudinal data shows positive associations between sex work, perceived stigma, and socially less acceptable drug use (for example, heroin and cocaine), and that stigma mediates part of the link between sex work and the use of these drugs. Our overall findings suggest that perceived stigma is pronounced among those who work in the sex industry and negatively affects health independently of sex work involvement. PMID- 25688451 TI - Simple and cost-effective fabrication of highly flexible, transparent superhydrophobic films with hierarchical surface design. AB - Optical transparency and mechanical flexibility are both of great importance for significantly expanding the applicability of superhydrophobic surfaces. Such features make it possible for functional surfaces to be applied to various glass based products with different curvatures. In this work, we report on the simple and potentially cost-effective fabrication of highly flexible and transparent superhydrophobic films based on hierarchical surface design. The hierarchical surface morphology was easily fabricated by the simple transfer of a porous alumina membrane to the top surface of UV-imprinted polymeric micropillar arrays and subsequent chemical treatments. Through optimization of the hierarchical surface design, the resultant superhydrophobic films showed superior surface wetting properties (with a static contact angle of >170 degrees and contact angle hysteresis of <3.5 degrees ) in the Cassie-Baxter wetting regime, considerable dynamic water repellency (with perfect bouncing of a water droplet dropped from an impact height of 30 mm), and good optical transparency (>82% at 550 nm wavelength). The superhydrophobic films were also experimentally found to be robust without significant degradation in the superhydrophobicity, even under repetitive bending and pressing for up to 2000 cycles. Finally, the practical usability of the proposed superhydorphobic films was clearly demonstrated by examining the antiwetting performance in real time while pouring water on the film and submerging the film in water. PMID- 25688452 TI - Successful treatment of generalized granuloma annulare with adalimumab. AB - We report the case of a 64 year-old woman who demonstrated resolution of recalcitrant, generalized granuloma annulare (GA) following treatment with adalimumab. After showing little response to other treatment techniques, such as steroids and a triple antibiotic regimen, the patient was started on adalimumab. Within 3 months, she showed almost complete resolution of lesions. Within 6 months, she was completely lesion-free, and remained clear following 12 months of adalimumab therapy. This case provides further evidence that tumour necrosis factor-alpha inhibitors may be a treatment option for patients with recalcitrant, generalized GA. PMID- 25688442 TI - Quantitative proteomic analysis of histone modifications. PMID- 25688453 TI - Probe-inspired nano-prodrug with dual-color fluorogenic property reveals spatiotemporal drug release in living cells. AB - The versatility of the fluorescent probes inspires us to design fluorescently traceable prodrugs, which enables tracking the drug delivery kinetics in living cells. Herein, we constructed a self-indicating nanoprodrug with two fluorescent moieties, an aggregation-induced emission molecule (tetraphenylethylene, TPE) and a luminant anticancer drug (doxorubicin, DOX), with a pH-responsive linker between them. Except when a low pH environment is encountered, an energy-transfer relay (ETR) occurs and inactivates the fluorescence of both, showing a dark background. Otherwise, the ETR would be interrupted and evoke a dual-color fluorogenic process, giving distinct fluorogenic read out. By observing the dual color fluorogenic scenario, we captured the kinetics of the drug release process in living cells. Because the separated TPE and DOX are both fluorescent but have a distinct spectrum, by examining the spatiotemporal pattern of TPE and DOX, we were able to precisely disclose the drug-releasing site, the releasing time, the destinations of the carriers, and the executing site of the drugs at subcellular level. Furthermore, different intracellular drug release kinetics between free doxorubicin and its nanoformulations were also observed in a real-time manner. PMID- 25688454 TI - How, why, and for whom do emergency medicine providers use prescription drug monitoring programs? AB - OBJECTIVE: The prescription opioid epidemic is currently responsible for the greatest number of unintentional deaths in the United States. One potential strategy for decreasing this epidemic is implementation of state-based Prescription Drug Monitoring Programs (PDMPs), which are designed for providers to identify patients who "doctor shop" for prescriptions. Emergency medicine physicians are some of the most frequent PDMP users and opioid prescribers, but little is known about how they actually use PDMPs, for which patients, and for what reasons. METHODS: We conducted and transcribed semistructured qualitative interviews with 61 physicians at a national academic conference in October 2012. Deidentified transcripts were entered into QSR NVivo 10.0, coded, and analyzed for themes using modified grounded theory. RESULTS: There is variation in pattern and frequency of PDMP access by emergency physicians. Providers rely on both structural characteristics of the PDMP, such as usability, and also their own clinical gestalt impression when deciding to use PDMPs for a given patient encounter. Providers use the information in PDMPs to alter clinical decisions and guide opioid prescribing patterns. Physicians describe alternative uses for the databases, such as improving their ability to facilitate discussions on addiction and provide patient education. CONCLUSION: PDMPs are used for multiple purposes, including identifying opioid misuse and enhancing provider-patient communication. Given variation in practice, standards may help direct indication and manner of physician use. Steps to minimize administrative barriers to PDMP access are warranted. Finally, alternative PDMP uses should be further studied to determine their appropriateness and potentially expand their role in clinical practice. PMID- 25688455 TI - Surrogate Motherhood and Abortion for Fetal Abnormality. AB - A diagnosis of fetal abnormality presents parents with a difficult - even tragic moral dilemma. Where this diagnosis is made in the context of surrogate motherhood there is an added difficulty, namely that it is not obvious who should be involved in making decisions about abortion, for the person who would normally have the right to decide - the pregnant woman - does not intend to raise the child. This raises the question: To what extent, if at all, should the intended parents be involved in decision-making? In commercial surrogacy it is thought that as part of the contractual agreement the intended parents acquire the right to make this decision. By contrast, in altruistic surrogacy the pregnant woman retains the right to make these decisions, but the intended parents are free to decide not to adopt the child. We argue that both these strategies are morally unsound, and that the problems encountered serve to highlight more fundamental defects within the commercial and altruistic models, as well as in the legal and institutional frameworks that support them. We argue in favour of the professional model, which acknowledges the rights and responsibilities of both parties and provides a legal and institutional framework that supports good decision-making. In particular, the professional model acknowledges the surrogate's right to decide whether to undergo an abortion, and the intended parents' obligation to accept legal custody of the child. While not solving all the problems that arise in surrogacy, the model provides a framework that supports good decision-making. PMID- 25688456 TI - Enhanced platelet reactivity in pediatric depression: an observational study. AB - Depression is associated with poor prognosis for cardiovascular disease (CVD) including mortality. Among multiple mechanisms linking depression and CVD, changes in platelet reactivity are known to be one of the major confounders of such adverse association. However, there are very limited data in children. Thus, we evaluated some conventional hemostatic indices including whole blood platelet aggregation in patients with documented pediatric depression and compared these data with those obtained from healthy children. The pediatric patients fulfilled criteria for major depression with a minimum score of 19 on the 21-item Beck Depression Inventory Scale. Plasma fibrinogen, D-dimer, platelet count, mean platelet volume, and platelet aggregation induced by ADP and collagen were measured in 67 pediatric patients with depression and matched by age and sex with 78 healthy controls. As expected, the depressed children had significantly higher BECK scales (P = 0.001) compared with the normal subjects. Platelet aggregation induced by ADP and collagen (P = 0.0001 for both) was significantly higher in depressed children. BECK scale scores correlated significantly with platelet aggregation induced by ADP (r = 0.3, P = 0.001) and collagen (r = 0.4, P = 0.01). In contrast, platelet counts, fibrinogen, D-dimer, mean platelet volume, and antithrombin-III levels were almost identical between both groups. Children with depression exhibit mostly intact hemostatic parameters, with the exception of significantly higher platelet activity when compared with healthy controls. These data match well with prior evidence from depressed adults supporting the hypothesis that platelets participate in the pathogenesis of depression. However, beyond pure assessment of platelet activity, other elements including serotonin content and cell receptor changes in pediatric depression should be elucidated before randomized trial(s) can be justified. PMID- 25688457 TI - Retrospective evaluation of the clinical use of prothrombin complex concentrate for the reversal of anticoagulation with vitamin K antagonists. AB - Anticoagulation reversal is a time-sensitive intervention for the prevention of life-threatening hemorrhagic events occurring with bleeding or surgery. Recommendations for the most effective and well tolerated reversal agent in these settings remain controversial. Several clinical guidelines for the management of intracerebral hemorrhage support use of prothrombin complex concentrates (PCCs) for the rapid reversal of warfarin-associated coagulopathy despite limited clinical data. The purpose of this investigation was to evaluate the efficacy and safety of PCC for the rapid reversal of anticoagulation by vitamin K antagonists for life-threatening bleeding or emergent surgery and to assess adherence to a hospital-based protocol. A retrospective chart review was conducted of adult patients receiving PCC for the reversal of anticoagulation. Patients were assessed according to indication for anticoagulation reversal. The primary outcome measure was adequacy of international normalized ratio reversal. Other outcomes included cessation of bleeding, thrombotic complications, and adherence to an institutional-based guideline for the use of PCC. ICU and hospital length of stay and 30-day mortality was assessed. There were 70 patients included in this study. Mean international normalized ratio was reduced from 3.1 to 1.6 following administration of at least one dose of PCC. Cessation of bleeding occurred in 65.7% of patients. Clinical assessment was unclear in 18.6%. Thrombotic complications were observed in 7.1% of patients. The 30-day mortality rate was found to be 14.3%. These data demonstrate that PCC is a well tolerated and effective method for anticoagulation reversal associated with a relatively high 30-day survival rate. PMID- 25688458 TI - Prevention of bleeding and hemorrhagic complications in surgical patients with inherited factor VII deficiency. AB - Inherited factor VII (FVII) deficiency is a rare autosomal recessive hemorrhagic disorder. The major clinical symptoms include: bleeding from the oral cavity, epistaxis, menorrhagia, spontaneous hemarthros, bleeding to the gastrointestinal tract and central nervous system, and perioperative bleeding. The aim of this study was to present our experience in preventing bleeding and hemorrhagic disorders in surgical patients with inherited FVII deficiency by using recombinant activated FVIIa (rFVIIa), and with prothrombin complex concentrates (PCCs). In 2002-2011, 17 patients with inherited FVII deficiency underwent surgery. Thirteen patients had isolated FVII deficiency below 10%, and four patients 10-25. To prevent bleeding and hemorrhagic complications, we administered small single doses of rFVIIa (Novo-Seven) at 12-h intervals to 15 patients on surgery day and on day 1 following surgery, then every 24 h; PCCs were administered (Prothromplex, Beriplex) to two patients. No symptoms of bleeding, hemorrhagic or thromboembolic complications were observed in the perioperative and 1-month observation period in surgical patients treated with rFVIIa. One patient treated with PCC (Prothromplex) developed distal deep vein thrombosis on postoperative day 7. The results suggest that small, single, every 12-h doses of rFVIIa (NovoSeven) and in next days after surgery one time every 24 h are well tolerated and effective for prevention of thromboembolic, bleeding and hemorrhagic complications in FVII-deficient patients. Antithrombotic prophylaxis with low-molecular-weight heparin should be applied in patients using PCCs. PMID- 25688459 TI - Postpartum thrombotic complication in a patient with paroxysmal nocturnal hemoglobinuria. AB - Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal nonneoplastic hematopoietic stem cell disease characterized by an acquired mutation of the PIG-A gene with reduction or absence of CD55 and CD59. The absence of these proteins renders PNH erythrocytes susceptible to complement-mediated hemolysis. We report the case of a PNH patient before and during pregnancy until delivery. We observed and treated some postpartum thrombotic complications. Eculizumab should be used with caution in pregnancy. There are several reports supporting its use in these patients. This case should be considered paradigmatic of a series of clinical situations that may occur in the course of a pregnancy in patients with PNH: increased need for transfusion, need to increase the dose of Eculizumab, and insurgence of fetal sufferance. Moreover, after delivery, the patient, despite adequate prophylaxis with low-molecular-weight heparins, presented severe complications: development of pleural and peritoneal effusion, pulmonary embolism, bilateral upper limbs thrombophlebitis, and a possible abdominal angina with a transient paralytic ileus. All these complications were overcome and now the baby is healthy and the mother has returned to the usual therapeutic regimen. PMID- 25688460 TI - A 35-year-old woman with influenza A-associated thrombotic thrombocytopenic purpura. AB - A previously healthy 35-year-old woman presented with severe thrombotic thrombocytopenic purpura (TTP) affecting several organs and concomitant influenza A infection. On admission to hospital, haemoglobin was 5.4 g/dl, platelet count 6 * 10/l, Schistocyte count in peripheral blood 5%, and throat swab positive for influenza A RNA. The patient was treated with antiviral medication and transfusions of fresh frozen plasma before plasma exchange therapy with excellent response. Plasmaphereses were attenuated after 5 days, resulting in TTP relapse 3 days later. A disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) protein was very low (<0.04 U/l) and anti-ADAMTS13 elevated (>2 U/l), consistent with acquired TTP. Platelet counts normalized after five additional plasma exchanges and oral corticosteroids. Antinuclear antibodies and subgroup anti-Ro/Sjogren's syndrome A antigen (SSA) were detected in serum and have remained borderline-elevated, although evaluation during TTP, recovery and follow-up have lacked clinical manifestations of connective tissue disease. Influenza A infection induced production of ADAMTS13 inhibitor, which resulted in TTP in a patient with circulating antinuclear antibodies, lacking other manifestations of connective tissue disease. PMID- 25688461 TI - Changes in bleeding patterns in von Willebrand disease after institution of long term replacement therapy: results from the von Willebrand Disease Prophylaxis Network. AB - Clinically, the leading symptom in von Willebrand disease (VWD) is bleeding, chiefly of mucosal type, for example, epistaxis, gingival, or gastrointestinal bleeding, and menorrhagia. In severe forms of VWD with secondary deficiency of factor VIII, spontaneous joint bleeding, resembling that observed in severe haemophilia A, may also be observed. The bleeding patterns of VWD can affect quality of life, and may be life-threatening. The von Willebrand Disease Prophylaxis Network is an international study group formed with the goal of investigating the role of prophylaxis in clinically severe VWD. The objective of the present study is to investigate the response to prophylaxis focusing primarily on epistaxis, joint bleeding, gastrointestinal bleeding, and heavy bleeding associated with menses. Data from 105 subjects, 10 enrolled in a prospective study and 95 in a retrospective study between 2008 and 2013, were available for analysis. The median annualized rate reductions in bleeding were significant for epistaxis (P < 0.0001), gastrointestinal bleeding (P = 0.0003), joint bleeding (P < 0.0001), and menorrhagia (P = 0.008). Doses on a group level were approximately the same prior to and during prophylaxis, but more patients with gastrointestinal bleeding had prophylaxis three or more times per week as well as higher dosages. Our study, which primarily used retrospective data, indicates that prospective studies are needed to better delineate the doses and dose intervals that should be used for prophylactic treatment of VWD. PMID- 25688462 TI - Homocysteine influences blood clot properties alone and in combination with total fibrinogen but not with fibrinogen gamma' in Africans. AB - Simultaneously increased fibrinogen and homocysteine (Hcy) in blood are believed to elevate the risk of cardiovascular disease mortality. However, the pathophysiological mechanisms involved are unknown. We sought to determine whether Hcy or its genetic determinants influence blood clot properties alone or in combination with fibrinogen. In addition, we investigated, for the first time, the gamma prime (gamma') isoform of fibrinogen with Hcy in relation to clot architecture and lysis. Single-nucleotide polymorphisms, Hcy and hemostatic variables, including clot lysis, determined with a global fibrinolytic assay [giving lag time, slope, maximum absorbance and clot lysis time (CLT)], were measured in 1867 healthy black South Africans and cross-sectionally analyzed. Increasing Hcy did not affect fiber cross-sectional area (maximum absorbance). However, it decreased the time needed to initiate the coagulation cascade and for fibrin fibers to grow (lag time), it increased the tempo of lateral aggregation (slope) and reduced CLT. None of the single-nucleotide polymorphisms measured had effects on clot properties. Combined effects were observed between Hcy and total fibrinogen in predicting CLT. Fibrinogen gamma', which affected markers of the fibrinolytic assay, did not have conjoint effects with Hcy. We believe that there is value in recognizing the combined effects of Hcy and fibrinogen, but not its gamma' isoform in relation to clot structure and lysis. The enhanced fibrinolysis rate observed in patients with low fibrinogen and high Hcy may have adverse consequences for health if it disturbs hemostasis and results in a bleeding tendency. PMID- 25688463 TI - Association between venous thromboembolism and iron-deficiency anemia: a population-based study. AB - Although iron-deficiency anemia (IDA) as a rare cause of cerebral sinus thrombosis was supported by several studies, the relationship between IDA and venous thromboembolisms (VTEs) remains unclear. In this study, we evaluated the association between IDA and subsequent VTEs based on a population-based coverage database. We retrieved data for this case-control study from the Taiwan Longitudinal Health Insurance Database 2000. In total, 2522 cases with VTE and 12 610 randomly selected controls were included. A conditional logistic regression was used to examine the association of VTEs with previously diagnosed IDA. The chi test indicated that there was a significant difference in the prevalence of prior IDA between subjects with a VTE and the controls (3.41 vs. 2.06%, respectively, P < 0.001). The conditional logistic regression analysis showed that the odds ratio (OR) of previous IDA for subjects with a VTE was 1.43 [95% confidence interval (CI): 1.10-1.87] compared with the controls after adjusting for monthly income, geographic region, urbanization level, cancer, inflammatory bowel disease, heart failure, hypertension, diabetes, coronary heart disease, hyperlipidemia, renal disease, obesity, and whether or not a subject was hospitalized and whether or not a subject had suffered from a fracture within 1 year prior to the index date. The adjusted OR for prior IDA in subjects with deep vein thrombosis was 1.43 (95% CI: 1.08-1.90) compared with the controls. However, there was no significant difference in the adjusted OR of prior IDA between subjects with a pulmonary embolism and the controls (OR: 1.10; 95% CI: 0.63 1.92). We concluded that there was an association between IDA and VTEs. PMID- 25688464 TI - Management of pregnancy in paroxysmal nocturnal hemoglobinuria on long-term eculizumab. AB - Pregnancy in women with paroxysmal nocturnal hemoglobinuria (PNH) is associated with increased maternal and fetal complications, to such an extent that PNH has for long been considered a relative contraindication for pregnancy. The most serious life-threatening complications are venous thromboembolic events, the risk of which is increased by the hypercoagulable state related to pregnancy. Eculizumab, a C5 complement inhibitor, has revolutionized the treatment of PNH. However, there are no published trials evaluating its use in pregnancy. Most recommendations are based on expert opinions and case reports. We report on the favorable outcome of a PNH patient who became pregnant while under eculizumab, suggesting that this drug can be given from conception to delivery. PMID- 25688465 TI - Calciphylaxis in catastrophic antiphospholipid antibody syndrome. AB - Antiphospholipid antibody syndrome (APS) is a multisystem disorder characterized by vascular thrombosis and presence of circulating autoantibodies. The presence of APS can predispose to macrovascular as well as microvascular thrombotic events. Renal involvement is a common occurrence especially in the background of systemic lupus erythematosus. Skin appears to be another frequent target organ and a significant proportion of patients may present with skin lesions at the time of diagnosis. We present the case of a patient who presented with skin necrosis secondary to antiphospholipid antibody syndrome despite being on therapeutic anticoagulation and then developed dystrophic calcification secondary to her renal insufficiency. This complex skin condition eventually leads to her demise, as she was not a candidate for surgical management of these lesions. Why is this important? This case brings to our attention the need to consider calciphylaxis as a cause of ecchymotic-appearing skin lesions in dialysis patients on warfarin in patients with antiphospholipid antibody syndrome. PMID- 25688466 TI - Maternal childhood adversity and child temperament: an association moderated by child 5-HTTLPR genotype. AB - We examined transgenerational effects of maternal childhood adversity on child temperament and a functional promoter polymorphism, 5-HTTLPR, in the serotonin transporter gene (SLC6A4) as potential moderators of such maternal influences in 154 mother-child dyads, recruited into a longitudinal birth cohort study. We examined the interactive effects of maternal childhood experience using an integrated measure derived from Childhood Trauma Questionnaire (CTQ) and Parental Bonding Index (PBI). Triallelic genotyping of 5-HTTLPR was performed. A measure of 'negative emotionality/behavioural dysregulation' was derived from the Early Childhood Behaviour Questionnaire at 18 and 36 months. Negative emotionality/behavioural dysregulation was highly stable between 18 and 36 months and predicted psychosocial problems at 60 months. After controlling multiple demographics as well as both previous and concurrent maternal depression there was a significant interaction effect of maternal childhood adversity and offspring 5-HTTLPR genotype on child negative emotionality/behavioural dysregulation (beta = 1.03, t(11,115) = 2.71, P < .01). The results suggest a transgenerational effect of maternal developmental history on emotional function in the offspring, describing a pathway that likely contributes to the familial transmission of vulnerability for psychopathology. PMID- 25688467 TI - Total ankle replacement in patients with von Willebrand disease: mid-term results of 18 procedures. AB - von Willebrand disease (VWD) is a recognized cause of secondary ankle osteoarthritis (OA). Few studies have examined orthopaedic complications and outcomes in VWD patients treated for end-stage ankle OA with total ankle replacement (TAR). To determine the clinical presentation, intraoperative and postoperative complications and evaluate the mid-term outcome in VWD patients treated with TAR. Eighteen patients with VWD with mean age 47.3 years (range = 34.0-68.7) were treated for end-stage ankle OA with TAR. The mean duration of follow-up was 7.5 years (range = 2.9-13.2). Intraoperative and perioperative complications were recorded. Component stability was assessed with weight-bearing radiographs. Clinical evaluation included range of motion (ROM) tests using a goniometer and under fluoroscopy using a lateral view. Clinical outcomes were analysed by a visual analogue scale, the American Orthopaedic Foot and Ankle Society hindfoot score and Short Form (36) Health Survey (SF-36) health survey. One patient sustained an intraoperative medial malleolar fracture. In two patients delayed wound healing was observed. Two secondary major surgeries were performed. Pain level decreased from 8.2 +/- 0.9 (range = 7-10) preoperatively to 1.1 +/- 1.2 (range = 0-4) postoperatively. Significant functional improvement including ROM was observed. All categories of SF-36 score showed significant improvement in quality of life. Mid-term results of TAR in patients with VWD are encouraging. The total rate of intraoperative and postoperative complications was 33.3%. However, longer term outcomes are necessary to fully understand the clinical benefit of TAR in patients with VWD. PMID- 25688468 TI - Actual reality: Using the Internet to assess everyday functioning after traumatic brain injury. AB - OBJECTIVES: The aim of this pilot study was to examine and compare the performance of everyday life activities in persons with traumatic brain injury (TBI) and healthy controls (HC) using a new assessment tool called 'actual reality' (AR). METHOD: A between-subjects design was utilized to compare 10 individuals with TBI and 10 healthy controls (HC) performing an AR task. Participants were asked to access the Internet to purchase a decorative arrangement of cookies and were administered a battery of neuropsychological tests and questionnaires to assess quality-of-life, functional status, affect symptomatology and prior Internet experience. RESULTS: Participants with TBI had significantly more difficulties than HC participants in accurately and independently completing the AR task-primarily due to cognitive impairment. In addition, self-reports of quality-of-life and everyday functional abilities were not correlated with AR performance. CONCLUSIONS: The results provide initial evidence supporting the use of the AR approach in assessing persons with TBI performing everyday life activities. The utilization and interpretation of the AR approach is a significant step forward in increasing the sensitivity, accessibility and relevancy of functional assessments in people with cognitive impairments. Actual reality will be discussed in terms of accessibility and directions for assessment and treatment. PMID- 25688469 TI - Interconnection of reactive oxygen species chemistry across the interfaces of atmospheric, environmental, and biological processes. AB - Oxidation reactions are ubiquitous and play key roles in the chemistry of the atmosphere, in water treatment processes, and in aerobic organisms. Ozone (O3), hydrogen peroxide (H2O2), hydrogen polyoxides (H2Ox, x > 2), associated hydroxyl and hydroperoxyl radicals (HOx = OH and HO2), and superoxide and ozonide anions (O2(-) and O3(-), respectively) are the primary oxidants in these systems. They are commonly classified as reactive oxygen species (ROS). Atmospheric chemistry is driven by a complex system of chain reactions of species, including nitrogen oxides, hydroxyl and hydroperoxide radicals, alkoxy and peroxy radicals, and ozone. HOx radicals contribute to keeping air clean, but in polluted areas, the ozone concentration increases and creates a negative impact on plants and animals. Indeed, ozone concentration is used to assess air quality worldwide. Clouds have a direct effect on the chemical composition of the atmosphere. On one hand, cloud droplets absorb many trace atmospheric gases, which can be scavenged by rain and fog. On the other hand, ionic species can form in this medium, which makes the chemistry of the atmosphere richer and more complex. Furthermore, recent studies have suggested that air-cloud interfaces might have a significant impact on the overall chemistry of the troposphere. Despite the large differences in molecular composition, concentration, and thermodynamic conditions among atmospheric, environmental, and biological systems, the underlying chemistry involving ROS has many similarities. In this Account, we examine ROS and discuss the chemical characteristics common to all of these systems. In water treatment, ROS are key components of an important subset of advanced oxidation processes. Ozonation, peroxone chemistry, and Fenton reactions play important roles in generating sufficient amounts of hydroxyl radicals to purify wastewater. Biochemical processes within living organisms also involve ROS. These species can come from pollutants in the environment, but they can also originate endogenously, initiated by electron reduction of molecular oxygen. These molecules have important biological signaling activities, but they cause oxidative stress when dysfunction within the antioxidant system occurs. Excess ROS in living organisms can lead to problems, such as protein oxidation-through either cleavage of the polypeptide chain or modification of amino acid side chains-and lipid oxidation. PMID- 25688470 TI - The clash of expectancies: Does the P300 amplitude reflect both passive and active expectations? AB - We investigated the clash of different types of expectations by studying event related potentials and behavioural correlates of passive and active expectations. In the three tasks we used, target stimuli could either confirm or disconfirm both expectations, or confirm one while disconfirming the other. Depending on the task, expected events were related to either increased or decreased P300 amplitude. This was contingent on whether the expected item was probable given the context, or whether it was a target match. This suggests that the effect of expectancy on the P300 amplitude can be direct or indirect. In the case of a direct effect, the evidence suggests that most likely only unconscious, automatic estimation of stimulus probability is reflected in the size of P300 amplitude. However, active, conscious expectancies can influence the P300 activity via indirect routes, by influencing stimulus significance, by leading to the closure of perceptual epoch, or by changing the level of difficulty of processing. Such indirect effect of expectancy can have an opposite direction to the effect of automatically formed expectancies-that is, expected stimuli could be related to larger P300 amplitudes. PMID- 25688471 TI - High prevalence of common respiratory viruses and no evidence of Middle East respiratory syndrome coronavirus in Hajj pilgrims returning to Ghana, 2013. AB - OBJECTIVE: The Middle East respiratory syndrome coronavirus (MERS-CoV) emerged in 2012 on the Arabian Peninsula and has caused severe respiratory disease with more than 800 laboratory-confirmed cases. The return of infected pilgrims to their home countries with a putative spread of MERS-CoV necessitates further surveillance. METHODS: A cross sectional study of 839 adult African Hajj pilgrims returning to Accra in Ghana, West Africa, was conducted in 2013 to assess the prevalence of respiratory symptoms as well as of MERS-CoV, human rhinovirus (HRV), respiratory syncytial virus (RSV) and influenza A virus (FLU A) infection. RESULTS: Six hundred and fifty-one (77.6%) pilgrims had respiratory symptoms. Tests were positive for at least one of the viruses other than MERS-CoV in 179 (21.3%) of all pilgrims, with 22.4% detection in symptomatic vs. 17.6% detection in asymptomatic pilgrims. No MERS-CoV was detected, although common respiratory viruses were prevalent, with positive findings for HRV in 141 individuals (16.8%), RSV in 43 individuals (5.1%) and FLU A in 11 individuals (1.3%). Results were positive for more than one virus in 16 (1.9%) individuals, including 14 (1.7%) RSV/HRV co-infections and 2 (0.2%) FLU A/HRV co-infections. A total 146 (22.4%) of the symptomatic returnees tested positive for at least one respiratory virus compared with 33 (17.6%) of the asymptomatic pilgrims who had at least one detectable virus in their sample. CONCLUSIONS: The prevalence of viral respiratory infections among Hajj pilgrims in both symptomatic and asymptomatic subjects was high. Although it is reassuring that MERS-CoV was not detected in the tested population, there is a need for active surveillance of Hajj pilgrims. PMID- 25688472 TI - Back from the brink: a mesenchymal stem cell infusion rescues kidney function in acute experimental rhabdomyolysis. AB - Systemic administration of mesenchymal stem (stromal) cells (MSCs) has shown benefit in a range of experimental models of acute kidney injury, although the reported mechanisms of action and requirement for MSC localization to the kidney have varied. Geng and colleagues now demonstrate that a single intravenous infusion of MSCs given 6 hours after induction of acute muscle necrosis (rhabdomyolysis) robustly ameliorates the resulting acute kidney injury and promotes early intra-renal accumulation of CD206+ (M2) macrophages. The benefit occurred in the absence of MSC localization to the kidney and could be reproduced by adoptive transfer of ex vivo-programmed M2 macrophages. PMID- 25688473 TI - A three-cohort comparison with videodermatoscopic evidence of the distinct homogeneous bushy capillary microvascular pattern in psoriasis vs atopic dermatitis and contact dermatitis. PMID- 25688474 TI - Mutations in the leptin receptor gene associated with delayed onset of puberty are also associated with decreased ovulation and lambing rates in prolific Davisdale sheep. AB - The aim of this study was to determine if single nucleotide polymorphisms (SNPs) in the leptin receptor (LEPR) gene associated with delayed onset of puberty are associated with changes in other reproductive traits in adult ewes. The ovulation rate of ewes homozygous for the SNPs was ~15% lower (PPLEPR SNPs than their wild type or heterozygous contemporaries. Partial failure of multiple ovulations was also increased (PLEPR had on average 0.2 fewer lambs at mid-pregnancy and at birth compared with the wild-type or heterozygous ewes (PLEPR were strongly associated with poorer reproductive performance in Davisdale ewes, which is likely to be linked to both a reduced number of ova available for fertilisation and an increased number of ewes failing to become pregnant. Increased partial failure of multiple ovulations in ewes with high ovulation rates (i.e. 3 or greater) may also contribute to the poor reproductive performance. PMID- 25688475 TI - Correction to Balticidins A-D, antifungal hassallidin-like lipopeptides from the Baltic Sea cyanobacterium Anabaena cylindrica Bio33. PMID- 25688476 TI - Energy and water quality management systems for water utility's operations: a review. AB - Holistic management of water and energy resources is critical for water utilities facing increasing energy prices, water supply shortage and stringent regulatory requirements. In the early 1990s, the concept of an integrated Energy and Water Quality Management System (EWQMS) was developed as an operational optimization framework for solving water quality, water supply and energy management problems simultaneously. Approximately twenty water utilities have implemented an EWQMS by interfacing commercial or in-house software optimization programs with existing control systems. For utilities with an installed EWQMS, operating cost savings of 8-15% have been reported due to higher use of cheaper tariff periods and better operating efficiencies, resulting in the reduction in energy consumption of ~6 9%. This review provides the current state-of-knowledge on EWQMS typical structural features and operational strategies and benefits and drawbacks are analyzed. The review also highlights the challenges encountered during installation and implementation of EWQMS and identifies the knowledge gaps that should motivate new research efforts. PMID- 25688477 TI - Bioaugmentation and biostimulation as strategies for the bioremediation of a burned woodland soil contaminated by toxic hydrocarbons: a comparative study. AB - In this work, the natural attenuation strategy (no soil amendments done) was compared with two different bioremediation approaches, namely bioaugmentation through soil inoculation with a suspension of Trichoderma sp. mycelium and biostimulation by soil addition with a microbial growth promoting formulation, in order to verify the effectiveness of these methods in terms of degradation efficiency towards toxic hydrocarbons, with particular attention to the high molecular weight (HMW) fraction, in a forest area impacted by recent wildfire in Northern Italy. The area under investigation, divided into three parcels, was monitored to figure out the dynamics of decay in soil concentration of C12-40 hydrocarbons (including isoalkanes, cycloalkanes, alkyl-benzenes and alkyl naphthalenes besides PAHs) and low molecular weight (LMW) PAHs, following the adoption of the foregoing different remediation strategies. Soil hydrocarbonoclastic potential was even checked by characterizing the autochthonous microbial cenoses. Field experiments proved that the best performance in the abatement of HMW hydrocarbons was reached 60 days after soil treatment through the biostimulation protocol, when about 70% of the initial concentration of HMW hydrocarbons was depleted. Within the same time, about 55% degradation was obtained with the bioaugmentation protocol, whilst natural attenuation allowed only a 45% removal of the starting C12-40 hydrocarbon fraction. Therefore, biostimulation seems to significantly reduce the time required for the remediation, most likely because of the enhancement of microbial degradation through the improvement of nutrient balance in the burned soil. PMID- 25688478 TI - Childhood Esophagitis Changes in 30 Years at 1 Center. AB - Eosinophils are nonspecific harbingers of esophageal disease. We report on the incidence and features of esophageal eosinophilia diagnosed at our center in 2011 and compare the findings with previously published results between 1980-1988 and 2000-2002. Eosinophils per high-power field were counted in esophageal biopsies from 675 patients who underwent 710 endoscopic procedures between January 1, 2011, and December 31, 2011. Of these, 209 (33%) patients were infiltrated with eosinophils; the other 466 (67%) showed no pathological changes. The highest concentrations of eosinophils were observed in the distal esophagus. Our findings also indicate that esophageal eosinophilia fluctuates over time. PMID- 25688479 TI - Apoptotic Enteropathy in a Neonate With Allergic Enterocolitis. PMID- 25688480 TI - Prevalence of Gallstones Compared in Children With Different Intravenous Lipids. AB - OBJECTIVE: The aetiology of biliary liver disease in children with intestinal failure treated with long-term parenteral nutrition (PN) is multifactorial. Risks include the lipid component of PN. The aim of the study was to compare prevalence and outcome of gallstones with different types of intravenous lipids. METHODS: Liver and biliary tract imaging and relevant clinical details were reviewed in 71 patients (37, 52% boys) treated with PN for >3 months. Types of lipid infused were compared with regard to hepatobiliary abnormalities. RESULTS: In total 369 abdominal ultrasounds were performed in 71 patients of age between 3 months and 17 years. Underlying diagnoses were short bowel syndrome in 20 (28%), small intestinal enteropathy in 34 (48%), and motility disorder in 17 (24%). A total of 67 (94%) children had 362/369 scans on lipid-containing PN. Of the total, 15 (21%) patients had gallstones, 8 (11%) had sludge, and both were detected in 7 (10%) children. The gallstones/sludge resolved in 7 patients (10%) and persisted in 10 (13%). In 6 patients, sludge progressed to form discrete gallstones, and in 9 children, gallstones led to biliary duct dilatation. Four (6%) patients underwent cholecystectomy. Fewer children had abnormalities with the newer mixed lipid emulsion (P = 0.005). There was a higher prevalence of sludge (P = 0.01) on pure soya lipid. Predictors for sludge were young age at PN (P = 0.001), lack of enteral feed (P < 0.001), and motility disorder with stoma (P = 0.002). CONCLUSIONS: Hepatobiliary pathology is common in children on PN. The use of mixed lipid was associated with less biliary complications and should be the first choice of treatment in children. PMID- 25688481 TI - Improvement of hepatic steatosis in cystic fibrosis with ivacaftor therapy. AB - Treatment of liver disease, including hepatic steatosis, in patients with cystic fibrosis (CF) is limited. With the development of ivacaftor, which corrects the gating defect of the CF transmembrane regulator channel, there is a potential new therapy available for this subgroup of the CF patient population. We present an adolescent with CF who had significant improvement in hepatic steatosis with ivacaftor treatment while hypothesizing on a mechanism of why it occurred. PMID- 25688482 TI - Reproductive and parental care physiology of Cichlasoma dimerus males. AB - The South American cichlid fish Cichlasoma dimerus presents a high breeding frequency and biparental care of the eggs and larvae. The male parental care period was divided in four different phases according to the developmental degree of the offspring: pre-spawning activity (MP, day 0), guarding eggs (ME, one day after fertilization (1 DAF)), guarding hatched larvae (MHL, 3 DAF), and guarding swimming larvae (MSL, 8 DAF). The aim of this study was to characterize male reproductive physiology by measuring steroid hormone plasma levels and analyzing testes cellular composition. Males exhibiting pre-spawning activity showed 8.4 times higher 11-ketotestosterone and 5.63 times higher testosterone levels than MHL. No differences were observed in estradiol and cortisol levels among the different phases. The cellular composition of the testes varied during the reproductive and parental care periods. Testes of MP were composed of 50% of spermatozoa, whereas spermatogonia type B and spermatocytes were predominant in the subsequent parental phases. A morphometric analysis of Leydig cells nuclear area revealed that MP and ME's Leydig cells averaged 1.27 times larger than that those of MHL and MSL and was positively correlated with circulating 11-KT and T levels. Hence, C. dimerus males showed important changes in its hormonal profiles and testicular cellular composition throughout the reproductive and parental care period. PMID- 25688483 TI - Probing peptide cation-radicals by near-UV photodissociation in the gas phase. Structure elucidation of histidine radical chromophores formed by electron transfer reduction. AB - Electron transfer reduction of gas-phase ions generated from histidine-containing peptides forms stable cation-radicals that absorb light at 355 nm, as studied for AAHAR, AAHAK, DSHAK, FHEK, HHGYK, and HHSHR. Laser photodissociation of mass selected cation-radicals chiefly resulted in loss of H atoms, contrasting dissociations induced by slow collisional heating. The 355 nm absorption was due to new chromophores created by electron transfer and radical rearrangements in the cation-radicals. The chromophores were identified by time-dependent density functional theory calculations as 2H,3H-imidazoline and 2H-dihydrophenol radicals, formed by hydrogen atom transfer to the histidine and tyrosine side chain groups, respectively. These radicals undergo facile C-H bond dissociations upon photon absorption. In contrast, dissociations of histidine peptide cation radicals containing the 1H,3H-imidazoline ring prefer loss of 4-methylimidazole via a multistep reaction pathway. The isomeric cation-radicals can be distinguished by a combination of collision-induced dissociation and near-UV photodissociation. The TD-DFT excitation energies in model imidazoline radicals were benchmarked on EOM-CCSD energies, and a satisfactory agreement was found for the M06-2X and omegaB97XD functionals. The combination of electron transfer, photodissociation, collisional activation, and theory is presented as a powerful tool for studying structures and electronic properties of peptide cation-radicals in the gas phase. PMID- 25688486 TI - Translational public health care perspective: intravitreal treatment of neovascular age-related macular degeneration has revolutionized clinical ophthalmology. PMID- 25688487 TI - Assessment and diagnosis of suspected glaucoma in patients with mucopolysaccharidosis. AB - PURPOSE: The mucopolysaccharidoses (MPS) are a group of rare lysosomal storage disorders, characterized by the accumulation of glycosaminoglycans within multiple organ systems including the eye. This study aimed to determine the prevalence of glaucoma in patients with MPS, as well as the characteristics, diagnosis and management of patients with MPS and glaucoma. METHODS: A multicentre retrospective case-note review was carried out by ophthalmologists from four tertiary referral centres to identify patients with MPS who had been treated for glaucoma. Clinical ophthalmological data were collected using standardized data collection forms. RESULTS: Fourteen patients were identified (27 eyes) of 294 patients with MPS. The prevalence of glaucoma ranged from 2.1% to 12.5%. The median age at diagnosis of glaucoma was 8 years. Diagnostic evaluation of glaucoma was incomplete in many patients: intraocular pressure was documented in all eyes, but optic disc appearance was only assessed in 67%, central corneal thickness in 26%, visual fields in 19% and iridocorneal angle in 15%. CONCLUSIONS: Patients with MPS need regular assessment for possible glaucoma including during childhood. Multiple factors contribute to the challenges of assessment, diagnosis and monitoring of glaucoma in these patients. PMID- 25688488 TI - High mobility and low density of trap states in dual-solid-gated PbS nanocrystal field-effect transistors. AB - Dual-gated PbS nanocrystal field-effect transistors employing SiO2 and Cytop as gate dielectrics are fabricated. The obtained electron mobility (0.2 cm(2) V(-1) s(-1) ) and the high on/off ratio (10(5) -10(6) ), show that the controlled nanocrystal assembly (obtained with self-assembled monolayers), as well as the trap density reduction (using Cytop as dielectric), are crucial steps for the future application of nanocrystals. PMID- 25688484 TI - Hitting the Bull's-Eye in Metastatic Cancers-NSAIDs Elevate ROS in Mitochondria, Inducing Malignant Cell Death. AB - Tumor metastases that impede the function of vital organs are a major cause of cancer related mortality. Mitochondrial oxidative stress induced by hypoxia, low nutrient levels, or other stresses, such as genotoxic events, act as key drivers of the malignant changes in primary tumors to enhance their progression to metastasis. Emerging evidence now indicates that mitochondrial modifications and mutations resulting from oxidative stress, and leading to OxPhos stimulation and/or enhanced reactive oxygen species (ROS) production, are essential for promoting and sustaining the highly metastatic phenotype. Moreover, the modified mitochondria in emerging or existing metastatic cancer cells, by their irreversible differences, provide opportunities for selectively targeting their mitochondrial functions with a one-two punch. The first blow would block their anti-oxidative defense, followed by the knockout blow-promoting production of excess ROS, capitulating the terminal stage-activation of the mitochondrial permeability transition pore (mPTP), specifically killing metastatic cancer cells or their precursors. This review links a wide area of research relevant to cellular mechanisms that affect mitochondria activity as a major source of ROS production driving the pro-oxidative state in metastatic cancer cells. Each of the important aspects affecting mitochondrial function are discussed including: hypoxia, HIFs and PGC1 induced metabolic changes, increased ROS production to induce a more pro-oxidative state with reduced antioxidant defenses. It then focuses on how the mitochondria, as a major source of ROS in metastatic cancer cells driving the pro-oxidative state of malignancy enables targeting drugs affecting many of these altered processes and why the NSAIDs are an excellent example of mitochondria-targeted agents that provide a one-two knockout activating the mPTP and their efficacy as selective anticancer metastasis drugs. PMID- 25688489 TI - Ancient vicariance and climate-driven extinction continental-wide disjunctions in Africa: the case of the Rand Flora genus Canarina (Campanulaceae). AB - Transoceanic distributions have attracted the interest of scientists for centuries. Less attention has been paid to the evolutionary origins of 'continent wide' disjunctions, in which related taxa are distributed across isolated regions within the same continent. A prime example is the 'Rand Flora' pattern, which shows sister taxa disjunctly distributed in the continental margins of Africa. Here, we explore the evolutionary origins of this pattern using the genus Canarina, with three species: C. canariensis, associated with the Canarian laurisilva, and C. eminii and C. abyssinica, endemic to the Afromontane region in East Africa, as case study. We infer phylogenetic relationships, divergence times and the history of migration events within Canarina using Bayesian inference on a large sample of chloroplast and nuclear sequences. Ecological niche modelling was employed to infer the climatic niche of Canarina through time. Dating was performed with a novel nested approach to solve the problem of using deep time calibration points within a molecular dataset comprising both above-species and population-level sampling. Results show C. abyssinica as sister to a clade formed by disjunct C. eminii and C. canariensis. Miocene divergences were inferred among species, whereas infraspecific divergences fell within the Pleistocene-Holocene periods. Although C. eminii and C. canariensis showed a strong genetic geographic structure, among-population divergences were older in the former than in the latter. Our results suggest that Canarina originated in East Africa and later migrated across North Africa, with vicariance and aridification-driven extinction explaining the 7000 km/7 million year divergence between the Canarian and East African endemics. PMID- 25688490 TI - Cancer during pregnancy: what is the role of maternal serum and placental biomarkers? A review and commentary. AB - Cancer during pregnancy, referred to as gestational cancer (GC), is infrequent but can occur in 1.0% of pregnant women. Hepatocellular carcinoma (HCC) is often lethal and is the fifth most common cancer worldwide, while breast adenocarcinoma (breast cancer) is the most common cancer seen during pregnancy. Liver and breast carcinomas are two examples of cancer types that present challenges to the obstetrician due to late and/or delayed diagnosis during pregnancy. Delays in diagnosis limit choices available to physicians regarding surgery, radiation, and chemotherapy. In view of such clinical situations, a role for maternal serum and placental biomarker (MSPB) screening results contributing to cancer diagnosis should be recognized; overlooking such data in GC could result from a lack of knowledge and understanding of MSPB biology, chemistry, and physiology. In this report, obstetricians and perinatologists seeking a diagnosis are urged to take advantage of available results from MSPB screening programs obtained from first- and second-trimester patient data. Using liver and breast cancer as examples, the present review and commentary seeks to demonstrate that MSPB levels, profiles, patterns, and cellular responses could provide foundational data in planning invasive or noninvasive methods and procedures (biopsy, imaging, scans, surgery) to attain a diagnosis as soon as possible in pregnancy. Finally, MSPB epidemiological and cancer risk studies could aid in providing baseline information for decisions regarding GC diagnosis from knowledge of their proposed roles in reducing lifetime risk of malignancies such as breast cancer. PMID- 25688491 TI - Antioxidant strategies in genetic syndromes with high neoplastic risk in infant age. AB - Oxidative stress plays a key role in carcinogenesis. Oxidative damage to cell components can lead to the initiation, promotion and progression of cancer. Oxidative stress is also a distinctive sign in several genetic disorders characterized by a cancer predisposition such as ataxia-telangiectasia, Fanconi anemia, Down syndrome, Beckwith-Wiedemann syndrome and Costello syndrome. Taking into account the link between oxidative stress and cancer, the capacity of antioxidant agents to prevent or delay neoplastic development has been tested in various studies, both in vitro and in vivo, with interesting and promising results. In recent years, research has been conducted into the molecular mechanisms linking oxidative stress to the pathogenesis of the genetic syndromes we consider in this review, with the resulting identification of possible new therapeutic targets. The aim of this review is to focus on the oxidative mechanisms intervening in carcinogenesis in cancer-prone genetic disorders and to analyze the current status and future prospects of antioxidants. PMID- 25688492 TI - Management of contralateral axillary lymph node metastasis from breast cancer: a clinical dilemma. AB - AIMS AND BACKGROUND: Contralateral axillary lymph node metastasis (CAM) in breast cancer patients is uncommon and the source uncertain. Management is complicated when CAM occurs as the first event of relapse after treatment of the primary tumor, especially in the absence of metastatic disease elsewhere. METHODS: We reviewed the records of all breast cancer patients treated during 1999-2012. All patients with pathologically confirmed metachronous CAM were included. The examined data were demographic characteristics, tumor features and management modalities. Data from an epidemiological report that described the pathological characteristics of breast cancer in China during 1999-2008 were employed to allow further comparison. Twenty-eight patients with CAM were included in the study; they comprised 0.81% of the total number of patients. The median patient age was 47 years (range, 27-60 years). Half of the initial breast cancers were located at inner and central sites. Initial cancers were generally locally advanced (stage III, 50%) and hormone receptor negative. Treatment modalities included axillary lymph node dissection (ALND), mastectomy, radiation, and chemotherapy (+/- targeted therapy). RESULTS: After 29 months of follow-up, 25 patients had disease progression with a median progression-free survival of 10 months. Regional recurrence was most commonly seen at sites including bilateral breast, chest wall and superficial lymph nodes, accounting for 44% (n = 11) of patients who progressed. Median progression-free survival was prolonged in patients treated with radiotherapy (10 months vs 22 months). During the observation period, 13 patients died of disease progression. We found that CAM was associated with tumors with aggressive pathological features and had a poor prognosis. CONCLUSION: CAM is most likely to be distant metastasis from the initial breast cancer through lymphatic drainage rather than regional metastasis from a new occult breast cancer. Comprehensive treatment including chemotherapy and radiotherapy can provide better control; however, ANLD alone is insufficient treatment and mastectomy is not recommended. PMID- 25688493 TI - Retreatment with trastuzumab after progression on lapatinib-based therapy in heavily pretreated HER2-positive metastatic breast cancer: a single-institution experience. AB - AIMS: The study aimed to determine if retreatment with trastuzumab after progression on treatment with lapatinib is feasible in a previously heavily pretreated population of HER2-positive metastatic breast cancer patients and if some range of activity and an acceptable toxicity profile could be shown. METHODS AND STUDY DESIGN: Women with HER2-positive metastatic breast carcinoma whose disease progressed after antracycline, taxane and trastuzumab-based regimens were treated at progression with lapatinib plus capecitabine. At progression on this combination, retreatment with trastuzumab combined with different cytotoxic agents was offered to most patients. The outcome of these patients was evaluated. RESULTS: Between April 2007 and February 2013, a total of 77 patients with HER2 positive metastatic breast cancer were identified who had been treated with lapatinib plus capecitabine at our institution. At progression, 43 (55%) were treated again with a trastuzumab-based regimen, mostly gemcitabine and vinorelbine. One complete response (CR) and 17 partial responses plus 4 prolonged stable periods longer than 6 months for a 51.1% overall clinical benefit were observed. No severe toxicities were encountered except one case of heart failure reported in a heavily antracycline-pretreated patient, who, however, recovered from this toxicity. CONCLUSIONS: Even if our sample is a favorably selected population of HER2-positive patients responding to sequential targeted therapies, our data suggest that trastuzumab can be used again in association with a different cytotoxic agent in patients heavily pretreated with trastuzumab and after progression on lapatinib plus capecitabine, without any significant toxicity and with an encouraging clinical benefit rate, suggesting there is an opportunity to continue blockade of the HER2 receptor. PMID- 25688494 TI - Nonmetastatic osteosarcoma of the extremity. Neoadjuvant chemotherapy with methotrexate, cisplatin, doxorubicin and ifosfamide. An Italian Sarcoma Group study (ISG/OS-Oss). AB - BACKGROUND: Based on the results of the ISG/OS-1 study, the MAP regimen (methotrexate [MTX], doxorubicin [ADM] and cisplatin [CDP] with the addition of ifosfamide [IFO] in poor-responder patients) was investigated in patients with nonmetastatic osteosarcoma of the extremity (ISG/OS-Oss study). PATIENTS AND METHODS: Compared with the ISG/OS-1 study (cumulative doses: ADM 420 mg/m(2), MTX 120 g/m(2), CDP 600 mg/m(2), IFO 30 g/m(2)), the ISG/OS-Oss study reduced the number of MTX cycles from 10 to 5 (cumulative MTX dose: 60 g/m(2)) in order to diminish treatment duration and toxicity. RESULTS: From January 2007 to June 2011, 171 patients (median age 16 years, 60% males) were registered. The limb salvage rate was 94% and the good pathologic response rate 51% (these figures were 92% and 48%, respectively, in the ISG/OS-1 study). At a median follow-up of 39 months (range, 4-80), the 5-year overall survival rate was 80% (95% CI, 73% 87%) and the event-free survival was 50% (95% CI, 39%-59%). For comparison, the 5 year overall and event-free survival rates in ISG/OS-1 were 73% (95% CI, 65%-81%) and 64% (95% CI, 56%-73%), respectively. CONCLUSIONS: This study confirms that in nonmetastatic osteosarcoma of the extremity, conservative surgery in more than 90% and a good pathologic response rate of 50% can be expected with primary chemotherapy based on the MAP regimen. The response and resection rates in the ISG/OS-Oss study are in the same range as those of the previous study, whereas the event-free survival is lower than that previously achieved. Since the only difference between the two studies was the cumulative dose of postoperatively given MTX, our data support the importance of the cumulative dose of MTX in the MAP regimen. PMID- 25688495 TI - A prospective randomised study of transvaginal ultrasound effects of tamoxifen and exemestane in postmenopausal women with early breast cancer. AB - AIM AND BACKGROUND: A reduction of gynaecological adverse events has been reported in trials comparing aromatase inhibitors with tamoxifen as adjuvant treatment in postmenopausal women with early breast cancer, but there is a paucity of randomised studies specifically investigating their effects on the uterus. We report here the results of a prospective phase III trial comparing the effects of tamoxifen and exemestane by transvaginal ultrasound (TVUS). PATIENTS AND METHODS: Postmenopausal patients with ER+ early breast cancer were randomised to receive tamoxifen 20 mg once daily or exemestane 25 mg once daily as adjuvant hormone therapy. TVUS was performed at baseline and at 6 and 12 months to measure endometrial thickness (ET) and uterine volume (UV). RESULTS: A total of 123 women were randomised to tamoxifen (n = 61) or exemestane (n = 62). A significantly higher proportion of patients in the tamoxifen group had increased ET at 6 and 12 months from randomisation compared with the exemestane group (66.1% and 64.3% versus 12.1% and 6.8%, respectively; P < 0.0001). Mean ET and UV also significantly increased with tamoxifen compared to exemestane at both time points (P < 0.01 for all comparisons). CONCLUSION: Tamoxifen is associated with endometrial thickening and increased uterine volume in a significant proportion of postmenopausal women with early breast cancer. Our study confirms the lack of endometrial effects of exemestane, which may be of interest to patients and clinicians when choosing among adjuvant endocrine options for breast cancer. PMID- 25688496 TI - Twenty years of radiobiology in clinical practice: the Italian contribution. AB - AIMS AND BACKGROUND: To present the Italian state-of-the-art contribution to radiobiology of external beam radiotherapy, brachytherapy, and radionuclide radiotherapy. METHODS AND STUDY DESIGN: A survey of the literature was carried out, using PubMed, by some independent researchers of the Italian group of radiobiology. Each paper was reviewed by researchers of centers not comprising its authors. The survey was limited to papers in English published over the last 20 years, written by Italian investigators or in Italian institutions, excluding review articles. RESULTS: A total of 135 papers have been published in journals with an impact factor, with an increase in the number of published papers over time, for external beam radiotherapy rather than radionuclide radiotherapy. The quantity and quality of the papers researched constitutes a proof of the enduring interest in clinical radiobiology among Italian investigators. CONCLUSIONS: The survey could be useful to individuate expert partners for an Italian network on clinical radiobiology, addressing future collaborative investigations. PMID- 25688497 TI - Impact of 11C-methionine positron emission tomography/computed tomography on radiation therapy planning and prognosis in patients with primary brain tumors. AB - AIMS AND BACKGROUND: There is limited evidence regarding the impact of 11C methionine positron emission tomography/computed tomography (MET-PET/CT) on radiation therapy planning of primary brain tumors. Our aim was to assess the effect of this imaging modality on treatment volumes and clinical outcome of patients eligible for radiation therapy in this oncologic setting. METHODS AND STUDY DESIGN: Between November 2009 and May 2012, 31 consecutive patients (male:female, 20:11; mean age, 53.0 years) with pathologically proven primary/relapsed glioma were treated with radiation therapy at the Humanitas Research Hospital. All patients were submitted to the same multi-imaging protocol including MET-PET/CT for biological target volume (PET) and contrast-enhanced magnetic resonance imaging/CT for gross tumor volume, in order to define the clinical target volume. Different volumes were compared and analyzed with respect to treatment planning modification after MET-PET/CT and impact on disease outcome. In 19/31 cases, patients were re-evaluated after completing radiotherapy, and in these cases, progression-free survival and overall survival were determined. The study was submitted to and data collection was approved by the local ethics committee. RESULTS: All patients completed the treatment. In 29 of 31 patients, a biological target volume was defined (mean volume, 18.3 cc), which in 20 cases (65%) resulted in a modification of the clinical target volume (mean, 65.9 cc; range, 8.5-165.6). In the other two cases, PET was negative and did not influence treatment planning. The mean percentage of added volume was 9.2%, ranging between -29% and 38%. With a mean follow-up of 5.4 months, treatment modification according to MET-PET/CT was the only predictor demonstrating a significant correlation with both progression-free survival ( P = 0.018) and overall survival (P = 0.003). None of the other factors evaluated in the analyses, including age, tumor histology, previous treatment, and tumor uptake, was correlated with the outcome. CONCLUSIONS: Despite the limited study population, our data indicate that MET-PET/CT can have a significant impact on radiation therapy planning in patients with primary brain tumors. Moreover, treatment modification according to PET appears to be a predictor of clinical outcome in this group of patients. PMID- 25688498 TI - Child-Pugh score maintenance in cirrhotic hepatocellular carcinoma patients after radiotherapy: aspects of gastroduodenal complications. AB - AIMS AND BACKGROUND: This study was designed to evaluate the prevalence of gastroduodenal complications and factors that contribute to the development of symptomatic GD toxicity in cirrhotic patients with perihilar hepatocellular carcinoma (HCC), after an acceptable dose of radiotherapy. METHODS: This was a retrospective study of 40 cirrhotic patients with perihilar HCC treated with radiotherapy from August 2008 to September 2010. Esophagogastroduodenoscopy was performed before and after radiotherapy. The maximum point dose to the gastroduodenum was 35.8 to 44 Gy (2 Gy equivalent, alpha/beta = 10). Gastroduodenal complications were graded using the Common Terminology Criteria for Adverse Events (CTCAE; version 3.0). Child-Pugh score was assessed 3 months after completion of radiotherapy, and compared with the score obtained before radiotherapy. RESULTS: Gastroduodenal complications were observed in 22 patients (55.0%) after radiotherapy. Twelve of these patients (30%) needed medical interventions. Although there were no significant factors that directly correlated with the prevalence of all-grade gastroduodenal complications, symptomatic complications (grade 2 or higher) were significantly related to the degree of Child-Pugh score elevation after radiotherapy (P = 0.002). CONCLUSIONS: Considerable gastroduodenal complications developed in cirrhotic patients with perihilar HCC after an acceptable dose of radiotherapy. The aspects of gastroduodenal toxicities and the maintenance of liver function after radiotherapy may be an important issue in patients who undergo this treatment. PMID- 25688499 TI - IMRT-SIB with concurrent and neo-adjuvant platinum-based chemotherapy for locally advanced head and neck squamous cell cancer: analysis of clinical outcomes in a retrospective series of a single institution. AB - AIMS AND BACKGROUND: To evaluate results of an intensity-modulated radiotherapy with simultaneous integrated boost schedule with concurrent and neo-adjuvant platinum-based chemotherapy for the definitive treatment of locally advanced head and neck cancer in a retrospective series. METHODS AND STUDY DESIGN: Between May 2007 and February 2010, 28 consecutive patients with locally advanced head and neck cancer (stage II, 11%; III, 18%; IV, 71%) received intensity-modulated radiotherapy with simultaneous integrated boost with concurrent and neoadjuvant (20/28 patients) chemotherapy, at 1.8 G/die to 54 Gy to the elective volume and 66 Gy (2.2 Gy/die) to the tumor volume. Acute and late toxicities were scored according to RTOG/EORTC. A quality of life questionnaire for late xerostomia was also administered. Locoregional control and overall survival were estimated using Kaplan-Meier analysis. RESULTS: Median follow-up was 50 months, there was no grade 4 acute/late toxicity. Major acute toxicities were grade 2+ mucositis, 79%; grade 2+ xerostomia, 54%; grade 2+ dysphagia, 86%; 54% of patients required parenteral nutrition. The most relevant late reaction was grade 1 xerostomia (64%), which gradually recovered with time. A linear correlation between the RTOG/EORTC scale and the quality of life questionnaire value (P = 0.0120, r2 = 0.2641) was found, receiver operating characteristic analysis (ROC) confirmed sensitivity of the quality of life questionnaire to define grade 2 late salivary toxicity (P = 0.019). Five-year actuarial locoregional control and overall survival were 81% +/- 7.7 SE and 82% +/- 7.3 SE, respectively. CONCLUSIONS: A prospective trial of the intensity-modulated radiotherapy with simultaneous integrated boost schedule tested in this retrospective series with concurrent and neoadjuvant chemotherapy seems warranted in order to establish this approach as a standard regimen of intensity-modulated radiotherapy with simultaneous integrated boost chemoradiation. PMID- 25688500 TI - Urinary modified nucleosides as novel biomarkers for diagnosis and prognostic monitoring of urothelial bladder cancer. AB - AIMS AND BACKGROUND: To ascertain the value of the detection of urinary modified nucleosides in the early diagnosis and prognostic monitoring of urothelial bladder cancer. METHODS: One hundred seventeen patients with urothelial bladder carcinoma and 66 healthy volunteers were included in the study. High-performance liquid chromatography/electrospray ionization quadrupole time-of-flight mass spectrometry (HPLC/ESI-Q-TOF-MS) was used to measure the levels of urinary modified nucleosides in the bladder cancer and control groups. Postoperative monitoring was done every 3 months in patients with noninvasive carcinoma; 85 patients attended the 1-year follow-up visit. RESULTS: The levels of m1A, ac4C, O6-MeG and 1-MeI were significantly higher in cases than controls (P < 0.05). The highest sensitivity (92.45%) and specificity (87.50%) were obtained when 1-MeI detection was combined with m1A detection. The m1A and 1-MeI levels 3 months after operation in both patient groups were significantly lower than the preoperative levels (P < 0.01). The no-recurrence group subsequently maintained low levels, but in the recurrence group the levels rose again almost to preoperative values. At 6, 9 and 12 months after operation, the m1A and 1-MeI levels of the recurrence group were higher than those of the no-recurrence group and the control group (P < 0.01). CONCLUSIONS: Urinary modified nucleosides might become novel tumor markers that will facilitate the clinical management and will be helpful in the diagnosis and follow-up of urothelial bladder cancer. m1A and 1 MeI appear to be most promising for clinical use and be worthy of further study in the near future. PMID- 25688501 TI - Overexpression of MTA1 and loss of KAI-1 and KiSS-1 expressions are associated with invasion, metastasis, and poor-prognosis of gallbladder adenocarcinoma. AB - AIMS AND BACKGROUND: Over 90% of patients with gallbladder cancer have invasion and/or metastasis when they are diagnosed at the clinic. Such patients usually have an extremely poor prognosis. The molecular mechanism responsible for the high prevalence of invasion and metastasis remains unknown. METHODS: We investigated the expression of two metastasis-suppression genes--KAI-1 and KiSS-1 -and a metastasis-associated gene--MTA1--in 108 adenocarcinomas, 15 gallbladder polyps, 35 chronic cholecystitis tissues, and 46 peritumoral tissues using in situ hybridization or immunohistochemistry. RESULTS: We demonstrated that positive MTA1 expression was significantly higher whereas positive expressions of KAI-1 and KiSS-1 genes were significantly lower in gallbladder adenocarcinoma than in peritumoral tissues, polyps, and chronic cholecystitis. Positive MTA1 expression was significantly lower, but positive KAI-1 and KiSS-1 expressions were significantly higher in cases with well-differentiated adenocarcinoma, smaller tumor mass, no metastasis of lymph node, and no invasion of regional tissues than in cases having poorly differentiated adenocarcinoma, larger tumor mass, metastasis and invasion. Univariate Kaplan-Meier analysis showed that increased expression of MTA1 and lowered expression of KAI-1 and KiSS-1 were significantly associated with decreased overall survival. Cox regression analysis showed that tumor mass, lymph node metastasis, invasion, and MTA1 expression levels negatively correlated with survival. CONCLUSIONS: Our study suggested that KAI-1, KiSS-1, and MTA1 might be important biological markers involved in the carcinogenesis, metastasis, and invasion of gallbladder adenocarcinoma, but MTA1 is an independent factor of prognosis. PMID- 25688502 TI - Evaluation of chemoradiotherapy with carbon ions and the influence of p53 mutational status in the colorectal carcinoma cell line HCT 116. AB - AIMS AND BACKGROUND: Heavy ion therapy has shown promising results in the treatment of recurrent colorectal carcinoma. The present study evaluates the effect of five different cytostatic agents in combination with radiotherapy with carbon (C12) ions and photons in two isogenic colorectal cancer cell lines differing in p53 status. METHODS AND STUDY DESIGN: Clonogenic survival analyses were performed using the human colon cancer cell lines HCT 116 wt and the isogenic p53 deficient cell line HCT 116 p53 -/-. Single photon doses (6 MV X rays) up to 10 Gy were applied using a linear accelerator. Carbon ion irradiation up to 3 Gy was performed at the Heidelberg Ion-Beam Therapy Center with the horizontal beamline delivering an extended Bragg peak with an average linear energy transfer of 103 keV/um. Five different cytostatic agents were applied in combinations with photon and carbon ion radiotherapy. RESULTS: Both cell lines showed a similar response to photons and carbon ions, whereas treatment with carbon ions resulted in a superior relative biological efficiency. Irinotecan and paclitaxel alone showed high toxicity in the treatment of wildtype cells. A notable difference was observed on the cell death of p53 -/- cell lines. Here, single treatment with paclitaxel and gemcitabine resulted in good response rates. Combinations of carbon ions with gemcitabine, irinotecan or paclitaxel revealed high response rates. After irradiation with carbon ions and temozolomide, cell survival rates depended on p53 status, with a decreased survival rate in wildtype cells. CONCLUSIONS: Irinotecan and paclitaxel are an effective treatment for HCT 116 wt cells, whereas HCT 116 cells with p53 deficiency can be treated successfully with paclitaxel and gemcitabine. Combined treatment modalities with carbon ions and chemotherapy provide great effectiveness that may offer new treatment opportunities for recurrent colorectal cancer in the future. PMID- 25688503 TI - The role of stereotactic ablative radiotherapy in oncological and non-oncological clinical settings: highlights from the 7th Meeting of AIRO--Young Members Working Group (AIRO Giovani). AB - Stereotactic ablative radiotherapy is a modern cancer treatment strategy able to deliver highly focused radiation in one or a few fractions with a radical intent in several clinical settings. Young radiation oncologists need a constant and tailored update in this context to improve patient care in daily clinical practice. A recent meeting of AIRO Giovani (AIRO--Young Members Working Group) was specifically addressed to this topic, presenting state-of-the-art knowledge, based on the latest evidence in this field. Highlights of the congress are summarized and presented in this report, including thorough contributions of the speakers dealing with the role of stereotactic ablative radiotherapy in both oncological and non-oncological diseases, divided according to anatomical and clinical scenarios: intra-cranial settings (brain malignant primary tumors, metastases, benign tumors and functional disorders) and extra-cranial indications (lung primary tumors and metastases, thoracic re-irradiation, liver, lymph node and bone metastases, prostate cancer). With literature data discussed during the congress as a background, stereotactic ablative radiotherapy has proved to be a consolidated treatment approach in specific oncological and non-oncological scenarios, as well as a promising option in other clinical settings, requiring a further prospective validation in the near future. We herein present an updated overview of stereotactic ablative radiotherapy use in the clinic. PMID- 25688504 TI - Extracellular chaperonin 10 augments apoptotic cell death induced by 5 fluorouracil in human colon cancer cells. AB - AIMS AND BACKGROUND: The molecular mechanisms involved in resistance to 5 fluorouracil (5-FU) in colon cancer patients remain to be elucidated. The purpose of this study was to identify proteins associated with 5-FU resistance in colon cancer. METHODS AND STUDY DESIGN: Proteins secreted from a 5-FU-resistant human colon cancer cell line (SNU-C4 5-FU 200) were analyzed by two-dimensional gel electrophoresis-based proteomics, and identified using matrix-associated laser desorption/ionization-mass spectroscopy analysis and SWISS-PROT database searches. The expression levels of candidate proteins were determined by Western blotting and cell proliferation was monitored by MTT assay. RESULTS: Chaperonin 10 (cpn10) was secreted at a lower level by 5-FU-resistant cells compared to the non-resistant parent cell line. The proliferation of both the parent and 5-FU resistant cell lines increased slightly when extracellular cpn10 alone was added. However, in the presence of 5-FU, cpn10 augmented 5-FU-induced apoptotic death in both cell lines. Cpn10 led to activation of extracellular signal-regulated kinase 1/2 (ERK 1/2), and a specific ERK 1/2 inhibitor, PD98059, completely inhibited cpn10-stimulated cell proliferation. CONCLUSIONS: Our findings indicate that concurrent treatment with cpn10 and 5-FU warrants further investigation in an effort to overcome 5-FU resistance and enhance the efficacy of 5-FU therapy for colon cancer. PMID- 25688505 TI - The PEDRO (Pocketable Electronic Devices in Radiation Oncology) project: how clinical practice is changing among young radiation oncologists. AB - PURPOSE: To evaluate the impact of mobile devices and apps on the daily clinical activity of young radiation oncologists. METHODS: A web-based questionnaire was sent to 382 young (<= 40 years) members of the Italian Association of Radiation Oncology (AIRO). The 14 items investigated the diffusion of mobile devices (smartphones and/or tablets), their impact on daily clinical activity, and possible differences perceived by the participants over time. RESULTS: A total of 158 questionnaires were available for statistical evaluation (response rate 41%). Up to 75% of respondents declared they used an electronic device during their clinical activity. Conversely, 82% considered the impact of smartphones/tables on daily practice low to moderate. Daily device use increased significantly from 2009 to 2012, with high daily use rates rising from 5% to 39.9%. Fulfillment of professional needs was declared by less than 42% of respondents and compliance with app indications by 32%. Almost all physicians desired in 2012 a comprehensive website concerning a variety of apps covering radiation oncologists' needs. CONCLUSIONS: Mobile devices are widely used by young Italian radiation oncologists in their daily clinical practice, while the indications so obtained are not always followed. Nevertheless, it would be important to verify the consistency of information found within apps, in order to avoid potential errors that might be detrimental to patients. PMID- 25688506 TI - Impact of a program for rapid diagnosis and treatment of lung cancer on hospital care delay and tumor stage. AB - AIMS AND BACKGROUND: Several countries have introduced programs for rapid diagnosis and treatment of cancer, but their impact on hospital care delay and tumor stage is not clear. We assessed the impact of a rapid diagnosis and treatment program (RDTP) for lung cancer on the diagnosis-to-treatment interval (DTI) and tumor stage. METHODS AND STUDY DESIGN: We performed a quasi experimental study in an intervention group of 191 patients with lung cancer attended through the RDTP circuit and a comparison group of 171 patients attended through the routine hospital circuit. Groups were matched for age and patterns of presentation. Multivariate analysis adjusting for different factors was performed. RESULTS: The median DTI was 36 days for the RDTP group and 45 days for the comparison group (P = 0.021). More patients in the RDTP group had advanced stage illness (III-IV) than in the comparison group (P = 0.032). In the multivariate analysis, none of these associations was statistically significant. Regardless of the type of circuit, a DTI <30 days was associated with disseminated disease (OR 3.28, P = 0.003). CONCLUSIONS: In this study, the RDTP circuit failed to reduce DTI and influence stage. Our results suggest tumor stage is the main determinant of both DTI and disease outcome. PMID- 25688507 TI - Evolution of surgery for Klatskin tumor demonstrates improved outcome: a single center analysis. AB - BACKGROUND AND OBJECTIVES: The rapid development of the Chinese economy has enabled advances to be made in the surgical treatment of Klatskin tumors. We retrospectively reviewed the surgical outcomes of hilar cholangiocarcinoma at a single Chinese center, focusing on the surgical procedures, radicality of the operative procedure (R0, R1 or R2), survival rates, and independent prognostic factors. This objective of the analysis was to evaluate improvements in perioperative and long-term outcomes of surgical resection of Klatskin tumors. METHODS: Between January 1998 and December 2007, 131 consecutive patients underwent operative resection for Klatskin tumor at Tianjin Medical University General Hospital, Tianjin, China. Clinicopathological data were analyzed to assess their impact on survival. RESULTS: The overall 3- and 5-year survival rates were 46% and 22%, respectively. Median overall survival for the entire cohort was 35 months. Survival increased progressively between 1998 and 2007. Preoperative biliary drainage represents a safe strategy before hepatectomy for hilar cholangiocarcinoma in patients with jaundice. Patients who underwent liver resection achieved significantly higher R0 rates than those undergoing biliary resection only. Preoperative total bilirubin level, lymph node metastasis and degree of radicality (R1 and 2 vs R0) were found to be independent factors that negatively affected overall survival. CONCLUSIONS: Surgical resection remains the mainstay of treatment for hilar cholangiocarcinoma. Development in surgical equipment, techniques, and perioperative management have increased long-term survival after curative liver resection, despite the more aggressive surgical procedures that are being performed. PMID- 25688508 TI - Hypoxia-inducible factor-1alpha G polymorphism and the risk of cancer: a meta analysis. AB - AIMS AND BACKGROUND: Hypoxia-inducible factor-1alpha (HIF-1alpha), a transcription factor, is associated with the initiation and progression of malignant tumors. HIF-1alpha G (A588T) polymorphism has been shown to lead to genetic susceptibility to malignant tumors but results have been controversial. METHODS AND STUDY DESIGN: We carried out a meta-analysis on 21 eligible case control studies with a total of 3892 cases and 6915 healthy controls to analyze the data with respect to the associations between HIF-1alpha G polymorphism and the risk of cancer. The overall odds ratio (OR) with a 95% confidence interval (CI) were used to assess the association. RESULTS: A statistically significant association between the HIF-1alpha GA/AA genotype and cancer risk was found in the meta-analysis (OR, 1.79; 95% CI, 1.12-2.86; P(heterogeneity) < 0.00001). In the subgroup analysis by ethnicity, significantly increased cancer risks were revealed among European and East Asian populations for the GA/AA genotype compared to the GG genotype (OR, 3.54; 95% CI, 1.34-9.30; P(heterogeneity) = 0.005; OR, 1.84; 95% CI, 1.06-3.17; P(heterogeneity) = 0.001, respectively). In the subgroup analysis by different tumor types, GA/AA genotype markedly increased the risk of oral cancer and digestive system cancers (OR, 3.15; 95% CI, 1.05 9.47; P(heterogeneity) = 0.004; OR, 2.20; 95% CI, 1.12-4.34; P(heterogeneity) = 0.002; respectively). Moreover, no publication bias was shown, which was assessed by Begg's funnel plots. CONCLUSIONS: Our findings revealed that GA/AA genotype might be related to increased risks of oral cancer and digestive system cancers. Moreover, HIF-1alpha G polymorphism might contribute to high susceptibility to malignant tumors, especially in European and East Asian populations. PMID- 25688509 TI - Correlation between deregulated expression of PER2 gene and degree of glioma malignancy. AB - AIMS AND BACKGROUND: Growing evidence indicates that disruption of circadian rhythms may be a risk factor for the development of glioma. However, the molecular mechanisms underlying the genetic regulation of circadian rhythms in glioma cells have yet to be explored. METHODS AND STUDY DESIGN: Using immunohistochemical staining and methylation-specific PCR techniques, we examined the expression of the period 2 (PER2) gene, one of the most important clock genes, epidermal growth factor receptor (EGFR), and proliferating cell nuclear antigen (PCNA) in 92 gliomas. RESULTS: Our results revealed disturbances in the expression of PER2 in most (52.17%) glioma cells compared with the expression in nearby noncancerous cells, and indicated that PER2 gene deregulation most likely occurs via methylation of PER2 promoters. The protein expression of PCNA and EGFR was significantly higher in high-grade than low-grade gliomas (P < 0.05). Furthermore, a negative correlation was detected between the protein expression of PER2 and PCNA and EGFR in glioma. CONCLUSIONS: Because the circadian clock regulates the expression of cell cycle-related genes, we suggest that disturbances in PER2 gene expression may disrupt the regulation of the circadian clock, thus enhancing the survival of cancer cells and promoting carcinogenesis. PMID- 25688510 TI - Dynamic expression changes between non-muscle-invasive bladder cancer and muscle invasive bladder cancer. AB - AIMS AND BACKGROUND: Despite elaborate characterization of the risk factors, bladder cancer is still a major epidemiological problem whose incidence continues to rise each year. We aim to investigate the dynamic expression changes between non-muscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC). METHODS: The gene expression profile GSE13507 was obtained from the Gene Expression Omnibus, and the R package was used to identify gene expression signatures (GESs) between NMIBC and MIBC. Gene ontology enrichment analysis was performed for GES function analysis. We used miRTarBase and TargetScan to identify the differentially regulated microRNAs, and TfactS to identify transcription factors between NMIBC and MIBC. Bionet was used to identify the differentially expressed subnetwork. RESULTS: A total of 802 upregulated NMIBC GESs and 668 downregulated MIBC GESs were identified. Functional enrichment analysis revealed that the MIBC GESs were majorly involved in cell cycle and inflammatory response. miR-29c and miR-9 were regarded as key microRNAs in MIBC. SMAD3 in MIBC and SMAD5 and SMAD7 in NMIBC were potential activated transcription factors. In addition, a subnetwork that was considered to capture the differences between MIBC and NMIBC was identified, of which GRB2 and UBC were the hub nodes. CONCLUSIONS: Some key microRNAs, activated transcription factors and hub nodes have been identified in this study, which may be used as potential biomarkers or targets for the diagnosis, treatment and detection of bladder cancer at different stages. PMID- 25688511 TI - Rationale and protocol of SOAP: a phase II study to evaluate the efficacy of sorafenib as second-line treatment after pazopanib in patients with advanced renal cell carcinoma. AB - The introduction of agents targeting vascular endothelial grow factors has radically changed the approach to metastatic renal cell carcinoma; however, cure is not within definitive reach. In many cases, the tumor will progress several months after the start of first-line therapy and new lines of therapy are required. Pazopanib and sorafenib are two frequently used targeted agents, and no sound data are currently available for patients who relapsed after pazopanib. In this paper we illustrate the SOAP study, which was designed to evaluate the safety and efficacy of sorafenib in terms of progression free-survival in 44 patients treated in 10 Italian centers who had relapsed after first-line pazopanib. Standard treatment with sorafenib will be administered until disease progression or unacceptable toxicity. Secondary endpoints include the evaluation of overall survival, safety and quality of life. A subanalysis to evaluate toxicities as predictive factors has also been planned. PMID- 25688512 TI - Rationale and protocol of the MetNET-1 trial, a prospective, single center, phase II study to evaluate the activity and safety of everolimus in combination with octreotide LAR and metformin in patients with advanced pancreatic neuroendocrine tumors. AB - Abnormal PI3K-AKT-mTOR pathway signalling and autocrine activation of the mTOR pathway, mediated through insulin-like growth factor-1, have been implicated in the proliferation of pancreatic neuroendocrine tumor (pNET) cells. Everolimus, an mTOR inhibitor, has shown antitumor benefit in pNETs alone and in combination with octreotide LAR in RADIANT-1 and RADIANT-3 studies. Although everolimus-based phase II/III trials have improved progression-free survival for pNET, its use has not impacted on prolonging overall survival. Metformin has recently shown some anti-cancer activity in both in vitro and in vivo studies by its indirect properties to decrease insulin and insulin-like growth factor-1 (IGF-1) levels and by its antitumour effect to promote AMPK activation and consequently inhibition to TSC1-2/mTOR complex. In light of even more retrospective evidence of metformin's anticancer activity, a prospective evaluation is required to either confirm or discard these preliminary findings. With the aim to evaluate the antiproliferative effect of metformin in combination with everolimus and octreotide LAR in pancreatic well-differentiated neuroendocrine tumor patients, a single arm, prospective, single center phase II study was designed (MetNET-1 trial, NCT 02294006). Forty-three patients are expected to be evaluated. The study is ongoing, and recruitment is estimated to be completed in August 2016. The results will be anticipated in 2017. PMID- 25688513 TI - The ORCHIDEE study: gathering new evidence on the use of everolimus in clinical practice. AB - Randomized clinical trials are the gold standard to test the efficacy of an intervention within a specified patient population. However, the results of the trials may not be generalizable to routine clinical practice. Observational cohort studies may provide information that complements trial results. Targeted therapies are characterized by tolerability profiles that may differ from those of 'traditional' chemotherapy. Therefore, the post-approval evaluation of these drugs by large, well-designed observational cohort studies in real life populations is warranted. Everolimus is an orally-administered inhibitor of the mammalian target of rapamycin. A number of observational cohort studies have been conducted to characterize the effectiveness and safety of everolimus in clinical practice. In particular, the ORCHIDEE study was designed to identify factors predictive of favorable outcome in patients treated with everolimus such as second-line treatment for metastatic renal cell carcinoma after failure of a first-line treatment with a VEGF TKI. ORCHIDEE is a multicenter, single-arm, phase IV study. The study will enroll approximately 200 metastatic renal cell carcinoma metastatic renal cell carcinoma patients from 20 Italian centers over a 24-month period. PMID- 25688514 TI - Targeted therapy in renal carcinoma: a case of long-term effect with complete control of toxicity. AB - Although advances in imaging techniques have allowed earlier diagnosis of renal cell carcinoma (RCC) in recent decades, one-third of patients who have undergone radical resection of organ-confined disease will eventually develop metastases. The treatment of metastatic RCC was revolutionized by the advent of targeted therapy with tyrosine kinase inhibitors. We have followed seven patients with metastatic RCC who were treated with first-line pazopanib at our center. The case of one of these patients is described here in detail. The patient was first diagnosed with RCC in 1999 and metastases were detected in 2006 and 2012. Treatment with pazopanib at the standard dose of 800 mg/day for 29 months led to a partial response that persisted over time. Side effects (hypertension and painful mucositis) were successfully managed with supportive care at our oral therapy clinic. Early management of adverse events using a multidisciplinary approach is paramount to the favorable outcome of treatment with pazopanib and other targeted agents. PMID- 25688515 TI - Cardiac metastasis from renal cell carcinoma successfully treated with pazopanib: impact of TKIs' antiangiogenic activity. AB - Cardiac metastasis from renal cell carcinoma, especially without neoplastic thrombosis of the vena cava, is extremely rare. The prognosis of patients with metastatic renal cell carcinoma has been radically influenced by the introduction of tyrosine kinase inhibitors, but very few reports in the literature have described their activity in heart metastasis. We report the case of a woman with a left ventricle metastasis from kidney cancer without renal vein involvement, who was treated with pazopanib. The patient achieved a prolonged partial response, with clear signs of metastasis devascularization and a favorable toxicity profile. PMID- 25688516 TI - Good tolerability, long-term survival and easy management of side effects in a patient with metastatic renal cell carcinoma treated with pazopanib. AB - In recent years many new agents have been introduced into clinical practice to treat metastatic renal cell carcinoma. Some of these agents are tyrosine kinase inhibitors, which have different adverse events compared to chemotherapy or immunotherapy. We describe the case of a man treated with pazopanib as first-line therapy for metastatic disease, demonstrating the efficacy, good tolerability and easy management of some side effects of this tyrosine kinase inhibitor. The patient, who presented with lung metastases, started therapy in November 2012 and was alive and in continuous response at the time of writing (November 2014). We controlled the elevation of transaminase levels with low-dose corticosteroid administration. The patient had no other significant adverse events (apart from dysgeusia and grade 1 diarrhea), he had good quality of life, and his performance status throughout the treatment was very good (ECOG 0). PMID- 25688517 TI - Long-term response to pazopanib in an elderly man with mRCC. A case report. AB - In recent years, the therapeutic scenario of metastatic renal cell carcinoma (mRCC) has been enriched by several new drugs that have revolutionized the natural history of this cancer. Pazopanib, an oral angiogenesis inhibitor, was recently approved for first-line and post-cytokine treatment of mRCC. The choice of the best first-line medical therapy is now the main clinical problem to be addressed. The decision-making is influenced by various factors: the results of pivotal trials including published face-to-face studies, the patient's medical history, and the safety profile of the drug. We present a case report of a long surviving elderly man with mRCC who did not undergo a cytoreductive nephrectomy and was treated with pazopanib. PMID- 25688518 TI - Chemotherapy-induced nausea and vomiting in Italian cancer centers: results of CINVDAY, a prospective, multicenter study. AB - PURPOSE: Guideline consistency in the prevention of chemotherapy-induced nausea and vomiting (CINV) remains low (29% in the Pan European Emesis Registry study) and very low (11%) in regimens with a high emetogenic risk. The aim of this study was to evaluate the guideline consistency of CINV prophylaxis for acute emesis in daily clinical practice in Italy. METHODS: This was a prospective, observational, multicenter study. Patients scheduled to receive antitumor treatment on a single prespecified day were included. Data on patient characteristics (demographic and clinical), type of anticancer therapy, and type of antiemetic therapy prescribed for acute emesis were collected on electronic data capture forms. Chemotherapy regimens and antiemetic prophylaxis were categorized according to the MASCC 2011 guidelines. The study was approved by the local ethics committees. RESULTS: From July 2013 to February 2014, a total of 502 patients were enrolled at 26 study sites. Median age was 62 years (range 27-87 years). Colorectal cancer and breast cancer were the most common malignancies. The emetogenic potential of the chemotherapy regimens used was high (HEC) (23.7%), moderate (MEC) (40.6%), low (31.3%) or minimal (4.4%). Overall, guideline consistency was 19.3%. Consistency reached 45% when the various 5HT3 receptor antagonists were considered equivalent and interchangeable in MEC regimens. Adherence to guidelines was lowest for MEC and Minimal risk groups. Ten percent of patients in HEC and MEC regimens did not receive any 5HT3 receptor antagonists. NK1 receptor antagonists were used in 8% of all regimens. CONCLUSIONS: Our study indicates that antiemetic guideline inconsistency remains an issue in daily clinical oncology practice in Italy. PMID- 25688519 TI - Synthesis and Biological Evaluation of Oxygen-containing Heterocyclic Ring-fused 23-Hydroxybetulinic Acid Derivatives as Antitumor Agents. AB - A collection of isoxazole and oxadiazole substituted 23-hydroxybetulinic acid (HBA) derivatives were designed, synthesized and evaluated for their antitumor activity. Most of the newly synthesized compounds exhibited more potent antiproliferative activity than patent compound 23-hydroxybetulinic acid, especially 13e and 14a were about four- to sevenfold more potent against all tested cancer cell lines than 23-hydroxybetulinic acid. Furthermore, the in vivo antitumor activity of 13e and 14a was validated in H22 liver cancer and B16 melanoma xenograft mouse models. The structure-activity relationships of these 23 hydroxybetulinic acid derivatives were also discussed based on the present investigation. PMID- 25688520 TI - Homeless and impaired: the burden of serious psychiatric illness. PMID- 25688521 TI - Electrochemistry of viologen dications in cholate media and competition between the cholate assemblies and the cucurbit[7]uril host. AB - The cathodic voltammetric behavior of N,N'-dimethyl-4,4'-bipyridinium (methylviologen, MV(2+)), N,N'-dipropyl-4,4'-bipyridinium (propylviologen, PV(2+)), N,N'-dibutyl-4,4'-bipyridinium (butylviologen, BV(2+)), and N-heptyl-N' ethyl-4,4'-bipyridinium (heptyl-ethylviologen, HEV(2+)) was investigated in aqueous solution containing variable concentrations of sodium cholate. In general, the presence of cholate was found to solubilize the more hydrophobic forms of the viologen probes. Among the three accessible viologen oxidation states (V(2+), V(+*), and V), the intermediate cation radical (V(+*)) was preferentially stabilized by the cholate aggregates regardless of the nature of the N-alkyl substituents. This stabilization leads to anodic shifts in the first half-wave potential (V(2+)/V(+*)) and cathodic shifts in the second half-wave potential (V(+*)/V) for viologen reduction. Both potential shifts were considerably more pronounced as the hydrophobic character of the viologen probe increased. The presence of the cucurbit[7]uril host in the solution leads to the formation of very stable inclusion complexes with the viologen probes, which tend to eliminate or substantially decrease the interactions between the viologens and the cholate micellar aggregates. PMID- 25688522 TI - Soil carbon, nitrogen and phosphorus changes under sugarcane expansion in Brazil. AB - Historical data of land use change (LUC) indicated that the sugarcane expansion has mainly displaced pasture areas in Central-Southern Brazil, globally the largest producer, and that those pastures were prior established over native forests in the Cerrado biome. We sampled 3 chronosequences of land use comprising native vegetation (NV), pasture (PA), and sugarcane crop (SC) in the sugarcane expansion region to assess the effects of LUC on soil carbon, nitrogen, and labile phosphorus pools. Thirty years after conversion of NV to PA, we found significant losses of original soil organic matter (SOM) from NV, while insufficient new organic matter was introduced from tropical grasses into soil to offset the losses, reflecting in a net C emission of 0.4 Mg ha(-1)yr(-1). These findings added to decreases in (15)N signal indicated that labile portions of SOM are preserved under PA. Afterwards, in the firsts five years after LUC from PA to SC, sparse variations were found in SOM levels. After more than 20 years of sugarcane crop, however, there were losses of 40 and 35% of C and N stocks, respectively, resulting in a rate of C emission of 1.3 Mg ha(-1)yr(-1) totally caused by the respiration of SOM from C4-cycle plants. In addition, conversion of pastures to sugarcane mostly increased (15)N signal, indicating an accumulation of more recalcitrant SOM under sugarcane. The microbe- and plant-available P showed site-specific responses to LUC as a function of different P-input managements, with the biological pool mostly accounting for more than 50% of the labile P in both anthropic land uses. With the projections of 6.4 Mha of land required by 2021 for sugarcane expansion in Brazil to achieve ethanol's demand, this explanatory approach to the responses of SOM to LUC will contribute for an accurate assessment of the CO2 balance of sugarcane ethanol. PMID- 25688523 TI - Reliability-oriented multi-objective optimal decision-making approach for uncertainty-based watershed load reduction. AB - Water quality management and load reduction are subject to inherent uncertainties in watershed systems and competing decision objectives. Therefore, optimal decision-making modeling in watershed load reduction is suffering due to the following challenges: (a) it is difficult to obtain absolutely "optimal" solutions, and (b) decision schemes may be vulnerable to failure. The probability that solutions are feasible under uncertainties is defined as reliability. A reliability-oriented multi-objective (ROMO) decision-making approach was proposed in this study for optimal decision making with stochastic parameters and multiple decision reliability objectives. Lake Dianchi, one of the three most eutrophic lakes in China, was examined as a case study for optimal watershed nutrient load reduction to restore lake water quality. This study aimed to maximize reliability levels from considerations of cost and load reductions. The Pareto solutions of the ROMO optimization model were generated with the multi-objective evolutionary algorithm, demonstrating schemes representing different biases towards reliability. The Pareto fronts of six maximum allowable emission (MAE) scenarios were obtained, which indicated that decisions may be unreliable under unpractical load reduction requirements. A decision scheme identification process was conducted using the back propagation neural network (BPNN) method to provide a shortcut for identifying schemes at specific reliability levels for decision makers. The model results indicated that the ROMO approach can offer decision makers great insights into reliability tradeoffs and can thus help them to avoid ineffective decisions. PMID- 25688524 TI - Chemistry of anthracene-acetylene oligomers XXV: on-surface chirality of a self assembled molecular network of a fan-blade-shaped anthracene-acetylene macrocycle with a long alkyl chain. AB - An anthracene cyclic dimer with two different linkers and a dodecyl group was synthesized by means of coupling reactions. The calculated structure had a planar macrocyclic pi core and a linear alkyl chain. Scanning tunneling microscopy observations at the 1-phenyloctane/graphite interface revealed that the molecules formed a self-assembled monolayer that consisted of linear striped bright and dark bands. In each domain, the molecular network consisted of either Re or Si molecules that differed in the two-dimensional chirality about the macrocyclic faces, which led to a unique conglomerate-type self-assembly. The molecular packing mode and the conformation of the alkyl chains are discussed in terms of the intermolecular interactions and the interactions between the molecules and the graphite surface with the aid of MM3 simulations of a model system. PMID- 25688525 TI - Intravascular magnetomotive optical coherence tomography of targeted early-stage atherosclerotic changes in ex vivo hyperlipidemic rabbit aortas. AB - We report the development of an intravascular magnetomotive optical coherence tomography (IV-MM-OCT) system used with targeted protein microspheres to detect early-stage atherosclerotic fatty streaks/plaques. Magnetic microspheres (MSs) were injected in vivo in rabbits, and after 30 minutes of in vivo circulation, excised ex vivo rabbit aorta samples specimens were then imaged ex vivo with our prototype IV-MM-OCT system. The alternating magnetic field gradient was provided by a unique pair of external custom-built electromagnetic coils that modulated the targeted magnetic MSs. The results showed a statistically significant MM-OCT signal from the aorta samples specimens injected with targeted MSs. PMID- 25688526 TI - Endoscopic endonasal anterior maxillotomy. PMID- 25688527 TI - [What does Process Management add in a Urology Department?]. AB - The search for quality starts with the identification of client's needs and expectations, as the essential foundation of any organization. In this search process, we identify improvement areas that enable specific actions that finish the closest to total client's and other interested agents' satisfaction (Workers, shareholders, suppliers, etc). This approach is equally valid in the health care environment. Development of a quality improvement plan based on process management is a resource of important value for the search of excellence in a clinical unit. Great part of this monographic issue is dedicated to show the experience recorded in a Urological unit. PMID- 25688528 TI - [Clinical Management: Basics and organization]. AB - OBJECTIVES: Many strategies have been proposed over the last years to ensure the Health Care System sustainability, mainly after the recent global economic crisis. One of the most attractive approaches is clinical management, which is a way of organizing health care units based on active participation of professionals who receive the transference of responsibilities dispoto achieve the objectives with the mission of ensuring a proper patient centered care, taking into consideration the rational use of resources (Efficiency) For the start up of Health Care structures based on clinical management, it is necessary a previous management culture within the departments involved and the center's executive board. Furthermore, to achieve the objectives proposed various tools must be used, such as evidence based medicine, clinical practice variability analysis, process management, in addition of quality and safety strategies. The units involved have to propose a management plan that will result in a management contract with the center's executive board. This agreement will establish some activity, expense and quality objectives that will be quantifiable through various indicators. Risk transference to the unit must include certain budget allocation and incentive decision capacity. Clinical management must not be employed as a savings tool from the part of macro and meso management. There is not a health care structure based on clinical management that have a general character for all health care organizations, existing a great variability in the adoption of various organizational formulas, so that every center must perform its own analysis and decide the most adequate model. In our country there are many clinical management experiences, although there is a long way to go. PMID- 25688529 TI - [Chairman of Clinical Departments planification, organizational and management portfolio]. AB - Portfolio methodology is widely applied to training, particularly in medical education and for medical trainees. Some Spanish Institutions (National University of Distance Learning and National School of Public Health) are using a seven dimension Portfolio in the field of Clinical Management, which could be used as conceptual framework and checklist for building up different documents for planning, programming and evaluating the new experiences of Clinical Units based on clinical management initiatives. This paper describe the Portfolio in short, takes into consideration its potential use, and concludes addressing the relevance of good governance and accountability for the medical professionalism. PMID- 25688530 TI - [Evaluation of the maturity of a Urology Department in terms of Quality. Management and Quality improvement operative objectives]. AB - OBJECTIVES: The objective of quality management is the identification of improvement areas to achieve total client and other involved agents satisfaction. In this paper we describe the start up of a Quality Improvement Plan (QIP) in a Urology Department. METHODS: We assessed the current maturity and performance of the Unit by means of self-evaluation with a questionnaire adapted to the 2009 ISO 9004 standard by all the professionals in the unit (Physicians and Nurses). All the items in the questionnaire are based in attributes and evaluation lines gathered in the five chapters of the Standard. The areas of improvement were identified and specific objectives were established and collected in the QIP with indicators for their measurement, responsible individuals, chronogram and results evaluation. After implementation of the quality improvement actions, a second self-evaluation was performed to start a new cycle. RESULTS: After the first evaluation we observed a high global performance (61%). Analyzed by sections, the highest level was achieved in the human resources management chapter (73%) and the lowest in quality management (30%) due to the absence of a process management approach. After identification of improvement areas, we defined projects and activities to be developed, in the process management context. The second evaluation, after the implementation of process management in the unit, showed an improvement in the maturity level of the Unit, reaching an 83%. CONCLUSIONS: The management of a clinical department cannot be limited to continuous improvisation. A process management approach is necessary, finishing with the usual defects of the generated product (variability, errors, omissions, waiting lists). Excellence in the quality of health care is an essential objective in every healthcare organization and standardization models, such as 2009 ISO 9004 standard, are the right way for that purpose. PMID- 25688531 TI - [Methodology for process documentation and stabilization]. AB - OBJECTIVES: The methodology for process management implantation consists of four phases with their corresponding stages: The first consists of mobilizing the organization and gaining support of the executive board of the center, as well as the people that will conform the working team. The second phase, once the processes have been identified and classified, is o document and implement them with their review performed. Once the process has been implanted, with time, there is a third phase that consists of its management control that ends with the evaluation. Once the processes are evaluated, both from the internal point of view and comparatively with other organizations with the same clinical mission, there are two possibilities: to put them in a gradual or sustained improvement or to a radical improvement if a lack of performance or quality is noticed. In this article we describe the first two phases of implantation that are fundamental for organizational processes documentation and stabilization. PMID- 25688532 TI - [Architecture and design of a processes map in a Urology Department]. AB - Every organization with the intention to be oriented to processes management must know it is a system and what are the factors that characterize it. Health care institutions are open and mixed systems. It is in this system where the chain of value of the productive process occurs, generating a very complex integrated management system, as the productive system main recipients are people with health needs. The process management approach in clinical centers, departments and units means that, once the processes have been identified, they have to be set depending on their mission, establishing a boxes and connections architecture known as process maps. Therefore, a map of processes is the graphical representation of the organizational management system, which may be deployed applying modeling techniques at various levels. In this article we will review the conceptual framework of the health care productive system and management with the focus on processes, incorporating didactic products based on experiences from various centers and health services. PMID- 25688533 TI - [Definition and stabilization of processes I. Management processes and support in a Urology Department]. AB - The implantation of total quality management models in clinical departments can better adapt to the 2009 ISO 9004 model. An essential part of implantation of these models is the establishment of processes and their stabilization. There are four types of processes: key, management, support and operative (clinical). Management processes have four parts: process stabilization form, process procedures form, medical activities cost estimation form and, process flow chart. In this paper we will detail the creation of an essential process in a surgical department, such as the process of management of the surgery waiting list. PMID- 25688534 TI - [Definition and stabilization of processes II. Clinical Processes in a Urology Department]. AB - New models in clinical management seek a clinical practice based on quality, efficacy and efficiency, avoiding variability and improvisation. In this paper we have developed one of the most frequent clinical processes in our speciality, the process based on DRG 311 or transurethral procedures without complications. Along it we will describe its components: Stabilization form, clinical trajectory, cost calculation, and finally the process flowchart. PMID- 25688535 TI - [High resolution for all in the clinics area of a Urology Department]. AB - OBJECTIVES: To evaluate the performance of a one-stop clinic in terms of proportion of diagnostic-therapeutic orientation during 2013. METHODS: All patients were referred from primary care facilities in the district of Fuenlabrada, Madrid, Spain (population 221.705). Previously, referral protocols were agreed. Seven senior urologists participated. 6674 referrals (January December 2013) were eligible. RESULTS: 4534 referrals (4535/6674, 68%) were eventually evaluable. Patients taking advantage of the one-stop format were significantly younger than those needing extra consultations (chi2<0,001). Overall, reasons for consultation clearly affected the feasibility of the one stop approach (chi2<0.001), the one-stop policy being substantiated in most consultations due to subfertility (89.4%), male sexual dysfunction (89.2%), testicular complains (88.3%) and other male genital complains (80.3%). On the contrary, extra consultations were the rule for degenerative diseases of the urinary tract (45%), malignancy (57%) and renal colic pain or urinary lithiasis (63.2%). No relationships could be identified between the referral centre and the feasibility of the one-stop approach (p=ns). The multivariate analysis confirmed the independent effect of the health problem (p<0.001) and patient age (p<0002) on the chances of having a successful one-stop approach. CONCLUSIONS: a one-stop philosophy should be the standard for all patients in urology clinics. PMID- 25688536 TI - [Adequacy of urology departments in a health care model of hospitals network]. AB - The traditional health care model is currently facing new health requirements. The implementation of integrated urologic health systems can be one of the possible solutions to these needs. It is mandatory to explore a new health care model, which includes structural and organizational changes. The adequacy of the urology departments of IDCsalud-Madrid network hospitals, creating URORed, is a new system adaptable to constant changes, in order to offer professionalism and quality health care. OBJECTIVE: To describe the administrative/clinic management in the urology service of a health care model of Hospitals network (URORed at IDCsalud. Madrid), that has been included in a model of an Integrated network in a health care service. METHODS: In the period between November 2007 to October 2014, the urology departments of IDCsalud Madrid Group, have been included in a new organizational system, including 4 hospitals, currently with 27 urologists. Each center offers specific urologic services, sharing benefits and human resources. The same directive line leads all centers. RESULTS: The model offers an integrated and uniform urologic service to a specific population of 811.390 habitants (Population Census 2012), with capability to treat specific urologic diseases and to perform a correct clinical follow-up. CONCLUSIONS: Belonging to a health care model in network involves a change of attitude. It creates an organizational change, based on the processes and the results, which enables control of the management analytically, detecting the points that need to be optimized as well as those that are satisfactory. It implies developing a culture of learning and cooperation, so that the processes are fluent and have quality, to create clinical and technological projects in favor of new resource-generating research, based on the needs of the joint management of the hospitals network. The complexity of this model requires a work focused on the human resources, their concerns and their ability to coordinate actions to get results in terms of quality health care and professionalism. PMID- 25688537 TI - [Inverse innovation models in the nurse clinic of a Urology Department]. AB - OBJECTIVES: In the urology clinics there is an important volume of limited complexity pathology that consumes an important part of resources. Delegating some tasks of this type to Nurses may imply a competitive advantage in economic terms without decrease in the quality of the care given to patients and their level of satisfaction. This is an example of the concept of inverse innovation. In this work we try to make public our experience in the management by nursing staff of features of the urology consultation traditionally reserved to physicians, as well as the design of the related processes. METHODS: We developed the most frequent processes competence of the nursing staff in the unit: 1) Care of ambulatory urological surgery pathology; 2) Urologic ultrasound; 3) Traditional urologic nurse consultation. RESULTS: During 2013 the nursing staff performed 423 ambulatory urologic surgery pathology clinic visits, 931 urologic ultrasounds and 1019 varied actions corresponding to traditional urological nurse work.We developed stabilization formularies and flow diagrams of the aforementioned processes. We performed a quantification of the amount of money saved in comparison with the costs generated if a nurse or a physician was employed. Such saving was 2,78 and 4,00 Euros in the ambulatory urological surgery pathology and urologic ultrasound, respectively. Total savings in both processes was 4900 Euros. CONCLUSIONS: Implication of urological nursing staff in certain care tasks traditionally reserved to the physician is possible without increase in quality defects, obtaining an advantage in terms of economic cost and flexibility in staff organization thanks to the expansion of the competence array. PMID- 25688538 TI - Structure, function, self-assembly, and applications of bottlebrush copolymers. AB - Bottlebrush polymers are a type of branched or graft polymer with polymeric side chains attached to a linear backbone, and the unusual architectures of bottlebrushes provide a number of unique and potentially useful properties. These include a high entanglement molecular weight, enabling rapid self-assembly of bottlebrush block copolymers into large domain structures, the self-assembly of bottlebrush block copolymer micelles in a selective solvent even at very low dilutions, and the functionalization of bottlebrush side-chains for recognition, imaging, or drug delivery in aqueous environments. This review article focuses on recent developments in the field of bottlebrush polymers with an emphasis on applications of bottlebrush copolymers. Bottlebrush copolymers contain two (or more) different types of polymeric side-chains. Recent work has explored the diverse properties and functions of bottlebrush polymers and copolymers in solutions, films, and melts, and applications explored include photonic materials, bottlebrush films for lithographic patterning, drug delivery, and tumor detection and imaging. We provide a brief introduction to bottlebrush synthesis and physical properties and then discuss work related to: (i) bottlebrush self-assembly in melts and bulk thin films, (ii) bottlebrushes for photonics and lithography, (iii) bottlebrushes for small molecule encapsulation and delivery in solution, and (iv) bottlebrush micelles and assemblies in solution. We briefly discuss three potential areas for future research, including developing a more quantitative model of bottlebrush self-assembly in the bulk, studying the properties of bottlebrushes at interfaces, and investigating the solution assembly of bottlebrush copolymers. PMID- 25688540 TI - A simple flow cytometry-based barcode for routine authentication of multiple myeloma and mantle cell lymphoma cell lines. PMID- 25688539 TI - Spatio-temporal dynamics of adaptation in the human visual system: a high-density electrical mapping study. AB - When sensory inputs are presented serially, response amplitudes to stimulus repetitions generally decrease as a function of presentation rate, diminishing rapidly as inter-stimulus intervals (ISIs) fall below 1 s. This 'adaptation' is believed to represent mechanisms by which sensory systems reduce responsivity to consistent environmental inputs, freeing resources to respond to potentially more relevant inputs. While auditory adaptation functions have been relatively well characterized, considerably less is known about visual adaptation in humans. Here, high-density visual-evoked potentials (VEPs) were recorded while two paradigms were used to interrogate visual adaptation. The first presented stimulus pairs with varying ISIs, comparing VEP amplitude to the second stimulus with that of the first (paired-presentation). The second involved blocks of stimulation (N = 100) at various ISIs and comparison of VEP amplitude between blocks of differing ISIs (block-presentation). Robust VEP modulations were evident as a function of presentation rate in the block-paradigm, with strongest modulations in the 130-150 ms and 160-180 ms visual processing phases. In paired presentations, with ISIs of just 200-300 ms, an enhancement of VEP was evident when comparing S2 with S1, with no significant effect of presentation rate. Importantly, in block-presentations, adaptation effects were statistically robust at the individual participant level. These data suggest that a more taxing block presentation paradigm is better suited to engage visual adaptation mechanisms than a paired-presentation design. The increased sensitivity of the visual processing metric obtained in the block-paradigm has implications for the examination of visual processing deficits in clinical populations. PMID- 25688541 TI - Gentamicin differentially alters cellular metabolism of cochlear hair cells as revealed by NAD(P)H fluorescence lifetime imaging. AB - Aminoglycoside antibiotics are implicated as culprits of hearing loss in more than 120,000 individuals annually. Research has shown that the sensory cells, but not supporting cells, of the cochlea are readily damaged and/or lost after use of such antibiotics. High-frequency outer hair cells (OHCs) show a greater sensitivity to antibiotics than high- and low-frequency inner hair cells (IHCs). We hypothesize that variations in mitochondrial metabolism account for differences in susceptibility. Fluorescence lifetime microscopy was used to quantify changes in NAD(P)H in sensory and supporting cells from explanted murine cochleae exposed to mitochondrial uncouplers, inhibitors, and an ototoxic antibiotic, gentamicin (GM). Changes in metabolic state resulted in a redistribution of NAD(P)H between subcellular fluorescence lifetime pools. Supporting cells had a significantly longer lifetime than sensory cells. Pretreatment with GM increased NAD(P)H intensity in high-frequency sensory cells, as well as the NAD(P)H lifetime within IHCs. GM specifically increased NAD(P)H concentration in high-frequency OHCs, but not in IHCs or pillar cells. Variations in NAD(P)H intensity in response to mitochondrial toxins and GM were greatest in high-frequency OHCs. These results demonstrate that GM rapidly alters mitochondrial metabolism, differentially modulates cell metabolism, and provides evidence that GM-induced changes in metabolism are significant and greatest in high-frequency OHCs. PMID- 25688542 TI - Noninvasive glucose sensing by transcutaneous Raman spectroscopy. AB - We present the development of a transcutaneous Raman spectroscopy system and analysis algorithm for noninvasive glucose sensing. The instrument and algorithm were tested in a preclinical study in which a dog model was used. To achieve a robust glucose test system, the blood levels were clamped for periods of up to 45 min. Glucose clamping and rise/fall patterns have been achieved by injecting glucose and insulin into the ear veins of the dog. Venous blood samples were drawn every 5 min and a plasma glucose concentration was obtained and used to maintain the clamps, to build the calibration model, and to evaluate the performance of the system. We evaluated the utility of the simultaneously acquired Raman spectra to be used to determine the plasma glucose values during the 8-h experiment. We obtained prediction errors in the range of ~1.5-2 mM. These were in-line with a best-case theoretical estimate considering the limitations of the signal-to-noise ratio estimates. As expected, the transition regions of the clamp study produced larger predictive errors than the stable regions. This is related to the divergence of the interstitial fluid (ISF) and plasma glucose values during those periods. Two key contributors to error beside the ISF/plasma difference were photobleaching and detector drift. The study demonstrated the potential of Raman spectroscopy in noninvasive applications and provides areas where the technology can be improved in future studies. PMID- 25688543 TI - Selective ruthenium labeling of the tryptophan residue in the bee venom Peptide melittin. AB - Melittin is a membrane-active peptide from bee venom with promising antimicrobial and anticancer activity. Herein we report on a simple and selective method for labeling of the tryptophan residue in melittin by the organometallic fragment [(C5 H5 )Ru](+) in aqueous solution and in air. Ruthenium coordination does not disturb the secondary structure of the peptide (as verified by 2D NMR spectroscopy), but changes the pattern of its intermolecular interactions resulting in an 11-fold decrease of hemolytic activity. The high stability of the organometallic conjugate allowed the establishment of the biodistribution of the labeled melittin in mice by inductively coupled plasma MS analysis of ruthenium. PMID- 25688544 TI - "Why can't I pass these exams?": providing individualized feedback for nursing students. AB - The nursing literature on examination remediation and testing feedback strategies focuses primarily on NCLEX-RN success and remediation, rather than on the course examinations taken by students throughout program curricula. Students deemed at risk for NCLEX-RN failure likely have displayed poor performance on examinations long before graduation and licensure testing. Individualized examination feedback that identifies students' specific weaknesses is superior to correct answer feedback. The feedback grid described in this article demonstrates one method of providing structured, individualized feedback using the nursing process, Bloom's taxonomy, and NCLEX-RN blueprints. The feedback grid helped students to identify patterns in knowledge gaps, determine the correct answers to missed examination questions, and improve test scores in a critical care nursing course. PMID- 25688545 TI - Total syntheses and biological evaluation of miuraenamides. AB - The miuraenamides, relatively simple representatives of a class of cyclodepsipeptides with high antitumor activity, can be easily and flexibly obtained by the concept of peptide modification. A reaction sequence consisting of an aldol reaction, oxidation, and methylation of the glycine subunit of the cyclodepsipeptides allows the incorporation of the unusual alpha,beta-unsaturated dehydroamino acid in one of the last steps of the synthesis. PMID- 25688546 TI - B-1 cells produce insulin and abrogate experimental streptozotocin-induced diabetes. AB - The participation of B-1 cells in a murine model of spontaneous diabetes has been recently reported. Here, we describe the role of B-1 cells in streptozotocin (STZ) induced diabetes in mice. We demonstrated that XID (B-1 cell-deficient) mice are more susceptible to STZ treatment than WT mice, as evidenced by their higher blood glucose level in response to STZ. Unexpectedly, the XID mice that were i.p. transferred with purified B-1 cells, either before or after the STZ treatment, did not develop diabetes. These cell transfers provided long-lasting protection for the XID mice against STZ-induced diabetes, suggesting that B-1 cells play an important role in the experimental diabetes pathobiology. We also showed that B-1 cell culture supernatants were able to regulate the blood glucose level of the diabetic XID mice, and we identified insulin-producing cells when B 1 cells were differentiated in B-1 cell-derived phagocyte in vitro. These findings provide a novel role for B-1 cells in metabolic processes, presenting a new mechanism to explain the pathogenesis of diabetes and a possible therapeutical target. PMID- 25688547 TI - Puromycin- and methotrexate-resistance cassettes and optimized Cre-recombinase expression plasmids for use in yeast. AB - Here we expand the set of tools for genetically manipulating Saccharomyces cerevisiae. We show that puromycin-resistance can be achieved in yeast through expression of a bacterial puromycin-resistance gene optimized to the yeast codon bias, which in turn serves as an easy-to-use dominant genetic marker suitable for gene disruption. We have constructed a similar DNA cassette expressing yeast codon-optimized mutant human dihydrofolate reductase (DHFR), which confers resistance to methotrexate and can also be used as a dominant selectable marker. Both of these drug-resistant marker cassettes are flanked by loxP sites, allowing for their excision from the genome following expression of Cre-recombinase. Finally, we have created a series of plasmids for low-level constitutive expression of Cre-recombinase in yeast that allows for efficient excision of loxP flanked markers. PMID- 25688548 TI - Ring-opening polymerization of cyclohexene oxide using aluminum amine-phenolate complexes. AB - Remarkably active (down to 0.001% Al) catalysts for ring-opening polymerization of cyclohexene oxide under neat reaction conditions are reported. High molecular weight polymers with uniform dispersity are produced. Kinetic data from NMR studies and MALDI-TOF MS data of the polymers provide some mechanistic insight. PMID- 25688549 TI - Interfaces in perovskite solar cells. AB - The interfacial atomic and electronic structures, charge transfer processes, and interface engineering in perovskite solar cells are discussed in this review. An effective heterojunction is found to exist at the window/perovskite absorber interface, contributing to the relatively fast extraction of free electrons. Moreover, the high photovoltage in this cell can be attributed to slow interfacial charge recombination due to the outstanding material and interfacial electronic properties. However, some fundamental questions including the interfacial atomic and electronic structures and the interface stability need to be further clarified. Designing and engineering the interfaces are also important for the next-stage development of this cell. PMID- 25688550 TI - N-Glycosylation with synthetic undecaprenyl pyrophosphate-linked oligosaccharide to oligopeptides by PglB oligosaccharyltransferase from Campylobacter jejuni. AB - The oligosaccharyltransferase PglB from Campylobacter jejuni catalyses the N glycosylation reaction with undecaprenyl-pyrophosphate-linked Glc1 GalNAc5 Bac1 (Und-PP-Glc1 GalNAc5 Bac1 ). Experiments using chemically synthesized donors coupled to fluorescently tagged peptides confirmed that biosynthetic intermediate Und-PP-Bac1 and Und-PP-GalNAc2 Bac1 are transferred efficiently to the Asn residue in the consensus sequence (D/E-X'-N-X-T/S, X',X?P). The products were analyzed in detail by tandem MS to confirm their chemical structures. PMID- 25688552 TI - A new extrinsic sample mean in the shape space with applications to the boundaries of anatomical structures. AB - Shape analysis is of great importance in many fields of medical imaging and computational biology. In this paper, we consider the shape space as the set of smooth planar immersed curves in R(2) (parameterized curves) and, using the property of being isometric to a classical manifold immersed in a Euclidean space, we introduce a new extrinsic sample mean and a new extrinsic variance for a finite set of shapes, which are not necessarily star shaped. This is a fundamental tool in medical image analysis, for instance, to assess uncertainties that arise in locating anatomical structures such as the prostate and the bladder. We apply it to a dataset consisting of parallel planar axial CT sections of human prostate, in order to study the variability between boundaries that have been manually delineated by several observers. PMID- 25688551 TI - Vesicular stomatitis virus enables gene transfer and transsynaptic tracing in a wide range of organisms. AB - Current limitations in technology have prevented an extensive analysis of the connections among neurons, particularly within nonmammalian organisms. We developed a transsynaptic viral tracer originally for use in mice, and then tested its utility in a broader range of organisms. By engineering the vesicular stomatitis virus (VSV) to encode a fluorophore and either the rabies virus glycoprotein (RABV-G) or its own glycoprotein (VSV-G), we created viruses that can transsynaptically label neuronal circuits in either the retrograde or anterograde direction, respectively. The vectors were investigated for their utility as polysynaptic tracers of chicken and zebrafish visual pathways. They showed patterns of connectivity consistent with previously characterized visual system connections, and revealed several potentially novel connections. Further, these vectors were shown to infect neurons in several other vertebrates, including Old and New World monkeys, seahorses, axolotls, and Xenopus. They were also shown to infect two invertebrates, Drosophila melanogaster, and the box jellyfish, Tripedalia cystophora, a species previously intractable for gene transfer, although no clear evidence of transsynaptic spread was observed in these species. These vectors provide a starting point for transsynaptic tracing in most vertebrates, and are also excellent candidates for gene transfer in organisms that have been refractory to other methods. PMID- 25688553 TI - Laboratory and field evaluation of the Partec CyFlow miniPOC for absolute and relative CD4 T-cell enumeration. AB - BACKGROUND: A new CD4 point-of-care instrument, the CyFlow miniPOC, which provides absolute and percentage CD4 T-cells, used for screening and monitoring of HIV-infected patients in resource-limited settings, was introduced recently. We assessed the performance of this novel instrument in a reference laboratory and in a field setting in Senegal. METHODOLOGY: A total of 321 blood samples were obtained from 297 adults and 24 children, all HIV-patients attending university hospitals in Dakar, or health centers in Ziguinchor. Samples were analyzed in parallel on CyFlow miniPOC, FACSCount CD4 and FACSCalibur to assess CyFlow miniPOC precision and accuracy. RESULTS: At the reference lab, CyFlow miniPOC, compared to FACSCalibur, showed an absolute mean bias of -12.6 cells/mm3 and a corresponding relative mean bias of -2.3% for absolute CD4 counts. For CD4 percentages, the absolute mean bias was -0.1%. Compared to FACSCount CD4, the absolute and relative mean biases were -31.2 cells/mm3 and -4.7%, respectively, for CD4 counts, whereas the absolute mean bias for CD4 percentages was 1.3%. The CyFlow miniPOC was able to classify HIV-patients eligible for ART with a sensitivity of >= 95% at the different ART-initiation thresholds (200, 350 and 500 CD4 cells/mm3). In the field lab, the room temperature ranged from 30 to 35 degrees C during the working hours. At those temperatures, the CyFlow miniPOC, compared to FACSCount CD4, had an absolute and relative mean bias of 7.6 cells/mm3 and 2.8%, respectively, for absolute CD4 counts, and an absolute mean bias of 0.4% for CD4 percentages. The CyFlow miniPOC showed sensitivity equal or greater than 94%. CONCLUSION: The CyFlow miniPOC showed high agreement with FACSCalibur and FACSCount CD4. The CyFlow miniPOC provides both reliable absolute CD4 counts and CD4 percentages even under the field conditions, and is suitable for monitoring HIV-infected patients in resource-limited settings. PMID- 25688554 TI - MR angiography follow-up 10 years after cryptogenic nonperimesencephalic subarachnoid hemorrhage. AB - OBJECTIVES: Long-term magnetic resonance angiography (MRA) follow-up studies regarding cryptogenic nonperimesencephalic subarachnoid hemorrhage (nSAH) are scarce. This single-centre study identified all patients with angiographically verified cryptogenic nSAH from 1998 to 2007: The two main objectives were to prospectively assess the incidence of de novo aneurysm with 3.0-MRI years after cryptogenic nSAH in patients without evidence for further hemorrhage, and retrospectively assess patient demographics and outcome. METHODS: From prospectively maintained report databases all patients with angiographically verified cryptogenic nSAH were identified. 21 of 29 patients received high resolution 3T-MRI including time-of-flight and contrast-enhanced angiography, 10.2 +/- 2.8 years after cryptogenic nSAH. MRA follow-up imaging was compared with initial digital subtraction angiography (DSA) and CT/MRA. Post-hemorrhage images were related to current MRI with reference to persistent lesions resulting from delayed cerebral ischemia (DCI) and post-hemorrhagic siderosis. Patient based objectives were retrospectively abstracted from clinical databases. RESULTS: 29 patients were identified with cryptogenic nSAH, 17 (59%) were male. Mean age at time of hemorrhage was 52.9 +/- 14.4 years (range 4 - 74 years). 21 persons were available for long-term follow-up. In these, there were 213.5 person years of MRI-follow-up. No de novo aneurysm was detected. Mean modified Rankin Scale (mRS) during discharge was 1.28. Post-hemorrhage radiographic vasospasm was found in three patients (10.3%); DCI-related lesions occurred in one patient (3.4%). Five patients (17.2%) needed temporary external ventricular drainage; long-term CSF shunt dependency was necessary only in one patient (3.4%). Initial DSA retrospectively showed a 2 x 2 mm aneurysm of the right distal ICA in one patient, which remained stable. Post-hemorrhage siderosis was detected 8.1 years after the initial bleeding in one patient (4.8%). CONCLUSION: Patients with cryptogenic nSAH have favourable outcomes and do not exhibit higher risks for de novo aneurysms. Therefore the need for long-term follow up after cryptogenic nSAH is questionable. PMID- 25688556 TI - Urban-rural disparity of breast cancer and socioeconomic risk factors in China. AB - Breast cancer is one of the most commonly diagnosed cancers worldwide. The primary aim of this work is the study of breast cancer disparity among Chinese women in urban vs. rural regions and its associations with socioeconomic factors. Data on breast cancer incidence were obtained from the Chinese cancer registry annual report (2005-2009). The ten socioeconomic factors considered in this study were obtained from the national population 2000 census and the Chinese city/county statistical yearbooks. Student's T test was used to assess disparities of female breast cancer and socioeconomic factors in urban vs. rural regions. Pearson correlation and ordinary least squares (OLS) models were employed to analyze the relationships between socioeconomic factors and cancer incidence. It was found that the breast cancer incidence was significantly higher in urban than in rural regions. Moreover, in urban regions, breast cancer incidence remained relatively stable, whereas in rural regions it displayed an annual percentage change (APC) of 8.55. Among the various socioeconomic factors considered, breast cancer incidence exhibited higher positive correlations with population density, percentage of non-agriculture population, and second industry output. On the other hand, the incidence was negatively correlated with the percentage of population employed in primary industry. Overall, it was observed that higher socioeconomic status would lead to a higher breast cancer incidence in China. When studying breast cancer etiology, special attention should be paid to environmental pollutants, especially endocrine disruptors produced during industrial activities. Lastly, the present work's findings strongly recommend giving high priority to the development of a systematic nationwide breast cancer screening program for women in China; with sufficient participation, mammography screening can considerably reduce mortality among women. PMID- 25688555 TI - Directed evolution of a yeast-displayed HIV-1 SOSIP gp140 spike protein toward improved expression and affinity for conformational antibodies. AB - Design of an envelope-based immunogen capable of inducing a broadly neutralizing antibody response is thought to be key to the development of a protective HIV-1 vaccine. However, the broad diversity of viral variants and a limited ability to produce native envelope have hampered such design efforts. Here we describe adaptation of the yeast display system and use of a combinatorial protein engineering approach to permit directed evolution of HIV envelope variants. Because the intrinsic instability and complexity of this trimeric glycoprotein has greatly impeded the development of immunogens that properly represent the structure of native envelope, this platform addresses an essential need for methodologies with the capacity to rapidly engineer HIV spike proteins towards improved homogeneity, stability, and presentation of neutralizing epitopes. We report for the first time the display of a designed SOSIP gp140 on yeast, and the in vitro evolution of derivatives with greatly improved expression and binding to conformation-dependent antibodies. These efforts represent an initial and critical step toward the ability to rapidly engineer HIV-1 envelope immunogens via directed evolution. PMID- 25688557 TI - Correction: correction: paraphyly of the subgenus Sintonius (Diptera, Psychodidae, Sergentomyia): status of the malagasy species. Creation of a new subgenus and description of a new species. PMID- 25688558 TI - The dynamic distribution of porcine microbiota across different ages and gastrointestinal tract segments. AB - Metagenome of gut microbes has been implicated in metabolism, immunity, and health maintenance of its host. However, in most of previous studies, the microbiota was sampled from feces instead of gastrointestinal (GI) tract. In this study, we compared the microbial populations from feces at four different developmental stages and contents of four intestinal segments at maturity to examine the dynamic shift of microbiota in pigs and investigated whether adult porcine fecal samples could be used to represent samples of the GI tract. Analysis results revealed that the ratio of Firmicutes to Bacteroidetes from the feces of the older pigs (2-, 3-, 6- month) were 10 times higher compared to those from piglets (1-month). As the pigs matured, so did it seem that the composition of microbiome became more stable in feces. In adult pigs, there were significant differences in microbial profiles between the contents of the small intestine and large intestine. The dominant genera in the small intestine belonged to aerobe or facultative anaerobe categories, whereas the main genera in the large intestine were all anaerobes. Compared to the GI tract, the composition of microbiome was quite different in feces. The microbial profile in large intestine was more similar to feces than those in the small intestine, with the similarity of 0.75 and 0.38 on average, respectively. Microbial functions, predicted by metagenome profiles, showed the enrichment associated with metabolism pathway and metabolic disease in large intestine and feces while higher abundance of infectious disease, immune function disease, and cancer in small intestine. Fecal microbes also showed enriched function in metabolic pathways compared to microbes from pooled gut contents. Our study extended the understanding of dynamic shift of gut microbes during pig growth and also characterized the profiles of bacterial communities across GI tracts of mature pigs. PMID- 25688559 TI - CD8 T cell response maturation defined by anentropic specificity and repertoire depth correlates with SIVDeltanef-induced protection. AB - The live attenuated simian immunodeficiency virus (LASIV) vaccine SIVDeltanef is one of the most effective vaccines in inducing protection against wild-type lentiviral challenge, yet little is known about the mechanisms underlying its remarkable protective efficacy. Here, we exploit deep sequencing technology and comprehensive CD8 T cell epitope mapping to deconstruct the CD8 T cell response, to identify the regions of immune pressure and viral escape, and to delineate the effect of epitope escape on the evolution of the CD8 T cell response in SIVDeltanef-vaccinated animals. We demonstrate that the initial CD8 T cell response in the acute phase of SIVDeltanef infection is mounted predominantly against more variable epitopes, followed by widespread sequence evolution and viral escape. Furthermore, we show that epitope escape expands the CD8 T cell repertoire that targets highly conserved epitopes, defined as anentropic specificity, and generates de novo responses to the escaped epitope variants during the vaccination period. These results correlate SIVDeltanef-induced protection with expanded anentropic specificity and increased response depth. Importantly, these findings render SIVDeltanef, long the gold standard in HIV/SIV vaccine research, as a proof-of-concept vaccine that highlights the significance of the twin principles of anentropic specificity and repertoire depth in successful vaccine design. PMID- 25688560 TI - Grazing and metabolism of Euphausia pacifica in the Yellow Sea. AB - Grazing and metabolism of Euphausia pacifica in the Yellow Sea were studied from September 2006 to August 2007. Euphausia pacifica is a selective-feeding omnivore and grazing rates among different months were monitored using a Coulter Counter and batch culture feeding experiments. Euphausia pacifica mainly grazed microzooplankton in August and September, which resulted in an increase in chlorophyll a concentration. Oxygen consumption rate of E. pacifica was 38.7-42.5 MUmol O2 g(-1) DW h(-1) in March, which was four times higher than the oxygen consumption rates in September and December. The vigorous metabolism of E. pacifica in March consumed 3.1% of body carbon daily, which is likely related to its high reproduction and grazing rate. Respiration and metabolism of E. pacifica in September and December were similar and were lower. O:N ratio of E. pacifica was the highest (17.3-23.8) in March when spawning activity occurred and when food was abundant. The energetic source of E. pacifica during September and December was mostly protein from eating a carnivorous diet, including such items as microzooplankton. Euphausia pacifica was found in cold water at the bottom of the Yellow Sea in summer and autumn and maintained a low consumption status. O:N ratios of E. pacifica in March, September, and December were negatively correlated with SSTs and no significant correlation was found between O:N ratios and chlorophyll a concentration. Seawater temperature is clearly the most important parameter influencing the metabolism of E. pacifica. PMID- 25688561 TI - Item order effects in the evaluation of posttraumatic stress disorder symptom structure. AB - Factor analytic research has demonstrated consistently that the 3-factor DSM-IV model of posttraumatic stress disorder (PTSD) symptom structure provides a poorer fit than alternative 4- and 5-factor models. In the current study we examined whether order of item presentation accounts for these findings. In a large sample (N = 1,311) of trauma-exposed undergraduates we conducted a series of confirmatory factor analyses using the PTSD Checklist and Posttraumatic Stress Diagnostic Scale, which present symptom items in the same order as DSM-IV, and the Detailed Assessment of Posttraumatic Stress, which presents items in a different order. Across all 3 measures the 3-factor DSM-IV model provided a relatively worse fit and the 5-factor dysphoric arousal model provided a relatively better fit compared with other tested models. We also examined the distinctiveness of 2 pairs of symptom clusters that appear in the dysphoric arousal model--avoidance versus numbing and dysphoric arousal versus anxious arousal--by comparing their patterns of associations with external correlates. Avoidance and numbing demonstrated differential associations with external correlates, as did dysphoric arousal and anxious arousal. Taken together, results indicate that order effects are unlikely to account for differences in relative fit between leading models of PTSD symptom structure. We discuss the need for future research in this area, especially studies designed to evaluate order effects more directly. PMID- 25688562 TI - Impediments to enhancement of CPT-11 anticancer activity by E. coli directed beta glucuronidase therapy. AB - CPT-11 is a camptothecin analog used for the clinical treatment of colorectal adenocarcinoma. CPT-11 is converted into the therapeutic anti-cancer agent SN-38 by liver enzymes and can be further metabolized to a non-toxic glucuronide SN 38G, resulting in low SN-38 but high SN-38G concentrations in the circulation. We previously demonstrated that adenoviral expression of membrane-anchored beta glucuronidase could promote conversion of SN-38G to SN-38 in tumors and increase the anticancer activity of CPT-11. Here, we identified impediments to effective tumor therapy with E. coli that were engineered to constitutively express highly active E. coli beta-glucuronidase intracellularly to enhance the anticancer activity of CPT-11. The engineered bacteria, E. coli (lux/betaG), could hydrolyze SN-38G to SN-38, increased the sensitivity of cultured tumor cells to SN-38G by about 100 fold and selectively accumulated in tumors. However, E. coli (lux/betaG) did not more effectively increase CPT-11 anticancer activity in human tumor xenografts as compared to non-engineered E. coli. SN-38G conversion to SN 38 by E. coli (lux/betaG) appeared to be limited by slow uptake into bacteria as well as by segregation of E. coli in necrotic regions of tumors that may be relatively inaccessible to systemically-administered drug molecules. Studies using a fluorescent glucuronide probe showed that significantly greater glucuronide hydrolysis could be achieved in mice pretreated with E. coli (lux/betaG) by direct intratumoral injection of the glucuronide probe or by intratumoral lysis of bacteria to release intracellular beta-glucuronidase. Our study suggests that the distribution of beta-glucuronidase, and possibly other therapeutic proteins, in the tumor microenvironment might be an important barrier for effective bacterial-based tumor therapy. Expression of secreted therapeutic proteins or induction of therapeutic protein release from bacteria might therefore be a promising strategy to enhance anti-tumor activity. PMID- 25688563 TI - OVCAR-3 spheroid-derived cells display distinct metabolic profiles. AB - INTRODUCTION: Recently, multicellular spheroids were isolated from a well established epithelial ovarian cancer cell line, OVCAR-3, and were propagated in vitro. These spheroid-derived cells displayed numerous hallmarks of cancer stem cells, which are chemo- and radioresistant cells thought to be a significant cause of cancer recurrence and resultant mortality. Gene set enrichment analysis of expression data from the OVCAR-3 cells and the spheroid-derived putative cancer stem cells identified several metabolic pathways enriched in differentially expressed genes. Before this, there had been little previous knowledge or investigation of systems-scale metabolic differences between cancer cells and cancer stem cells, and no knowledge of such differences in ovarian cancer stem cells. METHODS: To determine if there were substantial metabolic changes corresponding with these transcriptional differences, we used two dimensional gas chromatography coupled to mass spectrometry to measure the metabolite profiles of the two cell lines. RESULTS: These two cell lines exhibited significant metabolic differences in both intracellular and extracellular metabolite measurements. Principal components analysis, an unsupervised dimensional reduction technique, showed complete separation between the two cell types based on their metabolite profiles. Pathway analysis of intracellular metabolomics data revealed close overlap with metabolic pathways identified from gene expression data, with four out of six pathways found enriched in gene-level analysis also enriched in metabolite-level analysis. Some of those pathways contained multiple metabolites that were individually statistically significantly different between the two cell lines, with one of the most broadly and consistently different pathways, arginine and proline metabolism, suggesting an interesting hypothesis about cancerous and stem-like metabolic phenotypes in this pair of cell lines. CONCLUSIONS: Overall, we demonstrate for the first time that metabolism in an ovarian cancer stem cell line is distinct from that of more differentiated isogenic cancer cells, supporting the potential importance of metabolism in the differences between cancer cells and cancer stem cells. PMID- 25688564 TI - Uni-directional ciliary membrane protein trafficking by a cytoplasmic retrograde IFT motor and ciliary ectosome shedding. AB - The role of the primary cilium in key signaling pathways depends on dynamic regulation of ciliary membrane protein composition, yet we know little about the motors or membrane events that regulate ciliary membrane protein trafficking in existing organelles. Recently, we showed that cilium-generated signaling in Chlamydomonas induced rapid, anterograde IFT-independent, cytoplasmic microtubule dependent redistribution of the membrane polypeptide, SAG1-C65, from the plasma membrane to the periciliary region and the ciliary membrane. Here, we report that the retrograde IFT motor, cytoplasmic dynein 1b, is required in the cytoplasm for this rapid redistribution. Furthermore, signaling-induced trafficking of SAG1-C65 into cilia is unidirectional and the entire complement of cellular SAG1-C65 is shed during signaling and can be recovered in the form of ciliary ectosomes that retain signal-inducing activity. Thus, during signaling, cells regulate ciliary membrane protein composition through cytoplasmic action of the retrograde IFT motor and shedding of ciliary ectosomes. PMID- 25688565 TI - Viral-inducible Argonaute18 confers broad-spectrum virus resistance in rice by sequestering a host microRNA. AB - Viral pathogens are a major threat to rice production worldwide. Although RNA interference (RNAi) is known to mediate antiviral immunity in plant and animal models, the mechanism of antiviral RNAi in rice and other economically important crops is poorly understood. Here, we report that rice resistance to evolutionarily diverse viruses requires Argonaute18 (AGO18). Genetic studies reveal that the antiviral function of AGO18 depends on its activity to sequester microRNA168 (miR168) to alleviate repression of rice AGO1 essential for antiviral RNAi. Expression of miR168-resistant AGO1a in ago18 background rescues or increases rice antiviral activity. Notably, stable transgenic expression of AGO18 confers broad-spectrum virus resistance in rice. Our findings uncover a novel cooperative antiviral activity of two distinct AGO proteins and suggest a new strategy for the control of viral diseases in rice. PMID- 25688566 TI - Non-allelic gene conversion enables rapid evolutionary change at multiple regulatory sites encoded by transposable elements. AB - Transposable elements (TEs) allow rewiring of regulatory networks, and the recent amplification of the ISX element dispersed 77 functional but suboptimal binding sites for the dosage compensation complex to a newly formed X chromosome in Drosophila. Here we identify two linked refining mutations within ISX that interact epistatically to increase binding affinity to the dosage compensation complex. Selection has increased the frequency of this derived haplotype in the population, which is fixed at 30% of ISX insertions and polymorphic among another 41%. Sharing of this haplotype indicates that high levels of gene conversion among ISX elements allow them to 'crowd-source' refining mutations, and a refining mutation that occurs at any single ISX element can spread in two dimensions: horizontally across insertion sites by non-allelic gene conversion, and vertically through the population by natural selection. These results describe a novel route by which fully functional regulatory elements can arise rapidly from TEs and implicate non-allelic gene conversion as having an important role in accelerating the evolutionary fine-tuning of regulatory networks. PMID- 25688567 TI - Social phenotype extended to communities: expanded multilevel social selection analysis reveals fitness consequences of interspecific interactions. AB - In social species, fitness consequences are associated with both individual and social phenotypes. Social selection analysis has quantified the contribution of conspecific social traits to individual fitness. There has been no attempt, however, to apply a social selection approach to quantify the fitness implications of heterospecific social phenotypes. Here, we propose a novel social selection based approach integrating the role of all social interactions at the community level. We extended multilevel selection analysis by including a term accounting for the group phenotype of heterospecifics. We analyzed nest activity as a model social trait common to two species, the lesser kestrel (Falco naumanni) and jackdaw (Corvus monedula), nesting in either single- or mixed species colonies. By recording reproductive outcome as a measure of relative fitness, our results reveal an asymmetric system wherein only jackdaw breeding performance was affected by the activity phenotypes of both conspecific and heterospecific neighbors. Our model incorporating heterospecific social phenotypes is applicable to animal communities where interacting species share a common social trait, thus allowing an assessment of the selection pressure imposed by interspecific interactions in nature. Finally, we discuss the potential role of ecological limitations accounting for random or preferential assortments among interspecific social phenotypes, and the implications of such processes to community evolution. PMID- 25688568 TI - Nipple-like tumour of the shoulder in a male patient. PMID- 25688569 TI - One-photon and two-photon sensing of biothiols using a bis-pyrene-Cu(II) ensemble and its application to image GSH in the cells and tissues. AB - Glutathione (GSH), cysteine (Cys), and homocysteine (Hcy) are three major biothiols, which play key roles in various biological systems. Accordingly, the development of imaging probes has been actively studied. We report a new pyrene derivative 1, which showed large fluorescence quenching with Cu(2+) at pH 7.4. The ensemble 1-Cu(2+) was applied to detect biothiols. Among the various amino acids, GSH, Cys, and Hcy induced distinct turn-on fluorescence changes. The 1 Cu(2+) ensemble was further applied for GSH detection in living cells. PMID- 25688570 TI - Taking care of themselves: how long-term injection drug users remain HIV and Hepatitis C free. AB - Though prevalence of HIV and especially Hepatitis C is high among people who inject drugs (PWID) in New York, about a third of those who have injected for 8 15 years have avoided infection by either virus despite their long-term drug use. Based on life history interviews with 35 long-term PWID in New York, this article seeks to show how successful integration and performance of various drug using and non-drug using roles may have contributed to some of these PWID's staying uninfected with either virus. We argue that analysis of non-risk related aspects of the lives of the risk-takers (PWID) is very important in understanding their risk-taking behaviour and its outcomes (infection statuses). Drawing on work related, social and institutional resources, our double-negative informants underwent both periods of stability and turmoil without getting infected. PMID- 25688571 TI - Method for the detection of desmethylbromethalin in animal tissue samples for the determination of bromethalin exposure. AB - Bromethalin, a potent neurotoxin, is widely available for use as a rodenticide. As access to other rodenticides is reduced due to regulatory pressure, the use of bromethalin is likely to increase with a concomitant increase in poisonings in nontarget animals. Analytical methods for the detection of bromethalin residues in animals suspected to have been exposed to this rodenticide are needed to support post-mortem diagnosis of toxicosis. This paper describes a novel method for the analysis of desmethylbromethalin (DMB), bromethalin's toxic metabolite, in tissue samples such as liver, brain, and adipose. Samples were extracted with 5% ethanol in ethyl acetate, and an aliquot of the extract was evaporated dry, reconstituted, and analyzed by reverse phase ultrahigh-performance liquid chromatography-mass spectrometry. The mass spectrometer utilized electrospray ionization in negative ion mode with multiple reaction monitoring. This method was qualitatively validated at a level of 1.0 ng/g in liver tissue. The quantitative potential of the method was also evaluated, and a method detection limit of 0.35 ng/g wet weight was determined in fat tissue. DMB was detected in tissue samples from animals suspected to have been poisoned by this compound. To the authors' knowledge, there have been no other methods reported for analysis of DMB in tissue samples using LC-MS/MS. PMID- 25688572 TI - Structure and proposed mechanism of L-alpha-glycerophosphate oxidase from Mycoplasma pneumoniae. AB - The formation of H2 O2 by the FAD-dependent L-alpha-glycerophosphate oxidase (GlpO) is important for the pathogenesis of Streptococcus pneumoniae and Mycoplasma pneumoniae. The structurally known GlpO from Streptococcus sp. (SspGlpO) is similar to the pneumococcal protein (SpGlpO) and provides a guide for drug design against that target. However, M. pneumoniae GlpO (MpGlpO), having < 20% sequence identity with structurally known GlpOs, appears to represent a second type of GlpO that we designate as type II GlpOs. In the present study, the recombinant His-tagged MpGlpO structure is described at an approximate resolution of 2.5 A, solved by molecular replacement using, as a search model, the Bordetella pertussis protein 3253 (Bp3253), comprising a protein of unknown function solved by structural genomics efforts. Recombinant MpGlpO is an active oxidase with a turnover number of approximately 580 min(-1), whereas Bp3253 showed no GlpO activity. No substantial differences exist between the oxidized and dithionite-reduced MpGlpO structures. Although, no liganded structures were determined, a comparison with the tartrate-bound Bp3253 structure and consideration of residue conservation patterns guided the construction of a model for L-alpha-glycerophosphate (Glp) recognition and turnover by MpGlpO. The predicted binding mode also appears relevant for the type I GlpOs (such as SspGlpO) despite differences in substrate recognition residues, and it implicates a histidine conserved in type I and II Glp oxidases and dehydrogenases as the catalytic acid/base. The present study provides a solid foundation for guiding further studies of the mitochondrial Glp dehydrogenases, as well as for continued studies of M. pneumoniae and S. pneumoniae glycerol metabolism and the development of novel therapeutics targeting MpGlpO and SpGlpO. DATABASE: Structural data have been deposited in the Protein Data Bank under accession numbers 4X9M (oxidized) and 4X9N (reduced). PMID- 25688573 TI - Toxicologic and comparative clinical pathology externship scholarships broaden clinical pathology resident training opportunities. PMID- 25688574 TI - Functional analyses of cellulose synthase genes in flax (Linum usitatissimum) by virus-induced gene silencing. AB - Flax (Linum usitatissimum) bast fibres are located in the stem cortex where they play an important role in mechanical support. They contain high amounts of cellulose and so are used for linen textiles and in the composite industry. In this study, we screened the annotated flax genome and identified 14 distinct cellulose synthase (CESA) genes using orthologous sequences previously identified. Transcriptomics of 'primary cell wall' and 'secondary cell wall' flax CESA genes showed that some were preferentially expressed in different organs and stem tissues providing clues as to their biological role(s) in planta. The development for the first time in flax of a virus-induced gene silencing (VIGS) approach was used to functionally evaluate the biological role of different CESA genes in stem tissues. Quantification of transcript accumulation showed that in many cases, silencing not only affected targeted CESA clades, but also had an impact on other CESA genes. Whatever the targeted clade, inactivation by VIGS affected plant growth. In contrast, only clade 1- and clade 6-targeted plants showed modifications in outer-stem tissue organization and secondary cell wall formation. In these plants, bast fibre number and structure were severely impacted, suggesting that the targeted genes may play an important role in the establishment of the fibre cell wall. Our results provide new fundamental information about cellulose biosynthesis in flax that should facilitate future plant improvement/engineering. PMID- 25688575 TI - Antineoplastic agents. 600. From the South Pacific Ocean to the silstatins. AB - The recent advances in the development of antibody and other drug conjugates for targeted cancer treatment have further increased the need for powerful cancer cell growth inhibitors. Toward that objective we have extended our earlier discovery of the remarkable anticancer bacillistatins 1 and 2 from Bacillus silvestris to SAR and other structural modifications such as availability of a free hydroxy group for antibody-drug conjugate (ADC) and other prodrug linkage. That direction has resulted in seven structural modifications designated silstatins 1-8 (7a, 8a, 8b, 14a, 15a, 15b, 18a, and 18b), where the exceptional cancer cell growth inhibition of some of them are in the range GI50 10(-3)-10(-4) MUM/mL. Silstatin 7 (18a) was converted to a glucuronic conjugate (28) that displayed an impressive reduction in toxicity during transport. PMID- 25688576 TI - Floral diversity and pollination strategies of three rheophytic Schismatoglottideae (Araceae). AB - Homoplastic evolution of 'unique' morphological characteristics in the Schismatoglottideae - many previously used to define genera - prompted this study to compare morphology and function in connection with pollination biology for Aridarum nicolsonii, Phymatarum borneense and Schottarum sarikeense. Aridarum nicolsonii and P. borneense extrude pollen through a pair of horned thecae while S. sarikeense sheds pollen through a pair of pores on the thecae. Floral traits of spathe constriction, presence and movement of sterile structures on the spadix, the comparable role of horned thecae and thecae pores, the presence of stamen-associated calcium oxalate packages, and the timing of odour emission are discussed in the context of their roles in pollinator management. Pollinators for all investigated species were determined to be species of Colocasiomyia (Diptera: Drosophilidae). PMID- 25688577 TI - Optimized carbonation of magnesium silicate mineral for CO2 storage. AB - The global ambition of reducing the carbon dioxide emission makes sequestration reactions attractive as an option of storing CO2. One promising environmentally benign technology is based on forming thermodynamically stable carbonated minerals, with the drawback that these reactions usually have low conversion rates. In this work, the carbonation reaction of Mg rich olivine, Mg2SiO4, under supercritical conditions has been studied. The reaction produces MgCO3 at elevated temperature and pressure, with the addition of NaHCO3 and NaCl to improve the reaction rates. A sequestration rate of 70% was achieved within 2 h, using olivine particles of sub-10 MUm, whereas 100% conversion was achieved in 4 h. This is one of the fastest complete conversions for this reaction reported to date. The CO2 sequestration rate is found to be highly dependent on the applied temperature and pressure, as well as the addition of NaHCO3. In contrast, adding NaCl was found to have limited effect on the reaction rate. The roles of NaHCO3 and NaCl as catalysts are discussed and especially how their effect changes with increased olivine particle size. The products have been characterized by Rietveld refinement of powder X-ray diffraction, scanning electron microscopy (SEM), and energy-dispersive X-ray (EDX) spectroscopy revealing the formation of amorphous silica and micrometer-sized magnesium carbonate crystals. PMID- 25688578 TI - Relationship between non-alcoholic fatty liver disease and MIA syndrome. AB - Non-alcoholic fatty liver disease (NAFLD) is an important factor in the pathogenesis of cardiovascular diseases in the general population. Recently, it has been shown that NAFLD is highly prevalent in chronic kidney disease (CKD) patients. Ninety-four hemodialysis (HD) patients were followed for a time period of 18 months or until death. Patient's survival rate was determined in relation to their nutritional and inflammatory state, and the presence of NAFLD. We also investigated the association between the presence of NAFLD and the patients' nutritional and inflammatory state. We did not find any significant association between the clinical parameters of nutritional status and the mortality rate. However, the mortality rate was statistically significantly higher in patients with low serum albumin and high high-sensitive C-reactive protein (hs-CRP) levels and in those who had NAFLD. Surprisingly, patients who had received enteral nutrition did not have a better survival rate. The severity of liver steatosis was negatively correlated with the serum albumin levels, while it was positively correlated with hs-CRP values. Furthermore, serum albumin levels showed a negative correlation with hs-CRP levels. We did not find any significant association between the presence of NAFLD and clinical parameters of nutrition. We have shown that NAFLD could be one more possible example of reverse epidemiology in patients undergoing HD. NAFLD may be the missing link that causally ties malnutrition, inflammation, and atherosclerosis syndrome to the morbidity and mortality in patients undergoing HD. PMID- 25688579 TI - Susceptibility of Ureaplasma urealyticum to Methylene Blue-Mediated Photodynamic Antimicrobial Chemotherapy: An in vitro Study. AB - The aim of this study was to detect the susceptibility of Ureaplasma urealyticum to methylene blue-mediated photodynamic antimicrobial chemotherapy (PACT). Three U. urealyticum strains including the standard serotype 1 and 5, and a clinically collected strain were used in this study. Strains were first incubated in 96-well culture plates in the presence of methylene blue with decreasing concentrations (from 1 to 0.015625 mg mL(-1)) for 20 or 60 min, and then submitted to irradiation with a light-emitting diode laser with a power density of 100 mW cm( 2) for 8, 17, 34 or 68 min. Regrowth of the strains was performed soon after irradiation. A significant inactivation effect was observed after PACT. Longer incubation time induced more extensive inactivation of U. urealyticum. No difference in response to PACT was observed between the two biovars of U. urealyticum. It was concluded that PACT had a significant inactivation effect on U. urealyticum, and it might be a promising alternative treatment for resistant U. urealyticum infections. PMID- 25688580 TI - Factor VIII alloantibody inhibitors: cost analysis of immune tolerance induction vs. prophylaxis and on-demand with bypass treatment. AB - Development of inhibitors (alloantibodies to exogenous factor VIII) is the most significant treatment complication in patients with haemophilia A. The only proven way to eradicate inhibitors is through immune tolerance induction (ITI), while bypassing agents are typically employed to treat or prevent bleeds in patients with high titre inhibitors. Costs of these approaches have not been well studied. The aim of this study was to compare lifetime costs of treating patients with severe haemophilia A with inhibitors using on-demand or prophylaxis treatment with bypassing agents and ITI. A decision-analytic model was developed to compare the treatment costs and outcomes. Quantitation of the reduction in bleeding events for patients on prophylaxis and after eradication of inhibitors when on ITI and relapse of inhibitors was derived from published studies. Costs were obtained from standard US costing sources and are reported in 2014 US dollars. Costs and outcomes were discounted 3% per annum. Lifetime costs of treating patients with inhibitors are lower for ITI vs. on-demand or prophylaxis. Patients are also projected to live longer, have greater quality-adjusted life years, and have fewer bleeding events than patients treated on-demand. Treating patients via ITI to eradicate inhibitors may result in lower lifetime costs and greater life-years and quality-adjusted life-years than treating with bypassing agents. PMID- 25688581 TI - Long-term alkalinity decrease and acidification of estuaries in northwestern Gulf of Mexico. AB - More than four decades of alkalinity and pH data (late 1960s to 2010) from coastal bays along the northwestern Gulf of Mexico were analyzed for temporal changes across a climatic gradient of decreasing rainfall and freshwater inflow, from northeast to southwest. The majority (16 out of 27) of these bays (including coastal waters) showed a long-term reduction in alkalinity at a rate of 3.0-21.6 MUM yr(-1). Twenty-two bays exhibited pH decreases at a rate of 0.0014-0.0180 yr( 1). In contrast, a northernmost coastal bay exhibited increases in both alkalinity and pH. Overall, the two rates showed a significant positive correlation, indicating that most of these bays, especially those at lower latitudes, have been experiencing long-term acidification. The observed alkalinity decrease may be caused by reduced riverine alkalinity export, a result of precipitation decline under drought conditions, and freshwater diversion for human consumption, as well as calcification in these bays. A decrease in alkalinity inventory and accompanying acidification may have negative impacts on shellfish production in these waters. In addition, subsequent reduction in alkalinity export from these bays to the adjacent coastal ocean may also decrease the buffer capacity of the latter against future acidification. PMID- 25688582 TI - Atomic-scale recognition of surface structure and intercalation mechanism of Ti3C2X. AB - MXenes represent a large family of functionalized two-dimensional (2D) transition metal carbides and carbonitrides. However, most of the understanding on their unique structures and applications stops at the theoretical suggestion and lack of experimental support. Herein, the surface structure and intercalation chemistry of Ti3C2X are clarified at the atomic scale by aberration-corrected scanning transmission electron microscope (STEM) and density functional theory (DFT) calculations. The STEM studies show that the functional groups (e.g., OH( ), F(-), O(-)) and the intercalated sodium (Na) ions prefer to stay on the top sites of the centro-Ti atoms and the C atoms of the Ti3C2 monolayer, respectively. Double Na-atomic layers are found within the Ti3C2X interlayer upon extensive Na intercalation via two-phase transition and solid-solution reactions. In addition, aluminum (Al)-ion intercalation leads to horizontal sliding of the Ti3C2X monolayer. On the basis of these observations, the previous monolayer surface model of Ti3C2X is modified. DFT calculations using the new modeling help to understand more about their physical and chemical properties. These findings enrich the understanding of the MXenes and shed light on future material design and applications. Moreover, the Ti3C2X exhibits prominent rate performance and long-term cycling stability as an anode material for Na-ion batteries. PMID- 25688583 TI - Pulsed Radiofrequency of Dorsal Root Ganglia for the Treatment of Complex Regional Pain Syndrome in an Adolescent with Poliomyelitis Sequel: A Case Report. AB - OBJECTIVE: Complex regional pain syndrome (CRPS) is a painful and disabling syndrome in which the patient presents with neuropathic pain, edema, or vasomotor or pseudomotor abnormalities that are often refractory to treatment. Polio paralysis is caused by the damage or destruction of motor neurons in the spine, which lead to corresponding muscle paralysis. This report is a case report on the application of a pulsed radiofrequency (PRF) current to dorsal root ganglia (DRG) for the treatment of CRPS type 1 in an adolescent patient. DESIGN: Single case report. SETTING: Selcuk University Hospital. PATIENT: A 16-year-old girl who suffered from CRPS type 1 secondary to surgeries for the sequelae of poliomyelitis. INTERVENTIONS: PRF current application to the lumbar 4 and lumbar 5 DRG. OUTCOME MEASURES: Pain reduction. RESULTS: The patient had complete resolution of her symptoms, which was maintained at a 6-month follow-up. CONCLUSIONS: This case illustrates that PRF applied to lumbar 4 and lumbar 5 DRG may play a significant role in CRPS type 1 management after the surgical treatment of poliomyelitis sequelae in adolescent patients. Further randomized, controlled studies are needed to support this argument. PMID- 25688584 TI - Lipodystrophia centrifugalis abdominalis infantilis accompanied by idiopathic encephalopathy. PMID- 25688585 TI - Apparent vector-mediated parent-to-offspring transmission in an avian malaria like parasite. AB - Parasite transmission strategies strongly impact host-parasite co-evolution and virulence. However, studies of vector-borne parasites such as avian malaria have neglected the potential effects of host relatedness on the exchange of parasites. To test whether extended parental care in the presence of vectors increases the probability of transmission from parents to offspring, we used high-throughput sequencing to develop microsatellites for malaria-like Leucocytozoon parasites of a wild raptor population. We show that host siblings carry genetically more similar parasites than unrelated chicks both within and across years. Moreover, chicks of mothers of the same plumage morph carried more similar parasites than nestlings whose mothers were of different morphs, consistent with matrilineal transmission of morph-specific parasite strains. Ours is the first evidence of an association between host relatedness and parasite genetic similarity, consistent with vector-mediated parent-to-offspring transmission. The conditions for such 'quasi-vertical' transmission may be common and could suppress the evolution of pathogen virulence. PMID- 25688586 TI - Intraosseous vascular access in critically ill adults--a review of the literature. AB - BACKGROUND: The IO route is an established method of obtaining vascular access in children in acute and emergency situations and is now increasingly being used in adults as an alternative to intravenous access, yet a paucity of evidence exists regarding its use, effectiveness and implementation. AIM AND OBJECTIVES: The aim of this literature review is to present a detailed investigation critiquing contemporary practices of intraosseous (IO) vascular access in adult patients. Specific objectives identified led to the exploration of clinical contexts, IO device/s and anatomical sites; education and training requirements; implications and recommendations for emergency health care practice and any requirements for further research. SEARCH STRATEGIES: An exploratory literature review was undertaken in acknowledgement of the broad and complex nature of the project aim. Five electronic search engines were examined iteratively from June 2013 to February 2014. The search terms were 'intraosseous' and 'adult' which were purposely limited because of the exploratory nature of the review. Studies that met the inclusion criteria of primary research articles with an adult focus were included. Research with a paediatric focus was excluded. Secondary research, reviews, case reports, editorials and opinion papers were excluded. CONCLUSION: IO vascular access is considered an alternative intravascular access route although debate considering the preferred anatomical site is ongoing. Documented practices are only established in pre-hospital and specialist emergency department settings; however, variety exists in policy and actual practice. Achieving insertion competence is relatively uncomplicated following minimal preparation although ongoing skill maintenance is less clear. IO vascular access is associated with minimal complications although pain is a significant issue for the conscious patient especially during fluid administration. RELEVANCE TO CLINICAL PRACTICE: The IO route is clearly a valuable alternative to problematic intravascular access. However, further research, including cost effectiveness reviews, is required to gain clarity of whole acute care approaches. PMID- 25688587 TI - A choline oxidase amperometric bioassay for the detection of mustard agents based on screen-printed electrodes modified with Prussian Blue nanoparticles. AB - In this work a novel bioassay for mustard agent detection was proposed. The bioassay is based on the capability of these compounds to inhibit the enzyme choline oxidase. The enzymatic activity, which is correlated to the mustard agents, was electrochemically monitored measuring the enzymatic product, hydrogen peroxide, by means of a screen-printed electrode modified with Prussian Blue nanoparticles. Prussian Blue nanoparticles are able to electrocatalyse the hydrogen peroxide concentration reduction at low applied potential (-50 mV vs. Ag/AgCl), thus allowing the detection of the mustard agents with no electrochemical interferences. The suitability of this novel bioassay was tested with the nitrogen mustard simulant bis(2-chloroethyl)amine and the sulfur mustard simulants 2-chloroethyl ethyl sulfide and 2-chloroethyl phenyl sulfide. The bioassay proposed in this work allowed the detection of mustard agent simulants with good sensitivity and fast response, which are excellent premises for the development of a miniaturised sensor well suited for an alarm system in case of terrorist attacks. PMID- 25688588 TI - A stationary north-finding scheme for an azimuth rotational IMU utilizing a linear state equality constraint. AB - The Kalman filter (KF) has always been used to improve north-finding performance under practical conditions. By analyzing the characteristics of the azimuth rotational inertial measurement unit (ARIMU) on a stationary base, a linear state equality constraint for the conventional KF used in the fine north-finding filtering phase is derived. Then, a constrained KF using the state equality constraint is proposed and studied in depth. Estimation behaviors of the concerned navigation errors when implementing the conventional KF scheme and the constrained KF scheme during stationary north-finding are investigated analytically by the stochastic observability approach, which can provide explicit formulations of the navigation errors with influencing variables. Finally, multiple practical experimental tests at a fixed position are done on a postulate system to compare the stationary north-finding performance of the two filtering schemes. In conclusion, this study has successfully extended the utilization of the stochastic observability approach for analytic descriptions of estimation behaviors of the concerned navigation errors, and the constrained KF scheme has demonstrated its superiority over the conventional KF scheme for ARIMU stationary north-finding both theoretically and practically. PMID- 25688589 TI - A soft-hard combination-based cooperative spectrum sensing scheme for cognitive radio networks. AB - In this paper we propose a soft-hard combination scheme, called SHC scheme, for cooperative spectrum sensing in cognitive radio networks. The SHC scheme deploys a cluster based network in which Likelihood Ratio Test (LRT)-based soft combination is applied at each cluster, and weighted decision fusion rule-based hard combination is utilized at the fusion center. The novelties of the SHC scheme are as follows: the structure of the SHC scheme reduces the complexity of cooperative detection which is an inherent limitation of soft combination schemes. By using the LRT, we can detect primary signals in a low signal-to-noise ratio regime (around an average of -15 dB). In addition, the computational complexity of the LRT is reduced since we derive the closed-form expression of the probability density function of LRT value. The SHC scheme also takes into account the different effects of large scale fading on different users in the wide area network. The simulation results show that the SHC scheme not only provides the better sensing performance compared to the conventional hard combination schemes, but also reduces sensing overhead in terms of reporting time compared to the conventional soft combination scheme using the LRT. PMID- 25688590 TI - A high resolution on-chip delay sensor with low supply-voltage sensitivity for high-performance electronic systems. AB - An all-digital on-chip delay sensor (OCDS) circuit with high delay-measurement resolution and low supply-voltage sensitivity for efficient detection and diagnosis in high-performance electronic system applications is presented. Based on the proposed delay measurement scheme, the quantization resolution of the proposed OCDS can be reduced to several picoseconds. Additionally, the proposed cascade-stage delay measurement circuit can enhance immunity to supply-voltage variations of the delay measurement resolution without extra self-biasing or calibration circuits. Simulation results show that the delay measurement resolution can be improved to 1.2 ps; the average delay resolution variation is 0.55% with supply-voltage variations of +/-10%. Moreover, the proposed delay sensor can be implemented in an all-digital manner, making it very suitable for high-performance electronic system applications as well as system-level integration. PMID- 25688591 TI - Correction: Tang, C. Y. and Chen, X.Y. A class of coning algorithms based on a half-compressed structure. Sensors 2014, 14, 14289-14301. PMID- 25688592 TI - Mining personal data using smartphones and wearable devices: a survey. AB - The staggering growth in smartphone and wearable device use has led to a massive scale generation of personal (user-specific) data. To explore, analyze, and extract useful information and knowledge from the deluge of personal data, one has to leverage these devices as the data-mining platforms in ubiquitous, pervasive, and big data environments. This study presents the personal ecosystem where all computational resources, communication facilities, storage and knowledge management systems are available in user proximity. An extensive review on recent literature has been conducted and a detailed taxonomy is presented. The performance evaluation metrics and their empirical evidences are sorted out in this paper. Finally, we have highlighted some future research directions and potentially emerging application areas for personal data mining using smartphones and wearable devices. PMID- 25688593 TI - Architecture of a service-enabled sensing platform for the environment. AB - Recent technological advancements have led to the production of arrays of miniaturized sensors, often embedded in existing multitasking devices (e.g., smartphones, tablets) and using a wide range of radio standards (e.g., Bluetooth, Wi-Fi, 4G cellular networks). Altogether, these technological evolutions coupled with the diffusion of ubiquitous Internet connectivity provide the base-line technology for the Internet of Things (IoT). The rapid increase of IoT devices is enabling the definition of new paradigms of data collection and introduces the concept of mobile crowd-sensing. In this respect, new sensing methodologies promise to extend the current understanding of the environment and social behaviors by leveraging citizen-contributed data for a wide range of applications. Environmental sensing can however only be successful if all the heterogeneous technologies and infrastructures work smoothly together. As a result, the interconnection and orchestration of devices is one of the central issues of the IoT paradigm. With this in mind, we propose an approach for improving the accessibility of observation data, based on interoperable standards and on-device web services. PMID- 25688594 TI - Iron oxide nanoparticle-mediated development of cellular gap junction crosstalk to improve mesenchymal stem cells' therapeutic efficacy for myocardial infarction. AB - Electrophysiological phenotype development and paracrine action of mesenchymal stem cells (MSCs) are the critical factors that determine the therapeutic efficacy of MSCs for myocardial infarction (MI). In such respect, coculture of MSCs with cardiac cells has windowed a platform for cardiac priming of MSCs. Particularly, active gap junctional crosstalk of MSCs with cardiac cells in coculture has been known to play a major role in the MSC modification through coculture. Here, we report that iron oxide nanoparticles (IONPs) significantly augment the expression of connexin 43 (Cx43), a gap junction protein, of cardiomyoblasts (H9C2), which would be critical for gap junctional communication with MSCs in coculture for the generation of therapeutic potential-improved MSCs. MSCs cocultured with IONP-harboring H9C2 (cocultured MSCs: cMSCs) showed active cellular crosstalk with H9C2 and displayed significantly higher levels of electrophysiological cardiac biomarkers and a cardiac repair-favorable paracrine profile, both of which are responsible for MI repair. Accordingly, significantly improved animal survival and heart function were observed upon cMSC injection into rat MI models compared with the injection of unmodified MSCs. The present study highlights an application of IONPs in developing gap junctional crosstalk among the cells and generating cMSCs that exceeds the reparative potentials of conventional MSCs. On the basis of our finding, the potential application of IONPs can be extended in cell biology and stem cell-based therapies. PMID- 25688596 TI - Transferable next-generation force fields from simple liquids to complex materials. AB - Molecular simulations have had a transformative impact on chemists' understanding of the structure and dynamics of molecular systems. Simulations can both explain and predict chemical phenomena, and they provide a unique bridge between the microscopic and macroscopic regimes. The input for such simulations is the intermolecular interactions, which then determine the forces on the constituent atoms and therefore the time evolution and equilibrium properties of the system. However, in practice, accuracy and reliability are often limited by the fidelity of the description of those very same interactions, most typically embodied approximately in mathematical form in what are known as force fields. Force fields most often utilize conceptually simple functional forms that have been parametrized to reproduce existing experimental gas phase or bulk data. Yet, reliance on empirical parametrization can sometimes introduce limitations with respect to novel chemical systems or uncontrolled errors when moving to temperatures, pressures, or environments that differ from those for which they were developed. Alternatively, it is possible to develop force fields entirely from first principles, using accurate electronic structure calculations to determine the intermolecular interactions. This introduces a new set of challenges, including the transferability of the resulting force field to related chemical systems. In response, we recently developed an alternative approach to develop force fields entirely from first-principles electronic structure calculations based on intermolecular perturbation theory. Making use of an energy decomposition analysis ensures, by construction, that the resulting force fields contain the correct balance of the various components of intermolecular interaction (exchange repulsion, electrostatics, induction, and dispersion), each treated by a functional form that reflects the underlying physics. We therefore refer to the resulting force fields as physically motivated. We find that these physically motivated force fields exhibit both high accuracy and transferability, with the latter deriving from the universality of the fundamental physical laws governing intermolecular interactions. This basic methodology has been applied to a diverse set of systems, ranging from simple liquids to nanoporous metal-organic framework materials. A key conclusion is that, in many cases, it is feasible to account for nearly all of the relevant physics of intermolecular interactions within the context of the force field. In such cases, the structural, thermodynamic, and dynamic properties of the system become naturally emergent, even in the absence of explicit parameterization to bulk properties. We also find that, quite generally, the three-body contributions to the dispersion and exchange energies in bulk liquids are crucial for quantitative accuracy in a first-principles force field, although these contributions are almost universally neglected in existing empirical force fields. PMID- 25688595 TI - Concordant occipital and supraorbital neurostimulation therapy for hemiplegic migraine; initial experience; a case series. AB - INTRODUCTION: Hemiplegic migraine is a particularly severe form of the disease that often evolves to a debilitating chronic illness that is resistant to commonly available therapies. Peripheral neurostimulation has been found to be a beneficial therapy for some patients among several diagnostic classes of migraine, but its potential has not been specifically evaluated for hemiplegic migraine. MATERIALS AND METHODS: Four patients with hemiplegic migraine were treated with concordant, combined occipital and supraorbital neurostimulation over periods ranging 6-92 months. The clinical indicators followed included assessments of headache frequency and severity, frequency of hemiplegic episodes, functional impairment, medication usage, and patient satisfaction. RESULTS: All reported a positive therapeutic response, as their average headache frequency decreased by 92% (30 to 2.5 headache days/month); Visual Analog Score by 44% (9.5 to 5.3); frequency of hemiplegic episodes by 96% (7.5 to 0.25 hemiplegic episodes/month); headache medication usage by 96% (6 to 0.25 daily medications); and Migraine Disability Assessment score by 98% (249 to 6). All were satisfied and would recommend the therapy, and all preferred combined occipital supraorbital neurostimulation to occipital neurostimulation alone. CONCLUSIONS: Concordant combined occipital and supraorbital neurostimulation may provide effective therapy for both the pain and motor aura in some patients with hemiplegic migraine. PMID- 25688597 TI - Retinal changes in a patient with acquired partial lipodystrophy (Laignel Lavastine and Viard Syndrome). PMID- 25688598 TI - Differences in Aspergillus-specific immune recovery between T-cell-replete and T cell-depleted hematopoietic transplants. AB - BACKGROUND: After hematopoietic stem cell transplantation, invasive aspergillosis remains one of the most lethal infections. Susceptibility may be due to prophylaxis and treatment of graft-vs.-host disease in T-cell-replete transplants, and delayed immune rebuilding due to T-cell depletion in haploidentical transplantation. METHODS: We monitored CD4(+) T-cell recovery and anti-Aspergillus immune competence in pediatric recipients of T-cell-replete matched transplants and of prevalently adult recipients of T-cell-depleted matched or haploidentical transplants for hematological malignancies. RESULTS: Although CD4(+) T-cell counts were higher in T-cell-replete transplant recipients at all post-transplant time points, Aspergillus-specific T cells were first detected 15-18 months after T-cell-replete matched, 7-9 months after T-cell depleted matched, and 9-12 months after haploidentical transplantation, respectively. Incidence of invasive aspergillosis was 22% with 10% mortality after T-cell-replete transplants, 0% after T-cell-depleted matched, and 7% with 4% mortality after haploidentical transplants. CONCLUSIONS: Although T-cell counts were significantly higher after T-cell-replete transplants, post transplant immune suppression/GvHD appeared to impair their function. Specific Aspergillus immune competence recovered faster after T-cell-depleted transplants, whether matched or haploidentical. T-cell-replete transplants were associated with a higher incidence of invasive aspergillosis and Aspergillus-related deaths. These results showed that T-cell depletion without post-transplant immunosuppression is associated to a faster immune recovery than T-cell-replete transplantation. PMID- 25688599 TI - Postoperative changes in telemetry measurements after cochlear implantation and its impact on early activation. AB - INTRODUCTION: Cochlear implantation is a clinically routine treatment for patients with severe sensorineural hearing loss for over 20 years. Up to now, the general recommendation for speech processor activation was 4 weeks after cochlear implantation. The aim of this study was to determine whether activation is possible at <4 weeks postop and to show the postoperative change in telemetry over time. MATERIAL AND METHODS: The study was retrospectively carried out at the Karl Landsteiner University Hospital St. Polten, Austria. Patients who routinely received a CI between January and August 2013 were included in this study. Two weeks after the surgery clinical complications, the ability to wear the audio processor and the impedance values were analysed. RESULTS: Forty-five patients were included in this study. Forty patients were examined at the first postoperative visit, scheduled 2 weeks after the surgery. In nine cases, a mild wound-healing complication occurred; just in one patient, the activation could not carry out immediately. There were no statistically significant differences between the intraoperative, the 2- and 6-week postop impedance measurements for each channel. DISCUSSION: We used the minimally invasive approach and soft implantation technique in all of our patients and believe this to have been a major reason that earlier activation was possible. With this technique, you can reduce the wound-healing process, which makes it possible for the wound to heal fully and for the patient to wear the sound processor over the wound without problems. We found out that telemetry is not a predictor for the time of activation. CONCLUSION: Based on the results in this study, an earlier activation can be recommended. This will shorten the time the patient needs to wait following cochlear implantation, and rehabilitation can begin sooner. PMID- 25688600 TI - Shifting sugars and shifting paradigms. AB - No organism lives in a constant environment. Based on classical studies in molecular biology, many have viewed microbes as following strict rules for shifting their metabolic activities when prevailing conditions change. For example, students learn that the bacterium Escherichia coli makes proteins for digesting lactose only when lactose is available and glucose, a better sugar, is not. However, recent studies, including three PLOS Biology papers examining sugar utilization in the budding yeast Saccharomyces cerevisiae, show that considerable heterogeneity in response to complex environments exists within and between populations. These results join similar recent results in other organisms that suggest that microbial populations anticipate predictable environmental changes and hedge their bets against unpredictable ones. The classical view therefore represents but one special case in a range of evolutionary adaptations to environmental changes that all organisms face. PMID- 25688601 TI - Participation of elderly adults in randomized controlled trials addressing antibiotic treatment of pneumonia. AB - OBJECTIVES: To examine how relevant current evidence on antibiotic treatment of pneumonia is for elderly adults. DESIGN: Systematic review. SETTING: Randomized controlled trials (RCTs; N = 43) comparing different antibiotics and prospective observational studies (N = 182) published since 2005. PARTICIPANTS: Adults with community-acquired (CAP), healthcare-associated (HCAP), hospital-acquired (HAP), or ventilator-associated (VAP) pneumonia. MEASUREMENTS: Exclusion criteria that could preferentially limit participation of elderly adults were examined, subgroup or other adjusted analyses were searched for according to age, and treatment effects in participants younger than 65 in RCTs were compared with those in participants aged 65 and older. Mean participant ages in RCTs and observational studies were compared. Risk ratios (RRs) with 95% confidence intervals (CIs) for differences between older and younger adults were pooled using a fixed effect metaanalysis. RESULTS: No RCT reported exclusion based on an upper age limit; 100% of community CAP trials, 90% of hospitalized CAP trials, and 76% of HAP and VAP trials excluded individuals based on comorbidities. None of the RCTs reported a subgroup analysis for mortality according to age. The RR for the pooled difference in treatment failure rates between participants younger than 65 and those aged 65 and older was 1.25 (95% CI = 0.94-1.65, 12 RCTs) and between participants younger than 75 and aged 75 and older was 1.43 (95% CI = 0.98-2.09, 7 RCTs). RCT participants were significantly younger (54.0 +/- 9.6) than those in observational studies of CAP (66.2 +/- 8.1, P < .001). Age differences were not significant for HCAP, HAP, and VAP. CONCLUSION: Elderly adults are often excluded from RCTs of bacterial pneumonia. No data were found on the comparative efficacy of antibiotic treatment in elderly adults and the general population. PMID- 25688602 TI - Adverse events in mobility-limited and chronically ill elderly adults participating in an exercise intervention study supported by general practitioner practices. AB - OBJECTIVES: To present detailed adverse event (AE) data from a randomized controlled trial (RCT) of a home-based exercise program delivered to an elderly high-risk population by an exercise therapist after medical clearance from a general practitioner (GP). DESIGN: Randomized controlled trial. SETTING: General practitioner practices and participant homes. PARTICIPANTS: Community-dwelling, chronically ill, mobility-limited individuals aged 70 and older (mean 80 +/- 5) participating in a RCT of an exercise program (HOMEfit; ISRCTN17727272) (N = 209; n = 106 experimental, n = 103 control; 74% female). INTERVENTION: A 12-week multidimensional home-based exercise program (experimental) versus baseline physical activity counseling (control). An exercise therapist delivered both interventions to participants during counseling sessions at the GP's practice and on the telephone. MEASUREMENTS: Adverse events were documented at least at every counseling session and assessed by the GP and an AE manager. RESULTS: One hundred fifty-one AEs were reported in 47% (n = 99) of all participants. Twenty-one (14%) events were classified as serious. In six events (4%; n = 4 experimental, n = 2 control), participation in the study had to be discontinued immediately. In 25 events (17%; n = 9 experimental, n = 16 control), the intervention had to be suspended. The intervention was determined to have caused two events (both nonserious and in the experimental group). CONCLUSION: Even though the program appears to be safe, high morbidity unrelated to exercise can constitute a critical challenge for sustained exercise participation. PMID- 25688603 TI - Apolipoprotein E, carbon dioxide vasoreactivity, and cognition in older adults: effect of hypertension. AB - OBJECTIVES: To investigate the associations between the apolipoprotein E (APOE) epsilon4 allele, carbon dioxide (CO2 ) vasoreactivity, and cognitive performance and to explore the effect of CO2 vasoreactivity and hypertension on the associations between APOE and cognition. DESIGN: Observational. SETTING: Community. PARTICIPANTS: Older adults (N = 625) enrolled in the Maintenance of Balance, Independent Living, Intellect and Zest in the Elderly of Boston Study. MEASUREMENTS: Change in cerebral blood flow velocity in response to CO2 challenge (CO2 ), measured using transcranial Doppler ultrasonography, Trail-Making Test Part B - A (TMT), Hopkins Verbal Learning Test delayed recall (HVLT). RESULTS: APOE-epsilon4 was associated with lower CO2 vasoreactivity (P = .009) and poorer performance on the TMT (P < .001) and HVLT (P < .001). Having hypertension and APOE-epsilon4 was associated with worse cognitive and CO2 vasoreactivity measures than having neither or either alone (P < .001 for TMT and HVLT, P = .01 for CO2 vasoreactivity). The association between APOE-epsilon4 and cognition was only significant if it was present concurrent with low CO2 vasoreactivity, defined as below the median of the sample (APOE by CO2 vasoreactivity interaction: P = .04 for TMT, P = .04 for HVLT). In hypertension, the association between APOE epsilon4 and executive function was also only significant in participants with lower CO2 vasoreactivity (P = .005 for APOE by CO2 vasoreactivity). CONCLUSION: Individuals at risk of Alzheimer's disease (AD) because they have APOE-epsilon4 may have lower CO2 vasoreactivity, which in turn may be contributing to the observed lower cognitive performance associated with this allele. The cognitive effect of APOE-epsilon4 is magnified in hypertension and low CO2 vasoreactivity. This study offers evidence that APOE-epsilon4 may be associated with microvascular brain injury even in the absence of clinical AD. PMID- 25688604 TI - Unmet needs of caregivers of individuals referred to a dementia care program. AB - OBJECTIVES: To characterize caregiver strain, depressive symptoms, and self efficacy for managing dementia-related problems and the relationship between these and referring provider type. DESIGN: Cross-sectional observational cohort. SETTING: Urban academic medical center. PARTICIPANTS: Caregivers of community dwelling adults with dementia referred to a dementia care management program. MEASUREMENTS: Caregivers were surveyed and completed the Patient Health Questionnaire (PHQ-9) about themselves; the Modified Caregiver Strain Index; the Neuropsychiatric Inventory Questionnaire, which measures patient symptom severity and related caregiver distress; and a nine-item caregiver self-efficacy scale developed for the study. RESULTS: Of 307 patient-caregiver dyads surveyed over a 1-year period, 32% of caregivers reported confidence in managing dementia-related problems, 19% knew how to access community services to help provide care, and 28% agreed that the individual's provider helped them work through dementia care problems. Thirty-eight percent reported high levels of caregiver strain, and 15% reported moderate to severe depressive symptoms. Caregivers of individuals referred by geriatricians more often reported having a healthcare professional to help work through dementia care problems than those referred by internists, family physicians, or other specialists, but self-efficacy did not differ. Low caregiver self-efficacy was associated with higher caregiver strain, more caregiver depressive symptoms, and caring for an individual with more-severe behavioral symptoms. CONCLUSION: Most caregivers perceived inadequate support from the individual's provider in managing dementia-related problems, reported strain, and had low confidence in managing caregiving. New models of care are needed to address the complex care needs of individuals with dementia and their caregivers. PMID- 25688605 TI - Use of atypical antipsychotics in nursing homes and pharmaceutical marketing. AB - OBJECTIVES: To describe the current extent and type of pharmaceutical marketing in nursing homes (NHs) in one state and to provide preliminary evidence for the potential influence of pharmaceutical marketing on the use of atypical antipsychotics in NHs. DESIGN: Nested mixed-methods, cross-sectional study of NHs in a cluster randomized trial. SETTING: Forty-one NHs in Connecticut. PARTICIPANTS: NH administrators, directors of nursing, and medical directors (n = 93, response rate 75.6%). MEASUREMENTS: Quantitative data, including prescription drug dispensing data (September 2009-August 2010) linked with Nursing Home Compare data (April 2011), were used to determine facility-level prevalence of atypical antipsychotic use, facility-level characteristics, NH staffing, and NH quality. Qualitative data, including semistructured interviews and surveys of NH leaders conducted in the first quarter of 2011, were used to determine encounters with pharmaceutical marketing. RESULTS: Leadership at 46.3% of NHs (n = 19) reported pharmaceutical marketing encounters, consisting of educational training, written and Internet-based materials, and sponsored training. No association was detected between level of atypical antipsychotic prescribing and reports of any pharmaceutical marketing by at least one NH leader. CONCLUSION: NH leaders frequently encounter pharmaceutical marketing through a variety of ways, although the impact on atypical antipsychotic prescribing is unclear. PMID- 25688606 TI - Functional performance as a predictor of injurious falls in older adults. AB - OBJECTIVES: To determine whether a performance battery and its components aid in predicting injurious falls. DESIGN: Longitudinal analysis; prospective cohort study. SETTING: Clinical site. PARTICIPANTS: Boston-area community-dwelling adults (N = 755; mean age +/- SD 78.1 +/- 5.4, 64.1% female, 77.6% white). MEASUREMENTS: Baseline functional performance was determined according to the Short Physical Performance Battery (SPPB), measuring balance, gait speed, and five repeated chair stands. Fall history (past year) and efficacy in performing 10 daily activities without falling were assessed. Falls were assessed using a daily calendar over 4 years. Injurious falls were defined as resulting in fractures, sprains, dislocations, pulled or torn muscles, ligaments, or tendons or seeking medical attention. RESULTS: Poorest chair stand performance (>=16.7 seconds) was associated with greater hazard of injurious falls than in all other chair stand performance groups (hazard ratio (HR) = 1.96, 95% confidence interval (CI) = 1.18-3.26 for >= 16.7 vs. 13.7-16.6 seconds; HR = 1.65, 95% CI = 1.07-2.55 for >= 16.7 vs. 11.2-13.6 seconds, HR = 1.60, 95% CI = 1.03-2.48 for >= 16.7 vs. <11.2 seconds). SPPB did not predict injurious falls. Fall history predicted injurious falls (HR = 1.82, 95% CI = 1.39-2.39); falls efficacy did not. Fall history and a slow chair stand (<16.7 seconds) had a 2-year cumulative incidence rate of an injurious fall of 46% (95% CI = 0.34-0.58), nearly the combined rate of a positive fall history (0.29, 95% CI = 0.25-0.34) and a slow chair stand alone (0.21, 95% CI = 0.13-0.30). CONCLUSION: An easily administered chair stand test may be sufficient for evaluating performance as part of a risk stratification strategy for injurious falls. PMID- 25688607 TI - Impact of traditional Chinese medicine on age trajectories of health: evidence from the Taiwan Longitudinal Study on Aging. AB - Although traditional Chinese medicine (TCM) is widely used, its effect on health outcomes is not well understood. This study employed a cohort sequential design to investigate levels and rates of change in health from midlife to older adulthood in TCM users and nonusers. A sample of 1,302 community-dwelling adults aged 53 to 80 was selected from individuals interviewed in the 1999 Taiwan Longitudinal Study on Aging (TLSA) and reinterviewed in 2003 and 2007. TCM users were identified as participants who reported visiting a Chinese medicine clinic in the year before each of the three interviews. Health outcomes included physical function, self-rated health, cognitive function, and depressive symptoms. Approximately one in five adults reported that they used TCM in at least one wave of the 3 interview years, but less than one in twenty across all waves. Controlling for time-varying sociodemographic and health conditions, levels and rates of change in physical and cognitive function did not differ according to TCM use. Although adults who reported using TCM had higher depressive symptoms (betaTCM = 0.979, 95% confidence interval (CI) = 0.200-1.758) and poorer self-rated health (betaTCM = -0.267, 95% CI = -0.267 to -0.081) at baseline, their rates of change in these outcomes did not differ from those who did not use TCM. Subgroup analyses revealed that TCM use benefited adults with higher depressive symptoms by attenuating worsening depressive symptoms (betaTCM *Age = -0.221, 95% CI = -0.434 to -0.007). Further research aimed at understanding the specific mechanisms by which TCM affects health outcomes is warranted. PMID- 25688608 TI - Oral health care for older adults with serious illness: when and how? PMID- 25688609 TI - Relationship between dental health and nutrition risk factors in homebound older adults. PMID- 25688610 TI - Almost half of octogenarians and nonagenarians admitted acutely to internal medicine ward die during admission or within 6 months after discharge: time to redefine treatment goals? PMID- 25688611 TI - Memantine standard tablet and extended-release dosing considerations: a pharmacokinetic analysis. PMID- 25688612 TI - Primary percutaneous coronary intervention for ST elevation myocardial infarction in nonagenarians: a multicenter study. PMID- 25688613 TI - Exercise without digestive enzyme supplementation worsens nutritional status of frail older women. PMID- 25688614 TI - Continuous positive airway pressure therapy improves stage 1 and stage 2 sleep nocturia in individuals with obstructive sleep apnea. PMID- 25688615 TI - Regular aspirin use does not reduce risk of cognitive decline. PMID- 25688616 TI - Does physical activity change after progressive resistance exercise in functionally limited older adults? PMID- 25688617 TI - Effect of early diagnosis and lifestyle modification on depressive symptoms in community-dwelling elderly adults with glucose intolerance: 5-year longitudinal study. PMID- 25688618 TI - Comparison of effects of resistance and multicomponent training on falls prevention in institutionalized elderly women. PMID- 25688619 TI - Cognitive decline and polypharmacy in an elderly population. PMID- 25688620 TI - Nizatidine ameliorates slow transit constipation in Parkinson's disease. PMID- 25688621 TI - Complex percutaneous coronary intervention in a nonagenarian presenting with a non-ST elevation myocardial infarction: are we going too far? PMID- 25688622 TI - Ethnic differences in rates and causes of falls in an urban community-dwelling older population in South Africa. PMID- 25688623 TI - Takotsubo cardiomyopathy and elderly adults: still a benign condition? PMID- 25688624 TI - Low thyroid function and anemia in old age: the Leiden 85-plus study. PMID- 25688625 TI - Patent ductus arteriosus in older adults: incidental finding or relevant pathology? PMID- 25688626 TI - Elderly-onset neuromyelitis optica spectrum disorders. PMID- 25688627 TI - Black hairy tongue treated with oral antibiotics: a case report. PMID- 25688628 TI - Primary hyperparathyroidism in an older woman with multiple comorbidities: a case study. PMID- 25688629 TI - Evaluation of aortic inflammation using computed tomographic angiography: vasculitis, atherosclerosis, or both. PMID- 25688630 TI - Symptom improvement and cachexia reversal in an 84-year-old woman after percutaneous closure of atrial septal defect. PMID- 25688631 TI - Derailed dementia: Alzheimer's disease versus posterior cortical atrophy. PMID- 25688632 TI - Improvement of age-related memory impairment with infusion of young plasma: a role for the peripheral amyloid sink? PMID- 25688633 TI - Access of elderly adults to potentially inappropriate medications in the Brazilian health system. PMID- 25688635 TI - The Andreev reflection of zero line mode in graphene-superconductor hybrid junction. AB - The zero line mode (ZLM) in two dimensional materials provides a quasi-one dimensional path for electronic transport. We report the theoretical investigation of the Andreev reflection of ZLM by using the staggered graphene superconductor based models. For a two-terminal system in which the valley index is well preserved, when graphene is zigzag edged, the Andreev reflection coefficient can be either large or strongly suppressed depending on the symmetric properties of the transverse wave function in graphene ribbon. However, the Andreev reflection coefficient, independent of the staggering profile in the armchair edged model, is large due to the absence of wave function symmetry. When ZLM changes its direction in a vertical path, a perfect Andreev reflection could happen when the incident ZLM stems from a zigzag edged graphene ribbon. In a zigzag edged four-terminal hybrid model, the interference of reflected holes leads to perfect Andreev reflection with probability unity and the annihilation of the crossed Andreev reflection. For the armchair edged model, the interference effect disappears because the Andreev reflection from one of the paths is prohibited. The interference of Andreev reflections in four-terminal models is investigated by spacial local density of states in the central scattering region as well. PMID- 25688636 TI - Programming the brain and behaviour by early-life stress: a focus on neuroactive steroids. AB - Animal studies have amply demonstrated that stress exposure during pregnancy or in early postnatal life can adversely influence brain development and have long term 'programming' effects on future brain function and behaviour. Furthermore, a growing body of evidence from human studies supports the hypothesis that some psychiatric disorders may have developmental origins. Here, the focus is on three adverse consequences of early-life stress: dysregulation of the hypothalamic pituitary-adrenal (HPA) axis, heightened anxiety behaviour and cognitive impairments, with review of what is known about the underlying central mechanisms. Neuroactive steroids modulate neuronal activity and play a key role in neurodevelopment. Moreover they can negatively modulate activity of the HPA axis, exert anxiolytic actions and influence cognitive performance. Thus, neuroactive steroids may provide a link between early-life stress and the resultant adverse effects on the brain and behaviour. Here, a role for neuroactive steroids, in particular the 5alpha-reduced/3alpha-hydroxylated metabolites of progesterone, testosterone and deoxycorticosterone, is discussed in the context of early-life stress. Furthermore, the impact of early-life stress on the brain's capacity to generate neurosteroids is considered and the evidence for an ability of neuroactive steroids to over-write the negative effects of early-life stress on the brain and behaviour is examined. An enhanced understanding of the influence of early-life stress on brain neurosteroid systems could aid the identification of new targets for developing treatments for stress related conditions in humans. PMID- 25688637 TI - Adverse Effects of Grape Seed Extract Supplement: A Clinical Case and Long-Term Follow-Up. AB - Grape seed extract (GSE) supplement use is becoming more popular today for its potential chemopreventive and chemotherapeutic role. We report a 49-year-old male who presented with recurrent nausea, vomiting, diarrhea, and acute weakness following GSE use. A thorough medical workup ensued and no causes were identified clinically, procedurally, or with imaging. Symptoms resolved after GSE discontinuation and the patient remained symptom-free 5 years later. This case illustrates the paucity of documented detailed clinical cases and lack of controlled trials detailing a thorough and reproducible adverse effect profile of GSE supplement. PMID- 25688638 TI - Mitigation of Systemic Oxidative Stress by Curcuminoids in Osteoarthritis: Results of a Randomized Controlled Trial. AB - Oxidative stress is implicated in the pathogenesis of osteoarthritis. Curcuminoids are natural polyphenols with strong antioxidant capacity and may thus be helpful in the treatment of osteoarthritis. The present randomized double blind placebo-controlled trial investigated the efficacy of curcuminoids in reducing systemic oxidative burden in patients suffering from knee osteoarthritis. Forty patients with mild-to-moderate primary knee osteoarthritis were given curcuminoid capsules (1500 mg/day in 3 divided doses; n = 19) or matched placebo capsules (n = 21) for a period of 6 weeks. Curcuminoids were co administered with piperine (15 mg/day) in order to improve the bioavailability. Serum activities of superoxide dismutase (SOD) and concentrations of reduced glutathione (GSH) and malonedialdehyde (MDA) were determined spectrophotometrically at baseline and at the end of the treatment period in both groups. Serum activities of SOD as well as GSH and MDA concentrations were comparable between the study groups at baseline (p > 0.05). There was a significant elevation in serum SOD activities (mean change: 2.94 +/- 3.73 vs. 0.38 +/- 1.33; p < 0.001), a borderline significant elevation in GSH concentrations (mean change: 1.39 +/- 2.78 vs. -0.02 +/- 1.62; p = 0.064) and a significant reduction in MDA concentrations (mean change: -5.26 +/- 4.46 vs. 2.49 +/- 3.81; p = 0.044) in the curcuminoids compared with the placebo group. Changes in serum activities of SOD and concentrations of GSH and MDA during the course of trial were significantly correlated. Short-term supplementation with curcuminoids attenuates systemic oxidative stress in patients with osteoarthritis. These antioxidant effects may account for the reported therapeutic effects of curcuminoids in relieving osteoarthritis symptoms. PMID- 25688639 TI - Methicillin-Resistant Staphylococcus aureus central nervous system infections- Analysis and outcome. AB - INTRODUCTION: Methicillin-Resistant Staphylococcus aureus (MRSA)-associated infections are potentially devastating and fatal. It has two distinct pathogenic mechanisms: postoperative and spontaneous. In the study presented here, we review the epidemiology, clinical features, response to treatment, and outcome of MRSA central nervous system infections at our tertiary referral institute. MATERIAL AND METHODS: In this analysis, we reviewed the medical records of all patients who were diagnosed with S. aureus meningitis between January 2010 and December 2012. Clinical information included predisposing factors, past medical history, comorbidities, mode of acquisition of infection, as well as therapeutic management, length of treatment, and clinical outcomes were analyzed. RESULTS: A total of 34 cases of MRSA meningitis were diagnosed during the study period. There were 28 (82.4%) cases of postoperative meningitis and 6 (17.6%) cases of spontaneous meningitis. A majority (24/28) of the patients had one or the other predisposing conditions for the infection. Compared with patients with postoperative meningitis, patients with spontaneous meningitis had a significantly older (31.93 yrs vs 55.8 yrs; p = 0.021) and higher frequency of community-acquired infection (100% vs. 39%; p = 0.007). In patients with postoperative meningitis, the median postoperative day when the infection manifested clinically was day- 19 (range, 3-90 days). A total of 25/34 (74%) patients received definitive antibiotic (vancomycin and/or linezolid based) therapy. Nine patients were continued on empirical antimicrobial therapy (combination of ceftriaxone, amikacin, and metronidazole), as the organism was sensitive to those drugs. There were no in-hospital mortalities in our series, though 3/34 patients (8.8%) were discharged with Glasgow coma score (GCS)< 8 and 8/34 patients (23.5%) were discharged with GCS 9-12 from the hospital. CONCLUSION: In acute bacterial meningitis, there is a progressive shift from methicillin-sensitive strains to methicillin-resistant strains in recent years. Although most patients have a favorable response to vancomycin and linezolid, the beneficial effect of combined antimicrobial therapy or alternative antibiotics needs to be evaluated. PMID- 25688640 TI - Are we on the same page? The performance effects of congruence between supervisor and group trust. AB - Taking a multiple-stakeholder perspective, we examined the effects of supervisor work group trust congruence on groups' task and contextual performance using a polynomial regression and response surface analytical framework. We expected motivation experienced by work groups to mediate the positive influence of trust congruence on performance. Although hypothesized congruence effects on performance were more strongly supported for affective rather than for cognitive trust, we found significant indirect effects on performance (via work group motivation) for both types of trust. We discuss the performance effects of trust congruence and incongruence between supervisors and work groups, as well as implications for practice and future research. PMID- 25688641 TI - The interplay of diversity training and diversity beliefs on team creativity in nationality diverse teams. AB - Attaining value from nationality diversity requires active diversity management, which organizations often employ in the form of diversity training programs. Interestingly, however, the previously reported effects of diversity training are often weak and, sometimes, even negative. This situation calls for research on the conditions under which diversity training helps or harms teams. We propose that diversity training can increase team creativity, but only for teams with less positive pretraining diversity beliefs (i.e., teams with a greater need for such training) and that are sufficiently diverse in nationality. Comparing the creativity of teams that attended nationality diversity training versus control training, we found that for teams with less positive diversity beliefs, diversity training increased creative performance when the team's nationality diversity was high, but undermined creativity when the team's nationality diversity was low. Diversity training had less impact on teams with more positive diversity beliefs, and training effects were not contingent upon these teams' diversity. Speaking to the underlying process, we showed that these interactive effects were driven by the experienced team efficacy of the team members. We discuss theoretical and practical implications for nationality diversity management. PMID- 25688642 TI - Utilization of evidence-based psychotherapies in Veterans Affairs posttraumatic stress disorder outpatient clinics. PMID- 25688643 TI - Browning phenomenon of medieval stained glass windows. AB - In this work, three pieces of historical on-site glass windows dated from the 13th to 16th century and one archeological sample (8th century) showing Mn-rich brown spots at their surface or subsurface have been characterized by optical microscopy and Scanning Electron Microscopy coupled with Energy Dispersive X-ray spectroscopy. The oxidation state of Mn as well as the Mn environment in the alteration phase have been characterized by X-ray absorption spectroscopy at the Mn K-edge. Results show that the oxidation state of Mn and therefore the nature of the alteration phase varies according to the sample considered and is correlated with the extent of the brown alteration. The larger the brown areas the more oxidized the Mn. However, by contrast with literature, the samples presenting the more extended brown areas are not similar to pyrolusite and contain Mn mainly under a (+III) oxidation state. PMID- 25688644 TI - Headache editorial board declaration of conflicts of interest. PMID- 25688645 TI - Clinical and radiological findings suggesting disorders other than tolosa-hunt syndrome among ophthalmoplegic patients: a retrospective analysis. AB - OBJECTIVE: To investigate clinical and radiological features of Tolosa-Hunt syndrome (THS) and examine their diagnostic value, and to propose clinical and radiological features that indicate other symptomatic painful ophthalmoplegias (SPOs) in order to distinguish them from THS. BACKGROUND: Clinical presentations of THS are nonspecific and may overlap with many etiologies. Therefore, excluding other SPOs is essential for correct diagnosis. At the present time, the predictive value of the current International Classification of Headache Disorders (ICHD) criteria is not well established, and specific imaging markers that can discriminate SPOs from THS are lacking. METHODS: Patients referred with painful ophthalmoplegia over 12 years were recruited retrospectively and allocated into THS or SPO groups. Typical symptoms (episodic unilateral orbital pain preceding or developing with diplopia) and imaging of THS (inflammatory lesions in the cavernous sinus/orbit by magnetic resonance imaging) were proposed based on ICHD-3 beta criteria and previous literature. Atypical clinical and radiological features suggesting alternative diagnoses were also proposed to predict SPO. Initial presentations and imaging findings were registered and correlated with diagnostic outcomes. The predictive value of clinical and imaging findings was then evaluated. RESULTS: Of the 61 referred cases, 25 were classified as THS and 36 as SPO. Of the SPO cases, 52.8% manifested typical THS symptoms at onset. Patients with SPOs were prone to have atypical symptoms (47.2%) and radiographical findings (82.1%) in comparison to those with THS (4.0% and 4.2%, respectively; both P < .001). Both typical symptoms and imaging findings predicted a diagnosis of THS with high sensitivity (95.8% and 100%, respectively) but low specificity (47.2% and 28.6%, respectively). High sensitivity (82.1%) and specificity (95.8%) were achieved using atypical imaging features to predict SPO. CONCLUSION: A diagnosis of THS based strictly on clinical presentations or imaging results is not completely reliable. Identification of atypical imaging features may have a useful role in discriminating SPOs and thus avoid erroneous diagnoses of THS. Future studies with larger sample sizes are warranted to evaluate their validity in general population. PMID- 25688646 TI - The neuropsychology of cluster headache: cognition, mood, disability, and quality of life of patients with chronic and episodic cluster headache. AB - BACKGROUND: Cluster headache (CH) is commonly regarded as one of the most disabling headache conditions, and referred to as one of the most painful conditions known to humankind. Although there has been some research indicating the severe impact of CH, there is little comprehensive evidence of its impact on quality of life, disability, mood, and cognitive function in both its episodic (ECH) and chronic (CCH) variants. METHODS: This cross-sectional study investigates various aspects of cognitive function including intelligence, executive function, and memory, and mood, disability, and quality of life in 22 patients with ECH and CCH compared with age-matched healthy controls. RESULTS: The results showed that intelligence and executive functions are intact in patients with CH, but that patients with CH perform significantly worse than healthy controls on tests of working memory and (all P < .05) report greater cognitive failures (P < .05). Around one third of both the ECH and CCH groups achieved "caseness" for depression, while self-reported anxiety was higher in those with CCH than the ECH patients, with 75% of the former compared with 38% of the latter groups achieving "caseness" on the measure of anxiety. Patients with CH reported high levels of disability, which was not significantly different between the 2 groups (P > .05). The patients with CH reported poor quality of life compared with healthy controls; however, this difference was not statistically significant. CONCLUSION: Patients with CH show worse working memory, disturbance of mood, and poorer quality of life compared with healthy controls. The differences between patients with ECH and CCH, and the implications of these findings for the management of CH are discussed. PMID- 25688647 TI - Relationship between sleep bruxism and migraine in children--is it a different history? PMID- 25688648 TI - Bars and medals. AB - There can only be one gold medal in each event at the Olympics. In science, on the other hand, as. PMID- 25688649 TI - Supplementation of laying-hen feed with annatto tocotrienols and impact of alpha tocopherol on tocotrienol transfer to egg yolk. AB - Hens can efficiently transfer nutrients from their feed to the eggs. Tocotrienols (T3s) have various health benefits including lowering cholesterol. Annatto is the only known source of T3s without the presence of alpha-tocopherol; hence it can be used to study T3 transfer without the interference of alpha-tocopherol. In this study, hens were fed diets for 7 weeks containing annatto at 100, 500, or 2000 ppm (by weight) and also 2000 ppm annatto with 200, 600, or 1000 ppm of added alpha-tocopherol to study the effect of alpha-tocopherol on transfer of T3s. No significant differences were found in egg production or properties. Significant differences (p < 0.05) were found in transfer efficiencies of tocopherol and T3s to the yolks. alpha-Tocopherol was transferred more efficiently (21.19-49.17%) than gamma-T3 (0.50-0.96%) or delta-T3 (0.74-0.93%). Addition of 1000 ppm of alpha-tocopherol decreased the amount of gamma-T3 but did not impact the transfer of delta-T3 to the egg. These feeding treatments did not impact the cholesterol content of the eggs. PMID- 25688650 TI - Constructing the meaning of ultrasound viewing in abortion care. AB - As ultrasound scanning becomes increasingly routine in abortion care, scholars and activists have forwarded claims about how viewing the ultrasound image will affect pregnant women seeking abortion, speculating that it will dissuade them from abortion. These accounts, however, fail to appreciate how viewing is a social process. Little research has investigated how ultrasound workers navigate viewing in abortion care. We draw on interviews with twenty-six ultrasound workers in abortion care for their impressions and practices around ultrasound viewing. Respondents reported few experiences of viewing dissuading women from abortion, but did report that it had an emotional effect on patients that they believed was associated with gestational age. These impressions informed their practices, leading many to manage patient viewing based on the patient's gestational age. Other aspects of their accounts, however, undercut the assertion that the meaning of ultrasound images is associated with gestation and show the pervasiveness of cultural ideas associating developing foetal personhood with increasing gestational age. Findings demonstrate the social construction of ultrasound viewing, with implications in the ongoing contestation over abortion rights in the US. PMID- 25688651 TI - Simultaneous in vivo imaging of blood and lymphatic vessel growth in Prox1 GFP/Flk1::myr-mCherry mice. AB - The ability to visually observe angiogenesis and lymphangiogenesis simultaneously and repeatedly in living animals would greatly enhance our understanding of the inter-dependence of these processes. To generate a mouse model that allows such visualization via in vivo fluorescence imaging, we crossed Prox1-GFP mice with Flk1::myr-mCherry mice to generate Prox1-GFP/Flk1::myr-mCherry mice, in which lymphatic vessels emit green fluorescence and blood vessels emit red fluorescence. Corneal neovascularization was induced in these mice using three injury models: implantation of a vascular endothelial growth factor (VEGF) pellet, implantation of a basic fibroblast growth factor (bFGF) pellet, and alkali burn injury. Vessel growth was observed in vivo by stereomicroscopy on days 0, 3, 7 and 10 after pellet implantation or alkali injury as well as in flat mounted corneas via confocal microscopy after the final in vivo imaging time point. We observed blood and lymphatic vessel growth in all three models, with the most significant growth occurring from days 0-7. Upon VEGF stimulation, the growth kinetics of blood and lymphatic vessels were similar. Blood vessels exhibited similar growth patterns in VEGF- and bFGF-stimulated corneas. Alkali burn injury induced robust angiogenesis and lymphangiogenesis. The intrinsic fluorescence of blood and lymphatic endothelial cells in Prox1-GFP/Flk1::myr mCherry mice permitted simultaneous in vivo imaging of angiogenesis and lymphangiogenesis. This allowed us to differentiate the processes as well as observe their inter-dependence, and will be valuable in development of therapies targeting angiogenesis and/or lymphangiogenesis. PMID- 25688652 TI - Cell cannibalism by malignant neoplastic cells: three cases in dogs and a literature review. AB - Cell cannibalism refers to the engulfment of cells by nonprofessional phagocytic cells. Studies in human medicine have demonstrated a relationship between the presence of cell cannibalism by neoplastic cells and a poor outcome, and have shown a positive correlation with the presence of metastasis at the time of diagnosis. The biologic significance of cell cannibalism is unknown, but it is proposed that it may represent a novel mechanism of tumor immune evasion as a survival strategy in cases of unfavorable microenvironmental conditions. This report describes clinical and morphologic features of 3 cases of dogs with malignant neoplasia in which the presence of cellular cannibalism was observed in cytologic and histologic specimens. In the 1(st) case, a dog with a primary tonsillar squamous cell carcinoma with metastasis to retropharyngeal lymph nodes had neoplastic epithelial cells engulfing neutrophils noted in cytologic examination of the lymph nodes. In the 2(nd) case, neoplastic epithelial cells were seen engulfing each other in fine-needle aspirates from a primary mammary carcinoma with lung metastasis. In the 3(rd) case, poorly differentiated neoplastic mast cells from a recurrent, metastatic grade III mast cell tumor were observed cannibalizing eosinophils. A brief review of the literature describing known cell-into-cell relationships and the possible biologic significance and mechanisms involved in this phenomenon is provided. The relationship between cell cannibalism and distant metastasis should be explored in further studies, as it may prove to be a criterion of malignancy, as it is proposed in human medicine. PMID- 25688653 TI - Wound-related complications and clinical outcomes following open globe injury repair. AB - BACKGROUND: Careful surgical management of traumatic wounds is important in open globe injury repair. This study examines the clinical outcomes following repair of open globe injuries with particular focus on wound-related issues. DESIGN: Retrospective, cohort study of consecutive open globe injuries presenting to a tertiary referral eye hospital from 1 January 2009 to 31 December 2011. PARTICIPANTS: A total of 267 eyes of 263 patients, mainly male (82.5%) with a mean age of 44.8 (range: 4-97) years. Average follow up was 6.9 months. METHODS: All cases classified according to Ocular Trauma Classification Group. MAIN OUTCOME MEASURES: Visual outcomes, risk factors for and rates of postoperative complications and endophthalmitis. RESULTS: There were 83 globe ruptures, 182 penetrating and 2 perforating eye injuries, of which 43 cases had intraocular foreign body. Factors contributing to final visual acuity (VA) <6/60 were poor presenting VA (odds ratio [OR] = 16.0, 95% confidence interval [CI]: 4.81-53.1), globe rupture (OR = 4.64, [1.99-10.8]), retinal detachment (OR = 3.40, [1.19 9.74]) and age >=50 (OR = 2.45, [1.05-5.74]). Wound leak occurred in 44 eyes (16%). Of these, 18 (41%) proceeded to re-suturing. Factors contributing to wound leak were stellate-shaped wound (OR = 3.28, [1.39-7.73]) and delayed presentation (OR = 2.80, [1.02-7.71]). Ten eyes (3.7%) developed endophthalmitis. Factors associated with endophthalmitis were delayed presentation (OR = 8.91, [1.71 46.6]), microbial keratitis (OR = 12.5, [1.85-85.0]) and lens capsule breach (OR = 12.4, [1.85-83.1]). CONCLUSIONS: Wound leak is an important postoperative complication of open globe injury repair. Delayed presentation is an important risk factor for postoperative wound leak and endophthalmitis. Prompt and meticulous wound management of open globe injury may reduce these complications. PMID- 25688654 TI - Abutment emergence contours for single-unit implants. PMID- 25688655 TI - Critical appraisal. Evidence for sealing versus restoration of early caries lesions. AB - Resin-based pit and fissure sealants are established tools for prevention of dental caries. Conversely, the role of sealants for management of existing early dental caries lesions has been disputed despite the recommendation from the American Dental Association Council on Scientific Affairs. The development of more sensitive caries detection technologies has revealed that many sealants have likely been placed over incipient lesions inadvertently over the years. However, the issue remains whether sealing overt incipient occlusal caries lesions leads to a worse outcome versus restoring the surface. Certainly, there are diverse opinions regarding this topic. But what does the science say? This Critical Appraisal presents evidence from several clinical trials for sealing incipient occlusal caries lesions. PMID- 25688656 TI - Modulated two-dimensional charge-carrier density in LaTiO3-layer-doped LaAlO3/SrTiO3 heterostructure. AB - The highly mobile two-dimensional electron gas (2DEG) formed at the polar/nonpolar LaAlO3/SrTiO3 (LAO/STO) heterostructure (HS) is a matter of great interest because of its potential applications in nanoscale solid-state devices. To realize practical implementation of the 2DEG in device design, desired physical properties such as tuned charge carrier density and mobility are necessary. In this regard, polar perovskite-based transition metal oxides can act as doping layers at the interface and are expected to tune the electronic properties of 2DEG of STO-based HS systems dramatically. Herein, we investigated the doping effects of LaTiO3(LTO) layers on the electronic properties of 2DEG at n-type (LaO)(+1)/(TiO2)(0) interface in the LAO/STO HS using spin-polarized density functional theory calculations. Our results indicate an enhancement of orbital occupation near the Fermi energy, which increases with respect to the number of LTO unit cells, resulting in a higher charge carrier density of 2DEG than that of undoped system. The enhanced charge carrier density is attributed to an extra electron introduced by the Ti 3d(1) orbitals from the LTO dopant unit cells. This conclusion is consistent with the recent experimental findings (Appl. Phys. Lett. 2013, 102, 091601). Detailed charge density and partial density of states analysis suggests that the 2DEG in the LTO-doped HS systems primarily comes from partially occupied dyz and dxz orbitals. PMID- 25688657 TI - Haemophilia pseudotumours in patients with inhibitors. AB - Development of inhibitors against factor VIII (FVIII) or FIX is the most serious complication of replacement therapy in patients with haemophilia. Haemophilic pseudotumours in a patient with inhibitors can lead to devastating consequences. The aim of this study is to show our experience in the treatment of 10 pseudotumours in 7 patients with inhibitors who were treated by the same multidisciplinary team in the period between January 2000 and March 2013. Seven severe haemophilia A patients were treated at the Haemophilia Foundation in Buenos Aires, Argentina, for 10 pseudotumours. Eight were bone pseudotumours and two soft tissue. All patients underwent imaging studies at baseline to assess the size and content of the lesion. The patients received Buenos Aires protocol as conservative treatment of their pseudotumours for 6 weeks, after which they were evaluated. Only one patient responded to conservative treatment. Surgery was performed on the others six patients, since their pseudotumours did not shrink to less than half their original size. Any bleeding in the musculoskeletal system must be treated promptly in order to prevent pseudotumours. When pseudotumours do appear in inhibitor patients, they can be surgically removed when patients received proper haemostatic coverage, improving the quality of life of these patients. PMID- 25688658 TI - The role of executive functions in bilingual children with reading difficulties. AB - To explore the joint effect of reading difficulties (RD) and bilingualism on executive functions, 190 children of four groups of 9-12 year-olds (41 bilinguals with RD, 45 monolinguals with RD, 45 bilinguals without RD, and 59 monolinguals without RD) were examined on the Concentration game, Tower of Hanoi, and Stroop as measures of executive functioning tapping into inhibitory/attentional control, working memory and planning ability. The most prominent finding was that in terms of RD, the speed of performances decreased dramatically. This general decrease was more pronounced for bilingual children with RD than for their monolingual counterparts. In conclusion, the findings suggest that while bilinguals gain more from executive functions in normal reading, they lose in terms of RD. Such an outcome confirms that executive functions are essential components of both reading and bilingualism, which depending on whether reading conditions are normal or difficult will produce cognitive advantages or disadvantages. Further, it is argued that dissimilarity between the Farsi and Swedish languages may complicate handling of such a situation. PMID- 25688659 TI - Obesity and vitamin D deficiency: a systematic review and meta-analysis. AB - Over the past decade, there have been an increasing number of studies on the association between vitamin D deficiency and anthropometric state. However, we did not identify any meta-analyses of the relationship between obesity and vitamin D deficiency in different age groups. Thus, we evaluated the association between obesity and vitamin D deficiency. We searched for observational studies published up to April 2014 in PubMed/Medline, Web of Science and Scopus databases. We performed a meta-analysis in accordance with the random-effects model to obtain the summary measurement (prevalence ratio, PR). Among the 29,882 articles identified, 23 met the inclusion criteria. The prevalence of vitamin D deficiency was 35% higher in obese subjects compared to the eutrophic group (PR: 1.35; 95% CI: 1.21-1.50) and 24% higher than in the overweight group (PR: 1.24; 95% CI: 1.14-1.34). These results indicate that the prevalence of vitamin D deficiency was more elevated in obese subjects. The vitamin D deficiency was associated with obesity irrespective of age, latitude, cut-offs to define vitamin D deficiency and the Human Development Index of the study location. PMID- 25688660 TI - Heart Failure With Preserved Ejection Fraction: What Is in a Name? AB - Evidence-based management of heart failure (HF) with preserved left ventricular ejection fraction (LVEF; HFpEF) remains a major gap in the care of patients with HF. Clinical trials directed toward the population with HFpEF have been disappointing, although renin-angiotensin-aldosterone system blockade appears to prevent HF in populations predisposed to HFpEF. This paradox may partly be because of inhomogeneity within the HF populations studied. Although the term HFpEF is often used to imply a specific diagnosis, in fact this constellation may be due to a large variety of disease states with different underlying pathophysiologic mechanisms. Furthermore, in patients with HF, regardless of LVEF, myocardial dysfunction is common during both systole and diastole, and LVEF is influenced at least as much by the pattern of left ventricular remodeling as it is by myocardial contractility. The most common clinical-pathologic syndrome responsible for HFpEF is strongly associated with hypertension, with the metabolic syndrome, and with older age. Recent findings support that this condition is mediated via endothelial dysfunction, inflammation, oxidative stress, myocyte hypertrophy, and altered collagen turnover. We, therefore, propose the terms "metabolic HF" and "senile HF" to describe this specific disease state. The search for therapies designed to prevent, halt, or reverse HF should more strongly focus on populations carefully selected to represent specific underlying cardiovascular disease states. PMID- 25688661 TI - The cardiovascular effects of colchicine: a comprehensive review. AB - Colchicine is used extensively in the treatment of autoimmune and inflammatory disorders. Recent data have demonstrated additional benefit in a variety of cardiovascular disorders, including acute and recurrent pericarditis, postpericardiotomy syndrome, atrial fibrillation, stable ischemic heart disease, and possibly chronic heart failure. This article serves as a focused and updated discussion on the cardiovascular effects of colchicine and emphasizes the importance of randomized, placebo-controlled trials to further our clinical and pharmacological understanding of these findings. PMID- 25688662 TI - Why Does the Bicuspid Aortic Valve Keep Eluding Us? AB - The bicuspid aortic valve (BAV) is, by far, the most common congenital cardiovascular defect encountered by cardiovascular specialists. In the United States, the number of subjects alive is estimated to be 3 million, with an approximate 1% prevalence, more than 10 times higher than the second most common congenital lesion, ventricular septal defect. BAV is subjected to early degeneration and valve dysfunction, requiring surgical intervention in the course of a lifetime for most patients. BAV is also associated with ascending aortic dilatation, also known as BAV aortopathy. Surgical indications for a dysfunctional BAV are relatively straightforward and well established; the same as those for tricuspid aortic valve (TAV), usually triggered by symptoms or ventricular dysfunction. On the other hand, while sharing the same ultimate goal of preventing life-threatening consequences, such as aortic dissection and rupture, surgical thresholds for a dilated ascending aorta are different in the setting of BAV versus TAV; generally lower in BAV. Recently, the incidence of aortic dissection was reported to be much lower than believed, and the idea of more aggressive preemptive intervention on BAV aortopathy has become controversial. Instead, the importance of a more individualized approach is being highlighted. This article will provide a comprehensive review of (1) the typical clinical course of patients with BAV under contemporary management, (2) new risk stratifying parameters proposed to make an individualized approach possible, and (3) practical challenges all cardiovascular specialists need to know when implementing and interpreting future BAV-related studies. PMID- 25688663 TI - Iron Oxide Nanoparticles as Contrast Agents in Molecular Magnetic Resonance Imaging: Do They Open New Perspectives in Cardiovascular Imaging? AB - Molecular magnetic resonance imaging has recently emerged as a powerful tool for the detection and assessment of cardiovascular diseases. Contrast agents have an important role in this novel modality because molecular imaging requires highly sensitive, specific, and efficient imaging agents. Iron oxide nanoparticles (IONs) are a new class of contrast agents with unique properties that provide special opportunities in cardiovascular molecular imaging. IONs are captured by macrophages and can be successfully used in the detection and evaluation of atherosclerotic plaques, abdominal aortic aneurysms, and inflammations related to myocardial infarction. The purpose of this review is to provide a brief description of the basic characteristics of IONs, with a special focus on their role as molecular magnetic resonance imaging contrast agents and their cardiovascular applications. PMID- 25688664 TI - Sulfasalazine attenuates staphylococcal enterotoxin B-induced immune responses. AB - Staphylococcal enterotoxin B (SEB) and related exotoxins are important virulence factors produced by Staphylococcus aureus as they cause human diseases such as food poisoning and toxic shock. These toxins bind directly to cells of the immune system resulting in hyperactivation of both T lymphocytes and monocytes/macrophages. The excessive release of proinflammatory cytokines from these cells mediates the toxic effects of SEB. This study examined the inhibitory activities of an anti-inflammatory drug, sulfasalazine, on SEB-stimulated human peripheral blood mononuclear cells (PBMC). Sulfasalazine dose-dependently inhibited tumor necrosis factor alpha, interleukin 1 (IL-1) beta, IL-2, IL-6, interferon gamma (IFNgamma), and various chemotactic cytokines from SEB stimulated human PBMC. Sulfasalazine also potently blocked SEB-induced T cell proliferation and NFkappaB activation. These results suggest that sulfasalazine might be useful in mitigating the toxic effects of SEB by blocking SEB-induced host inflammatory cascade and signaling pathways. PMID- 25688665 TI - High-throughput and label-free single nanoparticle sizing based on time-resolved on-chip microscopy. AB - Sizing individual nanoparticles and dispersions of nanoparticles provides invaluable information in applications such as nanomaterial synthesis, air and water quality monitoring, virology, and medical diagnostics. Several conventional nanoparticle sizing approaches exist; however, there remains a lack of high throughput approaches that are suitable for low-resource and field settings, i.e., methods that are cost-effective, portable, and can measure widely varying particle sizes and concentrations. Here we fill this gap using an unconventional approach that combines holographic on-chip microscopy with vapor-condensed nanolens self-assembly inside a cost-effective hand-held device. By using this approach and capturing time-resolved in situ images of the particles, we optimize the nanolens formation process, resulting in significant signal enhancement for the label-free detection and sizing of individual deeply subwavelength particles (smaller than lambda/10) over a 30 mm(2) sample field-of-view, with an accuracy of +/-11 nm. These time-resolved measurements are significantly more reliable than a single measurement at a given time, which was previously used only for nanoparticle detection without sizing. We experimentally demonstrate the sizing of individual nanoparticles as well as viruses, monodisperse samples, and complex polydisperse mixtures, where the sample concentrations can span ~5 orders-of magnitude and particle sizes can range from 40 nm to millimeter-scale. We believe that this high-throughput and label-free nanoparticle sizing platform, together with its cost-effective and hand-held interface, will make highly advanced nanoscopic measurements readily accessible to researchers in developing countries and even to citizen-scientists, and might especially be valuable for environmental and biomedical applications as well as for higher education and training programs. PMID- 25688667 TI - Characteristic isotope fractionation patterns in s-triazine degradation have their origin in multiple protonation options in the s-triazine hydrolase TrzN. AB - s-Triazine herbicides (atrazine, ametryn) are groundwater contaminants which may undergo microbial hydrolysis. Previously, inverse nitrogen isotope effects in atrazine degradation by Arthrobacter aurescens TC1 (i) delivered highly characteristic (13C/12C, 15N/14N) fractionation trends for pathway identification and (ii) suggested that the s-triazine ring nitrogen was protonated in the enzyme s-triazine hydrolase (TrzN) where (iii) TrzN crystal structure and mutagenesis indicated H+-transfer from the residue E241. This study tested the general validity of these conclusions for atrazine and ametryn with purified TrzN and a TrzN-E241Q site-directed mutant. TrzN-E241Q lacked activity with ametryn; otherwise, degradation consistently showed normal carbon isotope effects (epsiloncarbon=-5.00/00+/-0.20/00 (atrazine/TrzN), epsiloncarbon=-4.20/00+/ 0.50/00 (atrazine/TrzN-E241Q), epsiloncarbon=-2.40/00+/-0.30/00 (ametryn/TrzN)) and inverse nitrogen isotope effects (epsilonnitrogen=2.50/00+/-0.10/00 (atrazine/TrzN), epsilonnitrogen=2.10/00+/-0.30/00 (atrazine/TrzN-E241Q), epsilonnitrogen=3.60/00+/-0.40/00 (ametryn/TrzN)). Surprisingly, TrzN-E241Q therefore still activated substrates through protonation implicating another proton donor besides E241. Sulfur isotope effects were larger in enzymatic (epsilonsulfur=-14.70/00+/-1.00/00, ametryn/TrzN) than in acidic ametryn hydrolysis (epsilonsulfur=-0.20/00+/-0.00/00, pH 1.75), indicating rate determining C-S bond cleavage in TrzN. Our results highlight a robust inverse 15N/14N fractionation pattern for identifying microbial s-triazine hydrolysis in the environment caused by multiple protonation options in TrzN. PMID- 25688668 TI - Pain can produce systematic distortions of autobiographical memory. AB - OBJECTIVES: Cognitive-behavioral models highlight the role of learning and memory biases in the development and maintenance of chronic pain. However, the extent to which a memory bias is a consequence of the clinical state of being a chronic pain subject is unknown. This article presents a study which delineates the influence of chronic and acute pain on autobiographical memory retrieval. METHODS: 16 healthy controls and 16 individuals with chronic pain participated in an autobiographical memory task during two sessions (a current pain and a pain free session for the chronic pain subjects) and received neutral words that served as a cue for the retrieval of past life events. RESULTS: The valence of remembered life events in individuals with chronic pain was more negative when they were in pain compared to pain-free states. Conversely, both groups did not differ in their ratings of the reported memories during the pain-free condition. In addition, no significant relationship between mood and the valence of retrieved memories was found. CONCLUSIONS: The present data demonstrate that current pain but not chronic pain per se can exert specific influences on remembering in participants with chronic pain. This memory bias could be a predisposition for the development of chronic pain but could also be a pain maintaining consequence of painful experiences. This should be addressed in longitudinal studies. PMID- 25688669 TI - Fluctuations within folded proteins: implications for thermodynamic and allosteric regulation. AB - Folded protein structures are both stable and dynamic. Historically, our clearest window into these structures came from X-ray crystallography, which generally provided a static image of each protein's singular "folded state", highlighting its stability. Deviations away from that crystallographic structure were difficult to quantify, and as a result, their potential functional consequences were often neglected. However, several dynamical and statistical studies now highlight the structural variability that is present within the protein's folded state. Here we review mounting evidence of the importance of these structural rearrangements; both experiment and computation indicate that folded proteins undergo substantial fluctuations that can greatly influence their function. Crucially, recent studies have shown that structural elements of proteins, especially their side-chain degrees of freedom, fluctuate in ways that generate significant conformational heterogeneity. The entropy associated with these motions contributes to the folded structure's thermodynamic stability. In addition, since these fluctuations can shift in response to perturbations such as ligand binding, they may play an important role in the protein's capacity to respond to environmental cues. In one compelling example, the entropy associated with side-chain fluctuations contributes significantly to regulating the binding of calmodulin to a set of peptide ligands. The neglect of fluctuations within proteins' native states was often justified by the dense packing within folded proteins, which has inspired comparisons with crystalline solids. Many liquids, however, can achieve similarly dense packing yet fluidity is maintained through correlated molecular motions. Indeed, the studies we discuss favor comparison of folded proteins not with solids but instead with dense liquids, where the internal side chain fluidity is facilitated by collective motions that are correlated over long distances. These correlated rearrangements can enable allosteric communication between different parts of a protein, through subtle and varied channels. Such long-range correlations appear to be an innate feature of proteins in general, manifest even in molecules lacking known allosteric regulators and arising robustly from the physical nature of their internal environment. Given their ubiquity, it is only to be expected that, over time, nature has refined some subset of these correlated motions and put them to use. Native state fluctuations increasingly appear to be vital for proteins' natural functions. Understanding the diversity, origin, and range of these rearrangements may provide novel routes for rationally manipulating biomolecular activity. PMID- 25688670 TI - A novel mutation in IL36RN underpins childhood pustular dermatosis. AB - BACKGROUND: Chronic pustular dermatoses are severe and debilitating autoinflammatory conditions that can have a monogenic basis. Their clinical features are, however, complex with considerable overlap. Null and missense mutations in the genes encoding interleukin (IL)-1 family (IL-1 and IL-36) anti inflammatory receptor antagonist (Ra) cytokines can underlie the development of severe pustular dermatoses. OBJECTIVE: We present a clinical and genetic study of four children of Pakistani descent with similar clinical presentations and treatment course, each of whom suffers from a severe pustular dermatosis, initially described as a pustular variant of psoriasis. We use DNA sequencing to refine the diagnosis of two of the children studied. METHODS: Bidirectional Sanger sequencing was performed on the coding regions of the IL-1Ra and IL-36Ra genes (IL1RN and IL36RN, respectively), for the four affected children and their parents. RESULTS: We identified a novel homozygous missense mutation in IL36RN in two siblings, and showed the molecular basis of the condition to be both distinct from psoriasis and distinct between the two families studied. CONCLUSIONS: We describe a novel mutation which underpins the diagnosis of childhood pustular dermatosis. Molecular diagnostics can be used to aid the clinical diagnosis and potential treatment of autoinflammatory conditions. PMID- 25688671 TI - The Nuclear Factor kappaB pathway: A link to the immune system in the radiation response. AB - Exposure to ionizing radiation modulates immune responses in a complex dose dependent pattern, with possible anti-inflammatory effects in the low dose range, expression of pro-inflammatory cytokines at moderate doses and immunosuppression after exposure to higher doses due to precursor cell death together with concomitant exacerbated innate immune responses. A central regulator in the immune system is the transcription factor Nuclear Factor kappaB (NF-kappaB). NF kappaB is involved in the regulation of cellular survival, immune responses and inflammation, resulting in eminent importance in cancerogenesis. After exposure to ionizing radiation, NF-kappaB activation is initially triggered by ATM which is activated by DNA double strand breaks. Together with the NF-kappaB essential modulator (NEMO), it serves as a nucleoplasmic shuttle. The pathway converges with the classical NF-kappaB pathway at IkappaB kinase (IKK) complex activation. Resulting cytokine expression can activate NF-kappaB in a positive feed forward loop. Danger signals released from dying cells can activate NF-kappaB via Toll like receptors (TLRs). The resulting immune activation can be beneficial or detrimental. In the low dose range, pro- and anticancerogenic effects are possible. In the radiotherapy-relevant dose range, tolerogenic immune responses should be avoided, and an anti-tumor immune response might be supported by TLR agonists activating NF-kappaB. PMID- 25688672 TI - Relationship between motor skill competency and executive function in children with Down's syndrome. AB - BACKGROUND: Previous studies suggest that children with Down's syndrome (DS), a genetically based neurodevelopmental disorder, demonstrate motor problems and cognitive deficits. The first aim of this study was to examine motor skills and executive functions (EFs) in school-age children with DS. The second aim was to investigate the relationship between these two performance domains. METHODS: The Test of Gross Motor Development (TGMD-2), the Movement Assessment Battery Children-2 checklist (MABC2-checklist) and the Trail-Making Test for young children (Trails-P) were used to assess motor and cognitive performances of 18 children (11 boys, 7 girls) with DS aged between 7 and 11 years (9.06 +/- 0.96) and an age- and sex-matched sample of 18 typically developing (TD) children (11 boys, 7 girls; 8.99 +/- 0.93). RESULTS: Individuals with DS showed the expected difficulties in attentional control, response suppression and distraction, as well as in locomotor and object control skills, as indicated by poorer performance than TD individuals. Motor performance (bottom-up as well as top-down measures) and EF correlated positively, with regard to the group with DS only though. In the most complex task (distraction), the children of the DS group achieving lower locomotor scores showed lower efficacy scores on the Trails-P. Additionally, strong relationships were found for the perspective of teachers on all sections of the MABC2-Checklist and EF. CONCLUSION: The findings from this study suggest that children with DS are not only impaired in higher-order EF, but showing also deficits in locomotor and object control skills. This study stresses the importance of early interventions facilitating cognitive abilities and motor skills. PMID- 25688673 TI - Synovial fluid and synovial membrane mesenchymal stem cells: latest discoveries and therapeutic perspectives. AB - Mesenchymal stem cells (MSCs) have the ability to differentiate into osteoblasts, chondroblasts, adipocytes, and even myoblasts. Most studies have focused on finding MSCs in different parts of the body for medical treatment. Every joint structure, including bone, joint fat, articular cartilage, and synovium, potentially contains resident MSCs. Recently, a progenitor cell population has been found in synovial fluid and showed similarities with both bone marrow and synovial membrane MSCs. Synovial fluid MSCs have been studied in healthy persons and osteoarthritic patients in order to explore its potential for treatment of some orthopedic disorders. Here, we briefly review the current knowledge on synovial fluid MSCs, their origin, relation to some orthopedic diseases, and future applications. PMID- 25688674 TI - High-throughput screening approaches to identify regulators of mammalian autophagy. AB - This article discusses the issues to consider in the development and implementation of high-throughput screens (HTSs) using both siRNA libraries and small molecule compound collections, in order to discover autophagy regulators in mammalian cells. We discuss how to develop the screen, focusing on the key parameters to establish in order to perform a successful screen. As our understanding of autophagy increases and its impact on human disease is elucidated, this technology can be further exploited to uncover novel genes, which may one day become new therapeutic targets. PMID- 25688675 TI - Post-ICU symptoms, consequences, and follow-up: an integrative review. AB - AIM: To determine the symptoms seen in patients after discharge from an intensive care unit (ICU) and the follow-up programmes offered to help patients deal with the problems that arise after an ICU stay. BACKGROUND: An increasing number of people are discharged from an ICU to continued treatment, care and rehabilitation in general hospital wards, rehabilitation facilities and at home. A prolonged stay in an ICU is associated with stressful memories that have long-term physical, mental and social consequences for health-related quality of life. We therefore conducted a data search to identify the programmes that have attempted to cope with these consequences. DATA SOURCES: Searches of six online databases were conducted in December 2013. REVIEW METHODS: Qualitative or quantitative, original, empirical studies on symptoms and consequences associated with ICU stay and the follow-up programmes offered were reviewed. Excluded were studies in ICU patients younger than 18 years published in languages other than Scandinavian or English. We analysed original empirical studies according to symptoms, consequences and follow-up programmes and added a category 'new ideas'. This was done to identify any possible evolution in the programmes offered to patients after ICU care. The review of the literature and the critical analysis were summarized in a figure in order to join the different parts together into a logical, coherent whole. CONCLUSIONS: Patients discharged from an ICU are heterogeneous, with a wide array of physical, mental and social problems. They and their close relatives can benefit from returning together to the ICU or participating in follow-up programmes. Little is known about the specific effects of the different types of follow-up. RELEVANCE TO CLINICAL PRACTICE: ICU staff as well as other professionals should prepare patients and relatives for the fact that they may need various types of help for many months after discharge from the ICU, and an overview of national and local opportunities for help should be offered. PMID- 25688676 TI - Particulate matter composition and respiratory health: the PIAMA Birth Cohort study. AB - BACKGROUND: Ambient particulate matter (PM) exposure is associated with children's respiratory health. Little is known about the importance of different PM constituents. We investigated the effects of PM constituents on asthma, allergy, and lung function until the age of 11-12 years. METHODS: For 3,702 participants of a prospective birth cohort study, questionnaire-reported asthma and hay fever and measurements of allergic sensitization and lung function were linked with annual average concentrations of copper, iron, potassium, nickel, sulfur, silicon, vanadium, and zinc in particles with diameters of less than 2.5 and 10 MUm (PM2.5 and PM10) at birth addresses and current addresses from land use regression models. Exposure-health relations were analyzed by multiple (repeated measures) logistic and linear regressions. RESULTS: Asthma incidence and prevalence of asthma symptoms and rhinitis were positively associated with zinc in PM10 at the birth address (odds ratio [95% confidence interval] per interquartile range increase in exposure 1.13 [1.02, 1.25], 1.08 [1.00, 1.17], and 1.16 [1.04, 1.30], respectively). Moreover, asthma symptoms were positively associated with copper in PM10 at the current address (1.06 [1.00, 1.12]). Allergic sensitization was positively associated with copper and iron in PM10 at the birth address (relative risk [95% confidence interval] 1.07 [1.01, 1.14] and 1.10 [1.03, 1.18]) and current address. Forced expiratory volume in 1 second was negatively associated with copper and iron in PM2.5 (change [95% confidence interval] -2.1% [-1.1, -0.1%] and -1.0% [-2.0, -0.0%]) and FEF75-50 with copper in PM10 at the current address (-2.3% [-4.3, -0.3%]). CONCLUSION: PM constituents, in particular iron, copper, and zinc, reflecting poorly regulated non-tailpipe road traffic emissions, may increase the risk of asthma and allergy in schoolchildren. PMID- 25688677 TI - Systemic opioid elimination after implantation of an intrathecal drug delivery system significantly reduced health-care expenditures. AB - OBJECTIVE: To compare health-care expenditures over a 12-month horizon for chronic pain patients with implanted intrathecal drug delivery systems (IDDS) who eliminated or continued systemic opioids postimplant. METHODS: Claims data from commercial and Medicare databases were searched for patients who had an IDDS, used systemic opioids before implant, and had 12 months pre- and 13 months postimplant continuous medical and pharmacy coverage. The number and characteristics of patients who eliminated or continued systemic opioids were determined at four times postimplant: 30 days (allowing a systemic opioid washout period), 120 days, 150 days, and 210 days. Multivariable models evaluated the effect of eliminating opioids on health-care expenditures at each of those times. RESULTS: Three hundred eighty-nine patients met inclusion criteria, and 51% completely eliminated systemic opioids (12% within the 30-day washout and an additional 39% by the end of the one-year horizon). Systemic opioid elimination within 120 to 210 days postimplant was associated with a reduction of $3,388 to $4,465 in inpatient and outpatient expenditures, and $4,689 to $5,571 in inpatient, outpatient, and drug expenditures. CONCLUSIONS: Fifty-one percent of patients completely eliminated systemic opioids in the year after IDDS implant. This elimination resulted in a 10% to 17% reduction in yearly inpatient, outpatient, and drug expenditures. PMID- 25688678 TI - Writing siblings: Alice James and her brothers. AB - This essay addresses the relationship of writing to embodiment, through representations of bodily sensation and fantasy in the journal of Alice James. It considers Alice James's writing in relation to her two writer brothers, William and Henry, and in light of their father's experiences of impairment and breakdown. PMID- 25688679 TI - Eyes, ears, lips, fingertips, secrets: Dora, psychoanalysis, and the body. AB - The topic of secrets will be expanded here to apply to complex secrets of the body, sex, and gender kept by both patients and analysts. Their detection is made harder by our field's current lack of interest in them compared to Freud's curiosity. We tend to ignore body narratives these days, with both men and women, keeping secret from ourselves daily challenges to theory that do indeed exist. Dora's case will be used to examine her own, her father's, and Freud's expectations of what constitutes a sexed and gendered portrait of grown-up males and females, and how they behave together. Contemporary embodied questions will emerge in discussion of Dora and her mother(s), the men in the story, and some male case vignettes. Ordinary secrets, hidden in broad daylight in both 1905 and in 2014, will be "revealed." PMID- 25688680 TI - Love and/in psychoanalysis: a commentary on Lacan's reading of Plato's Symposium in Seminar VIII: Transference. AB - What is love and what part does it play in psychoanalysis? Where are the analyst and the analysand situated in relation to the roles defined as those of the "lover" and the "beloved"? Jacques Lacan explores these and other questions in his soon-to-be-published Seminar VIII: Transference by providing an extensive commentary on Plato's most famous dialogue on love, the Symposium. This paper outlines some of the major points about love that grow out of Lacan's reading of the dialogue and examines their relevance to the analytic setting. Can the analyst be characterized as a sort of modern-day Socrates? PMID- 25688681 TI - Patience. AB - Patience is a multifaceted phenomenon consisting of acceptance of inner and outer reality, absence of resentment, retention of hope, and capacity to wait for better times without restlessness and haste. It originates in the childhood advance from pleasure principle to reality principle, though the attainment of secure attachment, object constancy, and frustration tolerance also contribute to it. Psychopathology involving patience generally manifests as endless waiting or chronic hurrying. Both the normative and morbid trajectories of patience have implications for psychoanalytic technique, which are illustrated here with the help of clinical vignettes. PMID- 25688682 TI - A phenomenological-contextual, existential, and ethical perspective on emotional trauma. AB - After a brief overview of the author's phenomenological-contextualist psychoanalytic perspective, the paper traces the evolution of the author's conception of emotional trauma over the course of three decades, as it developed in concert with his efforts to grasp his own traumatized states and his studies of existential philosophy. The author illuminates two of trauma's essential features: (1) its context-embeddedness-painful or frightening affect becomes traumatic when it cannot find a context of emotional understanding in which it can be held and integrated, and (2) its existential significance-emotional trauma shatters our illusions of safety and plunges us into an authentic Being-toward death, wherein we must face up to our finitude and the finitude of all those we love. The paper also describes the impact of trauma on the phenomenology of time and the sense of alienation from others that accompanies traumatic temporality. The author contends that the proper therapeutic comportment toward trauma is a form of emotional dwelling. He concludes with a discussion of the implications of all these formulations for the development of an ethics of finitude. PMID- 25688683 TI - Reporting for duty: the paternal function and clinical formulations. AB - The author highlights some developments in the theory of the preoedipal paternal function and paternal functionary and incorporates these ideas in developing clinical formulations for four clinical cases that privilege the preoedipal paternal function. In particular, four aspects of the preoedipal paternal function are identified, and for each a clinical case is discussed. Emphasis is placed on the necessity of widening clinical formulations to ensure clinicians have the widest possible set of clinical ideas and hence interventions and techniques at their fingertips. PMID- 25688685 TI - Robert Wallerstein (1920-2014). PMID- 25688687 TI - Ab initio study on the low-lying excited states of gas-phase PH(+) cation including spin-orbit coupling. AB - Ab initio calculations have been performed on the low-lying excited and ground states of PH(+). The potential energy curves (PECs) of the Lambda-S states were calculated with multi-reference configuration interaction (MRCI) method along with the basis sets at 5-xi level. In order to improve the PECs, the Davidson(+Q) correction and the Scalar relativistic effect are included. The corresponding spectroscopic constants were determined and good agreements with the available measurement were found. The interactions of the A(2)Delta-(4)Pi and 1(2)Sigma(+) (4)Pi by the spin-orbit coupling (SOC) effect were well described by the spin orbit matrix elements. The SOC effect makes the original 8 Lambda-S states split into 15Omega states. The Omega=1/2 state generated from the X(2)Pi state is confirmed to the ground Omega state. And the SOC splitting for the X(2)Pi is calculated to be 294cm(-1). The SOC effect has large effect on the PECs of the A(2)Delta and 1(2)Sigma(+) states, leading to much more shallow potential wells as well as potential barriers. The analysis of the wavefunction for the Omega states shows that the strong spin-orbit interaction exists near the crossing points of the PECs for the Lambda-S states. The transition dipole moments (TDMs) of transitions A(2)Delta-X(2)Pi and 1(2)Sigma(-)-X(2)Pi are evaluated with the MRCI wavefunction. Based on the TDMs along with the calculated Franck-Condon factors, the radiative lifetimes for the selected vibrational levels of A(2)Delta and 1(2)Sigma(-) states are predicted at the microseconds (MUs). Good agreement with the measurement shows that the lowest vibrational level for A(2)Delta state is almost uninfluenced by the perturbation via the SOC effect. PMID- 25688688 TI - Consumer sensory evaluation, fatty acid composition, and shelf-life of ground beef with subcutaneous fat trimmings from different carcass locations. AB - Brisket, chuck, plate, flank, and round subcutaneous fat trim were used to produce ground beef patties then evaluated for color, lipid oxidation, fatty acid composition, volatile chemical compounds and consumer sensory evaluation. Color, TBARS, consumer sensory evaluation, and cook/freezer loss did not differ (P>0.05) among carcass fat locations. Percentage stearic acid was lower (P=0.044) in the ground beef using brisket fat than using the chuck and flank fat. Patties made with brisket fat were higher in cis-vaccenic acid (P=0.016) and the saturated to monounsaturated fatty acid ratio (P=0.018) than all other sources of subcutaneous fat. Butanedione was highest (P=0.013) in patties using flank and plate fat. Ground beef with brisket fat was higher (P=0.003) than all other sources for beefy aroma. Altering the profile of non-polar, triglyceride fatty acids has no effect on sensory flavor or major volatile chemical compounds. PMID- 25688690 TI - Acute myeloid leukemia in the pregnant patient. AB - Although acute myeloid leukemia (AML) mostly occurs in older patients, it could be seen in women of childbearing age. It is therefore not surprising that in some patients the management of AML will be complicated by a coexistent pregnancy. However, the association of leukemia and pregnancy is uncommon. Its incidence is estimated to be 1 in 75,000 to 100,000 pregnancies. During pregnancy, most leukemias are acute: two thirds are myeloid and one third are lymphoblastic. There is no standard approach for this clinical dilemma, in part because of variables such as the type of AML, the seriousness of the symptoms, and the patient's personal beliefs. In many cases, the diagnostic work up has to be altered because of the pregnancy, and often available treatments have varying risks to the fetus. While chemotherapy is reported to have some risks during the first trimester, it is admitted that it can be administered safely during the second and the third trimesters. This article is protected by copyright. All rights reserved. PMID- 25688689 TI - Properties of bologna-type sausages with pork back-fat replaced with pork skin and amorphous cellulose. AB - Bologna-type sausages were produced with 50% of their pork back-fat content replaced with gels elaborated with different ratios of pork skin, water, and amorphous cellulose (1:1:0, 1:1:0.1, 1:1:0.2, 1:1:0.3, and 1:1:0.4). The impact of such replacement on the physico-chemical characteristics and the consumer sensory profiling was evaluated. The modified treatments had 42% less fat, 18% more protein, and 8% more moisture than the control group. Treatments with amorphous cellulose had a lower cooking loss and higher emulsion stability. High amorphous cellulose content (1:1:0.3 and 1:1:0.4) increased hardness, gumminess, and chewiness. The gel formulated with the ratio of 1:1:0.2 (pork skin: water: amorphous cellulose gel) provided a sensory sensation similar to that provided by fat and allowed products of good acceptance to be obtained. Therefore, a combination of pork skin and amorphous cellulose is useful in improving technological quality and producing healthier and sensory acceptable bologna-type sausages. PMID- 25688691 TI - Imidazole derivative KK-42 boosts pupal diapause incidence and delays diapause termination in several insect species. AB - The imidazole derivative KK-42 is a synthetic insect growth regulator known previously to be capable of averting embryonic diapause in several Lepidoptera, but whether it also affects diapauses occurring in other developmental stages remains unknown. In the present study, we examined the effect of KK-42 on pupal diapause in two species of Lepidoptera, the Chinese oak silkworm Antheraea pernyi and the corn earworm Helicoverpa zea, and in one species of Diptera, the flesh fly Sarcophaga crassipalpis. In A. pernyi, KK-42 delayed pupal diapause termination under the long day conditions that normally break diapause in this species. Likewise, in H. zea, KK-42 delayed termination of pupal diapause, a diapause that, in this species, is normally broken by high temperature. KK-42 treated pupae of these two species eventually terminated diapause and successfully emerged as adults, but the timing of diapause termination was significantly delayed. KK-42 also significantly increased the incidence of pupal diapause in H. zea and S. crassipalpis when administered to larvae that were environmentally programmed for diapause, but it was not capable of inducing pupal diapause in H. zea if larvae were reared under environmental conditions that do not normally evoke the diapause response. Experiments with H. zea showed that the effect of KK-42 on pupal diapause was dose- and stage-dependent, but not temperature-dependent. Results presented here are consistent with a link between KK-42 and the ecdysteroid signaling pathway that regulates pupal diapause. PMID- 25688692 TI - Phylogenetic analyses and nitrate-reducing activity of fungal cultures isolated from the permanent, oceanic oxygen minimum zone of the Arabian Sea. AB - Reports on the active role of fungi as denitrifiers in terrestrial ecosystems have stimulated an interest in the study of the role of fungi in oxygen-deficient marine systems. In this study, the culturable diversity of fungi was investigated from 4 stations within the permanent, oceanic, oxygen minimum zone of the Arabian Sea. The isolated cultures grouped within the 2 major fungal phyla Ascomycota and Basidiomycota; diversity estimates in the stations sampled indicated that the diversity of the oxygen-depleted environments is less than that of mangrove regions and deep-sea habitats. Phylogenetic analyses of 18S rRNA sequences revealed a few divergent isolates that clustered with environmental sequences previously obtained by others. This is significant, as these isolates represent phylotypes that so far were known only from metagenomic studies and are of phylogenetic importance. Nitrate reduction activity, the first step in the denitrification process, was recorded for isolates under simulated anoxic, deep sea conditions showing ecological significance of fungi in the oxygen-depleted habitats. This report increases our understanding of fungal diversity in unique, poorly studied habitats and underlines the importance of fungi in the oxygen depleted environments. PMID- 25688693 TI - Comorbidity has no impact on eosinophil inflammation in the upper airways or on severity of the sinonasal disease in patients with nasal polyps. AB - OBJECTIVE: The study was designed to determine whether there is an association between the comorbidity as atopy, bronchial asthma, aspirin intolerance and eosinophil infiltration of the upper airways, severity of the sinonasal disease and rate of revision sinus surgery in patients with nasal polyps. MATERIAL AND METHODS: One hundred and fifty patients were enrolled in the prospective study. Differences in CT score, rate of revision surgery, concentration of eotaxin and eosinophil cationic protein in nasal lavage fluid (NALF) and distribution of eosinophils in NALF and nasal tissue in patients with chronic rhinosinusitis with nasal polyps (CRSwNP), chronic rhinosinusitis without nasal polyps (CRSsNP) and control group were investigated. We focused on the relationship between presence of comorbidity (atopy, bronchial asthma and aspirin intolerance) and severity of the disease, the need of revision surgery and markers of eosinophil inflammation in upper airways in patients with CRSwNP. RESULTS: Patients with CRSwNP had more severe form of the sinonasal disease, higher rate of revision FESS and significant higher presence of markers of eosinophil inflammation in NALF and nasal tissue than patients with CRSsNP (P < 0.05). Atopic and non-atopic asthma as well as aspirin sensitivity significantly more often coexisted with CRSwNP. Comorbidity did not influence eosinophil infiltration or severity of the disease in patients with CRSwNP. CONCLUSION: Presence of comorbidity (atopy, bronchial asthma and aspirin intolerance) has no impact on severity of the disease or eosinophil content in the upper airways in patients with CRSwNP. PMID- 25688694 TI - Update on Prevalence of Periodontitis in Adults in the United States: NHANES 2009 to 2012. AB - BACKGROUND: This report describes prevalence, severity, and extent of periodontitis in the US adult population using combined data from the 2009 to 2010 and 2011 to 2012 cycles of the National Health and Nutrition Examination Survey (NHANES). METHODS: Estimates were derived for dentate adults, aged >=30 years, from the US civilian non-institutionalized population. Periodontitis was defined by combinations of clinical attachment loss (AL) and periodontal probing depth (PD) from six sites per tooth on all teeth, except third molars, using standard surveillance case definitions. For the first time in NHANES history, sufficient numbers of non-Hispanic Asians were sampled in 2011 to 2012 to provide reliable estimates of their periodontitis prevalence. RESULTS: In 2009 to 2012, 46% of US adults, representing 64.7 million people, had periodontitis, with 8.9% having severe periodontitis. Overall, 3.8% of all periodontal sites (10.6% of all teeth) had PD >=4 mm, and 19.3% of sites (37.4% teeth) had AL >=3 mm. Periodontitis prevalence was positively associated with increasing age and was higher among males. Periodontitis prevalence was highest in Hispanics (63.5%) and non-Hispanic blacks (59.1%), followed by non-Hispanic Asian Americans (50.0%), and lowest in non-Hispanic whites (40.8%). Prevalence varied two-fold between the lowest and highest levels of socioeconomic status, whether defined by poverty or education. CONCLUSIONS: This study confirms a high prevalence of periodontitis in US adults aged >=30 years, with almost fifty-percent affected. The prevalence was greater in non-Hispanic Asians than non-Hispanic whites, although lower than other minorities. The distribution provides valuable information for population based action to prevent or manage periodontitis in US adults. PMID- 25688695 TI - Filtering big data from social media--Building an early warning system for adverse drug reactions. AB - OBJECTIVES: Adverse drug reactions (ADRs) are believed to be a leading cause of death in the world. Pharmacovigilance systems are aimed at early detection of ADRs. With the popularity of social media, Web forums and discussion boards become important sources of data for consumers to share their drug use experience, as a result may provide useful information on drugs and their adverse reactions. In this study, we propose an automated ADR related posts filtering mechanism using text classification methods. In real-life settings, ADR related messages are highly distributed in social media, while non-ADR related messages are unspecific and topically diverse. It is expensive to manually label a large amount of ADR related messages (positive examples) and non-ADR related messages (negative examples) to train classification systems. To mitigate this challenge, we examine the use of a partially supervised learning classification method to automate the process. METHODS: We propose a novel pharmacovigilance system leveraging a Latent Dirichlet Allocation modeling module and a partially supervised classification approach. We select drugs with more than 500 threads of discussion, and collect all the original posts and comments of these drugs using an automatic Web spidering program as the text corpus. Various classifiers were trained by varying the number of positive examples and the number of topics. The trained classifiers were applied to 3000 posts published over 60 days. Top-ranked posts from each classifier were pooled and the resulting set of 300 posts was reviewed by a domain expert to evaluate the classifiers. RESULTS: Compare to the alternative approaches using supervised learning methods and three general purpose partially supervised learning methods, our approach performs significantly better in terms of precision, recall, and the F measure (the harmonic mean of precision and recall), based on a computational experiment using online discussion threads from Medhelp. CONCLUSIONS: Our design provides satisfactory performance in identifying ADR related posts for post-marketing drug surveillance. The overall design of our system also points out a potentially fruitful direction for building other early warning systems that need to filter big data from social media networks. PMID- 25688696 TI - Compensatory control and the appeal of a structured world. AB - People are motivated to perceive themselves as having control over their lives. Consequently, they respond to events and cognitions that reduce control with compensatory strategies for restoring perceived control to baseline levels. Prior theory and research have documented 3 such strategies: bolstering personal agency, affiliating with external systems perceived to be acting on the self's behalf, and affirming clear contingencies between actions and outcomes within the context of reduced control (here termed specific structure). We propose a 4th strategy: affirming nonspecific structure, or seeking out and preferring simple, clear, and consistent interpretations of the social and physical environments. Formulating this claim suggests that people will respond to reduced control by affirming structured interpretations that are unrelated to the control-reducing condition, and even those that entail otherwise adverse outcomes (e.g., pessimistic health prospects). Section 1 lays the conceptual foundation for our review, situating the proposed phenomenon in the literatures on control motivation and threat-compensation mechanisms. Section 2 reviews studies that have demonstrated that trait and state variations in perceived control predict a wide range of epistemic structuring tendencies, including pattern recognition and causal reasoning. We posit that these tendencies reflect a common desire for a structured understanding of one's environment. Accordingly, a new meta-analysis spanning the reviewed studies (k = 55) revealed that control reduction predicts nonspecific structure affirmation with a moderate effect size (r = .25). Section 3 reviews research on individual differences and situational moderators of this effect. The discussion addresses the interplay of compensatory control strategies and practical implications. PMID- 25688697 TI - Correlation between macular blood flow and central visual sensitivity in retinitis pigmentosa. AB - PURPOSE: To investigate the changes in macular blood flow and the correlation between those changes and central visual function in patients with retinitis pigmentosa (RP). METHODS: The mean blur rate (MBR), a quantitative blurring index of the laser speckle pattern that represents retinal and choroidal blood flow, was measured by laser speckle flowgraphy. Mean blur rate values in the macular area were compared between 70 patients with RP and 28 control subjects. The relationships between MBR on the one hand and, on the other, visual acuity (VA), mean deviation (MD) and averaged macular sensitivity of static perimetry tests (Humphrey Filed Analyzer, the central 10-2 program) were analysed in patients with RP. RESULTS: Macular MBR was decreased to 75% in patients with RP compared with control subjects (p < 0.0001, Student's t-test). Spearman's rank testing showed that macular MBR was significantly correlated with VA (r = -0.261, p = 0.0299), MD values (r = 0.438, p = 0.0002) and averaged macular sensitivity at the central 4 and 12 points of static perimetry tests (r = 0.426 and 0.442, p = 0.0003 and 0.0002, respectively). Multivariable-adjusted analysis confirmed that MBR was independently associated with MD (p = 0.0002) and macular sensitivity at the central 4 and 12 points (p < 0.0001 and 0.0002, respectively). CONCLUSIONS: Decreased macular blood flow was associated with reduced macular visual sensitivity in patients with RP. Although the cause-effect relationships remain to be elucidated, these findings suggest that vascular defects may be involved in the pathogenesis of RP such as central vision loss. PMID- 25688698 TI - Prognosis associated with cutaneous melanoma metastases. AB - BACKGROUND/OBJECTIVE: Information on the prognosis for patients with regional cutaneous melanoma metastases has been sparse and difficult to establish. In 2009 the American Joint Committee on Cancer (AJCC) melanoma staging has for the first time provided survival rates for patients who manifest intralymphatic metastases. We sought to validate the new staging system in this contemporary, prospectively collected cohort of patients following the development of cutaneous metastases as the first evidence of metastatic disease and explored the factors that influenced their prognosis. METHODS: The Victorian Melanoma Service database was searched to identify all patients with cutaneous melanoma metastases. Patients who were found to have lymph node or visceral metastases at the time they were diagnosed with cutaneous metastatic disease were excluded. Survival curves were generated and univariate and multivariate assessments of prognostic factors associated with survival were performed. RESULTS: In total, 72 patients presented with cutaneous metastases as the first evidence of metastatic disease. The median melanoma specific survival of patients with only regional cutaneous metastases (n = 56) was 5.07 years and their 5-year survival rate was 52%. Distant cutaneous metastases and thickness of the primary melanoma were found to be significant negative predictors of survival. CONCLUSION: We were able to validate the new AJCC melanoma staging system survival for patients with cutaneous metastatic disease. Patients presenting with regional cutaneous metastases have a much better prognosis than those with distant cutaneous metastases. PMID- 25688700 TI - Letter to the editor. PMID- 25688701 TI - Letter to the editor. PMID- 25688702 TI - Orf from deer: an Australian case. PMID- 25688703 TI - Calcific uraemic arteriolopathy in a patient with end-stage renal failure and chronic plaque psoriasis: could TNF-alpha inhibition help ameliorate disease progression? PMID- 25688704 TI - Obituary. PMID- 25688705 TI - Acute cutaneous graft-versus-host disease resembling type II (atypical adult) pityriasis rubra pilaris. AB - We present a case of cutaneous acute graft-versus-host disease (aGVHD) with confluent erythematous perifollicular hyperkeratosis and ichthyosiform scale in the clinical pattern of type II (atypical adult) pityriasis rubra pilaris (PRP), which developed 26 days after allogeneic peripheral blood stem cell transplant. Skin histology confirmed features of both aGVHD and PRP. The skin lesions were refractory to oral prednisolone and cyclosporine and only partially responsive to a combination of i.v. methylprednisolone, oral tacrolimus, oral mycophenolate mofetil, and infusions of anti-thymocyte globulin and the tumour necrosis factor alpha inhibitor, etanercept. PMID- 25688706 TI - Porokeratosis ptychotropica: a rare variant with discrete lesions. PMID- 25688707 TI - Sensory testing with the sharp point of a folded piece of paper. PMID- 25688708 TI - Long-term compassionate use of oclacitinib in dogs with atopic and allergic skin disease: safety, efficacy and quality of life. AB - BACKGROUND: Oclacitinib is safe and effective for treating dogs with pruritus associated with allergic and atopic dermatitis, based on randomized clinical trials of up to 4 months duration. HYPOTHESIS/OBJECTIVES: This study assessed long-term safety, efficacy and quality of life of oclacitinib-treated dogs enrolled in a compassionate use programme. ANIMALS: Two hundred and forty-seven client-owned dogs with allergic skin disease that had previously benefited from oclacitinib therapy. METHODS: Dogs were enrolled in an open-label study at 26 veterinary clinics. Dogs received 0.4-0.6 mg/kg oclacitinib twice a day for 14 days, then once a day for up to 630 days. Assessments were performed at ~90 day intervals. Owners completed a quality-of-life survey and assessed pruritus using a Visual Analog Scale (VAS) at each clinic visit. Veterinarians assessed dermatitis using a similar VAS. Abnormal health events, concomitant medication and clinical pathology results were summarized. RESULTS: Visual Analog Scale scores showed improvement from baseline at all time points. The percentage of dogs showing >=50% reduction from baseline on day 90 was 63.9% for pruritus and 66.4% for dermatitis. Owners saw a positive impact on quality of life in >91% of all dogs. Urinary tract infection/cystitis, vomiting, otitis, pyoderma and diarrhoea were the most frequently reported (>5% of dogs) abnormal clinical signs. Haematology and serum chemistry means remained within the normal reference ranges. Concomitant medications were well tolerated. CONCLUSIONS AND CLINICAL IMPORTANCE: Results indicated that oclacitinib was safe and efficacious for long term use and improved the quality of life for dogs in this study. PMID- 25688709 TI - Undercover diffusion of atoms: Pb on Si(5 5 3)-Au surface covered by graphene. AB - The diffusion of Pb atoms under a graphene layer deposited on a Si(5 5 3)-Au surface is studied by the first-principles density functional theory. The presence of graphene locks the moving Pb atoms inside tube-like closed objects, formed by grooves near steps of the Si(5 5 3)-Au surface and limited from the top by the graphene layer. As a result, the diffusion processes are well-separated from the environment. The methods of experimental verification of the undercover diffusion are also proposed. PMID- 25688710 TI - Explanations and expectations: drug narratives among young cannabis users in treatment. AB - This article analyses how young people enrolled in drug addiction treatment in Copenhagen, Denmark, explain their cannabis careers and how they view their possibilities for quitting drug use again. Inspired by Mead and narrative studies of health and illness, the article identifies four different drug use 'aetiologies' drawn upon by the interviewees. These cover childhood experiences, self-medication, the influence of friends and cannabis use as a specific lifestyle. A central argument of the article is that these explanations not only concern the past but also point towards the future by assigning the interviewee a more or less agential position in relation to drugs. Further, the drug narratives are viewed as interactional achievements, related to the social context in which they were produced, namely, the institutional setting of the treatment centres. The article is based on 30 qualitative interviews with young people in drug addiction treatment. PMID- 25688712 TI - Differentiation between single bladder cancer cells using principal component analysis of time-of-flight secondary ion mass spectrometry. AB - Time-of-flight-secondary ion mass spectrometry (TOF-SIMS) mass spectra measurements combined with an appropriate sample preparation protocol are the powerful tools to obtain unique information about the chemical composition of biological materials. In our studies, two questions were addressed, i.e., whether it is possible to develop a fixative-based sample preparation protocol and whether it allows one to distinguish between cells originating from various stages of cancer progression. Therefore, four human bladder cancer cell lines (with distinct malignancy degree) have been investigated. A chemical fixation protocol has been used for TOF-SIMS measurements, and mass spectra were obtained using a Bi3(+) primary ion beam. The principal component analysis (PCA) has been applied to analyze the whole range of mass spectra (without preselection of any particular masses) using two approaches of data preprocessing, namely, mean centering and autoscaling. The PC3 versus PC2 plot has showed significant differences between nonmalignant cancer cells and the cancerous ones for both of preprocessing approaches. The analysis of mass spectra of human bladder cells allows one to find a list of mass peaks with intensities significantly larger in cancerous bladder cells compared to nonmalignant cell cancer of the ureter (HCV29 cells). These findings show that TOF-SIMS in combination with PCA can be used to identify reference, human bladder cells from cancerous ones. PMID- 25688711 TI - Are acinic cell carcinomas of the breast and salivary glands distinct diseases? AB - AIMS: Acinic cell carcinomas (AcCC) of the breast have been reported to constitute the breast counterpart of salivary gland AcCCs, based on the similarities of their histological and immunohistochemical features. Breast AcCC is a vanishingly rare form of triple-negative breast cancer (TNBC). Recent studies have demonstrated that in TNBCs, the two driver genes most frequently mutated are TP53 (82%) and PIK3CA (10%). We sought to define whether breast AcCCs would harbour TP53 and PIK3CA somatic mutations, and if so, whether these would be present in salivary gland AcCCs. METHODS AND RESULTS: Sanger sequencing of the entire coding region of TP53 and of PIK3CA hotspot mutation sites of 10 breast and 20 salivary gland microdissected AcCCs revealed eight TP53 (80%) and one PIK3CA (10%) somatic mutations in breast AcCCs. No somatic mutations affecting these genes were found in the 20 salivary gland AcCCs analysed. CONCLUSIONS: Our findings demonstrate that breast AcCCs display TP53 and PIK3CA mutations at frequencies similar to those of common types of TNBCs, whereas these genes appear not to be altered in salivary gland AcCCs, suggesting that despite their similar histological appearances, AcCCs of the breast and salivary glands probably constitute unrelated diseases. PMID- 25688713 TI - Golden age of RyR and GABA-R diamide and isoxazoline insecticides: common genesis, serendipity, surprises, selectivity, and safety. AB - The serendipitous observation of the insecticidal activity of a candidate herbicide was the first in a series of surprises that changed the course of insecticide research and opened the "Golden Age of Diamide and Isoxazoline Insecticides" which have a common genesis. Two novel modes of action were discovered, one involving the gamma-aminobutyric acid (GABA) receptor of the chloride channel and the other the ryanodine receptor (RyR) of the calcium activated calcium channel. These are old insecticide targets, but physiological assays and radioligand binding studies reveal that the new diamides and isoxazolines act at previously unrecognized sites without cross-resistance to other chemotypes and more important differing between insects and mammals resulting in selective toxicity and mechanistically based safety. The phthalic diamide flubendiamide and anthranilic diamides chlorantraniliprole and cyantraniliprole act at an allosteric site of the RyR to activate calcium release in insects but not mammals. They are the most important insecticide introductions of the past decade. Isoxazoline and meta-diamide insecticides and their previously unrecognized GABA-R target are more recent discoveries. Isoxazolines are currently important in flea and tick control in dogs and cats, and meta diamides show promise for pest management and crop protection. These 21st century RyR and GABA-R diamides and isoxazolines were serendipitous discoveries and developments showing the importance of mechanism studies in maintaining the arsenal of safe and effective insecticides. PMID- 25688714 TI - Real-time monitoring of arsenic trioxide release and delivery by activatable T(1) imaging. AB - Delivery of arsenic trioxide (ATO), a clinical anticancer drug, has drawn much attention to improve its pharmacokinetics and bioavailability for efficient cancer therapy. Real-time and in situ monitoring of ATO behaviors in vivo is highly desirable for efficient tumor treatment. Herein, we report an ATO-based multifunctional drug delivery system that efficiently delivers ATO to treat tumors and allows real-time monitoring of ATO release by activatable T1 imaging. We loaded water-insoluble manganese arsenite complexes, the ATO prodrug, into hollow silica nanoparticles to form a pH-sensitive multifunctional drug delivery system. Acidic stimuli triggered the simultaneous release of manganese ions and ATO, which dramatically increased the T1 signal (bright signal) and enabled real time visualization and monitoring of ATO release and delivery. Moreover, this smart multifunctional drug delivery system significantly improved ATO efficacy and strongly inhibited the growth of solid tumors without adverse side effects. This strategy has great potential for real-time monitoring of theranostic drug delivery in cancer diagnosis and therapy. PMID- 25688715 TI - Shikonin and its derivatives inhibit the epidermal growth factor receptor signaling and synergistically kill glioblastoma cells in combination with erlotinib. AB - Overexpression and mutation of the epidermal growth factor receptor (EGFR) gene play a causal role in tumorigenesis and resistance to treatment of glioblastoma (GBM). EGFR inhibitors such as erlotinib are currently used for the treatment of GBM; however, their efficacy has been limited due to drug resistance. New treatment strategies are therefore urgently needed. Shikonin, a natural naphthoquinone, induces both apoptosis and necroptosis in human glioma cells, but the effectiveness of erlotinib-shikonin combination treatment as well as the underlying molecular mechanisms is unknown yet. In this study, we investigated erlotinib in combination with shikonin and 14 shikonin derivatives in parental U87MG and transfected U87MG.DeltaEGFR GBM cells. Most of the shikonin derivatives revealed strong cytotoxicity. Shikonin together with five other derivatives, namely deoxyshikonin, isobutyrylshikonin, acetylshikonin, beta,beta dimethylacrylshikonin and acetylalkannin showed synergistic cytotoxicity toward U87MG.DeltaEGFR in combination with erlotinib. Moreover, the combined cytotoxic effect of shikonin and erlotinib was further confirmed with another three EGFR expressing cell lines, BS153, A431 and DK-MG. Shikonin not only dose-dependently inhibited EGFR phosphorylation and decreased phosphorylation of EGFR downstream molecules, including AKT, P44/42MAPK and PLCgamma1, but also together with erlotinib synergistically inhibited DeltaEGFR phosphorylation in U87MG.DeltaEGFR cells as determined by Loewe additivity and Bliss independence drug interaction models. These results suggest that the combination of erlotinib with shikonin or its derivatives might be a potential strategy to overcome drug resistance to erlotinib. PMID- 25688716 TI - Drosophila blood cells and their role in immune responses. AB - Drosophila melanogaster has been extensively used to study the humoral arm of innate immunity because of the developmental and functional parallels with mammalian innate immunity. However, the fly cellular response to infection is far less understood. Investigative work on Drosophila haemocytes, the immunosurveillance cells of the insect, has revealed that they fulfil roles similar to mammalian monocytes and macrophages. They respond to wound signals and orchestrate the coagulation response. In addition, they phagocytose and encapsulate invading pathogens, and clear up apoptotic bodies controlling inflammation. This review briefly describes the Drosophila haematopoietic system and discusses what is currently known about the contribution of haemocytes to the immune response upon infection and wounding, during all stages of development. PMID- 25688717 TI - The brazilian contribution to the diagnosis and treatment of headache disorders. PMID- 25688718 TI - Reptilian Eosinophils: Beauty and Diversity by Light Microscopy. PMID- 25688719 TI - Prevention of brachial plexus injury-12 years of shoulder dystocia training: an interrupted time-series study. AB - OBJECTIVE: To investigate management and outcomes of incidences of shoulder dystocia in the 12 years following the introduction of an obstetric emergencies training programme. DESIGN: Interrupted time-series study comparing management and neonatal outcome of births complicated by shoulder dystocia over three 4-year periods: (i) Pre-training (1996-99), (ii) Early training (2001-04), and (iii) Late training (2009-12). SETTING: Southmead Hospital, Bristol, UK, with approximately 6000 births per annum. POPULATION: Infants and their mothers who experienced shoulder dystocia. METHOD: A bi-monthly multi-professional 1-day intrapartum emergencies training course, that included a 30-minute practical session on shoulder dystocia management, commenced in 2000. MAIN OUTCOMES: Neonatal morbidity (brachial plexus injury, humeral fracture, clavicular fracture, 5-minute Apgar score <7) and documented management of shoulder dystocia (resolution manoeuvres performed, traction applied, head-to-body delivery interval). RESULTS: Compliance with national guidance improved with continued training. At least one recognised resolution manoeuvre was used in 99.8% (561/562) of cases of shoulder dystocia in the late training period, demonstrating a continued improvement from 46.3% (150/324, P < 0.001) pre training, and 92% (241/262, P < 0.001) in the early training period. In parallel there was reduction in the brachial plexus injury at birth (24/324 [7.4%, P < 0.01], pre-training, 6/262 [2.3%] early training, and 7/562 [1.3%] late training. CONCLUSIONS: There are significant benefits to long-term, embedded training programmes with improvements in both management and outcomes. A decade after the introduction of training there were no cases of brachial plexus injury lasting over 12 months in 562 cases of shoulder dystocia. PMID- 25688720 TI - Increased endothelial progenitor cells and nitric oxide in young prehypertensive women. AB - This study investigated the effect of sex differences on circulating endothelial progenitor cells (EPCs) in prehypertension and its underlying mechanism. The authors found that premenopausal women show increased number and activity of circulating EPCs when compared with men, which was similar to enhanced nitric oxide (NO) level in plasma or culture medium. There was no difference in the number and activity of circulating EPCs and NO level between normotensive and prehypertensive premenopausal women. There was also no difference seen in levels of vascular endothelial growth factor and granulocyte macrophage colony stimulating factor. Both number and activity of circulating EPCs were correlated with the level of NO. The present study firstly demonstrated that the number and activity of circulating EPCs were preserved in prehypertensive premenopausal women, which was related to the restoration of NO production. The sex differences in EPCs in prehypertension may be involved in the mechanism underlying vascular protection in premenopausal women. PMID- 25688721 TI - Prerequisites for the analysis and sorting of extracellular vesicle subpopulations by high-resolution flow cytometry. AB - Submicron-sized vesicles released by cells are increasingly recognized for their role in intercellular communication and as biomarkers of disease. Methods for high-throughput, multi-parameter analysis of such extracellular vesicles (EVs) are crucial to further investigate their diversity and function. We recently developed a high-resolution flow cytometry-based method (using a modified BD Influx) for quantitative and qualitative analysis of EVs. The fact that the majority of EVs is <200 nm in size requires special attention with relation to specific conditions of the flow cytometer, as well as sample concentration and event rate. In this study, we investigated how (too) high particle concentrations affect high-resolution flow cytometry-based particle quantification and characterization. Increasing concentrations of submicron-sized particles (beads, liposomes, and EVs) were measured to identify coincidence and swarm effects, caused by the concurrent presence of multiple particles in the measuring spot. As a result, we demonstrate that analysis of highly concentrated samples resulted in an underestimation of the number of particles and an interdependent overestimation of light scattering and fluorescence signals. On the basis of this knowledge, and by varying nozzle size and sheath pressure, we developed a strategy for high-resolution flow cytometric sorting of submicron-sized particles. Using the adapted sort settings, subsets of EVs differentially labeled with two fluorescent antibodies could be sorted to high purity. Moreover, sufficient numbers of EVs could be sorted for subsequent analysis by western blotting. In conclusion, swarm effects that occur when measuring high particle concentrations severely hamper EV quantification and characterization. These effects can be easily overlooked without including proper controls (e.g., sample dilution series) or tools (e.g., oscilloscope). Providing that the event rate is well controlled, the sorting strategy we propose here indicates that high resolution flow cytometric sorting of different EV subsets is feasible. PMID- 25688722 TI - The interaction between the composition of preinjected fluids and duration of radiofrequency on lesion size. AB - BACKGROUND: Clinical recommendations for the duration of radiofrequency (RF) delivery have been based on no-fluid design, which may not be representative of clinical practice where fluid preinjection occurs. The purpose of this study was to examine the interaction between the preinjection of fluids of differing compositions and duration of RF on lesion size. The variability of lesion development under different preinjection conditions was also examined across the RF lesion duration. METHODS: Monopolar RF was performed with ex vivo chicken samples for 180 seconds without fluid preinjection or with fluid preinjected. Nonionic and ionic fluids were investigated. Lesion size parameters and and power levels were measured every 10 seconds. The surface area and efficiency index were calculated. RESULTS: The preinjection of specific fluid increased the maximum mean surface area. Lesion growth continued throughout the entire lesion cycle. When all groups were considered together, the largest mean surface area occurred at 180 seconds. The preinjection of specific fluids altered the rate of lesion growth and the time required to achieve maximum lesion size in a fluid-specific manner. Significant variability was documented in the rate and amount of lesion growth under each condition. Extending lesioning time resulted in reduced lesion variability. CONCLUSIONS: Fluid preinjection alters both final lesion size and the time required to achieve maximum lesion size. Extending the duration of RF lesion cycle beyond 90 seconds when fluid is preinjected allows for lesion size to be maximized while limiting lesion size variability, both of which assist in successfully lesioning a targeted nerve. PMID- 25688723 TI - Vloka sciatic nerve sheath: a tribute to a visionary. PMID- 25688724 TI - Adductor canal block--or subsartorial canal block? PMID- 25688725 TI - Block awake or asleep: still a conundrum? PMID- 25688726 TI - Wrong-side nerve blocks can be avoided. PMID- 25688727 TI - Thoracic paravertebral block and its effects on chronic pain and health-related quality of life after modified radical mastectomy. PMID- 25688728 TI - Polypyrrole-Ru(2,2'-bipyridine)3(2+)/MoSx structured composite film as a photocathode for the hydrogen evolution reaction. AB - The development of photoelectrochemical devices for solar light-driven water splitting and H2 production requires new strategies for the fabrication of materials that combine the necessary photoredox and catalytic properties, to allow the hydrogen evolution reaction (HER) to take place at a low overvoltage under visible light irradiation. We report the first example of a structured composite, synthesized by electrodeposition of MoSx cocatalyst into a photosensitive Ru complex film deposited onto carbon electrodes by electropolymerization of a pyrrole-functionalized Ru(II)(2,2'-bipyridine)3(2+). Composite films show efficient photocatalytic activity for HER. Our study highlights the great simplicity of this versatile electrochemical procedure to synthesize photocathodes. PMID- 25688729 TI - Calcium-catalyzed formal [2+2+2] cycloaddition. AB - A formal intermolecular [2+2+2] cycloaddition reaction of enynes to aldehydes is presented, which can be realized in the presence of a simple and benign calcium catalyst. The reaction proceeds with excellent chemo, regio- and diastereoselectivity and leads to a one-step assembly of highly interesting bicyclic building blocks containing up to three stereocenters from simple precursors via a new type of skeletal rearrangement of enynes. The observed diastereoselectivity is accounted for by two different mechanistic proposals. The first one engages mechanistic prospects arising from a gold catalyzed reaction in the absence of the stabilizing gold substituent. The second proposal involves an unprecedented cyclization-carbonyl allene ene reaction-hydroalkoxylation cascade. PMID- 25688730 TI - Contemporary applications of frontal sinus trephination: A systematic review of the literature. AB - Our objective was to perform a systematic review of the literature on contemporary indications and outcomes for frontal sinus trephination and present an illustrative case of an endoscopically assisted repair of a subcutaneous frontal sinus fistula by trephination technique. PubMed and Ovid databases were used as data sources. A systematic review of the English literature was completed to review reports of frontal trephination from 1980 to 2014. Articles meeting inclusion criteria for inflammatory and noninflammatory indications were reviewed. Articles were systematically reviewed and graded by evidence-based medicine level. An illustrative case from our institution is then presented. The systematic review identified 2,621 published studies. Thirty-eight studies were identified for inclusion. The indications, techniques, outcomes, safety, and complications were reviewed for noninflammatory and inflammatory conditions. There were 32 retrospective case series, reports, or cohort studies (level 4), four systematic reviews (level 3), one prospective analysis (level 3), and one meta-analysis (level 2). Due to the heterogeneity of study cases and inclusion criteria, a meta-analysis was not feasible. We also present a novel closure of an anterior skull base defect resulting in a subcutaneous fistula with use of a frontal trephination approach. The frontal sinus trephination should not be regarded as a procedure of the past, as it useful in the armamentarium of the modern sinus and skull base surgeon. This approach provides access for instrumentation for hard-to-reach frontal sinus disease either purely through a trephination approach or as a supplementation to the transnasal endoscopic approach. Evidence supporting frontal sinus trephination is of levels 2, 3, and 4. Level of evidence: NA. PMID- 25688731 TI - Examining the relationship between use of sexually explicit media and sexual risk behavior in a sample of men who have sex with men in Norway. AB - The purpose of this study was to investigate consumption patterns of gay-oriented sexually explicit media (SEM) among men who have sex with men (MSM) in Norway, with a particular emphasis on a possible relationship between gay SEM consumption and HIV risk behavior. Participants included 529 MSM living in Norway recruited online to complete a SEM consumption and sexual risk survey. Of the 507 participants who responded to the all items measuring exposure to SEM, 19% reported unprotected anal intercourse with a casual partner (UAI) in last 90 days, and 14% reported having had sero-discordant UAI. Among those with UAI experience, 23% reported receptive anal intercourse (R-UAI) and 37% reported insertive anal intercourse (I-UAI). SEM consumption was found to be significantly associated with sexual risk behaviors. Participants with increased consumption of bareback SEM reported higher odds of UAI and I-UAI after adjusting for other factors using multivariable statistics. MSM who started using SEM at a later age reported lower odds of UAI and I-UAI than MSM who started earlier. Future research should aim at understanding how MSM develop and maintain SEM preferences and the relationship between developmental and maintenance factors and HIV sexual risk behavior. PMID- 25688732 TI - Significant electronic thermal transport in the conducting polymer poly(3,4 ethylenedioxythiophene). AB - Suspended microdevices are employed to measure the in-plane electrical conductivity, thermal conductivity, and Seebeck coefficient of suspended poly(3,4 ethylenedioxythiophene) (PEDOT) thin films. The measured thermal conductivity is higher than previously reported for PEDOT and generally increases with the electrical conductivity. The increase exceeds that predicted by the Wiedemann Franz law for metals and can be explained by significant electronic thermal transport in PEDOT. PMID- 25688733 TI - Primary postpartum haemorrhage in women with von Willebrand disease or carriership of haemophilia despite specialised care: a retrospective survey. AB - Pregnant women with bleeding disorders require specialised peripartum care to prevent postpartum haemorrhage (PPH). If third trimester coagulation factor levels are <0.50 IU mL(-1) , prophylactic treatment is indicated and administered according to international guidelines. However, optimal dose and duration are unknown and bleeding may still occur. The aim of this study was to investigate the outcome in women with von Willebrand disease (VWD) or haemophilia carriership treated according to current practice guidelines. From the period 2002-2011, 185 deliveries in 154 VWD women or haemophilia carriers were retrospectively included. Data on blood loss, bleeding disorder characteristics and obstetric risk factors were obtained. The outcome was primary PPH, defined as blood loss >=500 mL within 24 h postpartum and severe PPH as blood loss >=1000 mL. Primary PPH was observed in 62 deliveries (34%), 14 (8%) of which resulted in severe PPH. In 26 deliveries prophylactic treatment was administered due to factor levels below the 0.50 IU mL(-1) cut-off in the third trimester, 14 of which (54%) were complicated by PPH. We found an increased PPH risk in deliveries given prophylactic treatment compared with deliveries without (OR 2.7, 95% CI 1.2-6.3). In conclusion, PPH incidence was highest in deliveries with the lowest factor levels in the third trimester. Currently, delivery outcome in women with bleeding disorders is unsatisfactory, given the high PPH incidence despite specialised care. Future studies are required to optimise management of deliveries in this patient population. PMID- 25688734 TI - Pyrochlore and perovskite potassium tantalate: enthalpies of formation and phase transformation. AB - Alkali niobates and tantalates are currently important lead-free functional oxides. The formation and decomposition energetics of potassium tantalum oxide compounds (K2 O-Ta2 O5 ) were measured by high-temperature oxide melt solution calorimetry. The enthalpies of formation from oxides of KTaO3 perovskite and defect pyrochlores with K/Ta ratio of less than 1 stoichiometry-K0.873 Ta2.226 O6 , K1.128 Ta2.175 O6 , and K1.291 Ta2.142 O6 -were experimentally determined, and the values are (-203.63 +/- 2.92) kJ mol(-1) for KTaO3 perovskite, and (-339.54 +/- 5.03) kJ mol(-1) , (-369.71 +/- 4.84) kJ mol(-1) , and (-364.78 +/- 4.24) kJ mol(-1) , respectively, for non-stoichiometric pyrochlores. That of stoichiometric defect K2 Ta2 O6 pyrochlore, by extrapolation, is (-409.87 +/- 6.89) kJ mol(-1) . Thus, the enthalpy of the stoichiometric pyrochlore and perovskite at K/Ta=1 stoichiometry are equal in energy within experimental error. By providing data on the thermodynamic stability of each phase, this work supplies knowledge on the phase-formation process and phase stability within the K2 O-Ta2 O5 system, thus assisting in the synthesis of materials with reproducible properties based on controlled processing. Additionally, the relation of stoichiometric and non-stoichiometric pyrochlore with perovskite structure in potassium tantalum oxide system is discussed. PMID- 25688735 TI - A high incidence of WT1 abnormality in bilateral Wilms tumours in Japan, and the penetrance rates in children with WT1 germline mutation. AB - BACKGROUND: Bilateral Wilms tumours (BWTs) occur by germline mutation of various predisposing genes; one of which is WT1 whose abnormality was reported in 17-38% of BWTs in Caucasians, whereas no such studies have been conducted in East Asians. Carriers with WT1 mutations are increasing because of improved survival. METHODS: Statuses of WT1 and IGF2 were examined in 45 BWTs from 31 patients with WT1 sequencing and SNP array-based genomic analyses. The penetrance rates were estimated in WT1-mutant familial Wilms tumours collected from the present and previous studies. RESULTS: We detected WT1 abnormalities in 25 (81%) of 31 patients and two families, which were included in the penetrance rate analysis of familial Wilms tumour. Of 35 BWTs from the 25 patients, 31 had small homozygous WT1 mutations and uniparental disomy of IGF2, while 4 had large 11p13 deletions with the retention of 11p heterozygosity. The penetrance rate was 100% if children inherited small WT1 mutations from their fathers, and 67% if inherited the mutations from their mothers, or inherited or had de novo 11p13 deletions irrespective of parental origin (P=0.057). CONCLUSIONS: The high incidence of WT1 abnormalities in Japanese BWTs sharply contrasts with the lower incidence in Caucasian counterparts, and the penetrance rates should be clarified for genetic counselling of survivors with WT1 mutations. PMID- 25688736 TI - Cytokine profile and prognostic significance of high neutrophil-lymphocyte ratio in colorectal cancer. AB - BACKGROUND: High circulating neutrophil-lymphocyte ratio (NLR) appears to be prognostic in metastatic colorectal cancer (mCRC). We investigated the relationship of NLR with circulating cytokines and molecular alterations. METHODS: We performed retrospective analyses on multiple cohorts of CRC patients (metastatic untreated (n=166), refractory metastatic (n=161), hepatectomy (n=198), stage 2/3 (n=274), and molecularly screened (n=342)). High NLR (ratio of absolute neutrophil-to-lymphocyte counts in peripheral blood) was defined as NLR>5. Plasma cytokines were evaluated using multiplex-bead assays. Kaplan-Meier estimates, non-parametric correlation analysis, and hierarchical cluster analyses were used. RESULTS: High NLR was associated with poor prognosis in mCRC (hazard ratio (HR) 1.73; 95% confidence interval (CI):1.03-2.89; P=0.039) independent of known prognostic factors and molecular alterations (KRAS/NRAS/BRAF/PIK3CA/CIMP). High NLR correlated with increased expression of interleukin 6 (IL-6), IL-8, IL 2Ralpha, hepatocyte growth factor, macrophage-colony stimulating factor, and vascular epidermal growth factor in exploratory (n=39) and validation (n=166) cohorts. Fourteen additional cytokines correlated with high NLR in the validation cohort. All 20 cytokines fell into three major clusters: inflammatory cytokines, angiogenic cytokines, and epidermal growth factor ligands. In mCRC, composite stratification based on NLR-cytokine score provided enhanced prognostic information (HR 2.09; 95% CI: 1.59-2.76; P<0.001) over and above NLR. CONCLUSIONS: High NLR is an independent poor prognostic marker in CRC and correlates with a distinct cytokine profile related to key biological processes involved in carcinogenesis. A composite NLR-cytokine stratification has enhanced prognostic value in mCRC. PMID- 25688737 TI - Frequency and prognostic significance of p16(INK4A) protein overexpression and transcriptionally active human papillomavirus infection in laryngeal squamous cell carcinoma. AB - BACKGROUND: Human papillomavirus (HPV) infection is a powerful prognostic biomarker in a subset of head and neck squamous cell carcinomas, specifically oropharyngeal cancers. However, the role of HPV in non-oropharyngeal sites, such as the larynx, remains unconfirmed. METHODS: We evaluated a cohort of 324 laryngeal squamous cell carcinoma (LSCC) patients for the expression of p16(INK4A) (p16) protein by immunohistochemistry (IHC) and for high-risk HPV E6 and E7 mRNA transcripts by RNA in situ hybridisation (ISH). p16 expression and HPV status were correlated with clinicopathological features and outcomes. RESULTS: Of 307 patients assessable for p16 IHC, 20 (6.5%) were p16 positive. Females and node-positive patients were more likely to be p16 positive (P<0.05). There were no other significant clinical or demographic differences between p16 positive and -negative cases. There was no difference in overall survival (OS) between p16-positive and -negative patients with 2-year survival of 79% in each group (HR=0.83, 95% CI 0.36-1.89, P=0.65). There was no statistically significant difference in failure-free survival (FFS) with 2-year FFS of 79% and 66% for p16 positive and -negative patients, respectively (HR=0.60, 95% CI 0.26-1.36, P=0.22). Only seven cases were found to be HPV RNA ISH positive, all of which were p16 IHC positive. There was no statistically significant difference in OS between patients with HPV RNA ISH-positive tumours compared with -negative tumours with 2-year survival of 86% and 71%, respectively (HR=0.76, 95% CI 0.23 2.5, P=0.65). The 2-year FFS was 86% and 59%, respectively (HR=0.62, 95% CI 0.19 2.03, P=0.43). CONCLUSIONS: p16 overexpression is infrequent in LSCC and the proportion of cases with high-risk HPV transcripts is even lower. There are no statistically significant correlations between p16 IHC or HPV RNA ISH status and OS or disease outcomes. PMID- 25688738 TI - Infertility and incident endometrial cancer risk: a pooled analysis from the epidemiology of endometrial cancer consortium (E2C2). AB - BACKGROUND: Nulliparity is an endometrial cancer risk factor, but whether or not this association is due to infertility is unclear. Although there are many underlying infertility causes, few studies have assessed risk relations by specific causes. METHODS: We conducted a pooled analysis of 8153 cases and 11 713 controls from 2 cohort and 12 case-control studies. All studies provided self reported infertility and its causes, except for one study that relied on data from national registries. Logistic regression was used to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI). RESULTS: Nulliparous women had an elevated endometrial cancer risk compared with parous women, even after adjusting for infertility (OR=1.76; 95% CI: 1.59-1.94). Women who reported infertility had an increased risk compared with those without infertility concerns, even after adjusting for nulliparity (OR=1.22; 95% CI: 1.13-1.33). Among women who reported infertility, none of the individual infertility causes were substantially related to endometrial cancer. CONCLUSIONS: Based on mainly self-reported infertility data that used study-specific definitions of infertility, nulliparity and infertility appeared to independently contribute to endometrial cancer risk. Understanding residual endometrial cancer risk related to infertility, its causes and its treatments may benefit from large studies involving detailed data on various infertility parameters. PMID- 25688739 TI - Complications following surgery with or without radiotherapy or radiotherapy alone for prostate cancer. AB - BACKGROUND: Men undergoing treatment of clinically localised prostate cancer may experience a number of treatment-related complications, which affect their quality of life. METHODS: On the basis of population-based retrospective cohort of men undergoing surgery, with or without subsequent radiotherapy, or radiotherapy alone for prostate cancer in Ontario, Canada, we measured the incidence of treatment-related complications using administrative and billing data. RESULTS: Of 36 984 patients, 15 870 (42.9%) underwent surgery alone, 4519 (12.2%) underwent surgery followed by radiotherapy, and 16 595 (44.9%) underwent radiotherapy alone. For all end points except urologic procedures, the 5-year cumulative incidence rates were lowest in the surgery only group and highest in the radiotherapy only group. Intermediary rates were seen in the surgery followed by radiotherapy group, except for urologic procedures where rates were the highest in this group. Although age and comorbidity were important predictors, radiotherapy as the primary treatment modality was associated with higher rates for all complications (adjusted hazard ratios 1.6-4.7, P=0.002 to <0.0001). CONCLUSIONS: In patients treated for prostate cancer, radiation after surgery increases the rate of complications compared with surgery alone, though these rates remain lower than patients treated with radiation alone. This information may inform patient and physician decision making in the treatment of prostate cancer. PMID- 25688740 TI - Assessing the benefit-risk of new treatments using generalised pairwise comparisons: the case of erlotinib in pancreatic cancer. AB - BACKGROUND: Efficacy and safety are the two considerations when characterising the effects of a new therapy. We sought to apply an innovative method of assessing the benefit-risk balance using data from a completed randomised controlled trial that compared erlotinib vs placebo added to gemcitabine in patients with advanced pancreatic cancer (NCIC CTG PA.3). METHODS: We applied generalised pairwise comparisons with several prioritised outcome measures (e.g., one or more benefit outcomes and one or more risk outcomes). Here, the first priority outcome was overall survival (OS) time. Differences in OS that exceeded 2 months were considered clinically meaningful. The second priority outcome was toxicity. The overall treatment effect was quantified using the proportion in favour of erlotinib, which can be interpreted as the net proportion of patients who have a better overall outcome with erlotinib as compared with placebo. Sensitivity analyses were performed. RESULTS: In this trial 569 patients were randomly assigned in a 1 : 1 ratio to receive gemcitabine plus either erlotinib or a matched placebo. Overall, the method indicated no statistically significant overall treatment effect in favour of erlotinib; if anything, the point estimate of the net proportion leaned in favour of the placebo group (overall proportion in favour of erlotinib=-3.6%, 95% CI, -14.2- 7.1%; P=0.51). The net proportion was never in favour of the erlotinib group throughout all sensitivity analyses. CONCLUSIONS: Generalised pairwise comparisons make it possible to assess the benefit-risk balance of new treatments using a single statistical test for any number of prioritised outcomes. The benefit-risk assessment was not in favour of adding erlotinib to gemcitabine for the treatment of patients with advanced pancreatic cancer. PMID- 25688742 TI - Mammography screening in three Finnish residential areas: comprehensive population-based study of breast cancer incidence and incidence-based mortality 1976-2009. AB - BACKGROUND: The aim of this study was to evaluate the effectiveness of a large scale screening programme for breast cancer (BC) in Turku, Finland. Incidence and incidence-based mortality (IBM) figures were compared with the areas applying different screening policies. METHODS: Deaths and person-time of women aged 40-84 were assessed for the period 1976-1986 (prescreening era) and the periods 1987 1997 and 1998-2009 (screening periods) using incidence and IBM by age at diagnosis and at death. There was a total of 40.7 million women-years, 83 497 invasive BCs obtained from the Finnish Cancer Registry; 17 508 BC deaths were linked with the data from Statistics Finland. RESULTS: In Turku, a significant (> 20%) reduction in IBM occurred during 1987-2009 among women aged 60-74 years at diagnosis compared with Helsinki (IBMRR: 0.75, 95% CI: 0.57-1.00), and in women aged 75-84 years at death compared with the rest of Finland (IBMRR: 0.72, 95% CI: 0.53-0.96). CONCLUSIONS: The wide mammography screening programme in Turku was effective in decreasing BC mortality in the elderly age groups. These results support the implementation of BC screening from age 50 up to 74 years. PMID- 25688741 TI - Checkpoint kinase1 (CHK1) is an important biomarker in breast cancer having a role in chemotherapy response. AB - BACKGROUND: Checkpoint kinase1 (CHK1), which is a key component of DNA-damage activated checkpoint signalling response, may have a role in breast cancer (BC) pathogenesis and influence response to chemotherapy. This study investigated the clinicopathological significance of phosphorylated CHK1 (pCHK1) protein in BC. METHOD: pCHK1 protein expression was assessed using immunohistochemistry in a large, well-characterized annotated series of early-stage primary operable invasive BC prepared as tissue microarray (n=1200). RESULT: pCHK1 showed nuclear and/or cytoplasmic expression. Tumours with nuclear expression showed positive associations with favourable prognostic features such as lower grade, lower mitotic activity, expression of hormone receptor and lack of expression of KI67 and PI3K (P<0.001). On the other hand, cytoplasmic expression was associated with features of poor prognosis such as higher grade, triple-negative phenotype and expression of KI67, p53, AKT and PI3K. pCHK1 expression showed an association with DNA damage response (ATM, RAD51, BRCA1, KU70/KU80, DNA-PKCalpha and BARD1) and sumoylation (UBC9 and PIASgamma) biomarkers. Subcellular localisation of pCHK1 was associated with the expression of the nuclear transport protein KPNA2. Positive nuclear expression predicted better survival outcome in patients who did not receive chemotherapy in the whole series and in ER-positive tumours. In ER negative and triple-negative subgroups, nuclear pCHK1 predicted shorter survival in patients who received cyclophosphamide, methotrexate and 5-florouracil chemotherapy. CONCLUSIONS: Our data suggest that pCHK1 may have prognostic and predictive significance in BC. Subcellular localisation of pCHK1 protein is related to its function. PMID- 25688743 TI - mTOR inhibition improves fibroblast growth factor receptor targeting in hepatocellular carcinoma. AB - BACKGROUND: Systemic therapy has proven only marginal effects in hepatocellular carcinoma (HCC) so far. The aim of this study was to evaluate the effect of targeting fibroblast growth factor receptor (FGFR) on tumour and stromal cells in HCC models. METHODS: Human and murine HCC cells, endothelial cells (ECs), vascular smooth muscle cells (VSMCs), hepatic stellate cells (HSCs), human HCC samples, FGFR inhibitor BGJ398 and mammalian target of rapamycin (mTOR) inhibitor rapamycin were used. Effects on growth, motility, signalling and angiogenic markers were determined. In vivo subcutaneous and syngeneic orthotopic tumour models were used. RESULTS: In tumour cells and ECs, targeting FGFR showed significant inhibitory effects on signalling and motility. Minor effects of FGFR inhibition were observed on VSMCs and HSCs, which were significantly enhanced by combining FGFR and mTOR blockade. In vivo daily (5 mg kg(-1)) treatment with BGJ398 led to a significant growth inhibition in subcutaneous tumour models, but only a combination of FGFR and mTOR blockade impaired tumour growth in the orthotopic model. This was paralleled by reduced tumour cell proliferation, vascularisation, pericytes and increased apoptosis. CONCLUSIONS: Targeting FGFR with BGJ398 affects tumour cells and ECs, whereas only a combination with mTOR inhibition impairs recruitment of VSMCs and HSCs. Therefore, this study provides evidence for combined FGFR/mTOR inhibition in HCC. PMID- 25688744 TI - Posterior approach to kidney dissection: An old surgical approach for integrated medical curricula. AB - Integrated medical curricular changes are altering the historical regional anatomy approach to abdominal dissection. The renal system is linked physiologically and biochemically to the cardiovascular and respiratory systems; yet, anatomists often approach the urinary system as part of the abdomen and pelvic regions. As part of an integrated curriculum, the renal system must be covered relatively quickly after the thorax in the cadaver laboratory, often without the opportunity to fully appreciate the rest of the abdominal contents. This article provides dissection instructions that follow one of the historical surgical approaches for nephrectomy, including preservation of the posterior abdominal wall neurovasclature. Dissection procedures were developed for first year medical students, intending this posterior approach to the kidneys to be their first introduction to the renal system. It has been successfully implemented with the first-year medical students at the University of New England, College of Osteopathic Medicine. Utilizing this posterior approach to the kidney enabled the study of the anatomy of the kidneys, suprarenal glands, and renal vessels, as well as the muscles of the lumbar spine, while maintaining the integrity of the anterior abdominal wall and peritoneal cavity for future gastrointestinal and reproductive system-based dissections. PMID- 25688745 TI - A Metal-Free, Free-Standing, Macroporous Graphene@g-C3N4 Composite Air Electrode for High-Energy Lithium Oxygen Batteries. AB - The nonaqueous lithium oxygen battery is a promising candidate as a next generation energy storage system because of its potentially high energy density (up to 2-3 kW kg(-1)), exceeding that of any other existing energy storage system for storing sustainable and clean energy to reduce greenhouse gas emissions and the consumption of nonrenewable fossil fuels. To achieve high energy density, long cycling stability, and low cost, the air electrode structure and the electrocatalysts play important roles. Here, a metal-free, free-standing macroporous graphene@graphitic carbon nitride (g-C3N4) composite air cathode is first reported, in which the g-C3N4 nanosheets can act as efficient electrocatalysts, and the macroporous graphene nanosheets can provide space for Li2O2 to deposit and also promote the electron transfer. The electrochemical results on the graphene@g-C3N4 composite air electrode show a 0.48 V lower charging plateau and a 0.13 V higher discharging plateau than those of pure graphene air electrode, with a discharge capacity of nearly 17300 mA h g( 1)(composite) . Excellent cycling performance, with terminal voltage higher than 2.4 V after 105 cycles at 1000 mA h g(-1)(composite) capacity, can also be achieved. Therefore, this hybrid material is a promising candidate for use as a high energy, long-cycle-life, and low-cost cathode material for lithium oxygen batteries. PMID- 25688746 TI - Carbon nitride in energy conversion and storage: recent advances and future prospects. AB - With the explosive growth of energy consumption, the exploration of highly efficient energy conversion and storage devices becomes increasingly important. Fuel cells, supercapacitors, and lithium-ion batteries are among the most promising options. The innovation of these devices mainly resides in the development of high-performance electrode materials and catalysts. Graphitic carbon nitride (g-C3 N4 ), due to structural and chemical properties such as semiconductor optical properties, rich nitrogen content, and tunable porous structure, has drawn considerable attention and shown great potential as an electrode material or catalyst in energy conversion and storage devices. This review covers recent progress in g-C3 N4 -containing systems for fuel cells, electrocatalytic water splitting devices, supercapacitors, and lithium-ion batteries. The corresponding catalytic mechanisms and future research directions in these areas are also discussed. PMID- 25688747 TI - Divinyl-end-functionalized polyethylenes: ready access to a range of telechelic polyethylenes through thiol-ene reactions. AB - Telechelic alpha,omega-iodo-vinyl-polyethylenes (Vin-PE-I) were obtained by catalytic ethylene polymerization in the presence of [(C5 Me5 )2 NdCl2 Li(OEt2 )2 ] in combination with a functionalized chain-transfer agent, namely, di(10 undecenyl)magnesium, followed by treatment of the resulting di(vinylpolyethylenyl)magnesium compounds ((vinyl-PE)2 Mg) with I2 . The iodo functionalized vinylpolyethylenes (Vin-PE-I) were transformed into unique divinyl functionalized polyethylenes (Vin-PE-Vin) by simple treatment with tBuOK in toluene at 95 degrees C. Thiol-ene reactions were then successfully performed on Vin-PE-Vin with functionalized thiols in the presence of AIBN. A range of homobifunctional telechelic polyethylenes were obtained on which a hydroxy, diol, carboxylic acid, amine, ammonium chloride, trimethoxysilyl, chloro, or fluoroalkyl group was installed quantitatively at each chain end. PMID- 25688748 TI - Turning peptides in comb silicone polymers. AB - We have recently reported on a new class of silicone-peptide' biopolymers obtained by polymerization of di-functionalized chlorodimethylsilyl hybrid peptides. Herein, we describe a related strategy based on dichloromethylsilane derived peptides, which yield novel polymers with a polysiloxane backbone, comparable with a silicone-bearing pendent peptide chains. Interestingly, polymerization is chemoselective toward amino acids side-chains and proceeds in a single step in very mild conditions (neutral pH, water, and room temperature). As potential application, a cationic sequence was polymerized and used for antibacterial coating. PMID- 25688749 TI - Daphnid life cycle responses to the insecticide chlorantraniliprole and its transformation products. AB - Chlorantraniliprole (CAP) is a newly developed, widely applied insecticide. In the aquatic environment, several transformation products are formed under natural conditions, one by dehydration and others by photoinduced degradation. Data on aquatic ecotoxicity of CAP can mainly be found in registration and regulatory evaluation reports. Moreover, the toxicity of its transformation products and especially effects upon chronic exposure remain completely unknown. Hence, our aim was to investigate the acute and chronic toxicity of CAP and its transformation products to the daphnid Daphnia magna. The results showed that CAP is extremely toxic to D. magna, with an acute and chronic LC50 of 9.4 and 3.7 MUg/L, respectively. No effects on daphnid reproduction were observed, but the impact on daphnid survival also affected population growth rate, with an EC50 of 3.5 MUg/L. In contrast, no negative effects of the two main degradation products were observed. The present study demonstrated a high sensitivity of nontarget microcrustaceans to CAP. However, the actual risk of CAP in water diminishes with its spontaneous or light-induced degradation into two transformation products, showing no toxicity to the daphnids in the present study. PMID- 25688750 TI - Syndrome of inappropriate secretion of antidiuretic hormone in a patient with drug-induced hypersensitivity syndrome. PMID- 25688752 TI - Barriers to Chronic Pain Measurement: A Qualitative Study of Patient Perspectives. AB - OBJECTIVE: Preliminary evidence suggests that chronic pain patients complete pain intensity measures using idiosyncratic methods. Our objective was to understand these methods and how they might impact the psychometric properties of the instruments. DESIGN: A qualitative focus-group based study. SETTING: An academic center in New York City. SUBJECTS: Outpatients (n = 36) with chronic low back pain, or neuropathic pain due to diabetes or HIV. METHODS: Participants were divided into three focus groups based on their pain condition, and asked to discuss pain intensity measures (visual analog and numeric rating scales for average pain over 24 hours; Brief Pain Inventory; and McGill Pain Questionnaire). Audio-recordings were transcribed and analyzed using an inductive thematic method. RESULTS: We discovered four main themes, and five sub-themes: 1) doubt that pain can be accurately measured (subthemes: pain measurement is influenced by things other than pain, the numbers used to rate pain do not have an absolute meaning, and preference for pain intensity ratings "in the middle" of the scale); 2) confusion regarding the definition of pain; 3) what experiences to use as referents (subthemes: appropriate comparator experiences and the interpretation of the anchors of the scale); and 4) difficulty averaging pain. CONCLUSIONS: The themes discovered suggest that patients include sensations and experiences other than pain intensity in their ratings, experience the rating of pain as a comparative task, and do not use the scale in a linear manner. These themes are relevant to understanding the validity and scale properties of commonly used pain intensity measures. PMID- 25688753 TI - Systemic mastocytosis in adults: 2015 update on diagnosis, risk stratification, and management. AB - DISEASE OVERVIEW: Systemic mastocytosis (SM) results from a clonal proliferation of abnormal mast cells (MC) in one or more extracutaneous organs. DIAGNOSIS: The major criterion is presence of multifocal clusters of morphologically abnormal MC in the bone marrow. Minor diagnostic criteria include elevated serum tryptase level, abnormal MC expression of CD25 and/or CD2, and presence of KITD816V. RISK STRATIFICATION: The 2008 World Health Organization classification of SM has been shown to be prognostically relevant. Classification of SM patients into indolent SM (ISM), aggressive SM (ASM), SM associated with a clonal non-MC lineage disease (SM-AHNMD), and mast cell leukemia (MCL) subgroups is a useful first step in establishing prognosis. MANAGEMENT: SM treatment is generally palliative. ISM patients have a normal life expectancy and receive symptom-directed therapy; infrequently, cytoreductive therapy may be indicated for refractory symptoms. ASM patients have disease-related organ dysfunction; interferon-alpha (+/ corticosteroids) can control dermatological, hematological, gastrointestinal, skeletal, and mediator-release symptoms, but is hampered by poor tolerability. Similarly, cladribine has broad therapeutic activity, with particular utility when rapid MC debulking is indicated; the main toxicity is myelosuppression. Imatinib has a therapeutic role in the presence of an imatinib-sensitive KIT mutation or in KITD816-unmutated patients. Treatment of SM-AHNMD is governed primarily by the non-MC neoplasm; hydroxyurea has modest utility in this setting; there is a role for allogeneic stem cell transplantation in select cases. Investigational Drugs: Recent data confirms midostaurin's significant anti-MC activity in patients with advanced SM. PMID- 25688754 TI - On-demand electrostatic coupling of individual precharacterized nano- and microparticles in a segmented Paul trap. AB - We present a novel versatile method for one-by-one coupling of single nano- and microparticles. The particles are levitated in a segmented linear Paul trap, which is ideal for fast particle characterization and assembly of two or more preselected particles by electrostatic attraction. The final compound particles remain in the trap or can be deposited on other structures. We present the assembly protocol with a theoretical background of particle stability. Results for different particle combinations showing electromagnetic coupling are presented as well as a method for the deposition on optical fibers. PMID- 25688755 TI - Alternative reagents for methotrexate as immobilizing anchor moieties in the optimization of MASPIT: synthesis and biological evaluation. AB - We report the evaluation of two alternative chemical dimerizer approaches aimed at increasing the sensitivity of MASPIT, a three-hybrid system that enables small molecule target protein profiling in intact human cells. To circumvent the potential limitations related to the binding of methotrexate (MTX) to endogenous human dihydrofolate reductase (DHFR), we explored trimethoprim (TMP) as an alternative prokaryote-specific DHFR ligand. MASPIT evaluation of TMP fusion compounds with tamoxifen, reversine, and simvastatin as model baits, resulted in dose-response curves shifted towards lower EC50 values than those of their MTX congeners. Furthermore, a scalable azido-TMP reagent was synthesized that displayed a similar improvement in sensitivity, possibly owing to increased membrane permeability relative to the MTX anchor. Applying the SNAP-tag approach to introduce a covalent bond into the system, on the other hand, produced an inferior readout than in the MTX- or TMP-tag based assay. PMID- 25688756 TI - Recombinant expression and characterization of biologically active protein delta homolog 1. AB - Obesity is characterized by an excessive accumulation of body fat, for which impaired adipogenesis is believed to play a crucial role. As a gatekeeper of early adipogenesis, protein delta homolog 1 (DLK1) has a pivotal role in deciding whether pre-adipocytes will differentiate, determining the balance between healthy and unhealthy fat tissue. Here, an expression system for the cysteine rich soluble human DLK1 was established. DLK1 was overexpressed in Escherichia coli BL21(DE3)pLysRARE, purified by affinity chromatography and refolded by stepwise dialysis. Identity, purity, secondary structure and refolding efficiency were determined. Proteolytic digestion followed by mass spectrometry analysis proved correct disulfide bridge formation. The biological activity of DLK1 was examined by differentiation assays in murine pre-adipocyte-like 3T3-L1 cells. Thereby, recombinantly produced DLK1 was shown to inhibit adipogenesis in a concentration- and time-dependent manner. All in all, our approach gives access to large amounts of active DLK1 and can be transferred to related proteins. PMID- 25688757 TI - Functional GIP receptors play a major role in islet compensatory response to high fat feeding in mice. AB - BACKGROUND: Consumption of high fat diet and insulin resistance induce significant changes in pancreatic islet morphology and function essential for maintenance of normal glucose homeostasis. We have used incretin receptor null mice to evaluate the role of gastric inhibitory polypeptide (GIP) in this adaptive response. METHODS: C57BL/6 and GIPRKO mice were fed high fat diet for 45 weeks from weaning. Changes of pancreatic islet morphology were assessed by immunohistochemistry. Body fat, glucose, insulin, glucagon, glucagon-like peptide 1 (GLP-1) and GIP were assessed by routine assays. RESULTS: Compared with normal diet controls, high fat fed C57BL/6 mice exhibited increased body fat, hyperinsulinaemia and insulin resistance, associated with decreased pancreatic glucagon, unchanged pancreatic GLP-1 and marked increases of insulin, islet number, islet size and both beta- and alpha-cell areas. Beta cell proliferation and apoptosis were increased under high fat feeding, but the overall effect favoured enhanced beta cell mass. A broadly similar pattern of change was observed in high fat fed GIPRKO mice but islet compensation was severely impaired in every respect. The inability to enhance beta cell proliferation was associated with the depletion of pancreatic GLP-1 and lack of hyperinsulinaemic response, resulting in non-fasting hyperglycaemia. GIP and GLP-1 were expressed in islets of all groups of mice but high fat fed GIPRKO mice displayed decreased numbers of GLP-1 containing alpha cells plus non-functional enhancement of pancreatic GIP content. GENERAL SIGNIFICANCE: These data suggest that GIP released from islet alpha-cells and intestinal K-cells plays an important role in islet adaptations to high fat feeding. PMID- 25688758 TI - New proline-rich oligopeptides from the venom of African adders: Insights into the hypotensive effect of the venoms. AB - BACKGROUND: The snakes from the Bitis genus are some of the most medically important venomous snakes in sub Saharan Africa, however little is known about the composition and effects of these snake venom peptides. Considering that the victims with Bitis genus snakes have exacerbate hypotension and cardiovascular disorders, we investigated here the presence of angiotensin-converting enzyme modulators on four different species of venoms. METHODS: The peptide fractions from Bitis gabonica gabonica, Bitis nasicornis, Bitis gabonica rhinoceros and Bitis arietans which showed inhibitory activity on angiotensin-converting enzyme were subjected to mass spectrometry analysis. Eight proline-rich peptides were synthetized and their potencies were evaluated in vitro and in vivo. RESULTS: The MS analysis resulted in over 150 sequences, out of which 32 are new proline-rich oligopeptides, and eight were selected for syntheses. For some peptides, inhibition assays showed inhibitory potentials of cleavage of angiotensin I ten times greater when compared to bradykinin. In vivo tests showed that all peptides decreased mean arterial pressure, followed by tachycardia in 6 out of 8 of the tests. CONCLUSION: We describe here some new and already known proline-rich peptides, also known as bradykinin-potentiating peptides. Four synthetic peptides indicated a preferential inhibition of angiotensin-converting enzyme C-domain. In vivo studies show that the proline-rich oligopeptides are hypotensive molecules. GENERAL SIGNIFICANCE: Although proline-rich oligopeptides are known molecules, we present here 32 new sequences that are inhibitors of the angiotensin-converting enzyme and consistent with the symptoms of the victims of Bitis spp, who display severe hypotension. PMID- 25688760 TI - Craving and substance use among patients with alcohol, tobacco, cannabis or heroin addiction: a comparison of substance- and person-specific cues. AB - BACKGROUND AND AIMS: It is well established that craving increases following exposure to substance-related 'cues', but the role of life-styles or substance use habits that are unique to each person remains poorly understood. This study examines the association of substance-specific and personal cues with craving and substance use in daily life. DESIGN: Ecological momentary assessment was used during a 2-week period. SETTING: Data were collected in a French out-patient addiction treatment centre. PARTICIPANTS: A total of 132 out-patients beginning treatment for alcohol, tobacco, cannabis or opiate addiction were included. MEASUREMENTS: Using mobile technologies, participants were questioned four times per day relative to craving, substance use and exposure to either substance specific cues (e.g. seeing a syringe) or personal cues unique to that individual (e.g. seeing the specific person with whom the substance is used). FINDINGS: Craving intensity was associated with the number of concurrently assessed substance-specific cues (t = 4.418, P < 0.001) and person-specific cues (t = 4.006, P < 0.001) when analysed jointly within the same model. However, only person-specific cues were associated with increases in craving over subsequent hours of the day (t = 2.598, P < 0.05). Craving intensity, in turn, predicted increases in later substance use (t = 4.076, P < 0.001). Causal mediation analyses demonstrated that the association of cues with later substance use was mediated by craving intensity (mediated effect = 0.007, 95% confidence interval = 0.004-0.011). CONCLUSIONS: Unique person-specific cues appear to have a robust effect on craving addictive substances, and the duration of this association may persist longer than for more general substance-specific cues. Mobile technologies provide new opportunities for understanding these person-specific risk factors and for providing individually tailored interventions. PMID- 25688759 TI - Physical developmental cues for the maturation of human pluripotent stem cell derived cardiomyocytes. AB - Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) are the most promising source of cardiomyocytes (CMs) for experimental and clinical applications, but their use is largely limited by a structurally and functionally immature phenotype that most closely resembles embryonic or fetal heart cells. The application of physical stimuli to influence hPSC-CMs through mechanical and bioelectrical transduction offers a powerful strategy for promoting more developmentally mature CMs. Here we summarize the major events associated with in vivo heart maturation and structural development. We then review the developmental state of in vitro derived hPSC-CMs, while focusing on physical (electrical and mechanical) stimuli and contributory (metabolic and hypertrophic) factors that are actively involved in structural and functional adaptations of hPSC-CMs. Finally, we highlight areas for possible future investigation that should provide a better understanding of how physical stimuli may promote in vitro development and lead to mechanistic insights. Advances in the use of physical stimuli to promote developmental maturation will be required to overcome current limitations and significantly advance research of hPSC-CMs for cardiac disease modeling, in vitro drug screening, cardiotoxicity analysis and therapeutic applications. PMID- 25688761 TI - Stereoselective Actions of Methylenedioxypyrovalerone (MDPV) To Inhibit Dopamine and Norepinephrine Transporters and Facilitate Intracranial Self-Stimulation in Rats. AB - The designer stimulant methylenedioxypyrovalerone (MDPV) is a potent reuptake inhibitor at transporters for dopamine (DAT) and norepinephrine (NET) that produces a constellation of abuse-related behavioral effects. MDPV possesses a chiral center, and the abused formulation of the drug is a racemic mixture, but no data are available on the pharmacology of its isomers. Here, the individual optical isomers of MDPV were prepared and examined with respect to their neurochemical actions on neurotransmitter reuptake and behavioral effects in an assay of intracranial self-stimulation (ICSS) in rats. In assays of DAT uptake inhibition, S(+)MDPV (EC50 = 2.13 nM) was more potent than either (+/-)MDPV (EC50 = 4.85 nM) or R(-)MDPV (EC50 = 382.80 nM); the three drugs were less potent at NET uptake inhibition, with the same rank order of potency. Neither racemic MDPV nor its optical isomers inhibited the reuptake of serotonin at concentrations up to 10 MUM. S(+)MDPV produced an abuse-related and dose-dependent facilitation of ICSS, and the potency of S(+)MDPV (significant facilitation at doses >= 0.1 mg/kg) was greater than that of the racemate (significant facilitation at doses >= 0.32 mg/kg). R(-)MDPV failed to alter ICSS at doses up to 100 times greater than the lowest effective dose of S(+)MDPV. The results indicate that abuse related neurochemical and behavioral effects of racemic MDPV reside primarily with its S(+) isomer. PMID- 25688762 TI - Skeletal muscle fatigue and decreased efficiency: two sides of the same coin? AB - During high-intensity submaximal exercise, muscle fatigue and decreased efficiency are intertwined closely, and each contributes to exercise intolerance. Fatigue and muscle inefficiency share common mechanisms, for example, decreased "metabolic stability," muscle metabolite accumulation, decreased free energy of adenosine triphosphate breakdown, limited O2 or substrate availability, increased glycolysis, pH disturbance, increased muscle temperature, reactive oxygen species production, and altered motor unit recruitment patterns. PMID- 25688763 TI - Heterogeneity of Muscle Blood Flow and Metabolism: Influence of Exercise, Aging, and Disease States. AB - The systematic increase in VO2 uptake and O2 extraction with increasing work rates conceals a substantial heterogeneity of O2 delivery (QO2)-to- VO2 matching across and within muscles and other organs. We hypothesize that whether increased/decreased QO2/VO2 heterogeneity can be judged as "good" or "bad," for example, after exercise training or in aged individuals or with disease (heart failure, diabetes) depends on the resultant effects on O2 transport and contractile performance. PMID- 25688764 TI - The critical power framework provides novel insights into fatigue mechanisms. PMID- 25688767 TI - House and street: Stuart Davis. PMID- 25688768 TI - Choosing wisely: changing clinicians, patients, or policies? PMID- 25688775 TI - Stealth research: is biomedical innovation happening outside the peer-reviewed literature? PMID- 25688776 TI - A piece of my mind. The other AMA. PMID- 25688777 TI - Corticosteroids for severe community-acquired pneumonia: not for everyone. PMID- 25688779 TI - Effect of corticosteroids on treatment failure among hospitalized patients with severe community-acquired pneumonia and high inflammatory response: a randomized clinical trial. AB - IMPORTANCE: In patients with severe community-acquired pneumonia, treatment failure is associated with excessive inflammatory response and worse outcomes. Corticosteroids may modulate cytokine release in these patients, but the benefit of this adjunctive therapy remains controversial. OBJECTIVE: To assess the effect of corticosteroids in patients with severe community-acquired pneumonia and high associated inflammatory response. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, randomized, double-blind, placebo-controlled trial conducted in 3 Spanish teaching hospitals involving patients with both severe community-acquired pneumonia and a high inflammatory response, which was defined as a level of C reactive protein greater than 150 mg/L at admission. Patients were recruited and followed up from June 2004 through February 2012. INTERVENTIONS: Patients were randomized to receive either an intravenous bolus of 0.5 mg/kg per 12 hours of methylprednisolone (n = 61) or placebo (n = 59) for 5 days started within 36 hours of hospital admission. MAIN OUTCOMES AND MEASURES: The primary outcome was treatment failure (composite outcome of early treatment failure defined as [1] clinical deterioration indicated by development of shock, [2] need for invasive mechanical ventilation not present at baseline, or [3] death within 72 hours of treatment; or composite outcome of late treatment failure defined as [1] radiographic progression, [2] persistence of severe respiratory failure, [3] development of shock, [4] need for invasive mechanical ventilation not present at baseline, or [5] death between 72 hours and 120 hours after treatment initiation; or both early and late treatment failure). In-hospital mortality was a secondary outcome and adverse events were assessed. RESULTS: There was less treatment failure among patients from the methylprednisolone group (8 patients [13%]) compared with the placebo group (18 patients [31%]) (P = .02), with a difference between groups of 18% (95% CI, 3% to 32%). Corticosteroid treatment reduced the risk of treatment failure (odds ratio, 0.34 [95% CI, 0.14 to 0.87]; P = .02). In hospital mortality did not differ between the 2 groups (6 patients [10%] in the methylprednisolone group vs 9 patients [15%] in the placebo group; P = .37); the difference between groups was 5% (95% CI, -6% to 17%). Hyperglycemia occurred in 11 patients (18%) in the methylprednisolone group and in 7 patients (12%) in the placebo group (P = .34). CONCLUSIONS AND RELEVANCE: Among patients with severe community-acquired pneumonia and high initial inflammatory response, the acute use of methylprednisolone compared with placebo decreased treatment failure. If replicated, these findings would support the use of corticosteroids as adjunctive treatment in this clinical population. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00908713. PMID- 25688780 TI - Effect of varenicline on smoking cessation through smoking reduction: a randomized clinical trial. AB - IMPORTANCE: Some cigarette smokers may not be ready to quit immediately but may be willing to reduce cigarette consumption with the goal of quitting. OBJECTIVE: To determine the efficacy and safety of varenicline for increasing smoking abstinence rates through smoking reduction. DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, placebo-controlled, multinational clinical trial with a 24-week treatment period and 28-week follow-up conducted between July 2011 and July 2013 at 61 centers in 10 countries. The 1510 participants were cigarette smokers who were not willing or able to quit smoking within the next month but willing to reduce smoking and make a quit attempt within the next 3 months. Participants were recruited through advertising. INTERVENTIONS: Twenty-four weeks of varenicline titrated to 1 mg twice daily or placebo with a reduction target of 50% or more in number of cigarettes smoked by 4 weeks, 75% or more by 8 weeks, and a quit attempt by 12 weeks. MAIN OUTCOMES AND MEASURES: Primary efficacy end point was carbon monoxide-confirmed self-reported abstinence during weeks 15 through 24. Secondary outcomes were carbon monoxide-confirmed self-reported abstinence for weeks 21 through 24 and weeks 21 through 52. RESULTS: The varenicline group (n = 760) had significantly higher continuous abstinence rates during weeks 15 through 24 vs the placebo group (n = 750) (32.1% for the varenicline group vs 6.9% for the placebo group; risk difference (RD), 25.2% [95% CI, 21.4%-29.0%]; relative risk (RR), 4.6 [95% CI, 3.5-6.1]). The varenicline group had significantly higher continuous abstinence rates vs the placebo group during weeks 21 through 24 (37.8% for the varenicline group vs 12.5% for the placebo group; RD, 25.2% [95% CI, 21.1%-29.4%]; RR, 3.0 [95% CI, 2.4-3.7]) and weeks 21 through 52 (27.0% for the varenicline group vs 9.9% for the placebo group; RD, 17.1% [95% CI, 13.3%-20.9%]; RR, 2.7 [95% CI, 2.1-3.5]). Serious adverse events occurred in 3.7% of the varenicline group and 2.2% of the placebo group (P = .07). CONCLUSIONS AND RELEVANCE: Among cigarette smokers not willing or able to quit within the next month but willing to reduce cigarette consumption and make a quit attempt at 3 months, use of varenicline for 24 weeks compared with placebo significantly increased smoking cessation rates at the end of treatment, and also at 1 year. Varenicline offers a treatment option for smokers whose needs are not addressed by clinical guidelines recommending abrupt smoking cessation. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01370356. PMID- 25688781 TI - Effect of oral eliglustat on splenomegaly in patients with Gaucher disease type 1: the ENGAGE randomized clinical trial. AB - IMPORTANCE: Gaucher disease type 1 is characterized by hepatosplenomegaly, anemia, thrombocytopenia, and skeletal disease. A safe, effective oral therapy is needed. OBJECTIVE: To determine whether eliglustat, a novel oral substrate reduction therapy, safely reverses clinical manifestations in untreated adults with Gaucher disease type 1. DESIGN, SETTING, AND PARTICIPANTS: Phase 3, randomized, double-blind, placebo-controlled trial conducted at 18 sites in 12 countries from November 2009 to July 2012 among eligible patients with splenomegaly plus thrombocytopenia and/or anemia. Of 72 patients screened, 40 were enrolled. INTERVENTIONS: Patients were stratified by spleen volume and randomized 1:1 to receive eliglustat (50 or 100 mg twice daily; n = 20) or placebo (n = 20) for 9 months. MAIN OUTCOMES AND MEASURES: The primary efficacy end point was percentage change in spleen volume in multiples of normal from baseline to 9 months; secondary efficacy end points were change in hemoglobin level and percentage changes in liver volume and platelet count. RESULTS: All patients had baseline splenomegaly and thrombocytopenia (mostly moderate or severe), most had mild or moderate hepatomegaly, and 20% had mild anemia. Least square mean spleen volume decreased by 27.77% (95% CI, -32.57% to -22.97%) in the eliglustat group (from 13.89 to 10.17 multiples of normal) vs an increase of 2.26% (95% CI, -2.54% to 7.06%) in the placebo group (from 12.50 to 12.84 multiples of normal) for an absolute treatment difference of -30.03% (95% CI, 36.82% to -23.24%; P < .001). For the secondary end points, the least-square mean absolute differences between groups all favored eliglustat, with a 1.22-g/dL increase in hemoglobin level (95% CI, 0.57-1.88 g/dL; P < .001), 6.64% decrease in liver volume (95% CI, -11.37% to -1.91%; P = .007), and 41.06% increase in platelet count (95% CI, 23.95%-58.17%; P < .001). No serious adverse events occurred. One patient in the eliglustat group withdrew (non-treatment related); 39 of the 40 patients transitioned to an open-label extension study. CONCLUSIONS AND RELEVANCE: Among previously untreated adults with Gaucher disease type 1, treatment with eliglustat compared with placebo for 9 months resulted in significant improvements in spleen volume, hemoglobin level, liver volume, and platelet count. The clinical significance of these findings is uncertain, and more definitive conclusions about clinical efficacy and utility will require comparison with the standard treatment of enzyme replacement therapy as well as longer-term follow-up. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00891202. PMID- 25688782 TI - Association between the use of fondaparinux vs low-molecular-weight heparin and clinical outcomes in patients with non-ST-segment elevation myocardial infarction. AB - IMPORTANCE: Fondaparinux was associated with reduced major bleeding events and improved survival compared with low-molecular-weight heparin (LMWH) in a large randomized clinical trial involving patients with non-ST-segment elevation myocardial infarction (NSTEMI). Large-scale experience of the use of fondaparinux vs LMWH in a nontrial setting is lacking. OBJECTIVE: To study the association between the use of fondaparinux vs LMWH and outcomes in patients with NSTEMI in Sweden. DESIGN, SETTING, AND PATIENTS: Prospective multicenter cohort study from the Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies registry involving 40,616 consecutive patients with NSTEMI who received fondaparinux or LMWH between September 1, 2006, through June 30, 2010, with the last follow-up on December 31, 2010. EXPOSURES: In-hospital treatment with fondaparinux or LMWH during the hospital stay. MAIN OUTCOMES AND MEASURES: In-hospital severe bleeding events and death and 30- and 180-day death, MI, stroke, and major bleeding events. Logistic regression models adjusted for calendar time, admitting hospital, baseline characteristics, and in-hospital revascularization. RESULTS: In total, 14,791 patients (36.4%) were treated with fondaparinux and 25,825 (63.6%) with LMWH. One hundred sixty-five patients (1.1%) in the fondaparinux group vs 461 patients (1.8%) in the LMWH group experienced in-hospital bleeding events (adjusted odds ratio [OR], 0.54; 95% CI, 0.42-0.70). A total of 394 patients (2.7%) in the fondaparinux group died while in the hospital vs 1022 (4.0%) in the LMWH group (adjusted OR, 0.75; 95% CI, 0.63-0.89). The differences in major bleeding events and mortality between the 2 treatments were similar at 30 and 180 days. There were no significant differences in the number of recurrent MI and stroke events at 30 or 180 days among the 2 treatment groups. CONCLUSIONS AND RELEVANCE: In routine clinical care of patients with NSTEMI, fondaparinux was associated with lower odds than LMWH of major bleeding events and death both in-hospital and up to 180 days afterward. PMID- 25688783 TI - Starting a new discussion about screening for lung cancer. PMID- 25688784 TI - Use of pneumococcal vaccine in adults. PMID- 25688785 TI - Shortness of breath after a choking incident. PMID- 25688786 TI - Heart rate and body temperature responses to extreme heat and humidity with and without electric fans. PMID- 25688787 TI - Fecal microbiota transplantation for Clostridium difficile infection. PMID- 25688788 TI - Fecal microbiota transplantation for Clostridium difficile infection--reply. PMID- 25688789 TI - Adapting to climate change. PMID- 25688790 TI - Adapting to climate change--reply. PMID- 25688791 TI - Goals of displaying health care prices to physicians. PMID- 25688792 TI - Goals of displaying health care prices to physicians--reply. PMID- 25688798 TI - The treatment of asthma: portion of a lecture delivered in the regular course of 1888-89. PMID- 25688800 TI - JAMA patient page. Pneumococcal vaccination. PMID- 25688801 TI - Perceptions of overweight in US and global cultures. AB - We explored the hypothesis that perceptions of overweight vary in accord with the prevalence of overweight in specific populations. The present study investigated this relationship in samples from diverse groups in the US and four other countries. The perceptual threshold for overweight is the scalar point at which individuals determine the transition from normal to overweight. Perceptual thresholds for overweight were obtained from 812 adults in Korea, Mexico, Ukraine, Tanzania, and the US (Black, Hispanic, White and college student samples). A linear relationship was observed between the perceptual threshold for overweight and the population prevalence (r=0.52, adjusted R(2)=0.22, F (1/15)=5.24, p<.05), and this relationship was considerably stronger in the non US samples. This finding links with the results of other studies documenting the influence of the social environment on both weight perception and weight transmission. Together, they suggest that the socio-cultural milieu and weight norms are components of the obesogenic environment and argue for the inclusion of weight norm interventions in weight management programs and public health initiatives. PMID- 25688802 TI - Reduced DNA methylation and hydroxymethylation in patients with systemic mastocytosis. AB - OBJECTIVE: As disruption of epigenetic control is a frequent event in solid tumors and leukemia, we investigated changes in DNA methylation (5mC) and hydroxymethylation (5hmC) in patients with systemic mastocytosis (SM), a rare myeloproliferative disease with a wide spectrum of severity, characterized by the accumulation of mast cells in various organs. METHODS: We measured overall genomic levels of 5hmC and 5mC in patients with SM by dot blot, as well as by quantitative immunofluorescence in samples of cutaneous mastocytosis. RESULTS: Overall 5hmC levels were reduced in all patients with SM, but to a greater extent in the presence of higher D816V mutational load in the KIT oncogene, which affects prognosis and therapeutic options in these patients. Loss of 5hmC was likely due to systemic effects of SM as it did not correlate with overall mast cell burden in these patients, nor it was due to inactivating mutations of TET2 or reduced TET2 expression. CONCLUSIONS: The correlation between SM diagnosis and significantly low 5hmC levels suggests that reduction of 5hmC represents a systemic effect of SM that may be useful for patient stratification and that measurements of 5hmC levels may serve as a better prognostic marker than TET2 mutations. PMID- 25688803 TI - FGFR3 unliganded dimer stabilization by the juxtamembrane domain. AB - Receptor tyrosine kinases (RTKs) conduct biochemical signals upon dimerization in the membrane plane. While RTKs are generally known to be activated in response to ligand binding, many of these receptors are capable of forming unliganded dimers that are likely important intermediates in the signaling process. All 58 RTKs consist of an extracellular (EC) domain, a transmembrane (TM) domain, and an intracellular domain that includes a juxtamembrane (JM) sequence and a kinase domain. Here we investigate directly the effect of the JM domain on unliganded dimer stability of FGFR3, a receptor that is critically important for skeletal development. The data suggest that FGFR3 unliganded dimers are stabilized by receptor-receptor contacts that involve the JM domains. The contribution is significant, as it is similar in magnitude to the stabilizing contribution of a pathogenic mutation and the repulsive contribution of the EC domain. Furthermore, we show that the effects of the JM domain and a TM pathogenic mutation on unliganded FGFR3 dimer stability are additive. We observe that the JM-mediated dimer stabilization occurs when the JM domain is linked to FGFR3 TM domain and not simply anchored to the plasma membrane. These results point to a coordinated stabilization of the unliganded dimeric state of FGFR3 by its JM and TM domains via a mechanism that is distinctly different from the case of another well studied receptor, EGFR. PMID- 25688804 TI - Lysine deacetylases regulate the heat shock response including the age-associated impairment of HSF1. AB - Heat shock factor 1 (HSF1) is critical for defending cells from both acute and chronic stresses. In aging cells, the DNA binding activity of HSF1 deteriorates correlating with the onset of pathological events including neurodegeneration and heart disease. We find that DNA binding by HSF1 is controlled by lysine deacetylases with HDAC7, HDAC9, and SIRT1 distinctly increasing the magnitude and length of a heat shock response (HSR). In contrast, HDAC1 inhibits HSF1 in a deacetylase-independent manner. In aging cells, the levels of HDAC1 are elevated and the HSR is impaired, yet reduction of HDAC1 in aged cells restores the HSR. Our results provide a mechanistic basis for the age-associated regulation of the HSR. Besides HSF1, the deacetylases differentially modulate the activities of unrelated DNA binding proteins. Taken together, our data further support the model that lysine deacetylases are selective regulators of DNA binding proteins. PMID- 25688805 TI - Impact of oxygen on the coexistence of nitrification, denitrification, and sulfate reduction in oxygen-based membrane aerated biofilm. AB - Membrane aerated biofilms (MABs) are subject to "counter diffusion" of oxygen and substrates. In a membrane aerated biofilm reactor, gases (e.g., oxygen) diffuse through the membrane into the MAB, and liquid substrates pass from the bulk liquid into the MAB. This behavior can result in a unique biofilm structure in terms of microbial composition, distribution, and community activity in the MAB. Previous studies have shown simultaneous aerobic oxidation, nitrification, and denitrification within a single MAB. Using molecular techniques, we investigated the growth of sulfate-reducing bacteria (SRB) in the oxygen-based MAB attached to a flat sheet membrane. Denaturing gradient gel electrophoresis of the amplified 16S rRNA gene fragments and functional gene fragments specific for ammonia oxidizing bacteria (amoA), denitrifying bacteria (nirK), and SRB (dsrB) demonstrated the coexistence of nitrifiers, denitrifiers, and SRB communities within a single MAB. The functional diversities of SRB and denitrifiers decreased with an increase in the oxygen concentration in the bulk water of the reactor. PMID- 25688807 TI - Differential effects of reinforcement on the self-monitoring of on-task behavior. AB - In the current study, the differential effects of reinforcement on a self monitoring intervention were evaluated. Three students nominated by their teachers for having a marked difficultly maintaining on-task behaviors participated in the study. Using an alternating treatments single-case design to assess self-monitoring with and without reinforcement, students self-monitored their on-task behavior while being prompted by a vibrating timer at 1-min intervals for 20-min sessions. The investigators collected data regarding the students' percentage of intervals on-task and the accuracy of their recordings. Accuracy was measured by calculating the percent of agreement between the observer and student. For half of the self-monitoring sessions, students were provided reinforcement for matching at least 80% of their self-monitored ratings with those of the observer. Results indicated that self-monitoring alone was effective for 2 students in increasing their on-task behaviors in a general education classroom and self-monitoring with reinforcement was effective for all 3. Two students demonstrated an increase in on-task behavior when self-monitoring was paired with the opportunity to receive reinforcement compared to self monitoring alone. Percentage of nonoverlapping data for self-monitoring without reinforcement ranged from 16.6% to 100%, and self-monitoring with reinforcement ranged from 83% to 100%. Additionally, the opportunity to receive reinforcement impacted students' accuracy in self-monitoring resulting in more accurate self recording of on-task behavior. Including reinforcement as a component of a self monitoring intervention package is an important consideration as it may impact the effectiveness of the intervention for students with significant difficulties maintaining attention to tasks. PMID- 25688806 TI - Adoption of preventive behaviors in response to the 2009 H1N1 influenza pandemic: a multiethnic perspective. AB - BACKGROUND: As public health leaders prepare for possible future influenza pandemics, the rapid spread of 2009 H1N1 influenza highlights the need to focus on measures the public can adopt to help slow disease transmission. Such measures may relate to hygiene (e.g., hand washing), social distancing (e.g., avoiding places where many people gather), and pharmaceutical interventions (e.g., vaccination). Given the disproportionate impact of public health emergencies on minority communities in the United States, it is important to understand whether there are differences in acceptance across racial/ethnic groups that could lead to targeted and more effective policies and communications. OBJECTIVES: This study explores racial/ethnic differences in the adoption of preventive behaviors during the 2009 H1N1 influenza pandemic. PATIENTS/METHODS: Data are from a national telephone poll conducted March 17 to April 11, 2010, among a representative sample of 1123 white, 330 African American, 317 Hispanic, 268 Asian, and 262 American Indian/Alaska Native adults in the USA. RESULTS: People in at least one racial/ethnic minority group were more likely than whites to adopt several behaviors related to hygiene, social distancing, and healthcare access, including increased hand washing and talking with a healthcare provider (P-values <0.05). Exceptions included avoiding others with influenza-like illnesses and receiving 2009 H1N1 and seasonal influenza vaccinations. After we controlled the data for socioeconomic status, demographic factors, healthcare access, and illness- and vaccine-related attitudes, nearly all racial/ethnic differences in behaviors persisted. CONCLUSIONS: Minority groups appear to be receptive to several preventive behaviors, but barriers to vaccination are more pervasive. PMID- 25688808 TI - Conjoint Behavioral Consultation for children with Autism Spectrum Disorder. AB - The present study examined the efficacy of Conjoint Behavioral Consultation (CBC) for children with Autism Spectrum Disorder (ASD) in early elementary school. In addition, the parent-teacher relationship, parent and teacher competence in problem solving, and CBC acceptability were examined. Participants included 3 children with ASD in early elementary school, and their parents and teachers. Findings suggested (a) CBC was efficacious for treating children's social behavior in classrooms, (b) 2 of 3 parent-teacher dyads reported improvements in the parent-teacher relationship, (c) all parents and teacher reported increases in their problem-solving competences, and (d) CBC was highly acceptable to parents and teachers. Implications for CBC research and interventions for children with ASD are discussed. (PsycINFO Database Record PMID- 25688809 TI - Nanostructured Mo-based electrode materials for electrochemical energy storage. AB - The development of advanced energy storage devices is at the forefront of research geared towards a sustainable future. Nanostructured materials are advantageous in offering huge surface to volume ratios, favorable transport features, and attractive physicochemical properties. They have been extensively explored in various fields of energy storage and conversion. This review is focused largely on the recent progress in nanostructured Mo-based electrode materials including molybdenum oxides (MoO(x), 2 <= x <= 3), dichalconides (MoX2, X = S, Se), and oxysalts for rechargeable lithium/sodium-ion batteries, Mg batteries, and supercapacitors. Mo-based compounds including MoO2, MoO3, MoO(3-y) (0 < y < 1), MMo(x)O(y) (M = Fe, Co, Ni, Ca, Mn, Zn, Mg, or Cd; x = 1, y = 4; x = 3, y = 8), MoS2, MoSe2, (MoO2)2P2O7, LiMoO2, Li2MoO3, etc. possess multiple valence states and exhibit rich chemistry. They are very attractive candidates for efficient electrochemical energy storage systems because of their unique physicochemical properties, such as conductivity, mechanical and thermal stability, and cyclability. In this review, we aim to provide a systematic summary of the synthesis, modification, and electrochemical performance of nanostructured Mo-based compounds, as well as their energy storage applications in lithium/sodium-ion batteries, Mg batteries, and pseudocapacitors. The relationship between nanoarchitectures and electrochemical performances as well as the related charge-storage mechanism is discussed. Moreover, remarks on the challenges and perspectives of Mo-containing compounds for further development in electrochemical energy storage applications are proposed. This review sheds light on the sustainable development of advanced rechargeable batteries and supercapacitors with nanostructured Mo-based electrode materials. PMID- 25688811 TI - Online suicide risk screening and intervention with college students: a pilot randomized controlled trial. AB - OBJECTIVE: This pilot randomized controlled trial examined the effect of an online intervention for college students at risk for suicide, Electronic Bridge to Mental Health Services (eBridge), which included personalized feedback and optional online counseling delivered in accordance with motivational interviewing principles. Primary outcomes were readiness to seek information or talk with family and friends about mental health treatment, readiness to seek mental health treatment, and actual treatment linkage. METHOD: Participants were 76 college students (45 women, 31 men; mean age = 22.9 years, SD = 5.0 years) at a large public university who screened positive for suicide risk, defined by at least 2 of the following: suicidal thoughts, history of suicide attempt, depression, and alcohol abuse. Racial/ethnic self-identifications were primarily Caucasian (n = 54) and Asian (n = 21). Students were randomized to eBridge or the control condition (personalized feedback only, offered in plain report format). Outcomes were measured at 2-month follow-up. RESULTS: Despite relatively modest engagement in online counseling (29% of students posted >=1 message), students assigned to eBridge reported significantly higher readiness for help-seeking scores, especially readiness to talk to family, talk to friends, and see a mental health professional. Students assigned to eBridge also reported lower stigma levels and were more likely to link to mental health treatment. CONCLUSIONS: Findings suggest that offering students personalized feedback and the option of online counseling, using motivational interviewing principles, has a positive impact on students' readiness to consider and engage in mental health treatment. Further research is warranted to determine the robustness of this effect, the mechanism by which improved readiness and treatment linkage occurs, and the longer term impact on student mental health outcomes. PMID- 25688812 TI - Trajectories of suicide ideation and nonsuicidal self-injury among adolescents in mainland China: Peer predictors, joint development, and risk for suicide attempts. AB - OBJECTIVE: This study expanded knowledge about the development of suicide ideation and nonsuicidal self-injury (NSSI) among adolescents by investigating (a) peer experiences as predictors of trajectories of suicide ideation and NSSI, (b) the joint development of suicide ideation and NSSI, and (c) the risk for suicide attempts (SA) across joint trajectories of suicide ideation and NSSI. METHOD: At baseline, 565 tenth-grade Chinese adolescents (48.3% males) reported depressive symptoms and friend support. Moreover, peer victimization and friendships were assessed using a sociometric procedure. After baseline, participants completed measures of suicide ideation, NSSI, and SA every 3 months for 2 years. RESULTS: Three similar trajectories of suicide ideation and NSSI were identified. After accounting for depressive symptoms, peer victimization differentiated adolescents in the high trajectory of suicide ideation and NSSI from those in the low and moderate trajectories of suicide ideation and NSSI, respectively. Friend support and friendlessness distinguished between the high and low and the moderate and low NSSI trajectories, respectively. Joint trajectory models revealed a strong overlap between the course of suicide ideation and NSSI: Adolescents in the chronically high suicide ideation trajectory were at the highest risk to follow a chronically high NSSI trajectory and vice versa. Finally, adolescents in the joint chronically high trajectory were approximately 5 times more likely to report SA than were their peers, above and beyond prior SA. CONCLUSIONS: Findings highlight the role of negative peer experiences as risk factors for NSSI and suicide ideation, which, in turn, can potentially increase risk for SA. (PsycINFO Database Record PMID- 25688813 TI - Ring-opening copolymerization (ROCOP): synthesis and properties of polyesters and polycarbonates. AB - Controlled routes to prepare polyesters and polycarbonates are of interest due to the widespread application of these materials and the opportunities provided to prepare new copolymers. Furthermore, ring-opening copolymerization may enable new poly(ester-carbonate) materials to be prepared which are inaccessible using alternative polymerizations. This review highlights recent advances in the ring opening copolymerization catalysis, using epoxides coupled with anhydrides or CO2, to produce polyesters and polycarbonates. In particular, the structures and performances of various homogeneous catalysts are presented for the epoxide anhydride copolymerization. The properties of the resultant polyesters and polycarbonates are presented and future opportunities highlighted for developments of both the materials and catalysts. PMID- 25688814 TI - Fetal growth: too big, too little, just right. PMID- 25688815 TI - New Zealand National GDM Guidelines: an alternative view of some good practice points. AB - The New Zealand Gestational Diabetes Mellitus (GDM) Guidelines, commissioned by the Ministry of Health, contains many good points, but several recommendations are creating controversy. This opinion piece discusses an alternative approach to early pregnancy screening for diabetes. We suggest that it is reasonable to refer women with an HbA1c >=41 mmol/mol (5.9%) for further management, rather than the recommended referral threshold of >=50 mmol/mol (6.7%). We also suggest that, for subsequent screening for GDM at 24-28 weeks' gestation, a 75 g oral glucose tolerance test should be offered rather than a 50 g glucose challenge test. PMID- 25688816 TI - Understanding gestational weight gain: the role of weight-related expectations and knowledge. AB - BACKGROUND: Health behaviour theories acknowledge that beliefs, attitudes and knowledge contribute to health behaviours, yet the role of these cognitions in predicting weight gain during pregnancy has not been widely researched. AIMS: To explore and compare the predictive nature of gestational weight gain (GWG) expectations and knowledge on weight gain during pregnancy. MATERIALS AND METHODS: One hundred and sixty-six women were tracked during pregnancy. Participants provided information on prepregnancy weight, height, GWG expectations and knowledge at 16-18 weeks' gestation (Time 1). To calculate gestational weight gain, prepregnancy weight was subtracted from weight at 36 weeks' gestation (collected at Time 2). Gestational weight gain above the Institute of Medicine's GWG recommendations was classified as excessive. A hierarchical regression examined the predictive nature of GWG expectations for actual GWG. Chi-square significance tests determined whether the accuracy of GWG knowledge differed depending on GWG status and prepregnancy BMI category. RESULTS: GWG expectations were a significant predictor of weight gain during pregnancy. Women who experienced excessive GWG were more likely to overestimate the minimum amount of weight that they needed to gain to have a healthy baby. CONCLUSIONS: GWG expectations are predictive of actual GWG, and GWG knowledge among women is generally poor. In particular, overestimating of the minimum amount of weight to gain during pregnancy is associated with excessive GWG. As such, it may be beneficial to design interventions to prevent excessive GWG that targets these cognitions. PMID- 25688817 TI - Exercise in pregnancy does not alter gestational weight gain, MCP-1 or leptin in obese women. AB - BACKGROUND: Increasing physical activity in pregnancy may improve pregnancy outcomes for obese women. Exercise could reduce gestational weight gain, improve the maternal circulating lipid profile as well as alter leptin, Interleukin-8 (IL 8) and Monocyte Chemoattractant Protein-1 (MCP-1) levels. AIM: The aim of this study was to investigate the effects of exercise on gestational weight gain, maternal circulating lipids, IL-8, MCP-1 and leptin levels in obese pregnant women. MATERIALS AND METHODS: The analysis was performed in the 35 obese women enrolled in the pilot BAMBINO randomised controlled trial who provided blood samples at 12- and 28-weeks gestation. Women in the exercise intervention arm received an individualised exercise plan. Blood samples, exercise diary and pedometer data were obtained at 12-, 20-, 28- and 36-weeks' gestation. Cord blood was obtained at delivery. RESULTS: Women in the exercise arm exercised more than those in the control arm (P = 0.038). There was no difference in gestational weight gain, excess gestational weight gain, MCP-1 and leptin levels between women in the exercise intervention (n = 19) or the control arm (n = 16). IL-8 was not detectable. Exercise did not alter the maternal lipid profile. CONCLUSIONS: The low level of physical activity achieved in obese women in the exercise intervention arm was insufficient to alter gestational weight gain, MCP-1, leptin or circulating lipid levels. PMID- 25688818 TI - Extreme macrosomia--obstetric outcomes and complications in birthweights >5000 g. AB - OBJECTIVE: Management of extremely large birthweight infants presents challenges during the period of labour and delivery. We sought to examine outcomes in infants with extreme macrosomia (birthweight > 5000 g), at an institution where the management of labour is standardised. MATERIALS AND METHODS: This is a retrospective analysis of prospectively gathered data on all infants with a birthweight >5000 g delivered at a tertiary level institution from 2008 to 2012. Details of labour characteristics and outcomes were examined; these were compared according to parity. RESULTS: During the study period, there were 46 128 deliveries at the hospital and 182 infants with a birthweight >5000 g, giving an incidence of 0.4%. The majority of women (133/182) were multiparous. Among nulliparas, 47% (23/49) had a vaginal delivery, while 53% (26/49) had a caesarean delivery. 86% (97/113) of multiparas had a vaginal delivery, and 14% (16/113) had a caesarean delivery. 43% (69/162) required induction of labour. This was more common in nulliparous compared with multiparous women (58% [29/49] vs 30% [40/133], P = 0.005, OR = 3.4, 95% CI = 1.7-6.6). A total of 30% (49/162) of women had their labour accelerated with oxytocin. There were higher rates of oxytocin use in nulliparas than in multiparas (55% [27/49] vs 16.5% [22/133], P < 0.0001, OR = 6.2, 95% CI = 3-12.8). Seventeen of the 120 infants delivered vaginally had a shoulder dystocia (14.2%), with three suffering an Erbs palsy, all of which had resolved before 6 months of age. One baby had a clavicular fracture. CONCLUSION: Extreme macrosomia affects 0.4% of pregnancies in contemporary practice. Multiparas have a low rate of caesarean section. Infants delivered vaginally are at increased risk of shoulder dystocia and associated complications. PMID- 25688819 TI - Comparison of neonatal outcomes in women with gestational diabetes with moderate hyperglycaemia on metformin or glibenclamide--a randomised controlled trial. AB - BACKGROUND: Two oral hypoglycaemic agents, metformin and glibenclamide, have been compared with insulin in separate large randomised controlled trials and have been found to be as effective as insulin in gestational diabetes. However, very few trials have compared metformin with glibenclamide. MATERIALS AND METHODS: Of 159 South Indian women with fasting glucose >=5.5 mmol/l and <=7.2 mmol/l and/or 2-h post-prandial value >=6.7 mmol/l and <=13.9 mmol/l after medical nutritional therapy consented to be randomised to receive either glibenclamide or metformin. 80 women received glibenclamide and 79 received metformin. Neonatal outcomes were assessed by neonatologists who were unaware that the mother was part of a study and were recorded by assessors blinded to the medication the mother was given. The primary outcome was a composite of neonatal outcomes namely macrosomia, hypoglycaemia, need for phototherapy, respiratory distress, stillbirth or neonatal death and birth trauma. Secondary outcomes were birthweight, maternal glycaemic control, pregnancy induced hypertension, preterm birth, need for induction of labour, mode of delivery and complications of delivery. RESULTS: Baseline characteristics were similar but for the higher fasting triglyceride levels in women on metformin. The primary outcome was seen in 35% of the glibenclamide group and 18.9% of the metformin group [95% CI 16.1 (2.5, 29.7); P = 0.02]. The difference in outcome related to a higher rate of neonatal hypoglycaemia in the glibenclamide group (12.5%) versus none in the metformin group [95% CI 12.5(5.3, 19.7); P = 0.001]. Secondary outcomes in both groups were similar. CONCLUSION: In a south Indian population with gestational diabetes, metformin was associated with better neonatal outcomes than glibenclamide. PMID- 25688820 TI - The effect of prophylactic intravenous tranexamic acid on blood loss after vaginal delivery in women at low risk of postpartum haemorrhage: a double-blind randomised controlled trial. AB - OBJECTIVE: To determine the effect of prophylactic tranexamic acid (TA) on calculated and measured blood loss after vaginal delivery in women at low risk of postpartum haemorrhage. METHODS: In this double-blind randomised controlled trial, 120 women with a singleton pregnancy were randomly allocated to receive either one gram intravenous TA or placebo in addition to 10 IU oxytocin after delivery of the fetus. Calculated blood loss was determined based on haematocrit before delivery and 12-24 h postdelivery. The quantity of blood loss was measured during two time periods: from delivery of the fetus to placental expulsion and from placental expulsion to the end of the second hour after childbirth. RESULTS: The mean (SD) calculated total blood loss (519 (320) vs 659 (402) mL, P = 0.036) and measured blood loss from placental delivery to 2 h postpartum (69 (39) vs 108 (53) mL, P < 0.001) was significantly lower in the intervention group compared with the control group. There was no significant difference between groups in terms of blood loss from delivery of the fetus until placental expulsion. The frequency of calculated blood loss > 1000 mL was lower in the TA group (7% vs 18%, P = 0.048). CONCLUSION: Prophylactic TA reduces blood loss after vaginal delivery in women with a low risk of postpartum haemorrhage. The prophylactic use of TA may reduce blood loss complications and enhance maternal health. PMID- 25688821 TI - Lymphovascular space invasion and cervical stromal invasion are independent risk factors for nodal metastasis in endometrioid endometrial cancer. AB - AIMS: The purpose of this study was to investigate the potential roles of pathological variables in the prediction of nodal metastasis in women with endometrioid endometrial cancer (EC). MATERIALS AND METHODS: Women who underwent surgery for endometrioid EC between 1995 and 2012 were retrospectively reviewed. Those who underwent prior neoadjuvant chemotherapy or radiotherapy and inadequate lymphadenectomy as well as those with nonendometrioid histology, synchronous cancers, International Federation of Gynecology and Obstetrics stage IV disease, gross uterine serosal and/or gross adnexal involvement were excluded. Lymph node dissemination was defined as occurring in the following circumstances: (i) when nodal metastasis with pelvic and/or para-aortic (P/PA) lymph node dissection (LND) was performed or (ii) when there was recurrence in the P/PA lymph nodes after a negative LND or when LND was not performed. Univariate and multivariate logistic regression models were used to identify the pathological predictors of lymphatic dissemination. RESULTS: A total of 827 women with endometrioid EC were assessed; 516 (62.4%) of whom underwent P/PA LND and 205 (24.8%) underwent P LND. Sixty-seven (13%) women in the P/PA LND group and 5 (2.4%) in the P LND group had positive lymph nodes. Multivariate analysis confirmed cervical stromal invasion (OR 4.04, 95% CI 2.02-8.07 (P < 0.001)) and lymphovascular space invasion (LVSI) (OR 110.18, 95% CI 38.43-315.87 (P < 0.001)) as independent predictors of lymphatic dissemination. CONCLUSION: Cervical stromal invasion and LVSI are highly associated with LN metastasis. These markers may serve as a surrogate for nodal metastasis. PMID- 25688822 TI - Response: Does preconception care improve perinatal outcome? PMID- 25688823 TI - Does preconception care improve perinatal outcome? PMID- 25688824 TI - Managing the breech presentation at term: the place of pelvimetry. PMID- 25688825 TI - The value of imaging pelvimetry in the management of the breech presentation at term. PMID- 25688826 TI - Asymptomatic thickened endometrium in postmenopausal women and unnecessary examinations. PMID- 25688827 TI - Discussion of best practice guidelines for asymptomatic postmenopausal endometrial thickening. PMID- 25688828 TI - Novel heteroleptic Ru(II) complexes: synthesis, characterization and application in dye-sensitized solar cells. AB - Six new heteroleptic Ru(II) complexes (MC118, MC120-123 and MC126), of general formula Ru(L1)(L2)(NCS)2, where L1 and L2 are respectively dicarboxylated and pi conjugated functionalized (dissymmetric) bipyridine ligands, were designed, synthesized and applied as sensitizers in dye-sensitized solar cells. These complexes were characterized both experimentally and theoretically, showing promising optical properties, with higher extinction coefficients compared to the prototypical N719 dye. When employed in working devices, in combination with a liquid I(-)/I3(-) redox electrolyte, the investigated sensitizers have shown power conversion efficiencies between 6.0 and 8.0%, comparable with the reference N719 dye tested under similar fabrication and evaluation conditions. PMID- 25688829 TI - Bonding in singlet and triplet butalene: insights from spin-coupled theory. AB - Spin-coupled (SC, equivalent to full generalized valence bond) calculations for the (1)A(g) ground state of butalene at its optimal D(2h) planar geometry show that cross-ring Dewar-like modes of spin coupling are of comparable importance to the more usually considered Kekule-like modes. There are marked similarities to the SC description of one of the isomers of benzo[1,2:4,5]dicyclobutadiene. A complication for both of these systems is the existence of SC solutions in which some of the orbitals resemble in- and out-of-phase combinations of semilocalized atom-centered orbitals. The lowest triplet state, for which a nonplanar C(2v) geometry is preferred, is somewhat more straightforward to analyze: the SC description of the (3)B2 state is dominated by a very simple pattern of two pi bonds and two well-localized triplet-coupled orbitals. PMID- 25688830 TI - Catalytic roles of betaLys87 in tryptophan synthase: (15)N solid state NMR studies. AB - The proposed mechanism for tryptophan synthase shows betaLys87 playing multiple catalytic roles: it bonds to the PLP cofactor, activates C4' for nucleophilic attack via a protonated Schiff base nitrogen, and abstracts and returns protons to PLP-bound substrates (i.e. acid-base catalysis). epsilon-15N-lysine TS was prepared to access the protonation state of betaLys87 using 15N solid-state nuclear magnetic resonance (SSNMR) spectroscopy for three quasi-stable intermediates along the reaction pathway. These experiments establish that the protonation state of the epsilon-amino group switches between protonated and neutral states as the beta-site undergoes conversion from one intermediate to the next during catalysis, corresponding to mechanistic steps where this lysine residue has been anticipated to play alternating acid and base catalytic roles that help steer reaction specificity in tryptophan synthase catalysis. This article is part of a Special Issue entitled: Cofactor-dependent proteins: evolution, chemical diversity and bio-applications. Guest Editors: Andrea Mozzarelli and Loredano Pollegioni. PMID- 25688831 TI - Ferredoxin, in conjunction with NADPH and ferredoxin-NADP reductase, transfers electrons to the IscS/IscU complex to promote iron-sulfur cluster assembly. AB - Fe-S cluster biogenesis is an essential pathway coordinated by a network of protein-protein interactions whose functions include desulfurase activity, substrate delivery, electron transfer and product transfer. In an effort to understand the intricacies of the pathway, we have developed an in vitro assay to follow the ferredoxin role in electron transfer during Fe-S cluster assembly. Previously, assays have relied upon the non-physiological reducing agents dithionite and dithiothreitol to assess function. We have addressed this shortcoming by using electron transfer between NADPH and ferredoxin-NADP reductase to reduce ferredoxin. Our results show that this trio of electron transfer partners are sufficient to sustain the reaction in in vitro studies, albeit with a rate slower compared with DTT-mediated cluster assembly. We also show that, despite overlapping with the CyaY protein in binding to IscS, Fdx does not interfere with the inhibitory activity of this protein. We suggest explanations for these observations which have important consequences for understanding the mechanism of cluster formation. Cofactor-dependent proteins: evolution, chemical diversity and bio-applications. PMID- 25688832 TI - Redox characteristics variations in the cation-ordered perovskite oxides BaLnMn2O5+delta (Ln = Y, Gd, Nd, and La) and Ca2Al1-xGaxMnO5+delta (0 <=x<= 1). AB - Two series of manganese-based oxygen storage materials, BaLnMn(2)O(5+delta) (Ln = Y, Gd, Nd, and La) and Ca(2)Al(1-x)GaxMnO(5+delta) (0 <=x<= 1), were synthesized and characterized to clarify cationic substitution effects on the oxygen intake/release behaviors of these materials. The thermogravimetric data revealed that the isovalent substitutions neighboring the active sites for oxygen intake/release are very effective. For BaLnMn(2)O(5+delta), fully-reduced delta~ 0 products with larger Ln ions showed oxygen intake starting at lower temperatures in flowing O(2) gas, resulting in a systematic relationship between the onset temperature and the ionic radius of Ln(3+). Furthermore, the delta vs. P(O(2)) plots at 700 degrees C indicated a systematic trend: the larger the ionic size of Ln(3+) is, the larger oxygen contents the Ln-products exhibit. For Ca(2)Al(1-x)GaxMnO(5+delta), on the other hand, the temperature-induced oxygen intake/release characteristics appeared to be influenced by Ga-for-Al substitution, where the onset temperatures of oxygen release (upon heating) and oxygen intake (upon cooling) are decreased with the increasing Ga content (x). PMID- 25688833 TI - Handheld tympanometer measurements in conscious dogs for the evaluation of the middle ear and auditory tube. AB - BACKGROUND: Otitis externa is frequently accompanied by otitis media, yet it can be difficult to evaluate the tympanum, middle ear and auditory tube without the use of advanced radiographic imaging. HYPOTHESIS/OBJECTIVES: The objective was to develop techniques for tympanometry testing in conscious dogs and to present normative data for clinical use of this equipment to enable assessment of the tympanum, middle ear and auditory tube. ANIMALS: Sixteen hounds (14 female) from a school teaching colony. METHODS: Dogs were gently restrained in a standing position. After cleaning of the ear canal, a tympanometer probe tip extension was placed in the vertical canal and automated testing performed using a handheld device. Both ears were tested in all dogs. RESULTS: Acceptable recordings were obtained from both ears of 13 dogs, from one ear in each of two dogs and from neither ear of one dog, resulting in data from 28 of 32 (88%) ears. Otoscopic examination confirmed the absence of inflammation or any other obvious explanation for the noncompliant dogs. No significant differences were seen between ears for any measure. Normative data are reported for peak compliance, peak compliance pressure, gradient and ear canal volume. CONCLUSIONS AND CLINICAL IMPORTANCE: Tympanograms can be recorded in conscious dogs to assist in the evaluation of the middle ear structures. PMID- 25688834 TI - Theoretical understanding on band engineering of Mn-doped lead chalcogenides PbX (X = Te, Se, S). AB - Electronic structures of Mn-doped PbX (X = Te, Se, S) are investigated by first principles calculations. It is found that the Mn-doping in PbTe enlarges the band gap and increases the valence bands degeneracy, showing good agreement with experimental measurements. This band adjustment is demonstrated to be from the anti-bonding of Te-p and Mn-d orbitals. Along the series of PbTe-PbSe-PbS, the band modification of Mn-doping undergoes a gradual transition from multiple valence bands type to resonant states type, owing to the downwards shifted anion p orbitals. This work provides essential understandings on the band engineering of Mn-doped lead chalcogenides thermoelectric materials. PMID- 25688835 TI - Moral distress in critical care nurses: a phenomenological study. AB - AIM: To explore and understand moral distress from the perspective of and as experienced by critical care nurses in Korea. BACKGROUND: The concept of moral distress among critical care nurses must be more broadly explored using a qualitative approach. DESIGN: Giorgi's phenomenological research approach was used. METHODS: A purposive sampling was used to select 14 critical care nurses. In-depth face-to-face interviews were performed in Korea from March 2012-December 2013. FINDINGS: Five main themes of moral distress emerged: (1) ambivalence towards treatment and care (notably prioritizing work tasks over human dignity, unnecessary medical treatments and the compulsory application of restraints); (2) suffering resulting from a lack of ethical sensitivity; (3) dilemmas resulting from nurses' limited autonomy in treatments; (4) conflicts with physicians; and (5) conflicts with institutional policy. CONCLUSION: Staff shortages are aggravated by high staff turnover caused by ethical suffering. The resulting lack of staff can, in turn, give rise to added ethical conflicts as part of a vicious circle, leading to decreased patient satisfaction. PMID- 25688836 TI - Direct analysis of intact biological macromolecules by low-energy, fiber-based femtosecond laser vaporization at 1042 nm wavelength with nanospray postionization mass spectrometry. AB - A fiber-based laser with a pulse duration of 435 fs and a wavelength of 1042 nm was used to vaporize biological macromolecules intact from the condensed phase into the gas phase for nanospray postionization and mass analysis. Laser vaporization of dried standard protein samples from a glass substrate by 10 Hz bursts of 20 pulses having 10 MUs pulse separation and <50 MUJ pulse energy resulted in signal comparable to a metal substrate. The protein signal observed from an aqueous droplet on a glass substrate was negligible compared to either a droplet on metal or a thin film on glass. The mass spectra generated from dried and aqueous protein samples by the low-energy, fiber laser were similar to the results from high-energy (500 MUJ), 45-fs, 800-nm Ti:sapphire-based femtosecond laser electrospray mass spectrometry (LEMS) experiments, suggesting that the fiber-based femtosecond laser desorption mechanism involves a nonresonant, multiphoton process, rather than thermal- or photoacoustic-induced desorption. Direct analysis of whole blood performed without any pretreatment resulted in features corresponding to hemoglobin subunit-heme complex ions. The observation of intact molecular ions with low charge states from protein, and the tentatively assigned hemoglobin alpha subunit-heme complex from blood suggests that fiber based femtosecond laser vaporization is a "soft" desorption source at a laser intensity of 2.39 * 10(12) W/cm(2). The low-energy, turnkey fiber laser demonstrates the potential of a more robust and affordable laser for femtosecond laser vaporization to deliver biological macromolecules into the gas phase for mass analysis. PMID- 25688837 TI - Aberrant activation of atypical protein kinase C in carbon tetrachloride-induced oxidative stress provokes a disturbance of cell polarity and sealing of bile canalicular lumen. AB - Polarized hepatocytes contain tight junctions (TJs), which are among the most important junctions for sealing the bile canalicular lumen from the sinusoidal space. Alterations in TJs are implicated in chronic cholestatic liver diseases, such as primary biliary cirrhosis and primary sclerosing cholangitis, which have lipid peroxidation marker elevations or antioxidant vitamin decreases. However, the effect of oxidative stress on hepatocyte polarity or liver morphology is unknown. We found that carbon tetrachloride (CCl4)-induced oxidative stress resulted in disassembly of TJs. Ultrastructural analysis revealed disruption in TJs, Golgi morphology, and expansion of the bile canalicular lumen size in CCl4 treated hepatocytes. The Par complex [Par-3-atypical protein kinase C (aPKC) and Par-6 ternary complex] regulates TJs and lumen formation, and the Par-3-aPKC complex formation was inhibited by CCl4 treatment. Moreover, the antioxidant compound vitamin E prohibited a CCl4-induced disturbance in TJs and Par-3-aPKC complex formation. aPKC phosphorylates Par-3 and down-regulates its own affinity with Par-3. Importantly, aPKC kinase activity and Par-3 phosphorylation were significantly increased in CCl4-treated rat livers. These results indicate that the Par-3-aPKC complex plays a crucial role in the maintenance of hepatocyte polarity and sealing of the bile canalicular lumen. Our findings suggest that bile canalicular lumen expansion might explain the presence of cholestasis in patients with primary biliary cirrhosis and primary sclerosing cholangitis. PMID- 25688838 TI - Nanoimprinting-induced nanomorphological transition in polymer solar cells: enhanced electrical and optical performance. AB - We have investigated the effects of a directly nanopatterned active layer on the electrical and optical properties of inverted polymer solar cells (i-PSCs). The capillary force in confined molds plays a critical role in polymer crystallization and phase separation of the film. The nanoimprinting process induced improved crystallization and multidimensional chain alignment of polymers for more effective charge transfer and a fine phase-separation between polymers and [6,6]-phenyl-C71-butyric acid methyl ester (PC71BM) to favor exciton dissociation and increase the generation rate of charge transfer excitons. Consequently, the power conversion efficiency with a periodic nanostructure was enhanced from 7.40% to 8.50% and 7.17% to 9.15% in PTB7 and PTB7-Th based i-PSCs, respectively. PMID- 25688839 TI - The effects of work-reinforcer schedules on performance and preference in students with autism. AB - This study investigated performance under and preference for continuous and discontinuous work-reinforcer schedules in 3 students who had been diagnosed with autism. Under continuous schedules, participants completed all work and consumed all reinforcers in contiguous units. Under discontinuous schedules, work and reinforcer access were broken up into smaller units. During the alternating schedules phase, session duration was shorter in the continuous schedule for 2 participants. During free choice, all 3 participants preferred the continuous work schedule. PMID- 25688840 TI - Should we change chest compression providers every 2 min when performing one handed chest compressions? AB - OBJECTIVE: Because the one-handed chest compression (OHCC) technique uses one hand, unlike the two-handed chest compression (THCC) technique, compression depth might be reduced more rapidly in OHCC than THCC. The present study was conducted to determine whether compression depth was affected within 2 min after the start of OHCC in a simulated in-hospital paediatric arrest model. METHODS: Forty medical doctors performed continuous OHCC on a child manikin lying on a hard floor using a CPRmeter for 2 min. The hand used to perform the OHCC technique was randomised to the right or left hand. The mean compression depth (MCD) and the mean compression rate (MCR) were calculated at 30 s intervals using the Q-CPR review software. RESULTS: MCD values decreased significantly with time (0-30 s: 44.3 +/- 4.1 mm, 30-60 s: 42.4 +/- 4.9 mm, 60-90 s: 40.5 +/- 5.8 mm, and 90-120 s: 38.7 +/- 5.7 mm; P < 0.001). The MCR also tended to decrease with time (0-30 s: 119.3 +/- 12.5/min, 30-60 s: 119.0 +/- 13.1/min, 60-90 s: 117.9 +/- 14.5/min, 90-120 s: 117.8 +/- 14.9/min), and the differences were statistically significant between 30-60 s and 60-90 s (P = 0.037) and between 30-60 s and 90-120 s (P = 0.043). CONCLUSIONS: Compression depth was decreased significantly from 30 s onwards after starting the OHCC technique using a simulated paediatric arrest model. The results of the present study suggest that future strategies should be established to prevent a decrease in compression depth within 1 min during OHCC. PMID- 25688841 TI - ICN and education: changing prospects for girls in Eastern and Southern Africa. PMID- 25688842 TI - Turning conference presentations into publications. PMID- 25688843 TI - Global voice, strategic leadership and policy impact: global citizens, global nursing. PMID- 25688845 TI - The Syrian War: nurses can be ambassadors of peace. PMID- 25688846 TI - Multicomponent synthesis of substituted and fused-ring imidazoles via phospha munchnone cycloaddition. AB - A new, one-pot synthesis of imidazoles from imines, acid chlorides, and N-nosyl imines or tethered nitriles is reported. The reaction is mediated by the phosphonite PPh(catechyl) and proceeds via regioselective cycloaddition with an in situ-generated phospha-munchnone 1,3-dipole. This provides an efficient route to construct both highly substituted and polycyclic imidazoles directly from available substrates, without metal catalysts, and with access to product diversity. PMID- 25688847 TI - Review of sampling, sample and data collection procedures in nursing research--An example of research on ethical climate as perceived by nurses. AB - OBJECTIVE: To report a review of quality regarding sampling, sample and data collection procedures of empirical nursing research of ethical climate studies where nurses were informants. Surveys are needed to obtain generalisable information about topics sensitive to nursing. Methodological quality of the studies is of key concern, especially the description of sampling and data collection procedures. DESIGN: Methodological literature review. DATA SOURCES AND METHODS: Using the electronic MEDLINE database, empirical nursing research articles focusing on ethical climate were accessed in 2013 (earliest-22 November 2013). Using the search terms 'ethical' AND ('climate*' OR 'environment*') AND ('nurse*' OR 'nursing'), 376 citations were retrieved. Based on a four-phase retrieval process, 26 studies were included in the detailed analysis. RESULTS: Sampling method was reported in 58% of the studies, and it was random in a minority of the studies (26%). The identification of target sample and its size (92%) was reported, whereas justification for sample size was less often given. In over two-thirds (69%) of the studies with identifiable response rate, it was below 75%. A variety of data collection procedures were used with large amount of missing data about the details of who distributed, recruited and collected the questionnaires. Methods to increase response rates were seldom described. Discussion about nonresponse, representativeness of the sample and generalisability of the results was missing in many studies. CONCLUSION: This review highlights the methodological challenges and developments that need to be considered in ensuring the use of valid information in developing health care through research findings. PMID- 25688848 TI - Managing Human Tissue Transfer Across National Boundaries - An Approach from an Institution in South Africa. AB - With biobank research on the increase and the history of exploitation in Africa, it has become necessary to manage the transfer of human tissues across national boundaries. There are many accepted templates of Material Transfer Agreements (MTAs) that currently exist internationally. However, these templates do not address the specific concerns of South Africa and even of Africa as a continent. This article will examine three significantly important ethico-legal concepts that were deliberated and carefully adapted by a South African Institution to suit the transfer of Human Biological Materials (HBMs) and associated data for biobank research, namely: informed consent; benefit sharing arrangements; and ownership together with intellectual property rights in human tissues. The discussion includes an analysis of current practice; the ethico-legal challenges in the South African/African context; the decisions made with regard to how the related ethico-legal challenges were addressed in the MTA; and justifications for implementing these decisions. The processes considered could be of benefit to other developing world countries who consider it necessary to manage the transfer of HBMs across national boundaries. PMID- 25688849 TI - Hypertension-related congestive heart failure in west Africa: a framework for global blood pressure control. PMID- 25688850 TI - Role of intestinal brush border peptidases in the simulated digestion of milk proteins. AB - SCOPE: This study aimed to assess the impact of the "often neglected" intestinal brush border membranes (BBMs) hydrolases on dietary peptides, exploring the possibility that the disintegration of proteins progressed in the small intestine up to a "core" of intrinsically stable oligopeptides, persisting independently on the up-stream breakdown. METHODS AND RESULTS: Samples of sodium caseinate, skim milk powder, and whey protein isolate were submitted to in vitro simulated gastropancreatic digestion using two different procedures: (i) a simplified model involving the main compartmental specific proteases; (ii) a static digestion method based on a frameset of parameters inferred from in vivo. The gastroduodenal digesta were further hydrolyzed with peptidases from porcine jejunal BBM. The peptidomes arising from the two digestion models, characterized by combined HPLC and MS techniques, differed to some extent. However, only specific protein domains survived digestion, among which are potential bioactive or immunogenic (food allergy) peptides. The degree of hydrolysis (DH) after BBM digestion (70-77%) practically did not differ between the digestion models and significantly increased the DH after duodenal steps. CONCLUSION: Any in vitro digestion model should be supplemented with a jejunal phase to realistically determine the bioaccessibility and bioavailability of dietary peptides. PMID- 25688851 TI - Room temperature C-P bond formation enabled by merging nickel catalysis and visible-light-induced photoredox catalysis. AB - A novel and efficient C-P bond formation reaction of diarylphosphine oxides with aryl iodides was achieved by combining nickel catalysis and visible-light-induced photoredox catalysis. This dual-catalytic reaction showed a broad substrate scope, excellent functional group tolerance, and afforded the corresponding products in good to excellent yields. Compared with the previously reported use of photoredox/nickel dual catalysis in the construction of C-C bonds, the methodology described herein was observed to be the first to allow for C heteroatom bond formation. PMID- 25688852 TI - Fetal brain injury in survivors of twin pregnancies complicated by demise of one twin as assessed by in utero MR imaging. AB - OBJECTIVE: The aim of this study was to quantify the risk of brain abnormalities in single-twin demise of monochorionic pregnancies and to describe the type of brain injuries using ultrasound and in utero magnetic resonance (iuMR) imaging. METHODS: Monochorionic twin pregnancies complicated by the demise of one twin referred between 2004 and 2013 were reviewed. Ultrasound was performed in a tertiary centre prior to iuMR. The cases were subdivided into those associated with co-twin loss following fetoscopic laser ablative treatment for twin-twin transfusion syndrome (TTTS) and those associated with spontaneous fetal demise. RESULTS: Sixty-eight cases were identified, 27/68 following treatment for TTTS and 41/68 with spontaneous fetal demise. Nine (13.2%) had brain abnormalities on iuMR, and the rate of brain abnormalities was similar in the two groups. Expert ultrasound and iuMR findings agreed in three out of nine of those cases, and in six out of nine cases, ultrasound underestimated or missed the pathology. CONCLUSION: Monochorionic twin pregnancies with single fetal demise are complex pregnancies with increased risk of acquired brain pathology, although the rate of brain abnormalities in our study is lower than that of other publications. iuMR in such complicated pregnancies is a useful adjuvant imaging technique that appears to detect brain pathologies better than prenatal ultrasonography. PMID- 25688853 TI - Measurement of plasma gentamicin concentrations postchemical ciliary body ablation in dogs with chronic glaucoma. AB - OBJECTIVE: To investigate the absorption of gentamicin into the plasma after an intravitreal injection in dogs and to report the success rate of this procedure in lowering the intraocular pressure. ANIMALS: Twenty-four client-owned dogs with chronic, end-stage glaucoma. PROCEDURES: Dogs received a unilateral (22) or bilateral (2) intravitreal injection of 25-40 mg of gentamicin (mean +/- SD dose 2.57 +/- 1.65 mg/kg and range 0.61-7.50 mg/kg) and 1 mg of dexamethasone per eye. Blood samples were collected at various time points following the intravitreal injection. Plasma concentrations of gentamicin were determined by liquid chromatography and mass spectrometry. RESULTS: The total plasma concentration of gentamicin ranged from 0.21 to 9.71 MUg/mL (mean +/- SD 2.15 +/- 2.03). The mean gentamicin CMAX was 2.29 MUg/mL at 2.54 h with a terminal half-life of 9.8 h. The success rate of the chemical ablation procedure was 86.4% (19/22 eyes) in dogs that had at least 1 month of follow-up. CONCLUSIONS: Intravitreal injection of gentamicin in eyes with chronic glaucoma resulted in detectable plasma levels in dogs and was successful in lowering the intraocular pressure in 86.4% of the eyes after the first procedure. PMID- 25688854 TI - A clinical governance framework for blood services. AB - BACKGROUND AND OBJECTIVES: The elements of clinical governance, which ensure excellence in clinical care, can be applied to blood services. In this survey, their application in a range of blood providers was gauged, with the aim of identifying best practice and producing a generalizable framework. MATERIALS AND METHODS: The Medical Directors of members of the Alliance of Blood Operators surveyed how different elements of clinical governance operated within their organizations and developed recommendations applicable in the blood service environment. RESULTS: The recommendations that emerged highlighted the importance of an organization's culture, with the delivery of optimal clinical governance being a corporate responsibility. Senior management must agree and promote a set of values to ensure that the system operates with the patient and donor at its heart. All staff should understand how their role fits into the 'journey to the patient', and a culture of openness promoted. Thus, reporting of errors and risks should be actively sought and praised, with penalties applied for concealment. Systems should exist to collect, analyse and escalate clinical outcomes, safety data, clinical risk assessments, incident reports and complaints to inform organizational learning. CONCLUSION: Clinical governance principles from general health care can be applied within blood services to complement good manufacturing practice. This requires leadership, accountability, an open culture and a drive for continuous improvement and excellence in clinical care. PMID- 25688855 TI - Bioinspired gas bubble spontaneous and directional transportation effects in an aqueous medium. AB - A series of well-ordered, 3D gradient porous interconnected network surfaces composed of micro-nano hierarchical geometries is constructed on a copper wire. A continuous gas film can be trapped around its interface in an aqueous medium acting as an effective channel for gas transportation. Driving by the difference of the Laplace pressure, gas bubbles can be transported spontaneously and directionally. PMID- 25688857 TI - Optimal vaccination in a stochastic epidemic model of two non-interacting populations. AB - Developing robust, quantitative methods to optimize resource allocations in response to epidemics has the potential to save lives and minimize health care costs. In this paper, we develop and apply a computationally efficient algorithm that enables us to calculate the complete probability distribution for the final epidemic size in a stochastic Susceptible-Infected-Recovered (SIR) model. Based on these results, we determine the optimal allocations of a limited quantity of vaccine between two non-interacting populations. We compare the stochastic solution to results obtained for the traditional, deterministic SIR model. For intermediate quantities of vaccine, the deterministic model is a poor estimate of the optimal strategy for the more realistic, stochastic case. PMID- 25688856 TI - Characterization of the RelBbu Regulon in Borrelia burgdorferi Reveals Modulation of Glycerol Metabolism by (p)ppGpp. AB - The bacterial stringent response is triggered by deficiencies of available nutrients and other environmental stresses. It is mediated by 5'-triphosphate guanosine-3'-diphosphate and 5'-diphosphate-guanosine-3'-diphosphate (collectively (p)ppGpp) and generates global changes in gene expression and metabolism that enable bacteria to adapt to and survive these challenges. Borrelia burgdorferi encounters multiple stressors in its cycling between ticks and mammals that could trigger the stringent response. We have previously shown that the B. burgdorferi stringent response is mediated by a single enzyme, RelBbu, with both (p)ppGpp synthase and hydrolase activities, and that a B. burgdorferi 297 relBbu null deletion mutant was defective in adapting to stationary phase, incapable of down-regulating synthesis of rRNA and could not infect mice. We have now used this deletion mutant and microarray analysis to identify genes comprising the rel regulon in B. burgdorferi cultured at 34 degrees C, and found that transcription of genes involved in glycerol metabolism is induced by relBbu. Culture of the wild type parental strain, the relBbu deletion mutant and its complemented derivative at 34 degrees C and 25 degrees C in media containing glucose or glycerol as principal carbon sources revealed a growth defect in the mutant, most evident at the lower temperature. Transcriptional analysis of the glp operon for glycerol uptake and metabolism in these three strains confirmed that relBbu was necessary and sufficient to increase transcription of this operon in the presence of glycerol at both temperatures. These results confirm and extend previous findings regarding the stringent response in B. burgdorferi. They also demonstrate that the stringent response regulates glycerol metabolism in this organism and is likely crucial for its optimal growth in ticks. PMID- 25688858 TI - Depressive symptoms are associated with analgesic use in people with Alzheimer's disease: Kuopio ALSOVA study. AB - Neuropsychiatric symptoms of Alzheimer's disease (AD) such as depression may be associated with pain, which according to the literature may be inadequately recognized and managed in this population. This study aimed to identify the factors associated with analgesic use in persons with AD; in particular, how AD severity, functional status, neuropsychiatric symptoms of AD, co-morbidities and somatic symptoms are associated with analgesic use. 236 community-dwelling persons with very mild or mild AD at baseline, and their caregivers, were interviewed over five years as part of the prospective ALSOVA study. Generalized Estimating Equations (GEEs) were used to estimate unadjusted and adjusted odds ratios (ORs) for the factors associated with analgesic use over a five year follow-up. The proportion of persons with AD using any analgesic was low (13.6%) at baseline and remained relatively constant during the follow-up (15.3% at Year 5). Over time, the most prevalent analgesic changed from non-steroidal anti inflammatories (8.1% of persons with AD at Year 1) to acetaminophen (11.1% at Year 5). Depressive symptoms (measured by the Beck Depression Inventory, BDI) were independently associated with analgesic use, after effects of age, gender, education, AD severity, comorbidities and somatic symptoms were taken into account. For every one unit increase in BDI, the odds of analgesic use increased by 4% (OR = 1.04, 95% confidence interval CI = 1.02-1.07). Caregiver depressive symptoms were not statistically significantly associated with analgesic use of the person with AD. Depressive symptoms were significantly associated with analgesic use during the five year follow-up period. Possible explanations warranting investigation are that persons with AD may express depressive symptoms as painful somatic complaints, or untreated pain may cause depressive symptoms. Greater awareness of the association between depressive symptoms and analgesic use may lead to safer and more effective prescribing for these conditions. PMID- 25688859 TI - Luminal progenitors restrict their lineage potential during mammary gland development. AB - The hierarchical relationships between stem cells and progenitors that guide mammary gland morphogenesis are still poorly defined. While multipotent basal stem cells have been found within the myoepithelial compartment, the in vivo lineage potential of luminal progenitors is unclear. Here we used the expression of the Notch1 receptor, previously implicated in mammary gland development and tumorigenesis, to elucidate the hierarchical organization of mammary stem/progenitor cells by lineage tracing. We found that Notch1 expression identifies multipotent stem cells in the embryonic mammary bud, which progressively restrict their lineage potential during mammary ductal morphogenesis to exclusively generate an ERalphaneg luminal lineage postnatally. Importantly, our results show that Notch1-labelled cells represent the alveolar progenitors that expand during pregnancy and survive multiple successive involutions. This study reveals that postnatal luminal epithelial cells derive from distinct self-sustained lineages that may represent the cells of origin of different breast cancer subtypes. PMID- 25688860 TI - Platelet surface-associated activation and secretion-mediated inhibition of coagulation factor XII. AB - Coagulation factor XII (fXII) is important for arterial thrombosis, but its physiological activation mechanisms are unclear. In this study, we elucidated the role of platelets and platelet-derived material in fXII activation. FXII activation was only observed upon potent platelet stimulation (with thrombin, collagen-related peptide, or calcium ionophore, but not ADP) accompanied by phosphatidylserine exposure and was localised to the platelet surface. Platelets from three patients with grey platelet syndrome did not activate fXII, which suggests that platelet-associated fXII-activating material might be released from alpha-granules. FXII was preferentially bound by phosphotidylserine-positive platelets and annexin V abrogated platelet-dependent fXII activation; however, artificial phosphotidylserine/phosphatidylcholine microvesicles did not support fXII activation under the conditions herein. Confocal microscopy using DAPI as a poly-phosphate marker did not reveal poly-phosphates associated with an activated platelet surface. Experimental data for fXII activation indicates an auto inhibition mechanism (ki/ka = 180 molecules/platelet). Unlike surface-associated fXII activation, platelet secretion inhibited activated fXII (fXIIa), particularly due to a released C1-inhibitor. Platelet surface-associated fXIIa formation triggered contact pathway-dependent clotting in recalcified plasma. Computer modelling suggests that fXIIa inactivation was greatly decreased in thrombi under high blood flow due to inhibitor washout. Combined, the surface associated fXII activation and its inhibition in solution herein may be regarded as a flow-sensitive regulator that can shift the balance between surface associated clotting and plasma-dependent inhibition, which may explain the role of fXII at high shear and why fXII is important for thrombosis but negligible in haemostasis. PMID- 25688861 TI - Cryoprotectants and extreme freeze tolerance in a subarctic population of the wood frog. AB - Wood frogs (Rana sylvatica) exhibit marked geographic variation in freeze tolerance, with subarctic populations tolerating experimental freezing to temperatures at least 10-13 degrees Celsius below the lethal limits for conspecifics from more temperate locales. We determined how seasonal responses enhance the cryoprotectant system in these northern frogs, and also investigated their physiological responses to somatic freezing at extreme temperatures. Alaskan frogs collected in late summer had plasma urea levels near 10 MUmol ml-1, but this level rose during preparation for winter to 85.5 +/- 2.9 MUmol ml-1 (mean +/- SEM) in frogs that remained fully hydrated, and to 186.9 +/- 12.4 MUmol ml-1 in frogs held under a restricted moisture regime. An osmolality gap indicated that the plasma of winter-conditioned frogs contained an as yet unidentified osmolyte(s) that contributed about 75 mOsmol kg-1 to total osmotic pressure. Experimental freezing to -8 degrees C, either directly or following three cycles of freezing/thawing between -4 and 0 degrees C, or -16 degrees C increased the liver's synthesis of glucose and, to a lesser extent, urea. Concomitantly, organs shed up to one-half (skeletal muscle) or two-thirds (liver) of their water, with cryoprotectant in the remaining fluid reaching concentrations as high as 0.2 and 2.1 M, respectively. Freeze/thaw cycling, which was readily survived by winter-conditioned frogs, greatly increased hepatic glycogenolysis and delivery of glucose (but not urea) to skeletal muscle. We conclude that cryoprotectant accrual in anticipation of and in response to freezing have been greatly enhanced and contribute to extreme freeze tolerance in northern R. sylvatica. PMID- 25688862 TI - Spred2 modulates the erythroid differentiation induced by imatinib in chronic myeloid leukemia cells. AB - Differentiation induction is currently considered as an alternative strategy for treating chronic myelogenous leukemia (CML). Our previous work has demonstrated that Sprouty-related EVH1 domainprotein2 (Spred2) was involved in imatinib mediated cytotoxicity in CML cells. However, its roles in growth and lineage differentiation of CML cells remain unknown. In this study, we found that CML CD34+ cells expressed lower level of Spred2 compared with normal hematopoietic progenitor cells, and adenovirus mediated restoration of Spred2 promoted the erythroid differentiation of CML cells. Imatinib could induce Spred2 expression and enhance erythroid differentiation in K562 cells. However, the imatinib induced erythroid differentiation could be blocked by Spred2 silence using lentiviral vector PLKO.1-shSpred2. Spred2 interference activated phosphorylated ERK (p-ERK) and inhibited erythroid differentiation, while ERK inhibitor, PD98059, could restore the erythroid differentiation, suggesting Spred2 regulated the erythroid differentiation partly through ERK signaling. Furthermore, Spred2 interference partly restored p-ERK level leading to inhibition of erythroid differentiation in imatinib treated K562 cells. In conclusion, Spred2 was involved in erythroid differentiation of CML cells and participated in imatinib induced erythroid differentiation partly through ERK signaling. PMID- 25688863 TI - The lyme disease pathogen has no effect on the survival of its rodent reservoir host. AB - Zoonotic pathogens that cause devastating morbidity and mortality in humans may be relatively harmless in their natural reservoir hosts. The tick-borne bacterium Borrelia burgdorferi causes Lyme disease in humans but few studies have investigated whether this pathogen reduces the fitness of its reservoir hosts under natural conditions. We analyzed four years of capture-mark-recapture (CMR) data on a population of white-footed mice, Peromyscus leucopus, to test whether B. burgdorferi and its tick vector affect the survival of this important reservoir host. We used a multi-state CMR approach to model mouse survival and mouse infection rates as a function of a variety of ecologically relevant explanatory factors. We found no effect of B. burgdorferi infection or tick burden on the survival of P. leucopus. Our estimates of the probability of infection varied by an order of magnitude (0.051 to 0.535) and were consistent with our understanding of Lyme disease in the Northeastern United States. B. burgdorferi establishes a chronic avirulent infection in their rodent reservoir hosts because this pathogen depends on rodent mobility to achieve transmission to its sedentary tick vector. The estimates of B. burgdorferi infection risk will facilitate future theoretical studies on the epidemiology of Lyme disease. PMID- 25688864 TI - Investigating the role of RIO protein kinases in Caenorhabditis elegans. AB - RIO protein kinases (RIOKs) are a relatively conserved family of enzymes implicated in cell cycle control and ribosomal RNA processing. Despite their functional importance, they remain a poorly understood group of kinases in multicellular organisms. Here, we show that the C. elegans genome contains one member of each of the three RIOK sub-families and that each of the genes coding for them has a unique tissue expression pattern. Our analysis showed that the gene encoding RIOK-1 (riok-1) was broadly and strongly expressed. Interestingly, the intestinal expression of riok-1 was dependent upon two putative binding sites for the oxidative and xenobiotic stress response transcription factor SKN-1. RNA interference (RNAi)-mediated knock down of riok-1 resulted in germline defects, including defects in germ line stem cell proliferation, oocyte maturation and the production of endomitotic oocytes. Taken together, our findings indicate new functions for RIOK-1 in post mitotic tissues and in reproduction. PMID- 25688866 TI - Current laboratory practices in the diagnosis and management of haemophilia: a global assessment. AB - Haemophilia management is complicated by the extreme variability in laboratory practices. Lack of consistency or comparability in testing makes it difficult to establish diagnostic criteria or disease severity, and complicates response assessment. A global survey was conducted to document current practices. A 35-min survey was completed by 30 laboratory scientists in each of seven countries (France, Germany, Italy, Japan, Spain, UK, USA; 210 in total); results were weighted by average country testing volume in haemophilia. Eighty-three per cent of participants reported participation in a Quality Assurance scheme. Ninety per cent reported using clotting tests in haemophilia A and 88% in haemophilia B (55% and 53% frequent use respectively). Sixty-eight per cent reported chromogenic assays were used in haemophilia A, with only 23% reporting frequent use, compared to only 11% reporting any use in haemophilia B. Twenty-nine separate activated partial thromboplastin time (aPTT) reagents were reported for haemophilia A and 27 aPTT reagents were reported for haemophilia B, with one-quarter or less obtaining reagents or kits from any single manufacturer. Fifty-four per cent run a calibration curve with every factor VIII (FVIII) assay. The mean number of plasma dilutions varied from 2 to 4 for FVIII assays and from 1 to 3 for FIX assays. Results indicate very low consistency in materials and practices used to test for factor activity in haemophilia. A number of responses suggest that some laboratory scientists' understanding of best practices or guidelines in haemophilia could be improved. More education and broader understanding is recommended regarding assay types, assay components, test material and instrument features and capabilities. PMID- 25688865 TI - Cleavage of host cytokeratin-6 by lysine-specific gingipain induces gingival inflammation in periodontitis patients. AB - BACKGROUND/PURPOSE: Lysine-specific gingipain (Kgp) is a virulence factor secreted from Porphyromonas gingivalis (P. gingivalis), a major etiological bacterium of periodontal disease. Keratin intermediate filaments maintain the structural integrity of gingival epithelial cells, but are targeted by Kgp to produce a novel cytokeratin 6 fragment (K6F). We investigated the release of K6F and its induction of cytokine secretion. METHODS: K6F present in the gingival crevicular fluid of periodontal disease patients and in gingipain-treated rat gingival epithelial cell culture supernatants was measured by matrix-assisted laser desorption/ionization time-of-flight mass spectrometer-based rapid quantitative peptide analysis using BLOTCHIP. K6F in gingival tissues was immunostained, and cytokeratin 6 protein was analyzed by immunofluorescence staining and flow cytometry. Activation of MAPK in gingival epithelial cells was evaluated by immunoblotting. ELISA was used to measure K6F and the cytokines release induced by K6F. Human gingival fibroblast migration was assessed using a Matrigel invasion chamber assay. RESULTS: We identified K6F, corresponding to the C-terminus region of human cytokeratin 6 (amino acids 359-378), in the gingival crevicular fluid of periodontal disease patients and in the supernatant from gingival epithelial cells cultured with Kgp. K6F antigen was distributed from the basal to the spinous epithelial layers in gingivae from periodontal disease patients. Cytokeratin 6 on gingival epithelial cells was degraded by Kgp, but not by Arg-gingipain, P. gingivalis lipopolysaccharide or Actinobacillus actinomycetemcomitans lipopolysaccharide. K6F, but not a scrambled K6F peptide, induced human gingival fibroblast migration and secretion of interleukin (IL)-6, IL-8 and monocyte chemoattractant protein-1. These effects of K6F were mediated by activation of p38 MAPK and Jun N-terminal kinase, but not p42/44 MAPK or p Akt. CONCLUSION: Kgp degrades gingival epithelial cell cytokeratin 6 to K6F that, on release, induces invasion and cytokine secretion by human gingival fibroblasts. Thus, Kgp may contribute to the development of periodontal disease. PMID- 25688867 TI - Tuning the basicity of cyano-containing ionic liquids to improve SO2 capture through cyano-sulfur interactions. AB - A new approach has been developed to improve SO2 sorption by cyano-containing ionic liquids (ILs) through tuning the basicity of ILs and cyano-sulfur interaction. Several kinds of cyano-containing ILs with different basicity were designed, prepared, and used for SO2 capture. The interaction between these cyano containing ILs and SO2 was investigated by FTIR and NMR methods. Spectroscopic investigations and quantum chemical calculations showed that dramatic effects on SO2 capacity originate from the basicity of the ILs and enhanced cyano-sulfur interaction. Furthermore, the captured SO2 was easy to release by heating or bubbling N2 through the ILs. This efficient and reversible process, achieved by tuning the basicity of ILs, is an excellent alternative to current technologies for SO2 capture. PMID- 25688868 TI - Facile Synthesis of Ultrasmall CoS2 Nanoparticles within Thin N-Doped Porous Carbon Shell for High Performance Lithium-Ion Batteries. AB - Cobalt sulfide (CoS2) is considered one of the most promising alternative anode materials for high-performance lithium-ion batteries (LIBs) by virtue of its remarkable electrical conductivity, high theoretical capacity, and low cost. However, it suffers from a poor cycling stability and low rate capability because of its volume expansion and dissolution of the polysulfide intermediates in the organic electrolytes during the battery charge/discharge process. In this study, a novel porous carbon/CoS2 composite is prepared by using nano metal-organic framework (MOF) templates for high-preformance LIBs. The as-made ultrasmall CoS2 (15 nm) nanoparticles in N-rich carbon exhibit promising lithium storage properties with negligible loss of capacity at high charge/discharge rate. At a current density of 100 mA g(-1), a capacity of 560 mA h g(-1) is maintained after 50 cycles. Even at a current density as high as 2500 mA g(-1), a reversible capacity of 410 mA h g(-1) is obtained. The excellent and highly stable battery performance should be attributed to the synergism of the ultrasmall CoS2 particles and the thin N-rich porous carbon shells derieved from nanosized MOF precusors. PMID- 25688869 TI - Interprofessional education and the basic sciences: Rationale and outcomes. AB - Interprofessional education (IPE) aims to improve patient outcomes and the quality of care. Interprofessional learning outcomes and interprofessional competencies are now included in many countries' health and social care professions' accreditation standards. While IPE may take place at any time in health professions curricula it tends to focus on professionalism and clinical topics rather than basic science activities. However generic interprofessional competencies could be included in basic science courses that are offered to at least two different professional groups. In developing interprofessional activities at the preclinical level, it is important to define explicit interprofessional learning outcomes plus the content and process of the learning. Interprofessional education must involve interactive learning processes and integration of theory and practice. This paper provides examples of IPE in anatomy and makes recommendations for course development and evaluation. PMID- 25688870 TI - New iron pyridylamino-bis(phenolate) catalyst for converting CO2 into cyclic carbonates and cross-linked polycarbonates. AB - The atom-efficient reaction of CO2 with a variety of epoxides has been efficiently achieved employing iron pyridylamino-bis(phenolate) complexes as bifunctional catalysts. The addition of a Lewis base co-catalyst allowed significant reduction in the amount of iron complex needed to achieve high epoxide conversions. The possibility of controlling the selectivity of the reaction towards either cyclic carbonate or polycarbonate was evaluated. An efficient switch in selectivity could be achieved when cyclic epoxides such as cyclohexene oxide and the seldom explored 1,2-epoxy-4-vinylcyclohexane were used as substrates. The obtained poly(vinylcyclohexene carbonate) presents pending vinyl groups, which allowed post-synthetic cross-linking by reaction with 1,3 propanedithiol. The cross-linked polycarbonate displayed a substantial increase in the glass transition temperature and chemical resistance, thus opening new opportunities for the application of these green polymers. PMID- 25688871 TI - Effect of atmospheric mercury deposition on selenium accumulation in rice (Oryza sativa L.) at a mercury mining region in southwestern China. AB - Selenium (Se) is an important trace element for human nutrition and has an interactive effect on mercury (Hg) uptake by plants and Hg toxicity in animals. Rice (Oryza sativa L.) is the dominant source of dietary Se in China, however the effect of soil Hg contamination on the Se concentration in rice is unknown. We collected 29 whole rice plant samples and corresponding soils from an active artisanal mercury mining area and an abandoned commercial mercury mining area. The soil Se concentration was similar across the two mining areas and greater than the background concentration for China. However, the Se concentration in rice grain was dramatically different (artisanal area 51+/-3 ng g(-1); abandoned area 235+/-99 ng g(-1)). The total gaseous mercury (TGM) concentration in ambient air at the artisanal mining site was significantly greater than at the abandoned area (231 and 34 ng m(-3), respectively) and we found a negative correlation between TGM and the Se concentration in grain for the artisanal area. Principal component analysis indicated that the source of Se in rice was the atmosphere for the artisanal area (no contribution from soil), and both the atmosphere and soil for the abandoned area. We propose that TGM falls to soil and reacts with Se, inhibiting the translocation of Se to rice grain. Our data suggest that Se intake by the artisanal mining community is insufficient to meet Se dietary requirements, predisposing this community to greater risk from Hg poisoning. PMID- 25688873 TI - A separation-integrated cascade reaction to overcome thermodynamic limitations in rare-sugar synthesis. AB - Enzyme cascades combining epimerization and isomerization steps offer an attractive route for the generic production of rare sugars starting from accessible bulk sugars but suffer from the unfavorable position of the thermodynamic equilibrium, thus reducing the yield and requiring complex work-up procedures to separate pure product from the reaction mixture. Presented herein is the integration of a multienzyme cascade reaction with continuous chromatography, realized as simulated moving bed chromatography, to overcome the intrinsic yield limitation. Efficient production of D-psicose from sucrose in a three-step cascade reaction using invertase, D-xylose isomerase, and D-tagatose epimerase, via the intermediates D-glucose and D-fructose, is described. This set up allowed the production of pure psicose (99.9%) with very high yields (89%) and high enzyme efficiency (300 g of D-psicose per g of enzyme). PMID- 25688872 TI - The subthalamic nucleus, oscillations, and conflict. AB - The subthalamic nucleus (STN), which is currently the most common target for deep brain stimulation (DBS) for Parkinson's disease (PD), has received increased attention over the past few years for the roles it may play in functions beyond simple motor control. In this article, we highlight several of the theoretical, interventional, and electrophysiological studies that have implicated the STN in response inhibition. Most influential among this evidence has been the reported effect of STN DBS in increasing impulsive responses in the laboratory setting. Yet, how this relates to pathological impulsivity in patients' everyday lives remains uncertain. PMID- 25688874 TI - Microbial transglutaminase and c-myc-tag: a strong couple for the functionalization of antibody-like protein scaffolds from discovery platforms. AB - Antibody-like proteins selected from discovery platforms are preferentially functionalized by site-specific modification as this approach preserves the binding abilities and allows a side-by-side comparison of multiple conjugates. Here we present an enzymatic bioconjugation platform that targets the c-myc-tag peptide sequence (EQKLISEEDL) as a handle for the site-specific modification of antibody-like proteins. Microbial transglutaminase (MTGase) was exploited to form a stable isopeptide bond between the glutamine on the c-myc-tag and various primary-amine-functionalized substrates. We attached eight different functionalities to a c-myc-tagged antibody fragment and used these bioconjugates for downstream applications such as protein multimerization, immobilization on surfaces, fluorescence microscopy, fluorescence-activated cell sorting, and in vivo nuclear imaging. The results demonstrate the versatility of our conjugation strategy for transforming a c-myc-tagged protein into any desired probe. PMID- 25688875 TI - Stem cells in genitourinary regeneration. PMID- 25688876 TI - Fatty acid synthase promoter: characterization, and transcriptional regulation by sterol regulatory element binding protein-1 in goat mammary epithelial cells. AB - Fatty acid synthase (FASN) is the central enzyme of the de novo fatty acid biosynthesis pathway. Although the FASN transcriptional regulatory mechanism has been elucidated clearly in many tumor cells, its mechanism is still not clear in the ruminant mammary gland. In this study, we cloned and sequenced a 1.8-kb fragment of the FASN 5' flanking region from goat genomic DNA. Multiple alignment analysis demonstrated that the entire 1.8-kb fragment has little homology but that the sub-section nearest the transcriptional start site (-203 to +1) is more conserved across species, in particular the binding motifs for transcriptional regulation. Deletion analysis revealed a putative core promoter region located in -297/-14 bp upstream of the transcription site within the high homology domain. Mutations of sterol response elements (SRE1 and SRE2) and the nuclear factor Y (NF-Y) binding site appeared to significantly down-regulate the FASN promoter activity in goat mammary epithelial cells (P<0.05). Further analysis showed that both SRE sites responded to sterol regulatory element-binding protein 1 (SREBP 1). SREBP-1 overexpression and knockdown by small interference RNA influenced the abundance of endogenous FASN. These data suggested that SREBP-1 may regulate FASN expression at the transcriptional level in the lactating goat mammary gland. Hence, the current work will contribute valuable information to understanding the molecular regulatory mechanisms of FASN during lactation. PMID- 25688877 TI - Defective cellular trafficking of the bone morphogenetic protein receptor type II by mutations underlying familial pulmonary arterial hypertension. AB - Familial pulmonary arterial hypertension (FPAH) is a relatively rare but fatal disorder characterized by elevated arterial pressure caused by abnormal proliferation of endothelial cells of the arteries, which eventually leads to heart failure and death. FPAH is inherited as an autosomal dominant trait and is caused by heterozygous mutations in the BMPR2 gene encoding the bone morphogenetic protein type II receptor (BMPR2). BMPR2 belongs to the TGF beta/BMP super-family of receptors involved in a signal transduction cascade via the SMAD signaling pathway. The BMPR2 polypeptide is composed of 1038 amino acids and consists of a ligand binding domain, a kinase domain and a cytoplasmic tail. To investigate the cellular and functional consequence of BMPR2 mutations, C terminally FLAG-tagged constructs of eighteen pathogenic BMPR2 missense mutants were generated by site directed mutagenesis and expressed in HeLa and HEK-293T cell lines. The subcellular localizations of the mutant proteins were investigated using immunostaining and confocal microscopy. Post-translational modifications of the proteins were analyzed by Endoglycosidase H deglycosylation assay. Our results indicated that mutations in the ligand binding domain affecting highly conserved cysteine residues resulted in retention of the mutant proteins in the endoplasmic reticulum (ER), as evident from their co-localization with the ER resident protein calnexin. The kinase domain mutants showed both ER and plasma membrane (PM) distributions, while the cytoplasmic tail domain variants were localized exclusively to the PM. The subcellular localizations of the mutants were further confirmed by their characteristic glycosylation profiles. In conclusion, our results indicate that ER quality control (ERQC) is involved in the pathological mechanism of several BMPR2 receptor missense mutations causing FPAH, which can be explored as a potential therapeutic target in the future. PMID- 25688878 TI - Exploring genotype-phenotype relationships of the LHX3 gene on growth traits in beef cattle. AB - The LIM-homeobox gene 3 (LHX3) plays an essential role in pituitary gland and nervous system development. Sequence variants (SVs) in coding and non-coding regions of LHX3 gene have an impact on LHX3 transcription and growth traits in cattle. Previously, we have identified 3 single nucleotide polymorphisms (SNPs: 1 3) in all exons and intron 2 regions of the LHX3 gene in cattle. Here, 7 novel SNPs (SNPs: 4-10) were identified by DNA sequencing and polymerase chain reaction single-stranded conformational polymorphism (PCR-SSCP) methods. In the present study, a total of 10 SNPs were assessed linkage disequilibrium (LD) in 802 cows representing four main cattle breeds from China (Nanyang, Qinchuan, Jiaxian, and Chinese Holstein). The assessment results demonstrated that 17 haplotypes and 18 diplotypes were revealed in these cattle populations. Moreover, association analysis indicated that the genotypes of SNPs 1-6 are associated with the body weight at 6, 12 and 18months of age in Nanyang cattle (P<0.01 or P<0.05), whereas no significant association was found between the 18 diplotypes and growth traits. Our results provide evidence that some SNPs in LHX3 gene may be associated with body weight at certain age, and LHX3 gene may be used as candidate gene for marker-assisted selection (MAS) in beef cattle breeding. PMID- 25688879 TI - Nonsynonymous single nucleotide polymorphisms in the complement component 3 gene are associated with risk of age-related macular degeneration: a meta-analysis. AB - Nonsynonymous single nucleotide polymorphisms (SNPs) in complement component 3 (CC3) are associated with the risk of age-related macular degeneration (AMD), however, this association is not consistent among studies. To thoroughly address this issue, we performed an updated meta-analysis to evaluate the association between nine SNPs in the CC3 gene and AMD risk. A search was conducted of the PubMed database through 3rd Aug, 2014. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of associations. Based on the search criteria for manuscripts reporting AMD susceptibility related to CC3 in nine SNPs, 57 case-control studies from 22 different articles were retrieved. Significantly positive associations were found for the rs2230199 C/G SNP and AMD in the Caucasian population, as well as for the rs1047286 C/T SNP. Moreover, a relationship between the rs11569536 G/A SNP and AMD was detected. By contrast, a negative association was observed between rs2250656 A/G SNP and AMD risk. The present meta-analysis suggests that these four SNPs in the CC3 gene are potentially associated with the risk of AMD development. Further studies using larger sample sizes and accounting for gene-environment interactions should be conducted to elucidate the role of CC3 gene polymorphisms in AMD risk. PMID- 25688880 TI - Homotypic clustering of OsMYB4 binding site motifs in promoters of the rice genome and cellular-level implications on sheath blight disease resistance. AB - The promoter regions (1 kb upstream sequences) of 45,836 annotated genes of rice were analyzed for the presence of OsMYB4 binding sites using a Perl program algorithm. Based on the homotypic clustering concept, 113 promoters were found to have more than 4 binding site motifs. Among the downstream genes of these promoters, five genes which are known to have a role in disease resistance were selected and the binding capacity of OsMYB4 protein in the promoter regions was analyzed by docking studies. Expression level of these genes was analyzed by RT PCR in Rhizoctonia solani infected rice seedlings. Upon pathogen challenge, higher expression of aminotransferase, ankyrin and WRKY 12 genes was observed corresponding to higher expression of Osmyb4. Over-expression of Osmyb4 cDNA in rice leaf tissues by agro-infection failed to result in similar over-expression of aminotransferase, ankyrin and WRKY 12 as expected. Although the role of OsMYB4 in sheath blight resistance was found to be definitive based on our initial results, artificial over-expression of this TF was observed to be insufficient in regulating the disease resistance related genes. PMID- 25688881 TI - Comprehensive genomic analysis and expression profiling of diacylglycerol kinase gene family in Malus prunifolia (Willd.) Borkh. AB - Diacylglycerol kinase (DGK) is a pivotal enzyme that phosphorylates diacylglycerol (DAG) to form phosphatidic acid (PA). The production of PA from phospholipase D (PLD) and the coupled phospholipase C (PLC)/DGK route is a critical signaling process in animal and plant cells. Next to PLD, DGK is the second most important generator of PA in biotic and abiotic stress responses. We identified 8 DGK members within the apple genome and all of their putative proteins contain one DGK catalytic domain and one DGK accessory domain. Four coding sequences were confirmed by cloning from Malus prunifolia. Phylogenetic and gene structure analyses showed that the apple DGK genes could be assigned to Clusters I, II, or III. Expression analysis of 6 of them revealed that their transcript levels were highest in stems. Some apple DGK genes were also significantly up-regulated in response to salt and drought stresses. This suggested their possible roles in plant defenses against environmental challenges. As a first step toward genome-wide analyses of the DGK genes in woody plants, our results imply that apple DGK genes are involved in the signaling of stress responses. These findings will contribute to further functional dissection of this gene family. PMID- 25688882 TI - Hierarchical organization of fluxes in Escherichia coli metabolic network: using flux coupling analysis for understanding the physiological properties of metabolic genes. AB - Flux coupling analysis is a method for investigating the connections between reactions of metabolic networks. Here, we construct the hierarchical flux coupling graph for the reactions of the Escherichia coli metabolic network model to determine the level of each reaction in the graph. This graph is constructed based on flux coupling analysis of metabolic network: if zero flux through reaction a results in zero flux through reaction b (and not vice versa), then reaction a is located at the top of reaction b in the flux coupling graph. We show that in general, more important, older and essential reactions are located at the top of the graph. Strikingly, genes corresponding to these reactions are found to be the genes which are most regulated. PMID- 25688883 TI - CpG islands of hepatitis B virus genome isolated from Chinese patients. AB - There are differences in the distribution and length of HBV CpG islands and the viral mutations contribute greatly to the development of HBV-related diseases. However, little is known regarding the effects of such difference and mutations in HBV genotypes B and C sequences on the regulation of HBV gene expression and their clinical outcomes. To study the distribution, length and genetic trait of CpG islands in normal and mutant sequences of HBV genotypes B and C, 320 HBV isolates from Chinese patients were retrieved from GenBank. Programs CLUSTALX 1.83 and MethPrimer were employed to perform multiple sequence alignments and to predict CpG islands, respectively. 72.0% genotype B isolates contained three conventional CpG islands, and 76.1% genotype C only contained CpG islands II and III. 14.6% genotype B and 7.5% genotype C contained three novel CpG islands. In genotype B, lengths of conventional CpG islands between normal and mutant isolates exhibited substantial variations, but in genotype C, those were relatively stable. CpG island II could be "truncated" or "split". "Truncated" region mutations were associated with structural and functional abnormalities of HBV genes. Rate of "split" CpG island II in genotype B was much higher than that in genotype C. In the majority of isolates from HCC and HBV-ACLF, genotype C lacked CpG island I and novel islands. Distribution, length and genetic trait of CpG islands in HBV genotypes B and C might affect their methylation status, and further affect regulation of HBV gene expression, leading to different clinical outcomes. PMID- 25688884 TI - Polymorphism of rs7688672 and rs10033237 in cGKII/PRKG2 and gout susceptibility of Han population in northern China. AB - Gout is a genetic or acquired metabolic disease caused by increase of uric acid synthesis resulted from purine metabolic abnormalities. Whether cGMP-dependent protein kinase 2 (cGKII/PRKG2) is correlated with gout remains controversial. The objective of the present study was to investigate whether there is a correlation between polymorphism of cGKII/PRKG2 and gout susceptibility of Han population in northern China. Four hundred and five male patients with gout in the case group and 429 controls in the control group were collected from the Department of Endocrinology and Metabolic Disease, the Fourth Affiliated Hospital of Harbin Medical University. A case-control study method was used to study the correlation between cGKII/PRKG2 polymorphism rs7688672 and rs10033237 and gout susceptibility. The genotype frequencies of rs7688672 and rs10033237 polymorphisms of cGKII/PRKG2 in the case group and the control group both were in accordance with Hardy-Weinberg equilibrium. There were significant differences of rs10033237 in the allele frequencies and genotype distributions (P<0.05) between the two groups, while no association was found between rs7688672 and gout. Combined mutation sites AA(*) from rs7688672 and rs10033237 were negatively correlated with gout susceptibility, whereas haplotype GG(*) was positively correlated with gout susceptibility. In conclusion, patients with rs10033237 polymorphism of cGKII/PRKG2 gene are more likely to suffer from gout. With regard to haplotypes of rs10033237 and rs7688672, both AA(*) and GG(*) are related to gout. AA(*) is a gout susceptible gene, whereas GG(*) is a protective gene. PMID- 25688885 TI - Is there a link between per capita alcohol consumption and youth drinking? A time series analysis for Sweden in 1972-2012. AB - AIMS: To estimate the relationship between per capita alcohol consumption and youth drinking in Sweden during the last 40 years and to estimate the relationship between female and male youth drinking during the 40-year study period. DESIGN, SETTING, PARTICIPANTS AND MEASUREMENTS: Per capita alcohol consumption was proxied by official sales data, supplemented by data on unrecorded consumption. Youth consumption was measured by a question on heavy episodic drinking (HED) included in an annual school survey of alcohol and drug habits among Swedish 9th -grade students (15-16 years of age). The annual samples comprise approximately 5000 individuals (with roughly equal numbers of boys and girls) with response rates in the range 80-93%. The study spans the period 1972 2012. Autoregressive integrated moving average (ARIMA) time-series analysis was used to estimate the relation between per-capita alcohol consumption and youth drinking. Ocular inspection of the time-series data suggested a stronger synchronization between the two series in the early period, before the mid-1990s, than in the later period, indicating a structural shift in the relation at issue. We therefore conducted period specific time-series analyses with 1995 as the year of division. RESULTS: There was a statistically significant relation between per capita alcohol consumption and HED among youth for 1972-94. A 1% increase in per capita alcohol consumption was associated with an increase in HED of 1.52% (P = 0.008). The estimate for 1995-2012 (0.12) was well below statistical significance (P = 0.580). The estimated elasticity of the association between boys' and girls' HED during 1972-94 was close to unity (0.98, P < 0.001), suggesting proportional changes in boys' and girls' drinking. When controlling for per capita consumption, the association was halved (to 0.55) but still significant in table 3 (P = 0.045). CONCLUSIONS: Adult and youth drinking in Sweden were synchronized closely during the two last decades of the 20th century, but youth drinking developed an independent trajectory shortly before 2000. PMID- 25688886 TI - Probiotic Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14 exhibit strong antifungal effects against vulvovaginal candidiasis-causing Candida glabrata isolates. AB - AIMS: This study investigates the antagonistic effects of the probiotic strains Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14 against vulvovaginal candidiasis (VVC)-causing Candida glabrata. METHODS AND RESULTS: Growth inhibitory activities of Lact. rhamnosus GR-1 and Lact. reuteri RC-14 strains against C. glabrata were demonstrated using a spot overlay assay and a plate based microtitre assay. In addition, these probiotic lactobacilli strains also exhibited potent candidacidal activity against C. glabrata, as demonstrated by a LIVE/DEAD yeast viability assay performed using confocal laser scanning microscopy. The metabolic activities of all C. glabrata strains were completely shut down in response to the challenges by the probiotic lactobacilli strains. In addition, both probiotic lactobacilli strains exhibited strong autoaggregation and coaggregation phenotypes in the presence of C. glabrata, which indicate that these lactobacilli strains may exert their probiotic effects through the formation of aggregates and, thus the consequent prevention of colonization by C. glabrata. CONCLUSIONS: Probiotic Lact. rhamnosus GR-1 and Lact. reuteri RC-14 strains exhibited potent antagonistic activities against all of the tested C. glabrata strains. These lactobacilli exhibited antifungal effects, including those attributed to their aggregation abilities, and their presence caused the cessation of growth and eventual cell death of C. glabrata. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first study to report on the antagonistic effects of these probiotic lactobacilli strains against the non-Candida albicans Candida (NCAC) species C. glabrata. PMID- 25688887 TI - Delivery and tracking of quantum dot peptide bioconjugates in an intact developing avian brain. AB - Luminescent semiconductor ~9.5 nm nanoparticles (quantum dots: QDs) have intrinsic physiochemical and optical properties which enable us to begin to understand the mechanisms of nanoparticle mediated chemical/drug delivery. Here, we demonstrate the ability of CdSe/ZnS core/shell QDs surface functionalized with a zwitterionic compact ligand to deliver a cell-penetrating lipopeptide to the developing chick embryo brain without any apparent toxicity. Functionalized QDs were conjugated to the palmitoylated peptide WGDap(Palmitoyl)VKIKKP9GGH6, previously shown to uniquely facilitate endosomal escape, and microinjected into the embryonic chick spinal cord canal at embryo day 4 (E4). We were subsequently able to follow the labeling of spinal cord extension into the ventricles, migratory neuroblasts, maturing brain cells, and complex structures such as the choroid plexus. QD intensity extended throughout the brain, and peaked between E8 and E11 when fluorescence was concentrated in the choroid plexus before declining to hatching (E21/P0). We observed no abnormalities in embryonic patterning or embryo survival, and mRNA in situ hybridization confirmed that, at key developmental stages, the expression pattern of genes associated with different brain cell types (brain lipid binding protein, Sox-2, proteolipid protein and Class III-beta-Tubulin) all showed a normal labeling pattern and intensity. Our findings suggest that we can use chemically modified QDs to identify and track neural stem cells as they migrate, that the choroid plexus clears these injected QDs/nanoparticles from the brain after E15, and that they can deliver drugs and peptides to the developing brain. PMID- 25688888 TI - Small Hepatocellular Carcinoma: Radiofrequency Ablation versus Nonanatomic Resection--Propensity Score Analyses of Long-term Outcomes. AB - PURPOSE: To compare radiofrequency (RF) ablation with nonanatomic resection (NAR) as first-line treatment in patients with a single Barcelona Clinic Liver Cancer (BCLC) stage 0 or A hepatocellular carcinoma (HCC) and to evaluate the long-term outcomes of both therapies. MATERIALS AND METHODS: This retrospective study was approved by the institutional review board. The requirement for informed consent was waived. Data were reviewed from 580 patients with HCCs measuring 3 cm or smaller (BCLC stage 0 or A) who underwent ultrasonographically (US) guided percutaneous RF ablation (n = 438) or NAR (n = 142) as a first-line treatment. Local tumor progression, intrahepatic distant recurrence, disease-free survival, and overall survival rates were analyzed by using propensity score matching to compare therapeutic efficacy. In addition, major complications and length of postoperative hospital stay were compared. RESULTS: Before propensity score matching (n = 580), the 5-year cumulative rates of local tumor progression for RF ablation and NAR (20.9% vs 12.7%, respectively; P = .093) and overall survival rates (85.5% vs 90.9%, respectively; P = .194) were comparable, while the 5-year cumulative intrahepatic distant recurrence rates (62.7% vs 36.6%, respectively; P < .001) and disease-free survival rates (31.7% vs 61.1%, respectively; P < .001) in the NAR group were significantly better than those in the RF ablation group. After matching (n = 198), there were no significant differences in therapeutic outcomes between the RF ablation and NAR groups, including 5-year cumulative intrahepatic distant recurrence (47.0% vs 40.2%, respectively; P = .240) and disease-free survival rates (48.9% vs 54.4%, respectively; P = .201). RF ablation was superior to NAR for major complication rates and length of postoperative hospital stay (P < .001). CONCLUSION: In patients with one BCLC stage 0 or A (<= 3 cm) HCC who received RF ablation or NAR as first-line treatment, there were no significant differences in long-term therapeutic outcomes; however, RF ablation was associated with fewer major complications and a shorter hospital stay after treatment. PMID- 25688889 TI - Absence of rickets in infants with fatal abusive head trauma and classic metaphyseal lesions. AB - PURPOSE: To determine if rickets is present in cases of infant homicide with classic metaphyseal lesions (CMLs) and other skeletal injuries. MATERIALS AND METHODS: This study was exempt from the institutional human subjects board review because all infants were deceased. An archival review (1984-2012) was performed of the radiologic and histopathologic findings of 46 consecutive infant fatalities referred from the state medical examiner's office for the evaluation of possible child abuse. Thirty infants with distal femoral histologic material were identified. Additional inclusion criteria were as follows: (a) The medical examiner determined that the infant had sustained a head injury and that the manner of death was a homicide, (b) at least one CML was evident at skeletal survey, (c) CMLs were confirmed at autopsy, and (d) non-CML fractures were also present. Nine infants (mean age, 3.9 months; age range, 1-9 months) were identified. Two pediatric radiologists independently reviewed the skeletal surveys for rachitic changes at the wrists and knees. A bone and soft tissue pathologist reviewed the distal femoral histologic slices for rickets. RESULTS: There were no radiographic or pathologic features of rickets in the cohort. CONCLUSION: The findings provide no support for the view that the CML is due to rickets. Rather, they strengthen a robust literature that states that the CML is a traumatic injury commonly encountered in physically abused infants. PMID- 25688890 TI - Risk assessment and management of anthracycline and HER2 receptor inhibitor induced cardiomyopathy. AB - With the advent and increased use of chemotherapeutic agents and radiation therapy, cancer survival rates have increased. With increased survival, both acute and chronic cardiotoxic adverse effects have emerged. The growing need for managing the treatment of individuals with chemotherapy-induced cardiotoxicity has led to the formation of cardio-oncology programs throughout the United States. These programs concentrate on many aspects of cardiac disease in the oncology patient. Of these, the cardiotoxic effects (particularly cardiomyopathy) of anthracyclines and HER2 receptor inhibitors are a large focus of cardio oncology practice. Despite the increasing availability of these programs, no consensus guidelines have been established to provide a framework for treating these patients. This review describes the initial evaluation, risk assessment, and management of individuals receiving anthracycline and HER2 receptor inhibitor therapy for cardiomyopathy. These recommendations are supported by the current literature in this field. PMID- 25688891 TI - Body mass index and self-reported compliance with general health care. AB - OBJECTIVES: The relation between elevated body mass index (BMI)/overweight obesity and compliance with health care remains unclear; some studies have demonstrated a relation whereas others have not. To add to the confusion, a number of studies have examined specialized populations (eg, patients with diabetes mellitus) and/or only one parameter of compliance (eg, taking medication). In the present study, we examined primary care outpatients for relations between BMI and multiple parameters of healthcare adherence/compliance. METHODS: Using a cross-sectional approach and a self-report survey methodology, we examined 250 primary care outpatients using three measures of healthcare compliance: conscientiousness in following through with medical treatment; a 5 item questionnaire examining compliance with general healthcare behaviors such as regular dental checkups and arrival to doctors' appointments on time; and the Medical Outcomes Study General Adherence Items, a general measure of compliance with physician directives. RESULTS: With the exceptions of regular dental checkups, on-time arrival for doctors' appointments, and timely completion of laboratory work, the remaining variables demonstrated statistical significance at minimally the P & 0.05 level. CONCLUSIONS: Patients with higher BMIs self-report less willingness to adhere to general healthcare requests/recommendations than patients with lower BMIs. PMID- 25688892 TI - Sodium-glucose cotransporter 2 inhibitors: the new option for diabetes mellitus management. AB - Type 2 diabetes mellitus continues to be a challenging disease to manage successfully. Beyond the first-line option metformin, there are a number of classes of medications from which to select. This article reviews the new sodium glucose cotransporter 2 inhibitors canagliflozin and dapagliflozin, including their benefits, adverse effects, and potential place in therapy. Upon review, the use of these medications has led to an A1c reduction between -0.37% and -1.16%. These medications also have been shown to reduce A1c when used with insulin. Some adverse effects were noted when using canagliflozin and dapagliflozin, with the most frequent being urinary tract infections and genital mycotic infections. We review the sodium-glucose cotransporter 2 inhibitors approved by the US Food and Drug Administration and their potential roles in the management of type 2 diabetes mellitus. PMID- 25688893 TI - Use of sodium-glucose cotransporter type 2 inhibitors in older adults with type 2 diabetes mellitus. AB - Sodium-glucose cotransporter type 2 (SGLT2) inhibitors such as canagliflozin and dapagliflozin have been approved for the treatment of type 2 diabetes mellitus. A PubMed search was conducted of the literature from April 1996 to August 2014 to identify all human studies related to SGLT2 inhibitors. Pertinent guidelines of experts and the prescribing information for canagliflozin and dapagliflozin are reviewed. SGLT2 inhibitors may be used as an add-on therapy in select and relatively healthy older patients with type 2 diabetes mellitus who are overweight and have uncontrolled hypertension. These medications should be avoided in patients who are frail, who have chronic kidney disease, and in conjunction with insulin or sulfonylureas. PMID- 25688894 TI - Rules for improving pharmacotherapy in older adult patients: part 1 (rules 1-5). AB - The population of older adult patients in the United States is growing each year. Appropriate pharmacotherapy has allowed many older patients to live longer and maintain healthy lives. Unfortunately, the inappropriate utilization of medications can be harmful to older adult patients. Inappropriate pharmacotherapy may lead to overusing medications and polypharmacy. Polypharmacy can contribute to a higher incidence of adverse effects, increase the risk of dangerous drug interactions, cause noncompliance with appropriate medication use, and significantly increase the cost of health care. The polypharmacy issue with geriatric patients has been described as an epidemic and this issue must be addressed. This review provides objective rules that may help prevent polypharmacy. Consideration of these rules when prescribing, dispensing, and caring for older adult patients will improve the overall pharmacotherapy regimens instituted by healthcare providers. PMID- 25688895 TI - Commentary on "rules for improving pharmacotherapy in older adult patients: part 1 (rules 1-5)". PMID- 25688896 TI - Regional variation in HIV clinical trials participation in the United States. AB - OBJECTIVES: To ensure generalizability of clinical research results, it is important to enroll a heterogeneous population that is representative of the target clinical population. Earlier studies have found regional variation in participation in human immunodeficiency virus (HIV) clinical trials, with the lowest rates seen in the southern United States. Rates of new HIV diagnoses are highest in the South, highlighting the need for in-depth understanding of disparities in clinical trial participation. We evaluated whether regional variation in study participation remains, and describe factors that facilitate or prevent HIV clinical trial participation by region. METHODS: A one-time, anonymous, bilingual, self-administered survey was conducted among HIV-infected adults receiving HIV care at all 47 domestic AIDS Clinical Trials Group clinical research sites, with a goal of completing 50 surveys per site. chi(2) tests were used to evaluate differences in knowledge of and participation in HIV clinical trials by region, including Northeast, Midwest, South, and West regions. Multivariable logistic regression was used to estimate odds ratios and 95% confidence intervals (CIs) for the effect of region on knowledge of and participation in HIV clinical trials. RESULTS: Of 2263 completed surveys, 2125 were included in this analysis. The proportion of respondents in the South who reported knowledge of studies (66%) was significantly lower than in the Northeast (76%), Midwest (77%), and West (73%) (P = 0.001). Respondents in the South also were the least likely group to report ever having tried to or having participated in a research study (51%) compared with respondents in the Northeast (60%), Midwest (57%), and West (69%; P < 0.001). After adjusting for age, sex, education, race/ethnicity, tobacco use, and alcohol use, the odds ratio for knowledge of and participation in clinical trials for the Northeast (1.36; 95% CI 1.07-1.72) and West (1.85; 95% CI 1.39-2.45) remained significant compared with the South. African American respondents in the South were the most likely population group to report not understanding research studies (15%) as a reason for not participating, compared with the Northeast (9%), Midwest (8%), and West (6%; P < 0.001). CONCLUSIONS: Significant regional variations in knowledge of and participation in HIV clinical trials exist. Our results suggest that increasing awareness and understanding of research studies, particularly among African Americans in the South, may facilitate HIV clinical trial participation that is more representative of the HIV-infected population across the United States. PMID- 25688897 TI - Commentary on "regional variation in HIV clinical trials participation in the United States". PMID- 25688898 TI - Epidemiology of falls in older adults in Texas. AB - OBJECTIVES: The expected increase in the US older adult population implies an increased risk of fall-related injury among these individuals. We describe the epidemiology of fall morbidity among older adults in Texas, a large US state with a diverse population base. METHODS: Texas Behavioral Risk Factor Surveillance System 2010 data were analyzed. The falls outcome was defined as falling: any fall in the past 3 months and a serious fall: a fall resulting in limited activities for at least 1 day or requiring medical attention. RESULTS: A total of 5996 subjects were included in this analysis; 17.6% (n = 1055) reported falling 1 to 5 times in the previous 3 months, and 361 (6%) experienced serious falls. Risk of falling had a significant positive association among respondents who rated their general health as fair to poor (relative risk [RR] 2.39, 95% confidence interval [CI] 1.55-3.68) and a negative association for those who reported regular physical activity (RR 0.59, 95% CI 0.42-0.82). A similar model examined the risk of serious falls and found statistically positive associations in respondents who reported fair or poor general health (RR 3.29, 95% CI 2.00-5.43). Negative associations were found for those who reported regular physical activity (RR 0.56, 95% CI 0.38-0.83) and for men (RR 0.62, 95% CI 0.39-0.98). No statistically significant correlations for either of the fall outcomes were found with residence, obesity, education, income, age, ethnicity, employment, marital status, diabetes mellitus, or cardiovascular disease. CONCLUSIONS: Interventions aimed at the prevention of falls should focus on maintaining and improving general health and promoting physical activity among older adults. PMID- 25688899 TI - School-based adolescent obesity prevention programming: perceptions of school personnel in Southern Appalachia. AB - OBJECTIVES: Coordinated School Health (CSH) is a systematic approach to improving the health and well-being of school-age children. It is recommended for its potential to promote healthy weight in adolescents through strategic programming. Resources and programming for adolescent obesity prevention varies among schools, thereby limiting the intended benefits of CSH. The purpose of this study was to understand gaps in schools' approaches to healthy weight promotion and support for overweight/obese students. We evaluated perceptions of adolescent obesity and environmental factors and programs facilitating healthy weight in high schools in Appalachian Tennessee. METHODS: In 2012, 17 key school personnel from 5 randomly selected high schools were interviewed. Questions addressed their perceptions of adolescent obesity, school-based physical activity and nutrition programming, and support available to overweight/obese students. Thematic analysis was conducted to identify emerging themes. RESULTS: Participants consistently identified adolescent obesity and/or associated risk factors as major health problems within their schools. Barriers to physical activity and healthful eating were identified at multiple levels. Because of the sensitivity surrounding overweight/obesity, no particular programs or curricula targeted overweight/obese adolescents specifically, but they were available to all students. Support is not explicitly available; therefore, overweight/obese students must seek out these resources. CONCLUSIONS: Findings suggest that although school personnel are concerned about the impact of adolescent obesity on health outcomes, there is wide variation across schools on the types and quality of programming available to address the issue. Results can be used to encourage school-based strengths and identify gaps in the CSH infrastructure in school systems. PMID- 25688900 TI - Effects of cocaine-positive urine screens on serum thyrotropin levels in patients admitted to an inpatient mental health unit. AB - OBJECTIVE: To assess the effect of a positive urine screen for cocaine on thyrotropin (TSH, also thyroid-stimulating hormone) concentrations. METHODS: In this retrospective cohort study, patients admitted to the mental health unit at an academic inpatient setting with a diagnosis of cocaine dependence or cocaine intoxication were routinely screened with urine drug toxicology tests and TSH concentrations. TSH concentrations from patients who tested positive for cocaine on urine toxicology were compared with patients having negative cocaine screenings. RESULTS: A total of 192 patients were included: 122 with a positive cocaine screen and 70 with a negative cocaine screen. All patients were screened using a highly sensitive TSH assay. A positive cocaine screen was not associated with a statistically significant difference in TSH concentrations compared with a negative cocaine screen. The percentage of patients with hypothyroidism (TSH >4.50 MUIU/mL) or hyperthyroidism (TSH <0.40 MUIU/mL) were similar in both study groups. CONCLUSIONS: The study failed to show that a positive urine screen for cocaine was associated with a significant effect on serum TSH levels in patients admitted to a mental health unit with a diagnosis of cocaine dependence or cocaine intoxication. Our findings support those of a prior study that cocaine use does not affect routine thyroid function tests. The present study does not support the clinical practice of ordering a serum TSH screening test on patients admitted to inpatient psychiatry units soley because the urine screen is positive for cocaine. PMID- 25688901 TI - Teaching international medicine to medical students: a clinical imperative. PMID- 25688902 TI - Early laparoscopic cholecystectomy for acute cholecystitis: is it safe for patients? PMID- 25688903 TI - Proposed clinical and endoscopic predictors for diagnosis of gastrointestinal Kaposi sarcoma. PMID- 25688905 TI - An investigation of the efficacy of acceptance-based behavioral therapy for academic procrastination. AB - Procrastination among college students is both prevalent and troublesome, harming both academic performance and physical health. Unfortunately, no "gold standard" intervention exists. Research suggests that psychological inflexibility may drive procrastination. Accordingly, interventions using acceptance and mindfulness methods to increase psychological flexibility may decrease procrastination. This study compared time management and acceptance-based behavioral interventions. College students' predictions of how much assigned reading they should complete were compared to what they did complete. Procrastination, anxiety, psychological flexibility, and academic values were also measured. Although a trend suggested that time management intervention participants completed more reading, no group differences in procrastination were revealed. The acceptance-based behavioral intervention was most effective for participants who highly valued academics. Clinical implications and future research are discussed. PMID- 25688906 TI - Everyday musical experience is sufficient to perceive the speech-to-song illusion. AB - Speech and song are readily differentiated from each other in everyday communication, yet sometimes listeners who have formal music training will hear a spoken utterance transform from speech to song when it is repeated (Deutsch, Henthorn, & Lapidis, 2011). It remains unclear whether music training is required to perceive this illusory transformation or whether implicit knowledge of musical structure is sufficient. The current study replicates Deutsch et al.'s findings with musicians and demonstrates the generalizability of this auditory illusion to casual music listeners with no formal training. We confirm that the illusory transformation is disrupted when the pitch height of each repetition of the utterance is transposed, and we find that raising the pitch height has a different effect on listeners' ratings than does lowering it. Auditory illusions such as this may offer unique opportunities to compare domain-specific and domain general processing in the brain while holding acoustic characteristics constant. PMID- 25688907 TI - The cost of learning: interference effects in memory development. AB - Learning often affects future learning and memory for previously learned information by exerting either facilitation or interference effects. Several theoretical accounts of interference effects have been proposed, each making different developmental predictions. This research examines interference effects across development, with the goal of better understanding mechanisms of interference and of memory development. Preschool-aged children and adults participated in a 3-phased associative learning paradigm containing stimuli that were either unique or repeated across phases. Both age groups demonstrated interference effects, but only for repeated items. Whereas proactive interference effects were comparable across age groups, retroactive interference reached catastrophic-like levels in children. Additionally, retroactive interference increased in adults when contextual differences between phases were minimized (Experiment 2), and decreased in adults who were more successful at encoding repeated pairs of stimuli during a training phase (Experiment 3). These results are discussed with respect to theories of memory and memory development. PMID- 25688908 TI - Automatic integration of social information in emotion recognition. AB - This study investigated the automaticity of the influence of social inference on emotion recognition. Participants were asked to recognize dynamic facial expressions of emotion (fear or anger in Experiment 1 and blends of fear and surprise or of anger and disgust in Experiment 2) in a target face presented at the center of a screen while a subliminal contextual face appearing in the periphery expressed an emotion (fear or anger) or not (neutral) and either looked at the target face or not. Results of Experiment 1 revealed that recognition of the target emotion of fear was improved when a subliminal angry contextual face gazed toward-rather than away from-the fearful face. We replicated this effect in Experiment 2, in which facial expression blends of fear and surprise were more often and more rapidly categorized as expressing fear when the subliminal contextual face expressed anger and gazed toward-rather than away from-the target face. With the contextual face appearing for 30 ms in total, including only 10 ms of emotion expression, and being immediately masked, our data provide the first evidence that social influence on emotion recognition can occur automatically. PMID- 25688909 TI - Mechanistic insight into water-modulated cycloisomerization of enynyl esters using an Au(I) catalyst. AB - By carrying out density functional theoretical calculations, we have performed a detailed mechanistic study of the Au(I)-catalyzed cycloisomerization of 1,6 enylnyl ester in a dry and wet dichloromethane solvent corresponding to hydrogenation and hydrolysis processes, respectively. The hydrogenation and hydrolysis mechanisms proposed in the previous literature starting from an enol ketal intermediate without the involvement of an Au(I) catalyst are found to involve high barriers and thus contradict the observed experimental findings. Alternatively, based on the theoretical calculations, a novel hydrogenation mechanism (i.e., Au-induced H-shift followed by enol intermediate self-promoted H shift) and a hydrolysis mechanism (i.e., Au-stabilized H-shift/C-O binding with subsequent H2O-assisted H-shift) from an Au-enol ketal adduct corroborate the experimental observations. The calculated results indicate that under unchanged wet conditions, the formation of a hydrolysis product is not involved in the intermediacy of the hydrogenation product. However, if the initial dry environment is provided, a hydrogenation product will be afforded. And then it will relentlessly evolve into a hydrolysis product in the subsequent wet conditions. The present theoretical results not only rationalize the experimental observations well but provide new insight into the mechanisms of the significant water-mediated cycloisomerization reaction. PMID- 25688911 TI - The Type III Effector AvrBs2 in Xanthomonas oryzae pv. oryzicola Suppresses Rice Immunity and Promotes Disease Development. AB - Xanthomonas oryzae pv. oryzicola, the causal agent of bacterial leaf streak, is one of the most important bacterial pathogens in rice. However, little is known about the functions of individual type III effectors in virulence and pathogenicity of X. oryzae pv. oryzicola. Here, we examined the effect of the mutations of 23 putative nontranscription activator-like effector genes on X. oryzae pv. oryzicola virulence. The avrBs2 knock-out mutant was significantly attenuated in virulence to rice. In contrast, the xopAA deletion caused enhanced virulence to a certain rice cultivar. It was also demonstrated that six putative effectors, including XopN, XopX, XopA, XopY, XopF1, and AvrBs2, caused the hypersensitive response on nonhost Nicotiana benthamiana leaves. Virulence function of AvrBs2 was further confirmed by transgenic technology. Pathogen associated molecular pattern-triggered immune responses including the generation of reactive oxygen species and expression of pathogenesis-related genes were strongly suppressed in the AvrBs2-expressing transgenic rice lines. Although not inhibiting flg22-induced activation of mitogen-activated protein kinases, heterologous expression of AvrBs2 greatly promotes disease progression in rice caused by two important bacterial pathogens X. oryzae pvs. oryzae and oryzicola. Collectively, these results indicate that AvrBs2 is an essential virulence factor that contributes to X. oryzae pv. oryzicola virulence through inhibiting defense responses and promoting bacterial multiplication in monocot rice. PMID- 25688912 TI - TCL1 expression predicts overall survival in patients with mantle cell lymphoma. AB - OBJECTIVES: Mantle cell lymphoma (MCL) has a heterogeneous clinical course. Although most cases show a poor prognosis, a minority has an indolent course. It is difficult to identify indolent MCL cases prospectively. T-cell leukemia/lymphoma protein 1 (TCL1) is expressed by several B-cell lymphomas, including MCL. This study examined the expression of TCL1 and its prognostic relevance for MCL. METHODS: Clinical data for 162 patients with MCL were collected. Of these, 144 cases with available tissues for tissue microarray construction and immunostaining were included in the analysis. TCL1 staining was quantified using the Nuclear Quant application with PannoramicTM Viewer v. 1.14. High TCL1 expression was defined as moderate to strong nuclear and/or cytoplasmic staining in 40% or more of the cells. RESULTS: High TCL1 expression was observed in 39 of 144 samples (27.1%). Patients with low TCL1 expression were more likely to present with blastoid/pleomorphic morphology (P = 0.010). Low TCL1 expression was associated with significantly shorter overall survival (OS, P = 0.006). Multivariate analysis identified low TCL1 expression (P = 0.003), high-risk MIPI (P = 0.027), and anemia (P = 0.018) as adverse prognostic factors. CONCLUSIONS: Our study suggests that TCL1 expression profile may have a role in the prediction of overall outcome in patient with MCL and call for prospective studies. PMID- 25688914 TI - Retraction: "Loss in the Last Day of 2014: a Eulogy for Prof. Bing XIA" by Shu Dong XIAO and Zhi Hua RAN. PMID- 25688913 TI - Time-stepping techniques to enable the simulation of bursting behavior in a physiologically realistic computational islet. AB - Physiologically realistic simulations of computational islets of beta cells require the long-time solution of several thousands of coupled ordinary differential equations (ODEs), resulting from the combination of several ODEs in each cell and realistic numbers of several hundreds of cells in an islet. For a reliable and accurate solution of complex nonlinear models up to the desired final times on the scale of several bursting periods, an appropriate ODE solver designed for stiff problems is eventually a necessity, since other solvers may not be able to handle the problem or are exceedingly inefficient. But stiff solvers are potentially significantly harder to use, since their algorithms require at least an approximation of the Jacobian matrix. For sophisticated models, systems of several complex ODEs in each cell, it is practically unworkable to differentiate these intricate nonlinear systems analytically and to manually program the resulting Jacobian matrix in computer code. This paper demonstrates that automatic differentiation can be used to obtain code for the Jacobian directly from code for the ODE system, which allows a full accounting for the sophisticated model equations. This technique is also feasible in source code languages Fortran and C, and the conclusions apply to a wide range of systems of coupled, nonlinear reaction equations. However, when we combine an appropriately supplied Jacobian with slightly modified memory management in the ODE solver, simulations on the realistic scale of one thousand cells in the islet become possible that are several orders of magnitude faster than the original solver in the software Matlab, a language that is particularly user friendly for programming complicated model equations. We use the efficient simulator to analyze electrical bursting and show non-monotonic average burst period between fast and slow cells for increasing coupling strengths. We also find that interestingly, the arrangement of the connected fast and slow heterogeneous cells impacts the peak bursting period monotonically. PMID- 25688915 TI - Impact of the LSVT on vowel articulation and coarticulation in Parkinson's disease. AB - The purpose of this study was to investigate the impact of the Lee Silverman Voice Treatment (LSVT(r)) on vowel articulation and consonant-vowel (C-V) coarticulation in dysarthric speakers with Parkinson's disease (PD). Nine Quebec French speakers diagnosed with idiopathic PD underwent the LSVT(r). Speech characteristics were compared before and after treatment. Vowel articulation was measured using acoustic vowel space and calculated with the first (F1) and second formant (F2) of the vowels /i/, /u/ and /a/. C-V coarticulation was measured using locus equations, an acoustic metric based on the F2 transitions within vowels in relation to the preceding consonant. The relationship between these variables, speech loudness and vowel duration was also analysed. Results showed that vowel contrast increased in F1/F2 acoustic space after administration of the LSVT(r). This improvement was associated with the gain in speech loudness and longer vowel duration. C-V coarticulation patterns between consonant contexts showed greater distinctiveness after the treatment. This improvement was associated with the gain in speech loudness only. These results support the conclusions of previous studies investigating the relationship between the LSVT(r), speech loudness and articulation in PD. These results expand clinical understanding of the treatment and indicate that loud speech changes C-V coarticulation patterns. Clinical applications and theoretical considerations are discussed. PMID- 25688916 TI - Proteome and transcript analysis of Vitis vinifera cell cultures subjected to Botrytis cinerea infection. AB - Gray mold caused by Botrytis cinerea is one of the most important diseases of grapevine resulting in significant reductions in yield and fruit quality. In order to examine the molecular mechanisms that characterize the interaction between B. cinerea and the host plant, the grapevine cytoplasmic proteome was analyzed by two-dimensional polyacrylamide gel electrophoresis. The interaction between Vitis vinifera cv. Gamay cells and B. cinerea was characterized by the increase in spot abundance of 30 proteins, of which 21 were successfully identified. The majority of these proteins were related to defence and stress responses and to cell wall modifications. Some of the modulated proteins have been previously found to be affected by other pathogens when they infect V. vinifera but interestingly, the proteins related to cell wall modification that were influenced by B. cinerea have not been shown to be modulated by any other pathogen studied to date. Transcript analysis using the quantitative real time polymerase chain reaction additionally revealed the up-regulation of several acidic, probably extracellular, chitinases. The results indicate that cell wall strengthening, accumulation of PR proteins and excretion of lytic enzymes are likely to be important mechanisms in the defence of grapevine against B. cinerea. BIOLOGICAL SIGNIFICANCE: Although gray mold caused by Botrytis cinerea is one of the most important diseases of grapevine, little information is available about proteomic changes in this pathosystem. These results suggest that cell wall strengthening, accumulation of PR proteins and excretion of lytic enzymes are important molecular mechanisms in the defence of grapevine against B. cinerea. Surprisingly, the proteins related to cell wall modification that were modulated by B. cinerea have not been shown to be affected by any other pathogen studied to date. PMID- 25688917 TI - Unveiling the nature of black mamba (Dendroaspis polylepis) venom through venomics and antivenom immunoprofiling: Identification of key toxin targets for antivenom development. AB - The venom proteome of the black mamba, Dendroaspis polylepis, from Eastern Africa, was, for the first time, characterized. Forty- different proteins and one nucleoside were identified or assigned to protein families. The most abundant proteins were Kunitz-type proteinase inhibitors, which include the unique mamba venom components 'dendrotoxins', and alpha-neurotoxins and other representatives of the three-finger toxin family. In addition, the venom contains lower percentages of proteins from other families, including metalloproteinase, hyaluronidase, prokineticin, nerve growth factor, vascular endothelial growth factor, phospholipase A2, 5'-nucleotidase, and phosphodiesterase. Assessment of acute toxicity revealed that the most lethal components were alpha-neurotoxins and, to a lower extent, dendrotoxins. This venom also contains a relatively high concentration of adenosine, which might contribute to toxicity by influencing the toxin biodistribution. ELISA immunoprofiling and preclinical assessment of neutralization showed that polyspecific antivenoms manufactured in South Africa and India were effective in the neutralization of D. polylepis venom, albeit showing different potencies. Antivenoms had higher antibody titers against alpha neurotoxins than against dendrotoxins, and displayed high titers against less toxic proteins of high molecular mass. Our results reveal the complexity of D. polylepis venom, and provide information for the identification of its most relevant toxins to be neutralized by antivenoms. BIOLOGICAL SIGNIFICANCE: The black mamba, D. polylepis, is one of the most feared snakes in the world, owing to the potency of its venom, the severity and rapid onset of clinical manifestations of envenomings, and its ability to strike fast and repeatedly. The present study reports the first proteomic analysis of this venom. Results revealed a complex venom constituted predominantly by proteins belonging to the Kunitz-type proteinase inhibitor family, which comprises the dendrotoxins, and to alpha-neurotoxins of the three-finger toxin family. The proteins showing highest acute toxicity were alpha-neurotoxins, which induce post-synaptic blockade of the neuromuscular junctions, followed by dendrotoxins, which inhibit the voltage dependent potassium channels. The combination of these two types of toxins in the venom underscores the presence of a dual strategy that results in a highly effective mechanism for prey subduction. This complex toxic arsenal is likely to provide D. polylepis with high trophic versatility. The rapid onset and severity of neurotoxic clinical manifestations in envenomings by D. polylepis demand the rapid administration of effective and safe antivenoms. Preclinical tests showed that an antivenom from South Africa and two antivenoms from India were effective in the neutralization of this venom, albeit differing in their potency. Moreover, ELISA immunoprofiling of these antivenoms against all venom fractions revealed that antivenoms have higher titers against alpha-neurotoxins than against dendrotoxins, thus underscoring the need to develop improved immunization strategies. The results of this investigation identified the most relevant toxins present in D. polylepis venom, which need to be targeted by antivenoms or other type of inhibitors. PMID- 25688918 TI - KRAS and BRAF mutations are prognostic biomarkers in patients undergoing lung metastasectomy of colorectal cancer. AB - BACKGROUND: We evaluated KRAS (mKRAS (mutant KRAS)) and BRAF (mBRAF (mutant BRAF)) mutations to determine their prognostic potential in assessing patients with colorectal cancer (CRC) for lung metastasectomy. METHODS: Data were reviewed from 180 patients with a diagnosis of CRC who underwent a lung metastasectomy between January 1998 and December 2011. RESULTS: Molecular analysis revealed mKRAS in 93 patients (51.7%), mBRAF in 19 patients (10.6%). In univariate analyses, overall survival (OS) was influenced by thoracic nodal status (median OS: 98 months for pN-, 27 months for pN+, P<0.0001), multiple thoracic metastases (75 months vs 101 months, P=0.008) or a history of liver metastases (94 months vs 101 months, P=0.04). mBRAF had a significantly worse OS than mKRAS and wild type (WT) (P<0.0001). The 5-year OS was 0% for mBRAF, 44% for mKRAS and 100% for WT, with corresponding median OS of 15, 55 and 98 months, respectively (P<0.0001). In multivariate analysis, WT BRAF (HR: 0.005 (95% CI: 0.001-0.02), P<0.0001) and WT KRAS (HR: 0.04 (95% CI: 0.02-0.1), P<0.0001) had a significant impact on OS. CONCLUSIONS: mKRAS and mBRAF seem to be prognostic factors in patients with CRC who undergo lung metastasectomy. Further studies are necessary. PMID- 25688919 TI - Regulatory function of glycosphingolipids in the inflammation and degeneration. AB - Recent progress in the biological sciences has revealed that a number of extrinsic and intrinsic environmental factors may cause chronic inflammation. When these insults are persistent or intermittently repeated, regardless of extrinsic or intrinsic origins, homeostasis of our bodies would be disturbed and undergo long-term impact. These situations might give rise to chronic inflammation, leading to various diseases as results of accumulative effects of various inflammatory reactions. Complex carbohydrates expressed mainly on the cell surface have been demonstrated to play roles in fine-tuning of various biological processes to maintain homeostasis of cells, organs and our bodies. When abnormal physicochemical insults and harmful pathogens invade, the fine tuning including modification of the glycosylation patterns is continuously exerted. Therefore, defects in the proper response with proper glycosylation lead to chronic inflammation and subsequent deterioration of individual tissues and organs. Genetic depletion of sialic acid-containing glycolipids, gangliosides resulted in the inflammation of CNS and neurodegeneration. Lactosylceramide was also reported to mediate neuroinflammation, leading to chronic inflammatory diseases. Defects of globoseries glycolipids resulted in the increased sensitivity to LPS toxicity. Thus, possibilities that manipulation of synthesis and expression of glycosphingolipids may be applicable for the disease control are now proposed. PMID- 25688921 TI - Telehealth Monitoring of Patients with Schizophrenia and Suicidal Ideation. AB - A telehealth system was developed to monitor risk following hospitalization for suicidal ideation. We hypothesized that 3 months of telehealth monitoring will result in a greater reduction in suicidal ideation. Veterans with schizophrenia admitted with recent suicidal ideation and/or a suicidal attempt were recruited into a discharge program of VA Usual Care with daily Health Buddy(c) monitoring (HB) or Usual Care (UC) alone. Fifteen of 25 were randomized to HB and 10 received UC. Daily adherence in the use of the HB system during months 1-3 was, respectively, 86.9%, 86.3%, and 84.1%. There were significant improvements in Beck Scale for Suicide Ideation scores in HB participants. There were no changes in depressive symptoms. Telehealth monitoring for this population of patients appears to be feasible. PMID- 25688920 TI - Inactivation of myeloperoxidase by benzoic acid hydrazide. AB - Myeloperoxidase (MPO) is expressed by myeloid cells for the purpose of catalyzing the formation of hypochlorous acid, from chloride ions and reaction with a hydrogen peroxide-charged heme covalently bound to the enzyme. Most peroxidase enzymes both plant and mammalian are inhibited by benzoic acid hydrazide (BAH) containing compounds, but the mechanism underlying MPO inhibition by BAH compounds is largely unknown. Recently, we reported MPO inhibition by BAH and 4 (trifluoromethyl)-BAH was due to hydrolysis of the ester bond between MPO heavy chain glutamate 242 ((HC)Glu(242)) residue and the heme pyrrole A ring, freeing the heme linked light chain MPO subunit from the larger remaining heavy chain portion. Here we probed the structure and function relationship behind this ester bond cleavage using a panel of BAH analogs to gain insight into the constraints imposed by the MPO active site and channel leading to the buried protoporphyrin IX ring. In addition, we show evidence that destruction of the heme ring does not occur by tracking the heme prosthetic group and provide evidence that the mechanism of hydrolysis follows a potential attack of the (HC)Glu(242) carbonyl leading to a rearrangement causing the release of the vinyl-sulfonium linkage between (HC)Met(243) and the pyrrole A ring. PMID- 25688922 TI - Against Permitted Exploitation in Developing World Research Agreements. AB - This paper examines the moral force of exploitation in developing world research agreements. Taking for granted that some clinical research which is conducted in the developing world but funded by developed world sponsors is exploitative, it asks whether a third party would be morally justified in enforcing limits on research agreements in order to ensure more fair and less exploitative outcomes. This question is particularly relevant when such exploitative transactions are entered into voluntarily by all relevant parties, and both research sponsors and host communities benefit from the resulting agreements. I show that defenders of the claim that exploitation ought to be permitted rely on a mischaracterization of certain forms of interference as unjustly paternalistic and two dubious empirical assumptions about the results of regulation. The view I put forward is that by evaluating a system of constraints on international research agreements, rather than individual transaction-level interference, we can better assess the alternatives to permitting exploitative research agreements. PMID- 25688923 TI - Molecular genetics of blood-fleshed peach reveals activation of anthocyanin biosynthesis by NAC transcription factors. AB - Anthocyanin pigmentation is an important consumer trait in peach (Prunus persica). In this study, the genetic basis of the blood-flesh trait was investigated using the cultivar Dahongpao, which shows high levels of cyanidin-3 glucoside in the mesocarp. Elevation of anthocyanin levels in the flesh was correlated with the expression of an R2R3 MYB transcription factor, PpMYB10.1. However, PpMYB10.1 did not co-segregate with the blood-flesh trait. The blood flesh trait was mapped to a 200-kb interval on peach linkage group (LG) 5. Within this interval, a gene encoding a NAC domain transcription factor (TF) was found to be highly up-regulated in blood-fleshed peaches when compared with non-red fleshed peaches. This NAC TF, designated blood (BL), acts as a heterodimer with PpNAC1 which shows high levels of expression in fruit at late developmental stages. We show that the heterodimer of BL and PpNAC1 can activate the transcription of PpMYB10.1, resulting in anthocyanin pigmentation in tobacco. Furthermore, silencing the BL gene reduces anthocyanin pigmentation in blood fleshed peaches. The transactivation activity of the BL-PpNAC1 heterodimer is repressed by a SQUAMOSA promoter-binding protein-like TF, PpSPL1. Low levels of PpMYB10.1 expression in fruit at early developmental stages is probably attributable to lower levels of expression of PpNAC1 plus the presence of high levels of repressors such as PpSPL1. We present a mechanism whereby BL is the key gene for the blood-flesh trait in peach via its activation of PpMYB10.1 in maturing fruit. Partner TFs such as basic helix-loop-helix proteins and NAC1 are required, as is the removal of transcriptional repressors. PMID- 25688924 TI - 'We had to change to single beds because I itch in the night': a qualitative study of the experiences, attitudes and approaches to coping of patients with cutaneous T-cell lymphoma. AB - BACKGROUND: Primary cutaneous T-cell lymphoma (CTCL) is a rare but prevalent condition which can have a significant impact on many aspects of quality of life. However, there is little evidence of patients' lived experience of CTCL. OBJECTIVES: To understand in greater depth patients' experiences of living and coping with CTCL, and to inform the development of models of care for this population in line with U.K. METHODS: Semi-structured interviews were conducted with a purposive sample of patients with CTCL who attended an inner-city teaching hospital. Participants were purposively selected according to their disease stage, age, sex and ethnicity. RESULTS: Nineteen patients with CTCL (stages IB IVB), aged between 41 and 83 years, participated in a single interview. This included 10 men; 15 people identified themselves as white British. Interviews lasted a median of 55 (range 28-170) min. Two main themes emerged: issues regarding diagnosis, particularly a perceived delay in diagnosis, and the impact of CTCL (subthemes related to physical well-being, practical concerns and psychological and social well-being and coping). CONCLUSIONS: Findings from this study illuminate the diverse effects of CTCL on patients' lives. The universal experience of delays in diagnosis was striking and a concern to patients. The disease, particularly its physical symptoms, had a significant impact on patients' lives, including employment, leisure and relationships. Despite the symptom burden and its impact, participants described effective coping strategies such as drawing on social support, maintaining normal lives and becoming well informed about CTCL. Proactive holistic assessment and management of the range of patient concerns is needed in providing care for patients with CTCL and their family and friends. PMID- 25688925 TI - Theoretical examination of the S-C-P anomeric effect. AB - Three decades after the discovery of a strong S-C-P anomeric effect in 2 diphenylphosphinoyl-1,3-dithiane (1) and 2-trimethylphosphonium-1,3-dithiane (4), its definitive interpretation is still lacking. The present study reports DFT geometry optimizations of 1-ax, 1-eq, 4-ax, and 4-eq, which do reproduce the S-C P anomeric effect in 1 and 4, worth 5.45 and 3.08 kcal/mol, respectively (in chloroform solvent). Weinhold's NBO analysis supports the existence of dominant nX -> sigma*C-Y stereoelectronic interactions that stabilize the axial conformers. PMID- 25688926 TI - Contrasting effects of fresh and fermented kimchi consumption on gut microbiota composition and gene expression related to metabolic syndrome in obese Korean women. AB - Accumulating evidence suggests relationship of compositional changes of gut microbiota with onset of metabolic disorders and obesity. Kimchi, a traditional Korean side dish, is known for its beneficial impact on metabolic parameters and anti-obesity effects. The current study was designed to evaluate the association between gut microbiota and human genome after kimchi intervention in an effort to understand the molecular mechanism(s) underlying the antiobesity impact of kimchi. Twenty-four obese women were randomly assigned to either fresh or fermented kimchi group for eight weeks of kimchi intervention. Pyrosequencing of fecal microbiota and microarray analyses of blood samples revealed that fresh and fermented kimchi interventions exerted differential effects on the obesity related clinical parameters. Correlations of these effects with changes in blood gene expression and gut microbial population were more evident in the fermented kimchi group than the fresh kimchi group. PMID- 25688927 TI - Two components for one resistivity in LaVO3/SrTiO3 heterostructure. AB - A series of 100 nm LaVO3 thin films have been synthesized on (0 0 1)-oriented SrTiO3 substrates using the pulsed laser deposition technique, and the effects of growth temperature are analyzed. Transport properties reveal a large electronic mobility and a non-linear Hall effect at low temperature. In addition, a cross over from a semiconducting state at high-temperature to a metallic state at low temperature is observed, with a clear enhancement of the metallic character as the growth temperature increases. Optical absorption measurements combined with the two-bands analysis of the Hall effect show that the metallicity is induced by the diffusion of oxygen vacancies in the SrTiO3 substrate. These results allow us to understand that the film/substrate heterostructure behaves as an original semiconducting-metallic parallel resistor, and electronic transport properties are consistently explained. PMID- 25688928 TI - Involvement of NMDA receptor subtypes in cortical spreading depression in rats assessed by fMRI. AB - Cortical spreading depression (CSD) is a phenomenon implicated in migraine with aura and associated with other neurological disorders (e.g. stroke, brain trauma). Current evidence points to the essential role of NMDA receptors in CSD mechanisms. However, the roles of multiple subunits of NMDA receptors expressed in neurons, glia and blood vessels in vivo, are little explored. Using BOLD fMRI of urethane anesthetized rats as an integrative CSD readout, we tested the involvement of different NMDA receptor subtypes in CSD induction and propagation. Rats were treated with a non-selective NMDA blocker (MK-801), NR2B antagonist (ifenprodil) or a NR2A selective antagonist (TCN-201). CSD was induced during fMRI scanning by application of KCl onto the cerebral cortex and fMRI data were collected by 9.4 T MRI. The non-specific NMDA antagonist MK-801 completely blocked CSD, which was not observed in the NR2A group where TCN-201 did not alter the CSD features. Unexpectedly, the NR2B specific antagonist ifenprodil largely promoted the initial negative phase of the BOLD CSD response, likely due to altered neurovascular coupling. Our data suggest key roles and differential involvement of NMDA receptor subtypes in CSD generation and propagation, highlighting an important role for the NR2B subtype. PMID- 25688929 TI - Multiple idiopathic cervical root resorption: a case report. AB - AIM: To report a severe and rare case of multiple idiopathic cervical root resorption (MICRR) in an adult female. SUMMARY: A healthy 27-year-old Chinese female, with no significant associated factors, presented with MICRR. Resorption progressed quickly and lesions varied in severity, involving 29 teeth and leading to the loss of 23 teeth over a period of only 3 years. The inner surface of the crown showed extensive areas with worm-eaten lacunar resorption, and the resorptive lesions had abundant lysosomes throughout their cytoplasm. Further, heavy deposits of reaction products were shown in variously sized lysosomes. PMID- 25688930 TI - New Zealand Emergency Medicine Network: a collaboration for acute care research in New Zealand. AB - The specialty of emergency medicine in Australasia is coming of age. As part of this maturation there is a need for high-quality evidence to inform practice. This article describes the development of the New Zealand Emergency Medicine Network, a collaboration of committed emergency care researchers who share the vision that New Zealand/Aotearoa will have a world-leading, patient-centred emergency care research network, which will improve emergency care for all, so that people coming to any ED in the country will have access to the same world class emergency care. PMID- 25688931 TI - Using TAGteach to improve the proficiency of dance movements. AB - Behavioral research to enhance sports performance has been conducted in numerous sports domains and often involves feedback from the coach to the student. One promising form of feedback is the use of an acoustical stimulus such as a clicker to provide more immediate feedback. Similar to clicker training with animals, acoustical stimuli are used with humans to reinforce desired behavior in a procedure called TAGteach, which involves using a clicker as a conditioned reinforcer in training. The purpose of this study was to evaluate the effectiveness of TAGteach, implemented by dance teachers, to increase the fluency of 3 dance movements in a multiple baseline design across behaviors with 4 students of dance. Target behaviors included a turn, kick, and leap. The targeted dance movements remained at relatively low levels of performance during baseline and improved for each participant after the introduction of the TAGteach intervention. Implications for future research are discussed. PMID- 25688932 TI - Hypertensive heart failure in Nigerian Africans: insights from the Abeokuta Heart Failure Registry. AB - Data from the Abeokuta Heart Failure Registry were used to determine the clinical characteristics, mode of treatment, and short- and medium-term outcomes of patients with hypertensive heart failure. A total of 320 patients were consecutively studied, comprising 184 men (57.5%) and 136 women (42.5%) aged 58.4+/-12.4 and 60.6+/-14.5 years, respectively. Most patients (80%) presented with New York Heart Association functional class III or IV and around one third (35%) had preserved systolic function. Median hospital stay was 9 days (interquartile range 5-21) while intra-hospital mortality was 3.4%. The 30-day, 90-day, and 180-day mortality rates were 0.9% (95% confidence interval, -0.2 to 3.5), 3.5% (95% confidence interval, -1.7 to 7.3), and 11.7% (95% confidence interval, -7.8 to 17.5), respectively. In a multiple logistic regression analysis, only serum creatinine was an independent predictor of mortality at 180 days (adjusted odds ratio, 1.76; 95% confidence interval, -1.17 to 2.64). Hypertension is the most common etiological risk factor for heart failure in Nigeria. Most patients present in the fourth decade of life with severe heart failure and secondary valvular dysfunction and significant in-hospital mortality. PMID- 25688933 TI - Thomas Willis, a pioneer in translational research in anatomy (on the 350th anniversary of Cerebri anatome). AB - The year 2014 marked the 350th anniversary of the publication in London of Cerebri anatome, a ground-breaking work of neuroscience heavily influenced by the political and cultural context of Baroque Europe and mid-17th century England. This article aims to review the work of the English physician and anatomist Thomas Willis, specifically with regard to the contents of his Cerebri anatome. Willis's academic and professional career was influenced by the turbulent period of the English Civil War during which he studied medicine. Willis went from chemistry to dissection arguably because of his need to justify the body-brain soul relationship. As a result, he became a fellow of a select club of eminent experimentalists, and afterward was a Fellow of the Royal Society. Later on, he went to London, leaving the academic life to dedicate himself fully to the profession of medicine. As a physician, Willis did not base his practice on aphorisms but on a 'bench to bedside' approach to medicine, while studying neuroanatomy--covering embryology, comparative anatomy and pathological anatomy- as a basis for the comprehension of neurological pathology. He developed innovative anatomical methods for the preservation and dissection of the brain, injection of coloured substances and illustration of his findings. In Cerebri anatome, Willis recognized the cerebral cortex as the substrate of cognition. He also claimed that the painful stimuli came from the meninges, but not from the brain itself. He explained for the first time the pathological and functional meaning of the brain's circular arterial anastomosis, which is named after him. He also specified some features of the cranial origin of the sympathetic nerves and coined the term 'neurologie'. Cerebri anatome marked the transition between the mediaeval and modern notions of brain function, and thus it is considered a cornerstone of clinical and comparative anatomy of the nervous system. The new contributions and methods employed by Willis justify his place as a father of neurology and a pioneer of translational research. PMID- 25688934 TI - In situ bioconjugation and ambient surface modification using reactive charged droplets. AB - Molecular ions are generated in induced electrospray ionization, and they can be transported to grounded ambient surfaces in the form of charged microdroplets. Efficient amide bonds formation between amines and carboxylic acids were observed inside charged droplets during transfer to the surface. Biomolecules derivatized using this method were self-assembled on a bare gold surface via Au-S bonds under the charged microdroplet environment. Cyclic voltammetric analysis of the self assembled molecular film showed accelerated protein derivatization with cysteine, which allowed the covalent immobilization of the protein to the gold surface. Cytochrome C-functionalized electrodes prepared using the induced dual nanoelectrospray process showed bioactivity toward aqueous solutions of hydrogen peroxide below 50 MUM. In effect, we have developed a method that allows derivatization of biomolecules and their immobilization at ambient surfaces in a single experimental step. PMID- 25688935 TI - Direct C-H amidation of benzoic acids to introduce meta- and para-amino groups by tandem decarboxylation. AB - The Ir-catalyzed mild C-H amidation of benzoic acids with sulfonyl azides was developed to give reactions with high efficiency and functional-group compatibility. Subsequent protodecarboxylation of ortho-amidated benzoic acid products afforded meta- or para-substituted (N-sulfonyl)aniline derivatives, the latter being inaccessible by other C-H functionalization approaches. The decarboxylation step was compatible with the amidation conditions, enabling a convenient one-pot, two-step process. PMID- 25688936 TI - Dried blood spot measurement of pregnancy-associated plasma protein A (PAPP-A) and free beta-subunit of human chorionic gonadotropin (beta-hCG) from a low resource setting. AB - OBJECTIVES: The objectives of the article is to compare pregnancy-associated plasma protein A (PAPP-A) and free beta-subunit of human chorionic gonadotropin (beta-hCG) concentrations in dried blood spots (DBSs) with serum of samples obtained from a public hospital in a low-resource setting and to evaluate their stability. METHODS: Serum and DBS samples were obtained by venipuncture and finger prick from 50 pregnant participants in a cohort study in a public hospital in Accra, Ghana. PAPP-A and beta-hCG concentrations from serum and DBS were measured with an AutoDELFIA(r) (PerkinElmer, PerkinElmer, Turku, Finland) automatic immunoassay. Correlation and Passing-Bablok regression analyses were performed to compare marker levels. RESULTS: High correlation (>0.9) was observed for PAPP-A and beta-hCG levels between various sampling techniques. The beta-hCG concentration was stable between DBS and serum, PAPP-A concentration consistently lower in DBS. CONCLUSION: Our findings suggest that beta-hCG can be reliably collected from DBS in low-resource tropical settings. The exact conditions of the clinical workflow necessary for reliable PAPP-A measurement in these settings need to be further developed in the future. These findings could have implications for prenatal screening programs feasibility in low-income and middle income countries, as DBS provides an alternative minimally invasive sampling method, with advantages in sampling technique, stability, logistics, and potential application in low-resource settings. PMID- 25688939 TI - New York City Panel on Climate Change 2015 Report introduction. PMID- 25688937 TI - Impact of defined clinical population and missing data on temporal trends in HIV viral load estimation within a health care system. AB - OBJECTIVES: Community viral load (CVL) estimates vary based on analytic methods. We extended the CVL concept and used data from the Veterans Health Administration (VA) to determine trends in the health care system viral load (HSVL) and its sensitivity to varying definitions of the clinical population and assumptions regarding missing data. METHODS: We included HIV-infected patients in the Veterans Aging Cohort Study, 2000-2010, with at least one documented CD4 count, HIV-1 RNA or antiretroviral prescription (n = 37 318). We created 6-month intervals including patients with at least one visit in the past 2 years. We assessed temporal trends in clinical population size, patient clinical status and mean HSVL and explored the impact of varying definitions of the clinical population and assumptions about missing viral load. RESULTS: The clinical population size varied by definition, increasing from 16 000-19 000 patients in 2000 to 23 000-26 000 in 2010. The proportion of patients with suppressed HIV-1 RNA increased over time. Over 20% of patients had no viral load measured in a given interval or the past 2 years. Among patients with a current HIV-1 RNA, mean HSVL decreased from 97 800 HIV-1 RNA copies/mL in 2000 to 2000 copies/mL in 2010. When current HIV-1 RNA data were unavailable and the HSVL was recalculated using the last available HIV-1 RNA, HSVL decreased from 322 300 to 9900 copies/mL. HSVL was underestimated when using only current data in each interval. CONCLUSIONS: The CVL concept can be applied to a health care system, providing a measure of health care quality. Like CVL, HSVL estimates depend on definitions of the clinical population and assumptions about missing data. PMID- 25688940 TI - Foreword to Building the Knowledge Base for Climate Resiliency: New York City Panel on Climate Change 2015 Report. PMID- 25688941 TI - Preface to Building the Knowledge Base for Climate Resiliency: New York City Panel on Climate Change 2015 Report. PMID- 25688942 TI - New York City Panel on Climate Change 2015 Report. Executive summary. PMID- 25688943 TI - New York City Panel on Climate Change 2015 Report. Chapter 1: Climate observations and projections. PMID- 25688944 TI - New York City Panel on Climate Change 2015 Report. Chapter 2: Sea level rise and coastal storms. PMID- 25688945 TI - New York City Panel on Climate Change 2015 Report. Chapter 3: Static coastal flood mapping. PMID- 25688946 TI - New York City Panel on Climate Change 2015 Report. Chapter 4: Dynamic coastal flood modeling. PMID- 25688948 TI - New York City Panel on Climate Change 2015 Report. Chapter 6: Indicators and monitoring. PMID- 25688947 TI - New York City Panel on Climate Change 2015 Report. Chapter 5: Public health impacts and resiliency. PMID- 25688949 TI - New York City Panel on Climate Change 2015 Report. Conclusions and recommendations. PMID- 25688950 TI - Appendix I: Climate risk and projections NPCC 2015 infographics. PMID- 25688951 TI - Appendix II: NPCC 2015 technical details. PMID- 25688952 TI - Internet support for ?point-of-care testing in primary care. AB - One of the few and largest randomised controlled trials of point-of-care testing (PoCT) in general practice was conducted in Australia. This trial showed PoCT provided the same or better clinical effectiveness than central laboratory testing for HbA1c, urinary albumin/creatinine ratio, cholesterol and triglyceride measurements but not for the international normalised ratio (INR) or high-density lipoprotein (HDL) cholesterol. For most tests, however, testing in the central laboratory was more cost-effective than PoCT. One factor that contributed to the higher cost of PoCT was the considerable amount of resources devoted to training and monitoring the PoCT operators throughout the trial, many of whom were in remote locations. PMID- 25688953 TI - Travel advice and vaccination. AB - Over the decade to June 2014, the number of annual short-term resident departures from Australia more than doubled, from 3.9 million to 8.9 million per year. A large number of these journeys involved destinations with known risk of exposure to vector-borne and enteric diseases. Many of these disease risks are preventable if travellers seek advice about the areas they choose to visit, and are vaccinated in the appropriate time frame before their departure. Vaccination is an essential component of national control of travel-associated infectious diseases. General practitioners (GPs) are well-placed to inform patients about potential disease risks in their intended travel regions and to vaccinate patients before their departure. PMID- 25688954 TI - Medical tourism. AB - BACKGROUND: Medical tourism is a burgeoning industry in our region. It involves patients travelling outside of their home country for medical treatment. OBJECTIVE: This article provides an outline of the current research around medical tourism, especially its impact on Australians. DISCUSSION: Patients are increasingly seeking a variety of medical treatments abroad, particularly those involving cosmetic surgery and dental treatment, often in countries in South-East Asia. Adverse events may occur during medical treatment abroad, which raises medico-legal and insurance issues, as well as concerns regarding follow-up of patients. General practitioners need to be prepared to offer advice, including travel health advice, to patients seeking medical treatment abroad. PMID- 25688955 TI - Heat illnesses: a hot topic in the setting of global climate change. AB - BACKGROUND: Heat illnesses affect a large number of people every year and are becoming an increasing cause of pathology as climate change results in increasing global temperatures. OBJECTIVE: This article will review the physiological responses to heat, as well as the pathophysiological processes that result in heat illnesses. The emphasis will be on providing general practitioners (GPs) with an understanding of how to prevent heat illness in their patients and how to predict who is most at risk. DISCUSSION: Heat illnesses may be thought of as minor or major illnesses, any of which may present to the GP. Consideration must be given to identifying those who need more critical intervention and on when to transfer for higher-level of care. PMID- 25688956 TI - Marine envenomations. AB - BACKGROUND: Marine stings are common but most are minor and do not require medical intervention. Severe and systemic marine envenoming is uncommon, but includes box jellyfish stings, Irukandji syndrome, major stingray trauma and blue ringed octopus envenoming. Almost all marine injuries are caused by jellyfish stings, and penetrating injuries from spiny fish, stingrays or sea urchins. OBJECTIVE: This article describes the presentation and management of marine envenomations and injuries that may occur in Australia. DISCUSSION: First aid for jellyfish includes tentacle removal, application of vinegar for box jellyfish, and hot water immersion (45 degrees C for 20 min) for bluebottle jellyfish stings. Basic life support is essential for severe marine envenomings that result in cardiac collapse or paralysis. Irukandji syndrome causes severe generalised pain, autonomic excess and minimal local pain, which may require large amounts of analgesia, and, uncommonly, myocardial depression and pulmonary oedema occur. Penetrating marine injuries can cause significant trauma depending on location of the injury. Large and unclean wounds may have delayed healing and secondary infection if not adequately irrigated, debrided and observed. PMID- 25688957 TI - Advising travellers about management of travellers' diarrhoea. AB - BACKGROUND: Travellers' diarrhoea (TD) affects a large proportion of international travellers. These people will often present to general practice for advice before they travel. OBJECTIVE: This article will review the current concepts and practical issues for advising people planning to travel about their risks of TD and how to manage symptoms if they develop during the trip. DISCUSSION: Avoidance, immunisation, non-antibiotic interventions and antibiotic prophylaxis are all methods for preventing TD. However, advice regarding self management through rehydration, antibiotic treatment and appropriate seeking of medical advice are most important. PMID- 25688958 TI - Interventions to improve adherence to exercise for chronic musculoskeletal pain in adults. AB - BACKGROUND: This article is facilitated by the Australian Cochrane Musculoskeletal Group (CMSG) editorial base. The CMSG is one of the largest Cochrane review groups and produces reliable, up-to-date systematic reviews of interventions for the prevention, treatment or rehabilitation of musculoskeletal disorders. OBJECTIVE: Our aim is to place the findings of recent Cochrane musculoskeletal reviews in a context immediately relevant to general practitioners (GPs) by summarising the findings of a review of interventions to improve adherence to exercise for adults with chronic musculoskeletal pain (CMP). DISCUSSION: The findings indicate that there are various strategies that may be effective in increasing adherence to exercise and physical activity in patients suffering from CMP. These strategies are discussed in detail and general practice scenarios are presented to show how the results can be applied in practice. PMID- 25688959 TI - Diverse presentations of acral melanoma. AB - BACKGROUND: Acral melanoma (AM) is an uncommon melanoma subtype occurring on the palms, soles and nail apparatus. It often lacks the typical features of primary melanoma resulting in delayed diagnosis. OBJECTIVE: This article aims to raise awareness of AM and promote a high index of clinical suspicion to enable early diagnosis and improve outcomes for patients with AM. DISCUSSION: The diagnosis of AM is often delayed because its presentation mimics other benign conditions such as fungal infections and ulcers. When lesions that were thought to be benign fail to respond to appropriate therapies, biopsy is critically important to exclude AM or other malignant pathology. Clinician awareness of the diversity of AM presentations, maintaining AM as part of their differential diagnosis and facilitating early biopsy are essential for early diagnosis and improving outcomes in patients with AM. PMID- 25688960 TI - Investigation and management of an ovarian mass. AB - BACKGROUND: Ovarian masses are very common in pre- and postmenopausal women and are typically an incidental finding. OBJECTIVE: This article aims to provide a systematic approach to an ovarian mass for general practitioners including investigations, risk of ovarian cancer and referral considerations. DISCUSSION: Investigation for an ovarian mass includes both transvaginal and transabdominal ultrasound. Simple, anechoic cysts 200. Complications of ovarian cysts include cyst rupture and torsion. Torsion is a gynaecological emergency and requires urgent review. PMID- 25688961 TI - Ketoacidosis in a patient with type 2 diabetes - flatbush diabetes. AB - There is increasing recognition of a group of patients with type 2 diabetes who can present with ketoacidosis. Most reports have been of patients of African descent; however, the condition has been reported in other groups. This is a case of a Caucasian patient who has had three presentations with ketoacidosis and whose diabetes is not usually insulin-dependent. PMID- 25688962 TI - Dirt-like hyperpigmented plaques on the face. PMID- 25688963 TI - Nail and oral cavity pigmentation. PMID- 25688964 TI - A challenging case of chronic diarrhoea. PMID- 25688965 TI - Utilisation of co-testing ?(human papillomavirus DNA testing and cervical cytology) after treatment of CIN: - a survey of GPs' awareness and knowledge. AB - BACKGROUND: Patients have an increased risk of persistent/recurrent cervical disease if they received treatment for a high-grade squamous intraepithelial lesion (HSIL). Consequently, understanding whether co-testing (human papillomavirus [HPV] DNA testing and cervical cytology) is fully utilised by general practitioners (GPs) is paramount. METHODS: After consultation with key stakeholders, an anonymous, self-completion questionnaire was developed and disseminated to GPs who had provided cervical cytology. RESULTS: Responses were received from 745 GPs (30.9% response rate). A significant number (34.3%) of GPs were unaware of the use of co-testing (HPV DNA testing and cervical cytology) for the management of patients after HSIL treatment. Additionally, the majority of GPs reported they did not 'always' receive a clear follow-up plan for patients after treatment of an HSIL. DISCUSSION: GPs require further support and education to ensure successful adoption of co-testing (HPV DNA testing and cervical cytology), specifically, for patients treated for an HSIL. PMID- 25688966 TI - Hepatitis C polymerase chain reaction testing by GPs. AB - BACKGROUND: Approximately 75% of patients exposed to the hepatitis C virus will become chronically infected. Polymerase chain reaction (PCR) testing more than 6 months after exposure is necessary to identify this group. This pilot study assessed the practical ap-plication of PCR testing in the general practice context. METHODS: General practitioners of patients newly notified as positive for hepatitis C antibody between 1 August 2007 and 1 August 2012 were invited to participate. They completed a self-administered survey, recording details on the use of hepatitis C PCR testing in their patients. RESULTS: The survey found that 16 patients (46%) did not undergo any PCR testing for hepatitis C. Of those who underwent PCR testing, 11 (58%) were positive on PCR testing but only six (55%) of those with a positive PCR test were retested 6 months later. DISCUSSION: Appropriate use of PCR is necessary to identify patients with chronic hepatitis C and offer appropriate referral and treatment. PMID- 25688967 TI - General practice service use and satisfaction among female survivors of childhood sexual abuse. AB - BACKGROUND: Because childhood sexual abuse (CSA) and adult violence are associated with poorer physical and mental health of women, our aim was to investigate the associations between CSA, adult violence experiences and general practice service use and satisfaction in a community sample of Australian women aged 28-33 years. METHODS: Data of 9058 women from the 1973-78 cohort who completed Survey 4 of the Australian Longitudinal Study on Women's Health were analysed. RESULTS: Logistic regressions conducted indicated that after controlling for demographic variables, women with experiences of lifetime violence were more likely to have higher general practice service use compared to those without violence experiences. CSA was not associated with an increase in service use but was significantly associated with a decrease in service satisfaction. This find-ing remained significant even when they visited the general practice more frequently. DISCUSSION: Implementing trauma-informed care is suggested as a way to improve the satisfaction of this patient group with complex needs. PMID- 25688968 TI - A is for aphorisms - feed a fever, starve a cold? Or could it be starve a fever, feed a cold? AB - The recommendations for management of fever have changed throughout the course of history, as has the very concept of fever. It has changed from something viewed as a diagnosis in its own right to a sign of something to be measured and as a trigger for a diagnostic trail to be made. PMID- 25688969 TI - Lithium-sulfur batteries: progress and prospects. AB - Development of advanced energy-storage systems for portable devices, electric vehicles, and grid storage must fulfill several requirements: low-cost, long life, acceptable safety, high energy, high power, and environmental benignity. With these requirements, lithium-sulfur (Li-S) batteries promise great potential to be the next-generation high-energy system. However, the practicality of Li-S technology is hindered by technical obstacles, such as short shelf and cycle life and low sulfur content/loading, arising from the shuttling of polysulfide intermediates between the cathode and anode and the poor electronic conductivity of S and the discharge product Li2 S. Much progress has been made during the past five years to circumvent these problems by employing sulfur-carbon or sulfur polymer composite cathodes, novel cell configurations, and lithium-metal anode stabilization. This Progress Report highlights recent developments with special attention toward innovation in sulfur-encapsulation techniques, development of novel materials, and cell-component design. The scientific understanding and engineering concerns are discussed at the end in every developmental stage. The critical research directions needed and the remaining challenges to be addressed are summarized in the Conclusion. PMID- 25688970 TI - Genomic characterization of novel circular ssDNA viruses from insectivorous bats in Southern Brazil. AB - Circoviruses are highly prevalent porcine and avian pathogens. In recent years, novel circular ssDNA genomes have recently been detected in a variety of fecal and environmental samples using deep sequencing approaches. In this study the identification of genomes of novel circoviruses and cycloviruses in feces of insectivorous bats is reported. Pan-reactive primers were used targeting the conserved rep region of circoviruses and cycloviruses to screen DNA bat fecal samples. Using this approach, partial rep sequences were detected which formed five phylogenetic groups distributed among the Circovirus and the recently proposed Cyclovirus genera of the Circoviridae. Further analysis using inverse PCR and Sanger sequencing led to the characterization of four new putative members of the family Circoviridae with genome size ranging from 1,608 to 1,790 nt, two inversely arranged ORFs, and canonical nonamer sequences atop a stem loop. PMID- 25688971 TI - Environmental isolation of Cryptococcus gattii VGII from indoor dust from typical wooden houses in the deep Amazonas of the Rio Negro basin. AB - Cryptococcosis is a human fungal infection of significant mortality and morbidity, especially in the meningoencephalitis form. Cryptococcosis is distributed worldwide and its agents, C. neoformans and C. gattii, present eight major molecular types-VNI-VNIV and VGI-VGIV respectively. The primary cryptococcosis caused by molecular type VGII (serotype B, MAT alpha) prevails in immunocompetent patients in the North and Northeast of Brazil, revealing an endemic regional pattern to this molecular type. Since 1999, C. gattii VGII has been involved in an ongoing outbreak in Canada, and is expanding to the Northwest of the United States, two temperate regions. Exposure to propagules dispersed in the environment, related to various organic substrates, mainly decomposing wood in and around dwellings, initiates the infection process. The present study investigated the presence of the agents of cryptococcosis in dust from dwellings in the upper Rio Negro, municipality of Santa Isabel do Rio Negro in Amazonas state. Indoor dust was collected from 51 houses, diluted and plated on bird seed agar. Dark brown colonies were identified phenotypically, and genotypically by URA5 restriction fragment length polymorphism analysis and multilocus sequence typing (MLST). The mating type was identified using pheromone-specific primers. Three of the 51 houses were positive for C. gattii molecular type VGII, MATalpha and MATa, showing a high prevalence of this agent. MLST studies identified eight subtypes, VGIIb (ST7), VGIIa (ST20), (ST5) and 5 new subtypes unique to the region. For the first time in the state of Amazonas, C. gattii VGII MATalpha and MATa were isolated from the environment and correlates with endemic cryptococcosis in this state. This is the first description of MLST subtypes on environmental isolates in the Brazilian Amazon, indicating domiciliary dust as a potential source for human infection with different subtypes of C. gattii VGII MATalpha and MATa. PMID- 25688972 TI - Excitability changes in intracortical neural circuits induced by differentially controlled walking patterns. AB - Our previous single-pulse transcranial magnetic stimulation (TMS) study revealed that excitability in the motor cortex can be altered by conscious control of walking relative to less conscious normal walking. However, substantial elements and underlying mechanisms for inducing walking-related cortical plasticity are still unknown. Hence, in this study we aimed to examine the characteristics of electromyographic (EMG) recordings obtained during different walking conditions, namely, symmetrical walking (SW), asymmetrical walking 1 (AW1), and asymmetrical walking 2 (AW2), with left to right stance duration ratios of 1:1, 1:2, and 2:1, respectively. Furthermore, we investigated the influence of three types of walking control on subsequent changes in the intracortical neural circuits. Prior to each type of 7-min walking task, EMG analyses of the left tibialis anterior (TA) and soleus (SOL) muscles during walking were performed following approximately 3 min of preparative walking. Paired-pulse TMS was used to measure short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF) in the left TA and SOL at baseline, immediately after the 7-min walking task, and 30 min post-task. EMG activity in the TA was significantly increased during AW1 and AW2 compared to during SW, whereas a significant difference in EMG activity of the SOL was observed only between AW1 and AW2. As for intracortical excitability, there was a significant alteration in SICI in the TA between SW and AW1, but not between SW and AW2. For the same amount of walking exercise, we found that the different methods used to control walking patterns induced different excitability changes in SICI. Our research shows that activation patterns associated with controlled leg muscles can alter post-exercise excitability in intracortical circuits. Therefore, how leg muscles are activated in a clinical setting could influence the outcome of walking in patients with stroke. PMID- 25688973 TI - How the brain analyzes object shape to support grasping behavior. PMID- 25688974 TI - Lrp4 domains differentially regulate limb/brain development and synaptic plasticity. AB - Apolipoprotein E (ApoE) genotype is the strongest predictor of Alzheimer's Disease (AD) risk. ApoE is a cholesterol transport protein that binds to members of the Low-Density Lipoprotein (LDL) Receptor family, which includes LDL Receptor Related Protein 4 (Lrp4). Lrp4, together with one of its ligands Agrin and its co receptors Muscle Specific Kinase (MuSK) and Amyloid Precursor Protein (APP), regulates neuromuscular junction (NMJ) formation. All four proteins are also expressed in the adult brain, and APP, MuSK, and Agrin are required for normal synapse function in the CNS. Here, we show that Lrp4 is also required for normal hippocampal plasticity. In contrast to the closely related Lrp8/Apoer2, the intracellular domain of Lrp4 does not appear to be necessary for normal expression and maintenance of long-term potentiation at central synapses or for the formation and maintenance of peripheral NMJs. However, it does play a role in limb development. PMID- 25688975 TI - Transgenic and mutation-based suppression of a berberine bridge enzyme-like (BBL) gene family reduces alkaloid content in field-grown tobacco. AB - Motivation exists to develop tobacco cultivars with reduced nicotine content for the purpose of facilitating compliance with expected tobacco product regulations that could mandate the lowering of nicotine levels per se, or the reduction of carcinogenic alkaloid-derived tobacco specific nitrosamines (TSNAs). A berberine bridge enzyme-like (BBL) gene family was recently characterized for N. tabacum and found to catalyze one of the final steps in pyridine alkaloid synthesis for this species. Because this gene family acts downstream in the nicotine biosynthetic pathway, it may represent an attractive target for genetic strategies with the objective of reducing alkaloid content in field-grown tobacco. In this research, we produced transgenic doubled haploid lines of tobacco cultivar K326 carrying an RNAi construct designed to reduce expression of the BBL gene family. Field-grown transgenic lines carrying functional RNAi constructs exhibited average cured leaf nicotine levels of 0.684%, in comparison to 2.454% for the untransformed control. Since numerous barriers would need to be overcome to commercialize transgenic tobacco cultivars, we subsequently pursued a mutation breeding approach to identify EMS-induced mutations in the three most highly expressed isoforms of the BBL gene family. Field evaluation of individuals possessing different homozygous combinations of truncation mutations in BBLa, BBLb, and BBLc indicated that a range of alkaloid phenotypes could be produced, with the triple homozygous knockout genotype exhibiting greater than a 13-fold reduction in percent total alkaloids. The novel source of genetic variability described here may be useful in future tobacco breeding for varied alkaloid levels. PMID- 25688976 TI - Encapsulation of an interpenetrated diamondoid inorganic building block in a metal-organic framework. AB - The first example of an inorganic-organic composite framework with an interpenetrated diamondoid inorganic building block, featuring unique {InNa}n helices and {In12 Na16 } nano-rings, has been constructed and structurally characterized. This framework also represents a unique example of encapsulation of an interpenetrated diamondoid inorganic building block in a metal-organic framework. PMID- 25688977 TI - Importance of a nanoscience approach in the understanding of major aqueous contamination scenarios: case study from a recent coal ash spill. AB - A coal ash spill that occurred from an ash impoundment pond into the Dan River, North Carolina, provided a unique opportunity to study the significance and role of naturally occurring and incidental nanomaterials associated with contaminant distribution from a large-scale, acute aquatic contamination event. Besides traditional measurements of bulk watercolumn and sediment metal concentrations, the nanoparticle (NP) analyses are based on cross-flow ultrafiltration (CFUF) and advanced transmission electron microscopy (TEM) techniques. A drain pipe fed by coal ash impoundment seepage showed a high level of arsenic, with concentrations many times over the EPA limit. The majority of the arsenic was found sorbed to large aggregates dominated by incidental iron oxyhydroxide (ferrihydrite) NPs, while the remainder of the arsenic was truly dissolved. These ferrihydrites were probably formed in situ where Fe(II) was leached through subsurface flowpaths into an aerobic environment, and further act as a significant contributor to the elevated As concentrations in downstream sediments after the spill. In addition, we discovered and describe a photocatalytic nano-TiO2 phase (anatase) present in the coal ash impacted river water that was also carrying/transporting transition metals (Cu, Fe), which may also have environmental consequences. PMID- 25688978 TI - Life Event Stress and Binge Eating Among Adolescents: The Roles of Early Maladaptive Schemas and Impulsivity. AB - This study examined the relationships between life event stress, early maladaptive schemas, impulsivity and binge eating among adolescents and investigated the effects of early maladaptive schemas and impulsivity on the relationship between life event stress and binge eating. Specifically, we examined a moderated mediation model in which early maladaptive schemas mediated this relationship and impulsivity moderated the mediation effect. Life event stress, early maladaptive schemas, impulsivity and binge eating were investigated in a sample of 2172 seventh-, eighth- and tenth-grade middle and high school students (mean age = 14.55 years, standard deviation = 1.29). The results indicated that adolescents with greater life event stress, more early maladaptive schemas and higher levels of impulsivity displayed more severe binge eating. In addition, early maladaptive schemas mediated the relationship between life event stress and binge eating, while impulsivity moderated this relationship. Furthermore, impulsivity also moderated the mediation effect of early maladaptive schemas; as impulsivity levels increased, the strength of the association between life event stress and early maladaptive schemas increased. This study illustrates the importance of understanding individual differences and their effects on the relationship between life event stress and binge eating. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 25688979 TI - The role of student surgical interest groups and surgical Olympiads in anatomical and surgical undergraduate training in Russia. AB - Traditional department-based surgical interest groups in Russian medical schools are useful tools for student-based selection of specialty training. They also form a nucleus for initiating research activities among undergraduate students. In Russia, the Departments of Topographical Anatomy and Operative Surgery play an important role in initiating student-led research and providing learners with advanced, practical surgical skills. In tandem with department-led activities, student surgical interest groups prepare learners through surgical competitions, known as "Surgical Olympiads," which have been conducted in many Russian centers on a regular basis since 1988. Surgical Olympiads stimulate student interest in the development of surgical skills before graduation and encourage students to choose surgery as their postgraduate specialty. Many of the participants in these surgical Olympiads have become highly qualified specialists in general surgery, orthopedic surgery, neurosurgery, urology, gynecology, and emergency medicine. The present article emphasizes the role of student interest groups and surgical Olympiads in clinical anatomical and surgical undergraduate training in Russia. PMID- 25688980 TI - Examining levels of risk behaviors among black men who have sex with Men (MSM) and the association with HIV acquisition. AB - Seroadaptation is defined as the practice of modifying sexual behavior based on one's own HIV serostatus, the perceived HIV serostatus of sexual partners, and differences in risk of HIV transmission by sexual acts. Because this definition implies intent, we use the term "seroprotection" to describe HIV negative participants reporting condomless anal sex (CAS) either exclusively with seronegative partners, or only as the insertive partner with HIV positive or unknown serostatus partners. Little is known about seroprotection in Black men who have sex with men (MSM). We evaluated the independent association of seroprotection and HIV acquisition among the 1144 HIV-negative Black MSM enrolled in HPTN 061 using Cox models; we stratified by city of enrollment, and controlled for number of partners, age, and drug use. Behaviors reported at 0, 6, and 12 months were assigned to three mutually exclusive categories: (1) No CAS; (2) Seroprotection; and (3) CAS without seroprotection. In 2,861 six-month intervals; 28 HIV seroconversions occurred. No CAS was reported at 33.3% of visits, seroprotection at 46.6% of visits, and CAS without seroprotection at 20.1% of visits. The seroconversion rate per 100 person-years for no CAS was 0.98 (95% CI: 0.27, 2.51), compared with 2.39 (95% CI: 1.03, 4.71) and 13.33 (95% CI: 7.62, 21.66) for seroprotection and CAS without seroprotection, respectively. Compared to CAS without seroprotection, intervals without CAS were associated with an 87% reduction (aHR: 0.13, 95% CI: 0.03-0.46) in HIV acquisition and intervals with seroprotection with a 78% reduction (aHR: 0.22, 95% CI: 0.09-0.57). No CAS is the safest behavior to prevent HIV acquisition. Seroprotective behaviors significantly reduced risk, but HIV incidence was still >2/100 person-years, suggesting that additional strategies, such as pre-exposure prophylaxis, are warranted for this population. PMID- 25688981 TI - Next-generation sequencing identifies deregulation of microRNAs involved in both innate and adaptive immune response in ALK+ ALCL. AB - Anaplastic large cell lymphoma (ALCL) is divided into two systemic diseases according to the expression of the anaplastic lymphoma kinase (ALK). We investigated the differential expression of miRNAs between ALK+ ALCL, ALK- ALCL cells and normal T-cells using next generation sequencing (NGS). In addition, a C/EBPbeta-dependent miRNA profile was generated. The data were validated in primary ALCL cases. NGS identified 106 miRNAs significantly differentially expressed between ALK+ and ALK- ALCL and 228 between ALK+ ALCL and normal T cells. We identified a signature of 56 miRNAs distinguishing ALK+ ALCL, ALK- ALCL and T-cells. The top candidates significant differentially expressed between ALK+ and ALK- ALCL included 5 upregulated miRNAs: miR-340, miR-203, miR-135b, miR-182, miR-183; and 7 downregulated: miR-196b, miR-155, miR-146a, miR-424, miR-503, miR 424*, miR-542-3p. The miR-17-92 cluster was also upregulated in ALK+ cells. Additionally, we identified a signature of 3 miRNAs significantly regulated by the transcription factor C/EBPbeta, which is specifically overexpressed in ALK+ ALCL, including the miR-181 family. Of interest, miR-181a, which regulates T-cell differentiation and modulates TCR signalling strength, was significantly downregulated in ALK+ ALCL cases. In summary, our data reveal a miRNA signature linking ALK+ ALCL to a deregulated immune response and may reflect the abnormal TCR antigen expression known in ALK+ ALCL. PMID- 25688982 TI - Reply: DBS with versus without MER: clinical equipoise or malpractice? PMID- 25688983 TI - Vocal traits and diet explain avian sensitivities to anthropogenic noise. AB - Global population growth has caused extensive human-induced environmental change, including a near-ubiquitous transformation of the acoustical environment due to the propagation of anthropogenic noise. Because the acoustical environment is a critical ecological dimension for countless species to obtain, interpret and respond to environmental cues, highly novel environmental acoustics have the potential to negatively impact organisms that use acoustics for a variety of functions, such as communication and predator/prey detection. Using a comparative approach with 308 populations of 183 bird species from 14 locations in Europe, North American and the Caribbean, I sought to reveal the intrinsic and extrinsic factors responsible for avian sensitivities to anthropogenic noise as measured by their habitat use in noisy versus adjacent quiet locations. Birds across all locations tended to avoid noisy areas, but trait-specific differences emerged. Vocal frequency, diet and foraging location predicted patterns of habitat use in response to anthropogenic noise, but body size, nest placement and type, other vocal features and the type of anthropogenic noise (chronic industrial vs. intermittent urban/traffic noise) failed to explain variation in habitat use. Strongly supported models also indicated the relationship between sensitivity to noise and predictive traits had little to no phylogenetic structure. In general, traits associated with hearing were strong predictors - species with low frequency vocalizations, which experience greater spectral overlap with low frequency anthropogenic noise tend to avoid noisy areas, whereas species with higher frequency vocalizations respond less severely. Additionally, omnivorous species and those with animal-based diets were more sensitive to noise than birds with plant-based diets, likely because noise may interfere with the use of audition in multimodal prey detection. Collectively, these results suggest that anthropogenic noise is a powerful sensory pollutant that can filter avian communities nonrandomly by interfering with birds' abilities to receive, respond to and dispatch acoustic cues and signals. PMID- 25688984 TI - Tips and tricks in endoscopic papillectomy of ampullary tumors: single-center experience with large case series (with videos). AB - Endoscopic papillectomy (EP) has been recognized as a safe and reliable treatment for ampullary adenomas. In this article, we describe important tips and tricks in EP of ampullary tumors on the basis of our large case series outcome. Between May 1999 and April 2014, 115 patients underwent EP at Tokyo Medical University hospital. The mean tumor diameter was 16.2 (6-35) mm. The final pathological diagnoses were adenoma, cancer in adenoma, cancer, and hyperplasia in 85, 13, 10, and seven patients, respectively. "En bloc" or "piecemeal" EP was performed with a polypectomy snare forceps using "Endocut(r) mode". Prophylactic pancreatic duct stents were placed after EP. Consequently, a single treatment session was possible in 93 (80.9%) patients. Additional treatment was required in the remaining 22 (19.1%) patients. For these 22 patients, the postresection pathological diagnoses were adenoma in 15 patients and cancer in seven patients. Two patients with cancer and venous permeation required surgical operation. The final complete resection rate was 98.2%. Several complications observed included pancreatitis (10.4%), bleeding (18.2%), perforation (2.6%), cholangitis (1.7%), and papillary stenosis (4.3%). One patient died of procedure-related complications. In conclusion, endoscopic papillectomy showed a high technical success rate. However, possible complications and occasional fatal complications should be considered when using EP. PMID- 25688985 TI - New insights into the methodology of L-arginine-induced acute pancreatitis. AB - Animal models are ideal to study the pathomechanism and therapy of acute pancreatitis (AP). The use of L-arginine-induced AP model is nowadays becoming increasingly popular in mice. However, carefully looking through the literature, marked differences in disease severity could be observed. In fact, while setting up the L-arginine (2*4 g/kg i.p.)-induced AP model in BALB/c mice, we found a relatively low rate (around 15%) of pancreatic necrosis, whereas others have detected much higher rates (up to 55%). We suspected that this may be due to differences between mouse strains. We administered various concentrations (5-30%, pH = 7.4) and doses (2*4, 3*3, or 4*2.5 g/kg) of L-arginine-HCl in BALB/c, FVB/n and C57BL/6 mice. The potential gender-specific effect of L-arginine was investigated in C57BL/6 mice. The fate of mice in response to the i.p. injections of L arginine followed one of three courses. Some mice (1) developed severe AP or (2) remained AP-free by 72 h, whereas others (3) had to be euthanized (to avoid their death, which was caused by the high dose of L-arginine and not AP) within 12 h., In FVB/n and C57BL/6 mice, the pancreatic necrosis rate (about 50%) was significantly higher than that observed in BALB/c mice using 2*4 g/kg 10% L arginine, but euthanasia was necessary in a large proportion of animals, The i.p. injection of lower L-arginine concentrations (e.g. 5-8%) in case of the 2*4 g/kg dose, or other L-arginine doses (3*3 or 4*2.5 g/kg, 10%) were better for inducing AP. We could not detect any significant differences between the AP severity of male and female mice. Taken together, when setting up the L-arginine-induced AP model, there are several important factors that are worth consideration such as the dose and concentration of the administered L arginine-HCl solution and also the strain of mice. PMID- 25688986 TI - The HIV-1 Gp120/CXCR4 axis promotes CCR7 ligand-dependent CD4 T cell migration: CCR7 homo- and CCR7/CXCR4 hetero-oligomer formation as a possible mechanism for up-regulation of functional CCR7. AB - During human immunodeficiency virus (HIV) infection, enhanced migration of infected cells to lymph nodes leads to efficient propagation of HIV-1. The selective chemokine receptors, including CXCR4 and CCR7, may play a role in this process, yet the viral factors regulating chemokine-dependent T cell migration remain relatively unclear. The functional cooperation between the CXCR4 ligand chemokine CXCL12 and the CCR7 ligand chemokines CCL19 and CCL21 enhances CCR7 dependent T cell motility in vitro as well as cell trafficking into the lymph nodes in vivo. In this study, we report that a recombinant form of a viral CXCR4 ligand, X4-tropic HIV-1 gp120, enhanced the CD4 T cell response to CCR7 ligands in a manner dependent on CXCR4 and CD4, and that this effect was recapitulated by HIV-1 virions. HIV-1 gp120 significantly enhanced CCR7-dependent CD4 T cell migration from the footpad of mice to the draining lymph nodes in in vivo transfer experiments. We also demonstrated that CXCR4 expression is required for stable CCR7 expression on the CD4 T cell surface, whereas CXCR4 signaling facilitated CCR7 ligand binding to the cell surface and increased the level of CCR7 homo- as well as CXCR4/CCR7 hetero-oligomers without affecting CCR7 expression levels. Our findings indicate that HIV-evoked CXCR4 signaling promotes CCR7-dependent CD4 T cell migration by up-regulating CCR7 function, which is likely to be induced by increased formation of CCR7 homo- and CXCR4/CCR7 hetero oligomers on the surface of CD4 T cells. PMID- 25688987 TI - Lin28a protects against cardiac ischaemia/reperfusion injury in diabetic mice through the insulin-PI3K-mTOR pathway. AB - The insulin-PI3K-mTOR pathway exhibits a variety of cardiovascular activities including protection against I/R injury. Lin28a enhanced glucose uptake and insulin-sensitivity via insulin-PI3K-mTOR signalling pathway. However, the role of lin28a on experimental cardiac I/R injury in diabetic mice are not well understood. Diabetic mice underwent 30 min. of ischaemia followed by 3 hrs of reperfusion. Animals were randomized to be treated with lentivirus carrying lin28a siRNA (siLin28a) or lin28a cDNA (Lin28a) 72 hrs before coronary artery ligation. Myocardial infarct size (IS), cardiac function, cardiomyocyte apoptosis and mitochondria morphology in diabetic mice who underwent cardiac I/R injury were compared between groups. The target proteins of lin28a were examined by western blot analysis. Lin28a overexpression significantly reduced myocardial IS, improved LV ejection fraction (LVEF), decreased myocardial apoptotic index and alleviated mitochondria cristae destruction in diabetic mice underwent cardiac I/R injury. Lin28a knockdown exacerbated cardiac I/R injury as demonstrated by increased IS, decreased LVEF, increased apoptotic index and aggravated mitochondria cristae destruction. Interestingly, pre-treatment with rapamycin abolished the beneficial effects of lin28a overexpression. Lin28a overexpression increased, while Lin28a knockdown decreased the expression of IGF1R, p-Akt, p mTOR and p-p70s6k after cardiac I/R injury in diabetic mice. Rapamycin pre treatment abolished the effects of increased p-mTOR and p-p70s6k expression exerted by lin28a overexpression. This study indicates that lin28a overexpression reduces IS, improves cardiac function, decreases cardiomyocyte apoptosis index and alleviates cardiomyocyte mitochondria impairment after cardiac I/R injury in diabetic mice. The mechanism responsible for the effects of lin28a is associated with the insulin-PI3K-mTOR dependent pathway. PMID- 25688988 TI - Density functional theory and hydrogen bonds: are we there yet? AB - Density functional theory (DFT) has become more successful at introducing dispersion interactions, and can be thus applied to a wide range of systems. Amongst these are systems that contain hydrogen bonds, which are extremely important for the biological regime. Here, the description of hydrogen-bonded interactions by DFT with and without dispersion corrections is investigated. For small complexes, for which electrostatics are the determining factor in the intermolecular interactions, the inclusion of dispersion with most functionals yields large errors. Only for larger systems, in which van der Waals interactions are more important, do dispersion corrections improve the performance of DFT for hydrogen-bonded systems. None of the studied functionals, including double hybrid functionals (with the exception of DSD-PBEP86 without dispersion corrections), are more accurate than MP2 for the investigated species. PMID- 25688989 TI - Rhodium(II) metallopeptide catalyst design enables fine control in selective functionalization of natural SH3 domains. AB - Chemically modified proteins are increasingly important for use in fundamental biophysical studies, chemical biology, therapeutic protein development, and biomaterials. However, chemical methods typically produce heterogeneous labeling and cannot approach the exquisite selectivity of enzymatic reactions. While bioengineered methods are sometimes an option, selective reactions of natural proteins remain an unsolved problem. Here we show that rhodium(II) metallopeptides combine molecular recognition with promiscuous catalytic activity to allow covalent decoration of natural SH3 domains, depending on choice of catalyst but independent of the specific residue present. A metallopeptide catalyst succeeds in modifying a single SH3-containing kinase at endogenous concentrations in prostate cancer (PC-3) cell lysate. PMID- 25688990 TI - Gambling in the Czech Republic. AB - AIM: To provide an overview of gambling and associated problems in the Czech Republic, including an overview of the historical context, legislation, prevalence, treatment and research base and agenda. METHODS: A review of literature and relevant sources. RESULTS: The trajectory of gambling patterns in the territory of the Czech Republic in the 20th century reflected broad socio political changes. Those included significant expansion between the wars, strict state control and bans on some gambling activities during the communist regime and finally dynamic development characterized by a boom in electronic gaming machines (EGMs) and increasing accessibility of gambling facilities after 1989, which aggravated gambling-related problems. Many municipalities have banned EGMs, which has created conflict in regulation at state and municipal levels. The draft gambling law prepared in 2014 aims to clarify the regulatory framework. Before 2012 there was only sporadic research interest in gambling, but in 2012 the first complex research on gaming and problem gambling in the Czech population took place. The estimated prevalence of problem gambling is currently 2% in the population aged 15-64 years. Preventive measures, counselling and treatment services for problem gamblers are limited. CONCLUSIONS: Weak and ineffective regulation of the gambling market in the Czech Republic during the past 20 years, despite the large growth in gambling, has led to inadequate prevention and response to problem gambling which has become a considerable public health, social and political issue. PMID- 25688991 TI - Diabetes mellitus and its association with central obesity and disability among older adults: a global perspective. AB - The aim of the study was to evaluate the association between various factors and diabetes type II (DM) with a particular emphasis on indicators of central obesity, and to compare the effect of DM on disability among elder populations (>= 50 years old) in nine countries. Data were available for 52,946 people aged >= 18 years who participated in the WHO Study on global AGEing and adult health and the Collaborative Research on Ageing in Europe studies conducted between 2007 and 2012. DM was defined as self-report of physician diagnosis. Height, weight, and waist circumference were measured. Disability status was assessed with the WHODAS II questionnaire. The overall prevalence of DM was 7.9% and ranged from 3.8% (Ghana) to 17.6% (Mexico). A 10 cm increase in waist circumference and waist to-height ratio of >0.5 were associated with a significant 1.26 (India) to 1.77 (Finland), and 1.68 (China, Spain) to 5.40 (Finland) times higher odds for DM respectively. No significant associations were observed in Mexico and South Africa. DM was associated with significantly higher disability status in all countries except Mexico in the model adjusted for demographics and smoking. The inclusion of chronic conditions associated with diabetes in the model attenuated the coefficients in varying degrees depending on the country. A considerable proportion of the studied older population had DM. Central obesity may be a key factor for the prevention of DM among older populations globally. Prevention of DM especially among the older population globally may contribute to reducing the burden of disability. PMID- 25688992 TI - Growth-dependent photoinactivation kinetics of Enterococcus faecalis. AB - AIMS: To investigate how the growth stage of Enterococcus faecalis affects its photoinactivation in clear water. METHODS AND RESULTS: Enterococcus faecalis were grown in batch cultures to four different growth stages or grown in chemostats set at four different dilution rates, then harvested and exposed to full spectrum or UVB-blocked simulated sunlight. Experiments were conducted in triplicate in clear water with no added sensitizers. Decay curves were shoulder-log linear and were generally not statistically different in experiments conducted under full spectrum light. Shoulders were longer and first order inactivation rates smaller when experiments were seeded with cells grown to stationary as compared to exponential phase, and for slower growing cells when experiments were done under UVB-blocked light. Chemostat-sourced bacteria generally showed less variability among replicates than batch-sourced cells. CONCLUSIONS: The physiological state of cells and the method via which they are being generated may affect the photoinactivation experimental results. SIGNIFICANCE AND IMPACT OF THE STUDY: Photoinactivation experiments conducted with exponential phase cells may overestimate the photoinactivation kinetics in the environment, particular if UVB independent mechanisms predominate. Chemostat-sourced cells are likely to provide more consistent experimental results than batch-sourced cells. PMID- 25688993 TI - Differential effects of glucagon-like peptide-1 on microvascular recruitment and glucose metabolism in short- and long-term insulin resistance. AB - KEY POINTS: Acute glucagon-like peptide-1 (GLP-1) infusion reversed the high fat diet-induced microvascular insulin resistance that occurred after both 5 days and 8 weeks of a high fat diet intervention. When GLP-1 was co-infused with insulin it had overt effects on whole body insulin sensitivity as well as insulin mediated skeletal muscle glucose uptake after 5 days of a high fat diet, but not after 8 weeks of high fat diet intervention. Acute GLP-1 infusion did not have an additive effect to that of insulin on microvascular recruitment or skeletal muscle glucose uptake in the control group. Here we demonstrate that GLP-1 potently increases the microvascular recruitment in rat skeletal muscle but does not increase glucose uptake in the fasting state. Thus, like insulin, GLP-1 increased the microvascular recruitment but unlike insulin, GLP-1 had no direct effect on skeletal muscle glucose uptake. ABSTRACT: Acute infusion of glucagon like peptide-1 (GLP-1) has potent effects on blood flow distribution through the microcirculation in healthy humans and rats. A high fat diet induces impairments in insulin-mediated microvascular recruitment (MVR) and muscle glucose uptake, and here we examined whether this could be reversed by GLP-1. Using contrast enhanced ultrasound, microvascular recruitment was assessed by continuous real time imaging of gas-filled microbubbles in the microcirculation after acute (5 days) and prolonged (8 weeks) high fat diet (HF)-induced insulin resistance in rats. A euglycaemic hyperinsulinaemic clamp (3 mU min(-1) kg(-1) ), with or without a co-infusion of GLP-1 (100 pmol l(-1) ), was performed in anaesthetized rats. Consumption of HF attenuated the insulin-mediated MVR in both 5 day and 8 week HF interventions which was associated with a 50% reduction in insulin mediated glucose uptake compared to controls. Acute administration of GLP-1 restored the normal microvascular response by increasing the MVR after both 5 days and 8 weeks of HF intervention (P < 0.05). This effect of GLP-1 was associated with a restoration of both whole body insulin sensitivity and increased insulin-mediated glucose uptake in skeletal muscle by 90% (P < 0.05) after 5 days of HF but not after 8 weeks of HF. The present study demonstrates that GLP-1 increases MVR in rat skeletal muscle and can reverse early stages of high fat diet-induced insulin resistance in vivo. PMID- 25688994 TI - Spicing up endogenous neural stem cells: aromatic-turmerone offers new possibilities for tackling neurodegeneration. AB - There is a growing interest in the therapeutic utility of compounds derived from Curcuma longa, an herb of the Zingiberaceae family that has been part of traditional medicine for centuries. Recent reports suggest that bioactive compounds isolated from the rhizome of these plants can address two key aspects of brain injury following stroke that must be dealt with for functional recovery to occur: the moderation of neuroinflammation, and the mobilization of endogenous stem cells resident in the nervous system. Defining their mechanism of action remains a question, but emerging evidence may point towards one shared with more classic modulators of neural stem cell proliferation and survival. PMID- 25688995 TI - Comparison of the genotoxic effects induced by 50 Hz extremely low-frequency electromagnetic fields and 1800 MHz radiofrequency electromagnetic fields in GC-2 cells. AB - Extremely low-frequency electromagnetic fields (ELF-EMF) and radiofrequency electromagnetic fields (RF-EMF) have been considered to be possibly carcinogenic to humans. However, their genotoxic effects remain controversial. To make experiments controllable and results comparable, we standardized exposure conditions and explored the potential genotoxicity of 50 Hz ELF-EMF and 1800 MHz RF-EMF. A mouse spermatocyte-derived GC-2 cell line was intermittently (5 min on and 10 min off) exposed to 50 Hz ELF-EMF at an intensity of 1, 2 or 3 mT or to RF EMF in GSM-Talk mode at the specific absorption rates (SAR) of 1, 2 or 4 W/kg. After exposure for 24 h, we found that neither ELF-EMF nor RF-EMF affected cell viability using Cell Counting Kit-8. Through the use of an alkaline comet assay and immunofluorescence against gamma-H2AX foci, we found that ELF-EMF exposure resulted in a significant increase of DNA strand breaks at 3 mT, whereas RF-EMF exposure had insufficient energy to induce such effects. Using a formamidopyrimidine DNA glycosylase (FPG)-modified alkaline comet assay, we observed that RF-EMF exposure significantly induced oxidative DNA base damage at a SAR value of 4 W/kg, whereas ELF-EMF exposure did not. Our results suggest that both ELF-EMF and RF-EMF under the same experimental conditions may produce genotoxicity at relative high intensities, but they create different patterns of DNA damage. Therefore, the potential mechanisms underlying the genotoxicity of different frequency electromagnetic fields may be different. PMID- 25688996 TI - Pathology of fractionated whole-brain irradiation in rhesus monkeys ( Macaca mulatta ). AB - Fractionated whole-brain irradiation (fWBI), used to treat brain metastases, often leads to neurologic injury and cognitive impairment. The cognitive effects of irradiation in nonhuman primates (NHP) have been previously published; this report focuses on corresponding neuropathologic changes that could have served as the basis for those effects in the same study. Four rhesus monkeys were exposed to 40 Gy of fWBI [5 Gy * 8 fraction (fx), 2 fx/week for four weeks] and received anatomical MRI prior to, and 14 months after fWBI. Neurologic and histologic sequelae were studied posthumously. Three of the NHPs underwent cognitive assessments, and each exhibited radiation-induced impairment associated with various degrees of vascular and inflammatory neuropathology. Two NHPs had severe multifocal necrosis of the forebrain, midbrain and brainstem. Histologic and MRI findings were in agreement, and the severity of cognitive decrement previously reported corresponded to the degree of observed pathology in two of the animals. In response to fWBI, the NHPs showed pathology similar to humans exposed to radiation and show comparable cognitive decline. These results provide a basis for implementing NHPs to examine and treat adverse cognitive and neurophysiologic sequelae of radiation exposure in humans. PMID- 25688997 TI - Attention modeled as information in learning multisensory integration. AB - Top-down cognitive processes affect the way bottom-up cross-sensory stimuli are integrated. In this paper, we therefore extend a successful previous neural network model of learning multisensory integration in the superior colliculus (SC) by top-down, attentional input and train it on different classes of cross modal stimuli. The network not only learns to integrate cross-modal stimuli, but the model also reproduces neurons specializing in different combinations of modalities as well as behavioral and neurophysiological phenomena associated with spatial and feature-based attention. Importantly, we do not provide the model with any information about which input neurons are sensory and which are attentional. If the basic mechanisms of our model-self-organized learning of input statistics and divisive normalization-play a major role in the ontogenesis of the SC, then this work shows that these mechanisms suffice to explain a wide range of aspects both of bottom-up multisensory integration and the top-down influence on multisensory integration. PMID- 25688998 TI - Early-adolescents' reading comprehension and the stability of the middle school classroom-language environment. AB - This study examined teachers' language use across the school year in 6th grade urban middle-school classrooms (n = 24) and investigated the influence of this classroom-based linguistic input on the reading comprehension skills of the students (n = 851; 599 language minority learners and 252 English-only) in the participating classrooms. Analysis of speech transcripts revealed substantial variability in teachers' use of sophisticated vocabulary and total amount of talk and that individual teacher's language use was consistent across the school year. Analyses using Hierarchical Linear Modeling showed that when controlling for students' reading comprehension and vocabulary knowledge at the start of the year, teachers' use of sophisticated vocabulary was significantly related to students' reading comprehension outcomes, as was the time spent on vocabulary instruction. These findings suggest that the middle school classroom language environment plays a significant role in the reading comprehension of adolescent learners. PMID- 25688999 TI - Multiple aspects of self-regulation uniquely predict mathematics but not letter word knowledge in the early elementary grades. AB - The relation of self-regulation measured prior to school entry to developing math and reading ability in prekindergarten through the second grade was examined in a prospective longitudinal sample of 1,292 children and families in predominantly rural and low-income communities in 2 regions of high poverty in the United States. Direct assessments of executive function, effortful control, and stress response physiology (indexed by resting levels of cortisol and alpha amylase obtained from saliva) were measured at child age 48 months and parents and teachers reported on children's effortful control using temperament rating scales at child age approximately 60 months. Math and reading ability, as measured by the Woodcock-Johnson III applied problems and letter-word subtests, respectively, were measured at prekindergarten through the second grade. Effects for self regulation measures were seen primarily for initial level and to some extent growth in both mathematics and reading, even when controlling for family demographic characteristics that represent relevant selection factors into higher levels of both self-regulation and academic achievement. These effects persisted for mathematics but not for reading with the inclusion of child cognitive abilities, vocabulary, and speed of processing measured in prekindergarten, concurrent with the first time point for the academic measures. Results are interpreted as indicating a role for self-regulation in learning ability generally, likely through support for attention and reasoning abilities that are most specific to the assessment of mathematics in this analysis. Implications for instruction and for assessment and the best ways to support the development of early math and reading ability for children at risk for school failure are discussed. PMID- 25689000 TI - Infants' social and motor experience and the emerging understanding of intentional actions. AB - During the first year of life, infants possess some of the key social-cognitive abilities required for success in a social world: Infants interpret others' actions in terms of their intentions and can use this understanding prospectively to generate predictions about others' behavior. Exactly how these foundational abilities develop is currently unknown. The goal of this study was to shed light on the developmental mechanisms underlying changes in infants' understanding of intentional actions by documenting relations between infants' intention understanding and other emerging social (joint attention) and motor (means-end and self-locomotion) abilities. Using eye tracking, 8- to 11-month-olds infants' (N = 80) ability to visually predict the goal of an ongoing successful or failed intentional action was examined in relation to their developing means-end, self locomotion, and joint attention abilities. Results confirmed previous findings showing improvements in infants' ability to interpret and make predictions about others' failed intentional actions. Importantly, results also indicated that parent-report measures of infants' initiating-joint-attention and self-locomotion abilities were associated with the ability to visually predict the outcome of a failed reaching action. These data support the view that infants' social and motor experiences may contribute to changes in their social-cognitive abilities. In particular, joint-attentive social interactions that occur with increasing frequency as infants learn to crawl and walk may shape infants' understanding of others as intentional agents. PMID- 25689001 TI - Verbal and nonverbal cognitive control in bilinguals and interpreters. AB - The present study explored the relation between language control and nonverbal cognitive control in different bilingual populations. We compared monolinguals, Dutch-French unbalanced bilinguals, balanced bilinguals, and interpreters on the Simon task (Simon & Rudell, 1967) and the Attention Network Test (ANT; Fan, McCandliss, Sommer, Raz, & Posner, 2002). All bilingual groups showed a smaller congruency effect in the Simon task than the monolingual group. They were also faster overall in the ANT. Furthermore, interpreters outperformed unbalanced, but not balanced, bilinguals in terms of overall accuracy on both tasks. In the ANT, the error congruency effect was significantly smaller for interpreters and balanced bilinguals. Using a measure of switching fluency in language production, this study also found direct evidence for a relation between language control and executive control. This relation was only observed in balanced bilinguals, where fluent switching was correlated with the Simon effect. These findings support the existence of a bilingual advantage and also indicate that different patterns of bilingual language use modulate the nature and extent of a cognitive control advantage in multilingual populations. PMID- 25689002 TI - Expectations and experience: Dissociable bases for cognitive control? AB - Classic theories emphasized the role of expectations in the intentional control of attention and action. However, recent theorizing has implicated experience dependent, online adjustments as the primary basis for cognitive control- adjustments that appear to be implicit (Blais, Harris, Guerrero, & Bunge, 2012). The purpose of the current study was to evaluate whether explicit expectations play any role in cognitive control above and beyond experience. In a novel precued lists paradigm, participants were administered abbreviated lists of Stroop trials. For half of the lists, precues led participants to validly expect lists of varying proportion congruency (e.g., mostly congruent [MC], mostly incongruent [MI]; Experiments 1 to 4). The Stroop effect was greater in cued MC relative to uncued MC lists. By contrast, the Stroop effect was equivalent in cued MI and uncued MI lists. Only when preparation was encouraged via a speed manipulation (Experiment 3) or incentives (Experiment 4) did we find evidence of heightened control when an MI list was expected, in the form of a short-lived reduction in the Stroop effect on the first (experience-free) trial. These patterns suggest (a) expectations play a role in the relaxation of cognitive control, independent of experience (as also shown in Experiment 5, wherein expectations were varied while holding experience constant across lists), but (b) experience is the dominant basis for the sustained heightening of cognitive control (after the first trial). Theoretical implications of dissociating the contributions of expectations and experience to cognitive control are discussed, including interpretations of the list-wide proportion congruence effect. PMID- 25689005 TI - [The physician's different roles and responsibility for the patient's medication list]. AB - A common understanding of roles and responsibilities regarding both individual prescriptions and the patient's full list of treatments, including the responsibility for monitoring of treatment, is necessary to have for physicians treating the same patient. Qualitative studies of attitudes expressed by Swedish physicians have identified at least four different roles of a physician when prescribing drugs. A model on how to share responsibility in different situations of drug prescribing is described. The described model on how to share responsibilities between different physicians treating the same patient with drugs constitutes the basis for a joint recommendation by the Swedish Medical Association and the network of Swedish Drug and Therapeutics Committees. PMID- 25689006 TI - [PCSK9 inhibition--A new era in cholesterol treatment]. AB - The discovery of PCSK9 and its function in liver homeostasis has led to new therapeutic possibilities for blood cholesterol lowering. Three monoclonal antibodies are under clinical investigation in Sweden and internationally. Subcutaneous injections of the substance with 2 to 4 weeks interval decrease LDL cholesterol by 60 to 70 percent. Side effects are few. Special target groups for therapy should be patients with familial hypercholesterolaemia, who do not reach treatment targets on conventional statin therapy and statin intolerant patients. The treatment may result in subphysiological LDL cholesterol levels. Special programs have been developed for monitoring potential risks with very low LDL cholesterol levels. All three PCSK9 inhibitors are presently undergoing interventional studies with hard clinical endpoints. The first PCSK9 inhibitor is supposed to reach the market in 2015. PMID- 25689007 TI - [GallRiks 10 years. Quality registry for gallstone surgery have improved health care]. AB - The Swedish Registry for cholecystectomy and endoscopic retrograde cholangiopancreatography (ERCP) (GallRiks) is a validated register with high coverage. The registry started on May 1, 2005 and serves as a base for audit on gallstone disease treatment and also provides a database for clinical research. The aim of this study is to present an overview of the clinical consequences and implementations in patient care that GallRiks research may have contributed to during a 10-year period. Results from studies on GallRiks data have reduced the use of antibiotic and thromboembolic prophylaxis as well as showed the importance of intraoperative cholangiography. Furthermore, the studies on GallRiks data have most probably changed the treatment strategies in ERCP. Studies on GallRiks data have changed and improved the management of patients in Sweden who undergo gallstone surgery or ERCP. PMID- 25689008 TI - [Consideration on this side of the double-blind to re-establish the therapeutic meeting]. PMID- 25689009 TI - [The art of practising private care in a vulnerable neighborhood. "With the business itself at the center"]. PMID- 25689011 TI - [In Process Citation]. PMID- 25689010 TI - [Accidental fall and care]. PMID- 25689012 TI - [Licorice--so much more than candy]. PMID- 25689013 TI - [In Process Citation]. PMID- 25689014 TI - [Reply from the Public Health Agency: Important first step to estimate the cost of resistance]. PMID- 25689015 TI - [Large differences in blood pressure treatment in diabetes]. PMID- 25689016 TI - [The Swedish Society of Medicine and the Swedish Medical Association: We call for a regulated and quality assured continuing education]. PMID- 25689017 TI - Cutting the Gordian helix--regulating genomic testing in the era of precision medicine. PMID- 25689018 TI - Sodium triflate decreases interaggregate repulsion and induces phase separation in cationic micelles. AB - Dodecyltrimethylammonium triflate (DTATf) micelles possess lower degree of counterion dissociation (alpha), lower hydration, and higher packing of monomers than other micelles of similar structure. Addition of sodium triflate ([NaTf] > 0.05 M) to DTATf solutions promotes phase separation. This phenomenon is commonly observed in oppositely charged surfactant mixtures, but it is rare for ionic surfactants and relatively simple counterions. While the properties of DTATf have already been reported, the driving forces for the observed phase separation with added salt remain unclear. Thus, we propose an interpretation for the observed phase separation in cationic surfactant solutions. Addition of up to 0.03 M NaTf to micellar DTATf solutions led to a limited increase of the aggregation number, to interface dehydration, and to a progressive decrease in alpha. The viscosity of DTATf solutions of higher concentration ([DTATf] >= 0.06 M) reached a maximum with increasing [NaTf], though the aggregation number slightly increased, and no shape change occurred. We hypothesize that this maximum results from a decrease in interaggregate repulsion, as a consequence of increased ion binding. This reduction in micellar repulsion without simultaneous infinite micellar growth is, probably, the major driving force for phase separation at higher [NaTf]. PMID- 25689019 TI - Pharmacological stress is required for the anti-alcohol effect of the alpha3beta4* nAChR partial agonist AT-1001. AB - Alcohol and nicotine are often taken together. The mechanisms underlying this frequent co-abuse are not well known. Genetic and pharmacological evidence suggests that the nicotinic acetylcholine receptors (nAChRs) containing the alpha3 and beta4 subunits play a role in alcohol as well as nicotine addiction. AT-1001 is a high affinity alpha3beta4 nAChR partial agonist recently found to block nicotine self-administration and relapse-like behavior in rats. Here, to study the involvement of alpha3beta4 nAChRs in the mechanisms that regulate alcohol abuse we evaluated the effects of AT-1001 on alcohol taking and seeking in Sprague-Dawley rats. AT-1001 reduced operant alcohol self-administration at the highest dose examined (3.0 mg/kg), an effect also observed for food self administration. A dose of 1.5 mg/kg AT-1001, which had no effect on alcohol or food self-administration, essentially eliminated reinstatement of alcohol seeking induced by yohimbine (0.625 mg/kg) whereas, reinstatement induced by alcohol associated cues was not altered, nor did AT-1001 induce reinstatement of extinguished self-administration on its own. Finally, AT-1001 showed an anxiolytic activity when measured in the presence or absence of yohimbine stress in the elevated plus maze paradigm. Together, these observations do not support a specific involvement of the alpha3beta4 nAChR in mediating alcohol reward or cue induced relapse to alcohol seeking but rather indicate that the alpha3beta4 nAChR partial agonism may constitute an attractive approach for treating alcohol use disorders exacerbated by elevated stress response. PMID- 25689020 TI - Acute Liver Failure and Hepatic Encephalopathy After Cleft Palate Repair. AB - Paracetamol is the most commonly used analgesic after cleft palate repair. It has rarely caused acute hepatic failure at therapeutic or supratherapeutic doses. Only one case of therapeutic paracetamol toxicity after cleft palate repair had been reported previously. Here, we present a similar patient who developed acute liver failure and hepatic encephalopathy after an uncomplicated cleft palate surgery. Lack of large prospective trials in young children due to ethical concerns increases the value of the case reports of acetaminophen toxicity at therapeutic doses. The dosing recommendations of paracetamol may need to be reconsidered after cleft palate surgery. PMID- 25689021 TI - Msb2 is a Ste11 membrane concentrator required for full activation of the HOG pathway. AB - The high osmolarity glycerol (HOG) pathway, composed of membrane-associated osmosensors, adaptor proteins and core signaling kinases, is essential for the survival of yeast cells under hyper-osmotic stress. Here, we studied how the MAPKKK Ste11 might change its protein interaction profile during acute stress exposure, with an emphasis on the sensory system of the so-called Sho1/Msb2 signaling branch. To characterize the transience of protein-protein interactions we utilized a recently described enzymatic in vivo protein proximity assay (M track). Accordingly, interaction signals between Ste11 and many of its signaling partners can already be detected even under basal conditions. In most cases these signals increase after stress induction. All the interactions are completely dependent on the function of the Ste11-adaptor protein Ste50. Moreover, the presence of either Msb2 or Hkr1 is necessary for observing the interaction between Ste11 and scaffolding factors such as Sho1 and Pbs2. Additional assays suggest that Msb2 is not only in close proximity to Ste11 but might function as an individual Ste11 concentrator at the plasma membrane. Our results confirm the existence of negative feedback systems targeting the protein levels of Ste11 and Msb2 and also hint at changes in the dissociation rates of intermediate signaling complexes. PMID- 25689022 TI - Nitrogen loss by anaerobic oxidation of ammonium in rice rhizosphere. AB - Anaerobic oxidation of ammonium (anammox) is recognized as an important process for nitrogen (N) cycling, yet its role in agricultural ecosystems, which are intensively fertilized, remains unclear. In this study, we investigated the presence, activity, functional gene abundance and role of anammox bacteria in rhizosphere and non-rhizosphere paddy soils using catalyzed reporter deposition fluorescence in situ hybridization, isotope-tracing technique, quantitative PCR assay and 16S rRNA gene clone libraries. Results showed that rhizosphere anammox contributed to 31-41% N2 production with activities of 0.33-0.64 nmol N2 g(-1) soil h(-1), whereas the non-rhizosphere anammox bacteria contributed to only 2-3% N2 production with lower activities of 0.08-0.26 nmol N2 g(-1) soil h(-1). Higher anammox bacterial cells were observed (0.75-1.4 * 10(7) copies g(-1) soil) in the rhizosphere, which were twofold higher compared with the non-rhizosphere soil (3.7-5.9 * 10(6) copies g(-1) soil). Phylogenetic analysis of the anammox bacterial 16S rRNA genes indicated that two genera of 'Candidatus Kuenenia' and 'Candidatus Brocadia' and the family of Planctomycetaceae were identified. We suggest the rhizosphere provides a favorable niche for anammox bacteria, which are important to N cycling, but were previously largely overlooked. PMID- 25689023 TI - Positive selection is the main driving force for evolution of citrus canker causing Xanthomonas. AB - Understanding the evolutionary history and potential of bacterial pathogens is critical to prevent the emergence of new infectious bacterial diseases. Xanthomonas axonopodis subsp. citri (Xac) (synonym X. citri subsp. citri), which causes citrus canker, is one of the hardest-fought plant bacterial pathogens in US history. Here, we sequenced 21 Xac strains (14 XacA, 3 XacA* and 4 XacA(w)) with different host ranges from North America and Asia and conducted comparative genomic and evolutionary analyses. Our analyses suggest that acquisition of beneficial genes and loss of detrimental genes most likely allowed XacA to infect a broader range of hosts as compared with XacA(w) and XacA*. Recombination was found to have occurred frequently on the relative ancient branches, but rarely on the young branches of the clonal genealogy. The ratio of recombination/mutation rho/theta was 0.0790+/-0.0005, implying that the Xac population was clonal in structure. Positive selection has affected 14% (395 out of 2822) of core genes of the citrus canker-causing Xanthomonas. The genes affected are enriched in 'carbohydrate transport and metabolism' and 'DNA replication, recombination and repair' genes (P<0.05). Many genes related to virulence, especially genes involved in the type III secretion system and effectors, are affected by positive selection, further highlighting the contribution of positive selection to the evolution of citrus canker-causing Xanthomonas. Our results suggest that both metabolism and virulence genes provide advantages to endow XacA with higher virulence and a wider host range. Our analysis advances our understanding of the genomic basis of specialization by positive selection in bacterial evolution. PMID- 25689024 TI - Feeding currents facilitate a mixotrophic way of life. AB - Mixotrophy is common, if not dominant, among eukaryotic flagellates, and these organisms have to both acquire inorganic nutrients and capture particulate food. Diffusion limitation favors small cell size for nutrient acquisition, whereas large cell size facilitates prey interception because of viscosity, and hence intermediately sized mixotrophic dinoflagellates are simultaneously constrained by diffusion and viscosity. Advection may help relax both constraints. We use high-speed video microscopy to describe prey interception and capture, and micro particle image velocimetry (micro-PIV) to quantify the flow fields produced by free-swimming dinoflagellates. We provide the first complete flow fields of free swimming interception feeders, and demonstrate the use of feeding currents. These are directed toward the prey capture area, the position varying between the seven dinoflagellate species studied, and we argue that this efficiently allows the grazer to approach small-sized prey despite viscosity. Measured flow fields predict the magnitude of observed clearance rates. The fluid deformation created by swimming dinoflagellates may be detected by evasive prey, but the magnitude of flow deformation in the feeding current varies widely between species and depends on the position of the transverse flagellum. We also use the near-cell flow fields to calculate nutrient transport to swimming cells and find that feeding currents may enhance nutrient uptake by ~75% compared with that by diffusion alone. We argue that all phagotrophic microorganisms must have developed adaptations to counter viscosity in order to allow prey interception, and conclude that the flow fields created by the beating flagella in dinoflagellates are key to the success of these mixotrophic organisms. PMID- 25689025 TI - The microbe-mediated mechanisms affecting topsoil carbon stock in Tibetan grasslands. AB - Warming has been shown to cause soil carbon (C) loss in northern grasslands owing to accelerated microbial decomposition that offsets increased grass productivity. Yet, a multi-decadal survey indicated that the surface soil C stock in Tibetan alpine grasslands remained relatively stable. To investigate this inconsistency, we analyzed the feedback responses of soil microbial communities to simulated warming by soil transplant in Tibetan grasslands. Whereas microbial functional diversity decreased in response to warming, microbial community structure did not correlate with changes in temperature. The relative abundance of catabolic genes associated with nitrogen (N) and C cycling decreased with warming, most notably in genes encoding enzymes associated with more recalcitrant C substrates. By contrast, genes associated with C fixation increased in relative abundance. The relative abundance of genes associated with urease, glutamate dehydrogenase and ammonia monoxygenase (ureC, gdh and amoA) were significantly correlated with N2O efflux. These results suggest that unlike arid/semiarid grasslands, Tibetan grasslands maintain negative feedback mechanisms that preserve terrestrial C and N pools. To examine whether these trends were applicable to the whole plateau, we included these measurements in a model and verified that topsoil C stocks remained relatively stable. Thus, by establishing linkages between microbial metabolic potential and soil biogeochemical processes, we conclude that long-term C loss in Tibetan grasslands is ameliorated by a reduction in microbial decomposition of recalcitrant C substrates. PMID- 25689026 TI - Microbial community successional patterns in beach sands impacted by the Deepwater Horizon oil spill. AB - Although petroleum hydrocarbons discharged from the Deepwater Horizon (DWH) blowout were shown to have a pronounced impact on indigenous microbial communities in the Gulf of Mexico, effects on nearshore or coastal ecosystems remain understudied. This study investigated the successional patterns of functional and taxonomic diversity for over 1 year after the DWH oil was deposited on Pensacola Beach sands (FL, USA), using metagenomic and 16S rRNA gene amplicon techniques. Gamma- and Alphaproteobacteria were enriched in oiled sediments, in corroboration of previous studies. In contrast to previous studies, we observed an increase in the functional diversity of the community in response to oil contamination and a functional transition from generalist populations within 4 months after oil came ashore to specialists a year later, when oil was undetectable. At the latter time point, a typical beach community had reestablished that showed little to no evidence of oil hydrocarbon degradation potential, was enriched in archaeal taxa known to be sensitive to xenobiotics, but differed significantly from the community before the oil spill. Further, a clear succession pattern was observed, where early responders to oil contamination, likely degrading aliphatic hydrocarbons, were replaced after 3 months by populations capable of aromatic hydrocarbon decomposition. Collectively, our results advance the understanding of how natural benthic microbial communities respond to crude oil perturbation, supporting the specialization-disturbance hypothesis; that is, the expectation that disturbance favors generalists, while providing (microbial) indicator species and genes for the chemical evolution of oil hydrocarbons during degradation and weathering. PMID- 25689027 TI - Expression profiling of the bloom-forming cyanobacterium Nodularia CCY9414 under light and oxidative stress conditions. AB - Massive blooms of toxic cyanobacteria frequently occur in the central Baltic Sea during the summer. In the surface scum, cyanobacterial cells are exposed to high light (HL) intensity, high oxygen partial pressure and other stresses. To mimic these conditions, cultures of Nodularia spumigena CCY9414, which is a strain isolated from a cyanobacterial summer bloom in the Baltic Sea, were incubated at a HL intensity of 1200 MUmol photons m(-2) s(-1) or a combination of HL and increased oxygen partial pressure. Using differential RNA sequencing, we compared the global primary transcriptomes of control and stressed cells. The combination of oxidative and light stresses induced the expression of twofold more genes compared with HL stress alone. In addition to the induction of known stress responsive genes, such as psbA, ocp and sodB, Nodularia cells activated the expression of genes coding for many previously unknown light- and oxidative stress-related proteins. In addition, the expression of non-protein-coding RNAs was found to be stimulated by these stresses. Among them was an antisense RNA to the phycocyanin-encoding mRNA cpcBAC and the trans-encoded regulator of photosystem I, PsrR1. The large genome capacity allowed Nodularia to harbor more copies of stress-relevant genes such as psbA and small chlorophyll-binding protein genes, combined with the coordinated induction of these and many additional genes for stress acclimation. Our data provide a first insight on how N. spumigena became adapted to conditions relevant for a cyanobacterial bloom in the Baltic Sea. PMID- 25689028 TI - Keloidal basal cell carcinoma possibly developed from classical nodulo-ulcerative type of basal cell carcinoma: report of a case. PMID- 25689029 TI - An exploratory study of the views of community pharmacy staff on the management of patients with undiagnosed skin problems. AB - OBJECTIVE: The aim of this study was to explore pharmacist and medicine counter assistant (MCA) perceptions of community pharmacy management of patients presenting with symptomatic skin problems. METHODS: The study involved semi structured telephone interviews with 10 pharmacists and 15 MCAs from seven pharmacies. Interviews focused on perceptions of their role in managing symptomatic skin problems and views on why people sought pharmacy advice and any barriers to management. Advice from the local ethics committee was that approval was not required for the study. We analysed the interviews using the framework approach. KEY FINDING: Pharmacists identified two key themes that defined their role; triage and reassurance. In contrast, MCAs defined their role as information gatherers and independent advisors. Themes identified by both pharmacists and MCAs relating to the use of pharmacy as a source of advice were convenience, the perceived non-serious nature of conditions and inaccessibility of the GP. Additionally, MCAs believed familiarity with the pharmacist was important. Both pharmacists and MCAs identified their lack of dermatological knowledge as a barrier with pharmacists reporting insufficient time to deal effectively with patients. MCAs identified the potential for misdiagnosis by pharmacists as another potential barrier. CONCLUSION: Our findings suggest that the role of pharmacists and MCAs is complementary; MCAs screen and provide the necessary information to pharmacists who then decide upon an appropriate course of action for the patient. Nevertheless, a major barrier to pharmacy-supported self-care of symptomatic skin problems is a perceived lack of knowledge and training in dermatology. PMID- 25689030 TI - Minding and mending the gap: Social psychological interventions to reduce educational disparities. AB - BACKGROUND: Achievement gaps continue to garner a great deal of attention both in academic and in popular circles. Many students continue to struggle despite broad educational reforms aimed at narrowing these gaps in learning and performance. AIMS: In this article, we review a number of social psychological interventions that show promise in reducing gaps in achievement, not by addressing structural barriers to achievement, but by helping students cope with threats to their identity that impair intellectual functioning and motivation. For example, interventions involving meditation, role models, emotional reappraisal, growth mindsets, imagining possible selves, self-affirmations, belongingness and cooperative learning have been shown to ameliorate threats to identity and raise achievement. We describe and evaluate these social psychological interventions. ARGUMENTS: Many achievement gaps involve a psychological predicament: a threat to one's social identity or to one's sense of belonging. Students' implicit theories - how they mind the gap - can act as barriers to their success. By helping students cope with these threats, these theory-based interventions represent a genuine advance in the way schools may reduce gaps in achievement. CONCLUSION: These interventions show how students' educational success depends partly on fluid aspects of context - how tasks are framed, who else is in the room, or what they believe about intelligence. Because of this fluidity, these interventions may not work in all settings. Achievement gaps are ultimately caused by a variety of factors, both objective and subjective that produce inequality. The research reviewed here suggests that even without changes in objective barriers to success, brief psychological interventions can narrow what many see as intractable gaps in academic achievement. PMID- 25689032 TI - Indium(III)-catalyzed knoevenagel condensation of aldehydes and activated methylenes using acetic anhydride as a promoter. AB - The combination of a catalytic amount of InCl3 and acetic anhydride remarkably promotes the Knoevenagel condensation of a variety of aldehydes and activated methylene compounds. This catalytic system accommodates aromatic aldehydes containing a variety of electron-donating and -withdrawing groups, heteroaromatic aldehydes, conjugate aldehydes, and aliphatic aldehydes. Central to successfully driving the condensation series is the formation of a geminal diacetate intermediate, which was generated in situ from an aldehyde and an acid anhydride with the assistance of an indium catalyst. PMID- 25689034 TI - Control of Andreev bound state population and related charge-imbalance effect. AB - Motivated by recent experimental research, we study a superconducting constriction subject to a dc and ac phase bias. We consider the processes whereby the ac drive promotes one quasiparticle from an Andreev bound state to a delocalized state outside the superconducting gap. We demonstrate that with these processes one can control the population of the Andreev bound states in the constriction. We stress an interesting charge asymmetry of these processes that may produce a charge imbalance of accumulated quasiparticles, which depends on the phase. PMID- 25689033 TI - Role of intestinal microbiota in the generation of polyphenol-derived phenolic acid mediated attenuation of Alzheimer's disease beta-amyloid oligomerization. AB - SCOPE: Grape seed polyphenol extract (GSPE) is receiving increasing attention for its potential preventative and therapeutic roles in Alzheimer's disease (AD) and other age-related neurodegenerative disorders. The intestinal microbiota is known to actively convert many dietary polyphenols, including GSPE, to phenolic acids. There is limited information on the bioavailability and bioactivity of GSPE derived phenolic acid in the brain. METHODS AND RESULTS: We orally administered GSPE to rats and investigated the bioavailability of 12 phenolic acids known to be generated by microbiota metabolism of anthocyanidins. GSPE treatment significantly increased the content of two of the phenolic acids in the brain: 3 hydroxybenzoic acid and 3-(3'-hydroxyphenyl)propionic acid, resulting in the brain accumulations of the two phenolic acids at micromolar concentrations. We also provided evidence that 3-hydroxybenzoic acid and 3-(3' hydroxyphenyl)propionic acid potently interfere with the assembly of beta-amyloid peptides into neurotoxic beta-amyloid aggregates that play key roles in AD pathogenesis. CONCLUSION: Our observation suggests important contribution of the intestinal microbiota to the protective activities of GSPE (as well as other polyphenol preparations) in AD. Outcomes from our studies support future preclinical and clinical investigations exploring the potential contributions of the intestinal microbiota in protecting against the onset/progression of AD and other neurodegenerative conditions. PMID- 25689035 TI - A PCR procedure for the detection of Giardia intestinalis cysts and Escherichia coli in lettuce. AB - Giardia intestinalis is a pathogen associated with foodborne outbreaks and Escherichia coli is commonly used as a marker of faecal contamination. Implementation of routine identification methods of G. intestinalis is difficult for the analysis of vegetables and the microbiological detection of E. coli requires several days. This study proposes a PCR-based assay for the detection of E. coli and G. intestinalis cysts using crude DNA isolated from artificially contaminated lettuce. The G. intestinalis and E. coli PCR assays targeted the beta-giardin and uidA genes, respectively, and were 100% specific. Forty lettuces from local markets were analysed by both PCR and light microscopy and no cysts were detected, the calculated detection limit was 20 cysts per gram of lettuce; however, by PCR, E. coli was detected in eight of ten randomly selected samples of lettuce. These data highlight the need to validate procedures for routine quality assurance. These PCR-based assays can be employed as alternative methods for the detection of G. intestinalis and E. coli and have the potential to allow for the automation and simultaneous detection of protozoa and bacterial pathogens in multiple samples. Significance and impact of the study: There are few studies for Giardia intestinalis detection in food because methods for its identification are difficult for routine implementation. Here, we developed a PCR-based method as an alternative to the direct observation of cysts in lettuce by light microscopy. Additionally, Escherichia coli was detected by PCR and the sanitary quality of lettuce was evaluated using molecular and standard microbiological methods. Using PCR, the detection probability of Giardia cysts inoculated onto samples of lettuce was improved compared to light microscopy, with the advantage of easy automation. These methods may be employed to perform timely and affordable detection of foodborne pathogens. PMID- 25689036 TI - Expression of CYP3A4 and CYP3A7 in Human Foetal Tissues and its Correlation with Nuclear Receptors. AB - Previous reports have suggested that the nuclear receptors vitamin D receptor (VDR), peroxisome proliferator-activated receptor alpha (PPARalpha), pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are involved in the regulation of the drug-metabolizing enzyme cytochrome P450 (CYP) 3A4 expression in adults. The aim of this study was to investigate the gene expression of CYP3A4 and the foetal CYP3A7 in human foetal tissues and their relation to gene expression and genetic variations in the nuclear receptors VDR, PPARalpha, PXR and CAR. We determined the relative expression of CYP3A4 and CYP3A7 and these nuclear receptors in foetal livers, intestines and adrenals, using quantitative PCR. In addition, the expression of these enzymes was also analysed in adult liver. There was a high interindividual variability in CYP3A4 and CYP3A7, 49 times and 326 times, respectively. Both CYP3A4 and CYP3A7 had the highest expression in the liver. There were significant correlations (p < 0.001) between the nuclear receptors studied and the expression of CYP3A4 and CYP3A7 in foetal liver, as well as the expression of CYP3A4 in foetal intestine. Polymorphisms in the VDR gene, rs1544410 and rs1523130 (TaqI), in the PXR gene, rs1523130, and in the PPARalpha gene, rs4253728, were not correlated with CYP3A4 or CYP3A7 expression. However, C-homozygous individuals of the TaqI VDR polymorphism had 60% lower VDR gene expression (p < 0.05), than individuals carrying one or two T alleles. In conclusion, differences in the expression of nuclear receptors might determine the variability in CYP3A4 and CYP3A7 expression observed in foetal liver. PMID- 25689037 TI - Teaching children with autism to discriminate the reinforced and nonreinforced responses of others: implications for observational learning. AB - We taught 4 participants with autism to discriminate between the reinforced and nonreinforced responses of an adult model and evaluated the effectiveness of this intervention using a multiple baseline design. During baseline, participants were simply exposed to adult models' correct and incorrect responses and the respective consequences of each. During discrimination training, in the presence of target pictures, we taught participants to imitate the reinforced responses of an adult model and to say "I don't know" when an adult model's response was not reinforced. Test sessions were conducted after baseline, discrimination training, and generalization sessions to measure responding to target pictures in the absence of the model, prompts, and reinforcement. All 4 participants showed acquisition in the discrimination of reinforced and nonreinforced responses of the adult model during test sessions. Generalization to stimuli not associated with training was variable across the 4 participants. Implications for teaching observational learning responses to children with autism are discussed. PMID- 25689038 TI - Resources for Blood Pressure Screening Programs in Low Resource Settings: A Guide From the World Hypertension League. PMID- 25689039 TI - Tooth counts through growth in diapsid reptiles: implications for interpreting individual and size-related variation in the fossil record. AB - Tooth counts are commonly recorded in fossil diapsid reptiles and have been used for taxonomic and phylogenetic purposes under the assumption that differences in the number of teeth are largely explained by interspecific variation. Although phylogeny is almost certainly one of the greatest factors influencing tooth count, the relative role of intraspecific variation is difficult, and often impossible, to test in the fossil record given the sample sizes available to palaeontologists and, as such, is best investigated using extant models. Intraspecific variation (largely manifested as size-related or ontogenetic variation) in tooth counts has been examined in extant squamates (lizards and snakes) but is poorly understood in archosaurs (crocodylians and dinosaurs). Here, we document tooth count variation in two species of extant crocodylians (Alligator mississippiensis and Crocodylus porosus) as well as a large varanid lizard (Varanus komodoensis). We test the hypothesis that variation in tooth count is driven primarily by growth and thus predict significant correlations between tooth count and size, as well as differences in the frequency of deviation from the modal tooth count in the premaxilla, maxilla, and dentary. In addition to tooth counts, we also document tooth allometry in each species and compare these results with tooth count change through growth. Results reveal no correlation of tooth count with size in any element of any species examined here, with the exception of the premaxilla of C. porosus, which shows the loss of one tooth position. Based on the taxa examined here, we reject the hypothesis, as it is evident that variation in tooth count is not always significantly correlated with growth. However, growth trajectories of smaller reptilian taxa show increases in tooth counts and, although current samples are small, suggest potential correlates between tooth count trajectories and adult size. Nevertheless, interspecific variation in growth patterns underscores the importance of considering and understanding growth when constructing taxonomic and phylogenetic characters, in particular for fossil taxa where ontogenetic patterns are difficult to reconstruct. PMID- 25689040 TI - An NHC-catalyzed in situ activation strategy to beta-functionalize saturated carboxylic acid: an enantioselective formal [3+2] annulation for spirocyclic oxindolo-gamma-butyrolactones. AB - An in situ NHC-catalyzed activation strategy to beta-functionalize saturated carboxylic acid was developed. This asymmetric formal [3+2] annulation could deliver spirocyclic oxindolo-gamma-butyrolactones from saturated carboxylic acid and isatin in good yields with high to excellent enantioselectivities. The easy availability of the starting materials, direct installation of functional units at unreactive carbon atom and the convergent assembly make this protocol attractive in the field of organic synthesis. PMID- 25689041 TI - What is cancer nursing research? PMID- 25689042 TI - Malabsorption blood test: Assessing fat absorption in patients with cystic fibrosis and pancreatic insufficiency. AB - The malabsorption blood test (MBT), consisting of pentadecanoic acid (PA), a free fatty acid, and triheptadecanoic acid (THA), a triglyceride that requires pancreatic lipase for absorption of the heptadecanoic acid (HA), was developed to assess fat malabsorption in patients with cystic fibrosis (CF) and pancreatic insufficiency (PI). The objective was to construct a population pharmacokinetic (PK) model to describe PA and HA disposition in healthy subjects and CF subjects. A model was simultaneously fit to PA and HA concentrations, consisting of 1 compartment disposition and a transit model to describe absorption. PA bioavailability estimates for CF subjects without pancreatic enzyme administration (1.07 [0.827, 1.42]) and with enzymes (0.88 [0.72, 1.09]) indicated PA absorption comparable to healthy subjects. HA bioavailability in CF without enzyme administration was 0.0292 (0.0192, 0.0459) and with enzymes increased to 0.606 (0.482, 0.823). In CF, compared with taking enzymes with the MBT, HA bioavailability was further decreased by factors of 0.829 (0.664, 0.979) and 0.78 (0.491, 1.13) with enzymes taken 30 and 60 minutes after MBT, respectively. The MBT detected differences in fat absorption in subjects with CF with and without enzyme administration and with changes in enzyme timing. Future studies will address application of the MBT in CF and other malabsorption diagnoses. PMID- 25689043 TI - A Meier-Gorlin syndrome mutation impairs the ORC1-nucleosome association. AB - Recent studies have identified several genetic mutations within the BAH domain of human Origin Recognition Complex subunit 1 (hORC1BAH), including the R105Q mutation, implicated in Meier-Gorlin Syndrome (MGS). However, the pathological role of the hORC1 R105Q mutation remains unclear. In this study, we have investigated the interactions of the hORC1BAH domain with histone H4K20me2, DNA, and the nucleosome core particle labeled with H4Kc20me2, a chemical analog of H4K20me2. Our study revealed a nucleosomal DNA binding site for hORC1BAH. The R105Q mutation reduces the hORC1BAH-DNA binding affinity, leading to impaired hORC1BAH-nucleosome interaction, which likely influences DNA replication initiation and MGS pathogenesis. This study provides an etiologic link between the hORC1 R105Q mutation and MGS. PMID- 25689044 TI - Contraceptive options for HIV-positive women: making evidence-based, patient centred decisions. AB - OBJECTIVES: Women of reproductive age represent a large proportion of the global population living with HIV/AIDS. With improvements in morbidity and mortality since the advent of combination antiretroviral therapy, contraception and pregnancy planning are an increasingly important issue for women living with HIV. This review aims to outline the key considerations when choosing contraceptive methods in HIV-positive women and provides a review of the literature to inform decision-making. METHODS: Pubmed was searched using the terms 'HIV', 'contraception', 'HIV progression', 'HIV acquisition', 'HIV transmission' and the combination of 'antiretroviral' and 'contraception'. Abstracts were reviewed and relevant articles were retrieved. Reference lists were also reviewed for pertinent citations. RESULTS: HIV and contraceptive methods can interact in several clinically meaningful ways. Concomitant use may result in altered contraceptive efficacy, drug-drug interactions, or increased toxicity. Hormonal contraceptives have not been shown to affect HIV progression. Notably, the impact of hormonal contraceptives on HIV transmission and acquisition remains unclear, particularly for injectable forms. Data are lacking on several newer methods of contraception including contraceptive rings, patches and intrauterine systems. CONCLUSIONS: Effective, reliable contraception is important for HIV-positive women. Efficacy, toxicity, drug interactions, and potential impacts on HIV disease progression, transmission, and acquisition must be assessed when making clinical decisions. PMID- 25689045 TI - Characterization of the native form and the carboxy-terminally truncated halotolerant form of alpha-amylases from Bacillus subtilis strain FP-133. AB - Two amylases, amylase I and amylase II from Bacillus subtilis strain FP-133, were purified to homogeneity and characterized. Their stabilities toward temperature, pH, and organic solvents, and their substrate specificities toward polysaccharides and oligosaccharides were similar. Under moderately high salt conditions, both amylases were more stable than commercial B. licheniformis amylase, and amylase I retained higher amylase activity than amylase II. The N terminal amino acid sequence, genomic southern blot analysis, and MALDI-TOFF-MS analysis indicated that the halotolerant amylase I was produced by limited carboxy-terminal truncation of the amylase II peptide. The deduced amino acid sequence of amylase II was >95% identical to that of previously reported B. subtilis alpha-amylases, but their carboxy-terminal truncation points differed. Three recombinant amylases--full-length amylase corresponding to amylase II, an artificially truncated amylase corresponding to amylase I, and an amylase with a larger artificial C-terminal truncation--were expressed in B. subtilis. The artificially truncated recombinant amylases had the same high amylase activity as amylase I under moderately high salt conditions. Sequence comparisons indicated that an increased ratio of Asp/Glu residues in the enzyme may be one factor responsible for increasing halotolerance. PMID- 25689046 TI - The circadian clock functions as a potent regulator of allergic reaction. AB - Symptoms and laboratory parameters of allergic diseases exhibit prominent ~24-h variations. For instance, in most allergic rhinitis patients, symptoms worsen overnight or early in the morning. Accordingly, there are benefits to nighttime dosing of anti-allergy medications in such patients. Although the circadian pathophysiology of allergic diseases is well documented, the biological basis of this phenomenon remains poorly understood. Recent studies have begun to reveal that the internal timekeeping system termed the circadian clock plays a key role in temporal regulation of allergic reaction, and may therefore underlie the circadian pathophysiology of allergic diseases. Here, we review new knowledge that highlights the emerging role of the circadian clock as a potent regulator of allergic reactions. Given the strong influence of circadian rhythms on allergic diseases, we believe that research on how the time of day impacts allergic reaction which we may call 'chronoallergology' will provide new insight into previously unknown aspects of the biology of allergies. Such knowledge should facilitate novel strategies for prevention and treatment of these diseases. PMID- 25689047 TI - Evaluation of simultaneous nutrient and COD removal with polyhydroxybutyrate (PHB) accumulation using mixed microbial consortia under anoxic condition and their bioinformatics analysis. AB - Simultaneous nitrate-N, phosphate and COD removal was evaluated from synthetic waste water using mixed microbial consortia in an anoxic environment under various initial carbon load (ICL) in a batch scale reactor system. Within 6 hours of incubation, enriched DNPAOs (Denitrifying Polyphosphate Accumulating Microorganisms) were able to remove maximum COD (87%) at 2 g/L of ICL whereas maximum nitrate-N (97%) and phosphate (87%) removal along with PHB accumulation (49 mg/L) was achieved at 8 g/L of ICL. Exhaustion of nitrate-N, beyond 6 hours of incubation, had a detrimental effect on COD and phosphate removal rate. Fresh supply of nitrate-N to the reaction medium, beyond 6 hours, helped revive the removal rates of both COD and phosphate. Therefore, it was apparent that in spite of a high carbon load, maximum COD and nutrient removal can be maintained, with adequate nitrate-N availability. Denitrifying condition in the medium was evident from an increasing pH trend. PHB accumulation by the mixed culture was directly proportional to ICL; however the time taken for accumulation at higher ICL was more. Unlike conventional EBPR, PHB depletion did not support phosphate accumulation in this case. The unique aspect of all the batch studies were PHB accumulation was observed along with phosphate uptake and nitrate reduction under anoxic conditions. Bioinformatics analysis followed by pyrosequencing of the mixed culture DNA from the seed sludge revealed the dominance of denitrifying population, such as Corynebacterium, Rhodocyclus and Paraccocus (Alphaproteobacteria and Betaproteobacteria). Rarefaction curve indicated complete bacterial population and corresponding number of OTUs through sequence analysis. Chao1 and Shannon index (H') was used to study the diversity of sampling. "UCI95" and "LCI95" indicated 95% confidence level of upper and lower values of Chao1 for each distance. Values of Chao1 index supported the results of rarefaction curve. PMID- 25689048 TI - Effective connectivity of depth-structure-selective patches in the lateral bank of the macaque intraparietal sulcus. AB - Extrastriate cortical areas are frequently composed of subpopulations of neurons encoding specific features or stimuli, such as color, disparity, or faces, and patches of neurons encoding similar stimulus properties are typically embedded in interconnected networks, such as the attention or face-processing network. The goal of the current study was to examine the effective connectivity of subsectors of neurons in the same cortical area with highly similar neuronal response properties. We first recorded single- and multi-unit activity to identify two neuronal patches in the anterior part of the macaque intraparietal sulcus (IPS) showing the same depth structure selectivity and then employed electrical microstimulation during functional magnetic resonance imaging in these patches to determine the effective connectivity of these patches. The two IPS subsectors we identified-with the same neuronal response properties and in some cases separated by only 3 mm-were effectively connected to remarkably distinct cortical networks in both dorsal and ventral stream in three macaques. Conversely, the differences in effective connectivity could account for the known visual-to-motor gradient within the anterior IPS. These results clarify the role of the anterior IPS as a pivotal brain region where dorsal and ventral visual stream interact during object analysis. Thus, in addition to the anatomical connectivity of cortical areas and the properties of individual neurons in these areas, the effective connectivity provides novel key insights into the widespread functional networks that support behavior. PMID- 25689049 TI - Time-course effect of electrical stimulation on nerve regeneration of diabetic rats. AB - BACKGROUND: Electrical stimulation (ES) has been shown to promote nerve regeneration in rats with experimental diabetes induced using streptozotocin (STZ). However, the time-course effect of ES on nerve regeneration of diabetic animals has not been reported in previous studies. The present study attempted to examine the effect of different timing of ES after peripheral nerve transection in diabetic rats. METHODOLOGY/FINDINGS: Fifty Sprague-Dawley rats were used in the study. They were classified into five groups. STZ-induced diabetes was created in groups A to D. Normal animals in group E were used as the non-diabetic controls. The sciatic nerve was transected and repaired using a silicone rubber conduit across a 10-mm gap in all groups. Groups A to C received ES for 15 minutes every other day for 2 weeks. Stimulation was initiated on day 1 following the nerve repair for group A, day 8 for group B, and day 15 for group C. The diabetic control group D and the normal control group E received no ES. At 30 days after surgery in group A, histological evaluations showed a higher success percentage of regeneration across the 10-mm nerve gap, and the electrophysiological results showed significantly larger mean values of evoked muscle action potential area and amplitude of the reinnervated gastrocnemius muscle compared with group D. CONCLUSIONS/SIGNIFICANCE: It is concluded that an immediate onset of ES may improve the functional recovery of large nerve defect in diabetic animals. PMID- 25689050 TI - Microbial community dynamics during the bioremediation process of chlorimuron ethyl-contaminated soil by Hansschlegelia sp. strain CHL1. AB - Long-term and excessive application of chlorimuron-ethyl has led to a series of environmental problems. Strain Hansschlegelia sp. CHL1, a highly efficient chlorimuron-ethyl degrading bacterium isolated in our previous study, was employed in the current soil bioremediation study. The residues of chlorimuron ethyl in soils were detected, and the changes of soil microbial communities were investigated by phospholipid fatty acid (PLFA) analysis. The results showed that strain CHL1 exhibited significant chlorimuron-ethyl degradation ability at wide range of concentrations between 10MUg kg-1 and 1000MUg kg-1. High concentrations of chlorimuron-ethyl significantly decreased the total concentration of PLFAs and the Shannon-Wiener indices and increased the stress level of microbes in soils. The inoculation with strain CHL1, however, reduced the inhibition on soil microbes caused by chlorimuron-ethyl. The results demonstrated that strain CHL1 is effective in the remediation of chlorimuron-ethyl-contaminated soil, and has the potential to remediate chlorimuron-ethyl contaminated soils in situ. PMID- 25689051 TI - Beryllium increases the CD14(dim)CD16+ subset in the lung of chronic beryllium disease. AB - CD14dimCD16+ and CD14brightCD16+ cells, which compose a minor population of monocytes in human peripheral blood mononuclear cells (PBMC), have been implicated in several inflammatory diseases. The aim of this study was to investigate whether this phenotype was present as a subset of lung infiltrative alveolar macrophages (AMs) in the granulomatous lung disease, chronic beryllium disease (CBD). The monocytes subsets was determined from PBMC cells and bronchoalveolar lavage (BAL) cells from CBD, beryllium sensitized Non-smoker (BeS NS) and healthy subjects (HS) using flow cytometry. The impact of smoking on the AMs cell phenotype was determined by using BAL cells from BeS smokers (BeS-S). In comparison with the other monocyte subpopulations, CD14dimCD16+ cells were at decreased frequency in PBMCs of both BeS-NS and CBD and showed higher HLA-DR expression, compared to HS. The AMs from CBD and BeS-NS demonstrated a CD14dimCD16+phenotype, while CD14brightCD16+ cells were found at increased frequency in AMs of BeS, compared to HS. Fresh AMs from BeS-NS and CBD demonstrated significantly greater CD16, CD40, CD86 and HLA-DR than HS and BeS-S. The expression of CD16 on AMs from both CBD and BeS-NS was downregulated significantly after 10MUM BeSO4 stimulation. The phagocytic activity of AMs decreased after 10MUM BeSO4 treatment in both BeS-NS and CBD, although was altered or reduced in HS and BeS-S. These results suggest that Be increases the CD14dimCD16+ subsets in the lung of CBD subjects. We speculate that Be-stimulates the compartmentalization of a more mature CD16+ macrophage phenotype and that in turn these macrophages are a source of Th1 cytokines and chemokines that perpetuate the Be immune response in CBD. The protective effect of cigarette smoking in BeS-S may be due to the low expression of co-stimulatory markers on AMs from smokers as well as the decreased phagocytic function. PMID- 25689053 TI - High-performance sodium ion batteries based on a 3D anode from nitrogen-doped graphene foams. AB - A 3D N-doped graphene foam with a 6.8 at% nitrogen content is prepared by annealing a freeze-dried graphene oxide foam in ammonia. It is used as an anode in sodium ion batteries to deliver a high initial reversible capacity of 852.6 mA h g(-1) at 1 C between 0.02 and 3 V with a long-term retention of 69.7% after 150 cycles. PMID- 25689052 TI - Ru-catalysed C-H arylation of indoles and pyrroles with boronic acids: scope and mechanistic studies. AB - The Ru-catalysed C2-H arylation of indoles and pyrroles by using boronic acids under oxidative conditions is reported. This reaction can be applied to tryptophan derivatives and tolerates a wide range of functional groups on both coupling partners, including bromides and iodides, which can be further derivatised selectively. New indole-based ruthenacyclic complexes are described and investigated as possible intermediates in the reaction. Mechanistic studies suggest the on-cycle intermediates do not possess a para-cymene ligand and that the on-cycle metalation occurs through an electrophilic attack by the Ru centre. PMID- 25689054 TI - Mechanism of self-assembly process and seeded supramolecular polymerization of perylene bisimide organogelator. AB - The mechanism of supramolecular polymerization has been elucidated for an archetype organogelator molecule composed of a perylene bisimide aromatic scaffold and two amide substituents. This molecule self-assembles into elongated one-dimensional nanofibers through a cooperative nucleation-growth process. Thermodynamic and kinetic analyses have been applied to discover conditions (temperature, solvent, concentration) where the spontaneous nucleation can be retarded by trapping of the monomers in an inactive conformation, leading to lag times up to more than 1 h. The unique kinetics in the nucleation process was confirmed as a thermal hysteresis in a cycle of assembly and disassembly processes. Under appropriate conditions within the hysteresis loop, addition of preassembled nanofiber seeds leads to seeded polymerization from the termini of the seeds in a living supramolecular polymerization process. These results demonstrate that seeded polymerizations are not limited to special situations where off-pathway aggregates sequester the monomeric reactant species but may be applicable to a large number of known and to be developed molecules from the large family of molecules that self-assemble into one-dimensional nanofibrous structures. Generalizing from the mechanistic insight into our seeded polymerization, we assert that a cooperative nucleation-growth supramolecular polymerization accompanied by thermal hysteresis can be controlled in a living manner. PMID- 25689055 TI - Threshold-free estimation of functional antibody titers of a group B streptococcus opsonophagocytic killing assay. AB - Opsonophagocytic killing assays (OPKA) are routinely used for the quantification of bactericidal antibodies in blood serum samples. Quantification of the OPKA readout, the titer, provides the basis for the statistical analysis of vaccine clinical trials having functional immune response endpoints. Traditional OPKA titers are defined as the maximum serum dilution yielding a predefined bacterial killing threshold value, and they are estimated by fitting a dose-response model to the dilution-killing curve. This paper illustrates a novel definition of titer, the threshold-free titer, which preserves biological interpretability while not depending on any killing threshold or on a postulated shape of the dose response curve. These titers are shown to be more precise than the traditional threshold-based titers when using simulated and experimental group B streptococcus OPKA experimental data. Also, titer linearity is shown to be not measurable when using threshold-based titers, whereas it becomes measurable using threshold-free titers. The biological interpretability and operational characteristics demonstrated here indicate that threshold-free titers are an appropriate tool for the routine analysis of OPKA data. PMID- 25689056 TI - Estimation of organic and elemental carbon emitted from wood burning in traditional and improved cookstoves using controlled cooking test. AB - Emission of various climate- and health-related pollutant species from solid biomass burning in traditional cookstoves is a global concern. Improved cookstoves serve as a possible solution to mitigate the associated impacts. However, there is a need to intensify the efforts in order to increase the data availability and promote revision of existing metrics of cookstove testing. In this study, the effect of different phases of a cooking cycle of Northern India on emission factors of OC and EC (char and soot) was assessed for four cookstoves (advanced, improved, and traditional) using Acacia nilotica. Lowest EFs for OC (0.04 g/MJ) and EC (0.02 g/MJ) were observed in case of the forced draft cookstove; while the traditional and natural draft top feed cookstove emitted the highest OC (0.07 g/MJ) and EC (0.09 g/MJ), respectively. Variation in terms of EFs for OC and EC (char and soot) within the cooking cycle was also found to be significant. PMID- 25689057 TI - How spatial abilities and dynamic visualizations interplay when learning functional anatomy with 3D anatomical models. AB - The emergence of dynamic visualizations of three-dimensional (3D) models in anatomy curricula may be an adequate solution for spatial difficulties encountered with traditional static learning, as they provide direct visualization of change throughout the viewpoints. However, little research has explored the interplay between learning material presentation formats, spatial abilities, and anatomical tasks. First, to understand the cognitive challenges a novice learner would be faced with when first exposed to 3D anatomical content, a six-step cognitive task analysis was developed. Following this, an experimental study was conducted to explore how presentation formats (dynamic vs. static visualizations) support learning of functional anatomy, and affect subsequent anatomical tasks derived from the cognitive task analysis. A second aim was to investigate the interplay between spatial abilities (spatial visualization and spatial relation) and presentation formats when the functional anatomy of a 3D scapula and the associated shoulder flexion movement are learned. Findings showed no main effect of the presentation formats on performances, but revealed the predictive influence of spatial visualization and spatial relation abilities on performance. However, an interesting interaction between presentation formats and spatial relation ability for a specific anatomical task was found. This result highlighted the influence of presentation formats when spatial abilities are involved as well as the differentiated influence of spatial abilities on anatomical tasks. PMID- 25689058 TI - The up-to-date review of epidemiological pancreatic neuroendocrine tumors in Japan. AB - Pancreatic neuroendocrine tumors (PNETs) were considered an extremely rare disease. However, in recent years, the number of patients with PNET has increased rapidly. According to an epidemiological survey conducted in Japan, the number of treated patients with PNETs in 2010 was approximately 1.2-times that in 2005, and the number of new incidences of non-functional PNETs in 2010 was approximately 1.7-times that in 2005. Among functional PNETs, insulinoma was most prevalent, followed by gastrinoma. To diagnose PNETs, correct histological diagnosis is most important. According to the World Health Organization 2010 classification criteria, neuroendocrine tumors (NETs) are categorized into well-differentiated NETs and poorly differentiated neuroendocrine carcinomas (NECs). NECs accounted for 7.6% of all NETs, and functional and non-functional PNETs accounted for 2.1% and 10.1%, respectively. Patients with distant metastasis accounted for 19.9%, and those with multiple endocrine neoplasia type 1 accounted for 4.3%. When treating PNETs, it is necessary to correctly evaluate the functionality and progression of tumors, the presence or absence of metastasis, and the degrees of differentiation and malignant potential of tumors. A new registration system from the Japan Neuroendocrine Tumor Society will start to be used in 2015, which will help further dissemination of Japanese epidemiological information to the world. PMID- 25689059 TI - Long-term Exercise Adherence After High-intensity Interval Training in Cardiac Rehabilitation: A Randomized Study. AB - BACKGROUND AND PURPOSE: Exercise adherence in general is reported to be problematic after cardiac rehabilitation. Additionally, vigorous exercise is associated with impaired exercise adherence. As high-intensity interval training (HIT) is frequently used as a therapy to patients with coronary artery disease in cardiac rehabilitation, the objective was to assess long-term exercise adherence following an HIT cardiac rehabilitation programme. METHODS: A multicentre randomized study was carried out. Eligible participants were adults who had previously attended a 12-week HIT cardiac rehabilitation programme, as either a home-based or hospital-based HIT (treadmill exercise or group exercise). The primary outcome was change in peak oxygen uptake; secondary outcomes were self reported and objectively measured physical activity. RESULTS: Out of 83 eligible participants, 76 were available for assessment (68 men/8 women, mean age 59 (8) years) at a one-year follow-up. Peak oxygen uptake was significantly elevated above baseline values, (treadmill exercise: 35.8 (6.4) vs. 37.4 (7.4) ml kg(-1) min(-1) , group exercise: 32.7 (6.5) vs. 34.1 (5.8) ml kg(-1) min(-1) and home based exercise: 34.5 (4.9) vs. 36.7 (5.8) ml kg(-1) min(-1) at baseline and follow-up, respectively), with no significant differences between groups. The majority of the participants (>90%) met the recommended daily level of 30 minutes of moderate physical activity. The home-based group showed a strong trend towards increased physical activity compared with the hospital-based groups. DISCUSSION: The results from this study have shown that both home-based and hospital-based HIT in cardiac rehabilitation induce promising long-term exercise adherence, with maintenance of peak oxygen uptake significantly above baseline values at a one year follow-up. The implication for physiotherapy practice is that HIT in cardiac rehabilitation induces satisfactory long-term exercise adherence. PMID- 25689060 TI - The spectrum of mutations in Southern Spanish patients with von Willebrand disease. PMID- 25689061 TI - Excessive neural synchrony in Machado-Joseph disease responsive to subthalamic nucleus stimulation. PMID- 25689062 TI - The biophysical properties of Basal lamina gels depend on the biochemical composition of the gel. AB - The migration of cells within a three-dimensional extracellular matrix (ECM) depends sensitively on the biochemical and biophysical properties of the matrix. An example for a biological ECM is given by reconstituted basal lamina gels purified from the Engelbreth-Holm-Swarm sarcoma of mice. Here, we compare four different commercial variants of this ECM, which have all been purified according to the same protocol. Nevertheless, in those gels, we detect strong differences in the migration behavior of leukocyte cells as well as in the Brownian motion of nanoparticles. We show that these differences correlate with the mechanical properties and the microarchitecture of the gels which in turn arise from small variations in their biochemical composition. PMID- 25689063 TI - Significance of tumour cell HLA-G5/-G6 isoform expression in discrimination for adenocarcinoma from squamous cell carcinoma in lung cancer patients. AB - Human leucocyte antigen (HLA)-G has seven isoforms, of which HLA-G1-G4 are membrane-bound and HLA-G5-G7 are soluble. Previous studies reinforced HLA-G expression was strongly related to poor prognosis in different types of cancers. Among these studies, the monoclonal antibody (mAb) 4H84 was used which detects all HLA-G isoform heavy chain; unfortunately, leaves the specific types of isoforms expressed in lesions undistinguished and its clinical significance needs to be clarified. To explore clinical significance of lesion soluble HLA-G (sHLA G) in non-small-cell lung cancer (NSCLC), mAb 5A6G7 recognizing HLA-G5/-G6 molecules was used. Tumour cell sHLA-G expression in 131 primary NSCLC lesions (66 squamous cell carcinoma, 55 adenocarcinoma and 10 adenosquamous carcinoma) were analysed with immunohistochemistry. Data showed that sHLA-G expression was observed in 34.0% (45/131) of the NSCLC lesions, which was unrelated to patient age, sex, lymph nodal status, tumour-node-metastasis stage and patient survival. However, tumour cell sHLA-G expression in lesions was predominately observed in adenocarcinoma lesions (73.0%, 40/55) which was significantly higher than that in squamous cell carcinoma (6.0%, 4/66) and adenosquamous carcinoma lesions (10.0%, 1/10, P < 0.001). The area under the receiver operating characteristic curve for lesion sHLA-G was 0.833 (95% CI: 0.754-0.912, P < 0.001) for adenocarcinoma versus squamous cell carcinoma. Our findings for the first time showed that tumour cell sHLA-G was predominately expressed in lung adenocarcinoma, which could be a useful biomarker to discriminate adenocarcinoma from squamous cell carcinoma in NSCLC patients. PMID- 25689064 TI - Scoliosis related information on the internet in China: can patients benefit from this information? AB - BACKGROUND: There has been an increasing popularity of searching health related information online in recent years. Despite that considerable amount of scoliosis patients have shown interest in obtaining scoliosis information through Internet, previous studies have demonstrated poor quality of online information. However, this conclusion may vary depending on region and culture. Since China has a restricted Internet access outside of its borders, the aim of this study is to evaluate the quality of scoliosis information available online using recognized scoring systems and to analyze the Internet as a source of health information in China. METHODS: A survey-based questionnaire was distributed to 280 respondents at outpatient clinics. Information on demographics and Internet use was collected. Binary logistic analysis was performed to identify possible predictors for the use of Internet. In addition, the top 60 scoliosis related websites assessed through 4 search engines were reviewed by a surgeon and the quality of online information was evaluated using DISCERN score and JAMA benchmark. RESULTS: Use of the Internet as a source for scoliosis related information was confirmed in 87.8% of the respondents. College education, Internet access at home and urban residence were identified as potential predictors for Internet use. However, the quality of online scoliosis related information was poor with an average DISCERN score of 27.9+/-11.7 and may be misleading for scoliosis patients. CONCLUSION: The study outlines the profile of scoliosis patients who use the Internet as a source of health information. It was shown that 87.8% of the scoliosis patients in outpatient clinics have searched for scoliosis related information on Internet. Urban patients, higher education and Internet access at home were identified as potential predictors for Internet search. However, the overall quality of online scoliosis related information was poor and confusing. Physician based websites seemed to contain more reliable information. PMID- 25689065 TI - Should the Woodward-Hoffmann Rules be Applied to Mechanochemical Reactions? AB - Since decades, pericyclic reactions have been well-understood by means of the Woodward-Hoffmann rules and their classification as thermally or photochemically "allowed" or "forbidden". Recently, stunning results on such reactions subject to mechanochemical activation by external forces instead of heat or light have revealed reaction pathways at sufficiently large forces, which are not expected from the Woodward-Hoffmann rules. This led to the much reiterated idea that the "Woodward-Hoffmann rules are broken in mechanochemistry". Here, by studying ring opening of cyclopropane, we show that the electronic structure underlying the dis and conrotatory pathways, which are greatly distorted upon applying forces to an extent that eventually the "thermally forbidden" process becomes "mechanochemically allowed", does not change along both pathways. It is rather the mechanical work that lowers the activation barrier of the thermally forbidden conrotatory process relative to the disrotatory one at large forces. PMID- 25689066 TI - Proteomic signature of the murine intervertebral disc. AB - Low back pain is the most common musculoskeletal problem and the single most common cause of disability, often attributed to degeneration of the intervertebral disc. Lack of effective treatment is directly related to our limited understanding of the pathways responsible for maintaining disc health. While transcriptional analysis has permitted initial insights into the biology of the intervertebral disc, complete proteomic characterization is required. We therefore employed liquid chromatography electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) protein/peptide separation and mass spectrometric analyses to characterize the protein content of intervertebral discs from skeletally mature wild-type mice. A total of 1360 proteins were identified and categorized using PANTHER. Identified proteins were primarily intracellular/plasma membrane (35%), organelle (30%), macromolecular complex (10%), extracellular region (9%). Molecular function categorization resulted in three distinct categories: catalytic activity (33%), binding (molecule interactions) (29%), and structural activity (13%). To validate our list, we confirmed the presence of 14 of 20 previously identified IVD-associated markers, including matrix proteins, transcriptional regulators, and secreted proteins. Immunohistochemical analysis confirmed distinct localization patterns of select protein with the intervertebral disc. Characterization of the protein composition of healthy intervertebral disc tissue is an important first step in identifying cellular processes and pathways disrupted during aging or disease progression. PMID- 25689067 TI - Increasing complexity while maintaining a high degree of symmetry in nanocrystal growth. AB - Learning from classics: Crystal growth is a complex process, and there are multiple paths for going from dissolved ions to solid crystals. Highlighted herein is the application of traditional chemistry concepts to new ways for increasing the complexity of nanocrystals while maintaining a high degree of symmetry. PMID- 25689068 TI - The impact of extended closing times of alcohol outlets on alcohol-related injuries in the nightlife areas of Amsterdam: a controlled before-and-after evaluation. AB - BACKGROUND AND AIMS: The municipality of Amsterdam implemented a new alcohol policy allowing alcohol outlets in two of the five nightlife areas to extend their closing times from 1 April 2009 onwards. We investigated how levels and trends of alcohol-related injuries changed after implementation of this alcohol policy, by comparing areas with extended closing times to those without. DESIGN: A controlled before-and-after evaluation to compare changes in alcohol-related injuries between intervention and control areas. SETTING: Central district of Amsterdam, The Netherlands. PARTICIPANTS: Alcohol-related ambulance attendances for control and intervention areas between 1 April 2006 and 1 April 2009 (respectively, n = 544 and n = 499) and between 1 April 2009 and 1 April 2011 (respectively, n = 357 and n = 480). MEASUREMENTS: Alcohol-related injuries were defined as ambulance attendances for people who suffered from direct or indirect consequences of alcohol consumption. Injuries were counted per month in two intervention and three control nightlife areas. We used Poisson regression to assess changes in injuries. FINDINGS: After 1 April 2009, intervention areas showed a larger change in the level of alcohol-related injuries than control areas [incidence rate ratio 1.34, 95% confidence interval (CI) = 1.12, 1.61], but trends remained stable in all areas. This increase was only statistically significant for the following subgroups: 2.00-5.59 a.m., weekend days, men, individuals aged 25-34 years, and people transported to a hospital. However, the increase did not differ between subgroups with statistical significance. CONCLUSIONS: A 1-hour extension of alcohol outlet closing times in some of Amsterdam's nightlife areas was associated with 34% more alcohol-related injuries. PMID- 25689069 TI - Manifestations of perihepatic lymph nodes in acute flare of chronic hepatitis B: association with HBeAg status and with HBeAg seroconversion. AB - It has been observed that enlargement of perihepatic lymph nodes may be seen in patients with chronic hepatitis B, particularly during acute flares of CHB. We hypothesized that there may be a correlation between the nodal change patterns in CHB patients with acute flare and HBeAg status. Perihepatic lymph node sizes of 87 patients with acute flares of CHB were documented, with a median follow up of 43 months. Patients were separated into 3 groups, HBeAg-positive with HBe seroconversion (group 1), HBeAg-positive without HBe seroconversion (group 2), and HBeAg-negative (group 3). Group 1 has the highest incidence of enlarged lymph nodes (92.3%) compared with group 2 (75.8%) and group 3 (46.8%) (p = 0.003). And if nodal width at acute flare was > 8mm and interval change of nodal width was >3mm, the incidence of HBeAg seroconversion will be 75% (p<0.001). CONCLUSION: Larger perihepatic lymph nodes are seen in CHB acute flare patients with positive HBeAg and the magnitude of nodal width change may predict HBeAg seroconversion at recovery. PMID- 25689070 TI - Impaired function of CD4+ T follicular helper (Tfh) cells associated with hepatocellular carcinoma progression. AB - BACKGROUND AND AIMS: CD4+ T follicular helper (Tfh) cells, a new subset of immune cells, have been demonstrated to be involved in the development and prognosis of tumors. However, their functional role in human hepatocellular carcinoma (HCC) is relatively unknown, and the detailed mechanisms in HCC development remain to be described. METHODS: A total of 85 HCC patients with hepatitis B virus (HBV) infection, 25 HBV-relative liver cirrhosis (LC) patients, and 20 healthy controls (HC) were randomly enrolled. Flow cytometric analysis, immunohistochemical staining, and relative function (i.e., cytokine secretion, B cell maturation) assays were used to analyze the properties of CXCR5+CD4+ T cells. In addition, the relationship between the frequency of CXCR5+CD4+ T cells and overall survival rates or disease-free survival rates was also analyzed by the Kaplan-Meier method. RESULTS: The frequency of circulating CXCR5+CD4+ T cells was significantly decreased in HCC patients compared with HBV-relative liver cirrhosis (LC) patients and healthy controls, and the decrease in circulating CXCR5+CD4+ T cells correlated with disease progression. The proportion of infiltrated CXCR5+CD4+ T cells was significantly decreased in tumor regions compared with nontumor regions. Furthermore, compared with healthy controls, the function of circulating CXCR5+CD4+ T cells in HCC was impaired, with reduced IL 21 secretion and dysfunction in promoting B cell maturation. Importantly, follow up data indicated that a decreased frequency of circulating CXCR5+CD4+ T cells was also associated with reduced disease-free survival time in HCC patients. CONCLUSIONS: Impairment of CD4+ T follicular helper cells may influence the development of HBV-associated HCC. Decreased CD4+ T follicular helper cells may represent a potential prognostic marker and serve as a novel therapeutic target for HCC patients. PMID- 25689071 TI - Bacteriophages as indicators of human and animal faecal contamination in raw and treated wastewaters from Tunisia. AB - AIMS: We aimed at quantifying bacteriophages in raw and treated wastewaters of human and animal origin in Tunisia to assess their usefulness for tracking the origin of faecal pollution and in the follow-up of effectiveness of water treatments process. METHODS AND RESULTS: The concentrations of bacteriophages in wastewater samples were determined by double layer agar technique. Somatic coliphages and F-specific RNA bacteriophages were present in all types of samples in high concentrations. The values of Escherichia coli were variable depending on geographical location. On the other hand, bacteriophages infecting strain GA17 were detected preferably when human faecal contamination was occurred. CONCLUSIONS: Bacteriophages appear as a feasible and widely applicable manner to detect faecal contamination in Tunisia. On the other hand, phages infecting GA17 could be good markers for tracking the origin of faecal pollution in the area studied. SIGNIFICANCE AND IMPACT OF THE STUDY: The reuse of treated wastewaters can be a solution to meet the needs of water in the geographical area of study. Bacteriophages seem to predict differently the presence of faecal contamination in water than bacterial indicators. Consequently, they can be a valuable additional tool to improve water resources management for minimizing health risks. PMID- 25689072 TI - Recombinant CBM-fusion technology - Applications overview. AB - Carbohydrate-binding modules (CBMs) are small components of several enzymes, which present an independent fold and function, and specific carbohydrate-binding activity. Their major function is to bind the enzyme to the substrate enhancing its catalytic activity, especially in the case of insoluble substrates. The immense diversity of CBMs, together with their unique properties, has long raised their attention for many biotechnological applications. Recombinant DNA technology has been used for cloning and characterizing new CBMs. In addition, it has been employed to improve the purity and availability of many CBMs, but mainly, to construct bi-functional CBM-fused proteins for specific applications. This review presents a comprehensive summary of the uses of CBMs recombinantly produced from heterologous organisms, or by the original host, along with the latest advances. Emphasis is given particularly to the applications of recombinant CBM-fusions in: (a) modification of fibers, (b) production, purification and immobilization of recombinant proteins, (c) functionalization of biomaterials and (d) development of microarrays and probes. PMID- 25689073 TI - Tailored functionalization of iron oxide nanoparticles for MRI, drug delivery, magnetic separation and immobilization of biosubstances. AB - In this critical review, we outline various covalent and non-covalent approaches for the functionalization of iron oxide nanoparticles (IONPs). Tuning the surface chemistry and design of magnetic nanoparticles are described in relation to their applicability in advanced medical technologies and biotechnologies including magnetic resonance imaging (MRI) contrast agents, targeted drug delivery, magnetic separations and immobilizations of proteins, enzymes, antibodies, targeting agents and other biosubstances. We review synthetic strategies for the controlled preparation of IONPs modified with frequently used functional groups including amine, carboxyl and hydroxyl groups as well as the preparation of IONPs functionalized with other species, e.g., epoxy, thiol, alkane, azide, and alkyne groups. Three main coupling strategies for linking IONPs with active agents are presented: (i) chemical modification of amine groups on the surface of IONPs, (ii) chemical modification of bioactive substances (e.g. with fluorescent dyes), and (iii) the activation of carboxyl groups mainly for enzyme immobilization. Applications for drug delivery using click chemistry linking or biodegradable bonds are compared to non-covalent methods based on polymer modified condensed magnetic nanoclusters. Among many challenges, we highlight the specific surface engineering allowing both therapeutic and diagnostic applications (theranostics) of IONPs and magnetic/metallic hybrid nanostructures possessing a huge potential in biocatalysis, green chemistry, magnetic bioseparations and bioimaging. PMID- 25689074 TI - Hyperglycemia diverts dividing stem cells to pathological adipogenesis. AB - This commentary proposes a mechanism for why murine diabetic adipose tissue contains very few remaining stem cells compared with normal adipose tissue. The mechanism involves the diversion of stem cells to pathological adipocytes when they divide in hyperglycemia. PMID- 25689075 TI - Student Triads: A Collaborative Approach to Practicum Experiences for Master's Nursing Students. AB - This article presents an approach for a collaborative practicum experience for master's degree nursing students. The students were placed into triads and then assigned as a group to work in a large health care organization. A triad consisted of 1 student from each concentration of study: nursing administration, nursing education, or nursing informatics, and the group was immersed in real time problem-solving and decision-making processes over the course of the year. PMID- 25689076 TI - DNP and PhD Collaboration: Bringing Together Practice and Research Expertise as Predegree and Postdegree Scholars. AB - A deliberate course of predegree intraprofessional DNP and PhD student collaboration can yield relationships that will facilitate postdegree teamwork. Working together, DNP-prepared nurses can use their practice expertise, and PhD prepared nurses can use their research expertise to improve and change health care. This article presents 3 contexts in which predegree collaboration can occur between DNP and PhD students. Postdegree DNP and PhD collaboration can occur in 2 contexts. PMID- 25689077 TI - Preparing Patient Safety Advocates: Evaluation of Nursing Students' Reported Experience With Authority Gradients in a Hospital Setting. AB - In this post hoc review, prelicensure students' observations of communication interactions were evaluated to assess the students' ability to recognize ineffective professional communication due to an authority gradient and the resultant impact on the patient, other team members, and self. By expanding curricular content to include structured communication strategies using simulation, interprofessional education, and debriefing, students' advocacy skills should improve and potential patient safety risks should decrease as authority gradients are effectively challenged. PMID- 25689078 TI - Preparing Nursing Students for Leadership Using a Disaster-Related Simulation. AB - Increasing numbers and severity of disasters across the globe require nurses to be prepared to provide leadership in disaster situations. To address this need, a combination of didactic and simulation exercises was used to provide a daylong experience emphasizing application of nursing leadership skills in disasters to senior baccalaureate students. Evaluation of learning outcomes demonstrated significant improvement in student self-efficacy related to leadership in disasters. PMID- 25689079 TI - Simulation: rehearsing lines or clinical reasoning? PMID- 25689080 TI - Telehealth Education in Nursing Curricula. AB - Telehealth care is a fast-growing avenue of providing health care services at a distance. A descriptive study was conducted to identify trends of telehealth education in 43 schools of nursing. Findings reflected inadequate integration of telehealth in classroom content, simulation, and clinical experiences. Interviews with 4 nursing leaders of telehealth provided some recommendations on how to integrate telehealth education in nursing curricula. PMID- 25689081 TI - Makeup Exam Policy. PMID- 25689082 TI - Influenza virus-like particles engineered by protein transfer with tumor associated antigens induces protective antitumor immunity. AB - Delivery of antigen in particulate form using either synthetic or natural particles induces stronger immunity than soluble forms of the antigen. Among naturally occurring particles, virus-like particles (VLPs) have been genetically engineered to express tumor-associated antigens (TAAs) and have shown to induce strong TAA-specific immune responses due to their nano-particulate size and ability to bind and activate antigen-presenting cells. In this report, we demonstrate that influenza VLPs can be modified by a protein transfer technology to express TAAs for induction of effective antitumor immune responses. We converted the breast cancer HER-2 antigen to a glycosylphosphatidylinositol (GPI) anchored form and incorporated GPI-HER-2 onto VLPs by a rapid protein transfer process. Expression levels on VLPs depended on the GPI-HER-2 concentration added during protein transfer. Vaccination of mice with protein transferred GPI-HER-2 VLPs induced a strong Th1 and Th2-type anti-HER-2 antibody response and protected mice against a HER-2-expressing tumor challenge. The Soluble form of GPI-HER-2 induced only a weak Th2 response under similar conditions. These results suggest that influenza VLPs can be enriched with TAAs by protein transfer to develop effective VLP-based subunit vaccines against cancer without chemical or genetic modifications and thus preserve the immune stimulating properties of VLPs for easier production of antigen-specific therapeutic cancer vaccines. PMID- 25689083 TI - A reversal phase arrest uncoupling the bone formation and resorption contributes to the bone loss in glucocorticoid treated ovariectomised aged sheep. AB - Large animals as sheep are often used as models for human osteoporosis. Our aim was therefore to determine how glucocorticoid treatment of ovariectomised sheep affects the cancellous bone, determining the cellular events within the bone remodelling process that contributes to their bone loss. Twenty female sheep were assigned for two groups; an untreated control group and an ovariectomised group treated with glucocorticoids (0.6 mg/kg/day, 5 times weekly) for 7 months. At 7 months the glucocorticoid-treated ovariectomised sheep showed a significant change in the bone microstructure revealed by a decreased trabecular bone volume and thickness compared to the control sheep. The treatment led to a temporary elevation of the bone resorption marker CTX (c-terminal collagen telopeptide), while the bone formation marker osteocalcin remained suppressed all 7 months. Histomorphometrically, the treated sheep had a complete absence of osteoid surfaces, and a 5-fold increase in the extent of eroded/reversal surfaces after 7 months. Most of these reversal surfaces were actually arrested reversal surfaces, defined as reversal surfaces without the presence of neighbouring osteoid surfaces or osteoclasts, which is classically observed next to active reversal surfaces. As in humans, these arrested reversal surfaces had compared to active reversal surfaces a reduced canopy coverage, a significantly decreased cell density, and a decreased immunoreactivity for the osteoblastic markers osterix, runx2 and smooth muscle actin in the mononuclear reversal cells colonising the surfaces. In conclusion, glucocorticoid treatment of ovariectomised sheep induced a significant bone loss, caused by an arrest of the reversal phase, resulting in an uncoupling of the bone formation and resorption during the reversal phase, as recently demonstrated in postmenopausal women with glucocorticoid-induced osteoporosis. This supports the relevance of the sheep model to the pathophysiology of glucocorticoid-induced osteoporosis in postmenopausal women, making it a relevant preclinical model for orthopaedic implant and biomaterial research. PMID- 25689085 TI - Arrhythmogenic cardiomyopathy with biventricular involvement and noncompaction. PMID- 25689084 TI - The two faces of miR-29. AB - Diabetes mellitus is a metabolic homeostasis disease that contributes to additional comorbidities such as cardiovascular disease (CVD) and cancer. It has a long undiagnosed latent period during which there can be irreparable damage to the pancreas and cardiovascular tissues. Recent studies have highlighted the roles of several microRNAs in CVD. Determining the microRNAs that link diabetes mellitus and CVD is an important topic to be explored. In the present review, we discuss the microRNAs that contribute to the progression of diabetes mellitus and CVD and focus on the miR-29 family microRNAs whose expression is upregulated by hyperglycemia and proinflammatory cytokines, the hallmarks of diabetes mellitus. Upregulation of miR-29 expression is a key factor in the loss of pancreatic beta cells and development of the first stage of type 1 diabetes mellitus (T1DM). Additionally, miR-29-mediated suppression of myeloid cell leukemia 1 (MCL-1), an important prosurvival protein, underlies Marfan's syndrome, abdominal aortic aneurysm, and diabetes mellitus-associated cardiomyocyte disorganization. Suppression of miR-29 expression and subsequent increase in the prosurvival MCL 1, however, promotes tumor development. Therefore, miR-29 mimics that suppress MCL-1 are hailed as tumor suppressors. The critical question is whether an increase in miR-29 levels is well tolerated in conditions of comorbidities in which insulin resistance is an underlying disease. In light of increasing awareness of the interconnection of diabetes mellitus, CVD, and cancer, it is of utmost importance to understand the mechanism of action of current treatment options on all of the comorbidities and careful evaluation of cardiovascular toxicity must accompany any treatment paradigm that increases miR-29 levels. PMID- 25689086 TI - Expression of a metalloproteinase family of ADAMTS in human vulnerable carotid lesions. AB - AIMS: ADAMTS family of metalloproteases (a disintegrin and metalloprotease with thrombospondin motifs) possesses high proteolytic activity especially regarding proteoglycans. Their expression pattern in carotid plaques is as-yet unknown. The aim of the study was therefore the analysis of expression of ADAMTS1, 4, 5, and 13 and their inhibitors TIMP-1 and TIMP-3 in stable and unstable carotid plaques. METHODS: Atherosclerotic plaques were collected from 40 patients (29 men, 11 women, mean age 70 years) undergoing carotid endarterectomy. The specimens were categorized into two groups (stable/unstable) according to Redgrave und Rothwell (The Oxford Plaque Study, 2008). SYBR Green-based real-time PCR, histology, and immunohistochemistry were performed. RESULTS: All ADAMTS tested in our study were expressed in both stable and unstable plaques, especially in smooth muscle cells (SMCs) and macrophages. Analysis of the expression pattern on mRNA level showed significant higher expression of ADAMTS1 in unstable plaques compared with stable plaques (1.7-fold, P = 0.049). The expression of ADAMTS4 and 5 was also increased in unstable lesions; however, these changes were not statistically significant (1.2-fold, P = 0.667 and 1.6-fold, P = 0.077). Expression of TIMP-1 was significantly reduced in unstable plaques compared with stable ones (1.9-fold, P = 0.014). CONCLUSION: SMCs seem to be an important source of ADAMTS analyzed in our study. Furthermore, expression of ADAMTS1 was found to be increased in unstable carotid lesions and might potentially contribute to plaque vulnerability. PMID- 25689087 TI - Role of different vascular approaches on transcatheter aortic valve implantation outcome: a single-center study. AB - OBJECTIVE: To compare different vascular approaches on clinical outcome of patients undergoing transcatheter aortic valve implantation (TAVI) with self expandable bioprosthesis. METHODS: We included all the patients undergoing CoreValve implantation at our institute between September 2007 and March 2014. They were divided into four groups based on the vascular approach: percutaneous transfemoral (pTF), cut-down transfemoral (cTF), transaxillary (TAx) and transaortic (TAo). Clinical outcomes were evaluated according to Valve Academic Research Consortium-2 recommendations. RESULTS: Out of 322 consecutive patients, 170 (53%) underwent pTF, 76 (23%) cTF, 32 (10%) TAx and 44 (14%) TAo approach. Although the TAx and TAo patients had a higher risk profile, they had a similar outcome compared with the pTF and cTF groups; in particular, there were no differences regarding cardiovascular and all-cause mortality at 30 days, 1 and 2 years, as well as stroke, myocardial infarction, bleeding, major vascular complications, permanent pacemaker implantation and acute kidney injury rates. The observed device success rate was higher in the TAo than in the other approaches (88.6 versus 65.9, 68.7 and 76.3% in the pTF, cTF and TAx groups, respectively; P = 0.019). No differences occurred regarding 30-day early safety and 1-year clinical efficacy across the four groups. Fluoroscopy time, amount of contrast medium used and minor vascular complications were significantly higher in pTF patients, as well as in-hospital stay in the TAo group. Atrial fibrillation and prosthetic valve regurgitation, but not the vascular approach, were independent predictors of all-cause mortality. CONCLUSION: A more invasive vascular approach, for CoreValve implantation, even in higher risk patients, does not affect early-term, mid-term and long-term outcomes. PMID- 25689088 TI - 18 F-FDG uptake in focal organising pneumonia mimicking bronchial carcinoma. AB - BACKGROUND AND AIMS: Organising pneumonia (OP) is not a well-known cause of increased 18 F-FDG uptake, and the relationship of the increased 18 F-FDG uptake to clinical parameters has not been clearly identified. This study aims to assess the role of positron emission tomography-computed tomography (PET-CT) for the diagnosis of focal organised pneumonia that may mimic malignity because of mass like lesions on the radiological images it causes. METHODS: Among 40 patients of whom histopathological exams were consistent with OP, medical records of 14 focal OP patients diagnosed with surgical biopsy were evaluated retrospectively. RESULTS: There were 10 male (71.4%) and 4 female (28.6%) patients. The mean age at the time of diagnosis was 57.2 +/- 11.7 years, ranging from 38 to 85 years. Nine subjects (64.3%) were smokers. Eleven patients (78.5%) had symptoms, the remaining 3 patients (21.5%) were asymptomatic. Three patients (21.3%) had a history of malignancy. Focal lung lesion was initially detected by chest radiography in 10 patients (71.4%) and by computed tomography (CT) scan in all patients. CT scan showed a single lesion in 12 (85.7%) patients. The lesions were located in the right lung of the half of patients (50%) and in the left lung of the other half. The median diameter of the lesions was 3.4 cm (range, 1.8-6.0 cm). PET with 18 F-FDG was performed in all patients, and hypermetabolic activity of the focal lung lesion was demonstrated in all cases. The median values of maximum standardized uptake value was 3.5 +/- 2.7 (min 2.1-max 13.1). CONCLUSION: Focal OP is a discrete form of OP that is associated with unifocal lesions on radiological images, and it can easily mimic lung cancer because of positivity on PET scans. There are no specific findings of PET scan for the diagnosis of OP. PMID- 25689089 TI - The validity of retrospectively reported conflict interactions in couples. AB - This study investigated the extent to which researchers and clinicians can obtain valid retrospective self-reports of couples' conflict interactions outside a laboratory setting. A distinction was made between relationship attribute variance, regarding a shared perspective of both partners, and informant-specific variance, regarding the unique vantage point of each partner. By examining convergent and divergent associations for each type of variance, this study clarified the risk that responses might be influenced by informant-specific biases related to levels of relationship satisfaction. This study also investigated potential moderators of validity. Participants included both members of 269 married and cohabiting couples (538 individuals) who completed online questionnaires. Results were analyzed using a correlated trait-correlated method minus one model. The total true variance included large components of both shared relationship attribute variance and informant-specific variance. Although the shared component was moderately correlated with relationship satisfaction, the informant-specific component was mostly distinct from satisfaction, suggesting minimal bias. Convergent correlations between partners were strong and mostly unrelated to potential moderating variables, albeit slightly smaller than reported in studies conducted in laboratory settings. The results generally support the validity for retrospective self-reports of conflict interactions, especially when reports are obtained from both members of a couple. PMID- 25689090 TI - Emulating real-life situations with a play task to observe parenting skills and child behaviors. AB - Play tasks that use standardized procedures and materials are a practical way to assess parenting skills, child behaviors, and the ways in which parents and children interact. We describe a systematic process for developing the parent child play task (PCPT) to assess mother-child interactions for a randomized controlled trial of a video-based parenting program. Participants were 307 mothers and their 3- to 6-year-old children who presented oppositional and disruptive behavior challenges. The validity of the PCPT was investigated by testing (a) the extent to which the tasks elicited the specific parent and child behaviors of interest, (b) the consistency of individuals' behavior across the play tasks, and (c) the concurrent associations of the PCPT-observed child behaviors and mother reports of child behavior. The different tasks elicited the mother and child behaviors that they were designed to elicit. Behavior consistency across tasks for individual mothers and children was fair to good, with the exception of 2 task-specific behaviors. Mother's guidance (provision of instructions to foster a skill) during the teaching task and children's interruptions while mother was busy during the questionnaire task were highly task specific. Modest associations were found between observed children's noncompliance and inappropriate behaviors and mother-reported conduct problems and oppositional behaviors. Implications for clinical and research assessments are discussed. PMID- 25689091 TI - Near infrared fluorescence imaging for early detection, monitoring and improved intervention of diseases involving the joint. AB - Joints consist of different tissues, such as bone, cartilage and synovium, which are at risk for multiple diseases. The current imaging modalities, such as magnetic resonance imaging, Doppler ultrasound, X-ray, computed tomography and arthroscopy, lack the ability to detect disease activity before the onset of anatomical and significant irreversible damage. Optical in vivo imaging has recently been introduced as a novel imaging tool to study the joint and has the potential to image all kinds of biological processes. This tool is already exploited in (pre)clinical studies of rheumatoid arthritis, osteoarthritis and cancer. The technique uses fluorescent dyes conjugated to targeting moieties that recognize biomarkers of the disease. This review will focus on these new imaging techniques and especially where Near Infrared (NIR) fluorescence imaging has been used to visualize diseases of the joint. NIR fluorescent imaging is a promising technique which will soon complement established radiological, ultrasound and MRI imaging in the clinical management of patients with respect to early disease detection, monitoring and improved intervention. PMID- 25689092 TI - Power and challenges of using zebrafish as a model for skeletal tissue imaging. AB - The zebrafish (Danio rerio) is now a widely used model organism in biomedical research. The species is also increasingly used for studying skeletal development and regeneration and for understanding human skeletal diseases. The small size of this model organism is an advantage and an extreme challenge for visualizing and diagnosing the animals' skeleton. This applies especially to early stages of skeletal development. Similar challenges arise for the analysis of the skeleton of other small fish species, such as medaka (Oryzias latipes). High quality histological preparations and knowledge about the special quality of the zebrafish skeleton remain prerequisites for a correct analysis. In addition, new methods for fast and high-resolution 2D and 3D skeletal tissue screening are required for a maximal understanding of skeletal development. We, in this study, review advantages and limitations of adapting current visualization techniques for zebrafish skeletal research. We discuss the methods for in toto visualization, such as X-raying, micro-CT, Alizarin red staining and optical projection tomography. Techniques for in vivo imaging, such as second harmonic generation microscopy and two-photon excitation fluorescence, are also discussed. Finally, we explore the possibilities of light-sheet microscopy for the analysis of the zebrafish skeleton. PMID- 25689094 TI - Specific detection of avidin-biotin binding using liquid crystal droplets. AB - Poly(acrylicacid-b-4-cynobiphenyl-4'-undecylacrylate) (PAA-b-LCP)-functionalized 4-cyano-4'-pentylbiphenyl (5CB) droplets were made by using microfluidic technique. The PAA chains on the 5CB droplets, were biotinylated, and used to specifically detect avidin-biotin binding at the 5CB/aqueous interface. The avidin-biotin binding was characterized by the configurational change (from radial to bipolar) of the 5CB droplets, as observed through a polarized optical microscope. The maximum biotinylation was obtained by injecting a >100 MUg/mL biotin aqueous solution, which enabled a limit of detection of 0.5 MUg/mL avidin. This droplet biosensor could specifically detect avidin against other proteins such as bovine serum albumin, lysozyme, hemoglobin, and chymotrypsinogen solutions. Avidin detection with 5CBPAA-biotin droplets having high sensitivity, specificity, and stability demonstrates new applications of the functionalized liquid crystal droplets that can detect specific proteins or other analytes through a ligand/receptor model. PMID- 25689095 TI - Molecular targeted therapy in the treatment of advanced stage non-small cell lung cancer (NSCLC). AB - Historically, patients with advanced stage non-small cell lung cancer (NSCLC) were treated with chemotherapy alone, but a therapeutic plateau has been reached. Advances in the understanding of molecular genetics have led to the recognition of multiple molecularly distinct subsets of NSCLC. This in turn has led to the development of rationally directed molecular targeted therapy, leading to improved clinical outcomes. Tumour genotyping for EGFR mutations and ALK rearrangement has meant chemotherapy is no longer given automatically as first line treatment but reserved for when patients do not have a 'druggable' driver oncogene. In this review, we will address the current status of clinically relevant driver mutations and emerging new molecular subsets in lung adenocarcinoma and squamous cell carcinoma, and the role of targeted therapy and mechanisms of acquired resistance to targeted therapy. PMID- 25689096 TI - The features of interventions associated with long-term effectiveness of physical activity interventions in adults aged 55-70 years: a systematic review and meta analysis. AB - Content, delivery and effects of physical activity (PA) interventions are heterogeneous. There is a need to identify intervention features (content and delivery) related to long-term effectiveness. Behaviour change techniques (BCTs) and modes of intervention delivery were coded in 19 randomised controlled trials included in a systematic review of PA interventions for adults aged 55-70 years, published between 2000 and 2010, with PA outcomes >= 12 months after randomisation; protocol registration: PROSPERO CRD42011001459. Meta-analysis, moderator analyses and meta-regression were conducted. Meta-analysis revealed that interventions were effective in promoting PA compared with no/minimal intervention comparators [d = 0.29, 95% CI = 0.19-0.40, I(2) = 79.8%, Q-value = 89.16 (df = 18, p < 0.01)]. Intervention features often concurred and goal setting was the most commonly used BCT. Subgroup analyses suggested that interventions using the BCT feedback may be more effective, whilst interventions using printed materials or the BCTs information on where and when to perform the behaviour and information on consequences of behaviour to the individual may be less effective. Meta-regression revealed that neither the number of BCTs nor self regulatory BCTs significantly related to effect size. Feedback appears to be a potentially effective candidate BCT for future interventions promoting long-term PA. Considering concurrence of intervention features alongside moderator analyses is important. PMID- 25689098 TI - Targeted metabolomics in the expanded newborn screening for inborn errors of metabolism. AB - Inborn errors of metabolism are genetic disorders due to impaired activity of enzymes, transporters, or cofactors resulting in accumulation of abnormal metabolites proximal to the metabolic block, lack of essential products or accumulation of by-products. Many of these disorders have serious clinical consequences for affected neonates, and an early diagnosis allows presymptomatic treatment which can prevent severe permanent sequelae and in some cases death. Expanded newborn screening for these diseases is a promising field of targeted metabolomics. Here we report the application, between 2007 and 2014, of this approach to the identification of newborns in southern Italy at risk of developing a potentially fatal disease. The analysis of amino acids and acylcarnitines in dried blood spots by tandem mass spectrometry revealed 24 affected newborns among 45,466 infants evaluated between 48 and 72 hours of life (overall incidence: 1 : 1894). Diagnoses of newborns with elevated metabolites were confirmed by gas chromatography-mass spectrometry, biochemical studies, and genetic analysis. Five infants were diagnosed with medium-chain acyl CoA dehydrogenase deficiency, 1 with methylmalonic acidemia with homocystinuria type CblC, 2 with isolated methylmalonic acidemia, 1 with propionic acidemia, 1 with isovaleric academia, 1 with isobutyryl-CoA dehydrogenase deficiency, 1 with beta ketothiolase deficiency, 1 with short branched chain amino acid deficiency, 1 with 3-methlycrotonyl-CoA carboxylase deficiency, 1 with formimino-transferase cyclodeaminase deficiency, and 1 with cystathionine-beta-synthase deficiency. Seven cases of maternal vitamin B12 deficiency and 1 case of maternal carnitine uptake deficiency were detected. This study supports the widespread application of metabolomic-based newborn screening for these genetic diseases. PMID- 25689097 TI - Advanced age protects microvascular endothelium from aberrant Ca(2+) influx and cell death induced by hydrogen peroxide. AB - KEY POINTS: Calcium signalling in endothelial cells of resistance arteries is integral to blood flow regulation. Oxidative stress and endothelial dysfunction can prevail during advanced age and we questioned how calcium signalling may be affected. Intact endothelium was freshly isolated from superior epigastric arteries of Young (~4 months) and Old (~24 months) male C57BL/6 mice. Under resting conditions, with no difference in intracellular calcium levels, hydrogen peroxide (H2 O2 ) availability was ~1/3 greater in endothelium of Old mice while vascular catalase activity was reduced by nearly half. Compared to Old, imposing oxidative stress (200 MUm H2 O2 ) for 20 min increased intracellular calcium to 4 fold greater levels in endothelium of Young in conjunction with twice the calcium influx. Prolonged (60 min) exposure to H2 O2 induced 7-fold greater cell death in endothelium of Young. Microvascular adaptation to advanced age may protect endothelial cells during elevated oxidative stress to preserve functional viability of the intima. ABSTRACT: Endothelial cell Ca(2+) signalling is integral to blood flow control in the resistance vasculature yet little is known of how its regulation may be affected by advancing age. We tested the hypothesis that advanced age protects microvascular endothelium by attenuating aberrant Ca(2+) signalling during oxidative stress. Intact endothelial tubes (width, ~60 MUm; length, ~1000 MUm) were isolated from superior epigastric arteries of Young (3-4 months) and Old (24-26 months) male C57BL/6 mice and loaded with Fura-2 dye to monitor [Ca(2+) ]i . At rest there was no difference in [Ca(2+) ]i between age groups. Compared to Young, the [Ca(2+) ]i response to maximal stimulation with acetylcholine (3 MUm, 2 min) was ~25% greater in Old, confirming signalling integrity with advanced age. Basal H2 O2 availability was ~33% greater in Old while vascular catalase activity was reduced by half. Transient exposure to elevated H2 O2 (200 MUm, 20 min) progressively increased [Ca(2+) ]i to ~4-fold greater levels in endothelium of Young versus Old. With no difference between age groups at rest, Mn(2+) quench of Fura-2 fluorescence revealed 2-fold greater Ca(2+) influx in Young during elevated H2 O2 ; this effect was attenuated by ~75% using ruthenium red (5 MUm) as a broad-spectrum inhibitor of transient receptor potential channels. Prolonged exposure to H2 O2 (200 MUm, 60 min) induced ~7-fold greater cell death in endothelium of Young versus Old. Thus, microvascular endothelium can adapt to advanced age by reducing Ca(2+) influx during elevated oxidative stress. Protection from cell death during oxidative stress will sustain endothelial integrity during ageing. PMID- 25689100 TI - Chronic social defeat, but not restraint stress, alters bladder function in mice. AB - BACKGROUND: Voiding disorders in humans, particularly in children are associated with increased incidence of behavioral issues as well as past history of childhood abuse. We hypothesized that creating stress in mice, utilizing either a chronic social defeat model (SD) or restraint stress in shallow water model (RSSW) would engender changes in bladder function, morphology, and behavior, thereby enabling us to study the resultant voiding dysfunction. METHODS: For SD stress (14 days), C57BL/6 male mice were exposed daily to a larger aggressive CD 1 male for 10 min, followed by sensory exposure in a barrier cage for 24h. Control mice were similarly housed with no exposure. For RSSW (21 days), C57BL/6 mice were put in a perforated conical tube with feet immersed in water daily for 4h, then returned to single housing cages. Control mice were also in single housing. After the stress period, voiding patterns were obtained on filter paper, followed by behavioral tests. At necropsy, blood was taken for corticosterone analysis, and bladder and body weights measured. Bladder cryosections were stained with hematoxylin and eosin (H&E) for morphological assessment. Sequential sections were immunostained with antibodies to Ki-67 as a proliferation marker, CD31 (endothelial cell marker), and uroplakin-II. ImageJ software was used to measure bladder wall thickness on blinded H&E photomicrographs as well as quantitate CD31 staining. Both Ki-67-positive and -negative nuclei were counted with Imaris software to obtain a proliferation index. RESULTS: Only SD mice had a single large void pattern. Bladder-to-body weight ratios increased in SD mice (p<=0.02) but not in RSSW mice. Plasma corticosterone levels were elevated in all stressed mice. SD mice exhibited lower levels of locomotor activity compared with controls; RSSW mice were hyperactive. In SD mice, bladder wall thickness was increased (p <= 0.003) but no change was seen in Ki-67 proliferation index, consistent with hypertrophy. No difference with control mice was seen in vascularity as visualized by CD31 staining. Uniform uroplakin-II staining lined the urothelium of both SD and control mice. CONCLUSIONS: Mice exposed to repeated SD (14 days) respond with altered voiding indicative of urine retention, and exhibit bladder wall changes consistent with hypertrophy while the urothelial barrier is maintained. These changes were not observed with repeated RSSW. SD, in contrast to RSSW, provides a model of psychological stress to further study the interplay of behavior and bladder dysfunction, enabling an improved understanding of voiding dysfunction, and the ability to create innovative and more effective management pathways for children who present with voiding dysfunction. PMID- 25689102 TI - Active inference and epistemic value. AB - We offer a formal treatment of choice behavior based on the premise that agents minimize the expected free energy of future outcomes. Crucially, the negative free energy or quality of a policy can be decomposed into extrinsic and epistemic (or intrinsic) value. Minimizing expected free energy is therefore equivalent to maximizing extrinsic value or expected utility (defined in terms of prior preferences or goals), while maximizing information gain or intrinsic value (or reducing uncertainty about the causes of valuable outcomes). The resulting scheme resolves the exploration-exploitation dilemma: Epistemic value is maximized until there is no further information gain, after which exploitation is assured through maximization of extrinsic value. This is formally consistent with the Infomax principle, generalizing formulations of active vision based upon salience (Bayesian surprise) and optimal decisions based on expected utility and risk sensitive (Kullback-Leibler) control. Furthermore, as with previous active inference formulations of discrete (Markovian) problems, ad hoc softmax parameters become the expected (Bayes-optimal) precision of beliefs about, or confidence in, policies. This article focuses on the basic theory, illustrating the ideas with simulations. A key aspect of these simulations is the similarity between precision updates and dopaminergic discharges observed in conditioning paradigms. PMID- 25689104 TI - Stability properties of surfactant-free thin films at different ionic strengths: measurements and modeling. AB - Foam lamellae are the smallest structural elements in foam. Such lamellae can experimentally be studied by analysis of thin liquid films in glass cells. These thin liquid films usually have to be stabilized against rupture by surface active substances, such as proteins or low molecular weight surfactants. However, horizontal thin liquid films of pure water with a radius of 100 MUm also show remarkable stability when created in closed Sheludko cells. To understand thin film stability of surfactant-free films, the drainage behavior and rupture times of films of water and NaCl solutions were determined. The drainage was modeled with an extended Derjaguin-Landau-Verwey-Overbeek (DLVO) model, which combines DLVO and hydrophobic contributions. Good correspondence between experiment and theory is observed, when hydrophobic interactions are included, with fitted values for surface potential (psi(0,water)) of -60 +/- 5 mV, hydrophobic strength (B(hb,water)) of 0.22 +/- 0.02 mJ/m(2), and a range of the hydrophobic interaction (lambda(hb, water)) of 15 +/- 1 nm in thin liquid films. In addition, Vrij's rupture criterion was successfully applied to model the stability regions and rupture times of the films. The films of pure water are stable over long time scales (hours) and drain to a final thickness >40 nm if the concentration of electrolytes is low (resistivity 18.2 MQ). With increasing amounts of ions (NaCl) the thin films drain to <40 nm thickness and the rupture stability of the films is reduced from hours to seconds. PMID- 25689103 TI - Autoantibodies to Multiple Epitopes on the Non-Collagenous-1 Domain of Type VII Collagen Induce Blisters. AB - Epidermolysis bullosa acquisita (EBA) is an autoimmune blistering disease of the skin and mucous membranes, characterized by autoantibodies against type VII collagen (COL7), a major component of anchoring fibrils. Different clinical EBA phenotypes are described, including mechanobullous and inflammatory variants. Most EBA patients' sera react with epitopes located within the non-collagenous 1 (NC1) domain of human COL7. However, it has remained unclear whether antibody binding to these different epitopes is pathogenically relevant. To address this issue, we generated recombinant proteins covering the entire NC1 domain. IgG reactivity with these proteins was analyzed in sera of 69 EBA patients. Most recognized clusters of epitopes throughout the NC1 domain. No correlation was detected between antibody specificity and clinical phenotype. To study the pathogenicity of antibodies specific to different NC1 subdomains, rabbit antibodies were generated. All these antibodies caused dermal-epidermal separation ex vivo. Antibodies against two of these subdomains were injected into mice carrying null mutations of mouse COL7 and the human COL7 transgene and induced subepidermal blisters. We here document that autoantibodies to COL7, independent of the targeted epitopes, induce blisters both ex vivo and in vivo. In addition, using COL7-humanized mice, we provide in vivo evidence of pathogenicity of autoantibodies binding to human COL7. PMID- 25689105 TI - Tumourigenic canine osteosarcoma cell lines associated with frizzled-6 up regulation and enhanced side population cell frequency. AB - An increased serum alkaline phosphatase concentration is known to be associated with a negative prognosis in canine and human osteosarcoma. To expand upon previous studies regarding the biological relevance of increased serum alkaline phosphatase as a negative prognostic factor, xenogeneic heterotopic transplants were performed using six canine primary osteosarcoma cell lines generated from patients with differing serum alkaline phosphatase concentrations (three normal and three increased). Three of the six cell lines were capable of generating tumours and tumour formation was independent of the serum alkaline phosphatase status of the cell line. Microarray analysis identified 379 genes as being differentially expressed between the tumourigenic and non-tumourigenic cell lines. Frizzled-6 was upregulated to the greatest extent (7.78-fold) in tumourigenic cell lines compared with non-tumourigenic cell lines. Frizzled-6, a co-receptor for Wnt ligands has been associated with enhanced tumour-initiating cells and poor prognosis for other tumours. The increased expression of frizzled 6 was confirmed by quantitative reverse transcription polymerase chain reaction (QPCR) and Western blot analysis. Additionally, the tumourigenic cell lines also had an increase in the percentage of side population cells compared with non tumourigenic cell lines (5.89% versus 1.58%, respectively). There were no differences in tumourigenicity, frizzled-6 or percentage of side population cells noted between osteosarcoma cell lines generated from patients of differing serum alkaline phosphatase concentration. However, to our knowledge this is the first study to identified frizzled-6 as a possible marker of osteosarcoma cell populations with enhanced tumourigenicity and side population cells. Future work will focus on defining the role of frizzled-6 in osteosarcoma tumourigenesis and tumour-initiating cells. PMID- 25689106 TI - Molecular cloning and characterization of a sigma-class glutathione S-transferase from the freshwater mussel Hyriopsis cumingii. AB - A full-length cDNA of a sigma-like glutathione S-transferase (GST) was identified from Hyriopsis cumingii (HcGSTS). The deduced amino acid sequence of HcGSTS was found to comprise 203 amino acid residues and to contain the distinct highly conserved glutathione binding site of N-terminal and the relatively diverse substrate binding site of C-terminal. Alignment analysis and phylogenetic relationship suggested that the HcGSTS is a sigma-class GST. The mRNA of HcGSTS was constitutively expressed in all tested tissues, the strongest expression being in the hepatopancreas. The mRNA expression of HcGSTS was significantly up regulated (P < 0.05) in all assessed tissues after stimulation of the mussels with peptidoglycan (PGN) and LPS, the only exception being when the gills were challenged with PGN. The expression of HcGSTS mRNA in kidney and foot was also significantly up-regulated (P < 0.05) by microcystin-LR. Recombinant HcGSTS exhibited high activity towards the substrate 1-chloro-2,4-dinitrobenzene. The optimal pH was 8.0 and temperature 35 degrees C. PMID- 25689107 TI - Risk factor-related lifestyle habits of hospital-admitted stroke patients - an exploratory study. AB - AIMS AND OBJECTIVES: To describe and explain the lifestyle habits of hospital admitted stroke patients by identifying relationships between the different lifestyle habits and by examining associations between them and clinical measurements. BACKGROUND: Stroke is associated with several risk factors that are closely intertwined. However, lifestyle factors have profound effects on its incidence. It has been shown that healthy lifestyle habits are associated with a reduced stroke risk both in combination and independently. DESIGN: A cross sectional, exploratory study. METHODS: Data were collected from stroke and transient ischemic attack (TIA) patients (n = 150) in an acute neurology unit in Finland between January 2010 and October 2011 using the Lifestyle Instrument. Data analysis was performed by cross-tabulation of variables, factor analysis, analysis of variance and logistic regression. RESULTS: Patients with a mean age of 56.5 participated. Based on their body mass index, most were overweight (43.2%) or obese (31.8%). Their waist circumference levels indicated significant health problems in most cases (70%). Their mean glucose (5.6 mmol/l) and blood pressure (149.9/86.7 mmHg) levels were also above the guideline values. The participants had diverse risk factor-related lifestyle habits. There were several statistically significant differences between the different lifestyle habits and most of the clinical data were at least partly explained by the lifestyle habits. CONCLUSIONS: The participants in this study had many lifestyle habits that are associated with stroke risk factors, exposing them to an elevated risk of a new stroke in the future. RELEVANCE TO CLINICAL PRACTICE: It is an important obligation for nursing staff courageously to bring up the lifestyle habits at the hospital phase and point out that there is a relationship between them and stroke incidence and that secondary stroke can be prevented or made less likely by adopting a healthy lifestyle. PMID- 25689108 TI - Thermal AND Gate Using a Monolayer Graphene Nanoribbon. AB - The first ever implementation of a thermal AND gate, which performs logic calculations with phonons, is presented using two identical thermal diodes composed of asymmetric graphene nanoribbons (GNRs). Employing molecular dynamics simulations, the characteristics of this AND gate are investigated and compared with those for an electrical AND gate. The thermal gate mechanism originates through thermal rectification due to asymmetric phonon boundary scattering in the two diodes, which is only effective at the nanoscale and at the temperatures much below the room temperature. Due to the high phonon velocity in graphene, the gate has a fast switching time of ~100 ps. PMID- 25689109 TI - Rhodium-catalyzed 1,4-addition of arylboronic acids to 3-benzylidene-1H pyrrolo[2,3-b]pyridin-2(3H)-one derivatives. AB - 7-Azaindoles are versatile building blocks, especially in medicinal chemistry, where they serve as bioisosteres of indoles or purines. Herein, we present a novel rhodium-catalyzed asymmetric 1,4-addition of arylboronic acids to 3 benzylidene-1H-pyrrolo[2,3-b]pyridin-2(3H)-ones, as these substrates are exocyclic methylene lactamyl Michael acceptors. Ten new original derivatives of 1H-pyrrolo[2,3-b]pyridin-2(3H)-one have been obtained. PMID- 25689110 TI - Exploring the social integration of sexual minority youth across high school contexts. AB - Mental health disparities between sexual minority and other youth have been theorized to result in part from the effects of the stigmatization on social integration. Stochastic actor-based modeling was applied to complete network data from two high schools in the National Longitudinal Study of Adolescent Health (Mage = 15 years, N = 2,533). Same-sex attracted youth were socially marginalized in a smaller predominantly White school but not in a larger, more racially diverse school. For both schools, homophily was a critical network feature, and could represent social support for and social segregation of such youth. These findings emphasize the school context in studying the social lives of sexual minority youth and suggest that youth may be better off socially in larger and more diverse schools. PMID- 25689111 TI - Quantum chemistry calculation-aided structural optimization of combretastatin A-4 like tubulin polymerization inhibitors: improved stability and biological activity. AB - A potent combretastatin A-4 (CA-4) like tubulin polymerization inhibitor 22b was found with strong antitumor activity previously. However, it easily undergoes cis trans isomerization under natural light, and the resulting decrease in activity limits its further applications. In this study, we used quantum chemistry calculations to explore the molecular basis of its instability. Aided by the calculations, two rounds of structural optimization of 22b were conducted. Accelerated quantitative light stability testing confirmed that the stability of these designed compounds was significantly improved as predicted. Among them, compounds 1 and 3b displayed more potent inhibitory activity on tumor cell growth than 22b. In addition, the potent in vivo antitumor activity of compound 1 was confirmed. Quantum chemistry calculations were used in the optimization of stilbene-like molecules, providing new insight into stilbenoid optimization and important implications for the future development of novel CA-4-like tubulin polymerization inhibitors. PMID- 25689112 TI - Charge order and resistivity transition of Zn-doped cuprate superconductors. AB - Impurity doping using Zn atoms was largely studied in cuprates because this process substantially reduces the superconducting critical temperature T(c) without any effect on the pseudogap onset T*. Earlier theories missed the recently established ubiquitous presence of incommensurate charge modulations in these materials. The charge order is a consequence of a phase separation transition which we describe by a continuity equation of the local free energy density. The Zn atoms generate a local magnetic moment, freezing their neighbors' spins, slowing down the electronic segregation process. Then the Zn-doped properties are that of a granular superconductor whose size of the charge order modulations are dictated by the degree of phase separation. PMID- 25689113 TI - Sleep Blood Pressure Self-Measured at Home as a Novel Determinant of Organ Damage: Japan Morning Surge Home Blood Pressure (J-HOP) Study. AB - To study whether sleep blood pressure (BP) self-measured at home is associated with organ damage, the authors analyzed the data of 2562 participants in the J HOP study who self-measured sleep BP using a home BP monitoring (HBPM) device, three times during sleep (2 am, 3 am, 4 am), as well as the home morning and evening BPs. The mean sleep home systolic BPs (SBPs) were all correlated with urinary albumin/creatinine ratio (UACR), left ventricular mass index (LVMI), brachial-ankle pulse wave velocity (baPWV), maximum carotid intima-media thickness, and plasma N-terminal pro-hormone pro-brain-type natriuretic peptide (NTproBNP) (all P<.001). After controlling for clinic SBP and home morning and evening SBPs, associations of home sleep SBP with UACR, LVMI, and baPWV remained significant (all P<.008). Even in patients with home morning BP <135/85 mm Hg, 27% exhibited masked nocturnal hypertension with home sleep SBP >=120 mm Hg and had higher UACR and NTproBNP. Masked nocturnal hypertension, which is associated with advanced organ damage, remains unrecognized by conventional HBPM. PMID- 25689114 TI - Host preferences of ornithophilic biting midges of the genus Culicoides in the Eastern Balkans. AB - Many biting midges of the genus Culicoides Latreille, 1809 (Diptera: Ceratopogonidae) are competent vectors of a diverse number of pathogens. The identification of their feeding behaviour and of vector-host associations is essential for understanding their transmission capacity. By applying two different nested polymerase chain reaction (PCR) assays, of which one targeted the avian cyt b gene and the other targeted the COI gene of a wide range of vertebrates, we identified the blood hosts of six biting midge species including Culicoides circumscriptus, Culicoides festivipennis, Culicoides punctatus, Culicoides pictipennis, Culicoides alazanicus and Culicoides cf. griseidorsum, the latter two of which are reported in Bulgaria for the first time. Bird DNA was found in 50.6% of 95 investigated bloodmeals, whereas mammalian DNA was identified in 13.7%. Two Culicoides species were found to feed on both birds and mammals. There was remarkable diversity in the range of avian hosts: 23 species from four orders were identified in the abdomens of four Culicoides species. The most common bird species identified was the magpie, Pica pica (n = 7), which was registered in all four ornithophilic biting midge species. Six bloodmeals from the great tit, Parus major, were recorded only in C. alazanicus. None of the studied species of Culicoides appeared to be restricted to a single avian host. PMID- 25689116 TI - Prevalence of endocrine and metabolic disorders in subjects with erectile dysfunction: a comparative study. AB - INTRODUCTION: Alterations of gonadal, thyroid, and pituitary hormones, along with metabolic disorders, might be involved in causing erectile dysfunction (ED). AIM: The prevalence of endocrine abnormalities in two different cohorts from the general and the symptomatic populations of Florence was compared. METHODS: The first group is a general population sample derived from a Florentine spin-off of the European Male Aging Study (EMAS cohort; n = 202); the second group is a series of n = 3,847 patients attending our clinic for ED (UNIFI cohort). RESULTS: Both primary and secondary hypogonadism were more often observed in the UNIFI than in the EMAS cohort (2.8 vs. 0%; P < 0.05 and 18.9 vs. 8%; P < 0.001, respectively). However, only the second association retained statistical significance after adjusting for age. Compensated hypogonadism was more common in the EMAS cohort (4.4 vs. 8.1%; P < 0.05). No statistically significant difference in the prevalence of overt thyroid disorders was observed. Conversely, subclinical hyperthyroidism was more prevalent in the EMAS cohort (2 vs. 4.1%, P < 0.05). No significant difference in the prevalence of hyperprolactinemia was detected, while the prevalence of hypoprolactinemia was significantly higher in the UNIFI than in the EMAS cohort (28.2% vs. 17.8%, P = 0.001), even after the adjustment for age, BMI, and testosterone (P = 0.001). Central obesity (waist >=102 cm), impaired fasting glucose (IFG), and type 2 diabetes mellitus (T2DM) were more often detected in UNIFI patients (31.7 vs. 22.8%, P < 0.05; 44.5 vs. 33.3%, P < 0.05; 20.1% vs. 1.0%, P < 0.001 in the UNIFI and EMAS cohort, respectively), even after adjusting for age. In contrast, the prevalence of overweight and obesity did not differ between the two groups. CONCLUSION: T2DM, IFG, central obesity, secondary hypogonadism, and hypoprolactinemia are more frequent in subjects consulting for ED than in the general population of the same geographic area. Our data suggest that these conditions could play a central role in determining consultation for ED. PMID- 25689115 TI - Engineering Biomaterial-Drug Conjugates for Local and Sustained Chemotherapeutic Delivery. AB - The standard of care for cancer patients includes surgical resection, radiation, and chemotherapy with cytotoxic chemotherapy drugs usually part of the treatment. However, these drugs are commonly associated with cardiotoxicity, ototoxicity, nephrotoxicity, peripheral neuropathy, and myelosuppression. Strategies to deliver cytotoxic chemotherapy drugs while reducing secondary toxicity and increasing tumor dosing would therefore be desirable. This goal can be achieved through the use of controlled release drug carrier systems. The aim of this review is to provide an overview of clinically used drug carrier systems and recently developed approaches for drug-biomaterial conjugation. PMID- 25689117 TI - Montanide ISA 71 VG is Advantageous to Freund's Adjuvant in Immunization Against S. aureus Infection of Mice. AB - The enormous capacity of Staphylococcus aureus to acquire antibiotic resistance makes it a permanent task to search for and to develop new anti-infectives. One of the possible approaches is the early active immunization of risk patients and animal stocks to prevent S. aureus infections. Based on a S. aureus proteome screen with S. aureus-specific human antiserum, we have previously identified several anchorless cell wall proteins to be used as novel vaccine candidates. To develop an efficient anti-S. aureus vaccine, the supplemented adjuvants Montanide(TM) ISA 71 VG and ISA 206 were compared to Freund's adjuvant in terms of handling, induction of cytokine profile, triggering antigen-specific immunoglobulin production of different IgG subclasses and provision of increased survival rates in our S. aureus sepsis mouse model. Immunization with ISA 71 VG in comparison with Freund's adjuvant induced slightly delayed but comparably strong increase of antigen-specific antibody titres and conferred protective effect against S. aureus challenge. In contrast using ISA 206 as adjuvant, significantly lower IgG titres and consequently, no protective effect against S. aureus infection were observed. Handling and tolerability of the Montanide is superior to Freund's adjuvant. Montanide(TM) ISA 71 VG can serve as an effective adjuvant replacement for Freund's adjuvant in research with a prospective usage in animal and human vaccines against bacterial pathogens. PMID- 25689118 TI - New Face for Chromatin-Related Mesenchymal Modulator: n-CHD9 Localizes to Nucleoli and Interacts With Ribosomal Genes. AB - Mesenchymal stem cells' differentiation into several lineages is coordinated by a complex of transcription factors and co-regulators which bind to specific gene promoters. The Chromatin-Related Mesenchymal Modulator, CHD9 demonstrated in vitro its ability for remodeling activity to reposition nucleosomes in an ATP dependent manner. Epigenetically, CHD9 binds with modified H3-(K9me2/3 and K27me3). Previously, we presented a role for CHD9 with RNA Polymerase II (Pol II) dependent transcription of tissue specific genes. Far less is known about CHD9 function in RNA Polymerase I (Pol I) related transcription of the ribosomal locus that also drives specific cell fate. We here describe a new form, the nucleolar CHD9 (n-CHD9) that is dynamically associated with Pol I, fibrillarin, and upstream binding factor (UBF) in the nucleoli, as shown by imaging and molecular approaches. Inhibitors of transcription disorganized the nucleolar compartment of transcription sites where rDNA is actively transcribed. Collectively, these findings link n-CHD9 with RNA pol I transcription in fibrillar centers. Using chromatin immunoprecipitation (ChIP) and tilling arrays (ChIP- chip), we find an association of n-CHD9 with Pol I related to rRNA biogenesis. Our new findings support the role for CHD9 in chromatin regulation and association with rDNA genes, in addition to its already known function in transcription control of tissue specific genes. PMID- 25689119 TI - Oncostatin m modulation of lipid storage. AB - Oncostatin M (OSM) is a cytokine belonging to the gp130 family, whose members serve pleiotropic functions. However, several actions of OSM are unique from those of other gp130 cytokines, and these actions may have critical roles in inflammatory mechanisms influencing several metabolic and biological functions of insulin-sensitive tissues. In this review, the actions of OSM in adipose tissue and liver are discussed, with an emphasis on lipid metabolism. PMID- 25689120 TI - Early glial activation precedes neurodegeneration in the cerebral cortex after SIV infection: a 3D, multivoxel proton magnetic resonance spectroscopy study. AB - OBJECTIVES: As ~40% of HIV-infected individuals experience neurocognitive decline, we investigated whether proton magnetic resonance spectroscopic imaging ((1) H-MRSI) detects early metabolic abnormalities in the cerebral cortex of a simian immunodeficiency virus (SIV)-infected rhesus monkey model of neuroAIDS. METHODS: The brains of five rhesus monkeys before and 4 or 6 weeks after SIV infection (with CD8(+) T-cell depletion) were assessed with T2 -weighted quantitative magnetic resonance imaging (MRI) and 16*16*4 multivoxel (1) H-MRSI (echo time/repetition time = 33/1440 ms). Grey matter and white matter masks were segmented from the animal MRIs and used to produce cortical masks co-registered to (1) H-MRSI data to yield cortical metabolite concentrations of the glial markers myo-inositol (mI), creatine (Cr) and choline (Cho), and of the neuronal marker N-acetylaspartate (NAA). The cortex volume within the large, 28 cm(3) (~35% of total monkey brain) volume of interest was also calculated for each animal pre- and post-infection. Mean metabolite concentrations and cortex volumes were compared pre- and post-infection using paired sample t-tests. RESULTS: The mean (+/- standard deviation) pre-infection concentrations of the glial markers mI, Cr and Cho were 5.8 +/- 0.9, 7.2 +/- 0.4 and 0.9 +/- 0.1 mM, respectively; these concentrations increased 28% (p ~ 0.06), 15% and 10% (both p < 0.05), respectively, post-infection. The mean concentration of neuronal marker NAA remained unchanged (7.0 +/- 0.6 mM pre-infection vs. 7.3 +/- 0.8 mM post infection; p ~ 0.37). The mean cortex volume was also unchanged (8.1 +/- 1.1 cm(3) pre-infection vs. 8.3 +/- 0.5 cm(3) post-infection; p ~ 0.76). CONCLUSIONS: These results support the hypothesis that early cortical glial activation occurs after SIV infection prior to the onset of neurodegeneration. This suggests HIV therapeutic interventions should potentially target early glial activation in the cerebral cortex. PMID- 25689121 TI - Mesenteric ischemia. AB - PURPOSE OF REVIEW: Diagnosis of acute mesenteric ischemia in the early stages is now possible with modern computed tomography (CT), using intravenous contrast enhancement and imaging in the arterial and/or portal venous phase. The availability of CT around the clock means that more patients with acute mesenteric ischemia may be treated with urgent intestinal revascularization. RECENT FINDINGS: The establishment of a hybrid operation room is most important to be able to perform explorative laparotomy for evaluation of the extent of mesenteric ischemia and successful intestinal revascularization. Endovascular recanalization and stenting has become an important alternative, especially in patients with both acute and chronic thrombotic superior mesenteric artery (SMA) occlusion. Aspiration embolectomy, thrombolysis and open surgical embolectomy, followed by on-table angiography, are the treatment options for embolic SMA occlusion. Endovascular therapy may be an option in the few patients with mesenteric venous thrombosis who do not respond to anticoagulation therapy. The concept of damage-control surgery is recommended after intestinal revascularization. SUMMARY: Intestinal revascularization in patients with arterial occlusive mesenteric ischemia reduces bowel morbidity and mortality. Observational studies report that both endovascular and open vascular therapy options are effective, but endovascular technique may be preferred in these often elderly and fragile patients. PMID- 25689122 TI - Why is diagnosing brain death so confusing? AB - PURPOSE OF REVIEW: Although detailed practice parameters have been developed to help guide physicians in brain death determination, guidelines based on these parameters widely vary. The recent case of Jahi McMath not only highlights social misconceptions but also serves as a call to action to decrease medical variability and confusion regarding brain death determination. This review discusses common sources of variations in brain death determination - we divide these sources into before, during, and after brain death declaration. RECENT FINDINGS: We use four key studies to elucidate variable practice in brain death determination. Poor training of examiners and patient qualifications for brain death examination prior to testing, incomplete apnea testing, repeat examinations during testing, and the sometimes unjustified use of ancillary testing are highlighted as main areas for improvement. Improved physician training and certification, as well as better standardization of hospital protocols, may be answers to more universal practice. SUMMARY: Diagnosing brain death is confusing because of numerous variations in practice, but this variation can be improved. Improved and standardized physician training can help create a formal certification process for examiners and help create uniformity in brain death determination. National standards will also help decrease variability of practice. PMID- 25689123 TI - Recommendations for the use of multimodal monitoring in the neurointensive care unit. AB - PURPOSE OF REVIEW: Multimodal monitoring (MMM) is routinely applied in neurointensive care. Unfortunately, there is no robust evidence on which MMM derived physiologic variables are the most clinically relevant, how and when they should be monitored, and whether MMM impacts outcome. The complexity is even higher because once the data are continuously collected, interpretation and integration of these complex physiologic events into targeted individualized care is still embryonic. RECENT FINDINGS: Recent clinical investigation mainly focused on intracranial pressure, perfusion of the brain, and oxygen availability along with electrophysiology. Moreover, a series of articles reviewing the available evidence on all the MMM tools, giving practical recommendations for bedside MMM, has been published, along with other consensus documents on the role of neuromonitoring and electroencephalography in this setting. SUMMARY: MMM allows comprehensive exploration of the complex pathophysiology of acute brain damage and, depending on the different configuration of the pathological condition we are treating, the application of targeted individualized care. Unfortunately, we still lack robust evidence on how to better integrate MMM-derived information at the bedside to improve patient management. Advanced informatics is promising and may provide us a supportive tool to interpret physiologic events and guide pathophysiological-based therapeutic decisions. PMID- 25689124 TI - Reversal of the novel oral anticoagulants dabigatran, rivoraxaban, and apixaban. AB - PURPOSE OF REVIEW: We summarize the available data related to reversing the anticoagulant effect of the oral direct thrombin and factor Xa inhibitors and provide our opinion on treating patients presenting with severe and life threatening hemorrhage related to these agents. RECENT FINDINGS: No specific antidotes are currently available for the oral direct thrombin and factor Xa inhibitors but two promising agents are under investigation in phase 3 trials. No data are available on reversing these agents in bleeding patients. Activated charcoal may be effective in reducing factor Xa inhibitor absorption up to 6 h after ingestion. Animal models suggest that unactivated 4-factor prothrombin complex concentrate may be an effective reversal agent. Recent data in warfarin treated patients suggest that 4-factor prothrombin complex concentrate may provide more rapid and effective hemostasis than fresh frozen plasma. SUMMARY: In the absence of evidence in bleeding patients, animal models and ex-vivo studies suggest administration of coagulant factors in the form of hemostatic agents may be of benefit in reversing the effect of direct thrombin and factor Xa inhibitors. Specific reversal agents and clinical data in patients with hemorrhage remain an unmet need. PMID- 25689125 TI - Blood pressure management in acute intracerebral hemorrhage: current evidence and ongoing controversies. AB - PURPOSE OF REVIEW: Spontaneous intracerebral hemorrhage (ICH) is associated with high rates of morbidity and mortality. Although treatment options are limited, a potential acute medical intervention is blood pressure (BP) reduction. The review will summarize the current evidence and remaining knowledge gaps with respect to acute BP management in acute ICH. RECENT FINDINGS: More than 3000 patients were enrolled in seven prospective randomized-controlled clinical trials assessing the safety and efficacy of intensive BP reduction (target <140-150 mmHg systolic) compared with current guideline-recommended BP target (<180 mmHg) in acute ICH. Overall, these trials demonstrated that intensive BP reduction is well tolerated and may be associated with a modest improvement in functional outcomes. There is still no conclusive evidence that aggressive BP reduction is associated with attenuation of hematoma growth or mortality rates. Delayed time to enrolment and difficulty in achieving intensive BP targets in a timely fashion without stringent antihypertensive protocols may partially account for the absence of proven benefit. SUMMARY: Recent trials have shown that BP lowering (<140 mmHg systolic) is well tolerated and may improve functional outcomes. Ongoing trials will provide insight into the overall benefit of early aggressive BP reduction in acute ICH. PMID- 25689126 TI - Recommendations for management of large hemispheric infarction. AB - PURPOSE OF REVIEW: Large hemispheric infarction is a devastating disease that continues to be associated with significant mortality and morbidity. Most often these patients are admitted to the ICU requiring significant physician and nursing resources. This review will address some of the ICU management issues and review the evidence supporting medical and surgical management of malignant cerebral edema. RECENT FINDINGS: The most recent changes in management of large hemispheric infarct include the American Heart Association and Neurocritical Care Guidelines. These guidelines address airway management and mechanical ventilation, blood pressure control, fluid management, and glucose and temperature control. In addition, they addressed the indication for surgical management of cerebral edema. We review the recent guidelines updates and trials of surgical management of large hemispheric infarcts. SUMMARY: Large hemispheric infarcts continue to have significant morbidity and mortality. Recent guidelines have provided an excellent framework to help intensivists manage these complicated patients. Recent surgical data continue to support early hemicraniectomy even in elderly patients. PMID- 25689127 TI - Update on acute liver failure. AB - PURPOSE OF REVIEW: Although advances in critical care management and liver transplantation have improved survival in acute liver failure (ALF), mortality remains significant. An evidence base to support management has been lacking, due to the condition's rarity, severity and heterogeneity. The purpose of this review is to critically appraise the latest evidence, updating clinicians on the current understanding of the best management. RECENT FINDINGS: Transplant-free survival in acetaminophen-related ALF has improved considerably, such that reconsidering thresholds for transplant is required, perhaps utilizing biomarkers of liver regeneration. Autoimmune hepatitis-related ALF may be too advanced to permit rescue with corticosteroids, which could be deleterious in the sickest patients. Acute kidney injury is commoner in ALF than previously suspected. Intracranial pressure monitoring does not appear to alter mortality. Despite altered traditional indices of coagulation, new thrombin generation assays suggest a rebalanced coagulation in liver failure. Antimicrobial prophylaxis may not be required in all patients. Liver support systems remain controversial and require further evaluation. SUMMARY: Traditional dogma in ALF management is questioned: transplant thresholds for acetaminophen overdose, steroid use in autoimmune ALF, routine antimicrobial prophylaxis, the coagulopathy of liver disease, the value of intracranial pressure monitoring and extracorporeal liver support. PMID- 25689128 TI - Outcome in fetal lower urinary tract obstruction: a prospective registry study. AB - OBJECTIVE: To describe influences on decision-making and prognostic variables in the prenatal management of fetal lower urinary tract obstruction (LUTO). METHODS: This was a prospective registry study of pregnant women with a male fetus with LUTO from centers within the British Isles and The Netherlands. Women and/or their clinicians were given the treatment option of either conservative management or vesicoamniotic shunting (VAS). Baseline characteristics of women in the registry, reasons for entry to the registry and pregnancy outcomes were assessed. The main study outcomes were survival to 28 days after delivery, further survival to 2 years and renal function. Logistic regression analysis was used to examine prognostic variables that affected outcome. Results were compared with those of women in a randomized controlled trial (RCT) who were allocated randomly to a treatment option. RESULTS: Forty-five women were registered, of whom 78% (35/45) underwent conservative management. Twenty-seven women entered the registry owing to their clinician's preference for management and 18 because of their own preference. Compared to the conservative-management group of the RCT, a higher proportion of women in the registry opting for conservative management had a normal amniotic fluid volume at diagnosis (P = 0.05) and a diagnosis of LUTO >= 24 weeks' gestation (P = 0.003). On multivariable logistic regression analysis, these variables showed a significant association with perinatal survival (P < 0.001). Survival to 28 days after delivery was higher in the conservative-management group, at 69% (24/35), compared to 40% (4/10) in the VAS group (P = 0.02) but this difference had limited statistical significance owing to small study size (relative risk, 0.58 (95% CI, 0.26-1.29); P = 0.14). CONCLUSION: In our prospective registry, the majority of fetuses with LUTO received conservative management, which was associated with better short- and long-term outcomes. A significant proportion of these pregnancies had normal amniotic fluid volume and a gestational age at diagnosis of >= 24 weeks, characteristics shown to be associated with improved survival. PMID- 25689129 TI - Direct estimation of austenitic grain dimensions in heat affected zones of a martensitic steel from EBSD images. AB - In the context of automated analyses of electron-backscattered-diffraction images, we present in this paper a novel method to automatically extract morphological properties of prior austenitic grains in martensitic steels based on raw crystallographic orientation maps. This quantification includes the estimation of the mean chord length in specific directions, with in addition the reconstruction of the mean shape of austenitic grains inducing anisotropic shape properties. The approach is based on the morphological measure of covariance on a decision curve of grain fidelity per disorientation angle. These efforts have been motivated by the need of realistic microstructures to perform micromechanical studies of grain boundary localized damage phenomenons in steels, one example being the type IV fracture phenomenon occurring in welded joints of grade P91/P92 steel. This failure is attributed to a change of the microstructure due to thermal gradients arising during the welding process. To precisely capture the relationships between microstructural changes and mechanical fields localization in a polycrystalline aggregate, we first need to achieve a reasonable stochastic model of its microstructure, which relies on a detailed knowledge of the microstructural morphology. As martensitic steels possess multiscale microstructures composed of prior austenitic grains, packets and laths, a relevant modelling strategy has to be proposed to account for the observed hierarchies. With this objective, this paper focuses on the larger scale entities present in the microstructure, namely, the austenitic grains. PMID- 25689130 TI - Impact of an experimental PRRSV and Streptococcus suis coinfection on the pharmacokinetics of ceftiofur hydrochloride after intramuscular injection in pigs. AB - This study determined the impact of porcine reproductive and respiratory syndrome virus (PRRSV) and Streptococcus suis coinfection on the pharmacokinetic (PK) profile of ceftiofur hydrochloride in pigs after intramuscular (i.m.) injection. Eighteen clinically normal crossbred gilts were assigned by weight into a challenge group (10 pigs) and control group (eight pigs). Pigs in both groups received a single i.m. injection of ceftiofur hydrochloride (Excenel RTU Sterile Suspension; Zoetis) at a 5 mg/kg BW dose. Serial blood samples were collected to characterize the plasma concentration curve. After a 10 days drug washout period, the challenge group was inoculated with 2 mL of PRRSV isolate VR-2385 (10(5.75) 50% tissue culture infective doses per mL) intranasally and 8 days later inoculated S. suis. When clinical disease was evident, the second PK assessment began in both challenge and control groups. Coinfected pigs demonstrated lower values of AUC and CMAX , but higher values of Cl/F and Vz/F indicating drug kinetics were altered by infection. The data from this study have implications on ceftiofur treatment regimens in diseased pigs. PMID- 25689131 TI - Chemogenomic profiling of endogenous PARK2 expression using a genome-edited coincidence reporter. AB - Parkin, an E3 ubiquitin ligase, is a central mediator of mitochondrial quality control and is linked to familial forms of Parkinson's disease (PD). Removal of dysfunctional mitochondria from the cell by Parkin is thought to be neuroprotective, and pharmacologically increasing Parkin levels may be a novel therapeutic approach. We used genome-editing to integrate a coincidence reporter into the PARK2 gene locus of a neuroblastoma-derived cell line and developed a quantitative high-throughput screening (qHTS) assay capable of accurately detecting subtle compound-mediated increases in endogenous PARK2 expression. Interrogation of a chemogenomic library revealed diverse chemical classes that up regulate the PARK2 transcript, including epigenetic agents, drugs controlling cholesterol biosynthesis, and JNK inhibitors. Use of the coincidence reporter eliminated wasted time pursuing reporter-biased false positives accounting for ~2/3 of the actives and, coupled with titration-based screening, greatly improves the efficiency of compound selection. This approach represents a strategy to revitalize reporter-gene assays for drug discovery. PMID- 25689132 TI - Quantitative proteomics and network analysis of SSA1 and SSB1 deletion mutants reveals robustness of chaperone HSP70 network in Saccharomyces cerevisiae. AB - Molecular chaperones play an important role in protein homeostasis and the cellular response to stress. In particular, the HSP70 chaperones in yeast mediate a large volume of protein folding through transient associations with their substrates. This chaperone interaction network can be disturbed by various perturbations, such as environmental stress or a gene deletion. Here, we consider deletions of two major chaperone proteins, SSA1 and SSB1, from the chaperone network in Sacchromyces cerevisiae. We employ a SILAC-based approach to examine changes in global and local protein abundance and rationalise our results via network analysis and graph theoretical approaches. Although the deletions result in an overall increase in intracellular protein content, correlated with an increase in cell size, this is not matched by substantial changes in individual protein concentrations. Despite the phenotypic robustness to deletion of these major hub proteins, it cannot be simply explained by the presence of paralogues. Instead, network analysis and a theoretical consideration of folding workload suggest that the robustness to perturbation is a product of the overall network structure. This highlights how quantitative proteomics and systems modelling can be used to rationalise emergent network properties, and how the HSP70 system can accommodate the loss of major hubs. PMID- 25689134 TI - Vanadium(V) Oxo and imido calix[8]arene complexes: synthesis, structural studies, and ethylene homo/copolymerisation capability. AB - Interaction of p-tert-butylcalix[8]areneH8 (L(8) H8 ) with [NaVO(OtBu)4 ] (formed in situ from VOCl3 ) afforded the complex [Na(NCMe)5 ][(VO)2 L(8) H]?4 MeCN (1?4 MeCN). Increasing [NaVO(OtBu)4 ] to 4 equiv led to [Na(NCMe)6 ]2 [(Na(VO)4 L(8) )(Na(NCMe))3 ]2 ?10 MeCN (2?10 MeCN). With adventitious oxygen, reaction of 4 equiv of [VO(OtBu)3 ] with L(8) H8 afforded the alkali-metal-free complex [(VO)4 L(8) (MU(3) -O)2 ] (3); solvates 3?3 MeCN and 3?3 CH2 Cl2 were isolated. For the lithium analogue, the order of addition had to be reversed such that lithium tert butoxide was added to L(8) H8 and then treated with 2 equiv of VOCl3 ; crystallisation afforded [(VO2 )2 Li6 [L(8) ](thf)2 (OtBu)2 (Et2 O)2 ]?Et2 O (4?Et2 O). Upon extraction into acetonitrile, [Li(NCMe)4 ][(VO)2 L(8) H]?8 MeCN (5?8 MeCN) was formed. Use of the imido precursors [V(NtBu)(OtBu)3 ] and [V(Np tolyl)(OtBu)3 ] and L(8) H8 , afforded [tBuNH3 ][{V(p-tolylN)}2 L(8) H]?3 1/2 MeCN (6?3 1/2 MeCN). The molecular structures of 1 to 6 are reported. Complexes 1, 3, and 4 were screened as precatalysts for the polymerisation of ethylene in the presence of cocatalysts at various temperatures and for the copolymerisation of ethylene with propylene. Activities as high as 136 000 g (mmol(V) h)(-1) were sometimes achieved; higher molecular weight polymers could be obtained versus the benchmark [VO(OEt)Cl2 ]. For copolymerisation, incorporation of propylene was 7.1 10.9 mol % (compare 10 mol % for [VO(OEt)Cl2 ]), although catalytic activities were lower than [VO(OEt)Cl2 ]. PMID- 25689133 TI - Diguanylate cyclase null mutant reveals that C-Di-GMP pathway regulates the motility and adherence of the extremophile bacterium Acidithiobacillus caldus. AB - An understanding of biofilm formation is relevant to the design of biological strategies to improve the efficiency of the bioleaching process and to prevent environmental damages caused by acid mine/rock drainage. For this reason, our laboratory is focused on the characterization of the molecular mechanisms involved in biofilm formation in different biomining bacteria. In many bacteria, the intracellular levels of c-di-GMP molecules regulate the transition from the motile planktonic state to sessile community-based behaviors, such as biofilm development, through different kinds of effectors. Thus, we recently started a study of the c-di-GMP pathway in several biomining bacteria including Acidithiobacillus caldus. C-di-GMP molecules are synthesized by diguanylate cyclases (DGCs) and degraded by phosphodiesterases (PDEs). We previously reported the existence of intermediates involved in c-di-GMP pathway from different Acidithiobacillus species. Here, we report our work related to At. caldus ATCC 51756. We identified several putative-ORFs encoding DGC and PDE and effector proteins. By using total RNA extracted from At. caldus cells and RT-PCR, we demonstrated that these genes are expressed. We also demonstrated the presence of c-di-GMP by mass spectrometry and showed that genes for several of the DGC enzymes were functional by heterologous genetic complementation in Salmonella enterica serovar Typhimurium mutants. Moreover, we developed a DGC defective mutant strain (Deltac1319) that strongly indicated that the c-di-GMP pathway regulates the swarming motility and adherence to sulfur surfaces by At. caldus. Together, our results revealed that At. caldus possesses a functional c-di-GMP pathway which could be significant for ores colonization during the bioleaching process. PMID- 25689135 TI - A catalytic path for electrolyte reduction in lithium-ion cells revealed by in situ attenuated total reflection-Fourier transform infrared spectroscopy. AB - Although controlling the interfacial chemistry of electrodes in Li-ion batteries (LIBs) is crucial for maintaining the reversibility, electrolyte decomposition has not been fully understood. In this study, electrolyte decomposition on model electrode surfaces (Au and Sn) was investigated by in situ attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopy. Simultaneously obtained ATR-FTIR spectra and cyclic voltammetry measurements show that lithium ethylene dicarbonate and lithium propionate form on the Au electrode at 0.6 V, whereas diethyl 2,5-dioxahexane dicarboxylate and lithium propionate form on the Sn electrode surface at 1.25 V. A noncatalytic reduction path on the Au surface and a catalytic reduction path on the Sn surface are introduced to explain the surface dependence of the overpotential and product selectivity. This represents a new concept for explaining electrolyte reactions on the anode of LIBs. The present investigation shows that catalysis plays a dominant role in the electrolyte decomposition process and has important implications in electrode surface modification and electrolyte recipe selection, which are critical factors for enhancing the efficiency, durability, and reliability of LIBs. PMID- 25689137 TI - Novel hybrid organic thermoelectric materials:three-component hybrid films consisting of a nanoparticle polymer complex, carbon nanotubes, and vinyl polymer. AB - A novel class of hybrid organic thermoelectric materials is demonstrated for the first time for constructing flexible thermoelectric devices on polyimide substrates with high output power by using nanotechnology instead of conducting polymers such as poly(3,4-ethylenedioxythiophene). The hybrid organic thermoelectric materials are composed of nanoparticles of a polymer complex, carbon nanotubes, and poly(vinyl chloride), and show high performance (dimensionless thermoelectric figure-of-merit, ZT ~ 0.3, based on the thermal conductivity through the film). PMID- 25689136 TI - A biologically constrained, mathematical model of cortical wave propagation preceding seizure termination. AB - Epilepsy--the condition of recurrent, unprovoked seizures--manifests in brain voltage activity with characteristic spatiotemporal patterns. These patterns include stereotyped semi-rhythmic activity produced by aggregate neuronal populations, and organized spatiotemporal phenomena, including waves. To assess these spatiotemporal patterns, we develop a mathematical model consistent with the observed neuronal population activity and determine analytically the parameter configurations that support traveling wave solutions. We then utilize high-density local field potential data recorded in vivo from human cortex preceding seizure termination from three patients to constrain the model parameters, and propose basic mechanisms that contribute to the observed traveling waves. We conclude that a relatively simple and abstract mathematical model consisting of localized interactions between excitatory cells with slow adaptation captures the quantitative features of wave propagation observed in the human local field potential preceding seizure termination. PMID- 25689138 TI - Early postoperative continuous glucose monitoring in pancreas transplant recipients. AB - Continuous glucose monitoring (CGM) is used in people with type 1 diabetes to help with insulin treatment regimens. Its value in whole-organ pancreas transplantation (PT) is largely unknown. This study aimed to use CGM to assess the metabolic profile of pancreas transplant recipients in the early post transplant period. We studied CGM data in 30 PT recipients and related findings to an early oral glucose tolerance test (OGTT). Complete data were available for 26 recipients. Seven days after a PT, normoglycaemia was present 77.9% of the time. Hypoglycaemic events (glucose <3.9 mmol/l) occurred in 10 of 26 (38.5%) of the cohort, but were infrequent (present 1.4% of the time). Hyperglycaemia (glucose >7.8 mmol/l) was present for 20.7% of the study period and correlated with a diagnosis of abnormal glucose tolerance. Whilst normoglycaemia is successfully achieved for the majority of the time after PT, hypoglycaemia can occur. Hyperglycaemia is more common and correlates well with the early postoperative OGTT, which is associated with graft failure. CGM is easier to perform and provides 24-h data that could inform clinical decision-making in patients in the postoperative period. PMID- 25689139 TI - Aerobic oxidation of alcohols and the synthesis of benzoxazoles catalyzed by a cuprocupric coordination polymer (Cu(+)-CP) assisted by TEMPO. AB - A Cu(+)-CP based on the tetranuclear unit {[(HSQPA)2Cu4(bipy)4].2H2O}n.2nH2O has been constructed through Cu(2+) salt, 2-(sulfonylquinlium-8-yloxy)phthalic acid (H3SQPA), and 4,4'-bipyridine (bipy). This Cu(+)-CP combined with 2,2,6,6 tetramethylpiperidine-1-oxyl as the cocatalyst is an effective catalyst for aerobic oxidation of alcohols and the synthesis of benzoxazoles and can be recycled at least four times without losing its catalytic activity. PMID- 25689140 TI - Morphometry, bite-force, and paleobiology of the late miocene caiman Purussaurus brasiliensis. AB - Purussaurus brasiliensis thrived in the northwestern portion of South America during the Late Miocene. Although substantial material has been recovered since its early discovery, this fossil crocodilian can still be considered as very poorly understood. In the present work, we used regression equations based on modern crocodilians to present novel details about the morphometry, bite-force and paleobiology of this species. According to our results, an adult Purussaurus brasiliensis was estimated to reach around 12.5 m in length, weighing around 8.4 metric tons, with a mean daily food intake of 40.6 kg. It was capable of generating sustained bite forces of 69,000 N (around 7 metric tons-force). The extreme size and strength reached by this animal seems to have allowed it to include a wide range of prey in its diet, making it a top predator in its ecosystem. As an adult, it would have preyed upon large to very large vertebrates, and, being unmatched by any other carnivore, it avoided competition. The evolution of a large body size granted P. brasiliensis many advantages, but it may also have led to its vulnerability. The constantly changing environment on a large geological scale may have reduced its long-term survival, favoring smaller species more resilient to ecological shifts. PMID- 25689141 TI - Effects of type I collagen degradation on the durability of three adhesive systems in the early phase of dentin bonding. AB - OBJECTIVE: This study was designed to evaluate the effects of type I collagen degradation on the durability of three adhesive systems in the early phase of dentin bonding. METHODS: Bonded dentin specimens were prepared using three different types of adhesive systems. Micro-tensile bond strength and degradation of collagen were tested before, and after 1 month or 4 months of aging in artificial saliva. The relationship between micro-tensile bond strength and collagen degradation was analyzed by calculating their Pearson's correlation coefficient. RESULTS: Aging induced time-dependent reduction in micro-tensile bond strengths for all the tested adhesive systems, although such reduction for the single-step self-etching adhesive G-Bond (GB) was not statistically significant. The bond strength of the two-step self-etching primer adhesive system Clearfil SE Bond (SEB) was similar to that of the two-step etch-and-rinse self-priming adhesive system Single Bond 2 (SB), and they were both significantly reduced after one or four months of aging. A negative correlation was found between the degree of collagen degradation and magnitude of micro-tensile bond strength (r = -0.65, p = 0.003). The Pearson's correlation coefficient was 0.426, indicating that 42.6% of the aging-induced reduction in bond strength can be explained by the degradation of collagen. CONCLUSIONS: In the early phase of dentin bonding, there was a negative correlation between the degree of collagen degradation and the magnitude of micro-tensile bond strength. The reduction of bond strength was accompanied by the degradation of collagen. These results provide evidence for the causative relationship between the degradation of collagen and the deterioration of dentin-adhesive interface. PMID- 25689142 TI - Influence of intracellular zinc on cultures of rat cardiac neural crest cells. AB - BACKGROUND: Developmental zinc (Zn) deficiency increases the incidence of heart anomalies in rat fetuses, in regions and structures derived from the outflow tract. Given that the development of the outflow tract requires the presence of cardiac neural crest cells (cNCC), we speculated that Zn deficiency selectively kills cNCC and could lead to heart malformations. METHODS: Cardiac NCC were isolated from E10.5 rat embryos and cultured in control media (CTRL), media containing 3 MUM of the cell permeable metal chelator N, N, N', N'-tetrakis (2 pyridylmethyl) ethylene diamine (TPEN), or in TPEN-treated media supplemented with 3 MUM Zn (TPEN + Zn). Cardiac NCC were collected after 6, 8, and 24 h of treatment to assess cell viability, proliferation, and apoptosis. RESULTS: The addition of TPEN to the culture media reduced free intracellular Zn pools and cell viability as assessed by low ATP production, compared to cells grown in control or Zn-supplemented media. There was an accumulation of reactive oxygen species, a release of mitochondrial cytochrome c into the cytoplasm, and an increased cellular expression of active caspase-3 in TPEN-treated cNCC compared to cNCC cultured in CTRL or TPEN + Zn media. CONCLUSION: Zn deficiency can result in oxidative stress in cNCC, and subsequent decreases in their population and metabolic activity. These data support the concept that Zn deficiency associated developmental heart defects may arise in part as a consequence of altered cNCC metabolism. PMID- 25689143 TI - Biotherapy of pancreatic neuroendocrine tumors using somatostatin analogs. AB - Basically, pancreatic neuroendocrine tumor (PNET) should be treated surgically; however, in unresectable cases, a treatment that aims to improve the prognosis by inhibiting the growth of the tumor and control the clinical symptoms becomes necessary. In the case of functional tumors, the quality of life of patients is decreased by not only the symptoms with tumor invasion and/or metastasis but also by the symptoms of hormone excess. The efficacy of somatostatin analogs against the latter has been previously reported, and their sustained release formulations have been developed. Somatostatin analogs are recommended to treat the endocrine symptoms of functional PNET; however, in case they can cause hypoglycemia in patients with insulinoma. On the other hand, results from the PROMID study demonstrated a tumor-stabilizing effect when octreotide LAR (long acting repeatable) was used to treat patients with advanced midgut NET; however, there has been no consensus regarding its antitumor effect for PNET. Additionally, a recent result from the CLARINET study suggests that lanreotide autogel has an antitumor effect against nonfunctional NET including PNET. Further clinical study results are awaited. PMID- 25689144 TI - Do Chest Expansion Exercises Aid Re-shaping the Diaphragm Within the First 72 Hours Following Lung Transplantation in a Usual Interstitial Pneumonia Patient? AB - BACKGROUND AND PURPOSE: Usual interstitial pneumonia is a chronic pulmonary disease, and it is characterized by progressive and rapid lung fibrosis and typically affects patients older than 50 years. This study sought to discuss the use of chest expansion exercises during the immediate post-operative phase in a lung transplantation recipient. METHODS: This was a non-experimental case report study. A 58-year-old man who was affected by usual interstitial pneumonia with severe respiratory insufficiency requiring continuous oxygen therapy underwent double lung transplantation. Pre-operative x-ray showed elevation of the diaphragm. Rehabilitation treatment started within the first 24 h. Pain intensity was assessed using a numeric rating scale, and pulmonary function was evaluated based on variation in tidal volume. Each treatment lasted about 1 h, and the sessions were initially carried out twice daily, increasing over the intensive care unit stay to three or four times daily. RESULTS: At 72 h, the tidal volume increased to 850-900 mL (approximately 400 mL more than baseline) during the chest expansion exercises. The diaphragm began to gradually lower. Chest x-ray examination on post-operative day 6 showed further reshaping of the diaphragm. CONCLUSION: Chest expansion exercises seem to be suitable in order to re establish lung volume and diaphragmatic function as early as within the first 72 h after bilateral lung transplantation. PMID- 25689145 TI - Human body donation programs in Sri Lanka: Buddhist perspectives. AB - Considerable attention is being given to the availability of bodies for anatomical education. This raises the question of the manner in which they are obtained, that is, whether they are unclaimed or donated. With increasing emphasis upon the ethical desirability of using body bequests, the spotlight tends to be focused on those countries with factors that militate against donations. However, little attention has been paid to cultures where donations are readily available. One such country is Sri Lanka where the majority of the Buddhist population follows Theravada Buddhism. Within this context, the expectation is that donations will be given selflessly without expecting anything in return. This is because donation of one's body has blessings for a better outcome now and in the afterlife. The ceremonies to honor donors are outlined, including details of the "Pirith Ceremony." The relevance for other cultures of these features of body donation is discussed paying especial attention to the meaning of altruism and consent, and justification for the anonymization of cadavers. The degree to which anatomy is integrated into the surrounding culture also emerges as significant. PMID- 25689146 TI - A randomized, placebo-controlled trial of AFQ056 for the treatment of chorea in Huntington's disease. AB - BACKGROUND: This study investigated the hypothesis that AFQ056 (mavoglurant), a selective metabotropic glutamate receptor 5 antagonist, reduces chorea in Huntington's disease (HD). METHODS: This 32-day randomized, double-blind, parallel-group, proof-of-concept study investigated AFQ056 (25-150 mg [incremental doses], twice-daily) versus placebo in patients with HD. Primary efficacy assessments were the chorea-sum score and orientation index (nondominant hand) from the quantitative motor (Q-Motor) grasping task at day 28. Key secondary efficacy assessments included finger-tapping in the Unified Huntington's Disease Rating Scale-Total Motor Score and Q-Motor measures. Safety and tolerability were assessed. RESULTS: Overall, 42 patients were randomized. At day 28, no improvement was observed on the primary efficacy assessments (P > 0.10) with AFQ056 versus placebo. The Q-Motor speeded-tapping interonset interval variability was reduced with AFQ056 versus placebo for the nondominant hand (P = 0.01). The incidence of adverse events was 66.7% with AFQ056 and 57.1% with placebo. CONCLUSIONS: AFQ056 did not reduce choreatic movements in HD, but was well tolerated. The clinical relevance of the Q-Motor findings (speeded-tapping) are unknown and may warrant further investigation. PMID- 25689147 TI - Interleukin-8 transcripts in mononuclear cells determine impaired graft function after kidney transplantation. AB - OBJECTIVE: Interleukin-8 (IL-8) has been associated with ischemia reperfusion injury after renal allograft transplantation. Impaired allograft function may cause major impact on patient morbidity and health care costs. We investigated whether transcript levels in mononuclear cells including IL-8 on the first postoperative day may be involved in immediate allograft dysfunction as defined by reduced relative change in plasma creatinine at the first postoperative day. METHODS: We performed a single center, prospective-cohort study of 113 patients receiving kidney transplants. Peripheral blood mononuclear cells were harvested within 24 hours after transplantation. Transcripts were measured using quantitative RT-PCR. RESULTS: Transcript levels of IL-8 and S100A8 were significantly lower in patients with relative change in plasma creatinine less than 10% at the first postoperative day. Receiver-operator characteristic curves showed that IL-8 predicted the relative change in plasma creatinine less than 10% (area under curve (AUC), 0.80; P = 0.0007). Multivariate analyses showed that lower IL-8 transcripts, longer time on dialysis, higher recipient body mass index and deceased donor type were associated with relative change in plasma creatinine at the first postoperative day less than 10%. CONCLUSION: Reduced levels of IL-8 transcripts in peripheral mononuclear cells predict immediate graft dysfunction and delayed graft function. PMID- 25689148 TI - Reliability, validity and evaluation of the haemophilia coping and perception test. PMID- 25689149 TI - Chern half metals: a new class of topological materials to realize the quantum anomalous Hall effect. AB - New topological insulators that demonstrate the quantum anomalous Hall effect (QAHE) are a cutting-edge research topic in condensed matter physics and materials science. So far, the QAHE has been observed only in Cr-doped (Bi,Sb)2Te3 at extremely low temperature. Therefore, it is important to find new materials with large topological band gap and high thermal stability for the realization of the QAHE. On the basis of first-principles and tight-binding model calculations, we discovered a new class of topological phase, Chern half metal, which manifests the QAHE in one spin channel while is metallic in the other spin channel, in Co or Rh deposited graphene. The QAHE is robust in these sytems for the adatom coverage ranging from 2% to 6%. Meanwhile, these systems have large perpendicular magnetic anisotropy energies of 5.3 and 11.5 meV, necessary for the observation of the QAHE at reasonably high temperature. PMID- 25689150 TI - Autophagy modulates the effects of bis-anthracycline WP631 on p53-deficient prostate cancer cells. AB - Treatment of p53-deficient PC-3 human prostate carcinoma cells with nanomolar concentrations of bis-anthracycline WP631 induced changes in gene expression, which resulted in G2/M cell cycle arrest, autophagy and cell death. The presence of 2-deoxy-D-glucose (2-DG), which induces metabolic stress and autophagy, enhanced the antiproliferative effects of WP631. Changes induced by WP631, 2-DG, or co-treatments with both compounds, in the expression of a variety of genes involved in autophagy and apoptosis were quantified by real-time PCR. They were consistent with a raise in autophagy followed by cell death. Some cells dying from G2/M phase showed features of necrosis like early changes in membrane permeability, while others were dying by apoptosis that occurred in presence of little caspase-3 activity. Our results indicate that WP631 is not only an antiproliferative agent acting on gene transcription, but it can also induce autophagy regardless of the presence of other pro-autophagy stimuli. The development of autophagy seemed to improve the cytotoxicity of WP631 in PC-3 cells. Our results indicate that autophagy would enhance the activity of DNA binding drugs like WP631 that are potent inhibitors of gene transcription. PMID- 25689151 TI - Crude extract of Rheum palmatum L. Induces cell cycle arrest S phase and apoptosis through mitochondrial-dependent pathways in U-2 OS human osteosarcoma cells. AB - Cancer is the second cause of death in children. Osteosarcoma is the most common primary malignancy of solid bone cancer primarily affecting adolescents and young adults. In the Chinese population, the crude extract of Rheum palmatum L. (CERP) has been used for treating different diseases, including SARS, rheumatoid arthritis, coxsackievirus B3, and human colon cancer cell, pancreatic cancer. There are no reports on CERP and human osteosarcoma cells. The present study examined effects of CERP on cytotoxicity including cell cycle distribution and cell death (apoptosis) in U-2 OS human osteosarcoma cells. CERP significantly induced S phase arrest in U-2 OS cells in a dose-dependent. CERP produced DNA damage and DNA condensation. Other effects of CERP were stimulation of ROS and Ca(2+) , mitochondria impairment, and activation of caspase-3, -8, and -9. CERP increased the levels of Bax, Bak, Bad, cyclin B, Fas, PARP, GRP78, GADD153, AIF, Endo G, Calpain-2, p21, and p27, but decreased the levels of Bcl-2, BCL-X, XIAP, Akt, CDC25A, CDK2, Cyclin A, and Cyclin E of U-2 OS cells. It was also observed that CERP promoted the expression of AIF, Endo G, GADD153, and cytochrome c. These results indicate that CERP has anticancer effects in vitro and provide the foundation for in vivo studies of animal models of osteosarcoma. (c) 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 957-969, 2016. PMID- 25689152 TI - An unusual terpene cyclization mechanism involving a carbon-carbon bond rearrangement. AB - Terpene cyclization reactions are fascinating owing to the precise control of connectivity and stereochemistry during the catalytic process. Cyclooctat-9-en-7 ol synthase (CotB2) synthesizes an unusual 5-8-5 fused-ring structure with six chiral centers from the universal diterpene precursor, the achiral C20 geranylgeranyl diphosphate substrate. An unusual new mechanism for the exquisite CotB2-catalyzed cyclization that involves a carbon-carbon backbone rearrangement and three long-range hydride shifts is proposed, based on a powerful combination of in vivo studies using uniformly (13)C-labeled glucose and in vitro reactions of regiospecifically deuterium-substituted geranylgeranyl diphosphate substrates. This study shows that CotB2 elegantly demonstrates the synthetic virtuosity and stereochemical control that evolution has conferred on terpene synthases. PMID- 25689153 TI - Heterogeneous dose-response and college student drinking: examining problem risks related to low drinking levels. AB - BACKGROUND AND AIMS: Previous research demonstrates that the number of problems related to each additional drink consumed on any drinking occasion, dose response, varies non-linearly across average drinking quantities. We test predictions from a dynamic model of drinking behavior that locates this heterogeneity in drinkers' efforts to equilibrate between costs and benefits of use. DESIGN: Equations derived from the theoretical model are used to assess dose response across drinking quantity subgroups using censored regressions. SETTING: Fourteen California, USA, college campuses surveyed from 2003 to 2011. PARTICIPANTS: A total of 37 762 undergraduate college students 18 years of age and older. MEASUREMENTS: Drinking patterns, five physiological problems related to alcohol use (hangover, memory loss, medical treatment for overdose, nausea/vomiting, passing out) and student demographics. FINDINGS: The number of physiological problems related to each additional drink consumed was an inverse function of average drinking quantities (b = 0.2947, Z = 21.92, P<0.001), differed by drinker age (of-age drinker b = -0.1144, Z = -3.95, P < 0.001) and gender (male b = -0.3379, Z = -18.56, P<0.001) and, at the population level, drinking three drinks per occasion was associated with the greatest number of problems. CONCLUSIONS: Among US college students, all drinkers exhibit greater risks for physiological problems related to alcohol use (hangover, memory loss, medical treatment for overdose, nausea/vomiting, passing out) when drinking greater amounts of alcohol, but heavier drinkers (those who consume more on average) exhibit fewer problems for each additional drink consumed (less dose response) than light and moderate drinkers. Light and moderate drinkers exhibit greater dose-response, with three drinks per occasion associated with the greatest number of problems. PMID- 25689154 TI - Maternal antibiotic-induced early changes in microbial colonization selectively modulate colonic permeability and inducible heat shock proteins, and digesta concentrations of alkaline phosphatase and TLR-stimulants in swine offspring. AB - Elevated intake of high energy diets is a risk factor for the development of metabolic diseases and obesity. High fat diets cause alterations in colonic microbiota composition and increase gut permeability to bacterial lipopolysaccharide, and subsequent low-grade chronic inflammation in mice. Chronic inflammatory bowel diseases are increasing worldwide and may involve alterations in microbiota-host dialog. Metabolic disorders appearing in later life are also suspected to reflect changes in early programming. However, how the latter affects the colon remains poorly studied. Here, we hypothesized that various components of colonic physiology, including permeability, ion exchange and protective inducible heat shock proteins (HSP) are influenced in the short- and long-terms by early disturbances in microbial colonization. The hypothesis was tested in a swine model. Offspring were born to control mothers (n = 12) or mothers treated with the antibiotic (ATB) amoxicillin around parturition (n = 11). Offspring were slaughtered between 14 and 42 days of age to study short-term effects. For long-term effects, young adult offspring from the same litters consumed a normal or a palm oil-enriched diet for 4 weeks between 140 and 169 days of age. ATB treatment transiently modified maternal fecal microbiota although the minor differences observed for offspring colonic microbiota were nonsignificant. In the short-term, consistently higher HSP27 and HSP70 levels and transiently increased horseradish peroxidase permeability in ATB offspring colon were observed. Importantly, long-term consequences included reduced colonic horseradish peroxidase permeability, and increased colonic digesta alkaline phosphatase (AP) and TLR2- and TLR4-stimulant concentrations in rectal digesta in adult ATB offspring. Inducible HSP27 and HSP70 did not change. Interactions between early ATB treatment and later diet were noted for paracellular permeability and concentrations of colonic digesta AP. In conclusion, our data suggest that early ATB-induced changes in bacterial colonization modulate important aspects of colonic physiology in the short- and long-terms. PMID- 25689155 TI - Clinical intuition ratings are associated with morbidity and hospitalisation. AB - OBJECTIVE: To evaluate how the rating of the severity of sickness - as performed by the physician, nurse and patient - is associated with hospitalisation and acute morbidity. METHODS: Prospective observational study, performed in the emergency department of a tertiary hospital. Patients, physicians and nurses were interviewed separately after the first contact from 21 October through to 11 November 2013. RESULTS: Of 2426 presenting patients, 1861 were screened, and 1196 were included. A total of 299 (25%) were hospitalised, 504 (42%) suffered acute morbidity. In the univariate analysis, the physician's, nurse's and patient's rating of severity of sickness, expressed on a scale from 0 to 10, was significantly associated with hospitalisation (physicians: OR 1.61, 95% CI 1.50 1.73; nurses: OR 1.52, 1.41-1.64; patients: OR 1.16, 1.10-1.22), and with acute morbidity (OR 1.49, 1.40-1.59; OR 1.39, 1.30-1.48 and OR 1.05, 1.003-1.09 respectively). The area under the curve of the receiver operating characteristic curves was 0.77, 0.72 and 0.61 for hospitalisation, and 0.72, 0.68 and 0.54 for acute morbidity. The interrater reliability was estimated by the intraclass correlation, which was 0.49 for physician/nurse, 0.17 for nurse/patient and 0.07 for physician/patient. In a multivariable analysis model consisting of age, male sex, ethnic origin, ratings of severity of sickness, symptoms, ability to go home and hospitalisation during the preceding 12 months, only age, and the physician's and nurses' rating of severity of sickness remained significantly associated with both outcomes. CONCLUSION: The first impression of severity of sickness was associated with hospitalisation and morbidity. PMID- 25689156 TI - The tonotopicity of styrene-induced hearing loss depends on the associated noise spectrum. AB - The neuropharmacological and cochleotoxic effects of styrene can exacerbate the impact of noise on the peripheral auditory receptor. The mechanisms through which co-exposure to noise and styrene impairs hearing are complex as the slowly developing cochleotoxic process can be masked in the short-term by the rapid pharmacological effect on the central nervous system. The current investigation was therefore designed to delineate the auditory frequency range sensitive to noise, to styrene, and to noise and styrene combined. In case of different frequency ranges targeted by noise and styrene, it would be possible to point out the main factor responsible for cases of deafness by looking at the location of the audiometric deficits. Male Brown-Norway rats were exposed to 600-ppm styrene, to an octave band noise centered at 8 kHz, or to both noise and styrene. The noise exposure was of two different types: impulse noise with a LEX,8h (equivalent continuous noise level averaged over 8 h) of 80 dB and continuous noise with a LEX,8 h of 85 dB SPL. Hearing was tested using a non-invasive technique based on distortion product otoacoustic emissions. Hearing data were completed with histological analysis of cochleae. The results showed that exposure to styrene alone caused outer hair cell losses in the apical cochlear region, which discriminates low frequencies. In contrast, noise-induced hearing loss was located at half an octave above the central frequency of the spectrum, around 10-12 kHz. Damage due to impulse noise was significantly exacerbated by styrene, and the noise spectrum defined the location of the cochlear trauma. Combined exposure caused greater cell losses than the sum of losses measured with the impulse noise and styrene alone. The fact that the tonotopicity of the styrene-induced damage depends on the associated noise spectrum complicates the diagnosis of styrene-related hearing loss with a tone-frequency audiometric approach. In conclusion, there is not really a frequency specificity of impairments due to styrene. PMID- 25689157 TI - Cardiovascular regeneration. AB - Heart disease remains the number one cause of death in developed countries. Loss of cardiomyocytes (CMs) due to aging or pathophysiological conditions (for example, myocardial infarction) is generally considered irreversible, and can lead to lethal conditions from cardiac arrhythmias to heart failure. Human pluripotent stem cells (PSCs), including embryonic stem cells and induced pluripotent stem cells (iPSCs), can self-renew while maintaining their pluripotency to differentiate into all cell types, including CMs. As such, PSCs represent an unprecedented unlimited ex vivo cell source. In the present thematic series, we have solicited seven review articles to discuss the current state-of the-art PSC-based approaches for such applications as disease modeling, discovery of novel drugs and therapeutics, cardiotoxicity screening and cell-based myocardial repair, as well as the associated hurdles and potential solutions. PMID- 25689158 TI - Value of DSA in the diagnostic workup of pulsatile tinnitus. AB - OBJECTIVES: Pulsatile tinnitus (PT) is a rare complaint, but can be a symptom of life-threatening disease. It is often caused by vascular pathologies, e.g. dural arteriovenous fistula (dAVF), arteriovenous malformation (AVM) or vascularized tumors. The current diagnostic pathway includes clinical examination, cranial MRI and additional DSA. The aim of this study was to evaluate the diagnostic impact of DSA in the diagnostic workup of patients with PT in comparison to MRI alone. METHODS: Retrospectively, 54 consecutive patients with pulsatile tinnitus were evaluated. All patients had a diagnostic workup including cranial MRI and DSA. MRI examinations were blinded to the results of DSA and retrospectively analyzed in consensus by two experienced neuroradiologists. The MR-examinations were evaluated for each performed sequence separately: time-of-flight-angiography, ce MRA, T2, ce-T1-sequence and ce-T1-sequence with fat saturation. RESULTS: 37 of the 54 patients revealed a pathology explaining PT on MRI, which was detected by the readers in 100% and proofed by means of DSA. 24 dAVF, four paraganglioma, two AVM and seven more pathologies were described. All patients without pathology on MRI did also not show any pathology in DSA. CONCLUSIONS: MR imaging is sufficient to exclude pathology in patients with pulsatile tinnitus. PMID- 25689159 TI - Correction: intracellular long-chain acyl CoAs activate TRPV1 channels. PMID- 25689160 TI - Annotation of additional evolutionary conserved microRNAs in CHO cells from updated genomic data. AB - MicroRNAs are small non-coding RNAs that play a critical role in post transcriptional control of gene expression. Recent publications of genomic sequencing data from the Chinese Hamster (CGR) and Chinese hamster ovary (CHO) cells provide new tools for the discovery of novel miRNAs in this important production system. Version 20 of the miRNA registry miRBase contains 307 mature miRNAs and 200 precursor sequences for CGR/CHO. We searched for evolutionary conserved miRNAs from miRBase v20 in recently published genomic data, derived from Chinese hamster and CHO cells, to further extend the list of known miRNAs. With our approach we could identify several hundred miRNA sequences in the genome. For several of these, the expression in CHO cells could be verified from multiple next-generation sequencing experiments. In addition, several hundred unexpressed miRNAs are awaiting further confirmation by testing for their transcription in different Chinese hamster tissues. PMID- 25689161 TI - Age and grip strength predict hand dexterity in adults. AB - In the scientific literature, there is much evidence of a relationship between age and dexterity, where increased age is related to slower, less nimble and less smooth, less coordinated and less controlled performances. While some suggest that the relationship is a direct consequence of reduced muscle strength associated to increased age, there is a lack of research that has systematically investigated the relationships between age, strength and hand dexterity. Therefore, the aim of this study was to examine the associations between age, grip strength and dexterity. 107 adults (range 18-93 years) completed a series of hand dexterity tasks (i.e. steadiness, line tracking, aiming, and tapping) and a test of maximal grip strength. We performed three phases of analyses. Firstly, we evaluated the simple relationships between pairs of variables; replicating the existing literature; and found significant relationships of increased age and reduced strength; increased age and reduced dexterity, and; reduced strength and reduced dexterity. Secondly, we used standard Multiple Regression (MR) models to determine which of the age and strength factors accounted for the greater variance in dexterity. The results showed that both age and strength made significant contributions to the data variance, but that age explained more of the variance in steadiness and line tracking dexterity, whereas strength explained more of the variance in aiming and tapping dexterity. In a third phase of analysis, we used MR analyses to show an interaction between age and strength on steadiness hand dexterity. Simple Slopes post-hoc analyses showed that the interaction was explained by the middle to older aged adults showing a relationship between reduced strength and reduced hand steadiness, whereas younger aged adults showed no relationship between strength and steadiness hand dexterity. The results are discussed in terms of how age and grip strength predict different types of hand dexterity in adults. PMID- 25689162 TI - An exploratory trial of intravenous immunoglobulin therapy for idiopathic pulmonary fibrosis: a preliminary multicenter report. AB - BACKGROUND AND AIMS: Idiopathic pulmonary fibrosis (IPF) is a fatal disorder without specific treatments. Although the efficacy of intravenous immunoglobulin (IVIG) therapy for autoimmune diseases has been reported, that for IPF remains unknown. This study aims to determine the efficacy and safety of IVIG for IPF. METHODS: In an exploratory, multicenter, non-randomized and prospective trial, patients with progressive IPF were enrolled. Patients were treated with IVIG for five consecutive days (5-day IVIG) or once monthly for five consecutive months (5 month IVIG). Changes in the vital capacity (VC), diffusion capacity of the lung for carbon monoxide (DLCO), 6-min walk test (6MWT) and high-resolution computed tomography (HRCT) findings were evaluated. RESULTS: A total of 10 patients with IPF were treated with IVIG: 6 were in 5-day IVIG and 4 were in 5-month IVIG group. In 5-day IVIG group, the treatment effects were temporal, and physiological and HRCT findings deteriorated in three of six patients. In 5-month IVIG group, changes in %VC, %DLCO and walk distance in 6MWT at 6 months were -0.9 +/- 5.3%, 6.9 +/- 12.6% and 79 +/- 58 m (mean +/- standard deviation), respectively, and the treatment effects were long lasting. The change in VC 6 months after starting IVIG was smaller than that of 6-12 months after starting IVIG (after cessation of IVIG) (-0.02 +/- 0.15 vs -0.33 +/- 0.14 L, P = 0.022). Ground glass opacities were diminished in two of four patients. Adverse events were mild and tolerable. CONCLUSION: This preliminary study shows that once monthly IVIG treatment may be effective and tolerable in patients with IPF. PMID- 25689163 TI - Reporting of Posttraumatic Stress Disorder and Cardiac Misconceptions Following Cardiac Rehabilitation. AB - PURPOSE: Approximately 15% of cardiac patients experience posttraumatic stress disorder (PTSD), double the incidence seen in the general community. Posttraumatic stress disorder can seriously affect psychological and physical recovery. This study assessed how many patients reported symptoms of PTSD following a cardiac event and examined whether there was any change after completing a cardiac rehabilitation (CR) program. Associations between PTSD and anxiety, depression, and cardiac misconceptions were also explored. METHODS: This was a prospective cohort study using repeated measures. All patients eligible for the hospital CR program were invited to complete questionnaires assessing psychological distress and beliefs about heart disease before (T1) and after (T2) completing the CR program. RESULTS: Questionnaires at T1 were returned by 105 patients. Of these, 24% reported symptoms of PTSD, 18% high anxiety, and 9% high levels of depression. At T2, 67 patients returned questionnaires, showing that 9% of patients continued to experience PTSD. These patients experienced significantly higher levels of anxiety (t = -4.77; P < .001) and depression (t = 3.64; P < .001). Intrusive thoughts and hyperarousal were significantly lower at T2 (t = 2.32; P = .02 and t = 3.01; P = .01, respectively). More misconceptions were associated with higher levels of anxiety and depression; however, the number of cardiac misconceptions remained similar throughout. Caucasians reported significantly fewer misconceptions than non-Caucasian patients, except for beliefs about myocardial infarction. Patients had fewer misconceptions about their own specific condition. CONCLUSIONS: These findings suggest that screening for symptoms of PTSD after completion of a CR program would be helpful in identifying patients who would benefit from specialist psychological support. PMID- 25689164 TI - Association between diabetes treatment adherence and parent-child agreement regarding treatment responsibilities. AB - When primary responsibility for Type 1 diabetes (DM1) treatment adherence transfers from parents to adolescents, glycemic control often suffers. Low rates of treatment adherence during this transition are possibly attributable to decreased parental involvement, disagreements between parents and children regarding treatment responsibilities, and increased family conflict. The current investigation assessed the relationships between each of these variables and glycemic control among youth diagnosed with DM1. Parent and child report questionnaires were completed by 64 parent-child dyads (ages 8-18) with a child diagnosed with DM1. HbA1c readings served as measures of glycemic control. Parental involvement in their children's treatment was reported to decline with age, however absolute levels of parent involvement were not significantly correlated with youth HbA1c levels. Parent-child agreement regarding treatment responsibility and reports of diabetes-related conflict were significant predictors of glycemic control. Results support previous findings implicating parent-child agreement regarding treatment responsibilities and family conflict as predictors of treatment adherence among youth with DM1. The current study found this relationship to be significant for a larger population of children for which past research has failed to find such an effect. Taken together, these findings suggest further research is warranted to identify effective methods for transferring treatment responsibilities from parents to children. PMID- 25689165 TI - Identification of aortic arch-specific quantitative trait loci for atherosclerosis by an intercross of DBA/2J and 129S6 apolipoprotein E-deficient mice. AB - The genetic background of apolipoprotein E (apoE) deficient mice influences atherosclerotic plaque development. We previously reported three quantitative trait loci (QTL), Aath1-Aath3, that affect aortic arch atherosclerosis independently of those in the aortic root in a cross between C57BL6 apoEKO mice (B6-apoE) and 129S6 apoEKO mice (129-apoE). To gain further insight into genetic factors that influence atherosclerosis at different vascular locations, we analyzed 335 F2 mice from an intercross between 129-apoE and apoEKO mice on a DBA/2J genetic background (DBA-apoE). The extent of atherosclerosis in the aortic arch was very similar in the two parental strains. Nevertheless, a genome-wide scan identified two significant QTL for plaque size in the aortic arch: Aath4 on Chromosome (Chr) 2 at 137 Mb and Aath5 on Chr 10 at 51 Mb. The DBA alleles of Aath4 and Aath5 respectively confer susceptibility and resistance to aortic arch atherosclerosis over 129 alleles. Both QTL are also independent of those affecting plaque size at the aortic root. Genome analysis suggests that athero susceptibility of Aath4 in DBA may be contributed by multiple genes, including Mertk and Cd93, that play roles in phagocytosis of apoptotic cells and modulate inflammation. A candidate gene for Aath5 is Stab2, the DBA allele of which is associated with 10 times higher plasma hyaluronan than the 129 allele. Overall, our identification of two new QTL that affect atherosclerosis in an aortic arch specific manner further supports the involvement of distinct pathological processes at different vascular locations. PMID- 25689166 TI - Influence on the physicochemical properties of fish collagen gels using self assembly and simultaneous cross-linking with the N-hydroxysuccinimide adipic acid derivative. AB - Collagen gels from Southern catfish (Silurus meridionalis Chen) skins were prepared via the self-assembly of collagen molecules and simultaneous cross linking with the N-hydroxysuccinimide adipic acid derivative (NHS-AA). The doses of NHS-AA were converted to [NHS-AA]/[NH2] ratios (0.025-1.6, calculated by the [active ester group] of NHS-AA and [epsilon-NH2] of lysine and hydroxylysine residues of collagen). When the ratio < 0.05, collagen gels were formed by collagen molecule self-assembly, resulting in the opalescent appearance of collagen gels and the characteristic D-periodicity of partial collagen fibrils, the collagen gel ([NHS-AA]/[NH2] = 0.05) displayed a small increase in denaturation temperature (Td, 42.8 degrees C), remaining weight (12.59%), specific water content (SWC 233.7) and elastic modulus (G' 128.4 Pa) compared with uncross-linked collagen gel (39.1 degrees C, 9.12%, 222.4 and 85.4 Pa, respectively). As the ratio > 0.05, disappearance of D-periodicity and a gradual change in appearance from opalescent to transparent suggested that the inhibition of NHS-AA in the self-assembly of collagen molecules was more obvious. As a result, the collagen gel ([NHS-AA]/[NH2] = 0.2) had the lowest Td (35.8 degrees C), remaining weight (7.96%), SWC (130.9) and G' (31.9 Pa). When the ratio was 1.6, the collagen molecule self-assembly was markedly suppressed and the formation of collagen gel was predominantly via the covalent cross-linking bonds which led to the transparent appearance, and the maximum values of Td (47.0 degrees C), remaining weight (45.92%) and G' (420.7 Pa) of collagen gel. These results indicated that collagen gels with different properties can be prepared using different NHS-AA doses. PMID- 25689167 TI - Bioconcentration and trophic transfer of polychlorinated biphenyls and polychlorinated dibenzo-p-dioxins and dibenzofurans in aquatic animals from an e waste dismantling area in East China. AB - Eight aquatic biota species were collected from an e-waste dismantling area in East China to investigate bioconcentration and trophic transfer of polychlorinated biphenyls (PCBs), polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs). The mean concentrations of PCBs varied widely from 6.01 * 10(4) to 2.27 * 10(6) pg per g dry weight (dw). The ?25PCB concentrations in eels were significantly higher than those in other species. The levels of PCDD/Fs changed from 8.13 pg per g dw in toads to 617 pg per g dw in stone snails. World Health Organization-toxic equivalents (WHO2005-TEQs) ranged from 2.57 to 2352 pg WHO-TEQ per g dw with a geometric mean value of 64.7 pg WHO TEQ per g dw, which greatly exceeded the maximum levels of 4 pg per g ww set by the European Commission. The log-transferred bioconcentration factors (BCFs) of 25 PCB congeners ranged from 1.0 to 6.6, with the highest value for CB-205 in crucian carp and the lowest value for CB-11 in frog. A parabolic correlation was observed between log BCF and log Kow (R(2) = 0.53, p < 0.001), where the maximum value occurred at a log Kow of approximately 7. A similar correlation was also found in the plot of log BCF against the number of chlorine atoms of PCBs (R(2) = 0.57, p < 0.001), indicating that medium-halogenated congeners of PCBs are more easily accumulated by aquatic biota species. There were no significant correlations between the log-transferred concentrations and trophic levels of aquatic species, suggesting that trophic magnification for PCBs and PCDD/Fs was not observed in this study. PMID- 25689168 TI - Melatonin administration enhances the reproductive capacity of young rams under a southern Mediterranean environment. AB - This study tested the effect of melatonin treatment, initiated in late February on reproductive traits of young rams. A total of 14 young Barbarine rams were used. Seven animals were treated with three melatonin subcutaneous implants (Melatonin) on 28 February while the remaining rams remained untreated (Control). After 60 days of melatonin administration, scrotal circumference reached average values of 32.1 +/- 1.54 and 29.5 +/- 1.0 cm for Melatonin and Control animals, respectively (P < 0.05). Semen characteristics did not differ between groups; melatonin treatment tended (P = 0.091) to increase sperm concentration 60 days after implantation when means reached 5.87 +/- 0.703 and 4.61 +/- 0.654 * 10(9) spermatozoa/mL for Melatonin and Control rams, respectively. Melatonin treatment significantly affected total activity time, number of lateral approaches and mount attempts in comparison to controls. During a 6-h sampling period, mean plasma testosterone concentrations increased as a result of melatonin treatment (P < 0.001) and testosterone pulse frequency averaged 3.45 +/- 2.24 and 1.25 +/- 1.0 (P = 0.086) for Melatonin and Control rams. Data clearly suggest that abrupt treatment of young rams with melatonin implants in winter is sufficient to improve reproductive traits. PMID- 25689169 TI - Differing autonomic responses to dobutamine stress in the presence and absence of myocardial ischaemia. AB - KEY POINTS: Dobutamine stress echocardiography is a validated tool for the non invasive evaluation of myocardial ischaemia and enables the recording of heart rate variability in non-resting conditions. In this study we determined whether individuals with transient myocardial ischaemia had different autonomic responses to the stress of dobutamine infusion compared to non-ischaemic (normal) responders. Non-ischaemic responders had a residual predominance of parasympathetic over sympathetic activity. However, under conditions of myocardial ischaemia, there was a directionally opposite cardiac autonomic response with a residual increase of sympathetic over parasympathetic modulation. The sympathetic response to dobutamine stress is augmented as the burden of myocardial ischaemia is increased. ABSTRACT: Cardiac autonomic dysfunction has prognostic significance in patients with coronary artery disease. This investigation aimed to assess changes in autonomic modulation induced by dobutamine stress in the presence and absence of myocardial ischaemia. In total, 314 individuals underwent dobutamine stress echocardiography to detect or exclude myocardial ischaemia. Simultaneous autonomic and haemodynamic data were obtained using a plethysmographic device. Total power spectral density and associated low frequency (LF) and high-frequency (HF) power spectral components in absolute (ms(2) ) and normalised units (nu) were determined. Participants were categorised as non-ischaemic (NI) or ischaemic (IS) responders. There were no significant differences in LFnu or HFnu between groups at baseline. At peak stress, LFnu decreased from baseline in NI (43 +/- 1.8 to 40 +/- 1.8%), but increased from baseline in IS responders (39.5 +/- 2 to 56 +/- 2%, P < 0.05). In contrast, HFnu increased in NI patients (57 +/- 1.8 to 60 +/- 1.8%) but decreased in IS responders (60.5 +/- 2 to 44 +/- 2%, P < 0.05). Those with a high ischaemic burden [more than three ischaemic left ventricular (LV) segments] had a greater increase in LFnu (41 +/- 4.8 to 65 +/- 3.2% vs. 44.8 +/- 3.8 to 57.7 +/- 3.1%, P < 0.05) and greater decrease in HFnu (59 +/- 4.8 to 35 +/- 3.2% vs. 55.2 +/- 3.8 to 42.3 +/- 3.1%, P < 0.05) compared to patients with a low ischaemic burden (1-3 ischaemic LV segments) respectively, at peak stress. In the absence of myocardial ischaemia, dobutamine stress is associated with a residual predominance of parasympathetic over sympathetic activity. Under conditions of ischaemia, there is a directionally opposite autonomic response with a significant residual increase of sympathetic over parasympathetic modulation. This response is augmented as the burden of ischaemia is increased. PMID- 25689172 TI - Ionic liquid-assisted exfoliation and dispersion: stripping graphene and its two dimensional layered inorganic counterparts of their inhibitions. AB - Research on graphene-monolayers of carbon atoms arranged in a honeycomb lattice is proceeding at a relentless pace as scientists of both experimental and theoretical bents seek to explore and exploit its superlative attributes, including giant intrinsic charge mobility, record-setting thermal conductivity, and high fracture strength and Young's modulus. Of course, fully exploiting the remarkable properties of graphene requires reliable, large-scale production methods which are non-oxidative and introduce minimal defects, criteria not fully satisfied by current approaches. A major advance in this direction is ionic liquid-assisted exfoliation and dispersion of graphite, leading to the isolation of few- and single-layered graphene sheets with yields two orders of magnitude higher than the earlier liquid-assisted exfoliation approaches using surface energy-matched solvents such as N-methyl-2-pyrrolidone (NMP). In this Minireview, we discuss the emerging use of ionic liquids for the practical exfoliation, dispersion, and modification of graphene nanosheets. These developments lay the foundation for strategies seeking to overcome the many challenges faced by current liquid-phase exfoliation approaches. Early computational and experimental results clearly indicate that these same approaches can readily be extended to inorganic graphene analogues (e.g., BN, MoX2 (X = S, Se, Te), WS2, TaSe2, NbSe2, NiTe2, and Bi2Te3) as well. PMID- 25689174 TI - A novel synthetic derivative of melatonin, 5-hydroxy-2'-isobutyl-streptochlorin (HIS), inhibits inflammatory responses via regulation of TRIF-dependent signaling and inflammasome activation. AB - Melatonin is substantially reported to possess anti-inflammatory properties. In the present study, we synthesized a novel melatonin derivative, 5-hydroxy-2' isobutyl-streptochlorin (HIS), which displayed superior anti-inflammatory properties to its parent compound. Further, we explored its underlying mechanisms in cellular and experimental animal models. Lipopolysaccharide was used to induce in vitro inflammatory responses in RAW 264.7 macrophages. LPS-primed macrophages were pulsed with biologically unrelated toxic molecules to evaluate the role of HIS on inflammasome activation. In vivo verifications were carried out using acute lung injury (ALI) and Escherichia coli-induced septic shock mouse models. HIS inhibited the production of proinflammatory mediators and cytokines such as nitric oxide, cyclooxygenase 2, IL-1beta, IL-6 and TNF-alpha in LPS-stimulated RAW 264.7 macrophages. HIS suppressed the infiltration of immune cells into the lung and the production of pro-inflammatory cytokines such as IL-6 and TNF-alpha in broncho-alveolar lavage fluid in the ALI mouse model. Mechanistic studies revealed that the inhibitory effects of HIS were mediated through the regulation of the TIR domain-containing, adaptor-inducing, interferon-beta (TRIF)-dependent signaling pathway from toll-like receptors. Further, HIS attenuated IL-1beta secretion via the inhibition of NLRP3 inflammasome activation independent of mitochondrial ROS production. Furthermore, HIS suppressed IL-1beta, IL-6 and interferon-beta production in peritoneal lavage in the Escherichia coli-induced sepsis mouse model. In conclusion, HIS exerted potent anti-inflammatory effects via the regulation of TRIF-dependent signaling and inflammasome activation. Notably, the superior anti-inflammatory properties of this derivative compared with its parent compound could be a promising lead for treating various inflammatory-mediated diseases. PMID- 25689173 TI - A rat model of nerve agent exposure applicable to the pediatric population: The anticonvulsant efficacies of atropine and GluK1 antagonists. AB - Inhibition of acetylcholinesterase (AChE) after nerve agent exposure induces status epilepticus (SE), which causes brain damage or death. The development of countermeasures appropriate for the pediatric population requires testing of anticonvulsant treatments in immature animals. In the present study, exposure of 21-day-old (P21) rats to different doses of soman, followed by probit analysis, produced an LD50 of 62MUg/kg. The onset of behaviorally-observed SE was accompanied by a dramatic decrease in brain AChE activity; rats who did not develop SE had significantly less reduction of AChE activity in the basolateral amygdala than rats who developed SE. Atropine sulfate (ATS) at 2mg/kg, administered 20 min after soman exposure (1.2*LD50), terminated seizures. ATS at 0.5mg/kg, given along with an oxime within 1 min after exposure, allowed testing of anticonvulsants at delayed time-points. The AMPA/GluK1 receptor antagonist LY293558, or the specific GluK1 antagonist UBP302, administered 1h post-exposure, terminated SE. There were no degenerating neurons in soman-exposed P21 rats, but both the amygdala and the hippocampus were smaller than in control rats at 30 and 90days post-exposure; this pathology was not present in rats treated with LY293558. Behavioral deficits present at 30 days post-exposure, were also prevented by LY293558 treatment. Thus, in immature animals, a single injection of atropine is sufficient to halt nerve agent-induced seizures, if administered timely. Testing anticonvulsants at delayed time-points requires early administration of ATS at a low dose, sufficient to counteract only peripheral toxicity. LY293558 administered 1h post-exposure, prevents brain pathology and behavioral deficits. PMID- 25689175 TI - Marshaling the evidence: the prioritized public health accreditation research agenda. AB - A national public health department accreditation program was recently developed and implemented by the Public Health Accreditation Board (PHAB) to improve the quality and performance of public health departments. Because of its potential to transform public health, it is critical that the evidence base around accreditation be strong. With input from public health practitioners and researchers, PHAB developed a research agenda that highlights priority questions related to barriers and facilitators to seeking and obtaining accreditation, the PHAB standards and review process, metrics to determine the impact of accreditation, and benefits and outcomes associated with accreditation for the departments that undergo the process. We present that agenda, discuss the potential challenges of conducting accreditation research, and call on researchers to build a greater base of evidence related to accreditation. PMID- 25689176 TI - Importance of scientific resources among local public health practitioners. AB - OBJECTIVES: We examined the perceived importance of scientific resources for decision-making among local health department (LHD) practitioners in the United States. METHODS: We used data from LHD practitioners (n = 849). Respondents ranked important decision-making resources, methods for learning about public health research, and academic journal use. We calculated descriptive statistics and used logistic regression to measure associations of individual and LHD characteristics with importance of scientific resources. RESULTS: Systematic reviews of scientific literature (24.7%) were most frequently ranked as important among scientific resources, followed by scientific reports (15.9%), general literature review articles (6.5%), and 1 or a few scientific studies (4.8%). Graduate-level education (adjusted odds ratios [AORs] = 1.7-3.5), larger LHD size (AORs = 2.0-3.5), and leadership support (AOR = 1.6; 95% confidence interval = 1.1, 2.3) were associated with a higher ranking of importance of scientific resources. CONCLUSIONS: Graduate training, larger LHD size, and leadership that supports a culture of evidence-based decision-making may increase the likelihood of practitioners viewing scientific resources as important. Targeting communication channels that practitioners view as important can also guide research dissemination strategies. PMID- 25689177 TI - Simulating the dynamic effect of land use and transport policies on the health of populations. AB - OBJECTIVES: We identified the features of a land use-transportation system that optimizes the health and well-being of the population. METHODS: We developed a quantitative system dynamics model to represent relationships among land use, transport, economic development, and population health. Simulation experiments were conducted over a 10-year simulation period to compare the effect of different baseline conditions and land use-transport policies on the number of motor vehicle crash deaths and disability-adjusted life years lost. RESULTS: Optimal reduction in the public health burden attributable to land transport was demonstrated when transport safety risk reduction policies were combined with land use and transport polices that minimized reliance on individual motorized transport and maximized use of active transport modes. The model's results were particularly sensitive to the level of development that characterized each city at the start of the simulation period. CONCLUSIONS: Local, national, and international decision-makers are encouraged to address transport, land use, and health as an integrated whole to achieve the desired societal benefits of traffic safety, population health, and social equity. PMID- 25689178 TI - Regulatory enforcement and fiscal impact in local health agencies. AB - OBJECTIVES: We used a cross-sectional, retrospective study design to analyze the association between local health agency regulatory activities and revenues from nonclinical fees and fines (NFF). METHODS: We extracted data from the 2010 National Association of County and City Health Officials (NACCHO) Profile Survey, the most recent report including NFF information, and used 2-part multivariable regression models to identify relationships between regulatory activities and revenue. We also interviewed LHD directors on access to revenue from fines. RESULTS: NFFs generated substantial revenue for most LHDs, increasing in scope and amount with jurisdiction size for all but the largest municipalities. The greatest proportion of net revenue came from public pools, campgrounds and recreational vehicles, and solid waste disposal. For small and mid-sized LHDs, enforcement activities generated revenue in a dose-response pattern, with higher returns for increased activities. LHDs in decentralized governance states collected more NFF revenue than those in centralized states. States vary regarding LHD access to revenue from sanctions. CONCLUSIONS: The fiscal impact of changes in regulatory activity needs careful assessment to avoid unanticipated consequences of applicable law. PMID- 25689179 TI - Relationships among providing maternal, child, and adolescent health services; implementing various financial strategy responses; and performance of local health departments. AB - OBJECTIVES: We explored the relationships between local health department (LHD) structure, capacity, and macro-context variables and performance of essential public health services (EPHS). METHODS: In 2012, we assessed a stratified, random sample of 195 LHDs that provided data via an online survey regarding performance of EPHS, the services provided or contracted out, the financial strategies used in response to budgetary pressures, and the extent of collaborations. We performed weighted analyses that included analysis of variance, pairwise correlations by jurisdiction population size, and linear regressions. RESULTS: On average, LHDs provided approximately 13 (36%) of 35 possible services either directly or by contract. Rather than cut services or externally consolidating, LHDs took steps to generate more revenue and maximize capacity. Higher LHD performance of EPHS was significantly associated with delivering more services, initiating more financial strategies, and engaging in collaboration, after adjusting for the effects of the Affordable Care Act and jurisdiction size. CONCLUSIONS: During changing economic and health care environments, we found that strong structural capacity enhanced local health department EPHS performance for maternal, child, and adolescent health. PMID- 25689180 TI - Local health department factors associated with performance in the successful implementation of community-based strategies: a mixed-methods approach. AB - OBJECTIVES: We examined which local health department (LHD)-level factors contributed to successful implementation of policy, systems, and environmental change strategies in Minnesota. METHODS: We used a retrospective mixed-methods design to evaluate the relationship between the Statewide Health Improvement Plan (SHIP) grant initiative and key predictor variables (2009-2011). We obtained quantitative capacity data for 91 cities and counties in Minnesota; in addition, we conducted 15 key informant interviews to examine factors that facilitated and acted as barriers to LHD performance. RESULTS: Grantee performance was distributed as follows: exceeds expectations (29.7%), meets expectations (55.0%), and is approaching expectations (15.3%). Organizational quality improvement (QI) maturity was strongly positively associated with grantee performance on SHIP. Organizations with high QI maturity, effective leadership, efficient decision making, and successful regional or cross-jurisdictional partnerships were more likely to be rated as exceeding expectations. CONCLUSIONS: This study successfully translated practice-based research findings into tangible outcomes, including new system-level performance measures for local public health and recommendations for shaping the statewide initiative examined in this study. The approach taken in this study to systematically monitor communications, dissemination, and translation may be a model for others. PMID- 25689181 TI - Advancing the use of evidence-based decision-making in local health departments with systems science methodologies. AB - OBJECTIVES: We assessed how systems science methodologies might be used to bridge resource gaps at local health departments (LHDs) so that they might better implement evidence-based decision-making (EBDM) to address population health challenges. METHODS: We used the New York Academy of Medicine Cardiovascular Health Simulation Model to evaluate the results of a hypothetical program that would reduce the proportion of people smoking, eating fewer than 5 fruits and vegetables per day, being physically active less than 150 minutes per week, and who had a body mass index (BMI) of 25 kg/m(2) or greater. We used survey data from the Behavioral Risk Factor Surveillance System to evaluate health outcomes and validate simulation results. RESULTS: Smoking rates and the proportion of the population with a BMI of 25 kg/m(2) or greater would have decreased significantly with implementation of the hypothetical program (P < .001). Two areas would have experienced a statistically significant reduction in the local population with diabetes between 2007 and 2027 (P < .05). CONCLUSIONS: The use of systems science methodologies might be a novel and efficient way to systematically address a number of EBDM adoption barriers at LHDs. PMID- 25689182 TI - Assessing entrepreneurship in governmental public health. AB - OBJECTIVES: We assessed the feasibility and desirability of public health entrepreneurship (PHE) in governmental public health. METHODS: Using a qualitative case study approach with semistructured interview protocols, we conducted interviews between April 2010 and January 2011 at 32 local health departments (LHDs) in 18 states. Respondents included chief health officers and senior LHD staff, representatives from national public health organizations, health authorities, and public health institutes. RESULTS: Respondents identified PHE through 3 overlapping practices: strategic planning, operational efficiency, and revenue generation. Clinical services offer the strongest revenue-generating potential, and traditional public health services offer only limited entrepreneurial opportunities. Barriers include civil service rules, a risk averse culture, and concerns that PHE would compromise core public health values. CONCLUSIONS: Ongoing PHE activity has the potential to reduce LHDs' reliance on unstable general public revenues. Yet under the best of circumstances, it is difficult to generate revenue from public health services. Although governmental public health contains pockets of entrepreneurial activity, its culture does not sustain significant entrepreneurial activity. The question remains as to whether LHDs' current public revenue sources are sustainable and, if not, whether PHE is a feasible or desirable alternative. PMID- 25689183 TI - Improving access and provision of preventive oral health care for very young, poor, and low-income children through a new interdisciplinary partnership. AB - OBJECTIVES: We provided oral health care services at 2 sites using a nurse practitioner-dietitian team to increase dental workforce capacity and improve access to care for low-income preschool children. METHODS: Our team provided oral health assessments and education, fluoride varnish application, and dentist referrals. The primary endpoint was participants' access to oral health care. Secondary endpoints included increasing the practice scope of registered dietitians through training programs for oral health assessment and the application of fluoride varnishes for children. The oral health and hygiene and dietary habits of the participants were also determined. RESULTS: From 2010 to 2013, 4360 children received fluoride varnishes in 7195 total visits. Although the proportion of children with dental caries at the first visit was greater at the urban site, both sites were similar by visits 2 and 3. The number of caries declined with increased program visits, which coincided with an increase in the proportion of participants visiting a dentist. CONCLUSIONS: Progress toward eliminating dental health disparities requires addressing barriers to dental care access. We showed that expanding access to oral health services through nurse practitioner-dietitian cooperation improved access to preventive fluoride varnishing use in low-income children. PMID- 25689184 TI - Collaboration among Missouri nonprofit hospitals and local health departments: content analysis of community health needs assessments. AB - OBJECTIVES: We identified the levels of joint action that led to collaboration between hospitals and local health departments (LHDs) using the hospital's community health needs assessments (CHNAs). METHODS: In 2014, we conducted a content analysis of Missouri nonprofit hospitals (n = 34) CHNAs, and identified hospitals based on previously reported collaboration with LHDs. We coded the content according to the level of joint action. A comparison sample (n = 50) of Missouri nonprofit hospitals provided the basic comparative information on hospital characteristics. RESULTS: Among the hospitals identified by LHDs, 20.6% were "networking," 20.6% were "coordinating," 38.2% were "cooperating," and 2.9% were "collaborating." Almost 18% of study hospitals had no identifiable level of joint action with LHDs based on their CHNAs. In addition, comparison hospitals were more often part of a larger system (74%) compared with study hospitals (52.9%). CONCLUSIONS: The results of our study helped develop a better understanding of levels of joint action from a hospital perspective. Our results might assist hospitals and LHDs in making more informed decisions about efficient deployment of resources for assessment processes and implementation plans. PMID- 25689185 TI - Defining and assessing quality improvement outcomes: a framework for public health. AB - We describe an evidence-based framework to define and assess the impact of quality improvement (QI) in public health. Developed to address programmatic and research-identified needs for articulating the value of public health QI in aggregate, this framework proposes a standardized set of measures to monitor and improve the efficiency and effectiveness of public health programs and operations. We reviewed the scientific literature and analyzed QI initiatives implemented through the Centers for Disease Control and Prevention's National Public Health Improvement Initiative to inform the selection of 5 efficiency and 8 effectiveness measures. This framework provides a model for identifying the types of improvement outcomes targeted by public health QI efforts and a means to understand QI's impact on the practice of public health. PMID- 25689186 TI - Local health department food safety and sanitation expenditures and reductions in enteric disease, 2000-2010. AB - OBJECTIVES: In collaboration with Public Health Practice-Based Research Networks, we investigated relationships between local health department (LHD) food safety and sanitation expenditures and reported enteric disease rates. METHODS: We combined annual infection rates for the common notifiable enteric diseases with uniquely detailed, LHD-level food safety and sanitation annual expenditure data obtained from Washington and New York state health departments. We used a multivariate panel time-series design to examine ecologic relationships between 2000-2010 local food safety and sanitation expenditures and enteric diseases. Our study population consisted of 72 LHDs (mostly serving county-level jurisdictions) in Washington and New York. RESULTS: While controlling for other factors, we found significant associations between higher LHD food and sanitation spending and a lower incidence of salmonellosis in Washington and a lower incidence of cryptosporidiosis in New York. CONCLUSIONS: Local public health expenditures on food and sanitation services are important because of their association with certain health indicators. Our study supports the need for program-specific LHD service-related data to measure the cost, performance, and outcomes of prevention efforts to inform practice and policymaking. PMID- 25689187 TI - Defining the functions of public health governance. AB - We conducted a literature review in 2011 to determine if accepted governance functions continue to reflect the role of public health governing entities. Reviewing literature and other source documents, as well as consulting with practitioners, resulted in an iterative process that identified 6 functions of public health governance and established definitions for each of these: policy development; resource stewardship; continuous improvement; partner engagement; legal authority; and oversight of a health department. These functions provided context for the role of governing entities in public health practice and aligned well with existing public health accreditation standards. Public health systems research can build from this work in future explorations of the contributions of governance to health department performance. PMID- 25689188 TI - Association between HIV programs and quality of maternal health inputs and processes in Kenya. AB - We assessed whether quality of maternal and newborn health services is influenced by presence of HIV programs at Kenyan health facilities using data from a national facility survey. Facilities that provided services to prevent mother-to child HIV transmission had better prenatal and postnatal care inputs, such as infrastructure and supplies, and those providing antiretroviral therapy had better quality of prenatal and postnatal care processes. HIV-related programs may have benefits for quality of care for related services in the health system. PMID- 25689189 TI - The value of the "system" in public health services and systems research. PMID- 25689190 TI - Social Network Diagramming as an Applied Tool for Public Health: Lessons Learned From an HCV Cluster. AB - OBJECTIVES: We present an applied example of social network diagramming from 2010 to 2012 that was used to guide follow-up in a large HCV cluster in rural Wisconsin. METHODS: In addition to collecting standard individual-level attributes, we also obtained partner-level information. Both sets of data were input into a network diagramming program to create a series of diagrams that emphasized variables, such as risk factors, key location in the network, and number of partners. RESULTS: The visualization and cluster analysis guided testing and intervention priorities, were useful in sharing de-identified information about the cluster between health departments and community organizations and illustrated the key role young females played in holding the cluster together. CONCLUSIONS: Social network diagramming should be considered a practical and important public health tool for use in cluster management. PMID- 25689191 TI - Improving population health by learning from systems and services. PMID- 25689192 TI - Profile of the public health workforce: registered TRAIN learners in the United States. AB - OBJECTIVES: We analyzed data from the TrainingFinder Real-time Affiliate Integrated Network (TRAIN), the most widely used public health workforce training system in the United States, to describe the public health workforce and characteristics of individual public health workers. METHODS: We extracted self reported demographic data of 405,095 learners registered in the TRAIN online system in 2012. RESULTS: Mirroring the results of other public health workforce studies, TRAIN learners are disproportionately women, college educated, and White compared with the populations they serve. TRAIN learners live in every state and half of all zip codes, with a concentration in states whose public health departments are TRAIN affiliates. TRAIN learners' median age is 46 years, and one third of TRAIN learners will reach retirement age in the next 10 years. CONCLUSIONS: TRAIN data provide a limited but useful profile of public health workers and highlight the utility and limitations of using TRAIN for future research. PMID- 25689193 TI - The impacts of local health department consolidation on public health expenditures: evidence from Ohio. AB - We examined the effects of local health department (LHD) consolidations on the total and administrative expenditures of LHDs in Ohio from 2001 to 2011. We obtained data from annual records maintained by the state of Ohio and through interviews conducted with senior local health officials and identified 20 consolidations of LHDs occurring in Ohio in this time period. We found that consolidating LHDs experienced a reduction in total expenditures of approximately 16% (P = .017), although we found no statistically significant change in administrative expenses. County health officials who were interviewed concurred that their consolidations yielded financial benefits, and they also asserted that their consolidations yielded public health service improvements. PMID- 25689194 TI - Environmental Factors Associated With Social Participation of Older Adults Living in Metropolitan, Urban, and Rural Areas: The NuAge Study. AB - OBJECTIVES: We compared the social participation of older adults living in metropolitan, urban, and rural areas, and identified associated environmental factors. METHODS: From 2004 to 2006, we conducted a cross-sectional study using an age-, gender-, and area-stratified random sample of 1198 adults (aged 67-82 years). We collected data via interviewer-administered questionnaires and derived from Canadian censuses. RESULTS: Social participation did not differ across living areas (P = .09), but after controlling for potential confounding variables, we identified associated area-specific environmental variables. In metropolitan areas, higher social participation was associated with greater proximity to neighborhood resources, having a driver's license, transit use, and better quality social network (R(2) = 0.18). In urban areas, higher social participation was associated with greater proximity to neighborhood resources and having a driver's license (R(2) = 0.11). Finally, in rural areas, higher social participation was associated with greater accessibility to key resources, having a driver's license, children living in the neighborhood, and more years lived in the current dwelling (R(2) = 0.18). CONCLUSIONS: To enhance social participation of older adults, public health interventions need to address different environmental factors according to living areas. PMID- 25689195 TI - New perspectives on the "silo effect": initial comparisons of network structures across public health collaboratives. AB - OBJECTIVES: We explored to what extent "silos" (preferential partnering) persist in interorganizational boundaries despite advances in working across boundaries. We focused on organizational homophily and resulting silo effects within networks that might both facilitate and impede success in public health collaboratives (PHCs). METHODS: We analyzed data from 162 PHCs with a series of exponential random graph models to determine the influence of uniform and differential homophily among organizations and to identify the propensity for partnerships with similar organizations. RESULTS: The results demonstrated a low presence (8%) of uniform homophily among networks, whereas a greater number (30%) of PHCs contained varying levels of differential homophily by 1 or more types of organization. We noted that the higher frequency among law enforcement, nonprofits, and public health organizations demonstrated a partner preference with similar organizations. CONCLUSIONS: Although we identified only a modest occurrence of partner preference in PHCs, overall success in efforts to work across boundaries might be problematic when public health members (often leaders of PHCs) exhibit the tendency to form silos. PMID- 25689196 TI - Measuring public health practice and outcomes in chronic disease: a call for coordination. AB - A strategic opportunity exists to coordinate public health systems and services researchers' efforts to develop local health department service delivery measures and the efforts of divisions within the Centers for Disease Control and Prevention's National Center for Chronic Disease Prevention and Health Promotion (NCCDPHP) to establish outcome indicators for public health practice in chronic disease. Several sets of outcome indicators developed by divisions within NCCDPHP and intended for use by state programs can be tailored to assess outcomes of interventions within smaller geographic areas or intervention settings. Coordination of measurement efforts could potentially allow information to flow from the local to the state to the federal level, enhancing program planning, accountability, and even subsequent funding for public health practice. PMID- 25689197 TI - Effect of systems change and use of electronic health records on quit rates among tobacco users in a public hospital system. AB - OBJECTIVES: We examined electronic health records (EHRs) to assess the impact of systems change on tobacco use screening, treatment, and quit rates among low income primary care patients in Louisiana. METHODS: We examined EHR data on 79,777 patients with more than 1.2 million adult primary care encounters from January 1, 2009, through January 31, 2012, for evidence of systems change. We adapted a definition of "systems change" to evaluate a tobacco screening and treatment protocol used by medical staff during primary care visits at 7 sites in a public hospital system. RESULTS: Six of 7 sites met the definition of systems change, with routine screening rates for tobacco use higher than 50%. Within the first year, a 99.7% screening rate was reached. Sites had a 9.5% relative decrease in prevalence over the study period. Patients were 1.03 times more likely to sustain quit with each additional intervention (95% confidence interval = 1.02, 1.04). CONCLUSIONS: EHRs can be used to demonstrate that routine clinical interventions with low-income primary care patients result in reductions in tobacco use and sustained quits. PMID- 25689198 TI - Building a culture of health: a critical role for public health services and systems research. PMID- 25689199 TI - Cervical cancer screening in a sexually transmitted disease clinic: screening adoption experiences from a midwestern clinic. AB - OBJECTIVES: We examined whether a sexually transmitted disease (STD) clinic could reach women who had not received a Papanicolau (Pap) test in the past 3 years. We also explored staff attitudes and implementation of cervical cancer screening. METHODS: Women (n = 123) aged 30 to 50 years were offered cervical cancer screening in an Indiana STD clinic. We measured effectiveness by the patients' self-reported last Pap test. We explored adoption of screening through focus groups with 34 staff members by documenting their attitudes about cervical cancer screening and screening strategy adaptation. We also documented recruitment and screening implementation. RESULTS: Almost half (47.9%) of participants reported a last Pap test 3 or more years previously; 30% had reported a last Pap more than 5 years ago, and 11.4% had a high-risk test outcome that required referral to colposcopy. Staff supported screening because of mission alignment and perceived patient benefit. Screening adaptations included eligibility, results provision, and follow-up. CONCLUSIONS: Cervical cancer screening was possible and potentially beneficial in STD clinics. Future effectiveness-implementation studies should expand to include all female patients, and should examine the degree to which adaptation of selected adoption frameworks is feasible. PMID- 25689200 TI - Relationship between quality improvement implementation and accreditation seeking in local health departments. AB - OBJECTIVES: We examined the relationship between quality improvement (QI) maturity and accreditation attributes of US local health departments (LHDs), specifically those in Nebraska. METHODS: Using 2011 Nebraska LHD QI survey data, we conducted Spearman correlation analyses between QI maturity domains and accreditation attributes. Using the 2010 National Association of County and City Health Officials' National Profile of LHDs, we conducted logistic regression analyses to examine the relationships between specific QI strategies and attitude toward seeking accreditation. RESULTS: Leaders' commitment to and length of time engaged in QI were positively associated with LHDs' general attitude toward seeking accreditation. Use of QI strategies and integration of QI policies and practices were positively associated with LHDs' confidence in their capacity to obtain accreditation. LHDs that had used at least 1 QI framework and at least 1 QI technique in the past year were more likely to agree that they would seek accreditation within 2 years of the national accreditation program. CONCLUSIONS: Experience with and expertise in QI implementation play an important role in LHDs' decision to seek accreditation, and their accreditation-seeking efforts may benefit from prior implementation of systematic QI strategies. PMID- 25689201 TI - Economic shocks and public health protections in US metropolitan areas. AB - OBJECTIVES: We examined public health system responses to economic shocks using longitudinal observations of public health activities implemented in US metropolitan areas from 1998 to 2012. METHODS: The National Longitudinal Survey of Public Health Systems collected data on the implementation of 20 core public health activities in a nationally representative cohort of 280 metropolitan areas in 1998, 2006, and 2012. We used generalized estimating equations to estimate how local economic shocks relate to the scope of activities implemented in communities, the mix of organizations performing them, and perceptions of the effectiveness of activities. RESULTS: Public health activities fell by nearly 5% in the average community between 2006 and 2012, with the bottom quintile of communities losing nearly 25% of their activities. Local public health delivery fell most sharply among communities experiencing the largest increases in unemployment and the largest reductions in governmental public health spending. CONCLUSIONS: Federal resources and private sector contributions failed to avert reductions in local public health protections during the recession. New financing mechanisms may be necessary to ensure equitable public health protections during economic downturns. PMID- 25689202 TI - Network interventions on physical activity in an afterschool program: an agent based social network study. AB - OBJECTIVES: We studied simulated interventions that leveraged social networks to increase physical activity in children. METHODS: We studied a real-world social network of 81 children (average age = 7.96 years) who lived in low socioeconomic status neighborhoods, and attended public schools and 1 of 2 structured afterschool programs. The sample was ethnically diverse, and 44% were overweight or obese. We used social network analysis and agent-based modeling simulations to test whether implementing a network intervention would increase children's physical activity. We tested 3 intervention strategies. RESULTS: The intervention that targeted opinion leaders was effective in increasing the average level of physical activity across the entire network. However, the intervention that targeted the most sedentary children was the best at increasing their physical activity levels. CONCLUSIONS: Which network intervention to implement depends on whether the goal is to shift the entire distribution of physical activity or to influence those most adversely affected by low physical activity. Agent-based modeling could be an important complement to traditional project planning tools, analogous to sample size and power analyses, to help researchers design more effective interventions for increasing children's physical activity. PMID- 25689203 TI - Minimum package of public health services: the adoption of core services in local public health agencies in Colorado. AB - OBJECTIVES: We examined the effect of a state law in Colorado that required local public health agencies to deliver a minimum package of public health services. METHODS: We used a longitudinal, pre-post study design, with baseline data collected in 2011 and follow-up data collected in 2013. We conducted means testing to analyze the change in service delivery and activities. We conducted linear regression to test for system structure effects on the implementation of core services. RESULTS: We observed statistically significant increases in several service areas within communicable disease, prevention and population health promotion, and environmental health. In addition to service and program areas, specific activities had significant increases. The significant activity increases were all in population- and systems-based services. CONCLUSIONS: This project provided insight into the likely effect of national adoption of a minimum package as recommended by the Institute of Medicine. The implementation of a minimum package showed significant changes in service delivery, with specific service delivery measurement over a short period of time. Our research sets up a research framework to further explore core service delivery measure development. PMID- 25689204 TI - A Low-Cost Partner Notification Strategy for the Control of Sexually Transmitted Diseases: A Case Study From Louisiana. AB - OBJECTIVES: We estimated the costs and effectiveness of implementing a partner notification (PN) strategy for highly prevalent sexually transmitted diseases (STDs) within the Louisiana STD/HIV Program. METHODS: We carried out a telephone based PN approach on an experimental basis in 2 public STD clinics in Louisiana from June 2010 to May 2012. We monitored data on the resources used for identifying, tracing, treating, and managing the infected cases and their partners to estimate the intervention costs. RESULTS: Our results indicated that implementation of telephone-based PN should not increase the STD control program's expenses by more than 4.5%. This low-cost PN approach could successfully identify and treat 1 additional infected case at a cost of only $171. We found that the cost per disability-adjusted life year averted (a health outcome measure), because of the adoption of selective screening with partner tracing, was $4499. This was significantly lower than the gross domestic product per capita of the United States, a threshold used for defining highly cost effective health interventions. CONCLUSIONS: Adoption of PN for gonorrhea and chlamydia should be considered a national strategy for prevention and control of these diseases. PMID- 25689205 TI - Rural populations and early periodic screening, diagnosis, and treatment services: challenges and opportunities for local public health departments. AB - OBJECTIVES: We examined geographic differences in Early Periodic Screening, Diagnosis, and Treatment (EPSDT) visits as the South Carolina Department of Health and Environmental Control (SCDHEC) transitioned from direct service provision (DSP) to assuring delivery within the larger health care system. METHODS: We examined infant cohorts with continuous Medicaid coverage and normal birth weights from 1995 to 2010. Outcome variables included any EPSDT visit and the ratio of observed to expected visits. Change in SCDHEC market share over time by residence was the primary variable of interest. We used growth curve models to examine changes in EPSDT visits by rural areas and levels of DSP over time. RESULTS: A small proportion of the study population (10%) resided in rural counties that were more dependent on SCDHEC for DSP. The trajectory of not having visits among counties with high DSPs was steeper in rural areas (0.208; P = .001) compared with urban areas (0.145; P = .002). In counties with high DSPs, the slope of the predicted ratio in rural areas (-0.033; P < .001) was steeper than that of urban areas (-0.013; P < .001). CONCLUSIONS: Health departments operations continue to transition from DSP, which might decrease access to well child care in rural communities. Health care reform provides opportunities for health departments to work with community partners to facilitate DSP from public to private sectors. PMID- 25689206 TI - How Connecticut health directors deal with public health budget cuts at the local level. AB - OBJECTIVES: We investigated the perspectives of local health jurisdiction (LHJ) directors on coping mechanisms used to respond to budget reductions and constraints on their decision-making. METHODS: We conducted in-depth interviews with 17 LHJ directors. Interviews were audio recorded, transcribed, and analyzed using the constant comparative method. RESULTS: LHJ directors use a range of coping mechanisms, including identifying alternative revenue sources, adjusting services, amending staffing arrangements, appealing to local political leaders, and forming strategic partnerships. LHJs also face constraints on their decision making because of state and local statutory requirements, political priorities, pressures from other LHJs, and LHJ structure. CONCLUSIONS: LHJs respond creatively to budget cuts to maintain important public health services. Some LHJ adjustments to administrative resources may obscure the long-term costs of public health budget cuts in such areas as staff morale and turnover. Not all coping strategies are available to each LHJ because of the contextual constraints of its locality, pointing to important policy questions on identifying optimum jurisdiction size and improving efficiency. PMID- 25689207 TI - Economies of scale in the production of public health services: an analysis of local health districts in Florida. AB - OBJECTIVES: We examined the existence and the extent of scale and scope economies in the delivery of public health services. We also tested the strength of agency, population, and community characteristics that moderate scale and scope economies. METHODS: We collected service count and cost data for all Florida local health districts for 2008 and 2010, complemented with data on agency, population, and community characteristics. Using translog cost functions, we built models of operating efficiencies for 5 core public health activities: communicable disease surveillance, chronic disease prevention, food hygiene, on site sewage treatment, and vital records. RESULTS: Economies of scale were found in most activities, with cost per unit decreasing as volume increased. The models did not, however, identify meaningful economies of scope. CONCLUSIONS: Consolidation or regionalization might lower cost per unit for select public health activities. This could free up resources for use in other areas, further improving the public's health. PMID- 25689208 TI - Laying the groundwork for evidence-based public health: why some local health departments use more evidence-based decision-making practices than others. AB - We examined variation in the use of evidence-based decision-making (EBDM) practices across local health departments (LHDs) in the United States and the extent to which this variation was predicted by resources, personnel, and governance. We analyzed data from the National Association of County and City Health Officials Profile of Local Health Departments, the Association of State and Territorial Health Officials State Health Departments Profile, and the US Census using 2-level multilevel regression models. We found more workforce predictors than resource predictors. Thus, although resources are related to LHDs' use of EBDM practices, the way resources are used (e.g., the types and qualifications of personnel hired) may be more important. PMID- 25689209 TI - A new era for population health: government, academia, and community moving upstream together. PMID- 25689210 TI - Trends and characteristics of the state and local public health workforce, 2010 2013. AB - OBJECTIVES: We assessed state and local public health workforce characteristics by occupational category from 2010 to 2013. We also examined health department characteristics to determine whether workforce size and composition varied across these domains. METHODS: We analyzed Association of State and Territorial Health Officials (2010, 2012) and National Association of County and City Health Officials (2010, 2013) profile study data, including 47 state health departments and 2005 and 1953 local health departments (LHDs) in 2010 and 2013, respectively. We determined number of workers and percentage of change by occupation, population size, geographic region, and governance structure. RESULTS: The LHD workforce remained stable between 2010 and 2013. In states, the workforce decreased by 4%, with notable decreases in public information (-33%) and public health informatics (-29%); state health departments in small (-9%), New England ( 13%), and centralized (-7%) states reported the largest decrease in number of workers. CONCLUSIONS: Study findings provide evidence of a shifting public health workforce profile, primarily at the state level. Future research should seek to explain changing workforce patterns and determine whether they are planned or forced responses to changing budgets and service priorities. PMID- 25689211 TI - A case study examination of structure and function in a state health department chronic disease unit. AB - OBJECTIVES: I explored the structural and operational practices of the chronic disease prevention and control unit of a state health department and proposed a conceptual model of structure, function, and effectiveness for future study. METHODS: My exploratory case study examined 7 elements of organizational structure and practice. My interviews with staff and external stakeholders of a single chronic disease unit yielded quantitative and qualitative data that I coded by perspective, process, relationship, and activity. I analyzed these for patterns and emerging themes. RESULTS: Chi-square analysis revealed significant correlations among collaboration with goal ambiguity, political support, and responsiveness, and evidence-based decisions with goal ambiguity and responsiveness. CONCLUSIONS: Although my study design did not permit conclusions about causality, my findings suggested that some elements of the model might facilitate effectiveness for chronic disease units and should be studied further. My findings might have important implications for identifying levers around which capacity can be built that may strengthen effectiveness. PMID- 25689212 TI - Persons with disabilities as an unrecognized health disparity population. AB - Disability is an emerging field within public health; people with significant disabilities account for more than 12% of the US population. Disparity status for this group would allow federal and state governments to actively work to reduce inequities. We summarize the evidence and recommend that observed differences are sufficient to meet the criteria for health disparities: population-level differences in health outcomes that are related to a history of wide-ranging disadvantages, which are avoidable and not primarily caused by the underlying disability. We recommend future research and policy directions to address health inequities for individuals with disabilities; these include improved access to health care and human services, increased data to support decision-making, strengthened health and human services workforce capacity, explicit inclusion of disability in public health programs, and increased emergency preparedness. PMID- 25689213 TI - State barriers to appropriating public health emergency response funds during the 2009 H1N1 response. AB - OBJECTIVES: We examined state-specific administrative barriers to allocating 2009 H1N1 influenza public health emergency response (PHER) funds. METHODS: We conducted a qualitative review of PHER grants management reports to identify and code barriers reported by states in allocating funds. Using linear regression, we examined the relationship between the percentage of funds allocated and each individual barrier and, separately, the cumulative effect of multiple barriers. RESULTS: States reported 6 barrier types, including regulatory issues (n = 14, or 28%), contracting issues (n = 14, or 28%), purchasing issues (n = 6, or 12%), legislative issues (n = 5, or 10%), staffing issues (n = 5, or 10%), and issues transferring funds between state and local health departments (n = 4, or 8%). In multivariate models, having experienced a purchasing barrier was associated with a significant decrease in PHER allocation (B = -26.4; P = .018). Separately, the cumulative effect of having 3 barriers was associated with a decrease in PHER allocation (B = -16.0; P = .079). CONCLUSIONS: Purchasing barriers were associated with delayed use of PHER funds. Moreover, the cumulative effect of any 3 barriers hampered the allocation of funds. Understanding barriers to using funds can inform future funding guidance for improved efficiency of response efforts. PMID- 25689214 TI - Public health accreditation: rubber stamp or roadmap for improvement. AB - OBJECTIVES: We identified the characteristics of local health departments (LHDs) that intended to seek accreditation, and also examined the association between that intent and a complete community health assessment (CHA), community health improvement plan, agency strategic plan, or other specific accreditation requirements. METHODS: We analyzed data from the 2010 profile survey of LHDs conducted by the National Association of County and City Health Officials (n = 267). RESULTS: Those LHDs that conducted a CHA (adjusted odds ratio [AOR] = 0.62; 95% confidence interval [CI] = 0.38, 1.00; P = .05) and developed a strategic plan (AOR = 0.30; 95% CI = 0.12, 0.74; P = .01) were less likely to have an intent to pursue accreditation in the first 2 years of the program. By contrast, those LHDs that were engaged in quality improvement (QI) activities were approximately 2.6 times more likely to pursue accreditation compared with those LHDs that did not have any QI activities (P < .001). CONCLUSIONS: Based on our findings, national public health accreditation might be the vehicle LHDs could use to improve their operating environments, better manage their resources, and reap the rewards associated with meeting national industry standards. PMID- 25689215 TI - Building the evidence for decision-making: the relationship between local public health capacity and community mortality. AB - OBJECTIVES: We examined associations between local health department (LHD) spending, staffing, and services and community health outcomes in North Carolina. METHODS: We analyzed LHD investments and community mortality in North Carolina from 2005 through 2010. We obtained LHD spending, staffing, and services data from the National Association of City and County Health Officials 2005 and 2008 profile surveys. Five mortality rates were constructed using Centers for Disease Control and Prevention mortality files, North Carolina vital statistics data, and census data for LHD service jurisdictions: heart disease, cancer, diabetes, pneumonia and influenza, and infant mortality. RESULTS: Spending, staffing, and services varied widely by location and over time in the 85 North Carolina LHDs. A 1% increase in full-time-equivalent staffing (per 1000 population) was associated with decrease of 0.01 infant deaths per 1000 live births (P < .05). Provision of women and children's services was associated with a reduction of 1 to 2 infant deaths per 1000 live births (P < .05). CONCLUSIONS: Our findings, in the context of other studies, provide support for investment in local public health services to improve community health. PMID- 25689216 TI - XAS and TRLIF spectroscopy of uranium and neptunium in seawater. AB - Seawater contains radionuclides at environmental levels; some are naturally present and others come from anthropogenic nuclear activity. In this report, the molecular speciation in seawater of uranium(VI) and neptunium(V) at a concentration of 5 * 10(-5) M has been investigated for the first time using a combination of two spectroscopic techniques: Time-resolved laser-induced fluorescence (TRLIF) for U and extended X-ray absorption fine structure (EXAFS) for U and Np at the LIII edge. In parallel, the theoretical speciation of uranium and neptunium in seawater at the same concentration is also discussed and compared to spectroscopic data. The uranium complex was identified as the neutral carbonato calcic complex UO2(CO3)3Ca2, which has been previously described in other natural systems. In the case of neptunium, the complex identified is mainly a carbonato complex whose exact stoichiometry is more difficult to assess. The knowledge of the actinide molecular speciation and reactivity in seawater is of fundamental interest in the particular case of uranium recovery and more generally regarding the actinide life cycle within the biosphere in the case of accidental release. This is the first report of actinide direct speciation in seawater medium that can complement inventory data. PMID- 25689218 TI - Field measurement of ventilation rates. AB - Ventilation rates have significant impacts on building energy use and indoor contaminant concentrations, making them key parameters in building performance. Ventilation rates have been measured in buildings for many decades, and there are mature measurement approaches available to researchers and others who need to know actual ventilation rates in buildings. Despite the fact that ventilation rates are critical in interpreting indoor concentration measurements, it is disconcerting how few Indoor Air Quality field studies measure ventilation rates or otherwise characterize the ventilation design of the study building(s). This paper summarizes parameters of interest in characterizing building ventilation, available methods for quantifying these parameters, and challenges in applying these methods to different types of buildings and ventilation systems. These parameters include whole-building air change rates, system outdoor air intake rates, and building infiltration rates. Tracer gas methods are reviewed as well as system airflow rate measurements using, for example, duct traverses. Several field studies of ventilation rates conducted over the past 75 years are described to highlight the approaches employed and the findings obtained. PMID- 25689219 TI - Evolutionary aspects of ABO blood group in humans. AB - The antigens of the ABO blood group system (A, B and H determinants) are complex carbohydrate molecules expressed on red blood cells and on a variety of other cell lines and tissues. Growing evidence is accumulating that ABO antigens, beyond their key role in transfusion medicine, may interplay with the pathogenesis of many human disorders, including infectious, cardiovascular and neoplastic diseases. In this narrative review, after succinct description of the current knowledge on the association between ABO blood groups and the most severe diseases, we aim to elucidate the particularly intriguing issue of the possible role of ABO system in successful aging. In particular, focus will be placed on studies evaluating the ABO phenotype in centenarians, the best human model of longevity. PMID- 25689220 TI - Maternal X chromosome copy number variations are associated with discordant fetal sex chromosome aneuploidies detected by noninvasive prenatal testing. AB - BACKGROUND: The sensitivity and specificity of noninvasive prenatal testing (NIPT) for detection of sex chromosome aneuploidies (SCAs) compared to common autosomal trisomies are significantly lower. We speculated that in addition to altered maternal X chromosome karyotype, maternal X chromosome copy number variations (CNVs) may also contribute to discordant NIPT SCA results. METHODS: Clinical NIPT was performed for pregnant women at a single hospital. Copy number variation sequencing (CNV-Seq) was used to identify and quantitate the copy number of maternal X chromosome CNVs for each positive SCA pregnancy. RESULTS: Two out of 25 SCA positive NIPT samples had slightly abnormal ChrX/ChrY z-scores and were referred for invasive test confirmation. However, fetal karyotypes were found to be normal. CNV-Seq analysis of the maternal white blood cell DNA archived from the original two NIPT blood samples identified small CNVs spanning the STS gene, which is associated with X-linked ichthyosis. Correcting for the altered plasma levels of X chromosome DNA caused by the two CNVs and, taking into consideration the phenotypic consequences for X-linked disease, both fetuses were diagnosed as normal. CONCLUSIONS: Maternal DNA sequencing is recommended for all positive NIPT SCA results to avoid unnecessary referral for invasive testing and also to evaluate the risk to the fetus of X-linked disease. PMID- 25689221 TI - Characteristics of statewide protocols for emergency medical services in the United States. AB - OBJECTIVE: We sought to categorize and characterize the utilization of statewide emergency medical services (EMS) protocols as well as state recognition of specialty receiving facilities for trauma and time-sensitive conditions in the United States. METHODS: A survey of all state EMS offices was conducted to determine which states use mandatory or model statewide EMS protocols and to characterize these protocols based on the process for authorizing such protocols. The survey also inquired as to which states formally recognize specialty receiving facilities for trauma, STEMI, stroke, cardiac arrest, and burn as well as whether or not states have mandatory or model statewide destination protocols for these specialty centers. RESULTS: Thirty-eight states were found to have either mandatory or model statewide EMS protocols. Twenty-one states had mandatory statewide EMS protocols at either the basic life support (BLS) or advanced life support (ALS) level, and in 16 of these states, mandatory protocols covered both BLS and ALS levels of care. Seventeen states had model statewide protocols at either the BLS or ALS level, and in 14 of these states, the model protocols covered both BLS and ALS levels of care. Twenty states had separate protocols for the care of pediatric patients, while 18 states combined pediatric and adult care within the same protocols. When identified, the median age used to consider a patient for pediatric care was <=14 years (range <=8 to <=17 years). Three states' protocols used a child's height based on a length-based dosage tool as the threshold for identifying a pediatric patient for care using their pediatric protocols. States varied in recognition of receiving centers for EMS patients with special medical needs: 46 recognized trauma centers, 25 recognized burn centers, 22 recognized stroke centers, 11 recognized centers capable of percutaneous coronary intervention for ST-elevation myocardial infarction, and 3 recognized centers for patients surviving cardiac arrest. CONCLUSION: Statewide mandated EMS treatment protocols exist in 21 states, and optional model protocol guidelines are provided by 17 states. There is wide variation in the format and characteristics of these protocols and the recognition of specialty receiving centers for patients with time-sensitive illnesses. PMID- 25689222 TI - Hierarchical nanoparticle topography in amphiphilic copolymer films controlled by thermodynamics and dynamics. AB - This study systematically investigates how polymer composition changes nanoparticle (NP) grafting and diffusion in solvated random copolymer thin films. By thermal annealing from 135 to 200 degrees C, thin films with a range of hydrophobicity are generated by varying acrylic acid content from 2% (SAA2) to 29% (SAA29). Poly(styrene-random-tert butyl acrylate) films, 100 nm thick, that are partially converted to poly(styrene-random-acrylic acid), SAA, reversibly swell in ethanol solutions containing amine-functionalized SiO2 nanoparticles with a diameter of 45 nm. The thermodynamics and kinetics of NP grafting are directly controlled by the AA content in the SAA films. At low AA content, namely SAA4, NP attachment saturates at a monolayer, consistent with a low solubility of NPs in SAA4 due to a weakly negative chi parameter. When the AA content exceeds 4%, NPs sink into the film to form multilayers. These films exhibit hierarchical surface roughness with a RMS roughness greater than the NP size. Using a quartz crystal microbalance, NP incorporation in the film is found to saturate after a mass equivalence of about 3 close-packed layers of NPs have been incorporated within the SAA. The kinetics of NP grafting is observed to scale with AA content. The surface roughness is greatest at intermediate times (5-20 min) for SAA13 films, which also exhibit superhydrophobic wetting. Because clustering and aggregation of the NPs within SAA29 films reduce film transparency, SAA13 films provide both maximum hydrophobicity and transparency. The method in this study is widely applicable because it can be applied to many substrate types, can cover large areas, and retains the amine functionality of the particles which allows for subsequent chemical modification. PMID- 25689223 TI - RNAi-Mediated CCR5 Knockdown Provides HIV-1 Resistance to Memory T Cells in Humanized BLT Mice. AB - Transplantation of hematopoietic stem/progenitor cells (HSPC) modified with a lentiviral vector bearing a potent nontoxic short hairpin RNA (sh1005) directed to the HIV coreceptor CCR5 is capable of continuously producing CCR5 downregulated CD4+ T lymphocytes. Here, we characterized HIV-1 resistance of the sh1005-modified CD4+ T lymphocytes in vivo in humanized bone marrow/liver/thymus (hu BLT) mice. The sh1005-modified CD4+ T lymphocytes were positively selected in CCR5-tropic HIV-1-challenged mice. The sh1005-modified memory CD4+ T lymphocytes (the primary target of CCR5-tropic HIV-1) expressing sh1005 were maintained in lymphoid tissues in CCR5-tropic HIV-1-challenged mice. Frequencies of HIV-1 p24 expressing cells were significantly reduced in the sh1005-modified splenocytes by ex vivo cell stimulation confirming that CCR5 downregulated sh1005 modified cells are protected from viral infection. These results demonstrate that stable CCR5 downregulation through genetic modification of human HSPC by lentivirally delivered sh1005 is highly effective in providing HIV-1 resistance. Our results provide in vivo evidence in a relevant small animal model that sh1005 is a potent early-step anti-HIV reagent that has potential as a novel anti-HIV-1 HSPC gene therapeutic reagent for human applications. PMID- 25689224 TI - High-affinity RNA Aptamers Against the HIV-1 Protease Inhibit Both In Vitro Protease Activity and Late Events of Viral Replication. AB - HIV-1 aspartyl protease (PR) plays a key role in virion morphogenesis, underscoring the effectiveness of protease inhibitors (PI). Despite their utility, side effects and drug-resistance remains a problem. We report the development of RNA aptamers as inhibitors of HIV-1 PR for potential use in anti HIV gene therapy. Employing Systematic Evolution of Ligands by Exponential Enrichment (SELEX), we isolated four unique families of anti-HIV-1 PR RNA aptamers displaying moderate binding affinities (Kd = 92-140 nmol/l) and anti-PR inhibitory activity (Kis = 138-647 nmol/l). Second-generation RNA aptamers selected from partially randomized pools based on two of the aptamer sequences displayed striking enhancements in binding (Kds = 2-22 nmol/l) and inhibition (Kis = 31-49 nmol/l). The aptamers were specific in that they did not bind either the related HIV-2 protease, or the cellular aspartyl protease, Cathepsin D. Site directed mutagenesis of a second-generation aptamer to probe the predicted secondary structure indicated that the stem-loops SL2 and SL3 and the stem P1 were essential for binding and that only the 3'-most 17 nucleotides were dispensable. Anti-PR aptamers inhibited HIV replication in vitro and the degree of inhibition was higher for second-generation aptamers with greater affinity and the inhibition was abrogated for a nonbinding aptamer variant. PMID- 25689225 TI - Safety, tolerability and pharmacokinetic properties of the novel triazene TriN 2755 in tumour bearing dogs - a phase I study?. AB - TriN 2755 is an alkylating antineoplastic agent for intravenous (IV) use, carrying the triazene group as the cytotoxic principal. Using a standard 3 + 3 design, a phase I study was performed in tumour bearing dogs to determine the maximum tolerated dose (MTD), the dose limiting toxicity (DLT), and pharmacokinetic (PK) profile of TriN 2755. Thirty dogs were included in the study. TriN 2755 was administered over 20 min on two consecutive weeks per month for a total of three cycles. The starting dose was 25 mg kg-1 and the MTD was 74.6 mg kg-1 . Three dogs experienced DLT, which was characterized by gastrointestinal adverse events. The PKs of TriN 2755 and its main metabolites in plasma and sputum are described in a two-compartment model. The response rate for 19 of 30 dogs was 47.3% (six partial remission, three stable disease) and the median progression-free interval (PFI) for the responders was 47 days (range: 21 450 days). PMID- 25689226 TI - Progression of diabetic retinopathy after bariatric surgery. AB - AIM: To assess the impact of bariatric surgery on the progression of diabetic retinopathy in patients with Type 2 diabetes. METHOD: We conducted a retrospective, observational study of patients with Type 2 diabetes who underwent bariatric surgery between 1 January 2001 and 31 December 2012 and had hospital based retinal screening records. Data were collected from four surgical centres. Those who had pre-operative retinal screening and at least one post-operative retinal screen were eligible for analysis. A generalized linear mixed model was used to explore significant clinical predictors on the post-operative grade severity over time, controlling for important baseline characteristics. RESULTS: Three hundred and eighteen patients were eligible for analysis. Of these, 68.6% had no diabetic retinopathy pre-operatively compared with 18.9%, 8.5% and 4% with a diabetic retinopathy grade of minimal, mild or moderate and higher, respectively. First post-operative retinal screening results showed that after surgery 73% had no change in their diabetic retinopathy grade, 11% regressed and 16% progressed. The probability of having a diabetic retinopathy grade of moderate or higher over time post surgery was significantly associated with the magnitude of HbA1c reduction from pre-surgery HbA1c levels, a shorter post operative retinal screening duration, more severe pre-operative retinal screening grade, male gender and non-Maori/Pacific ethnicity. CONCLUSIONS: A higher pre operative diabetic retinopathy grade, and a large decrease in HbA1c post surgery warrant closer monitoring of diabetic retinopathy after bariatric surgery. Further prospective, randomized studies are required to investigate the gender and ethnic differences found. PMID- 25689227 TI - Factors Ruling the Uptake of Silica Nanoparticles by Mesenchymal Stem Cells: Agglomeration Versus Dispersions, Absence Versus Presence of Serum Proteins. AB - The results of a systematic investigation of the role of serum proteins on the interaction of silica nanoparticles (NP) doped in their bulk with fluorescent molecules (IRIS Dots, 50 nm in size), with human mesenchymal stem cells (hMSCs) are reported. The suspension of IRIS Dots in bare Dulbecco-modified Eagle's medium results in the formation of large agglomerates (~1.5 MUm, by dynamic light scattering), which become progressively smaller, down to ~300 nm in size, by progressively increasing the fetal bovine serum (FBS) content of the solutions along the series 1.0%, 2.5%, 6.0%, and 10.0% v/v. Such difference in NP dispersion is maintained in the external cellular microenvironment, as observed by confocal microscopy and transmission electron microscopy. As a consequence of the limited diffusion of proteins in the inter-NP spaces, the surface of NP agglomerates is coated by a protein corona independently of the agglomerate size/FBS concentration conditions (zeta-potential and UV circular dichroism measurements). The protein corona appears not to be particularly relevant for the uptake of IRIS Dots by hMSCs, whereas the main role in determining the internalization rate is played by the absence/presence of serum proteins in the extracellular media. PMID- 25689228 TI - Light-enabled synthesis of anhydrides and amides. AB - Recently, we have demonstrated that the photogeneration of Vilsmeier-Haack reagents is possible using only dimethylformamide (DMF) and tetrabromomethane (CBr4) in the bromination of alcohols. Extending these findings to carboxylic acid substrates has produced a mild and facile approach to the in situ formation of symmetric anhydrides, which were conveniently converted to amide derivatives in a one-pot process. The efficient protocols discussed herein are marked by use of UVA LEDs (365 nm), which have reduced the reaction times and come with a low setup cost. PMID- 25689229 TI - TTAGG-repeat telomeres and characterization of telomerase in the beet armyworm, Spodoptera exigua (Lepidoptera: Noctuidae). AB - Telomeres are maintained usually by telomerase, a specialized reverse transcriptase that adds this sequence to chromosome ends. In this study, telomerase activity was detected in the in different somatic tissues, such as midgut and fat bodies, by the telomeric repeat amplification protocol (TRAP) in Spodoptera exigua. The structure of the telomeres of S. exigua was evaluated by sequence analysis of the TRAP products, revealing that the telomerase synthesized a (TTAGG)n repeat. The presence of a telomerase reverse transcriptase (TERT) subunit coding gene has been cloned, sequenced and expressed in vitro successively. Notably, the S. exigua telomerase (SpexTERT) gene structure lacks the N-terminal GQ motif. Telomerase contains a large RNA subunit, TER, and a protein catalytic subunit, TERT. Here we report an in vitro system that was reconstructed by all components of the telomerase complex, a purified recombinant SpexTERT without a N-terminal GQ motif and a mutant human telomerase RNA (TER), showed telomerase activity. Together, these results suggest the GQ motif is not essential for telomerase catalysis. PMID- 25689230 TI - Autoimmunity, Not a Developmental Defect, is the Cause for Subfertility of Autoimmune Regulator (Aire) Deficient Mice. AB - Autoimmune regulator's (AIRE) best characterized role is in the generation immunological tolerance, but it is also involved in many other processes such as spermatogenesis. Loss-of-function mutations in AIRE cause a disease called autoimmune polyendocrinopathy, candidiasis and ectodermal dystrophy (APECED; also called autoimmune polyendocrinopathy syndrome type 1, APS-1) that is dominated by various autoimmune manifestations, mainly endocrinopathies. Both patients with APECED and Aire(-/-) mice suffer from varying levels of infertility, but it is not clear if it is a result of an autoimmune tissue damage or more of a developmental defect. In this study, we wanted to resolve whether or not the reduced fertility of Aire(-/-) mice is dependent on the adaptive immune system and therefore a manifestation of autoimmunity in these mice. We generated lymphopenic mice without Aire expression that were devoid of the autoimmune manifestations previously reported in immunocompetent Aire(-/-) mice. These Aire( /-) Rag1(-/-) mice regained full fertility. This confirms that the development of infertility in Aire(-/-) mice requires a functional adaptive immune system. We also show that only the male Aire(-/-) mice are subfertile, whereas Aire(-/-) females produce litters normally. Moreover, the male subfertility can be adoptively transferred with lymphocytes from Aire(-/-) donor mice to previously fertile lymphopenic Aire(-/-) recipients. Our data show that subfertility in Aire(-/-) mice is dependent on a functional adaptive immune system thus confirming its autoimmune aetiology. PMID- 25689231 TI - Undiagnosed metabolic dysfunction and sudden infant death syndrome--a case control study. AB - BACKGROUND: Decades of research has yielded few clues about causes of sudden infant death syndrome (SIDS). While some studies have shown a link to inborn errors of metabolism (IEMs), few have examined the link in a large population based sample. This population-based case-control study assessed the association between undiagnosed IEMs and SIDS. METHODS: Children born in California during 2005-08 who died from SIDS were obtained from death records and linked to the newborn screening, birth certificate, and hospital discharge databases. Individuals with known chromosomal and neural tube defects, genetic disorders, and non-singleton births were excluded. Five controls were matched to each case on tandem mass spectrometry testing date and lab code. Rates of undiagnosed IEMs were compared between cases and controls using conditional logistic regression adjusting for known confounding factors. RESULTS: After adjusting for known confounding factors, SIDS cases had similar risk of having IEMs as controls (adjusted hazard ratio [HR] 1.3, 95% confidence interval [CI] 0.3, 5.5). Infants who were male, Black, and born preterm had higher risk of SIDS with the highest risk observed for those born preterm [adjusted HR = 1.7, 95% CI 1.3, 2.2]. Younger maternal age at delivery, mother being born in the US, parity after current birth >3, and delayed prenatal care were also significantly associated with higher risk of SIDS. CONCLUSIONS: While many maternal and infant factors are associated with an increased risk of SIDS, there is no evidence that undiagnosed IEMs are associated with increased risk. PMID- 25689232 TI - Strong antibacterial properties of anion transporters: a result of depolarization and weakening of the bacterial membrane. AB - The development of low molecular weight anionophores is an emerging topic in chemistry, as the need for these compounds increases with the continuous discovery of pathologies involving anomalies in anion transport processes. Development of new concepts to initiate anion imbalance in living cells while fighting multidrug-resistant bacteria is a paramount topic. In this study, three series of compounds including N,N'-diphenylethynylbenzyl benzimidazolium salts (1 and 2), 1,1'-(pyridine-2,6-diyl)bis(3-(4-(phenylethynyl)benzyl)-1H benzo[d]imidazol-3-ium) salts (3-5), and 1,1'-(pyridine-2,6 diylbis(methylene))bis(3-(4-(phenyl ethynyl)benzyl)-1H-benzo[d]imidazol-3-ium) salts (6-8) displaying high antimicrobial activity and low toxicity against human cells were designed, synthesized, and studied. The most potent compound displayed micromolar minimal inhibitory concentrations in different Gram-negative and Gram positive bacteria, while its hemolytic activity remained around 10% or less, even after a prolonged period of exposure. The mechanism of action of these benzimidazolium salts on bacterial membrane was assessed by bioanalytical techniques including assays in model membrane liposomes, membrane depolarization studies, and scanning electron microscopy (SEM) in living bacteria. PMID- 25689233 TI - Sexual satisfaction and distress in sexual functioning in a sample of the BDSM community: a comparison study between BDSM and non-BDSM contexts. AB - INTRODUCTION: Little attention has been paid to distress in sexual functioning or the sexual satisfaction of people who practice BDSM (Bondage and Discipline, Domination and Submission, Sadism and Masochism). AIM: The purpose of this study was to describe sociodemographic characteristics and BDSM practices and compare BDSM practitioners' sexual outcomes (in BDSM and non-BDSM contexts). METHODS: A convenience sample of 68 respondents completed an online survey that used a participatory research framework. Cronbach's alpha and average inter-item correlations assessed scale reliability, and the Wilcoxon paired samples test compared the total scores between BDSM and non-BDSM contexts separately for men and women. Open-ended questions about BDSM sexual practices were coded using a preexisting thematic tree. MAIN OUTCOME MEASURES: We used self-reported demographic factors, including age at the onset of BDSM interest, age at first BDSM experience, and favorite and most frequent BDSM practices. The Global Measure of Sexual Satisfaction measured the amount of sexual distress, including low desire, arousal, maintaining arousal, premature orgasm, and anorgasmia. RESULTS: The participants had an average age of 33.15 years old and were highly educated and waited 6 years after becoming interested in BDSM to act on their interests. The practices in which the participants most frequently engaged did not coincide with the practices in which they were most interested and were overwhelmingly conducted at home. Comparisons between genders in terms of distress in sexual functioning in BDSM and non-BDSM contexts demonstrate that, with the exception of maintaining arousal, we found distress in sexual functioning to be statistically the same in BDSM and non-BDSM contexts for women. For men, we found that distress in sexual functioning, with the exception of premature orgasm and anorgasmia, was statistically significantly lower in the BDSM context. There were no differences in sexual satisfaction between BDSM and non-BDSM contexts for men or women. CONCLUSION: Our findings suggest that BDSM sexual activity should be addressed in clinical settings that account for BDSM identities, practices, relationships, preferences, sexual satisfaction, and distress in sexual function for men and women. Additional research needs are identified, such as the need to define distressful sexual functioning experiences and expand our understanding of the development of BDSM sexual identities. PMID- 25689234 TI - Molecular recognition of PTS-1 cargo proteins by Pex5p: implications for protein mistargeting in primary hyperoxaluria. AB - Peroxisomal biogenesis and function critically depends on the import of cytosolic proteins carrying a PTS1 sequence into this organelle upon interaction with the peroxin Pex5p. Recent structural studies have provided important insights into the molecular recognition of cargo proteins by Pex5p. Peroxisomal import is a key feature in the pathogenesis of primary hyperoxaluria type 1 (PH1), where alanine:glyoxylate aminotransferase (AGT) undergoes mitochondrial mistargeting in about a third of patients. Here, we study the molecular recognition of PTS1 cargo proteins by Pex5p using oligopeptides and AGT variants bearing different natural PTS1 sequences, and employing an array of biophysical, computational and cell biology techniques. Changes in affinity for Pex5p (spanning over 3-4 orders of magnitude) reflect different thermodynamic signatures, but overall bury similar amounts of molecular surface. Structure/energetic analyses provide information on the contribution of ancillary regions and the conformational changes induced in Pex5p and the PTS1 cargo upon complex formation. Pex5p stability in vitro is enhanced upon cargo binding according to their binding affinities. Moreover, we provide evidence that the rational modulation of the AGT: Pex5p binding affinity might be useful tools to investigate mistargeting and misfolding in PH1 by pulling the folding equilibria towards the native and peroxisomal import competent state. PMID- 25689235 TI - The prognostic value of self-assessed nocturnal blood pressure. PMID- 25689236 TI - Skilled players' and novices' difficulty anticipating left- vs. right-handed opponents' action intentions varies across different points in time. AB - A left-handers' performance advantage in interactive sports is assumed to result from their relative rarity compared to right-handers. Part of this advantage may be explained by athletes facing difficulties anticipating left-handers' action intentions, particularly when anticipation is based on kinematic cues available at an early stage of an opponent's movement. Here we tested whether the type of volleyball attack is predicted better against right- vs. left-handed opponents' movements and whether such handedness effects are evident at earlier time points in skilled players than novices. In a video-based experiment volleyball players and novices predicted the type of shot (i.e., smash vs. lob) of left- and right handed volleyball attacks occluded at six different time points. Overall, right handed attacks were better anticipated than left-handed attacks, volleyball players outperformed novices, and performance improved in later occlusion conditions. Moreover, in skilled players the handedness effect was most pronounced when attacks were occluded 480 ms prior to hand-ball-contact, whereas in novices it was most evident 240 ms prior to hand-ball-contact. Our findings provide further evidence of the effect of an opponent's handedness on action outcome anticipation and suggest that its occurrence in the course of an opponent's unfolding action likely depends on an observers' domain-specific skill. PMID- 25689237 TI - Prenatal diagnosis and management of monoamniotic twins. AB - PURPOSE OF REVIEW: The purpose of this article is to investigate the perinatal outcomes of monoamniotic twins under current standards of prenatal management involving intensive fetal surveillance. RECENT FINDINGS: The incidence of perinatal mortality in monoamniotic twins has fallen over the last 2 decades. Umbilical cord entanglement has long been considered one of the main causes of poor outcome among monoamniotic twins; however, new evidence shows that it appears to be less important than prematurity and congenital anomalies. If intensive fetal surveillance is provided, the risk of perinatal mortality is acceptably low regardless of setting. In uncomplicated monoamniotic twin pregnancies, delivery at around 33 weeks of gestation might reduce the risk of neonatal adverse events without increasing the risk of perinatal death. SUMMARY: Perinatal outcome in monoamniotic twins improved if intensive fetal surveillance was performed under either outpatient or inpatient management. Planned delivery in uncomplicated monoamniotic twin pregnancies can be considered at around 33 weeks of gestation. PMID- 25689238 TI - Elective cesarean delivery at 38 and 39 weeks: neonatal and maternal risks. AB - PURPOSE OF REVIEW: The purpose of this article is to critically review the existing literature with regard to neonatal and maternal outcomes after elective cesarean delivery at 38 completed weeks versus 39 completed weeks of gestation. RECENT FINDINGS: Recent observational studies have consolidated previous findings of an increased risk of neonatal composite morbidity, respiratory morbidity, and neonatal admission with elective cesarean delivery at 38 compared with 39 weeks of gestation. In opposition, results from the first randomized trial were recently reported in which there was no significant difference in the risk of neonatal admission with elective cesarean delivery at the two gestational weeks. In the mothers, the risk of adverse outcomes is similar with elective cesarean delivery at 38 or 39 weeks.Though evidence of long-term adverse effects of early term delivery (primarily spontaneous and vaginally) is accumulating, no data exist to elucidate whether these findings apply to children electively delivered by cesarean section. SUMMARY: Neonatal but not maternal adverse events are more frequent with elective cesarean delivery performed at 38 than 39 weeks' gestation. The difference, however, may be significantly smaller than previously anticipated. Further prospective studies, including investigations with focus on the impact of labor onset prior to cesarean delivery, are warranted. VIDEO ABSTRACT: http://links.lww.com/COOG/A18. PMID- 25689239 TI - Soft markers for aneuploidy following reassuring first trimester screening: what should be done? AB - PURPOSE OF REVIEW: The present article aims to review the current role of the soft markers on the second trimester ultrasound (STUS) in women after reassuring first trimester screening (FTS) in singleton pregnancies. RECENT FINDINGS: Improvements in the FTS and the recent implementation of noninvasive prenatal testing (NIPT) for common aneuploidies have important impact on the prevalence of these conditions in the STUS. Some studies suggest that soft markers in the second trimester of the fetus without structural anomalies have a minor or no role in Down syndrome detection in a prescreened population with reassuring results. However, NIPT could be offered as a next step in the management of such pregnancies if the calculated new composite risk (NCR) for aneuploidy is increased. In the case of reassuring results, pregnancy follow-up for certain markers is advised. SUMMARY: NIPT has emerged as a new method of prenatal testing and is feasible in the second trimester in women with increased NCR. However, apart from the Down syndrome screening, STUS screening remains a powerful tool in screening for other fetal aneuploidies, structural anomalies and pathological placental conditions and detection of specific soft markers that require pregnancy follow-up. PMID- 25689240 TI - Early fetal anatomy screening: who, what, when and why? AB - PURPOSE OF REVIEW: This article reviews the potential benefits and downsides of early anatomy screening. RECENT FINDINGS: There is increasing evidence that about 50% of severe fetal anomalies can be diagnosed prior to 14 weeks of gestation. 'Red flags' such as an increased nuchal or intracranial translucency, tricuspid valve regurgitation, a small biparietal diameter, a single umbilical artery or an abnormal retronasal triangle should raise the sonographer's suspicion of a congenital defect and warrant a more thorough fetal assessment, which often includes transvaginal scanning. Care should, however, be taken not to overinterpret first-trimester findings as false-positive rates of 3-4% have been reported. With more subtle findings, and especially if a heart defect is suspected, a sonographic reassessment after 15 weeks' gestation is indicated. Patients should be counseled that findings could worsen but also improve with time. SUMMARY: Basic fetal anomaly screening should be recommended, piggybacked on the routine first-trimester (aneuploidy screening) ultrasound, both for low and high-risk populations. First-trimester anatomy screening seems particularly useful in obese women, whose fetuses are difficult to screen at the midtrimester ultrasound and in multiple gestation. Noninvasive prenatal testing using cell free fetal DNA can complement but should not replace first-trimester ultrasound. PMID- 25689241 TI - Reducing maternal anxiety and stress in pregnancy: what is the best approach? AB - PURPOSE OF REVIEW: To briefly review results of the latest research on approaching antenatal maternal anxiety and stress as distinct constructs within a broad spectrum of maternal antenatal distress and the preventive strategic role of the maternal healthcare practitioner. RECENT FINDINGS: Maternal antenatal anxiety and stress are predominant contributors to short and long-term ill health and reduction of these psychological constructs is evident. Anxiety and stress belong to a broad spectrum of different psychological constructs. Various psychometric instruments are available to measure different individual constructs of antenatal maternal emotional health. Using multiple measures within antenatal care would imply a one-dimensional approach of individual constructs, resulting in inadequate management of care and inefficient use of knowledge and skills of maternity healthcare practitioners. A case-finding approach with slight emphasis on antenatal anxiety with subsequent selection of at-risk women and women suffering from maternal distress are shown to be effective preventive strategies and are consistent with the update of the National Institute for Health and Care Excellence guideline 'Antenatal and postnatal mental health'. Educational aspects of this approach are related to screening and assessment. SUMMARY: A shift in perception and attitude towards a broad theoretical and practical approach of antenatal maternal mental health and well-being is required. Case finding with subsequent selective and indicated preventive strategies during pregnancy would conform to this approach and are evidence based. PMID- 25689242 TI - The rapid test in Spanish pharmacies: a novel programme to reach heterosexual men? AB - OBJECTIVES: Spain has been a pioneer in the implementation of rapid HIV testing programmes in pharmacies to increase access to testing. However, no formal evaluation of the effectiveness of these programmes has been carried out to date. Our aim was to evaluate the ability of a novel in-pharmacy rapid HIV testing programme to promote diagnosis and reach vulnerable populations. METHODS: Between 2011 and 2012, 2168 people underwent testing in 16 urban pharmacies in 10 cities of a Spanish region with a low prevalence of HIV infection. The main outcomes of the programme were compared with those of the regional surveillance system for new HIV diagnoses (RHSS-CyL). RESULTS: Overall, 52.8% of those tested were heterosexual men, 15.8% were men who have sex with men (MSM) and 25.3% were women. Nine per cent were immigrants and 41.9% were < 30 years old. In total, 59.5% of the heterosexual men, 44.6% of the MSM and 65.3% of the women were previously untested. There were 23 positive results, representing 6% of all new regional diagnoses in 2011. The global prevalence was 1.1% (95% confidence interval 0.6-1.5%) and the prevalence in MSM was 3.8%. Of the reactive results, 60.9% were in MSM, 34.8% in heterosexual men and only 4.3% in women, vs. 35.4%, 37.5% and 15.0%, respectively, reported by the RHSS-CyL. The mean age of those testing positive was 32.7 years vs. 38.7 years in the RHSS-CyL. Fifty per cent of MSM and 75% of heterosexual men testing positive were previously untested. CONCLUSIONS: In Spain, this is the first programme not targeted at the most at risk populations, and has been shown to be effective in reaching and diagnosing heterosexual men, who are the group most affected by delayed diagnoses. Heterosexual men accounted for over half of those tested and a third of those diagnosed, and most of them were previously untested. Young and previously untested MSM also greatly benefitted from the programme. PMID- 25689243 TI - Risk factors for systemic vancomycin exposure following administration of oral vancomycin for the treatment of Clostridium difficile infection. AB - OBJECTIVE: To identify risk factors for systemic exposure to vancomycin (VAN) following administration of oral vancomycin (POV) for the treatment of Clostridium difficile infection (CDI). DESIGN: Prospective, observational, single center case series. SETTING: Academic medical center. PATIENTS: Hospitalized patients with suspected or confirmed CDI who received POV for at least 5 days. INTERVENTION: Random VAN serum levels were obtained on days 5, 10, and weekly thereafter in patients treated for >= 5 days with POV without concomitant intravenous VAN. MEASUREMENTS AND RESULTS: Of 117 random VAN serum levels from 85 patients, 58 patients (68.2%) had one or more detectable (>= 0.05 MUg/ml) levels and 15 (17.6%) of 85 patients had one or more levels > 2.5 MUg/ml. Risk factors for detectable VAN exposure following administration of POV included POV dosages > 500 mg/day (odds ratio [OR] 35.83, 95% confidence interval [CI] 7.56-169.8), the presence of severe CDI (OR 4.11, 95% CI 2.76-10.83, p=0.028), intensive care unit (ICU) admission (OR 3.80, 95% CI 1.02-14.21, p=0.032), and the administration of POV >= 10 days (OR 6.71, 95% CI 1.81-24.83, p=0.0025). Risk factors for exposure to serum VAN concentrations > 2.5 MUg/ml included the presence of gastrointestinal (GI) pathology (OR 5.22, 95% CI 3.45-18.3, p=0.031), ICU admission (OR 3.21, 95% CI 1.40-10.28, p=0.022), the use of VAN retention enemas (OR 4.73, 95% CI 2.42-20.39, p=0.036), and having a creatinine clearance <= 50 ml/minute or undergoing hemodialysis or continuous renal replacement therapy (OR 4.03, 95% CI 1.26-12.84, p=0.039). CONCLUSIONS: Serum VAN levels were detected in 58 (68.2%) of 85 patients receiving POV for CDI. Risk factors for systemic exposure to VAN following administration of POV included ICU admission; VAN dosages > 500 mg/day; administration >= 10 days or as retention enemas; and the presence of severe CDI, renal dysfunction, or inflammatory conditions of the GI tract. Unique to our study, we identified ICU admission and the concomitant use of VAN retention enemas to be significant risk factors for systemic exposure to VAN. PMID- 25689244 TI - Differential impact of selective serotonin reuptake inhibitors on platelet response to clopidogrel: a randomized, double-blind, crossover trial. AB - STUDY OBJECTIVE: To assess the effect of two selective serotonin reuptake inhibitors (SSRIs), fluvoxamine and citalopram, that markedly differ in their level of cytochrome P450 (CYP) 2C19 inhibition, on the laboratory response to clopidogrel, a prodrug requiring metabolism by the CYP system, and especially CYP2C19, to produce its active form. DESIGN: Randomized, double-blind, crossover trial. SETTING: Clinical research unit of an academic medical center. SUBJECTS: Fifteen healthy male volunteers. INTERVENTION: All subjects received clopidogrel as a 300-mg loading dose on day 1, followed by 75 mg/day on days 2 and 3. Platelet function was tested at baseline and then after clopidogrel treatment on day 3. After a washout period of 2 weeks, subjects were randomly assigned in a double-blind manner to receive either citalopram 20 mg/day or fluvoxamine 100 mg/day for 7 days. On day 5, platelet function was tested while receiving the SSRI treatment alone; then, a 300-mg clopidogrel loading dose was administered, followed by clopidogrel 75 mg/day on days 6 and 7. Platelet function was then reassessed on day 7 while receiving the combination of the SSRI and clopidogrel. The treatment protocol was then repeated after a washout period of 2 weeks in all subjects with the other SSRI. MEASUREMENTS AND MAIN RESULTS: The antiplatelet effects of fluvoxamine and citalopram and their interactions with clopidogrel were assessed. The response to these three drugs was assessed by light transmittance aggregometry and vasodilator-stimulated phosphoprotein phosphorylation, reporting P2Y12 receptor reactivity. Both fluvoxamine and citalopram tended to reduce adenosine diphosphate-induced aggregation: 80.8 +/- 3.4% at baseline, 67.3 +/- 6.3% while receiving citalopram, and 65.8 +/- 6.4% while receiving fluvoxamine. All subjects had a good laboratory response to clopidogrel, with a mean aggregation of 23.5 +/- 3.2% and a mean platelet reactivity index of 47.7 +/- 3.9% (p<0.001 compared with baseline for both methods). Laboratory response to clopidogrel was significantly attenuated in the presence of fluvoxamine compared with the response in the presence of citalopram as tested both by aggregometry (32.3 +/- 4.2% vs 23.4 +/- 3%, p=0.04) and by vasodilator-stimulated phosphoprotein phosphorylation (52.7 +/- 5.1% vs 35.9 +/- 4.2%, p=0.02). CONCLUSION: Fluvoxamine attenuated the laboratory response to clopidogrel, possibly through inhibition of CYP2C19, whereas citalopram did not affect this response. These potential drug interactions should be taken into consideration in the selection of the appropriate antidepressant agent for patients who are treated with clopidogrel. PMID- 25689245 TI - Effectiveness of regular versus glargine insulin in stable critical care patients receiving parenteral nutrition: a randomized controlled trial. AB - STUDY OBJECTIVE: To compare the effectiveness and safety of two glycemic control regimens in stable critical care patients receiving parenteral nutrition (PN). DESIGN: Prospective, randomized open-label clinical trial. METHODS: Eligible postoperative critical care patients in the ICU began PN on the first to the seventh day of ICU admission. The PN admixture included regular insulin, in doses sufficient to maintain 3 or more goal blood glucose (BG) levels between 110 and 180 mg/dl. After 3 to 5 days of PN containing regular insulin, patients were randomized to 3 more days of regular insulin at the same dose or 80% of their total daily regular insulin dose provided in PN solution as glargine insulin. Capillary BG monitoring was performed every 6 hours. RESULTS: Twenty one patients were randomized to each treatment group. Median APACHE II scores were not significantly different between the two groups within the first 24-hour of ICU admission. There were no significant differences between the two groups at day 3 for mean daily dextrose (306.9 +/- 46.2 vs. 305.2 +/- 52.2 g; p=0.913) or insulin (18.3 +/- 8.8 vs. 19.5 +/- 10.0 units; p=0.696) doses. The percentage of BG values in the goal (110-180 mg/dl), hyperglycemic (> 180 mg/dl), and hypoglycemic (< 70 mg/dl) BG levels were similar between the two groups (69.0% vs. 66.7%, p=0.567; 11.9% vs. 11.1%, p=0.780; 0% vs. 1.6%, p=0.124, respectively). Mean daily BG levels were not significantly different between the two groups on each of the 3 study days (day 1: 140 +/- 20 vs. 131 +/- 25 mg/dl, p=0.194; day 2: 136 +/- 20 vs. 140 +/- 18 mg/dl, p=0.498; day 3: 142 +/- 15 vs. 140 +/- 19 mg/dl; p=0.741). CONCLUSION: These data suggest that, compared with regular insulin added to PN, glargine insulin results in similar glycemic control and rates of hyperglycemia and hypoglycemia in stable critical care patients. PMID- 25689246 TI - A literature review of quetiapine for generalized anxiety disorder. AB - To evaluate the efficacy and tolerability of quetiapine for the treatment of generalized anxiety disorder (GAD), a literature search of the Medline database was conducted from inception to May 2014. The search was not restricted by language. Keywords used in the search were quetiapine and generalized anxiety disorder or anxiety. All studies assessing the use of quetiapine as monotherapy or adjunct therapy for the primary management of GAD in adults 18-65 years of age were included in this review. The nine studies included in this review were three studies evaluating the use of quetiapine extended release (XR) as monotherapy for acute GAD treatment, one study evaluating quetiapine XR monotherapy for maintenance treatment of GAD, and five studies evaluating quetiapine (2 XR, 3 immediate release) as adjunct therapy for acute GAD treatment. Quetiapine displayed both efficacy and tolerability in all monotherapy trials evaluating its use for acute and long-term treatment of GAD. Despite some limitations to and heterogeneity among the five adjunct therapy studies, three studies showed that quetiapine resulted in statistically significant changes in the Hamilton Anxiety Rating Scale or Clinical Global Impressions-Severity of Illness Scale scores. Although future studies of longer duration with broader inclusion criteria are needed to further evaluate the benefits and risks of quetiapine for GAD, in patients failing to respond to conventional antidepressant therapy, quetiapine may be a potential treatment option. With appropriate monitoring and management of adverse effects, the potential benefits of quetiapine in patients with treatment-refractory GAD may outweigh the risks associated with its use. PMID- 25689247 TI - Gut/brain axis and the microbiota. AB - Tremendous progress has been made in characterizing the bidirectional interactions between the central nervous system, the enteric nervous system, and the gastrointestinal tract. A series of provocative preclinical studies have suggested a prominent role for the gut microbiota in these gut-brain interactions. Based on studies using rodents raised in a germ-free environment, the gut microbiota appears to influence the development of emotional behavior, stress- and pain-modulation systems, and brain neurotransmitter systems. Additionally, microbiota perturbations by probiotics and antibiotics exert modulatory effects on some of these measures in adult animals. Current evidence suggests that multiple mechanisms, including endocrine and neurocrine pathways, may be involved in gut microbiota-to-brain signaling and that the brain can in turn alter microbial composition and behavior via the autonomic nervous system. Limited information is available on how these findings may translate to healthy humans or to disease states involving the brain or the gut/brain axis. Future research needs to focus on confirming that the rodent findings are translatable to human physiology and to diseases such as irritable bowel syndrome, autism, anxiety, depression, and Parkinson's disease. PMID- 25689248 TI - WNT signaling drives cholangiocarcinoma growth and can be pharmacologically inhibited. AB - Cholangiocarcinoma (CC) is typically diagnosed at an advanced stage and is refractory to surgical intervention and chemotherapy. Despite a global increase in the incidence of CC, little progress has been made toward the development of treatments for this cancer. Here we utilized human tissue; CC cell xenografts; a p53-deficient transgenic mouse model; and a non-transgenic, chemically induced rat model of CC that accurately reflects both the inflammatory and regenerative background associated with human CC pathology. Using these systems, we determined that the WNT pathway is highly activated in CCs and that inflammatory macrophages are required to establish this WNT-high state in vivo. Moreover, depletion of macrophages or inhibition of WNT signaling with one of two small molecule WNT inhibitors in mouse and rat CC models markedly reduced CC proliferation and increased apoptosis, resulting in tumor regression. Together, these results demonstrate that enhanced WNT signaling is a characteristic of CC and suggest that targeting WNT signaling pathways has potential as a therapeutic strategy for CC. PMID- 25689249 TI - An NLRP3 inflammasome-triggered Th2-biased adaptive immune response promotes leishmaniasis. AB - Leishmaniasis is a major tropical disease that can present with cutaneous, mucocutaneous, or visceral manifestation and affects millions of individuals, causing substantial morbidity and mortality in third-world countries. The development of a Th1-adaptive immune response is associated with resistance to developing Leishmania major (L. major) infection. Inflammasomes are key components of the innate immune system that contribute to host defense against bacterial and viral pathogens; however, their role in regulating adaptive immunity during infection with protozoan parasites is less studied. Here, we demonstrated that the NLRP3 inflammasome balances Th1/Th2 responses during leishmaniasis. Mice lacking the inflammasome components NLRP3, ASC, or caspase 1 on a Leishmania-susceptible BALB/c background exhibited defective IL-1beta and IL 18 production at the infection site and were resistant to cutaneous L. major infection. Moreover, we determined that production of IL-18 propagates disease in susceptible BALB/c mice by promoting the Th2 cytokine IL-4, and neutralization of IL-18 in these animals reduced L. major titers and footpad swelling. In conclusion, our results indicate that activation of the NLRP3 inflammasome is detrimental during leishmaniasis and suggest that IL-18 neutralization has potential as a therapeutic strategy to treat leishmaniasis patients. PMID- 25689250 TI - Kruppel-like factor 6 regulates mitochondrial function in the kidney. AB - Maintenance of mitochondrial structure and function is critical for preventing podocyte apoptosis and eventual glomerulosclerosis in the kidney; however, the transcription factors that regulate mitochondrial function in podocyte injury remain to be identified. Here, we identified Kruppel-like factor 6 (KLF6), a zinc finger domain transcription factor, as an essential regulator of mitochondrial function in podocyte apoptosis. We observed that podocyte-specific deletion of Klf6 increased the susceptibility of a resistant mouse strain to adriamycin induced (ADR-induced) focal segmental glomerulosclerosis (FSGS). KLF6 expression was induced early in response to ADR in mice and cultured human podocytes, and prevented mitochondrial dysfunction and activation of intrinsic apoptotic pathways in these podocytes. Promoter analysis and chromatin immunoprecipitation studies revealed that putative KLF6 transcriptional binding sites are present in the promoter of the mitochondrial cytochrome c oxidase assembly gene (SCO2), which is critical for preventing cytochrome c release and activation of the intrinsic apoptotic pathway. Additionally, KLF6 expression was reduced in podocytes from HIV-1 transgenic mice as well as in renal biopsies from patients with HIV-associated nephropathy (HIVAN) and FSGS. Together, these findings indicate that KLF6-dependent regulation of the cytochrome c oxidase assembly gene is critical for maintaining mitochondrial function and preventing podocyte apoptosis. PMID- 25689251 TI - Moving upstream in the war on WNTs. AB - Cholangiocarcinoma is a relatively rare cancer of the biliary ducts that is highly refractory to treatment. The factors that drive cholangiocarcinoma are poorly understood, though chronic liver fluke infection is a risk factor for disease. In this issue of the JCI, Boulter and colleagues demonstrate that the WNT/beta-catenin signaling pathway is upregulated in patients with sporadic cholangiocarcinoma. The authors determined that macrophages generate WNT ligands in cholangiocarcinomas and depletion or inhibition of this cell population in animal models of cholangiocarcinoma reduced tumor burden and proliferation. Moreover, pharmacological inhibition of WNT secretion or beta-catenin activity was efficacious in animal models. Together the results of this study suggest that targeting WNT has potential as a therapeutic strategy for cholangiocarcinoma. PMID- 25689252 TI - Emerging roles for enteric glia in gastrointestinal disorders. AB - Enteric glia are important components of the enteric nervous system (ENS) and also form an extensive network in the mucosa of the gastrointestinal (GI) tract. Initially regarded as passive support cells, it is now clear that they are actively involved as cellular integrators in the control of motility and epithelial barrier function. Enteric glia form a cellular and molecular bridge between enteric nerves, enteroendocrine cells, immune cells, and epithelial cells, depending on their location. This Review highlights the role of enteric glia in GI motility disorders and in barrier and defense functions of the gut, notably in states of inflammation. It also discusses the involvement of enteric glia in neurological diseases that involve the GI tract. PMID- 25689253 TI - Longitudinal study of living kidney donor glomerular dynamics after nephrectomy. AB - BACKGROUND: Over 5,000 living kidney donor nephrectomies are performed annually in the US. While the physiological changes that occur early after nephrectomy are well documented, less is known about the long-term glomerular dynamics in living donors. METHODS: We enrolled 21 adult living kidney donors to undergo detailed long-term clinical, physiological, and radiological evaluation pre-, early post- (median, 0.8 years), and late post- (median, 6.3 years) donation. A morphometric analysis of glomeruli obtained during nephrectomy was performed in 19 subjects. RESULTS: Donors showed parallel increases in single-kidney renal plasma flow (RPF), renocortical volume, and glomerular filtration rate (GFR) early after the procedure, and these changes were sustained through to the late post-donation period. We used mathematical modeling to estimate the glomerular ultrafiltration coefficient (Kf), which also increased early and then remained constant through the late post-donation study. Assuming that the filtration surface area (and hence, Kf) increased in proportion to renocortical volume after donation, we calculated that the 40% elevation in the single-kidney GFR observed after donation could be attributed exclusively to an increase in the Kf. The prevalence of hypertension in donors increased from 14% in the early post-donation period to 57% in the late post-donation period. No subjects exhibited elevated levels of albuminuria. CONCLUSIONS: Adaptive hyperfiltration after donor nephrectomy is attributable to hyperperfusion and hypertrophy of the remaining glomeruli. Our findings point away from the development of glomerular hypertension following kidney donation. TRIAL REGISTRATION: Not applicable. FUNDING. NIH (R01DK064697 and K23DK087937); Astellas Pharma US; the John M. Sobrato Foundation; the Satellite Extramural Grant Foundation; and the American Society of Nephrology. PMID- 25689254 TI - Preexisting human antibodies neutralize recently emerged H7N9 influenza strains. AB - The emergence and seasonal persistence of pathogenic H7N9 influenza viruses in China have raised concerns about the pandemic potential of this strain, which, if realized, would have a substantial effect on global health and economies. H7N9 viruses are able to bind to human sialic acid receptors and are also able to develop resistance to neuraminidase inhibitors without a loss in fitness. It is not clear whether prior exposure to circulating human influenza viruses or influenza vaccination confers immunity to H7N9 strains. Here, we demonstrate that 3 of 83 H3 HA-reactive monoclonal antibodies generated by individuals that had previously undergone influenza A virus vaccination were able to neutralize H7N9 viruses and protect mice against homologous challenge. The H7N9-neutralizing antibodies bound to the HA stalk domain but exhibited a difference in their breadth of reactivity to different H7 influenza subtypes. Mapping viral escape mutations suggested that these antibodies bind at least two different epitopes on the stalk region. Together, these results indicate that these broadly neutralizing antibodies may contribute to the development of therapies against H7N9 strains and may also be effective against pathogenic H7 strains that emerge in the future. PMID- 25689255 TI - Loss of Kruppel-like factor 6 cripples podocyte mitochondrial function. AB - Kruppel-like factors (KLFs) are zinc finger transcription factors that share homology in three C-terminal zinc finger domains. KLF family members are expressed in most if not all tissues and have diverse roles in organismal development and cell differentiation, function, and death. The glomerular podocyte is particularly sensitive to mitochondrial dysfunction, as seen in various genetic disorders manifesting as progressive glomerulosclerosis. In this issue of the JCI, Mallipattu and coworkers show that KLF6 expression is reduced in mouse and human glomerular disease. Podocyte-specific deletion of Klf6 expression in mice leads to mitochondrial dysfunction and apoptosis, followed by glomerulosclerosis. This is the first demonstration that defective transcriptional regulation of nuclear-encoded mitochondrial genes can result in experimental glomerular disease. PMID- 25689256 TI - Vessel maturation schedule determines vulnerability to neuronal injuries of prematurity. AB - Premature birth is a major risk factor for multiple brain pathologies, notably periventricular leukomalacia (PVL), which is distinguished by bilateral necrosis of neural tissue around the ventricles and a sequela of neurological disturbances. The 2 hallmarks of brain pathologies of prematurity are a restricted gestational window of vulnerability and confinement of injury to a specific cerebral region. Here, we examined the proposition that both of these features are determined by the state of blood vessel immaturity. We developed a murine genetic model that allows for inducible and reversible VEGF blockade during brain development. Using this system, we determined that cerebral vessels mature in a centrifugal, wave-like fashion that results in sequential acquisition of a functional blood-brain barrier and exit from a VEGF-dependent phase, with periventricular vessels being the last to mature. This developmental program permitted selective ablation of periventricular vessels via episodic VEGF blockade within a specific, vulnerable gestational window. Enforced collapse of ganglionic eminence vessels and resultant periventricular neural apoptosis resulted in a PVL-like phenotype that recapitulates the primary periventricular lesion, ventricular enlargement, and the secondary cortical deficit in out migrating GABAergic inhibitory interneurons. These findings provide an animal model that reproduces the temporal and spatial specificities of PVL and indicate that damage to VEGF-dependent, immature periventricular vessels contributes to PVL development. PMID- 25689257 TI - Spare hypoxia, spoil the child? PMID- 25689258 TI - Safety and tolerability of intracerebroventricular PDGF-BB in Parkinson's disease patients. AB - BACKGROUND. Recombinant human PDGF-BB (rhPDGF-BB) reduces Parkinsonian symptoms and increases dopamine transporter (DAT) binding in several animal models of Parkinson's disease (PD). Effects of rhPDGF-BB are the result of proliferation of ventricular wall progenitor cells and reversed by blocking mitosis. Based on these restorative effects, we assessed the safety and tolerability of intracerebroventricular (i.c.v.) rhPDGF-BB administration in individuals with PD. METHODS. We conducted a double-blind, randomized, placebo-controlled phase I/IIa study at two clinical centers in Sweden. Twelve patients with moderate PD received rhPDGF-BB via an implanted drug infusion pump and an investigational i.c.v. catheter. Patients were assigned to a dose cohort (0.2, 1.5, or 5 MUg rhPDGF-BB per day) and then randomized to active treatment or placebo (3:1) for a 12-day treatment period. The primary objective was to assess safety and tolerability of i.c.v.-delivered rhPDGF-BB. Secondary outcome assessments included several clinical rating scales and changes in DAT binding. The follow-up period was 85 days. RESULTS. All patients completed the study. There were no unresolved adverse events. Serious adverse events occurred in three patients; however, these were unrelated to rhPDGF-BB administration. Secondary outcome parameters did not show dose-dependent changes in clinical rating scales, but there was a positive effect on DAT binding in the right putamen. CONCLUSION. At all doses tested, i.c.v. administration of rhPDGF-BB was well tolerated. Results support further clinical development of rhPDGF-BB for patients with PD. TRIAL REGISTRATION. Clinical Trials.gov NCT00866502. FUNDING. Newron Sweden AB (former NeuroNova AB) and Swedish Governmental Agency for Innovation Systems (VINNOVA). PMID- 25689259 TI - Can Parkinson's disease be cured by stimulating neurogenesis? AB - There have been many attempts at slowing down or even reversing the neurodegenerative process of Parkinson's disease (PD). To date, there are no treatments of proven value in this regard. One underexplored route to slow the neurodegenerative process is the use of agents that may stimulate neurogenesis in the subventricular zone. In animal models of PD, PDGF-BB has been shown to restore/protect against dopaminergic deficits caused by neurotoxins via increased neurogenesis in the subventricular zone. Previous work suggests that these new cells are not themselves dopaminergic but have trophic effects on residual dopaminergic cells in the substantia nigra. In this issue of the JCI, Paul et al. evaluate this agent in individuals with PD and show that i.c.v. administration of PDGF-BB is safe and well tolerated. This study lays the foundation for formal dose-finding studies and clinical trials to assess the efficacy of this agent as a potential neuroprotective treatment for PD. PMID- 25689260 TI - Challenges and opportunities for reinvigorating the physician-scientist pipeline. AB - Physician-scientists, with in-depth training in both medicine and research, are uniquely poised to address pressing challenges at the forefront of biomedicine. In recent years, a number of organizations have outlined obstacles to maintaining the pipeline of physician-scientists, classifying them as an endangered species. As in-training and early-career physician-scientists across the spectrum of the pipeline, we share here our perspective on the current challenges and available opportunities that might aid our generation in becoming independent physician scientists. These challenges revolve around the difficulties in recruitment and retention of trainees, the length of training and lack of support at key training transition points, and the rapidly and independently changing worlds of medical and scientific training. In an era of health care reform and an environment of increasingly sparse NIH funding, these challenges are likely to become more pronounced and complex. As stakeholders, we need to coalesce behind core strategic points and regularly assess the impact and progress of our efforts with appropriate metrics. Here, we expand on the challenges that we foresee and offer potential opportunities to ensure a more sustainable physician-scientist workforce. PMID- 25689261 TI - Disturbed flow-activated p90RSK kinase accelerates atherosclerosis by inhibiting SENP2 function. AB - Disturbed blood flow (d-flow) causes endothelial cell (EC) dysfunction, leading to atherosclerotic plaque formation. We have previously shown that d-flow increases SUMOylation of p53 and ERK5 through downregulation of sentrin/SUMO specific protease 2 (SENP2) function; however, it is not known how SENP2 itself is regulated by d-flow. Here, we determined that d-flow activated the serine/threonine kinase p90RSK, which subsequently phosphorylated threonine 368 (T368) of SENP2. T368 phosphorylation promoted nuclear export of SENP2, leading to downregulation of eNOS expression and upregulation of proinflammatory adhesion molecule expression and apoptosis. In an LDLR-deficient murine model of atherosclerosis, EC-specific overexpression of p90RSK increased EC dysfunction and lipid accumulation in the aorta compared with control animals; however, these pathologic changes were not observed in atherosclerotic mice overexpressing dominant negative p90RSK (DN-p90RSK). Moreover, depletion of SENP2 in these mice abolished the protective effect of DN-p90RSK overexpression. We propose that p90RSK-mediated SENP2-T368 phosphorylation is a master switch in d-flow-induced signaling, leading to EC dysfunction and atherosclerosis. PMID- 25689262 TI - Benign hyperfiltration after living kidney donation. AB - Almost one-third of transplanted kidneys come from living donors, who sacrifice approximately 30% of their pre-donation glomerular filtration rate (GFR) after they experience compensatory hypertrophy and hyperfiltration in their remaining kidney. Although hyperfiltration can cause glomerular injury, many studies have suggested that donor nephrectomy itself does not cause long-term loss of GFR at a higher rate than what is seen in the normal aging population. However, when post donation kidney diseases occur in an unfortunate few, recent studies suggest that GFR loss at donor nephrectomy increases the risk of eventual end-stage renal disease (ESRD). In this issue of the JCI, Lenihan and colleagues evaluated glomerular dynamics in a cohort of kidney donors prior to, within 1 year of, and several years after kidney donation. Their results suggest that adaptive hyperfiltration in the remaining kidney occurs without glomerular hypertension, furthering our understanding of the relatively benign renal outcomes for most living kidney donors. PMID- 25689264 TI - Indole-based cyanine as a nuclear RNA-selective two-photon fluorescent probe for live cell imaging. AB - We have demonstrated that the subcellular targeting properties of the indole based cyanines can be tuned by the functional substituent attached onto the indole moiety in which the first example of a highly RNA-selective and two-photon active fluorescent light-up probe for high contrast and brightness TPEF images of rRNA in the nucleolus of live cells has been developed. It is important to find that this cyanine binds much stronger toward RNA than DNA in a buffer solution as well as selectively stains and targets to rRNA in the nucleolus. Remarkably, the TPEF brightness (Phisigmamax) is dramatically increased with 11-fold enhancement in the presence of rRNA, leading to the record high Phisigmamax of 228 GM for RNA. This probe not only shows good biocompatibility and superior photostability but also offers general applicability to various live cell lines including HeLa, HepG2, MCF-7, and KB cells and excellent counterstaining compatibility with commercially available DNA or protein trackers. PMID- 25689263 TI - Dynamic increases in AMPA receptor phosphorylation in the rat hippocampus in response to amphetamine. AB - Increasing evidence supports the critical role of alpha-amino-3-hydroxy-5-methyl 4-isoxazolepropionic acid (AMPA) glutamate receptors in psychostimulant action. These receptors are regulated via a phosphorylation-dependent mechanism in their trafficking, distribution, and function. The hippocampus is a brain structure important for learning and memory and is emerging as a critical site for processing psychostimulant effects. To determine whether the hippocampal pool of AMPA receptors is regulated by stimulants, we investigated and characterized the impact of amphetamine (AMPH) on phosphorylation of AMPA receptors in the adult rat hippocampus in vivo. We found that AMPH markedly increased phosphorylation of AMPA receptor GluA1 subunits at serine 845 (S845) in the hippocampus. The effect of AMPH was dose dependent. A single dose of AMPH induced a rapid and transient increase in S845 phosphorylation. Among different hippocampal subfields, AMPH primarily elevated S845 phosphorylation in the Cornu Ammonis area 1 and dentate gyrus. In contrast to S845, serine 831 phosphorylation of GluA1 and serine 880 phosphorylation of GluA2 were not altered by AMPH. In addition, surface expression of hippocampal GluA1 was up-regulated, while the amount of intracellular GluA1 fraction was concurrently reduced in response to AMPH. GluA2 protein levels in either the surface or intracellular pool were insensitive to AMPH. These data demonstrate that the AMPA receptor in the hippocampus is sensitive to dopamine stimulation. Acute AMPH administration induces dose-, time , site-, and subunit-dependent phosphorylation of AMPA receptors and facilitates surface trafficking of GluA1 AMPA receptors in hippocampal neurons in vivo. Acute injection of amphetamine increased phosphorylation of alpha-Amino-3-hydroxy-5 methyl-4-isoxazolepropionic acid (AMPA) receptor GluA1 subunits at a protein kinase A (PKA)-sensitive site (S845) in the rat hippocampus. This increase was dose- and time-dependent and correlated with an increase in surface GluA1 expression. Thus, amphetamine can upregulate GluA1 phosphorylation and surface trafficking of GluA1 in hippocampal neurons in vivo. PMID- 25689265 TI - Silicon-Heteroaromatic [FeFe] hydrogenase model complexes: insight into protonation, electrochemical properties, and molecular structures. AB - To learn from Nature how to create an efficient hydrogen-producing catalyst, much attention has been paid to the investigation of structural and functional biomimics of the active site of [FeFe]-hydrogenase. To understand their catalytic activities, the MU-S atoms of the dithiolate bridge have been considered as possible basic sites during the catalytic processes. For this reason, a series of [FeFe]-H2 ase mimics have been synthesized and characterized. Different [FeFe] hydrogenase model complexes containing bulky Si-heteroaromatic systems or fluorene directly attached to the dithiolate moiety as well as their mono-PPh3 substituted derivatives have been prepared and investigated in detail by spectroscopic, electrochemical, X-ray diffraction, and computational methods. The assembly of the herein reported series of complexes shows that the MU-S atoms can be a favored basic site in the catalytic process. Small changes in the (hetero) aromatic system of the dithiolate moiety are responsible for large differences in their structures. This was elucidated in detail by DFT calculations, which were consistent with the experimental results. PMID- 25689266 TI - Bioactivity and bone healing properties of biomimetic porous composite scaffold: in vitro and in vivo studies. AB - Tissue engineering (TE) represents a valid alternative to traditional surgical therapies for the management of bone defects that do not regenerate spontaneously. Scaffolds, one of the most important component of TE strategy, should be biocompatible, bioactive, osteoconductive, and osteoinductive. The aim of this study was to evaluate the biological properties and bone regeneration ability of a porous poly(E-caprolactone) (PCL) scaffold, incorporating MgCO3 doped hydroxyapatite particles, uncoated (PCL_MgCHA) or coated by apatite-like crystals via biomimetic treatment (PCL_MgCHAB). It was observed that both scaffolds are not cytotoxic and, even if cell viability was similar on both scaffolds, PCL_MgCHAB showed higher alkaline phosphatase and collagen I (COLL I) production at day 7. PCL_MgCHA induced more tumor necrosis factor-alpha release than PCL_MgCHAB, while osteocalcin was produced less by both scaffolds up to 7 days and no significant differences were observed for transforming growth factor beta synthesis. The percentage of new bone trabeculae growth in wide defects carried out in rabbit femoral distal epiphyses was significantly higher in PCL_MgCHAB in comparison with PCL_MgCHA at 4 weeks and even more at 12 weeks after implantation. This study highlighted the role of a biomimetic composite scaffold in bone regeneration and lays the foundations for its future employment in the clinical practice. PMID- 25689267 TI - Abundant storage protein depletion from tuber proteins using ethanol precipitation method: Suitability to proteomics study. AB - High-abundance proteins (HAPs) hamper in-depth proteome study necessitating development of a HAPs depletion method. Here, we report a novel ethanol precipitation method (EPM) for HAPs depletion from total tuber proteins. Ethanol showed a dose-dependent effect on depletion of sporamin from sweet potato and patatin from potato tubers, respectively. The 50% ethanol was an optimal concentration. 2DE analysis of EPM-prepared sweet potato proteins also revealed enrichment of storage proteins (SPs) in ethanol supernatant (ES) resulting in detection of new low-abundance proteins in ethanol pellet (EP), compared to total fraction. The ES fraction showed even higher trypsin inhibitor activity than total proteins, further showing the efficacy of EPM in enrichment of sporamin in ES fraction. Application of this method was demonstrated for comparative proteomics of two sweet potato cultivars (Hwang-geum and Ho-bac) and purification of SP (sporamin) in its native form, as examples. Comparative proteomics identified many cultivar specific protein spots and selected spots were confidently assigned for their protein identity using MALDI-TOF-TOF analysis. Overall, the EPM is simple, reproducible, and economical for depletion of SPs and is suitable for downstream proteomics study. This study opens a door for its potential application to other tuber crops or fruits rich in carbohydrates. PMID- 25689268 TI - Network propagation with dual flow for gene prioritization. AB - Based on the hypothesis that the neighbors of disease genes trend to cause similar diseases, network-based methods for disease prediction have received increasing attention. Taking full advantage of network structure, the performance of global distance measurements is generally superior to local distance measurements. However, some problems exist in the global distance measurements. For example, global distance measurements may mistake non-disease hub proteins that have dense interactions with known disease proteins for potential disease proteins. To find a new method to avoid the aforementioned problem, we analyzed the differences between disease proteins and other proteins by using essential proteins (proteins encoded by essential genes) as references. We find that disease proteins are not well connected with essential proteins in the protein interaction networks. Based on this new finding, we proposed a novel strategy for gene prioritization based on protein interaction networks. We allocated positive flow to disease genes and negative flow to essential genes, and adopted network propagation for gene prioritization. Experimental results on 110 diseases verified the effectiveness and potential of the proposed method. PMID- 25689269 TI - Broadband and tunable high-performance microwave absorption of an ultralight and highly compressible graphene foam. AB - The broadband and tunable high-performance microwave absorption properties of an ultralight and highly compressible graphene foam (GF) are investigated. Simply via physical compression, the microwave absorption performance can be tuned. The qualified bandwidth coverage of 93.8% (60.5 GHz/64.5 GHz) is achieved for the GF under 90% compressive strain (1.0 mm thickness). This mainly because of the 3D conductive network. PMID- 25689270 TI - Pilot study of a novel vacuum-assisted method for decellularization of tracheae for clinical tissue engineering applications. AB - Tissue engineered tracheae have been successfully implanted to treat a small number of patients on compassionate grounds. The treatment has not become mainstream due to the time taken to produce the scaffold and the resultant financial costs. We have developed a method for decellularization (DC) based on vacuum technology, which when combined with an enzyme/detergent protocol significantly reduces the time required to create clinically suitable scaffolds. We have applied this technology to prepare porcine tracheal scaffolds and compared the results to scaffolds produced under normal atmospheric pressures. The principal outcome measures were the reduction in time (9 days to prepare the scaffold) followed by a reduction in residual DNA levels (DC no-vac: 137.8+/ 48.82 ng/mg vs. DC vac 36.83+/-18.45 ng/mg, p<0.05.). Our approach did not impact on the collagen or glycosaminoglycan content or on the biomechanical properties of the scaffolds. We applied the vacuum technology to human tracheae, which, when implanted in vivo showed no significant adverse immunological response. The addition of a vacuum to a conventional decellularization protocol significantly reduces production time, whilst providing a suitable scaffold. This increases clinical utility and lowers production costs. To our knowledge this is the first time that vacuum assisted decellularization has been explored. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 25689271 TI - A practical model for economic evaluation of tissue-engineered therapies. AB - Tissue-engineered therapies are being developed across virtually all fields of medicine. Some of these therapies are already in clinical use, while others are still in clinical trials or the experimental phase. Most initial studies in the evaluation of new therapies focus on demonstration of clinical efficacy. However, cost considerations or economic viability are just as important. Many tissue engineered therapies have failed to be impactful because of shortcomings in economic competitiveness, rather than clinical efficacy. Furthermore, such economic viability studies should be performed early in the process of development, before significant investment has been made. Cost-minimization analysis combined with sensitivity analysis is a useful model for the economic evaluation of new tissue-engineered therapies. The analysis can be performed early in the development process, and can provide valuable information to guide further investment and research. The utility of the model is illustrated with the practical real-world example of tissue-engineered constructs for corneal endothelial transplantation. CONFLICT OF INTEREST: The authors have declared no conflicts of interest for this article. PMID- 25689272 TI - Enrichment and encapsulation of uranium with iron nanoparticle. AB - The ability to recover uranium from water is significant because of its potential applications on nuclear fuel capture and mitigation of nuclear wastes. In this work, a unique nanostructure is presented by which trace level (2.32-882.68 MUg/L) uranium can be quickly separated from water and encapsulated at the center of zero-valent iron nanoparticles. Over 90% of the uranium is recovered with 1 g/L nanoparticles in less than 2 min. Near atomic-resolution elemental mapping on the U(VI) intraparticle reactions in a single iron nanoparticle is obtained with aberration corrected scanning transmission electron microscopy, which provides direct evidence on U(VI) diffusion, reduction to U(IV), and deposition in the core area. PMID- 25689273 TI - Genomic selection and association mapping in rice (Oryza sativa): effect of trait genetic architecture, training population composition, marker number and statistical model on accuracy of rice genomic selection in elite, tropical rice breeding lines. AB - Genomic Selection (GS) is a new breeding method in which genome-wide markers are used to predict the breeding value of individuals in a breeding population. GS has been shown to improve breeding efficiency in dairy cattle and several crop plant species, and here we evaluate for the first time its efficacy for breeding inbred lines of rice. We performed a genome-wide association study (GWAS) in conjunction with five-fold GS cross-validation on a population of 363 elite breeding lines from the International Rice Research Institute's (IRRI) irrigated rice breeding program and herein report the GS results. The population was genotyped with 73,147 markers using genotyping-by-sequencing. The training population, statistical method used to build the GS model, number of markers, and trait were varied to determine their effect on prediction accuracy. For all three traits, genomic prediction models outperformed prediction based on pedigree records alone. Prediction accuracies ranged from 0.31 and 0.34 for grain yield and plant height to 0.63 for flowering time. Analyses using subsets of the full marker set suggest that using one marker every 0.2 cM is sufficient for genomic selection in this collection of rice breeding materials. RR-BLUP was the best performing statistical method for grain yield where no large effect QTL were detected by GWAS, while for flowering time, where a single very large effect QTL was detected, the non-GS multiple linear regression method outperformed GS models. For plant height, in which four mid-sized QTL were identified by GWAS, random forest produced the most consistently accurate GS models. Our results suggest that GS, informed by GWAS interpretations of genetic architecture and population structure, could become an effective tool for increasing the efficiency of rice breeding as the costs of genotyping continue to decline. PMID- 25689274 TI - pH controlled pathway and systematic hydrothermal phase diagram for elaboration of synthetic lead nickel selenites. AB - The PbO-NiO-SeO2 ternary system was fully studied using constant hydrothermal conditions at 473 K. It yields the establishment of the corresponding phase diagram using a systematic assignment of reaction products by both powder and single-crystal X-ray diffraction. It leads to the preparation of three novel lead nickel selenites, alpha-PbNi(SeO3)2 (I), beta-PbNi(SeO3)2 (II), and PbNi2(SeO2OH)2(SeO3)2 (III), and one novel lead cobalt selenite, alpha PbCo(SeO3)2 (IV), which have been structurally characterized. The crystal structures of the alpha-forms I, IV, and III are based on a 3D complex nickel selenite frameworks, whereas the beta-PbNi(SeO3)2 modification (II) consists of nickel selenite sheets stacked in a noncentrosymmetric structure, second-harmonic generation active. The pH value of the starting solution was shown to play an essential role in the reactive processes. Magnetic measurements of I, III, and IV are discussed. PMID- 25689275 TI - Cobalt-promoted dimerization of aminoquinoline benzamides. AB - A method for aminoquinoline-directed, cobalt-promoted dimerization of benzamides has been developed. Reactions proceed in ethanol solvent in the presence of Mn(OAc)2 cocatalyst and Na2CO3 base and use oxygen as a terminal oxidant. Bromo, iodo, nitro, ether, and ester moieties are compatible with the reaction conditions. Cross-coupling of electronically dissimilar aminoquinoline benzamides proceeds with modest yields and selectivities. PMID- 25689276 TI - Immunisation in children and adolescents with inflammatory bowel disease. AB - Inflammatory bowel disease (IBD) patients may be at a higher risk for developing infections due to underlying disease, malnutrition, surgery, or immunosuppressive therapy. Therefore, protecting this group against infections is of particular importance. Immunisation against vaccine-preventable diseases is strongly recommended. This article for the first time summarises data on immunogenicity and safety of vaccines in IBD children and provides an update on some important issues regarding immunisation in these group of children. PMID- 25689277 TI - Dissecting spatiotemporal biomass accumulation in barley under different water regimes using high-throughput image analysis. AB - Phenotyping large numbers of genotypes still represents the rate-limiting step in many plant genetic experiments and in breeding. To address this issue, novel automated phenotyping technologies have been developed. We investigated for a core set of barley cultivars if high-throughput image analysis can help to dissect vegetative biomass accumulation in response to two different watering regimes under semi-controlled greenhouse conditions. We found that experiments, treatments, genotypes and genotype by environment interaction (G * E) can be characterized at any time point by certain digital traits. Biomass accumulation under control and stress conditions was highly heritable. Growth model-derived maximum vegetative biomass (K max), inflection point (I) and regrowth rate (k) were identified as promising candidate traits for genome-wide association studies. Drought stress symptoms can be visualized, dissected and modelled. Especially the highly heritable regrowth rate, which had the biggest influence on biomass accumulation in stress treatment, seems promising for future studies to improve drought tolerance in different crop species. A proof of concept study revealed potential correlations between digital traits obtained from pot experiments under greenhouse conditions and agronomic traits from field experiments. Overall, non-invasive, imaging-based phenotyping platforms under greenhouse conditions offer excellent possibilities for trait discovery, trait development and industrial applications. PMID- 25689278 TI - Presentation and management of acute coronary syndromes among adult persons with haemophilia: results of an international, retrospective, 10-year survey. AB - Sparse data are available on presentation and management of acute coronary syndromes (ACS), including unstable angina and non-ST- and ST-elevation myocardial infarction, among persons with haemophilia (PWH). The aim of this study was to determine demographics, bleeding disorder characteristics, cardiovascular risk factors (CRFs), interventions, haemostatic protocol, revascularization outcomes and complications among PWH with ACS. Members of an international consortium comprising >2000 adult PWH retrospectively completed case report forms for episodes of ACS in a >10-year follow-up period (2003-2013). Twenty ACS episodes occurred among 19 patients [rate, 0.8% (95% CI 0.4, 1.2)]. Seven patients (37%) were aged <50 years; 10 (53%) had >=3 CRFs. In 5/20 episodes (25%), the initial ACS management protocol was altered because of the bleeding disorder. None of the eight patients with severe haemophilia underwent coronary artery bypass grafting (CABG), compared with 54.5% of patients with non-severe disease (P = 0.02). Revascularization with percutaneous coronary intervention (PCI) or CABG was rated successful in 13/13 cases, with no excessive bleeding during initial management. During chronic exposure to antiplatelet agents, secondary haemophilia prophylaxis was more prevalent in patients with severe haemophilia compared with non-severe haemophilia (85.7% vs. 30%, P = 0.05). No ACS-related deaths occurred during initial management, but one patient with severe haemophilia A died of undetermined cause 36 months after the ACS event while on aspirin therapy. ACS occurs even among relatively younger PWH, typically in association with multiple CRFs. Revascularization with PCI/CABG is feasible, and antiplatelet agents plus secondary prophylaxis appears to be well tolerated in selected PWH with ACS. PMID- 25689279 TI - Azilsartan reduced TNF-alpha and IL-1beta levels, increased IL-10 levels and upregulated VEGF, FGF, KGF, and TGF-alpha in an oral mucositis model. AB - Oral mucositis (OM) is a common complication of treatments for head and neck cancer, particularly radiotherapy with or without chemotherapy. OM is characterised by oral erythema, ulceration, and pain. The aim of this study was to evaluate the effect of azilsartan (AZT), an angiotensin II receptor antagonist, on 5-fluorouracil (5-FU)-induced oral mucositis (OM) in Syrian hamsters. OM was induced by the intraperitoneal administration of 5-FU on experimental days 1 (60 mg/Kg) and 2 (40 mg/Kg). Animals were pretreated with oral AZT (1, 5, or 10 mg/kg) or vehicle 30 min before 5-FU injection and daily until day 10. Experimental treatment protocols were approved by the Animal Ethics Committee Use/CEUA (Number 28/2012) of the UFRN. Macroscopic analysis and cheek pouch samples were removed for histopathologic analysis. Myeloperoxidase (MPO), Malonyldialdehyde (MDA), interleukin-1 beta (IL-1beta), interleukin-10 (IL-10), and tumour necrosis factor-alpha (TNF-alpha) were analysed by Enzyme Linked Immuno Sorbent Assay (ELISA). Vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), keratinocyte growth factor (KGF), and transforming growth factor (TGF)-alpha were measured by immunohistochemistry. Analysis of variance followed by Bonferroni's test was used to calculate the means of intergroup differences (p <= 0.05). Treatment with 1 mg/kg AZT reduced levels MPO (p<0.01), MDA (p<0.5) and histological inflammatory cell infiltration, and increased the presence of granulation tissue. AZT treatment at 1 mg/kg reduced the TNF-alpha (p<0.05) and IL-1beta (p<0.05) levels, increased the cheek pouch levels of IL-10 (p<0.01), and upregulated VEGF, FGF, KGF, and TGF-alpha. Administration of AZT at higher doses (5 and 10 mg/kg) did not significantly reverse the OM. AZT at a dose of 1 mg/kg prevented the mucosal damage and inflammation associated with 5-FU-induced OM, increasing granulation and tissue repair. PMID- 25689280 TI - Graft and patient outcomes of zero-human leucocyte-antigen-mismatched deceased and live donor kidney transplant recipients. AB - Greater compatibility of human leucocyte antigen (HLA) alleles between kidney donors and recipients may lead to improved graft outcomes. This study aimed to compare the incidence of acute rejection and graft failure in zero-HLA-mismatched recipients of living-related (LD) and deceased donor (DD) kidney transplants. Using data from the Australia and New Zealand Dialysis and Transplant Registry, we compared the risk of any acute rejection and biopsy-proven acute rejection (BPAR) and graft failure in recipients of zero-HLA-mismatched kidneys between LD and DD using logistic and Cox regression models. Of the 931 zero-HLA-mismatched recipients transplanted between 1990 and 2012, 19 (2.0%) received kidneys from monozygotic/dizygotic twins (twin), 500 (53.7%) from nontwin LD and 412 (44.3%) from DD. Twin kidney transplant recipients did not experience rejection. Compared to DD transplant recipients, the risk of any acute rejection (adjusted odds ratio 0.52, 95%CI 0.34-0.79, P = 0.002) and overall graft failure (adjusted hazard ratio 0.55, 95%CI 0.41-0.73, P < 0.001) was significantly lower in LD recipients independent of initial immunosuppression, but not for BPAR (adjusted odds ratio 0.52, 95%CI 0.16-1.64, P = 0.263). Zero-HLA-mismatched DD kidney transplant recipients have a significantly higher risk of any acute rejection episodes and graft loss compared to zero-HLA-mismatched LD kidney transplant recipients. A cautious and careful approach in reducing immunosuppression appears to be warranted in this group of transplant recipients. PMID- 25689281 TI - Local and global limits on visual processing in schizophrenia. AB - Schizophrenia has been linked to impaired performance on a range of visual processing tasks (e.g. detection of coherent motion and contour detection). It has been proposed that this is due to a general inability to integrate visual information at a global level. To test this theory, we assessed the performance of people with schizophrenia on a battery of tasks designed to probe voluntary averaging in different visual domains. Twenty-three outpatients with schizophrenia (mean age: 40+/-8 years; 3 female) and 20 age-matched control participants (mean age 39+/-9 years; 3 female) performed a motion coherence task and three equivalent noise (averaging) tasks, the latter allowing independent quantification of local and global limits on visual processing of motion, orientation and size. All performance measures were indistinguishable between the two groups (ps>0.05, one-way ANCOVAs), with one exception: participants with schizophrenia pooled fewer estimates of local orientation than controls when estimating average orientation (p = 0.01, one-way ANCOVA). These data do not support the notion of a generalised visual integration deficit in schizophrenia. Instead, they suggest that distinct visual dimensions are differentially affected in schizophrenia, with a specific impairment in the integration of visual orientation information. PMID- 25689282 TI - Enhanced responsiveness to selective serotonin reuptake inhibitors during lactation. AB - The physiology of mood regulation in the postpartum is poorly understood despite the fact that postpartum depression (PPD) is a common pathology. Serotonergic mechanisms and their dysfunction are widely presumed to be involved, which has led us to investigate whether lactation induces changes in central or peripheral serotonin (5-HT) systems and related affective behaviors. Brain sections from lactating (day 10 postpartum) and age-matched nulliparous (non-pregnant) C57BL/6J mice were processed for 5-HT immunohistochemistry. The total number of 5-HT immunostained cells and optical density were measured. Lactating mice exhibited lower immunoreactive 5-HT and intensity in the dorsal raphe nucleus when compared with nulliparous controls. Serum 5-HT was quantified from lactating and nulliparous mice using radioimmunoassay. Serum 5-HT concentrations were higher in lactating mice than in nulliparous controls. Affective behavior was assessed in lactating and non-lactating females ten days postpartum, as well as in nulliparous controls using the forced swim test (FST) and marble burying task (MBT). Animals were treated for the preceding five days with a selective serotonin reuptake inhibitor (SSRI, citalopram, 5mg/kg/day) or vehicle. Lactating mice exhibited a lower baseline immobility time during the FST and buried fewer marbles during the MBT as compared to nulliparous controls. Citalopram treatment changed these behaviors in lactating mice with further reductions in immobility during the FST and decreased marble burying. In contrast, the same regimen of citalopram treatment had no effect on these behaviors in either non-lactating postpartum or nulliparous females. Our findings demonstrate changes in both central and peripheral 5-HT systems associated with lactation, independent of pregnancy. They also demonstrate a significant interaction of lactation and responsiveness to SSRI treatment, which has important implications in the treatment of PPD. Although recent evidence has cast doubt on the effectiveness of SSRIs, these results support their therapeutic use in the treatment of PPD. PMID- 25689283 TI - Protease-activated receptor (PAR)-2 is required for PAR-1 signalling in pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis is the most devastating diffuse fibrosing lung disease of unknown aetiology. Compelling evidence suggests that both protease activated receptor (PAR)-1 and PAR-2 participate in the development of pulmonary fibrosis. Previous studies have shown that bleomycin-induced lung fibrosis is diminished in both PAR-1 and PAR-2 deficient mice. We thus have been suggested that combined inactivation of PAR-1 and PAR-2 would be more effective in blocking pulmonary fibrosis. Human and murine fibroblasts were stimulated with PAR-1 and PAR-2 agonists in the absence or presence of specific PAR-1 or PAR-2 antagonists after which fibrotic markers like collagen and smooth muscle actin were analysed by Western blot. Pulmonary fibrosis was induced by intranasal instillation of bleomycin into wild-type and PAR-2 deficient mice with or without a specific PAR 1 antagonist (P1pal-12). Fibrosis was assessed by hydroxyproline quantification and (immuno)histochemical analysis. We show that specific PAR-1 and/or PAR-2 activating proteases induce fibroblast migration, differentiation and extracellular matrix production. Interestingly, however, combined activation of PAR-1 and PAR-2 did not show any additive effects on these pro-fibrotic responses. Strikingly, PAR-2 deficiency as well as pharmacological PAR-1 inhibition reduced bleomycin-induced pulmonary fibrosis to a similar extent. PAR 1 inhibition in PAR-2 deficient mice did not further diminish bleomycin-induced pulmonary fibrosis. Finally, we show that the PAR-1-dependent pro-fibrotic responses are inhibited by the PAR-2 specific antagonist. Targeting PAR-1 and PAR 2 simultaneously is not superior to targeting either receptor alone in bleomycin induced pulmonary fibrosis. We postulate that the pro-fibrotic effects of PAR-1 require the presence of PAR-2. PMID- 25689284 TI - The effect of self-regulated caffeine use on cognition in young adults. AB - OBJECTIVE: Based on previous observational studies that have suggested self regulated caffeine use by older adults may enhance reaction time performance and vigilance on cognitive tasks, the current study sought to examine whether this effect held true for young adults as well. METHODS: One hundred and four young adults from two major metropolitan areas, ages 18-29 years, not meeting the criteria for a current psychiatric disorder, completed several cognitive tasks related to decision-making (Cambridge Gamble Task), response inhibition and reaction time (stop-signal task), and vigilance and reaction time (Rapid Visual Information Processing). Caffeine usage was self-reported using a reliable quantity and frequency questionnaire. RESULTS: Self-reported caffeine usage was not significantly associated with any of the cognitive measures used in this study after controlling for age, gender, cigarette smoking, alcohol use, cannabis use, and gambling frequency. CONCLUSIONS: These data suggest that self-regulated caffeine usage may not have a significant impact on reaction time, vigilance, response inhibition, or decision-making in young adults, or that these effects are contingent upon other variables not accounted for in the current study. PMID- 25689285 TI - Photoswitching the cytotoxic properties of platinum(II) compounds. AB - The photoactivation of potential anticancer metal complexes is a hot topic of current research as it may lead to the development of more selective drugs. Photoactivated chemotherapy (PACT) with coordination compounds is usually based on a (photo)chemical reaction taking place at the metal center. Herein, a new strategy is exploited that consists of "photomodifying" a ligand coordinated to metal ions. Platinum(II) complexes from photoswitchable 1,2-dithienylethene containing ligands have been prepared, which exhibit two interconvertible photoisomeric forms that present distinct DNA-interacting properties and cytotoxic behaviors. PMID- 25689286 TI - Cytogenetic evaluation of functionalized single-walled carbon nanotube in mice bone marrow cells. AB - With their unique structure and physicochemical properties, single?-walled carbon nanotubes (SWCNTs) have many potential new applications in medicine and industry. However, there is lack of detailed information concerning their impact on human health and the environment. The aim of this study was to assess the effects, after intraperitoneal injection of functionalized SWCNTs (f-SWCNT) on the induction of reactive oxygen species (ROS), frequency of structural chromosomal aberrations (SCA), frequency of micronuclei induction, mitotic index, and DNA damage in Swiss-Webster mice. Three doses of f-SWCNTs (0.25, 0.5, and 0.75 mg/kg) and two controls (negative and positive) were administered to mice, once a day for 5 days. Bone marrow and peripheral blood samples were collected 24 h after the last treatment following standard protocols. F-SWCNT exposure significantly enhanced ROS, increased (p < 0.05) the number of SCA and the frequency of micronucleated cells, increased DNA damage, and decreased the mitotic index in exposed groups compared to negative control. The scientific findings reported here suggest that purified f-SWCNT have the potential to induce oxidative stress mediated genotoxicity in Swiss-Webster mice at higher level of exposure. Further characterization of their systemic toxicity, genotoxicity, and carcinogenicity is also essential. (c) 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1091-1102, 2016. PMID- 25689287 TI - Collaboration and involvement of persons with lived experience in planning Canada's At Home/Chez Soi project. AB - Planning the implementation of evidence-based mental health services entails commitment to both rigour and community relevance, which entails navigating the challenges of collaboration between professionals and community members in a planning environment which is neither 'top-down' nor 'bottom-up'. This research focused on collaboration among different stakeholders (e.g. researchers, service providers, persons with lived experience [PWLE]) at five project sites across Canada in the planning of At Home/Chez Soi, a Housing First initiative for homeless people with mental health problems. The research addressed the question of what strategies worked well or less well in achieving successful collaboration, given the opportunities and challenges within this complex 'hybrid' planning environment. Using qualitative methods, 131 local stakeholders participated in key informant or focus group interviews between October 2009 and February 2010. Site researchers identified themes in the data, using the constant comparative method. Strategies that enhanced collaboration included the development of a common vision, values and purpose around the Housing First approach, developing a sense of belonging and commitment among stakeholders, bridging strategies employed by Site Co-ordinators and multiple strategies to engage PWLE. At the same time, a tight timeline, initial tensions, questions and resistance regarding project and research parameters, and lack of experience in engaging PWLE challenged collaboration. In a hybrid planning environment, clear communication and specific strategies are required that flow from an understanding that the process is neither fully participatory nor expert-driven, but rather a hybrid of both. PMID- 25689288 TI - Microcomputed tomography: approaches and applications in bioengineering. AB - Microcomputed tomography (microCT) has become a standard and essential tool for quantifying structure-function relationships, disease progression, and regeneration in preclinical models and has facilitated numerous scientific and bioengineering advancements over the past 30 years. In this article, we recount the early events that led to the initial development of microCT and review microCT approaches for quantitative evaluation of bone, cartilage, and cardiovascular structures, with applications in fundamental structure-function analysis, disease, tissue engineering, and numerical modeling. Finally, we address several next-generation approaches under active investigation to improve spatial resolution, acquisition time, tissue contrast, radiation dose, and functional and molecular information. PMID- 25689289 TI - Driving performance under alcohol in simulated representative driving tasks: an alcohol calibration study for impairments related to medicinal drugs. AB - Comparing drug-induced driving impairments with the effects of benchmark blood alcohol concentrations (BACs) is an approved approach to determine the clinical relevance of findings for traffic safety. The present study aimed to collect alcohol calibration data to validate findings of clinical trials that were derived from a representative test course in a dynamic driving simulator. The driving performance of 24 healthy volunteers under placebo and with 0.05% and 0.08% BACs was measured in a double-blind, randomized, crossover design. Trained investigators assessed the subjects' driving performance and registered their driving errors. Various driving parameters that were recorded during the simulation were also analyzed. Generally, the participants performed worse on the test course (P < 0.05 for the investigators' assessment) under the influence of alcohol. Consistent with the relevant literature, lane-keeping performance parameters were sensitive to the investigated BACs. There were significant differences between the alcohol and placebo conditions in most of the parameters analyzed. However, the total number of errors was the only parameter discriminating significantly between all three BAC conditions. In conclusion, data show that the present experimental setup is suitable for future psychopharmacological research. Thereby, for each drug to be investigated, we recommend to assess a profile of various parameters that address different levels of driving. On the basis of this performance profile, the total number of driving errors is recommended as the primary endpoint. However, this overall endpoint should be completed by a specifically sensitive parameter that is chosen depending on the effect known to be induced by the tested drug. PMID- 25689290 TI - Mirtazapine in pregnancy and lactation: data from a case series. AB - Depression is a common disorder in pregnancy and associated with adverse effects for both mother and neonate. Pharmacological treatment and prevention options include mirtazapine. In a series of 56 cases, we investigated neonatal outcome after intrauterine exposure to mirtazapine and exposure through lactation in the first days postpartum.No increase in any neonatal complication was observed. None of the infants exposed to mirtazapine in the first trimester were born with a major malformation. Of the 54 infants exposed to mirtazapine in the third trimester, 14 were diagnosed with poor neonatal adaptation syndrome (PNAS). This incidence (25.9%) is similar to the incidence of PNAS after intrauterine exposure to other antidepressants. The incidence of PNAS after exposure to mirtazapine was significantly diminished in children who were partially or fully breastfed (18.6% versus 54.5%, P = 0.024). PMID- 25689291 TI - Diagnosis, treatment and outcome of adrenocortical cancer. AB - BACKGROUND: Adrenocortical cancer (ACC) is a rare disease with a dismal prognosis. The majority of patients are diagnosed with advanced disease and raise difficult management challenges. METHODS: All references identified in PubMed, published between 2004 and 2014, using the keywords 'adrenocortical cancer' or 'adrenal surgery' or both, were uploaded into a database. The database was interrogated using keywords specific for each field studied. RESULTS: In all, 2049 publications were identified. There is ongoing debate about the feasibility and oncological outcomes of laparoscopic adrenalectomy for small ACCs, and data derived from institutional case series have failed to provide an evidence level above expert opinion. The use of mitotane (1-(2-chlorophenyl)-1-(4-chlorophenyl) 2,2-dichloroethane) in combination with chemotherapy in the treatment of metastatic disease has been assessed in an international randomized trial (FIRM ACT trial) involving patients with ACC. Based on this trial, mitotane plus etoposide, doxorubicin and cisplatin is now the established first-line cytotoxic therapy owing to a higher response rate and longer median progression-free survival than achieved with streptozocin-mitotane. For patients with tumours smaller than 5 cm and with no signs of lymph node or distant metastases, survival is favourable with a median exceeding 10 years. However, the overall 5-year survival rate for all patients with ACC is only 30 per cent. CONCLUSION: Open and potentially laparoscopic adrenalectomy for selected patients is the main treatment for non-metastatic ACC, but the overall 5-year survival rate remains low. PMID- 25689292 TI - Introduction of laparoscopic abdominal aortic aneurysm repair. AB - BACKGROUND: The aim was to review a consecutive series of patients treated with laparoscopic abdominal aortic aneurysm (AAA) repair. These patients were compared with patients having elective open AAA repair. METHODS: Demographic and operative details were collected prospectively and outcomes recorded for all patients undergoing laparoscopic or open AAA repair. RESULTS: A total of 316 patients underwent laparoscopic (51), open (53) or endovascular (EVAR; 212) AAA repair between 2007 and 2013. The median age of patients who had laparoscopic or open repair was 72 (i.q.r. 66-75) years, and 92.3 per cent were men. There was no significant difference in sex distribution, age or V-POSSUM physiology score between laparoscopic and open repair. Of the 51 laparoscopic procedures, six were totally laparoscopic, 43 were laparoscopically assisted and two were converted to open repair. Pain scores were similar on days 1 and 3 after laparoscopic and open repair, even though epidurals were used in the open group, and were lower on days 5 and 7 after laparoscopic procedures. Patients who had laparoscopic repair had significantly fewer postoperative cardiorespiratory and renal complications (P = 0.017), and were discharged from hospital sooner (median 5 (i.q.r. 3-7) versus 8 (6-11) days; P = 0 .001). CONCLUSION: Laparoscopic AAA repair was performed safely, and with at least equivalent outcomes to open repair, in patients unfavourable for EVAR. PMID- 25689293 TI - Experimental study of survival of pedicled perforator flap with flow-through and flow-end blood supply. AB - BACKGROUND: Flap viability after transfer depends on blood flow from the arterial blood supply below the fascia. This study evaluated survival of a pedicle flap with a perforator lateral branch and flow-through blood supply, compared with that of a flap with a flow-end blood supply and perforator terminal branch. METHODS: Forty Sprague-Dawley rats, 20 in each group, were assigned to transfer of a superficial epigastric artery pedicle island flap with a flow-through or flow-end configuration of blood supply. Laser Doppler imaging was used to evaluate flap perfusion 2 h, 3 days and 5 days after surgery. The rats were killed on day 5, and lead oxide-gelatine-enhanced flap angiography and histology with haematoxylin and eosin staining was performed. Dorsal midline tissue was excised for quantification of vascular endothelial growth factor by western blot assay. RESULTS: On day 5 after surgery, the flow-through group exhibited a significantly greater mean(s.d.) flap survival area (97.8(3.5) versus 80.8(10.2) per cent; P = 0.003), microvascular density (303(19) versus 207(41) per mm(2) ; P < 0.001) and perfusion (8.64(0.14) versus 5.95(0.14) perfusion units; P < 0.001) than the flow-end group. The flow-through group exhibited more angiosomes connected by dilated vascular anastomoses between the skin and subcutaneous fasciae. CONCLUSION: The flow-through blood supply improved pedicle perforator flap survival. Surgical relevance Perforator flap failure is mainly the result of impaired blood supply, as a flow-end blood configuration is nourished only by the perforator terminal branch of the artery. This work showed that the flow-through blood supply nourished by the perforator lateral branch improved flap survival, with dilatation of collateral vascular anastomoses and increased neoangiogenesis. The use of a flow-through configuration improves perforator flap survival and could therefore minimize morbidity resulting from flap necrosis. PMID- 25689294 TI - Long-term outcomes of sacral nerve stimulation for faecal incontinence (Br J Surg 2015; 102: 407-415). PMID- 25689297 TI - Study of drug resistance in pulmonary tuberculosis cases in south coastal Karnataka. AB - The present cross-sectional study was conducted for the first time from the Udupi district of coastal Karnataka to know the prevalence of drug resistance and comparative analysis of MDR and non-MDR cases of pulmonary tuberculosis. Details of 862 smear positive cases of pulmonary tuberculosis with age ?15 years from 12 designated microscopy centres of the Udupi district were studied. Initially 2 sputum samples trailed by one follow-up sample were collected from each patient and processed for culture and drug sensitivity on the Lowenstein-Jensen medium. A total resistance of 33.4% was observed that includes the mono-resistance of 22.5%, multidrug resistance (MDR) of 6.3% and extensive drug resistance (XDR) of 0.3%. Significant odds ratio (OR) was observed in category 2 cases (OR 3.9) for the development of MDR tuberculosis. A significant statistical association was observed using Fisher's exact test while comparing mortality rate (19.3% vs. 1.8%), treatment failure (8.8% vs. 3.8%) and cure rate (68.4% vs. 85.4%) between MDR and non-MDR cases (p<0.001). Category 2 patients are important risk factors for the development of MDR in pulmonary tuberculosis. Due to high mortality and low cure rate in MDR cases it is imperative to know the drug sensitivity report before institution of anti-tubercular treatment. PMID- 25689298 TI - Daily variation in global and local DNA methylation in mouse livers. AB - DNA methylation is one of the best-characterized epigenetic modifications and has an important biological relevance. Here we showed that global DNA methylation level in mouse livers displayed a daily variation where the peak phases occurred during the end of the day and the lowest level at the beginning of the day in the light-dark or dark-dark cycles. Typical repeat sequence long interspersed nucleotide element-1 (LINE-1) had a similar methylation rhythm to global DNA. DNA methyltransferase 3A (DNMT3A) and ratio of S-adenosylmethionine (SAM) to S adenosylhomocysteine (SAH) brought a relative forward daily variation to global DNA methylation, and the temporary change in ratio of SAM to SAH had no influence on the DNA methylation level. The rhythm of global DNA methylation was lost and DNA methylation level was increased in Per1-/-Per2-/- double knockout mice, which were in accordance with changes of Dnmt3a mRNA levels and its rhythm. Our results suggest that the daily variation in global DNA methylation was associated with the change of Dnmt3a expression rather than ratio of SAM to SAH. PMID- 25689299 TI - Clinical diagnostic approach to congenital agenesis of right lung with dextrocardia: a case report with review of literature. AB - BACKGROUND AND AIM: Congenital lung agenesis is extremely rare. The aim of this article is to evaluate the clinical diagnostic approach to congenital lung agenesis with a case report. METHODS: We described a 44-day-old male child with right pulmonary agenesis presented to us with severe respiratory distress. He was misdiagnosed as a case of foreign body bronchus at emergency room according chest X-ray. Right lung agenesis was confirmed by CT scan. Echocardiography showed dextrocardia, absence of right pulmonary artery and small atrial septal defect. Then we reviewed the related literature with Medline and Pubmed databases. CONCLUSION: It is recommended that CT scan is the key diagnostic approach for lung agenesis and invasive diagnostic procedures and prophylactic surgery should not be done in asymptomatic cases. PMID- 25689300 TI - Framing and personalizing informed consent to prevent negative expectations: An experimental pilot study. AB - OBJECTIVE: Informing patients about medical treatments and their possible side effects is ethically and legally obligatory but may trigger negative expectations and nocebo-related side effects. This pilot study aims to investigate the effect of different informed consent procedures on treatment expectations for adjuvant breast cancer treatments (Study 1: endocrine therapy; Study 2: chemotherapy). METHOD: Using an experimental 2-factorial design, healthy women were informed about endocrine therapy (n = 60) or chemotherapy (n = 64) within a hypothetical scenario. Information was framed with or without treatment benefit information and delivered in a personalized or standardized interaction. Primary outcomes were necessity-concern beliefs about the treatment and side-effect expectations, secondary outcomes were decisional conflicts. RESULTS: In Study 1, side-effect expectations (eta2p= .08) and decisional conflicts (eta2p = .07) were lower when framed treatment information was given. Providing personalized information resulted in more functional necessity-concern beliefs (eta2p = .06) and lower decisional conflicts (eta2p = .07). Personalizing and framing of information resulted in more functional necessity-concern beliefs (eta2p = .10) and lower decisional conflicts. In Study 2, necessity-concern beliefs were more functional with framing (eta2p = .06). Participants in the personalized groups reported lower decisional conflicts (eta2p = .06). No differences in side-effect expectations were revealed. CONCLUSIONS: This is the first study to provide evidence for optimized treatment expectations through altered informed consent strategies. The results emphasize that framing and personalizing informed consent can positively influence treatment expectations and reduce decisional conflicts. However, generalizations are impaired by the study's pilot character. The potential to prevent nocebo responses in clinical practice should be analyzed. (PsycINFO Database Record PMID- 25689301 TI - Quality of relationships with parents and friends in adolescence predicts metabolic risk in young adulthood. AB - OBJECTIVE: This study was designed to examine whether family and peer relationships in adolescence predict the emergence of metabolic risk factors in young adulthood. METHOD: Participants from a large, nationally representative cohort study (N = 11,617 for these analyses) reported on their relationship experiences with parents and close friends during adolescence. Fourteen years later, interviewers collected blood samples, as well as anthropometric and blood pressure measurements. Blood samples were analyzed for HbA1c. RESULTS: Ordered logistic regressions revealed that for females, supportive parent-child relationships and close male friendships in adolescence were associated with reduced odds of having elevated metabolic risk markers in young adulthood. These effects remained significant even after controlling for baseline measures of body mass index (BMI) and health and demographic covariates. The protective effects of close relationships were not significant for males, however. Exploratory analyses with 2-parent families revealed that supportive father-child relationships were especially protective for females. CONCLUSIONS: These findings suggest that, for females, close and supportive relationships with parents and male friends in adolescence may reduce the risk of metabolic dysregulation in adulthood. PMID- 25689302 TI - Early stage lung cancer detection in systemic sclerosis does not portend survival benefit: a cross sectional study. AB - BACKGROUND: Systemic Sclerosis (SSc) is a rare connective tissue disorder associated with an increased risk of malignancy including lung cancer. METHODS: A single center review of all cases of lung cancer in patients with SSc was conducted. Clinical, radiographic, and detailed pathologic data was collected. Risk factors were compared with our center's SSc Registry. Cancer characteristics were compared with the National Cancer Institute SEER Cancer Statistics (NCI SEER) data. RESULTS: 17 cases were identified; the majority were females (82%) with the lung cancers diagnosed after the onset of SSc (88%). Tobacco use was identified in 65% of cases. Serologic testing showed 50% of cases were Scl-70 positive. Twelve cases had radiographic evidence of SSc lung involvement, however only 6 had restrictive physiology on pulmonary function testing. Thirteen cases had pulmonary nodules preceding lung cancer. Thirteen of the cancers were adenocarcinoma. Ten underwent molecular mutational profiling: 2/8 had KRAS mutation and 1/10 had EGFR mutation. More of the non-small cell lung cancers were diagnosed at localized disease (56%) than in the NCI SEER database. However, 5 years survival among the stage I cases was 25% versus an expected survival of 54%. CONCLUSIONS: The high proportion of adenocarcinomas seen in our study is different from that reported in the literature. Lung cancers were diagnosed at an early stage, likely due to our center's practice of radiographic screening for SSc associated lung involvement, however this did not confer a survival advantage. A high proportion of patients who developed lung cancer had interstitial lung disease. PMID- 25689303 TI - HSPA5/Dna K may be a useful target for human disease therapies. AB - The chaperone protein HSPA5/Dna K is conserved throughout evolution from higher eukaryotes down to prokaryotes. The celecoxib derivative OSU-03012 (also called AR-12) interacts with Viagra or Cialis in eukaryotic cells to rapidly reduce HSPA5 levels as well as blunt the functions of many other chaperone proteins. Because multiple chaperones are modulated in eukaryotes, the expression of cell surface virus receptors is reduced and because HSPA5 in blocked viruses cannot efficiently replicate. Because DnaK levels are reduced in prokaryotes by OSU 03012, the levels of DnaK chaperone proteins such as Rec A decline, which is associated with bacterial cell death and a resensitization of so-called drug resistant superbugs to standard of care antibiotics. In Alzheimer's disease, HSPA5 has been shown to play a supportive role for the progression of tau phosphorylation and neurodegeneration. Thus, in eukaryotes, HSPA5 represents a target for anticancer, antiviral, and anti-Alzheimer's therapeutics and in prokaryotes, DnaK and bacterial phosphodiesterases represent novel antibiotic targets that should be exploited in the future by pharmaceutical companies. PMID- 25689304 TI - Reflecting on fifty years of progress for women in science. PMID- 25689306 TI - Correction: UltiMatch-NL: a web service matchmaker based on multiple semantic filters. PMID- 25689307 TI - Non-ionic surfactants do not consistently improve the enzymatic hydrolysis of pure cellulose. AB - Non-ionic surfactants have been frequently reported to improve the enzymatic hydrolysis of pretreated lignocellulosic biomass and pure cellulose. However, how the hydrolysis condition, substrate structure and cellulase formulation affect the beneficial action of surfactants has not been well elucidated. In this work, it was found that the enzymatic hydrolysis of pure cellulose was not consistently improved by surfactants. Contrarily, high surfactant concentration, e.g. 5 g/L, which greatly improved the hydrolysis of dilute acid pretreated substrates, actually showed notable inhibition to pure cellulose conversion in the late phase of hydrolysis. Under an optimal hydrolysis condition, the improvement by surfactant was limited, but under harsh conditions surfactant indeed could enhance cellulose conversion. It was proposed that non-ionic surfactants could interact with substrates and cellulases to impact the adsorption behaviors of cellulases. Therefore, the beneficial action of surfactants on pure cellulose hydrolysis is influenced by hydrolysis condition, cellulose structural features and cellulase formulation. PMID- 25689308 TI - Effects of light and temperature on open cultivation of desert cyanobacterium Microcoleus vaginatus. AB - Microalgae cultivation has recently been recognized as an important issue to deal with the increasingly prominent resource and environmental problems. In this study, desert cyanobacterium Microcoleus vaginatus was open cultivated in 4 different cultivation conditions in Qubqi Desert, and it was found Chlorella sp., Scenedesmus sp. and Navicula sp. were the main contaminating microalgal species during the cultivation. High light intensity alone was responsible for the green algae contamination, but the accompanied high temperature was beneficial to cyanobacterial growth, and the maximum biomass productivity acquired was 41.3mgL( 1)d(-1). Low temperature was more suitable for contaminating diatoms' growth, although all the microalgae (including the target and contaminating) are still demand for a degree of light intensity, at least average daily light intensity >5MUEm(-2)s(-1). As a whole, cultivation time, conditions and their interaction had a significant impact on microalgal photosynthetic activity (Fv/Fm), biomass and exopolysaccharides content (P<0.001). PMID- 25689309 TI - Improving performance of flat-plate photobioreactors by installation of novel internal mixers optimized with computational fluid dynamics. AB - A novel mixer was developed to improve the performance of flat-plate photobioreactors (PBRs). The effects of mixer were theoretically evaluated using computational fluid dynamics (CFD) according to radial velocity of fluid and light/dark cycles within reactors. The structure parameters, including the riser width, top clearance, clearance between the baffles and walls, and number of the chambers were further optimized. The microalgae culture test aiming at validating the simulated results was conducted indoor. The results showed the maximum biomass concentrations in the optimized and archetype reactors were 32.8% (0.89 g L(-1)) and 19.4% (0.80 g L(-1)) higher than that in the control reactor (0.67 g L(-1)). Therefore, the novel mixer can significantly increase the fluid velocity along the light attenuation and light/dark cycles, thus further increased the maximum biomass concentration. The PBRs with novel mixers are greatly applicable for high-efficiency cultivation of microalgae. PMID- 25689310 TI - Separation of phenolic compounds with modified adsorption resin from aqueous phase products of hydrothermal liquefaction of rice straw. AB - Hydrothermal liquefaction can be used to convert rice straw into an aqueous phase product that contains valuable phenolic compounds. In experiments, commercial adsorption resin XAD-4 was modified by a benzene ring - alpha,alpha'-dichloro-p xylene (DCX) - in order to separate the phenolic compounds from the aqueous phase product; and, the optimal conditions for separation were explored. The results showed that, after modification of the resin, its adsorption capacity improved by 50%, due to increases in surface area, pore volume and micropore volume. The selectivity of the resin increased when the benzene ring was introduced as the ring formed hydrogen bonds with the compounds. The optimal conditions for separation were desorption agent of 40%, 45% and 55% ethanol solution, a flow rate of 2.5-5 mL/min, and a ratio of the sample volume to the column volume was 1:1. The total content of phenolic compounds in aqueous solution increased from 18% to 78% after separation. PMID- 25689311 TI - Phenyllactic acid production by simultaneous saccharification and fermentation of pretreated sorghum bagasse. AB - Dilute acid-pretreated sorghum bagasse, which was predominantly composed of glucan (59%) and xylose (7.2%), was used as a lignocellulosic feedstock for d phenyllactic acid (PhLA) production by a recombinant Escherichia coli strain expressing phenylpyruvate reductase from Wickerhamia fluorescens. During fermentation with enzymatic hydrolysate of sorghum bagasse as a carbon source, the PhLA yield was reduced by 35% compared to filter paper hydrolysate, and metabolomics analysis revealed that NAD(P)H regeneration and intracellular levels of erythrose-4-phosphate and phosphoenolpyruvate for PhLA biosynthesis markedly reduced. Compared to separate hydrolysis and fermentation (SHF) with sorghum bagasse hydrolysate, simultaneous saccharification and fermentation (SSF) of sorghum bagasse under glucose limitation conditions yielded 4.8-fold more PhLA with less accumulation of eluted components, including p-coumaric acid and aldehydes, which inhibited PhLA fermentation. These results suggest that gradual enzymatic hydrolysis during SSF enhances PhLA production under glucose limitation and reduces the accumulation of fermentation inhibitors, collectively leading to increased PhLA yield. PMID- 25689312 TI - Use of pulmonary artery catheter in coronary artery bypass graft. Costs and long term outcomes. AB - BACKGROUND: Pulmonary artery catheters (PAC) are used widely to monitor hemodynamics in patients undergoing coronary bypass graft (CABG) surgery. However, recent studies have raised concerns regarding both the effectiveness and safety of PAC. Therefore, our aim was to determine the effects of the use of PAC on the short- and long-term health and economic outcomes of patients undergoing CABG. METHODS: 1361 Chinese patients who consecutively underwent isolated, primary CABG at the Cardiovascular Institute of Fuwai Hospital from June 1, 2012 to December 31, 2012 were included in this study. Of all the patients, 453 received PAC during operation (PAC group) and 908 received no PAC therapy (control group). Short-term and long-term mortality and major complications were analyzed with multivariate regression analysis and propensity score matched-pair analysis was used to yield two well-matched groups for further comparison. RESULTS: The patients who were managed with PAC more often received intraoperative vasoactive drugs dopamine (70.9% vs. 45.5%; P<0.001) and epinephrine (7.7% vs. 2.6%; P<0.001). In addition, costs for initial hospitalization were higher for PAC patients ($14,535 vs. $13,873, respectively, p = 0.004). PAC use was neither associated with the perioperative mortality or major complications, nor was it associated with long-term mortality and major adverse cardiac and cerebrovascular events. In addition, comparison between two well-matched groups showed no significant differences either in baseline characteristics or in short-term and long-term outcomes. CONCLUSIONS: There is no clear indication of any benefit or harm in managing CABG patients with PAC. However, use of PAC in CABG is more expensive. That is, PAC use increased costs without benefit and thus appears unjustified for routine use in CABG surgery. PMID- 25689313 TI - Two novel SNPs in ATXN3 3' UTR may decrease age at onset of SCA3/MJD in Chinese patients. AB - Spinocerebellar ataxia type 3 (SCA3), or Machado-Joseph disease (MJD), is an autosomal dominantly-inherited disease that produces progressive problems with movement. It is caused by the expansion of an area of CAG repeats in a coding region of ATXN3. The number of repeats is inversely associated with age at disease onset (AO) and is significantly associated with disease severity; however, the degree of CAG expansion only explains 50 to 70% of variance in AO. We tested two SNPs, rs709930 and rs910369, in the 3' UTR of ATXN3 gene for association with SCA3/MJD risk and with SCA3/MJD AO in an independent cohort of 170 patients with SCA3/MJD and 200 healthy controls from mainland China. rs709930 genotype frequencies were statistically significantly different between patients and controls (p = 0.001, alpha = 0.05). SCA3/MJD patients carrying the rs709930 A allele and rs910369 T allele experienced an earlier onset, with a decrease in AO of approximately 2 to 4 years. The two novel SNPs found in this study might be genetic modifiers for AO in SCA3/MJD. PMID- 25689314 TI - The stability analysis of an SVEIR model with continuous age-structure in the exposed and infectious classes. AB - In this paper, an Susceptible-Vaccines-Exposed-Infectious-Recovered model with continuous age-structure in the exposed and infectious classes is investigated. These two ages are assumed to have arbitrary distributions that are represented by age-specific rates leaving the exposed and the infectious classes. We investigate the global dynamics of this model in the sense of basic reproduction number via constructing Lyapunov functions. The asymptotic smoothness of solutions and uniform persistence of the system is shown from reformulating the system as a system of Volterra integral equations. PMID- 25689315 TI - A compact field guide to the study of microsaccades: Challenges and functions. AB - Following a period of quiescence at the end of last century, the study of microsaccades has now regained strong impetus and broad attention within the vision research community. This wave of interest, partly fueled by the advent of user-friendly high-resolution eyetrackers, has attracted researchers and led to novel ideas. Old hypothesis have been revisited and new ones formulated. This article is designed to serve as a practical guide for researchers in the field. Because of the history of the field and the difficulty of measuring very small eye movements, the study of microsaccades presents peculiar challenges. Here, we summarize some of the main challenges and describe methods for assessing and improving the quality of the recordings. Furthermore, we examine how these experimental challenges have influenced analysis of the visual functions of microsaccades and critically review current evidence on three long-debated proposals: the maintenance of fixation, the prevention of visual fading, and the exploration of fine spatial detail. PMID- 25689316 TI - Efficiency of [2 + 2] photodimerization of various stilbene derivatives within the DNA duplex scaffold. AB - A DNA duplex was used as a scaffold to evaluate the intrinsic reactivity of [2 + 2] photodimerization between stilbene derivatives; the duplex pre-organizes the substrates avoiding the need for an association step. Unmodified stilbenes were first introduced at base-pairing positions on complementary DNA strands. The duplex was then irradiated with 340 nm UV light. HPLC analyses revealed that [2 + 2] photodimerization proceeded rapidly without side reactions. Thus, it was confirmed that the DNA duplex could be used as an ideal scaffold for [2 + 2] photodimerization of stilbenes. Next, we examined homo-photodimerization abilities of various stilbene derivatives. Homo-photodimerization of p cyanostilbene, p-methylstilbazolium, and p-stilbazole occurred efficiently, whereas homo-photodimerization of p-dimethylaminostilbene and p-nitrostilbene did not proceed at all, probably because the reaction was quenched by dimethylamino and nitro groups. Time-dependent density functional theory calculations revealed that excitation energy was correlated with quantum yield. We further investigated hetero-photodimerization. These reactions were made possible by the use of two complementary oligodeoxyribonucleotides tethering different stilbene derivatives. Reactivities in hetero-photodimerization were highly dependent on the combination of derivatives. A high correlation was observed between the quantum yields and energy gaps of HOMO and LUMO between reactive derivatives. Unexpectedly, nitrostilbene, which was non-reactive in homo-photodimerization, cross-reacted with p-methylstilbazolium and p-stilbazole, both of which had close HOMO or LUMO with nitrostilbene. Evaluation of the intrinsic reactivity of homo- and hetero photodimerization of stilbene derivatives was made possible by the use of DNA as a scaffold. PMID- 25689318 TI - Unraveling the swine genome: implications for human health. AB - The pig was first used in biomedical research in ancient Greece and over the past few decades has quickly grown into an important biomedical research tool. Pigs have genetic and physiological traits similar to humans, which make them one of the most useful and versatile animal models. Owing to these similarities, data generated from porcine models are more likely to lead to viable human treatments than those from murine work. In addition, the similarity in size and physiology to humans allows pigs to be used for many experimental approaches not feasible in mice. Research areas that employ pigs range from neonatal development to translational models for cancer therapy. Increasing numbers of porcine models are being developed since the release of the swine genome sequence, and the development of additional porcine genomic and epigenetic resources will further their use in biomedical research. PMID- 25689319 TI - Animal models of aging research: implications for human aging and age-related diseases. AB - Aging is characterized by an increasing morbidity and functional decline that eventually results in the death of an organism. Aging is the largest risk factor for numerous human diseases, and understanding the aging process may thereby facilitate the development of new treatments for age-associated diseases. The use of humans in aging research is complicated by many factors, including ethical issues; environmental and social factors; and perhaps most importantly, their long natural life span. Although cellular models of human disease provide valuable mechanistic information, they are limited in that they may not replicate the in vivo biology. Almost all organisms age, and thus animal models can be useful for studying aging. Herein, we review some of the major models currently used in aging research and discuss their benefits and pitfalls, including interventions known to extend life span and health span. Finally, we conclude by discussing the future of animal models in aging research. PMID- 25689321 TI - Primary and secondary consequences of indoor air cleaners. AB - Air cleaning is broadly applied to reduce contaminant concentrations in many buildings. Although diverse in underlying technology, mode of application, target contaminants, and effectiveness, there are also commonalities in the framework for understanding their primary impact (i.e. concentration reductions) and secondary impacts (e.g. energy use and by-product production). Furthermore, both primary and secondary impacts are moderated by the specific indoor context in which an air cleaner is used. This investigation explores the dynamics of removal efficiency in a variety of air cleaners and combines efficiency and flow rate to put air cleaning in the context of real indoor environments. This allows for the direct comparison to other indoor pollutant loss mechanisms (ventilation and deposition) and further suggests that effective air cleaner use is context and contaminant specific. The concentration reduction impacts of air cleaning need to be contrasted with the secondary consequences that arise from the use of air cleaners. This study emphasizes two important secondary consequences: energy use of the air cleaning process and primary and secondary emissions from air cleaners. This study also identifies current research challenges and areas for large leaps in our understanding of the role of air cleaners in improving indoor environmental quality. PMID- 25689322 TI - Characteristics of Patients Transported by a Paramedic-staffed Helicopter Emergency Medical Service in Victoria, Australia. AB - OBJECTIVE: The optimal staffing of helicopter emergency medical services (HEMS) is uncertain. An intensive care paramedic-staffed HEMS has operated in the state of Victoria, Australia for over 28 years, with paramedics capable of performing advanced procedures, including rapid sequence intubation, decompression of tension pneumothorax, and cricothyroidotomy. Administration of a wide range of vasoactive, anesthetic, and analgesic medications is also permitted. We sought to explore the characteristics of patients transported by HEMS in Victoria, and describe paramedic utilization of their skill set in the prehospital environment. METHODS: A retrospective data review was conducted of patients transported by the HEMS between 1 July 2012 and 30 June 2013. Data were sourced from the Ambulance Victoria data warehouse and the Victorian State Trauma Registry. Interhospital transfers were excluded. RESULTS: HEMS attended 1,519 cases during the study period. A total of 825 primary transport cases were included in analyses. Most patients were male (69.5%) and the majority of cases involved trauma (86.1%). Rapid sequence intubation (RSI) was performed in 36.8% of pediatric and 29.9% of adult major trauma patients, with a procedural success rate of 100%. Ketamine was administered to 18.5% of all trauma patients. The proportion of patients with a severe pain score (>=7) decreased from 33.8 to 3.2% (p < 0.001) between initial and final paramedic assessments. A clinically significant pain reduction of >=2 points was achieved by 87.0% (95% CI 82.9-90.4%) of adult trauma patients who had an initial pain score >2 points and a valid final pain score. In-hospital mortality following major-trauma was 7.6% (95% CI 5.0-11.0%). CONCLUSIONS: The skill set of HEMS intensive care paramedics in Victoria is broad, including a large number of prehospital critical care procedures commonly utilized by physician-staffed HEMS in other jurisdictions. A high RSI procedural success rate was observed across the study period, as were significant improvements in patient physiological parameters and pain scores. PMID- 25689317 TI - The Genome 10K Project: a way forward. AB - The Genome 10K Project was established in 2009 by a consortium of biologists and genome scientists determined to facilitate the sequencing and analysis of the complete genomes of 10,000 vertebrate species. Since then the number of selected and initiated species has risen from ~26 to 277 sequenced or ongoing with funding, an approximately tenfold increase in five years. Here we summarize the advances and commitments that have occurred by mid-2014 and outline the achievements and present challenges of reaching the 10,000-species goal. We summarize the status of known vertebrate genome projects, recommend standards for pronouncing a genome as sequenced or completed, and provide our present and future vision of the landscape of Genome 10K. The endeavor is ambitious, bold, expensive, and uncertain, but together the Genome 10K Consortium of Scientists and the worldwide genomics community are moving toward their goal of delivering to the coming generation the gift of genome empowerment for many vertebrate species. PMID- 25689323 TI - Self-assembly of miktoarm star-like ABn block copolymers: from wet to dry brushes. AB - Self-assembly of miktoarm star-like ABn block copolymer in both selective solvent (A- or B-selective) and miscible homopolymer matrix (A or B homopolymer), that is, formation of micelles, was for the first time investigated by theoretical calculations based on self-consistent mean field theory. Interestingly, the calculation revealed that the size of micelles in solvent was smaller than that in homopolymer under the same conditions. In B-selective solvent, with increasing number of B blocks n in miktoarm star-like ABn block copolymer at a fixed volume fraction of A block, the micellar size decreased gradually. In stark contrast, when miktoarm star-like ABn block copolymer dissolved in B homopolymer matrix at molecular weight ratio of B homopolymer to ABn block copolymer fH = 0.30, the overall micellar size decreased nonmonotonically as the number of B blocks n in ABn block copolymer increased. The largest micelle was formed in AB2 (i.e., n = 2). This intriguing finding can be attributed to a wet-to-dry brush transition that occurred from n = 1 to n = 2 in the micellization of miktoarm star-like ABn block copolymer. Moreover, the micellization behaviors of miktoarm star-like ABn block copolymer in A-selective solvent and A homopolymer matrix were also explored, where the overall micellar size in both scenarios was found to decrease monotonically as n in ABn block copolymer increased. These self-assembled nanostructures composed of miktoarm star-like ABn block copolymers may promise a wide range of applications in size-dependent drug delivery and bionanotechnology. PMID- 25689325 TI - Multiple risks for long-term cognitive impairments following preterm birth. PMID- 25689332 TI - Protein aggregation: close encounters of the greasy kind. PMID- 25689333 TI - Natural products: untwisting the antibiotic'ome. PMID- 25689334 TI - Stress response: PARP1 911. PMID- 25689335 TI - Metabolism: 'channeling' Hans Krebs. PMID- 25689337 TI - Subcellular metal imaging identifies dynamic sites of Cu accumulation in Chlamydomonas. PMID- 25689336 TI - Collective antibiotic tolerance: mechanisms, dynamics and intervention. AB - Bacteria have developed resistance against every antibiotic at a rate that is alarming considering the timescale at which new antibiotics are developed. Thus, there is a critical need to use antibiotics more effectively, extend the shelf life of existing antibiotics and minimize their side effects. This requires understanding the mechanisms underlying bacterial drug responses. Past studies have focused on survival in the presence of antibiotics by individual cells, as genetic mutants or persisters. Also important, however, is the fact that a population of bacterial cells can collectively survive antibiotic treatments lethal to individual cells. This tolerance can arise by diverse mechanisms, including resistance-conferring enzyme production, titration-mediated bistable growth inhibition, swarming and interpopulation interactions. These strategies can enable rapid population recovery after antibiotic treatment and provide a time window during which otherwise susceptible bacteria can acquire inheritable genetic resistance. Here, we emphasize the potential for targeting collective antibiotic tolerance behaviors as an antibacterial treatment strategy. PMID- 25689338 TI - Corrigendum: Hydrolysis of 2'3'-cGAMP by ENPP1 and design of nonhydrolyzable analogs. PMID- 25689340 TI - Erratum: Rick Morimoto. PMID- 25689339 TI - Erratum: Covalent docking of large libraries for the discovery of chemical probes. PMID- 25689341 TI - Exploiting verdazyl radicals to assemble 2p-3d-4f one-dimensional chains. AB - A series of one dimensional chain complexes [Ln(hfac)3]2.[Cu(hfac)2]2.4(3pyvd).n C7H16 (Ln = Gd(1), Tb(2), Dy(3)) containing 2p, 3d and 4f spin carriers have been successfully synthesized and magnetically characterized where the verdazyl radicals represent the bridge linking copper(II) and lanthanide(III) ions. Rough estimation of magnetic behaviors of complex 1 revealed that the coupling between a Gd(III) ion and a radical is weakly ferromagnetic, while alternating-current susceptibilities of complexes 2 and 3 suggest no slow magnetic relaxations exist at low temperature. PMID- 25689342 TI - Does surgeon subjective nerve sparing score predict recovery time of erectile function following robot-assisted radical prostatectomy? AB - INTRODUCTION: During robot-assisted radical prostatectomy (RARP), the quality of nerve sparing (NS) was usually classified by laterality of NS (none, unilateral, and bilateral) or degree of NS (none, partial, and full). Recently, side-specific NS have been more frequently performed, but previous NS grading system might not reflect the differential NS in each side. AIM: Herein, we assessed whether a subjective NS score (NSS) incorporating both degree of NS and NS laterality can predict the time to potency recovery following RARP. METHODS: Data were analyzed from 1,898 patients who had left and right neurovascular bundle sparing quality scores and at least one year of follow-up after RARP was performed between January 2008 and October 2011. MAIN OUTCOME MEASURES: Cox proportional hazard method analyses were used to determine predictive factors for early recovery. Multivariate linear regression models were used to assess subjective NSS in an effort to predict time to potency recovery. Subjective NSSs were compared to a model based on the three grades according to laterality and degree. RESULTS: Time to potency recovery showed a statistically significant difference in favor of higher NSS by the Cox proportional hazard regression analysis (NSS 0 vs. NSS 5-6, 7-8, and 9-10; P < 0.01). The regression model indicated that the statistical significance of the subjective NSS covering the differential NS is not different from that of the conventional three-grade scales, while it has a higher R(2). The regression equation with subjective NSS was as follows: Log (Time) = 5.163 - (0.035 * SHIM Score) + 0.028 Age - (0.101 * Subjective NSS). CONCLUSION: The subjective NSS can reflect NS degree for each side based on the visual cues. Regression model can be used to help inform the patient about the time to postoperative potency regain, which is an important patient concern following RARP. PMID- 25689343 TI - Porphyromonas gingivalis B cell Antigen Epitope Vaccine, pIRES-ragB'-mGITRL, Promoted RagB-Specific Antibody Production and Tfh Cells Expansion. AB - The outer membrane protein RagB is one of the major virulence factors of Porphyromonas gingivalis (P. gingivalis). To prevent periodontitis and associated systemic diseases induced by P. gingivalis, we built B cell antigen epitope vaccine characterized by pIRES-ragB'-mGITRL to induce a protective immune responses. The B cell antigen epitope and scrambled peptide of ragB were predicted, cloned into pIRES and constructed pIRES-ragB', pIRES-scrambled epitopes and pIRES-ragB'-mGITRL. pIRES-ragB'-mGITRL was transfected into COS-7 cells. Subsequently, the 6-week-old female BALB/c mice were challenged by P. gingivalis following three time immunization by pIRES, pIRES-ragB', pIRES scrambled epitopes and pIRES-ragB'-mGITRL. The levels of RagB-specific antibody in the serum and Tfh cells in the spleen were measured by ELISA and flow cytometry, respectively. And higher levels of RagB-specific IgG were produced in the immunized mice with pIRES-ragB'-mGITRL. Additionally, the number of Tfh cells was also expanded and lesions were diminished in pIRES-ragB'-mGITRL mice comparing with control groups. Our results clearly demonstrated that P. gingivalis B cell antigen epitope vaccine, pIRES-ragB'-mGITRL, could induce protective immune responses. Furthermore, our data also indicated that pIRES ragB'-mGITRL was a potential therapeutic vaccine against P. gingivalis. PMID- 25689344 TI - Failures of Imagination: Disability and the Ethics of Selective Reproduction. AB - The article addresses the problem of disability in the context of reproductive decisions based on genetic information. It poses the question of whether selective procreation should be considered as a moral obligation of prospective parents. To answer this question, a number of different ethical approaches to the problem are presented and critically analysed: the utilitarian; Julian Savulescu's principle of procreative beneficence; the rights-based. The main thesis of the article is that these approaches fail to provide any appealing principles on which reproductive decisions should be based. They constitute failures of imagination which may result in counter-intuitive moral judgments about both life with disability and genetic selection. A full appreciation of the ethical significance of recognition in procreative decisions leads to a more nuanced and morally satisfying view than other leading alternatives presented in the article. PMID- 25689345 TI - Synthesis of the beta3-adrenergic receptor agonist solabegron and analogous N-(2 ethylamino)-beta-amino alcohols from O-acylated cyanohydrins - expanding the scope of minor enantiomer recycling. AB - A novel methodology to produce highly enantioenriched N-(2-ethylamino)-beta-amino alcohols was developed. These compounds were obtained from O-(alpha-bromoacyl) cyanohydrins, which were synthesized by the minor enantiomer methodology employing a Lewis acid and a biocatalyst, followed by nucleophilic substitution with amines and reduction. The importance of the developed methodology was demonstrated by completing a highly enantioselective total synthesis of the beta3 adrenergic receptor agonist Solabegron. PMID- 25689346 TI - Metal-organic frameworks based on rigid ligands as separator membranes in supercapacitor. AB - Two thermally stable MOFs formulated as CoL(1,4-bdc).2DMF (L = 3,5-bis(5-(pyridin 4-yl)-4H-1,2,4-triazol-3-yl)pyridine), 1,4-H2bdc = 1,4-benzenedicarboxylic acid) (1) and CdL(4,4'-bpc).3DMF (4,4'-H2bpc = 4,4'-biphenyldicarboxylic acid) (2) have been solvothermally synthesized and exhibit a similar uninodal 6-connected 3D architecture with {4(12).6(3)}-pcu topology. MOF1 shows a non-interpenetrated network with larger channel, whereas MOF 2 exhibits a 3-fold interpenetrating framework with smaller pore size. When the two MOFs are used as separator membranes in a supercapacitor, the equivalent series resistance (Res) is larger than the Res in the blank supercapacitor, and the smaller the current density, the more the Res. After being charged and discharged at the low current density, the supercapacitor with MOF 1 as separator membrane (denoted as 1a) possesses a much larger specific capacitance (SC) than the blank supercapacitor, and the amorphous separator membrane 1a shows a more porous morphology than the original MOF membrane 1. PMID- 25689347 TI - Exploitation of the ability of gamma-tocopherol to facilitate membrane co localization of Akt and PHLPP1 to develop PHLPP1-targeted Akt inhibitors. AB - Previously, we reported that Akt inactivation by gamma-tocopherol (2) in PTEN negative prostate cancer cells resulted from its unique ability to facilitate membrane co-localization of Akt and PHLPP1 (PH domain leucine-rich repeat protein phosphatase isoform 1), a Ser473-specific Akt phosphatase, through pleckstrin homology (PH) domain binding. This finding provided a basis for exploiting 2 to develop a novel class of PHLPP1-targeted Akt inhibitors. Here, we used 3 (gamma VE5), a side chain-truncated 2 derivative, as a scaffold for lead optimization. The proof-of-concept of this structural optimization was obtained by 20, which exhibited higher antitumor efficacy than 3 in PTEN-negative cancer cells through PHLPP1-facilitated Akt inactivation. Like 3, 20 preferentially recognized the PH domains of Akt and PHLPP1, as its binding affinities for other PH domains, including those of ILK and PDK1, were an order-of-magnitude lower. Moreover, 20 was orally active in suppressing xenograft tumor growth in nude mice, which underlines the translational potential of this new class of Akt inhibitor in PTEN deficient cancers. PMID- 25689348 TI - Chemical characterization of outdoor and subway fine (PM(2.5-1.0)) and coarse (PM(10-2.5)) particulate matter in Seoul (Korea) by computer-controlled scanning electron microscopy (CCSEM). AB - Outdoor and indoor (subway) samples were collected by passive sampling in urban Seoul (Korea) and analyzed with computer-controlled scanning electron microscopy coupled with energy dispersive x-ray spectroscopy (CCSEM-EDX). Soil/road dust particles accounted for 42%-60% (by weight) of fine particulate matter larger than 1 um (PM(2.5-1.0)) in outdoor samples and 18% of PM2.5-1.0 in subway samples. Iron-containing particles accounted for only 3%-6% in outdoor samples but 69% in subway samples. Qualitatively similar results were found for coarse particulate matter (PM(10-2.5)) with soil/road dust particles dominating outdoor samples (66%-83%) and iron-containing particles contributing most to subway PM(10 2.5) (44%). As expected, soil/road dust particles comprised a greater mass fraction of PM(10-2.5) than PM(2.5-1.0). Also as expected, the mass fraction of iron-containing particles was substantially less in PM(10-2.5) than in PM(2.5 1.0). Results of this study are consistent with known emission sources in the area and with previous studies, which showed high concentrations of iron containing particles in the subway compared to outdoor sites. Thus, passive sampling with CCSEM-EDX offers an inexpensive means to assess PM(2.5-1.0) and PM(10-2.5) simultaneously and by composition at multiple locations. PMID- 25689349 TI - Perceived environmental and personal factors associated with walking and cycling for transportation in Taiwanese adults. AB - This study examined perceived environmental and personal factors associated with walking and cycling as means of transportation for Taiwanese adults. A random digit-dialing telephone-based cross-sectional survey was conducted with Taiwanese adults aged 20 to 64 years. Data on time spent walking and cycling for transportation and perceptions of neighborhood environment and personal characteristics were obtained from 1065 adults by using the International Physical Activity Questionnaire-long version and its environmental module. Adjusted binary logistic regression was performed. The results showed that, after adjusting potential confounders, common and different personal and perceived environmental factors were associated with walking and cycling for transportation. For common personal factors, adults who had employment were less likely to engage in 150 min of walking per week (odds ratio [OR] = 0.41; 95% confidence interval (CI): 0.27-0.62) and to use cycling as a means of transportation (OR = 0.51; 95% CI: 0.32-0.79). For common perceived environmental factors, adults who perceived good connectivity of streets were more likely to walk (OR = 1.95; 95% CI: 1.20-3.16) and cycle (OR = 2.02; 95% CI: 1.16-3.54) for transportation. Targeting employed adults and improving the connectivity of streets should be a priority for developing transport policies and intervention strategies to promote active transportation. PMID- 25689350 TI - Exploring the care relationship between grandparents/older carers and children infected with HIV in south-western Uganda: implications for care for both the children and their older carers. AB - The care of children orphaned by HIV/AIDS in sub-Saharan Africa is often undertaken by grandparents, yet little is known about the care relationship between grandparent and grandchild. Our aim was to examine this relationship to understand the needs and responsibilities of both the HIV positive child and older carer and the nature of the relationship, and to assess the implications for care for the children and the older carers. A qualitative study was conducted with 40 purposively sampled children (13-17 years) and their older carers (50 years and above). Participants were recruited from two clinics in south-western Uganda. Up to three semi-structured interviews were held with each participant. Data were analysed using a thematic framework approach. We found that the care relationship was mostly reciprocal: HIV positive children depended on carers for basic and health needs and carers counted on the children for performing tedious household tasks. The relationship was also characterised by challenges, sometimes causing tension between child and carer. We conclude that: (1) interventions targeting HIV positive children need to also address the needs of older carers, and (2) carers and children would benefit from psychosocial support and social protection. PMID- 25689351 TI - What is the Ambulatory Stiffness Index and What Is Its Role in Patients With Lacunar Infarcts? PMID- 25689352 TI - Evaluation of screening and treatment of cryptococcal antigenaemia among HIV infected persons in Soweto, South Africa. AB - OBJECTIVES: We retrospectively evaluated clinic-based screening to determine the prevalence of cryptococcal antigenaemia and management and outcome of patients with antigenaemia. METHODS: Cryptococcal antigen (CrAg) screening of HIV-infected adults who attended the HIV clinic at Chris Hani Baragwanath Hospital was conducted over 19 months. Data collected from CrAg-positive patients included CD4 T-lymphocyte count at screening, prior or subsequent cryptococcal meningitis (CM), antifungal and antiretroviral treatment and outcome after at least 8 months. RESULTS: Of 1460 patients with no prior CM, 30 (2.1%) had a positive CrAg test. The prevalence of antigenaemia among patients with a CD4 count < 100 cells/MUl and no prior CM was 2.8% (20 of 708). Of 29 evaluable CrAg-positive patients with no prior CM, 14 (48%) did not return for post-screening follow-up. Of these 14, five developed CM and one (7%) was known to be alive at follow-up. Of 15 patients who returned for follow-up, two already had evidence of nonmeningeal cryptococcosis. Overall, 11 received fluconazole, one did not and fluconazole treatment was unknown for three. Among these 15, one developed CM and 10 (67%) were known to be alive at follow-up. Overall, 18 (62%) of 29 CrAg positive patients died or were lost to follow-up. Seven (0.5%) of 1430 CrAg negative patients developed CM a median of 83 days post-screening (range 34 to 219 days). CONCLUSIONS: Loss to follow-up is the major operational issue relevant to scale-up of screen-and-treat. Patient outcomes may be improved by rapid access to CrAg results and focus on linkage to and retention in HIV care. PMID- 25689353 TI - Cell type classifiers for breast cancer microscopic images based on fractal dimension texture analysis of image color layers. AB - Having a classifier of cell types in a breast cancer microscopic image (BCMI), obtained with immunohistochemical staining, is required as part of a computer aided system that counts the cancer cells in such BCMI. Such quantitation by cell counting is very useful in supporting decisions and planning of the medical treatment of breast cancer. This study proposes and evaluates features based on texture analysis by fractal dimension (FD), for the classification of histological structures in a BCMI into either cancer cells or non-cancer cells. The cancer cells include positive cells (PC) and negative cells (NC), while the normal cells comprise stromal cells (SC) and lymphocyte cells (LC). The FD feature values were calculated with the box-counting method from binarized images, obtained by automatic thresholding with Otsu's method of the grayscale images for various color channels. A total of 12 color channels from four color spaces (RGB, CIE-L*a*b*, HSV, and YCbCr) were investigated, and the FD feature values from them were used with decision tree classifiers. The BCMI data consisted of 1,400, 1,200, and 800 images with pixel resolutions 128 * 128, 192 * 192, and 256 * 256, respectively. The best cross-validated classification accuracy was 93.87%, for distinguishing between cancer and non-cancer cells, obtained using the Cr color channel with window size 256. The results indicate that the proposed algorithm, based on fractal dimension features extracted from a color channel, performs well in the automatic classification of the histology in a BCMI. This might support accurate automatic cell counting in a computer assisted system for breast cancer diagnosis. PMID- 25689354 TI - Understanding heterogeneity of treatment effect in prostate cancer. AB - PURPOSE OF REVIEW: In the era of personalized medicine, oncologists seek to tailor treatments for their patients based on indicators of differential response to treatment. We first provide a conceptual explanation of heterogeneity of treatment effect using prostate cancer as a case study and review studies that test whether Gleason score has a role in modifying the effectiveness of androgen deprivation therapy in men newly diagnosed with metastatic prostate cancer. RECENT FINDINGS: Depending on the study design, setting, and population, the median time to develop castration-resistant prostate cancer ranges from 12 to 23 months among men with M1 disease on androgen deprivation therapy, and the median time from diagnosis to mortality in such patients ranges from 23 to 37 months. Patients with higher Gleason scores have a significantly shorter time to developing castration-resistant prostate cancer compared with patients with lower Gleason scores. However, data suggest that Gleason score does not have a role in modifying the survival benefit associated with androgen deprivation therapy. SUMMARY: Androgen deprivation therapy has heterogeneous effects in men with metastatic prostate cancer related to the time of developing castration resistance. However, survival benefit from androgen deprivation therapy does not appear to depend on Gleason score. PMID- 25689355 TI - High sequence variations in the region containing genes encoding a cellular morphogenesis protein and the repressor of sexual development help to reveal origins of Aspergillus oryzae. AB - Aspergillus oryzae and Aspergillus flavus are closely related fungal species. The A. flavus morphotype that produces numerous small sclerotia (S strain) and aflatoxin has a unique 1.5 kb deletion in the norB-cypA region of the aflatoxin gene cluster (i.e. the S genotype). Phylogenetic studies have indicated that an isolate of the nonaflatoxigenic A. flavus with the S genotype is the ancestor of A. oryzae. Genome sequence comparison between A. flavus NRRL3357, which produces large sclerotia (L strain), and S-strain A. flavus 70S identified a region (samA rosA) that was highly variable in the two morphotypes. A third type of samA-rosA region was found in A. oryzae RIB40. The three samA-rosA types were later revealed to be commonly present in A. flavus L-strain populations. Of the 182 L strain A. flavus field isolates examined, 46%, 15% and 39% had the samA-rosA type of NRRL3357, 70S and RIB40, respectively. The three types also were found in 18 S strain A. flavus isolates with different proportions. For A. oryzae, however, the majority (80%) of the 16 strains examined had the RIB40 type and none had the NRRL3357 type. The results suggested that A. oryzae strains in the current culture collections were mostly derived from the samA-rosA/RIB40 lineage of the nonaflatoxigenic A. flavus with the S genotype. PMID- 25689356 TI - Assessing potentially time-dependent treatment effect from clinical trials and observational studies for survival data, with applications to the Women's Health Initiative combined hormone therapy trial. AB - For risk and benefit assessment in clinical trials and observational studies with time-to-event data, the Cox model has usually been the model of choice. When the hazards are possibly non-proportional, a piece-wise Cox model over a partition of the time axis may be considered. Here, we propose to analyze clinical trials or observational studies with time-to-event data using a certain semiparametric model. The model allows for a time-dependent treatment effect. It includes the important proportional hazards model as a sub-model and can accommodate various patterns of time-dependence of the hazard ratio. After estimation of the model parameters using a pseudo-likelihood approach, simultaneous confidence intervals for the hazard ratio function are established using a Monte Carlo method to assess the time-varying pattern of the treatment effect. To assess the overall treatment effect, estimated average hazard ratio and its confidence intervals are also obtained. The proposed methods are applied to data from the Women's Health Initiative. To compare the Women's Health Initiative clinical trial and observational study, we use the propensity score in building the regression model. Compared with the piece-wise Cox model, the proposed model yields a better model fit and does not require partitioning of the time axis. PMID- 25689357 TI - Regulation of RAGE splicing by hnRNP A1 and Tra2beta-1 and its potential role in AD pathogenesis. AB - The receptor for advanced glycation end products (RAGE) gene expresses two major alternative splicing isoforms, full-length membrane-bound RAGE (mRAGE) and secretory RAGE (esRAGE). Both isoforms play important roles in Alzheimer's disease (AD) pathogenesis, either via interaction of mRAGE with beta-amyloid peptide (Abeta) or inhibition of the mRAGE-activated signaling pathway. In the present study, we showed that heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) and Transformer2beta-1 (Tra2beta-1) were involved in the alternative splicing of mRAGE and esRAGE. Functionally, two factors had an antagonistic effect on the regulation. Glucose deprivation induced an increased ratio of mRAGE/esRAGE via up regulation of hnRNP A1 and down-regulation of Tra2beta-1. Moreover, the ratios of mRAGE/esRAGE and hnRNP A1/Tra2beta-1 were increased in peripheral blood mononuclear cells from AD patients. The results provide a molecular basis for altered splicing of mRAGE and esRAGE in AD pathogenesis. The receptor for advanced glycation end products (RAGE) gene expresses two major alternative splicing isoforms, membrane-bound RAGE (mRAGE) and secretory RAGE (esRAGE). Both isoforms play important roles in Alzheimer's disease (AD) pathogenesis. Mechanism for imbalanced expression of these two isoforms in AD brain remains elusive. We proposed here a hypothetic model to illustrate that impaired glucose metabolism in AD brain may increase the expression of splicing protein hnRNP A1 and reduce Tra2beta-1, which cause the imbalanced expression of mRAGE and esRAGE. PMID- 25689358 TI - The use of the Molt mouth gag to assist in oral fiberoptic tracheal intubation of a developmentally challenged patient presenting with severe trismus. AB - Airway management in developmentally challenged, and often uncooperative, patients presents difficulty for the anesthesiologist and may be further complicated by severe trismus. We describe a case wherein the use of the Molt mouth gag significantly facilitated airway control using fiberoptic tracheal intubation. PMID- 25689359 TI - Perimortem cesarean delivery in a pregnant patient with goiter, preeclampsia, and morbid obesity. AB - Cardiopulmonary arrest during pregnancy is a devastating event necessitating rapid intervention from experienced practitioners to reduce the incidence and severity of adverse maternal and fetal outcomes. Perimortem cesarean delivery is rarely performed within the recommended time frame to meet these goals. We describe a case of a successful perimortem cesarean delivery after the "4-minute rule" in a morbidly obese parturient with goiter and preeclampsia. PMID- 25689360 TI - Postoperative oxycodone toxicity in a patient with chronic pain and end-stage renal disease. AB - We present this case to review the metabolism of oxycodone and the effects of end stage renal disease on the elimination of oxycodone and its metabolites. A 42 year-old female with end-stage renal disease who was dependent on hemodialysis presented for left hamstring posterior capsule release. She had been receiving methadone for 2 years for chronic leg pain. On postoperative day 1, the patient's medication was changed from IV hydromorphone to oral oxycodone to treat breakthrough pain. By the next day, the patient was unarousable with notable respiratory depression. She did not fully recover after urgent hemodialysis but did have full recovery after receiving an IV naloxone infusion for 22 hours. Further study of the safety of oxycodone in hemodialysis patients is warranted. PMID- 25689361 TI - Anesthesia considerations for cesarean delivery in a patient with Loeys-Dietz syndrome. AB - A 28-year-old primigravida female with Loeys-Dietz syndrome presented at 36 weeks' gestation for scheduled primary elective cesarean delivery. The patient had clinical findings consistent with this diagnosis, including mild aortic root dilation, chronic right vertebral artery dissection with 2 intracerebral aneurysms, and small ectasias of the thecal sac in the lumbar region. Pregnant patients with Loeys-Dietz syndrome have significant risks, including aneurysm rupture, new aneurysm formation, and uterine rupture. After a thorough preoperative evaluation, the patient underwent successful general anesthesia focused on maintenance of intraoperative hemodynamic stability and minimal intraoperative blood loss. PMID- 25689362 TI - PH responsive polypeptide based polymeric micelles for anticancer drug delivery. AB - A pH-responsive polymeric micelle based on poly(aspartamide) derivative was explored as an efficient acid-triggered anticancer drug delivery system. Poly(alpha,beta-l-asparthydrazide) (PAHy) was prepared by aminolysis reaction of polysuccinimide with hydrazine hydrate. Poly(ethylene glycol) and aliphatic chain (C18) were conjugated onto PAHy to afford an amphiphilic copolymer with acid liable hydrazone bonds. The structure of the resulting copolymer and its self assembled micelles were confirmed by (1) H NMR, FTIR, DLS, and TEM. Furthermore, doxorubicin (DOX) was loaded into the polymeric micelles via the hydrophobic interaction between the C18 group and DOX molecules, and the pi-pi staking between the hydrazone conjugated DOX and free DOX molecules. Results showed that the DOX loaded nanoparticle (NP) was relatively stable under physiological conditions, while the DOX was quickly released in response to acidity due to the shedding of mPEG shells and dissociating of C18 segments because of the pH cleavage of intermediate hydrazone bonds. In addition, the DOX loaded micelles presented a high cytotoxic activity against tumor cells in vitro. This pH responsive NP has appeared highly promising for the targeted intracellular delivery of hydrophobic chemotherapeutics in cancer therapy. PMID- 25689363 TI - Reduced parasite motility and micronemal protein secretion by a p38 MAPK inhibitor leads to a severe impairment of cell invasion by the apicomplexan parasite Eimeria tenella. AB - E. tenella infection is associated with a severe intestinal disease leading to high economic losses in poultry industry. Mitogen activated protein kinases (MAPKs) are implicated in early response to infection and are divided in three pathways: p38, extracellular signal-regulated protein kinase (ERK) and c-Jun N terminal kinase (JNK). Our objective was to determine the importance of these kinases on cell invasion by E. tenella. We evaluated the effect of specific inhibitors (ERK: PD98059, JNKII: SP600125, p38 MAPK: SB203580) on the invasion of epithelial cells. Incubation of SP600125 and SB203580 with epithelial cells and parasites significantly inhibited cell invasion with the highest degree of inhibition (90%) for SB203580. Silencing of the host p38alpha MAPK expression by siRNA led to only 20% decrease in cell invasion. In addition, when mammalian epithelial cells were pre-treated with SB203580, and washed prior infection, a 30% decrease in cell invasion was observed. This decrease was overcome when a p38 MAPK activator, anisomycin was added during infection. This suggests an active but limited role of the host p38 MAPK in this process. We next determined whether SB203580 has a direct effect on the parasite. Indeed, parasite motility and secretion of micronemal proteins (EtMIC1, 2, 3 and 5) that are involved in cell invasion were both decreased in the presence of the inhibitor. After chasing the inhibitor, parasite motility and secretion of micronemal proteins were restored and subsequently cell invasion. SB203580 inhibits cell invasion by acting partly on the host cell and mainly on the parasite. PMID- 25689364 TI - A primary care nurse-delivered walking intervention in older adults: PACE (pedometer accelerometer consultation evaluation)-Lift cluster randomised controlled trial. AB - BACKGROUND: Brisk walking in older people can increase step-counts and moderate to vigorous intensity physical activity (MVPA) in >=10-minute bouts, as advised in World Health Organization guidelines. Previous interventions have reported step-count increases, but not change in objectively measured MVPA in older people. We assessed whether a primary care nurse-delivered complex intervention increased objectively measured step-counts and MVPA. METHODS AND FINDINGS: A total of 988 60-75 year olds, able to increase walking and randomly selected from three UK family practices, were invited to participate in a parallel two-arm cluster randomised trial; randomisation was by household. Two-hundred-ninety eight people from 250 households were randomised between 2011 and 2012; 150 individuals to the intervention group, 148 to the usual care control group. Intervention participants received four primary care nurse physical activity (PA) consultations over 3 months, incorporating behaviour change techniques, pedometer step-count and accelerometer PA intensity feedback, and an individual PA diary and plan. Assessors were not blinded to group status, but statistical analyses were conducted blind. The primary outcome was change in accelerometry assessed average daily step-counts between baseline and 3 months, with change at 12 months a secondary outcome. Other secondary outcomes were change from baseline in time in MVPA weekly in >=10-minute bouts, accelerometer counts, and counts/minute at 3 months and 12 months. Other outcomes were adverse events, anthropometric measures, mood, and pain. Qualitative evaluations of intervention participants and practice nurses assessed the intervention's acceptability. At 3 months, eight participants had withdrawn or were lost to follow-up, 280 (94%) individuals provided primary outcome data. At 3 months changes in both average daily step counts and weekly MVPA in >=10-minute bouts were significantly higher in the intervention than control group: by 1,037 (95% CI 513-1,560) steps/day and 63 (95% CI 40-87) minutes/week, respectively. At 12 months corresponding differences were 609 (95% CI 104-1,115) steps/day and 40 (95% CI 17-63) minutes/week. Counts and counts/minute showed similar effects to steps and MVPA. Adverse events, anthropometry, mood, and pain were similar in the two groups. Participants and practice nurses found the intervention acceptable and enjoyable. CONCLUSIONS: The PACE-Lift trial increased both step-counts and objectively measured MVPA in >=10 minute bouts in 60-75 year olds at 3 and 12 months, with no effect on adverse events. To our knowledge, this is the first trial in this age group to demonstrate objective MVPA increases and highlights the value of individualised support incorporating objective PA assessment in a primary care setting. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN42122561. PMID- 25689365 TI - Enantiomers of 3-methylspermidine selectively modulate deoxyhypusine synthesis and reveal important determinants for spermidine transport. AB - Eukaryotic translation initiation factor 5A (eIF5A) is essential for cell proliferation, becoming functionally active only after post-translational conversion of a specific Lys to hypusine [N(epsilon)-(4-amino-2 hydroxybutyl)lysine]. Deoxyhypusine synthase (DHS) is the rate-limiting enzyme of this two-step process, and the polyamine spermidine is the only natural donor of the butylamine group for this reaction, which is very conserved-hypusine biosynthesis suffers last when the intracellular spermidine pool is depleted. DHS has a very strict substrate specificity, and only a few spermidine analogs are substrates of the enzyme and can support long-term growth of spermidine-depleted cells. Herein, we compared the biological properties of earlier unknown enantiomers of 3-methylspermidine (3-MeSpd) in deoxyhypusine synthesis, in supporting cell growth and in polyamine transport. Long-term treatment of DU145 cells with alpha-difluoromethylornithine (inhibitor of polyamine biosynthesis) and (R)-3-MeSpd did not cause depletion of hypusinated eIF5A, and the cells were still able to grow, whereas the combination of alpha-difluoromethylornithine with a racemate or (S)-3-MeSpd caused cessation of cell growth. Noticeably, DHS preferred the (R)- over the (S)-enantiomer as a substrate. (R)-3-MeSpd competed with [(14)C]-labeled spermidine for cellular uptake less efficiently than the (S) 3-MeSpd (Ki = 141 MUM vs 19 MUM, respectively). The cells treated with racemic 3 MeSpd accumulated intracellularly mainly (S)-3-MeSpd, but not DHS substrate (R)-3 MeSpd, explaining the inability of the racemate to support long-term growth. The distinct properties of 3-MeSpd enantiomers can be exploited in designing polyamine uptake inhibitors, facilitating drug delivery and modulating deoxyhypusine synthesis. PMID- 25689366 TI - Recycling tires? Reversible crosslinking of poly(butadiene). AB - Furan-modified poly(butadiene) prepared by the thiol-ene click reaction is crosslinked with bismaleimides through the Diels-Alder reaction, giving rise to a novel recyclable elastomer. This is possible because of the thermal reversibility of the adducts responsible for the formation of the network. The use of this strategy provides the possibility to produce recyclable tires. PMID- 25689367 TI - The 20th anniversary of proteomics and some of its origins. AB - The term "proteome" was first introduced into the scientific literature in July 1995. Almost 20 years ago attempts to characterize the "total protein complement able to be encoded by a given genome" only became possible due to privileged access to what were then the world's most complete sets of genomic data. Today, proteomics has become an important pillar in the fields of disease diagnosis and drug research and development, while also playing a critical role in the much larger field of Healthcare Analytics and Biomarker Discovery and Detection. It is important to note that this industry originated mostly from building blocks in analytical science that predated the term "proteomics" by many decades. However, proteomics, as a discipline, has allowed protein scientists to more favorably compete in the face of highly fashionable Big Science and, more specifically, genomics. PMID- 25689368 TI - 3-Deoxyglucosone: a potential glycating agent accountable for structural alteration in H3 histone protein through generation of different AGEs. AB - Advanced glycation end-products (AGEs) are heterogeneous group of compounds, known to be implicated in diabetic complications. One of the consequences of the Maillard reaction is attributed to the production of reactive intermediate products such as alpha-oxoaldehydes. 3-deoxyglucosone (3-DG), an alpha oxoaldehyde has been found to be involved in accelerating vascular damage during diabetes. In the present study, calf thymus histone H3 was treated with 3 deoxyglucosone to investigate the generation of AGEs (Nepsilon carboxymethyllysine, pentosidine), by examining the degree of side chain modifications and formation of different intermediates and employing various physicochemical techniques. The results clearly indicate the formation of AGEs and structural changes upon glycation of H3 by 3-deoxyglucosone, which may hamper the normal functioning of H3 histone, that may compromise the veracity of chromatin structures and function in secondary complications of diabetes. PMID- 25689369 TI - Alcohol drinking and heart failure: where do we stand? PMID- 25689370 TI - A rapid paper-based test for quantifying sickle hemoglobin in blood samples from patients with sickle cell disease. AB - Quantification of sickle hemoglobin (HbS) in patients with sickle cell disease (SCD) undergoing hydroxyurea or chronic transfusion therapy is essential to monitoring the effectiveness of these therapies. The clinical monitoring of %HbS using conventional laboratory methods is limited by high per-test costs and long turnaround times usually associated with these methods. Here we demonstrate a simple, rapid, inexpensive paper-based assay capable of quantifying %HbS in blood samples from patients with SCD. A 20 MUL droplet of whole blood and hemoglobin solubility buffer was deposited on chromatography paper. The relative color intensities of regions of the resulting blood stain, determined by automated image analysis, are used to estimate %HbS. We compared the paper-based assay with hemoglobin electrophoresis (comparison method) using blood samples from 88 subjects. The test shows high correlation (R(2) = 0.86) and strong agreement (standard deviation of difference = 7%HbS) with conventional Hb electrophoresis measurement of %HbS, and closely approximates clinically predicted change in %HbS with transfusion therapy (mean difference 2.6%HbS, n = 5). The paper-based assay can be completed in less than 35 min and has a per-test cost less than $0.25. The assay is accurate across a wide range of HbS levels (10-97%) and hemoglobin concentrations (5.6-12.9 g/dL) and is unaffected by high levels of HbF (up to 80.6%). This study demonstrates the feasibility of the paper-based %HbS assay. The paper-based test could improve clinical care for SCD, particularly in resource-limited settings, by enabling more rapid and less expensive %HbS monitoring. PMID- 25689371 TI - The impact of traditional cardiovascular risk factors on cardiovascular outcomes in patients with rheumatoid arthritis: a systematic review and meta-analysis. AB - BACKGROUND: Rheumatoid arthritis (RA) is known to increase the risk of cardiovascular (CV) disease. However, the individual impact of traditional CV risk factors in RA is unknown. OBJECTIVE: To assess the strength of the association between individual CV risk factors and rate of either myocardial infarction (MI), combined CV morbidity (MI, angina pectoris, heart failure, stroke, and peripheral arterial disease (PAD)) or CV mortality in RA patients. METHODS: RA studies reporting traditional CV risk factors [hypertension, type 2 diabetes (T2D), smoking, hypercholesterolaemia, obesity, and physical inactivity] as exposures and MI, CV morbidity (MI, angina, heart failure, stroke, and PAD combined) or CV mortality alone as outcomes were searched until March 2013 using MEDLINE, Scopus and Cochrane. Meta-analyses combined relative risk (RR) estimates from each study where either the RR and 95% confidence intervals or where raw counts were available. RESULTS: Ten studies reporting sufficient data for inclusion into meta-analyses were identified. Relevant data was available for each risk factor and MI and CV morbidity but no studies reported on CV mortality. Risk of MI increased in RA patients with hypertension (RR 1.84, 95% CI 1.38, 2.46) and T2D (RR 1.89, 95% CI 1.36, 2.63). CV morbidity increased with hypertension (RR 2.24, 95% CI 1.42, 3.06), T2D (RR 1.94, 95% CI 1.58, 2.30), smoking (RR 1.50, 95% CI 1.15, 1.84), hypercholesterolaemia (RR 1.73, 95% CI 1.03, 2.44) and obesity (RR 1.16, 95% CI 1.03, 1.29) but not with physical inactivity (RR 1.00, 95% CI 0.71, 1.29). CONCLUSION: Hypertension, T2D, smoking, hypercholesterolaemia and obesity increased CV risk in patients with RA. These results highlight the importance of managing CV risk factors in RA, similarly to non-RA patients. PMID- 25689372 TI - KINATEST-ID: a pipeline to develop phosphorylation-dependent terbium sensitizing kinase assays. AB - Nonreceptor protein tyrosine kinases (NRTKs) are essential for cellular homeostasis and thus are a major focus of current drug discovery efforts. Peptide substrates that can enhance lanthanide ion luminescence upon tyrosine phosphorylation enable rapid, sensitive screening of kinase activity, however design of suitable substrates that can distinguish between tyrosine kinase families is a huge challenge. Despite their different substrate preferences, many NRTKs are structurally similar even between families. Furthermore, the development of lanthanide-based kinase assays is hampered by incomplete understanding of how to integrate sequence selectivity with metal ion binding, necessitating laborious iterative substrate optimization. We used curated proteomic data from endogenous kinase substrates and known Tb(3+)-binding sequences to build a generalizable in silico pipeline with tools to generate, screen, align, and select potential phosphorylation-dependent Tb(3+)-sensitizing substrates that are most likely to be kinase specific. We demonstrated the approach by developing several substrates that are selective within kinase families and amenable to high-throughput screening (HTS) applications. Overall, this strategy represents a pipeline for developing efficient and specific assays for virtually any tyrosine kinase that use HTS-compatible lanthanide-based detection. The tools provided in the pipeline also have the potential to be adapted to identify peptides for other purposes, including other enzyme assays or protein-binding ligands. PMID- 25689373 TI - The burden of MDR/XDR tuberculosis in coastal plains population of China. AB - BACKGROUND: We conducted a first baseline survey in Jilin Province of China to determine the proportion of drug-resistant tuberculosis (TB), and to analyze risk factors associated with the emergence of drug-resistance. METHODOLOGY/PRINCIPAL FINDINGS: Thirty counties in Jilin Province were randomly selected as survey sites using a stratified cluster sampling method. People enrolled in the survey were new and re-treated, smear-positive pulmonary TB patients newly enrolled in local TB control and prevention institutions during the survey period. Sputum samples were collected, and the susceptibility of bacterial strains to anti-TB drugs was analyzed by proportion method. Based on the survey results, we estimated the number of drug-resistant TB patients and analyzed the risk factors associated with the emergence of drug resistance. Of 1,174 new TB patients and 597 re-treated TB patients, 8.6% and 23.2% were multi-drug resistant (MDR)-TB patients, respectively. Approximately 12% of MDR-TB patients were extensively drug-resistant. We estimate that approximately 1,290 new MDR-TB cases develop in Jilin Province every year. Of these, 810 cases would be new patients, and 480 cases would involve re-treated patients. Risk factors associated with MDR-TB include employment status, educational background, and income level. CONCLUSIONS/SIGNIFICANCE: Jilin Province remains one of the highest-burden areas in China for drug-resistant TB. The higher number of MDR-TB among new cases suggested that the transmission of drug-resistant strains in Jilin is an urgent problem in the MDR-TB control and prevention system of Jilin Province. Improving the treatment compliance of TB patients and the quality of medical care in public health institutions is urgently needed. PMID- 25689374 TI - Flow-enabled self-assembly of large-scale aligned nanowires. AB - One-dimensional nanowires enable the realization of optical and electronic nanodevices that may find applications in energy conversion and storage systems. Herein, large-scale aligned DNA nanowires were crafted by flow-enabled self assembly (FESA). The highly oriented and continuous DNA nanowires were then capitalized on either as a template to form metallic nanowires by exposing DNA nanowires that had been preloaded with metal salts to an oxygen plasma or as a scaffold to direct the positioning and alignment of metal nanoparticles and nanorods. The FESA strategy is simple and easy to implement and thus a promising new method for the low-cost synthesis of large-scale one-dimensional nanostructures for nanodevices. PMID- 25689375 TI - Enhanced restoration of in situ-damaged hairs by intradermal transplantation of trichogenous dermal cells. AB - We developed a nude rat model for determining the capacity of trichogenous cells to restore in vivo-damaged hair follicles (HFs). A surgical scalpel was inserted into the rat's dermis to generate the in vivo-damaged pelage HFs, the HFs whose lower parts were lost, but the upper parts containing sebaceous and bulge regions remained intact. Dermal papilla cells (DPCs) and dermal sheath cells (DSCs) from EGFP transgenic rat vibrissae were propagated in culture, and each alone (DPC or DSC) or a mixture (DPC/DSC) was transplanted into the intradermal path made by a scalpel. It was found that the in vivo-damaged HFs had hair self-restoration ability, and the transplanted trichogenic dermal cells prominently enhanced this ability, DPC/DSC transplants being more effective in enhancement than DPC or DSC alone. The restored bulbs contained EGFP-positive cells, shed their original straight shafts, generated new shafts, and further developed into hairs with a sebaceous gland and bulge structures by ~6 weeks post-transplantation. Compared to the preceding animal models, this model is less invasive, requires fewer donor cells and allows repeated operations with higher reproducibility and accuracy. The present study suggests that conditions causing in situ-damaged HFs, such as androgenic alopecia, in which HFs are damaged and miniaturized, can be restored by functional trichogenous dermal cell transplantation therapy. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 25689376 TI - 2015: an opportunity for rural health in Australia. PMID- 25689377 TI - There is another gap to narrow. PMID- 25689378 TI - Cancer outcomes for Aboriginal and Torres Strait Islander Australians in rural and remote areas. AB - OBJECTIVE: To examine the association between residential remoteness and stage of cancer at diagnosis, treatment uptake, and survival within the Australian Indigenous population. DESIGN: Systematic review and matched retrospective cohort study. SETTING: Australia. PARTICIPANTS: Systematic review: published papers that included a comparison of cancer stage at diagnosis, treatment uptake, mortality and/or survival for Indigenous people across remoteness categories were identified (n = 181). Fifteen papers (13 studies) were included in the review. Original analyses: new analyses were conducted using data from the Queensland Indigenous Cancer Study (QICS) comparing cancer stage at diagnosis, treatment uptake, and survival for Indigenous cancer patients living in rural/remote areas (n = 627, 66%) and urban areas (n = 329, 34%). MAIN OUTCOME MEASURES: Systematic review: Papers were included if there were related to stage of disease at diagnosis, treatment, mortality and survival of cancer. Restrictions were not placed on the outcome measures reported (e.g. standardised mortality ratios versus crude mortality rates). Original analyses: Odds ratios (OR, 95%CI) were used to compare stage of disease and treatment uptake between the two remoteness groups. Treatment uptake (treated/not treated) was analysed using logistic regression analysis. Survival was analysed using Cox proportional hazards regression. The final multivariate models included stage of cancer at diagnosis and area-level socioeconomic status (SEIFA). RESULTS: Existing evidence of variation in cancer outcomes for Indigenous people in remote compared with metropolitan areas is limited. While no previous studies have reported on differences in cancer stage and treatment uptake by remoteness within the Indigenous population, the available evidence suggests Indigenous cancer patients are less likely to survive their cancer the further they live from urban centres. New analysis of QICS data indicates that Indigenous cancer patients in rural/remote Queensland were less likely to be diagnosed with localised disease and less likely to receive treatment for their cancer compared to their urban counterparts. CONCLUSION: More research is needed to fully understand geographic differentials in cancer outcomes within the Indigenous population. Knowing how geographical location interacts with Indigenous status can help to identify ways of improving cancer outcomes for Indigenous Australians. PMID- 25689379 TI - Specialist cancer care through telehealth models. AB - OBJECTIVE: Disparities in outcomes are experienced between people who live in rural and remote areas and those who live in larger cities. This paper explores the ability to deliver specialist cancer care through the use of telehealth models. DESIGN: Review of telehealth models for cancer care. SETTING, PARTICIPANTS AND INTERVENTION: Cancer patients in rural, remote and Indigenous communities who receive their care through telehealth. OUTCOME MEASURES AND RESULTS: Telehealth models seem to be applicable to all fields of oncology and all health professionals. These models not only facilitate the provision of specialist services closer to home in an acceptable, safe and cost-effective manner, but also help expand the rural scope of practice and enhance service capabilities at rural centres. CONCLUSION: New models of telehealth are another avenue to help further decrease the disparity of access and survival outcomes between rural and urban patients. Implementation of these models requires health system wide approach for development key performance indicators and allocation of resources. PMID- 25689380 TI - Who provides care for people dying of cancer? A comparison of a rural and metropolitan cohort in a South Australian bereaved population study. AB - OBJECTIVE: To examine and compare urban and rural palliative care service availability and patterns of care from randomised, population-based surveys of caregivers of people at the end of life. DESIGN, SETTING & PARTICIPANTS: Survey responses on the death of 'someone close' from 23,588 interviews of South Australians conducted between 2001 and 2007 are analysed. INTERVENTIONS: A randomised population survey. MAIN OUTCOME MEASURES: Explored palliative care service availability, caregiving provided, and characteristics of the deceased and their caregivers. RESULTS: There was no difference in reported rates of accessing specialist palliative care services between rural and urban respondents (in unadjusted and adjusted analyses) nor did the proportion of people for whom cancer was their life-limiting illness. There was greater reliance on friends than first degree relatives in hands-on care provided at the end of life in rural settings. The rates of reported need for more support did not differ between urban and rural respondents for caregivers of people at the end of life. CONCLUSION: Use of palliative care services was similar for rural and urban caregivers for someone close at the end of life with similar levels of met and unmet needs. PMID- 25689381 TI - Improving regional and rural cancer services in Western Australia. AB - OBJECTIVE: This paper examines health reform which has been designed to improve cancer services across Western Australia. SETTING: Western Australia is a large state divided into nine regions each with differing demographics. The diversity of the state and the distribution of the population over a large area of land create significant challenge in ensuring equality in service delivery. DESIGN: A comparison was conducted looking at cancer services in Western Australia pre-2005 and service delivery in 2014. A review of the partnership initiatives and programs provides a clear discussion on the need for coordination of care between service providers. MAIN OUTCOME: The approach undertaken in Western Australia has seen an increase in the delivery of cancer services closer to the patient's home as well as greater involvement of primary care professionals in cancer care. This work has resulted in demonstrated improvements in patient care and support. CONCLUSION: Services for cancer patients need to be accessible closer to home with distance being an appreciable barrier to treatment access.A statewide approach needs to be developed to ensure all people have equitable access to service delivery. PMID- 25689382 TI - Oncology service initiatives and research in regional Australia. AB - OBJECTIVE: This paper reflects on the recent growth of cancer research being conducted through some of Australia's rural centres. It encompasses work being done across the fields of clinical, translational and health services research. DESIGN: This is a collaborative piece with contributions from rural health researchers, clinical and cancer services staff from several different regions. CONCLUSION: The past decade has seen an expansion in cancer research in rural and regional Australia driven in part by the recognition that cancer patients in remote areas experience poorer outcomes than their metropolitan counterparts. This work has led to the development of more effective cancer networks and new models of care designed to meet the particular needs of the rural cancer patient. It is hoped that the growth of cancer research in regional centres will, in time, reduce the disparity between rural and urban communities and improve outcomes for cancer patients across both populations. PMID- 25689383 TI - Survival from breast, colon, lung, ovarian and rectal cancer by geographical remoteness in New South Wales, Australia, 2000-2008. AB - OBJECTIVE: This study aims to compare survival from breast, colon, lung, ovarian and rectal cancer by geographical remoteness in New South Wales (NSW). DESIGN: Retrospective population-wide registry study. SETTING: NSW, Australia. PARTICIPANTS: A total of 107 060 NSW residents, who were diagnosed with any of the five cancers between 01 January 2000 and 31 December 2008. MAIN OUTCOME MEASURES: Kaplan-Meier survival curves and proportional hazards regression were used to compare survival by geographical remoteness of residence at diagnosis, controlling for gender, age and extent of disease at diagnosis. Remoteness was classified using standard definitions: major city, inner regional (InnReg), outer regional (OutReg) and remote (including very remote). RESULTS: Significant differences in survival (likelihood of death) were identified in all five cancers: breast (adjusted hazard ratio(HR) = 1.22 (95% confidence interval (CI), 1.001-1.48) in regionalised and HR = 1.30 (1.02-1.64) in metastatic disease for OutReg areas); colon (HR = 1.14 (1.01-1.29) for OutReg areas in metastatic disease); lung (HR range = 1.08-1.35 (1.01-1.48) for most non-metropolitan areas in all stages of disease excepting regionalised); ovarian (HR = 1.32 (1.06-1.65) for OutReg areas in metastatic disease, HR = 1.40 (1.04-1.90) for InnReg areas and HR = 1.68 (1.02-2.77) for OutReg areas in unknown stage of disease) and rectal (HR = 1.37 (1.05-1.78) for OutReg areas in localised and HR = 1.14 (1.002 1.30) for InnReg areas in regionalised disease). Where significant differences were found, major cities tended to show the best survival, whereas OutReg areas tended to show the worst. Although no definitive interpretation could be made regarding remote areas due to small patient numbers, their survival appeared relatively favourable. CONCLUSIONS: Reasons that contribute to the differences observed and the disparate results between cancer types need to be further explored in order to facilitate targeted solutions in reducing survival inequality between NSW regions. PMID- 25689385 TI - Driving down injuries and deaths on country roads. PMID- 25689386 TI - Pd-catalyzed enantioselective hydroalkoxylation of alkoxyallenes with phenol for construction of acyclic O,O-acetals. AB - Palladium-catalyzed asymmetric intermolecular hydroalkoxylation of allenes has been developed by using phenol as a pronucleophile. Acyclic O,O-acetals were obtained in high yields (up to 98%) with good to excellent enantiomeric excesses (up to 94% ee). PMID- 25689387 TI - Utilizing systems biology to unravel stomatal function and the hierarchies underpinning its control. AB - Stomata control the concomitant exchange of CO2 and transpiration in land plants. While a constant supply of CO2 is need to maintain the rate of photosynthesis, the accompanying water losses must be tightly regulated to prevent dehydration and undesired metabolic changes. The factors affecting stomatal movement are directly coupled with the cellular networks of guard cells. Although the guard cell has been used as a model for characterization of signaling pathways, several important questions about its functioning remain elusive. Current modeling approaches describe the stomatal conductance in terms of relatively few easy-to measure variables being unsuitable for in silico design of genetic manipulation strategies. Here, we argue that a system biology approach, combining modeling and high-throughput experiments, may be used to elucidate the mechanisms underlying stomata control and to determine targets for modulation of stomatal responses to environment. In support of our opinion, we review studies demonstrating how high throughput approaches have provided a systems-view of guard cells. Finally, we emphasize the opportunities and challenges of genome-scale modeling and large scale data integration for in silico manipulation of guard cell functions to improve crop yields, particularly under stress conditions which are of pertinence both to climate change and water use efficiency. PMID- 25689388 TI - Guest editorial: endovascular treatment of acute ischemic stroke: what's next? PMID- 25689392 TI - Chiral perylene diimides: building blocks for ionic self-assembly. AB - A chiral perylene diimide building block has been prepared based on an amine derivative of the amino acid L-phenylalanine. Detailed studies were carried out into the self-assembly behaviour of the material in solution and the solid state using UV/Vis, circular dichroism (CD) and fluorescence spectroscopy. For the charged building block BTPPP, the molecular chirality of the side chains is translated into the chiral supramolecular structure in the form of right-handed helical aggregates in aqueous solution. Temperature-dependent UV/Vis studies of BTPPP in aqueous solution showed that the self-assembly behaviour of this dye can be well described by an isodesmic model in which aggregation occurs to generate short stacks in a reversible manner. Wide-angle X-ray diffraction studies (WXRD) revealed that this material self-organises into aggregates with pi-pi stacking distances typical for pi-conjugated materials. TEM investigations revealed the formation of self-assembled structures of low order and with no expression of chirality evident. Differential scanning calorimetry (DSC) and polarised optical microscopy (POM) were used to investigate the mesophase properties. Optical textures representative of columnar liquid-crystalline phases were observed for solvent-annealed samples of BTPPP. The high solubility, tunable self-assembly and chiral ordering of these materials demonstrate their potential as new molecular building blocks for use in the construction of chiro-optical structures and devices. PMID- 25689393 TI - Bone-forming capacity of adult human nasal chondrocytes. AB - Nasal chondrocytes (NC) derive from the same multipotent embryological segment that gives rise to the majority of the maxillofacial bone and have been reported to differentiate into osteoblast-like cells in vitro. In this study, we assessed the capacity of adult human NC, appropriately primed towards hypertrophic or osteoblastic differentiation, to form bone tissue in vivo. Hypertrophic induction of NC-based micromass pellets formed mineralized cartilaginous tissues rich in type X collagen, but upon implantation into subcutaneous pockets of nude mice remained avascular and reverted to stable hyaline-cartilage. In the same ectopic environment, NC embedded into ceramic scaffolds and primed with osteogenic medium only sporadically formed intramembranous bone tissue. A clonal study could not demonstrate that the low bone formation efficiency was related to a possibly small proportion of cells competent to become fully functional osteoblasts. We next tested whether the cues present in an orthotopic environment could induce a more efficient direct osteoblastic transformation of NC. Using a nude rat calvarial defect model, we demonstrated that (i) NC directly participated in frank bone formation and (ii) the efficiency of survival and bone formation by NC was significantly higher than that of reference osteogenic cells, namely bone marrow-derived mesenchymal stromal cells. This study provides a proof-of principle that NC have the plasticity to convert into bone cells and thereby represent an easily available cell source to be further investigated for craniofacial bone regeneration. PMID- 25689394 TI - Coronary artery disease in primary biliary cirrhosis: A systematic review and meta-analysis of observational studies. AB - AIM: To investigate the association between primary biliary cirrhosis (PBC) and risk of coronary artery disease (CAD). METHODS: We conducted a systematic review and meta-analysis of published observational studies that reported relative risks, odd ratios, hazard ratios or standardized incidence ratios with 95% confidence intervals (CI) comparing CAD risk in patients with PBC versus non-PBC controls. Pooled risk ratios and 95% confidence intervals were combined using a random-effect model and generic inverse variance of DerSimonian and Laird methods. RESULT: Four studies with 3362 patients with PBC were identified and included in our data analysis. The pooled risk ratio of CAD in patients with PBC was 1.57 (95% CI, 1.21-2.06). The statistical heterogeneity was low with an I(2) of 38%. CONCLUSION: Our study demonstrated a statistically significant increased risk of CAD among patients with PBC. PMID- 25689395 TI - The effects of anti-hypertensives and type 2 diabetes on salivary flow and total antioxidant capacity. AB - OBJECTIVE: The present cross-sectional study aimed to determine the effect of first-line anti-hypertensive drugs (enalapril, metoprolol, and combinations of enalapril with metoprolol and/or hydrochlorothiazide) on salivary gland function and salivary total antioxidant capacity (TAC) in hypertensive patients with/without diabetes mellitus (DM) type 2. MATERIALS AND METHODS: Salivary gland function was measured as xerostomia (interview) and unstimulated whole saliva flow rate (UWSFR) in 447 subjects (387 hypertensive and 60 healthy). Salivary TAC was evaluated by spectrophotometric assay. RESULTS: Enalapril is not xerogenic, while metoprolol and drug combinations are. In the presence of DM type 2, all drugs, except metoprolol, had pronounced xerogenic effect. Binary logistic regression analysis found enalapril to be significantly associated with decreased risk of xerogenic effect development, while DM type 2 with increased risk. In the presence of enalapril in hypertensive patients with/without DM type 2 salivary TAC was similar to that in healthy subjects, while for metoprolol was reduced. CONCLUSIONS: Enalapril is not xerogenic but is antioxidant, which moderately reduces the risk of xerogenic effect development even in the presence of DM type 2. However, metoprolol and drug combinations exhibit xerogenic effect. In DM type 2, xerogenic effect of all drugs was pronounced except of metoprolol. PMID- 25689396 TI - Effects of tea or tea extract on metabolic profiles in patients with type 2 diabetes mellitus: a meta-analysis of ten randomized controlled trials. AB - As consumption of tea has been confirmed as a protective factor for type 2 diabetes mellitus (T2DM), it would be interesting to know if T2DM patients could benefit from tea. Because of small sample sizes and inconsistent results of previous studies, we performed this meta-analysis to reevaluate the effects of tea or tea extract on all available outcomes in patients with T2DM. We systematically searched electronic databases of PubMed, Cochrane Library and EMBASE to identify randomized controlled trials of tea in T2DM patients up to January 2015. Weight mean differences for the changes in all outcomes were pooled by Review Manager 5.2 (Cochrane Collaboration, Oxford, England). A total of ten trials including 608 subjects were identified. The meta-analysis found that tea could alleviate the decrease of fasting blood insulin [1.30 U/L, 95% CI (0.36, 2.24)], and reduced waist circumference only in more than 8-week intervention [ 2.70 cm, 95% CI (-4.72, -0.69)], whereas there were no statistically significant differences with regard to homeostasis model of insulin resistance 0.38 (-0.18, 0.95), fasting blood glucose -0.05 mmol/L (-0.51, 0.40), low density lipoprotein cholesterol 0.07 mmol/L (-0.15, 0.29), high density lipoprotein-cholesterol 0.01 mmol/L (-0.08, 0.09), body mass index -0.15 kg/m(2) (-0.50, 0.21), SBP 0.35 mmHg (-3.54, 4.24), DBP -1.02 mmHg (-3.53, 1.48), triglycerides -0.11 mmol/L (-0.28, 0.05) and fasting cholesterol -0.05 mmol/L (-0.20, 0.11) in patients with T2DM, and leptin, ADPN, CRE and UA were also non-significant. The intervention of tea or tea extraction could maintain a stable fasting blood insulin and reduce waist circumference in the T2DM patients; however, the effects on other outcomes were not significant. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 25689397 TI - The effect of delayed graft function on graft and patient survival in kidney transplantation: an approach using competing events analysis. AB - OBJECTIVE: In kidney transplantation, the impact of delayed graft function (DGF) on long-term graft and patient survival is controversial. We examined the impact of DGF on graft and recipient survival by accounting for the possibility that death with graft function may act as a competing risk for allograft failure. STUDY DESIGN AND SETTING: We used data from 1281 adult primary deceased-donor kidney recipients whose allografts functioned at least 1 year. RESULTS: The probability of graft loss occurrence is overestimated using the complement of Kaplan-Meier estimates (1-KM). Both the cause-specific Cox proportional hazard regression model (standard Cox) and the subdistribution hazard regression model proposed by Fine and Gray showed that DGF was associated with shorter time to graft failure (csHR = 2.0, P = 0.002; sHR = 1.57, P = 0.009), independent of acute rejection (AR) and after adjusting for traditional factors associated with graft failure. Regarding patient survival, DGF was a predictor of patient death using the cause-specific Cox model (csHR = 1.57, P = 0.029) but not using the subdistribution model. CONCLUSIONS: The probability of graft loss from competing end points should not be reported with the 1-KM. Application of a regression model for subdistribution hazard showed that, independent of AR, DGF has a detrimental effect on long-term graft survival, but not on patient survival. PMID- 25689398 TI - Is pindolol augmentation effective in depressed patients resistant to selective serotonin reuptake inhibitors? A systematic review and meta-analysis. AB - OBJECTIVE: This systematic review and meta-analysis was conducted to assess the use of pindolol augmentation in depressed patients resistant to selective serotonin reuptake inhibitor (SSRI) therapy. METHODS: A comprehensive search of PubMed, Cochrane, Embase, Web of Science, and PsychINFO databases from 1970 through December 2013 was conducted. Only randomized controlled trials (RCTs) studied on unipolar SSRI-resistant depressed adults were included. The primary outcome was mean change scores of depressive symptom on the depression rating scales, assessed with standardized mean differences. RESULTS: Five RCTs consisting of 154 patients met all inclusion and exclusion criteria. The overall pooled effect size in the primary and secondary efficacy analysis showed no significant effects of pindolol plus SSRI therapy (standardized mean difference = -0.43, p = 0.24; OR = 1.92, p = 0.39, respectively). In terms of acceptability, there was no statistical difference in either tolerability or safety between the two groups (OR = 0.46, p = 0.40; OR = 0.90, p = 0.94, respectively). These estimates remained robust through several sensitivity and subgroup analyses, except 7.5 mg-qd pindolol augmentation did show a significant benefit over 2.5-mg tid pindolol augmentation. CONCLUSIONS: Pindolol augmentation may not be suitable for treatment-resistant depression patients with SSRI-resistant depression. However, once-daily high-dose pindolol (7.5 mg qd) appears to show a promising benefit in these patients. PMID- 25689399 TI - Rational Design of Metal Nanoframes for Catalysis and Plasmonics. AB - Recently, metal nanoframes have received increased attention due to their unique spatial and physicochemical, e.g., catalytic and plasmonic properties. So far, a variety of synthetic procedures have been developed to fabricate metal nanoframes with different shapes, sizes and compositions. Typical synthesis of metal nanoframes involves two stages: 1) formation of solid nanocrystals and 2) hollowing out the interiors and side faces. In this review, solution-phase synthetic strategies are summarized, based on galvanic replacement reactions, oxidative etching, the Kirkendall effect, electrodeposition, and template assisted growth, as well as one-pot synthesis. Their potential applications in catalysis and optical sensing are overviewed as well. PMID- 25689400 TI - Sitagliptin attenuated brain damage and cognitive impairment in mice with chronic cerebral hypo-perfusion through suppressing oxidative stress and inflammatory reaction. AB - BACKGROUND: Sitagliptin, a new antidiabetic drug that inhibits dipeptidyl peptidase (DPP)-4 enzyme activity, has been reported to possess neuroprotective property. We tested the protective effects of sitagliptin against chronic cerebral hypoperfusion (CHP) in mice after bilateral carotid artery stenosis (BCAS). METHOD: Thirty C57BL/6 mice were divided into three groups: sham control (n = 10), CHP (n = 10) and CHP-sitagliptin (orally 600 mg/kg/day) (n = 10). Working memory was assessed with novel-object recognition test. MRI was performed at day 0 and day 90 after BCAS procedure prior to sacrifice. RESULTS: Immunohistochemical (IHC) staining showed significantly enhanced white matter lesions, microglia activation and astrocytosis of white matter in CHP group than in sham control, but the changes were significantly suppressed after sitagliptin treatment (all P < 0.01). The mRNA expressions of inflammatory [tumour necrosis factor-alpha (TNF-alpha), monocyte chemoattractant protein (MCP-1) and matrix metalloproteinase (MMP)-2] and apoptotic (Bax) biomarkers showed an identical pattern, whereas the anti-inflammatory (interleukin, IL-10) and antiapoptotic (Bcl-2) biomarkers showed an opposite pattern compared with that of IHC among all groups (all P < 0.01). The protein expressions of oxidative stress (NOX-I, NOX II, nitrotyrosin, oxidized protein), inflammatory [nuclear factor-kappa B (NF kappaB), TNF-alpha and MMP-2], apoptotic [mitochondrial Bax, cleaved poly(ADP ribose) polymerase (PARP)] and DNA-damage (gamma-H2AX) markers showed an identical pattern, while expression pattern of antiapoptotic marker (Bcl-2) was opposite to that of IHC (all P < 0.01). Glycogen-like peptide-1 receptor protein expression progressively increased from sham control to CHP-sitagliptin (P < 0.01). The short-term working-memory loss and MRI/diffusion tensor imaging (DTI) showed a pattern identical to that of IHC in all groups (all P < 0.01). CONCLUSION: Sitagliptin protected against cognitive impairment and brain damage in a murine CHP model. PMID- 25689401 TI - Sildenafil ameliorates long term peripheral neuropathy in type II diabetic mice. AB - Diabetic peripheral neuropathy is a common complication of long-standing diabetes mellitus. To mimic clinical trials in which patients with diabetes enrolled have advanced peripheral neuropathy, we investigated the effect of sildenafil, a specific inhibitor of phosphodiesterase type 5 enzyme, on long term peripheral neuropathy in middle aged male mice with type II diabetes. Treatment of diabetic mice (BKS.Cg-m+/+Leprdb/J, db/db) at age 36 weeks with sildenafil significantly increased functional blood vessels and regional blood flow in the sciatic nerve, concurrently with augmentation of intra-epidermal nerve fiber density in the skin and myelinated axons in the sciatic nerve. Functional analysis showed that the sildenafil treatment considerably improved motor and sensory conduction velocities in the sciatic nerve and peripheral thermal stimulus sensitivity compared with the saline treatment. In vitro studies showed that mouse dermal endothelial cells (MDE) cultured under high glucose levels exhibited significant down regulation of angiopoietin 1 (Ang1) expression and reduction of capillary like tube formation, which were completely reversed by sildenafil. In addition, incubation of dorsal root ganglia (DRG) neurons with conditioned medium harvested from MDE under high glucose levels suppressed neurite outgrowth, where as conditional medium harvested from MDE treated with sildenafil under high glucose levels did not inhibit neurite outgrowth of DRG neurons. Moreover, blockage of the Ang1 receptor, Tie2, with a neutralized antibody against Tie2 abolished the beneficial effect of sildenafil on tube formation and neurite outgrowth. Collectively, our data indicate that sildenafil has a therapeutic effect on long term peripheral neuropathy of middle aged diabetic mice and that improvement of neurovascular dysfunction by sildenafil likely contributes to the amelioration of nerve function. The Ang1/Tie2 signaling pathway may play an important role in these restorative processes. PMID- 25689402 TI - Two new Beggiatoa species inhabiting marine mangrove sediments in the Caribbean. AB - Beggiatoaceae, giant sulphur-oxidizing bacteria, are well known to occur in cold and temperate waters, as well as hydrothermal vents, where they form dense mats on the floor. However, they have never been described in tropical marine mangroves. Here, we describe two new species of benthic Beggiatoaceae colonizing a marine mangrove adjacent to mangrove roots. We combined phylogenetic and lipid analysis with electron microscopy in order to describe these organisms. Furthermore, oxygen and sulphide measurements in and ex situ were performed in a mesocosm to characterize their environment. Based on this, two new species, Candidatus Maribeggiatoa sp. and Candidatus Isobeggiatoa sp. inhabiting tropical marine mangroves in Guadeloupe were identified. The species identified as Candidatus Maribeggiatoa group suggests that this genus could harbour a third cluster with organisms ranging from 60 to 120 MUm in diameter. This is also the first description of an Isobeggiatoa species outside of Arctic and temperate waters. The multiphasic approach also gives information about the environment and indications for the metabolism of these bacteria. Our study shows the widespread occurrence of members of Beggiatoaceae family and provides new insight in their potential role in shallow-water marine sulphide-rich environments such as mangroves. PMID- 25689403 TI - Correction: promoted relationship of cardiovascular morbidity with air pollutants in a typical Chinese urban area. PMID- 25689404 TI - Untested, unproven, and unethical: the promotion and provision of autologous stem cell therapies in Australia. AB - An increasing number of private clinics in Australia are marketing and providing autologous stem cell therapies to patients. Although advocates point to the importance of medical innovation and the primacy of patient choice, these arguments are unconvincing. First, it is a stark truth that these clinics are flourishing while the efficacy and safety of autologous stem cell therapies, outside of established indications for hematopioetic stem cell transplantation, are yet to be shown. Second, few of these therapies are offered within clinical trials. Third, patients with chronic and debilitating illnesses, who are often the ones who take up these therapies, incur significant financial burdens in the expectation of benefiting from these treatments. Finally, the provision of these stem cell therapies does not follow the established pathways for legitimate medical advancement. We argue that greater regulatory oversight and professional action are necessary to protect vulnerable patients and that at this time the provision of unproven stem cell therapies outside of clinical trials is unethical. PMID- 25689405 TI - Pre-transplant donor-specific T-cell alloreactivity is strongly associated with early acute cellular rejection in kidney transplant recipients not receiving T cell depleting induction therapy. AB - Preformed T-cell immune-sensitization should most likely impact allograft outcome during the initial period after kidney transplantation, since donor-specific memory T-cells may rapidly recognize alloantigens and activate the effector immune response, which leads to allograft rejection. However, the precise time frame in which acute rejection is fundamentally triggered by preformed donor specific memory T cells rather than by de novo activated naive T cells is still to be established. Here, preformed donor-specific alloreactive T-cell responses were evaluated using the IFN-gamma ELISPOT assay in a large consecutive cohort of kidney transplant patients (n = 90), to assess the main clinical variables associated with cellular sensitization and its predominant time-frame impact on allograft outcome, and was further validated in an independent new set of kidney transplant recipients (n = 67). We found that most highly T-cell sensitized patients were elderly patients with particularly poor HLA class-I matching, without any clinically recognizable sensitizing events. While one-year incidence of all types of biopsy-proven acute rejection did not differ between T-cell alloreactive and non-alloreactive patients, Receiver Operating Characteristic curve analysis indicated the first two months after transplantation as the highest risk time period for acute cellular rejection associated with baseline T cell sensitization. This effect was particularly evident in young and highly alloreactive individuals that did not receive T-cell depletion immunosuppression. Multivariate analysis confirmed preformed T-cell sensitization as an independent predictor of early acute cellular rejection. In summary, monitoring anti-donor T cell sensitization before transplantation may help to identify patients at increased risk of acute cellular rejection, particularly in the early phases after kidney transplantation, and thus guide decision-making regarding the use of induction therapy. PMID- 25689406 TI - Ventilation onset prior to umbilical cord clamping (physiological-based cord clamping) improves systemic and cerebral oxygenation in preterm lambs. AB - BACKGROUND: As measurement of arterial oxygen saturation (SpO2) is common in the delivery room, target SpO2 ranges allow clinicians to titrate oxygen therapy for preterm infants in order to achieve saturation levels similar to those seen in normal term infants in the first minutes of life. However, the influence of the onset of ventilation and the timing of cord clamping on systemic and cerebral oxygenation is not known. AIM: We investigated whether the initiation of ventilation, prior to, or after umbilical cord clamping, altered systemic and cerebral oxygenation in preterm lambs. METHODS: Systemic and cerebral blood flows, pressures and peripheral SpO2 and regional cerebral tissue oxygenation (SctO2) were measured continuously in apnoeic preterm lambs (126+/-1 day gestation). Positive pressure ventilation was initiated either 1) prior to umbilical cord clamping, or 2) after umbilical cord clamping. Lambs were monitored intensively prior to intervention, and for 10 minutes following umbilical cord clamping. RESULTS: Clamping the umbilical cord prior to ventilation resulted in a rapid decrease in SpO2 and SctO2, and an increase in arterial pressure, cerebral blood flow and cerebral oxygen extraction. Ventilation restored oxygenation and haemodynamics by 5-6 minutes. No such disturbances in peripheral or cerebral oxygenation and haemodynamics were observed when ventilation was initiated prior to cord clamping. CONCLUSION: The establishment of ventilation prior to umbilical cord clamping facilitated a smooth transition to systemic and cerebral oxygenation following birth. SpO2 nomograms may need to be re-evaluated to reflect physiological management of preterm infants in the delivery room. PMID- 25689407 TI - Comparative pharmacokinetic and pharmacodynamic response of single and double intraruminal doses of ivermectin and moxidectin in nematode-infected lambs. AB - AIMS: To compare the pharmacokinetics, distribution and efficacy (pharmacodynamic response) of intraruminal ivermectin (IVM) and moxidectin (MXD) administered at 0.2 and 0.4 mg/kg to naturally nematode-infected lambs, and to determine the ex vivo accumulation of these anthelmintics by Haemonchus contortus. METHODS: Romney Marsh lambs, naturally infected with IVM-resistant H. contortus, were allocated to treatment groups based on faecal nematode egg counts. They received 0.2 or 0.4 mg/kg IVM or MXD (n=10 per group), or no treatment (Control; n=6), on Day 0. Samples from four animals from each treatment group, including abomasal parasites, were obtained on Day 1. Plasma samples were also collected from Day 0 to 14, and a faecal egg count reduction test (FECRT) and a controlled efficacy trial were carried out on Day 14. Concentrations of IVM and MXD in plasma, in abomasal and intestinal tissues and in H. contortus were evaluated by high performance liquid chromatography. Additionally, the ex vivo drug accumulation of IVM and MXD by H. contortus was determined. RESULTS: Peak plasma concentrations and the area under the concentration vs. time curve for both IVM and MXD were higher for 0.4 than 0.2 mg/kg treatments (p<0.05), but there were no differences for other parameters. Concentrations of IVM and MXD in the gastrointestinal target tissues and in H. contortus were higher compared to those measured in plasma. Concentrations of both drugs in H. contortus were correlated with those observed in the abomasal content (r=0.86; p<0.0001). The exposure of H. contortus to IVM and MXD was related to the administered dose. Mean FECRT and efficacy for removal of adult H. contortus was 0% for IVM at 0.2 and 0.4 mg/kg. For MXD, FECRT were >95% for both treatments, and efficacy against H. contortus was 85.1% and 98.1% for 0.2 and 0.4 mg/kg, respectively. The ex vivo accumulation of IVM and MXD in H. contortus was directly related to the drug concentration present in the environment and was influenced by the duration of exposure. CONCLUSION: Administration of IVM and MXD at 0.4 compared with 0.2 mg/kg accounted for enhanced drug exposure in the target tissues, as well as higher drug concentrations within resistant nematodes. The current work is a further contribution to the evaluation of the relationship between drug efficacy and basic pharmacological issues in the presence of resistant parasite populations. PMID- 25689409 TI - Correction to Hiday, Wales, and Ray (2013). : "effectiveness of a short-term mental health court: criminal recidivism on year postexit". AB - Reports an error in "Effectiveness of a short-term mental health court: Criminal recidivism one year postexit" by Virginia Aldige Hiday, Heathcote W. Wales and Bradley Ray (Law and Human Behavior, 2013[Dec], Vol 37[6], 401-411). Results for two groups were reversed, once in text at the end of the Multivariate Analyses section on page 406, and in Figure 2 on page 408. The erratum provides the correct results. (The following abstract of the original article appeared in record 2013-20572-001.) This article investigated criminal recidivism 1 year postexit from a mental health court (MHC), which has, unlike prior MHCs studied, relatively short periods of court supervision. It benefits from a federal pretrial services agency that screens all arrestees for mental illness and dedicates a specialized supervision unit (SSU) to provide supervision and services while on pretrial release to all screened positive, including MHC participants. We compared criminal activity prior to key arrest with criminal activity post court disposition in MHC participants (N = 408) and MHC-eligible mentally ill arrestees in SSU (N = 687) receiving the same supervision and services while controlling for possible confounders. The proportion of MHC participants arrested was significantly lower in the year after MHC exit and significantly lower than that of the comparison group. They also averaged fewer rearrests and had a longer time to rearrest. MHC graduates made the greatest gains and accounted for the recidivism differences between MHC participants and the comparison group. This study adds to the accumulating evidence of the effectiveness of MHCs in reducing recidivism among offenders with severe mental illness. PMID- 25689410 TI - Callous-unemotional traits and adolescents' role in group crime. AB - The current study examined the association of callous-unemotional (CU) traits with group offending (i.e., committing a crime with others; gang involvement) and with the role that the offender may play in a group offense (e.g., being the leader). This analysis was conducted in an ethnically and racially diverse sample (N = 1,216) of justice-involved adolescents (ages 13 to 17) from 3 different sites. CU traits were associated with a greater likelihood of the adolescent offending in groups and being in a gang. Importantly, both associations remained significant after controlling for the adolescent's age, level of intelligence, race and ethnicity, and level of impulse control. The association of CU traits with gang membership also remained significant after controlling for the adolescent's history of delinquent behavior. Further, CU traits were associated with several measures of taking a leadership role in group crimes. CU traits were also associated with greater levels of planning in the group offense for which the adolescent was arrested, although this was moderated by the adolescent's race and was not found in Black youth. These results highlight the importance of CU traits for understanding the group process involved in delinquent acts committed by adolescents. They also underscore the importance of enhancing the effectiveness of treatments for these traits in order to reduce juvenile delinquency. PMID- 25689411 TI - Synthesis of bottlebrush polystyrenes with uniform, alternating, and gradient distributions of brushes via living anionic polymerization and hydrosilylation. AB - By combining living anionic polymerization and hydrosilylation, densely grafted bottlebrush polymers with controlled spacing of branch points are prepared. Dimethyl(4-vinylphenyl)silane and dimethyl(4-(1-phenylvinyl)phenyl)silane are anionically (co)polymerized to synthesize uniform, alternating, and gradient in chain silyl-hydride (Si-H) functionalized backbones. The spacing of branch points is controlled effectively by regulating the distribution of Si-H groups along the backbones. Three backbones with a similar number of Si-H groups but variable distributions are used to synthesize corresponding bottlebrush polymers via hydrosilylation between the backbones and chain-end vinyl functionalized polystyrene. The uniformly grafted bottlebrush exhibits the highest hydrodynamic radius (Rh ) of 5.6 nm and the lowest Tg of 79 degrees C which may be attributed to its compact grafted structure. This methodology exhibits high efficiency and convenience for the construction of bottlebrushes with controlled distribution of brushes. PMID- 25689412 TI - Systematic mining of salt-tolerant genes in halophyte-Zoysia matrella through cDNA expression library screening. AB - Though a large number of salt-tolerant genes were identified from Glycophyte in previous study, genes involved in salt-tolerance of halophyte were scarcely studied. In this report, an important halophyte turfgrass, Zoysia matrella, was used for systematic excavation of salt-tolerant genes using full-length cDNA expression library in yeast. Adopting the Gateway-compatible vector system, a high quality entry library was constructed, containing 3 * 10(6) clones with an average inserted fragments length of 1.64 kb representing a 100% full-length rate. The yeast expression library was screened in a salt-sensitive yeast mutant. The screening yielded dozens of salt-tolerant clones harboring 16 candidate salt tolerant genes. Under salt-stress condition, these 16 genes exhibited different transcription levels. According to the results, we concluded that the salt tolerance of Z. matrella might result from known genes involved in ion regulation, osmotic adjustment, as well as unknown pathway associated with protein folding and modification, RNA metabolism, and mitochondrial membrane translocase, etc. In addition, these results shall provide new insight for the future researches with respect to salt-tolerance. PMID- 25689415 TI - Effects of URB597 as an inhibitor of fatty acid amide hydrolase on WIN55, 212-2 induced learning and memory deficits in rats. AB - Cannabinoid and endocannabinoid systems have been implicated in several physiological functions including modulation of cognition. In this study we evaluated the effects and interaction between fatty-acid amide hydrolase (FAAH) inhibitor URB597 and CB1 receptor agonist WIN55, 212-2 on memory using object recognition and passive avoidance learning (PAL) tests. Learning and memory impairment was induced by WIN 55, 212-2 administration (1mg/kg, i.p.) 30min before the acquisition trial. URB597 (0.1, 0.3 and 1mg/kg, i.p.) or SR141716A (1mg/kg, i.p.) was injected to rats 10min before WIN 55, 212-2 or URB597 respectively. URB597 (0.3 and 1mg/kg) but not 0.1mg/kg induced higher discrimination index (DI) in object recognition test and enhanced memory acquisition in PAL test. The cognitive enhancing effect of URB597 was blocked by a CB1 receptor antagonist, SR141716A which at this dose alone had no effect on cognition. WIN55, 212-2 caused cognition deficits in both tests. URB597 (0.3 and 1mg/kg) treatment could alleviate the negative influence of WIN 55, 212-2 on cognition and memory. These results indicate URB597 potential to protect against memory deficits induced by cannabinoid. Therefore, in combination with URB597 beneficial effects, this study suggests that URB597 has recognition and acquisition memory enhancing effects. It may also constitute a novel approach for the treatment of cannabinoid induced memory deficits and lead to a better understanding of the brain mechanisms underlying cognition. PMID- 25689416 TI - Accommodating Autistics and Treating Autism: Can We Have Both? AB - One of the central claims of the neurodiversity movement is that society should accommodate the needs of autistics, rather than try to treat autism. People have variously tried to reject this accommodation thesis as applicable to all autistics. One instance is Pier Jaarsma and Stellan Welin, who argue that the thesis should apply to some but not all autistics. They do so via separating autistics into high- and low-functioning, on the basis of IQ and social effectiveness or functionings. I reject their grounds for separating autistics. IQ is an irrelevant basis for separating autistics. Charitably rendering it as referring to more general capacities still leaves us mistaken about the roles they play in supporting the accommodation thesis. The appeal to social effectiveness or functionings relies on standards that are inapplicable to autistics, and which risks being deaf to the point of their claims. I then consider if their remaining argument concerning autistic culture may succeed independently of the line they draw. I argue that construing autistics' claims as beginning from culture mistakes their status, and may even detract from their aims. Via my discussion of Jaarsma and Welin, I hope to point to why the more general strategy of separating autistics, in response to the accommodation thesis, does not fully succeed. Finally, I sketch some directions for future discussions, arguing that we should instead shift our attention to consider another set of questions concerning the costs and extent of change required to accommodate all autistics. PMID- 25689414 TI - Role of epigenetic modifications in luminal breast cancer. AB - Luminal breast cancers represent approximately 75% of cases. Explanations into the causes of endocrine resistance are complex and are generally ascribed to genomic mechanisms. Recently, attention has been drawn to the role of epigenetic modifications in hormone resistance. We review these here. Epigenetic modifications are reversible, heritable and include changes in DNA methylation patterns, modification of histones and altered microRNA expression levels that target the receptors or their signaling pathways. Large-scale analyses indicate distinct epigenomic profiles that distinguish breast cancers from normal and benign tissues. Taking advantage of the reversibility of epigenetic modifications, drugs that target epigenetic modifiers, given in combination with chemotherapies or endocrine therapies, may represent promising approaches to restoration of therapy responsiveness in these cases. PMID- 25689417 TI - Liver injury with novel oral anticoagulants: assessing post-marketing reports in the US Food and Drug Administration adverse event reporting system. AB - AIM: We assessed the hepatic safety of novel oral anticoagulants (NOACs) analyzing the publicly available US-FDA adverse event reporting system (FAERS). METHODS: We extracted reports of drug-induced liver injury (DILI) associated with NOACs, including acute liver failure (ALF) events. Based on US marketing authorizations, we performed disproportionality analyses, calculating reporting odds ratios (RORs) with 95% confidence interval (CI), also to test for event- and drug-related competition bias, and case-by-case evaluation for concomitant medications. RESULTS: DILI reports represented 3.7% (n = 146) and 1.7% (n = 222) of all reports for rivaroxaban and dabigatran, respectively. No statistically significant association was found for dabigatran, in primary and secondary analyses. Disproportionality signals emerged for rivaroxaban in primary analysis (ALF: n = 25, ROR = 2.08, 95% CI 1.34, 3.08). In a large proportion of DILI reports concomitant hepatotoxic and/or interacting drugs were recorded: 42% and 37% (rivaroxaban and dabigatran, respectively), especially statins, paracetamol and amiodarone. Among ALF reports, fatal outcome occurred in 49% of cases (44% and 51%, rivaroxaban and dabigatran, respectively), whereas rapid onset of the event (<1 week) was detected in 46% of patients (47% and 44%, respectively). CONCLUSIONS: The disproportionality signal for rivaroxaban calls for further comparative population-based studies to characterize and quantify the actual DILI risk of NOACs, taking into account drug- and patient-related risk factors. As DILI is unpredictable, our findings strengthen the role of (a) timely pharmacovigilance to detect post-marketing signals of DILI through FAERS and other data sources, (b) clinicians to assess early, on a case-by-case basis, the potential responsibility of NOACs when they diagnose a liver injury. PMID- 25689418 TI - Hepatitis B virus mutation may play a role in hepatocellular carcinoma recurrence: A systematic review and meta-regression analysis. AB - BACKGROUND AND AIMS: A number of studies have confirmed that antiviral therapy with nucleotide analogs (NAs) can improve the prognosis of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) after curative therapy. However, what factors affected the prognosis of HBV-HCC after removal of the primary tumor and inhibition of HBV replication? A meta-regression analysis was conducted to explore the prognostic factor for this subgroup of patients. METHODS: MEDLINE, EMBASE, Web of Science, and Cochrane library were searched from January 1995 to February 2014 for clinical trials evaluating the effect of NAs on the prognosis of HBV-HCC after curative therapy. Data were extracted for host, viral, and intervention information. Single-arm meta-analysis was performed to assess overall survival (OS) rates and HCC recurrence. Meta-regression analysis was carried out to explore risk factors for 1-year OS rate and HCC recurrence for HBV HCC patients after curative therapy and antiviral therapy. RESULTS: Fourteen observational studies with 1284 patients met the inclusion criteria. Influential factors for prognosis of HCC were mainly baseline HBeAg positivity, cirrhotic stage, advanced Tumor-Node-Metastasis (TNM) stage, macrovascular invasion, and antiviral agent type. The 1-year OS rate decreased by more than four times (coefficient -4.45, P<0.001) and the 1-year HCC recurrence increased by more than one time (coefficient 1.20, P=0.003) when lamivudine was chosen for HCC after curative therapy, relative to entecavir for HCC. CONCLUSIONS: HBV mutation may play a role in HCC recurrence. Entecavir or tenofovir, a high genetic barrier to resistance, should be recommended for HBV-HCC patients. PMID- 25689419 TI - Overexpression in yeast, photocycle, and in vitro structural change of an avian putative magnetoreceptor cryptochrome4. AB - Cryptochromes (CRYs) have been found in a wide variety of living organisms and can function as blue light photoreceptors, circadian clock molecules, or magnetoreceptors. Non-mammalian vertebrates have CRY4 in addition to the CRY1 and CRY2 circadian clock components. Though the function of CRY4 is not well understood, chicken CRY4 (cCRY4) may be a magnetoreceptor because of its high level of expression in the retina and light-dependent structural changes in retinal homogenates. To further characterize the photosensitive nature of cCRY4, we developed an expression system using budding yeast and purified cCRY4 at yields of submilligrams of protein per liter with binding of the flavin adenine dinucleotide (FAD) chromophore. Recombinant cCRY4 dissociated from anti-cCRY4 C1 mAb, which recognizes the C-terminal region of cCRY4, in a light-dependent manner and showed a light-dependent change in its trypsin digestion pattern, suggesting that cCRY4 changes its conformation with light irradiation in the absence of other retinal factors. Combinatorial analyses with UV-visible spectroscopy and immunoprecipitation revealed that there is chromophore reduction in the cCRY4 photocycle and formation of a flavosemiquinone radical intermediate that is likely accompanied by a conformational change in the carboxyl-terminal region. Thus, cCRY4 seems to be an intrinsically photosensitive and photoswitchable molecule and may exemplify a vertebrate model of cryptochrome with possible function as a photosensor and/or magnetoreceptor. PMID- 25689420 TI - A high-intensity, intermittent exercise protocol and dynamic postural control in men and women. AB - CONTEXT: Deficits in dynamic postural control predict lower limb injury. Differing fatiguing protocols negatively affect dynamic postural control. The effect of high-intensity, intermittent exercise on dynamic postural control has not been investigated. OBJECTIVE: To investigate the effect of a high-intensity, intermittent exercise protocol (HIIP) on the dynamic postural control of men and women as measured by the Star Excursion Balance Test (SEBT). DESIGN: Descriptive laboratory study. SETTING: University gymnasium. PATIENTS OR OTHER PARTICIPANTS: Twenty male (age = 20.83 +/- 1.50 years, height = 179.24 +/- 7.94 cm, mass = 77.67 +/- 10.82 kg) and 20 female (age = 20.45 +/- 1.34 years, height = 166.08 +/ 5.83 cm, mass = 63.02 +/- 6.67 kg) athletes. INTERVENTION(S): We recorded SEBT measurements at baseline, pre-HIIP, and post-HIIP. The HIIP consisted of 4 repetitions of 10-m forward sprinting with a 90 degrees change of direction and then backward sprinting for 5 m, 2 repetitions of 2-legged jumping over 5 hurdles, 2 repetitions of high-knee side stepping over 5 hurdles, and 4 repetitions of lateral 5-m shuffles. Participants rested for 30 seconds before repeating the circuit until they reported a score of 18 on the Borg rating of perceived exertion scale. MAIN OUTCOME MEASURE(S): A mixed between- and within subjects analysis of variance was conducted to assess time (pre-HIIP, post-HIIP) * sex interaction effects. Subsequent investigations assessed the main effect of time and sex on normalized maximal SEBT scores. We used intraclass correlation coefficients to determine the test-retest reliability of the SEBT and paired samples t tests to assess the HIIP effect on circuit times. RESULTS: We found a time * sex effect (F(8,69) = 3.5; P range, <.001-.04; eta(2) range, 0.057-0.219), with women less negatively affected. We also noted a main effect for time, with worse normalized maximal SEBT scores postfatigue (F(8,69) = 22.39; P < .001; eta(2) range, 0.324-0.695), and for sex, as women scored better in 7 SEBT directions (F(8,69) = 0.84; P range, <.001-008; eta(2) range, 0.088-0.381). The intraclass correlation coefficients demonstrated high (0.77-0.99) test-retest repeatability. Paired-samples t tests demonstrated increases in circuit time post HIIP (P < .001). CONCLUSIONS: The HIIP-induced fatigue negatively affected normalized maximal SEBT scores. Women had better scores than men and were affected less negatively by HIIP-induced fatigue. PMID- 25689423 TI - Functional properties of the catalytic domain of mouse acidic mammalian chitinase expressed in Escherichia coli. AB - Mouse acidic mammalian chitinase (AMCase) plays important physiological roles in defense and nutrition. AMCase is composed of an N-terminal catalytic domain (CatD) and a C-terminal chitin-binding domain (CBD). We expressed CatD of mouse AMCase as a recombinant fusion protein with Protein A and V5-His in Escherichia coli (Protein A-CatD-V5-His), evaluated its functional properties and compared them to the full-length AMCase (Protein A-AMCase-V5-His). Under our experimental conditions, the chitinolytic activity of both proteins against 4-nitrophenyl N,N' diacetyl-beta-D-chitobioside was equivalent with regard to their specific enzymatic activities, optimal pH and temperature as well as to the pH and temperature stability. CatD bound to chitin beads and cleaved the N acetylglucosamine hexamer, colloidal and crystalline chitin as well as the shrimp shell, and released primarily N,N'-diacetylchitobiose fragments at pH 2.0. These results indicate that the primary structure of CatD is sufficient to form a proper tertiary structure required for chitinolytic activity, recognize chitin substrates and degrade them in the absence of a CBD. Our recombinant proteins can be used for further studies evaluating pathophysiological roles of AMCase in different diseases. PMID- 25689424 TI - Induced pluripotent stem cells and their use in cardiac and neural regenerative medicine. AB - Stem cells are unique pools of cells that are crucial for embryonic development and maintenance of adult tissue homeostasis. The landmark Nobel Prize winning research by Yamanaka and colleagues to induce pluripotency in somatic cells has reshaped the field of stem cell research. The complications related to the usage of pluripotent embryonic stem cells (ESCs) in human medicine, particularly ESC isolation and histoincompatibility were bypassed with induced pluripotent stem cell (iPSC) technology. The human iPSCs can be used for studying embryogenesis, disease modeling, drug testing and regenerative medicine. iPSCs can be diverted to different cell lineages using small molecules and growth factors. In this review we have focused on iPSC differentiation towards cardiac and neuronal lineages. Moreover, we deal with the use of iPSCs in regenerative medicine and modeling diseases like myocardial infarction, Timothy syndrome, dilated cardiomyopathy, Parkinson's, Alzheimer's and Huntington's disease. Despite the promising potential of iPSCs, genome contamination and low efficacy of cell reprogramming remain significant challenges. PMID- 25689425 TI - The 15q11.2 BP1-BP2 microdeletion syndrome: a review. AB - Patients with the 15q11.2 BP1-BP2 microdeletion can present with developmental and language delay, neurobehavioral disturbances and psychiatric problems. Autism, seizures, schizophrenia and mild dysmorphic features are less commonly seen. The 15q11.2 BP1-BP2 microdeletion involving four genes (i.e., TUBGCP5, CYFIP1, NIPA1, NIPA2) is emerging as a recognized syndrome with a prevalence ranging from 0.57%-1.27% of patients presenting for microarray analysis which is a two to four fold increase compared with controls. Review of clinical features from about 200 individuals were grouped into five categories and included developmental (73%) and speech (67%) delays; dysmorphic ears (46%) and palatal anomalies (46%); writing (60%) and reading (57%) difficulties, memory problems (60%) and verbal IQ scores <=75 (50%); general behavioral problems, unspecified (55%) and abnormal brain imaging (43%). Other clinical features noted but not considered as common were seizures/epilepsy (26%), autism spectrum disorder (27%), attention deficit disorder (ADD)/attention deficit hyperactivity disorder (ADHD) (35%), schizophrenia/paranoid psychosis (20%) and motor delay (42%). Not all individuals with the deletion are clinically affected, yet the collection of findings appear to share biological pathways and presumed genetic mechanisms. Neuropsychiatric and behavior disturbances and mild dysmorphic features are associated with genomic imbalances of the 15q11.2 BP1-BP2 region, including microdeletions, but with an apparent incomplete penetrance and variable expressivity. PMID- 25689426 TI - Autophagy as a regulatory component of erythropoiesis. AB - Autophagy is a process that leads to the degradation of unnecessary or dysfunctional cellular components and long-lived protein aggregates. Erythropoiesis is a branch of hematopoietic differentiation by which mature red blood cells (RBCs) are generated from multi-potential hematopoietic stem cells (HSCs). Autophagy plays a critical role in the elimination of mitochondria, ribosomes and other organelles during erythroid terminal differentiation. Here, the modulators of autophagy that regulate erythroid differentiation were summarized, including autophagy-related (Atg) genes, the B-cell lymphoma 2 (Bcl 2) family member Bcl-2/adenovirus E1B 19 kDa interacting protein 3-like (Nix/Binp3L), transcription factors globin transcription factor 1 (GATA1) and forkhead box O3 (FoxO3), intermediary factor KRAB-associated protein1 (KAP1), and other modulators, such as focal adhesion kinase family-interacting protein of 200 kDa (FIP200), Ca2+ and 15-lipoxygenase. Understanding the modulators of autophagy in erythropoiesis will benefit the autophagy research field and facilitate the prevention and treatment of autophagy-related red blood cell disorders. PMID- 25689427 TI - The actin depolymerizing factor (ADF)/cofilin signaling pathway and DNA damage responses in cancer. AB - The actin depolymerizing factor (ADF)/cofilin protein family is essential for actin dynamics, cell division, chemotaxis and tumor metastasis. Cofilin-1 (CFL-1) is a primary non-muscle isoform of the ADF/cofilin protein family accelerating the actin filamental turnover in vitro and in vivo. In response to environmental stimulation, CFL-1 enters the nucleus to regulate the actin dynamics. Although the purpose of this cytoplasm-nucleus transition remains unclear, it is speculated that the interaction between CFL-1 and DNA may influence various biological responses, including DNA damage repair. In this review, we will discuss the possible involvement of CFL-1 in DNA damage responses (DDR) induced by ionizing radiation (IR), and the implications for cancer radiotherapy. PMID- 25689428 TI - Genetic polymorphisms in estrogen-related genes and the risk of breast cancer among Han Chinese women. AB - Exposure to high levels of estrogen is considered an important risk factor for susceptibility to breast cancer. Common polymorphisms in genes that affect estrogen levels may be associated with breast cancer risk, but no comprehensive study has been performed among Han Chinese women. In the present study, 32 single nucleotide polymorphisms (SNPs) in estrogen-related genes were genotyped using the MassARRAY IPLEX platform in 1076 Han Chinese women. Genotypic and allelic frequencies were compared between case and control groups. Unconditional logistic regression was used to assess the effects of SNPs on breast cancer risk. Associations were also evaluated for breast cancer subtypes stratified by estrogen receptor (ER) and progesterone receptor (PR) status. Case-control analysis showed a significant relation between heterozygous genotypes of rs700519 and rs2069522 and breast cancer risk (OR = 0.723, 95% CI = 0.541-0.965, p = 0.028 and OR = 1.500, 95% CI = 1.078-2.087, p = 0.016, respectively). Subgroup comparisons revealed that rs2446405 and rs17268974 were related to ER status, and rs130021 was associated with PR status. Our findings suggest that rs700519 and rs2069522 are associated with susceptibility to breast cancer among the Han Chinese population and have a cumulative effect with three other identified SNPs. Further genetic and functional studies are needed to identify additional SNPs, and to elucidate the underlying molecular mechanisms. PMID- 25689429 TI - Oximes induce erection and are resistant to oxidative stress. AB - INTRODUCTION: Because of their nitric oxide (NO)-donating capacities, oxime derivatives have shown to offer some therapeutic perspective for the treatment of erectile dysfunction (ED) as well as cardiovascular diseases. However, to date the in vivo effect of these oximes on erectile function remains unknown. In many disease states oxidative stress occurs, impairing NO-mediated relaxations. Hence the influence of oxidative stress on oxime-induced effects is also of interest. AIMS: This study aimed to evaluate the in vivo effect of formaldoxime (FAL) and formamidoxime (FAM) on blood pressure and intracavernosal pressure (ICP); and to examine the role of soluble guanylyl cyclase (sGC) and the influence of oxidative stress on the FAL and FAM responses. METHODS: Blood pressure and ICP were monitored in vivo after resp. intravenous or intracavernosal injection of FAL and FAM. Moreover isometric tension was measured in vitro on isolated mice corpora cavernosa (CC), thoracic aorta, and femoral artery in organ baths. The role of sGC was investigated using transgenic mice lacking the alpha 1 subunit of sGC. MAIN OUTCOME MEASURES: Mean arterial pressure (MAP) and ICP were measured after FAL/FAM injection. In vitro relaxation of CC strips was evaluated in response to addition of FAL/FAM. RESULTS: In vivo both FAL and FAM elicit a dose-dependent lowering of blood pressure (maximal DeltaMAP: 33.66 +/- 4.07 mm Hg [FAL] and 20.43 +/- 2.06 mm Hg [FAM] ) as well as an increase of ICP (maximal increase of ICP/MAP: 70.29 +/- 2.88% [FAL] and 52.91 +/- 8.61% [FAM] ). The FAL/FAM effect is significantly lower in knockout vs. wild-type mice. Oxidative stress has an inhibitory effect on corporal NO-mediated relaxations induced by electrical field stimulation, acetylcholine, and sodium nitroprusside whereas the responses to 8 (4-chlorophenylthio)-guanosine 3',5'-cyclic monophosphate sodium salt, FAL and FAM were not influenced. CONCLUSIONS: Oximes induce erection which is mediated by sGC. The oxime-induced relaxations are resistant to oxidative stress, which increases their therapeutic potential for the treatment of ED. PMID- 25689430 TI - Acredinones A and B, voltage-dependent potassium channel inhibitors from the sponge-derived fungus Acremonium sp. F9A015. AB - Two new benzophenones, acredinones A (1) and B (2), were isolated from a marine sponge-associated Acremonium sp. fungus. Their chemical structures were elucidated on the interpretation of spectroscopic data. The structure of 1 was confirmed by palladium-catalyzed hydrogenation, followed by spectroscopic data analysis. Acredinones A (1) and B (2) inhibited the outward K(+) currents of the insulin secreting cell line INS-1 with IC50 values of 0.59 and 1.0 MUM, respectively. PMID- 25689431 TI - Ambulatory arterial stiffness index is not associated with magnetic resonance imaging markers of cerebral small vessel disease in lacunar stroke patients. AB - Ambulatory arterial stiffness index (AASI) is associated with microvascular damage in other organs, but the association with microvascular brain damage is unknown. The association of AASI with magnetic resonance imaging (MRI) markers of cerebral small vessel disease in 143 patients with lacunar stroke was investigated. We performed 24-hour ambulatory blood pressure monitoring and scored the presence of lacunes, white matter hyperintensities, perivascular spaces, and cerebral microbleeds on brain MRI. In logistic regression analyses, AASI was associated with white matter hyperintensities, but, after adjustment for age and sex, this association lost significance. AASI was not associated with lacunes, microbleeds, or perivascular spaces. Systolic and diastolic 24-hour blood pressure values were associated with lacunes, perivascular spaces, and microbleeds independent of age and sex. Despite its significance and growing interest as a possible prognostic and therapeutic target in (micro)vascular diseases, AASI seems to have no added value over standard 24-hour blood pressure in cerebral small vessel disease. PMID- 25689432 TI - Feeding immunity: skepticism, delicacies and delights. AB - Immunologists studying the relationship between nutrition and immunological function face many challenges. We discuss here some of the historical skepticism with which nutritional research has often been faced and the complexities that need to be overcome in order to provide meaningful mechanistic insights. PMID- 25689433 TI - LincRNA signatures in human lymphocytes. PMID- 25689434 TI - Profiling the diversity of innate lymphoid cells. PMID- 25689435 TI - It takes CK2 to suppress TH2. PMID- 25689436 TI - IL-1 watches the watchmen. PMID- 25689444 TI - Corrigendum: Direct extracellular interaction between the early secreted antigen ESAT-6 of Mycobacterium tuberculosis and TLR2 inhibits TLR signaling in macrophages. PMID- 25689443 TI - Innate immunity in Alzheimer's disease. AB - Alzheimer's disease (AD) is the world's most common dementing illness, affecting over 150 million patients. Classically AD has been viewed as a neurodegenerative disease of the elderly, characterized by the extracellular deposition of misfolded amyloid-beta (Abeta) peptide and the intracellular formation of neurofibrillary tangles. Only recently has neuroinflammation emerged as an important component of AD pathology. Experimental, genetic and epidemiological data now indicate a crucial role for activation of the innate immune system as a disease-promoting factor. The sustained formation and deposition of Abeta aggregates causes chronic activation of the immune system and disturbance of microglial clearance functions. Here we review advances in the molecular understanding of the inflammatory response in AD that point to novel therapeutic approaches for the treatment of this devastating disease. PMID- 25689445 TI - Corrigendum: The RIP1-RIP3 complex initiates mitochondrial fission to fuel NLRP3. PMID- 25689446 TI - Corrigendum: Intestinal immune homeostasis is regulated by the crosstalk between epithelial cells and dendritic cells. PMID- 25689447 TI - Gain high-quality colloidal quantum dots directly from natural minerals. AB - Green and simple synthesis of high-quality colloidal quantum dots (CQDs) is of great importance and highly anticipated yet not fully implemented. Herein, we achieve the direct conversion of natural minerals to highly uniform, crystalline lead sulfide CQDs based on laser irradiation in liquid. The trivial fragmentation of mineral particles by an intense nanosecond laser was found to create a localized high degree of monomer supersaturation in oleic acid, initiating the LaMer growth of uniform CQDs. The photoconductive device made of these CQDs exhibits a competitive temporal response of photocurrent with those highly sensitive photodetectors based on PbS CQDs reported in the literature. Our synthesis strategy paves the way for the most environmentally friendly and convenient mass production of high-quality uniform CQDs. PMID- 25689448 TI - Efficacy and safety of conversion to monotherapy with eslicarbazepine acetate in adults with uncontrolled partial-onset seizures: a randomized historical-control phase III study based in North America. AB - OBJECTIVE: To assess the efficacy and safety of eslicarbazepine acetate (ESL) as monotherapy in North American patients with partial-onset seizures (POS). METHODS: This multicenter, randomized, double-blind "withdrawal to monotherapy" study used historical control data as the comparator. Adults with POS medically uncontrolled by one to two antiepileptic drugs gradually converted to ESL monotherapy. Following an 8-week baseline period, patients were randomized 2:1 to receive ESL 1,600 mg (n = 128) or 1,200 mg QD (n = 65) for 18 weeks. The primary end point was the proportion of patients meeting predefined exit criteria (signifying worsening seizure control). Treatment was considered effective if the 95% upper confidence limit (UCL) for the Kaplan-Meier estimated exit rate was lower than the exit rate threshold calculated from the historical control (65.3%). RESULTS: Kaplan-Meier estimated exit rates were: ESL 1,600 mg, 28.7% (95% CI 21.2-38.1%) and 1,200 mg, 44.4% (32.5-58.3%). The difference between doses was not significant (p = 0.07). For both doses, the 95% UCLs for the exit rate were ? 65.3%; ESL monotherapy was considered superior to the historical control. There was no statistically significant increase in the risk of study exit related to carbamazepine use. Nine (7.6%) and five patients (8.3%) remained seizure-free during the 10-week monotherapy period, while taking ESL 1,600 and 1,200 mg, respectively. The reductions in median standardized seizure frequency (seizures per 28 days) between baseline and the 18-week treatment period were: ESL 1,600 mg, 42% and 1,200 mg, 31%. Treatment-emergent adverse events (TEAEs) occurring in >= 10% of patients were dizziness, headache, fatigue, somnolence, nausea, and nasopharyngitis. The TEAE most frequently leading to discontinuation was hyponatremia (2.1%). SIGNIFICANCE: ESL was efficacious and well tolerated as monotherapy in North American patients, and led to a reduction in seizure frequency. Exit rates for ESL 1,600 and 1,200 mg QD were superior to the historical control; the difference in exit rates between doses was not statistically significant. PMID- 25689449 TI - Abstracts of the Singapore Urological Association Meeting: UROFAIR 2015, 12-14 March, 2015, Singapore. PMID- 25689450 TI - Liquid crystals of self-assembled DNA bottlebrushes. AB - Early theories for bottlebrush polymers have suggested that the so-called main chain stiffening effect caused by the presence of a dense corona of side chains along a central main chain should lead to an increased ratio of effective persistence length (lp,eff) over the effective thickness (Deff) and, hence, ultimately to lyotropic liquid crystalline behavior. More recent theories and simulations suggest that lp,eff ~ Deff, such that no liquid crystalline behavior is induced by bottlebrushes. In this paper we investigate experimentally how lyotropic liquid crystalline behavior of a semiflexible polymer is affected by a dense coating of side chains. We use semiflexible DNA as the main chain. A genetically engineered diblock protein polymer C4K12 is used to physically adsorb long side chains on the DNA. The C4K12 protein polymer consists of a positively charged binding block (12 lysines, K12) and a hydrophilic random coil block of 400 amino acids (C4). From light scattering we find that, at low ionic strength (10 mM Tris-HCl), the thickness of the self-assembled DNA bottlebrushes is on the order of 30 nm and the effective grafting density is 1 side chain per 2.7 nm of DNA main chain. We find these self-assembled DNA bottlebrushes form birefringent lyotropic liquid crystalline phases at DNA concentrations as low as 8 mg/mL, roughly 1 order of magnitude lower than for bare DNA. Using small-angle X-ray scattering (SAXS) we show that, at DNA concentrations of 12 mg/mL, there is a transition to a hexagonal phase. We also show that, while the effective persistence length increases due to the bottlebrush coating, the effective thickness of the bottlebrush increases even more, such that in our case the bottlebrush coating reduces the effective aspect ratio of the DNA. This is in agreement with theoretical estimates that show that, in most cases of practical interest, a bottlebrush coating will lead to a decrease of the effective aspect ratio, whereas, only for bottlebrushes with extremely long side chains at very high grafting densities, a bottlebrush coating may be expected to lead to an increase of the effective aspect ratio. PMID- 25689451 TI - Long-chain polyunsaturated fatty acids supplementation in preterm infants. AB - PURPOSE OF REVIEW: Extremely low birth weight and very low birth weight infants are born immature and are commonly sick and are, therefore, not able to receive appropriate enteral or sufficient parenteral nutrition to meet the needs for optimal brain, lung and gut growth and development. RECENT FINDINGS: We provide an updated view of essential fatty acid metabolism and discuss the potential protective effect of fatty acids that serve as precursors for eicosanoids and docosanoids. The balance of n-3 or n-6 long-chain polyunsaturated fatty acids (LCPUFAs) supplied may enhance or ameliorate the effects of hypoxia, inflammation, infection, thrombosis and oxidative damage of key organs (lung, brain and retina). In addition, n-3 and n-6 LCPUFAs are necessary for normal structure and function of the central nervous system and sensory organ development. These lipids generate eicosanoids that are mediators of oxidative damage, as well as potential protectors of retina, brain cortex, lung and vascular endothelium. SUMMARY: n-3 and n-6 LCPUFAs may condition in part the long term consequences of preterm birth. Early n-3 and n-6 LCPUFA supply may moderate the impact of hypoxia and oxidative damage, thus affecting the recovery from injury, later organ (brain, retina, lung, gut, liver and skin) growth and neurodevelopmental outcomes. PMID- 25689452 TI - What's new with common, uncommon and rare rashes in childhood. AB - PURPOSE OF REVIEW: Children with rashes account for many of the outpatient visits to a general pediatrician. As such, pediatricians are often the first to identify and treat these rashes. Establishing an approach to common, uncommon and rare pediatric rashes assists in accurate assessment. This review highlights newly identified clinical patterns and disease severity. RECENT FINDINGS: Group A beta hemolytic streptococci (GABHS) have been shown to be an important cause of intertrigo and to cause more widespread disease in some instances. Superficial skin infections with GABHS have been associated with strains secreting exfoliating toxins, whereas deeper infections have been associated with superantigen toxins. Hand-foot-and-mouth disease (HFMD) outbreaks have occurred with more virulent strains, causing more widespread disease that may be confused with eczema herpeticum or varicella. Mycoplasma pneumoniae has been shown to be an important cause of common disorders such as urticaria, and less common disorders such as Stevens-Johnson syndrome and Mycoplasma-associated mucositis. Recurrent toxin-mediated erythema is a recently described entity that must be differentiated from Kawasaki disease. SUMMARY: The number of rashes acquired in childhood is vast, requiring the pediatrician to be able to identify worrisome rashes from those with a more benign course. Key clinical signs may assist in clinical diagnosis and treatment. PMID- 25689453 TI - Donor human milk for very low birth weights: patterns of usage, outcomes, and unanswered questions. AB - PURPOSE OF REVIEW: Donor milk usage in the United States has increased substantially over the past 10 years. Between 2007 and 2011, donor milk use in level 3 and 4 neonatal ICUs increased from 25 to 45%. RECENT FINDINGS: Most centers have written protocols based on birth weight or gestational age, and give donor milk in an effort to prevent necrotizing enterocolitis. The evidence for protection against necrotizing enterocolitis using bovine-fortified donor milk vs. formula is limited, although the exclusive human milk diet seems to offer protection compared to diets containing formula. Adequate growth can be achieved with donor milk fortified with either bovine or human milk-derived fortifiers, but use of additional fortification and protein supplementation may be required. Several randomized trials of donor milk vs. formula are ongoing in the very low birth weight population in North America that can answer important questions. SUMMARY: Further research is needed before donor milk and the exclusive human milk diet are considered the standard of care. PMID- 25689454 TI - Therapeutic hypothermia for neonatal encephalopathy. AB - PURPOSE OF REVIEW: Hypothermia for neonatal encephalopathy is now the standard of care. The purpose of this review is to evaluate recent publications (during the past 18 months) that impact the practice of hypothermia as neuroprotection for neonatal hypoxic-ischemic encephalopathy. RECENT FINDINGS: The review will examine recent publications that influence clinical care, including committee opinion, meta-analysis, and reports of how this practice has evolved in the clinical arena. Biomarkers of acute injury and outcome will be examined. Research involving the future of hypothermia will be noted. SUMMARY: The rate of death or disability following hypothermia therapy has been reduced substantially; the challenge is to evaluate whether mortality or disability can be reduced further following combination therapy. PMID- 25689455 TI - Clinical manifestations of autosomal recessive polycystic kidney disease. AB - PURPOSE OF REVIEW: To describe the recent increase in the understanding of the clinical manifestation of autosomal recessive polycystic kidney disease (ARPKD), which is caused by mutations in the PKHD1 gene. The change in nomenclature reflects the genetic contribution to the understanding of pleiotropic disease manifestations. The term 'hepatorenal fibrocystic disorder' or 'ARPKD-congenital hepatic fibrosis (CHF)' addresses the major organ manifestations of the disease. RECENT FINDINGS: More than 300 different mutations in the PKHD1 gene have been described; however, there is no genotype-phenotype correlation. Cystic phenotype in the kidneys is highly variable. Renal oligohydramnios before 28 weeks of gestation may be lethal, whereas perinatal manifestations have a better prognosis. More than 60% of neonates with pulmonary hypoplasia may survive; about 25% need postnatal dialysis. After 10 years, 60% require renal replacement therapy. Liver fibrosis is always found and cholangiodysplasia is common. The Caroli phenotype is seen in up to 80% with perinatal manifestation. Recurrent cholangitis and cirrhosis may require liver transplantation in about 10% of patients. Neurocognitive development is in the usual range of children with moderate renal failure, but deserves further research. SUMMARY: The pleiotropic manifestations of ARPKD-CHF require multidisciplinary efforts to anticipate organ complications and to improve a possible good prognosis. PMID- 25689456 TI - What is new for patent ductus arteriosus management in premature infants in 2015? AB - PURPOSE OF REVIEW: A patent ductus arteriosus (PDA) in premature infants is common and is associated with a number of adverse outcomes. The purpose of this review is to discuss recent literature in PDA diagnosis and management. RECENT FINDINGS: The diagnosis of a 'hemodynamically significant' PDA is challenging and a robust definition is lacking. The risks and benefits of therapies, either medical or surgical, designed to close the PDA, are controversial. Oral acetaminophen has gained increasing attention as an alternative pharmaceutical agent for PDA closure in premature infants, although safety concerns remain. Compared to surgical ligation, transcatheter PDA closure may be associated with less risk and fewer adverse events. Both aggressive and conservative management of PDA has similar clinically important outcomes, although the strength of evidence is derived mostly from cohort studies. SUMMARY: Clinicians should weigh the potential adverse effects of pharmaceutical or surgical PDA closure against the likelihood of spontaneous closure. The infant population most likely to benefit from PDA closure remains ill-defined and clinical context is recommended. PMID- 25689457 TI - Pulmonary hypertension in chronic lung disease of infancy. AB - PURPOSE OF REVIEW: Advances in neonatal care have improved the survival of extremely preterm infants. Chronic lung disease (CLD) is a common complication of prematurity, seen in about a third of preterm babies. Further, pulmonary hypertension complicates the hospital course in about 18% of preterm infants, and the incidence is much higher in infants with established CLD. There is increasing interest in studying this population and understanding the underlying pathobiology behind the development of pulmonary hypertension, which could lead to better identification of at-risk patients as well as improved management strategies and therapeutic targets. RECENT FINDINGS: Acknowledgement of this growing population of infants with pulmonary hypertension has led to modifications in the current WHO classification of pulmonary hypertension and the establishment of a subcategory for developmental lung disease with pulmonary hypertension. A number of recent publications have evaluated the use of targeted therapies in this population; however, there is a need for large controlled studies, to study the long-term efficacy and safety of these medications. SUMMARY: This review will discuss the pathobiology of CLD with pulmonary hypertension and enumerate the current diagnostic and treatment modalities used by experts in the field. It will also suggest a diagnosis and management algorithm for infants suspected to have pulmonary hypertension in the newborn unit. PMID- 25689458 TI - Therapies for polycystic kidney disease. AB - PURPOSE OF REVIEW: All polycystic diseases of the kidney exhibit tubular or saccular cysts. The cysts can either be open to the tubule or isolated sacs that have lost their connections. Polycystic kidney diseases derived from different genetic mutations share basic mechanisms of cytogenesis, formation, and progressive enlargement, involving a cellular organelle called the primary cilium. Given the mechanistic commonalities, this review will focus on the therapeutic approaches currently available or under development that likely apply to all inherited renal cystic diseases. RECENT FINDINGS: Recent advances in clinical trials and preclinical experiments have illuminated common signaling pathway involvement. SUMMARY: Avoidance of nephrotoxic drugs or radio-contrast and maintaining normal BMI are routine preventive measures. Limiting the intake of calories, salt, and protein, together with increased intake of fruits, vegetables, and water are dietary treatments that should be started early in the course of the disease. Potential pharmacological treatments targeting cyst initiation and progression are on the horizon. PMID- 25689459 TI - Sustained inflation during neonatal resuscitation. AB - PURPOSE OF REVIEW: Sustained inflation performed shortly after birth to help clear lung fluid and establish functional residual capacity in preterm infants is gaining popularity, but definitive evidence for its effectiveness is lacking. Although there is a sound physiologic basis for this approach, and much preclinical experimental evidence of effectiveness, the results of recent animal studies and clinical trials have been inconsistent. RECENT FINDINGS: The most recent data from a multicenter randomized trial suggest a modest benefit of sustained inflation in reducing the need for mechanical ventilation in extremely low-birth-weight infants. However, the impact may be more modest than earlier retrospective cohort comparisons suggested. The trend toward more airleak and a higher rate of intraventricular hemorrhage is worrisome. Sustained inflation may be ineffective unless some spontaneous respiratory effort is present. Several on going trials should further clarify the putative benefits of sustained inflation. SUMMARY: Delivery room sustained inflation is an attractive concept that holds much promise, but widespread clinical application should await definitive evidence from on-going clinical trials. PMID- 25689460 TI - Complaints, complainants, and rulings regarding drug promotion in the United Kingdom and Sweden 2004-2012: a quantitative and qualitative study of pharmaceutical industry self-regulation. AB - BACKGROUND: In many European countries, medicines promotion is governed by voluntary codes of practice administered by the pharmaceutical industry under its own system of self-regulation. Involvement of industry organizations in policing promotion has been proposed to deter illicit conduct, but few detailed studies on self-regulation have been carried out to date. The objective of this study was to examine the evidence for promotion and self-regulation in the UK and Sweden, two countries frequently cited as examples of effective self-regulation. METHODS AND FINDINGS: We performed a qualitative content analysis of documents outlining the constitutions and procedures of these two systems. We also gathered data from self-regulatory bodies on complaints, complainants, and rulings for the period 2004-2012. The qualitative analysis revealed similarities and differences between the countries. For example, self-regulatory bodies in both countries are required to actively monitor promotional items and impose sanctions on violating companies, but the range of sanctions is greater in the UK where companies may, for instance, be audited or publicly reprimanded. In total, Swedish and UK bodies ruled that 536 and 597 cases, respectively, were in breach, equating to an average of more than one case/week for each country. In Sweden, 430 (47%) complaints resulted from active monitoring, compared with only two complaints (0.2%) in the UK. In both countries, a majority of violations concerned misleading promotion. Charges incurred on companies averaged ?447,000 and ?765,000 per year in Sweden and the UK, respectively, equivalent to about 0.014% and 0.0051% of annual sales revenues, respectively. One hundred cases in the UK (17% of total cases in breach) and 101 (19%) in Sweden were highlighted as particularly serious. A total of 46 companies were ruled in breach of code for a serious offence at least once in the two countries combined (n = 36 in the UK; n = 27 in Sweden); seven companies were in serious violation more than ten times each. A qualitative content analysis of serious violations pertaining to diabetes drugs (UK, n = 15; Sweden, n = 6; 10% of serious violations) and urologics (UK, n = 6; Sweden, n = 13; 9%) revealed various types of violations: misleading claims (n = 23; 58%); failure to comply with undertakings (n = 9; 23%); pre-licensing (n = 7; 18%) or off-label promotion (n = 2; 5%); and promotion of prescription drugs to the public (n = 6; 15%). Violations that go undetected or unpunished by self regulatory bodies are the main limitation of this study, since they are likely to lead to an underestimate of industry misconduct. CONCLUSIONS: The prevalence and severity of breaches testifies to a discrepancy between the ethical standard codified in industry Codes of Conduct and the actual conduct of the industry. We discuss regulatory reforms that may improve the quality of medicines information, such as pre-vetting and intensified active monitoring of promotion, along with larger fines, and giving greater publicity to rulings. But despite the importance of improving regulatory arrangements in an attempt to ensure unbiased medicines information, such efforts alone are insufficient because simply improving oversight and increasing penalties fail to address additional layers of industry bias. PMID- 25689461 TI - Characterising the exchangeability of phenanthrene associated with naturally occurring soil colloids using an isotopic dilution technique. AB - The association of polycyclic aromatic hydrocarbons (PAHs) with inorganic and organic colloids is an important factor influencing their bioavailability, mobility and degradation in the environment. Despite this, our understanding of the exchangeability and potential bioavailability of PAHs associated with colloids is limited. The objective of this study was to use phenanthrene as a model PAH compound and develop a technique using (14)C phenanthrene to quantify the isotopically exchangeable and non-exchangeable forms of phenanthrene in filtered soil water or sodium tetraborate extracts. The study was also designed to investigate the exchangeability of colloidal phenanthrene as a function of particle size. Our findings suggest that the exchangeability of phenanthrene in sodium tetraborate is controlled by both inorganic and organic colloids, while in aqueous solutions inorganic colloids play the dominant role (even though coating of these by organic matter cannot be excluded). Filter pore size did not have a significant effect on phenanthrene exchangeability. PMID- 25689462 TI - The acetate/ACSS2 switch regulates HIF-2 stress signaling in the tumor cell microenvironment. AB - Optimal stress signaling by Hypoxia Inducible Factor 2 (HIF-2) during low oxygen states or hypoxia requires coupled actions of a specific coactivator/lysine acetyltransferase, Creb binding protein (CBP), and a specific deacetylase, Sirtuin 1 (SIRT1). We recently reported that acetylation of HIF-2 by CBP also requires a specific acetyl CoA generator, acetate-dependent acetyl CoA synthetase 2 (ACSS2). In this study, we demonstrate that ACSS2/HIF-2 signaling is active not only during hypoxia, but also during glucose deprivation. Acetate levels increase during stress and coincide with maximal HIF-2alpha acetylation and CBP/HIF-2alpha complex formation. Exogenous acetate induces HIF-2alpha acetylation, CBP/HIF 2alpha complex formation, and HIF-2 signaling. ACSS2 and HIF-2 are required for maximal colony formation, proliferation, migration, and invasion during stress. Acetate also stimulates flank tumor growth and metastasis in mice in an ACSS2 and HIF-2 dependent manner. Thus, ACSS2/CBP/SIRT1/HIF-2 signaling links nutrient sensing and stress signaling with cancer growth and progression in mammals. PMID- 25689463 TI - Biofunctionalizing devitalized bone allografts through polymer-mediated short and long term growth factor delivery. AB - According to 5- and 10-year clinical follow-up studies large-scale bone allografts have a high failure rate, largely due to poor allograft incorporation with adjacent bone and subsequent poor remodeling. The goal of this study was to develop a methodology to deliver growth factors from large-scale bone allografts in a temporally controlled manner. Intact long bone allografts were coated with a micron-scale thick layer of degradable polymer that maintained inherent pore structures and acted as a delivery vehicle for bone morphogenetic protein-2 and vascular endothelial growth factor. VEGF was loaded onto the surface of the polymer to produce rapid release, to encourage initial vascularization at the defect site, while BMP-2 was encapsulated within the polymer layer to promote a more sustained release, to encourage bone formation over time. Release kinetics from factor-loaded polymer-coated allografts show an early burst release of VEGF over the first 7 days followed by a more sustained release of BMP-2 over the second and third week. In vitro cell studies using human mesenchymal stem cells confirm the bioactivity of the released BMP-2. In-vivo results show robust bone formation over the first 8 weeks of healing in femoral segmental defects in rats implanted with BMP-2 loaded polymer-coated allografts. A microscale thin coating of degradable polymer on a large-scale bone allograft provides temporal control over the delivery of growth factor loaded onto one allograft, while maintaining its microscale pore structure. Enhancing the incorporation and subsequent remodeling of allografts would reduce the incidence of allograft failure over time, and potentially speed healing at the earliest stages after implantation. PMID- 25689464 TI - Antagonistic mechanism of iturin A and plipastatin A from Bacillus amyloliquefaciens S76-3 from wheat spikes against Fusarium graminearum. AB - Controlling toxigenic Fusarium graminearum (FG) is challenging. A bacterial strain (S76-3, identified as Bacillus amyloliquefaciens) that was isolated from diseased wheat spikes in the field displayed strong antifungal activity against FG. Reverse-phase high performance liquid chromatography and electrospray ionization mass spectrometry analyses revealed that S76-3 produced three classes of cyclic lipopeptides including iturin, plipastatin and surfactin. Each class consisted of several different molecules. The iturin and plipastatin fractions strongly inhibited FG; the surfactin fractions did not. The most abundant compound that had antagonistic activity from the iturin fraction was iturin A (m/z 1043.35); the most abundant active compound from the plipastatin fraction was plipastatin A (m/z 1463.90). These compounds were analyzed with collision induced dissociation mass spectrometry. The two purified compounds displayed strong fungicidal activity, completely killing conidial spores at the minimal inhibitory concentration range of 50 ug/ml (iturin A) and 100 ug/ml (plipastatin A). Optical and fluorescence microscopy analyses revealed severe morphological changes in conidia and substantial distortions in FG hyphae treated with iturin A or plipastatin A. Iturin A caused leakage and/or inactivation of FG cellular contents and plipastatin A caused vacuolation. Time-lapse imaging of dynamic antagonistic processes illustrated that iturin A caused distortion and conglobation along hyphae and inhibited branch formation and growth, while plipastatin A caused conglobation in young hyphae and branch tips. Transmission electron microscopy analyses demonstrated that the cell walls of conidia and hyphae of iturin A and plipastatin A treated FG had large gaps and that their plasma membranes were severely damaged and separated from cell walls. PMID- 25689465 TI - Positional impact of fluorescently modified G-tetrads within polymorphic human telomeric G-quadruplex structures. AB - Emissive C8-aryl-2'-deoxyguanosines placed within G-tetrads of G-quadruplex structures are useful probes for distinguishing G-quadruplexes from duplex structures using fluorescence spectroscopy. Here, we report the positional impact of C8-furyl-dG ((Fur)dG) on G-quadruplex folding in the human telomere 22-mer oligonucleotide (HTelo22, (d[AG3(T2AG3)3])). The (Fur)dG probe was inserted into four different positions within the three unique G-tetrads of HTelo22, and G quadruplex folding was monitored by UV-vis thermal denaturation, circular dichroism, and fluorescence spectroscopy. Our studies demonstrate the impacts of C8-aryl-dG adduct formation on G-quadruplex polymorphism in K(+) solution and in the presence of the additives and cosolutes, CH3CN, polyethylene glycol (PEG 600), and N-methyl mesoporphyrin IX (NMM). Our experiments predict that C8-aryl dG derivatives can serve as useful tools for various in vitro studies aimed at understanding both the implications of DNA adduct formation within G-quadruplex structures and the unique implications imposed by various folding topologies on biological function/recognition. PMID- 25689466 TI - Glutamine enema regulates colonic ubiquitinated proteins but not proteasome activities during TNBS-induced colitis leading to increased mitochondrial activity. AB - Ubiquitin proteasome system contributes to the regulation of intestinal inflammatory response as its inhibition is associated with tissue damage improvement. We aimed to evaluate whether glutamine is able to limit inflammation by targeting ubiquitin proteasome system in experimental colitis. Colitis was induced in male rats by intrarectal instillation of 2-4-6-trinitrobenzen sulfonic acid (TNBS) at day 1. From day 2 to day 6, rats daily received either an intrarectal instillation of PBS (TNBS/PBS group) or glutamine (TNBS/Gln). Rats were euthanized at day 7 and colonic samples were taken to evaluate ubiqutinated proteins by proteomic approach combining 2D electrophoresis and immunoblots directed against ubiquitin. Results were then confirmed by evaluating total expression of proteins and mRNA levels. Survival rate, TNFalpha, and IL-1beta mRNA were improved in TNBS/Gln compared with TNBS/PBS (p < 0.05). Proteasome activities were affected by TNBS but not by glutamine. We identified eight proteins that were less ubiquitinated in TNBS/PBS compared with controls with no effect of glutamine. Four proteins were more ubiquitinated in TNBS/PBS group and restored in TNBS/Gln group. Finally, 12 ubiquitinated proteins were only affected by glutamine. Among proteins affected by glutamine, eight proteins (GFPT1, Gapdh, Pkm2, LDH, Bcat2, ATP5a1, Vdac1, and Vdac2) were involved in metabolic pathways. In conclusion, glutamine may regulate ubiquitination process during intestinal inflammation. PMID- 25689467 TI - Serum beta-2 microglobulin as a prognostic biomarker in patients with mantle cell lymphoma. AB - Although serum beta-2 microglobulin (B2M) has been suggested as a prognostic factor for mantle cell lymphoma (MCL), additional data are necessary to confirm its role. Between November 2005 and July 2014, a total of 52 patients with MCL were identified from the database of Asan Medical Center, Seoul, Korea. Pretreatment serum B2M information was available in 50 patients (96%). Overall survival (OS) was compared according to the serum B2M level with a cut-off value of 2.5 mg/L. The median MCL international prognostic index (MIPI) score was 5.84 (range 4.72-7.80), and the median biologic MIPI (MIPI-b) score was 6.27 (4.93 8.47). Pretreatment serum B2M was elevated in 30 patients (60%) and was significantly related to advanced stage (p = 0.02) and high MIPI (p = 0.03) and MIPI-b (p = 0.03) scores. With median follow-up duration of 29.8 months (range 0.8-87.0 months), the median OS was 56.2 months [95% confidence interval (CI) 36.6-75.9 months] in all patients, and serum B2M was significantly associated with OS (p = 0.001). In multivariate analyses adjusted for MIPI or MIPI-b scores and rituximab, elevated serum B2M was significantly associated with poor OS (when adjusting MIPI, hazard ratio = 26.4, 95% CI 2.9-241.3, p = 0.004; when adjusting MIPI-b, hazard ratio = 20.1, 95% CI 2.4-170.1, p = 0.006). Thus, pretreatment serum B2M may be an independent and significant prognostic factor in patients with MCL. PMID- 25689468 TI - Benford's Law: textbook exercises and multiple-choice testbanks. AB - Benford's Law describes the finding that the distribution of leading (or leftmost) digits of innumerable datasets follows a well-defined logarithmic trend, rather than an intuitive uniformity. In practice this means that the most common leading digit is 1, with an expected frequency of 30.1%, and the least common is 9, with an expected frequency of 4.6%. Currently, the most common application of Benford's Law is in detecting number invention and tampering such as found in accounting-, tax-, and voter-fraud. We demonstrate that answers to end-of-chapter exercises in physics and chemistry textbooks conform to Benford's Law. Subsequently, we investigate whether this fact can be used to gain advantage over random guessing in multiple-choice tests, and find that while testbank answers in introductory physics closely conform to Benford's Law, the testbank is nonetheless secure against such a Benford's attack for banal reasons. PMID- 25689469 TI - Burden and correlates of HIV risk among men who have sex with men in Nagaland, India: analysis of sentinel surveillance data. AB - BACKGROUND: Dynamics of HIV epidemic are largely understudied among men having sex with men (MSM) in India, while their potentially critical role in HIV spread is often stressed. Unfortunately, the epidemic has probably concentrated in this hard-to-reach population in the north-eastern high HIV-prevalent areas, especially in the bordering state of Nagaland, where HIV prevalence among MSM was found to be 2nd highest in the whole country. Dearth of information regarding the socio-behavioral correlates of HIV acquisition among MSM in this remote hilly region thus called for detailed analyses of the HIV Sentinel Surveillance (HSS) data. METHODS: During the first ever conducted HSS among MSM in Nagaland, between March and May, 2011, as per the operational guideline of Indian National AIDS Control Program, 243 MSM were recruited, interviewed and tested for HIV. Anonymous data on socio-demographics, sexual behavior and laboratory results were analyzed using SAS version-9.2 to conduct descriptive and logistic regression analyses. RESULTS: Among the recruited MSM, mean age was 28.30 years, 46.09% were illiterate, 27.16% were unemployed, 57.02% identified them as Kothi (predominantly receptive anal sex partner), 14.81% were bisexual, 19.75% exchanged money for sex (within last 1 year) with men and 13.58% were HIV sero positive. Increasing age (for 25-34yrs, adjusted odds ratio: AOR = 3.89, p = 0.046; reference = <25yrs), middle school (AOR = 3.44, p = 0.046) or higher (AOR = 4.47, p = 0.034) education (reference = illiterate), being Kothi [AOR = 3.60, p = 0.026; reference = double-decker: (involved in both insertive and receptive roles)] and having paid and received money for sex with a man (AOR = 7.32, p = 0.026; reference = didn't exchange money) were strongly associated with higher risk of HIV in both bivariate and multivariate analyses. CONCLUSION: HIV burden was found to be alarmingly high among MSM in Nagaland. Targeted interventions for high-risk MSM, especially those who were older, educated, self-identified as kothis and involved in paid sex, seemed to be the need of the hour. PMID- 25689470 TI - Targeting cyclin D3/CDK6 activity for treatment of Parkinson's disease. AB - At present, treatment for Parkinson's disease (PD) is only symptomatic; therefore, it is important to identify new targets tackling the molecular causes of the disease. We previously found that lymphoblasts from sporadic PD patients display increased activity of the cyclin D3/CDK6/pRb pathway and higher proliferation than control cells. These features were considered systemic manifestations of the disease, as aberrant activation of the cell cycle is involved in neuronal apoptosis. The main goal of this work was to elucidate whether the inhibition of cyclin D3/CDK6-associated kinase activity could be useful in PD treatment. For this purpose, we investigated the effects of two histone deacetylase (HDAC) inhibitors, suberoylanilide hydroxamic (SAHA) acid and sodium butyrate (NaB), and the m-TOR inhibitor rapamycin on cell viability and cyclin D3/CDK6 activity. Moreover, the potential neuroprotective action of these drugs was evaluated in 6-hydroxy-dopamine (6-OHDA) treated dopaminergic SH-SY5Y cells and primary rat mesencephalic cultures. Here, we report that both compounds normalized the proliferative activity of PD lymphoblasts and reduced the 6-OHDA induced cell death in neuronal cells by preventing the over-activation of the cyclin D3/CDK6/pRb cascade. Considering that these drugs are already used in clinic for treatment of other diseases with good tolerance, it is plausible that they may serve as novel therapeutic drugs for PD. We report here that peripheral cells from Parkinson's disease (PD) patients show an enhanced proliferative activity due to the activation of cyclin D3/CDK6-mediated phosphorylation of retinoblastoma protein (pRb). Treatment of PD lymphoblasts with inhibitors of histone deacetylases like suberoylanilide hydroxamic acid (SAHA) and sodium butyrate (NaB), or with rapamycin, inhibitor of mechanistic target of rapamycin (mTOR) normalized the proliferation of PD lymphoblasts by preventing the over activation of the cyclin D3/CDK6/pRb cascade. These drugs were shown to have neuroprotective effects in both human neuroblastoma SH-SY5Y cells and primary rat mid-brain dopaminergic neuronal cultures toxicity induced by 6-hidroxydopamine. Considering that these drugs are already used in clinic for treatment of other diseases with good tolerance, it seems reasonable to believe that the repositioning of these drugs toward PD holds promise as a novel therapeutic strategy. PMID- 25689471 TI - Idarubicin, cytarabine, and pravastatin as induction therapy for untreated acute myeloid leukemia and high-risk myelodysplastic syndrome. AB - Previous studies suggest that idarubicin/cytarabine(ara-C)/pravastatin (IAP) is an active salvage regimen for patients with AML. We therefore investigated this regimen in patients with newly-diagnosed AML or MDS (>=10% blasts). Patients were eligible if the anticipated treatment-related mortality (TRM) was <10%. Patients received pravastatin (1,280 mg/day po; days 1-8), cytarabine (1.5 g/m(2) /day; days 4-7), and idarubicin (12 mg/m(2) /day, days 4-6). Up to 3 cycles of consolidation with a shortened course was permitted. The primary endpoints were "good CR" rate (CR on day 35 without minimal residual disease) and TRM in the first 28 days. The study was to stop if after each cohort of 5 patients (a) the Bayesian posterior probability was < 5% that the true "good CR rate" was >= 70% or (b) the posterior probability was >25% that the TRM rate was >=5%. Twenty-four patients were included. Conventional CR was achieved in 15 (63%) patients but only 12 (50%) achieved "good CR". 4 of 12 (33%) patients with "good CR" relapsed at median of 16 weeks (10.5-19). Five (21%) patients had refractory disease. Survival probability at 1 year was 72% (48.7-64). Two (8.3%) patients died within 28 days from multiorgan failure. The most common grade 3-4 adverse effects were febrile neutropenia (75%) and diarrhea (25%). Based on the stopping rules accrual ceased after entry of these 24 patients. IAP did not meet the predefined efficacy criteria for success. Therefore, we would not recommend this regimen for phase three testing in this patient subset. PMID- 25689472 TI - Enantioselective synthesis of allenylenol silyl ethers via chiral lithium amide mediated reduction of ynenoyl silanes and their Diels-Alder reactions. AB - An enantioselective Meerwein-Ponndorf-Verley-type reduction of ynenoylsilanes by a chiral lithium amide followed by a Brook rearrangement and anti-mode protonation across conjugated 1,3-enynes provides allene derivatives bearing a 2 siloxyvinyl moiety in high enantioselectivity. The E/Z geometry of enol silyl ethers is controlled by the geometry of the starting enyne moiety. Thus, (E)- and (Z)-enol silyl ethers are obtained from (Z)- and (E)-ynenoylsilans, respectively. The 2-siloxyvinylallene products can participate in Diels-Alder reactions with reactive dienophiles such as PTAD, which can be achieved in a one-pot operation from ynenoylsilanes. PMID- 25689473 TI - Natural variation in flavonol and anthocyanin metabolism during cold acclimation in Arabidopsis thaliana accessions. AB - In plants from temperate climates such as Arabidopsis thaliana, low, non-freezing temperatures lead to increased freezing tolerance in a process termed cold acclimation. During cold acclimation, massive changes in gene expression and in the content of primary metabolites and lipids have been observed. Here, we have analysed the influence of cold acclimation on flavonol and anthocyanin content and on the expression of genes related to flavonoid metabolism in 54 Arabidopsis accessions covering a wide range of freezing tolerance. Most flavonols and anthocyanins accumulated upon cold exposure, but the extent of accumulation varied strongly among the accessions. This was also true for most of the investigated transcripts. Correlation analyses revealed a high degree of coordination among metabolites and among transcripts, but only little correlation between metabolites and transcripts, indicating an important role of post transcriptional regulation in flavonoid metabolism. Similarly, levels of many flavonoid biosynthesis genes were correlated with freezing tolerance after cold acclimation, but only the pool sizes of a few flavonols and anthocyanins. Collectively, our data provide evidence for an important role of flavonoid metabolism in Arabidopsis freezing tolerance and point to the importance of post transcriptional mechanisms in the regulation of flavonoid metabolism in response to cold. PMID- 25689476 TI - 50 years ago ... PMID- 25689480 TI - Sex and ethnic-origin specific BMI cut points improve prediction of 40-year mortality: the Israel GOH study. AB - BACKGROUND: Although obesity has been associated with a higher risk for premature death, the sex and ethnic-origin specific body mass index (BMI) levels that are associated with increased mortality are controversial. We investigated the 40 year cumulative all-cause mortality, in relation to the BMI in adult life, among men and women originating from Yemen, Europe/America, Middle East and North Africa, using sex and ethnic-origin specific BMI cut points. METHODS: A random stratified cohort (n = 5710) was sampled from the central population registry and followed since 1969 for vital status. Weight, height and blood pressure were measured, and smoking status was recorded at baseline. BMI was analysed according to conventional categories and according to sex and ethnic-origin specific quintiles. RESULTS: Elevated and significant mortality hazard ratios (HRs) of 1.21 [95% confidence interval (CI) 1.00-1.45] for women and 1.22 (95%CI 1.03 1.44) for men were found for the highest origin-specific BMI quintile. In men, the lowest ethnic-origin specific quintile was also significantly associated with increased mortality (HR of 1.22 95% CI 1.03-1.45), adjusting for age, smoking and blood pressure. Obesity was associated with mortality in non-smokers (HR = 1.29, 95% CI 1.04-1.61 in men and HR = 1.46, 95% CI 1.19-1.79 in women), whereas leanness was associated with mortality only among smoking men (HR = 1.39, 95% CI 1.09-1.77). CONCLUSION: Refinement of BMI categories using country of origin specific quintiles demonstrated significantly increased mortality in the upper quintile in both sexes, while according to the conventional values this association did not prevail in men. We propose the establishment of sex and origin-specific BMI categories when setting goals for disease prevention. PMID- 25689481 TI - Targeting and function of proteins mediating translation initiation in organelles of Plasmodium falciparum. AB - The malaria parasite Plasmodium falciparum has two translationally active organelles - the apicoplast and mitochondrion, which import nuclear-encoded translation factors to mediate protein synthesis. Initiation of translation is a complex step wherein initiation factors (IFs) act in a regulated manner to form an initiation complex. We identified putative organellar IFs and investigated the targeting, structure and function of IF1, IF2 and IF3 homologues encoded by the parasite nuclear genome. A single PfIF1 is targeted to the apicoplast. Apart from its critical ribosomal interactions, PfIF1 also exhibited nucleic-acid binding and melting activities and mediated transcription anti-termination. This suggests a prominent ancillary function for PfIF1 in destabilisation of DNA and RNA hairpin loops encountered during transcription and translation of the A+T rich apicoplast genome. Of the three putative IF2 homologues, only one (PfIF2a) was an organellar protein with mitochondrial localisation. We additionally identified an IF3 (PfIF3a) that localised exclusively to the mitochondrion and another protein, PfIF3b, that was apicoplast targeted. PfIF3a exhibited ribosome anti-association activity, and monosome splitting by PfIF3a was enhanced by ribosome recycling factor (PfRRF2) and PfEF-G(Mit). These results fill a gap in our understanding of organellar translation in Plasmodium, which is the site of action of several anti malarial compounds. PMID- 25689482 TI - Machine learning approaches for integrating clinical and imaging features in late life depression classification and response prediction. AB - OBJECTIVE: Currently, depression diagnosis relies primarily on behavioral symptoms and signs, and treatment is guided by trial and error instead of evaluating associated underlying brain characteristics. Unlike past studies, we attempted to estimate accurate prediction models for late-life depression diagnosis and treatment response using multiple machine learning methods with inputs of multi-modal imaging and non-imaging whole brain and network-based features. METHODS: Late-life depression patients (medicated post-recruitment) (n = 33) and older non-depressed individuals (n = 35) were recruited. Their demographics and cognitive ability scores were recorded, and brain characteristics were acquired using multi-modal magnetic resonance imaging pretreatment. Linear and nonlinear learning methods were tested for estimating accurate prediction models. RESULTS: A learning method called alternating decision trees estimated the most accurate prediction models for late-life depression diagnosis (87.27% accuracy) and treatment response (89.47% accuracy). The diagnosis model included measures of age, Mini-mental state examination score, and structural imaging (e.g. whole brain atrophy and global white mater hyperintensity burden). The treatment response model included measures of structural and functional connectivity. CONCLUSIONS: Combinations of multi-modal imaging and/or non-imaging measures may help better predict late-life depression diagnosis and treatment response. As a preliminary observation, we speculate that the results may also suggest that different underlying brain characteristics defined by multi-modal imaging measures-rather than region-based differences-are associated with depression versus depression recovery because to our knowledge this is the first depression study to accurately predict both using the same approach. These findings may help better understand late-life depression and identify preliminary steps toward personalized late-life depression treatment. PMID- 25689483 TI - The c-MYC-ABCB5 axis plays a pivotal role in 5-fluorouracil resistance in human colon cancer cells. AB - c-MYC overexpression is frequently observed in various cancers including colon cancer and regulates many biological activities such as aberrant cell proliferation, apoptosis, genomic instability, immortalization and drug resistance. However, the mechanism by which c-MYC confers drug resistance remains to be fully elucidated. In this study, we found that the c-MYC expression level in primary colorectal cancer tissues correlated with the recurrence rate following 5-fluorouracil (5-FU)-based adjuvant chemotherapy. Supporting this finding, overexpression of exogenous c-MYC increased the survival rate following 5-FU treatment in human colon cancer cells, and knockdown of endogenous c-MYC decreased it. Furthermore, c-MYC knockdown decreased the expression level of ABCB5, which is involved in 5-FU resistance. Using a chromatin immunoprecipitation assay, we found that c-MYC bound to the ABCB5 promoter region. c-MYC inhibitor (10058-F4) treatment inhibited c-MYC binding to the ABCB5 promoter, leading to a decrease in ABCB5 expression level. ABCB5 knockdown decreased the survival rate following 5-FU treatment as expected, and the ABCB5 expression level was increased in 5-FU-resistant human colon cancer cells. Finally, using a human colon cancer xenograft murine model, we found that the combined 5-FU and 10058-F4 treatment significantly decreased tumorigenicity in nude mice compared with 5-FU or 10058-F4 treatment alone. 10058-F4 treatment decreased the ABCB5 expression level in the presence or absence of 5-FU. In contrast, 5-FU treatment alone increased the ABCB5 expression level. Taken together, these results suggest that c-MYC confers resistance to 5-FU through regulating ABCB5 expression in human colon cancer cells. PMID- 25689484 TI - Covalency in lanthanides. An X-ray absorption spectroscopy and density functional theory study of LnCl6(x-) (x = 3, 2). AB - Covalency in Ln-Cl bonds of Oh-LnCl6(x-) (x = 3 for Ln = Ce(III), Nd(III), Sm(III), Eu(III), Gd(III); x = 2 for Ln = Ce(IV)) anions has been investigated, primarily using Cl K-edge X-ray absorption spectroscopy (XAS) and time-dependent density functional theory (TDDFT); however, Ce L3,2-edge and M5,4-edge XAS were also used to characterize CeCl6(x-) (x = 2, 3). The M5,4-edge XAS spectra were modeled using configuration interaction calculations. The results were evaluated as a function of (1) the lanthanide (Ln) metal identity, which was varied across the series from Ce to Gd, and (2) the Ln oxidation state (when practical, i.e., formally Ce(III) and Ce(IV)). Pronounced mixing between the Cl 3p- and Ln 5d orbitals (t2g* and eg*) was observed. Experimental results indicated that Ln 5d orbital mixing decreased when moving across the lanthanide series. In contrast, oxidizing Ce(III) to Ce(IV) had little effect on Cl 3p and Ce 5d-orbital mixing. For LnCl6(3-) (formally Ln(III)), the 4f-orbitals participated only marginally in covalent bonding, which was consistent with historical descriptions. Surprisingly, there was a marked increase in Cl 3p- and Ce(IV) 4f-orbital mixing (t1u* + t2u*) in CeCl6(2-). This unexpected 4f- and 5d-orbital participation in covalent bonding is presented in the context of recent studies on both tetravalent transition metal and actinide hexahalides, MCl6(2-) (M = Ti, Zr, Hf, U). PMID- 25689485 TI - The expression of nitrate transporter genes reveals different nitrogen statuses of dominant diatom groups in the southern East China Sea. AB - In this study, the mRNA levels of the Nrt2 nitrate transporter gene were used as a molecular indicator of nitrogen status in two dominant diatom groups, Skeletonema and Chaetoceros, which inhabit the southern East China Sea (ECS). To accurately interpret the abundance of Nrt2 transcripts in situ, maximum and minimum expression levels were determined under conditions of nitrogen deprivation and ammonium addition, respectively. In August 2010, Nrt2 transcript levels in Skeletonema at the inner shelf region exhibited a mean of 111 mmole/(mole EFL); at the mid-shelf region, the mean Nrt2 mRNA levels were 298 mmole/(mole EFL), which was very close to the maximum levels observed under nitrogen starvation. By contrast, the Nrt2 transcript levels in Chaetoceros were low at all of the shelf locations, except at one station in the mid-shelf region. The cross-shelf mean was 2.86 mmole/(mole EFL), which was similar to the expression levels observed in cultured Chaetoceros under conditions of sufficient ammonium. Similar expression patterns were observed in diatoms in the southern ECS in June 2011, but the Nrt2 transcript levels in Skeletonema at the inner shelf region were reduced to a mean of 28.6 mmole/(mole EFL). Regression analysis indicated that cell abundance and Nrt2 expression were closely related to the nutricline depth in the coastward half of the southern ECS for Skeletonema but not for Chaetoceros. These results indicate that the evaluated species differ in nitrogen status, which may reflect their evolutionary strategies to survive in a fluctuating marine environment. PMID- 25689486 TI - Dipolar rotors orderly aligned in mesoporous fluorinated organosilica architectures. AB - New mesoporous covalent frameworks, based on hybrid fluorinated organosilicas, were prepared to realize a periodic architecture of fast molecular rotors containing dynamic dipoles in their structure. The mobile elements, designed on the basis of fluorinated p-divinylbenzene moieties, were integrated into the robust covalent structure through siloxane bonds, and showed not only the rapid dynamics of the aromatic rings (ca. 10(8) Hz at 325 K), as detected by solid state NMR spectroscopy, but also a dielectric response typical of a fast dipole reorientation under the stimuli of an applied electric field. Furthermore, the mesochannels are open and accessible to diffusing in gas molecules, and rotor mobility could be individually regulated by I2 vapors. The iodine enters the channels of the periodic structure and reacts with the pivotal double bonds of the divinyl-fluoro-phenylene rotors, affecting their motion and the dielectric properties. PMID- 25689487 TI - High incidence of the hepatitis C virus recombinant 2k/1b in Georgia: Recommendations for testing and treatment. AB - AIM: The first hepatitis C virus (HCV) recombinant, RF2k/1b, was initially described from Russia and has since then been identified from patients in Ireland, Estonia, Uzbekistan and Cyprus. Many of these patients originated from Georgia; however, there is no information on its prevalence in Georgia or its susceptibility to antiviral treatment. METHODS: We retrospectively sequenced the non-structural region 5B (NS5B) of the HCV genome in samples from 72 Georgian patients, 36 of whom had been treated with pegylated interferon and ribavirin. RESULTS: The HCV genotype was determined using the Versant HCV Genotype v2 kit. Based on this typing, 32 patients (44.4%) were infected with genotype 1, 21 (29.1%) genotype 2 and 19 (26.3%) genotype 3. Partial NS5B of these strains was sequenced and analyzed for type, with concordant genotype results for all type 1 and 3 strains. Discrepant results were observed for genotyped 2 strains, with 16 (76%) having NS5B of subtype 1b. On phylogenetic analysis, 15 NS5B sequences of these strains were found in a clade formed by recombinant RF2k/1b strains. The remaining discordant sequence was found within a clade formed by 1b strains. CONCLUSION: Our findings show that the RF2k/1b recombinant strain is common among Georgian patients previously assumed to be infected with genotype 2. Because genotyping is mainly performed to decide treatment strategies, there is a need to determine the genotype by analysis of at least two genomic regions in strains from Georgian patients considered infected with genotype 2 based on standard HCV genotyping methods. PMID- 25689488 TI - Dynamics of Gold Nanoparticles on Carbon Nanostructures Driven by van der Waals and Electrostatic Interactions. AB - Transmission electron microscopy studies on the assembly and growth of gold nanoparticles on carbon nanotubes supported on few-layer graphene and amorphous carbon reveal a competition between van der Waals forces and electrostatic interactions, enabling controlled positioning and sizing of adsorbed nanoparticles at the nanochannels formed between the carbon nanotube and the few layer graph-ene surface. PMID- 25689489 TI - Decarbonylative C-C bond-forming reactions of saccharins by nickel catalysis: homocoupling and cycloaddition. AB - Decarbonylation of saccharins by nickel catalysis enables two kinds of C?C bond forming reactions; homocoupling of saccharins to form biaryls and cycloaddition with alkynes to form benzosultams. The former represents the first reported nickel-catalyzed decarbonylative C?C homocoupling reaction, whereas the latter constitutes a powerful method to pharmaceutically relevant benzosultams. The reactions proceed with good functional-group tolerance and excellent regioselectivity. PMID- 25689490 TI - Uzbekistan: health system review. AB - Uzbekistan is a central Asian country that became independent in 1991 with the break-up of the Soviet Union. Since then, it has embarked on several major health reforms covering health care provision, governance and financing, with the aim of improving efficiency while ensuring equitable access. Primary care in rural areas has been changed to a two-tiered system, while specialized polyclinics in urban areas are being transformed into general polyclinics covering all groups of the urban population. Secondary care is financed on the basis of past expenditure and inputs (and increasingly self-financing through user fees), while financing of primary care is increasingly based on capitation. There are also efforts to improve allocative efficiency, with a slowly increasing share of resources devoted to the reformed primary health care system. Health care provision has largely remained in public ownership but nearly half of total health care expenditure comes from private sources, mostly in the form of out-of-pocket expenditure. There is a basic benefits package, which includes primary care, emergency care and care for certain disease and population categories. Yet secondary care and outpatient pharmaceuticals are not included in the benefits package for most of the population, and the reliance on private health expenditure results in inequities and catastrophic expenditure for households. While the share of public expenditure is slowly increasing, financial protection thus remains an area of concern. Quality of care is another area that is receiving increasing attention. PMID- 25689491 TI - Identification and characterization of a novel Foxo transcription factors in Apostichopus japonicus. AB - The forkhead box O (Foxo) transcription factors are involved in multiple signaling pathways and play key roles in immunoregulation in vertebrates. In the present study, we firstly identified a novel Foxo gene in Apostichopus japonicus coelomocytes using transcriptome sequencing and RACE approaches (denoted as AjFoxo). The full-length cDNA of AjFoxo was of 2248 bp with a 5' untranslated region (UTR) of 177 bp, a 3' UTR of 367 bp and an ORF of 1704 bp encoding a polypeptide of 567 amino acid residues. The highly conserved forkhead domain was also identified in AjFoxo with remarkably higher degree of structural conservation. AjFoxo transcripts could be detected in all examined tissues with predominant expression in the coelomocytes and muscle, and slightly weak in the tissues of tentacle, intestine and respiratory trees. Concerning the time-course expression of AjFoxo in coelomocytes, the relative expression of AjFoxo was dramatically decreased to 0.44-fold at 48 h compared with that in the control group after Vibrio splendidus challenge, which was consistent with that of AjIkappaB. RNA interference of AjFoxo in primary coelomocytes also significantly depressed the relative expression of AjIkappaB with a 0.37-fold decrease compared with control group. Taken together, these results indicated that AjFoxo was a novel immune regulator and might be involved in the processes of anti-bacteria response in sea cucumber through activating the transcription of AjIkappaB. PMID- 25689492 TI - Parenteral immunization of PLA/PLGA nanoparticle encapsulating outer membrane protein (Omp) from Aeromonas hydrophila: Evaluation of immunostimulatory action in Labeo rohita (rohu). AB - Advanced vaccine research approaches needs to explore on biodegradable nanoparticles (NPs) based vaccine carrier that can serve as antigen delivery systems as well as immuno-stimulatory action to induce both innate and adaptive immune response in fish. Immunogenicity of PLA and PLGA NPs encapsulating outer membrane protein (Omp) antigen of Aeromonas hydrophila were evaluated through intra-peritoneal injection in fish, Labeo rohita. Antigen loaded PLA-Omp (223.5 +/- 13.19 nm) and PLGA-Omp (166.4 +/- 21.23 nm) NPs were prepared using double emulsion method by efficiently encapsulating the antigen reaching the encapsulation efficiency 44 +/- 4.58% and 59.33 +/- 5.13% respectively. Our formulated PLA Omp and PLGA-Omp NPs were in nanometer range (<500 nm) and could be successfully endocyted in the body. Despite low antigen loading in PLA-Omp, it showed considerably slower antigen release in vitro than PLGA-Omp NPs. Other physical properties like zetapotential values and poly dispersity index (PDI) confirmed the stability as well as monodisperse nature of the formulated nanoparticles. The spherical and isolated nature of PLA-Omp and PLGA-Omp NPs were revealed by SEM analysis. Upon immunization of all antigenic formulations (PLA Omp NP, PLGA-Omp NP, FIA-Omp, PLA NP, PLGA NP, PBS as control), significant higher bacterial agglutination titre and haemolytic activity were observed in case of PLA-Omp and PLGA-Omp immunized groups than rest groups at both 21 days and 42 days. The specific antibody response was significantly increased and persisted up to 42 days of post immunization by PLA-Omp, PLGA-Omp, FIA-Omp. PLA Omp NPs showed better immune response (higher bacterial agglutination titre, haemolytic activity, specific antibody titre, higher percent survival upon A. hydrophila challenge) than PLGA-Omp in L. rohita confirming its better efficacy. Comparable antibody response of PLA-Omp and PLGA-Omp with FIA-Omp treated groups suggested that PLA and PLGA could be replacement for Freund's adjuvant (for stimulating antibody response) to overcome many side effects offering long lasting immunity. Our encouraging results suggest that PLA/PLGA nanoparticles based delivery system could be a novel antigen carrier for parenteral immunization in fish. PMID- 25689494 TI - The baccalaureate big 5: what Magnet(r) hospitals should expect from a baccalaureate generalist nurse. AB - The Association of Colleges of Nursing Baccalaureate Essentials outcomes in an organizing framework, called the Baccalaureate Big 5, can have a similar effect in clearly communicating the scope and expectations of baccalaureate generalist nursing education. PMID- 25689493 TI - N-myristoylated ubiquitin ligase Cbl-b inhibitor prevents on glucocorticoid induced atrophy in mouse skeletal muscle. AB - A DGpYMP peptide mimetic of tyrosine(608)-phosphorylated insulin receptor substrate-1 (IRS-1), named Cblin, was previously shown to significantly inhibit Cbl-b-mediated IRS-1 ubiquitination. In the present study, we developed N myristoylated Cblin and investigated whether it was effective in preventing glucocorticoid-induced muscle atrophy. Using HEK293 cells overexpressing Cbl-b, IRS-1 and ubiquitin, we showed that the 50% inhibitory concentrations of Cbl-b mediated IRS-1 ubiquitination by N-myristoylated Cblin and Cblin were 30 and 120 MUM, respectively. Regarding the DEX-induced atrophy of C2C12 myotubes, N myristoylated Cblin was more effective than Cblin for inhibiting the DEX-induced decreases in C2C12 myotube diameter and IRS-1 degradation. The inhibitory efficacy of N-myristoylated Cblin on IRS-1 ubiquitination in C2C12 myotubes was approximately fourfold larger than that of Cblin. Furthermore, N-myristoylation increased the incorporation of Cblin into HEK293 cells approximately 10-folds. Finally, we demonstrated that N-myristoylated Cblin prevented the wet weight loss, IRS-1 degradation, and MAFbx/atrogin-1 and MuRF-1 expression in gastrocnemius muscle of DEX-treated mice approximately fourfold more effectively than Cblin. Taken together, these results suggest that N-myristoylated Cblin prevents DEX-induced skeletal muscle atrophy in vitro and in vivo, and that N myristoylated Cblin more effectively prevents muscle atrophy than unmodified Cblin. PMID- 25689495 TI - Orchestrating energy for shifting busyness to strategic work. AB - This department highlights change management strategies that may be successful in strategically planning and executing organizational change initiatives. In this article, the authors discuss the elements of busy work and offers strategies for shifting to focused, strategic work. A useful energy preservation framework is introduced to promote vitality that drives engagement, productivity, and innovation. PMID- 25689496 TI - Designing tomorrow: transitioning from participation to governance. AB - Nurse executives are challenged with seemingly endless transitions, fueled by healthcare transformation that regularly exposes us to new risks and opportunities. Structures are being redesigned in pursuit of a vision of population health. Roles are evolving to accommodate management structures that extend far beyond traditional walls and disciplines. Models of care are redesigned with the focus on interprofessional collaboration and the patient as partner. We grapple to understand the implications of volume to value and define the transitions we must navigate to land on our feet. Everything we thought we knew is subject to reevaluation. Some topics we thought were long settled; perhaps, even yesterday's news must be reexamined. Shared governance is 1 such topic. PMID- 25689497 TI - Pioneering through chaos. AB - The 2014 International Nursing Administration Research Conference, "Pioneering Through Chaos: Leadership for a Changing World," was held at the Texas Woman's University in Dallas, Texas, in the fall of 2014. The program drew more than 100 attendees from 4 countries. The conference informed attendees from both academe and practice about the role of nursing administration in navigating the dynamic healthcare climate. This article will report on the insights from the conference presenters. PMID- 25689498 TI - Supporting influenza vaccination intent among nurses: effects of leadership and attitudes toward adoption of evidence-based practice. AB - OBJECTIVE: The leadership styles of healthcare organizations and the attitudes of nurses toward the adoption of evidence-based practice (EBP) were examined to provide a predictor of influenza vaccination intent (VI) and improve the current inadequate vaccination rate among nurses. BACKGROUND: Influenza is a costly and potentially serious disease. The United States has set a benchmark of a 90% influenza vaccination rate among healthcare personnel by 2020. METHODS: A sample of 354 registered nurses completed a survey assessing demographic data, the leadership styles of their organization, their attitudes toward EBP, and their VI. RESULTS: A significant positive correlation was found between transformational leadership and VI, but not between transactional leadership and VI. Attitudes toward EBP correlated weakly, but insignificantly, with VI. CONCLUSIONS: Transformational leadership can predict and positively influence vaccination rates among nurses, thus decreasing vaccine preventable illness and improving patient outcomes. PMID- 25689499 TI - Development and psychometric evaluation of the patient care associates' work environment scale. AB - OBJECTIVE: The purpose of this study is to examine the psychometric properties of the Patient Care Associates' Work Environment Scale (PCA-WES). BACKGROUND: Few studies exist examining patient care associates (PCAs) working in acute care settings, and no instruments are available to examine the impact of the work environment on their practice. METHODS: A psychometric evaluation using a nonprobability purposive sample of 390 PCAs was undertaken. RESULTS: Cronbach's alpha internal consistency reliability of the total score was .95. Principal components analysis with varimax rotation and Kaiser normalization identified 5 components that accounted for 57.2% of variance and confirmed the original theoretical structure. The resulting 35-item scale had subscale Cronbach's alpha reliability estimates that ranged from .84 to .93. CONCLUSIONS: The multidimensional PCA-WES is a psychometrically sound measure of 5 components of the PCA practice environment in the acute care setting and is sufficiently reliable and valid for use as independent subscales in healthcare research. PMID- 25689500 TI - Hospital employment of supplemental registered nurses and patients' satisfaction with care. AB - The aim of this study is to determine whether use of supplemental registered nurses (SRNs) from agencies is associated with patients' satisfaction. BACKGROUND: Employment of SRNs is common, but little is known about whether their use is associated with patients' satisfaction with hospital care. METHODS: Cross sectional survey data from nurses in 427 hospitals were linked to American Hospital Association data and patient data from the Hospital Consumer Assessment of Healthcare Providers and Systems survey. RESULTS: We found little evidence that patients' satisfaction with care is related to the use of SRNs. After other hospital and nursing characteristics were controlled, greater use of SRNs was not associated with patients' global satisfaction, including whether they would rank their hospital highly or recommend their hospital, nor was it associated with nurse communication, medication explanation, or pain control. CONCLUSIONS: Employment of SRNs does not detract from patients' overall satisfaction or satisfaction with nurses specifically. PMID- 25689501 TI - The experience of Latino parents of hospitalized children during family-centered rounds. AB - OBJECTIVE: The aim of this study is to describe the experience of Latino parents of hospitalized children during family-centered rounds (FCRs). BACKGROUND: Family centered rounds provide a mechanism to exchange information and facilitate shared decision making. Latino parents may have a suboptimal experience during FCRs. Understanding this experience helps nurse leaders improve patient satisfaction. METHODS: Using a convenience sample, written surveys in Spanish were given to 20 parents who had attended at least 2 FCRs. The surveys were translated into English for data analysis. RESULTS: The narrative data were analyzed for common themes using content analysis. Four themes were identified: valued perception, inclusion and care, facilitated communication, and meeting expectations. CONCLUSIONS: Parents in this study felt that their participation and input were valued and that these positively impacted care. Family-centered rounds helped them understand the plan and facilitated communication when done in Spanish. Nurse leaders play a key role in improving satisfaction and increasing access to translation services or bilingual staff. PMID- 25689502 TI - Nurses' research capacity and use of evidence in acute care: baseline findings from a partnership study. AB - OBJECTIVE: The aim of this study is to report baseline findings from a research focused academic-service partnership. BACKGROUND: Despite widespread efforts, the research-practice gap remains considerable. A research-focused academic-service partnership may offer a strategy for decreasing this gap. METHODS: With the use of a shared model and a descriptive correlational design, 75 acute care nurses were sampled from July to October 2013. RESULTS: Attitudes toward evidence-based practice (EBP) were favorable, but knowledge of common research language was low and EBP confidence was reported as moderate. Evidence-based practice confidence had the strongest relationship to EBP use and was greatest in those who held professional certification and were more educated. CONCLUSION: Findings continue to demonstrate the need for new approaches to reduce the research-practice gap. PMID- 25689503 TI - Filling the gap: a postgraduate fellowship in oncology nursing. AB - To ensure a well-prepared advanced practice oncology nursing workforce, we developed a unique yearlong fellowship promoting expertise in cancer care and focusing on the development of in-depth knowledge and evidence-based clinical oncology practice. This article describes the process for developing and implementing the fellowship and its components, outcomes, and attributes for success. PMID- 25689504 TI - Organizational culture and climate for promoting innovativeness. AB - OBJECTIVE: The aim of this study is to explore the experiences of nurse leaders and nurses in a hospital whose patient care mission was stated as innovation. BACKGROUND: Nurses are critically positioned to provide creative and innovative solutions that make a difference in the lives of patients, organizations, communities, and the profession. METHODS: This 2-phase qualitative study used a content analysis and thematic analysis approach to describe experiences and to generate a beginning conceptual framework of the experience. RESULTS: Results from phase 1 and phase 2 of this study demonstrate that innovativeness in nursing is a multifaceted phenomenon consisting of workplace antecedents followed by a social process. CONCLUSIONS: Nursing innovation requires organizational commitment to allow employees to inquire and question organizational practices and issues on behalf of the mission, patient care, and nursing practice. PMID- 25689505 TI - The value of thesis advisers. PMID- 25689506 TI - Cognitive behavioral therapy: current status and future research directions. AB - Cognitive behavioral therapy (CBT), an umbrella term that includes a diverse group of treatments, is defined by a strong commitment to empiricism. While CBT has a robust empirical base, areas for improvement remain. This article reviews the status of the current empirical base and its limitations, and presents future directions for advancement of the field. Ultimately, studies are needed that will identify the predictors, mediators, and moderators of treatment response in order to increase knowledge on how to personalize interventions for each client and to strengthen the impact of CBT. Efforts to advance the dissemination and implementation of CBT, innovative approaches such as practice-oriented research, and the advantages of incorporating new and existing technologies, are discussed as well. PMID- 25689507 TI - Conserved surface accessible nucleoside ABC transporter component SP0845 is essential for pneumococcal virulence and confers protection in vivo. AB - Streptococcus pneumoniae is a leading cause of bacterial pneumonia, sepsis and meningitis. Surface accessible proteins of S. pneumoniae are being explored for the development of a protein-based vaccine in order to overcome the limitations of existing polysaccharide-based pneumococcal vaccines. To identify a potential vaccine candidate, we resolved surface-associated proteins of S. pneumoniae TIGR4 strain using two-dimensional gel electrophoresis followed by immunoblotting with antisera generated against whole heat-killed TIGR4. Ten immunoreactive spots were identified by mass spectrometric analysis that included a putative lipoprotein SP0845. Analysis of the inferred amino acid sequence of sp0845 homologues from 36 pneumococcal strains indicated that SP0845 was highly conserved (>98% identity) and showed less than 11% identity with any human protein. Our bioinformatic and functional analyses demonstrated that SP0845 is the substrate-binding protein of an ATP-binding cassette (ABC) transporter that is involved in nucleoside uptake with cytidine, uridine, guanosine and inosine as the preferred substrates. Deletion of the gene encoding SP0845 renders pneumococci avirulent suggesting that it is essential for virulence. Immunoblot analysis suggested that SP0845 is expressed in in vitro grown pneumococci and during mice infection. Immunofluorescence microscopy and flow cytometry data indicated that SP0845 is surface exposed in encapsulated strains and accessible to antibodies. Subcutaneous immunization with recombinant SP0845 induced high titer antibodies in mice. Hyperimmune sera raised against SP0845 promoted killing of encapsulated pneumococcal strains in a blood bactericidal assay. Immunization with SP0845 protected mice from intraperitoneal challenge with heterologous pneumococcal serotypes. Based on its surface accessibility, role in virulence and ability to elicit protective immunity, we propose that SP0845 may be a potential candidate for a protein-based pneumococcal vaccine. PMID- 25689509 TI - Pharmacokinetic characteristics, pharmacodynamic effect and in vivo antiviral efficacy of liver-targeted interferon alpha. AB - Interferon alpha (IFNalpha) is used for the treatment of hepatitis B virus infection, and whilst efficacious, it is associated with multiple adverse events caused by systemic exposure to interferon. We therefore hypothesise that targeting IFN directly to the intended site of action in the liver would reduce exposure in blood and peripheral tissue and hence improve the safety and tolerability of IFNalpha therapy. Furthermore we investigated whether directing IFN to the reservoir of infection in the liver may improve antiviral efficacy by increasing local concentration in target organs and tissues. Our previous results show that the mIFNalpha2 fused to an ASGPR specific liver targeting antibody, DOM26h-196-61, results in a fusion protein which retains the activity of both fusion partners when measured in vitro. In vivo targeting of the liver by mIFNalpha2-DOM26h-196-61, hereafter referred to as targeted mIFNalpha2, was observed in microSPECT imaging studies in mice. In this study we show by pharmacokinetic analysis that antibody mediated liver-targeting results in increased uptake and exposure of targeted mIFNalpha2 in target tissues, and correspondingly reduced uptake and exposure in systemic circulation, clearance organs and non-target tissues. We also show that cytokine activity and antiviral activity of liver-targeted IFN is observed in vivo, but that, contrary to expectations, liver-targeting of mIFNalpha2 using ASGPR specific dAbs actually leads to a reduced pharmacodynamic effect in target organs and lower antiviral activity in vivo when compared to non-targeted mIFNalpha2-dAb fusions. PMID- 25689510 TI - Self-referencing and false memory in mild cognitive impairment due to Alzheimer's disease. AB - OBJECTIVE: The present study explored the role of self-referencing on false alarm rates among people with mild cognitive impairment suggestive of the early signs of the Alzheimer's disease pathophysiologic process (MCI-AD). Given that people with MCI-AD demonstrate higher rates of false alarms and that false alarms have been shown to increase for self-relevant information, it was predicted that people with MCI-AD would experience a disproportionate increase in memory errors for highly self-related information. METHOD: Patients with a diagnosis of MCI-AD (n = 23) and healthy control participants (n = 27) rated words for self descriptiveness or commonness and completed a surprise recognition test. RESULTS: Contrary to expectations, results indicated that people with MCI-AD were at no greater risk for false alarms than were control participants as a function of self-descriptiveness, relative to a control condition. Despite the MCI-ADs' greater bias to say "yes" in the self condition, increasing self-descriptiveness did not lead to higher false alarm rates and did not impair performance in the self condition relative to commonness judgments. CONCLUSIONS: Therefore, although people with MCI-AD may be more susceptible to memory errors, they are at no greater risk of self-related errors than healthy control participants. PMID- 25689511 TI - Mechanism-independent optimization of combinatorial nanodiamond and unmodified drug delivery using a phenotypically driven platform technology. AB - Combination chemotherapy can mediate drug synergy to improve treatment efficacy against a broad spectrum of cancers. However, conventional multidrug regimens are often additively determined, which have long been believed to enable good cancer killing efficiency but are insufficient to address the nonlinearity in dosing. Despite improved clinical outcomes by combination treatment, multi-objective combination optimization, which takes into account tumor heterogeneity and balance of efficacy and toxicity, remains challenging given the sheer magnitude of the combinatorial dosing space. To enhance the properties of the therapeutic agents, the field of nanomedicine has realized novel drug delivery platforms that can enhance therapeutic efficacy and safety. However, optimal combination design that incorporates nanomedicine agents still faces the same hurdles as unmodified drug administration. The work reported here applied a powerful phenotypically driven platform, termed feedback system control (FSC), that systematically and rapidly converges upon a combination consisting of three nanodiamond-modified drugs and one unmodified drug that is simultaneously optimized for efficacy against multiple breast cancer cell lines and safety against multiple control cell lines. Specifically, the therapeutic window achieved from an optimally efficacious and safe nanomedicine combination was markedly higher compared to that of an optimized unmodified drug combination and nanodiamond monotherapy or unmodified drug administration. The phenotypically driven foundation of FSC implementation does not require any cellular signaling pathway data and innately accounts for population heterogeneity and nonlinear biological processes. Therefore, FSC is a broadly applicable platform for both nanotechnology-modified and unmodified therapeutic optimizations that represent a promising path toward phenotypic personalized medicine. PMID- 25689512 TI - The effects of Jieduquyuzishen prescription-treated rat serum on the BAFF/BAFF-R signal pathway. AB - Systemic lupus erythematosus (SLE) is a chronic inflammatory disease mainly characterized by B cell hyperactivity. Glucocorticoid (GC) is widely used in SLE for its potent anti-inflammatory and immunosuppressive effects. Despite its important clinical efficacy, high-dose or long-term use of GC can cause severe side effects, such as osteoporosis, osteonecrosis, cataracts, hyperglycemia, coronary heart disease and cognitive impairment. Our early clinical studies have shown that Jieduquyuzishen prescription (JP) can effectively reduce the adverse effects and improve the curative effect of GC in the treatment of SLE. The BAFF/BAFF-R signaling pathway plays an important role in the development of SLE and has been regarded as a potential target for the therapy of SLE. In this study, we attempt to investigate the effect of JP on the BAFF/BAFF-R signaling pathway to explore the mechanism of JP in reducing the toxicity and enhancing the efficacy of GC. YAC-1 cells, isolated rat peripheral blood lymphocytes, polymorphonuclear neutrophils and spleen lymphocytes were treated with drug containing serum. The results of RT-PCR, Western blot and dual-luciferase reporter gene assays indicate that either JP or GC can inhibit the mBAFF-induced up-regulation of BAFF, BAFF-R, Bcl-2, IL-10 and NF-kappaB in YAC-1 cells and WEHI 231 cells. Furthermore, MTS, flow cytometry and CFSE results reveal that the proliferation and survival of lymphocytes activated by mBAFF are suppressed by JP, GC and their combination. Contrary to GC, JP can reduce the apoptosis and raise the survival of polymorphonuclear neutrophils and can't increase the apoptosis of the peripheral blood lymphocytes and spleen lymphocytes. Therefore, it is possible that JP can down-regulate the BAFF/BAFF-R signaling pathway as effectively as GC, which may result in the dosage reduction of GC, thus decreasing the toxicity and improving the efficacy of GC-based treatment of SLE. PMID- 25689513 TI - Short-term effect of strontium- and zinc-containing toothpastes and mouthrinses on volatile sulphur compounds in morning breath: a randomized, double-blind, cross-over clinical study. AB - Zinc (Zn) reduces the formation of volatile sulphur compounds (VSCs) associated with oral malodour. Although strontium (Sr) is included in some products for reducing dental hypersensitivity, it may also have anti-halitosis properties. This randomized, double-blind, cross-over clinical study compared the anti-VSC effect of brushing with commercial toothpastes and rinses containing Zn and Sr. The volunteers (n = 30) either brushed/rinsed with/without tongue brushing using Zn-containing toothpaste/rinse, Sr-containing toothpaste/rinse, or placebo (control). Volatile sulphur compounds [hydrogen sulphide (H2 S) and methyl mercaptan (CH3 SH)] were measured, in morning breath, using gas chromatography. The anti-VSC effects of the test toothpastes and test rinses were significantly better than the anti-VSC effects of the respective controls. Toothbrushing with test toothpastes gave median reductions, compared with the control, of 70% for H2 S and 55-57% for CH3 SH. Rinsing with the Sr- and Zn-containing solutions had the same anti-VSC effect as toothbrushing and tooth- and tongue brushing with the Sr- and Zn-containing toothpastes. Zinc-containing rinse resulted in a significantly higher median salivary level of Zn compared with brushing with Zn-containing toothpaste, although this effect did not correlate with the anti-VSC effect. It can be concluded that the Sr- and Zn-containing toothpastes and the Zn- and Sr containing rinses, when used in the evening, are equally effective in reducing morning-breath VSCs the following day. PMID- 25689514 TI - Intraperitoneally administered biliverdin protects against UVB-induced skin photo damage in hairless mice. AB - Oxidative stress is shown to be responsible for ultraviolet B (UVB) irradiation induced skin cancer and premature aging. Biliverdin (BVD), a product of heme oxygenase-1, has strong anti-oxidant and anti-inflammatory properties. In the present study, we investigated the effects of BVD on UVB-induced skin photo damage in hairless mice. Mice were divided into three groups: control group, UVB group (only UVB irradiation) and BVD+UVB group (mice were intraperitoneally injected with BVD before each UVB irradiation). Intraperitoneal BVD injection resulted in a significant photoprotective effect by reducing morphological and histopathological changes to the skin. BVD also exhibited a significant antioxidant effect by increasing the superoxide dismutase (SOD) level and decreasing the thiobarbituric acid reactive substances (TBARS) level compared with the control group. In addition, BVD activated biliverdin reductase (BVR) expression and inhibited the UVB-induced increase of p38 mitogen-activated protein kinase phosphorylation (p-p38MAPK), MMP (matrix metalloproteinase)-1 and MMP-3 expression (p<0.05). It also significantly decreased the interleukin (IL)-6 level compared with the UVB group (p<0.05). In conclusion, these data suggest that the intraperitoneally administered BVD can prevent UVB irradiation-induced skin photo-damage in hairless mice and that this is likely mediated by its antioxidant and anti-inflammatory mechanisms and cell signal regulatory action. PMID- 25689515 TI - Chemical cross-linking of polypropylenes towards new shape memory polymers. AB - In this work, syndiotactic polypropylene (sPP) as well as isotactic polypropylene (iPP) are cross-linked to gain a shape memory effect. Both prepared PP networks exhibit maximum strains of 700%, stored strains of up to 680%, and recoveries of nearly 100%. While x-iPP is stable for many cycles, x-sPP ruptures after the first shape-memory cycle. It is shown by wide-angle X-ray scattering (WAXS) experiments that cross-linked iPP exhibits homoepitaxy in the temporary, stretched shape but in contrast to previous reports it contains a higher amount of daughter than mother crystals. PMID- 25689516 TI - Correction: establishment of a murine graft-versus-myeloma model using allogeneic stem cell transplantation. PMID- 25689517 TI - Unraveling the Wheat Stem Rust Infection Process on Barley Genotypes Through Relative qPCR and Fluorescence Microscopy. AB - The infection process of wheat stem rust (Puccinia graminis f. sp. tritici) on barley (Hordeum vulgare) is often observed as a mesothetic infection type at the seedling stages, and cultivars containing the same major resistance genes often show variation in the level of resistance provided against the same pathogen race or isolate. Thus, robust phenotyping data based on quantification of fungal DNA can improve the ability to elucidate host-pathogen interaction, especially at early time points of infection when disease symptoms are not yet evident. Quantitative real-time polymerase chain reaction (qPCR) was used to determine the amount of fungal DNA relative to host DNA in infected tissue, providing new insights about fungal development and host resistance during the infection process in this pathosystem. The stem rust susceptible 'Steptoe', resistant cultivars containing only Rpg1 ('Beacon', 'Morex', and 'Chevron'), and the resistant line Q21861 containing Rpg1 and the rpg4/Rpg5 complex were evaluated using the traditional 0-to-4 rating scale, fluorescence microscopy, and qPCR. Statistical differences (P<0.05) were observed in fungal development as early as 24 h postinoculation using the qPCR assay. Fungal development observed using fluorescence microscopy displayed the same hierarchal ordering observed using the qPCR assay. The fungal development occurring at 24 and 48 h postinoculation was vastly different than what was expected using the traditional disease phenotyping methodology; with Steptoe appearing more resistant than the barley lines harboring the known Rpg1 and rpg4/Rpg5 resistance complex. These data indicate potential early prehaustorial resistance contributions in a cultivar considered susceptible based on infection type. Moreover, the temporal differences in resistance suggest pre- and post-haustorial resistance mechanisms in the barley wheat stem rust infection process, indicating potential host genotype contributions related to basal defense during the wheat stem rust infection process. PMID- 25689518 TI - Comparison of Next-Generation Sequencing Versus Biological Indexing for the Optimal Detection of Viral Pathogens in Grapevine. AB - A bioassay is routinely used to determine the viral phytosanitary status of commercial grapevine propagation material in many countries around the world. That test is based on the symptoms developed in the field by specific indicator host plants that are graft-inoculated from the vines being tested. We compared the bioassay against next-generation sequencing (NGS) analysis of grapevine material. NGS is a laboratory procedure that catalogs the genomic sequences of the viruses and other pathogens extracted as DNA and RNA from infected vines. NGS analysis was found to be superior to the standard bioassay in detection of viruses of agronomic significance, including virus infections at low titers. NGS was also found to be superior to the bioassay in its comprehensiveness, the speed of its analysis, and for the discovery of novel, uncharacterized viruses. PMID- 25689519 TI - Characterization of a Gene Identified in Pathotype 5 of the Clubroot Pathogen Plasmodiophora brassicae. AB - Clubroot caused by Plasmodiophora brassicae is an important disease of crucifers worldwide. Isolates of the pathogen can be classified into pathotypes according to their pathogenicity on differential hosts. In this study, the presence or absence of all database-available nonhousekeeping P. brassicae genes (118 in total) were assessed by polymerase chain reaction (PCR) analysis in isolates belonging to five P. brassicae pathotypes (2, 3, 5, 6, and 8 according to Williams' differential set). One gene, designated Cr811, was present exclusively in the isolate of pathotype 5. This was further confirmed by dot blot hybridization and by PCR using alternative DNA preparations and primers. Reverse transcription quantitative PCR analysis indicated that in planta expression of Cr811 was up-regulated during canola infection, especially in the stage of secondary plasmodia. Primers specific to Cr811 could distinguish a field isolate of P. brassicae belonging to pathotype 5 from two other field isolates representing pathotypes 3 and 8. These findings suggest that Cr811 is a gene that is potentially involved in clubroot pathogenesis and that it also might serve as a molecular marker for differentiation of pathotype 5 from other pathotypes. PMID- 25689521 TI - Moral hypocrisy on the basis of construal level: to be a utilitarian personal decision maker or to be a moral advisor? AB - BACKGROUND: People encounter various moral issues that involve making decisions for others by giving advice. OBJECTIVE: This study investigated the characteristics of providing suggestions for oneself versus providing suggestions for others in ethical decision-making and the differences between them based on Construal Level Theory (CLT). METHODS: A total of 768 undergraduate students from three universities in China were randomly assigned to eight groups on the basis of a grid of two Construal Levels (self or others) by two different numbers of people saved (5 people or 15 people) by two problem situations (trolley problem vs. footbridge problem). The investigation examined participants' decisions to opt to take action or refrain from action that would have the consequence of saving more people. RESULTS: The main effects of Construal Level (F1, 752 = 6.46, p = .011), saving number (F1, 752 = 35.81, p < .001), and problem situation type (F1, 752 = 330.55, p < .001) were all significant. The interaction of the problem situation and saving number (F1, 752 = 1.01, p = .31), and social distance and saving number (F1, 752 = 0.85, p = .36), and interaction of the three independent factors (F1, 752 = 0.47, p = .49) were not significant. However, the interaction of social distance and problem situation (F1, 752 = 9.46, p = .002) was significant. Results indicated the participants utilized a component of utilitarian reasoning in the decision-making, and their behaviors appeared more utilitarian at low Construal Levels (CLs) compared to high. CONCLUSION: CLs, saving numbers, and problem situation significantly affected moral decision making and exhibited significant interaction. Making decisions for oneself (low construal) rather than giving advice to others (high-construal) was one important factor that determined whether the people were utilitarian or not. Utilitarian considerations are more relevant in impersonal dilemmas. PMID- 25689522 TI - Polyion complex micelles composed of pegylated polyasparthydrazide derivatives for siRNA delivery to the brain. AB - In order to achieve efficient siRNA delivery to the brain, we designed a novel polyion complex (PIC) micelles composed of rabies virus glycoprotein (RVG) peptide tagged PEGylated polyasparthydrazide (PAHy) derivatives. The synthesized derivatives were characterized using (1)H NMR. The PIC micelles were formed by electrostatic attraction between the polymer and siRNA. Then the micelles were decorated with RVG using PEG as a linker. The physiochemical properties of micelles, such as gel retardation assay, zeta potential, particle size, morphology and serum stability, were investigated. Moreover, the cytotoxicity, cellular uptake, gene silencing efficiency and in vivo distribution of micelles were also evaluated systematically. Compared with unmodified micelles, RVG modified micelles can be more easily internalized by the neuro2a cells and efficiently silence gene expression. In vivo animal experiments further confirmed that RVG modified micelles had brain targeting ability. These results demonstrated that RVG-modified micelles were promising carriers for siRNA delivery to the brain. PMID- 25689523 TI - New insights into how RGO influences the photocatalytic performance of BiOIO3/RGO nanocomposites under visible and UV irradiation. AB - Reduced graphene oxide (RGO) has been demonstrated to be effective in enhancing the photocatalytic activity of various semiconductors. However, an important issue that has been overlooked is the role of RGO in UV-induced photocatalysis of RGO-based nanocomposites. In the present work, novel BiOIO3/RGO nanocomposites were prepared by a simple one-pot hydrothermal method, during which BiOIO3 nanoplates were formed in situ on RGO sheets resulting from partial reduction of RGO. The two components of the composite displayed intimate interfacial contact. The as-prepared BiOIO3/RGO nanocomposites exhibited highly enhanced visible photocatalytic activity, relative to that of pure BiOIO3, toward removal of NO from air. However, the BiOIO3/RGO nanocomposites showed only slightly increased photocatalytic activity, relative to pure, under UV irradiation. The limited enhancement of UV activity can be ascribed to the fact that BiOIO3 would be expected to compete with RGO with regard to absorption and utilization of UV light. Evidence shows that RGO can act as a semiconductor rather than a photosensitizer or electron reservoir in BiOIO3/RGO nano-composites. In addition, the active species responsible for photoactivity have been investigated by a DMPO spin-trapping electron spin resonance technique. Photo-generated holes were found to be the main active species inducing the photo-oxidation of NO under visible light, whereas holes and OH radicals are considered to be responsible for photo activity under UV light. This work points to BiOIO3/RGO nano-composites as new and efficient visible light photocatalysts for environmental remediation applications, and also as a source of new insights into the pivotal role of RGO in photocatalysis of RGO-based nanocomposites under visible as well as UV light. PMID- 25689524 TI - Hindered Brownian diffusion in a square-shaped geometry. AB - We study the spatial dependence of the mobility of microparticles diffusing close to an edge of a square microtube. Confocal particle tracking is used to measure the local diffusion coefficients of fluorescent latex 1.1MUm particles suspended in an aqueous solution in a borosilicate square capillary of 50MUm section side. Observations are made for a set of planes obtained by confocal sectioning of the capillary volume. The translational diffusion coefficients parallel to the axis channel and perpendicular to one of the walls are measured as a function of the distance from both the two channel walls concurring in an edge. A complete 3D spatial map of the colloid diffusion coefficients is thus obtained. Near the corner, the diffusion is hindered up to about 40% as compared to its bulk value. The three translational diffusion coefficients pertaining to the motions along the channel axis and within the channel cross-section turn out to be different from each other and differently affected by the confinement, i.e., we are in the presence of an anisotropic diffusion. The hindered diffusion phenomenon is also examined by finite element numerical simulations, and the numerical predictions fairly agree with the measured diffusion coefficients. PMID- 25689525 TI - Microscale microbial culture. PMID- 25689526 TI - Crohn's disease therapy with Dietzia: the end of anti-inflammatory drugs. PMID- 25689527 TI - Ceftolozane/tazobactam for the treatment of complicated urinary tract and intra abdominal infections. AB - High rates of morbidity and mortality have been linked to the emergence of antimicrobial-resistant Gram-negative pathogens, especially in the hospital setting. Infections due to extended-spectrum-beta-lactamase producing Enterobacteriaceae (e.g., Escherichia coli, Klebsiella pneumoniae) and multidrug resistant Pseudomonas aeruginosa pose a major health threat and dramatically reduce the therapeutic options to achieve an appropriate treatment. There is a need for novel antimicrobials that could provide clinical efficacy toward multidrug-resistant Gram-negative pathogens, including extended-spectrum-beta lactamase and carbapenemase producers. Ceftolozane/tazobactam is a novel antipseudomonal cephalosporin associated with a well-established beta-lactamase inhibitor currently in clinical development for the treatment of complicated intra-abdominal infections, complicated urinary tract infections and nosocomial pneumonia. Phase II and III trials have shown high efficacy and good tolerability in complicated urinary and intra-abdominal infections compared with standard therapy. A study for the treatment of nosocomial pneumonia is planned. PMID- 25689528 TI - Impact of risk stratification on the duration of caspofungin therapy for invasive fungal disease in acute leukemic patients. AB - AIM: We retrospectively analyzed 141 acute leukemia patients with unclassified invasive fungal disease episodes during chemotherapy to determine the optimum duration of antifungal treatment. PATIENTS & METHODS: Patients were divided into standard-risk and high-risk groups and treated with intravenous caspofungin for either 1 or 2 weeks, followed by oral voriconazole. RESULTS: Favorable responses occurred in 75.9% of patients (107/141) overall. Although there were no significant differences in response rates between patients receiving 1 or 2 weeks in the standard-risk group (p = 0.12 and p = 0.19, respectively), in the high risk group, response rates were significantly higher in the 2-week than the 1 week treatment group (p = 0.01 and p = 0.02, respectively). CONCLUSION: The duration of caspofungin treatment for patients with unclassified invasive fungal diseases may be optimized by risk stratification. PMID- 25689529 TI - Prevention of hemodialysis catheter-related blood stream infections using a cotrimoxazole-lock technique. AB - BACKGROUND & AIM: This trial assessed the efficacy of cotrimoxazole lock solution in reducing catheter-related blood stream infections (CRBSIs) among hemodialysis (HD) patients who were dialyzed using tunneled catheters. METHOD: Patients randomly received either heparin (2500 U/ml) (control group) or a mixture of 10 mg/ml cotrimoxazole (based on trimethoprim) and 2500 U/ml heparin (antibiotic group) as catheters lock solution. RESULTS: Compared with the control group, CRBSIs rates per 1000 catheter-days was significantly lower (0.58 vs 4.4 events; p = 0.002) and cumulative infection-free catheter survival was significantly higher (log rank statistic 5.88; p = 0.015) in the antibiotic group. There were no statistical differences regarding incidences of catheter removal (8.7% in the antibiotic group vs 22% in the control group; p = 0.116) or thrombosis (2.2% in the antibiotic group vs 9.8% in the control group; p = 0.129) between the two groups. CONCLUSION: cotrimoxazole containing catheter lock solution is effective in reducing CRBSIs incidence and prolonging dialysis catheter survival in HD patients. PMID- 25689530 TI - Effects of hyperbaric oxygen on Pseudomonas aeruginosa susceptibility to imipenem and macrophages. AB - BACKGROUND: The seriousness to treat burn wounds infected with Pseudomonas aeruginosa led us to examine whether the effect of the carbapenem antibiotic imipenem is enhanced by hyperbaric oxygen (HBO). MATERIALS & METHODS: The effects of HBO (100% O2, 3 ATA, 5 h) in combination with imipenen on bacterial counts of six isolates of P. aeruginosa and bacterial ultrastructure were investigated. Infected macrophages were exposed to HBO (100% O2, 3 ATA, 90 min) and the production of reactive oxygen species monitored. RESULTS: HBO enhanced the effects of imipenen. HBO increased superoxide anion production by macrophages and likely kills bacteria by oxidative mechanisms. CONCLUSION: HBO in combination with imipenem can be used to kill P. aeruginosa in vitro and such treatment may be beneficial for the patients with injuries containing the P. aeruginosa. PMID- 25689532 TI - Phages targeting infected tissues: novel approach to phage therapy. AB - While the true efficacy of phage therapy still requires formal confirmation in clinical trials, it continues to offer realistic potential treatment in patients in whom antibiotics have failed. Novel developments and approaches are therefore needed to ascertain that future clinical trials would evaluate the therapy in its optimal form thus allowing for reliable conclusions regarding the true value of phage therapy. In this article, we present our vision to develop and establish a bank of phages specific to most threatening pathogens and armed with homing peptides enabling their localization in infected tissues in densities assuring efficient and stable eradication of infection. PMID- 25689531 TI - Aging: an emergent phenotypic trait that contributes to the virulence of Cryptococcus neoformans. AB - The pathogenic fungus, Cryptococcus neoformans, is known to undergo phenotypic variation, which affects its virulence in the host. Recent investigations on C. neoformans cells in humans have validated the concept that phenotypic variation is present and relevant for the outcome of chronic cryptococcosis. The C. neoformans capsule is not the only trait that varies among strains. An emerging variant is the "old cell phenotype" generated when C. neoformans undergoes replicative aging. This phenotype, which other than larger size also exhibits a thickened cell wall, inhibits phagocytosis and killing by antifungals in vitro. In concert with the finding that old cells accumulate in vivo, this emergent trait could have significant impact on cryptococcal virulence and infection, and contribute to treatment failure. PMID- 25689533 TI - Differential diagnostic assays for discriminating mycobacteria, especially for nontuberculous mycobacteria: what does the future hold? AB - Mycobacteria infections are an important medical problem, and many are regarded as emerging and re-emerging diseases. Mycobacterium tuberculosis, the causative agent of tuberculosis, remains a leading cause of human morbidity and mortality worldwide, with approximately 8.6 million cases and 1.3 million deaths in 2012. In addition, the incidence of nontuberculous Mycobacterium infection has significantly increased, especially among developed countries. Although phenotypical appearances such as culture characteristics and/or susceptibility to anti-Mycobacterium drugs are variable between different mycobacterial species, early diagnosis is crucial in terms of patient treatment and clinical outcome. In this manuscript, we describe the development of diagnostic techniques, from the classical/conventional to the most recent advances, and provide an overview of the future direction of discrimination procedures. PMID- 25689535 TI - Small colony variants of Pseudomonas aeruginosa in chronic bacterial infection of the lung in cystic fibrosis. AB - Pseudomonas aeruginosa is the most common pathogen that colonizes the lungs of patients with cystic fibrosis. Isolates from sputum are typically all derived from the same strain of bacterium but show extensive phenotypic heterogeneity. One of these variants is the so-called small colony variant, which also shows increased ability to form a biofilm and is frequently resistant to multiple antibiotics. The presence of small colony variants in the sputum of patients with cystic fibrosis is associated with a worse clinical condition. The underlying mechanism responsible for generation of the small colony phenotype remains unclear, but a final common pathway would appear to be elevation of intracellular levels of cyclic di-GMP. This phenotypic variant is thus not just a laboratory curiosity, but a significant bacterial adaptation that favors survival within the lung of patients with cystic fibrosis and contributes to the pulmonary damage caused by P. aeruginosa. PMID- 25689534 TI - The future for early-stage tuberculosis drug discovery. AB - There is an urgent need for new and better drugs to treat tuberculosis due to lengthy and complex treatment regimens and a rising problem of drug resistance. Drug discovery efforts have increased over the past few years, with a larger focus on modern high-throughput screening technologies. A combination of target based approaches, with the traditional empirical means of drug identification, has been complemented by the use of target-based phenotypic screens only recently made possibly with newer genetic tools. Using these approaches, a number of promising compound series have been discovered. However, significant problems remain in developing these into drugs. This review highlights recent advances in TB drug discovery, including an overview of screening campaigns, lessons learned and future directions. PMID- 25689536 TI - Investigating pertussis toxin and its impact on vaccination. AB - Whooping cough, caused by Bordetella pertussis, remains a major global health problem. Each year around 40 million of pertussis cases resulting in 200,000 400,000 annual deaths occur worldwide. Pertussis toxin is a major virulence factor of B. pertussis. Murine studies have shown its importance in bacterial colonization and in immunomodulation to evade innate or adaptive immunity. The toxin is composed of an A protomer expressing ADP-ribosyltransferase activity and a B oligomer, responsible for toxin binding to target cells. The toxin is also a major protective antigen in all currently available vaccines. However, vaccine escape mutants with altered toxin expression have recently been isolated in countries with high vaccination coverage illustrating the need for improved pertussis vaccines. PMID- 25689537 TI - Low-level laser therapy as an antimicrobial and antibiofilm technology and its relevance to wound healing. AB - The biostimulative effect of low-level laser therapy (LLLT) in tissues has been noted in reference to the treatment of various diseases but little information exists on its effectiveness on chronic wounds and biofilm. The scope of this review was to identify literature reporting on LLLT alone, without photodynamic agents, as an antimicrobial/antibiofilm technology and determine its effects on wound healing. Overall the beneficial effects of LLLT in promoting wound healing in animal and human studies has been demonstrated. However, the lack of credible studies using reproducible models and light dosimetry restricts the analysis of current data. Efforts must be addressed to standardize phototherapy procedures as well as to develop suitable in vitro and in vivo biofilm models to test LLLT efficacy in promoting biofilm eradication and wound healing. PMID- 25689538 TI - Melioidosis in Africa: should we be looking more closely? AB - Melioidosis is a life-threatening infection caused by the Gram-negative bacterium Burkholderia pseudomallei, mainly found in Southeast Asia. Recently, African foci have been identified, although reports remain mostly anecdotal. In Africa, multiple febrile diseases have been erroneously attributed to malaria in the past, and many cases of fever remain mis- or undiagnosed. Vigilance for previously under-recognized pathogens may enhance our understanding of disease epidemiology and facilitate improvement of patient care. Melioidosis may be such a condition. We summarize data on melioidosis in Africa and discuss the future directions for epidemiological, clinical and bacteriological studies. We conclude that searching for old bugs in new places is no academic treasure hunt but a clinically relevant activity to pursue. PMID- 25689539 TI - Critical issues for Klebsiella pneumoniae KPC-carbapenemase producing K. pneumoniae infections: a critical agenda. AB - The wide dissemination of carbapenemase producing K. pneumoniae (KPC-Kp) has caused a public health crisis of global dimensions, due to the serious infections in hospitalized patients associated with high mortality. In 2014, we aim to review clinical data on KPC-Kp at a time when a pro-active strategy (combating the problem before it is established) is no longer useful, focusing on epidemiology, patient risk profile, infection control, digestive tract colonization and treatment issues such as the role of carbapenems or carbapenem sparing strategies, colistin and resistance, dual carbapenem administration and the role of tigecycline. All these issues are illustrated prospectively to provide a forum for a Consensus strategy when not only intensive care units but also medical and surgical wards are affected by the epidemics. PMID- 25689540 TI - A comparison of three policy approaches for tobacco retailer reduction. AB - BACKGROUND: The Institute of Medicine recommends that public health agencies restrict the number and regulate the location of tobacco retailers as a means of reducing tobacco use. However, the best policy strategy for tobacco retailer reduction is unknown. PURPOSE: The purpose of this study is to test the percent reduction in the number and density of tobacco retailers in North Carolina resulting from three policies: (1) prohibiting sales of tobacco products in pharmacies or stores with a pharmacy counter, (2) restricting sales of tobacco products within 1000 ft of schools, and (3) regulating to 500 ft the minimum allowable distance between tobacco outlets. METHODS: This study uses data from two lists of tobacco retailers gathered in 2012, one at the statewide level, and another "gold standard" three-county list. Retailers near schools were identified using point and parcel boundaries in ArcMap. Python programming language generated a random lottery system to remove retailers within 500 ft of each other. Analyses were conducted in 2014. RESULTS: A minimum allowable distance policy had the single greatest impact and would reduce density by 22.1% at the state level, or 20.8% at the county level (range 16.6% to 27.9%). Both a pharmacy and near-schools ban together would reduce density by 29.3% at the state level, or 29.7% at the county level (range 26.3 to 35.6%). CONCLUSIONS: The implementation of policies restricting tobacco sales in pharmacies, near schools, and/or in close proximity to another tobacco retailer would substantially reduce the number and density of tobacco retail outlets. PMID- 25689541 TI - Photocatalytic property of a Bi2O3 nanoparticle modified BiOCl composite with a nanolayered hierarchical structure synthesized by in situ reactions. AB - A Bi2O3 nanoparticle modified BiOCl composite was synthesized by a solvothermal method combined with in situ reduction and oxidation in KBH4 and H2O2 solutions respectively. The thickness of a BiOCl nanosheet and the amount of Bi2O3 nanoparticle can be adjusted by changing the KBH4 concentration. The structure, morphology, elemental composition and optical absorption performance were characterized by using an X-ray diffraction diffractometer, a scanning electron microscope, a high resolution transmission electron microscope, an X-ray photoelectron spectroscope and a UV-Vis diffuse reflection spectroscope respectively. A nanolayered hierarchical structure of BiOCl was observed, and Bi2O3 nanoparticles were found to be evenly distributed on the surface/interface of the nanosheets. The photocatalytic activity of the composite was tested by the degradation of 40 mg L(-1) methyl orange solution under UV light illumination. The Bi2O3/BiOCl composite prepared in a KBH4 concentration of 0.02 M achieved the highest photocatalytic rate of 95.7% in 8 min under UV light illumination with a kinetic constant of 0.3125 l min(-1). The photocatalytic mechanism of the composite has been discussed. PMID- 25689542 TI - Ethical, Legal, and Clinical Considerations when Disclosing a High-Risk Syndrome for Psychosis. AB - There are complex considerations when planning to disclose an attenuated psychosis syndrome (APS) diagnosis. In this review, we evaluate ethical, legal, and clinical perspectives as well as caveats related to full, non- and partial disclosure strategies, discuss societal implications, and provide clinical suggestions. Each of the disclosure strategies is associated with benefits as well as costs/considerations. Full disclosure promotes autonomy, allows for the clearest psychoeducation about additional risk factors, helps to clarify and/or correct previous diagnoses/treatments, facilitates early intervention and bolsters communication between providers but there are important considerations involving heritability, comorbidity, culture, and stigma. Non-disclosure advances nonmaleficence by limiting stigma and stress (which may inadvertently exacerbate the condition), and confusion (related to the rapidly evolving diagnosis) in a sensitive developmental period but is complicated by varying patient preferences and the possibility that, as new treatments without adverse effects become available, the risk with false positives no longer justifies the accompanying loss of autonomy. Partial disclosure balances ethical considerations by focusing on symptoms instead of labels, but evidence that laypersons may interpret this information as a pseudo-diagnosis and that symptoms alone also contribute to stigma limits the efficacy of this approach. In addition, there are notable societal considerations relating to disclosure involving conservatorship, the reach of insurance companies, and discrimination. We advocate a hybrid approach to disclosure and recommend future research aimed at understanding the effects of stigma on clinical course and a renewed focus on those help-seeking cases that do not transition but remain clinically relevant. PMID- 25689543 TI - Communication elements supporting patient safety in psychiatric inpatient care. AB - Communication is important for safe and quality health care. The study provides needed insight on the communication elements that support patient safety from the psychiatric care view. Fluent information transfer between the health care professionals and care units is important for care planning and maintaining practices. Information should be documented and implemented accordingly. Communication should happen in an open communication culture that enables discussion, the opportunity to have debriefing discussions and the entire staff can feel they are heard. For effective communication, it is also important that staff are active themselves in information collecting about the essential information needed in patient care. In mental health nursing, it is important to pay attention to all elements of communication and to develop processes concerning communication in multidisciplinary teams and across unit boundaries. The study aims to describe which communication elements support patient safety in psychiatric inpatient care from the viewpoint of the nursing staff. Communication is an essential part of care and one of the core competencies of the psychiatric care. It enables safe and quality patient care. Errors in health care are often connected with poor communication. The study brings needed insight from the psychiatric care view to the topic. The data were gathered from semi-structured interviews in which 26 nurses were asked to describe the elements that constitute patient safety in psychiatric inpatient care. The data were analysed inductively from the viewpoint of communication. The descriptions connected with communication formed a main category of communication elements that support patient safety; this main category was made up of three subcategories: fluent information transfer, open communication culture and being active in information collecting. Fluent information transfer consists of the practical implementation of communication; open communication culture is connected with the cultural issues of communication; and being active in information collecting is related to a nurse's personal working style, which affects communication. It is important to pay attention to all the three areas and use this knowledge in developing patient safety practices and strategies where communication aspect and culture are noted and developed. In mental health nursing, it is important to develop processes concerning communication in multidisciplinary teams and across unit boundaries. PMID- 25689544 TI - Preventive versus culprit-only percutaneous coronary intervention in ST-elevation myocardial infarction patients with multivessel disease: a meta-analysis. AB - BACKGROUND: Although previous studies have suggested clinical benefits of complete revascularization in patients with multivessel coronary artery disease, it is still controversial whether preventive percutaneous coronary intervention (PCI) leads to better clinical outcomes in the clinical setting of ST-segment elevation myocardial infarction (STEMI). METHODS: Relevant studies through September 2014 were searched and identified in the electronic databases.Primary endpoint was all-cause mortality at the longest follow-up. Secondary endpoints included myocardial infarction (MI), repeat revascularization, and major adverse cardiac events (MACE). RESULTS: From 836 initial citations, 7 randomized trials, and 23 observational studies with 44,256 patients (8,087 preventive and 36,169 culprit-only) were included in this study. Preventive PCI was associated with a significant reduction in repeat revascularization (odds ratios [OR]: 0.71; 95% CI: 0.51-0.99) with no differences in all-cause mortality (OR: 0.99; 95% CI: 0.76 1.29) or MI (OR: 1.08; 95% CI: 0.62-1.87) as compared with culprit-only PCI.Comparison of preventive PCI to the culprit-only PCI group revealed OR for MACE of 0.80 (95% CI: 0.57-1.12).Stratified analysis according to revascularization strategy demonstrated a significant survival benefit of culprit only PCI over multivessel PCI during the index procedure and a significantly lower incidence of all-cause mortality with staged PCI as compared with culprit only or multivessel PCI during the index procedure. CONCLUSIONS: Preventive PCI strategy appears to be effective in reducing the risk of repeat revascularization without significant benefits for mortality or MI when compared with culprit-only revascularization in STEMI patients with multivessel disease. PMID- 25689545 TI - Outcomes by day and night for patients bypassing the emergency department presenting with ST-segment elevation myocardial infarction identified with a pre hospital electrocardiogram. AB - BACKGROUND: Pre-hospital ECG and emergency department (ED) bypass direct to the catheter laboratory may optimize reperfusion times for patients with ST-segment elevation myocardial infarction. Questions remain over feasibility and safety during off hours. AIMS: To determine if presenting time of day is associated with differences in in-hospital and 30-day mortality and key reperfusion times. METHODS/RESULTS: Seven hundred and twenty consecutive patients with STEMI triaged directly from the field to the catheter laboratory between June 2004-May 2013. Vital status was reported as of August 2013. The mean age was 65 +/- 14 years, and 75.1% were male. Overall mortality (in-hospital/30 days) did not significantly differ for patients (3.4% in hours and 3.1% off hours; P = N/S). Symptom onset-to-arrival to the heart attack was non-significantly lower (100 minutes off hours (IQR 78-174) versus 110 minutes in hours (IQR 75-199), P = N/S). Call-to-balloon time was not significantly affected by the time of presentation: 150 min in hours (IQR 111-239) versus 154 minutes during off hours (IQR 115-225) P = N/S. Overall door-to-balloon time was 36 minutes (IQR 25-51), 34 minutes in hours (IQR 24-49) versus 40 minutes off hours (IQR 29-55) P = N/S. The overall false positive activation rate was only 13.1%, (in hours 12.2% vs. off hours 14.6%, respectively, P = N/S). CONCLUSIONS: In a unit with an established field triage system facilitating ED bypass, reperfusion times and mortality are not significantly influenced by whether the patient presents during standard working hours or outside of these hours. PMID- 25689546 TI - Patients with 3-vessel coronary artery disease and impaired ventricular function undergoing PCI with Impella 2.5 hemodynamic support have improved 90-day outcomes compared to intra-aortic balloon pump: a sub-study of the PROTECT II trial. AB - OBJECTIVES: To evaluate the efficacy of hemodynamic support using Impella 2.5 (IR2.5) vs intra-aortic balloon pump (IABP) in patients with 3-vessel coronary artery disease (3VD). BACKGROUND: PROTECT II demonstrated favorable 90-day outcomes in patients with impaired LVEF and left main or 3VD undergoing PCI with hemodynamic support with IR2.5 compared to IABP. It is unclear if this was due to a specific benefit in a patient sub-population and if certain patients may derive particular benefit from PCI with IR2.5 support. METHODS: Patients in PROTECT II were stratified upon enrollment into the left main/last patent vessel or 3VD subgroups and randomized to IR2.5 or IABP within those groups. Patients in the 3VD substratum were required to have LVEF <=30%. RESULTS: Among the 3VD subgroup (n = 325 patients; IR2.5 167, IABP 158) patients were well matched, except for prior heart failure or CABG, which were more common in the IR2.5 group (both P <= 0.01). Mean number of lesions treated was 3.0 +/- 1.5 vs. 2.9 +/- 1.4 (P = 0.61). At 30 days after PCI, patients that received IR2.5 compared to IABP support trended toward a reduction in incidence of major adverse events (MAE): 32.9% vs. 42.4% (P = 0.078). At 90 days after PCI, there was a significant difference favoring IR2.5 for incidence of MAE: 39.5% vs. 51.0% (P = 0.039), with this effect being consistent across multiple clinical subgroups. Use of IR2.5 was an independent predictor of improved 90-day outcomes. CONCLUSIONS: Patients with 3VD and reduced LVEF show improved outcomes when PCI is performed with IR2.5 hemodynamic support. PMID- 25689547 TI - The use of Impella 2.5 in severe refractory cardiogenic shock complicating an acute myocardial infarction. AB - OBJECTIVES: To investigate the outcome of patients with acute myocardial infarction (AMI) complicated by refractory cardiogenic shock (CS) who underwent mechanical circulatory support with Impella 2.5. BACKGROUND: AMI complicated by CS remains a highly fatal condition. A potent and minimally invasive left ventricular assist device might improve patient outcomes. METHODS: We analyzed the procedural characteristics and outcomes of 22 consecutive patients who underwent, between July 2008 and December 2012, a percutaneous coronary intervention and Impella 2.5 support for AMI complicated by CS refractory to first-line therapy with inotropes and/or Intra-aortic balloon pump. RESULTS: In this analysis, patients were relatively young with a mean age of 57.9 +/- 11.6 year old and 59.1% were male. The majority of patients (77.3%) were admitted in CS and 40.9% sustained cardiac arrest prior to admission. Hemodynamics improved significantly upon initiation of support, end-organ and tissue perfusion improved subsequently demonstrated by a significant decrease in lactate levels from 6.37 +/- 5.3 mmol/L to 2.41 +/- 2.1 mmo/L, (P = 0.008) after 2 days of support. Thirteen (59.1%) patients were successfully weaned-off Impella 2.5 and 4 (18.2%) were transitioned to another device. We observed a functional recovery of the left ventricle when compared to baseline (43 +/- 10% vs. 27 +/- 9%, P < 0.0001). The survival rate at 6 months and 1 year was 59.1% and 54.5%, respectively. CONCLUSION: Impella 2.5 was initiated as a last resort therapy to support very sick patients with refractory CS after failed conventional therapy. The use of the device yielded favorable short and mid-term survival results with recovery being the most frequently observed outcome. PMID- 25689548 TI - First-in-man study of dedicated bifurcation sirolimus-eluting stent: 12-month results of BiOSS LIM(r) Registry. AB - OBJECTIVES: The aim was to assess the effectiveness and safety profile of a new dedicated bifurcation stent - sirolimus-eluting BiOSS LIM(r) (Balton, Poland) in 12-month Registry. BACKGROUND: The optimal approach to coronary bifurcations treatment by percutaneous coronary intervention (PCI) has been still a subject of debate. Dedicated bifurcation stents are one of the proposed solutions. METHODS: This was the international, 3-center registry, which enrolled patients with non ST-elevation acute coronary syndrome (NSTE-ACS) and stable angina. Provisional T stenting was the obligatory strategy of the treatment. Angiographic control was planned at 12 months. The primary endpoint was cumulative rate of death, myocardial infarction (MI) and target lesion revascularization (TLR) at 12 months. RESULTS: A total of 60 patients with coronary bifurcations were enrolled (mean age 66.4 +/- 11 years, 28.3% of female). There were 21.7% of patients with NSTE-ACS, 78.3% with hypertension, 38.3% with diabetes, 28.3% had previous MI, and 46.7% and 10% underwent prior revascularization, respectively, PCI and coronary artery bypass graft. The device success rate was 100%. Side branch was treated with an additional classical drug-eluting stent implantation in 23.3% of cases. At 12 months, the cumulative major adverse cardiovascular events rate was 11.7%. During follow-up (11 +/- 1 months) there was 1 non-cardiac death (1.7%), 1 non-ST-elevated myocardial infarction (1.7%) due to restenosis and no case of stroke or in-stent thrombosis. Overall TLR was 8.3% (clinically driven TLR - 1.7%, angiographically driven - 6.6%). Mean late lumen loss was as follows: In main vessel - 0.35 +/- 0.33 mm, in main branch - 0.34 +/- 0.27 mm and in side branch - 0.18 +/- 0.38 mm. CONCLUSION: Dedicated bifurcation stent BiOSS(r) LIM proved to be feasible device, with promising safety and long-term clinical effectiveness in the treatment of coronary bifurcation lesions, including distal left main stem stenosis. PMID- 25689549 TI - Effectiveness of MitraClip therapy in patients with refractory heart failure. AB - OBJECTIVES: To assess outcomes for MitraClip therapy in patients with refractory heart failure (HF) and mitral regurgitation (MR) >=3+. BACKGROUND: The beneficial role of Mitraclip also in patients with severe HF has been reported. METHODS: Out of 45 patients undergoing MitraClip implantation at our institute, 16 were on refractory HF defined as diuretics and/or inotropics infusion and/or IABP dependence (group A) or labile haemodynamic balance (group B). RESULTS: Patients were aged 69 +/- 13 years and 75% were males. Group A (8 patients) had a mean hospitalization length before MitraClip procedure of 5333 days. Group B (8 patients) had a mean rate of hospitalization, in the last 50 days before procedure, of 254 days. Acute procedural success was observed in 94% of patients. All but one patients of group A were quickly weaned from pharmacologic and/or mechanical supports within 5 +/- 3 days from procedure and discharged at 20+/-10 days. All patients of group B were discharged after 10+/-8 days from MitraClip. At 1 year: a) cumulative survival rate was 78%; b) all patients were in NYHA functional class <= II; c) residual MR <= 2 was observed in 90%; d) systolic pulmonary arterial pressure was significantly reduced compared to the baseline (from 5410 to 398; p = 0,008); e) significant reduction of cumulative HF hospitalization days in the post-procedure year (10 days) compared to the pre implantation year (280 days; p = 0.023) was observed. CONCLUSIONS: In patients with refractory HF and MR >=3+, MitraClip implantation resulted in acute and persistent clinical benefit and net reduction of HF re-hospitalization. PMID- 25689550 TI - (Meta)-analysis of safety and efficacy following edge-to-edge mitral valve repair using the MitraClip system. AB - OBJECTIVES: The authors investigated safety and efficacy of the MitraClip-System (MCS) using a systematic analysis. BACKGROUND: The safety and efficacy of the MCS continues to be debated, and randomized trials are still lacking. METHOD: A systematic literature search was conducted using common medical and scientific databases. The following kinds of data were obtained: at baseline, 30 days, 6 and 12 month post-procedure. For safety and efficacy mortality-rate (survival), mitral regurgitation <2+ (MR), adverse event rate (AE), NYHA class and reoperation-rate were documented. A meta-analysis with quantitative summary was performed. RESULTS: Twenty-six studies including 3821 patient's who were treated with MCS, were analyzed. Weighted mean age was 73.9 +/- 2.3 years and LogEuroScore was 25.2 +/- 6.0%. Post-procedural MR<2+ was achieved in 86.4% and 66.3% of the patients were in NYHA class I/II within 30 days, AE-rate was 18.3%, mortality-rate was 2.8% and reoperation-rate was 3.5%. Freedom from MR>3 + -4 was 80.2% (80.1%), from NYHA III/IV was 78.6% (66.1%) and freedom from death was 82.6% (87.8%) and from reoperation 95.6% (88.6%) at 6 and 12 month. CONCLUSION: Based on the analysis of the current literature treatment with MCS is associated with good short-term success and low mortality. MCS is safe and effective for patients with limited surgical options. The results are comparable with open mitral valve repair (oMVR) but patients are markedly older and have a higer risk profile than patients who undergo oMVR. Prospective randomized controlled trials are warranted to determine potential AEs, device durability and long-term follow up. PMID- 25689551 TI - Safety of transcatheter aortic valve implantation in a hospital with visiting on site cardiac surgery. AB - OBJECTIVES: To describe the feasibility and safety of transcatheter aortic valve implantation (TAVI) with a visiting on-site cardiac surgery program for surgical back-up. BACKGROUND: Both European and American guidelines recommend institutional cardiac surgery back-up for TAVI. However, the conversion to cardiac surgery is very rare, many complications of TAVI can be managed by catheter techniques and a visiting team can also provide surgical stand-by. Therefore, the need for institutional cardiac surgery (by a surgeon who routinely performs conventional surgical valve replacement at the institution performing TAVI) has been questioned. METHODS: A retrospective review of consecutive TAVI cases with visiting on-site cardiac surgery was performed. Key demographic, echocardiographic, and procedural data were collected prospectively. RESULTS: A total of 97 patients (81.9 +/- 6.3 years) with high-risk criteria (log Euroscore 21.6 +/- 14.4, chronic renal failure 39.2%, severe systolic dysfunction 24.7%) underwent TAVI with visiting on-site cardiac surgery at our institution. Local anesthesia with or without conscious sedation was used in 94.8% of patients. Procedural technical success was 100%, with 2 episodes of tamponade (both treated with pericardiocentesis) and a 16.5% vascular complication rate (all treated conservatively or percutaneously). Thirty-day mortality was 3.1%, with 5.2% rate of stroke and 8.2% rate of major bleeding. There were no conversions to surgery. CONCLUSIONS: TAVI can be done safely in the setting of a hospital with visiting on-site cardiac surgery. This requires careful patient selection, experienced operators and surgeons in experienced centers with well-established criteria and processes of care. In this setting, it may be an option for hospitals without institutional cardiac surgery. PMID- 25689552 TI - Incidence and predictors of late complete heart block after alcohol septal ablation treatment of hypertrophic obstructive cardiomyopathy. AB - OBJECTIVES: This study was designed to identify the incidence of late complete heart block (CHB) first identified at least 48 hours post alcohol septal ablation (ASA). BACKGROUND: Septal reduction with ASA is a therapeutic option for patients with symptomatic hypertrophic obstructive cardiomyopathy (HCM). CHB, resulting from the septal infarct, is a known complication with a reported incidence of 9 22%. The incidence of CHB more than 48 hours post-procedure is unknown. METHODS: Consecutive patients who underwent ASA were analyzed and clinical characteristics associated with late CHB were assessed. Late CHB was defined as first identification of CHB more than 48 hours after ASA. RESULTS: From 2002-2013, 145 subjects underwent 168 ASA procedures and were followed for a mean of 3.2 +/- 2.3 years. The incidence of late CHB was 8.9% (15/168 ASA procedures). Heart block occurred from 48 hours to 3-years post-procedure. In a multivariable model, patients with any CHB were more likely to have had multiple ASA procedures (OR 4.14; 95% CI: 1.24, 13.9; P < 0.05) and high resting and provoked left ventricular outflow tract (LVOT) gradient assessed by catheterization (OR per 10 mmHg gradient 1.14; 95% CI: 1.0, 1.20; P < 0.05). After multivariable adjustment, only a high provokable LVOT gradient remained an independent predictor of late CHB (OR per 10 mmHg gradient 1.14 [95% CI 1.02-1.29]). CONCLUSIONS: Late CHB is a common complication of ASA for treatment of symptomatic HCM. Post-discharge electrocardiographic surveillance for atrioventricular conduction disease should be considered after ASA, especially for those with a high provokable LVOT gradient. PMID- 25689553 TI - Tissue properties of the fossa ovalis as they relate to transseptal punctures: a translational approach. AB - OBJECTIVES: This study focused on how catheter size affects transseptal puncture, what transseptal indication means, and whether the swine model is predictive for humans. BACKGROUND: Transseptal puncture is a common procedure that gains access to the left atrium, allowing percutaneous mitral valve repair, left atrial appendage closure, and left-sided ablations. The basic approach has not changed in many years; however, the frequency of transseptal punctures and the size of devices are increasing with emerging treatments. METHODS: A broad range of devices (4 F to 18 F) were advanced through atrial septa of swine hearts; some devices were inserted in both swine and human hearts using 10 F catheters. RESULTS: Greater forces were required to puncture through the septa of human hearts compared to those of swine. Larger catheters used in swine hearts required greater force to advance them through the septa, causing greater dilation of tissue and sometimes tearing the floor of the fossa ovalis; analyses indicated an exponential increase in the size of the iatrogenic atrial septal defect. Specific tissue property testing of the septum primum showed that this tissue sheared at a lower exerted force in a superior to inferior direction. CONCLUSIONS: Results may provide physicians with important knowledge about what to expect when treating a possible iatrogenic atrial septal defect or help them understand the consequences of transseptal punctures. Comparative data between swine and human atrial septal tissue properties provide critical insights between the species and offer clinicians and device designers important information relative to differences in tissue behaviors. PMID- 25689554 TI - First experience with the new generation Edwards Sapien 3 aortic bioprosthesis: procedural results and short term outcome. AB - BACKGROUND: TAVR has become an established treatment for severe symptomatic aortic stenosis in patients with high surgical risk. The latest generation of the balloon-expandable Edwards Sapien device, the Sapien 3, together with its new transfemoral Commander delivery system has been designed to reduce paravalvular regurgitation and vascular access site complications. OBJECTIVES: To evaluate procedural results and short term outcome with the third generation Sapien 3 device. METHODS: We retrospectively evaluated 125 consecutive TAVR patients and analyzed the first 51 patients in whom we implanted the new Sapien 3 device via transfemoral access. RESULTS: In patients implanted with the Sapien 3 device significant residual paravalvular regurgitation after TAVR was virtually absent with the vast majority having none or trace postinterventional aortic regurgitation on angiography or echocardiography (92.2% and 80.4% respectively). None of the patients had more than mild paravalvular regurgitation. Major vascular access site complications or major bleeding according to the VARC II criteria were not observed in our cohort, minor vascular complications and minor bleeding occurred in 7.8% and 5.9% respectively. If vascular complications occurred, they were related to closure device failure. Thirty day outcome showed a 1.9% major stroke rate and 3.9% death rate. However, we observed a 25.5% permanent pacemaker rate in our Sapien 3 cohort. CONCLUSIONS: Implantation of the new third generation Sapien 3 device resulted in excellent procedural and short term outcome. Significant paravalvular regurgitation was virtually absent. However, the increased rate of postinterventional pacemaker implantations needs to be analyzed in a larger cohort of patients. PMID- 25689555 TI - Aortic dissection flap imitating intracoronary thrombus: an extremely rare angiographic presentation of acute myocardial infarction. PMID- 25689556 TI - Hydrogen-hydrogen bonding: the current density perspective. AB - Current density plots of closed-shell intermolecular H-H interactions characterized by a bond critical point (BCP) show two vortices separated by a saddle, a pattern which allows for a clear definition of a pair current strength. This H-H current strength turns out to be roughly related to the potential energy density at the BCP and then to the dissociation energy. The same pattern is also recognizable, at least for an azimuthal orientation of a field perpendicular to the H-H line, for the intramolecular interactions previously investigated to propose the H-H bonding. In the case of the H atoms of the bay region of polycyclic aromatic hydrocarbons, the current of the H-H delocalized diatropic vortex gives a quantitative indication of stabilization; however, on rotation of the field and the subsequent onset of a bay-delocalized paratropic vortex (a typical signature of antiaromaticity), the diatropic vortex can be reshaped or it can even disappear, consistently with its smallness, and thus showing the effect of other more relevant interactions. PMID- 25689559 TI - Athletic training services in public secondary schools: a benchmark study. AB - CONTEXT: Authors of the most recent study of athletic training (AT) services have suggested that only 42% of secondary schools have access to athletic trainers. However, this study was limited by a small sample size and was conducted more than 10 years ago. OBJECTIVE: To determine current AT services in public secondary schools. DESIGN: Cross-sectional study. SETTING: Public secondary schools in the United States. PATIENTS OR OTHER PARTICIPANTS: A total of 8509 (57%) of 14,951 secondary schools from all 50 states and Washington, DC, responded to the survey. MAIN OUTCOME MEASURE(S): Data on AT services were collected for individual states, National Athletic Trainers' Association districts, and the nation. RESULTS: Of the 8509 schools that responded, 70% (n = 5930) had AT services, including full-time (n = 3145, 37%), part-time (n = 2619, 31%), and per diem (n = 199, 2%) AT services, and 27% (n = 2299) had AT services from a hospital or physical therapy clinic. A total of 4075 of 8509 schools (48%) provided coverage at all sports practices. Eighty-six percent (2,394,284/2,787,595) of athletes had access to AT services. CONCLUSIONS: Since the last national survey, access to AT services increased such that 70% of respondent public secondary schools provided athletic trainers at sports games or practices. Approximately one-third of all public secondary schools had full-time athletic trainers. This number must increase further to provide appropriate medical coverage at athletic practices and games for secondary school athletes. PMID- 25689560 TI - Physical activity participation and constraints among athletic training students. AB - CONTEXT: Researchers have examined the physical activity (PA) habits of certified athletic trainers; however, none have looked specifically at athletic training students. OBJECTIVE: To assess PA participation and constraints to participation among athletic training students. DESIGN: Cross-sectional study. SETTING: Entry level athletic training education programs (undergraduate and graduate) across the United States. PATIENTS OR OTHER PARTICIPANTS: Participants were 1125 entry level athletic training students. MAIN OUTCOME MEASURE(S): Self-reported PA participation, including a calculated PA index based on a typical week. Leisure constraints and demographic data were also collected. RESULTS: Only 22.8% (252/1105) of athletic training students were meeting the American College of Sports Medicine recommendations for PA through moderate-intensity cardiorespiratory exercise. Although 52.3% (580/1105) were meeting the recommendations through vigorous-intensity cardiorespiratory exercise, 60.5% (681/1125) were meeting the recommendations based on the combined total of moderate or vigorous cardiorespiratory exercise. In addition, 57.2% (643/1125) of respondents met the recommendations for resistance exercise. Exercise habits of athletic training students appear to be better than the national average and similar to those of practicing athletic trainers. Students reported structural constraints such as lack of time due to work or studies as the most significant barrier to exercise participation. CONCLUSIONS: Athletic training students experienced similar constraints to PA participation as practicing athletic trainers, and these constraints appeared to influence their exercise participation during their entry-level education. Athletic training students may benefit from a greater emphasis on work-life balance during their entry-level education to promote better health and fitness habits. PMID- 25689561 TI - Serratus anterior and lower trapezius muscle activities during multi-joint isotonic scapular exercises and isometric contractions. AB - CONTEXT: Proper scapular function during humeral elevation, such as upward rotation, external rotation, and posterior tilting of the scapula, is necessary to prevent shoulder injury. However, the appropriate intensity of rehabilitation exercise for the periscapular muscles has yet to be clarified. OBJECTIVE: To identify the serratus anterior, lower trapezius, infraspinatus, and posterior deltoid muscle activities during 2 free-motion exercises using 3 intensities and to compare these muscle activities with isometric contractions during quadruped shoulder flexion and external rotation and abduction of the glenohumeral joint. DESIGN: Cross-sectional study. SETTING: Health Science Laboratory. PATIENTS OR OTHER PARTICIPANTS: A total of 16 uninjured, healthy, active, male college students (age = 19.5 +/- 1.2 years, height = 173.1 +/- 6.5 cm, weight = 68.8 +/- 6.6 kg). MAIN OUTCOME MEASURE(S): Mean electromyographic activity normalized by the maximal voluntary isometric contraction was analyzed across 3 intensities and 5 exercises. Intraclass correlation coefficients were calculated for electromyographic activity of the 4 muscles in each free-motion exercise. RESULTS: Significant interactions in electromyographic activity were observed between intensities and exercises (P < .05). The quadruped shoulder-flexion exercise activated all 4 muscles compared with other exercises. Also, the modified robbery free-motion exercise activated the serratus anterior, lower trapezius, and infraspinatus compared with the lawn-mower free-motion exercise. However, neither exercise showed a difference in posterior deltoid electromyographic activity. CONCLUSIONS: Three intensities exposed the nature of the periscapular muscle activities across the different exercises. The free motion exercise in periscapular muscle rehabilitation may not modify serratus anterior, lower trapezius, and infraspinatus muscle activities unless knee-joint extension is limited. PMID- 25689562 TI - The visceromotor and somatic afferent nerves of the penis. AB - INTRODUCTION: Innervation of the penis supports erectile and sensory functions. AIM: This article aims to study the efferent autonomic (visceromotor) and afferent somatic (sensory) nervous systems of the penis and to investigate how these systems relate to vascular pathways. METHODS: Penises obtained from five adult cadavers were studied via computer-assisted anatomic dissection (CAAD). MAIN OUTCOME MEASURES: The number of autonomic and somatic nerve fibers was compared using the Kruskal-Wallis test. RESULTS: Proximally, penile innervation was mainly somatic in the extra-albugineal sector and mainly autonomic in the intracavernosal sector. Distally, both sectors were almost exclusively supplied by somatic nerve fibers, except the intrapenile vascular anastomoses that accompanied both somatic and autonomic (nitrergic) fibers. From this point, the neural immunolabeling within perivascular nerve fibers was mixed (somatic labeling and autonomic labeling). Accessory afferent, extra-albugineal pathways supplied the outer layers of the penis. CONCLUSIONS: There is a major change in the functional type of innervation between the proximal and distal parts of the intracavernosal sector of the penis. In addition to the pelvis and the hilum of the penis, the intrapenile neurovascular routes are the third level where the efferent autonomic (visceromotor) and the afferent somatic (sensory) penile nerve fibers are close. Intrapenile neurovascular pathways define a proximal penile segment, which guarantees erectile rigidity, and a sensory distal segment. PMID- 25689563 TI - Effects of n-3 polyunsaturated fatty acids (omega-3) supplementation on some cardiovascular risk factors with a ketogenic Mediterranean diet. AB - BACKGROUND: the ketogenic diet (KD) has become a widely used nutritional approach for weight loss. Some of the KD's positive effects on metabolism and cardiovascular risk factors are similar to those seen after n-3 polyunsaturated fatty acids (omega-3) supplementation. We hypothesized that a ketogenic Mediterranean diet with phytoextracts combined with omega-3 supplementation may have increased positive effects on cardiovascular risk factors and inflammation. METHODS: We analyzed 34 male overweight subjects; aged between 25 and 65 years who were overall healthy apart from overweight. The subjects followed a ketogenic diet protocol for four weeks; with (KDO3) or without (KD) omega-3 supplementation. RESULTS: All subjects experienced a significant loss of body weight and body fat and there was no significant differences between treatment (body weight: KD-4.7 kg, KDO3-4.03 kg, body fat KD-5.41 kg, KDO3-5.86 kg). There were also significant decreases in total cholesterol, LDL-c, and glucose levels. Triglycerides and insulin levels decreased more in KDO3 vs. KD subjects, with a significant difference. All the investigated inflammatory cytokines (IL-1beta, IL 6, TNF-alpha) decreased significantly in KDO3 subjects whilst only TNF-alpha showed a significant decrease in KD subjects over the 12 month study period. No significant changes were observed in anti-inflammatory cytokines (IL-10 and IL 1Ra), creatinine, urea and uric acid. Adiponectin increased significantly only in the KDO3 group. CONCLUSIONS: omega-3 supplementation improved the positive effects of a ketogenic Mediterranean diet with phytoextracts on some cardiovascular/metabolic risk factors and inflammatory state. PMID- 25689564 TI - Marine bromophenol bis (2,3-dibromo-4,5-dihydroxy-phenyl)-methane inhibits the proliferation, migration, and invasion of hepatocellular carcinoma cells via modulating beta1-integrin/FAK signaling. AB - Bis (2,3-dibromo-4,5-dihydroxy-phenyl)-methane (BDDPM) is a natural bromophenol compound derived from marine algae. Previous reports have shown that BDDPM possesses antimicrobial activity. In the present study, we found that BDDPM has cytotoxic activity on a wide range of tumor cells, including BEL-7402 cells (IC50 = 8.7 MUg/mL). Further studies have shown that prior to the onset of apoptosis, the BDDPM induces BEL-7402 cell detachment by decreasing the adherence of cells to the extracellular matrix (ECM). Detachment experiments have shown that the treatment of BEL-7402 cells with low concentrations of BDDPM (5.0 MUg/mL) significantly inhibits cell adhesion to fibronectin and collagen IV as well as cell migration and invasion. High doses of BDDPM (10.0 MUg/mL) completely inhibit the migration of BEL-7402 cells, and the expression level of MMPs (MMP-2 and MMP 9) is significantly decreased. Moreover, the expression of beta1-integrin and focal adhesion kinase (FAK) is found to be down-regulated by BDDPM. This study suggests that BDDPM has a potential to be developed as a novel anticancer therapeutic agent due to its anti-metastatic activity and also indicates that BDDPM, which has a unique chemical structure, could serve as a lead compound for rational drug design and for future development of anticancer agents. PMID- 25689565 TI - Omega-3 fatty acid intervention suppresses lipopolysaccharide-induced inflammation and weight loss in mice. AB - Bacterial endotoxin lipopolysaccharide (LPS)-induced sepsis is a critical medical condition, characterized by a severe systemic inflammation and rapid loss of muscle mass. Preventive and therapeutic strategies for this complex disease are still lacking. Here, we evaluated the effect of omega-3 (n-3) polyunsaturated fatty acid (PUFA) intervention on LPS-challenged mice with respect to inflammation, body weight and the expression of Toll-like receptor 4 (TLR4) pathway components. LPS administration induced a dramatic loss of body weight within two days. Treatment with n-3 PUFA not only stopped loss of body weight but also gradually reversed it back to baseline levels within one week. Accordingly, the animals treated with n-3 PUFA exhibited markedly lower levels of inflammatory cytokines or markers in plasma and tissues, as well as down-regulation of TLR4 pathway components compared to animals without n-3 PUFA treatment or those treated with omega-6 PUFA. Our data demonstrate that n-3 PUFA intervention can suppress LPS-induced inflammation and weight loss via, at least in part, down regulation of pro-inflammatory targets of the TLR4 signaling pathway, and highlight the therapeutic potential of n-3 PUFA in the management of sepsis. PMID- 25689566 TI - Briarenolides K and L, new anti-inflammatory briarane diterpenoids from an octocoral Briareum sp. (Briareidae). AB - Two new briarane-type diterpenoids, briarenolides K (1) and L (2), were isolated from an octocoral identified as Briareum sp. The structures of new briaranes 1 and 2 were elucidated by spectroscopic methods. In the in vitro anti-inflammatory effects test, briaranes 1 and 2 were found to significantly inhibit the accumulation of the pro-inflammatory iNOS protein of the lipopolysaccharide (LPS) stimulated RAW264.7 macrophage cells. PMID- 25689567 TI - Systemic hemodynamic atherothrombotic syndrome: a blind spot in the current management of hypertension. PMID- 25689568 TI - Antineoplastic agents. 599. Total synthesis of dolastatin 16. AB - The first 23-step total synthesis of the cyclodepsipeptide dolastatin 16 (1) has been achieved. Synthesis of the dolaphenvaline and dolamethylleuine amino acid units using simplified methods improved the overall efficiency. The formation of the 25-membered macrocycle employing lactonization with 2-methyl-6-nitrobenzoic anhydride completed a key step in the synthesis. Regrettably, the synthetic dolastatin 16 (1), while otherwise identical (by X-ray crystal structure and spectral analyses) with the natural product, did not reproduce the powerful (nanomolar) cancer cell growth inhibition displayed by the natural isolate. Presumably this result can be attributed to conformation(s) of the synthetic dolastatin 16 (1) or to a chemically undetected component isolated with the natural product. PMID- 25689569 TI - Prenatal maternal depression alters amygdala functional connectivity in 6-month old infants. AB - Prenatal maternal depression is associated with alterations in the neonatal amygdala microstructure, shedding light on the timing for the influence of prenatal maternal depression on the brain structure of the offspring. This study aimed to examine the association between prenatal maternal depressive symptomatology and infant amygdala functional connectivity and to thus establish the neural functional basis for the transgenerational transmission of vulnerability for affective disorders during prenatal development. Twenty-four infants were included in this study with both structural magnetic resonance imaging (MRI) and resting-state functional MRI (fMRI) at 6 months of age. Maternal depression was assessed at 26 weeks of gestation and 3 months after delivery using the Edinburgh Postnatal Depression Scale. Linear regression was used to identify the amygdala functional networks and to examine the associations between prenatal maternal depressive symptoms and amygdala functional connectivity. Our results showed that at 6 months of age, the amygdala is functionally connected to widespread brain regions, forming the emotional regulation, sensory and perceptual, and emotional memory networks. After controlling for postnatal maternal depressive symptoms, infants born to mothers with higher prenatal maternal depressive symptoms showed greater functional connectivity of the amygdala with the left temporal cortex and insula, as well as the bilateral anterior cingulate, medial orbitofrontal and ventromedial prefrontal cortices, which are largely consistent with patterns of connectivity observed in adolescents and adults with major depressive disorder. Our study provides novel evidence that prenatal maternal depressive symptomatology alters the amygdala's functional connectivity in early postnatal life, which reveals that the neuroimaging correlates of the familial transmission of phenotypes associated with maternal mood are apparent in infants at 6 months of age. PMID- 25689570 TI - Regulation of neural responses to emotion perception by ketamine in individuals with treatment-resistant major depressive disorder. AB - The glutamate N-methyl-D-aspartate receptor antagonist ketamine has demonstrated antidepressant effects in individuals with treatment-resistant major depressive disorder (TRD) within 24 h of a single dose. The current study utilized functional magnetic resonance imaging (fMRI) and two separate emotion perception tasks to examine the neural effects of ketamine in patients with TRD. One task used happy and neutral facial expressions; the other used sad and neutral facial expressions. Twenty patients with TRD free of concomitant antidepressant medication underwent fMRI at baseline and 24 h following administration of a single intravenous dose of ketamine (0.5 mg kg(-1)). Adequate data were available for 18 patients for each task. Twenty age- and sex-matched healthy volunteers were scanned at one time point for baseline comparison. Whole-brain, voxel-wise analyses were conducted controlling for a family-wise error rate (FWE) of P<0.05. Compared with healthy volunteers, TRD patients showed reduced neural responses to positive faces within the right caudate. Following ketamine, neural responses to positive faces were selectively increased within a similar region of right caudate. Connectivity analyses showed that greater connectivity of the right caudate during positive emotion perception was associated with improvement in depression severity following ketamine. No main effect of group was observed for the sad faces task. Our results indicate that ketamine specifically enhances neural responses to positive emotion within the right caudate in depressed individuals in a pattern that appears to reverse baseline deficits and that connectivity of this region may be important for the antidepressant effects of ketamine. PMID- 25689571 TI - Altered emotionality and neuronal excitability in mice lacking KCTD12, an auxiliary subunit of GABAB receptors associated with mood disorders. AB - Gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the brain, is fundamental to brain function and implicated in the pathophysiology of several neuropsychiatric disorders. GABA activates G-protein-coupled GABAB receptors comprising principal GABAB1 and GABAB2 subunits as well as auxiliary KCTD8, 12, 12b and 16 subunits. The KCTD12 gene has been associated with bipolar disorder, major depressive disorder and schizophrenia. Here we compare Kctd12 null mutant (Kctd12(-/-)) and heterozygous (Kctd12(+/-)) with wild-type (WT) littermate mice to determine whether lack of or reduced KCTD12 expression leads to phenotypes that, extrapolating to human, could constitute endophenotypes for neuropsychiatric disorders with which KCTD12 is associated. Kctd12(-/-) mice exhibited increased fear learning but not increased memory of a discrete auditory conditioned stimulus. Kctd12(+/-) mice showed increased activity during the inactive (light) phase of the circadian cycle relative to WT and Kctd12(-/-) mice. Electrophysiological recordings from hippocampal slices, a region of high Kctd12 expression, revealed an increased intrinsic excitability of pyramidal neurons in Kctd12(-/-) and Kctd12(+/-) mice. This is the first direct evidence for involvement of KCTD12 in determining phenotypes of emotionality, behavioral activity and neuronal excitability. This study provides empirical support for the polymorphism and expression evidence that KCTD12 confers risk for and is associated with neuropsychiatric disorders. PMID- 25689572 TI - MicroRNA regulation of central glial cell line-derived neurotrophic factor (GDNF) signalling in depression. AB - Although multiple studies have reported that peripheral glial cell line-derived neurotrophic factor (GDNF) is reduced in depression, cerebral GDNF signalling has yet to be examined in this condition. Here, we report an isoform-specific decrease in GDNF family receptor alpha 1 (GFRA1) mRNA expression, resulting in lowered GFRalpha1a protein levels in basolateral amygdala (BLA) samples from depressed subjects. Downregulation of GFRalpha1a was associated with increased expression of microRNAs, including miR-511, predicted to bind to long 3' untranslated region (3'-UTR)-containing transcripts (GFRA1-L) coding for GFRalpha1a. Transfection of human neural progenitor cells (NPCs) with a miR-511 mimic was sufficient to repress GFRA1-L/GFRalpha1a without altering GFRalpha1b, and resulted in pathway-specific changes in immediate early gene activity. Unexpectedly, GFRalpha1a knockdown did not reduce NPC responses to GDNF. Rather, it greatly enhanced mitogen-activated protein kinase signalling. This effect appeared to be mediated by GDNF/soluble GFRalpha1/neural cell adhesion molecule binding, and substituting the soluble GFRalpha1a/GFRalpha1b content of miR-511 transfected NPCs with that of controls rescued signalling. In light of previous reports suggesting that GFRalpha1b can inhibit GFRalpha1a-induced neuroplasticity, we also assessed the association between GFRalpha1 and doublecortin (DCX; a hyperplastic marker) in human BLA. Although controls displayed coordinated expression of GFRalpha1a and b isoforms and these correlated positively with DCX, the only significant association observed among depressed subjects was a strongly negative correlation between GFRalpha1b and DCX. Taken together, these results suggest that microRNA-mediated reductions of GFRalpha1a in depression change the quality, rather than the quantity, of GDNF signalling. They also suggest that central GDNF signalling may represent a novel target for antidepressant treatment. PMID- 25689573 TI - A role for D-aspartate oxidase in schizophrenia and in schizophrenia-related symptoms induced by phencyclidine in mice. AB - Increasing evidence points to a role for dysfunctional glutamate N-methyl-D aspartate receptor (NMDAR) neurotransmission in schizophrenia. D-aspartate is an atypical amino acid that activates NMDARs through binding to the glutamate site on GluN2 subunits. D-aspartate is present in high amounts in the embryonic brain of mammals and rapidly decreases after birth, due to the activity of the enzyme D aspartate oxidase (DDO). The agonistic activity exerted by D-aspartate on NMDARs and its neurodevelopmental occurrence make this D-amino acid a potential mediator for some of the NMDAR-related alterations observed in schizophrenia. Consistently, substantial reductions of D-aspartate and NMDA were recently observed in the postmortem prefrontal cortex of schizophrenic patients. Here we show that DDO mRNA expression is increased in prefrontal samples of schizophrenic patients, thus suggesting a plausible molecular event responsible for the D aspartate imbalance previously described. To investigate whether altered D aspartate levels can modulate schizophrenia-relevant circuits and behaviors, we also measured the psychotomimetic effects produced by the NMDAR antagonist, phencyclidine, in Ddo knockout mice (Ddo(-)(/-)), an animal model characterized by tonically increased D-aspartate levels since perinatal life. We show that Ddo( /-) mice display a significant reduction in motor hyperactivity and prepulse inhibition deficit induced by phencyclidine, compared with controls. Furthermore, we reveal that increased levels of D-aspartate in Ddo(-/-) animals can significantly inhibit functional circuits activated by phencyclidine, and affect the development of cortico-hippocampal connectivity networks potentially involved in schizophrenia. Collectively, the present results suggest that altered D aspartate levels can influence neurodevelopmental brain processes relevant to schizophrenia. PMID- 25689574 TI - Burden, causes, and outcomes of people with epilepsy admitted to a rural hospital in Kenya. AB - OBJECTIVE: People with epilepsy (PWE) develop complications and comorbidities often requiring admission to hospital, which adds to the burden on the health system, particularly in low-income countries. We determined the incidence, disability-adjusted life years (DALYs), risk factors, and causes of admissions in PWE. We also examined the predictors of prolonged hospital stay and death using data from linked clinical and demographic surveillance system. METHODS: We studied children and adults admitted to a Kenyan rural hospital, between January 2003 and December 2011, with a diagnosis of epilepsy. Poisson regression was used to compute incidence and rate ratios, logistic regression to determine associated factors, and the DALY package of the R-statistical software to calculate years lived with disability (YLD) and years of life lost (YLL). RESULTS: The overall incidence of admissions was 45.6/100,000 person-years of observation (PYO) (95% confidence interval [95% CI] 43.0-48.7) and decreased with age (p < 0.001). The overall DALYs were 3.1/1,000 (95% CI, 1.8-4.7) PYO and comprised 55% of YLD. Factors associated with hospitalization were use of antiepileptic drugs (AEDs) (odds ratio [OR] 5.36, 95% CI 2.64-10.90), previous admission (OR 11.65, 95% CI 2.65-51.17), acute encephalopathy (OR 2.12, 95% CI 1.07-4.22), and adverse perinatal events (OR 2.87, 95% CI 1.06-7.74). Important causes of admission were epilepsy-related complications: convulsive status epilepticus (CSE) (38%), and postictal coma (12%). Age was independently associated with prolonged hospital stay (OR 1.02, 95% CI 1.00-1.04) and mortality (OR, 1.07, 95% CI 1.04-1.10). SIGNIFICANCE: Epilepsy is associated with significant number of admissions to hospital, considerable duration of admission, and mortality. Improved supply of AEDs in the community, early initiation of treatment, and adherence would reduce hospitalization of PWE and thus the burden of epilepsy on the health system. PMID- 25689575 TI - Comparison of pulmonary artery and transpulmonary thermodilution cardiac output measurements in unsedated newborn calves. AB - OBJECTIVE: To compare the agreement, repeatability and trending ability of transpulmonary thermodilution (TPTD) and pulmonary artery thermodilution (PATD) cardiac output (Qt) measurements in unsedated newborn calves. STUDY DESIGN: Prospective experimental trial. ANIMALS: Eight newborn calves weighing a median (range) of 53 (46-59) kg. METHODS: Pulmonary and femoral artery thermodilution catheters were placed under local anaesthesia. A total of 382 PATD and TPTD Qt measurements were performed simultaneously. Cardiac output was influenced by intravenous doxapram and theophylline in a randomized crossover fashion. Bland Altman analysis for multiple comparisons, concordance and polar plots were used to assess TPTD against PATD. RESULTS: Median (range) cardiac index values measured with PATD and TPTD were 197 mL kg(-1) minute(-1) (74-335 mL kg(-1) minute(-1)) and 196 mL kg(-1) minute(-1) (59-395 mL kg(-1) minute(-1)), respec tively. A small mean bias of -3 mL kg(-1) minute(-1) with limits of agreement (LOA) of -64 to 58 mL kg(-1) minute(-1) and a percentage error of 31% were found. Eighty-two mean values were calculated. This reduced the LOA to -50 to 41 mL kg( 1) minute(-1) with a similar small bias and a percentage error of 23%. Mean TPTD tracked changes in Qt compared with mean PATD with 90% concordance, a mean polar angle of 6 degrees and radial LOA of 43 degrees , indicating marginal trending ability. Keeping the femoral artery catheter patent and obtaining acceptable measurements were very challenging because the calves were not used to being restrained. Calf movement had less influence on PATD. CONCLUSIONS AND CLINICAL RELEVANCE: We recommend that PATD remains the reference method to measure Qt in unsedated newborn calves. However, the robust results of the evaluation of the less invasive TPTD technique warrants further evaluation taking into account the difficulties reported in this study. PMID- 25689576 TI - How do mindfulness-based cognitive therapy and mindfulness-based stress reduction improve mental health and wellbeing? A systematic review and meta-analysis of mediation studies. AB - Given the extensive evidence base for the efficacy of mindfulness-based stress reduction (MBSR) and mindfulness-based cognitive therapy (MBCT), researchers have started to explore the mechanisms underlying their therapeutic effects on psychological outcomes, using methods of mediation analysis. No known studies have systematically reviewed and statistically integrated mediation studies in this field. The present study aimed to systematically review mediation studies in the literature on mindfulness-based interventions (MBIs), to identify potential psychological mechanisms underlying MBCT and MBSR's effects on psychological functioning and wellbeing, and evaluate the strength and consistency of evidence for each mechanism. For the identified mechanisms with sufficient evidence, quantitative synthesis using two-stage meta-analytic structural equation modelling (TSSEM) was used to examine whether these mechanisms mediate the impact of MBIs on clinical outcomes. This review identified strong, consistent evidence for cognitive and emotional reactivity, moderate and consistent evidence for mindfulness, rumination, and worry, and preliminary but insufficient evidence for self-compassion and psychological flexibility as mechanisms underlying MBIs. TSSEM demonstrated evidence for mindfulness, rumination and worry as significant mediators of the effects of MBIs on mental health outcomes. Most reviewed mediation studies have several key methodological shortcomings which preclude robust conclusions regarding mediation. However, they provide important groundwork on which future studies could build. PMID- 25689577 TI - Capillary foams: stabilization and functionalization of porous liquids and solids. AB - Liquid foams are two-phase systems in which a large volume of gas is dispersed as bubbles in a continuous liquid phase. These foams are ubiquitous in nature. In addition, they are found in industrial applications, such as pharmaceutical formulation, food processing, wastewater treatment, construction, and cosmetics. Recently, we reported a new type of foam material, capillary foam, which is stabilized by the synergistic action of particles and a small amount of an immiscible secondary liquid. In this study, we explore in more detail the foam preparation routes. To illustrate some of the potential applications, we create vividly colored wet and dried foams, which are difficult to prepare using traditional methods, and load-bearing porous solids. The combined action of particles and immiscible secondary fluid confers exceptional stability to capillary foams and many options for functionalization, suggesting a wide range of possible applications. PMID- 25689578 TI - Disulfide-bond scrambling promotes amorphous aggregates in lysozyme and bovine serum albumin. AB - Disulfide bonds are naturally formed in more than 50% of amyloidogenic proteins, but the exact role of disulfide bonds in protein aggregation is still not well understood. The intracellular reducing agents and/or improper use of antioxidants in extracellular environment can break proteins disulfide bonds, making them unstable and prone to misfolding and aggregation. In this study, we report the effect of disulfide-reducing agent dithiothreitol (DTT) on hen egg white lysozyme (lysozyme) and bovine serum albumin (BSA) aggregation at pH 7.2 and 37 degrees C. BSA and lysozyme proteins treated with disulfide-reducing agents form very distinct amorphous aggregates as observed by scanning electron microscope. However, proteins with intact disulfide bonds were stable and did not aggregate over time. BSA and lysozyme aggregates show unique but measurable differences in 8-anilino-1-naphthalenesulfonic acid (ANS) and 4,4'-dianilino-1,1'-binaphthyl 5,5'-disulfonic acid (bis-ANS) fluorescence, suggesting a loose and flexible aggregate structure for lysozyme but a more compact aggregate structure for BSA. Scrambled disulfide-bonded protein aggregates were observed by nonreducing sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) for both proteins. Similar amorphous aggregates were also generated using a nonthiol-based reducing agent, tris(2-carboxyethyl)phosphine (TCEP), at pH 7.2 and 37 degrees C. In summary, formation of distinct amorphous aggregates by disulfide-reduced BSA and lysozyme suggests an alternate pathway for protein aggregation that may be relevant to several proteins. PMID- 25689579 TI - Syntheses of the smallest carbon nanohoops and the emergence of unique physical phenomena. AB - The design and construction of non-natural products have fascinated and perplexed organic chemists for years. Their assembly, akin to what has been accomplished for the total synthesis of natural products, has stretched the limits of what can be prepared in the laboratory. Unlike many natural products, however, carbon-rich structures often lack heteroatoms, further complicating their construction. Consider some of the classical molecules in this genre: cubane and dodecahedrane. While highly symmetric, their assembly is far from trivial. These fascinating hydrocarbon targets have fueled the development of carbon-carbon bond-forming reactions, as new methods are needed to access these types of compounds. Among these carbon-rich structures, polycyclic aromatics such as helicenes, fullerenes, and some fullerenes share common ground due to the distortion of one or more aromatic rings out of planarity. Recently added to this group are the [n]cycloparaphenylenes ([n]CPPs), "carbon nanohoops". Here, a linear string of benzene rings connected at the para positions is wrapped back upon itself to form a cyclic structure. Clearly a simple linear p-oligophenylene cannot be cyclized in this manner without extremely harsh reaction conditions. In order to access these structures using solution-phase organic chemistry, clever synthetic strategies that can compensate for this severe distortion are required. Although cycloparaphenylenes can be considered the smallest possible fragment of an armchair carbon nanotube (CNT), they were envisioned as synthetic targets long before CNTs were discovered in 1991. CPP synthesis was first attempted in 1934, almost 70 years before Iijima's first report on CNTs. The long-forgotten targets reemerged in 1993 with a report from Vogtle, though he ultimately was unsuccessful in achieving their synthesis. More than a decade later, in 2008, CPPs succumbed to total synthesis by Jasti and Bertozzi, allowing access to three different-sized carbon nanohoops in milligram quantities. Since then, the Jasti group has embraced the smallest CPPs as inspiring synthetic targets, challenging us to develop new methodology to construct increasingly strained macrocycles. Having recently synthesized [5]-, [6]- and [7]CPP, the three smallest nanohoops synthesized to date, we have been able to realize a variety of new physical phenomena unique to these structures. Perhaps most significantly, unlike linear p phenylenes and inorganic quantum dots, the HOMO-LUMO gaps of the CPPs narrow with decreasing CPP size. The smallest CPPs discussed in this Account illustrate this feature exceptionally well, as their HOMO-LUMO gaps become narrower than those of even the longest p-polyphenylenes. The smaller CPPs are fascinating from a structural standpoint as well because of the high amount of distortion in each benzene ring. From the synthesis of [7]CPP (84 kcal/mol of strain energy) to that of [5]CPP (119 kcal/mol of strain energy), our laboratory has been able to test the boundaries of synthetic and physical organic chemistry. In this Account, we detail how these challenging macrocycles were synthesized and the unique properties these structures possess. PMID- 25689580 TI - Evaluation of nanostructure and microstructure of bone regenerated by BMP-2 porous scaffolds. AB - In this study, three systems containing BMP-2 were fabricated, including two electrospun sandwich-like-systems of PLGA 75:25 and PLGA 50:50 and a microsphere system of PLGA 50:50 to be implanted in a critical size defect in rat calvaria. The in vivo BMP-2 release profiles of the three systems were similar. The total dose was released during the first two weeks. To evaluate the nano and microstructure of the regenerated bone a multi-technique analysis was used, including stereo microscope, X-Ray; AFM, micro-CT, and histological analyses. The progression of bone regeneration was followed at 4, 8, and 12 weeks after the microsphere system implantation whereas the two electrospun systems were evaluated at fixed 12 weeks. All the techniques applied showed high bone regeneration. The average values of bone volume density, bone mineral density, Young's modulus, and the percent of bone repair were ~70% of the values of the native bone. Besides, SEM-EDX analysis indicated that the main chemical elements in the new bone were oxygen, calcium, and phosphorus in a ratio similar to that of native bone. In comparison, the micro-CT may provide an alternative to histology for the evaluation of bone formation at the defect size. PMID- 25689581 TI - Correction to Fermentative conditions modulating sweetness in dry wines: genetics and environmental factors influencing the expression level of the Saccharomyces cerevisiae HSP12 gene. PMID- 25689582 TI - Facile synthesis of magnetic poly(styrene-co-4-vinylbenzene-boronic acid) microspheres for selective enrichment of glycopeptides. AB - In this work, the composites of magnetic Fe3 O4 @SiO2 @poly (styrene-co-4 vinylbenzene-boronic acid) microspheres with well-defined core-shell-shell structure were facilely synthesized and applied to selectively enrich glycopeptides. Due to the relatively large amount of vinyl groups introduced by 3 methacryloxy-propyl-trimethoxysilane on the core-shell surface, the poly(styrene co-4-vinylbenzeneboronic acid) (PSV) was coated with high efficiency, resulting in a large amount of boronic acid on the outermost polymer shell of the Fe3 O4 @SiO2 @PSV microspheres, which is of great importance to improve the enrichment efficiency for glycopeptides. The obtained Fe3 O4 @SiO2 @PSV microspheres were successfully applied to the enrichment of glycopeptides with strong specificity and high selectivity, evaluated by capturing glycopeptides from tryptic digestion of model glycoprotein HRP diluted to 0.05 ng/MUL (1.25 * 10(-13) mol, 100 MUL), tryptic digest of HRP and nonglycosylated BSA up to the ratio of 1:120 w/w and the real complex sample human serum with 103 unique N-glycosylation peptides of 46 different glycoproteins enriched. PMID- 25689583 TI - Orally administrated Lactobacillus pentosus var. plantarum C29 ameliorates age dependent colitis by inhibiting the nuclear factor-kappa B signaling pathway via the regulation of lipopolysaccharide production by gut microbiota. AB - To evaluate the anti-inflammaging effect of lactic acid bacteria (LAB) on age dependent inflammation, we first screened and selected a tumor necrosis factor (TNF)-alpha and reactive oxygen species (ROS)-inhibitory LAB, Lactobacillus pentosus var. plantarum C29, among the LABs isolated from fermented vegetables using LPS-stimulated mouse peritoneal macrophages. Oral administration of C29 (2 * 109 CFU/rat) for 8 weeks in aged Fischer 344 rats (age, 16 months) inhibited the expression of the inflammatory markers myeloperoxidase, inducible nitric oxide (NO) synthase, cyclooxygenase-2, pro-inflammatory cytokines tumor necrosis factor (TNF)-alpha and IL-6 and the activation of nuclear factor kappa-light chain-enhancer of activated B cells (NF-kappaB), activator protein 1 (AP1), and mitogen-activated protein kinases (MAPKs). Treatment with C29 induced the expression of tight junction proteins ZO-1, occludin, and claudin-1, and reduced intestinal microbial LPS and plasmatic LPS levels and ROS, as well as the Firmicutes to Bacteroidetes ratio, which is significantly higher in aged rats than in young rats. C29 treatment also reduced plasmatic reactive oxygen species, malondialdehyde, C-reactive protein, and TNF-alpha, and suppressed expression of senescence markers p16 and p53 in the colon of the aged rats, but increased SIRT 1 expression. Based on these findings, we concluded that C29 treatment may suppress aging-dependent colitis by inhibiting NF-kappaB, AP1, and MAPK activation via the inhibition of gut microbiota LPS production and the induction of tight junction protein expression. PMID- 25689584 TI - High-dose cytarabine as salvage therapy for relapsed or refractory acute myeloid leukemia--is more better or more of the same? AB - Cytarabine is the backbone of most chemotherapeutic regimens for acute myeloid leukemia (AML), yet the optimal dose for salvage therapy of refractory or relapsed AML (RR-AML) has not been established. Very high dose single-agent cytarabine at 36 g/m(2) (ARA-36) was previously shown to be effective and tolerable in RR-AML. In this retrospective analysis, we aim to describe the toxicity and efficacy of ARA-36 as salvage therapy for patients with AML who are primary refractory to intensive daunorubicin-containing induction or those relapsing after allogeneic stem cell transplant (alloSCT). Fifteen patients, median age 53 years, were included in the analysis. Six patients were treated for induction failure, one had resistant APL, and eight relapsed after alloSCT. Complete remission was achieved in 60% of patients. Surviving patients were followed for a median of 8.5 months. One-year overall survival was 54% (95% CI 30%-86%), and relapse rate from remission (n = 9) was 56%. Grade III/IV pulmonary, infectious, ocular and gastrointestinal toxicities occurred in 26%, 20%, 20% and 20% of patients respectively. Salvage therapy with ARA-36 regimen for RR-AML has considerable efficacy with manageable toxicity in patients with induction failure or post-transplant relapse. Overall survival in these high-risk patients still remains poor. PMID- 25689585 TI - Disaggregating census data for population mapping using random forests with remotely-sensed and ancillary data. AB - High resolution, contemporary data on human population distributions are vital for measuring impacts of population growth, monitoring human-environment interactions and for planning and policy development. Many methods are used to disaggregate census data and predict population densities for finer scale, gridded population data sets. We present a new semi-automated dasymetric modeling approach that incorporates detailed census and ancillary data in a flexible, "Random Forest" estimation technique. We outline the combination of widely available, remotely-sensed and geospatial data that contribute to the modeled dasymetric weights and then use the Random Forest model to generate a gridded prediction of population density at ~100 m spatial resolution. This prediction layer is then used as the weighting surface to perform dasymetric redistribution of the census counts at a country level. As a case study we compare the new algorithm and its products for three countries (Vietnam, Cambodia, and Kenya) with other common gridded population data production methodologies. We discuss the advantages of the new method and increases over the accuracy and flexibility of those previous approaches. Finally, we outline how this algorithm will be extended to provide freely-available gridded population data sets for Africa, Asia and Latin America. PMID- 25689590 TI - Continued rapid growth in (68) Ga applications: update 2013 to June 2014. AB - The worldwide utilization of (68) Ga-radionuclide for the fundamental research and clinical applications is growing exponentially. A broad range of (68) Ga based imaging agents has been explored during recent years. The development of new clinically useful agents is encouraged by many factors; for example, increasing role of positron emission tomography (PET) in nuclear medicine, discovery of new biomarkers, accessibility of (68) Ga, and establishment of PET radiopharmaceutical regulation and legislation. The focus of this review resides on the reports regarding (68) Ga-related research and applications published during 2013 to June 2014. PMID- 25689591 TI - Palladium-catalyzed carbonylative cyclization of aryl alkenes/alkenols: a new reaction mode for the synthesis of electron-rich chromanes. AB - The Pd(II)-catalyzed intramolecular carbonylative cyclization reaction of aryl alkenes and aryl alkenols is reported for the synthesis of structurally diverse chromanes. PdCl2(CH3CN)2 was used as the catalyst and CuCl2 as the oxidant under the balloon pressure of CO. The reaction is conducted under mild conditions, and chromane-type esters and lactones can be generated in a highly regio- and stereoselective manner. PMID- 25689586 TI - APOE-modulated Abeta-induced neuroinflammation in Alzheimer's disease: current landscape, novel data, and future perspective. AB - Chronic glial activation and neuroinflammation induced by the amyloid-beta peptide (Abeta) contribute to Alzheimer's disease (AD) pathology. APOE4 is the greatest AD-genetic risk factor; increasing risk up to 12-fold compared to APOE3, with APOE4-specific neuroinflammation an important component of this risk. This editorial review discusses the role of APOE in inflammation and AD, via a literature review, presentation of novel data on Abeta-induced neuroinflammation, and discussion of future research directions. The complexity of chronic neuroinflammation, including multiple detrimental and beneficial effects occurring in a temporal and cell-specific manner, has resulted in conflicting functional data for virtually every inflammatory mediator. Defining a neuroinflammatory phenotype (NIP) is one way to address this issue, focusing on profiling the changes in inflammatory mediator expression during disease progression. Although many studies have shown that APOE4 induces a detrimental NIP in peripheral inflammation and Abeta-independent neuroinflammation, data for APOE-modulated Abeta-induced neuroinflammation are surprisingly limited. We present data supporting the hypothesis that impaired apoE4 function modulates Abeta-induced effects on inflammatory receptor signaling, including amplification of detrimental (toll-like receptor 4-p38alpha) and suppression of beneficial (IL 4R-nuclear receptor) pathways. To ultimately develop APOE genotype-specific therapeutics, it is critical that future studies define the dynamic NIP profile and pathways that underlie APOE-modulated chronic neuroinflammation. In this editorial review, we present data supporting the hypothesis that impaired apoE4 function modulates Abeta-induced effects on inflammatory receptor signaling, including amplification of detrimental (TLR4-p38alpha) and suppression of beneficial (IL-4R-nuclear receptor) pathways, resulting in an adverse NIP that causes neuronal dysfunction. NIP, Neuroinflammatory phenotype; P.I., pro inflammatory; A.I., anti-inflammatory. PMID- 25689593 TI - Sugar as a key component of the shoot branching regulation network. PMID- 25689592 TI - HZ08 reverse P-glycoprotein mediated multidrug resistance in vitro and in vivo. AB - BACKGROUND: Multidrug efflux transporter P-glycoprotein (P-gp) is highly expressed on membrane of tumor cells and is implicated in resistance to tumor chemotherapy. HZ08 is synthesized and studied in order to find a novel P-gp inhibitor. METHODS: MDCK-MDR1 monolayer transport, calcein-AM P-gp inhibition and P-gp ATPase assays were used to confirm the P-gp inhibition capability of HZ08. Furthermore, KB-WT and KB-VCR cells were used to evaluate the P-gp inhibitory activity of HZ08 both in vitro and in vivo. RESULTS: Results showed that HZ08 was more potent than verapamil in MDCK-MDR1 monolayer transportation model. Meanwhile, P-gp ATPase assay and calcein-AM P-gp inhibition assay confirmed that HZ08 inhibited P-gp ATPase with a calcein-AM IC50 of 2.44+/-0.31MUM. In addition, significantly greater in vitro multidrug resistance reversing effects were observed when vincristine or paclitaxel was used in combination with 10MUM HZ08 compared with 10MUM verapamil. Moreover, HZ08 could significantly enhance the sensitivity of vincristine with a similar effect like verapamil in both KB-WT and KB-VCR tumor xenograft models. CONCLUSIONS: The novel structure HZ08 could be a potent P-gp inhibitor. PMID- 25689594 TI - Microcirculatory perfusion during different perioperative hemodynamic strategies. AB - OBJECTIVE: We investigated whether hemodynamic optimization of systemic tissue perfusion based on PPV and CI improves microcirculatory perfusion when compared to a MAP-based strategy in patients undergoing elective abdominal surgery. METHODS: Patients were randomized into a PPV/CI guided group (n = 13, target PPV <12%, CI >2.5 L/min/m(2) , and MAP >70 mmHg) or MAP-guided group (n = 18, target MAP >70 mmHg). PPV, CI, and MAP were measured using noninvasive arterial blood pressure measurements. Sublingual microcirculatory perfusion was measured at one, two, and three hours following anesthesia induction, and quantified as TVD, PVD or the proportion of perfused vessels. Data were analyzed using ANOVA RM. RESULTS: Patients in the PPV/CI group required more fluid administration than control patients (1927 +/- 747 mL versus 1283 +/- 582 mL, respectively; p = 0.01). Despite this difference, we observed similar values for TVD (RM; F(1.28) = 0.01; p = 0.92), PVD (RM; F(1.28) = 0.09; p = 0.77) and the proportion of perfused vessels (RM; F(1.28) = 0.01; p = 0.76) in both groups. CONCLUSION: Hemodynamic optimization of systemic tissue perfusion is not associated with improvement of microcirculatory perfusion compared to a MAP-guided protocol in patients undergoing abdominal surgery. PMID- 25689595 TI - Spatially resolved quantification of gadolinium(III)-based magnetic resonance agents in tissue by MALDI imaging mass spectrometry after in vivo MRI. AB - Gadolinium(III)-based contrast agents improve the sensitivity and specificity of magnetic resonance imaging (MRI), especially when targeted contrast agents are applied. Because of nonlinear correlation between the contrast agent concentration in tissue and the MRI signal obtained in vivo, quantification of certain biological or pathophysiological processes by MRI remains a challenge. Up to now, no technology has been able to provide a spatially resolved quantification of MRI agents directly within the tissue, which would allow a more precise verification of in vivo imaging results. MALDI imaging mass spectrometry for spatially resolved in situ quantification of gadolinium(III) agents, in correlation to in vivo MRI, were evaluated. Enhanced kinetics of Gadofluorine M were determined dynamically over time in a mouse model of myocardial infarction. MALDI imaging was able to corroborate the in vivo imaging MRI signals and enabled in situ quantification of the gadolinium probe with high spatial resolution. PMID- 25689596 TI - Virtual reconstruction of modern and fossil hominoid crania: consequences of reference sample choice. AB - Most hominin cranial fossils are incomplete and require reconstruction prior to subsequent analyses. Missing data can be estimated by geometric morphometrics using information from complete specimens, for example, by using thin-plate splines. In this study, we estimate missing data in several virtually fragmented models of hominoid crania (Homo, Pan, Pongo) and fossil hominins (e.g., Australopithecus africanus, Homo heidelbergensis). The aim is to investigate in which way different references influence estimations of cranial shape and how this information can be employed in the reconstruction of fossils. We used a sample of 64 three-dimensional digital models of complete human, chimpanzee, and orangutan crania and a set of 758 landmarks and semilandmarks. The virtually knocked out neurocranial and facial areas that were reconstructed corresponded to those of a real case found in A.L. 444-2 (A. afarensis) cranium. Accuracy of multiple intraspecies and interspecies reconstructions was computed as the maximum square root of the mean squared difference between the original and the reconstruction (root mean square). The results show that the uncertainty in reconstructions is a function of both the geometry of the knockout area and the dissimilarity between the reference sample and the specimen(s) undergoing reconstruction. We suggest that it is possible to estimate large missing cranial areas if the shape of the reference is similar enough to the shape of the specimen reconstructed, though caution must be exercised when employing these reconstructions in subsequent analyses. We provide a potential guide for the choice of the reference by means of bending energy. PMID- 25689597 TI - Unravelling the role of SNM1 in the DNA repair system of Trypanosoma brucei. AB - All living cells are subject to agents that promote DNA damage. A particularly lethal lesion are interstrand cross-links (ICL), a property exploited by several anti-cancer chemotherapies. In yeast and humans, an enzyme that plays a key role in repairing such damage are the PSO2/SNM1 nucleases. Here, we report that Trypanosoma brucei, the causative agent of African trypanosomiasis, possesses a bona fide member of this family (called TbSNM1) with expression of the parasite enzyme able to suppress the sensitivity yeast pso2Delta mutants display towards mechlorethamine, an ICL-inducing compound. By disrupting the Tbsnm1 gene, we demonstrate that TbSNM1 activity is non-essential to the medically relevant T. brucei life cycle stage. However, trypanosomes lacking this enzyme are more susceptible to bi- and tri-functional DNA alkylating agents with this phenotype readily complemented by ectopic expression of Tbsnm1. Genetically modified variants of the null mutant line were subsequently used to establish the anti parasitic mechanism of action of nitrobenzylphosphoramide mustard and aziridinyl nitrobenzamide prodrugs, compounds previously shown to possess potent trypanocidal properties while exhibiting limited toxicity to mammalian cells. This established that these agents, following activation by a parasite specific type I nitroreductase, produce metabolites that promote formation of ICLs leading to inhibition of trypanosomal growth. PMID- 25689598 TI - Evaluation of phantom-based education system for acupuncture manipulation. AB - BACKGROUND: Although acupuncture manipulation has been regarded as one of the important factors in clinical outcome, it has been difficult to train novice students to become skillful experts due to a lack of adequate educational program and tools. OBJECTIVES: In the present study, we investigated whether newly developed phantom acupoint tools would be useful to practice-naive acupuncture students for practicing the three different types of acupuncture manipulation to enhance their skills. METHODS: We recruited 12 novice students and had them practice acupuncture manipulations on the phantom acupoint (5% agarose gel). We used the Acusensor 2 and compared their acupuncture manipulation techniques, for which the target criteria were depth and time factors, at acupoint LI11 in the human body before and after 10 training sessions. The outcomes were depth of needle insertion, depth error from target criterion, time of rotating, lifting, and thrusting, time error from target criteria and the time ratio. RESULTS: After 10 training sessions, the students showed significantly improved outcomes in depth of needle, depth error (rotation, reducing lifting/thrusting), thumb forward time error, thumb-backward time error (rotation), and lifting time (reinforcing lifting/thrusting). CONCLUSIONS: The phantom acupoint tool could be useful in a phantom-based education program for acupuncture-manipulation training for students. For advanced education programs for acupuncture manipulation, we will need to collect additional information, such as patient responses, acupoint specific anatomical characteristics, delicate tissue-like modeling, haptic and visual feedback, and data from an acupuncture practice simulator. PMID- 25689599 TI - Controlling coordination reactions and assembly on a Cu(111) supported boron nitride monolayer. AB - We report the formation of a metal-organic network on a BN/Cu(111) template by codeposition of carbonitrile-functionalized porphyrin derivatives (2H-TPCN) with Co atoms in an ultrahigh vacuum environment. The resulting metallo-supramolecular structure explored by scanning tunneling microscopy and spectroscopy features a distinct 4-fold coordination motif. Furthermore, we demonstrate an in situ metalation of the tetrapyrrole macrocycles with deposited Co atoms yielding Co TPCN directly on the BN sheet. Our results provide perspectives for the formation of coordination networks on BN and related systems featuring structural, electronic, and magnetic properties unachievable on metallic supports. PMID- 25689600 TI - Screening for significant refractive error using a combination of distance visual acuity and near visual acuity. AB - PURPOSE: To explore the effectiveness of using a series of tests combining near visual acuity (NVA) and distance visual acuity (DVA) for large-scale screenings for significant refractive error (SRE) in primary school children. METHOD: Each participant underwent DVA, NVA and cycloplegic autorefraction measurements. SREs, including high myopia, high hyperopia and high astigmatism were analyzed. Cycloplegic refraction results were considered to be the gold standard for the comparison of different screening measurements. Receiver-operating characteristic (ROC) curves were constructed to compare the area under the curve (AUC) and the Youden index among DVA, NVA and the series combined tests of DVA and NVA. The efficacies (including sensitivity, specificity, positive predictive value, and negative predictive value) of each test were evaluated. Only the right eye data of each participant were analysed for statistical purpose. RESULT: A total of 4416 children aged 6 to 12 years completed the study, among which 486 students had right eye SRE (SRE prevalence rate = 11.01%). There was no difference in the prevalence of high hyperopia and high astigmatism among different age groups. However, the prevalence of high myopia significantly increased with the age (chi2 = 381.81, p<0.01). High hyperopia was the biggest SRE factor associated with amblyopia(p<0.01,OR = 167.40, 95% CI: 75.14~372.94). The DVA test was better than the NVA test for detecting high myopia (Z = 2.71, p<0.01), but the NVA test was better for detecting high hyperopia (Z = 2.35, p = 0.02) and high astigmatism (Z = 4.45, p<0.01). The series combined DVA and NVA test had the biggest AUC and the highest Youden Index for detecting high hyperopia, myopia, astigmatism, as well as all of the SREs (all p<0.01). CONCLUSION: The series combined DVA and NVA test was more accurate for detecting SREs than either of the two tests alone. This new method could be applied to large-scale SRE screening of children, aged 6 to 12, in areas that are less developed. PMID- 25689601 TI - Cyclopropene derivatives as precursors to enantioenriched cyclopropanols and n butenals possessing quaternary carbon stereocenters. AB - The diastereoselective carbocupration reaction of cyclopropenylmethyl ethers followed by addition of oxenoid leads to the formation of diastereo- and enantiomerically enriched 2,2,3,3-tetrasubstituted cyclopropanol derivatives. Ring fragmentation of the copper cyclopropanolate leads to acyclic butenal derivatives possessing enantiomerically enriched alpha-quaternary carbon stereocenters in a single-pot operation. PMID- 25689602 TI - Heterogeneity in recent-onset type 1 diabetes - a clinical trial perspective. AB - BACKGROUND: Type 1 diabetes (T1D) TrialNet is a National Institutes of Health sponsored clinical trial network aimed at altering the disease course of T1D. The purpose of this study is to evaluate age-dependent heterogeneity in clinical, metabolic and immunologic characteristics of individuals with recent-onset T1D, to identify cohorts of interest and to aid in planning of future studies. METHODS: Eight hundred eighty-three individuals with recent-onset T1D involved in five TrialNet studies were categorized by age as follows: >=18 years, 12-17 years, 8-12 years and <8 years. Data were compared with healthy age-matched subjects in the National Health and Nutrition Examination Survey. RESULTS: Only 2.0% of the individuals overall were excluded from trial participation because of insufficient C-peptide values (<0.2 pmol/mL). A disproportionate number of these subjects were <8 years old. Leukopenia was present in 21.2% of individuals and lymphopenia in 11.6%; these frequencies were markedly higher than age-matched healthy National Health and Nutrition Examination Survey population. Of the cohort, 24.5% were overweight or obese. Neither high-risk human leukocyte antigen type DR3 nor DR4 was present in 31% of adults and 21% of children. CONCLUSIONS: The ability of recent-onset T1D patients to meet key entry criteria for TrialNet studies, including C-peptide >0.2 pmol/mL, varies by age. Lower C-peptide level requirements for younger participants and other aspects of heterogeneity of recent-onset T1D patients, such as white blood cell count abnormalities and body mass index should be considered in the design of future clinical studies. PMID- 25689603 TI - Differential proteomic responses of selectively bred and wild-type Sydney rock oyster populations exposed to elevated CO2. AB - Previous work suggests that larvae from Sydney rock oysters that have been selectively bred for fast growth and disease resistance are more resilient to the impacts of ocean acidification than nonselected, wild-type oysters. In this study, we used proteomics to investigate the molecular differences between oyster populations in adult Sydney rock oysters and to identify whether these form the basis for observations seen in larvae. Adult oysters from a selective breeding line (B2) and nonselected wild types (WT) were exposed for 4 weeks to elevated pCO2 (856 MUatm) before their proteomes were compared to those of oysters held under ambient conditions (375 MUatm pCO2 ). Exposure to elevated pCO2 resulted in substantial changes in the proteomes of oysters from both the selectively bred and wild-type populations. When biological functions were assigned, these differential proteins fell into five broad, potentially interrelated categories of subcellular functions, in both oyster populations. These functional categories were energy production, cellular stress responses, the cytoskeleton, protein synthesis and cell signalling. In the wild-type population, proteins were predominantly upregulated. However, unexpectedly, these cellular systems were downregulated in the selectively bred oyster population, indicating cellular dysfunction. We argue that this reflects a trade-off, whereby an adaptive capacity for enhanced mitochondrial energy production in the selectively bred population may help to protect larvae from the effects of elevated CO2 , whilst being deleterious to adult oysters. PMID- 25689604 TI - A rare case of Cryptococcus gattii pneumonia in a renal transplant patient. AB - Cryptococcus neoformans and Cryptococcus gattii are environmental fungi that can cause fever, cough, pneumonia, meningoencephalitis, dissemination, and death. C. gattii causes cryptococcomas more frequently than does C. neoformans and may require prolonged antifungal treatment. We present a rare case of C. gattii pneumonia in a renal transplant patient. A 44-year-old man, living in a rural area endemic for C. gattii and who had received a kidney transplant, was admitted to the hospital with fever, vomiting, weight loss, and diarrhea. A chest computed tomography revealed 2 alveolar, nodular, subpleural infiltrates in the periphery of the lungs. Differential diagnoses included infectious infiltrates, granulomatosis, embolization, and hemorrhage. C. gattii, molecular type VGI, was confirmed on day 28. Treatment consisted of amphotericin B at 1 mg/kg/day or fluconazole at 800 mg/day for first 6 weeks, followed by fluconazole at 400 mg/day for the subsequent 12 months. Response to the therapy has been slow. Because of the occurrence of outbreaks and its high morbidity and mortality rates, physicians must be aware of this complication in transplant recipients to avoid delays in diagnosis and to provide prompt management. PMID- 25689605 TI - Underwater Thermoresponsive Surface with Switchable Oil-Wettability between Superoleophobicity and Superoleophilicity. AB - An underwater thermoresponsive surface that can switch between superoleophobicity and superoleophilicity is fabricated with a combination of mixed brushes, containing thermoresponsive poly(N-isopropylacrylamide) and underwater oleophilic heptadecafluorodecyltrimethoxysilane, and nanostructured silicon nanowire arrays. Temperature-induced underwater adhesion switching between low-adhesive superoleophobicity and high-adhesive superoleophobicity is achieved on a pure poly(N-isopropylacrylamide)-modified nanostructured silicon nanowire array. PMID- 25689606 TI - Photobiochemical production of carbon monoxide by Thermus thermophilus ba3 cytochrome c oxidase. AB - We report the photobiochemical production of carbon monoxide by a terminal ba3 cytochrome c oxidase from T. thermophilus HB8. FTIR and time-resolved step-scan FTIR spectroscopies were combined to probe this process and also monitor the concomitant binding of the produced gas to other intact ba3 molecules forming the ba3 -CO complex. The activation of this mechanism by ba3 -oxidase under visible excitation raises the question as to whether such a mechanism is physiologically relevant to the extreme environment in which it operates. PMID- 25689607 TI - Resolving phylogenetic relationships of the recently radiated carnivorous plant genus Sarracenia using target enrichment. AB - The North American carnivorous pitcher plant genus Sarracenia (Sarraceniaceae) is a relatively young clade (<3 million years ago) displaying a wide range of morphological diversity in complex trapping structures. This recently radiated group is a promising system to examine the structural evolution and diversification of carnivorous plants; however, little is known regarding evolutionary relationships within the genus. Previous attempts at resolving the phylogeny have been unsuccessful, most likely due to few parsimony-informative sites compounded by incomplete lineage sorting. Here, we applied a target enrichment approach using multiple accessions to assess the relationships of Sarracenia species. This resulted in 199 nuclear genes from 75 accessions covering the putative 8-11 species and 8 subspecies/varieties. In addition, we recovered 42kb of plastome sequence from each accession to estimate a cpDNA derived phylogeny. Unsurprisingly, the cpDNA had few parsimony-informative sites (0.5%) and provided little information on species relationships. In contrast, use of the targeted nuclear loci in concatenation and coalescent frameworks elucidated many relationships within Sarracenia even with high heterogeneity among gene trees. Results were largely consistent for both concatenation and coalescent approaches. The only major disagreement was with the placement of the purpurea complex. Moreover, results suggest an Appalachian massif biogeographic origin of the genus. Overall, this study highlights the utility of target enrichment using multiple accessions to resolve relationships in recently radiated taxa. PMID- 25689608 TI - SimQ: real-time retrieval of similar consumer health questions. AB - BACKGROUND: There has been a significant increase in the popularity of Web-based question-and-answer (Q&A) services that provide health care information for consumers. Large amounts of Q&As have been archived in these online communities, which form a valuable knowledge base for consumers who seek answers to their health care concerns. However, due to consumers' possible lack of professional knowledge, it is still very challenging for them to find Q&As that are closely relevant to their own health problems. Consumers often repeatedly ask similar questions that have already been answered previously by other users. OBJECTIVE: In this study, we aim to develop efficient informatics methods that can retrieve similar Web-based consumer health questions using syntactic and semantic analysis. METHODS: We propose the "SimQ" to achieve this objective. SimQ is an informatics framework that compares the similarity of archived health questions and retrieves answers to satisfy consumers' information needs. Statistical syntactic parsing was used to analyze each question's syntactic structure. Standardized Unified Medical Language System (UMLS) was employed to annotate semantic types and extract medical concepts. Finally, the similarity between sentences was calculated using both semantic and syntactic features. RESULTS: We used 2000 randomly selected consumer questions to evaluate the system's performance. The results show that SimQ reached the highest precision of 72.2%, recall of 78.0%, and F-score of 75.0% when using compositional feature representations. CONCLUSIONS: We demonstrated that SimQ complements the existing Q&A services of Netwellness, a not-for-profit community-based consumer health information service that consists of nearly 70,000 Q&As and serves over 3 million users each year. SimQ not only reduces response delay by instantly providing closely related questions and answers, but also helps consumers to improve the understanding of their health concerns. PMID- 25689609 TI - The TIC complex uncovered: The alternative view on the molecular mechanism of protein translocation across the inner envelope membrane of chloroplasts. AB - Chloroplasts must import thousands of nuclear-encoded preproteins synthesized in the cytosol through two successive protein translocons at the outer and inner envelope membranes, termed TOC and TIC, respectively, to fulfill their complex physiological roles. The molecular identity of the TIC translocon had long remained controversial; two proteins, namely Tic20 and Tic110, had been proposed to be central to protein translocation across the inner envelope membrane. Tic40 also had long been considered to be another central player in this process. However, recently, a novel 1-megadalton complex consisting of Tic20, Tic56, Tic100, and Tic214 was identified at the chloroplast inner membrane of Arabidopsis and was demonstrated to constitute a general TIC translocon which functions in concert with the well-characterized TOC translocon. On the other hand, direct interaction between this novel TIC transport system and Tic110 or Tic40 was hardly observed. Consequently, the molecular model for protein translocation across the inner envelope membrane of chloroplasts might need to be extensively revised. In this review article, I intend to propose such alternative view regarding the TIC transport system in contradistinction to the classical view. I also would emphasize importance of reevaluation of previous works in terms of with what methods these classical Tic proteins such as Tic110 or Tic40 were picked up as TIC constituents at the very beginning as well as what actual evidence there were to support their direct and specific involvement in chloroplast protein import. This article is part of a Special Issue entitled: Chloroplast Biogenesis. PMID- 25689610 TI - Vaccines against dengue virus. PMID- 25689612 TI - Correction: The first synthesis of N-acetylneuraminic acid 1,7-lactone. PMID- 25689613 TI - Ideomotor-compatible tasks partially escape dual-task interference in both young and elderly adults. AB - Under most circumstances, it is not possible to carry out central processing for 2 tasks at the same time; effectively there is a bottleneck. Nevertheless, in 2 experiments it is demonstrated here that both younger and older adults are able to partially bypass the bottleneck in a psychological refractory period procedure, even without extensive training, when the 2nd of the 2 tasks is a saccade or a body tilt in the direction of rotation of a visual stimulus. Consistent with earlier research, the findings showed that younger adults can bypass when the second task has ideomotor-compatible stimuli and responses. Most strikingly, they demonstrated that bypass can also occur in older adults. Overall, the findings are inconsistent with any categorical claim that younger adults can bypass the dual-task bottleneck whereas older adults cannot. The construct of ideomotor-compatible tasks may comprise 2 quite different classes of experimental procedures. PMID- 25689615 TI - A multifunctional polymer-graphene thin-film transistor with tunable transport regimes. AB - Here we describe a strategy to fabricate multifunctional graphene-polymer hybrid thin-film transistors (PG-TFT) whose transport properties are tunable by varying the deposition conditions of liquid-phase exfoliated graphene (LPE-G) dispersions onto a dielectric surface and via thermal annealing post-treatments. In particular, the ionization energy (IE) of the LPE-G drop-cast on SiO2 can be finely adjusted prior to polymer deposition via thermal annealing in air environment, exhibiting values gradually changing from 4.8 eV up to 5.7 eV. Such a tunable graphene's IE determines dramatically different electronic interactions between the LPE-G and the semiconducting polymer (p- or n-type) sitting on its top, leading to devices where the output current of the PG-TFT can be operated from being completely turned off up to modulable. In fact upon increasing the surface coverage of graphene nanoflakes on the SiO2 the charge transport properties within the top polymer layer are modified from being semiconducting up to truly conductive (graphite-like). Significantly, when the IE of LPE-G is outside the polymer band gap, the PG-TFT can operate as a multifunctional three terminal switch (transistor) and/or memory device featuring high number of erase write cycles. Our PG-TFT, based on a fine energy level engineering, represents a memory device operating without the need of a dielectric layer separating a floating gate from the active channel. PMID- 25689614 TI - Impact of skin capsular distance on the performance of controlled attenuation parameter in patients with chronic liver disease. AB - BACKGROUND & AIMS: Controlled attenuation parameter (CAP) is a non-invasive method for evaluating hepatic steatosis. However, larger skin capsular distance (SCD) can affect the accuracy. The aim of this study was to investigate the impact of SCD on the diagnostic performance of CAP and liver stiffness measurement (LSM). METHODS: Of 101 patients with non-alcoholic fatty liver disease (NAFLD) and 280 patients with chronic hepatitis B (CHB) who underwent liver biopsy were prospectively recruited. CAP, LSM and SCD were performed using FibroScan with M probe. The areas under receiver operating characteristics curves (AUROCs) were calculated to determine the diagnostic efficacy. The optimal thresholds were defined by the maximum Youden index. RESULTS: SCD (B 30.34, P < 0.001) and hepatic steatosis (B 23.04, P < 0.001) were independently associated with CAP by multivariate analysis. The AUROCs were slightly higher for SCD <25 mm compared to those for SCD >=25 mm for steatosis >=5% (0.88 vs. 0.81), >33% (0.90 vs. 0.85) and >66% (0.84 vs. 0.72). For SCD <25 mm, the optimal CAP cut-offs for differentiating steatosis >=5%, >33% and >66% were 255.0 dB/m, 283.5 dB/m and 293.5 dB/m. However, cut-offs were elevated by approximately 60-70 dB/m for SCD >=25 mm. When stratified by fibrosis grade, LSM was significantly affected by SCD >=25 mm for advanced fibrosis (>=F3) in NAFLD, but not in CHB. CONCLUSION: CAP is a promising tool for detecting and quantifying hepatic steatosis. SCD >=25 mm may cause overestimation of steatosis. Similarly, SCD >=25 mm affects the detection of advanced fibrosis by LSM in NAFLD patients. PMID- 25689616 TI - G-CSF treatment can attenuate dexamethasone-induced reduction in C2C12 myotube protein synthesis. AB - Granulocyte-colony stimulating factor (G-CSF) has been demonstrated to enhance skeletal muscle recovery following injury and increases muscle function in the context of neuromuscular disease in rodent models. However, understanding of the underlying mechanisms used by G-CSF to mediate these functions remains poor. G CSF acts on responsive cells through binding to a specific membrane spanning receptor, G-CSFR. Recently identified, the G-CSFR is expressed in myoblasts, myotubes and mature skeletal muscle tissue. Therefore, elucidating the actions of G-CSF in skeletal muscle represents an important prerequisite to consider G-CSF as a therapeutic agent to treat skeletal muscle. Here we show for the first time that treatment with moderate doses (4 and 40ng/ml) of G-CSF attenuates the effects of dexamethasone in reducing protein synthesis in C2C12 myotubes. However, a higher dose (100ng/ml) of G-CSF exacerbates the dexamethasone-induced reduction in protein synthesis. In contrast, G-CSF had no effect on basal or dexamethasone-induced protein degradation, nor did G-CSF influence the phosphorylation of Akt, STAT3, Erk1/2, Src, Lyn and Erk5 in C2C12 myotubes. In conclusion, physiologically relevant doses of G-CSF may attenuate reduced skeletal muscle protein synthesis during catabolic conditions, thereby improving recovery. PMID- 25689617 TI - Orosomucoid 1 drives opportunistic infections through the polarization of monocytes to the M2b phenotype. AB - Orosomucoid (ORM, composed of two isoforms, ORM1 and ORM2) has been described as an inducer of M2 macrophages, which are cells that decrease host antibacterial innate immunities. However, it is unknown which phenotypes of M2 macrophages are induced by ORM. In this study, healthy donor monocytes stimulated with ORM (ORM monocytes) were characterized phenotypically and biologically. CCL1 (a biomarker of M2b macrophages) and IL-10 were detected in monocyte cultures supplemented with ORM1; however, CCL17 (a biomarker of M2a macrophages) and CXCL13 (a biomarker of M2c macrophages) were not produced in these cultures. All of these soluble factors were not detected in the culture fluids of monocytes stimulated with ORM2. Monocytes stimulated with ORM1 were characterized as CD64(-)CD209( )CD163(+)CCL1(+) cells. MRSA and Enterococcus faecalis infections were accelerated in chimeras (NOD/scid IL-2Rgamma(null) mice reconstituted with white blood cells) after inoculation with monocytes stimulated with ORM1 or treatment with ORM1; however, the infections were greatly mitigated in both chimeras inoculated with ORM1-stimulated monocytes and treated with ORM1, after an additional treatment with an inhibitor of M2b macrophages (CCL1 antisense ODN). These results indicate that ORM1 stimulates quiescent monocytes to polarize to M2b monocytes. The regulation of M2b macrophages may be beneficial in controlling opportunistic infections in patients with a large amount of plasma ORM1. PMID- 25689618 TI - Serum ENA78/CXCL5, SDF-1/CXCL12, and their combinations as potential biomarkers for prediction of the presence and distant metastasis of primary gastric cancer. AB - BACKGROUND: Chemokines play important roles in cancer development and progression. Epithelial-derived neutrophil-activating peptide-78 (ENA78/CXCL5) and stromal cell-derived factor (SDF-1/CXCL12) supposedly contribute to gastric cancer (GC) development and progression. This study aims to evaluate serum levels of ENA78/CXCL5 and SDF-1/CXCL12 along the GC carcinogenesis, and analyze their clinical significance, and diagnostic potentials through human serum samples. METHODS: A total of 300 subjects were enrolled in this study. Serum levels of ENA78/CXCL5 and SDF-1/CXCL12, measured by chemiluminescent immunoassay, were compared among 4 disease groups; normal, high-risk (intestinal metaplasia and adenoma), early GC (EGC), and advanced GC (AGC) groups in both training (n=25 per group) and validation dataset (n=70, 30, 50, 50, respectively) by ANOVA test (post hoc Bonferroni). Correlations between serum ENA78/CXCL5 or SDF-1/CXCL12 levels and clinicopathological parameters of GC patients were evaluated (Spearman's correlation; gammas). To validate the diagnostic accuracy, receiver operating characteristic (ROC) curve and logistic regression analysis was performed. RESULTS: Serum ENA78/CXCL5 and SDF-1/CXCL12 levels were significantly higher in AGC groups than EGC, high-risk and normal groups in both training and validation dataset (Bonferroni, from p<0.01 to p<0.001). Clinicopathologically, serum ENA78/CXCL5 was correlated with T-stage (gammas=0.231, p=0.021) and distant metastasis (gammas=0.357, p<0.001), while serum SDF-1/CXCL12 was correlated with lymph node (gammas=0.220, p=0.029) and distant (gammas=0.425, p<0.001) metastasis. ROC curve and logistic regression demonstrated that serum ENA78/CXCL5 and SDF-1/CXCL12 showed higher diagnostic accuracy compared with carcinoembryonic antigen (CEA) in predicting GC. Serum ENA78/CXCL5 could predict both the presence of GC and distant metastasis, while serum SDF-1/CXCL12 could mainly predict its distant metastasis. All combination of serum ENA78/CXCL5, SDF-1/CXCL12, and CEA achieved 92.8% specificity at 75.0% sensitivity to predict distant metastasis of GC. CONCLUSIONS: Combinations of initial serum ENA78/CXCL5, SDF-1/CXCL12, and CEA before any treatment for GC can produce valuable serum biomarker panels to predict the presence and distant metastasis of GC. PMID- 25689619 TI - The effects of high fat diet and moderate exercise on TGFbeta1 and collagen deposition in mouse skeletal muscle. AB - Obesity is a primary cause of muscle insulin resistance and is also associated with morphological and functional changes in the skeletal muscle including fibrosis. Studies suggest that macrophages in obese skeletal muscle may be primed to secrete transforming growth factor beta1 (TGFbeta1), a factor that can stimulate type I collagen gene expression via Smad3 activation but the extent to which exercise could modulate high fat (HF) diet-induced inflammation and fibrosis in skeletal muscle remains to be determined. The purpose of this study was to determine the extent to which moderate intensity exercise training can attenuate pro-inflammatory cytokine gene expression and markers of fibrosis in skeletal muscle in response to concomitant HF diet. Male C57BL/6J mice (6 wk old) were randomly assigned to one of four treatment groups: (1) Control diet-No Exercise (CON-No Ex), (2) CON-Ex, (3) HF-No Ex, or (4) HF-Ex. Mice were exercised on a motorized treadmill 40min/day at 12m/min, 5% grade, 5days/wk, for 12weeks. Macrophage (F4/80, CD11c, CD206), inflammatory cytokine (TNFalpha, IL-6, IL-10), TGFbeta1, and collagen (Col1alpha) gene expression were evaluated in skeletal muscle by qPCR. Frozen muscle sections were stained to assess collagen content and fiber cross sectional area (CSA). F4/80, CD206 and IL-6 gene expression were increased by HF diet, and exercise only attenuated the increase in F4/80 and IL-6 (p<0.05). No differences in CD11c, TNFalpha and IL-10 gene expression were found between the groups. HF diet increased TGFbeta1 protein expression, Smad3 activation, and collagen deposition in skeletal muscle, and exercise attenuated TGFbeta1 protein expression and collagen deposition in skeletal muscle (p<0.05). Muscle fiber CSA was not different between the groups. The results from this study suggest that HF diet can increase skeletal muscle macrophage gene expression and fibrosis and that exercise can attenuate these changes. PMID- 25689620 TI - Galectin-3 is a sensor-regulator of toll-like receptor pathways in synovial fibroblasts. AB - Galectin-3 is a beta-galactoside-binding lectin that plays an important role in the modulation of immune responses. It has been shown to aggravate joint inflammation and destruction in experimental arthritis. We investigated the role of galectin-3 in TLR-induced cell activation in human synovial fibroblasts (SF) in order to better understand the mechanism(s) of the proinflammatory function of galectin-3 in arthritis. Galectin-3 expression in SF obtained from rheumatoid arthritis and osteoarthritis patients was inhibited by siRNA mediated gene knockdown. Galectin-3 was also inhibited with modified citrus pectin (MCP), a polysaccharide galectin-3 ligand. Galectin-3 knockdown inhibited TLR-2, -3 and -4 induced IL-6 secretion, but not TLR-2, -3 and -4-mediated matrix metalloproteinase-3 or CC chemokine ligand-5 secretion. When the SF were stimulated with phorbol 12-myristate 13-acetate, a protein kinase C activator that bypasses the membranal receptors, galectin-3 knockdown no longer influenced IL-6 secretion. MCP reduced IL-6 levels in a dose-dependent manner. Our results indicate that galectin-3 is a positive sensor-regulator of TLR-induced IL-6 secretion in human synovial fibroblasts, thus adding new insights into the mechanisms by which galectin-3 augments synovial inflammation. These findings corroborate the potential role of glycan inhibitors of galectin-3 as a therapeutic approach for the treatment of inflammatory arthritis. PMID- 25689621 TI - Nothing About Us Without Us? A Comparison of Adolescent and Adult Health-State Values for the Child Health Utility-9D Using Profile Case Best-Worst Scaling. AB - The main objective of this study was to compare and contrast adolescent and adult values for the Child Health Utility-9D (CHU9D), a new generic preference-based measure of health-related quality of life designed for application in the economic evaluation of treatment and preventive programmes for children and adolescents. Previous studies have indicated that there may be systematic differences in adolescent and adult values for identical health states. An online survey including a series of best-worst scaling discrete choice experiment questions for health states defined by the CHU9D was administered to two general population samples comprising adults and adolescents, respectively. The results highlight potentially important age-related differences in the values attached to CHU9D dimensions. Adults, in general, placed less weight upon impairments in mental health (worried, sad, annoyed) and more weight upon moderate to severe levels of pain relative to adolescents. The source of values (adults or adolescents) has important implications for economic evaluation and may impact significantly upon healthcare policy. PMID- 25689622 TI - Genetic architecture of fusarium head blight resistance in four winter triticale populations. AB - Fusarium head blight (FHB) is a devastating disease that causes significant reductions in yield and quality in wheat, rye, and triticale. In triticale, knowledge of the genetic architecture of FHB resistance is missing but essential due to modern breeding requirements. In our study, four doubled-haploid triticale populations (N=120 to 200) were evaluated for resistance to FHB caused by artificial inoculation with Fusarium culmorum in four environments. DArT markers were used to genotype triticale populations. Seventeen quantitative trait loci (QTL) for FHB resistance were detected across all populations; six of them were derived from rye genome and located on chromosomes 4R, 5R, and 7R, which are here reported for the first time. The total cross-validated ratio of the explained phenotypic variance for all detected QTL in each population was 41 to 68%. In all, 17 QTL for plant height and 18 QTL for heading stage were also detected across all populations; 3 and 5 of them, respectively, were overlapping with QTL for FHB. In conclusion, FHB resistance in triticale is caused by a multitude of QTL, and pyramiding them contributes to higher resistance. PMID- 25689624 TI - Subsarcolemmal and interfibrillar mitochondria display distinct superoxide production profiles. AB - Cardiac subsarcolemmal mitochondria (SSM) and interfibrillar mitochondria (IFM) subpopulations display distinct biochemical, morphological, and functional characteristics. Moreover, they appear to be differently influenced during cardiac pathologies or toxic injuries. Although mitochondrial reactive oxygen species seem to play a critical role in cardiac function and diseases, limited information exists about the superoxide production characteristics of these mitochondrial subpopulations. In this work, using direct measurement of superoxide by electron paramagnetic resonance, we showed that differences in superoxide production profiles were present between cardiac IFM and SSM, in terms of intensity and major sites of superoxide generation. In SSM incubated with glutamate plus malate as substrates, the total observed superoxide levels were significantly higher than those observed with IFM, with an important contribution of the NADH-oxidizing site of complex I (site If) and the quinol-oxidizing site of complex III (site IIIQ0). In both IFM and SSM, succinate leads to similar rates of total superoxide levels with a substantial role for contribution of reverse electron transfer. Finally, using two spin probes with different membrane permeabilities, our data on complex III showed direct intra- and extra mitochondrial superoxide release whereas complex I- and II-dependent superoxide were exclusively released inside the mitochondria, confirming previous studies. Feasibility of this approach to measure intra- and extra-mitochondrial superoxide levels and to characterize distinct superoxide production profiles of cardiac IFM and SSM has been demonstrated. PMID- 25689625 TI - Best method for analysis of brain oscillations in healthy subjects and neuropsychiatric diseases. AB - The research related to brain oscillations and their connectivity is in a new take-off trend including the applications in neuropsychiatric diseases. What is the best strategy to learn about functional correlation of oscillations? In this report, we emphasize combined application of several analytical methods as power spectra, adaptive filtering of Event Related Potentials, inter-trial coherence and spatial coherence. These combined analysis procedure gives the most profound approach to understanding of EEG responses. Examples from healthy subjects, Alzheimer's Diseases, schizophrenia, and Bipolar Disorder are described. PMID- 25689626 TI - The evidence for increased L1 activity in the site of human adult brain neurogenesis. AB - Retroelement activity is a common source of polymorphisms in human genome. The mechanism whereby retroelements contribute to the intraindividual genetic heterogeneity by inserting into the DNA of somatic cells is gaining increasing attention. Brain tissues are suspected to accumulate genetic heterogeneity as a result of the retroelements somatic activity. This study aims to expand our understanding of the role retroelements play in generating somatic mosaicism of neural tissues. Whole-genome Alu and L1 profiling of genomic DNA extracted from the cerebellum, frontal cortex, subventricular zone, dentate gyrus, and the myocardium revealed hundreds of somatic insertions in each of the analyzed tissues. Interestingly, the highest concentration of such insertions was detected in the dentate gyrus-the hotspot of adult neurogenesis. Insertions of retroelements and their activity could produce genetically diverse neuronal subsets, which can be involved in hippocampal-dependent learning and memory. PMID- 25689627 TI - Rawlsian Justice and Palliative Care. AB - Palliative care serves both as an integrated part of treatment and as a last effort to care for those we cannot cure. The extent to which palliative care should be provided and our reasons for doing so have been curiously overlooked in the debate about distributive justice in health and healthcare. We argue that one prominent approach, the Rawlsian approach developed by Norman Daniels, is unable to provide such reasons and such care. This is because of a central feature in Daniels' account, namely that care should be provided to restore people's opportunities. Daniels' view is both unable to provide pain relief to those who need it as a supplement to treatment and, without justice-based reasons to provide palliative care to those whose opportunities cannot be restored. We conclude that this makes Daniels' framework much less attractive. PMID- 25689628 TI - Vasoactivity of rucaparib, a PARP-1 inhibitor, is a complex process that involves myosin light chain kinase, P2 receptors, and PARP itself. AB - Therapeutic inhibition of poly(ADP-ribose) polymerase (PARP), as monotherapy or to supplement the potencies of other agents, is a promising strategy in cancer treatment. We previously reported that the first PARP inhibitor to enter clinical trial, rucaparib (AG014699), induced vasodilation in vivo in xenografts, potentiating response to temozolomide. We now report that rucaparib inhibits the activity of the muscle contraction mediator myosin light chain kinase (MLCK) 10 fold more potently than its commercially available inhibitor ML-9. Moreover, rucaparib produces additive relaxation above the maximal degree achievable with ML-9, suggesting that MLCK inhibition is not solely responsible for dilation. Inhibition of nitric oxide synthesis using L-NMMA also failed to impact rucaparib's activity. Rucaparib contains the nicotinamide pharmacophore, suggesting it may inhibit other NAD+-dependent processes. NAD+ exerts P2 purinergic receptor-dependent inhibition of smooth muscle contraction. Indiscriminate blockade of the P2 purinergic receptors with suramin abrogated rucaparib-induced vasodilation in rat arterial tissue without affecting ML-9 evoked dilation, although the specific receptor subtypes responsible have not been unequivocally identified. Furthermore, dorsal window chamber and real time tumor vessel perfusion analyses in PARP-1-/- mice indicate a potential role for PARP in dilation of tumor-recruited vessels. Finally, rucaparib provoked relaxation in 70% of patient-derived tumor-associated vessels. These data provide tantalising evidence of the complexity of the mechanism underlying rucaparib mediated vasodilation. PMID- 25689629 TI - Loss of normal anagen hair in pemphigus vulgaris. AB - BACKGROUND: Pemphigus vulgaris (PV) is a known cause of loss of 'normal' anagen hair; that is, shedding of intact anagen hairs covered by root sheaths. However, studies on this subject are limited. AIM: To investigate anagen hair shedding in patients with PV, and ascertain its association with disease severity. METHODS: In total, 96 consecutive patients with PV (new patients or patients in relapse) who were admitted to the dermatology wards of a tertiary hospital were enrolled in this study. Demographic data, PV phenotype, disease severity and presence of scalp lesions were recorded. A group of 10-20 hairs were pulled gently from different areas of the scalp (lesional and nonlesional skin) in all patients, and anagen hairs were counted. Disease severity was graded according to Harman score. RESULTS: Anagen hair was obtained by pull test in 59 of the 96 patients (61.5%), of whom 2 had normal scalp. The mean +/- SD anagen hair count was 5.9 +/- 7.6 (range 0-31). In univariate analysis, anagen hair loss (P < 0.01) and the presence of scalp lesions (P = 0.01) were associated with severe disease. Mean anagen hair count was significantly higher in the severe (mean 6.83 +/- 7.89) than the moderate (mean 1.06 +/- 1.94) subgroup (P < 0.001). Multivariate analysis confirmed anagen hair loss (OR = 1.16, 95% CI = 1.05-1.28, P < 0.01), but not scalp lesions (P = 0.69) as an independent predictor of disease severity. CONCLUSIONS: According to our study, normal anagen effluvium is a frequent finding in patients with PV, and interestingly, this was observed in nonlesional as well as lesional scalp. In addition, severe anagen hair loss was an independent predictor of the disease severity. PMID- 25689630 TI - Pareidolia in infants. AB - Faces convey primal information for our social life. This information is so primal that we sometimes find faces in non-face objects. Such illusory perception is called pareidolia. In this study, using infants' orientation behavior toward a sound source, we demonstrated that infants also perceive pareidolic faces. An image formed by four blobs and an outline was shown to infants with or without pure tones, and the time they spent looking at each blob was compared. Since the mouth is the unique sound source in a face and the literature has shown that infants older than 6 months already have sound-mouth association, increased looking time towards the bottom blob (pareidolic mouth area) during sound presentation indicated that they illusorily perceive a face in the image. Infants aged 10 and 12 months looked longer at the bottom blob under the upright-image condition, whereas no differences in looking time were observed for any blob under the inverted-image condition. However, 8-month-olds did not show any difference in looking time under both the upright and inverted conditions, suggesting that the perception of pareidolic faces, through sound association, comes to develop at around 8 to 10 months after birth. PMID- 25689631 TI - Effect of Pre-Stressing on the Acid-Stress Response in Bifidobacterium Revealed Using Proteomic and Physiological Approaches. AB - Weak acid resistance limits the application of Bifidobacteria as a probiotic in food. The acid tolerance response (ATR), caused by pre-stressing cells at a sublethal pH, could improve the acid resistance of Bifidobacteria to subsequent acid stress. In this study, we used Bifidobacterium longum sub. longum BBMN68 to investigate the effect of the ATR on the acid stress response (ASR), and compared the difference between the ATR and the ASR by analyzing the two-dimensional-PAGE protein profiles and performing physiological tests. The results revealed that a greater abundance of proteins involved in carbohydrate metabolism and protein protection was present after the ASR than after the ATR in Bifidobacterium. Pre stressing cells increased the abundance of proteins involved in energy production, amino acid metabolism, and peptidoglycan synthesis during the ASR of Bifidobacterium. Moreover, after the ASR, the content of ATP, NH3, thiols, and peptidoglycan, the activity of H+-ATPase, and the maintenance of the intracellular pH in the pre-stressed Bifidobacterium cells was significantly higher than in the uninduced cells. These results provide the first explanation as to why the resistance of Bifidobacterium to acid stress improved after pre stressing. PMID- 25689632 TI - Interaction of Abeta(1-42) amyloids with lipids promotes "off-pathway" oligomerization and membrane damage. AB - The toxicity of amyloids, as Abeta(1-42) involved in Alzheimer disease, is a subject under intense scrutiny. Many studies link their toxicity to the existence of various intermediate structures prior to fiber formation and/or their specific interaction with membranes. In this study we focused on the interaction between membrane models and Abeta(1-42) peptides and variants (L34T, mG37C) produced in E. coli and purified in monomeric form. We evaluated the interaction of a toxic stable oligomeric form (oG37C) with membranes as comparison. Using various biophysical techniques as fluorescence and plasmon waveguide resonance, we clearly established that the oG37C interacts strongly with membranes leading to its disruption. All the studied peptides destabilized liposomes and accumulated slowly on the membrane (rate constant 0.02 min(-1)). Only the oG37C exhibited a particular pattern of interaction, comprising two steps: the initial binding followed by membrane reorganization. Cryo-TEM was used to visualize the peptide effect on liposome morphologies. Both oG37C and mG37C lead to PG membrane fragmentation. The PG membrane promotes peptide oligomerization, implicated in membrane disruption. WT (Abeta(1-42)) also perturbs liposome organization with membrane deformation rather than disruption. For all the peptides studied, their interaction with the membranes changes their fibrillization process, with less fibers and more small aggregates being formed. These studies allowed to establish, a correlation between toxicity, fiber formation, and membrane disruption. PMID- 25689633 TI - Iron status is associated with asthma and lung function in US women. AB - BACKGROUND: Asthma and iron deficiency are common conditions. Whether iron status affects the risk of asthma is unclear. OBJECTIVE: To determine the relationship between iron status and asthma, lung function, and pulmonary inflammation. METHODS: Relationships between measures of iron status (serum ferritin, serum soluble transferrin receptor (sTfR), and sTfR/log10ferritin (sTfR-F Index)) and asthma, lung function, and pulmonary inflammation were examined in women 20-49 years in the National Health and Nutrition Examination Survey. Logistic, linear, and quadratic regression models accounting for the survey design of NHANES were used to evaluate associations between iron status and asthma-related outcomes and were adjusted for race/ethnicity, age, smoking status, income, and BMI. RESULTS: Approximately 16% reported a lifetime history of asthma, 9% reported current asthma, and 5% reported a recent asthma episode/attack (n = 2906). Increased ferritin (iron stores) was associated with decreased odds of lifetime asthma, current asthma, and asthma attacks/episodes in the range of ferritin linearly correlated with iron stores (20-300ng/ml). The highest quintile of ferritin (>76 ng/ml) was also associated with a decreased odds of asthma. Ferritin levels were not associated with FEV1. Increased values of the sTfR-F Index and sTfR, indicating lower body iron and higher tissue iron need, respectively, were associated with decreased FEV1, but neither was associated with asthma. None of the iron indices were associated with FeNO. CONCLUSION: In US women, higher iron stores were inversely associated with asthma and lower body iron and higher tissue iron need were associated with lower lung function. Together, these findings suggest that iron status may play a role in asthma and lung function in US women. PMID- 25689634 TI - Neuromyelitis optica: a positive appraisal of seronegative cases. AB - Neuromyelitis optica (NMO) is a rare inflammatory disorder of the central nervous system. The hallmark of NMO is the presence of specific autoantibodies directed against aquaporin 4 (AQP4-IgG). AQP4-IgG, included in diagnostic criteria, has enlarged the clinical spectrum of NMO and serves to predict relapses. Moreover AQP4-IgG has provided unprecedented insight in the immunopathology of NMO, representing a rationale for therapeutic intervention with relevant novel treatment strategies specific for NMO. However, some patients remain seronegative for AQP4-IgG despite a definite diagnosis of NMO and the use of the finest methods for antibody detection. Interestingly, seronegative NMO (NMO(neg)) patients exhibit different demographic and disease-related characteristics in comparison to seropositive patients. The recent association with autoantibodies specific for myelin oligodendrocyte glycoprotein (MOG) is the main indication that disease mechanisms might differ in NMO(pos) and NMO(neg), challenging the position of NMO(neg) patients in the spectrum of demyelinating diseases and therapeutic strategies to be adopted. Thus, a reappraisal of the NMO(neg) population is needed to improve NMO care. Here the current knowledge regarding NMO(neg) is reviewed and hypotheses on its pathogenesis are made including a comprehensive description of detection methods and the prevalence of AQP4-IgG and a review of the epidemiological, clinical and paraclinical characteristics of NMO(neg); finally an integrated view of the general pathophysiological mechanisms underlying NMO(neg) is provided. PMID- 25689635 TI - Has the time come to reevaluate prognostic factors and to rebuild staging systems for multiple myeloma? PMID- 25689636 TI - Perspectives on the increased risk of second cancer in patients with essential thrombocythemia, polycythemia vera and myelofibrosis. PMID- 25689637 TI - Deformation of single-walled carbon nanotubes by interaction with graphene: a first-principles study. AB - The interaction between single-walled carbon nanotubes (SWNTs) and graphene were studied with first-principles calculations. Both SWNTs and single-layer graphene (SLG) or double-layer graphene (DLG) display more remarkable deformations with the increase of SWNT diameter, which implies a stronger interaction between SWNTs and graphene. Besides, in DLG, deformation of the upper-layer graphene is less than in SLG. Zigzag SWNTs show stronger interactions with SLG than armchair SWNTs, whereas the order is reversed for DLG, which can be interpreted by the mechanical properties of SWNTs and graphene. Density of states and band structures were also studied, and it was found that the interaction between a SWNT and graphene is not strong enough to bring about obvious influence on the electronic structures of SWNTs. PMID- 25689638 TI - The association of CTLA-4 A49G polymorphism with colorectal cancer risk in a Chinese Han population. AB - Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is expressed in T cells and plays an important role in the regulation of T cell. CTLA-4 has long been considered to be associated with various kinds of diseases. With the attempt to examine the association between CTLA-4 A49G polymorphism and colorectal cancer risk in a Chinese Han population, we employed TaqMan assay to genotype the CTLA-4 A49G polymorphism in 311 colorectal cancer cases and 389 cancer-free controls. We found evidence of the association between CTLA-4 A49G polymorphism and colorectal cancer risk (GG vs. AA: OR = 2.01, 95% CI = 1.29-3.07, P = 0.002; GA vs. AA: OR = 2.32, 95% CI = 1.53-3.57, P = 0.001; GA + GG vs. AA: OR = 2.16, 95% CI = 1.46 3.21, P = 0.001). Next, we performed a meta-analysis to comprehensively examine the association between CTLA-4 A49G polymorphism and colorectal cancer risk. We found a significant association between CTLA-4 A49G polymorphism and colorectal cancer risk among Asians, which is consistent with our result. However, we found no evidence for the association between CTLA-4 A49G polymorphism and colorectal cancer risk among Caucasians. In conclusion, we demonstrated that the CTLA-4 A49G polymorphism increased the susceptibility of colorectal cancer in Asian population. PMID- 25689639 TI - Urine and serum metabolite profiling of rats fed a high-fat diet and the anti obesity effects of caffeine consumption. AB - In this study, we investigated the clinical changes induced by a high fat diet (HFD) and caffeine consumption in a rat model. The mean body weight of the HFD with caffeine (HFDC)-fed rat was decreased compared to that of the HFD-fed rat without caffeine. The levels of cholesterol, triglycerides (TGs), and free fatty acid, as well as the size of adipose tissue altered by HFD, were improved by caffeine consumption. To investigate the metabolites that affected the change of the clinical factors, the urine and serum of rats fed a normal diet (ND), HFD, and HFDC were analyzed using ultra performance liquid chromatography quadruple time-of-flight mass spectrometry (UPLC-Q-TOF-MS), gas chromatography (GC-TOF-MS), and linear trap quadruple mass spectrometry (LTQ-XL-MS) combined with multivariate analysis. A total of 68 and 52 metabolites were found to be different in urine and serum, respectively. After being fed caffeine, some glucuronide-conjugated compounds, lysoPCs, CEs, DGs, TGs, taurine, and hippuric acid were altered compared to the HFD group. In this study, caffeine might potentially inhibit HFD-induced obesity and we suggest possible biomarker candidates using MS-based metabolite profiling. PMID- 25689640 TI - Potential quality evaluation method for Radix Astragali based on sweetness indicators. AB - Sweetness is a traditional sensory indicator used to evaluate the quality of the popular Chinese herb Radix Astragali (RA). RA roots with strong sweetness are considered to be of good quality. However, neither a thorough analysis of the component(s) contributing to RA sweetness, nor a scientific investigation of the reliability of this indicator has been conducted to date. In this study, seven kinds of sweetness components were identified in RA and a quality evaluation method based on these components was established and used to characterize the quality of 48 RA samples. The sweetness evaluation method of RA was first built based on the sweetness components, and a comprehensive evaluation index commonly used in quality control of RA was also derived, which was based on the contents of four indicators (astragaloside IV, calycosin glucoside, polysaccharides and extracts). After evaluating the correlation of these indexes the results showed that the level of sweetness exhibited a strong positive correlation with the proposed comprehensive index. Our results indicate that sweetness is one of the most important quality attributes of RA and thus provide a scientific basis for the utility of the sweetness indicator in quality assessment of this Chinese herb. PMID- 25689641 TI - Spectroscopic (FT-IR, FT-Raman, 1H- and 13C-NMR), theoretical and microbiological study of trans o-coumaric acid and alkali metal o-coumarates. AB - This work is a continuation of research on a correlation between the molecular structure and electronic charge distribution of phenolic compounds and their biological activity. The influence of lithium, sodium, potassium, rubidium and cesium cations on the electronic system of trans o-coumaric (2-hydroxy-cinnamic) acid was studied. We investigated the relationship between the molecular structure of the tested compounds and their antimicrobial activity. Complementary molecular spectroscopic techniques such as infrared (FT-IR), Raman (FT-Raman), ultraviolet-visible (UV-VIS) and nuclear magnetic resonance (1H- and 13C-NMR) were applied. Structures of the molecules were optimized and their structural characteristics were calculated by the density functional theory (DFT) using the B3LYP method with 6-311++G** as a basis set. Geometric and magnetic aromaticity indices, atomic charges, dipole moments and energies were also calculated. Theoretical parameters were compared to the experimental characteristics of investigated compounds. Correlations between certain vibrational bands and some metal parameters, such as electronegativity, ionization energy, atomic and ionic radius, were found. The microbial activity of studied compounds was tested against Escherichia coli, Bacillus subtilis, Pseudomonas aeruginosa, Staphylococcus aureus, Proteus vulgaris and Candida albicans. PMID- 25689642 TI - Synthesis and antimicrobial activity of N-substituted-beta-amino acid derivatives containing 2-hydroxyphenyl, benzo[b]phenoxazine and quinoxaline moieties. AB - 3-[(2-Hydroxyphenyl)amino]butanoic and 3-[(2-hydroxy-5 methyl(chloro)phenyl)amino]butanoic acids were converted to a series of derivatives containing hydrazide, pyrrole and chloroquinoxaline moieties. The corresponding benzo[b]phenoxazine derivatives were synthesized by the reaction of the obtained compounds with 2,3-dichloro-1,4-naphthoquinone. Five of the synthesized compounds exhibited good antimicrobial activity against Staphylococcus aureus and Mycobacterium luteum, whereas three compounds showed significant antifungal activity against Candida tenuis and Aspergillus niger. PMID- 25689643 TI - The power of story in delivering cancer care. PMID- 25689644 TI - The unique supportive care needs of a mother with acute myeloid leukemia during treatment. AB - Acute myeloid leukemia (AML) is an aggressive cancer of the blood that is linked with poor survival. The disease requires immediate intensive chemotherapy treatment that leaves patients hospitalized for at least one month and often longer, depending on their supportive care needs. Mothers undergoing treatment for AML may benefit from having attention paid to their supportive care needs during that time. PMID- 25689645 TI - Improving patient safety in the inpatient setting through risk assessment and mitigation. AB - This article describes a working tool for clinicians in an inpatient oncology unit, aimed at preventing adverse events and increasing the clinical safety of patients with cancer. With the development of a catalog of adverse events and a risk map, healthcare providers are able to implement safe, best practices in daily activities. PMID- 25689646 TI - Watson will see you now: a supercomputer to help clinicians make informed treatment decisions. AB - IBM has collaborated with several cancer care providers to develop and train the IBM supercomputer Watson to help clinicians make informed treatment decisions. When a patient is seen in clinic, the oncologist can input all of the clinical information into the computer system. Watson will then review all of the data and recommend treatment options based on the latest evidence and guidelines. Once the oncologist makes the treatment decision, this information can be sent directly to the insurance company for approval. Watson has the ability to standardize care and accelerate the approval process, a benefit to the healthcare provider and the patient. PMID- 25689647 TI - A nurse-led evidence-based practice project to monitor and improve the management of chemotherapy-induced nausea and vomiting. AB - Chemotherapy-induced nausea and vomiting (CINV) is a common and severe symptom experienced by patients undergoing cancer treatment during the acute or delayed period. Individual characteristics can compound risk for CINV. Identification of risk factors for CINV and structured, nurse-led telephone follow-up are effective, evidence-based methods to support patients undergoing cancer treatment. The authors successfully implemented a structured, nurse-led CINV intervention to improve assessment, follow-up, and support for 30 patients undergoing chemotherapy within an adult ambulatory oncology clinic. PMID- 25689648 TI - Radiation safety in the management of patients undergoing radioactive iodine ablation therapy. AB - High-dose radioiodine therapy for thyroid cancer poses risks to healthcare workers, family members, and the public. Oncology nurses can effectively manage these risks by employing the three key principles of time, distance, and shielding. PMID- 25689649 TI - Cognitive changes associated with cancer and cancer treatment: state of the science. AB - BACKGROUND: Cognitive impairment is a distressing, disruptive, and potentially debilitating symptom that can occur as a direct result of cancer or its treatment. National organizations have identified cognitive impairment as a challenge many survivors face and call for research to address this problem. Despite the priority, research is still relatively limited and questions remain unanswered about prevalence and impact on survivors, as well as coping strategies and effective treatment options available to address this potentially debilitating problem. OBJECTIVES: The purpose of this article is to (a) analyze the prevalence and types of cognitive impairment that commonly affect survivors; (b) delineate the impact that cognitive impairment after cancer and cancer treatment has on self-esteem, social relationships, work ability, and overall quality of life among survivors; and (c) synthesize and appraise commonly used coping strategies used by survivors to address cognitive impairment and evidence based interventions that may be incorporated into clinical practice. METHODS: A comprehensive review and synthesis of the literature was conducted. FINDINGS: Evidence-based interventions to address cognitive changes after cancer and cancer treatment are limited. However, emerging research has demonstrated that nonpharmacologic treatments, such as cognitive training, are likely to be effective. PMID- 25689650 TI - Biologic, demographic, and social factors affecting triple negative breast cancer outcomes. AB - BACKGROUND: Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype that disproportionately affects women who are African American, younger, or carriers of the BRCA1 gene. No targeted treatments exist for the disease, which has distinct features and presents unique challenges to patients who have been diagnosed with it. OBJECTIVES: TNBC is reviewed in this article according to incidence, tumor grade, stage of diagnosis, biologic and social risk factors, mortality, and treatment. METHODS: Published articles pertaining to TNBC and located through online database searches were reviewed. Articles were selected either because they offered the most current information about TNBC or contributed to the understanding of TNBC. FINDINGS: Biologic, demographic, and social factors present unique challenges in the treatment of women with TNBC. Knowing about the characteristics of TNBC and the populations who are most at risk for the disease might help healthcare providers better respond to their patients. It may also facilitate responsiveness to patients' needs and enhance their quality of life. PMID- 25689651 TI - Bladder cancer: a focus on sexuality. AB - BACKGROUND: A bladder cancer diagnosis and the effects of treatment can have a significant impact on a patient's physical, emotional, and psychological well being. Because healthcare providers tend to focus on these aspects of care, a patient's concerns with changes regarding sexual health are often overlooked. OBJECTIVES: The purpose of this article is to provide oncology nurses with an overview of causes of and treatment for sexual dysfunction as it relates to patients with bladder cancer. METHODS: Data were extracted using key words and phrases such as bladder cancer, cystoscopy, cystectomy, pelvic exenteration, and sexual dysfunction. FINDINGS: Oncology nurses are ideal healthcare providers to assess the sexual health concerns of patients with bladder cancer. Oncology nurses can be valuable resources for patients by giving them permission to discuss sexual health, educating them and their partners about potential implications of treatment on sexuality, reviewing treatment options, and facilitating referrals to other providers who specialize in treating sexual dysfunction. PMID- 25689652 TI - The impact of an oral hygiene education module on patient practices and nursing documentation. AB - BACKGROUND: Oral hygiene is inconsistent among patients with cancer and is a national patient care issue. To promote comfort and nutritional status, oral hygiene for patients with cancer is important. OBJECTIVES: The purpose of this study was to develop an evidence-based oral hygiene educational module (EM) for nursing and patient care technician (PCT) staff to promote consistent oral hygiene patient education; evaluate patient understanding of oral hygiene practices post-EM; and determine staff documentation frequency of oral hygiene care. METHODS: Pre- and post-EM data were collected using a developed oral hygiene assessment tool; nursing documentation data were collected by chart review. Post-EM data were collected eight weeks post-EM. Data were analyzed using frequencies and the Mann-Whitney U test. FINDINGS: Twenty-two patient documentation pairs were collected. Compared to pre-EM, admission teaching, patient education, and patient oral hygiene practices improved post-EM. Post-EM oral hygiene documentation and PCT teaching increased. PMID- 25689653 TI - Self-reported sleep problems in adolescent survivors of childhood cancer. AB - BACKGROUND: Although sleep problems are common among adult cancer survivors, little is known about sleep problems in adolescent survivors of childhood cancer (ASCC). OBJECTIVES: This study sought to describe (a) the prevalence of self reported sleep problems among ASCC before treatment, during treatment, following treatment, and in survivorship follow-up; (b) the relationship between sleep problems and self-reported adverse psychosocial outcomes; and (c) the relationship between sleep problems, treatment, and disease. METHODS: Baseline surveys were received from 173 ASCC aged 13-19 years. Chi-square analyses and odds ratios were used to determine associations between sleep problems and adverse psychosocial outcomes and treatment-related variables. FINDINGS: Sleep problems were reported before treatment (6%), during treatment (18%), after treatment (15%), and at present (11%). ASCC reporting sleep problems reported more adverse psychosocial outcomes than those without. Significant associations (p <= 0.05) between sleep problems and difficulty in school were identified at all time points. Sleep problems were associated with depressive symptoms, memory problems, and anxiety during and after treatment and at present. PMID- 25689654 TI - Understanding colorectal screening behaviors and factors associated with screening in a community hospital setting. AB - BACKGROUND: Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the second leading cause of cancer death in the United States. More than 2,000 Kentuckians are diagnosed with CRC annually, and more than 800 die from the disease. Little research has been conducted in Kentucky to better understand why individuals are not screened for CRC and what strategies might encourage them to do so. OBJECTIVES: The purpose of this study was to evaluate the efficacy of educational materials mailed to participants supporting the need for CRC screening on the decision to complete screening post-hospital discharge. An additional focus was to identify the characteristics of individuals screened and not screened. METHODS: A quasi-experimental study was conducted on 167 adult patients discharged from a 383-bed Magnet-designated hospital. An investigator designed, semistructured telephone interview was conducted to collect data on research-based factors identified to influence CRC screening rates. FINDINGS: Although not statistically significant, slightly more patients who remembered receiving educational materials in the mail completed screening. Future educational efforts should focus on the importance of screening and financial resource availability. PMID- 25689655 TI - Epstein-Barr virus-associated post-transplantation lymphoproliferative disorder: potential treatments and implications for nursing practice. AB - BACKGROUND: Considered to be a secondary malignancy, Epstein-Barr virus (EBV) associated post-transplantation lymphoproliferative disorder (PTLD) is a potentially fatal complication of hematopoietic cell transplantation (HCT). With 50%-70% of all reported cases of PTLD being associated with EBV, the incidence in HCT is relatively low. However, mortality rates in this population of patients are 70%-90%. OBJECTIVES: The focus of this article is to discuss published literature regarding the risk factors, clinical manifestations, diagnosis, prevention, and potential treatment options for EBV-PTLD, as well as nursing implications and the importance of patient education in high-risk HCT recipients. METHODS: This review of literature focused on locating, summarizing, and synthesizing data from published clinical studies that focused on treatment options, guidelines, and recommendations for EBV-PTLD. CINAHL(r) and PubMed databases were used to search for articles published within the past 10 years that included the following key words: post-transplantation lymphoproliferative disorder, Epstein-Barr virus, and hematopoietic cell transplantation. FINDINGS: Prevention and preemptive therapy are paramount when caring for patients undergoing HCT. Early determination of risk, close observation of EBV DNA levels in the blood, and prompt initiation of therapy are essential to improving patients' overall prognosis. Reduction in immunosuppression is considered first line therapy for those diagnosed with EBV-PTLD. The literature also supports rituximab-based therapies, administration of EBV-specific cytotoxic T cells, and donor lymphocyte infusion as treatment strategies. PMID- 25689656 TI - Sperm banking: fertility preservation for male patients with cancer. AB - Sperm banking (SB) involves collecting and freezing sperm for potential future use. It is a simple, noninvasive way for male patients with cancer to preserve their ability to have biologic children. This article provides the information needed by nurses to effectively discuss SB with their patients. PMID- 25689657 TI - Fecal microbiota transplantation in patients with cancer undergoing treatment. AB - Fecal microbiota transplantation (FMT) is a technique used to restore the normal body flora to the gut in cases of Clostridium difficile infection (CDI). It involves instillation of the stool of a healthy donor through a nasogastric tube or colonoscopy into the gastrointestinal tract of the patient. More research is needed to determine the parameters of FMT use in patients with cancer. PMID- 25689658 TI - Stress among new oncology nurses. AB - New oncology nurses face multiple stressors related to the predicted nursing shortage,demanding work responsibilities, and growing complexity of cancer care. The confluence of these stressors often causes new nurses to leave their profession. The loss of new nurses leads to staffing, economic, and safety concerns, which have a significant impact on the quality of oncology nursing care. PMID- 25689659 TI - Personalized risk communication for informed decision making about screening tests. PMID- 25689660 TI - Scars of survivorship. PMID- 25689662 TI - Effect of nurse navigation on patient care satisfaction and distress associated with breast biopsy. AB - BACKGROUND: Navigation during the biopsy period is a superior approach to delivering care, with those patients receiving services experiencing less distress. Critical nurse navigator roles include providing information and facilitating access to the healthcare system, both of which are influential on distress. The information in this article supports the expansion of navigation programs to include women undergoing biopsy and aids in promoting a higher standard of care. OBJECTIVES: To evaluate the effect of navigation on care satisfaction and distress in women undergoing breast biopsy. METHODS: A descriptive, cross-sectional survey design from two outpatient radiology clinics in Appalachia was used. FINDINGS: Navigated women had lower scores on every distress measure and were less likely to seek information from an outside source. Women who were more satisfied with their care reported decreased distress; the factors influencing distress varied depending on whether they were the recipient of navigation services. In the non-navigated population, general satisfaction with care and accessibility were more likely to influence distress. PMID- 25689663 TI - Caring for the continuum of patients with pancreatic cancer: the importance of survivorship care planning. AB - BACKGROUND: Pancreatic cancer is widely recognized as one of the most formidable cancer diagnoses. However, whether aggressive treatment is undertaken or not, it is critical for all care providers to understand the treatment plan. Survivorship care plans are a new trend in improving communication between the providers and the patient. OBJECTIVES: The current article will outline the pathophysiology, risk factors, diagnosis and prognosis, treatment, and potential complications of pancreatic cancer. METHODS: The importance of survivorship care planning will be demonstrated through a case study presentation and evidence-based discussion. In addition, a general template for a survivorship care plan has been included. FINDINGS: Based on a review of current literature and recommendations, it can be concluded that survivorship care planning would be beneficial for all patients with cancer. This simple tool has the potential to improve coordination of care and patient satisfaction. PMID- 25689664 TI - Management of tumor lysis syndrome in patients with multiple myeloma during bortezomib treatment. AB - BACKGROUND: Tumor lysis syndrome (TLS) is a severe, life-threatening complication that typically occurs in highly proliferative malignancies. Although TLS is unusual in multiple myeloma (MM), it is still associated with significant morbidity. Bortezomib has been widely used for the treatment of MM with encouraging results, but TLS seems to occur more frequently in patients with MM receiving bortezomib than in patients receiving other conventional agents. OBJECTIVES: The purpose of this article is to present and examine several significant risk factors for the development of TLS, based on the results of a study involving patients with MM who developed TLS during bortezomib treatment. METHODS: Patients with MM were treated with bortezomib-containing regimens. FINDINGS: The early identification and intervention of high-risk patients with MM is imperative. Timely and efficient management could decrease TLS incidence rates and improve the efficacy of treatment outcomes. PMID- 25689665 TI - Preventive measures for cyclophosphamide-related hemorrhagic cystitis in blood and bone marrow transplantation: an Italian multicenter retrospective study. AB - BACKGROUND: Hemorrhagic cystitis (HC) is a troublesome and potentially life threatening complication of bone marrow transplantation (BMT). HC can appear within a few hours after chemotherapy or after weeks or months. Early-onset HC (EOHC) is usually associated with the conditioning regimen. OBJECTIVES: The main aim of this study was to describe the incidence of EOHC in patients undergoing BMT regimens including high-dose cyclophosphamide (CY) and the effects of the main preventive measures adopted in Italian nursing practice. METHODS: The authors retrospectively analyzed the clinical records of 158 Italian patients who underwent BMT from 2006-2008. FINDINGS: Thirty-one patients (19.6%) developed EOHC. One hundred and forty-seven patients (93%) given high-dose CY were treated with hyperhydration combined with 2-mercaptoethane sulphonate (mesna) and diuresis alkalinization, and only 51 (32.3%) patients were preventively catheterized and received continuous bladder irrigation (CBI). By univariate analysis, prophylactic urethral catheterization and CBI did not decrease EOHC incidence questioning if these measures were to be routinely recommended. Previous studies showed increased discomfort and urinary tract infection in catheterized patients; therefore, nurses may fulfill an important role in balancing the benefits and harms of preventive catheterization and CBI in patients who received BMT conditioning including high-dose CY. PMID- 25689666 TI - Mister Sandman, bring me good marks! On the relationship between sleep quality and academic achievement. AB - There is growing evidence that health factors affect tertiary education success in a causal way. This study assesses the effect of sleep quality on academic achievement at university. To this end, we surveyed 804 students about their sleep quality by means of the Pittsburgh Sleep Quality Index (PSQI) before the start of their first exam period in December 2013 at Ghent University. PSQI scores were merged with course marks in this exam period. Instrumenting PSQI scores by sleep quality during secondary education, we find that increasing total sleep quality with one standard deviation leads to 4.85 percentage point higher course marks. Based on this finding, we suggest that higher education providers might be incentivised to invest part of their resources for social facilities in professional support for students with sleep and other health problems. PMID- 25689667 TI - Health policy for the poor: an exploration on the take-up of means-tested health benefits in Turkey. AB - Recent healthcare reform in Turkey aims at achieving universal coverage with the introduction of General Health Insurance (GHI). As part of GHI, the state assumes the provision of health insurance coverage to those unable to afford the public health insurance premiums conditional on a means-testing procedure where the official threshold is set as one-third of the gross minimum wage. This article aims at exploring in Turkey the prevalence of non-take up of means-tested health insurance for the poor and the consequent financial burdens for those poor segments outside the coverage. Based upon Statistics of Income and Living Conditions micro data, the non-take-up rate is estimated to be around 44%, where the prevalence of non-take-up is lower yet still high, i.e. around 30%, for households with very low incomes as well as those with elderly or ill members. The results from a separate health expenditure survey on urban poor, which is specifically designed and implemented by the authors, reveal that poor households without health insurance coverage are faced with significant out-of-pocket expenditures. About 5% of those households without coverage were found to have inpatient expenditures that exceeded 20% of their annual disposable household income. Also, among the households without coverage but with at least one inpatient visit over the last two years, the median expenditure was reported as high as 8% of the annual household income as opposed to 0% median value for those with GHI. The results highlight that a large proportion of poor population still lacks public health insurance despite the overarching aim of universal coverage. PMID- 25689668 TI - Unemployment in Scandinavia during an economic crisis: cross-national differences in health selection. AB - Are people with ill health more prone to unemployment during the ongoing economic crisis? Is this health selection more visible among people with low education, women, or the young? The current paper investigates these questions in the Scandinavian context using the longitudinal part of the EU-SILC data material. Generalized least squares analysis indicates that people with ill health are laid off to a higher degree than their healthy counterparts in Denmark, but not in Norway and Sweden. Additionally, young individuals (<30 years) with ill health have a higher probability of unemployment in both Norway and Sweden, but not in Denmark. Neither women with ill health, nor individuals with low educational qualifications and ill health, are more likely to lose their jobs in Scandinavia. Individual level (and calendar year) fixed effects analysis confirms the existence of health selection out of employment in Denmark, whereas there is no suggestion of health selection in Sweden and Norway, except among young individuals. This finding could be related to the differing labor market demand the three Scandinavian countries have experienced during and preceding the study period (2007-2010). Another possible explanation for the cross-national differences is connected to the Danish "flexicurity" model, where the employment protection is rather weak. People with ill health, and hence more unstable labor market attachment, could be more vulnerable in such an arrangement. PMID- 25689669 TI - Genome-wide survey of artificial mutations induced by ethyl methanesulfonate and gamma rays in tomato. AB - Genome-wide mutations induced by ethyl methanesulfonate (EMS) and gamma irradiation in the tomato Micro-Tom genome were identified by a whole-genome shotgun sequencing analysis to estimate the spectrum and distribution of whole genome DNA mutations and the frequency of deleterious mutations. A total of ~370 Gb of paired-end reads for four EMS-induced mutants and three gamma-ray irradiated lines as well as a wild-type line were obtained by next-generation sequencing technology. Using bioinformatics analyses, we identified 5920 induced single nucleotide variations and insertion/deletion (indel) mutations. The predominant mutations in the EMS mutants were C/G to T/A transitions, while in the gamma-ray mutants, C/G to T/A transitions, A/T to T/A transversions, A/T to G/C transitions and deletion mutations were equally common. Biases in the base composition flanking mutations differed between the mutagenesis types. Regarding the effects of the mutations on gene function, >90% of the mutations were located in intergenic regions, and only 0.2% were deleterious. In addition, we detected 1,140,687 spontaneous single nucleotide polymorphisms and indel polymorphisms in wild-type Micro-Tom lines. We also found copy number variation, deletions and insertions of chromosomal segments in both the mutant and wild-type lines. The results provide helpful information not only for mutation research, but also for mutant screening methodology with reverse-genetic approaches. PMID- 25689670 TI - Batesian mimicry promotes pre- and postmating isolation in a snake mimicry complex. AB - We evaluated whether Batesian mimicry promotes early-stage reproductive isolation. Many Batesian mimics occur not only in sympatry with their model (as expected), but also in allopatry. As a consequence of local adaptation within both sympatry (where mimetic traits are favored) and allopatry (where nonmimetic traits are favored), divergent, predator-mediated natural selection should disfavor immigrants between these selective environments as well as any between environment hybrids. This selection might form the basis for both pre- and postmating isolation, respectively. We tested for such selection in a snake mimicry complex by placing clay replicas of sympatric, allopatric, or hybrid phenotypes in both sympatry and allopatry and measuring predation attempts. As predicted, replicas with immigrant phenotypes were disfavored in both selective environments. Replicas with hybrid phenotypes were also disfavored, but only in a region of sympatry where previous studies have detected strong selection favoring precise mimicry. By fostering immigrant inviability and ecologically dependent selection against hybrids (at least in some habitats), Batesian mimicry might therefore promote reproductive isolation. Thus, although Batesian mimicry has long been viewed as a mechanism for convergent evolution, it might play an underappreciated role in fueling divergent evolution and possibly even the evolution of reproductive isolation and speciation. PMID- 25689671 TI - An integrated approach to bovine oocyte quality: from phenotype to genes. AB - In cattle, early embryonic failure plays a major role in the limitation of reproductive performance and is influenced by genetic effects. Suboptimal oocyte quality, including an inadequate store of maternal factors, is suspected to contribute to this phenomenon. In the present study, 13 Montbeliarde cows were phenotyped on oocyte quality, based on their ability to produce viable embryos after in vitro maturation, fertilisation and culture for 7 days. This discriminated two groups of animals, exhibiting developmental rates below 18.8% or above 40.9% (relative to cleaved embryos). Using microarrays, transcriptomic profiles were compared between oocytes collected in vivo from these two groups of animals. The difference in oocyte development potential was associated with changes in transcripts from 60 genes in immature oocytes and 135 genes in mature oocytes (following Bonferroni 5% correction). Of these, 16 and 32 genes were located in previously identified fertility quantitative trait loci. A subset of differential genes was investigated on distinct samples by reverse transcription quantitative polymerase chain reaction. For SLC25A16, PPP1R14C, ROBO1, AMDHD1 and MEAF6 transcripts, differential expression was confirmed between high and low oocyte potential animals. Further sequencing and searches for polymorphisms will pave the way for implementing their use in genomic selection. PMID- 25689672 TI - Photopatterning of stable, low-density, self-assembled monolayers on gold. AB - Photoinitiated thiol-yne chemistry is utilized as a click reaction for grafting of acid-terminated alkynes to thiol-terminated monolayers on a gold substrate to create stable, low-density monolayers. The resulting monolayers are compared with a well-packed 11-mercaptoundecanoic acid monolayer and the analogous low-density monolayers prepared through a solution phase synthetic approach. The overall structuring of the monolayer prepared by solid-phase grafting is characterized by contact angle goniometry and Fourier transform infrared spectroscopy. The results show that the product monolayer has an intermediate surface energy and a more disordered chemical structuring compared to a traditional well-packed self assembled monolayer, showing a low-packing density of the chains at the monolayer surface. The monolayer's structure and electrochemical stability were studied by reductive desorption of the thiolates. The prepared low-density monolayers have a higher electrochemical stability than traditional well-packed monolayers, which results from the crystalline structure at the gold interface. This technique allows for simple, fast preparation of low-density monolayers of higher stability than well-packed monolayers. The use of a photomask to restrict light access to the substrate yielded these low-density monolayers in patterned regions defined by light exposure. This general thiol-yne approach is adaptable to a variety of analogous low-density monolayers with diverse chemical functionalities. PMID- 25689673 TI - Two-quartet G-quadruplexes formed by DNA sequences containing four contiguous GG runs. AB - The DNA sequence containing four contiguous GG runs (G2NxG2NyG2NzG2, G2 sequence) has the potential to form a two-quartet G-quadruplex. However, the prevalence, structure, and function of G2 sequences have not been well-studied. Here, bioinformatics analysis reveals the abundance of G2 sequences in the human genome and their enrichment in promoter regions. The density of G2 sequences in the genome and promoters is much higher than that of the G3 sequence (G3NxG3NyG3NzG3). Experiments show that the conformations and thermal stabilities of the two-quartet G-quadruplexes of G2 sequences are highly sensitive to the length and composition of the loops. Among the two-quartet G-quadruplexes, the parallel G-quadruplex with a loop length of 1 and the antiparallel G-quadruplex with a loop length of 3 show high thermal stabilities. Additionally, the stable parallel G-quadruplexes are stacked into intermolecular higher-order structures. This work determines the prevalence of G2 sequences in the human genome and demonstrates that the G-quadruplex structures for certain loop lengths and compositions may be stable in vivo. Thus, more attention should be paid to the structure and function of the two-quartet G-quadruplex. PMID- 25689674 TI - beta-Keto-dioxinones and beta,delta-diketo-dioxinones in biomimetic resorcylate total synthesis. AB - Resorcylates are a large group of bioactive natural products that are biosynthesized from acetate and malonate units via the intermediacy of polyketides. These polyketides undergo cyclization reactions to introduce the aromatic core. The bioactivities of the resorcylates including resorcylate macrocyclic lactones include anticancer, antimalarial, mycotoxicity, antifungal, and antibiotic properties, and several compounds in the series are already in use in medicine. Examples are prodrugs derived from mycophenolic acid as immunosuppressants and the Hsp-90 inhibitor, AT13387, which is in phase-II clinical trials for the treatment of small cell lung cancer and melanoma. In consequence of these biological activities, methods for the concise synthesis of diverse resorcylates are of considerable importance. In natural product chemistry, biomimetic total synthesis can have significant advantages including functional group tolerance in key steps, the minimization of the use of protection and deprotection reactions and the shortening of the total number of synthetic steps. This Account provides a description of our adaption of the dioxinone chemistry of Hyatt, Clemens, and Feldman for the synthesis and retro Diels-Alder reactions of diketo-dioxinones. Such dioxinones, which were synthesized by a range of C-acylation reactions, were found to undergo retro Diels-Alder reactions on heating to provide the corresponding triketo-ketenes with the loss of acetone. The ketene reactive intermediates were rapidly trapped both inter- and intramolecularly with alcohols to provide the corresponding beta,delta,zeta-triketo-esters. These compounds, which consist of keto-enol mixtures, readily undergo cycloaromatization to produce resorcylate esters and macrocyclic lactones. We have established the use of diketo-dioxinones as key general intermediates for the synthesis of diverse resorcylate natural products and for the synthesis of new classes of compounds for the generation of medicinal chemistry lead structures. Many of the methods used were found to be tolerant of multiple sensitive functional groups. These include enolate C-acylations with acyl chlorides, 1-acyl-benzotriazoles, acyl imidazolides, or Weinreb amides to prepare diketo-dioxinones and their subsequent use to prepare beta,delta,zeta triketo-esters and lactones and hence resorcylates. In addition, in most cases, phenol protection was avoided. As an alternative to the synthesis of beta,delta,zeta-triketo-esters, diketo-dioxinones were also found to undergo cycloaromatization with retention of the ketal entity via a nonketene pathway. Finally, diketo-dioxinones with an allyl, prenyl, geranyl, or other 2-alkenyl carboxylate esters at the gamma-carbon underwent decarboxylative rearrangement with tetrakis(triphenylphosphine)palladium catalysis to produce alpha-substituted diketo-dioxinones and resorcylates with 3-allyl, prenyl, geranyl, or other 2 alkenyl groups. Such diketo-dioxinone chemistry was used in the total synthesis of natural products including aigialomycin, cruentaren A, and the oligomeric resorcylate antibiotics ent-W1278 A, B, and C. Additionally, tandem use of the decarboxylative rearrangement process and cycloaromatization was used in the total synthesis of natural products including the methyl ester of cristatic acid, mycophenolic acid, and hongoquercin B. The methodology was also applied to the synthesis of 9,10-anthraquinones, o-aminoalkyl resorcylates, dihydroxyisoindolinones, oligomers, and resorcinamides. The development of this methodology is described in this Account, showcasing its applicability and versatility for the synthesis of complex resorcylate products. PMID- 25689675 TI - Osteoblast biocompatibility of novel chitosan crosslinker, hexamethylene-1,6 diaminocarboxysulfonate. AB - Chitosan is a naturally occurring polysaccharide, which has proven to be an attractive candidate for bone tissue engineering, due to its ability to promote osteoblast mineralization. Electrospinning has become a well-established cell scaffold processing technique, as it produces a high surface area to volume fibrous material that can mimic the three dimensionality of the extracellular matrix of a cell. In this study, we have investigated the osteoblast response to two different chemically crosslinked (hexamethylene-1,6-diaminocarboxysulfonate (HDACS) and genipin) electrospun chitosan scaffolds and their film counterparts in order to determine how material chemistry influences cellular behavior in conjunction with material topology. In addition, material properties of each fiber scaffold such as porosity and tensile strength were considered. MLO-A5 osteoblast cells grown on chitosan-HDACS scaffolds were found to display a more organized cellular network, along with significantly more filopodia extensions, compared to those grown on chitosan-genipin scaffolds. After 2 days of growth on chitosan-HDACS fibers, a higher level of alkaline phosphatase expression in MLO A5 cells was reported compared to that of either chitosan-genipin fibers or films. These results indicate that not only chemistry, but also surface topology is an important effecter of cellular behavior. Ultimately, chitosan-HDACS fiber scaffolds provided an adequate substrate for osteoblast attachment and proliferation. PMID- 25689676 TI - Optimization of Aqueous SI-ATRP Grafting of Poly(Oligo(Ethylene Glycol) Methacrylate) Brushes from Benzyl Chloride Macroinitiator Surfaces. AB - Poly(oligo(ethylene glycol) methacrylate) (pOEGMA) brushes were grafted via surface-initiated atom transfer radical polymerization (SI-ATRP) from a poly(styrene-co-vinylbenzyl chloride) macroinitiator. While bromoisobutyryl initiator groups are most commonly used for this purpose, benzyl chloride initiators may be advantageous for some applications due to superior stability. Water-only graft solutions produced thicker brush coatings with superior low fouling properties (low protein adsorption and cell adhesion) versus mixed water/alcohol solutions. Coatings produced using 475 Da OEGMA (methyl ether terminated) further reduced non-specific interactions compared to 360 Da OEGMA (hydroxyl terminated). Initiator density had minimal effect on low fouling properties. PMID- 25689677 TI - N-acetyltransferase polymorphisms are associated with risk of lymphoma subtypes. AB - Genes encoding for arylamine N-acetyltransferase 1 and 2 (NAT1 and NAT2) have been investigated with alternate findings in relation to risk of non-Hodgkin lymphoma (NHL). We tested functional haplotype-based NAT1 and NAT2 gene polymorphisms in relation to risk of lymphoma overall and its major B cell subtypes, diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL) and chronic lymphocytic leukaemia (CLL). We used allele specific primers and multiplex PCR to detect NAT1 and NAT2 haplotypes in 248 patients with incident lymphoma and 208 population controls. We inferred the NAT1 rapid and slow acetylator and the NAT2 rapid, intermediate or slow acetylator phenotype, based on published functional data on the respective genotypes. Odds ratios and 95% confidence intervals (95% CIs) for lymphoma, B-NHL, DLBCL, FL, CLL, and other B NHL combined associated with the inferred rapid NAT1 acetylator and with the intermediate and slow NAT2 acetylator phenotypes were estimated with unconditional and polytomous logistic regression analysis, adjusting for age, gender and education. NAT1 rapid acetylators showed a 2.8-fold excess risk (95% CI 1.5-5.2) for lymphoma (all subtypes combined). Risk was highest for CLL and FL, with significant heterogeneity detected across subtypes. Risk also increased with decreasing NAT2 acetylating capacity with no heterogeneity detected across B cell lymphoma subtypes. Risks did not vary by gender. Although poor statistical power was a major limitation in our study, larger studies and pooled analyses are warranted to test whether NAT1 and NAT2 gene polymorphisms might modulate risk of specific lymphoma subtypes through the varying metabolic activity of their products. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 25689678 TI - Self-assembly and gelation of poly(aryl ether) dendrons containing hydrazide units: factors controlling the formation of helical structures. AB - Self-assembly of AB2 and AB3 type low molecular weight poly(aryl ether) dendrons that contain hydrazide units were used to investigate mechanistic aspects of helical structure formation during self-assembly. The results suggest that there are three important aspects that control helical structure formation in such systems with acyl hydrazide/hydrazone linkage: i) J-type aggregation, ii) the hydrogen-bond donor/acceptor ability of the solvent, and iii) the dielectric constant of the solvent. The monomer units self-assemble to form dimer structures through hydrogen-bonding and further assembly of the hydrogen-bonded dimers leads to macroscopic chirality in the present case. Dimer formation was confirmed by NMR spectroscopy and by mass spectrometry. The self-assembly in the system was driven by hydrogen-bonding and pi-pi stacking interactions. The morphology of the aggregates formed was examined by scanning electron microscopy, and the analysis suggests that aprotic solvent systems facilitate helical fibre formation, whereas introduction of protic solvents results in the formation of flat ribbons. This detailed mechanistic study suggests that the self-assembly follows a nucleation elongation model to form helical structures, rather than the isodesmic model. PMID- 25689679 TI - [(11) C]Carbon monoxide in labeling chemistry and positron emission tomography tracer development: scope and limitations. AB - [(11) C]Carbon monoxide is an attractive precursor for labeling carbonyl position in a wide range of organic compounds. The use of [(11) C]carbon monoxide in transition metal-mediated coupling reactions has been explored by several groups during the last 15 years, and an impressive number of the synthesis of [carbonyl (11) C]compounds have been published to date. The application of radical-mediated [(11) C]carbonylation has also been explored in some extent. However, the main limitations to apply this potential precursor in (11) C-labeling chemistry are low concentration, poor solubility in commonly used organic solvents, and low reactivity. A couple of technical solutions such as high-pressure reactor system, microfluidic system, and different approaches to confine [(11) C]CO to the reaction media at ambient pressure have been developed over the years. Although considerable advances in [(11) C]carbon monoxide chemistry have been reported in recent years, its application in positron emission tomography tracer development is still an area of work in progress. This review summarizes all contributions to the area of radiolabeling using [(11) C]carbon monoxide published between 1995 and 2014 and discusses the scope and limitations of this method in clinical positron emission tomography tracer development. PMID- 25689680 TI - Photo-attachment of biomolecules for miniaturization on wicking Si-nanowire platform. AB - We demonstrated the surface functionalization of a highly three-dimensional, superhydrophilic wicking substrate using light to immobilize functional biomolecules for sensor or microarray applications. We showed here that the three dimensional substrate was compatible with photo-attachment and the performance of functionalization was greatly improved due to both increased surface capacity and reduced substrate reflectivity. In addition, photo-attachment circumvents the problems induced by wicking effect that was typically encountered on superhydrophilic three-dimensional substrates, thus reducing the difficulty of producing miniaturized sites on such substrate. We have investigated various aspects of photo-attachment process on the nanowire substrate, including the role of different buffers, the effect of wavelength as well as how changing probe structure may affect the functionalization process. We demonstrated that substrate fabrication and functionalization can be achieved with processes compatible with microelectronics processes, hence reducing the cost of array fabrication. Such functionalization method coupled with the high capacity surface makes the substrate an ideal candidate for sensor or microarray for sensitive detection of target analytes. PMID- 25689682 TI - Radical C-H arylation of the BODIPY core with aryldiazonium salts: synthesis of highly fluorescent red-shifted dyes. AB - We describe herein the first radical C-H arylation of BODIPY dyes. This novel, general, one-step synthetic procedure uses ferrocene to generate aryl radical species from aryldiazonium salts and allows the straightforward synthesis of brightly fluorescent (Phi>0.85) 3,5-diarylated and 3-monoarylated boron dipyrrins in up to 86 % yield for a broad range of aryl substituents. In this way, new and complex dyes with red-shifted spectra can be easily prepared. PMID- 25689681 TI - Identification of modulators of the nuclear receptor peroxisome proliferator activated receptor alpha (PPARalpha) in a mouse liver gene expression compendium. AB - The nuclear receptor family member peroxisome proliferator-activated receptor alpha (PPARalpha) is activated by therapeutic hypolipidemic drugs and environmentally-relevant chemicals to regulate genes involved in lipid transport and catabolism. Chronic activation of PPARalpha in rodents increases liver cancer incidence, whereas suppression of PPARalpha activity leads to hepatocellular steatosis. Analytical approaches were developed to identify biosets (i.e., gene expression differences between two conditions) in a genomic database in which PPARalpha activity was altered. A gene expression signature of 131 PPARalpha dependent genes was built using microarray profiles from the livers of wild-type and PPARalpha-null mice after exposure to three structurally diverse PPARalpha activators (WY-14,643, fenofibrate and perfluorohexane sulfonate). A fold-change rank-based test (Running Fisher's test (p-value <= 10(-4))) was used to evaluate the similarity between the PPARalpha signature and a test set of 48 and 31 biosets positive or negative, respectively for PPARalpha activation; the test resulted in a balanced accuracy of 98%. The signature was then used to identify factors that activate or suppress PPARalpha in an annotated mouse liver/primary hepatocyte gene expression compendium of ~1850 biosets. In addition to the expected activation of PPARalpha by fibrate drugs, di(2-ethylhexyl) phthalate, and perfluorinated compounds, PPARalpha was activated by benzofuran, galactosamine, and TCDD and suppressed by hepatotoxins acetaminophen, lipopolysaccharide, silicon dioxide nanoparticles, and trovafloxacin. Additional factors that activate (fasting, caloric restriction) or suppress (infections) PPARalpha were also identified. This study 1) developed methods useful for future screening of environmental chemicals, 2) identified chemicals that activate or suppress PPARalpha, and 3) identified factors including diets and infections that modulate PPARalpha activity and would be hypothesized to affect chemical-induced PPARalpha activity. PMID- 25689683 TI - Immunology in wild nonmodel rodents: an ecological context for studies of health and disease. AB - Transcriptomic methods are set to revolutionize the study of the immune system in naturally occurring nonmodel organisms. With this in mind, the present article focuses on ways in which the use of 'nonmodel' rodents (not the familiar laboratory species) can advance studies into the classical, but ever relevant, epidemiologic triad of immune defence, infectious disease and environment. For example, naturally occurring rodents are an interesting system in which to study the environmental stimuli that drive the development and homeostasis of the immune system and, by extension, to identify where these stimuli are altered in anthropogenic environments leading to the formation of immunopathological phenotypes. Measurement of immune expression may help define individual heterogeneity in infectious disease susceptibility and transmission and facilitate our understanding of infection dynamics and risk in the natural environment; furthermore, it may provide a means of surveillance that can filter individuals carrying previously unknown acute infections of potential ecological or zoonotic importance. Finally, the study of immunology in wild animals may reveal interactions within the immune system and between immunity and other organismal traits that are not observable under restricted laboratory conditions. Potentiating much of this is the possibility of combining gene expression profiles with analytical tools derived from ecology and systems biology to reverse engineer interaction networks between immune responses, other organismal traits and the environment (including symbiont exposures), revealing regulatory architecture. Such holistic studies promise to link ecology, epidemiology and immunology in natural systems in a unified approach that can illuminate important problems relevant to human health and animal welfare and production. PMID- 25689684 TI - The Prevalence of Helicobacter pylori Remains High in African American and Hispanic Veterans. AB - BACKGROUND: Helicobacter pylori in the United States has been declining in the 1990s albeit less so among blacks and Hispanics. As the socioeconomic status of racial groups has evolved, it remains unclear whether the prevalence or the racial and ethnic disparities in the prevalence of H. pylori have changed. METHODS: This is a cross-sectional study from a Veteran Affairs center among patients aged 40-80 years old who underwent a study esophagogastroduodenoscopy with gastric biopsies, which were cultured for H. pylori irrespective of findings on histopathology. Positive H. pylori was defined as positive culture or histopathology (stained organism combined with active gastritis). We calculated age-, race-, and birth cohort-specific H. pylori prevalence rates and examined predictors of H. pylori infection in logistic regression models. RESULTS: We analyzed data on 1200 patients; most (92.8%) were men and non-Hispanic white (59.9%) or black (28.9%). H. pylori was positive in 347 (28.9%) and was highest among black males aged 50-59 (53.3%; 44.0-62.4%), followed by Hispanic males aged 60-69 (48.1%; 34.2-62.2%), and lowest in non-Hispanic white males aged 40-49 (8.2%; 2.7-20.5%). In multivariate analysis, age group 50-59 was significantly associated with H. pylori (adjusted odds ratio (OR), 2.32; 95% confidence interval (CI), 1.21-4.45) compared with those aged 40-49, and with black race (adjusted OR, 2.57; 95% CI, 1.83-3.60) and Hispanic ethnicity (adjusted OR, 3.01; 95% CI, 1.70-5.34) compared with non-Hispanic white. Irrespective of age group, patients born during 1960-1969 had a lower risk of H. pylori (adjusted OR, 0.45; 95% CI, 0.22-0.96) compared to those born in 1930-1939. Those with some college education were less likely to have H. pylori compared to those with no college education (adjusted OR 0.51; 95% CI, 0.37-0.69). CONCLUSION: Among veterans, the prevalence of active H. pylori remains high (28.9%) with even higher rates in blacks and Hispanics with lower education levels. PMID- 25689685 TI - Fundamental factors determining the nature of parasite aggregation in hosts. AB - The distribution of parasites in hosts is typically aggregated: a few hosts harbour many parasites, while the remainder of hosts are virtually parasite free. The origin of this almost universal pattern is central to our understanding of host-parasite interactions; it affects many facets of their ecology and evolution. Despite this, the standard statistical framework used to characterize parasite aggregation does not describe the processes generating such a pattern. In this work, we have developed a mathematical framework for the distribution of parasites in hosts, starting from a simple statistical description in terms of two fundamental processes: the exposure of hosts to parasites and the infection success of parasites. This description allows the level of aggregation of parasites in hosts to be related to the random variation in these two processes and to true host heterogeneity. We show that random variation can generate an aggregated distribution and that the common view, that encounters and success are two equivalent filters, applies to the average parasite burden under neutral assumptions but it does not apply to the variance of the parasite burden, and it is not true when heterogeneity between hosts is incorporated in the model. We find that aggregation decreases linearly with the number of encounters, but it depends non-linearly on parasite success. We also find additional terms in the variance of the parasite burden which contribute to the actual level of aggregation in specific biological systems. We have derived the formal expressions of these contributions, and these provide new opportunities to analyse empirical data and tackle the complexity of the origin of aggregation in various host-parasite associations. PMID- 25689686 TI - Diversity-oriented stereoselective synthesis of beta,gamma-disubstituted tert homoallylic alcohols. AB - The successive treatment of beta-(trimethylsilyl)allyl phenyl sulfides with titanocene(II)-1-butene complex and ketones produced tertiary gamma (trimethylsilyl)homoallylic alcohols with good anti-selectivity, which reacted with a variety of organic halides in the presence of copper(I) tert-butoxide to afford the cross-coupling products, gamma-substituted homoallylic alcohols. PMID- 25689687 TI - Preliminary evidence of an effect of cerebellar volume on postural sway in FMR1 premutation males. AB - Recent evidence suggests that early changes in postural control may be discernible among females with premutation expansions (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene at risk of developing fragile X associated tremor ataxia syndrome (FXTAS). Cerebellar dysfunction is well described in males and females with FXTAS, yet the interrelationships between cerebellar volume, CGG repeat length, FMR1 messenger RNA (mRNA) levels and changes in postural control remain unknown. This study examined postural sway during standing in a cohort of 22 males with the FMR1 premutation (ages 26-80) and 24 matched controls (ages 26-77). The influence of cerebellar volume, CGG repeat length and FMR1 mRNA levels on postural sway was explored using multiple linear regression. The results provide preliminary evidence that increasing CGG repeat length and decreasing cerebellar volume were associated with greater postural sway among premutation males. The relationship between CGG repeat length and postural sway was mediated by a negative association between CGG repeat size and cerebellar volume. While FMR1 mRNA levels were significantly elevated in the premutation group and correlated with CGG repeat length, FMR1 mRNA levels were not significantly associated with postural sway scores. These findings show for the first time that greater postural sway among males with the FMR1 premutation may reflect CGG repeat-mediated disruption in vulnerable cerebellar circuits implicated in postural control. However, longitudinal studies in larger samples are required to confirm whether the relationships between cerebellar volume, CGG repeat length and postural sway indicate greater risk for neurological decline. PMID- 25689688 TI - Afp14 is involved in regulating the length of Anti-feeding prophage (Afp). AB - The anti-feeding prophage (Afp), a phage-tail-like particle that causes cessation of feeding in the New Zealand grass grub, Costelytra zealandica, is encoded by 18 open reading frames (afp1-18). C-terminal truncations of afp14 resulted in shortened Afp particles, suggesting that Afp14 is involved in Afp length determination. We constructed an Afp assembly system (afp1-18), wherein Afp14 was truncated after the N-terminal 88 residues. This construct, when expressed in trans in Escherichia coli expressing a N-terminal 98-amino acid Afp14 construct, yielded fully assembled Afp but no assembled Afp was detected in the case of a N terminal 96-amino acid Afp14 construct. These results suggested that the 98 N terminal, amino acid residues of Afp14 is crucial for the initiation of Afp assembly via baseplate formation. Trans-based expression of wild-type afp14 resulted in Afp particles of varying lengths, all of which were shorter than the wild-type Afp particle. On the other hand, similar expression of Afp14 harboring a C-terminal extension (KLLEH(6)) resulted in elongated Afp particles. This information, combined with bioinformatics data, allowed us to propose a model delineating the mechanism and role of Afp14 in the maturation of the Afp particle. PMID- 25689689 TI - Association between recent internal travel and malaria in Ugandan highland and highland fringe areas. AB - OBJECTIVE: To examine the association between travel (recency of travel, transmission intensity at destination compared to origin and duration of travel) and confirmed malaria in Uganda. METHODS: Health facility-based case-control study in highland (~2200 m), and highland fringe (~1500 m) areas with adjustment for other covariates. RESULTS: In the highland site, patients who had travelled to areas of higher transmission intensity than their home (origin) areas recently were nearly seven times more likely to have confirmed malaria than those who had not (OR 6.9; P = 0.01, 95% CI: 1.4-33.1). In the highland fringe site, there was also a statistically significant association between travel and malaria (OR 2.1; P = 0.04, 95% CI: 1.1-3.9). CONCLUSIONS: For highland areas, or areas of low malaria transmission, health authorities need to consider internal migrants when designing malaria control programs. Control interventions should include information campaigns reminding residents in these areas of the risk of malaria infection through travel and to provide additional mosquito nets for migrants to use during travel. Health authorities may wish to improve diagnosis in health facilities in highland areas by adding travel history to malaria case definitions. Where routine monitoring data are used to evaluate the impact of interventions on the malaria burden in highland areas, health authorities and donors need ensure that only cases from the local area and not 'imported cases' are counted. PMID- 25689690 TI - Serum Adenosine Deaminase (ADA) Activity: A Novel Screening Test to Differentiate HIV Monoinfection From HIV-HBV and HIV-HCV Coinfections. AB - BACKGROUND: CD4(+) cell count, the common HIV infection screening test, is costly and unable to differentiate HIV monoinfection from its concurrent infection with hepatitis B or C virus. We aimed to ascertain diagnostic value of serum adenosine deaminase (ADA) activity as a useful tool to differentiate HIV mono- and co infection. METHODS: Blood samples were collected from 30 HIV-HBV and 30 HIV-HCV coinfected patients, 33 HIV positive subjects, and 72 controls. CD4(+) cell count, serum total ADA (tADA), and ADA1, and ADA2 isoenzyme activities were determined and their sensitivity and specificity were computed. RESULTS: tADA and ADA2 activities were significantly higher and CD4(+) counts were markedly lower in all patients compared with controls. Strong inverse agreements between CD4(+) cell counts and both tADA and ADA2 activities were observed. Serum tADA and ADA1 activities showed the highest specificity and the highest sensitivity, respectively, for differentiating HIV monoinfection from HIV-HBV and HIV-HCV coinfections. CONCLUSIONS: We showed strong agreement and correlation between CD4(+) cell count and ADA enzyme activity. Based on high ADA sensitivity and specificity, it is concluded that determination of ADA activity might be a novel diagnostic tool to distinguish of HIV monoinfection from its coinfection with HBV or HCV. PMID- 25689691 TI - tert-Butyl(tert-butoxy)zinc hydroxides: hybrid models for single-source precursors of ZnO nanocrystals. AB - Alkylzinc alkoxides, [RZnOR']4, have received much attention as efficient precursors of ZnO nanocrystals (NCs), and their "Zn4O4 " heterocubane core has been regarded as a "preorganized ZnO". A comprehensive investigation of the synthesis and characterization of a new family of tert-butyl(tert-butoxy)zinc hydroxides, [(tBu)4 Zn4 (MU3-OtBu)x (MU3-OH)4-x], as model single-source precursors of ZnO NCs is reported. The direct reaction between well-defined [tBuZnOH]6 (16) and [tBuZnOtBu]4 (24) in various molar ratios allows the isolation of new mixed cubane aggregates as crystalline solids in a high yield: [(tBu)4 Zn4 (MU3-OtBu)3 (MU3-OH)] (3), [(tBu)4Zn4 (MU3-OtBu)2 (MU3-OH)2] (4), [(tBu)4 Zn4 (MU3-OtBu)(MU3-OH)3] (5). The resulting products were characterized in solution by (1) H NMR and IR spectroscopy, and in the solid state by single crystal X-ray diffraction. The thermal transformations of 2-5 were monitored by in situ variable-temperature powder X-ray diffraction and thermogravimetric measurements. The investigation showed that the Zn-OH groups appeared to be a desirable feature for the solid-state synthesis of ZnO NCs that significantly decreased the decomposition temperature of crystalline precursors 3-5. PMID- 25689692 TI - Impact of body mass index on long-term clinical outcomes after second-generation drug eluting stent implantation: Insights from the international global RESOLUTE program. AB - BACKGROUND: An increased body mass index (BMI) is associated with a high risk of cardiovascular disease and reduction in life expectancy. However, several studies reported improved clinical outcomes in obese patients treated for cardiovascular diseases. The aim of the present study is to investigate the impact of BMI on long-term clinical outcomes after implantation of zotarolimus eluting stents. METHODS: Individual patient data were pooled from the RESOLUTE Clinical Program comprising five trials worldwide. The study population was sorted according to BMI tertiles and clinical outcomes were evaluated at 2-year follow-up. RESULTS: Data from a total of 5,127 patients receiving the R-ZES were included in the present study. BMI tertiles were as follow: I tertile (<= 25.95 kg/m(2) -Low or normal weight) 1,727 patients; II tertile (>25.95 <= 29.74 kg/m(2) -overweight) 1,695 patients, and III tertile (>29.74 kg/m(2) -obese) 1,705 patients. At 2 years follow-up no difference was found for patients with high BMI (III tertile) compared with patients with normal or low BMI (I tertile) in terms of target lesion failure (I-III tertile, HR [95% CI] = 0.89 [0.69, 1.14], P = 0.341; major adverse cardiac events (I-III tertile, HR [95% CI] = 0.90 [0.72, 1.14], P = 0.389; cardiac death (I-III tertile, HR [95% CI] = 1.20 [0.73, 1.99], P = 0.476); myocardial infarction (I-III tertile, HR [95% CI] = 0.86 [0.55, 1.35], P = 0.509; clinically-driven target lesion revascularization (I-III tertile, HR [95% CI] = 0.75 [0.53, 1.08], P = 0.123; definite or probable stent thrombosis (I-III tertile, HR [95% CI] = 0.98 [0.49, 1.99], P = 0.964. CONCLUSIONS: In the present study, the patients' body mass index was found to have no impact on long-term clinical outcomes after coronary artery interventions. PMID- 25689693 TI - Efficient Perovskite Hybrid Solar Cells Through a Homogeneous High-Quality Organolead Iodide Layer. AB - Fabricating homogeneous and high-quality perovskite thin films via low temperature solution processing is a challenge to realizing high-efficiency perovskite hybrid solar cells (pero-HSCs). Here, an approach is reported to realize smooth surface morphology of methylammonium lead iodide (CH3 NH3 PbI3 ) perovskite thin films via using strong-polar ethanol solution rather than less polar isopropanol solution, which was previously used as the solvent for preparing perovskite thin films. In comparison with the pero-HSCs processed from isopropanol solution, more than 40% enhanced efficiency is observed from pero HSCs processed from ethanol solution. The enhanced efficiency is attributed to a homogeneous high-quality perovskite thin film with dramatically low root-mean square roughness and completely conversion of lead (II) iodide (PbI2 ) to CH3 NH3 PbI3 . The findings provide a simple way to realize high-efficiency high reproducible pero-HSCs. PMID- 25689695 TI - A new class of enzymes discovered: a non-heme oxidase produces medium-chain 1 alkenes. PMID- 25689694 TI - Contrasting population genetic structure among freshwater-resident and anadromous lampreys: the role of demographic history, differential dispersal and anthropogenic barriers to movement. AB - The tendency of many species to abandon migration remains a poorly understood aspect of evolutionary biology that may play an important role in promoting species radiation by both allopatric and sympatric mechanisms. Anadromy inherently offers an opportunity for the colonization of freshwater environments, and the shift from an anadromous to a wholly freshwater life history has occurred in many families of fishes. Freshwater-resident forms have arisen repeatedly among lampreys (within the Petromyzontidae and Mordaciidae), and there has been much debate as to whether anadromous lampreys, and their derived freshwater resident analogues, constitute distinct species or are divergent ecotypes of polymorphic species. Samples of 543 European river lamprey Lampetra fluviatilis (mostly from anadromous populations) and freshwater European brook lamprey Lampetra planeri from across 18 sites, primarily in the British Isles, were investigated for 13 polymorphic microsatellite DNA loci, and 108 samples from six of these sites were sequenced for 829 bp of mitochondrial DNA (mtDNA). We found contrasting patterns of population structure for mtDNA and microsatellite DNA markers, such that low diversity and little structure were seen for all populations for mtDNA (consistent with a recent founder expansion event), while fine-scale structuring was evident for nuclear markers. Strong differentiation for microsatellite DNA loci was seen among freshwater-resident L. planeri populations and between L. fluviatilis and L. planeri in most cases, but little structure was evident among anadromous L. fluviatilis populations. We conclude that postglacial colonization founded multiple freshwater-resident populations with strong habitat fidelity and limited dispersal tendencies that became highly differentiated, a pattern that was likely intensified by anthropogenic barriers. PMID- 25689696 TI - Multiplex genotyping of cytokine gene SNPs using fluorescence bead array. AB - Single nucleotide polymorphisms (SNPs) of genes that affect cytokine production and function are known to influence the susceptibility and progression of immune related conditions such as infection, autoimmune diseases, transplantation, and cancer. We established a multiplex genotyping method to analyze the SNPs of cytokine genes by combining the multiplex PCR and bead array platform. Thirteen cytokine gene regions, including 20 SNPs, were amplified, and allele-specific primer extension was performed in a single tube. High-quality allele-specific primers were selected for signals greater than 1000 median fluorescence intensity (MFI) for positive alleles, and less than 500 MFI for negative alleles. To select and improve the extension primers, modifications for the reverse direction, length or refractory were performed. 24 primers in the forward or reverse direction step and 12 primers in length or refractory modifications were selected and showed high concordance with results by nucleotide sequencing. Among the 13 candidate cytokine genes, the SNPs of 12 cytokine genes, including IL-1alpha, IL 1R, IL-1RA, IL-1beta, IL-2, IL-4, IL-4Ralpha, IL-6, IL-10, IL-12, TGF-beta1, and TNF-alpha, were successfully defined with the selected allele-specific primers in healthy Korean subjects. Our genotyping system provides a fast and accurate detection for SNPs of multiple cytokine genes to investigate their association with immune-related diseases and transplantation outcomes. PMID- 25689697 TI - Asporin and osteoarthritis. AB - OBJECTIVE: To provide an overview of the literature describing the role of asporin, a small leucine-rich proteoglycan (SLRP), in osteoarthritis (OA). METHOD: A literature search was performed and reviewed using the narrative approach. RESULTS: As a class I SLRP member, asporin, is distinct from other SLRPs. Accumulating evidence demonstrates the involvement of asporin in OA pathogenesis. Many human studies have been conducted to explore the association between the D-repeat polymorphisms and OA susceptibility, but these yield inconsistent results. Possible mechanisms for the involvement of asporin in OA pathology include its influence on TGF-beta (transforming growth factor-beta) signaling pathways and collagen mineralization. To date, no studies were found to use an asporin-deficient animal model that would help to understand disease mechanisms. Many issues must be addressed to clarify the link between asporin and OA to provide a novel therapeutic strategy for OA, perhaps through controlling and modifying the TGF-beta-ECM system. CONCLUSIONS: Studies examined demonstrate the involvement of asporin in OA pathogenesis, and possible mechanisms by which asporin may be involved in this process have been proposed. However, large-scale interracial studies should be conducted to investigate the association between asporin and OA, and further investigations are needed to obtain a better understanding of the disease mechanism, develop novel therapeutic strategies, and explore new approaches for diagnosis of OA. PMID- 25689698 TI - Assisted suicide should be an option. PMID- 25689700 TI - Infective endocarditis: what you need to know. PMID- 25689702 TI - The sneaky prevalence of substance abuse in nursing. PMID- 25689703 TI - A winning hand: medication cards improve patient safety. PMID- 25689704 TI - A graduate nurse externship initiative. PMID- 25689705 TI - The Roper-Logan-Tierney model of nursing: a framework to complement the nursing process. PMID- 25689709 TI - Thinking outside the box. PMID- 25689710 TI - Float pool nurses come to the rescue. PMID- 25689711 TI - Preeclampsia: the pressure's on. PMID- 25689712 TI - How informatics nurses use bar code technology to reduce medication errors. PMID- 25689714 TI - Preventing urinary tract infections with a two-person catheter insertion procedure. PMID- 25689716 TI - Training with virtual patients in transcultural psychiatry: do the learners actually learn? AB - BACKGROUND: The rapid increase in the number of patients with diverse ethnic backgrounds and previous exposure to severe mental trauma dictates the need for improvement in the quality of transcultural psychiatric health care through the development of relevant and effective training tools. OBJECTIVE: This study aimed to evaluate the impact of training with a virtual patient on the learner's knowledge of posttraumatic stress disorder symptoms, clinical management, and basic communication skills. METHODS: The authors constructed an interactive educational tool based on virtual patient methodology that portrayed a refugee with severe symptoms of posttraumatic stress disorder and depression. A total of 32 resident psychiatrists tested the tool and completed a pre-interaction and post-interaction knowledge test, including skills, at the time and several weeks later. RESULTS: All of the participants (N=32) completed the pre-interaction and post-interaction test, and 26 (81%) of them completed the online follow-up test. The mean pre-interaction score was 7.44 (male: 7.08, female: 7.65, no statistical significance). The mean post-interaction score was 8.47, which was significantly higher (P<.001) than the pre-interaction score (mean score 7.44). The mean score for the follow-up test several weeks later was 8.38, higher than the pre interaction score by 0.69 points but not statistically significant. CONCLUSIONS: Our results suggest that virtual patients can successfully facilitate the acquisition of core knowledge in the field of psychiatry, in addition to developing skills such as clinical reasoning, decision making, and history taking. Repeated training sessions with virtual patients are proposed in order to achieve sustainable educational effects. PMID- 25689717 TI - G protein coupled receptor 50 promotes self-renewal and neuronal differentiation of embryonic neural progenitor cells through regulation of notch and wnt/beta catenin signalings. AB - G protein-coupled receptor 50 (GPR50), a risk factor for major depressive disorder and bipolar affective disorder, is expressed in both the developmental and adult brain. However, the function of GPR50 in the brain remains unknown. We here show GPR50 is expressed by neural progenitor cells (NPCs) in the ventricular zone of embryonic brain. Knockdown of GPR50 with a small interference RNA (siRNA) decreased self-renewal and neuronal differentiation, but not glial differentiation of NPCs. Moreover, overexpression of either full-length GPR50 or the intracellular domain of GPR50, rather than the truncated GPR50 in which the intracellular domain is deleted in, increased neuronal differentiation, indicating that GPR50 promotes neuronal differentiation of NPCs in an intracellular domain-dependent manner. We further described that the transcriptional activity of the intracellular domain of notch on Hes1 gene was repressed by overexpression of GPR50. In addition, decreased levels of transcription factor 7-like 2 (TCF7L2) mRNA was observed in GPR50 siRNA transfected NPCs, suggesting that knockdown of GPR50 impairs wnt/beta-catenin signaling. Moreover, the mRNA levels of neurogenin (Ngn) 1, Ngn2 and cyclin D1, the target genes of notch and wnt/beta-catenin signalings, in NPCs were reduced by knockdown of GPR50. Therefore, GPR50 promotes self-renewal and neuronal differentiation of NPCs possibly through regulation of notch and wnt/beta-catenin signalings. PMID- 25689718 TI - Expression of autophagy-related proteins ATG5 and FIP200 predicts favorable disease-free survival in patients with breast cancer. AB - Autophagy is a self-digesting process that is primarily responsible for the removal and recycling of long-lived proteins and damaged organelles to maintain the homeostasis of the cell. Recent studies have indicated dual roles for autophagy in cancer: suppression of tumor progression and promotion of survival. In this study, we sought to investigate the prognostic value of two autophagy related proteins, autophagy-related gene 5 (ATG5) and FAK family kinase interacting protein of 200 kDa (FIP200), in patients with operable breast cancer. More specifically, the expression of ATG5 and FIP200 was evaluated by immunohistochemistry (IHC) in surgical specimens collected from 200 patients who were diagnosed with histologically proven invasive ductal breast cancer. A stepwise Cox multivariate analysis was then performed to construct a risk prediction model. In this retrospective cohort study, both ATG5 (HR = 0.465, 95% CI 0.247-0.872, P = 0.017) and FIP200 (HR = 0.521, 95% CI 0.278-0.979, P = 0.043) correlated with prolonged disease-free survival (DFS). In a receiver operating characteristic (ROC) analysis, the addition of ATG5 and FIP200 expression led to a significantly improved area under the time-dependent ROC curve (AUC) at 3 years (0.748 versus 0.680, P < 0.001) and 5 years (0.756 versus 0.699, P < 0.001). Collectively, our findings established the prognostic significance of ATG5 and FIP200 in patients with breast cancer. PMID- 25689719 TI - HDGF-related protein-2 (HRP-2) acts as an oncogene to promote cell growth in hepatocellular carcinoma. AB - HDGFRP2 (HRP-2) belongs to the Hepatoma-derived growth factor (HDGF)-related proteins (HRPs) family, which are characterized by a conserved HATH/PWWP domain at a well-conserved region of the N-terminus. However, the cellular function of HRP-2 remains unknown. In this study, we showed for the first time that HRP-2 is frequently overexpressed in human HCC tissues at mRNA and protein levels. We further showed that HRP-2 can promote HCC cells growth in vitro and xenograft tumors in vivo. Using protein affinity purification methods, we searched for functional partners of HRP-2, and found that HRP-2 interacts with various proteins known to be involved in transcription elongation and processing. Furthermore, we demonstrate HRP-2 interacts and co-localizes with RNA processing regulator IWS1, and positively regulated the mRNA level of Cyclin D1. Together, our study suggests HRP-2 may act as an mRNA processing co-factor to promote cells growth by regulating the mRNA of key oncogenes, which can be explored further for cancer treatment. PMID- 25689720 TI - Recombinant adenovirus infection suppresses hTERT expression through virus associated RNA-mediated induction of type 1 interferon. AB - Adenovirus vector is one of the most widely used vectors in gene therapy applications for the treatment of diverse human diseases including cancer. In this study, we showed that infection with E1E3-deleted recombinant human adenovirus serotype 5 reduced human telomerase reverse transcriptase (hTERT) mRNA levels in hepatoma cell lines. We defined the mechanisms by which the recombinant adenovirus vector reduces hTERT mRNA levels as follows: Using the virus associated RNA I/II (VAI/II) expression construct, we demonstrated that the expression of VAI and VAII RNAs led to an increase in IFN-alpha2 level, and IFN alpha2 induction was responsible for the decrease in hTERT mRNA levels. We showed that the effects of VA RNAs were specific for the replication-incompetent E1E3 deleted adenovirus vector, because wild-type adenovirus affected neither IFN alpha2 nor hTERT mRNA levels. Moreover, we demonstrated that adenovirus vector mediated delivery of the hTERT-targeting anti-cancer reagent could additively reduce the levels of hTERT mRNA that were specifically overexpressed in most of the cancer cells. This study showed that E1E3-deleted adenovirus vector system reduced hTERT mRNA levels through VA RNA-mediated induction of type 1 interferon; hence the recombinant adenovirus itself could have anti-cancer activity. These results indicate that recombinant adenovirus vector could be an effective means to deliver anti-cancer reagents for combating cancerous cells more effectively. PMID- 25689722 TI - Yap/Taz gets under your skin. PMID- 25689721 TI - Ursolic acid attenuates diabetic mesangial cell injury through the up-regulation of autophagy via miRNA-21/PTEN/Akt/mTOR suppression. AB - OBJECTIVE: To investigate the effect of ursolic acid on autophagy mediated through the miRNA-21-targeted phosphoinositide 3 kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway in rat mesangial cells cultured under high glucose (HG) conditions. METHODS: Rat glomerular mesangial cells were cultured under normal glucose, HG, HG with the PI3K inhibitor LY294002 or HG with ursolic acid conditions. Cell proliferation and hypertrophy were assayed using an MTT assay and the ratio of total protein to cell number, respectively. The miRNA-21 expression was detected using RT-qPCR. The expression of phosphatase and tensin homolog (PTEN)/AKT/mTOR signaling signatures, autophagy associated protein and collagen I was detected by western blotting and RT-qPCR. Autophagosomes were observed using electron microscopy. RESULTS: Compared with mesangial cells cultured under normal glucose conditions, the cells exposed to HG showed up-regulated miRNA-21 expression, down-regulated PTEN protein and mRNA expression, up-regulated p85PI3K, pAkt, pmTOR, p62/SQSTMI, and collagen I expression and down-regulated LC3II expression. Ursolic acid and LY294002 inhibited HG-induced mesangial cell hypertrophy and proliferation, down-regulated p85PI3K, pAkt, pmTOR, p62/SQSTMI, and collagen I expression and up-regulated LC3II expression. However, LY294002 did not affect the expression of miRNA-21 and PTEN. Ursolic acid down-regulated miRNA-21 expression and up-regulated PTEN protein and mRNA expression. CONCLUSIONS: Ursolic acid inhibits the glucose induced up-regulation of mesangial cell miRNA-21 expression, up-regulates PTEN expression, inhibits the activation of PI3K/Akt/mTOR signaling pathway, and enhances autophagy to reduce the accumulation of the extracellular matrix and ameliorate cell hypertrophy and proliferation. PMID- 25689723 TI - Possible health effects of living in proximity to mining sites near Potosi, Bolivia. AB - OBJECTIVE: The goal of this study was to determine the health effects of living downstream from mines in the Potosi region of Bolivia. METHODS: Histories, physical examinations, and urinalyses were completed on adults recruited from mining and nonmining villages in Bolivia. Blood concentrations of Cd, Hg, and Pb were determined in a subset of participants. Multiple logistic regression analyses were performed. RESULTS: Mining region participants had significantly higher frequencies of hypertension, hematuria, and ketonuria. Hematuria was significantly elevated among those watering livestock downstream from mines and eating grains from their own farm (odds ratio = 4.3; 95% confidence interval, 1.1 to 17.7). Significantly higher blood concentrations of Pb were observed in a subsample of participants with hematuria (4.80 MUg/dL vs 10.91 MUg/dL; P = 0.026). CONCLUSIONS: Efforts to abate environmental exposure to toxic metals seem warranted. PMID- 25689724 TI - Applying Strategies of Selection, Optimization, and Compensation to Maintain Work Ability-A Psychosocial Resource Complementing the Job Demand-Control Model? Results From the Representative lidA Cohort Study on Work, Age, and Health in Germany. AB - OBJECTIVE: To investigate whether aging employees' selection, optimization, and compensation (SOC) strategies were associated with work ability over and above job demand and control variables, as well as across professions. METHODS: Multivariable linear regressions were conducted using a representative sample of German employees born in 1959 and 1965 (N = 6057). RESULTS: SOC was assessed to have an independent effect on work ability. Associations of job demands and control variables with work ability were more prominent. The SOC tended to enhance the positive association between decision authority and work ability. CONCLUSIONS: Individual strategies of selection, optimization, and compensation could be considered as psychosocial resources adding up to a better work ability and complement prevention programs. Workplace interventions should deal with job demands and control to maintain older employees' work ability in times of working population shrinkage. PMID- 25689725 TI - Maintained superiority of chronotherapeutics vs. exercise in a 20-week randomized follow-up trial in major depression. AB - OBJECTIVE: To investigate the long-term antidepressant effect of a chronotherapeutic intervention. METHOD: In this randomized controlled trial 75 patients with major depression were allocated to fixed duloxetine and either a chronotherapeutic intervention (wake group) with three initial wake therapies, daily bright light therapy, and sleep time stabilization or to a group using daily exercise. Patients were followed 29 weeks. We report the last 20 weeks, a follow-up phase, where medication could be altered. Patients were assessed every 4 weeks. Remission rates were primary outcome. RESULTS: Patients in the wake group had a statistically significant higher remission rate of 61.9% vs. 37.9% in the exercise group at week 29 (OR = 2.6, CL = 1.3-5.6, P = 0.01). This indicated continued improvement compared with the 9 weeks of treatment response (44.8% vs. 23.4%) with maintenance of the large difference between groups. HAM-D17 endpoint scores were statistically lower in the wake group with endpoint scores of 7.5 (SE = 0.9) vs. 10.1 (SE = 0.9) in the exercise group (difference 2.7, CL = 0.5-4.8, P = 0.02). CONCLUSION: In this clinical study patients continued to improve in the follow-up phase and obtained very high remission rates. This is the first study to show adjunct short-term wake therapy and long-term bright light therapy as an effective and feasible method to attain and maintain remission. PMID- 25689726 TI - High performance gas diffusion layer with hydrophobic nanolayer under a supersaturated operation condition for fuel cells. AB - Reliable operation of a proton exchange membrane fuel cell requires proper water management to prevent water flooding in porous carbon materials such as the gas diffusion layer (GDL). In contrast to the conventional GDL that uses the "wet" dip-coating process with solvent and expensive polytetrafluoroethylene, we have proposed a novel GDL with a controlled hydrophobic silicone (i.e., hexamethyldisiloxane) nanolayer by a highly efficient and cost-effective "dry" deposition process. The GDL with the nanolayer exhibited an increased contact angle, decreased contact angle hysteresis, and suppressed water condensation. Even though the GDL with the nanolayer had a higher electrical resistance than the pristine GDL, the cell performance of the GDL with an optimum nanolayer thickness of 8.6 nm was practically the same as that of the pristine GDL under normal operating conditions. Under a supersaturated condition, the GDL with optimum nanolayer thickness exhibited much higher cell performance than the pristine GDL over all current densities due to enhanced hydrophobicity. Long-term operational stability and dynamic response of the GDL with the nanolayer were much improved over those of the pristine GDL. PMID- 25689727 TI - A non-symmetric pillar[5]arene based on triazole-linked 8-oxyquinolines as a sequential sensor for thorium(IV) followed by fluoride ions. AB - A novel non-symmetric pillar[5]arene bearing triazole-linked 8-oxyquinolines at one rim was synthesized and demonstrated as a sequential fluorescence sensor for thorium(iv) followed by fluoride ions with high sensitivity and selectivity. PMID- 25689728 TI - Band-gap deformation potential and elasticity limit of semiconductor free standing nanorods characterized in situ by scanning electron microscope cathodoluminescence nanospectroscopy. AB - Modern field-effect transistors or laser diodes take advantages of band-edge structures engineered by large uniaxial strain epsilonzz, available up to an elasticity limit at a rate of band-gap deformation potential azz (= dEg/depsilonzz). However, contrary to aP values under hydrostatic pressure, there is no quantitative consensus on azz values under uniaxial tensile, compressive, and bending stress. This makes band-edge engineering inefficient. Here we propose SEM-cathodoluminescence nanospectroscopy under in situ nanomanipulation (Nanoprobe-CL). An apex of a c-axis-oriented free-standing ZnO nanorod (NR) is deflected by point-loading of bending stress, where local uniaxial strain (epsiloncc = r/R) and its gradient across a NR (depsiloncc/dr = R(-1)) are controlled by a NR local curvature (R(-1)). The NR elasticity limit is evaluated sequentially (epsiloncc = 0.04) from SEM observation of a NR bending deformation cycle. An electron beam is focused on several spots crossing a bent NR, and at each spot the local Eg is evaluated from near-band-edge CL emission energy. Uniaxial acc (= dEg/depsiloncc) is evaluated at regulated surface depth, and the impact of R(-1) on observed acc is investigated. The acc converges with -1.7 eV to the R(-1) = 0 limit, whereas it quenches with increasing R(-1), which is attributed to free-exciton drift under transversal band-gap gradient. Surface sensitive CL measurements suggest that a discrepancy from bulk acc = -4 eV may originate from strain relaxation at the side surface under uniaxial stress. The nanoprobe-CL technique reveals an Eg(epsilonij) response to specific strain tensor epsilonij (i, j = x, y, z) and strain-gradient effects on a minority carrier population, enabling simulations and strain-dependent measurements of nanodevices with various structures. PMID- 25689730 TI - Concomitant anterior and posterior urethral valves in pediatrics: A single center experience over 12 years and long-term follow up after endoscopic treatment. AB - OBJECTIVE: To report our 12-year experience with endoscopic management of patients with concomitant anterior and posterior urethral valves. METHODS: We retrospectively reviewed the charts of patients referred to us for management of urethral valves from 2000 to 2012 to find cases with concomitant anterior and posterior valves. The diagnosis of valves was first suspected on voiding cystourethrography and confirmed by urethrocystoscopy. We collected available data on patients' age at diagnosis, clinical presentations, ultrasound and urodynamic findings, and surgical treatments. The final outcome at last follow up was also recorded. RESULTS: From 38 cases with anterior urethral valve, six (15.8%) presented concomitant anterior and posterior valves. The age at diagnosis in these patients ranged from antenatal diagnosis to 13 years. Initial presenting symptoms were recurrent urinary tract infection, incontinence, urosepsis and poor urinary stream. All valves were ablated by transurethral fulguration/resection using small-sized urethrocystoscopes. Among those with concomitant anterior and posterior valves, four patients had vesicoureteral reflux at presentation that resolved in two patients after valve ablation. One patient progressed to renal failure and required dialysis. Bladder hypercontractility and detrusor overactivity were the main urodynamic patterns in these patients. CONCLUSIONS: Concomitant anterior and posterior valves seem to be more prevalent than previously assumed, and might be missed on initial assessment. Oblique view voiding cystourethrography with full-length delineation of the urethra is of paramount diagnostic importance when obstruction is suspected. A meticulous urethrocystoscopy should follow for confirming the diagnosis and endoscopic ablation/resection of the valves. PMID- 25689729 TI - On human disease-causing amino acid variants: statistical study of sequence and structural patterns. AB - Statistical analysis was carried out on large set of naturally occurring human amino acid variations, and it was demonstrated that there is a preference for some amino acid substitutions to be associated with diseases. At an amino acid sequence level, it was shown that the disease-causing variants frequently involve drastic changes in amino acid physicochemical properties of proteins such as charge, hydrophobicity, and geometry. Structural analysis of variants involved in diseases and being frequently observed in human population showed similar trends: disease-causing variants tend to cause more changes in hydrogen bond network and salt bridges as compared with harmless amino acid mutations. Analysis of thermodynamics data reported in the literature, both experimental and computational, indicated that disease-causing variants tend to destabilize proteins and their interactions, which prompted us to investigate the effects of amino acid mutations on large databases of experimentally measured energy changes in unrelated proteins. Although the experimental datasets were linked neither to diseases nor exclusory to human proteins, the observed trends were the same: amino acid mutations tend to destabilize proteins and their interactions. Having in mind that structural and thermodynamics properties are interrelated, it is pointed out that any large change in any of them is anticipated to cause a disease. PMID- 25689732 TI - Abstracts of presentations at the 2014 Caribbean division meeting. PMID- 25689731 TI - Organocatalytic enantioselective Friedel-Crafts reaction: an efficient access to chiral isoindolo-beta-carboline derivatives. AB - An organocatalytic asymmetric Friedel-Crafts reaction between indole and indole derived hydroxylactams has been realized to furnish isoindolo-beta-carbolines in good to excellent yields (up to >99%) and generally high enantioselectivities (up to >99% ee). The methodology offers an efficient access to functionalization of isoindolo-beta-carbolines and preparation of chiral isoindolo-beta-carboline derivatives. PMID- 25689733 TI - Abstracts of presentations at the 2014 northeastern division meeting. PMID- 25689734 TI - Carbon isotope analysis of dissolved organic carbon in fresh and saline (NaCl) water via continuous flow cavity ring-down spectroscopy following wet chemical oxidation. AB - This work examines the performance and limitations of a wet chemical oxidation carbon analyser interfaced with a cavity ring-down spectrometer (WCO-CRDS) in a continuous flow (CF) configuration for measuring delta(13)C of dissolved organic carbon (delta(13)C-DOC) in natural water samples. Low-chloride matrix (<5 g Cl/L) DOC solutions were analysed with as little as 2.5 mg C/L in a 9 mL aliquot with a precision of 0.5 0/00. In high-chloride matrix (10-100 g Cl/L) DOC solutions, bias towards lighter delta(13)C-DOC was observed because of incomplete oxidation despite using high-concentration oxidant, extended reaction time, or post-wet chemical oxidation gas-phase combustion. However, through a combination of dilution, chloride removal, and increasing the oxidant:sample ratio, high salinity samples with sufficient DOC (>22.5 ug C/aliquot) may be analysed. The WCO-CRDS approach requires more total carbon (ug C/aliquot) than conventional CF isotope ratio mass spectrometer, but is nonetheless applicable to a wide range of DOC concentration and water types, including brackish water, produced water, and basinal brines. PMID- 25689735 TI - Bioconjugates for targeted delivery of therapeutic oligonucleotides. AB - Bioconjugates have been used to deliver therapeutic oligonucleotides to their pharmacological targets in diseased cells. Molecular-scale conjugates can be prepared by directly linking targeting ligands with oligonucleotides and the resultant conjugates can selectively bind to cell surface receptors in target cells in diseased tissues. Besides targeted delivery, additional functionality can be incorporated in the conjugates by utilization of carrier molecules, and these larger conjugates are called carrier-associated conjugates. Both molecular and carrier-associated conjugates have achieved initial successes in clinical trials for treating liver diseases; therefore, currently the greater challenge is to deliver oligonucleotides to extrahepatic tissues such as tumors. This review will provide an update on the application of oligonucleotide conjugates for targeted delivery during the last decade. By identifying key elements for successful delivery, it is suggested that oligonucleotide conjugates with intermediate size, cell targeting ability, and endosomal release functionality are superior systems to advance oligonucleotides to achieve their full therapeutic potentials. PMID- 25689736 TI - Studies and methodologies on vaginal drug permeation. AB - The vagina stands as an important alternative to the oral route for those systemic drugs that are poorly absorbed orally or are rapidly metabolized by the liver. Drug permeation through the vaginal tissue can be estimated by using in vitro, ex vivo and in vivo models. The latter ones, although more realistic, assume ethical and biological limitations due to animal handling. Therefore, in vitro and ex vivo models have been developed to predict drug absorption through the vagina while allowing for simultaneous toxicity and pathogenesis studies. This review focuses on available methodologies to study vaginal drug permeation discussing their advantages and drawbacks. The technical complexity, costs and the ethical issues of an available model, along with its accuracy and reproducibility will determine if it is valid and applicable. Therefore every model shall be evaluated, validated and standardized in order to allow for extrapolations and results presumption, and so improving vaginal drug research and stressing its benefits. PMID- 25689738 TI - Development and validation of a high-performance liquid chromatography-tandem mass spectrometry method for the simultaneous determination of irinotecan and its main metabolites in human plasma and its application in a clinical pharmacokinetic study. AB - Irinotecan is currently used in several cancer regimens mainly in colorectal cancer (CRC). This drug has a narrow therapeutic range and treatment can lead to side effects, mainly neutropenia and diarrhea, frequently requiring discontinuing or lowering the drug dose. A wide inter-individual variability in irinotecan pharmacokinetic parameters and pharmacodynamics has been reported and associated to patients' genetic background. In particular, a polymorphism in the UGT1A1 gene (UGT1A1*28) has been linked to an impaired detoxification of SN-38 (irinotecan active metabolite) to SN-38 glucuronide (SN-38G) leading to increased toxicities. Therefore, therapeutic drug monitoring of irinotecan, SN-38 and SN-38G is recommended to personalize therapy. In order to quantify simultaneously irinotecan and its main metabolites in patients' plasma, we developed and validated a new, sensitive and specific HPLC-MS/MS method applicable to all irinotecan dosages used in clinic. This method required a small plasma volume, addition of camptothecin as internal standard and simple protein precipitation. Chromatographic separation was done on a Gemini C18 column (3 MUM, 100 mm x 2.0 mm) using 0.1% acetic acid/bidistilled water and 0.1% acetic acid/acetonitrile as mobile phases. The mass spectrometer worked with electrospray ionization in positive ion mode and selected reaction monitoring. The standard curves were linear (R2 >=0.9962) over the concentration ranges (10-10000 ng/mL for irinotecan, 1-500 ng/mL for SN-38 and SN-38G and 1-5000 ng/mL for APC) and had good back-calculated accuracy and precision. The intra- and inter-day precision and accuracy, determined on three quality control levels for all the analytes, were always <12.3% and between 89.4% and 113.0%, respectively. Moreover, we evaluated this bioanalytical method by re-analysis of incurred samples as an additional measure of assay reproducibility. This method was successfully applied to a pharmacokinetic study in metastatic CRC patients enrolled in a genotype guided phase Ib study of irinotecan administered in combination with 5 fluorouracil/leucovorin and bevacizumab. PMID- 25689737 TI - Spatial reorganization of the endoplasmic reticulum during mitosis relies on mitotic kinase cyclin A in the early Drosophila embryo. AB - Mitotic cyclin-dependent kinase with their cyclin partners (cyclin:Cdks) are the master regulators of cell cycle progression responsible for regulating a host of activities during mitosis. Nuclear mitotic events, including chromosome condensation and segregation have been directly linked to Cdk activity. However, the regulation and timing of cytoplasmic mitotic events by cyclin:Cdks is poorly understood. In order to examine these mitotic cytoplasmic events, we looked at the dramatic changes in the endoplasmic reticulum (ER) during mitosis in the early Drosophila embryo. The dynamic changes of the ER can be arrested in an interphase state by inhibition of either DNA or protein synthesis. Here we show that this block can be alleviated by micro-injection of Cyclin A (CycA) in which defined mitotic ER clusters gathered at the spindle poles. Conversely, micro injection of Cyclin B (CycB) did not affect spatial reorganization of the ER, suggesting CycA possesses the ability to initiate mitotic ER events in the cytoplasm. Additionally, RNAi-mediated simultaneous inhibition of all 3 mitotic cyclins (A, B and B3) blocked spatial reorganization of the ER. Our results suggest that mitotic ER reorganization events rely on CycA and that control and timing of nuclear and cytoplasmic events during mitosis may be defined by release of CycA from the nucleus as a consequence of breakdown of the nuclear envelope. PMID- 25689739 TI - The multieffects of DMF and DBU on the [5 + 1] benzannulation of nitroethane and alpha-alkenoyl ketene-(S,S)-acetals: hydrogen bonding and electrostatic interactions. AB - A density functional theory (DFT) study was performed to elucidate the mechanism for the [5 + 1] benzannulation of nitroethane and alpha-alkenoyl ketene-(S,S) acetals. The calculation results are consistent with experimental findings, showing that the reaction proceeds via deprotonation of nitroethane, nucleophilic addition, intramolecular cyclization, elimination of HNO2 , and the keto-enol tautomerization sequence. It was disclosed that N,N-dimethylformamide (DMF) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) act as not only solvent and nonnucleophilic base, respectively, but also catalysts in the reaction by stabilizing the transition states (TSs) and intermediates via intermolecular hydrogen bonds and electrostatic interactions. Besides, the effective orbital interaction of the reaction site in TS also contributes to the intramolecular cyclization step. The new mechanistic insights obtained by DFT calculations highlight that the hydrogen bonds and electrostatic interactions are key factors for the [5 + 1] benzannulation of nitroethane and alpha-alkenoyl ketene-(S,S) acetals. PMID- 25689740 TI - Tissue engineering for human urethral reconstruction: systematic review of recent literature. AB - BACKGROUND: Techniques to treat urethral stricture and hypospadias are restricted, as substitution of the unhealthy urethra with tissue from other origins (skin, bladder or buccal mucosa) has some limitations. Therefore, alternative sources of tissue for use in urethral reconstructions are considered, such as ex vivo engineered constructs. PURPOSE: To review recent literature on tissue engineering for human urethral reconstruction. METHODS: A search was made in the PubMed and Embase databases restricted to the last 25 years and the English language. RESULTS: A total of 45 articles were selected describing the use of tissue engineering in urethral reconstruction. The results are discussed in four groups: autologous cell cultures, matrices/scaffolds, cell-seeded scaffolds, and clinical results of urethral reconstructions using these materials. Different progenitor cells were used, isolated from either urine or adipose tissue, but slightly better results were obtained with in vitro expansion of urothelial cells from bladder washings, tissue biopsies from the bladder (urothelium) or the oral cavity (buccal mucosa). Compared with a synthetic scaffold, a biological scaffold has the advantage of bioactive extracellular matrix proteins on its surface. When applied clinically, a non-seeded matrix only seems suited for use as an onlay graft. When a tubularized substitution is the aim, a cell-seeded construct seems more beneficial. CONCLUSIONS: Considerable experience is available with tissue engineering of urethral tissue in vitro, produced with cells of different origin. Clinical and in vivo experiments show promising results. PMID- 25689741 TI - GenInfoGuard--a robust and distortion-free watermarking technique for genetic data. AB - Genetic data, in digital format, is used in different biological phenomena such as DNA translation, mRNA transcription and protein synthesis. The accuracy of these biological phenomena depend on genetic codes and all subsequent processes. To computerize the biological procedures, different domain experts are provided with the authorized access of the genetic codes; as a consequence, the ownership protection of such data is inevitable. For this purpose, watermarks serve as the proof of ownership of data. While protecting data, embedded hidden messages (watermarks) influence the genetic data; therefore, the accurate execution of the relevant processes and the overall result becomes questionable. Most of the DNA based watermarking techniques modify the genetic data and are therefore vulnerable to information loss. Distortion-free techniques make sure that no modifications occur during watermarking; however, they are fragile to malicious attacks and therefore cannot be used for ownership protection (particularly, in presence of a threat model). Therefore, there is a need for a technique that must be robust and should also prevent unwanted modifications. In this spirit, a watermarking technique with aforementioned characteristics has been proposed in this paper. The proposed technique makes sure that: (i) the ownership rights are protected by means of a robust watermark; and (ii) the integrity of genetic data is preserved. The proposed technique-GenInfoGuard-ensures its robustness through the "watermark encoding" in permuted values, and exhibits high decoding accuracy against various malicious attacks. PMID- 25689742 TI - High connectivity of the crocodile shark between the Atlantic and Southwest Indian Oceans: highlights for conservation. AB - Among the various shark species that are captured as bycatch in commercial fishing operations, the group of pelagic sharks is still one of the least studied and known. Within those, the crocodile shark, Pseudocarcharias kamoharai, a small sized lamnid shark, is occasionally caught by longline vessels in certain regions of the tropical oceans worldwide. However, the population dynamics of this species, as well as the impact of fishing mortality on its stocks, are still unknown, with the crocodile shark currently one of the least studied of all pelagic sharks. Given this, the present study aimed to assess the population structure of P. kamoharai in several regions of the Atlantic and Indian Oceans using genetic molecular markers. The nucleotide composition of the mitochondrial DNA control region of 255 individuals was analyzed, and 31 haplotypes were found, with an estimated diversity Hd = 0.627, and a nucleotide diversity pi = 0.00167. An analysis of molecular variance (AMOVA) revealed a fixation index PhiST = 0.01118, representing an absence of population structure among the sampled regions of the Atlantic Ocean, and between the Atlantic and Indian Oceans. These results show a high degree of gene flow between the studied areas, with a single genetic stock and reduced population variability. In panmictic populations, conservation efforts can be concentrated in more restricted areas, being these representative of the total biodiversity of the species. When necessary, this strategy could be applied to the genetic maintenance of P. kamoharai. PMID- 25689744 TI - [The EMBRACE study]. PMID- 25689743 TI - Effects of two dietary fibers as part of ready-to-eat cereal (RTEC) breakfasts on perceived appetite and gut hormones in overweight women. AB - The effects of an enzyme-hydrolyzed arabinoxylan from wheat (AXOS) versus an intact arabinoxylan from flax (FLAX) added to a ready-to-eat cereal (RTEC) on the postprandial appetitive, hormonal, and metabolic responses in overweight women (BMI 25.0-29.9 kg/m2) were evaluated. Subsequent meal energy intake was also assessed. Two randomized, double-blind, crossover design studies were completed. For trial 1, the participants consumed the following RTEC breakfast, matched for total weight and varied in energy content: low-fiber (LF, 4 g); high-fiber (HF, 15 g) as either AXOS or FLAX. For trial 2, the participants consumed LF, HF-AXOS, and HF-FLAX RTECs but also consumed another LF breakfast that was isocaloric (LF iso) to that of the HF breakfasts. Perceived appetite and blood samples (trial 2 only) were assessed before and after breakfast. An ad libitum lunch was offered 4 h post-breakfast. No differences in postprandial appetite responses were observed among any breakfasts in either trial. The HF-AXOS and HF-FLAX led to increased postprandial GLP-1 and peptide YY (PYY) concentrations vs. LF-iso. No differences were observed in lunch meal energy intake among breakfast meals in either trial. Collectively, these data suggest that 15 g of low molecular weight fiber added to RTECs did not affect perceived appetite or subsequent energy intake despite differences in satiety hormone signaling in overweight females. PMID- 25689745 TI - [The SERAPHIN study]. PMID- 25689746 TI - [Episodes of apparent transient loss of consciousness: disorders a cardiologist should not ignore]. AB - Affections such as psychogenic (functional) pseudosyncope and cataplexy are characterized by transient attacks without impairment of consciousness, but with loss of postural control and unresponsiveness. Therefore, these disorders should be differentiated from syncope and should not be ignored by the cardiologist, who is usually a reference point for patients with syncope or suspected syncope. Clinical findings that suggest psychogenic pseudosyncope include frequent attacks always in the presence of audience, a fall to the ground that may develop slowly enough to allow the patient to stagger and break the fall before hitting the floor, prolonged attacks (>10 min), many psychosomatic symptoms as the clinical context. In most cases, the differential diagnosis should be made with neurally mediated syncope; to this end, tilt test appears to be very useful. Cataplexy is a relevant symptom of narcolepsy; the differential diagnosis between cataplexy and syncope should be made only when symptoms of narcolepsy are mild. Clinical findings that suggest cataplexy include an emotional trigger - above all if the emotion is positive -, an "unreal" fall similar to that observed in patients with psychogenic pseudosyncope, repeated attacks in a daytime, symptoms of narcolepsy as the clinical context. Since cataleptic attacks are triggered by emotion, in most cases the differential diagnosis should be made with vasovagal syncope; a positive emotion as a trigger suggests a cataleptic attack. PMID- 25689747 TI - [Vitamin D deficiency and cardiovascular diseases]. AB - Vitamin D deficiency is a condition that affects a high percentage of individuals of all ages. Considerable attention has been paid recently to the possible role of deficiency of this vitamin in the development of several chronic diseases, including cardiovascular and metabolic diseases. In particular, vitamin D deficiency is associated with an increase in conditions such as obesity, insulin resistance, hypertension, diabetes, and an increased risk of death from these pathologies. There is also a significant correlation with mortality for major cardiovascular events such as heart failure, myocardial infarction, sudden cardiac death, stroke, atrial fibrillation, and peripheral vascular disease. The pathophysiological mechanisms of these correlations are yet to be determined, but hyperactivity of the renin-angiotensin-aldosterone system seems to play a leading role. The role of therapy with vitamin D supplements in improving cardiovascular outcome in patients with low levels of vitamin D remains to be determined. PMID- 25689748 TI - [Clinical scores in chronic heart failure: does an ideal score exist?]. AB - Numerous prognostic markers have shown to be predictive of patient outcome in heart failure (HF). The recent guidelines of the European Society of Cardiology for the diagnosis and treatment of acute and chronic HF have identified as many as 57 individual markers in patients with HF, including demographic data, etiology, comorbidities, clinical, radiological, hemodynamic, echocardiographic and biochemical parameters. If more accurate risk stratification is required, several scoring systems have been proposed. This article reviews scoring systems for HF prognostication. Although most of the models include readily available clinical information, usually NYHA functional class, left ventricular ejection fraction (LVEF) and comorbidities, quite a few of them comprise Doppler echocardiographic variables, other than LVEF, and circulating levels of natriuretic peptides. In order to achieve a better prediction of the outcome, an ideal score should be based on a comprehensive Doppler echocardiographic examination, the assessment of circulating biomarkers, and a more objective evaluation of exercise tolerance. PMID- 25689749 TI - [Prognostication in heart failure]. PMID- 25689750 TI - [The serotonin syndrome: why should cardiologists be aware and scared of it]. AB - The serotonin syndrome (SS) represents a life-threatening adverse drug reaction, caused by serotonin overload in the central and peripheral nervous system, producing autonomic instability, neuromuscular and cardiovascular abnormalities, and cognitive alterations. The incidence of SS has been growing over the last few years, as a consequence of population aging and the steadily increasing use of pro-serotoninergic agents in clinical practice, in the presence of various comorbidities, mainly cardiovascular. Cardiologists often use combination therapies including serotoninergic agents, and should therefore consider the risk of serotoninergic adverse events caused by inappropriate drug interactions. SS is often difficult to diagnose and may be life-threatening if not adequately managed. Considering the several published case reports of overdose or not recommended associations, a greater awareness by clinicians about the potential risks associated with inappropriate use of these drugs is needed, as well as better information on the clinical features and therapeutic approaches to SS. PMID- 25689751 TI - [Lipid control in high-risk patients: focus on PCSK9 inhibitors]. AB - Low-density lipoprotein (LDL)-cholesterol levels are strictly related to the risk of major cardiovascular events. Statins have been demonstrated to significantly reduce LDL-cholesterol levels, contributing to cardiovascular risk reduction especially in high-risk patients. However, low adherence to statins, due to adverse effects, is often observed and many patients in secondary prevention exhibit LDL-cholesterol levels >70 mg/dl. As a consequence, there is the need for new therapeutic approaches with different mechanisms of action to reach recommended lipid targets in high-risk patients. One potential approach is to inhibit PCSK9, a serum protein with an active role in controlling the expression of LDL receptors, by reducing their recycling and targeting it for lysosomal destruction. Monoclonal antibodies against PCSK9, in particular alirocumab and evolocumab, have been shown to reduce LDL substantially, either with or without concomitant statin therapy with good tolerability. Ongoing trials will further define the efficacy of these drugs as an emerging approach to the treatment of hypercholesterolemia in primary and secondary prevention of high-risk patients. PMID- 25689752 TI - [Percutaneous implantation of a left ventricular restoration device [Parachute(TM)] for the treatment of ischemic heart failure]. AB - Congestive heart failure secondary to myocardial infarction is associated with significant morbidity and mortality despite currently available therapies. A novel catheter-based left ventricular partitioning device (ParachuteTM, CardioKinetix, Inc., Menlo Park, CA) is currently available for the treatment of patients with severe systolic dysfunction after antero-apical myocardial infarction with regional wall motion abnormalities. Preliminary clinical data showed that the ParachuteTM implantation could be associated with favorable clinical and left ventricular hemodynamic improvements post-implantation. Here, we present the case of a patient with symptomatic congestive heart failure after myocardial infarction implanted with the ParachuteTM device and we briefly review the current literature on this left ventricular partitioning system. PMID- 25689753 TI - Hatching asynchrony aggravates inbreeding depression in a songbird (Serinus canaria): an inbreeding-environment interaction. AB - Understanding how the intensity of inbreeding depression is influenced by stressful environmental conditions is an important area of enquiry in various fields of biology. In birds, environmental stress during early development is often related to hatching asynchrony; differences in age, and thus size, impose a gradient in conditions ranging from benign (first hatched chick) to harsh (last hatched chick). Here, we compared the effect of hatching order on growth rate in inbred (parents are full siblings) and outbred (parents are unrelated) canary chicks (Serinus canaria). We found that inbreeding depression was more severe under more stressful conditions, being most evident in later hatched chicks. Thus, consideration of inbreeding-environment interactions is of vital importance for our understanding of the biological significance of inbreeding depression and hatching asynchrony. The latter is particularly relevant given that hatching asynchrony is a widespread phenomenon, occurring in many bird species. The exact causes of the observed inbreeding-environment interaction are as yet unknown, but may be related to a decrease in maternal investment in egg contents with laying position (i.e. prehatching environment), or to performance of the chicks during sibling competition and/or their resilience to food shortage (i.e. posthatching environment). PMID- 25689754 TI - Use of an organotypic mammalian in vitro follicle growth assay to facilitate female reproductive toxicity screening. AB - Screening of pharmaceutical, chemical and environmental compounds for their effects on reproductive health relies on in vivo studies. More robust and efficient methods to assess these effects are needed. Herein we adapted and validated an organotypic in vitro follicle growth (IVFG) assay to determine the impact of compounds on markers of ovarian function. We isolated mammalian follicles and cultured them in the presence of compounds with: (1) known fertotoxicity (i.e. toxicity to the reproductive system; cyclophosphamide and cisplatin); (2) no known fertotoxicity (nalbuphine); and (3) unknown fertotoxicity (Corexit EC 9500 A; CE, Nalco, Chicago, IL, USA). For each compound, we assayed follicle growth, hormone production and the ability of follicle-enclosed oocytes to resume meiosis and produce a mature egg. Cyclophosphamide and cisplatin caused dose-dependent disruption of follicle dynamics, whereas nalbuphine did not. The reproductive toxicity of CE, an oil dispersant used heavily during the 2010 Deepwater Horizon oil spill, has never been examined in a mammalian system. In the present study, CE compromised follicle morphology and functional parameters. Our findings demonstrate that this IVFG assay system can be used to distinguish fertotoxic from non-toxic compounds, providing an in vitro tool to assess the effects of chemical compounds on reproductive function and health. PMID- 25689755 TI - Effects of fluid shear stress on polyelectrolyte multilayers by neutron scattering studies. AB - The structure of layer-by-layer (LbL) deposited nanofilm coatings consists of alternating polyethylenimine (PEI) and polystyrenesulfonate (PSS) films deposited on a single crystal quartz substrate. LbL-deposited nanofilms were investigated by neutron reflectomery (NR) in contact with water in the static and fluid shear stress conditions. The fluid shear stress was applied through a laminar flow of the liquid parallel to the quartz/polymer interface in a custom-built solid liquid interface cell. The scattering length density profiles obtained from NR results of these polyelectrolyte multilayers (PEM), measured under different shear conditions, showed proportional decrease of volume fraction of water hydrating the polymers. For the highest shear rate applied (ca. 6800 s(-1)) the water volume fraction decreased by approximately 7%. The decrease of the volume fraction of water was homogeneous through the thickness of the film. Since there were not any significant changes in the total polymer thickness, it resulted in negative osmotic pressures in the film. The PEM films were compared with the behavior of thin films of thermoresponsive poly(N-isopropylacrylamide) (pNIPAM) deposited via spin-coating. The PEM and pNIPAM differ in their interactions with water molecules, and they showed opposite behaviors under the fluid shear stress. In both cases the polymer hydration was reversible upon the restoration of static conditions. A theoretical explanation is given to explain this difference in the effect of shear on hydration of polymeric thin films. PMID- 25689756 TI - Patient-centered endpoints for perioperative outcomes research. PMID- 25689757 TI - Measurement of disability-free survival after surgery. AB - BACKGROUND: Survival and freedom from disability are arguably the most important patient-centered outcomes after surgery, but it is unclear how postoperative disability should be measured. The authors thus evaluated the World Health Organization Disability Assessment Schedule 2.0 in a surgical population. METHODS: The authors examined the psychometric properties of World Health Organization Disability Assessment Schedule 2.0 in a diverse cohort of 510 surgical patients. The authors assessed clinical acceptability, validity, reliability, and responsiveness up to 12 months after surgery. RESULTS: Criterion and convergent validity of World Health Organization Disability Assessment Schedule 2.0 were supported by good correlation with the 40-item quality of recovery scale at 30 days after surgery (r = -0.70) and at 3, 6, and 12 months after surgery with physical functioning (The Katz index of independence in Activities of Daily Living; r = -0.70, r = -0.60, and rho = -0.47); quality of life (EQ-5D; r = -0.57, -0.60, and -0.52); and pain interference scores (modified Brief Pain Inventory Short Form; r = 0.72, 0.74, and 0.81) (all P < 0.0005). Construct validity was supported by increased hospital stay (6.9 vs. 5.3 days, P = 0.008) and increased day 30 complications (20% vs. 11%, P = 0.042) in patients with new disability. There was excellent internal consistency with Cronbach's alpha and split-half coefficients greater than 0.90 at all time points (all P < 0.0005). Responsiveness was excellent with effect sizes of 3.4, 3.0, and 1.0 at 3, 6, and 12 months after surgery, respectively. CONCLUSIONS: World Health Organization Disability Assessment Schedule 2.0 is a clinically acceptable, valid, reliable, and responsive instrument for measuring postoperative disability in a diverse surgical population. Its use as an endpoint in future perioperative studies can provide outcome data that are meaningful to clinicians and patients alike. PMID- 25689758 TI - "Rube" goldberg asks is there a doctor in the house? PMID- 25689759 TI - McGill's gaseous ambiguity? "Certainly not!". PMID- 25689760 TI - The pentothal tubing bag of frank L. Faust, M.D. PMID- 25689761 TI - Presence or absence of elevated acute total serum tryptase by itself is not a definitive marker for an allergic reaction. PMID- 25689762 TI - In reply. PMID- 25689763 TI - More attention to respiration: a simple but effective approach to reduce postoperative mortality? PMID- 25689764 TI - In reply. PMID- 25689770 TI - Quality of life: measuring disability-free survival. PMID- 25689771 TI - Toward a standard lexicon for ecosystem services. AB - The complex, widely dispersed, and cumulative environmental challenges currently facing society require holistic, transdisciplinary approaches to resolve. The concept of ecosystem services (ES) has become more widely accepted as a framework that fosters a broader systems perspective of sustainability and can make science more responsive to the needs of decision makers and the public. Successful transdisciplinary approaches require a common language and understanding of key concepts. Our primary objective is to encourage the ES research and policy communities to standardize terminology and definitions, to facilitate mutual understanding by multidisciplinary researchers and policy makers. As an important step toward standardization, we present a lexicon developed to inform ES research conducted by the US Environmental Protection Agency and its partners. We describe a straightforward conceptualization of the relationships among environmental decisions, their effects on ecological systems and the services they provide, and human well-being. This provides a framework for common understanding and use of ES terminology. We encourage challenges to these definitions and attempts to advance standardization of a lexicon in ways that might be more meaningful to our ultimate objective: informing environmental decisions in ways that promote the sustainability of the environment upon which we all depend. PMID- 25689772 TI - A high proportion of cells carrying trisomy 12 is associated with a worse outcome in patients with chronic lymphocytic leukemia. AB - The prognosis of chronic lymphocytic leukemia (CLL) patients displaying trisomy 12 (+12) remains unclear. In this study, we analyzed the influence of the proportion of cells with +12, and other clinical and biologic factors, in time to first therapy (TTFT) and overall survival (OS), in 289 patients diagnosed with CLL carrying +12. Median OS was 129 months. One hundred seventy-four patients (60.2%) presented +12 in <60% of cells. TTFT and OS for this subgroup were longer than for the subgroup with +12 in >=60% of cells, with a median TTFT of 49 months (CI95%, 39-58) vs 30 months (CI95%, 22-38) (P = 0.001); and a median OS of 159 months (CI95%, 119-182), vs 96 months (CI95%, 58-134) (P = 0.015). Other factors associated with a shorter TTFT were: Binet stage, B symptoms, lymphadenopathy, splenomegaly, high lymphocyte count, 11q-, high beta2 microglobulin, and high LDH. In the multivariate analysis, clinical stage, +12 in >=60% of cells, high lymphocyte count, B symptoms, and 11q- in addition, resulted of significance in predicting shorter TTFT. Significant variables for OS were: Binet stage, lymphadenopathy, splenomegaly, high LDH, high beta2 microglobulin, 11q-, and CD38. In the multivariate analysis, only Binet stage, 11q-, and high beta2microglobulin significantly predicted shorter OS. CLL with +12 entails a heterogeneous group with intermediate prognosis. However, a high proportion of cells carrying +12 separates a subgroup of patients with poor outcome. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 25689773 TI - Solvent influence on cellulose 1,4-beta-glycosidic bond cleavage: a molecular dynamics and metadynamics study. AB - We explore the influence of two solvents, namely water and the ionic liquid 1 ethyl-3-methylimidazolium acetate (EmimAc), on the conformations of two cellulose models (cellobiose and a chain of 40 glucose units) and the solvent impact on glycosidic bond cleavage by acid hydrolysis by using molecular dynamics and metadynamics simulations. We investigate the rotation around the glycosidic bond and ring puckering, as well as the anomeric effect and hydrogen bonds, in order to gauge the effect on the hydrolysis mechanism. We find that EmimAc eases hydrolysis through stronger solvent-cellulose interactions, which break structural and electronic barriers to hydrolysis. Our results indicate that hydrolysis in cellulose chains should start from the ends and not in the centre of the chain, which is less accessible to solvent. PMID- 25689774 TI - Catalytic asymmetric diels-alder reaction of quinone imine ketals: a site divergent approach. AB - The catalytic asymmetric Diels-Alder reaction of quinone imine ketals with diene carbamates catalyzed by axially chiral dicarboxylic acids is reported herein. A variety of primary and secondary alkyl-substituted quinone derivatives which have not been applied in previous asymmetric quinone Diels-Alder reactions could be employed using this method. More importantly, we succeeded in developing a strategy to divert the reaction site in unsymmetrical 3-alkyl quinone imine ketals from the inherently favored unsubstituted C=C bond to the disfavored alkyl substituted C=C bond. PMID- 25689775 TI - Atomistic modeling of IR action spectra under circularly polarized electromagnetic fields: toward action VCD spectra. AB - The nonlinear response and dissociation propensity of an isolated chiral molecule, camphor, to a circularly polarized infrared laser pulse was simulated by molecular dynamics as a function of the excitation wavelength. The results indicate similarities with linear absorption spectra, but also differences that are ascribable to dynamical anharmonic effects. Comparing the responses between left- and right-circularly polarized pulses in terms of dissociation probabilities, or equivalently between R- and S-camphor to a similarly polarized pulse, we find significant differences for the fingerprint C = O amide mode, with a sensitivity that could be sufficient to possibly enable vibrational circular dichroism as an action technique for probing molecular chirality and absolute conformations in the gas phase. PMID- 25689776 TI - Graphene oxide nanoribbons: improved synthesis and application in MALDI mass spectrometry. AB - Graphene nanoribbon is a novel variety of graphene with high length-to-width ratio and straight edges. Herein, we report an improved method for the synthesis of graphene oxide nanoribbons (GONRs) from longitudinal unraveling of multiwalled carbon nanotubes by means of a one-step, one-pot pressurized oxidation reaction. The obtained GONRs were characterized by different techniques. Furthermore, owing to their unique properties such as strong optical absorption and good water dispersibility, we show that GONRs can be used as an excellent matrix or probe in matrix-assisted or surface-enhanced laser desorption/ionization mass spectrometry (MALDI or SELDI MS) for the first time. In MALDI MS, GONRs generated significantly higher signals than conventional organic matrix and other graphene based matrices in the detection of low-mass compounds. We also demonstrate the use of GONRs as a sensitive SELDI probe for simultaneous detection of multiple small molecules and profiling of small molecules in complex environmental samples, thus revealing its application potential in rapid screening of low-mass pollutants in complex media. PMID- 25689777 TI - In vitro activity of rifampicin and verapamil combination in multidrug-resistant mycobacterium tuberculosis. AB - The aim of the present study was to evaluate the effect of the combination of rifampicin (RIF) and verapamil (VP) against the Mycobacterium tuberculosis H37Rv reference strain and six multidrug-resistant (MDR) M. tuberculosis clinical isolates by determining Time-Kill Curves and the ability to efflux drug by fluorometry. The RIF+VP combination showed synergism in one MDR clinical isolate. For the other five MDR clinical isolates, the drug combination showed no interaction. The MDR clinical isolate had lower ethidium bromide (EtBr) accumulation when exposed to the RIF+VP combination, compared with RIF and VP exposure alone. The other MDR clinical isolates showed no significant difference in EtBr accumulation. These results suggest greater efflux action in one of the MDR clinical isolates compared with the M. tuberculosis H37Rv reference strain. The other five MDR isolates may have additional mechanisms of drug resistance to RIF. The use of the RIF+VP combination made one MDR bacillus more susceptible to RIF probably by inhibiting efflux pumps, and this combination therapy, in some cases, may contribute to a reduction of resistance to RIF in M. tuberculosis. PMID- 25689778 TI - Scrub typhus, a disease with increasing threat in Guangdong, China. AB - There has been a rapid increase in the number of scrub typhus cases in Guangdong Province, China. For this reason, an epidemiologic study was conducted to understand the characteristics of scrub typhus epidemics in Guangdong. From 2006 to 2013, the incidence of human cases increased from 0.4321 to 3.5917 per 100,000 with a bimodal peak in human cases typically occurring between May and November. To detect the prevalence of Orientia tsutsugamushi among suspected human cases and rodents, we performed ELISA tests of IgM/IgG and nested PCR tests on 59 whole blood samples from the suspected cases and 112 spleen samples from the rodents. Suspected cases tested positive for anti-O. tsutsugamushi IgM and IgG 66.1% (39/59) and 50.8% (30/59) of the time, respectively. Additionally, 20.3% (12/59) of blood samples and 13.4% (15/112) of spleen samples were positive for PCR. Phylogenetic analysis revealed that there were four definable clusters among the 27 nucleotide sequences of the 56-kDa antigen genes: 44.4% Karp (12/27), 25.9% Kato (7/27), 22.2% Gilliam (6/27) and 7.4% TA763 (2/27). We concluded many suspected cases may result in diagnostic errors; therefore, it is necessary to perform laboratory tests on suspected cases in hospitals. The high infection rate of O. tsutsugamushi among the limited rodents tested suggested that further rodent sampling throughout the province is necessary to further define high-risk areas. Furthermore, the multiple co-circulating genotypes of O. tsutsugamushi play a key role in the pervasiveness of scrub typhus in the Guangdong area. PMID- 25689779 TI - Long- and short-term effects of smothering and burial by drill cuttings on calcareous algae in a static-renewal test. AB - Discharge of drill cuttings into the ocean during drilling of offshore oil wells can impact benthic communities through an increase in the concentrations of suspended particles in the water column and sedimentation of particles on the seafloor around the drilling installation. The present study assessed effects of water-based drill cuttings, barite, bentonite, and natural sediments on shallow- and deep-water calcareous algae in short-term (30 d) and long-term (90 d) experiments, using 2 species from Peregrino's oil field at Campos Basin, Brazil: Mesophyllum engelhartii and Lithothamnion sp. The results were compared with the shallow-water species Lithothamnion crispatum. Smothering and burial exposures were simulated. Oxygen production and fluorescence readings were recorded. Although less productive, M. engelhartii was as sensitive to stress as Lithothamnion sp. Mesophyllum engelhartii was sensitive to smothering by drill cuttings, barite, and bentonite after 60 d of exposure and was similarly affected by natural sediments after 90 d. These results indicate that smothering by sediments caused physical effects that might be attributable to partial light attenuation and partial restriction on gas exchange but did not kill the calcareous algae in the long term. However, 1-mo burial by either natural sediments or drill cuttings was sufficient after 60 d for both species to reduce oxygen production, and the algae were completely dead under both sources of sediments. PMID- 25689780 TI - A SERS-Assisted 3D Barcode Chip for High-Throughput Biosensing. AB - A surface enhanced Raman scattering (SERS)-assisted 3D barcode chip has been developed for high-throughput biosensing. The 3D barcode is realized through joint 2D spatial encoding with the Raman spectroscopic encoding, which stores the SERS fingerprint information in the format of a 2D array. Here, the concept of SERS-assisted 3D barcode is demonstrated through multiplex immunoassay, where simultaneous detection of multiple targets in different samples has been achieved using a microfluidic platform. First, multiple proteins in different samples are spatially separated using a microfluidic patterned antibody barcode substrate, forming a 2D hybridization array. Then the SERS probes are used to identify and quantify the proteins. As different SERS probes are labeled with different Raman reporters, they could be employed as "SERS tags" to incorporate spectroscopic information into the 3D barcode. In this 3D barcode, the 2D spatial information helps to differentiate the samples and targets while the SERS information allows quantitative multiplex detection. It is found that the SERS-assisted 3D barcode chip can not only accomplish one-step multiplex detection within 30 min but also achieve an ultrasensitivity down to 10 fg mL(-1) (~70 aM), which is expected to provide a promising tool for high-throughput biomedical applications. PMID- 25689781 TI - Rapid identification of medically important Candida isolates using high resolution melting analysis. AB - An increasing trend in non albicans infections and various susceptibility patterns to antifungal agents implies a requirement for the quick and reliable identification of a number of medically important Candida species. Real-time PCR followed by high resolution melting analysis (HRMA) was developed, tested on 25 reference Candida collection strains and validated on an additional 143 clinical isolates in this study. All reference strains and clinical isolates inconclusive when using phenotypic methods and/or HRMA were analysed using ITS2 sequencing. Considering reference and clinical strains together, 23 out of 27 Candida species could be clearly distinguished by HRMA, while the remaining 4 species were grouped in 2 pairs, when applying the mean Tm +/- 3 SD values, the shape of the derivative melting curve (dMelt curve) and, in some cases, the normalized and temperature-shifted difference plot against C. krusei. HRMA as a simple, rapid and inexpensive tool was shown to be useful in identifying a wide spectrum of clinically important Candida species. It may complement the current clinical diagnostic approach based on commercially available biochemical kits. PMID- 25689783 TI - Scanning Electron Microscopic Features of Nasolacrimal Silastic Stents Retained for Prolong Durations Following Dacryocystorhinostomy. AB - PURPOSE: The aims of this study were to examine the scanning electron microscopic features of silastic nasolacrimal duct stents retained for long durations following a dacryocystorhinostomy. METHODS: A prospective interventional study was performed on stents retrieved from patients who were lost to follow up after a dacryocystorhinostomy with Crawford stent insertion. Long duration was defined as stents retrieved at a minimum of 1 year following a dacryocystorhinostomy. None of the patients had any evidence of postoperative infection. After removal, the stent segments were subjected to biofilm and physical deposit analysis using standard protocols of scanning electron microscopy. These stent segments were compared against sterile stents which acted as controls. RESULTS: A total of 7 stents were studied. Five were consecutive patient samples, and 2 were sterile stents. All the 5 stents were retrieved from patients who were lost to follow up for a minimum of 12 months following surgery. The mean duration of intubation at retrieval was 21 months. All the stents demonstrated evidence of biofilm formation and physical deposits. However, as the duration of retention increased, the deposits and biofilms were noted to be progressively denser, multilayered and extensive. Certain areas demonstrated thick biofilm integration with the deposits. Polymicrobial communities were noted within the exopolysaccharide matrix. CONCLUSIONS: This is the first study to exclusively report on scanning electron microscopic features of lacrimal stents retained for long durations. Further studies on physical elements within the deposits and protein analysis would provide more insights into stent-tissue interactions. PMID- 25689782 TI - Variation in promiscuity and sexual selection drives avian rate of Faster-Z evolution. AB - Higher rates of coding sequence evolution have been observed on the Z chromosome relative to the autosomes across a wide range of species. However, despite a considerable body of theory, we lack empirical evidence explaining variation in the strength of the Faster-Z Effect. To assess the magnitude and drivers of Faster-Z Evolution, we assembled six de novo transcriptomes, spanning 90 million years of avian evolution. Our analysis combines expression, sequence and polymorphism data with measures of sperm competition and promiscuity. In doing so, we present the first empirical evidence demonstrating the positive relationship between Faster-Z Effect and measures of promiscuity, and therefore variance in male mating success. Our results from multiple lines of evidence indicate that selection is less effective on the Z chromosome, particularly in promiscuous species, and that Faster-Z Evolution in birds is due primarily to genetic drift. Our results reveal the power of mating system and sexual selection in shaping broad patterns in genome evolution. PMID- 25689784 TI - Langerhans Cell Histiocytosis of the Orbit: Spectrum of Disease and Risk of Central Nervous System Sequelae in Unifocal Cases. AB - PURPOSE: To describe the spectrum of disease extent and clinical response in Langerhans cell histiocytosis (LCH) presenting with orbital involvement and to determine if unifocal orbital disease increases the risk for central nervous system sequelae (CNS-LCH). METHODS: Retrospective chart review of patients with orbital LCH representing a range of severity treated at the Children's Hospital of Wisconsin from 2003 to 2011; analysis of current international treatment protocols; literature review. RESULTS: Six patients presenting with orbital LCH are described: 1 with unifocal orbital disease completely responsive to local measures; 1 with multifocal bone disease completely responsive to local intervention; 1 with unifocal orbital disease incompletely responsive to surgical intervention, and requiring systemic chemotherapy; and 3 with multisystem disease at presentation. Literature review identified 806 cases of CNS-LCH. Orbital involvement could be determined in 11 cases. Of these, 6 had multisystem disease and 3 had multifocal bone disease; 1 presented with unifocal orbital disease but progressed to multifocal bone involvement; 1 had insufficient clinical information to distinguish unifocal from multisite presentation. No cases of CNS LCH directly resulted from isolated unifocal orbital disease. CONCLUSIONS: Initial treatment of orbital LCH should depend on disease extent at diagnosis. Unifocal cases that completely respond to biopsy, curettage, and/or corticosteroid instillation may be managed with initial oncologic staging and careful long-term observation, with default to chemotherapy for local recurrence or multisite progression. There is currently little evidence that unifocal orbital disease increases the risk for CNS-LCH and therefore warrants prophylactic systemic chemotherapy in all patients. PMID- 25689785 TI - Forget Me Not: A Case of Gossypiboma (Textiloma) Mimicking an Orbital Tumor. AB - Retained foreign bodies are not infrequent following surgical procedures and are associated with medico-legal issues. Gossypiboma following ocular surgeries is rare but should be included in the differential diagnosis of a postoperative patient presenting with pain or mass. We report on one such case of gossypiboma following surgical excision of lacrimal gland. PMID- 25689786 TI - Modified wound closure technique in periorbital necrotizing fasciitis. AB - PURPOSE: To describe a modified wound closure technique in cases of necrotizing fasciitis and to describe its efficacy and usefulness. METHODS: The clinical characteristics of patients that underwent extensive debridement and modified wound closure were recorded and documented. RESULTS: Seven patients (5 males, 2 females; mean age = 40.9 years, standard deviation = 25.3 years) underwent debridement and modified wound closure. At discharge from the hospital, 6 patients (84.7%) achieved vision of 20/25 of better, although 1 patient lost all vision in the affected eye. Six patients (84.7%) experienced improvement in their visual acuity between admission to and discharge from the hospital. After a mean follow-up interval of 6.3 months, 5 patients (71.4%) did not require additional reconstructive interventions. CONCLUSIONS: In cases of periorbital necrotizing fasciitis, extensive debridement with a modified wound closure is a technically feasible intervention and produced excellent clinical, functional, and aesthetic results. PMID- 25689787 TI - Periorbital Nodular Fasciitis in Pregnancy: Case Report and Review of the Literature. AB - Nodular fasciitis is a comparatively common benign soft tissue tumor, which may rarely occur in the periorbital and orbital regions. It can be confused with a malignant sarcoma both in its clinical behavior and histologic appearance. Trauma is a suspected risk factor for nodular fasciitis and pregnancy may also be a risk factor. This may be due to the hormone-related changes occurring in pregnancy, which are suspected to be responsible for the growth of some orbital masses in pregnancy. However, there are other cases of orbital masses, which have grown in pregnancy and were not proven positive for estrogen or progesterone receptors, suggesting another mechanism for tumor growth. In any case, awareness of nodular fasciitis in the differential diagnosis of a rapidly growing, soft tissue mass in the periorbital and orbital regions is important to avoid misdiagnosis of a malignancy and unnecessary treatment. PMID- 25689788 TI - Tension Pneumocephalus Following Orbital Exenteration. AB - Pneumocephalus is a known complication of skull base surgery, but is rarely seen by orbital surgeons. We report a case of postoperative mental status changes after exenteration due to tension pneumocephalus. After surgical and medical management, the patient's pneumocephalus resolved and she recovered fully. Risk factors for tension pneumocephalus, mechanism, clinical presentation, and management techniques are discussed. PMID- 25689789 TI - Content of endothelial progenitor cells in autologous stem cell grafts predict survival after transplantation for multiple myeloma. AB - Multiple myeloma (MM) is considered an incurable B cell malignancy, although many patients can benefit from high-dose therapy with autologous stem cell transplantation (ASCT) as a first-line treatment. In non-Hodgkin lymphoma (NHL), ASCT is usually performed after relapse with curative intent. Disease progression is often associated with increased angiogenesis, in which endothelial progenitor cells (EPC) may have a central role. Here, we investigated the clinical impact of EPC levels in peripheral blood stem cell (PBSC) autografts for MM and NHL patients who received ASCT. EPC were identified by flow cytometry as aldehyde dehydrogenase(hi) CD34(+) vascular endothelial growth factor receptor 2(+) CD133(+) cells in both MM and NHL autografts. In MM, there was a positive correlation between EPC percentage and serum (s)-beta2-microglobulin levels (r(2) = .371, P = .002). Unlike for NHL patients, MM patients with high numbers of infused EPC (EPC cells per kilogram) during ASCT had significant shorter progression-free survival (PFS) (P = .035), overall survival (P = .044) and time to next treatment (P = .009). In multivariate analysis, EPC cells per kilogram was a significant independent negative prognostic indicator of PFS (P = .03). In conclusion, the presence of high number of EPC in PBSC grafts is associated with adverse prognosis after ASCT in MM. PMID- 25689791 TI - Avoiding introduction of bias in the analysis of the methylation of free circulating DNA. PMID- 25689790 TI - Finding a depression app: a review and content analysis of the depression app marketplace. AB - BACKGROUND: Depression is highly prevalent and causes considerable suffering and disease burden despite the existence of wide-ranging treatment options. Mobile phone apps offer the potential to help close this treatment gap by confronting key barriers to accessing support for depression. OBJECTIVES: Our goal was to identify and characterize the different types of mobile phone depression apps available in the marketplace. METHODS: A search for depression apps was conducted on the app stores of the five major mobile phone platforms: Android, iPhone, BlackBerry, Nokia, and Windows. Apps were included if they focused on depression and were available to people who self-identify as having depression. Data were extracted from the app descriptions found in the app stores. RESULTS: Of the 1054 apps identified by the search strategy, nearly one-quarter (23.0%, 243/1054) unique depression apps met the inclusion criteria. Over one-quarter (27.7%, 210/758) of the excluded apps failed to mention depression in the title or description. Two-thirds of the apps had as their main purpose providing therapeutic treatment (33.7%, 82/243) or psychoeducation (32.1%, 78/243). The other main purpose categories were medical assessment (16.9%, 41/243), symptom management (8.2%, 20/243), and supportive resources (1.6%, 4/243). A majority of the apps failed to sufficiently describe their organizational affiliation (65.0%, 158/243) and content source (61.7%, 150/243). There was a significant relationship (chi(2) 5=50.5, P<.001) between the main purpose of the app and the reporting of content source, with most medical assessment apps reporting their content source (80.5%, 33/41). A fifth of the apps featured an e-book (20.6%, 50/243), audio therapy (16.9%, 41/243), or screening (16.9%, 41/243) function. Most apps had a dynamic user interface (72.4%, 176/243) and used text as the main type of media (51.9%, 126/243), and over a third (14.4%, 35/243) incorporated more than one form of media. CONCLUSION: Without guidance, finding an appropriate depression app may be challenging, as the search results yielded non-depression specific apps to depression apps at a 3:1 ratio. Inadequate reporting of organization affiliation and content source increases the difficulty of assessing the credibility and reliability of the app. While certification and vetting initiatives are underway, this study demonstrates the need for standardized reporting in app stores to help consumers select appropriate tools, particularly among those classified as medical devices. PMID- 25689792 TI - An update on laboratory diagnosis in myasthenia gravis. AB - This review describes the state of the art for the use of laboratory testing in myasthenia gravis. The review brings a detailed description of the different clinical forms of auto-immune myasthenia and of the Lambert Eaton Myasthenic Syndrome (LEMS). The stress the differences between the different forms of acquired (auto-immune) myasthenia. Then they present a summary of the different antibodies found in the disease. They insist on the advantage of the RIPA assay to measure antibodies to the acetylcholine receptor. They stress the different types of contribution of each of these antibodies to the clinical diagnosis. They also describe the methods to measure each of the specific antibodies that have recently permitted to split the diagnosis: Abs to omega-conotoxin receptor in Lambert Eaton Myasthenic Syndrome (LEMS), abs to the acetylcholine receptor (AchR) in MG, Abs to muscle specific tyrosine kinase (MuSK) in Ab negative MG, and Abs to low molecular weight receptor related low-density lipo protein-4 (LRP 4). They also broach over the striated antibodies, less frequent and clinically less useful such as anti-titin, -ryanodine, -agrin and -rapsyn. This represent a 360 degrees view of the field as presented in Toronto in October 2014. PMID- 25689793 TI - Pre-clinical validation study of a miniaturized electrochemical immunoassay based on square wave voltammetry for early detection of carcinoembryonic antigen in human serum. AB - BACKGROUND: The ELISA format for measuring carcinoembryonic antigen (CEA) serves as a reference standard against which other assays are compared. Because the World Health Organization (WHO) increasingly recommends the use of serum CEA as a diagnostic tool for cancer, it is relevant to explore the reliability of the new decentralized CEA point-of-care-testing (POCT) technologies that are available to physicians and patients, in compliance with mandates of the clinical laboratories' regulatory agencies. METHODS: Electrochemical immunoassay (ECIA) based on trace lead (Pb) analysis by anodic stripping techniques using sandwich type immunocomplex conjugates: (MB)Ab/AgCEA/Ab(PbS), and a commercial ELISA test system with optical transmission. RESULTS: The ECIA provides better analytical performance than does the ELISA. The within assay precision coefficient of variance (%CVw) of the ECIA is lower than the value recommended by the Hong Kong Association of Medical Laboratories (HKAML), and the recoveries of CEA at 1.0, 5.0, 10.0, 25.0 and 50.0 ng/ml are in the range of 99-110% for control serum samples. The ECIA showed a minimal positive bias of 0.0267 +/- 0.3270 ng/ml (P=0.9389). CONCLUSIONS: The proposed CEA screening technology can be practically employed for decentralized clinical analysis of CEA in human serum. Therefore, it can be viewed as a control method for personalized therapy. PMID- 25689794 TI - Clinical impact of human breast milk metabolomics. AB - Metabolomics is a research field concerned with the analysis of metabolome, the complete set of metabolites in a given cell, tissue, or biological sample. Being able to provide a molecular snapshot of biological systems, metabolomics has emerged as a functional methodology in a wide range of research areas such as toxicology, pharmacology, food technology, nutrition, microbial biotechnology, systems biology, and plant biotechnology. In this review, we emphasize the applications of metabolomics in investigating the human breast milk (HBM) metabolome. HBM is the recommended source of nutrition for infants since it contains the optimal balance of nutrients for developing babies, and it provides a range of benefits for growth, immunity, and development. The molecular mechanisms beyond the inter- and intra-variability of HBM that make its composition unique are yet to be well-characterized. Although still in its infancy, the study of HBM metabolome has already proven itself to be of great value in providing insights into this biochemical variability in relation to mother phenotype, diet, disease, and lifestyle. The results of these investigations lay the foundation for further developments useful to identify normal and aberrant biochemical changes as well as to develop strategies to promote healthy infant feeding practices. PMID- 25689795 TI - Using circular RNA as a novel type of biomarker in the screening of gastric cancer. AB - BACKGROUND: Circular RNAs (circRNAs), a class of endogenous RNAs, have emerged as an enigmatic class of RNAs. Little is known about their value in the diagnosis of cancers. METHODS: The targeted circRNA of this study was selected using two circRNA databases: CircBase (http://circbase.org/) and circ2Traits (http://gyanxet-beta.com/circdb/). Divergent primers, rather than commonly used convergent primers, for the circRNA were designed. The circRNA levels in 101 paired gastric cancer tissues and adjacent nontumorous tissues from surgical gastric cancer patients and 36 paired plasma samples from preoperative and postoperative gastric cancer patients were analyzed by real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The specificity of the amplified products was measured by melting curve analysis and DNA sequencing. To observe the stability of circRNA, three randomly selected samples of gastric cancer tissues were stored at room temperature, 4 degrees C and -20 degrees C, and then, their circRNA levels were analyzed. To verify the reproducibility of qRT-PCR, circRNA levels were detected in a set of specimens (n=15) in two independent experiments with an interval of one day. Then, the correlation of their Ct values was determined. The relationships between circRNA expression levels and clinicopathological factors of patients with gastric cancer were further analyzed by one-way analysis of variance. A receiver operating characteristic (ROC) curve was established to evaluate the diagnostic value. RESULTS: Hsa_circ_002059, a typical circular RNA, was first found to be significantly downregulated in gastric cancer tissues compared with paired adjacent nontumorous tissues (p<0.001). Its levels in plasma collected from postoperative gastric cancer patients were found significantly different from those from preoperative gastric cancer patients. The area under the ROC curve was 0.73. Importantly, we further found that lower expression levels were significantly correlated with distal metastasis (P=0.036), TNM stage (P=0.042), gender (P=0.002) and age (P=0.022). The stability of circRNAs and the reproducibility of the qRT-PCR method for detecting circRNA levels were determined. CONCLUSION: These results suggested that circRNAs are highly stable in mammalian cells and that one specific circRNA, hsa_circ_002059, may be a potential novel and stable biomarker for the diagnosis of gastric carcinoma. PMID- 25689796 TI - Germ-free mice deficient of reactive oxygen species have increased arthritis susceptibility. AB - The NADPH oxidase 2 (NOX2) complex is responsible for the production of ROS in phagocytic cells. Genetic defects in NOX2 lead to opportunistic infections and inflammatory manifestations such as granulomas in humans, also known as chronic granulomatous disease (CGD). This condition is mirrored in mice with defective ROS production and interestingly both species are predisposed to autoimmune diseases. An unresolved question is whether the hyper-inflammation and tendency to develop autoimmunity are secondary to the increased infections, or whether these are parallel phenomena. We generated germ-free ROS deficient Ncf1 mutant mice that when reared in specific pathogen-free condition, are highly susceptible to collagen-induced arthritis compared with wild-type mice. Strikingly, arthritis incidence and severity was almost identical in germ-free and specific pathogen free ROS-deficient mice. In addition, partial reduction of the microbial flora by antibiotics treatment did not alter the disease course. Taken together, this shows that ROS has a clear immune regulatory function that is decoupled from its function in host defence. PMID- 25689800 TI - One-step hydrothermal synthesis of 3D petal-like Co9S8/RGO/Ni3S2 composite on nickel foam for high-performance supercapacitors. AB - Co9S8, Ni3S2, and reduced graphene oxide (RGO) were combined to construct a graphene composite with two mixed metal sulfide components. Co9S8/RGO/Ni3S2 composite films were hydrothermal-assisted synthesized on nickel foam (NF) by using a modified "active metal substrate" route in which nickel foam acted as both a substrate and Ni source for composite films. It is found that the Co9S8/RGO/Ni3S2/NF electrode exhibits superior capacitive performance with high capability (13.53 F cm(-2) at 20 mA cm(-2), i.e., 2611.9 F g(-1) at 3.9 A g(-1)), excellent rate capability, and enhanced electrochemical stability, with 91.7% retention after 1000 continuous charge-discharge cycles even at a high current density of 80 mA cm(-2). PMID- 25689801 TI - Spirocyclic, macrocyclic and ladder complexes of coinage metals and mercury with dichalcogeno P2N2-supported anions. AB - Metathetical reactions of alkali-metal derivatives of the dianion [(t)BuN(Se)P(MU N(t)Bu)2P(Se)N(t)Bu](2-) ((2Se2-)) with Ag(NHC)Cl, Ag[BF4], AuCl(THT) and HgCl2, as well as the reaction of 2S(2-) with AuCl(THT) were investigated. The observed products all incorporate the monoprotonated ligands 2SeH(-) or 2SH(-) in a variety of structural arrangements around the metal centres, including tetrameric and trimeric macrocycles [Ag and Au (E = Se)], a ladder (Au, E = S) and a spirocycle (Hg); the ladder contains both the dianion 2S(2-) and the monoanion 2SH(-) as ligands linking three Au2 units. All complexes have been characterised in the solid state by single crystal X-ray analyses and in solution by multinuclear ((1)H, (31)P and (77)Se) NMR spectra. PMID- 25689802 TI - Modeling chemotherapeutic neurotoxicity with human induced pluripotent stem cell derived neuronal cells. AB - There are no effective agents to prevent or treat chemotherapy-induced peripheral neuropathy (CIPN), the most common non-hematologic toxicity of chemotherapy. Therefore, we sought to evaluate the utility of human neuron-like cells derived from induced pluripotent stem cells (iPSCs) as a means to study CIPN. We used high content imaging measurements of neurite outgrowth phenotypes to compare the changes that occur to iPSC-derived neuronal cells among drugs and among individuals in response to several classes of chemotherapeutics. Upon treatment of these neuronal cells with the neurotoxic drug paclitaxel, vincristine or cisplatin, we identified significant differences in five morphological phenotypes among drugs, including total outgrowth, mean/median/maximum process length, and mean outgrowth intensity (P < 0.05). The differences in damage among drugs reflect differences in their mechanisms of action and clinical CIPN manifestations. We show the potential of the model for gene perturbation studies by demonstrating decreased expression of TUBB2A results in significantly increased sensitivity of neurons to paclitaxel (0.23 +/- 0.06 decrease in total neurite outgrowth, P = 0.011). The variance in several neurite outgrowth and apoptotic phenotypes upon treatment with one of the neurotoxic drugs is significantly greater between than within neurons derived from four different individuals (P < 0.05), demonstrating the potential of iPSC-derived neurons as a genetically diverse model for CIPN. The human neuron model will allow both for mechanistic studies of specific genes and genetic variants discovered in clinical studies and for screening of new drugs to prevent or treat CIPN. PMID- 25689803 TI - Therapeutic update on vitiligo. PMID- 25689804 TI - Time to consider psoriasis an autoimmune disorder? PMID- 25689805 TI - Amitriptyline/Ketamine as therapy for neuropathic pruritus and pain secondary to herpes zoster. AB - Frequent causes of morbidity secondary to herpes zoster include acute pain, secondary infection, and postherpetic neuralgia. A less documented complication is pruritus, which can be either acute or postinfectious when it persists more than 3 months after the rash has healed. We discuss a case of severe, acute neuropathic pruritus and pain secondary to active herpes zoster that was unresponsive to standard medical therapy, including oral antihistamines, topical lidocaine, oral gabapentin, and local wound care. Modest control of the pruritus and pain was achieved with continued multimodal therapy and the addition of topical 2% amitriptyline/0.5% ketamine gel. PMID- 25689806 TI - Clearance of psoriasis: the impact of private versus public insurance. AB - BACKGROUND: Psoriasis treatments and therapeutic response as they relate to private versus public patient insurance in the United States have not yet been reviewed. Improved understanding could clarify factors challenging optimal psoriasis management and offer insight for dermatologists treating psoriasis within our healthcare system. METHODS: 258 subjects were included from a database of psoriasis patients seen at Tufts Medical Center (Boston, MA) during 2008-2014. Insurance was classified as primarily private or public (Medicare or MassHealth/Medicaid). Patients required a minimum of two consecutive visits per treatment and at least 8 weeks within one of four treatment categories: biologics, oral systemics/ phototherapy, combined biologics and oral systemics/phototherapy, or topicals only. Primary endpoint was the Simple-Measure for Assessing Psoriasis Activity (S-MAPA) calculated by multiplying Physician Global Assessment by Body Surface Area. S-MAPA<3 constituted absolute clearance. Insurance type was evaluated as a predictor of prescribed treatment categories, maximum S-MAPA improvement from baseline, and total drugs used per treatment course ("drug-switching"). RESULTS: 80.2% (n=207) and 19.8% (n=51) had primarily private and public insurance, respectively. 69.6% with private insurance were prescribed biologics versus 66.7% (public insurance) (P=0.689). 54% (private) versus 49% (public) achieved clearance (P=0.514). However, S-MAPA decreased 78.35% from baseline in those with private insurance compared to 61.48% (public) (P=0.036). On average, privately insured patients used at least twice as many same-category treatments, most commonly biologics, than publicly insured individuals (P=0.003). Drug-switching was significantly associated with clearance (P=0.024). Multivariate analysis demonstrated no significant differences in prescribed treatment categories, drug efficacy, clearance, S-MAPA, or drugswitching with respect to patient age. CONCLUSIONS: Treatment categories were comparably prescribed between insurance subgroups. However, privately insured patients achieved significantly greater degrees of clearance and switched between more medications within biologic and systemic categories, potentially explaining their overall improved therapeutic response. Further studies including cost analysis could clarify any difference in the effectiveness of prescribed therapy for these two patient populations. PMID- 25689807 TI - The skin microbiome: is there a role in the pathogenesis of atopic dermatitis and psoriasis? AB - Skin microbiome studies have elucidated clinically pertinent information regarding its potential role in the pathogenesis of certain inflammatory skin disorders. Two of the most commonly diagnosed chronic inflammatory skin disorders that have been connected to perturbation of the skin microbiome are psoriasis (PS) and atopic dermatitis (AD). The objective of this brief review is to recapitulate some of the novel findings concerning the microbiome's role in AD and PS. PMID- 25689808 TI - Comparison of photographic methods. AB - BACKGROUND: Photo documentation has become increasing important in medicine, especially given the demand for cosmetic procedures. Standard photography is not always adequate; newer techniques exploring the use of polarized, cross and ultraviolet photography can give detailed information on subtle skin lesions including skin pigmentation and skin surface characteristics. OBJECTIVE: To use various methods of photography including standard photography, cross polarized light, parallel polarized light and ultraviolet passing photography to assess which method most effectively captures skin features such as texture, pigment, and/ or vascularity. METHODS: A prospective analysis comparing advanced photographic techniques including standard photography, polarized light photography, cross-polarized light photography and ultraviolet light passing photography. The photos were then evaluated and scored by two experts and a blinded observer to characterize the differences visualized in each type of photography compared to standard photography in terms of subsurface skin features, hypopigmentation, hyperpigmentation, and rhytids. RESULTS: 9 subjects completed the study. Overall, of the 3 photographic methods compared to standard photography, UV passing most enhanced the visualization of subsurface features and hypopigmentation, with increased hyperpigmentation as well. Enhancement of these features made UV passing best for capturing photodamage. Cross-polarized photography was best for visualizing hyperpigmentation, but also heightened visualization of hypopigmentation and subsurface features such as vascularity. Parallel-polarized photography enhanced visualization of skin texture. CONCLUSIONS: These methods of photography show a quantifiable and reproducible selective ability to evaluate and document elements such as skin texture, vascularity, and pigmentation. Each of these techniques has unique properties that can add to the precision of the clinical evaluation and can be of particular value to providers of cosmetic procedures where photo documentation has become increasingly important in providing an objective means of evaluating outcomes. PMID- 25689809 TI - Impact of female acne on patterns of health care resource utilization. AB - BACKGROUND: Limited data are available on acne treatment patterns in females through their adult years. OBJECTIVE: The purpose of this analysis was to evaluate health care resource utilization (HRU) and treatment patterns in cohorts with and without the use of acne medication and predictors of use. METHODS: A cross-sectional, web-based survey was administered to US females (25-45 years) with facial acne (>= 25 visible lesions). Data collected included: sociodemographics and self-reported clinical characteristics, acne treatments, and health care professional (HCP) visits. Subject characteristics associated with medication use were examined by logistic regression. RESULTS: Approximately half of the total sample (N=208, mean age: 35 +/- 6) ever visited an HCP for acne and reported more over-the counter (OTC) medication use (51.0%) than prescription (Rx) medication use (15.4%). Subjects did not use medications daily, averaging from 12-18 days over the previous 4 weeks. Logistic regression showed that race and prior HCP visits for acne were significant predictors of medication use (P<.05). CONCLUSIONS: Adult females generally self-treated their acne using primarily OTC medications; however, poor compliance was observed for Rx and OTC. Race and prior HCP visits for acne were significant predictors of current medication use. PMID- 25689810 TI - An update on the diagnosis and management of hereditary angioedema with abnormal C1 inhibitor. AB - Hereditary angioedema (HAE) is a rare genetic disease caused by a deficiency in functional C1-esterase inhibitor characterized by recurrent episodes of angioedema in the absence of associated urticaria. Subcutaneous swellings are experienced by virtually all patients with HAE, and dermatologists are likely to encounter this manifestation, requiring that they be knowledgeable about diagnosis and treatment options. Diagnosis of HAE is often delayed because several of the symptoms can mimic other disease states. Delays in diagnosis can lead to increased inappropriate treatment and decreased patient quality of life. Once a proper diagnosis is made, treatment needs to be targeted to the individual patient and includes on-demand therapy and an option for short- and long-term prophylaxis. On-demand therapy is required for all patients who are diagnosed with HAE and effective options include plasma-derived and recombinant C1 inhibitors, kallikrein inhibitors, and bradykinin B2-receptor antagonists. Options available for prophylaxis include plasma-derived C1 inhibitors, attenuated androgens, and antifibrinolytic agents, although the latter 2 options are associated with significant adverse events. This article reviews the diagnosis and options for effective management of patients with HAE. PMID- 25689811 TI - No association between TNF inhibitor and methotrexate therapy versus methotrexate in changes in hemoglobin A1C and fasting glucose among psoriasis, psoriatic arthritis, and rheumatoid arthritis patients. AB - BACKGROUND: The use of tumor necrosis factor inhibitors (TNFi) has been associated with a reduced incidence of type 2 diabetes mellitus. OBJECTIVE: To compare changes in hemoglobin A1C and fasting glucose for patients exposed to TNFi. METHODS: In this retrospective cohort study, patients with at least 3 recorded diagnosis codes for psoriasis, psoriatic arthritis, or rheumatoid arthritis between January 1, 2004 and July 31, 2011. Patients were Kaiser Permanente Southern California members for at least 1 year prior to the index date. RESULTS: For hemoglobin A1C, there were 344 patients in the MTX cohort, and 118 patients in the TNFi+MTX cohort. In the covariate adjusted main effects ANCOVA model, the TNFi+MTX cohort had a lower mean change in hemoglobin A1C of 0.18 mg/dL (95% CI: -0.35, -0.01) compared to the MTX cohort, although the difference is small and this model was not complete as there were significant interactions. For fasting glucose, there were 524 patients in the MTX cohort, and 121 patients in the TNFi+MTX cohort. In the covariate adjusted main effects ANCOVA model, change in fasting glucose was not significantly different between groups: -0.58 mg/dL (95% CI: -5.05, 3.88) for the TNFi+MTX cohort compared to the MTX cohort, although this model was not complete as there was a significant interaction. CONCLUSIONS: The use of TNF inhibitors with MTX was not associated with a significant difference in the change of hemoglobin A1C or fasting glucose compared to MTX alone. PMID- 25689812 TI - Cost-effectiveness study of pediatric atopic dermatitis in Asia: atopiclair vs. regular emollient (AD-ATOP). AB - BACKGROUND: Atopic dermatitis (AD) is a highly prevalent, chronic relapsing condition in childhood with significant financial burden and impact on the quality of life of patients and caregivers. Proactive maintenance treatment with moisturizing agents is the mainstay AD therapy. OBJECTIVES: The aim of this study was to assess the cost-effectiveness of a non-steroidal barrier cream (Atopiclair), compared to regular emollient in pediatric patients with mild-to moderate AD. METHODS: A Markov decision model was developed to evaluate the cost effectiveness of Atopiclair versus regular emollient in 12 Asia-Pacific countries, grouped by income categories based on gross domestic product (GDP) per capita. Data was obtained from structured literature review, expert opinion, fee schedules, and findings from a 2012 survey of 12 Asia-Pacific countries. Analysis was performed a societal perspective. RESULTS: In the base case analysis, Atopiclair was cost-effective against regular emollient, with USD786, USD499, and USD289 in cost savings per year for high, middle, and low-income countries, respectively. Sensitivity analyses showed that Atopiclair remained cost-effective versus regular emollient. CONCLUSIONS: Modelling analysis showed that Atopiclair is a cost-effective treatment compared to regular emollient for mild-to-moderate pediatric AD in the countries included in the study. PMID- 25689813 TI - A novel microgel complex delivers acne medicine deep into follicles while demonstrating high patient tolerance. AB - Acne vulgaris is a common skin disease that is difficult to treat due to its multifactorial etiology. The presence of sebum and keratinocytes within the hair follicle often prevent medication from penetrating deep into the follicle where the causal bacteria are to be found. Medications able to penetrate into the follicle are often irritating to the skin. Recently, a technology has been developed that can penetrate sebum and deliver medication deep in the follicle while also being gentle on the skin. This novel microgel complex is therefore a critical next step in the treatment of acne and also an important tool for people who suffer from a lower quality of life due to persistent acne breakouts. PMID- 25689814 TI - Dermatologists' attitudes, prescription, and counseling patterns for isotretinoin: a questionnaire-based study. AB - Isotretinoin, the most effective therapy for severe acne, has engendered controversy. These controversies impact dermatologists' opinions of isotretinoin and prescription behaviors. This study was designed to characterize dermatologists' opinions of controversies surrounding isotretinoin, as well as counseling and prescribing practices. A 25-question survey was emailed to 7,013 dermatologists included in a proprietary database (MBD, Inc.) and anonymous responses were collected. 591 board-certified dermatologists participated. Thirty seven percent of the responding dermatologists believe that isotretinoin may cause psychiatric disturbances. Dermatologists' opinions on this relationship did not significantly impact prescription practices in patients with history of depression (P=0.056) or in patients being treated with an antidepressant (P=0.118). A larger percentage of dermatologists surveyed believe there is a causal relationship between isotretinoin and psychiatric disturbances than isotretinoin and IBD. Of the surveyed dermatologists, 2.7% believe there is a causal association between isotretinoin and inflammatory bowel disease IBD. In addition, physicians with 20 or fewer years of experience, which included 50% of the responding dermatologists, were significantly less likely to have read the patient brochure (P=0.004), and more likely to prescribe isotretinoin to patients who had not failed systemic antibiotics (P=0.015). This questionnaire also may highlight a practice gap, as more recently trained dermatologists appear less likely to require failure of systemic antibiotics prior to initiating isotretinoin. PMID- 25689815 TI - Hypopigmented mycosis fungoides: a clinical mimicker of vitiligo. AB - Hypopigmented mycosis fungoides (HMF) is a rare variant of cutaneous T-cell lymphoma (CTCL) that often manifests in younger patients with darker skin types in a centripetal distribution.(1) Average age of diagnosis is often 14 years.(2) The diagnosis is often missed due to its low incidence and lack of clinical suspicion. Misdiagnosis and failure to obtain biopsies lead to a long latency period from onset of hypopigmented patches to diagnosis and treatment. HMF has a clinically benign course and responds well to therapy; however, relapse is common.(3) We report a case of HMF misdiagnosed as vitiligo in order to illuminate diagnostic, histopathological, and treatment modalities. PMID- 25689816 TI - Pruritus associated with onabotulinumtoxinA treatment of neuromuscular pain. AB - OnabotulinumtoxinA is one of the most widely used agents for cosmetic and medical treatment. Studies have shown that onabotulinumtoxinA is safe and effective with minimal adverse events, and is often well tolerated by patients. We present a patient who developed neuropathic pruritus five days after treatment with onabotulinumtoxinA for neuromuscular pain. This case highlights the treatment of pruritus associated with onabotulinumtoxinA and the therapeutic method to resolve the patient's pruritus. PMID- 25689817 TI - Comprehensive microbial analysis of combined mesophilic anaerobic-thermophilic aerobic process treating high-strength food wastewater. AB - A combined mesophilic anaerobic-thermophilic aerobic process was used to treat high-strength food wastewater in this study. During the experimental period, most of solid residue from the mesophilic anaerobic reactor (R1) was separated by centrifugation and introduced into the thermophilic aerobic reactor (R2) for further digestion. Then, thermophilic aerobically-digested sludge was reintroduced into R1 to enhance reactor performance. The combined process was operated with two different Runs: Run I with hydraulic retention time (HRT) = 40 d (corresponding OLR = 3.5 kg COD/m(3) d) and Run II with HRT = 20 d (corresponding OLR = 7 kg COD/m(3)). For a comparison, a single-stage mesophilic anaerobic reactor (R3) was operated concurrently with same OLRs and HRTs as the combined process. During the overall digestion, all reactors showed high stability without pH control. The combined process demonstrated significantly higher organic matter removal efficiencies (over 90%) of TS, VS and COD and methane production than did R3. Quantitative real-time PCR (qPCR) results indicated that higher populations of both bacteria and archaea were maintained in R1 than in R3. Pyrosequencing analysis revealed relatively high abundance of phylum Actinobacteria in both R1 and R2, and a predominance of phyla Synergistetes and Firmicutes in R3 during Run II. Furthermore, R1 and R2 shared genera (Prevotella, Aminobacterium, Geobacillus and Unclassified Actinobacteria), which suggests synergy between mesophilic anaerobic digestion and thermophilic aerobic digestion. For archaea, in R1 methanogenic archaea shifted from genus Methanosaeta to Methanosarcina, whereas genera Methanosaeta, Methanobacterium and Methanoculleus were predominant in R3. The results demonstrated dynamics of key microbial populations that were highly consistent with an enhanced reactor performance of the combined process. PMID- 25689818 TI - Hypothalamic neuropeptide signaling in alcohol addiction. AB - The hypothalamus is now known to regulate alcohol intake in addition to its established role in food intake, in part through neuromodulatory neurochemicals termed neuropeptides. Certain orexigenic neuropeptides act in the hypothalamus to promote alcohol drinking, although they affect different aspects of the drinking response. These neuropeptides, which include galanin, the endogenous opioid enkephalin, and orexin/hypocretin, appear to stimulate alcohol intake not only through mechanisms that promote food intake but also by enhancing reward and reinforcement from alcohol. Moreover, these neuropeptides participate in a positive feedback relationship with alcohol, whereby they are upregulated by alcohol intake to promote even further consumption. They contrast with other orexigenic neuropeptides, such as melanin-concentrating hormone and neuropeptide Y, which promote alcohol intake under limited circumstances, are not consistently stimulated by alcohol, and do not enhance reward. They also contrast with neuropeptides that can be anorexigenic, including the endogenous opioid dynorphin, corticotropin-releasing factor, and melanocortins, which act in the hypothalamus to inhibit alcohol drinking as well as reward and therefore counter the ingestive drive promoted by orexigenic neuropeptides. Thus, while multiple hypothalamic neuropeptides may work together to regulate different aspects of the alcohol drinking response, excessive signaling from orexigenic neuropeptides or inadequate signaling from anorexigenic neuropeptides can therefore allow alcohol drinking to become dysregulated. PMID- 25689819 TI - Pathogenetic and therapeutic applications of microRNAs in major depressive disorder. AB - As a class of noncoding RNAs, microRNAs (miRNAs) regulate gene expression by inhibiting translation of messenger RNAs. These miRNAs have been shown to play a critical role in higher brain functioning and actively participate in synaptic plasticity. Pre-clinical evidence demonstrates that expression of miRNAs is differentially altered during stress. On the other hand, depressed individuals show marked changes in miRNA expression in brain. MiRNAs are also target of antidepressants and electroconvulsive therapy. Moreover, these miRNAs are present in circulating blood and can be easily detected. Profiling of miRNAs in blood plasma/serum provides evidence that determination of miRNAs in blood can be used as possible diagnostic and therapeutic tool. In this review article, these aspects are critically reviewed and the role of miRNAs in possible etiopathogenesis and therapeutic implications in the context of major depressive disorder is discussed. PMID- 25689820 TI - Resting-state regional homogeneity as a biological marker for patients with Internet gaming disorder: A comparison with patients with alcohol use disorder and healthy controls. AB - OBJECTIVE: Internet gaming disorder (IGD) shares core clinical features with other addictive disorders, such as gambling disorder and substance use disorder. Designation of IGD as a formal disorder requires elucidation of its neurobiological features and comparison of these with those of other addictive disorders. The aims of the present study were to identify the neurobiological features of the resting-state brain of patients with IGD, alcohol use disorder (AUD), and healthy controls, and to examine brain regions related to the clinical characteristics of IGD. METHOD: Functional magnetic resonance imaging was performed on 16 subjects with IGD, 14 subjects with AUD, and 15 healthy controls during the resting-state. We computed regional homogeneity (ReHo) measures to identify intrinsic local connectivity and to explore associations with clinical status and impulsivity. RESULTS: We found significantly increased ReHo in the posterior cingulate cortex (PCC) of the IGD and AUD groups, and decreased ReHo in the right superior temporal gyrus (STG) of those with IGD, compared with the AUD and HC groups. We also found decreased ReHo in the anterior cingulate cortex of patients with AUD. Scores on Internet addiction severity were positively correlated with ReHo in the medial frontal cortex, precuneus/PCC, and left inferior temporal cortex (ITC) among those with IGD. Furthermore, impulsivity scores were negatively correlated with that in the left ITC in individuals with IGD. CONCLUSION: Our results provide evidence of distinctive functional changes in the resting-state of patients with IGD and demonstrate that increased ReHo in the PCC may be a common neurobiological feature of IGD and AUD and that reduced ReHo in the STG may be a candidate neurobiological marker for IGD, differentiating individuals with this disorder from those with AUD and healthy controls. PMID- 25689821 TI - ADIOL protects against 3-NP-induced neurotoxicity in rats: Possible impact of its anti-oxidant, anti-inflammatory and anti-apoptotic actions. AB - Huntington's disease (HD) is a progressive neurodegenerative disorder with a wide spectrum of cognitive, behavioral and motor abnormalities. The mitochondrial toxin 3-nitropropionic acid (3-NP) effectively induces specific behavioral changes and selective striatal lesions similar to that observed in HD. Some neurosteroids, synthesized in neurons and glial cells, previously showed neuroprotective abilities. 5-Androstene-3beta-17beta-diol (ADIOL) is a major metabolite of dehydroepiandrosterone (DHEA) with previously reported anti inflammatory, anti-apoptotic and neuroprotective activities. The neuroprotective potential of ADIOL in HD was not previously investigated. Therefore, the present study investigated the neuroprotective effects of ADIOL against 3-NP-induced behavioral changes, oxidative stress, inflammation and apoptosis. Intraperitoneal administration of 3-NP (20mg/kg) for 4 consecutive days in rats caused significant loss in body weight, reduced prepulse inhibition (PPI) of acoustic startle response, locomotor hypoactivity with altered cortical/striatal histological structure, increased cortical/striatal oxidative stress, inflammation and apoptosis. Administration of ADIOL (25mg/kg, s.c.) for two days before 3-NP significantly attenuated the reduction in body weights and PPI, increased locomotor activity and restored cortical/striatal histological structure nearly to normal. Moreover, it displayed anti-oxidant, anti inflammatory and anti-apoptotic activities as evidenced by the elevation of cortical and striatal reduced glutathione levels, reductions of cortical and striatal malondialdehyde, striatal tumor necrosis factor alpha and interleukin-6 levels. Only a small number of iNOS and caspase-3 positive cells were detected in sections from rats pretreated with ADIOL. This study suggests a potential neuroprotective role of ADIOL against 3-NP-induced Huntington's disease-like manifestations. Such neuroprotection can be attributed to its anti-oxidant, anti inflammatory and anti-apoptotic activities. PMID- 25689823 TI - Evaluation of different drying temperatures on physico-chemical and antioxidant properties of water-soluble tomato powders and on their use in pork patties. AB - BACKGROUND: Tomato and tomato products provide various antioxidant activities, which could be changed by the processing method. This study was performed to evaluate the antioxidant activity of water-soluble tomato powder (WSTP) as affected by different oven temperatures (60, 80 and 100 degrees C), and to evaluate the physico-chemical properties and antioxidative activities of pork patties containing these powders. RESULTS: The contents of total phenolic compounds of WSTP ranged from 22.2 to 69.6 g kg(-1) dry matter. The antioxidant activities increased significantly with increasing drying temperatures (P < 0.05). The physico-chemical properties of pork patties containing tomato powders were also evaluated. WSTP at 100 degrees C showed the highest redness value compared to those dried at 60 and 80 degrees C. Lipid oxidation of pork patties was retarded by 7 days with the addition of WSTP. In particular, pork patties containing WSTP showed antimicrobial activity at 14 days of refrigerated storage, regardless of drying temperatures. CONCLUSION: WSTP, especially prepared at 100 degrees C, could be used as a natural antioxidant and antimicrobial agent in meat products. PMID- 25689822 TI - Adventitial vessel growth and progenitor cells activation in an ex vivo culture system mimicking human saphenous vein wall strain after coronary artery bypass grafting. AB - Saphenous vein graft disease is a timely problem in coronary artery bypass grafting. Indeed, after exposure of the vein to arterial blood flow, a progressive modification in the wall begins, due to proliferation of smooth muscle cells in the intima. As a consequence, the graft progressively occludes and this leads to recurrent ischemia. In the present study we employed a novel ex vivo culture system to assess the biological effects of arterial-like pressure on the human saphenous vein structure and physiology, and to compare the results to those achieved in the presence of a constant low pressure and flow mimicking the physiologic vein perfusion. While under both conditions we found an activation of Matrix Metallo-Proteases 2/9 and of microRNAs-21/146a/221, a specific effect of the arterial-like pressure was observed. This consisted in a marked geometrical remodeling, in the suppression of Tissue Inhibitor of Metallo-Protease-1, in the enhanced expression of TGF-beta1 and BMP-2 mRNAs and, finally, in the upregulation of microRNAs-138/200b/200c. In addition, the veins exposed to arterial-like pressure showed an increase in the density of the adventitial vasa vasorum and of cells co-expressing NG2, CD44 and SM22alpha markers in the adventitia. Cells with nuclear expression of Sox-10, a transcription factor characterizing multipotent vascular stem cells, were finally found in adventitial vessels. Our findings suggest, for the first time, a role of arterial-like wall strain in the activation of pro-pathologic pathways resulting in adventitial vessels growth, activation of vasa vasorum cells, and upregulation of specific gene products associated to vascular remodeling and inflammation. PMID- 25689824 TI - Unitary group adapted state specific multireference perturbation theory: Formulation and pilot applications. AB - We present here a comprehensive account of the formulation and pilot applications of the second-order perturbative analogue of the recently proposed unitary group adapted state-specific multireference coupled cluster theory (UGA-SSMRCC), which we call as the UGA-SSMRPT2. We also discuss the essential similarities and differences between the UGA-SSMRPT2 and the allied SA-SSMRPT2. Our theory, like its parent UGA-SSMRCC formalism, is size-extensive. However, because of the noninvariance of the theory with respect to the transformation among the active orbitals, it requires the use of localized orbitals to ensure size-consistency. We have demonstrated the performance of the formalism with a set of pilot applications, exploring (a) the accuracy of the potential energy surface (PES) of a set of small prototypical difficult molecules in their various low-lying states, using natural, pseudocanonical and localized orbitals and compared the respective nonparallelity errors (NPE) and the mean average deviations (MAD) vis a-vis the full CI results with the same basis; (b) the efficacy of localized active orbitals to ensure and demonstrate manifest size-consistency with respect to fragmentation. We found that natural orbitals lead to the best overall PES, as evidenced by the NPE and MAD values. The MRMP2 results for individual states and of the MCQDPT2 for multiple states displaying avoided curve crossings are uniformly poorer as compared with the UGA-SSMRPT2 results. The striking aspect of the size-consistency check is the complete insensitivity of the sum of fragment energies with given fragment spin-multiplicities, which are obtained as the asymptotic limit of super-molecules with different coupled spins. PMID- 25689825 TI - Comparative mitogenomics of the assassin bug genus Peirates (Hemiptera: Reduviidae: Peiratinae) reveal conserved mitochondrial genome organization of P. atromaculatus, P. fulvescens and P. turpis. AB - In this study, we sequenced four new mitochondrial genomes and presented comparative mitogenomic analyses of five species in the genus Peirates (Hemiptera: Reduviidae). Mitochondrial genomes of these five assassin bugs had a typical set of 37 genes and retained the ancestral gene arrangement of insects. The A+T content, AT- and GC-skews were similar to the common base composition biases of insect mtDNA. Genomic size ranges from 15,702 bp to 16,314 bp and most of the size variation was due to length and copy number of the repeat unit in the putative control region. All of the control region sequences included large tandem repeats present in two or more copies. Our result revealed similarity in mitochondrial genomes of P. atromaculatus, P. fulvescens and P. turpis, as well as the highly conserved genomic-level characteristics of these three species, e.g., the same start and stop codons of protein-coding genes, conserved secondary structure of tRNAs, identical location and length of non-coding and overlapping regions, and conservation of structural elements and tandem repeat unit in control region. Phylogenetic analyses also supported a close relationship between P. atromaculatus, P. fulvescens and P. turpis, which might be recently diverged species. The present study indicates that mitochondrial genome has important implications on phylogenetics, population genetics and speciation in the genus Peirates. PMID- 25689826 TI - Cyclometallated gold(III) aryl-pyridine complexes as efficient catalysts for three-component synthesis of substituted oxazoles. AB - Cyclometallated aryl-pyridine gold(iii) complexes are shown to be efficient catalysts for the multicomponent reaction between N-benzyl imines, alkynes, and acyl chlorides to form trisubstituted oxazoles. The reaction typically proceeds in good yields (up to over 80%) and short reaction times (~15 minutes). The high stability of the investigated cyclometallated catalysts enables a retained efficiency for this reaction in terms of rate and yield using as little as 0.5 mol% catalyst, a reduction by an order of magnitude compared to previously used Au(iii)-salen complexes. An attractive feature of the present catalytic system is that active catalysts can be formed from simple pre-catalysts under the reaction conditions. Both cyclometallated and non-cyclometallated complexes were characterized in the solid state by single crystal X-ray diffraction. PMID- 25689827 TI - Mindfulness and compassion: an examination of mechanism and scalability. AB - Emerging evidence suggests that meditation engenders prosocial behaviors meant to benefit others. However, the robustness, underlying mechanisms, and potential scalability of such effects remain open to question. The current experiment employed an ecologically valid situation that exposed participants to a person in visible pain. Following three-week, mobile-app based training courses in mindfulness meditation or cognitive skills (i.e., an active control condition), participants arrived at a lab individually to complete purported measures of cognitive ability. Upon entering a public waiting area outside the lab that contained three chairs, participants seated themselves in the last remaining unoccupied chair; confederates occupied the other two. As the participant sat and waited, a third confederate using crutches and a large walking boot entered the waiting area while displaying discomfort. Compassionate responding was assessed by whether participants gave up their seat to allow the uncomfortable confederate to sit, thereby relieving her pain. Participants' levels of empathic accuracy was also assessed. As predicted, participants assigned to the mindfulness meditation condition gave up their seats more frequently than did those assigned to the active control group. In addition, empathic accuracy was not increased by mindfulness practice, suggesting that mindfulness-enhanced compassionate behavior does not stem from associated increases in the ability to decode the emotional experiences of others. PMID- 25689828 TI - The historical demography and genetic variation of the endangered Cycas multipinnata (Cycadaceae) in the red river region, examined by chloroplast DNA sequences and microsatellite markers. AB - Cycas multipinnata C.J. Chen & S.Y. Yang is a cycad endemic to the Red River drainage region that occurs under evergreen forest on steep limestone slopes in Southwest China and northern Vietnam. It is listed as endangered due to habitat loss and over-collecting for the ornamental plant trade, and only several populations remain. In this study, we assess the genetic variation, population structure, and phylogeography of C. multipinnata populations to help develop strategies for the conservation of the species. 60 individuals from six populations were used for chloroplast DNA (cpDNA) sequencing and 100 individuals from five populations were genotyped using 17 nuclear microsatellites. High genetic differentiation among populations was detected, suggesting that pollen or seed dispersal was restricted within populations. Two main genetic clusters were observed in both the cpDNA and microsatellite loci, corresponding to Yunnan China and northern Vietnam. These clusters indicated low levels of gene flow between the regions since their divergence in the late Pleistocene, which was inferred from both Bayesian and coalescent analysis. In addition, the result of a Bayesian skyline plot based on cpDNA portrayed a long history of constant population size followed by a decline in the last 50,000 years of C. multipinnata that was perhaps affected by the Quaternary glaciations, a finding that was also supported by the Garza-Williamson index calculated from the microsatellite data. The genetic consequences produced by climatic oscillations and anthropogenic disturbances are considered key pressures on C. multipinnata. To establish a conservation management plan, each population of C. multipinnata should be recognized as a Management Unit (MU). In situ and ex situ actions, such as controlling overexploitation and creating a germplasm bank with high genetic diversity, should be urgently implemented to preserve this species. PMID- 25689829 TI - Microbiota-Independent Ameliorative Effects of Antibiotics on Spontaneous Th2 Associated Pathology of the Small Intestine. AB - We have previously generated a mouse model of spontaneous Th2-associated disease of the small intestine called TRAF6DeltaDC, in which dendritic cell (DC) intrinsic expression of the signaling mediator TRAF6 is ablated. Interestingly, broad-spectrum antibiotic treatment ameliorates TRAF6DeltaDC disease, implying a role for commensal microbiota in disease development. However, the relationship between the drug effects and commensal microbiota status remains to be formally demonstrated. To directly assess this relationship, we have now generated TRAF6DeltaDC bone marrow chimera mice under germ-free (GF) conditions lacking commensal microbiota, and found, unexpectedly, that Th2-associated disease is actually exacerbated in GF TRAF6DeltaDC mice compared to specific pathogen-free (SPF) TRAF6DeltaDC mice. At the same time, broad-spectrum antibiotic treatment of GF TRAF6DeltaDC mice has an ameliorative effect similar to that observed in antibiotics-treated SPF TRAF6DeltaDC mice, implying a commensal microbiota independent effect of broad-spectrum antibiotic treatment. We further found that treatment of GF TRAF6DeltaDC mice with broad-spectrum antibiotics increases Foxp3+ Treg populations in lymphoid organs and the small intestine, pointing to a possible mechanism by which treatment may directly exert an immunomodulatory effect. To investigate links between the exacerbated phenotype of the small intestines of GF TRAF6DeltaDC mice and local microbiota, we performed microbiotic profiling of the luminal contents specifically within the small intestines of diseased TRAF6DeltaDC mice, and, when compared to co-housed control mice, found significantly increased total bacterial content characterized by specific increases in Firmicutes Lactobacillus species. These data suggest a protective effect of Firmicutes Lactobacillus against the spontaneous Th2-related inflammation of the small intestine of the TRAF6DeltaDC model, and may represent a potential mechanism for related disease phenotypes. PMID- 25689830 TI - Census parcels cropping system classification from multitemporal remote imagery: a proposed universal methodology. AB - A procedure named CROPCLASS was developed to semi-automate census parcel crop assessment in any agricultural area using multitemporal remote images. For each area, CROPCLASS consists of a) a definition of census parcels through vector files in all of the images; b) the extraction of spectral bands (SB) and key vegetation index (VI) average values for each parcel and image; c) the conformation of a matrix data (MD) of the extracted information; d) the classification of MD decision trees (DT) and Structured Query Language (SQL) crop predictive model definition also based on preliminary land-use ground-truth work in a reduced number of parcels; and e) the implementation of predictive models to classify unidentified parcels land uses. The software named CROPCLASS-2.0 was developed to semi-automatically perform the described procedure in an economically feasible manner. The CROPCLASS methodology was validated using seven GeoEye-1 satellite images that were taken over the LaVentilla area (Southern Spain) from April to October 2010 at 3- to 4-week intervals. The studied region was visited every 3 weeks, identifying 12 crops and others land uses in 311 parcels. The DT training models for each cropping system were assessed at a 95% to 100% overall accuracy (OA) for each crop within its corresponding cropping systems. The DT training models that were used to directly identify the individual crops were assessed with 80.7% OA, with a user accuracy of approximately 80% or higher for most crops. Generally, the DT model accuracy was similar using the seven images that were taken at approximately one-month intervals or a set of three images that were taken during early spring, summer and autumn, or set of two images that were taken at about 2 to 3 months interval. The classification of the unidentified parcels for the individual crops was achieved with an OA of 79.5%. PMID- 25689831 TI - Affinity proteomics discovers decreased levels of AMFR in plasma from Osteoporosis patients. AB - PURPOSE: Affinity proteomic approaches by antibody bead arrays enable multiplexed analysis of proteins in body fluids. In the presented study, we investigated blood plasma within osteoporosis to discovery differential protein profiles and to propose novel biomarkers candidates for subsequent studies. EXPERIMENTAL DESIGN: Starting with 4608 antibodies and plasma samples from 22 women for an untargeted screening, a set of 72 proteins were suggested for further analysis. Complementing these with targets from literature and other studies, a targeted bead array of 180 antibodies was built to profile for 92 proteins in plasma samples of 180 women from two independent population-based studies. RESULTS: Differential profiles between osteoporosis patients and matched controls were discovered for 12 proteins in at least one of the two study sets. Among these targets, the levels of autocrine motility factor receptor (AMFR) were concordantly lower in plasma of female osteoporosis patients. Subsequently, verification of anti-AMFR antibody selectivity was conducted using high-density peptide and protein arrays, and Western blotting. CONCLUSIONS AND CLINICAL RELEVANCE: Further validation in additional study sets will be needed to determine the clinical value of the observed decrease in AMFR plasma levels in osteoporosis patients, but AMFR may aid our understanding of disease mechanisms and could support existing tools for diagnosis and monitoring of patient mobility within osteoporosis. PMID- 25689833 TI - First-row transition-metal-diborane and -borylene complexes. AB - A combined experimental and quantum chemical study of Group 7 borane, trimetallic triply bridged borylene and boride complexes has been undertaken. Treatment of [{Cp*CoCl}2 ] (Cp*=1,2,3,4,5-pentamethylcyclopentadienyl) with LiBH4 ?thf at -78 degrees C, followed by room-temperature reaction with three equivalents of [Mn2 (CO)10 ] yielded a manganese hexahydridodiborate compound [{(OC)4 Mn}(eta(6) -B2 H6 ){Mn(CO)3 }2 (MU-H)] (1) and a triply bridged borylene complex [(MU3 BH)(Cp*Co)2 (MU-CO)(MU-H)2 MnH(CO)3 ] (2). In a similar fashion, [Re2 (CO)10 ] generated [(MU3 -BH)(Cp*Co)2 (MU-CO)(MU-H)2 ReH(CO)3 ] (3) and [(MU3 -BH)(Cp*Co)2 (MU-CO)2 (MU-H)Co(CO)3 ] (4) in modest yields. In contrast, [Ru3 (CO)12 ] under similar reaction conditions yielded a heterometallic semi-interstitial boride cluster [(Cp*Co)(MU-H)3 Ru3 (CO)9 B] (5). The solid-state X-ray structure of compound 1 shows a significantly shorter boron-boron bond length. The detailed spectroscopic data of 1 and the unusual structural and bonding features have been described. All the complexes have been characterized by using (1) H, (11) B, (13) C NMR spectroscopy, mass spectrometry, and X-ray diffraction analysis. The DFT computations were used to shed light on the bonding and electronic structures of these new compounds. The study reveals a dominant B-H-Mn, a weak B-B-Mn interaction, and an enhanced B-?B bonding in 1. PMID- 25689832 TI - Zevalin and BEAM (Z-BEAM) versus rituximab and BEAM (R-BEAM) conditioning chemotherapy prior to autologous stem cell transplantation in patients with mantle cell lymphoma. AB - Early relapse is common in patients with mantle cell lymphoma (MCL) highlighting the unmet need for further improvement of therapeutic options for these patients. CD20 inhibition combined with induction chemotherapy as well as consolidation with high-dose chemotherapy (HDCT) is increasingly considered cornerstones within current therapy algorithms of MCL whereas the role of radioimmunotherapy is unclear. This retrospective single center study compared 46 consecutive MCL patients receiving HDCT in first or second remission. Thirty-five patients had rituximab and BEAM (R-BEAM), and 11 patients received ibritumomab tiuxetan (Zevalin(r)), an Yttrium-90 labeled CD20 targeting antibody, prior to BEAM (Z BEAM) followed by autologous stem cell transplantation (ASCT). We observed that the 5-year overall survival (OS) in the R-BEAM and Z-BEAM groups was 55% and 71% (p = 0.288), and the 4-year progression free survival (PFS) was 32% and 41%, respectively (p = 0.300). There were no treatment related deaths in both groups, and we observed no differences in toxicities, infection rates or engraftment. Our data suggest that the Z-BEAM conditioning regimen followed by ASCT is well tolerated, but was not associated with significantly improved survival compared to R-BEAM. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 25689834 TI - The direct heat measurement of mechanical energy storage metal-organic frameworks. AB - In any process, the heat exchanged is an essential property required in its development. Whilst the work related to structural transitions of some flexible metal-organic frameworks (MOFs) has been quantified and linked with potential applications such as molecular springs or shock absorbers, the heat related to such transitions has never been directly measured. This has now been carried out with MIL-53(Al) using specifically devised calorimetry experiments. We project the importance of these heats in devices such as molecular springs or dampers. PMID- 25689835 TI - Biomimetic fibers made of recombinant spidroins with the same toughness as natural spider silk. AB - Using a self-assembly of recombinant spidroins, biomimetic spinning dopes are produced and wet-spun into fibers. Upon varying the molecular design of the underlying recombinant spidroins, the influence of the amino- and carboxy terminal domains, as well as the size of the repetitive core domain on fiber mechanics, is determined. Fiber toughness upon biomimetic processing equals and even slightly exceeds that of natural ones. PMID- 25689836 TI - Highly selective hydrothiolation of unsaturated organosilicon compounds catalyzed by scandium(III) triflate. AB - The first use of a Lewis acid catalyst in the addition reaction of both aromatic and aliphatic thiols to unsaturated organosilicon compounds is reported. In catalytic tests, scandium(III) triflate demonstrates high catalytic activity in this process. Under mild conditions (25 degrees C, room temperature, 1-10 h) a number of thioether-functionalized organosilicon species are obtained with appreciable selectivity. This study constitutes the first example of allylsilane hydrothiolation that gives the Markovnikov regioisomer as the main product. Ethynylsilanes are also successfully used in the hydrothiolation reaction in the presence of Sc(OTf)3 . PMID- 25689837 TI - Ultrafast Tracking of a Single Live Virion During the Invagination of a Cell Membrane. AB - The first step in most viral infections is the penetration of the cell membrane via endocytosis. However, the underlying mechanism of this important process has not been quantitatively characterized; for example, the velocity and force of a single virion during invagination remain unknown. Here, the endocytosis of a single live virion (Singapore grouper iridovirus, SGIV) through the apical membranes of a host cell is monitored by developing and using a novel ultrafast (at the microsecond level) tracking technique: force tracing. For the first time, these results unambiguously reveal that the maximum velocity during the cell entry of a single SGIV by membrane invagination is approximately 200 nm s(-1), the endocytic force is approximately 60.8 +/- 18.5 pN, and the binding energy density increases with the engulfment depth. This report utilizing high temporospatial resolution (subnanometer and microsecond levels) approaches provides new insight into the dynamic process of viral infection via endocytosis and the mechanism of membrane invagination at the single-particle level. PMID- 25689838 TI - Formulation of highly functionalizable DNA nanoparticles based on 1,2-dithiolane derivatives. AB - We describe the formulation of synthetic virus models based on ionic compounds bearing the polymerizable 1,2-dithiolane moiety. First, cationic amphiphiles containing the polymeric inducer were prepared and used to efficiently condense a DNA plasmid (pDNA) into a highly monodisperse population of small polymeric cationic DNA nanoparticles (NPs; Dh ~100 nm). These nonspecific cationic particles were then functionalized with anionic PEGylated conjugates, also based on the 1,2-dithiolane motifs, in order to produce stable and fully dispersible stealth DNA nanoparticles. Our results show that both ionic interactions and polymerization based on the 1,2-dithiolane pattern occur and that they produce highly functionalizable nonviral DNA NPs. PMID- 25689839 TI - Placebo-controlled vagus nerve stimulation paired with tones in a patient with refractory tinnitus: a case report. AB - OBJECTIVE: Classical neuromodulation consists of applying electrical or magnetic stimuli to the nervous system to modulate ongoing activity and connectivity. However, recently, an exciting novel neuromodulation technique was developed in which stimulation of the vagal nerve was paired with simultaneous presentation of tones, demonstrating that it reverses a tinnitus percept in noise-exposed rats. STUDY DESIGN: To determine whether this therapy could also be effective in humans, we delivered a similar therapy in a patient with chronic tinnitus unresponsive to previous therapies. In this report, we describe the case of a 59 year-old man who suffered from bilateral tinnitus for 14 years that arose after a cervical fusion operation. Pharmacotherapy, transcranial magnetic stimulation, transcranial direct current stimulation, neurofeedback, and bilateral auditory cortex stimulation via implanted electrodes did not improve the tinnitus. After implanting the vagal nerve stimulator, the patient received daily vagus nerve stimulation tone pairings for 4 weeks in a non-placebo-controlled way. RESULTS: At the end of therapy, the patient experienced a significant reduction in tinnitus symptoms that lasted for 2 months after treatment. Tinnitus Handicap Inventory and Tinnitus Reaction Questionnaire were reduced by 48% and 68%, respectively. Symptoms of depression were also improved by 40%, as quantified by the Beck Depression Inventory. Three months after ending therapy, placebo stimulation was performed consisting of only tone presentation without the simultaneous electrical stimuli. This resulted in further continuation of the gradual relapse to the baseline state, without renewed improvement. CONCLUSION: Our results suggest that vagus nerve stimulation paired with tones could become an effective therapy for the treatment of tinnitus. PMID- 25689840 TI - Secondary care clinic for chronic disease: protocol. AB - BACKGROUND: The complexity of chronic disease management activities and the associated financial burden have prompted the development of organizational models, based on the integration of care and services, which rely on primary care services. However, since the institutions providing these services are continually undergoing reorganization, the Centre hospitalier affilie universitaire de Quebec wanted to innovate by adapting the Chronic Care Model to create a clinic for the integrated follow-up of chronic disease that relies on hospital-based specialty care. OBJECTIVE: The aim of the study is to follow the project in order to contribute to knowledge about the way in which professional and management practices are organized to ensure better care coordination and the successful integration of the various follow-ups implemented. METHODS: The research strategy adopted is based on the longitudinal comparative case study with embedded units of analysis. The case study uses a mixed research method. RESULTS: We are currently in the analysis phase of the project. The results will be available in 2015. CONCLUSIONS: The project's originality lies in its consideration of the macro, meso, and micro contexts structuring the creation of the clinic in order to ensure the integration process is successful and to allow a theoretical generalization of the reorganization of practices to be developed. PMID- 25689841 TI - NFATc1 deficiency in T cells protects mice from experimental autoimmune encephalomyelitis. AB - NFATc1 is a member of the nuclear factor of activated T cells (NFAT) family of transcription factors. NFAT is activated upon T-cell receptor activation followed by intracytoplasmatic calcium influx where calmodulin, a calcium sensor protein, activates the phosphatase calcineurin that dephosphorylates NFAT proteins and results in NFAT nuclear import. Here, we show the analysis of conditional NFATc1 deficient mice bearing a deletion of NFATc1 in CD4(+) and CD8(+) T cells. NFATc1 deficient CD4(+) T cells polarized under Th17 conditions express reduced levels of the Th17-associated transcription factor RORgammaT (where ROR is RAR-related orphan receptor) as well as the Th17-associated cytokines IL-17A, IL-17F, IL-21, and IL-10. In the murine model of experimental EAE, we found a strong reduction of the disease outcome in conditional NFATc1-deficient mice, as compared with control littermates. This was accompanied by a diminished inflammation in the brain and spinal cord and reduced IL-17A and IFN-gamma expression by antigen specific spleen, spinal cord, and brain cells. Altogether, these results reveal an important role of NFATc1 in inducing Th17-cell responses and IFN-gamma, both being relevant for the EAE development. PMID- 25689842 TI - Nonspecific cytotoxic cell antimicrobial protein (NCAMP-1): a novel alarmin ligand identified in zebrafish. AB - Cells from the coelomic cavity of adult zebrafish (zf) were used to study the alarmin-like activities of nonspecific cytotoxic cell antimicrobial protein-1 (NCAMP-1). Immunohistochemistry studies using polyclonal anti-NCAMP-1 identified constitutive NCAMP-1 in epithelial cells of the zf anterior kidney, in liver parenchyma and in the lamina propria of the intestine. NCAMP-1 was also located in the cytosol of mononuclear cells in these tissues. Cytosolic NCAMP-1 was detected in a diverse population of coelomic cells (CC) using confocal microscopy and polyclonal anti-NCAMP-1 staining. Large mononuclear and heterophil-like CC had intracellular NCAMP-1. These studies indicated that NCAMP-1 is constitutively found in epithelial cells and in ZFCC. To establish a relationship between NCAMP 1 and the alarmin functions of ATP, a stimulation-secretion model was initiated using zf coelomic cells (ZFCC). ZFCCs treated with the alarmin ATP secreted NCAMP 1 into culture supernatants. Treatment of ZFCC with either ATP or NCAMP-1 activated purinergic receptor induced pore formation detected by the ZFCC uptake of the dye YO-PRO-1. ATP induced YO-PRO-1 uptake was inhibited by antagonists oxidized-ATP, KN62, or CBB. These antagonists did not compete with NCAMP-1 induced YO-PRO-1 uptake. Binding of ZFCC by both ATP and NCAMP-1 produced an influx of Ca2+. Combined treatment of ZFCC with ATP and NCAMP-1 increased target cell cytotoxicity. Individually NCAMP-1 or ATP treatment did not produce target cell damage. Similar to ATP, NCAMP-1 activates cellular pore formation, calcium influx and cytotoxicity. PMID- 25689843 TI - Explaining the role of proximate determinants on fertility decline among poor and non-poor in Asian countries. AB - OBJECTIVES: We examined the overall contributions of the poor and non-poor in fertility decline across the Asian countries. Further, we analyzed the direct and indirect factors that determine the reproductive behaviour of two distinct population sub-groups. DESIGN: Data from several new rounds of DHS surveys are available over the past few years. The DHS provides cross-nationally comparable and useful data on fertility, family planning, maternal and child health along with the other information. Six selected Asian countries namely: Bangladesh, India, Indonesia, Nepal, Philippines, and Vietnam are considered for the purpose of the study. Three rounds of DHS surveys for each country (except Vietnam) are considered in the present study. METHODS: Economic status is measured by computing a "wealth index", i.e. a composite indicator constructed by aggregating data on asset ownership and housing characteristics using principal components analysis (PCA). Computed household wealth index has been broken into three equal parts (33.3 percent each) and the lowest and the highest 33.3 percent is considered as poor and non-poor respectively. The Bongaarts model was employed to quantify the contribution of each of the proximate determinants of fertility among poor and non-poor women. RESULTS: Fertility reduction across all population subgroups is now an established fact despite the diversity in the level of socio economic development in Asian countries. It is clear from the analysis that fertility has declined irrespective of economic status at varying degrees within and across the countries which can be attributed to the increasing level of contraceptive use especially among poor women. Over the period of time changing marriage pattern and induced abortion are playing an important role in reducing fertility among poor women. CONCLUSIONS: Fertility decline among majority of the poor women across the Asian countries is accompanied by high prevalence of contraceptive use followed by changing marriage pattern and induced abortion. PMID- 25689844 TI - Metal-organic framework derived ZnO/ZnFe2O4/C nanocages as stable cathode material for reversible lithium-oxygen batteries. AB - Tremendous efforts have been devoted to exploring various Li-O2 cathode catalysts for oxygen reduction reaction (ORR) and oxygen evolution reaction (OER). However, most of the high-activity ORR/OER catalysts can also accelerate side-reactions, such as electrolyte degradation on cycling. To address this issue, we change our strategy from pursuing highly active catalysts to developing stable cathodes that are compatible with the electrolyte. In this work, hierarchical mesoporous ZnO/ZnFe2O4/C (ZZFC) nanocages are synthesized from the templates of metal organic framework (MOF) nanocages. Such ZZFC nanocages have lower ORR/OER catalytic activity as compared with the widely used catalysts for fuel cells, but they do not catalyze the degradation of organic electrolyte during operation. Furthermore, the optimized porosity and conductivity can fit well the needs of the Li-O2 cathode. When employed in a Li-O2 battery, the ZZFC cathode delivers a primary discharge/charge capacity exceeding 11 000 mAh g(-1) at a current density of 300 mA g(-1) and an improved cyclability with capacity of 5000 mAh g(-1) for 15 cycles. The superior electrochemical performance is ascribed to the hierarchical porosity and little degradation of the organic electrolyte. PMID- 25689845 TI - Composition and hydrophilicity control of Mn-doped ferrite (MnxFe3-xO4) nanoparticles induced by polyol differentiation. AB - Manganese doped ferrite (MnxFe3-xO4) nanoparticles with x = 0.29-0.77 were prepared under solvothermal conditions in the presence solely of a polyol using the trivalent manganese and iron acetylacetonates as precursors. In this facile approach, a variety of polyols such as polyethylene glycol (PEG 8000), tetraethylene glycol (TEG), propylene glycol (PG) and a mixture of TEG and PG (1 : 1) were utilized in a triple role as a solvent, a reducing agent and a surface functionalizing agent. The composition of the fine cubic-spinel structures was found to be related to the reductive ability of each polyol, while determination of structural characteristics plus the inversion parameter (i = 0.18-0.38) were provided by X-ray absorption near edge structure (XANES) and extended X-ray absorption fine structure (EXAFS) spectroscopy at both the Fe and Mn K-edges. The saturation magnetization increased up to 80 emu g(-1) when x = 0.35 and i = 0.22. In addition, the as-prepared nanocrystals coated with PEG, PG and PG&TEG showed excellent colloidal stability in water, while the TEG-coated particles were not water dispersible and converted to hydrophilic when were extra PEGylated. Measurements of the (1)H NMR relaxation in water were carried out and the nanoprobes were evaluated as potential contrast agents. PMID- 25689847 TI - NAF-1 antagonizes starvation-induced autophagy through AMPK signaling pathway in cardiomyocytes. AB - NAF-1 (nutrient-deprivation autophagy factor-1), an autophagy-related gene related (ATG) protein, has been implicated in the autophagic pro-survival response. However, its role in autophagy has not been examined in the cardiomyocytes. In this study, we found that nutritional stress (NS) induced by glucose deprivation strongly induced autophagy in cultured neonatal rat cardiomyocytes, which was associated with NAF-1 down-regulation in cardiomyocytes under NS conditions. Furthermore, we demonstrate that ectopic expression of NAF-1 was sufficient to inhibit autophagy in cardiomyocytes under glucose deprivation conditions. Moreover, results of the co-immunoprecipitation assay indicate that NAF-1 antagonized autophagy by promoting the interaction between Beclin1 and Bcl 2 in NS-induced cardiomyocytes. Importantly, our results indicate that overexpression of NAF-1 significantly inhibited AMPK activity and protected cardiomyocytes from NS-induced cell death. Taken together, these data show that ectopic expression of NAF-1 antagonizes the degree of autophagy in cardiomyocytes and enhances cell survival during starvation conditions. PMID- 25689846 TI - Comparison of treatment safety and patient survival in elderly versus nonelderly patients with advanced hepatocellular carcinoma receiving sorafenib combined with transarterial chemoembolization: a propensity score matching study. AB - AIMS: This retrospective study was carried out to compare the outcomes between elderly (>=70 years of age) and nonelderly patients (<70 years of age) with advanced hepatocellular carcinoma (HCC) who received sorafenib combined with transarterial chemoembolization (TACE). METHODS: 88 patients with a confirmed diagnosis of advanced HCC were enrolled in this study. Of these, 24 elderly patients were matched with 48 nonelderly patients at a 1:2 ratio using propensity score matching to minimize selection bias. The related adverse events and survival benefits were compared between the two groups. RESULTS: Sorafenib combined with TACE was equally well tolerated in both age groups, and grade 3 or 4 adverse events were similarly observed in 54.2% of elderly and 50.0% of nonelderly patients (P = 0.739). There were no significant differences in survival time between the elderly and nonelderly patients (P = 0.876). Significant prognostic factors for overall survival as identified by multivariate analysis were the Child-Pugh score and portal vein invasion. CONCLUSIONS: Sorafenib combined with TACE may be well tolerated and effective in elderly patients with advanced HCC. Age alone is not a parameter for the treatment of advanced HCC patients. PMID- 25689848 TI - Nanophotonic implementation of optoelectrowetting for microdroplet actuation. AB - The development and ultimate operation of a nanocomposite high-aspect-ratio photoinjection (HARP) device is presented in this work. The device makes use of a nanocomposite material as the optically active layer and the device achieves a large optical penetration depth with a high aspect ratio which provides a strong actuation force far away from the point of photoinjection. The nanocomposite material can be continuously illuminated and the position of the microdroplets can, therefore, be controlled to diffraction limited resolution. The nanocomposite HARP device shows great potential for future on-chip applications. PMID- 25689849 TI - Uptake of colorectal cancer screening among Ontarians with intellectual and developmental disabilities. AB - Under-screening for cancer may contribute to a greater disease burden in individuals with intellectual and developmental disabilities (IDD) as their life expectancy increases. In 2008, the province of Ontario launched Canada's first population-based colorectal cancer screening program. Our objectives were to compare the proportions of Ontarians with and without IDD who have undergone colorectal cancer screening and to examine factors associated with screening uptake among Ontarians with IDD. Records for Ontario residents 50-64 years of age were linked across various administrative health and social services datasets to identify individuals with IDD and to select a random sample of the age-equivalent Ontario population without IDD as a comparison group. Logistic regression models were fit to examine the odds of screening uptake among individuals with IDD while controlling for age, sex, urban or rural residence, neighbourhood income quintile, expected use of health care resources, and being enrolled with or seeing a physician in a patient enrolment model (any of several primary care practice models designed to improve patient access and quality of care in Ontario), and to examine the association between these variables and colorectal cancer screening in the IDD population. The odds of having had a fecal occult blood test in the previous two years and being up-to-date with colorectal tests were 32% and 46% lower, respectively, for Ontarians with IDD compared to those without IDD. Being older, female, having a greater expected use of health care resources, and being enrolled with or seeing a physician in a primary care patient enrolment model were all significantly associated with higher odds of having been screened for colorectal cancer in the IDD population. These findings underscore the need for targeted interventions aimed at making colorectal cancer screening more equitable. PMID- 25689850 TI - Multivariate analysis of prognostic factors for idiopathic sudden sensorineural hearing loss in children. AB - OBJECTIVES/HYPOTHESIS: To evaluate clinical characteristics and possible associated factors of idiopathic sudden sensorineural hearing loss (ISSNHL) in children using univariate and multivariate analyses. STUDY DESIGN: A retrospective case series with comparisons. METHODS: From January 2007 to December 2013, medical records of 37 pediatric ISSNHL patients were reviewed to assess hearing recovery rate and examine factors associated with prognosis (gender; side of hearing loss; opposite side hearing loss; treatment onset; presence of vertigo, tinnitus, and ear fullness; initial hearing threshold), using univariate and multivariate analysis, and compare them with 276 adult ISSNHL patients. RESULTS: Pediatric patients comprised only 6.6% of pediatric/adult cases of ISSNHL, and those below 10 years old were only 0.7%. The overall recovery rates (complete and partial) of the pediatric and adult patients were 57.4% and 47.2%, respectively. The complete recovery rate of the pediatric group (46.6%) was higher than that of the adult group (30.8%, P = .040). According to multivariate analysis, absence of tinnitus, later onset of treatment, and higher hearing threshold at initial presentation were associated with a poor prognosis in pediatric ISSNHL. CONCLUSIONS: The recovery rate of ISSNHL in pediatric patients is higher than in adults, and the presence of tinnitus and earlier treatment onset is associated with favorable outcomes. LEVEL OF EVIDENCE: 4. PMID- 25689851 TI - Molten salt synthesis, visible and near-IR region spectral properties of europium or neodymium doped CoNb2O6 columbite niobate. AB - Pure Nd(3+)- or Eu(3+)-doped CoNb2O6 powders have been prepared by a molten salt synthesis method using a Li2SO4-Na2SO4 or NaCl-KCl salt mixture as a flux at relatively low temperatures as compared to the solid state reaction method. X-ray diffraction patterns of pure CoNb2O6 samples indicated an orthorhombic single phase. For Eu(3+)-doped CoNb2O6 samples, the luminescence of Eu(3+) was observed at 615 nm as red emission while the Nd(3+) doped sample showed a typical emission at 1064 nm varying with the Eu(3+) or Nd(3+) doping concentrations. These luminescence characteristics of the doped samples may be attributed to the energy transfer between rare earth ions and CoO6 octahedral groups in the columbite structure. PMID- 25689852 TI - Establishment of a patient-derived orthotopic Xenograft (PDOX) model of HER-2 positive cervical cancer expressing the clinical metastatic pattern. AB - Squamous cell carcinoma of the cervix, highly prevalent in the developing world, is often metastatic and treatment resistant with no standard treatment protocol. Our laboratory pioneered the patient-derived orthotopic xenograft (PDOX) nude mouse model with the technique of surgical orthotopic implantation (SOI). Unlike subcutaneous transplant patient-derived xenograft (PDX) models, PDOX models metastasize. Most importantly, the metastasis pattern correlates to the patient. In the present report, we describe the development of a PDOX model of HER-2 positive cervical cancer. Metastasis after SOI in nude mice included peritoneal dissemination, liver metastasis, lung metastasis as well as lymph node metastasis reflecting the metastatic pattern in the donor patient. Metastasis was detected in 4 of 6 nude mice with primary tumors. Primary tumors and metastases in the nude mice had histological structures similar to the original tumor and were stained by an anti-HER-2 antibody in the same pattern as the patient's cancer. The metastatic pattern, histology and HER-2 tumor expression of the patient were thus preserved in the PDOX model. In contrast, subcutaneous transplantation of the patient's cervical tumors resulted in primary growth but not metastasis. PMID- 25689853 TI - Classification of Beta-lactamases and penicillin binding proteins using ligand centric network models. AB - beta-lactamase mediated antibiotic resistance is an important health issue and the discovery of new beta-lactam type antibiotics or beta-lactamase inhibitors is an area of intense research. Today, there are about a thousand beta-lactamases due to the evolutionary pressure exerted by these ligands. While beta-lactamases hydrolyse the beta-lactam ring of antibiotics, rendering them ineffective, Penicillin-Binding Proteins (PBPs), which share high structural similarity with beta-lactamases, also confer antibiotic resistance to their host organism by acquiring mutations that allow them to continue their participation in cell wall biosynthesis. In this paper, we propose a novel approach to include ligand sharing information for classifying and clustering beta-lactamases and PBPs in an effort to elucidate the ligand induced evolution of these beta-lactam binding proteins. We first present a detailed summary of the beta-lactamase and PBP families in the Protein Data Bank, as well as the compounds they bind to. Then, we build two different types of networks in which the proteins are represented as nodes, and two proteins are connected by an edge with a weight that depends on the number of shared identical or similar ligands. These models are analyzed under three different edge weight settings, namely unweighted, weighted, and normalized weighted. A detailed comparison of these six networks showed that the use of ligand sharing information to cluster proteins resulted in modules comprising proteins with not only sequence similarity but also functional similarity. Consideration of ligand similarity highlighted some interactions that were not detected in the identical ligand network. Analysing the beta-lactamases and PBPs using ligand-centric network models enabled the identification of novel relationships, suggesting that these models can be used to examine other protein families to obtain information on their ligand induced evolutionary paths. PMID- 25689854 TI - miR-30 family microRNAs regulate myogenic differentiation and provide negative feedback on the microRNA pathway. AB - microRNAs (miRNAs) are short non-coding RNAs that can mediate changes in gene expression and are required for the formation of skeletal muscle (myogenesis). With the goal of identifying novel miRNA biomarkers of muscle disease, we profiled miRNA expression using miRNA-seq in the gastrocnemius muscles of dystrophic mdx4cv mice. After identifying a down-regulation of the miR-30 family (miR-30a-5p, -30b, -30c, -30d and -30e) when compared to C57Bl/6 (WT) mice, we found that overexpression of miR-30 family miRNAs promotes differentiation, while inhibition restricts differentiation of myoblasts in vitro. Additionally, miR-30 family miRNAs are coordinately down-regulated during in vivo models of muscle injury (barium chloride injection) and muscle disuse atrophy (hindlimb suspension). Using bioinformatics tools and in vitro studies, we identified and validated Smarcd2, Snai2 and Tnrc6a as miR-30 family targets. Interestingly, we show that by targeting Tnrc6a, miR-30 family miRNAs negatively regulate the miRNA pathway and modulate both the activity of muscle-specific miR-206 and the levels of protein synthesis. These findings indicate that the miR-30 family may be an interesting biomarker of perturbed muscle homeostasis and muscle disease. PMID- 25689855 TI - Immune responses to HBsAg conjugated to protein D of non-typeable Haemophilus influenzae in mice. AB - BACKGROUND: Hepatitis B vaccine that contains an aluminum hydroxide adjuvant induces apoptotic death of Hepa 1-6 cells. Difficult-to-degrade chemical additives in vaccines effectively enhance vaccine immunogenicity, but also affect the host tissue. Identification of bio-molecules that are readily degraded and compatible in vivo as an adjuvant is important for vaccine research. The hapten carrier effect suggests that stimulation of helper T (Th) cells by carrier adjuvants is feasible. Protein D (PD) of non-typeable Haemophilus influenzae covalently conjugated to some polysaccharide vaccines has been confirmed to convert T-cell independent (TI) antigens into T-cell dependent (TD) antigens, and elicit strong T-cell responses ultimately. Herein, we would substitube PD for aluminum hydroxide adjuvant in Hepatitis B vaccine. METHODS AND RESULTS: Truncated PD (amino acids 20-364) was expressed in Escherichia coli and purified by (NH4)2SO4 precipitation and DEAE chromatography. After evaluation of antigenicity by western blotting, PD was covalently conjugated to yeast-derived recombinant HBsAg by cross-linking with glutaraldehyde. Intramuscular immunization with the conjugate induced higher level of HBsAg-specific antibody than did HBsAg alone (p < 0.05), and was comparable to commercial Hepatitis B vaccine. During the surveillance period (days 35-105), anti-HBs titers were hold high. Moreover, the conjugated vaccine enhanced Th1 immune responses, while Th2 responses were also activated and induced an antibody response, as determined by IFN-gamma ELISPOT and IgG1/IgG2a ratio assays. CONCLUSIONS: Recombinant truncated PD covalently conjugated to HBsAg antigen enhanced the immunogenicity of the antigen in mice simultaneously by humoral and cellular immune response, which would facilitate therapeutic hepatitis B vaccines. PMID- 25689856 TI - Enhancing the early differential diagnosis of plateau iris and pupillary block using a-scan ultrasonography. AB - PURPOSE: To distinguish the frequently misdiagnosed plateau iris eyes from pupillary block group and normal group, we compared the ocular biometrical parameters of them by A-scan ultrasongraphy. METHODS: In total, we retrospectively reviewed general characteristics and ocular findings including ocular biometric measurements of 71 normal, 39 plateau iris, and 83 pupillary block eyes. RESULTS: The normal controls, plateau iris group and pupillary block group were significantly different in age, but not in gender. The anterior chamber depth tended to decrease and the lens thickness tended to increase from normal to plateau iris to pupillary block eyes. Compared to those of plateau iris group, the pupillary block group had significantly shallower anterior chamber depth (2.90mm vs. 2.33mm; p<0.001), thicker lens (4.77mm vs. 5.11mm; p<0.001), shorter axial length (23.16mm vs. 22.63mm; p<0.001), smaller relative lens position (2.28 vs. 2.16; p<0.001) and larger lens/axial length factor (2.06 vs. 2.26; p<0.001). However, when comparing plateau iris and normal eyes, only axial length and lens/axial length factor were significantly different (23.16 vs. 23.54; p<0.05 and 2.06 vs. 1.96; p<0.05). CONCLUSIONS: Measured by A-scan ultrasonography, the ocular biometrics of plateau iris were significantly different from those of pupillary block eyes. However, our A-scan ultrasongraphy generally found no significant biometric differences between plateau iris and normal eyes. These findings suggest that while A-scan ultrasonography might be used as a practical tool for differentiating plateau iris and papillary block eyes, a more meticulous gonioscopy and other assessments may be necessary to distinguish plateau iris from normal eyes. PMID- 25689857 TI - Preventing effect of L-type calcium channel blockade on electrophysiological alterations in dentate gyrus granule cells induced by entorhinal amyloid pathology. AB - The entorhinal cortex (EC) is one of the earliest affected brain regions in Alzheimer's disease (AD). EC-amyloid pathology induces synaptic failure in the dentate gyrus (DG) with resultant behavioral impairment, but there is little known about its impact on neuronal properties in the DG. It is believed that calcium dyshomeostasis plays a pivotal role in the etiology of AD. Here, the effect of the EC amyloid pathogenesis on cellular properties of DG granule cells and also possible neuroprotective role of L-type calcium channel blockers (CCBs), nimodipine and isradipine, were investigated. The amyloid beta (Abeta) 1-42 was injected bilaterally into the EC of male rats and one week later, electrophysiological properties of DG granule cells were assessed. Voltage clamp recording revealed appearance of giant sIPSC in combination with a decrease in sEPSC frequency which was partially reversed by CCBs in granule cells from Abeta treated rats. EC amyloid pathogenesis induced a significant reduction of input resistance (Rin) accompanied by a profound decreased excitability in the DG granule cells. However, daily administration of CCBs, isradipine or nimodipine (i.c.v. for 6 days), almost preserved the normal excitability against Abeta. In conclusion, lower tendency to fire AP along with reduced Rin suggest that DG granule cells might undergo an alteration in the membrane ion channel activities which finally lead to the behavioral deficits observed in animal models and patients with early-stage Alzheimer's disease. PMID- 25689858 TI - The cerebellum predicts the temporal consequences of observed motor acts. AB - It is increasingly clear that we extract patterns of temporal regularity between events to optimize information processing. The ability to extract temporal patterns and regularity of events is referred as temporal expectation. Temporal expectation activates the same cerebral network usually engaged in action selection, comprising cerebellum. However, it is unclear whether the cerebellum is directly involved in temporal expectation, when timing information is processed to make predictions on the outcome of a motor act. Healthy volunteers received one session of either active (inhibitory, 1 Hz) or sham repetitive transcranial magnetic stimulation covering the right lateral cerebellum prior the execution of a temporal expectation task. Subjects were asked to predict the end of a visually perceived human body motion (right hand handwriting) and of an inanimate object motion (a moving circle reaching a target). Videos representing movements were shown in full; the actual tasks consisted of watching the same videos, but interrupted after a variable interval from its onset by a dark interval of variable duration. During the 'dark' interval, subjects were asked to indicate when the movement represented in the video reached its end by clicking on the spacebar of the keyboard. Performance on the timing task was analyzed measuring the absolute value of timing error, the coefficient of variability and the percentage of anticipation responses. The active group exhibited greater absolute timing error compared with the sham group only in the human body motion task. Our findings suggest that the cerebellum is engaged in cognitive and perceptual domains that are strictly connected to motor control. PMID- 25689859 TI - Antiplaque effect of essential oils and 0.2% chlorhexidine on an in situ model of oral biofilm growth: a randomised clinical trial. AB - OBJECTIVE: To evaluate the in situ antiplaque effect after 4 days of using of 2 commercial antimicrobial agents in short term on undisturbed plaque-like biofilm. TRIAL DESIGN AND PARTICIPANTS: An observer-masked, crossover randomised clinical trial on 15 oral and systemically healthy volunteers between 20-30 years who were randomly and sequentially allocated in the same group which performed 3 interventions in different randomised sequences. INTERVENTION: The participants wore an appliance in 3 different rinsing periods doing mouthwashes twice a day (1/0/1) with essential oils, 0.2% chlorhexidine or sterile water (negative control). At the end of each 4-day mouthwash period, samples were removed from the appliance. Posteriorly, after bacterial vital staining, samples were analysed using a Confocal Laser Scanning Microscope. MAIN OUTCOME MEASURES: Bacterial vitality, thickness and covering grade by the biofilm after 4 days of applying each of the mouthwashes. RESULTS: The essential oils and the 0.2% chlorhexidine were significantly more effective than the sterile water at reducing bacterial vitality, thickness and covering grade by the biofilm. No significant differences were found between the 0.2% chlorhexidine and the essential oils at reducing the bacterial vitality (13.2% vs. 14.7%). However, the 0.2% chlorhexidine showed more reduction than the essential oils in thickness (6.5 MUm vs. 10.0 MUm; p<0.05) and covering grade by the biofilm (20.0% vs. 54.3%; p<0.001). CONCLUSION: The essential oils and 0.2% chlorhexidine showed a high antiplaque effect. Although the 0.2% chlorhexidine showed better results with regard to reducing the thickness and covering grade by the biofilm, both antiseptics showed a high and similar antibacterial activity. CLINICAL RELEVANCE: Daily essential oils or 0.2% chlorhexidine mouthwashes are effective when reducing dental plaque formation in the short term. Although 0.2% chlorhexidine continues to be the "gold standard" in terms of antiplaque effect, essential oils could be considered a reliable alternative. TRIAL REGISTRATION: ClinicalTrials.gov NCT02124655. PMID- 25689860 TI - Lysosomal-associated protein transmembrane 4 Beta-35 overexpression is a novel independent prognostic marker for gastric carcinoma. AB - OBJECTIVE: The purpose of this work was to analyze the relationships between the expression status of Lysosomal-associated protein transmembrane-4 beta 35 (LAPTM4B-35) in cancerous tissues and clinicopathological characteristics and prognosis of the patients with gastric carcinoma (GC). METHODS: The GC samples from 157 patients in a discovery cohort and 148 patients in a testing cohort with follow-up data were used to validate the feasibility of expression of LAPTM4B-35 protein in predicting GC prognosis. Immunohistochemical staining was used to determine the expression of LAPTM4B-35 protein in precancerous gastric lesions and gastric carcinomas. The correlation between the expression of LAPTM4B-35 and clinicopathologic characteristics of patients with gastric carcinoma was analyzed using chi-square test. Univariate and multivariate analyses were performed to determine the association between LAPTM4B-35 expression and prognosis. RESULTS: LAPTM4B-35 expression was increased steadily in sequential stages of precancerous gastric lesions. Positive LAPTM4B-35 expression was more frequently detected in patients with distant metastasis (P = 0.023) and III+IV TNM stages (P = 0.042) in the discovery cohort. Kaplan-Meier survival curves and univariate analysis showed that expression of LAPTM4B-35 had a significant impact on overall survival of patients with gastric carcinoma in discovery cohort (P<0.001) and testing cohort (P = 0.001). LAPTM4B-35 expression was an independent prognostic indicator for the overall survival of patients with gastric carcinoma in both cohorts. CONCLUSIONS: The present research demonstrated that LAPTM4B-35 over-expression was an independent factor in gastric carcinoma prognosis. LAPTM4B gene may be a useful target of interventions slowing the progression of precancerous gastric lesions and a new therapy method to improve the prognosis of gastric carcinoma. PMID- 25689861 TI - Control of Paternally Expressed Imprinted UPWARD CURLY LEAF1, a Gene Encoding an F-Box Protein That Regulates CURLY LEAF Polycomb Protein, in the Arabidopsis Endosperm. AB - Genomic imprinting, an epigenetic process in mammals and flowering plants, refers to the differential expression of alleles of the same genes in a parent-of-origin specific manner. In Arabidopsis, imprinting occurs primarily in the endosperm, which nourishes the developing embryo. Recent high-throughput sequencing analyses revealed that more than 200 loci are imprinted in Arabidopsis; however, only a few of these imprinted genes and their imprinting mechanisms have been examined in detail. Whereas most imprinted loci characterized to date are maternally expressed imprinted genes (MEGs), PHERES1 (PHE1) and ADMETOS (ADM) are paternally expressed imprinted genes (PEGs). Here, we report that UPWARD CURLY LEAF1 (UCL1), a gene encoding an E3 ligase that degrades the CURLY LEAF (CLF) polycomb protein, is a PEG. After fertilization, paternally inherited UCL1 is expressed in the endosperm, but not in the embryo. The expression pattern of a beta-glucuronidase (GUS) reporter gene driven by the UCL1 promoter suggests that the imprinting control region (ICR) of UCL1 is adjacent to a transposable element in the UCL1 5' upstream region. Polycomb Repressive Complex 2 (PRC2) silences the maternal UCL1 allele in the central cell prior to fertilization and in the endosperm after fertilization. The UCL1 imprinting pattern was not affected in paternal PRC2 mutants. We found unexpectedly that the maternal UCL1 allele is reactivated in the endosperm of Arabidopsis lines with mutations in cytosine DNA METHYLTRANSFERASE 1 (MET1) or the DNA glycosylase DEMETER (DME), which antagonistically regulate CpG methylation of DNA. By contrast, maternal UCL1 silencing was not altered in mutants with defects in non-CpG methylation. Thus, silencing of the maternal UCL1 allele is regulated by both MET1 and DME as well as by PRC2, suggesting that divergent mechanisms for the regulation of PEGs evolved in Arabidopsis. PMID- 25689862 TI - Phosphorylation of ERK5 on Thr732 is associated with ERK5 nuclear localization and ERK5-dependent transcription. AB - Extracellular signal-regulated kinases (ERKs) play critical roles in numerous cellular processes, including proliferation and differentiation. ERK5 contains a kinase domain at the N-terminal, and the unique extended C-terminal includes multiple autophosphorylation sites that enhance ERK5-dependent transcription. However, the impact of phosphorylation at the various sites remain unclear. In this study, we examined the role of phosphorylation at the ERK5 C-terminal. We found that a constitutively active MEK5 mutant phosphorylated ERK5 at the TEY motif, resulting in the sequential autophosphorylation of multiple C-terminal residues, including Thr732 and Ser769/773/775. However, when ERK1/2 was selectively activated by an oncogenic RAS mutant, ERK5 phosphorylation at Thr732 was induced without affecting the phosphorylation status at TEY or Ser769/773/775. The Thr732 phosphorylation was U0126-sensitive and was observed in a kinase-dead mutant of ERK5 as well, suggesting that ERK1/2 can phosphorylate ERK5 at Thr732. This phosphorylation was also promoted by epidermal growth factor and nerve growth factor in HEK293 and PC12 cells, respectively. The ERK5-T732A mutant was localized in the cytosol under basal conditions. In contrast, ERK5 phosphorylated at Thr732 via the RAS-ERK1/2 pathway and ERK5-T732E, which mimics the phosphorylated form, were localized in both the nucleus and cytosol. Finally, ER-32A and U0126 blocked ERK5-dependent MEF2C transcriptional activity. Based on these findings, we propose a novel cross-talk mechanism in which ERK1/2, following activation by growth factor stimulation, phosphorylates ERK5 at Thr732. This phosphorylation event is responsible for ERK5 nuclear localization and ERK5 dependent transcription. PMID- 25689863 TI - Correction: a novel missense mutation in ADAMTS10 in Norwegian Elkhound primary glaucoma. PMID- 25689864 TI - A simple method for encapsulating single cells in alginate microspheres allows for direct PCR and whole genome amplification. AB - Microdroplets are an effective platform for segregating individual cells and amplifying DNA. However, a key challenge is to recover the contents of individual droplets for downstream analysis. This paper offers a method for embedding cells in alginate microspheres and performing multiple serial operations on the isolated cells. Rhodobacter sphaeroides cells were diluted in alginate polymer and sprayed into microdroplets using a fingertip aerosol sprayer. The encapsulated cells were lysed and subjected either to conventional PCR, or whole genome amplification using either multiple displacement amplification (MDA) or a two-step PCR protocol. Microscopic examination after PCR showed that the lumen of the occupied microspheres contained fluorescently stained DNA product, but multiple displacement amplification with phi29 produced only a small number of polymerase colonies. The 2-step WGA protocol was successful in generating fluorescent material, and quantitative PCR from DNA extracted from aliquots of microspheres suggested that the copy number inside the microspheres was amplified up to 3 orders of magnitude. Microspheres containing fluorescent material were sorted by a dilution series and screened with a fluorescent plate reader to identify single microspheres. The DNA was extracted from individual isolates, re amplified with full-length sequencing adapters, and then a single isolate was sequenced using the Illumina MiSeq platform. After filtering the reads, the only sequences that collectively matched a genome in the NCBI nucleotide database belonged to R. sphaeroides. This demonstrated that sequencing-ready DNA could be generated from the contents of a single microsphere without culturing. However, the 2-step WGA strategy showed limitations in terms of low genome coverage and an uneven frequency distribution of reads across the genome. This paper offers a simple method for embedding cells in alginate microspheres and performing PCR on isolated cells in common bulk reactions, although further work must be done to improve the amplification coverage of single genomes. PMID- 25689865 TI - Behavioral characterization of mouse models of neuroferritinopathy. AB - Ferritin is the main intracellular protein of iron storage with a central role in the regulation of iron metabolism and detoxification. Nucleotide insertions in the last exon of the ferritin light chain cause a neurodegenerative disease known as Neuroferritinopathy, characterized by iron deposition in the brain, particularly in the cerebellum, basal ganglia and motor cortex. The disease progresses relentlessly, leading to dystonia, chorea, motor disability and neuropsychiatry features. The characterization of a good animal model is required to compare and contrast specific features with the human disease, in order to gain new insights on the consequences of chronic iron overload on brain function and behavior. To this aim we studied an animal model expressing the pathogenic human FTL mutant 498InsTC under the phosphoglycerate kinase (PGK) promoter. Transgenic (Tg) mice showed strong accumulation of the mutated protein in the brain, which increased with age, and this was accompanied by brain accumulation of ferritin/iron bodies, the main pathologic hallmark of human neuroferritinopathy. Tg-mice were tested throughout development and aging at 2-, 8- and 18-months for motor coordination and balance (Beam Walking and Footprint tests). The Tg-mice showed a significant decrease in motor coordination at 8 and 18 months of age, with a shorter latency to fall and abnormal gait. Furthermore, one group of aged naive subjects was challenged with two herbicides (Paraquat and Maneb) known to cause oxidative damage. The treatment led to a paradoxical increase in behavioral activation in the transgenic mice, suggestive of altered functioning of the dopaminergic system. Overall, data indicate that mice carrying the pathogenic FTL498InsTC mutation show motor deficits with a developmental profile suggestive of a progressive pathology, as in the human disease. These mice could be a powerful tool to study the neurodegenerative mechanisms leading to the disease and help developing specific therapeutic targets. PMID- 25689867 TI - Evidence appraisal of Balkissoon R, Nayfeh T, Adams KL, Belkoff SM, Riedel S, Mears SC. Microbial surface contamination after standard operating room cleaning practices following surgical treatment of infection. Orthopedics. 2014;37(4):e339 e344. PMID- 25689866 TI - The ER stress-mediated mitochondrial apoptotic pathway and MAPKs modulate tachypacing-induced apoptosis in HL-1 atrial myocytes. AB - BACKGROUND AND OBJECT: Cell apoptosis is a contributing factor in the initiation, progression and relapse of atrial fibrillation (AF), a life-threatening illness accompanied with stroke and heart failure. However, the regulatory cascade of apoptosis is intricate and remains unidentified, especially in the setting of AF. The aim of this study was to explore the roles of endoplasmic reticulum (ER) stress, mitochondrial apoptotic pathway (MAP), mitogen-activated protein kinases (MAPKs), and their cross-talking in tachypacing-induced apoptosis. METHODS AND RESULTS: HL-1 cells were cultured in the presence of tachypacing for 24 h to simulate atrial tachycardia remodeling. Results showed that tachypacing reduced cell viability measured by the cell counting kit-8, dissipated mitochondrial membrane potential detected by JC-1 staining and resulted in approximately 50% apoptosis examined by Hoechst staining and annexin V/propidium iodide staining. In addition, the proteins involved in ER stress, MAP and MAPKs were universally up-regulated or activated via phosphorylation, as confirmed by western blotting; and reversely silencing of ER stress, caspase-3 (the ultimate executor of MAP) and MAPKs with specific inhibitors prior to pacing partially alleviated apoptosis. An inhibitor of ER stress was applied to further investigate the responses of mitochondria and MAPKs to ER stress, and results indicated that suppression of ER stress comprehensively but incompletely attenuated the activation of MAP and MAPKs aroused by tachypacing, with the exception of ERK1/2, one branch of MAPKs. CONCLUSIONS: Our study suggested tachypacing-induced apoptosis is regulated by ER stress-mediated MAP and MAPKs. Thus, the above three components are all promising anti-apoptotic targets in AF patients and ER stress appears to play a dominant role due to its comprehensive effects. PMID- 25689868 TI - Guideline first look: autologous tissue management. PMID- 25689869 TI - Implementing an active shooter training program. PMID- 25689870 TI - Factors that affect surgical instrument availability and turnover time. PMID- 25689871 TI - Calcium and bone health--goodbye, calcium supplements? AB - This review assesses (1) the potential role of calcium supplements in the prevention and treatment of osteoporosis and osteoporotic fractures, and (2) the safety of calcium supplements with respect to cardiovascular health as well. With regard to (1), a total calcium intake of < 800 mg/day is associated with increased loss of bone mineral density in peri- and postmenopausal women with an increase in fracture risk. Hereby, the effect of calcium supplements on fracture prevention is dependent primary on baseline calcium intake. The strongest protective effect has been reported in individuals with a calcium intake < 700 mg/day and in high-risk groups. A calcium intake of about 1000-1200 mg/day seems to be sufficient for general fracture prevention. With regard to (2), an analysis of the data based on the Hill criteria does not demonstrate convincing evidence that calcium supplements increase cardiovascular risk. In the long term, total calcium intake of 2500 mg/day (from food and supplements) continues to be classified as safe. This value should not be exceeded for an extended period of time. PMID- 25689872 TI - Safety of human papillomavirus vaccines: a review. AB - INTRODUCTION: Between 2006 and 2009, two different human papillomavirus virus (HPV) vaccines were licensed for use: a quadrivalent (qHPVv) and a bivalent (bHPVv) vaccine. Since 2008, HPV vaccination programmes have been implemented in the majority of the industrialized countries. Since 2013, HPV vaccination has been part of the national programs of 66 countries including almost all countries in North America and Western Europe. Despite all the efforts made by individual countries, coverage rates are lower than expected. Vaccine safety represents one of the main concerns associated with the lack of acceptance of HPV vaccination both in the European Union/European Economic Area and elsewhere. AREAS COVERED: Safety data published on bivalent and quadrivalent HPV vaccines, both in pre licensure and post-licensure phase, are reviewed. EXPERT OPINION: Based on the latest scientific evidence, both HPV vaccines seem to be safe. Nevertheless, public concern and rumors about adverse events (AE) represent an important barrier to overcome in order to increase vaccine coverage. Passive surveillance of AEs is an important tool for detecting safety signals, but it should be complemented by activities aimed at assessing the real cause of all suspect AEs. Improved vaccine safety surveillance is the first step for effective communication based on scientific evidence. PMID- 25689873 TI - Survival Outcomes Following Pediatric Liver Transplantation (Pedi-SOFT) Score: A Novel Predictive Index. AB - A prognostic index to predict survival after liver transplantation could address several clinical needs. Here, we devised a scoring system that predicts recipient survival after pediatric liver transplantation. We used univariate and multivariate analysis on 4565 pediatric liver transplant recipients data and identified independent recipient and donor risk factors for posttransplant mortality at 3 months. Multiple imputation was used to account for missing variables. We identified five factors as significant predictors of recipient mortality after pediatric liver transplantation: two previous transplants (OR 5.88, CI 2.88-12.01), one previous transplant (OR 2.54, CI 1.75-3.68), life support (OR 3.68, CI 2.39-5.67), renal insufficiency (OR 2.66, CI 1.84-3.84), recipient weight under 6 kilograms (OR 1.67, CI 1.12-2.36) and cadaveric technical variant allograft (OR 1.38, CI 1.03-1.83). The Survival Outcomes Following Pediatric Liver Transplant score assigns weighted risk points to each of these factors in a scoring system to predict 3-month recipient survival after liver transplantation with a C-statistic of 0.74. Although quite accurate when compared with other posttransplant survival models, we would not advocate individual clinical application of the index. PMID- 25689874 TI - Children's night waking among toddlers: relationships with mothers' and fathers' parenting approaches and children's behavioural difficulties. AB - AIMS: To explore associations between children's sleep problems, and behavioural difficulties and parenting approaches. BACKGROUND: Children commonly have problematic night waking; however, relationships between parenting cognitions and behaviours and children's sleep problems are rarely examined. DESIGN: Longitudinal children's cohort study from 5-29 months post birth. METHODS: Data were taken from the Quebec Longitudinal Study of Child Development (1998-2007) at three phases: 5, 17 and 29 months of age. Thousand four hundred and eighty-seven families were included in our study based on: participation from phase 1 (5 months old), both parents' reports on parenting cognitions/behaviours and child behavioural difficulties at 29 months, and mothers' reports of children's sleep at 29 months. In 2013, we conducted repeated measures anovas and manovas including children's gender. RESULTS: Extended night-time waking patterns (wakes of >=20 minutes) were associated with mothers' and fathers' lower sense of parenting impact and higher overprotectiveness and mothers' lower self-efficacy and higher coerciveness for 29-month-old children. In the extended waking group, mothers consistently reported lower self-efficacy, higher overprotectiveness and lower parenting impact at 5, 17 and 29 months. For those children, fathers were only more overprotective at 5 and 29 months. Regarding 29-month-old children's behaviour, children in the extended night waking group had highest scores on externalizing and internalizing behaviours. Girls had higher scores on shyness/inhibition and boys had higher scores on aggression/hyperactivity. CONCLUSION: Mothers' and fathers' parenting cognitions and behaviours are affected by 29-month-old children's night waking patterns and night waking patterns are associated with children's behavioural problems. PMID- 25689875 TI - Changes in stone composition over two decades: evaluation of over 10,000 stone analyses. AB - To examine the changes in stone composition from 1990 to 2010. A retrospective review was performed of all renal and ureteral stones submitted from the state of Massachusetts to a single laboratory (Laboratory for Stone Research, Newton, MA) for the years 1990 and 2010. Stone composition was determined by infrared spectroscopy and/or polarizing microscopy. A total of 11,099 stones were evaluated (56.7% from 1990, 43.3% from 2010). From 1990 to 2010, the percentage of stones from females (i.e., female/male ratio) increased significantly (29.8% in 1990 to 39.1% in 2010, p < 0.001). Among women, from 1990 to 2010, there was a significant increase in stones which were >50% uric acid (7.6-10.2%, p < 0.005) and a significant decrease in struvite stones (7.8-3.0%, p < 0.001). Among women with calcium stones, the % apatite per stone decreased significantly (20.0 vs. 11.7%, p < 0.001). Among men, there were no changes in stones which were majority uric acid (11.7-10.8%, p = 0.2). Among men with calcium stones, the % apatite per stone increased significantly (9.8 vs. 12.5%, p < 0.001). Males also demonstrated a significant increase in both cystine (0.1-0.6%, p < 0.001) and struvite stones (2.8-3.7%, p = 0.02). The epidemiology of stone disease continues to evolve and appears to vary according to gender. While some of these findings may be related to population changes in body mass index and obesity, the etiology of others remains unclear. PMID- 25689876 TI - End-stage renal disease from hemolytic uremic syndrome in the United States, 1995 2010. AB - Management of hemolytic uremic syndrome (HUS) has evolved rapidly, and optimal treatment strategies are controversial. However, it is unknown whether the burden of end-stage renal disease (ESRD) from HUS has changed, and outcomes on dialysis in the United States are not well described. We retrospectively examined data for patients initiating maintenance renal replacement therapy (RRT) (n = 1,557,117), 1995-2010, to define standardized incidence ratios (SIRs) and outcomes of ESRD from HUS) (n = 2241). Overall ESRD rates from HUS in 2001-2002 were 0.5 cases/million per year and were higher for patients characterized by age 40-64 years (0.6), >=65 years (0.7), female sex (0.6), and non-Hispanic African American race (0.7). Standardized incidence ratios remained unchanged (P >= 0.05) between 2001-2002 and 2009-2010 in the overall population. Compared with patients with ESRD from other causes, patients with HUS were more likely to be younger, female, white, and non-Hispanic. Over 5.4 years of follow-up, HUS patients differed from matched controls with ESRD from other causes by lower rates of death (8.3 per 100 person-years in cases vs. 10.4 in controls, P < 0.001), listing for renal transplant (7.6 vs. 8.6 per 100 person-years, P = 0.04), and undergoing transplant (6.9 vs. 9 per 100 person-years, P < 0.001). The incidence of ESRD from HUS appears not to have risen substantially in the last decade. However, given that HUS subtypes could not be determined in this study, these findings should be interpreted with caution. PMID- 25689878 TI - Productive performance, meat quality and fatty acid profile of steers finished in confinement or supplemented at pasture. AB - Thirty Aberdeen Angus crossbred steers (281 +/- 16 kg) were used to test the effect of finishing feeding system on growth performance, meat quality and fatty acid (FA) profile in intramuscular fat. Steers were fed in confinement (forage:concentrate ratio of 50 : 50; DM basis) or with different levels of energy supplementation (0, 0.4, 0.8 and 1.2% BW) at pasture (Avena strigosa Schreb and Lolium multiflorum L.). There were no differences between treatments for ADG (average=1.60 kg/day), hot carcass weight (HCW) (average=229 kg) and subcutaneous fat depth (average=3 mm). Dressing % (P=0.06; tendency) and carcass ADG (P=0.02) linearly increased with level of supplementation for pasture steers. No differences were observed between treatments for tenderness, marbling, pH, color b*, or cooking loss and drip loss in samples of Longissimus dorsi. However L* increased linearly (P=0.05) with level of supplementation. The concentrations of myristic, palmitic, estearic and linoleic FA did not differ among treatments. The concentration of n-3 FA increased (P<0.001) in steers at pasture compared with confinement, but n-6 FA concentrations did not differ between feeding system. Supplementation up to 0.4% BW increase (P<0.001) conjugated linoleic acid (CLA) and linolenic FA concentrations in intramuscular fat when compared with confinement. The level of supplementation on pasture linearly decreased (P<0.001) n-3 and CLA and linearly increased (P=0.001) the n-6 : n-3 ratio. Finishing of steers grazing winter pasture with energy supplementation or in confinement fed a medium-concentrate diet did not affect meat quality (tenderness, marbling, parameter b* on the CIE L*a*b* scale, cooking and drip losses) except for a* and L*. However, intramuscular fat of animals finished at pasture with moderate level of supplementation compared to animals fed in confinement had greater concentration of CLA, linolenic, and n-3, and lower n-6 : n-3 in intramuscular fat. PMID- 25689879 TI - Mobility restrictions and glass transition behaviour of an epoxy resin under confinement. AB - Confinement can have a big influence on the dynamics of glass formers in the vicinity of the glass transition. Already 40 to 50 K above the glass transition temperature, thermal equilibration of glass formers can be strongly influenced by the confining substrate. We investigate the linear thermal expansion and the specific heat capacity cp of an epoxy resin (diglycidyl ether of bisphenol A, DGEBA) in a temperature interval of 120 K around the glass transition temperature. The epoxy resin is filled into controlled pore glasses with pore diameters between 4 and 111 nm. Since DGEBA can form H-bonds with silica surfaces, we also investigate the influence of surface silanization of the porous substrates. In untreated substrates a core/shell structure of the epoxy resin can be identified. The glass transition behaviours of the bulk phase and that of the shell phase are different. In silanized substrates, the shell phase disappears. At a temperature well above the glass transition, a second transition is found for the bulk phase - both in the linear expansion data as well as in the specific heat capacity. The cp data do not allow excluding the glass transition of a third phase as being the cause for this transition, whereas the linear expansion data do so. The additional transition temperature is interpreted as a separation between two regimes: above this temperature, macroscopic flow of the bulk phase inside the porous structure is possible to balance the mismatch of thermal expansion coefficients between DGEBA and the substrate. Below the transition temperature, this degree of freedom is hindered by geometrical constraints of the porous substrates. Moreover, this second transition could also be found in the linear expansion data of the shell phase. PMID- 25689880 TI - Modified liver-free multivisceral transplantation for a metastatic small bowel neuroendocrine tumor: a case report. AB - Neuroendocrine tumors originating from the small bowel frequently metastasize to the lymph nodes and/or liver. Although surgical extirpation of the primary tumor and locoregional metastases epitomizes the management of patients with such tumors, this is not always possible with conventional surgical techniques. Nonresectable, slow-growing tumors involving the mesenteric root represent a generally accepted indication for deceased donor intestinal and multivisceral transplantation. Furthermore, vascularized sentinel forearm flaps offer opportunities for monitoring graft rejection and tailoring immunosuppression regimens. Here, we report the first documented case of modified liver-free multivisceral transplantation preceded by neoadjuvant 177-lutetium peptide receptor radionuclide therapy in a patient with a small bowel neuroendocrine tumor and extensive lymph node metastases in the mesenterium. At a follow-up of 21 months the patient is biochemically and radiologically disease-free. PMID- 25689881 TI - The impact of rituximab in ABO-incompatible pediatric living donor liver transplantation: the experience of a single center. AB - Previous studies have demonstrated the safety of ABO-incompatible pediatric LDLT using preoperative plasmapheresis and rituximab; however, no reports have described the timing and dosage of rituximab administration for pediatric LDLT. This study aimed to describe a safe and effective dosage and timing of rituximab for patients undergoing pediatric ABO-incompatible LDLT based on the experience of our single center. A total of 192 LDLTs in 187 patients were examined. These cases included 29 ABO-incompatible LDLTs in 28 patients. Rituximab was used beginning in January 2004 in recipients older than two yr of age (first period: 375 mg/m(2) in two cases; second period: 50 mg/m(2) in two cases; and 200 mg/m(2) in eight cases). Two patients who received 375 mg/m(2) rituximab died of Pneumocystis carinii pneumonia and hemophagocytic syndrome. One patient who received 50 mg/m(2) rituximab required retransplantation as a consequence of antibody-mediated complications. All eight patients administered 200 mg/m(2) survived, and the mean CD20(+) lymphocyte count was 0.1% at the time of LDLT. In the preoperative management of patients undergoing pediatric ABO-incompatible LDLT, the administration of 200 mg/m(2) rituximab three wk prior to LDLT was safe and effective. PMID- 25689883 TI - Risk Perception and the Public Acceptance of Drones. AB - Unmanned aircraft, or drones, are a rapidly emerging sector of the aviation industry. There has been limited substantive research, however, into the public perception and acceptance of drones. This article presents the results from two surveys of the Australian public designed to investigate (1) whether the public perceive drones to be riskier than existing manned aviation, (2) whether the terminology used to describe the technology influences public perception, and (3) what the broader concerns are that may influence public acceptance of the technology. We find that the Australian public currently hold a relatively neutral attitude toward drones. Respondents did not consider the technology to be overly unsafe, risky, beneficial, or threatening. Drones are largely viewed as being of comparable risk to that of existing manned aviation. Furthermore, terminology had a minimal effect on the perception of the risks or acceptability of the technology. The neutral response is likely due to a lack of knowledge about the technology, which was also identified as the most prevalent public concern as opposed to the risks associated with its use. Privacy, military use, and misuse (e.g., terrorism) were also significant public concerns. The results suggest that society is yet to form an opinion of drones. As public knowledge increases, the current position is likely to change. Industry communication and media coverage will likely influence the ultimate position adopted by the public, which can be difficult to change once established. PMID- 25689882 TI - A Single Amphetamine Infusion Reverses Deficits in Dopamine Nerve-Terminal Function Caused by a History of Cocaine Self-Administration. AB - There are ~ 1.6 million people who meet the criteria for cocaine addiction in the United States, and there are currently no FDA-approved pharmacotherapies. Amphetamine-based dopamine-releasing drugs have shown efficacy in reducing the motivation to self-administer cocaine and reducing intake in animals and humans. It is hypothesized that amphetamine acts as a replacement therapy for cocaine through elevation of extracellular dopamine levels. Using voltammetry in brain slices, we tested the ability of a single amphetamine infusion in vivo to modulate dopamine release, uptake kinetics, and cocaine potency in cocaine-naive animals and after a history of cocaine self-administration (1.5 mg/kg/infusion, fixed-ratio 1, 40 injections/day * 5 days). Dopamine kinetics were measured 1 and 24 h after amphetamine infusion (0.56 mg/kg, i.v.). Following cocaine self administration, dopamine release, maximal rate of uptake (Vmax), and membrane associated dopamine transporter (DAT) levels were reduced, and the DAT was less sensitive to cocaine. A single amphetamine infusion reduced Vmax and membrane DAT levels in cocaine-naive animals, but fully restored all aspects of dopamine terminal function in cocaine self-administering animals. Here, for the first time, we demonstrate pharmacologically induced, immediate rescue of deficits in dopamine nerve-terminal function in animals with a history of high-dose cocaine self-administration. This observation supports the notion that the DAT expression and function can be modulated on a rapid timescale and also suggests that the pharmacotherapeutic actions of amphetamine for cocaine addiction go beyond that of replacement therapy. PMID- 25689884 TI - Momentum is building. PMID- 25689886 TI - Epidemiology of epilepsy and its burden in Kolkata, India. AB - BACKGROUND: Disability-adjusted life year (DALY) is a time-based measure of disease burden incorporating both disability and mortality. Our study aimed to determine the DALY lost from epilepsy in an Indian metropolis. METHODS: A population-based prospective study on epilepsy was conducted over 5 years (2003 8) in Kolkata, India, on randomly selected 100,802 subjects (males 53,209, females 47,593) to assess prevalence as well as to capture incident cases of epilepsy and those incident cases that died. Standard case definitions were used. The data were used to estimate years of life lost (YLL) due to premature mortality, years of life lived with disability (YLD), and DALY, utilizing the prevalence-based Global Burden of Disease (GBD) 2010 approach. Age- and gender specific figures were computed. RESULTS: During 2003-2004, a total of 476 subjects with active epilepsy were detected and the age-adjusted prevalence rate was 4.71 per 1000. Over 5 years, there were 197 incident cases of epilepsy of whom 26 died. The age-adjusted annual incidence rate of epilepsy was 38.3 per 100,000. The all-cause standardized mortality rate (SMR) of epilepsy was 2.4. The burden of epilepsy in the year 2007-8 revealed the overall YLL was 755 per 100,000, and the overall YLD ranged from 14.45 to 31.0 per 100,000 persons depending on the clinical severity of the epilepsy. Both YLL and YLD values were higher in males than in females. The overall DALY lost due to epilepsy in 2007-8 was found to be 846.96 (males 1183.04, females 463.81) per 100,000. CONCLUSIONS: This is the first study in India to determine the DALY of epilepsy using GBD 2010. The results reveal a substantial burden of epilepsy in our setting. Similar such studies are needed in other parts of India in both urban and rural settings. PMID- 25689887 TI - Antigen production using heterologous expression of dengue virus-2 non-structural protein 1 (NS1) in Nicotiana tabacum (Havana) for immunodiagnostic purposes. AB - KEY MESSAGE: Expression of dengue-2 virus NS1 protein in Nicotiana tabacum plants for development of dengue immunodiagnostic kits. Dengue is one of the most important diseases caused by arboviruses in the world. A significant increase in its geographical distribution has been noticed over the last 20 years, with continuous transmission of several serotypes and emergence of the hemorrhagic fever in areas where the disease was previously not prevalent. Although the methodological processes for dengue diagnosis are in deep development and improvement, a limitation for the realization of dengue diagnostic tests is the difficulty of large-scale production of the antigen to be used in diagnostic tests. Due to this demand, the purpose of this study was to obtain the non structural protein 1 (NS1) from dengue-2 serotype by heterologous expression in Nicotiana tabacum (Havana). After confirmation of the NS1 protein gene integration in the plant genome, the heterologous protein was characterized using SDS-PAGE and immunoblotting. In an immunoenzymatic test, the recombinant NS1 protein presents an antigen potential for development of dengue immunodiagnostic kits. PMID- 25689888 TI - NMR-based structural validation of therapeutic antibody produced in Nicotiana benthamiana. AB - KEY MESSAGE: We successfully developed a method for metabolic isotope labeling of recombinant proteins produced in transgenic tobacco. This enabled assessment of structural integrity of plant-derived therapeutic antibodies by NMR analysis. A variety of expression vehicles have been developed for the production of promising biologics, including plants, fungi, bacteria, insects, and mammals. Glycoprotein biologics often experience altered folding and post-translational modifications that are typified by variant glycosylation patterns. These differences can dramatically affect their efficacy, as exemplified by therapeutic antibodies. However, it is generally difficult to validate the structural integrity of biologics produced using different expression vehicles. To address this issue, we have developed and applied a stable-isotope-assisted nuclear magnetic resonance (NMR) spectroscopy method for the conformational characterization of recombinant antibodies produced in plants. Nicotiana benthamiana used as a vehicle for the production of recombinant immunoglobulin G (IgG) was grown in a (15)N-enriched plant growth medium. The Fc fragment derived from the (15)N-labeled antibody thus prepared was subjected to heteronuclear two dimensional (2D) NMR measurements. This approach enabled assessment of the structural integrity of the plant-derived therapeutic antibodies by comparing their NMR spectral properties with those of an authentic IgG-Fc derived from mammalian cells. PMID- 25689890 TI - Elastofibroma: management and surgical outcome. AB - Elastofibroma is a benign slow-growing neoplasm of soft tissues, originally defined Elastofibroma dorsi because of the typical localization in the connective tissue placed between the bottom corner of the scapula and the chest wall. From 1990 to 2013 at our center, 115 patients underwent elestofibroma surgical removal, including 2 bilateral and one relapsed. For all the patients ultrasound preoperative examination was requested, sometimes with a diagnosis of lipoma or fibrolipoma because of the rarity of this type of lesion and therefore the lack of experience of the radiologists. In all 115 patients the lesion was detected and removed, only in 7 cases it was necessary, intraoperatively, to mobilize the upper limb and shoulder in order to better visualize the lesion. On the operating table the lesion was situated below the muscle planes and looks like a solid mass, oval, with a pole firmly attached to the periosteum of the ribs and intercostal ligaments, with net margins and a diameter of 5-10 cm. The sides not attached to the chest wall were in continuity with the adipose tissue. The cutting surface was pink-graysh, with fibrous appearance. Foci of cystic degeneration interspersed with islands of fat that are vaguely reminiscent of the fibrolipoma could be found. The treatment of choice is the surgical excision and subsequent histological examination solve the diagnostic dilemma. If the removal is radical, it is definitve because the lesion has no tendency to relapse. PMID- 25689889 TI - Arabidopsis Qc-SNARE gene AtSFT12 is involved in salt and osmotic stress responses and Na(+) accumulation in vacuoles. AB - KEY MESSAGE: AtSFT12, an Arabidopsis Qc-SNARE protein, is localized to Golgi organelles and is involved in salt and osmotic stress responses via accumulation of Na (+) in vacuoles. To reduce the detrimental effects of environmental stresses, plants have evolved many defense mechanisms. Here, we identified an Arabidopsis Qc-SNARE gene, AtSFT12, involved in salt and osmotic stress responses using an activation-tagging method. Both activation-tagged plants and overexpressing transgenic plants (OXs) of the AtSFT12 gene were tolerant to high concentrations of NaCl, LiCl, and mannitol, whereas loss-of-function mutants were sensitive to NaCl, LiCl, and mannitol. AtSFT12 transcription increased under NaCl, ABA, cold, and mannitol stresses but not MV treatment. GFP-fusion AtSFT12 protein was juxtaposed with Golgi marker, implying that its function is associated with Golgi-mediated transport. Quantitative measurement of Na(+) using induced coupled plasma atomic emission spectroscopy revealed that AtSFT12 OXs accumulated significantly more Na(+) than WT plants. In addition, Na(+)-dependent fluorescence analysis of Sodium Green showed comparatively higher Na(+) accumulation in vacuoles of AtSFT12 OX cells than in those of WT plant cells after salt treatments. Taken together, our findings suggest that AtSTF12, a Golgi Qc-SNARE protein, plays an important role in salt and osmotic stress responses and functions in the salt stress response via sequestration of Na(+) in vacuoles. PMID- 25689891 TI - The occlusion effects in capacitive contact imaging for in vivo skin damage assessments. AB - OBJECTIVE: The aim of this study was to investigate the occlusion effects in capacitive contact imaging, and to develop a new quantitative methodology for in vivo skin assessments using capacitive contact imaging and condenser-TEWL (transepidermal water loss) method. METHODS: Two measurement technologies were used in this study, i.e., capacitive contact imaging and condenser-TEWL method. Three types of skin damages were studied, intensive washes, tape stripping and sodium lauryl sulphate (SLS) irritation. The test skin sites were chosen on the volar forearms of healthy volunteers (aged 25-45); the measurements were taken both before and periodically after the damages. RESULTS: The results show that the time-dependent occlusion curves of the capacitive contact imaging can reflect the types of damages, and by analysing the shapes of the curves, we can get information about the skin surface water content level and stratum corneum thickness. The results also show that the combination of capacitive contact imaging and condenser-TEWL method gives extra information about the skin damages, such as the types of the damages and status of the damages. CONCLUSION: We have developed a potential new quantitative methodology for skin damage assessments using capacitive contact imaging and condenser-TEWL method. The combination of the two technologies can provide useful information for skin damage assessments. We have also developed a mathematical model for analysing the occlusion curves. PMID- 25689892 TI - High Levels of Concomitant Behavioral Health Disorders Among Patients Presenting for HIV Non-occupational Post-exposure Prophylaxis at a Boston Community Health Center Between 1997 and 2013. AB - A paucity of information regarding mental health exists for patients presenting for HIV non-occupational post-exposure prophylaxis (nPEP). We reviewed electronic medical records of 894 adult nPEP patients seen at a large Boston community health center between 1997 and 2013. Of 821 patients with consensual sexual exposures, 88.3 % were men who have sex with men, and 40.0 % had a mental health diagnosis. Diagnoses included: depression (24.4 %), anxiety (21.9 %), attention deficit disorder (7.8 %), post-traumatic stress disorder (3.3 %), and psychotic disorders (3.3 %). Of 129 patients with substance use disorders, alcohol dependence (65.9 %) and crystal methamphetamine (43.4 %) predominated. Unprotected receptive anal intercourse was associated with psychotic disorders (aOR = 4.86; 95 %CI:1.76-13.5) and substance use disorders (aOR = 1.89; 95 %CI:1.28-2.80). Substance use at the time of exposure was associated with: depression (aOR = 1.95; 95 %CI:1.36-2.80), anxiety (aOR = 2.22; 95 %CI:1.51 3.25), attention deficit disorder (aOR = 1.96; 95 %CI:1.18-3.27), and substance use disorder (aOR = 4.78; 95 %CI:3.30-6.93). Mental illness should be screened for and addressed at nPEP visits to optimize HIV risk-reduction. PMID- 25689893 TI - The effect of SCF and ouabain on small intestinal motility dysfunction induced by gastric cancer peritoneal metastasis. AB - The interstitial cells of Cajal (ICCs) play an important role in maintaining the normal function of gastrointestinal dynamics. In our previous study, we reported that, in advanced gastric cancer, the frequency of bowel movement is always reduced, due in part to the decreased number of ICCs. To investigate the impact of ICCs in gastric cancer, we established a mouse model of gastric cancer peritoneal metastasis using SGC-7901 gastric adenocarcinoma cells and their supernatant. Then, stem cell factor (SCF) and ouabain were used as therapeutic agents to improve gut dynamics. Our data showed that, compared with the normal mice, treatment with SGC-7901 cells and their supernatant led to a significant reduction of the muscle layer thickness, a decreased number of ICCs, broadened gaps between ICCs and surrounding cells, degeneration and necrosis of smooth muscle cells (SMCs), and infiltration of inflammatory cells. In contrast to SGC 7901 cell and supernatant treatment, SCF intervention caused mild submucosal edema and mitochondrial proliferation in the ICCs and SMCs. Additionally, ouabain treatment led to inflammatory cells infiltration into the submucosa and a decreased volume of ICCs. In conclusion, our data illustrated that, under the condition of gastric cancer peritoneal metastasis, the dysfunction of intestinal peristalsis may be related to pathological changes in ICCs. Moreover, we demonstrated that SCF treatment may help to improve intestinal dynamics by regulating the number and function of ICCs. PMID- 25689894 TI - T-Spot.TB outperforms tuberculin skin test in predicting development of active tuberculosis among household contacts. AB - BACKGROUND AND OBJECTIVE: In Hong Kong, neonatal Bacillus Calmette-Guerin (BCG) vaccination is practiced with 99% coverage. This study was to compare the performance of T-Spot.TB and tuberculin skin test (TST) in predicting tuberculosis (TB) among household contacts. METHODS: From 1 March 2006 to 31 July 2010, 1049 asymptomatic household contacts of smear-positive patients were simultaneously tested with T-Spot.TB and TST, and then followed for up to 5 years for development of TB. Attending clinicians and subjects were blinded to the results of T-Spot.TB. RESULTS: T-Spot.TB gave a significantly higher positive rate (32.7% vs 22.1%) and better association with exposure time than TST at the 15 mm cut-off. Agreement between T-Spot.TB and TST using cut-offs of 5, 10 and 15 mm were relatively poor (kappa 0.25-0.41) irrespective of presence or absence of BCG scar. Only T-Spot.TB positivity was negatively associated with BCG scar. Both T-Spot.TB (incidence rate ratio between test-positive and test-negative subjects, IRR: 8.2) and TST (IRR: 4.1, 6.1 and 2.8, using cut-offs of 5 mm, 10 mm and 15 mm, respectively) helped to predict TB. Using a TST cut-off of 15 mm, 56% of future TB cases and 62.5% of bacteriologically confirmed cases were missed. Lowering the TST cut-off to 10 mm or 5 mm could achieve sensitivity comparable with that of T-Spot.TB, but at the expense of lower specificities, with more positive tests (thus requiring treatment) per case of TB predicted. CONCLUSIONS: T-Spot.TB outperformed TST in predicting TB among household contacts in a high income area with widespread BCG vaccination coverage. PMID- 25689895 TI - Seminal fluid: a useful source of prostate cancer biomarkers? PMID- 25689896 TI - TMEM: a novel breast cancer dissemination marker for the assessment of metastatic risk. PMID- 25689897 TI - MyCartis NV. AB - MyCartis NV, a new player on the clinical and translational research market, aims at revolutionizing current healthcare systems. These are mostly based on treating the diseased rather than on caring better and longer for the healthy. The 'one size fits all' model is no longer sufficient and is unsustainable in the long run. Although it comes very scattered, today's access to molecular information has the potential to make healthcare more personal and effective, shifting it from treating diseases to improving quality of life. MyCartis wants to contribute to this process by developing broadly available next generation multiplex biomarker analysis solutions both at the technical and content levels. The EvalutionTM platform provides a 'one technology fits all' solution to enable researchers to validate their biomarkers and assay providers to utilize them, no matter their physical nature: multiplexing in its true sense. The ability to quantify different types of markers on a single platform will help produce more comprehensive and coherent multiplex datasets, which will facilitate the integration into syndromic assay formats. PMID- 25689898 TI - Plasma near-infrared spectroscopy for diagnosis of idiopathic Parkinson's disease: the SPIN-PD study. AB - AIM: There are no established chemical biomarkers of idiopathic Parkinson's disease (PD). The results of a prior metabolomics-based biomarker study suggested that near-infrared spectroscopy of blood plasma samples may distinguish idiopathic PD from neurologically normal controls. METHODS: Near-infrared spectroscopy was used to detect and quantify substrate modifications in blood plasma samples derived from 71 PD subjects enrolled in the PostCEPT observational study and 68 normal control subjects. RESULTS: Near-infrared spectra values were significantly higher in the PD group compared with the control group when adjusted for age and gender (PD: adjusted mean 0.49 [95% CI: 0.45-0.53]; control: adjusted mean 0.40 [95% CI: 0.36-0.44]; p = 0.004, multiple regression). CONCLUSION: Near-infrared spectra of blood plasma in early-stage idiopathic PD differ from those of non-neurological control subjects. However, the degree of overlap between the groups limits the use of this technique in its present form as a PD biomarker for routine clinical practice. PMID- 25689899 TI - Four-year stability of anthropometric and cardio-metabolic parameters in a prospective cohort of older adults. AB - AIM: To examine the medium-term stability of anthropometric and cardio-metabolic parameters in the general population. MATERIALS & METHODS: Participants were 5160 men and women from the English Longitudinal Study of Ageing (age >=50 years) assessed in 2004 and 2008. Anthropometric data included height, weight, BMI and waist circumference. Cardio-metabolic parameters included blood pressure, serum lipids (total cholesterol, HDL, LDL, triglycerides), hemoglobin, fasting glucose, fibrinogen and C-reactive protein. RESULTS: Stability of anthropometric variables was high (all intraclass correlations >0.92), although mean values changed slightly (-0.01 kg weight, +1.33 cm waist). Cardio-metabolic parameters showed more variation: correlations ranged from 0.43 (glucose) to 0.81 (HDL). The majority of participants (71-97%) remained in the same grouping relative to established clinical cut-offs. CONCLUSION: Over a 4-year period, anthropometric and cardio-metabolic parameters showed good stability. These findings suggest that when no means to obtain more recent data exist, a one-time sample will give a reasonable approximation to average levels over the medium-term, although reliability is reduced. PMID- 25689900 TI - Cardiotrophin-1 is associated with increased risk of arterial stiffness. AB - AIM: Cardiotrophin-1 null mice presented decreased arterial stiffness. The aim of this study is to investigate the relationship between cardiotrophin-1 and arterial stiffness, assessed by brachial-ankle pulse-wave velocity (baPWV). METHODS: We enrolled 300 subjects, 200 with baPWV >1400 and 100 with baPWV <=1400 cm/s. RESULTS: Cardiotrophin-1 levels were significantly higher in subjects with baPWV >1400 than those with baPWV <=1400 cm/s. The multivariate logistic regression analysis showed that age, prehypertension, hypertension and cardiotrophin-1 were independently associated with baPWV >1400 cm/s after adjusting for gender, obesity, diabetes, homeostasis model assessment-insulin resistance, total cholesterol, high-density lipoprotein cholesterol, triglyceride, high-sensitivity C-reactive protein, creatinine, smoking and habitual exercise. CONCLUSION: Cardiotrophin-1 is positively related to baPWV independent of traditional cardiometabolic risk factors for arterial stiffness. PMID- 25689901 TI - Circulating microRNAs: potential biomarkers for common malignancies. AB - MicroRNAs (miRNAs) belong to a class of small noncoding RNAs (ncRNAs), which regulate gene expression at the post-transcriptional level. They are approximately 22 nucleotide sequences in length and have been predicted to control expression of up to 30-60% of all protein-coding genes in mammals. Considering this wide involvement in gene control, aberrant miRNA expression has a strong association with the presence and progression of a disease, hence generating much anticipation in using miRNAs as biomarkers for the diagnosis and prognosis of human cancers. The majority of these miRNAs are intracellular, but recently they have been discovered in bodily fluids. This review will provide an insight into these circulatory miRNA molecules and discuss their potential as cancer biomarkers. PMID- 25689902 TI - Lipidomics applications for disease biomarker discovery in mammal models. AB - Lipidomics is a lipid-targeted metabolomics approach focusing on comprehensive analysis of all lipids with which they interact in biology systems. Recent technological advances in MS and chromatography have greatly enhanced the developments and applications of metabolic profiling of diverse lipids in complex biological samples. Lipidomics will not only provide insights into the specific functions of lipid species in health and disease, but will also identify potential biomarkers for establishing preventive or therapeutic programs for human disease. In this review, recent applications of lipidomics to understand animal models of disease such as metabolic syndromes, neurodegenerative diseases, cancer and infectious diseases are considered. We also discuss the lipidomics for the future perspectives and their potential problems. PMID- 25689903 TI - Plant vacuoles. PMID- 25689904 TI - Whisking. AB - Eyes may be 'the window to the soul' in humans, but whiskers provide a better path to the inner lives of rodents. The brain has remarkable abilities to focus its limited resources on information that matters, while ignoring a cacophony of distractions. While inspecting a visual scene, primates foveate to multiple salient locations, for example mouths and eyes in images of people, and ignore the rest. Similar processes have now been observed and studied in rodents in the context of whisker-based tactile sensation. Rodents use their mechanosensitive whiskers for a diverse range of tactile behaviors such as navigation, object recognition and social interactions. These animals move their whiskers in a purposive manner to locations of interest. The shapes of whiskers, as well as their movements, are exquisitely adapted for tactile exploration in the dark tight burrows where many rodents live. By studying whisker movements during tactile behaviors, we can learn about the tactile information available to rodents through their whiskers and how rodents direct their attention. In this primer, we focus on how the whisker movements of rats and mice are providing clues about the logic of active sensation and the underlying neural mechanisms. PMID- 25689905 TI - Molecular evidence for the loss of three basic tastes in penguins. AB - Sensing its biotic and abiotic environmental cues is critical to the survival and reproduction of any organism. Of the five traditionally recognized senses of vertebrates, taste is dedicated to the differentiation between nutritious and harmful foods, triggering either appetitive or rejective behaviors. Vertebrates typically can detect five basic taste qualities: sweet, umami, bitter, sour and salty. Remarkable progress in understanding the molecular basis of taste has opened the door to inferring taste abilities from genetic data. Based on genome and relevant gene sequences, we infer that the sweet, umami, and bitter tastes have been lost in all penguins, an order of aquatic flightless birds originating and still occupying the coldest ecological niche on Earth, the Antarctic. PMID- 25689906 TI - Spatial cognition: a tabula rasa for the sense of direction. AB - Two recent studies have shown that neurons which fire in a compass-like way--head direction cells--are present before rat pups open their eyes. Upon eye opening, the firing direction of these cells is anchored rapidly to visual landmarks. PMID- 25689907 TI - Olfaction: smells like fly food. AB - Fruit flies love foods containing yeast. A new study now shows that they are attracted to and have dedicated olfactory neurons for detecting the scents produced by yeast metabolizing common phenolic compounds in fruit. PMID- 25689908 TI - Neuromodulation: letting sources of spinal dopamine speak for themselves. AB - A recent study of dopaminergic neurons in the brain of larval zebrafish has important implications for interpreting the natural actions of neuromodulators in the spinal cord. PMID- 25689909 TI - Photoreceptor evolution: ancient 'cones' turn out to be rods. AB - Vertebrate rod photoreceptors are thought to have evolved from cone photoreceptors only after the divergence of the jawed and jawless fishes, but this idea is questioned by new evidence that the short 'cones' of jawless sea lampreys are physiologically equivalent to rods. PMID- 25689910 TI - Membrane trafficking: ER export encounters dualism. AB - Cytoplasmic coat protein complexes perform central roles in sorting protein constituents within the endomembrane system. A new study reveals that the COPII coat operates through dual recognition of signals in a sorting receptor and its bound cargo to promote efficient export from the endoplasmic reticulum. PMID- 25689911 TI - Sensory neurobiology: demystifying the sick sense. AB - The vomeronasal organ, a sensory structure within the olfactory system, detects chemical signals that affect social and sexual behaviors and that elicit responses to predator odors. A recent study demonstrates that innate avoidance of sick conspecifics requires an intact vomeronasal organ, expanding the repertoire of biological functions known to be mediated by this olfactory subsystem. PMID- 25689912 TI - Blindsight: post-natal potential of a transient pulvinar pathway. AB - More vision is preserved after removal of primary visual cortex in infant than adult primates. A recent study suggests that this is due to the preservation of a retina-to-pulvinar-to-cortex pathway that normally regresses during development. PMID- 25689913 TI - Cognitive neuroscience: integration of sight and sound outside of awareness? AB - A recent study found that auditory and visual information can be integrated even when you are completely unaware of hearing or seeing the paired stimuli--but only if you have received prior, conscious exposure to the paired stimuli. PMID- 25689914 TI - Sensorimotor control: retuning the body-world interface. AB - A new study reveals the action of a rapid process by which our perceptual systems adapt to improve the localization of touches when our limbs are in novel postures. PMID- 25689915 TI - Microtubule minus-end-targeting proteins. AB - Microtubules are cytoskeletal filaments that are intrinsically polarized, with two structurally and functionally distinct ends, the plus end and the minus end. Over the last decade, numerous studies have shown that microtubule plus-end dynamics play an important role in many vital cellular processes and are controlled by numerous factors, such as microtubule plus-end-tracking proteins (+TIPs). In contrast, the cellular machinery that controls the behavior and organization of microtubule minus ends remains one of the least well-understood facets of the microtubule cytoskeleton. The recent characterization of the CAMSAP/Patronin/Nezha family members as specific 'minus-end-targeting proteins' ('-TIPs') has provided important new insights into the mechanisms governing minus end dynamics. Here, we review the current state of knowledge on how microtubule minus ends are controlled and how minus-end regulators contribute to non centrosomal microtubule organization and function during cell division, migration and differentiation. PMID- 25689916 TI - Reactivity of TCNE and TCNQ derivatives of quinonoid zwitterions with Cu(I). AB - The reactions of TCNE- and TCNQ-functionalized (TCNE: tetracyanoethylene and TCNQ: 7,7',8,8'-tetracyanoquinodimethane) zwitterionic benzoquinonemonoimines with a Cu(I)-BIAN complex (BIAN = bis(o,o' bisisopropylphenyl)acenaphthenequinonediimine) have been investigated and found to follow a diversity of interesting patterns. The complexes [Cu(BIAN)(NCMe)(L2)]BF4 (2) and [Cu(BIAN)(L2)2]BF4 (4) were obtained by reacting [Cu(BIAN)(NCMe)2]BF4 (1) with one and two equivalents of L2, respectively. Following similar procedures, the complexes [Cu(BIAN)(NCMe)(L3)]BF4 (6) and [Cu(BIAN)(L3)2]BF4 (7) were obtained by reaction of 1 with L3. The reaction of 2 with 0.5 equiv. of 4,4'-bipyridine afforded [{Cu(BIAN)(L2)}2(MU-4,4' bipyridine)](BF4)2 (3). The complexes were characterized by multinuclear NMR, IR and UV-Vis spectroscopic techniques, mass spectrometry, cyclic voltammetry and elemental analysis. The molecular structures of complexes 3 .4CH2Cl2 and 4 .CH2Cl2 were determined by single crystal X-ray diffraction. An unexpected coordination polymer [Cu((L2-))2]infinity (5) was also structurally characterized, which contains Cu(II) centres chelated by two N,O-bound ligands resulting from the monodeprotonation of L2. PMID- 25689917 TI - Beneficial effect of lycopene on anti-diabetic nephropathy through diminishing inflammatory response and oxidative stress. AB - Lycopene is widely used for nutritional supplementation, but the potential benefits in diabetic nephropathy (DN) remains unknown. This study aimed to highlight the therapeutic prospect of lycopene against streptozotocin (STZ) induced kidney injury in mice. During the process of the experiments, biochemical kits were employed to determine the diabetes-metabolic parameters in STZ-lesioned mice. Routine pathological and ultrastructural observations were screened for the histological changes of kidney tissue. Moreover, immunohistochemical staining was used to investigate the inflammatory conditions expressed in kidney tissue. Furthermore, intrarenal heme oxygenase 1 (HO-1) mRNA level was assayed via RT-PCR and Western blot analyses. The results showed that lycopene alleviated the lesioned signs of DN mice induced by STZ, accompanied with the increase in body weight, reduced serum concentrations of blood sugar and low-density lipoprotein cholesterol (LDL-C), elevated high-density lipoprotein cholesterol (HDL-C) level, and the decrease in urine protein content. In addition, oxidative defense patterns in the kidneys of DN mice were ameliorated, as shown in augmented bioactivities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and in turn lowered malondialdehyde (MDA) content. The immunohistochemical experiment exhibited that lycopene intake contributed to attenuation of nuclear factor-kappa B (NF-kappaB) and tumor necrosis factor alpha (TNF-alpha) expressions in kidney tissue. Moreover, intrarenal HO-1 level was up-regulated in the presence of lycopene. Our findings provide the evidence that lycopene protects kidney cells from STZ-induced lesions via inhibiting NF-kappaB signal pathway for anti inflammation and attenuating oxidative stress for anti-dysmetabolism. PMID- 25689918 TI - Utilization of reverse osmosis (RO) for reuse of MBR-treated wastewater in irrigation-preliminary tests and quality analysis of product water. AB - Membrane bioreactor (MBR) effluent collected from a wastewater treatment plant installed at an industrial zone was used for reverse osmosis (RO) membrane tests in the laboratory. For this, two different GE Osmonics RO membranes (AK-BWRO and AD-SWRO) were employed. The results showed that AK-brackish water reverse osmosis (AK-BWRO) and AD-seawater reverse osmosis (AD-SWRO) membranes have almost similar rejection performances regarding analyzed parameters such as conductivity, salinity, color, chemical oxygen demand (COD), and total organic carbon (TOC). On the other hand, these membranes behaved quite differently considering their permeate water flux at the same applied pressure of 10 bar. AD-SWRO membrane was also tested at 20 bar. The results revealed that AD-SWRO membrane had almost the same rejections either at 10 or at 20 bar of applied pressure. Compared with irrigation water standards, AK-BWRO and AD-SWRO gave an effluent with low salinity value and sodium adsorption ratio (SAR) which makes it unsuitable for irrigation due to the infiltration problems risi0ng from unbalanced values of salinity and SAR. Combination of MBR effluent and RO effluent at respective proportions of 0.3:0.7 and 0.4:0.6 for AK-BWRO and AD-SWRO, respectively, are the optimum mixing ratios to overcome the infiltration hazard problem. Choice of less sensitive crops to chloride and sodium ions is another strategy to overcome all hazards which may arise from above suggested mixing proportions. PMID- 25689919 TI - Clinical features of pancreatic neuroendocrine tumors. AB - Pancreatic neuroendocrine tumors (PNETs), also known as islet cell tumors, are rare neoplasms that arise in the endocrine tissues of the pancreas. Most of pancreatic NETs (50-75%) are nonfunctioning (not associated with a hormonal clinical syndrome); however, in up to one third they can secrete a variety of peptide hormones, including insulin, gastrin, glucagon, vasoactive intestinal peptide, somatostatin etc., resulting in rare but unique clinical syndromes. In this article, the clinical features of the different types of PNETs will be reviewed. Other aspects of the management of these tumors (surgery, treatment of advanced disease, tumor localization) are not dealt with here, as they are covered by other papers in this volume. PMID- 25689920 TI - Contemporary diagnostics: sarcoma pathology update. AB - Sarcoma diagnosis continues to evolve as new information is discovered. Certain tumors have been downgraded (dermal leiomyosarcoma) and an atypical category designed for others. Recently entities include myxoinflammatory fibroblastic sarcoma, myoepithelioma, and pseudomyogenic hemangioendothelioma. The terms malignant fibrous histiocytoma and hemangiopericytoma are outdated. New immunostains (STAT6, SOX10, ERG) add diagnostic specificity, and new risk assessment models are described for sarcomas where grading and staging has failed to provide adequate prognosis. PMID- 25689921 TI - Cytomorphology of neuroendocrine tumours of the gallbladder. AB - OBJECTIVE: Gallbladder neuroendocrine tumours (GB-NETs) are rare and account for 0.5% of all NETs. GB-NETs have an aggressive behaviour, which depends on the tumour grade. The cytomorphological spectrum of these tumours has never been described in detail. The present study evaluates the cytological features of GB NETs and grades them according to the World Health Organization (WHO) classification. Furthermore, the expression of thyroid transcription factor-1 (TTF-1) has not been investigated previously in GB-NETs, although found in a subset of extrapulmonary NETs. METHODS: Twenty cases of GB-NET among 875 gallbladder carcinomas diagnosed by ultrasound-guided fine needle aspiration cytology (FNAC) over a period of nearly 4 years were studied. The following parameters were evaluated: architectural pattern, nuclear chromatin, nucleoli, mitoses, necrosis, moulding, apoptosis and smudge cells. Cases were categorized into well-differentiated (grades 1 and 2), small cell carcinoma (SCC) (grade 3) and mixed adenoneuroendocrine carcinoma. Nuclear positivity for TTF-1 was considered as positive. RESULTS: Morphologically, tumour cells were mainly arranged in rosettes in the well-differentiated category; sudden anisonucleosis and rare nuclear moulding with or without mitotic figures were other features. Eleven cases of SCC showed prominent nuclear moulding with frequent smudge cells, mitoses, apoptosis and necrosis. Three mixed adenoneuroendocrine carcinomas showed papillary fragments and an acinar arrangement of tumour cells. Four of the nine SCCs in which TTF-1 was evaluated on de-stained smears showed nuclear positivity. Histopathology was available in two SCCs and showed morphology similar to FNAC. CONCLUSION: Cytology plays an important role in the diagnosis of GB-NETs for appropriate subtype characterization, which is necessary for the prognostication of these tumours. TTF-1 may not be used for the differentiation of gallbladder SCCs from pulmonary SCCs. PMID- 25689922 TI - Ecotype variability in growth and secondary metabolite profile in Moringa oleifera: impact of sulfur and water availability. AB - Moringa oleifera is widely cultivated in plantations in the tropics and subtropics. Previous cultivation studies with M. oleifera focused primarily only on leaf yield. In the present study, the content of potentially health-promoting secondary metabolites (glucosinolates, phenolic acids, and flavonoids) were also investigated. Six different ecotypes were grown under similar environmental conditions to identify phenotypic differences that can be traced back to the genotype. The ecotypes TOT4880 (origin USA) and TOT7267 (origin India) were identified as having the best growth performance and highest secondary metabolite production, making them an ideal health-promoting food crop. Furthermore, optimal cultivation conditions-exemplarily on sulfur fertilization and water availability for achieving high leaf and secondary metabolite yields were investigated for M. oleifera. In general, plant biomass and height decreased under water deficiency compared to normal cultivation conditions, whereas the glucosinolate content increased. The effects depended to a great extent on the ecotype. PMID- 25689923 TI - Noradrenergic alpha2 receptor attenuated inflammatory pain through STEP61/ERK signalling. AB - BACKGROUND: Activation of noradrenergic alpha2 receptor in spinal dorsal horn effectively alleviates the pathological pain. However, the precise mechanisms underlying noradrenergic pain suppression are not fully understood. Convincing evidence has indicated that extracellular signal-regulated kinases 1 and 2 (ERK1/2) play a key role in spinal sensitization. The present study investigated the potential influence of noradrenergic alpha2 receptor agonist clonidine on ERK1/2 activity. METHOD: Clonidine was intrathecally given after intraplantar injection of complete Freund's adjuvant (CFA) in mice. The possible changes of ERK1/2 signalling were detected by Western blot, immunohistochemistry, co immunoprecipitation and behavioural tests. RESULTS: CFA significantly enhanced ERK1/2 activity in spinal dorsal horn, which was, however, greatly attenuated by clonidine application. Pretreatment with pertussis toxin abolished the inhibitory effect of clonidine on ERK1/2, suggesting the involvement of Gialpha subunit (Gi protein). Noradrenergic alpha2 receptor/Gi protein might repress ERK1/2 through cAMP-dependent protein kinase (PKA) pathway, because direct ERK1/2 activation by PKA agonist forskolin was also suppressed by clonidine. We found that 61 kD isoform of striatal-enriched protein phosphatase (STEP61) was a key intermediary for alpha2 receptor/Gi protein/PKA signalling to manipulate ERK1/2 activity. By reducing PKA-mediated phosphorylation of STEP61 at Ser221, clonidine significantly resumed the inhibition conferred by STEP61 on ERK1/2. Direct expression of STEP61 mutant devoid of Ser221 phosphorylation mimicked clonidine by inhibiting ERK1/2 and pain sensitization in CFA-injected mice. CONCLUSION: The analgesic action produced by noradrenergic alpha2 receptor agonist clonidine involved the reversal of ERK1/2 hyperactivity in spinal dorsal horn of inflamed mice. PMID- 25689924 TI - Y-chromosome diversity in Catalan surname samples: insights into surname origin and frequency. AB - The biological behavior of the Y chromosome, which is paternally inherited, implies that males sharing the same surname may also share a similar Y chromosome. However, socio-cultural factors, such as polyphyletism, non paternity, adoption, or matrilineal surname transmission, may prevent the joint transmission of the surname and the Y chromosome. By genotyping 17 Y-STRs and 68 SNPs in ~2500 male samples that each carried one of the 50 selected Catalan surnames, we could determine sets of descendants of a common ancestor, the population of origin of the common ancestor, and the date when such a common ancestor lived. Haplotype diversity was positively correlated with surname frequency, that is, rarer surnames showed the strongest signals of coancestry. Introgression rates of Y chromosomes into a surname by non-paternity, adoption, and transmission of the maternal surname were estimated at 1.5-2.6% per generation, with some local variation. Average ages for the founders of the surnames were estimated at ~500 years, suggesting a delay between the origin of surnames (twelfth and thirteenth centuries) and the systematization of their paternal transmission. We have found that, in general, a foreign etymology for a surname does not often result in a non-indigenous origin of surname founders; however, bearers of some surnames with an Arabic etymology show an excess of North African haplotypes. Finally, we estimate that surname prediction from a Y chromosome haplotype, which may have interesting forensic applications, has a ~60% sensitivity but a 17% false discovery rate. PMID- 25689925 TI - Quality issues concerning genetic counselling for presymptomatic testing: a European Delphi study. AB - Genetic counselling for presymptomatic testing is complex, bringing both ethical and practical questions. There are protocols for counselling but a scarcity of literature regarding quality assessment of such counselling practice. Generic quality assessment tools for genetic services are not specific to presymptomatic testing (PST). Therefore, the aim of this study was to identify aspects of effective counselling practice in PST for late-onset neurological disorders. We used the Delphi method to ascertain the views of relevant European experts in genetic counselling practice, ascertained via published literature and nomination by practitioners. Ethical approval was obtained. Questionnaires were sent electronically to a list of 45 experts, (Medical Doctors, Geneticists, Genetic Counsellors and Genetic Nurses), who each contributed to one to three rounds. In the first round, we provided a list of relevant indicators of quality of practice from a literature review. Experts were requested to evaluate topics in four domains: (a) professional standards; (b) service standards; (c) the consultant's perspective; and (d) protocol standards. We then removed items receiving less than 65% approval and added new issues suggested by experts. The second round was performed for the refinement of issues and the last round was aimed at achieving final consensus on high-standard indicators of quality, for inclusion in the assessment tool. The most relevant indicators were related to (1) consultant centred practice and (2) advanced counselling and interpersonal skills of professionals. Defined high-standard indicators can be used for the development of a new tool for quality assessment of PST counselling practice. PMID- 25689926 TI - Comprehensive clinical studies in 34 patients with molecularly defined UPD(14)pat and related conditions (Kagami-Ogata syndrome). AB - Paternal uniparental disomy 14 (UPD(14)pat) and epimutations and microdeletions affecting the maternally derived 14q32.2 imprinted region lead to a unique constellation of clinical features such as facial abnormalities, small bell shaped thorax with a coat-hanger appearance of the ribs, abdominal wall defects, placentomegaly, and polyhydramnios. In this study, we performed comprehensive clinical studies in patients with UPD(14)pat (n=23), epimutations (n=5), and microdeletions (n=6), and revealed several notable findings. First, a unique facial appearance with full cheeks and a protruding philtrum and distinctive chest roentgenograms with increased coat-hanger angles to the ribs constituted the pathognomonic features from infancy through childhood. Second, birth size was well preserved, with a median birth length of +/-0 SD (range, -1.7 to +3.0 SD) and a median birth weight of +2.3 SD (range, +0.1 to +8.8 SD). Third, developmental delay and/or intellectual disability was invariably present, with a median developmental/intellectual quotient of 55 (range, 29-70). Fourth, hepatoblastoma was identified in three infantile patients (8.8%), and histological examination in two patients showed a poorly differentiated embryonal hepatoblastoma with focal macrotrabecular lesions and well-differentiated hepatoblastoma, respectively. These findings suggest the necessity of an adequate support for developmental delay and periodical screening for hepatoblastoma in the affected patients, and some phenotypic overlap between UPD(14)pat and related conditions and Beckwith-Wiedemann syndrome. On the basis of our previous and present studies that have made a significant contribution to the clarification of underlying (epi)genetic factors and the definition of clinical findings, we propose the name 'Kagami-Ogata syndrome' for UPD(14)pat and related conditions. PMID- 25689927 TI - CHARGE syndrome: a review of the immunological aspects. AB - CHARGE syndrome is caused by a dominant variant in the CHD7 gene. Multiple organ systems can be affected because of haploinsufficiency of CHD7 during embryonic development. CHARGE syndrome shares many clinical features with the 22q11.2 deletion syndrome. Immunological abnormalities have been described, but are generally given little attention in studies on CHARGE syndrome. However, structured information on immunological abnormalities in CHARGE patients is necessary to develop optimal guidelines for diagnosis, treatment and follow-up in these patients. Here, we provide an overview of the current literature on immunological abnormalities in CHARGE syndrome. We also explore immunological abnormalities in comparable multiple congenital anomaly syndromes to identify common immunological phenotypes and genetic pathways that might regulate the immune system. Finally, we aim to identify gaps in our knowledge on the immunological aspects in CHARGE syndrome that need further study. PMID- 25689928 TI - Clinical utility gene card for: CHARGE syndrome - update 2015. PMID- 25689929 TI - Reversal of enantioselective Friedel-Crafts C3-alkylation of pyrrole by slightly tuning the amide units of N,N'-dioxide ligands. AB - Chiral Ni(ii)-complexes of N,N'-dioxides show high catalytic activity and enantioselectivity in catalysing the asymmetric Friedel-Crafts C3-alkylation of 2,5-dimethyl pyrrole to beta,gamma-unsaturated alpha-ketoesters. A dramatic reversal of enantioselectivity is realized with ligands derived from the same type of chiral source of l-ramipril, by slightly tuning the amide units. PMID- 25689930 TI - The Development of Coordinated Communication in Infants at Heightened Risk for Autism Spectrum Disorder. AB - This study evaluated the extent to which developmental change in coordination of social communication in early infancy differentiates children eventually diagnosed with ASD from those not likely to develop the disorder. A prospective longitudinal design was used to compare nine infants at heightened risk for ASD (HR) later diagnosed with ASD, to 13 HR infants with language delay, 28 HR infants with no diagnosis, and 30 low risk infants. Hierarchical linear modeling analyses revealed that ASD infants exhibited significantly slower growth in coordinations overall and in gestures coordinated with vocalizations, even relative to HR infants with language delay. Disruption in the development of gesture-vocalization coordinations may result in negative cascading effects that adversely impact later social and linguistic development. PMID- 25689931 TI - The Scientometric Bubble Considered Harmful. AB - This article deals with a modern disease of academic science that consists of an enormous increase in the number of scientific publications without a corresponding advance of knowledge. Findings are sliced as thin as salami and submitted to different journals to produce more papers. If we consider academic papers as a kind of scientific 'currency' that is backed by gold bullion in the central bank of 'true' science, then we are witnessing an article-inflation phenomenon, a scientometric bubble that is most harmful for science and promotes an unethical and antiscientific culture among researchers. The main problem behind the scenes is that the impact factor is used as a proxy for quality. Therefore, not only for convenience, but also based on ethical principles of scientific research, we adhere to the San Francisco Declaration on Research Assessment when it emphasizes "the need to eliminate the use of journal-based metrics in funding, appointment and promotion considerations; and the need to assess research on its own merits rather on the journal in which the research is published". Our message is mainly addressed to the funding agencies and universities that award tenures or grants and manage research programmes, especially in developing countries. The message is also addressed to well established scientists who have the power to change things when they participate in committees for grants and jobs. PMID- 25689932 TI - Oxygen limitations on marine animal distributions and the collapse of epibenthic community structure during shoaling hypoxia. AB - Deoxygenation in the global ocean is predicted to induce ecosystem-wide changes. Analysis of multidecadal oxygen time-series projects the northeast Pacific to be a current and future hot spot of oxygen loss. However, the response of marine communities to deoxygenation is unresolved due to the lack of applicable data on component species. We repeated the same benthic transect (n = 10, between 45 and 190 m depths) over 8 years in a seasonally hypoxic fjord using remotely operated vehicles equipped with oxygen sensors to establish the lower oxygen levels at which 26 common epibenthic species can occur in the wild. By timing our surveys to shoaling hypoxia events, we show that fish and crustacean populations persist even in severe hypoxia (<0.5 mL L(-1) ) with no mortality effects but that migration of mobile species occurs. Consequently, the immediate response to hypoxia expansion is the collapse of community structure; normally partitioned distributions of resident species coalesced and localized densities increased. After oxygen renewal and formation of steep oxygen gradients, former ranges re established. High frequency data from the nearby VENUS subsea observatory show the average oxygen level at our site declined by ~0.05 mL L(-1) year(-1) over the period of our study. The increased annual duration of the hypoxic (<1.4 mL L(-1) ) and severely hypoxic periods appears to reflect the oxygen dynamics demonstrated in offshore source waters and the adjacent Strait of Georgia. Should the current trajectory of oxygen loss continue, community homogenization and reduced suitable habitat may become the dominant state of epibenthic systems in the northeast Pacific. In situ oxygen occurrences were not congruent with lethal and sublethal hypoxia thresholds calculated across the literature for major taxonomic groups indicating that research biases toward laboratory studies on Atlantic species are not globally applicable. Region-specific hypoxia thresholds are necessary to predict future impacts of deoxygenation on marine biodiversity. PMID- 25689933 TI - Genetic interaction between Pax6 and beta-catenin in the developing retinal pigment epithelium. AB - Wnt/beta-catenin signaling plays an essential role in the retinal pigment epithelium (RPE) determination. Since activity of Pax6 (together with Pax2) is also required for the RPE determination, we investigated a possible genetic interaction between Pax6 and Wnt/beta-catenin signaling pathway by analyzing Pax6, beta-catenin, and Pax6/beta-catenin conditional knockout mice. Although Pax6 inactivation alone had no impact on initial specification determined by the expression of Mitf and Otx2, melanin pigmentation was reduced in the RPE. This suggests that along with Mitf and Otx2, Pax6 is required for the full differentiation of RPE. Reporter gene assays in vitro suggest that hypopigmentation is at least in part due to the direct regulation of genes encoding enzymes involved in melanin synthesis by Pax6, Mitf, and beta-catenin. The RPE of a beta-catenin/Pax6 double mutant was differentiated into the neural retina; however, the tissue was thinner than that of the conditional beta-catenin mutant due to reduced proliferation. Together, our data demonstrate that Pax6 is required for the RPE differentiation by regulating pigmentation and accountable for hyperproliferation in the transdifferentiated RPE. In this context, Pax6 appears to function as a pleiotropic regulator, directing development of ocular tissues in concert with the signaling pathway and, at the same time, regulating expression of structural component of the eye, such as shielding pigment. PMID- 25689934 TI - An alternative option for "resect and discard" strategy, using magnifying narrow band imaging: a prospective "proof-of-principle" study. AB - BACKGROUND: The "resect and discard" strategy is beneficial for cost savings on screening and surveillance colonoscopy, but it has the risk to discard lesions with advanced histology or small invasive cancer (small advanced lesion; SALs). The aim of this study was to prove the principle of new "resect and discard" strategy with consideration for SALs using magnifying narrow-band imaging (M NBI). METHODS: Patients undergoing colonoscopy at a tertiary center were involved in this prospective trial. For each detected polyp <10 mm, optical diagnosis (OD) and virtual management ("leave in situ", "discard" or "send for pathology") were independently made using non-magnifying NBI (N-NBI) and M-NBI, and next surveillance interval were predicted. Histological and optical diagnosis results of all polyps were compared. RESULTS: While the management could be decided in 82% of polyps smaller than 10 mm, 24/31 (77%) SALs including two small invasive cancers were not discarded based on OD using M-NBI. The sensitivity [90% confidence interval (CI)] of M-NBI for SALs was 0.77 (0.61-0.89). The risk for discarding SALs using N-NBI was significantly higher than that using M-NBI (53 vs. 23%, p = 0.02). The diagnostic accuracy (95% CI) of M-NBI in distinguishing neoplastic from non-neoplastic lesions [0.88 (0.86-0.90)] was significantly better than that of N-NBI [0.84 (0.82-0.87)] (p = 0.005). CONCLUSIONS: The results of our study indicated that our "resect and discard" strategy using M-NBI could work to reduce the risk for discarding SALs including small invasive cancer (UMIN-CTR, UMIN000003740). PMID- 25689935 TI - Helicobacter pylori infection causes hepatic insulin resistance by the c-Jun/miR 203/SOCS3 signaling pathway. AB - BACKGROUND: Epidemiological studies have indicated that patients with chronic Helicobacter pylori infection have an increased risk of developing type 2 diabetes mellitus, but the underlying mechanisms remain largely unknown. This study aimed to investigate whether H. pylori infection contributes to the development of insulin resistance, as well as the underlying mechanisms both in vivo and in vitro. METHODS: The effect of H. pylori infection on glucose metabolism was evaluated in humans and mouse models. The role of the c-Jun/miR 203/suppressor of cytokine signaling 3 (SOCS3) pathway in H. pylori-induced insulin resistance was determined in vitro and was validated in vivo. RESULTS: Average fasting glucose levels were increased in patients (P = 0.012) and mice (P = 0.004) with H. pylori infection. Diabetic mice with H. pylori infection showed impaired glucose metabolism and insulin tolerance and hyperinsulinemia. Furthermore, H. pylori infection impaired insulin signaling in primary hepatocytes. H. pylori infection could upregulate SOCS3, a well-known insulin signaling inhibitor, by downregulating miR-203. SOCS3 overexpression interfered with insulin signaling proteins, and knockdown of SOCS3 alleviated H. pylori induced impairment of insulin signaling. The transcription factor c-Jun, which affects gene expression, was induced by H. pylori infection and suppressed miR 203 expression. CONCLUSIONS: Our results demonstrated that H. pylori infection induced hepatic insulin resistance by the c-Jun/miR-203/SOCS3 signaling pathway and provide possible implications with regard to resolving insulin resistance. PMID- 25689936 TI - Can serum albumin level affect the pharmacological action of tolvaptan in patients with liver cirrhosis? A post hoc analysis of previous clinical trials in Japan. AB - BACKGROUND: Patients with hypoalbuminemia often fail to respond to increased doses of loop diuretics. We therefore performed a post hoc analysis to investigate the pharmacological action of tolvaptan and whether it is dependent on the serum albumin level. METHODS: This analysis was based on four previous clinical trials of tolvaptan in patients with liver cirrhosis who exhibited insufficient response to conventional diuretics. We analyzed the correlation between the change in the initial 24-h cumulative urine volume from baseline and the serum albumin level at baseline, and assessed potential predictive factors of response to tolvaptan. RESULTS: The correlation coefficient was 0.029 in the placebo group and -0.112 in the 7.5 mg tolvaptan group of patients with liver cirrhosis. Administration of tolvaptan provoked a stable response regardless of the serum albumin level. Tolvaptan use was identified as a significant predictor of pharmacological action, and was shown to change the initial urine volume by 885 mL (P < 0.0001) in liver cirrhosis patients. CONCLUSIONS: In this post hoc analysis, tolvaptan increased the initial urine volume from baseline regardless of serum albumin levels. Use of tolvaptan as an add-on therapy to loop diuretics can be considered an optimal therapeutic option in patients with insufficient response to loop diuretics. PMID- 25689937 TI - Fetal middle cerebral artery and umbilical artery pulsatility index: effects of maternal characteristics and medical history. AB - OBJECTIVE: To define the contribution of maternal variables which influence the measured fetal middle cerebral artery (MCA) and umbilical artery (UA) pulsatility index (PI) in the assessment of fetal wellbeing. METHODS: Maternal characteristics and medical history were recorded and fetal MCA-PI and UA-PI (n = 36,818) were measured in women with singleton pregnancies attending a routine hospital visit at 30 + 0 to 37 + 6 weeks' gestation. For pregnancies delivering phenotypically normal live births or stillbirths >= 30 weeks' gestation, variables among maternal demographic characteristics and medical history that are important in the prediction of MCA-PI and UA-PI were determined by multiple linear regression analysis. RESULTS: Significant independent contributions to MCA PI were provided by gestational age at assessment, East Asian racial origin, being parous and birth-weight Z-score of the neonate of the previous pregnancy. Significant independent contributions to UA-PI were provided by gestational age at assessment, Afro-Caribbean, East Asian and mixed racial origin, cigarette smoking, being parous and birth-weight Z-score of the neonate of the previous pregnancy. Multiple linear regression analysis was used to define the contribution of maternal variables that influence the measured MCA-PI and UA-PI and express the values as multiples of the median (MoMs). The cerebroplacental ratio (CPR) MoM was calculated by dividing MCA-PI MoM by UA-PI MoM. The model was shown to provide an adequate fit of MoM values for all covariates, both in pregnancies that delivered small-for-gestational-age neonates and in those without this pregnancy complication. CONCLUSIONS: A model was fitted to express MCA-PI, UA-PI and CPR as MoMs after adjusting for variables from maternal characteristics and medical history that affect this measurement. PMID- 25689938 TI - Traumatic injury pattern analysis in a light rail transit death: a retrospective case study. AB - Within the context of medical examiner's offices, forensic anthropologists are increasingly being asked to assist with the interpretation of traumatic skeletal injury. This case study presents an example of trauma analysis performed by forensic anthropologists at the Maricopa County Forensic Science Center in Phoenix, Arizona. The primary goal of this study is to document an uncommon pattern of traumatic injury-severe grinding abrasions of the lower appendage that macroscopically resemble sharp force trauma, especially as observed in dismemberment cases-resulting from an individual being dragged beneath a Light Rail train for c. 1.7 miles. The abraded skeletal elements include a femoral shaft fragment, a femoral head portion, and the right foot. Second, this study aims to illustrate the efficacy of forensic anthropological analysis of patterned skeletal trauma. Finally, this study demonstrates the critical importance of analyzing scene information before drawing conclusions as to the etiology of a traumatic injury pattern. PMID- 25689939 TI - Laser radiation effect on chondrocytes and intercellular matrix of costal and articular cartilage impregnated with magnetite nanoparticles. AB - BACKGROUND AND OBJECTIVE: Magnetic nanoparticles with the ability to absorb laser radiation are the perspective agents for the early diagnostics and laser therapy of degenerative cartilage. The effect of starch stabilized magnetite nanoparticles (SSNPs) on the cartilage structure components has never been studied before. The aim of the work is to establish the Erbium:glass laser effect on costal and articular cartilage impregnated with SSNPs. MATERIALS AND METHODS: Porcine articular and costal cartilage disks (2.0 mm in diameter and 1.5-2 mm in thickness) were impregnated with SSNPs and irradiated using a 1.56 MUm laser in therapeutic laser setting. The one sample group underwent the second irradiation after the SSNPs impregnation. The samples were analyzed by the means of histology, histochemistry and transmission electron microscopy (TEM) to reveal the alterations of cells, glycosaminoglycans and collagen network. RESULTS: The irradiated cartilage demonstrates the higher content of cell alterations than the intact one due to the heat and mechanical affection in the course of laser irradiation. However the alterations are localized at the areas near the irradiated surfaces and not dramatic. The impregnation of SSNPs does not cause any additional cell alterations. For both costal and articular cartilage the matrix alterations of irradiated samples are not critical: there is the slight decrease in acid proteoglycan content at the irradiated areas while the collagen network is not altered. Distribution and localization of impregnated SSNPs is described: agglomerates of 150-230 nm are observed located at the borders between matrix and cell lacunas of articular cartilage; SSNPs of 15-45 nm are found in the collagen network of costal cartilage. CONCLUSIONS: It was shown that SSNPs do not appreciably affect the structural components of both articular and costal cartilage and can be safely used for the laser diagnostics and therapy. The area of structural alterations is diffuse and local as the result of the mechanical and heat effect of laser impact. SSNPs reveal the areas of the structural alterations of cartilage matrix and give information about the size of the pores and defects. PMID- 25689940 TI - Third universal definition of myocardial infarction. PMID- 25689941 TI - Our time: a call to save preventable death from cardiovascular disease (heart disease and stroke). PMID- 25689942 TI - Why Do South Asians Have High Risk for CAD? AB - South Asians have a higher risk for coronary artery disease (CAD) due to both pathophysiological and life course-related risk factors. We performed a literature search and used qualitative synthesis to present evidence for CAD risk factors among South Asians. A large proportion of the higher risk of South Asians for CAD can be explained by conventional risk factors. However, several conditioning factors such as education, socioeconomic status, and fetal programming, and early life influences may contribute to excess CAD risk in South Asians, suggesting the need for a life course approach. Evidence on unconventional risk factors is provocative but comes from small studies. Large scale, well-designed epidemiological studies are needed for an in-depth understanding of the CAD risk among South Asians. PMID- 25689943 TI - The Asia pacific cohort studies collaboration: a decade of achievements. AB - The Asia Pacific Cohort Studies Collaboration (APCSC) was established in the late 1990s when there was a distinct shortfall in evidence of the importance of risk factors for cardiovascular disease in Asia. With few exceptions, most notably from Japan, most of the published reports on cardiovascular disease in the last century were from Western countries, and there was uncertainty how far etiological associations found in the West could be assumed to prevail in the East. Against this background, APCSC was set up as a pooling project, combining individual participant data (about 600,000 subjects) from all available leading cohort studies (36 from Asia and 8 from Australasia) in the region, to fill the knowledge gaps. In the past 10 years, APCSC has published 50 peer-reviewed publications of original epidemiological research, primarily concerned with coronary heart disease, stroke, and cancer. This work has established that Western risk factors generally act similarly in Asia and in Australasia, just as they do in other parts of the world. Consequently, strategies to reduce the prevalence of elevated blood pressure, obesity, and smoking are at least as important in Asia as elsewhere- and possibly more important when the vast size of Asia is considered. This article reviews the achievements of APCSC in the past decade, with an emphasis on coronary heart disease. PMID- 25689944 TI - Sudden cardiac death in low- and middle-income countries. AB - Cardiovascular disease, and the incidence of sudden cardiac death (SCD), will increase significantly in low- and middle-income countries (LMIC). Thus, SCD threatens to become a global public health problem. We present a summary of the current research that has investigated the epidemiology of SCD in LMIC. Few studies of SCD in LMIC exist, and they are of variable methodological quality. Risk factors for SCD are described, taking into account recent global burden of disease and risk factor statistics. We describe 1 proposal for a community-based, prospective, multiple-source methodology for SCD monitoring and surveillance that can be implemented in LMIC. Further research into the epidemiology of SCD in LMIC, using standardized methodology, would allow investigators and policy makers to determine the regions, communities, and individuals most at need for SCD prevention. Focusing on SCD and its prevention in LMIC should be a priority for the global health community. PMID- 25689945 TI - Trends in secondary prevention of coronary heart disease in Tunisia: prevention of recurrences of MI and stroke. AB - OBJECTIVES: The survival benefits achieved by prescription of antiplatelet agents, B-adrenoreceptor antagonists (beta-blockers), angiotensin II receptor blockers (ARB), and lipid lowering agents in patients surviving the myocardial infarction (MI) have been well documented in large clinical trial. Despite well established benefits, these pharmacological agents continue to be underutilized. The main objective of this study was to evaluate the progress of cardiovascular secondary prevention practices in Tunisia. METHODS: The PREMISE (Prevention of Recurrence of Myocardial Infarction and Stroke) is a descriptive, cross-sectional study conducted in Tunisia in two phases (2002 and 2009). Seven hundred eighty two patients were recruited. The recruitment criteria were: previous MI, stable angina, unstable angina, percutaneous transluminal coronary angioplasty (PTCA), coronary artery bypass graft (CABG), stroke, transient ischemic attack (TIA) or carotid endarterectomy. This analysis is limited to coronary heart disease (CHD) patients. Five hundred hospital patients were interviewed and their medical records were reviewed: 250 in 2002 and 250 in 2009. Patients were included if they had confirmed diagnosis of MI, angina, CABG or PTCA, and if their first cardiovascular event had occurred more than one month but not later than 3 years ago. We compared the total of both patient groups, using the prevalence of Cardio Vascular Risk Factors (CVRF) and the treatment prescribed at hospital discharge. RESULTS: The proportion of patients with reported hypertension, diabetes, hypercholesterolemia and current smoker patients had decreased. Concerning pharmacological prescriptions, a significant increase was observed in prescribing statins (38.9% vs. 70.3%) and ACE inhibitors (49.3% vs. 69.9%), non pharmacological prescriptions as healthy diet or tobacco cessation had opposite trends. Adherence to treatment did not change substantially. CONCLUSION: Although the use of cardioprotective drugs had increased in CHD patients, there are still gaps in secondary prevention in Tunisia. The recommended strategies of secondary prevention need to be applied more intensively in clinical practice. PMID- 25689946 TI - WHO Framework Convention on Tobacco Control and the United Nations' High Level Meeting on NCD: Progress and Global Expectations. PMID- 25689947 TI - The Best Prevention Efforts begin with Compassion. PMID- 25689948 TI - New universal definition of myocardial infarction: global implications, applicability, and need for flexibility. PMID- 25689949 TI - Aliphatic alcohols in spirits inhibit phagocytosis by human monocytes. AB - A large volume of alcoholic beverages containing aliphatic alcohols is consumed worldwide. Previous studies have confirmed the presence of ethanol-induced immunosuppression in heavy drinkers, thereby increasing susceptibility to infectious diseases. However, the aliphatic alcohols contained in alcoholic beverages might also impair immune cell function, thereby contributing to a further decrease in microbicidal activity. Previous research has shown that aliphatic alcohols inhibit phagocytosis by granulocytes but their effect on human monocytes has not been studied. This is important as they play a crucial role in engulfment and killing of pathogenic microorganisms and a decrease in their phagocytic activity could lead to impaired antimicrobial defence in heavy drinkers. The aim of this study was to measure monocyte phagocytosis following their treatment with those aliphatic alcohols detected in alcoholic beverages. Monocytes were separated from human peripheral blood and phagocytosis of opsonized zymosan particles by monocytes treated with ethanol and aliphatic alcohols individually and in combination was determined. It was shown that these alcohols could suppress the phagocytic activity of monocytes in a concentration dependent manner and when combined with ethanol, they caused a further decrease in phagocytosis. Due to their additive effects, it is possible that they may inhibit phagocytosis in a clinically meaningful way in alcoholics and episodic heavy drinkers thereby contribute to their increased susceptibility to infectious diseases. However, further research is needed to address this question. PMID- 25689950 TI - Evaluation of anti-inflammatory, anti-nociceptive, and anti-arthritic activities of Indian Apis dorsata bee venom in experimental animals: biochemical, histological, and radiological assessment. AB - Traditionally venoms are used from thousands of years to treat pain, inflammation, and arthritis. In Ayurveda "Suchika Voron" and "Shodhona" were practiced against pain. In the present study, venom composition of the Indian honeybee Apis florea (AF), Apis dorsata (AD), and Apis cerana indica (AC) were analyzed using electrophoresis (SDS-PAGE). This venom analysis was used to shed light upon the correlation in structure and the venom composition among the three species in Indian fields. Among the three species, Indian Apis dorsata bee venom (ADBV) is evaluated for an anti-inflammatory, anti-nociceptive activity, and antiarthritic activity in different animal models. The effect of ADBV is revealed for its anti-arthritic activity in the FCA- and CIA-induced arthritis model in male Wistar rats. The immunosuppressant action of ADBV was studied by hemagglutination antibody titer. It has been found that ADBV possesses anti inflammatory and antinociceptive activities. In FCA- and CIA-induced arthritis, ADBV able to decrease rheumatoid factor, pain perception parameters, C-reactive protein, erythrocytes sedimentation rate, urinary hydroxyproline, serum transaminase level, and serum nitric oxide level when compared with diseased control arthritic rats. IL-6, TNF-alpha level was found to be decrease by ADBV treatment in collagen induced arthritis model. Thus this study confirmed the scientific validation behind utilization of venom in Indian Apis dorsata bees in arthritis and inflammatory diseases which has been not reported till date. PMID- 25689951 TI - Osthole inhibits inflammatory cytokine release through PPARalpha/gamma-mediated mechanisms in LPS-stimulated 3T3-L1 adipocytes. AB - CONTEXT: Peroxisome proliferator-activated receptor (PPAR) alpha/gamma may control inflammatory response by regulating the nuclear factor-kappa B (NF kappaB). Osthole may be a dual agonist of PPARalpha/gamma, but whether or not osthole may inhibit inflammatory cytokines in cultured 3T3-L1 adipocytes is unclear. OBJECTIVE: We investigated the action of osthole and its potential mechanisms in lipopolysaccharide (LPS)-stimulated 3T3-L1 adipocytes. MATERIALS AND METHODS: The 3T3-L1 adipocytes stimulated with LPS were cultured and treated with different concentrations of osthole. The inflammatory cytokines including tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in cultured supernatants were detected by the enzyme-linked immunosorbent assay (ELISA) method, and the protein expressions of PPARalpha/gamma and NF-kappaB p65 in adipocytes were detected by the Western blot method, respectively. RESULTS: Following treatment of adipocytes with osthole 0.1-1.6 MUM, the TNF-alpha and IL 6 levels in cultured supernatants were decreased, and the NF-kappaB p65 protein expression in adipocytes was also decreased, while the PPARalpha/gamma protein expressions were increased. After pretreatment of adipocytes with specific inhibitor(s) of PPARalpha and /or PPARgamma, the inhibitory effects of osthole on TNF-alpha and IL-6 were decreased or almost cancelled, and the effects on NF kappaB p65 protein expression also exhibited similar variations. CONCLUSION: Osthole could inhibit the TNF-alpha and IL-6 production in LPS-stimulated adipocytes, and its mechanism might be related to reduction of NF-kappaB expression via activation of PPARalpha/gamma. PMID- 25689952 TI - Direct immunomodulatory influence of IFN-beta on human astrocytoma cells. AB - Astrocytes actively play a pivotal role in inflammatory disease intensity of central nervous system especially multiple sclerosis (MS). Although IFN-beta is a selective therapy for MS but the role of IFN-beta in stimulating the astrocytes to produce cytokines is not clearly revealed. Therefore, it is encouraging to assess the modulatory role of IFN-beta on astrocytes of brain tissue. The aim of our study was to analyze the molecular mechanisms of recombinant IFN-beta 1a directly affecting IL-10, iNOS, MMP-9 and TIMP-1 expression in central nervous system for the first time. In this way, in vitro procedures conducted by human astrocytoma A172 and 1321N1 cell lines as a model system. The total RNA from A172 and 1321N1 cells treated with IFN-beta and LPS/IFN-gamma/IFN-beta and untreated cells were extracted and evaluated for IL-10, iNOS, MMP-9 and TIMP-1 expression by real-time RT-PCR. We found a significant dose-dependent increase in IL-10 gene expression in A172 and 1321N1 cells treated with IFN-beta or LPS/IFN-gamma/IFN beta. Moreover, a significant decrease was observed in iNOS expression suggesting a similar mechanism of action for both cells. Eventually there were no significant changes concerning the modulation of the MMP-9 and TIMP-1 in response to IFN-beta treatment. In part, the immunomodulatory effect of IFN-beta may be due to increase of IL-10 and suppression of iNOS expression in astrocytes of brain tissue. PMID- 25689953 TI - A comparative study to evaluate the effect of limited access dressing (LAD) on burn wound healing. AB - Biochemical and histopathological analyses are commonly used objective parameters in research and clinical fields to assess the healing status of burn wounds. In this study, the effect of newer intermittent negative-pressure wound therapy in combination with moist environment [limited access dressing (LAD)] on burn wound healing is studied. Various biochemical parameters like hydroxyproline, hexosamine and total protein, and antioxidants like reduced glutathione (GSH), glutathione peroxidase (GPx) and oxidative biomarker malondialdhyde (MDA) were measured in the granulation tissue. Histopathologically, necrotic tissue, amount of inflammatory infiltrate, angiogenesis and extracellular matrix deposition (ECM) were studied to determine wound healing. A total of 55 patients were divided into two groups as follows: LAD group (n = 28) and conventional dressing group (n = 27). Patients treated with LAD have shown significant increase in the mean levels of (+/-SD) hydroxyproline (75.2 +/- 26.30 versus 27.8 +/- 15.5; P = 0.010), hexosamine (9.0 +/- 1.99 versus 8.0 +/- 1.18; P = 0.038), total protein (15.6 +/- 8.23 versus 10.26 +/- 4.94; P = 0.003), GSH (7.40 +/- 1.91 versus 5.1 +/- 1.28; P = 0.037), GPx (112.6 +/- 46.4 versus 92 +/- 32.4; P = 0.016), and decrease in MDA (6.5 +/- 2.24 versus 1 0.6 +/- 3.8; P = 0.002). Histopathologically, between LAD and conventional dressing groups, there was a significant difference after 10 days of treatment (mean+/-SE) in necrotic tissue of (LAD versus conventional dressing groups = 10 +/- 1.8 versus 11.9 +/- 2.6; P = 0.033), inflammatory cells (8.4 +/- 1.9 versus 13 +/- 3.46; P = 0.021), new blood vessels (12.5 +/- 2.87 versus 9.4 +/- 1.7; P = 0.047), ECM deposit (12.9 +/- 2.41 versus 9.68 +/- 1.3; P = 0.018) and showed comparatively fewer inflammatory cells, increased and well-organised extracellular matrix deposit, more angiogenesis in LAD group as compared with that in conventional dressing group. To conclude, LAD exerts its beneficial effects on wound healing by reducing oxidative stress, decreasing necrotic tissue and amount of inflammatory infiltrate, and increasing ECM deposition and angiogenesis. PMID- 25689954 TI - Cancer metabolism and the Warburg effect: the role of HIF-1 and PI3K. AB - Cancer cells have been shown to have altered metabolism when compared to normal non-malignant cells. The Warburg effect describes a phenomenon in which cancer cells preferentially metabolize glucose by glycolysis, producing lactate as an end product, despite being the presence of oxygen. The phenomenon was first described by Otto Warburg in the 1920s, and has resurfaced as a controversial theory, with both supportive and opposing arguments. The biochemical aspects of the Warburg effect outline a strong explanation for the cause of cancer cell proliferation, by providing the biological requirements for a cell to grow. Studies have shown that pathways such as phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) as well as hypoxia inducible factor-1 (HIF-1) are central regulators of glycolysis, cancer metabolism and cancer cell proliferation. Studies have shown that PI3K signaling pathways have a role in many cellular processes such as metabolism, inflammation, cell survival, motility and cancer progression. Herein, the cellular aspects of the PI3K pathway are described, as well as the influence HIF has on cancer cell metabolism. HIF-1 activation has been related to angiogenesis, erythropoiesis and modulation of key enzymes involved in aerobic glycolysis, thereby modulating key processes required for the Warburg effect. In this review we discuss the molecular aspects of the Warburg effect with a particular emphasis on the role of the HIF-1 and the PI3K pathway. PMID- 25689955 TI - Weightlifting pulling derivatives: rationale for implementation and application. AB - This review article examines previous weightlifting literature and provides a rationale for the use of weightlifting pulling derivatives that eliminate the catch phase for athletes who are not competitive weightlifters. Practitioners should emphasize the completion of the triple extension movement during the second pull phase that is characteristic of weightlifting movements as this is likely to have the greatest transference to athletic performance that is dependent on hip, knee, and ankle extension. The clean pull, snatch pull, hang high pull, jump shrug, and mid-thigh pull are weightlifting pulling derivatives that can be used in the teaching progression of the full weightlifting movements and are thus less complex with regard to exercise technique. Previous literature suggests that the clean pull, snatch pull, hang high pull, jump shrug, and mid thigh pull may provide a training stimulus that is as good as, if not better than, weightlifting movements that include the catch phase. Weightlifting pulling derivatives can be implemented throughout the training year, but an emphasis and de-emphasis should be used in order to meet the goals of particular training phases. When implementing weightlifting pulling derivatives, athletes must make a maximum effort, understand that pulling derivatives can be used for both technique work and building strength-power characteristics, and be coached with proper exercise technique. Future research should consider examining the effect of various loads on kinetic and kinematic characteristics of weightlifting pulling derivatives, training with full weightlifting movements as compared to training with weightlifting pulling derivatives, and how kinetic and kinematic variables vary between derivatives of the snatch. PMID- 25689956 TI - A philosophical debate on the morality of doping is interesting but beyond the scope of our meta-analysis. PMID- 25689957 TI - IL-1beta and IL-8 are scavenged by the hexadecylamide derivative of hyaluronic acid: a new mechanism. AB - This study aimed to investigate, using an in vitro model, the mechanisms involved in the effects linked to a novel hexadecylamide derivative of hyaluronic acid (HA), HYADD(r)4 (HS), on some inflammatory aspects related to the osteoarthritis process. The human leukemic monocytic cell line THP-1 was stimulated with calcium pyrophosphate (CPP) crystals or lipopolysaccaride (LPS) and cultured in the presence of HS or two unmodified HAs (500-730 kDa and >1500 kDa, respectively). The effects of the three HA derivatives were compared by examining the inhibition of IL-1beta and IL-8 release, the phagocytic capacity of THP-1, and HA's physical interference with the cytokines and their biological activity. Adding HS simultaneously with the stimuli led to a marked (nearly 100%) decrease in cytokine release and biological activity with respect to the two unmodified HAs. The effect was not altered when a CD44 function-blocking monoclonal antibody was used. Incubation of the three derivatives with IL-1beta and IL-8 led to a reduced bioavailability of the cytokines in the medium in the presence of HS but not of unmodified HA. This study examines a novel mechanism inhibiting cytokine bioactivity. The HA hexadecylamide derivative was found to suppress, in vitro, the inflammatory response induced by CPP crystals and LPS by reducing the bioavailability of the two cytokines that were analyzed. PMID- 25689958 TI - Systemic manifestations in children with scorpion sting envenomation: how to manage? PMID- 25689959 TI - Vesiculobullous Disorders in Children. AB - OBJECTIVE: To study the frequency and clinical pattern of vesiculobullous disorders in children. METHODS: A retrospective chart review of all children diagnosed with vesiculobullous disorders over a period of 36 mo from January 2011 through December 2013 was performed. All children 18 y and below were included in the study. RESULTS: A total of 213 children presenting with vesiculobullous lesions were examined during the study period. Vesiculobullous disorders constituted 3.6 % of the total 5889 dermatoses seen during this period. The most common vesiculobullous disorder in children was infections (129, 60.6 %), followed by genodermatoses (35, 16.4 %), inflammatory disorders (33, 15.5 %), drug reaction (7, 3.3 %) and trauma (5, 2.3 %). Autoimmune and metabolic disorders constituted 1.4 % (three children) and 0.5 % (one child) respectively. CONCLUSIONS: This study highlights the varied spectrum of vesiculobullous disorders seen in the pediatric population. Cutaneous infections and inherited disorders were the most common disorders observed in the present study. PMID- 25689960 TI - Stress and Coping among Adolescents in Selected Schools in the Capital City of India. AB - OBJECTIVE: To find out various life stressors of adolescents, coping strategies adopted by them and the impact of stress on adolescent mental health. METHODS: A descriptive, cross sectional study was conducted in the schools in south zone of Delhi, capital city of the country. Data was collected on 360 adolescents between the age group of 13-17 y on socio-demographic profile, Adolescent Life Event Stress Scale, Brief Cope and Youth Self Report for ages 11-18 y. RESULTS: Stress related to uncontrollable events such as family events, relocation events, accident events, ambiguous events and controllable events such as sexual events, deviance events and autonomy events was significantly higher as compared to distressful events (p < 0.0) such as death of a pet, arguments with friends, appearing for exams, failure or low grades. Adolescent stress was significantly correlated with various demographic variables in the study. The most frequently used coping strategies by the adolescents were positive reframing, planning, active coping, and instrumental support. It has also been found that stress has a significant impact on adolescent mental health in the form of either internalizing problems such as anxiety, withdrawal and somatic problems or externalizing problems such as rule breaking and aggressive behaviors. CONCLUSIONS: A significant correlation was found between most of the stressful life event domains and the syndrome subscale of the youth self report form which indicate that out of the total sample of 360 adolescents 150 were identified as having psycho-social morbidity, including 59 borderline cases and 91 high-risk cases. The study pointed out the need for mental health screening among the adolescents and also indicated the need for mental health inputs in educational institutions. PMID- 25689961 TI - Variability in survival of very low birth weight neonates in hospitals of India. AB - This prospective cohort study was conducted to evaluate variability in mortality of very low birth weight (VLBW) neonates during their birth hospitalization in different hospitals of India. A liveborn neonate was eligible for inclusion in the study if it was born or admitted in a participating hospital between 1st January and 31st December 2012 and weighed 1500g or less at birth. Neonates were given clinical care as per standard protocols. Standardized neonatal mortality ratio (SNMR) was calculated as the ratio of the observed mortality to the expected mortality. Expected mortality rate for each unit was calculated by adjusting for various prognostic factors at the time of birth or admission in the participating unit. Among 1345 neonates [mean birth weight: 1168 +/- 240g, median gestation: 30wk (IQR: 28-32)] enrolled in the study 199 (14.8%) died before hospital discharge. Although variation in inter-hospital SNMR was statistically insignificant (P 0.49), 95% CI of SNMR of most hospitals was broad reaching level of clinical significance on both sides of line of equivalence. This indicates the need to establish an ongoing quality-improvement collaborative network to identify and adopt clinical practices associated with decreased mortality. PMID- 25689962 TI - Probiotics in pediatrics. PMID- 25689963 TI - Applying evidence from economic evaluations to translate cancer survivorship research into care. AB - PURPOSE: This paper summarizes recommendations stemming from the meeting, Applying Evidence from Economic Evaluations to Translate Cancer Survivorship Research into Care, hosted by the National Cancer Institute. METHODS: The meeting convened funded investigators, experts in cancer control, survivorship, health economics, and team science to identify the economic and health services data needed to facilitate the dissemination of cancer survivorship interventions into care and how survivorship and health economic investigators can successfully collaborate together and with other stakeholders. RESULTS: Recommendations from the meeting are as follows. First, investigators must engage key stakeholders early in the planning process to understand the outcomes and cost domains on which they base decisions. Second, evaluations of intervention efficacy and value should be conducted using standardized and comparable measures and analytic approaches to enable comparisons across studies. Finally, a health economist should be included during the planning phase of the study so that the economic evaluation is pursued in concert with the survivorship intervention. CONCLUSIONS: Economic analyses, from the perspective of key stakeholders, must be incorporated into survivorship intervention research. The results from these analyses should be disseminated in a manner that is transparent, accessible, and comparable across studies. IMPLICATIONS FOR CANCER SURVIVORS: To optimize cancer survivors' health and quality of life, it is essential deliver high-quality and high-value care. Incorporating economic analyses into survivorship intervention research can inform the translation of effective interventions into practice. PMID- 25689964 TI - Sick leave and disability pension in Hodgkin lymphoma survivors by stage, treatment, and follow-up time--a population-based comparative study. AB - PURPOSE: This study seeks to investigate the long-term public health burden of Hodgkin lymphoma (HL) in terms of work loss following contemporary treatment protocols and associations with established treatment complications and lymphoma relapse. METHODS: We identified 1,989 Swedish HL patients (1,082 with clinical information) aged 18-60 (median 33) years at diagnosis 1992-2009, and matched 1:4 to population comparators. Sick leave, disability pension (work loss), and comorbidity were retrieved through September 2013. Relative risks (RR) with 95% confidence intervals (CI) were calculated using Poisson regression, and mean lost work days were estimated yearly during follow-up. RESULTS: The risk of annual work loss was elevated in HL survivors versus comparators up to the 15th year post-diagnosis (RR(5th year) 1.64, 95% CI 1.46-1.84; RR(10th year) 1.33, 95% CI 1.15-1.34; and RR(15th year) 1.30, 95% CI 1.04-1.62). The risk remained elevated up to the 10th year after adjustment for secondary malignancies and cardiovascular disease (RR(10th year) 1.31, 95% CI 1.13-1.52). Advanced-stage patients had more lost days than comparators (mean number(5th year) 66 versus 33, mean difference 34, 95% CI 20-48) as did patients receiving 6-8 chemotherapy courses (62 versus 33, mean difference(5th year) 30, 95 % CI 17-43). Among patients in the first complete remission, a difference was still observed for advanced-stage (51 versus 33, mean difference(5th year) 19, 95% CI 5-34) but not early-stage disease. CONCLUSIONS: Advanced-stage HL survivors treated with full dose chemotherapy were at increased risk of work loss, not only explained by relapse, secondary malignancies, or cardiovascular disease. IMPLICATIONS FOR CANCER SURVIVORS: The results call for increased awareness and evaluation of reasons for long-term work disability following intensive chemotherapy among young HL survivors. PMID- 25689965 TI - Nanoparticle mediated micromotor motion. AB - In this paper, we report the utilization of nanoparticles to mediate the motion of a polymer single crystal catalytic micromotor. Micromotors have been fabricated by directly self-assembling functional nanoparticles (platinum and iron oxide nanoparticles) onto one or both sides of two-dimensional polymer single crystals. We show that the moving velocity of these micromotors in fluids can be readily tuned by controlling the nanoparticles' surface wettability and catalytic activity. A 3 times velocity increase has been achieved for a hydrophobic micromotor as opposed to the hydrophilic ones. Furthermore, we demonstrate that the catalytic activity of platinum nanoparticles inside the micromotor can be enhanced by their synergetic interactions with iron oxide nanoparticles and an electric field. Both strategies lead to dramatically increased moving velocities, with the highest value reaching ~200 MUm s(-1). By decreasing the nanoparticles' surface wettability and increasing their catalytic activity, a maximum of a ~10-fold increase in the moving speed of the nanoparticle based micromotor can be achieved. Our results demonstrate the advantages of using nanoparticles in micromotor systems. PMID- 25689966 TI - New insights into the ideal adsorbed solution theory. AB - The GCMC technique is used for simulation of adsorption of CO2-CH4, CO2-N2 and CH4-N2 mixtures (at 298 K) on six porous carbon models. Next we formulate a new condition of the IAS concept application, showing that our simulated data obey this condition. Calculated deviations between IAS predictions and simulation results increase with the rise in pressure as in the real experiment. For the weakly adsorbed mixture component the deviation from IAS predictions is higher, especially when its content in the gas mixture is low, and this is in agreement with the experimental data. Calculated activity coefficients have similar plots to deviations between IAS and simulations, moreover obtained from simulated data activity coefficients are similar qualitatively as well as quantitatively to experimental data. Since the physical interpretation of activity coefficients is completely lacking we show for the first time that they can be described by the formulas derived from the expression for G(ex) for the ternary mixture. Finally we also for the first time show the linear relationship between the chemical potentials of nonideal and ideal solutions and the reduced temperature of interacting mixture components, and it is proved that the deviation from ideality is larger if adsorption occurs in a more microporous system. PMID- 25689967 TI - Carbon-14 radiolabeling and in vivo biodistribution of a potential anti-TB compound. AB - A potential anti-TB compound bearing a nitroimidazole moiety from iThemba Pharmaceuticals TB chemical library exhibits promising in vitro activity in the microplate almar blue assay (MABA) with a minimum inhibitory concentration (MIC) value of 3 ug/mL. It is equipotent to the front-line drug Isoniazid, but the compound is less toxic with an IC50 of >100 ug/mL. Therefore, this potential iThemba nitroimidazole, 4-([1,1'-[(14)C6]biphenyl]-4-ylmethyl)-9-nitro-3,4,5,6 tetrahydro-2H-imidazo[2,1-b][1,3,6]oxadiazocine, was radiolabeled with the C-14 isotope. The synthesis of the (14)C-labeled nitroimidazole was accomplished in seven steps from diethanolamine with a final specific radioactivity of 3.552 GBq/mmol, a radiochemical yield of 87%, and a radiochemical purity of >=96%. The source of the C-14 radiolabel was bromobenzene which was introduced by the Suzuki Miyaura reaction. Tissue distribution results showed that the radiotracer has a high accumulation in the lungs of TB-infected mice, statistically significantly higher than in healthy mice. However, the clearance (for both TB-infected and non TB-infected mice) from all organs (except the small intestine) from 1 to 2 h as well as the low percentage of injected dose per gram values achieved indicates breakdown of the compound in vivo and subsequent clearance from the body. The latter suggests that the compound might not be useful as an anti-TB drug in humans. PMID- 25689968 TI - Synthesis of 3H, 13C,2H3,15N and 14C-labelled SCH 466036, a histamine 3 receptor antagonist. AB - The synthesis of [(3)H]SCH 466036, [Me-(3)H3]SCH 466036, [(13)C,(2)H3,(15)N]SCH 466036 and [(14)C]SCH 466036 is described. [(3)H]SCH 466036 was prepared in two steps via Raney Ni-catalysed exchange with tritiated water. [Me-(3)H3]SCH 466036 was prepared in a single step from [(3)H]methyl iodide in 45% yield. [(13)C,(2)H3,(15)N]SCH 466036 was prepared in two steps from [(15)N]hydroxylamine and [(13)C,(2)H3]methyl iodide with an overall yield of 16%. [(14)C]SCH 466036 was prepared in seven steps from [(14)C]potassium cyanide in an overall yield of 13%. PMID- 25689969 TI - A simple convenient synthesis of L-[4-13C]glutamine. AB - L-[4-(13)C]Glutamine was synthesized from sodium [2-(13)C]acetate in 12 steps and 18% overall yield. A Wittig reaction of (R)-benzyl 4-formyl-2,2 dimethyloxazolidine-3-carboxylate and ethyl 2-(triphenylphosphoranylidene)[2 (13)C]acetate prepared from D-serine and sodium [2-(13)C]acetate, respectively, gave (4S)-4-(2-ethoxycarbonyl[2-(13)C]vinyl)-2,2-dimethyloxazolidine-3-carboxylic acid alpha,beta-isopropylidene group, oxidation of the resulting hydroxyl group to a carboxyl group and transamidation of the ester moiety gave L-N-Cbz-[4 (13)C]glutamine (Cbz = benzyloxycarbonyl). Finally, removal of the Cbz group gave L-[4-(13)C]glutamine. L-[4-(13)C]Glutamine can be prepared in fewer steps and higher yield by this method compared with previously reported methods. PMID- 25689970 TI - Genotyping and phylogenetic analysis of Giardia duodenalis isolates from Turkish children. AB - BACKGROUND: Giardiasis is caused by the intestinal protozoan parasite Giardia duodenalis (synonyms: G. lamblia, G. intestinalis), which is one of the most frequent parasites that infect Turkish children. However, molecular characterization of G. duodenalis in Turkey is relatively scarce. The present work aimed at genotyping G. duodenalis isolates from Turkey using molecular techniques. MATERIAL AND METHODS: In the present study, 145 fecal samples from children were collected to search for the presence of Giardia by microscopy and PCR screening. PCR generated a 384 bp fragment for beta-giardin. The PCR products were sequenced and the sequences were subjected to phylogenetic analysis by using PHYLIP. RESULTS: Based on the phylogenetic analysis of the sequences, assemblage A, B, and mixed subtypes were determined. Of 22 isolates, 11 were identified as assemblage A (50%), 7 were assemblage B (31.8%), and 4 were assemblage AB (18.2%). Association between G. duodenalis assemblages and the epidemiological data was analyzed. No correlation was found between symptoms and infection with specific assemblages (P>0.05), but we found statistically significant association between age and the assemblage AB (P=0.001). CONCLUSIONS: The association between G. duodenalis and the epidemiologic data were analyzed. Since assemblage A is the more prevalent subgroup compared with assemblage B, this subgroup might be responsible for common Giardia infections in Turkey. This is the first study that included a detailed phylogenetic analysis of Giardia strains from Turkey. PMID- 25689971 TI - A single-port operator-controlled flexible endoscope system for endoscopic skull base surgery. AB - OBJECTIVE: In a human cadaver study, a single-port operator-controlled flexible endoscope (Flex(r) System), facilitated with a high-definition camera and two accessory channels was tested for skull base surgery. DESIGN: Skull base surgery was performed on human cadavers (n=4) using the Flex(r) System. A modified surgical midfacial approach, performed by rigid standard tools, was used for access to the sinus system, the skull base, and the middle cranial fossa. RESULTS: Endoscopic skull base visualization with the Flex(r) System is feasible. Surgical procedures performed included extended sinus surgery, anterior skull base approach, and visualization of the brain stem in the posterior cranial fossa. Important landmarks of the anterior skull base were visualized and manipulated by flexible compatible tools. CONCLUSION: The Flex(r) System allows for manipulation of the anterior skull base and visualization of the posterior cranial fossa in a preclinical setting. Further studies as well as development of supplemental tools are in progress. PMID- 25689972 TI - Epidemiology of Huntington disease: first post-HTT gene analysis of prevalence in Italy. AB - Huntington disease (HD) prevalence shows geographic variability and has been recently updated by taking into account the mutation diagnostic test. In Italy, the last epidemiological estimation was reported well before the HTT gene discovery and the availability of the corresponding genetic test. It reported a prevalence of affected subjects ranging between 2.3 and 4.8/100,000 in some restricted areas of Northern Italy. We have performed a service-based epidemiological analysis in a very restricted geographic area named Molise, where our institutions currently operate and represent the only point of reference for rare neuropsychiatric diseases. The estimated prevalence rate found was 10.85/100,000 (95% confidence interval (CI): 7.20-14.50), remarkably higher than that previously described before the gene test analysis was available, and expected to an increase of an additional 17% by 2030, because of Italian population aging. According to our analysis, we estimate that about 6500 subjects are currently affected by HD in Italy, and that this number will further increase in the next decades because of population aging, variable phenotype penetrance and improved life expectancy. PMID- 25689973 TI - Acute restraint stress induces endothelial dysfunction: role of vasoconstrictor prostanoids and oxidative stress. AB - We hypothesized that acute stress would induce endothelial dysfunction. Male Wistar rats were restrained for 2 h within wire mesh. Functional and biochemical analyses were conducted 24 h after the 2-h period of restraint. Stressed rats showed decreased exploration on the open arms of an elevated-plus maze (EPM) and increased plasma corticosterone concentration. Acute restraint stress did not alter systolic blood pressure, whereas it increased the in vitro contractile response to phenylephrine and serotonin in endothelium-intact rat aortas. NG nitro-l-arginine methyl ester (l-NAME; nitric oxide synthase, NOS, inhibitor) did not alter the contraction induced by phenylephrine in aortic rings from stressed rats. Tiron, indomethacin and SQ29548 reversed the increase in the contractile response to phenylephrine induced by restraint stress. Increased systemic and vascular oxidative stress was evident in stressed rats. Restraint stress decreased plasma and vascular nitrate/nitrite (NOx) concentration and increased aortic expression of inducible (i) NOS, but not endothelial (e) NOS. Reduced expression of cyclooxygenase (COX)-1, but not COX-2, was observed in aortas from stressed rats. Restraint stress increased thromboxane (TX)B(2) (stable TXA(2) metabolite) concentration but did not affect prostaglandin (PG)F2alpha concentration in the aorta. Restraint reduced superoxide dismutase (SOD) activity, whereas concentrations of hydrogen peroxide (H(2)O(2)) and reduced glutathione (GSH) were not affected. The major new finding of our study is that restraint stress increases vascular contraction by an endothelium-dependent mechanism that involves increased oxidative stress and the generation of COX derived vasoconstrictor prostanoids. Such stress-induced endothelial dysfunction could predispose to the development of cardiovascular diseases. PMID- 25689974 TI - Oncoplastic and reconstructive breast surgery in the elderly. AB - BACKGROUND: The recommendations of the UK All Party Parliamentary Group on Breast Cancer (2013) have been endorsed recently by the UK Association of Breast Surgeons and are in line with the 2007 Cancer Reform Strategy, which states that treatment in older British women should be equivalent to that in younger patients unless precluded by co-morbidity or patient choice. Oncoplastic and reconstructive techniques are increasingly available to women with breast cancer. A review of the literature was carried out to investigate use of these techniques in older patients. METHODS: A MEDLINE search was conducted to identify studies relating to oncoplastic and reconstructive surgery in the elderly. RESULTS AND CONCLUSION: Nine studies were identified and included in the review. Older patients undergoing reconstruction, particularly autologous reconstruction, have outcomes that are at least as good as those achieved in younger patients, yet are far less likely to be offered these techniques. Issues influencing oncoplastic and reconstructive surgery in the elderly include: lack of standard pathways of care, concerns regarding higher operative risk, lack of evidence regarding outcomes, preconceptions regarding body image and lack of engagement with the decision-making process. A minority of older women are likely to accept reconstruction, but those who do are pleased with the results and experience good quality of life. There is now a range of safe oncoplastic and reconstructive options that could be considered as an alternative to standard mastectomy or wide local excision in older patients. PMID- 25689975 TI - Melatonin-related genes expressed in the mouse uterus during early gestation promote embryo implantation. AB - Melatonin, a superior antioxidant, is an important molecule which regulates female reproduction due to its receptor-mediated and receptor-independent antioxidant actions. In this study, we investigated the effect of melatonin on early gestation in a mouse model. During early gestation, the expression of the melatonin's rate-limiting enzyme, AANAT, gradually increased - in the uterus while the MT2 melatonin receptor was only expressed at day 2 of gestation and no MT1 was detected. Based on these findings, we conducted a melatonin injection experiment which demonstrated that 15 mg/kg melatonin significantly improved the number of implantation sites and the litter size. Also, the blastocyst and uterus were collected to identify the local action of melatonin. In the melatonin treated mice, the endometrium was thicker than in the control mice; melatonin also caused an increase in density of uterine glands, and the uterine gland index (UGI) was significantly elevated over that of the control. Serum steroid hormone measurements revealed that at day 6 of gestation (postimplantation), melatonin significantly downregulated the E2 level, with no obvious effects on progesterone. Gene expression assay revealed that melatonin significantly upregulated expression of HB-EGF, a crucial gene involved in implantation as well as its receptor ErbB1 in the blastocyst. In addition, PRA, an important gene which influences the decidual response and luminal cell differentiation, p53, which regulates uterine through leukaemia inhibitory factor (LIF), were both increased after melatonin treatment. These data suggest that melatonin and its MT2 receptor influence early gestation. Exogenous melatonin treatment can improve mouse embryo implantation and litter size, which may have important applications in human reproductive health and animal husbandry. PMID- 25689977 TI - A 32-channel combined RF and B0 shim array for 3T brain imaging. AB - PURPOSE: We add user-controllable direct currents (DC) to the individual elements of a 32-channel radio-frequency (RF) receive array to provide B0 shimming ability while preserving the array's reception sensitivity and parallel imaging performance. METHODS: Shim performance using constrained DC current (+/- 2.5A) is simulated for brain arrays ranging from 8 to 128 elements. A 32-channel 3-tesla brain array is realized using inductive chokes to bridge the tuning capacitors on each RF loop. The RF and B0 shimming performance is assessed in bench and imaging measurements. RESULTS: The addition of DC currents to the 32-channel RF array is achieved with minimal disruption of the RF performance and/or negative side effects such as conductor heating or mechanical torques. The shimming results agree well with simulations and show performance superior to third-order spherical harmonic (SH) shimming. Imaging tests show the ability to reduce the standard frontal lobe susceptibility-induced fields and improve echo planar imaging geometric distortion. The simulation of 64- and 128-channel brain arrays suggest that even further shimming improvement is possible (equivalent to up to 6th-order SH shim coils). CONCLUSION: Including user-controlled shim currents on the loops of a conventional highly parallel brain array coil is feasible with modest current levels and produces improved B0 shimming performance over standard second-order SH shimming. PMID- 25689976 TI - Linking RNA Dysfunction and Neurodegeneration in Amyotrophic Lateral Sclerosis. AB - The degeneration of motor neurons in amyotrophic lateral sclerosis (ALS) inevitably causes paralysis and death within a matter of years. Mounting genetic and functional evidence suggest that abnormalities in RNA processing and metabolism underlie motor neuron loss in sporadic and familial ALS. Abnormal localization and aggregation of essential RNA-binding proteins are fundamental pathological features of sporadic ALS, and mutations in genes encoding RNA processing enzymes cause familial disease. Also, expansion mutations occurring in the noncoding region of C9orf72-the most common cause of inherited ALS-result in nuclear RNA foci, underscoring the link between abnormal RNA metabolism and neurodegeneration in ALS. This review summarizes the current understanding of RNA dysfunction in ALS, and builds upon this knowledge base to identify converging mechanisms of neurodegeneration in ALS. Potential targets for therapy development are highlighted, with particular emphasis on early and conserved pathways that lead to motor neuron loss in ALS. PMID- 25689978 TI - Downstaging of hepatocellular cancer before liver transplant: long-term outcome compared to tumors within Milan criteria. AB - We report on the long-term intention-to-treat (ITT) outcome of 118 patients with hepatocellular carcinoma (HCC) undergoing downstaging to within Milan/United Network for Organ Sharing T2 criteria before liver transplantation (LT) since 2002 and compare the results with 488 patients listed for LT with HCC meeting T2 criteria at listing in the same period. The downstaging subgroups include 1 lesion >5 and <=8 cm (n = 43), 2 or 3 lesions at least one >3 and <=5 cm with total tumor diameter <=8 cm (n = 61), or 4-5 lesions each <=3 cm with total tumor diameter <=8 cm (n = 14). In the downstaging group, 64 patients (54.2%) had received LT and 5 (7.5%) developed HCC recurrence. Two of the five patients with HCC recurrence had 4-5 tumors at presentation. The 1- and 2-year cumulative probabilities for dropout (competing risk) were 24.1% and 34.2% in the downstaging group versus 20.3% and 25.6% in the T2 group (P = 0.04). Kaplan Meier's 5-year post-transplant survival and recurrence-free probabilities were 77.8% and 90.8%, respectively, in the downstaging group versus 81% and 88%, respectively, in the T2 group (P = 0.69 and P = 0.66, respectively). The 5-year ITT survival was 56.1% in the downstaging group versus 63.3% in the T2 group (P = 0.29). Factors predicting dropout in the downstaging group included pretreatment alpha-fetoprotein >=1,000 ng/mL (multivariate hazard ratio [HR]: 2.42; P = 0.02) and Child's B versus Child's A cirrhosis (multivariate HR: 2.19; P = 0.04). CONCLUSION: Successful downstaging of HCC to within T2 criteria was associated with a low rate of HCC recurrence and excellent post-transplant survival, comparable to those meeting T2 criteria without downstaging. Owing to the small number of patients with 4-5 tumors, further investigations are needed to confirm the efficacy of downstaging in this subgroup. PMID- 25689979 TI - The effects of pH and surfactants on the absorption and fluorescence properties of ochratoxin A and zearalenone. AB - The pH and surfactant dependencies of the absorption and fluorescence properties of ochratoxin A (OTA) and zearalenone (ZEN), the main mycotoxins found as contaminants in foods and feeds, were evaluated. Three surfactants with different ionic properties were investigated, namely sodium dodecyl sulfate (SDS, anionic), Tween 20 (nonionic) and hexadecyltrimethylammonium bromide (CTAB, cationic). The results show that the effects of pH on the absorption wavelength maxima and fluorescence efficiencies of the mycotoxins, which are a consequence of the presence of acidic phenol and/or carboxyl containing fluorophores, are dependent on the ionic nature of the added surfactants. Specifically, the fluorescence responses to pH changes of OTA and ZEN are similar in the presence or absence of Tween 20 and SDS. By contrast, the pH-dependent fluorescence properties of these mycotoxins are altered when CTAB is present in the solutions. Moreover, unlike OTA, ZEN in aqueous solution displays almost no fluorescence. However, fluorescence enhancement takes place when surfactants are present in aqueous solutions of this mycotoxin. The results of this study demonstrate that the different microenvironments, present in the organized micellar systems created by the individual surfactants, can be potentially employed to modulate the sensitivities and selectivities of the fluorescence detection of OTA or ZEN. PMID- 25689980 TI - Medulloblastoma subgroups remain stable across primary and metastatic compartments. AB - Medulloblastoma comprises four distinct molecular variants with distinct genetics, transcriptomes, and outcomes. Subgroup affiliation has been previously shown to remain stable at the time of recurrence, which likely reflects their distinct cells of origin. However, a therapeutically relevant question that remains unanswered is subgroup stability in the metastatic compartment. We assembled a cohort of 12-paired primary-metastatic tumors collected in the MAGIC consortium, and established their molecular subgroup affiliation by performing integrative gene expression and DNA methylation analysis. Frozen tissues were collected and profiled using Affymetrix gene expression arrays and Illumina methylation arrays. Class prediction and hierarchical clustering were performed using existing published datasets. Our molecular analysis, using consensus integrative genomic data, establishes the unequivocal maintenance of molecular subgroup affiliation in metastatic medulloblastoma. We further validated these findings by interrogating a non-overlapping cohort of 19 pairs of primary metastatic tumors from the Burdenko Neurosurgical Institute using an orthogonal technique of immunohistochemical staining. This investigation represents the largest reported primary-metastatic paired cohort profiled to date and provides a unique opportunity to evaluate subgroup-specific molecular aberrations within the metastatic compartment. Our findings further support the hypothesis that medulloblastoma subgroups arise from distinct cells of origin, which are carried forward from ontogeny to oncology. PMID- 25689981 TI - The effect of diluted triple and double antibiotic pastes on dental pulp stem cells and established Enterococcus faecalis biofilm. AB - OBJECTIVES: To investigate the effect of various dilutions of antibiotic medicaments used in endodontic regeneration on the survival of human dental pulp stem cells (DPSCs) and to determine their antibacterial effect against established Enterococcus faecalis biofilm. MATERIALS AND METHODS: The cytotoxic and antibacterial effects of different triple (TAP) and double antibiotic paste (DAP) dilutions (0.125, 0.25, 0.5, 1, and 10 mg/ml) were tested against Enterococcus faecalis established biofilm and DPSC. Established bacterial biofilm were exposed to antibiotic dilutions for 3 days. Then, biofilms were collected, spiral plated, and the numbers of bacterial colony forming units (CFU/ml) were determined. For the cytotoxic effect, lactate dehydrogenase activity assays (LDH) and cell viability assays (WST-1) were used to measure the percentage of DPSC cytotoxicity after 3-day treatment with the same antibiotic dilutions. A general linear mixed model was used for statistical analyses (alpha = 0.05). RESULTS: All antibiotic dilutions significantly decreased the bacterial CFU/ml. For WST-1 assays, all antibiotic dilutions except 0.125 mg/ml significantly reduced the viability of DPSC. For LDH assays, the three lowest tested concentrations of DAP (0.5, 0.25, 0.125 mg/ml) and the two lowest concentrations of TAP (0.25 and 0.125 mg/ml) were non-toxic to DPSC. CONCLUSIONS: All tested dilutions had an antibacterial effect against E. faecalis. However, 0.125 mg/ml of DAP and TAP showed a significant antibacterial effect with no cytotoxic effects on DPSCs. CLINICAL RELEVANCE: Using appropriate antibiotic concentrations of intracanal medicament during endodontic regeneration procedures is critical to disinfect root canal and decrease the adverse effects on stem cells. PMID- 25689982 TI - Evaluation of salivary mucins in children with deciduous and mixed dentition: comparative analysis between high and low caries-risk groups. AB - OBJECTIVES: The aim of this study was to examine levels of salivary mucins in children with deciduous and mixed dentition and to determine correlations between salivary mucins and dental caries status in two dentition stages. MATERIALS AND METHODS: Saliva samples were collected from preschool children with deciduous dentition aged between 4 and 6 years (n = 60) and school children with mixed dentition aged between 9 and 11 years (n = 60). In each age group, the subjects were divided into two categories: high and low caries risk (n = 30 each). Salivary mucins (MUC5B and MUC7) were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: There were no significant differences in MUC5B and MUC7 levels between high and low caries-risk groups in preschool children. Significantly increased MUC5B (p = 0.01) and decreased MUC7 (p = 0.04) levels in a low caries-risk group were demonstrated in school children. No significant correlations were observed between salivary mucins and dental caries in preschool children, whereas a significantly negative correlation (r = -0.29, p = 0.03) between MUC5B and the number of decayed teeth was observed in school children. CONCLUSION: Patterns of salivary mucin expression in relation to dental caries were different between preschool and school children. The present findings suggest that changes in oral environment from deciduous to mixed dentition may affect the secretion of salivary mucins in response to dental caries. CLINICAL RELEVANCE: The present study provides additional information that changes in oral environment from deciduous to mixed dentition stage possibly affect the secretion of salivary mucins in response to dental caries. PMID- 25689983 TI - Enamel demineralization after different methods of interproximal polishing. AB - OBJECTIVES: The aim of this in vitro study was to investigate the demineralization rate in human enamel after interproximal polishing (IPP) and to detect possible correlations with the IPP method used, with special emphasis on the surface characteristics of the enamel being treated. MATERIALS AND METHODS: This in vitro study tested five IPP systems (Profin Directional System(r), Intensiv ProxoStrip(r), OS discs(r), ARS Safe-Tipped Bur Kit(r) and Ortho-Strips Set(r)) that are currently available on the market. Each of the five examination groups comprised 12 randomly selected teeth, while the control group consisted of six teeth. The teeth were placed in an artificial model for each group. The proximal contacts were then resolved by IPP. To allow detection of any surface characteristics, one surface was not further processed after IPP, while the other side was additionally polished. After IPP, the teeth were exposed to a pH-cycling model with alternating phases of demineralization and remineralization. Substance loss was analyzed using optical emission spectrometry. Data were subjected to simple analysis of variance (ANOVA) performed with Tukey's test. Comparison between the groups with and without polishing was conducted using the t test for independent samples. The significance level was set at p < 0.05. RESULTS: Demineralization significantly increased after IPP. The rates of demineralization differed significantly among the examination groups, with the greatest loss of substance being produced with Sheridan's Air-Rotor Stripping(r) system (ARS; 145.34 +/- 20.37 MUm). In all of the examination groups, subsequent polishing of the surfaces did not significantly reduce the amount of demineralization (polished 119.64 +/- 28.61 MUm; unpolished 114.16 +/- 28.61 MUm). CONCLUSION: No correlation between surface morphology and the degree of susceptibility of human enamel was detected. However, it must be taken into consideration that there was no potential bacterial colonization in this in vitro erosive set-up. Thus, in contrast to previous explanations, the outermost fluorapatite layer and the individual composition of the enamel may have a greater impact on the solubility of the enamel and the amount of enamel loss after IPP than the type of system used and the resulting surface texture. CLINICAL RELEVANCE: Whenever the outermost layer of enamel is reduced, the practitioner must expect an increase in demineralization. Subsequent polishing does not appear to affect the amount of demineralization. PMID- 25689984 TI - Association of hospital volume with readmission rates: a retrospective cross sectional study. PMID- 25689985 TI - Simultaneous Determination of Trantinterol and One of Its Major Metabolites, 1 Carbonyl Trantinterol, in Human Plasma by LC-MS-MS. AB - A highly selective and sensitive liquid chromatography-tandem mass spectrometry method was developed and validated for the simultaneous determination of trantinterol and one of its major metabolites, 1-carbonyl trantinterol, in human plasma. An Oasis MCX 96-well solid-phase extraction cartridge and a SeQuantTM ZIC((r))-HILIC LC column were used for sample preparation and chromatographic separation, respectively. The analytes were monitored by a QTrap 5500 mass spectrometer with positive electrospray ionization. Multiple reaction monitoring was used for quantification using the precursor to product ion pairs of m/z 311.1 -> 237.9 (trantinterol), m/z 325.1 -> 251.9 (1-carbonyl trantinterol) and m/z 368.4 -> 294.0 (bambuterol as internal standard). The assay had a calibration range from 0.2 to 50 pg/mL and a lower limit of quantification of 0.2 pg/mL for both trantinterol and 1-carbonyl trantinterol. The inter-day and intra-day precisions were <12.0% and the accuracies were within the range of 87.1-111%. The mean recovery ranged from 82.0 to 97.7% and internal standard normalized matrix effect from 0.813 to 0.899. The analytes were stable under all tested conditions. This validated method was successfully applied to a pilot pharmacokinetic study in healthy subjects administered a single 50 MUg oral dose. PMID- 25689986 TI - The short-term effects of acupuncture on patients with diabetic gastroparesis: a randomised crossover study. AB - BACKGROUND: Acupuncture may improve gastrointestinal symptoms in patients with various disorders, but its efficacy in diabetic gastroparesis is unclear. OBJECTIVE: To evaluate the short-term effects of acupuncture on gastric emptying and gastroparesis symptoms in patients with diabetic gastroparesis. METHODS: In a single-blind controlled crossover trial, 25 patients with diabetic gastroparesis were randomly assigned to undergo 1 week of real acupuncture (RA) treatment followed by 1 week of sham acupuncture (SA) treatment, or vice versa, with a washout of 1 month in between. Before and after each intervention, gastric retention, the Gastroparesis Cardinal Symptom Index (GCSI), fasting blood glucose (FBG) and HbA1c levels were measured. RESULTS: 21 patients completed the study. Compared with SA treatment, RA treatment was associated with significantly greater reductions in gastric retention at 2 h (-11.1+/-7.0%; 95% CI -13.6% to 6.2%; p<0.01) and at 4 h (-5.0+/-2.8%; 95% CI -6.0% to -0.2%; p=0.04) and in GCSI score (-8.0+/-3.4; 95% CI -8.4 to -2.8; p<0.01). There were no significant differences in FBG and HbA1c levels between RA and SA treatments. CONCLUSIONS: In patients with diabetic gastroparesis, 1 week of short-term manual acupuncture reduces gastric retention and improves gastroparesis symptoms. PMID- 25689987 TI - 3D printed reproductions of orbital dissections: a novel mode of visualising anatomy for trainees in ophthalmology or optometry. AB - BACKGROUND: The teaching of human head, neck and orbital anatomy forms a critical part of undergraduate and postgraduate medical and allied health professional training, including optometry. While still largely grounded in cadaveric dissection, this method of instruction is constrained in some countries and regional areas by access to real human cadavers, costs of cadaver bequest programmes, health and safety of students and staff and the shortage of adequate time in modern curricula. Many candidates choosing a postgraduate pathway in ophthalmological training, such as those accepted into the Royal Colleges of Ophthalmology in the UK, Australia and New Zealand programmes and the American Academy of Ophthalmologists in the USA, are compelled as adult learners to revise or revisit human orbital anatomy, ocular anatomy and select areas of head and neck anatomy. These candidates are often then faced with the issue of accessing facilities with dissected human cadaveric material. METHODS: In light of these difficulties, we developed a novel means of creating high-resolution reproductions of prosected human cadaver orbits suitable for education and training. RESULTS: 3D printed copies of cadaveric orbital dissections (superior, lateral and medial views) showing a range of anatomical features were created. DISCUSSION: These 3D prints offer many advantages over plastinated specimens as they are suitable for rapid reproduction and as they are not human tissue they avoid cultural and ethical issues associated with viewing cadaver specimens. In addition, they are suitable for use in the office, home, laboratory or clinical setting in any part of the world for patient and doctor education. PMID- 25689988 TI - Cortical Specializations Underlying Fast Computations. AB - The time course of behaviorally relevant environmental events sets temporal constraints on neuronal processing. How does the mammalian brain make use of the increasingly complex networks of the neocortex, while making decisions and executing behavioral reactions within a reasonable time? The key parameter determining the speed of computations in neuronal networks is a time interval that neuronal ensembles need to process changes at their input and communicate results of this processing to downstream neurons. Theoretical analysis identified basic requirements for fast processing: use of neuronal populations for encoding, background activity, and fast onset dynamics of action potentials in neurons. Experimental evidence shows that populations of neocortical neurons fulfil these requirements. Indeed, they can change firing rate in response to input perturbations very quickly, within 1 to 3 ms, and encode high-frequency components of the input by phase-locking their spiking to frequencies up to 300 to 1000 Hz. This implies that time unit of computations by cortical ensembles is only few, 1 to 3 ms, which is considerably faster than the membrane time constant of individual neurons. The ability of cortical neuronal ensembles to communicate on a millisecond time scale allows for complex, multiple-step processing and precise coordination of neuronal activity in parallel processing streams, while keeping the speed of behavioral reactions within environmentally set temporal constraints. PMID- 25689989 TI - Specific Cleavage of the Nucleoprotein of Fish Rhabdovirus. AB - Siniperca chuatsi rhabdovirus (SCRV) is one of myriad rhabdoviruses recorded in fish. Preliminary data show that inhibition of the SCRV nucleoprotein (N) could significantly reduce the progeny virus titers in infected Epithelioma papulosum cyprinid (EPC) cells. Here, the authors propose that cleavage of the viral 47-kDa N protein is caspase-mediated based on caspase inhibition experiments, transient expression in EPC transfection, and analysis of cleavage sites. Cleavage of the SCRV N protein in culture was prevented by a pan-caspase inhibitor, z-VAD-FMK (z Val-Ala-DL-Asp-fluoromethyl ketone). Subsequently, N was transiently expressed in EPC cells, the results of which indicated that the specific cleavage of N also occurred in the cells transfected with N-GFP plasmid. Several truncated fragments of the N gene were constructed and transiently transfected into EPC cells. Immunoblotting results indicated that D324 and D374 are the cleavage sites of N by caspases. The authors also found that z-VAD-FMK could inhibit the cytopathic effect in SCRV-infected EPC cells but not affect the production of infectious progeny, suggesting that the caspase-mediated cleavage of N protein is not required for in vitro SCRV replication. To the authors' knowledge, this is the first report on the cleavage of rhabdovirus proteins. PMID- 25689990 TI - The effect of hyperammonemia on myostatin and myogenic regulatory factor gene expression in broiler embryos. AB - Myogenesis is facilitated by four myogenic regulatory factors and is significantly inhibited by myostatin. The objective of the current study was to examine embryonic gene regulation of myostatin/myogenic regulatory factors, and subsequent manipulations of protein synthesis, in broiler embryos under induced hyperammonemia. Broiler eggs were injected with ammonium acetate solution four times over 48 h beginning on either embryonic day (ED) 15 or 17. Serum ammonia concentration was significantly higher (P<0.05) in ammonium acetate injected embryos for both ED17 and ED19 collected samples when compared with sham-injected controls. Expression of mRNA, extracted from pectoralis major of experimental and control embryos, was measured using real-time quantitative PCR for myostatin, myogenic regulatory factors myogenic factor 5, myogenic determination factor 1, myogenin, myogenic regulatory factor 4 and paired box 7. A significantly lower (P<0.01) myostatin expression was accompanied by a higher serum ammonia concentration in both ED17 and ED19 collected samples. Myogenic factor 5 expression was higher (P<0.05) in ED17 collected samples administered ammonium acetate. In both ED17 and ED19 collected samples, myogenic regulatory factor 4 was lower (P?0.05) in ammonium acetate injected embryos. No significant difference was seen in myogenic determination factor 1, myogenin or paired box 7 expression between treatment groups for either age of sample collection. In addition, there was no significant difference in BrdU staining of histological samples taken from treated and control embryos. Myostatin protein levels were evaluated by Western blot analysis, and also showed lower myostatin expression (P<0.05). Overall, it appears possible to inhibit myostatin expression through hyperammonemia, which is expected to have a positive effect on embryonic myogenesis and postnatal muscle growth. PMID- 25689991 TI - Surveillance of hepatitis E virus contamination in shellfish in China. AB - BACKGROUND: Hepatitis E virus (HEV) has been confirmed to be a zoonotic virus of worldwide distribution. HEV contamination in the water environment has not been well examined in China. The objective of this study was to evaluate HEV contamination in shellfish in a coastal area of China. Such contamination would be significant for evaluating public health risks. METHODS: samples of three species shellfish were collected from thirteen points of estuarine tidal flats around the Bohai Gulf and screened for HEV RNA using an in-house nested RT-PCR assay. The detected HEV-positive samples were further verified by gene cloning and sequencing analysis. RESULTS: the overall HEV-positive detection rate is approximately 17.5% per kilogram of shellfish. HEV was more common among S. subcrenata (28.2%), followed by A. granosa (14.3%) and R. philippinarum (11.5%). The phylogenetic analysis of the 13 HEV strains detected revealed that gene fragments fell into two known 4 sub-genotypes (4b/4d) groups and another unknown group. CONCLUSIONS: 13 different sub-genotype 4 HEVs were found in contaminated shellfish in the Bohai Gulf rim. The findings suggest that a health risk may exist for users of waters in the Bonhai area and to consumers of shellfish. Further research is needed to assess the sources and infectivity of HEV in these settings, and to evaluate additional shellfish harvesting areas. PMID- 25689992 TI - Smoking-related knowledge, attitudes, behaviors, smoking cessation idea and education level among young adult male smokers in Chongqing, China. AB - INTRODUCTION: In 2012 in China, 52.9% of men were reported to smoke while only 2.4% of women smoked. This study explored the smoking-related Knowledge, Attitudes and Practices (KAP) among young adult male smokers. METHODS: A cross sectional study was conducted in four municipal areas of Chongqing using a questionnaire administered to 536 natives young male smokers aged 18-45 years old. RESULTS: The total score of smoking cognition, the total score of smoking attitude and the total score of positive behavior to quit smoking was significantly different among the three groups by education. Besides, 30.97% of male smokers never seriously thought about quitting smoking. Logistic regression analysis found smoking-related knowledge, attitudes, behaviors and sociodemographic factors affect having smoking cessation idea. But no statistically significant correlation was observed between smoking cognition and positive behavior to quit smoking in a sample of higher education. No statistically significant correlation was observed between smoking cognition and positive behavior to quit smoking (Pearson correlation coefficient = 0.03012, p = 0.6811), and also no statistically significant correlation was observed between smoking cognition and positive behavior to quit smoking (Pearson correlation coefficient = 0.08869, p = 0.2364) in the sample of higher education young adult males CONCLUSIONS: Young adult males with higher education have a better knowledge of smoking hazards and a more positive attitude toward smoking, however, this knowledge and attitude do not necessarily translate into health behavioral outcomes such as not smoking. Overall the present findings indicate that no statistically significant correlation between the education level and quitting smoking idea exists among young adult male smokers in China. This survey gives a snapshot of the impact of education on smoking-related KAP among young adults male smokers. PMID- 25689993 TI - Antimicrobial resistance in commensal Escherichia coli from pigs during metaphylactic trimethoprim and sulfamethoxazole treatment and in the post exposure period. AB - The prevalence of trimethoprim (TMP) and sulfamethoxazole (SMX) resistance in commensal E. coli from pigs was tested in this study. E. coli was derived from three groups of piglets in successive stages of metaphylactic therapy and from two groups of sows 10 and 18 weeks after the treatment. MIC values of TMP and SMX were determined for a total of 352 strains. The presence of resistance genes (dfrA1, dfrA5, dfrA7, dfrA12, dfrA17, sul1, sul2, sul3) and class 1 and 2 integron-associated dfrA gene cassettes was tested. Resistance to TMP was very high during the administration of the antimicrobial (from 97 to 100%) and amounted to 86% and 69% in the post-exposure period; MIC > 32 mg/L. The isolates from all groups of pigs were resistant to sulfamethoxazole, with MIC > 1028 mg/L. The dfrA1 and sul1 genes (as part of integrons) dominated in E. coli from piglets, but the dfrA12 and sul1 genes were prevalent in E. coli from sows. Coexistence of the different dfrA genes was detected in 71 isolates from all groups of swine. Transcription analysis revealed that most of these genes were not transcribed, particularly gene cassettes of class 1 integrons. The research revealed a high level of resistance associated with the metaphylactic treatment, persistence and circulation of resistance in bacterial populations. Diverse genetic background with multiple and not transcribed resistance genes was observed. PMID- 25689994 TI - Production of the allergenic protein Alt a 1 by Alternaria isolates from working environments. AB - The aim of the study was to evaluate the ability of Alternaria isolates from workplaces to produce Alt a 1 allergenic protein, and to analyze whether technical materials (cellulose, compost, leather) present within the working environment stimulate or inhibit Alt a 1 production (ELISA test). Studies included identification of the isolated molds by nucleotide sequences analyzing of the ITS1/ITS2 regions, actin, calmodulin and Alt a 1 genes. It has been shown that Alternaria molds are significant part of microbiocenosis in the archive, museum, library, composting plant and tannery (14%-16% frequency in the air). The presence of the gene encoding the Alt a 1 protein has been detected for the strains: Alternaria alternata, A. lini, A. limoniasperae A. nobilis and A. tenuissima. Environmental strains produced Alt a 1 at higher concentrations (1.103-6.528 ng/mL) than a ATCC strain (0.551-0.975 ng/mL). It has been shown that the homogenization of the mycelium and the use of ultrafiltration allow a considerable increase of Alt a 1 concentration. Variations in the production of Alt a 1 protein, depend on the strain and extraction methods. These studies revealed no impact of the technical material from the workplaces on the production of Alt a 1 protein. PMID- 25689995 TI - Childhood leukemia and 50 Hz magnetic fields: findings from the Italian SETIL case-control study. AB - We report on an Italian case-control study on childhood leukemia and exposure to extremely low frequency magnetic fields (ELF-MF). Eligible for inclusion were 745 leukemia cases, aged 0-10 years at diagnosis in 1998-2001, and 1475 sex- and age matched population controls. Parents of 683 cases and 1044 controls (92% vs. 71%) were interviewed. ELF-MF measurements (24-48 h), in the child's bedroom of the dwelling inhabited one year before diagnosis, were available for 412 cases and 587 controls included in the main conditional regression analyses. The magnetic field induction was 0.04 MUT on average (geometric mean), with 0.6% of cases and 1.6% of controls exposed to >0.3 MUT. The impact of changes in the statistical model, exposure metric, and data-set restriction criteria was explored via sensitivity analyses. No exposure-disease association was observed in analyses based on continuous exposure, while analyses based on categorical variables were characterized by incoherent exposure-outcome relationships. In conclusion, our results may be affected by several sources of bias and they are noninformative at exposure levels >0.3 MUT. Nonetheless, the study may contribute to future meta- or pooled analyses. Furthermore, exposure levels among population controls are useful to estimate attributable risk. PMID- 25689996 TI - Health-related quality of life and health service utilization in Chinese rural-to urban migrant workers. AB - OBJECTIVES: The number of rural-to-urban migrant workers has been increasing rapidly in China over recent decades, but there is a scarcity of data on health related quality of life (HRQOL) and health service utilization among Chinese rural-to-urban migrant workers in comparison to local urban residents. We aimed to address this question. METHODS: This was a cross-sectional study of 2315 rural to-urban migrant workers and 2347 local urban residents in the Shenzhen-Dongguan economic zone (China) in 2013. Outcomes included HRQOL (measured by Health Survey Short Form 36) and health service utilization (self-reported). RESULTS: Compared to local urban residents, rural-to-urban migrant workers had lower scores in all domains of HRQOL, and were more likely to report chronic illnesses (9.2% vs. 6.0%, adjusted OR = 1.62, 95% CI 1.28-2.04) and recent two-week morbidity (21.3% vs. 5.0%, adjusted OR = 5.41, 95% CI 4.26-6.88). Among individuals who reported sickness in the recent two weeks, migrant workers were much less likely to see a doctor (32.7% vs. 66.7%, adjusted OR = 0.21, 95% CI 0.13-0.36). CONCLUSIONS: Chinese rural-to-urban migrant workers have lower HRQOL, much more frequent morbidity, but are also much less likely to see a doctor in times of sickness as compared to local urban residents, indicating the existence of significant unmet medical care needs in this population. PMID- 25689997 TI - Application of QUAL2K model to assess ecological purification technology for a polluted river. AB - Industrialization and urbanization have caused water pollution and ecosystem degradation, especially in urban canals and rivers in China; accordingly, effective water quality improvement programs are needed. In this study, the Tianlai River in Jiangsu, China was taken as a research site, and a combination of ecological purification technologies consisting of biological rope, phytoremediation, and activated carbon were applied in a laboratory-scale study to examine degradation coefficients under dynamic water conditions. Coefficients were then input into the QUAL2K model to simulate various hypothetical scenarios and determine the minimum density of ecological purification combination and hydraulic retention time (HRT) to meet Grade V or IV of the China standard for surface water. The minimum densities for Grade V and IV were 1.6 times and 2 times the experimental density, while the minimum HRTs for Grade V and IV were 2.4 day and 3 day. The results of this study should provide a practical and efficient design method for ecological purification programs. PMID- 25689998 TI - Dynamic assessment of water quality based on a variable fuzzy pattern recognition model. AB - Water quality assessment is an important foundation of water resource protection and is affected by many indicators. The dynamic and fuzzy changes of water quality lead to problems for proper assessment. This paper explores a method which is in accordance with the water quality changes. The proposed method is based on the variable fuzzy pattern recognition (VFPR) model and combines the analytic hierarchy process (AHP) model with the entropy weight (EW) method. The proposed method was applied to dynamically assess the water quality of Biliuhe Reservoir (Dailan, China). The results show that the water quality level is between levels 2 and 3 and worse in August or September, caused by the increasing water temperature and rainfall. Weights and methods are compared and random errors of the values of indicators are analyzed. It is concluded that the proposed method has advantages of dynamism, fuzzification and stability by considering the interval influence of multiple indicators and using the average level characteristic values of four models as results. PMID- 25689999 TI - Older male physicians have lower risk of trochanteric but not cervical hip fractures. AB - BACKGROUND: Osteoporosis is pathophysiologically related to trochanteric fractures, and this condition is more preventable by lifestyle modifications than cervical fractures. We investigated whether older physicians, who are health conscious people, are at a lower risk of hip fractures because of fewer trochanteric fractures. METHODS: Data regarding older (>=65 years) physicians (n = 4303) and matched non-medical persons (control) were retrieved from Taiwan's National Health Insurance claims. All of the subjects were obtained from NHIRD with index dates from 1 January 2000 to 31 December 2008. Cox proportional hazard and competing risk regression models were established to estimate the hazard ratio (HR) of hip fracture associated with older physicians. RESULTS: The incidence rates of trochanteric fractures were lower in older physicians than in controls (1.73 and 3.07 per 1000 person-years, respectively), whereas the rates of cervical fractures were similar between the two groups (2.45 and 2.12 per 1000 person-years, respectively). Older physicians yielded 46% lower hazard of trochanteric fractures than controls (adjusted HR 0.54, 95% confidence interval 0.37-0.79); by contrast, hazards of cervical fractures were comparable between the two groups. The HRs estimated from the competing risk models remained unchanged. CONCLUSIONS: Our findings indicated that health risk awareness may pose a significant preventive effect on trochanteric hip fractures. PMID- 25690000 TI - Relation between overweight/obesity and self-rated health among adolescents in Germany. Do socio-economic status and type of school have an impact on that relation? AB - This study investigates the relation between overweight/obesity and self-rated health (SRH), and whether this relation varies by social factors. Data was taken from the German Health Interview and Examination Survey for Children and Adolescents (KiGGS, baseline 2003-2006). For the definition of overweight and obesity, body mass index was calculated based on standardized height and weight measurements. SRH of adolescents (n = 6813, 11-17 years) was raised with the question: "How would you describe your health in general?" The response categories were "very good", "good", "fair", "poor", and "very poor". We dichotomized these responses into: "very good/good" vs. "fair/poor/very poor". Socio-economic status (SES) in the family of origin and adolescents' school type were analyzed as modifying factors. Prevalence and age-adjusted odds ratios with 95% confidence intervals were calculated by binary logistic regression models. We found that overweight and obese boys and obese girls reported fair to very poor SRH more often than their normal weight peers, and that these differences were more apparent in early than late adolescence. In addition, the relation between obesity and SRH was similarly strong in all sub-groups, but there was seldom a relation between overweight and SRH. In summary, the results show that obesity is linked to poor SRH regardless of SES and school type, while the relation between overweight and SRH varies by social factors among adolescents. PMID- 25690001 TI - Air pollution and daily clinic visits for headache in a subtropical city: Taipei, Taiwan. AB - This study was undertaken to determine whether there was an association between air pollutant levels and daily clinic visits for headache in Taipei, Taiwan. Daily clinic visits for headache and ambient air pollution data for Taipei were obtained for the period from 2006-2011. The odds ratio of clinic visits for headache was estimated using a case-crossover approach, controlling for weather variables, day of the week, seasonality, and long-term time trends. In the single pollutant models, on warm days (>=23 degrees C) statistically significant positive associations were found for increased rate of headache occurrence and levels of particulate matter (PM10), sulfur dioxide (SO2), nitrogen dioxide (NO2), carbon monoxide (CO), and ozone (O3). On cool days (<23 degrees C), all pollutants were significantly associated with increased headache visits except SO2. For the two-pollutant models, PM10, O3 and NO2 were significant for higher rate of headache visits in combination with each of the other four pollutants on cool days. On warm days, CO remained statistically significant in all two pollutant models. This study provides evidence that higher levels of ambient air pollutants increase the risk of clinic visits for headache. PMID- 25690002 TI - Impact of air pollutants on oxidative stress in common autophagy-mediated aging diseases. AB - Atmospheric pollution-induced cellular oxidative stress is probably one of the pathogenic mechanisms involved in most of the common autophagy-mediated aging diseases, including neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Alzheimer's, disease, as well as Paget's disease of bone with or without frontotemporal dementia and inclusion body myopathy. Oxidative stress has serious damaging effects on the cellular contents: DNA, RNA, cellular proteins, and cellular organelles. Autophagy has a pivotal role in recycling these damaged non-functional organelles and misfolded or unfolded proteins. In this paper, we highlight, through a narrative review of the literature, that when autophagy processes are impaired during aging, in presence of cumulative air pollution induced cellular oxidative stress and due to a direct effect on air pollutant, autophagy-mediated aging diseases may occur. PMID- 25690003 TI - Overweight and obese adolescent girls: the importance of promoting sensible eating and activity behaviors from the start of the adolescent period. AB - The adolescent period is associated with changes in eating and activity behaviors in girls. Less reliance on parental provision and choice of food, coupled with a decrease in participation in physical activity and sport, can create an energy imbalance, predisposing to weight gain. Physiological alterations to body composition, reduction in insulin sensitivity, and psychological adjustments may further amplify the risk of becoming overweight and maintaining an unhealthy level of body fat into childbearing years. During pregnancy excess body fat is a risk factor for poor pregnancy outcomes and may predispose an infant to a lifelong heightened risk of being overweight and developing chronic disease. Interventions aimed at preventing the accumulation of body fat in adolescent girls and young women may have far reaching impact and be critically important in reducing intergenerational weight gain. Lifestyle interventions in adolescence have the potential to modify adult obesity risk by switching at-risk individuals from a high to lower obesity risk trajectory. This paper discusses multiple approaches to assist at-risk individuals reduce obesity risk. A key focus is placed on engagement in food preparation and choice, and opportunities for physical activity and sport. Support, education, and opportunity at home and at school, are often associated with the success of lifestyle interventions, and may enable adolescents to make positive choices, and engage in health promoting behaviors during adolescence and childbearing years. PMID- 25690004 TI - Microvascular Complications in Childhood-Onset Type 1 Diabetes and Celiac Disease: A Multicenter Longitudinal Analysis of 56,514 Patients From the German Austrian DPV Database. AB - OBJECTIVE: To investigate whether celiac disease (CD) associated with type 1 diabetes increases the risk of microvascular complications. RESEARCH DESIGN AND METHODS: Patients (n = 56,514) aged >10 years with diabetes duration <20 years from 392 centers in Germany and Austria were assigned to one of three categories (n): no CD (50,933), biopsy-confirmed CD (812), or suspected CD (4,769; clinical diagnosis or positive antibodies). The confirmed and suspected groups were combined and analyzed for retinopathy or nephropathy. Cox proportional hazards regression was used to adjust for potential confounders (glycated hemoglobin [HbA1c], age at diabetes onset, sex, smoking, dyslipidemia, and hypertension). RESULTS: Kaplan-Meier analysis revealed that retinopathy and nephropathy occurred earlier in the presence versus absence of CD: retinopathy at age 26.7 years (95% CI 23.7-30.2) in 25% of patients with CD vs. age 33.7 years (33.2-34.4) in 25% without CD and microalbuminuria at age 32.8 years (29.7-42.5) vs. 42.4 years (41.4-43.3). The adjusted risk for both retinopathy (hazard ratio 1.263 [95% CI 1.078-1.481]) and nephropathy (1.359 [1.228-1.504]) was higher in patients with diabetes and CD versus those without CD. Cox regression revealed CD as an independent risk factor for microvascular complications after adjustment for confounders. CONCLUSIONS: CD is an independent risk factor for retinopathy and nephropathy in patients with type 1 diabetes. Our study therefore supports the recommendation for regular serologic testing for CD, even in the absence of clinical CD. Further prospective studies are required to investigate whether a gluten-free diet might reduce the risk of microvascular disorders in patients with diabetes and CD. PMID- 25690005 TI - Cognitive Behavioral Therapy Versus Sertraline in Patients With Depression and Poorly Controlled Diabetes: The Diabetes and Depression (DAD) Study: A Randomized Controlled Multicenter Trial. AB - OBJECTIVE: This study compared the long-term efficacy of a diabetes-specific cognitive behavioral group therapy (CBT) with sertraline in patients with diabetes and depression who initially responded to short-term depression treatment. RESEARCH DESIGN AND METHODS: A randomized controlled single-blind trial was conducted in 70 secondary care centers across Germany comparing 12 weeks of CBT with sertraline in 251 patients with type 1 or 2 diabetes (mean HbA1c 9.3%, 78 mmol/mol) and major depression (Structured Clinical Interview for DSM-IV [SCID]). After 12 weeks, treatment responders (>=50% reduction Hamilton Depression Rating Scale [HAMD-17]) were included in the 1-year study phase where CBT patients were encouraged to use bibliotherapy and sertraline patients received continuous treatment. We analyzed differences for HbA1c (primary outcome) and reduction (HAMD-17) or remission (SCID) of depression from baseline to the 1-year follow-up using ANCOVA or logistic regression analysis. RESULTS: After 12 weeks, 45.8% of patients responded to antidepressant treatment and were included in the 1-year study phase. Adjusted HbA1c mean score changes from baseline to the end of the long-term phase (-0.27, 95% CI -0.62 to 0.08) revealed no significant difference between interventions. Depression improved in both groups, with a significant advantage for sertraline (HAMD-17 change: -2.59, 95% CI 1.15-4.04, P < 0.05). CONCLUSIONS: Depression improved under CBT and sertraline in patients with diabetes and depression, with a significant advantage for sertraline, but glycemic control remained unchanged. CBT and sertraline as single treatment are insufficient to treat secondary care diabetes patients with depression and poor glycemic control. PMID- 25690006 TI - On the interplay of microvasculature, parenchyma, and memory in type 2 diabetes. AB - OBJECTIVE: Type 2 diabetes is associated with accelerated cognitive decline, especially regarding memory for which the hippocampus plays an essential role. The pathophysiological mechanisms still remain to be elucidated. The purpose of this study is to examine whether hippocampal microvascular and microstructural changes are related to type 2 diabetes (based on status or based on fasting blood glucose [FBG] levels) and verbal memory performance. RESEARCH DESIGN AND METHODS: Thirty-nine participants with type 2 diabetes (64.5 +/- 6.1 years old) and 34 participants without type 2 diabetes (58.3 +/- 9.2 years old) underwent detailed cognitive assessments and 3-Tesla MRI using intravoxel incoherent motion (IVIM) MRI. Multivariate regression analyses controlling for age, sex, education level, BMI, systolic blood pressure, hematocrit level, and relative hippocampal volume were performed to examine associations between hippocampal IVIM measures, type 2 diabetes (status and FBG), and memory performance. RESULTS: For the microvasculature, blood perfusion volume (f) was larger in participants with type 2 diabetes, f and blood flow (fD*) increased with higher FBG levels, and microvascular pseudodiffusion (D*) and fD*, which are indicative of altered microvasculature, were higher in participants with both relatively high FBG levels and low memory performance. In addition, fD* increased with lower memory performance. For the parenchymal microstructure, the diffusion (D), indicative of injured microstructure, was higher with reduced memory performance. CONCLUSIONS: In addition to the parenchymal microstructure, especially the microvascular properties of the hippocampus are altered in participants with both type 2 diabetes and memory problems and possibly hint at an underlying vascular mechanism. PMID- 25690007 TI - Regulation of melanosome number, shape and movement in the zebrafish retinal pigment epithelium by OA1 and PMEL. AB - Analysis of melanosome biogenesis in the retinal pigment epithelium (RPE) is challenging because it occurs predominantly in a short embryonic time window. Here, we show that the zebrafish provides an ideal model system for studying this process because in the RPE the timing of melanosome biogenesis facilitates molecular manipulation using morpholinos. Morpholino-mediated knockdown of OA1 (also known as GPR143), mutations in the human homologue of which cause the most common form of human ocular albinism, induces a major reduction in melanosome number, recapitulating a key feature of the mammalian disease where reduced melanosome numbers precede macromelanosome formation. We further show that PMEL, a key component of mammalian melanosome biogenesis, is required for the generation of cylindrical melanosomes in zebrafish, which in turn is required for melanosome movement into the apical processes and maintenance of photoreceptor integrity. Spherical and cylindrical melanosomes containing similar melanin volumes co-exist in the cell body but only cylindrical melanosomes enter the apical processes. Taken together, our findings indicate that melanosome number and shape are independently regulated and that melanosome shape controls a function in the RPE that depends on localisation in the apical processes. PMID- 25690008 TI - Sep(t)arate or not - how some cells take septin-independent routes through cytokinesis. AB - Cytokinesis is the final step of cell division, and is a process that requires a precisely coordinated molecular machinery to fully separate the cytoplasm of the parent cell and to establish the intact outer cell barrier of the daughter cells. Among various cytoskeletal proteins involved, septins are known to be essential mediators of cytokinesis. In this Commentary, we present recent observations that specific cell divisions can proceed in the absence of the core mammalian septin SEPT7 and its Drosophila homolog Peanut (Pnut) and that thus challenge the view that septins have an essential role in cytokinesis. In the pnut mutant neuroepithelium, orthogonal cell divisions are successfully completed. Similarly, in the mouse, Sept7-null mutant early embryonic cells and, more importantly, planktonically growing adult hematopoietic cells undergo productive proliferation. Hence, as discussed here, mechanisms must exist that compensate for the lack of SEPT7 and the other core septins in a cell-type-specific manner. Despite there being crucial non-canonical immune-relevant functions of septins, septin depletion is well tolerated by the hematopoietic system. Thus differential targeting of cytokinesis could form the basis for more specific anti proliferative therapies to combat malignancies arising from cell types that require septins for cytokinesis, such as carcinomas and sarcomas, without impairing hematopoiesis that is less dependent on septin. PMID- 25690009 TI - Pombe's thirteen - control of fission yeast cell division by the septation initiation network. AB - The septation initiation network (SIN) regulates aspects of cell growth and division in Schizosaccharomyces pombe and is essential for cytokinesis. Insufficient signalling results in improper assembly of the contractile ring and failure of cytokinesis, generating multinucleated cells, whereas too much SIN signalling uncouples cytokinesis from the rest of the cell cycle. SIN signalling is therefore tightly controlled to coordinate cytokinesis with chromosome segregation. Signalling originates from the cytoplasmic face of the spindle pole body (SPB), and asymmetric localisation of some SIN proteins to one of the two SPBs during mitosis is important for regulation of the SIN. Recent studies have identified in vivo substrates of the SIN, which include components involved in mitotic control, those of the contractile ring and elements of the signalling pathway regulating polarised growth. The SIN is also required for spore formation following meiosis. This has provided insights into how the SIN performs its diverse functions in the cell cycle and shed new light on its regulation. PMID- 25690010 TI - Ultrasound investigation of the glenohumeral joint by anterior access in patients with rheumatoid arthritis and healthy controls. AB - BACKGROUND: The aim of this study was to measure glenohumeral joint (GHJ) parameters via the anterior access through ultrasound and to compare to data from posterior and inferior accesses. MATERIAL AND METHODS: Twenty healthy controls (M: F=15: 5, aged 45.1+/-11.2 years) and 16 patients (M: F=5: 11, aged 54.6+/ 14.7 years) with active rheumatoid arthritis (RA) (DAS 28 4.6+/-1.2) were investigated (SonoSite-Titan). To make the GHJ visible on the anterior access, we used the original GHJ opening maneuver. The GHJ width was measured for every transducer position at 2 points. The positions were: posterior transversal, inferior longitudinal, anterior longitudinal along the articular line, anterior transversal upper, middle and lower. The joint width included thickness of cartilage plus synovial fluid/pannus. Rotator interval (RI) width and height (upper biceps channel) were measured. RESULTS: Our normal GHJ values by posterior and inferior accesses were within previously estimated values (<2 mm and <3 mm, respectively). We acquired the first values of GHJ width from the anterior access. The last were within a range of 0.7-1.7 mm for healthy controls. Patients with RA showed significantly enlarged joint cavities. RI was not inflamed. Posterior and inferior data of GHJ width were significantly correlated (p=0.01). The data did not correlate with anterior values (p=+0.44, p=-0.56). Synovitis was much more prominent in posterior, upper anterior transversal, and anterior longitudinal accesses. CONCLUSIONS: The GHJ may be visualized by anterior access using a special maneuver. Synovitis in the anterior region of the GHJ may develop at an independent rate. Anterior GHJ sonography may be complementary to the classic access. PMID- 25690011 TI - Sympathetic vasoconstriction takes an unexpected pannexin detour. AB - Sympathetic vasoconstriction plays an important role in the control of blood pressure and the distribution of blood flow. In this issue of Science Signaling, Billaud et al. show that sympathetic vasoconstriction occurs through a complex scheme involving the activation of large-pore pannexin 1 channels and the subsequent release of adenosine triphosphate that promotes contraction in an autocrine and paracrine manner. This elaborate mechanism may function as a point of intercept for other signaling pathways-for example, in relation to the phenomenon "functional sympatholysis," in which exercise abrogates sympathetic vasoconstriction in skeletal muscle. Because pannexin 1 channels are inhibited by nitric oxide, they may function as a switch to turn off adrenergic signaling in skeletal muscle during exercise. PMID- 25690013 TI - The tyrosine phosphatase PTPN14 (Pez) inhibits metastasis by altering protein trafficking. AB - Factors secreted by tumor cells shape the local microenvironment to promote invasion and metastasis, as well as condition the premetastatic niche to enable secondary-site colonization and growth. In addition to this secretome, tumor cells have increased abundance of growth-promoting receptors at the cell surface. We found that the tyrosine phosphatase PTPN14 (also called Pez, which is mutated in various cancers) suppressed metastasis by reducing intracellular protein trafficking through the secretory pathway. Knocking down PTPN14 in tumor cells or injecting the peritoneum of mice with conditioned medium from PTPN14-deficient cell cultures promoted the growth and metastasis of breast cancer xenografts. Loss of catalytically functional PTPN14 increased the secretion of growth factors and cytokines, such as IL-8 (interleukin-8), and increased the abundance of EGFR (epidermal growth factor receptor) at the cell surface of breast cancer cells and of FLT4 (vascular endothelial growth factor receptor 3) at the cell surface of primary lymphatic endothelial cells. We identified RIN1 (Ras and Rab interactor 1) and PRKCD (protein kinase C-delta) as binding partners and substrates of PTPN14. Similar to cells overexpressing PTPN14, receptor trafficking to the cell surface was inhibited in cells that lacked PRKCD or RIN1 or expressed a nonphosphorylatable RIN1 mutant, and cytokine secretion was decreased in cells treated with PRKCD inhibitors. Invasive breast cancer tissue had decreased expression of PTPN14, and patient survival was worse when tumors had increased expression of the genes encoding RIN1 or PRKCD. Thus, PTPN14 prevents metastasis by restricting the trafficking of both soluble and membrane-bound proteins. PMID- 25690012 TI - A molecular signature in the pannexin1 intracellular loop confers channel activation by the alpha1 adrenoreceptor in smooth muscle cells. AB - Both purinergic signaling through nucleotides such as ATP (adenosine 5' triphosphate) and noradrenergic signaling through molecules such as norepinephrine regulate vascular tone and blood pressure. Pannexin1 (Panx1), which forms large-pore, ATP-releasing channels, is present in vascular smooth muscle cells in peripheral blood vessels and participates in noradrenergic responses. Using pharmacological approaches and mice conditionally lacking Panx1 in smooth muscle cells, we found that Panx1 contributed to vasoconstriction mediated by the alpha1 adrenoreceptor (alpha1AR), whereas vasoconstriction in response to serotonin or endothelin-1 was independent of Panx1. Analysis of the Panx1-deficient mice showed that Panx1 contributed to blood pressure regulation especially during the night cycle when sympathetic nervous activity is highest. Using mimetic peptides and site-directed mutagenesis, we identified a specific amino acid sequence in the Panx1 intracellular loop that is essential for activation by alpha1AR signaling. Collectively, these data describe a specific link between noradrenergic and purinergic signaling in blood pressure homeostasis. PMID- 25690014 TI - Plasma membrane Ca2+-ATPases can shape the pattern of Ca2+ transients induced by store-operated Ca2+ entry. AB - Calcium (Ca(2+)) is a critical cofactor and signaling mediator in cells, and the concentration of cytosolic Ca(2+) is regulated by multiple proteins, including the plasma membrane Ca(2+)-ATPases (adenosine triphosphatases) (PMCAs), which use ATP to transport Ca(2+) out of cells. PMCA isoforms exhibit different kinetic and regulatory properties; thus, the presence and relative abundance of individual isoforms may help shape Ca(2+) transients and cellular responses. We studied the effects of three PMCA isoforms (PMCA4a, PMCA4b, and PMCA2b) on Ca(2+) transients elicited by conditions that trigger store-operated Ca(2+) entry (SOCE) and that blocked Ca(2+) uptake into the endoplasmic reticulum in HeLa cells, human embryonic kidney (HEK) 293 cells, or primary endothelial cell isolated from human umbilical cord veins (HUVECs). The slowly activating PMCA4b isoform produced long lasting Ca(2+) oscillations in response to SOCE. The fast-activating isoforms PMCA2b and PMCA4a produced different effects. PMCA2b resulted in rapid and highly PMCA abundance-sensitive clearance of SOCE-mediated Ca(2+) transients, whereas PMCA4a reduced cytosolic Ca(2+), resulting in the establishment of a higher than baseline cytosolic Ca(2+) concentration. Mathematical modeling showed that slow activation was critical to the sustained oscillation induced by the "slow" PMCA4b pump. The modeling and experimental results indicated that the distinct properties of PMCA isoforms differentially regulate the pattern of SOCE-mediated Ca(2+) transients, which would thus affect the activation of downstream signaling pathways. PMID- 25690015 TI - Tunneling through finite graphene superlattices: resonance splitting effect. AB - An exact expression of the transmission probability through a finite graphene superlattice with an arbitrary number of potential barriers n is derived in two cases of the periodic potential: rectangular electric potential and delta function magnetic potential. Obtained transmission probabilities show two types of resonance energy: barrier-induced resonance energies unchanged as n varies and well-induced resonance energies that have undergone the (n - 1)-fold splitting as n increases. Supported by numerical calculations for various types of graphene superlattices, these analytical findings are assumed to be equally applied to all of the finite graphene superlattices regardless of their potential nature (electric or magnetic) and potential barrier shapes. PMID- 25690016 TI - From phenotyping towards breeding strategies: using in vivo indicator traits and genetic markers to improve meat quality in an endangered pig breed. AB - In endangered and local pig breeds of small population sizes, production has to focus on alternative niche markets with an emphasis on specific product and meat quality traits to achieve economic competiveness. For designing breeding strategies on meat quality, an adequate performance testing scheme focussing on phenotyped selection candidates is required. For the endangered German pig breed 'Bunte Bentheimer' (BB), no breeding program has been designed until now, and no performance testing scheme has been implemented. For local breeds, mainly reared in small-scale production systems, a performance test based on in vivo indicator traits might be a promising alternative in order to increase genetic gain for meat quality traits. Hence, the main objective of this study was to design and evaluate breeding strategies for the improvement of meat quality within the BB breed using in vivo indicator traits and genetic markers. The in vivo indicator trait was backfat thickness measured by ultrasound (BFiv), and genetic markers were allele variants at the ryanodine receptor 1 (RYR1) locus. In total, 1116 records of production and meat quality traits were collected, including 613 in vivo ultrasound measurements and 713 carcass and meat quality records. Additionally, 700 pigs were genotyped at the RYR1 locus. Data were used (1) to estimate genetic (co)variance components for production and meat quality traits, (2) to estimate allele substitution effects at the RYR1 locus using a selective genotyping approach and (3) to evaluate breeding strategies on meat quality by combining results from quantitative-genetic and molecular-genetic approaches. Heritability for the production trait BFiv was 0.27, and 0.48 for backfat thickness measured on carcass. Estimated heritabilities for meat quality traits ranged from 0.14 for meat brightness to 0.78 for the intramuscular fat content (IMF). Genetic correlations between BFiv and IMF were higher than estimates based on carcass backfat measurements (0.39 v. 0.25). The presence of the unfavorable n allele was associated with increased electric conductivity, paler meat and higher drip loss. The allele substitution effect on IMF was unfavorable, indicating lower IMF when the n allele is present. A breeding strategy including the phenotype (BFiv) combined with genetic marker information at the RYR1 locus from the selection candidate, resulted in a 20% increase in accuracy and selection response when compared with a breeding strategy without genetic marker information. PMID- 25690018 TI - Pharmacogenetics and breast cancer management: current status and perspectives. AB - INTRODUCTION: Breast cancer has benefited from a number of innovative therapeutics over the last decade. Cytotoxics, hormone therapy, targeted therapies and biologics can now be given to ensure optimal management of patients. As life expectancy of breast cancer patients has been significantly stretched and that several lines of treatment are now made available, determining the best drug or drug combinations to be primarily given and the best dosing and scheduling for each patient is critical for ensuring an optimal toxicity/efficacy balance. AREAS COVERED: Defining patient's characteristics at the tumor level (pharmacogenomics) and the constitutional level (pharmacogenetics) is a rising trend in oncology. This review covers the latest strategies based upon the search of relevant biomarkers for efficacy, resistance and toxicity to be undertaken at the bedside to shift towards precision medicine in breast cancer patients. EXPERT OPINION: In the expanding era of bioguided medicine, identifying relevant and clinically validated biomarkers from the plethora of published material remains an uneasy task. Sorting the variety of genetic and molecular markers that have been investigated over the last decade on their level of evidence and addressing the issue of drug exposure should help to improve the management of breast cancer therapy. PMID- 25690019 TI - How can information on the risk of breast cancer and hormone therapy be better understood? AB - OBJECTIVES: To evaluate postmenopausal women's knowledge of the risk of breast cancer associated with the use of hormone therapy (HT) and their perception of this risk when presented as a relative risk (RR), absolute risk (AbR) or attributable risk (AR). METHODS: A cross-sectional study was conducted with 402 postmenopausal women. The participants answered a self-response questionnaire in which data on the risk of breast cancer associated with HT were presented in the form of RR, AbR and AR. The women's concern with respect to this risk and their changes of opinion when the data were presented according to the different risk models were evaluated. RESULTS: More than 87% of the women mentioned breast cancer as one of the risks associated with the use of HT, with more women being concerned when the risk was presented as an RR. In contrast, most were unconcerned when the risk was presented as an AbR or AR. For the group as a whole, there was a significant change in opinion with respect to the women's concern regarding the risks when they were presented as an AbR or AR (p < 0.001); however, this was not the case for those women who had initially stated that breast cancer was a risk associated with HT. CONCLUSIONS: Providing information on breast cancer risk using examples that quantify the incidence of the disease provokes less concern in users and candidate users of HT. Changes of opinion occur when explanations regarding the risk are provided as RR, AbR and AR. PMID- 25690020 TI - Identification of ribosomal RNA methyltransferase gene ermF in Riemerella anatipestifer. AB - Riemerella anatipestifer is a major bacterial pathogen of waterfowl, globally responsible for avian septicaemic disease. As chemotherapy is the predominant method for the prevention and treatment of R. anatipestifer infection in poultry, the widespread use of antibiotics has favoured the emergence of antibiotic resistant strains. However, little is known about R. anatipestifer susceptibility to macrolide antibiotics and its resistance mechanism. We report for the first time the identification of a macrolide resistance mechanism in R. anatipestifer that is mediated by the ribosomal RNA methyltransferase ermF. We identified the presence of the ermF gene in 64/206 (31%) R. anatipestifer isolates from different regions in China. An ermF deletion strain was constructed to investigate the function of the ermF gene on the resistance to high levels of macrolides. The ermF mutant strain showed significantly decreased resistance to macrolide and lincosamide, exhibiting 1024-, 1024-, 4- and >2048-fold reduction in the minimum inhibitory concentrations for erythromycin, azithromycin, tylosin and lincomycin, respectively. Furthermore, functional analysis of ermF expression in E. coli XL1-blue showed that the R. anatipestifer ermF gene was functional in E. coli XL1-blue and conferred resistance to high levels of erythromycin (100 ug/ml), supporting the hypothesis that the ermF gene is associated with high level macrolide resistance. Our work suggests that ribosomal RNA modification mediated by the ermF methyltransferase is the predominant mechanism of resistance to erythromycin in R. anatipestifer isolates. PMID- 25690021 TI - Endocrine factors, memory and perceptual capacities and aging in Asian men. AB - BACKGROUND: This cross-sectional study examined the associations of hormones and age with short-term memory and perceptual capacity in 472 healthy Asian men. METHODS: The symbol digit and digit span tests from the Swedish Performance Evaluation System were used to assess perceptual capacity and memory. Linear regression analyses with the stepwise method were carried out with the SPSS 21.0 package. RESULTS: Age was associated with lower dehydorepiandrosterone sulphate (DHEA/S), insulin growth factor-1 (IGF-1), thyroxine (T4), testosterone (T), bioavailable T (BioT) and error rate (Err) but higher glucose (GLU), sex hormone binding globulin (SHBG), estradiol (E2) and retention time (RT). High GLU was associated with higher error rate, longer RT of the perceptual capacity domain and shorter digit span (DSpan) of the short-term memory domain. Higher insulin like growth factor binding protein-3 (BP3) was associated with longer DSpan. High cortisol (Cor) was associated with higher Err, while high DHEA/S was associated with shorter RT. All other hormones from the adrenal, somatotrophic and gonadal were not significantly associated with cognition. CONCLUSION: The findings suggest (1) a role for tighter control of blood glucose levels in cognitive decline with aging in men, (2) different hormones may be related to different parameters of cognition and "cognition" is not a unitary phenomenon and (3) further investigation of the potential for exogenous DHEA/S to slow cognitive decline in aging, especially as it relates to reaction time. PMID- 25690022 TI - Nocturia in patients with benign prostatic hyperplasia: evaluating the significance of ageing, co-morbid illnesses, lifestyle and medical therapy in treatment outcome in real life practice. AB - AIM: The aim of study was to evaluate the influence of ageing, lifestyle, and co morbid illnesses on treatment outcome of nocturia among men with BPH. METHODS: Patients with BPH on medical therapy of least 6 months and up to 48 months were interviewed. Nocturia episodes, co morbid illnesses, beverage intake frequency, medications and work history were documented. Body Mass Index (BMI), waist circumference (WC), prostate volume, and prostate specific antigen (PSA) were recorded. Treatment failure is defined as persistent nocturia despite on medical therapy for BPH. RESULTS: In 156 patients, the prevalence of nocturia was 96.7% while nocturia of 2 or more was 85.9%. Factors associated with treatment failure was older age (p < 0.01), usage of diuretics (p = 0.03), and antimuscarinics (p < 0.01), while active working status (p < 0.01), use of desmopression (p = 0.01), and increased coffee intake (p = 0.02) were associated with nocturia improvement. Co-morbid illnesses, obesity, WC, alcohol intake, PSA, prostate volume, and use of BPH medical therapy did not influence treatment outcome. CONCLUSION: Advancing age has a significance negative outcome on nocturia treatment, while standard BPH medical therapy and co morbid illnesses have an insignificant impact. However, alleviation of bothersome symptoms is possible with the understanding of its patho-physiology and individual-based approach to treatment and expected outcome. PMID- 25690023 TI - Ballistic thermal transport by phonons in three dimensional periodic nanostructures. AB - Ballistic thermal transport properties by phonons in three dimensional (3D) periodic nanostructures is investigated. Results show that thermal transport properties in 3D periodic nanostructures can be efficiently tuned by modulating structural parameters of systems. When the incident frequency is below the first cutoff frequency, the quasi/formal-periodic oscillations of the transmission coefficient versus the periodic number/length can be observed. When the incident frequency is above the first cutoff frequency, however, these quasi/formal periodic oscillations cannot be observed. As the periodic number is increased, the thermal conductance undergoes a prominent transition from the decrease to the constant. We also observe other intriguing physics properties such as stop frequency gaps and quantum thermal conductance in 3D periodic nanostructures. Some similarities and differences between 2D and 3D periodic systems are identified. PMID- 25690024 TI - Essential oils for dairy calves: effects on performance, scours, rumen fermentation and intestinal fauna. AB - The first cause of death of dairy calves is often diarrhea which is mainly caused by pathogenic bacteria, which can result in excessive use of antibiotics. However, facing the increase concern by the industry and consumers, the use of antibiotics not only to control pathogens, but also to manipulate growth, has become a challenge. Alternative additives, such essential oils, have the potential to decrease antibiotic use, without reducing performance or increasing mortality of dairy calves. The objective of this study was to evaluate the use of a commercial blend of essential oils, incorporated into the calf starter and/or milk replacer to monitor the effect on overall calf performance, fecal scores and rumen fermentation parameters. A total of 30 Holstein calves received 6 l/day of a liquid diet, consisting of a commercial milk replacer containing 20% CP : 15% fat (EE). Calves had free choice access to water and calf starter. Weaning occurred at week 8, and calves were followed until the 10th week of age. Calves were assigned to one of the three treatment groups in a randomized block design. TREATMENTS: (1) control without essential oils supplementation (C); (2) essential oils blend in the milk replacer at 400 mg/kg (MR) and (3) essential oils blend in the milk replacer (200 mg/kg) and starter feed (200 mg/kg) (MRS). From the 2nd week, calves were weighed and body measurements were taken, while concentrate intake and fecal scores were monitored daily. Blood samples were drawn weekly for determination of glucose and beta-hydroxybutyrate. Fecal samples were collected weekly and analyzed for lactic acid bacteria and Enterobacteria; and ruminal fluid for determination of pH, short chain fatty acids, ammonia-N and counts of amylolytic and cellulolytic bacteria, and protozoa. Performance, fecal scores and intestines microorganisms were not affected by the essential oils supplementation. Ruminal and blood parameters were also not affected, with the exception the rumen ammonia-N concentration, with higher values when essential oils were supplemented in a combination of milk replacer and starter feed. Most of the evaluated parameters were affected by age of calves, mainly as a response to the increase in concentrate intake as animals' aged. Essential oils are promising substitutes for antibiotics. However, the dose and routes of administration deserve further studies, allowing a better animal performance and health to be achieved. PMID- 25690025 TI - Placental expression of endothelial and inducible nitric oxide synthase and NO metabolism in gestational hypertension: a case-control study. AB - OBJECTIVE: Hypertension is one of the most common medical disorders in pregnancy and a role of nitric oxide (NO) metabolism has been described. Thus, the present work aimed at determining placental gene expression of eNOS and iNOS, to measure NO and ONOO(-) levels in patients with gestational hypertension (GH). METHODS: Fifteen patients with GH and 15 healthy pregnant controls were enrolled in the study. Placental tissue was taken immediately after delivery and was stored at 80 degrees C until analysis. A piece of frozen tissue was homogenized in the appropriate buffer. Total RNA was extracted and was reverse transcribed to obtain complementary DNA that was used for real-time PCR for iNOS and eNOS expression, whereas NO and ONOO(-) production were measured by commercially available kits. RESULTS: Placental eNOS and iNOS mRNA levels were significantly reduced in GH when compared to controls. NO and ONOO(-) production were both significantly higher in GH than controls. CONCLUSIONS: The reduced eNOS and iNOS gene expression in women with GH reinforces the hypothesis that the mechanisms involving NO pathways, may promote oxidative damage, by contributing to the reduced blood flow and increased resistance in the feto-maternal circulation and suggests the use of NO modulators as useful tools in GH management. PMID- 25690026 TI - Maternal and cord blood vitamin D status in high-altitude pregnancy. AB - OBJECTIVE: We aimed to explore the risk factors that may lead to vitamin D deficiency in pregnant women living in moderately high-altitude regions. METHODS: The study was conducted prospectively between November 2012 and July 2013. City of Erzurum is located at an altitude of 1900-2200 m, north Turkey at 39 degrees 4' latitude. Healthy mothers that gave birth after completing 37th week of their pregnancies and healthy neonates weighting >2500 g were included in the study. For 25-hydroxyvitamin D (25(OH)D) analyses venous blood samples of 2 ml were obtained from the umbilical cord and the mother. Questionnaires were developed covering the demographical characteristics and possible risk factors for mothers. RESULTS: Totally 81 mothers and neonates were included into the study. The mean 25(OH)D level of mothers was 7.1 +/- 6.5 ng/ml. It was noted that 45 (55.7%) mothers had severe deficiency. Multivariate linear regression analysis showed that the dressing style and the level of sunlight received by the house were independent factors affecting the level of 25(OH)D. CONCLUSION: Our findings showed that cultural factors had significant effects on vitamin D levels. We believe that appropriate dose of vitamin D prophylaxis should be administered to pregnant women, considering the risk factors as well as the geographical features. PMID- 25690027 TI - Intraoperative mapping and monitoring in supratentorial tumor surgery. AB - With the increasing strive for complete resections of supratentorial low or high grade gliomas, the necessity for intraoperative electrical stimulation methods to map and monitor functional important cortical or subcortical brain areas increased. While many brain functions can be assessed during awake surgery using electrical stimulation, motor function as well as visual function can be mapped and monitored in the asleep patient, as well. Several different methods reviewed in this article are available which lead to an improved functional outcome while increasing the extent of tumor resection and thereby potentially the oncological outcome of the patient. PMID- 25690028 TI - Current status of photodynamic therapy in digestive tract carcinoma in Japan. AB - Photodynamic therapy (PDT) is an effective local treatment modality as a cancer specific laser ablation in malignancy of some organs including digestive tracts or bile duct. In Japan, PDT has been applied at the early period after the first clinical induction in 1980's. Although the useful efficacy was clarified, PDT has not been fully applied because of the phototoxicity of the porfimer sodium. The next generated talaporfin-sodium was used for PDT, in which phototoxicity was reduced and, however, the clinical efficacy for digestive tract malignancy has not yet been clarified. By proceeding the experimental and clinical trials, it is necessary to clarify the evidence of efficacy as a local powerful treatment with the conventional surgery, brachiotherapy and chemotherapy in the future step. PMID- 25690029 TI - Development of biodegradable nanocarriers loaded with a monoclonal antibody. AB - Treatments utilizing monoclonal antibody therapeutics against intracellular protein-protein interactions in cancer cells have been hampered by several factors, including poor intracellular uptake and rapid lysosomal degradation. Our current work examines the feasibility of encapsulating monoclonal antibodies within poly(lactic-co-glycolic acid) (PLGA) nanoparticles using a water/oil/water double emulsion solvent evaporation technique. This method can be used to prepare protective polymeric nanoparticles for transporting functional antibodies to the cytoplasmic compartment of cancer cells. Nanoparticles were formulated and then characterized using a number of physical and biological parameters. The average nanoparticle size ranged from 221 to 252 nm with a low polydispersity index. Encapsulation efficiency of 16%-22% and antibody loading of 0.3%-1.12% were observed. The antibody molecules were released from the nanoparticles in a sustained manner and upon release maintained functionality. Our studies achieved successful formulation of antibody loaded polymeric nanoparticles, thus indicating that a PLGA-based antibody nanoformulation is a promising intracellular delivery vehicle for a large number of new intracellular antibody targets in cancer cells. PMID- 25690030 TI - Isolation and molecular characterization of 1-aminocyclopropane-1-carboxylic acid synthase genes in Hevea brasiliensis. AB - Ethylene is an important factor that stimulates Hevea brasiliensis to produce natural rubber. 1-Aminocyclopropane-1-carboxylic acid synthase (ACS) is a rate limiting enzyme in ethylene biosynthesis. However, knowledge of the ACS gene family of H. brasiliensis is limited. In this study, nine ACS-like genes were identified in H. brasiliensis. Sequence and phylogenetic analysis results confirmed that seven isozymes (HbACS1-7) of these nine ACS-like genes were similar to ACS isozymes with ACS activity in other plants. Expression analysis results showed that seven ACS genes were differentially expressed in roots, barks, flowers, and leaves of H. brasiliensis. However, no or low ACS gene expression was detected in the latex of H. brasiliensis. Moreover, seven genes were differentially up-regulated by ethylene treatment. These results provided relevant information to help determine the functions of the ACS gene in H. brasiliensis, particularly the functions in regulating ethylene stimulation of latex production. PMID- 25690031 TI - Major peptides from amaranth (Amaranthus cruentus) protein inhibit HMG-CoA reductase activity. AB - The objective of this study was to identify the major peptides generated by the in vitro hydrolysis of Amaranthus cruentus protein and to verify the effect of these peptides on the activity of 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG CoA reductase), a key enzyme in cholesterol biosynthesis. A protein isolate was prepared, and an enzymatic hydrolysis that simulated the in vivo digestion of the protein was performed. After hydrolysis, the peptide mixture was filtered through a 3 kDa membrane. The peptide profile of this mixture was determined by reversed phase high performance chromatography (RP-HPLC), and the peptide identification was performed by LC-ESI MS/MS. Three major peptides under 3 kDa were detected, corresponding to more than 90% of the peptides of similar size produced by enzymatic hydrolysis. The sequences identified were GGV, IVG or LVG and VGVI or VGVL. These peptides had not yet been described for amaranth protein nor are they present in known sequences of amaranth grain protein, except LVG, which can be found in amaranth alpha-amylase. Their ability to inhibit the activity of HMG-CoA reductase was determined, and we found that the sequences GGV, IVG, and VGVL, significantly inhibited this enzyme, suggesting a possible hypocholesterolemic effect. PMID- 25690032 TI - Biological functions of thyroid hormone in placenta. AB - The thyroid hormone, 3,3,5-triiodo-L-thyronine (T3), modulates several physiological processes, including cellular growth, differentiation, metabolism, inflammation and proliferation, via interactions with thyroid hormone response elements (TREs) in the regulatory regions of target genes. Infection and inflammation are critical processes in placental development and pregnancy related diseases. In particular, infection is the leading cause of neonatal mortality and morbidity worldwide. However, to date, no successful approach has been developed for the effective diagnosis of infection in preterm infants. Pre eclampsia (PE) is a serious disorder that adversely affects ~5% of human pregnancies. Recent studies identified a multiprotein complex, the inflammasome, including the Nod-like receptor (NLR) family of cytosolic pattern recognition receptors, the adaptor protein apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and caspase-1, which plays a vital role in the placenta. The thyroid hormone modulates inflammation processes and is additionally implicated in placental development and disease. Therefore, elucidation of thyroid hormone receptor-regulated inflammation-related molecules, and their underlying mechanisms in placenta, should facilitate the identification of novel predictive and therapeutic targets for placental disorders. This review provides a detailed summary of current knowledge with respect to identification of useful biomarkers and their physiological significance in placenta. PMID- 25690033 TI - Genetic variant in interleukin-18 is associated with idiopathic recurrent miscarriage in Chinese Han population. AB - Levels of IL-18 were significantly lower in women with recurrent miscarriage (RM) than those without idiopathic RM. IL-18 promoter single nucleotide polymorphisms were previously identified to have an impact on IL18 gene transcription activity and influence the level of IL-18 protein production. The aim of this study was to evaluate whether IL-18 gene polymorphisms are risk factors for idiopathic RM in Chinese Han population. Study subjects comprised of 484 idiopathic RM patients and 468 controls. Three polymorphisms (rs360717, rs187238, rs1946518) in IL-18 gene and serum IL-18 concentrations were assessed. rs187238 variant exhibits significant association with RM in additive and recessive genetic model (additive model p = 1.05 * 10(-4), dominant model p = 0.025, recessive model p = 2.43 * 10( 5)). In contrast, rs360717 and rs1946518 are not significantly associated with RM. Serum IL-18 levels are significantly lower in RM cases than in control (111.98 +/- 93.13 versus 148.74 +/- 130.51 pg/mL, p = 7.42 * 10(-7)). There are lower levels of serum IL-18 in rs187238 homozygous mutant (CC) than homozygous wild-type (GG) in this study population, including cases and control groups (98.31 +/- 86.46 versus 131.87 +/- 115.02 pg/mL, p = 0.015). These results suggest that reduced IL-18 levels and rs187238 variant may contribute to pathogenesis of idiopathic RM in Chinese Han population. PMID- 25690034 TI - The role of BH3-mimetic drugs in the treatment of pediatric hepatoblastoma. AB - Pediatric hepatoblastoma (HB) is commonly treated by neoadjuvant chemotherapy and surgical tumor resection according to international multicenter trial protocols. Complete tumor resection is essential and survival rates up to 95% have now been achieved in those tumors classified as standard-risk HB. Drug resistance and occurrence of metastases remain the major challenges in the treatment of HB, especially in high-risk tumors. These conditions urgently require the development of alternative therapeutic strategies. One of those alternatives is the modulation of apoptosis in HB cells. HBs regularly overexpress anti-apoptotic proteins of the Bcl-family in comparison to healthy liver tissue. This fact may contribute to the development of chemoresistance of HB cells. Synthetic small inhibitory molecules with BH3-mimetic effects, such as ABT-737 and obatoclax, enhance the susceptibility of tumor cells to different cytotoxic drugs and thereby affect initiator proteins of the apoptosis cascade via the intrinsic pathway. Besides additive effects on HB cell viability when used in combination with cytotoxic drugs, BH3-mimetics also play a role in preventing metastasation by reducing adhesion and inhibiting cell migration abilities. Presumably, including additive BH3-mimetic drugs into existing therapeutic regimens in HB patients might allow dose reduction of established cytotoxic drugs and thereby associated immanent side effects, while maintaining the antitumor activity. Furthermore, reduction of tumor growth and inhibition of tumor cell dissemination may facilitate complete surgical tumor resection, which is mandatory in this tumor type resulting in improved survival rates in high-risk HB. Currently, there are phase I and phase II clinical trials in several cancer entities using this potential target. This paper reviews the available literature regarding the use of BH3-mimetic drugs as single agents or in combination with chemotherapy in various malignancies and focuses on results in HB cells. PMID- 25690035 TI - Phosphoproteomic analysis of the highly-metastatic hepatocellular carcinoma cell line, MHCC97-H. AB - Invasion and metastasis of hepatocellular carcinoma (HCC) is a major cause for lethal liver cancer. Signaling pathways associated with cancer progression are frequently reconfigured by aberrant phosphorylation of key proteins. To capture the key phosphorylation events in HCC metastasis, we established a methodology by an off-line high-pH HPLC separation strategy combined with multi-step IMAC and LC MS/MS to study the phosphoproteome of a metastatic HCC cell line, MHCC97-H (high metastasis). In total, 6593 phosphopeptides with 6420 phosphorylation sites (p sites) of 2930 phosphoproteins were identified. Statistical analysis of gene ontology (GO) categories for the identified phosphoproteins showed that several of the biological processes, such as transcriptional regulation, mRNA processing and RNA splicing, were over-represented. Further analysis of Kyoto Encyclopedia of Genes and Genomes (KEGG) annotations demonstrated that phosphoproteins in multiple pathways, such as spliceosome, the insulin signaling pathway and the cell cycle, were significantly enriched. In particular, we compared our dataset with a previously published phosphoproteome in a normal liver sample, and the results revealed that a number of proteins in the spliceosome pathway, such as U2 small nuclear RNA Auxiliary Factor 2 (U2AF2), Eukaryotic Initiation Factor 4A-III (EIF4A3), Cell Division Cycle 5-Like (CDC5L) and Survival Motor Neuron Domain Containing 1 (SMNDC1), were exclusively identified as phosphoproteins only in the MHCC97-H cell line. These results indicated that the phosphorylation of spliceosome proteins may participate in the metastasis of HCC by regulating mRNA processing and RNA splicing. PMID- 25690037 TI - Cultivation of Chlorella vulgaris and Arthrospira platensis with recovered phosphorus from wastewater by means of zeolite sorption. AB - In this study, zeolite was employed for the separation and recovery of P from synthetic wastewater and its use as phosphorus (P) source for the cultivation of the green microalga Chlorella vulgaris and the cyanobacterium Arthrospira (Spirulina) platensis. At P-loaded zeolite concentration of 0.15-1 g/L, in which P was limited, the two species displayed quite different behavior regarding their growth and biomass composition. C. vulgaris preferred to increase the intracellular P and did not synthesize biomass, while A. platensis synthesized biomass keeping the intracellular P as low as possible. In addition under P limitation, C. vulgaris did display some little alteration of the biomass composition, while A. platensis did it significantly, accumulating carbohydrates around 70% from about 15%-20% (control). Both species could desorb P from zeolite biologically. A. platensis could recover over 65% and C. vulgaris 25% of the P bounded onto zeolite. When P-loaded zeolite concentration increased to 5 g/L, P was adequate to support growth for both species. Especially in the case of C. vulgaris, growth was stimulated from the presence of P-loaded zeolite and produced more biomass compared to the control. PMID- 25690036 TI - Potential role of dipeptidyl peptidase IV in the pathophysiology of heart failure. AB - Dipeptidyl peptidase IV (DPPIV) is a widely expressed multifunctional serine peptidase that exists as a membrane-anchored cell surface protein or in a soluble form in the plasma and other body fluids. Numerous substrates are cleaved at the penultimate amino acid by DPPIV, including glucagon-like peptide-1 (GLP-1), brain natriuretic peptide (BNP) and stromal cell-derived factor-1 (SDF-alpha), all of which play important roles in the cardiovascular system. In this regard, recent reports have documented that circulating DPPIV activity correlates with poorer cardiovascular outcomes in human and experimental heart failure (HF). Moreover, emerging evidence indicates that DPPIV inhibitors exert cardioprotective and renoprotective actions in a variety of experimental models of cardiac dysfunction. On the other hand, conflicting results have been found when translating these promising findings from preclinical animal models to clinical therapy. In this review, we discuss how DPPIV might be involved in the cardio renal axis in HF. In addition, the potential role for DPPIV inhibitors in ameliorating heart disease is revised, focusing on the effects of the main DPPIV substrates on cardiac remodeling and renal handling of salt and water. PMID- 25690038 TI - beta-Hydroxybutyric sodium salt inhibition of growth hormone and prolactin secretion via the cAMP/PKA/CREB and AMPK signaling pathways in dairy cow anterior pituitary cells. AB - beta-hydroxybutyric acid (BHBA) regulates the synthesis and secretion of growth hormone (GH) and prolactin (PRL), but its mechanism is unknown. In this study, we detected the effects of BHBA on the activities of G protein signaling pathways, AMPK-alpha activity, GH, and PRL gene transcription, and GH and PRL secretion in dairy cow anterior pituitary cells (DCAPCs). The results showed that BHBA decreased intracellular cAMP levels and a subsequent reduction in protein kinase A (PKA) activity. Inhibition of PKA activity reduced cAMP response element binding protein (CREB) phosphorylation, thereby inhibiting GH and PRL transcription and secretion. The effects of BHBA were attenuated by a specific Galphai inhibitor, pertussis toxin (PTX). In addition, intracellular BHBA uptake mediated by monocarboxylate transporter 1 (MCT1) could trigger AMPK signaling and result in the decrease in GH and PRL mRNA translation in DCAPCs cultured under low-glucose and non-glucose condition when compared with the high-glucose group. This study identifies a biochemical mechanism for the regulatory action of BHBA on GH and PRL gene transcription, translation, and secretion in DCAPCs, which may be one of the factors that regulate pituitary function during the transition period in dairy cows. PMID- 25690039 TI - Personalization of the immunosuppressive treatment in renal transplant recipients: the great challenge in "omics" medicine. AB - Renal transplantation represents the most favorable treatment for patients with advanced renal failure and it is followed, in most cases, by a significant enhancement in patients' quality of life. Significant improvements in one-year renal allograft and patients' survival rates have been achieved over the last 10 years primarily as a result of newer immunosuppressive regimens. Despite these notable achievements in the short-term outcome, long-term graft function and survival rates remain less than optimal. Death with a functioning graft and chronic allograft dysfunction result in an annual rate of 3%-5%. In this context, drug toxicity and long-term chronic adverse effects of immunosuppressive medications have a pivotal role. Unfortunately, at the moment, except for the evaluation of trough drug levels, no clinically useful tools are available to correctly manage immunosuppressive therapy. The proper use of these drugs could potentiate therapeutic effects minimizing adverse drug reactions. For this purpose, in the future, "omics" techniques could represent powerful tools that may be employed in clinical practice to routinely aid the personalization of drug treatment according to each patient's genetic makeup. However, it is unquestionable that additional studies and technological advances are needed to standardize and simplify these methodologies. PMID- 25690040 TI - Comprehensive analysis suggests overlapping expression of rice ONAC transcription factors in abiotic and biotic stress responses. AB - NAC (NAM/ATAF/CUC) transcription factors comprise a large plant-specific gene family that contains more than 149 members in rice. Extensive studies have revealed that NAC transcription factors not only play important roles in plant growth and development, but also have functions in regulation of responses to biotic and abiotic stresses. However, biological functions for most of the members in the NAC family remain unknown. In this study, microarray data analyses revealed that a total of 63 ONAC genes exhibited overlapping expression patterns in rice under various abiotic (salt, drought, and cold) and biotic (infection by fungal, bacterial, viral pathogens, and parasitic plants) stresses. Thirty-eight ONAC genes exhibited overlapping expression in response to any two abiotic stresses, among which 16 of 30 selected ONAC genes were upregulated in response to exogenous ABA. Sixty-five ONAC genes showed overlapping expression patterns in response to any two biotic stresses. Results from the present study suggested that members of the ONAC genes with overlapping expression pattern may have pleiotropic biological functions in regulation of defense response against different abiotic and biotic stresses, which provide clues for further functional analysis of the ONAC genes in stress tolerance and pathogen resistance. PMID- 25690041 TI - Introducing a semi-coated model to investigate antibacterial effects of biocompatible polymers on titanium surfaces. AB - Peri-implant infections from bacterial biofilms on artificial surfaces are a common threat to all medical implants. They are a handicap for the patient and can lead to implant failure or even life-threatening complications. New implant surfaces have to be developed to reduce biofilm formation and to improve the long term prognosis of medical implants. The aim of this study was (1) to develop a new method to test the antibacterial efficacy of implant surfaces by direct surface contact and (2) to elucidate whether an innovative antimicrobial copolymer coating of 4-vinyl-N-hexylpyridinium bromide and dimethyl(2 methacryloyloxyethyl) phosphonate (VP:DMMEP 30:70) on titanium is able to reduce the attachment of bacteria prevalent in peri-implant infections. With a new in vitro model with semi-coated titanium discs, we were able to show a dramatic reduction in the adhesion of various pathogenic bacteria (Streptococcus sanguinis, Escherichia coli, Staphylococcus aureus, Staphylococcus epidermidis), completely independently of effects caused by soluble materials. In contrast, soft tissue cells (human gingival or dermis fibroblasts) were less affected by the same coating, despite a moderate reduction in initial adhesion of gingival fibroblasts. These data confirm the hypothesis that VP:DMMEP 30:70 is a promising antibacterial copolymer that may be of use in several clinical applications. PMID- 25690042 TI - Metastatic melanoma cells evade immune detection by silencing STAT1. AB - Transcriptional activation of major histocompatibility complex (MHC) I and II molecules by the cytokine, interferon gamma (IFN-gamma), is a key step in cell mediated immunity against pathogens and tumors. Recent evidence suggests that suppression of MHC I and II expression on multiple tumor types plays important roles in tumor immunoevasion. One such tumor is malignant melanoma, a leading cause of skin cancer-related deaths. Despite growing awareness of MHC expression defects, the molecular mechanisms by which melanoma cells suppress MHC and escape from immune-mediated elimination remain unknown. Here, we analyze the dysregulation of the Janus kinase (JAK)/STAT pathway and its role in the suppression of MHC II in melanoma cell lines at the radial growth phase (RGP), the vertical growth phase (VGP) and the metastatic phase (MET). While RGP and VGP cells both express MHC II, MET cells lack not only MHC II, but also the critical transcription factors, interferon response factor (IRF) 1 and its upstream activator, signal transducer and activator of transcription 1 (STAT1). Suppression of STAT1 in vitro was also observed in patient tumor samples, suggesting STAT1 silencing as a global mechanism of MHC II suppression and immunoevasion. PMID- 25690043 TI - Biological activity of pyrazole and imidazole-dehydroepiandrosterone derivatives on the activity of 17beta-hydroxysteroid dehydrogenase. AB - The enzyme type 5 17beta-hydroxysteroid dehydrogenase 5 (17beta-HSD5) catalyzes the transformation of androstenedione (4-dione) to testosterone (T) in the prostate. This metabolic pathway remains active in cancer patients receiving androgen deprivation therapy. Since physicians seek to develop advantageous and better new treatments to increase the average survival of these patients, we synthesized several different dehydroepiandrosterone derivatives. These compounds have a pyrazole or imidazole function at C-17 and an ester moiety at C-3 and were studied as inhibitors of 17beta-HSD5. The kinetic parameters of this enzyme were determined for use in inhibition assays. Their pharmacological effect was also determined on gonadectomized hamsters treated with Delta(4)-androstenedione (4 dione) or testosterone (T) and/or the novel compounds. The results indicated that the incorporation of a heterocycle at C-17 induced strong 17beta-HSD5 inhibition. These derivatives decreased flank organ diameter and prostate weight in castrated hamsters treated with T or 4-dione. Inhibition of 17beta-HSD5 by these compounds could have therapeutic potential for the treatment of prostate cancer and benign prostatic hyperplasia. PMID- 25690044 TI - Electronic, magnetic, and transport properties of the isotypic aluminides SmT2Al10 (T = Fe, Ru). AB - We report the results of a comprehensive physical and magnetic property study of the new isotypic aluminides SmT2Al10 (T = Fe, Ru). These two compounds are members of a rare-earth based system which has become an exemplary case study of the interplay of magnetism and correlated electron phenomena. SmFe2Al10 and SmRu2Al10 are found to order in a putative antiferromagnetic spin arrangement at T(N) = 14.5 K and 12.5 K, respectively. Moreover, SmRu2Al10 shows a further phase transition at T(SR) = 5 K which is likely due to spin reorientation. The susceptibility of SmFe2Al10 points to a valence instability of the Sm ionic state at intermediate temperatures well above T(N). Electronic and thermal transport confirm that SmFe2Al10 undergoes an antiferromagnetic superzone gap formation below T(N), whereas SmRu2Al10 suffers a lattice anomaly driven magnetoelastic coupling at T(N). Below T(N), the physical properties of SmT2Al10 (T = Fe, Ru) are governed by magnons with an antiferromagnetic spin-wave spectrum that reveals spin-gap opening. Our findings in this work have exposed a new anomalous correlated compound in the RT2Al10 series. SmFe2Al10 has a magnetic ordered ground state in spite of an unstable valence at higher temperature. This is comparable with CeRu2Al10, which is a unique and controversial Kondo insulator that orders antiferromagnetic at T(N) = 27 K. Among the series of rare-earth RT2Al10 compounds, the presented Sm compounds are two new members with anomalously high magnetic ordering temperatures, and it is envisaged that together with the two very well studied compounds CeRu2Al10 and CeOs2Al10 our presented studies will enable a broader approach towards understanding the fascinating properties of this materials class. PMID- 25690045 TI - Peripapillary choroidal thickness in patients with chronic obstructive pulmonary disease. AB - OBJECTIVE: To evaluate the peripapillary choroidal thickness of patients with chronic obstructive pulmonary disease (COPD) via enhanced depth imaging optical coherence tomography (EDI-OCT). MATERIALS AND METHODS: A total of 80 patients with COPD (80 eyes) and 50 control subjects (50 eyes) were enrolled. Choroidal scans and the retinal nerve fiber layer (RNFL) thickness were obtained for all eyes using OCT. RESULTS: The average peripapillary choroidal thickness measurements of the COPD group (147.58 +/- 53.53 MUm) were lower than the control group (160.84 +/- 44.73 MUm) (p = 0.068). Inferior segment thicknesses were significantly thinner than the other segments (p < 0.05). Subfoveal choroidal thickness and RNFL thickness measurements of the COPD group were also lower than those of the control group (p = 0.111). CONCLUSION: Hypoxia in COPD seems to affect the choroidal thickness. Thinning of the choroid may be attributed to increased vascular resistance and reduced blood flow in patients with COPD. The possible effects of the disease to the eye may be clarified through the role of the choroidal vasculature in the blood supply of the anterior optic nerve head. PMID- 25690046 TI - Global Health Security Demands a Strong International Health Regulations Treaty and Leadership From a Highly Resourced World Health Organization. AB - If the Ebola tragedy of West Africa has taught us anything, it should be that the 2005 International Health Regulations (IHR) Treaty, which gave unprecedented authority to the World Health Organization (WHO) to provide global public health security during public health emergencies of international concern, has fallen severely short of its original goal. After encouraging successes with the 2003 severe acute respiratory syndrome (SARS) pandemic, the intent of the legally binding Treaty to improve the capacity of all countries to detect, assess, notify, and respond to public health threats has shamefully lapsed. Despite the granting of 2-year extensions in 2012 to countries to meet core surveillance and response requirements, less than 20% of countries have complied. Today it is not realistic to expect that these gaps will be solved or narrowed in the foreseeable future by the IHR or the WHO alone under current provisions. The unfortunate failures that culminated in an inadequate response to the Ebola epidemic in West Africa are multifactorial, including funding, staffing, and poor leadership decisions, but all are reversible. A rush by the Global Health Security Agenda partners to fill critical gaps in administrative and operational areas has been crucial in the short term, but questions remain as to the real priorities of the G20 as time elapses and critical gaps in public health protections and infrastructure take precedence over the economic and security needs of the developed world. The response from the Global Outbreak Alert and Response Network and foreign medical teams to Ebola proved indispensable to global health security, but both deserve stronger strategic capacity support and institutional status under the WHO leadership granted by the IHR Treaty. Treaties are the most successful means the world has in preventing, preparing for, and controlling epidemics in an increasingly globalized world. Other options are not sustainable. Given the gravity of ongoing failed treaty management, the slow and incomplete process of reform, the magnitude and complexity of infectious disease outbreaks, and the rising severity of public health emergencies, a recommitment must be made to complete and restore the original mandates as a collaborative and coordinated global network responsibility, not one left to the actions of individual countries. The bottom line is that the global community can no longer tolerate an ineffectual and passive international response system. As such, this Treaty has the potential to become one of the most effective treaties for crisis response and risk reduction worldwide. Practitioners and health decision-makers worldwide must break their silence and advocate for a stronger Treaty and a return of WHO authority. PMID- 25690047 TI - Outcomes of aortic arch repair with extended (>= 90 minutes) antegrade cerebral perfusion. AB - OBJECTIVES: To analyze outcomes with extended duration of antegrade cerebral perfusion (ACP) during hypothermic circulatory arrest (HCA) for total arch repair (TAR). DESIGN: Retrospective study of consecutive patients undergoing TAR with HCA and ACP. Patients were divided into group A (ACP >= 90 min, n = 12) and group B (ACP < 90 min, n = 17) and compared regarding in-hospital mortality and neurological complications (primary outcome measures) and major complications, biochemical markers of organ damage, and blood product use (secondary outcome measures). Complications were analyzed according to standards of the International Aortic Arch Surgery Study Group. RESULTS: Overall in-hospital mortality was 4/29 (14%); 1/12 (8.3%) in group A versus 3/17 (18%) in group B, p = 0.62. No grade-V (lethal) neurological complication occurred, but five patients (all in group B) had grade-IV neurological complications: one general and two each focal and spinal neurological deficit (p = 0.047, overall). Prevalence of grade-II (temporary) general neurological deficit was 17% (group A) versus 27% (group B), p = 0.66. None of the patients suffered >= grade-IV respiratory or renal complications. Other complications, biochemical markers, and blood product usage were not significantly different. CONCLUSION: Outcomes in TAR with HCA and extended (>= 90 min) three-vessel ACP were encouraging and could be contemplated with anticipated time-consuming TAR. PMID- 25690048 TI - Statin therapy in critically-ill patients with severe sepsis: a review and meta analysis of randomized clinical trials. AB - While statins are indicated to reduce blood cholesterol levels, they also have anti-inflammatory and immunomodulatory effects. Several observational cohort studies suggested that statins may improve survival and reduce complications in patients with sepsis. Recent randomized controlled studies in critically ill patients have been conducted and published. In this paper we present a meta analysis of these randomized trials. METHODS: An electronic article search through PubMed was performed. Only randomized controlled trials including critically ill adult patients with severe sepsis were retained. A meta-analysis was performed as detailed in text below. Overall analysis including 1818 patients total from 4 studies showed that there was no difference in 60-day mortality between statins (223/903) and placebo (233/899) [risk ratio, 0.930; 95% CI, 0.722 to 1.198]. Similarly, no difference in 28-day mortality was observed between groups (statins 191/907, placebo 199/911; risk ratio 0.953; 95% CI, 0.715 to 1.271). The results of this meta-analysis confirm that the use of statin therapy should not be recommended in the management of severe sepsis in critically ill patients. Statins should be continued with caution and only if necessary, as one study reported that the statin group had a higher rate of hepatic and renal failure. PMID- 25690049 TI - The incidence of complications associated with lip and/or tongue piercings: a systematic review. AB - OBJECTIVE: This review determines the incidence of complications associated with lip and/or tongue piercings based on a systematic evaluation of the available literature. MATERIAL AND METHODS: MEDLINE-PubMed, Cochrane-CENTRAL and EMBASE databases were comprehensively searched through June 2014 to identify appropriate studies. The incidence of complications, as established by a dental professional associated with oral and peri-oral piercings, was evaluated in populations with lip and/or tongue piercings. The quality of the case-control studies was assessed using the Newcastle-Ottawa Scale. For case series studies, the risk of bias was assessed using the National Institute for Health and Clinical Excellence scale. RESULTS: An independent screening of 1580 unique titles and abstracts revealed 15 publications that met the eligibility criteria. The incidence of gingival recessions appeared to be 50% in subjects with lip piercings and 44% in subjects with a tongue piercing. Tooth injuries were observed in 26% individuals with lip piercings and in up to 37% of individuals with tongue piercings. Subjects with a lip piercing were 4.14 times (P = 0.005) more likely to develop gingival recession than those without a lip piercing. Subjects with a tongue piercing were more likely than non-pierced subjects to experience gingival recession (relative risk (RR) 2.77; P = 0.00001) and tooth injuries (RR 2.44; P = 0.003). CONCLUSION: Both lip and tongue piercings are highly associated with the risk of gingival recession, and tongue piercings are also associated with tooth injuries. PMID- 25690050 TI - The complete mitochondrial genome of Schizopygopsis pylzovi (Teleostei, Cyprinidae, Schizopygopsis). AB - Schizopygopsis pylzovi, an endemic species in the Qinghai-Tibetan Plateau, has a unique ability to adapt to the extreme ecological condition of the plateau. In this study, we successfully sequenced the first mitochondrial genome of S. pylzovi. The mitogenome is 16,814 bp in length, containing 13 protein-coding genes, 2 rRNA genes, 22 tRNA genes and a control region (D-loop). The overall base composition of the heavy strand (H-strand) is 28.3% A, 26.1% C, 18.6% G, and 27.0% T, with a slight AT bias of 55.3%. Most of the genes are encoded on H strand, except for eight tRNAs (tRNA(Gln), tRNA(Ala), tRNA(Asn), tRNA(Cys), tRNA(Tyr), tRNA(Ser), tRNA(Glu) and tRNA(Pro)) and ND6 genes. PMID- 25690051 TI - Mitochondrial genome of Sargassum thunbergii: conservation and variability of mitogenomes within the subgenus Bactrophycus. AB - Sargassum thunbergii (Mertens ex Roth) Kuntze is a common brown seaweed in rocky intertidal zones along the northwestern Pacific coast. In the present study, we sequenced and annotated the complete mitochondrial genome of S. thunbergii. The circular S. thunbergii mitogenome is 34,748 bp in size and contains the same set of 65 genes as other mtDNAs in four Sargassum species. The genome organization including the gene order, overlapping regions between genes and the total length of inter-genic regions is highly similar to the other Bactrophycus species. The comparison by genome scale alignment displays only minor differences in gene lengths, but higher divergence in inter-genic spacer regions, especially the cox3 atp6 inter-genic spacer. Mitochondrial phylogenomics suggests that S. thunbergii is tightly combined with Sargassum muticum and Sargassum hemiphyllum forming the sect. Teretia clade with strong support values (NJ/ML, 100%). The present data illustrate that the complete mtDNAs could provide a more complete assessment of their phylogenetic relationships. PMID- 25690052 TI - The complete mitochondrial genome of the Jacobin pigeon (Columba livia breed Jacobin). AB - The Jacobin is a breed of fancy pigeon developed over many years of selective breeding that originated in Asia. In the present work, we report the complete mitochondrial genome sequence of Jacobin pigeon for the first time. The total length of the mitogenome was 17,245 bp with the base composition of 30.18% for A, 23.98% for T, 31.88% for C, and 13.96% for G and an A-T (54.17 %)-rich feature was detected. It harbored 13 protein-coding genes, 2 ribosomal RNA genes, 22 transfer RNA genes and 1 non-coding control region. The arrangement of all genes was identical to the typical mitochondrial genomes of pigeon. The complete mitochondrial genome sequence of Jacobin pigeon would serve as an important data set of the germplasm resources for further study. PMID- 25690053 TI - Complete sequence and characterization of mitochondrial and chloroplast genome of Chlorella variabilis NC64A. AB - The complete nucleotide sequences of the mitochondrial (mtDNA) and chloroplast (cpDNA) genomes of Chlorella variabilis NC64A (Trebouxiophyceae) have been determined in this study (GenBank accession no. KP271968 and KP271969, respectively). The mt genome assembles as a circle of 78,500 bp and contains 62 genes, including 32 protein-coding, 27 tRNA and 3 rRNA genes. The overall GC content is 28.2%, while the coding sequence is 34%. The cp genome forms a circle of 124,793 bp, containing 114 genes, including 79 protein-coding, 32 tRNA and 3 rRNA genes. The overall GC content is 33,9%, while the coding sequence is 50%. PMID- 25690054 TI - Complete mitochondrial DNA genome of Polytremis nascens (Lepidoptera: Hesperiidae). AB - In this study, the complete mitochondrial DNA (mtDNA) sequence of Polytremis nascens (Lepidoptera: Hesperiidae) was determined. The 15,392 bp mitogenome with GenBank accession number KM981865 contained 13 protein genes, 22 tRNAs, 2 rRNAs, and a non-coding control region (D-loop). All the 37 typical animal mitochondrial genes were found. The overall base composition was 39.7% A, 40.7% T, 7.7% G and 11.9% C, with a high A + T content (80.4%). This complete mitogenome of P. nascens provides a basic data for studies on species identification, molecular systematics and conservation genetics. PMID- 25690055 TI - The complete mitochondrial genome of the toad-headed lizard, Phrynocephalus forsythii (Reptilia, Squamata, Agamidae). AB - In this study, we report the complete mitochondrial genome of Phrynocephalus forsythii (Reptilia, Squamata, Agamidae), which is a circular molecule of 16,143 bp in size and consists of 13 protein-coding genes, 22 transfer RNAs, 2 ribosomal RNAs and 2 non-coding sequence (D-loop). The mitogenome of P. forsythii was similar to the typical mtDNA of vertebrates in gene arrangement and composition. The control region composed of two parts: one (348 bp) between tRNA(Phe) and the other (636 bp) between tRNA(Pro) and 12S rRNA. The A + T content of overall base of the composition of H-strand is 62.0% (T: 25.6%, C: 25.7%, A: 36.3% and G: 12.3%). The whole mitogenomic sequence of P. forsythii provides powerful data to study of its phylogenetic position within toad-headed lizards. PMID- 25690056 TI - Complete mitochondrial genome of the geophilous grasshopper Trilophidia annulata (Acrididae: Oedipodinae: Trilophidia). AB - The complete mitogenome of the geophilous grasshopper Trilophidia annulata was reconstructed from whole-genome Illumina sequencing data. After annotation, the circular genome was obtained with 16,501 bp in length, and typically consisted of 37 genes, including 13 protein-coding genes (PCGs), 22 transfer RNAs (tRNAs), 2 ribosomal RNAs (rRNAs) and 1 D-loop region. All PCGs were initiated with ATN codons, except ND2 with the start codon GTG. Most of the PCGs used TAA as their stop codons, while the others used TAG as stop codons (COX1, COX3&ND1). The nucleotide composition was asymmetric (42.3% A, 15.0% C, 11.0% G, 31.8% T) with an overall GC content of 25.9%. These data would contribute to the design of novel molecular markers for population and evolutionary research of T. annulata. PMID- 25690057 TI - Lichenoid drug eruption after human papillomavirus vaccination. AB - Lichenoid drug reactions have been linked to a long and growing list of medications, most of which are used mainly in adults, making these reactions exceedingly rare in children. To the best of our knowledge, this case report is the first of a lichenoid drug eruption in a child after human papillomavirus vaccination. PMID- 25690059 TI - A life well lived: Professor Michele Leonardi Darby, BSDH, MS. PMID- 25690060 TI - Is non-surgical periodontal therapy cost effective? AB - The purpose of Linking Research to Clinical Practice is to present evidence based information to clinical dental hygienists so that they can make informed decisions regarding patient treatment and recommendations. Each issue will feature a different topic area of importance to clinical dental hygienists with a Conclusion to translate the research findings into clinical application. PMID- 25690058 TI - Microtubule motors power plasma membrane tubulation in clathrin-independent endocytosis. AB - How the plasma membrane is bent to accommodate clathrin-independent endocytosis remains uncertain. Recent studies suggest Shiga and cholera toxin induce membrane curvature required for their uptake into clathrin-independent carriers by binding and cross-linking multiple copies of their glycosphingolipid receptors on the plasma membrane. But it remains unclear if toxin-induced sphingolipid crosslinking provides sufficient mechanical force for deforming the plasma membrane, or if host cell factors also contribute to this process. To test this, we imaged the uptake of cholera toxin B-subunit into surface-derived tubular invaginations. We found that cholera toxin mutants that bind to only one glycosphingolipid receptor accumulated in tubules, and that toxin binding was entirely dispensable for membrane tubulations to form. Unexpectedly, the driving force for tubule extension was supplied by the combination of microtubules, dynein and dynactin, thus defining a novel mechanism for generating membrane curvature during clathrin-independent endocytosis. PMID- 25690061 TI - Enhancing dental and dental hygiene student awareness of the lesbian, gay, bisexual and transgender population. AB - PURPOSE: Although cultural competence education is being incorporated into most health care curricula, content addressing sexual minorities is lacking or, if present, inadequate. This void can result in compromised health care and can contribute to the social stigma surrounding the lesbian, gay, bisexual and transgender (LGBT) community. Increasing the knowledge and demystifying sexual minority issues can enhance the confidence and attitudes of health care workers when treating LGBT individuals. Suggestions for creating a more welcoming health care environment for LGBT individuals in different health care settings such as private clinics, public health settings and school based programs are offered. The purpose of this literature review was to systematically review available literature on health care providers' delivery of culturally competent care to the LGBT community. The investigators searched electronic databases that included Medline (Ovid), Eric and PubMed with consultation from information specialists at the Health Sciences and Human Services Library at the University of Maryland. The information was categorized into content areas. Discussion of the findings and future directions regarding health care delivery for the LGBT community are provided. PMID- 25690062 TI - Evaluating the impact of expanded practice dental hygienists in Oregon: an outcomes assessment. AB - PURPOSE: Currently the dental hygiene practice model in Oregon includes the Expanded Practice Dental Hygienist (EPDH), which allows dental hygienists with an Expanded Practice Permit (EPP) to provide care to limited access populations without the supervision of a dentist. The number and types of services provided by EPDH practitioners is thus far undocumented. The purpose of this study is to conduct an outcomes assessment of EPDH practitioners in order to quantify the impact, defined by count of services, on the access to care crisis in Oregon. METHODS: A 16 question confidential survey was developed and approved by the Pacific University institutional review board. The mail-based survey was sent to 181 EPDHs in Oregon in November 2011 (all EPDHs except pilot testers and one author). A second mailing was sent to non-respondents. Data were analyzed using descriptive statistics and chi-square analysis in SPSS. RESULTS: The response rate was 39% (n = 71). Approximately 41% (n = 29) of the respondents were currently using their EPP to provide care to limited access patients with an additional 21% (n = 15) planning to start their own expanded practice. The majority of practicing EPDHs provide care in residential care facilities (n = 21) and in school settings (n=13). Of the current practicing EPP holders, 76% practice <= 10 hours per week, and 66% make < $10,000 per year. Total services reported in an average month from all responding EPDH practitioners were: 254 adult prophylaxes, 1,003 child prophylaxes, 106 adult fluorides, 901 child fluorides and 1,994 fluoride varnishes, among many other preventive procedures. CONCLUSION: To a limited extent, the amount and type of services provided by EPDHs has now been quantified, and EPDHs are making an impact on the access to care crisis in Oregon. Continued outcomes assessment is needed to further quantify the impact of EPDHs. PMID- 25690063 TI - Assuring dental hygiene clinical competence for licensure: a national survey of dental hygiene program directors. AB - PURPOSE: To conduct a national survey of dental hygiene program directors to gain their opinions of alternative assessments of clinical competency, as qualifications for initial dental hygiene licensure. METHODS: A 22 question survey, comprised of statements eliciting Likert-scale responses, was developed and distributed electronically to 341 U.S. dental hygiene program directors. Responses were tabulated and analyzed using University of California, San Francisco Qualtrics(r) computer software. Data were summarized as frequencies of responses to each item on the survey. RESULTS: The response rate was 42% (n=143). The majority of respondents (65%) agreed that graduating from a Commission on Dental Accreditation (CODA)-approved dental hygiene program and passing the national board examination was the best measure to assure competence for initial licensure. The addition of "successfully completing all program's competency evaluations" to the above core qualifications yielded a similar percentage of agreement. Most (73%) agreed that "the variability of live patients as test subjects is a barrier to standardizing the state and regional examinations," while only 29% agreed that the "use of live patients as test subjects is essential to assure competence for initial licensure." The statement that the one time state and regional examinations have "low validity in reflecting the complex responsibilities of the dental hygienist in practice" had a high (77%) level of agreement. CONCLUSION: Most dental hygiene program directors agree that graduating from a CODA-approved dental hygiene program and passing the national board examination would ensure that a graduate has achieved clinical competence and readiness to provide comprehensive patient-centered care as a licensed dental hygienist. PMID- 25690064 TI - The Cultural Climate of Southwest Dental Colleges: Dentistry and Dental Hygiene. AB - PURPOSE: The purpose of this study was to identify the cultural climate of southwestern dental colleges, from the perspective of dental hygiene and dental students. METHODS: The Cultural Attitudes and Climate Questionnaire was used to measure cultural climate. It contained 57 items related to campus experiences, cultural comfort, diversity awareness, racial pressures, fair treatment, respect, lack of support, patient care and overall satisfaction. The survey was administered to 508 dental and dental hygiene students at 5 dental colleges. RESULTS: The response rate was 41% (n=239/508). Students reported not experiencing racial conflict or pressures (71 to 90%), being treated fairly and with respect (86 to 90%) and being comfortable interacting with and treating other cultures (70 to 91%). They also practiced culturally appropriate behaviors (54 to 92%). Those reporting diversity training (77.8%) were more likely to engage in 3 of the 6 awareness practices (p<0.033). Although all groups agreed their educational experience was rewarding (89.5%), African-Americans reported a significantly lower level of agreement than Whites (p=0.003) and Asians (p=0.008). Among all groups, satisfaction with their educational experience was significantly correlated with fair treatment (rho=0.441 to 0.511, p<0.001) and respect for other cultures (rho=0.391 to 0.441, p<0.001). CONCLUSION: The students generally reported a positive cultural climate. Improvements could be made by focusing on fair treatment, respect for cultures and the African-American experience. Cultural competence training could be key to improving cultural climate, as positive outcomes from training were identified. PMID- 25690065 TI - A study of statistics anxiety levels of graduate dental hygiene students. AB - PURPOSE: In light of increased emphasis on evidence-based practice in the profession of dental hygiene, it is important that today's dental hygienist comprehend statistical measures to fully understand research articles, and thereby apply scientific evidence to practice. Therefore, the purpose of this study was to investigate statistics anxiety among graduate dental hygiene students in the U.S. METHODS: A web-based self-report, anonymous survey was emailed to directors of 17 MSDH programs in the U.S. with a request to distribute to graduate students. The survey collected data on statistics anxiety, sociodemographic characteristics and evidence-based practice. Statistic anxiety was assessed using the Statistical Anxiety Rating Scale. Study significance level was alpha=0.05. RESULTS: Only 8 of the 17 invited programs participated in the study. Statistical Anxiety Rating Scale data revealed graduate dental hygiene students experience low to moderate levels of statistics anxiety. Specifically, the level of anxiety on the Interpretation Anxiety factor indicated this population could struggle with making sense of scientific research. A decisive majority (92%) of students indicated statistics is essential for evidence-based practice and should be a required course for all dental hygienists. CONCLUSION: This study served to identify statistics anxiety in a previously unexplored population. The findings should be useful in both theory building and in practical applications. Furthermore, the results can be used to direct future research. PMID- 25690066 TI - Knowledge, attitudes and practices of dental hygienists regarding caries management by risk assessment. AB - PURPOSE: The purpose of this study was to survey dental hygienists to determine their knowledge, attitudes and practices regarding the implementation of caries risk assessment, particularly caries management by risk assessment (CAMBRA), in private dental practices. METHODS: A 17 item survey was developed to evaluate dental hygienists' knowledge, attitudes and practices related to CAMBRA and perceived barriers to CAMBRA implementation in private dental practice. Surveys were mailed to a randomized sample of 1,000 dental hygienists licensed to practice in California. Responses were tabulated for each respondent, and the response frequency for each survey item was calculated. Respondents' comments to the open-ended question were compiled, according to themes. RESULTS: The response rate was 18%. Only 66% of the respondents were familiar with the term CAMBRA, although 89% agreed with its underlying principles of risk assessment. CAMBRA protocol had been implemented in 40% of the respondents' employment sites. Respondents disagreed that time (45%) and cost of products (68%) were barriers to implementation. Many did not know their employers' knowledge or attitudes about CAMBRA and its implementation, as evidenced by a "don't know" response range of 29 to 48% for the 4 relevant statements. Respondents' comments included both successes and barriers implementing CAMBRA. CONCLUSION: CAMBRA protocol has not been widely implemented in private practice, although the current data do not indicate insurmountable barriers. Broader dissemination may be feasible if dental hygienists would obtain more comprehensive knowledge of evidence-based risk assessment protocols and would assume a leadership role in implementing CAMBRA protocols and procedures in private dental practices. PMID- 25690067 TI - The Use of Fluorescence Technology versus Visual and Tactile Examination in the Detection of Oral Lesions: A Pilot Study. AB - PURPOSE: This study compared the effectiveness of the VELscope(r) Vx versus visual and tactile intraoral examination in detecting oral lesions in an adult, high risk population. METHODS: The pilot study compared the intra oral findings between 2 examination types. The sample was comprised of 30 participants who were addicted to either cigarettes or a dual addiction (cigarettes plus hookah). High risk population was defined as males who were current cigarette smokers or had a dual addiction. Two trained and experienced licensed dental hygienists conducted all examinations. Throughout the study, all visual and tactile intraoral examinations were conducted first by one dental hygienist first, followed by the VELscope(r) Vx fluorescence examinations by the second dental hygienist. All subjects received an inspection of the lips, labial and buccal mucosa, floor of the mouth, dorsal, ventral and lateral sides of the tongue, hard and soft palate, and visual inspection of the oropharynx and uvula. Both evaluations took place in 1 visit in the Dental Hygiene Research Center at Old Dominion University and external sites. All participants received oral cancer screening information, recommendations, referrals for tobacco cessation programs and brochures on the 2 types of examinations conducted. RESULTS: Participants were considered high risk based on demographics (current smokers and mostly males). Neither visual and tactile intraoral examination nor the VELscope(r) Vx examination showed positive lesions. No lesions were detected; therefore, no referrals were made. Data indicated the duration of tobacco use was significantly higher in cigarette smokers (14.1 years) than dual addiction smokers (5 years) (p>0.005). The average numbers of cigarettes smoked per day were 13.5 compared to 14.2 cigarettes for dual addiction smokers. CONCLUSION: Results from this study suggest the visual and tactile intraoral examination produced comparative results to the VELscope(r) Vx examination. Findings from this study support that the VELscope(r) Vx is still considered an adjunct technology and cannot be used exclusively for oral cancer screening. PMID- 25690068 TI - Phosphate binders and metabolic acidosis. PMID- 25690070 TI - [Practice guideline on 'Acute diarrhoea' from the Dutch College of General Practitioners]. AB - The revised guideline on 'Acute diarrhoea' from the Dutch College of General Practitioners covers the diagnosis and management of suspected acute infectious diarrhoea. Acute diarrhoea resulting from infectious gastroenteritis is often caused by a virus and is usually self-limiting; stool testing is rarely indicated. The main complication of acute diarrhoea is dehydration, although this is rare in the Netherlands. Children under 2 years old and patients over 70 are at an increased risk of dehydration. Dehydration is a clinical diagnosis based on a combination of patient history and physical examination. DNA diagnostic methods such as polymerase chain reaction (PCR) are now available for stool testing, in addition to stool culture and the triple faeces test (TFT). PCR is preferred for its better test properties. Treatment with oral rehydration salts (ORS) is indicated for patients with dehydration and may also be useful in patients at an increased risk of this event. Acute diarrhoea after hospitalisation or after visiting the tropics or subtropics merits special attention on account of the risk of infection with unusual pathogens and the consequences with regard to management. PMID- 25690069 TI - Activation of MU opioid receptors modulates inflammation in acute experimental colitis. AB - BACKGROUND: MU opioid receptors (MUORs) are expressed by neurons and inflammatory cells, and mediate immune response. We tested whether activation of peripheral MUORs ameliorates the acute and delayed phase of colitis. METHODS: C57BL/6J mice were treated with 3% dextran sodium sulfate (DSS) in water, 5 days with or without the peripherally acting MUOR agonist, [D-Ala2, N-Me-Phe4, Gly5-ol] Enkephalin (DAMGO) or with DAMGO+MUOR antagonist at day 2-5, then euthanized. Other mice received DSS followed by water for 4 weeks, or DSS with DAMGO starting at day 2 of DSS for 2 or 3 weeks followed by water, then euthanized at 4 weeks. Disease activity index (DAI), histological damage, and myeloperoxidase assay (MPO), as index of neutrophil infiltration, were evaluated. Cytokines and MUOR mRNAs were measured with RT-PCR, and nuclear factor-kB (NF-kB), the antiapoptotic factor Bcl-xL, and caspase 3 and 7 with Western blot. KEY RESULTS: DSS induced acute colitis with elevated DAI, tissue damage, apoptosis and increased MPO, cytokines, MUOR mRNA, and NF-kB. DAMGO significantly reduced DAI, inflammatory indexes, cytokines, caspases, and NF-kB, and upregulated Bcl-xL, effects prevented by MUOR antagonist. In DSS mice plus 4 weeks of water, DAI, NF-kB, and MUOR were normal, whereas MPO, histological damage, and cytokines were still elevated; DAMGO did not reduce inflammation, and did not upregulate Bcl-xL. CONCLUSIONS & INFERENCES: MUOR activation ameliorated the acute but not the delayed phase of DSS colitis by reducing cytokines, likely through activation of the antiapoptotic factor, Bcl-xL, and suppression of NF-kB, a potentiator of inflammation. PMID- 25690071 TI - [Chikungunya in children]. AB - Chikungunya is a rapidly spreading infectious disease throughout the Caribbean, reaching epidemic proportions in Suriname, with more than 1200 registered cases in 2014. Similar to dengue, classic symptoms are high fever, rash and arthralgia. However, the presentation differs in adults and children. At the Academic Hospital Paramaribo in Suriname, three children had different presentations of chikungunya. An 11-year-old girl was referred to the paediatric centre with acute onset fever of 40.5oC, painful knees and a rash on face and arms. Koplik spots were visible on the inside of her mouth. A 13-year-old boy attended the ER with acute-onset fever and a state of reduced consciousness. Physical examination revealed hypotension, tachycardia and fever. No rash was observed. A 2.5-month old baby with fever, vomiting, diarrhoea and a rash was brought to the ER. She was agitated and had signs of meningism. The symptoms resolved quickly in all patients after rehydration and pain medication. PMID- 25690072 TI - [Mild traumatic brain injury in children: can we predict intracranial complications?]. AB - OBJECTIVE: To investigate whether clinical signs and symptoms can predict intracranial bleeding (ICB) in children with mild traumatic brain injury. DESIGN: Retrospective chart review. METHOD: We analysed clinical records from all children (0-18 years) who presented at the Emergency Department or were admitted to the paediatric ward of Isala, a regional trauma centre in Zwolle, the Netherlands, with mild traumatic brain injury between 2011 and 2013. We investigated the predictive value of vomiting, drowsiness, headache, periorbital haematoma, change in behaviour, seizures, amnesia, loss of consciousness and mild neurological symptoms for the presence of ICB by calculating sensitivity, specificity, odds ratio and likelihood ratio. RESULTS: We analysed data from 410 patients (248 boys; mean [SD] age 4.5 [5.1] years). Most (n = 381, 93%) had normal consciousness on presentation. A CT scan was performed on admission in 84 patients (20.5%); 282 children (68.8%) were admitted for clinical observation (with or without head CT scan) and 51 children (12.4%) were discharged home immediately without imaging or observation. We found ICB in 10 patients (2.4%), only one of whom required neurosurgical intervention. None of the investigated clinical signs and symptoms showed a statistically significant association with bleeding or skull fractures on head CT scan. CONCLUSION: In this study, no clinical sign or symptom could predict the risk of ICB in children with mild traumatic brain injury. Taking the low likelihood of ICB and the radiation damage associated with CT scanning into account, we conclude that a wait-and-see approach without initial imaging is justified and safe in children with mild traumatic brain injury without serious neurological symptoms. PMID- 25690073 TI - [The prevention of renal failure has to improve]. AB - For some years there has been evidence at population level that prevention of end stage kidney disease is feasible. However, the number of people receiving renal replacement therapy is still rising as a consequence of population ageing. With a greater focus on prevention through better screening and more active treatment, the number of people with end-stage kidney disease can be reduced. The authors argue that screening for chronic kidney damage should be improved, not only in people with diabetes but also in those with hypertension or a family history of cardiovascular disease, those eligible for a Prevention Consultation, and those from lower socio-economic classes. There is also a need for better treatment of people diagnosed with chronic kidney damage. PMID- 25690074 TI - [CT scans in children with head/brain injury: five years after the revision of the guideline on "mild traumatic head/brain injury"]. AB - In 2010 the guideline on mild traumatic head/ brain injury for both adults and children was revised under the supervision of the Dutch Neurology Society. The revised guideline endorsed rules for decisions on whether to carry out diagnostic imaging investigations (brain CT scanning) and formulates indications for admission. Unfortunately, 5 years after its introduction, it is clear that the guideline rules result in excessive brain CT scanning, in which no more serious head injury is diagnosed. Brain injury may be present in (small) children even if symptoms are absent at first presentation. Also, clinical signs do not predict intracranial complications. This was nicely demonstrated in a study by Tilma, Bekhof and Brand of 410 children with mTBI: no clinical symptom or sign reliably predicted the risk of intracranial bleeding. They advise hospitalisation for observation instead of brain CT scanning. It may be necessary to review part of the Dutch guideline on mTBI. PMID- 25690075 TI - The Inverse Relation Between Risks and Benefits: The Role of Affect and Expertise. AB - Although risk and benefits of risky activities are positively correlated in the real world, empirical results indicate that people perceive them as negatively correlated. The common explanation is that confounding benefits and losses stems from affect. In this article, we address the issue that has not been clearly established in studies on the affect heuristic: to what extent boundary conditions, such as judgments' generality and expertise, influence the presence of the inverse relation in judgments of hazards. These conditions were examined in four studies in which respondents evaluated general or specific benefits and risks of "affect-rich" and "affect-poor" hazards (ranging from investments to applications of stem cell research). In line with previous research, affect is defined as good or bad feelings integral to a stimulus. In contrast to previous research, affect is considered as related both to personal feelings and to social controversies associated with a hazard. Expertise is related to personal knowledge (laypersons vs. experts) as well as to objective knowledge (targets well vs. poorly known to science). The direct comparison of the input from personal and objective ignorance into the inverse relation has not been investigated previously. It was found that affect invoked by a hazard guides general but not specific judgments of its benefits and risks. Technical expertise helps to avoid simplified evaluations of consequences as long as they are well known to science. For new, poorly understood hazards (e.g., stem cell research), expertise does not protect from the perception of the inverse relation between benefits and risks. PMID- 25690076 TI - Periprocedural management of rivaroxaban-treated patients. AB - INTRODUCTION: The increasing and widespread use of direct oral anticoagulants (DOACs) demands guidelines and experts' consensus for their rational and safe use, especially in certain situations for which there is no evidence-based consensus, such as the periprocedural setting. Rivaroxaban is an oral factor Xa inhibitor approved for stroke prevention in atrial fibrillation (AF) and for treatment and prevention of venous thromboembolism (VTE) in major orthopedic surgery. This article is addressed to all the clinicians involved in the periprocedural approach of patients treated with rivaroxaban, with the aim to give practical recommendations to improve patients' management during and after surgery. AREAS COVERED: This article is based on a consensus of specialists involved in anticoagulant treatment and in periprocedural setting, including experts in thrombosis, cardiologists, internists, clinical pathologists and anesthesiologists. The authors performed a review of the literature and expressed statements based on the results of the review as well as on personal experience. EXPERT OPINION: Rivaroxaban is a safe and effective drug that simplifies management of anticoagulation also in patients undergoing invasive procedures. However, periprocedural management could be challenging and physicians must carefully balance the risk of bleeding and the risk of thrombosis. PMID- 25690077 TI - Recent advances in porous silicon-based therapeutic delivery. PMID- 25690078 TI - Conventional formulations and emerging delivery systems for the topical treatment of Cutaneous Leishmaniasis. PMID- 25690079 TI - Pharmaceutical aerosol electrostatics: a field with much potential for development. PMID- 25690081 TI - Nanoparticle-based cisplatin therapy for cancer. PMID- 25690082 TI - Tobramycin inhalation powder: an efficient and efficacious therapy for the treatment of Pseudomonas aeruginosa infection in cystic fibrosis. AB - Inhaled antipseudomonal therapies are critical components in the management of cystic fibrosis (CF) and have significantly contributed to improved patient outcomes. Dry powder inhaler technologies represent a significant advance in drug delivery, alleviating treatment burden and potentially improving adherence associated with traditional CF nebulized therapies. Tobramycin inhalation powder (TIP) uses PulmoSphere((r)) technology for very efficient drug delivery into the lower airways. In placebo-controlled and comparative studies with traditional tobramycin formulations, TIP is equally efficacious and is associated with increased patient convenience and satisfaction. TIP has been recommended in the 2013 CF Foundation and the 2014 European guidelines as a therapy in CF for the maintenance of lung health. Going forward, TIP may offer a therapeutic advantage over traditional formulations of tobramycin as recent prospective 'real world' studies of TIP have demonstrated high patient tolerance and improved adherence compared with traditional formulations. PMID- 25690083 TI - Enhanced serum proteolysis resistance of cell-penetrating peptides. AB - AIM: Before starting preclinical studies, we have analyzed the integrity in serum of DPT-C9h, a promising therapeutic peptide, and performed modifications in order to improve its stability. MATERIALS & METHODS: Mutant peptides exchanging arginine 8 for either lysine, asparagine or alanine were synthesized and compared with the parental peptide. RESULTS: All mutants clearly improved peptide stability while keeping their functional activity. PK studies showed an enhanced stability, being Mut3DPT-C9h the most promising candidate. Biodistribution studies demonstrate that the modified peptide is able to reach the targeted tumor and accumulate there at higher concentration than the parental peptide. DISCUSSION: Small modifications in the peptide sequence result in improvements allowing the selection of better candidates for preclinical studies. PMID- 25690084 TI - Challenges in the delivery of peptide drugs: an industry perspective. AB - Due mainly to their poor stability and short plasma half-life, peptides are usually administered by injection, often several times daily. Injectable sustained-release formulations of peptides based on biodegradable polymer microparticles or implants early demonstrated the power of drug delivery technologies to enhance patient adherence and convenience, and increase safety and efficacy. Injectable sustained-release formulations are likely to remain a significant part of new peptide products. However, a new generation of technologies that enable solvent-free formulations and manufacturing processes, injection through narrow gauge needles and ready-to-use presentations will be increasingly used. In addition, the tremendous developments in noninvasive routes of delivery are likely to result in more and more peptides being delivered by the oral, transdermal, nasal or inhalation routes. PMID- 25690086 TI - Nanotherapeutic strategies for the treatment of Alzheimer's disease. AB - Alzheimer's disease (AD), the most common form of dementia, is now representing one of the largest unmet medical needs. However, no effective treatment is now available to impede the progression of AD or delay its onset. There are two major challenges for the development of effective therapy for AD. First, the exact cause for AD onset is still unknown. Second, brain drug delivery is significantly hindered by the blood-brain barrier (BBB). In this review, we will summarize the pathological understanding about AD and the related treatments, compare BBB and its effect on brain drug delivery under normal and AD conditions and review the nanotherapeutic strategies that have been developed for AD therapy in recent years. PMID- 25690085 TI - Pain management via local anesthetics and responsive hydrogels. AB - Acute and chronic pain control is a significant clinical challenge that has been largely unmet. Local anesthetics are widely used for the control of post operative pain and in the therapy of acute and chronic pain. While a variety of approaches are currently used to prolong the duration of action of local anesthetics, an optimal strategy to achieve neural blockage for several hours to days with minimal toxicity has yet to be identified. Several drug delivery systems such as liposomes, microparticles and nanoparticles have been investigated as local anesthetic delivery vehicles to achieve prolonged anesthesia. Recently, injectable responsive hydrogels raise significant interest for the localized delivery of anesthetic molecules. This paper discusses the potential of injectable hydrogels to prolong the action of local anesthetics. PMID- 25690087 TI - Formulation design for topical drug and nanoparticle treatment of skin disease. AB - The skin has evolved to resist the penetration of foreign substances and particles. Topical therapeutic and cosmeceutical delivery is a growing field founded on selectively overcoming this barrier. Both the biology of the skin and the nature of the formulation/active ingredient must be aligned for efficient transcutaneous delivery. This review discusses the biological changes in the skin barrier that occur with common dermatological conditions. This context is the foundation for the discussion of formulation strategies to improve penetration profiles of common active ingredients in dermatology. Finally, we compare and contrast those approaches to recent advances described in the research literature with an eye toward the future of topical formulation design. PMID- 25690089 TI - Nanocarriers: a versatile approach for mucosal vaccine delivery. AB - Infectious agents generally use mucosal surfaces as entry port to the body thereby necessitating the need of development of mucosal vaccine as vaccination is important for disease avoidance and suppression. Vaccination through mucosal route is a promising strategy to elicit efficient immune response as parentally administered vaccines induce poor mucosal immunity in general. Safety, economy and stability are highly desired with vaccines and this can be achieved with use of delivery cargos. This review focuses on challenges related with mucosal vaccines and use of nanocarriers as suitable cargos to cater the antigen effectively to the desired site. The review also includes different factors which are to be considered regarding the performance of the nanocarriers and clinical status of these systems. PMID- 25690088 TI - Current and emerging formulation strategies for the effective transdermal delivery of HIV inhibitors. AB - Current and emerging formulation strategies for skin permeation are poised to open the transdermal drug delivery to a broader range of small molecule compounds that do not fit the traditional requirements for successful transdermal drug delivery, allowing the development of new patch technologies to deliver antiretroviral drugs that were previously incapable of being delivered through transdermal means. Transdermal drug delivery offers several distinct advantages over traditional dosage forms. Current antiretroviral drugs used for the treatment of HIV infection include a variety of highly active small molecule compounds with significantly limited skin permeability, and thus new and novel means of enhancing transport through the skin are needed. Current and emerging formulation strategies are poised to open the transdermal drug delivery to a broader range of compounds that do not fit the traditional requirements for successful transdermal drug delivery, allowing the development of new patch technologies to deliver antiretroviral drugs that were previously incapable of being delivered through transdermal means. Thus, with continuing research into skin permeability and patch formulation strategies, there is a large potential for antiretroviral transdermal drug delivery. PMID- 25690090 TI - Amorphous solid dispersions: a robust platform to address bioavailability challenges. AB - Amorphous solid dispersions (ASDs) are being used with increasing frequency for poorly soluble pharmaceutical compounds in development. These systems consist of an amorphous active pharmaceutical ingredient stabilized by a polymer to produce a system with improved physical and solution stability. ASDs are commonly considered as a means of improving the apparent solubility of an active pharmaceutical ingredient. This review will discuss methods of preparation and characterization of ASDs with an emphasis on understanding and predicting stability. Theoretical understanding of supersaturation and predicting in vivo performance will be stressed. Additionally, a summary of preclinical and clinical development efforts will be presented to give the reader an understanding of risks and key pitfalls when developing an ASD. PMID- 25690091 TI - Including a subject-paced trial may make the PASAT more acceptable for MS patients. AB - The Paced Auditory Serial Addition Test (PASAT) is regularly used in the evaluation of cognition in multiple sclerosis (MS). However, the test may impose frustration, distress, and anxiety in patients, which may result in refusal to participate by many patients. OBJECTIVES: In this study, a subject- and experimenter-paced PASAT was compared and analyzed, with regard to independent measures of cognitive functions, as well as disability, fatigue, depression, and anxiety. METHODS: A population-based sample of patients with MS (n = 34; mean age 47.2 +/- 8.6) was examined with the PASAT, including a subject-paced condition, in addition to the standard experimenter-paced conditions using three levels of interstimuli intervals (ISI: 3.0, 2.5, and 2.0 s). A comprehensive set of neuropsychological tests, measures of disease severity, fatigue, anxiety, and depression were studied as potentially associated factors. RESULTS: Subject- and experimenter-paced PASAT performance correlated significantly and the subject paced administration correlated even higher with measures of information processing speed, executive function, attention, and working memory than standard experimenter-paced administration of PASAT. DISCUSSION: The associations between PASAT performance and measures of fatigue, anxiety, and depression were not significant. CONCLUSION: The results indicate that the altered PASAT procedure measures the same cognitive functions in MS as the standard procedure. At the same time, the altered procedure may make the PASAT more user-friendly for patients with MS. PMID- 25690092 TI - Comprehensive identification of mutations induced by heavy-ion beam irradiation in Arabidopsis thaliana. AB - Heavy-ion beams are widely used for mutation breeding and molecular biology. Although the mutagenic effects of heavy-ion beam irradiation have been characterized by sequence analysis of some restricted chromosomal regions or loci, there have been no evaluations at the whole-genome level or of the detailed genomic rearrangements in the mutant genomes. In this study, using array comparative genomic hybridization (array-CGH) and resequencing, we comprehensively characterized the mutations in Arabidopsis thaliana genomes irradiated with Ar or Fe ions. We subsequently used this information to investigate the mutagenic effects of the heavy-ion beams. Array-CGH demonstrated that the average number of deleted areas per genome were 1.9 and 3.7 following Ar ion and Fe-ion irradiation, respectively, with deletion sizes ranging from 149 to 602,180 bp; 81% of the deletions were accompanied by genomic rearrangements. To provide a further detailed analysis, the genomes of the mutants induced by Ar-ion beam irradiation were resequenced, and total mutations, including base substitutions, duplications, in/dels, inversions, and translocations, were detected using three algorithms. All three resequenced mutants had genomic rearrangements. Of the 22 DNA fragments that contributed to the rearrangements, 19 fragments were responsible for the intrachromosomal rearrangements, and multiple rearrangements were formed in the localized regions of the chromosomes. The interchromosomal rearrangements were detected in the multiply rearranged regions. These results indicate that the heavy-ion beams led to clustered DNA damage in the chromosome, and that they have great potential to induce complicated intrachromosomal rearrangements. Heavy-ion beams will prove useful as unique mutagens for plant breeding and the establishment of mutant lines. PMID- 25690093 TI - Fucoidan from Fucus vesiculosus protects against alcohol-induced liver damage by modulating inflammatory mediators in mice and HepG2 cells. AB - Fucoidan is an l-fucose-enriched sulfated polysaccharide isolated from brown algae and marine invertebrates. In this study, we investigated the protective effect of fucoidan from Fucus vesiculosus on alcohol-induced murine liver damage. Liver injury was induced by oral administration of 25% alcohol with or without fucoidan (30 mg/kg or 60 mg/kg) for seven days. Alcohol administration increased serum aspartate aminotransferase and alanine aminotransferase levels, but these increases were suppressed by the treatment of fucoidan. Transforming growth factor beta 1 (TGF-beta1), a liver fibrosis-inducing factor, was highly expressed in the alcohol-fed group and human hepatoma HepG2 cell; however, the increase in TGF-beta1 expression was reduced following fucoidan administration. Treatment with fucoidan was also found to significantly reduce the production of inflammation-promoting cyclooygenase-2 and nitric oxide, while markedly increasing the expression of the hepatoprotective enzyme, hemeoxygenase-1, on murine liver and HepG2 cells. Taken together, the antifibrotic and anti inflammatory effects of fucoidan on alcohol-induced liver damage may provide valuable insights into developing new therapeutics or interventions. PMID- 25690094 TI - Fish oil N-3 fatty acids increase adiponectin and decrease leptin levels in patients with systemic lupus erythematosus. AB - Cardiovascular disease (CVD) has emerged as an important cause of death in patients with systemic lupus erythematosus (SLE). Reduced adiponectin and elevated leptin levels may contribute to CVD in SLE patients. The purpose of this study was to verify the effects of fish oil (FO) on adiponectin and leptin in patients with SLE. Biochemical and disease activity analysis were performed. Patients with SLE were divided in two groups: patients who used fish oil for four months and patients who did not use fish oil. Patients with SLE who used FO had a significant decrease in SLE disease activity index (SLEDAI) score (p ? 0.023) in relation to baseline. SLE patients who used fish oil had increased adiponectin levels (p ? 0.026) and decreased leptin levels (p ? 0.024) compared to baseline values, whereas there were no differences in adiponectin and leptin levels in patients with SLE who did not use fish oil. In conclusion, the findings of increased serum adiponectin an decreased leptin levels after 120 days in the fish oil group, reinforce the importance of evaluating prospective studies of fish and fish oil fish ingestion on these adipokines in an attempt to decrease cardiovascular risk factors in patients with SLE. PMID- 25690095 TI - Genome-wide transposon mutagenesis indicates that Mycobacterium marinum customizes its virulence mechanisms for survival and replication in different hosts. AB - The interaction of environmental bacteria with unicellular eukaryotes is generally considered a major driving force for the evolution of intracellular pathogens, allowing them to survive and replicate in phagocytic cells of vertebrate hosts. To test this hypothesis on a genome-wide level, we determined for the intracellular pathogen Mycobacterium marinum whether it uses conserved strategies to exploit host cells from both protozoan and vertebrate origin. Using transposon-directed insertion site sequencing (TraDIS), we determined differences in genetic requirements for survival and replication in phagocytic cells of organisms from different kingdoms. In line with the general hypothesis, we identified a number of general virulence mechanisms, including the type VII protein secretion system ESX-1, biosynthesis of polyketide lipids, and utilization of sterols. However, we were also able to show that M. marinum contains an even larger set of host-specific virulence determinants, including proteins involved in the modification of surface glycolipids and, surprisingly, the auxiliary proteins of the ESX-1 system. Several of these factors were in fact counterproductive in other hosts. Therefore, M. marinum contains different sets of virulence factors that are tailored for specific hosts. Our data imply that although amoebae could function as a training ground for intracellular pathogens, they do not fully prepare pathogens for crossing species barriers. PMID- 25690096 TI - Motor rotation is essential for the formation of the periplasmic flagellar ribbon, cellular morphology, and Borrelia burgdorferi persistence within Ixodes scapularis tick and murine hosts. AB - Borrelia burgdorferi must migrate within and between its arthropod and mammalian hosts in order to complete its natural enzootic cycle. During tick feeding, the spirochete transmits from the tick to the host dermis, eventually colonizing and persisting within multiple, distant tissues. This dissemination modality suggests that flagellar motor rotation and, by extension, motility are crucial for infection. We recently reported that a nonmotile flaB mutant that lacks periplasmic flagella is rod shaped and unable to infect mice by needle or tick bite. However, those studies could not differentiate whether motor rotation or merely the possession of the periplasmic flagella was crucial for cellular morphology and host persistence. Here, we constructed and characterized a motB mutant that is nonmotile but retains its periplasmic flagella. Even though DeltamotB bacteria assembled flagella, part of the mutant cell is rod shaped. Cryoelectron tomography revealed that the flagellar ribbons are distorted in the mutant cells, indicating that motor rotation is essential for spirochetal flat wave morphology. The DeltamotB cells are unable to infect mice, survive in the vector, or migrate out of the tick. Coinfection studies determined that the presence of these nonmotile DeltamotB cells has no effect on the clearance of wild-type spirochetes during murine infection and vice versa. Together, our data demonstrate that while flagellar motor rotation is necessary for spirochetal morphology and motility, the periplasmic flagella display no additional properties related to immune clearance and persistence within relevant hosts. PMID- 25690097 TI - ExsB is required for correct assembly of the Pseudomonas aeruginosa type III secretion apparatus in the bacterial membrane and full virulence in vivo. AB - Pseudomonas aeruginosa is responsible for high-morbidity infections of cystic fibrosis patients and is a major agent of nosocomial infections. One of its most potent virulence factors is a type III secretion system (T3SS) that injects toxins directly into the host cell cytoplasm. ExsB, a lipoprotein localized in the bacterial outer membrane, is one of the components of this machinery, of which the function remained elusive until now. The localization of the exsB gene within the exsCEBA regulatory gene operon suggested an implication in the T3SS regulation, while its similarity with yscW from Yersinia spp. argued in favor of a role in machinery assembly. The present work shows that ExsB is necessary for full in vivo virulence of P. aeruginosa. Furthermore, the requirement of ExsB for optimal T3SS assembly and activity is demonstrated using eukaryotic cell infection and in vitro assays. In particular, ExsB promotes the assembly of the T3SS secretin in the bacterial outer membrane, highlighting the molecular role of ExsB as a pilotin. This involvement in the regulation of the T3S apparatus assembly may explain the localization of the ExsB-encoding gene within the regulatory gene operon. PMID- 25690098 TI - Pharmacological activation of Rap1 antagonizes the endothelial barrier disruption induced by exotoxins ExoS and ExoT of Pseudomonas aeruginosa. AB - Most clinical strains of Pseudomonas aeruginosa, a leading agent of nosocomial infections, are multiresistant to antibiotherapy. Because of the paucity of new available antibiotics, the investigation of strategies aimed at limiting the action of its major virulence factors has gained much interest. The type 3 secretion system of P. aeruginosa and its effectors are known to be major determinants of toxicity and are required for bacterial dissemination in the host. Bacterial transmigration across the vascular wall is considered to be an important step in the infectious process. Using human endothelial primary cells, we demonstrate that forskolin (FSK), a drug inducing cyclic AMP (cAMP) elevation in eukaryotic cells, strikingly reduced the cell retraction provoked by two type 3 toxins, ExoS and ExoT, found in the majority of clinical strains. Conversely, cytotoxicity of a strain carrying the type 3 effector ExoU was unaffected by FSK. In addition, FSK altered the capacity of two ExoS/ExoT strains to transmigrate across cell monolayers. In agreement with these findings, other drugs and a cytokine inducing the increase of cAMP intracellular levels have also protected cells from retraction. cAMP is an activator of both protein kinase A and EPAC, a GTPase exchange factor of Rap1. Using activators or inhibitors of either pathway, we show that the beneficial effect of FSK is exerted by the activation of the EPAC/Rap1 axis, suggesting that its protective effect is mediated by reinforcing cell-cell and cell-substrate adhesion. PMID- 25690099 TI - Alga-produced malaria transmission-blocking vaccine candidate Pfs25 formulated with a human use-compatible potent adjuvant induces high-affinity antibodies that block Plasmodium falciparum infection of mosquitoes. AB - A vaccine to prevent the transmission of malaria parasites from infected humans to mosquitoes is an important component for the elimination of malaria in the 21st century, yet it remains neglected as a priority of malaria vaccine development. The lead candidate for Plasmodium falciparum transmission-blocking vaccine development, Pfs25, is a sexual stage surface protein that has been produced for vaccine testing in a variety of heterologous expression systems. Any realistic malaria vaccine will need to optimize proper folding balanced against cost of production, yield, and potentially reactogenic contaminants. Here Chlamydomonas reinhardtii microalga-produced recombinant Pfs25 protein was formulated with four different human-compatible adjuvants (alum, Toll-like receptor 4 [TLR-4] agonist glucopyranosal lipid A [GLA] plus alum, squalene-oil in-water emulsion, and GLA plus squalene-oil-in-water emulsion) and compared for their ability to induce malaria transmission-blocking antibodies. Alga-produced recombinant Pfs25 plus GLA plus squalene-oil-in-water adjuvant induced the highest titer and avidity in IgG antibodies, measured using alga-produced recombinant Pfs25 as the enzyme-linked immunosorbent assay (ELISA) antigen. These antibodies specifically reacted with the surface of P. falciparum macrogametes and zygotes and effectively prevented parasites from developing within the mosquito vector in standard membrane feeding assays. Alga-produced Pfs25 in combination with a human-compatible adjuvant composed of a TLR-4 agonist in a squalene-oil-in-water emulsion is an attractive new vaccine candidate that merits head-to-head comparison with other modalities of vaccine production and administration. PMID- 25690100 TI - Staphylococcus aureus adapts to oxidative stress by producing H2O2-resistant small-colony variants via the SOS response. AB - The development of chronic and recurrent Staphylococcus aureus infections is associated with the emergence of slow-growing mutants known as small-colony variants (SCVs), which are highly tolerant of antibiotics and can survive inside host cells. However, the host and bacterial factors which underpin SCV emergence during infection are poorly understood. Here, we demonstrate that exposure of S. aureus to sublethal concentrations of H2O2 leads to a specific, dose-dependent increase in the population frequency of gentamicin-resistant SCVs. Time course analyses revealed that H2O2 exposure caused bacteriostasis in wild-type cells during which time SCVs appeared spontaneously within the S. aureus population. This occurred via a mutagenic DNA repair pathway that included DNA double-strand break repair proteins RexAB, recombinase A, and polymerase V. In addition to triggering SCV emergence by increasing the mutation rate, H2O2 also selected for the SCV phenotype, leading to increased phenotypic stability and further enhancing the size of the SCV subpopulation by reducing the rate of SCV reversion to the wild type. Subsequent analyses revealed that SCVs were significantly more resistant to the toxic effects of H2O2 than wild-type bacteria. With the exception of heme auxotrophs, gentamicin-resistant SCVs displayed greater catalase activity than wild-type bacteria, which contributed to their resistance to H2O2. Taken together, these data reveal a mechanism by which S. aureus adapts to oxidative stress via the production of a subpopulation of H2O2-resistant SCVs with enhanced catalase production. PMID- 25690101 TI - Transforming growth factor beta2 promotes transcription of COX2 and EP4, leading to a prostaglandin E2-driven autostimulatory loop that enhances virulence of Theileria annulata-transformed macrophages. AB - Transforming growth factor beta (TGF-beta) is a pleiotropic cytokine known to regulate cell growth, differentiation, and motility and is a potent modulator of immune function. TGF-beta consequently plays a central role in carcinogenesis, and a dampened TGF-beta2 response by Theileria annulata-infected monocytes/macrophages underpins disease resistance to tropical theileriosis. Here, we show that concomitant with the loss of TGF-beta2 production, there is ablated expression of COX2 and EP4, which leads to a drop in cyclic AMP (cAMP) levels and, consequently, reduced activation of protein kinase A (PKA) and EPAC. This ablated phenotype can be rescued in attenuated macrophages by the addition of exogenous TGF-beta2, which reactivates the expression of COX2 and EP4 while repressing that of protein kinase inhibitor gamma (PKIG) to the levels in virulent macrophages. TGF-beta2 therefore promotes the adhesion and invasiveness of virulent macrophages by modulating COX2, EP4, and PKIG transcription to initiate a prostaglandin E2 (PGE2)-driven autostimulatory loop that augments PKA and EPAC activities. A virulence phenotype stemming from the double activation of PKA and EPAC is the induction of a CREB-mediated transcriptional program and the upregulation of JAM-L- and integrin 4alphabeta1-mediated adhesion of Theileria infected macrophages. PMID- 25690102 TI - Adhesive properties of YapV and paralogous autotransporter proteins of Yersinia pestis. AB - Yersinia pestis is the causative agent of plague. This bacterium evolved from an ancestral enteroinvasive Yersinia pseudotuberculosis strain by gene loss and acquisition of new genes, allowing it to use fleas as transmission vectors. Infection frequently leads to a rapidly lethal outcome in humans, a variety of rodents, and cats. This study focuses on the Y. pestis KIM yapV gene and its product, recognized as an autotransporter protein by its typical sequence, outer membrane localization, and amino-terminal surface exposure. Comparison of Yersinia genomes revealed that DNA encoding YapV or each of three individual paralogous proteins (YapK, YapJ, and YapX) was present as a gene or pseudogene in a strain-specific manner and only in Y. pestis and Y. pseudotuberculosis. YapV acted as an adhesin for alveolar epithelial cells and specific extracellular matrix (ECM) proteins, as shown with recombinant Escherichia coli, Y. pestis, or purified passenger domains. Like YapV, YapK and YapJ demonstrated adhesive properties, suggesting that their previously related in vivo activity is due to their capacity to modulate binding properties of Y. pestis in its hosts, in conjunction with other adhesins. A differential host-specific type of binding to ECM proteins by YapV, YapK, and YapJ suggested that these proteins participate in broadening the host range of Y. pestis. A phylogenic tree including 36 Y. pestis strains highlighted an association between the gene profile for the four paralogous proteins and the geographic location of the corresponding isolated strains, suggesting an evolutionary adaption of Y. pestis to specific local animal hosts or reservoirs. PMID- 25690104 TI - C-reactive protein protects mice against pneumococcal infection via both phosphocholine-dependent and phosphocholine-independent mechanisms. AB - The mechanism of action of C-reactive protein (CRP) in protecting mice against lethal Streptococcus pneumoniae infection is unknown. The involvement of the phosphocholine (PCh)-binding property of CRP in its antipneumococcal function previously has been explored twice, with conflicting results. In this study, using three different intravenous sepsis mouse models, we investigated the role of the PCh-binding property of CRP by employing a CRP mutant incapable of binding to PCh. The ability of wild-type CRP to protect mice against infection was found to differ in the three models; the protective ability of wild-type CRP decreased when the severity of infection was increased, as determined by measuring mortality and bacteremia. In the first animal model, in which we used 25 MUg of CRP and 10(7) CFU of pneumococci, both wild-type and mutant CRP protected mice against infection, suggesting that the protection was independent of the PCh binding activity of CRP. In the second model, in which we used 25 MUg of CRP and 5 * 10(7) CFU of pneumococci, mutant CRP was not protective while wild-type CRP was, suggesting that the protection was dependent on the PCh-binding activity of CRP. In the third model, in which we used 150 MUg of CRP and 10(7) CFU of pneumococci, mutant CRP was as protective as wild-type CRP, again indicating that the protection was independent of the PCh-binding activity of CRP. We conclude that both PCh-dependent and PCh-independent mechanisms are involved in the CRP mediated decrease in bacteremia and the resulting protection of mice against pneumococcal infection. PMID- 25690105 TI - Changes in heart rate variability and QT variability during the first trimester of pregnancy. AB - The risk of new-onset arrhythmia during pregnancy is high, presumably relating to changes in both haemodynamic and cardiac autonomic function. The ability to non invasively assess an individual's risk of developing arrhythmia during pregnancy would therefore be clinically significant. We aimed to quantify electrocardiographic temporal characteristics during the first trimester of pregnancy and to compare these with non-pregnant controls. Ninety-nine pregnant women and sixty-three non-pregnant women underwent non-invasive cardiovascular and haemodynamic assessment during a protocol consisting of various physiological states (postural manoeurvres, light exercise and metronomic breathing). Variables measured included stroke volume, cardiac output, heart rate, heart rate variability, QT and QT variability and QTVI (a measure of the variability of QT relative to that of RR). Heart rate (p < 0.0005, p < 0.0005, p < 0.0005) and cardiac output (p = 0.043, p < 0.0005, p < 0.0005) were greater in pregnant women in all physiological states (respectively for the supine position, light exercise and metronomic breathing state), whilst stroke volume was lower in pregnancy only during the supine position (p < 0.0005). QTe (Q wave onset to T wave end) and QTa (T wave apex) were significantly shortened (p < 0.05) and QTeVI and QTaVI were increased in pregnancy in all physiological states (p < 0.0005). QT variability (p < 0.002) was greater in pregnant women during the supine position, whilst heart rate variability was reduced in pregnancy in all states (p < 0.0005). Early pregnancy is associated with substantial changes in heart rate variability, reflecting a reduction in parasympathetic tone and an increase in sympathetic activity. QTVI shifted to a less favourable value, reflecting a greater than normal amount of QT variability. QTVI appears to be a useful method for quantifying changes in QT variability relative to RR (or heart rate) variability, being sensitive not only to physiological state but also to gestational age. We support the use of non-invasive markers of cardiac electrical variability to evaluate the risk of arrhythmic events in pregnancy, and we recommend the use of multiple physiological states during the assessment protocol. PMID- 25690103 TI - Proteomic-based approach to gain insight into reprogramming of THP-1 cells exposed to Leishmania donovani over an early temporal window. AB - Leishmania donovani, a protozoan parasite, is the causative agent of visceral leishmaniasis. It lives and multiplies within the harsh environment of macrophages. In order to investigate how intracellular parasite manipulate the host cell environment, we undertook a quantitative proteomic study of human monocyte-derived macrophages (THP-1) following infection with L. donovani. We used the isobaric tags for relative and absolute quantification (iTRAQ) method and liquid chromatography-tandem mass spectrometry (LC-MS/MS) to compare expression profiles of noninfected and L. donovani-infected THP-1 cells. We detected modifications of protein expression in key metabolic pathways, including glycolysis and fatty acid oxidation, suggesting a global reprogramming of cell metabolism by the parasite. An increased abundance of proteins involved in gene transcription, RNA splicing (heterogeneous nuclear ribonucleoproteins [hnRNPs]), histones, and DNA repair and replication was observed at 24 h postinfection. Proteins involved in cell survival and signal transduction were more abundant at 24 h postinfection. Several of the differentially expressed proteins had not been previously implicated in response to the parasite, while the others support the previously identified proteins. Selected proteomics results were validated by real-time PCR and immunoblot analyses. Similar changes were observed in L. donovani-infected human monocyte-derived primary macrophages. The effect of RNA interference (RNAi)-mediated gene knockdown of proteins validated the relevance of the host quantitative proteomic screen. Our findings indicate that the host cell proteome is modulated after L. donovani infection, provide evidence for global reprogramming of cell metabolism, and demonstrate the complex relations between the host and parasite at the molecular level. PMID- 25690106 TI - Increased mortality for pregnancy-associated melanoma: systematic review and meta analysis. AB - Among women, pregnancy-associated melanomas may have a poorer prognosis than other melanomas, but evidence is inconsistent. We conducted a systematic review and meta-analysis to assess the effect on melanoma outcome of a coinciding pregnancy. The objective of the study was to conduct a systematic review and meta analysis of risk of death from, or recurrence of, pregnancy-associated melanomas compared with other melanomas in women of reproductive age. Cochrane (1996-2013), MEDLINE (1950-2013), EMBASE (1966-2013), CINAHL (1982-2013), and PUBMED (1951 2013) databases were searched for studies assessing the risk of death and recurrence in pregnancy-associated melanomas. Eligible studies investigated melanoma outcomes in women with pregnancy-associated melanomas (diagnosed during pregnancy or in 12 months following pregnancy), included a comparison group and reported measures of risk of melanoma death or disease-free survival. Eligible study designs were cohort studies of women of childbearing age with confirmed diagnoses of cutaneous melanoma. Individual study effect estimates were pooled using the weighted average method. Studies that did not report a quantitative estimate were summarized narratively. Of 304 citations identified, 14 studies met the inclusion criteria, with assessed outcomes being melanoma death (7), recurrence (3), or both (4). Pooled estimates of mortality risk from four studies showed increased risk of melanoma death after adjustment for patient age and stage of melanoma (pHR 1.56, 95% CI 1.23-1.99) for pregnancy-associated melanoma compared with other melanomas. Based on limited quantitative evidence, pregnancy associated melanomas appear to have poorer outcomes than other melanomas. PMID- 25690107 TI - Cyclic adenosine monophosphate protects renal cell lines against amphotericin B toxicity in a PKA-independent manner. AB - Amphotericin B is the "gold standard" agent in the management of serious systemic fungal infections. However, this drug can cause nephrotoxicity, which contributes up to 25% of all acute kidney injuries in critically ill patients. Cyclic adenosine monophosphate can protect kidney cells from death due to injury or drug exposure in some cases. Hence, the objective of this work was to evaluate if cAMP could prevent cell death that occurs in renal cell lines subjected to AmB treatment and, if so, to assess the involvement of PKA in the transduction of this signal. Two different renal cell lines (LLC-PK1 and MDCK) were used in this study. MTT and flow cytometry assays showed increased cell survival when cells were exposed to cAMP in a PKA-independent manner, which was confirmed by western blot. This finding suggests that cAMP (db-cAMP) may prevent cell death caused by exposure to AmB. This is the first time this effect has been identified when renal cells are exposed to AmB's nephrotoxic potential. PMID- 25690108 TI - Foreword. PMID- 25690109 TI - Brain structural and functional development: genetics and experience. AB - Brain development is the result of the combined work of genes and environment. In this paper we first briefly discuss how, in terms of cellular and molecular plasticity mechanisms, the richness of early environment can control developmental trajectories and can induce long-term changes in neural circuits that underlie enduring changes in brain structure and function. We then see that experience most effectively moulds neural circuit development during specific time windows called critical periods. After the closure of these privileged windows for plasticity, it is very difficult to promote repair from 'errors' in brain development. As an example, congenital cataracts, refractive defects, or strabismus, if not precociously corrected during development, cause permanent deficit in visual acuity of the affected eye, a condition known as amblyopia. Little or no recovery from amblyopia is possible in the adult. However, recent results show that by using protocols of enriched environment it is possible to design interventions, which, by acting on specific plasticity factors, enhance adult cortical plasticity and allow recovery from amblyopia. This suggests that a better knowledge of how experience and environment engage endogenous plasticity factors could help to design interventions aimed at promoting recovery from neurodevelopmental defects, even after the end of critical periods. PMID- 25690110 TI - Translational studies exploring neuroplasticity associated with motor skill learning and the regulatory role of the dopamine system. AB - Cerebral palsy (CP) is a heterogeneous group of neurodevelopmental disorders associated with lifelong motor impairment and disability. Current intervention programmes aim to capitalize on the neuroplasticity of the undamaged part of the brain to improve motor functions, by engaging individuals in active motor learning and training. In this review, we highlight recent animal studies (1) exploring cellular and molecular mechanisms contributing to neuroplasticity during motor training, (2) assessing the functional role of the mesocortical dopaminergic system in motor skill learning, and (3) exploring the impact of naturally occurring genetic variation in dopamine-related gene expression on the acquisition and performance of fine motor skills. Finally, the potential influence of the dopamine system on the outcome of motor learning interventions in cerebral palsy is discussed. PMID- 25690111 TI - New paradigms and tests for evaluating and remediating visuospatial deficits in children. AB - This review suggests several hypotheses about the cognitive developmental mechanisms involved in the motor deficits of children with cerebral palsy. We suggest a new theory that visuospatial deficits involving the manipulation of multiple spatial reference frames are crucial components of the disorder in spatial orientation, manipulation, locomotion, navigation, and even social interactions. We review basic knowledge about the brain networks involved in spatial memory and cognition. We then present several potential paradigms for studying specific deficits. We consider first the use of vestibular signals for egocentric spatial orientation in children and the 'locomotor trajectory paradigm' for studying gaze anticipation and perceptual components of walking. We then describe new paradigms for studying egocentric and allocentric strategies in spatial tasks: the 'virtual path length', the 'virtual palace' and the 'virtual star maze'. We also consider paradigms involving the use of other persons and perspective change from a first person's to a third person's viewpoint as reference in spatial tasks or social interactions: the 'designation' paradigm, the 'harlequin', and the 'tightrope walker'. Finally, we briefly present a new experimental set up involving a 'virtual carpet', which follows previous studies of cognitive strategies for generating locomotor trajectories using the 'magic carpet' and which will allow a large variety of studies involving executive functions and inhibition of the first-appearing strategies during development. Several of these new paradigms could be used for remediation. PMID- 25690112 TI - Inhibition of misleading heuristics as a core mechanism for typical cognitive development: evidence from behavioural and brain-imaging studies. AB - Cognitive development is generally conceived as incremental with knowledge of increasing complexity acquired throughout childhood and adolescence. However, several studies have now demonstrated not only that infants possess complex cognitive abilities but also that older children, adolescents, and adults tend to make systematic errors even in simple logical reasoning tasks. Therefore, one of the main issues for any theory of typical cognitive development is to provide an explanation of why at some age and in some contexts children, adolescents, and adults do not express a knowledge or cognitive principle that they already acquired when they were younger. In this review, we present convergent behavioural and neurocognitive evidence that cognitive development is more similar to a non-linear dynamic system than to a linear, stage-like system. In this theoretical framework, errors can emerge in problems similar to the ones infants or young children were succeeding when older children, adolescents, and adults rely on a misleading heuristic rather than on the correct logical algorithm to solve such problems. And the core mechanism for overcoming these errors is inhibitory control (i.e. the ability to inhibit the misleading heuristics). Therefore, typical cognitive development relies not only on the ability to acquire knowledge of incremental complexity but also to inhibit previously acquired knowledge. PMID- 25690113 TI - Brain representation of action observation in human infants. AB - Imitative learning has long been established as extremely important for early development. However, neural mechanisms involved in early imitative behaviours are still areas of active research. Neurophysiological and brain-imaging studies have been recently performed that provide initial evidence of brain activation associated with action observation in the first months of life. In this review we examine all studies exploring the effects of action observation on brain function assessed by means of non-invasive brain-mapping techniques. Seventeen papers were selected as a result of our literature search. The strongest evidence for a neural signature of action observation comes from studies exploring the desynchronization of the MU-rhythm, which was reported for both occluded and visible goal-directed grasp, and was correlated with the totality of the infant's own action experience. The effects of action observation were reported on event related potentials (ERPs) or near infrared spectroscopy. Taken together, these studies suggest that, in early infancy, a direct visual-motor matching process is already detectable as early as 6 months, suggesting a matching between action perception and execution already in infancy. If confirmed by future studies, these findings will shed light on the mechanisms of early motor development and imitation, and will be key to informing novel rehabilitation strategies in infants with congenital brain damage. PMID- 25690114 TI - Cognitive strategies for locomotor navigation in normal development and cerebral palsy. AB - Visual-spatial impairment is a fundamental disorder in cerebral palsy (CP). However, current spatial testing is restricted to reaching space, whereas navigational space is seldom assessed. The Magic Carpet test, derived from the Corsi Block-tapping Task (CBT) for visual-spatial memory, is a new developmental test for navigation. The performances of the Magic Carpet test and CBT were assessed in 17 children with unilateral and bilateral spastic CP. The results were compared with an equal number of typically developing children, matched for age and sex. Magnetic resonance imaging scans of children with CP were scored according to a newly validated semi-quantitative classification. CBT span was significantly lower in CP, especially in bilateral forms, than in the comparison group, whereas the Magic Carpet test span did not significantly differ between the groups. CBT span, but not the Magic Carpet span, was related to gestational age at birth and to basic visual function. Both the CBT span and the Magic Carpet test were related to overall right-hemispheric impairment. In addition, CBT correlated with right periventricular impairment. In CP, navigation is differently impaired than visual spatial memory, and less tightly related to preterm birth, basic visual function, and deep white matter injury. The exploration of navigational space could prove useful in enhancing spatial representation and reference-frame manipulation in CP. PMID- 25690115 TI - What assessments evaluate use of hands in infants? A literature review. AB - AIM: To identify assessments, applicable to infants aged 3 months to 12 months, measuring hand function, and to discuss their usefulness in assessing infants at risk of developing unilateral cerebral palsy (CP). METHOD: Instruments described in two previous systematic reviews were scrutinized for inclusion of fine motor components. Additionally, a new literature search was performed in Medline, PsychInfo, PubMed, and Cinahl (2007-2013) to identify newly developed assessments of infant motor functioning. RESULTS: Five assessments from the two previous systematic reviews included fine motor components but only three provided separate measures of fine motor performance: the Peabody Developmental Motor Scales--version 2 (PDMS-2), the Bayley Scale of Infant and Toddler Development- version III, and the Posture and Fine Motor Assessment of Infants, each of which provided measures of the preferred hand only. From 531 papers retrieved, 10 new assessments were found, three of which met our inclusion criteria: the Infant Motor Profile (IMP), the Grasping and Reaching Assessment of Brisbane (GRAB), and the Hand Assessment for Infants (HAI). Only the GRAB and the HAI provide measures relevant for assessing infants at risk of developing unilateral cerebral palsy; however, both measures are still under construction. INTERPRETATION: No currently available assessment for infants aged 3 to 12 months old measures aspects of hand function suitable for quantifying asymmetry between hands or quality of bimanual performance. PMID- 25690116 TI - Activating the motor system through action observation: is this an efficient approach in adults and children? AB - Observing an action performed by another person to learn a new movement is a frequent experience in adult daily life, such as in sports. However, it is an especially common circumstance during the development of motor skills in childhood. Studies on healthy humans indicate that action observation induces a facilitation in the observer's motor system. This effect is supported by an action-perception matching mechanism available both in adults and in children. Because of the simplicity of action observation, it has been proposed to apply this method in clinical contexts. After a brief, non-exhaustive introduction of the essential features underlying action observation in healthy people, we review recent studies reporting beneficial effects of rehabilitative training based on a combination of action perception and execution. We focus on therapeutic interventions for patients with upper-limb motor disabilities such as adults after stroke or children with hemiplegia due to cerebral palsy. Further, we consider data from basic science demonstrating that the facilitation induced by visual perception of the action can be modulated by the combination of multimodal stimuli related to the movement (e.g. visual and acoustic action-related inputs). In line with this, we discuss possible new directions to improve basic knowledge and therapeutic applications of action observation. PMID- 25690117 TI - Visual-perceptual impairment in children with cerebral palsy: a systematic review. AB - AIM: Visual perception is one of the cognitive functions often impaired in children with cerebral palsy (CP). The aim of this systematic literature review was to assess the frequency of visual-perceptual impairment (VPI) and its relationship with patient characteristics. METHOD: Eligible studies were relevant papers assessing visual perception with five common standardized assessment instruments in children with CP published from January 1990 to August 2011. RESULTS: Of the 84 studies selected, 15 were retained. In children with CP, the proportion of VPI ranged from 40% to 50% and the mean visual perception quotient from 70 to 90. None of the studies reported a significant influence of CP subtype, IQ level, side of motor impairment, neuro-ophthalmological outcomes, or seizures. The severity of neuroradiological lesions seemed associated with VPI. The influence of prematurity was controversial, but a lower gestational age was more often associated with lower visual motor skills than with decreased visual perceptual abilities. INTERPRETATION: The impairment of visual perception in children with CP should be considered a core disorder within the CP syndrome. Further research, including a more systematic approach to neuropsychological testing, is needed to explore the specific impact of CP subgroups and of neuroradiological features on visual-perceptual development. PMID- 25690118 TI - Phenotypic plasticity and the perception-action-cognition-environment paradigm in neurodevelopmental genetic disorders. AB - Careful study of the phenotype can have implications at several levels, namely clinical diagnosis, pathophysiological reasoning, management planning, and outcome measurement. Behavioural phenotypes involve cognition, communication, social skills, and motor control. They can be documented in a host of neurodevelopmental conditions and approached with the recently refined perception action-cognition-environment (PACE) paradigm, which focuses on the neurodevelopmental processes that underlie learning and adaption to the environment through perception, action, and cognitive processing. Although this paradigm was originally developed in the context of cerebral palsy, it can be applied along developmental trajectories in several neurogenetic conditions, including Down syndrome, fragile X syndrome, Rett syndrome, Angelman syndrome, and Williams syndrome, to name but a few. It must be recognized, however, that relevant, valid tools for assessment and management strategies still need to be developed. PMID- 25690119 TI - Perception-action coupling and imitation in autism spectrum disorder. AB - This paper focuses on the key function of imitation in motor and social development of typically developing infants and low-functioning children with autism spectrum disorder (ASD). We suggest that it might also be a developmental cornerstone for other neurodevelopmental disorders. Why this suggestion? First, imitation just requires relating one's motor patterns to perceived motor patterns. This is always possible if the actions seen are not beyond the individual's motor scope; for instance, newborn infants can already imitate tongue protrusion, eye blinking, or mouth opening, because these movements are part of their foetal repertoire. Second, imitation is a 'use it or lose it' capacity: the more it is used, the more the repertoire grows (plasticity). Finally, imitation is an efficient tool for two main adaptive functions: learning and communication. Imitation-based communication is available through the use of the two facets of imitation: imitating and being imitated. The two facets afford two roles that the partners can exchange as a turn-taking while they synchronize matched activities. Neuroimaging studies of interactive imitation have shown that such communicative systems involve a coordination of bottom-up and top-down processes. In this line, imitation is a booster of development that can also be of benefit for children with neurodevelopmental disorders. PMID- 25690120 TI - Rare Varicella zoster virus infection in an ALT free flap. PMID- 25690121 TI - Identification of Saliva Using MicroRNA Biomarkers for Forensic Purpose. AB - In the forensic science community, microRNA (miRNA) profiling has started to be explored as an alternative tool for body fluid identification. Several origins of body fluid can be distinguished by measuring differential expression patterns of particular miRNAs. However, most of reported saliva miRNAs are nonoverlapping and debatable. The aim of this study was to develop a strategy of identifying saliva using miRNA biomarkers for forensic purpose. Eight miRNA candidates were selected to examine expression abundance in forensically relevant body fluids using hydrolysis probes quantitative real-time PCR (TaqMan qPCR). Results revealed that none of them was truly saliva specific, and only miR-200c-3p, miR-203a, and miR 205-5p were higher or more moderate expression in saliva. A stepwise strategy that combines each of three miRNAs with different body fluid-specific miRNAs was developed, and three miRNA combinations could effectively differentiate saliva from other body fluids. PMID- 25690122 TI - Variations in health care delivery within the European Union. PMID- 25690123 TI - ECHO: health care performance assessment in several European health systems. AB - BACKGROUND: Strengthening health-care effectiveness, increasing accessibility and improving resilience are key goals in the upcoming European Union health-care agenda. European Collaboration for Health-Care Optimization (ECHO), an international research project on health-care performance assessment funded by the seventh framework programme, has provided evidence and methodology to allow the attainment of those goals. This article aims at describing ECHO, analysing its main instruments and discussing some of the ECHO policy implications. METHODS: Using patient-level administrative data, a series of observational studies (ecological and cross-section with associated time-series analyses) were conducted to analyze population and patients' exposure to health care. Operationally, several performance dimensions such as health-care inequalities, quality, safety and efficiency were analyzed using a set of validated indicators. The main instruments in ECHO were: (i) building a homogeneous data infrastructure; (ii) constructing coding crosswalks to allow comparisons between countries; (iii) making geographical units of analysis comparable; and (iv) allowing comparisons through the use of common benchmarks. CONCLUSION: ECHO has provided some innovations in international comparisons of health-care performance, mainly derived from the massive pooling of patient-level data and thus: (i) has expanded the usual approach based on average figures, providing insight into within and across country variation at various meaningful policy levels, (ii) the important effort made on data homogenization has increased comparability, increasing stakeholders' reliance on data and improving the acceptance of findings and (iii) has been able to provide more flexible and reliable benchmarking, allowing stakeholders to make critical use of the evidence. PMID- 25690124 TI - Comparing variation across European countries: building geographical areas to provide sounder estimates. AB - BACKGROUND: In geographical studies, population distribution is a key issue. An unequal distribution across units of analysis might entail extra-variation and produce misleading conclusions on healthcare performance variations. This article aims at assessing the impact of building more homogeneous units of analysis in the estimation of systematic variation in three countries. METHODS: Hospital discharges for six conditions (congestive heart failure, short-term complications of diabetes, hip fracture, knee replacement, prostatectomy in prostate cancer and percutaneous coronary intervention) produced in Denmark, England and Portugal in 2008 and 2009 were allocated to both original geographical units and new ad hoc areas. New areas were built using Ward's minimum variance methods. The impact of the new areas on variability was assessed using Kernel distribution curves and different statistic of variation such as Extremal Quotient, Interquartile Interval ratio, Systematic Component of Variation and Empirical Bayes statistic. RESULTS: Ward's method reduced the number of areas, allowing a more homogeneous population distribution, yet 20% of the areas in Portugal exhibited less than 100 000 inhabitants vs. 7% in Denmark and 5% in England. Point estimates for Extremal Quotient and Interquartile Interval Ratio were lower in the three countries, particularly in less prevalent conditions. In turn, the Systematic Component of Variation and Empirical Bayes statistic were slightly lower in more prevalent conditions. CONCLUSIONS: Building new geographical areas produced a reduction of the variation in hospitalization rates in several prevalent conditions mitigating random noise, particularly in the smallest areas and allowing a sounder interpretation of the variation across countries. PMID- 25690125 TI - Comparing the performance of the Charlson/Deyo and Elixhauser comorbidity measures across five European countries and three conditions. AB - BACKGROUND: The Charlson and Elixhauser comorbidity measures are commonly used methods to account for patient comorbidities in hospital-level comparisons of clinical quality using administrative data. Both have been validated in North America, but there is less evidence of their performance in Europe and in pooled cross-country data, which are features of the European Collaboration for Healthcare Optimization (ECHO) project. This study compares the performance of the Charlson/Deyo and Elixhauser comorbidity measures in predicting in-hospital mortality using data from five European countries in three inpatient groups. METHODS: Administrative data is used from five countries in 2008-2009 for three indicators commonly used in hospital quality comparisons: mortality rates following acute myocardial infarction, coronary artery bypass graft surgery and stroke. Logistic regression models are constructed to predict mortality controlling for age, gender and the relevant comorbidity measure. Model discrimination is evaluated using c-statistics. Model calibration is evaluated using calibration slopes. Overall goodness-of-fit is evaluated using Nagelkerke's R(2) and the Akaike information criterion. All models are validated internally by using bootstrapping and externally by using the 2009 model parameters to predict mortality in 2008. RESULTS: The Elixhauser measure has better overall predictive ability in terms of discrimination and goodness-of-fit than the Charlson/Deyo measure or the age-sex only model. There is no clear difference in model calibration. These findings are robust to the choice of country, to pooling all five countries and to internal and external validation. CONCLUSIONS: The Elixhauser list contains more comorbidities, which may enable it to achieve better discrimination than the Charlson measure. Both measures achieve similar calibration, so for the purpose of ECHO we judged the Elixhauser measure to be preferable. PMID- 25690126 TI - Socioeconomic inequality in hip replacement in four European countries from 2002 to 2009--area-level analysis of hospital data. AB - BACKGROUND: Cross-country comparisons of socioeconomic equity in health care typically use sample survey data on general services such as physician visits. This study uses comprehensive administrative data on a specific service: hip replacement. METHODS: We analyse 651 652 publicly funded hip replacements, excluding fractures and accidents, in adults over 35 in Denmark, England, Portugal and Spain from 2002 to 2009. Sub-national administrative areas are split into socioeconomic quintile groups comprising approximately one-fifth of the national population. Area-level Poisson regression with Huber-White standard errors is used to calculate age-sex standardised hip replacement rates by quintile group, together with gaps and ratios between richest and poorest groups (Q5 and Q1) and the middle group (Q3). RESULTS: We find pro-rich-area inequality in England (2009 Q5/Q1 ratio 1.35 [CI 1.25-1.45]) and Spain (2009 Q5/Q1 ratio 1.43 [CI 1.17-1.70]), pro-poor-area inequality in Portugal (2009 Q5/Q1 ratio 0.67 [CI 0.50-0.83]) and no significant inequality in Denmark. Pro-rich-area inequality increased over time in England and Spain but not significantly. Within country differences between socioeconomic quintile groups are smaller than between-country differences in general population averages: hip replacement rates are substantially lower in Portugal and Spain (8.6 and 7.4 per 10 000 in 2009) than England and Denmark (20.2 and 27.8 per 10 000 in 2009). CONCLUSION: Despite limitations regarding individual-level inequality and area heterogeneity, analysis of area-level data on publicly funded hospital activity can provide useful cross-country comparisons and longitudinal monitoring of socioeconomic inequality in specific health services. Although this kind of analysis cannot provide definitive answers, it can raise important questions for decision makers. PMID- 25690127 TI - Comparing hospital performance within and across countries: an illustrative study of coronary artery bypass graft surgery in England and Spain. AB - OBJECTIVE: To assess the feasibility, strengths and weaknesses of using administrative data to compare hospital performance across countries, using mortality after coronary artery bypass graft (CABG) surgery as an illustrative example. METHODS: Country specific and pooled models using individual-level data and logistic regression methods assess individual hospital performance using funnel plots accounting for multiple testing. Outcomes are adjusted for age, sex, comorbidities and indicators of patient severity. Data includes patients from all publicly funded hospitals delivering CABG surgery in England and Spain. Inpatient hospital-level standardized mortality rates within 30 days of CABG surgery are calculated for 83 999 CABG patients between 2007 and 2009. RESULTS: Unadjusted national mortality rates are 5% in Spain and 2.3% in England. Country-specific models identified similar patterns of excess mortality 'alerts' and 'alarms' in hospitals in Spain or England. Pooling data from both countries identifies larger numbers of alerts and alarms in Spanish hospitals, and risk-adjustment increased the already large national mortality difference. This was reduced but not eliminated by accounting for lower volume in Spanish hospitals. CONCLUSION: Cross national comparisons potentially add value by providing international performance benchmarks. Hospital-level analysis across countries can illuminate differences in hospital performance, which might not be identified using country-specific data or incomplete registry data, and can test hypotheses that may explain national differences. Difficulties of making data comparable between countries, however, compound the usual within-country measurement problems. PMID- 25690128 TI - Potentially avoidable hospitalizations in five European countries in 2009 and time trends from 2002 to 2009 based on administrative data. AB - INTRODUCTION: Potentially avoidable hospitalizations in chronic conditions are used to evaluate health-care performance. However, evidence comparing different countries at small geographical areas is still scarce. The aim of the present study is to describe and discuss differences in rates and time-trends across health-care areas from five European countries. METHODS: Observational, ecological study, on virtually all discharges produced in five European countries between 2002 and 2009. Potentially avoidable hospitalizations were operationally defined as a joint indicator composed of six chronic conditions. Episodes flagged as potentially avoidable were allocated to 913 geographical health-care areas. Age-sex standardized rates and standardized hospitalization ratios, as well as several statistics of variation, were estimated. RESULTS: Four hundred sixty-two thousand seven hundred and ninety-two episodes were flagged as potentially avoidable. Variation in rates across countries was notable, from 93.7 cases per 10,000 inhabitants in Denmark to 34.8 cases per 10,000 inhabitants in Portugal. Within-country variation was also noteworthy, from 3.12 times among extreme areas in Spain to a 1.46-fold difference in Denmark. The highest systematic variation was found in Denmark (empirical Bayes 0.45) and the lowest in England (empirical Bayes 0.08). Rates and systematic variation remained fairly stable over time, with Denmark and England experiencing a statistically significant decrease (20% and 10%, respectively). Income and educational level, hospital utilization propensity, and region of residence were found to be associated with avoidable admissions. CONCLUSION: The dramatic variation across countries, beyond age and sex differences, and its consistency over time, implies systemic, although differential, behaviour of the five health-care systems with regard to chronic care. PMID- 25690129 TI - Potential of geographical variation analysis for realigning providers to value based care. ECHO case study on lower-value indications of C-section in five European countries. AB - BACKGROUND: Although C-section is a highly effective procedure, literature abounds with evidence of overuse and particularly misuse, in lower-value indications such as low-risk deliveries. This study aims to quantify utilization of C-section in low-risk cases, mapping out areas showing excess-usage in each country and to estimate excess-expenditure as a proxy of the opportunity cost borne by healthcare systems. METHODS: Observational, ecologic study on deliveries in 913 sub-national administrative areas of five European countries (Denmark, England, Portugal, Slovenia and Spain) from 2002 to 2009. The study includes a cross-section analysis with 2009 data and a time-trend analysis for the whole period. Main endpoints: age-standardized utilization rates of C-section in low risk pregnancies and deliveries per 100 deliveries. Secondary endpoints: Estimated excess-cases per geographical unit of analysis in two scenarios of minimized utilization. RESULTS: C-section is widely used in all examined countries (ranging from 19% of Slovenian deliveries to 33% of deliveries in Portugal). With the exception of Portugal, there are no systematic variations in intensity of use across areas in the same country. Cross-country comparison of lower-value C-section leaves Denmark with 10% and Portugal with 2%, the highest and lowest. Such behaviour was stable over the period of analysis. Within each country, the scattered geographical patterns of use intensity speak for local drivers playing a major role within the national trend. CONCLUSION: The analysis conducted suggests plenty of room for enhancing value in obstetric care and equity in women's access to such within the countries studied. The analysis of geographical variations in lower-value care can constitute a powerful screening tool. PMID- 25690130 TI - Measuring hospital efficiency--comparing four European countries. AB - BACKGROUND: Performing international comparisons on efficiency usually has two main drawbacks: the lack of comparability of data from different countries and the appropriateness and adequacy of data selected for efficiency measurement. With inpatient discharges for four countries, some of the problems of data comparability usually found in international comparisons were mitigated. The objectives are to assess and compare hospital efficiency levels within and between countries, using stochastic frontier analysis with both cross-sectional and panel data. METHODS: Data from English (2005-2008), Portuguese (2002-2009), Spanish (2003-2009) and Slovenian (2005-2009) hospital discharges and characteristics are used. Weighted hospital discharges were considered as outputs while the number of employees, physicians, nurses and beds were selected as inputs of the production function. Stochastic frontier analysis using both cross sectional and panel data were performed, as well as ordinary least squares (OLS) analysis. The adequacy of the data was assessed with Kolmogorov-Smirnov and Breusch-Pagan/Cook-Weisberg tests. RESULTS: Data available results were redundant to perform efficiency measurements using stochastic frontier analysis with cross sectional data. The likelihood ratio test reveals that in cross-sectional data stochastic frontier analysis (SFA) is not statistically different from OLS in Portuguese data, while SFA and OLS estimates are statistically different for Spanish, Slovenian and English data. In the panel data, the inefficiency term is statistically different from 0 in the four countries in analysis, though for Portugal it is still close to 0. CONCLUSIONS: Panel data are preferred over cross section analysis because results are more robust. For all countries except Slovenia, beds and employees are relevant inputs for the production process. PMID- 25690131 TI - Commentary: Translating ECHO findings into practice: lessons from local dissemination groups. PMID- 25690133 TI - Sodium-glucose co-transporter inhibition in the treatment of diabetes: sweetening the pot. PMID- 25690134 TI - Development of sotagliflozin, a dual sodium-dependent glucose transporter 1/2 inhibitor. AB - The sodium-dependent glucose transporter 2 (SGLT2) inhibitors are an important emerging class for the treatment of diabetes. Development of SGLT2 inhibitors has been oriented around a desire for high selectivity for the SGLT2 protein relative to the SGLT1 protein. More recently, genetic and pharmacology research in mice has indicated that gastrointestinal SGLT1 inhibition may also be an appropriate therapeutic target to treat diabetes. Combining SGLT1 and SGLT2 inhibition in a single molecule would provide complementary insulin-independent mechanisms to treat diabetes. Therefore, sotagliflozin (LX4211) has been developed as a dual inhibitor of SGLT1 and SGLT2. The differentiating clinical features of dual inhibitor of SGLT1 and SGLT2 include a large postprandial glucose reduction, elevation of glucagon-like peptide 1 and modest urinary glucose excretion. These features may have clinical implications for the use of sotagliflozin in the treatment of both type 1 and type 2 diabetes. PMID- 25690135 TI - Inhibition of low-grade inflammation by anthocyanins from grape extract in an in vitro epithelial-endothelial co-culture model. AB - BACKGROUND: Anthocyanins (ACNs) are the most prevalent flavonoids in berries and their health promoting effects on vascular functions are still discussed. The aim of the present study was to identify the anti-inflammatory effect of ACNs on activated human umbilical vein endothelial cells (HUVECs) after their transport across an epithelial monolayer. STUDY DESIGN: We established a transwell epithelial-endothelial co-culture system with Caco-2/HT29-B6 cells mimicking the intestinal layer and HUVECs as endothelial cells mimicking the vascular layer. Caco-2 were seeded alone (100%) or together with HT29-B6 cells (10 and 20%) on transwell inserts in order to simulate different metabolization sides of the gut. ACNs as well as malvidin-3-glucoside (M3G) were applied to the luminal compartment of the transwell-system. Transport and degradation rates were determined by high performance liquid chromatography with ultraviolet detection (HPLC-UV) or by ultra-PLC coupled to mass spectrometry (UPLC-MS). After 4 hours incubation time, co-cultured HUVECs were used immediately (short-term incubation) or after 20 hours (long-term incubation). Thereafter, HUVECs were stimulated for 3 hours with 1 ng mL(-1) TNF-alpha to mimic a low-grade or 10 ng mL(-1) to mimic a high-grade inflammation. Afterwards, (1.) leukocyte adhesion, (2.) expression of cell adhesion molecules (ICAM-1, VCAM-1 and E-selectin) and (3.) cytokine expression and secretion (IL-6 and IL-8) were determined using flow cytometry and real-time PCR. RESULTS: Degradation and incubation studies revealed that ACNs were differently degraded depending on the ACN structure and the seeding densities. Incubation of ACNs and M3G to Caco-2 cells (100%) led to a fast decrease, which was not observed when HT29-B6 cells were co-cultured (10 and 20%). Concomitantly, anti-inflammatory effects were only observed using 100% Caco 2 cells, whereas mixtures of Caco-2 and HT29-B6 cells failed to induce an effect. ACN extract and M3G significantly attenuated TNF-alpha-stimulated low-grade leukocyte adhesion, expression of adhesion molecules E-selectin, VCAM-1 and ICAM 1 and cytokine expression and secretion (IL-8 and IL-6) as well as NF-kappaB mRNA expression. No effects were observed with high TNF-alpha (10 ng mL(-1)) or after short-term incubation (4 hours). CONCLUSIONS: ACNs in physiological concentrations reached the serosal compartment and reduced inflammation-related parameters, which were related to the initial steps during the pathogenesis of atherosclerosis. PMID- 25690136 TI - Cupriavidus yeoncheonense sp. nov., isolated from soil of ginseng. AB - A novel bacterial strain, DCY86(T) (=KCTC 42053(T) = JCM 19890(T)) was isolated from soil of a ginseng field in Yeoncheon province (38 degrees 04'00"N 126 degrees 57'00"E), Republic of Korea using a serial dilution method. Strain DCY86(T) was observed to be Gram-stain negative, strictly aerobic, to grow optimally at 25-30 degrees C, at pH 7-7.5 and on tryptic soya agar medium. The cells were found to be sensitive to ceftazidine and tetracycline. Based on 16S rRNA gene sequence comparisons, strain DCY86(T) was found to be most closely related to Cupriavidus basilensis LMG 18990(T) (98.48 %), Cupriavidus numazensis LMG 26411(T) (98.34 %), Cupriavidus pinatabonesis KCTC 22125(T) (98.34 %) and Cupriavidus laharis KCTC 22126(T) (98.00 %). The G+C content was determined to be 64.23 mol %. The only isoprenoid quinone detected in strain DCY86(T) was ubiquinone Q-8. The major polar lipids were identified as diphosphatidylglycerol, phosphtidylethanolamine, phosphatidylglycerol, unidentified aminophosphoglycolipids and unidentified phospholipids. The major fatty acids were identified as C16:0 summed feature 3 (C16:1 omega7c/omega6c and/or iso-C15 : 0 2-OH) and summed feature 8 (C18:1 omega7c and/or C18:1 omega6c). These data support the affiliation of strain DCY86(T) to the genus Cupriavidus. Strain DCY86(T) was also found to be able to solubilize phosphate and produce siderophores. The results of physiological and biochemical tests enabled strain DCY86(T) to be differentiated genotypically and phenotypically from the recognized species of the genus Cupriaividus. Therefore, the novel isolate can be considered to represent a novel species, for which the name Cupriavidus yeoncheonense sp. nov. is proposed here. The type strain is DCY86(T) (=KCTC 42053(T) = JCM 19890(T)). PMID- 25690137 TI - Real-time analysis of multiple anion mixtures in aqueous media using a single receptor. AB - Bambusuril-based receptors have been used in conjunction with (1)H NMR spectroscopy to recognize mixtures of inorganic anions in aqueous solutions. This was achieved by examining complexation-induced changes in the receptors' (1)H NMR fingerprints. This approach enables the simultaneous identification of up to 9 anions and the quantification of up to 5 anions using a single receptor in DMSO d6 containing 5% D2O. Toxic perchlorate was recognized and quantified at 0.1 MUM (1.8 ppb, mol mol(-1)) concentration in pure water. PMID- 25690138 TI - Immunohistochemical distinction of metastases of renal cell carcinoma to the adrenal from primary adrenal nodules, including oncocytic tumor. AB - Metastases of clear cell renal cell carcinoma to the adrenal can mimic primary adrenal cortical neoplasms or normal adrenal, especially in biopsy material. We compared 34 cases of clear cell renal cell carcinoma metastasis to the adrenal with 49 primary adrenal lesions (16 carcinoma, 22 adenoma, 9 oncocytic tumor, and 2 hyperplasia). Normal adrenal was available in 59 cases. Each entity was represented on tissue microarrays by duplicate-triplicate evaluable spots taken from spatially separate areas. Two pathologists evaluated all reactivity from 0 to 3+. A panel of 12 immunohistochemical stains was performed, including the first diagnostic uses of steroid receptor coactivator (SRC1) and equilibrative nucleoside transporter 1 (ENT1). The most sensitive and specific renal cell carcinoma markers were membranous reactivity for carbonic anhydrase IX (CAIX) and RCC marker and nuclear reactivity for PAX8. For adrenal cortical carcinomas, best markers were synaptophysin, SRC1, and MelanA; and for adrenal oncocytic tumor, synaptophysin and ENT1. Optimal markers for adrenal cortical adenoma and normal adrenal were ENT1 (more specific) and either MelanA or SRC1 (more sensitive). Calretinin, cytokeratin 34betaE12 and CAM5.2, inhibin, and steroidogenic factor 1 (SF1) proved less valuable to the panel. Nonspecific cytoplasmic biotin reactivity was frequent for CAIX and PAX8. Tumors with high-grade cytology should be worked up with 2 of the 3 stains: CAIX, PAX8, or RCC marker; and either SRC1 or MelanA. Adrenal adenoma, or normal adrenal, versus low-grade renal cell carcinoma are distinguished by a panel of: CAIX, PAX8, or RCC Marker; ENT1 and either SRC1 or MelanA. PMID- 25690139 TI - [Betalactams in clinical practice]. PMID- 25690140 TI - [Prevention of an outbreak of Acinetobacter baumannii in intensive care units: study of the efficacy of different mathematical methods]. AB - INTRODUCTION: Although in past decades, Acinetobacter baumanni infections have been sporadically identified in hospitals, nowadays the nosocomial infections due to this pathogen have notably increased. Its importance is due to its multidrug- resistance, morbidity and mortatility in healthcare settings. Consequently, it is important to predict the evolution of these outbreaks in order to stablish the most efficient control measures. There are several experimental studies shown that the compliance with hand and environmental hygiene and the efficient management of the healthcare work help to control the evolution of these outbreaks. The goal of this work is to formally proof these experimental results by means of the analysis of the results provided by the model. METHODS: A stochastic mathematical model based on cellular automata was developed. The variables and parameters involved in it have been identified from the knowledge of the epidemiology and main characteristics of Acinetobacter infections. RESULTS: The model provides several simulations from different initial conditions. The analysis of these results proofs in a formal way that the compliance with hand and environmental hygiene and an efficient plannification of the work of healtcare workers yield a decrease in the colonized patients. Moreover, this is the unique model proposed studying the dynamics of an outbreak of A. baumanni. CONCLUSIONS: The computational implementation of the model provides us an efficient tool in the management of outbreaks due to A. baumanni. The analysis of the simulations obtained allows us to obtain a formal proof of the behaviour of the measures for control and prevention. PMID- 25690141 TI - [Acceptability of the HPV vaccine among Spanish university students in the pre vaccine era: a cross-sectional study]. AB - INTRODUCTION: Cervical cancer (CC), the second most common cause of cancer deaths in women, is associated with the infection of human papillomavirus (HPV) and is more prevalent in women between the ages of 20 and 24. This research is aimed to determine the background about CC, the human papillomavirus infection and its vaccine, assessing its acceptability in university students. METHODS: Cross sectional study over 1,750 students from the University of Alicante (2008) selected at random, proportional associated to gender and studies, by a validated ad-hoc questionnaire. Percentages were computed, confidence intervals, contingency tables according to sex, age and type of studies, calculating adjusted odd ratios (OR). RESULTS: A sample with 58.6 % of women and 6.6% of biohealth students was obtained. 87.3% were willing to have the vaccine to prevent human papillomavirus (HPV), 94.3% would give this vaccine to their daughters, and 48.0% had heard someone talk about the vaccine. 90.6% didn't have a lot of knowledge about the HPV infection and 82.2% didn't know much about the vaccine. 22.4% had knowledge of the association between HPV and CC. Women register higher OR in acknowledging the problem and are more receptive to having the vaccine. The HPV vaccine acceptability is associated to the sex, the confidence of vaccines as a preventive method; the influence of the background is low in relation to the vaccine predisposition. CONCLUSIONS: A high acceptability of the vaccine was observed in the period of the study. Raising confidence in people about the vaccines can influence for a better predisposition to be vaccinated. PMID- 25690142 TI - [Prevalence of serotypes causing invasive pneumococcal disease in the region of Tarragona, Spain, 2006-2009: vaccine-serotype coverage for the distinct antipneumococcal vaccine formulations]. AB - BACKGROUND: Pneumococcal infections remain a major health problem worldwide. This study analysed the distribution of distinct Streptococcus pneumoniae serotypes causing invasive pneumococcal disease (IPD) among all-age population in the region of Tarragona (Spain) throughout 2006-2009. METHODS: An amount of 237 strains were evaluated, of which 203 (85.7%) were isolated from blood cultures, 14 (5.9%) from pleural fluids, 13 (5.5%) from CSF samples and 7 (3%) from other sterile sites. Forty-seven cases (19.8%) were children <= 14 years, 94 (39.7%) were patients 15-64 years and 96 (40.5%) were patients >= 65 years. RESULTS: Seven serotypes (1, 3, 6A, 7F, 12F, 14 and 19A) caused almost two thirds (63.3%) of cases among all-age patients. Serotype 1 was the most common serotype among children (44.7%) and among people 15-64 years (21.3%), whereas serotype 19A was the most common among people >= 65 years (12.5%).Among all-age population, serotype-vaccine coverage for the distinct pneumococcal polysaccharide vaccine (PPV) and conjugate vaccines (PCVs) were 17.3% for the PCV7, 49.8% for the PCV10, 73% for the PCV13 and 80.2% for the PPV23 (p < 0.001). Among children, vaccine serotype coverage was 23.4% for the PCV7, 72.3% for the PCV10 and 83% for the PCV13. Among people >= 65 years, vaccine-serotype coverage was 62.5% for the PCV13 and 68.8% for the PPV23. CONCLUSION: A considerable proportion of IPD cases among our population would not be covered by the current pneumococcal vaccines. PMID- 25690143 TI - [Salmonella enterica with nonclassical quinolone resistance phenotype in pediatric patients]. AB - INTRODUCTION: Decreased susceptibility to fluoroquinolones in Salmonella spp. may lead to treatment failures. The use of ciprofloxacin for extraintestinal and serious intestinal Salmonella infections in children is controversial and therefore the clinical relevance of these strains is not significant. Consequently little is know about the quinolone resistance of strains Salmonella of our paediatric population. The objective of this study was to assess the incidence of nonclassical quinolone resistance phenotype in paediatric patients. MATERIAL AND METHODS: Two hundred and sixty eight Salmonella spp. from Hospital Infantil Universitario Nino Jesus of Madrid (2009-2013) were tested against nalidixic acid and ciprofloxacin by microdilution. Moreover, 146 strains (2011 2013) were tested against ciprofloxacin by E-test. Reduced ciprofloxacin susceptibility was defined as a MIC of 0.125-1 mg/L. RESULTS: Of 42 isolates with reduced ciprofloxacin susceptibility, four isolates showing nonclassical quinolone resistance phenotype. Three were confirmed as carrying of plasmid mediated quinolone resistance-conferring genes qnr. CONCLUSIONS: The percentage of strains with a genotype that confers a nonclassical quinolone resistance phenotype is low in our series. The identification of these isolates is difficult using conventional methods, but its ability of horizontal spread recommends an appropriate identification. Taking into account the low isolation rate of these strains in this study, evaluation of ciprofloxacin MIC on every nalidixic acid susceptible strain would not be cost effective. Alternatively, we propose to evaluate periodically any changing trend. PMID- 25690144 TI - [Burden of influenza virus type B and mismatch with the flu vaccine in Spain]. AB - INTRODUCTION: Since the 80s two lineages of type B viruses are co - circulating in the world. Antigenic differences between them are important and it leads to lack of cross-reactivity. The impact on the burden of disease due to influenza B virus, poor foresight in estimating which of the two lineages of B viruses circulate in the season, and the consequent lack of immunity in case of including the wrong strain make that the availability of the quadrivalent vaccine is very useful. The aim of this paper is to analyze the past influenza seasons in Spain to assess the burden of disease, divergence between the vaccine strain and the circulating B and viral characteristics associated with type B in each seasonal epidemic. MATERIAL AND METHODS: Review of all reports issued by the Influenza Surveillance System in Spain since the 2003-2004 season to 2012-2013. RESULTS: Over the past influenza seasons, although type A was present mostly, circulation of influenza B virus in each season was observed, even being co - dominant in some of them. In a high number of seasons the divergence between the vaccine strain and the circulating strain lineage has been observed CONCLUSIONS: The protective effect of influenza vaccine has varied depending on the type / subtype of influenza virus studied. The vaccine effectiveness against influenza infection by influenza B virus has varied greatly depending on the season analyzed. PMID- 25690145 TI - A practice-based observational study identifying factors associated with the use of high-dose tigecycline in the treatment of secondary peritonitis in severely ill patients. AB - INTRODUCTION: Based on tigecycline linear pharmacokinetic/pharmacodynamics, dose increases have been advocated to maximise activity especially when severe infections with high bacterial load and/or multidrug resistance are suspected. This practice-based observational study explored factors associated with tigecycline administration (100 mg/12h, 200 mg loading dose) in severely ill patients with complicated intra-abdominal infection (cIAI) admitted to four Surgical Critical Care Units (SCCUs). METHODS: Medical records of all consecutive adult patients with cIAI and controlled infection source requiring surgery and admission for >= 48 h to SCCU were reviewed and divided into patients treated with a regimen including tigecycline (tigecycline group) and those that not (control group). A logistic regression model was performed using "tigecycline administration" (dependent variable) and variables showing differences (p <= 0.1) in bivariate analyses (independent variables). RESULTS: One hundred and twenty one patients were included. In the tigecycline group, higher percentage of patients (vs. controls) presented colon as surgical site (66.7% vs. 41.8%, p = 0.006), nosocomial infection (55.6% vs. 26.9%, p = 0.001), mechanical ventilation (48.1% vs. 28.4%, p = 0.025), chronic renal replacement therapy (40.7% vs. 19.4%, p =0.008), septic shock (72.2% vs. 46.3%, p = 0.004), and higher values of SAPS II (48.0 +/- 15.0 vs. 39.6 +/- 15.5, p = 0.003), SOFA at admission (7.0 +/- 3.3 vs. 5.5 +/- 3.7, p = 0.020), lactate-24h (2.5 +/- 2.8 vs. 1.6 +/- 0.9, p = 0.029) and CRP-72 h (207.4 +/- 87.9 vs. 163.7 +/- 76.8, p = 0.021). In the multivariate analysis (R2 = 0.187, p < 0.001) nosocomial infection (OR = 7.721; 95%CI = 2.193, 27.179; p = 0.001), colon as infection site (OR = 4.338; 95%CI = 1.432, 13.145; p = 0.009) and CRP-72 h (OR = 1.009 per-unit; 95%CI = 1.002, 1.016; p = 0.012) were associated with tigecycline administration. CONCLUSIONS: In severely ill patients with cIAI, high-dose tigecycline administration was associated with nosocomial origin of cIAI and colon as source infection site. PMID- 25690146 TI - [Rectal bleeding and microabscesses in a not immunosuppressed patient]. PMID- 25690147 TI - [Fulminant hepatitis B as a result of reactivation in hematologic patient after chemotherapy combined with rituximab]. PMID- 25690148 TI - Severe Mucor necrotizing fasciitis associated to dipyrone-induced agranulocytosis. PMID- 25690149 TI - Genetic Effects of eNOS Polymorphisms on Biomarkers Related to Cardiovascular Status in a Population Coexposed to Methylmercury and Lead. AB - The aim of the present study was to evaluate possible effects of endothelial nitric oxide synthase (eNOS) polymorphisms on systolic (SBP) and diastolic blood pressure (DBP) and on nitrite levels in plasma (NitP) in a population coexposed to methylhemoglobin (MeHg) and lead (Pb) in the Amazonian region, Brazil. Plasmatic levels of hemoglobin Hg (HgP) and Pb (PbP) were determined by inductively coupled plasma-mass spectrometry, whereas NitP were quantified by chemiluminescence. Genotyping was performed by conventional and restriction fragment length polymorphism-polymerase chain reaction assay. The population age ranged from 18 to 87 years (mean 40 +/- 16), and the distribution between the sexes was homogenous (63 men and 50 women). Mean HgP and PbP were 7.1 +/- 6.1 and 1.1 +/- 1.1 ug L(-1), respectively. PbP was correlated to SBP and DBP, whereas no effects were observed for HgP on blood pressure. Subjects carrying the 4b allele in intron 4 presented greater SBP and DBP compared with those who had the 4a4a genotype. In addition, interactions between alcohol consumption and the -786 T/C polymorphism were observed on NitP, i.e., individuals carrying the polymorphic allele and drinkers had lower NitP. Taken together, our data give new insights concerning the genetic effects of eNOS polymorphisms on biomarkers related to cardiovascular status in populations coexposed to Hg and Pb. PMID- 25690150 TI - Nonsynonymous polymorphisms in PLA2G7 gene are associated with the risk of coronary heart disease in a southern Chinese population. AB - Lipoprotein-associated phospholipase A2 (Lp-PLA2) plays an important role in coronary heart disease (CHD). This study was aimed to investigate the associations of polymorphisms (R92H, V279F, I198T, and A379V) in PLA2G7 with CHD. A total of 322 patients with CHD and 414 CHD-free controls were included in the study. Polymorphisms in PLA2G7 were sequenced by DNA Sequencer and statistical analyses were performed to study the associations between polymorphisms and CHD. RH + HH genotype, RH genotype, and H allele of R92H were significantly associated with an increased risk of CHD (P = 0.005, P = 0.009, and P = 0.003, respectively), while no associations were observed between V279F and I198T and CHD (A379V was not analyzed because of deviation from Hardy-Weinberg equilibrium). Correlations between R92H and CHD still existed after adjustment for confounding risk factors of CHD (P = 0.001). Furthermore, stratified analyses showed subgroups of the senior, hypertension, non-smoking, non-diabetics, and male subjects brought a higher risk for CHD (P = 0.015, P = 0.001, P = 0.001, P = 0.002, and P = 0.004, respectively). We also observed a lower level of protective factor HDL-C in CHD patients carrying genotype RH + HH than patients with RR (P = 0.047). Furthermore, we conducted haplotype analysis and detected more harmful effects of haplotypes HVI and RVT as compared with other haplotypes (P = 2.538 * 10(-3) and P = 0.031). These findings indicated that R92H variant in PLA2G7 gene might contribute to CHD susceptibility in a southern Chinese population. PMID- 25690151 TI - Disordered surface vibrations in jammed sphere packings. AB - We study the vibrational properties near a free surface of disordered spring networks derived from jammed sphere packings. In bulk systems, without surfaces, it is well understood that such systems have a plateau in the density of vibrational modes extending down to a frequency scale omega*. This frequency is controlled by DeltaZ = - 2d, the difference between the average coordination of the spheres and twice the spatial dimension, d, of the system, which vanishes at the jamming transition. In the presence of a free surface we find that there is a density of disordered vibrational modes associated with the surface that extends far below omega*. The total number of these low-frequency surface modes is controlled by DeltaZ, and the profile of their decay into the bulk has two characteristic length scales, which diverge as DeltaZ(-1/2) and DeltaZ(-1) as the jamming transition is approached. PMID- 25690152 TI - On-chip surface acoustic wave lysis and ion-exchange nanomembrane detection of exosomal RNA for pancreatic cancer study and diagnosis. AB - There has been increasing evidence that micro and messenger RNA derived from exosomes play important roles in pancreatic and other cancers. In this work, a microfluidics-based approach to the analysis of exosomal RNA is presented based on surface acoustic wave (SAW) exosome lysis and ion-exchange nanomembrane RNA sensing performed in conjunction on two separate chips. Using microRNA hsa-miR 550 as a model target and raw cell media from pancreatic cancer cell lines as a biological sample, SAW-based exosome lysis is shown to have a lysis rate of 38%, and an ion-exchange nanomembrane sensor is shown to have a limit of detection of 2 pM, with two decades of linear dynamic range. A universal calibration curve was derived for the membrane sensor and used to detect the target at a concentration of 13 pM in a SAW-lysed sample, which translates to 14 target miRNA per exosome from the raw cell media. At a total analysis time of ~1.5 h, this approach is a significant improvement over existing methods that require two overnight steps and 13 h of processing time. The platform also requires much smaller sample volumes than existing technology (~100 MUL as opposed to ~mL) and operates with minimal sample loss, a distinct advantage for studies involving mouse models or other situations where the working fluid is scarce. PMID- 25690153 TI - Peer worker roles and risk in mental health services: a qualitative comparative case study. AB - New peer worker roles are being introduced into mental health services internationally. This paper addresses a lack of research exploring issues of risk in relation to the role. In-depth interviews were carried out with 91 peer workers, service users, staff and managers. A grounded analysis revealed protective practice in minimising risk to peer worker well-being that restricted the sharing of lived experience, and a lack of insight into how peer workers might be involved in formal risk management. Alternatively, analysis revealed potential new understandings of risk management based on the distinctive, experiential knowledge that peer workers brought to the role. PMID- 25690154 TI - Quality of Life and Social Isolation Among Caregivers of Adults with Schizophrenia: Policy and Outcomes. AB - Services have been increasingly directed at supporting carers of people living with mental illness but it is difficult to evaluate the impact of service change where benchmarks for carer functioning are sparse. Sixty Australian carers were assessed regarding their quality of life, psychological distress, social isolation and caregiving experience. Their scores were compared with two matched community samples and previous studies. Carers were ten times more likely to be socially isolated and quality of life was significantly less than matched community samples. Over 40 % of the carer sample met criteria for probable psychiatric disorder. Comparison of caregiving experiences with a study 15 years ago showed no improvement in negative caregiving experiences. Carers still face considerable challenges to their wellbeing as they support people living with mental illness, in spite of progress in the development of policy and services. PMID- 25690155 TI - Reciprocal Regulation of Substance P and IL-12/IL-23 and the Associated Cytokines, IFNgamma/IL-17: A Perspective on the Relevance of This Interaction to Multiple Sclerosis. AB - The neuropeptide substance P (SP) exhibits cytokine-like properties and exerts different effects in autoimmune inflammation. Various immune cells express SP and its neurokinin-1 receptor (NK1R) isoforms. A role for SP has been demonstrated in a number of autoimmune conditions, including multiple sclerosis (MS). In this work, we studied the role of SP and NK1R in human immune cells with a focus on their relationship with IL-12/IL-23 family cytokines and the associated IFN gamma/IL-17. AIMS: (1) To determine the role of SP mediated effects on induction of various inflammatory cytokines in peripheral blood mononuclear cells (PBMC); (2) to investigate the expression of SP and its receptor in T cells and the effects of stimulation with IL-12 and IL-23. Quantitative real-time PCR, flow cytometry, ELISA, promoter studies on PBMC and primary T cells from healthy volunteers, and Jurkat cell line. Treatment with SP significantly increased the expression of IL-12/IL-23 subunit p40, IL-23 p19 and IL-12 p35 mRNA in human PBMC. Expression of NK1R and SP in T cells was upregulated by IL-23 but a trend was observed with IL-12. The IL-23 effect likely involves IL-17 production that additionally mediates IL-23 effects. Mutual interactions exist with SP enhancing the cytokines IL-23 and IL-12, and SP and NK1R expression being differentially but potentially synergistically regulated by these cytokines. These findings suggest a proinflammatory role for SP in autoimmune inflammation. We propose a model whereby immunocyte derived SP stimulates Th1 and Th17 autoreactive cells migrating to the central nervous system (CNS), enhances their crossing the blood brain barrier and perpetuates inflammation in the CNS by being released from damaged nerves and activating both resident glia and infiltrating immune cells. SP may be a therapeutic target in MS. PMID- 25690156 TI - Chronic thromboembolic pulmonary hypertension. PMID- 25690157 TI - A predictive model for blastocyst formation based on morphokinetic parameters in time-lapse monitoring of embryo development. AB - PURPOSE: The aim of the study was to create a predictive model of blastocyst development based on morphokinetic parameters of time-lapse embryoscope monitoring. METHODS: Time-lapse recordings of 432 embryos (obtained from 77 patients), monitored in Embryoscope, were involved in the study. Patients underwent in vitro fertilization according to standard procedure between June 2012 and April 2013. A retrospective analysis of morphokinetic features, focused on duration of time from the Intracytoplasmic Sperm Injection (ICSI) procedure to consecutive embryo division for 2, 3, 4 and 5 blastomeres, as well as time intervals between each division, was conducted. All embryos were observed for 5 days. RESULTS: Based on the distribution of analyzed morphokinetic parameters and number of embryos developed to blastocyst, a range denoting the possibility of an embryo reaching blastocyst stage was determined. According to the obtained results, univariate and multivariate logistic regression analyses were performed. Based on the times of division for two and five blastomeres and intervals between the second and third division, a multivariate predictive model was created. The predictive equation was constructed based on the parameters of logistic regression analysis (odds ratios). Statistically significant differences (p < 0.001) in the size of the prediction parameter between the group of embryos developed to blastocyst (the median value: Me = 9.95, and quartiles: Q1 = 7.59, Q3 = 12.30) and embryos that did not develop to the blastocyst stage (Me = 4.66, Q1 = 2.33, Q3 = 8.19) were found. A Receiver Operating Characteristic (ROC) curve was created for the constructed predictive model. The Area Under the Curve was AUC = 0.806 with a 95 % confidence interval (0.747, 0.864). The predictive model constructed in this study has been validated using an independent data set, which indicates that the model is reliable and repeatable. CONCLUSIONS: Time-lapse imaging presents a new diagnostic tool for parametric evaluation of embryo development, from the oocyte stage, through fertilization, up to the blastocyst stage. The assessment of morphokinetic parameters can help us to provide more accurate information about the reproductive potential of embryos. It allows for early selection of embryos with high reproductive potential and shortens embryo incubation. PMID- 25690158 TI - Associations between TNF-alpha and interleukin gene polymorphisms with polycystic ovary syndrome risk: a systematic review and meta-analysis. AB - BACKGROUND: The associations between TNF-alpha and Interleukin gene polymorphisms and polycystic ovary syndrome (PCOS) risk have been studied in numerous epidemiological studies, but the results remain controversial. To investigate whether these polymorphisms facilitate susceptibility to PCOS, we conducted a comprehensive systematic review and meta-analysis. METHODS: PubMed, Embase, Web of Science, Medline, CNKI, and Google Scholar were searched to obtain the genetic association studies according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Odds ratios (OR) with corresponding 95 % confidence intervals (CI) were used to assess the strengths of the associations. Funnel plots and Egger's tests were performed to test for possible publication bias. All statistical analyses were performed using Review Manager 5.2 and STATA11.0. RESULTS: Eighteen articles were included in the final meta-analysis. The studies involved the following polymorphisms: TNF-alpha -308G > A, TNF-alpha -805C>T, TNF-alpha -1031 T>C, IL-1A -889C>T, IL-1B -511C>T, IL-1B +3953 T>C, IL-6 -174G>C, IL-10 -819C>T, IL-10 -1082A>G, IL-18 -607C>A, and IL-18 137G>C. Our results show a significant association between PCOS risk and the TNF alpha -1031 T>C polymorphism (For TC+CC vs. TT: OR=2.09, 95 % CI=1.58-2.76, p<0.0001. For C allele vs. T allele: OR=1.67, 95 % CI=1.33-2.09, p<0.0001) and between PCOS risk and the IL-6 -174>C polymorphism (For CC+GC vs. GG: OR=0.49, 95 % CI=0.25-0.95, p=0.03. For CC vs. GG: OR=0.48, 95 % CI=0.28-0.80, p=0.005. For C vs. G: OR=0.60, 95 % CI=0.42-0.87, p=0.007). No associations were found with the other genetic models. CONCLUSION: The results of the meta-analysis suggest positive associations between the TNF-alpha -1031 T>C and IL-6 -174G>C polymorphisms and the risk of PCOS. No associations are found between PCOS risk and the TNF-alpha -308G>A, TNF-alpha -805C>T, IL-1A -889C>T, IL-1B -511C>T, IL-1B +3953C>T, IL-10 -819C>T, IL-10 -1082 A>G, IL-18 -607C>A, and IL-18 -137G>C polymorphisms. However, due to the heterogeneity and low quality of the studies related to PCOS polymorphisms in the meta-analysis, the results should be interpreted with caution. Future multi-ethnicity studies of homogeneous populations of PCOS patients with larger sample sizes and well-matched controls are needed. PMID- 25690159 TI - Distribution of Keratinophilic Fungi in Soil Across Tunisia: A Descriptive Study and Review of the Literature. AB - Data on the frequency and distribution of keratinophilic fungi in soil of Tunisia are scanty. The present survey aimed to describe the distribution of keratinophilic fungi in soils collected in Tunisia. Keratinophilic fungi were isolated using Vanbreuseghem's hair-baiting technique from 354 soil samples collected in 15 governorates of Tunisia and identified according to their morphology with further DNA and MALDI-TOF analysis when necessary. Keratinophilic fungi were isolated from 46.3 % of the samples from 14 governorates. Chrysosporium keratinophilum was the predominant species (30.5 %) followed by Microsporum gypseum (27.4 %). Other isolated species included C. tropicum (14.0 %), C. indicum (11.0 %), Chaetomium sp. (4.9 %), Arthroderma curreyi, Arthroderma cuniculi (3.7 % each), C. merdarium (3.1 %), Anixiopsis stercoraria, C. parvum, Paecilomyces lilacinus, Auxarthron zuffianum (2.4 % each), Fusarium oxysporum, Aphanoascus verrucosus, Gymnascella dankaliensis (1.2 % each) and 12 other species (0.6 % each). Two to five distinct fungal species were associated with 11.5 % of the positive samples. Keratinophilic fungi were more frequently isolated in rural (54.8 %) than in urban (41.1 %) areas (p = 0.012). The highest (100 %) positive culture rate was noted in soil collected in stables. Keratinophilic fungi are frequent throughout Tunisian territory, particularly in soils with a high organic matter content that should be regarded as humans and animals mycoses reservoir. PMID- 25690160 TI - Intravesical injection of botulinum toxin A for treatment of interstitial cystitis/bladder pain syndrome: 10 years of experience at a single center in China. AB - INTRODUCTION AND HYPOTHESIS: To evaluate the efficacy and safety of the intravesical injection of Chinese botulinum toxin A (BTX-A) in patients with interstitial cystitis/bladder pain syndrome (IC/BPS). METHODS: Between January 2003 and June 2013, 124 women with IC/BPS were studied. Of these 124 patients, 66 were treated with BTX-A and 58 underwent bladder hydrodistention plus sodium hyaluronate (Cystistat) instillation. Intravesical injection of 100 U of Chinese BTX-A was immediately followed by cystoscopic hydrodistention under intravenous general anesthesia. The patients were evaluated using the O'Leary-Saint score, a visual analog scale pain score, a urinary frequency record and a quality of life questionnaire before treatment and 1 week, and 1, 3, 6 and 12 months after treatment. RESULTS: Of the patients who received BTX-A injection, only 2 had acute urinary retention, 23 received a repeat injection, and 20 were lost to follow-up. Of the patients treated with hydrodistention plus Cystistat instillation, 2 had urinary tract infection, 11 switched to BTX-A injection at 6 months, and 23 were lost to follow-up. BTX-A was shown to remain effective for up to 6 months after treatment. After repeated Chinese BTX-A injections, symptoms improved significantly. Hydrodistention plus Cystistat remained effective for up to 3 months after treatment. CONCLUSIONS: Intravesical injection of Chinese BTX-A is a safe and effective therapeutic option for patients with IC/BPS. The average duration of the effect of one dose of Chinese BTX-A amongst the responders was 6 months. Repeated injection of Chinese BTX-A is safe and effective. PMID- 25690161 TI - The divergent roles of growth differentiation factor-15 (GDF-15) in benign and malignant skin pathologies. AB - GDF-15 (Growth Differentiation Factor-15) is a member of the transforming growth factor beta (TGF-beta) superfamily. GDF-15 is not only involved in cancer development, progression, angiogenesis and metastasis, but also controls stress responses, bone formation, hematopoietic development, adipose tissue function and cardiovascular diseases. GDF-15, which is regulated by p53, has shown antitumorigenic and proapoptotic activities in vivo and in vitro. Also, GDF-15 is involved in skin biology and histamine-induced melanogenesis; it is overexpressed in melanoma cells and is associated with depth of tumor invasion and metastasis. GDF-15 level is increased in patients with systemic sclerosis and is related with the degree of skin sclerosis and intensity of pulmonary fibrosis. In the future, GDF-15 may be a potential target for therapy in benign disorders with skin fibrosis and malignant lesions of the skin. PMID- 25690162 TI - Regulation of lipid production by light-emitting diodes in human sebocytes. AB - Light-emitting diodes (LED) have been used to treat acne vulgaris. However, the efficacy of LED on sebaceous lipid production in vitro has not been examined. This study investigated the efficacy of 415 nm blue light and 630 nm red light on lipid production in human sebocytes. When applied to human primary sebocytes, 415 nm blue light suppressed cell proliferation. Based on a lipogenesis study using Oil Red O, Nile red staining, and thin-layered chromatography, 630 nm red light strongly downregulated lipid production in sebocytes. These results suggest that 415 nm blue light and 630 nm red light influence lipid production in human sebocytes and have beneficial effects on acne by suppressing sebum production. PMID- 25690163 TI - Omentin-1 plasma levels and omentin-1 expression are decreased in psoriatic lesions of psoriasis patients. AB - Previous studies have suggested that psoriasis is associated with individuals who are overweight or obese. Omentin is a recently discovered adipokine that is involved in chronic inflammatory processes. This study evaluated the relationship between omentin and psoriasis, focusing on omentin-1 serum levels, skin expression of omentin-1, and omentin-1 gene polymorphism (rs2274907; Val109Asp). Levels of omentin-1 in serum samples from 44 patients with psoriasis and 38 healthy controls were analyzed by enzyme-linked immunosorbent assay. The expressions of omentin-1 were measured by immunohistochemistry in 3 psoriasis affected skins and 3 normal skins. The rs2274907 variant was typed using a SNaPshot assay in 354 cases and 214 controls. We found significantly lower serum levels of omentin-1 in psoriasis patients compared with healthy controls (p < 0.001) with an inverse correlation with the Psoriasis Area and Severity Index (p < 0.01). The comparison of genotype and allele distribution revealed no significant difference in genotype frequency between psoriasis patients and controls. Therefore, omentin-1 may have a role in the pathogenesis of psoriasis and might be a potential biological marker for psoriasis severity. PMID- 25690164 TI - Prediction of functional outcomes in stroke patients: the role of motor patterns according to limb synergies. AB - BACKGROUND AND AIMS: To address the relationships among motor patterns evaluated according to the limb synergies and functional outcomes in stroke patients and clarify which motor pattern was the most important predictor of functional outcomes. METHODS: The study was conducted on 208 patients with primary diagnosis of stroke admitted for in-hospital rehabilitation. At entry, the Fugl-Meyer Scale was administered to assess motor function according to limb synergies. Pearson's correlation was used to assess the relationship between variables, and backward stepwise regression analysis was used to identify the outcome determinants. Final functional independence measure (FIM) scores and length of in-hospital stay were the outcome measures. RESULTS: At the end of rehabilitation, motor-FIM scores of patients with extensor and flexor synergies, mixing synergies, and no dependence from the synergies were higher than those of no movements and flexor synergy. Multivariate regression analysis showed that extensor synergy of upper limb was an independent predictor of final motor-FIM, personal care and mobility, extensor synergy of lower limb of locomotion, while mixing synergies of upper limb was an independent predictor of length of in-hospital stay. CONCLUSIONS: In stroke rehabilitation, the patients' motor patterns according to the synergies strongly relate with functional outcomes and are important outcome predictors. PMID- 25690165 TI - Medicolegal sidebar: the law and social values: conformity to norms. PMID- 25690166 TI - Clinical Faceoff: Routine Electrodiagnostic Testing is Not Helpful in the Management of Carpal Tunnel Syndrome. PMID- 25690167 TI - Women Build Long Bones With Less Cortical Mass Relative to Body Size and Bone Size Compared With Men. AB - BACKGROUND: The twofold greater lifetime risk of fracturing a bone for white women compared with white men and black women has been attributed in part to differences in how the skeletal system accumulates bone mass during growth. On average, women build more slender long bones with less cortical area compared with men. Although slender bones are known to have a naturally lower cortical area compared with wider bones, it remains unclear whether the relatively lower cortical area of women is consistent with their increased slenderness or is reduced beyond that expected for the sex-specific differences in bone size and body size. Whether this sexual dimorphism is consistent with ethnic background and is recapitulated in the widely used mouse model also remains unclear. QUESTIONS/PURPOSES: We asked (1) do black women build bones with reduced cortical area compared with black men; (2) do white women build bones with reduced cortical area compared with white men; and (3) do female mice build bones with reduced cortical area compared with male mice? METHODS: Bone strength and cross sectional morphology of adult human and mouse bone were calculated from quantitative CT images of the femoral midshaft. The data were tested for normality and regression analyses were used to test for differences in cortical area between men and women after adjusting for body size and bone size by general linear model (GLM). RESULTS: Linear regression analysis showed that the femurs of black women had 11% lower cortical area compared with those of black men after adjusting for body size and bone size (women: mean=357.7 mm2; 95% confidence interval [CI], 347.9-367.5 mm2; men: mean=400.1 mm2; 95% CI, 391.5-408.7 mm2; effect size=1.2; p<0.001, GLM). Likewise, the femurs of white women had 12% less cortical area compared with those of white men after adjusting for body size and bone size (women: mean=350.1 mm2; 95% CI, 340.4-359.8 mm2; men: mean=394.3 mm2; 95% CI, 386.5-402.1 mm2; effect size=1.3; p<0.001, GLM). In contrast, female and male femora from recombinant inbred mouse strains showed the opposite trend; femurs from female mice had a 4% larger cortical area compared with those of male mice after adjusting for body size and bone size (female: mean=0.73 mm2; 95% CI, 0.71-0.74 mm2; male: mean=0.70 mm2; 95% CI, 0.68-0.71 mm2; effect size=0.74; p=0.04, GLM). CONCLUSIONS: Female femurs are not simply a more slender version of male femurs. Women acquire substantially less mass (cortical area) for their body size and bone size compared with men. Our analysis questions whether mouse long bone is a suitable model to study human sexual dimorphism. CLINICAL RELEVANCE: Identifying differences in the way bones are constructed may be clinically important for developing sex-specific diagnostics and treatment strategies to reduce fragility fractures. PMID- 25690168 TI - Is the Control of Applied Digital Forces During Natural Five-digit Grasping Affected by Carpal Tunnel Syndrome? AB - BACKGROUND: The impaired sensory function of the hand induced by carpal tunnel syndrome (CTS) is known to disturb dexterous manipulations. However, force control during daily grasping configuration among the five digits has not been a prominent focus of study. Because grasping is so important to normal function and use of a hand, it is important to understand how sensory changes in CTS affect the digit force of natural grasp. QUESTIONS/PURPOSES: We therefore examined the altered patterns of digit forces applied during natural five-digit grasping in patients with CTS and compared them with those seen in control subjects without CTS. We hypothesized that the patients with CTS will grasp by applying larger forces with lowered pair correlations and more force variability of the involved digits than the control subjects. Specifically, we asked: (1) Is there a difference between patients with CTS and control subjects in applied force by digits during lift-hold-lower task? (2) Is there a difference in force correlation coefficient of the digit pairs? (3) Are there force variability differences during the holding phase? METHODS: We evaluated 15 female patients with CTS and 15 control subjects matched for age, gender, and hand dominance. The applied radial forces (Fr) of the five digits were recorded by respective force transducers on a cylinder simulator during the lift-hold-lower task with natural grasping. The movement phases of the task were determined by a video-based motion capture system. RESULTS: The applied forces of the thumb in patients with CTS (7 +/- 0.8 N; 95% CI, 7.2-7.4 N) versus control subjects (5 +/- 0.8 N; 95% CI, 5.1 5.3 N) and the index finger in patients with CTS (3 +/- 0.3 N; 95% CI, 3.2-3.3 N) versus control subjects (2 +/- 0.3 N; 95% CI, 2.2-2.3 N) observed throughout most of the task were larger in the CTS group (p ranges 0.035-0.050 for thumb and 0.016-0.050 for index finger). In addition, the applied force of the middle finger in patients with CTS (1 +/- 0.1 N; 95% CI, 1.3-1.4 N) versus the control subjects (2 +/- 0.2 N; 95% CI, 1.9-2.0 N) during the lowering phase was larger in CTS group (p ranges 0.039-0.050). The force correlations of the thumb-middle finger observed during the lowering phase in the patients with CTS (0.8 +/- 0.2; 95% CI, 0.6-0.9) versus the control subjects (0.9 +/- 0.1; 95% CI, 0.8-1.0; p = 0.04) were weaker in the CTS group. The thumb-little finger during holding in the patients with CTS (0.5 +/- 0.2; 95% CI, 0.3-0.7) versus the control subjects (0.8 +/- 0.2; 95% CI, 0.6-0.9; p = 0.02), and the lowering phase in the patients with CTS (0.6 +/- 0.2; 95% CI, 0.3-0.8) versus the control subjects (0.9 +/- 0.1; 95% CI, 0.8-1.0; p = 0.01) also were weaker. The force variabilities of patients with CTS were greater in the CTS group than in the control subjects: in the thumb ([0.26 +/- 0.11 N, 95% CI, 0.20-0.32 N] versus [0.19 +/- 0.06 N; 95% CI, 0.16 0.22 N], p = 0.03); index finger ([0.09 +/- 0.07 N; 95% CI, 0.05-0.13 N] versus [0.05 +/- 0.03 N; 95% CI, 0.04-0.07 N], p = 0.03); middle finger ([0.06 +/- 0.04 N; 95% CI, 0.04-0.08 N] versus [0.03 +/- 0.01 N; 95% CI, 0.02-0.04 N], p = 0.02), and ring finger ([0.04 +/- 0.03 N; 95% CI, 0.20-0.06 N] versus [0.02 +/- 0.01 N; 95% CI, 0.02-0.02 N], p = 0.01). CONCLUSIONS: Patients with CTS grasped with greater digit force associated with weaker correlation and higher variability on specific digits in different task demands. These altered patterns in daily grasping may lead to secondary problems, which will need to be assessed in future studies with this model to see if they are reversible in patients undergoing carpal tunnel release. CLINICAL RELEVANCE: The current results helped to identify altered patterns of grasping force during simulated daily function in patients with CTS and to provide the clinician with potential information that might help guide the rehabilitation of grasp in these patients. PMID- 25690169 TI - Twenty Percent of Patients May Remain Colonized With Methicillin-resistant Staphylococcus aureus Despite a Decolonization Protocol in Patients Undergoing Elective Total Joint Arthroplasty. AB - BACKGROUND: Staphylococcus aureus is the most commonly isolated organism in periprosthetic joint infection (PJI). Resistant strains such as methicillin resistant S aureus (MRSA) are on the rise, and many programs have instituted decolonization protocols. There are limited data on the success of S aureus nasal decolonization programs and their impact on PJI. QUESTIONS/PURPOSES: The purposes of this study were to (1) determine the proportion of patients successfully decolonized using a 2-week protocol; (2) compare infection risks between our surveillance and decolonization protocol group against a historical control cohort to evaluate changes in proportions of S aureus infections; and (3) assess infection risk based on carrier type, comparing S aureus carriers with noncarrier controls. METHODS: We retrospectively evaluated a group of 3434 patients who underwent elective primary and revision hip and knee arthroplasty over a 2-year period; each patient in the treatment group underwent a surveillance protocol, and a therapeutic regimen of mupurocin and chlorhexidine was instituted when colonization criteria were met. A 2009 to 2010 comparative historical cohort was chosen as the control group. We compared risks of infection between our treatment group and the historical control cohort. Furthermore, in patients who developed surgical site infections (SSIs), we compared the proportions of each S aureus type between the two cohorts. Finally, we compared infection rates based on carrier status. Surveillance for infection was carried out by the hospital infection control coordinator using the Centers for Disease Control and Prevention (CDC) criteria. During the time period of this study, the CDC defined hospital-acquired infection related to a surgical procedure as any infection diagnosed within 1 year of the procedure. With the numbers available, we had 41% power to detect a difference of 0.3% in infection rate between the treatment and control groups. To achieve 80% power, a total of 72,033 patients would be needed. RESULTS: Despite the protocol, 22% (26 of 121) of patients remained colonized with MRSA. With the numbers available, there were no differences in infection risk between the protocoled group (27 of 3434 [0.8%]) and the historical control group (33 of 3080 [1.1%]; relative risk [RR], 0.74; 95% confidence interval [CI], 0.44-1.22; p = 0.28). In terms of infecting organism in those who developed SSI, S aureus risk decreased slightly (treatment: 13 of 3434 patients [0.38%]; control: 21 of 3080 patients [0.68%]; RR, 0.56; CI, 0.28-1.11; p = 0.11). Within the protocoled group, carriers had a slightly higher risk of developing SSI (carrier: seven of 644 [1.1%]; noncarrier: 18 of 2763 [0.65%]; RR, 1.77; CI, 0.74 4.24; p = 0.20). CONCLUSIONS: The screening and decolonization protocol enabled a substantial reduction in nasal carriage of MRSA, but some patients remained colonized. However, our nasal decolonization protocol before elective total joint arthroplasty did not demonstrate a decrease in the proportion of patients developing SSI. Future meta-analyses and systematic reviews will be needed to pool the results of studies like these to ascertain whether small improvements in infection risk are achieved by protocols like ours and to determine whether any such improvements warrant the costs and potential risks of surveillance and intervention. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 25690170 TI - Platelet-rich concentrates differentially release growth factors and induce cell migration in vitro. AB - BACKGROUND: Platelet-rich concentrates are used as a source of growth factors to improve the healing process. The diverse preparation protocols and the gaps in knowledge of their biological properties complicate the interpretation of clinical results. QUESTIONS/PURPOSES: In this study we aimed to (1) analyze the concentration and kinetics of growth factors released from leukocyte- and platelet-rich fibrin (L-PRF), leukocyte- and platelet-rich plasma (L-PRP), and natural blood clot during in vitro culture; (2) investigate the migration of mesenchymal stem cells (MSCs) and human umbilical vein endothelial cells (HUVECs) as a functional response to the factors released; and (3) uncover correlations between individual growth factors with the initial platelet/leukocyte counts or the induced cell migration. METHODS: L-PRF, L-PRP, and natural blood clot prepared from 11 donors were cultured in vitro for 28 days and media supernatants collected after 8 hours and 1, 3, 7, 14, and 28 days. Released transforming growth factor beta1 (TGF-beta1), vascular endothelial growth factor (VEGF), insulin growth factor (IGF-1), platelet-derived growth factor AB (PDGF-AB), and interleukin-1beta (IL-1beta) were measured in the supernatants with enzyme-linked immunosorbent assay. Migration of MSC and HUVEC induced by the supernatants was evaluated in Boyden chambers. RESULTS: More TGF-beta1 was released (mean +/- SD in pg/mL of blood) from L-PRF (37,796 +/- 5492) compared with L-PRP (23,738 +/- 6848; p < 0.001) and blood clot (3739 +/- 4690; p < 0.001), whereas more VEGF and IL-1beta were released from blood clot (1933 +/- 704 and 2053 +/- 908, respectively) compared with both L-PRP (642 +/- 208; p < 0.001 and 273 +/- 386; p < 0.001, respectively) and L-PRF (852 +/- 376; p < 0.001 and 65 +/- 56, p < 0.001, respectively). No differences were observed in IGF-1 and PDGF-AB released from any of the concentrates. TGF-beta1 release peaked at Day 7 in L-PRF and at 8 hours and Day 7 in L-PRP and 8 hours and Day 14 in blood clot. In all concentrates, main release of VEGF occurred between 3 and 7 days and of IL-1beta between Days 1 and 7. IGF-1 and PDGF-AB were released until Day 1 in L-PRP and blood clot, in contrast to sustained release over the first 3 days in L-PRF. The strongest migration of MSC occurred in response to L-PRF, and more HUVEC migration was seen in L-PRF and blood clot compared with L-PRP. TGF-beta1 correlated with initial platelet counts in L-PRF (Pearson r = 0.66, p = 0.0273) and initial leukocyte counts in L-PRP (Pearson r = 0.83, p = 0.0016). A positive correlation of IL-1beta on migration of MSC and HUVEC was revealed (Pearson r = 0.16, p = 0.0208; Pearson r = 0.31, p < 0.001). CONCLUSIONS: In comparison to L PRP, L-PRF had higher amounts of released TGF-beta1, a long-term release of growth factors, and stronger induction of cell migration. Future preclinical studies should confirm these data in a defined injury model. CLINICAL RELEVANCE: By characterizing the biologic properties of different platelet concentrates in vitro, we may gain a better understanding of their clinical effects and develop guidelines for specific future applications. PMID- 25690171 TI - CORR Insights((r)): do glycemic markers predict occurrence of complications after total knee arthroplasty in patients with diabetes? PMID- 25690172 TI - CORR Insights((r)): The Alpha-defensin Test for Periprosthetic Joint Infection Responds to a Wide Spectrum of Organisms. PMID- 25690173 TI - CORR Insights((r)): Is There an Advantage to Knotless Barbed Suture in TKA Wound Closure? A Randomized Trial in Simultaneous Bilateral TKAs. PMID- 25690174 TI - When was the last time you induced general anesthesia for cesarean section? PMID- 25690176 TI - [Editorial]. PMID- 25690175 TI - Kinetic intermediates of holo- and apo-myoglobin studied using HDX-TIMS-MS and molecular dynamic simulations. AB - In the present work, the kinetic intermediates of holo- and apo-myoglobin were studied by correlating the ion-neutral collision cross section and time resolved H/D back exchange rate simultaneously in a trapped ion mobility spectrometer coupled to a mass spectrometer (HDX-TIMS-MS). The high mobility resolution of the TIMS cell permitted the observation of multiple IMS bands and complementary molecular dynamics simulations resulted in the assignment of candidate structures for each experimental condition studied (e.g., holo [M + 8H](+8)-[M + 9H](+9) and apo [M + 9H](+9)-[M + 19H](+19)). Inspection of the kinetic intermediates suggests that the tertiary structure of apomyoglobin unfolds quickly upon the loss of the Fe protoporphyrin IX that stabilizes the interactions between the A, G, and H helices. In the absence of the porphyrin heme, the apomyoglobin unfolds to Xn kinetic intermediates that vary in the extent of unfolding as a result of the observed charge state. PMID- 25690177 TI - [Hypertension : What is the status quo?]. PMID- 25690178 TI - Fractional flow reserve and instantaneous wave free ratio in 2015. AB - In the recent years it has become apparent that angiography-based assessment of coronary artery stenosis suffers from considerable inaccuracy and pitfalls. Besides interobserver variability in assessing stenosis severity, the correlation between angiographic severity and ischemia is suboptimal. Percutaneous coronary intervention (PCI) guided by the physiologic lesion assessment employing fractional flow reserve (FFR) is rendered superior to angiographic lesion assessment and proven to improve cardiovascular outcomes and reduce cost. In this manuscript we discuss the accepted and emerging clinical indications for FFR use. The correlation between FFR and symptoms, stress imaging and intravascular ultrasound are reviewed along with the inherent limitations and pitfalls of these diagnostic technologies. The data regarding the correlation between Instantaneous (vasodilator free) wave-free ratio (iFR) and conventional FFR is summarized. PMID- 25690179 TI - Constraints on the evolution of phenotypic plasticity: limits and costs of phenotype and plasticity. AB - Phenotypic plasticity is ubiquitous and generally regarded as a key mechanism for enabling organisms to survive in the face of environmental change. Because no organism is infinitely or ideally plastic, theory suggests that there must be limits (for example, the lack of ability to produce an optimal trait) to the evolution of phenotypic plasticity, or that plasticity may have inherent significant costs. Yet numerous experimental studies have not detected widespread costs. Explicitly differentiating plasticity costs from phenotype costs, we re evaluate fundamental questions of the limits to the evolution of plasticity and of generalists vs specialists. We advocate for the view that relaxed selection and variable selection intensities are likely more important constraints to the evolution of plasticity than the costs of plasticity. Some forms of plasticity, such as learning, may be inherently costly. In addition, we examine opportunities to offset costs of phenotypes through ontogeny, amelioration of phenotypic costs across environments, and the condition-dependent hypothesis. We propose avenues of further inquiry in the limits of plasticity using new and classic methods of ecological parameterization, phylogenetics and omics in the context of answering questions on the constraints of plasticity. Given plasticity's key role in coping with environmental change, approaches spanning the spectrum from applied to basic will greatly enrich our understanding of the evolution of plasticity and resolve our understanding of limits. PMID- 25690180 TI - Detecting adaptive evolution based on association with ecological gradients: orientation matters! AB - Population genetic signatures of local adaptation are frequently investigated by identifying loci with allele frequencies that exhibit high correlation with ecological variables. One difficulty with this approach is that ecological associations might be confounded by geographic variation at selectively neutral loci. Here, we consider populations that underwent spatial expansion from their original range, and for which geographical variation of adaptive allele frequency coincides with habitat gradients. Using range expansion simulations, we asked whether our ability to detect genomic regions involved in adaptation could be impacted by the orientation of the ecological gradients. For three ecological association methods tested, we found, counter-intuitively, fewer false-positive associations when ecological gradients aligned along the main axis of expansion than when they aligned along any other direction. This result has important consequences for the analysis of genomic data under non-equilibrium population genetic models. Alignment of gradients with expansion axes is likely to be common in scenarios in which expanding species track their ecological niche during climate change while adapting to changing environments at their rear edge. PMID- 25690181 TI - Synergism between soluble and dietary fiber bound antioxidants. AB - This study investigates the synergism between antioxidants bound to dietary fibers (DF) of grains and soluble antioxidants of highly consumed beverages or their pure antioxidants. The interaction between insoluble fractions of grains containing bound antioxidants and soluble antioxidants was investigated using (i) a liposome-based system by measuring the lag phase before the onset of oxidation and (ii) an ESR-based system by measuring the reduction percentage of Fremy's salt radical. In both procedures, antioxidant capacities of DF-bound and soluble antioxidants were measured as well as their combinations, which were prepared at different ratios. The simple addition effects of DF-bound and soluble antioxidants were compared with measured values. The results revealed a clear synergism for almost all combinations in both liposome- and ESR-based systems. The synergism observed in DF-bound-soluble antioxidant system paints a promising picture considering the role of fiber in human gastrointestinal (GI) tract health. PMID- 25690182 TI - Ligand-exchange mechanism: new insight into solid-phase extraction of uranium based on a combined experimental and theoretical study. AB - In numerous reports on selective solid-phase extraction (SPE) of uranium, the extraction of uranium is generally accepted as a direct coordination of the ligands on the solid matrix with the uranyl, in which the critical effect of the hydration shell on the uranyl is neglected. The related mechanism in the extraction process remains unclear. Herein, the detailed calculation of activation energy and the geometry of the identified transition states reveal that the uranium extraction by a newly-synthesized urea-functionalized graphite oxide (Urea-GO) is in essence an exchange process between the ligands on Urea-GO and the coordinated water molecules in the first hydration shell of the uranyl. Moreover, we demonstrate that it is the ketone oxygen in the urea ligand to displace the coordinated water molecule of uranyl due to its stronger bonding ability and lower steric-hindrance, whereas the nitrogen atom in the same ligand is proved to be an electron donor that enables the oxygen atom to have stronger affinity for uranium through electron delocalization effects evaluated on the basis of calculations of the second-order interaction energy between donor and acceptor orbitals. We therefore propose a new ligand-exchange mechanism for the SPE process. This study advances the fundamental understanding of uranium extraction, and provides theoretical and practical guidance on ligand design for selective complexation of uranium(VI) and other metal ions in aqueous solution. Finally, the effect of nitrate ions on the extraction of uranyl was successfully explained based on the experimental and theoretical study. PMID- 25690183 TI - Dr Carter's legacy to the RCN and the profession. PMID- 25690184 TI - Wales' proposed safe staffing law could benefit care in England too. AB - Legislation similar to the Safe Nurse Staffing Bill that has been proposed in Wales could benefit England, where staffing levels are often 'dangerously low', according to an expert on patient outcomes. PMID- 25690185 TI - End of era as Carter steps down at RCN. AB - Peter Carter has announced that he will be leaving the RCN after eight years as chief executive and general secretary. PMID- 25690187 TI - Guidance for families turning to surveillance to expose poor care. AB - The Care Quality Commission has published guidance for families or friends considering installing hidden cameras in care homes. PMID- 25690188 TI - Nurses to face fresh NMC registration fee hike. AB - The Nursing and Midwifery Council could be forced to increase the registration fee for nurses again in order to pay L1.7 million towards the annual running costs of its own regulator. PMID- 25690189 TI - Students who speak out are promised same support as staff. AB - Nursing students who report poor care should have access to the same support as staff, in a move described as a 'very positive step forward' by the RCN. PMID- 25690190 TI - 'New whistleblower guardian role must be accountable to the CQC'. AB - The work of 'whistleblowing guardians' in every NHS organisation must be scrutinised by the Care Quality Commission to ensure they are doing the job properly, according to the nurse whose courage inspired the new role. PMID- 25690194 TI - Laundering uniforms at less than 60 degrees C may increase risk of HCAIs. AB - More than 40 per cent of ward staff are not washing their uniforms at high temperatures, leading to concerns about infection prevention, a study reveals. PMID- 25690196 TI - Wales and Scotland gets much needed nurse training boost. AB - There will be 305 extra nursing students trained in Wales and Scotland this year. PMID- 25690200 TI - NHS to close residential hospitals for people with learning disabilities. AB - Many residential hospitals for people with learning disabilities will be shut over the next two years as part of a government pledge to move people out of these settings following the Winterbourne View abuse scandal. PMID- 25690201 TI - Full circle at privately-run NHS trust as operator hands it back. AB - The only private company to run an NHS hospital announced last month it was pulling out of its contract early because it could not cope with funding cuts and rising patient numbers. PMID- 25690207 TI - Gord. AB - Essential facts Bringing up food after eating is a normal process that can occur in healthy infants, children and young people. Gastro-oesophageal reflux (GOR) is most common in babies, affecting four in ten infants. Gastro-oesophageal reflux disease (GORD) is reflux that is so severe medical treatment is required. Differentiating between GOR and GORD is difficult because the terms are often used interchangeably. PMID- 25690208 TI - Seamless service. AB - Under the five year plan for the NHS in England, new models of care based around GP practices will provide community and hospital services. In some areas, acute trusts will run community services. The changes have huge implications for nurses. PMID- 25690209 TI - Helping patients who go it alone. PMID- 25690210 TI - Feeling the strain. PMID- 25690225 TI - Peter Carter played a key role in pressing for better Hospital Food. AB - I was sorry to hear that Peter Carter has decided to leave his role as chief executive and general secretary of the RCN. PMID- 25690226 TI - NHS whistleblowers are heroes for some and villains for others. AB - Sir Robert Francis QC, who reported on the Mid Staffs scandal two years ago, is concerned that NHS whistleblowers continue to be vilified for speaking out and raising the alarm about poor care. PMID- 25690227 TI - The RCN is losing one of the best leaders it has had in recent years. AB - Peter Carter has announced that he is standing down from his role as general secretary and chief executive of the RCN (Online News February 11). PMID- 25690229 TI - The mother figure of matron should take charge of feeding. PMID- 25690230 TI - Small actions will make a big difference on NHS Change Day. PMID- 25690231 TI - Taking the time to listen and value others costs nothing. PMID- 25690232 TI - Family-centred care is not about having all the answers. PMID- 25690234 TI - Washing uniforms at home: adherence to hospital policy. AB - Infection control is a priority for all hospitals to reduce the spread of healthcare-associated infections (HCAIs). Textiles especially uniforms, are a possible route of HCAI transmission. There are protocols to ensure hospital laundry services meet accepted standards, however healthcare uniforms are laundered by staff at home and variations in practice occur. A questionnaire was used to conduct a service evaluation at four hospitals in different NHS trusts to determine how closely healthcare staff followed hospital guidelines on laundering and aftercare of uniforms at home. Responses showed that not all staff followed these guidelines; 44% of staff washed their uniforms below the recommended temperature of 60 degrees C, which presents a potential route for cross contamination and infection. PMID- 25690235 TI - Care, compassion and communication. AB - Care, compassion and effective communication are essential elements of nursing, which must be demonstrated by all nurses and nursing students. These requirements form the basis of the first essential skills cluster, which stipulates key skills and behaviours that must be demonstrated to meet the standards for registration with the Nursing and Midwifery Council. This article discusses the core aspects of compassionate care and effective communication and, in doing so, uses examples to demonstrate their use within nursing. PMID- 25690236 TI - Presentation skills for nurses. AB - This article emphasises the importance of effective presentation skills. Such skills allow nurses to share knowledge and expertise and to communicate clearly in a range of workplace scenarios. Nurses are increasingly being asked to present in formal and informal situations, such as conferences, poster presentations, job interviews, case reports and ward-based teaching. This article explores the principles underpinning the development of these skills, discusses the situations in which they could be applied and demonstrates how nurses might improve and develop as presenters. PMID- 25690237 TI - Paracetamol overdose. AB - Paracetamol is safe and effective at the therapeutic dose. It is beneficial as an analgesic and is an effective antipyretic. Paracetamol is cheap and easy to buy over the counter, which makes it a common choice in intentional overdose. PMID- 25690238 TI - The cost of justice. AB - Recently introduced employment tribunal fees of up to L1,200 are costing unions and their members thousands of pounds a year, as well as limiting access to justice, experts say. PMID- 25690240 TI - Calling on some foreign aid. AB - Hospitals are becoming increasingly reliant on overseas nurses, according to figures showing that the UK imports more nurses than it exports for the first time in eight years. PMID- 25690241 TI - What's really in a name? AB - The 'little things' can be extremely important when a nurse is building a relationship with a patient. PMID- 25690242 TI - Student life - every student's responsibility. AB - In the first year of my adult nursing degree I undertook a public health promotion module and found it to be a subject that gripped my attention. PMID- 25690243 TI - Putting HCAs on the map. AB - The European Union is required to ensure human health is protected through its policies. The brief was to establish a pilot network and database of nurse educators and regulators to improve the qualifications of healthcare assistants (HCAs), with a particular emphasis on cross-border mobility. PMID- 25690246 TI - More than just a daily ritual. AB - Personal hygiene is fundamental to patient care, improving self-esteem and physical wellbeing. Most of us go through personal hygiene rituals before leaving home in the morning to face the day, and so we may take this process for granted. PMID- 25690247 TI - 'A few grateful words can make your day'. PMID- 25690248 TI - Better prepared for stroke care. AB - Stroke units across the UK employ untrained healthcare assistants (HCAs) to assist with nursing care. PMID- 25690249 TI - Taking on a supporting role. AB - A new professional known as a physician associate is helping doctors to spend more time with their patients. PMID- 25690250 TI - Reducing your risk of back injury at work. AB - Many patient-care activities performed by healthcare assistants involve lifting, turning and moving patients. These activities can cause back strain and even contribute to chronic back injuries. PMID- 25690251 TI - Best interests. AB - Healthcare assistants must always act in a patient's best interests. PMID- 25690252 TI - Help to spot deterioration. AB - Patient deterioration is not always detected, resulting in avoidable deaths. PMID- 25690253 TI - Invasive urothelial carcinoma with chordoid features may be an ominous sign predicting sarcomatoid change: a case report of a bladder carcinoma. AB - Invasive urothelial carcinoma with chordoid features has not been reported since being first documented in 2009. Here we report a further case of it, involving an 85-year-old man with a papillary tumor of the urinary bladder, measuring 3 cm in diameter. This case is unique in that an epithelial-mesenchymal transition was suspected to have occurred in the transformation of a conventional urothelial carcinoma to a sarcomatoid variant, with invasive urothelial carcinoma with chordoid features acting as an intermediate stage. Based on this finding, we recommend that the presence of invasive urothelial carcinoma with chordoid features should be reported as it may predict the coexistence or future development of an aggressive sarcomatoid variant. PMID- 25690254 TI - Subclinical hyperthyroidism impacts left ventricular deformation: 2D and 3D echocardiographic study. AB - BACKGROUND: We sought to investigate left ventricular (LV) function and mechanics assessed by three-dimensional echocardiography (3DE) and speckle tracking in patients with subclinical hyperthyroidism (SCH). METHODS: We included 35 untreated women with SCH and 35 healthy control women matched by age. All participants underwent laboratory analyses which included thyroid hormone levels, and complete 2DE and 3DE examination. RESULTS: 2DE LV longitudinal and circumferential strain was significantly decreased in the SCH subjects. 2DE LV systolic and early diastolic strain rates in longitudinal and circumferential directions were reduced, whereas late diastolic strain rates were increased in SCH individuals. 3DE LV end-diastolic volume and cardiac output were significantly elevated in the SCH patients. 3DE LV deformation in all three directions, as well as 3DE area strain, were significantly lower in the SCH group. Serum thyroid-stimulating hormone (TSH) and free thyroxine (FT4) levels correlated with 2DE LV mass index, 2DE longitudinal strain, and 3DE LV area strain in the whole study population. CONCLUSION: LV deformation evaluated by 3DE and speckle tracking imaging are significantly impaired in SCH subjects. TSH and FT4 levels correlate with 2DE and 3DE LV structure and mechanics. PMID- 25690255 TI - The utility of cantharidin for the treatment of molluscum contagiosum. PMID- 25690256 TI - Successful control of radicular pain in a pediatric patient with Guillain-Barre syndrome. AB - A 10-year-old boy was diagnosed as having the axonal form of Guillain-Barre syndrome (GBS). The patient noticed progressive weakness of the lower legs on the 1st day of illness. Intravenous immunoglobulin therapy was immediately started on the 2nd day of illness. Despite the favorable recovery of muscle weakness, he complained of severe needle-like pain in the thighs and buttocks and also painful numbness over the gastrocnemius regions. Acetaminophen and hydroxyzine therapy was ineffective for the pain control. Oral prednisolone therapy (0.7 mg/kg/day) led to drastic pain-relief with favorable improvement of the weakness. Corticosteroid therapy is not typically used in the management of GBS patients. Although GBS-associated pain frequently occurs in children, only a few reports have indicated the analgesic utility of steroids in the treatment of pediatric GBS. This observation may suggest the alternative of this therapy as for the as the limited, but potentially rapid, control of GBS-associated acute radicular pain in pediatric patients. PMID- 25690257 TI - A longitudinal study of magnetic resonance spectroscopy Huntington's disease biomarkers. AB - Putaminal metabolites examined using cross-sectional magnetic resonance spectroscopy (MRS) can distinguish pre-manifest and early Huntington's Disease (HD) individuals from controls. An ideal biomarker, however, will demonstrate longitudinal change over short durations. The objective here was to evaluate longitudinal in vivo brain metabolite profiles in HD over 24 months. Eighty-four participants (30 controls, 25 pre-manifest HD, 29 early HD) recruited as part of TRACK-HD were imaged at baseline, 12 months, and 24 months using 3T MRS of left putamen. Automated putaminal volume measurement was performed simultaneously. To quantify partial volume effects, spectroscopy was performed in a second, white matter voxel adjacent to putamen in six subjects. Subjects underwent TRACK-HD motor assessment. Statistical analyses included linear regression and one-way analysis of variance (ANOVA). At all time-points N-acetyl aspartate and total N acetyl aspartate (NAA), neuronal integrity markers, were lower in early HD than in controls. Total NAA was lower in pre-manifest HD than in controls, whereas the gliosis marker myo-inositol (MI) was robustly elevated in early HD. Metabolites were stable over 24 months with no longitudinal change. Total NAA was not markedly different in adjacent white matter than putamen, arguing against partial volume confounding effects in cross-sectional group differences. Total NAA correlations with disease burden score suggest that this metabolite may be useful in identifying neurochemical responses to therapeutic agents. We demonstrate almost consistent group differences in putaminal metabolites in HD-affected individuals compared with controls over 24 months. Future work establishing spectroscopy as an HD biomarker should include multi-site assessments in large, pathologically diverse cohorts. PMID- 25690258 TI - A Subset of Sinonasal Non-Intestinal Type Adenocarcinomas are Truly Seromucinous Adenocarcinomas: A Morphologic and Immunophenotypic Assessment and Description of a Novel Pitfall. AB - While sinonasal intestinal type adenocarcinoma (ITAC) is defined by an intestinal phenotype, non-intestinal type adenocarcinoma (non-ITAC) is traditionally viewed as a diagnosis of exclusion, despite previous implication of a seromucinous phenotype and similarity to sinonasal seromucinous hamartomas (SSH). We performed a comparison of clinicopathologic and immunophenotypic features of ITAC, non-ITAC and SSH using traditional discriminatory markers and new markers of seromucinous differentiation. Twenty-three non-ITAC, 17 ITAC, and 5 SSH were retrieved (1987 2014). As expected, ITAC occurred predominantly in the nasal cavity in elderly patients (mean age 65 years) with a striking male predilection (15:2). Regardless of grade/subtype, all ITAC were invariably CK20 and CDX2 positive, and many (11/15) showed some CK7 positivity. Non-ITAC occurred in younger individuals (mean age 51 years) with a slight female predilection (male to female ratio: 10:13) and showed diverse morphologic patterns and grades, some with morphologic similarity to SSH. SSH occurred in younger individuals (mean age 33 years). Non ITAC and SSH were invariably CK7 positive and CK20 negative, however, 4/22 non ITAC and 2/5 SSH showed squamoid morular metaplasia that aberrantly expressed CDX2 and co-expressed nuclear beta-catenin. Markers of seromucinous differentiation (S100, DOG1, and SOX10) were essentially absent in ITAC, but present to varying degrees in the majority of non-ITAC and all SSH. Thus, the term 'seromucinous adenocarcinoma' is the more appropriate designation for non ITAC. Squamoid morules in non-ITAC and SSH may be an immunophenotypic pitfall given the aberrant CDX2 expression. PMID- 25690259 TI - Framingham heart study: an enduring legacy. PMID- 25690260 TI - Legacy of the framingham heart study: rationale, design, initial findings, and implications. AB - With the dramatic rise in coronary heart disease (CHD) during the first half of the 20th century, the newly formed National Heart Institute realized the significant gap in knowledge about the causes of CHD and embarked in 1947 on planning what was to become the renowned Framingham Heart Study. Dr. Thomas Royal Dawber's initial paper on the design of the project described studying up to 6,000 persons in a single geographic area and the formation of a technical advisory committee of 11 physicians in cardiology and public health to determine the hypotheses and protocol. A comprehensive physical examination and series of measurements and laboratory work were proposed and the initial examination was completed in 1952. The first paper describing 4 years of follow-up was published in 1957, and this was followed by a subsequent report in 1959 describing 6 years of follow-up. The first follow-up report described sex and age group differences in incidence of CHD and pointed out the noteworthy prominence of sudden cardiac death as the first manifestation of CHD and the initial observations regarding the significance of elevated blood pressure, cholesterol, and overweight in predicting future CHD. Importantly, the significance of a combination of risk factors for identifying those at highest risk was described as well as how the number of risk factors related to risk (the beginnings of what was decades later to become the famous risk scores from Framingham). Dr. William Kannel's 1961 publication, "Factors of Risk in the Development of Coronary Heart Disease," first highlighted the term risk factors, and it described how specific levels of cholesterol, blood pressure, as well as how electrocardiographic left ventricular hypertrophy predicted future CHD incidence. The standardized measurement of risk factors and follow-up in Framingham served as an important precedent for future observational studies designed and directed by what is now the National Heart, Lung, and Blood Institute, including the ARIC (Atherosclerosis Risk in Communities) study, the CARDIA (Coronary Artery Risk Development in Young Adults) study, the CHS (Cardiovascular Health Study), and the MESA (Multiethnic Study of Atherosclerosis). These studies and others continue the legacy that Framingham began more than 60 years ago into the investigation of the epidemiology of cardiovascular diseases. PMID- 25690261 TI - Lipids and vascular disease: a framingham perspective. AB - Research related to lipid levels, correlates of lipid levels, and how lipid levels are related to vascular disease outcomes in the Framingham cohorts are summarized for data obtained from 1948 to the present day. Initial lipid data in Framingham participants were largely confined to cholesterol and triglycerides. Technology evolved to later include lipoprotein cholesterol quantification using ultracentrifugation, apolipoproteins, genetics, lipid particle size and number, and use of lipid information in multivariable equations to estimate risk for the development of initial cardiovascular disease outcomes. The information is presented chronologically to highlight the developments related to the lipids and heart disease over the past 50 years. PMID- 25690262 TI - Cigarette smoking and cardiovascular disease: lessons from framingham. AB - Cigarette smoking, causing acute and chronic diseases, is a serious threat to the health of the public. The association of smoking with lung cancer was recognized first, but the relationship of smoking to cardiovascular disease was debated into the 1960s and early data from the Framingham cohort found no association. However, in 1962, an analysis combining the data from the Framingham men with the Albany, New York, male cohort found cigarette smoking predicted myocardial infarction, coronary heart disease mortality, and all-cause mortality. The same year, Framingham investigators wrote that smoking was a cardiovascular risk factor independent of other characteristics, such as blood pressure, cholesterol, and smoking cessation, and should be included in any prevention program. The first surgeon general's report was released in 1964 and Framingham investigators were participants in the report's development and provided important data on the association of cigarettes with cardiovascular disease. Subsequent analyses confirmed the early findings on the benefits of quitting for primary prevention of cardiovascular disease and secondary prevention after myocardial infarction. The Framingham investigators and cohort data played a crucial role in the current understanding of the dangers of cigarettes and the subsequent decline of smoking in industrialized countries. PMID- 25690263 TI - Hypertension and cardiovascular disease: contributions of the framingham heart study. AB - This is a historical review of the contribution of the Framingham Heart Study to our understanding of the epidemiology of blood pressure (BP) and cardiovascular disease (CVD). Framingham investigators initially explored the epidemiological relationship of various BP components to coronary heart disease in men and women and how this risk is further modified by age, that is, how diastolic blood pressure (DBP) is the stronger predictor of coronary heart disease risk in young people versus systolic blood pressure (SBP) in middle-aged and elderly people. Framingham investigators then examined the natural history of various BP components over a 30-year follow-up in normotensive and untreated hypertensive individuals and showed how this provides hemodynamic insights into the importance of pulse pressure as a marker of large artery stiffness in middle-aged and elderly people. Importantly, pulse pressure was also found to be superior to SBP or DBP as a predictor of coronary heart disease in a middle-aged and elderly Framingham population. Lastly, dual models of SBP with DBP and pulse pressure with mean arterial pressure were superior to single BP component models for predicting CVD events; thus, increases in both peripheral vascular resistance and central large artery stiffness contribute to CVD in varying proportions depending on age. Furthermore, the Framingham Heart Study provided evidence that DBP <70 mm Hg with SBP >=120 mm Hg was associated with a CVD risk equivalent to approximately 20 mm Hg of additional elevation in SBP, thus further supporting the importance of large artery stiffness as a CVD risk factor in elderly people. These original Framingham studies have contributed greatly to BP risk classification tables for the "Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure" and for the European Society for Hypertension. Moreover, Framingham originally brought attention to hypertension, which is now the leading cause of mortality globally. PMID- 25690264 TI - 'When nursing care became science. The first decades 1970-2000'. PMID- 25690265 TI - Individual inconsistencies in basal and summit metabolic rate highlight flexibility of metabolic performance in a wintering passerine. AB - Resident passerines inhabiting high latitude environments are faced with strong seasonal changes in thermal conditions and energy availability. Summit metabolic rate (maximal metabolic rate elicited by shivering during cold exposure: M(sum)) and basal metabolic rate (BMR) vary in parallel among seasons and increase in winter due to cold acclimatization, and these adjustments are thought to be critical for survival. Wintering individuals expressing consistently higher M(sum) and BMR could therefore be seen as better performers with higher chances of winter survival than those exhibiting lower metabolic performance. In this study, we calculated repeatability to evaluate temporal consistency of body mass, BMR and M(sum) within and across three consecutives winters in black-capped chickadees (Poecile atricapillus). We found that body mass was significantly repeatable both within and across winters (R 0.51-0.90). BMR (R 0.29-0.47) was only repeatable within winter while M(sum) was repeatable both among (R 0.33 0.49) and within winters (R 0.33-0.49) with the magnitude and significance of repeatability in both variables depending on the year and whether they were corrected for body mass or body size. The patterns of repeatability observed among years also differed between the two variables. Our findings suggest that the relative ranking of individuals in winter metabolic performance is affected by local ecological conditions and can change within relatively short periods of time. PMID- 25690266 TI - The clinical effectiveness and cost-effectiveness of telephone triage for managing same-day consultation requests in general practice: a cluster randomised controlled trial comparing general practitioner-led and nurse-led management systems with usual care (the ESTEEM trial). AB - BACKGROUND: Telephone triage is proposed as a method of managing increasing demand for primary care. Previous studies have involved small samples in limited settings, and focused on nurse roles. Evidence is limited regarding the impact on primary care workload, costs, and patient safety and experience when triage is used to manage patients requesting same-day consultations in general practice. OBJECTIVES: In comparison with usual care (UC), to assess the impact of GP-led telephone triage (GPT) and nurse-led computer-supported telephone triage (NT) on primary care workload and cost, patient experience of care, and patient safety and health status for patients requesting same-day consultations in general practice. DESIGN: Pragmatic cluster randomised controlled trial, incorporating economic evaluation and qualitative process evaluation. SETTING: General practices (n = 42) in four regions of England, UK (Devon, Bristol/Somerset, Warwickshire/Coventry, Norfolk/Suffolk). PARTICIPANTS: Patients requesting same day consultations. INTERVENTIONS: Practices were randomised to GPT, NT or UC. Data collection was not blinded; however, analysis was conducted by a statistician blinded to practice allocation. MAIN OUTCOME MEASURES: Primary - primary care contacts [general practice, out-of-hours primary care, accident and emergency (A&E) and walk-in centre attendances] in the 28 days following the index consultation request. Secondary - resource use and costs, patient safety (deaths and emergency hospital admissions within 7 days of index request, and A&E attendance within 28 days), health status and experience of care. RESULTS: Of 20,990 eligible randomised patients (UC n = 7283; GPT n = 6695; NT n = 7012), primary outcome data were analysed for 16,211 patients (UC n = 5572; GPT n = 5171; NT n = 5468). Compared with UC, GPT and NT increased primary outcome contacts (over 28-day follow-up) by 33% [rate ratio (RR) 1.33, 95% confidence interval (CI) 1.30 to 1.36] and 48% (RR 1.48, 95% CI 1.44 to 1.52), respectively. Compared with GPT, NT was associated with a marginal increase in primary outcome contacts by 4% (RR 1.04, 95% CI 1.01 to 1.08). Triage was associated with a redistribution of primary care contacts. Although GPT, compared with UC, increased the rate of overall GP contacts (face to face and telephone) over the 28 days by 38% (RR 1.38, 95% CI 1.28 to 1.50), GP face-to-face contacts were reduced by 39% (RR 0.61, 95% CI 0.54 to 0.69). NT reduced the rate of overall GP contacts by 16% (RR 0.84, 95% CI 0.78 to 0.91) and GP face-to-face contacts by 20% (RR 0.80, 95% CI 0.71 to 0.90), whereas nurse contacts increased. The increased rate of primary care contacts in triage arms is largely attributable to increased telephone contacts. Estimated overall patient-clinician contact time on the index day increased in triage (GPT = 10.3 minutes; NT = 14.8 minutes; UC = 9.6 minutes), although patterns of clinician use varied between arms. Taking account of both the pattern and duration of primary outcome contacts, overall costs over the 28-day follow-up were similar in all three arms (approximately L75 per patient). Triage appeared safe, and no differences in patient health status were observed. NT was somewhat less acceptable to patients than GPT or UC. The process evaluation identified the complexity associated with introducing triage but found no consistency across practices about what works and what does not work when implementing it. CONCLUSIONS: Introducing GPT or NT was associated with a redistribution of primary care workload for patients requesting same-day consultations, and at similar cost to UC. Although triage seemed to be safe, investigation of the circumstances of a larger number of deaths or admissions after triage might be warranted, and monitoring of these events is necessary as triage is implemented. TRIAL REGISTRATION: Current Controlled Trials ISRCTN20687662. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 19, No. 13. See the NIHR Journals Library website for further project information. PMID- 25690267 TI - Ambulatory blood pressure monitoring to assess the white-coat effect in an elderly East African population. AB - The authors hypothesized that published hypertension rates in Tanzania were influenced by the physiological response of individuals to blood pressure (BP) testing, known as the white-coat effect (WCE). To test this, a representative sample of 79 participants from a baseline cohort of 2322 people aged 70 years and older were followed to assess BP using conventional BP measurement (CBPM) and ambulatory BP monitoring (ABPM). There was a significant difference between daytime ABPM and CBPM for both systolic BP (mean difference 29.7 mm Hg) and diastolic BP (mean difference 7.4 mm Hg). Rates of hypertension were significantly lower when measured by 24-hour ABPM (55.7%) than by CBPM (78.4%). The WCE was observed in 54 participants (68.4%). The WCE was responsible for an increase in recorded BP. Accurate identification of individuals in need of antihypertensive medication is important if resources are to be used efficiently, especially in resource-poor settings. PMID- 25690269 TI - Enhancing clinically-relevant shoulder function assessment using only essential movements. AB - Kinematic functional evaluation with body-worn sensors provides discriminative and responsive scores after shoulder surgery, but the optimal movements' combination has not yet been scientifically investigated. The aim of this study was the development of a simplified shoulder function kinematic score including only essential movements. The P Score, a seven-movement kinematic score developed on 31 healthy participants and 35 patients before surgery and at 3, 6 and 12 months after shoulder surgery, served as a reference. Principal component analysis and multiple regression were used to create simplified scoring models. The candidate models were compared to the reference score. ROC curve for shoulder pathology detection and correlations with clinical questionnaires were calculated. The B-B Score (hand to the Back and hand upwards as to change a Bulb) showed no difference to the P Score in time*score interaction (P > .05) and its relation with the reference score was highly linear (R(2) > .97). Absolute value of correlations with clinical questionnaires ranged from 0.51 to 0.77. Sensitivity was 97% and specificity 94%. The B-B and reference scores are equivalent for the measurement of group responses. The validated simplified scoring model presents practical advantages that facilitate the objective evaluation of shoulder function in clinical practice. PMID- 25690270 TI - Donepezil across the spectrum of Alzheimer's disease: dose optimization and clinical relevance. AB - Alzheimer's disease (AD) is an irreversible and progressive neurodegenerative disorder. AD is the most common cause of dementia worldwide, and its incidence is increasing in line with population aging. The primary feature of AD is progressive cognitive decline, and severe AD is characterized by reduced communication skills and mobility. However, successful treatment can substantially improve quality of life. Donepezil is an acetylcholinesterase inhibitor approved for use across the full spectrum of mild, moderate, and severe AD. Donepezil has been available at doses of 5 or 10 mg once daily for more than a decade and, more recently, a single high once-daily sustained-release 23-mg dose has been approved for treatment of patients with moderate to severe AD. The rationale for the higher dose formulation was the expected increase in acetylcholinesterase inhibition given the dose-response relationship of donepezil, with the benefits of the higher dose being most apparent in patients with more advanced AD. Donepezil 5 and 10 mg/day have been well studied in mild to-moderate AD, and a clinical trial has confirmed the benefits of donepezil 23 mg/day in patients with moderate to severe AD, particularly for language and visuospatial ability. This review presents an overview of the evidence for donepezil across the spectrum of AD, with a focus on dose optimization for disease progression. PMID- 25690271 TI - Controversies in bariatric surgery. AB - BACKGROUND: There are many controversies related to bariatric surgery. This review explores selected areas. METHODS: A combination of randomized clinical trials (RCTs), systematic reviews and expert opinion have been brought together to highlight areas of importance or conflict. RESULTS AND CONCLUSION: Metabolic surgery is an increasingly preferred term rather than bariatric or obesity surgery. Reporting should be standardized to include appropriate weight measures, valid disease measures and data on loss to follow-up. There are many putative mechanisms of effect of key bariatric procedures, but satiety and early satiation appear central. Weight loss must be durable. Long-term outcome studies (more than 10-year follow-up) show that biliopancreatic diversion is most effective, with 72 per cent excess weight loss (EWL). Roux-en-Y gastric bypass and laparoscopic adjustable gastric banding (LAGB) are equally effective, with 54 per cent EWL. There are no long-term data on vertical sleeve gastrectomy. Type II diabetes is a common and serious disease, usually associated with increased weight. Multiple RCTs have shown that bariatric surgery provides clear benefits over continuing with non-surgical therapies. The earlier the treatment, the more likely and durable will be the remission. Bariatric surgery should be available to all who are obese (body mass index over 30 kg/m(2) ). LAGB, a safe, effective, reversible outpatient procedure, is the author's preferred primary option. PMID- 25690272 TI - Activation of molecular hydrogen by a singlet carbene through quantum mechanical tunneling. AB - Carbenes are among the few metal-free molecules that are able to activate molecular hydrogen. Whereas triplet carbenes have been shown to insert into H2 through a two-step mechanism that at low temperature is assisted by quantum mechanical tunneling (QMT), singlet carbenes insert in concerted reactions with considerable activation barriers, and are thus unreactive towards H2 at cryogenic temperatures. Here we show that 1-azulenylcarbene with a singlet ground state readily inserts into H2 , and that QMT governs the insertion into both H2 and D2 . This is the first example that shows that QMT can also be important for singlet carbenes inserting into dihydrogen. PMID- 25690268 TI - Presentation and effectiveness of early treatment of type 2 diabetes in youth: lessons from the TODAY study. AB - OBJECTIVE: The objectives were to (i) describe the characteristics of a large ethnically/racially and geographically diverse population of adolescents with recent-onset type 2 diabetes (T2D), and (ii) assess the effects of short-term diabetes education and treatment with metformin on clinical and biochemical parameters in this cohort. RESEARCH DESIGN AND METHODS: Descriptive characteristics were determined for subjects screened for Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) who met criteria for diagnosis of T2D (n = 1092). Changes in clinical and biochemical parameters were determined for those who completed at least 8 wk of the run-in phase of the trial, which included standardized diabetes education and treatment with metformin. Further analysis determined whether these changes differed according to the treatment at screening. MAIN OUTCOME MEASURES: Demographic, biochemical measurements, and anthropometrics at screening and changes over 8 wk of run-in were the outcome measures. RESULTS: Subjects screened for TODAY had a median age of 14 yr and median hemoglobin A1c (HbA1c) of 6.9% (52 mM/M), 2/3 were female, and ethnic/racial minorities were overrepresented. Dyslipidemia and hypertension were common comorbidities. During run-in, HbA1c, body mass index, low-density lipoprotein cholesterol, triglycerides, and blood pressure significantly improved. Nearly all participants on insulin therapy at screening were able to attain target HbA1c following insulin discontinuation. CONCLUSIONS: Treatment with metformin and diabetes education provided short-term improvements in glycemic control and cardiometabolic risk factors in a large adolescent T2D cohort. Nearly all insulin-treated youth could be successfully weaned off insulin with continued improvement in glycemic control. PMID- 25690273 TI - Assessment of irrigation dynamics in magnetic-resonance guided laser induced thermal therapy (MRgLITT). AB - BACKGROUND AND OBJECTIVES: Magnetic-Resonance Guided Laser-Induced Thermal Therapy (MRgLITT) is a minimally-invasive ablation procedure for treating intracranial pathology using laser energy delivered through a fiber-optic. Saline irrigation is used to cool the fiber-optic, but factors affecting irrigation efficacy are not well studied, and quantitative information regarding irrigation speed and volume during MRgLITT procedures have not been reported. Here, we aimed to characterize variables affecting irrigation efficacy in MRgLITT. METHODS: We investigated the irrigation setup of the Visualase thermal therapy system during MRgLITT procedures (Visualase Inc., Houston, TX). Using the system's peristaltic pump, irrigation flow rate was quantitated by measuring volume over five one minute intervals. Pump settings 1-10 were assessed with and without the position locking, resistance-imparting bone anchor in both single and double-catheter setups. Multiple tightness settings of the bone anchor were tested, and flow rates were analyzed. RESULTS: Rate of flow increased non-linearly with pump setting (F(1,4) = 2168.86; P < 0.001) in both single and double catheter setups. The lowest pump setting had a flow rate of 24 cc/min, while the highest setting was 36 cc/min. The rate of change in flow successively decreased without plateau. Tightness setting of the bone anchor affected flow in a reverse sigmoid pattern, with no impact on rate until after two quarter-turns, which produced a marked decrease in flow up to one-half of the initial rate (F(1,4) = 12818.96; P < 0.001). CONCLUSION: Flow rate through the cooling catheter in MRgLITT follows a non-linear pattern with increasing peristaltic pump speed. This rate is subject to significant changes when the bone anchor is tightened more than two quarter turns. These findings serve as a foundation for future studies aimed at understanding the effect of irrigation speeds in achieving optimal ablation volumes. PMID- 25690274 TI - Being overweight or obese is associated with inhibition control in children from six to ten years of age. AB - AIM: This study investigated the relationship between being overweight or obese and executive function in six- to ten-year-olds. METHODS: The participants were 515 children (250 boys) from schools in Reus, Spain. The initial sample was measured and weighed and assessed with the Children's Color Trail Test. Children classified as overweight, including obese, and their age- and gender-matched controls (n = 221), were assessed in a second phase with the Five Digit Test (FDT) and the Symbol Digit Modalities Test. Logistic regression models were applied to analyse the effect of executive functions on being overweight, including obese. RESULTS: We found that 28.9% of the children were overweight and 7.2% were obese. The FDT showed that inhibition (odds risk of 1.04, range 1.00 1.08, p = 0.04) and flexibility (odds risk of 1.04, range 1.00-1.07, p = 0.02) were significantly associated with overweight, including obesity, regardless of sociodemographic and psychopathological variables. CONCLUSION: These results suggest that children who were overweight or obese had a reduced ability to mobilise the cognitive effort required to inhibit involuntary responses and to switch between different mental operations. A developmental trajectory would provide important insights into the relationship between executive functioning pattern and the risk of being overweight or obese. PMID- 25690275 TI - Designing care for people with mixed mental and physical multimorbidity. PMID- 25690276 TI - Buy or rent? PMID- 25690277 TI - Seven Signs Your Boss Is Toxic. PMID- 25690278 TI - Incidence and characteristics of breakthrough pain in parturients using computer integrated patient-controlled epidural analgesia. AB - INTRODUCTION: The computer-integrated patient-controlled epidural analgesia (CIPCEA) system can automatically adjust the background infusion rate during combined spinal-epidural analgesia based on the parturient's need, as labor progresses. OBJECTIVES: The objective is to identify risk factors associated with breakthrough pain during labor as well as identify obstetric and fetal outcomes that are affected by breakthrough pain. DESIGN: This is a retrospective review of prospectively collected data. SETTING: The setting is in a delivery room. PARTICIPANTS: The participants are 280 nulliparous women in early labor (<=5 cm cervical dilatation) who received combined spinal-epidural analgesia with CIPCEA. INTERVENTIONS: The intervention is CIPCEA. MEASUREMENTS: The primary outcome is the incidence of breakthrough pain (>=1 episodes of pain or pressure that required supplemental epidural medications) during labor. Relevant demographic, anesthetic, obstetric, and fetal characteristics were also measured. Univariate and multivariate analyses were performed to identify obstetric and anesthetic factors that were associated with increased incidence of breakthrough pain as well as to evaluate the impact of breakthrough pain on obstetric and fetal outcomes. RESULTS: The incidence of breakthrough pain was 9.6%. Independent factors associated with incidence of breakthrough pain are the presence of dysfunctional labor, increased maternal body mass index, and decreased successful to-total-bolus-demand ratio. The postlabor characteristics independently associated with breakthrough pain were increased duration of labor, decreased duration of effective analgesia, increased total local anesthetic consumption, and decreased maternal satisfaction. CONCLUSIONS: Low successful to total patient demand bolus ratio was the factor with the strongest association with breakthrough pain. Breakthrough pain was also associated with dysfunctional labor and poorer maternal satisfaction. PMID- 25690279 TI - Pectral nerve blocks and serratus-intercostal plane block for intractable postthoracotomy syndrome. PMID- 25690280 TI - Log odds of positive lymph nodes as a prognostic indicator in stage IV colorectal cancer patients undergoing curative resection. AB - BACKGROUND: Recent studies have proposed the use of log odds of positive lymph nodes (LODDS) as a prognostic indicator in colorectal cancer (CRC) patients without distant synchronous metastasis. In the present study, we aimed to evaluate the prognostic impact of the LODDS in Stage IV CRC patients who have undergone curative resection. METHODS: We performed a retrospective review of 117 Stage IV CRC patients who underwent curative resection at our institute from 1998 to 2011. Patients were categorized into 3 groups (LODDS1-3) according to the ratio of their LODDS. The relationship between the LODDS and disease-free survival (DFS) and overall survival (OS) rates were assessed. RESULTS: DFS was not significantly different between patients in each LODDS group. The association between the LODDS classification and OS was statistically significant (P = 0.021). Multivariate analysis indicated that LODDS classification was an independent prognostic factor for OS, with a hazard ratio of 2.95 for LODDS2 (95% confidence interval [CI]: 1.18-8.35; P = 0.021), and 2.98 for LODDS3 (95% CI: 1.20-8.37; P = 0.017). CONCLUSIONS: The LODDS is a good prognostic indicator in Stage IV CRC patients who have undergone curative resection. PMID- 25690281 TI - XRCC1 and ERCC1 polymorphisms are related to susceptibility and survival of colorectal cancer in the Chinese population. AB - Excision repair cross complementing group 1 (ERCC1) and X-ray repair cross complementing groups 1 (XRCC1) are DNA repair enzymes. Polymorphisms in DNA repair genes may be important factors affecting cancer susceptibility, prognosis and therapy outcome. The purpose of this study was to investigate the correlation of ERCC1 and XRCC1 polymorphisms with colorectal cancer (CRC) risk, and explore the effect of polymorphisms on event-free, overall survival and oxaliplatin-based therapy in CRC patients. Genotyping was examined with the iMLDR technique. An unconditional logistic regression model was used to estimate the association of certain polymorphisms with CRC risk. The Kaplan-Meier method, log-rank test and Cox regression model were employed to evaluate the effects of polymorphisms on survival analysis. Results showed that Trp/Trp genotype of XRCC1 Arg194Trp and AA genotype of ERCC1 rs2336219 have a significantly increased risk of CRC; Trp allele of XRCC1 Arg194Trp and CC genotype of ERCC1 rs735482 were associated with lower response to oxaliplatin-based chemotherapy, a shorter survival and a higher risk of relapse or metastasis. 194Trp/280Arg/399Arg haplotype was associated with a significant resistance, and the ERCC1 protein expression was statistically higher in tumours with rs735482 CC genotype than with AA genotype. Our studies indicate that XRCC1 and ERCC1 polymorphisms probably affect susceptibility, chemotherapy response and survival of CRC patients. PMID- 25690282 TI - Novel zinc-catalytic systems for ring-opening polymerization of epsilon caprolactone. AB - Polycaprolactone (PCL) is a biodegradable synthetic polymer that is currently widely used in many pharmaceutical and medical applications. In this paper we describe the coordination ring-opening polymerization of epsilon-caprolactone in the presence of two newly synthesized catalytic systems: diethylzinc/gallic acid and diethylzinc/propyl gallate. The chemical structures of the obtained PCLs were characterized by 1H- or 13C-NMR, FTIR spectroscopy and MALDI TOF mass spectrometry. The average molecular weight of the resulting polyesters was analysed by gel permeation chromatography and a viscosity method. The effects of temperature, reaction time and type of catalytic system on the polymerization process were examined. Linear PCLs with defined average molecular weight were successfully obtained. Importantly, in some cases the presence of macrocyclic products was not observed during the polymerization process. This study provides an effective method for the synthesis of biodegradable polyesters for medical and pharmaceutical applications due to the fact that gallic acid/propyl gallate are commonly used in the pharmaceutical industry. PMID- 25690283 TI - New cytotoxic sesquiterpenoids from Siegesbeckia glabrescens. AB - Two new sesquiterpenoids, siegenolides A (1) and B (2), and two known sesquiterpenes 3 and 4 were isolated from Siegesbeckia glabrescens. Their structures were elucidated by spectroscopic analyses, and they were further evaluated for their cytotoxic activities against human cancer cells (MCF-7, AsPC 1, SW480, HCT 116, HepG2, HeLa). Compounds 1-4 showed differential cytotoxic effects on the target cancer cells with IC50 values in the range of 0.9-33.3 MUM. PMID- 25690284 TI - Development of bioorthogonal reactions and their applications in bioconjugation. AB - Biomolecule labeling using chemical probes with specific biological activities has played important roles for the elucidation of complicated biological processes. Selective bioconjugation strategies are highly-demanded in the construction of various small-molecule probes to explore complex biological systems. Bioorthogonal reactions that undergo fast and selective ligation under bio-compatible conditions have found diverse applications in the development of new bioconjugation strategies. The development of new bioorthogonal reactions in the past decade has been summarized with comments on their potentials as bioconjugation method in the construction of various biological probes for investigating their target biomolecules. For the applications of bioorthogonal reactions in the site-selective biomolecule conjugation, examples have been presented on the bioconjugation of protein, glycan, nucleic acids and lipids. PMID- 25690285 TI - Inhibitory effect of triterpenoids from Dillenia serrata (Dilleniaceae) on prostaglandin E2 production and quantitative HPLC analysis of its koetjapic acid and betulinic acid contents. AB - The crude methanol extracts and fractions of the root and stem barks of Dillenia serrata Thunb. showed 64% to 73% inhibition on the production of prostaglandin E2 (PGE2) in lipopolysaccharide-induced human whole blood using a radioimmunoassay technique. Three triterpenoids isolated from the root bark of the plant, koetjapic (1), 3-oxoolean-12-en-30-oic (2), and betulinic (3) acids, exhibited significant concentration-dependent inhibitory effects on PGE2 production with IC50 values of 1.05, 1.54, and 2.59 MUM, respectively, as compared with the positive control, indomethacin (IC50 = 0.45 MUM). Quantification of compounds 1 and 3 in the methanol extracts and fractions were carried out by using a validated reversed-phase high performance liquid chromatography (RP-HPLC) method. The ethyl acetate fraction of the stem bark showed the highest content of both compound 1 (15.1%) and compound 3 (52.8%). The strong inhibition of the extracts and fractions on cyclooxygenase-2 (COX-2) enzymatic activity was due to the presence of their major constituents, especially koetjapic and betulinic acids. PMID- 25690286 TI - Isolation and characterisation of in vitro and cellular free radical scavenging peptides from corn peptide fractions. AB - Corn gluten meal, a corn processing industry by-product, is a good source for the preparation of bioactive peptides due to its special amino acid composition. In the present study, the in vitro and cellular free radical scavenging activities of corn peptide fractions (CPFs) were investigated. Results indicated that CPF1 (molecular weight less than 1 kDa) and CPF2 (molecular weight between 1 and 3 kDa) exhibited good hydroxyl radical, superoxide anion radical and 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulphonicacid) diammonium salt (ABTS) radical scavenging activity and oxygen radical absorbance capacity (ORAC). Meanwhile, the in vitro radical scavenging activity of CPF1 was slightly higher than that of CPF2. Both CPF1 and CPF2 also exhibited significant cytoprotective effects and intracellular reactive oxygen species scavenging activity in Caco-2 cells exposed to hydrogen peroxide (H2O2). The amino acid composition analysis revealed that the CPF were rich in hydrophobic amino acids, which comprised of more than 45% of total amino acids. An antioxidant peptide sequence of Tyr-Phe-Cys-Leu-Thr (YFCLT) was identified from CPF1 using matrix-assisted laser desorption/ionization time of-flight/time-of-flight mass spectrometry (MALDI TOF/TOF MS). The YFCLT exhibited excellent ABTS radical scavenging activity with a 50% effective concentration (EC50) value of 37.63 uM, which was much lower than that of Trolox. In conclusion, corn gluten meal might be a good source to prepare antioxidant peptides. PMID- 25690287 TI - Toxicity of amorphigenin from the seeds of Amorpha fruticosa against the larvae of Culex pipiens pallens (Diptera: Culicidae). AB - The larvicidal activity of the crude petroleum ether, ethyl acetate, acetone, chloroform and ethanol extracts of Amorpha fruticosa seeds was individually assayed for toxicity against the early fourth-instar larva of the mosquito, Culex pipiens pallens after 24 h exposure. Of the tested extracts, the ethanol one exhibited the highest larvicidal activity (LC50 = 22.69 mg/L). Amorphigenin (8' hydroxyrotenone), a rotenoid compound which exhibits a strong larvicidal activity with LC50 and LC90 values of 4.29 and 11.27 mg/L, respectively, was isolated from the ethanol extract by column chromatograpy. Its structure was elucidated by 1H NMR, UV and IR spectral data. Furthermore, investigation of amorphigenin's effects on mitochondrial complex I activity and protein synthesis in C. pipiens pallens larvae reveals that amorphigenin decreases mitochondrial complex I activities to 65.73% at 10.45 MUmol/L, compared to the control, when NADH were used as the substrate. Meanwhile, amorphigenin at 10.45 MUmol/L also caused a 1.98-fold decrease in protein content, compared to the control larvae treated with acetone only. PMID- 25690288 TI - Design, synthesis, and cytotoxicity of perbutyrylated glycosides of 4beta triazolopodophyllotoxin derivatives. AB - A series of novel perbutyrylated glycosides of 4beta-triazolopodophyllotoxin derivatives were synthesized by utilizing the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. Evaluation of cytotoxicity against a panel of five human cancer cell lines (HL-60, SMMC-7721, A-549, MCF-7, SW480) using the MTT assay shows that some of these glycosylated derivatives have good anticancer activity. Among the synthesized compounds, compound 21a shows the highest activity, with IC50 values ranging from 0.49 to 6.70 MUM, which is more potent than the control drugs etoposide and cisplatin. Compound 21a is characterized by a perbutyrylated alpha-D(+)-galactosyl residue, the absence of an additional linking spacer between the sugar residue and the triazole ring, as well as a 4' OH group on the E ring of the podophyllotoxin scaffold. PMID- 25690289 TI - Three new lanostanoids from the mushroom Ganoderma tropicum. AB - Three new lanostanoid triterpenes--ganotropic acid (1), 3beta,7beta,15alpha,24 tetra- hydroxy-11,23-dioxo-lanost-8-en-26-oic acid (2) and 3beta,7beta,15alpha,28 tetrahydroxy-11,23- dioxo-lanost-8,16-dien-26-oic acid (3)--were isolated from the n-BuOH extract of the fruiting bodies of the mushroom Ganoderma tropicum. Their structures were elucidated by 1D and 2D NMR spectroscopy, as well as HR-EI MS data. PMID- 25690290 TI - Study of coumarin-resveratrol hybrids as potent antioxidant compounds. AB - In the present work we synthesized a selected series of hydroxylated 3 phenylcoumarins 5-8, with the aim of evaluating in detail their antioxidant properties. From an in depth study of the antioxidant capacity data (ORAC-FL, ESR, CV and ROS inhibition) it was concluded that these derivatives are very good antioxidants, with very interesting profiles in all the performed assays. The study of the effect of the number and position of the hydroxyl groups on the antioxidant activity was the principal aim of this study. In particular, 7 hydroxy-3-(3'-hydroxy)phenylcoumarin (8) proved to be the most active and effective antioxidant of the selected series in four of the performed assays (ORAC-FL = 11.8, capacity of scavenging hydroxyl radicals = 54%, Trolox index = 2.33 and AI30 index = 0.18). However, the presence of two hydroxyl groups on this molecule did not increase greatly the activity profile. Theoretical evaluation of ADME properties of all the derivatives was also carried out. All the compounds can act as potential candidates for preventing or minimizing the free radical overproduction in oxidative-stress related diseases. These preliminary findings encourage us to perform a future structural optimization of this family of compounds. PMID- 25690291 TI - Prevention of protein glycation by natural compounds. AB - Non-enzymatic protein glycosylation (glycation) contributes to many diseases and aging of organisms. It can be expected that inhibition of glycation may prolong the lifespan. The search for inhibitors of glycation, mainly using in vitro models, has identified natural compounds able to prevent glycation, especially polyphenols and other natural antioxidants. Extrapolation of results of in vitro studies on the in vivo situation is not straightforward due to differences in the conditions and mechanism of glycation, and bioavailability problems. Nevertheless, available data allow to postulate that enrichment of diet in natural anti-glycating agents may attenuate glycation and, in consequence, ageing. PMID- 25690292 TI - Lactones with methylcyclohexane systems obtained by chemical and microbiological methods and their antimicrobial activity. AB - Eight new lactones (delta-chloro-, delta-bromo- and delta-iodo-gamma-lactones), each with a methylcyclohexane ring, were obtained by chemical means from (4 methylcyclohex-2-en-1-yl) acetic acid or (6-methylcyclohex-2-en-1-yl) acetic acid. Whole cells of ten fungal strains (Fusarium species, Syncephalastrum racemosum and Botrytis cinerea) were tested on their ability to convert these lactones into other products. Some of the tested fungal strains transformed chloro-, bromo- and iodolactone with a methyl group at C-5 into 2-hydroxy-5 methyl-9-oxabicyclo[4.3.0]nonan-8-one during hydrolytic dehalogenation. When the same lactones had the methyl group at C-3, no structural modifications of halolactones were observed. In most cases, the optical purity of the product was low or medium, with the highest rate for chlorolactone (45.4%) and iodolactone (45.2% and 47.6%). All of the obtained compounds were tested with reference to their smell. Seven halolactones and the hydroxylactone obtained via biotransformation of halolactones with 5-methylcyclohexane ring were examined for their antimicrobial activity. These compounds were capable of inhibiting growth of some bacteria, yeasts and fungi. PMID- 25690293 TI - Investigation of structural mimetics of natural phosphate ion binding motifs. AB - Phosphates are ubiquitous in biology and nearly half of all proteins interact with their partners by means of recognition of phosphate residues. Therefore, a better understanding of the phosphate ion binding by peptidic structures is highly desirable. Two new receptors have been designed and synthesized and their anion binding properties in an acetonitrile solution have been determined. The structure of hosts mimics a part of the kinase active site that is responsible for the recognition of the phosphate residue. New hosts contain additional free amino groups with the aim to facilitate coordination of protonated anions, such as dihydrogen phosphate. According to spectrophotometric measurements, stepwise 1:1 and 1:2 binding modes have been observed for both receptors in the presence of acetate, hydrogen sulfate and dihydrogen phosphate. Compared with the acyclic receptor, the macrocyclic receptor has demonstrated a remarkably enhanced selectivity for dihydrogen phosphate over other anions. Fluorometric measurements have revealed different responses of the acyclic and macrocyclic receptors towards anions. However, in both cases, a 5-8 nm hypsochromic shift of fluorescence maximum has been observed upon interaction of acetate and dihydrogen phosphate with receptors. PMID- 25690294 TI - A density functional tight binding study of acetic acid adsorption on crystalline and amorphous surfaces of titania. AB - We present a comparative density functional tight binding study of an organic molecule attachment to TiO2 via a carboxylic group, with the example of acetic acid. For the first time, binding to low-energy surfaces of crystalline anatase (101), rutile (110) and (B)-TiO2 (001), as well as to the surface of amorphous (a ) TiO2 is compared with the same computational setup. On all surfaces, bidentate configurations are identified as providing the strongest adsorption energy, Eads = -1.93, -2.49 and -1.09 eV for anatase, rutile and (B)-TiO2, respectively. For monodentate configurations, the strongest Eads = -1.06, -1.11 and -0.86 eV for anatase, rutile and (B)-TiO2, respectively. Multiple monodentate and bidentate configurations are identified on a-TiO2 with a distribution of adsorption energies and with the lowest energy configuration having stronger bonding than that of the crystalline counterparts, with Eads up to -4.92 eV for bidentate and 1.83 eV for monodentate adsorption. Amorphous TiO2 can therefore be used to achieve strong anchoring of organic molecules, such as dyes, that bind via a COOH group. While the presence of the surface leads to a contraction of the band gap vs. the bulk, molecular adsorption caused no appreciable effect on the band structure around the gap in any of the systems. PMID- 25690295 TI - Investigation of chemomarkers of astragali radix of different ages and geographical origin by NMR profiling. AB - Astragalus roots from Astragalus membranaceus Bunge or Astragalus membranaceus var. mongholicus (Bunge) Hsiao are among the most popular traditional medicinal plants due to their diverse therapeutic uses based on their tonic, antinephritic, immunostimulant, hepatoprotectant, diuretic, antidiabetic, analgesic, expectorant and sedative properties. Currently, the herb is produced or cultivated in various sites, including 10 different locations in China with very diverse environmental conditions. These differences affect their metabolic pools and consequently their medicinal properties. The comparative metabolic profiling of plants of different geographical origins or ages could contribute to detect biomarkers for their quality control and thus guarantee the efficacy of the herbal medicines produced with this drug. In this paper nuclear magnetic resonance spectroscopy (NMR)-based metabolomics was applied for to plants of different origins and age for this purpose. The results of this study show that in the set of samples evaluated, age is more discriminating than geographical location. The quantity of individual flavonoids and some primary metabolites contributed most to this age differentiation. On the other hand, based on the analysis of orthogonal partial least square (OPLS) modeling, the marker metabolites for the geographical origin were saponins and isoflavonoids. PMID- 25690296 TI - Anti-proliferative effect and induction of apoptosis in androgen-independent human prostate cancer cells by 1,5-bis(2-hydroxyphenyl)-1,4-pentadiene-3-one. AB - Curcumin has poor in vivo absorption and bioavailability, highlighting a need for new curcumin analogues with better characteristics in these aspects. The aim of this study is to determine the anti-cancer properties of four selected curcumin analogues, on the cytotoxicity, proliferative and apoptotic effects on androgen independent human prostate cancer cells (PC-3 and DU 145). Initial cytotoxicity screening showed MS17 has the highest cell inhibitory effect, with EC50 values of 4.4 +/- 0.3 and 4.1 +/- 0.8 uM, followed by MS13 (7.5 +/- 0.1 and 7.4 +/- 2.6 uM), MS49 (14.5 +/- 1.2 and 12.3 +/- 2.3 uM) and MS40E (28.0 +/- 7.8 and 30.3 +/- 1.9 uM) for PC-3 and DU 145 cells, respectively. Time-dependent analysis also revealed that MS13 and MS17 displayed a greater anti-proliferative effect than the other compounds. MS17 was chosen based on the high selectivity index value for further analysis on the morphological and biochemical hallmarks of apoptosis. Fluorescence microscopy analysis revealed apoptotic changes in both treated prostate cancer cells. Relative caspase-3 activity increased significantly at 48 h in PC-3 and 12 h in DU 145 cells. Highest enrichment of free nucleosomes was noted at 48 h after treatment with MS17. In conclusion, MS17 demonstrated anti proliferative effect and induces apoptosis in a time and dose-dependent manner suggesting its potential for development as an anti-cancer agent for androgen independent prostate cancer. PMID- 25690297 TI - Analysis of phenolic and cyclic compounds in plants using derivatization techniques in combination with GC-MS-based metabolite profiling. AB - Metabolite profiling has been established as a modern technology platform for the description of complex chemical matrices and compound identification in biological samples. Gas chromatography coupled with mass spectrometry (GC-MS) in particular is a fast and accurate method widely applied in diagnostics, functional genomics and for screening purposes. Following solvent extraction and derivatization, hundreds of metabolites from different chemical groups can be characterized in one analytical run. Besides sugars, acids, and polyols, diverse phenolic and other cyclic metabolites can be efficiently detected by metabolite profiling. The review describes own results from plant research to exemplify the applicability of GC-MS profiling and concurrent detection and identification of phenolics and other cyclic structures. PMID- 25690298 TI - Nkrp1 family, from lectins to protein interacting molecules. AB - The C-type lectin-like receptors include the Nkrp1 protein family that regulates the activity of natural killer (NK) cells. Rat Nkrp1a was reported to bind monosaccharide moieties in a Ca2+-dependent manner in preference order of GalNac > GlcNAc >> Fuc >> Gal > Man. These findings established for rat Nkrp1a have been extrapolated to all additional Nkrp1 receptors and have been supported by numerous studies over the past two decades. However, since 1996 there has been controversy and another article showed lack of interactions with saccharides in 1999. Nevertheless, several high affinity saccharide ligands were synthesized in order to utilize their potential in antitumor therapy. Subsequently, protein ligands were introduced as specific binders for Nkrp1 proteins and three dimensional models of receptor/protein ligand interaction were derived from crystallographic data. Finally, for at least some members of the NK cell C-type lectin-like proteins, the "sweet story" was impaired by two reports in recent years. It has been shown that the rat Nkrp1a and CD69 do not bind saccharide ligands such as GlcNAc, GalNAc, chitotetraose and saccharide derivatives (GlcNAc PAMAM) do not directly and specifically influence cytotoxic activity of NK cells as it was previously described. PMID- 25690299 TI - Nutritional value and volatile compounds of black cherry (Prunus serotina) seeds. AB - Prunus serotina (black cherry), commonly known in Mexico as capulin, is used in Mexican traditional medicine for the treatment of cardiovascular, respiratory, and gastrointestinal diseases. Particularly, P. serotina seeds, consumed in Mexico as snacks, are used for treating cough. In the present study, nutritional and volatile analyses of black cherry seeds were carried out to determine their nutraceutical potential. Proximate analysis indicated that P. serotina raw and toasted seeds contain mostly fat, followed by protein, fiber, carbohydrates, and ash. The potassium content in black cherry raw and toasted seeds is high, and their protein digestibility-corrected amino acid scores suggest that they might represent a complementary source of proteins. Solid phase microextraction and gas chromatography/flame ionization detection/mass spectrometry analysis allowed identification of 59 and 99 volatile compounds in the raw and toasted seeds, respectively. The major volatile compounds identified in raw and toasted seeds were 2,3-butanediol and benzaldehyde, which contribute to the flavor and odor of the toasted seeds. Moreover, it has been previously demonstrated that benzaldehyde possesses a significant vasodilator effect, therefore, the presence of this compound along with oleic, linoleic, and alpha-eleostearic fatty acids indicate that black cherry seeds consumption might have beneficial effects on the cardiovascular system. PMID- 25690300 TI - The combined impact of adherence to five lifestyle factors on all-cause, cancer and cardiovascular mortality: a prospective cohort study among Danish men and women. AB - Individual lifestyle factors have been associated with lifestyle diseases and premature mortality by an accumulating body of evidence. The impact of a combination of lifestyle factors on mortality has been investigated in several studies, but few have applied a simple index taking national guidelines into account. The objective of the present prospective cohort study was to investigate the combined impact of adherence to five lifestyle factors (smoking, alcohol intake, physical activity, waist circumference and diet) on all-cause, cancer and cardiovascular mortality based on international and national health recommendations. A Cox proportional hazards model was used to estimate hazard ratios (HR) with 95 % CI. During a median follow-up of 14 years, 3941 men and 2827 women died. Among men, adherence to one additional health recommendation was associated with an adjusted HR of 0.73 (95 % CI 0.71, 0.75) for all-cause mortality, 0.74 (95 % CI 0.71, 0.78) for cancer mortality and 0.70 (95 % CI 0.65, 0.75) for cardiovascular mortality. Among women, the corresponding HR was 0.72 (95 % CI 0.70, 0.75) for all-cause mortality, 0.76 (95 % CI 0.73, 0.80) for cancer mortality and 0.63 (95 % CI 0.57, 0.70) for cardiovascular mortality. In the present study, adherence to merely one additional health recommendation had a protective effect on mortality risk, indicating a huge potential in enhancing healthy lifestyle behaviours of the population. PMID- 25690301 TI - A systematic review on the effects of air polishing devices on oral tissues. AB - OBJECTIVES: Air-polishing devices are used for the instrumentation of the root surface. Their potential of harm to the hard and/or soft tissues needs to be considered during periodontal treatment. The objective of this systematic review was to analyse the effects of air polishing devices on oral tissues. METHODS: The electronic databases MEDLINE, EMBASE and the Cochrane Library were screened for studies published through 18 November 2013. The surface modifications on human cementum, dentine or gingiva after the instrumentation were considered as outcomes. RESULTS: Of the 1266 abstracts screened, 17 studies were included in the analysis. Different air polishing powders consisting of sodium bicarbonate, calcium carbonate, pumice or glycine were used in different ex vivo or in vitro settings. Thirteen publications reported data on the effects of air polishing devices on cementum and dentine. Hard tissue modifications, including defect depths and volume, caused by sodium bicarbonate or calcium carbonate powders were significantly greater compared to powders consisting of glycine. The soft tissue modifications using different modes of instrumentation were assessed in four publications. The data demonstrate less potential of harm to the gingiva after spraying with glycine powder compared to sodium bicarbonate powder or instrumentation with curettes. CONCLUSION: Glycine powder air polishing may be safely applied to human root surfaces and gingivae. PMID- 25690302 TI - Immunolocalization of loricrin in the maturing alpha-layer of normal and regenerating epidermis of the lizard Anolis carolinensis. AB - Numerous corneous proteins are produced during the differentiation of the complex lizard epidermis, comprising hard beta-layers and softer alpha-layers. In the present ultrastructural and immunocytochemical study, we have localized a homolog of the mammalian skin barrier protein loricrin in the skin of the green anole lizard (Anolis carolinensis). We used an antibody specific to the carboxyterminus of loricrin 1, a gene of the epidermal differentiation complex (EDC) of A. carolinensis. Lizard loricrin is present in the maturing alpha-layer (lacunar cells) of normal scale epidermis and in the accumulating corneocytes of the wound epidermis (lacunar cells) of the regenerating epidermis. The protein appears as a component of the alpha-layer but not of the beta-layer. Lizard loricrin is diffused in the cytoplasm of pre-corneous alpha-keratinocytes but eventually concentrates in the packing corneous material of the maturing corneocytes of the alpha-layer (lacunar) in normal epidermis or in the wound epidermis of regenerating epidermis. The protein likely contributes to the composition and pliability of the corneous material but is not specifically accumulated on the corneous cell envelope (marginal layer) that is scarcely differentiated in these cells. The study contributes to the knowledge on the distribution of specific corneous proteins that give rise to the different material properties of alpha layers versus beta-layers in lizard epidermis. PMID- 25690303 TI - Enhancing the biological activity of chitosan and controlling the degradation by nanoscale interaction with bioglass. AB - A nonuniform degradation of physical mixture of organic-inorganic biomaterials increases their risk of failure. In this study a chemical bonding between chitosan and bioglass was used as an alternative product to address this issue. To prepare a homogenous composite, chitosan was functionalized with gamma glycidoxypropyl trimethoxysilane and chemically bonded with bioglass during sol gel method. The gelation time of these hybrids samples was optimized by varying parameters such as composition of chitosan and temperature. It was shown that gelation time was reduced from 7 days for pure bioglass at 25 degrees C to less than six minutes at 70 degrees C for chitosan 40 vol % bioglass hybrid. Furthermore, the enzymatic degradation after 4 weeks was decreased from 80% mass loss for pure chitosan to 32% for chitosan 40 vol % bioglass hybrid. The results of in vitro study demonstrated that the presence of nanoscale interaction enhanced the bioactivity of chitosan. Additionally, hybrid scaffolds were fabricated with pore sizes in the range of 200-400 um. These scaffolds were prepared by the addition of sodium bicarbonate during sol-gel method as a gas foaming agent and a neutralizer that resulted in decreasing the gelation time of hybrids to less than three minutes. The hybrids fabricated in this study possessed superior characteristics compared to chitosan, also physical mixture of chitosan-bioglass and are promising alternatives for bone tissue engineering applications. PMID- 25690304 TI - 18F-FP-(+)-DTBZ positron emission tomography detection of monoaminergic deficient network in patients with carbon monoxide related parkinsonism. AB - BACKGROUND AND PURPOSE: Although parkinsonism after carbon monoxide (CO) intoxication is well known, neurotransmitter deficient networks that are responsible for the severity of parkinsonism have rarely been systemically evaluated. METHODS: Eighteen patients with CO-related parkinsonism and nine age- and sex-matched controls were enrolled for detailed neurological examinations, three-dimensional T1-weighted images, diffusion tensor imaging and (18)F-9 fluoropropyl-(+)-dihydrotetrabenzazine ((18)F-FP-(+)-DTBZ) positron emission tomography (PET). The structural analysis included voxel-based morphometry to assess grey matter atrophy and tract-based spatial statistics related to white matter involvement. For presynaptic monoaminergic assessment, volume of interest analysis in six subcortical regions and non-parametric voxel-wise comparison were performed on PET images with estimation of registration parameters from magnetic resonance images. All the imaging modalities were compared between the patients and controls. For the patients, a regression model for correlation with cognitive behaviour and Unified Parkinson's Disease Rating Scale (UPDRS) score was used. RESULTS: In the patients, monoaminergic deficit networks were found in the caudate, anterior putamen, anterior insular, thalamus and anterior cingulate cortex. The UPDRS revealed significant correlations with the prefrontal white matter fractional anisotropy values and with the (18)F-FP-(+)-DTBZ uptake values in the caudate nucleus, insular, medial prefrontal and dorsomedial thalamus. The neuropsychiatric inventory score correlated with the (18)F-FP-(+)-DTBZ uptake values in the anterior cingulate cortex and dorsolateral prefrontal cortex. CONCLUSIONS: Our study demonstrated monoaminergic deficits and white matter damage networks in CO-related parkinsonism that determined the severity of parkinsonism or behaviour changes. As the substantia nigra was spared, the monoaminergic topography of involvement suggests a different pathophysiology in CO-related parkinsonism. PMID- 25690305 TI - Treatment of petroleum refinery wastewater containing heavily polluting substances in an aerobic submerged fixed-bed reactor. AB - Petroleum refineries produce large amount of wastewaters, which often contain a wide range of different compounds. Some of these constituents may be recalcitrant and therefore difficult to be treated biologically. This study evaluated the capability of an aerobic submerged fixed-bed reactor (ASFBR) containing a corrugated PVC support material for biofilm attachment to treat a complex and high-strength organic wastewater coming from a petroleum refinery. The reactor operation was divided into five experimental runs which lasted more than 250 days. During the reactor operation, the applied volumetric organic load was varied within the range of 0.5-2.4 kgCOD.m(-3).d(-1). Despite the inherent fluctuations on the characteristics of the complex wastewater and the slight decrease in the reactor performance when the influent organic load was increased, the ASFBR showed good stability and allowed to reach chemical oxygen demand, dissolved organic carbon and total suspended solids removals up to 91%, 90% and 92%, respectively. Appreciable ammonium removal was obtained (around 90%). Some challenging aspects of reactor operation such as biofilm quantification and important biofilm constituents (e.g. polysaccharides (PS) and proteins (PT)) were also addressed in this work. Average PS/volatile attached solids (VAS) and PT/VAS ratios were around 6% and 50%, respectively. The support material promoted biofilm attachment without appreciable loss of solids and allowed long-term operation without clogging. Microscopic observations of the microbial community revealed great diversity of higher organisms, such as protozoa and rotifers, suggesting that toxic compounds found in the wastewater were possibly removed in the biofilm. PMID- 25690306 TI - Micro- and macrostructural characterization of polyvinylpirrolidone rotary-spun fibers. AB - The application of high-speed rotary spinning can offer a useful mean for either preparation of fibrous intermediate for conventional dosage forms or drug delivery systems. Polyvinylpyrrolidone (PVP) and poly(vinylpyrrolidone vinylacetate) (PVP VA) micro- and nanofibers of different polymer concentrations and solvent ratios were prepared with a high-speed rotary spinning technique. In order to study the influence of parameters that enable successful fiber production from polymeric viscous solutions, a complex micro- and macrostructural screening method was implemented. The obtained fiber mats were subjected to detailed morphological analysis using scanning electron microscope (SEM), and rheological measurements while the microstructural changes of fiber samples, based on the free volume changes, was analyzed by positron annihilation lifetime spectroscopy (PALS) and compared with their mechanical characteristics. The plasticizing effect of water tracked by ortho-positronium lifetime changes in relation to the mechanical properties of fibers. A concentration range of polyvinylpyrrolidone solutions was defined for the preparation of fibers of optimum fiber morphology and mechanical properties. The method enabled fiber formulation of advantageous functionality-related properties for further formulation of solid dosage forms. PMID- 25690307 TI - Accuracy of three-dimensional ultrasound compared with magnetic resonance imaging in diagnosis of Mullerian duct anomalies using ESHRE-ESGE consensus on the classification of congenital anomalies of the female genital tract. AB - OBJECTIVE: To establish the accuracy of three-dimensional ultrasound (3D-US), compared with magnetic resonance imaging (MRI), for diagnosing uterine anomalies, using the European Society of Human Reproduction and Embryology-European Society for Gynaecological Endoscopy (ESHRE-ESGE) consensus on the classification of congenital anomalies of the female genital tract. METHODS: Sixty women with uterine anomalies suspected after examination by conventional two-dimensional ultrasound were evaluated with 3D-US and MRI. These data were analyzed retrospectively to confirm the presence and type of uterine malformation in accordance with the ESHRE-ESGE consensus. Sensitivity, specificity and positive (PPV) and negative (NPV) predictive values were calculated, using MRI as the gold standard, and agreement between the two methods was evaluated by kappa index. RESULTS: Compared with MRI, for the diagnosis of normal uteri, 3D-US had a sensitivity of 83.3%, specificity of 100%, PPV of 100%, NPV of 98.2% and kappa index of 0.900. For dysmorphic uteri and for hemi-uteri, the sensitivity, specificity, PPV and NPV were all 100%, and kappa was 1.00. For septate uteri, the sensitivity was 100%, specificity was 88.9%, PPV was 95.5%, NPV was 100% and kappa was 0.918. For bicorporeal uteri, the sensitivity was 83.3%, specificity was 100%, PPV was 100%, NPV was 98.2% and kappa was 0.900. CONCLUSIONS: 3D-US is highly accurate for diagnosing uterine malformations, having a good level of agreement with MRI in the classification of different anomaly types based on the ESHRE-ESGE consensus. PMID- 25690308 TI - Age distribution of emergency department presentations in Victoria. AB - OBJECTIVES: To describe patterns of ED utilisation over time, by patient age group and triage classification. METHODS: Secondary analysis of data from all patients presenting to EDs in Victoria utilising the Victorian Emergency Minimum Dataset (VEMD) for the years 2002-2013. The VEMD includes all hospitals in Victoria with 24 h EDs. RESULTS: The absolute number of presentations to EDs in Victoria has grown by over 52% in the last 11 years. The triage categories of highest urgency (1-3) grew by 89% whereas the categories of lowest urgency (4-5) grew by 33%. Over this period, the 5 year age band with the greatest number of ED presentations has consistently been, by far, children 0-4 years of age. This age group has seen an increase of 29% in ED presentations overall with a >55% increase in Triage 1-3, and an increase of 16% in triage 4-5. For all age groups, there has been little change in the number of triage category 4-5 presentations since 2007/2008. However, for triage categories 1-3, there have been consistent increases in presentations across all age groups. CONCLUSION: The age range with the greatest absolute number of ED presentations in Victoria is children 0-4 years of age. This finding is consistent over time and across all triage classifications. The age range with the second highest absolute number of ED presentations is comprised of those 20-24 years of age. This is in contrast to the frequent public attention placed on the volume of ED presentations by the elderly. PMID- 25690309 TI - Discovery of novel S. aureus autolysins and molecular engineering to enhance bacteriolytic activity. AB - Staphylococcus aureus is a dangerous bacterial pathogen whose clinical impact has been amplified by the emergence and rapid spread of antibiotic resistance. In the search for more effective therapeutic strategies, great effort has been placed on the study and development of staphylolytic enzymes, which benefit from high potency activity toward drug-resistant strains, and a low inherent susceptibility to emergence of new resistance phenotypes. To date, the majority of therapeutic candidates have derived from either bacteriophage or environmental competitors of S. aureus. Little to no consideration has been given to cis-acting autolysins that represent key elements in the bacterium's endogenous cell wall maintenance and recycling machinery. In this study, five putative autolysins were cloned from the S. aureus genome, and their activities were evaluated. Four of these novel enzymes, or component domains thereof, demonstrated lytic activity toward live S. aureus cells, but their potencies were 10s to 1000s of times lower than that of the well-characterized therapeutic candidate lysostaphin. We hypothesized that their poor activities were due in part to suboptimal cell wall targeting associated with their native cell wall binding domains, and we sought to enhance their antibacterial potential via chimeragenesis with the peptidoglycan binding domain of lysostaphin. The most potent chimera exhibited a 140-fold increase in lytic rate, bringing it within 8-fold of lysostaphin. While this enzyme was sensitive to certain biologically relevant environmental factors and failed to exhibit a measurable minimal inhibitory concentration, it was able to kill lysostaphin-resistant S. aureus and ultimately proved active in lung surfactant. We conclude that the S. aureus proteome represents a rich and untapped reservoir of novel antibacterial enzymes, and we demonstrate enhanced bacteriolytic activity via improved cell wall targeting of autolysin catalytic domains. PMID- 25690310 TI - Screening of a novel strong promoter by RNA sequencing and its application to H2 production in a hyperthermophilic archaeon. AB - A strong promoter increases transcription of the genes of interest and enhances the production of various valuable substances. For a hyperthermophilic archaeon Thermococcus onnurineus NA1, which can produce H2 from carbon monoxide oxidation, we searched for a novel endogenous strong promoter by transcriptome analysis using high-throughput RNA sequencing. Based on the relative transcript abundance, we selected one promoter to encode a hypothetical gene, of which homologs were found only in several Thermococcales strains. This promoter, P TN0510 , was introduced into the front of CO-responsible hydrogenase gene cluster encoding a carbon monoxide dehydrogenase (CODH), a hydrogenase, and a Na(+)/H(+) antiporter. In the resulting mutant strain, KS0510, transcription and translation level of the gene cluster increased by 4- to 14-folds and 1.5- to 1.9-folds, respectively, in comparison with those of the wild-type strain. Additionally, H2 production rate of KS0510 mutant was 4.8-fold higher than that of the wild-type strain. The P TN0510 was identified to be much stronger than the well-known two strong promoters, gdh and slp promoters from Thermococcus strains, through RT-qPCR and Western blotting analyses and kinetics of H2 production. In this study, we demonstrated that the RNA-seq approach is a good strategy to mine novel strong promoters of use to a Thermococcus strain when developed as a biotechnologically promising strain to produce valuable products such as enzymes and metabolites through metabolic engineering. PMID- 25690311 TI - The feasibility of using irreversible electroporation to introduce pores in bacterial cellulose scaffolds for tissue engineering. AB - This work investigates the feasibility of the use of irreversible electroporation (IRE) in the biofabrication of 3D cellulose nanofibril networks via the bacterial strain Gluconacetobacter xylinus. IRE uses electrical pulses to increase membrane permeability by altering the transmembrane potential; past a threshold, damage to the cell becomes too great and leads to cell death. We hypothesized that using IRE to kill the bacteria at specific locations and particular times, we could introduce conduits in the overall scaffold by preventing cellulose biosynthesis locally. Through mathematical modeling and experimental techniques, electrical effects were investigated and the parameters for IRE of G. xylinus were determined. We found that for a specific set of parameters, an applied electric field of 8 to 12.5 kV/cm, producing a local field of 3 kV/cm, was sufficient to kill most of the bacteria and create a localized pore. However, an applied electric field of 17.5 kV/cm was required to kill all. Results suggest that IRE may be an effective tool to create scaffolds with appropriate porosity for orthopedic applications. Ideally, these engineered scaffolds could be used to successfully treat osteochondral defects. PMID- 25690312 TI - Allopurinol-mediated lignocellulose-derived microbial inhibitor tolerance by Clostridium beijerinckii during acetone-butanol-ethanol (ABE) fermentation. AB - In addition to glucans, xylans, and arabinans, lignocellulosic biomass hydrolysates contain significant levels of nonsugar components that are toxic to the microbes that are typically used to convert biomass to biofuels and chemicals. To enhance the tolerance of acetone-butanol-ethanol (ABE)-generating Clostridium beijerinckii NCIMB 8052 to these lignocellulose-derived microbial inhibitory compounds (LDMICs; e.g., furfural), we have been examining different metabolic perturbation strategies to increase the cellular reductant pools and thereby facilitate detoxification of LDMICs. As part of these efforts, we evaluated the effect of allopurinol, an inhibitor of NAD(P)H-generating xanthine dehydrogenase (XDH), on C. beijerinckii grown in furfural-supplemented medium and found that it unexpectedly increased the rate of detoxification of furfural by 1.4-fold and promoted growth, butanol, and ABE production by 1.2-, 2.5-, and 2 fold, respectively. Since NAD(P)H/NAD(P)(+) levels in C. beijerinckii were largely unchanged upon allopurinol treatment, we postulated and validated a possible basis in DNA repair to account for the solventogenic gains with allopurinol. Following the observation that supplementation of allopurinol in the C. beijerinckii growth media mitigates the toxic effects of nalidixic acid, a DNA damaging antibiotic, we found that allopurinol elicited 2.4- and 6.7-fold increase in the messenger RNA (mRNA) levels of xanthine and hypoxanthine phosphoribosyltransferases, key purine-salvage enzymes. Consistent with this finding, addition of inosine (a precursor of hypoxanthine) and xanthine led to 1.4- and 1.7-fold increase in butanol production in furfural-challenged cultures of C. beijerinckii. Taken together, our results provide a purine salvage-based rationale for the unanticipated effect of allopurinol in improving furfural tolerance of the ABE-fermenting C. beijerinckii. PMID- 25690313 TI - Occurrence and importance of anaerobic ammonium-oxidising bacteria in vegetable soils. AB - The quantitative importance of anaerobic ammonium oxidation (anammox) has been described in paddy fields, while the presence and importance of anammox in subsurface soil from vegetable fields have not been determined yet. Here, we investigated the occurrence and activity of anammox bacteria in five different types of vegetable fields located in Jiangsu Province, China. Stable isotope experiments confirmed the anammox activity in the examined soils, with the potential rates of 2.1 and 23.2 nmol N2 g(-1) dry soil day(-1), and the anammox accounted for 5.9-20.5% of total soil dinitrogen gas production. It is estimated that a total loss of 7.1-78.2 g N m(-2) year(-1) could be linked to the anammox process in the examined vegetable fields. Phylogenetic analyses showed that multiple co-occurring anammox genera were present in the examined soils, including Candidatus Brocadia, Candidatus Kuenenia, Candidatus Anammoxoglobus and Candidatus Jettenia, and Candidatus Brocadia appeared to be the most common anammox genus. Quantitative PCR further confirmed the presence of anammox bacteria in the examined soils, with the abundance varying from 2.8 * 10(5) to 3.0 * 10(6) copies g(-1) dry soil. Correlation analyses suggested that the soil ammonium concentration had significant influence on the activity and abundance of anammox bacteria in the examined soils. The results of our study showed the presence of diverse anammox bacteria and indicated that the anammox process could serve as an important nitrogen loss pathway in vegetable fields. PMID- 25690314 TI - A smart DNA-gold nanoparticle probe for detecting single-base changes on the platform of a quartz crystal microbalance. AB - A design of DNA-gold nanoparticle probe-fueled DNA strand displacements for detecting single-base changes on the platform of a quartz crystal microbalance with random sequences was developed. After optimizing and testing the detection system, it has been successfully applied to detect mutation of a realistic sequence associated with human cancer, thereby indicating that this method has potential applicability in general. PMID- 25690315 TI - Attitudes and emotions towards pain and sensitivity to painful stimuli among people routinely engaging in masochistic behaviour. AB - BACKGROUND: People engaged in masochistic behaviour (MB) seek to experience pain and the pleasure it evokes in sadomasochistic (S&M) sessions. The sensitivity and attitude to pain in these individuals has hardly been tested. We evaluated pain perception among these individuals and tested whether their experiences and attitudes towards pain are context-related. METHODS: Thirty-four healthy subjects participated; 17 routinely engaged in MB and 17 controls. Pressure pain threshold (PPT) was measured in two body regions. A structured questionnaire on S&M activities and context-related pain experiences and emotions was completed, as well as the pain catastrophizing (CAT) and fear of pain (FOP) questionnaires. RESULTS: PPT was significantly higher among MB individuals and positively correlated with the frequency of S&M sessions. MB individuals also had lower levels of CAT, and FOP correlated negatively with the frequency of MB and the number of body regions involved. Pleasure evoked during S&M sessions correlated positively with pain intensity and number of body regions involved. Pain in everyday life correlated negatively with MB activities. However, the emotional attitude to everyday pain was ambivalent: MB individuals perceived pain intensity and unpleasantness similar to the controls, but simultaneously gained pleasure from the pain. CONCLUSIONS: MB individuals exhibited pain hyposensitivity, presumably resulting from frequent engagement in MB. Alternatively, these subjects may have a predisposition which enables this engagement. Attitudes towards pain in MB individuals are complex. They appear to be context-related with pain experienced as pleasurable and rewarding during S&M sessions, and negative but still pleasurable in everyday life. PMID- 25690316 TI - Inhibition of radical reactions for an improved potassium tert-butoxide-promoted (11) C-methylation strategy for the synthesis of alpha-(11) C-methyl amino acids. AB - alpha-(11) C-Methyl amino acids are useful tools for biological imaging studies. However, a robust procedure for the labeling of amino acids has not yet been established. In this study, the (11) C-methylation of Schiff-base-activated alpha amino acid derivatives has been optimized for the radiosynthesis of various alpha (11) C-methyl amino acids. The benzophenone imine analog of methyl 2-amino butyrate was (11) C-methylated with [(11) C]methyl iodide following its initial deprotonation with potassium tert-butoxide (KOtBu). The use of an alternative base such as tetrabutylammonium fluoride, triethylamine, and 1,8 diazabicyclo[5.4.0]undec-7-ene did not result in the (11) C-methylated product. Furthermore, the KOtBu-promoted (11) C-methylation of the Schiff-base-activated amino acid analog was enhanced by the addition of 1,2,4,5-tetramethoxybenzene or 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) and inhibited by the addition of 1,10-phenanthroline. These results suggest that inhibition of radical generation induced by KOtBu improves the alpha-(11) C-methylation of the Schiff-base activated amino acids. The addition of a mixture of KOtBu and TEMPO to a solution of Schiff-base-activated amino acid ester and [(11) C]methyl iodide provided optimal results, and the tert-butyl ester and benzophenone imine groups could be readily hydrolyzed to give the desired alpha-(11) C-methyl amino acids with a high radiochemical conversion. This strategy could be readily applied to the synthesis of other alpha-(11) C-methyl amino acids. PMID- 25690317 TI - Investigating the genetic basis of fever-associated syndromic epilepsies using copy number variation analysis. AB - Fever-associated syndromic epilepsies ranging from febrile seizures plus (FS+) to Dravet syndrome have a significant genetic component. However, apart from SCN1A mutations in >80% of patients with Dravet syndrome, the genetic underpinnings of these epilepsies remain largely unknown. Therefore, we performed a genome-wide screening for copy number variations (CNVs) in 36 patients with SCN1A-negative fever-associated syndromic epilepsies. Phenotypes included Dravet syndrome (n = 23; 64%), genetic epilepsy with febrile seizures plus (GEFS+) and febrile seizures plus (FS+) (n = 11; 31%) and unclassified fever-associated epilepsies (n = 2; 6%). Array comparative genomic hybridization (CGH) was performed using Agilent 4 * 180K arrays. We identified 13 rare CNVs in 8 (22%) of 36 individuals. These included known pathogenic CNVs in 4 (11%) of 36 patients: a 1q21.1 duplication in a proband with Dravet syndrome, a 14q23.3 deletion in a proband with FS+, and two deletions at 16p11.2 and 1q44 in two individuals with fever associated epilepsy with concomitant autism and/or intellectual disability. In addition, a 3q13.11 duplication in a patient with FS+ and two de novo duplications at 7p14.2 and 18q12.2 in a patient with atypical Dravet syndrome were classified as likely pathogenic. Six CNVs were of unknown significance. The identified genomic aberrations overlap with known neurodevelopmental disorders, suggesting that fever-associated epilepsy syndromes may be a recurrent clinical presentation of known microdeletion syndromes. PMID- 25690318 TI - International multi-institutional experience with the vessel-sparing technique to reconstruct the proximal bulbar urethra: mid-term results. AB - OBJECTIVE: To present mid-term outcomes from an international, multi institutional cohort of patients undergoing vessel-sparing excision and primary anastomosis urethroplasty for the reconstruction of the anterior urethra. MATERIALS AND METHODS: From June 2003 to December 2011, 68 patients underwent vessel-sparing anterior urethral reconstruction at five different international institutions using the vessel-sparing technique described by Jordan et al. (J Urol 177(5):1799-1802, 2007). RESULTS: Patients' age range was from 3 to 82 years (mean 51.2). Stricture length ranged from 1 to 3 cm (mean 1.78). After a mean follow-up of 17.6 months, 95.6 % of patients had a widely patent urethral lumen. Three patients failed the procedure, requiring either direct vision internal urethrotomy or urethral dilation, after which all were free of symptoms and did not require further instrumentation. Complications were minimal and as expected following open urethroplasty. CONCLUSION: Preservation of blood supply is a noble pursuit in surgery; however, it can be technically difficult and often requires more time and effort. This vessel-sparing technique for anterior urethral reconstruction is reproducible and appears to be reliable in this international cohort. Larger studies and longer follow-up are needed to support these encouraging results. PMID- 25690319 TI - Tenascin-C induces resistance to apoptosis in pancreatic cancer cell through activation of ERK/NF-kappaB pathway. AB - As a glycol-protein located in extracellular matrix (ECM), tenascin-C (TNC) is absent in most normal adult tissues but is highly expressed in the majority of malignant solid tumors. Pancreatic cancer is characterized by an abundant fibrous tissue rich in TNC. Although it was reported that TNC's expression increased in the progression from low-grade precursor lesions to invasive cancer and was associated with tumor differentiation in human pancreatic cancer, studies on the relations between TNC and tumor progression in pancreatic cancer were rare. In this study, we performed an analysis to determine the effects of TNC on modulating cell apoptosis and chemo-resistance and explored its mechanisms involving activation in pancreatic cancer cell. The expressions of TNC, ERK1/2/p ERK1/2, Bcl-xL and Bcl-2 were detected by immunohistochemistry and western blotting. Then the effects of exogenous and endogenous TNC on the regulation of tumor proliferation, apoptosis and gemcitabine cytotoxicity were investigated. The associations among the TNC knockdown, TNC stimulation and expressions of ERK1/2/NF-kappaB/p65 and apoptotic regulatory proteins were also analyzed in cell lines. The mechanism of TNC on modulating cancer cell apoptosis and drug resistant through activation of ERK1/2/NF-kappaB/p65 signals was evaluated. The effect of TNC on regulating cell cycle distribution was also tested. TNC, ERK1/2/p-ERK1/2, and apoptotic regulatory proteins Bcl-xL and Bcl-2 were highly expressed in human pancreatic cancer tissues. In vitro, exogenous TNC promoted pancreatic cancer cell growth also mediates basal as well as starved and drug induced apoptosis in pancreatic cancer cells. The effects of TNC on anti apoptosis were induced by the activation state of ERK1/2/NF-kappaB/p65 signals in pancreatic cell. TNC phosphorylate ERK1/2 to induce NF-kappaB/p65 nucleus translocation. The latter contributes to promote Bcl-xL, Bcl-2 protein expressions and reduce caspase activity, which inhibit cell apoptotic processes. TNC mediated gemcitabine chemo-resistance via modulating cell apoptosis in pancreatic cancer. TNC resulted in the enrichment of pancreatic cancer cells in S phase with a concomitant decrease in number of cells in G1 phase. The present study indicated TNC in cellular matrix induces an activation of ERK1/2/NF kappaB/p65 signaling cascade and thereby mediates resistance to apoptosis in pancreatic cancer. TNC could serve as a diagnostic marker and predictor of gemcitabine response and potentially as a target for chemotherapy of pancreatic cancer. PMID- 25690320 TI - A highly sensitive DNA sensor for attomolar detection of the BRCA1 gene: signal amplification with gold nanoparticle clusters. AB - Single stranded DNA fragments were conjugated onto gold nanoparticles leading to the formation of gold nanoparticle clusters upon hybridization with complementary strands. These clusters were successfully implemented for signal amplification in an electrochemical DNA sensor based on a graphene substrate. The sensor exhibited excellent sensitivity and selectivity with a detection limit of 50 attomolar target DNA. PMID- 25690321 TI - Sexual dimorphism in auricular surface projection and postauricular sulcus morphology. AB - The presence of an elevated auricular surface and a postauricular sulcus is presented in numerous reference books as osteological indicators of sex, but the validity of these traits has not been adequately evaluated. The ilia of 322 (181 male, 141 female) adults were examined, the auricular surface was scored as completely, partially, or nonelevated, and the postauricular sulcus was scored as present or absent. Complete elevation occurred almost exclusively in females (67% of females and 0.6% of males). The postauricular sulcus was present in 27% of males and 85% of females. When present, an elevated auricular surface is a reliable indicator that the individual is female. However, the absence of the trait is a less reliable indicator of sex. The postauricular sulcus is a moderately accurate estimator of sex. PMID- 25690322 TI - Induced pluripotent stem cells model personalized variations in liver disease resulting from alpha1-antitrypsin deficiency. AB - In the classical form of alpha1-antitrypsin deficiency (ATD), aberrant intracellular accumulation of misfolded mutant alpha1-antitrypsin Z (ATZ) in hepatocytes causes hepatic damage by a gain-of-function, "proteotoxic" mechanism. Whereas some ATD patients develop severe liver disease (SLD) that necessitates liver transplantation, others with the same genetic defect completely escape this clinical phenotype. We investigated whether induced pluripotent stem cells (iPSCs) from ATD individuals with or without SLD could model these personalized variations in hepatic disease phenotypes. Patient-specific iPSCs were generated from ATD patients and a control and differentiated into hepatocyte-like cells (iHeps) having many characteristics of hepatocytes. Pulse-chase and endoglycosidase H analysis demonstrate that the iHeps recapitulate the abnormal accumulation and processing of the ATZ molecule, compared to the wild-type AT molecule. Measurements of the fate of intracellular ATZ show a marked delay in the rate of ATZ degradation in iHeps from SLD patients, compared to those from no liver disease patients. Transmission electron microscopy showed dilated rough endoplasmic reticulum in iHeps from all individuals with ATD, not in controls, but globular inclusions that are partially covered with ribosomes were observed only in iHeps from individuals with SLD. CONCLUSION: iHeps model the individual disease phenotypes of ATD patients with more rapid degradation of misfolded ATZ and lack of globular inclusions in cells from patients who have escaped liver disease. The results support the concept that "proteostasis" mechanisms, such as intracellular degradation pathways, play a role in observed variations in clinical phenotype and show that iPSCs can potentially be used to facilitate predictions of disease susceptibility for more precise and timely application of therapeutic strategies. PMID- 25690323 TI - The addition of entropy-based regularity parameters improves sleep stage classification based on heart rate variability. AB - The work considers automatic sleep stage classification, based on heart rate variability (HRV) analysis, with a focus on the distinction of wakefulness (WAKE) from sleep and rapid eye movement (REM) from non-REM (NREM) sleep. A set of 20 automatically annotated one-night polysomnographic recordings was considered, and artificial neural networks were selected for classification. For each inter heartbeat (RR) series, beside features previously presented in literature, we introduced a set of four parameters related to signal regularity. RR series of three different lengths were considered (corresponding to 2, 6, and 10 successive epochs, 30 s each, in the same sleep stage). Two sets of only four features captured 99 % of the data variance in each classification problem, and both of them contained one of the new regularity features proposed. The accuracy of classification for REM versus NREM (68.4 %, 2 epochs; 83.8 %, 10 epochs) was higher than when distinguishing WAKE versus SLEEP (67.6 %, 2 epochs; 71.3 %, 10 epochs). Also, the reliability parameter (Cohens's Kappa) was higher (0.68 and 0.45, respectively). Sleep staging classification based on HRV was still less precise than other staging methods, employing a larger variety of signals collected during polysomnographic studies. However, cheap and unobtrusive HRV only sleep classification proved sufficiently precise for a wide range of applications. PMID- 25690324 TI - Looking good or doing good? Motivations for organisational citizenship behaviour in Turkish versus South Korean collectivists. AB - The purpose of this article is to explore potential motivations to perform organisational citizenship behaviour (OCB) in collectivistic Turkish and South Korean societies. Although collectivism has been proposed as a predictor of OCB, previous research has not fully explored the possibility that collectivistic individuals' OCB may result from their self-oriented motives (i.e. social desirability concerns) or their future-oriented motives (i.e. long-term orientation concerns). We predicted that OCB stems from social desirability concerns among Turkish collectivists, meaning it is used for maintaining a positive image within the organisation. However, for South Korean collectivists, we predicted that OCB stems from their long-term orientation concerns, meaning it is used to make the organisation better. The results were in line with our predictions, and the findings are discussed in terms of their implications for firms in collectivistic societies. PMID- 25690325 TI - Historical perspective on Chlamydomonas as a model for basic research: 1950-1970. AB - During the period 1950-1970, groundbreaking research on the genetic mapping of Chlamydomonas reinhardtii and the use of mutant strains to analyze photosynthesis was conducted in the laboratory of R. Paul Levine at Harvard University. An account of this era, based in part on interviews with Levine, is presented. PMID- 25690326 TI - Visual imagery and functional connectivity in blindness: a single-case study. AB - We present a case report on visual brain plasticity after total blindness acquired in adulthood. SH lost her sight when she was 27. Despite having been totally blind for 43 years, she reported to strongly rely on her vivid visual imagery. Three-Tesla magnetic resonance imaging (MRI) of SH and age-matched controls was performed. The MRI sequence included anatomical MRI, resting-state functional MRI, and task-related functional MRI where SH was instructed to imagine colours, faces, and motion. Compared to controls, voxel-based analysis revealed white matter loss along SH's visual pathway as well as grey matter atrophy in the calcarine sulci. Yet we demonstrated activation in visual areas, including V1, using functional MRI. Of the four identified visual resting-state networks, none showed alterations in spatial extent; hence, SH's preserved visual imagery seems to be mediated by intrinsic brain networks of normal extent. Time courses of two of these networks showed increased correlation with that of the inferior posterior default mode network, which may reflect adaptive changes supporting SH's strong internal visual representations. Overall, our findings demonstrate that conscious visual experience is possible even after years of absence of extrinsic input. PMID- 25690327 TI - A three-dimensional digital atlas of the starling brain. AB - Because of their sophisticated vocal behaviour, their social nature, their high plasticity and their robustness, starlings have become an important model species that is widely used in studies of neuroethology of song production and perception. Since magnetic resonance imaging (MRI) represents an increasingly relevant tool for comparative neuroscience, a 3D MRI-based atlas of the starling brain becomes essential. Using multiple imaging protocols we delineated several sensory systems as well as the song control system. This starling brain atlas can easily be used to determine the stereotactic location of identified neural structures at any angle of the head. Additionally, the atlas is useful to find the optimal angle of sectioning for slice experiments, stereotactic injections and electrophysiological recordings. The starling brain atlas is freely available for the scientific community. PMID- 25690328 TI - Potential protective effects of extra virgin olive oil on the hepatotoxicity induced by co-exposure of adult rats to acrylamide and aluminum. AB - Extra virgin olive oil has been shown to be effective against oxidative stress associated diseases. In addition to the high quantities of oleic acid, it is rich in phenolic compounds. We investigated the protective efficacy of extra virgin olive oil (EVOO) against the hepatotoxicity induced by both aluminum and acrylamide. Animals were divided into four groups containing six rats each: group 1, serving as controls, received distilled water; group 2 received drinking water containing aluminum chloride (50 mg kg(-1) body weight) and acrylamide (20 mg kg( 1) body weight) by gavage; group 3 received both aluminum and acrylamide in the same ways as well as EVOO (300 MUl) by gavage; group 4 received only EVOO by gavage for 3 weeks. The rats exposed to both aluminum and acrylamide exhibited oxidative stress observed by an increase in MDA, AOPP and a decrease in GSH, NPSH and vitamin C levels. The activities of CAT and GPx were decreased, while SOD activity was increased. The liver metallothioneins, such as MT1 and MT2 genes expression, were also increased. EVOO supplementation improved all the parameters mentioned above. The plasma transaminases (AST and ALT), LDH activities, glucose and albumin levels, TC, LDL-C levels, TC/HDL-C and LDL-C/HDL-C ratios were increased, while high density lipoprotein-cholesterol (HDL-C) and TG decreased. The co-administration of EVOO to acrylamide and aluminum treated rats restored their hepatic markers to near-normal values. Liver histological studies confirmed the biochemical parameters and the beneficial role of EVOO. These results suggest that extra virgin olive oil, when added to the diet, may have a beneficial role in decreasing the liver damage induced by both aluminum and acrylamide. PMID- 25690329 TI - Tetrachloroethene recovery and hazard reduction of spent powders from dry cleaning process. AB - Dry cleaning facilities using perchloroethylene produce a solid waste consisting of spent filtering powders with a high content of residual perchloroethylene, together with dyes and non-volatile residues. Untreated spent powders, classified as hazardous waste, cannot be disposed in landfill and incineration represents the only viable alternative. In this study, together with a full characterisation of the waste, the removal and recovery of the residual perchloroethylene by means of different heat treatments was investigated. In particular, tests of distillation and stripping with air and steam were carried out, evaluating the effectiveness of the treatments by quantifying the residual perchloroethylene in the samples treated. The results obtained show that the spent filtering powders contained about 25% wt. of perchloroethylene and that the maximum perchloroethylene recovery was obtained by steam stripping; approximately 98% after only 50 minutes. However, this treatment accounted for the production of a liquid mixture containing perchloroethylene and of a solid waste that required a further washing with boiling water to decrease the residual organic content below the eligibility criteria for landfill disposal. PMID- 25690330 TI - Distal modulation of bacterial cell-cell signalling in a synthetic ecosystem using partitioned microfluidics. AB - The human gut is over a meter in length, liquid residence times span several hours. Recapitulating the human gut microbiome "on chip" holds promise to revolutionize therapeutic strategies for a variety of diseases, as well as for maintaining homeostasis in healthy individuals. A more refined understanding of bacterial-bacterial and bacterial-epithelial cell signalling is envisioned and such a device is a key enabler. Indeed, significant advances in the study of bacterial cell-cell signalling have been reported, including at length and time scales of the cells and their responses. Few reports exist, however, where signalling events that span physiologically relevant time scales are monitored and coordinated. Here, we employ principles of biofabrication to assemble, in situ, cell communities that are (i) spatially adjacent within partitioned microchannels for studying near communication and (ii) distally connected within longitudinal microfluidic networks so as to mimic long distance signalling among intestinal flora. We observed native signalling processes of the bacterial quorum sensing autoinducer-2 (AI-2) system among and between these communities. Cells in an upstream device successfully self-reported their activities and also secreted autoinducers that were carried downstream to the assembled networks of bacteria that reported on their presence. Furthermore, active signal modulation of among distal populations was demonstrated in a "programmed" manner where "enhancer" and "reducer" communities were assembled adjacent to the test population or "reporter" cells. The modulator cells either amplified or attenuated the cell cell signalling between the distal, already communicating cell populations. Modulation was quantified with a bioassay, and the reaction rates of signal production and consumption were further characterized using a first principles mathematical model. Simulated distribution profiles of signalling molecules in the cell-gel composites agreed well with the observed cellular responses. We believe this simple platform and the ease by which it is assembled can be applied to other cell-cell interaction studies among various species or kingdoms of cells within well-regulated microenvironments. PMID- 25690331 TI - Purple skin nodules - what lies beneath? PMID- 25690332 TI - Spatiotemporal expression of Prdm genes during Xenopus development. AB - Epigenetic regulation is known to be important in embryonic development, cell differentiation and regulation of cancer cells. Molecular mechanisms of epigenetic modification have DNA methylation and histone tail modification such as acetylation, phosphorylation and ubiquitination. Until now, many kinds of enzymes that modify histone tail with various functional groups have been reported and regulate the epigenetic state of genes. Among them, Prdm genes were identified as histone methyltransferase. Prdm genes are characterized by an N terminal PR/SET domain and C-terminal some zinc finger domains and therefore they are considered to have both DNA-binding ability and methylation activity. Among vertebrate, fifteen members are estimated to belong to Prdm genes family. Even though Prdm genes are thought to play important roles for cell fate determination and cell differentiation, there is an incomplete understanding of their expression and functions in early development. Here, we report that Prdm genes exhibit dynamic expression pattern in Xenopus embryogenesis. By whole mount in situ hybridization analysis, we show that Prdm genes are expressed in spatially localized manners in embryo and all of Prdm genes are expressed in neural cells in developing central nervous systems. Our study suggests that Prdm genes may be new candidates to function in neural cell differentiation. PMID- 25690333 TI - In vitro genotoxicity assessment of the synthetic plant growth regulator, 1 naphthaleneacetamide. AB - 1-Naphthaleneacetamide (NAAm) is a synthetic plant growth regulator in the auxin family that is widely used in agriculture to promote the growth of numerous fruits, for root cuttings and as a fruit thinning agent. The potential genotoxic effects of NAAm were investigated in vitro by the chromosome aberrations (CAs), and cytokinesis-block micronucleus assays in human peripheral blood lymphocytes (PBLs) for the first time. The human PBLs were treated with 20, 40, 80, and 160 ug/mL of NAAm for 24 and 48 h. The results of this study showed that NAAm significantly induced the formation of structural CA and MN for all concentrations (20, 40, 80 and 160 ug/mL) and treatment periods (24 and 48 h) when compared with the negative and the solvent control. In addition, the higher concentrations of NAAm (80 and 160 ug/mL) caused a statistically significant increase in nuclear bud (NBUD) formation for both 24 and 48 h treatment times. With regard to the cell cycle kinetics, at all the tested concentrations, NAAm caused a statistically significant reduction in the mitotic index (MI) only for 48 h treatment period and also in the nuclear division index (NDI) for both 24 and 48 h treatment periods as compared to the control groups. The reductions in the MI and NDI occured in a concentration-dependent manner for both treatment times. In conclusion, the present results indicate that in the tested experimental conditions, NAAm was genotoxic and cytotoxic on human PBLs in vitro. PMID- 25690334 TI - Fluorescence decay of dyed protozoa: differences between stressed and non stressed cysts. AB - Several series of tests have shown that fresh, intact samples of Giardia duodenalis and Cryptosporidium parvum (oo)cysts are not marked by fluorescent probes such as carboxyfluorcein-succinimidyl-diacetate-ester (CFDA-SE), C12 resazurin and SYTOX(r) Green, probably because of their robust cell walls. These dyes fail to indicate the viability of such protozoa and allow negative responses to be recorded from living and infectious samples. Cryptosporidium parvum showed stronger isolation from chemicals, with living oocysts remaining unstained by the probe for up to 90 days after extraction. However, in further fluorescence decay (FD) experiments run with G. duodenalis samples stained using CFDA-SE (comprising living, non-stressed but aged cysts, heat-killed samples and UV-C-stressed samples) each showed a different FD decay profile, here studied in seven series of tests of five replicates each. The FD profiles were fitted by double exponential decay kinetics, with the decay constant k2 being five times higher than k1. This FD procedure is fast and can be easily reproduced in 10 steps, taking ~ 1 h of laboratory work for already purified samples. PMID- 25690335 TI - New contributions to the development of a plastination technique at room temperature with silicone. AB - The aim of this work is to present a room-temperature plastination technique developed in our laboratories and its results. This technique emphasizes the use of silicones, catalysts, and generic hardeners, and some variations of the traditional technique resulted in low cost and high-speed implementation. Two hands, a heart, and a brain were dissected from Caucasian adult undefined-gender cadavers previously kept in 5 % formalin solution. Also dissected was a pig heart kept in 5 % formalin solution. Dehydration was performed for 1 month at room temperature to favor defatting. Afterwards, forced impregnation took place. The average process for each specimen lasted 3 or 4 days, 8 h a day (active forced impregnation), halting the forced impregnation overnight (passive forced impregnation). Once 5 mmHg had been reached without bubbling and the vacuum process had ended, specimens were drained and positioned. Finally, curing was performed by subjecting the specimens to cross-linker. The different morphological characteristics of the specimens determined variations in the forced impregnation time, as well as curing. Once polymerization was complete, specimens were stored in plastic bags, facilitating internal curing. Three kinds of silicones were used: Biodur, North Carolina, and a local generic. The catalyst and the hardener were generic products also acquired locally. Based on our technique, we obtained completely dry and rigid specimens, of excellent quality and durability, which kept their original color and anatomical shape. PMID- 25690336 TI - Multicentre comparison Of shock efficacy using single-vs. Dual-coil lead systems and Anodal vs. cathodaL polarITY defibrillation in patients undergoing transvenous cardioverter-defibrillator implantation. The MODALITY study. AB - PURPOSE: An optimal active-can lead configuration during implantable cardioverter defibrillator (ICD) placement is important to obtain an adequate defibrillation safety margin. The purpose of this multicenter study was to evaluate the rate of the first shock success at defibrillation testing according to the type of lead implant (single vs. dual coil) and shock polarity (cathodal and anodal) in a large series of consecutive patients who received transvenous ICDs. METHODS: This was a multicenter study enrolling 469 consecutive patients. Single- versus dual coil leads and cathodal versus anodal polarity were evaluated at defibrillation testing. In all cases, the value of the energy for the first shock was set to 20 J less than the maximum energy deliverable from the device. RESULTS: A total of 469 patients underwent defibrillation testing: 158 (34 %) had dual-coil and 311 (66 %) had single-coil lead systems configuration, 254 (54 %) received anodal shock and 215 (46 %) received cathodal shock. In 35 (7.4 %) patients, the shock was unsuccessful. No significant differences in the outcome of defibrillation testing using single- versus dual-coil lead were observed but the multivariate analysis showed an increased risk of shock failure using cathodal shock polarity (OR 2.37, 95 % CI 1.12-5.03). CONCLUSIONS: Both single- and dual-coil transvenous ICD lead systems were associated with high rates of successful ICD implantation, and we found no significant differences in ventricular arrhythmias interruption between the two ICD lead systems configuration. Instead, anodal defibrillation was more likely to be successful than cathodal defibrillation. PMID- 25690337 TI - The demographics of developmental hip dysplasia in the Midwestern United States (Indiana). AB - BACKGROUND: Today's society is much more mobile than in the past. This increased mobility has resulted in different marriage/parenting groups. We wished to study the demographics of developmental dysplasia of the hip (DDH) in our area and compare/contrast our findings with those in the literature and specifically look for new findings compared to previous studies. METHODS: A retrospective review of all children with DDH from 2003 through 2012 was performed. The age at first visit, gestational age, pregnancy number, gender, race, and family history of DDH was collected. Statistical significance was a p-value < 0.05. RESULTS: There were 424 children (363 girls, 61 boys). Ethnicity was White in 80.8 %, Hispanic in 13.8 %, Black in 4.0 %, and Indo-Malay and Indo-Mediterranean in 0.7 % each; 66.8 % were unilateral; 14.2 % had a positive family history. The average gestational age was 38.1 weeks; 94.4 % were full term. The child was vertex presentation in 67.6 % and breech in 32.4 %; 52.8 % were delivered vaginally and 47.2 % by Cesarean section. The child was the first-born in 48.3 %. When compared to the birth statistics of our state, there was a higher proportion of Whites and Hispanics with DDH, and a lower, but not inconsequential, proportion of Blacks (p = 0.0018). CONCLUSION: Mixing of gene pools and infant carrying methods (lack of swaddling or marked abduction) occurring with societal change likely explains the higher than expected proportion of DDH amongst those of Hispanic ethnicity and a lower than expected, but not rare, proportion in those of African ancestry. LEVEL OF EVIDENCE: Level IV-retrospective case series. PMID- 25690338 TI - Re-evaluating the relationships among filtering activity, unnecessary storage, and visual working memory capacity. AB - The amount of task-irrelevant information encoded in visual working memory (VWM), referred to as unnecessary storage, has been proposed as a potential mechanism underlying individual differences in VWM capacity. In addition, a number of studies have provided evidence for additional activity that initiates the filtering process originating in the frontal cortex and basal ganglia, and is therefore a crucial step in the link between unnecessary storage and VWM capacity. Here, we re-examine data from two prominent studies that identified unnecessary storage activity as a predictor of VWM capacity by directly testing the implied path model linking filtering-related activity, unnecessary storage, and VWM capacity. Across both studies, we found that unnecessary storage was not a significant predictor of individual differences in VWM capacity once activity associated with filtering was accounted for; instead, activity associated with filtering better explained variation in VWM capacity. These findings suggest that unnecessary storage is not a limiting factor in VWM performance, whereas neural activity associated with filtering may play a more central role in determining VWM performance that goes beyond preventing unnecessary storage. PMID- 25690339 TI - Predictive ability of heel quantitative ultrasound for incident fractures: an individual-level meta-analysis. AB - The relationship between bone quantitative ultrasound (QUS) and fracture risk was estimated in an individual level data meta-analysis of 9 prospective studies of 46,124 individuals and 3018 incident fractures. Low QUS is associated with an increase in fracture risk, including hip fracture. The association with osteoporotic fracture decreases with time. INTRODUCTION: The aim of this meta analysis was to investigate the association between parameters of QUS and risk of fracture. METHODS: In an individual-level analysis, we studied participants in nine prospective cohorts from Asia, Europe and North America. Heel broadband ultrasonic attenuation (BUA dB/MHz) and speed of sound (SOS m/s) were measured at baseline. Fractures during follow-up were collected by self-report and in some cohorts confirmed by radiography. An extension of Poisson regression was used to examine the gradient of risk (GR, hazard ratio per 1 SD decrease) between QUS and fracture risk adjusted for age and time since baseline in each cohort. Interactions between QUS and age and time since baseline were explored. RESULTS: Baseline measurements were available in 46,124 men and women, mean age 70 years (range 20-100). Three thousand and eighteen osteoporotic fractures (787 hip fractures) occurred during follow-up of 214,000 person-years. The summary GR for osteoporotic fracture was similar for both BUA (1.45, 95 % confidence intervals (CI) 1.40-1.51) and SOS (1.42, 95 % CI 1.36-1.47). For hip fracture, the respective GRs were 1.69 (95 % CI, 1.56-1.82) and 1.60 (95 % CI, 1.48-1.72). However, the GR was significantly higher for both fracture outcomes at lower baseline BUA and SOS (p < 0.001). The predictive value of QUS was the same for men and women and for all ages (p > 0.20), but the predictive value of both BUA and SOS for osteoporotic fracture decreased with time (p = 0.018 and p = 0.010, respectively). For example, the GR of BUA for osteoporotic fracture, adjusted for age, was 1.51 (95 % CI 1.42-1.61) at 1 year after baseline, but at 5 years, it was 1.36 (95 % CI 1.27-1.46). CONCLUSIONS: Our results confirm that quantitative ultrasound is an independent predictor of fracture for men and women particularly at low QUS values. PMID- 25690340 TI - Human monoclonal antibody fragments targeting matrilin-3 in growth plate cartilage. AB - PURPOSE: Many genetic disorders, including chondrodysplasias, and acquired disorders impair growth plate function, resulting in short and sometimes malformed bones. There are multiple endocrine and paracrine factors that promote chondrogenesis at the growth plate, which could potentially be used to treat these disorders. Targeting these growth factors specifically to the growth plate might augment the therapeutic skeletal effect while diminishing undesirable effects on non-target tissues. METHODS: Using yeast display technology, we selected single-chain variable antibody fragments that bound to human and mouse matrilin-3, an extracellular matrix protein specifically expressed in cartilage tissue. The ability of the selected antibody fragments to bind matrilin-3 and to bind cartilage tissue in vitro and in vivo was assessed by ELISA and immunohistochemistry. RESULTS: We identified antibody fragments that bound matrilin-3 with high affinity and also bound with high tissue specificity to cartilage homogenates and to cartilage structures in mouse embryo sections. When injected intravenously in mice, the antibody fragments specifically homed to cartilage. CONCLUSIONS: Yeast display successfully selected antibody fragments that are able to target cartilage tissue in vivo. Coupling these antibodies to chondrogenic endocrine and paracrine signaling molecules has the potential to open up new pharmacological approaches to treat childhood skeletal growth disorders. PMID- 25690341 TI - pH Dependent but not P-gp Dependent Bidirectional Transport Study of S propranolol: The Importance of Passive Diffusion. AB - PURPOSE: Recent controversial publications, citing studies purporting to show that P-gp mediates the transport of propranolol, proposed that passive biological membrane transport is negligible. Based on the BDDCS, the extensively metabolized highly permeable-highly soluble BDDCS class 1 drug, propranolol, shows a high passive permeability at concentrations unrestricted by solubility that can overwhelm any potential transporter effects. Here we reinvestigate the effects of passive diffusion and carrier-mediated transport on S-propranolol. METHODS: Bidirectional permeability and inhibition of efflux transport studies were carried out in MDCK, MDCK-MDR1 and Caco-2 cell lines at different concentrations. Transcellular permeability studies were conducted at different apical pHs in the rat jejunum Ussing chamber model and PAMPA system. RESULTS: S-propranolol exhibited efflux ratios lower than 1 in MDCK, MDCK-MDR1 and Caco-2 cells. No significant differences of Papp, B->A in the presence and absence of the efflux inhibitor GG918 were observed. However, an efflux ratio of 3.63 was found at apical pH 6.5 with significant decrease in Papp, A->B and increase in Papp, B->A compared to apical pH 7.4 in Caco-2 cell lines. The pH dependent permeability was confirmed in the Ussing chamber model. S-propranolol flux was unchanged during inhibition by verapamil and rifampin. Furthermore, pH dependent permeability was also observed in the PAMPA system. CONCLUSIONS: S-propranolol does not exhibit active transport as proposed previously. The "false" positive efflux ratio can be explained by the pH partition theory. As expected, passive diffusion, but not active transport, plays the primary role in the permeability of the BDDCS class 1 drug propranolol. PMID- 25690342 TI - Prediction of Drug Transfer into Milk Considering Breast Cancer Resistance Protein (BCRP)-Mediated Transport. AB - PURPOSE: Drug transfer into milk is of concern due to the unnecessary exposure of infants to drugs. Proposed prediction methods for such transfer assume only passive drug diffusion across the mammary epithelium. This study reorganized data from the literature to assess the contribution of carrier-mediated transport to drug transfer into milk, and to improve the predictability thereof. METHODS: Milk to-plasma drug concentration ratios (M/Ps) in humans were exhaustively collected from the literature and converted into observed unbound concentration ratios (M/Punbound,obs). The ratios were also predicted based on passive diffusion across the mammary epithelium (M/Punbound,pred). An in vitro transport assay was performed for selected drugs in breast cancer resistance protein (BCRP) expressing cell monolayers. RESULTS: M/Punbound,obs and M/Punbound,pred values were compared for 166 drugs. M/Punbound,obs values were 1.5 times or more higher than M/Punbound,pred values for as many as 13 out of 16 known BCRP substrates, reconfirming BCRP as the predominant transporter contributing to secretory transfer of drugs into milk. Predictability of M/P values for selected BCRP substrates and non-substrates was improved by considering in vitro-evaluated BCRP mediated transport relative to passive diffusion alone. CONCLUSIONS: The current analysis improved the predictability of drug transfer into milk, particularly for BCRP substrates, based on an exhaustive data overhaul followed by focused in vitro transport experimentation. PMID- 25690343 TI - Microneedle-Mediated Delivery of Copper Peptide Through Skin. AB - PURPOSE: Copper peptide (GHK-Cu) plays an important role in skin regeneration and wound healing. However, its skin absorption remains challenging due to its hydrophilicity. Here we use polymeric microneedle array to pre-treat skin to enhance GHK-Cu skin penetration. METHODS: Two in vitro skin models were used to assess the capability of microneedles in facilitating skin delivery of GHK-Cu. Histological assay and confocal laser scanning microscopy were performed to characterize and quantify the microconduits created by the microneedles inside skin. Cellular and porcine models were used to evaluate the safety of microneedle assisted copper peptide delivery. RESULTS: The depth and percentage of microneedle penetration were correlated with application forces, which in turn influenced the extent of enhancement in the skin permeability of GHK-Cu. In 9 h, 134 +/- 12 nanomoles of peptide and 705 +/- 84 nanomoles of copper permeated though the microneedle treated human skin, while almost no peptide or copper permeated through intact human skin. No obvious signs of skin irritation were observed with the use of GHK-Cu after microneedle pretreatment. CONCLUSIONS: It is effective and safe to enhance the skin permeation of GHK-Cu by using microneedles. This approach may be useful to deliver similar peptides or minerals through skin. PMID- 25690345 TI - The role of perceived barriers and objectively measured physical activity in adults aged 65-100. AB - OBJECTIVE: to test the predictive utility of perceived barriers to objectively measured physical activity levels in a stratified sample of older adults when accounting for social-cognitive determinants proposed by the Theory of Planned Behaviour (TPB), and economic and demographic factors. METHODS: data were analysed from the Physical Activity Cohort Scotland survey, a representative and stratified (65-80 and 80+ years; deprived and affluent) sample of 584 community dwelling older people, resident in Tayside, Scotland. Physical activity was measured objectively by accelerometry. RESULTS: perceived barriers clustered around the areas of poor health, lack of interest, lack of safety and lack of access. Perceived poor health and lack of interest, but not lack of access or concerns about personal safety, predicted physical activity after controlling for demographic, economic and TPB variables. DISCUSSION: perceived person-related barriers (poor health and lack of interest) seem to be more strongly associated with physical activity levels than perceived environmental barriers (safety and access) in a large sample of older adults. Perceived barriers are modifiable and may be a target for future interventions. PMID- 25690346 TI - Relationship Between Amino Acid and Energy Intake and Long-Term Growth and Neurodevelopmental Outcomes in Very Low Birth Weight Infants. AB - BACKGROUND: Inadequate nutrition may contribute to adverse neurodevelopmental and growth outcomes in very low birth weight (VLBW) infants. MATERIALS AND METHODS: A retrospective cohort study was conducted of infants born weighing <1250 g between 2009 and 2010 in a tertiary neonatal intensive care unit. The aim was to investigate whether there was a correlation between the amount of amino acid and calories received in the first 4 weeks of life and neurodevelopment and growth at 2 years. RESULTS: Parenteral amino acid intake in week 2 of life correlated with higher language and motor scores on the 2-year Bayley Scales of Infant and Toddler Development Third Edition (Bayley III). Conversely, higher total amino acid intake during week 1 of life (>=1.5 g/kg/d) was associated with a shorter duration of hospitalization, shorter intensive care stay, fewer days receiving mechanical ventilation, fewer days receiving supplemental oxygen, and a lower incidence of chronic lung disease (CLD). Higher caloric intake in the first 4 weeks correlated strongly with shorter duration of hospitalization, shorter intensive care stay, fewer days on the ventilator, and fewer days receiving supplemental oxygen. In patients with CLD, week 1 and 2 parenteral and total amino acid intake correlated with higher cognitive and motor scores on the Bayley III at 2 years old. Weeks 1-4 amino acid and calorie intake correlated with fewer days on the ventilator, fewer days of supplemental oxygen, and fewer days of hospitalization. CONCLUSION: Amino acid intake within the first weeks of life correlated positively with neurodevelopmental outcomes at 2 years, and patients with CLD were found to be particularly at risk. Caloric intake may affect protein accretion. PMID- 25690347 TI - Surgical management of anal cancer. AB - Squamous cell carcinoma (SCC) is the most common malignancy of the anal canal and anal region. The prevalence of transformation to SCC is much higher in patients with a concomitant human immundefficiency virus (HIV) infection. Historically, treatment of anal SCC consisted of surgical resection with wide local excision for small sized tumors and abdominoperineal resection (APR) for larger and locally invasive cancer. The introduction of chemoradiation by Nigro et al. revolutionized the treatment of SCC. It has improved local recurrence rates as well as survival and need for colostomy. Nowadays, primary surgical treatment is indicated for anal margin tumors that are smaller than 2 cm, and are not poorly differentiated. However, extensive surgery is reserved for those with persistent, progressing and recurrent disease after treatment with the Nigro protocol. Surgical approach for anal canal and margin cancer is to be discussed in this review. PMID- 25690348 TI - Sarcopenia and sarcopenic leg as potential risk factors for acute osteoporotic vertebral fracture among older women. AB - PURPOSE: Sarcopenia-related falls and fractures among women with osteoporosis are becoming an emerging problem because of rapid aging worldwide. We aimed to investigate the association between sarcopenia, given by the muscle mass of the arms and legs, and osteoporotic vertebral fracture (OVF) among female patients. METHODS: This cross-sectional study examined 216 women with fresh OVF (OVF group) diagnosed by magnetic resonance imaging and 1,608 women from an outpatient clinic who did not have a OVF [non-fracture (NF) group]. We performed whole-body dual energy X-ray absorptiometry to analyze body composition, including skeletal muscle mass index (SMI; lean mass/height2) and bone mineral density (BMD). We used stepwise logistic regression analysis to determine the risk factors associated with OVF. RESULTS: After controlling for age, the OVF group showed lower appendicular SMI (5.62 vs. 5.97 kg/m2, P < 0.001), lower arm SMI (1.36 vs. 1.42 kg/m2, P = 0.004), lower leg SMI (4.27 vs. 4.55 kg/m2, P < 0.001), and higher prevalence of sarcopenia (42.3 vs. 25.9 %, P < 0.001), compared with the NF group. Reduced leg muscle mass and presence of sarcopenia were independent risk factors for acute OVF in multivariate analysis (odds ratio = 1.4, P = 0.002; odds ratio = 1.96, P < 0.001, respectively). CONCLUSIONS: We found higher prevalence of sarcopenia and lower leg muscle mass among patients with acute OVF compared with patients who did not have an OVF. These results suggest that sarcopenia may be a risk factor for OVF. PMID- 25690349 TI - The Importance of Understanding Military Culture. PMID- 25690350 TI - Simulation of X-ray absorption spectra with orthogonality constrained density functional theory. AB - Orthogonality constrained density functional theory (OCDFT) [F. A. Evangelista, P. Shushkov and J. C. Tully, J. Phys. Chem. A, 2013, 117, 7378] is a variational time-independent approach for the computation of electronic excited states. In this work we extend OCDFT to compute core-excited states and generalize the original formalism to determine multiple excited states. Benchmark computations on a set of 13 small molecules and 40 excited states show that unshifted OCDFT/B3LYP excitation energies have a mean absolute error of 1.0 eV. Contrary to time-dependent DFT, OCDFT excitation energies for first- and second-row elements are computed with near-uniform accuracy. OCDFT core excitation energies are insensitive to the choice of the functional and the amount of Hartree-Fock exchange. We show that OCDFT is a powerful tool for the assignment of X-ray absorption spectra of large molecules by simulating the gas-phase near-edge spectrum of adenine and thymine. PMID- 25690351 TI - Improvement of biomass production by Chlorella sp. MJ 11/11 for use as a feedstock for biodiesel. AB - Algal biomass is gaining importance for biofuel production as it is rich in lipids. It becomes more significant when biomass is produced by capturing atmospheric greenhouse gas, CO2. In the present study, the effect of different physicochemical parameters were studied on the biomass and lipid productivity in Chlorella sp. MJ 11/11. The different parameters viz. initial pH, nitrate concentration, and phosphate concentration were optimized using single-parameter studies. The interactions between the parameters were determined statistically using the Box-Behnken design of optimization. The optimal values were decided by analyzing them with response surface methodology. The optimum levels of the parameters (pH 6.5, nitrate concentration 0.375 g L(-1), and phosphate concentration 0.375 mL L(-1)) yielded a maximum biomass concentration of 1.26 g L(-1) at a constant light intensity of 100 MUmol m(-2) s(-1) and temperature of 30 degrees C. The effect of CO2 concentration on the biomass production was also investigated and was found to be a maximum of 4 g L(-1) at 5 % air-CO2 mixture (v/v). Maximum lipid content of 24.6 % (w/w) was observed at 2 % air-CO2 mixture (v/v). Fatty acid analyses of the obtained algal biomass suggested that they could be a suitable feedstock for biodiesel production. PMID- 25690352 TI - Manganese peroxidases from Ganoderma applanatum degrade beta-carotene under alkaline conditions. AB - A beta-carotene-degrading enzyme activity was observed in liquid cultures of the basidiomycete Ganoderma applanatum. Supplementing the cultures with beta-carotene induced the bleaching activity. Purification via hydrophobic interaction, ion exchange and size exclusion chromatography followed by sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) resulted in a single protein band. LC-ion-trap-MS analyses and gene amplification identified two manganese peroxidase isoenzymes with 97.8 % identity on the amino acid level. These showed an estimated molecular mass of 48 kDa and an isoelectric point of 2.6. Properties not yet described for other manganese peroxidases were hydrogen-peroxide independent catalysis and two maxima of the bleaching activity, a distinct one at pH 5 and a lower one at pH 8. During simulated washing studies, the applicability of the isoenzymes for the brightening of carotenoids under alkaline conditions was proven. The new enzymes may replace common bleaching agents to produce environmentally more compatible detergent formulations. PMID- 25690353 TI - Engineering tobacco to remove mercury from polluted soil. AB - Tobacco is an ideal plant for modification to remove mercury from soil. Although several transgenic tobacco strains have been developed, they either release elemental mercury directly into the air or are only capable of accumulating small quantities of mercury. In this study, we constructed two transgenic tobacco lines: Ntk-7 (a tobacco plant transformed with merT-merP-merB1-merB2-ppk) and Ntp 36 (tobacco transformed with merT-merP-merB1-merB2-pcs1). The genes merT, merP, merB1, and merB2 were obtained from the well-known mercury-resistant bacterium Pseudomonas K-62. Ppk is a gene that encodes polyphosphate kinase, a key enzyme for synthesizing polyphosphate in Enterobacter aerogenes. Pcs1 is a tobacco gene that encodes phytochelatin synthase, which is the key enzyme for phytochelatin synthesis. The genes were linked with LP4/2A, a sequence that encodes a well known linker peptide. The results demonstrate that all foreign genes can be abundantly expressed. The mercury resistance of Ntk-7 and Ntp-36 was much higher than that of the wild type whether tested with organic mercury or with mercuric ions. The transformed plants can accumulate significantly more mercury than the wild type, and Ntp-36 can accumulate more mercury from soil than Ntk-7. In mercury-polluted soil, the mercury content in Ntp-36's root can reach up to 251 MUg/g. This is the first report to indicate that engineered tobacco can not only accumulate mercury from soil but also retain this mercury within the plant. Ntp 36 has good prospects for application in bioremediation for mercury pollution. PMID- 25690354 TI - Breast feeding and timing of introduction of gluten in infant foods are not predictors of coeliac disease at age 5. PMID- 25690355 TI - Cystodienoic acid: a new diterpene isolated from the myxobacterium Cystobacter sp. PMID- 25690356 TI - Structure and biosynthetic implication of 5R-(N-acetyl-L-cysteinyl)-14S-hydroxy dihydrokalafungin from a mutant of the actVA-ORF4 gene for actinorhodin biosynthesis in Streptomyces coelicolor A3(2). PMID- 25690357 TI - Identification of novel endophenaside antibiotics produced by Kitasatospora sp. MBT66. AB - Actinomycetes are a major source of bioactive secondary metabolites and are a focal point in the search for novel antimicrobial compounds that are needed to combat multidrug-resistant pathogens. Here, we report the discovery of several novel phenazine-type antibiotics produced by Kitasatospora sp. MBT66. These include the novel glycosylated endophenazines A-E (1-5), together with N prenylated endophenazine F1 (6). Compounds 1 and 3 contain a 2'-O-methylation of the sugar moiety, which is rare in nature and reported for the first time in connection with phenazines. The structures of the new compounds were determined on the basis of their spectral data, including 1D and 2D NMR, HR-MS and the gene cluster responsible for the biosynthesis of phenazines was identified. All phenazine derivatives showed antimicrobial activity against the Gram-positive Bacillus subtilis, while compounds 1-3 and 5 also inhibited growth of the Gram negative Escherichia coli. PMID- 25690358 TI - Dandamycin and chandrananimycin E, benzoxazines from Streptomyces griseus. AB - Two new benzoxazines were isolated from Streptomyces griseus (HKI 0545) and assigned as chandrananimycin E (1) and dandamycin (2). Although a number of phenoxazinone-type compounds have been reported from nature, phenoxazines are rarer, and carbon substitution at N-10 such as in 1 is unprecedented. The cyclopentene-containing ring structure of dandamycin (2) is also unique. Chandrananimycin E (1) was found to possess moderate antiproliferative activity against HUVEC cells (GI50 35.3 MUM) and weak cytotoxic activity towards HeLa cells (CC50 56.9 MUM). Dandamycin showed neither antiproliferative activity nor cytotoxicity towards these cell lines. Structure activity comparisons with phenoxazinones isolated from S. griseus HKI 0545 suggested that the alteration of the core ring systems in 1 and 2 diminishes their activity. Natural products 1 and 2 are interesting additions to the rich secondary metabolome of S. griseus and constitute an important addition to the body of knowledge on phenoxazinone derived metabolites. PMID- 25690359 TI - Two herbimycin analogs, 4,5-dihydro-(4S)-4-hydroxyherbimycin B and (15S)-15 hydroxyherbimycin B, from Streptomyces sp. CPCC 200291. PMID- 25690360 TI - Streptosporangium terrae sp. nov., a novel actinomycete isolated from the rhizosphere of Callistemon citrinus (Curtis), India. AB - A novel actinomycete strain, designated VRC21(T), was isolated from the rhizosphere of Callistemon citrinus collected from Hyderabad, India. The morphological and chemotaxonomic properties of strain VRC21(T) was consistent with the characteristics of members of the genus Streptosporangium, that is, the formation of sporangia on aerial mycelium, coiled unbranched hyphae within the spore vesicle, the presence of meso-diaminopimelic acid in the cell wall, and madurose and galactose as major whole-cell sugars. Diagnostic polar lipids were phosphatidylethanolamine, diphosphatidylglycerol, phosphatidylglycerol, phosphatidylinositol and phosphatidylinositol-mannosides. The predominant menaquinones were MK-9(H2) and MK-9(H4). The major cellular fatty acids were iso C14:0, iso-C16:0, C17:0 10-methyl, C18:1w9c and C18:0 10-methyl. 16S rRNA gene sequence analyses revealed that strain VRC21(T) was a member of the genus Streptosporangium. The highest similarity values were observed with S. carneum DSM 44125(T) (98.2%) and S. fragile DSM 43847(T) (98.2%); the values of the remaining type strains were below 98%. The values of DNA-DNA relatedness between the strain VRC21(T) and the type strains of the related species were below 70%. On the basis of the polyphasic evidence, the strain VRC21(T) should be classified as novel species Streptosporangium terrae sp. nov. in the genus Streptosporangium. The type strain is VRC21(T) (=KCTC 29207(T)=MTCC 11724(T)). PMID- 25690361 TI - Study of efflux pump gene expression in rifampicin-monoresistant Mycobacterium tuberculosis clinical isolates. AB - Rifampicin (RIF) resistance is a risk factor for poor outcome in tuberculosis (TB). In Mycobacterium tuberculosis, both target gene mutation and efflux pumps have major roles in the resistance to anti-TB drugs. This study aimed to determine whether RIF induces efflux pump activation in RIF-monoresistant M. tuberculosis strains. Here, we took advantage of 16 RIF-monoresistant M. tuberculosis clinical isolates to evaluate the expression of 27 putative drug efflux pump genes and measured the influence of four drug efflux pump inhibitors, carbonyl cyanide m-chlorophenyl hydrazone (CCCP), verapamil (VP), thioridazine (TZ) and chlorpromazine (CPZ), on the RIF MICs of these strains. Eight of the 16 RIF-monoresistant isolates carried mutations in rpoB and overexpressed one or two of the following putative efflux pump genes: Rv2333, drrB, drrC, Rv0842, bacA and efpA. CCCP, VP, TZ and CPZ lowered the RIF MICs greater than fourfold in 6, 12, 9 and 12 isolates, respectively. The lowered RIF MICs by VP and CPZ were identical and stronger than CCCP (P-values were all 0.033). In conclusion, the efflux pumps Rv2333, DrrB, DrrC, Rv0842, BacA and EfpA may have a role in RIF resistance in addition to classical mutations in the rpoB gene, and the addition of VP and CPZ could significantly increase RIF susceptibility in RIF-monoresistant M. tuberculosis. PMID- 25690362 TI - Antimalarial activity of kinase inhibitor, nilotinib, in vitro and in vivo. PMID- 25690363 TI - N-H?O versus O-H?O: density functional calculation and first principle molecular dynamics study on a quinoline-2-carboxamide N-oxide. AB - N-oxide-type compounds are the object of current research interest due to the presence of resonance-assisted N-H?O hydrogen bonds. Here, the metric and spectroscopic parameters of N-methyl-quinoline-2-carboxamide 1-oxide were computed on the basis of density functional theory and Car-Parrinello molecular dynamics. Computations were performed in vacuo and in solid state; for both phases additional simulations with Grimme's dispersion correction were carried out. The approaches used were able to reproduce correctly the structural aspects of the studied compound and shed more light on the hydrogen bonding with special focus on bridge proton mobility. Proton transfer phenomena were found not to occur in the investigated compound, and the bridge proton was localized to the donor site. This observation is in agreement with the classical theory of the acidity of donor-acceptor sites. The presence of hydrogen bonding was confirmed using atoms-in-molecules theory. The computational results were compared with available experimental data. PMID- 25690364 TI - A density functional theory study of hydrocarbon combustion and synthesis on Ni surfaces. AB - Combustion and synthesis of hydrocarbons may occur directly (CH -> C + H and CO > C + O) or via a formyl (CHO) intermediate. Density functional theory (DFT) calculations were performed to calculate the activation and reaction energies of these reactions on Ni(111), Ni(110), and Ni(100) surfaces. The results show that the energies are sensitive to the surface structure. The dissociation barrier for methylidyne (CH -> C + H: catalytic hydrocarbon combustion) is lower than that for its oxidation reaction (CH + O -> CHO) on the Ni(110) and Ni(100) surfaces. However the oxidation barrier is lower than that for dissociation on the Ni(111) surface. The dissociation barrier for methylidyne dissociation decreases in the order Ni(111) > Ni(100) > Ni(110). The barrier of formyl dissociation to CO and H is almost the same on the Ni(111) and Ni(110) surfaces and is lower compared to the Ni(100) surface. The energy barrier for carbon monoxide dissociation (CO -> C + O: catalytic hydrocarbon synthesis) is higher than that of for its hydrogenation reaction (CO + H -> CHO) on all three surfaces. This means that the hydrogenation to CHO is favored on these nickel surfaces. The energy barrier for both reactions decreases in the order Ni(111) > Ni(100) > Ni(110). The barrier for formyl dissociation to CH + O decreases in the order Ni(100) > Ni(111) > Ni(110). Based on these DFT calculations, the Ni(110) surface shows a better catalytic activity for hydrocarbon combustion compared to the other surfaces, and Ni is a better catalyst for the combustion reaction than for hydrocarbon synthesis, where the reaction rate constants are small. The reactions studied here support the BEP principles with R(2) values equal to 0.85 for C-H bond breaking/forming and 0.72 for C-O bond breaking /forming reactions. PMID- 25690365 TI - Electronic and optical properties of N-doped Bi2O3 polymorphs for visible light induced photocatalysis. AB - The effect of N doping on the crystal structure, electronic, and optical properties of alpha-Bi2O3 and beta-Bi2O3 has been studied in detail based with first principle calculations. The crystallographic features of Bi2O3 polymorphs are not substantially changed through N doping, whereas charge transfer from Bi to N results in large variations of charge density distribution. N-doped beta Bi2O3 exhibits improved thermal stability due to stronger Bi-N covalent bonds and lower defect formation energy, and the convenient preparative access agrees well with experimental observations. Calculated band structures and optical properties indicate that N doping does not induce major band gap narrowing, but leads to the presence of isolated bands above the VBM induced by N 2p for both alpha-Bi2O3 and beta-Bi2O3 which induce large red-shifts of their visible light absoprtion properties. These isolated bands act as acceptor levels and facilitate electron transition under visible light illumination through introduction of steps between VB and CB, thereby rendering the materials quite promising for photocatalytic applications. PMID- 25690366 TI - Binding properties of SUMO-interacting motifs (SIMs) in yeast. AB - Small ubiquitin-like modifier (SUMO) conjugation and interaction play an essential role in many cellular processes. A large number of yeast proteins is known to interact non-covalently with SUMO via short SUMO-interacting motifs (SIMs), but the structural details of this interaction are yet poorly characterized. In the present work, sequence analysis of a large dataset of 148 yeast SIMs revealed the existence of a hydrophobic core binding motif and a preference for acidic residues either within or adjacent to the core motif. Thus the sequence properties of yeast SIMs are highly similar to those described for human. Molecular dynamics simulations were performed to investigate the binding preferences for four representative SIM peptides differing in the number and distribution of acidic residues. Furthermore, the relative stability of two previously observed alternative binding orientations (parallel, antiparallel) was assessed. For all SIMs investigated, the antiparallel binding mode remained stable in the simulations and the SIMs were tightly bound via their hydrophobic core residues supplemented by polar interactions of the acidic residues. In contrary, the stability of the parallel binding mode is more dependent on the sequence features of the SIM motif like the number and position of acidic residues or the presence of additional adjacent interaction motifs. This information should be helpful to enhance the prediction of SIMs and their binding properties in different organisms to facilitate the reconstruction of the SUMO interactome. PMID- 25690367 TI - On the origin of surface imposed anisotropic growth of salicylic and acetylsalicylic acids crystals during droplet evaporation. AB - In this paper droplet evaporative crystallization of salicylic acid (SA) and acetylsalicylic acid (ASA) crystals on different surfaces, such as glass, polyvinyl alcohol (PVA), and paraffin was studied. The obtained crystals were analyzed using powder X-ray diffraction (PXRD) technique. In order to better understand the effect of the surface on evaporative crystallization, crystals deposited on glass were scraped off. Moreover, evaporative crystallization of a large volume of solution was performed. As we found, paraffin which is non-polar surface promotes formation of crystals morphologically similar to those obtained via bulk evaporative crystallization. On the other hand, when crystallization is carried out on the polar surfaces (glass and PVA), there is a significant orientation effect. This phenomenon is manifested by the reduction of the number of peaks in PXRD spectrum recorded for deposited on the surface crystals. Noteworthy, reduction of PXRD signals is not observed for powder samples obtained after scraping crystals off the glass. In order to explain the mechanism of carboxylic crystals growth on the polar surfaces, quantum-chemical computations were performed. It has been found that crystal faces of the strongest orientation effect can be characterized by the highest surface densities of intermolecular interactions energy (IIE). In case of SA and ASA crystals formed on the polar surfaces the most dominant faces are characterized by the highest adhesive and cohesive properties. This suggests that the selection rules of the orientation effect comes directly from surface IIE densities. PMID- 25690368 TI - Mechanical properties of chiral and achiral silicon carbide nanotubes under oxygen chemisorption. AB - In this paper, the mechanical properties of fully oxygenated silicon carbide nanotubes (O2-SiCNTs) are explored using a molecular mechanics model joined with the density functional theory (DFT). The closed-form analytical expressions suggested in this study can easily be adapted for nanotubes with different chiralities. The force constants of molecular mechanics model proposed herein are derived through DFT within a generalized gradient approximation. Moreover, the mechanical properties of fully oxygenated silicon carbide (O2-SiC) sheet are evaluated for the case that the oxygen atoms are adsorbed on one side of the SiC sheet. According to the results obtained for the bending stiffness of O2-SiC sheet, one can conclude that the O2-SiC sheet has isotropic characteristics. PMID- 25690369 TI - Pigmented purpuric dermatosis: clinicopathologic characterization in a pediatric series. AB - Pigmentary purpuras (PPs) are a group of chronic disorders of unknown origin seldom described in children. With this study we sought to better characterize PP eruptions, including clinical evolution and management. A retrospective chart review from 2003 to 2013 querying characteristics of children with a biopsy proven diagnosis of PP in the Centre Hospitalier Universitaire Ste-Justine dermatology clinic (Montreal, Quebec, Canada) was performed. Follow-up was obtained through telephone interviews. Descriptive statistical analysis was used. Of the 17 subjects, 8 were male and the mean age of onset was 9 years. PP was asymptomatic in 11 patients, pruritic in 3, and of cosmetic concern in 3. Schamberg's disease was the most frequent subtype in 12 cases. Resolution of PP was found in 13 cases with a median duration of less than 1 year (range 6 months 9 years). Five patients experienced spontaneous clearing without treatment, and improvement was observed in 75% of cases treated with topical corticosteroids and 100% with narrowband ultraviolet B (nbUVB). No associated disease, significant drug exposure, or contact allergens were found. Those findings support that PPs in children are idiopathic, chronic eruptions that can benefit from watchful waiting, although topical corticosteroids or nbUVB are may be useful if the patient or family desires faster resolution. This study was limited by its small size, its retrospective nature, and selection and recall bias. PMID- 25690370 TI - Effectiveness of Cognitive Behavioural Self-Help for the Treatment of Depression and Anxiety in People with Long-Term Physical Health Conditions: a Systematic Review and Meta-Analysis of Randomised Controlled Trials. AB - BACKGROUND: Depression and anxiety are prevalent comorbidities in people with long-term physical health conditions; however, there is limited access to evidence-based treatments for comorbid mental health difficulties. PURPOSE: This study is a meta-analysis examining the effectiveness of cognitive behavioural self-help for physical symptoms, depression and anxiety in people with long-term conditions. METHODS: This study involves a systematic search of electronic databases supplemented by expert contact, reference and citation checking and grey literature. RESULTS: The meta-analysis yielded a small effect size for 11 studies reporting primary outcomes of depression (g = -0.20) and 8 studies anxiety (g = -0.21) with a large effect size (g = -1.14) for 1 study examining physical health symptoms. There were no significant moderators of the main effect. CONCLUSIONS: Limited evidence supports cognitive behavioural self-help for depression, anxiety and physical symptoms in people with long-term conditions. Small effect sizes for depression and anxiety may result from failure to recruit participants with clinical levels of these difficulties at baseline. PMID- 25690371 TI - Hepatocyte growth factor is elevated in amniotic fluid from obese women and regulates placental glucose and fatty acid metabolism. AB - INTRODUCTION: To evaluate the impact of the pro-inflammatory cytokine hepatocyte growth factor (HGF) on the regulation of glucose and lipid placental metabolism. METHODS: HGF levels were quantified in amniotic fluid and placenta from control and obese women. 2-deoxy-glucose (2-DOG) uptake, glycolysis, fatty acid oxidation (FAO), fatty acid esterification, de novo fatty acid synthesis, triglyceride levels and carnitine palmitoyltransferase activities (CPT) were measured in placental explants upon addition of pathophysiological HGF levels. RESULTS: In obese women, total- and -activated-HGF levels in amniotic fluid were elevated ~24%, and placental HGF levels were ~3-fold higher than in control women. At a similar dose to that present in amniotic fluid of obese women, HGF (30 ng/mL) increased Glut-1 levels and 2-DOG uptake by ~25-30% in placental explants. HGF mediated effect on 2-DOG uptake was dependent on the activation of phosphatidylinositol 3-kinase signaling pathway. In addition, HGF decreased ~20% FAO, whereas esterification and de novo fatty acid synthesis increased ~15% and ~25% respectively, leading to 2-fold triglyceride accumulation in placental explants. In parallel, HGF reduced CPT-I activity ~70%. DISCUSSION: HGF is a cytokine elevated in amniotic fluid and placental tissue of obese women, which through its ability to stimulate 2-DOG uptake and metabolism impairs FAO and enhances esterification and de novo fatty acid synthesis, leading to accumulation of placental triglycerides. PMID- 25690372 TI - Rapid Screening for Subclinical Atherosclerosis by Carotid Ultrasound Examination: The HAPPY (Heart Attack Prevention Program for You) Substudy. AB - BACKGROUND: Cardiovascular disease (CVD)-related death rates have been escalating in emerging economies such as India. A strategy to initiate prophylactic medical intervention by direct identification of subclinical atherosclerotic burden may be appropriate in rural populations where assessment based on traditional risk factors is not available. OBJECTIVES: This study sought to investigate the feasibility of performing rapid automated carotid ultrasound studies in a rural setting and to measure the prevalence of carotid plaques and age-specific distribution of carotid intima-media thickness (IMT) as an index of subclinical atherosclerosis. METHODS: Screening of the extracranial carotid system with automated B-mode ultrasound was performed along with health questionnaire assessments in 771 asymptomatic volunteers (ages 40 +/- 14 years; 626 men and 145 women) with no known CVD. Measurements of IMT were recorded as the mean of 24 spatial measurements performed over a 1-cm region in the far wall of the common carotid artery at end diastole; the prevalence of the plaque (focal IMT >1.5 mm) was determined. RESULTS: A total of 69 (8.9%) subjects had atherosclerotic plaques. Of these, 16 (2.1%) exhibited bilateral plaques, 28 (3.6%) left carotid plaque only, and 25 (3.2%) had right carotid plaques. Patients even under 50 years showed a high prevalence of carotid plaques (7%), which increased with age (25% and 35% for 51 to 70 and >70 years, respectively). Only 3 (4.3%) participants with plaques were former smokers. Global mean IMT was 0.55 +/- 0.13 mm and correlated with age for both left and right carotid arteries (r = 0.61 and 0.60, p < 0.001 for both) in male as well as female subjects (r = 0.70 and 0.67, p < 0.001 for both), respectively. CONCLUSIONS: Rapid community screening for subclinical atherosclerosis is feasible with automated carotid ultrasound examination and may be beneficial in rural communities of industrializing nations where traditional CVD risk factor data are not yet readily available. PMID- 25690373 TI - Rapid Detection of Subclinical Atherosclerosis: Potential Implications for Primary Prevention in LMIC. PMID- 25690374 TI - Coronary artery disease in women: a 2013 update. AB - Coronary artery disease (CAD) is a leading cause of death of women and men worldwide. CAD's impact on women traditionally has been underappreciated due to higher rates at younger ages in men. Microvascular coronary disease disproportionately affects women. Women have unique risk factors for CAD, including those related to pregnancy and autoimmune disease. Trial data indicate that CAD should be managed differently in women. In this review, we will examine risk assessment for CAD in women, CAD's impact on women, as well as CAD's female specific presentation and management strategies. PMID- 25690375 TI - Sex differences in diabetes, heart disease, and beyond. PMID- 25690376 TI - Prevention and Control Program for Cardiovascular Diseases in Turkish Population: PRE-CONTROL Study Group. AB - BACKGROUND: Cardiovascular disease (CVD) is the leading cause of death throughout the world. Despite its high prevalence, the atherosclerotic process can be slowed and its consequences markedly reduced by preventive measures. The lack of risk factor awareness is a major barrier. OBJECTIVES: We aimed to assess total CV risk, determine the knowledge and awareness regarding CVD, and evaluate the effectiveness of education program in urban population of Turkey. METHODS: A 24 item questionnaire was used to detect CV risk factors and the awareness of participants about CVD. The feedback data for the education program were collected by either questionnaires or individual interviews with participants. For comparison of total CVD risk in men and women in different age groups, a sample t test was used. The level of statistical significance was set at p < 0.05. RESULTS: The prevalence of hyperlipidemia was established to be 41.3%. Nearly one-quarter of the women and one-third of the men were smokers (p < 0.001). One-quarter of the responders had a history of hypertension (men: 21.5%, women: 18.6%), and one-tenth were diabetic. The high CV risk rate was more pronounced among men (p < 0.01) and those with low socioeconomic level (p < 0.01). Awareness regarding CV risk factors following the educational program increased from 6.6% to 12.7% for high blood pressure, from 3.9% to 9.2% for diabetes mellitus, and from 10.2% to 15.1% for elevated cholesterol levels. All the increases were statistically significant. The educational program significantly increased the awareness of CVD and risk factors. CONCLUSIONS: The prevalence of CV risk factors was higher in low socioeconomic level groups. The knowledge and awareness of the risk factors for CVD before the education program was very low in our study group. The awareness of CVD and risk factors significantly increased following our education programs. PMID- 25690377 TI - Burden of Cardio- and Cerebro-vascular Diseases and the Conventional Risk Factors in South Asian Population. AB - Similar to most populations, South Asian countries are also witnessing the dramatic transitions in health during the last few decades with the major causes of adverse health shifting from a predominance of nutritional deficiencies and infectious diseases to chronic diseases such as cardio and cerebrovascular disease (CVD). We summarized the available information of the burden of CVD and risk factors in the South Asian populations. The prevalence of conventional cardiovascular has been increasing among all South Asian populations. Extensive urbanization, shift in dietary pattern and sedentary daily life style is contributing towards the worsening of the CVD risk factor scenario. The burdens of the chronic cardiovascular risk factors are much prevalent in the South Asian populations. These are also rising alarmingly which ought to influence the already existed heavy CVD burden. Similar to the rest of the world, management for the conventional cardiovascular risk factors is very important for the prevention of CVD in South Asia. PMID- 25690378 TI - Nutrition research in India: underweight, stunted, or wasted? AB - India has experienced dramatic economic growth in the past 2 decades accompanied by a rising burden of noncommunicable diseases, which coexists with the unfinished agenda of undernutrition. Tackling these dual challenges requires strong investment in nutrition research. We compared India's research output with another rapidly developing country (China) and an established developed country (USA). We analyzed trends for each country between the periods 2000 to 2005 and 2006 to 2010, in terms of quantity and quality of the publications. India produced 2,712 articles (1.9% of the global total) in the 2000 to 2005 period and 3,999 articles (2.1%) in the 2006 to 2010 period, and the country impact factor was 191 and 174, respectively. The contributions to the top 10 nutrition journals during 2006 to 2010 was 1%. India must increase investment in and attention towards quality nutrition research and address potential barriers to publish. PMID- 25690379 TI - Cardiovascular disease prevention in South Asia: gathering the evidence. PMID- 25690380 TI - Practice guidelines for the diagnosis and management of systolic heart failure in low- and middle-income countries. PMID- 25690381 TI - The Digital Health Scorecard: A New Health Literacy Metric for NCD Prevention and Care. AB - According to the World Health Organization, 3 out of 5 deaths worldwide are due to common, chronic conditions, such as heart and respiratory diseases, cancer, and diabetes. These noncommunicable diseases (NCDs) are linked to multiple lifestyle risk factors, including smoking, the harmful use of alcohol, and physical inactivity. They are associated with other "intermediate" risk factors, such as elevated body mass index (BMI), hypertension, hyperlipidemia, and hyperglycemia. Taking action to reduce these 7 risk factors can help people protect themselves against leading causes of death. All of these risk factors are measurable and modifiable, but globally available, cost-effective, and easy-to use outcome metrics that can drive action on all levels do not yet exist. The Digital Health Scorecard is being proposed as a dynamic, globally available digital tool to raise public, professional, and policy maker NCD health literacy (the motivation and ability to access, understand, communicate, and use information to improve health and reduce the incidence of NCD). Its aim is to motivate and empower individuals to make the behavioral and choice changes needed to improve their health and reduce NCD risk factors by giving unprecedented access to global data intelligence, creating awareness, making links to professional and community-based support services and policies, and providing a simple way to measure and track risk changes. Moreover, it provides health care professionals, communities, institutions, workplaces, and nations with a simple metric to monitor progress toward agreed local, national, and global NCD targets. PMID- 25690382 TI - Scorecard for NCDs. PMID- 25690383 TI - World health day. PMID- 25690384 TI - Diagnostic accuracy of the inverted grayscale rib series for detection of rib fracture in minor chest trauma. AB - STUDY OBJECTIVE: To assess whether inverted grayscale rib series, used alone or as an additional imaging modality, improves diagnostic accuracy of rib fractures of emergency medicine (EM) residents in minor chest trauma. METHODS: Twenty readers, including 5 junior and 5 senior EM residents and 10 fourth-year medical students, independently reviewed 110 patients' radiographs during 3 sessions. Session 1 used conventional grayscale rib series, session 2 used inverted grayscale rib series, and session 3 used both conventional and inverted grayscale images. The McNemar test was used to compare the sensitivities and specificities of the diagnostic methods, and to compare their sensitivities and specificities for detecting more than 3 rib fractures. Interobserver agreement was assessed using Cohen kappa analysis. RESULTS: For senior EM residents, there was no difference in sensitivity (P = .283) and accuracy (P = .888) between conventional rib series and the double-modality method. For junior EM residents and medical students, the double modality offered higher diagnostic sensitivity (P < .001, P = .001) and accuracy (P = .006, P = .002) than did conventional radiography. In cases with more than 3 rib fractures, who required specialist trauma care, the double modality provided greater sensitivity and accuracy among junior EM residents (P = .035 and P = .035, respectively) and medical students (P = .010, P = .010) than did conventional radiography. CONCLUSIONS: In the diagnosis of rib fractures, the combined use of conventional and inverted grayscale rib series increases the diagnostic accuracy of less biased readers by conventional grayscale image like junior EM residents and medical students. PMID- 25690385 TI - TGFbeta3 secretion by three-dimensional cultures of human dental apical papilla mesenchymal stem cells. AB - Mesenchymal stem cells (MSCs) can be isolated from dental tissues, such as pulp and periodontal ligament; the dental apical papilla (DAP) is a less-studied MSC source. These dental-derived MSCs are of great interest because of their potential as an accessible source for cell-based therapies and tissue-engineering (TE) approaches. Much of the interest regarding MSCs relies on the trophic mediated repair and regenerative effects observed when they are implanted. TGFbeta3 is a key growth factor involved in tissue regeneration and scarless tissue repair. We hypothesized that human DAP-derived MSCs (hSCAPs) can produce and secrete TGFbeta3 in response to micro-environmental cues. For this, we encapsulated hSCAPs in different types of matrix and evaluated TGFbeta3 secretion. We found that dynamic changes of cell-matrix interactions and mechanical stress that cells sense during the transition from a monolayer culture (two-dimensional, 2D) towards a three-dimensional (3D) culture condition, rather than the different chemical composition of the scaffolds, may trigger the TGFbeta3 secretion, while monolayer cultures showed almost 10-fold less secretion of TGFbeta3. The study of these interactions is provided as a cornerstone in designing future strategies in TE and cell therapy that are more efficient and effective for repair/regeneration of damaged tissues. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 25690386 TI - Composition-property relationships for radiopaque composite materials: pre-loaded drug-eluting beads for transarterial chemoembolization. AB - The purpose of this study was to synthesize and optimize intrinsically radiopaque composite embolic microspheres for sustained release of doxorubicin in drug eluting bead transarterial chemoembolization. Using a design of experiments approach, 12 radiopaque composites composed of polylactic-co-glycolic acid and a radiopaque glass (ORP5) were screened over a range of compositions and examined for radiopacity (computed tomography) and density. In vitro cell viability was determined using an extract assay derived from each composition against the human hepatocellular carcinoma cell line, HepG2. Mathematical models based on a D Optimal response surface methodology were used to determine the preferred radiopaque composite. The resulting radiopaque composite was validated and subsequently loaded with doxorubicin between 0 and 1.4% (wt% of polylactic-co glycolic acid) to yield radiopaque composite drug-eluting beads. Thereafter, the radiopaque composite drug-eluting beads were subjected to an elution study (up to 168 h) to determine doxorubicin release profiles (UV-Vis spectroscopy) and in vitro cell viability. Radiopaque composites evaluated for screening purposes had densities between 1.28 and 1.67 g.cm(-3), radiopacity ranged between 211 and 1450HU and cell viabilities between 91 and 106% were observed. The optimized radiopaque composite comprised 23 wt% polylactic-co-glycolic acid and 60 wt% ORP5 with a corresponding density of 1.63 +/- 0.001 g.cm(-3), radiopacity at 1930 +/- 44HU and cell viability of 89 +/- 7.6%. Radiopaque composite drug-eluting beads provided sustained doxorubicin release over 168 h. In conclusion, the mathematical models allowed for the identification and synthesis of a unique radiopaque composite. The optimized radiopaque composite had similar density and cell viability to commercially available embolic microspheres. It was possible to preload doxorubicin into radiopaque composite drug-eluting beads, such that sustained release was possible under simulated physiological conditions. PMID- 25690387 TI - Synthetic biology: GMOs in lockdown. PMID- 25690388 TI - Human evolution: phoneme-genome data set evolves. PMID- 25690392 TI - Gene expression: layers of gene regulation. PMID- 25690396 TI - Nutrition and maternal metabolic health in relation to oocyte and embryo quality: critical views on what we learned from the dairy cow model. AB - Although fragmented and sometimes inconsistent, the proof of a vital link between the importance of the physiological status of the mother and her subsequent reproductive success is building up. High-yielding dairy cows are suffering from a substantial decline in fertility outcome over past decades. For many years, this decrease in reproductive output has correctly been considered multifactorial, with factors including farm management, feed ratios, breed and genetics and, last, but not least, ever-rising milk production. Because the problem is complex and requires a multidisciplinary approach, it is hard to formulate straightforward conclusions leading to improvements on the 'work floor'. However, based on remarkable similarities on the preimplantation reproductive side between cattle and humans, there is a growing tendency to consider the dairy cow's negative energy balance and accompanying fat mobilisation as an interesting model to study the impact of maternal metabolic disorders on human fertility and, more specifically, on oocyte and preimplantation embryo quality. Considering the mutual interest of human and animal scientists studying common reproductive problems, this review has several aims. First, we briefly introduce the 'dairy cow case' by describing the state of the art of research into metabolic imbalances and their possible effects on dairy cow reproduction. Second, we try to define relevant in vitro models that can clarify certain mechanisms by which aberrant metabolite levels may influence embryonic health. We report on recent advances in the assessment of embryo metabolism and meantime critically elaborate on advantages and major limitations of in vitro models used so far. Finally, we discuss hurdles to be overcome to successfully translate the scientific data to the field. PMID- 25690397 TI - Frequency and temperature dependence of skin bioimpedance during a contralateral cold test. AB - A study of the alpha- and beta-dispersion of skin bioimpedance dependence on temperature and micro-hemodynamics is presented. The vascular tone changes during the cold test are verified by the wavelet-analysis of skin temperature signals obtained simultaneously with impedance measurements. Thirty three normal healthy subjects of 28 +/- 7 years old were entered into the study. The tetra-polar electrode system was used to record the resistance and reactance; measurements were carried out at 67 frequencies, in a frequency range from 2 Hz to 50 kHz. It has been found that the impedance decreases with vasodilation and increases with vasoconstriction. The high values of correlation among thermal oscillation amplitudes and Nyquist diagram parameters prove the impedance dependence on blood flow in three frequency bands corresponding to the myogenic, neurogenic and endothelial vascular tone regulation mechanisms. Using an equivalent RC circuit, we obtained the changes in the Nyquist diagram matching the experimental data. The proposed descriptive alpha-dispersion model can be used to study mechanisms responsible for intercellular interaction. PMID- 25690398 TI - Highly sensitive and robust linear probe for detection of mRNA in cells. AB - A stemless linear probe was designed that robustly detects mRNA in cells with high sensitivity. The probe is modified at some positions with base surrogates prepared from D-threoninol, with anthraquinone moieties near the 5'- and 3' termini, and with perylene moieties. Even in cell lysate that involves various proteins and enzymes, background emission was very low. When the probe was hybridized with RNA, chromophores are intercalated between the base pairs, resulting in a remarkable light-up signal. The signal-to-background ratio was as high as 1600 under our standard buffer conditions. In the HeLa cell lysate, the linear probe had sufficient signal-to-background ratio (S/B=40) for reliable mRNA detection. No degradation was observed after a 24 h incubation in HeLa cell lysate. In cells, a probe designed to target DsRed resulted in distinct blue fluorescence only in cells transfected with plasmid encoding DsRed; no fluorescence was observed in control cells. PMID- 25690399 TI - Prodromal dementia with Lewy bodies. AB - Dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementing disorder after Alzheimer's disease (AD), but there is limited information regarding the prodromal DLB state compared with that of AD. Parkinson's disease (PD) and DLB share common prodromal symptoms with Lewy body disease (LBD), allowing us to use a common strategy for identifying the individuals with an underlying pathophysiology of LBD. Dysautonomia, olfactory dysfunction, rapid eye movement sleep behavior disorder (RBD) and psychiatric symptoms antedate the onset of dementia by years or even decades in patients with DLB. Although RBD is the most potentially accurate prodromal predictor of DLB, disease progression before the onset of dementia could differ between the prodromal DLB state with and without RBD. Experts who specialize in idiopathic RBD and DLB might need communication in order to clarify the clinical relevance of RBD with the disease progression of DLB. The presence of prodromal LBD symptoms or findings of occipital hypoperfusion/hypometabolism helps us to predict the possible pathophysiological process of LBD in non-demented patients. This approach might provide the opportunity for additional neuroimaging, including cardiac (123) I-metaiodobenzylguanidine scintigraphy and dopamine transporter imaging. Although limited radiological findings in patients with prodromal DLB states have been reported, there is now a need for larger clinical multisite studies with pathological verification. The long prodromal phase of DLB provides a critical opportunity for potential intervention with disease-modifying therapy, but only if we are able to clearly identify the diversity in the clinical courses of DLB. In the present article, we reviewed the limited literature regarding the clinical profiles of prodromal DLB. PMID- 25690400 TI - Resting heart rate and incident atrial fibrillation in the elderly. AB - BACKGROUND: Alterations in autonomic tone and/or sinus node dysfunction are common with aging. We hypothesized that older persons with low or high heart rates represent a population with subclinical abnormalities who are more likely to develop atrial fibrillation (AF). METHODS: A total of 5,226 participants aged 65 years or more (85% white; 42% male) with complete data from the Cardiovascular Health Study were used in this analysis. AF cases were identified during the yearly study electrocardiograms, participant history of a physician diagnosis, or by hospitalization data. Cox regression was used to compute hazard ratios (HR) and 95% confidence intervals (CI) for the association between resting heart rate and incident AF using clinically relevant categories (heart rate <=60 beats/min, 60< heart rate beats/min <=90 beats/min (reference), heart rate >90 beats/min) and as a continuous variable per 5 beats/min decrease. RESULTS: Over a median follow-up of 12.7 years, a total of 532 (10.2%) participants developed AF. In a multivariable Cox regression analysis, heart rates <=60 beats/min (HR = 1.3, 95% CI = 1.1, 1.5), but not >90 beats/min (HR = 1.1, 95% CI = 0.52, 2.3), were associated with an increased risk of AF. Additionally, heart rate per 5 beats/min decrease was associated with an increased risk of AF (HR = 1.06, 95% CI = 1.01, 1.1). The results were consistent in subgroup analyses stratified by age, sex, race, and baseline cardiovascular disease. CONCLUSION: In the elderly, low heart rates are associated with an increased risk of AF. Potentially, underlying alterations in autonomic tone and/or subclinical sinus node dysfunction manifested as slow heart rate predispose to AF. PMID- 25690401 TI - From the Epidemiologist to the Physician: A Complex Issue for a Labile Risk. PMID- 25690402 TI - Development and validation of the multiple sclerosis questionnaire for the evaluation of job difficulties (MSQ-Job). AB - OBJECTIVE: Multiple sclerosis (MS) affects young adults of working age. Difficulties in work-related activities are usually ascribed to MS symptoms, while the impact of workplace features is underestimated. This article presents the Multiple Sclerosis Questionnaire for Job Difficulties (MSQ-Job), designed to assess working difficulties due to MS symptoms and workplace features. METHODS: A sample of employed MS patients completed the MSQ-Job, the WHO-Disability Assessment Schedule (WHODAS 2.0) and the 54-items MS Quality of Life Questionnaires (MSQOL-54); the expanded disability status scale (EDSS) was used to define MS severity. Factor structure was evaluated using principal component extraction and Oblimin rotation; internal consistency was assessed with Cronbach's alpha; construct and discriminant validity using t-test (EDSS 0-2 vs >2; patients self-reporting need for support vs patients reporting no needs; full time vs part-time employees); and Pearson's correlation with WHODAS 2.0 and MSQOL 54. RESULTS: The MSQ-Job is a 42-item questionnaire with six scales and an overall factor. Scores range on a 0-100 scale (higher scores indicate more and more severe difficulties); patients with EDSS>2 and self-reporting support needs had worse scores than those with EDSS 0-2 and without needs. Correlations with WHODAS 2.0 and MSQOL-54 were generally significant (P < 0.0007) and below 0.70. CONCLUSIONS: The MSQ-Job jointly measures the impact of respondents' symptoms and workplace features on work activities and enables to assess the effects of clinical and occupational interventions and better describe the impact of MS indirect costs. PMID- 25690403 TI - New oral small molecules in the treatment of chronic lymphocytic leukemia. AB - There has been a dramatic change in therapy for chronic lymphocytic leukemia (CLL) over the last 20 years. In 1990, available therapy produced complete responses in <5% of treated patients. This is in marked contrast to modern regimens, which are reported to reliably produce complete responses in approximately 40% to 50% of patients. This remarkable improvement has been attributable to combination chemoimmunotherapy agents that have contributed to the backbone of therapy for patients with CLL. However, the disease is still incurable and these modern treatment regimens have been somewhat limited to the treatment of younger, physically "fit" patients with CLL due to their increased toxicity, including enhanced myelosuppression and immunosuppression. In addition, because patients receive multiple therapies during the course of their lifetime, the mounting toxicities as well as decreased efficacy often limit the repeated use of these more aggressive combination therapies. Fortunately, over the past 5 years, there has been an explosion of new active agents that have demonstrated remarkable activity in patients with recurrent/refractory disease as well as those who harbor poor cytogenetic abnormalities. The current review focuses on some of the novel small molecules that have either been approved or are at the forefront of clinical development in the treatment of patients with CLL. PMID- 25690404 TI - Inter-individual and intra-individual variation of the effects of pulsed RF EMF exposure on the human sleep EEG. AB - Pulse-modulated radiofrequency electromagnetic fields (RF EMF) can alter brain activity during sleep; increases of electroencephalographic (EEG) power in the sleep spindle (13.75-15.25 Hz) and delta-theta (1.25-9 Hz) frequency range have been reported. These field effects show striking inter-individual differences. However, it is still unknown whether individual subjects react in a similar way when repeatedly exposed. Thus, our study aimed to investigate inter-individual variation and intra-individual stability of field effects. To do so, we exposed 20 young male subjects twice for 30 min prior to sleep to the same amplitude modulated 900 MHz (2 Hz pulse, 20 Hz Gaussian low-pass filter and a ratio of peak to-average of 4) RF EMF (spatial peak absorption of 2 W/kg averaged over 10 g) 2 weeks apart. The topographical analysis of EEG power during all-night non-rapid eye movement sleep revealed: (1) exposure-related increases in delta-theta frequency range in several fronto-central electrodes; and (2) no differences in spindle frequency range. We did not observe reproducible within-subject RF EMF effects on sleep spindle and delta-theta activity in the sleep EEG and it remains unclear whether a biological trait of how the subjects' brains react to RF EMF exists. PMID- 25690405 TI - Clinical neuropathy scales in neuropathy associated with impaired glucose tolerance. AB - AIMS: Disagreement exists on effective and sensitive outcome measures in neuropathy associated with impaired glucose tolerance (IGT). Nerve conduction studies and skin biopsies are costly, invasive and may have their problems with reproducibility and clinical applicability. A clinical measure of neuropathy that has sufficient sensitivity and correlates to invasive measures would enable significant future research. METHODS: Data was collected prospectively on patients with IGT and symptomatic early neuropathy (neuropathy symptoms <2years) and normal controls. The seven scales that were examined were the Neuropathy Impairment Score of the Lower Limb (NIS-LL), Michigan Diabetic Neuropathy Score (MNDS), modified Toronto Clinical Neuropathy Scale (mTCNS), Total Neuropathy Score (Clinical) (TNSc), The Utah Early Neuropathy Scale (UENS), the Early Neuropathy Score (ENS), and the Neuropathy Disability Score (NDS). RESULTS: All seven clinical scales were determined to be excellent in discriminating between patients with neuropathy from controls without neuropathy. The strongest discrimination was seen with the mTCNS. The best sensitivity and specificity for the range of scores obtained, as determined by using receiver operating characteristic curves, was seen for the mTCNS followed by the TNSc. Most scales show a stronger correlation with measures of large rather than small fiber neuropathy. CONCLUSIONS: All seven scales identify patients with neuropathy. For the purpose of screening potential patients for a clinical study, the mTCNS followed by the TNSc would be most helpful to select patients with neuropathy. PMID- 25690406 TI - Implementation of NICE guidance on urinary tract infections in children in primary and secondary care. AB - AIM: To audit compliance with the 2007 National Institute of Clinical Excellence guidelines on the management of urinary tract infection in children under the age of 16 years across primary and secondary care services in England. METHODS: A retrospective multisite audit of 10 general practice, 3 paediatric, 2 paediatric emergency and 2 emergency general units. Four distinct geographical areas were represented. Data were collected between 1 January 2010 and 31 December 2010. Six criteria were audited, which focused on the following: improving the rate of diagnosis, management of the very young child with UTI and selection of children for imaging. RESULTS: A total of 1149 children were audited (682 from primary care and 467 from secondary care). Overall compliance was as follows: criterion 1: 28%; criterion 2: 68%; criterion 3: 89%; criterion 4: 43%; criterion 5 (comprising 12 subcriteria): 13% and for criterion 6: 45%. CONCLUSION: The results indicate significant shortcomings in the implementation of NICE guidance on childhood UTI in England. The guidance is complex and this makes its implementation challenging. It was difficult to identify children presenting with nonspecific fever from clinical data systems. Adequate IT systems throughout the NHS are a key step to improving implementation of this and other NICE guidance. PMID- 25690407 TI - Factors associated with response to treatment of pulmonary exacerbations in cystic fibrosis patients. AB - BACKGROUND: Pulmonary exacerbations are associated with significant lung function decline from baseline in cystic fibrosis (CF) and it is not well understood why some patients do not respond to antibiotic therapy. The objective of this study was to identify factors associated with lung function response to antibiotic treatment of pulmonary exacerbations. METHODS: As a secondary analysis of a randomized, controlled trial of intravenous antibiotic treatment for pulmonary exacerbations in CF patients, we investigated whether baseline factors and changes in sputum bacterial density, serum or sputum inflammatory markers were associated with recovery of lung function and risk of subsequent exacerbation. RESULTS: In 36 of the 70 exacerbations (51%), patients' lung function returned to >100% of their baseline at day 14 of antibiotic treatment; 34 exacerbations were classified as non-responders. Baseline characteristics were not significantly different between responders and non-responders. Less of a drop in FEV1 from baseline to exacerbation (OR 1.09, 95% CI 1.0, 1.18, p=0.04) as well as a greater decrease in sputum neutrophil elastase (OR 2.94, 95% CI 1.07, 8.06, p=0.04) were associated with response to antibiotic treatment at day 14. In addition, higher CRP (HR 1.35 (95% CI: 1.01, 1.78), p=0.04) and sputum neutrophil elastase (HR 1.71 (95% CI: 1.02, 2.88), p=0.04) at day 14 of antibiotic therapy were associated with an increased risk of subsequent exacerbation. CONCLUSIONS: Inadequate reduction of inflammation during an exacerbation is associated with failure to recover lung function and increased risk of subsequent re-exacerbation in CF patients. PMID- 25690408 TI - The association of environmental heat stress with performance: analysis of the 2014 FIFA World Cup Brazil. AB - OBJECTIVE: The 2014 FIFA World Cup Brazil included 64 matches in temperate to tropical environmental conditions. We analysed performance data in relation to the environmental conditions to identify potential association. METHODS: Wet-bulb globe temperature (WBGT) parameters were obtained at the centre of the field 1 h before the start of play. Environmental stress was estimated (low, moderate and high) for each match using WBGT and relative humidity. Various physical and technical performance indices were recorded during each match (average of both teams). RESULTS: Over the 64 matches, 28 were played under low, 20 under moderate and 16 under high environmental stress. There was no difference in actual playing time (p=0.517), total distance covered (p=0.491), number of goals scored (p=0.485) and number of cards (p=0.618) between the matches played under different environmental stress categories. The number of sprints was lower in high than in moderate or low environmental stress (-10%, p<0.05) but peak speed was unaffected. The distance covered at high intensity was also lower under high (24.8+/-2.8 m/min/player) than low environmental stress (26.9+/-2.3 m/min/player, p=0.02). Number of passes was not different but the rate of successful passes was higher under high (76.8+/-4.4%) than low (73.6+/-10.8%) environmental stress (p=0.031). CONCLUSIONS: Top-level players seem to modulate their activity pattern during matches in a hot and humid environment (ie, less high-intensity but more low-intensity running and successful passes) to preserve the global match characteristics (ie, similar actual playing time, total distance covered, peak running speed and goals scored). PMID- 25690409 TI - The effect of eccentric exercise in improving function or reducing pain in lateral epicondylitis is unclear. PMID- 25690410 TI - On the current state of the Hydrologic Evaluation of Landfill Performance (HELP) model. AB - The Hydrologic Evaluation of Landfill Performance (HELP) model is the most widely applied model to calculate the water balance of cover and bottom liner systems for landfills. The paper summarizes the 30 year history of the model from HELP version 1 to HELP 3.95 D and includes references to the three current and simultaneously available versions (HELP 3.07, Visual HELP 2.2, and HELP 3.95 D). A sufficient validation is an essential precondition for the use of any model in planning. The paper summarizes validation approaches for HELP 3 focused on cover systems in the literature. Furthermore, measurement results are compared to simulation results of HELP 3.95 D for (1) a test field with a compacted clay liner in the final cover of the landfill Hamburg-Georgswerder from 1988 to 1995 and (2) a test field with a 2.3m thick so-called water balance layer on the landfill Deetz near Berlin from 2004 to 2011. On the Georgswerder site actual evapotranspiration was well reproduced by HELP on the yearly average as well as in the seasonal course if precipitation data with 10% systematic measurement errors were used. However, the increase of liner leakage due to the deterioration of the clayey soil liner was not considered by the model. On the landfill Deetz HELP overestimated largely the percolation through the water balance layer resulting from an extremely wet summer due to an underestimation of the water storage in the layer and presumably also due to an underestimation of the actual evapotranspiration. Finally based on validation results and requests from the practice, plans for improving the model to a future version HELP 4 D are described. PMID- 25690411 TI - Pollution control and metal resource recovery for low grade automobile shredder residue: a mechanism, bioavailability and risk assessment. AB - Automobile shredder residue (ASR) is considered as hazardous waste in Japan and European countries due to presence of heavy metals. This study was carried on the extraction characteristics of heavy metals (Mn, Fe, Ni, and Cr) from automobile shredder residue (ASR). The effects of pH, temperature, particle size, and liquid/solid ratio (L/S) on the extraction of heavy metals were investigated. The recovery rate of Mn, Fe, Ni, and Cr increased with increasing extraction temperature and L/S ratio. The lowest pH 2, the highest L/S ratio, and the smallest particle size showed the highest recovery of heavy metals from ASR. The highest recovery rates were in the following order: Mn > Ni > Cr > Fe. Reduction of mobility factor for the heavy metals was observed in all the size fractions after the recovery. The results of the kinetic analysis for various experimental conditions supported that the reaction rate of the recovery process followed a second order reaction model (R(2) ? 0.95). The high availability of water-soluble fractions of Mn, Fe, Ni, and Cr from the low grade ASR could be potential hazards to the environment. Bioavailability and toxicity risk of heavy metals reduced significantly with pH 2 of distilled water. However, water is a cost-effective extracting agent for the recovery of heavy metals and it could be useful for reducing the toxicity of ASR. PMID- 25690412 TI - Household waste compositional analysis variation from insular communities in the framework of waste prevention strategy plans. AB - Waste management planning requires reliable data regarding waste generation, affecting factors on waste generation and forecasts of waste quantities based on facts. In order to decrease the environmental impacts of waste management the choice of prevention plan as well as the treatment method must be based on the features of the waste that are produced in a specific area. Factors such as culture, economic development, climate, and energy sources have an impact on waste composition; composition influences the need of collecting waste more or less frequently of waste collection and disposition. The research question was to discover the main barriers concerning the compositional analysis in Insular Communities under warm climate conditions and the findings from this study enabled the main contents of a waste management plan to be established. These included advice to residents on waste minimisation, liaison with stakeholders and the expansion of kerbside recycling schemes. PMID- 25690413 TI - Does vegetation affect the methane oxidation efficiency of passive biosystems? AB - It is often reported in the technical literature that the presence of vegetation improves the methane oxidation efficiency of biosystems; however, the phenomena involved and biosystem performance results are still poorly documented, particularly in the field. This triggered a study to assess the importance of vegetation in methane oxidation efficiency (MOE). In this study, 4 large scale columns, each filled with sand, topsoil and a mixture of compost and topsoil were tested under controlled conditions in the laboratory and partially controlled conditions in the field. Four series of laboratory tests and two series of field tests were performed. 4 different plant covers were tested for each series: Trifolium repens L. (White clover), Phleum pratense L. (Timothy grass), a mixture of both, and bare soil as the control biosystem. The study results indicated that up to a loading equal to 100 g CH4/m(2)/d, the type of plant cover did not influence the oxidation rates, and the MOE was quite high (? 95%) in all columns. Beyond this point, the oxidation rate continued to increase, reaching 253 and 179 g CH4/m(2)/d in laboratory and field tests respectively. In the end, the bare soil achieved as high or higher MOEs than vegetated biosystems. Despite the fact that the findings of this study cannot be generalized to other types of biosystems and plants and that the vegetation types tested were not fully grown, it was shown that for the short-term tests performed and the types of substrates and plants used herein, vegetation does not seem to be a key factor for enhancing biosystem performance. This key conclusion does not corroborate the conclusion of the relatively few studies published in the technical literature assessing the importance of vegetation in MOE. PMID- 25690414 TI - The quest for population-level cancer recurrence data; current deficiencies and targets for improvement. AB - BACKGROUND: Cancer recurrence is a critical outcome in cancer care. However, population-level recurrence information is currently unavailable. Tumor registries provide an opportunity to generate this information, but require major reform. Our objectives were to (1) determine causes for variability in collection of recurrence, and (2) identify targets for intervention. METHODS: On-site interviews and observations of tumor registry follow-up procedures were conducted at Commission on Cancer (CoC) accredited hospitals. Information regarding registry resources (caseload, staffing, chart availability), follow-up methods and perceived causes for difficulty in obtaining recurrence information was obtained. RESULTS: Seven NCI/academic, 5 comprehensive community and 2 community centers agreed to participate. Hospitals were inconsistent in their investigation of cancer recurrence, resulting in underreporting of rates of recurrence. Hospital characteristics, registry staffing, staff qualifications and medical chart access influenced follow-up practices. Coding standards and definitions for recurrence were suboptimal, resulting in hospital variability of recurrence reporting. Finally, inability to identify cases lost to follow-up in collected data prevents accurate analysis of recurrence rates. CONCLUSION: Tumor registries collect varying degrees of recurrence information and provide the underpinnings to capture population-level cancer recurrence data. Targets for intervention are listed, and provide a roadmap to obtain this critical information in cancer care. PMID- 25690415 TI - Visualization of proteomics data using R and bioconductor. AB - Data visualization plays a key role in high-throughput biology. It is an essential tool for data exploration allowing to shed light on data structure and patterns of interest. Visualization is also of paramount importance as a form of communicating data to a broad audience. Here, we provided a short overview of the application of the R software to the visualization of proteomics data. We present a summary of R's plotting systems and how they are used to visualize and understand raw and processed MS-based proteomics data. PMID- 25690416 TI - INTERACTIVE WORKSHOPS TO PROMOTE GENDER EQUITY AND FAMILY PLANNING IN RURAL COMMUNITIES OF GUATEMALA: RESULTS OF A COMMUNITY RANDOMIZED STUDY. AB - In Guatemala, especially in rural areas, gender norms contribute to high fertility and closely spaced births by discouraging contraceptive use and constraining women from making decisions regarding the timing of their pregnancies and the size of their families. Community workshops for men, women and couples were conducted in 30 rural communities in Guatemala to test the hypothesis that the promotion of gender equity in the context of reproductive health will contribute to gender-equitable attitudes and strengthen the practice of family planning. Communities were randomly assigned to intervention and control groups. Pre/post surveys were conducted. Odds ratios estimated with mixed effect models to account for community-level randomization and repeated measures per participant were compared. The analyses showed statistically significant effects of the intervention on two of the three outcomes examined: gender attitudes and contraceptive knowledge. Findings regarding contraceptive use were suggestive but not significant. The results suggest that it is possible to influence both inequitable gender norms and reproductive health knowledge and, potentially, behaviours in a short span of time using appropriately designed communications interventions that engage communities in re-thinking the inequitable gender norms that act as barriers to health. PMID- 25690417 TI - Glycaemic index and load values tested in normoglycemic adults for five staple foodstuffs: pounded yam, pounded cassava-plantain, placali, attieke and maize meal stiff porridge. AB - There is currently an increased global interest in the published glycaemic index (GI) and glycaemic load (GL) values of foods. However, data on the GI and GL values of different varieties of foods within Cote d'Ivoire are very limited. The study therefore aimed at finding the GI and GL of the main food staples in Cote d'Ivoire. Following the International Standard Organisation's protocol (ISO/FDI 26642:2010), a selection of five staple foodstuffs were tested for their GI and GL. Fasted healthy subjects were given 50 g of available carbohydrate servings of a glucose reference, which was tested twice, and test foods which were tested once, on separate occasions. Excepted attieke (GI 63), the majority of foods tested have a high GI (GI>70). Attieke (agbodjama) had a high GL (GL 29) while placali (GL 17) and maize meal stiff porridge (GL 16) had medium GLs. The GLs of pounded cassava-plantain and pounded yam are 26 and 22. Consumption of attieke could minimize postprandial blood glucose spikes, in spite of high GL and potentially have benefit in the management and prevention of some chronic diseases. PMID- 25690418 TI - Pilot dietary intervention with heat-stabilized rice bran modulates stool microbiota and metabolites in healthy adults. AB - Heat-stabilized rice bran (SRB) has been shown to regulate blood lipids and glucose, modulate gut mucosal immunity and inhibit colorectal cancer in animal and human studies. However, SRB's effects on gut microbial composition and metabolism and the resulting implications for health remain largely unknown. A pilot, randomized-controlled trial was developed to investigate the effects of eating 30 g/day SRB on the stool microbiome and metabolome. Seven healthy participants consumed a study meal and snack daily for 28 days. The microbiome and metabolome were characterized using 454 pyrosequencing and gas chromatography mass spectrometry (GC-MS) at baseline, two and four weeks post-intervention. Increases in eight operational taxonomic units (OTUs), including three from Bifidobacterium and Ruminococcus genera, were observed after two and four weeks of SRB consumption (p<0.01). Branched chain fatty acids, secondary bile acids and eleven other putative microbial metabolites were significantly elevated in the SRB group after four weeks. The largest metabolite change was a rice bran component, indole-2-carboxylic acid, which showed a mean 12% increase with SRB consumption. These data support the feasibility of dietary SRB intervention in adults and support that SRB consumption can affect gut microbial metabolism. These findings warrant future investigations of larger cohorts evaluating SRB's effects on intestinal health. PMID- 25690419 TI - Association of polyphenols from oranges and apples with specific intestinal microorganisms in systemic lupus erythematosus patients. AB - Our group has recently shown the existence of a gut microbial dysbiosis in systemic lupus erythematosus (SLE), supporting previous evidence involving intestinal bacteria in the initiation and amplification of autoimmune diseases. While several studies have addressed the use of dietary fibres to modify intestinal microbiota, information about other correlated components, such as polyphenols, is scarce. The aim of this work was to identify dietary components able to influence this altered microbiota in 20 SLE women and 20 age-matched controls. Food intake was recorded by means of a food frequency questionnaire. The intake of fibres was calculated from Marlett tables, and Phenol-Explorer was used for polyphenol consumption. Results showed positive associations between flavone intake and Blautia, flavanones and Lactobacillus, and dihydrochalcones and Bifidobacterium in the SLE group. Regarding the controls, dihydroflavonols were directly associated with Faecalibacterium, whereas flavonol intake was inversely associated with Bifidobacterium. From the food sources of these polyphenols related to microbiota, orange intake was directly associated with Lactobacillus and apple with Bifidobacterium in SLE, whilst red wine was the best contributor to Faecalibacterium variation. The association between common foods and particular microbial genera, reported to be decreased in SLE, could be of great importance for these patients. PMID- 25690420 TI - Association between dietary patterns during pregnancy and birth size measures in a diverse population in Southern US. AB - Despite increased interest in promoting nutrition during pregnancy, the association between maternal dietary patterns and birth outcomes has been equivocal. We examined maternal dietary patterns during pregnancy as a determinant of offspring's birth weight-for-length (WLZ), weight-for-age (WAZ), length-for-age (LAZ), and head circumference (HCZ) Z-scores in Southern United States (n=1151). Maternal diet during pregnancy was assessed by seven dietary patterns. Multivariable linear regression models described the association of WLZ, WAZ, LAZ, and HCZ with diet patterns controlling for other maternal and child characteristics. In bivariate analyses, WAZ and HCZ were significantly lower for processed and processed-Southern compared to healthy dietary patterns, whereas LAZ was significantly higher for these patterns. In the multivariate models, mothers who consumed a healthy-processed dietary pattern had children with significantly higher HCZ compared to the ones who consumed a healthy dietary pattern (HCZ beta: 0.36; p=0.019). No other dietary pattern was significantly associated with any of the birth outcomes. Instead, the major outcome determinants were: African American race, pre-pregnancy BMI, and gestational weight gain. These findings justify further investigation about socio environmental and genetic factors related to race and birth outcomes in this population. PMID- 25690421 TI - Rhizoma Dioscoreae extract protects against alveolar bone loss in ovariectomized rats via microRNAs regulation. AB - The aim of this study was to evaluate the osteoprotective effect of aqueous Rhizoma Dioscoreae extract (RDE) on the alveolar bone of rats with ovariectomy induced bone loss. Female Wistar rats underwent either ovariectomy or sham operation (SHAM). The ovariectomized (OVX) rats were treated with vehicle (OVX), estradiol valerate (EV), or RDE. After treatments, the bone mineral density (BMD) and the three-dimensional microarchitecture of the alveolar bone were analyzed to assess bone mass. Microarrays were used to evaluate microRNA expression profiles in alveolar bone from RDE-treated and OVX rats. The differential expression of microRNAs was validated using real-time quantitative RT-PCR (qRT-PCR), and the target genes of validated microRNAs were predicted and further analyzed using Ingenuity Pathway Analysis (IPA). The key findings were verified using qRT-PCR. Our results show that RDE inhibits alveolar bone loss in OVX rats. Compared to the OVX rats, the RDE-treated rats showed upregulated expression levels of 8 microRNAs and downregulated expression levels of 8 microRNAs in the alveolar bone in the microarray analysis. qRT-PCR helped validate 13 of 16 differentially expressed microRNAs, and 114 putative target genes of the validated microRNAs were retrieved. The IPA showed that these putative target genes had the potential to code for proteins that were involved in the transforming growth factor (TGF) beta/bone morphogenetic proteins (BMPs)/Smad signaling pathway (Tgfbr2/Bmpr2, Smad3/4/5, and Bcl-2) and interleukin (IL)-6/oncostatin M (OSM)/Jak1/STAT3 signaling pathway (Jak1, STAT3, and Il6r). These experiments revealed that RDE could inhibit ovariectomy-induced alveolar bone loss in rats. The mechanism of this anti-osteopenic effect in alveolar bone may involve the simultaneous inhibition of bone formation and bone resorption, which is associated with modulation of the TGF-beta/BMPs/Smad and the IL-6/OSM/Jak1/STAT3 signaling pathways via microRNA regulation. PMID- 25690423 TI - Dokha: an emerging smoking habit with possible oral effects. PMID- 25690424 TI - Introducing loupes to clinical practice: dental hygienists experiences and opinions. AB - OBJECTIVES: Recent literature has identified a number of potential advantages in wearing loupes for dental hygienists, including improved quality of care and ergonomics. The aim of the study was to determine dental hygienists' opinions about wearing loupes. METHODS: A short online survey was distributed to all dental hygienists who had recently participated in a study investigating the efficacy of loupes on musculoskeletal disorders; all had only worn loupes for a 6 month period, and prior to the study had not worn loupes. All of those invited completed the survey (n = 12), achieving a 100% response rate. RESULTS: The majority of respondents noted that the loupes were adaptable to wear; however, only one-quarter of hygienists surveyed were wearing them often following the study. Respondents identified that the biggest advantage to loupes was calculus removal (91.7%), and most indicated that they felt the quality of their work increased when wearing loupes (75%). The biggest disadvantage to wearing loupes was the adjustment period (50%), with limited depth of vision, headache, vertigo and infection control noted by at least one-third of respondents. CONCLUSIONS: This study revealed that hygienists identify both benefits and limitations to wearing loupes, and therefore, ongoing support may be required for hygienists adopting their use in clinical practice. PMID- 25690422 TI - Low-normal thyroid function and novel cardiometabolic biomarkers. AB - The concept is emerging that low-normal thyroid function, i.e., either higher thyroid-stimulating hormone or lower free thyroxine levels within the euthyroid reference range, could contribute to the development of atherosclerotic cardiovascular disease. It is possible that adverse effects of low-normal thyroid function on cardiovascular outcome may be particularly relevant for specific populations, such as younger people and subjects with high cardiovascular risk. Low-normal thyroid function probably relates to modest increases in plasma total cholesterol, low density lipoprotein cholesterol, triglycerides and insulin resistance, but effects on high density lipoprotein (HDL) cholesterol and non alcoholic fatty liver disease are inconsistent. Low-normal thyroid function may enhance plasma cholesteryl ester transfer, and contribute to an impaired ability of HDL to inhibit oxidative modification of LDL, reflecting pro-atherogenic alterations in lipoprotein metabolism and HDL function, respectively. Low-normal thyroid function also confers lower levels of bilirubin, a strong natural anti oxidant. Remarkably, all these effects of low-normal thyroid functional status appear to be more outspoken in the context of chronic hyperglycemia and/or insulin resistance. Collectively, these data support the concept that low-normal thyroid function may adversely affect several processes which conceivably contribute to the pathogenesis of atherosclerotic cardiovascular disease, beyond effects on conventional lipoprotein measures. PMID- 25690425 TI - Association between extra- and intracranial calcifications of the internal carotid artery: a CBCT imaging study. AB - OBJECTIVES: This study aimed to evaluate the association between the extracranial and intracranial calcification depiction of the internal carotid artery (ICA), incidentally found in CBCT examinations in adults, and to discuss the conspicuous clinical implications. METHODS: Out of a series of 1085 CBCT examinations, 705 CBCT scans were selected according to pre-defined criteria. The extra- and intracranial calcifications depicted along the course of the ICA were documented according to a comprehensive set of descriptive criteria. RESULTS: In total, 799 findings were detected, 60.1% (n = 480) were intracranially and 39.9% (n = 319) were extracranially allocated. The chi(2) test showed associations between all variables (p < 0.001). Also, most of the combinations of variables showed statistically significant results in the McNemar's test (p < 0.001). CONCLUSIONS: We found that a significant correlation exists between extra- and intracranial calcifications of the ICA. It is clear that in cases of the presence of a calcification in the ICA extracranially, the artery's intracranial portion has an increased risk of showing the same findings. CBCT imaging is widely used as a diagnostic tool, thus, our results contribute to the identification of a subgroup of patients who should undergo further medical evaluation of the atherosclerosis of the ICAs. PMID- 25690426 TI - An exceptional case of xanthomatous infiltration of the musculoskeletal and integumentary systems. AB - Tendinous and subcutaneous xanthomas are most commonly associated with primary hyperlipidemia. Xanthomatosis caused by cholesterol deposition can be a high risk marker for cardiovascular disease related to premature atherosclerosis; thus, early recognition of this diagnosis may reduce mortality and morbidity. Achilles tendon involvement is most common, followed by the extensor tendons of the hand and elbow. We present an exceptional case of tendinous and tuberous xanthomas, with intraoperative and histologic correlation, in a 34-year-old female manifesting with xanthomatous deposits of nearly all ankle tendons, plantar aponeurosis, extensor tendons of the hands, and various locations within the integumentum. To the authors' knowledge, only four studies to date have focused specifically on imaging findings of multifocal xanthomas. Thus, the radiographic and MR imaging descriptions of xanthomas in this report further add to the existing literature by helping to identify imaging characteristics of this multifocal systemic disease. The diagnosis of this condition should alert the physician to the presence of a dyslipidemia that can be treated with dietary modifications and/or drug therapy. PMID- 25690428 TI - Guidelines for hiring health promotion professionals in higher education--second edition, May 2014. PMID- 25690429 TI - Standards of practice for health promotion in higher education--third edition, May 2012. PMID- 25690431 TI - In vitro and in vivo study of hazardous effects of Ag nanoparticles and Arginine treated multi walled carbon nanotubes on blood cells: application in hemodialysis membranes. AB - One of the novel applications of the nanostructures is the modification and development of membranes for hemocompatibility of hemodialysis. The toxicity and hemocompatibility of Ag nanoparticles and arginine-treated multiwalled carbon nanotubes (MWNT-Arg) and possibility of their application in membrane technology are investigated here. MWNT-Arg is prepared by amidation reactions, followed by characterization by FTIR spectroscopy, Raman spectroscopy, and thermogravimetric analysis. The results showed a good hemocompatibility and the hemolytic rates in the presence of both MWNT-Arg and Ag nanoparticles. The hemolytic rate of Ag nanoparticles was lower than that of MWNT-Arg. In vivo study revealed that Ag nanoparticle and MWNT-Arg decreased Hematocrit and mean number of red blood cells (RBC) statistically at concentration of 100 ug mL(-1) . The mean decrease of RBC and Hematocrit for Ag nanoparticles (18% for Hematocrit and 5.8 * 1,000,000/uL) was more than MWNT-Arg (20% for Hematocrit and 6 * 1000000/uL). In addition, MWNT Arg and Ag nanoparticles had a direct influence on the White Blood Cell (WBC) drop. Regarding both nanostructures, although the number of WBC increased in initial concentration, it decreased significantly at the concentration of 100 ug mL(-1) . It is worth mentioning that the toxicity of Ag nanoparticle on WBC was higher than that of MWNT-Arg. Because of potent antimicrobial activity and relative hemocompatibility, MWNT-Arg could be considered as a new candidate for biomedical applications in the future especially for hemodialysis membranes. PMID- 25690432 TI - Uncommon case of symptomatic left renal vein compression caused by neurofibroma. PMID- 25690433 TI - Surgical resection of a giant cardiac fibroma. AB - A 42-year-old woman presented to a regional hospital emergency room with palpitations and was found to be in ventricular tachycardia. Chest radiography demonstrated a massively enlarged cardiac silhouette. Echocardiography and cardiac magnetic resonance imaging demonstrated a mass within the left ventricular free wall, consistent with a cardiac fibroma. The patient proceeded to have surgical resection of the mass. Left ventricular function was preserved postoperatively. PMID- 25690434 TI - Factors precipitating erythropoiesis-stimulating agent responsiveness in a European haemodialysis cohort: case-crossover study. AB - PURPOSE: Hyporesponsiveness to erythropoiesis-stimulating agents (ESAs) is clinically and economically important in the treatment of anaemia in chronic kidney disease (CKD) patients. Previous studies focused on baseline predictors of ESA hyporesponsiveness, rather than factors associated with the transition to this state. Reversibility of ESA hyporesponsiveness has also not been studied previously. METHODS: Case-crossover methodology was applied to a cohort of 6645 European CKD patients undergoing haemodialysis and prescribed ESAs. Ninety-day ESA exposure periods were defined, haemoglobin (Hb) response was calculated using the last 30 days of one period and the first 30 days of the next, and periods were classified based on a median ESA dose (80.8 IU/kg/week) and a 10 g/dL Hb threshold. Clinical, dialysis and laboratory data from patients' first hyporesponsive 'case' period was compared with the preceding responsive 'control' period using conditional logistic regression. A similar approach was applied to hyporesponsiveness reversal. RESULTS: Of the patients, 672 experienced hyporesponsiveness periods with preceding responsive periods; 711 reversed to normality from hyporesponsiveness periods. Transition to hyporesponsiveness was associated with hospitalization, vascular access changes or worsening inflammation, with these factors accounting for over two-thirds of transitions. Findings were largely insensitive to alternative ESA doses and Hb thresholds. Continued hospitalization, catheter insertion and uncontrolled secondary hyperparathyroidism were associated with a lack of regain of responsiveness. CONCLUSIONS: Transition to hyporesponsiveness is linked to the development of conditions such as hospitalization events, vascular access issues or episodes of systemic inflammation. However, a third of hyporesponsive episodes remain unexplained. PMID- 25690435 TI - Response of urinary purine derivatives excretion to different levels of ruminal glucose infusion in heifers. AB - This study investigated the response of urinary purine derivatives (PD) excretion to increasing levels of intraruminal glucose infusion to evaluate how well this indicator reflects induced changes in microbial crude protein flow. Four rumen cannulated heifers (482 +/- 25 kg body weight) were fed at maintenance energy level with a basal diet (on fresh matter basis) of 4 kg/d hay, 1.5 kg/d concentrate and 60 g/d minerals in two equal meals. The trial comprised a control period (Control I) without glucose infusion followed by four consecutive periods in which all animals received 125 g, 250 g, 500 g or 1000 g/d of glucose, respectively. For this, daily dosages of glucose and urea (90 g/d during all periods) were divided into three portions that were dissolved in water and directly administered into the rumen during morning and afternoon feedings and once during noon. After the highest glucose dosage, a second control period was carried out (Control II). Urinary PD excretion increased with glucose infusion of 125 g/d (71.4 mmol/d) and 1000 g/d (74.2 mmol/d) over the level at Control I (53.9 mmol/d (standard error of the mean (SEM) 3.4; p = 0.012). After withdrawing glucose infusion, PD excretion (79.0 mmol/d) did not return to Control I level (p = 0.001). In contrast, faecal nitrogen (N) excretions linearly increased with incremental glucose infusion (p < 0.001) from 33.9 g/d at Control I to 39.7 g/d (SEM 0.5) at 1000 g/d of glucose and were similar in Control I and II (p = 0.086). The contradicting responses in the excretions of faecal N and urinary PD to increasing glucose infusions highlight the limited accuracy of the PD excretion as a non-invasive indicator when incremental dosages of rapidly fermentable carbohydrates are supplied. PMID- 25690436 TI - A Cp*CoI2-dimer as a precursor for cationic Co(III)-catalysis: application to C-H phosphoramidation of indoles. AB - C2-selective indole C-H phosphoramidation was achieved through improved Cp*Co(III) catalysis. A cationic Co(III) species generated in situ from a Cp*CoI2 dimer showed the best catalytic activity, giving phosphoramidated indoles in 60 86% yield. PMID- 25690437 TI - Local government funding issues are forcing public health leaders to be "crafty" with resources. PMID- 25690438 TI - Interventions to address deficits of pharmacological pain management in nursing home residents--A cluster-randomized trial. AB - BACKGROUND: To evaluate the effect of interventions for general practitioners and nursing home staff to improve pain severity and appropriateness of pain medication in nursing home residents (NHR). METHODS: This cluster-randomized controlled trial was conducted in six nursing homes in the intervention and control group, respectively. Pain management was analysed before (T0) and after (T1, T2) an educational intervention in 239 NHR, aged >=65 years, without moderate or severe cognitive impairment. Primary and secondary outcomes were average pain severity and appropriateness of pain medication as determined with the Numeric Rating Scale and Pain Medication Appropriateness Scale (PMASD ), respectively. RESULTS: At T0, 72.2% and 73.7% of NHR (mean age 83 years) reported pain (average pain severity 2.4) in the intervention and control group, respectively. The PMASD at T0 was 53.9 in the intervention group and 60.8 in the control group (p = 0.12), while 20.6% compared to 6.9% (p = 0.009) received no pain medication in the two groups. At T2, non-significant improvements in the average pain severity (1.59) and PMASD (61.07) were observed in the intervention group. Moreover, the mean individual PMASD increased by 8.09 (p = 0.03) and the proportion of NHR without pain medication decreased by 50% (p = 0.03) in the intervention group. No appreciable changes were found in the control group at T2. CONCLUSIONS: NHR exhibited a high prevalence of pain with overall low severity, while a high proportion of individuals received inappropriate pain medications. Both findings were not significantly improved by the intervention, although some aspects of drug treatment were meaningful improved. PMID- 25690439 TI - Long-term risk of seizures and epilepsy in patients with posterior reversible encephalopathy syndrome. AB - OBJECTIVE: Seizures are common in patients with posterior reversible encephalopathy syndrome (PRES), which is reported in up to 70% of cases, and antiepileptic drugs (AEDs) are commonly prescribed. There is a paucity of data regarding the risk of subsequent seizures following resolution of PRES, and therefore the optimal duration of treatment with AEDs is currently unknown. The objective of this study was to identify the frequency of recurrent seizures and epilepsy following recovery from PRES. METHODS: We performed a retrospective review of consecutive adults diagnosed with PRES between 2000 and 2010. RESULTS: One hundred twenty-seven patients, median age 53 years (interquartile range [IQR] 37-64), were included in the analysis. The most common causes of PRES were hypertension (72%) and immunosuppression (20%). Renal failure was present in 47%. Eighty-four patients (66%) had seizures at presentation (39 focal, 45 generalized), and 13 (15%) of them presented with status epilepticus. Median duration of follow-up was 3.2 years (IQR 4 months to 6.9 years). Patients with seizures were treated with AEDs for a median of 3 months (IQR 2-7). Fifteen patients (12%) had provoked seizures during the follow-up period; in eight (53%) patients seizures were caused by recurrent PRES. Only three patients had subsequent unprovoked seizures, one of whom was considered to have developed epilepsy. SIGNIFICANCE: We conclude that unprovoked seizures and epilepsy are uncommon in patients who have recovered from PRES. Discontinuation of AEDs following resolution of PRES should be considered, provided there is adequate control of risk factors, and absence of factors that could substantially lower the seizure threshold. PMID- 25690440 TI - Simulation as a high stakes assessment tool in emergency medicine. AB - The Australasian College for Emergency Medicine (ACEM) will introduce high stakes simulation-based summative assessment in the form of Objective Structured Clinical Examinations (OSCEs) into the Fellowship Examination from 2015. Miller's model emphasises that, no matter how realistic the simulation, it is still a simulation and examinees do not necessarily behave as in real life. OSCEs are suitable for assessing the CanMEDS domains of Medical Expert, Communicator, Collaborator and Manager. However, the need to validate the OSCE is emphasised by conflicting evidence on correlation with long-term faculty assessments, between essential actions checklists and global assessment scores and variable interrater reliability within individual OSCE stations and for crisis resource management skills. Although OSCEs can be a valid, reliable and acceptable assessment tool, the onus is on the examining body to ensure construct validity and high interrater reliability. PMID- 25690441 TI - Maintenance of reduction with suture button fixation devices for ankle syndesmosis repair. AB - BACKGROUND: Malreduction of the syndesmosis can lead to increased peak pressures and subsequent arthritis. The purpose of this study was to evaluate the initial syndesmotic reduction and radiographic maintenance when using a knotless suture button fixation device for treatment of syndesmotic injury. METHODS: A retrospective chart and radiographic review was performed to identify patients who underwent open reduction internal fixation of ankle syndesmosis ruptures treated with a knotless, suture button fixation system. Radiographic measurements included medial clear space, tibiofibular overlap, tibiofibular clear space, and the distance between buttons. Fifty-six patients underwent repair of an ankle fracture with syndesmotic rupture over a 3-year period, with a mean follow-up of 160.9 days. RESULTS: The tibiofibular clear space and tibiofibular overlap significantly improved from pre- to first postoperative, but also demonstrated some loss of fixation at final follow-up (P < .001). The distance between the buttons increased on average 1.1 mm from immediate postoperative to final follow up, demonstrating some postoperative creep and loss of fixation in the system. A low complication rate and need for a revision operation was found in our patient cohort. Some loss of reduction did occur postoperatively, although this did not correlate to adverse patient outcomes. CONCLUSION: Syndesmotic stabilization, using a knotless suture button fixation device demonstrated adequate initial syndesmotic reduction, but also exhibited an increase in the tibiofibular clear space and tibiofibular overlap, relative to initial postfixation position, at short-term follow-up. LEVEL OF EVIDENCE: Level IV, retrospective case series. PMID- 25690442 TI - Fracture-Dislocations Demonstrate Poorer Postoperative Functional Outcomes Among Pronation External Rotation IV Ankle Fractures. AB - BACKGROUND: Pronation external rotation (PER) ankle fractures are relatively uncommon but serious ankle injuries. Although recent studies have demonstrated good outcomes of PER IV fractures after operative treatment, the effect of dislocation on functional outcomes has not yet been evaluated. The objective of this study was to compare short-term functional outcomes in PER IV ankle fractures with and without dislocation. METHODS: Our database of ankle fractures surgically treated using an anatomic fixation approach by the senior author from 2003 to 2013 was reviewed. All PER IV ankle fracture patients older than 18 years with a minimum of 12 months of follow-up, including Foot and Ankle Outcome Score (FAOS), were included for analysis. Patient demographics, injury characteristics, FAOS, ankle range of motion (ROM), and rate of postoperative complications were compared in PER IV fractures with and without dislocation. Of the 47 PER IV fractures included for analysis, 20 (43%) were fracture-dislocations and 27 (57%) had no dislocation. Mean age of the study cohort was 49 years (range, 24-91 years). RESULTS: The fracture-dislocation cohort demonstrated significantly poorer FAOS (symptoms, 46 vs 70, P = .002; pain, 56 vs 82, P < .001; activities of daily living, 61 vs 84, P = .002; sports, 37 vs 59, P = .036; quality of life, 25 vs 59, P < .001) than the nondislocation cohort. Articular malreduction (33% vs 14%, P = .147) was also more common in the PER IV dislocation group. Rates of syndesmotic malreduction (44% vs 48%, P = .951) were similar between PER IV fractures with and without dislocation. CONCLUSION: PER IV fracture-dislocations had higher rates of articular malreduction and demonstrated statistically poorer functional outcomes than PER IV fractures with no dislocation. Dislocation in this select subset of ankle fracture patients likely represents a higher energy injury resulting in substantial articular damage and should spur appropriate preoperative patient counseling by the orthopaedic surgeon concerning functional outcome expectations. LEVEL OF EVIDENCE: Level III clinical outcome comparison. PMID- 25690443 TI - Long-Term Follow-Up of Adults with Gender Identity Disorder. AB - The aim of this study was to re-examine individuals with gender identity disorder after as long a period of time as possible. To meet the inclusion criterion, the legal recognition of participants' gender change via a legal name change had to date back at least 10 years. The sample comprised 71 participants (35 MtF and 36 FtM). The follow-up period was 10-24 years with a mean of 13.8 years (SD = 2.78). Instruments included a combination of qualitative and quantitative methods: Clinical interviews were conducted with the participants, and they completed a follow-up questionnaire as well as several standardized questionnaires they had already filled in when they first made contact with the clinic. Positive and desired changes were determined by all of the instruments: Participants reported high degrees of well-being and a good social integration. Very few participants were unemployed, most of them had a steady relationship, and they were also satisfied with their relationships with family and friends. Their overall evaluation of the treatment process for sex reassignment and its effectiveness in reducing gender dysphoria was positive. Regarding the results of the standardized questionnaires, participants showed significantly fewer psychological problems and interpersonal difficulties as well as a strongly increased life satisfaction at follow-up than at the time of the initial consultation. Despite these positive results, the treatment of transsexualism is far from being perfect. PMID- 25690444 TI - Intersecting Race and Gender Cues are Associated with Perceptions of Gay Men's Preferred Sexual Roles. AB - Preferences for anal sex roles (top/bottom) are an important aspect of gay male identity, but scholars have only recently begun to explore the factors that covary with these preferences. Here, we argue that the gendered nature of both racial stereotypes (i.e., Black men are masculine, Asian men are feminine) and sexual role stereotypes (i.e., tops are masculine, bottoms are feminine) link the categories Asian/bottom and the categories Black/top. We provide empirical evidence for these claims at three levels of analysis: At the cultural level based upon gay men's stereotypic beliefs about others (Study 1), at the interpersonal level based upon gay men's perceptions of others' sexual role preferences (Study 2), and at the intrapersonal level based upon racially diverse men's self-reported sexual roles on a public hookup website (Study 3). These studies offer the first systematic evidence of linkages between race categories and sexual roles in gay male communities. PMID- 25690445 TI - Indirect Measurement of Sexual Orientation: Comparison of the Implicit Relational Assessment Procedure, Viewing Time, and Choice Reaction Time Tasks. AB - The present study was conducted to validate an adaptation of the Implicit Relational Assessment Procedure (IRAP) as an indirect latency-based measure of sexual orientation. Furthermore, reliability and criterion validity of the IRAP were compared to two established indirect measures of sexual orientation: a Choice Reaction Time task (CRT) and a Viewing Time (VT) task. A sample of 87 heterosexual and 35 gay men completed all three indirect measures in an online study. The IRAP and the VT predicted sexual orientation nearly perfectly. Both measures also showed a considerable amount of convergent validity. Reliabilities (internal consistencies) reached satisfactory levels. In contrast, the CRT did not tap into sexual orientation in the present study. In sum, the VT measure performed best, with the IRAP showing only slightly lower reliability and criterion validity, whereas the CRT did not yield any evidence of reliability or criterion validity in the present research. The results were discussed in the light of specific task properties of the indirect latency-based measures (task relevance vs. task-irrelevance). PMID- 25690446 TI - The Role of Selection Effects in the Contact Hypothesis: Results from a U.S. National Survey on Sexual Prejudice. AB - Empirical research has documented that contact with lesbians and gays is associated with more positive feelings toward and greater support for legal rights for them, but we know less about whether these effects extend to informal aspects of same-sex relationships, such as reactions to public displays of affection. Furthermore, many studies have assumed that contact influences levels of sexual prejudice; however, the possibility of selection effects, in which less sexually prejudiced people have contact, and more sexually prejudiced people do not, raises some doubts about this assumption. We used original data from a nationally representative sample of heterosexuals to determine whether those reporting contact with a lesbian, gay, bisexual, or transgender friend or relative exhibited less sexual prejudice toward lesbian and gay couples than those without contact. This study examined the effect of contact on attitudes toward formal rights and a relatively unexplored dimension, informal privileges. We estimated the effect of having contact using traditional (ordinary least squares regression) methods before accounting for selection effects using propensity score matching. After accounting for selection effects, we found no significant differences between the attitudes of those who had contact and those who did not, for either formal or informal measures. Thus, selection effects appeared to play a pivotal role in confounding the link between contact and sexual prejudice, and future studies should exercise caution in interpreting results that do not account for such selection effects. PMID- 25690447 TI - How children learn about sex: a cross-species and cross-cultural analysis. AB - Scattered and not widely disseminated evidence from primatology, anthropology, and history of childhood sexuality support the hypothesis that throughout much of human behavioral evolution that human children have learned about sex through observing parental sexuality and then imitating it in sexual rehearsal play with peers. Contemporary theories of psychosexual development have not considered the possibility that young children are predisposed to learn about sex through observational learning and sexual rehearsal play during early childhood, a primate-wide trait that is conserved in humans but suppressed in contemporary contexts. PMID- 25690448 TI - Erratum to: Sex work among students of higher education: a survey-based, cross sectional study. PMID- 25690449 TI - The postirradiation incidence of cavernous angioma is higher in patients with childhood pineoblastoma or primitive neuroectodermal tumors than medulloblastoma. AB - PURPOSE: The purpose of this study is to investigate the incidence of cavernous angioma (CVA) in long-term survivors of childhood embryonal tumors treated by cranial irradiation. MATERIALS AND METHODS: Between 1990 and 2012, we treated 25 patients (13 males, 12 females) with embryonal tumors (17 medulloblastomas, 5 primitive neuroectodermal tumors (PNET), 3 pineoblastomas) with craniospinal irradiation. Follow-up ranged from 15.5 to 289.9 months, the irradiation dose to the whole neural axis from 18 to 36 Gy, and the total local dose from 49.6 to 60 Gy. All patients underwent follow-up magnetic resonance imaging (MRI) studies at least once a year, and the diagnosis of posttreatment CVA was based solely on MRI findings. RESULTS: At the time of this writing, 18 were alive and free of the recurrence of the original disease or the development of secondary neoplasms other than CVA; another 2 were alive with medulloblastoma or diffuse astrocytoma. Posttreatment, 14 patients developed CVAs in the course of a median of 56.7 months; 13 of these presented with multiple CVAs. Patients who underwent radiation therapy (RT) at an age younger than 6 years developed multiple CVAs significantly earlier than those treated at a later age (p = 0.0110). Patients with PNET or pineoblastoma developed Zabramski type 1 and 2 CVA significantly earlier than did medulloblastoma patients (p = 0.0042). CONCLUSION: We attribute the high rate of post-RT CVA in our long-term follow-up study of pediatric patients to the delivery of cranial irradiation for embryonal tumors, especially PNET and pineoblastoma, and recommend the regular, long-term follow-up of patients whose embryonal tumors were treated by cranial irradiation. PMID- 25690450 TI - Schizencephaly-diagnostics and clinical dilemmas. AB - BACKGROUND: Schizencephaly is an uncommon congenital disorder of cerebral cortical development. The defect is characterized by the presence of a cleft in the brain extending from the surface of the pia mater to the cerebral ventricles. The margins of the cleft are lined with heterotropic, dysplastic gray matter. The causes of schizencephaly are heterogeneous and can include teratogens, prenatal infection, maternal trauma, or EMX2 mutations. METHOD: In the present paper, the authors described difficulties in employing diagnostic imaging in differentiating between type II (open-lip) schizencephaly and much more common intracranial fluid spaces of a different origin (arachnoid cysts and hydrocephalus). RESULT: In all the three cases, the treatment consisted in implantation of a shunt system; nevertheless, it should be emphasized that a surgical intervention in the third presented case (type II schizencephaly) aimed at relieving the symptoms of intracranial hypertension-a directly life-threatening condition-since shunting is not a method of treating schizencephaly itself. CONCLUSIONS: Although proper interpretation of the character of intracranial fluid spaces is of significance for further therapeutic management, yet, the key decision as to the surgical intervention is made based on clinical presentation, predominantly on symptoms of intracranial hypertension. PMID- 25690451 TI - Histological structure of the medial and lateral walls of cavernous sinus in human fetuses. AB - PURPOSE: The aim of this study is to elucidate the architecture of these fine structures in human fetuses. METHODS: The histological examination of medial wall (MW) and lateral wall (LW) was performed in 15 normal human fetuses. Eleven fetuses were female and four were male. The gestational age ranged between 14 and 35 weeks. The weight ranged between 180 and 1750 g. The wall samples (two MW and two LW from each fetus) were obtained by microsurgical technique and underwent histological examination. Each wall was examined for the structure and composition of collagen and elastic fibers, ganglions, peripheral nerves, and vessels. RESULTS: A total of 60 wall samples (30 MW and 30 LW) were examined in 15 fetuses. Loose connective tissue composed of type III collagen was observed in both of the walls. Elastic fibers were observed only in three wall samples (two MW and one LW). Ganglion was detected in 11 samples (nine in LW and two in MW), and peripheral nerve was found in 28 walls (18 LW and 10 MW). Vessels were observed in 51 samples (26 LW and 25 MW). None of the walls was stained with type I collagen. CONCLUSIONS: The structure of LW and MW of the cavernous sinus (CS) in fetuses is mainly composed of collagen tissue while some elastic fibers are supported by this tissue. Type III collagen is the main component of fetal CS walls. Because of the weak histological structure, CS may be more prone to tumor invasion in infants. PMID- 25690452 TI - Synthesis of [(18) F] 4-amino-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1,2,5 oxadiazole-3-carboximidamide (IDO5L): a novel potential PET probe for imaging of IDO1 expression. AB - To synthesize (18) F-labeled positron emission tomography (PET) ligands, reliable labeling techniques inserting (18) F into a target molecule are necessary. The (18) F-fluorobenzene moiety has been widely utilized in the synthesis of (18) F labeled compounds. The present study utilized [(18) F]-labeled aniline as intermediate in [(18) F]-radiolabeling chemistry for the facile radiosynthesis of 4-amino-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1,2,5-oxadiazole-3-carboximidamide ([(18) F]IDO5L) as indoleamine 2,3-dioxygenase 1 (IDO1) targeted tracer. IDO5L is a highly potent inhibitor of IDO1 with low nanomolar IC50 . [(18) F]IDO5L was synthesized via coupling [(18) F]3-chloro-4-fluoroaniline with carboximidamidoyl chloride as a potential PET probe for imaging IDO1 expression. Under the optimized labeling conditions, chemically and radiochemically pure (>98%) [(18) F]IDO5L was obtained with specific radioactivity ranging from 11 to 15 GBq/umol at the end of synthesis within ~90 min, and the decay-corrected radiochemical yield was 18.2 +/- 2.1% (n = 4). PMID- 25690453 TI - Preconception diet or exercise intervention in obese fathers normalizes sperm microRNA profile and metabolic syndrome in female offspring. AB - Obesity and type 2 diabetes are increasingly prevalent across all demographics. Paternal obesity in humans and rodents can program obesity and impair insulin sensitivity in female offspring. It remains to be determined whether these perturbed offspring phenotypes can be improved through targeted lifestyle interventions in the obese father. Using a mouse model, we demonstrate that diet or exercise interventions for 8 wk (2 rounds of spermatogenesis) in obese founder males restores insulin sensitivity and normalized adiposity in female offspring. Founder diet and/or exercise also normalizes abundance of X-linked sperm microRNAs that target genes regulating cell cycle and apoptosis, pathways central to oocyte and early embryogenesis. Additionally, obesity-associated comorbidities, including inflammation, glucose intolerance, stress, and hypercholesterolemia, were good predictors for sperm microRNA abundance and offspring phenotypes. Interventions aimed at improving paternal metabolic health during specific windows prior to conception can partially normalize aberrant epigenetic signals in sperm and improve the metabolic health of female offspring. PMID- 25690454 TI - A Sensitive Medium-Throughput Method to Predict Intestinal Absorption in Humans Using Rat Intestinal Tissue Segments. AB - A range of in vitro, ex vivo, and in vivo approaches are currently used for drug development. Highly predictive human intestinal absorption models remain lagging behind the times because of numerous variables concerning permeability through gastrointestinal tract in humans. However, there is a clear need for a drug permeability model early in the drug development process that can balance the requirements for high throughput and effective predictive potential. The present study developed a medium throughput screening Snapwell (MTS-Snapwell) ex vivo model to provide an alternative method to classify drug permeability. Rat small intestine tissue segments were mounted in commercial SnapwellTM inserts. Unidirectional drug transport (A-B) was measured by collecting samples at different time points. Viability of intestinal tissue segments was measured by examining transepithelial electric resistance (TEER) and phenol red and caffeine transport. As a result, the apparent permeability (Papp; *10(-6) cm/s) was determined for atenolol (10.7 +/- 1.2), caffeine (17.6 +/- 3.1), cimetidine (6.9 +/- 0.1), metoprolol (12.6 +/- 0.7), theophylline (15.3 +/- 1.6) and, ranitidine (3.8 +/- 0.4). All drugs were classified in high/low permeability according to Biopharmaceutics Classification System showing high correlation with human data (r = 0.89). These findings showed a high correlation with human data (r = 0.89), suggesting that this model has potential predictive capacity for paracellular and transcellular passively absorbed molecules. PMID- 25690455 TI - Acute safety and efficacy of the NeoChord procedure?. AB - OBJECTIVES: Transapical off-pump mitral valve repair using the NeoChord device has been proposed to treat degenerative mitral valve regurgitation. This prospective study sought to evaluate acute safety and efficacy of this innovative, minimally invasive, transcatheter mitral valve repair approach. METHODS: Symptomatic patients with severe mitral regurgitation (MR) were selected if they presented a favourable valve anatomy (the presence of leaflet flail/prolapse with consistent overlap of tissue). Early device success was defined as placement of at least two neochordae with residual mitral regurgitation <= 2+ after the procedure. The primary acute safety and efficacy end points were evaluated at 30 days. RESULTS: Between February 2013 and June 2014, in Padua and Vilnius University Hospitals, a total of 62 patients were treated, with a median age of 66 years (IQR 52-76) and a median EuroSCORE I of 1.9% (IQR 0.9-6). Fifty-six patients (88.9%) presented with a posterior leaflet prolapse, 4 (6%) with an anterior leaflet prolapse and 3 (5%) with a combined disease. Early procedural success was achieved in all patients. Two neochordae were implanted in 2 patients (3%), 3 in 20 (32%), 4 in 28 (44%), 5 in 10 (16%), 6 in 2 (3%) and 7 in 1 (2%). At 30 days, major adverse events included only 1 acute myocardial infarction (2%) successfully treated percutaneously and 2 cases of sepsis (3%). Mitral regurgitation at 30 days was absent in 29 patients (46%), Grade 1+ in 16 (25%), Grade 2+ in 10 (16%), Grade 3+ in 7 (11%) and Grade 4+ in 1 (2%). All 8 patients with MR >2+ were successfully reoperated with conventional surgery or NeoChord reintervention. CONCLUSIONS: Initial results with the NeoChord procedure in a small number of patients indicate that transapical off pump mitral valve repair is feasible and safe. Efficacy is maintained up to the 30-day follow-up with significant clinical benefit for patients. PMID- 25690456 TI - Aortic valve reimplantation for large root aneurysm and high-grade aortic regurgitation: incidence and implications of additional cusp and commissure repair. AB - OBJECTIVES: Large-sized root aneurysm and high-grade aortic regurgitation (AR) might be contraindications for a valve-sparing aortic root replacement procedure (V-SARR) and aortic valve repair. The impact of a combination of root reimplantation and additional cusp/commissure repair on valve sufficiency in this setting was investigated with respect to early- and mid-term functional outcome. METHODS: Out of a cohort of 220 patients treated with V-SARR, 73 with an aneurysm size >= 55 mm were identified. As a cut-off for high-grade preoperative AR, a grade of >= 3 was defined. End points were absolute early and mid-term aortic regurgitation grades, new incidence of AR and AR progression. The mean echocardiographic follow-up time was 3.8 years. T-tests, Kaplan-Meier and log rank calculations were employed. RESULTS: Within the studied cohort of large aneurysms >= 55 mm [total, n = 73; mean age, 56 +/- 14 years; female, n = 22 (30%); Marfan, n = 9 (12%); bicuspid valve n = 6 (8%)], 21 (29%) individuals had AR grades >= 3+. The rest had lower grade AR (63%) and 6 (8%) had a normally functioning aortic valve. The incidence rate of additional cusp procedures was 27% (n = 20) and included cusp plication, Trussler Stitch, cusp shaving and commissure resuspension. Incidence of additional cusp/commissure repair was 2 (9.5%) among patients with higher grade AR >= 3+, while it was 18 (30%) among patients with lower grade AR or a normally functioning valve (P = 0.03). The mean early postoperative AR was 0.5 (median, 1.0). The rate of freedom from early failure, valve replacement and AR >= 2 was 96%. The rate of freedom from AR progression was 96% and from new onset AR was 100%. CONCLUSIONS: The setting of a large proximal thoracic aortic aneurysm size and high-grade AR does not result in a higher need for cusp/commissure procedures in order to achieve a satisfactory mid-term functional outcome. Large aneurysm size and high-grade AR per se do not increase the complexity of repair. The choice of reimplantation technique and prosthesis size selection might impact on mid-term valve function. PMID- 25690457 TI - Risk factors for postoperative recurrence of spontaneous pneumothorax treated by video-assisted thoracoscopic surgery?. AB - OBJECTIVES: Over the past two decades, video-assisted thoracoscopic blebectomy and pleurodesis have been used as a safe and reliable option for treatment of spontaneous pneumothorax. The aim of this study is to evaluate the long-term outcome of video-assisted thoracoscopic surgery (VATS) treatment of spontaneous pneumothorax in young patients, and to identify risk factors for postoperative recurrence. METHODS: We retrospectively analysed the outcome of VATS treatment of spontaneous pneumothorax in our institution in 150 consecutive young patients (age <= 40 years) in the years 1997-2010. Treatment consisted of stapling blebectomy and partial parietal pleurectomy. After excluding 16 patients lost to follow-up, in 134 cases [110 men, 24 women; mean age, 25 +/- 7 standard deviation years; median follow-up, 79 months (range: 36-187 months)], we evaluated postoperative complications, focusing on pneumothorax recurrence, thoracic dysaesthesia and chronic chest pain. Risk factors for postoperative pneumothorax recurrence were analysed by logistic regression. RESULTS: Of 134 treated patients, 3 (2.2%) required early reoperation (2 for bleeding; 1 for persistent air leaks). Postoperative (90-day) mortality was nil. Ipsilateral pneumothorax recurred in 8 cases (6.0%) [median time of recurrence, 43 months (range: 1-71 months)]. At univariate analysis, the recurrence rate was significantly higher in women (4/24) than in men (4/110; P = 0.026) and in patients with >7-day postoperative air leaks (P = 0.021). Multivariate analysis confirmed that pneumothorax recurrence correlated independently with prolonged air leaks (P = 0.037) and with female gender (P = 0.045). Chronic chest wall dysaesthesia was reported by 13 patients (9.7%). In 3 patients, (2.2%) chronic thoracic pain (analogical score >4) was recorded, but only 1 patient required analgesics more than once a month. CONCLUSIONS: VATS blebectomy and parietal pleurectomy is a safe procedure for treatment of spontaneous pneumothorax in young patients, with a 6% long-term recurrence rate in our experience. Postoperative recurrence significantly correlates with female gender and with prolonged air leakage after surgery. PMID- 25690458 TI - Atrio-ventricular valve regurgitation in univentricular hearts: outcomes after repair?. AB - OBJECTIVES: The aim was to describe the early and mid-term outcome after atrio ventricular valve (AVV) repair in patients with univentricular hearts (UVHs) and to identify risk factors for AVV reoperation and death. METHODS: This study is a retrospective review of patients undergoing valve repair for AVV regurgitation at any stage of univentricular palliation from 1998 to 2014. Patient- and procedure related variables were analysed. RESULTS: A total of 31 consecutive patients underwent 38 procedures for >= moderate AVV regurgitation at a median age of 3.6 years. Thirty-two percent of patients had a common AVV, 26% had two AVVs, 22% had a dominant tricuspid valve and 19% had a dominant mitral valve. All patients underwent valve repair as a first procedure without early mortality. At discharge, patients preserved their ventricular function (fractional shortening <30%: preoperative 16% vs postoperative 22.5%, NS). In 19% (n = 6) of patients, the procedure was considered as failed because of significant residual regurgitation. There were three late deaths [median delay: 1 year (range 0.7 13.6)] and three heart transplantations. Six patients underwent seven AVV reoperations [median delay: 2 years (range 0.2-7.6)]. Longer intensive care stay (P = 0.022), longer total postoperative hospital stay (P = 0.039), higher total number of surgeries (P = 0.039), lower body mass index (P = 0.042) and higher preoperative mean pulmonary pressure (P = 0.047) were univariate risk factors for death/transplantation. Failed first AVV repair (P = 0.01), higher total number of surgeries (P = 0.026), lower body mass index (P = 0.031), male gender (P = 0.031) and need for valve repair before bidirectional cavopulmonary connection (P = 0.036) were univariate risk factors for AVV reoperation. In multivariate analysis, no univariate risk factor reached statistical significance. Freedom from death/transplantation was 84% (CI 95%: 70%-98%) at 5 and 10 years. Survival free from AVV reoperation was 72% (CI 95%: 52%-92%) at 5 years and 62% at 10 years (CI 95%: 36%-88%). Mean follow-up of survivors was 4.7 years (SD +/- 4.3; range 0.2-15.6). At last visit, 96% of survivors were in NYHA Class I-II. Ninety two percent had a <= mild residual regurgitation. CONCLUSIONS: In patients with a UVH and >= moderate AVV regurgitation, AVV repair is feasible without postoperative deterioration of their ventricular function. Nevertheless, these patients remain at increased risk for death/transplantation and AVV reoperation. PMID- 25690459 TI - Provider's and user's perspective about immunization coverage among migratory and non-migratory population in slums and construction sites of Chandigarh. AB - Strengthening routine immunization is a corner stone for countries to achieve the United Nations Millennium Development Goal 4 (MDG 4) which aims to reduce under five mortality by two-thirds and MDG 5 improving maternal health compared to 1990 estimates by 2015. The poor urban newborns are more vulnerable to many health and nutrition problems compared to the non-poor urban counterparts. Therefore there is a need to strengthen health system to cater the needs of urban poor. Standardized WHO30*7 cluster sampling for slums and convenience sampling for construction sites. In depth interviews were conducted for user's as well as provider's perspective about immunization coverage. Two hundred ten children and 210 mothers were enrolled in slums and 100 were sampled from construction sites. The slum workers are considered as non-migratory groups whereas construction site workers are considered as migratory population. Among children, 23 % were fully immunized, 73 % were partially immunized and 3 % were unimmunized in non migratory population whereas 3 % were fully immunized, 91 % were partially immunized and 6 % were unimmunized in migratory population. Among mothers, 43 and 39 % were fully immunized, 13 and 15 % partially immunized and 43 and 46 % were unimmunized in non-migratory and migratory population, respectively. The various reasons attributed for low coverage are (a) dissatisfaction of the users with the service delivery and procedural delays (bureaucracy), (b) lack of faith in health workers, PMID- 25690460 TI - Urea-assisted aqueous exfoliation of graphite for obtaining high-quality graphene. AB - Urea-assisted aqueous exfoliation of graphite was found to be more efficient than exfoliation in N,N-dimethylformamide (DMF), and high-quality graphene was obtained with a yield up to 2.4%. The mechanism in which a primary amine facilitates aqueous exfoliation was proposed and experimentally validated, which may inspire new strategies for efficient liquid exfoliation. PMID- 25690461 TI - From Mysterious Supernatant Entity to miRNA-150 in Antigen-Specific Exosomes: a History of Hapten-Specific T Suppressor Factor. AB - Soon after the discovery of T suppressor cells by Gershon in 1970, it was demonstrated that one subpopulation of these lymphocytes induced by i.v. hapten injection suppresses contact sensitivity response mediated by effector CD4+ or CD8+ T cells in mice through the release of soluble T suppressor factor (TsF) that acts antigen specifically. Our experiments showed that biologically active TsF is a complex entity consisting of two subfactors, one antigen specific and other non-specific, produced by differently induced populations of cells. In following years, we found that the antigen-specific subfactor is a light chain of IgM antibody that is produced by B1a lymphocytes. However, the exact nature of non-specific part remained a mystery for about 30 years. Our current studies characterized TsF as regulatory miRNA-150 carried by T suppressor cell-derived exosomes that are antigen specific due to a surface coat of IgM antibody light chains produced by B1a cells. The present communication briefly summarizes our studies on TsF that led to discovery of regulating miRNA that acts antigen specifically to suppress immune response. PMID- 25690462 TI - Identification of the Babesia-responsive leucine-rich repeat domain-containing protein from the hard tick Haemaphysalis longicornis. AB - Haemaphysalis longicornis is a tick known for transmitting Babesia parasites, including Babesia gibsoni, in East Asian countries. The vector tick must have strategies to control Babesia parasites, while Babesia parasites are also considered to establish an evasive mechanism from the tick's innate immunity. Due to this mutual tolerance, H. longicornis is considered to be a vector of Babesia parasites. Recent studies have shown the important roles of leucine-rich repeat (LRR) domain-containing proteins in innate immunity in many living organisms. Some LRR domain-containing proteins were identified in ticks; however, their functions are still unknown. In this study, a novel LRR domain-containing protein was identified from H. longicornis (HlLRR). HlLRR contains two LRR domains, and the expression levels of mRNA and proteins were upregulated during blood feeding, particularly in the salivary glands and midgut. In addition, recombinant HlLRR (rHlLRR) demonstrated growth inhibition activity against B. gibsoni in vitro without a hemolytic effect at any concentration used. Moreover, the diameters of Babesia merozoites treated with rHlLRR were significantly larger than those of the control group. These results strongly indicate the key roles of HlLRR in the tick's innate immunity against Babesia parasites. Furthermore, HlLRR might be a potential alternative drug to treat babesiosis. PMID- 25690463 TI - Altered urinary sodium excretion response after central cholinergic and adrenergic stimulation of adult spontaneously hypertensive rats. AB - In this study, we hypothesized that blunting of the natriuresis response to intracerebroventricularly (i.c.v.) microinjected cholinergic and adrenergic agonists is involved in the development of hypertension in spontaneously hypertensive rats (SHR). We evaluated the effect of i.c.v. injection of cholinergic and noradrenergic agonists, at increasing concentrations, and of muscarinic cholinergic and alpha1 and alpha2-adrenoceptor antagonists on blood pressure and urinary sodium handling in SHR, compared with age-matched Wistar Kyoto rats (WR). We confirmed that CCh and NE microinjected into the lateral ventricle (LV) of conscious rats leads to enhanced natriuresis. This response was associated with increased proximal and post-proximal sodium excretion accompanied by an unchanged rate of glomerular filtration. We showed that cholinergic-induced natriuresis in WR and SHR was attenuated by previous i.c.v. administration of atropine and was significantly lower in the hypertensive strain than in WR. In both groups the natriuretic effect of injection of noradrenaline into the LV was abolished by previous local injection of an alpha1-adrenoceptor antagonist (prazosin). Conversely, LV alpha2-adrenoceptor antagonist (yohimbine) administration potentiated the action of noradrenaline. The LV yohimbine pretreatment normalized urinary sodium excretion in SHR compared with age-matched WR. In conclusion, these are, as far as we are aware, the first results showing the importance of interaction of central cholinergic and/or noradrenergic receptors in the pathogenesis of spontaneous hypertension. These experiments also provide good evidence of the existence of a central adrenergic mechanism consisting of alpha1 and alpha2-adrenoceptors which works antagonistically on regulation of renal sodium excretion. PMID- 25690464 TI - Widening the scope for early cancer detection: identification of alarm symptoms by community pharmacies. AB - BACKGROUND: Cancers are one of the leading causes of death in the world and, due to the aging population, incidence rates are set to rise. As such, considerable effort has been placed on initiatives that aid the early detection of cancer, as this may improve patient survival outcome. One such initiative is the development of guidelines that explain how and when patient reported alarm symptoms suggestive of an underlying malignancy should be referred to a specialist. However, despite being conveniently placed to deliver interventions to promote the early detection of cancer, it is not clear what role community pharmacists could have in the development and implementation of these guidelines. OBJECTIVE: To: (1) assess the frequency and mean of patient reported alarm symptoms in a community pharmacy setting; (2) determine the demographics of patients presenting with the alarm symptom; and (3) explore the relationship between deprivation index of the community pharmacy and average frequency of alarm symptoms per pharmacy. SETTING: Thirty-three community pharmacies in the North of England. METHOD: A prospective study from September 2013 to February 2014. Each community pharmacy team was provided training in relation to alarm symptoms to ensure there was consistency in reporting. Deprivation tertiles for each community pharmacy were calculated using the IMD 2010 deprivation index. The data were analysed using a Kruskal-Wallis test in order to determine whether there were any statistically significant associations between average frequency of alarm symptoms presented per pharmacy and the deprivation tertile. MAIN OUTCOME MEASURE: Frequency of patient reported alarm symptoms. PMID- 25690465 TI - Not taking the easy road: When similarity hurts learning. AB - Two experimental studies examined the effects of example format and example similarity on mathematical problem solving across different learning contexts. Participants were more successful inducing a correct problem-solving rule when they were provided with annotated examples rather than nonannotated examples. The effects of example similarity varied depending on learning context. In Experiment 1, by presenting an example and problem simultaneously, a direct comparison was possible between the cases. When the examples were similar, participants relied on superficial analogies that hurt learning. When an example was dissimilar from the given problem, participants appeared to study the example first to induce a solution procedure and then apply the rule to the problem, thus resulting in better learning and transfer. However, in Experiment 2 where the example and problem were presented in a sequential manner, the effect disappeared because the learning context did not support a direct comparison. We conclude that comparison is not inherently good for promoting learning and transfer, rather its effect depends on whether it supports relational mapping that is essential for schema acquisition. PMID- 25690466 TI - NITRIC OXIDE-ASSOCIATED PROTEIN1 (AtNOA1) is essential for salicylic acid-induced root waving in Arabidopsis thaliana. AB - Root waving responses have been attributed to both environmental and genetics factors, but the potential inducers and transducers of root waving remain elusive. Thus, the identification of novel signal elements related to root waving is an intriguing field of research. Genetic, physiological, cytological, live cell imaging, and pharmacological approaches provide strong evidence for the involvement of Arabidopsis thaliana NITRIC OXIDE-ASSOCIATED PROTEIN1 (AtNOA1) in salicylic acid (SA)-induced root waving. SA specially induced root waving, with an overall decrease in root elongation in A. thaliana, and this SA-induced response was disrupted in the Atnoa1 mutant, as well as in nonexpresser of pathogenesis-related genes 1 (npr1), which is defective in SA-mediated plant defense signal transduction, but not in npr3/4 single and double mutants. The expression assays revealed that the abundance of AtNOA1 was significantly increased by application of SA. Genetic and pharmacological analyses showed that SA-induced root waving involved an AtNOA1-dependent Ca(2+) signal transduction pathway, and PIN-FORMED2 (PIN2) -based polar auxin transport possibly plays a crucial role in this process. Our work suggests that SA signaling through NPR1 and AtNOA1 is involved in the control of root waving, which provides new insights into the mechanisms that control root growth behavior on a hard agar surface. PMID- 25690467 TI - John L. Gollan, M.D., Ph.D., March 3, 1942-January 6, 2015. PMID- 25690468 TI - Allopurinol induced DRESS syndrome without eosinophilia and pronounced mucosal involvement. PMID- 25690469 TI - Normobaric oxygen worsens outcome after a moderate traumatic brain injury. AB - Traumatic brain injury (TBI) is a multifaceted injury and a leading cause of death in children, young adults, and increasingly in Veterans. However, there are no neuroprotective agents clinically available to counteract damage or promote repair after brain trauma. This study investigated the neuroprotective effects of normobaric oxygen (NBO) after a controlled cortical impact in rats. The central hypothesis was that NBO treatment would reduce lesion volume and functional deficits compared with air-treated animals after TBI by increasing brain oxygenation thereby minimizing ischemic injury. In a randomized double-blinded design, animals received either NBO (n = 8) or normal air (n = 8) after TBI. Magnetic resonance imaging (MRI) was performed 0 to 3 hours, and 1, 2, 7, and 14 days after an impact to the primary forelimb somatosensory cortex. Behavioral assessments were performed before injury induction and before MRI scans on days 2, 7, and 14. Nissl staining was performed on day 14 to corroborate the lesion volume detected from MRI. Contrary to our hypothesis, we found that NBO treatment increased lesion volume in a rat model of moderate TBI and had no positive effect on behavioral measures. Our results do not promote the acute use of NBO in patients with moderate TBI. PMID- 25690470 TI - Convexity subarachnoid hemorrhage in cerebral amyloid angiopathy: the saga continues. PMID- 25690471 TI - Reduced microvascular volume and hemispherically deficient vasoreactivity to hypercapnia in acute ischemia: MRI study using permanent middle cerebral artery occlusion rat model. AB - Vasoreactivity to hypercapnia has been used for assessing cerebrovascular tone and control altered by ischemic stroke. Despite the high prognostic potential, traits of hypercapnia-induced hemodynamic changes have not been fully characterized in relation with baseline vascular states and brain tissue damage. To monitor cerebrovascular responses, T2- and T2*-weighted magnetic resonance imaging (MRI) images were acquired alternatively using spin- and gradient-echo echo plannar imaging (GESE EPI) sequence with 5% CO2 gas inhalation in normal (n=5) and acute stroke rats (n=10). Dynamic relative changes in cerebrovascular volume (CBV), microvascular volume (MVV), and vascular size index (VSI) were assessed from regions of interest (ROIs) delineated by the percent decrease of apparent diffusion coefficient (ADC). The baseline CBV was not affected by middle cerebral artery occlusion (MCAO) whereas the baseline MVV in ischemic areas was significantly lower than that in the rest of the brain and correlated with ADC. Vasoreactivity to hypercapnic challenge was considerably attenuated in the entire ipsilesional hemisphere including normal ADC regions, in which unsolicited, spreading depression-associated increases of CBV and MVV were observed. The lesion-dependent inhomogeneity in baseline MVV indicates the effective perfusion reserve for accurately delineating the true ischemic damage while the cascade of neuronal depolarization is probably responsible for the hemispherically lateralized changes in overall neurovascular physiology. PMID- 25690472 TI - A mouse model of small-vessel disease that produces brain-wide-identified microocclusions and regionally selective neuronal injury. AB - We developed a mouse model of small-vessel disease where occlusions are produced through endovascular injection of fluorescent microspheres that target ~12 MUm diameter penetrating arterioles and can be localized in histology. Using Thy1-GFP transgenic mice, we visualized the impact of microocclusions on neuronal structure. Microocclusions in the hippocampus produce cell loss or neuronal atrophy (~7% of lodged microspheres led to microinfarcts), while axons within white matter tracts, as well as the striatum and thalamus became blebbed or disrupted. Although the neocortex contained more occlusions than other structures, labeled layer 5 neurons were relatively resistant to structural damage, with <2% of the lodged microspheres producing obvious neuronal damage. PMID- 25690473 TI - Hemostasis and fibrinolysis in delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage: a systematic review. AB - Delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH) has been associated with microthrombosis, which can result from activated hemostasis, inhibited fibrinolysis, or both. We systematically searched the PUBMED and EMBASE databases to identify hemostatic or fibrinolytic parameters that can be used for the prediction or diagnosis of DCI, or that inform on the pathogenesis of DCI and may serve as treatment targets. We included 24 studies that fulfilled predefined criteria and described 39 biomarkers. Only one study fulfilled predefined criteria for high quality. Since no parameter on admission was associated with DCI and in none of the included studies blood was drawn at the time of clinical deterioration, none of the studied parameters can presently be used for the prediction or diagnosis of DCI. Regarding the pathogenesis of DCI, it was shown that compared with patients without DCI those with DCI had higher levels of von Willebrand factor and platelet activating factor in plasma 5 to 9 days after aSAH, membrane tissue factor in cerebrospinal fluid 5 to 9 days after aSAH, and D-dimer in plasma 11 to 14 days after aSAH. Confirmation in high quality studies is needed to investigate whether these parameters can serve as targets for new intervention studies. PMID- 25690474 TI - The contribution of arterial blood gases in cerebral blood flow regulation and fuel utilization in man at high altitude. AB - The effects of partial acclimatization to high altitude (HA; 5,050 m) on cerebral metabolism and cerebrovascular function have not been characterized. We hypothesized (1) increased cerebrovascular reactivity (CVR) at HA; and (2) that CO2 would affect cerebral metabolism more than hypoxia. PaO2 and PaCO2 were manipulated at sea level (SL) to simulate HA exposure, and at HA, SL blood gases were simulated; CVR was assessed at both altitudes. Arterial-jugular venous differences were measured to calculate cerebral metabolic rates and cerebral blood flow (CBF). We observed that (1) partial acclimatization yields a steeper CO2-H(+) relation in both arterial and jugular venous blood; yet (2) CVR did not change, despite (3) mean arterial pressure (MAP)-CO2 reactivity being doubled at HA, thus indicating effective cerebral autoregulation. (4) At SL hypoxia increased CBF, and restoration of oxygen at HA reduced CBF, but neither had any effect on cerebral metabolism. Acclimatization resets the cerebrovasculature to chronic hypocapnia. PMID- 25690475 TI - A turn-on coordination nanoparticle-based fluorescent probe for phosphate in human serum. AB - Coordination nanoparticles (CNPs) are becoming attractive platforms for chemical sensing applications because their unique adjustable properties offer the opportunity to design various luminescent nanoprobes. Here, we present a CNP based fluorescent nanoprobe, in which fluorophores (rhodamine B, RB) and quenchers (methylene blue, MB) were spontaneously enfolded by coordination networks self-assembled of adenine, biphenyl-4,4'-dicarboxylic acid (BDA) and zinc ions. The aggregation of fluorophores and quenchers in CNPs resulted in a quenched state fluorescence of RB. RB and MB could be released from CNPs in the presence of phosphate, which triggered the fluorescence of RB. On the basis of recognition-driven disassembly principle, a novel turn-on fluorescent probe for the determination of PO4(3-) with a wide response range (0.5-50 MUM) has been successfully applied in the detection of phosphate in human serum samples. This work not only develops a probe for phosphate but also provides a general strategy for designing nanoprobes or nanocarriers towards various targets by altering organic linkers or metal ions. PMID- 25690477 TI - Abstracts of the 23rd Sylvester O'Halloran Perioperative Scientific Symposium, March 6-7, 2015, Limerick, Ireland. PMID- 25690476 TI - Modeling Cardiovascular Diseases with Patient-Specific Human Pluripotent Stem Cell-Derived Cardiomyocytes. AB - The generation of cardiomyocytes from human induced pluripotent stem cells (hiPSCs) provides a source of cells that accurately recapitulate the human cardiac pathophysiology. The application of these cells allows for modeling of cardiovascular diseases, providing a novel understanding of human disease mechanisms and assessment of therapies. Here, we describe a stepwise protocol developed in our laboratory for the generation of hiPSCs from patients with a specific disease phenotype, long-term hiPSC culture and cryopreservation, differentiation of hiPSCs to cardiomyocytes, and assessment of disease phenotypes. Our protocol combines a number of innovative tools that include a codon-optimized mini intronic plasmid (CoMiP), chemically defined culture conditions to achieve high efficiencies of reprogramming and differentiation, and calcium imaging for assessment of cardiomyocyte phenotypes. Thus, this protocol provides a complete guide to use a patient cohort on a testable cardiomyocyte platform for pharmacological drug assessment. PMID- 25690478 TI - Effective communication enhances the patients' endoscopy experience. AB - BACKGROUND: Undergoing an endoscopy is a stressful experience for patients. AIMS: To audit the endoscopy pathway to improve patient satisfaction. METHODS: A prospective survey of endoscopy patients to identify system improvements that were then implemented. RESULTS: The survey was performed before (N = 71) and after (N = 60) process improvements identified by the initial survey. Information provision and staff communication skills were identified for optimisation. Patient anxiety at home was significantly reduced (median 2 vs. 1, p < 0.01). Education of endoscopy staff significantly improved the quality of information provided before and after the procedure with regard to sedation (median 4 vs. 5, p < 0.01), discomfort (median 4 vs. 5, p < 0.01), complications (28 vs. 82 %, p < 0.01), findings (89 vs. 100 %, p < 0.01) and follow-up (73 vs. 90 %, p = 0.015). Gloucester Comfort Scores during endoscopy improved (median 1 vs. 0, p < 0.01) without increasing sedation levels. Patient feelings of invasion/trauma significantly decreased. Overall 95 % of patients were satisfied. CONCLUSION: Structured information leaflets and improved staff communication skills reduce anxiety and enhance patients' experiences. They are now standard operating procedures. PMID- 25690479 TI - Colored pencil-core granuloma on the forehead. AB - We often encounter injuries caused by pencils or colored pencils in toddlers and young children, but subsequent segmental tumor formation is rare. Here we report the case of a 4-year-old boy who had been stabbed under his left eyebrow with a red pencil. Colored pencil-core granuloma, a foreign body granuloma arising from an injury with a colored pencil, was diagnosed on the basis of intraoperative and histopathologic findings. Because of the severe tissue damage that the colorant causes, this type of tumor grows rapidly within a few days and may be accompanied by resorption of the skull if it occurs on the head or face. PMID- 25690480 TI - Longitudinal assessment of oxytocin efficacy on bone and bone marrow fat masses in a rabbit osteoporosis model through 3.0-T magnetic resonance spectroscopy and micro-CT. AB - This study aims to longitudinally assess the effect of oxytocin on bone and bone fat masses using micro-CT, in vivo magnetic resonance spectroscopy (MRS), and histopathological adipocyte quantification. Early in vivo oxytocin (OT) treatment to the osteoporosis (OP) rabbit model may reliably inhibit bone degeneration and reduce bone marrow fat accumulation by decreasing marrow adipocyte size and density. INTRODUCTION: This study aims to longitudinally assess the effect of early OT treatment on bone and bone fat masses in a rabbit OP model by comparing the results of MRS and micro-CT with histopathological findings. METHODS: Sixty 20-week-old female rabbits were randomly assigned into three groups. The control and OP groups were subjected to either sham surgery or bilateral ovariectomy (OVX). The OT group was subcutaneously injected with OT daily from the second week after OVX for 8 weeks. The left proximal femurs of the rabbits were evaluated through MRS, micro-CT, and histopathological examination at 0, 4, 8, 10, and 12 weeks after operation. Differences in fat fraction (FF) values, micro CT parameters, and calculated pathological marrow adipocytes among three groups were analyzed. RESULTS: The FF values of the OP group significantly increased (p = 0.019), but the tissue mineral density (TMD) decreased (p = 0.037) from eighth week compared with those of the control group. The FF values of the OT group significantly decreased (p = 0.044), but the TMD values increased (p = 0.042) from eighth week compared with those of the OP group. The adypocyte diameter of the OT group significantly decreased (p = 0.041) from eighth week and then adypocyte density did so too from tenth week, compared with those of the OP group at the same time point. No difference in adypocyte calculation was found between the OT and control groups until the 12th week after operation. CONCLUSION: Early in vivo OT treatment slowed down bone deterioration and reduced bone marrow adiposity accumulation in a rabbit OP model, which is consistent with pathologic findings. OT treatment is a promising preventive OP therapy. PMID- 25690481 TI - Recent trends of cervical cancer and Cervical Intraepithelial Neoplasia 3 (CIN3) in Israel. AB - PURPOSE: This study describes time trends of cervical cancer and Cervical Intraepithelial Neoplasia 3 (CIN3) in Israel in the years 1986-2010 and characterizes these patients by demographics. METHODS: A retrospective survey based on cervical cancer and CIN3 data documented in the computerized system of the second largest Health Maintenance Organizations (HMO) in Israel, "Maccabi Healthcare Services" (MHS) between 1986 and 2010. RESULTS: 737 cervical cancer patients and 3,459 patients of CIN3 were reported between 1986 and 2010. The mean age of women with cervical cancer was significantly higher (mean 49.1 years) than that of CIN3 patients (mean 36.3 years) (p-value < 0.0001). The annual age adjusted incidence rate of cervical cancer increased significantly from 1.6 per 100,000 in 1986 to 3.7 per 100,000 in 2010 (p for trend = 0.0001) and for CIN3, from 3.9 per 100,000 in 1986 to 40.4 per 100,000 in 2010 (p for trend = 0.0001). For cervical cancer, using the Joinpoint software we demonstrated an increase in the age-adjusted incidence rate between 1986 and 2003 and since then, a decrease was observed. Cervical cancer and CIN3 were mostly common in the Tel Aviv District. CONCLUSIONS: Although quite low to begin with, the incidence rates of cervical cancer and CIN3 in Israel may be further lowered by implementing an organized screening program and introduction of the HPV vaccine into the national immunization program. PMID- 25690482 TI - Lipodystrophy: Syndrome of severe insulin resistance. AB - CONTEXT: Lipodystrophy (LD) is a relatively rare complex collection of diseases that can be congenital or acquired. It is commonly missed in the clinical setting. Thus, the spectrum of disease presentation mandates clinician expertise in the pathophysiology and management of all forms of LD, obesity, and insulin resistance. METHODS AND MATERIALS: An extensive literature search of clinical trials, systematic reviews, and narrative reviews was completed in PubMed for the years 1970 to 2013. The search terms were lipodystrophy, congenital LD, acquired LD, HIV-associated LD, severe insulin resistance, adiposity, obesity, and dyslipidemia. EVIDENCE SYNTHESIS: Lipodystrophies are a heterogeneous group of disorders with abnormal adipose tissue distribution, utilization, and metabolism. Adipose tissue can undergo significant changes in composition (hypertrophy and atrophy) in response to a nutritional state. Paradoxically, both excess and deficient adipose tissue is associated with insulin resistance and the metabolic syndrome. Bone density scan (DEXA) for body fat composition analysis or magnetic resonance imaging are optimal modalities for the assessment of abnormal adipose tissue distribution. Ongoing clinical studies suggest thiazolidinediones, insulin like growth factor-1, leptin, and growth hormone-releasing hormone as possible treatment for LPD; however, none of them is approved to reverse fat loss or treat severe insulin resistance due to LPD. CONCLUSION: The underlying mechanisms for LPD causing insulin resistance may be lipotoxicity and derangements in adipose tissue-derived proteins (adipocytokines). However, the lack of evidence to support this model means that clinicians are on their own as they navigate through the phenotypic presentation of lipodystrophies, obesity, insulin resistance, and the metabolic syndrome. PMID- 25690483 TI - UV radiation induces CXCL5 expression in human skin. AB - CXCL5 has recently been identified as a mediator of UVB-induced pain in rodents. To compare and to extend previous knowledge of cutaneous CXCL5 regulation, we performed a comprehensive study on the effects of UV radiation on CXCL5 regulation in human skin. Our results show a dose-dependent increase in CXCL5 protein in human skin after UV radiation. CXCL5 can be released by different cell types in the skin. We presumed that, in addition to immune cells, non-immune skin cells also contribute to UV-induced increase in CXCL5 protein. Analysis of monocultured dermal fibroblasts and keratinocytes revealed that only fibroblasts but not keratinocytes displayed up regulated CXCL5 levels after UV stimulation. Whereas UV treatment of human skin equivalents, induced epidermal CXCL5 mRNA and protein expression. Up regulation of epidermal CXCL5 was independent of keratinocyte differentiation and keratinocyte-keratinocyte interactions in epidermal layers. Our findings provide first evidence on the release of CXCL5 in UV-radiated human skin and the essential role of fibroblast-keratinocyte interaction in the regulation of epidermal CXCL5. PMID- 25690484 TI - Primary care professionals and abused women have differing awareness of domestic abuse: a new framework may help facilitate discussions. PMID- 25690485 TI - Clinical and electrophysiology findings in Slovene patients with Leber hereditary optic neuropathy. AB - BACKGROUND: To report clinical and electrophysiology findings in Slovene patients with Leber hereditary optic neuropathy (LHON). METHODS: Eight patients with LHON (11-26 years; one female and seven males) were examined in acute stages and at follow-up visits by means of Snellen visual acuity, Ishihara color vision, Goldmann or Octopus G2TOP perimetry, fluorescein angiography (FAG), pattern electroretinogram (PERG), visual evoked potentials (VEP) and genetic testing. RESULTS: Patients presented with typical LHON phenotype with bilateral visual acuity loss, abnormal color vision, central scotoma and hyperemic discs with no leakage on FAG. In the acute stage, electrophysiology was performed in 7/8 patients. The PERG P50 component was normal in 14/14 eyes, while the N95 component was reduced in 7/14 eyes. VEP wave P100 was reduced and delayed in 14/14 eyes. In this stage, temporal pallor of the optic disc was visible in 4/7 eyes with reduced PERG N95. At follow-up (1-11 months after), a reduced PERG N95 component was seen in 13/14 eyes and severely affected VEP in all eyes. In the only eye with a normal PERG N95, hyperemic optic disc was seen 5 months after visual acuity loss, while it was atrophic in all the others. Known mutations (14484T>C, 3460G>A) were found in 2/8 patients, while in others high-throughput sequencing identified new potentially pathogenic mutations. CONCLUSIONS: In Leber hereditary optic neuropathy, a reduced N95 component of PERG and severely reduced VEP P100 may be present already in the acute stage of disease, before optic disc pallor appears, suggesting primary dysfunction of retinal ganglion cells. PMID- 25690486 TI - The International Immune Tolerance Induction Study and its follow-up study on Japanese hemophilia A patients with inhibitors. AB - The International Immune Tolerance Induction (I-ITI) Study in hemophilia A patients with inhibitors included 16 Japanese patients among a total of 115 test subjects. The results within this group of Japanese patients were 11 cases of I ITI off-study, three cases of I-ITI on-study, and two cases of tolerance on prophylaxis. There was no significant difference in success rate between the low dose and high-dose groups (Study I). Successively, independent follow-up survey in Japan was conducted in 14 cases, with consent (Study II). Ten cases were off study at the end of the I-ITI Study. Of these 10 cases, seven of seven successful cases remained clinical successes at the end of the follow-up study, one partial success became a full success while a second relapsed, and one failure was subsequently evaluated as a partial success. Four cases that were on-study at the end of I-ITI Study were classified as three successes and one failure at the end of the follow-up study. As a result, the status at the end of follow-up study was: 11 ITI successes (78.6 %); one partial success; one failure; and one relapse. Thus, the ITI follow-up study was helpful in providing a long-term prognostic determination of inhibitors. PMID- 25690487 TI - Genetic and molecular characterization of myelodysplastic syndromes and related myeloid neoplasms. AB - Whole exome next generation sequencing systematically applied as a discovery tool in myelodysplastic syndromes (MDS) has led to the identification of a large number of novel mutations. Despite hundreds of patients studied, mutational saturation has not been reached and it is expected that new driver mutations will be discovered in this very heterogeneous condition. Serial samples and deep sequencing of the identified alterations has allowed for a dynamic/chronologic analysis of clonal architecture and identification of a subset of ancestral and secondary molecular lesions. Chromosomal gains and losses have been incorporated into the mutational analyses because they can either cooperate with mutations or produce a functional phenocopy. In addition to the search for somatic defects in MDS, similar discovery studies have been also performed to identify germ line mutations/alterations. Clinical analysis showed applicability of multiplexed somatic mutational panels that would complement current pathomorphologic diagnosis, allow for subclassification of nosologic entities, and enhance predictive power of current prognostic algorithms. Overall, comprehensive genomic analysis in MDS has revealed a tremendous heterogeneity of somatic lesions and their combinations further enhanced by the heterogeneity of clonal architecture and chromosomal lesions. PMID- 25690488 TI - Pharmacotherapeutic strategies for patients treated for depression in UK primary care: a database analysis. AB - OBJECTIVE: To investigate long-term patterns of antidepressant treatment in patients in primary care in the UK, and to assess their healthcare resource use and disease outcomes. RESEARCH DESIGN AND METHODS: A retrospective longitudinal cohort study was conducted using the Clinical Practice Research Datalink. The study population comprised patients aged >=18 years with depression receiving a prescription for antidepressant monotherapy between 1 January 2006 and 31 December 2011 with no antidepressants within the preceding 6 months. Recovery was defined by timing of antidepressant prescriptions (>=6 months without treatment). Treatment lines and strategies (switching, combining, augmenting and resuming medication) were analyzed. Healthcare resource use for the different treatment strategies and periods of no therapy was assessed. RESULTS: Data from 123,662 patients (287,564 treatment lines) were analyzed. Switching and resumption of treatment were more frequent than other strategies. Recovery was highest with first-line monotherapy (45% of patients), while as a second-line strategy switching was more successful (43%) than combination or augmentation. In subsequent lines of treatment, switching was associated with successively lower rates of recovery (31% in the third line and 24% from the fourth line onwards). Similar rates were observed for resumption. Healthcare resource use was greater during antidepressant use than treatment-free periods. Augmentation was associated with the highest proportions of patients with a psychiatrist referral, psychologist referral and psychiatric hospitalization. CONCLUSIONS: This study provides extensive real-world information on the prescribing patterns and treatment outcomes for a large cohort of patients treated for depression with antidepressants in primary care. Switching is more frequently used than augmentation or combination treatment, with decreasing effectiveness across successive lines. Key limitations of the study were: (i) risk of selection bias due to the use of inclusion criteria based on depression diagnoses recorded by the practitioner; and (ii) reliance on prescribing patterns as proxies for clinical outcomes, such as recovery. PMID- 25690489 TI - A model of mild hypoglycemia. AB - OBJECTIVE: To investigate the impact associated with mild hypoglycemia among patients with type 2 diabetes (T2DM) in the United States and to identify risk factors among different subpopulations. METHODS: We performed a literature search to gather available data allowing estimation of rates of mild hypoglycemia. Because risk factors are interdependent, risk factors included in the model were based on those reported within multivariate analyses or judged to be biologically plausible by the medical community. Based on literature search results, we built a mathematical model predicting the rates of mild hypoglycemia in individual patients as a function of the patient's antidiabetic medications, hemoglobin A1c levels, duration of diabetes, kidney function, and body mass index. RESULTS: We estimated an overall average rate of mild hypoglycemia among US patients with T2DM of 2.2 +/- 0.8 events per person per year. Patients taking oral antidiabetic medications only had an average rate of 1.9 +/- 0.8 events per person per year. The average rate for all patients taking insulin, including those combining it with other antidiabetic medications, was 4.9 +/- 2.0 events per person per year. Mild hypoglycemia rates increased with age, with 80-year-old patients experiencing 1.5 times the risk of 40-year-old patients. Based on published values for direct and indirect medical costs for mild hypoglycemia events, we determined that the economic impact in the US of mild hypoglycemic events is approximately $900 million per year, roughly equal to that of severe hypoglycemic events. One of the key limitations to our model is that it applies to the US population under standard medical care and not to clinical trials and does not include certain known risk factors such as rigorous exercise. CONCLUSIONS: Understanding the benefit versus risk of glycemic control and hypoglycemia is fundamental to the successful management of patients with T2DM. Our validated hypoglycemia model is an important step in addressing this issue and may be helpful to researchers, clinicians, and payers to determine the patients who are at the highest risk for hypoglycemia, whether a patient is experiencing events at 'higher-than-expected' rates, and the corresponding economic burden. PMID- 25690490 TI - A comprehensive review of the role of the hedgehog pathway and vismodegib in the management of basal cell carcinoma. AB - BACKGROUND: Basal cell carcinoma (BCC) is the most common cancer. Most cases of BCCs are treated with only optimal surgical resection. However, unresectable, locally advanced or metastatic tumors might have potential to progress. In this patient group, there is no standardized treatment approach. Vismodegib is a new selective inhibitor of the hedgehog (Hh) pathway. This manuscript is aimed to review the efficacy of the Hh pathway inhibitor vismodegib in BCC patients with locally advanced or metastatic disease. SCOPE: Vismodegib showed positive results in clinical studies. A computerized search of the PubMed and American Society of Clinical Oncology Meeting abstracts was performed, by searching for the following keywords: 'vismodegib', 'pathway', 'inhibitor', and 'targeted therapies for BCC'. The last search was done on 1 September 2014. Most of the vismodegib data depend on phase I and II trials. FINDINGS: Preclinical and clinical studies have shown that Hh pathway activation occurs in BCC. In BCC patients the role of chemotherapy is not completely known. Although conventional chemotherapies like cisplatins increase the response rate in BCC, improvement in overall survival and progression free survival were not demonstrated. Results of both phase I and phase II studies have shown that vismodegib is a potential new treatment strategy for patients with locally advanced and metastatic BCC. As in previously published phase I trials, in the ERIVANCE BCC study the primary endpoint, objective response rate, significantly increased by 43% and 30% in patients with locally advanced and metastatic BCC, respectively. Because of the promising results in phase I and II trials, vismodegib was approved by the Food and Drug Administration (FDA) in the treatment of patients with BCC who are not suitable for surgery or radiotherapy or with relapsed locally advanced disease following surgery or metastatic disease. CONCLUSION: Recent trials have shown that vismodegib has produced promising activity in patients with locally advanced and metastatic BCC. The ongoing studies with vismodegib in other solid tumors and BCC will shed light on more certain treatment pathways. PMID- 25690492 TI - Surgery for endometriomas before IVF: what are the benefits and risks? AB - Endometriosis is present in up to one-third of infertility patients. In a subset of these patients, work-up will reveal the presence of an endometrioma. When the endometrioma is causing pelvic pain or dysmenorrhea, removal can greatly improve pain and quality of life. However, in the patient preparing for an in-vitro fertilization (IVF) cycle removal of an endometrioma can delay treatment. It is critical to know the benefits and risk of such a procedure prior to proceeding with surgical endometrioma removal. A great deal of literature had been published on the effect of endometriomas on fertility and IVF outcomes. In this review, we will summarize the current literature addressing the effects of endometrioma removal on ovarian response and pregnancy rates following IVF. PMID- 25690491 TI - Developing an Atrial Fibrillation Guideline Support Tool (AFGuST) for shared decision making. AB - OBJECTIVE: Patient values and preferences are an important component to decision making when tradeoffs exist that impact quality of life, such as tradeoffs between stroke prevention and hemorrhage in patients with atrial fibrillation (AF) contemplating anticoagulant therapy. Our objective is to describe the development of an Atrial Fibrillation Guideline Support Tool (AFGuST) to assist the process of integrating patients' preferences into this decision. MATERIALS AND METHODS: CHA2DS2VASc and HAS-BLED were used to calculate risks for stroke and hemorrhage. We developed a Markov decision analytic model as a computational engine to integrate patient-specific risk for stroke and hemorrhage and individual patient values for relevant outcomes in decisions about anticoagulant therapy. RESULTS: Individual patient preferences for health-related outcomes may have greater or lesser impact on the choice of optimal antithrombotic therapy, depending upon the balance of patient-specific risks for ischemic stroke and major bleeding. These factors have been incorporated into patient-tailored booklets which, along with an informational video, were developed through an iterative process with clinicians and patient focus groups. KEY LIMITATIONS: Current risk prediction models for hemorrhage, such as the HAS-BLED, used in the AFGuST, do not incorporate all potentially significant risk factors. Novel oral anticoagulant agents recently approved for use in the United States, Canada, and Europe have not been included in the AFGuST. Rather, warfarin has been used as a conservative proxy for all oral anticoagulant therapy. CONCLUSIONS: We present a proof of concept that a patient-tailored decision-support tool could bridge the gap between guidelines and practice by incorporating individual patient's stroke and bleeding risks and their values for major bleeding events and stroke to facilitate a shared decision making process. If effective, the AFGuST could be used as an adjunct to published guidelines to enhance patient-centered conversations about the anticoagulation management. PMID- 25690493 TI - Continued challenge of rheumatic heart disease: the gap of understanding or the gap of implementation? PMID- 25690494 TI - Public Sector Prevention of RF and RHD in South Africa. PMID- 25690495 TI - Estimates of the global burden of rheumatic heart disease. AB - In this review, we make the case that currently available figures used to define the global burden of acute rheumatic fever and rheumatic heart disease, although crucial to control efforts, are imperfect. Data have been hindered by methodological differences between studies, by patchy coverage within countries and across regions, and by an incomplete understanding of the relationship between echocardiographic detection of asymptomatic mild disease and progression to symptomatic disease. We argue that in order to advocate effectively for patients with rheumatic heart disease now and into the future, true burden of disease estimates on local, national, and international levels are urgently required. We critically review previous burden of disease estimates and outline the issues in defining the "true" burden of rheumatic heart disease, and we propose a new model for rheumatic heart disease epidemiologic studies. This is of particular relevance in 2012 with an ever-increasing burden of cardiovascular disease globally. PMID- 25690496 TI - Echocardiographic screening for rheumatic heart disease: issues for the cardiology community. AB - The advent of portable echocardiography has led to screening for rheumatic heart disease (RHD) with high disease prevalence found in many countries. Data are presented from studies from India, Africa, and New Zealand. The natural history of subclinical echocardiographically detected RHD is the most important research question to be answered before more widespread screening is endorsed. The 2012 World Heart Federation (WHF) criteria for the echocardiographic diagnosis of RHD provide standardization of RHD diagnosis, increasing the specificity for definite RHD and raising the threshold for borderline RHD. Use of the criteria should reduce the false positive rate for minor echocardiographic changes due to physiological valvular regurgitation. This review highlights issues of screening for RHD that are of relevance to the cardiology community. PMID- 25690497 TI - Echocardiographic diagnosis of chronic rheumatic valvular lesions. AB - Rheumatic heart disease continues to be a significant public health problem in many developing countries and in some of the aboriginal populations in developed countries. Echocardiography has become indispensable in the assessment of valve lesions secondary to rheumatic heart disease. It confirms the rheumatic etiology of valvular abnormality as the features are quite typical in most cases. It also helps to exclude nonrheumatic causes of valve lesions. M-mode and cross-sectional echo helps to assess the severity of valve abnormality and its hemodynamic effects on the heart. Further, color flow imaging evaluates the flow across a valve, both qualitatively and quantitatively. Serial echocardiography plays a crucial role in the follow-up of patients with rheumatic heart disease and is very helpful for determining the timing of intervention. Recently, addition of real-time 3-dimensional echocardiography has further improved imaging of cardiac valves, especially the mitral valve. PMID- 25690498 TI - Priorities in cardiac surgery for rheumatic heart disease. AB - This review outlines a philosophy of surgical cardiac care for rheumatic heart disease, which has evolved over the past 2 decades, in the young in the Oceania region. Topics covered include the optimal timing of surgery, recommended strategies for mitral and aortic valve disease, and the importance of the team approach to these patients. There is a global priority for more cardiac surgeons to become skilled in repair of the rheumatic mitral valve. Surgeons operating on patients from remote regions with RHD are encouraged to audit outcomes and help these communities develop their health services to optimize continued RHD care. PMID- 25690499 TI - Primary prevention for rheumatic Fever: progress, obstacles, and opportunities. AB - Acute rheumatic fever and rheumatic heart disease are noninfectious sequelae of group A streptococcal pharyngeal infection. These diseases represent a huge public health burden in developing countries with significant mortality and morbidity. Early diagnosis and appropriate antibiotic treatment with group A streptococcal pharyngitis provides an opportunity for prevention of acute rheumatic fever and rheumatic heart disease. The use of locally adapted clinical algorithms for diagnosing group A streptococcal pharyngitis has great potential in resource-poor settings for earlier diagnosis and early treatment. Intramuscular penicillin is the drug of choice in developing country settings. Recent work has demonstrated the cost-effectiveness of a treat-all strategy with intramuscular penicillin, whereas incorporating a clinical decision rule remains the preferred strategy. We strongly support the adoption of a comprehensive prevention and control program for acute rheumatic fever and rheumatic heart disease, incorporating primary prevention, as critical to underpinning the efforts in many parts of the world to stem the tide of this devastating disease. PMID- 25690500 TI - Benzathine Penicillin G for the Management of RHD: Concerns About Quality and Access, and Opportunities for Intervention and Improvement. AB - Benzathine penicillin G is an important antibiotic for the treatment and prevention of group A streptococcal infections associated with rheumatic fever and rheumatic heart disease. However, as rheumatic heart disease has receded as a public health priority in most high-income settings, attention to the supply, manufacture, and accessibility of benzathine penicillin G has declined. Concerns about the quality, efficacy, and innovation of the drug have emerged following plasma analysis and anecdotal reports from low-resource settings. This review collates core issues in supply and delivery of benzathine penicillin G as a foundation for concerted efforts to improve global quality and access. Opportunities for intervention and improvement are explored. PMID- 25690501 TI - The Importance of Awareness and Education in Prevention and Control of RHD. AB - Acute rheumatic fever and rheumatic heart disease are diseases of poverty, low socioeconomic status, and inadequate access to health care. These preventable diseases remain largely ignored by the developed world while they continue to cause significant mortality and morbidity in the developing world. In the face of no existing cure, we need to focus on prevention and control methods. To this end, creating awareness of the disease and its effects on millions of people in the world is critically important. In this review, we will outline the importance of these efforts, discuss the barriers to awareness and education, and highlight some important models in this arena. We strongly support awareness-raising and health promotion strategies as an integral part of a rheumatic heart disease prevention and control program. PMID- 25690502 TI - A conceptual framework for comprehensive rheumatic heart disease control programs. AB - The World Health Organization, World Heart Federation, and other organizations recommend comprehensive control programs for rheumatic fever (RF) and rheumatic heart disease (RHD). However, advice on components of control programs are simple lists, with little guidance on program structure or priorities. In particular, there are limited recommendations on "stepwise" implementation and few guidelines on which program components should take temporal priority. An evidence-based framework for describing, prioritizing, and implementing comprehensive RF/RHD control programs is needed. A literature review of existing RF/RHD control program recommendations generated a list of program components. Descriptions and analysis of RF/RHD control programs informed temporal prioritizing of component parts. Relevant programmatic research from other vertical disease control programs was reviewed for generalizable implementation experiences. Twenty-five individual components of comprehensive RF/RHD control programs were identified. These fell into "baseline" program requirements (including burden of disease data, treatment guidelines, and human resources) and requirements for providing primary, secondary, and tertiary interventions. Primordial prevention and research priorities were overarching themes. These components were developed into a conceptual framework schema. Existing literature contains valuable lessons on the design and implementation of comprehensive RF/RHD control programs. Fashioning these guidelines and programmatic experiences into a conceptual framework schema benefits clinicians, policy makers, and RHD advocates. PMID- 25690503 TI - Prevention of rheumatic Fever and heart disease: nepalese experience. AB - Rheumatic heart disease (RHD) is a major public health problem in Nepal that affects young children and adolescents. Historically, many young people suffered severe valvular disease and died awaiting heart valve replacement. For some years, the Nepal Heart Foundation (NHF) advocated for a more comprehensive program to reduce the burden of RHD. In 2007, the government of Nepal announced funding for an RHD control program to be implemented by the NHF. The core focus of the program was to deliver antibiotics for the secondary prophylaxis of RHD. The NHF has developed a program of community awareness, free medication, RHD register development, health worker training, guideline development, and clinical audit. These services are being implemented with expanding geographic scope. This paper provides a narrative overview of the Nepalese experience designing, implementing, and beginning to evaluate this program. Challenges and successes relevant to register-based programs are highlighted. PMID- 25690504 TI - The second rheumatic heart disease forum report. AB - The second rheumatic heart disease (RHD) forum was held on February 18, 2013, at the Sixth World Congress of Pediatric Cardiology and Cardiac Surgery in Cape Town, South Africa, to focus attention on key areas in global RHD control, management, and prevention. Building on the foundation of the first RHD forum, over 150 interested participants met to discuss critical issues on the RHD landscape. Unique to this meeting was a mixture of diverse backgrounds and disciplines, all crucially important to the conversation around RHD control and prevention. Some clear priorities have emerged for RHD activities in the next era: the necessity for political intervention and policy change; increasing the health workforce by incorporating teaching, training, and task-shifting; revitalizing the research agenda by merging basic, clinical, and translational research; and obtaining universal access to high-quality penicillin. There was also an urgent request for new resources; for existing resources to be further developed, improved, and shared across platforms; and for resources to be supported in the nonmedical arena. Finally, the necessity of involving the patient community in the ongoing discussion was highlighted. The participants of both the first and second RHD forum represent a new, thriving, and growing community of RHD activists who should usher in a new era of significant improvements in RHD control and prevention. PMID- 25690505 TI - Aiming at strategies for a complex problem of medical nonadherence. AB - The deteriorating health of the population and the increasing prevalence of chronic diseases are global problems whose causes are multifactorial and complex. The Western lifestyle does not promote healthy living, and the consequences are most devastating when social inequalities, together with the economic and population explosion of recent decades, are considered. The expansion of poor nutritional habits, obesity, sedentarism, and hypertension are increasingly contributing to the development of a cardiovascular disease epidemic. Recent data on the rates of compliance with lifestyle modification and adherence to prescribed medication are alarming. Over 50% of patients, on average, decide to abandon the treatment prescribed, and the objectives to improve their habits (quit smoking, lose weight, or engage in physical activity) are met by an equal or lower percentage. Beyond the impact it has on individual health, it carries a huge economic cost, as it is associated with a failure in achieving therapeutic goals, higher rate of hospitalization, and death. Improving communication between doctors and patients, the active involvement of other health professionals, and the development of combination drug formulations (polypill) are potential strategies for improving adherence and reducing costs. PMID- 25690506 TI - Visceral Adipose Tissue: At the Intersection of Lipoprotein Associated CV Risk. PMID- 25690507 TI - Rebuilding the rheumatic heart disease program in Sudan. PMID- 25690508 TI - Abstract-concept learning of difference in pigeons. AB - Many species have demonstrated the capacity to learn abstract concepts. Recent studies have shown that the quantity of stimuli used during training plays a critical role in how subjects learn abstract concepts. As the number of stimuli available in the training set increases, so too does performance on novel combinations. The role of set size has been explored with learning the concept of matching and same/different but not with learning the concept of difference. In the present study, pigeons were trained in a non-matching-to-sample task with an initial training set of three stimuli followed by transfer tests to novel stimuli. The training set was progressively doubled eight times with learning and transfer following each expansion. Transfer performance increased from chance level (50 %) at the smallest set size to a level equivalent to asymptotic training performance at the two largest training set sizes (384, 768). This progressive novel-stimulus transfer function of a non-matching (difference) rule is discussed in comparison with results from a similar experiment where pigeons were trained on a matching rule. PMID- 25690509 TI - Impact of boiling on phytochemicals and antioxidant activity of green vegetables consumed in the Mediterranean diet. AB - The effect of boiling (10 minutes) on eleven green vegetables frequently consumed in the Mediterranean diet was evaluated. For that, some physicochemical parameters and the contents of vitamin C, phenolics and carotenoids, as well as the antioxidant activity, were determined in raw and boiled samples. The raw vegetables analysed in this study were good sources of vitamin C, carotenoids and phenolic compounds, with contents ranging from 10.6 to 255.1 mg/100 g, 0.03 to 3.29 mg/100 g and 202.9 to 1010.7 mg/100 g, respectively. Boiling promoted losses in different extensions considering both the different bioactive compounds and the distinct vegetables analysed. Contrary to phenolics (more resistant), vitamin C was the most affected compound. Boiling also originated significant losses in the antioxidant activity of the vegetables. Considering all the parameters analysed, the vegetables most affected by boiling were broccoli and lettuce. The least affected ones were collard and tronchuda cabbage. PMID- 25690510 TI - Regulation of glucose and insulin release following acute and repeated treatment with the synthetic galanin analog NAX-5055. AB - The neuropeptide galanin is widely expressed in both the central and peripheral nervous systems. However there is limited understanding of how individual galanin receptor (GalR1, 2, and 3) subtypes mediate the physiological activity of galanin in vivo. To address this issue we utilized NAX-5055, a systemically available, metabolically stable galanin analog. NAX-5055 displays a preference for GalR1 receptors and possesses potent anticonvulsant activity in vivo, suggesting that NAX-5055 engages central galanin receptors. To determine if NAX-5055 also modulates the activity of peripheral galanin receptors, we evaluated the effect of NAX-5055 on blood glucose and insulin levels in mice. Acute and repeated (once daily for four days) systemic administration of NAX-5055 (4 mg/kg) significantly increased blood glucose levels compared to vehicle treated mice. However, a hyperglycemic response was not observed following systemic administration of NAX 805-1, a scrambled analog of NAX-5055, with critical receptor binding residues, Trp(2) and Tyr(9), reversed. These results suggest that chemical modifications independent of the galanin backbone of NAX-5055 are not responsible for the hyperglycemic response. The effect of NAX-5055 on glucose homeostasis was further evaluated with a glucose tolerance test (GTT). Mice administered either acute or repeated (once daily for four days) injections of NAX-5055 (4 mg/kg) displayed impaired glucose handling and reduced insulin response to an acute glucose (1g/kg) challenge. Here we have shown that systemic administration of a centrally active GalR1-preferring galanin analog produces acute hyperglycemia and an inhibition of insulin release in vivo and that these effects are not attenuated with repeated administration. NAX-5055 thus provides a new pharmacological tool to further the understanding of function of both central and peripheral GalR1 receptors in vivo. PMID- 25690511 TI - Molecular dynamics simulations of the structural, mechanical and visco-elastic properties of polymer nanocomposites filled with grafted nanoparticles. AB - Through coarse-grained molecular dynamics simulations, we have studied the effects of grafting density (Sigma) and grafted chain length (Lg) on the structural, mechanical and visco-elastic properties of end-grafted nanoparticles (NPs) filled polymer nanocomposites (PNCs). It is found that increasing the grafting density and grafted chain length both enhance the brush/matrix interface thickness and improve the dispersion of NPs, but there seems to exist an optimum grafting density, above which the end-grafted NPs tend to aggregate. The uniaxial stress-strain behavior of PNCs is also examined, showing that the tensile stress is more enhanced by increasing Lg compared to increasing Sigma. The tensile modulus as a function of the strain is fitted following our previous work (Soft Matter, 2014, 10, 5099), exhibiting a gradually reduced non-linearity with the increase of Sigma and Lg. Meanwhile, by imposing a sinusoidal external shear strain, for the first time we probe the effects of Sigma and Lg on the visco elastic properties such as the storage modulus G', loss modulus G'' and loss factor tan delta of end-grafted NPs filled PNCs. It is shown that the non-linear relation of G' and G'' as a function of shear strain amplitude decreases with the increase of Sigma and Lg, which is consistent with experimental observations. We infer that the increased mechanical and reduced non-linear visco-elastic properties are correlated with the enhanced brush/matrix interface and therefore better dispersion of NPs and stronger physical cross-linking. This work may provide some rational means to tune the mechanical and visco-elastic properties of end-grafted NPs filled polymer nanocomposites. PMID- 25690513 TI - The safety and efficacy of proximal splenic artery embolization after liver transplantation are still not clearly defined. PMID- 25690512 TI - The Chlamydomonas cell cycle. AB - The position of Chlamydomonas within the eukaryotic phylogeny makes it a unique model in at least two important ways: as a representative of the critically important, early-diverging lineage leading to plants; and as a microbe retaining important features of the last eukaryotic common ancestor (LECA) that has been lost in the highly studied yeast lineages. Its cell biology has been studied for many decades and it has well-developed experimental genetic tools, both classical (Mendelian) and molecular. Unlike land plants, it is a haploid with very few gene duplicates, making it ideal for loss-of-function genetic studies. The Chlamydomonas cell cycle has a striking temporal and functional separation between cell growth and rapid cell division, probably connected to the interplay between diurnal cycles that drive photosynthetic cell growth and the cell division cycle; it also exhibits a highly choreographed interaction between the cell cycle and its centriole-basal body-flagellar cycle. Here, we review the current status of studies of the Chlamydomonas cell cycle. We begin with an overview of cell-cycle control in the well-studied yeast and animal systems, which has yielded a canonical, well-supported model. We discuss briefly what is known about similarities and differences in plant cell-cycle control, compared with this model. We next review the cytology and cell biology of the multiple fission cell cycle of Chlamydomonas. Lastly, we review recent genetic approaches and insights into Chlamydomonas cell-cycle regulation that have been enabled by a new generation of genomics-based tools. PMID- 25690514 TI - Blood transfusion and risk of infection in frail elderly after hip fracture surgery: the TRIFE randomized controlled trial. AB - OBJECTIVES: It is still under debate that red blood cell (RBC) transfusions might increase the risk of healthcare-associated infections after hip fracture surgery. Previously, we found that a liberal RBC transfusion strategy improved survival in nursing home residents. Our aim, therefore, was to investigate whether a more liberal RBC transfusion strategy was associated with a higher infection risk in frail elderly hip fracture patients. DESIGN: Prospective, assessor-blinded, randomized and controlled trial. SETTINGS: Orthopedic ward, Geriatric ward, and Hospital-at-home. PATIENTS: 284 consecutively hospital-admitted elderly with hip fracture from nursing homes or sheltered housing facilities were included. INTERVENTION: A restrictive RBC transfusion strategy (hemoglobin <9.7 g/dL; 6 mmol/L) compared with a liberal strategy (hemoglobin <11.3 g/dL; 7 mmol/L) administered within 30 days after surgery. MAIN OUTCOME MEASUREMENTS: Leukocytes and C-reactive protein (CRP) in repeated blood samples within 30 days, and number of all infections (pneumonia, urinary tract infection, and other infections) within 10 days. RESULTS: 88 % of the patients received a RBC transfusion. A median of 1 RBC unit (interquartile range (IQR): 1-2) was transfused for the restrictive strategy group versus 3 RBC units (IQR: 2-5) for the liberal group. Leukocytes and CRP measurements were similar for both groups. Rates of infection were 72 % for the restrictive group compared to 66 % for the liberal group (risk ratio 1.08; 95 % confidence interval 0.93-1.27, p value 0.29). CONCLUSIONS: A more liberal RBC transfusion strategy was not associated with higher risk of infection among residents from nursing homes or sheltered housing undergoing hip fracture surgery. PMID- 25690515 TI - Safer-drinking strategies used by chronically homeless individuals with alcohol dependence. AB - Chronically homeless individuals with alcohol dependence experience severe alcohol-related consequences. It is therefore important to identify factors that might be associated with reduced alcohol-related harm, such as the use of safer drinking strategies. Whereas effectiveness of safer-drinking strategies has been well-documented among young adults, no studies have explored this topic among more severely affected populations, such as chronically homeless individuals with alcohol dependence. The aims of this study were thus to qualitatively and quantitatively document safer-drinking strategies used in this population. Participants (N=31) were currently or formerly chronically homeless individuals with alcohol dependence participating in a pilot study of extended-release naltrexone and harm-reduction counseling. At weeks 0 and 8, research staff provided a list of safer-drinking strategies for participants to endorse. Implementation of endorsed safer-drinking strategies was recorded at the next appointment. At both time points, strategies to buffer the effects of alcohol on the body (e.g., eating prior to and during drinking) were most highly endorsed, followed by changing the manner in which one drinks (e.g., spacing drinks), and reducing alcohol consumption. Quantitative analyses indicated that all participants endorsed safer-drinking strategies, and nearly all strategies were implemented (80-90% at weeks 0 and 8, respectively). These preliminary findings indicate that chronically homeless people with alcohol dependence use strategies to reduce harm associated with their drinking. Larger randomized controlled trials are needed to test whether interventions that teach safer-drinking strategies may reduce overall alcohol-related harm in this population. PMID- 25690516 TI - Seed Priming with Selenium: Consequences for Emergence, Seedling Growth, and Biochemical Attributes of Rice. AB - The present study was undertaken to appraise the role of selenium priming for improving emergence and seedling growth of basmati rice. Seeds of two fine rice cultivars (Super and Shaheen Basmati) were primed with concentrations of 15, 30, 45, 60, 75, 90, and 105 MUmol L(-1) selenium. Untreated dry- and hydro-primed seeds were maintained as the control and positive control, respectively. Selenium priming resulted in early commencement of emergence, triggered seedling growth irrespective of rice cultivar over untreated control, and was more effective than hydro-priming except at higher concentrations. Lower electrical conductivity of seed leachates, reduced lipid peroxidation, greater alpha-amylase activity, higher soluble sugars, and enhanced activities of enzymatic antioxidants (superoxide dismutase (SOD), peroxidase (POX), catalase (CAT), and glutathione peroxidase (GPX)) were observed in seeds primed with selenium. Rice seedlings derived from selenium-primed seeds exhibited more chlorophyll contents, while total phenolics were comparable with those of the control seedlings. The improved starch metabolism, greater membrane stability, and increased activity of antioxidants were considered as possible mechanisms responsible for such improvements in emergence and seedling vigor of rice mediated by selenium priming. Priming with selenium (15-60 MUmol L(-1)) favored rice emergence and seedling growth. Nevertheless, soaking seeds in relatively concentrated (90 and 105 MUmol L(-1)) selenium solution had overall detrimental effects. PMID- 25690517 TI - Effect of Excessive Potassium Iodide on Rat Aorta Endothelial Cells. AB - The aim of the current study was to investigate the effect of excess iodine on rat aorta endothelial cells and the potential underlying mechanisms. Rat aorta endothelial cells were cultured with iodide ion (3506, 4076, 4647, 5218, 5789, 6360, 6931, and 7512 mg/L) for 48 h. Morphological changes of cells were observed with microscope after Wright-Giemsa staining and acridine orange staining. Cell proliferation was determined with 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assay, and cell apoptosis was assessed with flow cytometry. The activity of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), endothelial nitric oxide synthase (eNOS), induced nitric oxide synthase (iNOS), and concentrations of malondialdehyde (MDA), glutathione (GSH), and protein carbonyl in culture medium were determined with colorimetric method. The expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) was detected by enzyme linked immunosorbent assay. The results showed that excess iodine induced abnormal morphologic changes of cells, inhibited cell proliferation, and increased apoptosis rate. Iodine also reduced the activity of SOD, GSH-Px, and concentrations of GSH and increased the concentrations of MDA and protein carbonyl in a dose-dependent manner. Moreover, excess iodine decreased the activity of eNOS and increased the activity of iNOS and the expression of ICAM-1 and VCAM-1 in culture medium. Our results suggested that excess iodine exposure increased oxidative stress, caused damage of vascular endothelial cells, and altered the expression of adhesion factors and the activity of NOS. These changes may explain the mechanisms underlying excess iodine-induced vascular injury. PMID- 25690518 TI - Large animal in vivo evaluation of a binary blend polymer scaffold for skeletal tissue-engineering strategies; translational issues. AB - Binary blend polymers offer the opportunity to combine different desirable properties into a single scaffold, to enhance function within the field of tissue engineering. Previous in vitro and murine in vivo analysis identified a polymer blend of poly(l-lactic acid)-poly(epsilon-caprolactone) (PLLA:PCL 20:80) to have characteristics desirable for bone regeneration. Polymer scaffolds in combination with marrow-derived skeletal stem cells (SSCs) were implanted into mid-shaft ovine 3.5 cm tibial defects, and indices of bone regeneration were compared to groups implanted with scaffolds alone and with empty defects after 12 weeks, including micro-CT, mechanical testing and histological analysis. The critical nature of the defect was confirmed via all modalities. Both the scaffold and scaffold/SSC groups showed enhanced quantitative bone regeneration; however, this was only found to be significant in the scaffold/SSCs group (p = 0.04) and complete defect bridging was not achieved in any group. The mechanical strength was significantly less than that of contralateral control tibiae (p < 0.01) and would not be appropriate for full functional loading in a clinical setting. This study explored the hypothesis that cell therapy would enhance bone formation in a critical-sized defect compared to scaffold alone, using an external fixation construct, to bridge the scale-up gap between small animal studies and potential clinical translation. The model has proved a successful critical defect and analytical techniques have been found to be both valid and reproducible. Further work is required with both scaffold production techniques and cellular protocols in order to successfully scale-up this stem cell/binary blend polymer scaffold. (c) 2015 The Authors. Journal of Tissue Engineering and Regenerative Medicine published by John Wiley & Sons, Ltd. PMID- 25690519 TI - Aging-like changes in the transcriptome of irradiated microglia. AB - Whole brain irradiation remains important in the management of brain tumors. Although necessary for improving survival outcomes, cranial irradiation also results in cognitive decline in long-term survivors. A chronic inflammatory state characterized by microglial activation has been implicated in radiation-induced brain injury. We here provide the first comprehensive transcriptional profile of irradiated microglia. Fluorescence-activated cell sorting was used to isolate CD11b+ microglia from the hippocampi of C57BL/6 and Balb/c mice 1 month after 10 Gy cranial irradiation. Affymetrix gene expression profiles were evaluated using linear modeling and rank product analyses. One month after irradiation, a conserved irradiation signature across strains was identified, comprising 448 and 85 differentially up- and downregulated genes, respectively. Gene set enrichment analysis demonstrated enrichment for inflammation, including M1 macrophage associated genes, but also an unexpected enrichment for extracellular matrix and blood coagulation-related gene sets, in contrast previously described microglial states. Weighted gene coexpression network analysis confirmed these findings and further revealed alterations in mitochondrial function. The RNA-seq transcriptome of microglia 24-h postradiation proved similar to the 1-month transcriptome, but additionally featured alterations in apoptotic and lysosomal gene expression. Reanalysis of published aging mouse microglia transcriptome data demonstrated striking similarity to the 1-month irradiated microglia transcriptome, suggesting that shared mechanisms may underlie aging and chronic irradiation-induced cognitive decline. GLIA 2015;63:754-767. PMID- 25690520 TI - New biomarkers in the selection of patients for talcage of pleural cavity in the palliative therapy of malign pleural exudate. AB - BACKGROUND: Chemical pleurodesis using videothoracoscopically applied powdered talc under general anaesthesia and selective pulmonary ventilation is the most effective method of palliative therapy for malign pleural exudate. Talc produces an intense systemic inflammatory reaction with the development of aseptic pleurisy. The result is obliteration of the pleural cavity provided there is an intense inflammatory reaction in the pleural cavity and good contact of both pleural leaves. The course of the adherence of pleural leaves can be followed using skiascopy. In routine practice, the course of local inflammatory markers is difficult to evaluate. Selection of suitable patients who will respond to this procedure is another principal obstacle of this surgical method. AIM: To evaluate the course of local inflammatory changes in the pleural cavity following application of talc and to quantify their dynamics. Selection of specific biomarkers to predict the intensity of inflammation in the pleural exudate for targeted selection of patients suitable for talcage was the second aim of this study. MATERIALS AND METHODS: 114 patients were retrospectively divided into Group A (N1 = 98) or patients without relapse and Group B (N2 = 16), patients with relapse of exudate formation. The need for repeated thoracic punctures or drainage over the course of a 12-month monitoring period was a criterion of treatment failure. Quantification of the effusion was performed by ultrasonic examination over a one year observational period at 3-monthly intervals. The concentration of soluble CD163 scavenger receptor and soluble Apo/Fas molecule was determined in exudate by ELISA. RESULTS: Soluble receptors in the 2 groups differed significantly. Group B showed higher sCD163 levels before talcage (P0 = 0.00024), faster dynamic decline in 2 h (P2 = 0.0092) and in 24 h (P24 = 0.0087). During monitoring, decrease in group B was statistically significant at 2 h (P2 = 0.056) and at 24 hrs (P24 = 0.0066). CONCLUSION: This pilot study showed that high values of sCD163 and sApo/Fas in the pleural exudate can predict treatment failure. Unsuitable candidates for this type of therapy couldbe selected in this way. PMID- 25690521 TI - The effects of novel 7-MEOTA-donepezil like hybrids and N-alkylated tacrine analogues in the treatment of quinuclidinyl benzilate-induced behavioural deficits in rats performing the multiple T-maze test. AB - AIMS: The number of approved drugs for the clinical treatment of Alzheimer disease remains limited. For this reason, there is extensive search for novel therapies. Of these, cholinesterase inhibitors have some proven benefit in slowing the disease progression and still remain the first-line therapeutic approach. In this study, the pro-cognitive effect of four novel tacrine-related inhibitors was evaluated and compared with the standards, tacrine and donepezil. METHODS: Wistar rats trained to perform the multiple T-maze were treated intra peritoneally with the anticholinergic agent 3-quinuclidinyl benzilate (QNB, 2.0 mg/kg), followed 30 min later by another injection containing a therapeutic dose of standard or novel cholinesterase inhibitor. The rats were repeatedly subjected to the multiple T-maze task at several time points following QNB administration (1, 24, 48 and 72 h). The passage time and number of errors were recorded. The inhibitory potential of selected therapeutic doses was assessed in a separate in vivo experiment using a spectrophotometric method. RESULTS: QNB significantly impaired the performance of the rats within 48 h. The four novel cholinesterase inhibitors attenuated the effect of QNB at 1 h, 24 h and 48 h test intervals. The novel compounds resulted in brain cholinesterase inhibition ranging from 5.4 to 11.3 %, and their effect on the QNB-induced deficit recorded in the T-maze performance was comparable to that of the standards or higher at some time points. CONCLUSION: The best result was achieved with derivative 4, followed by derivatives 2 and 3, suggesting that these compounds could be candidates for the treatment of Alzheimer disease. PMID- 25690522 TI - Contribution of sVEP visual acuity testing in comparison with subjective visual acuity. AB - AIMS: Visual acuity determination is an important task in ophthalmology and optometry practices. Visual acuity can be examined objectively or subjectively. The objective examination method, sVEP, allows for quick objective measurements of patient's visual acuity. Previous studies have not demonstrated the repeatability of this objective sVEP method. This study aims to evaluate the sVEP method and compare it to a subjective method. METHODS AND RESULTS: The sample was divided into two groups. For the first group, visual acuity was measured with sVEP and Snellen methods on only one patient twelve times. In the second group, visual acuity was measured twice with sVEP followed twice with the Snellen method with Landolt's rings and logMAR modification on 32 non-pathological patients. Results showed significant differences between average values of visual acuity obtained with both methods (sVEP and Snellen) in both samples (T-test, P < 0.01; Wilcoxon test, P = 0.02 in second group). In the second group, significant correlations between repeated sVEP measurements (Spearman test, P < 0.05, r = 0.69) were found but no significant correlation between average sVEP measurement and average Snellen measurement (Spearman test, P > 0.05, r = 0.15) was found. CONCLUSION: Objective measurement of visual acuity with sVEP is a valid and reliable method, but is recommended only when it is not possible to use a subjective method for measuring visual acuity, e.g. children, patients with mental retardation or simulating/dissimulating patients. PMID- 25690523 TI - Oculocutaneous albinism in a patient with 17p13.2-pter duplication - a review on the molecular syndromology of 17p13 duplication. AB - BACKGROUND: Chromosomal duplications involving 17p13.3 have recently been defined as a new distinctive syndrome with several diagnosed patients. Some variation is known to occur in the breakpoints of the duplicated region and, consequently, in the phenotype as well. AIMS: We report on a patient, the fifth to our knowledge, a 4-year-old girl with a pure de novo subtelomeric 17p13.2-pter duplication. She presents all of the facial features described so far for this duplication and in addition, a unilateral palmar transversal crease and oculocutaneous albinism which has not been reported previously. METHODS: A detailed molecular description of the reported aberration and correlation with the observed phenotypical features based on a literature review. We discuss the possible molecular etiology of albinism in regard to the mode of inheritance. CONCLUSION: The new data provided here may be useful for further genotype correlations in syndromes with oculocutaneous albinism, especially of autosomal dominant inheritance. PMID- 25690524 TI - Can we diagnose isolated, exercise-induced heart failure with normal ejection fraction? AB - BACKGROUND: A significant proportion of patients with exertional dyspnea require exercise to diagnose heart failure with normal ejection fraction (HFNEF). METHODS AND RESULTS: In this review article, we evaluate current data on the prevalence, clinical significance and specifically the establishment of a diagnosis of isolated, exercise-induced HFNEF. Despite the unquestioned clinical importance and high prevalence of exercise-induced HFNEF, there are limited and conflicting data on making a diagnosis of exercise-induced HFNEF. This mostly relies on the evidence of exercise-induced elevation in left ventricular filling pressure (LVFP). At present, there is no agreement on the ability of exercise echocardiographic parameteres to predict exercise-induced LVFP elevation. In addition, even invasively measured exercise LVFP faces the problem of defining normal exercise LVFP values. More data and probably new diagnostic approaches are necessary to reliably diagnose exercise HFNEF. CONCLUSIONS: There are conflicting results and significant problems associated with the diagnosis of exercise HFNEF. This review hopefully will encourage further research in this difficult but clinically important area of heart failure. PMID- 25690525 TI - Brain metastases of parathyroid carcinoma: Review of the literature and a case report. AB - BACKGROUND: Parathyroid carcinoma is a rare tumor typically presenting with marked elevations of serum calcium concentrations and associated renal and skeletal symptoms. Parathyroid carcinoma grows slowly, but may recur in regional lymph nodes, and, in about 25% of patients, metastasizes to the lungs. METHOD: Description of a new case and review of the literature. RESULTS: We present here a patient with parathyroid carcinoma that had aggressive biological behavior with synchronous lung metastases and manifestation of brain metastases 18 month after the initial diagnosis and review earlier reports on this rare presentation. These metastases could be detected with [(18)F] fluorodeoxyglucose positron-emission tomography/computed tomography as well as with (99m)technetium-sestamibi scan. CONCLUSIONS: Except for surgery in case of isolated solitary metastases, therapeutic options in patients with brain metastases of parathyroid carcinoma are currently very limited. PMID- 25690526 TI - In vitro arrhythmia generation by mild hypothermia: a pitchfork bifurcation type process. AB - The neurological damage after cardiac arrest presents a huge challenge for hospital discharge. Therapeutic hypothermia (34 degrees C - 32 degrees C) has shown its benefits in reducing cerebral oxygen demand and improving neurological outcomes after cardiac arrest. However, it can have many adverse effects, among them cardiac arrhythmia generation which represents an important part (up to 34%, according different clinical studies). A monolayer cardiac culture is prepared with cardiomyocytes from a newborn rat, directly on a multi-electrode array, which allows the acquisition of the extracellular potential of the culture. The temperature range is 37 degrees C - 30 degrees C-37 degrees C, representing the cooling and rewarming process of therapeutic hypothermia. Experiments showed that at 35 degrees C, the acquired signals are characterized by period-doubling phenomenon, compared with signals at other temperatures. Spiral waves, commonly considered to be a sign of cardiac arrhythmia, are observed in the reconstructed activation map. With an approach from nonlinear dynamics, phase space reconstruction, it is shown that at 35 degrees C, the trajectories of these signals formed a spatial bifurcation, even trifurcation. Another transit point is found between 30 degrees C-33 degrees C, which agreed with other clinical studies that induced hypothermia after cardiac arrest should not fall below 32 degrees C. The process of therapeutic hypothermia after cardiac arrest can be represented by a pitchfork bifurcation type process, which could explain the different ratios of arrhythmia among the adverse effects after this therapy. This nonlinear dynamic suggests that a variable speed of cooling/rewarming, especially when passing 35 degrees C, would help to decrease the ratio of post-hypothermia arrhythmia and then improve the hospital output. PMID- 25690527 TI - High-affinity anion binding by steroidal squaramide receptors. AB - Exceptionally powerful anion receptors have been constructed by placing squaramide groups in axial positions on a steroidal framework. The steroid preorganizes the squaramide NH groups such that they can act cooperatively on a bound anion, while maintaining solubility in nonpolar media. The acidic NH groups confer higher affinities than previously-used ureas or thioureas. Binding constants exceeding 10(14) M(-1) have been measured for tetraethylammonium salts in chloroform by employing a variation of Cram's extraction procedure. The receptors have also been studied as transmembrane anion carriers in unilamellar vesicles. Unusually their activities do not correlate with anion affinities, thus suggesting an upper limit for binding strength in the design of anion carriers. PMID- 25690528 TI - Effect of self-reported quality of sleep on mobility in older adults. AB - AIM: Quality of sleep (QOS) has been shown to have an affect on mental and physical well-being, and quality of life. However, few studies have investigated how sleep affects mobility in older adults. The aim of the present study was to examine the relationship between QOS and mobility disorder (MD) in community dwelling older adults. METHODS: Data collected through self-administered questionnaires was analyzed for 4564 Japanese older adults. Sleep outcomes included two self-reported questions regarding QOS. Logistic regression analysis was used to analyze the association between sleep and MD both by the QOS questions independently and grouped together by the two QOS questions into three groups: often sleeps well and good awakening (GG), does not often sleep well and bad awakening (BB) and a group with one of each (GB/BG). RESULTS: After adjustment for age, sex and depression, both those who did not often sleep well and those with poor awakening were more likely to show MD (OR 1.45, 95% CI 1.29 1.75), (OR 1.77, 95% CI 1.50-2.08), respectively. When grouped by both questions, those in the BB group had the least favorable outcome with increased odds ratio for possessing a MD (OR 1.95, 95% CI 1.61-2.37), compared with GB group (OR 1.40, 95% CI 1.18-1.67). CONCLUSIONS: Often sleeping well and good morning awakening were both associated with MD, suggesting that self reported QOS is associated with MD. Further research is required to investigate whether improving sleep quality could be a possible means of preventing and reversing MD in older adults. PMID- 25690529 TI - Hospital nurses' lived experience of power. AB - PURPOSE: The purpose of this study was to explore hospital nurses' lived experience of power. DESIGN: A hermeneutic phenomenological approach informed by Merleau-Ponty's philosophy of the phenomenology of perception was used to further an understanding of nurses' embodiment of power. Fourteen hospital clinical nurses employed in intensive care units and on medical floors in two major medical centers in the northeastern United States participated in 1-hr semistructured interviews about their lived experience of power. FINDINGS: A hermeneutic analytic approach and reflexive (cultural) bracketing produced three relational themes of power: (a) knowing my patients and speaking up for them; (b) working to build relationships that benefit patients; and (c) identifying my powerful self. CONCLUSIONS: Hospital clinical nurses develop a sense of power. Nurses believe power develops through acquisition of knowledge, experience, and self-confidence; this process is enhanced by exposure to good mentors. Nurses use their power to build relationships and advocate for patients. They consciously use power to improve patient care. Nurses' voices need to be heard and acknowledged. To do this in the clinical setting and beyond, hospital nurses must invite themselves or find ways to be invited into the authoritative discourse of hospital organizations. CLINICAL RELEVANCE: Nurses use their power to advocate for positive outcomes for patients and families. The satisfaction that comes from these positive relationships may improve nurses' perceptions of their work environment. Nurses' understanding and use of sociopolitical knowing needs further study, so that nurses may understand how to participate in current and future debates and decisions about our changing healthcare delivery systems and services. PMID- 25690530 TI - Active and latent tuberculosis among HIV-positive injecting drug users in Indonesia. AB - INTRODUCTION: Injecting drug use (IDU) is associated with tuberculosis but few data are available from low-income settings. We examined IDU in relation to active and latent tuberculosis (LTBI) among HIV-positive individuals in Indonesia, which has a high burden of tuberculosis and a rapidly growing HIV epidemic strongly driven by IDU. METHODS: Active tuberculosis was measured prospectively among 1900 consecutive antiretroviral treatment (ART)-naive adult patients entering care in a clinic in West Java. Prevalence of LTBI was determined cross-sectionally in a subset of 518 ART-experienced patients using an interferon-gamma release assay. RESULTS: Patients with a history of IDU (53.1%) more often reported a history of tuberculosis treatment (34.8% vs. 21.9%, p < 0.001), more often received tuberculosis treatment during follow-up (adjusted HR = 1.71; 95% CI: 1.25-2.35) and more often had bacteriologically confirmed tuberculosis (OR = 1.67; 95% CI: 0.94-2.96). LTBI was equally prevalent among people with and without a history of IDU (29.1 vs. 30.4%, NS). The risk estimates did not change after adjustment for CD4 cell count or ART. CONCLUSIONS: HIV positive individuals with a history of IDU in Indonesia have more active tuberculosis, with similar rates of LTBI. Within the HIV clinic, LTBI screening and isoniazid preventive therapy may be prioritized to patients with a history of IDU. PMID- 25690531 TI - Genetic variants and response to cancer treatments. PMID- 25690532 TI - Clinical and stabilometric measures predicting falls in Parkinson disease/parkinsonisms. AB - OBJECTIVES: Clinical predictors of falls in patients with Parkinson disease (PD) are fairly inaccurate. Stabilometric measures appear useful in investigating the relationship between balance, sensory disturbance, and falls. The aim of the study was to identify the best combination of clinical and stabilometric tests to predict falls prospectively. MATERIALS & METHODS: Fifty-three consecutive subjects with PD or parkinsonisms at risk of falls were included and followed for 6 months. Clinical variables were used as fall predictors: the Unified Parkinson Disease's Rating Scale (motor section) and the Longitudinal Aging study Amsterdam Physical Activity Questionnaire (LAPAQ). Variables from stabilometric platform underwent a principal component analysis. Multivariate logistic models were used to predict fallers using fall status (fallers: 1 + falls; recurrent fallers: 2 + falls) as dependent variable. RESULTS: Seven patients were lost to follow up, leaving 46 evaluable subjects. Of these, 32 (70%) were fallers and 22 (48%) were recurrent fallers. The only variable predicting fallers was the LAPAQ (odd ratio [OR] 0.99 (95% confidence interval [CI] 0.98-1.00); accuracy 71.7%; sensitivity 87.5%; specificity 35.7%). For recurrent fallers, Factor 2 (body sway velocity) (OR 2.37; 95% CI 1.01-5.58) and, in part, LAPAQ (OR 0.99; 95% CI 0.98-1.00) retained significance in the multivariate model, showing an accuracy of 76.9%, a sensitivity of 77.8%, and a specificity of 76.2%. CONCLUSIONS: A combination of clinical and instrumental tools is useful to identify fallers in PD or parkinsonisms. Body sway velocity and ability to perform the activities of daily living are the best predictors of recurrent falls. PMID- 25690533 TI - The effect of a methyl-deficient diet on the global DNA methylation and the DNA methylation regulatory pathways. AB - Methyl-deficient diets are known to induce various liver disorders, in which DNA methylation changes are implicated. Recent studies have clarified the existence of the active DNA demethylation pathways that start with oxidization of 5 methylcytosine (5meC) to 5-hydroxymethylcytosine by ten-eleven translocation (Tet) enzymes, followed by the action of base-excision-repair pathways. Here, we investigated the effects of a methionine-choline-deficient (MCD) diet on the hepatic DNA methylation of mice by precisely quantifying 5meC using a liquid chromatography-electrospray ionization-mass spectrometry and by investigating the regulatory pathways, including DNA demethylation. Although feeding the MCD diet for 1 week induced hepatic steatosis and lower level of the methyl donor S adenosylmethionine, it did not cause a significant reduction in the 5meC content. On the other hand, the MCD diet significantly upregulated the gene expression of the Tet enzymes, Tet2 and Tet3, and the base-excision-repair enzymes, thymine DNA glycosylase and apurinic/apyrimidinic-endonuclease 1. At the same time, the gene expression of DNA methyltransferase 1 and a, was also significantly increased by the MCD diet. These results suggest that the DNA methylation level is precisely regulated even when dietary methyl donors are restricted. Methyl-deficient diets are well known to induce oxidative stress and the oxidative-stress-induced DNA damage, 8-hydroxy-2'-deoxyguanosine (8OHdG), is reported to inhibit DNA methylation. In this study, we also clarified that the increase in 8OHdG number per DNA by the MCD diet is approximately 10 000 times smaller than the reduction in 5meC number, suggesting the contribution of 8OHdG formation to DNA methylation would not be significant. PMID- 25690534 TI - Association between scapula bony morphology and snapping scapula syndrome. AB - HYPOTHESIS AND BACKGROUND: Scapular incongruity has been described as a contributing factor to the development of snapping scapula syndrome (SSS). The purpose of this retrospective case-control study was to determine the association between scapula bony morphology on magnetic resonance imaging (MRI) and the diagnosis of SSS. METHODS: Bony morphologies of the scapula were evaluated on MRI scans of 26 patients with SSS and 19 patients with non-SSS pathologies. The medial scapula corpus angle (MSCA) was measured on axial MRI sequences. Scapulae were categorized as straight, S shaped, or concave. Two independent observers performed the measurements. Interobserver and intraobserver agreements of MSCA measurements were determined with intraclass correlation coefficients. RESULTS: Axial scapula bony morphology identified 28 scapulae of the straight type, 14 S shaped scapulae, and 5 concave scapulae. All 5 concave scapulae had confirmed SSS. Measurement of the MSCA showed excellent interobserver agreement of 0.80 (95% confidence interval [CI], 0.67 to 0.89) and intraobserver agreement of 0.70 (95% CI, 0.52 to 0.82). There were significant differences in the mean MSCAs between shoulders with SSS (14.4 degrees +/- 19.3 degrees ) and non-SSS shoulders (-3.3 degrees +/- 15.3 degrees , P = .001). The odds ratio was 8.4 (95% CI, 2.2 to 31.8) for positive MSCA and SSS. The scapulothoracic distance was significantly decreased in the SSS group (14.9 +/- 5.8 mm) compared with the non SSS patients (24.0 +/- 6.7 mm, P < .001). DISCUSSION AND CONCLUSION: Anterior angulation of the medial scapula in the axial plane was associated with SSS. Patients with a concave-shaped scapula and a positive MSCA have a 12-fold increased risk of SSS. The MSCA may prove helpful in determining the location and amount of scapular resection needed for patients with SSS. PMID- 25690535 TI - Selective retromastoid vestibular neurectomy for intractable Meniere's disease: a technical note. AB - BACKGROUND: Retrosigmoid vestibular neurectomy is considered to be the most effective and safe procedure to control intractable vertigo associated with Meniere's disease while preserving hearing. The surgical procedure of retrosigmoid vestibular neurectomy at the cerebellopontine angle has been well established. Here, we provide for otologic surgeons additional details about the procedure, with special attention to the anatomic features to emphasize our technique, which enables an adequate sectioning of the vestibular fibers on the cochlear nerve close to the overlapping zone containing large-caliber vestibular fibers and small-caliber cochlear fibers. METHODS: We used the lateral decubitus position to enter the cerebellopontine angle. The cerebellum was gently retracted to expose the cerebellomedullary cistern, which was then opened to drain the cerebrospinal fluid for slacking of the cerebellum. The underlying lower cranial nerves IX, X, and XI were identified. The retractor was then moved upward to locate the internal acoustic meatus and the complexes VIII-VII. Adjacent to the internal auditory canal, a longitudinal incision, about 3 mm long and 0.5 mm away from the landmarks of arteriole or cochleovestibular cleavage plane, was made on the cochlear nerve. A surgical separation plane was bluntly created using a microdissector between the two components, and the vestibular nerve was sharply sectioned with microscissors. RESULTS: We re-examined the patients' hearing status, word recognition (speech discrimination) skill, functional levels, and frequency of vertiginous episodes 1 month and at all 6-month intervals after the surgery. At 2 years after surgery, vertigo was completely controlled, indicating a 100% cure rate. CONCLUSION: Sectioning of vestibular fibers was performed along the cochleovestibular cleavage landmark on the cochlear nerve where the overlapping zone was located, allowing for a safe and adequate vestibular neurectomy, while most of the cochlear fibers were spared. PMID- 25690536 TI - Native species as goods. PMID- 25690537 TI - Tea waste: an effective and economic substrate for oyster mushroom cultivation. AB - BACKGROUND: Tea waste is the residue that remains after tea leaves have been extracted by hot water to obtain water-soluble components. The waste contains a re-usable energy substrate and nutrients which may pollute the environment if they are not dealt with appropriately. Other agricultural wastes have been widely studied as substrates for cultivating mushrooms. In the present study, we cultivated oyster mushroom using tea waste as substrate. To study the feasibility of re-using it, tea waste was added to the substrate at different ratios in different experimental groups. Three mushroom strains (39, 71 and YOU) were compared and evaluated. Mycelia growth rate, yield, biological efficiency and growth duration were measured. RESULTS: Substrates with different tea waste ratios showed different growth and yield performance. The substrate containing 40 60% of tea waste resulted in the highest yield. CONCLUSION: Tea waste could be used as an effective and economic substrate for oyster mushroom cultivation. This study also provided a useful way of dealing with massive amounts of tea waste. PMID- 25690538 TI - Vemurafenib for BRAF V600 mutated advanced melanoma: results of treatment beyond progression. AB - BACKGROUND: Selective BRAF inhibition (BRAFi) by vemurafenib or dabrafenib has become approved standard treatment in BRAF V600 mutated advanced stage melanoma. While the response rate is high, the response duration is limited with a progression-free survival (PFS) of 5-6months. Our observation of accelerated disease progression within some patients after stopping vemurafenib treatment has fostered the idea of treatment beyond progression (BRAFi TBP). METHOD: In this retrospective study, we analysed 70 metastatic melanoma patients, treated at our institute, who experienced progression after prior objective response upon treatment with vemurafenib. Thirty-five patients that continued treatment beyond progression are compared with 35 patients who stopped BRAFi treatment at disease progression. RESULTS: Median overall survival beyond documented progression was found to be 5.2months versus 1.4months (95% confidence interval (CI): 3.8-7.4 versus 0.6-3.4; Log-Rank p=0.002) in favour of BRAFi TBP. In the multivariate survival analysis, stopping treatment at disease progression was significantly associated with shorter survival (hazard ratio: 1.92; 95% CI: 1.04-3.55; p=0.04). CONCLUSION: Our results suggest that continuing vemurafenib treatment beyond progression may be beneficial in advanced melanoma patients, who prior to progression responded to vemurafenib. PMID- 25690539 TI - Identification of nodule-specific cysteine-rich plant peptides in endosymbiotic bacteria. AB - The symbiosis of Medicago truncatula with Sinorhizobium meliloti or Sinorhizobium medicae soil bacteria results in the formation of root nodules where bacteria inside the plant cells are irreversibly converted to polyploid, nondividing nitrogen-fixing bacteroids. Bacteroid differentiation is host-controlled and the plant effectors are symbiosis-specific secreted plant peptides. In the M. truncatula genome there are more than 600 symbiotic peptide genes including 500 small genes coding for nodule-specific cysteine-rich (NCR) peptides. While NCR transcripts represent >5% of the nodule transcriptome, the existence of only eight NCR peptides has been demonstrated so far. The predicted NCRs are secreted peptides targeted to the endosymbionts. Correspondingly, all the eight detected peptides were present in the bacteroids. Here, we report on large-scale detection of NCR peptides from nodules and from isolated, semipurified endosymbionts at various stages of their differentiation. In total 138 NCRs were detected in the bacteroids; 38 were cationic while the majority was anionic. The presence of early NCRs in nitrogen-fixing bacteroids indicates their high stability, and their long-term maintenance suggests persisting biological roles in the bacteroids. PMID- 25690540 TI - Nursing patients with chronic critical illness and their families: a qualitative study. AB - BACKGROUND: chronic critical illness (CCI) is a complex syndrome with a high risk of dying in hospital. Intensive care unit nurses are well-positioned to lead conversations integrating palliative and end-of-life care, yet have reported limited involvement. AIM: To generate further understanding of nurses' experiences of patients with CCI and their families. DESIGN AND METHODS: This qualitative study followed Thorne's interpretive description methods. In 2012, 16 intensive care unit nurses from one academic hospital participated in interviews. RESULTS: Our primary theme was that of internal tension generated through participants' knowledge of patients' anticipated and protracted dying, while wanting to shield families from suffering. This internal tension resulted from responsibilities to preserve hope for patients and families, while at the same time wanting to provide them prognostic information. Participants experienced challenges of: (i) preserving family trust, (ii) determining when and how to engage families in discussions and (iii) providing possibilities of a 'good' death. A secondary theme described constraints to acting on their insights because of interprofessional team dynamics or limited communication, within the team and with the family. CONCLUSION AND RELEVANCE TO CLINICAL PRACTICE: Internal tension, as experienced by participants reflects the challenges of transition from acute to palliation and end-of-life care, made more complex in CCI, because of its poorly defined terminal stage. Nurses' ability to manage the complex process of supporting hope while gradually providing information to build family understanding of CCI highlights their central role in facilitating what and how prognostic information is given, while managing the emotional implications and family response. To better support nurses do this, we advocate for formal structures enabling nurses to participate in decision-making regarding timing of transitions using palliation and end-of-life care. PMID- 25690541 TI - Effect of adjunctive use of green tea dentifrice in periodontitis patients - A Randomized Controlled Pilot Study. AB - OBJECTIVES: Green tea is known to possess anti-inflammatory, antibacterial and antioxidant activities. This study evaluated the effect of a locally prepared green tea dentifrice on specific parameters assessing gingival inflammation and severity of periodontal disease, when used as an adjunct to scaling and root planing (SRP) in the management of chronic periodontitis by comparing with a fluoride-triclosan-containing control dentifrice. MATERIALS AND METHODS: Thirty patients, with mild to moderate chronic periodontitis, were randomly allocated into two treatment groups, 'test' and 'control' after initial SRP. The test group was given green tea dentifrice with instructions on method of brushing, while the control group received a commercially available fluoride and triclosan containing dentifrice. Clinical parameters of Gingival Index (GI), Plaque Index (PI), percentage of sites with bleeding on probing (BOP), probing depth (PD) and clinical attachment level (CAL) along with biochemical parameters of total antioxidant capacity (TAOC) and glutathione-S-transferase (GST) activity in gingival crevicular fluid (GCF) were recorded at baseline line and 4 weeks post SRP. RESULTS: Intragroup analysis at 4 weeks showed statistically significant improvements of GI, PI, BOP, PD, CAL and TAOC in both groups. GST activity however, was increased only in the test group. At the end of the study period, the test group showed statistically significant improvements in GI, BOP, CAL, TAOC and GST levels compared to the control group. CONCLUSION: On comparison with fluoride-triclosan dentifrice, green tea showed greater reduction of gingival inflammation and improved periodontal parameters. Green tea dentifrice may serve as a beneficial adjunct to non-surgical periodontal therapy. PMID- 25690542 TI - Sex-related clustering of intracranial aneurysms within families. AB - BACKGROUND AND PURPOSE: Family history is important risk factor for intracranial aneurysms (ICA), but the pattern of inheritance is unsettled. If ICA within families would cluster according to sex, this may have implications for risk prediction and screening advice within families. We assessed the relationship between the sex of probands and their affected first-degree relatives (FDRs) within families with ICA. METHODS: We used data from our prospectively collected database of families with known familial ICA. We calculated relative risks for a female affected proband having a female affected FDR as compared with a male affected proband having female affected FDR with corresponding 95% confidence intervals. RESULTS: We included 148 families with 376 affected FDR. For a female proband the relative risk for having a female affected FDR compared with a male proband having an affected female FDR was 1.2 (95% confidence interval, 1.0-1.6). CONCLUSIONS: The clustering of ICA within families is greater in women than in men, with an excess of affected female FDR in female probands. However, because this excess is modest, our findings indicate that sex is not a relevant factor in risk prediction or screening advice in families with ICA. PMID- 25690543 TI - Astrocyte overexpression of heme oxygenase-1 improves outcome after intracerebral hemorrhage. AB - BACKGROUND AND PURPOSE: Heme oxygenase-1 (HO-1) catalyzes the rate-limiting reaction of heme breakdown and may have both antioxidant and pro-oxidant effects. In previous studies, HO-1 overexpression protected astrocytes from heme-mediated injury in vitro. In the present study, we tested the hypothesis that selective astrocyte overexpression of HO-1 improves outcome after intracerebral hemorrhage. METHODS: Male and female transgenic mice overexpressing human HO-1 driven by the GFAP promoter (GFAP.HMOX1) and wild-type controls received striatal injections of autologous blood (25 MUL). Blood-brain barrier disruption was assessed by Evans blue assay and striatal cell viability by methylthiazolyldiphenyl-tetrazolium bromide assay. Neurological deficits were quantified by digital analysis of spontaneous cage activity, adhesive removal, and elevated body swing tests. RESULTS: Mortality rate for wild-type mice was 34.8% and was similar for males and females; all GFAP.HMOX1 mice survived. Striatal Evans blue leakage at 24 hours was 23.4+/-3.2 ng in surviving wild-type mice, compared with 10.9+/-1.8 ng in transgenics. Perihematomal cell viability was reduced to 61+/-4% of contralateral at 3 days in wild-type mice, versus 80+/-4% in transgenics. Focal neurological deficits were significantly reduced and spontaneous cage activity was increased in GFAP.HMOX1 mice. CONCLUSIONS: Selective HO-1 overexpression in astrocytes reduces mortality, blood-brain barrier disruption, perihematomal cell injury, and neurological deficits in an autologous blood injection intracerebral hemorrhage model. Genetic or pharmacological therapies that acutely increase astrocyte HO-1 may be beneficial after intracerebral hemorrhage. PMID- 25690544 TI - Early mobilization after stroke: early adoption but limited evidence. PMID- 25690545 TI - Cortical activity during olfactory stimulation in multiple chemical sensitivity: a (18)F-FDG PET/CT study. AB - PURPOSE: To investigate the differences in brain glucose consumption during olfactory stimulation between subjects affected by multiple chemical sensitivity (MCS) and a group of healthy individuals. METHODS: Two (18)F-FDG PET/CT scans were performed in 26 subjects (6 men and 20 women; mean age 46.7 +/- 11 years) with a clinical diagnosis of MCS and in 11 healthy controls (6 women and 5 men; mean age 45.7 +/- 11 years), the first scan after a neutral olfactory stimulation (NS) and the second after a pure olfactory stimulation (OS). Differences in (18)F FDG uptake were analysed by statistical parametric mapping (SPM2). RESULTS: In controls OS led to an increase in glucose consumption in BA 18 and 19 and a reduction in glucose metabolism in BA 10, 11, 32 and 47. In MCS subjects, OS led to an increase in glucose consumption in BA 20, 23, 18 and 37 and a reduction in glucose metabolism in BA 8, 9 and 10. CONCLUSION: The results of our study suggest that cortical activity in subjects with MCS differs from that in healthy individuals during olfactory stimulation. PMID- 25690546 TI - Phase interrogation used for a wireless passive pressure sensor in an 800 degrees C high-temperature environment. AB - A wireless passive pressure measurement system for an 800 degrees C high temperature environment is proposed and the impedance variation caused by the mutual coupling between a read antenna and a LC resonant sensor is analyzed. The system consists of a ceramic-based LC resonant sensor, a readout device for impedance phase interrogation, heat insulating material, and a composite temperature-pressure test platform. Performances of the pressure sensor are measured by the measurement system sufficiently, including pressure sensitivity at room temperature, zero drift from room temperature to 800 degrees C, and the pressure sensitivity under the 800 degrees C high temperature environment. The results show that the linearity of sensor is 0.93%, the repeatability is 6.6%, the hysteretic error is 1.67%, and the sensor sensitivity is 374 KHz/bar. The proposed measurement system, with high engineering value, demonstrates good pressure sensing performance in a high temperature environment. PMID- 25690547 TI - Phospholipid fatty acids as physiological indicators of Paracoccus denitrificans encapsulated in silica sol-gel hydrogels. AB - The phospholipid fatty acid (PLFA) content was determined in samples of Paracoccus denitrificans encapsulated in silica hydrogel films prepared from prepolymerized tetramethoxysilane (TMOS). Immediately after encapsulation the total PLFA concentration was linearly proportional to the optical density (600 nm) of the input microbial suspension (R2 = 0.99). After 7 days this relationship remained linear, but with significantly decreased slope, indicating a higher extinction of bacteria in suspensions of input concentration 108 cells/mL and higher. trans-Fatty acids, indicators of cytoplasmatic membrane disturbances, were below the detection limit. The cy/pre ratio (i.e., ratio of cyclopropylated fatty acids (cy17:0 + cy19:0) to their metabolic precursors (16:1omega7 + 18:1omega7)), an indicator of the transition of the culture to a stationary growth-phase, decreased depending on co-immobilization of nutrients in the order phosphate buffer > mineral medium > Luria Broth rich medium. The ratio, too, was logarithmically proportional to cell concentration. These results confirm the applicability of total PLFA as an indicator for the determination of living biomass and cy/pre ratio for determination of nutrient limitation of microorganisms encapsulated in sol-gel matrices. This may be of interest for monitoring of sol-gel encapsulated bacteria proposed as optical recognition elements in biosensor construction, as well as other biotechnological applications. PMID- 25690548 TI - Amplification of the signal intensity of fluorescence-based fiber-optic biosensors using a Fabry-Perot resonator structure. AB - Fluorescent biosensors have been widely used in biomedical applications. To amplify the intensity of fluorescence signals, this study developed a novel structure for an evanescent wave fiber-optic biosensor by using a Fabry-Perot resonator structure. An excitation light was coupled into the optical fiber through a laser-drilled hole on the proximal end of the resonator. After entering the resonator, the excitation light was reflected back and forth inside the resonator, thereby amplifying the intensity of the light in the fiber. Subsequently, the light was used to excite the fluorescent molecules in the reactive region of the sensor. The experimental results showed that the biosensor signal was amplified eight-fold when the resonator reflector was formed using a 92% reflective coating. Furthermore, in a simulation, the biosensor signal could be amplified 20-fold by using a 99% reflector. PMID- 25690549 TI - Use of multispectral imaging in varietal identification of tomato. AB - Multispectral imaging is an emerging non-destructive technology. In this work its potential for varietal discrimination and identification of tomato cultivars of Nepal was investigated. Two sample sets were used for the study, one with two parents and their crosses and other with eleven cultivars to study parents and offspring relationship and varietal identification respectively. Normalized canonical discriminant analysis (nCDA) and principal component analysis (PCA) were used to analyze and compare the results for parents and offspring study. Both the results showed clear discrimination of parents and offspring. nCDA was also used for pairwise discrimination of the eleven cultivars, which correctly discriminated upto 100% and only few pairs below 85%. Partial least square discriminant analysis (PLS-DA) was further used to classify all the cultivars. The model displayed an overall classification accuracy of 82%, which was further improved to 96% and 86% with stepwise PLS-DA models on high (seven) and poor (four) sensitivity cultivars, respectively. The stepwise PLS-DA models had satisfactory classification errors for cross-validation and prediction 7% and 7%, respectively. The results obtained provide an opportunity of using multispectral imaging technology as a primary tool in a scientific community for identification/discrimination of plant varieties in regard to genetic purity and plant variety protection/registration. PMID- 25690550 TI - Design and simulation of material-integrated distributed sensor processing with a code-based agent platform and mobile multi-agent systems. AB - Multi-agent systems (MAS) can be used for decentralized and self-organizing data processing in a distributed system, like a resource-constrained sensor network, enabling distributed information extraction, for example, based on pattern recognition and self-organization, by decomposing complex tasks in simpler cooperative agents. Reliable MAS-based data processing approaches can aid the material-integration of structural-monitoring applications, with agent processing platforms scaled to the microchip level. The agent behavior, based on a dynamic activity-transition graph (ATG) model, is implemented with program code storing the control and the data state of an agent, which is novel. The program code can be modified by the agent itself using code morphing techniques and is capable of migrating in the network between nodes. The program code is a self-contained unit (a container) and embeds the agent data, the initialization instructions and the ATG behavior implementation. The microchip agent processing platform used for the execution of the agent code is a standalone multi-core stack machine with a zero operand instruction format, leading to a small-sized agent program code, low system complexity and high system performance. The agent processing is token queue-based, similar to Petri-nets. The agent platform can be implemented in software, too, offering compatibility at the operational and code level, supporting agent processing in strong heterogeneous networks. In this work, the agent platform embedded in a large-scale distributed sensor network is simulated at the architectural level by using agent-based simulation techniques. PMID- 25690551 TI - Real-time strap pressure sensor system for powered exoskeletons. AB - Assistive and rehabilitative powered exoskeletons for spinal cord injury (SCI) and stroke subjects have recently reached the clinic. Proper tension and joint alignment are critical to ensuring safety. Challenges still exist in adjustment and fitting, with most current systems depending on personnel experience for appropriate individual fastening. Paraplegia and tetraplegia patients using these devices have impaired sensation and cannot signal if straps are uncomfortable or painful. Excessive pressure and blood-flow restriction can lead to skin ulcers, necrotic tissue and infections. Tension must be just enough to prevent slipping and maintain posture. Research in pressure dynamics is extensive for wheelchairs and mattresses, but little research has been done on exoskeleton straps. We present a system to monitor pressure exerted by physical human-machine interfaces and provide data about levels of skin/body pressure in fastening straps. The system consists of sensing arrays, signal processing hardware with wireless transmission, and an interactive GUI. For validation, a lower-body powered exoskeleton carrying the full weight of users was used. Experimental trials were conducted with one SCI and one able-bodied subject. The system can help prevent skin injuries related to excessive pressure in mobility-impaired patients using powered exoskeletons, supporting functionality, independence and better overall quality of life. PMID- 25690552 TI - An instantaneous low-cost point-of-care anemia detection device. AB - We present a small, compact and portable device for point-of-care instantaneous early detection of anemia. The method used is based on direct hematocrit measurement from whole blood samples by means of impedance analysis. This device consists of a custom electronic instrumentation and a plug-and-play disposable sensor. The designed electronics rely on straightforward standards for low power consumption, resulting in a robust and low consumption device making it completely mobile with a long battery life. Another approach could be powering the system based on other solutions like indoor solar cells, or applying energy harvesting solutions in order to remove the batteries. The sensing system is based on a disposable low-cost label-free three gold electrode commercial sensor for 50 uL blood samples. The device capability for anemia detection has been validated through 24 blood samples, obtained from four hospitalized patients at Hospital Clinic. As a result, the response, effectiveness and robustness of the portable point-of-care device to detect anemia has been proved with an accuracy error of 2.83% and a mean coefficient of variation of 2.57% without any particular case above 5%. PMID- 25690553 TI - Online sensor fault detection based on an improved strong tracking filter. AB - We propose a method for online sensor fault detection that is based on the evolving Strong Tracking Filter (STCKF). The cubature rule is used to estimate states to improve the accuracy of making estimates in a nonlinear case. A residual is the difference in value between an estimated value and the true value. A residual will be regarded as a signal that includes fault information. The threshold is set at a reasonable level, and will be compared with residuals to determine whether or not the sensor is faulty. The proposed method requires only a nominal plant model and uses STCKF to estimate the original state vector. The effectiveness of the algorithm is verified by simulation on a drum-boiler model. PMID- 25690554 TI - Viability prediction of Ricinus cummunis L. seeds using multispectral imaging. AB - The purpose of this study was to highlight the use of multispectral imaging in seed quality testing of castor seeds. Visually, 120 seeds were divided into three classes: yellow, grey and black seeds. Thereafter, images at 19 different wavelengths ranging from 375-970 nm were captured of all the seeds. Mean intensity for each single seed was extracted from the images, and a significant difference between the three colour classes was observed, with the best separation in the near-infrared wavelengths. A specified feature (RegionMSI mean) based on normalized canonical discriminant analysis, were employed and viable seeds were distinguished from dead seeds with 92% accuracy. The same model was tested on a validation set of seeds. These seeds were divided into two groups depending on germination ability, 241 were predicted as viable and expected to germinate and 59 were predicted as dead or non-germinated seeds. This validation of the model resulted in 96% correct classification of the seeds. The results illustrate how multispectral imaging technology can be employed for prediction of viable castor seeds, based on seed coat colour. PMID- 25690555 TI - Effect of nano-hydroxyapatite-coated magnetic nanoparticles on axonal guidance growth of rat dorsal root ganglion neurons. AB - Proper extracellular substrate can stimulate neural regeneration in nerve tissue engineering, including magnetic nanoparticles (iron oxide nanoparticles, Fe3 O4 ), but they are always neurotoxic, with low saturation magnetization and so on. These nanomaterials cannot be used to stimulate the growth and elongation of axons. Therefore, this work attempts to overcome these deficiencies. Nano hydroxyapatite (n-HA) coated magnetic nanoparticles were using an ultrasound assisted co-precipitation method. X-ray diffraction and transmission electron microscopy were used to characterize the structure and chemical composition of the produced samples. These synthesized nanomaterials were added into the primary cultured dorsal root ganglion (DRG) neurons; our results showed that n-HA-coated magnetic nanoparticles (Fe3 O4 +n-HA) can effectively increase cell viability and promote axonal elongation, which enhanced saturation magnetization. In addition, we demonstrated that axonal guidance cues Netrin-1 increase significantly after n HA-coated magnetic nanoparticles treatment by Western blots assay. n-HA-coated magnetic particles maybe applied to enhance or accelerate nerve regeneration, and it may provide guidance for regenerating axons in future. PMID- 25690556 TI - Posttraumatic stress and depressive symptoms in renal cell carcinoma: association with quality of life and utility of single-item distress screening. AB - OBJECTIVE: The purpose of this study was to examine the prevalence of posttraumatic stress symptoms (PTSS) in patients with renal cell carcinoma (RCC), the associations and co-occurrence between PTSS, depressive, and other cancer related symptoms and the ability of a single-item distress question to identify patients with PTSS. METHODS: Patients with stage I-IV RCC completed assessments of depressive symptoms (Center for Epidemiologic Studies Depression Scale), PTSS (Impact of Event Scale), cancer-related symptoms (MD Anderson Symptom Inventory), fatigue (Brief Fatigue Inventory), and sleep disturbance (Pittsburgh Sleep Quality Index). We used the distress item on the MD Anderson Symptom Inventory as a distress screener and general linear model analyses to test study hypotheses. RESULTS: Of the 287 patients (29% stage IV; 42% female; mean age = 58 years), 46% (n = 131) reported psychiatric symptoms with 15% (n = 44) reporting comorbid clinical levels of depressive symptoms and PTSS, 24% (n = 70) PTSS alone, and 6% (n = 17) depressive symptoms alone. Controlling for age, gender, and stage, patients with comorbid depressive symptoms and PTSS reported more cancer-related symptoms (p < 0.0001), fatigue (p < 0.0001), and sleep disturbance (p = 0.0003) than those with PTSS alone and more cancer-related symptoms (p = 0.002) and fatigue (p = 0.09) than those with depressive symptoms alone. Sensitivity analyses revealed that 26.9% of negative cases on the distress item fell within the clinical range of the Impact of Event Scale and 9.3% of negative cases met caseness on the Center for Epidemiologic Studies Depression Scale. CONCLUSIONS: Posttraumatic stress symptoms occurred both independently and comorbid with depressive symptoms in patients with RCC. PTSS were correlated with overall cancer symptom burden. Single-item distress screening was less sensitive in detecting PTSS than depressive symptoms. Therefore, additional screening strategies are required in the clinical setting. PMID- 25690557 TI - Endogenous praecaecal and total tract losses of nitrogen in pancreatic duct ligated minipigs. AB - The pancreatic duct-ligated minipig (PL) is an established model of pancreatic exocrine insufficiency (PEI) with a significant decrease of nutrient digestibility. This study aimed to quantify and compare endogenous losses of nitrogen (N) (ileal and faecal) in minipigs receiving an almost N-free diet. Altogether, 12 Gottingen minipigs (7 PL and 5 control animals) fitted with an re entrant ileo-caecal fistula were used. In Study 1, ileal digesta was collected over a period of 12 h on seven consecutive days, including one 24 h collection, when animals were fed a diet containing 0.49 g N/kg dry matter (DM). In Study 2, faeces were collected for 10 consecutive days. In Group PL, the amount and DM content of ileal digesta were higher (p < 0.05), while N concentration was lower than in the Control. The ileo-caecal N flux [g/kg DM intake] was about 2.5 times higher in Group PL (5.47 +/- 1.15) than in the Control (1.91 +/- 0.59) (p < 0.05). The amount of faeces did not differ, but faecal N losses were higher in Group PL (p < 0.05). Endogenous faecal N losses [g N/kg DM intake] of the Control group (1.17 +/- 0.72) were comparable with earlier studies, while those of Group PL were 2.6 times higher (3.09 +/- 1.34). In contrast, urinary excretion of N did not differ between the Control and Group PL. In conclusion, PEI caused markedly increased endogenous N losses. Therefore, the impact of reduced digestibility of nutrients on endogenous N losses might be relevant for apparent protein digestibility rates and should be taken into account. PMID- 25690558 TI - Intended and unintended (sensory-)motor coupling between the affected and unaffected upper limb in complex regional pain syndrome. AB - BACKGROUND: Motor dysfunction in complex regional pain syndrome (CRPS) has been associated with bilateral malfunction of sensory and motor circuits, which hints at abnormal coupling between the affected and the contralateral unaffected limb. In addition, clinical observations suggest that motor performance may depend on the (voluntary or automatic) context in which movements are executed. The present study aimed to examine the role of voluntary and automatic aspects of interlimb coupling in CRPS. METHODS: Twenty patients with unilateral chronic CRPS and 40 healthy controls performed a set of unimanual and bimanual motor tasks that differed in the degree to which intended bilateral planning, intended afference based error correction and unintended reflex-like entrainment were involved. RESULTS: Stability of interlimb coordination was reduced in CRPS patients compared to controls, especially for tasks involving active control of the affected side. In CRPS patients, intended coupling between the hands (planning, error correction) was markedly impaired, whereas unintended coupling between the hands (entrainment) appeared normal. CONCLUSIONS: Impaired motor control of the affected limb interfered with bimanual coordination, in particular for tasks involving voluntary (intended) as opposed to automatic (unintended) interlimb coupling. Our findings suggest inappropriate functioning of higher order centres involved in motor control of the affected limb, probably due to pain-related processes and impaired processing of proprioceptive information. Motor function of the affected limb may benefit from intended synchronization with movements of the unaffected contralateral limb, suggesting that bilateral training may be useful in patients with unilateral CRPS. PMID- 25690559 TI - Synthesis of a mixed valence state Ce-MOF as an oxidase mimetic for the colorimetric detection of biothiols. AB - We demonstrate a facile and rapid in situ partial oxidation synthetic strategy for the fabrication of a mixed valence state Ce-MOF (MVCM) which exhibits intrinsic oxidase-like activity. Furthermore, on the basis of the excellent catalytic activity of the MCVM, a colorimetric approach for the high-throughput detection of biothiols in serum samples was established. PMID- 25690560 TI - Low-normal thyroid function and the pathogenesis of common cardio-metabolic disorders. AB - BACKGROUND: Subclinical hypothyroidism may adversely affect the development of cardiovascular disease (CVD). Less is known about the role of low-normal thyroid function, that is higher thyroid-stimulating hormone and/or lower free thyroxine levels within the euthyroid reference range, in the development of cardio metabolic disorders. This review is focused on the relationship of low-normal thyroid function with CVD, plasma lipids and lipoprotein function, as well as with metabolic syndrome (MetS), chronic kidney disease (CKD) and nonalcoholic fatty liver disease (NAFLD). MATERIALS AND METHODS: This narrative review, which includes results from previously published systematic reviews and meta-analyses, is based on clinical and basic research papers, obtained via MEDLINE and PubMed up to November 2014. RESULTS: Low-normal thyroid function could adversely affect the development of (subclinical) atherosclerotic manifestations. It is likely that low-normal thyroid function relates to modest increases in plasma total cholesterol, LDL cholesterol and triglycerides, and may convey pro-atherogenic changes in lipoprotein metabolism and in HDL function. Most available data support the concept that low-normal thyroid function is associated with MetS, insulin resistance and CKD, but not with high blood pressure. Inconsistent effects of low-normal thyroid function on NAFLD have been reported so far. CONCLUSIONS: Observational studies suggest that low-normal thyroid function may be implicated in the pathogenesis of CVD. Low-normal thyroid function could also play a role in the development of MetS, insulin resistance and CKD, but the relationship with NAFLD is uncertain. The extent to which low-normal thyroid function prospectively predicts cardio-metabolic disorders has been insufficiently established so far. PMID- 25690561 TI - Genetic and environmental contributions to the relationships between brain structure and average lifetime cigarette use. AB - Chronic cigarette use has been consistently associated with differences in the neuroanatomy of smokers relative to nonsmokers in case-control studies. However, the etiology underlying the relationships between brain structure and cigarette use is unclear. A community-based sample of male twin pairs ages 51-59 (110 monozygotic pairs, 92 dizygotic pairs) was used to determine the extent to which there are common genetic and environmental influences between brain structure and average lifetime cigarette use. Brain structure was measured by high-resolution structural magnetic resonance imaging, from which subcortical volume and cortical volume, thickness and surface area were derived. Bivariate genetic models were fitted between these measures and average lifetime cigarette use measured as cigarette pack-years. Widespread, negative phenotypic correlations were detected between cigarette pack-years and several cortical as well as subcortical structures. Shared genetic and unique environmental factors contributed to the phenotypic correlations shared between cigarette pack-years and subcortical volume as well as cortical volume and surface area. Brain structures involved in many of the correlations were previously reported to play a role in specific aspects of networks of smoking-related behaviors. These results provide evidence for conducting future research on the etiology of smoking-related behaviors using measures of brain morphology. PMID- 25690562 TI - Regulation of testicular descent. AB - Testicular descent occurs in two morphologically distinct phases, each under different hormonal control from the testis itself. The first phase occurs between 8 and 15 weeks when insulin-like hormone 3 (Insl3) from the Leydig cells stimulates the gubernaculum to swell, thereby anchoring the testis near the future inguinal canal as the foetus grows. Testosterone causes regression of the cranial suspensory ligament to augment the transabdominal phase. The second, or inguinoscrotal phase, occurs between 25 and 35 weeks, when the gubernaculum bulges out of the external ring and migrates to the scrotum, all under control of testosterone. However, androgen acts mostly indirectly via the genitofemoral nerve (GFN), which produces calcitonin gene-related peptide (CGRP) to control the direction of migration. In animal models the androgen receptors are in the inguinoscrotal fat pad, which probably produces a neurotrophin to masculinise the GFN sensory fibres that regulate gubernacular migration. There is little direct evidence that this same process occurs in humans, but CGRP can regulate closure of the processus vaginalis in inguinal hernia, confirming that the GFN probably mediates human testicular descent by a similar mechanism as seen in rodent models. Despite increased understanding about normal testicular descent, the common causes of cryptorchidism remain elusive. PMID- 25690563 TI - Nanomedicine as an innovative therapeutic strategy for pediatric cancer. AB - Childhood cancer is the leading cause of mortality in children between 1 and 14 years of age. Malignancy accounts for 18 % of overall childhood mortality. Therapeutic advances in the field of pediatric oncology have helped to increase survival. Nanotechnology is the modification of materials at a nanoscale and can be used to deliver therapeutic agents. Examples of nanotechnology applications are organic self-assembled amphiphilic polymers, non-organic nanocarriers such as nanotubes and quantum dots. Each of these has their own utility in different settings. Application of nanotechnology in medicine has been extensively studied. Examples of pediatric tumors that received special attention are: neuroblastoma, retinoblastoma, central nervous system tumors and musculoskeletal tumors. This review will summarize the application of nanomedicine as an innovative management strategy in pediatric oncology. PMID- 25690564 TI - Design, synthesis and in vitro study of 5,6-diaryl-1,2,4-triazine-3-ylthioacetate derivatives as COX-2 and beta-amyloid aggregation inhibitors. AB - In order to find novel cyclooxygenase (COX)-2 inhibitors for treating inflammatory-based diseases such as Alzheimer's disease (AD), an ethyl carboxylate side chain was added to 5-(4-chlorophenyl)-6-(4 (methylsulfonyl)phenyl)-3-(methylthio)-1,2,4-triazine (lead compound II) to maintain residual inhibition of COX-1 through interacting with Arg120. A preliminary molecular docking study on both the COX-1/COX-2 active sites truly confirmed our hypothesis. Accordingly, a series of ethyl 5,6-diaryl-1,2,4 triazine-3-ylthioacetate derivatives were synthesized and their chemical structures were confirmed by NMR, IR and MS spectra. Further in vitro COX-1/COX-2 evaluations revealed that compound 6c (COX-2 IC50 = 10.1 MUM, COX-1 IC50 = 88.8 MUM) is the most selective COX-2 inhibitor while maintaining residual inhibition of COX-1. In order to evaluate their potential use against AD, an in vitro evaluation of beta-amyloid fibril formation was performed. The results indicated that the prototype compounds 6 are effective beta-amyloid destabilizing agents while compound 6c could inhibit 94% of the beta-amyloid fibril formation after 48 h. Finally, the in silico assessment results of their blood-brain barrier permeability were satisfactory. PMID- 25690565 TI - Prospective Predictions of Human Pharmacokinetics for Eighteen Compounds. AB - Quantitative predictions of pharmacokinetics (PKs) and concentration-time profiles using in vitro and in vivo preclinical data are critical to estimate systemic exposures for first-in-human studies. Prospective prediction accuracies of human PKs for 18 compounds across all Biopharmaceutics Classification System/Biopharmaceutics Drug Disposition Classification System classes were evaluated. The a priori predicted profiles were then compared with clinical profiles. Predictions were conducted using advanced compartmental absorption and transit (ACAT) physiology based PK models. Human intravenous profiles were predicted with in vivo preclinical intravenous data using Wajima formulas. Human oral profiles were generated by combining intravenous PKs together with either physiologically based oral ACAT models utilizing solubility and permeability data or by using the average bioavailability (F) and absorption rate constant (ka ) from preclinical species. Key PK parameters evaluated were the maximum plasma concentration (Cmax ), the area under the plasma concentration-time curve (AUC), CL/F, and Vdss /F. A decision tree was provided to guide human PK and ACAT predictions. Our prospective human PK prediction methods yielded good prediction results. The predictions were within a twofold error for 80% (Cmax ), 65% (AUC), 65% (CL/F), and 80% (Vz /F) of the compounds. The methods described can be readily implemented with available in vitro and in vivo data during early drug development. PMID- 25690566 TI - Flower-like CdSe ultrathin nanosheet assemblies for enhanced visible-light-driven photocatalytic H2 production. AB - Flower-like CdSe architectures composed of ultrathin nanosheets were prepared via a facile solvothermal method. A relationship was established between the solvothermal temperature and the product structure, and thus the photocatalytic activity. When compared with well-studied CdSe quantum dots, the ultrathin nanosheet assemblies exhibited a better photocatalytic H2 evolution activity under visible light irradiation. PMID- 25690567 TI - Bencycloquidium bromide inhibits nasal hypersecretion in a rat model of allergic rhinitis. AB - OBJECT AND DESIGN: This study is aimed at exploring the effect of Bencycloquidium bromide (BCQB), a novel M1/M3 receptor antagonist, on mucus secretion in a murine model of allergic rhinitis (AR). MATERIALS AND METHODS: Sprague-Dawley rats were sensitized with ovalbumin to induce AR. After BCQB treatment, nasal symptoms were evaluated. Nasal lavage fluid was used to detect the protein level of cytokines and histamine by the method of enzyme-linked immunosorbent assay. The nasal mucosa of all animals was prepared for western blot, quantitative real-time polymerase chain reaction and histochemical analysis. RESULTS: BCQB could not only alleviate typical AR symptoms including rhinorrhea, nasal itching and sneezing, but also inhibit the overexpression of mucin 5AC at the level of protein and mRNA. The release of histamine, the mRNA and protein level of IL-6, IL-13 and TNF-alpha, and the nuclear translocation of NF-kappaB (p65 and p50) were inhibited by BCQB. In addition, histological studies showed BCQB dramatically inhibited ovalbumin-induced nasal lesions, eosinophil infiltration, aggregation of mast cells, globlet cell hyperplasia and metaplasia. CONCLUSIONS: BCQB attenuates mucus hypersecretion in AR, possibly involving in the NF-kappaB signaling pathway. PMID- 25690568 TI - Repurposing of the Open Access Malaria Box for Kinetoplastid Diseases Identifies Novel Active Scaffolds against Trypanosomatids. AB - Phenotypic screening had successfully been used for hit generation, especially in the field of neglected diseases, in which feeding the drug pipeline with new chemotypes remains a constant challenge. Here, we catalyze drug discovery research using a publicly available screening tool to boost drug discovery. The Malaria Box, assembled by the Medicines for Malaria Venture, is a structurally diverse set of 200 druglike and 200 probelike compounds distilled from more than 20,000 antimalarial hits from corporate and academic libraries. Repurposing such compounds has already identified new scaffolds against cryptosporidiosis and schistosomiasis. In addition to initiating new hit-to-lead activities, screening the Malaria Box against a plethora of other parasites would enable the community to better understand the similarities and differences between them. We describe the screening of the Malaria Box and triaging of the identified hits against kinetoplastids responsible for human African trypanosomiasis (Trypanosoma brucei), Chagas disease (Trypanosoma cruzi), and visceral leishmaniasis (Leishmania donovani and Leishmania infantum). The in vitro and in vivo profiling of the most promising active compounds with respect to efficacy, toxicity, pharmacokinetics, and complementary druggable properties are presented and a collaborative model used as a way to accelerate the discovery process discussed. PMID- 25690569 TI - A Fragment-Based Ligand Screen Against Part of a Large Protein Machine: The ND1 Domains of the AAA+ ATPase p97/VCP. AB - The ubiquitous AAA+ ATPase p97 functions as a dynamic molecular machine driving several cellular processes. It is essential in regulating protein homeostasis, and it represents a potential drug target for cancer, particularly when there is a greater reliance on the endoplasmic reticulum-associated protein degradation pathway and ubiquitin-proteasome pathway to degrade an overabundance of secreted proteins. Here, we report a case study for using fragment-based ligand design approaches against this large and dynamic hexamer, which has multiple potential binding sites for small molecules. A screen of a fragment library was conducted by surface plasmon resonance (SPR) and followed up by nuclear magnetic resonance (NMR), two complementary biophysical techniques. Virtual screening was also carried out to examine possible binding sites for the experimental hits and evaluate the potential utility of fragment docking for this target. Out of this effort, 13 fragments were discovered that showed reversible binding with affinities between 140 uM and 1 mM, binding stoichiometries of 1:1 or 2:1, and good ligand efficiencies. Structural data for fragment-protein interactions were obtained with residue-specific [U-(2)H] (13)CH3-methyl-labeling NMR strategies, and these data were compared to poses from docking. The combination of virtual screening, SPR, and NMR enabled us to find and validate a number of interesting fragment hits and allowed us to gain an understanding of the structural nature of fragment binding. PMID- 25690570 TI - Single-nucleotide polymorphisms in CD8A and their associations with T lymphocyte subpopulations in pig. AB - Findings from previous studies suggested that the cluster of the differentiation 8 alpha (CD8A) gene plays a prominent role in human T lymphocyte subpopulations. However, the evidence from pig population is still rare. To determine whether the important role of the CD8A gene is conserved in pig, a candidate gene analysis was performed herein through genotype-phenotype associations. Five single nucleotide polymorphisms (SNPs) locating in the regulatory region of porcine CD8A gene were detected and tested for association analysis with seven T lymphocyte subpopulations (proportion of CD4(-)CD8(-), CD4(+)CD8(+), CD4(+)CD8(-), CD4( )CD8(+), CD4(+), CD8(+), and the ratio of CD4(+) to CD8(+) T cells in peripheral blood) in 382 Large White piglets. After Bonferroni correction for multiple testing, four SNPs were significantly associated with some or all of the seven T lymphocyte subpopulations. Analyses of pairwise D' measures of linkage disequilibrium between all SNPs were also explored. Two haplotype blocks was inferred and the association study on haplotype level revealed similar effects on T lymphocyte subpopulations. In addition, the tissue-specific RNA expression pattern and electrophoretic mobility shift assay offered further explanation of the link between the CD8A gene with porcine T lymphocyte subpopulations. The findings presented here provide strong evidence for associations of CD8A variants with T lymphocyte subpopulations and may be applied in porcine breeding programs. PMID- 25690571 TI - Infection prevention in transfusion practice. PMID- 25690572 TI - Probiotic Properties of Leuconostoc mesenteroides Isolated from Aguamiel of Agave salmiana. AB - Four lactic acid bacteria, Leuconostoc mesenteroides subsp. mesenteroides, were isolated from aguamiel the sap obtained from Agave salmiana from Mexico and identified by 16S rRNA gene sequence analysis. The probiotic potential of these strains was evaluated and compared with a commercial probiotic (Lactobacillus plantarum 299v) from human origin. All the strains survived the in vitro gastrointestinal simulation conditions: the stomach simulation (3 h, pH 2, 37 degrees C) and the intestinal simulation (4 h, bile salts 0.5%, 37 degrees C). All the strains showed a strong hydrophilic character with n-hexadecane and chloroform assays, and all the strains showed a mucin adhesion rate similar to that of L. plantarum 299v. The strains of L. mesenteroides subsp. mesenteroides exhibited similar antimicrobial activity against some pathogens in comparison with L. plantarum 299v. Some antibiotics inhibited the growth of the strains. L. mesenteroides subsp. mesenteroides exhibited in vitro probiotic potential, and it could be better characterized through future in vivo tests. PMID- 25690573 TI - Standardised packs cut adult smoking as well as discouraging young people, evidence indicates. PMID- 25690574 TI - [Focal therapy for prostate cancer: German version]. AB - Focal therapy is a treatment strategy for men with localized prostate cancer that may serve as an alternative option to radical therapy. A number of minimally invasive ablative technologies are available to deliver treatment, and the energies most commonly used include high-intensity focused ultrasound and cryotherapy. The benefit of a tissue-preserving approach is the limitation of damage to key structures such as the neurovascular bundles, external urinary sphincter, rectal mucosa and bladder neck. This in turn minimizes side effects typically associated with radical therapies whilst also aiming to maintain oncological control. Over 30 single-centre studies of focal therapy have been published to date reporting excellent continence rates, good potency rates and acceptable short-term oncological outcomes. However, there are a number of controversial aspects associated with focal therapy including the index lesion hypothesis, patient selection criteria, assessment of treatment effect and the lack of medium- and long-term oncological outcomes. In the process of the adoption of new technology, there is a limited window of opportunity to provide this evidence in well-designed prospective trials. Men should be allowed to benefit from the potential advantages of this novel treatment whilst under close surveillance. An English version of this article is available under dx.doi.org/10.1007/s00120-014-3734-7. PMID- 25690575 TI - [Percutaneous radiofrequency ablation of renal tumors: update 2015]. AB - BACKGROUND: Stage I renal cell carcinoma is a malignancy with a relatively good prognosis. The incidence of all renal cell carcinomas is approximately 9/100,000 persons. There are nearly 15,000 newly diagnosed patients every year (men twice as often as women). TREND: In the last decade, a trend away from radical open resection towards nephron-sparing approaches has been observed. Currently, partial nephrectomy is the surgical gold standard for the treatment of small renal tumors. However, excellent clinical results are obtained using percutaneous radiofrequency ablation (RFA): low complication rates and preservation of the renal function. RESULTS: Primary and secondary technical success rates are 69 100% and 90-100%, respectively. In large series, major complication rates of RFA of 0-14% are reported. A relevant deterioration of renal function after RFA is very rare. The 5-year local recurrence-free survival rates, metastasis-free survival rates, cancer-specific survival rates, and overall survival rates are 88 93, 95-100, 98-100, and 58.3-85%, respectively. In this context, the lack of appropriate long-term data is often cited as a limitation. CONCLUSION: Different meta-analyses come to the conclusion that in case of adequate tumor and patient selection RFA shows oncologic results comparable with surgical resection. Accepted indications for RFA are T1 renal tumors in patients with advanced age, significant comorbidities, reduced renal function, single kidney, and/or no wish for operation. Predictors for the success include tumor size and location as well as operator experience. To define the real efficacy of RFA in the treatment of renal tumors, randomized controlled clinical long-term studies are indicated. PMID- 25690579 TI - [Objects from scientific collections in demand: the value of the various collections of the Urologic History Center of the German Society of Urology for modern teaching purposes in urology]. AB - The use of artifacts and objects from scientific medical collections and museums for academic teaching purposes are one of the main qualifying tasks of those institutions. In recent years, this aspect of scientific collections has again become on focus within academics. The collections offer a unique chance for visual and haptic forms of teaching in many fields. Due to the potential of scientific collections, educators in all branches in academic learning should be familiar with handling objects for such purposes. PMID- 25690576 TI - [Neurogenic bladder function disorders in patients with meningomyelocele: S2k guidelines on diagnostics and therapy]. AB - The treatment of children and adolescents with meningomyelocele has experienced a clear change in the last 30 years. The establishment of pharmacotherapy, clean intermittent catheterization (CIC) and infection prophylaxis have improved the prognosis for patients and have led to new therapeutic strategies. The interdisciplinary cooperation between neonatologists, neurosurgeons, pediatric neurologists, pediatric urologists, pediatric nephrologists, pediatric orthopedists and pediatric surgeons leads to optimization of individualized therapy. These guidelines present definitions and classifications, investigations and timing which are described in detail. The conservative and operative therapy options for neurogenic bladder function disorders are described and discussed with reference to the current literature. The brief overview provides in each case assistance for the treating physician in the care of this patient group and facilitates the interdisciplinary cooperation. PMID- 25690580 TI - The role of depth of encoding in attentional capture. AB - The aim of the current study was to examine whether depth of encoding influences attentional capture by recently attended objects. In Experiment 1, participants first had to judge whether a word referred to a living or a nonliving thing (deep encoding condition) or whether the word was written in lower- or uppercase (shallow encoding condition), and they then had to identify a digit displayed midway in a rapid serial visual presentation (RSVP) stream of 8 pictures. A picture corresponding to the previously processed word was presented either before or after the target digit. The results showed that this picture captured attention, thus resulting in an attentional blink for identification of a target digit, in the deep encoding condition but not in the shallow encoding condition. In Experiment 2, this capture effect was found to be abolished when an additional working-memory (WM) task was performed directly after the word-judgment task, suggesting that the capture effect stemmed from residual WM activation that could be erased by means of a secondary WM task. Taken together, these results suggest that deep and shallow encoding result in different degrees of WM activation, which in turn influences the likelihood of memory-driven attentional capture. PMID- 25690581 TI - Effects of word length on eye movement control: The evidence from Arabic. AB - The finding that word length plays a fundamental role in determining where and for how long readers fixate within a line of text has been central to the development of sophisticated models of eye movement control. However, research in this area is dominated by the use of Latinate languages (e.g., English, French, German), and little is known about eye movement control for alphabetic languages with very different visual characteristics. To address this issue, the present experiment undertook a novel investigation of the influence of word length on eye movement behavior when reading Arabic. Arabic is an alphabetic language that not only is read from right to left but has visual characteristics fundamentally different from Latinate languages, and so is ideally suited to testing the generality of mechanisms of eye movement control. The findings reveal that readers were more likely to fixate and refixate longer words, and also that longer words tended to be fixated for longer. In addition, word length influenced the landing positions of initial fixations on words, with the effect that readers fixated the center of short words and fixated closer to the beginning letters for longer words, and the location of landing positions affected both the duration of the first fixation and probability of refixating the word. The indication now, therefore, is that effects of word length are a widespread and fundamental component of reading and play a central role in guiding eye-movement behavior across a range of very different alphabetic systems. PMID- 25690582 TI - On the complexity of triggering evolutionary radiations. AB - Recent developments in phylogenetic methods have made it possible to reconstruct evolutionary radiations from extant taxa, but identifying the triggers of radiations is still problematic. Here, we propose a conceptual framework to explore the role of variables that may impact radiations. We classify the variables into extrinsic conditions vs intrinsic traits, whether they provide background conditions, trigger the radiation, or modulate the radiation. We used three clades representing angiosperm phylogenetic and structural diversity (Ericaceae, Fagales and Poales) as test groups. We located radiation events, selected variables potentially associated with diversification, and inferred the temporal sequences of evolution. We found 13 shifts in diversification regimes in the three clades. We classified the associated variables, and determined whether they originated before the relevant radiation (backgrounds), originated simultaneously with the radiations (triggers), or evolved later (modulators). By applying this conceptual framework, we establish that radiations require both extrinsic conditions and intrinsic traits, but that the sequence of these is not important. We also show that diversification drivers can be detected by being more variable within a radiation than conserved traits that only allow occupation of a new habitat. This framework facilitates exploration of the causative factors of evolutionary radiations. PMID- 25690583 TI - Trends in worker hearing loss by industry sector, 1981-2010. AB - BACKGROUND: The purpose of this study was to estimate the incidence and prevalence of hearing loss for noise-exposed U.S. workers by industry sector and 5-year time period, covering 30 years. METHODS: Audiograms for 1.8 million workers from 1981-2010 were examined. Incidence and prevalence were estimated by industry sector and time period. The adjusted risk of incident hearing loss within each time period and industry sector as compared with a reference time period was also estimated. RESULTS: The adjusted risk for incident hearing loss decreased over time when all industry sectors were combined. However, the risk remained high for workers in Healthcare and Social Assistance, and the prevalence was consistently high for Mining and Construction workers. CONCLUSIONS: While progress has been made in reducing the risk of incident hearing loss within most industry sectors, additional efforts are needed within Mining, Construction and Healthcare and Social Assistance. PMID- 25690584 TI - The Brown and Black rule: a simple clue to differentiate common naevi from spitzoid neoplasms with a dermoscopic uniform globular (clod) pattern. PMID- 25690586 TI - The distance-to-source trend in vanadium and arsenic exposures for residents living near a petrochemical complex. AB - Biological monitoring of vanadium (V) and arsenic (As) for residents living near a big petrochemical complex has not been previously studied. This study aims to investigate distance-to-source trends in urinary levels and dispersion-estimated concentrations of V and As in areas surrounding a petrochemical complex in central Taiwan. Our study subjects were 1424 residents living in the townships up to ~40 km from the petrochemical complex, and categorized as near (Zone A), further (Zone B) and furthest (Zone C) from the complex. Urinary and ambient V and As levels were analyzed by inductively coupled plasma mass spectrometry. Two stage dispersion model was used to estimate V and As concentrations at each study subject's address. Multiple linear regression models were used to study the effects of distance-to-source and estimated air concentrations of V and As on the urinary V and As levels of study subjects. Area-wide levels of both V and As showed a high-to-low trend in urinary levels (MUg/g-creatinine) from Zone A (V with 2.86+/-2.30 and As with 104.6+/-147.9) to Zone C (V with 0.73+/-0.72 and As with 73.8+/-90.8). For study subjects, urinary V and As levels were decreased by 0.09 and 1.17 MUg/g-creatinine, respectively, with 1 km away from the emission source of the petrochemical complex, and urinary V levels were significantly elevated by 0.38 MUg/g-creatinine with a 1 ng/m(3) increase in estimated ambient V concentrations at their addresses. Our study concludes a distance-to-source gradient in V and As exposures exists for residents living near a petrochemical complex with oil refineries and coal-fired power plants and two-stage dispersion model can predict such a trend for V when inhalation is the major exposure route, but not for As that exposure may be from multiple sources and exposure routes. PMID- 25690585 TI - Vinyl flooring in the home is associated with children's airborne butylbenzyl phthalate and urinary metabolite concentrations. AB - Prior studies have shown that vinyl flooring as well as the vinyl-softening plasticizers butylbenzyl phthalate (BBzP) and di(2-ethylhexyl) phthalate (DEHP) are associated with asthma and airway inflammation. Although DEHP exposure is primarily dietary, whether home vinyl flooring contributes to indoor air and urinary metabolite concentrations for these two phthalates is unclear. Exposures to BBzP and DEHP were examined in a prospective birth cohort of New York City children (n=239) using: (i) visual observation of potential phthalate containing flooring, (ii) a 2-week home indoor air sample, and (iii) concurrent urinary metabolites in a subset (n=193). The category "vinyl or linoleum" flooring was observed in 135 (56%) of monitored rooms; these rooms had statistically significantly higher indoor air geometric mean concentrations of BBzP (23.9 ng/m(3)) than rooms with wood or carpet flooring (10.6 ng/m(3)). Children from homes with "vinyl or linoleum" flooring also had significantly higher urinary BBzP metabolite concentrations than other children. Indoor air BBzP and urinary metabolite concentrations were correlated positively (Spearman's rho 0.40). By contrast, indoor air DEHP was not associated with flooring type nor with its urinary metabolite concentrations. Vinyl flooring in the home may be an important source of children's exposure to BBzP via indoor air. PMID- 25690587 TI - Amido-bridged nucleic acids with small hydrophobic residues enhance hepatic tropism of antisense oligonucleotides in vivo. AB - High scalability of a novel bicyclic nucleoside building block, amido-bridged nucleic acid (AmNA), to diversify pharmacokinetic properties of therapeutic antisense oligonucleotides is described. N2'-functionalization of AmNA with a variety of hydrophobic groups is straightforward. Combinations of these modules display similar antisense knockdown effects and improve cellular uptake, relative to sequence-matched conventional 2',4'-bridged nucleic acid (2',4'-BNA) in vivo. PMID- 25690588 TI - The recent national lipid association recommendations: how do they compare to other established dyslipidemia guidelines? AB - The National Lipid Association (NLA) recently released recommendations for the treatment of dyslipidemias. These recommendations have commonalities and differences with those of other major societies with respect to risk assessment, lifestyle therapy, targets of therapy, and the use of non-statin agents. In this review, we compare the basic elements of the guidelines from each major society to provide clinicians with a comprehensive document reviewing the key principles of each. PMID- 25690589 TI - Shared genetic aetiology of coronary artery disease and atherosclerotic stroke - 2015. AB - In the last years, genome-wide association studies have allowed to identify multiple genetic variants associated with atherosclerosis. In this review, we highlight the identification of genomic variants associated with coronary artery disease and myocardial infarction as well as large-vessel stroke. We will focus on genetic variants that displayed overlap for these atherosclerotic diseases. Current research is focusing on the identification of the functional mechanisms underlying these associations. As frequent variants are often only associated with small increases in risk, the search for the identification of rare variants with large increases in risk is ongoing. Whole-exome sequencing recently revealed rare variants dramatically increasing cardiovascular risk. Taken together, the developments of the past few years light the vision of improved prevention and therapy of coronary artery disease and stroke. PMID- 25690590 TI - FXR agonists as therapeutic agents for non-alcoholic fatty liver disease. AB - Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome and a risk factor for both cardiovascular and hepatic related morbidity and mortality. The increasing prevalence of this disease requires novel therapeutic approaches to prevent disease progression. Farnesoid X receptors are bile acid receptors with roles in lipid, glucose, and energy homeostasis. Synthetic farnesoid X receptor (FXR) agonists have been developed to specifically target these receptors for therapeutic use in NAFLD patients. Here, we present a review of bile acid physiology and how agonism of FXR receptors has been examined in pre-clinical and clinical NAFLD. Early evidence suggests a potential role for synthetic FXR agonists in the management of NAFLD; however, additional studies are needed to clarify their effects on lipid and glucose parameters in humans. PMID- 25690591 TI - Nevus anemicus: a distinctive cutaneous finding in neurofibromatosis type 1. AB - Nevus anemicus (NA) is a cutaneous anomaly characterized by pale, well-defined patches with limited vascularization after rubbing. They are largely known to be associated with neurofibromatosis 1 (NF1) and have received little attention in the literature until recently. We sought to characterize the prevalence and clinical features of patients with NA and NF1. We conducted an observational prospective study of 99 children with NF1 at the Hospital Nino Jesus, Madrid, Spain, from January 1, 2012, through July 31, 2013, and reviewed three other series of patients with NF1 and NA recently reported. The prevalence of NA in children with NF1 ranged from 8.8% to 51%, being much more prevalent at younger ages. Prospective studies yielded a higher prevalence than retrospective studies. NA was located most commonly on the trunk, particularly on the anterior chest wall, and was often multiple. Patients with segmental NF1 or isolated cafe au lait spots rarely had NA, and NA was absent in other genodermatoses. The collection of data was not homogeneous in all studies. NA has a high prevalence in individuals with NF1 patients but seems to be absent in connection with other genodermatoses, therefore its presence can assist in the diagnosis of suspected cases of NF1. The subtle clinical appearance of NA makes its detection difficult, and physicians involved in the care of children with NF1 must be aware of its possible presence and significance. PMID- 25690592 TI - Sex-Based Differences in Multiple Sclerosis (MS): Part II: Rising Incidence of Multiple Sclerosis in Women and the Vulnerability of Men to Progression of this Disease. AB - It is well known that a number of autoimmune diseases including multiple sclerosis (MS) predominantly affect women and there has been much attention directed toward understanding why this is the case. Past research has revealed a number of sex differences in autoimmune responses that can account for the female bias in MS. However, much less is known about why the incidence of MS has increased exclusively in women over the past half century. The recency of this increase suggests that changing environmental or lifestyle factors are interacting with biological sex to increase MS risk predominantly in females. Indeed, a number of recent studies have identified sex-specific differences in the effect of environmental factors on MS incidence. The first part of this chapter will overview this evidence and will discuss the possible scenarios of how the environment may be interacting with autoimmune mechanisms to contribute to the preferential rise in MS incidence in women. Despite the strong female bias in MS incidence, culminating evidence from natural history studies, and imaging and pathology studies suggests that males who develop MS may exhibit a more rapid decline in disability and cognitive functioning than women. Very little is known about the biological basis of this more rapid deterioration, but some insights have been provided by studies in rodent models of demyelination/remyelination. The second part of this chapter will overview the evidence that males with relapsing-onset MS undergo a more rapid progression of disease than females and will discuss potential biological mechanisms that account for this sex difference. PMID- 25690593 TI - Sex-Based Differences in Multiple Sclerosis (Part I): Biology of Disease Incidence. AB - Multiple sclerosis (MS) is a chronic autoimmune demyelinating disease that leads to neuron damage and progressive disability. One major feature of multiple sclerosis (MS) is that it affects women three times more often than men. In this chapter, we overview the evidence that the autoimmune component of MS, which predominates in the early stages of this disease, is more robust in women than in men and undergoes a sharp increase with the onset of puberty. In addition, we discuss the common rodent models of MS that have been used to study the sex-based differences in the development of central nervous system (CNS) autoimmunity. We then address the biological underpinnings of this enhanced MS risk in women by first reviewing the autoimmune mechanisms that are thought to lead to the initiation of this disease and then honing in on how these mechanisms differ between the sexes. Finally, we review what is known about the hormonal and genetic basis of these sex differences in CNS autoimmunity. PMID- 25690594 TI - Synthesis and cellular internalization of spindle hematite/polymer hybrid nanoparticles. AB - Nonspherical spindle-shaped hematite/polymer hybrid nanoparticles (SPNPs) were synthesized via surface-initiated atom transfer radical polymerization (SI-ATRP). The long axis of the SPNPs was 370 +/- 65 nm, and the short axis was 80 +/- 15 nm with an aspect ratio of 4.6-4.7. The SPNPs were characterized by transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FT-IR), and X ray photoelectron spectroscopy (XPS). Thermogravimetric analysis (TGA) was used to estimate the content of grafted polymer. Light-scattering measurement was used to detect the particle size distribution of SPNPs in water and in cell culture medium. HeLa cells internalized the SPNPs within 1 h, and the uptake reached equilibrium in 8 h. These observations contribute to better understanding of the interactions between nonspherical nanoparticles and cells, which may have implication for designing drug delivery vehicles. PMID- 25690595 TI - Medicare innovation center oncology care model: a toe in the water when a plunge is needed. PMID- 25690596 TI - Centers for medicare and medicaid services: using an episode-based payment model to improve oncology care. AB - PURPOSE: Cancer is a medically complex and expensive disease with costs projected to rise further as new treatment options increase and the United States population ages. Studies showing significant regional variation in oncology quality and costs and model tests demonstrating cost savings without adverse outcomes suggest there are opportunities to create a system of oncology care in the US that delivers higher quality care at lower cost. DESIGN: The Centers for Medicare and Medicaid Services (CMS) have designed an episode-based payment model centered around 6 month periods of chemotherapy treatment. Monthly per-patient care management payments will be made to practices to support practice transformation, including additional patient services and specific infrastructure enhancements. Quarterly reporting of quality metrics will drive continuous quality improvement and the adoption of best practices among participants. Practices achieving cost savings will also be eligible for performance-based payments. Savings are expected through improved care coordination and appropriately aligned payment incentives, resulting in decreased avoidable emergency department visits and hospitalizations and more efficient and evidence based use of imaging, laboratory tests, and therapeutic agents, as well as improved end of life care. CONCLUSION: New therapies and better supportive care have significantly improved cancer survival in recent decades. This has come at a high cost, with cancer therapy consuming $124 billion in 2010. CMS has designed an episode-based model of oncology care that incorporates elements from several successful model tests. By providing care management and performance based payments in conjunction with quality metrics and a rapid learning environment, it is hoped that this model will demonstrate how oncology care in the US can transform into a high value, high quality system. PMID- 25690597 TI - Improving Documentation of Pain Management at MedStar Washington Cancer Institute. AB - PURPOSE: Appropriate cancer pain documentation is one of the quality measures in the American Society of Clinical Oncology (ASCO) Quality Oncology Practice Initiative (QOPI). MedStar Washington Cancer Institute has participated in QOPI since 2008, and documenting a plan of care for moderate to severe pain (which was defined as a pain score of >= 4 on a scale of 0 to 10, with 10 being the worst) was identified as an area for improvement. METHODS: We undertook a structured approach to improve documentation of the plan of care for moderate/severe pain with support from ASCO's Quality Training Program. Our team used standard plan-do study-act (PDSA) methodology to achieve our goal of 90% documentation. We used a statistical process control chart (p chart) to determine whether our process was under control and to monitor the improvement in the documentation of pain management. RESULTS: The baseline rate of a documented plan of care for pain was 70%. In January 2014, we implemented action plans including an electronic health record trigger for a pain score of >= 4, education for fellows and midlevel providers, and establishment of a faculty consensus on documenting management of pain unrelated to cancer. After these interventions, the pain documentation rate improved to 90%. CONCLUSION: After one cycle of PDSA, we achieved our goal of a 90% pain documentation rate. To sustain our project, we continued to monitor the pain documentation rate quarterly in 2014 and continue the process of education and orientation to new staff, rotating residents, and fellows. PMID- 25690598 TI - Dolutegravir in HIV-2-Infected Patients With Resistant Virus to First-line Integrase Inhibitors From the French Named Patient Program. AB - BACKGROUND: Dolutegravir has shown in vitro activity against human immunodeficiency virus type 2 (HIV-2). We report safety and efficacy data of regimens containing dolutegravir (50 mg twice daily) in antiretroviral experienced, HIV-2-infected patients. METHODS: HIV-2-infected patients experiencing virological failure to raltegravir received dolutegravir with optimized background antiretroviral combinations within the French Named Patient Program (NPP). Plasma HIV-2 RNA (pVL) was assessed at time of dolutegravir initiation (baseline), month 3, and month 6. Antiretroviral trough plasma concentrations (C12h) were determined using liquid chromatography coupled with tandem mass spectrometry. RESULTS: Thirteen HIV-2-infected-patients, with a median duration of 15 years' infection and given 16 previous antiretroviral regimens, were included in NPP. Median follow-up was 9 months (min-max, 3-15 months). Median baseline pVL and CD4 cell count were 9544 copies/mL (inter quartile range [IQR], 3096-23 120 copies/mL) and 100 cells/uL (IQR, 77-171 cells/uL), respectively. Available integrase genotypic resistance patterns were Y143C/G/H/R (n = 5), Q148R/K (n = 2), and N155H (n = 4). Optimized background antiretroviral regimens conferring a genotypic sensitivity score <=2 in 10 patients included nucleoside reverse transcriptase inhibitors associated with darunavir/ritonavir (n = 12), saquinavir/ritonavir (n = 2), and maraviroc (n = 3). At months 3 and 6, pVL was undetectable in 6 of 13 and 4 of 12 patients, respectively, and median CD4 count was 161 (101-188) cells/uL and 167 (135-1353) cells/uL, respectively. Median dolutegravir C12h was 4086 (1756-5717 ng/mL) ng/mL in 9 patients. No serious events were notified except 1 death from progressive multifocal leukoencephalopathy at month 4. CONCLUSIONS: Optimized dolutegravir containing antiretroviral regimens supported by good plasma exposure provide a substantial initial efficacy rate for salvage therapy in heavily antiretroviral experienced HIV-2-infected patients with virus harboring resistance to first generation integrase inhibitors. Larger numbers of patients and longer follow-up are needed to confirm these findings. PMID- 25690599 TI - Evidence gathered from randomized clinical trials and observational studies on the equivalence of emtricitabine and Lamivudine. PMID- 25690600 TI - Audit of intrathecal drug delivery for patients with difficult-to-control cancer pain shows a sustained reduction in pain severity scores over a 6-month period. AB - BACKGROUND: Intrathecal drug delivery is known to be effective in alleviating cancer pain in patients for whom the conventional World Health Organization approach has proved insufficient. A multidisciplinary interventional cancer pain service was established in the West of Scotland in 2008 with the aim of providing a safe and effective intrathecal drug delivery service for patients with difficult-to-control cancer pain. AIM: The aim of the intrathecal drug delivery service is to improve pain scores as evaluated by pain scores before and after insertion of an intrathecal drug delivery device. DESIGN: Pain is monitored before and after intrathecal drug delivery implantation using the Brief Pain Inventory. Following implantation, pumps are refilled fortnightly and repeat Brief Pain Inventory assessments are undertaken. This prospective case series analyses change in Brief Pain Inventory domains for patients who had an intrathecal drug delivery implanted using a paired sample t-test. RESULTS: Data are presented from 2008-2013 for 22 patients receiving an intrathecal drug delivery system who experienced an immediate improvement in their pain that was both clinically and statistically significant. One week after insertion, the average pain score on the Brief Pain Inventory fell from 6.8 (pre-intrathecal drug delivery) to 3.0 (post-intrathecal drug delivery). Improvement in pain scores was sustained over a 6-month period. CONCLUSION: Evaluation of results of this case series shows that with the appropriate use of intrathecal drug delivery systems, patients with difficult-to-control cancer pain can benefit from effective pain relief for many months. PMID- 25690601 TI - 'Less ticking the boxes, more providing support': A qualitative study on health professionals' concerns towards the Liverpool Care of the Dying Pathway. AB - BACKGROUND: Despite being widely used, research into the effectiveness of the Liverpool Care of the Dying Pathway (LCP) and associated cases of malpractice does not match dissemination. No study exists focusing on concerns voiced by professionals. AIM: To explore the views of professionals who, during the hospital implementation of the Italian version of the Liverpool Care of the Dying Pathway (LCP-I), voiced or showed concerns towards it. DESIGN: A qualitative study nested within the LCP-I randomized cluster trial, with semi-structured interviews analysed using thematic analysis. SETTING AND PARTICIPANTS: Six nurses and five physicians from six out of the eight hospital wards who completed the LCP-I implementation were interviewed. Eligibility criteria were having taken part in all steps of the LCP-I Programme, voiced or somehow shown concerns, or failed to fully engage with the implementation process. RESULTS: A total of 12 categories were identified, referring to four topics: the Implementation Programme, the LCP-I clinical documentation, the hospital environment and the educational and professional background of hospital healthcare staff. Issues raised by participants concerned both 'real' characteristics of the LCP-I and a misinterpretation of the LCP-I approach and clinical documentation. Furthermore, difficulties were reported which were not linked to the Programme but rather to end-of-life care. CONCLUSION: This study provides insights into the experience of professionals with negative opinions of or concerns with the LCP-I. A more comprehensive approach to professional training in palliative care is needed and may envisage the development of new interventions aimed at improving the quality of care throughout the illness trajectory. PMID- 25690602 TI - Comfort goal of care and end-of-life outcomes in dementia: A prospective study. AB - BACKGROUND: Many people with dementia die in a nursing home. A comfort care goal may be beneficial. Little research has examined the relationship between care goals and outcome. AIM: To investigate whether family satisfaction with end-of life care and quality of dying is associated with whether or not dementia patients have a comfort goal shortly after admission. DESIGN AND SETTING: Prospective data collection from 28 long-term care facilities (the Dutch End of Life in Dementia study). We included 148 patients who died after prospective follow-up. Main outcomes were family satisfaction (End-of-Life in Dementia Satisfaction with Care scale; range: 10-40) and quality of dying (End-of-Life in Dementia-Comfort Assessment in Dying; range: 14-42). We performed generalized estimating equations regression analyses to analyze whether these outcomes are associated with a comfort goal established shortly after admission compared with another or no care goal as reported by the physician. RESULTS: Families of patients were more satisfied with end-of-life care when a comfort goal was established shortly after admission. We found this pattern only for patients who died within 6 months of admission (adjusted b: 4.5; confidence interval: 2.8, 6.3 vs -1.2; confidence interval: -3.0, 0.6 for longer stay). For quality of dying, no such association was found. CONCLUSION: We found that family satisfaction with care is related to a comfort care goal shortly after admission, but quality of dying did not. Establishing a comfort goal at an early stage may be important to the family. Advance care planning interventions should be studied for their effects on patient and family outcome. PMID- 25690603 TI - Choosing the place of death: Empowering motor neurone disease/amyotrophic lateral sclerosis patients in end-of-life care decision making. PMID- 25690604 TI - Full-length genomic characterizations of two canine parvoviruses prevalent in Northwest China. AB - Canine parvovirus (CPV) can cause acute hemorrhagic diarrhea and fatal myocarditis in young dogs. Currently, most studies have focused on the evolution of the VP2 gene, whereas the full-length genome of CPV has been rarely reported. In this study, the whole genomes of CPV-LZ1 and CPV-LZ2 strains prevalent in Northwest China were determined and analyzed in comparison with those of the reference CPVs. The genome sequences of both LZ strains consisted of 5053 nucleotides. CPV-LZ1 and CPV-LZ2 strains were designated as new CPV-2a and CPV 2b, respectively. Sequence alignment analysis results revealed that these two new strains underwent specific unique variations during the process of local adaption. The left non-translated regions of these strains formed a Y-shaped hairpin structure, whereas the right non-translated regions lacked the reiteration of DNA sequence. A phylogenetic tree constructed from 33 whole coding regions of CPVs showed a strong spatial clustering, and these two strains belonged to the Chinese strain cluster lineage. This study provides a method to obtain the full-length genome of CPV. The isolation and characterization of these viruses adds incrementally to the knowledge of the full-length genome of CPV. The results from this study also provide insight into the molecular epidemiology and genetic diversity of the CPV field isolates from Northwest China and can be useful in preventing and controlling CPV infection in this region. PMID- 25690605 TI - Otology Jubilee: 150 years of the Archiv fur Ohrenheilkunde "Where do we come from?--Where are we?--Where are we going?". PMID- 25690606 TI - Long-term monitoring of arsenic, copper, selenium, and other elements in Great Salt Lake (Utah, USA) surface water, brine shrimp, and brine flies. AB - This paper presents long-term monitoring data for 19 elements with a focus on arsenic (As), copper (Cu), and selenium (Se), in surface water (2002-2011), brine shrimp (2001-2011), and brine flies (1995-1996) collected from Great Salt Lake (GSL, Utah, USA). In open surface waters, mean (+/-standard deviation [SD]; range; n) As concentrations were 112 (+/-22.1; 54.0-169; 47) and 112 MUg/L (+/ 35.6; 5.1-175; 68) in filtered and unfiltered surface water samples, respectively, and 16.3 MUg/g (+/-5.6; 5.1-35.2; 62) dry weight (dw) in brine shrimp. Mean (+/-SD; range; n) Cu concentrations were 4.2 (+/-2.1; 1.3-12.5; 47) and 6.9 MUg/L (+/-6.6; 1.9-38.1; 68) in filtered and unfiltered surface water samples, respectively, and 20.6 MUg/g (+/-18.4; 5.4-126; 62) dw in brine shrimp. Finally, mean (+/-SD; range; n) dissolved and total recoverable Se concentrations were 0.6 (+/-0.1; 0.4-1.2; 61) and 0.9 MUg/L (+/-0.7; 0.5-3.6; 89), respectively, and 3.6 MUg/g (+/-2.2; 1.1-14.9; 98) dw in brine shrimp. Thus, Se in open lake surface waters was most often in the range of 0.5-1 MUg/L, and concentrations in both surface water and brine shrimp were comparable to concentrations measured in other monitoring programs for the GSL. Temporally, the statistical significance of differences in mean dissolved or total recoverable As, Cu, and Se concentrations between years was highly variable depending which test statistic was used, and there was no clear evidence of increasing or decreasing trends. In brine shrimp, significant differences in annual mean concentrations of As, Cu, and Se were observed using both parametric and nonparametric statistical approaches, but, as for water, there did not appear to be a consistent increase or decrease in concentrations of these elements over time. PMID- 25690607 TI - Potential for the wider application of national forest inventories to estimate the contagion metric for landscapes. AB - National forest inventories (NFIs) have traditionally been designed to assess the production value of forests as well as forest biodiversity. However, in this study, the aim is to show a new application of NFIs, namely the estimation of the landscape metric contagion. This metric is commonly calculated on raster-based land cover/use maps. In this study, a sample-based dataset from the Swedish NFI was used. The estimated contagion metric is based on a distance-dependent function so that the value of the metric is small for longer distances, whereas the corresponding estimated variance is large for longer distances. With this procedure, comparisons can be made for different landscapes at a given time and or to compare any given landscape over time. The main advantages are that the approach can be applied where raster-based land cover/use maps of the landscape are not available and that the data obtained from NFIs (e.g., land cover type) typically are of high quality in comparison with remotely sensed data due to being based on direct observation in the field survey. The procedure applied here accommodates both the patch-mosaic and the gradient-based model approach to landscape structure. PMID- 25690608 TI - Combining ecosystem service relationships and DPSIR framework to manage multiple ecosystem services. AB - Ecosystem service (ES) relationship occurs due to two types of mechanisms: (1) interact directly or (2) interact through the impact of a shared factor. Identifying such mechanisms behind ES relationship within a single land-use/land cover category and combining it with a system thinking framework is especially necessary for effective decision-making to manage multiple ESs generated by this land-use/land-cover. In this study, we use tea plantations in China to investigate mechanisms behind ES relationships. We find that tea production is positively correlated with four regulating services (i.e., carbon sequestration, soil N protection, soil P protection, and water conservation). Several regulating services, such as carbon sequestration and soil N, P, and K protection, have positive correlations with each other. Tea production, carbon sequestration, and soil retention are significantly correlated with local annual mean temperature and precipitation. We then establish driver-pressure-state-impact-response (DPSIR) framework for tea plantations, which has been widely used for environmental management issues. Integrating our findings of ES relationship into DPSIR framework, we can estimate how ES change is responding to two types of responses: response to control drivers and response to maintain or restore state. Scenario analysis showed that the responses to control drivers have a larger impact on ES. We discuss that DPSIR would favor managing multiple ES because it enables a more precise understanding of how ES interacts through the effects of factors from various hierarchies. Finally, we suggest integrating ES direct interaction into DPSIR framework. We think such integration could improve the ability of DPSIR framework to support decision-making in multiple ES management, specifically in at least three aspects: (1) favor to identify all possible response alternatives, (2) enable us to evaluate ES which cannot be assessed if without such combining, and (3) help to identify ecological leverage points where small management investment can yield substantial benefits. PMID- 25690609 TI - The effects of a remediated fly ash spill and weather conditions on reproductive success and offspring development in tree swallows. AB - Animals are exposed to natural and anthropogenic stressors during reproduction that may individually or interactively influence reproductive success and offspring development. We examined the effects of weather conditions, exposure to element contamination from a recently remediated fly ash spill, and the interaction between these factors on reproductive success and growth of tree swallows (Tachycineta bicolor) across nine colonies. Females breeding in colonies impacted by the spill transferred greater concentrations of mercury (Hg), selenium (Se), strontium, and thallium to their eggs than females in reference colonies. Parental provisioning of emerging aquatic insects resulted in greater blood Se concentrations in nestlings in impacted colonies compared to reference colonies, and these concentrations remained stable across 2 years. Egg and blood element concentrations were unrelated to reproductive success or nestling condition. Greater rainfall and higher ambient temperatures during incubation were later associated with longer wing lengths in nestlings, particularly in 2011. Higher ambient temperatures and greater Se exposure posthatch were associated with longer wing lengths in 2011 while in 2012, blood Se concentrations were positively related to wing length irrespective of temperature. We found that unseasonably cold weather was associated with reduced hatching and fledging success among all colonies, but there was no interactive effect between element exposure and inclement weather. Given that blood Se concentrations in some nestlings exceeded the lower threshold of concern, and concentrations of Se in blood and Hg in eggs are not yet declining, future studies should continue to monitor exposure and effects on insectivorous wildlife in the area. PMID- 25690610 TI - Persistence and risk assessment of cypermethrin residues on chilli (Capsicum annuum L.). AB - The study was conducted to observe the persistence pattern and risk assessment of cypermethrin in chilli fruits following three applications of cypermethrin (Super fighter 25 EC) at 50 and 100 g a.i. ha(-1) at 10-day interval. Residues of cypermethrin in chilli were estimated by gas liquid chromatography (GLC) and were confirmed by gas chromatography-mass spectrometry (GC-MS). The average initial deposits of cypermethrin in chilli fruits were found to be 1.46 and 3.11 mg kg( 1), at recommended and double the recommended dosages, respectively, following third application of the insecticide. Half-life periods for cypermethrin were found to be 4.43 and 4.70 days at recommended and double the recommended dosages, respectively. Residues of cypermethrin declined below its limit of quantification (LOQ) of 0.05 mg kg(-1) after 25 days at both the application dosages. Theoretical maximum residue contribution (TMRC) values were calculated from the residue data generated and were found to be below maximum permissible intake (MPI) even on 0 day. Therefore, according to our risk assessment studies, a waiting period of 1 day is suggested for consumption of chilli sprayed with cypermethrin at the recommended dosages. PMID- 25690611 TI - Global mean estimation using a self-organizing dual-zoning method for preferential sampling. AB - Giving an appropriate weight to each sampling point is essential to global mean estimation. The objective of this paper was to develop a global mean estimation method with preferential samples. The procedure for this estimation method was to first zone the study area based on self-organizing dual-zoning method and then to estimate the mean according to stratified sampling method. In this method, spreading of points in both feature and geographical space is considered. The method is tested in a case study on the metal Mn concentrations in Jilin provinces of China. Six sample patterns are selected to estimate the global mean and compared with the global mean calculated by direct arithmetic mean method, polygon method, and cell method. The results show that the proposed method produces more accurate and stable mean estimates under different feature deviation index (FDI) values and sample sizes. The relative errors of the global mean calculated by the proposed method are from 0.14 to 1.47 % and they are the largest (4.83-8.84 %) by direct arithmetic mean method. At the same time, the mean results calculated by the other three methods are sensitive to the FDI values and sample sizes. PMID- 25690612 TI - Letter to the editor. PMID- 25690613 TI - Letter to the editor. PMID- 25690614 TI - Toward Best Practice in Evaluation: A Study of Australian Health Promotion Agencies. AB - Evaluation makes a critical contribution to the evidence base for health promotion programs and policy. Because there has been limited research about the characteristics and determinants of evaluation practice in this field, this study audited evaluations completed by health promotion agencies in Victoria, Australia, and explored the factors that enabled or hindered evaluation performance. Twenty-four agencies participated. A systematic assessment of 29 recent evaluation reports was undertaken, and in-depth interviews were carried out with 18 experienced practitioners. There was wide variability in the scope of evaluations and the level of reporting undertaken. Formative evaluation was uncommon, but almost all included process evaluation, especially of strategy reach and delivery. Impact evaluation was attempted in the majority of cases, but the designs and measures used were often not specified. Practitioners strongly endorsed the importance of evaluation, but the reporting requirements and inconsistent administrative procedures of the funding body were cited as significant barriers. Budget constraints, employment of untrained coworkers, and lack of access to measurement tools were other major barriers to evaluation. Capacity building to strengthen evaluation needs to encompass system, organizational, and practitioner-level action. This includes strengthening funding and reporting arrangements, fostering partnerships, and tailoring workforce development opportunities for practitioners. PMID- 25690615 TI - Can a Box of Mailed Materials Achieve the Triple Aims of Health Care? The Mailed Chronic Disease Self-Management Tool Kit Study. AB - Not all patients with chronic conditions are able or willing to participate in small-group or Internet self-management programs. Based on the Arthritis Mailed Took Kit Program and the Chronic Disease Self-Management Program, a mailed Chronic Disease Self-Management Tool Kit, delivered in a onetime mailing, was developed as an alternative mode of delivery. Kits were mailed to a national sample of 255 participants with varying chronic conditions and evaluated in a longitudinal (6-month) trial. Outcomes reflected the triple aims of health care. At 6 months, participants demonstrated better health care indicators, better health indicators, and less health care utilization. There were significant improvements in two health care indicators and six health indicators and reductions in physician visits. Follow-up response rate was high (85%). There were no significant baseline differences between responders and nonresponders. Subgroup analyses were performed for a number of subgroups, including those with arthritis (58%) and/or depression (43%), and for African Americans (14%). Subgroups demonstrated improvements equal to or better than the overall group. The Mailed Chronic Disease Self-Management Tool Kit represents a third mode, along with small groups and Internet, of delivering self-management patient education, and appears to contribute to meeting the triple aims of health care for those who actively chose this mode of delivery. PMID- 25690616 TI - Nanoporous silica nanoparticles as biomaterials: evaluation of different strategies for the functionalization with polysialic acid by step-by-step cytocompatibility testing. AB - Nanoporous silica materials have become a prominent novel class of biomaterials which are typically applied as nanoparticles or thin films. Their large surface area combined with the rich surface chemistry of amorphous silica affords the possibility to equip this material with variable functionalities, also with several different ones on the same particle or coating. Although many studies have shown that nanoporous silica is apparently non-toxic and basically biocompatible, any surface modification may change the surface properties considerably and, therefore, the modified materials should be checked for their biocompatibility at every step. Here we report on different silane-based functionalization strategies, firstly a conventional succinic anhydride-based linker system and, secondly, copper-catalyzed click chemistry, to bind polysialic acid, a polysaccharide important in neurogenesis, onto nanoporous silica nanoparticles (NPSNPs) of MCM-41 type. At each of the different modification steps, the materials are characterized by cell culture experiments. The results show that polysialic acid can be immobilized on the surface of NPSNPs by using different strategies. The cell culture experiments show that the kind of surface immobilization has a strong influence on the toxicity of the material versus the cells. Whereas most modifications appear inoffensive, NPSNPs modified by click reactions are toxic, probably due to residues of the Cu catalyst used in these reactions. PMID- 25690617 TI - Exploiting the inflammatory response on biomaterials research and development. AB - Exploiting the inflammatory response on biomaterials research and development requires an in-depth understanding of the cellular and molecular mechanisms involved in the events comprising the tissue response continuum. Examples of how the biomaterial surface chemistry may modulate the foreign body reaction to biomaterials. The utilization of different surface chemistries on biomaterials may provide biological design criteria for the appropriate use and function of biomaterials when used in medical devices and prostheses. PMID- 25690618 TI - Soybean-based biomaterial granules induce biomineralization in MG-63 human osteosarcoma osteoblast-like cells through ultrastructural changes and phagocytic activity. PMID- 25690619 TI - Infusion of iodine-based contrast agents into poly(p-dioxanone) as a radiopaque resorbable IVC filter. AB - To determine the feasibility of infusing resorbable inferior vena cava (IVC) filter with iodine-based contrast agents to produce a radiopaque, computed tomography (CT)-visible IVC filter. Infused poly(p-dioxanone) (PPDO) was obtained by incubating PPDO in different concentrations of 4-iodobenzoyl chloride (IBC) and 2,3,5-triiodobenzoic acid (TIBA). Characterizations of infused and nascent PPDO were done using elemental analysis, micro-CT, tensile strength analysis, scanning electron microscopy, and differential scanning calorimetry. Elemental analysis showed percentage loading of 1.07 +/- 0.08 for IBC and 0.73 +/- 0.01 for TIBA. The iodine loading remained the same within 2 weeks for TIBA but decreased to about 80 % with IBC when subjected to physiological conditions. Micro-CT images showed increased attenuation of the infused PPDO compared with the nascent PPDO. The Hounsfield unit values for infused and nascent sutures were 110 +/- 40 and 153 +/- 53 for PPDO infused with 2 mg/mL IBC and TIBA, respectively, but only 11.35 +/- 2 for nascent PPDO. In contrast the HU for bone was 116 +/- 37. Tensile strength analysis showed maximum loads of 1.01 +/- 0.43 kg and 10.02 +/- 0.54 kg for IBC and TIBA, respectively, and 10.10 +/- 0.64 kg for nascent PPDO. Scanning electron microscopy showed that the morphology of the PPDO surface did not change after coating and preliminary cytotoxicity assay showed no killing effect on Hela cells. PPDO infused with a contrast agent is significantly more radiopaque than nascent PPDO on micro-CT imaging. This radiopacity could allow the position and integrity of infused resorbable IVC filter to be monitored while it is in place, thus increasing its safety and efficacy as a medical device. PMID- 25690620 TI - Lumbar interbody fusion with porous biphasic calcium phosphate enhanced by recombinant bone morphogenetic protein-2/silk fibroin sustained-released microsphere: an experimental study on sheep model. AB - Biphasic calcium phosphate (BCP) has been investigated extensively as a bone substitute nowadays. However, the bone formation capacity of BCP is limited owing to lack of osteoinduction. Silk fibroin (SF) has a structure similar to type I collagen, and could be developed to a microsphere for the sustained-release of rhBMP-2. In our previous report, bioactivity of BCP could be enhanced by rhBMP 2/SF microsphere (containing 0.5 ug rhBMP-2) in vitro. However, the bone regeneration performance of the composite in vivo was not investigated. Thus, the purpose of this study was to evaluate the efficacy of BCP/rhBMP-2/SF in a sheep lumbar fusion model. A BCP and rhBMP-2/SF microsphere was developed, and then was integrated into a BCP/rhBMP-2/SF composite. BCP, BCP/rhBMP-2 and BCP/rhBMP-2/SF were implanted randomly into the disc spaces of 30 sheep at the levels of L1/2, L3/4 and L5/6. After sacrificed, the fusion segments were evaluated by manual palpation, CT scan, biomechanical testing and histology at 3 and 6 months, respectively. The composite demonstrated a burst-release of rhBMP-2 (39.1 +/- 2.8 %) on the initial 4 days and a sustained-release (accumulative 81.3 +/- 4.9 %) for more than 28 days. The fusion rates, semi-quantitative CT scores, fusion stiffness in bending in all directions and histologic scores of BCP/rhBMP-2/SF were significantly greater than BCP and BCP/rhBMP-2 at each time point, respectively (P < 0.05). These findings indicate that the SF microspheres containing a very low dose of rhBMP-2 improve fusion in sheep using BCP constructs. PMID- 25690621 TI - Cryogel-PCL combination scaffolds for bone tissue repair. AB - The present work describes the development and the evaluation of cryogel-poly epsilon-caprolactone combinatory scaffolds for bone tissue engineering. Gelatin was selected as cell-interactive biopolymer to enable the adhesion and the proliferation of mouse calvaria pre-osteoblasts while poly-epsilon-caprolactone was applied for its mechanical strength required for the envisaged application. In order to realize suitable osteoblast carriers, methacrylamide-functionalized gelatin was introduced into 3D printed poly-epsilon-caprolactone scaffolds created using the Bioplotter technology, followed by performing a cryogenic treatment which was concomitant with the redox-initiated, covalent crosslinking of the gelatin derivative (i.e. cryogelation). In a first part, the efficiency of the cryogelation process was determined using gel fraction experiments and by correlating the results with conventional hydrogel formation at room temperature. Next, the optimal cryogelation parameters were fed into the combinatory approach and the scaffolds developed were characterized for their structural and mechanical properties using scanning electron microscopy, micro-computed tomography and compression tests respectively. In a final part, in vitro biocompatibility assays indicated a good colonization of the pre-osteoblasts and the attachment of viable cells onto the cryogenic network. However, the results also show that the cellular infiltration throughout the entire scaffold is suboptimal, which implies that the scaffold design should be optimized by reducing the cryogel density. PMID- 25690622 TI - Superparamagnetic MFe2O 4 (M = Ni, Co, Zn, Mn) nanoparticles: synthesis, characterization, induction heating and cell viability studies for cancer hyperthermia applications. AB - Superparamagnetic nanoferrites are prepared by simple and one step refluxing in polyol synthesis. The ferrite nanoparticles prepared by this method exhibit particle sizes below 10 nm and high degree of crystallinity. These ferrite nanoparticles are compared by means of their magnetic properties, induction heating and cell viability studies for its application in magnetic fluid hyperthermia. Out of all studied nanoparticles in present work, only ZnFe2O4 and CoFe2O4 MNPs are able to produce threshold hyperthermia temperature. This rise in temperature is discussed in detail in view of their magneto-structural properties. Therefore ZnFe2O4 and CoFe2O4 MNPs with improved stability, magnetic induction heating and cell viability are suitable candidates for magnetic hyperthermia. PMID- 25690623 TI - Conflicts of interest in government-funded studies. AB - Conflict of interest in scientific publications has become a topic of critical importance. A primary focus has been the relationship between authors, journals and the pharmaceutical industry. That focus must be expanded to include government funding organizations. There are significant benefits to authors and investigators in participating in government-funded research, and to journals in publishing it. There are substantial risks to patients in not considering the potential for conflict of interest. PMID- 25690624 TI - Second-generation immigrant children: health prevention for a new population in terms of vaccination coverage and health assessment. AB - BACKGROUND: In recent years the total number of foreigners taking up residence in Italy is increasing: the number of children born in Italy to foreign parents currently account for 15% of all babies born in the country. This population is generally referred to as "second-generation immigrants". We evaluated the health conditions of this particular population by investigating the vaccination coverage and auxological data in a group of foreign children living in a foster care setting and by comparing them to those regarding a group of foreign children living with their own parents. METHODS: This study was conducted in a foster care association in Rome. The Pediatric Unit of "A. Gemelli" Hospital, Rome, provided all data for comparison. Two groups of children (group 1: 60 children from a foster care association; group 2: 91 children living with their parents; group 3: 112 healthy controls) with similar characteristics were taken into consideration. RESULTS: There were statistical differences between groups: the administration rate of hexavalent vaccine was significantly higher in group 2 than in group 1 (84.6% vs. 65.0%) (P<0.01); the administration rate of measles, mumps and rubella vaccine, again, was significantly higher in group 2 compared to group 1 (69.0% vs. 47.5%) (P<0.05); the administration rate of heptavalent pneumococcal vaccine, however, was higher in group 1 (21/60; 35.0%) than in group 2 (20/91; 21.9%) (P>0.05), although the administration rate of serogroup C meningococcal vaccine was lower in group 1 (10/60; 16.7%) compared to group 2 (17/91; 18.7%) (P>0.05). As for auxological parameters, there were no statistical differences between groups. CONCLUSIONS: The data presented in this study seem to suggest the need for a special health programme to be promoted by the Italian National Health System in order to address the needs of the particular risk group of second generation immigrant children. Vaccination coverage should be especially boosted, and pediatricians should have a key role in terms of awareness raising and education of immigrant families. PMID- 25690625 TI - Biomechanical performance of baseball pitchers with a history of ulnar collateral ligament reconstruction. AB - BACKGROUND: A relatively high number of active professional baseball pitchers have a history of ulnar collateral ligament reconstruction (UCLr) on their throwing elbow. Controversy exists in the literature about whether professional baseball pitchers regain optimal performance after return from UCLr. It has been suggested that pitchers may have different biomechanics after UCLr, but this has not been previously tested. HYPOTHESIS: It was hypothesized that, compared with a control group without a history of UCLr, professional pitchers with a history of UCLr would have (1) significantly different throwing elbow and shoulder biomechanics; (2) a shortened stride, insufficient trunk forward tilt, and excessive shoulder horizontal adduction, characteristics associated with "holding back" or being tentative; (3) late shoulder rotation; and (4) improper shoulder abduction and trunk lateral tilt. STUDY DESIGN: Controlled laboratory study. METHODS: A total of 80 active minor league baseball pitchers (and their 8 Major League Baseball organizations) agreed to participate in this study. Participants included 40 pitchers with a history of UCLr and a matched control group of 40 pitchers with no history of elbow or shoulder surgery. Passive ranges of motion were measured for each pitcher's elbows and shoulders, and then 23 reflective markers were attached to his body. The pitcher took as many warm-up pitches as desired and then threw 10 full-effort fastballs for data collection. Ball speed was recorded with a radar gun. The reflective markers were tracked with a 10 camera, 240-Hz automated motion analysis system. Eleven biomechanical parameters were computed for each pitch and then averaged for each participant. Demographic, range of motion, and biomechanical parameters were compared between the UCLr group and the control group by use of Student t tests (significance set at P<.05). RESULTS: All hypotheses were rejected, as there were no differences in pitching biomechanics between the UCLr group and the control group. There were also no differences in passive range of motion between the 2 groups. CONCLUSION: Compared with a control group, active professional pitchers with a history of UCLr displayed no significant differences in shoulder and elbow passive range of motion and no significant differences in elbow and shoulder biomechanics. CLINICAL RELEVANCE: Clinical studies have previously shown that 10% to 33% of professional pitchers do not return to their preinjury level; however, the current study showed that those pitchers who successfully return to professional baseball after UCLr pitch with biomechanics similar to that of noninjured professionals. PMID- 25690626 TI - An osteophyte in the tibial plateau is a risk factor for allograft extrusion after meniscus allograft transplantation. AB - BACKGROUND: Osteophytes can be observed on the tibial plateau during meniscus allograft transplantation (MAT). However, no studies to date have evaluated the effect of these osteophytes on meniscus allograft extrusion. HYPOTHESIS: Osteophyte excision in the tibial plateau could reduce extrusion of the transplanted meniscus and improve short-term clinical outcomes with meniscus allograft transplantation. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Between October 2004 and July 2012, a total of 323 patients underwent MAT at a single institution. Of these, 88 patients had a peripheral osteophyte in their tibial plateau, and they were enrolled in the study retrospectively. The mean age of the patients was 35.3 years (range, 15-56 years); there were 57 male and 31 female patients. Forty-four patients underwent osteophyte excision concomitantly with MAT and 44 patients underwent MAT only. The 2 groups showed no difference in terms of age, body mass index, time after meniscectomy, and preoperative knee scores. A medial meniscus allograft was transplanted in 13 cases (15%) and a lateral meniscus in 75 (85%). The absolute extrusion and relative percentage of extrusion were measured to evaluate allograft extrusion 12 months after MAT. The modified Lysholm scoring system and the Hospital for Special Surgery score at 2 years after MAT were used to evaluate clinical outcomes. RESULTS: The mean absolute extrusions at 1 year postoperatively in the excision and nonexcision groups were 3.5+/-1.5 and 5.5+/-1.6 mm, respectively. The mean relative percentages of extrusion were 34.1%+/-15.9% and 54.7%+/-20.7%, respectively. The rates of allograft extrusion (>3 mm) were 28 of 44 (63.6%) and 41 of 44 (93.2%) in the excision and nonexcision groups, respectively. The intergroup differences in absolute extrusion, relative percentage of extrusion, and rate of allograft extrusion were statistically significant (P<.001 for all 3 parameters). There were no significant differences in the clinical outcomes (modified Lysholm or Hospital of Special Surgery scores) at 2-year follow-up (P<.762 and <.298, respectively). CONCLUSION: The excision of a peripheral osteophyte larger than 2 mm in the proximal tibial plateau was associated with less allograft extrusion after MAT. PMID- 25690627 TI - How Relevant Is Point-of-Care Ultrasound in LMIC? PMID- 25690628 TI - Differential diagnosis of cardiovascular symptoms: setting the expectations for the ultrasound examination and medical education. AB - Within the past several decades, dramatic changes have been made in the field of diagnostic imaging. Many of these changes have been with ultrasound, which has been transformative in the efficiency and accuracy of diagnostics. Emergency physicians, intensivists, and other acute care clinicians are using and relying on critical care ultrasound imaging to better triage and diagnose patients at the point of care. As this new frontier of medicine continues to forge forward using this new and improving technology, we strongly believe in integrating ultrasound training earlier into the medical education curriculum. This paper reviews and discusses the transformation of medical diagnostics within the last few decades and describes changes that should be expected as point-of-care cardiac ultrasound evolves within medical education. PMID- 25690629 TI - Point-of-Care Cardiac Ultrasound: Feasibility of Performance by Noncardiologists. AB - Cardiac ultrasound has been used for decades to assess a wide variety of structural and functional pathology, as well as to monitor response to therapy. It offers the advantages of noninvasive, real-time dynamic functional assessment without the risk of radiation. Cardiologists have traditionally employed this modality and have established robust guidelines on the use of echocardiography. However, other specialties such as emergency medicine and critical care have realized the benefit of cardiac ultrasound and have established specialty guidelines in its use. There is growing evidence for the benefit of cardiac ultrasound at the point of care on hospital wards, clinics, and even pre-hospital environments as well. The pervasive use of focused ultrasound is perhaps most evident in the advent of ultrasound training in undergraduate medical curricula. This paper reviews some of the key literature on the use of focused, point-of care ultrasound by noncardiologists. Feasibility, clinical utility, and emerging trends are reviewed. PMID- 25690630 TI - Focused cardiac ultrasound. AB - The use of point-of-care ultrasound of the heart is becoming more widespread. A variety of users have joined traditional users of cardiac ultrasound, cardiologists, and are imaging their patients in real time at the point of care. Patients with undifferentiated shock, hypotension, chest pain, or dyspnea are ideal candidates for focused cardiac ultrasound (FOCUS). In addition, any patient in whom the diagnosis of pericardial effusion or tamponade, pulmonary embolism, or left ventricular dysfunction is suspected would benefit from FOCUS. Of particular importance is the use of FOCUS to rapidly determine the etiology of cardiac arrest. This review will detail the indications, techniques, and limitations of FOCUS in these patients. PMID- 25690631 TI - Advanced Point-of-Care Cardiac Ultrasound Examination: Doppler Applications, Valvular Assessment, and Advanced Right Heart Examination. AB - Basic point-of-care cardiac ultrasound involves assessment of left ventricular systolic function, right ventricular size and systolic function, intravascular volume status, and the pericardium. These simple tools are sufficient to aid in the hemodynamic management of most acutely ill patients; more complex patients may benefit from the use of advanced echocardiographic techniques. This paper describes the use of ultrasound in the advanced evaluation of the right heart, in the assessment of valvular function, and touches on several advanced Doppler applications. PMID- 25690632 TI - Pulmonary ultrasound examination for edema, effusion, and thromboembolism. AB - Bedside, or point-of-care, ultrasound (US) has increasingly been used in various clinical settings to provide clinicians with rapid clinical information without the use of ionizing radiation. Lung US has been demonstrated as a valuable tool in the diagnosis and evaluation of pulmonary edema, pleural effusions, and pulmonary thromboembolism. Lung US enables the clinician to more quickly identify and initiate treatment for these potentially life-threatening conditions without the need for patient transportation to the radiology suite. Additionally, lung US can repeatedly be implemented to assess clinical changes without concern for repeated radiation exposure and is cost-effective given its ability to decrease the need for additional radiological and laboratory testing to confirm a suspected diagnosis. This review focuses on the application of lung US in the evaluation and management of pulmonary edema, pleural effusions, and pulmonary thromboembolism. PMID- 25690633 TI - Inferior Vena Cava Assessment: Correlation with CVP and Plethora in Tamponade. AB - Bedside assessment of intravascular volume status plays an important role in the management of critically ill patients, guiding fluid replacement therapy and the use of vasopressor agents. Despite controversy in the existing evidence, many clinicians advocate the use of inferior vena cava ultrasound (IVC-US) in the assessment of intravascular volume status in critically ill patients. Respirophasic variation in IVC diameter may provide useful information regarding intravascular volume status, particularly in patients with high and low caval indices. However, due to conflicting results of small-scale clinical trials of divergent sample populations, there is insufficient evidence to support routine US assessment of the IVC to determine fluid responsiveness in spontaneous breathing with circulatory compromise. Additional large-scale clinical trials are required to determine the accuracy of IVC-US measurements in diverse populations and to ascertain the effects on IVC dimensions that result from cardiac dysfunction and intra-abdominal hypertension. PMID- 25690634 TI - Point-of-Care Ultrasound for a Deep Venous Thrombosis. AB - Patients presenting to the emergency department with lower extremity symptoms suggestive of venous thromboembolic disease require a diagnostic evaluation. Although contrast venography was the diagnostic standard, this has largely been replaced by duplex ultrasound as the first-line imaging modality. This review presents a summary of the literature on the evolution and performance of B-mode point-of-care compression ultrasound as an alternative to duplex ultrasound evaluation. The 2-point compression and 2-region compression techniques are described. The limitations of point-of-care ultrasound of the lower extremity as a diagnostic modality for this disease entity, the role of a D-dimer assay in the emergency department evaluation and future directions for this diagnostic modality are discussed. PMID- 25690635 TI - Point-of-Care Ultrasound and the Rapid Response System. AB - Over the years, the use of ultrasound has moved solely from the domain of the radiologist to that of the intensivist and emergentologist for use in acute care settings. By virtue of its ease of use and rapid learning curve to proficiency, we are now seeing an increased desire by internists to learn the modality and apply it at the patient's bedside. The rapid response system represents a rational starting point for the introduction of point-of-care ultrasound to the inpatient ward setting. PMID- 25690636 TI - Coronary heart disease and risk factors in latin america. AB - Cardiovascular diseases are the leading cause of death in Latin America, with ischemic heart disease as the principal cause in most countries. Risk factors for cardiovascular disease are highly prevalent in the region, but there are international variations in the pattern and level of risk factors. Overweight and obesity are increasing. In the 2012 Mexican National Survey, overweight or obesity was found in 64.9% of men and 73% of women, and they were strongly associated with sedentarism. The most characteristic dyslipidemia abnormality in the region is low high-density lipoprotein cholesterol, followed by elevated low density lipoprotein cholesterol and increased levels of triglycerides. National diabetes mellitus prevalence ranges from 2.8% to 9.4% and tobacco smoking from 12.8% to 42%. According to the INTERHEART (A Study of Risk Factors for First Myocardial Infarction in 52 Countries and Over 27,000 Subjects) data for Latin America, the highest attributable risks for myocardial infarction were related to abdominal obesity, dyslipidemia, and smoking. PMID- 25690637 TI - Metabolic syndrome in andean populations. AB - The metabolic syndrome, a cluster of metabolic abnormalities, has been linked to both cardiovascular disease and type 2 diabetes mellitus risk. Several studies have shown that ethnicity is an important determinant for risk of developing the metabolic syndrome; therefore, further understanding of the prevalence and presentation of the metabolic syndrome in various ethnic groups is needed. Latin American communities, and particularly Andean countries, are largely understudied in relation to the metabolic syndrome and until recently, the prevalence of this metabolic disturbance in Andean Hispanics was unknown. Nonetheless, recent (and ongoing) population studies are providing important data regarding the prevalence and patterns of the metabolic syndrome in various Andean countries. This review aims to summarize and interpret the information provided by these studies in an effort to better characterize the metabolic syndrome in Andean Hispanics. PMID- 25690638 TI - The MOGE(S) Classification for a Phenotype-Genotype Nomenclature of Cardiomyopathy: Endorsed by the World Heart Federation. PMID- 25690639 TI - Moving from political declaration to action on reducing the global burden of cardiovascular diseases: a statement from the global cardiovascular disease taskforce. PMID- 25690640 TI - Autopsy-like MRI findings: report on Creutzfeldt-Jakob disease in the end-stage. PMID- 25690641 TI - An integrated metabolomics approach for the research of new cerebrospinal fluid biomarkers of multiple sclerosis. AB - Multiple Sclerosis (MuS) is a disease caused due to an autoimmune attack against myelin components in which non proteic mediators may play a role. Recent research in metabolomics and lipidomics has been driven by rapid advances in technologies such as mass spectrometry and computational methods. They can be used to study multifactorial disorders like MuS, highlighting the effects of disease on metabolic profiling, regardless of the multiple trigger factors. We coupled MALDI TOF-MS untargeted lipidomics and targeted LC-MS/MS analysis of acylcarnitines and aminoacids to compare cerebrospinal fluid metabolites in 13 MuS subjects and in 12 patients with Other Neurological Diseases (OND). After data processing and statistical evaluation, we found 10 metabolites that significantly (p < 0.05) segregate the two clinical groups. The most relevant result was the alteration of phospholipids levels in MuS and the correlation between some of them with clinical data. In particular lysophosphatidylcholines (m/z = 522.3 Da, 524.3 Da) and an unidentified peak at m/z = 523.0 Da correlated to the Link index, lysophosphatidylinositol (m/z = 573.3 Da) correlated to EDSS and phosphatidylinositol (m/z = 969.6 Da) correlated to disease duration. We also found high levels of glutamate in MuS. In conclusion, our integrated mass spectrometry approach showed high potentiality to find metabolic alteration in cerebrospinal fluid. These data, if confirmed in a wider clinical study, could open the door for the discovery of novel candidate biomarkers of MuS. PMID- 25690642 TI - Splendore-Hoeppli reaction and muscular arteritis in pancreatic panniculitis. PMID- 25690644 TI - Spin decontamination of broken-symmetry density functional theory calculations: deeper insight and new formulations. AB - This work re-examines the problem of the broken-symmetry Density-Functional Theory (DFT) solutions in diradical systems, in particular for the calculation of magnetic couplings. The Ms = 0 solution is not an eigenfunction of the S(2) spin operator and the evaluation of the singlet state energy requires a spin decontamination. A popular approximation is provided by the so-called Yamaguchi formula, which operates using the expectation values of S(2) relative to both Ms = 1 and Ms =0 solutions. Referring to a previous decomposition of the magnetic coupling in terms of direct exchange, kinetic exchange and core polarization, it is shown that this expression will lead to unreliable values of the singlet triplet energy gap when the spin polarization of the core orbitals becomes large. The here-proposed method of spin-decontamination is based on the Effective Hamiltonian Theory and uses the overlap between the two degenerate Ms = 0 solutions. An approximate and convenient formula, which uses the expectation values of S(2) of the Ms = 0 solutions before and after core polarization is proposed, which is free from the Yamaguchi's formula artefact, as illustrated on an organic diradical presenting a very high value of for the Ms = 0 solution, the antiferromagnetic coupling being due to the spin polarization mechanism. PMID- 25690645 TI - Patient-reported stressful events and coping strategies in post-menopausal women with breast cancer. AB - The objective of this paper was to explore what stressful events post-menopausal women with primary or recurrent breast cancer experience, how bothersome these events were and which coping strategies these women used. Data were collected from 131 patients diagnosed with primary or recurrent breast cancer. The Daily Coping Assessment was used. Thematic analysis was applied to form themes of stressful events. Six types of stressful events were extracted. The most frequently experienced events for women with primary cancer and those with recurrent cancer were 'distressing bodily symptoms'. The most bothersome event among primary cancer was 'everyday concerns' and in the recurrent group, 'distressing psychological reactions'. The most commonly used strategies were 'acceptance', 'distraction' and 'relaxation'. This study shows that women in different parts of the cancer trajectory differ in what they perceive to be stressful events when reporting them in their own words in a diary. The differences have an impact on the subsequent coping strategies they used. PMID- 25690646 TI - Urea production during normothermic machine perfusion: Price of success? PMID- 25690647 TI - Lipid accumulation product and visceral adiposity index are effective markers for identifying the metabolically obese normal-weight phenotype. AB - AIM: Studies have identified the metabolically obese normal-weight (MONW) phenotype, which carries increased risk of diabetes and cardiovascular disease. We aimed to investigate the ability of lipid accumulation product (LAP) and visceral adiposity index (VAI), two markers of visceral obesity, to identify the MONW phenotype. METHODS: Normal-weight participants [body mass index (BMI) being of 18.5-23 kg/m(2)] (n = 3,552; 46.9 % men) in the 2009 nationwide China Health and Nutrition Survey were included in our analysis. Four different criteria that have been published were used to define the MONW phenotype. LAP and VAI were calculated according to published formula. RESULTS: Receiver operating characteristic (ROC) curve analysis revealed that, regardless of the definition used to define MONW phenotype, both LAP [area under the ROC curve (AUC) ranging from 0.606 to 0.807 depending on the criteria used for MONW phenotype] and VAI (AUC ranging from 0.611 to 0.835 depending on the criteria used for MONW phenotype) outperformed anthropometric parameters including BMI, waist circumference, waist-to-hip ratio, and waist-to-height ratio for identifying MONW phenotype. Both LAP and VAI were strongly related to the MONW phenotype, irrespective of the criteria used to define the MONW phenotype. The associations between the 4th quartile of LAP and the MONW phenotype or between the 4th quartile of VAI and the MONW phenotype were consistently seen in various subgroups. CONCLUSION: Our study demonstrates that both LAP and VAI are effective markers for identifying the Chinese adults with MONW phenotype. PMID- 25690648 TI - Ultrasonic dissection versus conventional electrocautery during gastrectomy for gastric cancer: a meta-analysis of randomized controlled trials. AB - OBJECTIVE: Use of ultrasonic surgical instrument is gaining popularity for dissection and coagulation in open surgery. However, there is still no consensus on the efficacy and safety of its use compared with conventional surgical technique in open gastrectomy for gastric cancer. The aim of this meta-analysis was to evaluate the role and surgical outcomes of ultrasonic dissection (UD) compared with conventional electrocautery (EC). METHODS: A systematic literature search was performed to identify all studies comparing UD and EC in gastric cancer surgery. Intraoperative and postoperative outcomes were compared using weighted mean differences (WMDs) and odds ratios (ORs). RESULTS: Five studies were included in this meta-analysis, comprising 489 patients. Meta-analysis results showed that compared with EC, UD was associated with significantly shorter operation time (P = 0.03), less intraoperative blood loss (P = 0.002), lower morbidity (P = 0.02), and reduced postoperative hospital stay (P = 0.03). However, there was no significant difference between the two surgical techniques with regards to postoperative abdominal drainage (P = 0.17), and total cost in hospital (P = 0.59). CONCLUSIONS: Compared to EC, the use of UD during open gastrectomy can provide several improved outcomes for operation time, intraoperative blood loss, overall morbidity, and postoperative hospital stay. It appears that UD can be used instead of conventional EC in open gastric cancer surgery, although more larger trials with long follow-up should be performed. PMID- 25690649 TI - Multiple genetic variants associated with primary biliary cirrhosis in a Han Chinese population. AB - Multiple genome-wide association studies of primary biliary cirrhosis (PBC) in both European and Japanese ancestries have shown significant associations of many genetic loci contributing to the susceptibility to PBC. Major differences in susceptibility loci between these two population groups were observed. In this study, we examined whether the most significant loci observed in either European and/or Japanese cohorts are associated with PBC in a Han Chinese population. In 1070 PBC patients and 1198 controls, we observed highly significant associations at CD80 (rs2293370, P = 2.67 * 10(-8)) and TNFSF15 (rs4979462, P = 3.86 * 10(-8)) and significant associations at 17q12-21 (rs9303277), PDGFB (rs715505), NF kappaB1 (rs7665090), IL12RB2 (rs11209050), and STAT4 (rs7574865; all corrected P values <0.01). However, no association was observed for POU2AF1 (rs4938534), IL12A (rs485499 and rs2366408), IL7R (rs6897932), CXCR5 (rs715412), SOCS1 (rs725613), and TNFRSF1A (rs1800693). STAT4 (rs7574865) was strongly associated after additional control samples were analyzed. Our study is the first large scale genetic analysis in a Han Chinese PBC cohort. These results do not only reflect that Han Chinese PBC patients share common genetic susceptibility genes with both their Japanese and European counterparts but also suggest a distinctly different genetic susceptibility profile. PMID- 25690650 TI - Targeting formyl peptide receptor 2 reduces leukocyte-endothelial interactions in a murine model of stroke. AB - Ischemia/reperfusion (I/R) injury following stroke can worsen patient outcome through excess inflammation. This study investigated the pharmacologic potential of targeting an endogenous anti-inflammatory circuit via formyl peptide receptor (FPR) 2/lipoxin receptor (ALX) (Fpr2/3 in mouse) in global cerebral I/R. Mice (C57BL/6 and Fpr2/3(-/-)) were subjected to bilateral common carotid artery occlusion, followed by reperfusion and treatment with FPR agonists: AnxA1Ac2-26 [Annexin A1 mimetic peptide (Ac-AMVSEFLKQAWFIENEEQEYVQTVK), 2.5 MUg/kg] and 15 epimer-lipoxin A4 (15-epi-LXA4; FPR2/ALX specific, 12.5 and 100 ng/kg). Leukocyte endothelial (L-E) interactions in the cerebral microvasculature were then quantified in vivo using intravital fluorescence microscopy. 15-epi-LXA4 administration at the start of reperfusion reduced L-E interactions after 40 min (which was sustained at 2 h with high-dose 15-epi-LXA4) to levels seen in sham operated animals. AnxA1Ac2-26 treatment decreased leukocyte adhesion at 40 min and all L-E interactions at 2 h (up to 95%). Combined treatment with AnxA1Ac2-26 plus FPR antagonists t-Boc-FLFLF (250 ng/kg) or WRW4 (FPR2/ALX selective, 1.4 MUg/kg) abrogated the effects of AnxA1Ac2-26 fully at 40 min. Antagonists were less effective at 2 h, which we demonstrate is likely because of their impact on early L-E interactions. Our findings indicate that FPR2/ALX activity elicits considerable control over vascular inflammatory responses during cerebral I/R and, therefore, provide evidence that targeting FPR2/ALX may be beneficial for patients who suffered from stroke. PMID- 25690652 TI - Deposition of bioactive human epidermal growth factor in the egg white of transgenic hens using an oviduct-specific minisynthetic promoter. AB - Currently, transgenic animals have found a wide range of industrial applications and are invaluable in various fields of basic research. Notably, deposition of transgene-encoded proteins in the egg white (EW) of hens affords optimal production of genetically engineered biomaterials. In the present study, we developed a minisynthetic promoter modulating transgene transcription specifically in the hen's oviduct, and assayed the bioactivity of human epidermal growth factor (hEGF) driven by that promoter, after partial purification of epidermal growth factor (EGF) from transgenic hen eggs. Our minisynthetic promoter driving expression of chicken codon-optimized human epidermal growth factor (cEGF) features 2 consecutive estrogen response elements of the ovalbumin (OV) promoter, ligated with a 3.0 kb OV promoter region carrying OV regulatory elements, and a 5'-UTR. Subsequently, a 3'-UTR carrying the poly-A tail sequence of the OV gene was added after incorporation of the cEGF transgene. Finally, we partially purified cEGF from transgenic hen eggs and evaluated the biofunctional activities thereof in vitro and in vivo. In the in vitro assay, EW-derived hEGF exhibited a proliferative effect on HeLa cells similar to that of commercial hEGF. In the in vivo assay, compared to the nontreated control, transgenic hen egg-derived EGF afforded slightly higher levels of re-epithelialization (via fibroplasia) and neovascularization of wounded skin of miniature pigs than did the commercial material. In conclusion, transgenic hens may be used to produce genetically engineered bioactive biomaterials driven by an oviduct-specific minisynthetic promoter. PMID- 25690651 TI - The atypical N-glycosylation motif, Asn-Cys-Cys, in human GPR109A is required for normal cell surface expression and intracellular signaling. AB - Asparagine-linked glycosylation (N-glycosylation) is necessary for the proper folding of secreted and membrane proteins, including GPCRs. Thus, many GPCRs possess the N-glycosylation motif Asn-X-Ser/Thr at their N-termini and/or extracellular loops. We found that human GPR109A (hGPR109A) has an N glycosylation site at Asn(17) in the N-terminal atypical motif, Asn(17)-Cys(18) Cys(19). Why does hGPR109A require the atypical motif, rather than the typical sequence? Here we show that Asn(17)-Cys(18)-Cys(19) sequence of hGPR109A possesses 2 biologic roles. First, Asn(17)-X-Cys(19) contributed to hGPR109A N glycosylation by acting as an atypical motif. This modification is required for the normal surface expression of hGPR109A, as evidenced by the reduced surface expression of the nonglycosylated mutants, hGPR109A/N17A, and the finding that hGPR109A/C19S and hGPR109A/C19T, which are N-glycosylated at Asn(17), exhibited expression similar to the wild-type receptor. Second, the X-Cys(18)-Cys(19) dicysteine is indispensable for hGPR109A function. Substitution of Cys(18) or Cys(19) residue to Ala impaired Gi-mediated signaling via hGPR109A. We propose the disulfide bond formations of these residues with other Cys existed in the extracellular loops for the proper folding. Together, these results suggest that the atypical motif Asn(17)-Cys(18)-Cys(19) is crucial for the normal surface trafficking and function of hGPR109A. PMID- 25690653 TI - Long noncoding RNAs as a novel component of the Myc transcriptional network. AB - Myc is a well-known transcription factor with important roles in cell cycle, apoptosis, and cellular transformation. Long noncoding RNAs (lncRNAs) have recently emerged as an important class of regulatory RNAs. Here, we show that lncRNAs are a main component of the Myc-regulated transcriptional program using the P493-6 tetracycline-repressible myc model. We demonstrate that both Myc induced mRNAs and lncRNAs are significantly enriched for Myc binding sites. In contrast to Myc-repressed mRNAs, Myc-repressed lncRNAs are significantly enriched for Myc binding sites. Subcellular localization analysis revealed that compared to mRNAs, lncRNAs more often have a specific subcellular localization with a markedly higher percentage of nuclear enrichment within the Myc-repressed lncRNA set. Parallel analysis of differentially expressed lncRNAs and mRNAs identified 105 juxtaposed lncRNA-mRNA pairs, indicative for regulation in cis. To support the potential relevance of the Myc-regulated lncRNAs in cellular transformation, we analyzed their expression in primary Myc-high and Myc-low B-cell lymphomas. In total, 54% of the lncRNAs differentially expressed between the lymphoma subsets were identified as Myc-regulated in P493-6 cells. This study is the first to show that lncRNAs are an important factor within the Myc-regulated transcriptional program and indicates a marked difference between Myc-repressed lncRNAs and mRNAs. PMID- 25690654 TI - Actin polymerization-enhancing drugs promote ovarian follicle growth mediated by the Hippo signaling effector YAP. AB - Hippo signaling pathway consists of conserved serine/threonine kinases to maintain optimal organ sizes. Studies have demonstrated that fragmentation of murine ovaries increases actin polymerization and disrupts Hippo signaling, leading to nuclear translocation of Hippo signaling effector Yes-associated protein (YAP) in ovarian follicles and follicle growth. For patients with polycystic ovarian syndrome showing follicle arrest, ovarian wedge resection and laser drilling promote follicle growth. Because these damaging procedures likely involve actin polymerization, we tested whether actin polymerization-promoting drugs could promote YAP translocation and stimulate follicle growth. Treatment of murine ovaries with MUM Jasplakinolide (JASP), an actin polymerization-promoting cyclic peptide, or sphingosine-1-phosphate (S1P), a follicular fluid constituent known to promote actin polymerization, increased the conversion of globular actin to the filamentous form, followed by increased nuclear YAP and expression of downstream connective tissue growth factor (CCN2). After short-term treatments with JASP or S1P, in vitro cultured and in vivo grafted ovaries showed follicle growth. Furthermore, induction of constitutively active YAP in ovarian grafts of transgenic mice enhanced follicle development, whereas treatment of human ovarian cortices with JASP or S1P increased CCN2 expression. Thus, JASP and S1P stimulate follicle growth and are potential therapeutic agents for treating polycystic ovarian syndrome and other ovarian disorders. PMID- 25690655 TI - Multicolor time-resolved Forster resonance energy transfer microscopy reveals the impact of GPCR oligomerization on internalization processes. AB - Identifying the interacting partners and the dynamics of the molecular networks constitutes the key point in understanding cellular processes. Different methods often based on energy transfer strategies have been developed to examine the molecular dynamics of protein complexes. However, these methods suffer a couple of drawbacks: a single complex can be studied at a time, and its localization and tracking cannot generally be investigated. Here, we report a multicolor time resolved Forster resonance energy transfer microscopy method that allows the identification of up to 3 different complexes simultaneously, their localization in cells, and their tracking after activation. Using this technique, we studied GPCR oligomerization and internalization in human embryonic kidney 293 cells. We definitively show that receptors can internalize as oligomers and that receptor coexpression deeply impacts oligomer internalization processes. PMID- 25690656 TI - Metabolic reconfiguration of the central glucose metabolism: a crucial strategy of Leishmania donovani for its survival during oxidative stress. AB - Understanding the mechanism that allows the intracellular protozoan parasite Leishmania donovani (Ld) to respond to reactive oxygen species (ROS) is of increasing therapeutic importance because of the continuing resistance toward antileishmanial drugs and for determining the illusive survival strategy of these parasites. A shift in primary carbon metabolism is the fastest response to oxidative stress. A (14)CO2 evolution study, expression of glucose transporters together with consumption assays, indicated a shift in metabolic flux of the parasites from glycolysis toward pentose phosphate pathway (PPP) when exposed to different oxidants in vitro/ex vivo. Changes in gene expression, protein levels, and enzyme activities all pointed to a metabolic reconfiguration of the central glucose metabolism in response to oxidants. Generation of glucose-6-phosphate dehydrogenase (G6PDH) (~5-fold) and transaldolase (TAL) (~4.2-fold) overexpressing Ld cells reaffirmed that lethal doses of ROS were counterbalanced by effective manipulation of NADPH:NADP(+) ratio and stringent maintenance of reduced thiol content. The extent of protein carbonylation and accumulation of lipid peroxidized products were also found to be less in overexpressed cell lines. Interestingly, the LD50 of sodium antimony gluconate (SAG), amphotericin-B (AmB), and miltefosine were significantly high toward overexpressing parasites. Consequently, this study illustrates that Ld strategizes a metabolic reconfiguration for replenishment of NADPH pool to encounter oxidative challenges. PMID- 25690657 TI - Mammalian actin-binding protein 1/HIP-55 is essential for the scission of clathrin-coated pits by regulating dynamin-actin interaction. AB - Actin and dynamin work cooperatively to drive the invagination and scission of clathrin-coated pits (CCPs). However, little is known about the mechanism that orchestrates the spatiotemporal recruitment of dynamin and actin. Here, we have identified the mammalian actin-binding protein 1 (mAbp1; also called HIP-55 or SH3P7), which could bind to clathrin, actin, as well as dynamin, as an adaptor that links the dynamic recruitment of dynamin and actin for the scission of CCPs. Live-cell imaging reveals that mAbp1 is specifically recruited at a late stage of the long-lived CCPs. mAbp1 knockdown impaired CCP scission by reducing dynamin recruitment at the plasma membrane. However, actin disruption remarkably eliminates mAbp1 recruitment and thus dynamin recruitment. These data suggest that by binding to both clathrin and F-actin, mAbp1 is specifically recruited at a late stage of CCP formation, which subsequently recruits dynamin to CCPs. PMID- 25690658 TI - The P2X7 receptor directly interacts with the NLRP3 inflammasome scaffold protein. AB - The P2X7 receptor (P2X7R) is a known and powerful activator of the NOD-like receptor (NLR)P3 inflammasome; however, the underlying pathways are poorly understood. Thus, we investigated the molecular mechanisms involved. The effect of P2X7R expression and activation on NLRP3 expression and recruitment was investigated by Western blot, RT-PCR, coimmunoprecipitation, and confocal microscopy in microglial mouse cell lines selected for reduced P2X7R expression and in primary cells from P2X7R(-/-) C57BL/6 mice. We show here that P2X7R activation by ATP (EC50 = 1 mM) or benzoyl-ATP (EC50 = 300 MUM) and P2X7R down modulation caused a 2- to 8-fold up-regulation of NLRP3 mRNA in mouse N13 microglial cells. Moreover, NLRP3 mRNA was also up-regulated in primary microglial and macrophage cells from P2X7R(-/-) mice. Confocal microscopy and immunoprecipitation assays showed that P2X7R and NLRP3 closely interacted at discrete subplasmalemmal sites. Finally, P2X7R stimulation caused a transient (3 4 min) cytoplasmic Ca(2+) increase localized to small (2-3 um wide) discrete subplasmalemmal regions. The Ca(2+) increase drove P2X7R recruitment and a 4-fold increase in P2X7R/NLRP3 association within 1-2 min. These data show a close P2X7R and NLRP3 interaction and highlight the role of P2X7R in the localized cytoplasmic ion changes responsible for both NLRP3 recruitment and activation. PMID- 25690659 TI - DOTS-Finder: a comprehensive tool for assessing driver genes in cancer genomes. AB - A key challenge in the analysis of cancer genomes is the identification of driver genes from the vast number of mutations present in a cohort of patients. DOTS Finder is a new tool that allows the detection of driver genes through the sequential application of functional and frequentist approaches, and is specifically tailored to the analysis of few tumor samples. We have identified driver genes in the genomic data of 34 tumor types derived from existing exploratory projects such as The Cancer Genome Atlas and from studies investigating the usefulness of genomic information in the clinical settings. DOTS-Finder is available at https://cgsb.genomics.iit.it/wiki/projects/DOTS Finder/. PMID- 25690660 TI - A DAP12-dependent signal promotes pro-inflammatory polarization in microglia following nerve injury and exacerbates degeneration of injured neurons. AB - Under pathological conditions, activated microglia play paradoxical roles and could have neurotoxic or neuroprotective effects. However, the signal determining how activated microglia affects the fate of neuronal cells remains largely unknown. Here we demonstrate that DNAX-activating protein of 12 kDa (DAP12), a transmembrane adaptor protein that contains an immunoreceptor tyrosine-based activation motif, is a critical regulator of microglial function after nerve injury. In a model of mouse hypoglossal nerve injury, the duration of microglial increase after nerve injury became shorter in mice lacking DAP12, although microglial morphology and total cell numbers were not significantly affected during early phase after nerve injury. Intriguingly, expressions of M1-phenotype markers including pro-inflammatory cytokines were suppressed in DAP12-deficient microglia. Furthermore, axotomy-induced motor neuron death was markedly prevented in DAP12-deficient mice. Collectively, DAP12-mediated microglial activation following axotomy promotes pro-inflammatory responses, and thereby accelerates nerve injury-induced neuron death, suggesting that DAP12 is a potential therapeutic target for the protection of neuronal degeneration caused by microglial activation. PMID- 25690661 TI - Increased susceptibility of dyslipidemic LSR+/- mice to amyloid stress is associated with changes in cortical cholesterol levels. AB - Alzheimer's disease (AD) is a neurodegenerative disease that has been linked to changes in cholesterol metabolism. Neuronal cholesterol content significantly influences the pro-apoptotic effect of amyloid-beta peptide42 (Abeta42), which plays a key role in AD development. We previously reported that aged mice with reduced expression of the lipolysis stimulated lipoprotein receptor (LSR+/-), demonstrate membrane cholesterol accumulation and decreased intracellular lipid droplets in several brain regions, suggesting a potential role of LSR in brain cholesterol distribution. We questioned if these changes rendered the LSR+/- mouse more susceptible to Abeta42-induced cognitive and biochemical changes. Results revealed that intracerebroventricular injection of oligomeric Abeta42 in male 15-month old LSR+/+ and LSR+/- mice led to impairment in learning and long term memory and decreased cortical cholesterol content of both groups; these effects were significantly amplified in the Abeta42-injected LSR+/- group. Total latency of the Morris test was significantly and negatively correlated with cortical cholesterol content of the LSR+/- mice, but not of controls. Significantly lower cortical PSD95 and SNAP-25 levels were detected in Abeta42 injected LSR+/- mice as compared to Abeta42-injected LSR+/+ mice. In addition, 24S-hydroxy cholesterol metabolite levels were significantly higher in the cortex of LSR+/- mice. Taken together, these results suggest that changes in cortex cholesterol regulation as a result of the LSR+/- genotype were linked to increased susceptibility to amyloid stress, and we would therefore propose the aged LSR+/- mouse as a new model for understanding the link between modified cholesterol regulation as a risk factor for AD. PMID- 25690662 TI - Elevated plasma angiogenesis factors in Alzheimer's disease. AB - Evidence has shown that aberrant angiogenesis is an integral part of Alzheimer's disease (AD). Angiogenesis is a complex process requiring successive activation of a rather large series of factors. The aim of this study was to determine which angiogenesis molecule(s) abnormalities were changed in plasma of AD subjects and whether plasma levels of angiogenesis factors were associated with cognitive function and risk of AD. Discovery-phase antibody arrays were used to detect plasma concentrations of 55 angiogenesis-related factors. Enzyme-linked immunosorbent assays (ELISAs) in a large cohort were further performed to identify the association of plasma angiogenesis factors with AD. We found that plasma angiogenin (ANG) and tissue inhibitor of matrix metalloproteinase-4 (TIMP 4) levels were higher in patients with AD than those in normal subjects. Significantly higher ANG and TIMP-4 were observed in the severe AD group relative to the mild AD. There were different levels of plasma ANG and TIMP-4 compared with vascular dementia and other dementias. Age or gender had no major effects on levels of these proteins. Plasma ANG and TIMP-4 levels tended to be higher in ApoE epsilon4 carriers compared with non-carriers, but not significantly. A multiple regression analysis after adjusting for covariates revealed correlations between plasma ANG and TIMP-4 and the MMSE and CDR. Higher plasma ANG and TIMP-4 levels were associated with significant AD risk. These results demonstrate that plasma ANG and TIMP-4 may reflect the severity of cognitive function impairment, and higher levels were associated with risk of AD. PMID- 25690663 TI - A combined measure of vascular risk for white matter lesions. AB - BACKGROUND: Though hypertension is a commonly studied risk factor for white matter lesions (WMLs), measures of blood pressure may fluctuate depending on external conditions resulting in measurement error. Indicators of arterial stiffening and reduced elasticity may be more sensitive indicators of risk for WMLs in aging; however the interdependent nature of vascular indicators creates statistical complications. OBJECTIVE: The purpose of the study was to determine whether a factor score comprised of multiple vascular indicators would be a stronger predictor of WMLs than traditional measures of blood pressure. METHODS: In a sample of well-characterized nondemented older adults, we used a factor analytic approach to account for variance common across multiple vascular measures while reducing measurement error. The result was a single factor score reflecting arterial stiffness and reduced elasticity. We used this factor score to predict white matter lesion volumes acquired via fluid attenuated inversion recovery (FLAIR) magnetic resonance imaging. RESULTS: The combined vascular factor score was a stronger predictor of deep WML (beta = 0.42, p < 0.001) and periventricular WML volumes (beta = 0.49, p < 0.001). After accounting for the vascular factor, systolic and diastolic blood pressure measurements were not significant predictors. CONCLUSIONS: This suggests that a combined measure of arterial elasticity and stiffening may be a stronger predictor of WMLs than systolic and diastolic blood pressure accounting for the multicollinearity associated with a variety of interrelated vascular measures. PMID- 25690664 TI - The combination of aricept with a traditional Chinese medicine formula, smart soup, may be a novel way to treat Alzheimer's disease. AB - Alzheimer's disease (AD) is a common neurodegenerative disease affecting cognitive function in the elderly, which is characterized by the presence of extracellular deposits of insoluble amyloid-beta plaques and neuronal loss. Modern pharmacology and drug development usually follow a single-target principle, which might contribute to the failure of most compounds in clinical trials against AD. Considering AD is a multifactorial disease, a combination therapeutic strategy that applies drugs with different mechanisms would be an alternative way. Smart Soup (SS), a Traditional Chinese Medicine formula, is composed of three herbaceous plants and has been applied in the treatment of amnesia in China for hundreds of years. In this work, we studied the clinical potency of the combination of SS and Aricept in AD therapy. In the in vivo model, both longevity and locomotive activity of AD transgenic Drosophila were improved remarkably in the combined medicine treated group. We also observed less amyloid beta deposition and retarded neuronal loss following the combined drug treatment. In the retrospective cohort study, we found the combination therapy exerted better therapeutic effect on AD patients. Our study revealed that combination therapy with multiple drug targets did have a better therapeutic outcome. It provides a new strategy to develop an optimum pharmaceutical approach against AD. PMID- 25690666 TI - From an electron-rich bis(boraketenimine) to an electron-poor diborene. AB - The reaction of the bisboracumulene (CAAC)2 B2 (CAAC=1-(2,6-diisopropylphenyl) 3,3,5,5-tetramethylpyrrolidin-2-ylidene) with excess tert-butylisocyanide resulted in complexation of the isocyanide at boron. Though this compound might be formally drawn with a lone pair on boron, these electrons are highly delocalized throughout a conjugated pi-network consisting of the pi-acidic CAAC and isocyanide ligands. Heating this compound to 110 degrees C liberated the organic periphery of both isocyanide ligands, yielding the first example of a dicyanodiborene. Cyclic voltammetry conducted on this diborene indicated the presence of reduction waves, making this compound unique among diborenes, which are otherwise highly reducing. PMID- 25690667 TI - Infliximab-induced anterior uveitis in a patient with ulcerative Colitis. PMID- 25690665 TI - Comprehensive gene- and pathway-based analysis of depressive symptoms in older adults. AB - Depressive symptoms are common in older adults and are particularly prevalent in those with or at elevated risk for dementia. Although the heritability of depression is estimated to be substantial, single nucleotide polymorphism-based genome-wide association studies of depressive symptoms have had limited success. In this study, we performed genome-wide gene- and pathway-based analyses of depressive symptom burden. Study participants included non-Hispanic Caucasian subjects (n = 6,884) from three independent cohorts, the Alzheimer's Disease Neuroimaging Initiative (ADNI), the Health and Retirement Study (HRS), and the Indiana Memory and Aging Study (IMAS). Gene-based meta-analysis identified genome wide significant associations (ANGPT4 and FAM110A, q-value = 0.026; GRM7-AS3 and LRFN5, q-value = 0.042). Pathway analysis revealed enrichment of association in 105 pathways, including multiple pathways related to ERK/MAPK signaling, GSK3 signaling in bipolar disorder, cell development, and immune activation and inflammation. GRM7, ANGPT4, and LRFN5 have been previously implicated in psychiatric disorders, including the GRM7 region displaying association with major depressive disorder. The ERK/MAPK signaling pathway is a known target of antidepressant drugs and has important roles in neuronal plasticity, and GSK3 signaling has been previously implicated in Alzheimer's disease and as a promising therapeutic target for depression. Our results warrant further investigation in independent and larger cohorts and add to the growing understanding of the genetics and pathobiology of depressive symptoms in aging and neurodegenerative disorders. In particular, the genes and pathways demonstrating association with depressive symptoms may be potential therapeutic targets for these symptoms in older adults. PMID- 25690668 TI - von Willebrand factor arginine 1205 substitution results in accelerated macrophage-dependent clearance in vivo. AB - BACKGROUND: Enhanced von Willebrand factor (VWF) clearance is important in the etiology of type 1 and type 2 von Willebrand disease (VWD). More than 20 different VWF point mutations have already been reported in patients with enhanced clearance. These include the VWD-Vicenza variant, which is characterized by an Arg1205His substitution in the VWF D3 domain. Critically, however, the molecular mechanisms through which single amino acid substitutions in VWF result in enhanced clearance of this complex multimeric glycoprotein have not been defined. OBJECTIVES: In this study, we have investigated the biological basis underlying the enhanced clearance of the VWF-R1205H variant. METHODS: Using VWF( /-) mice, in vivo clearance rates were determined for a series of full-length and truncated recombinant VWF variants. In addition, the role of macrophages in modulating enhanced VWD-Vicenza clearance was investigated using clodronate liposome administration. RESULTS: Our findings demonstrate that substitutions of R1205 with histidine, cysteine or serine all result in markedly reduced survival of full-length recombinant VWF. Importantly, D'A3 fragments containing these same R1205 substitutions also demonstrated significantly enhanced clearance. In contrast to the reduced in vivo survival observed with R1205H, clearance of R1204H was not enhanced. Recent studies have demonstrated that hepatic and splenic macrophages play key roles in regulating VWF clearance. Importantly, macrophage-depletion also served to markedly attenuate the enhanced clearance phenotypes associated with VWF-R1205H, VWF-R1205S and VWF-R1205C. CONCLUSIONS: Collectively, these novel findings demonstrate a specific and critical role for the R1205 residue in modulating macrophage-mediated clearance of VWF in vivo. PMID- 25690669 TI - Heterozygous p53 knockout mouse model for dehydropyrrolizidine alkaloid-induced carcinogenesis. AB - Dehydropyrrolizidine alkaloids (DHPA) are a large, structurally diverse group of plant-derived protoxins that are potentially carcinogenic. With worldwide significance, these alkaloids can contaminate or be naturally present in the human food supply. To develop a small animal model that may be used to compare the carcinogenic potential of the various DHPAs, male heterozygous p53 knockout mice were administered a short-term treatment of riddelliine 5, 15 or 45 mg kg( 1) bodyweight day(-1) by oral gavage for 14 days, or dosed a long-term treatment of riddelliine 1 mg kg(-1) bodyweight day(-1) in pelleted feed for 12 months. Exposure to riddelliine increased the odds of tumor development in a dose responsive manner (odds ratio 2.05 and Wald 95% confidence limits between 1.2 and 3.4). The most common neoplastic process was hepatic hemangiosarcoma, which is consistent with published lifetime rodent riddelliine carcinogenesis studies. Angiectasis (peliosis hepatis) and other previously unreported lesions were also identified. The results of this research demonstrate the utility of the heterozygous p53 knockout mouse model for further investigation of comparative carcinogenesis of structurally and toxicologically different DHPAs and their N oxides. PMID- 25690670 TI - Genetic variations in angiopoietin and pericyte pathways and clinical outcome in patients with resected colorectal liver metastases. AB - BACKGROUND: Genes involved in the angiopoietin and pericyte pathways may become escape mechanisms under antivascular endothelial growth factor (anti-VEGF) therapy. The authors investigated whether variations within genes in these pathways are associated with clinical outcome in patients with colorectal liver metastases who undergo liver resection and receive perioperative, bevacizumab based chemotherapy. METHODS: Single nucleotide polymorphisms (SNPs) in 9 genes (angiopoietin-1 [ANGPT1]; ANGPT2; TEK tyrosine kinase, endothelial [TEK]; platelet-derived growth factor beta [PDGFB]; beta-type platelet-derived growth factor receptor [PDGFRB]; insulin-like growth factor 1 [IGF1]; transforming growth factor beta1 [TGFB1]; RalA binding protein 1 [RALBP1]; and regulator of G protein signaling 5 [RGS5]) were analyzed in samples of genomic DNA from 149 patients and were evaluated for associations with clinical outcome. RESULTS: RALBP1 reference SNP 329007 (rs329007) A>G resulted in a significant difference in recurrence-free survival (A/A genotype, 14.0 months; A/G or G/G genotype, 9.2 months; hazard ratio [HR], 1.60; P = .024). PDGFB rs1800818 A>G was associated with 3-year overall survival rates (A/A genotype, 78%; A/G genotype, 69%; [HR 1.37]; G/G genotype, 53%; [HR 2.12]; P = .048). In multivariate analysis, RALBP1 rs329007 A>G remained significant (HR, 1.99; P = .002). PDGFB rs1800818 A>G and RALBP1 rs329007 A>G were correlated with radiologic response (A/A or A/G genotype, 86%; G/G genotype, 71% [P = .042]; A/A genotype, 78%; A/G or G/G genotype, 94% [P = .018], respectively). RALBP1 rs329007 A>G demonstrated significantly different rates of histologic response (A/A genotype: major histologic response, 35%; partial histologic response, 34%; no histologic response, 30%; A/G or G/G genotype: 46%, 13%, and 41%, respectively; P = .029). Recursive partitioning analysis revealed that ANGPT2 rs2442599 T>C and RALBP1 rs329007 A>G were the main SNPs that predicted histologic response and recurrence free survival, whereas PDGFB rs1800818 A>G was the leading SNP that predicted overall survival. ANGPT2 rs2916702 C>T and rs2442631 G>A were significantly associated with the probability of achieving a cure. CONCLUSIONS: The current data suggest that variations in genes involved in the angiopoietin and pericyte pathways may be predictive and/or prognostic biomarkers in patients with resected colorectal liver metastases who receive bevacizumab-based chemotherapy. PMID- 25690671 TI - Potential for combination of dipeptidyl peptidase-4 inhibitors and sodium-glucose co-transporter-2 inhibitors for the treatment of type 2 diabetes. AB - In individuals with advanced type 2 diabetes (T2DM), combination therapy is often unavoidable to maintain glycaemic control. Currently metformin is considered the first line of defence, but many patients experience gastrointestinal adverse events, necessitating an alternative treatment approach. Established therapeutic classes, such as sulphonylureas and thiazolidinediones, have some properties undesirable in individuals with T2DM, such as hypoglycaemia risk, weight gain and fluid retention, highlighting the need for newer agents with more favourable safety profiles that can be combined and used at all stages of T2DM. New treatment strategies have focused on both dipeptidyl peptidase (DPP)-4 inhibitors, which improve hyperglycaemia by stimulating insulin secretion in a glucose-dependent fashion and suppressing glucagon secretion, and sodium-glucose co-transporter-2 (SGLT2) inhibitors, which reduce renal glucose reabsorption and induce urinary glucose excretion, thereby lowering plasma glucose. The potential complimentary mechanism of action and good tolerance profile of these two classes of agents make them attractive treatment options for combination therapy with any of the existing glucose-lowering agents, including insulin. Together, the DPP-4 and SGLT2 inhibitors fulfill a need for treatments with mechanisms of action that can be used in combination with a low risk of adverse events, such as hypoglycaemia or weight gain. PMID- 25690672 TI - A novel prognostic nomogram accurately predicts hepatocellular carcinoma recurrence after liver transplantation: analysis of 865 consecutive liver transplant recipients. AB - BACKGROUND: Although radiologic size criteria (Milan/University of California, San Francisco [UCSF]) have led to improved outcomes after liver transplantation (LT) for hepatocellular carcinoma (HCC), recurrence remains a significant challenge. We analyzed our 30-year experience with LT for HCC to identify predictors of recurrence. STUDY DESIGN: A novel clinicopathologic risk score and prognostic nomogram predicting post-transplant HCC recurrence was developed from a multivariate competing-risk Cox regression analysis of 865 LT recipients with HCC between 1984 and 2013. RESULTS: Overall patient and recurrence-free survivals were 83%, 68%, 60% and 79%, 63%, and 56% at 1-, 3-, and 5-years, respectively. Hepatocellular carcinoma recurred in 117 recipients, with a median time to recurrence of 15 months, involving the lungs (59%), abdomen/pelvis (38%), liver (35%), bone (28%), pleura/mediastinum (12%), and brain (5%). Multivariate predictors of recurrence included tumor grade/differentiation (G4/poor diff hazard ratio [HR] 8.86; G2-3/mod-poor diff HR 2.56), macrovascular (HR 7.82) and microvascular (HR 2.42) invasion, nondownstaged tumors outside Milan criteria (HR 3.02), nonincidental tumors with radiographic maximum diameter >= 5 cm (HR 2.71) and <5 cm (HR 1.55), and pretransplant neutrophil-to-lymphocyte ratio (HR 1.77 per log unit), maximum alpha fetoprotein (HR 1.21 per log unit), and total cholesterol (HR 1.14 per SD). A pretransplantation model incorporating only known radiographic and laboratory parameters had improved accuracy in predicting HCC recurrence (C statistic 0.79) compared with both Milan (C statistic 0.64) and UCSF (C statistic 0.64) criteria alone. A novel clinicopathologic prognostic nomogram included explant pathology and had an excellent ability to predict post transplant recurrence (C statistic 0.85). CONCLUSIONS: In the largest single institution experience with LT for HCC, excellent long-term survival was achieved. Incorporation of routine pretransplantation biomarkers to existing radiographic size criteria significantly improves the ability to predict post transplant recurrence, and should be considered in recipient selection. A novel clinicopathologic prognostic nomogram accurately predicts HCC recurrence after LT and may guide frequency of post-transplantation surveillance and adjuvant therapy. PMID- 25690673 TI - Development and validation of a risk stratification score for ventral incisional hernia after abdominal surgery: hernia expectation rates in intra-abdominal surgery (the HERNIA Project). AB - BACKGROUND: Ventral incisional hernias (VIH) develop in up to 20% of patients after abdominal surgery. No widely applicable preoperative risk-assessment tool exists. We aimed to develop and validate a risk-assessment tool to predict VIH after abdominal surgery. STUDY DESIGN: A prospective study of all patients undergoing abdominal surgery was conducted at a single institution from 2008 to 2010. Variables were defined in accordance with the National Surgical Quality Improvement Project, and VIH was determined through clinical and radiographic evaluation. A multivariate Cox proportional hazard model was built from a development cohort (2008 to 2009) to identify predictors of VIH. The HERNIAscore was created by converting the hazards ratios (HR) to points. The predictive accuracy was assessed on the validation cohort (2010) using a receiver operator characteristic curve and calculating the area under the curve (AUC). RESULTS: Of 625 patients followed for a median of 41 months (range 0.3 to 64 months), 93 (13.9%) developed a VIH. The training cohort (n = 428, VIH = 70, 16.4%) identified 4 independent predictors: laparotomy (HR 4.77, 95% CI 2.61 to 8.70) or hand-assisted laparoscopy (HAL, HR 4.00, 95% CI 2.08 to 7.70), COPD (HR 2.35; 95% CI 1.44 to 3.83), and BMI >= 25 kg/m(2) (HR1.74; 95% CI 1.04 to 2.91). Factors that were not predictive included age, sex, American Society of Anesthesiologists (ASA) score, albumin, immunosuppression, previous surgery, and suture material or technique. The predictive score had an AUC = 0.77 (95% CI 0.68 to 0.86) using the validation cohort (n = 197, VIH = 23, 11.6%). Using the HERNIAscore: HERNIAscore = 4(*)Laparotomy+3(*)HAL+1(*)COPD+1(*) BMI >= 25, 3 classes stratified the risk of VIH: class I (0 to 3 points),5.2%; class II (4 to 5 points),19.6%; and class III (6 points), 55.0%. CONCLUSIONS: The HERNIAscore accurately identifies patients at increased risk for VIH. Although external validation is needed, this provides a starting point to counsel patients and guide clinical decisions. Increasing the use of laparoscopy, weight-loss programs, community smoking prevention programs, and incisional reinforcement may help reduce rates of VIH. PMID- 25690674 TI - A meta-ethnographic synthesis on phenomenographic studies of patients' experiences of chronic illness. AB - Phenomenography is a qualitative research approach developed within an educational framework, focusing on the qualitative experience of learning. It is also being used, to a lesser degree, in healthcare research. In the present study, we conducted a meta-ethnographic synthesis of phenomenographic studies on chronic illness, in order to give a broader perspective of how chronic illness can be experienced. Our aim was not to describe patients' various individual experiences of illness, but instead to identify the different ways chronic illness can be experienced by patients. Our synthesis and phenomenographic interpretation of 12 selected articles found that patients' experiences of chronic illness can be described in terms of a different lived body, a struggle with threat to identity and self-esteem, a diminished lifeworld, and a challenging reality. These experiences relate to each other in a process of recurring loops, where the different ways of experiencing continue to influence each other over time. According to these findings, the use of phenomenography as a research approach has the potential to add to the understanding of how chronic illness can be experienced. Patients may benefit from seeing that their illness can be experienced in many different ways and that it has many aspects, which then can lead to a better understanding and coping with their illness. We suggest that it may be worthwhile to expand the scope of phenomenography outside pedagogics. This presupposes a revision of the application to include a wider and more comprehensive description, for instance, of the different ways illness and healthcare phenomena can be experienced, and how these different ways are related to each other, with less focus on hierarchical relations. PMID- 25690675 TI - A melting pot world of species: reply to Speziale et al. PMID- 25690676 TI - Silicon biofortification of leafy vegetables and its bioaccessibility in the edible parts. AB - BACKGROUND: The mineral silicon (Si) is an essential element for humans and a general component of the diet found mainly in plant-based foods. The aim of this study was to obtain Si biofortificated leafy vegetables (tatsoi, mizuna, purslane, basil, Swiss chard, and chicory) to use for the fresh-cut products (ready to use). For the production of biofortified plants, a floating system with 0, 50 and 100 mg L(-1) of Si in nutrient solution, was used. In addition, the assessment of bioaccessibility of biofortified plants, by in vitro gastro digestion process, was performed. RESULTS: The added silicon in nutrient solution did not influence yield and colour of vegetables but a species-related accumulation of Si (expressed as SiO2) was found: from 18 to 69 mg kg(-1) fresh weight (FW) in tatsoi, from 19 to 106 mg kg(-1) FW in mizuna, from 15 to 93 mg kg(-1) FW in purslane, from 41 to 294 mg kg(-1) FW in basil, from 17 to 76 mg kg( 1) FW in Swiss chard, and from 23 to 76 mg kg(-1) FW in chicory. The Si became bioaccessible in all species considered in a range from 23% (basil) to 64% (chicory). CONCLUSION: The application of Si to the nutrient solution in the range of 50-100 mg L(-1) allows biofortification of leafy vegetables. In addition, the biofortified vegetables showed, on average, more bioaccessible Si, with respect to unbiofortified vegetables. PMID- 25690677 TI - Follow-up visit in an ICU: receiving a sense of coherence. AB - AIM: To describe patients' experiences of a follow-up visit to an intensive care unit (ICU) after being critically ill and nursed there. BACKGROUND: Knowledge about the follow-up visit needs to be developed, with the previously critically ill patient in focus. DESIGN: Qualitative descriptive. METHOD: Semi-structured interviews were conducted with nine patients and analysed using qualitative content analysis. The data collection occurred during spring 2014. FINDINGS: During the follow-up visits in ICU, the relatives, the patient diary, and those who took part in the care contribute to fill memory gaps to create a picture and an explanation of the care period. CONCLUSION: The follow-up visit is an important tool in the patients' struggle to create a context and coherence from a missing or unreal time. The patient diary is essential to subsequently be able to relate to the period of care. RELEVANCE TO CLINICAL PRACTICE: The follow-up visit, together with a personal diary, after an ICU stay could be seen as significant for strengthening the patients' feeling of coherence and better health. PMID- 25690678 TI - Identification of the PRMT1v1 and PRMT1v2 specific interactomes by quantitative mass spectrometry in breast cancer cells. AB - Arginine methylation is catalyzed by a family of enzymes called protein arginine methyltransferases (PRMTs). The PRMT1 gene generates at least seven distinct alternatively spliced isoforms (PRMT v1-v7), which together contribute a significant portion of the cellular arginine methylome. The distinct biochemical and biological functions of these PRMT1 isoforms have not been well characterized. Previously we have shown that while both PRMT1v1 and PRMT1v2 are overexpressed in breast cancer cells, PRMT1v2 specifically promotes breast cancer cell survival and invasion. These isoforms also have distinct subcellular localizations, PRMT1v1 is mainly nuclear and PRMT1v2 cytosolic. To gain further knowledge into their isoform-specific roles within cells we used a SILAC-based quantitative affinity purification/MS approach to identify their individual protein interactomes in breast cancer cells. This analysis has uncovered distinct interactomes for PRMT1v1 and PRMT1v2. Consistent with their distinct subcellular localizations, PRMT1v1 enriched a mainly nuclear protein interactome, while PRMT1v2 enriched predominantly cytoplasmic interactors from whole-cell extracts. Furthermore, these interactomes revealed that PRMT1v1 has a role in regulating gene expression, while PRMT1v2 functions in cytoskeletal dynamics. These results highlight the unique functions of these isoforms and the distinct roles they may play within cells, with potential implications for breast cancer and other diseases. PMID- 25690679 TI - The application of activated carbon for the treatment and reuse of the aqueous phase derived from the hydrothermal liquefaction of a halophytic Tetraselmis sp. AB - The aim of this study was to determine how the treatment of the HTL AP with activated carbon would affect both growth and chemical composition of the microalgae. Tetraselmis MUR233 was grown in HTL AP (filtered and unfiltered) at 500 *, 1000 *, and 2000 * dilutions in hyper saline conditions. The organic nitrogen and carbon component of the HTL AP was greatly reduced with the activated carbon treatment (TKN 52,000 +/- 520 mg/L to 5900 +/- 59 mg/L; TOC 19,000 +/- 190 mg/L to 13,000 +/- 130 mg/L). Growth of Tetraselmis MUR233 was achieved on all dilutions of HTL AP, with a maximum growth observed in the AP filtered 1000 * dilution treatment (0.41 +/- 0.09 g/L), this compares to a yield of 0.49 +/- 0.10 g/L when grown in traditional culture media. PMID- 25690680 TI - High-capacity adsorption of dissolved hexavalent chromium using amine functionalized magnetic corn stalk composites. AB - Easily separable amine-functionalized magnetic corn stalk composites (AF-MCS) were employed for effective adsorption and reduction of toxic hexavalent chromium [Cr(VI)] to nontoxic Cr(III). The saturated magnetization of AF-MCS reached 6.2emu/g, and as a result, it could be separated from aqueous solution by a magnetic process for its superparamagnetism. The studies of various factors influencing the sorption behavior indicated that the optimum AF-MCS dosage for Cr(VI) adsorption was 1g/L, and the maximum adsorption capacity was observed at pH 3.0. The chromium adsorption perfectly fitted the Langmuir isotherm model and pseudo second order kinetic model. Furthermore, characterization of AF-MCS was investigated by means of XRD, SEM, TEM, FT-IR, BET, VSM and XPS analysis to discuss the uptake mechanism. Basically, these results demonstrated that AF-MCS prepared in this work has shown its merit in effective removal of Cr(VI) and rapid separation from effluents simultaneously. PMID- 25690681 TI - Selective release of phosphorus and nitrogen from waste activated sludge with combined thermal and alkali treatment. AB - Selective release characteristics of phosphorus and nitrogen from waste activated sludge (WAS) were investigated during combined thermal and alkali treatment. Alkali (0.001-1.0N NaOH) treatment and combined thermal-alkali treatment were applied to WAS for releasing total P(T-P) and total nitrogen(T-N). Combined thermal-alkali treatment released 94%, 76%, and 49% of T-P, T-N, and COD, respectively. Release rate was positively associated with NaOH concentration, while temperature gave insignificant effect. The ratio of T-N and COD to T-P that released with alkali treatment ranged 0.74-0.80 and 0.39-0.50, respectively, while combined thermal-alkali treatment gave 0.60-0.90 and 0.20-0.60, respectively. Selective release of T-P and T-N was negatively associated with NaOH. High NaOH concentration created cavities on the surface of WAS, and these cavities accelerated the release rate, but reduced selectivity. Selective release of P and N from sludge has a beneficial effect on nutrient recovery with crystallization processes and it can also enhance methane production. PMID- 25690682 TI - Typical low cost biosorbents for adsorptive removal of specific organic pollutants from water. AB - Specific organic pollutants (SOPs) such as phenolic compounds, PAHs, organic pesticides, and organic herbicides cause health and environmental problems due to their excessive toxic properties and poor biodegradability. Low-cost biosorbents are considered as a promising alternative for conventional adsorbents to remove SOPs from water. These materials have several advantages such as high sorption capacities, good modifiability and recoverability, insensitivity to toxic substances, simple operation in the treatment processes. However, previous reports on various types of biosorbents for removing SOPs are still moderately fragmented. Hence, this paper provides a comprehensive review on using typical low-cost biosorbents obtained from lignocellulose and chitin/chitosan for SOPs adsorption. Especially, their characteristics, biosorption mechanism together with utilization for eliminating SOPs are presented and discussed. The paper also gives a critical view regarding future applications of low-cost biosorbents in SOPs-contaminated water treatment. PMID- 25690683 TI - Obtaining fermentable sugars by dilute acid hydrolysis of hemicellulose and fast pyrolysis of cellulose. AB - The objective of this study was to get fermentable sugars by dilute acid hydrolysis of hemicellulose and fast pyrolysis of cellulose from sugarcane bagasse. Hemicellulose could be easily hydrolyzed by dilute acid as sugars. The remained solid residue of acid hydrolysis was utilized to get levoglucosan by fast pyrolysis economically. Levoglucosan yield from crystalline cellulose could be as high as 61.47%. Dilute acid hydrolysis was also a promising pretreatment for levoglucosan production from lignocellulose. The dilute acid pretreated sugarcane bagasse resulted in higher levoglucosan yield (40.50%) in fast pyrolysis by micropyrolyzer, which was more effective than water washed (29.10%) and un-pretreated (12.84%). It was mainly ascribed to the effective removal of alkali and alkaline earth metals and the accumulation of crystalline cellulose. This strategy seems a promising route to achieve inexpensive fermentable sugars from lignocellulose for biorefinery. PMID- 25690684 TI - Assessment of spasticity after stroke using clinical measures: a systematic review. AB - PURPOSE: To identify and appraise the literature on clinical measures of spasticity that has been investigated in people after stroke. METHODS: The literature search involved four databases (PubMed, CINAHL, Embase and The Cochrane Library) up to February 2014. The selected studies included those that aimed to measure spasticity using a clinical assessment tool among adult patients post-stroke. Two independent raters reviewed the included articles using a critical appraisal scale and a structured data extraction form. RESULTS: A total of 40 studies examining 15 spasticity assessment tools in patients post-stroke were reviewed. None of the reviewed measurement tools demonstrated satisfactory results for all psychometric properties evaluated, and the majority lacked evidence concerning validity and absolute reliability. CONCLUSION: This systematic review found limited evidence to support the use of most of clinical measures of spasticity for people post-stroke. Future research examining the application and psychometric properties of these measures is warranted. Implications for Rehabilitation There is a need for objective clinical tools for measuring spasticity that are clinically feasible and easily interpreted by clinicians. This review identified various clinical measures of spasticity that have been investigated in people after stroke. Insufficient evidence of psychometric properties precludes recommending one tool over the others. Future research should focus on investigating the psychometric properties of clinical measures of spasticity. PMID- 25690686 TI - The antimycotic agent clotrimazole inhibits melanogenesis by accelerating ERK and PI3K-/Akt-mediated tyrosinase degradation. AB - Azole antimycotic agents are known to have anti-inflammatory and anti-cancer effects, which are mediated through their effects on the p38-cyclooxygenase-2 (COX-2)-prostaglandin E2 (PGE2) pathway, as well as anti-oxidant effects. Furthermore, pyridinyl imidazole compounds, such as SB203580 have recently been shown to inhibit melanogenesis. Accordingly, we hypothesized that azole antifungal agents might affect skin pigmentation. We herein investigated the effect of clotrimazole, the most commonly used azole antifungal agent, on melanogenesis. Intriguingly, clotrimazole reduced the melanin content in human melanocytes and mouse melanocytes, as well as in B16F10 mouse melanoma cells. Clotrimazole reduced levels of tyrosinase protein without altering mRNA expression. Simultaneous treatment with a proteasomal inhibitor restored both the suppression of melanin synthesis, and the downregulation of tyrosinase level, by clotrimazole. Clotrimazole also induced the phosphorylation of extracellular signal-regulated kinase (ERK) and PI3K/Akt, while each inhibitor of these two signals abolished the decrease of melanin synthesis by clotrimazole. Thus, our data suggest that clotrimazole inhibits melanin synthesis by promoting the proteasomal degradation of tyrosinase, which is mediated through activation of the ERK and Akt signaling pathways. These results may indicate a new role for clotrimazole as a molecular-mechanism-based, safe depigmenting agent for topical management of hyper-pigmentary sequelae related to fungal infection, or for other skin inflammatory disorders. PMID- 25690685 TI - Personal health technology: A new era in cardiovascular disease prevention. AB - Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality worldwide yet the majority of related risk factors are largely preventable (primary prevention [PP]) and effectively treatable (secondary prevention [SP]) with healthy lifestyle behaviors. The use of information and communication technology (ICT) offers a unique approach to personal health and CVD prevention, as these mediums are relatively affordable, approachable, and accessible. The purpose of this review is to provide an overview of ICT-driven personal health technologies and their potential role in promoting and supporting self-care behaviors for PP and SP of CVD. In this review, we focus on technological interventions that have been successful at supporting positive behavior change in order to determine which tools, resources, and methods are most appropriate for delivering interventions geared towards CVD prevention. We conducted a literature search from a range of sources including scholarly, peer-reviewed journal articles indexed in PubMed and CINAHL, gray literature, and reputable websites and other Internet-based media. A synthesis of existing literature indicates that the overall efficacy of ICT-driven personal health technologies is largely determined by: 1) the educational resources provided and the extent to which the relayed information is customized or individually tailored; and 2) the degree of self-monitoring and levels of personalized feedback or other interactions (e.g. interpersonal communications). We conclude that virtually all the technological tools and resources identified (e.g. Internet-based communications including websites, weblogs and wikis, mobile devices and applications, social media, and wearable monitors) can be strategically leveraged to enhance self-care behaviors for CVD risk reduction and SP but further research is needed to evaluate their efficacy, cost-effectiveness, and long-term maintainability. PMID- 25690687 TI - The effect of the angle of instrumentation of the Piezoelectric Ultrasonic Scaler on root surfaces. AB - OBJECTIVES: To evaluate the influence of variations in the working angle of the piezoelectric ultrasonic scaler (PUS) on root surfaces. MATERIAL AND METHODS: Fifty-five uniradicular bovine teeth were used, of which 25 teeth were used for the analysis of the roughness and root wear, while the remaining 30 teeth were used for the analysis of morphology (MRS) and the attachment of blood components (ABC). The teeth were randomly divided into five groups according to the type of treatment (G1-G5: piezoelectric ultrasonic scaler; G6: manual curette) and to the PUS working angle applied (G1: 0 degrees ; G2: 30 degrees ; G3: 45 degrees ; G4: 60 degrees ; G5: 90 degrees ). For statistical analysis, the data describing the MRS and ABC were analysed by the Kruskal-Wallis and Dunn's tests, and the data describing the roughness and tooth wear were analysed by anova and Tukey's tests at the significance level of 5%. RESULTS: Manual curette (MC) promoted a smoother root surface than the application of the PUS. The PUS used at the angles of 30 degrees and 45 degrees resulted in a high level of ABC that was comparable to that obtained by MC. Additionally, the group in which the PUS was applied at an angle of 45 degrees exhibited less tooth wear than the other groups. CONCLUSIONS: Changes in the working angle of the PUS influenced the characteristics of root surfaces after instrumentation. PMID- 25690688 TI - Bisphenol A and nonylphenol have the potential to stimulate the migration of ovarian cancer cells by inducing epithelial-mesenchymal transition via an estrogen receptor dependent pathway. AB - Epithelial-mesenchymal transition (EMT) is an important process appearing in embryo development and tumor migration or progression, which is influenced by 17beta-estradiol (E2). Bisphenol A (BPA) and nonylphenol (NP) are suspected as endocrine disrupting chemicals (EDCs) because they can exert estrogenic properties. In this study, we examined whether E2, BPA, and NP can lead to the EMT process in BG-1 ovarian cancer cells expressing estrogen receptors (ERs). To confirm the effect of E2, BPA, and NP, BG-1 cells were cultured under treatment with E2, BPA, or NP, and the alteration of EMT markers such as vimentin was examined at mRNA levels by using real-time and reverse-transcription (RT)-PCR. The expressions of snail, slug, and vimentin were enhanced by the treatment of E2, BPA, or NP compared to a control (DMSO). In protein levels, vimentin protein was increased by E2 and two EDCs, while E-cadherin was decreased. In addition, the expression of snail protein was enhanced by the treatment of E2 and the two EDCs in comparison with that of the control. Since EMT response in cancer cells can affect metastasis, we also performed a scratch assay and Western blot assay to show the migration ability caused by E2, BPA, or NP. Consequently, E2, BPA, and NP enhanced the migration capability of BG-1 cells and increased the expression of MMP-9 protein. Furthermore, to examine whether EMT and migration of BG-1 cancer cells are induced by BPA or NP via the ER dependent pathway, we cotreated the cells with ER-antagonist, ICI 182,780, in the presence of E2, BPA, or NP. As a result, the expressions of E-cadherin, vimentin, snail, and slug were reversed following treatment with an ER antagonist. Moreover, we confirmed that ICI 182,780 reduced the migration ability of BPA and NP to the control level. Taken together, these results indicate that BPA and NP, the potential EDCs, may have the ability to influence ovarian cancer metastasis via regulating EMT markers and migration in ER-expressing BG-1 ovarian cancer cells. PMID- 25690689 TI - Ultrasound elastography: liver. AB - Ultrasound elastography, also termed sonoelastography, is being used increasingly in clinical practice to aid the diagnosis and management of diffuse liver disease. Elastography has been shown to be capable of differentiating advanced and early-stage liver fibrosis, and consequently a major application in clinical liver care includes progression to cirrhosis risk stratification through (1) assessment of liver fibrosis stage in HCV and HBV patients, (2) distinguishing non-alcoholic steatohepatitis from simple steatosis in non-alcoholic fatty liver disease patients, and (3) prognostic evaluation of liver disease is autoimmune liver disease. In addition, elastographic characterization of focal liver lesions and evaluation of clinically significant portal hypertension have the potential to be clinically useful and are areas of active clinical research. PMID- 25690690 TI - Chronic exposure to deoxynivalenol has no influence on the oral bioavailability of fumonisin B1 in broiler chickens. AB - Both deoxynivalenol (DON) and fumonisin B1 (FB1) are common contaminants of feed. Fumonisins (FBs) in general have a very limited oral bioavailability in healthy animals. Previous studies have demonstrated that chronic exposure to DON impairs the intestinal barrier function and integrity, by affecting the intestinal surface area and function of the tight junctions. This might influence the oral bioavailability of FB1, and possibly lead to altered toxicity of this mycotoxin. A toxicokinetic study was performed with two groups of 6 broiler chickens, which were all administered an oral bolus of 2.5 mg FBs/kg BW after three-week exposure to either uncontaminated feed (group 1) or feed contaminated with 3.12 mg DON/kg feed (group 2). No significant differences in toxicokinetic parameters of FB1 could be demonstrated between the groups. Also, no increased or decreased body exposure to FB1 was observed, since the relative oral bioavailability of FB1 after chronic DON exposure was 92.2%. PMID- 25690691 TI - Antivenom cross-neutralization of the venoms of Hydrophis schistosus and Hydrophis curtus, two common sea snakes in Malaysian waters. AB - Sea snake envenomation is a serious occupational hazard in tropical waters. In Malaysia, the beaked sea snake (Hydrophis schistosus, formerly known as Enhydrina schistosa) and the spine-bellied sea snake (Hydrophis curtus, formerly known as Lapemis curtus or Lapemis hardwickii) are two commonly encountered species. Australian CSL sea snake antivenom is the definitive treatment for sea snake envenomation; it is unfortunately extremely costly locally and is not widely available or adequately stocked in local hospitals. This study investigated the cross-neutralizing potential of three regionally produced anti-cobra antivenoms against the venoms of Malaysian H. schistosus and H. curtus. All three antivenoms conferred paraspecific protection from sea snake venom lethality in mice, with potency increasing in the following order: Taiwan bivalent antivenom < Thai monocled cobra monovalent antivenom < Thai neuro polyvalent antivenom (NPAV). NPAV demonstrated cross-neutralizing potencies of 0.4 mg/vial for H. schistosus venom and 0.8 mg/vial for H. curtus, which translates to a dose of less than 20 vials of NPAV to neutralize an average amount of sea snake venom per bite (inferred from venom milking). The cross-neutralization activity was supported by ELISA cross-reactivity between NPAV and the venoms of H. schistosus (58.4%) and H. curtus (70.4%). These findings revealed the potential of NPAV as a second-line treatment for sea snake envenomation in the region. Further profiling of the cross-neutralization activity should address the antivenomic basis using purified toxin-based assays. PMID- 25690692 TI - Identification and quantification of fumonisin A1, A2, and A3 in corn by high resolution liquid chromatography-orbitrap mass spectrometry. AB - Three compounds, hypothesized as fumonisin A1 (FA1), fumonisin A2 (FA2), and fumonisin A3 (FA3), were detected in a corn sample contaminated with mycotoxins by high-resolution liquid chromatography-Orbitrap mass spectrometry (LC-Orbitrap MS). One of them has been identified as FA1 synthesized by the acetylation of fumonisin B1 (FB1), and established a method for its quantification. Herein, we identified the two remaining compounds as FA2 and FA3, which were acetylated fumonisin B2 (FB2) and fumonisin B3 (FB3), respectively. Moreover, we examined a method for the simultaneous analysis of FA1, FA2, FA3, FB1, FB2, and FB3. The corn samples were prepared by extraction using a QuEChERS kit and purification using a multifunctional cartridge. The linearity, recovery, repeatability, limit of detection, and limit of quantification of the method were >0.99, 82.9%-104.6%, 3.7%-9.5%, 0.02-0.60 MUg/kg, and 0.05-1.98 MUg/kg, respectively. The simultaneous analysis of the six fumonisins revealed that FA1, FA2, and FA3 were present in all corn samples contaminated with FB1, FB2, and FB3. The results suggested that corn marketed for consumption can be considered as being contaminated with both the fumonisin B-series and with fumonisin A-series. This report presents the first identification and quantification of FA1, FA2, and FA3 in corn samples. PMID- 25690693 TI - Dual effects exerted in vitro by micromolar concentrations of deoxynivalenol on undifferentiated caco-2 cells. AB - Contamination of crops used for food and feed production with Fusarium mycotoxins, such as deoxynivalenol (DON), raise important health and economic issues all along the food chain. Acute exposure to high DON concentrations can alter the intestinal barrier, while chronic exposure to lower doses may exert more subtle effects on signal transduction pathways, leading to disturbances in cellular homeostasis. Using real-time cellular impedance measurements, we studied the effects exerted in vitro by low concentrations of DON (0.37-1.50 MUM), relevant for mycotoxin-contaminated food, on the proliferation of undifferentiated Caco-2 cells presenting a tumorigenic phenotype. A 1.5 MUM concentration of DON maintained cell adherence of non-proliferating Caco-2 cells, whilst arresting the growth of actively proliferating cells compared with control Caco-2 cells in vitro. At 0.37 MUM, DON enhanced Caco-2 cell metabolism, thereby triggering a moderate increase in cell proliferation. The results of the current study suggested that low concentrations of DON commonly detected in food may either limit or sustain the proliferation of colon cancer cells, depending on their proliferation status and on DON concentration. Soluble factors released by Lactobacillus strains can partially counteract the inhibitory action of DON on actively proliferating colon cancer cells. The study also emphasized that real time cellular impedance measurements were a valuable tool for investigating the dynamics of cellular responses to xenobiotics. PMID- 25690694 TI - Altered gene expression profiles of wheat genotypes against Fusarium head blight. AB - Fusarium graminearum is responsible for Fusarium head blight (FHB), which is a destructive disease of wheat that makes its quality unsuitable for end use. To understand the temporal molecular response against this pathogen, microarray gene expression analysis was carried out at two time points on three wheat genotypes, the spikes of which were infected by Fusarium graminearum. The greatest number of genes was upregulated in Nobeokabouzu-komugi followed by Sumai 3, whereas the minimum expression in Gamenya was at three days after inoculation (dai). In Nobeokabouzu-komugi, high expression of detoxification genes, such as multidrug resistant protein, multidrug resistance-associated protein, UDP glycosyltransferase and ABC transporters, in addition to systemic defense-related genes, were identified at the early stage of infection. This early response of the highly-resistant genotype implies a different resistance response from the other resistant genotype, Sumai 3, primarily containing local defense-related genes, such as cell wall defense genes. In Gamenya, the expression of all three functional groups was minimal. The differences in these molecular responses with respect to the time points confirmed the variation in the genotypes. For the first time, we report the nature of gene expression in the FHB-highly resistant cv. Nobeokabouzu-komugi during the disease establishment stage and the possible underlying molecular response. PMID- 25690695 TI - DXD motif-dependent and -independent effects of the chlamydia trachomatis cytotoxin CT166. AB - The Gram-negative, intracellular bacterium Chlamydia trachomatis causes acute and chronic urogenital tract infection, potentially leading to infertility and ectopic pregnancy. The only partially characterized cytotoxin CT166 of serovar D exhibits a DXD motif, which is important for the enzymatic activity of many bacterial and mammalian type A glycosyltransferases, leading to the hypothesis that CT166 possess glycosyltransferase activity. CT166-expressing HeLa cells exhibit actin reorganization, including cell rounding, which has been attributed to the inhibition of the Rho-GTPases Rac/Cdc42. Exploiting the glycosylation sensitive Ras(27H5) antibody, we here show that CT166 induces an epitope change in Ras, resulting in inhibited ERK and PI3K signaling and delayed cell cycle progression. Consistent with the hypothesis that these effects strictly depend on the DXD motif, CT166 with the mutated DXD motif causes neither Ras-ERK inhibition nor delayed cell cycle progression. In contrast, CT166 with the mutated DXD motif is still capable of inhibiting cell migration, suggesting that CT166 with the mutated DXD motif cannot be regarded as inactive in any case. Taken together, CT166 affects various fundamental cellular processes, strongly suggesting its importance for the intracellular survival of chlamydia. PMID- 25690696 TI - Risk factors for negative impacts on sexual activity and function in younger breast cancer survivors. AB - OBJECTIVE: We aim to examine changes in sexual activity and function among younger breast cancer survivors who were sexually active before diagnosis and to investigate risk factors for negative impacts on them. METHODS: An observational cohort study enrolled 304 premenopausal and sexually active women diagnosed with early stage breast cancer. Questionnaires were completed, and sexual activity was measured at two time points: after surgery, to assess sexual activity and function before diagnosis, and then at least 12 months after the completion of chemotherapy or endocrine therapy. For each domain of the Female Sexual Function Index, a score below 3 was classified as indicative of a sexual problem. Each sexual problem was considered to be dysfunctional if it was associated with distress. RESULTS: The median age at the last survey was 46.0 years (range: 23 57). Of the participants, 35 (11.5%) became sexually inactive after treatment. Among the 269 women who remained sexually active, 31.6% were currently experiencing sexual dysfunction, which was significantly higher compared with the frequency before diagnosis. In the multivariate logistic regression model, chemo related menopause, thyroid dysfunction, and depression were independent risk factors for sexual inactivity. Chemo-related menopause was a significant risk factor for sexual dysfunction. CONCLUSIONS: Chemo-related menopause was significantly associated with both sexual inactivity and dysfunction after treatment. Thyroid dysfunction and depression were risk factors for sexual inactivity in younger breast cancer survivors. PMID- 25690697 TI - Bone health and coronary artery calcification: The Rotterdam Study. AB - OBJECTIVES: Vascular calcification has been associated inconsistently to low bone mineral density and fractures. The aims of the present study were to investigate the associations between coronary artery calcification (CAC) and BMD change, BMD and fracture risk in elderly subjects of the population-based Rotterdam Study. METHODS: BMD was assessed through dual-energy X-ray absorptiometry and CAC through Electron-Beam Computed Tomography in 582 men and 694 women. We investigated the associations between BMD change (6.4 years follow-up) and CAC at follow-up and between BMD and CAC (measured simultaneously). In sensitivity analyses we stratified analyses for estradiol levels in women. The association between CAC and fracture risk (9 years follow-up) was tested through competing risks models. Models were sex-stratified and adjusted for age, body mass index, smoking, bisphosphonate use and age at menopause. RESULTS: There was no association between BMD change and CAC in men. In women, each 1% increase in annual BMD loss was significantly associated with higher follow-up CAC [beta = 0.22 (0.06-0.38), p=0.006; prevalence ratio: 4%]. Stratified analyses showed significant associations between BMD loss and follow-up CAC only in women with lower estradiol levels. We found no association between CAC and fracture risk and no association between BMD and CAC cross-sectionally. CONCLUSIONS: BMD loss was associated with higher follow-up CAC in women, which might be related to low estrogen levels. No association between CAC and BMD or fracture risk was found. Further studies are required to elucidate the mechanisms that might underlie the association between BMD change and coronary calcification in women. PMID- 25690698 TI - Rigidity of poly-L-glutamic acid scaffolds: Influence of secondary and supramolecular structure. AB - Poly-l-glutamic acid (PGA) is a widely used biomaterial, with applications ranging from drug delivery and biological glues to food products and as a tissue engineering scaffold. A biodegradable material with flexible conjugation functional groups, tunable secondary structure, and mechanical properties, PGA has potential as a tunable matrix material in mechanobiology. Recent studies in proteins connecting dynamics, nanometer length scale rigidity, and secondary structure suggest a new point of view from which to analyze and develop this promising material. We have characterized the structure, topology, and rigidity properties of PGA prepared with different molecular weights and secondary structures through various techniques including scanning electron microscopy, FTIR, light, and neutron scattering spectroscopy. On the length scale of a few nanometers, rigidity is determined by hydrogen bonding interactions in the presence of neutral species and by electrostatic interactions when the polypeptide is negatively charged. When probed over hundreds of nanometers, the rigidity of these materials is modified by long range intermolecular interactions that are introduced by the supramolecular structure. PMID- 25690699 TI - Local and distant acupuncture points stimulation for chronic musculoskeletal pain: A systematic review on the comparative effects. AB - One in four people suffers from chronic musculoskeletal pain (CMP). Acupuncture points stimulation is increasingly used for pain relief for CMP. Commonly, a combination of local and distant points is used. However, the difference between the effects of local and distant point stimulation is unknown. This systematic review aimed to determine if there was a difference in effects between stimulating local and distant points, and the combination of both when compared with either alone. English and Chinese electronic databases were searched to identify randomized controlled trials, where local or distant points were stimulated in adults with CMP. Pain intensity was the primary outcome measure. Nineteen were included in the qualitative analysis and 15 in the meta-analysis. Local and distant point stimulation was more effective than their respective controls in pain reduction immediately after treatment. Three studies directly compared the stimulation of local and distant points and found no significant difference between the two. No studies compared combined local and distant point stimulation with either alone. Subgroup analyses showed that, local tender point stimulation was more effective than local acupuncture points. Local and distant point stimulation induces similar degree of acupuncture analgesia. The benefit of combining local and distant point stimulation is unknown. However, subgroup analyses suggested that local tender points could be important in the treatment of CMP for short-term pain relief. PMID- 25690700 TI - No evidence that sex and transposable elements drive genome size variation in evening primroses. AB - Genome size varies dramatically across species, but despite an abundance of attention there is little agreement on the relative contributions of selective and neutral processes in governing this variation. The rate of sex can potentially play an important role in genome size evolution because of its effect on the efficacy of selection and transmission of transposable elements (TEs). Here, we used a phylogenetic comparative approach and whole genome sequencing to investigate the contribution of sex and TE content to genome size variation in the evening primrose (Oenothera) genus. We determined genome size using flow cytometry for 30 species that vary in genetic system and find that variation in sexual/asexual reproduction cannot explain the almost twofold variation in genome size. Moreover, using whole genome sequences of three species of varying genome sizes and reproductive system, we found that genome size was not associated with TE abundance; instead the larger genomes had a higher abundance of simple sequence repeats. Although it has long been clear that sexual reproduction may affect various aspects of genome evolution in general and TE evolution in particular, it does not appear to have played a major role in genome size evolution in the evening primroses. PMID- 25690701 TI - Theoretical examination of solvent and R group dependence in gold thiolate nanoparticle synthesis. AB - The growth of gold thiolate nanoparticles can be affected by the solvent and the R group on the ligand. In this work, the difference between methanol and benzene solvents as well as the effect of alkyl (methyl) and aromatic (phenyl) thiols on the reaction energies and barrier heights is investigated theoretically. Density functional theory (DFT) calculations using the BP86 functional and a triple zeta polarized basis set show that the overall reaction favors methylthiol over phenylthiol with reaction energies of -0.54 and -0.39 eV in methanol, respectively. At the same level of theory, the methanol solvent is favored over the benzene solvent for reactions forming ions; in benzene, the overall reaction energies for methylthiol and phenylthiol reacting with AuCl4(-) to form Au(HSR)2(+) are 0.37 eV and 0.44 eV, respectively. Methylthiol in methanol also has the lowest barrier heights at about 0.3 eV, whereas phenylthiol has barrier heights around 0.4 eV. Barrier heights in benzene are significantly larger than those in methanol. PMID- 25690702 TI - The Feasibility and Clinical Utility of Microsphere Contrast-enhanced Transthoracic Echocardiography in Adult Congenital Heart Disease. AB - BACKGROUND: Transthoracic echocardiography (TTE) plays a key role in adult congenital heart disease (ACHD). However, a significant number of studies are nondiagnostic due to poor image quality. Enhancement of the blood pool-tissue interface with contrast-enhanced TTE (CE-TTE) can improve image quality in suboptimal studies. The aim of this analysis was to evaluate feasibility and clinical utility of CE-TTE in the assessment of patients with ACHD. METHODS: A retrospective analysis of all CE-TTE performed in ACHD patients at our institution from August 2007 to May 2014 was performed. Endocardial definition scores (EDS) for each segment in the right and left ventricles were graded pre- and postcontrast imaging, as 1 = good, 2 = suboptimal, 3 = not seen. The endocardial border definition score index (EBDSI) was also calculated pre- and postcontrast imaging. RESULTS: Twenty patients with ACHD had 24 CE. Summation data for all ventricular EDS for unenhanced TTE vs. CE-TTE imaging was: EDS 1 = 136 vs. 314, EDS 2 = 119 vs. 72, EDS 3 = 162 vs. 31, respectively. Wilcoxon matched-pairs rank-signed test showed a significant ranking difference (improvement) pre- and postcontrast for the combined ventricular data (P < .0001) and the individual left and right ventricular data (all P < .0001). The EBDSI for combined ventricular data using CE-TTE was significantly lower than for noncontrast imaging (1.23 +/- 0.49 vs. 2.06 +/- 0.62, P < .0001). There was one minor contrast adverse reaction. CONCLUSIONS: CE-TTE resulted in significantly improved right and left ventricular endocardial definition and improved EDBSI. CE TTE should be viewed as an additional imaging technique that is available to help assess patients with ACHD, especially those with nondiagnostic images. PMID- 25690703 TI - Molecular self-recognition: a chiral [Mn(II)6] wheel via donor-acceptor pi...pi contacts and H-bonds. AB - A multinucleating ligand capable of establishing different types of intermolecular interactions, when combined with acetate groups leads to the assembly of a chiral [Mn(II)3] cluster poised for a process of self-recognition through a combination of perfectly complementary weak forces. PMID- 25690704 TI - Gastrointestinal Crohn-like disease following BCG therapy. PMID- 25690705 TI - A case of appendectomy as main therapeutic intervention for complex co-morbid ulcerative proctitis. PMID- 25690706 TI - Sigmoid volvulus is associated with a decrease in enteric plexuses and ganglion cells: a case-control study. AB - PURPOSE: Although sigmoid volvulus (SV) causes acute obstruction, its pathogenesis and mechanism of torsion are unknown, and few reports have described its pathological findings. Here, we evaluated the clinicopathological characteristics of volvulus and factors contributing to volvulus of the sigmoid colon. METHODS: We compared 14 patients with SV (10 men and 4 women; median age, 78.5 years) with 14 age- and sex-matched control patients for differences in clinical characteristics, focusing on dysmotility (enteric visceral myopathy, neuropathy, and mesenchymopathy). RESULTS: Of the 14 SV patients, 7 had recurrent volvulus, 11 had an associated condition, and 5 required emergency surgery. Atrophy and fibrosis of the inner muscle were more prevalent in the SV than control patients (p = 0.041). Median extent (per centimeter of muscularis propria) of the myenteric plexus (12.5 versus 17.5, p < 0.001) and submucous plexus (15.0 versus 25.5, p < 0.001) was lower in the SV patients, as were the median numbers of myenteric (9.7 versus 30.4, p < 0.001) and submucous ganglion cells (10.0 versus 23.2, p < 0.001). Inflammatory neuropathy was more prevalent in the SV than control patients (p = 0.046); whereas, the prevalence of mesenchymopathy did not differ (p = 0.481). CONCLUSIONS: A decrease in the extent of enteric plexus and ganglion cells precedes the clinical manifestation of SV. Although further elucidation is needed, this decrease may play an important role in the diagnosis of SV and in identifying the mechanism leading to torsion in SV. PMID- 25690708 TI - Incidental physiological sliding hiatal hernia: a single center comparison study between CT with water enema and CT colonography. AB - PURPOSE: Hiatal hernia is a well-known factor impacting on most mechanisms underlying gastroesophageal reflux, related with the risk of developing complications such as erosive esophagitis, Barrett's esophagus and ultimately, esophageal adenocarcinoma. It is our firm opinion that an erroneous reporting of hiatal hernia in CT exams performed with colonic distention may trigger a consecutive diagnostic process that is not only unnecessary, inducing a unmotivated anxiety in the patient, but also expensive and time-consuming for both the patient and the healthcare system. The purposes of our study were to determine whether colonic distention at CT with water enema and CT colonography can induce small sliding hiatal hernias and to detect whether hiatal hernias size modifications could be considered significant for both water and gas distention techniques. METHODS: We retrospectively evaluated 400 consecutive patients, 200 undergoing CT-WE and 200 undergoing CTC, including 59 subjects who also underwent a routine abdominal CT evaluation on a different time, used as internal control, while a separate group of 200 consecutive patients who underwent abdominal CT evaluation was used as external control. Two abdominal radiologists assessed the CT exams for the presence of a sliding hiatal hernia, grading the size as small, moderate, or large; the internal control groups were directly compared with the corresponding CT-WE or CTC study looking for a change in hernia size. We used the Student's t test applying a size-specific correction factor, in order to account for the effect of colonic distention: these "corrected" values were then individually compared with the external control group. RESULTS: A sliding hiatal hernia was present in 51 % (102/200) of the CT-WE patients and in 48.5 % (97/200) of the CTC patients. Internal control CT of the 31 patients with a hernia at CT WE showed resolution of the hernia in 58.1 % (18/31) of patients, including 76.5 % (13/17) and 45.5 % (5/11) of small and moderate hernias. Comparison CT of the 28 patients with a hiatal hernia at CTC showed the absence of the hernia in 57.1 % (16/28) patients, including 68.8 % (11/16) and 50 % (5/10) of small and moderate hernias. The prevalence of sliding hiatal hernias in the external control group was 22 % (44/200), significantly lower than the CT-WE and CTC cohorts' prevalence of 51 % (p < 0.0001) and 48.5 % (p < 0.0001). After applying the correction factors for the CT-WE and the CTC groups, the estimated residual prevalences (16 and 18.5 %, respectively) were much closer to that of the external control patients (p = 0.160 for CT-WE and p = 0.455 for CTC). CONCLUSIONS: We believe that incidental findings at CT-WE and CTC should be considered according to the clinical background, and that small sliding hiatal hernias should not be reported in patients with symptoms not related to reflux disease undergoing CT-WE or CTC: When encountering these findings, accurate anamnesis and review of medical history looking for GERD-related symptoms are essential, in order to address these patients to a correct diagnostic iter, taking advantage from more appropriate techniques such as endoscopy or functional techniques. PMID- 25690707 TI - Role of Rab GTPases and their interacting proteins in mediating metabolic signalling and regulation. AB - The vesicular transport pathways, which shuttle materials to and from the cell surface and within the cell, and the metabolic (growth factor and nutrient) signalling pathways, which integrate a variety of extracellular and intracellular signals to mediate growth, proliferation or survival, are both important for cellular physiology. There is evidence to suggest that the transport and metabolic signalling pathways intersect-vesicular transport can affect the regulation of metabolic signals and vice versa. The Rab family GTPases regulate the specificity of vesicular transport steps in the cell. Together with their interacting proteins, Rabs would likely constitute the points of intersection between vesicular transport and metabolic signalling pathways. Examples of these points would include growth factor signalling, glucose and lipid metabolism, as well as autophagy. Many of these processes involve mechanistic/mammalian target of rapamycin (mTOR) complex 1 (mTORC1) in downstream cascades, or are regulated by TORC signalling. A general functionality of the vesicular transport processes controlled by the Rabs is also important for spatial and temporal regulation of the transmission of metabolic signals between the cell surface and the nucleus. In other cases, specific Rabs and their interacting proteins are known to function in recruiting metabolism-related proteins to target membranes, or may compete with other factors in the TORC signalling pathway as a means of metabolic regulation. We review and discuss herein examples of how Rabs and their interacting proteins can mediate metabolic signalling and regulation in cells. PMID- 25690709 TI - Role of post-mortem computed tomography (PMCT) in the assessment of the challenging diagnosis of pericardial tamponade as cause of death in cases with hemopericardium. AB - OBJECTIVES: When hemopericardium (HP) is found at autopsy, it represents a challenge for the forensic pathologist when having to assess its role in causing death. In fact, a proper diagnosis of pericardial tamponade (PT) must be based on clinical and instrumental data, which are not often available at post-mortem investigation. The aim of this study was to individuate post-mortem (PMCT) findings indicative for the diagnosis of PT. MATERIALS AND METHODS: We revised PMCT images and autopsy reports of 14 cases with fatal HP and intact pericardium. From autopsy reports, we obtained volume and cause of HP. PMCT images were reviewed to describe appearance of HP and the presence of indirect signs of increased intrapericardial pressure. A control group of 11 cases submitted to PMCT prior to autopsy was selected with the following criteria: absence of relevant pericardial effusion, venous system congestion and bleeding. RESULTS: Of the 14 PT subjects, 13 had a double-concentric stratification of HP and compression of the coronary sinus and/or of the pulmonary trunk, all showing a flattening of the anterior surface of the heart; other findings indicative of venous system congestion were variably observed. In the control group, none of these findings was identified, with the exception of a distended or non completely collapsed superior vena cava (11/11 cases). CONCLUSIONS: PMCT is able to provide some findings indicative of PT. Based on this evidence, in other instances HP could be judged circumstantial rather than fatal. This study suggests the possibility to use PMCT findings to retrospectively demonstrate a clinical condition, such as PT. PMID- 25690710 TI - Reproducibility of retrobulbar blood flow velocity measurements in normal subjects using two different CDI devices. AB - PURPOSE: This study was done to evaluate the intra- and inter-operator reproducibility of colour Doppler imaging (CDI) in assessing blood flow velocity in the ophthalmic (OA), central retinal (CRA) and short posterior ciliary arteries (SPCA) in healthy subjects. MATERIALS AND METHODS: The right eye of two groups of eight healthy volunteers was examined. Two radiologists and two ophthalmologists, divided into pairs, measured peak systolic velocity (PSV), end diastolic velocity (EDV) and resistivity index (RI) of each vessel using a different CDI device for each group. The concordance between two measurements was evaluated with Lin's concordance correlation coefficient (CCC). RESULTS: Globally, very good degrees of intra-operator concordance were obtained for the PSV (0.859 cm/s), EDV (0.834 cm/s) and RI (0.859) of the OA. There was moderate concordance for PSV (0.574 cm/s) and EDV (0.594 cm/s) and good concordance for RI (0.694) for the CRA. Good degrees of concordance were obtained for the SPCA measurements. However, inter-operator concordance was found globally poor. CONCLUSIONS: These data show that CDI measurements in retrobulbar vessels are operator dependent. To increase the intra-operator and inter-operator concordance, rules should be adopted for timing of the examination and positioning of the probe to minimise the pressure applied on the eye. PMID- 25690711 TI - A new human leukocyte antigen class II allele, DRB1*09:12. AB - HLA-DRB1*09:12 allele differs from HLA-DRB1*09:01:02 by a single nucleotide substitution at codon 41 (AAG -> AAC). PMID- 25690712 TI - Individual-level niche specialization within populations: emerging areas of study. PMID- 25690713 TI - Dietary magnesium deficiency alters gut microbiota and leads to depressive-like behaviour. AB - OBJECTIVE: Gut microbiota (GM) has previously been associated with alterations in rodent behaviour, and since the GM is affected by the diet, the composition of the diet may be an important factor contributing to behavioural changes. Interestingly, a magnesium restricted diet has been shown to induce anxiety and depressive-like behaviour in humans and rodents, and it could be suggested that magnesium deficiency may mediate the effects through an altered GM. METHODS: The present study therefore fed C57BL/6 mice with a standard diet or a magnesium deficient diet (MgD) for 6 weeks, followed by behavioural testing in the forced swim test (FST) to evaluate depressive-like behaviour. An intraperitoneal glucose tolerance test (GTT) was performed 2 day after the FST to assess metabolic alterations. Neuroinflammatory markers were analysed from hippocampus. GM composition was analysed and correlated to the behaviour and hippocampal markers. RESULTS: It was found that mice exposed to MgD for 6 weeks were more immobile than control mice in the FST, suggesting an increased depressive-like behaviour. No significant difference was detected in the GTT. GM composition correlated positively with the behaviour of undisturbed C57BL/6 mice, feeding MgD diet altered the microbial composition. The altered GM correlated positively to the hippocampal interleukin-6. CONCLUSION: In conclusion, we hypothesise that imbalances of the microbiota-gut-brain axis induced by consuming a MgD diet, contributes to the development of depressive-like behaviour. PMID- 25690714 TI - Transient abdominal motor block after a transversus abdominis plane block in an elderly patient. PMID- 25690715 TI - Identification and mapping of quantitative trait loci (QTL) conferring resistance to Fusarium graminearum from soybean PI 567301B. AB - KEY MESSAGE: A major novel QTL was identified in a recombinant inbred line population derived from a cross of 'Wyandot' * PI 567301B for Fusarium graminearum, a seed and seedling pathogen of soybean. Fusarium graminearum is now recognized as a primary pathogen of soybean, causing root, seed rot and seedling damping-off in North America. In a preliminary screen, 'Wyandot' and PI 567301B were identified with medium and high levels of partial resistance to F. graminearum, respectively. The objective of this study was to characterise resistance towards F. graminearum using 184 recombinant inbred lines (RILs) derived from a cross of 'Wyandot' * PI 567301B. The parents and the RILs of the mapping population were evaluated for resistance towards F. graminearum using the rolled towel assay in a randomized incomplete block design. A genetic map was constructed from 2545 SNP markers and 2 SSR markers by composite interval mapping. One major and one minor QTL were identified on chromosomes 8 and 6, respectively, which explained 38.5 and 8.1 % of the phenotypic variance. The major QTL on chromosome 8 was mapped to a 300 kb size genomic region of the Williams 82 sequence. Annotation of this region indicates that there are 39 genes including the Rhg4 locus for soybean cyst nematode (SCN) resistance. Based on previous screens, PI 567301B is susceptible to SCN. Fine mapping of this locus will assist in cloning these candidate genes as well as identifying DNA markers flanking the QTL that can be used in marker-assisted breeding to develop cultivars with high levels of resistance to F. graminearum. PMID- 25690716 TI - Genome-wide association analysis reveals new targets for carotenoid biofortification in maize. AB - KEY MESSAGE: Genome-wide association analysis in CIMMYT's association panel revealed new favorable native genomic variations in/nearby important genes such as hydroxylases and CCD1 that have potential for carotenoid biofortification in maize. Genome-wide association studies (GWAS) have been used extensively to identify allelic variation for genes controlling important agronomic and nutritional traits in plants. Provitamin A (proVA) enhancing alleles of lycopene epsilon cyclase (LCYE) and beta-carotene hydroxylase 1 (CRTRB1), previously identified through candidate-gene based GWAS, are currently used in CIMMYT's maize breeding program. The objective of this study was to identify genes or genomic regions controlling variation for carotenoid concentrations in grain for CIMMYT's carotenoid association mapping panel of 380 inbred maize lines, using high-density genome-wide platforms with ~476,000 SNP markers. Population structure effects were minimized by adjustments using principal components and kinship matrix with mixed models. Genome-wide linkage disequilibrium (LD) analysis indicated faster LD decay (3.9 kb; r (2) = 0.1) than commonly reported for temperate germplasm, and therefore the possibility of achieving higher mapping resolution with our mostly tropical diversity panel. GWAS for various carotenoids identified CRTRB1, LCYE and other key genes or genomic regions that govern rate-critical steps in the upstream pathway, such as DXS1, GGPS1, and GGPS2 that are known to play important roles in the accumulation of precursor isoprenoids as well as downstream genes HYD5, CCD1, and ZEP1, which are involved in hydroxylation and carotenoid degradation. SNPs at or near all of these regions were identified and may be useful target regions for carotenoid biofortification breeding efforts in maize; for example a genomic region on chromosome 2 explained ~16% of the phenotypic variance for beta-carotene independently of CRTRB1, and a variant of CCD1 that resulted in reduced beta-cryptoxanthin degradation was found in lines that have previously been observed to have low proVA degradation rates. PMID- 25690717 TI - Disruption of a CAROTENOID CLEAVAGE DIOXYGENASE 4 gene converts flower colour from white to yellow in Brassica species. AB - In Brassica napus, yellow petals had a much higher content of carotenoids than white petals present in a small number of lines, with violaxanthin identified as the major carotenoid compound in yellow petals of rapeseed lines. Using positional cloning we identified a carotenoid cleavage dioxygenase 4 gene, BnaC3.CCD4, responsible for the formation of flower colour, with preferential expression in petals of white-flowered B. napus lines. Insertion of a CACTA-like transposable element 1 (TE1) into the coding region of BnaC3.CCD4 had disrupted its expression in yellow-flowered rapeseed lines. alpha-Ionone was identified as the major volatile apocarotenoid released from white petals but not from yellow petals. We speculate that BnaC3.CCD4 may use delta- and/or alpha-carotene as substrates. Four variations, including two CACTA-like TEs (alleles M1 and M4) and two insertion/deletions (INDELs, alleles M2 and M3), were identified in yellow flowered Brassica oleracea lines. The two CACTA-like TEs were also identified in the coding region of BcaC3.CCD4 in Brassica carinata. However, the two INDELs were not detected in B. napus and B. carinata. We demonstrate that the insertions of TEs in BolC3.CCD4 predated the formation of the two allotetraploids. PMID- 25690718 TI - Selenium in Gluten-free Products. AB - The nutritional value of gluten-free products is the subject of interest for food technologists and nutritionists, as the only effective treatment for celiac disease is a lifelong gluten-free diet. As selenium deficiencies in celiac disease are observed, the aim of the study was to determine the selenium content in 27 grain gluten-free products available on the European Union (EU) market. Moreover, selenium content in products based on popular gluten-free cereals like corn, rice, and buckwheat and in relatively new or less popular products based on oat, amaranth, teff, and quinoa was compared. Selenium content in the tested products ranged from 0.9 to 24.5 MUg/100 g. The average content of selenium in products based on popular gluten-free cereals was 2.8 MUg/100 g and in products based on oat, amaranth, teff, and quinoa was 10.8 MUg/100 g. It indicates that products based on less popular grains, especially on oat, should be more frequently chosen as a source of selenium by people on gluten-free diet than traditionally consumed gluten-free grains. PMID- 25690720 TI - Pigmented globules in dermoscopy as a clue for lentigomaligna mimicking non melanocytic skin neoplasms: a lesson from reflectance confocal microscopy. PMID- 25690722 TI - Response to "In vivo attenuation and genetic evolution of a ST247-SCCmecI MRSA clone after 13 years of pathogenic bronchopulmonary colonization in a patient with cystic fibrosis: implications of the innate immune response". PMID- 25690721 TI - Cellular senescence: a hitchhiker's guide. AB - Since its first description over 50 years ago, cellular senescence has gained increasing attention. The number of research publications on cellular senescence last year alone is more than the number of publications in the decade in 1990s. Laboratories solely studying senescence, scientific conferences and organisations dedicated to field of cellular senescence are also on the rise. These not only indicate the growing interest in this field but also highlight the importance of cellular senescence in cell biology from yeast to human. Cellular senescence is implicated in normal ageing, tumour suppression, tumourigenesis, chronic diseases and more recently, in embryogenesis. Thus, understanding senescence is crucial for the understanding of organismal biology. In addition, understanding of cellular senescence will be invaluable in the development of therapeutic targets in the fight against age-related comorbidities, cancer and chronic disease progression. PMID- 25690723 TI - Photoinduced formation of stable Ag-nanoparticles from a ternary ligand-DNA-Ag(+) complex. AB - The combination of (i) the light-harvesting nature and excited-state redox reactivity of a cationic DNA intercalator, (ii) a conjugated Ag(+)-binding crown ether, and (iii) the stabilizing effect of DNA on AgNPs in one integral ternary complex enables the mild photoinduced formation of Ag nanoparticles. PMID- 25690724 TI - A comparison of inpatient glucose management guidelines: implications for patient safety and quality. AB - Inpatient glucose management guidelines and consensus statements play an important role in helping to keep hospitalized patients with diabetes and hyperglycemia safe and in optimizing the quality of their glycemic control. In this review article, we compare and contrast seven prominent US guidelines on recommended glycemic outcome measures and processes of care, with the goal of highlighting how variation among them might influence patient safety and quality. The outcome measures of interest include definitions of glucose abnormalities and glycemic targets. The relevant process measures include detection and documentation of diabetes/hyperglycemia, methods of and indications for insulin therapy, management of non-insulin agents, blood glucose monitoring, management of special situations (e.g., parenteral/enteral nutrition, glucocorticoids, surgery, insulin pumps), and appropriate transitions of care. In addition, we address elements of quality improvement, such as glycemic control program infrastructure, glucometrics, insulin safety, and professional education. While most of these guidelines align with respect to outcome measures such as glycemic targets, there is significant heterogeneity among process measures, which we propose might introduce variation or even confusion in clinical practice and possibly affect quality of care. Guideline-related factors, such as rigor of development, clarity, and presentation, may also affect provider trust in and adherence to guidelines. There is a need for high-quality research to address knowledge gaps in optimal glucose management practice approaches in the hospital setting. PMID- 25690725 TI - Toxic epidermal necrolysis triggered by clobazam: a case report in a 13-year-old girl. AB - We present a case of toxic epidermal necrolysis (TEN) triggered by clobazam in a 13-year-old girl who was subsequently treated with intravenous immunoglobulin. In December 2013 the U.S. Food and Drug Administration released a warning that clobazam might cause "serious skin reactions" such as Stevens-Johnson syndrome or TEN and approved label changes. PMID- 25690726 TI - Culturing fibroblasts in 3D human hair keratin hydrogels. AB - Human hair keratins are readily available, easy to extract, and eco-friendly materials with natural bioactivities. Keratin-based materials have been studied for applications such as cell culture substrates, internal hemostats for liver injury, and conduits for peripheral nerve repair. However, there are limited reports of using keratin-based 3D scaffolds for cell culture in vitro. Here, we describe the development of a 3D hair keratin hydrogel, which allows for living cell encapsulation under near physiological conditions. The convenience of making the hydrogels from keratin solutions in a simple and controllable manner is demonstrated, giving rise to constructs with tunable physical properties. This keratin hydrogel is comparable to collagen hydrogels in supporting the viability and proliferation of L929 murine fibroblasts. Notably, the keratin hydrogels contract less significantly as compared to the collagen hydrogels, over a 16-day culture period. In addition, preliminary in vivo studies in immunocompetent animals show mild acute host tissue response. These results collectively demonstrate the potential of cell-loaded keratin hydrogels as 3D cell culture systems, which may be developed for clinically relevant applications. PMID- 25690727 TI - Severe neonatal holocarboxylase synthetase deficiency in west african siblings. AB - In multiple carboxylase deficiency (MCD), the biotin-dependent carboxylases have decreased activity due to either biotinidase deficiency or holocarboxylase synthetase (HS) deficiency. We report the case of two siblings from Ghana, the first of which presented shortly after birth with profound lactic acidosis and a urine organic acid profile consistent with MCD. In the first sibling, treatment with pulverized biotin tablets (20 mg) was begun immediately, but the patient died at 10 days of age from cardiac arrest secondary to refractory metabolic acidosis. Autopsy revealed a biotin bezoar. Sequencing of HCLS showed homozygosity for a novel missense variant (p.G241W). The second sibling had a similar presentation at birth: severe metabolic acidosis and respiratory distress. A urine organic acid profile was consistent with HS deficiency; he was treated with biotin powder (20 mg), and after 24 h, the lactate decreased significantly; by day 5 of life, the patient was tolerating 40 mg of biotin, feeding by mouth and off all other medications and support. This is the first report of the p.G241W mutation. To our knowledge, this is also the first mutation described in West African patients with HS deficiency and the cases demonstrate that it is biotin responsive. Additionally, our experience suggests that the powdered form of biotin supplementation may be more digestible than tablets for the treatment of severe neonatal HS deficiency. PMID- 25690728 TI - Innate and Adaptive Immune Response in Fabry Disease. AB - Fabry disease is an X-linked lysosomal storage disease in which mutations of the gene (GLA) cause a deficiency of the lysosomal hydrolase alpha-galactosidase A (alpha-Gal). This defect results in an accumulation of glycosphingolipids, primarily globotriaosylceramide (Gb3) which causes a multisystemic vasculopathy. Available since 2001 in Europe, enzyme replacement therapy consists in the administration of agalsidase, a recombinant form of alpha-galactosidase A. Enzyme replacement therapy was shown to improve the global prognosis but allowed partial success in preventing critical events such as strokes and cardiac arrests. As in most lysosomal storage diseases, frequent immune reactions have been described in naive Fabry disease patients. Humoral immune responses following enzyme replacement therapy have also been described, with unclear consequences on the progression of the disease. While cost-effectiveness of enzyme replacement therapy in Fabry disease begins to be questioned and new therapeutic strategies arise such as chaperone or gene therapy, it appears necessary to better understand the immune responses observed in the treatment of naive patients and during enzyme replacement therapy with agalsidase. We propose a comprehensive review of the available literature concerning both innate and adaptive responses observed in Fabry disease. We particularly highlight the probable role of the toll-like receptor 4 (TLR4) and CD1d pathways triggered by Gb3 accumulation in the development of local and systemic inflammation that could lead to irreversible organ damages. We propose an immunological point of view of Fabry disease pathogenesis involving immune cells notably the invariant natural killer T cells. We finally review anti-agalsidase antibodies, their development and impact on outcomes. PMID- 25690729 TI - Evaluation of Implementation, Adaptation and Use of the Recently Proposed Urea Cycle Disorders Guidelines. AB - BACKGROUND: Implementation of guidelines and assessment of their adaptation is not an extensively investigated process in the field of rare diseases. However, whether targeted recipients are reached and willing and able to follow the recommendations has significant impact on the efficacy of guidelines. In 2012, a guideline for the management of urea cycle disorders (UCDs) has been published. We evaluate the efficacy of implementation, adaptation, and use of the UCD guidelines by applying different strategies. METHODS: (i) Download statistics from online sources were recorded. (ii) Facilities relevant for the implementation of the guidelines were assessed in pediatric units in Germany and Austria. (iii) The guidelines were evaluated by targeted recipients using the AGREE instrument. (iv) A regional networking-based implementation process was evaluated. RESULTS: (i) Download statistics revealed high access with an increase in downloads over time. (ii) In 18% of hospitals ammonia testing was not available 24/7, and emergency drugs were often not available. (iii) Recipient criticism expressed in the AGREE instrument focused on incomplete inclusion of patients' perspectives. (iv) The implementation process improved the availability of ammonia measurements and access to emergency medication, patient care processes, and cooperation between nonspecialists and specialists. CONCLUSION: Interest in the UCD guidelines is high and sustained, but more precise targeting of the guidelines is advisable. Surprisingly, many hospitals do not possess all facilities necessary to apply the guidelines. Regional network and awareness campaigns result in the improvement of both facilities and knowledge. PMID- 25690730 TI - NF-kappaB in cancer therapy. AB - The transcription factor nuclear factor kappa B (NF-kappaB) has attracted increasing attention in the field of cancer research from last few decades. Aberrant activation of this transcription factor is frequently encountered in a variety of solid tumors and hematological malignancies. NF-kappaB family members and their regulated genes have been linked to malignant transformation, tumor cell proliferation, survival, angiogenesis, invasion/metastasis, and therapeutic resistance. In this review, we highlight the diverse molecular mechanism(s) by which the NF-kappaB pathway is constitutively activated in different types of human cancers, and the potential role of various oncogenic genes regulated by this transcription factor in cancer development and progression. Additionally, various pharmacological approaches employed to target the deregulated NF-kappaB signaling pathway, and their possible therapeutic potential in cancer therapy is also discussed briefly. PMID- 25690731 TI - Compromised MAPK signaling in human diseases: an update. AB - The mitogen-activated protein kinases (MAPKs) in mammals include c-Jun NH2 terminal kinase (JNK), p38 MAPK, and extracellular signal-regulated kinase (ERK). These enzymes are serine-threonine protein kinases that regulate various cellular activities including proliferation, differentiation, apoptosis or survival, inflammation, and innate immunity. The compromised MAPK signaling pathways contribute to the pathology of diverse human diseases including cancer and neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. The JNK and p38 MAPK signaling pathways are activated by various types of cellular stress such as oxidative, genotoxic, and osmotic stress as well as by proinflammatory cytokines such as tumor necrosis factor-alpha and interleukin 1beta. The Ras-Raf-MEK-ERK signaling pathway plays a key role in cancer development through the stimulation of cell proliferation and metastasis. The p38 MAPK pathway contributes to neuroinflammation mediated by glial cells including microglia and astrocytes, and it has also been associated with anticancer drug resistance in colon and liver cancer. We here summarize recent research on the roles of MAPK signaling pathways in human diseases, with a focus on cancer and neurodegenerative conditions. PMID- 25690732 TI - Protective role of melatonin in mitochondrial dysfunction and related disorders. AB - Mitochondria are the powerhouse of the eukaryotic cell through their use of oxidative phosphorylation to generate ATP. Mitochondrial dysfunction is considered an important contributing factor in a variety of physiopathological situations such as aging, heart ischemia/reperfusion injury, diabetes and several neurodegenerative and cardiovascular diseases, as well as in cell death. Increased formation of reactive oxygen species, altered respiratory chain complexes activity and opening of the mitochondrial permeability transition pore have been suggested as possible factors responsible for impaired mitochondrial function. Therefore, preventing mitochondrial dysfunction could be an effective therapeutic strategy against cellular degenerative processes. Cardiolipin is a unique phospholipid located at the level of inner mitochondrial membrane where it plays an important role in mitochondrial bioenergetics, as well as in cell death. Cardiolipin abnormalities have been associated with mitochondrial dysfunction in a variety of pathological conditions and aging. Melatonin, the major secretory product of the pineal gland, is a well-known antioxidant agent and thus an effective protector of mitochondrial bioenergetic function. Melatonin was reported to prevent mitochondrial dysfunction from oxidative damage by preserving cardiolipin integrity, and this may explain, at least in part, the beneficial effect of this compound in mitochondrial physiopathology. In this article, mechanisms through which melatonin exerts its protective role in mitochondrial dysfunction and related disorders are reviewed. PMID- 25690733 TI - Cytotoxin-induced NADPH oxides activation: roles in regulation of cell death. AB - Numerous studies have shown that a variety of cytotoxic agents can activate the NADPH oxidase system and induce redox-dependent regulation of cellular functions. Cytotoxin-induced NADPH oxidase activation may either exert cytoprotective actions (e.g., survival, proliferation, and stress tolerance) or cause cell death. Here we summarize the experimental evidence showing the context-dependent dichotomous effects of NADPH oxidase on cell fate under cytotoxic stress conditions and the potential redox signaling mechanisms underlying this phenomenon. Clearly, it is difficult to create a unified paradigm on the toxicological implications of NADPH oxidase activation in response to cytotoxic stimuli. We suggest that interventional strategies targeting the NADPH oxidase system to prevent the adverse impacts of cytotoxins need to be contemplated in a stimuli- and cell type-specific manner. PMID- 25690734 TI - Circulating tumor cells in lung cancer: detection methods and clinical applications. AB - Circulating tumor cells (CTCs) are tumor cells that have disseminated from primary and metastatic sites, and circulate in the bloodstream. Advanced immunological and molecular-based methods can be used to detect and analyze the cells with the characteristics of tumor cells, and can be detected and analyzed in the blood of cancer patients. The most commonly used methods in lung cancer combine the processes of immunomagnetic enrichment and immunocytochemical detection, morphology-based enrichment coupled with reverse transcriptase polymerase chain reaction (RT-PCR), and RT-PCR alone. CTC analysis is considered a liquid biopsy approach for early diagnosis, risk stratification, evaluation of curative efficacy, and early detection of lung cancer relapse. In this review, we discuss the present techniques for analyzing CTCs, and the restrictions of using these methods in lung cancer. We also review the clinical studies in lung cancer and discuss the underlying associations between these studies and their future applications to this disease. PMID- 25690735 TI - Modulating Drug Release and Enhancing the Oral Bioavailability of Torcetrapib with Solid Lipid Dispersion Formulations. AB - The development of drug dispersions using solid lipids is a novel formulation strategy that can help address the challenges of poor drug solubility and systemic exposure after oral administration. The highly lipophilic and poorly water-soluble drug torcetrapib could be effectively formulated into solid lipid microparticles (SLMs) using an anti-solvent precipitation strategy. Acoustic milling was subsequently used to obtain solid lipid nanoparticles (SLNs). Torcetrapib was successfully incorporated into the lipid matrix in an amorphous state. Spherical SLMs with mean particle size of approximately 15-18 MUm were produced with high drug encapsulation efficiency (>96%) while SLNs were produced with a mean particle size of 155 nm and excellent colloidal stability. The in vitro drug release and the in vivo absorption of the solid lipid micro- and nanoparticles after oral dosing in rats were evaluated against conventional crystalline drug powders as well as a spray dried amorphous polymer dispersion formulation. Interestingly, the in vitro drug release rate from the lipid particles could be tuned for immediate or extended release by controlling either the particle size or the precipitation temperature used when forming the drug lipid particles. This change in the rate of drug release was manifested in vivo with changes in Tmax as well. In addition, in vivo pharmacokinetic studies revealed a significant increase (~6 to 11-fold) in oral bioavailability in rats dosed with the SLMs and SLNs compared to conventional drug powders. Importantly, this formulation approach can be performed rapidly on a small scale, making it ideal as a formulation technology for use early in the drug discovery timeframe. PMID- 25690736 TI - Evidence that the capacity of nongenotoxic carcinogens to induce oxidative stress is subject to marked variability. AB - Many drugs and environmental chemicals which are not directly mutagenic have the capacity to increase the incidence of tumors in the liver and other tissues. For this reason, such compounds are known as nongenotoxic carcinogens. The mechanisms underlying their effects remain unclear; however, their capacity to induce oxidative stress is considered to be a critical step in the carcinogenic process, although the evidence that this is actually the case remains equivocal and sparse. We have exploited a novel heme oxygenase-1 reporter mouse to evaluate the capacity of nongenotoxic carcinogens with different mechanisms of action to induce oxidative stress in the liver in vivo. When these compounds were administered at doses reported to cause liver tumors, marked differences in activation of the reporter were observed. 1,4-Dichlorobenzene and nafenopin were strong inducers of oxidative stress, whereas phenobarbital, piperonyl butoxide, cyproterone acetate, and WY14,643 were, at best, only very weak inducers. In the case of phenobarbital and thioacetamide, the number of LacZ-positive hepatocytes increased with time, and for the latter also with dose. The data obtained demonstrate that although some nongenotoxic carcinogens can induce oxidative stress, it is not a dominant feature of the response to these compounds. Therefore in contrast to the current models, these data suggest that oxidative stress is not a key determinant in the mechanism of nongenotoxic carcinogenesis but may contribute to the effects in a compound-specific manner. PMID- 25690737 TI - Comparative Localization and Functional Activity of the Main Hepatobiliary Transporters in HepaRG Cells and Primary Human Hepatocytes. AB - The role of hepatobiliary transporters in drug-induced liver injury remains poorly understood. Various in vivo and in vitro biological approaches are currently used for studying hepatic transporters; however, appropriate localization and functional activity of these transporters are essential for normal biliary flow and drug transport. Human hepatocytes (HHs) are considered as the most suitable in vitro cell model but erratic availability and inter-donor functional variations limit their use. In this work, we aimed to compare localization of influx and efflux transporters and their functional activity in differentiated human HepaRG hepatocytes with fresh HHs in conventional (CCHH) and sandwich (SCHH) cultures. All tested influx and efflux transporters were correctly localized to canalicular [bile salt export pump (BSEP), multidrug resistance-associated protein 2 (MRP2), multidrug resistance protein 1 (MDR1), and MDR3] or basolateral [Na(+)-taurocholate co-transporting polypeptide (NTCP) and MRP3] membrane domains and were functional in all models. Contrary to other transporters, NTCP and BSEP were less abundant and active in HepaRG cells, cellular uptake of taurocholate was 2.2- and 1.4-fold and bile excretion index 2.8- and 2.6-fold lower, than in SCHHs and CCHHs, respectively. However, when taurocholate canalicular efflux was evaluated in standard and divalent cation free conditions in buffers or cell lysates, the difference between the three models did not exceed 9.3%. Interestingly, cell imaging showed higher bile canaliculi contraction/relaxation activity in HepaRG hepatocytes and larger bile canaliculi networks in SCHHs. Altogether, our results bring new insights in mechanisms involved in bile acids accumulation and excretion in HHs and suggest that HepaRG cells represent a suitable model for studying hepatobiliary transporters and drug-induced cholestasis. PMID- 25690738 TI - Polymorphisms of the XRCC1 gene and breast cancer risk in the Mexican population. AB - The purpose of this case-control study was to evaluate the association of XRCC1 Arg194Trp and Arg399Gln polymorphisms with susceptibility to breast cancer (BC) in a Mexican population. We analysed DNA samples from 345 BC patients and 352 control subjects by polymerase chain reaction-restriction fragment length polymorphism. The frequency of the 399Gln allele was 23% in controls and 29% in patients [OR 1.38 (1.08-1.76); p = 0.01]; genotypes in controls were 60, 36, and 4% for Arg/Arg, Arg/Gln, and Gln/Gln, respectively, while in patients they were 53, 36, and 11% [OR 2.71 (1.44-5.10); p = 0.0015 for the Gln/Gln genotype]. Regarding the Arg194Trp polymorphism, the frequency of Trp allele was 15% in controls and 16% in patients [OR 1.09 (0.82-1.46); p = 0.54]; the genotype frequencies in controls were 74, 23, and 3% for Arg/Arg, Arg/Trp and Trp/Trp, respectively, while in patients these were 73, 23, and 4% [OR 1.41 (0.64-3.14); p = 0.39 for the Trp/Trp genotype]. Allele frequencies were consistent with Hardy Weinberg equilibrium (p = 0.20 for Arg194Trp and p = 0.54 for Arg399Gln). Our results indicate that the 399Gln polymorphism is associated with an increased risk of BC. Additionally, we found that some covariates increase the risk of BC in Mexican women; namely, antecedent of abortions [OR 3.69 (2.17-6.27); p < 0.001], not breastfeeding [OR 2.46 (1.45-4.18); p = 0.001], family history of BC [OR 15.9 (5.09-50.23); p < 0.001], other type of family cancer [OR 31.5 (12.5 79.3); p < 0.001], alcoholism [OR 17.7 (5.2-60.42); p < 0.001], type 2 diabetes mellitus [OR 2.28 (1.26-4.10); p = 0.007], and contraceptive use [OR 2.28 (1.26 4.10); p < 0.001]. PMID- 25690739 TI - Clinical comparison of two new minimally invasive techniques in the treatment of benign prostatic hyperplasia: TwisterTM Diode Laser System vs. BiVap (Richard Wolf(r)) saline vaporization of the prostate. AB - AIM: The aim of this study was to evaluate complications and postoperative follow up outcomes of the recently developing endoscopic techniques of BiVap (Richard Wolf(r)) and TwisterTM system in patients with benign prostatic obstruction (BPO). METHODS: Eighty patients treated with BiVap (Richard Wolf(r)) (N.=46) and TwisterTM system (N.=34) were included in the study. Operation, hospitalization and catheter removal time were noted. Postoperative complications including urinary tract infection, transient hematuria, severe dysuria, and fever >38 degrees C, urinary incontinence and urethral stricture were also noted. All patients were evaluated at the postoperative 1st, 3rd, 6th and 12th month and preoperative and postoperative values of IPSS score, QoL score, total PSA, IIEF 15, PVR, Qmax and Qave were compared. Statistical analyses were performed with SPSS version 18. A P-value<0.05 was considered significant. RESULTS: Mean age of the patients was 64.1 +/- 7.1 years. Significant improvement was observed for IPSS, Qmax, Qave, PVR, and QoL score by the postoperative first month compared to the preoperative values in both groups. In group 1 maximum improvement in the IPSS, Qmax, Qave, QoL score and PVR were achieved at postoperative 3, 3, 12, 3 and 12th months, respectively. In group 2 maximum improvement in the IPSS, Qmax, Qave, QoL score and PVR were achieved at postoperative 6, 3, 6, 6 and 3rd months, respectively. There was no significant difference between the two groups in terms of IPSS, Qmax, Qave, QoL, PSA, PVR, IIEF (Total), IIEF-EF, IIEF-IS, IIEF-OF, IIEF SD and IIEF-OS during the 1 year follow-up period. Total IIEF and subgroup scores improved to their preoperative levels by the postoperative 3rd month in both groups. CONCLUSION: Both BiVap (Richard Wolf(r)) and TwisterTM systems are safe and highly effective minimal invasive techniques, which can be used in the surgical treatment of BPO. PMID- 25690740 TI - A chemical approach for site-specific identification of NMR signals from protein side-chain NH3+ groups forming intermolecular ion pairs in protein-nucleic acid complexes. AB - Protein-nucleic acid interactions involve intermolecular ion pairs of protein side-chain and DNA or RNA phosphate groups. Using three protein-DNA complexes, we demonstrate that site-specific oxygen-to-sulfur substitution in phosphate groups allows for identification of NMR signals from the protein side-chain NH3 (+) groups forming the intermolecular ion pairs. A characteristic change in their (1)H and (15)N resonances upon this modification (i.e., substitution of phosphate to phosphorodithioate) can represent a signature of an intermolecular ion pair. Hydrogen-bond scalar coupling between protein side-chain (15)N and DNA phosphorodithiaote (31)P nuclei provides direct confirmation of the intermolecular ion pair. The same approach is likely applicable to protein-RNA complexes as well. PMID- 25690741 TI - Non-dipping nocturnal blood pressure and psychosis parameters in Parkinson disease. AB - BACKGROUND: Non-motor symptoms are increasingly recognized in Parkinson disease (PD) and include physical as well as psychological symptoms. A psychological condition that has been well studied in PD is psychosis. Cardiovascular autonomic dysfunction in PD can include a reversed or loss of blood pressure (BP) circadian rhythm, referred to as nocturnal non-dipping. The aim of this study was to determine the relationship between 24 h ambulatory blood pressure measurements (ABPM), i.e., absence or presence of nocturnal dipping, and psychosis scores in PD. METHODS: Twenty-one patiens with PD underwent 24 h ABPM using an autonomic protocol. A decrease in nocturnal mean arterial blood pressure of less than 10% was defined as non-dipping. Patients were interviewed (including the brief psychiatric rating scale; BPRS) for the assessment of psychosis. RESULTS: Eleven patients were dippers and 10 were non-dippers. BPRS scores were higher in non dippers, who, on average, met the criteria for psychosis (mean non-dipper BPRS: 34.3 +/- 7.3 vs mean dipper BPRS: 27.5 +/- 5.3; cutoff for "mildly ill" 31). There was a correlation between BPRS scores and non-dipping, indicating that those patients who had a blunted nocturnal fall in BP were more prone to psychotic symptoms (Pearson's Correlation = 0.554, p = 0.009). CONCLUSION: These results suggest that, among PD patients, a non-dipping circadian rhythm is associated with more severe symptoms of psychosis than is a dipping circadian rhythm. This association warrants further investigation. PMID- 25690742 TI - The capacity to refuse psychiatric treatment: a guide to the law for clinicians and tribunal members. AB - OBJECTIVE: In some Australian states clinicians and mental health tribunal members are already required to assess a person's decision-making capacity before involuntary treatment can be applied. Professionals in other jurisdictions will likely soon be required to do the same as mental health law reform in most Australian jurisdictions makes the assessment of decision-making capacity a central component of the process of providing unconsented psychiatric treatment. We provide a guide to the legal issues around the capacity to refuse psychiatric treatment to assist with this task. METHOD: We review the legislation in the four Australian states most advanced in the mental health law reform process and use examples from clinical practice and the common law to describe how decision making capacity should be assessed by these statutory standards. RESULTS: Clinicians and tribunal members will primarily be required to judge whether a person with mental illness can understand the information relevant to the treatment decision and whether he or she can use or weigh that information to come to a decision. A person with a mental illness is presumed to have capacity, but that presumption can be rebutted. Capacity is specific to the decision at hand and cannot be determined by the nature of the decision made. CONCLUSIONS: The information provided should assist clinicians and tribunal members to make determinations of decision-making capacity around treatment refusal in the context of mental illness. PMID- 25690743 TI - Correlates of electroencephalographic resting states and erythrocyte membrane docosahexaenoic and eicosapentaenoic acid levels in individuals at ultra-high risk of psychosis. AB - OBJECTIVE: Abnormal levels of polyunsaturated fatty acids (PUFAs) have been reported in individuals suffering from schizophrenia. The main aim of the present study was to investigate the relationship between erythrocyte membrane fatty acid levels and resting-state brain activity occurring in individuals at ultra-high risk (UHR) of psychosis. METHOD: The association between erythrocyte membrane fatty acids levels and resting-state brain activity and its value in predicting psychosis was examined in 72 UHR individuals. RESULTS: In the frontal area, the activity in the fast frequency band Beta2 was positively associated with docosahexaenoic acid (DHA) levels (R = 0.321, P = 0.017), and in the fronto central area, Beta2 activity showed a positive correlation with eicosapentaenoic acid (EPA) levels (R = 0.305, P = 0.009), regardless of psychosis transition status. Conversely, the slow frequency band Theta was significantly negatively associated with EPA levels in the parieto-occipital region (R = -0.251, P = 0.033. Results also showed that Alpha power was negatively correlated with DHA levels in UHR individuals who did not transition to psychosis, while this correlation was not present in individuals who later transitioned. CONCLUSION: Our results suggest that individuals at UHR for psychosis who have higher basal omega-3 fatty acids levels present with resting EEG features associated with better states of alertness and vigilance. Furthermore, the improvement in the Alpha synchrony observed along with increased DHA levels in participants who did not transition to psychosis is disturbed in those who did transition. However, these interesting results are limited by the small sample size and low statistical power of the study. PMID- 25690744 TI - Sub-acute care from an 'insiders' perspective. PMID- 25690745 TI - SSRIs in Rett syndrome. PMID- 25690746 TI - Positive beliefs about anorexia nervosa and muscle dysmorphia are associated with eating disorder symptomatology. AB - OBJECTIVE: The ego-syntonic nature of anorexia nervosa means that sufferers often deny their symptoms or experience them as positive or comforting. Positive beliefs about eating disorder symptoms may contribute to the development and/or maintenance of eating-disordered behaviour. To date, however, research in this field has been confined to women and anorexia nervosa. Given increasing scientific interest in muscle dysmorphia, a potential eating disorder with ego syntonic qualities, there is a need to extend current research to include men and muscle dysmorphia. The present study examined whether positive beliefs about anorexia nervosa and muscle dysmorphia were associated with more marked eating disorder symptoms and explored sex differences in these associations. METHOD: Male and female university students (n = 492) read descriptions of a male or female character with clinically significant symptoms of anorexia nervosa or muscle dysmorphia. Participants subsequently answered questions about the characters and completed a measure of disordered eating. Knowledge, personal history and interpersonal familiarity with the conditions were assessed. RESULTS: Results from two simultaneous multiple regressions showed that more positive beliefs about anorexia nervosa and muscle dysmorphia were uniquely associated with more eating disorder symptoms for both male and female participants. Effect sizes for these relationships were medium to large (partial eta-squared = 0.09 0.10). The relationships were not moderated by the sex of the participant, nor the sex of the character. CONCLUSIONS: Although preliminary, these findings suggest that, among young men and women, positive beliefs about anorexia nervosa and muscle dysmorphia may contribute to the development and maintenance of these conditions. Some symptoms of muscle dysmorphia may be perceived as ego-syntonic, providing another parallel with anorexia nervosa. PMID- 25690747 TI - A systematic review: Identifying the prevalence rates of psychiatric disorder in Australia's Indigenous populations. AB - OBJECTIVE: This review aimed to draw on published literature to identify the prevalence rates of psychiatric disorders in Australia's Indigenous populations, Aboriginal and Torres Strait Islander peoples. METHOD: A systematic review following the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) model was conducted using the following electronic databases: PubMed, Scopus, Web of Science, MEDLINE, PsycINFO, PsycARTICLES, and Informit Indigenous and Health Collections. Studies were included for analysis if they were empirical quantitative studies reporting prevalence rates for any psychiatric disorder in Indigenous people. RESULTS: Of the 1584 papers extracted by the search strategy, 17 articles met the eligibility criteria and were reviewed in detail. Methodology, sampling strategy and study design varied greatly across these 17 studies. Prevalence rates varied by disorder and are as follows: major depressive disorder (4.3-51%); mood disorders (7.7-43.1%); post-traumatic stress disorder (14.2-55.2%); anxiety disorders (17.2-58.6%); substance dependence (5.9%-66.2%); alcohol dependence (21.4-55.4%); and psychotic disorders (1.68-25%). While the number of studies on community-based Indigenous populations was limited, available evidence suggested that prevalence rates are higher in prison populations compared with community-based studies. CONCLUSIONS: It was identified that there is limited evidence on the occurrence of psychiatric disorders for Indigenous people in the general community. More research in this area is essential to provide accurate and reliable estimates and to provide a baseline for evaluating the effectiveness of programs aimed at reducing the high mental health burden experienced by Indigenous Australians. Future research needs to ensure that standardised and validated methods are used to accurately estimate the prevalence of psychiatric disorders among Indigenous Australians. PMID- 25690748 TI - Schizophrenia: a multi-system disorder? PMID- 25690749 TI - Temperature dependence of the radiative lifetimes in Ge and Si nanocrystals. AB - The effect of finite temperature on the optical properties of nanostructures has been a longstanding problem for their theoretical description and its omission presents serious limits on the validity of calculated spectra and radiative lifetimes. Most ab initio calculations have been carried out neglecting temperature effects altogether, although progress has been made recently. In the present work, the temperature dependence of the intrinsic radiative lifetimes of excited electron-hole pairs in Ge and Si nanocrystals due to classical temperature effects is calculated using ab initio molecular dynamics. Fully hydrogen-saturated Ge and Si nanocrystals without surface reconstructions show opposite behavior: the very short lifetimes in Ge increase with temperature, while the much longer ones in Si decrease. However, the temperature effect is found to be strongly dependent on the surface structure: surface reconstructions cause partial localization of the wave functions and override the difference between Si and Ge. As a consequence, the temperature dependence in reconstructed nanocrystals is strongly attenuated compared to the fully saturated nanocrystals. Our calculations are an important step towards predictive modeling of the optical properties of nanostructures. PMID- 25690750 TI - Gamma knife stereotactic radiosurgical thalamotomy for intractable tremor: a systematic review of the literature. AB - Tremor markedly reduces quality of life and causes a significant psychological burden for patients who are severely affected by this movement disorder. Pharmacologic and surgical treatments for tremor exist, but for patients who have failed medical therapy and are not surgical candidates, stereotactic radiosurgery is the only available treatment option. Of available stereotactic radiosurgical techniques for intractable tremor, the authors chose to evaluate the safety and efficacy of gamma knife stereotactic radiosurgical thalamotomy. In order to qualitatively synthesize available data a systematic review was conducted by searching MEDLINE (OvidSP 1946-January Week 1 2014) and Embase (OvidSP 1974-2014 January). The search strategy was not limited by study design or language of publication. All searches were conducted on January 7, 2014. Treatment efficacy, adverse outcomes, and patient deaths were reviewed and tabulated. Complications appeared months to years post procedure and most commonly consisted of mild contralateral numbness and transient hemiparesis. Rarely, more severe complications were reported, including dysphagia and death. Though no data from randomized controlled trials are available, our analysis of the literature indicates that unilateral gamma knife thalamotomy using doses from 130 to 150Gy appears safe and well tolerated. PMID- 25690751 TI - Fragmentation dynamics in dissociative electron attachment to CO probed by velocity slice imaging. AB - Complete dissociation dynamics in electron attachment to carbon monoxide (CO) have been studied using the newly developed velocity slice imaging (VSI) technique. Both kinetic energy and angular distributions of O(-) ions formed by dissociative electron attachment (DEA) to CO molecules have been measured for 9, 9.5, 10, 10.5, 11, and 11.5 eV incident electron energies around the resonance. Detailed observations conclusively show that two separate DEA reactions lead to the formation of O(-) ions in the ground (2)P state along with the neutral C atoms in the ground (3)P state and the first excited (1)D state, respectively. Within the axial recoil approximation and involving four partial waves, our angular distribution results clearly indicate that the two reactions leading to O(-) formation proceed through the specific resonant state(s). For the first process, more than one intermediate state is involved. On the other hand, for the second process, only one state is involved. The observed forward-backward asymmetry is explained in terms of the interference between the different partial waves that are involved in the processes. PMID- 25690752 TI - Liver transplantation and whipple surgery combined with chemoradiotherapy for treatment of hilar cholangiocarcinoma in patients with primary sclerosing cholangitis. PMID- 25690754 TI - How Do I Get What I Need? Navigating the FDA's Custom, Compassionate Use, and HDE Pathways for Medical Devices and Implants. PMID- 25690753 TI - Nectin expression in pancreatic adenocarcinoma: nectin-3 is associated with a poor prognosis. AB - PURPOSE: Nectins are cell adhesion molecules that regulate the formation of adherens junctions and are linked with E-cadherin-based cell-cell adherens junctions. In pancreatic cancer, the expression of E-cadherin and nectins is considered to be related to metastasis, invasion and prognosis. METHODS: We evaluated the distribution of cells that were positive for nectin subtypes and E cadherin using immunohistochemistry in specimens of human pancreatic adenocarcinoma, and correlated these results with the clinicopathological features and patient outcomes. RESULTS: The immunohistochemical distribution of nectin-1 and E-cadherin showed a good correlation (r = 0.523, p < 0.01). Tumors over 4 cm in diameter had more intense staining for nectin-4 than smaller tumors (p = 0.035). Nectin-2 expression correlated with a poorer histological grade (p = 0.04). The cases that showed diffuse nectin-3 expression had a better prognosis than those with negative expression (p = 0.018). CONCLUSION: Our results showed that the expression of nectin-3 in pancreatic cancer can be a prognostic factor. PMID- 25690755 TI - The perceived causal structures of smoking: Smoker and non-smoker comparisons. AB - Despite the detrimental impact of smoking on health, its prevalence remains high. Empirical research has provided insight into the many causes and effects of smoking, yet lay perceptions of smoking remain relatively understudied. This study used a form of network analysis to gain insight into the causal attributions for smoking of both smoking and non-smoking college students. The analyses resulted in highly endorsed, complex network diagrams that conveyed the perceived causal structures of smoking. Differences in smoker and non-smoker networks emerged with smokers attributing less negative consequences to smoking behaviors. Implications for intervention are discussed. PMID- 25690756 TI - Thyroid-specific changes following treatment with biological therapies in patients with rheumatic diseases. AB - Biological anti-rheumatic agents (BAA) may induce autoimmune phenomena. Evidence on thyroid-specific effects of these agents is relatively limited. We studied prospectively, over 3 years, 36 rheumatic patients treated with BAA (18 Infliximab and 18 Rituximab) and no prior exposure to biological therapies (group 1), with respect to their thyroid function, thyroid antibody titers, and thyroid ultrasonographic parameters, such as left inferior thyroid artery peak systolic velocity (ITA PSV), left thyroid lobe vascularity index (TL VI), and echogenicity. Twenty-eight rheumatic patients treated with disease-modifying anti rheumatic drugs and/or glucocorticoids (group-2), 21 rheumatic patients not receiving any treatment (group-3), and 49 healthy individuals (group-4) were used for comparison. Thyroid function and autoantibody titers were not significantly altered at any stage irrespectively of the administered BAA, previously unknown autoimmune thyroid disease (AITD) status, and/or concomitant treatment with glucocorticoids. Left ITA PSV was significantly increased in group-1 patients (mean +/- SD start: 25.5 +/- 14.1 cm/s vs. end: 29.8 +/- 11.1 cm/s, p = 0.038 and p < 0.001, respectively). Six group-1, 7 group-2, and 3 group-3 patients developed reduced thyroid echogenicity during follow-up (start: p = 0.003 and end: p < 0.001). Left ITA PSV, left TL VI, and echogenicity changes were not related to alterations in thyroid volume, thyrotropin hormone levels, and/or underlying AITD. Infliximab and Rituximab do not cause any alterations in thyroid function and/or autoimmunity, even in patients with previously undiagnosed AITD. Elevated left ITA PSV and reduced thyroid echogenicity may be early features signaling progression to AITD in patients treated with BAA. PMID- 25690758 TI - Effect of stress and peripheral immune activation on astrocyte activation in transgenic bioluminescent Gfap-luc mice. AB - Neuroinflammation and the accompanying activation of glial cells is an important feature of many neurodegenerative conditions. It is known that factors such as peripheral infections and stress can influence immune processes in the brain. However, the effect of these stressors on astrocyte activation in vivo remains elusive. In this study, transgenic Gfap-luc mice expressing the luciferase gene under the transcriptional control of the glial fibrillary acidic protein promoter were used to quantify the kinetics of in vivo astrocyte activation following immune challenges relevant to clinical inflammation. It was found that astrocytes respond rapidly to peripheral immune activation elicited by either bacterial lipopolysaccharide (LPS) or the viral mimetic polyinosinic:polycytidylic acid (poly(I:C)). By measuring bioluminescence and 18-kDa translocator protein radioligand binding in the same animal it was observed that LPS induces both astrocyte as well as microglial activation at 6 h post-administration. Furthermore, the astrocyte response decreased upon repeated systemic LPS injections, indicating development of tolerance to the LPS challenge. Finally, restraining Gfap-luc mice for 1 h daily on 5 consecutive days did not affect brain bioluminescence, thereby indicating that sub-chronic stress does not influence astrocyte activation under unchallenged conditions. However, stressed animals showed a reduced response to a subsequent systemic LPS injection, suggesting that the immune system is compromised in these animals. Here, we demonstrate that Gfap-luc mice can be used to study astrocyte activation in response to stimuli relevant for clinical inflammation and that this approach may provide a more complete characterization of existing and novel models of neuroinflammation PMID- 25690759 TI - Corrigendum: Diversity of reductive dehalogenase genes from environmental samples and enrichment cultures identified with degenerate primer PCR screens. AB - [This corrects the article on p. 341 in vol. 4, PMID: 24312087.]. PMID- 25690760 TI - Development and characterization of an inclined air-curtain (IAC) fume hood. AB - An inclined air-curtain (IAC) fume hood was developed and characterized using the laser-assisted smoke flow visualization technique and tracer-gas (sulphur hexafluoride) concentration detection method. The IAC fume hood features four innovative design elements: (i) an elongated suction slot installed at the hood roof with an offset towards the rear wall, (ii) an elongated up-blowing planar jet issued from the work surface near the hood inlet, (iii) two deflection plates installed at the left and right side walls, and (iv) a boundary-layer separation controller installed at the sash bottom. Baffles employed in conventional hoods were not used. The suction slot and the up-blowing planar jet formed a rearward inclined push-pull air curtain. The deflection plates worked with the inclined air curtain to induce four rearward-inclined counter-rotating 'tornados.' The fumes generated in the hood were isolated behind the rearward-inclined air curtain, entrained by the low pressure within the vortical flows, moved up spirally, and finally exhausted through the suction slot. The risk of containment leakage due to the large recirculation vortex that usually exists behind the sash of conventional hoods was reduced by the boundary-layer separation controller. The results of the tracer-gas concentration detection method based on the EN 14175 method showed that the flow field created by the geometric configurations of the IAC hood presented characteristics of low leakage and high resistance to dynamic disturbances at low face velocities. The leakage levels measured by the static, sash movement, and walk-by tests were negligible at a face velocity of 0.26 m s(-1). PMID- 25690761 TI - Copper(I)-catalyzed alkylation of polyfluoroarenes through Direct C-H bond functionalization. AB - The copper(I)-catalyzed alkylation of electron-deficient polyfluoroarenes with N tosylhydrazones and diazo compounds has been developed. This reaction uses readily available starting materials and is operationally simple, thus representing a practical method for the construction of C(sp(2) )-C(sp(3) ) bonds with polyfluoroarenes through direct C-H bond functionalization. Mechanistically, copper(I) carbene formation and subsequent migratory insertion are proposed as the key steps in the reaction pathway. PMID- 25690762 TI - SNP and INDEL detection in a QTL region on chicken chromosome 2 associated with muscle deposition. AB - Genetic improvement is important for the poultry industry, contributing to increased efficiency of meat production and quality. Because breast muscle is the most valuable part of the chicken carcass, knowledge of polymorphisms influencing this trait can help breeding programs. Therefore, the complete genome of 18 chickens from two different experimental lines (broiler and layer) from EMBRAPA was sequenced, and SNPs and INDELs were detected in a QTL region for breast muscle deposition on chicken chromosome 2 between microsatellite markers MCW0185 and MCW0264 (105,849-112,649 kb). Initially, 94,674 unique SNPs and 10,448 unique INDELs were identified in the target region. After quality filtration, 77% of the SNPs (85,765) and 60% of the INDELs (7828) were retained. The studied region contains 66 genes, and functional annotation of the filtered variants identified 517 SNPs and three INDELs in exonic regions. Of these, 357 SNPs were classified as synonymous, 153 as non-synonymous, three as stopgain, four INDELs as frameshift and three INDELs as non-frameshift. These exonic mutations were identified in 37 of the 66 genes from the target region, three of which are related to muscle development (DTNA, RB1CC1 and MOS). Fifteen non-tolerated SNPs were detected in several genes (MEP1B, PRKDC, NSMAF, TRAPPC8, SDR16C5, CHD7, ST18 and RB1CC1). These loss-of-function and exonic variants present in genes related to muscle development can be considered candidate variants for further studies in chickens. Further association studies should be performed with these candidate mutations as should validation in commercial populations to allow a better explanation of QTL effects. PMID- 25690764 TI - A muddle of metrics - or how we neglected to recognize quality of scientific thought: Initial peer review should be an important "metric" in our move away from citation-based metrics. PMID- 25690763 TI - Survival advantage of heterozygous factor V Leiden carriers in murine sepsis. AB - BACKGROUND: The high allelic frequency of the prothrombotic Leiden polymorphism in human blood coagulation factor V (FV) has been speculated to reflect positive selection during evolution. Heterozygous Leiden carriers enrolled in the placebo arm of the PROWESS sepsis trial and heterozygous Leiden mice challenged with endotoxin both showed reduced mortality, whereas homozygous Leiden mice were not protected from lethal endotoxemia. Follow-up analyses of clinical outcomes and of mouse models of infection with various pathogens remained inconclusive. OBJECTIVE: To establish whether activated protein C resistance of FV Leiden modifies the outcome of bacterial infection in murine sepsis models. METHODS: Homozygous and heterozygous FV Leiden mice were subjected to gram-positive (S. aureus) or gram-negative (Y. pestis; E. coli) septic peritonitis or polymicrobial, focal septic peritonitis induced by cecal ligation and puncture. The effect of FV Leiden on 7-day survival and bacterial dissemination was assessed. Outcomes were compared with the sepsis survival of mice with genetically impaired hemostasis (hemophilia A, thrombocytopenia, thrombin receptor PAR4 [protease activated receptor 4] deficiency, endothelial protein C receptor [ProcR/EPCR] deficiency). RESULTS: Heterozygous, but not homozygous, Leiden mice were protected from lethal infection with highly virulent S. aureus and Y. pestis strains. FV Leiden did not affect the outcome of sepsis induced by cecal ligation and puncture, staphylokinase-deficient S. aureus, Pla-deficient Y. pestis, or E. coli. Thrombocytopenia, deficiency of PAR1 or PAR4 did not affect S. aureus sepsis survival, whereas hemophilia A increased mortality. ProcR deficiency selectively abolished the survival advantage of heterozygous Leiden mice. CONCLUSIONS: In mice, heterozygous FV Leiden carriers are protected from sepsis mortality after infection with clinically relevant human bacterial pathogens. PMID- 25690768 TI - A review of incidence and relevant risk factors in genitourinary malignancies. PMID- 25690769 TI - Use of Relative vs Fixed Offset Distance to Define Region of Interest at the Distal Radius and Tibia in High-Resolution Peripheral Quantitative Computed Tomography. AB - Although the region of interest in high-resolution peripheral quantitative computed tomography, defined based on the manufacturer's protocol for in vivo scanning, provides consistency and is practically convenient, it does not take into account possible variation in morphology in the regions adjacent to the measurement site. This study aimed at compare the morphologic variation in measurements using the standard fixed offset distance to define the distal starting slice against those obtained by using a relative measurement position scaled to the individual bone length at the distal radius and tibia in normal healthy adult subjects. A total of 40 healthy adult subjects (median height, 175.3 cm; range: 150.0-196.0 cm) were included in the study. High-resolution peripheral quantitative computed tomography at the distal radius and tibia was performed in all subjects, the region of interest defined by, first, the standard measurement protocol, where the most distal CT slice was 9.5 mm and 22.5 mm from the end plate of the radius and tibia, respectively, and second, the relative measurement method, where the most distal CT slice was at 4% and 7% of the radial and tibial lengths, respectively. Volumetric densities and microarchitectural parameters were compared between the 2 methods. Measurements of the total and cortical volumetric density and cortical thickness at the radius and tibia and cortical porosity, trabecular volumetric density, and trabecular number at the tibia were significantly different between the 2 methods (all p < 0.001). The predicted morphologic variation with varying measurement position was substantial at both the radius (up to 34%) and the tibia (up to 36%). A lack of consideration to height (and in turn the bone lengths) in the standard patient protocol could lead to the introduction of systematic errors in radial and tibial measurements. Although this may not be of particular significance in longitudinal studies in the same individual, it potentially assumes critical importance in cross sectional studies. PMID- 25690771 TI - It's a Matter of Perspective. PMID- 25690770 TI - Vcx1 and ESCRT components regulate intracellular pH homeostasis in the response of yeast cells to calcium stress. AB - Endosomal sorting complexes required for transport (ESCRTs) are involved in the formation of multivesicular bodies and sorting of targeted proteins to the yeast vacuole. The deletion of seven genes encoding components of the ESCRT machinery render Saccharomyces cerevisiae cells sensitive to high extracellular CaCl2 concentrations as well as to low pH in media. In this work, we focused on intracellular pH (pHin) homeostasis of these mutants. None of the studied ESCRT mutants exhibited an altered pHin level compared to the wild type under standard growth conditions. Nevertheless, 60 min of CaCl2 treatment resulted in a more significant drop in pHin levels in these mutants than in the wild type, suggesting that pHin homeostasis is affected in ESCRT mutants upon the addition of calcium. Similarly, CaCl2 treatment caused a bigger pHin decrease in cells lacking the vacuolar Ca(2+)/H(+) antiporter Vcx1 which indicates a role for this protein in the maintenance of proper pHin homeostasis when cells need to cope with a high CaCl2 concentration in media. Importantly, ESCRT gene deletions in the vcx1Delta strain did not result in an increase in the CaCl2-invoked drop in the pHin levels of cells, which demonstrates a genetic interaction between VCX1 and studied ESCRT genes. PMID- 25690772 TI - Improving support for parents of children with hearing loss: provider training on use of targeted communication strategies. AB - BACKGROUND: When proper protocols are followed, children who are identified with a permanent hearing loss early in life have opportunities to develop language on par with their typical hearing peers. Young children with hearing loss are dependent on their parents to manage intervention during early years critical to their development, and parents' ability to effectively integrate recommendations in daily life is foundational for intervention success. Audiologists and early intervention professionals not only need to provide current evidence-based services, but also must address parents' emotional and learning needs related to their child's hearing loss. PURPOSE: This study explored practice patterns related to education and support provided to parents of children with hearing loss and the influence of an in-service training on provider attitudes. RESEARCH DESIGN: This study used a prepost design with a self-report questionnaire to identify practice patterns related to communication skills and support used by providers when working with parents of children with hearing loss. STUDY SAMPLE: A total of 45 participants (21 professionals and 24 graduate students) currently working with children completed the pretraining questionnaire, and 29 participants (13 professionals and 16 graduate students) completed the postquestionnaire. DATA COLLECTION AND ANALYSIS: Data were collected using an online questionnaire before the training and 1 mo after training. Descriptive analyses were done to identify trends, and paired-samples t-tests were used to determine changes pretraining to posttraining. RESULTS: Findings revealed that professionals most frequently teach skills to mothers (91%) and infrequently teach skills to fathers (19%) and other caregivers (10%). Professionals reported frequently collaborating with other intervention providers (76%) and infrequently collaborating with primary care physicians (19%). One-third of the professionals reported addressing symptoms of depression and anxiety as an interfering factor with the ability to implement management recommendations. For providers who completed both the prequestionnaires and postquestionnaires, an increase in confidence was reported for several areas of communication; however, as expected, practices remained similar, and all of the practicing professionals and 94% of the graduate students indicated a desire for more training on how to be effective in supporting parents with implementing intervention recommendations. CONCLUSIONS: Providers do not necessarily use effective methods of communication, needed to adequately help parents, requiring additional focused training to change how providers interact with parents and how support is provided. PMID- 25690773 TI - High-frequency audibility: the effects of audiometric configuration, stimulus type, and device. AB - BACKGROUND: For the last decade, the importance of providing amplification up to 9-10 kHz has been supported by multiple studies involving children and adults. The extent to which a listener with hearing loss can benefit from bandwidth expansion is dependent on the audibility of high-frequency cues. The American National Standards Institute (ANSI) devised a standard method for measuring and reporting hearing aid bandwidth for quality-control purposes. However, ANSI bandwidth measurements were never intended to reflect the true frequency range that is audible for a speech stimulus for a person with hearing loss. PURPOSE: The purpose of this study was to (1) determine the maximum audible frequency of conventional hearing aids using a speech signal as the input through the hearing aid microphone for different degrees of hearing loss, (2) examine how the maximum audible frequency changes when the input stimulus is presented through hearing assistance technology (HAT) systems with cross-coupling of manufacturers' transmitters and receivers, and (3) evaluate how the maximum audible frequency compares with the upper limit of the ANSI bandwidth measure. RESEARCH DESIGN: Eight behind-the-ear hearing aids from five hearing aid manufacturers were selected based on a range of ANSI bandwidth upper frequency limits. Three audiometric configurations with varied degrees of high-frequency hearing loss were programmed into each hearing aid. Hearing aid responses were measured with the International Speech Test Signal (ISTS), broadband noise, and a short speech token (/asa/) as stimuli presented through a loudspeaker. HAT devices from three manufacturers were used to create five HAT scenarios. These instruments were coupled to the hearing aid programmed for the audiogram that provided the highest maximum audible frequency in the hearing aid analysis. The response from each HAT scenario was obtained using the same three stimuli as during the hearing aid analysis. STUDY SAMPLE: All measurements were collected in an audiometric sound booth on a Knowles Electronic Manikin for Acoustic Research (KEMAR). DATA COLLECTION AND ANALYSIS: A custom computer program was used to record responses from KEMAR. Maximum audible frequency was defined as the highest point where the Long-Term Average Speech Spectrum (LTASS) intersected the audiogram. RESULTS: The average maximum audible frequency measured through KEMAR ranged from 3.5 kHz to beyond 8 kHz and varied significantly across devices, audiograms, and stimuli. The specified upper limit of the ANSI bandwidth was not predictive of the maximum audible frequency across conditions. For most HAT systems, the maximum audible frequency for the hearing aid plus HAT condition was equivalent to the hearing aid for the same measurement configuration. In some cases, however, the HAT system imposed a lower maximum audible frequency than the hearing aid-only condition. CONCLUSIONS: The maximum audible frequency of behind-the-ear hearing aids is dependent on the degree of hearing loss, amplification device, and stimulus input. Estimating the maximum audible frequency by estimating the frequency where the speech spectrum intersects the audiogram in the high frequencies can assist clinicians in making decisions about which device or configuration of devices provides the greatest access to high-frequency information, as well as whether frequency-lowering technology should be used. PMID- 25690774 TI - Effect of a hybrid maneuver in treating posterior canal benign paroxysmal positional vertigo. AB - BACKGROUND: Benign paroxysmal positional vertigo (BPPV) is the most common disorder of the vestibular system of the inner ear, which is a vital part of maintaining balance. Although the efficacy of the Epley maneuver-also known as the canalith repositioning maneuver (CRM)-is well established, data comparing CRM versus a hybrid treatment are lacking. PURPOSE: The purpose of this study was to determine the effect of a hybrid treatment, the Gans repositioning maneuver (GRM) either with or without postmaneuver restrictions, compared with CRM on treatment of posterior canal BPPV (PC-BPPV). RESEARCH DESIGN: Study design was a randomized controlled trial. STUDY SAMPLE: A total of 45 patients (30 males and 15 females) with unilateral PC-BPPV were randomly allocated to one of three equal groups on the basis of the date of the first visit with matched assignment for gender: a GRMR group (GRM with postmaneuver restrictions), a GRM group, and a CRM group. INTERVENTION: Patients received weekly administration of the maneuver until resolution of symptoms. The Dix-Hallpike test was performed before treatment at every appointment, and finally after 1 mo from the last maneuver. DATA COLLECTION AND ANALYSIS: Nystagmus duration and vertigo intensity were recorded. The supine roll test was performed in case the Dix-Hallpike test was negative to test otoconial migration. Data were analyzed with repeated-measures analysis of variance, paired t-tests with a Bonferroni correction, and the Spearman rank correlation coefficient. RESULTS: All patients showed improvement within the groups, and PC-BPPV symptoms were resolved by an average of 2, 1.7, and 1.6 maneuvers for GRMR, GRM, and CRM, respectively, with no statistical differences among the three groups (p > 0.05). Only two patients had recurrence, and one patient had horizontal BPPV at 1 mo follow-up. CONCLUSION: We demonstrated that the GRM as a new treatment is effective in treating PC-BPPV with no benefits to postmaneuver restrictions. PMID- 25690775 TI - Preserved acoustic hearing in cochlear implantation improves speech perception. AB - BACKGROUND: With improved surgical techniques and electrode design, an increasing number of cochlear implant (CI) recipients have preserved acoustic hearing in the implanted ear, thereby resulting in bilateral acoustic hearing. There are currently no guidelines, however, for clinicians with respect to audiometric criteria and the recommendation of amplification in the implanted ear. The acoustic bandwidth necessary to obtain speech perception benefit from acoustic hearing in the implanted ear is unknown. Additionally, it is important to determine if, and in which listening environments, acoustic hearing in both ears provides more benefit than hearing in just one ear, even with limited residual hearing. PURPOSE: The purposes of this study were to (1) determine whether acoustic hearing in an ear with a CI provides as much speech perception benefit as an equivalent bandwidth of acoustic hearing in the nonimplanted ear, and (2) determine whether acoustic hearing in both ears provides more benefit than hearing in just one ear. RESEARCH DESIGN: A repeated-measures, within-participant design was used to compare performance across listening conditions. STUDY SAMPLE: Seven adults with CIs and bilateral residual acoustic hearing (hearing preservation) were recruited for the study. DATA COLLECTION AND ANALYSIS: Consonant-nucleus-consonant word recognition was tested in four conditions: CI alone, CI + acoustic hearing in the nonimplanted ear, CI + acoustic hearing in the implanted ear, and CI + bilateral acoustic hearing. A series of low-pass filters were used to examine the effects of acoustic bandwidth through an insert earphone with amplification. Benefit was defined as the difference among conditions. The benefit of bilateral acoustic hearing was tested in both diffuse and single-source background noise. RESULTS were analyzed using repeated-measures analysis of variance. RESULTS: Similar benefit was obtained for equivalent acoustic frequency bandwidth in either ear. Acoustic hearing in the nonimplanted ear provided more benefit than the implanted ear only in the wideband condition, most likely because of better audiometric thresholds (>500 Hz) in the nonimplanted ear. Bilateral acoustic hearing provided more benefit than unilateral hearing in either ear alone, but only in diffuse background noise. CONCLUSIONS: RESULTS support use of amplification in the implanted ear if residual hearing is present. The benefit of bilateral acoustic hearing (hearing preservation) should not be tested in quiet or with spatially coincident speech and noise, but rather in spatially separated speech and noise (e.g., diffuse background noise). PMID- 25690776 TI - The effects of hearing impairment in older adults on communication partners: a systematic review. AB - BACKGROUND: Hearing impairment is highly prevalent in older adults and can affect the daily activities of a person who is hard of hearing (HOH). The impact of hearing impairment may also have collateral effects on the primary communication partner (CP; e.g., spouse, close family member, or caregiver) of the person who is HOH. PURPOSE: We aimed to characterize the impact of hearing loss in a person who is HOH on his or her CP. RESEARCH DESIGN: We conducted a systematic review of manuscripts examining the consequences of hearing loss in a person who is HOH on the CP. We searched PubMed, Embase, Scopus, PyscINFO, CINAHL Plus with full text, and Web of Science for peer-reviewed articles using a predefined search string and hand-searched reference lists of relevant articles. DATA COLLECTION AND ANALYSIS: We initially screened abstracts blinded for author and journal to eliminate irrelevant and duplicate articles. Descriptive information on study populations, hearing assessments, outcome metrics, and study findings were extracted from full-length manuscripts. RESULTS: Of the 1,047 abstracts retrieved from database searching and 5 hand-searched articles, 24 articles met inclusion criteria. These articles included observational clinical studies, randomized clinical trials, and epidemiologic studies. Overall, CPs experienced a restricted social life, increased burden of communication, and poorer quality of life (QOL) and relationship satisfaction. Effects of hearing impairment on a CP's mental health were unclear. Treatment of hearing loss in the person who is HOH tended to improve QOL, communication, feelings toward the person who is HOH, and activity participation of the CP. CONCLUSIONS: This review highlights the broad effects of hearing impairment and the importance of involving CPs in hearing loss treatment decisions. PMID- 25690777 TI - Estimation of Signal-to-Noise Ratios in Realistic Sound Scenarios. AB - BACKGROUND: Both in the design of hearing-device features, such as noise reduction, and in the evaluation measurements of such features, there is a need for more information about the sound scenarios hearing-device users encounter. The limitations of adaptive speech tests as outcome measures in the evaluation of hearing-device features have been discussed. The obvious alternative to adaptive speech testing is to test at a fixed signal-to-noise ratio (SNR). However, the question is which SNRs should be used if the test reflects real-life situations. PURPOSE: The purpose of this study was to estimate SNRs in realistic sound environments encountered by hearing aid users. RESEARCH DESIGN: Research design was a descriptive study where recorded sound files were statistically analyzed. STUDY SAMPLE: A total of 20 experienced, bilaterally fitted hearing aid users, all satisfied with their current hearing aids, made recordings for 3-4 days. The informants were instructed to record different situations in daily life and were told that all situations were of equal importance. The informants ranged in age from 18-81 yr old, and they had various occupations and varying hearing-loss configurations. DATA COLLECTION AND ANALYSIS: The total duration of the recorded material for each informant was, on average, 84 min; the number of recordings was, on average, 17 per informant. The sound files were categorized based on the type of background noise and were analyzed with use of a manual noise estimation procedure. Segments of speech with noise present were cut out from the original recordings. Corresponding noise-only segments were also extracted. On the basis of power calculations for these two types of recorded segments, the SNR was estimated. Frequency-specific and overall SNRs, calculated both based on unweighted and A-weighted speech and noise levels, were derived. An estimation uncertainty measure was also developed. RESULTS: The range of SNRs found in the material was large. The most striking finding was that there were very few recorded situations where the SNR was negative or even close to 0 dB. For speech in-babble noise, the average SNR was approximately 5 dB. The estimation uncertainty was generally low but became higher in highly fluctuating noises and at very low SNRs. CONCLUSIONS: The estimated SNRs were higher than previously reported. The results can be used in the design and evaluation of hearing-device features. PMID- 25690778 TI - Social media utilization in the cochlear implant community. AB - BACKGROUND: More than 200,000 individuals worldwide have received a cochlear implant (CI). Social media Websites may provide a paramedical community for those who possess or are interested in a CI. The utilization patterns of social media by the CI community, however, have not been thoroughly investigated. PURPOSE: The purpose of this study was to investigate participation of the CI community in social media Websites. RESEARCH DESIGN: We conducted a systematic survey of online CI-related social media sources. Using standard search engines, the search terms cochlear implant, auditory implant, forum, and blog identified relevant social media platforms and Websites. Social media participation was quantified by indices of membership and posts. STUDY SAMPLE: Social media sources included Facebook, Twitter, YouTube, blogs, and online forums. Each source was assigned one of six functional categories based on its description. INTERVENTION: No intervention was performed. DATA COLLECTION AND ANALYSIS: We conducted all online searches in February 2014. Total counts of each CI-related social media source were summed, and descriptive statistics were calculated. RESULTS: More than 350 sources were identified, including 60 Facebook groups, 36 Facebook pages, 48 Twitter accounts, 121 YouTube videos, 13 forums, and 95 blogs. The most active online communities were Twitter accounts, which totaled 35,577 members, and Facebook groups, which totaled 17,971 members. CI users participated in Facebook groups primarily for general information/support (68%). Online forums were the next most active online communities by membership. The largest forum contained approximately 9,500 topics with roughly 127,000 posts. CI users primarily shared personal stories through blogs (92%), Twitter (71%), and YouTube (62%). CONCLUSIONS: The CI community engages in the use of a wide range of online social media sources. The CI community uses social media for support, advocacy, rehabilitation information, research endeavors, and sharing of personal experiences. Future studies are needed to investigate how social media Websites may be harnessed to improve patient-provider relationships and potentially used to augment patient education. PMID- 25690779 TI - Evaluation of iPod-Based Automated Tinnitus Pitch Matching. AB - BACKGROUND: Tinnitus is the perception of sound unrelated to any external source. Diagnostic approaches to assess tinnitus characteristics such as tinnitus pitch are crucial for new attempts of tinnitus therapy. PURPOSE: The purpose of this study was to develop and evaluate reliable tinnitus pitch-matching procedures. Existing procedures usually require audiometric equipment and are time consuming. However, some patients with tinnitus find it hard to match their tinnitus in one single session. Therefore, we developed an iPod-based application for self administered tinnitus pitch matching and compared it with a standardized audiometric procedure. STUDY SAMPLE: A total of 17 patients with chronic tonal tinnitus participated in two sessions including both pitch-matching procedures. METHOD: In the conventional audiometric test, the investigator adjusted the frequency and loudness of pure tones led by the responses of the patient. For the iPod-based procedure, we used a recursive two-interval forced-choice test that required no interaction with an investigator. Both procedures included loudness matching and testing for octave confusion. RESULTS: The iPod-based procedure resulted in lower pitch matches as compared with the conventional audiometry. Psychometric qualities such as test-retest reliability of both methods were comparable. Participants rated the iPod-based procedure as easier to perform and more comfortable to use. CONCLUSIONS: In conclusion, we find that the use of self administered tinnitus pitch-matching procedures on a mobile device is feasible and easier in practice without any loss of reliability and validity. A major advantage is the possibility of repeated measurements without expensive equipment and experienced staff. Repeated measurements of tinnitus pitch can provide more information about the stability of the tinnitus perception and may improve the ability of participants to match their tinnitus. PMID- 25690781 TI - Potential role of CC chemokine receptor 6 in prediction of late-onset cytomegalovirus infection following solid organ transplant. AB - CCR6 is a chemokine receptor involved in homing memory T cells, particularly Th17 cells, to sites of mucosal inflammation. Despite the critical role of memory T cells in long-term protective immunity against cytomegalovirus (CMV), a virus that reactivates at multiple mucosal sites, the ability of CCR6 or other Th17 marker expression to predict CMV reactivation following transplantation is not clear. Using 11-color flow cytometry, in this prospective single-center pilot study, we measured the expression of CCR6 and other markers of T-cell function in peripheral blood samples obtained from 21 SOT recipients at the time of discontinuation of anti-CMV prophylaxis. CMV viremia was monitored on a monthly basis after discontinuation of prophylaxis. Eleven patients (52%) developed CMV viremia during the six-month follow-up period. Late-onset CMV infection was preceded by an immune phenotype characterized by increased CCR6 expression on bulk CD4(+) T cells and a reduced number of circulating CMV IE-1-specific Th1 (CD4(+) IFN-gamma(+)) cells. Among the markers evaluated, CCR6 was the best single predictor of late-onset CMV infection. Our results suggest that CCR6 expression at the time of discontinuation of antiviral prophylaxis might be a useful predictor of late-onset CMV reactivation and provide the basis for future larger prospective studies. PMID- 25690782 TI - Evaluation of cytomegalovirus infection in low-birth weight children by breast milk using a real-time polymerase chain reaction assay. AB - Human Cytomegalovirus (CMV) is the most common cause of intrauterine and perinatal infections worldwide. Postnatal CMV transmission has usually no consequences, but in some cases it may produce disease in preterm infants. Literature reports a broad range of breast milk-acquired CMV infections (5.7 58.6%), which depends on the study's design and the treatment of the milk. To evaluate CMV transmission via breast milk, a prospective study using a real-time PCR assay was performed. One hundred and thirty-one mothers (accounting for 160 children) accepted the participation in the study. Urine samples from the infants and breast milk samples from their mothers were collected at 3, 15, 30, 60, and 90 days after delivery. CMV-DNA in breast milk was analysed by quantitative real time PCR assay Affigene(r) CMV Trender (Cepheid, Bromma, Sweden). The breast milk samples from 92 mothers (92 of 131, 70.2%) were positive for CMV by PCR. CMV infection was detected in thirteen children by PCR, and four of them (30.7%) had clinical symptoms. There were not significant differences in morbidity between symptomatic and non- symptomatic patients; nonetheless, the average length of hospitalization in symptomatic children was higher than that of non-symptomatic children (P < 0.05). The rtPCR technique is useful for detection of mothers with high viral loads of CMV-DNA in milk, and might be of help to decide whether to freeze the breast milk in preterm children less than 28 weeks. PMID- 25690783 TI - Salts employed in hydrophobic interaction chromatography can change protein structure - insights from protein-ligand interaction thermodynamics, circular dichroism spectroscopy and small angle X-ray scattering. AB - Key requirements of protein purification by hydrophobic interaction chromatography (HIC) are preservation of the tertiary/quaternary structure, maintenance of biological function, and separation of the correctly folded protein from its unfolded forms or aggregates. This study examines the relationship between the HIC retention behavior of hen egg white lysozyme (HEWL) in high concentrations of several kosmotropic salts and its conformation, assessed by circular dichroism (CD) spectroscopy. Further, the physicochemical properties of HEWL in the presence of high concentrations of ammonium sulfate, sodium chloride and magnesium chloride were investigated by small angle X-ray scattering (SAXS) at different temperatures. Radii of gyration were extrapolated from Guinier approximations and the indirect transform program GNOM with protein protein interaction and contrast variation taken into account. A bead model simulation provided information on protein structural changes using ab initio reconstruction with GASBOR. These results correlated to the secondary structure content obtained from CD spectroscopy of HEWL. These changes in SAXS and CD data were consistent with heat capacity DeltaCp -values obtained from van't Hoff plot analyses of the retention data. Collectively, these insights enable informed decisions to be made on the choice of chromatographic conditions, leading to improved separation selectivity and opportunities for innovative column-assisted protein refolding methods. PMID- 25690784 TI - Discovery of 7-azaindole derivatives as potent Orai inhibitors showing efficacy in a preclinical model of asthma. AB - Synthesis and SAR of a series of 7-azaindoles as Orai channel inhibitors showing good potency inhibiting IL-2 production in Jurkat cells is described. Compound 14d displaying best pharmacokinetic properties was further characterized in a model of allergen induced asthma showing inhibition in the number of eosinophils in BALF. High lipophilicity remains as one of the main challenges for this class of compounds. PMID- 25690785 TI - New clerodane diterpenoids from the twigs and leaves of Croton euryphyllus. AB - Three new nor-clerodane diterpenoids, crotoeurins A-C (1-3), together with four known ones were isolated from the twigs and leaves of Croton euryphyllus. Among them, crotoeurin A (1) is a new nor-clerodane diterpenoid dimer with a unique cyclobutane ring via a [2+2] cycloaddition. Their structures were elucidated by spectroscopic analyses and the stereochemistry of 1 was confirmed by single crystal X-ray diffraction analysis. Compounds 1-3 exhibited neurite outgrowth promoting activity on NGF-mediated PC12 cells at concentration of 10MUM. PMID- 25690787 TI - Implications of the small number of distinct ligand binding pockets in proteins for drug discovery, evolution and biochemical function. AB - Coincidence of the properties of ligand binding pockets in native proteins with those in proteins generated by computer simulations without selection for function shows that pockets are a generic protein feature and the number of distinct pockets is small. Similar pockets occur in unrelated protein structures, an observation successfully employed in pocket-based virtual ligand screening. The small number of pockets suggests that off-target interactions among diverse proteins are inherent; kinases, proteases and phosphatases show this prototypical behavior. The ability to repurpose FDA approved drugs is general, and minor side effects cannot be avoided. Finally, the implications to drug discovery are explored. PMID- 25690786 TI - Metabolic glycoengineering sensitizes drug-resistant pancreatic cancer cells to tyrosine kinase inhibitors erlotinib and gefitinib. AB - Metastatic human pancreatic cancer cells (the SW1990 line) that are resistant to the EGFR-targeting tyrosine kinase inhibitor drugs (TKI) erlotinib and gefitinib were treated with 1,3,4-O-Bu3ManNAc, a 'metabolic glycoengineering' drug candidate that increased sialylation by ~2-fold. Consistent with genetic methods previously used to increase EGFR sialylation, this small molecule reduced EGF binding, EGFR transphosphorylation, and downstream STAT activation. Significantly, co-treatment with both the sugar pharmacophore and the existing TKI drugs resulted in strong synergy, in essence re-sensitizing the SW1990 cells to these drugs. Finally, 1,3,4-O-Bu3ManNAz, which is the azido-modified counterpart to 1,3,4-O-Bu3ManNAc, provided a similar benefit thereby establishing a broad-based foundation to extend a 'metabolic glycoengineering' approach to clinical applications. PMID- 25690788 TI - Total synthesis of Herbarin A and B, determination of their antioxidant properties and toxicity in zebrafish embryo model. AB - Herbarin A and B were isolated from the fungal strains of Cladosporium herbarum found in marine sponges Aplysina aerophoba and Callyspongia aerizusa. Total synthesis of Herbarin A and B was achieved by carrying out a multi-step synthesis approach, and the antioxidant properties were evaluated using FRAP assay. Toxicity of these compounds was determined using a zebrafish embryo model. PMID- 25690789 TI - Design, synthesis, and evaluation of phenylglycinols and phenyl amines as agonists of GPR88. AB - Small molecule modulators of GPR88 activity (agonists, antagonists, or modulators) are of interest as potential agents for the treatment of a variety of psychiatric disorders including schizophrenia. A series of phenylglycinol and phenylamine analogs have been prepared and evaluated for their GPR88 agonist activity and pharmacokinetic (PK) properties. PMID- 25690790 TI - Paracrine crosstalk between human hair follicle dermal papilla cells and microvascular endothelial cells. AB - Human follicle dermal papilla cells (FDPC) are a specialized population of mesenchymal cells located in the skin. They regulate hair follicle (HF) development and growth, and represent a reservoir of multipotent stem cells. Growing evidence supports the hypothesis that HF cycling is associated with vascular remodeling. Follicular keratinocytes release vascular endothelial growth factor (VEGF) that sustains perifollicular angiogenesis leading to an increase of follicle and hair size. Furthermore, several human diseases characterized by hair loss, including Androgenetic Alopecia, exhibit alterations of skin vasculature. However, the molecular mechanisms underlying HF vascularization remain largely unknown. In vitro coculture approaches can be successfully employed to greatly improve our knowledge and shed more light on this issue. Here we used Transwell based co-cultures to show that FDPC promote survival, proliferation and tubulogenesis of human microvascular endothelial cells (HMVEC) more efficiently than fibroblasts. Accordingly, FDPC enhance the endothelial release of VEGF and IGF-1, two well-known proangiogenic growth factors. Collectively, our data suggest a key role of papilla cells in vascular remodeling of the hair follicle. PMID- 25690791 TI - Prostate cancer vaccines: the long road to clinical application. AB - Cancer vaccines as a modality of immune-based cancer treatment offer the promise of a non-toxic and efficacious therapeutic alternative for patients. Emerging data suggest that response to vaccination largely depends on the magnitude of the type I immune response generated, epitope spreading and immunogenic modulation of the tumor. Moreover, accumulating evidence suggests that cancer vaccines will likely induce better results in patients with low tumor burden and less aggressive disease. To induce long-lasting clinical responses, vaccines will need to be combined with immunoregulatory agents to overcome tumor-related immune suppression. Immunotherapy, as a treatment modality for prostate cancer, has received significant attention in the past few years. The most intriguing characteristics that make prostate cancer a preferred target for immune-based treatments are (1) its relative indolence which allows sufficient time for the immune system to develop meaningful antitumor responses; (2) prostate tumor associated antigens are mainly tissue-lineage antigens, and thus, antitumor responses will preferentially target prostate cancer cells. But, also in the event of eradication of normal prostate epithelium as a result of immune attack, this will have no clinical consequences because the prostate gland is not a vital organ; (3) the use of prostate-specific antigen for early detection of recurrent disease allows for the initiation of vaccine immunotherapy while tumor burden is still minimal. Finally, for improving clinical outcome further to increasing vaccine potency, it is imperative to recognize prognostic and predictive biomarkers of clinical benefit that may guide to select the therapeutic strategies for patients most likely to gain benefit. PMID- 25690792 TI - Outdoor temperature, blood pressure, and cardiovascular disease mortality among 23 000 individuals with diagnosed cardiovascular diseases from China. AB - INTRODUCTION: Blood pressure is a major cause of cardiovascular disease (CVD) and both may increase as outdoor temperatures fall. However, there are still limited data about seasonal variation in blood pressure and CVD mortality among patients with prior-CVD. METHODS: We analysed data on 23 000 individuals with prior-CVD who were recruited from 10 diverse regions into the China Kadoorie Biobank during 2004-8. After 7 years of follow-up, 1484 CVD deaths were recorded. Baseline survey data were used to assess seasonal variation in systolic blood pressure (SBP) and its association with outdoor temperature. Cox regression was used to examine the association of usual SBP with subsequent CVD mortality, and seasonal variation in CVD mortality was assessed by Poisson regression. All analyses were adjusted for age, sex, and region. RESULTS: Mean SBP was significantly higher in winter than in summer (145 vs. 136 mmHg, P < 0.001), especially among those without central heating. Above 5 degrees C, each 10 degrees C lower outdoor temperature was associated with 6.2 mmHg higher SBP. Systolic blood pressure predicted subsequent CVD mortality, with each 10 mmHg higher usual SBP associated with 21% (95% confidence interval: 16-27%) increased risk. Cardiovascular disease mortality varied by season, with 41% (21-63%) higher risk in winter compared with summer. CONCLUSION: Among adult Chinese with prior-CVD, there is both increased blood pressure and CVD mortality in winter. Careful monitoring and more aggressive blood pressure lowering treatment in the cold months are needed to help reduce the winter excess CVD mortality in high-risk individuals. PMID- 25690794 TI - Multiple regions of Kaposi's sarcoma-associated herpesvirus ORF59 RNA are required for its expression mediated by viral ORF57 and cellular RBM15. AB - KSHV ORF57 (MTA) promotes RNA stability of ORF59, a viral DNA polymerase processivity factor. Here, we show that the integrity of both ORF59 RNA ends is necessary for ORF57-mediated ORF59 expression and deletion of both 5' and 3' regions, or one end region with a central region, of ORF59 RNA prevents ORF57 mediated translation of ORF59. The ORF59 sequence between nt 96633 and 96559 resembles other known MTA-responsive elements (MREs). ORF57 specifically binds to a stem-loop region from nt 96596-96572 of the MRE, which also binds cellular RBM15. Internal deletion of the MRE from ORF59 led to poor export, but accumulation of nuclear ORF59 RNA in the presence of ORF57 or RBM15. Despite of being translatable in the presence of ORF57, this deletion mutant exhibits translational defect in the presence of RBM15. Together, our results provide novel insight into the roles of ORF57 and RBM15 in ORF59 RNA accumulation and protein translation. PMID- 25690795 TI - Poxviral ankyrin proteins. AB - Multiple repeats of the ankyrin motif (ANK) are ubiquitous throughout the kingdoms of life but are absent from most viruses. The main exception to this is the poxvirus family, and specifically the chordopoxviruses, with ANK repeat proteins present in all but three species from separate genera. The poxviral ANK repeat proteins belong to distinct orthologue groups spread over different species, and align well with the phylogeny of their genera. This distribution throughout the chordopoxviruses indicates these proteins were present in an ancestral vertebrate poxvirus, and have since undergone numerous duplication events. Most poxviral ANK repeat proteins contain an unusual topology of multiple ANK motifs starting at the N-terminus with a C-terminal poxviral homologue of the cellular F-box enabling interaction with the cellular SCF ubiquitin ligase complex. The subtle variations between ANK repeat proteins of individual poxviruses suggest an array of different substrates may be bound by these protein protein interaction domains and, via the F-box, potentially directed to cellular ubiquitination pathways and possible degradation. Known interaction partners of several of these proteins indicate that the NF-kappaB coordinated anti-viral response is a key target, whilst some poxviral ANK repeat domains also have an F box independent affect on viral host-range. PMID- 25690796 TI - eIF4E as a control target for viruses. AB - Translation is a complex process involving diverse cellular proteins, including the translation initiation factor eIF4E, which has been shown to be a protein that is a point for translational regulation. Viruses require components from the host cell to complete their replication cycles. Various studies show how eIF4E and its regulatory cellular proteins are manipulated during viral infections. Interestingly, viral action mechanisms in eIF4E are diverse and have an impact not only on viral protein synthesis, but also on other aspects that are important for the replication cycle, such as the proliferation of infected cells and stimulation of viral reactivation. This review shows how some viruses use eIF4E and its regulatory proteins for their own benefit in order to spread themselves. PMID- 25690798 TI - Bioinformatics tools for small genomes, such as hepatitis B virus. AB - DNA sequence analysis is undertaken in many biological research laboratories. The workflow consists of several steps involving the bioinformatic processing of biological data. We have developed a suite of web-based online bioinformatic tools to assist with processing, analysis and curation of DNA sequence data. Most of these tools are genome-agnostic, with two tools specifically designed for hepatitis B virus sequence data. Tools in the suite are able to process sequence data from Sanger sequencing, ultra-deep amplicon resequencing (pyrosequencing) and chromatograph (trace files), as appropriate. The tools are available online at no cost and are aimed at researchers without specialist technical computer knowledge. The tools can be accessed at http://hvdr.bioinf.wits.ac.za/SmallGenomeTools, and the source code is available online at https://github.com/DrTrevorBell/SmallGenomeTools. PMID- 25690797 TI - Aptamers in diagnostics and treatment of viral infections. AB - Aptamers are in vitro selected DNA or RNA molecules that are capable of binding a wide range of nucleic and non-nucleic acid molecules with high affinity and specificity. They have been conducted through the process known as SELEX (Systematic Evolution of Ligands by Exponential Enrichment). It serves to reach specificity and considerable affinity to target molecules, including those of viral origin, both proteins and nucleic acids. Properties of aptamers allow detecting virus infected cells or viruses themselves and make them competitive to monoclonal antibodies. Specific aptamers can be used to interfere in each stage of the viral replication cycle and also inhibit its penetration into cells. Many current studies have reported possible application of aptamers as a treatment or diagnostic tool in viral infections, e.g., HIV (Human Immunodeficiency Virus), HBV (Hepatitis B Virus), HCV (Hepatitis C Virus), SARS (Severe Acute Respiratory Syndrome), H5N1 avian influenza and recently spread Ebola. This review presents current developments of using aptamers in the diagnostics and treatment of viral diseases. PMID- 25690799 TI - Intranasal administration of maleic anhydride-modified human serum albumin for pre-exposure prophylaxis of respiratory syncytial virus infection. AB - Respiratory syncytial virus (RSV) is the leading cause of pediatric viral respiratory tract infections. Neither vaccine nor effective antiviral therapy is available to prevent and treat RSV infection. Palivizumab, a humanized monoclonal antibody, is the only product approved to prevent serious RSV infection, but its high cost is prohibitive in low-income countries. Here, we aimed to identify an effective, safe, and affordable antiviral agent for pre-exposure prophylaxis (PrEP) of RSV infection in children at high risk. We found that maleic anhydride (ML)-modified human serum albumin (HSA), designated ML-HSA, exhibited potent antiviral activity against RSV and that the percentages of the modified lysines and arginies in ML- are correlated with such anti-RSV activity. ML-HSA inhibited RSV entry and replication by interacting with viral G protein and blocking RSV attachment to the target cells, while ML-HAS neither bound to F protein, nor inhibited F protein-mediated membrane fusion. Intranasal administration of ML-HSA before RSV infection resulted in significant decrease of the viral titers in the lungs of mice. ML-HSA shows promise for further development into an effective, safe, affordable, and easy-to-use intranasal regimen for pre-exposure prophylaxis of RSV infection in children at high risk in both low- and high-income countries. PMID- 25690801 TI - Complete genome analysis of a rabbit rotavirus causing gastroenteritis in a human infant. AB - Group A rotaviruses (RVA) are responsible for causing infantile diarrhea both in humans and animals. The molecular characteristics of lapine RVA strains are only studied to a limited extent and so far G3P[14] and G3P[22] were found to be the most common G/P-genotypes. During the 2012-2013 rotavirus season in Belgium, a G3P[14] RVA strain was isolated from stool collected from a two-year-old boy. We investigated whether RVA/Human-wt/BEL/BE5028/2012/G3P[14] is completely of lapine origin or the result of reassortment event(s). Phylogenetic analyses of all gene segments revealed the following genotype constellation: G3-P[14]-I2-R2-C2-M3-A9 N2-T6-E5-H3 and indicated that BE5028 probably represents a rabbit to human interspecies transmission able to cause disease in a human child. Interestingly, BE5028 showed a close evolutionary relationship to RVA/Human wt/BEL/B4106/2000/G3P[14], another lapine-like strain isolated in a Belgian child in 2000. The phylogenetic analysis of the NSP3 segment suggests the introduction of a bovine(-like) NSP3 into the lapine RVA population in the past 12 years. Sequence analysis of NSP5 revealed a head-to-tail partial duplication, combined with two short insertions and a deletion, indicative of the continuous circulation of this RVA lineage within the rabbit population. PMID- 25690800 TI - The role of RNA interference (RNAi) in arbovirus-vector interactions. AB - RNA interference (RNAi) was shown over 18 years ago to be a mechanism by which arbovirus replication and transmission could be controlled in arthropod vectors. During the intervening period, research on RNAi has defined many of the components and mechanisms of this antiviral pathway in arthropods, yet a number of unexplored questions remain. RNAi refers to RNA-mediated regulation of gene expression. Originally, the term described silencing of endogenous genes by introduction of exogenous double-stranded (ds)RNA with the same sequence as the gene to be silenced. Further research has shown that RNAi comprises three gene regulation pathways that are mediated by small RNAs: the small interfering (si)RNA, micro (mi)RNA, and Piwi-interacting (pi)RNA pathways. The exogenous (exo )siRNA pathway is now recognized as a major antiviral innate immune response of arthropods. More recent studies suggest that the piRNA and miRNA pathways might also have important roles in arbovirus-vector interactions. This review will focus on current knowledge of the role of the exo-siRNA pathway as an arthropod vector antiviral response and on emerging research into vector piRNA and miRNA pathway modulation of arbovirus-vector interactions. Although it is assumed that arboviruses must evade the vector's antiviral RNAi response in order to maintain their natural transmission cycles, the strategies by which this is accomplished are not well defined. RNAi is also an important tool for arthropod gene knock down in functional genomics studies and in development of arbovirus-resistant mosquito populations. Possible arbovirus strategies for evasion of RNAi and applications of RNAi in functional genomics analysis and arbovirus transmission control will also be reviewed. PMID- 25690802 TI - A new Kruppel-like factor 1 mutation (c.947G > A or p.C316Y) in humans causes beta-thalassemia minor. AB - Here we describe a Japanese patient with mild beta-thalassemia (beta-thal) with an intact beta-globin gene but a new missense mutation of c.947G > A or p.C316Y in the erythroid Kruppel-Like Factor (KLF1) gene which is strongly associated with the expression of the beta-globin gene. The association of the KLF1 mutation with beta-thal, is here described. The p.C316Y mutation occurred at one of the cysteines that constitute the second zinc finger motif of KLF1, and would have changed the zinc finger conformation to impair the DNA binding properties or the promoter function of the beta-globin gene. Our expression study found that the mutant KLF1 gene had a markedly negative effect on the beta-globin gene expression, or 7.0% of that of its normal counterpart. A presumed heterozygous state, or equimolar presence of the mutant and normal KLF1s reduced the expression rate to 70.0% of the normal alone. This degree of the decrease may explain the very mild phenotype of the patient's beta-thal. Furthermore, the patient's whole-exome analysis using next-generation sequencing revealed that the beta-thal defect is caused by only this KLF1 gene mutation. The Hb A2 and Hb F levels that are frequently elevated in KLF1 mutations were elevated by 4.1 and 1.3%, respectively, in this case. The contribution to their elevation by KLF1: p.C316Y is uncertain. PMID- 25690803 TI - Association of an alpha-globin gene cluster duplication and heterozygous beta thalassemia in a patient with a severe thalassemia syndrome. AB - We describe a new case of a beta-thalassemia (beta-thal) heterozygote with the mutation IVS-II-654 (C>T) presenting with a transfusion-dependent phenotype. Multiplex ligation-dependent probe amplification (MLPA) and array comparative genomic hybridization (CGH) analyses of the alpha-globin gene cluster revealed a full duplication of the alpha-globin genes including the upstream regulatory element. The duplicated allele and the normal allele in trans resulted in a total of six active alpha-globin genes. The severe clinical phenotype seemed to be related to the considerable excess of the alpha- and beta-globin deficit caused by the presence of the beta-thal. alpha-Globin cluster duplication should be considered in patients heterozygous for beta-thal who show a more severe phenotype than beta-thal trait. PMID- 25690804 TI - A population-based, incidence cohort study of mid-back pain after traffic collisions: Factors associated with global recovery. AB - BACKGROUND: Traffic collisions often result in a wide range of symptoms included in the umbrella term whiplash-associated disorders. Mid-back pain (MBP) is one of these symptoms. The incidence and prognosis of different traffic injuries and their related conditions (e.g. neck pain, low back pain, depression or others) has been investigated previously; however, knowledge about traffic collision related MBP is lacking. The study objectives were to describe the incidence, course of recovery and prognosis of MBP after traffic collisions, in terms of global self-reported recovery. METHODS: Longitudinal data from a population-based inception cohort of all traffic injuries occurring in Saskatchewan, Canada, during a 2-year period were used. Annual overall and age-sex-specific incidence rates were calculated, the course of recovery was described using the Kaplan Meier technique, and associations between participant characteristics and time-to self-reported recovery were explored in 3496 MBP cases using Cox proportional hazards models. RESULTS: The yearly incidence rate was 236 per 100,000 population during the study period, and was highest in women and in young persons. The median time-to-first reported recovery was 101 days (95% CI: 99-104) and about 23% were still not recovered after 1 year. Participant's expectation for recovery, general health, extent of severely affecting comorbidities and having experienced a previous traffic injury were some of the prognostic factors identified. CONCLUSIONS: These findings show that MBP is common after traffic collisions, may result in a long recovery process and that a range of biopsychosocial factors are associated with recovery. PMID- 25690805 TI - Small-for-gestational-age in very-low-birth-weight infants: good or bad? PMID- 25690806 TI - Design and characterization of a conductive nanostructured polypyrrole polycaprolactone coated magnesium/PLGA composite for tissue engineering scaffolds. AB - A novel biodegradable and conductive composite consisting of magnesium (Mg), polypyrrole-block-ploycaprolactone (PPy-PCL), and poly(lactic-co-glycolic acid) (PLGA) is synthesized in a core-shell-skeleton manner for tissue engineering applications. Mg particles in the composite are first coated with a conductive nanostructured PPy-PCL layer for corrosion resistance via the UV-induced photopolymerization method. PLGA matrix is then added to tailor the biodegradability of the resultant composite. Composites with different composition ratios are examined through experiments, and their material properties are characterized. The in vitro experiments on culture of 293FT-GFP cells show that the composites are suitable for cell growth and culture. Biodegradability of the composite is also evaluated. By adding PLGA matrix to the composite, the degrading time of the composite can last for more than eight weeks, hence providing a longer period for tissue formation as compared to Mg composites or alloys. The findings of this research will offer a new opportunity to utilize a conductive, nanostructured-coated Mg/PLGA composite as the scaffold material for implants and tissue regeneration. PMID- 25690807 TI - Complementary needs behind complementary therapies in cancer patients. AB - OBJECTIVE: Although many studies indicate that the use of complementary and alternative medicine by cancer patients is common and widespread, few studies have focused on unmet needs of patients using complementary therapies (CTs). The aim of the present study was to evaluate, through a quantitative approach, possible associations between the use of CTs and the presence of specific unmet needs in cancer patients. METHODS: In six Italian oncology departments, 783 patients were interviewed about CTs use and completed the Needs Evaluation Questionnaire. Patients included in the study had different primary tumor sites and were in different phases of the disease and care process. RESULTS: At the time of the survey, 38.3% of patients were using one or more types of CTs. According to Needs Evaluation Questionnaire, the use of CTs was associated (p < .05) with the need to be more involved in therapeutic choices (40% vs. 31.7%), the need to have a better dialogue with clinicians (44.4% vs. 37.2%), and the need to have more economic-insurance information in relation to their illness (46.1% vs. 36.4%). Statistical significance was confirmed with multivariable analysis for the last two items, whereas three more needs were associated with the use of CTs after adjustment: to receive more explanation on treatments (46.8% vs. 41.0%), to receive more comprehensible information (38% vs. 31.9%), and to receive more attention from nurses (16% vs. 12.1%). CONCLUSIONS: Our study shows interesting differences regarding perceived needs between cancer patients who use and who do not use CTs. Unmet needs that are more expressed in CTs users should be known and, when possible, could be taken into account to improve both psychosocial interventions in the context of conventional care process and the quality of the relationship between patient and medical and nursing staff. PMID- 25690808 TI - Changes in Stepparents' Coparenting and Parenting Following Participation in a Community-Based Relationship Education Program. AB - Studies of coparents typically center on the relationship between parents who share a biological child; limited attention in research on community-based programs is given to the coparenting relationship within a stepfamily, even though clinicians note the challenges inherent in this relationship. We examined changes in coparenting agreement, parenting efficacy, and parental involvement for 96 stepparents following participation in a coparenting-focused community education program. A significant main effect of time was found for improvement in coparenting agreement, yet a significant time * gender interaction effect suggests that this is driven by improvements for stepmothers only. Parenting efficacy improved, regardless of gender, race, residence, or curriculum. A significant time * race interaction effect on change in parental involvement indicates increases in parental involvement for European American participants only. Finally, increases in coparenting agreement were associated with increases in parenting efficacy, and increases in parenting efficacy were associated with increases in parental involvement. PMID- 25690809 TI - Xenon NMR of liquid crystals confined to cylindrical nanocavities: a simulation study. AB - Applications of liquid crystals (LCs), such as smart windows and the ubiquitous display devices, are based on controlling the orientational and translational order in a small volume of LC medium. Hence, understanding the effects of confinement to the liquid crystal phase behaviour is essential. The NMR shielding of (129)Xe atoms dissolved in LCs constitutes a very sensitive probe to the details of LC environment. Linking the experimental results to microscopic phenomena calls for molecular simulations. In this work, the NMR shielding of atomic (129)Xe dissolved in a uniaxial thermotropic LC confined to nanosized cylindrical cavities is computed from coarse-grained (CG) isobaric Monte Carlo (MC) simulations with a quantum-chemically (QC) pre-parameterised pairwise additive model for the Xe nuclear shielding tensor. We report the results for the (129)Xe nuclear shielding and its connection to the structure and order of the LC appropriate to two different cavity sizes, as well as a comparison to the results of bulk (non-confined) simulations. We find that the confinement changes the LC phase structure dramatically and gives rise to the coexistence of varying degrees of LC order, which is reflected in the Xe shielding. Furthermore, we qualitatively reproduce the behaviour of the mean (129)Xe chemical shift with respect to temperature for atomic Xe dissolved in LC confined to controlled-pore glass materials. In the small-radius cavity the nematic - paranematic phase transition is revealed only by the anisotropic component of the (129)Xe nuclear shielding. In the larger cavity, the nematic - paranematic - isotropic transition is clearly seen in the Xe shielding. The simulated (129)Xe NMR shielding is insensitive to the smectic-A - nematic transition, since in the smectic-A phase, the Xe atoms largely occupy the imperfect layer structure near the cavity walls. The direct contribution of the cavity wall to (129)Xe nuclear shielding is dependent on the cavity size but independent of temperature. Our results show that the combination of CG simulations and a QC pre-parameterised (129)Xe NMR shielding allows efficient studies of the phase behaviour and structure of complex systems containing thousands of molecules, and brings us closer to the simulation of NMR experiments. PMID- 25690810 TI - Every nurse makes history. PMID- 25690812 TI - An analysis comparing "Sim Huddles" to traditional simulation for obstetric emergency preparedness. AB - Health care professionals in obstetrics must be prepared to respond when emergencies arise. Simulation provides the opportunity to train in a team setting but can be resource-intensive. A postprogram implementation analysis compared high-fidelity in-situ simulation to a novel approach called "Sim Huddles." Sim Huddles are conducted in a quick, informal, low-fidelity staff huddle format incorporating concepts of TeamSTEPPS(r). Postsimulation participant surveys from nine Sim Huddles were compared to nine traditional in-situ simulations. Results show similar achievement of learning goals and statistically significant improvement in self-reported confidence (p = .002) from the traditional in-situ format (mean = 4.32, sd = .771) compared to the Sim Huddle format (mean = 4.74, sd = .480). Sim Huddles can provide effective training with less time and fewer resources than what is required of traditional, high-fidelity simulation. PMID- 25690813 TI - A community-based walking program to promote physical activity among African American women. AB - The death rate from cardiovascular disease (CVD) is substantially higher among African American women than for white women. Physical activity has been linked to decreased risk factors and deaths related to CVD. Despite the health benefits of physical activity, reports show most African American women have low levels of physical activity. Home- or community-based walking interventions are effective strategies to promote increased levels of physical activity among African American women. This article describes the implementation of one such program. PMID- 25690814 TI - Enhancing neonatal wellness with home visitation. AB - We planned and implemented an evidence-based program to screen for jaundice and to try to increase the proportion of women breastfeeding for 6 months. The program involved home visitation by a registered nurse to provide education on and support of breastfeeding, and to perform physical assessment of both mothers and newborns, including screening for neonatal jaundice. Quantitative data showed increased breastfeeding rates at 6 months. In addition, readmission rates for jaundice were higher when compared to regional benchmarks. However, the average length of stay for treatment of jaundice was shorter than regional benchmarks. Qualitative data indicated that the program was effective at achieving its goals and was valued by participants. PMID- 25690815 TI - Intrahepatic cholestasis of pregnancy. AB - Itching is commonly reported by pregnant women and may be due to physiologic changes of pregnancy or could indicate a more serious health concern. Intrahepatic cholestasis of pregnancy, while classified as a pregnancy dermatosis, is actually a liver disease of pregnancy associated with significant fetal mortality and morbidity, as well as lifelong health risks for the offspring. In these challenging cases, nurses must understand the differential diagnoses and be prepared to provide comprehensive care, education and support to women with this condition. A case example is included. PMID- 25690816 TI - Urine-based HPV testing as a method to screen for cervical cancer. AB - Cervical cancer is a treatable and preventable cancer that remains a concern for women worldwide. Efforts to reduce rates of cervical cancer focus on the promotion of human papillomavirus (HPV) vaccination and the promotion of routine recommended cervical cancer screening, primarily done by cervical cytology and cervical HPV testing. Recently researchers have begun to examine urine-based HPV testing as a future potential alternative to the current cervical screening methodology. This column takes a second look at two recent U.S.-based studies in which researchers evaluated urine-based HPV testing as a simple and noninvasive approach to screen for cervical cancer. PMID- 25690817 TI - Inhaled insulin--a new delivery for an old drug. AB - Rates of diabetes continue to rise in the United States. It's estimated that more than 25 million people in the United States currently have either type 1 or type 2 diabetes. Insulin is the mainstay of treatment, and a new delivery option is available. In 2014, the U.S. Food and Drug Administration approved Afrezza(r) inhalation powder, a rapid-acting inhaled form of human insulin, to treat diabetes in adults. This article will provide an overview of the Afrezza system, indications for use, adverse reactions and implications for nurses who work with women with diabetes. PMID- 25690818 TI - Managing osteoarthritis. AB - Osteoarthritis (OA) is a degenerative disease that affects 27 million American women. All body joints can be affected. OA is more prevalent in women than men. Most women, with a diagnosis of OA report discomfort in the knee, hip, back and wrist joints. The discomforts of OA can be managed with life style changes before over the counter medications are introduced. Surgical interventions should be considered as the last treatment choice. Once a medication choice has been introduced, nurses can review methods to women that will improve their ability to continue activities of daily living and decrease the impact of the discomforts of OA. Nurses can be instrumental in the management of OA by providing education about different intervention choices for the management of OA symptoms. PMID- 25690820 TI - Competencies for women's health clinical nurse specialists. PMID- 25690821 TI - Breastfeeding. PMID- 25690822 TI - Role of the registered nurse in the care of the pregnant woman receiving analgesia and anesthesia by catheter techniques. PMID- 25690823 TI - Criminalization of pregnant women with substance use disorders. PMID- 25690824 TI - Quantification of blood loss: AWHONN practice brief number 1. PMID- 25690825 TI - Guidelines for oxytocin administration after birth: AWHONN practice brief number 2. PMID- 25690826 TI - Ebola: caring for pregnant and postpartum women and newborns in the United States: AWHONN practice brief number 3. PMID- 25690827 TI - A nightingale's sorrow. PMID- 25690829 TI - A betaine adduct of N-heterocyclic carbene and carbodiimide, an efficient ligand to produce ultra-small ruthenium nanoparticles. AB - The betaine adduct of N-heterocyclic carbene and carbodiimide (ICy.((p-tol))NCN) was found to be a very efficient ligand to prepare very small (1-1.3 nm) ruthenium nanoparticles (RuNPs). The coordination of the ligand on the metal surface takes place through the carbodiimide moiety. The resulting RuNPs led to decarbonylation of THF and showed size selectivity for styrene hydrogenation. PMID- 25690830 TI - Spectral Signatures of Saccade Target Selection. AB - Action generation relies on a widely distributed network of brain areas. However, little is known about the spatiotemporal dynamics of neuronal activity in the network that gives rise to voluntary action in humans. Here, we used magnetoencephalography (MEG) and source analysis (n = 15, 7 female subjects) to investigate the spectral signatures of human cortical networks engaged in active and intrinsically motivated viewing behavior. We compared neuronal activity of externally cued saccades with saccades to freely chosen targets. For planning and execution of both saccade types, we found an increase in gamma band (~64-128 Hz) activity and a concurrent decrease in beta band (~12-32 Hz) activity in saccadic control areas, including the intraparietal sulcus and the frontal eye fields. Guided compared to voluntary actions were accompanied by stronger transient increases in the gamma and low frequency (<16 Hz) range immediately following the instructional cue. In contrast, action selection between competing alternatives was reflected by stronger sustained fronto-parietal gamma increases that occurred later in time and persisted until movement execution. This sustained enhancement for free target selection was accompanied by a spatially widespread reduction of lower frequency power (~8-45 Hz) in parietal and extrastriate areas. Our results suggest that neuronal population activity in the gamma frequency band in a distributed network of fronto-parietal areas reflects the intrinsically driven process of selection among competing behavioral alternatives. PMID- 25690832 TI - A new bisphenol A derivative for estrogen receptor binding studies with surface plasmon resonance. AB - A new bisphenol A (BPA) derivative was synthesized and immobilized onto the surface of a CM5 sensor chip for a binding study with orphan estrogen-related receptor gamma using the surface plasmon resonance technique. The kinetic parameters, including dissociation and association constants and dissociation and association rate constants, were investigated. Moreover, a competitive inhibition assay was conducted to understand the competition relationship between the free BPA molecules in solution and the immobilized BPA molecules on the sensor chip surface. The CM5 sensor chip immobilized with the BPA derivative can be regenerated by using a high-concentration running buffer for repeated use more than 150 times without any adverse effect on its performance in the binding studies. The results indicate that the system has potential for further development as a sensitive surface plasmon resonance-based biosensor for endocrine-disrupting chemicals. PMID- 25690831 TI - Behavioral dependence of auditory cortical responses. AB - Neural responses in the auditory cortex have historically been measured from either anesthetized or awake but non-behaving animals. A growing body of work has begun to focus instead on recording from auditory cortex of animals actively engaged in behavior tasks. These studies have shown that auditory cortical responses are dependent upon the behavioral state of the animal. The longer ascending subcortical pathway of the auditory system and unique characteristics of auditory processing suggest that such dependencies may have a more profound influence on cortical processing in the auditory system compared to other sensory systems. It is important to understand the nature of these dependencies and their functional implications. In this article, we review the literature on this topic pertaining to cortical processing of sounds. PMID- 25690833 TI - Peripheral regional anaesthesia and outcome: lessons learned from the last 10 years. AB - BACKGROUND: Our aim was to review the recent evidence for the efficacy of peripheral regional anaesthesia. METHODS: Following a systematic literature search and selection of publications based on prospectively agreed upon criteria, we produced a narrative review of the most commonly performed peripheral regional anaesthetic blocks for surgery on the upper limb, the lower limb, and the trunk. We considered short-term and longer-term benefits and complications among the outcomes of interest. RESULTS: Where good quality evidence exists, the great majority of the blocks reviewed were associated with one or any combination of reduced postoperative pain, reduced opioid consumption, or increased patient satisfaction. For selected surgical procedures, the use of blocks avoided general anaesthesia and was associated with increased efficiency of the surgical pathway. The exceptions were supraclavicular block, where there was insufficient evidence, and transversus abdominis plane block, where the evidence for efficacy was conflicting. The evidence for the impact of the blocks on longer-term outcomes was, in general, inadequate to inform clinical decision making. Permanent complications are rare. CONCLUSIONS: The majority of peripheral regional anaesthetic techniques have been shown to produce benefits for patients and hospital efficiency. Further interventional trials are required to clarify such benefits for supraclavicular block and transversus abdominis plane block and to ascertain any longer-term benefits for almost all of the blocks reviewed. Permanent complications of peripheral regional anaesthetic blocks are rare but accurate estimates of their incidence are yet to be determined. PMID- 25690834 TI - Goal-Directed fluid therapy with closed-loop assistance during moderate risk surgery using noninvasive cardiac output monitoring: A pilot study. AB - BACKGROUND: Goal directed fluid therapy (GDFT) has been shown to improve outcomes in moderate to high-risk surgery. However, most of the present GDFT protocols based on cardiac output optimization use invasive devices and the protocols may require significant practitioner attention and intervention to apply them accurately. The aim of this prospective pilot study was to evaluate the clinical feasibility of GDFT using a closed-loop fluid administration system with a non invasive cardiac output monitoring device (NexfinTM, BMEYE, Amsterdam, Netherlands). METHODS: Patients scheduled for elective moderate risk surgery under general anaesthesia were enrolled. The primary anaesthesia team managing the case selected GDFT targets using the controller interface and all patients received a baseline 3 ml kg(-1) h(-1) crystalloid infusion. Colloid solutions were delivered by the closed-loop system for intravascular volume expansion using data from the NexfinTM monitor. Compliance with GDFT management was defined as acceptable when a patient spent more than 85% of the surgery time in a preload independent state (defined as pulse pressure variation <13%) or when average cardiac index during surgery was >2.5 litre min(-1) m(-2). RESULTS: A total of 13 patients were included in the study group. All patients met the established criteria for delivery of GDFT for greater than 85% of case time. The median length of stay in the hospital was 5 [3-6] days. CONCLUSION: In this pilot study, GDFT management using the closed-loop fluid administration system with a non invasive CO monitoring device was feasible and maintained a high rate of protocol compliance. CLINICAL TRIAL REGISTRATION: NCT02020863. PMID- 25690835 TI - Sink or swim? The difficulty of finding the correct level of independence and support for trainees. PMID- 25690836 TI - Perioperative stroke: a question of timing? PMID- 25690837 TI - MR Imaging Findings of Paget's Disease of the Spine. AB - Paget's disease (PD) is a common bone disorder of the aging population where the spine is the second most common involved location after the pelvis. Though imaging findings are well described on CT and radiographs, recognition on MRI can be challenging. We reviewed 16 cases with radiologic or histologic confirmation of uncomplicated PD of the spine. In most cases, MRI showed a mixed pattern of increased/ decreased T1 signal (fine trabecular or coarse) of the vertebral bodies. There was also associated band-like decreased T1 and T2 signal of the endplates. This correlates with the mixed osteolytic and blastic phase of the disease, the most common phase in the spine. Subtle or conspicuous "picture frame" appearance may also be identified. Present in most cases, but frequently overlooked manifestation on MRI, was the expansion of the vertebral body and/or posterior elements/ spinous process. We identified a subtle diffuse decreased T1 and T2 bone marrow signal, not corresponding to sclerosis on CT or radiographs, in two cases. We proposed this, as an earliest sign on MRI, likely representing early fibro-vascular bone marrow transformation and to our knowledge not previously described. Less commonly, sclerotic PD was also found which is perhaps the most difficult to evaluate given its broad differential. Most cases of PD of the spine were overlooked or confused with other entities by the radiologists. Interpretation of MR images of the spine in the absence of prior imaging is not uncommon. Thus, recognition of MRI manifestations is important to allow appropriate management, to avoid misinterpretations and in most cases to avoid biopsy. PMID- 25690838 TI - Drug Transporter Protein Quantification of Immortalized Human Lung Cell Lines Derived from Tracheobronchial Epithelial Cells (Calu-3 and BEAS2-B), Bronchiolar Alveolar Cells (NCI-H292 and NCI-H441), and Alveolar Type II-like Cells (A549) by Liquid Chromatography-Tandem Mass Spectrometry. AB - Understanding the mechanisms of drug transport in the human lung is an important issue in pulmonary drug discovery and development. For this purpose, there is an increasing interest in immortalized lung cell lines as alternatives to primary cultured lung cells. We recently reported the protein expression in human lung tissues and pulmonary epithelial cells in primary culture, (Sakamoto A, Matsumaru T, Yamamura N, Uchida Y, Tachikawa M, Ohtsuki S, Terasaki T. 2013. J Pharm Sci 102(9):3395-3406) whereas comprehensive quantification of protein expressions in immortalized lung cell lines is sparse. Therefore, the aim of the present study was to clarify the drug transporter protein expression of five commercially available immortalized lung cell lines derived from tracheobronchial cells (Calu 3 and BEAS2-B), bronchiolar-alveolar cells (NCI-H292 and NCI-H441), and alveolar type II cells (A549), by liquid chromatography-tandem mass spectrometry-based approaches. Among transporters detected, breast cancer-resistance protein in Calu 3, NCI-H292, NCI-H441, and A549 and OCTN2 in BEAS2-B showed the highest protein expression. Compared with data from our previous study,(Sakamoto A, Matsumaru T, Yamamura N, Uchida Y, Tachikawa M, Ohtsuki S, Terasaki T. 2013. J Pharm Sci 102(9):3395-3406) NCI-H441 was the most similar with primary lung cells from all regions in terms of protein expression of organic cation/carnitine transporter 1 (OCTN1). In conclusion, the protein expression profiles of transporters in five immortalized lung cell lines were determined, and these findings may contribute to a better understanding of drug transport in immortalized lung cell lines. PMID- 25690839 TI - A novel HLA-A allele, HLA-A*02:488, identified by sequence-based typing. AB - HLA-A*02:488 differs from HLA-A*02:01:01:01 by one nucleotide exchange at position 425(A > G) with an amino exchange. PMID- 25690840 TI - Prophylactic Swallowing Exercises in Head and Neck Cancer Radiotherapy. AB - Many head and neck cancer (HNC) survivors experience reduced quality of life due to radiotherapy (RT)-related dysphagia. The aim of this prospective randomized trial was to evaluate the impact of prophylactic swallowing exercises on swallowing-related outcomes in HNC patients treated with curative RT. Patients treated with primary RT for HNC were candidates for this randomized protocol. Participants in the exercise group were instructed to perform swallowing exercises at home. Participants in the control group were given standard care. Patients were evaluated with modified barium swallow and several other secondary outcome measures at four and nine different time points, respectively. Data were analyzed according to intention-to-treat analyses. A total of 44 consecutive patients were included; 22 in each group. In general, there was no difference between the two groups regarding any of the dysphagia outcomes during and after treatment. Adherence to exercises was poor and dropouts due to especially fatigue were very frequent in both groups. Systematic swallowing exercises had no impact on swallowing outcomes within the first year after RT. Despite repeated supervised sessions, adherence to exercises was a major issue and dropouts were frequent in both the intervention and control group. PMID- 25690841 TI - Environmental predictors of diarrhoeal infection for rural and urban communities in south India in children and adults. AB - Diarrhoeal diseases are major causes of morbidity and mortality in developing countries. This longitudinal study aimed to identify controllable environmental drivers of intestinal infections amidst a highly contaminated drinking water supply in urban slums and villages of Vellore, Tamil Nadu in southern India. Three hundred households with children (<5 years) residing in two semi-urban slums and three villages were visited weekly for 12-18 months to monitor gastrointestinal morbidity. Households were surveyed at baseline to obtain information on environmental and behavioural factors relevant to diarrhoea. There were 258 diarrhoeal episodes during the follow-up period, resulting in an overall incidence rate of 0.12 episodes/person-year. Incidence and longitudinal prevalence rates of diarrhoea were twofold higher in the slums compared to rural communities (P < 0.0002). Regardless of study site, diarrhoeal incidence was highest in infants (<1 year) at 1.07 episodes/person-year, and decreased gradually with increasing age. Increasing diarrhoeal rates were associated with presence of children (<5 years), domesticated animals and low socioeconomic status. In rural communities, open-field defecation was associated with diarrhoea in young children. This study demonstrates the contribution of site-specific environmental and behavioural factors in influencing endemic rates of urban and rural diarrhoea in a region with highly contaminated drinking water. PMID- 25690842 TI - Diabetic nephropathy in pregnancy: new insights from a retrospective cohort study. PMID- 25690843 TI - Integration of poly-3-(hydroxybutyrate-co-hydroxyvalerate) production by Haloferax mediterranei through utilization of stillage from rice-based ethanol manufacture in India and its techno-economic analysis. AB - Haloferax mediterranei has potential for economical industrial-scale production of polyhydroxyalkanoate (PHA) as it can utilize cheap carbon sources, has capacity for nonsterile cultivation and allows simple product recovery. Molasses based Indian distilleries are converting themselves to cereal-based distilleries. Waste stillage (14 l) of rice-based ethanol industry was used for the production of PHA by H. mediterranei in the simple plug-flow reactor configuration of the activated sludge process. Cells utilized stillage and accumulated 63 +/- 3 % PHA of dry cell weight and produced 13.12 +/- 0.05 g PHA/l. The product yield coefficient was 0.27 while 0.14 g/l h volumetric productivity was reached. Simultaneous lowering of 5-day biochemical oxygen demand and chemical oxygen demand values of stillage by 82 % was attained. The biopolymer was characterized as poly-3-(hydroxybutyrate-co-17.9 mol%-hydroxyvalerate) (PHBV). Directional properties of decanoic acid jointly with temperature-dependent water solubility in decanoic acid were employed for two-step desalination of the spent stillage medium in a cylindrical baffled-tank with an immersed heater and a stirrer holding axial and radial impellers. 99.3 % of the medium salts were recovered and re-used for PHA production. The cost of PHBV was estimated as US$2.05/kg when the annual production was simulated as 1890 tons. Desalination contributed maximally to the overall cost. Technology and cost-analysis demonstrate that PHA production integrated with ethanol manufacture is feasible in India. This study could be the basis for construction of a pilot plant. PMID- 25690844 TI - Aneurysmatic dermatofibroma with dermoscopic and reflectance confocal microscopic features. PMID- 25690845 TI - Incorporating ecology and social system into formal hypotheses to guide field studies of color vision in primates. AB - The X-linked gene polymorphism responsible for the variable color vision of most Neotropical monkeys and some lemurs is thought to be maintained by balancing selection, such that trichromats have an advantage over dichromats for some ecologically important task(s). However, evidence for such an advantage in wild primate populations is equivocal. The purpose of this study is to refine a hypothesis for a trichromat advantage by tailoring it to the ecology of territorial primates with female natal dispersal, such that dispersing trichromatic females have a foraging and, by extension, survival advantage over dichromats. I then examine the most practical way to test this hypothesis using field data. Indirect evidence in support of the hypothesis may take the form of differences in genotype frequencies among life stages and differences in disperser food item encounter rates. A deterministic evolutionary matrix population model and a stochastic model of food patch encounter rates are constructed to investigate the magnitude of such differences and the likelihood of statistical detection using field data. Results suggest that, although the sampling effort required to detect the hypothesized genotype frequency differences is impractical, a field study of reasonable scope may be able to detect differences in disperser foraging rates. This study demonstrates the utility of incorporating socioecological details into formal hypotheses during the planning stages of field studies of primate color vision. PMID- 25690846 TI - Mapping the anode surface-electrolyte interphase: investigating a life limiting process of lithium primary batteries. AB - Cathode solubility in batteries can lead to decreased and unpredictable long-term battery behavior due to transition metal deposition on the negative electrode such that it no longer supports high current. Analysis of negative electrodes from cells containing vanadium oxide or phosphorus oxide based cathode systems retrieved after long-term testing was conducted. This report demonstrates the use of synchrotron based X-ray microfluorescence (XRMUF) to map negative battery electrodes in conjunction with microbeam X-ray absorption spectroscopy (MUXAS) to determine the oxidation states of the metal centers resident in the solid electrolyte interphase (SEI) and at the electrode surface. Based on the empirical findings, a conceptual model for the location of metal ions in the SEI and their role in impacting lithium ion mobility at the electrode surfaces is proposed. PMID- 25690847 TI - Tenosynovitis: a rare presentation of tuberculosis better known by hand surgeons than infectious diseases specialists. AB - PURPOSE: Clinical presentation of tuberculosis is pleomorphic. Some forms are rare and better known by surgeons than infectious disease specialists. METHODS: We describe a rare case of isolated chronic tenosynovitis of the wrist due to Mycobacterium tuberculosis in a 66-year-old man and review similar cases in the literature. RESULTS: On literature search, only 23 other cases of tuberculous tenosynovitis were retrieved. Our case is similar, with an insidious classical presentation. The diagnosis was suggested at the surgical presentation by the presence of rice body masses. CONCLUSION: The diagnosis of tuberculous tenosynovitis should be considered in chronic tenosynovitis. Functional prognosis may be committed without adequate treatment. PMID- 25690848 TI - Risk factors and outcome of infections with Klebsiella pneumoniae carbapenemase producing K. pneumoniae in kidney transplant recipients. AB - INTRODUCTION: Solid organ transplant recipients are especially susceptible to healthcare-associated infections with Klebsiella pneumoniae carbapenemase producing K. pneumoniae (KPC-Kp-HAIs). The aim of the study was to evaluate risk factors and outcome of these infections in kidney transplant recipients. METHODS: This was a retrospective cohort of kidney transplant (KTx) recipients between January 2009 and December 2013. Cases were defined as patients who developed KPC Kp-HAI, confirmed by PCR for bla( KPC) gene after KTx during the study period. We analysed variables related to recipient; induction immunosuppressant therapy; delayed graft function; use of invasive devices; SOFA score on the first day of infection; type of therapy; time from positive culture to appropriate antimicrobial therapy; bacteraemia; and concomitant infection. Outcome measures were the occurrence of KPC-Kp-HAI and 30-day mortality after KPC-Kp-HAI. RESULTS: A total of 1,101 were submitted to KTx in the period, 21 patients were classified as infected with KPC-Kp. Another ten patients had KPC-Kp-HAI in the period and were transplanted before 2009. Of those 31 patients, 48.4 % showed evidence of prior colonization and 38.7 % had bacteraemia. The most common site of infection was the surgical wound. Risk factors for KPC-Kp-HAI were multi-organ transplantation and the use of a ureteral stent. Eight of the infected patients experienced recurrence of the infection. The 30-day mortality rate was 41.9 %. Survival was significantly lower among the patients with KPC-Kp-HAI (72 vs. 89.1 %; P = 0.002). The only risk factor independently associated with 30-day mortality was an elevated SOFA score on the first day of infection. CONCLUSIONS: In KTx recipients, the occurrence of KPC-Kp-HAI was related to invasive devices and type of transplant; these infections had a high rate of recurrence and reduced survival after KTx. PMID- 25690849 TI - Academic I.D. in jeopardy: the erosion of time, professional values, and physician satisfaction. AB - The American public entrusts academic medicine with a varied portfolio of critical responsibilities: the thoughtful mentoring of future generations of doctors, the engagement of cutting edge discoveries, and the empathic treatment of patients with complicated illnesses. The erosion of time to perform these duties has led to an estrangement of our key professional values and thus a loss of public trust, the inability to recognize new diseases, reduced communication in our ranks, and physician dissatisfaction. Much of this is driven by an unbalanced focus on the business model of medicine, highlighting rapid patient transactions linked to professional income with financial incentives for high volume care. Reversing the current trends requires a new type of leadership committed to long-held professional values and a recognition of what drives professional excellence. As internists and infectious diseases specialists without procedures in our practice, we are especially vulnerable to these trends. PMID- 25690850 TI - StringTie enables improved reconstruction of a transcriptome from RNA-seq reads. AB - Methods used to sequence the transcriptome often produce more than 200 million short sequences. We introduce StringTie, a computational method that applies a network flow algorithm originally developed in optimization theory, together with optional de novo assembly, to assemble these complex data sets into transcripts. When used to analyze both simulated and real data sets, StringTie produces more complete and accurate reconstructions of genes and better estimates of expression levels, compared with other leading transcript assembly programs including Cufflinks, IsoLasso, Scripture and Traph. For example, on 90 million reads from human blood, StringTie correctly assembled 10,990 transcripts, whereas the next best assembly was of 7,187 transcripts by Cufflinks, which is a 53% increase in transcripts assembled. On a simulated data set, StringTie correctly assembled 7,559 transcripts, which is 20% more than the 6,310 assembled by Cufflinks. As well as producing a more complete transcriptome assembly, StringTie runs faster on all data sets tested to date compared with other assembly software, including Cufflinks. PMID- 25690851 TI - Epigenomic annotation of genetic variants using the Roadmap Epigenome Browser. PMID- 25690852 TI - Inducible in vivo genome editing with CRISPR-Cas9. AB - CRISPR-Cas9-based genome editing enables the rapid genetic manipulation of any genomic locus without the need for gene targeting by homologous recombination. Here we describe a conditional transgenic approach that allows temporal control of CRISPR-Cas9 activity for inducible genome editing in adult mice. We show that doxycycline-regulated Cas9 induction enables widespread gene disruption in multiple tissues and that limiting the duration of Cas9 expression or using a Cas9(D10A) (Cas9n) variant can regulate the frequency and size of target gene modifications, respectively. Further, we show that this inducible CRISPR (iCRISPR) system can be used effectively to create biallelic mutation in multiple target loci and, thus, provides a flexible and fast platform to study loss-of function phenotypes in vivo. PMID- 25690853 TI - Large-scale imputation of epigenomic datasets for systematic annotation of diverse human tissues. AB - With hundreds of epigenomic maps, the opportunity arises to exploit the correlated nature of epigenetic signals, across both marks and samples, for large scale prediction of additional datasets. Here, we undertake epigenome imputation by leveraging such correlations through an ensemble of regression trees. We impute 4,315 high-resolution signal maps, of which 26% are also experimentally observed. Imputed signal tracks show overall similarity to observed signals and surpass experimental datasets in consistency, recovery of gene annotations and enrichment for disease-associated variants. We use the imputed data to detect low quality experimental datasets, to find genomic sites with unexpected epigenomic signals, to define high-priority marks for new experiments and to delineate chromatin states in 127 reference epigenomes spanning diverse tissues and cell types. Our imputed datasets provide the most comprehensive human regulatory region annotation to date, and our approach and the ChromImpute software constitute a useful complement to large-scale experimental mapping of epigenomic information. PMID- 25690854 TI - C2H2 zinc finger proteins greatly expand the human regulatory lexicon. AB - Cys2-His2 zinc finger (C2H2-ZF) proteins represent the largest class of putative human transcription factors. However, for most C2H2-ZF proteins it is unknown whether they even bind DNA or, if they do, to which sequences. Here, by combining data from a modified bacterial one-hybrid system with protein-binding microarray and chromatin immunoprecipitation analyses, we show that natural C2H2-ZFs encoded in the human genome bind DNA both in vitro and in vivo, and we infer the DNA recognition code using DNA-binding data for thousands of natural C2H2-ZF domains. In vivo binding data are generally consistent with our recognition code and indicate that C2H2-ZF proteins recognize more motifs than all other human transcription factors combined. We provide direct evidence that most KRAB containing C2H2-ZF proteins bind specific endogenous retroelements (EREs), ranging from currently active to ancient families. The majority of C2H2-ZF proteins, including KRAB proteins, also show widespread binding to regulatory regions, indicating that the human genome contains an extensive and largely unstudied adaptive C2H2-ZF regulatory network that targets a diverse range of genes and pathways. PMID- 25690855 TI - Blue scalp discoloration in infants caused by exogenous source. AB - A blue patch on the vertex scalp of an infant has a broad differential diagnosis, including vascular malformations, melanocytic lesions, trauma, and exogenous or endogenous pigmentation. We present two cases of infants who developed blue patches on the scalp. Extensive examination including MRI and biopsy was recommended for one of the patients to further characterize the lesion and its possible medical implications. In both, the blue discoloration had been due to repetitive contact with the sticker on a tub of baby wipes that had rubbed off onto the scalp. We present these infants to highlight this exogenous and benign cause of blue pigmentation and help practitioners avoid unnecessary examination. PMID- 25690856 TI - Hysteretic DC electrowetting by field-induced nano-structurations on polystyrene films. AB - Electrowetting (EW) offers executive wetting control of conductive liquids on several polymer surfaces. We report a peculiar electrowetting response for aqueous drops on a polystyrene (PS) dielectric surface in the presence of silicone oil. After the first direct current (DC) voltage cycle, the droplet failed to regain Young's angle, yielding contact angle hysteresis, which is close to a value found in ambient air. We conjecture that the hysteretic EW response appears from in situ surface modification using electric field induced water-ion contact with PS surface inducing nano-structuration by electro-hydrodynamic (EHD) instability. Atomic force microscopy confirms the formation of nano-structuration on the electrowetted surface. The effects of molecular weight, applied electric field, water conductivity and pH on nano-structuration are studied. Finally, the EW based nano-structuration on PS surface is used for the enhanced loading of aqueous dyes on hydrophobic surfaces. PMID- 25690857 TI - Cytodiagnosis of idiopathic calcinosis cutis: a case report. AB - We report a case of idiopathic calcinosis cutis diagnosed by fine needle aspiration cytology in a 50-yr-old female who presented with a subcutaneous swelling near the left iliac crest. Cytological finding of amorphous calcium salts with histiocytes and the appropriate clinical background led to the cytodiagnosis of idiopathic calcinosis cutis as subsequently confirmed on histopathology. Pitfalls in the diagnosis of calcinosis cutis on cytology smears are also discussed. PMID- 25690858 TI - Profile of head and neck cancers in Dr. Lutfi Kirdar Kartal Educational and Research Hospital. AB - OBJECTIVE: Head and neck cancers account for 17.6% of all malignant neoplasms. Data on the incidence of head and neck cancers and histological subtypes in Turkey are limited. This study aimed to provide an overview of statistics for head and neck cancers. MATERIAL AND METHOD: This retrospective and descriptive study included 1973 cases of in-situ carcinomas, malignant and borderline neoplasia from the head and neck region in a period of 5 years, diagnosed at Dr.Lutfi Kirdar Kartal Education and Research Hospital's Department of Pathology. Demographic data of patients and data from histopathological report were recorded. The topography of all tumours was coded according to the International Classification of Diseases for Oncology, 2nd and 3rd edition and histological and behavioral codes were given according to ICD-O-3. Data was entered and analyzed using Microsoft ExcelTM, version 2010. RESULTS: Male and female ratio was 1.03 for head and neck cancers. The most common sites for males were described as the ratio in head and neck cancers and all malignant tumours as follows: the skin (non-melanoma) (48.4%-8.2%), the larynx (12.6%-2.3%), the thyroid (11.1%-1.2%), the lips (7.8%-1.3%), and the nasopharynx (3.1%-0.5%). The most common sites for females were as follows: the thyroid (45.3%-8.3%), the skin (non-melanoma) (39.6% 7.3%), the lips (3.6%-0.6%), the nasopharynx (2.2%-0.4%) and the eye (1.7%-0.3%). The male: female ratio was 25.2 for larynx cancers. The most common histological types and rates for males and females were also given. CONCLUSION: This descriptive epidemiological pathology-based cancer incidence study has relative value for describing head and neck cancer incidences in the Istanbul region and shown that pathology report-based descriptive epidemiological studies are still valuable for determination of the regional distribution of cancer incidence out of the active cancer registration regions. PMID- 25690859 TI - Benign Malformative Lesion of the Skull: Hamartoma with Ectopic Elements or Choristoma? AB - Hamartoma and choristoma are terms that describe non-neoplastic, mass-forming malformative lesions. Although each lesion has a different composition, they have been used interchangeably in many reports, especially for malformative lesions containing ectopic or heterologous elements. We report a three month-old girl who was brought to the clinic with a mass lesion at the posterior fontanel, composed of predominantly osteo-cartilaginous tissue admixed with skeletal muscle, peripheral nerve tissue, and ganglion. The mass was resected completely. The composition of this benign lesion with ectopic elements was consistent with an osteo-cartilaginous hamartoma. We discuss the biological and clinical aspects such malformative lesions within the skull to highlight the inconsistencies of the nomenclature used in the literature. PMID- 25690860 TI - Immunohistochemical characteristics of cystic odontogenic lesions: a comparative study. AB - OBJECTIVE: Cystic ameloblastoma, keratocystic odontogenic tumor, dentigerous cyst, and radicular cyst are the most commonly encountered cystic odontogenic lesions. The aim of this study was to investigate the expressions of survivin, E cadherin, CD138, and CD38 in these lesions and their potential diagnostic usage. MATERIAL AND METHOD: A total of 20 cases, consisting 5 radicular cysts, 5 dentigerous cysts, 5 keratocystic odontogenic tumors and 5 cystic ameloblastomas were included in our series. For all cases, sections from the selected blocks were stained against the antibodies for survivin, E-cadherin, CD138, and CD38 on an automated device. RESULTS: All cystic ameloblastomas and keratocystic odontogenic tumors showed diffuse and strong nuclear survivin expression. No specific survivin immunoreactivity was observed in the dentigerous and radicular cysts. E-cadherin expression was stronger in all dentigerous cysts and radicular cysts when compared to others. CD138 expression in stromal cells was prominent in cystic ameloblastomas, but gradually decreased in the other three lesions. All cases were negative for CD38. CONCLUSION: In the present study, loss of E cadherin expression in epithelial cells, strong CD138 expression in stromal cells and strong nuclear survivin expression both in epithelial and stromal cells in cystic ameloblastomas and keratocystic odontogenic tumors were the most remarkable findings. These findings are also reinforced by the studies suggesting their role in the aggressiveness and pathogenesis of these tumors. PMID- 25690861 TI - Dedifferentiated Liposarcoma of the Gastroesophageal Junction. AB - Liposarcoma is one of the most common sarcomas in adults, but very rarely presents as a primary in the upper gastrointestinal system. Herein, we present a 71-year-old male patient who underwent wedge excision biopsy twice and then fine needle aspiration and total gastrectomy for a recurrent gastroeosophageal junction mass. In microscopic sections, both well-differentiated and dedifferentiated components were seen. Tumor cells were positive for MDM2, CDK4 and negative for CD117, DOG1, CD34, SMA, Desmin, S-100, HMB45, SOX10, AE1/AE3, CAM5.2, CK18. Fluorescence in situ hybridization (FISH) was performed and MDM2 gene (12q15) amplification was detected. According to these findings, a diagnosis of dedifferentiated liposarcoma was supported. We believe this is the first reported case of dedifferentiated liposarcoma of the gastroesophageal junction. PMID- 25690862 TI - Atypia and differential diagnosis in cellular blue nevi: clinicopathological study of 21 cases. AB - OBJECTIVE: Cellular blue nevus differs from the classic blue nevus with characteristics such as large size, cellularity, intense pigmentation, and growing pattern with subcutaneous infiltration. It is a dermal melanocytic tumor that can be confused with melanoma due to the atypia it may contain. MATERIAL AND METHOD: Hematoxylin-eosin and MIB-1 stained slides of 21 cases diagnosed between 2000-2014 were re-evaluated. In order to attract attention to this rare lesion, 21 cases are presented with the clinical and above-mentioned histopathological findings. RESULTS: Thirteen (61.9%) cases were females and eight (38.1%) were male. The mean age was 25.4 (2-73). The most frequent localization was the sacral and gluteal region (11 cases). The mean diameter was 14.4 mm (4-60 mm). From the parameters defined to assess the atypia, ulceration was identified in four cases. Prominent cellularity and subcutaneous infiltration were seen in three and 16 cases, respectively. Mitosis was seen in six tumors. Immunohistochemically, MIB-1 was present in two cases as 3% and 2% respectively, while in others it was 1% or less. Although there is no precise definition for the "atypical cellular blue nevus", five patients were assessed as atypical cellular blue nevus (a case with infiltrative development of six cm tumor diameter, two cases with two mitosis and a MIB-1 index 3% and 2%, a case with one mitosis and confluent development and a case with one mitosis in addition to focal necrosis areas). No lymph node and/or distant metastasis was observed during follow-up. CONCLUSION: We think it is more important to rule out the possibility of conventional melanoma in cellular blue nevus with exaggerated morphological findings alongside low proliferative activity rather than to determine the atypia. PMID- 25690863 TI - Attention to individual identities modulates face processing. AB - The ability of attention to apply in a flexible manner to several types of information at various stages of processing has been studied extensively. However, the susceptibility of these effects to the nature of the idiosyncratic items being attended is less understood. In the current study, we used symbolic cues to orient the attention of participants to the subsequent appearance of the face of a famous person (the former king of Spain) or an unfamiliar face. These were matched in perceptual characteristics. Behavioral effects showed that face specific attention optimized response speed in an orthogonal task when the target matched the cue (valid trials) compared to when it did not (invalid trials). According to topographical analyses of the electrophysiological data, the famous and unfamiliar faces engaged dissociable brain circuits in two different temporal windows, from 144 to 300 ms after target processing, and at a later 456-492 ms epoch. In addition, orienting attention to specific faces modulated the perceptual stages reflected in the P1 and N170 potentials but with a different laterality pattern that depended on the familiarity of the faces. Whereas only attention to the famous face enhanced the P1 potential at left posterior electrodes, with no corresponding effect for the unfamiliar face at this stage, the N170 was modulated at left posterior sites for the famous item and at right homologous electrodes for the unfamiliar face. Intermediate processing stages, previously linked to facial identity processing indexed by the P2 and N2 potentials, reflected item familiarity but were not affected by the cueing manipulation. At the P3 level, attention influenced again item processing but did so in an equivalent manner for the famous and unfamiliar face. Our results, showing that identity-specific attention modulates perceptual stages of facial processing at different locations depending on idiosyncratic stimulus familiarity, may inform comparison of studies employing items with different degrees of novelty. PMID- 25690864 TI - Astrocytic Cx 43 and Cx 40 in the mouse hippocampus during and after pilocarpine induced status epilepticus. AB - Astrocytes have now been well accepted to play important roles in epileptogenesis by controlling gliotransmitter release and neuronal excitability, contributing to blood-brain barrier dysfunction and involving in brain inflammation. Recent studies indicate that abnormal expression of gap junction protein connexin (Cx) may also be a contributing factor for seizure generation. To further address this issue, we investigated the progressive changes of Cx 43 and Cx 40 in the mouse hippocampus at 4 h, 1 day, 1 week and 2 months during and after pilocarpine induced status epilepticus (PISE). The co-localization of Cx 43 and Cx 40 with glial fibrillary acidic protein (GFAP) was also examined. We observed that Cx 43 and Cx 40 protein expression remained unaltered at 4 h during and at 1 day (acute stage) after PISE. However, their expression was significantly increased in CA1 and CA3 areas and in the dentate gyrus at 1 week (latent stage) and 2 months (chronic stage) after PISE. Double immunofluorescence labeling indicated the localization of Cx 43 and Cx 40 in astrocytes. Combined with progressive neuronal loss in the mouse hippocampus, our results suggest that the increase in gap junctions in the neuronoglial syncytium of reactive astrocytes may be implicated in synchronization of hippocampal hyperactivity leading to neuronal loss and epileptogenesis. PMID- 25690865 TI - Dietary patterns and their associations with general obesity and abdominal obesity among young Chinese women. AB - BACKGROUND/OBJECTIVES: Dietary patterns represent the combined effects of foods and efficaciously illustrate the impact of diet on health outcomes. This study identified the dietary patterns and determined their relationships with obesity among young Chinese women. SUBJECTS/METHODS: In 2011, the China Health and Nutrition Survey included 2363 young women aged 18-44 years. Factor analysis of data from three consecutive 24-h dietary recalls identified the dietary patterns. Weight, height and waist circumstance (WC) were measured, and body mass index (BMI) was calculated. General obesity was defined as BMI ?28 kg/m(2) and abdominal obesity as WC ?85 cm. RESULTS: Four dietary patterns were identified: traditional south; traditional north; snack; and high protein. After adjusting for confounders and energy intake, women in the highest-score quintiles of the traditional south pattern were less likely to have general obesity (odds ratio (OR)=0.48; 95% confidence interval (CI) 0.29-0.78) and abdominal obesity (OR=0.64; 95% CI 0.46-0.90). Subjects in the highest-score quintiles of the traditional north pattern had significantly greater risk of general obesity (OR=2.28; 95% CI 1.38-3.74) and of abdominal obesity (OR=2.32; 95% CI 1.66-3.24). CONCLUSION: The traditional south pattern of rice as the major staple food with pork and vegetable dishes is associated with lower risk of general and abdominal obesity. The traditional north pattern of high intake of wheat, other cereals and tubers is positively associated with general and abdominal obesity. This provides important information for interventions and policies addressing obesity prevention among young Chinese women. PMID- 25690866 TI - Weight loss with a modified Mediterranean-type diet using fat modification: a randomized controlled trial. AB - BACKGROUND/OBJECTIVES: There is evidence that Mediterranean diets with a high proportion of olive oil and nuts can be effective for weight management and prevention of cardiovascular disease. It might be difficult for populations with other eating habits to follow such diets. Therefore, a modified Mediterranean type diet using fat modification through neutral and butter-flavored canola oil, walnuts and walnut oil with two portion-controlled sweet daily snacks was tested in Germany. SUBJECTS/METHODS: Randomized waiting-list control study with overweight/grade 1 obese subjects: 12-week self-help modified Mediterranean-type diet, 6 weeks of diet plans and 6 weeks of weight loss maintenance training. Trial duration was 12 months. Intervention group (IG) included 100 participants (average age of 52.4 years, weight 85.1 kg and body mass index (BMI) 30.1 kg/m(2)), waiting-list control group (CG) included 112 participants (52.6 years, 84.1 kg and 30.1 kg/m(2)). RESULTS: Per-protocol weight loss after 12 weeks was 5.2 kg in IG vs 0.4 kg in CG (P ? 0.0001), BMI -1.8 vs -0.1 kg/m(2) (P ? 0.0001), waist circumference -4.7 vs -0.9 cm (P ? 0.0001). Triglycerides, total cholesterol and LDL cholesterol improved significantly in IG but not in CG. One year dropouts: 44% in IG and 53% in CG. Weight loss after 12 months: 4.2 kg (pooled data). CONCLUSION: A five-meal modified Mediterranean-type diet with two daily portion-controlled sweet snacks was effective for weight management in a self-help setting for overweight and grade 1 obese subjects. Fat modification through canola oil, walnuts and walnut oil improved blood lipids even at 12 months. PMID- 25690867 TI - Reducing salt in food; setting product-specific criteria aiming at a salt intake of 5 g per day. AB - BACKGROUND/OBJECTIVES: There is an increasing public health concern regarding high salt intake, which is generally between 9 and 12 g per day, and much higher than the 5 g recommended by World Health Organization. Several relevant sectors of the food industry are engaged in salt reduction, but it is a challenge to reduce salt in products without compromising on taste, shelf-life or expense for consumers. The objective was to develop globally applicable salt reduction criteria as guidance for product reformulation. SUBJECTS/METHODS: Two sets of product group-specific sodium criteria were developed to reduce salt levels in foods to help consumers reduce their intake towards an interim intake goal of 6 g/day, and-on the longer term-5 g/day. Data modelling using survey data from the United States, United Kingdom and Netherlands was performed to assess the potential impact on population salt intake of cross-industry food product reformulation towards these criteria. RESULTS: Modelling with 6 and 5 g/day criteria resulted in estimated reductions in population salt intake of 25 and 30% for the three countries, respectively, the latter representing an absolute decrease in the median salt intake of 1.8-2.2 g/day. CONCLUSIONS: The sodium criteria described in this paper can serve as guidance for salt reduction in foods. However, to enable achieving an intake of 5 g/day, salt reduction should not be limited to product reformulation. A multi-stakeholder approach is needed to make consumers aware of the need to reduce their salt intake. Nevertheless, dietary impact modelling shows that product reformulation by food industry has the potential to contribute substantially to salt-intake reduction. PMID- 25690868 TI - Determinants of vitamin D deficiency among undergraduate medical students in Saudi Arabia. AB - BACKGROUND/OBJECTIVES: The objectives of our study were to determine possible factors associated with low vitamin D levels in medical students. SUBJECTS/METHODS: A cross-sectional study was performed among 255 first- to fifth year male undergraduate medical students of one of the major universities in Saudi Arabia. Serum 25-hydroxyvitamin D (25(OH)D) levels were measured using electrochemiluminiscence. Multiple logistic regression analysis was performed. RESULTS: Majority of Saudi medical students (75.2%) had 25(OH)D levels <30 nmol/l, defined as risk for deficiency by the Institute of Medicine. Multivariate analysis showed that the odds of having 25(OH)D serum levels of ? 30 nmol/l were seven times higher both in students who took vitamin D (odds ratio (OR)=7.2, 95% confidence interval (CI)=1.8-29.9, P=0.006) or multivitamin supplements (OR=6.9, 95% CI=1.7-27.3, P=0.006) within 1 year. Students with a history of vitamin D testing >1 year before the study or moderate/vigorous physical activity (PA) had 4.4 (OR=4.4, 95% CI=1.7-11.4, P=0.003) and 2.7-fold (OR=2.7, 95% CI=1.3-5.3, P=0.006) higher odds of having 25(OH)D levels ? 30 nmol/l, respectively. There was no significant association between 25(OH)D serum levels and average time spent outdoors per day (P=0.369) and type of clothing (long-sleeved vs short sleeved; P=0.800). CONCLUSIONS: Vitamin D deficiency was highly prevalent in Saudi medical students. Modifiable factors such as vitamin D intake and PA could be targeted for intervention. Further studies with standardized laboratory measurements of 25(OH)D are needed to explore the role of vitamin D testing in behavioral change, which may lead to increased serum 25(OH)D levels. PMID- 25690869 TI - Application of a specific equation to calculate fat-free mass (FFM) in Australian aboriginals. PMID- 25690870 TI - Learning to memorize: Shedding new light on prefrontal functions. PMID- 25690871 TI - Molecular cloning and expression of two heat-shock protein genes (HSC70/HSP70) from Prenant's schizothoracin (Schizothorax prenanti). AB - Through the RT-PCR and rapid amplification of cDNA ends, two complementary deoxyribonucleic acid (cDNA) clones encoding heat-shock cognate 70 (HSC70, designated Sp-HSC70) and inducible heat-shock protein 70 (HSP70, designated Sp HSP70) were isolated from the liver of Prenant's schizothoracin (Schizothorax prenanti). The cDNAs were 2344- and 2292-bp in length and contained 1950- and 1932-bp open reading frames, encoded proteins of 649 and 643 amino acids, respectively. Amino acid sequence analysis indicated that both Sp-HSC70 and Sp HSP70 contained three signature sequences of HSP70 family, two partial overlapping bipartite nuclear localization signal sequences (an ATP-binding site motif, a bipartite nuclear targeting signal), and a cytoplasmic characteristic motif EEVD. Homology analysis revealed that Sp-HSC70 and Sp-HSP70 shared 77.5% identity and Sp-HSC70 shared more than 81.1% identity with the known HSC70s of other vertebrates, while Sp-HSP70 shared more than 77.5 % identity with the known HSP70s of other vertebrates. Fluorescent real-time quantitative RT-PCR showed that Sp-HSC70 and Sp-HSP70 mRNAs were found in all tested tissues, including blood, brain, heart, liver, spleen, head kidney, white muscle, skin, gonad, hypophysis, red muscle, and gill. The Sp-HSC70 and Sp-HSP70 mRNA expression level in blood and head kidney displayed a significant increase in vibrio-challenged group with the bacterium Aeromonas hydrophila at 24 h post-infection compared to a control group. Temporally, there was a clear time-dependent expression pattern of Sp-HSC70 or Sp-HSP70 gene after bacterial challenge, and the expression of Sp HSC70 and Sp-HSP70 mRNAs reached a maximum level at 12 and 6 h post-challenge, respectively. Both returned to control level after 7 * 24 h. The results suggest that Sp-HSC70 and Sp-HSP70 genes may play important roles in mediating the immune responses of A. hydrophila-related diseases in the Prenant's schizothoracin. PMID- 25690872 TI - The mapping of yeast's G-protein coupled receptor with an atomic force microscope. AB - An atomic force microscope (AFM) can measure the adhesion force between a sample and a cantilever while simultaneously applying a rupture force during the imaging of a sample. An AFM should be useful in targeting specific proteins on a cell surface. The present study proposes the use of an AFM to measure the adhesion force between targeting receptors and their ligands, and to map the targeting receptors. In this study, Ste2p, one of the G protein-coupled receptors (GPCRs), was chosen as the target receptor. The specific force between Ste2p on a yeast cell surface and a cantilever modified with its ligand, alpha-factor, was measured and found to be approximately 250 pN. In addition, through continuous measuring of the cell surface, a mapping of the receptors on the cell surface could be performed, which indicated the differences in the Ste2p expression levels. Therefore, the proposed AFM system is accurate for cell diagnosis. PMID- 25690873 TI - How lipids modulate mitochondrial protein import. AB - Mitochondria have to import the vast majority of their proteins, which are synthesized as precursors on cytosolic ribosomes. The translocase of the outer membrane (TOM complex) forms the general entry gate for the precursor proteins, which are subsequently sorted by protein machineries into the mitochondrial subcompartments: the outer and inner membrane, the intermembrane space and the mitochondrial matrix. The transport across and into the inner membrane is driven by the membrane potential, which is generated by the respiratory chain. Recent studies revealed that the lipid composition of mitochondrial membranes is important for the biogenesis of mitochondrial proteins. Cardiolipin and phosphatidylethanolamine exhibit unexpectedly specific functions for the activity of distinct protein translocases. Both phospholipids are required for full activity of respiratory chain complexes and thus to maintain the membrane potential for protein import. In addition, cardiolipin is required to maintain structural integrity of mitochondrial protein translocases. Finally, the low sterol content in the mitochondrial outer membrane may contribute to the targeting of some outer membrane proteins with a single alpha-helical membrane anchor. Altogether, mitochondrial lipids modulate protein import on various levels involving precursor targeting, membrane potential generation, stability and activity of protein translocases. PMID- 25690874 TI - Ca(2+)-dependent nonspecific permeability of the inner membrane of liver mitochondria in the guinea fowl (Numida meleagris). AB - This comparative study presents the results of the induction of Ca(2+)-dependent nonspecific permeability of the inner membrane (pore opening) of rat and guinea fowl liver mitochondria by mechanisms that are both sensitive and insensitive to cyclosporin A (CsA). It was established that energized rat and guinea fowl liver mitochondria incubated with 1 mM of inorganic phosphate (Pi) are capable of swelling upon addition of at least 125 and 875 nmol of CaCl2 per 1 mg protein, respectively. Under these conditions, the Ca(2+) release from the mitochondria of these animals and a drop in Deltapsi are observed. All of these processes are inhibited by 1 MUM of CsA. FCCP, causing organelle de-energization, induces pore opening in rat and guinea fowl liver mitochondria upon addition of 45 i 625 nmol of CaCl2 per 1 mg protein, respectively. These results suggest the existence of a CsA-sensitive mechanism for the induction of Ca(2+)-dependent pores in guinea fowl liver mitochondria, which has been reported in rat liver mitochondria. However, guinea fowl liver mitochondria have a significantly greater resistance to Ca(2+) as a pore inducer compared to rat liver mitochondria. It was found that the addition of alpha,omega-hexadecanedioic acid (HDA) to rat and guinea fowl liver mitochondria incubated with CsA and loaded with Ca(2+) causes organelle swelling and Ca(2+) release from the matrix. It is assumed that in contrast to the CsA-sensitive pore, the CsA-insensitive pore induced by HDA in the inner membrane of guinea fowl liver mitochondria, as well as in rat liver mitochondria, is lipid in nature. PMID- 25690875 TI - Evolution of antibiotic resistance in bacteria involved in urinary tract infections: a 3-year London experience. PMID- 25690876 TI - Impact of Clostridium difficile recurrence on hospital readmissions. AB - BACKGROUND: The impact of recurrent Clostridium difficile infections (CDIs) on hospital readmissions is unknown. The objective of this study was to determine whether recurrent CDI was independently associated with the number of hospital readmissions and days readmitted. METHODS: We performed a retrospective cohort study at an academic, urban, tertiary care hospital. Data were collected from electronic medical records and supplemented with chart review. CDI patients were followed for 180 days to ascertain the number of hospital readmissions and total days readmitted. Univariate and multivariable negative binomial regression models were used to evaluate factors, including CDI recurrence, associated with hospital readmissions. RESULTS: The study included 3,950 patients with CDI from 2003-2009, including 413 patients with recurrent CDI. Recurrent CDI patients were significantly more likely to have at least 1 readmission (85% vs 41%; P < .001) and had more days readmitted (mean = 18.6 vs 7.6; P < .001) than patients without recurrent CDI. In multivariable analysis, recurrent CDI was independently associated with number of readmissions (rate ratio = 2.54; 95% confidence interval [CI], 2.21-2.91) and days readmitted (rate ratio = 3.97; 95% CI, 3.11 5.08) after adjustment for demographics, comorbidities, and medications. CONCLUSION: Recurrent CDI patients are significantly more likely than patients without a recurrence to be readmitted and spend increased time readmitted to the hospital. PMID- 25690877 TI - Outbreak of coinfection with human metapneumovirus and measles virus resulting in the death of a child at a hospital in China. AB - Two children with different digestive diseases were admitted to the gastroenterology department of a children's hospital in Hangzhou, Zhejiang Province, China, in May 2010. They manifested successively acute lower respiratory tract infection symptoms during their stay in the hospital. The epidemiologic and experimental evidence supports that one child acquired nosocomial coinfection with measles virus and human metapneumovirus from another child while they shared the same ward. PMID- 25690878 TI - Risk of zoster in patients on immunosuppressant therapy: evaluation of current data. PMID- 25690879 TI - Cathepsin K inhibitors: emerging treatment options for osteoporosis. PMID- 25690880 TI - Poster advertisements in practice waiting rooms to recruit patients to the Treatment In Morning vs. Evening (TIME) online study. PMID- 25690881 TI - Macrosteatotic and nonmacrosteatotic grafts respond differently to intermittent hepatic inflow occlusion: Comparison of recipient survival. AB - Intermittent hepatic inflow occlusion (IHIO) during liver graft procurement is known to confer protection against graft ischemia/reperfusion injury and thus may benefit the recipient's outcome. We evaluated whether the protective effect of IHIO differs with the presence of macrosteatosis (MaS) and with an increase or decrease in the cumulative occlusion time. The subgroup of 188 recipients who received grafts with MaS was divided into 3 groups according to the number of total IHIO rounds during graft procurement: no IHIO, n = 70; 1 to 2 rounds of IHIO, n = 50; and >=3 rounds of IHIO, n = 68. Likewise, the subgroup of 200 recipients who received grafts without MaS was divided into 3 groups: no IHIO, n = 108; 1 to 2 rounds of IHIO, n = 40; and >=3 rounds of IHIO, n = 52. The Cox model was applied to evaluate the association between the number of total IHIO rounds and recipient survival separately in the subgroup of MaS recipients and the subgroup of non-MaS recipients. Analyzed covariables included the etiology, Milan criteria, transfusion, immunosuppression, and others. In the subgroup of MaS recipients, 1 to 2 rounds of IHIO were favorably associated with recipient survival [hazard ratio (HR), 0.29; 95% confidence interval (CI), 0.10-0.80; P = 0.03 after Bonferroni correction], whereas >=3 rounds of IHIO were not associated with recipient survival (HR, 0.56; 95% CI, 0.25-1.23). In the subgroup of non-MaS recipients, neither 1 to 2 rounds of IHIO (HR, 0.69; 95% CI, 0.30-1.61) nor >=3 rounds of IHIO (HR, 0.91; 95% CI, 0.42-1.96) were associated with recipient survival. In conclusion, 1 to 2 rounds of IHIO may be used for the procurement of MaS grafts with potential benefit for recipient survival, whereas IHIO has a limited impact on recipient survival regardless of the cumulative occlusion time when it is used for non-MaS grafts. PMID- 25690882 TI - N719- and D149-sensitized 3D hierarchical rutile TiO2 solar cells--a comparative study. AB - Poor dye loading on rutile TiO2 is one of the chief reasons for lower solar-to electric conversion efficiency (eta) in dye-sensitized solar cells (DSCs), compared to their anatase based counterparts. Previously, we showed that similar light harvesting for both rutile and anatase was realized by using a metal-free organic indoline dye, D149 [Sci. Rep., 2014, 4, 5769]. This was in contrast to the bulk of previous studies, which employed ruthenium based N719, leading to significant differences in light harvesting. To date, there has been no report directly comparing N719 and D149 for rutile based DSCs. In this work, three dimensional hierarchical rutile TiO2 architecture (HRTA), consisting of one dimensional nanorods, was successfully prepared via a facile hydrothermal method, and subsequently optimized as effective photoelectrodes for DSCs. Two dyes, N719 and D149, were used as sensitizers of the HRTA-based DSCs, with maximum eta of 5.6% and 5.8% achieved, respectively. The higher eta of the D149-sensitized DSC is ascribed to its higher extinction co-efficient, allowing a greater amount of light to be harvested with a thinner TiO2 layer. This study suggests that some of the limitations typically observed for rutile TiO2 based DSCs can be overcome through the use of strongly absorbing metal-free organic sensitizers. Furthermore, it reemphasises the importance of viewing DSCs as whole systems, rather than individual components. PMID- 25690883 TI - Evidence for an active rare biosphere within freshwater protists community. AB - Studies on the active rare biosphere at the RNA level are mainly focused on Bacteria and Archaea and fail to include the protists, which are involved in the main biogeochemical cycles of the earth. In this study, the richness, composition and activity of the rare protistan biosphere were determined from a temporal survey of two lakes by pyrosequencing. In these ecosystems, the always rare OTUs represented 77.2% of the total OTUs and 76.6% of the phylogenetic diversity. From the various phylogenetic indices computed, the phylogenetic units (PUs) constituted exclusively by always rare OTUs were discriminated from the other PUs. Therefore, the rare biosphere included mainly taxa that are distant from the reference databases compared to the dominant ones. In addition, the rarest OTUs represented 59.8% of the active biosphere depicted by rRNA and the activity (rRNA:rDNA ratio) increased with the rarity. The high rRNA:rDNA ratio determined in the rare fraction highlights that some protists were active at low abundances and contribute to ecosystem functioning. Interestingly, the always rare and active OTUs were characterized by seasonal changes in relation with the main environmental parameters measured. In conclusion, the rare eukaryotes represent an active, dynamic and overlooked fraction in the lacustrine ecosystems. PMID- 25690884 TI - Letter to the editor: another treatment choice for subdural effusion with ventricle dilation. PMID- 25690885 TI - Comment on: Evolution of multiple sclerosis in France since the beginning of hepatitis B vaccination. PMID- 25690886 TI - Aryl hydrocarbon receptor mediates both proinflammatory and anti-inflammatory effects in lipopolysaccharide-activated microglia. AB - The aryl hydrocarbon receptor (AhR) regulates peripheral immunity; but its role in microglia-mediated neuroinflammation in the brain remains unknown. Here, we demonstrate that AhR mediates both anti-inflammatory and proinflammatory effects in lipopolysaccharide (LPS)-activated microglia. Activation of AhR by its ligands, formylindolo[3,2-b]carbazole (FICZ) or 3-methylcholanthrene (3MC), attenuated LPS-induced microglial immune responses. AhR also showed proinflammatory effects, as evidenced by the findings that genetic silence of AhR ameliorated the LPS-induced microglial immune responses and LPS-activated microglia-mediated neurotoxicity. Similarly, LPS-induced expressions of tumor necrosis factor alpha (TNFalpha) and inducible nitric oxide synthase (iNOS) were reduced in the cerebral cortex of AhR-deficient mice. Intriguingly, LPS upregulated and activated AhR in the absence of AhR ligands via the MEK1/2 signaling pathway, which effects were associated with a transient inhibition of cytochrome P450 1A1 (CYP1A1). Although AhR ligands synergistically enhance LPS induced AhR activation, leading to suppression of LPS-induced microglial immune responses, they cannot do so on their own in microglia. Chromatin immunoprecipitation results further revealed that LPS-FICZ co-treatment, but not LPS alone, not only resulted in co-recruitment of both AhR and NFkappaB onto the kappaB site of TNFalpha gene promoter but also reduced LPS-induced AhR binding to the DRE site of iNOS gene promoter. Together, we provide evidence showing that microglial AhR, which can be activated by LPS, exerts bi-directional effects on the regulation of LPS-induced neuroinflammation, depending on the availability of external AhR ligands. These findings confer further insights into the potential link between environmental factors and the inflammatory brain disorders. PMID- 25690887 TI - Single-molecule kinetics and footprinting of DNA bis-intercalation: the paradigmatic case of Thiocoraline. AB - DNA bis-intercalators are widely used in molecular biology with applications ranging from DNA imaging to anticancer pharmacology. Two fundamental aspects of these ligands are the lifetime of the bis-intercalated complexes and their sequence selectivity. Here, we perform single-molecule optical tweezers experiments with the peptide Thiocoraline showing, for the first time, that bis intercalation is driven by a very slow off-rate that steeply decreases with applied force. This feature reveals the existence of a long-lived (minutes) mono intercalated intermediate that contributes to the extremely long lifetime of the complex (hours). We further exploit this particularly slow kinetics to determine the thermodynamics of binding and persistence length of bis-intercalated DNA for a given fraction of bound ligand, a measurement inaccessible in previous studies of faster intercalating agents. We also develop a novel single-molecule footprinting technique based on DNA unzipping and determine the preferred binding sites of Thiocoraline with one base-pair resolution. This fast and radiolabelling free footprinting technique provides direct access to the binding sites of small ligands to nucleic acids without the need of cleavage agents. Overall, our results provide new insights into the binding pathway of bis-intercalators and the reported selectivity might be of relevance for this and other anticancer drugs interfering with DNA replication and transcription in carcinogenic cell lines. PMID- 25690888 TI - Concerted and differential actions of two enzymatic domains underlie Rad5 contributions to DNA damage tolerance. AB - Many genome maintenance factors have multiple enzymatic activities. In most cases, how their distinct activities functionally relate with each other is unclear. Here we examined the conserved budding yeast Rad5 protein that has both ubiquitin ligase and DNA helicase activities. The Rad5 ubiquitin ligase activity mediates PCNA poly-ubiquitination and subsequently recombination-based DNA lesion tolerance. Interestingly, the ligase domain is embedded in a larger helicase domain comprising seven consensus motifs. How features of the helicase domain influence ligase function is controversial. To clarify this issue, we use genetic, 2D gel and biochemical analyses and show that a Rad5 helicase motif important for ATP binding is also required for PCNA poly-ubiquitination and recombination-based lesion tolerance. We determine that this requirement is due to a previously unrecognized contribution of the motif to the PCNA and ubiquitination enzyme interaction, and not due to its canonical role in supporting helicase activity. We further show that Rad5's helicase-mediated contribution to replication stress survival is separable from recombination. These findings delineate how two Rad5 enzymatic domains concertedly influence PCNA modification, and unveil their discrete contributions to stress tolerance. PMID- 25690889 TI - The nucleoporin Mlp2 is involved in chromosomal distribution during mitosis in trypanosomatids. AB - Nucleoporins are evolutionary conserved proteins mainly involved in the constitution of the nuclear pores and trafficking between the nucleus and cytoplasm, but are also increasingly viewed as main actors in chromatin dynamics and intra-nuclear mitotic events. Here, we determined the cellular localization of the nucleoporin Mlp2 in the 'divergent' eukaryotes Leishmania major and Trypanosoma brucei. In both protozoa, Mlp2 displayed an atypical localization for a nucleoporin, essentially intranuclear, and preferentially in the periphery of the nucleolus during interphase; moreover, it relocated at the mitotic spindle poles during mitosis. In T. brucei, where most centromeres have been identified, TbMlp2 was found adjacent to the centromeric sequences, as well as to a recently described unconventional kinetochore protein, in the periphery of the nucleolus, during interphase and from the end of anaphase onwards. TbMlp2 and the centromeres/kinetochores exhibited a differential migration towards the poles during mitosis. RNAi knockdown of TbMlp2 disrupted the mitotic distribution of chromosomes, leading to a surprisingly well-tolerated aneuploidy. In addition, diploidy was restored in a complementation assay where LmMlp2, the orthologue of TbMlp2 in Leishmania, was expressed in TbMlp2-RNAi-knockdown parasites. Taken together, our results demonstrate that Mlp2 is involved in the distribution of chromosomes during mitosis in trypanosomatids. PMID- 25690890 TI - Synergistic effects of ATP and RNA binding to human DEAD-box protein DDX1. AB - RNA helicases of the DEAD-box protein family form the largest group of helicases. The human DEAD-box protein 1 (DDX1) plays an important role in tRNA and mRNA processing, is involved in tumor progression and is also hijacked by several virus families such as HIV-1 for replication and nuclear export. Although important in many cellular processes, the mechanism of DDX1's enzymatic function is unknown. We have performed equilibrium titrations and transient kinetics to determine affinities for nucleotides and RNA. We find an exceptional tight binding of DDX1 to adenosine diphosphate (ADP), one of the strongest affinities observed for DEAD-box helicases. ADP binds tighter by three orders of magnitude when compared to adenosine triphosphate (ATP), arresting the enzyme in a potential dead-end ADP conformation under physiological conditions. We thus suggest that a nucleotide exchange factor leads to DDX1 recycling. Furthermore, we find a strong cooperativity in binding of RNA and ATP to DDX1 that is also reflected in ATP hydrolysis. We present a model in which either ATP or RNA binding alone can partially shift the equilibrium from an 'open' to a 'closed' state; this shift appears to be not further pronounced substantially even in the presence of both RNA and ATP as the low rate of ATP hydrolysis does not change. PMID- 25690891 TI - CHK1-driven histone H3.3 serine 31 phosphorylation is important for chromatin maintenance and cell survival in human ALT cancer cells. AB - Human ALT cancers show high mutation rates in ATRX and DAXX. Although it is well known that the absence of ATRX/DAXX disrupts H3.3 deposition at heterochromatin, its impact on H3.3 deposition and post-translational modification in the global genome remains unclear. Here, we explore the dynamics of phosphorylated H3.3 serine 31 (H3.3S31ph) in human ALT cancer cells. While H3.3S31ph is found only at pericentric satellite DNA repeats during mitosis in most somatic human cells, a high level of H3.3S31ph is detected on the entire chromosome in ALT cells, attributable to an elevated CHK1 activity in these cells. Drug inhibition of CHK1 activity during mitosis and expression of mutant H3.3S31A in these ALT cells result in a decrease in H3.3S31ph levels accompanied with increased levels of phosphorylated H2AX serine 139 on chromosome arms and at the telomeres. Furthermore, the inhibition of CHK1 activity in these cells also reduces cell viability. Our findings suggest a novel role of CHK1 as an H3.3S31 kinase, and that CHK1-mediated H3.3S31ph plays an important role in the maintenance of chromatin integrity and cell survival in ALT cancer cells. PMID- 25690892 TI - TEFM is a potent stimulator of mitochondrial transcription elongation in vitro. AB - A single-subunit RNA polymerase, POLRMT, transcribes the mitochondrial genome in human cells. Recently, a factor termed as the mitochondrial transcription elongation factor, TEFM, was shown to stimulate transcription elongation in vivo, but its effect in vitro was relatively modest. In the current work, we have isolated active TEFM in recombinant form and used a reconstituted in vitro transcription system to characterize its activities. We show that TEFM strongly promotes POLRMT processivity as it dramatically stimulates the formation of longer transcripts. TEFM also abolishes premature transcription termination at conserved sequence block II, an event that has been linked to primer formation during initiation of mtDNA synthesis. We show that POLRMT pauses at a wide range of sites in a given DNA sequence. In the absence of TEFM, this leads to termination; however, the presence of TEFM abolishes this effect and aids POLRMT in continuation of transcription. Further, we show that TEFM substantially increases the POLRMT affinity to an elongation-like DNA:RNA template. In combination with previously published in vivo observations, our data establish TEFM as an essential component of the mitochondrial transcription machinery. PMID- 25690893 TI - Highly efficient CRISPR/Cas9-mediated TAR cloning of genes and chromosomal loci from complex genomes in yeast. AB - Transformation-associated recombination (TAR) protocol allowing the selective isolation of full-length genes complete with their distal enhancer regions and entire genomic loci with sizes up to 250 kb from complex genomes in yeast S. cerevisiae has been developed more than a decade ago. However, its wide spread usage has been impeded by a low efficiency (0.5-2%) of chromosomal region capture during yeast transformants which in turn requires a time-consuming screen of hundreds of colonies. Here, we demonstrate that pre-treatment of genomic DNA with CRISPR-Cas9 nucleases to generate double-strand breaks near the targeted genomic region results in a dramatic increase in the fraction of gene-positive colonies (up to 32%). As only a dozen or less yeast transformants need to be screened to obtain a clone with the desired chromosomal region, extensive experience with yeast is no longer required. A TAR-CRISPR protocol may help to create a bank of human genes, each represented by a genomic copy containing its native regulatory elements, that would lead to a significant advance in functional, structural and comparative genomics, in diagnostics, gene replacement, generation of animal models for human diseases and has a potential for gene therapy. PMID- 25690894 TI - Single molecule analysis of Trypanosoma brucei DNA replication dynamics. AB - Eukaryotic genome duplication relies on origins of replication, distributed over multiple chromosomes, to initiate DNA replication. A recent genome-wide analysis of Trypanosoma brucei, the etiological agent of sleeping sickness, localized its replication origins to the boundaries of multigenic transcription units. To better understand genomic replication in this organism, we examined replication by single molecule analysis of replicated DNA. We determined the average speed of replication forks of procyclic and bloodstream form cells and we found that T. brucei DNA replication rate is similar to rates seen in other eukaryotes. We also analyzed the replication dynamics of a central region of chromosome 1 in procyclic forms. We present evidence for replication terminating within the central part of the chromosome and thus emanating from both sides, suggesting a previously unmapped origin toward the 5' extremity of chromosome 1. Also, termination is not at a fixed location in chromosome 1, but is rather variable. Importantly, we found a replication origin located near an ORC1/CDC6 binding site that is detected after replicative stress induced by hydroxyurea treatment, suggesting it may be a dormant origin activated in response to replicative stress. Collectively, our findings support the existence of more replication origins in T. brucei than previously appreciated. PMID- 25690895 TI - RNA polymerase-induced remodelling of NusA produces a pause enhancement complex. AB - Pausing during transcription elongation is a fundamental activity in all kingdoms of life. In bacteria, the essential protein NusA modulates transcriptional pausing, but its mechanism of action has remained enigmatic. By combining structural and functional studies we show that a helical rearrangement induced in NusA upon interaction with RNA polymerase is the key to its modulatory function. This conformational change leads to an allosteric re-positioning of conserved basic residues that could enable their interaction with an RNA pause hairpin that forms in the exit channel of the polymerase. This weak interaction would stabilize the paused complex and increases the duration of the transcriptional pause. Allosteric spatial re-positioning of regulatory elements may represent a general approach used across all taxa for modulation of transcription and protein RNA interactions. PMID- 25690896 TI - Inferential modeling of 3D chromatin structure. AB - For eukaryotic cells, the biological processes involving regulatory DNA elements play an important role in cell cycle. Understanding 3D spatial arrangements of chromosomes and revealing long-range chromatin interactions are critical to decipher these biological processes. In recent years, chromosome conformation capture (3C) related techniques have been developed to measure the interaction frequencies between long-range genome loci, which have provided a great opportunity to decode the 3D organization of the genome. In this paper, we develop a new Bayesian framework to derive the 3D architecture of a chromosome from 3C-based data. By modeling each chromosome as a polymer chain, we define the conformational energy based on our current knowledge on polymer physics and use it as prior information in the Bayesian framework. We also propose an expectation maximization (EM) based algorithm to estimate the unknown parameters of the Bayesian model and infer an ensemble of chromatin structures based on interaction frequency data. We have validated our Bayesian inference approach through cross validation and verified the computed chromatin conformations using the geometric constraints derived from fluorescence in situ hybridization (FISH) experiments. We have further confirmed the inferred chromatin structures using the known genetic interactions derived from other studies in the literature. Our test results have indicated that our Bayesian framework can compute an accurate ensemble of 3D chromatin conformations that best interpret the distance constraints derived from 3C-based data and also agree with other sources of geometric constraints derived from experimental evidence in the previous studies. The source code of our approach can be found in https://github.com/wangsy11/InfMod3DGen. PMID- 25690897 TI - Accurate multiplexing and filtering for high-throughput amplicon-sequencing. AB - Tagging amplicons with tag sequences appended to PCR primers allow the multiplexing of numerous samples for high-throughput sequencing (HTS). This approach is routinely used in HTS-based diversity analyses, especially in microbial ecology and biomedical diagnostics. However, amplicon library preparation is subject to pervasive sample sequence cross-contaminations as a result of tag switching events referred to as mistagging. Here, we sequenced seven amplicon libraries prepared using various multiplexing designs in order to measure the magnitude of this phenomenon and its impact on diversity analyses. Up to 28.2% of the unique sequences correspond to undetectable (critical) mistags in single- or saturated double-tagging libraries. We show the advantage of multiplexing samples following Latin Square Designs in order to optimize the detection of mistags and maximize the information on their distribution across samples. We use this information in designs incorporating PCR replicates to filter the critical mistags and to recover the exact composition of mock community samples. Being parameter-free and data-driven, our approach can provide more accurate and reproducible HTS data sets, improving the reliability of their interpretations. PMID- 25690898 TI - High-throughput data integration of RNA-miRNA-circRNA reveals novel insights into mechanisms of benzo[a]pyrene-induced carcinogenicity. AB - The chain of events leading from a toxic compound exposure to carcinogenicity is still barely understood. With the emergence of high-throughput sequencing, it is now possible to discover many different biological components simultaneously. Using two different RNA libraries, we sequenced the complete transcriptome of human HepG2 liver cells exposed to benzo[a]pyrene, a potent human carcinogen, across six time points. Data were integrated in order to reveal novel complex chemical-gene interactions. Notably, we hypothesized that the inhibition of MGMT, a DNA damage response enzyme, by the over-expressed miR-181a-1_3p induced by BaP, may lead to liver cancer over time. PMID- 25690899 TI - Epigenetic remodeling in B-cell acute lymphoblastic leukemia occurs in two tracks and employs embryonic stem cell-like signatures. AB - We investigated DNA methylomes of pediatric B-cell acute lymphoblastic leukemias (B-ALLs) using whole-genome bisulfite sequencing and high-definition microarrays, along with RNA expression profiles. Epigenetic alteration of B-ALLs occurred in two tracks: de novo methylation of small functional compartments and demethylation of large inter-compartmental backbones. The deviations were exaggerated in lamina-associated domains, with differences corresponding to methylation clusters and/or cytogenetic groups. Our data also suggested a pivotal role of polycomb and CTBP2 in de novo methylation, which may be traced back to bivalency status of embryonic stem cells. Driven by these potent epigenetic modulations, suppression of polycomb target genes was observed along with disruption of developmental fate and cell cycle and mismatch repair pathways and altered activities of key upstream regulators. PMID- 25690900 TI - 2-Thiouracil deprived of thiocarbonyl function preferentially base pairs with guanine rather than adenine in RNA and DNA duplexes. AB - 2-Thiouracil-containing nucleosides are essential modified units of natural and synthetic nucleic acids. In particular, the 5-substituted-2-thiouridines (S2Us) present in tRNA play an important role in tuning the translation process through codon-anticodon interactions. The enhanced thermodynamic stability of S2U containing RNA duplexes and the preferred S2U-A versus S2U-G base pairing are appreciated characteristics of S2U-modified molecular probes. Recently, we have demonstrated that 2-thiouridine (alone or within an RNA chain) is predominantly transformed under oxidative stress conditions to 4-pyrimidinone riboside (H2U) and not to uridine. Due to the important biological functions and various biotechnological applications for sulfur-containing nucleic acids, we compared the thermodynamic stabilities of duplexes containing desulfured products with those of 2-thiouracil-modified RNA and DNA duplexes. Differential scanning calorimetry experiments and theoretical calculations demonstrate that upon 2 thiouracil desulfuration to 4-pyrimidinone, the preferred base pairing of S2U with adenosine is lost, with preferred base pairing with guanosine observed instead. Therefore, biological processes and in vitro assays in which oxidative desulfuration of 2-thiouracil-containing components occurs may be altered. Moreover, we propose that the H2U-G base pair is a suitable model for investigation of the preferred recognition of 3'-G-ending versus A-ending codons by tRNA wobble nucleosides, which may adopt a 4-pyrimidinone-type structural motif. PMID- 25690902 TI - Retracted: Bayes clustering and structural support vector machines for segmentation of carotid artery plaques in multicontrast MRI. AB - [This retracts the article DOI: 10.1155/2012/549102.]. PMID- 25690903 TI - Fast, direct, low-cost route to scalable, conductive, and multipurpose poly(3,4 ethylenedixoythiophene)-coated plastic electrodes. AB - Poly(3,4-ethylenedioxythiophene) (PEDOT) films are deposited, using an electroless method, onto flexible plastic poly(ethylene terephthalate) (PET) substrates of approximately 20*6 cm(2). The sheet resistance of a PEDOT-PET film is approximately 600 Omega per square, and the nanoscale conductivity is 0.103 S cm(-1). A plastic electrochromic PEDOT-Prussian blue device is constructed. The device undergoes a color change of pale blue to deep violet-blue reversibly over 1000 cycles, thus demonstrating its use as a light-modulating smart window. The PEDOT-PET film is also used in a quantum dot solar cell, and the resulting photoelectrochemical performance and work function indicate that it is also promising for photovoltaic cells. The high homogeneity of the PEDOT deposit on PET, the optimal balance between conductivity and optical transparency, and the demonstration of its use in an electro-optical device and a solar cell, offer the opportunity to use this electrode material in a variety of low-cost optoelectronic devices. PMID- 25690901 TI - Identification of a second GTP-bound magnesium ion in archaeal initiation factor 2. AB - Eukaryotic and archaeal translation initiation processes involve a heterotrimeric GTPase e/aIF2 crucial for accuracy of start codon selection. In eukaryotes, the GTPase activity of eIF2 is assisted by a GTPase-activating protein (GAP), eIF5. In archaea, orthologs of eIF5 are not found and aIF2 GTPase activity is thought to be non-assisted. However, no in vitro GTPase activity of the archaeal factor has been reported to date. Here, we show that aIF2 significantly hydrolyses GTP in vitro. Within aIF2gamma, H97, corresponding to the catalytic histidine found in other translational GTPases, and D19, from the GKT loop, both participate in this activity. Several high-resolution crystal structures were determined to get insight into GTP hydrolysis by aIF2gamma. In particular, a crystal structure of the H97A mutant was obtained in the presence of non-hydrolyzed GTP. This structure reveals the presence of a second magnesium ion bound to GTP and D19. Quantum chemical/molecular mechanical simulations support the idea that the second magnesium ion may assist GTP hydrolysis by helping to neutralize the developing negative charge in the transition state. These results are discussed in light of the absence of an identified GAP in archaea to assist GTP hydrolysis on aIF2. PMID- 25690904 TI - Adjunctive intraventricular antibiotic therapy for bacterial central nervous system infections in critically ill patients with traumatic brain injury. AB - BACKGROUND: Limited data exist on the role of adjunctive intraventricular (IVT) antibiotics for the treatment of central nervous system (CNS) infections in traumatic brain injury (TBI) patients. OBJECTIVE: To evaluate differences in CNS infection cure rates for TBI patients who received adjunctive IVT antibiotics compared with intravenous (IV) antibiotics alone. METHODS: We retrospectively identified patients with TBI and bacterial CNS infections admitted to the trauma intensive care unit (ICU) from 1997 to 2013. Study patients received IV and IVT antibiotics, and control patients received IV antibiotics alone. Clinical and microbiological cure rates were determined from patient records, in addition to ICU and hospital lengths of stay (LOSs), ventilator days, and hospital mortality. RESULTS: A total of 83 patients were enrolled (32 study and 51 control). The duration of IV antibiotics was similar in both groups (10 vs 12 days, P = 0.14), and the study group received IVT antibiotics for a median of 9 days. Microbiological cure rates were 84% and 82% in study and control groups, respectively (P = 0.95). Clinical cure rates were similar at all time points. No significant differences were seen in days of mechanical ventilation, ICU or hospital LOS, or hospital mortality. When only patients with external ventricular drains were compared, cure rates remained similar between groups. CONCLUSIONS: TBI patients with CNS infections had similar microbiological and clinical cure rates whether they were treated with adjunctive IVT antibiotics or IV antibiotics alone. Shorter than recommended durations of antibiotic therapy still resulted in acceptable cure rates and similar clinically relevant outcomes. PMID- 25690905 TI - Photo-induced bending in a light-activated polymer laminated composite. AB - Light activated polymers (LAPs) have attracted increasing attention since these materials change their shape and/or behavior in response to light exposure, which serves as an instant, remote and precisely controllable stimulus that enables non contact control of the material shape and behavior through simple variation in light intensity, wavelength and spatially controlled exposure. These features distinguish LAPs from other active polymers triggered by other stimuli such as heat, electrical field or humidity. Previous examples have resulted in demonstrations in applications such as surface patterning, photo-induced shape memory behavior, and photo-origami. However, in many of these applications, an undesirable limitation has been the requirement to apply and maintain an external load during light irradiation. In this paper, a laminated structure is introduced to provide a pre-programmed stress field, which is then used for photo-induced deformation. This laminated structure is fabricated by bonding a stretched elastomer (NOA65) sheet between two LAP layers. Releasing the elastomer causes contraction and introduces a compressive stress in the LAPs, which are relaxed optically to trigger the desired deformation. A theoretical model is developed to quantitatively examine the laminated composite system, allowing exploration of the design space and optimum design of the laminate. PMID- 25690906 TI - DMRT3 is associated with gait type in Mangalarga Marchador horses, but does not control gait ability. AB - The Mangalarga Marchador (MM) is a Brazilian horse breed known for a uniquely smooth gait. A recent publication described a mutation in the DMRT3 gene that the authors claim controls the ability to perform lateral patterned gaits (Andersson et al. 2012). We tested 81 MM samples for the DMRT3 mutation using extracted DNA from hair bulbs using a novel RFLP. Horses were phenotypically categorized by their gait type (batida or picada), as recorded by the Brazilian Mangalarga Marchador Breeders Association (ABCCMM). Statistical analysis using the plink toolset (Purcell, 2007) revealed significant association between gait type and the DMRT3 mutation (P = 2.3e-22). Deviation from Hardy-Weinberg equilibrium suggests that selective pressure for gait type is altering allele frequencies in this breed (P = 1.00e-5). These results indicate that this polymorphism may be useful for genotype-assisted selection for gait type within this breed. As both batida and picada MM horses can perform lateral gaits, the DMRT3 mutation is not the only locus responsible for the lateral gait pattern. PMID- 25690907 TI - Clinician adherence to childhood overweight and obesity recommendations by race/ethnicity of the child. AB - PURPOSE: This study describes school-based health center (SBHC) providers' adherence to obesity guidelines. DESIGN AND METHODS: Providers (n = 28) were from SBHCs in six states serving children 5-12 years of age. A random sample of well child charts (n = 850) were audited for body mass index percentage, blood pressure percentage, overweight/obesity diagnosis, and laboratory assessment. RESULTS: Body mass index percentage was documented on 73% of charts and blood pressure percentage on 30.5%. Providers accurately diagnosed 40% overweight and 49.3% obese children. Laboratory guidelines were followed in 80.4% of cases. Assessments differed by child's race/ethnicity (p < .05), with most criteria having higher adherence in minority youth. PRACTICE IMPLICATIONS: There is a need for increased accuracy in how SBHC providers screen overweight/obese children. PMID- 25690908 TI - Acromiohumeral distance measurement in rotator cuff tendinopathy: is there a reliable, clinically applicable method? A systematic review. AB - BACKGROUND: Narrowing of the subacromial space has been noted as a common feature of rotator cuff (RC) tendinopathy. It has been implicated in the development of symptoms and forms the basis for some surgical and rehabilitation approaches. Various radiological methods have been used to measure the subacromial space, which is represented by a two-dimensional measurement of acromiohumeral distance (AHD). A reliable method of measurement could be used to assess the impact of rehabilitation or surgical interventions for RC tendinopathy; however, there are no published reviews assessing the reliability of AHD measurement. OBJECTIVES: The aim of this review was to systematically assess the evidence for the intrarater and inter-rater reliability of radiological methods of measuring AHD, in order to identify the most reliable method for use in RC tendinopathy. STUDY APPRAISAL AND SYNTHESIS: An electronic literature search was carried out and studies describing the reliability of any radiological method of measuring AHD in either healthy or RC tendinopathy groups were included. Eighteen studies met the inclusion criteria and were appraised by two reviewers using the Quality Appraisal for reliability Studies checklist. RESULTS: Eight studies were deemed to be of high methodological quality. Study weaknesses included lack of tester blinding, inadequate description of tester experience, lack of inclusion of symptomatic populations, poor reporting of statistical methods and unclear diagnosis. There was strong evidence for the reliability of ultrasound for measuring AHD, with moderate evidence for MRI and CT measures and conflicting evidence for radiographic methods. Overall, there was lack of research in RC tendinopathy populations, with only six studies including participants with shoulder pain. CONCLUSIONS: The results support the reliability of ultrasound and CT or MRI for the measurement of AHD; however, more studies in symptomatic populations are required. The reliability of AHD measurement using radiographs has not been supported by the studies reviewed. PMID- 25690909 TI - Factors associated with suicide in patients with genitourinary malignancies. AB - BACKGROUND: Approximately 70% of all suicides in patients aged >60 years are attributed to physical illness, with higher rates noted in patients with cancer. The purpose of the current study was to characterize suicide rates among patients with genitourinary cancers and identify factors associated with suicide in this specific cohort. METHODS: Patients with prostate, bladder, kidney, testis, and penile cancer were identified in the Surveillance, Epidemiology, and End Results database (1988-2010). Standardized mortality ratios (SMRs) and 95% confidence intervals (95% CIs) were calculated for each anatomic site. Multivariable logistic regression models generated odds ratios (ORs) for the identification of factors associated with suicide for each malignancy. RESULTS: There were 2268 suicides identified among 1,239,522 individuals with genitourinary malignancies observed for 7,307,377 person-years. The SMRs for patients with cancer were 1.37 for prostate cancer (95% CI, 0.99-1.86), 2.71 for bladder cancer (95% CI, 2.02 3.62), 1.86 for kidney cancer (95% CI, 1.32-2.62), 1.23 for testis cancer (95% CI, 0.88-1.73), and 0.95 for penile cancer (95% CI, 0.65-1.35). On multivariable analysis, male sex was found to be associated with odds of suicide among patients with bladder cancer (OR, 6.63) and kidney cancer (OR, 4.98). Increasing age was associated with suicide for patients with prostate, bladder, and testis cancer (OR range, 1.03-1.06). Distant disease was associated with suicide in patients with prostate, bladder, and kidney cancer (OR range, 2.82-5.43). Among patients with prostate, bladder, and kidney cancer, African American patients were less likely to commit suicide compared with white individuals (OR range, 0.26-0.46). CONCLUSIONS: Suicide in patients with genitourinary malignancies poses a public health dilemma, especially among men, the elderly, and those with aggressive disease. Clinicians should be aware of risk factors for suicide in these patients. PMID- 25690910 TI - The validation of forensic DNA extraction systems to utilize soil contaminated biological evidence. AB - The production of full DNA profiles from biological evidence found in soil has a high failure rate due largely to the inhibitory substance humic acid (HA). Abundant in various natural soils, HA co-extracts with DNA during extraction and inhibits DNA profiling by binding to the molecular components of the genotyping assay. To successfully utilize traces of soil contaminated evidence, such as that found at many murder and rape crime scenes in South Africa, a reliable HA removal extraction system would often be selected based on previous validation studies. However, for many standard forensic DNA extraction systems, peer-reviewed publications detailing the efficacy on soil evidence is either lacking or is incomplete. Consequently, these sample types are often not collected or fail to yield suitable DNA material due to the use of unsuitable methodology. The aim of this study was to validate the common forensic DNA collection and extraction systems used in South Africa, namely DNA IQ, FTA elute and Nucleosave for processing blood and saliva contaminated with HA. A forensic appropriate volume of biological evidence was spiked with HA (0, 0.5, 1.5 and 2.5 mg/ml) and processed through each extraction protocol for the evaluation of HA removal using QPCR and STR-genotyping. The DNA IQ magnetic bead system effectively removed HA from highly contaminated blood and saliva, and generated consistently acceptable STR profiles from both artificially spiked samples and crude soil samples. This system is highly recommended for use on soil-contaminated evidence over the cellulose card-based systems currently being preferentially used for DNA sample collection. PMID- 25690911 TI - Perinatal outcomes following an earlier post-term labour induction policy: a historical cohort study. AB - OBJECTIVE: To assess the changes in perinatal outcomes in children born from 37 weeks of gestation after implementation of a more proactive labour induction practice from 2009. DESIGN: Register-based cohort study. SETTING: Denmark, 2000 12. POPULATION: Newborns from 37 weeks of gestation. METHODS: Perinatal outcomes were estimated using a logistic regression analysis with adjustment for gestational age, maternal age, parity, plurality, smoking and body mass index. MAIN OUTCOME MEASURES: Perinatal outcomes. RESULTS: A total of 770 926 infants were included. Labour induction from 37 weeks increased from 9.7% in 2000-02 to 22.5% in 2011-12. From 2003-05 to 2011-12, the risk of umbilical cord pH < 7.0 decreased by 23%; odds ratio (OR) 0.77 (95% confidence interval 0.67-0.89), and the adjusted OR of Apgar score < 7 at 5 minutes was unchanged. The risk of admission to neonatal intensive care units increased by 56%; OR 1.56 (1.47-1.66), whereas the risk of neonatal deaths decreased by 44%; OR 0.56 (0.45-0.70). The risk of cerebral palsy was from 2000-02 to 2009-10 reduced by 26%; OR 0.74 (0.60 0.90). The proportion of infants born with fetal weight >= 4500 g decreased by one-third; OR 0.68 (0.65-0.71). However, the risk of shoulder dystocia increased by 32%; OR 1.32 (1.21-1.44), whereas the risk of peripheral nerve injuries was reduced by 43%; OR 0.57 (0.45-0.73). CONCLUSION: The results suggest an overall improvement in perinatal outcomes as a result of a more proactive post-term labour induction practice. PMID- 25690912 TI - Sexual orientation identity change and depressive symptoms: a longitudinal analysis. AB - Several new studies have documented high rates of sexual identity mobility among young adults, but little work has investigated the links between identity change and mental health. This study uses the National Longitudinal Study of Adolescent to Adult Health (N = 11,727) and employs multivariate regression and propensity score matching to investigate the impact of identity change on depressive symptoms. The results reveal that only changes in sexual identity toward more same-sex-oriented identities are associated with increases in depressive symptoms. Moreover, the negative impacts of identity change are concentrated among individuals who at baseline identified as heterosexual or had not reported same-sex romantic attraction or relationships. No differences in depressive symptoms by sexual orientation identity were found among respondents who reported stable identities. Future research should continue to investigate the factors that contribute to the relationship between identity change and depression, such as stigma surrounding sexual fluidity. PMID- 25690913 TI - Clinical Course and Prognosis of Non-Secretory Multiple Myeloma. AB - OBJECTIVE: To determine the prognosis of patients with non-secretory myeloma. Methods: We studied 124 patients diagnosed with multiple myeloma who had no monoclonal protein detected on serum and urine immunofixation at diagnosis and on all subsequent follow up testing (non-secretory myeloma). The overall survival (OS) of patients with non-secretory myeloma was compared with 7075 patients with typical myeloma seen during the same time period in whom a monoclonal protein was detected at the time of diagnosis. RESULTS: One hundred and twenty four patients met criteria for non-secretory multiple myeloma. The median follow-up was 102 months (range, 1-204 months). The median progression free survival with initial therapy was 28.6 months, and the median OS was 49.3 months. There was a significant improvement in OS since 2001; median survival 99.2 versus 43.8 months (prior to 2001) versus 99.2 months (2001-2012), P<0.001. OS was superior in patients with a normal baseline FLC ratio (n=10) compared to patients with an abnormal ratio (n=19), medians not reached in both groups. Prior to 2001, OS was similar in non-secretory myeloma (n=86) and secretory myeloma (n=4011), median 3.6 versus 3.5 years, respectively, P=0.63. However, among patients diagnosed between 2001-2012, OS was superior in non-secretory myeloma (n=36) compared to secretory myeloma (n=2942), median 8.3 versus 5.4 years, respectively, P=0.03. CONCLUSIONS: Non-secretory myeloma is an uncommon subtype of multiple myeloma. In the last decade, there has been an improvement in the survival of non-secretory myeloma, and appears superior to secretory myeloma. This article is protected by copyright. All rights reserved. PMID- 25690914 TI - CT dimensions, volumes and densities of normal canine eyes. AB - Although ultrasound and MRI are the imaging modalities of choice for the investigation of ocular diseases, the eyes are included in routine CT examinations of the head and should be examined as part of the complete evaluation. This report describes the dimensions, volumes and densities of the normal canine globe in CT. Forty-four eyes were studied. The mean axial length of the globe was 2.09 cm and its mean volume was 4.65 cm(3). The mean anteroposterior distance of the anterior chamber was 0.4 cm and of the vitreous chamber was 0.96 cm. There was a statistically significant difference between the mean aqueous humour density, 14.76 Hounsfield units (HU), and the mean vitreous humour density, 11.20 HU (P=0.0009). Statistically significant differences were also seen in both humours in precontrast and postcontrast studies. The mean anteroposterior dimension of the lens was 0.74 cm; its mean equatorial distance was 1.15 cm. The mean volume was 0.43 cm(3) and its mean density was 131.9 HU. There was contrast enhancement of the ciliary body, iris and retina/sclera/choroid complex. This study provides reference values to help in the interpretation of ocular structures on CT scans of the head, where incidental findings can change the medical management of specific cases. PMID- 25690915 TI - Association between birth conditions and glucose and cortisol profiles of periparturient dairy cows and neonatal calves. AB - Parturition in cattle is a stressful event for both the dam and the offspring. Stress and pain can alter the energy profile of calves and calving cows, producing a metabolic imbalance at birth. This study aimed to assess the effects of dystocia and oxytocin and calcium infusion on metabolic homeostasis in dairy cows and calves. Thirty Holstein cows and their calves were divided into three groups: an eutocia group (n=10), in which no calving assistance was needed; a dystocia group, which required mild-to-severe obstetric assistance (n=10); and a uterine inertia group, which was treated with oxytocin and calcium (n=10). To assess serum cortisol and blood glucose levels, blood samples were collected during the peripartum period from cows and during the first hour since birth from calves. All groups were hyperglycaemic following parturition. Infusion of oxytocin and calcium resulted in lower maternal glucose concentrations and lower levels of stress than in cows in the dystocia group. Birth condition was significantly associated with blood glucose and cortisol concentrations in calves. Glucose concentration was lower in calves born with oxytocin and calcium infusion than those born with fetal extraction. In conclusion, assisted calving with fetal extraction causes important metabolic changes for the dam and calf. Conversely, the practice of oxytocin and calcium infusion for hypotonic cows has no harmful effects on metabolic balance and can be safely employed as a medical treatment. PMID- 25690916 TI - Endogenous antiviral microRNAs determine permissiveness for hepatitis B virus replication in cultured human fetal and adult hepatocytes. AB - Superior cell culture models for hepatitis B virus (HBV) will help advance insights into host-virus interactions. To identify mechanisms regulating HBV replication, this study used cultured human HepG2 cells and adult or fetal hepatocytes transduced with adenoviral vector to express HBV upstream of green fluorescent protein. The vector efficiently transduced all cell types. In HepG2 cells, replicative viral intermediates, nucleocapsid-associated HBcAg, and HBsAg were expressed. However, in fetal or adult hepatocytes, pregenomic HBV RNA and viral RNAs were expressed, but nucleocapsid-associated HBcAg in cells or HBsAg in culture medium were absent, indicating interruptions in viral replication due to possible microRNA-related interference. MicroRNA profiling demonstrated that a large number of microRNAs with antiviral potential were differentially expressed in hepatocytes after culture. In transfection assays using HepG2 cells, candidate antiviral microRNAs, e.g., hsa-miR-24 or hsa-miR-638 decreased the levels of HBV transcripts or HBV gene products. Since candidate microRNAs could have targeted interferon response genes as an alternative explanation interferon signaling was examined. However, HBV replication in cultured hepatocytes was not restored despite successful inhibition of JAK1/2-STAT signaling by the inhibitor, ruxolitinib. Therefore, HBV was unable to complete replication in cultured hepatocytes due to expression of multiple antiviral microRNAs. This mechanism should help understand restrictions in HBV replication for developing HBV models in cultured cells while providing frameworks for pathophysiological studies of HBV replication in subsets of hepatocytes or stem/progenitor cells during hepatitis. PMID- 25690917 TI - Liposomes assembled from a dual drug-tailed phospholipid for cancer therapy. AB - We report a novel dual drug-tailed phospholipid which can form liposomes as a combination of prodrug and drug carrier. An amphiphilic dual chlorambucil-tailed phospholipid (DCTP) was synthesized by a straightforward esterification. With two chlorambucil molecules as hydrophobic tails and one glycerophosphatidylcholine molecule as a hydrophilic head, the DCTP, a phospholipid prodrug, undergoes assembly to form a liposome without any additives by the thin lipid film technique. The DCTP liposomes, as an effective carrier of chlorambucil, exhibited a very high loading capacity and excellent stability. The liposomes had higher cytotoxic effects to cancer cell lines than free DCTP and chlorambucil. The in vivo antitumor activity assessment indicated that the DCTP liposomes could inhibit the tumor growth effectively. This novel strategy of dual drug-tailed phospholipid liposomes may be also applicable to other hydrophobic anticancer drugs which have great potential in cancer therapy. PMID- 25690919 TI - Lost by Design. AB - In some common uses metals are lost by intent-copper in brake pads, zinc in tires, and germanium in retained catalyst applications being examples. In other common uses, metals are incorporated into products in ways for which no viable recycling approaches exist, examples include selenium in colored glass and vanadium in pigments. To determine quantitatively the scope of these "losses by design", we have assessed the major uses of 56 metals and metalloids, assigning each use to one of three categories: in-use dissipation, currently unrecyclable when discarded, or potentially recyclable when discarded. In-use dissipation affects fewer than a dozen elements (including mercury and arsenic), but the spectrum of elements dissipated increases rapidly if applications from which they are currently unrecyclable are considered. In many cases the resulting dissipation rates are higher than 50%. Among others, specialty metals (e.g., gallium, indium, and thallium) and some heavy rare earth elements are representative of modern technology, and their loss provides a measure of the degree of unsustainability in the contemporary use of materials and products. Even where uses are currently compatible with recycling technologies and approaches, end of life recycling rates are in most cases well below those that are potentially achievable. The outcomes of this research provide guidance in identifying product design approaches for reducing material losses so as to increase element recovery at end-of-life. PMID- 25690920 TI - Comparative results of percutaneous Achilles tenotomy to combined open Achilles tenotomy with posterior capsulotomy in the correction of equinus deformity in congenital talipes equinovarus. AB - PURPOSE: The purpose of this study is to compare the efficacy of percutaneous Achilles tenotomy (AT) to combined open Achilles tenotomy and posterior capsulotomy (PC+AT) in the correction of residual equinus deformity in congenital talipes equinovarus after Ponseti serial casting in both idiopathic and non idiopathic clubfeet. METHODS: The authors retrospectively reviewed 591 patients treated for congenital talipes equinovarus between January 1, 2001 and January 1, 2011. Available medical and operative records were reviewed for basic demographic data as well as ankle dorsiflexion pre-operatively, postoperatively and at latest follow up. RESULTS: A total of 167 children with 260 discrete clubfeet that met our inclusion criteria were identified. Of them, 189/260 clubfeet (72.7 %) were idiopathic and 71/260 clubfeet (27.3 %) were non-idiopathic with a mean total follow up of 4.8 +/- 2.4 years (minimum follow-up of two years). At latest follow up, there was no statistically significant difference in the mean ankle dorsiflexion (p = 0.333) or recurrence rate (p = 0.545) between PC+AT and AT groups in both idiopathic and non-idiopathic clubfeet. CONCLUSION: In our series, the addition of posterior capsulotomy to Achilles tenotomy did not improve the mean dorsiflexion at latest follow up or decrease the rate of recurrence of equinus deformity in both idiopathic and non-idiopathic clubfeet. It is therefore advisable that percutaneous Achilles tenotomy alone be used in the correction of equinus deformity in both idiopathic and non-idiopathic congenital talipes equinovarus after successful Ponseti serial casting. PMID- 25690921 TI - Arthroplasty in patients with extensive femoral head avascular necrosis: Cementless arthroplasty in extensive femoral head necrosis. AB - PURPOSE: The purpose of this study was to investigate the outcomes of using cementless femoral stem for extensive osteonecrosis of the femoral head involving the proximal femur. METHODS: A total of 21 patients (27 hips) in the study group defined as extensive ONFH involving proximal femur and 42 patients (52 hips) with the diagnosis of regular osteonecrosis of the femoral head in the control group were enrolled in the study. Clinical and radiographic follow-ups were documented at three, six, 12 and 24 months postoperatively. RESULTS: Results improved for Harris hip score in both groups. In the study group undersized stem implantation and lateralized mal-position were identified. Subsequent subsidence was also found. CONCLUSIONS: Pre-operative templating and intra-operative X-ray confirmation are necessary to avoid complications. PMID- 25690922 TI - Is the acetabular cup orientation after total hip arthroplasty on a two dimensional or three-dimensional model accurate? PMID- 25690923 TI - Post-traumatic thrombo-embolic complications in polytrauma patients. AB - INTRODUCTION: Thrombo-embolic events after trauma are considered to be life threatening complications. Our aim was to determine the incidence of arterial and venous thrombo-embolic events (TE) in severely-injured trauma patients, and its associated risk factors by using a large trauma registry. METHODS: Patients' data from the TraumaRegister DGU(r) (TR-DGU) were screened for TE (DVT [symptomatic deep vein thrombosis], PE [symptomatic pulmonary embolism], MI [myocardial infarction], and stroke) through the clinical course of severely injured adult trauma patients from January 2005 to December 2012. Univariate analysis was used to compare the clinical outcomes (endpoints: mortality, ICU and hospital length of stay, ventilator days), and a multivariate regression analysis was used to assess the independent risk factors associated with each TE event. RESULTS: From a cohort of 40,846 trauma patients, 1122 (2.8%) patients developed a TE during their post-traumatic clinical course (313, 0.8% DVT; 425, 1.0% PE; 160, 0.4% MI and 231, 0.6% stroke). ICU length of stay [LOS], total LOS, days on mechanical ventilation, and incidence of multiple organ failure (MOF) and sepsis were significantly increased in patients with TE complications. Injury severity, major pelvic injury, and one or more operations were found to be independent risk factors for the development of DVT. Age >= 60 years, male gender, and more than one operation were risk factors for PE development. For MI age was the only significant risk factor. The occurrence of a stroke is increased in patients with an age >= 60 years, major head injury (AIS head >= 3), and more than one operation. Finally, mortality rates were significantly higher in the TE group when compared to the non-TE cohort (21.8% vs. 12.7%; p < 0.001). CONCLUSION: TE complications were associated with longer ICU and hospital stay as well as a higher mortality. Overall, age and repeated operations were the most important risk factors for the development of TE events. PMID- 25690924 TI - Outcome of a modular tapered uncemented titanium femoral stem in revision hip arthroplasty. AB - PURPOSE: Revision hip arthroplasty using a modular tapered design gives the possibility for customising the prostheses to the individual anatomy intra operatively. The success of this kind of surgery is still controversial due to the relative lack of medium- to long-term follow-up. Therefore we analysed the clinical and radiological outcome of the modular MRP-TITAN stem with diaphyseal fixation in revision hip surgery. METHODS: In this retrospective study we included 136 consecutive patients with MRP-TITAN stem implanted during revision hip arthroplasty. The average follow-up was 55 months. For clinical evaluation we used the Harris Hip Score and the Merle d'Aubigne and Postel score. The health related quality of life was determined with the visual analogue pain scale. RESULTS: The surgeries were performed 109 months after primary total hip arthroplasty on average. The main indications for the MRP-TITAN revision stem were aseptic loosening, infection, and periprosthetic fracture. In the clinical outcome, patients achieved 75.1 points in the Harris Hip Score and 14.4 points in the Merle d'Aubigne and Postel Score. Mean level of persisting pain was 0.7 (VAS). The overall survival of the MRP stem in revision hip arthroplasty revealed 85.6% survival at 9.75 years' follow-up with a repeat revision rate of 6.8%. CONCLUSIONS: Performing revision hip arthroplasty using the MRP-TITAN stem revealed a good clinical outcome. There is a tendency for better results in comparison with the information given in literature for cementless modular revision stems including a lower rate in re-revisions. PMID- 25690925 TI - Vitiligo patient-derived keratinocytes exhibit characteristics of normal wound healing via epithelial to mesenchymal transition. AB - Vitiligo is an autoimmune disorder that leads to depigmentation of skin via melanocyte dysfunction. Keratinocyte-induced toxicity is one among the several etiological factors implicated for vitiligo, and hence, autologous keratinocyte grafting is projected as one of the primary mode of treatment for vitiligo. However, reports indicate that perilesional keratinocytes not only display signatures of apoptosis but also could secrete cytokines and mediators which have antagonistic effect on proliferation or survival. Therefore, we investigated how vitiligo patients' derived keratinocytes respond to surplus amounts of inflammatory cytokines and whether they recapitulate events that take place during conventional wound healing. The primary objective of our study was to determine whether keratinocytes isolated from a vitiligo patient would undergo epithelial-mesenchymal transition similar to their normal counterparts upon induction with inflammatory cytokines such as TGF-b1 and EGF. We found that these keratinocytes undergo EMT during wound repair accompanied with increase in the levels of mesenchymal markers and ECM proteins; decrease in the levels of epithelial markers and enhanced migratory ability. Besides, we also demonstrated that EMT induction leads to activation of SMAD and MAPK pathways via Ras, Raf, PAI 1, Snail, Slug and ZO1. To our knowledge, this is the first report on the characterization of primary keratinocytes isolated from vitiligo patients with respect to their wound healing capacity. PMID- 25690926 TI - Severe strongyloidiasis with negative serology after corticosteroid treatment. AB - BACKGROUND: Strongyloidiasis usually presents as a chronic and limited disease, but in some immunocompromised patients it may become a life-threatening disease. CASE REPORT: A 77-year-old Haitian male, with history of temporal arteritis on 40 mg of oral prednisone presented complaining of decreased oral intake, epigastric pain, and non-bloody diarrhea. He had bi-temporal wasting and a distended abdomen but without guarding or tenderness. Laboratory examination included mild leukocytosis, anemia, negative HIV antibody, negative parasite stool exam, and negative serology for Giardia and Strongyloides. CT of the abdomen showed multiple distended loops, without obstruction. During the admission he had a 4 g hemoglobin drop and a positive occult blood test, requiring blood transfusions, IV pantoprazole, and upper endoscopy. Findings included severe duodenitis, blunted villi, and intramucosal and luminal helminthic worms and eggs. Pathology showed Strongyloides stercoralis infection, confirmed by subsequent PCR. He was given 1 day of 15 mg oral ivermectin, diarrhea resolved, and was discharged with a percutaneous endoscopic gastrostomy tube because of the persistent lack of appetite. ConCLUSIONS: Given the persistent nature of strongyloidiasis and its high susceptibility to ivermectin, it potentially would be worth consider treating high-risk patients in the appropriate clinical and epidemiological setting, irrespective of screening test results, in order to avoid false-negative result consequences. PMID- 25690928 TI - Effect of industrial freezing on the stability of chemopreventive compounds in broccoli. AB - Broccoli (Brassica oleracea L. var. Italica) is largely consumed all over the world and has a high economic importance. Likewise, broccoli contains high levels of glucosinolates, carotenoids and total phenols, which are related with the prevention of chronic diseases. The present project's objective was to evaluate the effect of industrial freezing on the stability of bioactive molecules in seven commercial broccoli cultivars (Tlaloc(r), Endurance(r), Florapack(r), Domador(r), Steel(r), Iron Man(r) and Avenger(r)). In general, industrial freezing increased the extractability of total glucosinolates, whereas total phenols remained constant in most broccoli cultivars. Likewise, broccoli subjected to industrial freezing showed higher levels of total carotenoids (~60 300% higher) as compared with fresh broccoli. Results suggest that bioactive compounds in frozen broccoli would be more bioavailable than in raw. PMID- 25690927 TI - Molecular biology of pediatric brain tumors and impact on novel therapies. AB - Brain tumors are the leading cause of cancer-related death in children. For the past several decades, therapeutic strategies have centered on cytotoxic chemotherapy and radiation therapy due, in part, to limited understanding of genetic events that underlie tumor initiation and maintenance. Significant improvement in high-throughput genomic methods, such as next-generation sequencing, methylation array, and copy number array, in recent years has propelled the knowledge base from which novel therapies are derived. Translation of recent genomic findings into more effective therapies remains the most formidable challenge in improving the outcome for children with brain tumors. PMID- 25690929 TI - Immobilization stress sensitizes rat dorsal horn neurons having input from the low back. AB - BACKGROUND: Stress is known to promote several forms of muscle pain including non specific low back pain. However, the question if stress alone activates nociceptive central neurons has not been studied systematically. Here, we investigated the influence of repeated immobilization stress on dorsal horn neurons and behaviour in the rat. METHODS: The stress consisted of immobilization in a narrow tube for 1 h on 12 days. Single dorsal horn neurons were recorded with microelectrodes introduced into the spinal segment L2. In this segment, about 14% of the neurons responded to mechanical stimulation of the subcutaneous soft tissues of the low back in naive rats. The neurons often behaved like wide dynamic range cells in that they had a low mechanical threshold and showed graded responses to noxious stimuli. RESULTS: The stress-induced changes in neuronal response behaviour were (1) appearance of new receptive fields in the deep tissues of the hindlimb, (2) increased input from deep soft tissues, but unchanged input from the skin and (3) significant increase in resting activity. Surprisingly, the pressure-pain threshold of the low back remained unchanged, although dorsal horn neurons were sensitized. In the open field test, the rats showed signs of increased anxiety. CONCLUSIONS: This study shows that stress alone is sufficient to sensitize dorsal horn neurons. The data may explain the enhanced pain low back patients report when they are under stress. The increased resting discharge may lead to spontaneous pain. PMID- 25690930 TI - Examination of the safety of pediatric vaccine schedules in a non-human primate model: assessments of neurodevelopment, learning, and social behavior. AB - BACKGROUND: In the 1990s, the mercury-based preservative thimerosal was used in most pediatric vaccines. Although there are currently only two thimerosal containing vaccines (TCVs) recommended for pediatric use, parental perceptions that vaccines pose safety concerns are affecting vaccination rates, particularly in light of the much expanded and more complex schedule in place today. OBJECTIVES: The objective of this study was to examine the safety of pediatric vaccine schedules in a non-human primate model. METHODS: We administered vaccines to six groups of infant male rhesus macaques (n = 12-16/group) using a standardized thimerosal dose where appropriate. Study groups included the recommended 1990s Pediatric vaccine schedule, an accelerated 1990s Primate schedule with or without the measles-mumps-rubella (MMR) vaccine, the MMR vaccine only, and the expanded 2008 schedule. We administered saline injections to age matched control animals (n = 16). Infant development was assessed from birth to 12 months of age by examining the acquisition of neonatal reflexes, the development of object concept permanence (OCP), computerized tests of discrimination learning, and infant social behavior. Data were analyzed using analysis of variance, multilevel modeling, and survival analyses, where appropriate. RESULTS: We observed no group differences in the acquisition of OCP. During discrimination learning, animals receiving TCVs had improved performance on reversal testing, although some of these same animals showed poorer performance in subsequent learning-set testing. Analysis of social and nonsocial behaviors identified few instances of negative behaviors across the entire infancy period. Although some group differences in specific behaviors were reported at 2 months of age, by 12 months all infants, irrespective of vaccination status, had developed the typical repertoire of macaque behaviors. CONCLUSIONS: This comprehensive 5-year case-control study, which closely examined the effects of pediatric vaccines on early primate development, provided no consistent evidence of neurodevelopmental deficits or aberrant behavior in vaccinated animals. PMID- 25690931 TI - In vitro interactions of blood, platelet, and fibroblast with biodegradable magnesium-zinc-strontium alloys. AB - Magnesium (Mg) alloy is an attractive class of metallic biomaterial for cardiovascular applications due to its biodegradability and mechanical properties. In this study, we investigated the degradation in blood, thrombogenicity, and cytocompatibility of Magnesium-Zinc-Strontium (Mg-Zn-Sr) alloys, specifically four Mg-4 wt % Zn-xSr (x = 0.15, 0.5, 1, and 1.5 wt %) alloys, together with pure Mg control and relevant reference materials for cardiovascular applications. Human whole blood and platelet rich plasma (PRP) were used as the incubation media to investigate the degradation behavior of the Mg-Zn-Sr alloys. The results showed that the PRP had a greater pH increase and greater concentration of Mg(2+) ions when compared with whole blood after 2 h of incubation with the same respective Mg alloys, suggesting that the Mg alloys degraded faster in PRP than in whole blood. The Mg alloy with 4 wt % Zn and 0.15 wt % Sr (named as ZSr41A) was identified as the most promising alloy for cardiovascular stent applications, because it showed slower degradation and less thrombogenicity, as indicated by the lower concentrations of Mg(2+) ions released and less deposition of platelets. Additionally, ZSr41 alloys were cytocompatible with fibroblasts in direct exposure culture in which the cells adhered and proliferated around the samples, with no statistical difference in cell adhesion density compared with the blank reference. Future studies on the ZSr41 alloys are necessary to investigate their direct interactions with other important cells in cardiovascular system, such as vascular endothelial cells and smooth muscle cells. PMID- 25690932 TI - Results of the determination of He in cenozoic aquifers using the GC method. AB - Applications of the Helium (He) method known so far consisted mainly of 4He measurements using a special mass spectrometer. 4He measurements for groundwater dating purposes can be replaced by total He (3He+4He) concentration measurements because the content of 3He can be ignored. The concentrations of 3He are very low and 3He/4 He ratios do not exceed 1.0.10(-5) in most cases. In this study, the total He concentrations in groundwater were determined using the gas chromatographic (GC) method as an alternative to methods based on spectrometry measurement. He concentrations in groundwater were used for the determination of residence time and groundwater circulation. Additionally, the radiocarbon method was used to determine the value of the external He flux (JHe) in the study area. Obtained low He concentrations and their small variation within the ca. 65 km long section along which groundwater flows indicate that it is likely there is relatively short residence time and a strong hydraulic connection between the aquifers. The estimated residence time (ca. 3000 years) is heavily dependent on the great uncertainty of the He concentration resulting from the low concentrations of He, the external 4He flux value adopted for calculation purposes and the 14C ages used to estimate the external 4He flux. PMID- 25690933 TI - Modeling the response of a quartz crystal microbalance under nanoscale confinement and slip boundary conditions. AB - Nanorheology and boundary slip play an important role in the micro/nanofluidics, and micro/nano-electromechanical systems, especially for research on DNA, proteins and polymers. Herein, a nanoscale confinement structure, called a nanocell, is established by assembling a parallel plate on the quartz crystal microbalance (QCM) chip to study the nanorheology of liquids and the boundary slip on the interface. The corresponding analytical models are established and verified experimentally with high consistency. We reveal that the responses of QCM with the nanocell assembled are dependent on the nanocell confinement thickness, the acoustic impedance of the nanocell lid (parallel plate), as well as the boundary slip on the interface. A critical influence thickness of the assembled nanocell d = 2delta is indicated, above which the assembly of a nanocell has no influence on the QCM response. And the interfacial boundary slip results in obvious decreases of relative frequency shift and relative half bandwidth variation. We find that adopting a nanocell lid with the same acoustic impedance as the tested liquids will evidently simplify the experimental analysis. In the paper, the nanocell provides an effective method to investigate the nanorheology of confined liquids and the interfacial boundary slip, and the established models offer a theoretical basis for the analysis of the nanocell assembled QCM response. PMID- 25690934 TI - FRET-capable supramolecular polymers based on a BODIPY-bridged pillar[5]arene dimer with BODIPY guests for mimicking the light-harvesting system of natural photosynthesis. AB - AA/BB-type and A2/B3-type FRET-capable supramolecular polymers based on a BODIPY bridged pillar[5]arene dimer and two BODIPY derivative guests have been successfully constructed and their application in mimicking the light-harvesting system of natural photosynthesis was studied. PMID- 25690935 TI - The mismatch between patient life expectancy and the service life of implantable devices in current cardioverter-defibrillator therapy: a call for larger device batteries. AB - In 2005, Bob Hauser published a paper in the Journal of the American College of Cardiology entitled "The growing mismatch between patient longevity and the service life of Implantable Cardioverter-Defibrillators". Now, nearly a decade later, I would like to perform a second look on the problem of a mismatching between ICD device service life and the survival of ICD recipients. Since 2005, the demographics of the ICD population has changed significantly. Primary prevention has become the dominant indication in defibrillator therapy and device implantation is indicated more and more in earlier stages of cardiac diseases. In former larger scale ICD trials, the patient average 5-year survival probability was in a range of 68-71%; in newer CRT-D trials in a range of 72-88%. Due to a progressively widened ICD indication and implantation preferentially performed in patients with better life expectancy, the problem of inadequate device service life is of growing importance. The early days of defibrillator therapy started with a generator volume of 145 ccm and a device service life <18 months. In this early period, the device miniaturization and extension of service life were similar challenges for the technicians. Today, we have reached a formerly unexpected extent of device miniaturization. However, technologic improvements were often preferentially translated in further device miniaturization and not in prolonging device service life. In his analysis, Bob Hauser reported a prolonged device service life of 2.3 years in ICD models with a larger battery capacity of 0.54 up to 0.69 Ah. Between 2008 and 2014, several studies had been published on the problem of ICD longevity in clinical scenarios. These analyses included "older" and currently used single chamber, dual chamber and CRT devices. The reported average 5-year device service life ranged from 0 to 75%. Assuming today technology, larger battery capacities will only result in minimal increase in device volume. Selected ICD patients may further benefit from device miniaturization-but the vast majority may much more benefit from a significant prolongation in device service life. All published cost-effectiveness analyses in ICD therapy show that device costs and device service life are the dominant determinants of the results. The performed "second look-nearly a decade later" revealed that there are still relevant limitations regarding the device service life in current defibrillator therapy. Technical improvements were preferentially transformed into device miniaturization but not into prolonging device service life. But this optimization is strongly enforced. The most feasible solution might be the use of device batteries with larger capacities. The economic burden, mainly caused by non-adequate device service life, may limit the future realization of ICD therapy in a progressively growing patient population. In the former years, physicians and device manufacturers have ignored the patient perspective in defibrillator therapy. However, it is the patient viewpoint that prolonged device service life is much more important than smaller generator size. PMID- 25690936 TI - SPREDs (Sprouty related proteins with EVH1 domain) promote self-renewal and inhibit mesodermal differentiation in murine embryonic stem cells. AB - BACKGROUND: Pluripotency, self-renewal, and differentiation are special features of embryonic stem (ES) cells, thereby providing valuable perspectives in regenerative medicine. Developmental processes require a fine-tuned organization, mainly regulated by the well-known JAK/STAT, PI3K/AKT, and ERK/MAPK pathways. SPREDs (Sprouty related proteins with EVH1 domain) were discovered as inhibitors of the ERK/MAPK signaling pathway, whereas nothing was known about their functions in ES cells and during early differentiation, so far. RESULTS: We generated SPRED1 and SPRED2 overexpressing and SPRED2 knockout murine ES cells to analyze the functions of SPRED proteins in ES cells and during early differentiation. Overexpression of SPREDs increases significantly the self renewal and clonogenicity of murine ES cells, whereas lack of SPRED2 reduces proliferation and increases apoptosis. During early differentiation in embryoid bodies, SPREDs promote the pluripotent state and inhibit differentiation whereby mesodermal differentiation into cardiomyocytes is considerably delayed and inhibited. LIF- and growth factor-stimulation revealed that SPREDs inhibit ERK/MAPK activation in murine ES cells. However, no effects were detectable on LIF-induced activation of the JAK/STAT3, or PI3K/AKT signaling pathway by SPRED proteins. CONCLUSIONS: We show that SPREDs promote self-renewal and inhibit mesodermal differentiation of murine ES cells by selective suppression of the ERK/MAPK signaling pathway in pluripotent cells. PMID- 25690937 TI - DNA damage response markers are differentially expressed in BRCA-mutated breast cancers. AB - Cells have stringent DNA repair pathways that are specific for each different set of DNA lesions which is accomplished through the integration of complex array of proteins. However, BRCA-mutated breast cancer (BC) has defective DNA repair mechanisms. This study aims to investigate differential expression of a large panel of DNA repair markers to characterise DNA repair mechanisms in BRCA associated tumours compared to sporadic tumours in an attempt to characterise these tumours in routine practice. Immunohistochemistry and tissue microarray technology were applied to a cohort of clinically annotated series of sporadic (n = 1849), BRCA1-mutated (n = 48), and BRCA2-mutated (n = 27) BC. The following DNA damage response (DDR) markers are used; BRCA1, BRCA2, RAD51, Ku70/Ku80, BARD, PARP1 (cleaved), PARP1 (non-cleaved), and P53 in addition to basal cytokeratins, ER, PR, and HER2. A significant proportion of BRCA1 tumours were positive for PARP1 (non-cleaved), and negative for BARD1 and RAD51 compared with sporadic BC. BRCA2 tumours were significantly positive for PARP1 (non-cleaved) compared with sporadic tumours. RAD51 was significantly higher in BRCA1 compared with BRCA2 tumours (p = 0.005). When BRCA1/2 BCs were compared to triple-negative (TN) sporadic tumours of the studied DDR proteins, BARD1 (p < 0.001), PARP1 (non cleaved) (p < 0.001), and P53 (p = 0.002) remained significantly different in BRCA1/2 tumours compared with TN BC. DNA repair markers showed differential expression in BRCA-mutated tumours, with a substantial degree of disruption of DNA repair pathways in sporadic BC especially TN BC. DNA double-strand break (DSB) repair is assisted by PARP1 expression in BRCA-mutated tumours, whereas the loss of DSB repair via RAD51 is predominant in BRCA1 rather than BRCA2 BC. PMID- 25690938 TI - Aminomethylphosphonic acid has low chronic toxicity to Daphnia magna and Pimephales promelas. AB - Aminomethylphosphonic acid (AMPA) is the simplest member of a class of compounds known as aminomethylenephosphonates and the only environmental metabolite measured in significant amounts during the degradation of the herbicide glyphosate in soil. However, there are additional sources of AMPA in the environment, originating from organic phosphonates which are used in water treatment to inhibit scale formation and corrosion. Like glyphosate, AMPA has low acute toxicity to aquatic animals, and the no-observed-adverse effect concentration (NOAEC) obtained from a fish full-life cycle study for glyphosate was determined to be 26 mg/L. However, the chronic toxicity of AMPA to aquatic animals has not been evaluated before. The purpose of the present study was to assess the potential for chronic toxicity of AMPA to fathead minnow (Pimephales promelas) and Daphnia magna. Chronic toxicity to P. promelas was evaluated in a fish early-life stage study. The primary endpoints were larval survival, growth, and development. The NOAEC for P. promelas was determined to be 12 mg/L, the highest concentration tested. The chronic toxicity to D. magna was evaluated in a Daphnia reproduction test. The primary endpoints were survival, growth, and reproduction. The no-observed-effect concentration for D. magna was determined to be 15 mg/L. Conservatively predicted environmental surface water concentrations for AMPA from typical foliar agricultural application rates and values from surface water monitoring programs are 100 to 1000 times less than the NOAEC values from both studies. Consequently, there is a large and highly protective margin of safety between realistic environmental exposures to AMPA and chronic toxicity to aquatic vertebrates and invertebrates. PMID- 25690939 TI - Information preferences regarding cure rates and prognosis of Austrian patients with advanced lung cancer. AB - INTRODUCTION: Due to concerns about patients' wellbeing, open end-of-life communication is associated with reservation. Furthermore, sociocultural differences must be considered. The objective of this pilot study was therefore to investigate the information preferences of Austrian patients regarding cure rates and prognosis. PATIENTS AND METHODS: The information preferences of 50 advanced lung cancer patients were assessed at their first visit to the Department of Radiation Oncology, Medical University of Vienna. Preferences in terms of content (cure rates and/or prognosis) and depth of the information (additional quantitative estimates) were addressed. After the individually adapted medical consultation, patients' satisfaction with the consultation and the emotional responses to the information were evaluated. RESULTS: The majority of patients (76 %) requested information about cure rates and/or prognosis; nearly half of these (47 %) wanted additional quantitative estimates. Neither sociodemographic variables, disease characteristics, nor time since diagnosis had an impact on the information preferences. The individually adapted medical information showed no overall negative influence on the emotional responses; only patients receiving prognostic information had significantly higher distress scores after the consultation. High satisfaction with the individually adapted medical consultation was reported by 92 % of patients. CONCLUSION: Austrian physicians may offer end-of-life communication and directly ask patients about their information preferences, since patients seem able to decide whether or not prognostic information would overwhelm their emotional capacity and therefore to accept or reject the invitation. The disclosure of cure rates and/or prognosis with or without quantitative estimates-according to the patients' preferences shows overall no negative impact on emotional reactions. The individually adapted consultation results in high patient satisfaction. Nevertheless, prognostic information may lead to higher distress. PMID- 25690940 TI - Application of image-based particle size and shape characterization systems in the development of small molecule pharmaceuticals. AB - With the introduction of Quality by Design (QbD) to the pharmaceutical industry, there has been an increased focus on understanding the nature of particles and composites, with the aim of understanding and modeling how they interact in complex systems, leading to robust dosage forms. Particle characterization tools have evolved and now enable a greater level of understanding of powder systems and blends. Tools that can elucidate the size and shape of particulate systems can provide significantly more information about the nature of the particles being analyzed, than a conventional particle size measurement. Although accurate size and shape analysis has always been regarded as the "gold standard" in understanding the nature of particulate systems, neither imaging systems nor IT infrastructure was sufficiently developed to allow this to be performed with sufficient accuracy in a timely manner. The aim of this review is to provide an insight into developments in the field of size and shape analysis of pharmaceutical systems, and how these can now realistically be used as robust development tools. Examples of current uses of such technologies will be explored as well as investigating future applications such as combined image/spectroscopic analyses to track single components within blended systems. PMID- 25690941 TI - Senescent human fibroblasts show increased glycolysis and redox homeostasis with extracellular metabolomes that overlap with those of irreparable DNA damage, aging, and disease. AB - Cellular senescence can modulate various pathologies and is associated with irreparable DNA double-strand breaks (IrrDSBs). Extracellular senescence metabolomes (ESMs) were generated from fibroblasts rendered senescent by proliferative exhaustion (PEsen) or 20 Gy of gamma rays (IrrDSBsen) and compared with those of young proliferating cells, confluent cells, quiescent cells, and cells exposed to repairable levels of DNA damage to identify novel noninvasive markers of senescent cells. ESMs of PEsen and IrrDSBsen overlapped and showed increased levels of citrate, molecules involved in oxidative stress, a sterol, monohydroxylipids, tryptophan metabolism, phospholipid, and nucleotide catabolism, as well as reduced levels of dipeptides containing branched chain amino acids. The ESM overlaps with the aging and disease body fluid metabolomes, supporting their utility in the noninvasive detection of human senescent cells in vivo and by implication the detection of a variety of human pathologies. Intracellular metabolites of senescent cells showed a relative increase in glycolysis, gluconeogenesis, the pentose-phosphate pathway, and, consistent with this, pyruvate dehydrogenase kinase transcripts. In contrast, tricarboxylic acid cycle enzyme transcript levels were unchanged and their metabolites were depleted. These results are surprising because glycolysis antagonizes senescence entry but are consistent with established senescent cells entering a state of low oxidative stress. PMID- 25690942 TI - KIR3DS1*0130111: a novel KIR allele identified using molecular typing methods. AB - KIR3DS1*0130111 differs from KIR3DS1*0130101 with two previously undescribed single nucleotide polymorphisms. PMID- 25690943 TI - Recurrent focal segmental glomerulosclerosis after kidney transplantation. AB - Focal segmental glomerulosclerosis (FSGS) is an important cause of glomerular disease in children and adolescents and nearly 50 % of affected patients will progress to end-stage kidney disease over a 5 to 10-year period. Unfortunately, there is no established treatment for disease in the native kidney. Moreover, up to 55 % of patients develop recurrent disease after receiving a kidney transplant, with a substantially higher risk in patients who have already experienced recurrent disease in a prior transplant. A number of clinical and laboratory factors have been identified as risk factors for this complication. In addition, new investigations into podocyte biology and circulating permeability factors have shed light on the cause of recurrent the disease. While a number of novel therapeutic agents have been applied in the management of this problem, there still is no proven treatment. In this review, we summarize recent advances in the epidemiology, pathophysiology, and treatment of recurrent FSGS in pediatric patients who have received a kidney transplant. PMID- 25690944 TI - Adherence with early infant feeding and complementary feeding guidelines in the Cork BASELINE Birth Cohort Study. AB - OBJECTIVE: To describe adherence with infant feeding and complementary feeding guidelines. DESIGN: Prospective study of infant feeding and complementary feeding practices were collected as part of the Cork BASELINE Birth Cohort Study. SETTING: Cork, Ireland. SUBJECTS: Data are described for the 823 infants for whom a diary was completed. RESULTS: Breast-feeding was initiated in 81 % of infants, and 34 %, 14 % and 1 % of infants were exclusively breast-fed at hospital discharge, 2 and 6 months, respectively. Stage one infant formula decreased from 71 % at 2 months to 13 % at 12 months. The majority of infants (79 %) were introduced to solids between 17 and 26 weeks and 18 % were given solid foods before 17 weeks. Mothers of infants who commenced complementary feeding prior to 17 weeks were younger (29.8 v. 31.5 years; P<0.001) and more likely to smoke (18 v. 8 %; P=0.004). The first food was usually baby rice (69 %), infant breakfast cereals (14 %) or fruit/vegetables (14 %). Meals were generally home-made (49 %), cereal-based (35 %), manufactured (10 %), dairy (3 %) and dessert-based (3 %). The median gap between the first-second, second-third, third-fourth and fourth fifth new foods was 4, 2, 2 and 2 d, respectively. CONCLUSIONS: We present the largest prospective cohort study to date on early infant feeding in Ireland. The rate of breast-feeding is low by international norms. Most mothers introduce complementary foods between 4 and 6 months with lengthy gaps between each new food/food product. There is a high prevalence of exposure to infant breakfast cereals, which are composite foods, among the first foods introduced. PMID- 25690945 TI - Primary epiploic appendagitis: Laparoscopic diagnosis and treatment. PMID- 25690946 TI - Mesophyll conductance in leaves of Japanese white birch (Betula platyphylla var. japonica) seedlings grown under elevated CO2 concentration and low N availability. AB - To test the hypothesis that mesophyll conductance (gm ) would be reduced by leaf starch accumulation in plants grown under elevated CO2 concentration [CO2 ], we investigated gm in seedlings of Japanese white birch grown under ambient and elevated [CO2 ] with an adequate and limited nitrogen supply using simultaneous gas exchange and chlorophyll fluorescence measurements. Both elevated [CO2 ] and limited nitrogen supply decreased area-based leaf N accompanied with a decrease in the maximum rate of Rubisco carboxylation (Vc,max ) on a CO2 concentration at chloroplast stroma (Cc ) basis. Conversely, only seedlings grown at elevated [CO2 ] under limited nitrogen supply had significantly higher leaf starch content with significantly lower gm among the treatment combinations. Based on a leaf anatomical analysis using microscopic photographs, however, there were no significant difference in the area of chloroplast surfaces facing intercellular space per unit leaf area among treatment combinations. Thicker cell walls were suggested in plants grown under limited N by increases in leaf mass per area subtracting non-structural carbohydrates. These results suggest that starch accumulation and/or thicker cell walls in the leaves grown at elevated [CO2 ] under limited N supply might hinder CO2 diffusion in chloroplasts and cell walls, which would be an additional cause of photosynthetic downregulation as well as a reduction in Rubisco activity related to the reduced leaf N under elevated [CO2 ]. PMID- 25690947 TI - Domains of quality of life and social support across the trauma spectrum. AB - PURPOSE: To systematically compare specific domains of quality of life and social support as they pertain to the full trauma spectrum of (i) healthy individuals, (ii) those with ongoing post-traumatic stress disorder (PTSD), (iii) remitted PTSD, or (iv) those who failed to develop PTSD in spite of trauma exposure. METHODS: Data were from the first wave of a psychiatric epidemiological catchment area study based in Montreal, Canada (N = 2 433). PTSD diagnosis, quality of life, and social support outcomes were established by face-to-face structured interviews using standardized instruments. Outcomes were compared across the four groups. RESULTS: Although the between-group contrasts suggested that those currently suffering from PTSD generally had a poorer quality of life across domains, the group in remission from PTSD did not. Exploratory analyses concerning subscales for quality of life showed particular impairments for specific domains dependent on PTSD diagnosis, with remitted and ongoing PTSD showing significantly different quality of life for subscales such as daily life/social relationships, spare time activities and autonomy, but similar scores for subscales of housing/neighborhood and personal relationships. Contrary to most previous findings, individuals suffering from PTSD did not report lower overall social support. CONCLUSIONS: For both outcomes of quality of life and social support, longitudinal research is required to fully understand these complex relationships as they evolve along the full trauma spectrum. PMID- 25690949 TI - A Clinical and Experimental Comparison of Time of Flight PET/MRI and PET/CT Systems. AB - PURPOSE: The purpose of the study was to compare image quality and quantitative accuracy of positron emission tomography/magnetic resonance imaging (PET/MRI) and PET/computed tomography (PET/CT) systems with time of flight PET gantries, using phantom and clinical studies. PROCEDURES: Identical phantom experiments were performed on both systems. Calibration, uniformity, and standardized uptake value (SUV) recovery were measured. A clinical PET/CT versus PET/MRI comparison was performed using [(18)F]fluoromethylcholine ([(18)F]FCH). RESULTS: Calibration accuracy and image uniformity were comparable between systems. SUV recovery met EANM/EARL requirements on both scanners. Thirty-four lesions with comparable PET image quality were identified. Lesional SUVmax differences of 4 +/- 26% between PET/MRI and PET/CT data were observed (R (2) = 0.79, slope = 1.02). In healthy tissues, PET/MRI-derived SUVs were 16 +/- 11% lower than on PET/CT (R (2) = 0.98, slope = 0.86). CONCLUSION: PET/MRI and PET/CT showed comparable performance with respect to calibration accuracy, image uniformity, and SUV recovery. [(18)F]FCH uptake values for both healthy tissues and lesions corresponded reasonably well between MR- and CT-based systems, but only in regions free of MR-based attenuation artifacts. PMID- 25690950 TI - Hepatitis B-related serological events in hematopoietic stem cell transplant patients and efficacy of lamivudine prophylaxis against reactivation. AB - Reactivation of remote hepatitis B infection (RHBI) is an important cause of morbidity in hematopoietic cell transplant (HCT) patients. We analyzed the prevalence of RHBI in 205 patients who underwent HCT in our centre, serological events related to hepatitis B virus (HBV) reactivation and role of lamivudine prophylaxis in HCT patients with RHBI. The prevalence of RHBI was 14% (28/205 patients). Of these 28 patients, 15 received lamivudine prophylaxis (14 anti HBcIgG positive and 1 only anti-HBs positive) while 13 did not receive lamivudine prophylaxis (12 anti-HBs positive and 1 anti-HBcIgG positive). None in prophylaxis group developed HBV reactivation while 12 of 13 in no-prophylaxis group reactivated (P < 0.001). The rate of HBV reactivation was 10% (21/205 patients), which included 9 patients with no evidence of RHBI pre-transplant. We conclude that lamivudine prophylaxis protects against HBV reactivation in HCT patients with evidence of RHBI. Lamivudine prophylaxis should be used not only in patients with anti-HBcIgG positivity but also in those with isolated anti-HBs positivity pre-transplant given the high rate of HBV reactivation in these patients. HBV serology cannot identify all cases with RHBI and therefore does not preclude HBV reactivation post-transplant. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 25690951 TI - Nebulised liposomal amphotericin B for Aspergillus lung diseases: case series and literature review. AB - Over the past 10 years the incidence of Aspergillus spp. has significantly increased, and it is now the most widespread air transmission fungal pathogen in developed countries. Whatever the clinical expression of the pulmonary disease and despite recent progress in antifungal drug therapy, morbidity and mortality related to aspergillosis lung disease still constitute a serious threat for immunosuppressed or mildly immunocompromised patients. Moreover, the treatments currently used have many limitations due to adverse effects and drug interactions. Finally, subjects exposed to azoles present an increased risk of Aspergillus-resistant strain emergence. We have reported five cases with aspergillosis lung diseases that were either difficult to control or in which patients had a contra-indication to triazole therapy, but which showed durable improvement following the administration of nebulised liposomal amphotericin B. Our alternative strategy could be of interest for patients with aspergillosis lung disease who otherwise cannot be conventionally treated by triazoles. PMID- 25690952 TI - Ultrasmooth submicrometer carbon spheres as lubricant additives for friction and wear reduction. AB - Ultrasmooth submicrometer carbon spheres are demonstrated as an efficient additive for improving the tribological performance of lubricating oils. Carbon spheres with ultrasmooth surfaces are fabricated by ultrasound assisted polymerization of resorcinol and formaldehyde followed by controlled heat treatment. The tribological behavior of the new lubricant mixture is investigated in the boundary and mixed lubrication regimes using a pin-on-disk apparatus and cylinder-on-disk tribometer, respectively. The new lubricant composition containing 3 wt % carbon spheres suspended in a reference SAE 5W30 engine oil exhibited a substantial reduction in friction and wear (10-25%) compared to the neat oil, without change in the viscosity. Microscopic and spectroscopic investigation of the carbon spheres after the tribological experiments illustrated their excellent mechanical and chemical stability. The significantly better tribological performance of the hybrid lubricant is attributed to the perfectly spherical shape and ultrasmooth surface of carbon sphere additive filling the gap between surfaces and acting as a nanoscale ball bearing. PMID- 25690953 TI - Epidermolysis bullosa pruriginosa: a systematic review exploring genotype phenotype correlation. AB - INTRODUCTION: Epidermolysis bullosa pruriginosa (EBP) is a clinical variant of dystrophic epidermolysis bullosa (DEB), characterized by intense pruritus and hypertrophic, lichenified, prurigo-like papules, plaques, and nodules secondary to scratching. These clinical findings have been attributed to various mutations in the COL7A1 gene. Previous reports have yielded inconsistent findings regarding a possible genotype-phenotype relationship in EBP. OBJECTIVE: Our aim was to conduct a systematic review aimed at assessing the genotype-phenotype correlation in EBP. METHODS: A systematic review was conducted using PubMed, Medline, EMBASE, and Cochrane databases for all reports of mutation-verified EBP, published from 1946 to September 2014. Statistical comparison of clinical findings between mutation types was performed using logistic regression analysis. RESULTS: The review included a total of 28 articles with 74 individuals, which consisted of level 4 non-controlled case series (grade C) and level 5 case reports (grade D). Previous reported mutation types included glycine substitution (GS, 52.7%), in frame skipping (IFS, 33.8%), non-glycine substitution (NGS, 8.1%), and premature termination codon (PTC, 5.4%). The most common clinical findings were extremities involvement, linear configuration, and nail dystrophy. In comparison with GS mutation carriers, IFS carriers had a higher likelihood of (1) being male (OR 2.99; p = 0.043; 95% CI 1.27-11.4) and (2) presenting with blisters (OR 4.10; p = 0.013; 95% CI 1.34-12.5). CONCLUSIONS: To our knowledge, this study is the first systematic review examining the relationship between mutation type and clinical presentation in EBP. The findings in this review (1) identify common clinical characteristics of EBP that may help in the assessment of patients with possible EBP; and (2) indicate that certain mutation carriers may have a higher likelihood of exhibiting particular phenotypes. In the case of potential diagnostic challenge, assessment for presence of common clinical findings as well as molecular testing may facilitate correct identification and prognostication. PMID- 25690954 TI - Epigenetic and transcriptional determinants of the human breast. AB - While significant effort has been dedicated to the characterization of epigenetic changes associated with prenatal differentiation, relatively little is known about the epigenetic changes that accompany post-natal differentiation where fully functional differentiated cell types with limited lifespans arise. Here we sought to address this gap by generating epigenomic and transcriptional profiles from primary human breast cell types isolated from disease-free human subjects. From these data we define a comprehensive human breast transcriptional network, including a set of myoepithelial- and luminal epithelial-specific intronic retention events. Intersection of epigenetic states with RNA expression from distinct breast epithelium lineages demonstrates that mCpG provides a stable record of exonic and intronic usage, whereas H3K36me3 is dynamic. We find a striking asymmetry in epigenomic reprogramming between luminal and myoepithelial cell types, with the genomes of luminal cells harbouring more than twice the number of hypomethylated enhancer elements compared with myoepithelial cells. PMID- 25690955 TI - Growth Hormone Induces Recurrence of Infantile Hemangiomas After Apparent Involution: Evidence of Growth Hormone Receptors in Infantile Hemangioma. AB - Infantile hemangiomas (IHs) are the most common benign tumor of infancy, characterized by a natural history of early proliferation in the first months of life to eventual involution during childhood, often with residual fibrofatty tissue. Once involution has been achieved, IHs do not typically recur. We present two cases of exogenous growth hormone therapy resulting in the recurrence of IHs in late childhood, supported by radiological, immunohistochemical, in vitro, and in vivo evidence. PMID- 25690956 TI - Contemporary spiralian developmental biology. PMID- 25690957 TI - Spiralian model systems. AB - The "Spiralia" represent one of the three major clades of bilaterian metazoans. Though members of this clade exhibit tremendous diversity in terms of their larval and adult body plans, many share a highly conserved early pattern of development involving a stereotypic cleavage program referred to as spiral cleavage. This group therefore represents an excellent one in which to undertake comparative studies to understand the origins of such diversity from a seemingly common ground plan. These organisms also present varied and diverse modes in terms of their ecology, development and life history strategies. A number of well established and emerging model systems have been developed to undertake studies at the molecular, genetic, cell and organismal levels. The Special Issue of the Int. J. Dev. Biol. entitled "Spiralian Model Systems" focuses on these organisms and here, I introduce this clade, pointing out different types of studies being undertaken with representative spiralian model systems. PMID- 25690958 TI - Establishing the germline in spiralian embyos. AB - Elucidating the origin of germ cells in embryos and larvae is often obscured by the fact that the typical germ cell markers vasa, nanos and piwi are not exclusively expressed in primordial germ cells (PGCs), but are also commonly found in undifferentiated somatic tissues and stem cells as part of an evolutionary conserved 'germline multipotency program' (Juliano et al., 2010). Hidden in the crowd of undifferentiated cells, the PGCs have occasionally been overlooked and their formation during early embryogenesis was only revealed recently by new methodological approaches (e.g. Wu et al., 2011). Spiralians are excellent model organisms to deepen our understanding of PGC formation, given the highly stereotypical cleavage that occurs during embryogenesis. In these species, detailed cell lineage studies enable the tracing of single cells up to gastrulation stages. Here, I review our knowledge of the origin of PGCs in these invertebrates. Similarities in PGC formation among spiralian phyla as well as peculiarities of the highly derived clitellates are discussed with respect to developmental mode and evolution. Furthermore, the issue of gonad regeneration in platyhelminths and the asexually reproducing oligochaete Enchytraeus japonensis is addressed. An alternative strategy of compensating for caudal regeneration is presented for the polychaete Platynereis dumerilli. Finally, the molecular bases of PGC specification and the question of germplasm are discussed. PMID- 25690959 TI - Ins and outs of Spiralian gastrulation. AB - Gastrulation is a critical stage of metazoan development during which endodermal and mesodermal tissues are internalized, and morphogenesis transforms the early embryo into each animal's unique body-plan. While gastrulation has been studied extensively in classic model systems such as flies, worms, and vertebrates, less is known about gastrulation at a mechanistic level in other taxa. Surprisingly, one particularly neglected group constitutes a major branch of animals: the Spiralia. A unique feature of spiralian development is that taxa with diverse adult body-plans, such as annelids, molluscs, nemerteans and platyhelminths all share a highly stereotyped suite of characters during embryogenesis called spiral cleavage. The spiral cleavage program makes it possible to compare distantly related embryos using not only morphological features, and gene expression patterns, but also homologous cell lineages. Having all three criteria available for comparison is especially critical for understanding the evolution of a complex process like gastrulation. Thus studying gastrulation in spiralians is likely to lead to novel insights about the evolution of body-plans, and the evolution of morphogenesis itself. Here we review relevant literature about gastrulation in spiralians and frame questions for future studies. We describe the internalization of the endoderm, endomesoderm and ectomesoderm; where known, we review data on the cellular and molecular control of those processes. We also discuss several morphogenetic events that are tied to gastrulation including: axial elongation, origins of the mouth and anus, and the fate of the blastopore. Since spiral cleavage is ancestral for a major branch of bilaterians, understanding gastrulation in spiralians will contribute more broadly to ongoing debates about animal body-plan divergence, such as: the origin of the through gut, the emergence of indirect versus direct development, and the evolution of gene-regulatory networks that specify endomesoderm. We emphasize the fact that spiralian gastrulation provides the unique opportunity to connect well-defined embryonic cell lineages to variation in cell fate and cell behavior, making it an exceptional case study for evo-devo. PMID- 25690960 TI - Developmental biology of the leech Helobdella. AB - Glossiphoniid leeches of the genus Helobdella provide experimentally tractable models for studies in evolutionary developmental biology (Evo-Devo). Here, after a brief rationale, we will summarize our current understanding of Helobdella development and highlight the near term prospects for future investigations, with respect to the issues of: D quadrant specification; the transition from spiral to bilaterally symmetric cleavage; segmentation, and the connections between segmental and non-segmental tissues; modifications of BMP signaling in dorsoventral patterning and the O-P equivalence group; germ line specification and genome rearrangements. The goal of this contribution is to serve as a summary of, and guide to, published work. PMID- 25690961 TI - Developmental significance of D quadrant micromeres 2d and 4d in the oligochaete annelid Tubifex tubifex. AB - The annelidTubifex tubifex is a cosmopolitan freshwater oligochaete and a member of the Spiralia, a large group of invertebrate phyla displaying spiral development. Because its developing eggs are easily obtained in the laboratory, this animal has long been used as material for developmental studies, especially spiralian embryology. In spiralian embryos, it has long been known that one blastomere at the four-cell stage, the D cell, and its direct descendants play an important role in axial pattern formation. Various studies have suggested that the D quadrant functions as the organizer of the embryonic axes in molluscs and annelids, and it has recently been demonstrated that the D quadrant micromeres, 2d(11) and 4d, which had been transplanted to an ectopic position in an otherwise intact embryo induce a secondary embryonic axis to give rise to the formation of duplicated heads and/or tails. That 2d and 4d play a pivotal role in Tubifex embryonic development was first suggested from the classic cell-ablation experiments carried out in the early 1920s, and this has been confirmed by the recent cell-ablation/restoration experiments using cell-labeling with lineage tracers. These studies have also shown that in the operated embryos, none of the remaining cells can replace the missing 2d and 4d and that both 2d and 4d are determined as ectodermal and mesodermal precursors, respectively, at the time of their birth. The anteroposterior polarity of these micromeres is also specified at the time of their birth, suggesting that nascent 2d and 4d are specified in their axial properties as well as in cell fate decision. PMID- 25690962 TI - Variation in spiralian development: insights from polychaetes. AB - Spiralian development is characterized by the conservation of spindle orientation and cell geometry during early cleavage stages, as well as features of the ultimate fates of identified cells. This complex set of characters is shared by a number of animal lineages including nemerteans, polyclad platyhelminthes, annelids and mollusks. How a similar, highly stereotypical cleavage program can give rise to such diversity of larval and adult forms has intrigued researchers for many years. This review summarizes recent data from polychaete annelids, and highlights both conservation and variation in the cellular and molecular mechanisms that guide the spiral cleavage developmental program. There is a specific focus on comparisons of fate maps, patterns of cleavage, mechanisms of cell fate specification, organizing activity, and differences in molecular patterning. Some of the differences in early development represent intra-clade variation within annelids, and others hint at differences between annelids and other taxa. Because much of the classic work on spiralians has focused on mollusks, these new data from annelids have expanded our knowledge about the evolutionary flexibility in spiralian development and potentially its role in body plan evolution. PMID- 25690963 TI - Segment formation in Annelids: patterns, processes and evolution. AB - The debate on the origin of segmentation is a central question in the study of body plan evolution in metazoans. Annelids are the most conspicuously metameric animals as most of the trunk is formed of identical anatomical units. In this paper, I summarize the various patterns of evolution of the metameric body plan in annelids, showing the remarkable evolvability of this trait, similar to what is also found in arthropods. I then review the different modes of segment formation in the annelid tree, taking into account the various processes taking place in the life histories of these animals, including embryogenesis, post embryonic development, regeneration and asexual reproduction. As an example of the variations that occur at the cellular and genetic level in annelid segment formation, I discuss the processes of teloblastic growth or posterior addition in key groups in the annelid tree. I propose a comprehensive definition for the teloblasts, stem cells that are responsible for sequential segment addition. There are a diversity of different mechanisms used in annelids to produce segments depending on the species, the developmental time and also the life history processes of the worm. A major goal for the future will be to reconstitute an ancestral process (or several ancestral processes) in the ancestor of the whole clade. This in turn will provide key insights in the current debate on ancestral bilaterian segmentation. PMID- 25690964 TI - Sipuncula: an emerging model of spiralian development and evolution. AB - Sipuncula is an ancient clade of unsegmented marine worms that develop through a conserved pattern of unequal quartet spiral cleavage. They exhibit putative character modifications, including conspicuously large first-quartet micromeres and prototroch cells, postoral metatroch with exclusive locomotory function, paired retractor muscles and terminal organ system, and a U-shaped digestive architecture with left-right asymmetric development. Four developmental life history patterns are recognized, and they have evolved a unique metazoan larval type, the pelagosphera. When compared with other quartet spiral-cleaving models, sipunculan development is understudied, challenging and typically absent from evolutionary interpretations of spiralian larval and adult body plan diversity. If spiral cleavage is appropriately viewed as a flexible character complex, then understudied clades and characters should be investigated. We are pursuing sipunculan models for modern molecular, genetic and cellular research on evolution of spiralian development. Protocols for whole mount gene expression studies are established in four species. Molecular labeling and confocal imaging techniques are operative from embryogenesis through larval development. Next generation sequencing of developmental transcriptomes has been completed for two species with highly contrasting life history patterns, Phascolion cryptum (direct development) and Nephasoma pellucidum (indirect planktotrophy). Looking forward, we will attempt intracellular lineage tracing and fate-mapping studies in a proposed model sipunculan, Themiste lageniformis. Importantly, with the unsegmented Sipuncula now repositioned within the segmented Annelida, sipunculan worms have become timely and appropriate models for investigating the potential for flexibility in spiralian development, including segmentation. We briefly review previous studies, and discuss new observations on the spiralian character complex within Sipuncula. PMID- 25690966 TI - Spiral cleavages determine the left-right body plan by regulating Nodal pathway in monomorphic gastropods, Physa acuta. AB - The handedness of gastropods is genetically determined, but the molecular nature of the gene responsible and the associated mechanisms remain unknown. In order to characterize the chiromorphogenesis pathway starting from the gene to the left right asymmetric body plan, we have closely analyzed the cytoskeletal dynamics of the Physa (P.) acuta embryo, a fresh water non-dimorphic sinistral snail, during the early developmental stage by mechanically altering the handedness of the embryos at the critical spiral third cleavage. A fertile situs inversus was created and the nodal-Pitx gene expression patterns were completely mirror imaged to the wild type at the trochophore stage. Together with our previous work on Lymnaea (L.) stagnalis, we could show that chirality is established at the third cleavage, as dictated by the single handedness-determining gene locus, and then chirality information is transferred via subsequent spiral fourth and fifth cleavages to the later developmental stage, dictating the nodal-Pitx expression pathway. The cytoskeletal dynamics of manipulated and non-manipulated embryos of sinistral P. acuta and dextral dominant L. stagnalis are compared. PMID- 25690965 TI - A conserved set of maternal genes? Insights from a molluscan transcriptome. AB - The early animal embryo is entirely reliant on maternal gene products for a 'jump start' that transforms a transcriptionally inactive embryo into a fully functioning zygote. Despite extensive work on model species, it has not been possible to perform a comprehensive comparison of maternally-provisioned transcripts across the Bilateria because of the absence of a suitable dataset from the Lophotrochozoa. As part of an ongoing effort to identify the maternal gene that determines left-right asymmetry in snails, we have generated transcriptome data from 1 to 2-cell and ~32-cell pond snail (Lymnaea stagnalis) embryos. Here, we compare these data to maternal transcript datasets from other bilaterian metazoan groups, including representatives of the Ecydysozoa and Deuterostomia. We found that between 5 and 10% of all L. stagnalis maternal transcripts (~300-400 genes) are also present in the equivalent arthropod (Drosophila melanogaster), nematode (Caenorhabditis elegans), urochordate (Ciona intestinalis) and chordate (Homo sapiens, Mus musculus, Danio rerio) datasets. While the majority of these conserved maternal transcripts ("COMATs") have housekeeping gene functions, they are a non-random subset of all housekeeping genes, with an overrepresentation of functions associated with nucleotide binding, protein degradation and activities associated with the cell cycle. We conclude that a conserved set of maternal transcripts and their associated functions may be a necessary starting point of early development in the Bilateria. For the wider community interested in discovering conservation of gene expression in early bilaterian development, the list of putative COMATs may be useful resource. PMID- 25690967 TI - Evolution, divergence and loss of the Nodal signalling pathway: new data and a synthesis across the Bilateria. AB - Since the discovery that the TGF-beta signalling molecule Nodal and its downstream effector Pitx have a parallel role in establishing asymmetry between molluscs and deuterostomes the debate over the degree to which this signalling pathway is conserved across the Bilateria as a whole has been ongoing. Further taxon sampling is critical to understand the evolution and divergence of this signalling pathway in animals. Using genome and transcriptome mining we confirmed the presence of nodal and Pitx in a range of additional animal taxa for which their presence has not yet been described. In situ hybridization was used to show the embryonic expression of these genes in brachiopods and planarians. We show that both nodal and Pitx genes are broadly conserved across the Spiralia, and nodal likely appeared in the Bilaterian stem lineage after the divergence of the Acoelomorpha. Furthermore, both nodal and Pitx mRNA appears to be expressed in an asymmetric fashion in the brachiopod Terebratalia transversa. No evidence for the presence of a Lefty ortholog could be found in the non-deuterostome genomic resources examined. Nodal expression is asymmetric in a number of spiralian lineages, indicating a possible ancestral role of the Nodal/Pitx cascade in the establishment of asymmetries across the Bilateria. PMID- 25690968 TI - The Lophotrochozoan TGF-beta signalling cassette - diversification and conservation in a key signalling pathway. AB - TGF-beta signalling plays a key role in the patterning of metazoan body plans and growth. It is widely regarded as a 'module' capable of co-option into novel functions. The TGF-beta pathway arose in the Metazoan lineage, and while it is generally regarded as well conserved across evolutionary time, its components have been largely studied in the Ecdysozoa and Deuterostomia. The recent discovery of the Nodal molecule in molluscs has underlined the necessity of untangling this signalling network in lophotrochozoans in order to truly comprehend the evolution, conservation and diversification of this key pathway. Three novel genome resources, the mollusc Patella vulgata, annelid Pomatoceros lamarcki and rotifer Brachionus plicatilis, along with other publicly available data, were searched for the presence of TGF-beta pathway genes. Bayesian and Maximum Likelihood analyses, along with some consideration of conserved domain structure, was used to confirm gene identity. Analysis revealed conservation of key components within the canonical pathway, allied with extensive diversification of TGF-beta ligands and partial loss of genes encoding pathway inhibitors in some lophotrochozoan lineages. We fully describe the TGF-beta signalling cassette of a range of lophotrochozoans, allowing firm inference to be drawn as to the ancestral state of this pathway in this Superphylum. The TGF-beta signalling cascade's reputation as being highly conserved across the Metazoa is reinforced. Diversification within the activin-like complement, as well as potential wide loss of regulatory steps in some Phyla, hint at specific evolutionary implications for aspects of this cascade's functionality in this Superphylum. PMID- 25690969 TI - Ilyanassa Notch signaling implicated in dynamic signaling between all three germ layers. AB - Two cells (3D and 4d) in the mud snail Ilyanassa obsoleta function to induce proper cell fate. In this study, we provide support for the hypothesis that Notch signaling in Ilyanassa obsoleta functions in inductive signaling at multiple developmental stages. The expression patterns of Notch, Delta and Suppressor of Hairless (SuH) are consistent with a function for Notch signaling in endoderm formation, the function of 3D/4d and the sublineages of 4d. Veligers treated with DAPT show a range of defects that include a loss of endodermal structures, and varying degrees of loss of targets of 4d inductive signaling. Veligers that result from injection of Ilyanassa Delta siRNAi in general mimic the defects observed in the DAPT treated larvae. The most severe DAPT phenotypes mimic early ablations of 4d. However, the early specification of 4d itself appears normal and MAPK activation in both 3D/4d and the micromeres, which are known to activate MAPK as a result of 3D/4d induction, are normal in DAPT treated larvae. Treating larvae at successively later timepoints with DAPT suggests that Notch/Delta signaling is not only required during early 4d inductive signaling, but during subsequent stages of cell fate determination as well. Based on our results, combined with previous reports implicating the endoderm in maintaining induced fate specification in Ilyanassa, we propose a speculative model that Notch signaling is required to specify endoderm fates and 4d sublineages, as well as to maintain cell fates induced by 4d. PMID- 25690970 TI - Expression of the wnt gene complement in a spiral-cleaving embryo and trochophore larva. AB - The highly conserved wnt gene family has roles in developmental processes ranging from axis formation to cell fate determination. The polychaete Platynereis dumerilii has retained 12 of the 13 ancient wnt subfamilies and is a good model system to study the roles of the wnt ligands in spiralian development. While it has been shown that Platynereis uses a global beta-catenin-mediated binary cell fate specification module in development, the early roles of the 12 wnt genes present in Platynereis are unknown. Transcriptional profiling by RNA-Seq during early development and whole-mount in situ hybridization of embryo and larval stages were used to determine the temporal and spatial regulation of the wnt complement in Platynereis. None of the 12 wnt transcripts were maternally provided at significant levels. In pregastrula embryos, zygotic wntA, wnt4, and wnt5 transcripts exhibited distinctive patterns of differential gene expression. In contrast, in trochophore larvae, all 12 wnt ligands were expressed and each had a distinct expression pattern. While three wnt ligands were expressed in early development, none were expressed in the right place for a widespread role in beta-catenin-mediated binary specification in early Platynereis development. However, the expression patterns of the wnt ligands suggest the presence of numerous wnt signaling centers, with the most prominent being a bias for staggered posterior wnt expression in trochophore larvae. The similarity to wnt expression domains in cnidarians around the blastopore and the tail organizer in chordates supports a hypothesis of a common evolutionary origin of posterior organizing centers. PMID- 25690971 TI - Development of a feeding trochophore in the polychaete Hydroides elegans. AB - Hydroides elegans is an indirectly developing polychaete with equal spiral cleavage, gastrulation by invagination, and a feeding trochophore. Expression of several transcription factors and differentiation genes has been characterized. Comparative analysis reveals evolutionarily conserved roles. For example, the synexpression of transcription factors FoxA and Brachyury suggests homology of primary and secondary gut openings in protostomes and deuterostomes, and the expression of Sall suggests similar regulatory controls in the posterior growth zone of bilaterians. Differences in gene expression suggest regulatory differences control gastrulation by invagination in polychaetes with a feeding trochophore and gastrulation by epiboly in polychaetes without a feeding trochophore. Association of histone variant H2A.Z with transcriptional potency and its expression suggest a developmental role during both embryogenesis and the larva-to-adult transformation. Methods are being developed for experimental exploration of the gene regulatory networks involved in trochophore development in Hydroides. It is unknown if polychaete feeding trochophores evolved from a larval stage already present in the life cycle of the last common ancestor of protostomes and deuterostomes. Previous evolutionary scenarios about larval origins overemphasize the discontinuity between larval and adult development and require the early evolution of undifferentiated and transcriptionally potent "set aside" cells. Indirect development may proceed by developmental remodeling of differentiated cells and could have evolved after gradual transformation of juveniles into larvae; undifferentiated and transcriptionally potent cells would have evolved secondarily. Comprehensive characterization of gene regulatory networks for feeding trochophore development may help resolve these major evolutionary questions. PMID- 25690972 TI - From trochophore to pilidium and back again - a larva's journey. AB - Nemerteans, a phylum of marine lophotrochozoan worms, have a biphasic life history with benthic adults and planktonic larvae. Nemertean larval development is traditionally categorized into direct and indirect. Indirect development via a long-lived planktotrophic pilidium larva is thought to have evolved in one clade of nemerteans, the Pilidiophora, from an ancestor with a uniformly ciliated planuliform larva. Planuliform larvae in a member of a basal nemertean group, the Palaeonemertea, have been previously shown to possess a vestigial prototroch, homologous to the primary larval ciliated band in the trochophores of other spiralian phyla, such as annelids and mollusks. We review literature on nemertean larval development, and include our own unpublished observations. We highlight recent discoveries of numerous pilidiophoran species with lecithotrophic larvae. Some of these larvae superficially resemble uniformly ciliated planuliform larvae of other nemerteans. Others possess one or two transverse ciliary bands, which superficially resemble the prototroch and telotroch of some spiralian trochophores. We also summarize accumulating evidence for planktotrophic feeding by larvae of the order Hoplonemertea, which until now were considered to be lecithotrophic. We suggest that 1) non-feeding pilidiophoran larval forms are derived from a feeding pilidium; 2) such forms have likely evolved many times independently within the Pilidiophora; 3) any resemblance of such larvae to the trochophores of other spiralians is a result of convergence and that 4) the possibility of planktotrophy in hoplonemertean larvae may influence estimates of pelagic larval duration, dispersal, and population connectivity in this group. PMID- 25690973 TI - Dimorphic development in Streblospio benedicti: genetic analysis of morphological differences between larval types. AB - The marine polychaete Streblospio benedicti exhibits two distinct larval types, making it a model for the study of developmental evolution. Females produce either large eggs or small ones, which develop into distinct lecithotrophic or planktotrophic larvae with concomitant morphological and life-history differences. Here, we investigate the inheritance of key morphological traits that distinguish the larval types. We used genetic crosses to establish the influence of maternal and zygotic differences on larval phenotypes. We found a large maternal effect on larval size and the number of larval chaetae, while the number and length of these chaetae were also strongly influenced by zygotic genotype. Interestingly, the distribution of larval phenotypes produced by these crosses suggests traits intermediate to the two parental types should not be uncommon. Yet, despite gene flow between the types in natural populations, such intermediates are rarely found in nature, suggesting that selection may be maintaining distinct larval modes. PMID- 25690974 TI - The development of viable and nutritive embryos in the direct developing gastropod Crepidula navicella. AB - Adelphophagy occurs when encapsulated embryos complete development by feeding on their developing siblings, which are known as nutritive embryos. Nutritive embryos are found in a variety of animal groups, and are especially common in some groups of marine invertebrates. Although they have evolved numerous times independently in the calyptraeid gastropods, adelphophagic development with nutritive embryos has not been described in detail. Using light microscopy and time-lapse imaging of laboratory-reared embryos, we describe the development of Crepidula navicella, a direct developer with nutritive embryos that cleave and gastrulate. Early stages of nutritive and viable embryos do not show any obvious morphological differences, but do show asynchrony in early cleavage among embryos from the same capsule. We discovered that two classes of nutritive embryos are produced; gastrula-like nutritive embryos, which arrest after gastrulation, and post-gastrula-like nutritive embryos that are more variable in morphology, and show evidence of minor differentiation. This study provides a framework for future research on the developmental and molecular mechanisms of nutritive embryo development of C. navicella, which will allow us to address the role of nutritive embryos in the origins of developmental polyphenisms. Careful description of the developmental sequence is necessary before adaptive hypotheses can be addressed, and comparisons with other taxa can be made. Understanding the different ways that embryos and their development are disrupted to produce nutritive embryos will provide important insights into the normal process of development. PMID- 25690975 TI - An immunocytochemical window into the development of Platynereis massiliensis (Annelida, Nereididae). AB - The nereidid annelid Platynereis dumerilii emerged as a well-understood model organism. P. dumerilii and P. massiliensis are sister taxa, which are morphologically indistinguishable as adults. Interestingly, they exhibit highly contrasting life-histories: while P. dumerilii is a gonochorostic species with planktonic feeding larvae, P. massiliensis is a protandric hermaphrodite with lecitotrophic semi-direct -development in brood tubes. Using light microscopy and immunohistochemical methods coupled with confocal laser scanning microscopy, we describe the development of P. massiliensis. Musculature was stained with phalloidin-rhodamine. FMRFamide, acetylated alpha-tubulin, and serotonin were targeted by antibodies for the staining of neuronal structures. Additionally, eye development was investigated with the specific 22C10-antibody. The development of P. massiliensis is characterized by the absence of a free-swimming stage, a late development of food uptake, and the presence of a large amount of yolk even in late juvenile stages. Most notably, early juvenile stages already exhibit an organization of several organ systems that resembles those of adults. Larval characters present in the free-swimming feeding larvae of P. dumerilii, as e.g. the apical organ and larval eyes, are absent and regarded to be lost in developing stages of P. massiliensis. Many of the differences found in the development of these two species can be described in the context of heterochronic changes. We strongly advocate expanding evolutionary developmental studies from the well-established model annelid P. dumerilii to the closely related P. massiliensis to study the evolutionary conservation and divergence of genetic pathways involved in developmental processes. PMID- 25690976 TI - Regeneration in spiralians: evolutionary patterns and developmental processes. AB - Animals differ markedly in their ability to regenerate, yet still little is known about how regeneration evolves. In recent years, important advances have been made in our understanding of animal phylogeny and these provide new insights into the phylogenetic distribution of regeneration. The developmental basis of regeneration is also being investigated in an increasing number of groups, allowing commonalities and differences across groups to become evident. Here, we focus on regeneration in the Spiralia, a group that includes several champions of animal regeneration, as well as many groups with more limited abilities. We review the phylogenetic distribution and developmental processes of regeneration in four major spiralian groups: annelids, nemerteans, platyhelminths, and molluscs. Although comparative data are still limited, this review highlights phylogenetic and developmental patterns that are emerging regarding regeneration in spiralians and identifies important avenues for future research. PMID- 25690977 TI - The dynamics of alkaline phosphatase activity during operculum regeneration in the polychaete Pomatoceros lamarckii. AB - Alkaline phosphatase enzymes are found throughout the living world and fulfil a variety of functions. They have been linked to regeneration, stem cells and biomineralisation in a range of animals. Here we describe the pattern of alkaline phosphatase activity in a spiralian appendage, the operculum of the serpulid polychaete Pomatoceros lamarckii. The P. lamarckii operculum is reinforced by a calcified opercular plate and is capable of rapid regeneration, making it an ideal model system to study these key processes in annelids. Alkaline phosphatase activity is present in mesodermal tissues of both intact and regenerating opercular filaments, in a strongly regionalised pattern correlated with major morphological features. Based on the lack of epidermal activity and the broad distribution of staining in mesodermal tissues, calcification- or stem cell specific roles are unlikely. Transcriptomic data reveal that at least four distinct genes contribute to the detected activity. Opercular alkaline phosphatase activity is sensitive to levamisole. Phylogenetic analysis of metazoan alkaline phosphatases indicates homology of the P. lamarckii sequences to other annelid alkaline phosphatases, and shows that metazoan alkaline phosphatase evolution was characterised by extensive lineage-specific duplications. PMID- 25690978 TI - Spectral domain optical coherence tomography imaging of mucopolysaccharidoses I, II, and VI A. AB - PURPOSE: The purpose of this study was to describe the spectral domain optical coherence tomography (SD-OCT) characteristics of patients with retinal manifestations of mucopolysaccharidoses (MPSs) I, II, and IV A. DESIGN: The research was a prospective, observational study. METHODS: Fourteen consecutive patients with variants of MPS and 15 healthy subjects underwent ophthalmic assessments including fundus examinations and SD-OCT. RESULTS: The fundus examinations revealed that four patients (two MPS I and two MPS II) had pigmented retinopathy in both eyes. In addition, one MPS II patient had cystoid macular edema and two MPS II patients had abnormal disc morphology. SD-OCT revealed thinning of the parafoveal photoreceptor inner segment/outer segment (IS/OS; two MPS I and one MPS II) and perifoveal photoreceptor IS/OS (two MPS I and five MPS II). All MPS I and II patients exhibited thickening of the central foveal external limiting membrane (ELM). Fundus and SD-OCT findings were normal in MPS IV A and healthy subjects. The foveal ELM was significantly thicker in MPS I and II patients than in healthy subjects (P =0 .000 and P =0 .000, respectively). The foveal IS/OS was significantly thinner in MPS I, II, and IV A patients than in healthy subjects (P = 0.000, P = 0.000, and P = 0.030, respectively). The foveal retinal pigment epithelium layer was also thinner in MPS II patients than in healthy subjects (P = 0.007) CONCLUSIONS: In MPS, accumulation of glycosaminoglycans in retinal tissue induced retinal degeneration and pigmentary retinopathy. SD-OCT was a useful tool for detecting retinal pathology, particularly changes in ELM and IS/OS. PMID- 25690979 TI - Transplantation of PEDF-transfected pigment epithelial cells inhibits corneal neovascularization in a rabbit model. AB - BACKGROUND: The purpose of this study was to investigate the effect of recombinant pigment epithelium-derived factor (rPEDF), secreted by ARPE-19 cells transfected with the human PEDF gene and transplanted subconjunctivally in normal and in rabbits in which corneal neovascularization was elicited by a chemical burn. METHODS: Twenty grey Chinchilla Bastard rabbits were randomly assigned to four groups; neovascularization was induced in groups A, B, and C by alkali cauterization. Seven days later, group A received no cell implantation, non transfected ARPE-19 cells were implanted subconjunctivally in group B, and PEDF transfected ARPE-19 cells were implanted subconjunctivally in groups C and D (non cauterized). In-vivo rPEDF secretion was analyzed by immunoblotting, and ELISA of extracts of conjunctival tissue samples taken at different time points. Digital photographs acquired on days 7, 14, and 21 after cauterization were evaluated for lead vessel length, vascular invasion area, and overall neovascularization rate. RESULTS: At days 14 and 21 after cauterization, significant differences were observed between groups A, B, and C in lead vessel length (day 21: 5.91 +/- 0.45, 5.11 +/- 1.22, 3.79 +/- 0.59 mm, repectively), vascular invasion area (day 21: 35.5 +/- 8.65, 34.86 +/- 4.92, 19.2 +/- 5.03 mm(2) respectively), and rate of corneal neovascularization. Compared to controls, neovascularization was reduced by 37.5 % on day 14 and 47 % on day 21. Analysis of conjunctival tissue extracts showed that rPEDF was secreted by the transplanted PEDF-transfected cells. CONCLUSION: Subconjunctivally transplanted, PEDF-transfected ARPE-19 cells secrete rPEDF, which inhibits the corneal neovascularization elicited by alkali cauterization. PMID- 25690980 TI - Exit strategies in canaloplasty: intraoperative conversion into 180-degree trabeculotomy or 360-degree trabeculotomy in cases of unsuccessful catheterisation of Schlemm's canal: influence of degree of canal cleavage. AB - PURPOSE: To investigate the safety and efficacy of intraoperative conversion of unsuccessful canaloplasty technique into 180-degree metal or 360-degree suture trabeculotomy. METHODS: In this retrospective observational case series, 35 eyes of 35 patients with open-angle glaucoma (OAG) who had undergone unsuccessful canaloplasty technique and underwent intraoperative conversion were studied. In 17 eyes (group A), the procedure was converted into 180-degree metal trabeculotomy because of unsuccessful circumferential Schlemm's canal (SC) catheterisation. Group B included 18 eyes that were converted into 360-degree trabeculotomy because of cheese wiring of tension suture through the trabecular meshwork (TM) after successful complete catheterisation of SC. RESULTS: Median preoperative IOP was 22.0 mmHg (range 16-34) in group A, and 22.0 mmHg (range 15 48) in group B. Median IOP was significantly reduced in both groups postoperatively, at the 12-month examination to 15.0 mmHg (range 9-21) representing a reduction of 36 % in group A, and to 14.5 mmHg (range 8-21) representing a reduction of 34 % in group B. Median glaucoma medication number decreased significantly from 4 (range 2-4) and 3 (range 1-4) preoperatively to 2 (range 0-4) and 1 (range 0-3) at 12 months in groups A and B respectively. Hyphema was the commonest complication, with an incidence of 76 % in group A and 78 % in group B. CONCLUSION: 180-degree metal or 360-degree suture/catheter trabeculotomy are safe and effective surgical backup methods to control IOP in cases of unsuccessful intracanalicular placement of tension suture during canaloplasty surgery. PMID- 25690981 TI - Central serous chorioretinopathy fundus autofluorescence comparison with two different confocal scanning laser ophthalmoscopes. AB - PURPOSE: To compare the lesion characteristics of two different types of confocal scanning laser ophthalmoscopy (cSLO) autofluorescence (AF) images in central serous chorioretinopathy (CSC). METHODS: The study included 63 eyes of 61 patients; 63 pairs of fundus autofluorescence (FAF) images were compared before CSC resolution in 63 eyes, FAF images of 31 eyes were also compared after CSC resolution. The lesion characteristics (brightness and composite pattern) were compared between Heidelberg Retina Angiograph 2 (HRA2; Heidelberg Engineering, Germany) and Optomap Tx (Optomap; Optos, Scotland) FAF images. The lesion composite pattern was categorized as diffuse or granular. Diffuse AF was defined as homogenously increased or decreased AF, and granular AF was defined as dot like, coarse changes in AF. The mean disease duration and subretinal fluid (SRF) height in the spectral domain optical coherence tomography were compared according to the FAF image characteristics. RESULTS: Lesion brightness before CSC resolution was hypo-AF in 48 eyes (76.2 %), hyper-AF in three (4.8 %), and mixed AF in 12 (19.0 %) in HRA2 FAF images. In comparison, nine (14.3 %) images were hypo-AF, 44 (69.8 %) were hyper-AF, and 10 (15.9 %) were mixed-AF in Optomap FAF images (P < 0.0001). There was no significant difference in lesion composite pattern between the two FAF image wavelengths. Patients with lesions that were hyper-AF in Optomap FAF and hypo-AF in HRA2 FAF had a shorter disease duration and greater SRF height (1 month, 281 um) than those who were hyper-AF in both Optomap and HRA2 images (26 months, 153 um; P = 0.004, 0.001). CONCLUSIONS: The two types of FAF images of CSC showed different lesion brightness before and after CSC resolution but demonstrated similar lesion composite patterns. PMID- 25690982 TI - The alum-processing mechanism attenuating toxicity of Araceae Pinellia ternata and Pinellia pedatisecta. AB - The present study aimed at investigating the alum-processing mechanism attenuating toxicity of Araceae Pinellia ternata and Pinellia pedatisecta. Animal retroperitoneal inflammatory model in vivo and macrophagocyte release inflammatory factor model in vitro were used to detect the effect of alum processing on raphides and lectin. Scanning electron microscopy was used to observe the change in raphides during processing; HPLC method was used to determine the correlation between the dissolution and corrosion of raphides and ion in the alum solution; (27)Al-NMR technology was used to detect the relationship between aluminum oxalate complex formation and the dissolved and corrosion of raphides. The change in protein peptide sequence of lectin during the processing of alum solution was determined by Shotgun LC-MS assay. Raphides induced severe rabbit conjunctival edema and an intraperitoneal injection of lectin increased PGE2 and protein in mice peritoneal exudate, while decreased after treatment with alum solution processing. During the processing raphides was dissolved and corroded, then its structure was damaged. Raphides was soaked in the alum solution and significantly decreased the oxalate content, and the effect was related with Al(3+) in the alum. Al(3+) in the alum combined with C2O4(2-) of raphides into a stable complex compound promoted the dissolution of calcium oxalate. Raphides soaked in the alum made lectin proteins dissolve, whereas protein peptide sequence of lectin was changed and the protein structure was damaged. CONCLUSION: Alum solution could decrease the toxicity of P. ternata (Thunb.) Breit. and P. pedatisecta Schott. Since it made a special crystal structure of raphides damage and the protein of lectin dissolve. The structure of toxic substances significantly changed, which decreased the inflammatory effect. PMID- 25690983 TI - Development and evaluation of an algorithm to facilitate drug prescription for inpatients with feeding tubes. AB - PURPOSE: We aimed to develop and evaluate an algorithm to facilitate drug switching between primary and tertiary care for patients with feeding tubes. METHODS: An expert consortium developed an algorithm and applied it manually to 267 preadmission drugs of 46 patients admitted to a surgical ward of a tertiary care university hospital between June 12 and December 2, 2013, and requiring a feeding tube during their inpatient stay. RESULTS: The new algorithm considered the following principles: Drugs should be ideally listed on the hospital drug formulary (HDF). Additionally, drugs should include the same ingredient instead of a therapeutic equivalent. Preferred dosage forms were appropriate liquids, followed by solid drugs with liquid administration form, and solid drugs that could be crushed and/or suspended. Of all evaluated drugs, 83.5% could be switched to suitable drugs listed on the HDF and another 6.0% to drugs available on the German drug market. Additionally, for 4.1% of the drugs, the integration of individual switching rules allowed the switch from enteric-coated to immediate release drugs. Consequently, 6.4% of the drugs could not be automatically switched and required case-to-case decision by a clinical professional (e.g., from sustained-release to immediate-release). CONCLUSIONS: The predefined principles were successfully integrated in the new algorithm. Thus, the algorithm switched more than 90% of the evaluated preadmission drugs to suitable drugs for inpatients with feeding tubes. This finding suggests that the algorithm can readily be transferred to an electronic format and integrated into a clinical decision support system. PMID- 25690984 TI - STEM-EELS analysis of multipole surface plasmon modes in symmetry-broken AuAg nanowire dimers. AB - Surface plasmon coupling in nanowires separated by small gaps generates high field enhancements at the position of the gap and is thus of great interest for sensing applications. It is known that the nanowire dimensions and in particular the symmetry of the structures has strong influence on the plasmonic properties of the dimer structure. Here, we report on multipole surface plasmon coupling in symmetry-broken AuAg nanowire dimers. Our dimers, consisting of two nanowires with different lengths and separated by gaps of only 10 to 30 nm, were synthesized by pulsed electrochemical deposition in ion track-etched polymer templates. Electron energy-loss spectroscopy in scanning transmission electron microscopy allows us to resolve up to nine multipole order surface plasmon modes of these dimers spectrally separated from each other. The spectra evidence plasmon coupling between resonances of different multipole order, resulting in the generation of additional plasmonic modes. Since such complex structures require elaborated synthesis techniques, dimer structures with complex composition, morphology and shape are created. We demonstrate that finite element simulations on pure Au dimers can predict the generated resonances in the fabricated structures. The excellent agreement of our experiment on AuAg dimers with finite integration simulations using CST microwave studio manifests great potential to design complex structures for sensing applications. PMID- 25690985 TI - Reporting of patient-centred outcomes in heart failure trials: are patient preferences being ignored? AB - Older people often suffer from multiple diseases. Therefore, universal cross disease outcomes (e.g. functional status, quality of life, overall survival) are more relevant than disease-specific outcomes, and a range of potential outcomes are needed for medical decision-making. To assess how patient-relevant outcomes have penetrated randomized controlled trials (RCTs), reporting of these outcomes was reviewed in heart failure trials that included patients with multimorbidity. We systematically reviewed RCTs (Jan 2011-June 2012) and evaluated reported outcomes. Heart failure was chosen as condition of interest as this is common among older patients with multimorbidity. The main outcome was the proportion of RCTs reporting all-cause mortality, all-cause hospital admission, and outcomes in four domains of health, i.e. functional, signs and symptoms, psychological, and social domains. Of the 106 included RCTs, 50 (47 %) reported all-cause mortality and cardiovascular mortality and 29 (27 %) reported all-cause hospitalization and cardiovascular hospitalization. Of all trials, 68 (64 %) measured outcomes in the functional domain, 80 (75 %) in the domain of signs and symptoms, 65 (61 %) in the psychological domain, and 59 (56 %) in the social domain. Disease-specific instruments were more often used than non-disease-specific instruments. This review shows increasing attention for more patient-relevant outcomes; this is promising and indicates more awareness of the importance of a variety of outcomes desirable for patients. However, patients' individual goal attainments were universally absent. For continued progress in patient-centred care, efforts are needed to develop these outcomes, study their merits and pitfalls, and intensify their use in research. PMID- 25690986 TI - Assessment and mitigation of the environmental burdens to air from land applied food-based digestate. AB - Anaerobic digestion (AD) of putrescible urban waste for energy recovery has seen rapid growth over recent years. In order to ascertain its systems scale sustainability, however, determination of the environmental fate of the large volume of digestate generated during the process is indispensable. This paper evaluates the environmental burdens to air associated with land applied food based digestate in terms of primary pollutants (ammonia, nitrogen dioxide) and greenhouse gases (methane and nitrous oxide). The assessments have been made in two stages - first, the emissions from surface application of food-based digestate are quantified for the business as usual (BAU). In the next step, environmental burden minimisation potentials for the following three mitigation measures are estimated - mixed waste digestate (MWD), soil-incorporated digestate (SID), and post-methanated digestate (PMD). Overall, the mitigation scenarios demonstrated considerable NH3, CH4 and N2O burden minimisation potentials, with positive implications for both climate change and urban pollution. PMID- 25690987 TI - Ischemic optic neuropathies and their models: disease comparisons, model strengths and weaknesses. AB - Ischemic optic neuropathies (IONs) describe a group of diseases that specifically target the optic nerve and result in sudden vision loss. These include nonarteritic and arteritic anterior ischemic optic neuropathy (NAION and AAION) and posterior ischemic optic neuropathy (NPION, APION). Until recently, little was known of the mechanisms involved in ION damage, due to a lack of information about the mechanisms associated with these diseases. This review discusses the new models that closely mimic these diseases (rodent NAION, primate NAION, rodent PION). These models have enabled closer dissection of the mechanisms involved with the pathophysiology of these disorders and enable identification of relevant mechanisms and potential pathways for effective therapeutic intervention. Descriptions of the different models are included, and comparisons between the models, their relative similarities with the clinical disease, as well as differences are discussed. PMID- 25690988 TI - Glucose control and fatigue in type 2 diabetes: the mediating roles of diabetes symptoms and distress. AB - AIM: The purpose of this study was to examine the mediating influence of diabetes health characteristics (diabetes distress, depression symptoms and diabetes symptoms) on the relationship between glucose control and fatigue in adults with type 2 diabetes. BACKGROUND: In patients with type 2 diabetes, fatigue is common and can affect diabetes self-management behaviours. Although long thought to result from hyperglycaemia, little evidence supports a relationship between fatigue and glucose control. DESIGN: A cross-sectional, descriptive study design was used. METHOD: Data were combined from two studies conducted at a large urban university in the Midwestern United States, resulting in a total sample of 155 urban-dwelling adults with type 2 diabetes. Data were collected over the course of 6 days from 2013-March 2014. Fatigue and related biological and psychological phenomena were measured to perform path analyses using structural equation modelling methods. The STATA software was used to analyse the data. FINDINGS: In patients with A1C less than or equal to 7%, fatigue was related to diabetes distress and diabetes symptoms, but not to A1C directly or indirectly. In the group with A1C greater than 7%, fatigue was indirectly related to A1C; this relationship was mediated through diabetes symptoms, depression and diabetes distress. CONCLUSION: Our findings suggest that fatigue is indirectly related to glucose control, but only in patients who have elevated A1C levels. In those with adequate glucose control, fatigue is mainly influenced by the presence of diabetes symptoms and distress. In both groups, the number and severity of diabetes symptoms were the strongest predictors of fatigue, regardless of blood glucose control. PMID- 25690989 TI - Bridging generations. PMID- 25690991 TI - Tetsuo Nozoe's Autograph Books: poems, puzzles and playfulness. AB - The Nozoe Autograph Books contain entries from, literally, around the world of organic chemistry. Many of the inscriptions showed the poetic or even musical side of their signees. This Essay presents a diverse selection of the poetic entries of the autograph books, starting with a musical puzzle. This Essay and the interactive website that accompanies the Nozoe Autograph Book project are available free-access for at least a three-year period at http://www.tcr.wiley vch.de/nozoe. PMID- 25690992 TI - The Nozoe Autograph Books: "It ain't over 'til it's over". AB - All are welcome! This issue contains the final of the 15 segments of the original Nozoe Autograph Books. But this project couldn't just stop here. A modern extension of the autograph books-a 16(th) segment-will be published and will include signatures from around today's chemistry community. All are welcome to participate and add their mark on the legacy of the Nozoe Autograph Books. See the Essay for details. This Essay and the interactive website that accompanies the Nozoe Autograph Book project are available free-access for at least a three year period at http://www.tcr.wiley-vch.de/nozoe. PMID- 25690995 TI - Atmospheric pressure PECVD nanoparticles: mechanism of nanoparticle self organisation into micron sized fractal clusters on a solid surface. AB - This paper covers the results from a study of the formation mechanism of fractal clusters from nanoparticles synthesised in atmospheric pressure radio frequency discharge. Two-dimensional structures with random configuration and self similarity properties are formed by nanoparticles on a solid substrate surface. The typical linear dimensions of such structures are in the micron range. On the basis of the previously demonstrated experimental results, a physico-mathematical model of the nanoparticle self-organisation was developed. The physical model includes the electrical charge effect of the deposit surface, the spatial distribution of the surface electrical potential and the topography rearrangement phenomenon under the arising electrostatic forces. The threshold character of the agglomeration process initiation was found. The dependence of the formed structure topography on the character of the electrical potential change was demonstrated. The requisite conditions for the classical fractal formation were revealed. The results from the computational simulation, which was conducted with the use of fractal analysis, indicate a high level of coincidence with the experimental results. PMID- 25690996 TI - The nurse executive role in quality and high performing health services. AB - AIMS: To explore and identify the core elements of the nurse executive role and the contribution these posts make to health service organisations in terms of quality and performance. BACKGROUND: With the ongoing global reform of health services and, in particular, currently in Australia, this commentary paper explores the available evidence that explains and describes the role that nursing leaders can and do play at executive level in enabling quality services in high performing health-care organisations. EVALUATION: While the overall literature is limited in relation to the role and function of nurse executives, there are strong and recurrent themes indicating that nurses by virtue of their professional background and experience can provide effective and influential input to executive boards. Executive nurses are well positioned to influence and lead professional governance, quality improvement, service transformation and change and shared governance. CONCLUSION: At a time when the role of nursing executives may be questioned, the evidence supports the positive impact of highly skilled nursing executives in contributing to the implementation of effective health services. Successful health services should be engaging nurse executives who have the high level of expertise, education, the best leadership and management attributes to bring the art and science of nursing to produce outcomes for organisations. IMPLICATIONS FOR NURSING MANAGEMENT: Nurse executives must remain alert to the ongoing challenges and potential questioning on the value that nurses can bring to an executive board. The framework of nursing executive influence and leadership through professional governance, quality improvement, service transformation and change and shared governance is one possible approach that nurse executives may wish to apply to articulate their contribution and value in remaining at the executive board table. PMID- 25690997 TI - Development of a novel scheme for long-term body temperature monitoring: a review of benefits and applications. AB - Body temperature is a health or disease marker that has been in clinical use for centuries. The threshold currently applied to define fever, with small variations, is 38 degrees C. However, current approaches do not provide a full picture of the thermoregulation process and its correlation with disease. This paper describes a new non-invasive body temperature device that improves the understanding of the pathophysiology of diseases by integrating a variety of temperature data from different body locations. This device enables to gain a deeper insight into fever, endogenous rhythms, subject activity and ambient temperature to provide anticipatory and more efficient treatments. Its clinical use would be a big step in the overcoming of the anachronistic febrile/afebrile dichotomy and walking towards a system medicine approach to certain diseases. This device has already been used in some clinical applications successfully. Other possible applications based on the device features and clinical requirements are also described in this paper. PMID- 25690998 TI - Impact of initial norwood shunt type on right ventricular deformation: the single ventricle reconstruction trial. AB - BACKGROUND: The Single Ventricle Reconstruction trial demonstrated a transplantation-free survival advantage at 12-month follow-up for patients with right ventricle-pulmonary artery shunts (RVPAS) with the Norwood procedure compared with modified Blalock-Taussig shunts but similar survival and decreased global right ventricular (RV) function on longer term follow-up. The impact of the required ventriculotomy for the RVPAS remains unknown. The aim of this study was to compare echocardiography-derived RV deformation indices after stage 2 procedures in survivors with single RV anomalies enrolled in the Single Ventricle Reconstruction trial. METHODS: Global and regional RV systolic longitudinal and circumferential strain and strain rate, ejection fraction, and short-axis percentage fractional area change were all derived by speckle-tracking echocardiography from protocol echocardiograms obtained at 14.3 +/- 1.2 months. Student t tests or Wilcoxon rank sum tests were used to compare groups. RESULTS: The cohort included 275 subjects (129 in the modified Blalock-Taussig shunt group and 146 in the RVPAS group). Longitudinal deformation could be quantified in 214 subjects (78%) and circumferential measures in 182 subjects (66%). RV ejection fraction and percentage fractional area change did not differ between groups. There were no significant differences between groups for global or regional longitudinal deformation. Circumferential indices showed abnormalities in deformation in the RVPAS group, with decreased global circumferential strain (P = .05), strain rate (P = .09), and anterior regional strain rate (P = .07) that approached statistical significance. CONCLUSIONS: RV myocardial deformation at 14 months, after stage 2 procedures, was not significantly altered by the type of initial shunt placed. However, abnormal trends were appreciated in circumferential deformation for the RVPAS group in the area of ventriculotomy that may represent early myocardial dysfunction. These data provide a basis for longer term RV deformation assessment in survivors after Norwood procedures. PMID- 25690999 TI - Visualization and measurement of mitral valve chordae tendineae using three dimensional transesophageal echocardiography from the transgastric approach. AB - BACKGROUND: The evaluation of the submitral apparatus is challenging from the conventional transesophageal approach. The aim of this study was to test the feasibility of using three-dimensional (3D) transesophageal echocardiographic (TEE) imaging from the transgastric approach to visualize the submitral apparatus and quantify the lengths of the chordae tendineae by using multiplanar reconstruction analysis. METHODS: Twenty-two patients who had transgastric full volume 3D TEE data sets before mitral valve surgery underwent surgical measurement of chordal length. A short-axis plane at the chordal level was extracted from the 3D data set to identify leaflet segments and the corresponding primary chords. Then, for each chord, the optimal plane was selected to visualize and measure the entire chordal length from its origin at the leaflet margin to the papillary muscle tips. Measurements were performed at the phase of the cardiac cycle when chordal length reached its maximum. Measured values were compared with surgical measurements using linear regression and Bland-Altman analyses. RESULT: One hundred forty-six primary chords were measured intraoperatively. Three-dimensional TEE imaging was able to measure the lengths of all these chords. The surgical and 3D TEE measurements (mean, 1.96 +/- 0.56 vs 1.93 +/- 0.50 cm, respectively) correlated highly (r = 0.93, P < .0001), with a minimal bias of 0.03 cm and narrow limits of agreement from -0.39 to 0.45 cm. CONCLUSION: Transgastric 3D TEE imaging of the submitral apparatus allows visualization and accurate measurement of chordae tendineae lengths, which may be useful for planning mitral valve repair, including percutaneous transcatheter procedures. PMID- 25691000 TI - A practical guide to pediatric coronary artery imaging with echocardiography. AB - Few resources exist to educate cardiac sonographers regarding proper techniques and specific issues to consider when performing pediatric coronary artery imaging. The main objective of this report is to review the echocardiographic techniques used to image the coronary arteries of children when screening for anomalous origin of the coronary arteries, as well as coronary involvement in the setting of Kawasaki disease. The authors discuss the physics and instrumentation for developing optimal coronary artery imaging system settings and present the commonly used anatomic and echocardiographic views. Use of the correct settings and a thorough understanding of the associated ultrasound physics are crucial for obtaining quality images. With this report, the authors provide guidance to sonographers and a resource for pediatric echocardiography laboratories to help ensure high-quality echocardiographic imaging of the coronary arteries. PMID- 25691001 TI - Altered spatial distribution of the diastolic left ventricular pressure difference in heart failure. AB - BACKGROUND: The left ventricle fills in early diastole because of a progressive intraventricular pressure difference (IVPD) that extends from the left atrium to the left ventricular (LV). The aim of this study was to test the hypothesis that in patients with symptomatic heart failure (HF) regardless of LV ejection fraction (EF), an increase in left atrial (LA) pressure maintains early diastolic filling because of a preserved IVPD from the left atrium to the mid left ventricle, while the IVPD from the mid left ventricle to the apex is diminished because of reduced LV suction. METHODS: One hundred fifty-one patients with HF (50 with HF with preserved EF [HFpEF; EF >= 50%] and 101 with HF with reduced EF [HFrEF; EF < 50%]) and 28 normal controls were prospectively enrolled. The IVPDs from the left atrium to the LV apex (total IVPD), the left atrium to the mid left ventricle (basilar IVPD), and the mid left ventricle to the apex (apical IVPD) were determined using color M-mode Doppler echocardiographic data to integrate the Euler equation. The propagation of early diastolic filling was also assessed by color M-mode Doppler. RESULTS: The mean LV EF was 0.63 +/- 0.07 in patients with HFpEF, 0.32 +/- 0.09 in those with HFrEF, and 0.64 +/- 0.06 in controls. Peak early diastolic transmitral flow velocities (E) were similar among the groups, and basilar IVPDs were maintained in the HFpEF and HFrEF groups (HFpEF, 1.59 +/- 0.62 mm Hg; HFrEF, 1.49 +/- 0.75 mm Hg; controls, 1.80 +/- 0.61 mm Hg; P = NS, analysis of variance). However, apical IVPDs were decreased in both HF groups (HFpEF, 1.18 +/- 0.56 mm Hg [P < .01 vs controls]; HFrEF, 0.87 +/- 0.48 mm Hg [P < .01 vs controls]; controls, 1.65 +/- 0.62 mm Hg), resulting in decreased total IVPDs in patients with HF (HFpEF, 2.55 +/- 0.80 mm Hg [P < .01 vs controls]; HFrEF, 2.16 +/- 0.80 mm Hg [P < .01 vs controls]; controls, 3.17 +/- 0.91 mm Hg). E/e' ratios were increased in patients with HF, consistent with elevated LA pressure. In patients with HF, E was correlated with basilar IVPD but not with apical IVPD, whereas propagation of the filling was correlated with the apical IVPD but not with the basilar IVPD. CONCLUSIONS: In patients with HFpEF and those with HFrEF, apical IVPDs were reduced while basilar IVPDs were maintained by elevated LA pressure, resulting in preserved E. PMID- 25691002 TI - Physiological performance, secondary metabolite and expression profiling of genes associated with drought tolerance in Withania somnifera. AB - Physiological, biochemical, and gene expression responses under drought stress were studied in Withania somnifera. Photosynthesis rate, stomatal conductance, transpiration rate, relative water content, chlorophyll content, and quantum yield of photosystems I and II (PSI and PSII) decreased in response to drought stress. Comparative expression of genes involved in osmoregulation, detoxification, signal transduction, metabolism, and transcription factor was analyzed through quantitative RT-PCR. The genes encoding 1-pyrroline-5 carboxylate synthetase (P5CS), glutathione S-transferase (GST), superoxide dismutase (SOD), serine threonine-protein kinase (STK), serine threonine protein phosphatase (PSP), aldehyde dehydrogenase (AD), leucoanthocyanidin dioxygenase/anthocyanin synthase (LD/AS), HSP, MYB, and WRKY have shown upregulation in response to drought stress condition in leaf tissues. Enhanced detoxification and osmoregulation along with increased withanolides production were also observed under drought stress. The results of this study will be helpful in developing stress-tolerant and high secondary metabolite yielding genotypes. PMID- 25691003 TI - Astrocyte-targeted production of IL-10 induces changes in microglial reactivity and reduces motor neuron death after facial nerve axotomy. AB - Interleukin-10 (IL-10) is a cytokine that plays a crucial role in regulating the inflammatory response and immune reactions. In the central nervous system (CNS), IL-10 is mainly produced by astrocytes and microglia and it is upregulated after various insults, such as experimental autoimmune encephalomyelitis, middle cerebral artery occlusion, excitotoxicity and traumatic brain injury. To better understand the effects of IL-10 in the normal and injured CNS, we generated transgenic mice (termed GFAP-IL-10Tg) that expressed the murine IL-10 gene under the transcriptional control of the glial fibrillary acidic protein (GFAP) promoter. Previous studies demonstrated marked changes in the microglial phenotype in these mice under basal conditions. The objective of the present study was to investigate the effects of local astrocyte-targeted IL-10 production on glial activation, neuronal degeneration and leukocyte recruitment after axotomy. GFAP-IL-10Tg mice had marked changes in the phenotype of activated microglial cells, as well as in the number of microglial clusters and in microglial cell density. These microglial changes are accompanied by a twofold increase in lymphocyte infiltration in GFAP-IL-10Tg mice and around twofold decrease in neuronal cell death at 21 dpi. Altogether, our findings suggested that astrocyte-targeted production of IL-10 impacted the microglial response and lymphocyte recruitment and culminated in a beneficial effect on neuronal survival. PMID- 25691004 TI - Cohort-Based Identification of Predictors of Symptomatic Intracerebral Hemorrhage After IV Thrombolysis. AB - INTRODUCTION: Symptomatic intracranial hemorrhage (sICH) is a serious complication of IV rt-PA therapy after acute ischemic stroke. Independent sICH predictors have been previously derived using case-control studies. Here we utilized a novel cohort-based comparison to identify additional independent predictors of sICH. METHODS: We included 210 patients receiving IV rt-PA therapy from January 2009 through December 2013 at the Yale-New Haven Stroke Center. Clinical parameters were compared using Mann-Whitney tests, two-sample tests of proportions and two-sample t tests. Logistic regression was performed using sICH as the dependent variable. Predictive ability was assessed using areas under the receiver operating characteristic (ROC) curve. RESULTS: sICH rates were lowest from 2010 to 2012 and comprised the low sICH cohort (2.0 % sICH), compared to the high sICH cohort from 2009 to 2013 (9.2 % sICH, P = 0.025). Patients in the low sICH cohort had significantly more visual field deficits (38.6 vs. 24.8 %, P = 0.03) and decreased levels of consciousness (62.4 vs. 39.4 %, P < 0.001), but fewer hyperdense MCA signs (5 vs. 13.8 %, P = 0.03) and early CT hypodensities (14.9 vs. 29.4 %, P = 0.01). These four parameters together predicted sICH modestly (area under ROC curve 0.66, odds ratio 2.72, P = 0.03) CONCLUSIONS: Using a novel cohort-based approach, we identified two new independent predictors of sICH after IV rt-PA therapy: the presence of the hyperdense MCA sign and early CT hypodensities. Novel methods are needed to reduce the risk of sICH for patients receiving antithrombolytic therapy for ischemic stroke. PMID- 25691005 TI - Bioactive compounds from crocodile (Crocodylus siamensis) white blood cells induced apoptotic cell death in hela cells. AB - Crocodile (Crocodylus siamensis) white blood cell extracts (WBCex) were examined for anticancer activity in HeLa cell lines using the MTT assay. The percentage viability of HeLa cells significantly deceased after treatment with WBCex in a dose- and time-dependent manner. The IC50 dose was suggested to be approximately 225 MUg/mL protein. Apoptotic cell death occurred in a time-dependent manner based on investigation by flow cytometry using annexin V-FITC and PI staining. DAPI nucleic acid staining indicated increased chromatin condensation. Caspase-3, -8 and -9 activities also increased, suggesting the induction of the caspase dependent apoptotic pathway. Furthermore, the mitochondrial membrane potential (DeltaPsim ) of HeLa cells was lost as a result of increasing levels of Bax and reduced levels of Bcl-2, Bcl-XL, Bcl-Xs, and XIAP. The decreased DeltaPsim led to the release of cytochrome c and the activation of caspase-9 and -3. Apoptosis inducing factor translocated into the nuclei, and endonuclease G (Endo G) was released from the mitochondria. These results suggest that anticancer agents in WBCex can induce apoptosis in HeLa cells via both caspase-dependent and independent pathways. (c) 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 986 997, 2016. PMID- 25691006 TI - Association of the expression levels in the skeletal muscle and a SNP in the CDC10 gene with growth-related traits in Japanese Black beef cattle. AB - Growth performance, as well as marbling, is the main breeding objective in Japanese Black (JB) cattle, the major beef breed in Japan. The septin 7 (CDC10) gene, involved in cellular proliferation, is located within a genomic region of a quantitative trait locus for growth-related traits. In this study, we first showed that the expression levels of the CDC10 gene in the skeletal muscle were higher in JB steers with extremely high growth performance than in JB steers with extremely low growth, using real-time PCR. Further, a single nucleotide polymorphism (SNP), NC_007302.5:g.63264949G>C, was detected in the promoter region of the CDC10 gene and genotyped in three Japanese cattle breeds (known as 'Wagyu' in Japan) and the Brown Swiss dairy cattle breed. All four cattle populations showed a moderate genetic diversity at the SNP of the CDC10 gene. An association analysis indicated that the SNP was associated with growth-related traits in JB cattle. These findings suggest possible effects of the expression levels in the skeletal muscle and the SNP of the CDC10 gene on growth-related traits in JB cattle. The CDC10 SNP may be useful for effective marker-assisted selection to increase beef productivity in JB beef cattle. PMID- 25691007 TI - Mitochondria of a human multidrug-resistant hepatocellular carcinoma cell line constitutively express inducible nitric oxide synthase in the inner membrane. AB - Mitochondria play a crucial role in pathways of stress conditions. They can be transported from one cell to another, bringing their features to the cell where they are transported. It has been shown in cancer cells overexpressing multidrug resistance (MDR) that mitochondria express proteins involved in drug resistance such as P-glycoprotein (P-gp), breast cancer resistant protein and multiple resistance protein-1. The MDR phenotype is associated with the constitutive expression of COX-2 and iNOS, whereas celecoxib, a specific inhibitor of COX-2 activity, reverses drug resistance of MDR cells by releasing cytochrome c from mitochondria. It is possible that COX-2 and iNOS are also expressed in mitochondria of cancer cells overexpressing the MDR phenotype. This study involved experiments using the human HCC PLC/PRF/5 cell line with and without MDR phenotype and melanoma A375 cells that do not express the MDR1 phenotype but they do iNOS. Western blot analysis, confocal immunofluorescence and immune electron microscopy showed that iNOS is localized in mitochondria of MDR1-positive cells, whereas COX-2 is not. Low and moderate concentrations of celecoxib modulate the expression of iNOS and P-gp in mitochondria of MDR cancer cells independently from inhibition of COX-2 activity. However, A375 cells that express iNOS also in mitochondria, were not MDR1 positive. In conclusion, iNOS can be localized in mitochondria of HCC cells overexpressing MDR1 phenotype, however this phenomenon appears independent from the MDR1 phenotype occurrence. The presence of iNOS in mitochondria of human HCC cells phenotype probably concurs to a more aggressive behaviour of cancer cells. PMID- 25691008 TI - Epstein-Barr virus-negative Hodgkin lymphoma presenting as haemophagocytic lymphohistiocytosis. PMID- 25691009 TI - Ultrasound-assisted (R)-phenylephrine whole-cell bioconversion by S. marcescens N10612. AB - The strain Serratia marcescens N10612 is used to perform the bioconversion of 1 (3-hydroxyphenyl)-2-(methyamino)-ethanone (HPMAE) to (R)-phenylephrine ((R)-PE), which is an ephedrine drug substitute. The use of an ultrasound approach is found to improve the efficiency of the (R)-PE bioconversion. The optimization of the (R)-PE bioconversion is carried out by means of statistical experiment design. The optimal conditions obtained are 1.0mM HPMAE, 18.68 g/L glucose and ultrasound power of 120 W, where the predicted specific rate of the (R)-PE bioconversion is 31.46 +/- 2.22 (imol/h/g-cells) and the experimental specific rate is 33.27 +/- 1.46 (imol/h/g-cells), which is 3-fold higher than for the operation under ultrasound power of 200 W (11.11 imol/h/g-cells) and 4.3-fold higher than for the shaking operation (7.69 imol/h/g-cells). The kinetics study of the bioconversion also shows that under the ultrasound operation, the optimal rate (Vmax) of the (R)-PE bioconversion increases from 7.69 to 11.11 (MUmol/h/g-cells) and the substrate inhibition constant (KSi) increases from 1.063 mM for the shaking operation to 1.490 mM for ultrasound operation. PMID- 25691013 TI - Available screening tools for adults suffering from bipolar affective disorder in primary care: An integrative literature review. AB - PURPOSE: To assess the efficacy of six tools utilized in primary care for the screening of bipolar affective disorder (BPAD). BPAD has historically been underdiagnosed or misdiagnosed followed by inappropriate treatment leading to detrimental relapses, suicide, and increased risks for comorbidities. DATA SOURCES: An electronic search was conducted to identify articles in the following databases: MEDLINE, CINAHL, Cochrane Library, ERIC, National Guideline Clearinghouse, PsycINFO, Psychology and Behavioral Sciences collection, and PsycARTICLES. Other information was also collected from the NIH, CDC, Healthy People 2020, the Black Dog Institute, and the Center for Quality Assessment and Improvement for Mental Health. CONCLUSION: Evidence indicates that primary care providers are often the first and sometimes sole provider, which signifies the importance of early detection and screening of BPAD in primary care. By implementing the use of appropriate screening tools and following recommended treatment and intervention guidelines, the prevention of relapse is increased, and comorbidities are more frequently diagnosed leading to an overall improved quality of life. IMPLICATIONS FOR PRACTICE: Primary care practitioners play a vital role in appropriately screening for BPAD and implementing the recommended treatments to increase prevention of relapse and promote a healthier and more socially successful quality of life. PMID- 25691014 TI - Foreword. PMID- 25691015 TI - The 3rd North American/Global Dental Hygiene Research Conference. PMID- 25691016 TI - Beyond the boundaries: discovery, innovation and transformation through collaboration. PMID- 25691017 TI - Dental hygiene's scholarly identity and roadblocks to achieving it. PMID- 25691018 TI - Advancing the profession. PMID- 25691019 TI - Interrupting the disease of tobacco addiction. PMID- 25691020 TI - The oral microbiome and cancer. PMID- 25691021 TI - Creating a risk-based model for dental benefit design. PMID- 25691022 TI - Using prevention and measurement to drive quality improvement. PMID- 25691023 TI - Opportunities to increase prevention in dentistry. PMID- 25691024 TI - Interprofessional practice: translating evidence-based oral care to hospital care. PMID- 25691025 TI - Poor oral health literacy: why nobody understands you. PMID- 25691026 TI - Using the best evidence to enhance dental hygiene decision making. PMID- 25691027 TI - Overcoming the fear of statistics: survival skills for researchers. PMID- 25691028 TI - Millennials and dental education: utilizing educational technology for effective teaching. PMID- 25691029 TI - Getting your name in print. PMID- 25691030 TI - Becoming an effective journal reviewer. PMID- 25691031 TI - Successfully navigating the human subjects approval process. PMID- 25691032 TI - Data management 101: how to construct and maintain a usable dataset. PMID- 25691035 TI - Refinement in our ability to identify women most at risk for pelvic floor dysfunction following birth is needed. PMID- 25691037 TI - A Pivotal Moment for Global Cardiovascular Disease The World Heart Federation and the UN NCD Summit. PMID- 25691036 TI - Utility of labile plasma iron and transferrin saturation in addition to serum ferritin as iron overload markers in different underlying anemias before and after deferasirox treatment. AB - OBJECTIVES: Plasma markers in addition to serum ferritin (SF) may be useful for the assessment of iron overload; however, predictive utility may differ depending on underlying, transfusion-dependent, anemias. METHODS: Data were collected before and after 1 year of deferasirox treatment (end of study; EOS) from the large, 1-year EPIC (Evaluation of Patients' Iron Chelation with Exjade((r)) ) study. Trends were evaluated between liver iron concentration (LIC), transferrin saturation (TfSat), predose labile plasma iron (LPI) and their relationship to SF categories in 1530 patients: thalassemia major (TM; n = 1114), myelodysplastic syndromes (MDS, n = 336), and sickle-cell disease (SCD, n = 80). RESULTS: Baseline and EOS SF values showed a clear and similar relationship to LIC for all disease groups. TfSat also showed a relationship to SF, most clearly in patients with SCD, where TfSat was lowest in the lowest relative SF category. Unlike SF or LIC, TfSat did not decrease at EOS in any disease group. Baseline LPI was raised in TM and MDS, but not in patients with SCD, decreasing at EOS in both patient groups. After 1 year of chelation therapy, there was a significant trend for greater LPI reduction in patients with TM achieving LIC <7 mg Fe/g dw (P = 0.0137). CONCLUSIONS: Despite limitations, SF showed the clearest relationship, of the plasma markers evaluated, to LIC before and after 1 year of deferasirox in patients with TM, MDS, and SCD. In patients with TM, changes in LPI with chelation show a significant relationship to EOS LIC and may provide an additional indicator of chelation response (clinicaltrials.gov identifier: NCT00171821). PMID- 25691038 TI - Potential for global progress in control of chronic diseases a turning point in 2011. PMID- 25691039 TI - Summary of the institute of medicine report promoting cardiovascular health in the developing world. PMID- 25691040 TI - A Conceptual Strategy to Address CVD and Related Chronic Diseases in the Developing World. PMID- 25691041 TI - A framework for action to promote cardiovascular health in the developing world. PMID- 25691042 TI - Transforming the Education of Health Professionals to Confront the Burden of NCD Commission on Education of Health Professionals for the 21st Century. PMID- 25691043 TI - Preparing the university community to respond to 21st century global public health needs. PMID- 25691044 TI - Trans-Disciplinary Education and Training for NCD Prevention and Control. PMID- 25691045 TI - Non-communicable, chronic disease training and education needs in India. PMID- 25691046 TI - Youth manifesto on non-communicable diseases. PMID- 25691047 TI - Control of NCD: A Caribbean Perspective. PMID- 25691048 TI - United Nations High Level Meeting and NCD in South Africa. PMID- 25691049 TI - Health Workforce Development with a Focus on CVD in Zimbabwe CHRIS Program, a Medical Education Partnership Initiative. PMID- 25691050 TI - Mass Screening and Intervention by Mass Communication The HAPPY Program. PMID- 25691051 TI - Globally yours.... PMID- 25691052 TI - Activation of RAS family members confers resistance to ROS1 targeting drugs. AB - The ROS1 tyrosine kinase is activated in lung cancer as a consequence of chromosomal rearrangement. Although high response rates and disease control have been observed in lung cancer patients bearing rearranged ROS1 tumors (ROS1+) treated with the kinase inhibitor crizotinib, many of these patients eventually relapse.To identify mechanisms of resistance to ROS1 inhibitors we generated resistant cells from HCC78 lung cancer cells bearing the SLC34A2-ROS1 rearrangement. We found that activation of the RAS pathway in the HCC78 cell model, due to either KRAS/NRAS mutations or to KRAS amplification, rendered the cells resistant to ROS1 inhibition. These cells were cross-resistant to different ROS1 inhibitors, but sensitive to inhibitors of the RAS signaling pathway. Interestingly, we identified focal KRAS amplification in a biopsy of a tumor from a patient that had become resistant to crizotinib treatment.Altogether our data suggest that the activation of members of the RAS family can confer resistance to ROS1 inhibitors. This has important clinical implications as: (i) RAS genetic alterations in ROS1+ primary tumors are likely negative predictors of efficacy for targeted drugs and (ii) this kind of resistance is unlikely to be overcome by the use of more specific or more potent ROS1 targeting drugs. PMID- 25691053 TI - Gold nano-particles (AuNPs) carrying anti-EBV-miR-BART7-3p inhibit growth of EBV positive nasopharyngeal carcinoma. AB - Epstein-Barr virus (EBV) infection is a major etiological factor for nasopharyngeal carcinoma (NPC). Several EBV-encoded BART miRNAs have been associated with viral latency, immune escape, cell survival, cell proliferation and apoptosis. Here, we report that EBV-miR-BART7-3p, an EBV-encoded BART miRNA highly expressed in NPC, was correlated with cell-cycle progression in vitro and increased tumor formation in vivo. This viral miRNA stimulated the PTEN/PI3K/Akt pathway and induced c-Myc and c-Jun. Knockdown of PTEN mimicked EBV-miR-BART7-3p induced tumorigenic phenotype. Based on these results, we conducted a therapeutic experiment by using gold nano-particles (AuNPs) carrying anti-EBV-miR-BART7-3p. Silencing of EBV-miR-BART7-3p reduced tumor growth in animal model. We conclude that EBV-miR-BART7-3p favors carcinogenesis, representing a potential target for miRNA-based therapy. PMID- 25691054 TI - The multiple cellular functions of the oncoprotein Golgi phosphoprotein 3. AB - The highly conserved Golgi phosphoprotein 3 (GOLPH3) protein, a component of Trans-Golgi Network (TGN), has been defined as a "first-in-class Golgi oncoprotein" and characterized as a Phosphatidylinositol 4-phosphate [PI(4)P] effector at the Golgi. GOLPH3 is commonly amplified in several solid tumors. Furthermore this protein has been associated with poor prognosis in many cancers. Highly conserved from yeast to humans, GOLPH3 provides an essential function in vesicle trafficking and Golgi structure. Recent data have also implicated this oncoprotein in regulation of cytokinesis, modulation of mitochondrial mass and cellular response to DNA damage. A minute dissection of the molecular pathways that require GOLPH3 protein will be helpful to develop new therapeutic cancer strategies. PMID- 25691055 TI - Nutrient/serum starvation derived TRIP-Br3 down-regulation accelerates apoptosis by destabilizing XIAP. AB - TRIP-Br3 and TRIP-Br1 have shown to have important biological functions. However, the function of TRIP-Br3 in tumorigenesis is not well characterized compared to oncogenic TRIP-Br1. Here, we investigated the function of TRIP-Br3 in tumorigenesis by comparing with that of TRIP-Br1. Under nutrient/serum starvation, TRIP-Br3 expression was down-regulated slightly in cancer cells and significantly in normal cells. Unexpectedly, TRIP-Br1 expression was greatly up regulated in cancer cells but not in normal cells. Moreover, TRIP-Br3 activated autophagy while TRIP-Br1 inactivated it under serum starvation. In spite of different expression and roles of TRIP-Br3 and TRIP-Br1, both of them alleviate cell death by directly binding to and stabilizing XIAP, a potent apoptosis inhibitor, through blocking its ubiquitination. Taken together, we propose that TRIP-Br3 primarily activates the autophagy and suppresses apoptosis in nutrient sufficient condition. However, the prolonged extreme stressful condition of nutrient starvation causes a dramatic decrease of TRIP-Br3, which in turn induces apoptosis by destabilizing XIAP. Up-regulated TRIP-Br1 in cancer cells compensates this effect and delays apoptosis. This can be explained by the competitive alternative binding of TRIP-Br3 and TRIP-Br1 to the BIR2 domain of XIAP. In an extended study, our immunohistochemical analysis revealed a markedly lower level of TRIP-Br3 protein in human carcinoma tissues compared to normal epithelial tissues, implying the role of TRIP-Br3 as a tumor suppressor rather than onco-protein. PMID- 25691056 TI - Variants in CDA and ABCB1 are predictors of capecitabine-related adverse reactions in colorectal cancer. AB - Adverse reactions to capecitabine-based chemotherapy limit full administration of cytotoxic agents. Likewise, genetic variations associated with capecitabine related adverse reactions are associated with controversial results and a low predictive value. Thus, more evidence on the role of these variations is needed. We evaluated the association between nine polymorphisms in MTHFR, CDA, TYMS, ABCB1, and ENOSF1 and adverse reactions, dose reductions, treatment delays, and overall toxicity in 239 colorectal cancer patients treated with capecitabine based regimens. The ABCB1*1 haplotype was associated with a high risk of delay in administration or reduction in the dose of capecitabine, diarrhea, and overall toxicity. CDA rs2072671 A was associated with a high risk of overall toxicity. TYMS rs45445694 was associated with a high risk of delay in administration or reduction in the dose of capecitabine, HFS >1 and HFS >2. Finally, ENOSF1 rs2612091 was associated with HFS >1, but was a poorer predictor than TYMS rs45445694. A score based on ABCB1-CDA polymorphisms efficiently predicts patients at high risk of severe overall toxicity (PPV, 54%; sensitivity, 43%) in colorectal cancer patients treated with regimens containing capecitabine. Polymorphisms in ABCB1, CDA, ENOSF1,and TYMS could help to predict specific and overall severe adverse reactions to capecitabine. PMID- 25691058 TI - 2D-DIGE proteomic analysis identifies new potential therapeutic targets for adrenocortical carcinoma. AB - Adrenocortical carcinoma (ACC) is a rare aggressive tumor with poor prognosis when metastatic at diagnosis. The tumor biology is still mostly unclear, justifying the limited specificity and efficacy of the anti-cancer drugs currently available. This study reports the first proteomic analysis of ACC by using two-dimensional-differential-in-gel-electrophoresis (2D-DIGE) to evaluate a differential protein expression profile between adrenocortical carcinoma and normal adrenal. Mass spectrometry, associated with 2D-DIGE analysis of carcinomas and normal adrenals, identified 22 proteins in 27 differentially expressed 2D spots, mostly overexpressed in ACC. Gene ontology analysis revealed that most of the proteins concurs towards a metabolic shift, called the Warburg effect, in adrenocortical cancer. The differential expression was validated by Western blot for Aldehyde-dehydrogenase-6-A1,Transferrin, Fascin-1,Lamin A/C,Adenylate-cyclase associated-protein-1 and Ferredoxin-reductase. Moreover, immunohistochemistry performed on paraffin-embedded ACC and normal adrenal specimens confirmed marked positive staining for all 6 proteins diffusely expressed by neoplastic cells, compared with normal adrenal cortex.In conclusion, our preliminary findings reveal a different proteomic profile in adrenocortical carcinoma compared with normal adrenal cortex characterized by overexpression of mainly metabolic enzymes, thus suggesting the Warburg effect also occurs in ACC. These proteins may represent promising novel ACC biomarkers and potential therapeutic targets if validated in larger cohorts of patients. PMID- 25691057 TI - Combining lapatinib and pertuzumab to overcome lapatinib resistance due to NRG1 mediated signalling in HER2-amplified breast cancer. AB - Acquired resistance to lapatinib, an inhibitor of EGFR and HER2 kinases, is common. We found that reactivation of EGFR, HER2 and HER3 occurred within 24 hours of lapatinib treatment after their initial dephosphorylation. This was associated with increased expression of NRG1 in cells treated with lapatinib. Exogenous NRG1 partially rescued breast cancer cells from growth inhibition by lapatinib. In addition, both parental and lapatinib-resistant breast cancer cells were sensitive to SGP1, which inhibits binding of NRG1 and other HER3 ligands. Addition of pertuzumab to lapatinib further inhibited NRG1-induced signalling, which was not fully inhibited by either drug alone. In animal model, a combination of pertuzumab to lapatinib induced a greater tumor regression than either lapatinib or pertuzumab monotherapy. This novel combination treatment may provide a promising strategy in clinical HER2-targeted therapy and may inhibit a subset of lapatinib-resistant breast cancer, although the group of patients that will respond to this therapy requires further stratification. PMID- 25691059 TI - Cell-specific expression of artificial microRNAs targeting essential genes exhibit potent antitumor effect on hepatocellular carcinoma cells. AB - To achieve specific and potent antitumor effect of hepatocyte carcinoma cells, replication defective adenoviral vectors, namely rAd/AFP-amiRG, rAd/AFP-amiRE and rAd/AFP-amiRP, were constructed which were armed with artificial microRNAs (amiRs) targeting essential functional genes glyceraldehyde-3-phosphate dehydrogenase, eukaryotic translation initiation factor 4E and DNA polymerase alpha respectively under the control of a recombinant promoter comprised of human alpha-fetoprotein enhancer and basal promoter. The AFP enhancer/promoter showed specific high transcription activity in AFP-positive HCC cells Hep3B, HepG2 and SMMC7721, while low in AFP-negative cell Bcap37. All artificial microRNAs exhibited efficient knockdown of target genes. Decreased ATP production and protein synthesis was observed in rAd/AFP-amiRG and rAd/AFP-amiRE treated HCC cells. All three recombinant adenoviruses showed efficient blockage of cell cycle progression and significant suppression of HCC cells in vitro. In nude mice model bearing Hep3B xenograft, administration of rAd/AFP-amiRG showed potent antitumor effect. The strategy of tumor-specific knockdown of genes essential for cell survival and proliferation may suggest a novel promising approach for HCC gene therapy. PMID- 25691060 TI - Myeloid differentiation primary response gene 88-leukotriene B4 receptor 2 cascade mediates lipopolysaccharide-potentiated invasiveness of breast cancer cells. AB - Inflammation and local inflammatory mediators are inextricably linked to tumor progression through complex pathways in the tumor microenvironment. Lipopolysaccharide (LPS) exposure to tumor cells has been suggested to promote tumor invasiveness and metastasis. However, the detailed signaling mechanism involved has not been elucidated. In this study, we showed that LPS upregulated the expression of leukotriene B4 receptor-2 (BLT2) and the synthesis of BLT2 ligands in MDA-MB-231 and MDA-MB-435 breast cancer cells, thereby promoting invasiveness. BLT2 depletion with siRNA clearly attenuated LPS-induced invasiveness. In addition, we demonstrated that myeloid differentiation primary response gene 88 (MyD88) lies upstream of BLT2 in LPS-potentiated invasiveness and that this 'MyD88-BLT2' cascade mediates activation of NF-kappaB and the synthesis of IL-6 and IL-8, which are critical for the invasiveness and aggression of breast cancer cells. LPS-driven metastasis of MDA-MB-231 cells was also markedly suppressed by the inhibition of BLT2. Together, our results demonstrate, for the first time, that LPS potentiates the invasiveness and metastasis of breast cancer cells via a 'MyD88-BLT2'-linked signaling cascade. PMID- 25691061 TI - Somatic microsatellite variability as a predictive marker for colorectal cancer and liver cancer progression. AB - Microsatellites (MSTs) are short tandem repeated genetic motifs that comprise ~3% of the genome. MST instability (MSI), defined as acquired/lost primary alleles at a small subset of microsatellite loci (e.g. Bethesda markers), is a clinically relevant marker for colorectal cancer. However, these markers are not applicable to other types of cancers, specifically, for liver cancer which has a high mortality rate. Here we show that somatic MST variability (SMV), defined as the presence of additional, non-primary (aka minor) alleles at MST loci, is a complementary measure of MSI, and a genetic marker for colorectal and liver cancer. Re-analysis of Illumina sequenced exomes from The Cancer Genome Atlas indicates that SMV may distinguish a subpopulation of African American patients with colorectal cancer, which represents ~33% of the population in this study. Further, for liver cancer, a higher rate of SMV may be indicative of an earlier age of onset. The work presented here suggests that classical MSI should be expanded to include SMV, going beyond alterations of the primary alleles at a small number of microsatellite loci. This measure of SMV may represent a potential new diagnostic for a variety of cancers and may provide new information for colorectal cancer patients. PMID- 25691062 TI - Carboxyl-terminal domain of MUC16 imparts tumorigenic and metastatic functions through nuclear translocation of JAK2 to pancreatic cancer cells. AB - MUC16 (CA125) is a type-I transmembrane glycoprotein that is up-regulated in multiple cancers including pancreatic cancer (PC). However, the existence and role of carboxyl-terminal MUC16 generated following its cleavage in PC is unknown. Our previous study using a systematic dual-epitope tagged domain deletion approach of carboxyl-terminal MUC16 has demonstrated the generation of a 17-kDa cleaved MUC16 (MUC16-Cter). Here, we demonstrate the functional significance of MUC16-Cter in PC using the dual-epitope tagged version (N terminal FLAG- and C-terminal HA-tag) of 114 carboxyl-terminal residues of MUC16 (F114HA). In vitro analyses using F114HA transfected MiaPaCa-2 and T3M4 cells showed enhanced proliferation, motility and increased accumulation of cells in the G2/M phase with apoptosis resistance, a feature associated with cancer stem cells (CSCs). This was supported by enrichment of ALDH+ CSCs along with enhanced drug-resistance. Mechanistically, we demonstrate a novel function of MUC16-Cter that promotes nuclear translocation of JAK2 resulting in phosphorylation of Histone-3 up-regulating stemness-specific genes LMO2 and NANOG. Jak2 dependence was demonstrated using Jak2+/+ and Jak2-/- cells. Using eGFP-Luciferase labeled cells, we demonstrate enhanced tumorigenic and metastatic potential of MUC16-Cter in vivo. Taken together, we demonstrate that MUC16-Cter mediated enrichment of CSCs is partly responsible for tumorigenic, metastatic and drug-resistant properties of PC cells. PMID- 25691064 TI - About-face on the metabolic side effects of rapamycin. PMID- 25691063 TI - EBNA3C regulates p53 through induction of Aurora kinase B. AB - In multicellular organisms p53 maintains genomic integrity through activation of DNA repair, and apoptosis. EBNA3C can down regulate p53 transcriptional activity. Aurora kinase (AK) B phosphorylates p53, which leads to degradation of p53. Aberrant expression of AK-B is a hallmark of numerous human cancers. Therefore changes in the activities of p53 due to AK-B and EBNA3C expression is important for understanding EBV-mediated cell transformation. Here we show that the activities of p53 and its homolog p73 are dysregulated in EBV infected primary cells which can contribute to increased cell transformation. Further, we showed that the ETS-1 binding site is crucial for EBNA3C-mediated up-regulation of AK-B transcription. Further, we determined the Ser 215 residue of p53 is critical for functional regulation by AK-B and EBNA3C and that the kinase domain of AK-B which includes amino acid residues 106, 111 and 205 was important for p53 regulation. AK-B with a mutation at residue 207 was functionally similar to wild type AK-B in terms of its kinase activities and knockdown of AK-B led to enhanced p73 expression independent of p53. This study explores an additional mechanism by which p53 is regulated by AK-B and EBNA3C contributing to EBV-induced B-cell transformation. PMID- 25691065 TI - Post-mortem computed tomography and post-mortem computed tomography angiography following transcatheter aortic valve implantation?. AB - OBJECTIVES: At present, transcatheter aortic valve implantation (TAVI) is widely used. As with any interventional treatment, however, TAVI may also be accompanied by complications and may result in periprocedural mortality. This study aims to evaluate such complications and causes of death after TAVI. METHODS: The study included 32 deceased (59.4% female, n = 19, median age: 82 years) patients with TAVI, since 2008, in whom post-mortem computed tomography (PMCT) and PMCT angiography were performed with the intention of identifying complications. RESULTS: Altogether, we registered bleeding (28.1%, 9/32), perforation and rupture (25%, 8/32), cerebral infarction (18.8%, 6/32), injury of the conduction system (3.1%, 1/32), insufficiency of the aortic (12.5%, 4/32) and the mitral valve (9.4%, 3/32) and of valve-in-valve procedures (9.4%, 3/32). Furthermore, there were findings due to cardiopulmonary resuscitation and intensive care. PMCT and PMCT angiography has advantages over autopsy. The demonstration of bleeding vessels, ruptures, the position of the implanted aortic valve and its effects on the mitral valve and its suspensions were more easily accessible by computed tomography-imaging display than by customary autopsy photo-documentation. CONCLUSIONS: After TAVI, PMCT and PMCT angiography successfully demonstrated the complications leading to death. PMCT and PMCT angiography contribute to the post mortem analysis of causes of periprocedural death. PMID- 25691066 TI - Mechanical circulatory support in the Dutch National Paediatric Heart Transplantation Programme. AB - OBJECTIVES: Mechanical circulatory support (MCS) with a ventricular assist device (VAD) as a bridge to heart transplantation (HTx) or recovery may improve outcome in children with terminal heart failure. We report our experience with MCS in children eligible for HTx and its effect on waiting list mortality. METHODS: Retrospective single-centre cohort study, National Paediatric HTx Programme including all children eligible for HTx, since the introduction of MCS-VAD in 2006. RESULTS: A total of 43 patients were eligible for HTx, median age 11.7 years [Inter Quartile Range (IQR) 3.0-14.7]. In 18 patients, (42%) a VAD was implanted, 11 (61%) survived to HTx (n = 9) or recovery (n = 2). Techniques and devices used were left ventricular assist device (n = 16, 89%), in 4 cases preceded by extracorporeal membrane oxygenation (ECMO), and biventricular assist device (n = 2, 11%), both preceded by ECMO. In the VAD group, median time to death (n = 7) was 18 days (IQR 7-75), median time to HTx (n = 9) 66 days (IQR 33 223) and 2 patients recovered after 30 and 308 days. The main cause of death on MCS was neurological injury in 4 patients (22%) and systemic thrombo-embolic events in 2 (11%). The most common serious adverse events included confirmed thrombus requiring pump replacement (in 11 patients, 61%) and pericardial effusion leading to rethoracotomy (in 5 patients, 28%). Compared with the era before MCS (1998-2006), waiting list mortality decreased from 44 to 21%, and is now mainly related to complications of VAD support. CONCLUSIONS: Since the introduction of MCS-VAD, waiting list mortality halved and more children with end stage heart failure survived to heart transplantation, thus improving outcome. Although there is substantial mortality and morbidity, overall mortality decreases, making MCS-VAD an essential therapeutic tool. The need for donor organs remains critically urgent. PMID- 25691067 TI - The assessment of collateral communication after hybrid repair for Crawford extent II thoraco-abdominal aortic aneurysms. AB - OBJECTIVES: The repair of extensive thoraco-abdominal aortic aneurysms (TAAAs) is invasive and carries a high risk for spinal cord injury (SCI). The aim of this study was to assess the early results and collateral circulation to the spinal cord after hybrid repair for Crawford extent II aortic aneurysms. METHODS: Between 1997 and 2013, we performed 128 thoracic endovascular aortic repair (TEVAR) procedures for TAAAs. This study reviews 12 patients who underwent hybrid TEVAR for a Crawford extent II aortic aneurysm (mean age: 56 years, 6 men, chronic dissection: 10). Aortic arch repair was performed to create a proximal landing zone and visceral debranching bypass was performed to create a distal landing zone at separate stages prior to TEVAR. Subsequently, a stent graft was deployed to cover the residual downstream aorta. TEVAR was generally performed the day after the final debranching procedure. Cerebrospinal fluid drainage was performed, and the mean blood pressure was maintained at >90 mmHg in all cases. RESULTS: The median operation time for TEVAR was 94 min (range: 71-421 min) and the mean blood loss was 300 ml (range: 130-1350 ml). No SCI or in-hospital death was observed after TEVAR. Multidetector computed tomography identified three arteries (subclavian artery, external iliac artery and internal iliac artery) providing collateral circulation to spinal segmental arteries (SAs). In all cases, mid-thoracic SAs (Th5-8) and low lumbar SAs (L2-5) were fed by the subclavian artery and the internal iliac artery, respectively. Additionally, low thoracic to high lumbar SAs (Th9-L1) communicated with the subclavian artery via the lateral thoracic wall and/or the external iliac artery via the abdominal wall. CONCLUSIONS: We achieved satisfactory early and mid-term outcomes with hybrid repair for Crawford extent II TAAAs. Furthermore, collateral circulation to SAs was maintained during and after TEVAR regardless of the extent of the aortic repair. PMID- 25691068 TI - Development and validation of a risk score for predicting operative mortality in heart failure patients undergoing surgical ventricular reconstruction. AB - OBJECTIVES: Different risk models have been introduced and refined in the past in order to improve standards of care. However, the predictive power of any risk algorithms can decline over time due to changes in surgical practice and the population's risk profile. The present study aimed to develop and validate a risk model for predicting operative mortality in patients with ischaemic heart failure (HF) undergoing surgical ventricular reconstruction (SVR). METHODS: The study population included 525 patients with previous myocardial infarction and left ventricular remodelling referred to our centre for SVR. All patients underwent surgical reshaping; coronary artery bypass grafting was performed in 489 (93%) patients and mitral valve (MV) repair in 142 (27%). Operative mortality was defined as death within 30 days after surgery. All patients received an operative risk assessment using the logistic EuroSCORE and the ACEF score. RESULTS: Better accuracy was achieved by the ACEF score (0.771) compared with the EuroSCORE (0.747). On multivariable logistic regression analysis, forcing the ACEF score in the model, three additional factors remained as independent predictors of operative mortality: atrial fibrillation, NYHA Class 3-4 and MV surgery (odds ratio 2.2, 2.6 and 2.1, respectively) and were computed in the ACEF-SVR. The ACEF SVR score demonstrated an improved accuracy in respect of the ACEF score (from 0.771 to 0.792) and a better calibration (Hosmer-Lemeshow chi(2) of 5.40, P = 0.714). CONCLUSIONS: The ACEF-SVR score, starting from a simplified model of risk enabled improvement in the accuracy and calibration of the model, tailoring the risk to a specific population of patients with HF undergoing a specific surgical procedure. PMID- 25691069 TI - Design and synthesis of biotin analogues reversibly binding with streptavidin. AB - Two new biotin analogues, biotin carbonate 5 and biotin carbamate 6, have been synthesized. These molecules were designed to reversibly bind with streptavidin by replacing the hydrogen-bond donor NH group(s) of biotin's cyclic urea moiety with oxygen. Biotin carbonate 5 was synthesized from L-arabinose (7), which furnishes the desired stereochemistry at the 3,4-cis-dihydroxy groups, in 11% overall yield (over 10 steps). Synthesis of biotin carbamate 6 was accomplished from L-cysteine-derived chiral aldehyde 33 in 11% overall yield (over 7 steps). Surface plasmon resonance analysis of water-soluble biotin carbonate analogue 46 and biotin carbamate analogue 47 revealed that KD values of these compounds for binding to streptavidin were 6.7*10(-6) M and 1.7*10(-10) M, respectively. These values were remarkably greater than that of biotin (KD =10(-15) M), and thus indicate the importance of the nitrogen atoms for the strong binding between biotin and streptavidin. PMID- 25691070 TI - Genetic association of ARHGAP21 gene variant with mandibular prognathism. AB - Mandibular prognathism (MP) is a recognizable phenotype associated with dentoskeletal class III malocclusion. MP is a complex genetic trait, although familial recurrence also suggests the contribution of single inherited variations. To date, the genetic causes of MP have been investigated using linkage analysis or association studies in pooled families. Here for the first time, next-generation sequencing was used to study a single family with a large number of MP-affected members and to identify MP-related candidate genes. A 6 generation kindred with MP segregating as an autosomal dominant character was recruited. To identify family members affected by MP, a standard cephalometric procedure was used. In 5 MP subjects separated by the largest number of meioses, whole-exome sequencing was performed. Five promising missense gene variants (BMP3, ANXA2, FLNB, HOXA2, and ARHGAP21) associated with MP were selected and genotyped in most other family members. In this family, MP seemed to consist of 2 distinct genetic branches. Interestingly, the Gly1121Ser variant in the ARHGAP21 gene was found to be shared by all MP individuals in the larger branch of the family with nearly complete penetrance. This variant is rare in the Caucasian population (frequency 0.00034) and is predicted as damaging by all bioinformatic algorithms. ARHGAP21 protein strengthens cell-cell adhesions and may be regulated by bone morphogenetic factors, thus influencing mandibular growth. Further studies in both animal models and human patients are required to clarify the significance of this association. PMID- 25691071 TI - The human brain response to dental pain relief. AB - Local anesthesia has made dental treatment more comfortable since 1884, but little is known about associated brain mechanisms. Functional magnetic resonance imaging is a modern neuroimaging tool widely used for investigating human brain activity related to sensory perceptions, including pain. Most brain regions that respond to experimental noxious stimuli have recently been found to react not only to nociception alone, but also to visual, auditory, and other stimuli. Thus, presumed functional attributions have come under scrutiny regarding selective pain processing in the brain. Evidently, innovative approaches are warranted to identify cerebral regions that are nociceptive specific. In this study, we aimed at circumventing known methodological confounders by applying a novel paradigm in 14 volunteers: rather than varying the intensity and thus the salience of painful stimuli, we applied repetitive noxious dental stimuli at constant intensity to the left mandibular canine. During the functional magnetic resonance imaging paradigm, we suppressed the nociceptive barrage by a mental nerve block. Brain activity before and after injection of 4% articaine was compared intraindividually on a group level. Dental pain extinction was observed to correspond to activity reduction in a discrete region of the left posterior insular cortex. These results confirm previous reports demonstrating that direct electrical stimulation of this brain region-but not of others-evokes bodily pain sensations. Hence, our investigation adds further evidence to the notion that the posterior insula plays a unique role in nociceptive processing. PMID- 25691072 TI - Enhanced transport of materials into enamel nanopores via electrokinetic flow. AB - The ability to infiltrate various molecules and resins into dental enamel is highly desirable in dentistry, yet transporting materials into dental enamel is limited by the nanometric scale of their pores. Materials that cannot be infiltrated into enamel by diffusion/capillarity are often considered molecules with sizes above a critical threshold, which are often considered to be larger than the pores of enamel. We challenge this notion by reporting the use of electrokinetic flow to transport solutions with molecules with sizes above a critical threshold-namely, an aqueous solution with a high refractive index (Thoulet's solution) and a curable fluid resin infiltrant (without acid etching) deep into the normal enamel layer. Volume infiltration by Thoulet's solution is increased by 5- to 6-fold, and resin infiltration depths as large as 600 to 2,000 um were achieved, in contrast to ~10 um resulting from diffusion/capillarity. Incubation with demineralization solution for 192 h resulted in significant demineralization at noninfiltrated histologic points but not at resin infiltrated. These results open new avenues for the transport of materials in dental enamel. PMID- 25691073 TI - What research we no longer need in neurodegenerative disease at the end of life: the case of research in dementia. PMID- 25691074 TI - 'Peripheric' pancreatic cysts: performance of CT scan, MRI and endoscopy according to final pathological examination. AB - OBJECTIVE: To assess the accuracy of pre-operative staging in patients with peripheral pancreatic cystic neoplasms (pPCNs). METHODS: From 2005 to 2011, 148 patients underwent a pancreatectomy for pPCNs. The pre-operative examination methods of computed tomography (CT), magnetic resonance imaging (MRI), endoscopic ultrasonography (EUS) were compared for their ability to predict the suggested diagnosis accurately, and the definitive diagnosis was affirmed by pathological examination. RESULTS: A mural nodule was detected in 34 patients (23%): only 1 patient (3%) had an invasive pPCN at the final histological examination. A biopsy was performed in 79 patients (53%) during EUS: in 55 patients (70%), the biopsy could not conclude a diagnosis; the biopsy provided the correct and wrong diagnosis in 19 patients (24%) and 5 patients (6%), respectively. A correct diagnosis was affirmed by CT, EUS and pancreatic MRI in 60 (41%), 103 (74%) and 80 (86%) patients (when comparing EUS and MRI; P = 0.03), respectively. The positive predictive values (PPVs) of CT, EUS and MRI were 70%, 75% and 87%, respectively. CONCLUSIONS: Pancreatic MRI appears to be the most appropriate examination to diagnose pPCNs accurately. EUS alone had a poor PPV. Mural nodules in a PCN should not be considered an indisputable sign of pPCN invasiveness. PMID- 25691075 TI - Is there really a link between benzodiazepine use and the risk of dementia? AB - INTRODUCTION: Several studies have highlighted an increased risk of dementia in benzodiazepine users. As dementia incidence and benzodiazepine use are both high, particularly in the elderly, even a moderate increase in this risk would induce a tremendous number of cases and have a major public health impact. AREAS COVERED: The aim of this article was to systematically review published observational studies having assessed the relation between benzodiazepine use and dementia, to assess and rank their quality and to provide a balanced opinion about the plausibility of a causal relationship. EXPERT OPINION: Out of the ten studies retrieved, nine reported an increased risk of dementia in benzodiazepine users. The risk increased with cumulative dose and treatment duration and when long acting molecules were used. Even if the causal nature of this association remains unproved, the reviewed material provides arguments for evoking a causal link. Further research would be necessary to elucidate the mechanism of this effect, if any, to evaluate the risk of exposure in younger population and the influence of risk factors such as depression. In any case, the body of evidence seems sufficient for avoiding prescriptions or renewals that are not fully justified and indiscriminate long-term use. PMID- 25691076 TI - Differences in the outcomes of anterior versus posterior interbody fusion surgery of the lumbar spine: a propensity score-controlled cohort analysis of 10,941 patients. AB - Few studies have measured outcome differences between the various available spinal fusion techniques. We compare long-term outcomes of anterior versus posterior lumbar interbody fusion. Using the MarketScan database (Truven Health Analytics, Ann Arbor, MI, USA) we selected patients ?18 years old who underwent lumbar fusion surgery from 2000-2009 using either approach. Exclusion criteria included circumferential fusion, and having less than 1 year of preoperative or less than 2 years of postoperative follow-up. Using an inverse probability weighted propensity-score model we compared reoperation and 90 day complication rates, and postoperative health resource utilization of both approaches. A total of 10,941 patients were identified. Of these, 7460 (68.2%) and 3481 (31.8%) underwent posterior and anterior interbody fusion, respectively. Anterior fusion patients had a higher 2 year reoperation rate (odds ratio 1.43, 95% confidence interval [CI]: 1.21-1.70, p<0.0001), although differences became non-significant at maximum follow-up (p=0.0877). The 90 day complication rate was 15.7%, with anterior fusion patients being more likely to experience complications (relative risk 1.24, 95%CI: 1.13-1.36, p<0.0001). Anterior fusion patients also had greater levels of postoperative health utilization, surpassing posterior fusion patients by an average of $US7450 in total charges (95% CI: $4670-$10,220, p<0.0001). As currently practiced in the USA, anterior lumbar surgical approaches may be associated with higher postoperative morbidity and reoperation rates than posterior fusion approaches. PMID- 25691077 TI - Cerebrovascular neurosurgery 2014. AB - Continued advances in our understanding of the management of cerebrovascular disease were made in 2014. A randomized trial for management of unruptured brain arteriovenous malformation (ARUBA) (Mohr et al. Lancet 2014;383:614-21.) and the Scottish intracranial vascular malformation study (Al-Shahi Salman et al. JAMA 2014;311:1661-9) were published and contrasted with reports based on extensive surgical experience. We highlight the results from the simvastatin in aneurysmal subarachnoid hemorrhage study (STASH) (Kirkpatrick et al. Lancet Neurol 2014;13:666-75) which unfortunately did not demonstrate a benefit of simvastatin on outcome in patients with aneurysmal subarachnoid hemorrhage. The 10 year follow-up of the international subarachnoid aneurysm trial (ISAT) (Molyneux et al. Lancet 2014 [E-pub]) and the 3 year follow-up results from the stenting and aggressive medical management for preventing recurrent stroke in intracranial stenosis (SAMMPRIS) (Derdeyn et al. Lancet 2014;383:333-41) were also reported. Results from the Japan adult Moyamoya trial (JAM) (Miyamoto et al. Stroke 2014;45:1415-21) are also briefly reviewed. Furthermore, benefits of familial screening for relatives of intracranial aneurysm and arteriovenous malformation patients, a promising angioscopic experience for endovascular procedures, as well as a modified bypass technique for management of complex aneurysms are outlined. The largest literature series to date for coiling large and giant aneurysms together with the midterm results of the Solitaire stent (ev3, Irvine, CA, USA) aneurysm remodeling study in coiling wide-necked aneurysms (SOLARE) are also presented (Gory et al. Neurosurgery 2014;75:215-9). PMID- 25691078 TI - Evaluation of the current state of distributed watershed nutrient water quality modeling. AB - Watershed models have been widely used for creating the scientific basis for management decisions regarding nonpoint source pollution. In this study, we evaluated the current state of watershed scale, spatially distributed, process based, water quality modeling of nutrient pollution. Beginning from 1992, the year when Beven and Binley published their seminal paper on uncertainty analysis in hydrological modeling, and ending in 2010, we selected 257 scientific publications which (i) employed spatially distributed modeling approaches at a watershed scale; (ii) provided predictions of flow, nutrient/sediment concentrations or loads; and (iii) reported fit to measured data. Most "best practices" (optimization, validation, sensitivity, and uncertainty analysis) are not consistently employed during model development. There are no statistically significant differences in model performance among land uses. Studies which used more than one point in space to evaluate their distributed models had significantly lower median values of the Nash-Sutcliffe Efficiency (0.70 vs 0.56, p<0.005, nonparametric Mann-Whitney test), and r2 (p<0.005). This finding suggests that model calibration only to the basin outlet may mask compensation of positive and negative errors of source and transportation processes. We conclude by advocating a number of new directions for distributed watershed modeling, including in-depth uncertainty analysis and the use of additional information, not necessarily related to model end points, to constrain parameter estimation. PMID- 25691079 TI - Preservation of resin-dentin interfaces treated with benzalkonium chloride adhesive blends. AB - Reducing collagen degradation within hybrid layers may contribute to the preservation of adhesive interfaces. This study evaluated the stability of resin dentin interfaces treated with benzalkonium chloride (BAC)-modified adhesive blends and assessed collagen degradation in dentin matrices treated with BAC. The etch-and-rinse adhesive, Adper Single Bond Plus, modified with 0.5% and 1.0% BAC, was evaluated for microtensile bond strength (MUTBS) and nanoleakage (NL) after 24 h and 1 yr. Thirty completely demineralized dentin beams from human molars were dipped for 60 s in deionized water (DW; control), or in 0.5% or 1.0% BAC, and then incubated in simulated body fluid (SBF). Collagen degradation was assessed by quantification of the dry mass loss and the amount of hydroxyproline (HYP) released from hydrolyzed specimens after 1 or 4 wk. Although all groups demonstrated a significant increase in NL after 1 yr, adhesive modified with 0.5% BAC showed stable bond strength after 1 yr (9% decrease) relative to the control (44% decrease). Significantly less HYP release and dry mass loss were observed for both 0.5% and 1.0% BAC relative to the control. This in vitro study demonstrates that BAC contributes to the preservation of resin-dentin bonds for up to 1 yr by reducing collagen degradation. PMID- 25691080 TI - Metabolic effects of large-volume liposuction for obese healthy women: a meta analysis of fasting insulin levels. PMID- 25691081 TI - Anatomy of the superficial layer of superficial fascia around the nipple-areola complex. AB - BACKGROUND: The periareolar incision is the preferred method for mammaplasty because of the minimal scarring, and suturing of the superficial fascial system (SFS) is useful for avoiding hypertrophic scarring. In this report, we describe the anatomical location of the SFS around the nipple-areolar complex (NAC) and its histological structure. METHODS: To define the location of the SFS, 20 healthy women were assessed by ultrasonography, and sections of the NAC of 10 female cadavers were examined under a light microscope. RESULTS: Ultrasonographic examination of sagittal sections of the breast revealed a hyperdense line immediately beneath the skin, which ran parallel with the skin and turned under the NAC. At the turning point, the line thickened to an average of 3.09 mm. The distance between the nipple and the thickest point of the hyperdense line was 10.14 mm on average. Histological structures of the line were collagen and elastic fibers containing smooth muscles that were connected to the dermis and adipose tissue. At the turning point, nerves, blood vessels, and mammary ducts were irregularly observed in the area of collagen and elastic fibers. These structures were intermingled, and the fiber bundle was very thick. CONCLUSIONS: The thickest area of the turning point is an area of the superficial layer of superficial fascia, which is a key structure around the NAC. The detailed anatomical data shown in our study provide good morphological landmarks for the closure of periareolar incisions. NO LEVEL ASSIGNED: This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors http://www.springer.com/00266. PMID- 25691082 TI - A cadaveric feasibility study of the intraorbital cannula injections of hyaluronidase for initial salvation of the ophthalmic artery occlusion. AB - BACKGROUND: Phthisis bulbi may follow cosmetic filler injections. Early attempts to inject hyaluronidase into the orbit after detection of devastating signs and symptoms may potentially mitigate the complications. METHODS: Cannula routes along the orbital walls were studied. Depths of injections were determined in 30 dry skulls. Deep cannula insertions were carefully performed while avoiding exiting the orbit. Forty-six cadaveric orbits with intravascular latex injection were dissected to determine injection techniques, to verify structures at risk along the routes, and to evaluate substance dispersion. RESULTS: The limited depths of the superior, lateral, medial, and inferior injection routes were 4.2, 3.8, 3.6, and 2.5 cm respectively, while the orbital width was 3.9 cm. The superior parasagittal injection was effective and rarely tears the superior ophthalmic vein, artery, and the optic nerve. The medial injection should be avoided because it may injure the lacrimal sac, the ophthalmic artery, and the optic nerve. Without limited depth, the lateral injection may damage the lacrimal gland and artery and proceeds to damage the optic nerve. The inferior parasagittal injection tends to exit into the infratemporal fossa but the inferior oblique injection may be safer and effective but more complicate with the depth of 4.2 cm. CONCLUSION: The superior parasagittal injection is a recommended simple technique with a minimal chance of vascular injury. The inferior oblique injection requires more skill but it may be safer because of the lower position. For safety reasons, depth of each cannula insertion should not exceed the orbital width. NO LEVEL ASSIGNED: This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern BasicScience, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors http://www.springer.com/00266. PMID- 25691083 TI - Erratum to: A novel flap technique for repairing large lower lip defects. PMID- 25691084 TI - Effect of acupuncture for radioactive-iodine-induced anorexia in thyroid cancer patients: a randomized, double-blinded, sham-controlled pilot study. AB - OBJECTIVE: The aim of this study is to evaluate the efficacy and safety of acupuncture for radioactive iodine (RAI)-induced anorexia in thyroid cancer patients. METHODS: Fourteen thyroid cancer patients with RAI-induced anorexia were randomized to a true acupuncture or sham acupuncture group. Both groups were given 6 true or sham acupuncture treatments in 2 weeks. Outcome measures included the change of the Functional Assessment of Anorexia and Cachexia Treatment (FAACT; Anorexia/Cachexia Subscale [ACS], Functional Assessment of Cancer Therapy General [FACT-G]), Visual Analogue Scale (VAS), weight, body mass index (BMI), ACTH, and cortisol levels. RESULTS: The mean FAACT ACS scores of the true and sham acupuncture groups increased from baseline to exit in intention-to-treat (ITT) and per protocol (PP) analyses; the true acupuncture group showed higher increase but with no statistical significance. Between groups, from baseline to the last treatment, statistically significant differences were found in ITT analysis of the Table of Index (TOI) score (P = .034) and in PP analysis of the TOI (P = .016), FACT-G (P = .045), FAACT (P = .037) scores. There was no significant difference in VAS, weight, BMI, ACTH, and cortisol level changes between groups. CONCLUSION: Although the current study is based on a small sample of participants, our findings support the safety and potential use of acupuncture for RAI-induced anorexia and quality of life in thyroid cancer patients. PMID- 25691085 TI - Metaplastic breast cancer: clinical overview and molecular aberrations for potential targeted therapy. AB - Metaplastic breast cancer is a rare subtype of invasive mammary carcinoma, with an aggressive behavior and usually poor outcome. Responses to systemic chemotherapy are suboptimal compared to patients with standard invasive ductal carcinoma. Limited data are available in regards to best treatment modalities, including chemotherapy. This review gives an overview of metaplastic breast cancer and its clinical and pathologic characteristics, in addition to treatment strategies, clinical trials, and future directions. PMID- 25691086 TI - The neoadjuvant treatment of rectal cancer: a review. AB - Rectal adenocarcinoma is an important cause of cancer-related deaths worldwide, and key anatomic differences between the rectum and the colon have significant implications for management of rectal cancer, especially in the curative setting. For stage II and III rectal cancers, combined chemoradiotherapy offers the lowest rates of local and distant relapse, and is delivered neoadjuvantly to improve tolerability and optimize surgical outcomes, particularly when sphincter-sparing surgery is an endpoint. We review both pivotal trial data that has shaped the current standard of care, fluoropyrimidine-based chemoradiotherapy, while also presenting results from more recent studies, which aim to outperform this standard. Strategies combining 5FU radiotherapy with oxaliplatin, VEGF inhibition, EGFR inhibition, other targeted agents, and/or use of induction chemotherapy hold promise but thus far have failed to improve outcomes in randomized trials. Results of studies such as the ongoing PROSPECT trial may help further define our current therapeutic algorithm for stage II and III rectal cancer. PMID- 25691087 TI - Synergistic protective effects of ceftriaxone and ascorbic acid against subacute deltamethrin-induced nephrotoxicity in rats. AB - Deltamethrin (DLM) is a synthetic class II pyrethroid acaricide and insecticide widely used for veterinary and agricultural purposes. However, its animal and human exposure leads to nephrotoxicity. Our experimental objective was to evaluate protective effects of ceftriaxone and/or ascorbic acid against DLM induced renal injury in male Wistar albino rats. DLM-treated animals revealed significant alterations in serum biochemical parameters related to renal injury; urea, uric acid and creatinine. There was a significant increase in renal lipid peroxidation and a significant inhibition in antioxidant biomarkers. Moreover, DLM significantly reduced serum acetylcholinesterase (AChE) activity. In addition, It induced serum and kidney tumor necrosis factor-alpha (TNF-alpha). Both ceftriaxone and ascorbic acid protect against DLM-induced biochemical alterations in serum and renal tissue when used alone or in combination along with DLM-intoxication. Furthermore, both ceftriaxone and ascorbic acid produced synergetic nephroprotective and antioxidant effects. Therefore, it could be concluded that ceftriaxone and/or ascorbic acid administration able to minimize the toxic effects of DLM through their free radical-scavenging and potent antioxidant activity. PMID- 25691088 TI - The effect of exposure of rats during prenatal period to radiation spreading from mobile phones on renal development. AB - BACKGROUND: The aim of this study was to investigate the effects of exposure to a 900-MHz electromagnetic field (EMF) produced by mobile phones on the renal development of prenatal rats. Histopathological changes and apoptosis in the kidneys, together with levels of urea, creatinine and electrolyte in serum were determined. METHODS: A total of 14 Sprague-Dawley rats were studied. Pregnant rats were divided into two equal groups: a control group and an EMF-exposed group. The study group was exposed to 900-MHz of EMF during the first 20 days of pregnancy, while the control group was unexposed to EMF. Sections obtained from paraffin blocks were stained for caspase-3 by immunohistochemistry, hematoxylin eosin and Masson's trichrome. RESULTS: Mild congestion and tubular defects, and dilatation of Bowman's capsule were observed in the kidney tissues of rats in the exposed group. Apoptosis was evaluated using anti-caspase-3; stronger positive staining was observed in the renal tubular cells in the study group than those of the control group. Although there was a significant difference between the study and control groups in terms of K+ level (p<0.05), no significant difference was observed in the other parameters studied (p>0.05). CONCLUSION: Our study shows that the electromagnetic waves propagated from mobile phones have harmful effects on the renal development of prenatal rats. PMID- 25691089 TI - Aberrant IgG isotype generation in mice with abnormal behaviors. AB - BTBR T+tf/J (BTBR) mice were recently cited as a suitable animal model for the study of autism because of their behavioral characteristics and immunological changes similar to those reported from autistic subjects. The BTBR mouse was reported to have significantly higher levels of serum IgG, brain IgG deposits and anti-brain IgG than highly social C57BL/6 mice, suggesting involvement of aberrant immune responses in the occurrence of autism. Up-regulation of IgG production was investigated here, with a focus on the pattern of IgG isotype distribution compared with that in FVB/NJ (FVB) mice, another highly social control strain. The results indicated that levels of serum IgG1, IgG2b and IgG3 in post-natal day 21 BTBR mice was significantly higher than FVB mice, regardless of sex, resulting in higher IgG1:IgG2a ratios in BTBR mice than in FVB mice (statistical significance in males). A similar outcome regarding the IgG1:IgG2a ratio was observed in culture supernatants of bone marrow cells from these hosts. A presence of brain-reactive IgG in the sera of BTBR was higher than in FVB mice; levels of brain-reactive IgG against whole brain homogenates were higher in BTBR than in FVB mice, with significant differences seen in the striatum and substantia nigra regions. Levels of IgG1 deposited in the cerebellum, cortex, hippocampus or striatum of both BTBR male and female mice were significantly higher than in FVB counterparts. Overall, these results suggest that alterations in IgG isotype production or deposition in the brain could be implicated in the aberrant immune reactivities of BTBR mice. PMID- 25691091 TI - Scaffold materials from glycosylated and PEGylated bovine serum albumin. AB - Bovine serum albumin has been PEGylated and glycosylated to create mimetic materials for the extracellular matrix (ECM) with potential tissue engineering applications. Different surfaces for cell adhesion were achieved by crosslinking the initial albumin product and forming either a coating or a sponge-like three dimensional morphology to mimic the mesh structure of natural ECM. The biocompatibility of the albumin matrix with mammalian cells was evaluated using cell culture assays with NIH 3T3 cells. The results indicated that glycoprotein composition and specific morphology of the assembly can improve the cell growth environment. These ECM mimetic structures might eventually be considered to serve as alternatives for the more expensive collagen and elastin based ECM substances currently in use in tissue engineering. PMID- 25691090 TI - Behavior and emotion modulation deficits in preschoolers at risk for bipolar disorder. AB - BACKGROUND: Bipolar disorder (BD) is highly familial, but studies have yet to examine preschoolers at risk for BD using standardized, developmentally appropriate clinical assessment tools. We used such methods to test whether preschoolers at familial risk for BD have more observed difficulty modulating emotions and behaviors than do low-risk preschoolers. Identification of emotional and behavioral difficulties in at-risk preschoolers is crucial for developing new approaches for early intervention and prevention of BD. METHODS: Using the standardized disruptive behavior diagnostic observation schedule (DB-DOS) protocol for preschoolers, we compared 23 preschoolers (M(age): 4.53 +/- 0.73 years; 18 males) with a first-degree relative with BD to 21 preschoolers (M(age): 4.65 +/- 0.84 years; 11 males) without a family history of BD. We characterized psychopathology in this sample using the Preschool Aged Psychiatric Assessment and behavioral and emotional problems using the Child Behavior Checklist. RESULTS: High-risk preschoolers demonstrated significantly more intense, pervasive, and clinically concerning problems in anger modulation and behavior dysregulation on the DB-DOS than the low-risk group. High-risk relative to low risk preschoolers, were also more likely to have maternal-reported anxiety and oppositional defiant disorders and internalizing and externalizing problems. CONCLUSIONS: Clinically concerning problems in anger modulation and behavior regulation, measured during standardized laboratory observation, differentiate preschoolers at high familial risk for BD from those at low risk. Investigation in a large longitudinal sample is critical for replication and for determining whether these observed behavioral differences can be reliably used as prodromal indicators of mood disorders. PMID- 25691092 TI - Mechanism of siRNA production from repetitive DNA. AB - RNAi is a conserved genome defense mechanism in eukaryotes that protects against deleterious effects of transposons and viral invasion. Repetitive DNA loci are a major source for the production of eukaryotic small RNAs, but how these small RNAs are produced is not clear. Quelling in Neurospora is one of the first known RNAi-related phenomena and is triggered by the presence of multiple copies of transgenes. Here we showed that DNA tandem repeats and double-strand breaks are necessary and, when both are present, sufficient to trigger gene silencing and siRNA production. Introduction of a site-specific double-strand break or DNA fragile site resulted in homologous recombination of repetitive sequences, which is required for gene silencing. In addition to siRNA production, the quelling pathway also maintains tandem repeats by regulating homologous recombination. Our study identified the mechanistic trigger for siRNA production from repetitive DNA and established a role for siRNA in maintaining genome stability. PMID- 25691093 TI - Lithium increases platelet serine-9 phosphorylated GSK-3beta levels in drug-free bipolar disorder during depressive episodes. AB - BACKGROUND: Glycogen synthase kinase-3 beta (GSK3beta) is an intracellular enzyme directly implicated in several neural processes relevant to bipolar disorder (BD) pathophysiology. GSK3beta is also an important target for lithium and antidepressants. When phosphorylated at serine-9, GSK3beta becomes inactive. Few studies evaluated serine-9 phosphorylated GSK3beta (phospho-GSK3beta) levels in BD subjects in vivo and no study has assessed it specifically in bipolar depression. Also, the effect of lithium monotherapy on GSK3beta has never been studied in humans. METHODS: In 27 patients with bipolar depression, total GSK3beta and phospho-GSK3beta were assessed in platelets by enzyme immunometric assay. Subjects were evaluated before and after 6 weeks of lithium treatment at therapeutic levels. Healthy subjects (n = 22) were used as a control group. RESULTS: No differences in phospho-GSK3beta or total GSK3beta were observed when comparing drug-free BD subjects in depression and healthy controls. Baseline HAM D scores were not correlated with phospho-GSK3beta and total GSK3beta levels. From baseline to endpoint, lithium treatment inactivated GSK3beta by significantly increasing phospho-GSK3beta levels (p = 0.010). Clinical improvement (baseline HAM-D - endpoint HAM-D) negatively correlated with the increase in phospho-GSK3beta (p = 0.03). CONCLUSION: The present results show that lithium inactivates platelet GSK3beta in BD during mood episodes. No direct association with pathophysiology of BD was observed. Further studies are needed to clarify the role of GSK3beta as a key biomarker in BD and its association with treatment response as well as the relevance of GSK3beta in other neuropsychiatric disorders and as a new therapeutic target per se. PMID- 25691094 TI - Exceptionally Long MTBE Plumes of the Past Have Greatly Diminished. AB - Studies published in the late 1990s and early 2000s identified the presence of exceptionally long methyl tert-butyl ether (MTBE) plumes (more than 600 m or 2000 feet) in groundwater and have been cited in technical literature as characteristic of MTBE plumes. However, the scientific literature is incomplete in regard to the subsequent behavior and fate of these MTBE plumes over the past decade. To address this gap, this issue paper compiles recent groundwater monitoring records for nine exceptional plumes that were identified in prior studies. These nine sites exhibited maximum historical MTBE groundwater plume lengths ranging from 820 m (2700 feet) to 3200 m (10,500 feet) in length, exceeding the lengths of 99% of MTBE plumes, as characterized in multiple surveys at underground storage tank sites across the United States. Groundwater monitoring data compiled in our review demonstrate that these MTBE plumes have decreased in length over the past decade, with five of the nine plumes exhibiting decreases of 75% or more compared to their historical maximum lengths. MTBE concentrations within these plumes have decreased by 93% to 100%, with two of the nine sites showing significant decreases (98% and 99%) such that the regulatory authority has subsequently designated the site as requiring no further action. PMID- 25691095 TI - Correction: comprehensive genomic profiling of pancreatic acinar cell carcinomas identifies recurrent RAF fusions and frequent inactivation of DNA repair genes. PMID- 25691097 TI - SERS activity of Ag decorated nanodiamond and nano-beta-SiC, diamond-like-carbon and thermally annealed diamond thin film surfaces. AB - In the recent past surface enhanced Raman scattering (SERS) based bio-sensing has gained prominence owing to the simplicity and efficiency of the SERS technique. Dedicated and continuous research efforts have been made to develop SERS substrates that are not only stable, durable and reproducible but also facilitate real-time bio-sensing. In this context diamond, beta-SiC and diamond-like-carbon (DLC) and other related thin films have been promoted as excellent candidates for bio-technological applications including real time bio-sensing. In this work, SERS activities of nanodiamond, nano-beta-SiC, DLC, thermally annealed diamond thin film surfaces were examined. DLC and thermally annealed diamond thin films were found to show SERS activity without any metal nanostructures on their surfaces. The observed SERS activities of the considered surfaces are explained in terms of the electromagnetic enhancement mechanism and charge transfer resonance process. PMID- 25691098 TI - Statistical analysis of the individual variability of 1D protein profiles as a tool in ecology: an application to parasitoid venom. AB - Understanding the forces that shape eco-evolutionary patterns often requires linking phenotypes to genotypes, allowing characterization of these patterns at the molecular level. DNA-based markers are less informative in this aim compared to markers associated with gene expression and, more specifically, with protein quantities. The characterization of eco-evolutionary patterns also usually requires the analysis of large sample sizes to accurately estimate interindividual variability. However, the methods used to characterize and compare protein samples are generally expensive and time-consuming, which constrains the size of the produced data sets to few individuals. We present here a method that estimates the interindividual variability of protein quantities based on a global, semi-automatic analysis of 1D electrophoretic profiles, opening the way to rapid analysis and comparison of hundreds of individuals. The main original features of the method are the in silico normalization of sample protein quantities using pictures of electrophoresis gels at different staining levels, as well as a new method of analysis of electrophoretic profiles based on a median profile. We demonstrate that this method can accurately discriminate between species and between geographically distant or close populations, based on interindividual variation in venom protein profiles from three endoparasitoid wasps of two different genera (Psyttalia concolor, Psyttalia lounsburyi and Leptopilina boulardi). Finally, we discuss the experimental designs that would benefit from the use of this method. PMID- 25691099 TI - Multilocus sequence typing of bifidobacterial strains from infant's faeces and human milk: are bifidobacteria being sustainably shared during breastfeeding? AB - Bifidobacteria are considered to be one of the most important beneficial intestinal bacteria for infants, contributing to the priming of the mucosal immune system. These microbes can also be detected in mother's milk, suggesting a potential role of human milk in the colonisation of infant's gut. However, little is known about the timing of bacteria appearance in human milk, and whether human milk is the first source of inoculation. Here, we investigated whether specific strains are shared sustainably between maternal milk and infant's gut. Faecal samples and human milk were collected from 102 healthy mother-infant pairs (infant's faeces: meconium, 7, 30 days of age; mother's milk: once before delivery, colostrum, 7, 30 days after delivery). Bifidobacterial strains were isolated from these samples, and were discriminated by means of multilocus sequencing typing. No bifidobacteria were detected from human milk collected before delivery, or colostrum. Strains were isolated only from human milk samples obtained 7 days after birth or later. On the other hand, bifidobacterial strains were obtained from infant's faeces throughout the study period, sometimes as early as the first day of life (meconium). We have found that bifidobacterial species belonging to Bifidobacterium bifidum, Bifidobacterium breve, and Bifidobacterium longum subsp. longum could be identified as monophyletic between infant's faeces and their mother's milk. These strains were confirmed to be sustainably shared between maternal milk and infant's gut. Moreover, monophyletic strains were isolated at the same time point or earlier from infant's faeces than from human milk, and none were isolated earlier from human milk than from infant's faeces. Although it remains unclear whether human milk is the first source of microbes for infants, our results confirm that human milk is a reservoir of bifidobacteria, and specific strains are shared between infant's intestine and human milk during breastfeeding. PMID- 25691100 TI - Influence of Lactobacillus brevis 15 and Lactobacillus plantarum 13 on blood glucose and body weight in rats after high-fructose diet. AB - In recent years, many authors have investigated the possible antidiabetic effect of lactic acid bacteria. Lactobacillus species constitute a major part of the lactic acid bacteria group and have been found to exhibit beneficial effects on the development of diabetes and its complications. In the current study, we investigated the effects of newly characterised Bulgarian Lactobacillus strains, Lactobacillus brevis 15 and Lactobacillus plantarum 13, on blood glucose levels and body weight of rats fed a fructose-enriched diet. An experiment was conducted over a period of 8 weeks with 24 2-month-old Wistar rats randomly assigned to receive a standard diet (Con, control group), fructose-enriched diet (Fr group), standard diet with probiotics given twice a week (Pro group), and fructose enriched diet with probiotics given twice a week (Pro+Fr group). At the end of the experimental period, a statistically significant increase in body weight was observed in all experimental groups (P<0.0001). The highest rise was seen in the fructose group (Fr, 169+/-19 g), followed by the Pro+Fr group (153+/-15 g), Pro group (149+/-13 g), and Con group (141+/-5 g). Moreover, the final blood glucose levels had risen significantly in the groups receiving fructose either without (Fr; P<0.0001) or with lactobacilli (Pro+Fr; P=0.002), while the rise was insignificant in the group of rats given probiotic supplementation only (Pro, P=0.071) and inexistent in the Con group (P=0.999). The highest elevation of blood glucose levels was observed in the Fr group (3.18 mmol/l), followed by the Pro+Fr group (2.00 mmol/l) whereas the Pro group showed the lowest levels (0.60 mmol/l). The results of our study suggest that the newly characterised Bulgarian Lactobacillus strains, L. brevis 15 and L. plantarum 13, could be considered as possible probiotics and might be able to prevent some metabolic disturbances. PMID- 25691101 TI - Improving the bowel habits of elderly residents in a nursing home using probiotic fermented milk. AB - Our aim was to determine whether a fermented milk drink containing probiotics could improve the bowel habits of frail elderly individuals living in a nursing home. A total of 135 participants were enrolled in this pilot study. The bowel habits (stool quality and bowel movements) were recorded by nursing staff during a baseline period of 3 weeks. After this period participants received daily a fermented milk drink containing minimally 6.5*10(9) colony forming units of Lactobacillus casei Shirota (LcS) for 6 weeks. During this period, bowel habits were recorded and compared to baseline period. Forty-four participants (74-99 years old) were compliant and used for analysis. Consumption of fermented milk containing LcS significantly increased the percentage of ideal stool types per week (P<0.01), lowered the percentage of constipation stool types per week (P<0.01) and significantly lowered the percentage of diarrhoea stool types per week (P=0.016) as compared to the baseline period. The study product had no significant effect on bowel movements. During the study, no changes in laxative usage or adverse events associated with the study product were reported. Our results suggest that a fermented milk containing LcS significantly improves the bowel habits of frail elderly residents in a nursing home. These promising results should be further substantiated by a confirmatory study. PMID- 25691096 TI - A Large-Scale Analysis of Genetic Variants within Putative miRNA Binding Sites in Prostate Cancer. AB - Prostate cancer is the second most common malignancy among men worldwide. Genome wide association studies have identified 100 risk variants for prostate cancer, which can explain approximately 33% of the familial risk of the disease. We hypothesized that a comprehensive analysis of genetic variations found within the 3' untranslated region of genes predicted to affect miRNA binding (miRSNP) can identify additional prostate cancer risk variants. We investigated the association between 2,169 miRSNPs and prostate cancer risk in a large-scale analysis of 22,301 cases and 22,320 controls of European ancestry from 23 participating studies. Twenty-two miRSNPs were associated (P<2.3*10(-5)) with risk of prostate cancer, 10 of which were within 7 genes previously not mapped by GWAS studies. Further, using miRNA mimics and reporter gene assays, we showed that miR-3162-5p has specific affinity for the KLK3 rs1058205 miRSNP T-allele, whereas miR-370 has greater affinity for the VAMP8 rs1010 miRSNP A-allele, validating their functional role. SIGNIFICANCE: Findings from this large association study suggest that a focus on miRSNPs, including functional evaluation, can identify candidate risk loci below currently accepted statistical levels of genome-wide significance. Studies of miRNAs and their interactions with SNPs could provide further insights into the mechanisms of prostate cancer risk. PMID- 25691102 TI - Production of immune response mediators by HT-29 intestinal cell-lines in the presence of Bifidobacterium-treated infant microbiota. AB - The colonisation and establishment of the intestinal microbiota starts immediately at birth and is essential for the development of the intestine and the immune system. This microbial community gradually increases in number and diversity until the age of two or three years when it becomes a stable ecosystem resembling that of adults. This period constitutes a unique window of opportunity to modulate it through probiotic action, with a potential impact in later health. In the present work we have investigated how putative bifidobacterial probiotics modify the metabolic profiles and immune-modulatory properties of faecal microbiotas. An in vitro pH-controlled single-stage continuous-culture system (CCS) inoculated with infant faeces was employed to characterise the effects of two Bifidobacterium species on the intestinal microbiotas in three children, together with the effects of these modified microbiotas on cytokine production by HT-29 cells. Intestinal bacterial communities, production of short-chain fatty acids and lactate were determined by quantitative PCR and gas chromatography, respectively. Cytokines production by HT-29 cells was measured by ELISA. The combination of CCS with infant faeces and human intestinal cells provided a suitable model to evaluate the specific modulation of the intestinal microbiota and immune system by probiotics. In the CCS, infant faecal microbiotas were influenced by the addition of bifidobacteria, resulting in changes in their ability to induce the production of immune mediators by HT-29 cells. The different metabolic and immunological responses induced by the bifidobacterial species tested indicate the need to assess potential probiotics in model systems including complex intestinal microbiotas. Potential probiotic bifidobacteria can modulate the infant microbiota and its ability to induce the production of mediators of the immune response by intestinal cells. PMID- 25691103 TI - Effect of orally administered soy milk fermented with Lactobacillus plantarum LAB12 and physical exercise on murine immune responses. AB - Probiotics are live microorganisms that confer health benefits through the gastrointestinal microbiota. This nutritional supplement may benefit athletes who undergo rigorous training by maintaining their gastrointestinal functions and overall health. In this study the influence of moderate physical exercise using a graded treadmill exercise, alone or in combination with the consumption of a soy product fermented with Lactobacillus plantarum LAB12 (LAB12), on tumour necrosis factor alpha (TNF-alpha) responses was investigated in a murine model. Male BALB/c mice were randomly divided into four groups of six mice each (control, exercise alone, LAB12 and LAB12 + exercise). Mice treated with the potential probiotic LAB12 were orally gavaged for 42 days. At autopsy, blood and spleen from the animals were collected. The splenocytes were cultured in the presence of a mitogen, concanavalin A (Con A). The amount of TNF-alpha produced by the Con A stimulated splenocytes was quantified using ELISA, while their proliferation was determined using the [(3)H]-thymidine incorporation method. This study shows that LAB12-supplemented and exercise-induced mice showed marked increase (P<0.05) in cell proliferation compared to the control animals. TNF-alpha production was suppressed (P<0.05) in the LAB12 group compared to the untreated mice. These results demonstrate that supplementation with LAB12 has immunomodulatory effects, under conditions of moderate physical exercise, which may have implications for human athletes. Further investigation in human trials is warranted to confirm and extrapolate these findings. PMID- 25691104 TI - Quantification of Blautia wexlerae and Blautia luti in human faeces by real-time PCR using specific primers. AB - The Clostridium coccoides group, including the genus Blautia and other genera, is one of the predominant bacterial groups in the human intestine. We re-examined 266 human faecal clones and 58 isolates in the C. coccoides group isolated by Hayashi et al. (2002) in order to elucidate the detailed distribution of Blautia wexlerae and Blautia luti in human faeces. Subsequently, we designed a primer pair specific for B. wexlerae and B. luti based on the 16S ribosomal RNA (16S rRNA) gene sequence. The number of B. wexlerae and B. luti in faecal samples of 12 healthy Japanese subjects was examined by real-time PCR assay. The number of the C. coccoides group in the 12 faecal samples was also determined using C. coccoides group-specific primers. Re-examination of the human faecal clones and isolates revealed that B. wexlerae and B. luti accounted for 19.5% of the clones and 25.9% of the isolates. B. wexlerae and B. luti were detected in all faecal samples with 5.3+/-3.2*10(9) cells/g faeces (wet weight, average +/- standard deviation) as assessed by real-time PCR. Furthermore, B. wexlerae and B. luti constituted 32.3+/-12.7% (average +/- standard deviation) of the C. coccoides group (1.7+/-0.8*10(10) cells/g faeces). This demonstrates that B. wexlerae and B. luti were presented in human faeces with a high frequency as the dominant bacteria. PMID- 25691105 TI - [Mental health in adolescents in Germany: A comparison with regard to migration background and country of origin]. AB - Many children and adolescents in Germany grow up in families with a migration background. Different cultural, religious, and linguistic backgrounds have an influence on their behavior in various ways. Health status can be affected both negatively and positively by a migration background. The aim of this study was to analyze associations between migration background and self-reported psychological problems. In addition, it was tested whether country of origin had a differential effect on the associations found. Because of its migration-specific approach, the baseline survey (2003-2006) of the nationwide German Health Interview and Examination Survey for Children and Adolescents (KiGGS) offers a solid basis for migrant-specific analyses. Self-reported mental health problems were assessed using the Strengths and Difficulties Questionnaire (SDQ), which was completed by 6,719 adolescents aged 11-17 years. Adolescents with a two-sided migration background (i.e., both parents) reported higher SDQ total difficulties scores compared with adolescents without a migration background (16.9 vs 11.5%) or those with a one-sided migration background (16.9 vs 11.3%). Adolescents with a Turkish background had higher odds (boys: OR 2.0; 95%CI 1.3-3.2; girls: OR 2.0; 95%CI 1.2 3.4) of reporting mental health problems than adolescents without a migration background. Also, girls with a migration background from Western Europe, the USA or Canada had higher odds (OR 2.2; 95%CI 1.3-3.6). In some cases, adjusting for socioeconomic status led to insignificant associations with regard to the country of origin. The findings underline the importance of migrant-specific and culture sensitive prevention, which also takes the environment and culture-specific characteristics into account. PMID- 25691106 TI - Successful implementation of a rural extracorporeal photopheresis program for the treatment of cutaneous T-cell lymphoma and chronic graft-versus-host disease in a rural hospital. AB - OBJECTIVE: Extracorporeal photopheresis (ECP) is currently standard therapy for cutaneous T-cell lymphoma (CTCL) and Graft-versus-host disease (GVHD). Of the many challenges associated with outpatient ECP treatments, commuter travel to capable facilities can fragment and compromise the patient care. In 2008, our hospital implemented an ECP program providing patients to a treatment center over 120 minutes away. This study was undertaken to describe our experience with the establishment of a regional ECP program. METHODS: A retrospective review using a standardized template was performed of patients treated from May 2008 to 2012. The response to treatment was analyzed after a minimum of eight procedures. A partial response to treatment in individuals with CTCL, was more than 50% skin improvement, and GVHD, a reduction in steroid dose by 50%, liver function test improvement or documented improvement in skin findings. RESULTS: Of the 34 patients treated, 11 were for CTCL and 23 for GVHD. 95.8% of the 1,071 planned procedures were successfully. The average procedure time was 186 min for the UVAR XTSTM and 93 min for the CELLEXTM. Patients travelled a median of 65.7 miles (range 4-133 miles). The median duration of therapy was 6 months (range 2-23) for CTCL and 5 months (range 1-27) for GVHD. A clinical benefit was observed in 7 of 11 (63.6%) patients with CTCL and in 15 of 23 (65.2%) with GVHD. CONCLUSION: Our regional ECP program was a viable option in improving access to care for patients requiring treatment for CTCL and chronic GVHD. PMID- 25691107 TI - [Differential diagnosis of elevated liver transaminases in rheumatic diseases]. AB - During laboratory monitoring of patients with rheumatic diseases it is not uncommon to notice elevated liver transaminase levels. From a rheumatological perspective there are multiple causes for this. Liver dysfunction can be the result of certain rheumatological diseases, such as systemic lupus erythematosus. Primary biliary cirrhosis and primary sclerosing cholangitis are associated with rheumatic diseases. On the other hand, hepatological diseases, such as hepatitis C and autoimmune hepatitis show rheumatological symptoms. The most common cause of elevation of liver transaminase levels in rheumatic patients is without doubt the anti-rheumatic therapy. PMID- 25691108 TI - [A 58-year-old patient with temporal headache, jaw claudication and B symptoms]. AB - CASE REPORT: We report the case of a patient with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis with involvement of the temporal artery, presenting with clinical manifestations of giant cell arteritis and temporal arteritis, such as temporal headache, jaw claudication, weight loss, night sweats and increased inflammatory parameters. The ultrasound scan showed a typical halo sign of the temporal artery. DIAGNOSTICS: In the case of further atypical organ symptoms, e.g. hematuria and proteinuria, detailed differential diagnostic investigations are essential to clarify the situation. Histological findings from the affected organs play a decisive role. CONCLUSION: An involvement of the temporal artery due to ANCA-associated vasculitis is extremely rare and may mimic giant cell arteritis. The exact diagnosis of ANCA-associated vasculitis is, however, important because this leads to a different approach concerning therapy and prognosis. PMID- 25691109 TI - Effectiveness of aquatic exercise for treatment of knee osteoarthritis: Systematic review and meta-analysis. AB - OBJECTIVE: This paper presents a systematic review and meta-analysis of the effectiveness of aquatic exercise for treatment of knee osteoarthritis (OA). METHODS: PubMed, the Cochrane Library, Embase, CAMbase, and the Web of Science were screened through to June 2014. Only randomized controlled trials (RCTs) comparing aquatic exercise with control conditions were included. Two authors independently selected trials for inclusion, assessed the included trials, and extracted data. Outcome measures included pain, physical function, joint stiffness, quality of life (QOL), and safety. Pooled outcomes were analyzed using standardized mean difference (SMD). RESULTS: There is a lack of high quality studies in this area. Six RCTs (398 participants) were included. There was moderate evidence for a moderate effect on physical function in favor of aquatic exercise immediately after the intervention, but no evidence for pain or QOL when comparing aquatic exercise with nonexercise. Only one trial reported 3 months of follow-up measurements, which demonstrated limited evidence for pain improvement with aquatic exercise and no evidence for QOL or physical function when comparing aquatic exercise with nonexercise. There was limited evidence for pain improvement with land-based exercise and no evidence for QOL or physical function, when comparing aquatic exercise with land-based exercise according to follow-up measurements. No evidence was found for pain, physical function, stiffness, QOL, or mental health with aquatic exercise immediately after the intervention when comparing aquatic exercise with land-based exercise. Two studies reported aquatic exercise was not associated with serious adverse events. CONCLUSION: Aquatic exercise appears to have considerable short-term benefits compared with land-based exercise and nonexercise in patients with knee OA. Based on these results, aquatic exercise is effective and safe and can be considered as an adjuvant treatment for patients with knee OA. Studies in this area are still too scarce and too short-term to provide further recommendations on how to apply this therapy. PMID- 25691110 TI - Total number of lymph nodes in oncologic resections, is there more to be found? AB - Pathologic staging of oncologic specimens includes the identification of the accurate lymph node status. Retrieving more lymph nodes leads to a more reliable N0 status in the TNM classification. The aim of this prospective study was to evaluate whether more lymph nodes can be retrieved from oncologic resection specimens when more time is invested in the search and if this contributes to a more reliable N-status in the individual patient. A total of 67 gastrointestinal oncologic specimens were reexamined for additional lymph nodes. The mean number of lymph nodes collected in the prospective group was compared against two retrospective groups, one before minima for lymph node counts were set (retrospective group 1) and one after (retrospective group 2). More lymph nodes were dissected per specimen in the prospective group (24.1 lymph nodes), compared to the retrospective group (14.3 lymph nodes, P = <0.001). During the study period, more patients were diagnosed as pN+ compared to the two retrospective groups (62.7 vs. 47.8 % respectively, P = 0.082). Significantly more lymph nodes can be found in oncologic specimens when more time is invested in the search. This will result in more accurate staging of the tumor. PMID- 25691112 TI - Risk for bowel obstruction following laparoscopic and open appendectomy. PMID- 25691111 TI - Is antisecretory therapy after pancreatoduodenectomy necessary? Meta-analysis and contemporary practices of pancreatic surgeons. AB - BACKGROUND: Marginal ulcer (MU) is a well-described complication of pancreatoduodenectomy (PD) whose incidence remains unclear. Gastric antisecretory medications likely attenuate the risk of marginal ulceration after PD; however, the true relationship between antisecretory medication and marginal ulceration after PD is not precisely known. The aims of this study were to document the incidence of MU after PD, identify any relationship between MU and gastric antisecretory medication, and survey current practice of MU prophylaxis among experienced pancreatic surgeons. METHODS: the MEDLINE, EMBASE, Cochrane Central Registrar of Controlled Trials, and Cochrane Database of Systematic Reviews databases were searched from their inception to May 2014 for abstracts documenting ulceration after pancreatoduodenectomy. Two reviewers independently graded abstracts for inclusion in this review. Contemporary practice was assessed through a four-question survey distributed globally to 200 established pancreatic surgeons. RESULTS: After a review of 208 abstracts, 54 studies were graded as relevant. These represented a cohort of 212 patients with marginal ulcer after PD (n = 4794). A meta-analysis of the included references shows mean incidence of ulceration after PD of 2.5% (confidence interval (CI) 1.8-3.2%) with a median time to diagnosis of 15.5 months. Pylorus preservation was associated with a MU rate of 2.0% (CI 1.0-2.9%), while "classic" PD procedures report an overall rate of 2.6% (CI 1.6-3.6%). Documented use of postoperative antisecretory medication was associated with a reduced rate of 1.4% (CI 0.1-1.7%). One hundred forty-four of 200 (72%) surveys were returned, from which it was determined that 92% of pancreatic surgeons have dealt with this complication, and 86% routinely prescribe prophylactic antisecretory medication after PD. CONCLUSIONS: The incidence of MU after PD is 2.5% with a median time to occurrence of 15.5 months postoperatively. Gastric antisecretory medication prescription may affect the incidence of MU. The majority of pancreatic surgeons surveyed have encountered MU after PD; most (86%) routinely prescribe prophylactic gastric antisecretory medication. PMID- 25691113 TI - Appendiceal inflammatory mass. letter to the editor. PMID- 25691114 TI - Implementation of a surgical safety checklist and postoperative outcomes: a prospective randomized controlled study. AB - The implementation of a surgical safety checklist is said to minimize postoperative surgical complications. However, to our knowledge, no randomized controlled study has been done on the influence of checklists on postoperative outcomes in a developing country. We conducted a prospective randomized controlled study with parallel group study design of the implementation of WHO surgical safety checklist involving 700 consecutive patients undergoing operations in our hospital between February 2012 and April 2013. In 350 patients, the checklist was implemented with modifications-the Rc arm. The control group of 350 patients was termed the Rn arm. The checklist was filled in by a surgery resident, and only the participants in the study were blinded. Postoperative wound-related (p = 0.04), abdominal (p = 0.01), and bleeding (p = 0.03) complications were significantly lower in the Rc compared to the Rn group. The number of overall and higher-grade complications (Clavien-Dindo grades 3 and 4) per patient reduced from 0.97 and 0.33 in the Rn arm to 0.80 and 0.23 in the Rc arm, respectively. A significant reduction in mortality was noted in the Rc arm as compared to the Rn arm (p = 0.04). In a subgroup analysis, the number of overall and higher-grade complications per patient with incomplete checklists was higher than that with fully completed checklist group. Implementation of WHO surgical safety checklist results in a reduction in mortality as well as improved postoperative outcomes in a tertiary care hospital in a developing country. PMID- 25691115 TI - Syndioselective coordination polymerization of unmasked polar methoxystyrenes using a pyridenylmethylene fluorenyl yttrium precursor. AB - Unprecedented coordination-insertion polymerizations of polar methoxyl substituted styrene derivatives, in despite of the position of the substituent, have been achieved using a pyridyl methylene fluorenyl yttrium bis(alkyl) precursor with high activity to give polar polystyrenes of high molecular weight and perfect syndiotacticity. PMID- 25691116 TI - Home sleep study for patients with myasthenia gravis. AB - OBJECTIVES: The objective of the study was to examine predictors for sleep disordered breathing (SDB) in patients with myasthenia gravis (MG) using Watch PAT. MATERIALS AND METHODS: We prospectively studied 58 consecutive patients with MG without respiratory symptoms for a full-night Watch-PAT with concomitant recording of the MG score and acetylcholine receptor antibody concentration and analyzed potential risk factors of SDB. RESULTS: Twenty-four patients (41%) had definitive SDB, which was mild in 12 patients, moderate in six, and severe in six. Assessing risk factors with multivariate models, we found four significant predictors (BMI, age, male gender, and use of azathioprine); BMI was the most powerful predictor. The severity and prevalence of sleep-disordered breathing had no significant association with MG score, myasthenia stage, or seropositivity of acetylcholine receptor antibody. CONCLUSIONS: The prevalence of SDB in myasthenic patients with mild and moderate weakness was high when using the Watch-PAT. Both myasthenia-specific factors (use of azathioprine) and general predictors in terms of BMI, age, and male gender predisposed the development of SDB in patients with myasthenia gravis. Careful screening of patients with myasthenia gravis at risk of SDB using Watch-PAT might improve the quality of sleep and cardiovascular health through proper treatment of underlying SDB. PMID- 25691117 TI - Use of minipig skin biopsy model as an innovative tool to design topical formulation to achieve desired pharmacokinetics in humans. AB - In vitro cadaver skin permeation studies are often conducted to characterize the permeation profile of compounds for dermal delivery. However, its utility could be limited in the case of topical products because of lack of reliable prediction of in vivo skin kinetics. In this paper, the use of in vivo skin biopsy data to guide topical formulation development is described. A formulation was developed by compounding MK-0873, a phosphodiesterase 4 (PDE4) inhibitor, into a commercially available cream base. The cream was characterized by skin pharmacokinetic studies in minipigs, which demonstrated that MK-0873 concentrations in the epidermis and dermis were substantially higher than the IC80 for human whole blood PDE4 inhibition of ~200 nM, suggesting that cream should provide sufficient skin exposure to assess clinical efficacy. In toxicological studies, after 1 month repeat application in minipigs minor dermal irritation and minimal systemic exposure were observed. Based on these preclinical data, the cream formulation was chosen for single rising dose clinical studies, where plasma levels of MK-0873 were mostly below the LOQ, whereas skin biopsy concentrations ranged from 6.5 to 25.1 MUM. These data suggested that minipig skin biopsy model can be a valuable tool to assess performance of topical formulations and guide formulation development. PMID- 25691118 TI - Thermal conditions in freezing chambers and prediction of the thermophysiological responses of workers. AB - The present work is dedicated to the assessment of the cold thermal strain of human beings working within freezing chambers. To obtain the present results, both field measurements and a numerical procedure based on a modified version of the Stolwijk thermoregulation model were used. Eighteen freezing chambers were considered. A wide range of physical parameters of the cold stores, the workers clothing insulation, and the working and recovering periods were observed. The combination of these environmental and individual parameters lead to different levels of thermal stress, which were grouped under three categories. Some good practices were observed in the field evaluations, namely situations with appropriate level of clothing protection and limited duration of exposure to cold avoiding unacceptable level of hypothermia. However, the clothing ensembles normally used by the workers do not provide the minimum required insulation, which suggests the possibility of the whole body cooling for levels higher than admissible. The numerical predictions corroborate the main conclusions of the field survey. The results obtained with both methodologies clearly show that, for the low temperature of the freezing chambers, the clothing insulation is insufficient, the exposure periods are too long, and the recovering periods are inadequate. Thus, high levels of physiological strain can indeed be reached by human beings under such working environments. PMID- 25691119 TI - Prediction of cardiovascular risk in rheumatoid arthritis: performance of original and adapted SCORE algorithms. AB - OBJECTIVES: Predictive performance of cardiovascular disease (CVD) risk calculators appears suboptimal in rheumatoid arthritis (RA). A disease-specific CVD risk algorithm may improve CVD risk prediction in RA. The objectives of this study are to adapt the Systematic COronary Risk Evaluation (SCORE) algorithm with determinants of CVD risk in RA and to assess the accuracy of CVD risk prediction calculated with the adapted SCORE algorithm. METHODS: Data from the Nijmegen early RA inception cohort were used. The primary outcome was first CVD events. The SCORE algorithm was recalibrated by reweighing included traditional CVD risk factors and adapted by adding other potential predictors of CVD. Predictive performance of the recalibrated and adapted SCORE algorithms was assessed and the adapted SCORE was externally validated. RESULTS: Of the 1016 included patients with RA, 103 patients experienced a CVD event. Discriminatory ability was comparable across the original, recalibrated and adapted SCORE algorithms. The Hosmer-Lemeshow test results indicated that all three algorithms provided poor model fit (p<0.05) for the Nijmegen and external validation cohort. The adapted SCORE algorithm mainly improves CVD risk estimation in non-event cases and does not show a clear advantage in reclassifying patients with RA who develop CVD (event cases) into more appropriate risk groups. CONCLUSIONS: This study demonstrates for the first time that adaptations of the SCORE algorithm do not provide sufficient improvement in risk prediction of future CVD in RA to serve as an appropriate alternative to the original SCORE. Risk assessment using the original SCORE algorithm may underestimate CVD risk in patients with RA. PMID- 25691120 TI - The incorporation of nanoparticles into conventional glass-ionomer dental restorative cements. AB - Conventional glass-ionomer cements (GICs) are popular restorative materials, but their use is limited by their relatively low mechanical strength. This paper reports an attempt to improve these materials by incorporation of 10 wt% of three different types of nanoparticles, aluminum oxide, zirconium oxide, and titanium dioxide, into two commercial GICs (ChemFil(r) Rock and EQUIATM Fil). The results indicate that the nanoparticles readily dispersed into the cement matrix by hand mixing and reduced the porosity of set cements by filling the empty spaces between the glass particles. Both cements showed no significant difference in compressive strength with added alumina, and ChemFil(r) Rock also showed no significant difference with zirconia. By contrast, ChemFil(r) Rock showed significantly higher compressive strength with added titania, and EQUIATM Fil showed significantly higher compressive strength with both zirconia and titania. Fewer air voids were observed in all nanoparticle-containing cements and this, in turn, reduced the development of cracks within the matrix of the cements. These changes in microstructure provide a likely reason for the observed increases in compressive strength, and overall the addition of nanoparticles appears to be a promising strategy for improving the physical properties of GICs. PMID- 25691121 TI - Responding to the growing demand for practice education: are we building sustainable solutions? PMID- 25691122 TI - Ethical, legal and social issues in restoring genetic identity after forced disappearance and suppression of identity in Argentina. AB - Human genetic identification has been increasingly associated with the preservation, defence and reparation of human rights, in particular the right to genetic identity. The Argentinian military dictatorship of 1976-1983 engaged in a savage repression and egregious violations of human rights, including forced disappearance, torture, assassination and appropriation of children of the disappeared with suppression of their identity. The ethical, legal and social nuances in the use of forensic genetics to support the right to identity in Argentina included issues such as the best interest of children being raised by criminals, the right to learn the truth of one's origin and identity, rights of their biological families, the issue of voluntary versus compulsory testing of victims, as well as the duty of the state to investigate crimes against humanity, punish perpetrators and provide justice and reparation to the victims. In the 30 years following the return to democracy in 1984, the search, localization and DNA testing of disappeared children and young adults has led, so far, to the genetic identification of 116 persons who had been abducted as babies. The high value placed on DNA testing to identify victims of identity suppression did not conflict with the social consensus that personal identity is a complex and dynamic concept, attained by the interaction of genetics with historical, social, emotional, educational, cultural and other important environmental factors. The use of genetic identification as a tool to redress and repair human rights violations is a novel application of human genetics within a developing set of ethical and political circumstances. PMID- 25691123 TI - Inhibition of endogenous heat shock protein 70 attenuates inducible nitric oxide synthase induction via disruption of heat shock protein 70/Na(+) /H(+) exchanger 1-Ca(2+) -calcium-calmodulin-dependent protein kinase II/transforming growth factor beta-activated kinase 1-nuclear factor-kappaB signals in BV-2 microglia. AB - Inducible nitric oxide synthase (iNOS) critically contributes to inflammation and host defense. The inhibition of heat shock protein 70 (Hsp70) prevents iNOS induction in lipopolysaccharide (LPS)-stimulated macrophages. However, the role and mechanism of endogenous Hsp70 in iNOS induction in microglia remains unclear. This study addresses this issue in BV-2 microglia, showing that Hsp70 inhibition or knockdown prevents LPS-induced iNOS protein expression and nitric oxide production. Real-time PCR experiments showed that LPS-induced iNOS mRNA transcription was blocked by Hsp70 inhibition. Further studies revealed that the inhibition of Hsp70 attenuated LPS-stimulated nuclear translocation and phosphorylation of nuclear factor (NF)-kappaB as well as the degradation of inhibitor of kappaB (IkappaB)-alpha and phosphorylation of IkappaB kinase beta (IKKbeta). This prevention effect of Hsp70 inhibition on IKKbeta-NF-kappaB activation was found to be dependent on the Ca(2+) /calcium-calmodulin-dependent protein kinase II (CaMKII)/transforming growth factor beta-activated kinase 1 (TAK1) signals based on the following observations: 1) chelation of intracellular Ca(2+) or inhibition of CaMKII reduced LPS-induced increases in TAK1 phosphorylation and 2) Hsp70 inhibition reduced LPS-induced increases in CaMKII/TAK1 phosphorylation, intracellular pH value, [Ca(2+) ]i , and CaMKII/TAK1 association. Mechanistic studies showed that Hsp70 inhibition disrupted the association between Hsp70 and Na(+) /H(+) exchanger 1 (NHE1), which is an important exchanger responsible for Ca(2+) influx in LPS-stimulated cells. These studies demonstrate that the inhibition of endogenous Hsp70 attenuates the induction of iNOS, which likely occurs through the disruption of NHE1/Hsp70 Ca(2+) -CaMKII/TAK1-NF-kappaB signals in BV-2 microglia, providing further insight into the functions of Hsp70 in the CNS. PMID- 25691124 TI - Synchronous brain activity during cooperative exchange depends on gender of partner: A fNIRS-based hyperscanning study. AB - Previous studies have shown that brain activity between partners is synchronized during cooperative exchange. Whether this neural synchronization depends on the gender of partner (i.e., opposite or same to the participant) is open to be explored. In current study, we used functional near-infrared spectroscopy (fNIRS) based hyperscanning to study cooperation in a two-person game (female-female, female-male, and male-male) while assaying brain-to-brain interactions. Cooperation was greater in male-male pairs than in female-female pairs, with intermediate cooperation levels for female-male pairs. More importantly, in dyads with partners with opposite gender (female-male pairs), we found significant task related cross-brain coherence in frontal regions (i.e., frontopolar cortex, orbitofrontal cortex, and left dorsolateral prefrontal cortex) whereas the cooperation in same gender dyads (female-female pairs and male-male pairs) was not associated with such synchronization. Moreover, the changes of such interbrain coherence across task blocks were significantly correlated with change in degree of cooperation only in mixed-sex dyads. These findings suggested that different neural processes underlie cooperation between mixed-sex and same-sex dyadic interactions. PMID- 25691125 TI - Bifunctional magnetic-fluorescent nanoparticles: synthesis, characterization, and cell imaging. AB - A new type of bifunctional magnetic-fluorescent Fe3O4@SiO2-PDI-PAA/Ca(2+) nanoparticles has been prepared by coating PDI-cored star polymers (PDI-PAA) onto the surface of Fe3O4@SiO2 core-shell nanostructures. The morphology and properties of the composite nanoparticles are investigated by transmission electron microscopy, ultraviolet-visible spectrometry, fluorescence spectrometry, and vibrating sample magnetometry. The composite nanoparticles display a strong red emission and superparamagnetic behavior at room temperature. The cell viability and uptake assays reveal good biocompatibility of these hybrid nanoparticles. Hence, the composite nanoparticles are of potential to be further explored as therapeutic vector in biomedical field. PMID- 25691126 TI - [Infected hip arthroplasty]. PMID- 25691127 TI - Intermediate DNA methylation is a conserved signature of genome regulation. AB - The role of intermediate methylation states in DNA is unclear. Here, to comprehensively identify regions of intermediate methylation and their quantitative relationship with gene activity, we apply integrative and comparative epigenomics to 25 human primary cell and tissue samples. We report 18,452 intermediate methylation regions located near 36% of genes and enriched at enhancers, exons and DNase I hypersensitivity sites. Intermediate methylation regions average 57% methylation, are predominantly allele-independent and are conserved across individuals and between mouse and human, suggesting a conserved function. These regions have an intermediate level of active chromatin marks and their associated genes have intermediate transcriptional activity. Exonic intermediate methylation correlates with exon inclusion at a level between that of fully methylated and unmethylated exons, highlighting gene context-dependent functions. We conclude that intermediate DNA methylation is a conserved signature of gene regulation and exon usage. PMID- 25691128 TI - Productivity Losses Associated with Head and Neck Cancer Using the Human Capital and Friction Cost Approaches. AB - OBJECTIVES: Previous studies suggest that productivity losses associated with head and neck cancer (HNC) are higher than in other cancers. These studies have only assessed a single aspect of productivity loss, such as temporary absenteeism or premature mortality, and have only used the Human Capital Approach (HCA). The Friction Cost Approach (FCA) is increasingly recommended, although has not previously been used to assess lost production from HNC. The aim of this study was to estimate the lost productivity associated with HNC due to different types of absenteeism and premature mortality, using both the HCA and FCA. METHODS: Survey data on employment status were collected from 251 HNC survivors in Ireland and combined with population-level survival estimates and national wage data. The cost of temporary and permanent time off work, reduced working hours and premature mortality using both the HCA and FCA were calculated. RESULTS: Estimated total productivity losses per employed person of working age were EUR253,800 using HCA and EUR6800 using FCA. The main driver of HCA costs was premature mortality (38% of total) while for FCA it was temporary time off (73% of total). CONCLUSIONS: The productivity losses associated with head and neck cancer are substantial, and return to work assistance could form an important part of rehabilitation. Use of both the HCA and FCA approaches allowed different drivers of productivity losses to be identified, due to the different assumptions of the two methods. For future estimates of productivity losses, the use of both approaches may be pragmatic. PMID- 25691129 TI - Videolaryngoscopy versus direct laryngoscopy for tracheal intubation in neonates. AB - BACKGROUND: Establishment of secure airway is a critical part of neonatal resuscitation both in the delivery room and in the neonatal unit. Videolaryngoscopy is a new technique that has the potential to facilitate successful endotracheal intubation and decrease adverse consequences of delay in airway stabilization. Videolaryngoscopy may enhance visualization of the glottis and intubation success in neonates. OBJECTIVES: To determine the efficacy and safety of videolaryngoscopy compared to direct laryngoscopy in decreasing the time and attempts required and increasing the success rate for endotracheal intubation in neonates. SEARCH METHODS: We used the search strategy of the Cochrane Neonatal Review Group. We searched for randomized controlled trials evaluating videolaryngoscopy for neonatal endotracheal intubation in May 2013 in the electronic databases; the Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; EMBASE; CINAHL; abstracts of the Pediatric Academic Societies; websites for registered trials at www.clinicaltrials.gov and www.controlled-trials.com; and in the reference lists of relevant studies. SELECTION CRITERIA: Randomized or quasi-randomized trials in neonates evaluating videolaryngoscopy for endotracheal intubation compared with direct laryngoscopy. DATA COLLECTION AND ANALYSIS: Review authors performed data collection and analysis as recommended by the Cochrane Neonatal Review Group. Two review authors (KL and MP) independently assessed studies identified by the search strategy for inclusion. MAIN RESULTS: Our search strategy performed in May 2013 yielded 7057 references. Two review authors (MP and KL) independently assessed all references for inclusion. We did not find any completed studies for inclusion but identified three ongoing trials and one study awaiting classification. AUTHORS' CONCLUSIONS: There was insufficient evidence to recommend or refute the use of videolaryngoscopy for endotracheal intubation in neonates. Well-designed, adequately powered randomized controlled studies are necessary to address efficacy and safety of videolaryngoscopy for endotracheal intubation in neonates. PMID- 25691131 TI - Pediatric teledermatology: a survey of usage, perspectives, and practice. AB - Pediatric dermatology is one of the smallest subspecialties, and expanding the availability of care is of great interest. Teledermatology has been proposed as a way to expand access and improve care delivery, but no current assessment of pediatric teledermatology exists. The objective of the current study was to assess usage and perspectives on pediatric teledermatology. Surveys were distributed electronically to all 226 board-certified U.S. pediatric dermatologists; 44% (100/226) responded. Nearly all respondents (89%) have experience with teledermatology. Formal teledermatology reimbursement success rates have increased to 35%. Respondents were positive about teledermatology's present and future prospects, and 41% want to use teledermatology more often, although they viewed teledermatology as somewhat inferior to in-person care regarding accuracy of diagnosis and appropriation of management plans. Significant differences were found between formal teledermatology users and nonusers in salary structure, practice environment, sex, and region. Substantial increases in pediatric teledermatology have occurred in the last 5 to 10 years, and there remains cause for optimism for teledermatology's future. Concerns about diagnostic confidence and care quality indicate that teledermatology may be best for care of patients with characteristic clinical presentations or management of patients with established diagnoses. PMID- 25691132 TI - Modeling the diving bradycardia: Toward an "oxygen-conserving breaking point"? AB - PURPOSE: Although it has been demonstrated that the exponential decay model fits the heart rate (HR) kinetics in short static breath holding (BH), this model might be inaccurate when BH is maintained for several minutes. The aim of this study was to build a new meaningful model to quantify HR kinetics during prolonged static BH. METHODS: Nonlinear regression analysis was used to build a model able to quantify the beat-to-beat HR reduction kinetics observed in prolonged static BH performed both in air and in immersed condition by 11 trained breath-hold divers. Dynamic changes in cardiac autonomic regulation through heart rate variability indices [root mean square of successive difference of R-R intervals (RMSSD); short-term fractal scaling exponent: (DFAalpha1)] and peripheral oxygen saturation (SpO2) were also analyzed to strengthen the model. RESULTS: The tri-phasic model showed a sharp exponential drop in HR immediately followed by a slight linear rise up until a breaking point preceding a linear drop in HR. The breaking points had similar level of SpO2 whether in air or in immersed condition (95.1 +/- 2.1 vs. 95.2 +/- 3.0 %, respectively; P = 0.49), and the subsequent linear drop in HR was concomitant with a shift in cardiac autonomic regulation in air (RMSSD: +109.0 +/- 47.8 %; P < 0.001; DFAalpha1: 18.0 +/- 17.4 %; P < 0.05) and in immersion (RMSSD: +112.6 +/- 55.8 %; P < 0.001; DFAalpha1: -26.0 +/- 12 %; P < 0.001). CONCLUSION: In addition to accurately fitting the HR kinetics, the most striking finding is an "oxygen-conserving breaking point" highlighted by the model, which might be interpreted as unique adaptive feature against hypoxic damages in the human diving bradycardia. PMID- 25691133 TI - Production and characterization of a novel long-acting Herceptin-targeted nanobubble contrast agent specific for Her-2-positive breast cancers. AB - BACKGROUND: There is an unmet need for specific and sensitive imaging techniques to assess the efficacy of breast cancer therapy, particularly Her-2-expressing cancers. Ultrasonic microbubbles are being developed for use as diagnostic and therapeutic tools. However, nanobubbles circulate longer, are smaller, and diffuse into extravascular tissue to specifically bind target molecules. Here, we characterize a novel Herceptin-conjugated nanobubble for use against Her-2 expressing tumors. METHODS: Phospholipid-shelled nanobubbles conjugated with Herceptin (NBs-Her) were fabricated using a thin-film hydration method and characterized in vitro in breast cancer cell lines and in vivo in a mouse model. RESULTS: The average size of the unconjugated nanobubbles (NBs-Blank) and NBs-Her was 447.1 +/- 18.4 and 613.0 +/- 25.4 nm, respectively. In cell culture, the NBs Her adhered to Her-2-positive cells significantly better than to Her-2-negative cells (p < 0.05). In vivo, the peak intensity and the half-time to washout of the NBs-Her were significantly greater than those of the NBs-Blank (p < 0.05). In addition, contrast-enhanced ultrasound imaging quality was improved through the use of the NBs-Her. The nanobubbles were able to penetrate into tumor tissue to allow extravascular imaging, but did not penetrate normal skeletal muscle. CONCLUSIONS: The Herceptin-conjugated nanobubble had many properties that made it useful for in vivo imaging, including longer circulation time and better tumor selectivity. This platform may be able to provide targeted delivery of therapeutic drugs or genes. PMID- 25691134 TI - Conduction mechanism of a TaO(x)-based selector and its application in crossbar memory arrays. AB - The conduction mechanism of a Pd/TaOx/Ta/Pd selector device, which exhibits high non-linearity (~10(4)) and excellent uniformity, has been systematically investigated by current-voltage-temperature characterization. The measurement and simulation results indicate two dominant processes of selector current at opposite biases: thermionic emission and tunnel emission. The current-voltage temperature behaviors of the selector can be well explained using the Simmons' trapezoidal energy barrier model. The TaOx-based selective layer was further integrated with a HfO2-based resistive switching layer to form a selector-less resistive random access memory (RRAM) device structure. The integrated device showed a reliable resistive switching behavior with a high non-linearity (~5 * 10(3)) in the low resistance state (LRS), which can effectively mitigate the sneak path current issue in RRAM crossbar arrays. Evaluations of a crossbar array based on these selector-less RRAM cells show less than 4% degradation in read margin for arrays up to 1 Mbit in size. These results highlight the different conduction mechanisms in selector device operation and will provide insight into continued design and optimization of RRAM arrays. PMID- 25691135 TI - Re: Benign and malignant disease of the clivus. A reply. PMID- 25691136 TI - Antecedents of the expectation of remaining in nursing until retirement age. AB - AIMS: To identify job-related resources which strengthen nurses' expectation of remaining in the same job until retirement age. BACKGROUND: The dramatic shortage of qualified nurses in industrialized countries makes it necessary to take steps to retain nurses at work at all career stages. The study introduces to the nursing literature the construct 'expectation of remaining in the same job until retirement age' as an early indicator of attitudes responsible for employees leaving the job prematurely. DESIGN: Longitudinal questionnaire survey. METHODS: In 2010, a longitudinal study was carried out and data were collected from 387 nurses aged 21-63 years. To ensure predictive validity, the dependent variable was assessed again in 2011 after a time lag of 6 months. Data were analysed applying multiple regression analyses. FINDINGS: The expectation of remaining in the same job until retirement age is positively related to work-time control, role clarity and colleague support. Supervisor support exerts an indirect effect via job resources. Vitality partially mediates the relationship between job resources and the expectation of remaining in the same job until retirement age. Most importantly, as hypothesized, the analysed relationships are different for younger (<30 years), middle-aged (30-50 years) and older (>50 years) nurses. CONCLUSION: Our findings suggest that interventions that seek to retain nurses should promote different job resources along the working life span to strengthen nurses' vitality in all age groups. Future research should apply age differentiated measures to unveil work conditions that improve the retention of nurses. PMID- 25691137 TI - Necrotic cell death caused by exposure to graphitic carbon-coated magnetic nanoparticles. AB - We synthesized graphitic carbon-coated magnetic nanoparticles (Fe@C NPs) and evaluated their physicochemical properties and mechanism of cytotoxicity in vitro. The structure of these nanocomposites consisted of an iron core encapsulated by a graphitic-carbon shell. The diameter of these Fe@C NPs was 81 +/- 14 nm, and the thickness of the carbon layer encapsulating the core was 7.0 +/- 0.5 nm. Inhibition of cell proliferation was induced by exposure to Fe@C NPs at doses above 50 MUg mL(-1) . The exposed cells did not show increased activation of apoptosis biomarkers such as PARP, caspase-3, caspase-7, and caspase-9, and apoptosis-specific responses such as DNA laddering and annexin V binding to the cell membranes. In addition, the expression levels of autophagy specific biomarkers such as ATG5 and LC3 after exposure were not enhanced, either. Instead, we observed increased release of lactate dehydrogenase in the culture media and red-fluorescent cell cytosol stained with ethidium homodimer I after the exposure. These results indicated enhanced cell membrane permeability after exposure to Fe@C NPs, probably caused by necrosis. The analysis of the regulatory molecules of cell cycling and proliferation, ERK, p53, and AKT, implied that cell cycle arrest was initiated and the cells were sensitized to necrosis. This necrotic cell death was also observed in carbon shells from Fe@C NPs obtained by removing the metal core. In conclusion, the graphitic carbon encapsulated magnetic nanoparticles synthesized by one-pot synthesis induced necrotic cell death to human HEK293 cells, which was caused by graphitic carbon surface encapsulating the metal core. PMID- 25691138 TI - The effects of central metals on the photophysical and nonlinear optical properties of reduced graphene oxide-metal(II) phthalocyanine hybrids. AB - Reduced graphene oxide-metal(II) phthalocyanine (RGO-MPc, M = Cu, Zn and Pb) hybrid materials have been prepared by the covalent functionalization method. The resultant RGO-MPc hybrids are characterized by scanning electron microscopy, atomic force microscopy, X-ray photoelectron spectroscopy, Fourier transform infrared, ultraviolet-visible absorption and fluorescence spectroscopy. The RGO MPc hybrids exhibit strong fluorescence quenching by means of the photo-induced electron transfer or the energy transfer (PET/ET) process between the RGO and MPc moieties. The PET/ET process particularly depends on the fluorescence quantum yield of MPc molecules with different central metals. The nonlinear optical (NLO) properties of the RGO-MPc hybrids are investigated by using the Z-scan technique at 532 nm with 4 ns laser pulses. The results show that the NLO properties of MPc molecules increase in the order of Zn < Pb < Cu, but the RGO-MPc hybrids exhibit NLO performance in the inverse sequence of Zn > Pb > Cu, implying that the NLO response arising from the efficient PET/ET process between RGO and MPc may play a more important role in the NLO properties of RGO-MPc hybrids than that originating from the MPc moiety. PMID- 25691139 TI - Anti-inflammatory Activity of Magnesium Isoglycyrrhizinate Through Inhibition of Phospholipase A2/Arachidonic Acid Pathway. AB - Glycyrrhiza glabra (licorice) has been known to possess various pharmacological properties including anti-inflammatory, antioxidants, antiviral, and hepatoprotective activities. Magnesium isoglycyrrhizinate (MgIG), a magnesium salt of 18-alpha glycyrrhizic acid stereoisomer, is clinically used for the treatment of inflammatory liver diseases. However, the mechanism by which MgIG exerts its anti-inflammatory effects remains unknown. In the present study, we investigated the inhibitory potential of MgIG in phospholipase A2 (PLA2)/arachidonic acid (AA) pathway and release of the pathway-generated inflammatory lipid mediators in RAW264.7 macrophages. Results revealed that MgIG suppressed LPS-induced activation of PLA2 and production of AA metabolites such as prostaglandin E2 (PGE2), prostacyclin (PGI2), thromboxane 2 (TXB2), and leukotrienes (LTB4) in macrophages. Furthermore, LPS-induced AA-metabolizing enzymes including COX-2, COX-1, 5-LOX, TXB synthase, and PGI2 synthase were significantly inhibited by MgIG. Taken together, our data suggest that modulation of cyclooxygenase (COXs) and 5-lipoxygenase (LOX) pathways in AA metabolism could be a novel mechanism for the anti-inflammatory effects of MgIG. PMID- 25691140 TI - The real challenge for cookstoves and health: more evidence. PMID- 25691141 TI - Ebola economics: the case for an upstream approach to disease emergence. PMID- 25691142 TI - In Liberia, the end of the Ebola epidemic will be the beginning. PMID- 25691143 TI - Optimal excitation and emission wavelengths to analyze amino acids and optimize neurotransmitters quantification using precolumn OPA-derivatization by HPLC. AB - We describe an analytical methodology to obtain high sensitivity and better resolution through the study of fluorometric excitation (lambdaex) and emission (lambdaem) spectrum wavelengths of OPA-amino acids. The spectrum emission study revealed a maximum signal peak at 450 nm for aspartate and glutamine. For glycine, taurine, and GABA, the maximum signal peak was at 448 and for glutamate at 452 nm. The remaining amino acids analyzed showed a maximum emission around 450 nm. The best signal obtained within the spectrum excitation experiments was using 229- to 450-nm lambdaex-lambdaem. The drawbacks observed at these wavelengths were a baseline drift and negative peaks occurrence. Thus, the excitation wavelength of 240 nm was chosen (240- to 450-nm lambdaex-lambdaem) as a compromise between a very good signal response and a baseline stability to resolve the 18 amino acids studied. Furthermore, this protocol was properly validated. On the other hand, the elution gradient program used for neuroactive amino acids (aspartate, glutamate, glycine, taurine and GABA) showed separation to the baseline, in a 15-min run in all of them. Other amino acids, up to 18, also exhibited a very good separation in a 25-min run. In conclusion, we propose the use of 240- to 450-nm lambdaex-lambdaem wavelengths, in OPA-amino acids analysis, as the most suitable protocol to obtain the best signal response, maintaining an optimum chromatographic resolution. PMID- 25691144 TI - Differential regional and cellular distribution of TFF3 peptide in the human brain. AB - TFF3 is a member of the trefoil factor family (TFF) predominantly secreted by mucous epithelia. Minute amounts are also expressed in the immune system and the brain. In the latter, particularly the hypothalamo-pituitary axis has been investigated in detail in the past. Functionally, cerebral TFF3 has been reported to be involved in several processes such as fear, depression, learning and object recognition, and opiate addiction. Furthermore, TFF3 has been linked with neurodegenerative and neuropsychiatric disorders (e.g., Alzheimer's disease, schizophrenia, and alcoholism). Here, using immunohistochemistry, a systematic survey of the TFF3 localization in the adult human brain is presented focusing on extrahypothalamic brain areas. In addition, the distribution of TFF3 in the developing human brain is described. Taken together, neurons were identified as the predominant cell type to express TFF3, but to different extent; TFF3 was particularly enriched in various midbrain and brain stem nuclei. Besides, TFF3 immunostaining staining was observed in oligodendroglia and the choroid plexus epithelium. The wide cerebral distribution should help to explain its multiple effects in the CNS. PMID- 25691145 TI - Dynamic ultrasonography can demonstrate the mechanism of the palmaris profundus in carpal tunnel syndrome. PMID- 25691146 TI - ERRATUM: Corrected Figure Legend: Stroke Genetics: A Review and Update. AB - [This corrects the article on p. 114 in vol. 16, PMID: 25328870.]. PMID- 25691147 TI - Outcomes of benign breast papillomas diagnosed at image-guided vacuum-assisted core needle biopsy. AB - PURPOSE: To determine the upgrade rate of benign papillomas diagnosed at image guided vacuum-assisted core needle biopsy (VACNB) and to compare our results with the summarized literature. MATERIALS AND METHODS: A database search was performed to identify patients older than 18 years of age with benign papillomas diagnosed at VACNB between 2004 and 2013. A total of 199 papillomas in 184 patients were identified. Clinical, imaging, and pathological features for each were analyzed. Patients who were subsequently diagnosed with malignancy at the site of papilloma, either at surgical excision or upon imaging follow-up, were compared with those not upgraded. Upgrade was defined as a diagnosis of invasive carcinoma or ductal carcinoma in situ (DCIS). RESULTS: Of 199 papillomas, 110 (55.3%) were diagnosed at ultrasound-guided VACNB, 78 (39.2%) were diagnosed at stereotactic guided VACNB, and 11 (5.5%) were diagnosed at magnetic resonance imaging-guided VACNB. Surgical excision was performed for 89 (44.7%), and the remaining 110 (55.3%) underwent imaging follow-up. Two patients were subsequently diagnosed with invasive carcinoma and 4 were found with DCIS. The upgrade rate across both groups was 3% (6 of 199). Masses with calcifications (P=.001) and smaller needle gauge at VACNB (P=.02) had a significant association with upgrade. CONCLUSION: Benign papillomas diagnosed with VACNB demonstrated a 3% upgrade rate to malignancy, which is similar to the 2.9% upgrade rate calculated by compiling applicable published literature. Conservative management with imaging follow-up as opposed to surgical excision may be appropriate in cases where an initial diagnosis of benign papilloma is made with VACNB. Benign papillomas associated with calcifications on imaging should be considered for surgical excision given their increased association with malignancy. PMID- 25691148 TI - The social ties that bind: social anxiety and academic achievement across the university years. AB - Given that engagement and integration in university/college are considered key to successful academic achievement, the identifying features of social anxiety, including fear of negative evaluation and distress and avoidance of new or all social situations, may be particularly disadvantageous in the social and evaluative contexts that are integral to university/college life. Thus, the purpose of this study was to examine the direct effects of social anxiety on academic achievement, as well as investigate an indirect mechanism through which social anxiety might impact on academic achievement, namely, the formation of new social ties in university. The participants were 942 (71.7 % female; M = 19 years at Time 1) students enrolled in a mid-sized university in Southern Ontario, Canada. Students completed annual assessments of social anxiety, social ties, and academic achievement for three consecutive years. The results from an autoregressive cross-lag path analysis indicated that social anxiety had a significant and negative direct relationship with academic achievement. Moreover, the negative indirect effect of social anxiety on academic achievement through social ties was significant, as was the opposing direction of effects (i.e., the indirect effect of academic achievement on social anxiety through social ties). These findings highlight the critical role that social ties appear to play in successful academic outcomes and in alleviating the effects of social anxiety during university/college. PMID- 25691149 TI - Visible-near-infrared luminescent lanthanide ternary complexes based on beta diketonate using visible-light excitation. AB - We used the synthesized dinaphthylmethane (Hdnm) ligand whose absorption extends to the visible-light wavelength, to prepare a family of ternary lanthanide complexes, named as [Ln(dnm)3 phen] (Ln = Sm, Nd, Yb, Er, Tm, Pr). The properties of these complexes were investigated by Fourier transform infrared (FT-IR) spectroscopy, diffuse reflectance (DR) spectroscopy, thermogravimetric analyses, and excitation and emission spectroscopy. Generally, excitation with visible light is much more advantageous than UV excitation. Importantly, upon excitation with visible light (401-460 nm), the complexes show characteristic visible (Sm(3+)) as well as near-infrared (Sm(3+), Nd(3+), Yb(3+), Er(3+), Tm(3+), Pr(3+)) luminescence of the corresponding lanthanide ions, attributed to the energy transfer from the ligands to the lanthanide ions, an antenna effect. Now, using these near-infrared luminescent lanthanide complexes, the luminescent spectral region from 800 to 1650 nm, can be covered completely, which is of particular interest for biomedical imaging applications, laser systems, and optical amplification applications. PMID- 25691150 TI - Clinical implications of basic science discoveries: induced pluripotent stem cell therapy in transplantation--a potential role for immunologic tolerance. AB - Induced pluripotent stem cells (iPSCs) hold the potential for future development of genetically identical tissues from almost any mature cell lineage. For clinical applications in cell therapy and transplantation, it may provide a means to one-day restore dysfunctional or damaged tissue without the need for immunosuppression. A recent study by de Almeida et al published in the journal Nature Communications indicates that iPSCs may indeed elicit an immune response that evolves as cells differentiate toward maturity to induce a state of tolerance within a recipient animal. If these early findings hold true, it suggests a possible explanation for self-recognition of mature cells derived from iPSCs for use in future therapeutic interventions in transplantation such as cellular therapy or tissue engineering. PMID- 25691151 TI - PU.1 antisense lncRNA against its mRNA translation promotes adipogenesis in porcine preadipocytes. AB - Antisense long non-coding RNAs (AS lncRNAs) play important roles in refined regulation of animal gene expression. However, their functions and molecular mechanisms for domestic animal adipogenesis are largely unknown. Here, we found a novel AS lncRNA transcribed from the porcine PU.1 gene (also known as SPI1) by strand-specific RT-PCR. Results showed that PU.1 AS lncRNA was expressed and generally lower than the level of PU.1 mRNA in porcine subcutaneous adipose, heart, liver, spleen, lympha, skeletal muscle and kidney tissues. We further found that the levels of PU.1 mRNA and PU.1 protein were significantly lower in subcutaneous and intermuscular adipose than in mesenteric and greater omentum adipose, whereas the levels of PU.1 AS lncRNA showed no difference in porcine adipose tissues from four different parts of the body. During porcine adipogenesis, levels of PU.1 mRNA increased at day 2 and then gradually decreased. Meanwhile, PU.1 AS lncRNA exhibited an expression trend similar to PU.1 mRNA but sharply decreased after day 2. Interestingly, PU.1 protein level rose during differentiation. In addition, at day 6 after differentiation, knockdown of endogenous PU.1 promoted adipogenesis, whereas knockdown of endogenous PU.1 AS lncRNA had the opposite effect. Moreover, peroxisome proliferator-activated receptor gamma (PPARG) and fatty acid synthase (FASN) were significantly upregulated in the PU.1 shRNA treatment group (P < 0.05), whereas they were downregulated in the PU.1 AS shRNA treatment group (P < 0.05). Adipose triglyceride lipase [ATGL; also known as patatin-like phospholipase domain containing 2 (PNPLA2)] and hormone-sensitive lipase [HSL; also known as lipase, hormone-sensitive (LIPE)] contrasted with PPARG and FASN. Finally, the PU.1 mRNA/PU.1 AS lncRNA duplex was detected by an endogenous ribonuclease protection assay combined with RT-PCR. Based on the above results, we suggest that PU.1 AS lncRNA (vs. its mRNA translation) promotes adipogenesis through the formation of a sense-antisense RNA duplex with PU.1 mRNA. PMID- 25691152 TI - Neuropeptide W-Induced Hypophagia is Mediated Through Corticotropin-Releasing Hormone-Containing Neurons. AB - Neuropeptide W (NPW), which was originally isolated from the porcine hypothalamus, has been identified as the endogenous ligand for both the NPBWR1 (GPR7) and NPBWR2 (GPR8) receptors. These receptors, which belong to the orphan G protein-coupled receptor (GPCR) family, share a high sequence homology with the opioid and somatostatin receptor families. NPW and NPBWR1 are widely distributed in the rat central nervous system (CNS). While the intracerebroventricular (i.c.v.) injection of NPW elevates plasma corticosterone levels, the intravenous administration of NPW in conjunction with a corticotropin-releasing hormone (CRH) antagonist blocks NPW-induced corticosterone secretion. It has been reported that NPW is involved in regulating the hypothalamus-pituitary-adrenal cortex (HPA) axis and that i.c.v. administration of NPW decreases feeding behavior. The aim of the present study was to ascertain if NPW's role in feeding regulation is mediated (or not) through corticotropin-releasing hormone (CRH)-containing neurons. We found that NPW-containing axon terminals make synapses with CRH immunoreactive cell bodies and dendritic processes in the hypothalamic paraventricular nucleus (PVN). The central infusion of NPW significantly induced c-Fos expression in CRH-immunoreactive neurons in the mouse PVN, but not in vasopressin- or oxytocin-immunoreactive neurons. To determine if NPW regulates feeding behavior through CRH neurons, the feeding behavior of mice was studied following the i.c.v. administration NPW in the presence or absence of pretreatment with a CRH antagonist. While NPW administration decreased feeding activity, the CRH antagonist inhibited this effect. These results strongly suggest that NPW regulates feeding behavior through CRH neurons in the mouse brain. PMID- 25691153 TI - Thrombin Activity and Thrombin Receptor in Rat Glioblastoma Model: Possible Markers and Targets for Intervention? AB - High-grade gliomas constitute a group of aggressive CNS cancers that have high morbidity and mortality rates. Despite extensive research, current therapeutic approaches enable survival beyond 2 years in rare cases only. Thrombin and its main CNS target, protease-activated receptor-1, have been implicated in tumor progression and brain edema. Our aim was to study protease-activated receptor-1 (PAR-1) protein expression and thrombin-like activity levels in both in vitro and in vivo models of glioblastoma and correlate them with the volume of the surrounding edema. We measured the presence of PAR-1 protein using fluorescence immunohistochemistry and assessed thrombin activity in various glial and non glial cell lines and in a CNS-1 glioma rat model using a thrombin-specific fluorescent assay. Thrombin activity was found to be highly elevated in various high-grade glioma cell lines as well as in non-glial malignant cell lines. In the CNS-1 glioma model, the level of PAR-1 fluorescence in the tumor was significantly elevated compared to adjacent regions of reactive gliosis or distant brain areas. The elevated level of thrombin activity observed in the high grade glioma positively correlated with tumor-induced brain edema. In conclusion, thrombin is secreted from glioma cells and PAR-1 may be a new biological marker for high-grade gliomas. PMID- 25691155 TI - Studying cerebellar dysfunction in neuropathy-related tremor. PMID- 25691154 TI - Targeted inhibition of the deubiquitinating enzymes, USP14 and UCHL5, induces proteotoxic stress and apoptosis in Waldenstrom macroglobulinaemia tumour cells. AB - Deubiquitinase enzymes (DUBs) of the proteasomal 19S regulatory particle are emerging as important therapeutic targets in several malignancies. Here we demonstrate that inhibition of two proteasome-associated DUBs (USP14 and UCHL5) with the small molecule DUB inhibitor b-AP15, results in apoptosis of human Waldenstrom macroglobulinaemia (WM) cell lines and primary patient-derived WM tumour cells. Importantly, b-AP15 produced proteotoxic stress and apoptosis in WM cells that have acquired resistance to the proteasome inhibitor bortezomib. In silico modelling identified protein residues that were critical for the binding of b-AP15 with USP14 or UCHL5 and proteasome enzyme activity assays confirmed that b-AP15 does not affect the proteolytic capabilities of the 20S proteasome beta-subunits. In vitro toxicity from b-AP15 appeared to result from a build-up of ubiquitinated proteins and activation of the endoplasmic reticulum stress response in WM cells, an effect that also disrupted the mitochondria. Focused transcriptome profiling of b-AP15-treated WM cells revealed modulation of several genes regulating cell stress and NF-kappaB signalling, the latter whose protein translocation and downstream target activation was reduced by b-AP15 in vitro. This is the first report to define the effects and underlying mechanisms associated with inhibition of USP14 and UCHL5 DUB activity in WM tumour cells. PMID- 25691156 TI - The Ultrasound pattern sum score - UPSS. A new method to differentiate acute and subacute neuropathies using ultrasound of the peripheral nerves. AB - OBJECTIVE: Ultrasound differentiation of neuropathies is a great challenge. We, therefore, suggest a standardized score to operationalize differentiation between several acute and subacute onset neuropathies. METHOD: We retrospectively analyzed the ultrasound data of 61 patients with acute or subacute neuropathies, e.g. chronic immune-mediated neuropathies, Guillain-Barre syndrome (GBS), and axonal/vasculitic neuropathies. We compared these data to 28 healthy controls. Based on these results an ultrasound pattern sum score (UPSS) with three sub scores (UPS-A for the sensorimotor nerves, UPS-B for the cervical roots and the vagal nerve and UPS-C for the sural nerve) was developed. Afterwards, the applicability of the score was prospectively validated in 10 patients with chronic neuropathies and in 14 patients with unknown acute and subacute PNP before performing additional tests. RESULTS: UPS-A and UPSS were significantly higher in CIDP than in other neuropathies and controls (p<0.001). UPS-B was significantly more often pathologic in GBS than in CIDP and other neuropathies (p<0.001). Using receiver operation characteristics curve analysis boundary values for each score were defined. Positive predictive value (PPV) of these scores for CIDP and GBS was >85%. Vasculitic neuropathies showed an intermediate type of UPSS compared to other axonal neuropathies (p<0.001). In the prospective application the pattern score could be used with good accuracy in several types of neuropathy. CONCLUSION: UPS-A and UPSS operationalize to diagnose acute and subacute-onset CIDP and its variants with high sensitivity, specificity, and PPV. An increased UPS-B with normal UPSS and other sub scores may point to the diagnosis of GBS with high PPV and enables the differentiation from CIDP. SIGNIFICANCE: Using the UPSS and its sub-scores gives a new diagnostic power to the method of the peripheral nerve ultrasound. PMID- 25691157 TI - Arterial thrombosis is accelerated in mice deficient in histidine-rich glycoprotein. AB - Factor (F) XII, a key component of the contact system, triggers clotting via the intrinsic pathway, and is implicated in propagating thrombosis. Although nucleic acids are potent activators, it is unclear how the contact system is regulated to prevent uncontrolled clotting. Previously, we showed that histidine-rich glycoprotein (HRG) binds FXIIa and attenuates its capacity to trigger coagulation. To investigate the role of HRG as a regulator of the intrinsic pathway, we compared RNA- and DNA-induced thrombin generation in plasma from HRG deficient and wild-type mice. Thrombin generation was enhanced in plasma from HRG deficient mice, and accelerated clotting was restored to normal with HRG reconstitution. Although blood loss after tail tip amputation was similar in HRG deficient and wild-type mice, carotid artery occlusion after FeCl3 injury was accelerated in HRG-deficient mice, and HRG administration abrogated this effect. To confirm that HRG modulates the contact system, we used DNase, RNase, and antisense oligonucleotides to characterize the FeCl3 model. Whereas DNase or FVII knockdown had no effect, carotid occlusion was abrogated with RNase or FXII knockdown, confirming that FeCl3-induced thrombosis is triggered by RNA in a FXII dependent fashion. Therefore, in a nucleic acid-driven model, HRG inhibits thrombosis by modulating the intrinsic pathway of coagulation. PMID- 25691158 TI - Regulation of ribosomal RNA synthesis in T cells: requirement for GTP and Ebp1. AB - Mycophenolic acid (MPA) is the active metabolite of mycophenolate mofetil, an effective immunosuppressive drug. Both MPA and mycophenolate mofetil are highly specific inhibitors of guanine nucleotide synthesis and of T-cell activation. However, the mechanism by which guanine nucleotide depletion suppresses T-cell activation is unknown. Depletion of GTP inhibits ribosomal RNA synthesis in T cells by inhibiting transcription initiation factor I (TIF-IA), a GTP-binding protein that recruits RNA polymerase I to the ribosomal DNA promoter. TIF-IA-GTP binds the ErbB3-binding protein 1, and together they enhance the transcription of proliferating cell nuclear antigen (PCNA). GTP binding by TIF-IA and ErbB3 binding protein 1 phosphorylation by protein kinase C delta are both required for optimal PCNA expression. The protein kinase C inhibitor sotrastaurin markedly potentiates the inhibition of ribosomal RNA synthesis, PCNA expression, and T cell activation induced by MPA, suggesting that the combination of the two agents are more highly effective than either alone in inducing immunosuppression. PMID- 25691159 TI - Impaired thymic expression of tissue-restricted antigens licenses the de novo generation of autoreactive CD4+ T cells in acute GVHD. AB - During acute graft-versus-host disease (aGVHD) in mice, autoreactive T cells can be generated de novo in the host thymus implying an impairment in self-tolerance induction. As a possible mechanism, we have previously reported that mature medullary thymic epithelial cells (mTEC(high)) expressing the autoimmune regulator are targets of donor T-cell alloimmunity during aGVHD. A decline in mTEC(high) cell pool size, which purges individual tissue-restricted peripheral self-antigens (TRA) from the total thymic ectopic TRA repertoire, weakens the platform for central tolerance induction. Here we provide evidence in a transgenic mouse system using ovalbumin (OVA) as a model surrogate TRA that the de novo production of OVA-specific CD4(+) T cells during acute GVHD is a direct consequence of impaired thymic ectopic OVA expression in mTEC(high) cells. Our data, therefore, indicate that a functional compromise of the medullary mTEC(high) compartment may link alloimmunity to the development of autoimmunity during chronic GVHD. PMID- 25691160 TI - JMML and RALD (Ras-associated autoimmune leukoproliferative disorder): common genetic etiology yet clinically distinct entities. AB - Ras-associated autoimmune leukoproliferative disorder (RALD) is a chronic, nonmalignant condition that presents with persistent monocytosis and is often associated with leukocytosis, lymphoproliferation, and autoimmune phenomena. RALD has clinical and laboratory features that overlap with those of juvenile myelomonocytic leukemia (JMML) and chronic myelomonocytic leukemia (CMML), including identical somatic mutations in KRAS or NRAS genes noted in peripheral blood mononuclear cells. Long-term follow-up of these patients suggests that RALD has an indolent clinical course whereas JMML is fatal if left untreated. Immunophenotyping peripheral blood from RALD patients shows characteristic circulating activated monocytes and polyclonal CD10(+) B cells. Distinguishing RALD from JMML and CMML has implications for clinical care and prognosis. PMID- 25691161 TI - Stability of ion triplets in ionic liquid/lithium salt solutions: insights from implicit and explicit solvent models and molecular dynamics simulations. AB - Binding energies of ion triplets formed in ionic liquids by Li(+) with two anions have been studied using quantum-chemical calculations with implicit and explicit solvent supplemented by molecular dynamics (MD) simulations. Explicit solvent approach confirms variation of solute-ionic liquid interactions at distances up to 2 nm, resulting from structure of solvation shells induced by electric field of the solute. Binding energies computed in explicit solvent and from the polarizable continuum model approach differ largely, even in sign, but relative values generally agree between these two models. Stabilities of ion triplets obtained in quantum-chemical calculations for some systems disagree with MD results; the discrepancy is attributed to the difference between static optimized geometries used in quantum chemical modeling and dynamic structures of triplets in MD simulations. PMID- 25691162 TI - Meeting the Challenge of NCD: We Cannot Wait. PMID- 25691163 TI - An Evolving Approach to the Global Health Agenda: Countries Will Lead the Way on NCD Prevention and Control. PMID- 25691164 TI - Exploring country-level decision making for the control of chronic diseases: reflections from an institute of medicine workshop. PMID- 25691165 TI - Priority-setting institutions in health: recommendations from a center for global development working group. AB - The rationing problem is common to all health systems-the challenge of managing finite resources to address unlimited demand for services. In most low- and middle-income countries, rationing occurs as an ad hoc, haphazard series of nontransparent choices that reflect the competing interests of governments, donors, and other stakeholders. Yet in a growing number of countries, more explicit processes, with strengths and limitations, are under development that merit better support. Against this background, the purpose of the Center for Global Development Working Group, which is to examine how priorities are set currently, and to propose institutional arrangements that promote country ownership and improve health outcomes by more systematically managing this complex process of politics and economics, is discussed. Current global and national priority-setting practices in low- and middle-income countries, the potential for strengthened national institutions, and increased global support are reviewed. Recommendations for action are provided. PMID- 25691166 TI - Transforming South-South technical support to fight noncommunicable diseases. AB - At the UN High-Level Meeting on non-communicable diseases (NCD) in September 2011, each member state was challenged to create a multisectoral national policy and plan for the prevention and control of non-communicable disease by 2013. Few low-income countries, however, currently have such plans. Their governments are likely to turn for assistance in drafting and implementation to multilateral agencies and Contract Technical Support Organizations recommended by development partners. Yet because many NCD seen in the lowest-income countries differ significantly from those prevalent elsewhere, existing providers of external technical support may lack the necessary experience to support strategic planning for NCD interventions in these settings. This article reviews currently available mechanisms of technical support for health sector planning. It places them in the broader historical context of post- World War II international development assistance and the more recent campaigns for horizontal "South-South" cooperation and aid effectiveness. It proposes bilateral technical assistance by low income countries themselves as the natural evolution of development assistance in health. Such programs, it argues, may be able to improve the quality of technical support to low-income countries for strategic planning in the NCD area while directing resources to the regions where they are most needed. PMID- 25691167 TI - Policy depot: a tool to build global capacity in cardiovascular health policy. PMID- 25691168 TI - Resource needs for addressing noncommunicable disease in low- and middle-income countries: current and future developments. AB - Low and middle income countries are faced with a range of challenges related to providing efficient and affordable health care. With non-communicable diseases (NCD) on the rise, there is a growing need to be able to estimate resource requirements, costs and expected impact associated with various investment strategies related to prevention and control of NCD. In this article, recently developed costing and health impact models for non-communicable disease are reviewed, with a view to drawing out their main findings as well as methodological limitations. A key shortcoming is that earlier modelling efforts have taken a vertical approach to costing, when in reality a more integrated, horizontal approach is needed in order to effectively plan for scaled-up investment and system development. We subsequently describe how the integration of an NCD module into the joint United Nations OneHealth tool will enable low- and middle-income countries to bring NCD into an integrated process for national strategic health planning. PMID- 25691169 TI - Building on the AIDS response to tackle noncommunicable disease. PMID- 25691170 TI - NCD Prevention and Control in Latin America and the Caribbean: A Regional Approach to Policy and Program Development. AB - This article describes efforts from the Pan American Health Organization (PAHO) that have supported progress in country-driven planning and implementing of actions to address noncommunicable diseases (NCD), as well as mechanisms that PAHO has supported for countries in the Americas to share and build on each other's experiences. The Regional Strategy and Plan of Action for NCD, approved by all member states in 2006, is the major frame for this work. The strategy has 4 lines of action: policy and advocacy; surveillance; health promotion and disease prevention; and integrated management of NCD and risk factors. Cross cutting strategies include resource mobilization, communication, training, and networks and partnerships. The strategy is operationalized through biannual work plans for which countries link and commit to achieving specific objectives. PAHO then provides technical support toward achieving these plans, and countries report progress annually. The CARMEN (Collaborative Action for Risk Factor Prevention and Effective Management of NCD [Conjunto de Acciones para la Reduccion y el Manejo de las Enfermedades No transmisibles]) Network provides a major platform for sharing, and the multisector Pan American Forum for Action on NCD has been launched to extend the network to include business and civil society. PAHO also supported civil society capacity building. Almost all member states have made substantial progress in implementing their national chronic disease programs, in most instances reporting exceeding the indicators of the strategic plan related to chronic diseases. From the Caribbean countries, leadership has been provided to achieve the historic UN High-Level Meeting on NCD in September 2011. The region is on track to meet the mortality reduction target set for 2013, though much remains to be done to further increase awareness of and resources for scaling up NCD prevention and control programs, given the huge health and economic burden, increasing costs, and worrying increases of some conditions such as obesity. Major challenges include getting NCD into social protection packages, building the human resource capacity, strengthening surveillance, achieving true intersectoral and multipartner action, given that most determinants of the epidemic lie outside the health sector, and increasing investment in prevention. PMID- 25691171 TI - Non-communicable disease alliance moving forward: follow-up to the United nations high-level meeting. PMID- 25691172 TI - Maintaining polarization in polarimetric multiphoton microscopy. AB - Polarimetric measurements in multiphoton microscopy can reveal information about the local molecular order of a sample. However, the presence of a dichroic through which the excitation beam propagates will generally scramble its polarization. We propose a simple scheme whereby a second properly-oriented compensation dichroic is used to negate any alteration regardless of the wavelength and the initial polarization. We demonstrate how this robust and rapid approach simplifies polarimetric measurements in second-harmonic generation, two photon excited fluorescence and coherent anti-Stokes Raman scattering. Illustration of the polarization maintaining strategy with the compensating dichroic oriented such that its s- and p-axes are interchanged with these of the primary dichroic. PMID- 25691173 TI - 52nd National Conference of Indian Academy of Pediatrics 21-25 January, 2015, New Delhi. PMID- 25691174 TI - Commitment of measles elimination by 2020: challenges in India. AB - The eleven member states of World Health Organization South-East Asia Region committed to eliminate measles by 2020. In phased manner, Government of India is working on this goal, and has introduced two-dose strategy for measles vaccine in the routine immunization. Molecular epidemiology of measles in India has been considerably growing that would be useful for understanding the circulation of wild type measles in pre- and post-elimination period. However, importations of cases from other countries may be likely. This article describes major challenges to achieve the measles elimination goal in India. PMID- 25691175 TI - Fetal growth restriction and cardiovascular health among adolescents. PMID- 25691176 TI - The influence of fetal growth restriction on cardiovascular health among adolescents in Brazil: a retrospective cohort study. AB - OBJECTIVE: To investigate whether fetal growth restriction is associated with changes in cardiovascular risk factors later in life. DESIGN: A retrospective cohort study. SETTING: Tertiary-care hospital serving urban population from the Brazilian Northeast. PARTICIPANTS/PATIENTS: 172 adolescents aged 10-20 years were evaluated for the effects of fetal growth restriction on anthropometric measurements, blood pressure, lipids and fasting glucose and flow-mediated brachial artery dilatation. INTERVENTION: The adolescents' birth weight and their gestational age at birth were used to identify fetal growth restriction according to the 10th percentile and divided between exposed (<10th percentile) and not exposed (>=10th percentile). The Student-t test or the Mann-Whitney test and chi square were used. The significance level was considered to be 0.05. MAIN OUTCOME MEASURE(S): Current Anthropometric, metabolic and endothelial measures of subjects. RESULTS: The majority of the current anthropometric, metabolic and endothelial measures did not differ between groups. The unexposed group had a higher hip circumference (89.1 cm) and higher total cholesterol (196.4mg/dL) than those exposed (85.4 cm, 136.9mg/dL, respectively) (P=0.04). CONCLUSIONS: In the sample studied, no association was found between fetal growth restriction and changes in cardiovascular risk factors in adolescents. PMID- 25691177 TI - Effect of simultaneous administration of oral polio vaccine on local reaction of BCG vaccine in term infants. AB - OBJECTIVE: To study local reaction and to ascertain timing of scar formation in infants after BCG vaccination at birth, with and without simultaneous administration of trivalent OPV. DESIGN: Prospective observational study. SETTING: Teaching hospital in Lucknow, India. PARTICIPANTS: 152 term neonates born in the hospital and given BCG and OPV 0-dose simultaneously before discharge, within 7 days of birth (Group I) , and 122 infants born at home or in private health facility, not given OPV-0 dose, coming for vaccination within 7 days of age (Group 2). INTERVENTION/OBSERVATION: Follow up done at 6 week, 10 week, 14 week and 9 months. Local reaction was recorded at the site of BCG vaccination. RESULTS: Scar formed in <=14 wks in 51.3% and 89.3% babies in Group 1 and Group 2, respectively following BCG vaccination (P<0.001). At 9 months, scar developed in 93.9% infants in Group I and 94.3% babies in Group II. Abortive reaction and non-reactors were similar in both groups (P>0.05). CONCLUSIONS: Simultaneous administration of BCG vaccine with trivalent OPV to term infants in early neonatal period prolongs the time of scar formation but sequence of local reaction is not affected. PMID- 25691178 TI - Predictors of survival in children with methymalonic acidemia with homocystinuria in Beijing, China: a prospective cohort study. AB - OBJECTIVE: (i) To determine whether clinical features and biochemical parameters help to predict survival of methylmalonic acidemia with homocystinuria; (ii) To find the cutoff values of biochemical parameters for predicting survival of methylmalonic acidemia with homocystinuria. DESIGN: A prospective cohort study. SETTING: A pediatric tertiary hospital in Beijing; all patients were followed until death or June 2013. SUBJECTS: 45 pediatric patients diagnosed with methylmalonic acidemia with homocystinuria between 2006 and 2012. OUTCOME MEASURES: The data of clinical characteristics and pretreatment biochemical parameters were collected. The Cox regression analysis was performed to identify independent risk factors for survival of patients with methylmalonic acidemia and homocystinuria. The best cutoff values for these independent factors were determined by the receiver characteristic curve. RESULTS: Newborn onset (OR=6.856, 95%CI=2.241-20.976, P=0.001), high level of methylmalonic acid in urine (OR=1.022, 95%CI=1.011-1.033, P<0.001), and high level of urea in serum (OR=1.083, 95%CI=1.027-1.141, P=0.003) were independent negative risk factors for survival of patients with methylmalonic acidemia and homocystinuria. The cutoff values of maximum predictive accuracy of methylmalonic acid in urine and urea in serum were respectively 5.41 mmol/mmol creatinine and 7.80 mmol/L by receiver operating characteristic curve analysis. CONCLUSIONS: The patients of methylmalonic acidemia with homocystinuria tend to have an adverse outcome if they have newborn onsets. Elevated urea and urinary methylmalonic acid are predictors of adverse outcomes for the patients. They show similar effect for predicting severe adverse prognosis. The combination of methylmalonic acid in urine concentration and urea in serum concentration provided the most accurate predictive tool. PMID- 25691179 TI - Slower rise of exhaled breath temperature in cystic fibrosis. AB - OBJECTIVE: To measure exhaled breath temperature in patients with cystic fibrosis. METHODS: 17 patients (6-18 years) with cystic fibrosis and 15 age- and gender-matched healthy controls were recruited in this cross sectional study. Exhaled breath temperature was measured in subjects recruited in both the groups with a device X-halo and analyzed as plateau temperature achieved and rate of temperature rise. RESULTS: Patients with cystic fibrosis showed no significant difference in plateau temperature [34.4(32.3-34.6) versus 33.9 (33.0-34.4)oC; P=0.35] while mean (SEM.) rate of temperature rise was significantly less in patients [0.09 (0.01) versus 0.14 (0.02) ?oC/s ; P=0.04] as compared to controls. CONCLUSIONS: There was a slower rise of exhaled breath temperature in patients with cystic fibrosis whereas plateau temperature was not significantly different from controls. PMID- 25691180 TI - Safety and efficacy of intravenous colistin in children. AB - OBJECTIVE: To observe the safety and efficacy of Colistimethate sodium in children infected with gram-negative bacteria, susceptible only to colistimethate sodium. METHODS: This prospective observational study done over 2 years observed children who received colistin for >48 h, for renal failure as defined by p-RIFLE criteria. RESULTS: Out of 68 children, 52 (76.5%) survived. There were three children with evidence of acute kidney injury and none had neurotoxicity. Serum creatinine significantly decreased at 48 h and at end of treatment, from that at beginning of therapy (P=0.007). CONCLUSIONS: Colistimethate sodium is effective against carbapenem-resistant Gram-negative bacteria, and is safe in children. PMID- 25691181 TI - Overweight status in Indian children: prevalence and psychosocial correlates. AB - OBJECTIVE: To examine the association between overweight status and psycho-social risk factors in Indian children. METHODS: Data from India's nationally representative Global School-based Student Health Survey were analyzed using SPSS for all participating students (n=8130, 58% males). RESULTS: The likelihood of being overweight was significantly higher for children with fewer friends (OR=1.16, 95%CI=1.13-1.18) or friends who were not kind or helpful, children with symptoms of depression (OR=1.20, 95%CI=1.03-1.39) and anxiety (OR=1.09, 95%CI=1.07-1.15), children with little parental involvement (OR=1.06, 95%CI=1.02 1.10), and children who felt lonely or missed school days without permission. CONCLUSIONS: Psychosocial distress in overweight Indian children warrants comprehensive interventions for screening and treatment of pediatric obesity. PMID- 25691182 TI - Small for gestational age: growth and puberty issues. AB - CONTEXT: Small for gestational age infants have multifold increased risk of growth failure and adulthood disorders. Those who experience rapid catch up growth are at risk of developing metabolic syndrome, whereas those without catch up may end up with short stature. These children are also prone to an altered pubertal development. NEED AND PURPOSE: Scarcity of literature, lack of published guidelines on the follow-up and management plan of children born with small for gestational age. EVIDENCE ACQUISITION: Literature search in PubMed was conducted with regard to epidemiology, growth and puberty, comorbidities, its pathogenesis and management in small for gestational age, with particular relevance for developing countries. An algorithm for follow-up of these children is outlined, based on available empiric data. CONCLUSIONS: Being born small for gestational age predisposes to many metabolic and pubertal disorders. Special emphasis is needed for early detection and management through early surveillance in growth clinics, and regular follow-up to prevent associated comorbidities. PMID- 25691183 TI - The fifth edition of Diagnostic and Statistical Manual of Mental Disorders (DSM 5): what is new for the pediatrician? PMID- 25691184 TI - Immunogenicity and safety of a heptavalent (diphtheria, tetanus, pertussis, hepatitis B, poliomyelitis, Haemophilus influenzae b, and meningococcal serogroup C) vaccine. PMID- 25691187 TI - Preputial calculus in a neurologically-impaired child. AB - BACKGROUND: Preputial calculi are rarely encountered in childhood. CASE CHARACTERISTICS: A 5-year-old boy with symptoms of chronic balanoposthitis. OBSERVATION: A preputial stone was documented and removed at circumcision. OUTCOME: Uneventful postoperative recovery. MESSAGE: In children, association between phimosis and neurologic impairment represent predisposing condition for preputial stone formation. PMID- 25691188 TI - Benign infantile seizures. AB - BACKGROUND: Benign infantile seizures are a common form of idiopathic seizures in infants, but infrequently reported. CASE CHARACTERISTICS: Four cases identified over a 9-month period. OBSERVATION: All had a cluster of focal seizures, normal development and no abnormality on hematological and biochemical work-up. OUTCOME: No recurrence of seizures over a follow-up of 5 to 9 months. MESSAGE: Identification of this syndrome has important therapeutic and prognostic implications. PMID- 25691189 TI - Recurrent Kawasaki disease. AB - BACKGROUND: Recurrent Kawasaki disease is rare. CASE CHARACTERISTICS: An eight month old infant had classic Kawasaki disease with transient coronary artery dilatation. OBSERVATIONS: Recurrence of incomplete Kawasaki disease after two years of initial diagnosis. OUTCOME: The index episode of Kawasaki disease was resistant to single infusion of immunoglobulin, while repeat episode responded within 24 hours of institution of therapy. MESSAGE: Early recognition of recurrent Kawasaki disease requires a high index of suspicion. PMID- 25691190 TI - White matter changes in GM1 gangliosidosis. AB - BACKGROUND: GM1 gangliosidosis is a disorder due to GLB1 gene mutation. CASE CHARACTERISTICS: A 4-yr-old boy with neuroregression and optic atrophy with periventricular hyperintensity on magnetic resonance imaging. OUTCOME: Beta galactosidase enzyme activity was low which was confirmed by GLB1 sequencing. MESSAGE: We highlight the white matter changes in late infantile GM1 gangliosidosis. PMID- 25691191 TI - Incidence and risk factors for retinopathy of prematurity in neonates. AB - We screened 50 neonates fulfilling the inclusion criteria admitted during the study period in a teaching hospital in a north-eastern state of India. Out of 50 neonates screened, 22 (44%) developed retinopathy of prematurity. There was significant association between the birth weight and gestational age of the baby at the time of the delivery with the development of ROP. Multivariate analysis of risk factors for development of ROP using a stepwise method, after controlling for various potential confounders, showed that apnea was a significant risk factor for the development of retinopathy of prematurity. PMID- 25691192 TI - Bacteriological profile of neonatal sepsis in a tertiary-care hospital of Northern India. AB - With an objective to study the bacteriological profile of neonatal sepsis a retrospective study was conducted in the neonatal unit of a referral teaching hospital in Northern India. Among neonates born over 5-year period (n=22363) incidence of culture-positive sepsis was 7.5/1000 live births (7.5%). Staphylococcus aureus (47.3%), Klebsiella pneumonia (14.9%) and Acinetobacter (14.9%) were most common organisms isolated. Sensitivity pattern of isolated organisms is presented. PMID- 25691193 TI - Unique injury due to reuse of CPAP cannula. PMID- 25691194 TI - Bilateral parotid swelling after viper envenomation: an ominous sign? PMID- 25691195 TI - Esophageal stricture following retained foreign body in a child. PMID- 25691196 TI - Pamidronate for long-term control of hypercalcemia associated with Williams syndrome. PMID- 25691197 TI - Branding - a harmful practice. PMID- 25691198 TI - Severe anaphylaxis to egg at two months of age. PMID- 25691199 TI - Isolated pontine tuberculoma presenting as horizontal gaze palsy. PMID- 25691200 TI - Off-label drug use in neonatal intensive care unit. PMID- 25691201 TI - Off-label drug use: author's reply. PMID- 25691202 TI - Bronchoscopic removal of unusual foreign body through tracheostomy. PMID- 25691203 TI - Outbreaks of rubella indicate epidemiological shift in age. PMID- 25691204 TI - Klebsiella brain abscess in an infant with hereditary spherocytosis. PMID- 25691205 TI - Angiokeratoma corporis diffusum. PMID- 25691206 TI - Lymphangioma of tongue. PMID- 25691207 TI - Peutz Jegher syndrome. PMID- 25691208 TI - Cutaneous larva migrans. PMID- 25691209 TI - An exploration of how young people and parents use online support in the context of living with cystic fibrosis. AB - BACKGROUND: There is increasing recognition of the Internet's potential role in providing information and support for people living with long-term conditions. However, how young people and parents use online forms of self-care support in the context of living with childhood chronic illness has been under-researched. OBJECTIVE: To explore how online peer support is used by young people and parents to support self-care in relation to cystic fibrosis (CF). SETTING AND PARTICIPANTS: Online forum for young people and parents based on a CF charity website. A total of 279 individuals participated in the forum during the study. DESIGN: An online ethnographical approach, involving observing, downloading and analysing discussion group postings. All postings made over a random 4-month period were included (151 discussion threads). RESULTS: The online setting enabled a physically disconnected group to connect and create a safe space to collectively share experiences and receive support to manage and live with cystic fibrosis. Participants exchanged experientially derived advice and views on how to manage treatments, emotions, relationships, identity and support from services. While parents sought information and support on managing specific therapies/services and ways of maintaining their child's health, the information and support young people desired appeared to be more directed at how to 'fit' CF into their everyday lives. DISCUSSION AND CONCLUSIONS: Online support groups appear to supplement professional support in relation to self-management. They enable young people and parents to share experiences, feelings and strategies for living with long-term conditions with peers and develop the expertise to empower them in interactions with health-care professionals. PMID- 25691210 TI - Cyclopentitol as a scaffold for a natural product-like compound library for drug discovery. AB - A concise and efficient synthesis of cyclopentitols as a scaffold for a two dimensional compound library for drug discovery is described. Starting from d mannose, the key steps are Wittig olefination and ring-closing metathesis (RCM) followed by a [3,3]-sigmatropic Overmann rearrangement to form an sp(3)-rich, natural product-like scaffold from which a focused compound library with different functionalities is prepared. PMID- 25691211 TI - Improved radiosynthesis and preliminary in vivo evaluation of a (18)F-labeled glycopeptide-peptoid hybrid for PET imaging of neurotensin receptor 2. AB - The neurotensin receptor 2 (NTS2) is an attractive target for cancer imaging, as it is overexpressed in a variety of tumor types including prostate, pancreas and breast carcinoma. The aim of this study was the development of the first NTS2 subtype selective (18)F-labeled radioligand for imaging NTS2 expression in vivo by positron emission tomography (PET). The radiosynthesis of glycopeptoid (18)F-4 was realized by copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC), applying the prosthetic group 6-deoxy-6-[(18)F]fluoroglucosyl azide for (18)F fluoroglycosylation of the alkyne-terminated NT(8-13) analog Pra-N-Me-Arg-Arg-Pro N-homo-Tyr-Ile-Leu-OH. The binding affinity of the peptide-peptoid 4 for NTS2 was 7nM with excellent subtype selectivity over NTS1 (260-fold). In vitro autoradiography studies of rat brain slices confirmed the high selectivity of (18)F-4 for NTS2. Biodistribution experiments using HT29 and PC3 tumor-bearing nude mice revealed high renal and only moderate tumor uptake, while PET imaging experiments revealed specific binding of (18)F-4 in NTS2-positive tumors. As (18)F-4 displayed high stability in vitro but fast degradation in vivo, future work will focus on the development of metabolically more stable NT(8-13) analogs. PMID- 25691212 TI - Scandium and yttrium phosphasalen complexes as initiators for ring-opening polymerization of cyclic esters. AB - The synthesis and characterization of novel scandium and yttrium phosphasalen complexes is reported, where phosphasalen refers to two different bis(iminophosphorane) derivatives of the more ubiquitous salen ligands. The activity of the complexes as initiators for the ring-opening polymerization of cyclic esters is presented. The scandium complexes are inactive for lactide polymerization but slow and controlled initiators for epsilon-caprolactone polymerization. The lack of activity toward lactide exhibited by these compounds is probed, and a rare example of single-monomer insertion product, unable to undergo further reactions with lactide, is identified. In contrast, the analogous yttrium phosphasalen complex is a very active initiator for the ring-opening polymerization of rac-lactide (kobs = 1.5 * 10(-3) s(-1) at 1:500 [yttrium initiator]:[rac-lactide], 1 M overall concentration of lactide in THF at 298 K). In addition to being a very fast initiator, the yttrium complex also maintains excellent levels of polymerization control and a high degree of isoselectivity, with the probability of isotactic enchainment being Pi = 0.78 at 298 K. PMID- 25691213 TI - Editorial Comment to Therapeutic outcomes of neoadjuvant and concurrent androgen deprivation therapy and intensity-modulated radiation therapy with gold marker implantation for intermediate and high-risk prostate cancer. PMID- 25691214 TI - Limited surgery for benign tumours of the pancreas: a systematic review. AB - BACKGROUND: Limited surgical procedures for benign cystic neoplasms and endocrine tumours of the pancreas have the potential advantage of pancreatic tissue sparing compared to standard oncological resections. METHODS: Searching PubMed/MedLine, Embase and Cochrane Library identified 86 full papers: 25 reporting on enucleation (EN), 38 on central pancreatectomy (CP) and 23 on duodenum-preserving total/partial pancreatic head resection (DPPHRt/p). The results are based on analysis of data of 838, 912 and 431 patients for EN, CP and DPPHRt/s, respectively. RESULTS: The indication for EN for cystic neoplasms and neuro endocrine tumours to EN was 20.5 and 73 %; for CP 62.9 and 31 %; and for DPPHRt/p 69.6 and 10.2%, respectively. The estimated mean tumour sizes were in EN-group 2.4 cm, in CP-group 2.9 cm and in DPPHRt/p-group 3.1 cm (DPPHRt/p vs EN, p = 0.035). Postoperative severe complications developed after EN, CP and DPPHRt/p in 9.6, 16.8 and 11.5% of patients; pancreatic fistula in 36.7, 35.2 and 20.1%; and reoperation was required in 4.7, 6.5 and 1.8 %, respectively. Hospital mortality after EN was 0.95 %; after CP 0.72%; and after DPPHRt/p 0.49%. Compared to EN and CP, DPPHRt/p exhibited significant lower frequency of reoperation (p = 0.029, p < 0.001) and lower rate of fistula (p < 0.001; p = 0.001). CONCLUSION: EN, CP and DPPHRt/p applied for benign tumours are associated with low surgery-related early postoperative morbidity, a very low hospital mortality and the advantages of conservation of pancreatic functions. However, the level of evidence for EN and CP compared to standard oncological resections appears presently low. There is a high level of evidence from prospective controlled trials regarding the significant maintenance of exocrine and endocrine pancreatic functions after DPPHRt/p compared to pancreato-duodenectomy. PMID- 25691215 TI - Reducing healthcare costs facilitated by surgical auditing: a systematic review. AB - BACKGROUND: Surgical auditing has been developed in order to benchmark and to facilitate quality improvement. The aim of this review is to determine if auditing combined with systematic feedback of information on process and outcomes of care results in lower costs of surgical care. METHOD: A systematic search of published literature before 21-08-2013 was conducted in Pubmed, Embase, Web of Science, and Cochrane Library. Articles were selected if they met the inclusion criteria of describing a surgical audit with cost-evaluation. RESULTS: The systematic search resulted in 3608 papers. Six studies were identified as relevant, all showing a positive effect of surgical auditing on quality of healthcare and therefore cost savings was reported. Cost reductions ranging from $16 to $356 per patient were seen in audits evaluating general or vascular procedures. The highest potential cost reduction was described in a colorectal surgical audit (up to $1,986 per patient). CONCLUSIONS: All six identified articles in this review describe a reduction in complications and thereby a reduction in costs due to surgical auditing. Surgical auditing may be of greater value when high-risk procedures are evaluated, since prevention of adverse events in these procedures might be of greater clinical and therefore of greater financial impact. IMPLICATION OF KEY FINDINGS: This systematic review shows that surgical auditing can function as a quality instrument and therefore as a tool to reduce costs. Since evidence is scarce so far, further studies should be performed to investigate if surgical auditing has positive effects to turn the rising healthcare costs around. In the future, incorporating (actual) cost analyses and patient-related outcome measures would increase the audits' value and provide a complete overview of the value of healthcare. PMID- 25691216 TI - An alternative technique for harvesting marginal liver grafts with a replaced or accessory right hepatic artery. AB - The presence of a replaced or accessory right hepatic artery (R/A RHA) originating from the superior mesenteric artery represents one of the most common anatomical vascular variants of the hepatic artery and comprises the most frequently injured vessels during liver harvesting. Vascular arterial injuries following liver procurement are associated with decreased patient and graft survival and higher retransplantation rates. We describe an alternative technique for harvesting marginal liver grafts with replaced or accessory right hepatic arteries in the absence of pancreatic procurement. The entire procedure is divided and schematically described in six steps for didactical purposes. This technique has been used in 72 liver harvests over a three-year period with no R/A RHA injury. The technical advantages and limitations of this alternative method are discussed. PMID- 25691217 TI - 4-1BBL signaling promotes cell proliferation through reprogramming of glucose metabolism in monocytes/macrophages. AB - Obesity-induced monocyte/macrophage proliferation and activation play a crucial role in various chronic inflammatory metabolic disorders, such as insulin resistance, diabetes mellitus, and atherosclerosis. 4-1BBL, a member of the tumor necrosis factor superfamily expressed on monocytes/macrophages, provides inflammatory signals to modulate their proliferation, survival, and cytokine release. Previously, we demonstrated that 4-1BBL signaling promotes adipose inflammation through enhancement of macrophage activation. Here, we show that 4 1BBL stimulation on monocytes/macrophages enhanced reprogramming of glucose metabolism in the cells, and that this was accompanied by cell proliferation. 4 1BBL stimulation on macrophages increased glucose uptake, transcript/protein levels of glucose transporter 1 and glycolytic enzymes, and lactate production. It also enhanced transcript levels of genes involved in the pentose phosphate pathway and lipogenesis. The 4-1BBL-induced metabolic reprogramming was mediated by AKT-mammalian target of rapamycin signaling. The effect of 4-1BBL-induced macrophage proliferation was completely abolished by 2-deoxyglucose, a glycolytic inhibitor. These findings suggest that 4-1BBL signaling promotes cell proliferation through reprogramming of glucose metabolism in monocytes/macrophages to support their energy demands and biomass production. The 4-1BBL signaling pathway may be a valid target for controlling macrophage mediated chronic inflammation in obesity and metabolic diseases. PMID- 25691218 TI - Bone is Not Alone: the Effects of Skeletal Muscle Dysfunction in Chronic Kidney Disease. AB - Chronic kidney disease (CKD) is associated with a decline in muscle mass, strength, and function, collectively called "sarcopenia." Sarcopenia is associated with hospitalizations and mortality in CKD and is therefore important to understand and characterize. While the focus of skeletal health in CKD has traditionally focused on bone and mineral aberrations, it is now recognized that sarcopenia must also play a role in poor musculoskeletal health in this population. In this paper, we present an overview of skeletal muscle changes in CKD, including defects in skeletal muscle catabolism and anabolism in uremic tissue. There are many gaps in knowledge in this field that should be the focus for future research to unravel pathogenesis and therapies for musculoskeletal health in CKD. PMID- 25691219 TI - Sclerostin and CKD-MBD. AB - Declining kidney function is associated with sequential systemic changes in mineral homeostasis leading to pathologic alterations in the cardiovascular system and the skeleton. One of the earliest changes in response to renal injury is the increased osteocyte production of secreted factors including the anti anabolic protein, sclerostin. Elevated sclerostin is associated with reduced Wnt/beta-catenin signaling in bone and decreased osteoblast differentiation/activity. Agents that directly or indirectly inhibit beta-catenin signaling have differential skeletal effects suggesting additional mechanisms contribute to the diversity of renal osteodystrophies. Similarly, Wnt/beta catenin activation in smooth muscle cells contributes to cardiovascular calcification yet emerging data suggests that this pathway may also be protective when elevated in neighboring tissues. The ongoing epidemiology studies examining the relationship between circulating sclerostin and cardiovascular disease, particularly those that investigate stage specific and/or patient sub populations, will be useful in understanding the overall contributions of this pathway, its antagonist sclerostin, and the progression of CKD-MBD. PMID- 25691220 TI - Family Caregivers Define and Manage the Nursing Home Placement Process. AB - The nursing home placement process is complex and difficult for family caregivers. This qualitative descriptive study examines the experiences of caregivers involved in the management of care and placement of an older family member using the Family Management Style Framework. Ten caregivers were recruited from four nursing homes in the Midwest. The caregivers were interviewed shortly after placement and again 3 months post-placement. Results provide a unique understanding of care management and the nursing home placement process from the perspective of the primary family caregiver. Overall, there were similarities across the same types of caregiving dyads, for example, spousal and adult children caregivers. Caregivers expressed the need to maintain the identity of their older family member, a familial responsibility for caregiving, and change in their family relationship over time. Appreciating caregivers' challenges and needs gives health care professionals a better understanding for how to provide assistance for a smoother nursing home transition. PMID- 25691221 TI - Effect of unilateral and bilateral use of laterally wedged insoles with arch supports on impact loading in medial knee osteoarthritis. AB - BACKGROUND: Increased impact loading is implicated in knee osteoarthritis development and progression. OBJECTIVES: This study examined the impact ground reaction force (GRF) peak, its loading rate, its relative timing to stance phase timing, and walking speed during unilateral and bilateral use of laterally wedged insoles with arch supports. STUDY DESIGN: Within-subject design. METHODS: Thirty three female patients with medial knee osteoarthritis were examined with (unilateral 6 degrees and 11 degrees , and bilateral 0 degrees , 6 degrees , and 11 degrees ) and without insole use. RESULTS: Repeated measures MANOVA revealed that the impact force increased significantly in bilateral 11 degrees versus unilateral 6 degrees and without-insole conditions. The loading rate decreased significantly in unilateral 11 degrees versus bilateral 6 degrees insoles. The relative timing increased significantly in each of bilateral 6 degrees , bilateral 11 degrees , and unilateral 11 degrees versus bilateral 0 degrees insoles and in each of bilateral 11 degrees and unilateral 11 degrees versus without-insole condition. There were significant positive correlations between the walking speed and each of the force and loading rate. The Chi-square test revealed insignificant association between the insole condition and the presence of impact forces. CONCLUSION: Unilateral 11 degrees insoles are capable of reducing impact loading possibly through increasing foot pronation. Walking slowly is another possible strategy to reduce loading. CLINICAL RELEVANCE: Unilaterally applied 11 degrees laterally wedged insoles are capable of reducing and delaying the initial impact ground reaction forces and reducing their loading rates during walking in patients with medial knee osteoarthritis, thus reducing osteoarthritis progression. Walking slowly could also be used as a strategy to reduce impact loading. PMID- 25691222 TI - Psychosocial correlates of depression following spinal injury: A systematic review. AB - OBJECTIVES: Spinal cord injury (SCI) studies have identified a range of psychosocial risk and protective factors for depression post-injury. This study presents the first systematic and quantitative review of this body of research. METHODS: Twenty-four studies (N=3172 participants) were identified through electronic database searches. Studies were evaluated according to recommended guidelines on Strengthening the Reporting of Observational Studies in Epidemiology (STROBE). The significance and magnitude of the relationships between standardised measures of depression and psychosocial outcome were examined using Pearson's effect size r, 95% confidence intervals and fail-safe Ns. Effect sizes were categorised according to the ICF psychosocial domains. RESULTS: STROBE ratings indicated discrepancies in procedural detail and statistical analyses. Individual personal variables including affective feelings, and thoughts and beliefs specific to SCI demonstrated the strongest relationship with depression self-ratings. Life satisfaction, disability acceptance, environmental supports and community participation had a medium to strong association, helping to reduce vulnerability to depression. Longitudinal studies revealed that symptoms of depression continued to impact on psychosocial outcome up to 10 years post-injury, although this was based on limited data. CONCLUSIONS: Assessment of psychosocial factors in the acute stages of SCI rehabilitation can inform evidence-based interventions to treat and manage depressive symptomatology in the short to longer-term. Future studies would benefit from adopting a unified approach to the measurement of depression post-SCI to help inform targeted treatment. PMID- 25691223 TI - The significance of grafting collagen on polycaprolactone composite scaffolds: processing-structure-functional property relationship. AB - The study concerns processing-structure-functional property relationship in organic-inorganic hybrid scaffolds based on grafted collagen for bone tissue engineering. Biodegradable polyester, polycaprolactone (PCL) and nanohydroxyapatite were used to fabricate three-dimensional porous scaffolds by adopting a combination of solvent casting, particulate leaching, and polymer leaching approaches. The PCL scaffold was subsequently surface modified by chemical bonding of 1,6-hexanediamine to the ester groups of PCL to introduce free NH2 groups. The introduction of NH2 groups as active sites enabled immobilization of biocompatible macromolecule, collagen, on the aminolyzed PCL via a cross-linking agent, glutaraldehyde. The osteoblasts' functions, notably cell adhesion, proliferation, and mineralization, were favorably modulated because of the chemical interaction between Arg-Gly-Asp domains in collagen molecule and integrin receptor in the cell membrane. The study underscores the significance of grafting collagen on PCL-nHA scaffold in modulating cellular activity and biological functions expanding its current use in soft tissue engineering to hard tissue regeneration. PMID- 25691224 TI - Intimate partner violence and new-onset depression: a longitudinal study of women's childhood and adult histories of abuse. AB - BACKGROUND: Studies indicate that women victims of intimate partner violence are at increased risk for poor mental health. This research disentangled the effect of partner violence on new-onset depression and psychosis spectrum symptoms from effects of child maltreatment and other confounding factors, including substance abuse and antisocial personality. METHODS: Participants were 1,052 mothers involved in the Environmental Risk (E-Risk) Longitudinal Twin Study, a nationally representative cohort of families followed prospectively. To test the directionality of associations between partner violence and depression, only women without a history of depression at the beginning of the study were considered (n = 978). Partner violence and mental health were assessed during face-to-face interviews with women across three time points. RESULTS: Four of 10 women reported being the victim of violence from their partner in a 10-year period. They represent 33% of our cohort and they account for 51% of new-onset depression. These women had a twofold increase in their risk of suffering from new-onset depression once the effect of childhood maltreatment, socioeconomic deprivation, antisocial personality, and young motherhood were controlled. Women who were abused both in childhood and adulthood were four to seven times more likely to suffer from depression than never-abused women. We observed similar associations with psychosis spectrum symptoms. CONCLUSIONS: Women victims of partner violence account for more than their share of depression. Findings strengthen existing evidence that partner violence independently contributes to women's poor mental health. Psychological difficulties among a considerable number of women could be reduced by stopping partner violence. PMID- 25691225 TI - Concomitant psychiatric problems and hormonal treatment induced metabolic syndrome in gender dysphoria individuals: a 2 year follow-up study. AB - OBJECTIVE: Several studies indicate increased prevalence of metabolic syndrome (MetS) among patients with psychiatric disorders as well as among individuals with gender dysphoria (GD) treated by cross-sex hormonal treatment. However, the MetS prevalence among hormone treated GD individuals suffering from psychiatric problems has not been detected. METHODS: From a sample of 146 GD patients we selected 122 metabolically healthy individuals in order to investigate the prevalence of MetS after the beginning of the cross-sex hormonal treatment in a 2 year follow-up assessment. Furthermore, we assessed differences in MetS prevalence between hormone treated GD patients with and without concomitant psychiatric problems. RESULTS: When treated with hormone therapy, GD patients reported changes in several parameters which are clustered in MetS, with statistically significant differences compared to baseline. Glyco-insulinemic alterations were more pronounced in male to female patients (MtFs). However, weight gain, waist circumference increases, blood pressure increases, and lipid alterations were similar in MtFs and female to male patients (FtMs). 14.8% of the sample at year 1 and 17.2% at year 2 developed MetS. Among patients with concomitant psychiatric problems, 50% at year 1 and 55% at year 2 developed MetS against 8% at year 1 and 10% at year 2 of patients without concomitant psychiatric problems. CONCLUSION: This study indicates that sex hormones induce MetS in a relatively low proportion of healthy GD individuals and especially during the first year of hormonal treatment. Most importantly, concomitant psychiatric problems are associated with considerably greater MetS prevalence in hormone treated GD individuals. PMID- 25691226 TI - Is the developmentally immature immune response in paediatric sepsis a recapitulation of immune tolerance? AB - Immunologically immature neonates suffer the highest incidence of paediatric sepsis. Postnatal immunological maturation is characterized by a relatively hypo inflammatory immune response. The mechanisms that differentiate the mature and immature immune responses resemble those that differentiate the hyper- and hypo inflammatory responses in severe sepsis. Immunological maturational differences likely affect the neonate's ability to mount an appropriate hyper-inflammatory response, a counteractive hypo-inflammatory response, and subsequent return to immune system homeostasis. To better understand the role of the hypo-inflammatory response in paediatric sepsis, we will explore the maturation of the immune system and the effect it may have on the sepsis-induced hypo-inflammatory response. PMID- 25691227 TI - [Prevention and treatment of intraoperative complications of thoracic surgery]. AB - In order to achieve a minimal complication rate there is a need for a comprehensive strategy. This means in the first line preventive steps which include patient positioning, suitable approaches and access, an appropriately qualified surgical team as well as a carefully planned dissection and preparation. Furthermore, a supply of additional instrumentation, such as thrombectomy catheters, special vascular clamps and even extracorporeal membrane oxygenation (ECMO) and a heart-lung machine (HLM) in cases of centrally located lesions should be on stand-by. Control instruments, such as a bronchoscope and esophagoscope should not be forgotten. In selected cases a preoperative embolization (vascular malformation) or cream swallow (thoracic duct injury) can be helpful. Special interventions to overcome complications arising are described for the chest wall, lung parenchyma, pulmonary vessels, great vessels, bronchial arteries, trachea and bronchi, esophagus, thoracic duct, heart, vertebral column and sternum corresponding to the topography. PMID- 25691228 TI - Chronic kidney disease in disadvantaged populations. PMID- 25691231 TI - Capacitive charging and desalination dynamics of a packed-bed reactor. AB - We study theoretically the charging and desalination dynamics of a packed-bed reactor comprising two percolating granular aggregates that form two porous electrodes. The two porous electrodes are separated with an ion-permeable, electrically insulating spacer, are confined between two long, parallel, current collecting plates, and are saturated with an electrolyte solution. The porous electrodes are ideally polarizable. The electrolyte is binary, and dilute. The electric double layers next to the pore surface are thin. We use volume-averaging (homogenization) theory for porous electrodes and the Gouy-Chapman-Stern model for the electric double layer. Both the cases of finite and infinite aggregate electric conductivities subjected to step changes in the collecting plates' potentials are considered. We determine the potential and concentration distributions and the charging time as functions of space, time, and reactor characteristics. Significantly, we find that the charging time depends only weakly on the solid matrix conductivity as long as the solid matrix conductivity is of comparable magnitude or greater than that of the electrolyte. Furthermore, there is an optimal, finite solid matrix conductivity for which the charging time is minimized. PMID- 25691232 TI - Chondrocyte clusters adjacent to sites of cartilage degeneration have characteristics of progenitor cells. AB - The purpose of this study was to investigate the site-specific characteristics and roles of chondrocyte clusters in human knee osteoarthritis. Cartilage explants were obtained from 45 knees undergoing total knee replacement surgery. The explants were taken from 4 locations in the knee: the medial femoral condyle, the medial posterior femoral condyle (MPC), the lateral femoral condyle, and the lateral posterior femoral condyle (LPC). Cartilage degeneration, cell density, and cell arrangement were compared histologically. A live/dead cell viability assay and immunohistochemical analyses using antibodies against STRO-1, FGF2, and Ki-67 were performed. Cell proliferation and cartilaginous nodule production in MPC and LPC explants in monolayer culture were compared. Finally, MPC cartilage explants were cultured to observe histological changes. The cell density of the MPC explants was higher than that of the LPC because of clustering. MPC explants contained more live cells than the LPC did, and the expression of IHC markers in MPC explants was higher than that in LPC. Chondrocytes from MPC proliferated faster and produced more nodules in monolayer culture than those from the LPC and MPC explants were repaired during organ culture. In conclusion, chondrocyte clusters adjacent to severe cartilage degeneration have specific characteristics, with progenitor and proliferative potential. PMID- 25691233 TI - Comparing the metabolism of quercetin in rats, mice and gerbils. AB - PURPOSE: Several species of rodents are used to investigate the metabolism of quercetin in vivo. However, it is unclear whether they are a proper animal model. Thus, we compared the metabolism of quercetin in Wistar rats (rats), Balb/c mice (mice) and Mongolian gerbils (gerbils). METHODS: We determined the levels of quercetin metabolites, quercetin-3-glucuronide (Q3G), quercetin-3'-sulfate (Q3'S) and methyl-quercetin isorhamnetin (IH), in the plasma, lungs and livers of three species of animals by high-performance liquid chromatography after acute and/or chronic quercetin administration. The metabolic enzyme activities in the intestinal mucosal membrane and liver were also investigated. RESULTS: First, we found that after acute quercetin administration, the Q3'S level was the highest in gerbils. However, after long-term supplementation (20 weeks), Q3G was the dominant metabolite in the plasma, lungs and livers followed by IH and Q3'S in all animals, although the gerbils still had a higher Q3'S conversion ratio. The average concentrations of total quercetin concentration in the plasma of gerbils were the highest in both short- and long-term studies. The activities of uridine 5'-diphosphate-glucuronosyltransferase, phenolsulfotransferase and catechol-O methyltransferase were induced by quercetin in a dose- and tissue-dependent manner in all animals. CONCLUSIONS: Taken together, in general, after long-term supplementation the metabolism of quercetin is similar in all animals and is comparable to that of humans. However, the accumulation of quercetin and Q3'S conversion ratio in gerbils are higher than those in the other animals. PMID- 25691234 TI - Predictors for assessing electronic messaging between nurses and general practitioners as a useful tool for communication in home health care services: a cross-sectional study. AB - BACKGROUND: Nurses providing home health care services are dependent on access to patient information and communicating with general practitioners (GPs) to deliver safe and effective health care to patients. Information and communication technology (ICT) systems are viewed as powerful tools for this purpose. In Norway, a standardized electronic messaging (e-messaging) system is currently being established in health care. OBJECTIVE: The aim of this study was to explore home health care nurses' assessments of the utility of the e-messaging system for communicating with GPs and identify elements that influence the assessment of e messaging as a useful communication tool. METHODS: The data were collected using a self-developed questionnaire based on variables identified by focus group interviews with home health care nurses (n=425) who used e-messaging and existing research. Data were analyzed using logistic regression analyses. RESULTS: Over two-thirds (425/632, 67.2%) of the home health care nurses returned the questionnaire. A high proportion (388/399, 97.2%) of the home health care nurses who returned the questionnaire found the e-messaging system to be a useful tool for communication with GPs. The odds of reporting that e-messaging was a useful tool were over five times higher (OR 5.1, CI 2.489-10.631, P<.001) if the nurses agreed or strongly agreed that e-messaging was easy to use. The odds of finding e messaging easy to use were nearly seven times higher (OR 6.9, CI 1.713-27.899, P=.007) if the nurses did not consider the system functionality poor. If the nurses had received training in the use of e-messaging, the odds were over six times higher (OR 6.6, CI 2.515-17.437, P<.001) that they would consider e messaging easy to use. The odds that a home health care nurse would experience e messaging as easy to use increased as the full-time equivalent percentage of the nurses increased (OR 1.032, CI 1.001-1.064, P=.045). CONCLUSIONS: This study has shown that technical (ease of use and system functionality), organizational (training), and individual (full-time equivalent percentage) elements had an impact on home health care nurses' assessments of using e-messaging to communicate with GPs. By identifying these elements, it is easier to determine which interventions are the most important for the development and implementation of ICT systems in home health care services. PMID- 25691235 TI - Influence of glucogenic dietary supplementation and reproductive state of dairy cows on the composition of lipids in milk. AB - We studied the effects of the frequently used glucogenic dietary supplementation in dairy herds and the hormonal changes occurring during the normal estrous cycle on the composition and concentration of milk lipid components. Holstein dairy cows were synchronized with two injections of prostaglandin F2alpha (estrus=day 0). Animals were held as controls or drenched for 11 days (day -3 to day 8 of the cycle) with 850 ml/day liquid propylene glycol (treatment, n=13 per group). Blood and milk samples were collected on day 1 and 8 of the cycle. In both groups, plasma progesterone concentration increased ~10-fold between 1 and 8 days post estrus. Milk fatty acid composition was associated primarily with estrous-cycle day: polyunsaturated fatty acids increased by 16%, n-6 by 15% and n-3 by 1% from day 1 to 8 post-estrus. Polar lipid composition was also altered by cycle day: phosphatidylethanolamine concentration was 2-fold and 1.5-fold higher on day 1 v. day 8 post-estrus in the control and treatment groups, respectively. Phosphatidylserine concentration in milk was also affected by cycle day by treatment interaction (P=0.04). A progesterone level by treatment interaction influenced the triglyceride-to-phospholipid ratio in the milk (P=0.02). The results suggest that progesterone plays a role in modulating milk lipid composition and structure. Therefore, strategies designed to alter milk lipid composition should consider the cow's reproductive status. PMID- 25691236 TI - Functional Status and Hospital Readmissions Using the Medical Expenditure Panel Survey. AB - BACKGROUND: Hospital readmissions are expensive and they may signal poor quality of care. Whether functional status is related to hospital readmissions using a representative U.S sample remains unexplored . OBJECTIVE: We aimed to assess the relationship between functional status and all-cause 30-day hospital readmissions using a representative sample of the US population. DESIGN: This was a retrospective observational study (2003-2011). PATIENTS: The study included 3,772 patients who completed the SF-12 before being hospitalized. Three hundred and eighteen (8.4%) were readmitted within 30 days after being discharged. MEASUREMENTS: The Medical Expenditure Panel Survey (MEPS) was employed. Functional status was measured with the Short-Form 12-Item Health Survey Version 2(r) (SF-12). The probability of being readmitted was estimated using a logistic model controlling for demographic characteristics, comorbid conditions, insurance coverage, physical (PCS) and mental (MCS) summaries of the SF-12, reason for hospitalization, length of hospital stay, region, and residential area. RESULTS: A one-unit difference in PCS reduced the odds of readmission by 2% (odds ratio 0.98 [95% CI, 0.97 to 0.99]; p < 0.001), which implies an 18% reduction in the odds of readmissions for a ten-unit difference (one standard deviation) in PCS. The c-statistic of the model was 0.72. CONCLUSION: Baseline physical function is associated with hospital readmissions. The SF-12 improves the ability to identify patients at high risk of hospital readmission. PMID- 25691237 TI - A Randomized Controlled Trial of a CPR and Intubation Video Decision Support Tool for Hospitalized Patients. AB - BACKGROUND: Decisions about cardiopulmonary resuscitation (CPR) and intubation are a core part of advance care planning, particularly for seriously ill hospitalized patients. However, these discussions are often avoided. OBJECTIVES: We aimed to examine the impact of a video decision tool for CPR and intubation on patients' choices, knowledge, medical orders, and discussions with providers. DESIGN: This was a prospective randomized trial conducted between 9 March 2011 and 1 June 2013 on the internal medicine services at two hospitals in Boston. PARTICIPANTS: One hundred and fifty seriously ill hospitalized patients over the age of 60 with an advanced illness and a prognosis of 1 year or less were included. Mean age was 76 and 51% were women. INTERVENTION: Three-minute video describing CPR and intubation plus verbal communication of participants' preferences to their physicians (intervention) (N = 75) or control arm (usual care) (N = 75). MAIN MEASURES: The primary outcome was participants' preferences for CPR and intubation (immediately after viewing the video in the intervention arm). Secondary outcomes included: orders to withhold CPR/intubation, documented discussions with providers during hospitalization, and participants' knowledge of CPR/ intubation (five-item test, range 0-5, higher scores indicate greater knowledge). RESULTS: Intervention participants (vs. controls) were more likely not to want CPR (64% vs. 32%, p <0.0001) and intubation (72% vs. 43%, p < 0.0001). Intervention participants (vs. controls) were also more likely to have orders to withhold CPR (57% vs. 19%, p < 0.0001) and intubation (64% vs.19%, p < 0.0001) by hospital discharge, documented discussions about their preferences (81% vs. 43%, p < 0.0001), and higher mean knowledge scores (4.11 vs. 2.45; p < 0.0001). CONCLUSIONS: Seriously ill patients who viewed a video about CPR and intubation were more likely not to want these treatments, be better informed about their options, have orders to forgo CPR/ intubation, and discuss preferences with providers. TRIAL REGISTRATION: Clinicaltrials.gov NCT01325519 Registry Name: A prospective randomized trial using video images in advance care planning in seriously ill hospitalized patients. PMID- 25691238 TI - Association Between Receipt of Brief Alcohol Intervention and Quality of Care among Veteran Outpatients with Unhealthy Alcohol Use. AB - BACKGROUND: Brief alcohol intervention, including advice to reduce or abstain from drinking, is widely recommended for general medical outpatients with unhealthy alcohol use, but it is challenging to implement. Among other implementation challenges, providers report reluctance to deliver such interventions, citing concerns about negatively affecting their patient relationships. OBJECTIVE: The purpose of this study was to determine whether patient-reported receipt of brief intervention was associated with patient reported indicators of high-quality care among veteran outpatients with unhealthy alcohol use. DESIGN: Cross-sectional secondary data analysis was performed using the Veterans Health Administration (VA) Survey of Healthcare Experiences of Patients (SHEP). PARTICIPANTS: The study included veteran outpatients who (1) responded to the outpatient long-form SHEP (2009-2011), (2) screened positive for unhealthy alcohol use (Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) questionnaire score >= 3 for women, >= 4 for men), and (3) responded to questions assessing receipt of brief intervention and quality of care. MAIN MEASURES: We used logistic regression models to estimate the adjusted predicted prevalence of reporting two indicators of high-quality care--patient ratings of their VA provider and of overall VA healthcare (range 0-10, dichotomized as >= 9 indicating high quality)--for both patients who did and did not report receipt of brief intervention (receiving alcohol-related advice from a provider) within the previous year. KEY RESULTS: Among 10,612 eligible veterans, 43.8% reported having received brief intervention, and 84.2% and 79.1% rated their quality of care as high from their provider and the VA healthcare system, respectively. In adjusted analyses, compared to veterans who reported receiving no brief intervention, a higher proportion of veterans reporting receipt of brief intervention rated the quality of healthcare from their provider (86.9% vs. 82.0%, p < 0.01) and the VA overall (82.7% vs. 75.9%, p < 0.01) as high. CONCLUSIONS: In this cross-sectional analysis of veterans with unhealthy alcohol use, a higher proportion of those who reported receipt of brief intervention reported receiving high-quality care compared to those who reported having received no such intervention. These findings do not support provider concerns that delivering brief intervention adversely affects patients' perceptions of care. PMID- 25691239 TI - How Can eHealth Technology Address Challenges Related to Multimorbidity? Perspectives from Patients with Multiple Chronic Conditions. AB - BACKGROUND: Patient eHealth technology offers potential support for disease self management, but the value of existing applications for patients with multiple chronic conditions (MCCs) is unclear. OBJECTIVES: To understand self-management and health care navigation challenges that patients face due to MCCs and to identify opportunities to support these patients through new and enhanced eHealth technology. DESIGN: After administering a screening survey, we conducted 10 focus groups of 3-8 patients grouped by age, sex, and common chronic conditions. Patients discussed challenges associated with having MCCs and their use of (and desires from) technology to support self-management. Three investigators used standard content analysis methods to code the focus group transcripts. Emergent themes were reviewed with all collaborators, and final themes and representative quotes were validated with a sample of participants. PARTICIPANTS: Fifty-three individuals with >=3 chronic conditions and experience using technology for health-related purposes. KEY RESULTS: Focus group participants had an average of five chronic conditions. Participants reported using technology most frequently to search for health information (96%), communicate with health care providers (92%), track medical information (83%), track medications (77%), and support decision-making about treatment (55%). Three themes emerged to guide eHealth technology development: (1) Patients with MCCs manage a high volume of information, visits, and self-care tasks; (2) they need to coordinate, synthesize, and reconcile health information from multiple providers and about different conditions; (3) their unique position at the hub of multiple health issues requires self-advocacy and expertise. Focus groups identified desirable eHealth resources and tools that reflect these themes. CONCLUSIONS: Although patients with multiple health issues use eHealth technology to support self-care for specific conditions, they also desire tools that transcend disease boundaries. By addressing the holistic needs of patients with MCCs, eHealth technology can advance health care from a disease-centered to a patient-centered model. PMID- 25691240 TI - The effect of charge display on cost of care and physician practice behaviors: a systematic review. AB - BACKGROUND: While studies have been published in the last 30 years that examine the effect of charge display during physician decision-making, no analysis or synthesis of these studies has been conducted. OBJECTIVE: We aimed to determine the type and quality of charge display studies that have been published; to synthesize this information in the form of a literature review. METHODS: English language articles published between 1982 and 2013 were identified using MEDLINE, Web of Knowledge, ABI-Inform, and Academic Search Premier. Article titles, abstracts, and text were reviewed for relevancy by two authors. Data were then extracted and subsequently synthesized and analyzed. RESULTS: Seventeen articles were identified that fell into two topic categories: the effect of charge display on radiology and laboratory test ordering versus on medication choice. Seven articles were randomized controlled trials, eight were pre-intervention vs. post intervention studies, and two interventions had a concurrent control and intervention groups, but were not randomized. Twelve studies were conducted in a clinical environment, whereas five were survey studies. Of the nine clinically based interventions that examined test ordering, seven had statistically significant reductions in cost and/or the number of tests ordered. Two of the three clinical studies looking at medication expenditures found significant reductions in cost. In the survey studies, physicians consistently chose fewer tests or lower cost options in the theoretical scenarios presented. CONCLUSIONS: In the majority of studies, charge information changed ordering and prescribing behavior. PMID- 25691241 TI - A long story short. PMID- 25691242 TI - The Quality of Written Feedback by Attendings of Internal Medicine Residents. AB - BACKGROUND: Attending evaluations are commonly used to evaluate residents. OBJECTIVES: Evaluate the quality of written feedback of internal medicine residents. DESIGN: Retrospective. PARTICIPANTS: Internal medicine residents and faculty at the Medical College of Wisconsin from 2004 to 2012. MAIN MEASURES: From monthly evaluations of residents by attendings, a randomly selected sample of 500 written comments by attendings were qualitatively coded and rated as high , moderate-, or low-quality feedback by two independent coders with good inter rater reliability (kappa: 0.94). Small group exercises with residents and attendings also coded the utterances as high, moderate, or low quality and developed criteria for this categorization. In-service examination scores were correlated with written feedback. KEY RESULTS: There were 228 internal medicine residents who had 6,603 evaluations by 334 attendings. Among 500 randomly selected written comments, there were 2,056 unique utterances: 29% were coded as nonspecific statements, 20% were comments about resident personality, 16% about patient care, 14% interpersonal communication, 7% medical knowledge, 6% professionalism, and 4% each on practice-based learning and systems-based practice. Based on criteria developed by group exercises, the majority of written comments were rated as moderate quality (65%); 22% were rated as high quality and 13% as low quality. Attendings who provided high-quality feedback rated residents significantly lower in all six of the Accreditation Council for Graduate Medical Education (ACGME) competencies (p <0.0005 for all), and had a greater range of scores. Negative comments on medical knowledge were associated with lower in service examination scores. CONCLUSIONS: Most attending written evaluation was of moderate or low quality. Attendings who provided high-quality feedback appeared to be more discriminating, providing significantly lower ratings of residents in all six ACGME core competencies, and across a greater range. Attendings' negative written comments on medical knowledge correlated with lower in-service training scores. PMID- 25691243 TI - In-TOX-icating neurogenesis. AB - Early development of the mammalian cerebral cortex proceeds via a sequence of proliferative and differentiative steps from neural stem cells toward neurons and glia. However, how these steps are molecularly orchestrated is still only partially understood. In this issue of The EMBO Journal, Artegiani and colleagues implicate Tox, a HMG-box transcription factor previously known only for its role in lymphocyte development, in early cortical development. PMID- 25691245 TI - Clinical predictors of fever in stroke patients: relevance of nasogastric tube. AB - OBJECTIVES: Fever frequently occurs in stroke patients and worsens their prognosis. However, only few studies have assessed the determinants of fever in acute stroke, and no study has specifically addressed the possible prediction of the development of fever. MATERIALS AND METHODS: This investigation included 536 patients with acute stroke and a body temperature <=37 degrees C during the first 24 h of stay. Ninety-two of them (17.2%) subsequently developed fever (defined as a temperature >=37.5 degrees C starting after 24 h). Among the clinical variables available during the first 24 h from admission, those predictive of the subsequent appearance of fever were searched for. One hundred further patients had a temperature >37 degrees C during the first 24 h. RESULTS: In univariate analysis, many variables were predictive of the subsequent development of fever, but in multivariate analysis, only the following four predictors remained significant (odds ratio [95% confidence interval], P value): nasogastric tube (4.0 [2.2-7.4], <0.0001), atrial fibrillation (2.3 [1.4-3.8], 0.001), total anterior circulation syndrome (2.0 [1.2-3.5], 0.01), and urinary catheter (1.9 [1.1-3.3], 0.01). Among the 52 (9.7%) patients with three or four predictors, 31 (59.6%) subsequently developed fever. In addition, the factors independently associated with a temperature >37 degrees C during the first 24 h were as follows: National Institutes of Health Stroke Scale (P < 0.0001), hemorrhagic stroke (P = 0.0008), atrial fibrillation (P = 0.002), and total parenteral nutrition (P = 0.03). CONCLUSIONS: In patients with acute stroke, four clinical variables were found to be independently associated with the risk of developing fever and, of them, nasogastric tube was the strongest and most significant one. PMID- 25691244 TI - PI3P binding by Atg21 organises Atg8 lipidation. AB - Autophagosome biogenesis requires two ubiquitin-like conjugation systems. One couples ubiquitin-like Atg8 to phosphatidylethanolamine, and the other couples ubiquitin-like Atg12 to Atg5. Atg12~Atg5 then forms a heterodimer with Atg16. Membrane recruitment of the Atg12~Atg5/Atg16 complex defines the Atg8 lipidation site. Lipidation requires a PI3P-containing precursor. How PI3P is sensed and used to coordinate the conjugation systems remained unclear. Here, we show that Atg21, a WD40 beta-propeller, binds via PI3P to the preautophagosomal structure (PAS). Atg21 directly interacts with the coiled-coil domain of Atg16 and with Atg8. This latter interaction requires the conserved F5K6-motif in the N-terminal helical domain of Atg8, but not its AIM-binding site. Accordingly, the Atg8 AIM binding site remains free to mediate interaction with its E2 enzyme Atg3. Atg21 thus defines PI3P-dependently the lipidation site by linking and organising the E3 ligase complex and Atg8 at the PAS. PMID- 25691246 TI - Effect of tapped density, compacted density, and drug concentration on light induced fluorescence response as a process analytical tool. AB - The effect of tapped density, compacted density, and fluorescent drug concentration on the light-induced fluorescence (LIF) response is reported. The fluorescent response to powder mixtures containing 0.25%-10.00% w/w fluorescent active pharmaceutical ingredient (API) was evaluated over a density range of about 0.641-1.370 g/cm(3) . Blend concentrations up to 4.00% w/w API showed a linear trend in LIF response with increasing tapped and compacted density. API concentrations of 4.00% w/w or greater exhibited a negative parabolic trend in LIF response. The LIF responses were fitted to a quadratic model equation that included an interaction term between material density and API concentration (adjusted R(2) = 0.975 and p < 0.0001). All model terms were highly significant, including the material density-API concentration interaction (p < 0.0001). Being aware of the sensitivity of the LIF response to material density changes and the related changes in apparent concentration are important in implementing LIF as a process analytical tool for processes such as blending, roller compaction, and tableting. PMID- 25691247 TI - RE1 silencing transcription factor/neuron-restrictive silencing factor regulates expansion of adult mouse subventricular zone-derived neural stem/progenitor cells in vitro. AB - Adult neural stem cell (aNSC) activity is tuned by external stimuli through the recruitment of transcription factors. This study examines the RE1 silencing transcription factor (REST) in neural stem/progenitor cells isolated from the subventricular zone of adult mouse brain and provides the first extensive characterization of REST-mediated control of the cellular and molecular properties. This study shows that REST knockdown affects the capacity of progenitor cells to generate neurospheres, reduces cell proliferation, and triggers cell differentiation despite the presence of growth factors. Genome- and transcriptome-wide analyses show that REST binding sites are significantly enriched in genes associated with synaptic transmission and nervous system development and function. Seeking candidate regulators of aNSC function, this study identifies a member of the bone morphogenetic protein (BMP) family, BMP6, the mRNA and protein of which increased after REST knockdown. The results of this study extend previous findings, demonstrating a reciprocal control of REST expression by BMPs. Administration of exogenous BMP6 inhibits aNSC proliferation and induces the expression of the astrocytic marker glial fibrillary acidic protein, highlighting its antimitogenic and prodifferentiative effects. This study suggests that BMP6 produced in a REST-regulated manner together with other signals can contribute to regulation of NSC maintenance and fate. PMID- 25691248 TI - Iron-catalyzed oxidative biaryl cross-couplings via mixed diaryl titanates: significant influence of the order of combining aryl Grignard reagents with titanate. AB - The mixed diaryl titanates were used for the first time to modify the reactivity of two aryl Grignard reagents. Two titanate intermediates, Ar[Ar'Ti(OR)3]MgX and Ar'[ArTi(OR)3]MgX, formed via alternating the sequence of combining Grignard reagents with ClTi(OR)3 showed a significant reactivity difference. Taking advantage of such different reactivity, two highly structurally similar aryl groups could be facilely assembled through iron-catalyzed oxidative cross couplings using oxygen as the oxidant. PMID- 25691249 TI - Heart failure management: continuing to fail or signs of success? PMID- 25691250 TI - MiR-139-5p: promising biomarker for cancer. AB - MicroRNAs (miRNAs) were reported to be associated with cancer progression and carcinogenesis. MiRNAs are small, highly conserved, small non-coding RNA molecules, consisting of 18-25 nucleotides that control gene expression at the post-transcription level. By binding to complementary binding sites within the 3' untranslated region (3'UTR) of target messenger RNAs (mRNAs), inhibiting translation or promoting degradation of mRNAs. MicroRNAs not only play an important part in regulating gene expression but also controlling diverse physiological and pathological processes. Similarly, several studies have demonstrated that miRNAs have been involved in regulating various biological processes, including apoptosis, proliferation, cellular differentiation, metabolism, signal transduction, and carcinogenesis. MiRNA-139, which is located in 11q13.4 and has anti-oncogenic and antimetastatic activity in humans, meanwhile, was identified to be downregulated in previous studies. However, based on the pathogenetic relationship between cancer and the role of miR-139-5p in tumorigenesis, we consider that miR-139-5p may be the candidates to serve as promising biomarkers with sufficient sensitivity and specificity for the diagnosis of cancer in a clinical setting; moreover, it would offer a new safe and effective way in further molecular targeting cancer treatment, as well as improving overall survival of patients. PMID- 25691251 TI - AZD-4547 exerts potent cytostatic and cytotoxic activities against fibroblast growth factor receptor (FGFR)-expressing colorectal cancer cells. AB - Colorectal cancer (CRC) causes significant mortalities worldwide. Fibroblast growth factor (FGF) receptor (FGFR) signaling is frequently dysregulated and/or constitutively activated in CRCs, contributing to cancer carcinogenesis and progression. Here, we studied the activity of AZD-4547, a novel and potent FGFR kinase inhibitor, on CRC cells. AZD-4547 inhibited CRC cell growth in vitro, and its activity correlated with the FGFR-1/2 expression level. AZD-4547 was cytotoxic and pro-apoptotic in FGFR-1/2-expressed CRC cell lines (NCI-H716 and HCT-116), but not in FGFR-1/2 null HT-29 cells. Further, AZD-4547 inhibited cell cycle progression and attenuated the activation of FGFR1-FGFR substrate 2 (FRS 2), ERK/mitogen-activated protein kinase (MAPK), and AKT/mammalian target of rapamycin (AKT/mTOR) signalings in NCI-H716 and HCT-116 cells. In vivo, AZD-4547 oral administration at effective doses inhibited NCI-H716 (high FGFR-1/2 expression) xenograft growth in nude mice. Phosphorylation of FGFR-1, AKT, and ERK1/2 in xenograft specimens was also inhibited by AZD-4547 administration. Thus, our preclinical studies strongly support possible clinical investigations of AZD-4547 for the treatment of CRCs harboring deregulated FGFR signalings. PMID- 25691252 TI - Death receptor 4 variants enhanced prostate cancer risk in North Indian population. AB - Death receptor 4 (DR4) is a tumor suppressor gene and plays an important mediator of apoptosis. Polymorphism in DR4 gene may reduce apoptotic capacity and provoke proliferation of cell and cancer. We evaluated genetic polymorphisms of DR4 gene in association with risk of prostate cancer (PCa) in Northern Indian population. We have recruited 192 PCa patients and 225 cancer-free ages matched unrelated healthy control of similar ethnicity. They were genotyped for DR4, 141 (G > A), 209 (C > G), and 228 (A > C) polymorphisms using amplification refractory mutation system (ARMS) method. Variant genotype AA (OR = 2.54; p = 0.007) and A allele (OR = 1.51; p = 0.015) of DR4 141 demonstrated significant increased risk for PCa. Similarly, variant genotype GG (OR = 2.58; p = 0.003) and G allele carrier (CG + GG) (OR = 1.50; p = 0.043) of DR4 209 conferred increased risk. G allele (OR = 1.50, p = 0.005) was also statistically associated with PCa risk. High risk for PCa was also observed with respect to haplotypes A-G-A (OR = 2.86; Bonferroni correction Pc = 0.008) and A-G-C (OR = 3.18, Pc = 0.008). We observed significantly enhanced risk for PCa due to interaction between DR4 209 and 228 gene polymorphisms. Furthermore, a significantly increased risk of high Gleason grade tumor was found in the combined variant allele carrier (GA + AA) of DR4 141 compared with the GG genotype (OR = 2.27, Pc = 0.052). Interaction of smoking and genotypes did not further modulate the risk of PCa. Our observations suggested that genetic variants of the DR4 gene significantly influence the risk of PCa in North Indian population and might be involved in the etiology of PCa. PMID- 25691253 TI - Orienting of visuo-spatial attention in complex 3D space: Search and detection. AB - The ability to detect changes in the environment is necessary for appropriate interactions with the external world. Changes in the background go more unnoticed than foreground changes, possibly because attention prioritizes processing of foreground/near stimuli. Here, we investigated the detectability of foreground and background changes within natural scenes and the influence of stereoscopic depth cues on this. Using a flicker paradigm, we alternated a pair of images that were exactly same or differed for one single element (i.e., a color change of one object in the scene). The participants were asked to find the change that occurred either in a foreground or background object, while viewing the stimuli either with binocular and monocular cues (bmC) or monocular cues only (mC). The behavioral results showed faster and more accurate detections for foreground changes and overall better performance in bmC than mC conditions. The imaging results highlighted the involvement of fronto-parietal attention controlling networks during active search and target detection. These attention networks did not show any differential effect as function of the presence/absence of the binocular cues, or the detection of foreground/background changes. By contrast, the lateral occipital cortex showed greater activation for detections in foreground compared to background, while area V3A showed a main effect of bmC vs. mC, specifically during search. These findings indicate that visual search with binocular cues does not impose any specific requirement on attention-controlling fronto-parietal networks, while the enhanced detection of front/near objects in the bmC condition reflects bottom-up sensory processes in visual cortex. PMID- 25691255 TI - [Researcher of the month]. PMID- 25691256 TI - Epigenomic footprints across 111 reference epigenomes reveal tissue-specific epigenetic regulation of lincRNAs. AB - Tissue-specific expression of lincRNAs suggests developmental and cell-type specific functions, yet tissue specificity was established for only a small fraction of lincRNAs. Here, by analysing 111 reference epigenomes from the NIH Roadmap Epigenomics project, we determine tissue-specific epigenetic regulation for 3,753 (69% examined) lincRNAs, with 54% active in one of the 14 cell/tissue clusters and an additional 15% in two or three clusters. A larger fraction of lincRNA TSSs is marked in a tissue-specific manner by H3K4me1 than by H3K4me3. The tissue-specific lincRNAs are strongly linked to tissue-specific pathways and undergo distinct chromatin state transitions during cellular differentiation. Polycomb-regulated lincRNAs reside in the bivalent state in embryonic stem cells and many of them undergo H3K27me3-mediated silencing at early stages of differentiation. The exquisitely tissue-specific epigenetic regulation of lincRNAs and the assignment of a majority of them to specific tissue types will inform future studies of this newly discovered class of genes. PMID- 25691257 TI - Graphene aerogel/epoxy composites with exceptional anisotropic structure and properties. AB - 3D interconnected graphene aerogels (GAs) are prepared through one-step chemical reduction and rational assembly of graphene oxide (GO) sheets, so that the difficulties to uniformly disperse the individual graphene sheets in the polymer matrixes are avoided. Apart from ultralow density, high porosity, high electrical conductivity, and excellent compressibility, the resulting GAs possess a cellular architecture with a high degree of alignment when the graphene content is above a threshold, ~0.5 wt %. The composites prepared by infiltrating GA with epoxy resin present excellent electrical conductivities, together with high mechanical properties and fracture toughness. The unusual anisotropic structure gives rise to ~67% and ~113% higher electrical conductivity and fracture toughness of the composites, respectively, in the alignment direction than that transverse to it. PMID- 25691258 TI - Long-Standing Spicules in a Patient with Acute Lymphoblastic Leukemia. PMID- 25691259 TI - Erratum to: Tailored behavioral medicine intervention for enhanced physical activity and healthy eating in patients with obstructive sleep apnea syndrome and overweight. PMID- 25691260 TI - Dosing nucleoside reverse transcriptase inhibitors in adults receiving continuous veno-venous hemofiltration. AB - BACKGROUND AND OBJECTIVE: Characteristics of nucleoside reverse transcriptase inhibitors (NRTIs) make the drug class susceptible to elimination via continuous veno-venous hemofiltration (CVVH), potentially leading to suboptimal drug concentrations if given at the recommended anephric doses during CVVH. The objective of this study was to formulate NRTI dosing recommendations for adults receiving CVVH. METHODS: A mathematical formula that estimates the amount of drug likely to be removed during CVVH at various flow rates was used to calculate the supplemental NRTI dose required during CVVH. RESULTS: A proposed table of dosing recommendations for NRTIs during CVVH is presented. CONCLUSION: Clinicians should utilize these recommendations in the context of each individual patient, taking into consideration patient-specific factors and severity of illness. Future pharmacokinetic research correlating plasma and intracellular concentrations of NRTIs during CVVH is warranted to elucidate appropriate dosing. PMID- 25691262 TI - Altered dietary salt intake for people with chronic kidney disease. AB - BACKGROUND: Salt intake shows great promise as a modifiable risk factor for reducing heart disease incidence and delaying kidney function decline in people with chronic kidney disease (CKD). However, a clear consensus of the benefits of reducing salt in people with CKD is lacking. OBJECTIVES: This review evaluated the benefits and harms of altering dietary salt intake in people with CKD. SEARCH METHODS: We searched the Cochrane Renal Group's Specialised Register to 13 January 2015 through contact with the Trials' Search Co-ordinator using search terms relevant to this review. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared two or more levels of salt intake in people with any stage of CKD. DATA COLLECTION AND ANALYSIS: Two authors independently assessed studies for eligibility and conducted risk of bias evaluation. Results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes, and mean difference (MD) and 95% CI for continuous outcomes. Mean effect sizes were calculated using the random-effects models. MAIN RESULTS: We included eight studies (24 reports, 258 participants). Because duration of the included studies was too short (1 to 26 weeks) to test the effect of salt restriction on endpoints such as mortality, cardiovascular events or CKD progression, changes in salt intake on blood pressure and other secondary risk factors were applied. Three studies were parallel RCTs and five were cross-over studies. Selection bias was low in five studies and unclear in three. Performance and detection biases were low in two studies and unclear in six. Attrition and reporting biases were low in four studies and unclear in four. One study had the potential for high carryover effect; three had high risk of bias from baseline characteristics (change of medication or diet) and two studies were industry funded.There was a significant reduction in 24 hour sodium excretion associated with low salt interventions (range 52 to 141 mmol) (8 studies, 258 participants: MD -105.86 mmol/d, 95% CI -119.20 to -92.51; I(2) = 51%). Reducing salt intake significantly reduced systolic blood pressure (8 studies, 258 participants: MD -8.75 mm Hg, 95% CI -11.33 to -6.16; I(2) = 0%) and diastolic blood pressure (8 studies, 258 participants: MD -3.70 mm Hg, 95% CI 5.09 to -2.30; I(2) = 0%). One study reported restricting salt intake reduced the risk of oedema by 56%. Salt restriction significantly increased plasma renin activity (2 studies, 71 participants: MD 1.08 ng/mL/h, 95% CI 0.51 to 1.65; I(2) = 0%) and serum aldosterone (2 studies, 71 participants: 6.20 ng/dL (95% CI 3.82 to 8.58; I(2) = 0%). Antihypertensive medication dosage was significantly reduced with a low salt diet (2 studies, 52 participants): RR 5.48, 95% CI 1.27 to 23.66; I(2) = 0%). There was no significant difference in eGFR (2 studies, 68 participants: MD -1.14 mL/min/1.73 m(2), 95% CI -4.38 to 2.11; I(2) = 0%), creatinine clearance (3 studies, 85 participants): MD -4.60 mL/min, 95% CI -11.78 to 2.57; I(2) = 0%), serum creatinine (5 studies, 151 participants: MD 5.14 umol/L, 95% CI -8.98 to 19.26; I(2) = 59%) or body weight (5 studies, 139 participants: MD -1.46 kg; 95% CI -4.55 to 1.64; I(2) = 0%). There was no significant change in total cholesterol in relation to salt restriction (3 studies, 105 participants: MD -0.23 mmol/L, 95% CI -0.57 to 0.10; I(2) = 0%) or symptomatic hypotension (2 studies, 72 participants: RR 6.60, 95% CI 0.77 to 56.55; I(2) = 0%). Salt restriction significantly reduced urinary protein excretion in all studies that reported proteinuria as an outcome, however data could not be meta-analysed. AUTHORS' CONCLUSIONS: We found a critical evidence gap in long-term effects of salt restriction in people with CKD that meant we were unable to determine the direct effects of sodium restriction on primary endpoints such as mortality and progression to end-stage kidney disease (ESKD). We found that salt reduction in people with CKD reduced blood pressure considerably and consistently reduced proteinuria. If such reductions could be maintained long-term, this effect may translate to clinically significant reductions in ESKD incidence and cardiovascular events. Research into the long term effects of sodium-restricted diet for people with CKD is warranted, as is investigation into adherence to a low salt diet. PMID- 25691263 TI - Failure of high-flow nasal cannula therapy may delay intubation and increase mortality. AB - PURPOSE: Intubation in patients with respiratory failure can be avoided by high flow nasal cannula (HFNC) use. However, it is unclear whether waiting until HFNC fails, which would delay intubation, has adverse effects. The present retrospective observational study assessed overall ICU mortality and other hospital outcomes of patients who received HFNC therapy that failed. METHODS: All consecutive patients in one tertiary hospital who received HFNC therapy that failed and who then required intubation between January 2013 and March 2014 were enrolled and classified according to whether intubation started early (within 48 h) or late (at least 48 h) after commencing HFNC. RESULTS: Of the 175 enrolled patients, 130 (74.3 %) and 45 (25.7 %) were intubated before and after 48 h of HFNC, respectively. The groups were similar in terms of most baseline characteristics. The early intubated patients had better overall ICU mortality (39.2 vs. 66.7 %; P = 0.001) than late intubated patients. A similar pattern was seen with extubation success (37.7 vs. 15.6 %; P = 0.006), ventilator weaning (55.4 vs. 28.9 %; P = 0.002), and ventilator-free days (8.6 +/- 10.1 vs. 3.6 +/- 7.5; P = 0.011). In propensity-adjusted and -matched analysis, early intubation was also associated with better overall ICU mortality [adjusted odds ratio (OR) = 0.317, P = 0.005; matched OR = 0.369, P = 0.046]. CONCLUSIONS: Failure of HFNC might cause delayed intubation and worse clinical outcomes in patients with respiratory failure. Large prospective and randomized controlled studies on HFNC failure are needed to draw a definitive conclusion. PMID- 25691264 TI - Why not the best? Social anxiety symptoms and perfectionism among Israeli Jews and Arabs: a comparative Study. AB - BACKGROUND: Social Anxiety Disorder (SAD) has been repeatedly shown to be very prevalent in the Western society and is characterized by low self-esteem, pessimism, procrastination and also perfectionism. Very few studies on SAD have been done in the Middle East or in Arab countries, and no study tackled the relationship between social anxiety symptoms and perfectionism in non-Western samples. METHODS: We examined social anxiety symptoms and perfectionism in a group of 132 Israeli Jewish (IJ) and Israeli Arab (IA) students. Subjects completed the Liebowitz Social Anxiety Scale (LSAS), the Multidimensional Perfectionism Scale (MPS), the Negative Automatic Thoughts Questionnaire (ATQ-N), the Positive Automatic Thoughts Questionnaire (ATQ-P) and a socio-demographic questionnaire. RESULTS: The rate of SAD in our sample according to a LSAS score of 60 or more was 17.2% (IJ=13.8%, IA=19%, ns). The correlation between perfectionism and the LSAS was high in both groups, and in particular in the IJ group. The IA group had higher scores of social avoidance, of ATQ-P and of two of the MPS subscales: parental expectations and parental criticism. Concern over mistakes and negative automatic thoughts positively predicted social fear in the IJ group, whereas in the IA group being female, religious and less educated positively predicted social fear. Negative automatic thoughts and age positively predicted social avoidance in the IJ group. In general, the IJ and IA subjects showed higher social anxiety, higher ATQ-N scores and lower parental expectations as compared with non-clinical US samples. CONCLUSIONS: Social anxiety symptoms and perfectionism are prevalent in Arab and Jewish students in Israel and seem to be closely related. Further studies among non-western minority groups may detect cultural influences on social anxiety and might add to the growing body of knowledge on this intriguing condition. PMID- 25691265 TI - Sternotomy for substernal goiter: retrospective study of 52 operations. AB - PURPOSE: Surgical treatment of substernal goiter occasionally involves sternotomy. Classification and handling of these operations are widely discussed. We aimed to review surgical results after thyroid operations including median sternotomy. METHODS: A retrospective review of all thyroid operations performed in the department from 01.01.95 to 31.12.12. In 55 of 2065 thyroid operations (2.7 %), median sternotomy was performed. All hospital journals of the patients were collected and carefully reviewed. RESULTS: We included 52 of 55 identified patients. Pathologic examinations discovered malignant disease in 4 patients (8 %) and multinodular goiter in 48 patients (92 %). Mean operation time was 4 h and 5 min (n = 48). Mean estimated blood loss was 464 ml (n = 48). Blood transfusion was given in nine operations (17 %). Median duration of postoperative hospitalization was 7 days (range 4-27 days). Pulmonary complications occurred in 11 patients (21 %): six with pneumonia or atelectasis, three with pneumothorax, and two with pleural effusion. Three patients (6 %) had postoperative hypocalcaemia (permanent in two patients (4 %)). Three patients (6 %) had transient voice changes. Permanent vocal cord paresis was not observed in this series of patients. CONCLUSION: Thyroid operations with sternotomy are complicated procedures accompanied with considerable pulmonary complications. In spite of a large invasive procedure, the risk of hypoparathyroidism or recurrent laryngeal nerve injury was not increased. PMID- 25691266 TI - Recent developments of the in situ wet cell technology for transmission electron microscopies. AB - In situ wet cells for transmission electron microscopy (TEM) and scanning transmission electron microscopy (STEM) allow studying structures and processes in a liquid environment with high temporal and spatial resolutions, and have been attracting increasing research interests in many fields. In this review, we highlight the structural and functional developments of the wet cells for TEM and STEM. One of the key features of the wet cells is the sealing technique used to isolate the liquid sample from the TEM/STEM vacuum environments, thus the existing in situ wet cells are grouped by different sealing methods. In this study, the advantages and shortcomings of each type of in situ wet cells are discussed, the functional developments of different wet cells are presented, and the future trends of the wet cell technology are addressed. It is suggested that in the future the in situ wet cell TEM/STEM technology will have an increasing impact on frontier nanoscale research. PMID- 25691267 TI - Equivalent Isopropanol Concentrations of Aromatic Amino Acids Interactions with Lipid Vesicles. AB - We show that the interaction of aromatic amino acids with lipid bilayers can be characterized by conventional 1D [Formula: see text]H NMR spectroscopy using reference spectra obtained in isopropanol-d8/D[Formula: see text]O solutions. We demonstrate the utility of this method with three different peptides containing tyrosine, tryptophan, or phenylalanine amino acids in the presence of 1,2 dioleoyl-sn-glycero-3-phosphocholine or 1,2-dioleoyl-sn-glycero-3-phosphoserine lipid membranes. In each case, we determine an equivalent isopropanol concentration (EIC) for each hydrogen site of aromatic groups, in essence constructing a map of the chemical environment. These EIC maps provide information on relative affinities of aromatic side chains for either PC or PS bilayers and also inform on amino acid orientation preference when bound to membranes. PMID- 25691268 TI - A novel biointerface that suppresses cell morphological changes by scavenging excess reactive oxygen species. AB - During cell cultivation on conventional culture dishes, various events results in strong stresses that lead to the production of bioactive species such as reactive oxygen species (ROS) and nitric oxide. These reactive species cause variable damage to cells and stimulate cellular responses. Here, we report the design of a novel biocompatible surface that decreases stress by not only morphologically modifying the dish surface by using poly(ethylene glycol) tethered chains, but also actively scavenging oxidative stress by using our novel nitroxide radical containing polymer. A block copolymer, poly(ethylene glycol)-b-poly[(2,2,6,6 tetramethylpiperidine-N-oxyl)aminomethylstyrene] (PEG-b-PMNT) was used to coat the surface of a dish. Differentiation of undifferentiated human leukemia (HL-60) cells was found to be suppressed on the polymer-coated dish. Notably, HL-60 cell cultivation caused apoptosis under high-density conditions, while spontaneous apoptosis was suppressed in cells plated on the PEG-b-PMNT-modified surface, because a healthy mitochondrial membrane potential was maintained. In contrast, low molecular weight antioxidants did not have apparent effects on the maintenance of mitochondria. We attribute this to the lack of cellular internalization of our immobilized polymer and selective scavenging of excessive ROS generated outside of cells. These results demonstrate the utility of our novel biocompatible material for actively scavenging ROS and thus maintaining cellular morphology. PMID- 25691269 TI - Pontine Tegmental Cap Dysplasia: MR Evaluation of Vestibulocochlear Neuropathy. AB - Pontine tegmental cap dysplasia (PTCD) is recently recognized as a rare congenital brain stem malformation with typical neuroimaging hallmarks of ventral pontine hypoplasia and vaulted pontine tegmentum projecting into the fourth ventricle. PTCD patients also demonstrate variable cranial neuropathy with predilection for involvement of the vestibulocochlear and facial nerves. We present a case of PTCD diagnosed on MRI in the neonatal period. During early infancy, the patient displayed features of multiple cranial neuropathies and bilateral hearing loss. At the age of 2, the patient underwent further MRI assessment with dedicated high resolution T2 SPACE sequence to delineate the cranial nerve deficiencies. PMID- 25691270 TI - (Re)constructing Myself: the process of transition to motherhood for women with a disability. AB - AIM: This paper presents a substantive theory that explains the transition to motherhood for women with a disability. BACKGROUND: Over the last thirty years, interest in exploring women's experiences of motherhood has increased. Extant theories on transition to motherhood originate, primarily, from the perspective and experiences of non-disabled women with few exploring the phenomenon from the perspective and experiences of women with a disability. Those that do tend to focus on issues of accessibility, profiling the challenges that women with a disability encounter while accessing maternity services, attaining a maternal role and fulfilling the requirements of that role. Little is known about the experiences of women with a disability and their transition to motherhood and even less about the relationship of this process on the self. DESIGN: The study was conducted using a Strauss and Corbin approach to grounded theory. METHOD: Individual interviews (n = 22) were conducted over 4 years (2008-2012). Women were interviewed during pregnancy and in the postnatal period. All interviews were recorded, transcribed verbatim, imported into Nvivo 8 and analysed using the constant comparative method. FINDINGS: The substantive theory that emerged from the study provides a conceptual framework clinicians can reference when counselling, assisting and facilitating women with a disability during their preparation for and transition to motherhood. CONCLUSION: The substantive theory presented in this paper will increase clinicians' understanding of the process involved in the transition to motherhood for women with a disability. PMID- 25691271 TI - Synthesis and characterization of phosphorescent platinum and iridium complexes with cyclometalated corannulene. AB - Synthesis, structural and characterization data are provided for Pt(II) and Ir(III) complexes cyclometalated with 2-(corannulene)pyridine (corpy), (corpy)Pt(dpm) and (corpy)Ir(ppz)2 (dpm = dipivaloylmethanato, ppz = 1 phenylpyrazolyl). A third compound, (phenpy)Ir(ppz)2 (phenpy = 2-(5 phenanthryl)pyridyl), was also prepared to mimic the steric bulk of (corpy)Ir(ppz)2. X-ray analysis reveals bowl depths of 0.895 A for (corpy)Pt(dpm) and 0.837 A in (corpy)Ir(ppz)2. Neither complex displayed bowl-to-bowl stacking in the crystal lattice. A fluxional process for (corpy)Ir(ppz)2 attributed to bowl inversion of corrannulene is observed in solution with a barrier (DeltaG(?) = 13 kcal mol(-1)) and rate (k = 2.5 * 10(3) s(-1)) as determined using variable temperature (1)H NMR spectroscopy. All of the complexes display red phosphorescence at room temperature with quantum yields of 0.05 in solution and 0.2 in polymethyl methacrylate (PMMA). PMID- 25691272 TI - Clinical utility of attentional salience in treatment of auditory verbal hallucinations in schizophrenia using transcranial direct current stimulation (tDCS). PMID- 25691273 TI - Socioeconomic status is positively associated with measures of adiposity and insulin resistance, but inversely associated with dyslipidaemia in Colombian children. AB - BACKGROUND: Low socioeconomic status (SES) has been associated with higher risk of cardiometabolic diseases in developed societies, but investigation of SES and cardiometabolic risk in children in less economically developed populations is sparse. We aimed to examine associations among SES and cardiometabolic risk factors in Colombian children. METHODS: We used data from a population-based study of 1282 children aged 6-10 years from Bucaramanga, Colombia. SES was classified according to household wealth, living conditions and access to public utilities. Anthropometric and biochemical parameters were measured at a clinic visit. Cardiometabolic risk factors were analysed continuously using linear regression and as binary outcomes-according to established paediatric cut points using logistic regression to calculate OR and 95% CIs. RESULTS: Mean age of the children was 8.4 (SD 1.4) and 51.1% of the sample were boys. Odds of overweight/obesity, abdominal obesity and insulin resistance were greater among higher SES. Compared with the lowest SES stratum, children in the highest SES had higher odds of overweight/obesity (OR=3.25, 95% CI 1.89 to 5.57), abdominal obesity (OR=2.74, 95% CI 1.41 to 5.31) and insulin resistance (OR=2.60, 95% CI 1.81 to 3.71). In contrast, children in the highest SES had lower odds of hypertriglyceridaemia (triglycerides >=90th centile; OR=0.28, 95% CI 0.14 to 0.54) and low (<=10th centile) high-density lipoprotein (HDL) cholesterol (OR=0.35, 95% CI 0.15 to 0.78). CONCLUSIONS: In Colombian children, SES is directly associated with obesity and insulin resistance, but inversely associated with dyslipidaemia (hypertriglyceridaemia and low HDL cholesterol). Our findings highlight the need to analyse cardiometabolic risk factors separately in children and to carefully consider a population's level of economic development when studying their social determinants of cardiometabolic disease. PMID- 25691274 TI - Pulmonary function as a risk factor for dementia death: an individual participant meta-analysis of six UK general population cohort studies. AB - BACKGROUND: In addition to being associated with all-cause mortality and cardiovascular disease mortality, lung function has been linked with dementia. However, existing studies typically provide imprecise estimates due to small numbers of outcome events and are based on unrepresentative samples of the general population. METHODS: Individual participant meta-analysis of six cohort studies from the Health Survey for England and the Scottish Health Survey (total N=54 671). Dementia-related mortality was identified by mention of dementia on any part of the death certificate (mean follow-up 11.7 years). Study-specific Cox proportional hazard models of the association between lung function and dementia related death were pooled using random effect meta-analysis to produce overall results. RESULTS: There was a dose-response association between poorer lung function and a higher risk of dementia-related death (age- and sex-adjusted HR compared to highest quartile of forced expiratory volume in 1 s (FEV1), 95% CI: second quartile 1.32, 0.99 to 1.76; third quartile 1.78, 1.30 to 2.43; fourth (lowest) quartile 2.74, 1.73 to 4.32). There was no significant heterogeneity in study-specific estimates (I(2)=0%). Controlling for height, socioeconomic status, smoking and general health attenuated but did not remove the association (second quartile 1.15, 0.82 to 1.62; third quartile 1.37, 0.96 to 1.94; fourth quartile 2.09, 1.17 to 3.71). Results for forced vital capacity and peak flow were similar. CONCLUSIONS: In these general population samples, the relation between three measures of lung function and dementia death followed a dose-response gradient. Being in the bottom quartile of lung function was associated with a doubling of the risk. PMID- 25691275 TI - Socioeconomic marginalisation in the structural production of vulnerability to violence among people who use illicit drugs. AB - OBJECTIVE: Many people who use illicit drugs (PWUD) face challenges to their financial stability. Resulting activities that PWUD undertake to generate income may increase their vulnerability to violence. We therefore examined the relationship between income generation and exposure to violence across a wide range of income generating activities among HIV-positive and HIV-negative PWUD living in Vancouver, Canada. METHODS: Data were derived from cohorts of HIV seropositive and HIV-seronegative PWUD (n=1876) between December 2005 and November 2012. We estimated the relationship between different types of income generation and suffering physical or sexual violence using bivariate and multivariate generalised estimating equations, as well as the characteristics of violent interactions. RESULTS: Exposure to violence was reported among 977 (52%) study participants over the study period. In multivariate models controlling for sociodemographic characteristics, mental health status, and drug use patterns, violence was independently and positively associated with participation in street based income generation activities (ie, recycling, squeegeeing and panhandling; adjusted OR (AOR)=1.39, 95% CI 1.23 to 1.57), sex work (AOR=1.23, 95% CI 1.00 to 1.50), drug dealing (AOR=1.63, 95% CI 1.44 to 1.84), and theft and other acquisitive criminal activity (AOR=1.51, 95% CI 1.27 to 1.80). Engagement in regular, self-employment or temporary employment was not associated with being exposed to violence. Strangers were the most common perpetrators of violence (46.7%) and beatings the most common type of exposure (70.8%). CONCLUSIONS: These results suggest that economic activities expose individuals to contexts associated with social and structural vulnerability to violence. The creation of safe economic opportunities which can minimise vulnerability to violence among PWUD is therefore urgently required. PMID- 25691276 TI - Dynamic Parathyroid Computed Tomography (4DCT) Facilitates Reoperative Parathyroidectomy and Enables Cure of Missed Hyperplasia. AB - BACKGROUND: Four-dimensional computed tomography (4DCT) is an emerging imaging modality in the evaluation of primary hyperparathyroidism (PHPT). We assessed the role of 4DCT in patients presenting for reoperative parathyroidectomy. METHODS: A prospective database of patients with persistent or recurrent PHPT undergoing reoperative parathyroidectomy during the years 2006-2014 was analyzed. Patients treated before versus after the advent of 4DCT were compared for operative eligibility, operative success, operative time, and concordance of imaging results with surgical findings. RESULTS: Ninety patients were included in the study (61 before 4DCT, 29 after 4DCT). The post-4DCT group had a higher rate of surgical concordance with imaging results (63 vs. 90 %, p < 0.01) and shorter operative time (114 vs. 76 min, p < 0.05). The operative success rate was not different (87 vs. 86 %). A similar pattern was observed in the subset of sestamibi-negative patients, with post-4DCT patients having a higher rate of surgical concordance (12 vs. 83 %, p < 0.0001) and shorter operative time (181 vs. 89 min, p < 0.05). Among patients ultimately found to have parathyroid hyperplasia, 4DCT correctly identified multiple enlarged glands in 80 % (4 of 5) and correctly lateralized one or more glands in 100 % (5 of 5) of cases, facilitating successful subtotal parathyroidectomy in the reoperative setting. CONCLUSIONS: 4DCT enables successful and efficient reoperative parathyroidectomy. These benefits extend to difficult cases, including sestamibi-negative patients and those with missed hyperplasia. PMID- 25691277 TI - Optimal Treatment Strategy in Rectal Cancer Surgery: Should We Be Cowboys or Chickens? AB - BACKGROUND AND PURPOSE: Surgeons and hospitals are increasingly accountable for their postoperative complication rates, which may lead to risk adverse treatment strategies in rectal cancer surgery. It is not known whether a risk adverse strategy leads to providing better care. In this study, the association between the strategy of hospitals regarding defunctioning stoma construction and postoperative outcomes in rectal cancer treatment was evaluated. METHODS: Population-based data of the Dutch Surgical Colorectal Audit, including 3,104 patients undergoing rectal cancer resection between January 2009 and July 2012 in 92 hospitals, were used. Hospital variation in (case-mix-adjusted) defunctioning stoma rates was calculated. Anastomotic leakage and 30-day mortality rates were compared in hospitals with a high and low tendency towards stoma construction. RESULTS: Of all patients, 76 % received a defunctioning stoma; 9.6 % of all patients developed anastomotic leakage. Overall postoperative mortality rate was 1.8 %. The hospitals' adjusted proportion of defunctioning stomas varied from 0 to 100 %, and there was no significant correlation between the hospitals' adjusted stoma and anastomotic leakage rate. Severe anastomotic leakage was similar (7.0 vs. 7.1 %; p = 0.95) in hospitals with the lowest and highest stoma rates. Mild leakage and postoperative mortality rates were higher in hospitals with high stoma rates. CONCLUSIONS: A high tendency towards stoma construction in rectal cancer surgery did not result in lower overall anastomotic leakage or mortality rates. It seems that the ability to select patients for stoma construction is the key towards preferable outcomes, not a risk adverse strategy. PMID- 25691278 TI - Intramuscular Transplantation Improves Engraftment Rates for Esophageal Patient Derived Tumor Xenografts. AB - BACKGROUND: Recently, there has been an increase in the availability of targeted molecular therapies for cancer treatment. The application of these approaches to esophageal cancer, however, has been hampered by the relative lack of appropriate models for preclinical testing. Patient-derived tumor xenograft (PDTX) models are gaining popularity for studying many cancers. Unfortunately, it has proven difficult to generate xenografts from esophageal cancer using these models. The purpose of this study was to improve the engraftment efficiency of esophageal PDTXs. METHODS: Fresh pieces of esophageal tumors obtained from endoscopic biopsies or resected specimens were collected from 23 patients. The tumors were then coated in Matrigel and transplanted in immunocompromised mice subcutaneously (n = 6) and/or using a novel implantation technique whereby the tumor is placed in a dorsal intramuscular pocket (n = 18). They are then monitored for engraftment. RESULTS: With the novel intramuscular technique, successful engraftment was achieved for all 18 patient tumors. Among these PDTXs, 13 recapitulated the original patient tumors with respect to degree of differentiation, molecular and genetic profiles, and chemotherapeutic response. Lymphomatous transformation was observed in the other five PDTXs. Successful engraftment was achieved for only one of six patient tumors using the classic subcutaneous approach. DISCUSSION: We achieved a much higher engraftment rate of PDTXs using our novel intramuscular transplant technique than has been reported in other published studies. It is hoped that this advancement will help expedite the development and testing of new therapies for esophageal cancer. PMID- 25691279 TI - Systematic Review: Aesthetic Assessment of Breast Reconstruction Outcomes by Healthcare Professionals. AB - BACKGROUND: Achieving an aesthetic outcome following postmastectomy breast reconstruction is both an important goal for the patient and plastic surgeon. However, there is currently an absence of a widely accepted, standardized, and validated professional aesthetic assessment scale following postmastectomy breast reconstruction. METHODS: A systematic review was performed to identify all articles that provided professional assessment of the aesthetic outcome following postmastectomy, implant- or autologous tissue-based breast reconstruction. A modified version of the Scientific Advisory Committee's Medical Outcomes Trust (MOT) criteria was used to evaluate all professional aesthetic assessment scales identified by our systematic review. The criteria included conceptual framework formation, reliability, validity, responsiveness, interpretability, burden, and correlation with patient-reported outcomes. RESULTS: A total of 120 articles were identified: 52 described autologous breast reconstruction, 37 implant-based reconstruction, and 29 both. Of the 12 different professional aesthetic assessment scales that exist in the literature, the most commonly used scale was the four-point professional aesthetic assessment scale. The highest score on the modified MOT criteria was assigned to the ten-point professional aesthetic assessment scale. However, this scale has limited clinical usefulness due to its poor responsiveness to change, lack of interpretability, and wide range of intra- and inter-rater agreements (Veiga et al. in Ann Plast Surg 48(5):515-520, 2002). CONCLUSIONS: A "gold standard" professional aesthetic assessment scale needs to be developed to enhance the comparability of breast reconstruction results across techniques, surgeons, and studies to aid with the selection of procedures that produce the best aesthetic results from both the perspectives of the surgeon and patients. PMID- 25691280 TI - Prognostic Impact of Renin-Angiotensin System Blockade on Renal Cell Carcinoma After Surgery. AB - BACKGROUND: Angiotensin 2 is a key biologic peptide in the renin-angiotensin system (RAS) that regulates blood pressure and renal hemodynamics. The potential role of the RAS in the promotion of tumor growth, angiogenesis, and metastasis also has been shown in the past few decades. This study investigated the prognostic impact of RAS blockade on patients with renal cell carcinoma (RCC) after surgery. METHODS: The study identified 557 patients with pathologically diagnosed RCC (pT1-4 N0M0) and evaluated the prognostic factors after surgery for patients administered or not administered angiotensin-converting enzyme inhibitors (ACEs) or angiotensin 2 receptor blockers (ARBs). RESULTS: The median follow-up period was 5.1 years. Radical nephrectomy was performed for 349 patients (62.7 %), whereas the remaining 208 patients (37.3 %) underwent partial nephrectomy. A total of 104 patients (18.7 %) were administered RAS inhibitors: ACEs (n = 22) or ARBs (n = 82). Multivariate analysis showed that administration of RAS inhibitors (P = 0.044; HR 2.69), longer tumor length (P < 0.001; HR 1.02), high-grade tumor (P < 0.001; HR 3.55), and positive microvascular invasion (P < 0.003; HR 3.13) were not independent risk factors for a decrease in subsequent disease-specific survival after surgery for RCC. The 5-year disease-specific survival rate was 96.8 % among the patients administered RAS inhibitors and 89.8 % among their counterparts (P = 0.019). CONCLUSIONS: The authors propose renin angiotensin blockade as a possible potent choice for effective treatment after surgical treatment of RCC. PMID- 25691281 TI - Phase II Study of Docetaxel, Nedaplatin, and 5-Fluorouracil Combined Chemotherapy for Advanced Esophageal Cancer. AB - BACKGROUND: We performed a prospective, multi-institutional, phase-II, clinical trial of a docetaxel, nedaplatin, and 5-fluorouracil (DNF) regimen in patients with unresectable esophageal cancer. Our goal was to determine the efficacy and feasibility of this DNF protocol. METHODS: Thirty-four patients with unresectable esophageal cancer were enrolled and received DNF therapy. The DNF regimen was repeated every 4 weeks for up to 8 weeks, based on the following recommended doses: docetaxel, 60 mg/m(2) (day 1); nedaplatin, 70 mg/m(2) (day 1); and 5 fluorouracil, 700 mg/m(2) (days 1-5). The primary endpoint was the response rate. The secondary endpoints were overall survival and chemotherapy toxicities. RESULTS: The complete response rate and response rate were 5.9 and 47.1 %, respectively. The 2-year overall survival rate and progression-free survival rate were 44.3 and 27.3 %, respectively. The median survival time was 594 days. The median progression-free time was 277 days. No treatment-related deaths occurred. Thirty patients (30/34) with grade 3, 4 neutropenia improved relatively quickly with administration of granulocyte colony-stimulating factor. CONCLUSIONS: DNF combination chemotherapy is a useful regimen with relatively minor adverse events and may serve as an effective protocol in patients with unresectable esophageal cancer. PMID- 25691282 TI - Microscopic Omental Metastasis in Clinical Stage I Endometrial Cancer: A Meta analysis. AB - BACKGROUND: A patient with early-stage endometrial cancer may possibly have microscopic metastasis in the omentum, which is associated with a poor prognosis. The purpose of this study was to identify risk factors for microscopic omental metastasis in patients with clinical stage I endometrial cancer to establish the indications for selective omentectomy. METHODS: We searched the PubMed, EMBASE, and Cochrane Library databases for published studies from inception to August 2014, using terms such as 'endometrial cancer' or 'uterine cancer' for disease, 'omentectomy' or 'omental biopsy' for intervention, and 'metastasis' for outcome. Two reviewers independently identified the studies that matched the selection criteria. We calculated the pooled risk ratios (RRs) with 95 % confidence intervals (CI) of each surgicopathologic finding for microscopic omental metastases in clinical stage I endometrial cancer. We also calculated the prevalence of microscopic omental metastases. RESULTS: Among 1163 patients from ten studies, 22 cases (1.9 %) of microscopic omental metastases were found, which accounted for 26.5 % of all omental metastases. Positive lymph nodes (RR 8.71, 95 % CI 1.38-54.95), adnexal metastases (RR 16.76, 95 % CI 2.60-107.97), and appendiceal implants (RR 161.67, 95 % CI 5.16-5061.03) were highly associated with microscopic omental metastases. CONCLUSIONS: Microscopic omental metastases were not negligible in patients with clinical stage I endometrial cancer. Those with a risk factor of microscopic omental metastases were recommended for selective omentectomy. PMID- 25691283 TI - Molecular Characteristics of Basaloid Squamous Cell Carcinoma of the Esophagus: Analysis of KRAS, BRAF, and PIK3CA Mutations and LINE-1 Methylation. AB - BACKGROUND: Basaloid squamous cell carcinoma (BSCC) of the esophagus is a rare carcinoma with distinct characteristics, and was recently recognized as a variant of squamous cell carcinoma (SCC). We previously revealed genetic and epigenetic alterations associated with esophageal SCCs in relation to clinical outcome, including mutations in KRAS, BRAF, and PIK3CA, p53 expression, and long interspersed nucleotide element-1 (LINE-1) methylation, a surrogate marker for global DNA methylation level. In this study, we explored these features in BSCC. METHODS: A database of 502 esophageal cancers was used to evaluate the clinical and molecular characteristics of BSCC. KRAS, BRAF, and PIK3CA mutations and LINE 1 methylation were analyzed by pyrosequencing. RESULTS: Of 502 tumors, 22 (4.4 %) were pathologically diagnosed as BSCC, and 440 (87 %) as SCC. No prognostic differences between BSCC and SCC cases were identified (p = 0.41). KRAS or BRAF mutations were not observed in BSCCs. While 23 % of SCC tumors harbored a PIK3CA mutation, all BSCC cases were wild-type for PIK3CA (p = 0.002), and there were no differences in p53 expression between BSCCs and SCCs (p = 0.57), as assessed by immunohistochemistry. Furthermore, BSCC tissues exhibited significantly lower levels of LINE-1 methylation than SCC tissues (p < 0.0001). CONCLUSIONS: These findings imply that esophageal BSCC and SCC retain different cellular phenotypes with distinct genetic and epigenetic alterations; thus, tailored therapeutic strategies should be developed against each cancer type. PMID- 25691284 TI - The FRAX (r) as a predictor of mortality in Japanese incident hemodialysis patients: an observational, follow-up study. AB - The World Health Organization Fracture Risk Assessment Tool (FRAX((r))) was recently developed to estimate the 10-year absolute risk of osteoporotic fracture among the general population. However, the evidence for its use in chronic kidney disease patients has been lacking, and the association between the FRAX((r)) and mortality is unknown. Therefore, a hospital-based, prospective, cohort study was conducted to evaluate the predictive ability of the FRAX((r)) for mortality in hemodialysis patients. A total of 252 patients who had been started on maintenance hemodialysis, 171 men and 81 women, with a mean age of 67 +/- 14 years, was studied. The endpoint was defined as all-cause death. The Cox proportional hazards model was used to calculate hazard ratios and 95 % confidence intervals. During the mean follow-up period of 3.4 +/- 2.7 years, 61 deaths occurred. The median (interquartile range) of the FRAX((r)) for major osteoporotic fracture was 6.9 (4.6-12.0) % in men and 19.0 (7.6-33.0) % in women. Cumulative survival rates at 5 years after starting dialysis, with the FRAX((r)) levels above and below the median, were 51.9 and 87.9 %, respectively, in men and 67.4 and 83.7 %, respectively, in women. Overall, in men, the multivariate Cox regression analyses revealed that the log-transformed FRAX((r)) remained an independent predictor of death after adjusting by confounding variables. However, in women, the significant association between the FRAX((r)) value and the outcome was eliminated if age was put into these models. Among Japanese hemodialysis patients, the FRAX((r)) seems to be useful for predicting death, especially in men. PMID- 25691285 TI - Effect of retinoic acid and vitamin D3 on osteoblast differentiation and activity in aging. AB - Several studies have evidenced that in aging, osteoblast functional activity is impaired: osteoblast proliferation is slower and matrix deposition is less efficient. Because peroxisome-proliferator-activated receptor gamma2 (PPARgamma2) and fatty acids are important inhibitory signals in osteoblast development, we have investigated in human primary osteoblasts obtained from patients of different ages, the influence of retinoic acid and calcitriol on enzymes involved in differentiative (PPARgamma2, beta-catenin, and insulin-like growth factor 1) and metabolic (carnitine palmitoyltransferase 1) intracellular pathways, and on transglutaminase 2, as enzyme fundamental for stabilizing the newly deposited extracellular matrix in bone. Retinoic acid and calcitriol influenced, respectively, proliferation and differentiation of osteoblasts, and an increase in PPARgamma2 expression was observed following retinoic acid administration, whereas a decrease was observed following calcitriol administration. Aging widely influenced all parameters analyzed (the proliferation, differentiation, and new matrix deposition are significantly reduced in aged osteoblasts), with the exception of PPARgamma2, which we found to be constitutively overexpressed and not modulated by retinoic acid or calcitriol administration. Our findings show the impaired ability of aged osteoblasts to perform adequate functional response and draw attention to the therapeutic approaches for bone healing in elderly patients. PMID- 25691286 TI - Surface anatomy of the trunk based on CT data. PMID- 25691287 TI - Preparation of Ag/Au bimetallic nanostructures and their application in surface enhanced fluorescence. AB - An effective substrate for surface-enhanced fluorescence, which consists of cluster Ag/Au bimetallic nanostructures on a copper surface, was synthesized via a multi-stage galvanic replacement reaction of a Ag cluster in a chlorauric acid (HAuCl4) solution at room temperature. The fabricated silver/gold bimetallic cluster were found to yield large surface-enhanced fluorescence (SEF) enhancement factors for rhodamine 6G probe molecules deposited on the substrate, and also the fluorescence efficiency is critically dependent on the period of nanostructure growth. With the help of proper control reaction conditions, such as the reaction time, and concentration of reaction solutions, the maximum fluorescence enhanced effect was obtained. Therefore, the bimetallic nanostructure substrate also can be adapted to studies in SEF, which will expand the application of SEF. PMID- 25691288 TI - Erratum to: Deep sclerectomy with supraciliary hema implant (Esnoper(r) V-2000): results and complications. PMID- 25691289 TI - Simultaneous confidence bands for Cox regression from semiparametric random censorship. AB - Cox regression is combined with semiparametric random censorship models to construct simultaneous confidence bands (SCBs) for subject-specific survival curves. Simulation results are presented to compare the performance of the proposed SCBs with the SCBs that are based only on standard Cox. The new SCBs provide correct empirical coverage and are more informative. The proposed SCBs are illustrated with two real examples. An extension to handle missing censoring indicators is also outlined. PMID- 25691290 TI - Renal allograft fibrosis: biology and therapeutic targets. AB - Renal tubulointerstitial fibrosis is the final common pathway of progressive renal diseases. In allografts, it is assessed with tubular atrophy as interstitial fibrosis/tubular atrophy (IF/TA). IF/TA occurs in about 40% of kidney allografts at 3-6 months after transplantation, increasing to 65% at 2 years. The origin of renal fibrosis in the allograft is complex and includes donor-related factors, in particular in case of expanded criteria donors, ischemia-reperfusion injury, immune-mediated damage, recurrence of underlying diseases, hypertensive damage, nephrotoxicity of immunosuppressants, recurrent graft infections, postrenal obstruction, etc. Based largely on studies in the non transplant setting, there is a large body of literature on the role of different cell types, be it intrinsic to the kidney or bone marrow derived, in mediating renal fibrosis, and the number of mediator systems contributing to fibrotic changes is growing steadily. Here we review the most important cellular processes and mediators involved in the progress of renal fibrosis, with a focus on the allograft situation, and discuss some of the challenges in translating experimental insights into clinical trials, in particular fibrosis biomarkers or imaging modalities. PMID- 25691291 TI - Napping, development and health from 0 to 5 years: a systematic review. AB - BACKGROUND: Duration and quality of sleep affect child development and health. Encouragement of napping in preschool children has been suggested as a health promoting strategy. OBJECTIVES: The aim of this study is to assess evidence regarding the effects of napping on measures of child development and health. DESIGN: This study is a systematic review of published, original research articles of any design. SUBJECTS: Children aged 0-5 years. METHOD: Electronic database search was performed following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and assessment of research quality was carried out following a Grading of Recommendations, Assessment, Development and Evaluations (GRADE) protocol. RESULTS: Twenty-six articles met inclusion criteria. These were of heterogeneous quality; all had observational designs (GRADE-low). Development and health outcomes included salivary cortisol, night sleep, cognition, behaviour, obesity and accidents. The findings regarding cognition, behaviour and health impacts were inconsistent, probably because of variation in age and habitual napping status of the samples. The most consistent finding was an association between napping and later onset, shorter duration and poorer quality of night sleep, with evidence strongest beyond the age of 2 years. LIMITATIONS: Studies were not randomised. Most did not obtain data on the children's habitual napping status or the context of napping. Many were reliant on parent report rather than direct observation or physiological measurement of sleep behaviour. CONCLUSIONS: The evidence indicates that beyond the age of 2 years napping is associated with later night sleep onset and both reduced sleep quality and duration. The evidence regarding behaviour, health and cognition is less certain. There is a need for more systematic studies that use stronger designs. In preschool children presenting with sleep problems clinicians should investigate napping patterns. PMID- 25691292 TI - Risk analysis for U.S. offshore wind farms: the need for an integrated approach. AB - Wind power is becoming an increasingly important part of the global energy portfolio, and there is growing interest in developing offshore wind farms in the United States to better utilize this resource. Wind farms have certain environmental benefits, notably near-zero emissions of greenhouse gases, particulates, and other contaminants of concern. However, there are significant challenges ahead in achieving large-scale integration of wind power in the United States, particularly offshore wind. Environmental impacts from wind farms are a concern, and these are subject to a number of on-going studies focused on risks to the environment. However, once a wind farm is built, the farm itself will face a number of risks from a variety of hazards, and managing these risks is critical to the ultimate achievement of long-term reductions in pollutant emissions from clean energy sources such as wind. No integrated framework currently exists for assessing risks to offshore wind farms in the United States, which poses a challenge for wind farm risk management. In this "Perspective", we provide an overview of the risks faced by an offshore wind farm, argue that an integrated framework is needed, and give a preliminary starting point for such a framework to illustrate what it might look like. This is not a final framework; substantial work remains. Our intention here is to highlight the research need in this area in the hope of spurring additional research about the risks to wind farms to complement the substantial amount of on-going research on the risks from wind farms. PMID- 25691293 TI - Arterial infusion of 5-fluorouracil combined with subcutaneous injection of pegylated interferon alpha-2b in treating unresectable hepatocellular carcinoma with portal vein tumor thrombus. AB - This study aimed to evaluate the efficacy of arterial infusion of 5-fluorouracil (5-FU) combined with subcutaneous injection of pegylated interferon alpha-2b (PEG IFNalpha-2b) on unresectable HCC with PVTT and to determine the potential survival benefits of patients from this therapy. From January 2007 to August 2009, HCC patients with PVTT were assigned to undergo arterial infusion of 5-FU with subcutaneous injection of PEG-IFNalpha-2b or palliative therapy. A total of 105 HCC patients (94 males and 11 females) aged 24-78 years with portal vein thrombosis were randomly assigned to 5-FU/PEG-IFNalpha-2b group (n = 55) or control group (n = 50). The median progression-free survival (PFS) was 10 months, and the median overall survival (OS) was 12 months for all patients. The 6- and 12-month OS rates were significantly higher in 5-FU/PEG-IFNalpha-2b group than in control group (81.04 vs. 22.72%, 48.03 vs. 0%, both P < 0.05). The median OS and PFS were significantly longer in 5-FU/PEG-IFNalpha-2b group than in control group (14.7 vs. 4.5 months, 12.5 vs. 9 months, both P < 0.05). For unresectable HCC with PVTT, arterial infusion of 5-FU combined with subcutaneous injection of PEG IFNalpha-2b reduces tumor size obviously, prolongs patient survival, and causes no severe adverse events. PMID- 25691294 TI - p38 MAPK-dependent Nrf2 induction enhances the resistance of glioma cells against TMZ. AB - Temozolomide (TMZ) is an effective agent for clinical glioma treatment, but the innate and acquired resistance of glioma always limits its application. Although some advances have been achieved to elucidate the molecular mechanism underlying TMZ resistance, the role of Nrf2 (a principle regulator of cellular defense against drugs and oxidative stress) has not been well established in the acquisition of this phenotype. Our data showed that TMZ treatment induces the activation of Nrf2 and p38 MAPK signaling in glioma cells, while p38 inhibition abolished the effect of TMZ on Nrf2. Further study revealed that Nrf2 silencing was able to enhance the response of glioma cells to TMZ. Additionally, Nrf2 overexpression overrides the effect of p38 MAPK activation on Temozolomide resistance. In conclusions, we identified a p38 MAPK/Nrf2 signaling as a key molecular network contributing to TMZ resistance of glioma, and provided evidence that suppressing this signaling may be a promising strategy to improve TMZ's therapeutic efficiency. PMID- 25691295 TI - OCH-mediated shift of Th1 and Th2 cytokines by NKT cells in mice with aplastic anemia. AB - The immune-mediated destruction of bone marrow (BM) is the major cause of aplastic anemia (AA) in most patients. It has been shown that an imbalance of Th1 and Th2 cells is involved in immune-mediated destruction of BM in patients with AA. In the present study, we determined the role of NKT cells in regulating the balance of Th1 and Th2 cytokines. We found that the number of NKT cells from bone marrow mononuclear cells was lower in AA mice than normal mice. When treated with alpha-GalCer or its analog OCH, AA mice showed a significantly reduced capacity of NKT cell expansion. Furthermore, we found that the number of IFN-gamma producing NKT cells was higher in AA mice compared to normal counter-partners. However, OCH treatment inhibited IFN-gamma production and enhanced IL-4 production by NKT cells in which we saw a balanced Th1- to Th2-type cytokines in AA mice. Interestingly, we observed that OCH treatment promoted hematopoietic cell growth, as indicated by increased colony counts in AA mice. Taken together, our results not only demonstrated a role of OCH in the maintenance of Th1/Th2 balance and recovery of hematopoietic cell growth, but also revealed a therapeutic potential of OCH in AA. PMID- 25691296 TI - CCR9-CCL25 interaction suppresses apoptosis of lung cancer cells by activating the PI3K/Akt pathway. AB - CC chemokine receptor-9 (CCR9) is highly expressed in non-small cell lung cancer (NSCLC) tissues and cell lines. However, the biological functions and the signals elicited by the interaction between CCR9 and its natural ligand CCL25 in NSCLC are unknown. Here, we selectively depleted CCR9 and inhibited CCR9-CCL25 interaction in NSCLC cells using small recombinant lentivirus-mediated miRNA, and investigated the tumorigenic effects in vitro and in vivo. Compromised CCR9-CCL25 interaction promoted apoptosis in NSCLC cells by activating phosphoinositide 3 kinase (PI3K)/Akt in vitro. In addition, we showed that CCR9-CCL25 interaction mediated the activation of the PI3K/Akt pathway in NSCLC cells, resulting in the up-regulation of anti-apoptotic proteins, as well as the down-regulation of apoptotic proteins in a PI3K-/Akt-dependent manner. These CCR9-CCL25-mediated effects were abrogated in the presence of a PI3K inhibitor (wortmannin 10 nM) or by inhibiting the CCR9-CCL25 interaction through CCR9 silencing, which also suggested that the biological function of CCR9-CCL25 was mainly regulated by PI3K. In vivo studies also demonstrated a significantly lower tumor burden in mice receiving CCR9-silence cells than those in mice receiving control cells. Together, these data suggested that CCR9-CCL25 interaction induced tumorigenesis of NSCLC cells and that this induction might be accomplished through the activation of the PI3K/Akt pathway. These findings may lead to a better understanding of the biological effects of CCR9-CCL25 interaction and provide clues for identifying novel therapeutic and preventive molecular markers for NSCLC. PMID- 25691297 TI - Differentiation of benign and malignant focal liver lesions: value of virtual touch tissue quantification of acoustic radiation force impulse elastography. AB - The purpose of this study was to investigate the value of virtual tissue quantification (VTQ) of acoustic radiation force impulse elastography for the differential diagnosis of benign and malignant focal liver lesions (FLLs). Thus, a total of 134 FLLs in 134 patients were included. VTQ measurement was performed for each lesion in which the shear wave velocity (SWV) was measured. The difference in SWV and SWV ratio of FLL to surrounding liver between malignant and benign FLLs was evaluated, and the cutoff value was investigated. Receiver operating characteristic (ROC) curve was plotted to evaluate the diagnostic performance. A total of 134 lesions including 55 (41.0%) malignant FLLs and 79 (59.0%) benign ones were analyzed. The SWV of malignant and benign FLLs was 2.95 +/- 1.00 m/s and 1.69 +/- 0.89 m/s, respectively. Significant difference in SWV was presented between malignant and benign FLLs (p < 0.001). The SWV ratio of each FLL to the surrounding liver parenchyma was 1.83 +/- 1.32 for malignant and 1.26 +/- 0.78 for benign FLLs (p < 0.001). The area under the ROC curve in distinguishing malignant from benign lesions was 0.824 for SWV and 0.660 for SWV ratio. The cutoff value for differential diagnosis was 2.13 m/s for SWV and 1.37 for SWV ratio. The associated sensitivity and specificity were 83.3 and 77.9% for SWV and 59.6 and 77.3% for SWV ratio, respectively. In conclusion, VTQ provides quantitative stiffness information of FLLs and is helpful in the differential diagnosis between malignant and benign FLLs, particularly for the patients who are not candidates for contrast-enhanced imaging such as CT, MRI or contrast enhanced ultrasound. PMID- 25691298 TI - Phenotype analysis impacts testing strategy in patients with Currarino syndrome. AB - Currarino syndrome (OMIM 175450) presents with sacral, anorectal, and intraspinal anomalies and presacral meningocele or teratoma. Autosomal dominant loss-of function mutations in the MNX1 gene cause nearly all familial and 30% of sporadic cases. Less frequently, a complex phenotype of Currarino syndrome can be caused by microdeletions of 7q containing MNX1. Here, we report one familial and three sporadic cases of Currarino syndrome. To determine the most efficient genetic testing approach for these patients, we have compared results from MNX1 sequencing, chromosomal microarray, and performed a literature search with analysis of genotype-phenotype correlation. Based on the relationship between the type of mutation (intragenic MNX1 mutations vs 7q microdeletion) and the presence of intellectual disability, growth retardation, facial dysmorphism, and associated malformations, we propose a testing algorithm. Patients with the classic Currarino triad of malformations but normal growth, intellect, and facial appearance should have MNX1 sequencing first, and only in the event of a normal result should the clinician proceed with chromosomal microarray testing. In contrast, if growth delay and/or facial dysmorphy and/or intellectual disability are present, chromosomal microarray should be the first method of choice for genetic testing. PMID- 25691299 TI - Adherence to treatment in patient with severe cancer pain: A qualitative enquiry through illness narratives. AB - PURPOSE: Pain is a common symptom in cancer patients and often the most tangible sign of disease they and their families perceive. Despite currently available treatments, cancer pain frequently remains underrated and undertreated because of lack of adherence to the prescribed drug regimen. With this study we sought to identify elements that could facilitate pain management by exploring through narrative interviews the lived experiences of patients with severe chronic cancer pain in relation to their adherence to pain therapy. METHOD: A purposive sample of 18 cancer patients, treated at the Centre for Oncology and Haematology (COES), City Hospital for Health and Science, Turin, were interviewed. The interview contents were analysed using a qualitative phenomenological methodology as described by Giorgi. RESULTS: Three themes emerged from analysis of the interview transcripts: the significance of pain in subjective experience; the experience of being a patient pursuing a care pathway and the importance attributed to pain therapy. Factors facilitating adherence included the perception of the physical and psychological benefits of having and following a pain medications plan, subjective self-efficacy in pain control, and trust in the healthcare team. Barriers to adherence were negative attitudes toward opioid analgesic therapy, debilitating drug side effects, and denial of pain as a tangible sign of disease. CONCLUSION: Probing into the significance of the pain experience and its treatment through these narrative interviews revealed several core constituents of adherence. Healthcare providers can use this better understanding to build a trusting relationship with patients and foster adherence to treatment throughout the care pathway. PMID- 25691300 TI - Evaluation of Sisom: A computer-based animated tool to elicit symptoms and psychosocial concerns from children with cancer. AB - PURPOSE: In pediatric oncology, clear communication regarding symptom occurrence between clinicians and children is essential in order to provide safe and effective care. Mobile technology provides a means to enhance the standard clinician-patient interview, particularly among children, who are well versed in the use of technology. To help children identify and voice their concerns in the health care setting, researchers created Sisom, an animated computer tool for children and young people with serious and chronic illnesses. The purposes of this study of 100 dyads of patients 7-12 years of age and their parents were to: compare participants' reports of symptom occurrence using Sisom to a standard symptom checklist and determine the time requirements, ease of use, and perceived usefulness of the Sisom tool by children with cancer and their parents. METHODS: Child and parent participants completed both Sisom and the Memorial Symptom Assessment Scale. Symptoms on the two tools were compared and 20 items were similar to allow for comparisons. RESULTS: Children reported a significantly higher number of these 20 symptoms using Sisom as compared to the MSAS (i.e., 6.8 versus 4.9 symptoms, p < 0.001). A similar pattern was noted for parental proxy reports (i.e., 8.7 versus 5.7 symptoms, p < 0.001). Sisom was completed in less than 30 min, with high ratings of ease of use and perceived usefulness from parent participants. CONCLUSIONS: Sisom provides a systematic and engaging method to elicit symptom reports from children for use in clinical care and research. PMID- 25691301 TI - Psychometric evaluation of the Simplified Chinese Version of the Posttraumatic Growth Inventory for assessing breast cancer survivors. AB - PURPOSE: Due to the rapid increase in the number of breast cancer survivors in China, it is important to have a valid instrument to assess their posttraumatic growth. We carried out a study to validate the psychometric testing of the Simplified Chinese Version of the Posttraumatic Growth Inventory (PTGI-SC) in breast cancer survivors. METHODS AND SAMPLE: A convenience sampling method was used to collect data from 1227 breast cancer survivors at eight tertiary hospitals and some anticancer groups in Beijing between April 2010 and April 2012. We tested the item discrimination, content validity, construct validity, and internal consistency of the PTGI-SC. KEY RESULTS: The difficulties of the items ranged from 0.432 to 0.737, and their discrimination correlation coefficients ranged from 0.324 to 0.721. The content validity index of the inventory was 0.98. Five factors were extracted using exploratory factor analysis, and their cumulative contribution was determined to be 68.3%. The results of the confirmatory factor analysis include chi(2)/df=3.912, SRMR = 0.046, RMSEA = 0.055, IFI = 0.932, CFI = 0.932, and Cronbach's alpha = 0.90. CONCLUSION: The validity and reliability of the PTGI-SC support its use for evaluating Chinese breast cancer survivors. This reliable and valid inventory can be used in practice to measure PTG in breast cancer survivors and provide information about their psychological adjustment. It can also facilitate further psychological research among Chinese breast cancer survivors. PMID- 25691302 TI - Cannabinoids suppress acute and anticipatory nausea in preclinical rat models of conditioned gaping. AB - The sensation of nausea is one of the most debilitating human experiences. Current antiemetic therapies are effective in reducing vomiting, but are less effective in reducing acute and delayed nausea and are completely ineffective in reducing anticipatory nausea. Recent preclinical evidence using a selective rat model of nausea (conditioned gaping reactions) has revealed that cannabinoids have great promise as treatments for nausea and that their antinausea effects may be mediated by the interoceptive insular cortex. PMID- 25691303 TI - Cardiovascular risk surveillance to develop a nationwide health promotion strategy: the grenada heart project. AB - OBJECTIVE: The Grenada Heart Project aims to study the clinical, biological, and psychosocial determinants of the cardiovascular health in Grenada in order to develop and implement a nationwide cardiovascular health promotion program. METHODS: We recruited 2,827 adults randomly selected from the national electronic voter list. The main outcome measures were self-reported cardiovascular disease and behavioral risk factors, anthropometric measures, blood pressure, point-of care testing for glucose and lipids, and ankle-brachial index. Risk factors were also compared with the U.S. National Health and Nutritional Survey data. RESULTS: Prevalence of cardiovascular disease risk factors were: overweight and obesity 57.7% of the population, physical inactivity-23.4%, diabetes-13.3%, hypertension 29.7%, hypercholesterolemia-8.6%, and smoking-7%. Subjects who were physically active had a significantly lower 10-year Framingham risk score (p<0.001). Compared with the U.S. National Health and Nutrition Survey data, Grenadian women had higher rates of adiposity, diabetes, hypertension, and elevated low-density lipoprotein cholesterol, whereas Grenadian men had a higher rate of diabetes, a similar rate of hypertension, and lower rates of the other risk factors. Prevalence of peripheral arterial disease was 7.6%; stroke and coronary heart disease were equally prevalent at ~2%. CONCLUSIONS: This randomly selected adult sample in Grenada reveals prevalence rates of obesity, hypertension, and diabetes significantly exceeding those seen in the United States. The contrasting, paradoxically low levels of prevalent cardiovascular disease support the concept that Grenada is experiencing an obesity-related "risk transition." These data form the basis for the implementation of a pilot intervention program based on the Institute of Medicine recommendations and may serve as a model for other low- and middle-income countries. PMID- 25691304 TI - Tobacco and CVD: Challenges and Opportunities. PMID- 25691305 TI - Global tobacco surveys: information for action by cardiologists. AB - Critical to health promotion is surveillance of tobacco use that is a leading risk factor for cardiovascular diseases (CVDs). The objective of this paper is to analyze information from global tobacco surveys as relevant for CVD prevention and, hence, for cardiologists implying their role in clinical and policy settings for advancing tobacco control. This article uses MPOWER strategy as a framework to discuss information available from The Global Tobacco Surveillance System (GTSS) established in 1998. Data underline the need for cardiologists to 1) step up their efforts in promoting and providing cessation services in clinical settings; 2) become tobacco control advocates and support policy implementation in their countries; 3) raise patient and community awareness of harm caused by tobacco use and SHS exposure to health; 4) undertake policy relevant research where required; and 5) support national governments in effective implementation of provisions of the Framework Convention on Tobacco Control (FCTC). PMID- 25691306 TI - Tobacco and CVD: A Historical Perspective. PMID- 25691307 TI - Pathophysiological Mechanisms of Tobacco-Related CVD. AB - Cigarette smoking is a leading preventable risk factor for the development and progression of cardiovascular diseases (CVDs). Epidemiologic studies conclusively prove that both active smoking and secondhand smoke contribute significantly to morbidity and mortality related to CVD. Cigarette smoke is a mixture of several toxic chemicals, of which nicotine, carbon monoxide, and oxidant chemicals are most commonly implicated in the pathogenesis of cardiovascular disease. Tobacco causes endothelial dysfunction, inflammation, insulin resistance, alteration of lipid profile, hemodynamic alterations, and a hypercoagulable state. All of these act synergistically as pathobiologic mechanisms of atherothrombosis in tobacco users. PMID- 25691308 TI - Tobacco, Metabolic and Inflammatory Pathways, and CVD Risk. PMID- 25691309 TI - Tobacco Cessation Approaches and Impact on CVD. PMID- 25691310 TI - Death and taxes: epidemiological and economic evidence on smoking. PMID- 25691311 TI - Health promotion for primordial prevention of tobacco use. AB - Prevention of tobacco use is critical for primordial prevention of cardiovascular diseases. Low- and middle-income countries such as India face a burgeoning burden of tobacco-related cardiovascular diseases. A focus on adolescents and young people is consistent with a primordial approach to cardiovascular disease prevention and appropriate given the natural history of tobacco use, in regards to its onset and progression. The primordial prevention approach is feasible, because it attempts to bring about behavior change (sustained abstinence for nonusers) at the population level. This paper reviews effective strategies for population-based tobacco control among adolescents including settings-based interventions at school, at home, and in the community, as well as policy and media interventions. It goes on to briefly touch on the pivotal role that medical professionals, particularly cardiologists, play in fortifying such interventions and summarizes some key recommendations based on review of evidence on the effectiveness of these interventions. PMID- 25691312 TI - Role of mobile phone technology in tobacco cessation interventions. PMID- 25691313 TI - Noncigarette smoking patterns, their health effects and policy options. PMID- 25691314 TI - The Waterpipe: A New Global Threat to CV Health? PMID- 25691315 TI - Should the Legal Age for the Purchase of Tobacco Be Increased to 21Years? PMID- 25691316 TI - A Checklist for CVD Control in South Asia. PMID- 25691317 TI - Tobacco and CVD. PMID- 25691318 TI - IJLEW in its teens. PMID- 25691319 TI - A case of prolidase deficiency accompanying leg ulcers. AB - Prolidase deficiency (PD) is a rare autosomal recessive disorder that has symptoms such as skin ulcers, characteristic facies, mental retardation, skeletal deformities, hematological anomalies, splenomegaly, and chronic infections. Deficiency of prolidase leads to the increased excretion of proline in urine, which causes impaired collagen synthesis and delay in wound healing. This case reports a 40-year-old female who has had cutaneous ulcers since the age of 7 years. We also recognized borderline intellectual functioning as well as hematologic abnormalities and splenomegaly. We present this rare case to draw attention to consider prolidase deficiency in the differential diagnosis of leg ulcers. PMID- 25691320 TI - Chronic Expanding Organized Hematoma of the Lower Leg: A Rare Cause for Nonhealing Leg Ulcers. AB - Chronic expanding hematoma is a rare entity on the leg. A 55-year-old women presented with 2 small nonhealing leg ulcers. On examination we observed a painless bulky tumor-like mass that developed slowly after deep soft tissue infection almost 2 years ago. Vascular computed tomography suggested an organized hematoma. Important differential diagnoses include sarcoma and lymphoma. Treatment of choice is surgery. Histology confirmed the diagnosis of an organized hematoma. Chronic expanding hematoma is a rare cause of nonhealing leg ulcers. PMID- 25691321 TI - Enhanced conformational sampling method for proteins based on the TaBoo SeArch algorithm: application to the folding of a mini-protein, chignolin. AB - The conformational samplings are indispensible for obtaining reliable canonical ensembles, which provide statistical averages of physical quantities such as free energies. However, the samplings of vast conformational space of biomacromolecules by conventional molecular dynamics (MD) simulations might be insufficient, due to their inadequate accessible time-scales for investigating biological functions. Therefore, the development of methodologies for enhancing the conformational sampling of biomacromolecules still remains as a challenging issue in computational biology. To tackle this problem, we newly propose an efficient conformational search method, which is referred as TaBoo SeArch (TBSA) algorithm. In TBSA, an inverse energy histogram is used to select seeds for the conformational resampling so that states with high frequencies are inhibited, while states with low frequencies are efficiently sampled to explore the unvisited conformational space. As a demonstration, TBSA was applied to the folding of a mini-protein, chignolin, and automatically sampled the native structure (Calpha root mean square deviation < 1.0 A) with nanosecond order computational costs started from a completely extended structure, although a long time 1-us normal MD simulation failed to sample the native structure. Furthermore, a multiscale free energy landscape method based on the conformational sampling of TBSA were quantitatively evaluated through free energy calculations with both implicit and explicit solvent models, which enable us to find several metastable states on the folding landscape. PMID- 25691322 TI - Sorafenib- or 90Y-loaded resin microsphere radioembolization for locally advanced hepatocellular carcinoma, what should we trust? PMID- 25691323 TI - Novel synthetic bis-indolic derivatives with antistaphylococcal activity, including against MRSA and VISA strains. AB - OBJECTIVES: We report the synthesis, antibacterial activity and toxicity of 24 bis-indolic derivatives obtained during the development of new ways of synthesis of marine bis-indole alkaloids from the spongotine, topsentin and hamacanthin classes. METHODS: Innovative ways of synthesis and further structural optimizations led to bis-indoles presenting either the 1-(1H-indol-3'-yl)-1,2 diaminoethane unit or the 1-(1H-indol-3-yl)ethanamine unit. MIC determination was performed for reference and clinical strains of Staphylococcus aureus and CoNS species. MBC, time-kill kinetics, solubility, hydrophobicity index, plasma protein-binding and cytotoxicity assays were performed for lead compounds. Inhibition of the S. aureus NorA efflux pump was also tested for bis-indoles with no antistaphylococcal activity. RESULTS: Lead compounds were active against both S. aureus and CoNS species, with MICs between 1 and 4 mg/L. Importantly, the same MICs were found for MRSA and vancomycin-intermediate S. aureus strains. Early concentration-dependent bactericidal activity was observed for lead derivatives. Compounds with no intrinsic antibacterial activity could inhibit the S. aureus NorA efflux pump, which is involved in resistance to fluoroquinolones. At 0.5 mg/L, the most effective compound led to an 8-fold reduction of the ciprofloxacin MIC for the SA-1199B S. aureus strain, which overexpresses NorA. However, the bis indole compounds displayed a high hydrophobicity index and high plasma protein binding, which significantly reduced antibacterial activity. CONCLUSIONS: We have synthesized and characterized novel bis-indole derivatives as promising candidates for the development of new antistaphylococcal treatments, with preserved activity against MDR S. aureus strains. PMID- 25691324 TI - Aryl hydantoin Ro 13-3978, a broad-spectrum antischistosomal. AB - OBJECTIVES: Praziquantel is the only drug available for the treatment of schistosomiasis and the state of the exhausted drug discovery pipeline is alarming. We restarted investigations on the abandoned antischistosomal Ro 13 3978, an aryl hydantoin discovered in the early 1980s by Hoffmann La-Roche. METHODS: Newly transformed schistosomula and adult Schistosoma mansoni were studied in the presence of Ro 13-3978 in vitro. The metabolic stability of Ro 13 3978 was determined in vitro using human and mouse liver S9 fractions. Dose response relationship, stage specificity, hepatic shift and scanning electron microscopy studies were carried out in S. mansoni-infected mice. In addition, efficacy experiments were conducted in rodents infected with Echinostoma caproni and Fasciola hepatica as well as in S. mansoni-infected immunocompromised nude (Foxn1(nu)) mice. RESULTS: Ro 13-3978 showed minor in vitro activity and no damage to the tegument was found. No cytotoxicity was detected for Ro 13-3978. Ro 13-3978 was metabolically stable. ED50 values of 138.9 and 14.6 mg/kg were calculated for the treatment of juvenile and adult S. mansoni infections, respectively, with a single oral dose of Ro 13-3978. SEM studies revealed severe damage to the worms 48 h post-treatment of infected mice. A single oral dose of Ro 13-3978 (100 mg/kg) administered to S. mansoni-infected (Foxn1(nu)) mice reduced the worm burden by 88%. Ro 13-3978 was not active against E. caproni and F. hepatica in vivo. CONCLUSIONS: Ro 13-3978 has excellent antischistosomal properties in vivo. Structure-activity relationship studies with the aryl hydantoins have been launched in order to elucidate active pharmacophores, further investigate the mechanism of action and to identify a derivative with minimal antiandrogenic effects. PMID- 25691325 TI - Women need warnings about harmful effects of obesity in pregnancy, says European project. PMID- 25691326 TI - Virotherapy with a Semliki Forest Virus-Based Vector Encoding IL12 Synergizes with PD-1/PD-L1 Blockade. AB - Virotherapy and checkpoint inhibitors can be combined for the treatment of cancer with complementarity and potential for synergistic effects. We have developed a cytolytic but nonreplicative viral vector system based on Semliki Forest virus that encodes IL12 (SFV-IL12). Following direct intratumoral injection, infected cells release transgenic IL12, die, and elicit an inflammatory response triggered by both abundantly copied viral RNA and IL12. In difficult-to-treat mouse cancer models, such as those derived from MC38 and bilateral B16-OVA, SFV-IL12 synergized with an anti-PD-1 monoclonal antibody (mAb) to induce tumor regression and prolong survival. Similar synergistic effects were attained upon PD-L1 blockade. Combined SFV-IL12 + anti-PD-1 mAb treatment only marginally increased the elicited cytotoxic T-lymphocyte response over SFV-IL12 as a single agent, at least when measured by in vivo killing assays. In contrast, we observed that SFV IL12 treatment induced expression of PD-L1 on tumor cells in an IFNgamma dependent fashion. PD-L1-mediated adaptive resistance thereby provides a mechanistic explanation of the observed synergistic effects achieved by the SFV IL12 + anti-PD-1 mAb combination. PMID- 25691327 TI - Committing Cytomegalovirus-Specific CD8 T Cells to Eliminate Tumor Cells by Bifunctional Major Histocompatibility Class I Antibody Fusion Molecules. AB - Tumor cells escape immune eradication through multiple mechanisms, including loss of antigenicity and local suppression of effector lymphocytes. To counteract these obstacles, we aimed to direct the unique cytomegalovirus (CMV)-specific immune surveillance against tumor cells. We developed a novel generation of fusion proteins composed of a tumor antigen-specific full immunoglobulin connected to a single major histocompatibility class I complex bearing a covalently linked virus-derived peptide (pMHCI-IgG). Here, we show that tumor antigen-expressing cancer cells, which are decorated with pMHCI-IgGs containing a HLA-A*0201 molecule associated with a CMV-derived peptide, are specifically eliminated through engagement of antigen-specific CD8(+) T cells isolated from peripheral blood mononuclear cell preparations of CMV-infected humans. These CD8(+) T cells act without additional expansion, preactivation, or provision of costimulatory signals. Elimination of tumor cells is induced at similar concentrations and with similar time kinetics as those seen with bispecific T cell engagers (BiTE). However, while BiTE-like reagents indiscriminately activate T cells through binding to the T-cell receptor complex, pMHCI-IgGs selectively engage antigen-specific, constantly renewable, differentiated effector cytotoxic T lymphocytes to tumor cells, thereby representing a novel class of anticancer immunotherapeutics with potentially improved safety and efficacy profiles. PMID- 25691329 TI - Ten-year Retrospective Study on the Efficacy of a Manual Physical Therapy to Treat Female Infertility. AB - Background * Female infertility is a complex issue encompassing a wide variety of diagnoses, many of which are caused or affected by adhesions. Objectives * The study intended to examine the rates of successful treatment of infertile women using a protocol of manual physical therapy to address underlying adhesive disease leading to infertility. Methods * The research team designed a retrospective chart review. Setting * The study took place in a private physical therapy clinic. Participants * Participants were 1392 female patients who were treated at the clinic between the years of 2002 and 2011. They had varying diagnoses of infertility, including occluded fallopian tubes, hormonal dysfunction, and endometriosis, and some women were undergoing in vitro fertilization (IVF). Intervention * All patients underwent whole-body, patient centered treatments that used a protocol of manual physical therapy, which focused on restoring mobility and motility to structures affecting reproductive function. Outcome Measures * Improvements demonstrated in the condition(s) causing infertility were measured by improvements in tubal patency and/or improved hormone levels or by pregnancy. Results * The results included a 60.85% rate of clearing occluded fallopian tubes, with a 56.64% rate of pregnancy in those patients. Patients with endometriosis experienced a 42.81% pregnancy rate. The success rate was 49.18% for lowering elevated levels of follicle stimulating hormone (FSH), with a 39.34% pregnancy rate in that group, and 53.57% of the women with polycystic ovarian syndrome (PCOS) achieved pregnancy. The reported pregnancy rate for patients who underwent IVF after the therapy was 56.16%. The results also suggested that the treatment was effective for patients with premature ovarian failure (POF). Conclusion * The manual physical therapy represented an effective, conservative treatment for women diagnosed as infertile due to mechanical causes, independent of the specific etiology. PMID- 25691328 TI - Galectin-3 Shapes Antitumor Immune Responses by Suppressing CD8+ T Cells via LAG 3 and Inhibiting Expansion of Plasmacytoid Dendritic Cells. AB - Galectin-3 is a 31-kDa lectin that modulates T-cell responses through several mechanisms, including apoptosis, T-cell receptor (TCR) cross-linking, and TCR downregulation. We found that patients with pancreatic ductal adenocarcinoma (PDA) who responded to a granulocyte-macrophage colony-stimulating factor secreting allogeneic PDA vaccine developed neutralizing antibodies to galectin-3 after immunization. We show that galectin-3 binds activated antigen-committed CD8(+) T cells only in the tumor microenvironment. Galectin-3-deficient mice exhibit improved CD8(+) T-cell effector function and increased expression of several inflammatory genes. Galectin-3 binds to LAG-3, and LAG-3 expression is necessary for galectin-3-mediated suppression of CD8(+) T cells in vitro. Lastly, galectin-3-deficient mice have elevated levels of circulating plasmacytoid dendritic cells, which are superior to conventional dendritic cells in activating CD8(+) T cells. Thus, inhibiting galectin-3 in conjunction with CD8(+) T-cell directed immunotherapies should enhance the tumor-specific immune response. PMID- 25691330 TI - The conundrum of interferon-beta non-responsiveness in relapsing-remitting multiple sclerosis. AB - A series of controlled clinical trials have shown that exogenous interferon-beta (IFN-beta) benefits patients with relapsing-remitting multiple sclerosis (RRMS) by reducing relapse rate, disability progression, and the formation of new brain and spinal cord lesions on magnetic resonance imaging (MRI) scans. Unfortunately, however, the effectiveness of IFN-beta is limited in this setting by the occurrence of treatment non-responsiveness in nearly 25% of patients. Furthermore, clinicians who care for RRMS patients remain unable to accurately identify IFN-beta non-responders prior to the initiation of therapy, causing delays in the use of alternative treatments and sometimes requiring that patients turn to medications with more significant side effects to control their disease. Progress has been made toward understanding how both endogenous and exogenous IFN beta act to slow RRMS as well as the related mouse model, experimental autoimmune encephalomyelitis (EAE). Most studies point to its inhibitory actions on circulating immune cells as being important for suppressing both disorders, but multiple potential target cells and inflammatory pathways have been implicated and those essential to confer its benefits remain undefined. This review focuses on the role of both endogenous and exogenous IFN-beta in RRMS, paying particular attention to the issue of why certain individuals appear refractory to its disease-modifying effects. A continued goal in this field remains the identification of a convenient biomarker that accurately predicts IFN-beta treatment non-responsiveness in individual RRMS patients. Development of such an assay will allow clinicians to customize therapy for patients with this complex disorder. PMID- 25691331 TI - CO2 Hydrogenation Catalyzed by Iridium Complexes with a Proton-Responsive Ligand. AB - The catalytic cycle for the production of formic acid by CO2 hydrogenation and the reverse reaction have received renewed attention because they are viewed as offering a viable scheme for hydrogen storage and release. In this Forum Article, CO2 hydrogenation catalyzed by iridium complexes bearing sophisticated N^N bidentate ligands is reported. We describe how a ligand containing hydroxy groups as proton-responsive substituents enhances the catalytic performance by an electronic effect of the oxyanions and a pendent-base effect through secondary coordination sphere interactions. In particular, [(Cp*IrCl)2(TH2BPM)]Cl2 (Cp* = pentamethylcyclopentadienyl; TH2BPM = 4,4',6,6'-tetrahydroxy-2,2'-bipyrimidine) enormously promotes the catalytic hydrogenation of CO2 in basic water by these synergistic effects under atmospheric pressure and at room temperature. Additionally, newly designed complexes with azole-type ligands were applied to CO2 hydrogenation. The catalytic efficiencies of the azole-type complexes were much higher than that of the unsubstituted bipyridine complex [Cp*Ir(bpy)(OH2)]SO4. Furthermore, the introduction of one or more hydroxy groups into ligands such as 2-pyrazolyl-6-hydroxypyridine, 2-pyrazolyl-4,6 dihydroxypyrimidine, and 4-pyrazolyl-2,6-dihydroxypyrimidine enhanced the catalytic activity. It is clear that the incorporation of additional electron donating functionalities into proton-responsive azole-type ligands is effective for promoting further enhanced hydrogenation of CO2. PMID- 25691332 TI - Ionizing radiation-inducible miR-30e promotes glioma cell invasion through EGFR stabilization by directly targeting CBL-B. AB - MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression at the transcriptional and post-transcriptional levels. Here we show that miR-30e, which was previously identified as an ionizing radiation-inducible miRNA, enhances cellular invasion by promoting secretion of the matrix metalloproteinase MMP-2. The enhancement of cellular invasion by miR-30e involved up-regulation of the epidermal growth factor receptor (EGFR) and subsequent activation of its downstream signaling mediators, AKT and extracellular signal regulated kinase. EGFR up-regulation by miR-30e occurred due to stabilization of the EGFR protein. The E3 ubiquitin ligase casitas B-lineage lymphoma B (CBL-B) was down-regulated by miR-30e, and this led to increased EGFR abundance. A 3' UTR reporter assay confirmed that CBL-B is a direct target of miR-30e. Knocking down CBL-B expression phenocopied the effects of miR-30e, whereas ectopic expression of CBL-B suppressed miR-30e-induced EGFR up-regulation and invasion. Collectively, our results suggest that targeting miR-30e may limit the invasiveness induced during glioma radiotherapy. PMID- 25691333 TI - Postoperative risk of venous thromboembolism in rheumatic disease patients. AB - Both traditional and disease-related risk factors for venous thromboembolism (VTE) must be considered when assessing rheumatic disease patients preoperatively. While many studies suggest that patients with rheumatic diseases are at higher risk of VTE overall, studies in rheumatoid arthritis patients do not demonstrate an increased risk of postoperative VTE. Here, we review the literature on VTE risk in patients with rheumatoid arthritis, systemic lupus erythematosus, Behcet's disease, and vasculitis. The data suggest that disease activity is a driver of VTE risk. While rheumatoid arthritis patients undergoing elective arthroplasty are not at elevated VTE risk, patients with systemic lupus erythematosus and antiphospholipid antibody syndrome undergoing surgery have an elevated risk of postoperative VTE. PMID- 25691334 TI - Modulation of biomechanical properties of hyaluronic acid hydrogels by crosslinking agents. AB - Modulation of both mechanical properties and biocompatibilities of hyaluronic acid (HA) hydrogels is very importance for their applications in biomaterials. Pure HA solution was converted into a hydrogel by using butanediol diglycidyl ether (BDDE) as a crosslinking agent. Mechanical properties of the HA hydrogels have been evaluated by adding up different amount of BDDEs. While the mechanical properties of the obtained HA hydrogels were evaluated by measuring their crosslinking degrees, elastic modulus and viscosity, their in vitro biocompatibilities were done by measuring the degrees of anti-inflammatory reactions, cell viabilities and cytotoxicity. The degrees of anti-inflammatory reactions were determined by measuring the amount of nitric oxides (NOs) released from lipopolysaccharide(LPS)(+)-induced macrophages; cell viability was evaluated by observing differences in the behaviors of fibroblasts covered with the HA hydrogels, compared with those covered with the films of Teflon and Latex. Cytotoxicity of the HA hydrogels was also evaluated by measuring the degrees of viability of the cells exposed on the extracts of the HA hydrogels over those of Teflon, Latex and pure HA solutions by the assays of thiazoly blue tetrazolium bromide (MTT), neutral reds, and bromodeoxyuridine (BrdU). The results showed that employment of BDDEs beyond critical amounts showed lower biocompatibility of the crosslinked HA hydrogels but higher crosslinking degrees and mechanical properties, indicating the importance of controlling the HA concentrations, BDDE amounts and their reaction times for the synthesis of the crosslinked HA hydrogels for their clinical applications as biomaterials. PMID- 25691335 TI - Influences of domoic Acid exposure on cardiac development and the expression of cardiovascular relative genes in zebrafish (Daniorerio) embryos. AB - Domoic acid (DA) is a highly toxic phycotoxin that is generated from marine diatoms Pseudonitzschia spp. It has been found that bivalves or cephalopods can accumulate DA to a high level through their feeding activities and cause illness or death in consumers. Zebrafish have been used as a model to investigate and characterize the developmental toxicity of DA. However, there is no report about the relationship between DA and cardiac development in zebrafish. Here, zebrafish embryos were exposed to DA with at the dose of 1, 10, 100, and 1000 ng/L. High mortality and some developmental toxicity including pericardial and yolk sac edema, dorsal curvature, and cardiac defects were observed in the DA-treated larvae. We found that DA exposure not only disrupted normal cardiac development but also altered the expression of some cardiac development correlated genes and calcium ion channels, such as Anf, Bnp, Atp2a2a, Atp2a2b, Ncx1h, Ryr2b, and Tbx5. PMID- 25691336 TI - A systematic study to understand the effects of particle size distribution of magnetic fingerprint powders on surfaces with various porosities. AB - This study intends to design magnetite (Fe3 O4 )-based magnetic fingerprint powders with different particle size distributions. It also investigates the influence of particle size distribution on the visualization of latent fingermarks with as little background staining as possible on the surfaces with various porosities in a systematic way. Two strategies were used to prepare the magnetic fingerprint formulations for this study: milling of coarse magnetite particles for different durations, and mixing of sieved fine particles with different size ranges with coarse particles. Particle size analyses of the prepared magnetic powders, optical microscopy-based roughness analysis of the surfaces and SEM measurements of the visualized fingerprints and representative powders were performed. Mag2 of the formulations prepared through milling and Mag5 and Mag6 of the formulations prepared through sieving and mixing were more successful in the development of latent prints than the rest of the solutions. PMID- 25691338 TI - Isolation and characterization of T7-like lytic bacteriophages infecting multidrug resistant Pseudomonas aeruginosa isolated from Egypt. AB - In this study, two lytic phages designated as phiPSZ1 and phiPSZ2 infecting multidrug resistant Pseudomonas aeruginosa were isolated from sewage samples collected in Zagazig, Egypt. Morphological analysis by transmission electron microscopy revealed that both phages belong to the podoviridae family and resembles typical T7-like phages. phiPSZ1 has a head of about 60 +/- 5 nm in diameter with a short tail of 19 +/- 2 nm in length, while phiPSZ2 has a head of about 57 +/- 5 nm in diameter with a short tail of 14 +/- 2 nm in length. Both phages were shown to be able to infect 13 different P. aeruginosa strains and has no effect on other tested bacteria. In spite of morphological similarity, these phages showed diverged genomic sequences revealed by restriction enzyme digestion analysis. One-step growth curves of bacteriophages revealed eclipse and latent periods of 12 min for phiPSZ1 and 15 min for phiPSZ2, respectively, with burst sizes of about 100 per infected cell. Phage treatment prevented the growth of P. aeruginosa for up to 18 h with multiplicity of infection ratios of 1. These results suggest that both phages have a high potential for phage application to control P. aeruginosa. PMID- 25691337 TI - Display of fungi xylanase on Escherichia coli cell surface and use of the enzyme in xylan biodegradation. AB - The cell surface display technique allows expression of target proteins or peptides on microbial cell surface by fusing an appropriate protein as an anchoring motif. Herein, we constructed an Escherichia coli-based whole-cell biocatalyst displaying Thermomyces lanuginosus DSM 5826 xylanase (XynA) on the cell surface and endowed the E. coli cells with the ability to degrade xylan. The XynA was fused in frame to the C-terminus of Lpp-OmpA fusion previously shown to direct various other heterologous proteins to E. coli cell surface. The expressed Lpp-OmpA-XynA fusion protein has a molecular weight of approximately 37 kDa, which was confirmed by SDS-PAGE and Western blot analysis. The enzyme activity of the surface-displayed xylanase showed clear halo around the colony. The XynA displaying E. coli-based whole-cell biocatalyst xylanase activity was mainly detected with whole cells by determination of activity. The XynA-displaying E. coli-based whole-cell biocatalyst showed highest XynA activity at pH 6.2 and 65 degrees C, respectively. These results suggest that E. coli, which displayed the xylanase on its surface, could be used as a whole-cell biocatalyst in xylooligosaccharide production. PMID- 25691339 TI - Spatial assessment of the sewage contamination of Kuwait's marine areas. AB - Discharge of sewage to the coastal areas resulting in the deteriorating quality of seawater and polluted sediments has been one of important stressor in Kuwait. The objective of this study was to conduct spatial assessment of sewage contamination of coastal areas. The assessment was carried out by measuring fecal sterols as indicator of sewage contamination, in the marine sediments collected from 112 locations throughout the Kuwait's marine areas. The samples were extracted and sterols separated. Derivatized sterols were analyzed by GC/MS in selected ion monitoring mode. The results showed that areas in the vicinity of the sewage outfalls were heavily contaminated. The western part of Kuwait Bay was worst in terms of contamination level. Two off-shore sites in Kuwait Bay were also classified as contaminated. Coprostanol levels in Kuwait Bay ranged from 0 to 39,428 ng/g. Southern coastal areas were less severely contaminated. PMID- 25691340 TI - Changes to the biomass and species composition of Ulva sp. on Porphyra aquaculture rafts, along the coastal radial sandbank of the Southern Yellow Sea. AB - Compositions, changes and biomass of attached Ulva species on Porphyra rafts along the radial sandbank in the Yellow Sea were investigated, and potential contributions to green tides was analyzed. Ulva prolifera, Ulva flexuosa and Ulva linza were all appeared throughout the investigated period. U. prolifera and U. flexuosa dominated attached Ulva population on Porphyra rafts. Attached Ulva species biomass showed obviously spatial and temporal variations. Temperature, Ulva microscopic propagules and human activities were main factors to influence attached Ulva species biomass. The total attached Ulva species biomass was more than 20,000 fresh weight tons in April, and the green tide causative species U. prolifera accounted 51.03% in April 2013 before green tides occurred. The high biomass of attached Ulva species would contribute most to green tides in the Yellow Sea. But how attached Ulva species on Porphyra rafts contributing to green tides in the Yellow Sea should be further studied. PMID- 25691341 TI - [Molecular diagnostics in genodermatoses]. AB - Many genodermatoses present early in life with a chronic and often debilitating, progressive course with multi-organ involvement and significant morbidity or even mortality. Therefore, timely determination of the correct diagnosis is highly needed to improve approaches of patient care. Considering the common geno- and phenotypic variability of genodermatoses, this is most accurately provided by means of molecular diagnostics. Characterization of disease-causing genetic aberrations along an algorithmic diagnostic approach further paves the way for strategies of targeted therapeutic intervention. PMID- 25691342 TI - Proton irradiation of DNA nucleosides in the gas phase. AB - The four DNA nucleosides guanosine, adenosine, cytidine and thymidine have been produced in the gas phase by a laser thermal desorption source, and irradiated by a beam of protons with 5 keV kinetic energy. The molecular ions as well as energetic neutrals formed have been analyzed by mass spectrometry in order to shed light on the ionization and fragmentation processes triggered by proton collision. A range of 8-20 eV has been estimated for the binding energy of the electron captured by the proton. Glycosidic bond cleavage between the base and sugar has been observed with a high probability for all nucleosides, resulting in predominantly intact base ions for guanosine, adenosine, and cytidine but not for thymidine where intact sugar ions are dominant. This behavior is influenced by the ionization energies of the nucleobases (G < A < C < T), which seems to determine the localization of the charge following the initial ionization. This charge transfer process can also be inferred from the production of protonated base ions, which have a similar dependence on the base ionization potential, although the base proton affinity might also play a role. Other dissociation pathways have also been identified, including further fragmentation of the base and sugar moieties for thymidine and guanosine, respectively, and partial breakup of the sugar ring without glycosidic bond cleavage mainly for adenosine and cytidine. These results show that charge localization following ionization by proton irradiation is important in determining dissociation channels of isolated nucleosides, which could in turn influence direct radiation damage in DNA. PMID- 25691343 TI - [Nonischemic dilated cardiomyopathy. Parameters of autonomic tone]. AB - BACKGROUND: Nonischemic dilated cardiomyopathies (DCM) are the most common reason for heart failure in developed countries after ischemic disease. They often lead to device therapy. Left ventricular ejection fraction as a single parameter to identify patients at risk for sudden cardiac death revealed inconclusive data in patients with DCM. METHODS: Autonomic tone, measured by classical and innovative parameters of heart rate variability (HRV), heart rate turbulence or baroreceptor reflex, was demonstrated to give valuable prognostic information especially in patients with ischemic disease and after acute myocardial infarction. In patients with DCM, classical parameters of HRV showed inhomogeneous data in a heterogeneous patient collective caused by unsystematic measurement of single parameters in various patient collectives. RESULTS: Innovative parameters of HRV are promising in patients with DCM and showed prognostic relevance although patient numbers are limited and prospective data are missing. Further studies are needed in this field. CONCLUSION: Despite the in part convincing evidence for the relevance of autonomic tone as a prognostic marker in patients with DCM, their evaluation is still not part of clinical routine. Additional parameters to estimate the risk of sudden cardiac death are urgently needed. PMID- 25691344 TI - [Ischemic cardiomyopathy. Parameters of the autonomic tone]. AB - BACKGROUND: Despite significant improvements with respect to medical and interventional therapies, late mortality after myocardial infarction remains high. Therefore, the identification of high-risk patients who benefit from an intensified treatment approach is of great clinical interest. METHODS AND RESULTS: Experimental and clinical studies have shown that dysfunction of the cardiac autonomic innervation is associated with a poor prognosis in patients with ischemic cardiomyopathy. Clinical routine allows for noninvasive assessment of the cardiac autonomic innervation by means of ECG analysis. Parameters of heart rate variability reflect sympathetic and parasympathetic regulatory processes at the sinus node level. Recently, low frequency oscillatory modulations of the T-wave, which reflect sympathetic effects at the level of ventricular myocardium, have been identified. CONCLUSION: To optimize risk assessment, different parameters of the autonomic function can be combined. A large number of studies have proven the prognostic value of parameters of the autonomic nervous system. However, randomized controlled trials are needed to show whether patients with ischemic cardiomyopathy and autonomic dysfunction benefit from specific therapeutic interventions, i.e., intensified monitoring or ICD implantation. PMID- 25691345 TI - [Risk stratification for sudden cardiac death]. PMID- 25691346 TI - Development of a fully automated, web-based, tailored intervention promoting regular physical activity among insufficiently active adults with type 2 diabetes: integrating the I-change model, self-determination theory, and motivational interviewing components. AB - BACKGROUND: Type 2 diabetes is a major challenge for Canadian public health authorities, and regular physical activity is a key factor in the management of this disease. Given that fewer than half of people with type 2 diabetes in Canada are sufficiently active to meet the recommendations, effective programs targeting the adoption of regular physical activity (PA) are in demand for this population. Many researchers argue that Web-based, tailored interventions targeting PA are a promising and effective avenue for sedentary populations like Canadians with type 2 diabetes, but few have described the detailed development of this kind of intervention. OBJECTIVE: This paper aims to describe the systematic development of the Web-based, tailored intervention, Diabete en Forme, promoting regular aerobic PA among adult Canadian francophones with type 2 diabetes. This paper can be used as a reference for health professionals interested in developing similar interventions. We also explored the integration of theoretical components derived from the I-Change Model, Self-Determination Theory, and Motivational Interviewing, which is a potential path for enhancing the effectiveness of tailored interventions on PA adoption and maintenance. METHODS: The intervention development was based on the program-planning model for tailored interventions of Kreuter et al. An additional step was added to the model to evaluate the intervention's usability prior to the implementation phase. An 8-week intervention was developed. The key components of the intervention include a self monitoring tool for PA behavior, a weekly action planning tool, and eight tailored motivational sessions based on attitude, self-efficacy, intention, type of motivation, PA behavior, and other constructs and techniques. Usability evaluation, a step added to the program-planning model, helped to make several improvements to the intervention prior to the implementation phase. RESULTS: The intervention development cost was about CDN $59,700 and took approximately 54 full-time weeks. The intervention officially started on September 29, 2014. Out of 2300 potential participants targeted for the tailored intervention, approximately 530 people visited the website, 170 people completed the registration process, and 83 corresponded to the selection criteria and were enrolled in the intervention. CONCLUSIONS: Usability evaluation is an essential step in the development of a Web-based tailored intervention in order to make pre implementation improvements. The effectiveness and relevance of the theoretical framework used for the intervention will be analyzed following the process and impact evaluation. Implications for future research are discussed. PMID- 25691347 TI - Immunization of African Indigenous Pigs with Attenuated Genotype I African Swine Fever Virus OURT88/3 Induces Protection Against Challenge with Virulent Strains of Genotype I. AB - The attenuated African swine fever virus genotype I strain OURT88/3 has previously been shown to induce protection of European breeds of domestic pigs against challenge with virulent isolates. To determine whether protective immune responses could also be induced in indigenous breeds of pigs from the Kinshassa region in Democratic Republic of Congo, we immunized a group of eight pigs with OURT88/3 strain and challenged the pigs 3 weeks later with virulent genotype I strain OURT88/1. Four of the pigs were protected against challenge. Three of the eight pigs died from African swine fever virus and a fourth from an unknown cause. The remaining four pigs all survived challenge with a recent virulent genotype I strain from the Democratic Republic of Congo, DRC 085/10. Control groups of non-immune pigs challenged with OURT88/1 or DRC 085/10 developed signs of acute ASFV as expected and had high levels of virus genome in blood. PMID- 25691348 TI - Measurement properties of eating behavior self-assessment tools in adult bariatric surgery populations: a systematic review. AB - The present study aims to identify the range of eating behavior self-assessment tools reported in the adult bariatric surgery literature and evaluate the measurement properties of these tools using pre-established criteria. This systematic review follows the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines. This review revealed the use of 20 distinct tools; however, evidence for measurement properties specific to bariatric surgery populations was limited to only ten of these tools, as reported in 14 papers. Validity varied extensively and there was a widespread lack of information regarding measurement of change over time and patient burden. According to the evaluation criteria, there was adequate support for two tools. Several other tools show potential but would benefit from additional investigation of their measurement properties prior to continued use with bariatric surgery patients. PMID- 25691349 TI - Effects of Duodenal-Jejunal Bypass Liner (EndoBarrier(r)) on Gastric Emptying in Obese and Type 2 Diabetic Patients. AB - INTRODUCTION: The duodenal-jejunal bypass liner (DJBL) is a promising technique for treating obesity and type 2 diabetes mellitus (T2DM). However, despite promising results, its mechanism of action has not been elucidated. It is thought to promote changes in gastric emptying owing to the neuro-endocrine axis. OBJECTIVE: The aim of this paper was to study DJBL-induced changes in gastric emptying and the relationship of those changes with weight loss and T2DM. METHODS: Twenty-five patients with obesity and T2DM met inclusion criteria. Scintigraphic gastric emptying testing was performed prior to implantation, 16 weeks after implantation, and 4 weeks after removal. The average gastric retention was compared between tests, to examine the relationship between gastric emptying and those who lost more than 10 % of total body weight. Similarly, we compared average gastric retention between those who achieved a glycated hemoglobin target lower than 7 %. RESULTS: Average gastric retention was greater after DJBL implantation compared with the baseline (first hour, 74 +/- 16.3 %, p = 0.001; second hour, 45 +/- 25 %, p < 0.001; fourth hour, 15.8 +/- 15 %, p < 0.001). There was no difference between the baseline and 4 weeks after device removal (fourth hour, p = 0.057). Gastric retention was similar between patients who achieved T2DM control and those who did not (p = 0.73). Additionally, no difference was seen between patients who lost more than 10 % of body weight and those who did not (p = 0.275). CONCLUSIONS: DJBL delays gastric emptying but is reversible after withdrawal. The changes in gastric emptying have no relationship to weight loss and T2DM control. PMID- 25691350 TI - Mini-gastric bypass/one-anastomosis gastric bypass-standardizing the name. PMID- 25691351 TI - Prevalence of Alcohol Abuse Before and After Bariatric Surgery Associated With Nutritional and Lifestyle Factors: A Study Involving a Portuguese Population. AB - BACKGROUND: It has been hypothesized that the metabolism of alcohol is altered following bariatric surgery. However, few studies have evaluated preoperative and postoperative alcohol use. The aims of the study were to characterize alcohol use in the preoperative period and 2 years postoperatively as well as to identify factors associated. METHODS: A study was conducted using data from the electronic charts of patients submitted to laparoscopic adjustable gastric banding (LAGB) and Roux-en-Y gastric bypass (RYGB) surgery in the city of Porto, Portugal. Associations with the following variables were analyzed: age, marital status, schooling, alcohol use, body mass index, binge eating disorder, and lifestyle habits. RESULTS: Among the 659 patients, 42.0 % completed the 2 years of follow up. A total of 90.2 % were women; 67.4 % underwent LAGB, and 32.6 % underwent RYGB. The frequency of alcohol use was 24.2 % in the preoperative period and 9.4 % in the postoperative period (p = 0.000). Daily alcohol intake was two drinks in the preoperative period and 1.8 drinks in the postoperative period. Significant associations were found between postoperative alcohol use and the male gender (p = 0.001), age >= 45 years (p = 0.018), and preoperative BMI <40 kg/m(2) (p = 0.028). No significant associations were found with the surgical technique. No previous nondrinkers became drinkers, and no patients increased the quantity or frequency of alcohol intake in the postoperative period. CONCLUSIONS: The prevalence of alcohol use in the sample was low. Moreover, a lower prevalence rate was found in the postoperative period, independently of surgical technique, clinical factors, and percentage of weight loss. PMID- 25691352 TI - Breast milk macronutrient composition after bariatric surgery. AB - Breast milk samples from 12 lactating women with bariatric surgery were investigated by comparing the macronutrient and energy content with samples from 36 non-surgical controls. Samples were analyzed with the Human Milk Analyzer and the maternal diet 24 h prior to sampling with a food record. A higher fat, energy, and a slightly higher carbohydrate milk content was found in the surgical group compared to the non-surgical group (3.0 +/- 0.7 versus 2.2 +/- 0.9 g/100 ml, P = 0.008; 61.0 +/- 7.2 versus 51.7 +/- 9 kcal/100 ml, P = 0.002; and 6.6 +/- 0.6 versus 6.3 +/- 0.4 g/100 ml, P = 0.045, respectively). No correlations and no strong explanatory variance were found between milk macronutrient composition and corresponding maternal dietary intake. The nutritional value of breast milk after bariatric surgery appears to be at least as high as in non-surgical controls. PMID- 25691353 TI - Pharmacokinetics and distribution of voriconazole in body fluids of dogs after repeated oral dosing. AB - The goal of this project was to determine the pharmacokinetics of voriconazole and its concentration in cerebrospinal fluid (CSF), aqueous humor, and synovial fluid in five healthy dogs following once daily oral dose of 6 mg/kg for 2 weeks. Body fluid and plasma drug concentrations were determined by high-performance liquid chromatography (HPLC). Mild to moderate gastrointestinal adverse effects were seen. The mean AUC0-24 : minimum inhibitory concentration (MIC) ratio was 15.23 for a chosen MIC of 1 MUg/mL, which is lower than the recommended target of 20-25 and also lower than previously reported in dogs, perhaps reflecting induction of metabolizing enzymes by multiple dosing. Voriconazole concentrations in the CSF, aqueous humor, and synovial fluid were only 13-30% the concurrent plasma concentration, which is lower than previously reported in other species. Results of this study suggest that twice daily, administration may be necessary to maintain therapeutic plasma concentrations in dogs but further studies are warranted. PMID- 25691354 TI - Application of process analytical technology for monitoring freeze-drying of an amorphous protein formulation: use of complementary tools for real-time product temperature measurements and endpoint detection. AB - Process analytical technology (PAT) and quality by design have gained importance in all areas of pharmaceutical development and manufacturing. One important method for monitoring of critical product attributes and process optimization in laboratory scale freeze-drying is manometric temperature measurement (MTM). A drawback of this innovative technology is that problems are encountered when processing high-concentrated amorphous materials, particularly protein formulations. In this study, a model solution of bovine serum albumin and sucrose was lyophilized at both conservative and aggressive primary drying conditions. Different temperature sensors were employed to monitor product temperatures. The residual moisture content at primary drying endpoints as indicated by temperature sensors and batch PAT methods was quantified from extracted sample vials. The data from temperature probes were then used to recalculate critical product parameters, and the results were compared with MTM data. The drying endpoints indicated by the temperature sensors were not suitable for endpoint indication, in contrast to the batch methods endpoints. The accuracy of MTM Pice data was found to be influenced by water reabsorption. Recalculation of Rp and Pice values based on data from temperature sensors and weighed vials was possible. Overall, extensive information about critical product parameters could be obtained using data from complementary PAT tools. PMID- 25691355 TI - Modulation of red blood cell population dynamics is a fundamental homeostatic response to disease. AB - Increased red blood cell (RBC) volume variation (RDW) has recently been shown to predict a wide range of mortality and morbidity: death due to cardiovascular disease, cancer, infection, renal disease, and more; complications in heart failure and coronary artery disease, advanced stage and worse prognosis in many cancers, poor outcomes in autoimmune disease, and many more. The mechanisms by which all of these diseases lead to increased RDW are unknown. Here we use a semi mechanistic mathematical model of in vivo RBC population dynamics to dissect the factors controlling RDW and show that elevated RDW results largely from a slight reduction in the in vivo rate of RBC turnover. RBCs become smaller as they age, and a slight reduction in the rate of RBC turnover allows smaller cells to continue circulating, expanding the low-volume tail of the RBC population's volume distribution, and thereby increasing RDW. Our results show that mildly extended RBC lifespan is a previously unrecognized homeostatic adaptation common to a very wide range of pathologic states, likely compensating for subtle reductions in erythropoietic output. A mathematical model-based estimate of the clearance rate may provide a novel early-warning biomarker for a wide range of morbidity and mortality. PMID- 25691356 TI - Childhood idols, shifting from superheroes to public health heroes. AB - It is early Saturday morning: a day for heroes. Bogged down with various costumes, capes and action figures, young Nikoli bounds downstairs to catch reruns of Teen Titans He puts his newly acquired reading skills to work, studying comic books and recreating the adventures therein. Nikoli imagines himself as the hero in his comics, defeating villains and saving victims, imitating the poses and catchphrases in the mirror. Although children like Nikoli will never gain super strength or the ability to fly, the superheroes they emulate in play are examples of people they can aspire to be. They don't even have to be fictional heroes-if we widen the scope of children's superheroes to include those that address real-life issues, or even real-life heroes who have made breakthroughs in fields such as public health, the impact could be tremendous. Imagine a world where Superman is mentioned in the same breath as Ignaz Semmelweis, the man who revolutionized sanitation in health care by demonstrating that hand washing prevents the spread of infection. Children who idolize the champions of health care could someday grow up to be heroes themselves, fighting epidemics and saving lives through education, treatment and research. Their wildest fantasies could become a reality. PMID- 25691357 TI - Potential sonodynamic anticancer activities of artemether and liposome encapsulated artemether. AB - The potential application of artemether as a novel sonosensitizer for sonodynamic therapy (SDT) was explored and illustrated for the first time. In addition, liposome-encapsulated artemether exhibited significantly enhanced sonodynamic anticancer activity. Our findings indicated that artemisinin derivatives may serve as a new kind of sonosensitizer for SDT. PMID- 25691358 TI - A systematic review of meta-analyses of psychosocial treatment for attention deficit/hyperactivity disorder. AB - The present report synthesizes outcomes across meta-analyses of psychosocial (i.e., non-pharmacological) treatments for ADHD. A total of 12 meta-analyses were identified that met search criteria. The meta-analyses were notable in that there was surprisingly little overlap in studies included across them (range of overlap was 2-46 %). Further, there was considerable diversity across the meta-analyses in terms of the inclusion/exclusion criteria, types of psychosocial treatments reviewed, methodological characteristics, and magnitude of reported effect sizes, making it difficult to aggregate findings across meta-analyses or to investigate moderators of outcome. Effect sizes varied across the outcomes assessed, with meta-analyses reporting positive and significant effect sizes for measures of some areas of child impairment (e.g., social impairment) and small and more variable effect sizes for distal and/or untargeted outcomes (e.g., academic achievement). Results are reviewed in light of the larger literature on psychosocial interventions for ADHD, and specific recommendations for future meta analyses of psychosocial treatments for ADHD are offered. PMID- 25691359 TI - Efficacy and safety of a single-pill combination of vildagliptin and metformin in Japanese patients with type 2 diabetes mellitus: a randomized, double-blind, placebo-controlled trial. AB - INTRODUCTION: The use of dipeptidyl peptidase-4 inhibitors in combination with metformin is increasing in Japanese patients with type 2 diabetes mellitus (T2DM), but no single-pill combination (SPC) is currently available in Japan. The objective of this study was to assess the efficacy and safety of vildagliptin/metformin SPC in Japanese patients with T2DM inadequately controlled with vildagliptin monotherapy. METHODS: This was a 14-week, randomized, double blind, parallel-group, placebo-controlled trial. 171 patients with T2DM inadequately controlled [HbA1c (glycosylated hemoglobin) 7.0-10.0%] with vildagliptin 50 mg twice daily (bid) were randomized (2:1) to receive either a vildagliptin/metformin SPC (n = 115) or matching vildagliptin/placebo SPC (n = 56). RESULTS: Baseline demographics and background characteristics were generally comparable between the treatment groups. The change in HbA1c [mean +/- standard error (SE)] was -0.8 +/- 0.1% in the vildagliptin/metformin SPC (baseline HbA1c, 7.9 +/- 0.1%) group and 0.1 +/- 0.1% in the vildagliptin/placebo SPC (baseline HbA1c, 8.0 +/- 0.1%) group, with a between-treatment difference of -1.0 +/- 0.1% (P <0.001) in favor of the vildagliptin/metformin SPC group. The proportion of patients achieving target HbA1c <7.0% was significantly higher with vildagliptin/metformin SPC compared with vildagliptin/placebo SPC (45.8% vs. 13.5%, P <0.001). The overall incidences of adverse events (AEs) were 43.5% in the vildagliptin/metformin SPC and 67.9% in the vildagliptin/placebo SPC group. The incidences of serious AEs were low in both the treatment groups (0.9% vs. 3.6%, respectively). Body weight remained constant throughout the study in both the treatment groups. There were no deaths or hypoglycemic events during the study. CONCLUSIONS: Switching Japanese patients with T2DM requiring treatment intensification, from vildagliptin monotherapy to a vildagliptin/metformin SPC (50/250 or 50/500 mg) was efficacious and safe, eliciting significant reduction in HbA1c without increased risk of hypoglycemia and weight gain. PMID- 25691360 TI - Nerve injury-induced calcium channel alpha-2-delta-1 protein dysregulation leads to increased pre-synaptic excitatory input into deep dorsal horn neurons and neuropathic allodynia. AB - BACKGROUND: Up-regulation of voltage-gated calcium channel alpha2 delta1 subunit post spinal nerve ligation (SNL) injury or in alpha2 delta1 -overexpressing transgenic (Tg) mice correlates with tactile allodynia, a pain state mediated mainly by Abeta sensory fibres forming synaptic connections with deep dorsal horn (DDH) neurons. It is not clear, however, whether dysregulated alpha2 delta1 alters DDH synaptic neurotransmission that underlies tactile allodynia development post nerve injury. METHODS: Tactile allodynia was tested in the SNL and alpha2 delta1 Tg models. Miniature excitatory/inhibitory post-synaptic currents were recorded in DDH neurons from these animal models using whole-cell patch clamp slice recording techniques. RESULTS: There was a significant increase in the frequency, but not amplitude, of miniature excitatory post-synaptic currents (mEPSC) in DDH neurons that correlated with tactile allodynia in SNL and alpha2 delta1 Tg mice. Gabapentin, an alpha2 delta1 ligand that is known to block tactile allodynia in these models, also normalized mEPSC frequency dose dependently in DDH neurons from SNL and alpha2 delta1 Tg mice. In contrast, neither frequency nor amplitude of miniature inhibitory post-synaptic currents was altered in DDH neurons from SNL and alpha2 delta1 Tg mice. CONCLUSION: Our data suggest that alpha2 delta1 dysregulation is highly likely contributing to tactile allodynia through a pre-synaptic mechanism involving facilitation of excitatory synaptic neurotransmission in DDH of spinal cord. PMID- 25691361 TI - Models of survivorship care provision in adult patients with haematological cancer: an integrative literature review. AB - PURPOSE: Increasing numbers of haematology cancer survivors warrants identification of the most effective model of survivorship care to survivors from a diverse range of haematological cancers with aggressive treatment regimens. This review aimed to identify models of survivorship care to support the needs of haematology cancer survivors. METHOD: An integrative literature review method utilised a search of electronic databases (CINAHL, Medline, PsycInfo, PubMed, EMBASE, PsycArticles, and Cochrane Library) for eligible articles (up to July 2014). Articles were included if they proposed or reported the use of a model of care for haematology cancer survivors. RESULTS: Fourteen articles were included in this review. Eight articles proposed and described models of care, and six reported the use of a range of survivorship models of care in haematology cancer survivors. No randomised controlled trials or literature reviews were found to have been undertaken specifically with this cohort of cancer survivors. There was variation in the models described and who provided the survivorship care. CONCLUSION: Due to the lack of studies evaluating the effectiveness of models of care, it is difficult to determine the best model of care for haematology cancer survivors. Many different models of care are being put into practice before robust research is conducted. Therefore, well-designed high-quality pragmatic randomised controlled trials are required to inform clinical practice. PMID- 25691362 TI - Bogus visual feedback alters onset of movement-evoked pain in people with neck pain. AB - Pain is a protective perceptual response shaped by contextual, psychological, and sensory inputs that suggest danger to the body. Sensory cues suggesting that a body part is moving toward a painful position may credibly signal the threat and thereby modulate pain. In this experiment, we used virtual reality to investigate whether manipulating visual proprioceptive cues could alter movement-evoked pain in 24 people with neck pain. We hypothesized that pain would occur at a lesser degree of head rotation when visual feedback overstated true rotation and at a greater degree of rotation when visual feedback understated true rotation. Our hypothesis was clearly supported: When vision overstated the amount of rotation, pain occurred at 7% less rotation than under conditions of accurate visual feedback, and when vision understated rotation, pain occurred at 6% greater rotation than under conditions of accurate visual feedback. We concluded that visual-proprioceptive information modulated the threshold for movement-evoked pain, which suggests that stimuli that become associated with pain can themselves trigger pain. PMID- 25691363 TI - High-performance coils and yarns of polymeric piezoelectric nanofibers. AB - We report on highly stretchable piezoelectric structures of electrospun PVDF-TrFE nanofibers. We fabricated nanofibrous PVDF-TrFE yarns via twisting their electrospun ribbons. Our results show that the twisting process not only increases the failure strain but also increases overall strength and toughness. The nanofibrous yarns achieved a remarkable energy to failure of up to 98 J/g. Through overtwisting process, we fabricated polymeric coils out of twisted yarns that stretched up to ~740% strain. This enhancement in mechanical properties is likely induced by increased interactions between nanofibers, contributed by friction and van der Waals interactions, as well as favorable surface charge (Columbic) interactions as a result of piezoelectric effect, for which we present a theoretical model. The fabricated yarns and coils show great promise for applications in high-performance lightweight structural materials and superstretchable piezoelectric devices and flexible energy harvesting applications. PMID- 25691364 TI - Efficient Standard Error Formulas of Ability Estimators with Dichotomous Item Response Models. AB - This paper focuses on the computation of asymptotic standard errors (ASE) of ability estimators with dichotomous item response models. A general framework is considered, and ability estimators are defined from a very restricted set of assumptions and formulas. This approach encompasses most standard methods such as maximum likelihood, weighted likelihood, maximum a posteriori, and robust estimators. A general formula for the ASE is derived from the theory of M estimation. Well-known results are found back as particular cases for the maximum and robust estimators, while new ASE proposals for the weighted likelihood and maximum a posteriori estimators are presented. These new formulas are compared to traditional ones by means of a simulation study under Rasch modeling. PMID- 25691366 TI - A high-throughput RNAi screen for detection of immune-checkpoint molecules that mediate tumor resistance to cytotoxic T lymphocytes. AB - The success of T cell-based cancer immunotherapy is limited by tumor's resistance against killing by cytotoxic T lymphocytes (CTLs). Tumor-immune resistance is mediated by cell surface ligands that engage immune-inhibitory receptors on T cells. These ligands represent potent targets for therapeutic inhibition. So far, only few immune-suppressive ligands have been identified. We here describe a rapid high-throughput siRNA-based screening approach that allows a comprehensive identification of ligands on human cancer cells that inhibit CTL-mediated tumor cell killing. We exemplarily demonstrate that CCR9, which is expressed in many cancers, exerts strong immune-regulatory effects on T cell responses in multiple tumors. Unlike PDL1, which inhibits TCR signaling, CCR9 regulates STAT signaling in T cells, resulting in reduced T-helper-1 cytokine secretion and reduced cytotoxic capacity. Moreover, inhibition of CCR9 expression on tumor cells facilitated immunotherapy of human tumors by tumor-specific T cells in vivo. Taken together, this method allows a rapid and comprehensive determination of immune-modulatory genes in human tumors which, as an entity, represent the 'immune modulatome' of cancer. PMID- 25691367 TI - A review of pharmacokinetic drug-drug interactions with the anthelmintic medications albendazole and mebendazole. AB - Medications indicated for helminthes and other parasitic infections are frequently being used in mass populations in endemic areas. Currently, there is a lack of guidance for clinicians on how to appropriately manage drug interactions when faced with patients requiring short-term anthelmintic therapy with albendazole or mebendazole while concurrently taking other agents. The objective of this review was to systematically summarize and evaluate published literature on the pharmacokinetics of albendazole or mebendazole when taken with other interacting medications. A search of MEDLINE (1946 to October 2014), EMBASE (1974 to October 2014), International Pharmaceutical Abstracts (1970 to October 2014), Google, and Google Scholar was conducted for articles describing the pharmacokinetics of albendazole or mebendazole when given with other medications (and supplemented by a bibliographic review of all relevant articles). Altogether, 17 articles were included in the review. Studies reported data on pharmacokinetic parameters for albendazole or mebendazole when taken with cimetidine, dexamethasone, ritonavir, phenytoin, carbamazepine, phenobarbital, ivermectin, praziquantel, diethylcarbamazine, azithromycin, and levamisole. Cimetidine increased the elimination half-life of albendazole and maximum concentration (Cmax) of mebendazole; dexamethasone increased the area under the plasma concentration-time curve (AUC) of albendazole; levamisole decreased the Cmax of albendazole; anticonvulsants (phenytoin, phenobarbital, carbamazepine) decreased the AUC of albendazole; praziquantel increased the AUC of albendazole; and ritonavir decreased the AUC of both albendazole and mebendazole. No major interactions were found with ivermectin, azithromycin, or diethylcarbamazine. Future research is required to clarify the clinical relevance of the interactions observed. PMID- 25691368 TI - Poor osteochondral repair by a biomimetic collagen scaffold: 1- to 3-year clinical and radiological follow-up. AB - INTRODUCTION: Treatment of osteochondral injuries is challenging, and no gold standard has been established. Layered cell-free scaffolds are a new treatment option for these defects. The aim of this study was to evaluate the osteochondral repair in patients treated with the MaioRegen((r)) scaffold, a cell-free biomimetic scaffold consisting of type I collagen and hydroxyapatite. Treatment using this scaffold has previously shown promising clinical results. METHODS: Ten patients with osteochondral lesions in the knee (n = 6) or in the talus (n = 4) were enrolled. The patients underwent pre-operative MRI and CT scans and were assessed at 1- and 2.5-year timescales post-operatively. The cartilage and bone formations were evaluated semi-quantitatively using the MOCART score. Knee patients were clinically evaluated using KOOS, subjective IKDC and Tegner scores, whereas ankle patients were evaluated using AOFAS Hindfoot and Tegner scores. RESULTS: Two patients were re-operated and excluded from further follow-up due to treatment failure. None of the patients had complete regeneration of the subchondral bone evaluated using CT. At 2.5 years, 6/8 patients had no or very limited (<10 %) bone formation in the defects and 2/8 had 50-75 % bone formation in the treated defect. MRI showed no improvement in the MOCART score at any time point. The IKDC score improved from 41.3 to 80.7, and the KOOS pain subscale improved from 63.8 to 90.8 at 2.5-year follow-up. No improvement was found with the remaining KOOS subscales, the Tegner or AOFAS Ankle-Hindfoot score. CONCLUSION: Treatment of osteochondral defects in the ankle and knee joint with a biomimetic scaffold resulted in incomplete cartilage repair and poor subchondral bone repair at 1- and 2.5-year follow-up. Clinical significant improvements were observed. These results raise serious concerns about the biological repair potential of the MaioRegen((r)) scaffold, and we advise to use the MaioRegen((r)) scaffold with caution. LEVEL OF EVIDENCE: Prospective therapeutic study, Level IV. PMID- 25691369 TI - A reply to Wade. PMID- 25691370 TI - The importance of working memory updating in the Prisoner's dilemma. AB - Successful cooperation requires that humans can flexibly adjust choices to their partner's behaviour. This, in turn, presupposes a representation of a partner's past decisions in working memory. The aim of the current study was to investigate the role of working memory processes in cooperation. For that purpose, we tested the effects of working memory updating (Experiment 1) and working memory maintenance demands (Experiments 2 and 3) on cooperative behaviour in the Prisoner's dilemma game. We found that demands on updating, but not maintenance, of working memory contents impaired strategy use in the Prisoner's dilemma. Thus, our data show that updating a partner's past behaviour in working memory represents an important precondition for strategy use in cooperation. PMID- 25691371 TI - Application of tungsten as a carbon sink for synthesis of large-domain uniform monolayer graphene free of bilayers/multilayers. AB - We have found that tungsten (W) foils can be used for controlling the carbon diffusion within copper (Cu) enclosures to synthesize large-domain bi-/multi layer-free monolayer graphene via chemical vapor deposition. We have observed that bi-/multi-layer graphene that nucleate underneath the monolayer graphene can be selectively removed by a W foil placed inside of the Cu enclosure. Both X-ray photoelectron spectroscopy and X-ray diffraction reveal the formation of tungsten sub-carbide (W2C), suggesting the role of the W foil as a carbon sink that alters the carbon concentration inside of the enclosure. Consequently, the bi-/multi layers appear to dissolve. Utilizing this selective removal process, we were able to demonstrate large-domain (>200 MUm) monolayer graphene that is free of any bi /multi-layers by using Cu double enclosures. PMID- 25691372 TI - Cadmium causes vesicle leakage under conditions which favor reconstitution of tissue factor-vesicle complexes. AB - Cadmium has a singular ability to promote the functional reconstitution of tissue factor (coagulation factor III) apoprotein with vesicles formed from mixed bovine brain lipids. Cadmium causes rapid release of carboxyfluorescein from lipid vesicles which chromatograph in the included volume of Bio Gel A5m, and also promotes reconstitution of tissue factor with these vesicles. With larger vesicles, which are excluded on Bio Gel A5m, cadmium produces only low levels of reconstitution and leakage. Calcium has been shown to promote only low levels of tissue factor-vesicle reconstitution, and produces only low levels of carboxyfluorescein leakage when compared to cadmium. These results demonstrate that cadmium and calcium interact differently with the small mixed lipid vesicles, and suggest that the cadmium-promoted reconstitution of tissue factor vesicle-complexes accompanies cadmium-induced alterations in vesicle structure. The results also show that cadmium affects large and small vesicles differently. PMID- 25691373 TI - Impedance of the electrogenic Cl(-) pump inAcetabularia: Electrical frequency entrainements, voltage-sensitivity, and reaction kinetic interpretation. AB - Reaction kinetic analysis of the electrical properties of the electrogenic Cl(-) pump inAcetabularia has been extended from steady-state to nonsteady-state conditions: electrical frequency responses of theAcetabularia membrane have been measured over the range from 1 Hz to 10 kHz at transmembrane potential differences across the plasmalemma (V m ) between -70 and -240 mV using voltage clamp techniques. The results are well described by an electrical equivalent circuit with three parallel limbs: a conventional membrane capacitancec m , a steadystate conductanceg o (predominantly of the pump pathway plus a minor passive ion conductance) and a conductanceg s in series with a capacitancec p which are peculiar to the temporal behavior of the pump. The absolute values and voltage sensitivities of these four elements have been determined:c m of about 8 mF m(-2) turned out to be voltage insensitive; it is considered to be normal.g o is voltage sensitive and displays a peak of about 80 S m(-2) around -180 mV. Voltage sensitivity ofg s could not be documented due to large scatter ofg s (around 80 S m(-2)).c p behaved voltage sensitive with a notch of about 20 mF m( 2) around -180 mV, a peak of about 40 mF m(-2) at -120 mV and vanishing at -70 mV. When these data are compared with the predictions of nonsteady-state electrical properties of charge transport systems (U.-P. Hansen, J. Tittor, D. Gradmann, 1983,J. Membrane Biol. in press), model "A" (redistribution of states within the reaction cycle) consistently provides magnitude and voltage sensitivity of the elementsg o ,g s andc p of the equivalent circuit, when known kinetic parameters of the pump are used for the calculations. This analysis results in a density of pump elements in theAcetabularia plasmalemma of about 50 nmol m(-2). The dominating rate constants for the redistribution of the individual states of the pump in the electric field turn out to be in the range of 500 sec(-1), under normal conditions. PMID- 25691374 TI - Interpretation of current-voltage relationships for "active" ion transport systems: II. Nonsteady-state reaction kinetic analysis of class-I mechanisms with one slow time-constant. AB - The temporal behavior of current through a biological membrane can display more than one time constant. This study represents the reaction kinetic analysis of the nonsteady-state behavior of a class of membrane transporters with one voltage sensitive reaction step, one dominant (large) time constant, but arbitrary reaction scheme of the voltage-insensitive part of transporter. This class of transporters which shows uniform behavior under steady-state conditions splits into two fundamentally different subclasses, when nonsteady-state behavior is examined: Subclass (Model) A: the slow reaction controls the redistribution of states within the reaction cycle upon an (electrical) perturbation; model B: this redistribution is fast but the transporting cycle can slowly equilibrate with an inactive, "lazy" state. The electrical appearance of model A in a membrane requires specific features of the transporter in the membrane: high densities (10(-8) mol m(-2)), low turnover rates (10(3) sec(-1)) and high stoichiometry (z>1) of transported charges per cycle. The kinetics of both models can formally be described by an equivalent circuit with a steady-state slope conductance (G 0) shunted by a (transporter specific) capacitance (G t ) and a conductance (C t ) in series. The voltage dependence ofC t and ofG t can be used to identify model A or model B. In the range of maximumG 0 in the steady-state current-voltage curve,C t in model A displays a maximum (which may characteristically split into two maxima) and vanishes for larger voltage displacements.C t can be used for the determination of transporter densities in the membrane. In contrast to model A, the appearance of model B in the nonsteady-state behavior of a membrane does not depend on high densities, low turnover rates and high stoichiometry; it can, therefore, be found also in membranes with sparsely distributed, rapidly transporting channels of any stoichiometry. Particular to model B is a change in the signs ofC t andG t at the reversal potential of the steady-state current voltage relationship. This implies switching from capacitive to inductive behavior (under vanishing amplitudes). Also in model B, the nonsteady-state effects disappear for large voltage displacements from the reversal potential. Model B is expected to occur preferably in transporters subject to metabolic control. PMID- 25691375 TI - In vitro comparative survey of cell adhesion and proliferation of human induced pluripotent stem cells on surfaces of polymeric electrospun nanofibrous and solution-cast film scaffolds. AB - Extracellular matrix (ECM) components play a critical role in regulating cell behaviors. Interactions between ECM components and cells are important in various biological processes, including cell attachment, survival, morphogenesis, spreading, proliferation, and gene expression. In this study the in vitro responses of human induced pluripotent stem cells (hiPSCs) on polycaprolactone (PCL) electrospun nanofibrous scaffold were reported in comparison with those of the cells on corresponding solution-cast film scaffold. Our results demonstrated that the nanofibrous scaffold showed better support for the attachment and proliferation of hiPSCs than their corresponding film scaffold. Consequently, we emphasize that hiPSCs can sense the physical properties and chemical composition of the materials and regulate their behaviors accordingly. PMID- 25691376 TI - IPF Care: a support program for patients with idiopathic pulmonary fibrosis treated with pirfenidone in Europe. AB - Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and irreversible fibrotic lung disease that requires long-term treatment. Given the importance of adherence to treatment and management of adverse events (AEs), patients with IPF need long-term, high-quality support in living with their condition, and adhering to therapy so they can derive maximum benefit. The IPF Care Patient Support Program (IPF Care) provides support, education, and empowerment to patients receiving pirfenidone for the treatment of IPF in Europe, through the provision of frequent, patient-managed discussions with specialist IPF nurses. In this review, we describe the structure of IPF Care in the United Kingdom (UK) and Austria, two of the longest-running IPF Care programs to date, and describe the benefits that these programs provide to patients with IPF. Analysis of results demonstrates a low rate of discontinuation from the program, and provides insight into the questions and concerns that patients express, not only with respect to pirfenidone (the only approved treatment for IPF at the time of analysis), but also in relation to other aspects of living with IPF. Pirfenidone dose modifications are common in patients in IPF Care and AEs most commonly occur early in treatment, with the majority of affected patients continuing on a stable maintenance dose. This highlights the value of the advice and support that patients receive in IPF Care regarding management of AEs and staying on treatment. Patient satisfaction was high in a survey of the UK program, with patients reporting high scores regarding 'feeling in control of their condition', 'knowing what to expect from treatment', and 'feeling confident about how their disease is managed'. IPF Care in Europe will continue to evolve over time, striving to provide individually tailored support and patient-friendly information to improve treatment outcomes and quality of life for patients living with IPF. PMID- 25691377 TI - Paradigm shift redefining molecular, metabolic and structural events in Alzheimer's disease involves a proposed contribution by transition metals. Defined lengthy preclinical stage provides new hope to circumvent advancement of disease- and age-related neurodegeneration. AB - It is estimated that 5.5 Million North Americans suffer from varying degrees of Alzheimer's disease (AD) and by the year 2050 it may be one in 85 people globally (100 Million). It will be shown that heavy metal toxicity plays a significant role in sporadic AD. Although current literature speaks to involvement of metal ions (via Fenton reaction), studies and reviewers have yet to link cellular events including known structural changes such as amyloid plaque development to this metal toxicity the way it is proposed here. Contrary to the current AD model which positions BACE1 (beta-secretase) as an aberrant or AD-advancing enzyme, it is proposed herein that the neuron's protective counteraction to this metal toxicity is, in fact, a justified increase in BACE1 activity and amyloid precursor protein (APP) processing to yield more secreted APP (sAPP) and beta amyloid peptide in response to metal toxicity. This new perspective which justifies a functional role for APP, BACE1 enzyme activity and the peptide products from this activity may at first appear to be counterintuitive. Compelling evidence, however, is presented and a mechanism is shown herein that validate BACE1 recruitment and the resulting beta-amyloid protein as strategic countermeasures serving the cell effectively against neuro-impeding disease. It is proposed that beta-amyloid peptide chelates and sequesters free heavy metals in the extracellular medium to aggregate as amyloid plaque while unchelated beta amyloid migrates across the cell membrane to chelate intracellular free divalent metals. The sequestered intracellular metal is subsequently chaperoned as a metallo-peptide to cross the plasma membrane and aggregate as amyloid plaques extracellularly. The BACE1 countermeasure is not genetic or metabolic aberration; and this novel conclusion demonstrates that it must not be inhibited as currently targeted. APP, BACE1, beta-amyloid peptide, and sAPP play positive roles against the preclinical oxidative load that predates AD symptoms for as long as 20 years. A healthy neuron may tolerate free metal toxicity, such as iron in the case of injury-induced amyloid, for as long as twenty years due to this very BACE1 activity. In later stages, the uncontrolled metals and ROS are compounded by other factors which together overcome this BACE1/beta-amyloid protein countermeasure. This results in a sudden increase in IL-1 leading to Tau's hyperphosphorylation as cited and eventually to Tau dissociation from the microtubule cytoskeleton interrupting cell trafficking. At this later stage of AD the beta-amyloid protein which once served as a vehicle to escort toxic metals to the extracellular medium and a trap to form a relatively benign extraneuronal disposal site is no longer translocated due to interruption of trafficking and now accumulates intracellularly facilitating hyper-oxidative ROS levels and contributes to irreversible neuron apoptosis. PMID- 25691378 TI - The dormant cells of Mycobacterium tuberculosis may be resuscitated by targeting expression system of recombinant mycobacteriophage-Rpf: implication of shorter course of TB chemotherapy in the future. AB - Here we hypothesized that dormant cells of Mycobacterium tuberculosis (M. tuberculosis) may be resuscitated by a new expression system of recombinant mycobacteriophage-resuscitation-promoting factor (Rpf). In this system, gene of targeted Rpf was cloned into mycobacteriophage genome, since mycobacteriophages possess several characteristics, including automatic identification and specific infection of M. tuberculosis. Thus the targeted delivery and endogenous expression of Rpf to the infected area of M. tuberculosis can be realized, followed by resuscitating the dormant cells of M. tuberculosis. Finally, these resuscitated M. tuberculosis can be thoroughly killed by a strong short-term subsequent chemotherapy, which makes the course of TB chemotherapy much shorter in the future compared to simple chemotherapy. Early studies have confirmed that dormant cells of M. tuberculosis can be resuscitated by Rpf in vitro, but so far, there is no report that Rpf can succeed in resuscitating dormant cells of M. tuberculosis in vivo, the reason may be that it is difficult for purified Rpf to remain active in vivo, especially to achieve targeted delivery of exogenous Rpf to the infected area of dormant cells of M. tuberculosis. Mycobacteriophage is a virus, capable of specifically identifying and infecting mycobacterium, such as M. tuberculosis. Several studies show that motif 3-containing proteins have peptidoglycan-hydrolysing activity and that while this activity is not required for mycobacteriophage viability, it facilitates efficient infection and DNA injection of mycobacteriophage (including motif 3 protein) into stationary phase cells. Thus this expression system can achieve targeted delivery and endogenous expression of Rpf to infected area of dormant cells of M. tuberculosis. Finally, we discuss the implication of this recombinant expression system for shortening the course of TB chemotherapy. PMID- 25691379 TI - How Research on Charitable Giving Can Inform Strategies to Promote Human Milk Donations to Milk Banks. AB - Many hospitalized preterm infants do not exclusively receive mother's own milk, so milk from another mother may be sought. Previous research indicated that just 1% of US women who express breast milk actually donate it for another family. Therefore, strategies to boost donation rates should be identified. We draw upon the experimental literature on charitable giving of monetary donations to offer 6 strategies to promote breast milk donations to milk banks in North America. These strategies include (1) highlighting a potential identifiable recipient of donated breast milk as opposed to highlighting groups of potential recipients; (2) emphasizing similarities between the potential donor and potential beneficiaries; (3) emphasizing similarities between the potential donor and previous donors; (4) using negative arousal to promote donations; (5) emphasizing the self-interest of those asking for breast milk donations; and (6) highlighting the specific effect of breast milk donations. Potential limitations of these strategies are discussed. PMID- 25691380 TI - Transfer of methylprednisolone into breast milk in a mother with multiple sclerosis. AB - High-dose intravenous methylprednisolone, a glucocorticoid with powerful anti inflammatory activities, has become increasingly important in treating acute relapses of multiple sclerosis (MS). This is a case report of a 36-year-old lactating female who was receiving a 3-day course of high-dose methylprednisolone (1000 mg IV) to treat MS. Breast milk samples were obtained at 1, 2, 4, 8, and 12 hours following a 2-hour intravenous infusion on days 1, 2, and 3. The relative infant dose was found to be 1.45%, 1.35%, and 1.15% for days 1, 2, and 3, respectively. Using the average measured concentrations (C(avg)) for days 1, 2, and 3, the estimated infant exposure was 0.207, 0.194, and 0.164 mg/kg/day, respectively, which is below the recommended dose given to neonates requiring methylprednisolone drug therapy. Infant exposure is low and mothers could continue to breastfeed if treatment with IV methylprednisolone is very brief. However, if the mother wishes to limit infant exposure further, she could wait 2 to 4 hours after IV methylprednisolone administration, thus significantly limiting the amount of drug in the breast milk. PMID- 25691381 TI - The evidence behind noninvasive body contouring devices. AB - The demand for body contouring is rapidly increasing, and interest in noninvasive approaches has also grown. The author reviewed the evidence base behind the currently available devices and methods for nonsurgical body contouring. There is little high-level evidence in the present literature to support the effectiveness of any of these devices. PMID- 25691382 TI - STAT5 phosphorylation in T cell subsets from septic patients in response to recombinant human interleukin-7: a pilot study. AB - Septic shock is characterized by lymphocyte alterations associated with increased risk of nosocomial infections and mortality. IL-7, a cytokine required for T cell survival, is thought as a novel therapy for septic patients with severe lymphopenia. We assessed CD4(+) lymphocyte responsiveness to rhIL-7 in septic shock patients ex vivo. Thirteen septic shock patients and 10 controls were included. The MFI of pSTAT5, a key signaling molecule for IL-7, was measured by flow cytometry in CD4(+)FOXP3- (Teffs) and CD4(+)FOXP3(+) (Tregs) lymphocytes after whole-blood incubation with increasing doses of rhIL-7. The basal level of pSTAT5 in nonstimulated T cells was higher in patients. However, the maximal activation level in response to the highest doses of rhIL-7 was similar in both groups. Importantly, low doses of rhIL-7 preferentially activated Teff versus Treg in patients and nonsurvivors tended to present with decreased pSTAT5 expression. This pilot study is the first to highlight, in septic patients, the interest of pSTAT5 measurement in whole blood for the monitoring of rhIL-7 therapy. Such a method could represent an innovative, biologic tool for monitoring leukocyte pharmacological responses to biotherapies in daily clinical practice in other clinical contexts. PMID- 25691383 TI - Cocaine modulates HIV-1 integration in primary CD4+ T cells: implications in HIV 1 pathogenesis in drug-abusing patients. AB - Epidemiologic studies suggest that cocaine abuse worsens HIV-1 disease progression. Increased viral load has been suggested to play a key role for the accelerated HIV disease among cocaine-abusing patients. The goal of this study was to investigate whether cocaine enhances proviral DNA integration as a mechanism to increase viral load. We infected CD4(+) T cells that are the primary targets of HIV-1 in vivo and treated the cells with physiologically relevant concentrations of cocaine (1 uM-100 uM). Proviral DNA integration in the host genome was measured by nested qPCR. Our results illustrated that cocaine from 1 uM through 50 uM increased HIV-1 integration in CD4(+) T cells in a dose dependent manner. As integration can be modulated by several early postentry steps of HIV-1 infection, we examined the direct effects of cocaine on viral integration by in vitro integration assays by use of HIV-1 PICs. Our data illustrated that cocaine directly increases viral DNA integration. Furthermore, our MS analysis showed that cocaine is able to enter CD4(+) T cells and localize to the nucleus-. In summary, our data provide strong evidence that cocaine can increase HIV-1 integration in CD4(+) T cells. Therefore, we hypothesize that increased HIV-1 integration is a novel mechanism by which cocaine enhances viral load and worsens disease progression in drug-abusing HIV-1 patients. PMID- 25691385 TI - Citrus polyphenol for oral wound healing in oral ulcers and periodontal diseases. AB - BACKGROUND/PURPOSE: Various polyphenolic compounds from plants have been confirmed to have different pharmaceutical functions. The purpose of this study was to evaluate citrus polyphenol (CP) for dental applications. A medium with CP was developed to improve oral wound healing. The CP could be used as a supplemental compound in mouthwash for periodontal diseases. METHOD: In this study, the metabolic activity and cell toxicity of CP (1%, 0.1%, and 0.01%) for fibroblasts were investigated by MTT and lactate dehydrogenase assays (n = 6). The effect of CP on motility of fibroblast was also evaluated via a wound healing model. RESULTS: The growth of Hs68 cells on TCPS was greatly increased in the presence of 0.01% CP. In addition, the significant difference (p<0.01) of cell toxicity of fibroblast was observed after 6 days in 0.01% CP medium. Using the wound healing model, it was also found that CP could enhance the migratory ability of fibroblasts. CONCLUSION: The results confirm the feasibility of CP be a supplemental compound in mouthwash for treatment of periodontal diseases in dental application to improve wound healing in the mouth. PMID- 25691386 TI - Negative Trauma Appraisals and PTSD Symptoms in Sri Lankan Adolescents. AB - The cognitive model posits that negative appraisals play an important role in posttraumatic stress disorder, in children as well as in adults. This study examined correlates of negative appraisals in relation to trauma exposure and their relationship to posttraumatic stress symptoms (PTSS) in 414 Sri Lankan adolescents, aged 12 to 16, living in areas impacted in varying degrees by the 2004 tsunami. In 2008, participants completed measures of negative appraisals, lifetime traumatic events, posttraumatic stress symptoms, internalizing symptoms, ongoing adversity, and social support. The majority (70 %) of the participants reported multiple traumatic events; 25 % met DSM-IV criteria for full or partial PTSD. Adolescents who had experienced more severe events, abusive events, greater cumulative trauma, or greater current adversity reported more negative appraisals. In regression analyses controlling for known risk factors such as female gender, cumulative trauma, ongoing adversity, and low social support, negative appraisals were the best predictor of PTSS, explaining 22 % of the variance. This relationship appeared specific to PTSS, as negative appraisals did not predict internalizing symptoms. Findings confirm the link between negative cognitions concerning traumatic events and persistent PTSS in adolescents, but longitudinal studies are needed to determine whether appraisals contribute to symptom maintenance over time. PMID- 25691387 TI - A sensitive GC-EIMS method for simultaneous detection and quantification of JWH 018 and JWH-073 carboxylic acid and hydroxy metabolites in urine. AB - Synthetic cannabinoids, including JWH-018 and JWH-073, belong to a class of aminoalkylindoles (AAIs) that are smoked to produce an effect similar to tetrahydrocannabinol. Compounds in this class are often collectively known as 'Spice'. After ingestion, these compounds are extensively metabolized to their hydroxy and carboxylic acid metabolites. During forensic analysis, detection of these metabolites in urine is an indication of past exposure to the parent compounds. The analytical process involved hydrolysis of conjugated metabolites by glucuronidase, solvent extraction, derivatization by trifluoroacetic anhydride and hexafluoroisopropanol and GC-EIMS detection. Identification of the unknown was based on the criteria of GC retention time within +/-2% and mass spectral ion ratio within +/-20% of that of a standard. Deuterated internal standards of the carboxylic acid metabolites were used for quantification. The acid (JWH-018-COOH, JWH-073-COOH) and hydroxy (JWH-018-OH, JWH-073-OH) metabolites were linear over the concentration range of 0.1-10 and 0.2-10 ng/mL, respectively, with a correlation coefficient-square, R(2) > 0.999 (N = 5). Extraction recoveries of the metabolites were within 79 and 87%. The method was applied to 17 urine specimens collected as part of a military law enforcement investigation. Nine of the specimens tested positive for one or more of the metabolites. When the procedure was extended to screen other AAI compounds, two of the specimens were found to contain JWH-210, JWH-250 (JWH-302 or JWH-201) and JWH-250 (C4 isomers). The GC-EIMS method presented here was found to be suitable for detecting JWH-018 and JWH-073 metabolites and other AAI compounds in urine. PMID- 25691388 TI - Menopausal hot flushes and sweats persist longer than thought, study finds. PMID- 25691389 TI - Science for food: Molecular biology contributes to the production and preparation of food. PMID- 25691390 TI - Lung adenocarcinoma metastasizing into a renal angiomyolipoma. AB - Tumor-to-tumor metastasis is a very rare phenomenon. The most common donor and recipient of tumor-to-tumor metastasis are carcinomas of lung and renal cell carcinoma, respectively. We report a case of primary lung adenocarcinoma that metastasized into a renal angiomyolipoma 9 years after the resection of primary lung tumor. Comparisons in morphology, immunohistochemical profiles, and genetic mutations indicate that the tumor metastasizing into angiomyolipoma originated from the same clone of previous lung adenocarcinoma. Albeit rare, pathologists should be aware of the possibility of tumor-to-tumor metastasis when confronting a neoplasm exhibiting 2 distinct morphological features. PMID- 25691391 TI - Tissue love symbols. PMID- 25691392 TI - Prevalence and importance of hemosiderin pigments in uterine cervix stroma. PMID- 25691393 TI - Simple chemiluminescence determination of ketotifen using tris(1,10 phenanthroline)ruthenium(II)- Ce(IV) system. AB - A new method using chemiluminescence (CL) detection has been developed for the simple determination of ketotifen fumarate (KF). The method is based on the catalytic effect of KF in the CL reaction of tris(1,10 phenanthroline)ruthenium(II), Ru(phen)3 (2+), with Ce(IV) in sulfuric acid medium. The CL response was detected using a lab-made chemiluminometer. Effects of chemical variables were investigated and under optimum conditions, the CL intensity was proportional to the concentration of the drug over the range 0.34 34.00 ug mL(-1) KF. The limit of detection (S/N=3) was 0.09 ug mL(-1). Effects of common ingredients were investigated and the method was applied successfully for determining KF in pharmaceutical formulations and human plasma. The percent of relative standard deviation (n=11) at level of 3.4 ug mL(-1) of KF was 4.6% and the minimum sampling rate was 70 samples per hour. The possible CL mechanism is proposed based on the kinetic characteristic of the CL reaction, CL spectrum, UV Vis and phosphorescence spectra. PMID- 25691394 TI - No improvement in serological response among serofast latent patients retreated with benzathine penicillin. AB - Persistent non-treponemal titres after treatment are common among patients with latent syphilis. Although retreatment is often done in clinical practice, optimal management remains uncertain due to the paucity of data regarding serological response to retreatment and long-term outcomes. We compared the serological responses of serofast latent syphilis patients retreated with 7.2 million units of benzathine penicillin with the responses of patients who did not receive retreatment (control group). We retrospectively analysed the serological response to therapy following retreatment of 35 serofast latent syphilis patients at 12 months with benzathine penicillin 2.4 million units weekly for 3 weeks. In all, 74.3% (26/35) of the cases with latent syphilis who failed to achieve serological cure at 12 months after initial therapy achieved serological cure after retreatment and after an additional 12 months of follow-up. However, statistically similar serological cure rate was observed in 80.0% (28/35) of the control group (p > .05). Our findings illustrate no improvement in serological response among serofast latent patients retreated with three doses of benzathine penicillin. PMID- 25691395 TI - Coefficient of Friction Patterns Can Identify Damage in Native and Engineered Cartilage Subjected to Frictional-Shear Stress. AB - The mechanical loading environment encountered by articular cartilage in situ makes frictional-shear testing an invaluable technique for assessing engineered cartilage. Despite the important information that is gained from this testing, it remains under-utilized, especially for determining damage behavior. Currently, extensive visual inspection is required to assess damage; this is cumbersome and subjective. Tools to simplify, automate, and remove subjectivity from the analysis may increase the accessibility and usefulness of frictional-shear testing as an evaluation method. The objective of this study was to determine if the friction signal could be used to detect damage that occurred during the testing. This study proceeded in two phases: first, a simplified model of biphasic lubrication that does not require knowledge of interstitial fluid pressure was developed. In the second phase, frictional-shear tests were performed on 74 cartilage samples, and the simplified model was used to extract characteristic features from the friction signals. Using support vector machine classifiers, the extracted features were able to detect damage with a median accuracy of approximately 90%. The accuracy remained high even in samples with minimal damage. In conclusion, the friction signal acquired during frictional shear testing can be used to detect resultant damage to a high level of accuracy. PMID- 25691396 TI - A strain-based model for mechanical hemolysis based on a coarse-grained red blood cell model. AB - Mechanical hemolysis is a major concern in the design of cardiovascular devices, such as prosthetic heart valves and ventricular assist devices. The primary cause of mechanical hemolysis is the impact of the device on the local blood flow, which exposes blood elements to non-physiologic conditions. The majority of existing hemolysis models correlate red blood cell (RBC) damage to the imposed fluid shear stress and exposure time. Only recently more realistic, strain-based models have been proposed, where the RBC's response to the imposed hydrodynamic loading is accounted for. In the present work we extend strain-based models by introducing a high-fidelity representation of RBCs, which is based on existing coarse-grained particle dynamics approach. We report a series of numerical experiments in simple shear flows of increasing complexity, to illuminate the basic differences between existing models and establish their accuracy in comparison to the high-fidelity RBC approach. We also consider a practical configuration, where the flow through an artificial heart valve is computed. Our results shed light on the strengths and weaknesses of each approach and identify the key gaps that should be addressed in the development of new models. PMID- 25691397 TI - Pediatric Coronal Suture Fiber Alignment and the Effect of Interdigitation on Coronal Suture Mechanical Properties. AB - The morphological and mechanical properties of the pediatric skull are important in understanding pediatric head injury biomechanics. Although previous studies have analyzed the morphology of cranial sutures, none has done so in pediatric specimens nor have previous studies related the morphology to mechanical properties of human sutures. This study quantified the geometry of pediatric cranial sutures and investigated its correlation with the suture mechanical properties. First, the suture fiber alignment was quantified using histological analysis for four ages-neonate, 9 months-old, 11 months-old, and 18 months-old. For the morphometric investigation of the suture interdigitation, suture samples from a 6-year-old were scanned using micro-CT and the level of interdigitation was measured using two techniques. The first technique, the sinuosity index, was calculated by dividing the suture path along the surface of the skull by the suture distance from beginning to end. The second technique, the surface area interdigitation index, was calculated by measuring the surface area of the bone interface outlining the suture and dividing it by the cross-sectional area of the bone. The mechanical properties were obtained using methods reported in Davis et al.6. The results of the histological analysis showed a significant increase in fiber alignment in older specimen; where random fiber alignment has an average angle deviation of 45 degrees , neonatal suture fibers have an average deviation of 32.2 degrees and the 18-month-old fibers had an average deviation of 16.2 degrees (p < 0.0001). For the suture index measurements, only the sinuosity was positively correlated with the ultimate strain (R (2) = 0.62, Bonferroni corrected p = 0.011) but no other measurements showed a significant relationship, including the amount of interdigitation and elastic modulus. Our results demonstrate that there is a distinct developmental progression of the suture fiber alignment at a young age, but the differences in suture interdigitation can only predict the ultimate strain and no other mechanical properties. PMID- 25691398 TI - Enabling Surgical Placement of Hydrogels Through Achieving Paste-Like Rheological Behavior in Hydrogel Precursor Solutions. AB - Hydrogels are a promising class of materials for tissue regeneration, but they lack the ability to be molded into a defect site by a surgeon because hydrogel precursors are liquid solutions that are prone to leaking during placement. Therefore, although the main focus of hydrogel technology and developments are on hydrogels in their crosslinked form, our primary focus is on improving the fluid behavior of hydrogel precursor solutions. In this work, we introduce a method to achieve paste-like hydrogel precursor solutions by combining hyaluronic acid nanoparticles with traditional crosslinked hyaluronic acid hydrogels. Prior to crosslinking, the samples underwent rheological testing to assess yield stress and recovery using linear hyaluronic acid as a control. The experimental groups containing nanoparticles were the only solutions that exhibited a yield stress, demonstrating that the nanoparticulate rather than the linear form of hyaluronic acid was necessary to achieve paste-like behavior. The gels were also photocrosslinked and further characterized as solids, where it was demonstrated that the inclusion of nanoparticles did not adversely affect the compressive modulus and that encapsulated bone marrow-derived mesenchymal stem cells remained viable. Overall, this nanoparticle-based approach provides a platform hydrogel system that exhibits a yield stress prior to crosslinking, and can then be crosslinked into a hydrogel that is capable of encapsulating cells that remain viable. This behavior may hold significant impact for hydrogel applications where a paste-like behavior is desired in the hydrogel precursor solution. PMID- 25691399 TI - On Using Model Populations to Determine Mechanical Properties of Skeletal Muscle. Application to Concentric Contraction Simulation. AB - In the field of computational biomechanics, the experimental evaluation of the material properties is crucial for the development of computational models that closely reproduce real organ systems. When simulations of muscle tissue are concerned, stress/strain relations for both passive and active behavior are required. These experimental relations usually exhibit certain variability. In this study, a set of material parameters involved in a 3D skeletal muscle model are determined by using a system biology approach in which the parameters are randomly varied leading to a population of models. Using a set of experimental results from an animal model, a subset of the entire population of models was selected. This reduced population predicted the mechanical response within the window of experimental observations. Hence, a range of model parameters, instead of a single set of them, was determined. Rat Tibialis Anterior muscle was selected for this study. Muscles ([Formula: see text]) were activated through the sciatic nerve and during contraction the tissue pulled a weight fixed to the distal tendon (concentric contraction). Three different weights 1, 2 and 3 N were used and the time course of muscle stretch was analyzed obtaining values of (mean [Formula: see text] standard deviation): [Formula: see text], [Formula: see text] and [Formula: see text] respectively. A paired two-sided sign rank test showed significant differences between the muscle response for the three weights ([Formula: see text]). This study shows that the Monte Carlo method could be used for determine muscle characteristic parameters considering the variability of the experimental population. PMID- 25691400 TI - Low Impedance Carbon Adhesive Electrodes with Long Shelf Life. AB - A novel electrocardiogram (ECG) electrode film is developed by mixing carbon black powder and a quaternary salt with a visco-elastic polymeric adhesive. Unlike traditional wet gel-based electrodes, carbon/salt/adhesive (CSA) electrodes should theoretically have an infinite shelf life as they do not dehydrate even after a prolonged period of storage. The CSA electrodes are electrically activated for use through the process of electrophoresis. Specifically, the activation procedure involves sending a high voltage and current through the electrode, which results in significant reduction of impedance so that high fidelity ECG signals can be obtained. Using the activation procedure, the ideal concentration of carbon black powder in the mixture with the adhesive was examined. It was determined that the optimum concentration of carbon black which minimized post-activation impedance was 10%. Once the optimal carbon black powder concentration was determined, extensive signal analysis was performed to compare the performance of the CSA electrodes to the standard silver silver chloride (Ag/AgCl) electrodes. As a part of data analysis, electrode-skin contact impedance of the CSA was measured and compared to the standard Ag/AgCl electrodes; we found consistently lower impedance for CSA electrodes. For quantitative data analysis, we simultaneously collected ECG data with CSA and Ag/AgCl electrodes from 17 healthy subjects. Heart rate variability (HRV) indices and ECG morphological waveforms were calculated to compare CSA and Ag/AgCl electrodes. Non-significant differences for most of the HRV indices between CSA and Ag/AgCl electrodes were found. Of the morphological waveform metrics consisting of R-wave peak amplitude, ST-segment elevation and QT interval, only the first index was found to be significantly different between the two media. The response of CSA electrodes to motion artifacts was also tested, and we found in general no difference in the quality of the ECG signal between the two media. Hence, given that CSA electrodes are expected to have a very long shelf-life, with potentially less cost associated with their fabrication, and have ECG signal dynamics nearly identical to those of Ag/AgCl, the new electrodes provide an attractive alternative for ECG measurements. PMID- 25691401 TI - Diagnosis and treatment of Ewing sarcoma of the bone: a review article. AB - Ewing sarcoma (ES) is rare in Japanese people, and only 30-40 patients develop the disease annually. To diagnose ES, molecular techniques that aim to detect characteristic fusion genes are commonly used in combination with conventional histological and immunohistochemical examinations. The treatment strategy for ES is characterized by multi-disciplinary collaboration between pediatric oncologists, medical oncologists, radiation oncologists, and orthopedic surgeons. In recent years, numerous large-scale national or international multi institutional studies of ES have been performed. Pre- and postoperative intensive systemic chemotherapy with multiple anticancer drugs is the standard treatment method for ES. Depending on the obtained surgical margin, postoperative radiation might also be performed. If preoperative radiological examinations indicate that surgical excision would be difficult, preoperative radiation can be administered. As the treatment outcomes of ES have improved, late complications and secondary malignancies have become a problem. After treatment, patients with ES require very long-term follow-up in order to detect secondary malignancies and growth related musculoskeletal complications. PMID- 25691402 TI - Strategic career planning for physician-scientists. AB - Building a successful professional career in the physician-scientist realm is rewarding but challenging, especially in the dynamic and competitive environment of today's modern society. This educational review aims to provide readers with five important career development lessons drawn from the business and social science literatures. Lessons 1-3 describe career strategy, with a focus on promoting one's strengths while minimizing fixing one's weaknesses (Lesson 1); effective time management in the pursuit of long-term goals (Lesson 2); and the intellectual flexibility to abandon/modify previously made decisions while embracing emerging opportunities (Lesson 3). Lesson 4 explains how to maximize the alternative benefits of English-language fluency (i.e., functions such as signaling and cognition-enhancing capabilities). Finally, Lesson 5 discusses how to enjoy happiness and stay motivated in a harsh, zero-sum game society. PMID- 25691403 TI - Significant clinical benefits of molecular studies in the skeletal dysplasias. PMID- 25691404 TI - Copy number variations in children with brain malformations and refractory epilepsy. AB - Brain malformations are a major cause of therapy-refractory epilepsy as well as neurological and developmental disabilities in children. This study examined the frequency and the nature of copy number variations among children with structural brain malformations and refractory epilepsy. The medical records of all children born between 1990 and 2009 in the epilepsy registry at the Astrid Lindgren's Children's Hospital were reviewed and 86 patients with refractory epilepsy and various brain malformations were identified. Array-CGH analysis was performed in 76 of the patients. Pathogenic copy number variations were detected in seven children (9.2%). In addition, rearrangements of unclear significance, but possibly pathogenic, were detected in 11 (14.5%) individuals. In 37 (48.7%) patients likely benign, but previously unreported, copy number variants were detected. Thus, a large proportion of our patients had at least one rare copy number variant. Our results suggest that array-CGH should be considered as a first line genetic test for children with cerebral malformations and refractory epilepsy unless there is a strong evidence for a specific monogenic syndrome. PMID- 25691405 TI - Anirdia-like phenotype caused by 6p25 dosage aberrations. AB - Axenfeld-Rieger spectrum (ARS) includes the anterior segment abnormalities posterior embryotoxon, irido-corneal adhesions, corectopia, and other abnormalities of pupil size and shape. Glaucoma occurs in approximately 50% of affected children. It is often caused by mutations of FOXC1 or PITX2. Timing of expression and dosage of these transcription factors appear to be very critical in the development of the anterior segment. We report on one child with a deletion and another with a duplication involving 6p25, causing an anirdia-like phenotype. Classic anirdia is a pan-ophthalmic disorder caused by heterozygous mutations involving the paired homeobox gene PAX6 at 11p13. It is often associated with optic nerve hypoplasia, foveal hypoplasia, corneal pannus, nystagmus, and cataract. Microdeletion of 11p13 may be associated with life threatening Wilms tumor. Distinguishing these two syndromes has critical implications for prognosis and treatment. We demonstrate how chromosomal microarray can be instrumental in differentiating these phenotypes. PMID- 25691406 TI - Craniofacial dysmorphology in 22q11.2 deletion syndrome by 3D laser surface imaging and geometric morphometrics: illuminating the developmental relationship to risk for psychosis. AB - Persons with 22q11.2 deletion syndrome (22q11.2DS) are characterized inter alia by facial dysmorphology and greatly increased risk for psychotic illness. Recent studies indicate facial dysmorphology in adults with schizophrenia. This study evaluates the extent to which the facial dysmorphology of 22q11.2DS is similar to or different from that evident in schizophrenia. Twenty-one 22q11.2DS-sibling control pairs were assessed using 3D laser surface imaging. Geometric morphometrics was applied to 30 anatomical landmarks, 480 geometrically homologous semi-landmarks on curves and 1720 semi-landmarks interpolated on each 3D facial surface. Principal component (PC) analysis of overall shape space indicated PC2 to strongly distinguish 22q11.2DS from controls. Visualization of PC2 indicated 22q11.2DS and schizophrenia to be similar in terms of overall widening of the upper face, lateral displacement of the eyes/orbits, prominence of the cheeks, narrowing of the lower face, narrowing of nasal prominences and posterior displacement of the chin; they differed in terms of facial length (increased in 22q11.2DS, decreased in schizophrenia), mid-face and nasal prominences (displaced upwards and outwards in 22q11.2DS, less prominent in schizophrenia); lips (more prominent in 22q11.2DS; less prominent in schizophrenia) and mouth (open mouth posture in 22q11.2DS; closed mouth posture in schizophrenia). These findings directly implicate dysmorphogenesis in a cerebral-craniofacial domain that is common to 22q11.2DS and schizophrenia and which may repay further clinical and genetic interrogation in relation to the developmental origins of psychotic illness. PMID- 25691408 TI - Duplication Xp11.22-p14 in females: does X-inactivation help in assessing their significance? AB - In females, large duplications in Xp often lead to preferential inactivation of the aberrant X chromosome and a normal phenotype. Recently, a recurrent ~4.5 Mb microduplication of Xp11.22-p11.23 was found in females with developmental delay/intellectual disability and other neurodevelopmental disorders (speech development disorder, epilepsy or EEG anomalies, autism spectrum disorder, or behavioral disorder). Unexpectedly, most of them showed preferential inactivation of the normal X chromosome. We describe five female patients carrying de novo Xp duplications encompassing p11.23. Patient 1 carried the recurrent microduplication Xp11.22-p11.23, her phenotype and X-chromosome inactivation (XI) pattern was consistent with previous reports. The other four patients had novel Xp duplications. Two were monozygotic twins with a similar phenotype to Patient 1 and unfavorable XI skewing carrying an overlapping ~5 Mb duplication of Xp11.23 p11.3. Patient 4 showed a duplication of ~5.5 Mb comparable to the twins but had a more severe phenotype and unskewed XI. Patient 5 had a ~8.5 Mb duplication Xp11.23-p11.4 and presented with mild ID, epilepsy, behavioral problems, and inconsistent results of XI analysis. A comparison of phenotype, size and location of the duplications and XI patterns in Patients 1-5 and previously reported females with overlapping duplications provides further evidence that microduplications encompassing Xp11.23 are associated with ID and other neurodevelopmental disorders in females. To further assess the implication of XI for female carriers, we recommend systematic analysis of XI pattern in any female with X imbalances that are known or suspected to be pathogenic. PMID- 25691407 TI - Expanding the genetic and phenotypic spectrum of popliteal pterygium disorders. AB - The popliteal pterygia syndromes are a distinct subset of the hundreds of Mendelian orofacial clefting syndromes. Popliteal pterygia syndromes have considerable variability in severity and in the associated phenotypic features but are all characterized by cutaneous webbing across one or more major joints, cleft lip and/or palate, syndactyly, and genital malformations. Heterozygous mutations in IRF6 cause popliteal pterygium syndrome (PPS) while homozygous mutations in RIPK4 or CHUK (IKKA) cause the more severe Bartsocas-Papas syndrome (BPS) and Cocoon syndrome, respectively. In this study, we report mutations in six pedigrees with children affected with PPS or BPS. Using a combination of Sanger and exome sequencing, we report the first case of an autosomal recessive popliteal pterygium syndrome caused by homozygous mutation of IRF6 and the first case of uniparental disomy of chromosome 21 leading to a recessive disorder. We also demonstrate that mutations in RIPK4 can cause features with a range of severity along the PPS-BPS spectrum and that mutations in IKKA can cause a range of features along the BPS-Cocoon spectrum. Our findings have clinical implications for genetic counseling of families with pterygia syndromes and further implicate IRF6, RIPK4, and CHUK (IKKA) in potentially interconnected pathways governing epidermal and craniofacial development. PMID- 25691409 TI - Increased plasma chemokine levels in children with Prader-Willi syndrome. AB - Prader-Willi syndrome (PWS) is caused by loss of paternally expressed genes from the 15q11-q13 region and reportedly rearranged as a cause of autism. Additionally, increased inflammatory markers and features of autism are reported in PWS. Cytokines encoded by genes involved with inflammation, cell proliferation, migration, and adhesion play a role in neurodevelopment and could be disturbed in PWS as abnormal plasma cytokine levels are reported in autism. We analyzed 41 plasma cytokines in a cohort of well-characterized children with PWS between 5 and 11 years of age and unaffected unrelated siblings using multiplex sandwich immunoassays with the Luminex magnetic-bead based platform. Data were analyzed using ANOVA testing for effects of diagnosis, gender, body mass index (BMI) and age on the 24 cytokines meeting laboratory criteria for inclusion. No significant effects were observed for age, gender or BMI. The log-transformed levels of the 24 analyzable cytokines were examined simultaneously using MANOVA adjusting for age and gender and a main effect of diagnosis was found (P-value <0.03). Four of 24 plasma cytokine levels (MCP1, MDC, Eotaxin, RANTES) were significantly higher in children with PWS compared with controls and classified as bioinflammatory chemokines supporting a disturbed immune response unrelated to obesity status. BMI was not statistically different in the two subject groups (PWS or unaffected unrelated siblings) and chemokine levels were not correlated with percentage of total body fat. Additional studies are required to identify whether possible early immunological disturbances and chemokine inflammatory processes found in PWS may contribute to neurodevelopment and behavioral features. PMID- 25691410 TI - Are Angelman and Prader-Willi syndromes more similar than we thought? Food related behavior problems in Angelman, Cornelia de Lange, fragile X, Prader-Willi and 1p36 deletion syndromes. AB - Food-related behavior problems are well documented in Prader-Willi syndrome (PWS), with impaired satiety, preoccupation with food and negative food-related behaviors (such as taking and storing food) frequently reported as part of the behavioral phenotype of older children and adults. Food-related behavior problems in other genetic neurodevelopmental syndromes remain less well studied, including those seen in Angelman Syndrome (AS), the 'sister imprinted disorder' of PWS. Food-related behavior problems were assessed in 152 participants each with one of five genetic neurodevelopmental syndromes - PWS, AS, 1p36 deletion, Cornelia de Lange, and fragile X. Predictably, levels of food-related behavior problems reported in participants with PWS significantly exceeded those of at least one other groups in most areas (impaired satiety; preoccupation with food; taking and storing food; composite negative behavior). However, in some areas people with AS were reported to display food-related problems at least as severe as those with PWS, with the AS group reported to display significantly more food-related behavior problems than at least one comparison group on measures of taking and storing food, composite negative behaviors, impaired satiety and preoccupation with food. Over 50% of participants in the AS group scored above the median point of the distribution of PWS scores on a measure of taking and storing food. These findings indicate further investigation of eating problems in AS are warranted and have implications for current theoretical interpretations of the behavioral differences between AS and PWS. PMID- 25691411 TI - Renal complications in 6p duplication syndrome: microarray-based investigation of the candidate gene(s) for the development of congenital anomalies of the kidney and urinary tract (CAKUT) and focal segmental glomerular sclerosis (FSGS). AB - 6p duplication syndrome is a rare chromosomal disorder that frequently manifests renal complications, including proteinuria, hypoplastic kidney, and hydronephrosis. We report a girl with the syndrome, manifesting left hydronephrosis, proteinuria/hematuria, and focal segmental glomerular sclerosis (FSGS) resulting in chronic end-stage renal failure, successfully treated with renal transplantation. Microarray comparative genomic hybridization showed the derivative chromosome 6 to have a 6.4-Mb duplication at 6p25.3-p25.1 with 32 protein-coding genes and a 220-Kb deletion at 6p25.3 with two genes of no possible relation to the renal pathology. Review of the literature shows that variation of renal complications in the syndrome is compatible with congenital anomalies of the kidney and urinary tract (CAKUT). FSGS, observed in another patient with 6p duplication syndrome, could be a non-coincidental complication. FOXC1, located within the 6.4-Mb duplicated region at 6p25.3-p25.2, could be a candidate gene for CAKUT, but its single gene duplication effect would not be sufficient. FSGS would be a primary defect associated with duplicated gene(s) albeit no candidate could be proposed, or might occur in association with CAKUT. PMID- 25691412 TI - Apneas observed in trisomy 18 neonates should be differentiated from epileptic apneas. AB - Many children with trisomy 18 have apneas from the neonatal period. It has been reported that some children with trisomy 18 have epilepsy, including epileptic apneas. However, no previous report has described epileptic apneas in trisomy 18 neonates. We retrospectively reviewed the clinical records of neonates with trisomy 18 who were born at Anjo Kosei Hospital between July 2004 and October 2013 and investigated whether they had epileptic apneas during the neonatal period and whether antiepileptic drugs (AEDs) were effective for treating them. We identified 16 patients with trisomy 18. Nine patients who died within 3 days of birth were excluded. Five of the remaining seven patients had apneas. All five patients underwent electroencephalograms (EEGs) to assess whether they suffered epileptic apneas. Three of the five patients had EEG-confirmed seizures. In two patients, the apneas corresponded to ictal discharges. In one patient, ictal discharges were recorded when she was under mechanical ventilation, but no ictal discharges that corresponded to apneas were recorded after she was extubated. AEDs were effective for treating the apneas and stabilizing the SpO2 in all three patients. Among neonates with trisomy 18 who lived longer than 3 days, three of seven patients had EEG-confirmed seizures. AEDs were useful for treating their epileptic apneas and stabilizing their SpO2. Physicians should keep epileptic apneas in mind when treating apneas in neonates with trisomy 18. PMID- 25691413 TI - Further insight into the phenotype associated with a mutation in the ORC6 gene, causing Meier-Gorlin syndrome 3. AB - Mutations in genes encoding the origin recognition complex subunits cause Meier Gorlin syndrome. The disease manifests a triad of short stature, small ears, and small and/or absent patellae with variable expressivity. We report on the identification of a homozygous deleterious mutation in the ORC6 gene in previously described fetuses at the severe end of the Meier-Gorlin spectrum. The phenotype included severe intrauterine growth retardation, dislocation of knees, gracile bones, clubfeet, and small mandible and chest. To date, the clinical presentation of ORC6-associated Meier-Gorlin syndrome has been mild compared to other the phenotype associated with other loci. The present report expands the clinical phenotype associated with ORC6 mutations to include severely abnormal embryological development suggesting a possible genotype-phenotype correlation. PMID- 25691414 TI - Recurrent enlarged nuchal translucency: first trimester presentation of a familial 15q26->qter deletion. AB - A 15q26 terminal chromosomal microdeletion was associated with markedly enlarged 1st trimester nuchal translucency in three of four pregnancies of a couple seen in our prenatal diagnosis unit. Nuchal translucency was normal in the couple's fourth pregnancy, which did not carry the microdeletion. The diagnosis of a 15q26.2->qter microdeletion was first made when the couple's affected daughter displayed significant postnatal growth delay and minor malformations consistent with this contiguous gene syndrome. The microdeletion was confirmed on archived material from the first pregnancy, and identified prospectively on chorionic villi in the third pregnancy. This is the second reported case of familial recurrence of this microdeletion syndrome. As in the other reported family, no deletion or chromosomal rearrangement was identified in either parent, suggesting gonadal mosaicism as a possible cause. First trimester ultrasound findings in 15q26 terminal deletion syndrome have not previously been described. This family illustrates the utility of performing prenatal chromosomal microarray testing in the presence of ultrasound findings of enlarged nuchal translucency or structural abnormalities. PMID- 25691415 TI - Biochemical abnormalities in Pearson syndrome. AB - Pearson marrow-pancreas syndrome is a multisystem mitochondrial disorder characterized by bone marrow failure and pancreatic insufficiency. Children who survive the severe bone marrow dysfunction in childhood develop Kearns-Sayre syndrome later in life. Here we report on four new cases with this condition and define their biochemical abnormalities. Three out of four patients presented with failure to thrive, with most of them having normal development and head size. All patients had evidence of bone marrow involvement that spontaneously improved in three out of four patients. Unique findings in our patients were acute pancreatitis (one out of four), renal Fanconi syndrome (present in all patients, but symptomatic only in one), and an unusual organic aciduria with 3 hydroxyisobutyric aciduria in one patient. Biochemical analysis indicated low levels of plasma citrulline and arginine, despite low-normal ammonia levels. Regression analysis indicated a significant correlation between each intermediate of the urea cycle and the next, except between ornithine and citrulline. This suggested that the reaction catalyzed by ornithine transcarbamylase (that converts ornithine to citrulline) might not be very efficient in patients with Pearson syndrome. In view of low-normal ammonia levels, we hypothesize that ammonia and carbamylphosphate could be diverted from the urea cycle to the synthesis of nucleotides in patients with Pearson syndrome and possibly other mitochondrial disorders. PMID- 25691416 TI - Expanding the phenotype of Timothy syndrome type 2: an adolescent with ventricular fibrillation but normal development. AB - Timothy syndrome is a rare multiorgan disorder with prolonged QTc interval, congenital heart defects, syndactyly, typical facial features and neurodevelopmental problems. Ventricular tachyarrhythmia is the leading cause of death at early age. Classical Timothy syndrome type 1 (TS1) results from a recurrent de novo CACNA1C mutation, G406R in exon 8 A. An atypical form of Timothy syndrome type 2 (TS2) is caused by mutations in G406R and G402S in the alternatively spliced exon 8. Only one individual for each exon 8 mutations has been described. In contrast to multiorgan disease caused by the mutation in G406R either in exon 8 A or 8, the G402S carrier manifested only an isolated cardiac phenotype with LQTS and cardiac arrest. We describe a teenage patient resuscitated from ventricular fibrillation and treated with an implantable cardioverter defibrillator. She has no other organ manifestations, no syndactyly, normal neurodevelopment and her QTc has ranged between 440-480 ms. There is no family history of arrhythmias or sudden death. Targeted oligonucleotide-selective sequencing (OS-Seq) of channelopathy genes revealed a de novo substitution, G402S in exon 8 of CACNA1C. Direct sequencing of blood and saliva derived DNA showed an identical mutation peak suggesting ubiquitous expression in different tissues. The phenotype of our patient and the previously described patient show an isolated arrhythmia disease with no other organ manifestations of classical Timothy syndrome. PMID- 25691417 TI - Hepatoblastoma in a patient with methylmalonic aciduria. AB - Childhood malignant tumors and their treatment are not well described in the natural history of methylmalonic aciduria (MMA). Here we present a case of hepatoblastoma occurring in the native liver of a 19-month-old male with MMA. His tumor was unresectable at diagnosis and he received neoadjuvant chemotherapy with cisplatin, 5-fluorouracil and vincristine. He developed metabolic acidosis and hyperglycemia during chemotherapy. In addition, he developed anemia, thrombocytopenia and febrile neutropenia. He underwent a combined liver-kidney transplant for local control of his tumor and to treat MMA. He remains in remission more than five years after his transplant. In addition, his transplant has cured his MMA and he is able to tolerate a regular diet without developing metabolic crises. PMID- 25691418 TI - Association of achondroplasia with sagittal synostosis and scaphocephaly in two patients, an underestimated condition? AB - We report on two patients with an unusual combination of achondroplasia and surgically treated sagittal synostosis and scaphocephaly. The most common achondroplasia mutation, p.Gly380Arg in fibroblast growth factor receptor 3 (FGFR3), was detected in both patients. Molecular genetic testing of FGFR1, FGFR2, FGFR3 and TWIST1 genes failed to detect any additional mutations. There are several reports of achondroplasia with associated craniosynostosis, but no other cases of scaphocephaly in children with achondroplasia have been described. Recently it has been demonstrated that FGFR3 mutations affect not only endochondral ossification but also membranous ossification, providing new explanations for the craniofacial hallmarks in achondroplasia. Our report suggests that the association of isolated scaphocephaly and other craniosynostoses with achondroplasia may be under recognized. PMID- 25691419 TI - Interstitial duplication of chromosome region 1q25.1q25.3: report of a patient with mild cognitive deficits, tall stature and facial dysmorphisms. AB - Isolated interstitial duplications of chromosome band 1q25 are apparently very rare; no patients with detailed molecular and clinical characterization of duplications restricted to this region have been published to date. We report on a 9-year-old girl with mild cognitive deficits, tall stature, macrocephaly and discrete dysmorphic features in whom a de novo interstitial 7.5 Mb duplication of 1q25.1q25.3 was detected by SNP array analysis (arr[hg19] 1q25.1q25.3(173,925,505 181,381,242)x3 dn). The duplicated region was inversely inserted into chromosome band 1q42.2: 46,XX,der(1)(pter->q42.2::q25.3->q25.1::q42.2->qter). Overexpression of one or several of the 87 genes in the duplicated interval was presumably the major causative factor for the clinical manifestations. Reports of additional patients with overlapping duplications will be needed to establish detailed karyotype-phenotype correlations and to gain a better understanding of the underlying pathomechanisms. PMID- 25691420 TI - Kaufman oculocerebrofacial syndrome in sisters with novel compound heterozygous mutation in UBE3B. AB - A pair of sisters was ascertained for multiple congenital defects, including marked craniofacial dysmorphisms with blepharophimosis, and severe psychomotor delay. Two novel compound heterozygous mutations in UBE3B were identified in both the sisters by exome sequencing. These mutations include c.1A>G, which predicts p.Met1?, and a c.1773delC variant, predicted to cause a frameshift at p.Phe591fs. UBE3B encodes a widely expressed protein ubiquitin ligase E3B, which, when mutated in both alleles, causes Kaufman oculocerebrofacial syndrome. We report on the thorough clinical examination of the patients and review the state of art knowledge of this disorder. PMID- 25691421 TI - Partial MEF2C deletion in a Cypriot patient with severe intellectual disability and a jugular fossa malformation: review of the literature. AB - Deletions or intragenic mutations involving the MEF2C gene on chromosome 5q14.3 have generally been associated with a relatively uniform phenotype characterized by severe developmental delay, absent speech, stereotypies, absent or limited gait abilities, lack of a typical facial gestalt and scarcity of major malformations. We report on a patient of Cypriot descent with a de novo, approximately 147 kb in size, partial MEF2C deletion removing exons 1 to 3. He had a history of severe intellectual disability with absent speech, poor eye contact, hand stereotypies and a wide-based gait. A broad-based, shallow jugular pit with an overlying vascular malformation was also present. Partial MEF2C deletions have only been reported in a very small number of patients and have on occasion been associated with relatively milder phenotypes. We present a patient of Cypriot descent with such a deletion and review previously published literature on partial MEF2C gene deletions postulating a key role of the first few exons in the pathogenesis of the disease. PMID- 25691422 TI - A post GWAS association study of SNPs associated with cleft lip with or without cleft palate in submucous cleft palate. PMID- 25691423 TI - 17q12 microduplications: a challenge for clinicians. AB - In the recent years, some cases of 17q12 deletions and duplications have been reported, but the clinical impact of these imbalances is still to be fully elucidated. In particular, 17q12 duplications elude syndrome classification, since they are associated with a wide phenotypic spectrum, ranging from very mild to quite severe phenotypes. Here, two unrelated patients with the same 1.2 Mb microduplication of 17q12 are reported. Comparing these patients' phenotype with those previously published, it emerges that the more patients reported, the more difficult is finding common characteristics, even in presence of exactly the same genetic anomaly. The role of the genes duplicated in this region and the impact of this chromosomal imbalance are discussed. PMID- 25691424 TI - "X-linked mental retardation and conjuntival teleangectasias": correction of the previously reported karyotype. PMID- 25691425 TI - Response to "Prenatal genetic counseling in Klinefelter syndrome: comments on the article by Lalatta and Tint [2013] and a proposal of a new approach" by Pimpolari et al. PMID- 25691428 TI - Research delves into role of key proteins in fragile X syndrome: study explores relationship between enzymes, FXS symptoms; identifies candidate drug for targeted treatment. PMID- 25691429 TI - Benefits of genomic sequencing evident in pediatric diagnoses: recent study finds testing method less costly, more effective than other medical, genetic tests. PMID- 25691431 TI - ORMDL/serine palmitoyltransferase stoichiometry determines effects of ORMDL3 expression on sphingolipid biosynthesis. AB - The ORM1 (Saccharomyces cerevisiae)-like proteins (ORMDLs) and their yeast orthologs, the Orms, are negative homeostatic regulators of the initiating enzyme in sphingolipid biosynthesis, serine palmitoyltransferase (SPT). Genome-wide association studies have established a strong correlation between elevated expression of the endoplasmic reticulum protein ORMDL3 and risk for childhood asthma. Here we test the notion that elevated levels of ORMDL3 decrease sphingolipid biosynthesis. This was tested in cultured human bronchial epithelial cells (HBECs) (an immortalized, but untransformed, airway epithelial cell line) and in HeLa cells (a cervical adenocarcinoma cell line). Surprisingly, elevated ORMDL3 expression did not suppress de novo biosynthesis of sphingolipids. We determined that ORMDL is expressed in functional excess relative to SPT at normal levels of expression. ORMDLs and SPT form stable complexes that are not increased by elevated ORMDL3 expression. Although sphingolipid biosynthesis was not decreased by elevated ORMDL3 expression, the steady state mass levels of all major sphingolipids were marginally decreased by low level ORMDL3 over-expression in HBECs. These data indicate that the contribution of ORMDL3 to asthma risk may involve changes in sphingolipid metabolism, but that the connection is complex. PMID- 25691432 TI - One-electron images in real space: natural adaptive orbitals. AB - We introduce a general procedure to construct a set of one-electron functions in chemical bonding theory, which remain physically sound both for correlated and noncorrelated electronic structure descriptions. These functions, which we call natural adaptive orbitals, decompose the n-center bonding indices used in real space theories of the chemical bond into one-electron contributions. For the n = 1 case, they coincide with the domain natural orbitals used in domain-averaged Fermi hole analyses. We examine their interpretation in the two-center case, and show how they behave and evolve in simple cases. Orbital pictures obtained through this technique converge onto the chemist's molecular orbital toolbox if electron correlation may be ignored, and provide new insight if it may not. PMID- 25691433 TI - Standard deviation or the standard error of the mean. PMID- 25691434 TI - Spectroscopic, computational and electrochemical studies on the formation of the copper complex of 1-amino-4-hydroxy-9,10-anthraquinone and effect of it on superoxide formation by NADH dehydrogenase. AB - A 1 : 2 copper(II) complex of 1-amino-4-hydroxy-9,10-anthraquinone (QH) having the molecular formula CuQ2 was prepared and characterized by elemental analysis, NMR, FTIR, UV-vis and mass spectroscopy. The powder diffraction of the solid complex, magnetic susceptibility and ESR spectra were also recorded. The presence of the planar anthraquinone moiety in the complex makes it extremely difficult to obtain a single crystal suitable for X-ray diffraction studies. To overcome this problem, density functional theory (DFT) was used to evaluate an optimized structure of CuQ2. In the optimized structure, it was found that there is a tilt of the two planar aromatic anthraquinone rings of the complex with respect to each other in the two planes containing the O-Cu(II)-O plane. The present study is an important addition to the understanding of the structural aspects of metal anthracyclines because there are only a few reports on the actual structures of metal-anthracyclines. The theoretical vibrational spectrum of the complex was assigned with the help of vibrational energy distribution analysis (VEDA) using potential energy distribution (PED) and compared with experimental results. Being important in producing the biochemical action of this class of molecules, the electrochemical behavior of the complex was studied in aqueous and non-aqueous solvents to find certain electrochemical parameters. In aqueous media, reduction involves a kinetic effect during electron transfer at an electrode surface, which was characterized very carefully using cyclic voltammetry. Electrochemical studies showed a significant modification in the electrochemical properties of 1 amino-4-hydroxy-9,10-anthraquinone (QH) when bound to Cu(II) in the complex compared to those observed for free QH. This suggests that the copper complex might be a good choice as a biologically active molecule, which was reflected in the lack of stimulated superoxide generation by the complex. PMID- 25691435 TI - Effect of poly(vinyl alcohol-co-vinyl acetate) copolymer blockiness on the dynamic interfacial tension and dilational viscoelasticity of polymer-anionic surfactant complex at the water-1-chlorobutane interface. AB - Poly(vinyl alcohol-co-vinyl acetate) (PVA) copolymers obtained by partial hydrolysis of poly(vinyl acetate) (PVAc) are of practical importance for many applications, including emulsion and suspension polymerization processes. Their molecular characteristics have a major influence on the colloidal and interfacial properties. The most significant characteristics are represented by the average degree of hydrolysis DH, average degree of polymerization DPw but also by the average acetate sequence length n(VAc)(0) which designates the so-called blockiness. Colloidal aggregates were observed in the aqueous PVA solutions having a DH value of 73 mol%. The volume fraction of these aggregates at a given DH value is directly correlated to the blockiness. Three PVA samples with identical DH and DPw but different blockiness were examined. By pendant drop and oscillating pendant drop techniques it was shown that the PVA sample having the lowest blockiness and thus the lowest volume fraction of colloidal aggregates has lower interfacial tension and elastic modulus E' values. On the contrary, the corresponding values are highest for PVA sample of higher blockiness. In the presence of sodium dodecyl sulfate (SDS), the colloidal aggregates are disaggregated by complex formation due to the hydrophobic-hydrophobic interactions. The PVA-SDS complex acts as a partial polyelectrolyte that induces the stretching of the chains and thus a reduction of the interface thickness. In this case, the interfacial tension and the elastic modulus both increase with increasing SDS concentration for all three PVA samples and the most significant effect was noticed for the most "blocky" copolymer sample. PMID- 25691436 TI - Reply: To PMID 23996808. PMID- 25691437 TI - New perioperative fluid and pharmacologic management protocol results in reduced blood loss, faster return of bowel function, and overall recovery. AB - Cystectomy and urinary diversion have high morbidity, and strategies to reduce complications are of utmost importance. Epidural analgesia and optimized fluid management are considered key factors contributing to successful enhanced recovery after surgery. In colorectal surgery, there is strong evidence that an intraoperative fluid management aiming for a postoperative zero fluid balance results in lower morbidity including a faster return of bowel function. Recently, a randomized clinical trial focusing on radical cystectomy demonstrated that a restrictive intraoperative hydration combined with a concomitant administration of norepinephrine reduced intraoperative blood loss, the need for blood transfusion and morbidity. The purpose of this review is to highlight specific anesthesiological aspects which have been shown to improve outcome after RC with urinary diversion. PMID- 25691438 TI - Preoperative and modifiable factors to lower postoperative complications after radical cystectomy. AB - Radical cystectomy is the gold standard for muscle-invasive bladder cancer. It is a challenging procedure comprising of two steps: removal of the bladder followed by construction of a new urinary diversion. Despite advances in surgical and postoperative management within the last decades, postoperative complication rates for this procedure are still considerably high. Many complications are avoidable in the pre-/intra-/postoperative setting by carefully selecting patients eligible for this procedure and by considering prophylactic measures. Fast-track concepts demonstrate current intentions to optimize perioperative management. This review summarizes the most recent studies and findings on how to lower postoperative complications with the help of preoperative and modifiable factors. PMID- 25691439 TI - Contemporary assessment of renal stone complexity using cross-sectional imaging. AB - Recently, several scoring systems have been proposed to predict outcomes of percutaneous nephrolithotomy, objectively and quantitatively assessing kidney calculi complexity using cross-sectional imaging. These scoring systems are promising new tools that can guide surgical decision making, predict surgical outcomes, counsel patients undergoing stone surgery, and improve standardized academic reporting in percutaneous kidney stone surgery. In this article, we review features of each of these systems, their similarities and differences, and their applicability in clinical practice and relevance in academic reporting. PMID- 25691440 TI - An attachment-focused parent-child intervention for biting behaviour in a child with intellectual disability: A clinical case study. AB - Attachment and attachment-related psychopathology has increasingly gained focus since Bowlby introduced the concept into the clinical repertoire. However, little has been done to explore attachment, or attachment-based interventions, within the context of intellectual disability. Clinical experience, however, has demonstrated significant attachment-related problems in children with intellectual disability. This article explores one such case of a 13-year-old girl with moderate intellectual disability and severe and persistent externalizing behavioural difficulties - biting, in particular. Once the severity of the behaviour was formulated within the framework of attachment, a structured attachment-focused parent-child intervention was designed in order to repair the damaged attachment between mother and daughter as a way of addressing the problematic behaviour. Outcomes demonstrated a sustained - immediately, at 3- and 6-month follow-up - positive impact of the intervention not only on the presenting problem but also on the quality of the relationship between mother and daughter. Research and clinical implications are discussed. PMID- 25691441 TI - Intratumor heterogeneity and clonal evolution in an aggressive papillary thyroid cancer and matched metastases. AB - The contribution of intratumor heterogeneity to thyroid metastatic cancers is still unknown. The clonal relationships between the primary thyroid tumors and lymph nodes (LN) or distant metastases are also poorly understood. The objective of this study was to determine the phylogenetic relationships between matched primary thyroid tumors and metastases. We searched for non-synonymous single nucleotide variants (nsSNVs), gene fusions, alternative transcripts, and loss of heterozygosity (LOH) by paired-end massively parallel sequencing of cDNA (RNA Seq) in a patient diagnosed with an aggressive papillary thyroid cancer (PTC). Seven tumor samples from a stage IVc PTC patient were analyzed by RNA-Seq: two areas from the primary tumor, four areas from two LN metastases, and one area from a pleural metastasis (PLM). A large panel of other thyroid tumors was used for Sanger sequencing screening. We identified seven new nsSNVs. Some of these were early events clonally present in both the primary PTC and the three matched metastases. Other nsSNVs were private to the primary tumor, the LN metastases and/or the PLM. Three new gene fusions were identified. A novel cancer-specific KAZN alternative transcript was detected in this aggressive PTC and in dozens of additional thyroid tumors. The PLM harbored an exclusive whole-chromosome 19 LOH. We have presented the first, to our knowledge, deep sequencing study comparing the mutational spectra in a PTC and both LN and distant metastases. This study has yielded novel findings concerning intra-tumor heterogeneity, clonal evolution and metastases dissemination in thyroid cancer. PMID- 25691442 TI - Cell-cycle-dependent regulation of androgen receptor function. AB - The androgen receptor (AR) is a critical oncogene in prostate cancer (PCa) development and progression. In this study, we demonstrate cell-cycle-dependent regulation of AR activity, localization, and phosphorylation. We show that for three AR-target genes, androgen-stimulated AR transactivation is highest during the G1 phase, decreased during S-phase, and abrogated during G2/M. This change in AR transactivation parallels changes in AR localization and phosphorylation. A combination of imaging techniques and quantitative analysis reveals nuclear AR localization during interphase and the exclusion of the majority, but not all, AR from chromatin during mitosis. Flow cytometry analyses using a phospho-S308 AR specific antibody in asynchronous and chemically enriched G2/M PCa cells revealed ligand-independent induction of S308 phosphorylation in mitosis when CDK1 is activated. Consistent with our flow cytometry data, IP-western blotting revealed an increase in S308 phosphorylation in G2/M, and the results of an in vitro kinase assay indicated that CDK1 was able to phosphorylate the AR on S308. Pharmacological inhibition of CDK1 activity resulted in decreased S308 phosphorylation in PCa cells. Importantly, using a combination of anti-total AR and phospho-S308-specific antibodies in immunofluorescence experiments, we showed that the AR is excluded from condensed chromatin in mitotic cells when it was phosphorylated on S308. In summary, we show that the phosphorylation of the AR on S308 by CDK1 during mitosis regulates AR localization and correlates with changes in AR transcriptional activity. These findings have important implications for understanding the function of AR as an oncogene. PMID- 25691443 TI - Discriminating precursors of common fragments for large-scale metabolite profiling by triple quadrupole mass spectrometry. AB - MOTIVATION: The goal of large-scale metabolite profiling is to compare the relative concentrations of as many metabolites extracted from biological samples as possible. This is typically accomplished by measuring the abundances of thousands of ions with high-resolution and high mass accuracy mass spectrometers. Although the data from these instruments provide a comprehensive fingerprint of each sample, identifying the structures of the thousands of detected ions is still challenging and time intensive. An alternative, less-comprehensive approach is to use triple quadrupole (QqQ) mass spectrometry to analyze predetermined sets of metabolites (typically fewer than several hundred). This is done using authentic standards to develop QqQ experiments that specifically detect only the targeted metabolites, with the advantage that the need for ion identification after profiling is eliminated. RESULTS: Here, we propose a framework to extend the application of QqQ mass spectrometers to large-scale metabolite profiling. We aim to provide a foundation for designing QqQ multiple reaction monitoring (MRM) experiments for each of the 82 696 metabolites in the METLIN metabolite database. First, we identify common fragmentation products from the experimental fragmentation data in METLIN. Then, we model the likelihoods of each precursor structure in METLIN producing each common fragmentation product. With these likelihood estimates, we select ensembles of common fragmentation products that minimize our uncertainty about metabolite identities. We demonstrate encouraging performance and, based on our results, we suggest how our method can be integrated with future work to develop large-scale MRM experiments. AVAILABILITY AND IMPLEMENTATION: Our predictions, Supplementary results, and the code for estimating likelihoods and selecting ensembles of fragmentation reactions are made available on the lab website at http://pattilab.wustl.edu/FragPred. PMID- 25691444 TI - Cause of death in HIV-infected patients in South Carolina (2005-2013). AB - The life span of persons with HIV has been greatly extended over the past 30 years due to novel therapies. In the developed world and urban settings, this results in a lifespan rivaling the lifespan of a person without HIV. A retrospective study was conducted on 459 patients of an urban, academic medical center who died between 2005 and 2013 in a medium-sized US city. Using the established Cause of Death Project (CoDe) protocol, we measured multiple factors including comorbidities, risk behaviours, contributing and underlying causes of death. This study is one of the few US-based studies using this validated protocol. Among the deaths, 25.9% were sudden and 15.2% were unexpected. Almost one-fifth were related to AIDS-related infections; 47.5% related to non-AIDS causes; with the remainder unknown. Statistically significant increases in CD4 counts and decreasing viral loads were observed over the study period. There were no statistically significant differences observed by HIV risk behaviour, race, gender, age at death, or on antiretrovirals at death. In support of the existing literature, improved HIV management appears to reduce the AIDS-related attributable death among patients observed in this study. PMID- 25691445 TI - A pooled multisite analysis of the effects of atopic medical conditions in glioma risk in different ethnic groups. AB - PURPOSE: The incidences of atopic conditions (allergies, asthma, or eczema) and glioma vary by ethnicity. Atopic conditions are inversely associated with gliomas. We conducted a pooled multisite study investigating the associations of atopic conditions with glioma in different race/ethnicity groups. METHODS: Using glioma cases and healthy controls, unconditional logistic regression was conducted to assess the associations of atopic conditions with glioma separately in white, black, Asian, and Hispanic subpopulations. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. RESULTS: Glioblastoma multiforme cases were less likely than controls to report a history of atopic conditions in whites (OR = 0.46, [95% CI, 0.38-0.54]) and Asians (OR = 0.27, [95% CI, 0.10 0.73]). The same trend was seen when looking at glioma cases of all histologies. An inverse association was not seen in blacks for glioblastoma multiforme or all histologies combined. CONCLUSIONS: The inverse association between glioma and atopic conditions may vary by ethnicity due to a difference in the biology of atopic conditions in different ethnicities but may be due to chance because of the limitations of small nonwhite sample sizes. PMID- 25691446 TI - General hypervigilance in fibromyalgia: one swallow does not make a summer. PMID- 25691447 TI - Enantioselective aldol reaction between isatins and cyclohexanone catalyzed by amino acid sulphonamides. AB - Sulphonamides derived from primary alpha-amino acid were successfully applied to catalyze the aldol reaction between isatin and cyclohexanone under neat conditions. More interestingly, molecular sieves, as privileged additives, were found to play a vital role in achieving high enantioselectivity. Consequently, high yields (up to 99%) along with good enantioselectivities (up to 92% ee) and diastereoselectivities (up to 95:5 dr) were obtained. In addition, this reaction was also conveniently scaled up, demonstrating the applicability of this protocol. PMID- 25691448 TI - UK government is criticised for "political decisions" in response to Ebola epidemic. PMID- 25691449 TI - Prospective evaluation of the learning curve of fertiloscopy with and without ovarian drilling. AB - Fertiloscopy represents an alternative to laparoscopy in the diagnostic evaluation of unexplained infertility or for the purpose of ovarian drilling. The learning curve of fertiloscopy in an experienced laparoscopic surgeon was evaluated in a prospective multicentre observational trial. A total of 110 fertiloscopies were carried out. At Centre 1, a beginner, and at Centre 2, an expert in fertiloscopy, performed the procedures. In three cases in Centre 1, and in 0 cases in Centre 2, the procedure was converted to transabdominal laparoscopy owing to intraoperative complications. Median operating time was longer at Centre 1 during the first 40 procedures (P < 0.001) and equal thereafter. Analyzing fertiloscopies with and without ovarian drilling separately, operating time was only longer for the first 20 procedures in each group (P < 0.001 and P = 0.002). In a multivariate analysis, intraoperative complications and fertiloscopy with ovarian drilling (compared with diagnostic fertiloscopy) were associated with longer duration of surgery (P < 0.001 for both parameters). An increasing consecutive number of fertiloscopies was associated with shorter duration of surgery (P < 0.001). Experienced laparoscopists should consider a transition towards fertiloscopy in the diagnostic workup of unexplained infertility or for the purpose of ovarian drilling. PMID- 25691450 TI - Research in action: from AIDS to global health to impact. A symposium in recognition of the scientific contributions of Professor Joep Lange. PMID- 25691451 TI - Effect of age on the sensitivity of the rat thyroid gland to ionizing radiation. AB - Exposure to ionizing radiation during childhood is a well-known risk factor for thyroid cancer. Our study evaluated the effect of age on the radiosensitivity of rat thyroid glands. Four-week-old (4W), 7 -week-old (7W), and 8-month-old (8M) male Wistar rats were exposed to 8 Gy of whole-body X-ray irradiation. Thyroids were removed 3-72 h after irradiation, and non-irradiated thyroids served as controls. Ki67-positivity and p53 binding protein 1 (53BP1) focus formation (a DNA damage response) were evaluated via immunohistochemistry. Amounts of proteins involved in DNA damage response (p53, p53 phosphorylated at serine 15, p21), apoptosis (cleaved caspase-3), and autophagy (LC3, p62) were determined via western blotting. mRNA levels of 84 key autophagy-related genes were quantified using polymerase chain reaction arrays. Ki67-positive cells in 4W (with high proliferative activity) and 7W thyroids significantly decreased in number post irradiation. The number of 53BP1 foci and amount of p53 phosphorylated at serine 15 increased 3 h after irradiation, regardless of age. No increase in apoptosis or in the levels of p53, p21 or cleaved caspase-3 was detected for any ages. Levels of LC3-II and p62 increased in irradiated 4W but not 8M thyroids, whereas expression of several autophagy-related genes was higher in 4W than 8M irradiated thyroids. Irradiation increased the expression of genes encoding pro-apoptotic proteins in both 4W and 8M thyroids. In summary, no apoptosis or p53 accumulation was noted, despite the expression of some pro-apoptotic genes in immature and adult thyroids. Irradiation induced autophagy in immature, but not in adult, rat thyroids. PMID- 25691452 TI - New model for long-term investigations of cutaneous microcirculatory and inflammatory changes following irradiation. AB - Radiotherapy is used for curative and palliative treatment. However, its negative effect on normal tissue is a limiting factor for the deliverable dose. Microcirculatory breakdown and prolonged inflammation in particular are major features of late side effects. The purpose of this study was to develop a reliable animal model that will allow a long-term in vivo analysis of microcirculation and inflammation following irradiation. A single dose of 90 Gy was delivered to the ears of hairless mice (n = 15). Intravital fluorescent microscopy was used to assess microcirculatory parameters and leukocyte behaviour. Values for the identical (control) areas were obtained before as well as during the following days, weeks and months following irradiation. The arteriolar and venular diameter increased up to Day 14, decreased during the following months, and increased again after one year. The red blood cell velocity increased up to 145% on Day 3, decreased on Day 7 to 115%, and stayed above baseline value the whole year. The integrity loss of the endothelium increased up to Day 7 and continued up to Day 75 after radiation. After one year, the oedema was at the baseline level. Leukocytes showed their maximal activity at one year after trauma. An increase was measured up to Day 25; the lowest values were measured at Day 40 post-irradiation, followed by a repeated increase. The present model allows a certain visualization of microcirculatory disturbances and inflammation over a period of months. This permits the possibility of long-term investigations of the underlying pathophysiology following irradiation, including possible drug interactions. PMID- 25691453 TI - Survival outcomes after stereotactic body radiotherapy for 79 Japanese patients with hepatocellular carcinoma. AB - Stereotactic body radiotherapy (SBRT) is a relatively new treatment for liver tumor. Outcomes of SBRT for liver tumors unsuitable for ablation or surgical resection were evaluated. A total of 79 patients treated with SBRT for primary hepatocellular carcinoma (HCC) between 2004 and 2012 in six Japanese institutions were studied retrospectively. Patients treated with SBRT preceded by trans arterial chemoembolization were eligible. Their median age was 73 years, 76% were males, and their Child-Pugh scores were Grades A (85%) and B (11%) before SBRT. The median biologically effective dose (alpha/beta = 10 Gy) was 96.3 Gy. The median follow-up time was 21.0 months for surviving patients. The 2-year overall survival (OS), progression-free survival (PFS), and distant metastasis-free survival were 53%, 40% and 76%, respectively. Sex and serum PIVKA-II values were significant predictive factors for OS. Hypovascular or hypervascular types of HCC, sex and clinical stage were significant predictive factors for PFS. The 2 year PFS was 66% in Stage I vs 18% in Stages II-III. Multivariate analysis indicated that clinical stage was the only significant predictive factor for PFS. No Grade 3 laboratory toxicities in the acute, sub-acute, and chronic phases were observed. PFS after SBRT for liver tumor was satisfactory, especially for Stage I HCC, even though these patients were unsuitable for resection and ablation. SBRT is safe and might be an alternative to resection and ablation. PMID- 25691454 TI - A New Perspective of Lysosomal Cation Channel-Dependent Homeostasis in Alzheimer's Disease. AB - Studies have reported typically biophysical lysosomal cation channels including TPCs. Their plausible biological roles are being elucidated by pharmacological, genetic and conventional patch clamp procedures. The best characterized so far among these channels is the ML1 isoform of TRP. The reported TRPs and TPCs are bypass for cation fluxes and are strategic for homeostasis of ionic milieu of the acidic organelles they confine to. Ca(2+) homeostasis and adequate acidic pHL are critically influential for the regulation of a plethora of biological functions these intracellular cation channels perform. In lysosomal ion channel biology, we review: ML1 and TPC2 in Ca(2+) signaling, ML1 and TPC2 in pH(L) regulation. Using Abeta42 and tau proteins found along clathrin endolysosomal internalization pathway (Fig. 3), we proffer a mechanism of abnormal pH(L) and ML1/TPC2-dependent cation homeostasis in AD. PMID- 25691455 TI - The Roles of the Stem Cell-Controlling Sox2 Transcription Factor: from Neuroectoderm Development to Alzheimer's Disease? AB - Sox2 is a component of the core transcriptional regulatory network which maintains the totipotency of the cells during embryonic preimplantation period, the pluripotency of embryonic stem cells, and the multipotency of neural stem cells. This maintenance is controlled by internal loops between Sox2 and other transcription factors of the core such as Oct4, Nanog, Dax1, and Klf4, downstream proteins of extracellular ligands, epigenetic modifiers, and miRNAs. As Sox2 plays an important role in the balance between stem cells maintenance and commitment to differentiated lineages throughout the lifetime, it is supposed that Sox2 could regulate stem cells aging processes. In this review, we provide an update concerning the involvement of Sox2 in neurogenesis during normal aging and discuss its possible role in Alzheimer's disease. PMID- 25691456 TI - Resveratrol Protects from Toxin-Induced Parkinsonism: Plethora of Proofs Hitherto Petty Translational Value. AB - Parkinson's disease (PD) is a mysterious, chronic, multi-factorial and progressive disorder of the nervous system that is characterized by the selective loss of dopamine-producing cells of the substantia nigra leading to dopamine deficiency in the striatum. PD is exemplified by oxidative stress, alpha synuclein accumulation, mitochondrial dysfunction, defective ubiquitin proteasome system, aberrant autophagy, inflammation, and atypical apoptosis, which eventually lead to slowness of movement, resting tremor, stiffness, and loss of balance. Despite incomprehensible etiology, timely diagnosis, and permanent cure, a handful of synthetic and natural agents rescue from the symptomatic features and delay disease progression. At low doses, a natural polyphenol, trans-3,5,4' trihydroxystilbene (resveratrol), delays neurodegeneration in the cellular and animal models and lessens oxidative stress, mitochondrial dysfunction, aberrant apoptosis, and defective autophagy. The present article explains neuroprotective efficacy, advantages, and downsides of resveratrol in the conventional and preclinical models. This piece of writing also examines its probable neuroprotective mechanisms and constraints of realistic recital in clinical investigations and likely endeavors to minimize apprehensions. PMID- 25691457 TI - Interleukin-5 facilitates lung metastasis by modulating the immune microenvironment. AB - Although the lung is the most common metastatic site for cancer cells, biologic mechanisms regulating lung metastasis are not fully understood. Using heterotopic and intravenous injection models of lung metastasis in mice, we found that IL5, a cytokine involved in allergic and infectious diseases, facilitates metastatic colonization through recruitment of sentinel eosinophils and regulation of other inflammatory/immune cells in the microenvironment of the distal lung. Genetic IL5 deficiency offered marked protection of the lungs from metastasis of different types of tumor cells, including lung cancer, melanoma, and colon cancer. IL5 neutralization protected subjects from metastasis, whereas IL5 reconstitution or adoptive transfer of eosinophils into IL5-deficient mice exerted prometastatic effects. However, IL5 deficiency did not affect the growth of the primary tumor or the size of metastatic lesions. Mechanistic investigations revealed that eosinophils produce CCL22, which recruits regulatory T cells to the lungs. During early stages of metastasis, Treg created a protumorigenic microenvironment, potentially by suppressing IFNgamma-producing natural killer cells and M1 polarized macrophages. Together, our results establish a network of allergic inflammatory circuitry that can be co-opted by metastatic cancer cells to facilitate lung colonization, suggesting interventions to target this pathway may offer therapeutic benefits to prevent or treat lung metastasis. PMID- 25691458 TI - Spatially resolved metabolic phenotyping of breast cancer by desorption electrospray ionization mass spectrometry. AB - Breast cancer is a heterogeneous disease characterized by varying responses to therapeutic agents and significant differences in long-term survival. Thus, there remains an unmet need for early diagnostic and prognostic tools and improved histologic characterization for more accurate disease stratification and personalized therapeutic intervention. This study evaluated a comprehensive metabolic phenotyping method in breast cancer tissue that uses desorption electrospray ionization mass spectrometry imaging (DESI MSI), both as a novel diagnostic tool and as a method to further characterize metabolic changes in breast cancer tissue and the tumor microenvironment. In this prospective single center study, 126 intraoperative tissue biopsies from tumor and tumor bed from 50 patients undergoing surgical resections were subject to DESI MSI. Global DESI MSI models were able to distinguish adipose, stromal, and glandular tissue based on their metabolomic fingerprint. Tumor tissue and tumor-associated stroma showed evident changes in their fatty acid and phospholipid composition compared with normal glandular and stromal tissue. Diagnosis of breast cancer was achieved with an accuracy of 98.2% based on DESI MSI data (PPV 0.96, NVP 1, specificity 0.96, sensitivity 1). In the tumor group, correlation between metabolomic profile and tumor grade/hormone receptor status was found. Overall classification accuracy was 87.7% (PPV 0.92, NPV 0.9, specificity 0.9, sensitivity 0.92). These results demonstrate that DESI MSI may be a valuable tool in the improved diagnosis of breast cancer in the future. The identified tumor-associated metabolic changes support theories of de novo lipogenesis in tumor tissue and the role of stroma tissue in tumor growth and development and overall disease prognosis. PMID- 25691459 TI - Omega-3 Polyunsaturated Fatty Acids Upregulate 15-PGDH Expression in Cholangiocarcinoma Cells by Inhibiting miR-26a/b Expression. AB - Prostaglandin E2 (PGE2) is a proinflammatory lipid mediator that promotes cancer growth. The 15-hydroxyprostaglandin dehydrogenase (15-PGDH) catalyzes oxidation of the 15(S)-hydroxyl group of PGE2, leading to its inactivation. Therefore, 15 PGDH induction may offer a strategy to treat cancers that are driven by PGE2, such as human cholangiocarcinoma. Here, we report that omega-3 polyunsaturated fatty acids (omega-3 PUFA) upregulate 15-PGDH expression by inhibiting miR-26a and miR-26b, thereby contributing to omega-3 PUFA-induced inhibition of human cholangiocarcinoma cell growth. Treatment of human cholangiocarcinoma cells (CCLP1 and TFK-1) with omega-3 PUFA (DHA) or transfection of these cells with the Fat-1 gene (encoding Caenorhabditis elegans desaturase, which converts omega-6 PUFA to omega-3 PUFA) significantly increased 15-PGDH enzymes levels, but with little effect on the activity of the 15-PGDH gene promoter. Mechanistic investigations revealed that this increase in 15-PGDH levels in cells was mediated by a reduction in the expression of miR-26a and miR-26b, which target 15 PGDH mRNA and inhibit 15-PGDH translation. These findings were extended by the demonstration that overexpressing miR-26a or miR-26b decreased 15-PGDH protein levels, reversed omega-3 PUFA-induced accumulation of 15-PGDH protein, and prevented omega-3 PUFA-induced inhibition of cholangiocarcinoma cell growth. We further observed that omega-3 PUFA suppressed miR-26a and miR-26b by inhibiting c myc, a transcription factor that regulates miR-26a/b. Accordingly, c-myc overexpression enhanced expression of miR-26a/b and ablated the ability of omega 3 PUFA to inhibit cell growth. Taken together, our results reveal a novel mechanism for omega-3 PUFA-induced expression of 15-PGDH in human cholangiocarcinoma and provide a preclinical rationale for the evaluation of omega-3 PUFA in treatment of this malignancy. PMID- 25691460 TI - Evolutionary Action Score of TP53 Coding Variants Is Predictive of Platinum Response in Head and Neck Cancer Patients. AB - TP53 is the most frequently altered gene in head and neck squamous cell carcinoma (HNSCC), with mutations occurring in over two thirds of cases; however, the predictive response of these mutations to cisplatin-based therapy remains elusive. In the current study, we evaluate the ability of the Evolutionary Action score of TP53-coding variants (EAp53) to predict the impact of TP53 mutations on response to chemotherapy. The EAp53 approach clearly identifies a subset of high risk TP53 mutations associated with decreased sensitivity to cisplatin both in vitro and in vivo in preclinical models of HNSCC. Furthermore, EAp53 can predict response to treatment and, more importantly, a survival benefit for a subset of head and neck cancer patients treated with platinum-based therapy. Prospective evaluation of this novel scoring system should enable more precise treatment selection for patients with HNSCC. PMID- 25691461 TI - A Socioecological Framework to Assessing Depression Among Pregnant Teens. AB - To examine individual, interpersonal, family, and community correlates associated with moderate-to-severe depressive symptoms among pregnant adolescents. A total of 249 primarily African American and Hispanic pregnant adolescents ages 15-18 years were recruited into either an intervention group utilizing Centering Pregnancy prenatal care and case management, or to a comparison group receiving case management only. Moderate-to-severe depressive symptoms were defined as a score >=16 on the Center for Epidemiologic Studies Depression Scale (CES-D). Intervention and comparison groups did not significantly differ on demographic characteristics or depression scores at baseline. A total of 115 (46.1 %) participants met criteria for moderate-to-severe depressive symptoms at entry into the program. Pregnant adolescents who were moderately-to-severely depressed were more likely to be African American, to have reported limited contact with the father of the baby, and to have experienced prior verbal, physical or sexual abuse. Depressed adolescents also experienced high levels of family criticism, low levels of general support, and exposure to community violence. A significant number of pregnant adolescents were affected by depression and other challenges that could affect their health. Comprehensive interventions addressing these challenges and incorporating partners and families are needed. PMID- 25691462 TI - ARF-mediated SUMOylation of Apak antagonizes ubiquitylation and promotes its nucleolar accumulation to inhibit 47S pre-rRNA synthesis. AB - Ribosomes are among the most fundamental molecular machines in all cells, as they are required for protein synthesis. Most structural rRNA components are generated in the nucleolus and assembled into pre-ribosomal particles. Here we show Apak, a previously identified p53 inhibitor, as a novel ribosomal stress response protein. In unstressed cells, Apak is bound to the deSUMOylase SENP1 in the nucleoplasm and targeted for proteasomal degradation by MDM2 ubiquitin ligase. Upon ribosomal stress, SENP1 dissociates from Apak and the tumor suppressor protein ARF couples Ubc9 with Apak to promote Apak SUMOylation on zinc fingers. This results in Apak protein stabilization and translocation to the nucleolus, where Apak inhibits the pre-rRNA synthesis. These findings provide a molecular mechanism whereby ARF coordinates Apak to regulate ribosome biogenesis upon cellular stress. PMID- 25691463 TI - Classification of biliary tract cancers established by the Japanese Society of Hepato-Biliary-Pancreatic Surgery: 3(rd) English edition. AB - The 3(rd) English edition of the Japanese classification of biliary tract cancers was released approximately 10 years after the 5(th) Japanese edition and the 2(nd) English edition. Since the first Japanese edition was published in 1981, the Japanese classification has been in extensive use, particularly among Japanese surgeons and pathologists, because the cancer status and clinical outcomes in surgically resected cases have been the main objects of interest. However, recent advances in the diagnosis, management and research of the disease prompted the revision of the classification that can be used by not only surgeons and pathologists but also by all clinicians and researchers, for the evaluation of current disease status, the determination of current appropriate treatment, and the future development of medical practice for biliary tract cancers. Furthermore, during the past 10 years, globalization has advanced rapidly, and therefore, internationalization of the classification was an important issue to revise the Japanese original staging system, which would facilitate to compare the disease information among institutions worldwide. In order to achieve these objectives, the new Japanese classification of the biliary tract cancers principally adopted the 7(th) edition of staging system developed by the International Union Against Cancer (UICC) and the American Joint Committee on Cancer (AJCC). However, because there are some points pending in these systems, several distinctive points were also included for the purpose of collection of information for the future optimization of the staging system. Free mobile application of the new Japanese classification of the biliary tract cancers is available via http://www.jshbps.jp/en/classification/cbt15.html. PMID- 25691464 TI - Nuclear pore proteins and the control of genome functions. AB - Nuclear pore complexes (NPCs) are composed of several copies of ~30 different proteins called nucleoporins (Nups). NPCs penetrate the nuclear envelope (NE) and regulate the nucleocytoplasmic trafficking of macromolecules. Beyond this vital role, NPC components influence genome functions in a transport-independent manner. Nups play an evolutionarily conserved role in gene expression regulation that, in metazoans, extends into the nuclear interior. Additionally, in proliferative cells, Nups play a crucial role in genome integrity maintenance and mitotic progression. Here we discuss genome-related functions of Nups and their impact on essential DNA metabolism processes such as transcription, chromosome duplication, and segregation. PMID- 25691465 TI - The Ino80 complex prevents invasion of euchromatin into silent chromatin. AB - Here we show that the Ino80 chromatin remodeling complex (Ino80C) directly prevents euchromatin from invading transcriptionally silent chromatin within intergenic regions and at the border of euchromatin and heterochromatin. Deletion of Ino80C subunits leads to increased H3K79 methylation and noncoding RNA polymerase II (Pol II) transcription centered at the Ino80C-binding sites. The effect of Ino80C is direct, as it blocks H3K79 methylation by Dot1 in vitro. Heterochromatin stimulates the binding of Ino80C in vitro and in vivo. Our data reveal that Ino80C serves as a general silencing complex that restricts transcription to gene units in euchromatin. PMID- 25691466 TI - Cas9 function and host genome sampling in Type II-A CRISPR-Cas adaptation. AB - To acquire the ability to recognize and destroy virus and plasmid invaders, prokaryotic CRISPR-Cas systems capture fragments of DNA within the host CRISPR locus. Our results indicate that the process of adaptation by a Type II-A CRISPR Cas system in Streptococcus thermophilus requires Cas1, Cas2, and Csn2. Surprisingly, we found that Cas9, previously identified as the nuclease responsible for ultimate invader destruction, is also essential for adaptation. Cas9 nuclease activity is dispensable for adaptation. In addition, our studies revealed extensive, unbiased acquisition of the self-targeting host genome sequence by the CRISPR-Cas system that is masked in the presence of active target destruction. PMID- 25691467 TI - Suppression of pervasive noncoding transcription in embryonic stem cells by esBAF. AB - Approximately 75% of the human genome is transcribed, the majority of which does not encode protein. However, many noncoding RNAs (ncRNAs) are rapidly degraded after transcription, and relatively few have established functions, questioning the significance of this observation. Here we show that esBAF, a SWI/SNF family nucleosome remodeling factor, suppresses transcription of ncRNAs from ~57,000 nucleosome-depleted regions (NDRs) throughout the genome of mouse embryonic stem cells (ESCs). We show that esBAF functions to both keep NDRs nucleosome-free and promote elevated nucleosome occupancy adjacent to NDRs. Reduction of adjacent nucleosome occupancy upon esBAF depletion is strongly correlated with ncRNA expression, suggesting that flanking nucleosomes form a barrier to pervasive transcription. Upon forcing nucleosome occupancy near two NDRs using a nucleosome positioning sequence, we found that esBAF is no longer required to silence transcription. Therefore, esBAF's function to enforce nucleosome occupancy adjacent to NDRs, and not its function to maintain NDRs in a nucleosome-free state, is necessary for silencing transcription over ncDNA. Finally, we show that the ability of a strongly positioned nucleosome to repress ncRNA depends on its translational positioning. These data reveal a novel role for esBAF in suppressing pervasive transcription from open chromatin regions in ESCs. PMID- 25691468 TI - The E-Id protein axis modulates the activities of the PI3K-AKT-mTORC1-Hif1a and c myc/p19Arf pathways to suppress innate variant TFH cell development, thymocyte expansion, and lymphomagenesis. AB - It is now well established that the E and Id protein axis regulates multiple steps in lymphocyte development. However, it remains unknown how E and Id proteins mechanistically enforce and maintain the naive T-cell fate. Here we show that Id2 and Id3 suppressed the development and expansion of innate variant follicular helper T (TFH) cells. Innate variant TFH cells required major histocompatibility complex (MHC) class I-like signaling and were associated with germinal center B cells. We found that Id2 and Id3 induced Foxo1 and Foxp1 expression to antagonize the activation of a TFH transcription signature. We show that Id2 and Id3 acted upstream of the Hif1a/Foxo/AKT/mTORC1 pathway as well as the c-myc/p19Arf module to control cellular expansion. We found that mice depleted for Id2 and Id3 expression developed colitis and alphabeta T-cell lymphomas. Lymphomas depleted for Id2 and Id3 expression displayed elevated levels of c-myc, whereas p19Arf abundance declined. Transcription signatures of Id2- and Id3-depleted lymphomas revealed similarities to genetic deficiencies associated with Burkitt lymphoma. We propose that, in response to antigen receptor and/or cytokine signaling, the E-Id protein axis modulates the activities of the PI3K-AKT-mTORC1-Hif1a and c-myc/p19Arf pathways to control cellular expansion and homeostatic proliferation. PMID- 25691469 TI - A high-sensitivity phospho-switch triggered by Cdk1 governs chromosome morphogenesis during cell division. AB - The initiation of chromosome morphogenesis marks the beginning of mitosis in all eukaryotic cells. Although many effectors of chromatin compaction have been reported, the nature and design of the essential trigger for global chromosome assembly remain unknown. Here we reveal the identity of the core mechanism responsible for chromosome morphogenesis in early mitosis. We show that the unique sensitivity of the chromosome condensation machinery for the kinase activity of Cdk1 acts as a major driving force for the compaction of chromatin at mitotic entry. This sensitivity is imparted by multisite phosphorylation of a conserved chromatin-binding sensor, the Smc4 protein. The multisite phosphorylation of this sensor integrates the activation state of Cdk1 with the dynamic binding of the condensation machinery to chromatin. Abrogation of this event leads to chromosome segregation defects and lethality, while moderate reduction reveals the existence of a novel chromatin transition state specific to mitosis, the intertwist configuration. Collectively, our results identify the mechanistic basis governing chromosome morphogenesis in early mitosis and how distinct chromatin compaction states can be established via specific thresholds of Cdk1 kinase activity. PMID- 25691470 TI - Structural basis for corepressor assembly by the orphan nuclear receptor TLX. AB - The orphan nuclear receptor TLX regulates neural stem cell self-renewal in the adult brain and functions primarily as a transcription repressor through recruitment of Atrophin corepressors, which bind to TLX via a conserved peptide motif termed the Atro box. Here we report crystal structures of the human and insect TLX ligand-binding domain in complex with Atro box peptides. In these structures, TLX adopts an autorepressed conformation in which its helix H12 occupies the coactivator-binding groove. Unexpectedly, H12 in this autorepressed conformation forms a novel binding pocket with residues from helix H3 that accommodates a short helix formed by the conserved ALXXLXXY motif of the Atro box. Mutations that weaken the TLX-Atrophin interaction compromise the repressive activity of TLX, demonstrating that this interaction is required for Atrophin to confer repressor activity to TLX. Moreover, the autorepressed conformation is conserved in the repressor class of orphan nuclear receptors, and mutations of corresponding residues in other members of this class of receptors diminish their repressor activities. Together, our results establish the functional conservation of the autorepressed conformation and define a key sequence motif in the Atro box that is essential for TLX-mediated repression. PMID- 25691472 TI - Corrigendum: In vivo investigation of the transcription, processing, endonucleolytic activity, and functional relevance of the spatial distribution of a plant miRNA. PMID- 25691471 TI - Structures of regulatory machinery reveal novel molecular mechanisms controlling B. subtilis nitrogen homeostasis. AB - All cells must sense and adapt to changing nutrient availability. However, detailed molecular mechanisms coordinating such regulatory pathways remain poorly understood. In Bacillus subtilis, nitrogen homeostasis is controlled by a unique circuitry composed of the regulator TnrA, which is deactivated by feedback inhibited glutamine synthetase (GS) during nitrogen excess and stabilized by GlnK upon nitrogen depletion, and the repressor GlnR. Here we describe a complete molecular dissection of this network. TnrA and GlnR, the global nitrogen homeostatic transcription regulators, are revealed as founders of a new structural family of dimeric DNA-binding proteins with C-terminal, flexible, effector-binding sensors that modulate their dimerization. Remarkably, the TnrA sensor domains insert into GS intersubunit catalytic pores, destabilizing the TnrA dimer and causing an unprecedented GS dodecamer-to-tetradecamer conversion, which concomitantly deactivates GS. In contrast, each subunit of the GlnK trimer "templates" active TnrA dimers. Unlike TnrA, GlnR sensors mediate an autoinhibitory dimer-destabilizing interaction alleviated by GS, which acts as a GlnR chaperone. Thus, these studies unveil heretofore unseen mechanisms by which inducible sensor domains drive metabolic reprograming in the model Gram-positive bacterium B. subtilis. PMID- 25691473 TI - Vascular and circulating microRNAs in renal ischaemia-reperfusion injury. AB - Ischaemia-reperfusion (I/R) injury of the kidney is a major cause of acute kidney injury. It may result in worsening or even loss of organ function. Transient occlusion of the renal vessel is followed by a reperfusion period, which induces further tissue damage by release of reactive oxygen and nitrogen species. Ischaemia-reperfusion injury of the kidney may be associated with surgical interventions in native kidneys and is also a common and unavoidable phenomenon in kidney transplantation. MicroRNAs are fascinating modulators of gene expression. They are capable of post-transcriptional silencing of genetic information by targeting the 3'-untranslated region of mRNAs, culminating in a suppression of protein synthesis or an increase in mRNA degradation. They might therefore be useful diagnostic and therapeutic entities during renal I/R injury; for instance, miR-21 has been shown to be enriched in kidney tissue in mice and humans with acute kidney injury. Interestingly, most recent literature suggests that modulation of vascular microRNAs might result in the amelioration of kidney function during renal I/R injury. To that end, miR-126 and miR-24, which have been demonstrated to be highly enriched in endothelial cells, were therapeutically modulated and shown to ameliorate renal I/R injury in mice. MicroRNAs in plasma, urine or enriched in microvesicles have been shown to serve as non-invasive tools for disease monitoring and to have potential impact on downstream mechanisms in recipient cells. This review highlights the latest developments regarding the role of microRNAs in renal I/R injury. PMID- 25691474 TI - Reduced-dose fludarabine, cyclophosphamide, and rituximab (FCR-Lite) plus lenalidomide, followed by lenalidomide consolidation/maintenance, in previously untreated chronic lymphocytic leukemia. AB - Fludarabine, cyclophosphamide, and rituximab (FCR) remains the standard of care for fit chronic lymphocytic leukemia (CLL) patients requiring first therapy. However, side effects can be significant, and patients with poor risk features have inferior outcomes. The purpose of this study was to evaluate reduced-dose FCR (FCR-Lite) plus lenalidomide (FCR(2) ) followed by lenalidomide maintenance as a strategy to shorten immunochemotherapy in untreated CLL. Patients received four to six cycles of FCR(2) . Patients who were minimal residual disease (MRD) negative in peripheral blood (PB) and bone marrow (BM) initiated 12 months of lenalidomide maintenance after either four or six cycles (based on MRD status). The primary study endpoint was the complete response (CR) rate after four cycles of FCR(2) . Twenty patients were evaluable. After four cycles of FCR(2) , response rates were: CR, 45.0%; CR with incomplete blood count recovery (CRi), 5.0%; partial response (PR), 45.0%; and stable disease (SD), 5.0%. BM and PB samples from 27.8% and 52.9% of patients, respectively, were MRD negative. After six cycles, response rates were: CR, 58.3%; CRi, 16.7%; and PR, 25.0%. BM and PB samples from 50.0% and 72.7% of patients, respectively, were MRD negative. Overall, 75% of evaluable patients achieved a CR or CRi following FCR(2) . After 17.4 months of median follow-up, one progression and one death occurred. Our findings suggest that FCR(2) combines encouraging clinical activity with acceptable toxicity in previously untreated CLL. Lenalidomide can be safely added to FCR and may reduce chemotherapy exposure without compromising outcomes. PMID- 25691475 TI - Relationship of posttraumatic growth to symptoms of posttraumatic stress disorder and depression: A pilot study of Iraqi students. AB - Posttraumatic growth (PTG) and psychopathology are common outcomes following exposure to adversity and trauma. We examined the relationship of PTG to posttraumatic stress disorder (PTSD) and depression in a group of young Iraqi students with war trauma exposure. These young Iraqis had experienced an average of 13 different war-related adversities. The prevalence of probable PTSD was 17.2% and probable depression 23.1%. PTSD was associated with higher and depression with lower PTG. In addition, the relationship between PTG and PTSD was stronger among males than females. Although PTSD and depression were relatively common, they were related to PTG in opposite directions. PMID- 25691478 TI - Fosfomycin for multidrug treatment of Klebsiella pneumoniae carbapenemase bacteremia. PMID- 25691479 TI - Comment: evaluation of adjunctive ketamine to benzodiazepines for management of alcohol withdrawal syndrome. PMID- 25691480 TI - Reply: evaluation of adjunctive ketamine to benzodiazepines for management of alcohol withdrawal syndrome. PMID- 25691481 TI - Forest transitions in Eastern Europe and their effects on carbon budgets. AB - Forests often rebound from deforestation following industrialization and urbanization, but for many regions our understanding of where and when forest transitions happened, and how they affected carbon budgets remains poor. One such region is Eastern Europe, where political and socio-economic conditions changed drastically over the last three centuries, but forest trends have not yet been analyzed in detail. We present a new assessment of historical forest change in the European part of the former Soviet Union and the legacies of these changes on contemporary carbon stocks. To reconstruct forest area, we homogenized statistics at the provincial level for ad 1700-2010 to identify forest transition years and forest trends. We contrast our reconstruction with the KK11 and HYDE 3.1 land change scenarios, and use all three datasets to drive the LPJ dynamic global vegetation model to calculate carbon stock dynamics. Our results revealed that forest transitions in Eastern Europe occurred predominantly in the early 20th century, substantially later than in Western Europe. We also found marked geographic variation in forest transitions, with some areas characterized by relatively stable or continuously declining forest area. Our data suggest extensive deforestation in European Russia already prior to ad 1700, and even greater deforestation in the 18th and 19th centuries than in the KK11 and HYDE scenarios. Based on our reconstruction, cumulative carbon emissions from deforestation were greater before 1700 (60 Pg C) than thereafter (29 Pg C). Summed over our entire study area, forest transitions led to a modest uptake in carbon over recent decades, with our dataset showing the smallest effect (<5.5 Pg C) and a more heterogeneous pattern of source and sink regions. This suggests substantial sequestration potential in regrowing forests of the region, a trend that may be amplified through ongoing land abandonment, climate change, and CO2 fertilization. PMID- 25691482 TI - Household Air Pollution: An Emerging Risk Factor for CVD. PMID- 25691483 TI - On the Global Epidemic of CVD and Why Household Air Pollution Matters. PMID- 25691484 TI - Adult cardiopulmonary mortality and indoor air pollution: a 10-year retrospective cohort study in a low-income rural setting. AB - BACKGROUND: Indoor air pollution (IAP) due to solid fuel use is a major risk factor of respiratory and cardiovascular mortality and morbidity. Rural Matlab in Bangladesh has been partly supplied with natural gas since the early 1990s, which offered a natural experiment to investigate the long-term impact of IAP on cardiopulmonary mortality. OBJECTIVE: This study sought to compare adult cardiopulmonary mortality in relation to household fuel type as a surrogate for exposure to indoor air pollution. STUDY DESIGN: This was a retrospective cohort study. We identified all households in 11 villages in Matlab, Bangladesh, and categorized them as either supplied with natural gas or using solid fuel for cooking or heating since January 1, 2001. Cause-specific mortality data including cardiopulmonary deaths were obtained through verbal autopsy as part of a permanent surveillance. Person-years (PYs) of exposure were computed from baseline until the event. Subjects with missing information on cause of death, outward migration, or on fuel type were excluded. Event rates for each fuel category were calculated as well as the relative risk of dying with 95% confidence intervals (CI). SETTING: Rural Matlab, Bangladesh. PATIENTS: Adults 18 years of age or older. OUTCOME MEASURE: Death from cardiopulmonary diseases over a 10-year period. FINDINGS: In total, 946 cardiopulmonary deaths occurred with 884 in the solid-fuel and 62 in the gas-supplied households (n=7,565 and n=508, respectively) over the 10-year period. Cardiopulmonary death rate was 6.2 per 1,000 PYs in the solid-fuel group and 5.3 per 1,000 PYs in people living in households using gas. Mortality due to cardiovascular event was 5.1 and 4.8 per 1,000 PY in people from the solid-fuel and gas-supplied households, respectively, and the incident rate ratio was 1.07 (95% CI: 0.82 to 1.41). Mortality due to respiratory disease was 1.2 and 0.5 per 1,000 PYs in the solid-fuel and gas supplied groups, respectively, and the incident rate ratio was 2.26 (95% CI: 1.02 to 4.99). INTERPRETATION: Household solid-fuel use is associated with increased respiratory mortality and nonsignificantly increased risk of cardiovascular mortality. Reduction of exposure to pollution due to in-household solid-fuel use is likely to improve survival in Bangladeshi and similar populations. PMID- 25691485 TI - Household Air Pollution from Solid Fuel Use: Evidence for Links to CVD. PMID- 25691486 TI - Household Air Pollution in the Early Origins of CVD in Developing Countries. PMID- 25691487 TI - Reducing CVD Through Improvements in Household Energy: Implications for Policy Relevant Research. PMID- 25691488 TI - Household smoke pollution and chronic cor pulmonale. PMID- 25691489 TI - Household Air Pollution and CVD: Identifying Best Directions for Research. PMID- 25691490 TI - Mechanism of intracellular detection of glucose through nonenzymatic and boronic acid functionalized carbon dots. AB - The objective of the research described here is to elucidate the fundamental mechanism by which the new class of "inert" non-enzymatic and boronic acid functionalized carbon dots-based sensors facilitate intracellular detection of glucose. The study suggests that the mechanism of detection of glucose involved selective assembly and fluorescence quenching of the carbon dots with excellent dynamic response to varying concentration of glucose within the biological range (1-100 mM). The strong dynamic response was related to high selectivity to biomolecules and inertness of carbon dots. Furthermore, the functionalization of carbon dots with boronic acid was the governing factor response for the passive character of the carbon dots. The study lays the foundation for the new field of carbon-based nanochemosensors. PMID- 25691491 TI - Opportunities and challenges of current electrophysiology research: a plea to establish 'translational electrophysiology' curricula. AB - Cardiac electrophysiology has evolved into an important subspecialty in cardiovascular medicine. This is in part due to the significant advances made in our understanding and treatment of heart rhythm disorders following more than a century of scientific discoveries and research. More recently, the rapid development of technology in cellular electrophysiology, molecular biology, genetics, computer modelling, and imaging have led to the exponential growth of knowledge in basic cardiac electrophysiology. The paradigm of evidence-based medicine has led to a more comprehensive decision-making process and most likely to improved outcomes in many patients. However, implementing relevant basic research knowledge in a system of evidence-based medicine appears to be challenging. Furthermore, the current economic climate and the restricted nature of research funding call for improved efficiency of translation from basic discoveries to healthcare delivery. Here, we aim to (i) appraise the broad challenges of translational research in cardiac electrophysiology, (ii) highlight the need for improved strategies in the training of translational electrophysiologists, and (iii) discuss steps towards building a favourable translational research environment and culture. PMID- 25691492 TI - Myoblast differentiation of human mesenchymal stem cells on graphene oxide and electrospun graphene oxide-polymer composite fibrous meshes: importance of graphene oxide conductivity and dielectric constant on their biocompatibility. AB - Recently graphene and graphene based composites are emerging as better materials to fabricate scaffolds. Addition of graphene oxide (GO) nanoplatelets (GOnPs) in bioactive polymers was found to enhance its conductivity (sigma) and, dielectric permittivity (epsilon) along with biocompatibility. In this paper, human cord blood derived mesenchymal stem cells (CB-hMSCs) were differentiated to skeletal muscle cells (hSkMCs) on spin coated thin GO sheets composed of GOnPs and on electrospun fibrous meshes of GO-PCL (poly-caprolactone) composite. Both substrates exhibited excellent myoblast differentiations and promoted self alignedmyotubesformation similar to natural orientation. sigma, epsilon, microstructural and vibration spectroscopic studies were carried out for the characterizations of GO sheet and the composite scaffolds. Significantly enhanced values of both sigma and epsilon of the GO-PCL composite were considered to provide favourable cues for the formation of superior multinucleated myotubes on the electrospun meshes compared to those on thin GO sheets. The present results demonstrated that both substrates might be used as potential candidates for CB hMSCs differentiation and proliferation for human skeletal muscle tissue regeneration. PMID- 25691493 TI - Combination therapy with indacaterol and glycopyrronium bromide in the management of COPD: an update on the evidence for efficacy and safety. AB - The international guidelines on chronic obstructive pulmonary disease (COPD) recommend inhaled bronchodilators for maintenance treatment of the disease. These drugs include beta2-agonists and muscarinic antagonists, which are both available as short-acting agents (to be used as needed for dyspnea) and long-acting agents. To the latter belong salmeterol and formoterol (long-acting beta2-agonists) and indacaterol, vilanterol and olodaterol (very long-acting beta2-agonist) as beta2 agonists, and tiotropium, aclidinium and glycopyrronium bromide as long-acting muscarinic antagonists. The efficacy and safety of indacaterol and glycopyrronium as monotherapies has been demonstrated in several controlled trials. However, in some patients with moderate-to-severe COPD, symptoms are poorly controlled by bronchodilator monotherapy; in these cases the addition of a second bronchodilator from a different pharmacological class may be beneficial. Here we review the evidence from published randomized trials concerning the efficacy and safety of the once-daily fixed-dose dual bronchodilator combining indacaterol and glycopyrronium. PMID- 25691494 TI - China's ratio of male to female babies remains high despite sixth annual fall. PMID- 25691495 TI - Intestinal deletion of Claudin-7 enhances paracellular organic solute flux and initiates colonic inflammation in mice. AB - OBJECTIVE: To design novel anti-inflammation treatments, it is important to recognise two distinct steps of inflammation: initiation and acceleration. In IBDs, intestinal inflammation is reported to be accelerated by dysfunction in the epithelial paracellular barrier formed by tight junctions (TJs). However, it is unclear whether changes in paracellular barrier function initiate inflammation. Some of the intestinal claudin-family proteins, which form the paracellular barrier, show aberrant expression levels and localisations in IBDs. We aimed to elucidate the role of paracellular-barrier change in initiating colonic inflammation. DESIGN: We generated intestine-specific conditional knockout mice of claudin-7 (Cldn7), one of the predominant intestinal claudins. RESULTS: The intestine-specific Cldn7 deficiency caused colonic inflammation, even though TJ structures were still present due to other claudins. The paracellular flux (pFlux), determined by measuring the paracellular permeability across the colon epithelium, was enhanced by the Cldn7 deficiency for the small organic solute Lucifer Yellow (457 Da), but not for the larger organic solute FITC-Dextran (4400 Da). Consistent with these results, the intestine-specific claudin-7 deficiency enhanced the pFlux for N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP) (438 Da), a major bacterial product, to initiate colonic inflammation. CONCLUSIONS: These findings suggest that specific enhancement of the pFlux for small organic solutes across the claudin-based TJs initiates colonic inflammation. PMID- 25691496 TI - 3D printing of HEK 293FT cell-laden hydrogel into macroporous constructs with high cell viability and normal biological functions. AB - 3D printing has evolved into a versatile technology for fabricating tissue engineered constructs with spatially controlled cells and biomaterial distribution to allow biomimicking of in vivo tissues. In this paper, we reported a novel study of 3D printing of cell lines derived from human embryonic kidney tissue into a macroporous tissue-like construct. Nozzle temperature, chamber temperature and the composition of the matrix material were studied to achieve high cell viability (>90%) after 3D printing and construct formation. Long-term construct stability with a clear grid structure up to 30 days was observed. Cells continued to grow as cellular spheroids with strong cell-cell interactions. Two transfected cell lines of HEK 293FT were also 3D printed and showed normal biological functions, i.e. protein synthesis and gene activation in responding to small molecule stimulus. With further refinement, this 3D cell printing technology may lead to a practical fabrication of functional embryonic tissues in vitro. PMID- 25691497 TI - High levels of chorionic gonadotrophin attenuate insulin sensitivity and promote inflammation in adipocytes. AB - Gestational diabetes mellitus (GDM) presents with moderate inflammation, insulin resistance and impaired glucose uptake, which may result from increased maternal fat mass and increased circulation of placental hormones and adipokines. In this study, we set out to test whether the surge in chorionic gonadotrophin (CG) secretion is a cause of inflammation and impaired insulin sensitivity in GDM. We first found that LH/chorionic gonadotrophin receptors (CG/LHR) were expressed at low levels in insulin-sensitive murine 3T3-L1 adipocytes and murine C2C12 myocytes. CG treatment not only directly reduced insulin-responsive gene expression, including that of glucose transporter 4 (GLUT4), but also impaired insulin-stimulated glucose uptake in 3T3-L1 cells. Moreover, CG treatment increased the expression of the proinflammatory cytokine monocyte chemotactic protein 1 (MCP1) and upregulated nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) activity in 3T3-L1 cells. Clinically, pregnant women who had higher CG levels and elevated MCP1 developed GDM. Above all, apart from prepregnancy BMI and MCP1 level, CG level was associated with abnormal glucose tolerance. In summary, our findings confirmed that higher CG levels in pregnancy possibly played a role in GDM development partly by impairing the functions of insulin, such those involved in as glucose uptake, while promoting inflammation in adipocyte. PMID- 25691498 TI - GH/STAT5 signaling during the growth period in livers of mice overexpressing GH. AB - GH/STAT5 signaling is desensitized in the liver in adult transgenic mice overexpressing GH; however, these animals present greater body size. To assess whether the STAT5 pathway is active during the growth period in the liver in these animals, and how signaling modulators participate in this process, growing transgenic mice and normal siblings were evaluated. STAT5 does not respond to an acute GH-stimulus, but displays higher basal phosphorylation in the livers of growing GH-overexpressing mice. GH receptor and the positive modulators glucocorticoid receptor and HNF1 display greater abundance in transgenic animals, supporting the activity of STAT5. The negative modulators cytokine-induced suppressor and PTP1B are increased in GH-overexpressing mice. The suppressors SOCS2 and SOCS3 exhibit higher mRNA levels in transgenic mice but lower protein content, indicating that they are being actively degraded. Therefore, STAT5 signaling is increased in the liver in GH-transgenic mice during the growth period, with a balance between positive and negative effectors resulting in accelerated but controlled growth. PMID- 25691499 TI - Reproductive toxicity in male mice after exposure to high molybdenum and low copper concentrations. AB - To evaluate the effects of dietary high molybdenum (HMo) and low copper (LCu) concentrations on reproductive toxicity of male mice, 80 mice were divided into 4 groups of 20. These groups were fed with the following: (1) normal control (NC) diet (NC group); (2) NC and HMo diets (HMo group); (3) LCu diet (LCu group); and (4) HMo and LCu diets (HMoLCu group). On the 50th and 100th day, superoxide dismutase (SOD), malondialdehyde (MDA), glutathione peroxidase (GSH-Px), and total antioxidant capacity (T-AOC) were analyzed to determine oxidative stress states. Morphological changes in testicular tissue were evaluated with hematoxylin and eosin staining and ultrastructural changes were monitored by transmission electron microscopy. The results showed that administration of HMo, LCu, and HMoLCu not only decreased sperm density and motility but also increased the rate of teratosperm occurrence. A significant increase in MDA content and a decrease in SOD, GSH-Px, and T-AOC contents were observed in LCu, HMo, and HMoLCu groups. Testicular tissues and cells of mice were damaged by HMo and the damages were more serious in the case of Cu deficiency. Exposure to HMo adversely affected the reproductive system of male mice, and dietary LCu plays key roles in HMo-induced reproductive toxicity. PMID- 25691500 TI - Results of investigation into statin side effects due by end of year. PMID- 25691501 TI - The subjective experience of acute, experimentally-induced Salvia divinorum inebriation. AB - This study examined the overall psychological effects of inebriation facilitated by the naturally-occurring plant hallucinogen Salvia divinorum using a double blind, randomized, placebo-controlled trial. Thirty healthy individuals self administered Salvia divinorum via combustion and inhalation in a quiet, comfortable research setting. Experimental sessions, post-session interviews, and 8-week follow-up meetings were audio recorded and transcribed to provide the primary qualitative material analyzed here. Additionally, post-session responses to the Hallucinogen Rating Scale provided a quantitative groundwork for mixed methods discussion. Qualitative data underwent thematic content analysis, being coded independently by three researchers before being collaboratively integrated to provide the final results. Three main themes and 10 subthemes of acute intoxication emerged, encompassing the qualities of the experience, perceptual alterations, and cognitive-affective shifts. The experience was described as having rapid onset and being intense and unique. Participants reported marked changes in auditory, visual, and interoceptive sensory input; losing normal awareness of themselves and their surroundings; and an assortment of delusional phenomena. Additionally, the abuse potential of Salvia divinorum was examined post hoc. These findings are discussed in light of previous research, and provide an initial framework for greater understanding of the subjective effects of Salvia divinorum, an emerging drug of abuse. PMID- 25691502 TI - Detecting impairment: sensitive cognitive measures of dose-related acute alcohol intoxication. AB - The cognitive impairment that results from acute alcohol intoxication is associated with considerable safety risks. Other psychoactive substances, such as medications, pose a similar risk to road and workplace safety. However, there is currently no legal limit for operating vehicles or working while experiencing drug-related impairment. The current study sought to identify a brief cognitive task sensitive to a meaningful degree of impairment from acute alcohol intoxication to potentially stand as a reference from which to quantify impairment from other similar substances. A placebo-controlled single-blind crossover design was employed to determine the relative sensitivity of four commonly-administered cognitive tasks (Compensatory Tracking Task, Digit Symbol Substitution Test, Brief Stop Signal Task and Inspection Time Task) to alcohol related impairment in male social drinkers at ~0.05% ascending breath alcohol concentration (BrAC), ~0.08% peak BrAC and 0.05% descending BrAC. The Inspection Time Task was identified as the most sensitive task, detecting a medium to large magnitude increase in impairment (g ~ 0.60) at 0.05% ascending and descending BrAC, and a large magnitude effect size (g = 0.80) at 0.08% peak BrAC. The remaining tasks failed to demonstrate sensitivity to dose-dependent and limb dependent changes in alcohol-induced impairment. The Inspection Time Task was deemed the most sensitive task for screening alcohol-related impairment based on the present results. Confirmation of equivalence with other drug-related impairment and sensitivity to alcohol-induced impairment in real-world settings should be established in future research. PMID- 25691503 TI - Understanding responder neurobiology in schizophrenia using a quantitative systems pharmacology model: application to iloperidone. AB - The concept of targeted therapies remains a holy grail for the pharmaceutical drug industry for identifying responder populations or new drug targets. Here we provide quantitative systems pharmacology as an alternative to the more traditional approach of retrospective responder pharmacogenomics analysis and applied this to the case of iloperidone in schizophrenia. This approach implements the actual neurophysiological effect of genotypes in a computer-based biophysically realistic model of human neuronal circuits, is parameterized with human imaging and pathology, and is calibrated by clinical data. We keep the drug pharmacology constant, but allowed the biological model coupling values to fluctuate in a restricted range around their calibrated values, thereby simulating random genetic mutations and representing variability in patient response. Using hypothesis-free Design of Experiments methods the dopamine D4 R AMPA (receptor-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor coupling in cortical neurons was found to drive the beneficial effect of iloperidone, likely corresponding to the rs2513265 upstream of the GRIA4 gene identified in a traditional pharmacogenomics analysis. The serotonin 5-HT3 receptor-mediated effect on interneuron gamma-aminobutyric acid conductance was identified as the process that moderately drove the differentiation of iloperidone versus ziprasidone. This paper suggests that reverse-engineered quantitative systems pharmacology is a powerful alternative tool to characterize the underlying neurobiology of a responder population and possibly identifying new targets. PMID- 25691504 TI - Neural correlates of change in major depressive disorder anhedonia following open label ketamine. AB - Anhedonia is a cardinal symptom of major depression and is often refractory to standard treatment, yet no approved medication for this specific symptom exists. In this exploratory re-analysis, we assessed whether administration of rapid acting antidepressant ketamine was associated specifically with reduced anhedonia in medication-free treatment-refractory patients with major depressive disorder in an open-label investigation. Additionally, participants received either oral riluzole or placebo daily beginning 4 hours post-infusion. A subgroup of patients underwent fluorodeoxyglucose positron emission tomography scans at baseline (1-3 days pre-infusion) and 2 hours post-ketamine infusion. Anhedonia rapidly decreased following a single ketamine infusion; this was sustained for up to three days, but was not altered by riluzole. Reduced anhedonia correlated with increased glucose metabolism in the hippocampus and dorsal anterior cingulate cortex (dACC) and decreased metabolism in the inferior frontal gyrus and orbitofrontal cortex (OFC). The tentative relationship between change in anhedonia and glucose metabolism remained significant in dACC and OFC, and at trend level in the hippocampus, a result not anticipated, when controlling for change in total depression score. Results, however, remain tenuous due to the lack of a placebo control for ketamine. In addition to alleviating overall depressive symptoms, ketamine could possess anti-anhedonic potential in major depressive disorder, which speculatively, may be mediated by alterations in metabolic activity in the hippocampus, dACC and OFC. PMID- 25691505 TI - A homozygous PMS2 founder mutation with an attenuated constitutional mismatch repair deficiency phenotype. AB - BACKGROUND: Inherited mutations in DNA mismatch repair genes predispose to different cancer syndromes depending on whether they are mono-allelic or bi allelic. This supports a causal relationship between expression level in the germline and phenotype variation. As a model to study this relationship, our study aimed to define the pathogenic characteristics of a recurrent homozygous coding variant in PMS2 displaying an attenuated phenotype identified by clinical genetic testing in seven Inuit families from Northern Quebec. METHODS: Pathogenic characteristics of the PMS2 mutation NM_000535.5:c.2002A>G were studied using genotype-phenotype correlation, single-molecule expression detection and single genome microsatellite instability analysis. RESULTS: This PMS2 mutation generates a de novo splice site that competes with the authentic site. In homozygotes, expression of the full-length protein is reduced to a level barely detectable by conventional diagnostics. Median age at primary cancer diagnosis is 22 years among 13 NM_000535.5:c.2002A>G homozygotes, versus 8 years in individuals carrying bi-allelic truncating mutations. Residual expression of full-length PMS2 transcript was detected in normal tissues from homozygotes with cancers in their 20s. CONCLUSIONS: Our genotype-phenotype study of c.2002A>G illustrates that an extremely low level of PMS2 expression likely delays cancer onset, a feature that could be exploited in cancer preventive intervention. PMID- 25691506 TI - Clinical trials of Ebola vaccine must continue despite fall in number of cases. PMID- 25691507 TI - Capillaria hepatica infection in black rats (Rattus rattus) on Diego Garcia, British Indian Ocean Territory. AB - Rats (Rattus spp.) are among the most damaging invasive species worldwide. The accidental introduction of rats has caused significant detriment to native flora and fauna, crops, structures, and human livelihoods. Rats are vectors of disease and carriers of various zoonotic parasites. Capillaria hepatica (syn. Callodium hepaticum) is a parasitic nematode found primarily in rodents but is known to infect over 140 mammal species, including human beings and several species of domestic animals. In this case study, the presence of C. hepatica infection in black rats on Diego Garcia, British Indian Ocean Territory, is reported. Liver samples from 20 black rats (Rattus rattus) were collected during a concurrent population density estimation study. Histology revealed 15 (75%) of the rats sampled had a current or previous infection with C. hepatica. In addition, a larval cestode compatible in size and shape with Cysticercus fasciolaris, the larval stage of Taenia taeniaeformis of cats, was found in 3 (15%) of the rats sampled. The high prevalence of C. hepatica infection in rats on Diego Garcia has implications for human health given the high population density of rats found on the island. PMID- 25691508 TI - Coxiella burnetii total immunoglobulin G, phase I and phase II immunoglobulin G antibodies, and bacterial shedding in young dams in persistently infected dairy herds. AB - The current study examines Coxiella burnetii infection patterns in young dairy dams around the calving period in persistently infected high-producing dairy herds. Infection patterns were determined in terms of total immunoglobulin G (IgG) and phase-specific IgG antibodies by enzyme-linked immunosorbent assay and bacterial shedding by real-time polymerase chain reaction (qPCR). On days 171-177 of gestation, at parturition, and on days 15-21 and 91-97 postpartum, 7 first parity cows and 7 second-parity cows were sampled for serology and qPCR. Total phase-specific I (PhI) and II (PhII) IgG antibodies were detected in 2 animals at days 171-177 of gestation. Four additional animals underwent seroconversion on days 91-97 postpartum. Three of 6 seropositive dams according to total IgG, showed a PhI+/PhII+ profile, whereas dams that seroconverted exhibited a PhI /PhII+ (2/6) or PhI+/PhII- (1/6) profile. An indirect fluorescent antibody test for PhI and PhII immunoglobulin M (IgM) was performed on plasma samples from the shedding dams, confirming seropositivity in a first-parity dam that seroconverted, and detecting a sudden spike of PhI-IgM antibodies in 1 further dam. No relationship was detected in young C. burnetii-infected animals between total IgG, PhI and/or PhII antibodies, and bacterial shedding throughout the study period. The highest bacterial load measured by qPCR was recorded in a second-parity dam. This animal presented abnormal peripheral blood counts, which would be an indication of severe peripheral blood alterations in some infected cattle. This study suggests that young shedder cows are mostly seronegative in early stages of infection. PMID- 25691509 TI - Incidence and antiviral response of hepatitis C virus reactivation in lupus patients undergoing immunosuppressive therapy. AB - OBJECTIVE: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease and usually requires immunosuppressive therapy, which is a major cause of viral reactivation. The incidence and antiviral response in SLE patients with hepatitis C virus (HCV) reactivation is unclear and needs to be investigated. METHODS: One hundred and sixty-six SLE patients with antibody to HCV (anti-HCV) status were retrospectively reviewed regarding the events of HCV reactivation. Patients with HCV reactivation were treated with pegylated interferon plus ribavirin treatment. The virological response and relapse rate were evaluated. RESULTS: Twenty-six patients were positive for anti-HCV. During a mean 8.4 years of follow-up, 10 (38.5%) cases developed HCV reactivation. No clear relationship was noted between immunosuppressive therapy and the HCV reactivation. Eight patients underwent antiviral therapy and the rapid virological response (RVR), early virological response, and sustained virological response (SVR) rates were 37.5%, 87.5%, and 75.0%, respectively. However, late relapse (reappearance of HCV RNA in serum after archiving SVR) was found in two (33.3%) of six patients achieving SVR. The two cases were HCV genotype 1 b concurrent with corticosteroid treatment. CONCLUSIONS: HCV reactivation in anti-HCV-positive SLE patients was possibly associated with glucocorticoids. The virological response to interferon plus ribavirin treatment is not inferior to the general population. However, monitoring HCV RNA after SVR is necessary for patients concurrent with corticosteroid treatment due to the risk of late relapse. PMID- 25691510 TI - Impact of a pharmacoinvasive strategy when delays to primary PCI are prolonged. AB - OBJECTIVES: Primary percutaneous coronary intervention (P-PCI) is the preferred reperfusion option in ST-elevation myocardial infarction, but its benefits become attenuated as time to its potential delivery becomes prolonged. Based on the STrategic Reperfusion Early After Myocardial Infarction trial, we assessed the impact of increasing time delay on outcomes in patients randomised to a pharmacoinvasive strategy (PI) or P-PCI. METHODS: Thirty-day clinical outcomes were examined according to PCI-related delay (P-RD). Data from hospitals that enrolled >10 randomised patients were used and P-RD categorised as <=55 min, >55 97 min and >97 min. RESULTS: Composite of death/congestive heart failure/cardiogenic shock/myocardial infarction in PI and P-PCI arms occurred in 10.6% versus 10.3% (<=55 min, p=0.910); 13.9% versus 17.9% (>55-97 min, p=0.148) and 13.5% versus 16.2% (>97 min, p=0.470), respectively. While there was no worsening of outcomes for PI across the P-RD spectrum, this occurred in the P-PCI arm (p(trend)=0.038). For P-RD <=55 min, fewer events tended to occur with P-PCI than PI. Conversely, as P-RD increased to >55 min, PI-assigned patients had better outcomes than P-PCI, suggesting an event-free advantage with PI as P-RD increased (p(interaction)=0.094). Analysing P-RD continuously showed that for every 10-min increment there was an increasing trend towards benefit among PI assigned patients (p(interaction)=0.073). CONCLUSIONS: As P-RD increased, PI outcomes became superior to P-PCI when P-RD is prolonged and exceeds guideline mandated times. In such circumstances, a PI strategy may provide an alternative reperfusion option. Adverse time delays for delivery of P-PCI should be considered when evaluating reperfusion strategies. TRIAL REGISTRATION NUMBER: NCT00623623. PMID- 25691511 TI - A novel diagnostic protocol to identify patients suitable for discharge after a single high-sensitivity troponin. AB - OBJECTIVE: To establish whether a novel accelerated diagnostic protocol (ADP) for suspected acute coronary syndrome (ACS) could successfully identify low-risk patients suitable for discharge after a single high-sensitivity troponin T (hs cTnT) taken at presentation to the emergency department. We also compared the diagnostic accuracy of this ADP with strategies using initial undetectable hs cTnT. METHODS: This prospective observational study evaluated the ability of the Triage Rule-out Using high-Sensitivity Troponin (TRUST) ADP to identify low-risk patients with suspected ACS. The ADP incorporated a single presentation hs-cTnT of <14 ng/L, a non-ischaemic ECG and a modified Goldman risk score. Diagnostic performance of the ADP was compared with the detection limit cut-offs of hs-cTnT (<5 ng/L and <3 ng/L). The primary end point was fatal/non-fatal acute myocardial infarction (AMI) within 30 days. RESULTS: 960 participants were recruited, mean age 58.0 years, 80 (8.3%) had an AMI. The TRUST ADP classified 382 (39.8%) as low risk with a sensitivity for identifying AMI of 98.8% (95% CI 92.5% to 99.9%). hs cTnT detection limits (<5 ng/L and <3 ng/L) had a sensitivity of 100% (94.3 to 100) and 100% (94.4 to 100), respectively. The TRUST ADP identified more patients suitable for early discharge at 39.8% vs 29.3% (<5 ng/L) and 7.9% (<3 ng/L) (p<0.001) with a lower false-positive rate for AMI detection; specificity 43.3% (95% CI 42.7% to 43.4%) vs 32.0% (95% CI 31.5% to 32.0%) and 8.6% (95% CI 8.1% to 8.6%), respectively. CONCLUSIONS: The TRUST ADP, which incorporates structured risk-assessment and a single presentation hs-cTnT blood draw, has potential to allow early discharge in 40% of patients with suspected ACS and has greater clinical utility than undetectable hs-cTnT strategies. TRIAL REGISTRATION NUMBER: ISRCTN No. 21109279. PMID- 25691512 TI - Atrial fibrillation and stroke in adult patients with atrial septal defect and the long-term effect of closure. AB - OBJECTIVE: To estimate the risk of atrial fibrillation (AF) and stroke and the impact of closure in patients with atrial septal defect (ASD) compared with a general population cohort. METHODS: All adult Danish patients (>18 years) diagnosed with ASD from 1977 to 2009 (N=1168) were identified through population based registries. Using Cox regression, we compared ASD patients' risk of AF and stroke with an age-matched and gender-matched comparison cohort. We computed prevalence proportions of anticoagulation and antiarrhythmic medicine use before and after closure and described stroke-related mortality. RESULTS: Median follow up was 9.6 years (range 1-33 years). Patients with ASD had a higher risk of first time AF (adjusted HR 8.2; 95% CI 6.6 to 10.2) after closure than the comparison cohort, but with no difference between transcatheter and surgical closure (HR 1.5, 95% CI 0.6 to 3.5). Patients without prevalent AF had a 10-year cumulative incidence of AF of 11% (95% CI 9% to 14%) after closure compared with 2% (95% CI 1.8% to 2.5%) in the comparison cohort. Patients with ASD with prevalent AF continued to use anticoagulation medicine after closure/diagnosis. Patients with ASD had increased risk of stroke without closure (adjusted HR 2.6; 95% CI 1.4 to 3.0) and with closure (adjusted HR 2.0; 95% CI 1.4 to 2.7). Risk of stroke after closure was related to AF (HR adjusted for AF 1.3; 95% CI 0.9 to 1.9). CONCLUSIONS: Patients with ASD had a higher risk of first-time AF after closure than the comparison cohort. There was no effect of closure on the use of AF related medicine in patients with prevalent AF. PMID- 25691513 TI - Do communication disorders extend to musical messages? An answer from children with hearing loss or autism spectrum disorders. AB - BACKGROUND: Effective musical communication requires conveyance of the intended message in a manner perceptible to the receiver. Communication disorders that impair transmitting or decoding of structural features of music (e.g., pitch, timbre) and/or symbolic representation may result in atypical musical communication, which can have a negative impact on music therapy interventions. OBJECTIVE: This study compared recognition of symbolic representation of emotions or movements in music by two groups of children with different communicative characteristics: severe to profound hearing loss (using cochlear implants [CI]) and autism spectrum disorder (ASD). Their responses were compared to those of children with typical-development and normal hearing (TD-NH). Accuracy was examined as a function of communicative status, emotional or movement category, and individual characteristics. METHODS: Participants listened to recorded musical excerpts conveying emotions or movements and matched them with labels. Measures relevant to auditory and/or language function were also gathered. RESULTS: There was no significant difference between the ASD and TD-NH groups in identification of musical emotions or movements. However, the CI group was significantly less accurate than the other two groups in identification of both emotions and movements. Mixed effects logistic regression revealed different patterns of accuracy for specific emotions as a function of group. CONCLUSION: Conveyance of emotions or movements through music may be decoded differently by persons with different types of communication disorders. Because music is the primary therapeutic tool in music therapy sessions, clinicians should consider these differential abilities when selecting music for clinical interventions focusing on emotions or movement. PMID- 25691514 TI - Memory for sequences of events impaired in typical aging. AB - Typical aging is associated with diminished episodic memory performance. To improve our understanding of the fundamental mechanisms underlying this age related memory deficit, we previously developed an integrated, cross-species approach to link converging evidence from human and animal research. This novel approach focuses on the ability to remember sequences of events, an important feature of episodic memory. Unlike existing paradigms, this task is nonspatial, nonverbal, and can be used to isolate different cognitive processes that may be differentially affected in aging. Here, we used this task to make a comprehensive comparison of sequence memory performance between younger (18-22 yr) and older adults (62-86 yr). Specifically, participants viewed repeated sequences of six colored, fractal images and indicated whether each item was presented "in sequence" or "out of sequence." Several out of sequence probe trials were used to provide a detailed assessment of sequence memory, including: (i) repeating an item from earlier in the sequence ("Repeats"; e.g., AB A: DEF), (ii) skipping ahead in the sequence ("Skips"; e.g., AB D: DEF), and (iii) inserting an item from a different sequence into the same ordinal position ("Ordinal Transfers"; e.g., AB 3: DEF). We found that older adults performed as well as younger controls when tested on well-known and predictable sequences, but were severely impaired when tested using novel sequences. Importantly, overall sequence memory performance in older adults steadily declined with age, a decline not detected with other measures (RAVLT or BPS-O). We further characterized this deficit by showing that performance of older adults was severely impaired on specific probe trials that required detailed knowledge of the sequence (Skips and Ordinal Transfers), and was associated with a shift in their underlying mnemonic representation of the sequences. Collectively, these findings provide unambiguous evidence that the capacity to remember sequences of events is fundamentally affected by typical aging. PMID- 25691515 TI - Role of the ventral tegmental area in methamphetamine extinction: AMPA receptor mediated neuroplasticity. AB - The molecular mechanisms underlying drug extinction remain largely unknown, although a role for medial prefrontal cortex (mPFC) glutamate neurons has been suggested. Considering that the mPFC sends glutamate efferents to the ventral tegmental area (VTA), we tested whether the VTA is involved in methamphetamine (METH) extinction via conditioned place preference (CPP). Among various METH-CPP stages, we found that the amount of phospho-GluR1/Ser845 increased in the VTA at behavioral extinction, but not the acquisition or withdrawal stage. Via surface biotinylation, we found that levels of membrane GluR1 were significantly increased during METH-CPP extinction, while no change was observed at the acquisition stage. Specifically, the number of dendritic spines in the VTA was increased at behavioral extinction, but not during acquisition. To validate the role of the mPFC in METH-CPP extinction, we lesioned the mPFC. Ibotenic acid lesioning of the mPFC did not affect METH-CPP acquisition, however, it abolished the extinction stage and reversed the enhanced phospho-GluR1/Ser845 levels as well as increases in VTA dendritic spines during METH-CPP extinction. Overall, this study demonstrates that the mPFC plays a critical role in METH-CPP extinction and identifies the VTA as an alternative target in mediating the extinction of drug conditioning. PMID- 25691516 TI - Calcineurin inhibition blocks within-, but not between-session fear extinction in mice. AB - Memory extinction involves the formation of a new associative memory that inhibits a previously conditioned association. Nonetheless, it could also depend on weakening of the original memory trace if extinction is assumed to have multiple components. The phosphatase calcineurin (CaN) has been described as being involved in extinction but not in the initial consolidation of fear learning. With this in mind, we set to study whether CaN could have different roles in distinct components of extinction. Systemic treatment with the CaN inhibitors cyclosporin A (CsA) or FK-506, as well as i.c.v. administration of CsA, blocked within-session, but not between-session extinction or initial learning of contextual fear conditioning. Similar effects were found in multiple session extinction of contextual fear conditioning and in auditory fear conditioning, indicating that CaN is involved in different types of short-term extinction. Meanwhile, inhibition of protein synthesis by cycloheximide (CHX) treatment did not affect within-session extinction, but disrupted fear acquisition and slightly impaired between-session extinction. Our results point to a dissociation of within- and between-session extinction of fear conditioning, with the former being more dependent on CaN activity and the latter on protein synthesis. Moreover, the modulation of within-session extinction did not affect between-session extinction, suggesting that these components are at least partially independent. PMID- 25691517 TI - Relapse of extinguished fear after exposure to a dangerous context is mitigated by testing in a safe context. AB - Aversive events can trigger relapse of extinguished fear memories, presenting a major challenge to the long-term efficacy of therapeutic interventions. Here, we examined factors regulating the relapse of extinguished fear after exposure of rats to a dangerous context. Rats received unsignaled shock in a distinct context ("dangerous" context) 24 h prior to auditory fear conditioning in another context. Fear to the auditory conditioned stimulus (CS) was subsequently extinguished either in the conditioning context ("ambiguous" context) or in a third novel context ("safe" context). Exposure to the dangerous context 30 min before a CS retention test caused relapse to the CS in the ambiguous and safe test contexts relative to nonextinguished controls. When rats were tested 24 h later (with or without short-term testing), rats tested in the ambiguous context continued to exhibit relapse, whereas rats tested in the safe context did not. Additionally, exposure of rats to the conditioning context--in place of the unsignaled shock context--did not result in relapse of fear to the CS in the safe testing context. Our work highlights the vulnerabilities of extinction recall to interference, and demonstrates the importance of context associations in the relapse of fear after extinction. PMID- 25691518 TI - Dorsolateral striatal lesions impair navigation based on landmark-goal vectors but facilitate spatial learning based on a "cognitive map". AB - In three experiments, the nature of the interaction between multiple memory systems in rats solving a variation of a spatial task in the water maze was investigated. Throughout training rats were able to find a submerged platform at a fixed distance and direction from an intramaze landmark by learning a landmark goal vector. Extramaze cues were also available for standard place learning, or "cognitive mapping," but these cues were valid only within each session, as the position of the platform moved around the pool between sessions together with the intramaze landmark. Animals could therefore learn the position of the platform by taking the consistent vector from the landmark across sessions or by rapidly encoding the new platform position on each session with reference to the extramaze cues. Excitotoxic lesions of the dorsolateral striatum impaired vector based learning but facilitated cognitive map-based rapid place learning when the extramaze cues were relatively poor (Experiment 1) but not when they were more salient (Experiments 2 and 3). The way the lesion effects interacted with cue availability is consistent with the idea that the memory systems involved in the current navigation task are functionally cooperative yet associatively competitive in nature. PMID- 25691519 TI - Olfactory perceptual learning requires action of noradrenaline in the olfactory bulb: comparison with olfactory associative learning. AB - Noradrenaline contributes to olfactory-guided behaviors but its role in olfactory learning during adulthood is poorly documented. We investigated its implication in olfactory associative and perceptual learning using local infusion of mixed alpha1-beta adrenergic receptor antagonist (labetalol) in the adult mouse olfactory bulb. We reported that associative learning, as opposed to perceptual learning, was not affected by labetalol infusions in the olfactory bulb. Accordingly, this treatment during associative learning did not affect the survival of bulbar adult-born neurons. Altogether, our results suggest that the noradrenergic system plays different parts in specific olfactory learning tasks and their neurogenic correlates. PMID- 25691520 TI - Daily application of alprostadil topical cream (Vitaros) does not impact vaginal pH, flora, or histology in female cynomolgus monkeys. AB - Topical alprostadil cream (Vitaros) is approved in Canada and Europe for the treatment of erectile dysfunction. To determine the effects on the female urogenital tract with repeated administration of the entire dose (300 MUg alprostadil containing 2.5% dodecyl-2-n,n-dimethylaminopropionate hydrochloride), the vaginal pH, flora, and histology were assessed as a model for 100% transference from male to the female during unprotected sexual intercourse. Female cynomolgus monkeys were administered the entire dose of Vitaros for 14 days with a 7-day recovery. Relative to vehicle and placebo cream, the vaginal pH and microflora were determined at baseline and weekly, thereafter. Vaginal biopsies were evaluated at the end of dosing and recovery. All animals were clinically normal for the study duration, and the vaginal pH was consistent between dose groups and the dosing period. Vaginal microflora and histopathology findings of mild inflammation were generally similar across treatment groups. In conclusion, repeated vaginal exposure to Vitaros did not alter the pH, microflora, or histology after 14 daily doses, supporting the safety of Vitaros transference to the female partner. PMID- 25691521 TI - Genotoxicity of chemical compounds identification and assessment by yeast cells transformed with GFP reporter constructs regulated by the PLM2 or DIN7 promoter. AB - Yeast cells transformed with high-copy number plasmids comprising a green fluorescent protein (GFP)-encoding gene optimized for yeast under the control of the new DIN7 or PLM2 and the established RNR2 and RAD54 promoters were used to assess the genotoxic potential of chemical compounds. The activity of potential DNA-damaging agents was investigated by genotoxicity assays and by OxoPlate assay in the presence of various test compounds. The fluorescence signal generated by GFP in response to DNA damage was related to the different concentrations of analytes and the analyte-dependent GFP synthesis. The use of distinct DNA damage inducible promoters presents alternative genotoxicity testing strategies by selective induction of promoters in response to DNA damage. The new DIN7 and PLM2 systems show higher sensitivity than the RNR2 and RAD54 systems in detecting 4 nitroquinoline-N-oxide and actinomycin D. Both DIN7 and PLM2 systems are able to detect camptothecin while RNR2 and RAD54 systems are not. Automated laboratory systems with assay performance on 384-well microplates provide for cost-effective high-throughput screening of DNA-damaging agents, reducing compound consumption to about 53% as compared with existing eukaryotic genotoxicity bioassays. PMID- 25691523 TI - Structural basis of functional diversification of the HD-GYP domain revealed by the Pseudomonas aeruginosa PA4781 protein, which displays an unselective bimetallic binding site. AB - The intracellular level of the bacterial secondary messenger cyclic di-3',5'-GMP (c-di-GMP) is determined by a balance between its biosynthesis and degradation, the latter achieved via dedicated phosphodiesterases (PDEs) bearing a characteristic EAL or HD-GYP domain. We here report the crystal structure of PA4781, one of the three Pseudomonas aeruginosa HD-GYP proteins, which we have previously characterized in vitro. The structure shows a bimetallic active site whose metal binding mode is different from those of both HD-GYP PDEs characterized so far. Purified PA4781 does not contain iron in the active site as for other HD-GYPs, and we show that it binds to a wide range of transition metals with similar affinities. Moreover, the structural features of PA4781 indicate that this is preferentially a pGpG binding protein, as we previously suggested. Our results point out that the structural features of HD-GYPs are more complex than predicted so far and identify the HD-GYP domain as a conserved scaffold which has evolved to preferentially interact with a partner GGDEF but which harbors different functions obtained through diversification of the active site. IMPORTANCE: In bacteria, the capability to form biofilms, responsible for increased pathogenicity and antibiotic resistance, is almost universally stimulated by the second messenger cyclic di-GMP (c-di-GMP). To design successful strategies for targeting biofilm formation, a detailed characterization of the enzymes involved in c-di-GMP metabolism is crucial. We solved the structure of the HD-GYP domain of PA4781 from Pseudomonas aeruginosa, involved in c-di-GMP degradation. This is the third structure of this class of phosphodiesterases to be solved, and with respect to its homologues, it shows significant differences both in the nature and in the binding mode of the coordinated metals, indicating that HD-GYP proteins are able to fine-tune their function, thereby increasing the chances of the microorganism to adapt to different environmental needs. PMID- 25691524 TI - Genetic basis for metabolism of methylated sulfur compounds in Methanosarcina species. AB - Methanosarcina acetivorans uses a variety of methylated sulfur compounds as carbon and energy sources. Previous studies implicated the mtsD, mtsF, and mtsH genes in catabolism of dimethylsulfide, but the genes required for use of other methylsulfides have yet to be established. Here, we show that a four-gene locus, designated mtpCAP-msrH, is specifically required for growth on methylmercaptopropionate (MMPA). The mtpC, mtpA, and mtpP genes encode a putative corrinoid protein, a coenzyme M (CoM) methyltransferase, and a major facilitator superfamily (MFS) transporter, respectively, while msrH encodes a putative transcriptional regulator. Mutants lacking mtpC or mtpA display a severe growth defect in MMPA medium but are unimpaired during growth on other substrates. The mtpCAP genes comprise a transcriptional unit that is highly and specifically upregulated during growth on MMPA, whereas msrH is monocistronic and constitutively expressed. Mutants lacking msrH fail to transcribe mtpCAP and grow poorly in MMPA medium, consistent with the assignment of its product as a transcriptional activator. The mtpCAP-msrH locus is conserved in numerous marine methanogens, including eight Methanosarcina species that we showed are capable of growth on MMPA. Mutants lacking the mtsD, mtsF, and mtsH genes display a 30% reduction in growth yield when grown on MMPA, suggesting that these genes play an auxiliary role in MMPA catabolism. A quadruple DeltamtpCAP DeltamtsD DeltamtsF DeltamtsH mutant strain was incapable of growth on MMPA. Reanalysis of mtsD, mtsF, and mtsH mutants suggests that the preferred substrate for MtsD is dimethylsulfide, while the preferred substrate for MtsF is methanethiol. IMPORTANCE: Methylated sulfur compounds play pivotal roles in the global sulfur and carbon cycles and contribute to global temperature homeostasis. Although the degradation of these molecules by aerobic bacteria has been well studied, relatively little is known regarding their fate in anaerobic ecosystems. In this study, we identify the genetic basis for metabolism of methylmercaptopropionate, dimethylsulfide, and methanethiol by strictly anaerobic methanogens of the genus Methanosarcina. These data will aid the development of predictive sulfur cycle models and enable molecular ecological approaches for the study of methylated sulfur metabolism in anaerobic ecosystems. PMID- 25691525 TI - Interaction with enzyme IIBMpo (EIIBMpo) and phosphorylation by phosphorylated EIIBMpo exert antagonistic effects on the transcriptional activator ManR of Listeria monocytogenes. AB - Listeriae take up glucose and mannose predominantly through a mannose class phosphoenolpyruvate:carbohydrate phosphotransferase system (PTS(Man)), whose three components are encoded by the manLMN genes. The expression of these genes is controlled by ManR, a LevR-type transcription activator containing two PTS regulation domains (PRDs) and two PTS-like domains (enzyme IIA(Man) [EIIA(Man)]- and EIIB(Gat)-like). We demonstrate here that in Listeria monocytogenes, ManR is activated via the phosphorylation of His585 in the EIIA(Man)-like domain by the general PTS components enzyme I and HPr. We also show that ManR is regulated by the PTS(Mpo) and that EIIB(Mpo) plays a dual role in ManR regulation. First, yeast two-hybrid experiments revealed that unphosphorylated EIIB(Mpo) interacts with the two C-terminal domains of ManR (EIIB(Gat)-like and PRD2) and that this interaction is required for ManR activity. Second, in the absence of glucose/mannose, phosphorylated EIIB(Mpo) (P~EIIB(Mpo)) inhibits ManR activity by phosphorylating His871 in PRD2. The presence of glucose/mannose causes the dephosphorylation of P~EIIB(Mpo) and P~PRD2 of ManR, which together lead to the induction of the manLMN operon. Complementation of a DeltamanR mutant with various manR alleles confirmed the antagonistic effects of PTS-catalyzed phosphorylation at the two different histidine residues of ManR. Deletion of manR prevented not only the expression of the manLMN operon but also glucose-mediated repression of virulence gene expression; however, repression by other carbohydrates was unaffected. Interestingly, the expression of manLMN in Listeria innocua was reported to require not only ManR but also the Crp-like transcription activator Lin0142. Unlike Lin0142, the L. monocytogenes homologue, Lmo0095, is not required for manLMN expression; its absence rather stimulates man expression. IMPORTANCE: Listeria monocytogenes is a human pathogen causing the foodborne disease listeriosis. The expression of most virulence genes is controlled by the transcription activator PrfA. Its activity is strongly repressed by carbohydrates, including glucose, which is transported into L. monocytogenes mainly via a mannose/glucose-specific phosphotransferase system (PTS(Man)). Expression of the man operon is regulated by the transcription activator ManR, the activity of which is controlled by a second, low-efficiency PTS of the mannose family, which functions as glucose sensor. Here we demonstrate that the EIIB(Mpo) component plays a dual role in ManR regulation: it inactivates ManR by phosphorylating its His871 residue and stimulates ManR by interacting with its two C-terminal domains. PMID- 25691526 TI - Disruption of the membrane nuclease gene (MBOVPG45_0215) of Mycoplasma bovis greatly reduces cellular nuclease activity. AB - Although the complete genome sequences of three strains of Mycoplasma bovis are available, few studies have examined gene function in this important pathogen. Mycoplasmas lack the biosynthetic machinery for the de novo synthesis of nucleic acid precursors, so nucleases are likely to be essential for them to acquire nucleotide precursors. Three putative membrane nucleases have been annotated in the genome of M. bovis strain PG45, MBOVPG45_0089 and MBOVPG45_0310, both of which have the thermonuclease (TNASE_3) functional domain, and MBOVPG45_0215 (mnuA), which has an exonuclease/endonuclease/phosphatase domain. While previous studies have demonstrated the function of TNASE_3 domain nucleases in several mycoplasmas, quantitative comparisons of the contributions of different nucleases to cellular nuclease activity have been lacking. Mapping of a library of 319 transposon mutants of M. bovis PG45 by direct genome sequencing identified mutants with insertions in MBOVPG45_0310 (the Delta0310 mutant) and MBOVPG45_0215 (the Delta0215 mutant). In this study, the detection of the product of MBOVPG45_0215 in the Triton X-114 fraction of M. bovis cell lysates, its cell surface exposure, and its predicted signal peptide suggested that it is a surface exposed lipoprotein nuclease. Comparison of a DeltamnuA mutant with wild-type M. bovis on native and denatured DNA gels and in digestion assays using double stranded phage lambda DNA and closed circular plasmid DNA demonstrated that inactivation of this gene abolishes most of the cellular exonuclease and endonuclease activity of M. bovis. This activity could be fully restored by complementation with the wild-type mnuA gene, demonstrating that MnuA is the major cellular nuclease of M. bovis. IMPORTANCE: Nucleases are thought to be important contributors to virulence and crucial for the maintenance of a nutritional supply of nucleotides in mycoplasmas that are pathogenic in animals. This study demonstrates for the first time that of the three annotated cell surface nuclease genes in an important pathogenic mycoplasma, the homologue of the thermostable nuclease identified in Gram-positive bacteria is responsible for the majority of the nuclease activity detectable in vitro. PMID- 25691527 TI - Species-specific dynamic responses of gut bacteria to a mammalian glycan. AB - The mammalian intestine provides nutrients to hundreds of bacterial species. Closely related species often harbor homologous nutrient utilization genes and cocolonize the gut, raising questions regarding the strategies mediating their stable coexistence. Here we reveal that related Bacteroides species that can utilize the mammalian glycan chondroitin sulfate (CS) have diverged in the manner in which they temporally regulate orthologous CS utilization genes. Whereas certain Bacteroides species display a transient surge in CS utilization transcripts upon exposure to CS, other species exhibit sustained activation of these genes. Remarkably, species-specific expression dynamics are retained even when the key players governing a particular response are replaced by those from a species with a dissimilar response. Bacteroides species exhibiting distinct expression behaviors in the presence of CS can be cocultured on CS. However, they vary in their responses to CS availability and to the composition of the bacterial community when CS is the sole carbon source. Our results indicate that diversity resulting from regulation of polysaccharide utilization genes may enable the coexistence of gut bacterial species using a given nutrient. IMPORTANCE: Genes mediating a specific task are typically conserved in related microbes. For instance, gut Bacteroides species harbor orthologous nutrient breakdown genes and may face competition from one another for these nutrients. How, then, does the gut microbial composition maintain such remarkable stability over long durations? We establish that in the case of genes conferring the ability to utilize the nutrient chondroitin sulfate (CS), microbial species vary in how they temporally regulate these genes and exhibit subtle growth differences on the basis of CS availability and community composition. Similarly to how differential regulation of orthologous genes enables related species to access new environments, gut bacteria may regulate the same genes in distinct fashions to reduce the overlap with coexisting species for utilization of available nutrients. PMID- 25691528 TI - An Escherichia coli mutant that makes exceptionally long cells. AB - Although Escherichia coli is a very small (1- to 2-MUm) rod-shaped cell, here we describe an E. coli mutant that forms enormously long cells in rich media such as Luria broth, as long indeed as 750 MUm. These extremely elongated (eel) cells are as long as the longest bacteria known and have no internal subdivisions. They are metabolically competent, elongate rapidly, synthesize DNA, and distribute cell contents along this length. They lack only the ability to divide. The concentration of the essential cell division protein FtsZ is reduced in these eel cells, and increasing this concentration restores division. IMPORTANCE: Escherichia coli is usually a very small bacterium, 1 to 2 MUm long. We have isolated a mutant that forms enormously long cells, 700 times longer than the usual E. coli cell. E. coli filaments that form under other conditions usually die within a few hours, whereas our mutant is fully viable even when it reaches such lengths. This mutant provides a useful tool for the study of aspects of E. coli physiology that are difficult to investigate with small cells. PMID- 25691529 TI - A single serine residue determines selectivity to monovalent metal ions in metalloregulators of the MerR family. AB - MerR metalloregulators alleviate toxicity caused by an excess of metal ions, such as copper, zinc, mercury, lead, cadmium, silver, or gold, by triggering the expression of specific efflux or detoxification systems upon metal detection. The sensor protein binds the inducer metal ion by using two conserved cysteine residues at the C-terminal metal-binding loop (MBL). Divalent metal ion sensors, such as MerR and ZntR, require a third cysteine residue, located at the beginning of the dimerization (alpha5) helix, for metal coordination, while monovalent metal ion sensors, such as CueR and GolS, have a serine residue at this position. This serine residue was proposed to provide hydrophobic and steric restrictions to privilege the binding of monovalent metal ions. Here we show that the presence of alanine at this position does not modify the activation pattern of monovalent metal sensors. In contrast, GolS or CueR mutant sensors with a substitution of cysteine for the serine residue respond to monovalent metal ions or Hg(II) with high sensitivities. Furthermore, in a mutant deleted of the Zn(II) exporter ZntA, they also trigger the expression of their target genes in response to either Zn(II), Cd(II), Pb(II), or Co(II). IMPORTANCE: Specificity in a stressor's recognition is essential for mounting an appropriate response. MerR metalloregulators trigger the expression of specific resistance systems upon detection of heavy metal ions. Two groups of these metalloregulators can be distinguished, recognizing either +1 or +2 metal ions, depending on the presence of a conserved serine in the former or a cysteine in the latter. Here we demonstrate that the serine residue in monovalent metal ion sensors excludes divalent metal ion detection, as its replacement by cysteine renders a pan-metal ion sensor. Our results indicate that the spectrum of signals detected by these sensors is determined not only by the metal-binding ligand availability but also by the metal-binding cavity flexibility. PMID- 25691530 TI - Analysis of the activity and regulon of the two-component regulatory system composed by Cjj81176_1484 and Cjj81176_1483 of Campylobacter jejuni. AB - Campylobacter jejuni is a leading cause of bacterial diarrheal disease and a frequent commensal of the intestinal tract in poultry and other animals. For optimal growth and colonization of hosts, C. jejuni employs two-component regulatory systems (TCSs) to monitor environmental conditions and promote proper expression of specific genes. We analyzed the potential of C. jejuni Cjj81176_1484 (Cjj1484) and Cjj81176_1483 (Cjj1483) to encode proteins of a cognate TCS that influences expression of genes possibly important for C. jejuni growth and colonization. Transcriptome analysis revealed that the regulons of the Cjj81176_1484 (Cjj1484) histidine kinase and the Cjj81176_1483 (Cjj1483) response regulator contain many common genes, suggesting that these proteins likely form a cognate TCS. We found that this TCS generally functions to repress expression of specific proteins with roles in metabolism, iron/heme acquisition, and respiration. Furthermore, the TCS repressed expression of Cjj81176_0438 and Cjj81176_0439, which had previously been found to encode a gluconate dehydrogenase complex required for commensal colonization of the chick intestinal tract. However, the TCS and other specific genes whose expression is repressed by the TCS were not required for colonization of chicks. We observed that the Cjj1483 response regulator binds target promoters in both unphosphorylated and phosphorylated forms and influences expression of some specific genes independently of the Cjj1484 histidine kinase. This work further expands the signaling mechanisms of C. jejuni and provides additional insights regarding the complex and multifactorial regulation of many genes involved in basic metabolism, respiration, and nutrient acquisition that the bacterium requires for optimal growth in different environments. IMPORTANCE: Bacterial two-component regulatory systems (TCSs) link environmental cues to expression of specific genes that enable optimal bacterial growth or colonization of hosts. We found that the Campylobacter jejuni Cjj1484 histidine kinase and Cjj1483 response regulator function as a cognate TCS to largely repress expression of target genes encoding a gluconate dehydrogenase complex required for commensal colonization of the chick intestinal tract, as well as other genes encoding proteins for heme or iron acquisition, metabolism, and respiration. We also discovered different modes by which Cjj1483 may mediate repression with and without Cjj1484. This work provides insight into the signal transduction mechanisms of a leading cause of bacterial diarrheal disease and emphasizes the multifactorial and complex regulation of specific biological processes in C. jejuni. PMID- 25691531 TI - The quorum sensing regulator CinR hierarchically regulates two other quorum sensing pathways in ligand-dependent and -independent fashions in Rhizobium etli. AB - Many rhizobial species use complex N-acyl-homoserine lactone (AHL)-based quorum sensing (QS) systems to monitor their population density and regulate their symbiotic interactions with their plant hosts. There are at least three LuxRI type regulatory systems in Rhizobium etli CFN42: CinRI, RaiRI, and TraRI. In this study, we show that CinI, RaiI, and TraI are responsible for synthesizing all AHLs under the tested conditions. The activation of these AHL synthase genes requires their corresponding LuxR-type counterparts. We further demonstrate that CinRI is at the top of the regulatory cascade that activates RaiRI and TraRI QS systems. Moreover, we discovered that CinR possesses a specific affinity to bind cinI promoter in the absence of its cognate AHL ligand, thereby activating cinI transcription. Addition of AHLs leads to improved binding to the cinI promoter and enhanced cinI expression. Furthermore, we found that compared to the wild type, the cinR mutation displayed reduced nodule formation, and cinR, raiR, and traI mutants show significantly lower levels of nitrogen fixation activity than the wild type. These results suggest that the complex QS regulatory systems in R. etli play an important role in its symbiosis with legume hosts. IMPORTANCE: Many bacteria use quorum sensing (QS) to monitor their cell densities and coordinately regulate a number of physiological functions. Rhizobia often have diverse and complex LuxR/LuxI-type quorum sensing systems that may be involved in symbiosis and N2 fixation. In this study, we identified three LuxR/LuxI-type QS systems in Rhizobium etli CFN42: CinRI, RaiRI, and TraRI. We established a complex network of regulation between these QS components and found that these QS systems played important roles in symbiosis processes. PMID- 25691532 TI - Coordinated zinc homeostasis is essential for the wild-type virulence of Brucella abortus. AB - Metal homeostasis in bacterial cells is a highly regulated process requiring intricately coordinated import and export, as well as precise sensing of intracellular metal concentrations. The uptake of zinc (Zn) has been linked to the virulence of Brucella abortus; however, the capacity of Brucella strains to sense Zn levels and subsequently coordinate Zn homeostasis has not been described. Here, we show that expression of the genes encoding the zinc uptake system ZnuABC is negatively regulated by the Zn-sensing Fur family transcriptional regulator, Zur, by direct interactions between Zur and the promoter region of znuABC. Moreover, the MerR-type regulator, ZntR, controls the expression of the gene encoding the Zn exporter ZntA by binding directly to its promoter. Deletion of zur or zntR alone did not result in increased zinc toxicity in the corresponding mutants; however, deletion of zntA led to increased sensitivity to Zn but not to other metals, such as Cu and Ni, suggesting that ZntA is a Zn-specific exporter. Strikingly, deletion of zntR resulted in significant attenuation of B. abortus in a mouse model of chronic infection, and subsequent experiments revealed that overexpression of zntA in the zntR mutant is the molecular basis for its decreased virulence. IMPORTANCE: The importance of zinc uptake for Brucella pathogenesis has been demonstrated previously, but to date, there has been no description of how overall zinc homeostasis is maintained and genetically controlled in the brucellae. The present work defines the predominant zinc export system, as well as the key genetic regulators of both zinc uptake and export in Brucella abortus. Moreover, the data show the importance of precise coordination of the zinc homeostasis systems as disregulation of some elements of these systems leads to the attenuation of Brucella virulence in a mouse model. Overall, this study advances our understanding of the essential role of zinc in the pathogenesis of intracellular bacteria. PMID- 25691533 TI - Plasma concentrations of copeptin, C-reactive protein and procalcitonin are positively correlated with APACHE II scores in patients with sepsis. AB - OBJECTIVE: To evaluate the correlation between Acute Physiology and Chronic Health Evaluation II (APACHE II) score and plasma concentrations of copeptin, C reactive protein (CRP) and procalcitonin in patients with sepsis. METHODS: Patients with sepsis were prospectively enrolled. APACHE II scores were determined during the first 24 h after admission to the intensive care unit. Plasma copeptin, CRP and procalcitonin were quantified at admission, 24 h, 48 h, and 72 h. Survival at 28 days after admission was recorded. RESULTS: APACHE II score was significantly positively correlated with plasma copeptin, CRP and procalcitonin concentrations. Survivors (n = 15) had significantly lower APACHE II scores and copeptin, CRP and procalcitonin concentrations than nonsurvivors (n = 26). APACHE II score, copeptin at 72 h, CRP at 48 h and procalcitonin at 24 h were independent risk factors for death. CONCLUSION: Plasma copeptin, CRP and procalcitonin concentrations were positively correlated with APACHE II score in patients with sepsis, and reflected disease severity. PMID- 25691534 TI - BDNF 196 G/A and COMT Val158Met Polymorphisms and Susceptibility to ADHD: A Meta Analysis. AB - OBJECTIVE: The aim of this study was to determine whether the brain-derived neurotrophic factor ( BDNF) 196 G/A or catechol- O-methyltransferase ( COMT) Val158Met polymorphisms is associated with susceptibility to ADHD. METHOD: We conducted a meta-analysis of the associations between the BDNF 196 G/A and COMT Val158Met polymorphisms and ADHD. RESULTS: Sixteen studies consisting of 3,594 patients with ADHD and 4,040 controls were included in this meta-analysis. Our results showed no association between ADHD and the BDNF 196A allele in all participants (odds ratio [OR] = 0.958, 95% confidence interval [CI] = [0.800, 1.146], p = .638), European or Asian population. Meta-analysis indicated no association between ADHD and the COMT G allele in all study participants (OR = 1.078, 95% CI = [0.962, 1.207], p = .196), European or Asian population. CONCLUSION: This meta-analysis showed a lack of association between the BDNF 196 G/A and COMT Val158Met polymorphisms and ADHD. PMID- 25691535 TI - Galanin pathogenic mutations in temporal lobe epilepsy. AB - Temporal lobe epilepsy (TLE) is a common epilepsy syndrome with a complex etiology. Despite evidence for the participation of genetic factors, the genetic basis of TLE remains largely unknown. A role for the galanin neuropeptide in the regulation of epileptic seizures has been established in animal models more than two decades ago. However, until now there was no report of pathogenic mutations in GAL, the galanin-encoding gene, and therefore its role in human epilepsy was not established. Here, we studied a family with a pair of monozygotic twins affected by TLE and two unaffected siblings born to healthy parents. Exome sequencing revealed that both twins carried a novel de novo mutation (p.A39E) in the GAL gene. Functional analysis revealed that the p.A39E mutant showed antagonistic activity against galanin receptor 1 (GalR1)-mediated response, and decreased binding affinity and reduced agonist properties for GalR2. These findings suggest that the p.A39E mutant could impair galanin signaling in the hippocampus, leading to increased glutamatergic excitation and ultimately to TLE. In a cohort of 582 cases, we did not observe any pathogenic mutations indicating that mutations in GAL are a rare cause of TLE. The identification of a novel de novo mutation in a biologically-relevant candidate gene, coupled with functional evidence that the mutant protein disrupts galanin signaling, strongly supports GAL as the causal gene for the TLE in this family. Given the availability of galanin agonists which inhibit seizures, our findings could potentially have direct implications for the development of anti-epileptic treatment. PMID- 25691536 TI - Dual developmental role of transcriptional regulator Ets1 in Xenopus cardiac neural crest vs. heart mesoderm. AB - AIMS: Ets1 is an important transcription factor that is expressed in both the cardiac neural crest (NC) and heart mesoderm of vertebrate embryos. Moreover, Ets1 deletion in humans results in congenital heart abnormalities. To clarify the functional contributions of Ets1 in cardiac NC vs. heart mesoderm, we performed tissue-targeted loss-of-function analysis to compare the relative roles of Ets1 in these two tissues during heart formation using Xenopus embryos as a model system. METHODS AND RESULTS: We confirmed by in situ hybridization analysis that Ets1 is expressed in NC and heart mesoderm during embryogenesis. Using a translation-blocking antisense morpholino to knockdown Ets1 protein selectively in the NC, we observed defects in NC delamination from the neural tube, collective cell migration, as well as segregation of NC streams in the cranial and cardiac regions. Many cardiac NC cells failed to reach their destination in the heart, resulting in defective aortic arch artery formation. A different set of defects was noted when Ets1 knockdown was targeted to heart mesoderm. The formation of the primitive heart tube was dramatically delayed and the endocardial tissue appeared depleted. As a result, the conformation of the heart was severely disrupted. In addition, the outflow tract septum was missing, and trabeculae formation in the ventricle was abolished. CONCLUSION: Our study shows that Ets1 is required in both the cardiac NC and heart mesoderm, albeit for different aspects of heart formation. Our results reinforce the suggestion that proper interaction between these tissues is critical for normal heart development. PMID- 25691537 TI - The role of elastic restoring forces in right-ventricular filling. AB - AIMS: The physiological determinants of RV diastolic function remain poorly understood. We aimed to quantify the contribution of elastic recoil to RV filling and determine its sensitivity to interventricular interaction. METHODS AND RESULTS: High-fidelity pressure-volume loops and simultaneous 3-dimensional ultrasound sequences were obtained in 13 pigs undergoing inotropic modulation, volume overload, and acute pressure overload induced by endotoxin infusion. Using a validated method, we isolated elastic restoring forces from ongoing relaxation using conventional pressure-volume data. The RV contracted below the equilibrium volume in >75% of the data sets. Consequently, elastic recoil generated strong sub-atmospheric passive pressure at the onset of diastole [-3 (-4 to -2) mmHg at baseline]. Stronger restoring suction pressure was related to a shorter isovolumic relaxation period, a higher rapid filling fraction, and lower atrial pressures (all P < 0.05). Restoring forces were mostly determined by the position of operating volumes around the equilibrium volume. By this mechanism, the negative inotropic effect of beta-blockade reduced and sometimes abolished restoring forces. During acute pressure overload, restoring forces initially decreased, but recovered at advanced stages. This biphasic response was related to alterations of septal curvature induced by changes in the diastolic LV-RV pressure balance. The constant of elastic recoil was closely related to the constant of passive stiffness (R = 0.69). CONCLUSION: The RV works as a suction pump, exploiting contraction energy to facilitate filling by means of strong elastic recoil. Restoring forces are influenced by the inotropic state and RV conformational changes mediated by direct ventricular interdependence. PMID- 25691538 TI - Role of common and rare variants in SCN10A: results from the Brugada syndrome QRS locus gene discovery collaborative study. AB - AIMS: Brugada syndrome (BrS) remains genetically heterogeneous and is associated with slowed cardiac conduction. We aimed to identify genetic variation in BrS cases at loci associated with QRS duration. METHODS AND RESULTS: A multi-centre study sequenced seven candidate genes (SCN10A, HAND1, PLN, CASQ2, TKT, TBX3, and TBX5) in 156 Caucasian SCN5A mutation-negative BrS patients (80% male; mean age 48) with symptoms (64%) and/or a family history of sudden death (47%) or BrS (18%). Forty-nine variants were identified: 18 were rare (MAF <1%) and non synonymous; and 11/18 (61.1%), mostly in SCN10A, were predicted as pathogenic using multiple bioinformatics tools. Allele frequencies were compared with the Exome Sequencing and UK10K Projects. SKAT methods tested rare variation in SCN10A finding no statistically significant difference between cases and controls. Co segregation analysis was possible for four of seven probands carrying a novel pathogenic variant. Only one pedigree (I671V/G1299A in SCN10A) showed co segregation. The SCN10A SNP V1073 was, however, associated strongly with BrS [66.9 vs. 40.1% (UK10K) OR (95% CI) = 3.02 (2.35-3.87), P = 8.07 * 10-19]. Voltage-clamp experiments for NaV1.8 were performed for SCN10A common variants V1073, A1073, and rare variants of interest: A200V and I671V. V1073, A200V and I671V, demonstrated significant reductions in peak INa compared with ancestral allele A1073 (rs6795970). CONCLUSION: Rare variants in the screened QRS associated genes (including SCN10A) are not responsible for a significant proportion of SCN5A mutation negative BrS. The common SNP SCN10A V1073 was strongly associated with BrS and demonstrated loss of NaV1.8 function, as did rare variants in isolated patients. PMID- 25691539 TI - Microengineering in cardiovascular research: new developments and translational applications. AB - Microfluidic, cellular co-cultures that approximate macro-scale biology are important tools for refining the in vitro study of organ-level function and disease. In recent years, advances in technical fabrication and biological integration have provided new insights into biological phenomena, improved diagnostic measurements, and made major steps towards de novo tissue creation. Here we review applications of these technologies specific to the cardiovascular field, emphasizing three general categories of use: reductionist vascular models, tissue-engineered vascular models, and point-of-care diagnostics. With continued progress in the ability to purposefully control microscale environments, the detailed study of both primary and cultured cells may find new relevance in the general cardiovascular research community. PMID- 25691540 TI - Disrupted Slit-Robo signalling results in membranous ventricular septum defects and bicuspid aortic valves. AB - AIMS: The mesenchymal cushions lining the early embryonic heart undergo complex remodelling to form the membranous ventricular septum as well as the atrioventricular and semilunar valves in later life. Disruption of this process underlies the most common congenital heart defects. Here, we identified a novel role for Slit-Robo signalling in the development of the murine membranous ventricular septum and cardiac valves. METHODS AND RESULTS: Expression of Robo1 and Robo2 receptors and their ligands, Slit2 and Slit3, was present in or adjacent to all cardiac cushions/valves. Loss of Robo1 or both Robo1 and Robo2 resulted in membranous ventricular septum defects at birth, a defect also found in Slit3, but not in Slit2 mutants. Additionally, Robo1;Robo2 double mutants showed thickened immature semilunar and atrioventricular valves as well as highly penetrant bicuspid aortic valves. Slit2 mutants recapitulated the semilunar phenotype, whereas Slit3 mutants displayed thickened atrioventricular valves. Bicuspid aortic cushions were already observed at E12.5 in the Robo1;Robo2 double mutants. Expression of Notch- and downstream Hey and Hes genes was down-regulated in Robo1 mutants, suggesting that reduced Notch signalling in mice lacking Robo might underlie the defects. Luciferase assays confirmed regulation of Notch signalling by Robo. CONCLUSION: Cardiac defects in mutants for Robo or Slit range from membranous ventricular septum defects to bicuspid aortic valves. These ligands and receptors have unique functions during development of specific cardiac cushion derivatives, and the Slit-Robo signalling pathway likely enforces its role by regulating Notch signalling, making these mutants a valuable new model to study cardiac valve formation. PMID- 25691541 TI - Early subcellular Ca2+ remodelling and increased propensity for Ca2+ alternans in left atrial myocytes from hypertensive rats. AB - AIMS: Hypertension is a major risk factor for atrial fibrillation. We hypothesized that arterial hypertension would alter atrial myocyte calcium (Ca2+) handling and that these alterations would serve to trigger atrial tachyarrhythmias. METHODS AND RESULTS: Left atria or left atrial (LA) myocytes were isolated from spontaneously hypertensive rats (SHR) or normotensive Wistar Kyoto (WKY) controls. Early after the onset of hypertension, at 3 months of age, there were no differences in Ca2+ transients (CaTs) or expression and phosphorylation of Ca2+ handling proteins between SHR and WKY. At 7 months of age, when left ventricular (LV) hypertrophy had progressed and markers of fibrosis were increased in left atrium, CaTs (at 1 Hz stimulation) were still unchanged. Subcellular alterations in Ca2+ handling were observed, however, in SHR atrial myocytes including (i) reduced expression of the alpha1C subunit of and reduced Ca2+ influx through L-type Ca2+ channels, (ii) reduced expression of ryanodine receptors with increased phosphorylation at Ser2808, (iii) decreased activity of the Na+ / Ca2+ exchanger (at unaltered intracellular Na+ concentration), and (iv) increased SR Ca2+ load with reduced fractional release. These changes were associated with an increased propensity of SHR atrial myocytes to develop frequency-dependent, arrhythmogenic Ca2+ alternans. CONCLUSIONS: In SHR, hypertension induces early subcellular LA myocyte Ca2+ remodelling during compensated LV hypertrophy. In basal conditions, atrial myocyte CaTs are not changed. At increased stimulation frequency, however, SHR atrial myocytes become more prone to arrhythmogenic Ca2+ alternans, suggesting a link between hypertension, atrial Ca2+ homeostasis, and development of atrial tachyarrhythmias. PMID- 25691542 TI - Reconciling computer models and stem cell models of human cardiac repolarization: reply. PMID- 25691543 TI - Prolonged action potentials in HCM-derived iPSC--biology or artefact? PMID- 25691544 TI - CEP Cortelli Corrigendum for 515342. PMID- 25691545 TI - Common carotid artery end-diastolic velocity is independently associated with future cardiovascular events. AB - BACKGROUND: Carotid ultrasound is widely used to measure haemodynamic parameters, such as intima-media thickness and blood flow velocities (i.e. peak-systolic velocity [PSV], end-diastolic velocity [EDV], and resistive index [RI]). However, the association between blood flow velocities and cardiovascular events remains unclear. DESIGN AND METHODS: Baseline data, including quantitative ultrasonography, were obtained from 3146 adults as part of the Cardiovascular Diseases Risk Factor Two-Township Study. Occurrence of ischaemic heart disease (IHD) and stroke was determined from insurance claims and death certificates. The hazard ratio (HR) of CVD (IHD and stroke combined) was calculated for EDV and PSV of the common carotid artery using Cox models. Net reclassification index and integrated discrimination index were used to evaluate the capacity of EDV to predict IHD, stroke, and CVD. RESULTS: Median follow-up was 12.8 years. There were 220 cases of IHD and 247 cases of stroke. The HR (95% CI) for CVD from univariate analysis was 4.54 (3.51-5.85) for EDV <15 cm/s relative to EDV >= 20 cm/s (p < 0.0001), and 3.23 (2.51-4.15) for PSV < 65 cm/s relative to PSV >= 80 cm/s (p < 0.0001). The HR (95% CI) for CVD from multivariate analysis was 1.66 (1.22-2.26) for EDV < 15 cm/s relative to EDV >= 20 cm/s, and 1.39 (1.03-1.89) for PSV < 65 cm/s relative to PSV >= 80 cm/s. EDV slightly but significantly improved prediction of CVD (integrated discrimination index 0.56%, p = 0.016). CONCLUSIONS: Low common carotid EDV and PSV were independently associated with future CVD, and EDV improved the prediction of future CVD. More prospective studies are required in different ethnic groups to understand the significance and implication of these findings. PMID- 25691546 TI - The beneficial effects of raising high-density lipoprotein cholesterol depends upon achieved levels of low-density lipoprotein cholesterol during statin therapy: Implications for coronary atheroma progression and cardiovascular events. AB - AIMS: Controversy exists regarding benefits of raising HDL-C in statin-treated coronary artery disease (CAD) patients. We assessed the anti-atherosclerotic efficacy of raising HDL-C in statin-treated individuals with CAD across a range of achieved LDL-C, including lower (<70 mg/dL) versus higher (>=70 mg/dL) levels. METHODS AND RESULTS: In seven prospective randomized trials utilizing serial coronary intravascular ultrasound, 3469 statin-treated CAD patients were stratified according to achieved LDL-C (< vs >=70 mg/dL) and changes in HDL-C (>= vs < median), as well as across a broader spectrum of changes in HDL-C and achieved LDL-C levels. Changes in coronary percent atheroma volume and MACE (cardiovascular death, non-fatal MI, stroke, coronary revascularization, hospitalization for unstable angina) were evaluated across these groups. RESULTS: Overall, median change in HDL-C was +6.03%, and mean achieved LDL-C in the lower and higher LDL-C groups were 55.1 +/- 11 and 97.4 +/- 22 mg/dL, respectively. Following multivariable adjustment, in patients with achieved LDL-C < 70 mg/dL, greater HDL-C-raising did not associate with disease progression/regression. In those with achieved LDL-C >= 70 mg/dL, greater HDL-C-raising associated with less disease progression (OR 0.80 (95% CI 0.67, 0.97)) and MACE (HR 0.78 (95% CI 0.64, 0.96)). Greater increases in HDL-C (up to 25% from baseline) across the continuous range of on-treatment LDL-C levels associated with less disease progression )OR 0.90 (95% CI 0.83, 0.98)) and lower MACE (HR 0.87 (95% CI 0.77, 0.998)). CONCLUSIONS: Increasing HDL-C via a broad spectrum of mechanisms appears beneficial in statin-treated CAD patients, but is likely of greater benefit in patients with achieved LDL-C levels >=70 mg/dL. PMID- 25691547 TI - Association between number of live births and markers of subclinical atherosclerosis: The Dallas Heart Study. AB - AIMS: Higher parity has been associated with increased maternal risk of cardiovascular disease, but the mechanism is not well delineated. Whether the number of live births is associated with coronary and aortic subclinical atherosclerosis has not been fully evaluated. METHODS AND RESULTS: Women from the Dallas Heart Study, a multiethnic population-based cohort of subjects aged 30-65 years, were included if they had data on self-reported live births and coronary artery calcium (CAC) measured by computed tomography or aortic wall thickness (AWT) by MRI. Coronary artery calcium was positive if >10 Agatston units, and aortic wall thickness if greater than the 75(th) percentile reference point for age and gender. Among the 1644 women included in the study, the mean age was 45 years and 55% were Black. Sequential multivariable models were done adjusting for age, race, traditional cardiovascular risk factors, body mass index, income, education, hormone replacement therapy, oral contraceptives, and physical activity. Using women with 2-3 live births as the reference, those with four or more live births had an increased prevalence of elevated coronary artery calcium (odds ratio (OR) 2.2, 95% confidence interval (CI) 1.28-3.65) and aortic wall thickness (OR 1.6, 95% CI 1.04-2.41). Women with 0-1 live births also had increased coronary artery calcium (OR 1.9, 95% CI 1.16-3.03) and aortic wall thickness (OR 1.5, 95% CI 1.05-2.09) after multivariable adjustment. CONCLUSION: The number of live births is associated with subclinical coronary and aortic atherosclerosis, with an apparent U-shaped relationship. Further studies are needed to confirm this association and explore the biological underpinnings of these findings. PMID- 25691549 TI - Catheter ablation of persistent atrial fibrillation: how much is enough? PMID- 25691550 TI - Changes in the atrial transcriptome and atrial fibrillation: susceptibility, persistence, causes, and consequences. PMID- 25691551 TI - Left atrial appendage closure for stroke prevention in atrial fibrillation: response to an unmet need with an unclear direction. PMID- 25691552 TI - Ictal asystole: life-threatening vagal storm or a benign seizure self-termination mechanism? PMID- 25691553 TI - Biophysics of the second-generation cryoballoon: cryobiology of the big freeze. PMID- 25691554 TI - Interventional cardiac magnetic resonance imaging in electrophysiology: advances toward clinical translation. PMID- 25691555 TI - Troubleshooting implantable cardioverter-defibrillator sensing problems II. PMID- 25691556 TI - Management of ventricular arrhythmias in suspected channelopathies. PMID- 25691557 TI - Differentiating atrioventricular nodal re-entrant tachycardia from junctional tachycardia: conflicting reponses? PMID- 25691558 TI - Taking the slower pathway. PMID- 25691559 TI - Inappropriate shock because of triple counting in a patient with a subcutaneous implantable cardioverter defibrillator corrected by initiation of dual site left ventricular pacing. PMID- 25691560 TI - Left phrenic nerve pacing from the left subclavian vein: novel method to monitor for left phrenic nerve injury during catheter ablation. PMID- 25691561 TI - Letter by Chhabra et al regarding article, "Prevalence and prognostic significance of abnormal P terminal force in lead V1 of the electrocardiogram in the general population". PMID- 25691562 TI - Response to letter regarding article, "Prevalence and prognostic significance of abnormal P terminal force in lead V1 of the electrocardiogram in the general population". PMID- 25691563 TI - Letter by Petretta regarding article, "Catheter ablation of atrial fibrillation in patients with left ventricular systolic dysfunction: a systematic review and meta-analysis". PMID- 25691564 TI - Response to letter regarding "Catheter ablation of atrial fibrillation in patients with left ventricular systolic dysfunction: a systematic review and meta analysis". PMID- 25691566 TI - Correction. PMID- 25691565 TI - Correction. PMID- 25691567 TI - Antigenicity and immunogenicity of a trimeric envelope protein from an Indian clade C HIV-1 isolate. AB - Human immunodeficiency virus type 1 (HIV-1) isolates from India mainly belong to clade C and are quite distinct from clade C isolates from Africa in terms of their phylogenetic makeup, serotype, and sensitivity to known human broadly neutralizing monoclonal antibodies. Because many of these properties are associated with the envelope proteins of HIV-1, it is of interest to study the envelope proteins of Indian clade C isolates as part of the ongoing efforts to develop a vaccine against HIV-1. To this end, we purified trimeric uncleaved gp145 of a CCR5 tropic Indian clade C HIV-1 (93IN101) from the conditioned medium of 293 cells. The purified protein was shown to be properly folded with stable structure by circular dichroism. Conformational integrity was further demonstrated by its high affinity binding to soluble CD4, CD4 binding site antibodies such as b12 and VRC01, quaternary epitope-specific antibody PG9, and CD4-induced epitope-specific antibody 17b. Sera from rabbits immunized with gp145 elicited high titer antibodies to various domains of gp120 and neutralized a broad spectrum of clade B and clade C HIV-1 isolates. Similar to other clade B and clade C envelope immunogens, most of the Tier 1 neutralizing activity could be absorbed with the V3-specific peptide. Subsequent boosting of these rabbits with a clade B HIV-1 Bal gp145 resulted in an expanded breadth of neutralization of HIV-1 isolates. The present study strongly supports the inclusion of envelopes from Indian isolates in a future mixture of HIV-1 vaccines. PMID- 25691568 TI - The crystal structure of the PB2 cap-binding domain of influenza B virus reveals a novel cap recognition mechanism. AB - The influenza RNA-dependent RNA polymerase is a core enzyme required for both transcription and replication of the virus RNA genome, making it a potential drug target for the influenza virus. To detect the feature of cap-dependent transcription of influenza B virus (FluB) polymerase, we determined the crystal structures of the wild-type FluB polymerase PB2 subunit cap-binding domain (PB2cap) with bound GDP and the mutant FluB Q325F PB2cap with bound m(7)GDP or GDP. These structures revealed that, distinct from influenza A virus (FluA) PB2cap, the guanine and ribose moieties of substrates invert in FluB PB2caps. Moreover, we characterized the substrate specificity and affinity of the PB2caps using isothermal titration calorimetry. FluB PB2cap has a weaker affinity for m(7)GDP than FluA PB2cap. Unlike FluA PB2cap that has a preference for m(7)GDP in comparison with GDP, FluB PB2cap shows an analogous affinity for both substrates. Replacement of FluB PB2 Glu(325) by Phe, the corresponding residue of FluA PB2, increased the binding affinity of FluB PB2cap for m(7)GDP to a level approximate to that of FluA PB2cap and caused a significant higher affinity to GDP. This study indicated that FluB PB2cap has a unique cap recognition mechanism compared with FluA PB2cap, providing molecular insight into inhibitor design targeting FluB PB2cap. PMID- 25691569 TI - Activation of microtubule dynamics increases neuronal growth via the nerve growth factor (NGF)- and Galphas-mediated signaling pathways. AB - Signals that activate the G protein Galphas and promote neuronal differentiation evoke Galphas internalization in rat pheochromocytoma (PC12) cells. These agents also significantly increase Galphas association with microtubules, resulting in an increase in microtubule dynamics because of the activation of tubulin GTPase by Galphas. To determine the function of Galphas/microtubule association in neuronal development, we used real-time trafficking of a GFP-Galphas fusion protein. GFP-Galphas concentrates at the distal end of the neurites in differentiated living PC12 cells as well as in cultured hippocampal neurons. Galphas translocates to specialized membrane compartments at tips of growing neurites. A dominant-negative Galpha chimera that interferes with Galphas binding to tubulin and activation of tubulin GTPase attenuates neurite elongation and neurite number both in PC12 cells and primary hippocampal neurons. This effect is greatest on differentiation induced by activated Galphas. Together, these data suggest that activated Galphas translocates from the plasma membrane and, through interaction with tubulin/microtubules in the cytosol, is important for neurite formation, development, and outgrowth. Characterization of neuronal G protein dynamics and their contribution to microtubule dynamics is important for understanding the molecular mechanisms by which G protein-coupled receptor signaling orchestrates neuronal growth and differentiation. PMID- 25691570 TI - The reaction mechanism of methyl-coenzyme M reductase: how an enzyme enforces strict binding order. AB - Methyl-coenzyme M reductase (MCR) is a nickel tetrahydrocorphinoid (coenzyme F430) containing enzyme involved in the biological synthesis and anaerobic oxidation of methane. MCR catalyzes the conversion of methyl-2 mercaptoethanesulfonate (methyl-SCoM) and N-7-mercaptoheptanoylthreonine phosphate (CoB7SH) to CH4 and the mixed disulfide CoBS-SCoM. In this study, the reaction of MCR from Methanothermobacter marburgensis, with its native substrates was investigated using static binding, chemical quench, and stopped-flow techniques. Rate constants were measured for each step in this strictly ordered ternary complex catalytic mechanism. Surprisingly, in the absence of the other substrate, MCR can bind either substrate; however, only one binary complex (MCR.methyl-SCoM) is productive whereas the other (MCR.CoB7SH) is inhibitory. Moreover, the kinetic data demonstrate that binding of methyl-SCoM to the inhibitory MCR.CoB7SH complex is highly disfavored (Kd = 56 mM). However, binding of CoB7SH to the productive MCR.methyl-SCoM complex to form the active ternary complex (CoB7SH.MCR(Ni(I)).CH3SCoM) is highly favored (Kd = 79 MUM). Only then can the chemical reaction occur (kobs = 20 s(-1) at 25 degrees C), leading to rapid formation and dissociation of CH4 leaving the binary product complex (MCR(Ni(II)).CoB7S(-).SCoM), which undergoes electron transfer to regenerate Ni(I) and the final product CoBS-SCoM. This first rapid kinetics study of MCR with its natural substrates describes how an enzyme can enforce a strictly ordered ternary complex mechanism and serves as a template for identification of the reaction intermediates. PMID- 25691571 TI - High CO2 levels cause skeletal muscle atrophy via AMP-activated kinase (AMPK), FoxO3a protein, and muscle-specific Ring finger protein 1 (MuRF1). AB - Patients with chronic obstructive pulmonary disease, acute lung injury, and critical care illness may develop hypercapnia. Many of these patients often have muscle dysfunction which increases morbidity and impairs their quality of life. Here, we investigated whether hypercapnia leads to skeletal muscle atrophy. Mice exposed to high CO2 had decreased skeletal muscle wet weight, fiber diameter, and strength. Cultured myotubes exposed to high CO2 had reduced fiber diameter, protein/DNA ratios, and anabolic capacity. High CO2 induced the expression of MuRF1 in vivo and in vitro, whereas MuRF1(-/-) mice exposed to high CO2 did not develop muscle atrophy. AMP-activated kinase (AMPK), a metabolic sensor, was activated in myotubes exposed to high CO2, and loss-of-function studies showed that the AMPKalpha2 isoform is necessary for muscle-specific ring finger protein 1 (MuRF1) up-regulation and myofiber size reduction. High CO2 induced AMPKalpha2 activation, triggering the phosphorylation and nuclear translocation of FoxO3a, and leading to an increase in MuRF1 expression and myotube atrophy. Accordingly, we provide evidence that high CO2 activates skeletal muscle atrophy via AMPKalpha2-FoxO3a-MuRF1, which is of biological and potentially clinical significance in patients with lung diseases and hypercapnia. PMID- 25691572 TI - Roles of the cyclooxygenase 2 matrix metalloproteinase 1 pathway in brain metastasis of breast cancer. AB - Brain is one of the major sites of metastasis in breast cancer; however, the pathological mechanism of brain metastasis is poorly understood. One of the critical rate-limiting steps of brain metastasis is the breaching of blood-brain barrier, which acts as a selective interface between the circulation and the central nervous system, and this process is considered to involve tumor-secreted proteinases. We analyzed clinical significance of 21 matrix metalloproteinases on brain metastasis-free survival of breast cancer followed by verification in brain metastatic cell lines and found that only matrix metalloproteinase 1 (MMP1) is significantly correlated with brain metastasis. We have shown that MMP1 is highly expressed in brain metastatic cells and is capable of degrading Claudin and Occludin but not Zo-1, which are key components of blood-brain barrier. Knockdown of MMP1 in brain metastatic cells significantly suppressed their ability of brain metastasis in vivo, whereas ectopic expression of MMP1 significantly increased the brain metastatic ability of the cells that are not brain metastatic. We also found that COX2 was highly up-regulated in brain metastatic cells and that COX2 induced prostaglandins were directly able to promote the expression of MMP1 followed by augmenting brain metastasis. Furthermore, we found that COX2 and prostaglandin were able to activate astrocytes to release chemokine (C-C motif) ligand 7 (CCL7), which in turn promoted self-renewal of tumor-initiating cells in the brain and that knockdown of COX2 significantly reduced the brain metastatic ability of tumor cells. Our results suggest the COX2-MMP1/CCL7 axis as a novel therapeutic target for brain metastasis. PMID- 25691573 TI - Glucose deprivation triggers protein kinase C-dependent beta-catenin proteasomal degradation. AB - Autophagy is a conserved process that contributes to cell homeostasis. It is well known that induction mainly occurs in response to nutrient starvation, such as starvation of amino acids and insulin, and its mechanisms have been extensively characterized. However, the mechanisms behind cellular glucose deprivation induced autophagy are as of now poorly understood. In the present study, we determined a mechanism by which glucose deprivation induced the PKC-dependent proteasomal degradation of beta-catenin, leading to autophagy. Glucose deprivation was shown to cause a sub-G1 transition and enhancement of the LC3-II protein levels, whereas beta-catenin protein underwent degradation in a proteasome-dependent manner. Moreover, the inhibition of GSK3beta was unable to abolish the glucose deprivation-mediated beta-catenin degradation or up regulation of LC3-II protein levels, which suggested GSK3beta-independent protein degradation. Intriguingly, the inhibition of PKCalpha using a pharmacological inhibitor and transfection of siRNA for PKCalpha was observed to effectively block glucose deprivation-induced beta-catenin degradation as well as the increase in LC3-II levels and the accumulation of a sub-G1 population. Together, our results demonstrated a molecular mechanism by which glucose deprivation can induce the GSK3beta-independent protein degradation of beta-catenin, leading to autophagy. PMID- 25691574 TI - Identification of a novel regulatory sequence of actin nucleation promoting factor encoded by Autographa californica multiple nucleopolyhedrovirus. AB - Actin polymerization induced by nucleation promoting factors (NPFs) is one of the most fundamental biological processes in eukaryotic cells. NPFs contain a conserved output domain (VCA domain) near the C terminus, which interacts with and activates the cellular actin-related protein 2/3 complex (Arp2/3) to induce actin polymerization and a diverse regulatory domain near the N terminus. Autographa californica multiple nucleopolyhedrovirus (AcMNPV) nucleocapsid protein P78/83 is a virus-encoded NPF that contains a C-terminal VCA domain and induces actin polymerization in virus-infected cells. However, there is no similarity between the N terminus of P78/83 and that of other identified NPFs, suggesting that P78/83 may possess a unique regulatory mechanism. In this study, we identified a multifunctional regulatory sequence (MRS) located near the N terminus of P78/83 and determined that one of its functions is to serve as a degron to mediate P78/83 degradation in a proteasome-dependent manner. In AcMNPV infected cells, the MRS also binds to another nucleocapsid protein, BV/ODV-C42, which stabilizes P78/83 and modulates the P78/83-Arp2/3 interaction to orchestrate actin polymerization. In addition, the MRS is also essential for the incorporation of P78/83 into the nucleocapsid, ensuring virion mobility powered by P78/83-induced actin polymerization. The triple functions of the MRS enable P78/83 to serve as an essential viral protein in the AcMNPV replication cycle, and the possible roles of the MRS in orchestrating the virus-induced actin polymerization and viral genome decapsidation are discussed. PMID- 25691575 TI - The involvement of hydrogen-producing and ATP-dependent NADPH-consuming pathways in setting the redox poise in the chloroplast of Chlamydomonas reinhardtii in anoxia. AB - Photosynthetic microalgae are exposed to changing environmental conditions. In particular, microbes found in ponds or soils often face hypoxia or even anoxia, and this severely impacts their physiology. Chlamydomonas reinhardtii is one among such photosynthetic microorganisms recognized for its unusual wealth of fermentative pathways and the extensive remodeling of its metabolism upon the switch to anaerobic conditions. As regards the photosynthetic electron transfer, this remodeling encompasses a strong limitation of the electron flow downstream of photosystem I. Here, we further characterize the origin of this limitation. We show that it stems from the strong reducing pressure that builds up upon the onset of anoxia, and this pressure can be relieved either by the light-induced synthesis of ATP, which promotes the consumption of reducing equivalents, or by the progressive activation of the hydrogenase pathway, which provides an electron transfer pathway alternative to the CO2 fixation cycle. PMID- 25691576 TI - 5-Azacytidine-induced protein 2 (AZI2) regulates bone mass by fine-tuning osteoclast survival. AB - 5-Azacytidine-induced protein 2 (AZI2) is a TNF receptor (TNFR)-associated factor family member-associated NF-kappaB activator-binding kinase 1-binding protein that regulates the production of IFNs. A previous in vitro study showed that AZI2 is involved in dendritic cell differentiation. However, the roles of AZI2 in immunity and its pleiotropic functions are unknown in vivo. Here we report that AZI2 knock-out mice exhibit normal dendritic cell differentiation in vivo. However, we found that adult AZI2 knock-out mice have severe osteoporosis due to increased osteoclast longevity. We revealed that the higher longevity of AZI2 deficient osteoclasts is due to an augmented activation of proto-oncogene tyrosine-protein kinase Src (c-Src), which is a critical player in osteoclast survival. We found that AZI2 inhibits c-Src activity by regulating the activation of heat shock protein 90 (Hsp90), a chaperone involved in c-Src dephosphorylation. Furthermore, we demonstrated that AZI2 indirectly inhibits c Src by interacting with the Hsp90 co-chaperone Cdc37. Strikingly, administration of a c-Src inhibitor markedly prevented bone loss in AZI2 knock-out mice. Together, these findings indicate that AZI2 regulates bone mass by fine-tuning osteoclast survival. PMID- 25691577 TI - Acquired haemophilia A presenting at a District General Hospital. AB - We report a case of a 64-year-old man presented to A&E with a 2-week to 4-month history of right hip pain, right leg weakness and fasciculations, extensive bruising and a vesicular skin rash. He had a CT of the chest/abdomen/pelvis, which revealed multiple extensive haematomas including an iliopsoas haematoma causing a lumbar plexopathy and resulting in the right hip and leg symptoms. He had clotting studies showing a prolonged activated partial thromboplastin time. Haematology review together with mixing studies suggested a diagnosis of acquired haemophilia A. He was treated at the local tertiary centre with activated prothrombin complex concentrate and steroids and made a full recovery. PMID- 25691578 TI - Varicella-zoster meningitis with a late-onset of skin eruption. AB - Viral meningitis caused by varicella-zoster virus (VZV) is an uncommon neurological complication of herpes zoster. It may occur before or after the onset of the vesicular rash along the dermatomal distribution, which is the classic presentation of herpes zoster. We describe a case of a 51-year-old immunocompetent Caucasian man who presented with neck and severe right-sided facial pain. Eight days later, he had photophobia and papular rash on his forehead. Cerebrospinal fluid (CSF) examination confirmed aseptic meningitis and CSF PCR detected the presence of VZV DNA. Neurological complications of VZV infection, such as aseptic meningitis, may be difficult to diagnose and can cause delay in treatment, especially in cases with late onset of dermatological manifestations of herpes zoster. Definite diagnosis requires evidence of acute VZV infection in blood or cerebrospinal fluid. PMID- 25691579 TI - Delayed splenic abscess after laparoscopic sleeve gastrectomy. AB - Splenic abscesses complicating sleeve gastrectomies are extremely rare. We report the fourth recorded case of a splenic abscess; in our case it occurred 10 weeks after sleeve gastrectomy in a 44-year-old man. The clinical presentation was vague but included the triad of fever, left upper quadrant tenderness and leucocytosis. The presence of this triad after sleeve gastrectomy should prompt investigation with contrast CT scans to exclude a splenic abscess. PMID- 25691580 TI - Legionnaires disease presenting as acute kidney injury in the absence of pneumonia. AB - Legionnaires disease is a pneumonic illness with multisystem involvement. In 1987, Haines et al reported the only reported case of isolated renal disease of legionellosis without concurrent respiratory disease. A 62-year-old man presented with generalised weakness and malaise and watery diarrhoea, and was found to have acute kidney injury on admission. He was initially managed as acute gastroenteritis complicated with dehydration and acute kidney injury with intravenous hydration. Despite adequate hydration, his renal function was worsening day by day. Later in the course of his sickness he developed pneumonic illness and was diagnosed with Legionnaires disease after a positive urine antigen test. We are reporting the second case of Legionnaires disease presenting as an isolated acute kidney injury in the absence of respiratory symptoms on presentation. PMID- 25691581 TI - Delayed-onset postoperative endophthalmitis secondary to Exophiala. AB - Exophiala is a genus of slow-growing, melanin-producing, saprophytic fungi most commonly found in soil, faeces and decaying plant matter. It is an unusual fungal pathogen capable of causing a variety of ophthalmic manifestations, including keratitis, scleritis and endophthalmitis. In this report, we present a rare case of delayed-onset postoperative endophthalmitis confined to the anterior segment, secondary to Exophiala species. Previous reported cases of delayed-onset postoperative endophthalmitis have been treated medically, with suboptimal outcomes. Our experience supports the use of anterior segment surgery to clear the nidus of disease combined with intravitreal voriconazole to prevent recurrence of the infection. PMID- 25691582 TI - Effectiveness of resistance training on muscle strength and physical function in people with Parkinson's disease: a systematic review and meta-analysis. AB - OBJECTIVES: To systematically review the evidence investigating the effectiveness of resistance training on strength and physical function in people with Parkinson's disease. DATA SOURCES: Seven electronic databases (COCHRANE, CINAHL, Medline ISI, Psycinfo, Scopus, Web of Science ISI and Embase) were systematically searched for full-text articles published in English between 1946 and November 2014 using relevant search terms. REVIEW METHODS: Only randomized controlled trials investigating the effects of resistance training on muscle strength and physical function in people with Parkinson's disease were considered. The PEDro scale was used to assess study quality. Studies with similar outcomes were pooled by calculating standardized mean differences (SMD) using fixed or random effects model, depending on study heterogeneity. RESULTS: Seven studies, comprising of 401 participants with early to advanced disease (Hoehn & Yahr stage 1 to 4), were included. The median quality score was 6/10. The meta-analyses demonstrated significant SMD in favour of resistance training compared to non-resistance training or no intervention controls for muscle strength (0.61; 95% CI, 0.35 to 0.87; P <0.001), balance (0.36; 95% CI, 0.08 to 0.64; P = 0.01) and parkinsonian motor symptoms (0.48; 95% CI, 0.21 to 0.75; P < 0.001) but not for gait, balance confidence and quality of life. CONCLUSION: This review demonstrates that moderate intensity progressive resistance training, 2-3 times per week over 8-10 weeks can result in significant strength, balance and motor symptoms gains in people with early to moderate Parkinson's disease. PMID- 25691583 TI - Effects of exercise therapy on walking ability in individuals with knee osteoarthritis: a systematic review and meta-analysis of randomised controlled trials. AB - OBJECTIVE: To examine the effect of exercise therapy on the walking ability of individuals with knee osteoarthritis. DATA SOURCES: Randomised clinical trials (RCTs) were identified by searching through PubMed, Cochrane Central Register of Controlled Trials, Physiotherapy Evidence Database, and Cumulative Index to Nursing and Allied Health Literature. All literature published to October 2014 were included in the search. REVIEW METHODS: Data were collected from RCTs that compared the effects of exercise therapy on walking ability with the effects of no intervention or psychoeducational intervention in participants with knee osteoarthritis. The outcome data on the total distance walked (6-minute walk test); the amount of time spent walking (the time to walk arbitrary distances); and gait velocity were obtained and analysed. Standardized mean differences (SMDs) and 95% confidence intervals (CIs) were calculated. RESULTS: Twenty-eight RCTs were identified. Meta-analysis provided very-low-quality evidence that exercise therapy increased the total distance walked in the 6-minute walk test, in comparison with the effects of the control interventions (SMD = 0.44, 95% CI 0.27 to 0.60). Meta-analysis also provided low- or moderate-quality evidence that the amount of time spent walking and gait velocity were improved more by exercise therapy than by the control interventions (the amount of time spent walking: SMD = -0.50, 95% CI -0.70 to -0.30; gait velocity: SMD = 1.78, 95% CI 0.98 to 2.58). CONCLUSION: In individuals with knee osteoarthritis, exercise therapy can improve the amount of time spent walking, gait velocity, and maybe the total distance walked. PMID- 25691585 TI - Gammaherpesvirus small noncoding RNAs are bifunctional elements that regulate infection and contribute to virulence in vivo. AB - Many viruses express noncoding RNAs (ncRNAs). The gammaherpesviruses (gammaHVs), including Epstein-Barr virus, Kaposi's sarcoma-associated herpesvirus, and murine gammaHV68, each contain multiple ncRNA genes, including microRNAs (miRNAs). While these ncRNAs can regulate multiple host and viral processes in vitro, the genetic contribution of these RNAs to infection and pathogenesis remains largely unknown. To study the functional contribution of these RNAs to gammaHV infection, we have used gammaHV68, a small-animal model of gammaHV pathogenesis. gammaHV68 encodes eight small hybrid ncRNAs that contain both tRNA-like elements and functional miRNAs. These genes are transcribed by RNA polymerase III and are referred to as the gammaHV68 TMERs (tRNA-miRNA-encoded RNAs). To determine the total concerted genetic contribution of these ncRNAs to gammaHV acute infection and pathogenesis, we generated and characterized a recombinant gammaHV68 strain devoid of all eight TMERs. TMER-deficient gammaHV68 has wild-type levels of lytic replication in vitro and normal establishment of latency in B cells early following acute infection in vivo. In contrast, during acute infection of immunodeficient mice, TMER-deficient gammaHV68 has reduced virulence in a model of viral pneumonia, despite having an enhanced frequency of virus-infected cells. Strikingly, expression of a single viral tRNA-like molecule, in the absence of all other virus-encoded TMERs and miRNAs, reverses both attenuation in virulence and enhanced frequency of infected cells. These data show that gammaHV ncRNAs play critical roles in acute infection and virulence in immunocompromised hosts and identify these RNAs as a new potential target to modulate gammaHV-induced infection and pathogenesis. IMPORTANCE: The gammaherpesviruses (gammaHVs) are a subfamily of viruses associated with chronic inflammatory diseases and cancer, particularly in immunocompromised individuals. These viruses uniformly encode multiple types of noncoding RNAs (ncRNAs) that are not translated into proteins. It remains unclear how virus-expressed ncRNAs influence the course and outcome of infection in vivo. Here, we generated a mouse gammaHV that lacks the expression of multiple ncRNAs. Notably, this mutant virus is critically impaired in the ability to cause disease in immunocompromised hosts yet shows a paradoxical increase in infected cells early during infection in these hosts. While the original mouse virus encodes multiple ncRNAs, the expression of a single domain of one ncRNA can partially reverse the defects of the mutant virus. These studies demonstrate that gammaHV ncRNAs can directly contribute to virus-induced disease in vivo and that these RNAs may be multifunctional, allowing the opportunity to specifically interfere with different functional domains of these RNAs. PMID- 25691586 TI - Dynamic changes in the subgingival microbiome and their potential for diagnosis and prognosis of periodontitis. AB - The human microbiome influences and reflects the health or disease state of the host. Periodontitis, a disease affecting about half of American adults, is associated with alterations in the subgingival microbiome of individual tooth sites. Although it can be treated, the disease can reoccur and may progress without symptoms. Without prognostic markers, follow-up examinations are required to assess reoccurrence and disease progression and to determine the need for additional treatments. To better identify and predict the disease progression, we aim to determine whether the subgingival microbiome can serve as a diagnosis and prognosis indicator. Using metagenomic shotgun sequencing, we characterized the dynamic changes in the subgingival microbiome in periodontitis patients before and after treatment at the same tooth sites. At the taxonomic composition level, the periodontitis-associated microorganisms were significantly shifted from highly correlated in the diseased state to poorly correlated after treatment, suggesting that coordinated interactions among the pathogenic microorganisms are essential to disease pathogenesis. At the functional level, we identified disease associated pathways that were significantly altered in relative abundance in the two states. Furthermore, using the subgingival microbiome profile, we were able to classify the samples to their clinical states with an accuracy of 81.1%. Follow-up clinical examination of the sampled sites supported the predictive power of the microbiome profile on disease progression. Our study revealed the dynamic changes in the subgingival microbiome contributing to periodontitis and suggested potential clinical applications of monitoring the subgingival microbiome as an indicator in disease diagnosis and prognosis. IMPORTANCE: Periodontitis is a common oral disease. Although it can be treated, the disease may reoccur without obvious symptoms. Current clinical examination parameters are useful in disease diagnosis but cannot adequately predict the outcome of individual tooth sites after treatment. A link between the subgingival microbiota and periodontitis was identified previously; however, it remains to be investigated whether the microbiome can serve as a diagnostic and prognostic indicator. In this study, for the first time, we characterized the subgingival microbiome of individual tooth sites before and after treatment using a large scale metagenomic analysis. Our longitudinal study revealed changes in the microbiota in taxonomic composition, cooccurrence of subgingival microorganisms, and functional composition. Using the microbiome profiles, we were able to classify the clinical states of subgingival plaque samples with a high accuracy. Follow-up clinical examination of sampled sites indicates that the subgingival microbiome profile shows promise for the development of diagnostic and prognostic tools. PMID- 25691587 TI - Chromosome organization and replisome dynamics in Mycobacterium smegmatis. AB - Subcellular organization of the bacterial nucleoid and spatiotemporal dynamics of DNA replication and segregation have been studied intensively, but the functional link between these processes remains poorly understood. Here we use quantitative time-lapse fluorescence microscopy for single-cell analysis of chromosome organization and DNA replisome dynamics in Mycobacterium smegmatis. We report that DNA replication takes place near midcell, where, following assembly of the replisome on the replication origin, the left and right replication forks colocalize throughout the replication cycle. From its initial position near the cell pole, a fluorescently tagged chromosomal locus (attB, 245 degrees from the origin) moves rapidly to the replisome complex just before it is replicated. The newly duplicated attB loci then segregate to mirror-symmetric positions relative to midcell. Genetic ablation of ParB, a component of the ParABS chromosome segregation system, causes marked defects in chromosome organization, condensation, and segregation. ParB deficiency also results in mislocalization of the DNA replication machinery and SMC (structural maintenance of chromosome) protein. These observations suggest that ParB and SMC play important and overlapping roles in chromosome organization and replisome dynamics in mycobacteria. IMPORTANCE: We studied the spatiotemporal organization of the chromosome and DNA replication machinery in Mycobacterium smegmatis, a fast growing relative of the human pathogen Mycobacterium tuberculosis. We show that genetic ablation of the DNA-binding proteins ParB and SMC disturbs the organization of the chromosome and causes a severe defect in subcellular localization and movement of the DNA replication complexes. These observations suggest that ParB and SMC provide a functional link between chromosome organization and DNA replication dynamics. This work also reveals important differences in the biological roles of the ParABS and SMC systems in mycobacteria versus better-characterized model organisms, such as Escherichia coli and Bacillus subtilis. PMID- 25691588 TI - Identification of mammalian proteins that collaborate with type III secretion system function: involvement of a chemokine receptor in supporting translocon activity. AB - The type III secretion system (T3SS) is a highly conserved protein delivery system found in multiple Gram-negative pathogens, including Yersinia pseudotuberculosis. Most studies of Yersinia species type III intoxication of host cells have focused on the bacterial determinants that promote assembly and function of the secretion system. In this study, we performed a pooled RNA interference (RNAi) screen to identify mammalian host proteins required for the cytotoxic effects associated with the Yersinia translocated substrate YopE, a GTPase-activating protein (GAP) that inactivates the small Rho GTPases. Cell populations were positively selected for short hairpin RNAs (shRNAs) that interfere with YopE activity using a combination of fluorescence resonance energy transfer (FRET) and flow cytometry, and the degree of enrichment was determined by deep sequencing. Analysis of the candidates identified by the enrichment process revealed that many were important for the initial step of Y. pseudotuberculosis T3SS function, YopB/D pore formation. These candidates included shRNA that depleted downstream effectors of RhoA signaling, coated pit formation, and receptors involved in cell signaling, including the chemokine receptor CCR5 (chemokine [C-C motif] receptor 5). Depletion of CCR5 in 293T cells yielded a defect in YopB/D pore formation and effector translocation, while both phenotypes could be complemented by overexpression of CCR5 protein. Yop effector translocation was also decreased in isolated primary phagocytic cells from a Ccr5(-/-) knockout mouse. We postulate that CCR5 acts to promote translocation by modulating cytoskeletal activities necessary for proper assembly of the YopB/D translocation pore. Overall, this study presents a new approach to investigating the contribution of the host cell to T3SS in Y. pseudotuberculosis. IMPORTANCE: Many Gram-negative bacteria require type III secretion systems (T3SS) for host survival, making these highly specialized secretion systems good targets for antimicrobial agents. After the bacterium binds to host cells, T3SS deposit proteins into the cytosol of host cells through a needle-like appendage and a protein translocon channel. Translocation of proteins via this system is highly regulated, and the contribution of the host cell in promoting assembly and insertion of the channel into the plasma membrane, folding of the bacterial proteins, and trafficking of these substrates are all poorly characterized events. In this study, we identified host cell proteins important for activity of YopE, a Yersinia pseudotuberculosis T3SS-delivered protein. The results demonstrate that insertion and assembly of the translocon are complex processes, requiring a variety of membrane trafficking and cytoskeletal processes, as well as a surprising role for cell surface signaling molecules in supporting proper function. PMID- 25691589 TI - E6^E7, a novel splice isoform protein of human papillomavirus 16, stabilizes viral E6 and E7 oncoproteins via HSP90 and GRP78. AB - Transcripts of human papillomavirus 16 (HPV16) E6 and E7 oncogenes undergo alternative RNA splicing to produce multiple splice isoforms. However, the importance of these splice isoforms is poorly understood. Here we report a critical role of E6^E7, a novel isoform containing the 41 N-terminal amino acid (aa) residues of E6 and the 38 C-terminal aa residues of E7, in the regulation of E6 and E7 stability. Through mass spectrometric analysis, we identified that HSP90 and GRP78, which are frequently upregulated in cervical cancer tissues, are two E6^E7-interacting proteins responsible for the stability and function of E6^E7, E6, and E7. Although GRP78 and HSP90 do not bind each other, GRP78, but not HSP90, interacts with E6 and E7. E6^E7 protein, in addition to self-binding, interacts with E6 and E7 in the presence of GRP78 and HSP90, leading to the stabilization of E6 and E7 by prolonging the half-life of each protein. Knocking down E6^E7 expression in HPV16-positive CaSki cells by a splice junction-specific small interfering RNA (siRNA) destabilizes E6 and E7 and prevents cell growth. The same is true for the cells with a GRP78 knockdown or in the presence of an HSP90 inhibitor. Moreover, mapping and alignment analyses for splicing elements in 36 alpha-HPVs (alpha-HPVs) suggest the possible expression of E6^E7 mostly by other oncogenic or possibly oncogenic alpha-HPVs (HPV18, -30, -31, -39, -42, -45, -56, -59, -70, and -73). HPV18 E6^E7 is detectable in HPV18-positive HeLa cells and HPV18-infected raft tissues. All together, our data indicate that viral E6^E7 and cellular GRP78 or HSP90 might be novel targets for cervical cancer therapy. IMPORTANCE: HPV16 is the most prevalent HPV genotype, being responsible for 60% of invasive cervical cancer cases worldwide. What makes HPV16 so potent in the development of cervical cancer remains a mystery. We discovered in this study that, besides producing two well-known oncoproteins, E6 and E7, seen in other high-risk HPVs, HPV16 produces E6^E7, a novel splice isoform of E6 and E7. E6^E7, in addition to self-interacting, binds cellular chaperone proteins, HSP90 and GRP78, and viral E6 and E7 to increase the steady-state levels and half-lives of viral oncoproteins, leading to cell proliferation. The splicing cis elements in the regulation of HPV16 E6^E7 production are highly conserved in 11 oncogenic or possibly oncogenic HPVs, and we confirmed the production of HPV18 E6^E7 in HPV18 infected cells. This study provides new insight into the mechanism of splicing, the interplay between different products of the polycistronic viral message, and the role of the host chaperones as they function. PMID- 25691590 TI - Inflammasome activation in response to the Yersinia type III secretion system requires hyperinjection of translocon proteins YopB and YopD. AB - Type III secretion systems (T3SS) translocate effector proteins into target cells in order to disrupt or modulate host cell signaling pathways and establish replicative niches. However, recognition of T3SS activity by cytosolic pattern recognition receptors (PRRs) of the nucleotide-binding domain leucine rich repeat (NLR) family, either through detection of translocated products or membrane disruption, induces assembly of multiprotein complexes known as inflammasomes. Macrophages infected with Yersinia pseudotuberculosis strains lacking all known effectors or lacking the translocation regulator YopK induce rapid activation of both the canonical NLRP3 and noncanonical caspase-11 inflammasomes. While this inflammasome activation requires a functional T3SS, the precise signal that triggers inflammasome activation in response to Yersinia T3SS activity remains unclear. Effectorless strains of Yersinia as well as DeltayopK strains translocate elevated levels of T3SS substrates into infected cells. To dissect the contribution of pore formation and translocation to inflammasome activation, we took advantage of variants of YopD and LcrH that separate these functions of the T3SS. Notably, YopD variants that abrogated translocation but not pore forming activity failed to induce inflammasome activation. Furthermore, analysis of individual infected cells revealed that inflammasome activation at the single cell level correlated with translocated levels of YopB and YopD themselves. Intriguingly, LcrH mutants that are fully competent for effector translocation but produce and translocate lower levels of YopB and YopD also fail to trigger inflammasome activation. Our findings therefore suggest that hypertranslocation of YopD and YopB is linked to inflammasome activation in response to the Yersinia T3SS. IMPORTANCE: The innate immune response is critical to effective clearance of pathogens. Recognition of conserved virulence structures and activities by innate immune receptors such as NLRs constitute one of the first steps in mounting the innate immune response. However, pathogens such as Yersinia actively evade or subvert components of host defense, such as inflammasomes. The T3SS secreted protein YopK is an essential virulence factor that limits translocation of other Yops, thereby limiting T3SS-induced inflammasome activation. However, what triggers inflammasome activation in cells infected by YopK-deficient Yersinia is not clear. Our findings indicate that hypertranslocation of pore complex proteins promotes inflammasome activation and that YopK prevents inflammasome activation by the T3SS by limiting translocation of YopD and YopB themselves. PMID- 25691591 TI - Single-cell tracking reveals antibiotic-induced changes in mycobacterial energy metabolism. AB - ATP is a key molecule of cell physiology, but despite its importance, there are currently no methods for monitoring single-cell ATP fluctuations in live bacteria. This is a major obstacle in studies of bacterial energy metabolism, because there is a growing awareness that bacteria respond to stressors such as antibiotics in a highly individualistic manner. Here, we present a method for long-term single-cell tracking of ATP levels in Mycobacterium smegmatis based on a combination of microfluidics, time-lapse microscopy, and Forster resonance energy transfer (FRET)-based ATP biosensors. Upon treating cells with antibiotics, we observed that individual cells undergo an abrupt and irreversible switch from high to low intracellular ATP levels. The kinetics and extent of ATP switching clearly discriminate between an inhibitor of ATP synthesis and other classes of antibiotics. Cells that resume growth after 24 h of antibiotic treatment maintain high ATP levels throughout the exposure period. In contrast, antibiotic-treated cells that switch from ATP-high to ATP-low states never resume growth after antibiotic washout. Surprisingly, only a subset of these nongrowing ATP-low cells stains with propidium iodide (PI), a widely used live/dead cell marker. These experiments also reveal a cryptic subset of cells that do not resume growth after antibiotic washout despite remaining ATP high and PI negative. We conclude that ATP tracking is a more dynamic, sensitive, reliable, and discriminating marker of cell viability than staining with PI. This method could be used in studies to evaluate antimicrobial effectiveness and mechanism of action, as well as for high-throughput screening. IMPORTANCE: New antimicrobials are urgently needed to stem the rising tide of antibiotic-resistant bacteria. All antibiotics are expected to affect bacterial energy metabolism, directly or indirectly, yet tools to assess the impact of antibiotics on the ATP content of individual bacterial cells are lacking. The method described here for single-cell tracking of intracellular ATP in live bacteria has many advantages compared to conventional ensemble-averaged assays. It provides a continuous real-time readout of bacterial ATP content, cell vitality, and antimicrobial mechanism of action with high temporal resolution at the single-cell level. In combination with high throughput microfluidic devices and automated microscopy, this method also has the potential to serve as a novel screening tool in antimicrobial drug discovery. PMID- 25691592 TI - Differential expression and roles of Staphylococcus aureus virulence determinants during colonization and disease. AB - Staphylococcus aureus is a Gram-positive, commensal bacterium known to asymptomatically colonize the human skin, nares, and gastrointestinal tract. Colonized individuals are at increased risk for developing S. aureus infections, which range from mild skin and soft tissue infections to more severe diseases, such as endocarditis, bacteremia, sepsis, and osteomyelitis. Different virulence factors are required for S. aureus to infect different body sites. In this study, virulence gene expression was analyzed in two S. aureus isolates during nasal colonization, bacteremia and in the heart during sepsis. These models were chosen to represent the stepwise progression of S. aureus from an asymptomatic colonizer to an invasive pathogen. Expression of 23 putative S. aureus virulence determinants, representing protein and carbohydrate adhesins, secreted toxins, and proteins involved in metal cation acquisition and immune evasion were analyzed. Consistent upregulation of sdrC, fnbA, fhuD, sstD, and hla was observed in the shift between colonization and invasive pathogen, suggesting a prominent role for these genes in staphylococcal pathogenesis. Finally, gene expression data were correlated to the roles of the genes in pathogenesis by using knockout mutants in the animal models. These results provide insights into how S. aureus modifies virulence gene expression between commensal and invasive pathogens. IMPORTANCE: Many bacteria, such as Staphylococcus aureus, asymptomatically colonize human skin and nasal passages but can also cause invasive diseases, such as bacteremia, pneumonia, sepsis, and osteomyelitis. The goal of this study was to analyze differences in the expression of selected S. aureus genes during a commensal lifestyle and as an invasive pathogen to gain insight into the commensal-to-pathogen transition and how a bacterial pathogen adapts to different environments within a host (e.g., from nasal colonization to invasive pathogen). The gene expression data were also used to select genes for which to construct knockout mutants to assess the role of several proteins in nasal colonization and lethal bacteremia. These results not only provide insight into the factors involved in S. aureus disease pathogenesis but also provide potential therapeutic targets. PMID- 25691593 TI - In vivo transcriptional profiling of Yersinia pestis reveals a novel bacterial mediator of pulmonary inflammation. AB - Inhalation of Yersinia pestis results in primary pneumonic plague, a highly lethal and rapidly progressing necrotizing pneumonia. The disease begins with a period of extensive bacterial replication in the absence of disease symptoms, followed by the sudden onset of inflammatory responses that ultimately prove fatal. Very little is known about the bacterial and host factors that contribute to the rapid biphasic progression of pneumonic plague. In this work, we analyzed the in vivo transcription kinetics of 288 bacterial open reading frames previously shown by microarray analysis to be dynamically regulated in the lung. Using this approach combined with bacterial genetics, we were able to identify five Y. pestis genes that contribute to the development of pneumonic plague. Deletion of one of these genes, ybtX, did not alter bacterial survival but attenuated host inflammatory responses during late-stage disease. Deletion of ybtX in another lethal respiratory pathogen, Klebsiella pneumoniae, also resulted in diminished host inflammation during infection. Thus, our in vivo transcriptional screen has identified an important inflammatory mediator that is common to two Gram-negative bacterial pathogens that cause severe pneumonia. IMPORTANCE: Yersinia pestis is responsible for at least three major pandemics, most notably the Black Death of the Middle Ages. Due to its pandemic potential, ease of dissemination by aerosolization, and a history of its weaponization, Y. pestis is categorized by the Centers for Disease Control and Prevention as a tier 1 select agent most likely to be used as a biological weapon. To date, there is no licensed vaccine against Y. pestis. Importantly, an early "silent" phase followed by the rapid onset of nondescript influenza-like symptoms makes timely treatment of pneumonic plague difficult. A more detailed understanding of the bacterial and host factors that contribute to pathogenesis is essential to understanding the progression of pneumonic plague and developing or enhancing treatment options. PMID- 25691594 TI - BolA is a transcriptional switch that turns off motility and turns on biofilm development. AB - Bacteria are extremely versatile organisms that rapidly adapt to changing environments. When bacterial cells switch from planktonic growth to biofilm, flagellum formation is turned off and the production of fimbriae and extracellular polysaccharides is switched on. BolA is present in most Gram negative bacteria, and homologues can be found from proteobacteria to eukaryotes. Here, we show that BolA is a new bacterial transcription factor that modulates the switch from a planktonic to a sessile lifestyle. It negatively modulates flagellar biosynthesis and swimming capacity in Escherichia coli. Furthermore, BolA overexpression favors biofilm formation, involving the production of fimbria like adhesins and curli. Our results also demonstrate that BolA is a protein with high affinity to DNA and is able to regulate many genes on a genome-wide scale. Moreover, we show that the most significant targets of this protein involve a complex network of genes encoding proteins related to biofilm development. Herein, we propose that BolA is a motile/adhesive transcriptional switch, specifically involved in the transition between the planktonic and the attachment stage of biofilm formation. IMPORTANCE: Escherichia coli cells possess several mechanisms to cope with stresses. BolA has been described as a protein important for survival in late stages of bacterial growth and under harsh environmental conditions. BolA-like proteins are widely conserved from prokaryotes to eukaryotes. Although their exact function is not fully established at the molecular level, they seem to be involved in cell proliferation or cell cycle regulation. Here, we unraveled the role of BolA in biofilm development and bacterial motility. Our work suggests that BolA actively contributes to the decision of bacteria to arrest flagellar production and initiate the attachment to form structured communities, such as biofilms. The molecular studies of different lifestyles coupled with the comprehension of the BolA functions may be an important step for future perspectives, with health care and biotechnology applications. PMID- 25691595 TI - Novel components of the Toxoplasma inner membrane complex revealed by BioID. AB - The inner membrane complex (IMC) of Toxoplasma gondii is a peripheral membrane system that is composed of flattened alveolar sacs that underlie the plasma membrane, coupled to a supporting cytoskeletal network. The IMC plays important roles in parasite replication, motility, and host cell invasion. Despite these central roles in the biology of the parasite, the proteins that constitute the IMC are largely unknown. In this study, we have adapted a technique named proximity-dependent biotin identification (BioID) for use in T. gondii to identify novel components of the IMC. Using IMC proteins in both the alveoli and the cytoskeletal network as bait, we have uncovered a total of 19 new IMC proteins in both of these suborganellar compartments, two of which we functionally evaluate by gene knockout. Importantly, labeling of IMC proteins using this approach has revealed a group of proteins that localize to the sutures of the alveolar sacs that have been seen in their entirety in Toxoplasma species only by freeze fracture electron microscopy. Collectively, our study greatly expands the repertoire of known proteins in the IMC and experimentally validates BioID as a strategy for discovering novel constituents of specific cellular compartments of T. gondii. IMPORTANCE: The identification of binding partners is critical for determining protein function within cellular compartments. However, discovery of protein-protein interactions within membrane or cytoskeletal compartments is challenging, particularly for transient or unstable interactions that are often disrupted by experimental manipulation of these compartments. To circumvent these problems, we adapted an in vivo biotinylation technique called BioID for Toxoplasma species to identify binding partners and proximal proteins within native cellular environments. We used BioID to identify 19 novel proteins in the parasite IMC, an organelle consisting of fused membrane sacs and an underlying cytoskeleton, whose protein composition is largely unknown. We also demonstrate the power of BioID for targeted discovery of proteins within specific compartments, such as the IMC cytoskeleton. In addition, we uncovered a new group of proteins localizing to the alveolar sutures of the IMC. BioID promises to reveal new insights on protein constituents and interactions within cellular compartments of Toxoplasma. PMID- 25691596 TI - Electron tomography imaging of surface glycoproteins on human parainfluenza virus 3: association of receptor binding and fusion proteins before receptor engagement. AB - In order to deliver their genetic material to host cells during infection, enveloped viruses use specialized proteins on their surfaces that bind cellular receptors and induce fusion of the viral and host membranes. In paramyxoviruses, a diverse family of single-stranded RNA (ssRNA) viruses, including several important respiratory pathogens, such as parainfluenza viruses, the attachment and fusion machinery is composed of two separate proteins: a receptor binding protein (hemagglutinin-neuraminidase [HN]) and a fusion (F) protein that interact to effect membrane fusion. Here we used negative-stain and cryo-electron tomography to image the 3-dimensional ultrastructure of human parainfluenza virus 3 (HPIV3) virions in the absence of receptor engagement. We observed that HN exists in at least two organizations. The first were arrays of tetrameric HN that lacked closely associated F proteins: in these purely HN arrays, HN adopted a "heads-down" configuration. In addition, we observed regions of complex surface density that contained HN in an apparently extended "heads-up" form, colocalized with prefusion F trimers. This colocalization with prefusion F prior to receptor engagement supports a model for fusion in which HN in its heads-up state and F may interact prior to receptor engagement without activating F, and that interaction with HN in this configuration is not sufficient to activate F. Only upon receptor engagement by HN's globular head does HN transmit its activating signal to F. IMPORTANCE: Human parainfluenza virus 3 (HPIV3) is an enveloped, ssRNA virus that can cause serious respiratory illness, especially in children. HPIV3, like most other paramyxoviruses, uses two specialized proteins to mediate cell entry: the fusion protein (F) and the receptor binding protein, hemagglutinin-neuraminidase (HN). F becomes activated to mediate fusion during entry when it is triggered by a signal from HN. Here we used electron tomography to reconstruct the 3-dimensional ultrastructure of HPIV3. From these structures, we could discern the distribution and, in some cases, conformation of HN and F proteins, which provided an understanding of their interrelationship on virions. HN is found in arrays alone in one conformation and interspersed with prefusion F trimers in another. The data support a model of paramyxovirus membrane fusion in which HN associates with F before receptor engagement, and receptor engagement by the globular head of HN switches the HN-F interaction into one of fusion activation. PMID- 25691597 TI - A TALE of transposition: Tn3-like transposons play a major role in the spread of pathogenicity determinants of Xanthomonas citri and other xanthomonads. AB - Members of the genus Xanthomonas are among the most important phytopathogens. A key feature of Xanthomonas pathogenesis is the translocation of type III secretion system (T3SS) effector proteins (T3SEs) into the plant target cells via a T3SS. Several T3SEs and a murein lytic transglycosylase gene (mlt, required for citrus canker symptoms) are found associated with three transposition-related genes in Xanthomonas citri plasmid pXAC64. These are flanked by short inverted repeats (IRs). The region was identified as a transposon, TnXax1, with typical Tn3 family features, including a transposase and two recombination genes. Two 14 bp palindromic sequences within a 193-bp potential resolution site occur between the recombination genes. Additional derivatives carrying different T3SEs and other passenger genes occur in different Xanthomonas species. The T3SEs include transcription activator-like effectors (TALEs). Certain TALEs are flanked by the same IRs as found in TnXax1 to form mobile insertion cassettes (MICs), suggesting that they may be transmitted horizontally. A significant number of MICs carrying other passenger genes (including a number of TALE genes) were also identified, flanked by the same TnXax1 IRs and delimited by 5-bp target site duplications. We conclude that a large fraction of T3SEs, including individual TALEs and potential pathogenicity determinants, have spread by transposition and that TnXax1, which exhibits all of the essential characteristics of a functional transposon, may be involved in driving MIC transposition. We also propose that TALE genes may diversify by fork slippage during the replicative Tn3 family transposition. These mechanisms may play a crucial role in the emergence of Xanthomonas pathogenicity. IMPORTANCE: Xanthomonas genomes carry many insertion sequences (IS) and transposons, which play an important role in their evolution and architecture. This study reveals a key relationship between transposons and pathogenicity determinants in Xanthomonas. We propose that several transposition events mediated by a Tn3-like element carrying different sets of passenger genes, such as different type III secretion system effectors (including transcription activation-like effectors [TALEs]), were determinant in the evolution and emergence of Xanthomonas pathogenicity. TALE genes are DNA-binding effectors that modulate plant transcription. We also present a model for generating TALE gene diversity based on fork slippage associated with the replicative transposition mechanism of Tn3-like transposons. This may provide a mechanism for niche adaptation, specialization, host-switching, and other lifestyle changes. These results will also certainly lead to novel insights into the evolution and emergence of the various diseases caused by different Xanthomonas species and pathovars. PMID- 25691598 TI - Characterization of host and microbial determinants in individuals with latent tuberculosis infection using a human granuloma model. AB - Granulomas sit at the center of tuberculosis (TB) immunopathogenesis. Progress in biomarkers and treatment specific to the human granuloma environment is hindered by the lack of a relevant and tractable infection model that better accounts for the complexity of the host immune response as well as pathogen counterresponses that subvert host immunity in granulomas. Here we developed and characterized an in vitro granuloma model derived from human peripheral blood mononuclear cells (PBMCs) and autologous serum. Importantly, we interrogated this model for its ability to discriminate between host and bacterial determinants in individuals with and without latent TB infection (LTBI). By the use of this model, we provide the first evidence that granuloma formation, bacterial survival, lymphocyte proliferation, pro- and anti-inflammatory cytokines, and lipid body accumulation are significantly altered in LTBI individuals. Moreover, we show a specific transcriptional signature of Mycobacterium tuberculosis associated with survival within human granuloma structures depending on the host immune status. Our report provides fundamentally new information on how the human host immune status and bacterial transcriptional signature may dictate early granuloma formation and outcome and provides evidence for the validity of the granuloma model and its potential applications. IMPORTANCE: In 2012, approximately 1.3 million people died from tuberculosis (TB), the highest rate for any single bacterial pathogen. The long-term control of TB requires a better understanding of Mycobacterium tuberculosis pathogenesis in appropriate research models. Granulomas represent the characteristic host tissue response to TB, controlling the bacilli while concentrating the immune response to a limited area. However, complete eradication of bacteria does not occur, since M. tuberculosis has its own strategies to adapt and persist. Thus, the M. tuberculosis-containing granuloma represents a unique environment for dictating both the host immune response and the bacterial response. Here we developed and characterized an in vitro granuloma model derived from blood cells of individuals with latent TB infection that more accurately defines the human immune response and metabolic profiles of M. tuberculosis within this uniquely regulated immune environment. This model may also prove beneficial for understanding other granulomatous diseases. PMID- 25691599 TI - Choreography of the Mycobacterium replication machinery during the cell cycle. AB - It has recently been demonstrated that bacterial chromosomes are highly organized, with specific positioning of the replication initiation region. Moreover, the positioning of the replication machinery (replisome) has been shown to be variable and dependent on species-specific cell cycle features. Here, we analyzed replisome positions in Mycobacterium smegmatis, a slow-growing bacterium that exhibits characteristic asymmetric polar cell extension. Time-lapse fluorescence microscopy analyses revealed that the replisome is slightly off center in mycobacterial cells, a feature that is likely correlated with the asymmetric growth of Mycobacterium cell poles. Estimates of the timing of chromosome replication in relation to the cell cycle, as well as cell division and chromosome segregation events, revealed that chromosomal origin-of replication (oriC) regions segregate soon after the start of replication. Moreover, our data demonstrate that organization of the chromosome by ParB determines the replisome choreography. IMPORTANCE: Despite significant progress in elucidating the basic processes of bacterial chromosome replication and segregation, understanding of chromosome dynamics during the mycobacterial cell cycle remains incomplete. Here, we provide in vivo experimental evidence that replisomes in Mycobacterium smegmatis are highly dynamic, frequently splitting into two distinct replication forks. However, unlike in Escherichia coli, the forks do not segregate toward opposite cell poles but remain in relatively close proximity. In addition, we show that replication cycles do not overlap. Finally, our data suggest that ParB participates in the positioning of newly born replisomes in M. smegmatis cells. The present results broaden our understanding of chromosome segregation in slow-growing bacteria. In view of the complexity of the mycobacterial cell cycle, especially for pathogenic representatives of the genus, understanding the mechanisms and factors that affect chromosome dynamics will facilitate the identification of novel antimicrobial factors. PMID- 25691601 TI - All bundled up! PMID- 25691600 TI - Creating a "culture of research" in a community hospital: Strategies and tools from the National Cancer Institute Community Cancer Centers Program. AB - BACKGROUND: The value of community-based cancer research has long been recognized. In addition to the National Cancer Institute's Community Clinical and Minority-Based Oncology Programs established in 1983, and 1991 respectively, the National Cancer Institute established the National Cancer Institute Community Cancer Centers Program in 2007 with an aim of enhancing access to high-quality cancer care and clinical research in the community setting where most cancer patients receive their treatment. This article discusses strategies utilized by the National Cancer Institute Community Cancer Centers Program to build research capacity and create a more entrenched culture of research at the community hospitals participating in the program over a 7-year period. METHODS: To facilitate development of a research culture at the community hospitals, the National Cancer Institute Community Cancer Centers Program required leadership or chief executive officer engagement; utilized a collaborative learning structure where best practices, successes, and challenges could be shared; promoted site-to site mentoring to foster faster learning within and between sites; required research program assessments that spanned clinical trial portfolio, accrual barriers, and outreach; increased identification and use of metrics; and, finally, encouraged research team engagement across hospital departments (navigation, multidisciplinary care, pathology, and disparities) to replace the traditionally siloed approach to clinical trials. LIMITATIONS: The health-care environment is rapidly changing while complexity in research increases. Successful research efforts are impacted by numerous factors (e.g. institutional review board reviews, physician interest, and trial availability). The National Cancer Institute Community Cancer Centers Program sites, as program participants, had access to the required resources and support to develop and implement the strategies described. Metrics are an important component yet often challenging to identify and collect. The model requires a strong emphasis on outreach that challenges hospitals to improve and expand their reach, particularly into underrepresented populations and catchment areas. These efforts build on trust and a referral pipeline within the community which take time and significant commitment to establish. CONCLUSION: The National Cancer Institute Community Cancer Centers Program experience provides a relevant model to broadly address creating a culture of research in community hospitals that are increasingly networked via systems and consortiums. The strategies used align well with the National Cancer Institute-American Society of Clinical Oncology Accrual Symposium recommendations for patient-/community-, physician-/provider-, and site /organizational-level approaches to clinical trials; they helped sites achieve organizational culture shifts that enhanced their cancer research programs. The National Cancer Institute Community Cancer Centers Program hospitals reported that the strategies were challenging to implement yet proved valuable as they provided useful metrics for programmatic assessment, planning, reporting, and growth. While focused on oncology trials, these concepts may be useful within other disease-focused research as well. PMID- 25691602 TI - Practicing what we preach! PMID- 25691603 TI - NCCN: your best resource in the fight against cancer. PMID- 25691604 TI - Interdigitating dendritic cell sarcoma. AB - Interdigitating dendritic cell sarcoma (IDCS) is an extremely rare dendritic cell tumor with slightly more than 100 cases reported in the English literature. This report discusses a case of localized IDCS involving cervical lymph nodes and provides a literature review of clinicopathologic aspects and treatment outcomes. PMID- 25691605 TI - Metastatic insulinoma: current molecular and cytotoxic therapeutic approaches for metastatic well-differentiated panNETs. AB - Pancreatic neuroendocrine tumors (panNETs) are a type of neuroendocrine tumor with 5-year overall survival rates of approximately 50% when metastasis is present at diagnosis. Tumor grade, as defined by Ki-67 proliferation index, influences overall survival, with low-grade tumors portending a better outcome than intermediate- and high-grade tumors. This case report follows the clinical course and management of a patient with an insulin-secreting metastatic panNET who died 10 years after diagnosis after a treatment course with regional therapy and multiple forms of cytotoxic and molecularly targeted agents. This report presents the various treatment options available for patients with insulin secreting metastatic panNETs. PMID- 25691606 TI - Kidney cancer, version 3.2015. AB - The NCCN Guidelines for Kidney Cancer provide multidisciplinary recommendations for the clinical management of patients with clear cell and non-clear cell renal carcinoma. These NCCN Guidelines Insights highlight the recent updates/changes in these guidelines, and updates include axitinib as first-line treatment option for patients with clear cell renal carcinoma, new data to support pazopanib as subsequent therapy for patients with clear cell carcinoma after first-line treatment with another tyrosine kinase inhibitor, and guidelines for follow-up of patients with renal cell carcinoma. PMID- 25691607 TI - VATS versus open surgery for lung cancer resection: moving toward a minimally invasive approach. AB - The use of video-assisted thoracoscopic surgery (VATS) has become the standard approach for the surgical resection of early-stage lung cancer. Although no large prospective, randomized, controlled trial has compared VATS lobectomy with thoracotomy, well-designed retrospective studies have consistently shown that VATS has comparable oncologic outcomes and is associated with fewer complications, reduced length of hospital stay, improvement in patient quality of life, and superior tolerance of adjuvant therapies. PMID- 25691608 TI - VATS versus open surgery for lung cancer resection: moving beyond the incision. AB - Surgery remains the primary therapy in the treatment of early-stage lung cancer. Traditionally, anatomic resection via open thoracotomy has been the conventional approach, but as experience with minimally invasive lung surgery has increased, video-assisted thoracoscopic surgical (VATS) lobectomy is being performed more commonly for treatment of lung cancer. Proponents of VATS have argued that thoracoscopic resection for lung cancer is not only safe but is also superior to the open approach. VATS enthusiasts even have proposed that this approach should be the standard of care and a metric for quality in lung cancer surgery. Such zeal for promoting a "preferred" technique, however, obscures focus from other time-proven, but perhaps less fashionable, factors that have a tremendous impact on quality and lung cancer outcomes, namely cancer staging and quality of cancer surgery. Rather than debate incisions, thoracic surgeons should advocate for specialty care and surgical quality that assures the best short- and long-term outcomes for patients, regardless of the surgical approach. PMID- 25691609 TI - CT-based versus FDG-PET/CT-based NCCN international prognostic index risk stratification in DLBCL. AB - BACKGROUND: This study compared CT-based and (18)F-fluoro-2-deoxy-D-glucose PET/CT (FDG-PET/CT)-based NCCN International Prognostic Index (NCCN-IPI) risk stratification in newly diagnosed diffuse large B-cell lymphoma (DLBCL). MATERIALS AND METHODS: This retrospective study included 57 patients with newly diagnosed DLBCL who had undergone both (oral and intravenous contrast-enhanced full-dose) diagnostic CT and FDG-PET/CT. Diagnostic CT only and FDG-PET/CT were evaluated separately, and corresponding NCCN-IPI scores for the 2 datasets (NCCN IPICT and NCCN-IPIPET/CT) were calculated. Percentages of agreement and weighted k statistic between NCCN-IPICT and NCCN-IPIPET/CT scoring with regard to the formation of low-, low-intermediate-, high-intermediate-, and high-risk groups were calculated. RESULTS: In 47 of 57 patients (82.5%; 95% CI, 70.4-90.4), diagnostic CT alone was in agreement with FDG-PET/CT with regard to the formation of low-, low-intermediate-, high-intermediate-, and high-risk NCCN-IPI groups, but not in the remaining 10 patients (17.5%; 95% CI, 9.6%-29.6%). All NCCN-IPI disagreements between diagnostic CT and FDG-PET/CT were from the detection of additional lesions by the latter, most of them being bone marrow lesions. Agreement between NCCN-IPICT and NCCN-IPIPET/CT with regard to the formation of low-, low-intermediate-, high-intermediate-, and high-risk groups was considered good (k=0.771). CONCLUSIONS: Although agreement between NCCN-IPICT and NCCN IPIPET/CT risk stratification is generally good, FDG-PET/CT results in higher NCCN-IPI risk stratifications in a non-negligible proportion of patients. Future studies should investigate the prognostic implications of these imaging-based differences in NCCN-IPI scoring. PMID- 25691610 TI - Institutional review of compliance with NCCN guidelines for breast cancer: lessons learned from real-time multidimensional synoptic reporting. AB - BACKGROUND: Variations exist in compliance with NCCN Guidelines. Prior reports of adherence to NCCN Guidelines contain limitations because of lack of contemporary review and incomplete listing of reasons for noncompliance. PURPOSE: To assess institutional compliance and assist national quality improvement strategies through identifying valid reasons for noncompliance. METHODS: Compliance with NCCN Guidelines was recorded prospectively using electronic synoptic templates for patients with newly diagnosed breast cancer treated at a single institution between January 2010 and December 2011. Compliance with NCCN Guidelines was recorded. The accuracy of real-time synoptic auditing methods compared with retrospective chart review and reasons for noncompliance was assessed. SAS 9.3 software was used for data analysis. RESULTS: Compliance with NCCN Guidelines among 395 patients was 94% for initial staging evaluation, 97% for surgery, 91% for chemotherapy, 89% for hormone therapy, 91% for radiation therapy, 85% for follow-up, and 100% for determination of estrogen receptor/progesterone receptor and HER2 status. Age, comorbidities, and stage influenced guideline compliance. The most common reasons for noncompliance were patient refusal, patient choice after shared decision-making, and overuse of testing. Synoptic templated reporting was accurate in 97% patients. CONCLUSIONS: High compliance with NCCN Guidelines was demonstrated. Reasons for noncompliance were identifiable. Compliance and nonadherence can be evaluated quickly with electronic synoptic reporting. This allows real-time action plans to address quality concerns and aids national risk adjustment for comparison and benchmarking. PMID- 25691611 TI - The utility of routine chest radiography in the initial evaluation of adult patients with febrile neutropenia patients undergoing HSCT. AB - BACKGROUND: The routine use of chest radiographs (CXRs) in the initial evaluation of asymptomatic patients with febrile neutropenia undergoing hematopoietic stem cell transplant (HSCT) is controversial. OBJECTIVE: The goal of this study was to document the incidence of pneumonia demonstrated on CXR during an initial febrile neutropenic episode in adult patients undergoing HSCT. MATERIALS AND METHODS: Clinical records of 1083 adult patients undergoing autologous (n=766), allogeneic (n=269), or umbilical cord blood HSCT (n=48) between October 1, 2009, and December 31, 2012, were retrospectively reviewed. CXRs obtained at the initial febrile neutropenic episode were evaluated for radiologic features of pneumonia. The presence of clinical symptoms, length of stay (LOS), and readmission rates were assessed. RESULTS: A total of 817 (75%) febrile neutropenic episodes were noted. Of the patients with neutropenic fevers, 455 (55%) had CXRs. Of the 76 patients with respiratory symptoms at the time of CXR, 24 (31.6%) had findings suggestive of pneumonia. None of the 379 CXRs performed in the absence of symptoms revealed an infectious process (P=.0001). Moreover, the mean LOS was 23.8 days for patients receiving a CXR compared with 22.2 days (P=.04) in patients without a CXR. Additionally, in patients who had CXRs, 15.7% were readmitted within 30 days compared with 7.4% in those without CXRs (P=.0004). CONCLUSIONS: Indiscriminate routine CXR at the time of first neutropenic fever in asymptomatic adults undergoing HSCT is unlikely to reveal an infectious process or change clinical practice, and may be associated with increased LOS and readmission rates. PMID- 25691612 TI - Esophageal and esophagogastric junction cancers, version 1.2015. AB - Esophageal cancer is the sixth most common cause of cancer deaths worldwide. Adenocarcinoma is more common in North America and Western European countries, originating mostly in the lower third of the esophagus, which often involves the esophagogastric junction (EGJ). Recent randomized trials have shown that the addition of preoperative chemoradiation or perioperative chemotherapy to surgery significantly improves survival in patients with resectable cancer. Targeted therapies with trastuzumab and ramucirumab have produced encouraging results in the treatment of advanced or metastatic EGJ adenocarcinomas. Multidisciplinary team management is essential for patients with esophageal and EGJ cancers. This portion of the NCCN Guidelines for Esophageal and EGJ Cancers discusses management of locally advanced adenocarcinoma of the esophagus and EGJ. PMID- 25691613 TI - Multimodality approaches for the curative treatment of esophageal cancer. AB - Carcinoma of the esophagus and gastroesophageal junction tumors presenting with locoregional disease are potentially curable, although the cure rate is modest. Many different treatment approaches have been studied, with a multimodality approach associated with a 10% to 15% greater survival advantage compared with a single-modality approach. A systematic review was conducted to address 3 clinical questions: whether patients with resectable esophageal cancer should receive preoperative versus postoperative therapy, how to choose between these options, and whether surgery be avoided in patients who are candidates for both definitive chemoradiotherapy and definitive combined modality therapy. Recommendations from 3 recent treatment guidelines from Ontario, NCCN, and Belgium were consulted to address these questions. PMID- 25691614 TI - Value of functional imaging by PET in esophageal cancer. AB - In esophageal cancer, functional imaging using PET can provide important additional information beyond standard staging techniques that may eventually lead to therapeutic consequences. The most commonly used tracer is fluorodeoxyglucose (FDG), which has high avidity for both squamous cell cancer and adenocarcinoma of the esophagus. The value of FDG-PET is limited in early esophageal cancer, whereas additional information is provided in 15% to 20% of locally advanced tumors. Neoadjuvant treatment is currently the standard of care in locally advanced esophageal cancer in most countries because randomized studies have shown a significant survival benefit. Because responders and nonresponders have a significantly different prognosis, functional imaging to tailor preoperative treatment would be of interest. Metabolic imaging using FDG PET is an established method of response evaluation in clinical trials. The value of metabolic response evaluation is known to depend on the histologic subtype and the type of preoperative treatment delivered. An association of FDG-PET-based metabolic response with clinical response and prognosis was shown for absolute standardized uptake value (SUV) or a decrease of SUV levels before, during, and after therapy. However, contradictory findings exist in the literature and prospective validation is missing. Additionally, no consensus exists on time points or cutoff levels for metabolic response evaluation. Furthermore, correct prediction of a posttherapeutic pathologic complete remission is currently not possible using FDG-PET. Of high interest is early response monitoring during preoperative chemotherapy, with potential subsequent therapy modification. This tailored approach still needs validation in prospective multicenter trials. PMID- 25691615 TI - A discovery of significance (with apologies to epidemiologists everywhere). PMID- 25691617 TI - Early detection of dementia in multilingual populations: Visual Cognitive Assessment Test (VCAT). AB - BACKGROUND: Early diagnosis of cognitive impairment allows timely intervention with pharmacological and non-pharmacological measures. However, current cognitive evaluation tools do not cater for multilingual populations. OBJECTIVE: To develop and validate a visual-based cognitive evaluation tool, the Visual Cognitive Assessment Test (VCAT), which can be administered to multilingual populations without the need for translation or adaptation. METHOD: We designed a battery of tests to evaluate the domains of memory, executive function, visuospatial function, language and attention. Pilot testing of individual test items, followed by test refinement and development of a field version was performed. We subsequently validated VCAT for the diagnosis of mild cognitive impairment (MCI) and mild Alzheimer's disease (AD). Diagnostic performance was assessed by the area under the curve (AUC), sensitivity (Se) and specificity (Sp). RESULTS: VCAT was validated in a sample of 206 participants. The sample comprised 53.9% males; mean age (SD) was 67.8 (8.86) years; mean years of education was 10.5(6.0). AUC of VCAT for detection of cognitive impairment was found to be 93.3 (95% CI 90.1 to 96.4). Also, the Se and Sp of VCAT for the diagnosis of cognitive impairment (MCI and mild AD) were 85.6% and 81.1%, respectively. VCAT's diagnostic Se and Sp comparable to those of the Montreal Cognitive Assessment in the same cohort. Mean time-to-complete VCAT was 15.7 +/- 7.3 min. CONCLUSIONS: The VCAT has good Se and Sp for the diagnosis of MCI and mild AD. The visual-based test paradigm allows easy application to multilingual populations without the need for translation or adaptation. PMID- 25691618 TI - First report of the Global SYMPLICITY Registry on the effect of renal artery denervation in patients with uncontrolled hypertension. AB - This study aimed to assess the safety and effectiveness of renal denervation using the Symplicity system in real-world patients with uncontrolled hypertension (NCT01534299). The Global SYMPLICITY Registry is a prospective, open-label, multicenter registry. Office and 24-hour ambulatory blood pressures (BPs) were measured. Change from baseline to 6 months was analyzed for all patients and for subgroups based on baseline office systolic BP, diabetic status, and renal function; a cohort with severe hypertension (office systolic pressure, >=160 mm Hg; 24-hour systolic pressure, >=135 mm Hg; and >=3 antihypertensive medication classes) was also included. The analysis included protocol-defined safety events. Six-month outcomes for 998 patients, including 323 in the severe hypertension cohort, are reported. Mean baseline office systolic BP was 163.5+/-24.0 mm Hg for all patients and 179.3+/-16.5 mm Hg for the severe cohort; the corresponding baseline 24-hour mean systolic BPs were 151.5+/-17.0 and 159.0+/-15.6 mm Hg. At 6 months, the changes in office and 24-hour systolic BPs were -11.6+/-25.3 and 6.6+/-18.0 mm Hg for all patients (P<0.001 for both) and -20.3+/-22.8 and -8.9+/ 16.9 mm Hg for those with severe hypertension (P<0.001 for both). Renal denervation was associated with low rates of adverse events. After the procedure through 6 months, there was 1 new renal artery stenosis >70% and 5 cases of hospitalization for a hypertensive emergency. In clinical practice, renal denervation resulted in significant reductions in office and 24-hour BPs with a favorable safety profile. Greater BP-lowering effects occurred in patients with higher baseline pressures. CLINICAL TRIAL REGISTRATION: URL: www.clinicaltrials.gov. Unique identifier: NCT01534299. PMID- 25691619 TI - Novel retro-inverso peptide inhibitor reverses angiotensin receptor autoantibody induced hypertension in the rabbit. AB - Activating autoantibodies to the angiotensin II type 1 receptor (AT1R) have been implicated in hypertensive disorders. We investigated whether AT1R antibodies produced in immunized rabbits will activate AT1R and contribute to hypertension by a direct contractile effect on the vasculature and whether they can be blocked by a novel decoy peptide. A multiple antigenic peptide containing the AT1R epitope AFHYESQ, which is the receptor-binding epitope of AT1R-activating autoantibodies, was used to immunize 6 rabbits. AT1R antibody activity was analyzed in AT1R-transfected cells, and their contractile effects were assayed using isolated perfused rat cremaster resistance arterioles. A retro-inverso D amino acid epitope-mimetic peptide was tested for AT1R antibody inhibition in vitro and in vivo. All immunized animals produced high AT1R antibody titers and developed elevated blood pressure. No changes in measured blood chemistry values were observed after immunization. Rabbit anti-AT1R sera induced significant AT1R activation in transfected cells and vasoconstriction in the arteriole assay, both of which were blocked by losartan and the retro-inverso D-amino acid peptide. A single intravenous bolus injection of the retro-inverso d-amino acid peptide (1 mg/kg) into immunized rabbits dropped the mean arterial pressure from 122+/-11 to 82+/-6 mm Hg. Rabbit anti-AT1R sera partially suppressed angiotensin II-induced contraction of isolated rat cremaster arterioles, and the pressor response to angiotensin II infusion was attenuated in immunized animals. In conclusion, AT1R activating autoantibodies and the retro-inverso d-amino acid peptide, respectively, have important etiologic and therapeutic implications in hypertensive subjects who harbor these autoantibodies. PMID- 25691620 TI - Redox-regulated suppression of splenic T-lymphocyte activation in a model of sympathoexcitation. AB - Sympathoexcitation, increased circulating norepinephrine, and elevated levels of reactive oxygen species are driving forces underlying numerous cardiovascular diseases, including hypertension. However, the effects of elevated norepinephrine and subsequent reactive oxygen species production in splenic T-lymphocytes during hypertension are not currently understood. We hypothesized that increased systemic levels of norepinephrine inhibits the activation of splenic T lymphocytes via redox signaling. To address this hypothesis, we examined the status of T-lymphocyte activation in spleens of a mouse model of sympathoexcitation-driven hypertension (ie, norepinephrine infusion). Splenic T lymphocytes from norepinephrine-infused mice demonstrated decreased proliferation accompanied by a reduction in interferon gamma and tumor necrosis factor-alpha production as compared with T-lymphocytes from saline-infused mice. Additionally, norepinephrine directly inhibited splenic T-lymphocyte proliferation and cytokine production ex vivo in a dose-dependent manner. Furthermore, norepinephrine caused an increase in G1 arrest in norepinephrine-treated T-lymphocytes, and this was accompanied by a decrease in pro-growth cyclin D3, E1, and E2 mRNA expression. Interestingly, norepinephrine caused an increase in cellular superoxide, which was shown to be partially causal to the inhibitory effects of norepinephrine, as antioxidant supplementation (ie, Tempol) to norepinephrine-infused mice moderately restored T-lymphocyte growth and proinflammatory cytokine production. Our findings indicate that suppression of splenic T-lymphocyte activation occurs in a norepinephrine-driven model of hypertension due to, at least in part, an increase in superoxide. We speculate that further understanding of how norepinephrine mediates its inhibitory effects on splenic T-lymphocytes may elucidate novel pathways for therapeutic mimicry to suppress T-lymphocyte mediated inflammation in an array of diseases. PMID- 25691621 TI - Influence of maternal angiogenic factors during pregnancy on microvascular structure in school-age children. AB - Reduced placental growth factor (PlGF) levels and higher soluble fms-like tyrosine kinase (sFlt-1) levels in mothers during pregnancy may have persistent effects on vascular structures in their offspring. We examined whether angiogenic factors during pregnancy also affect childhood retinal microvasculature in a population-based prospective cohort study among 3505 mothers and their children. We measured maternal PlGF and sFlt-1 in the first and second trimester of pregnancy. At the age of 6, we measured childhood retinal arteriolar and venular calibers from digitized retinal photographs. We performed multiple linear regression models, taking maternal and childhood sociodemographic and lifestyle related characteristics, birth characteristics, and childhood current body mass index and blood pressure into account. We observed that first trimester maternal PlGF and sFlt-1 levels were not associated with childhood retinal arteriolar caliber. Lower second trimester maternal PlGF levels, but not sFlt-1 levels, were associated with narrower childhood retinal arteriolar caliber (difference: -0.09 SD score [95% confidence interval, -0.16 to 0.01], per SD score decrease in PlGF). This association was not explained by maternal and childhood sociodemographic and lifestyle-related characteristics, birth characteristics, or childhood current body mass index and blood pressure. Maternal PlGF and sFlt-1 levels in the first or second trimester were not associated with childhood retinal venular caliber. Our results suggest that lower maternal second trimester PlGF levels affect the microvascular development in the offspring, leading to narrower retinal arteriolar caliber in childhood. Further studies are needed to confirm these findings and to explore the underlying mechanisms and long-term cardiovascular consequences. PMID- 25691622 TI - Time-dependent effects of aspirin on blood pressure and morning platelet reactivity: a randomized cross-over trial. AB - Aspirin is used for cardiovascular disease (CVD) prevention by millions of patients on a daily basis. Previous studies suggested that aspirin intake at bedtime reduces blood pressure compared with intake on awakening. This has never been studied in patients with CVD. Moreover, platelet reactivity and CVD incidence is highest during morning hours. Bedtime aspirin intake may attenuate morning platelet reactivity. This clinical trial examined the effect of bedtime aspirin intake compared with intake on awakening on 24-hour ambulatory blood pressure measurement and morning platelet reactivity in patients using aspirin for CVD prevention. In this randomized open-label crossover trial, 290 patients were randomized to take 100 mg aspirin on awakening or at bedtime during 2 periods of 3 months. At the end of each period, 24-hour blood pressure and morning platelet reactivity were measured. The primary analysis population comprised 263 (blood pressure) and 133 (platelet reactivity) patients. Aspirin intake at bedtime did not reduce blood pressure compared with intake on awakening (difference systolic/diastolic: -0.1 [95% confidence interval, -1.0, 0.9]/-0.6 [95% confidence interval, -1.2, 0.0] mm Hg). Platelet reactivity during morning hours was reduced with bedtime aspirin intake (difference: -22 aspirin reaction units [95% confidence interval, -35, -9]). The intake of low-dose aspirin at bedtime compared with intake on awakening did not reduce blood pressure of patients with CVD. However, bedtime aspirin reduced morning platelet reactivity. Future studies are needed to assess the effect of this promising simple intervention on the excess of cardiovascular events during the high risk morning hours. PMID- 25691623 TI - Activation of nuclear factor erythroid 2-related factor 2 coordinates dimethylarginine dimethylaminohydrolase/PPAR-gamma/endothelial nitric oxide synthase pathways that enhance nitric oxide generation in human glomerular endothelial cells. AB - Dimethylarginine dimethylaminohydrolase (DDAH) degrades asymmetric dimethylarginine, which inhibits nitric oxide (NO) synthase (NOS). Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcriptional factor that binds to antioxidant response elements and transcribes many antioxidant genes. Because the promoters of the human DDAH-1 and DDAH-2, endothelial NOS (eNOS) and PPAR-gamma genes contain 2 to 3 putative antioxidant response elements, we hypothesized that they were regulated by Nrf2/antioxidant response element. Incubation of human renal glomerular endothelial cells with the Nrf2 activator tert-butylhydroquinone (20 MUmol.L(-1)) significantly (P<0.05) increased NO and activities of NOS and DDAH and decreased asymmetric dimethylarginine. It upregulated genes for hemoxygenase-1, eNOS, DDAH-1, DDAH-2, and PPAR-gamma and partitioned Nrf2 into the nucleus. Knockdown of Nrf2 abolished these effects. Nrf2 bound to one antioxidant response element on DDAH-1 and DDAH-2 and PPAR-gamma promoters but not to the eNOS promoter. An increased eNOS and phosphorylated eNOS (P-eNOSser 1177) expression with tert-butylhydroquinone was prevented by knockdown of PPAR gamma. Expression of Nrf2 was reduced by knockdown of PPAR-gamma, whereas PPAR gamma was reduced by knockdown of Nrf2, thereby demonstrating 2-way positive interactions. Thus, Nrf2 transcribes HO-1 and other genes to reduce reactive oxygen species, and DDAH-1 and DDAH-2 to reduce asymmetric dimethylarginine and PPAR-gamma to increase eNOS and its phosphorylation and activity thereby coordinating 3 pathways that enhance endothelial NO generation. PMID- 25691624 TI - Cys18-Cys137 disulfide bond in mouse angiotensinogen does not affect AngII dependent functions in vivo. AB - Renin cleavage of angiotensinogen (AGT) releases angiotensin I (AngI) in the initial step of producing all angiotensin peptides. It has been suggested recently that redox regulation of a disulfide bond in AGT involving Cys18-Cys137 may be important to its renin cleavage efficiency in vivo. The purpose of this study was to test this prediction in a mouse model by comparing AngII production and AngII-dependent functions in mice expressing wild-type AGT versus a mutated form of AGT lacking the disulfide bond. Wild-type (hepAGT+/+) and hepatocyte specific AGT-deficient (hepAGT-/-) littermates were developed in an low-density lipoprotein receptor -/- background. hepAGT+/+ mice were injected intraperitoneally with adeno-associated viral (AAV) vector containing a null insert. hepAGT-/- mice were injected with AAV containing a null insert, wild-type AGT or Cys18Ser and Cys137Ser mutated AGT. Two weeks after AAV injection, mice were fed a Western diet for 12 weeks. Administration of AAV containing either form of AGT led to similar plasma AGT concentrations in hepAGT-/- mice. High plasma renin concentrations in hepAGT-/- mice were suppressed equally by both forms of AGT, which were accompanied by comparable increases of plasma AngII concentrations similar to hepAGT+/+ mice. AAV-driven expression of both forms of AGT led to equivalent increases of systolic blood pressure and augmentation of atherosclerotic lesion size in hepAGT-/- mice. These measurements were comparable to systolic blood pressure and atherosclerotic lesions in hepAGT+/+ mice. These data indicate that the Cys18-Cys137 disulfide bond in AGT is dispensable for AngII production and AngII-dependent functions in mice. PMID- 25691625 TI - The Mu subunit of Plasmodium falciparum clathrin-associated adaptor protein 2 modulates in vitro parasite response to artemisinin and quinine. AB - The emergence of drug-resistant parasites is a serious threat faced by malaria control programs. Understanding the genetic basis of resistance is critical to the success of treatment and intervention strategies. A novel locus associated with antimalarial resistance, ap2-mu (encoding the mu chain of the adaptor protein 2 [AP2] complex), was recently identified in studies on the rodent malaria parasite Plasmodium chabaudi (pcap2-mu). Furthermore, analysis in Kenyan malaria patients of polymorphisms in the Plasmodium falciparum ap2-mu homologue, pfap2-mu, found evidence that differences in the amino acid encoded by codon 160 are associated with enhanced parasite survival in vivo following combination treatments which included artemisinin derivatives. Here, we characterize the role of pfap2-mu in mediating the in vitro antimalarial drug response of P. falciparum by generating transgenic parasites constitutively expressing codon 160 encoding either the wild-type Ser (Ser160) or the Asn mutant (160Asn) form of pfap2-mu. Transgenic parasites carrying the pfap2-mu 160Asn allele were significantly less sensitive to dihydroartemisinin using a standard 48-h in vitro test, providing direct evidence of an altered parasite response to artemisinin. Our data also provide evidence that pfap2-mu variants can modulate parasite sensitivity to quinine. No evidence was found that pfap2-mu variants contribute to the slow clearance phenotype exhibited by P. falciparum in Cambodian patients treated with artesunate monotherapy. These findings provide compelling evidence that pfap2-mu can modulate P. falciparum responses to multiple drugs. We propose that this gene should be evaluated further as a potential molecular marker of antimalarial resistance. PMID- 25691626 TI - Surveillance of artemisinin resistance in Plasmodium falciparum in India using the kelch13 molecular marker. AB - Malaria treatment in Southeast Asia is threatened with the emergence of artemisinin-resistant Plasmodium falciparum. Genome association studies have strongly linked a locus on P. falciparum chromosome 13 to artemisinin resistance, and recently, mutations in the kelch13 propeller region (Pfk-13) were strongly linked to resistance. To date, this information has not been shown in Indian samples. Pfk-13 mutations were assessed in samples from efficacy studies of artemisinin combination treatments in India. Samples were PCR amplified and sequenced from codon 427 to 727. Out of 384 samples, nonsynonymous mutations in the propeller region were found in four patients from the northeastern states, but their presence did not correlate with ACT treatment failures. This is the first report of Pfk-13 point mutations from India. Further phenotyping and genotyping studies are required to assess the status of artemisinin resistance in this region. PMID- 25691627 TI - Activity of Debio1452, a FabI inhibitor with potent activity against Staphylococcus aureus and coagulase-negative Staphylococcus spp., including multidrug-resistant strains. AB - Staphylococcus aureus and coagulase-negative staphylococci (CoNS) are responsible for a wide variety of human infections. The investigational antibacterial Debio1450 (previously AFN-1720), a prodrug of Debio1452 (previously AFN-1252), specifically targets staphylococci without significant activity against other Gram-positive or Gram-negative species. Debio1452 inhibits FabI, an enzyme critical to fatty acid biosynthesis in staphylococci. The activity of Debio1452 against CoNS, methicillin-susceptible S. aureus (MSSA), and methicillin-resistant S. aureus (MRSA), including significant clones, was determined. A globally diverse collection of 574 patient isolates from 35 countries was tested that included CoNS (6 species, 103 strains), MSSA (154 strains), MRSA (163 strains), and molecularly characterized strains (including spa-typed MRSA clones; 154 strains). The isolates were tested for susceptibility by CLSI broth microdilution methods against Debio1452 and 10 comparators. The susceptibility rates for the comparators were determined using CLSI and EUCAST breakpoint criteria. All S. aureus and CoNS strains were inhibited by Debio1452 concentrations of <= 0.12 and <= 0.5 MUg/ml, respectively. The MIC50s for MSSA, MRSA, and molecularly characterized MRSA strains were 0.004 MUg/ml, and the MIC90s ranged from 0.008 to 0.03 MUg/ml. The MICs were higher for the CoNS isolates (MIC50/90, 0.015/0.12 MUg/ml). Among S. aureus strains, resistance was common for erythromycin (61.6%), levofloxacin (49.0%), clindamycin (27.6%), tetracycline (15.7%), and trimethoprim sulfamethoxazole (7.0%). Debio1452 demonstrated potent activity against MSSA, MRSA, and CoNS. Debio1452 showed significantly greater activity overall (MIC50, 0.004 MUg/ml) than the other agents tested against these staphylococcal species, which included dominant MRSA clones and strains resistant to currently utilized antimicrobial agents. PMID- 25691628 TI - In vitro pharmacodynamics of various antibiotics in combination against extensively drug-resistant Klebsiella pneumoniae. AB - Extensively drug-resistant (XDR) Klebsiella pneumoniae is an emerging pathogen in Singapore. With limited therapeutic options available, combination antibiotics may be the only viable option. In this study, we aimed to elucidate effective antibiotic combinations against XDR K. pneumoniae isolates. Six NDM-1-producing and two OXA-181-producing K. pneumoniae strains were exposed to 12 antibiotics alone and in combination via time-kill studies. A hollow-fiber infection model (HFIM) with pharmacokinetic validation was used to simulate clinically relevant tigecycline-plus-meropenem dosing regimens against 2 XDR K. pneumoniae isolates over 240 h. The emergence of resistance against tigecycline was quantified using drug-free and selective (tigecycline at 3* the MIC) media. The in vitro growth rates were determined and serial passages on drug-free and selective media were carried out on resistant isolates obtained at 240 h. Both the polymyxin B and tigecycline MICs ranged from 1 to 4 mg/liter. In single time-kill studies, all antibiotics alone demonstrated regrowth at 24 h, except for polymyxin B against 2 isolates. Tigecycline plus meropenem was found to be bactericidal in 50% of the isolates. For the isolates that produced OXA-181-like carbapenemases, none of the 55 tested antibiotic combinations was bactericidal. Against 2 isolates in the HFIM, tigecycline plus meropenem achieved a >90% reduction in bacterial burden for 96 h before regrowth was observed until 10(9) CFU/ml at 240 h. Phenotypically stable and resistant isolates, which were recovered from tigecycline-supplemented plates post-HFIM studies, had lower growth rates than those of their respective parent isolates, possibly implying a substantial biofitness deficit in this population. We found that tigecycline plus meropenem may be a potential antibiotic combination for XDR K. pneumoniae infections, but its efficacy was strain specific. PMID- 25691629 TI - Polymyxin resistance caused by mgrB inactivation is not associated with significant biological cost in Klebsiella pneumoniae. AB - The inactivation of the mgrB gene, which encodes a negative-feedback regulator of the PhoPQ signaling system, was recently shown to be a common mutational mechanism responsible for acquired polymyxin resistance among carbapenemase producing Klebsiella pneumoniae strains from clinical sources. In this work, we show that mgrB mutants can easily be selected in vitro from different K. pneumoniae lineages, and mgrB inactivation is not associated with a significant biological cost. PMID- 25691630 TI - Raltegravir permeability across blood-tissue barriers and the potential role of drug efflux transporters. AB - The objectives of this study were to investigate raltegravir transport across several blood-tissue barrier models and the potential interactions with drug efflux transporters. Raltegravir uptake, accumulation, and permeability were evaluated in vitro in (i) P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), multidrug resistance-associated protein 1 (MRP1), or MRP4-overexpressing MDA-MDR1 (P-gp), HEK-ABCG2, HeLa-MRP1, or HEK-MRP4 cells, respectively; (ii) cell culture systems of the human blood-brain (hCMEC/D3), mouse blood-testicular (TM4), and human blood-intestinal (Caco-2) barriers; and (iii) rat jejunum and ileum segments using an in situ single-pass intestinal perfusion model. [(3)H]Raltegravir accumulation by MDA-MDR1 (P-gp) and HEK-ABCG2-overexpressing cells was significantly enhanced in the presence of PSC833 {6-[(2S,4R,6E)-4 methyl-2-(methylamino)-3-oxo-6-octenoic acid]-7-L-valine-cyclosporine}, a P-gp inhibitor, or Ko143 [(3S,6S,12aS)-1,2,3,4,6,7,12,12a-octahydro-9-methoxy-6-(2 methylpropyl)-1,4-dioxopyrazino[1',2':1,6]pyrido[3,4-b]indole-3-propanoic acid 1,1-dimethylethyl ester], a BCRP inhibitor, suggesting the inhibition of a P-gp- or BCRP-mediated efflux process, respectively. Furthermore, [(3)H]raltegravir accumulation by human cerebral microvessel endothelial hCMEC/D3 and mouse Sertoli TM4 cells was significantly increased by PSC833 and Ko143. In human intestinal Caco-2 cells grown on Transwell filters, PSC833, but not Ko143, significantly decreased the [(3)H]raltegravir efflux ratios. In rat intestinal segments, [(3)H]raltegravir in situ permeability was significantly enhanced by the concurrent administration of PSC833 and Ko143. In contrast, in the transporter inhibition assays, raltegravir (10 to 500 MUM) did not increase the accumulation of substrate for P-gp (rhodamine-6G), BCRP ([(3)H]mitoxantrone), or MRP1 [2',7' bis(2-carboxyethyl)-5(6)-carboxyfluorescein (BCECF)] by MDA-MDR1 (P-gp)-, HEK ABCG2-, or HeLa-MRP1-overexpressing cells, respectively. Our data suggest that raltegravir is a substrate but not an inhibitor of the drug efflux transporters P gp and BCRP. These transporters might play a role in the restriction of raltegravir permeability across the blood-brain, blood-testicular, and blood intestinal barriers, potentially contributing to its low tissue concentrations and/or low oral bioavailability observed in the clinic setting. PMID- 25691631 TI - Simultaneous administration of 2-aminoethyl diphenylborinate and chloroquine reverses chloroquine resistance in malaria parasites. AB - A nearly complete reversal of chloroquine (CQ) resistance in the CQ-resistant Plasmodium falciparum K-1 strain, with a significant decrease in the mean +/- standard deviation (SD) 50% inhibitory concentration (IC50) from 1,050 +/- 95 nM to 14 +/- 2 nM, was achieved in vitro by the simultaneous administration of 2 aminoethyl diphenylborinate (2-APB). The CQ resistance-reversing activity of 2 APB, which showed the same efficacy as verapamil, was also observed in an in vivo mouse infection model with the CQ-resistant Plasmodium chabaudi AS(30CQ) strain. PMID- 25691632 TI - Amplification of pfmdr1, pfcrt, pvmdr1, and K13 propeller polymorphisms associated with Plasmodium falciparum and Plasmodium vivax isolates from the China-Myanmar border. AB - Malaria in the China-Myanmar border region is still severe; local transmission of both falciparum and vivax malaria persists, and there is a risk of geographically expanding antimalarial resistance. In this research, the pfmdr1, pfcrt, pvmdr1, and K13-propeller genotypes were determined in 26 Plasmodium falciparum and 64 Plasmodium vivax isolates from Yingjiang county of Yunnan province. The pfmdr1 (11.5%), pfcrt (34.6%), and pvmdr1 (3.1%) mutations were prevalent at the China Myanmar border. The indigenous samples exhibited prevalences of 14.3%, 28.6%, and 14.3% for pfmdr1 N86Y, pfcrt K76T, and pfcrt M74I, respectively, whereas the samples from Myanmar showed prevalences of 10.5%, 21.1%, and 5.3%, respectively. The most prevalent genotypes of pfmdr1 and pfcrt were Y86Y184 and M74N75T76, respectively. No pvmdr1 mutation occurred in the indigenous samples but was observed in two cases coming from Myanmar. In addition, we are the first to report on 10 patients (38.5%) with five different K13 point mutations. The F446I allele is predominant (19.2%), and its prevalence was 28.6% in the indigenous samples of Yingjiang county and 15.8% in samples from Myanmar. The present data might be helpful for enrichment of the molecular surveillance of antimalarial resistance and useful for developing and updating guidance for the use of antimalarials in this region. PMID- 25691633 TI - Effects of raltegravir or elvitegravir resistance signature mutations on the barrier to dolutegravir resistance in vitro. AB - The recently approved HIV-1 integrase strand transfer inhibitor (INSTI) dolutegravir (DTG) (S/GSK1349572) has overall advantageous activity when tested in vitro against HIV-1 with raltegravir (RAL) and elvitegravir (EVG) resistance signature mutations. We conducted an in vitro resistance selection study using wild-type HIV-1 and mutants with the E92Q, Y143C, Y143R, Q148H, Q148K, Q148R, and N155H substitutions to assess the DTG in vitro barrier to resistance. No viral replication was observed at concentrations of >= 32 nM DTG, whereas viral replication was observed at 160 nM RAL or EVG in the mutants. In the Q148H, Q148K, or Q148R mutants, G140S/Q148H, E138K/Q148K, E138K/Q148R, and G140S/Q148R secondary mutations were identified with each INSTI and showed high resistance to RAL or EVG but limited resistance to DTG. E138K and G140S, as secondary substitutions to Q148H, Q148K, or Q148R, were associated with partial recovery in viral infectivity and/or INSTI resistance. In the E92Q, Y143C, Y143R, and N155H mutants, no secondary substitutions were associated with DTG. These in vitro results suggest that DTG has a high barrier to the development of resistance in the presence of RAL or EVG signature mutations other than Q148. One explanation for this high barrier to resistance is that no additional secondary substitution of E92Q, Y143C, Y143R, or N155H simultaneously increased the fold change in 50% effective concentration (EC50) to DTG and infectivity. Although increased DTG resistance via the Q148 pathway and secondary substitutions occurs at low concentrations, a higher starting concentration may reduce or eliminate the development of DTG resistance in this pathway in vitro. PMID- 25691634 TI - Functional characterization of the Pneumocystis jirovecii potential drug targets dhfs and abz2 involved in folate biosynthesis. AB - Pneumocystis species are fungal parasites colonizing mammal lungs with strict host specificity. Pneumocystis jirovecii is the human-specific species and can turn into an opportunistic pathogen causing severe pneumonia in immunocompromised individuals. This disease is currently the second most frequent life-threatening invasive fungal infection worldwide. The most efficient drug, cotrimoxazole, presents serious side effects, and resistance to this drug is emerging. The search for new targets for the development of new drugs is thus of utmost importance. The recent release of the P. jirovecii genome sequence opens a new era for this task. It can now be carried out on the actual targets to be inhibited instead of on those of the relatively distant model Pneumocystis carinii, the species infecting rats. We focused on the folic acid biosynthesis pathway because (i) it is widely used for efficient therapeutic intervention, and (ii) it involves several enzymes that are essential for the pathogen and have no human counterparts. In this study, we report the identification of two such potential targets within the genome of P. jirovecii, the dihydrofolate synthase (dhfs) and the aminodeoxychorismate lyase (abz2). The function of these enzymes was demonstrated by the rescue of the null allele of the orthologous gene of Saccharomyces cerevisiae. PMID- 25691635 TI - Characterization of a large cluster of influenza A(H1N1)pdm09 viruses cross resistant to oseltamivir and peramivir during the 2013-2014 influenza season in Japan. AB - Between September 2013 and July 2014, 2,482 influenza 2009 pandemic A(H1N1) [A(H1N1)pdm09] viruses were screened in Japan for the H275Y substitution in their neuraminidase (NA) protein, which confers cross-resistance to oseltamivir and peramivir. We found that a large cluster of the H275Y mutant virus was present prior to the main influenza season in Sapporo /: Hokkaido, with the detection rate for this mutant virus reaching 29% in this area. Phylogenetic analysis suggested the clonal expansion of a single mutant virus in Sapporo /: Hokkaido. To understand the reason for this large cluster, we examined the in vitro and in vivo properties of the mutant virus. We found that it grew well in cell culture, with growth comparable to that of the wild-type virus. The cluster virus also replicated well in the upper respiratory tract of ferrets and was transmitted efficiently between ferrets by way of respiratory droplets. Almost all recently circulating A(H1N1)pdm09 viruses, including the cluster virus, possessed two substitutions in NA, V241I and N369K, which are known to increase replication and transmission fitness. A structural analysis of NA predicted that a third substitution (N386K) in the NA of the cluster virus destabilized the mutant NA structure in the presence of the V241I and N369K substitutions. Our results suggest that the cluster virus retained viral fitness to spread among humans and, accordingly, caused the large cluster in Sapporo/Hokkaido. However, the mutant NA structure was less stable than that of the wild-type virus. Therefore, once the wild-type virus began to circulate in the community, the mutant virus could not compete and faded out. PMID- 25691636 TI - Eravacycline (TP-434) is efficacious in animal models of infection. AB - Eravacycline is a novel broad-spectrum fluorocycline antibiotic being developed for a wide range of serious infections. Eravacycline was efficacious in mouse septicemia models, demonstrating 50% protective dose (PD50) values of <= 1 mg/kg of body weight once a day (q.d.) against Staphylococcus aureus, including tetracycline-resistant isolates of methicillin-resistant S. aureus (MRSA), and Streptococcus pyogenes. The PD50 values against Escherichia coli isolates were 1.2 to 4.4 mg/kg q.d. In neutropenic mouse thigh infection models with methicillin-sensitive S. aureus (MSSA) and S. pyogenes, eravacycline produced 2 log10 reductions in CFU at single intravenous (i.v.) doses ranging from 0.2 to 9.5 mg/kg. In a neutropenic mouse lung infection model, eravacycline administered i.v. at 10 mg/kg twice a day (b.i.d.) reduced the level of tetracycline-resistant MRSA in the lung equivalent to that of linezolid given orally (p.o.) at 30 mg/kg b.i.d. At i.v. doses of 3 to 12 mg/kg b.i.d., eravacycline was more efficacious against tetracycline-resistant Streptococcus pneumoniae in a neutropenic lung infection model than linezolid p.o. at 30 mg/kg b.i.d. Eravacycline showed good efficacy at 2 to 10 mg/kg i.v. b.i.d., producing up to a 4.6 log10 CFU reduction in kidney bacterial burden in a model challenged with a uropathogenic E. coli isolate. Eravacycline was active in multiple murine models of infection against clinically important Gram-positive and Gram-negative pathogens. PMID- 25691637 TI - Placental transfer of rilpivirine in an ex vivo human cotyledon perfusion model. AB - Placental transfers of the HIV nonnucleoside reverse transcriptase inhibitor rilpivirine were investigated in 8 term human cotyledons perfused with rilpivirine (400 ng/ml) in the maternal-to-fetal direction. The mean fetal transfer rate (FTR) (fetal/maternal concentration at steady state from 15 to 90 min) was 26% +/- 8% (mean +/- standard deviation), and the clearance index (rilpivirine FTR/antipyrine FTR) was 61% +/- 20%. This shows that rilpivirine crosses the placenta at a relatively high rate, suggesting that the fetus is exposed to the compound during treatment of the mother. PMID- 25691638 TI - Comparison of antimicrobial susceptibilities of pharyngeal, rectal, and urethral Neisseria gonorrhoeae isolates among men who have sex with men. AB - U.S. surveillance for Neisseria gonorrhoeae antimicrobial susceptibilities is based exclusively on male urethral isolates. These data inform gonorrhea treatment guidelines, including recommendations for the treatment of extragenital infections, but data on the susceptibilities of extragenital isolates are limited. We compared the antimicrobial susceptibilities of pharyngeal, rectal, and urethral gonococcal isolates collected from men who have sex with men (MSM), at five sentinel sites throughout the United States. MICs were determined by the agar dilution method. Generalized linear models were used to compare (i) the proportions of isolates with elevated MICs and (ii) geometric mean MICs according to anatomic site, adjusted for city. In December 2011 to September 2013, totals of 205 pharyngeal, 261 rectal, and 976 urethral isolates were obtained. The proportions of isolates with elevated ceftriaxone MICs (>= 0.125 MUg/ml) did not differ according to anatomic site (0.5% of pharyngeal isolates, 1.5% of rectal isolates, and 1.7% of urethral isolates, with a city-adjusted odds ratio [aOR] of 0.4 [95% confidence interval {CI}, 0.0 to 3.9] for pharyngeal versus urethral isolates and an aOR of 0.9 [95% CI, 0.2 to 4.2] for rectal versus urethral isolates). The city-adjusted geometric mean ceftriaxone MICs of pharyngeal (0.0153 MUg/ml) and rectal (0.0157 MUg/ml) isolates did not differ from that of urethral isolates (0.0150 MUg/ml) (ratios of geometric mean MICs of 1.02 [95% CI, 0.90 to 1.17] and 1.05 [95% CI, 0.93 to 1.19], respectively). Similar results were observed for other antimicrobials, including cefixime and azithromycin. These findings suggest that, at the population level, gonococcal antimicrobial susceptibility surveillance based on urethral isolates from MSM adequately reflects the susceptibilities of N. gonorrhoeae strains circulating among MSM. PMID- 25691639 TI - Avibactam and inhibitor-resistant SHV beta-lactamases. AB - beta-Lactamase enzymes (EC 3.5.2.6) are a significant threat to the continued use of beta-lactam antibiotics to treat infections. A novel non-beta-lactam beta lactamase inhibitor with activity against many class A and C and some class D beta-lactamase variants, avibactam, is now available in the clinic in partnership with ceftazidime. Here, we explored the activity of avibactam against a variety of characterized isogenic laboratory constructs of beta-lactamase inhibitor resistant variants of the class A enzyme SHV (M69I/L/V, S130G, K234R, R244S, and N276D). We discovered that the S130G variant of SHV-1 shows the most significant resistance to inhibition by avibactam, based on both microbiological and biochemical characterizations. Using a constant concentration of 4 mg/liter of avibactam as a beta-lactamase inhibitor in combination with ampicillin, the MIC increased from 1 mg/liter for blaSHV-1 to 256 mg/liter for blaSHV S130G expressed in Escherichia coli DH10B. At steady state, the k2/K value of the S130G variant when inactivated by avibactam was 1.3 M(-1) s(-1), versus 60,300 M(-1) s(-1) for the SHV-1 beta-lactamase. Under timed inactivation conditions, we found that an approximately 1,700-fold-higher avibactam concentration was required to inhibit SHV S130G than the concentration that inhibited SHV-1. Molecular modeling suggested that the positioning of amino acids in the active site of SHV may result in an alternative pathway of inactivation when complexed with avibactam, compared to the structure of CTX-M-15-avibactam, and that S130 plays a role in the acylation of avibactam as a general acid/base. In addition, S130 may play a role in recyclization. As a result, we advance that the lack of a hydroxyl group at position 130 in the S130G variant of SHV-1 substantially slows carbamylation of the beta-lactamase by avibactam by (i) removing an important proton acceptor and donator in catalysis and (ii) decreasing the number of H bonds. In addition, recyclization is most likely also slow due to the lack of a general base to initiate the process. Considering other inhibitor-resistant mechanisms among class A beta-lactamases, S130 may be the most important amino acid for the inhibition of class A beta-lactamases, perhaps even for the novel diazabicyclooctane class of beta-lactamase inhibitors. PMID- 25691640 TI - Characterization of Tn6238 with a new allele of aac(6')-Ib-cr. AB - Here, we report that the genetic structure of Tn1331 remained conserved in Argentina from 1989 to 2013 (72 of 73 isolates), with the exception being the plasmid-borne Tn1331-like transposon Tn6238 containing a new aac(6')-Ib-cr allele recovered from a colistin-resistant Klebsiella pneumoniae clinical isolate. A bioinformatic analysis of aac(6')-Ib-like gene cassettes suggests that this new aac(6')-Ib-cr allele emerged through mutation or homologous recombination in the Tn1331 genetic platform. Tn6238 is a novel platform for the dissemination of aminoglycoside and fluoroquinolone resistance determinants. PMID- 25691641 TI - Ambush of Clostridium difficile spores by ramoplanin: activity in an in vitro model. AB - Clostridium difficile infection (CDI) is a gastrointestinal disease caused by C. difficile, a spore-forming bacterium that in its spore form is tolerant to standard antimicrobials. Ramoplanin is a glycolipodepsipeptide antibiotic that is active against C. difficile with MICs ranging from 0.25 to 0.50 MUg/ml. The activity of ramoplanin against the spores of C. difficile has not been well characterized; such activity, however, may hold promise, since posttreatment residual intraluminal spores are likely elements of disease relapse, which can impact more than 20% of patients who are successfully treated. C. difficile spores were found to be stable in deionized water for 6 days. In vitro spore counts were consistently below the level of detection for 28 days after even brief (30-min) exposure to ramoplanin at concentrations found in feces (300 MUg/ml). In contrast, suppression of spore counts was not observed for metronidazole or vancomycin at human fecal concentrations during treatment (10 MUg/ml and 500 MUg/ml, respectively). Removal of the C. difficile exosporium resulted in an increase in spore counts after exposure to 300 MUg/ml of ramoplanin. Therefore, we propose that rather than being directly sporicidal, ramoplanin adheres to the exosporium for a prolonged period, during which time it is available to attack germinating cells. This action, in conjunction with its already established bactericidal activity against vegetative C. difficile forms, supports further evaluation of ramoplanin for the prevention of relapse after C. difficile infection in patients. PMID- 25691642 TI - Assessment of SYBR green I dye-based fluorescence assay for screening antimalarial activity of cationic peptides and DNA intercalating agents. AB - The SYBR green I (SG) dye-based fluorescence assay for screening antimalarial compounds is based on direct quantitation of parasite DNA. We show that DNA interacting cationic cell-penetrating peptides (CPPs) and intercalating agents compete with SG dye to bind to DNA. Therefore, readouts of this assay, unlike those of the [(3)H]hypoxanthine incorporation assay, for the antimalarial activity of the above DNA binding agents may be erroneous. In the case of CPPs, false readouts can be improved by the removal of excess peptides. PMID- 25691643 TI - Analysis of ganciclovir-resistant human herpesvirus 6B clinical isolates using quenching probe PCR methodology. AB - Quenching probe PCR (QP-PCR) analysis was used to determine the frequency of ganciclovir (GCV) resistance among clinical isolates of human herpesvirus 6B (HHV 6B) obtained from patients with primary viral infection and viral reactivation. Forty-two HHV-6B clinical isolates were repeatedly recovered from 15 hematopoietic stem cell transplant (HSCT) recipients, and 20 isolates were recovered from 20 exanthem subitum (ES) patients. Of the 15 HSCT recipients, 9 received GCV during the observation period; however, none of the ES patients were treated with GCV. Two established laboratory strains, Z29 and HST, were used as standards in this study. Regions 1 and 2 of the U69 gene of all of the clinical isolates demonstrated the same melting temperature as regions 1 and 2 of the Z29 strain. For region 3, the melting temperatures of all clinical isolates fell between the melting temperature of the plasmid containing the A462D single nucleotide polymorphism (SNP) and the melting temperature of the Z29 strain, and the melting temperatures profiles of all clinical isolates were similar to the melting temperature profile of the Japanese HST strain. As expected, none of the 20 clinical isolates recovered from the ES patients and the 14 isolates recovered from the HSCT recipients who did not receive GCV treatment carried the six known SNPs associated with GCV resistance. Interestingly, these six SNPs were not detected in the 28 clinical isolates recovered from the 9 HSCT recipients who received GCV. Additional sequence analysis of the U69 gene from the 15 representative isolates from the 15 HSCT recipients identified other SNPs. These SNPs were identical to those identified in the HST strain. Therefore, the rate of emergence of GCV-resistant HHV-6B strains appears to be relatively low, even in HSCT recipients treated with GCV. PMID- 25691644 TI - Antileishmanial effect of 18beta-glycyrrhetinic acid is mediated by Toll-like receptor-dependent canonical and noncanonical p38 activation. AB - 18beta-Glycyrrhetinic acid (GRA), a natural immunomodulator, greatly reduced the parasite load in experimental visceral leishmaniasis through nitric oxide (NO) upregulation, proinflammatory cytokine expression, and NF-kappaB activation. For the GRA-mediated effect, the primary kinase responsible was found to be p38, and analysis of phosphorylation kinetics as well as studies with dominant-negative (DN) constructs revealed mitogen-activated protein kinase kinase 3 (MKK3) and MKK6 as the immediate upstream regulators of p38. However, detection of remnant p38 kinase activity in the presence of both DN MKK3 and MKK6 suggested alternative pathways of p38 activation. That residual p38 activity was attributed to an autophosphorylation event ensured by the transforming growth factor beta activated kinase 1 (TAK1)-binding protein 1 (TAB1)-p38 interaction and was completely abolished upon pretreatment with SB203580 in DN MKK3/6 double transfected macrophage cells. Further upstream signaling evaluation by way of phosphorylation kinetics and transfection studies with DN constructs identified TAK1, myeloid differentiation factor 88 (MyD88), interleukin 1 receptor (IL-1R) activated kinase 1 (IRAK1), and tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) as important contributors to GRA-mediated macrophage activation. Finally, gene knockdown studies revealed Toll-like receptor 2 (TLR2) and TLR4 as the membrane receptors associated with GRA-mediated antileishmanial activity. Together, the results of this study brought mechanistic insight into the antileishmanial activity of GRA, which is dependent on the TLR2/4-MyD88 signaling axis, leading to MKK3/6-mediated canonical and TAB1-mediated noncanonical p38 activation. PMID- 25691645 TI - Antibiotic-resistant Klebsiella pneumoniae and Escherichia coli high-risk clones and an IncFII(k) mosaic plasmid hosting Tn1 (blaTEM-4) in isolates from 1990 to 2004. AB - We describe the genetic background of bla(TEM-4) and the complete sequence of pRYC11::bla(TEM-4), a mosaic plasmid that is highly similar to pKpQIL-like variants, predominant among TEM-4 producers in a Spanish hospital (1990 to 2004), which belong to Klebsiella pneumoniae and Escherichia coli high-risk clones responsible for the current spread of different antibiotic resistance genes. Predominant populations of plasmids and host adapted clonal lineages seem to have greatly contributed to the spread of resistance to extended-spectrum cephalosporins. PMID- 25691646 TI - Colistin resistance mechanisms in Klebsiella pneumoniae strains from Taiwan. AB - Colistin is one of the antibiotics of last resort for the treatment of carbapenem resistant Klebsiella pneumoniae infection. This study showed that capsular type K64 (50%) and ST11 (53.9%) are the prevalent capsular and sequence types in the colistin-resistant strains in Taiwan. The interruption of transcripts (38.5%) and amino acid mutation (15.4%) in mgrB are the major mechanisms contributing to colistin resistance. In addition, novel single amino acid changes in MgrB (Stop48Tyr) and PhoQ (Leu26Pro) were observed to contribute to colistin resistance. PMID- 25691647 TI - Peptidyl aldehyde NK-1.8k suppresses enterovirus 71 and enterovirus 68 infection by targeting protease 3C. AB - Enterovirus (EV) is one of the major causative agents of hand, foot, and mouth disease in the Pacific-Asia region. In particular, EV71 causes severe central nervous system infections, and the fatality rates from EV71 infection are high. Moreover, an outbreak of respiratory illnesses caused by an emerging EV, EV68, recently occurred among over 1,000 young children in the United States and was also associated with neurological infections. Although enterovirus has emerged as a considerable global public health threat, no antiviral drug for clinical use is available. In the present work, we screened our compound library for agents targeting viral protease and identified a peptidyl aldehyde, NK-1.8k, that inhibits the proliferation of different EV71 strains and one EV68 strain and that had a 50% effective concentration of 90 nM. Low cytotoxicity (50% cytotoxic concentration, >200 MUM) indicated a high selective index of over 2,000. We further characterized a single amino acid substitution inside protease 3C (3C(pro)), N69S, which conferred EV71 resistance to NK-1.8k, possibly by increasing the flexibility of the substrate binding pocket of 3C(pro). The combination of NK-1.8k and an EV71 RNA-dependent RNA polymerase inhibitor or entry inhibitor exhibited a strong synergistic anti-EV71 effect. Our findings suggest that NK-1.8k could potentially be developed for anti-EV therapy. PMID- 25691648 TI - Heterosubtypic protection conferred by the human monoclonal antibody PN-SIA28 against influenza A virus lethal infections in mice. AB - PN-SIA28 is a human monoclonal antibody (Hu-MAb) targeting highly conserved epitopes within the stem portion of the influenza virus hemagglutinin (HA) (N. Clementi, et al, PLoS One 6:e28001, 2011, http://dx.doi.org/10.1371/journal.pone.0028001). Previous in vitro studies demonstrated PN-SIA28 neutralizing activities against phylogenetically divergent influenza A subtypes. In this study, the protective activity of PN-SIA28 was evaluated in mice inoculated with lethal influenza A/WSN/33 (H1N1), A/Quebec/144147/09 (H1N1)pdm09, and A/Victoria/3/75 (H3N2) viruses. At 24 h postinoculation (p.i.), animals received PN-SIA28 intraperitoneally (1 or 10 mg/kg of body weight) or 10 mg/kg of unrelated Hu-MAb (mock). Body weight loss and mortality rate (MR) were recorded for 14 days postinfection (p.i.). Lung viral titers (LVT) were determined at day 5 p.i. In A/WSN/33 (H1N1)-infected groups, all untreated and mock-receiving mice died, whereas MRs of 87.5% and 25% were observed in mice that received PN-SIA28 1 and 10 mg/kg, respectively. In influenza A(H1N1) pdm09-infected groups, an MR of 75% was recorded for untreated and mock-treated groups, whereas the PN-SIA28 1-mg/kg and 10-mg/kg groups had rates of 62.5% and 0%, respectively. In A/Victoria/3/75 (H3N2)-infected animals, untreated and mock-treated animals had MRs of 37.5% and 25%, respectively, and no mortalities were recorded after PN-SIA28 treatments. Accordingly, PN-SIA28 treatments significantly reduced weight losses and resulted in a >= 1-log reduction in LVT compared to the control in all infection groups. This study confirms that antibodies targeting highly conserved epitopes in the influenza HA stem region, like PN-SIA28, not only neutralize influenza A viruses of clinically relevant subtypes in vitro but also, more importantly, protect from a lethal influenza virus challenge in vivo. PMID- 25691649 TI - Discovery of itraconazole with broad-spectrum in vitro antienterovirus activity that targets nonstructural protein 3A. AB - There is currently no approved antiviral therapy for the prophylaxis or treatment of enterovirus infections, which remain a substantial threat to public health. To discover inhibitors that can be immediately repurposed for treatment of enterovirus infections, we developed a high-throughput screening assay that measures the cytopathic effect induced by enterovirus 71 (EV71) to screen an FDA approved drug library. Itraconazole (ITZ), a triazole antifungal agent, was identified as an effective inhibitor of EV71 replication in the low-micromolar range (50% effective concentrations [EC50s], 1.15 MUM). Besides EV71, the compound also inhibited other enteroviruses, including coxsackievirus A16, coxsackievirus B3, poliovirus 1, and enterovirus 68. Study of the mechanism of action by time-of-addition assay and transient-replicon assay revealed that ITZ targeted a step involved in RNA replication or polyprotein processing. We found that the mutations (G5213U and U5286C) conferring the resistance to the compound were in nonstructural protein 3A, and we confirmed the target amino acid substitutions (3A V51L and 3A V75A) using a reverse genetic approach. Interestingly, posaconazole, a new oral azole with a molecular structure similar to that of ITZ, also exhibited anti-EV71 activity. Moreover, ITZ-resistant viruses do not exhibit cross-resistance to posaconazole or the enviroxime-like compound GW5074, which also targets the 3A region, indicating that they may target a specific site(s) in viral genome. Although the protective activity of ITZ or posaconazole (alone or in combination with other antivirals) remains to be assessed in animal models, our findings may represent an opportunity to develop therapeutic interventions for enterovirus infection. PMID- 25691650 TI - Characterization of a mobilizable IncQ plasmid encoding cephalosporinase CMY-4 in Escherichia coli. PMID- 25691651 TI - Emergence of KPC-2-producing Pseudomonas aeruginosa sequence type 463 isolates in Hangzhou, China. AB - Thirty-nine Klebsiella pneumoniae carbapenemase (KPC)-producing Pseudomonas aeruginosa isolates, all exhibiting high-level resistance to carbapenems and other beta-lactam antibiotics, were isolated in Hangzhou, China. Molecular epidemiology analysis indicated the presence of two dominant clones, namely, clones A and B, both of which belong to sequence type 463 (ST463). A genetic environment analysis demonstrated that both clones harbor an ISKpn8 transposase, bla(KPC-2), and an ISKpn6-like transposase. These findings depict the features of clonal expansion and transmission of KPC-2-producing P. aeruginosa strains in Hangzhou, China. PMID- 25691652 TI - A novel tricyclic ligand-containing nonpeptidic HIV-1 protease inhibitor, GRL 0739, effectively inhibits the replication of multidrug-resistant HIV-1 variants and has a desirable central nervous system penetration property in vitro. AB - We report here that GRL-0739, a novel nonpeptidic HIV-1 protease inhibitor containing a tricycle (cyclohexyl-bis-tetrahydrofuranylurethane [THF]) and a sulfonamide isostere, is highly active against laboratory HIV-1 strains and primary clinical isolates (50% effective concentration [EC50], 0.0019 to 0.0036 MUM), with minimal cytotoxicity (50% cytotoxic concentration [CC50], 21.0 MUM). GRL-0739 blocked the infectivity and replication of HIV-1NL4-3 variants selected by concentrations of up to 5 MUM ritonavir or atazanavir (EC50, 0.035 to 0.058 MUM). GRL-0739 was also highly active against multidrug-resistant clinical HIV-1 variants isolated from patients who no longer responded to existing antiviral regimens after long-term antiretroviral therapy, as well as against the HIV-2ROD variant. The development of resistance against GRL-0739 was substantially delayed compared to that of amprenavir (APV). The effects of the nonspecific binding of human serum proteins on the anti-HIV-1 activity of GRL-0739 were insignificant. In addition, GRL-0739 showed a desirable central nervous system (CNS) penetration property, as assessed using a novel in vitro blood-brain barrier model. Molecular modeling demonstrated that the tricyclic ring and methoxybenzene of GRL-0739 have a larger surface and make greater van der Waals contacts with protease than in the case of darunavir. The present data demonstrate that GRL-0739 has desirable features as a compound with good CNS-penetrating capability for treating patients infected with wild-type and/or multidrug-resistant HIV-1 variants and that the newly generated cyclohexyl-bis-THF moiety with methoxybenzene confers highly desirable anti-HIV-1 potency in the design of novel protease inhibitors with greater CNS penetration profiles. PMID- 25691653 TI - A Negative Correlation Between Blood Glucose and Acetone Measured in Healthy and Type 1 Diabetes Mellitus Patient Breath. AB - BACKGROUND: Exhaled acetone analysis has long been recognized as a supplementary tool for diagnosis and monitoring diabetes, especially type 1 diabetes. It is essential, therefore to determine the relationship between exhaled acetone concentration and glucose in blood. Usually, a direct linear correlation between this both compounds has been expected. However, in some cases we can observe a reverse correlation. When blood glucose was increasing, breath acetone declined. METHODS: The breath analysis as a supplementary tool for diagnosing and monitoring diabetes makes sense only in case of utilization of portable analyzers. This need has created a market for gas sensors. However, commercially available acetone gas sensors are developed for measuring samples at several tens part per million. The exhaled acetone concentration was measured using commercial acetone gas sensor (TGS 822, 823 Figaro, Arlington Heights, IL, USA Inc) with micropreconcentrator in low temperature cofired ceramics. The reference analyzer mass spectrometry (HPR-20 QIC, Hiden Analytical, Warrington, UK) was used. RESULTS: Twenty-two healthy volunteers with no history of any respiratory disease participated in the research, as did 31 patients diagnosed with type 1 diabetes. Respectively, 3 healthy volunteer and 5 type 1 diabetes mellitus subjects with reverse trend were selected. The linear fitting coefficient various from 0.1139 to 0.9573. Therefore, it is necessary to determine the correlation between blood glucose concentrations and under different conditions, for example, insulin levels, as well as correlate the results with clinical tests, for example, Hb1Ac. CONCLUSIONS: It is well known that the concentration of acetone is strongly influenced by diet, insulin treatment, and so on. Therefore, much more complex analysis with long-term measurements are required. Thus, presented results should be regarded as tentative, and validation studies with the analysis of clinical test and in a large number of patients, including control groups, need to be carried out. PMID- 25691654 TI - Relationship between Basal insulin requirement and body mass index in children and adults with type 1 diabetes on insulin pump therapy. PMID- 25691655 TI - Quality of HbA1c Measurement in the Practice: The German Perspective. AB - Hemoglobin A1c (HbA1c) measurement has come to be a cornerstone in modern diabetes therapy. However, the methodological aspects of this type of measurement have been given little attention lately due to its position as an established method of choice. Nevertheless, quite a number of issues face practical application, such as clinically relevant differences between different measurement methods--both lab-based and point-of-care (POCT) systems will show better or worse diabetes management results after switching methods; and there are a number of possible reasons that need to be known and observed in practice. The aim of this review is to draw attention to these problems from a German point of view and provide suggestions for appropriate measures to improve the situation. PMID- 25691656 TI - Physiologic Concepts That May Revise the Interpretation and Implications of HbA1C in Clinical Medicine: An American Perspective. AB - HbA1c, a routinely used integrated measure of glycemic control, is traditionally thought to be equivalent to mean blood glucose in hematologically normal individuals. Therefore, particularly as the methodology of measuring HbA1c has been standardized, clinical decisions dependent on mean blood glucose are often predominantly decided based on the interpretation of measured HbA1c. In this commentary, however, now that a more routine method of measuring red cell life span has been developed, we present evidence that the relationship between HbA1c and mean blood glucose is influenced by variation in red blood cell survival even in the hematologically normal. This variation has consequences for the appropriate interpretation of HbA1c in diverse clinical conditions such as the diagnosis of diabetes and management of diabetes in chronic kidney disease. PMID- 25691657 TI - Effects of 49 Different Rare Hb Variants on HbA1c Measurement in Eight Methods. AB - BACKGROUND: Previous studies have shown interference with HbA1c measurement from the 4 most common heterozygous Hb variants (HbAS, HbAE, HbAC, and HbAD) with some assay methods. Here we examine analytical interference from 49 different less common variants with 7 different HbA1c methods using various method principles. METHODS: Hb variants were screened using the Bio-Rad Variant or Variant II beta thal short program, confirmed by alkaline and acid electrophoresis, and identified by sequence analysis. The Trinity ultra2 boronate affinity high performance liquid chromatography (HPLC) method and Roche Tinaquant immunoassay were used as primary and secondary comparative methods, respectively, since these methods are least likely to show interference from Hb variants. Other methods included were the Tosoh G7 and G8, Bio-Rad D-10 and Variant II Turbo, Diazyme Enzymatic, and Sebia Capillarys 2 Flex Piercing. To eliminate any inherent calibration bias, results for each method were adjusted using regression verses the ultra2 with nonvariant samples. Each method's calibration-adjusted results were compared and judged to be acceptable if within the 99% prediction interval of the regression line for nonvariant samples. RESULTS: Almost all variant samples were recognized as such by the ion-exchange HPLC methods by the presence of abnormal peaks or results outside the reportable range. For most variants, interference was seen with 1 or more of the ion-exchange methods. Following manufacturer instructions for interpretation of chromatograms usually, but not always, prevented reporting of inaccurate results. RESULTS: Laboratories must be cautious about reporting results when the presence of a variant is suspected. PMID- 25691658 TI - YAP regulates the expression of Hoxa1 and Hoxc13 in mouse and human oral and skin epithelial tissues. AB - Yes-associated protein (YAP) is a Hippo signaling transcriptional coactivator that plays pivotal roles in stem cell proliferation, organ size control, and tumor development. The downstream targets of YAP have been shown to be highly context dependent. In this study, we used the embryonic mouse tooth germ as a tool to search for the downstream targets of YAP in ectoderm-derived tissues. Yap deficiency in the dental epithelium resulted in a small tooth germ with reduced epithelial cell proliferation. We compared the gene expression profiles of embryonic day 14.5 (E14.5) Yap conditional knockout and YAP transgenic mouse tooth germs using transcriptome sequencing (RNA-Seq) and further confirmed the differentially expressed genes using real-time PCR and in situ hybridization. We found that YAP regulates the expression of Hoxa1 and Hoxc13 in oral and dental epithelial tissues as well as in the epidermis of skin during embryonic and adult stages. Sphere formation assay suggested that Hoxa1 and Hoxc13 are functionally involved in YAP-regulated epithelial progenitor cell proliferation, and chromatin immunoprecipitation (ChIP) assay implies that YAP may regulate Hoxa1 and Hoxc13 expression through TEAD transcription factors. These results provide mechanistic insights into abnormal YAP activities in mice and humans. PMID- 25691659 TI - Characterization of BRD4 during mammalian postmeiotic sperm development. AB - During spermiogenesis, the postmeiotic phase of mammalian spermatogenesis, transcription is progressively repressed as nuclei of haploid spermatids are compacted through a dramatic chromatin reorganization involving hyperacetylation and replacement of most histones with protamines. Although BRDT functions in transcription and histone removal in spermatids, it is unknown whether other BET family proteins play a role. Immunofluorescence of spermatogenic cells revealed BRD4 in a ring around the nuclei of spermatids containing hyperacetylated histones. The ring lies directly adjacent to the acroplaxome, the cytoskeletal base of the acrosome, previously linked to chromatin reorganization. The BRD4 ring does not form in acrosomal mutant mice. Chromatin immunoprecipitation followed by sequencing in spermatids revealed enrichment of BRD4 and acetylated histones at the promoters of active genes. BRD4 and BRDT show distinct and synergistic binding patterns, with a pronounced enrichment of BRD4 at spermatogenesis-specific genes. Direct association of BRD4 with acetylated H4 decreases in late spermatids as acetylated histones are removed from the condensing nucleus in a wave following the progressing acrosome. These data provide evidence of a prominent transcriptional role for BRD4 and suggest a possible removal mechanism for chromatin components from the genome via the progressing acrosome as transcription is repressed and chromatin is compacted during spermiogenesis. PMID- 25691660 TI - ShcA regulates thymocyte proliferation through specific transcription factors and a c-Abl-dependent signaling axis. AB - Signaling via the pre-T-cell receptor (pre-TCR), along with associated signals from Notch and chemokine receptors, regulates the beta-selection checkpoint that operates on CD4(-) CD8(-) doubly negative (DN) thymocytes. Since many hematopoietic malignancies arise at the immature developmental stages of lymphocytes, understanding the signal integration and how specific signaling molecules and distal transcription factors regulate cellular outcomes is of importance. Here, a series of molecular and genetic approaches revealed that the ShcA adapter protein critically influences proliferation and differentiation during beta-selection. We found that ShcA functions downstream of the pre-TCR and p56(Lck) and show that ShcA is important for extracellular signal-regulated kinase (ERK)-dependent upregulation of transcription factors early growth factor 1 (Egr1) and Egr3 in immature thymocytes and, in turn, of the expression and function of the Id3 and E2A helix-loop-helix (HLH) proteins. ShcA also contributes to pre-TCR-mediated induction of c-Myc and additional cell cycle regulators. Moreover, using an unbiased Saccharomyces cerevisiae (yeast) screen, we identified c-Abl as a binding partner of phosphorylated ShcA and demonstrated the relevance of the ShcA-c-Abl interaction in immature thymocytes. Collectively, these data identify multiple modes by which ShcA can fine-tune the development of early thymocytes, including a previously unappreciated ShcA-c-Abl axis that regulates thymocyte proliferation. PMID- 25691661 TI - Local mitochondrial-endolysosomal microfusion cleaves voltage-dependent anion channel 1 to promote survival in hypoxia. AB - The oxygen-limiting (hypoxic) microenvironment of tumors induces metabolic reprogramming and cell survival, but the underlying mechanisms involving mitochondria remain poorly understood. We previously demonstrated that hypoxia inducible factor 1 mediates the hyperfusion of mitochondria by inducing Bcl 2/adenovirus E1B 19-kDa interacting protein 3 and posttranslational truncation of the mitochondrial ATP transporter outer membrane voltage-dependent anion channel 1 in hypoxic cells. In addition, we showed that truncation is associated with increased resistance to drug-induced apoptosis and is indicative of increased patient chemoresistance. We now show that silencing of the tumor suppressor TP53 decreases truncation and increases drug-induced apoptosis. We also show that TP53 regulates truncation through induction of the mitochondrial protein Mieap. While we found that truncation was independent of mitophagy, we observed local microfusion between mitochondria and endolysosomes in hypoxic cells in culture and in patients' tumor tissues. Since we found that the endolysosomal asparagine endopeptidase was responsible for truncation, we propose that it is a readout of mitochondrial-endolysosomal microfusion in hypoxia. These novel findings provide the framework for a better understanding of hypoxic cell metabolism and cell survival through mitochondrial-endolysosomal microfusion regulated by hypoxia inducible factor 1 and TP53. PMID- 25691662 TI - Casein kinase 1gamma ensures monopolar growth polarity under incomplete DNA replication downstream of Cds1 and calcineurin in fission yeast. AB - Cell polarity is essential for various cellular functions during both proliferative and developmental stages, and it displays dynamic alterations in response to intracellular and extracellular cues. However, the molecular mechanisms underlying spatiotemporal control of polarity transition are poorly understood. Here, we show that fission yeast Cki3 (a casein kinase 1gamma homolog) is a critical regulator to ensure persistent monopolar growth during S phase. Unlike the wild type, cki3 mutant cells undergo bipolar growth when S phase is blocked, a condition known to delay transition from monopolar to bipolar growth (termed NETO [new end takeoff]). Consistent with this role, Cki3 kinase activity is substantially increased, and cells lose their viability in the absence of Cki3 upon an S-phase block. Cki3 acts downstream of the checkpoint kinase Cds1/Chk2 and calcineurin, and the latter physically interacts with Cki3. Autophosphorylation in the C terminus is inhibitory toward Cki3 kinase activity, and calcineurin is responsible for its dephosphorylation. Cki3 localizes to the plasma membrane, and this localization requires the palmitoyltransferase complex Erf2-Erf4. Membrane localization is needed not only for proper NETO timing but also for Cki3 kinase activity. We propose that Cki3 acts as a critical inhibitor of cell polarity transition under S-phase arrest. PMID- 25691663 TI - Fission yeast Cdk7 controls gene expression through both its CAK and C-terminal domain kinase activities. AB - Cyclin-dependent kinase (Cdk) activation and RNA polymerase II transcription are linked by the Cdk7 kinase, which phosphorylates Cdks as a trimeric Cdk-activating kinase (CAK) complex, and serine 5 within the polymerase II (Pol II) C-terminal domain (CTD) as transcription factor TFIIH-bound CAK. However, the physiological importance of integrating these processes is not understood. Besides the Cdk7 ortholog Mcs6, fission yeast possesses a second CAK, Csk1. The two enzymes have been proposed to act redundantly to activate Cdc2. Using an improved analogue sensitive Mcs6-as kinase, we show that Csk1 is not a relevant CAK for Cdc2. Further analyses revealed that Csk1 lacks a 20-amino-acid sequence required for its budding yeast counterpart, Cak1, to bind Cdc2. Transcriptome profiling of the Mcs6-as mutant in the presence or absence of the budding yeast Cak1 kinase, in order to uncouple the CTD kinase and CAK activities of Mcs6, revealed an unanticipated role of the CAK branch in the transcriptional control of the cluster of genes implicated in ribosome biogenesis and cell growth. The analysis of a Cdc2 CAK site mutant confirmed these data. Our data show that the Cdk7 kinase modulates transcription through its well-described RNA Pol II CTD kinase activity and also through the Cdc2-activating kinase activity. PMID- 25691664 TI - Requisite role for Nck adaptors in cardiovascular development, endothelial-to mesenchymal transition, and directed cell migration. AB - Development of the cardiovascular system is critically dependent on the ability of endothelial cells (ECs) to reorganize their intracellular actin architecture to facilitate migration, adhesion, and morphogenesis. Nck family cytoskeletal adaptors function as key mediators of actin dynamics in numerous cell types, though their role in EC biology remains largely unexplored. Here, we demonstrate an essential requirement for Nck within ECs. Mouse embryos lacking endothelial Nck1/2 expression develop extensive angiogenic defects that result in lethality at about embryonic day 10. Mutant embryos show immature vascular networks, with decreased vessel branching, aberrant perivascular cell recruitment, and reduced cardiac trabeculation. Strikingly, embryos deficient in endothelial Nck also fail to undergo the endothelial-to-mesenchymal transition (EnMT) required for cardiac valve morphogenesis, with loss of Nck disrupting expression of major EnMT markers, as well as suppressing mesenchymal outgrowth. Furthermore, we show that Nck-null ECs are unable to migrate downstream of vascular endothelial growth factor and angiopoietin-1, and they exhibit profound perturbations in cytoskeletal patterning, with disorganized cellular projections, impaired focal adhesion turnover, and disrupted actin-based signaling. Our collective findings thereby reveal a crucial role for Nck as a master regulator within the endothelium to control actin cytoskeleton organization, vascular network remodeling, and EnMT during cardiovascular development. PMID- 25691665 TI - An autoregulatory pathway establishes the definitive chromatin conformation at the pit-1 locus. AB - The transcription factor Pit-1 (POU1-F1) plays a dominant role in cell lineage expansion and differentiation in the anterior pituitary. Prior studies of the mouse Pit-1 (mPit-1) gene revealed that this master regulatory locus is activated at embryonic day 13.5 (E13.5) by an early enhancer (EE), whereas its subsequent expression throughout adult life is maintained by a more distal definitive enhancer (DE). Here, we demonstrate that the sequential actions of these two enhancers are linked to corresponding shifts in their proximities to the Pit-1 promoter. We further demonstrate that the looping of the definitive enhancer to the mPit-1 promoter is critically dependent on a self-sustaining autoregulatory mechanism mediated by the Pit-1 protein. These Pit-1-dependent actions are accompanied by localized recruitment of CBP and enrichment for H3K27 acetylation within the Pit-1 locus. These data support a model in which the sequential actions of two developmentally activated enhancers are linked to a corresponding shift in higher-order chromatin structures. This shift establishes an autoregulatory circuit that maintains durable expression of Pit-1 throughout adult life. PMID- 25691666 TI - A reply to critics of Creation Ethics. PMID- 25691667 TI - How health-related quality-of-life outcomes in patients with acute promyelocytic leukemia can help physicians in decision making. PMID- 25691668 TI - Can money really be no object when cancer care is the subject? PMID- 25691669 TI - First- and second-line bevacizumab in addition to chemotherapy for metastatic colorectal cancer: a United States-based cost-effectiveness analysis. AB - PURPOSE: The addition of bevacizumab to fluorouracil-based chemotherapy is a standard of care for previously untreated metastatic colorectal cancer. Continuation of bevacizumab beyond progression is an accepted standard of care based on a 1.4-month increase in median overall survival observed in a randomized trial. No United States-based cost-effectiveness modeling analyses are currently available addressing the use of bevacizumab in metastatic colorectal cancer. Our objective was to determine the cost effectiveness of bevacizumab in the first line setting and when continued beyond progression from the perspective of US payers. METHODS: We developed two Markov models to compare the cost and effectiveness of fluorouracil, leucovorin, and oxaliplatin with or without bevacizumab in the first-line treatment and subsequent fluorouracil, leucovorin, and irinotecan with or without bevacizumab in the second-line treatment of metastatic colorectal cancer. Model robustness was addressed by univariable and probabilistic sensitivity analyses. Health outcomes were measured in life-years and quality-adjusted life-years (QALYs). RESULTS: Using bevacizumab in first-line therapy provided an additional 0.10 QALYs (0.14 life-years) at a cost of $59,361. The incremental cost-effectiveness ratio was $571,240 per QALY. Continuing bevacizumab beyond progression provided an additional 0.11 QALYs (0.16 life years) at a cost of $39,209. The incremental cost-effectiveness ratio was $364,083 per QALY. In univariable sensitivity analyses, the variables with the greatest influence on the incremental cost-effectiveness ratio were bevacizumab cost, overall survival, and utility. CONCLUSION: Bevacizumab provides minimal incremental benefit at high incremental cost per QALY in both the first- and second-line settings of metastatic colorectal cancer treatment. PMID- 25691670 TI - Household net worth, racial disparities, and hormonal therapy adherence among women with early-stage breast cancer. AB - PURPOSE: Nonadherence to adjuvant hormonal therapy is common and is associated with increased prescription copayment amount and black race. Studies suggest that household wealth may partly explain racial disparities. We investigated the impact of net worth on disparities in adherence and discontinuation. PATIENTS AND METHODS: We used the OptumInsight insurance claims database to identify women older than age 50 years diagnosed with early breast cancer, from January 1, 2007, to December 31, 2011, who were using hormonal therapy. Nonadherence was defined as a medication possession ratio of <= 80% of eligible days over a 2-year period. We evaluated the association of demographic and clinical characteristics, annual household income, household net worth (< $250,000, $250,000 to $750,000, or > $750,000), insurance type, and copayments (< $10, $10 to $20, or > $20) with adherence to hormonal therapy. Logistic regression analyses were conducted by sequentially adding sociodemographic and financial variables to race. RESULTS: We identified 10,302 patients; 2,473 (24%) were nonadherent. In the unadjusted analyses, adherence was negatively associated with black race (odds ratio [OR], 0.76; P < .001), advanced age, comorbidity, and Medicare insurance. Adherence was positively associated with medium (OR, 1.33; P < .001) and high (OR, 1.66; P < .001) compared with low net worth. The negative association of black race with adherence (OR, 0.76) was reduced by adding net worth to the model (OR, 0.84; P < .05). Correcting for other variables had a minimal impact on the association between race and adherence (OR, 0.87; P = .08). The interaction between net worth and race was significant (P < .01). CONCLUSION: We found that net worth partially explains racial disparities in hormonal therapy adherence. These results suggest that economic factors may contribute to disparities in the quality of care. PMID- 25691671 TI - Phase III trial evaluating the addition of bevacizumab to endocrine therapy as first-line treatment for advanced breast cancer: the letrozole/fulvestrant and avastin (LEA) study. AB - PURPOSE: To test whether combining bevacizumab, an anti-vascular endothelial growth factor treatment, with endocrine therapy (ET) could potentially delay the emergence of resistance to ET. PATIENTS AND METHODS: A multicenter, randomized, open-label, phase III, binational (Spain and Germany) study added bevacizumab (15 mg/kg every 3 weeks) to ET (ET-B; letrozole or fulvestrant) as first-line therapy in postmenopausal patients with human epidermal growth factor receptor 2 (HER2) negative and hormone receptor-positive advanced breast cancer. We compared progression-free survival (PFS), overall survival (OS), overall response rate (ORR), response duration (RD), time to treatment failure (TTF), clinical benefit rate (CBR), and safety. RESULTS: From 380 patients recruited (2007 to 2011), 374 were analyzed by intent to-treat (184 patients on ET and 190 patients on ET-B). Median age was 65 years, 270 patients (72%) had Eastern Cooperative Oncology Group performance status of 0, 178 patients (48%) had visceral metastases, and 171 patients (46%) and 195 patients (52%) had received prior chemotherapy or ET, respectively. Median PFS was 14.4 months in the ET arm and 19.3 months in the ET B arm (hazard ratio, 0.83; 95% CI, 0.65 to 1.06; P = .126). ORR, CBR, and RD with ET versus ET-B were 22% versus 41% (P < .001), 67% versus 77% (P = .041), and 13.3 months versus 17.6 months (P = .434), respectively. TTF and OS were comparable in both arms. Grade 3 to 4 hypertension, aminotransferase elevation, and proteinuria were significantly higher in the ET-B arm. Eight patients (4.2%) receiving ET-B died during study or within 30 days of end of treatment. CONCLUSION: The addition of bevacizumab to ET in first-line treatment failed to produce a statistically significant increase in PFS or OS in women with HER2 negative/hormone receptor-positive advanced breast cancer. PMID- 25691672 TI - Diagnostic medical radiation exposure in surveillance of aggressive lymphoma: clinical trial design should reflect clinical practice. PMID- 25691673 TI - Quantitative positron emission tomography imaging for response assessment of [18F]fluorodeoxyglucose-avid lymphomas: should we report standard uptake value confidence limits? PMID- 25691674 TI - Will targeting Chk1 have a role in the future of cancer therapy? PMID- 25691675 TI - Do not abandon the bone marrow biopsy yet in diffuse large B-cell lymphoma. PMID- 25691676 TI - Value of positron emission tomography in diagnosing subcutaneous panniculitis like T-cell lymphoma. PMID- 25691677 TI - Final Report of the Intergroup Randomized Study of Combined Androgen-Deprivation Therapy Plus Radiotherapy Versus Androgen-Deprivation Therapy Alone in Locally Advanced Prostate Cancer. AB - PURPOSE: We have previously reported that radiotherapy (RT) added to androgen deprivation therapy (ADT) improves survival in men with locally advanced prostate cancer. Here, we report the prespecified final analysis of this randomized trial. PATIENTS AND METHODS: NCIC Clinical Trials Group PR.3/Medical Research Council PR07/Intergroup T94-0110 was a randomized controlled trial of patients with locally advanced prostate cancer. Patients with T3-4, N0/Nx, M0 prostate cancer or T1-2 disease with either prostate-specific antigen (PSA) of more than 40 MUg/L or PSA of 20 to 40 MUg/L plus Gleason score of 8 to 10 were randomly assigned to lifelong ADT alone or to ADT+RT. The RT dose was 64 to 69 Gy in 35 to 39 fractions to the prostate and pelvis or prostate alone. Overall survival was compared using a log-rank test stratified for prespecified variables. RESULTS: One thousand two hundred five patients were randomly assigned between 1995 and 2005, 602 to ADT alone and 603 to ADT+RT. At a median follow-up time of 8 years, 465 patients had died, including 199 patients from prostate cancer. Overall survival was significantly improved in the patients allocated to ADT+RT (hazard ratio [HR], 0.70; 95% CI, 0.57 to 0.85; P < .001). Deaths from prostate cancer were significantly reduced by the addition of RT to ADT (HR, 0.46; 95% CI, 0.34 to 0.61; P < .001). Patients on ADT+RT reported a higher frequency of adverse events related to bowel toxicity, but only two of 589 patients had grade 3 or greater diarrhea at 24 months after RT. CONCLUSION: This analysis demonstrates that the previously reported benefit in survival is maintained at a median follow up of 8 years and firmly establishes the role of RT in the treatment of men with locally advanced prostate cancer. PMID- 25691678 TI - Reply to B. Bennani-Baiti et al, H.J.A. Adams et al, E. Laffon et al, and E.A. Hawkes et al. PMID- 25691679 TI - Disparities in castration-resistant prostate cancer trials. PMID- 25691680 TI - Reply to M. Koehler et al. PMID- 25691681 TI - Long-term effects of the iron-based phosphate binder, sucroferric oxyhydroxide, in dialysis patients. AB - BACKGROUND: Hyperphosphatemia necessitates the use of phosphate binders in most dialysis patients. Long-term efficacy and tolerability of the iron-based phosphate binder, sucroferric oxyhydroxide (previously known as PA21), was compared with that of sevelamer carbonate (sevelamer) in an open-label Phase III extension study. METHODS: In the initial Phase III study, hemo- or peritoneal dialysis patients with hyperphosphatemia were randomized 2:1 to receive sucroferric oxyhydroxide 1.0-3.0 g/day (2-6 tablets/day; n = 710) or sevelamer 2.4-14.4 g/day (3-18 tablets/day; n = 349) for 24 weeks. Eligible patients could enter the 28-week extension study, continuing the same treatment and dose they were receiving at the end of the initial study. RESULTS: Overall, 644 patients were available for efficacy analysis (n = 384 sucroferric oxyhydroxide; n = 260 sevelamer). Serum phosphorus concentrations were maintained during the extension study. Mean +/- standard deviation (SD) change in serum phosphorus concentrations from extension study baseline to Week 52 end point was 0.02 +/- 0.52 mmol/L with sucroferric oxyhydroxide and 0.09 +/- 0.58 mmol/L with sevelamer. Mean serum phosphorus concentrations remained within Kidney Disease Outcomes Quality Initiative target range (1.13-1.78 mmol/L) for both treatment groups. Mean (SD) daily tablet number over the 28-week extension study was lower for sucroferric oxyhydroxide (4.0 +/- 1.5) versus sevelamer (10.1 +/- 6.6). Patient adherence was 86.2% with sucroferric oxyhydroxide versus 76.9% with sevelamer. Mean serum ferritin concentrations increased over the extension study in both treatment groups, but transferrin saturation (TSAT), iron and hemoglobin concentrations were generally stable. Gastrointestinal-related adverse events were similar and occurred early with both treatments, but decreased over time. CONCLUSIONS: The serum phosphorus-lowering effect of sucroferric oxyhydroxide was maintained over 1 year and associated with a lower pill burden, compared with sevelamer. Sucroferric oxyhydroxide was generally well tolerated long-term and there was no evidence of iron accumulation. PMID- 25691683 TI - Somatic mutations and atrial fibrillation: the end or just the beginning? PMID- 25691684 TI - Association between shortened leukocyte telomere length and cardio-metabolic outcomes. PMID- 25691685 TI - Biomarker discovery: searching for quality in quantity. PMID- 25691686 TI - Common and rare variants in SCN10A modulate the risk of atrial fibrillation. AB - BACKGROUND: Genome-wide association studies have shown that the common single nucleotide polymorphism rs6800541 located in SCN10A, encoding the voltage-gated Nav1.8 sodium channel, is associated with PR-interval prolongation and atrial fibrillation (AF). Single nucleotide polymorphism rs6800541 is in high linkage disequilibrium with the nonsynonymous variant in SCN10A, rs6795970 (V1073A, r(2)=0.933). We therefore sought to determine whether common and rare SCN10A variants are associated with early onset AF. METHODS AND RESULTS: SCN10A was sequenced in 225 AF patients in whom there was no evidence of other cardiovascular disease or dysfunction (lone AF). In an association study of the rs6795970 single nucleotide polymorphism variant, we included 515 AF patients and 2 control cohorts of 730 individuals free of AF and 6161 randomly sampled individuals. Functional characterization of SCN10A variants was performed by whole-cell patch-clamping. In the lone AF cohort, 9 rare missense variants and 1 splice site donor variant were detected. Interestingly, AF patients were found to have higher G allele frequency of rs6795970, which encodes the alanine variant at position 1073 (described from here on as A1073, odds ratio =1.35 [1.16-1.54]; P=2.3*10(-5)). Both of the common variants, A1073 and P1092, induced a gain-of channel function, whereas the rare missense variants, V94G and R1588Q, resulted in a loss-of-channel function. CONCLUSIONS: The common variant A1073 is associated with increased susceptibility to AF. Both rare and common variants have effect on the function of the channel, indicating that these variants influence susceptibility to AF. Hence, our study suggests that SCN10A variations are involved in the genesis of AF. PMID- 25691687 TI - Challenges of exercise recommendations and sports participation in genetic heart disease patients. PMID- 25691689 TI - Quantitative serum nuclear magnetic resonance metabolomics in cardiovascular epidemiology and genetics. AB - Metabolomics is becoming common in epidemiology due to recent developments in quantitative profiling technologies and appealing results from their applications for understanding health and disease. Our team has developed an automated high throughput serum NMR metabolomics platform that provides quantitative molecular data on 14 lipoprotein subclasses, their lipid concentrations and composition, apolipoprotein A-I and B, multiple cholesterol and triglyceride measures, albumin, various fatty acids as well as on numerous low-molecular-weight metabolites, including amino acids, glycolysis related measures and ketone bodies. The molar concentrations of these measures are obtained from a single serum sample with costs comparable to standard lipid measurements. We have analyzed almost 250 000 samples from around 100 epidemiological cohorts and biobanks and the new international set-up of multiple platforms will allow an annual throughput of more than 250 000 samples. The molecular data have been used to study type 1 and type 2 diabetes etiology as well as to characterize the molecular reflections of the metabolic syndrome, long-term physical activity, diet and lipoprotein metabolism. The results have revealed new biomarkers for early atherosclerosis, type 2 diabetes, diabetic nephropathy, cardiovascular disease and all-cause mortality. We have also combined genomics and metabolomics in diverse studies. We envision that quantitative high-throughput NMR metabolomics will be incorporated as a routine in large biobanks; this would make perfect sense both from the biological research and cost point of view - the standard output of over 200 molecular measures would vastly extend the relevance of the sample collections and make many separate clinical chemistry assays redundant. PMID- 25691688 TI - Does our gut microbiome predict cardiovascular risk? A review of the evidence from metabolomics. AB - Millions of microbes are found in the human gut, and are collectively referred as the gut microbiota. Recent studies have estimated that the microbiota genome contains 100-fold more genes than the host genome. These microbiota contribute to digestion by processing energy substrates unutilized by the host, with about half of the total genome of the gut microbiota being related to central carbon and amino acid metabolism as well as the biosynthesis of secondary metabolites. Therefore, the gut microbiome and its interaction with the host influences many aspects of health and disease, including the composition of biofluids such as urine and blood plasma. Metabolomics is uniquely suited to capture these functional host-microbe interactions. This review aims at providing an overview of recent metabolomics evidence of gut microbiota-host metabolic interactions with a specific focus on cardiovascular disease and related aspects of the metabolic syndrome. Furthermore, the emphasis is given on the complexities of translating these metabolite signatures as potential clinical biomarkers, as the composition and activity of gut microbiome change with many factors, particularly with diet, with special reference to trimethylamine-oxide. PMID- 25691690 TI - Top advances in functional genomics and translational biology for 2014. PMID- 25691691 TI - Cardiac regeneration: harnessing the power within. PMID- 25691692 TI - Long noncoding Mhrt RNA: molecular crowbar unravel insights into heart failure treatment. PMID- 25691693 TI - Changes in the EGFR amplification and EGFRvIII expression between paired primary and recurrent glioblastomas. AB - BACKGROUND: The efficacy of novel targeted therapies is often tested at the time of tumor recurrence. However, for glioblastoma (GBM) patients, surgical resections at recurrence are performed only in a minority of patients; therefore, molecular data are predominantly derived from the initial tumor. Molecular data of the initial tumor for patient selection into personalized medicine trials can therefore be used only when the specific genetic change is retained in the recurrent tumor. METHODS: In this study we determined whether EGFR amplification and expression of the most common mutation in GBMs (EGFRvIII) is retained at tumor recurrence. Because retention of genetic changes may be dependent on the initial treatment, we only used a cohort of GBM samples that were uniformly treated according to the current standard of care (ie, chemo-irradiation with temozolomide). RESULTS: Our data show that, in spite of some quantitative differences, the EGFR amplification status remains stable in the majority (84%) of tumors evaluated. EGFRvIII expression remained similar in 79% of GBMs. However, within the tumors expressing EGFRvIII at initial diagnosis, approximately one-half lose their EGFRvIII expression at tumor recurrence. CONCLUSIONS: The relative stability of EGFR amplification indicates that molecular data obtained in the primary tumor can be used to predict the EGFR status of the recurrent tumor, but care should be taken in extrapolating EGFRvIII expression from the primary tumor, particularly when expressed at first diagnosis. PMID- 25691694 TI - Endovascular treatment of jugular bulb diverticula causing debilitating pulsatile tinnitus. AB - We describe the case of a patient who presented with debilitating pulsatile tinnitus in association with two jugular bulb diverticula. The diverticula were treated with stenting of the jugular bulb and coil embolization of the diverticula over two procedures. This resulted in successful resolution of symptoms and at 10 months follow-up the patient is asymptomatic. The technique is discussed with regard to similar published cases and surrogate measures of safety taken from the literature pertaining to idiopathic intracranial hypertension. PMID- 25691695 TI - Reversible changes in diffusion- and perfusion-based imaging in cerebral venous sinus thrombosis. AB - Diffusion- and perfusion-based imaging studies are regularly used in patients with ischemic stroke. Cerebral venous sinus thrombosis (CVST) is a rare cause of stroke and is primarily treated by systemic anticoagulation. Endovascular intervention can be considered in cases of failed medical therapy, yet the prognostic value of diffusion- and perfusion-based imaging for CVST has not been clearly established. We present a patient with CVST whose abnormal findings on MRI and CT perfusion images were largely reversed after endovascular treatment. PMID- 25691697 TI - Ergodic theorem, ergodic theory, and statistical mechanics. AB - This perspective highlights the mean ergodic theorem established by John von Neumann and the pointwise ergodic theorem established by George Birkhoff, proofs of which were published nearly simultaneously in PNAS in 1931 and 1932. These theorems were of great significance both in mathematics and in statistical mechanics. In statistical mechanics they provided a key insight into a 60-y-old fundamental problem of the subject--namely, the rationale for the hypothesis that time averages can be set equal to phase averages. The evolution of this problem is traced from the origins of statistical mechanics and Boltzman's ergodic hypothesis to the Ehrenfests' quasi-ergodic hypothesis, and then to the ergodic theorems. We discuss communications between von Neumann and Birkhoff in the Fall of 1931 leading up to the publication of these papers and related issues of priority. These ergodic theorems initiated a new field of mathematical-research called ergodic theory that has thrived ever since, and we discuss some of recent developments in ergodic theory that are relevant for statistical mechanics. PMID- 25691696 TI - Short-term effects of particulate matter on mortality during forest fires in Southern Europe: results of the MED-PARTICLES Project. AB - BACKGROUND: An association between occurrence of wildfires and mortality in the exposed population has been observed in several studies with controversial results for cause-specific mortality. In the Mediterranean area, forest fires usually occur during spring-summer, they overlap with Saharan outbreaks, are associated with increased temperature and their health effects are probably due to an increase in particulate matter. AIM AND METHODS: We analysed the effects of wildfires and particulate matter (PM10) on mortality in 10 southern European cities in Spain, France, Italy and Greece (2003-2010), using satellite data for exposure assessment and Poisson regression models, simulating a case-crossover approach. RESULTS: We found that smoky days were associated with increased cardiovascular mortality (lag 0-5, 6.29%, 95% CIs 1.00 to 11.85). When the effect of PM10 (per 10 ug/m(3)) was evaluated, there was an increase in natural mortality (0.49%), cardiovascular mortality (0.65%) and respiratory mortality (2.13%) on smoke-free days, but PM10-related mortality was higher on smoky days (natural mortality up to 1.10% and respiratory mortality up to 3.90%) with a suggestion of effect modification for cardiovascular mortality (3.42%, p value for effect modification 0.055), controlling for Saharan dust advections. CONCLUSIONS: Smoke is associated with increased cardiovascular mortality in urban residents, and PM10 on smoky days has a larger effect on cardiovascular and respiratory mortality than on other days. PMID- 25691698 TI - Opinion: Addressing systemic problems in the biomedical research enterprise. PMID- 25691699 TI - Core concept: Ergodic theory plays a key role in multiple fields. PMID- 25691701 TI - Analysis of gene-environment interactions in postnatal development of the mammalian intestine. AB - Unlike mammalian embryogenesis, which takes place in the relatively predictable and stable environment of the uterus, postnatal development can be affected by a multitude of highly variable environmental factors, including diet, exposure to noxious substances, and microorganisms. Microbial colonization of the intestine is thought to play a particularly important role in postnatal development of the gastrointestinal, metabolic, and immune systems. Major changes in environmental exposure occur right after birth, upon weaning, and during pubertal maturation into adulthood. These transitions include dramatic changes in intestinal contents and require appropriate adaptations to meet changes in functional demands. Here, we attempt to both characterize and provide mechanistic insights into postnatal intestinal ontogeny. We investigated changes in global intestinal gene expression through postnatal developmental transitions. We report profound alterations in small and large intestinal transcriptional programs that accompany both weaning and puberty in WT mice. Using myeloid differentiation factor 88 (MyD88)/TIR domain-containing adapter-inducing interferon-beta (TRIF) double knockout littermates, we define the role of toll-like receptors (TLRs) and interleukin (IL)-1 receptor family member signaling in postnatal gene expression programs and select ontogeny-specific phenotypes, such as vascular and smooth muscle development and neonatal epithelial and mast cell homeostasis. Metaanalysis of the effect of the microbiota on intestinal gene expression allowed for mechanistic classification of developmentally regulated genes by TLR/IL-1R (TIR) signaling and/or indigenous microbes. We find that practically every aspect of intestinal physiology is affected by postnatal transitions. Developmental timing, microbial colonization, and TIR signaling seem to play distinct and specific roles in regulation of gene-expression programs throughout postnatal development. PMID- 25691702 TI - How low should we go? Hypothermia or strict normothermia after cardiac arrest? PMID- 25691703 TI - Extracorporeal membrane oxygenation in adults with cardiogenic shock. PMID- 25691705 TI - Structural valve deterioration 4 years after transcatheter aortic valve replacement: imaging and pathohistological findings. PMID- 25691706 TI - Intravascular ultrasound observation of an obstruction of the left main coronary artery caused by displaced leaflet calcification and hematoma after transcatheter aortic valve implantation. PMID- 25691707 TI - Letter by Reed et al regarding article, "Proteomic analysis implicates translationally controlled tumor protein as a novel mediator of occlusive vascular remodeling in pulmonary arterial hypertension". PMID- 25691708 TI - Letter by Monfredi et al regarding article, "Physical activity and heart rate variability in older adults: the cardiovascular health study". PMID- 25691709 TI - Response to letter regarding article, "physical activity and heart rate variability in older adults: the cardiovascular health study". PMID- 25691711 TI - Correction. PMID- 25691710 TI - Expression of concern. PMID- 25691712 TI - Population-wide trends in aortic stenosis incidence and outcomes. PMID- 25691713 TI - Materials in Manufacturing and Packaging Systems as Sources of Elemental Impurities in Packaged Drug Products: A Literature Review. AB - : Elemental impurities in drug products can arise from a number of different sources and via a number of different means, including the active pharmaceutical ingredient, excipients, the vehicle, and leaching of elemental entities that are present in the drug product's manufacturing or packaging systems. Thus, knowledge about the presence, level, and likelihood of leaching of elemental entities in manufacturing and packaging systems is relevant to understanding how these systems contribute to a drug product's total elemental impurity burden. To that end, a joint team from the Extractables and Leachables Safety Information Exchange (ELSIE) Consortium and the International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS) has conducted a review of the available literature on elemental entities in pharmaceutically relevant polymers and the presence of these elemental entities in material extracts and/or drug products. This review article contains the information compiled from the available body of literature and considers two questions: (1) What elemental entities are present in the relevant polymers and materials and at what levels are they present? (2) To what extent are these elemental entities leached from these materials under conditions relevant to the manufacturing and storage/distribution of solution drug products? Conclusions drawn from the compiled data are as follows: (1) Elemental entities are present in the materials used to construct packaging and manufacturing systems as these materials either contain these elemental entities as additives or are exposed to elemental entities during their production. (2) Unless the elemental entities are parts of the materials themselves (for example, SiO2 in glass) or intentionally added to the materials (for example, metal stearates in polymers), their incidental amounts in the materials are generally low. (3) When elemental entities are present in materials and systems, generally only a very small fraction of the total available amount of the entity can be leached under conditions that are relevant to packaged drug products. Thus, while sources of certain elemental impurities may be ubiquitous in the natural environment, they are not ubiquitous in materials used in pharmaceutical packaging and manufacturing systems and when they are present, they are not extensively leached under relevant conditions. The information summarized here can be utilized to aid the elemental impurity risk assessment process by providing the identities of commonly reported elements and data to support probability estimates of those becoming elemental impurities in the drug product. Furthermore, recommendations are made related to establishing elements of potential product impact for individual materials. LAY ABSTRACT: Extraneous impurities in drug products provide no therapeutic benefit and thus should be known and controlled. Elemental impurities can arise from a number of sources and by a number of means, including the leaching of elemental entities from drug product packaging and manufacturing systems. To understand the extent to which materials used in packaging systems contain elemental entities and the extent to which those entities leach into drug products to become elemental impurities, the Extractables and Leachables Safety Information Exchange (ELSIE) and International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS) Consortia have jointly performed a literature review on this subject. Using the compiled information, it was concluded that while packaging materials may contain elemental entities, unless those entities are intentional parts of the materials, the amounts of those elemental entities are generally low. Furthermore, generally only a very small fraction of the total available amount of the entity can be leached under conditions that are relevant to packaged drug products. Thus, risk assessment of sources of elemental impurities in drug products that may be related to materials used in pharmaceutical packaging and manufacturing systems can utilize the information and recommendations presented here. PMID- 25691714 TI - Extractables analysis of single-use flexible plastic biocontainers. AB - Studies of the extractable profiles of bioprocessing components have become an integral part of drug development efforts to minimize possible compromise in process performance, decrease in drug product quality, and potential safety risk to patients due to the possibility of small molecules leaching out from the components. In this study, an effective extraction solvent system was developed to evaluate the organic extractable profiles of single-use bioprocess equipment, which has been gaining increasing popularity in the biopharmaceutical industry because of the many advantages over the traditional stainless steel-based bioreactors and other fluid mixing and storage vessels. The chosen extraction conditions were intended to represent aggressive conditions relative to the application of single-use bags in biopharmaceutical manufacture, in which aqueous based systems are largely utilized. Those extraction conditions, along with a non targeted analytical strategy, allowed for the generation and identification of an array of extractable compounds; a total of 53 organic compounds were identified from four types of commercially available single-use bags, the majority of which are degradation products of polymer additives. The success of this overall extractables analysis strategy was reflected partially by the effectiveness in the extraction and identification of a compound that was later found to be highly detrimental to mammalian cell growth. LAY ABSTRACT: The usage of single-use bioreactors has been increasing in biopharmaceutical industry because of the appealing advantages that it promises regarding to the cleaning, sterilization, operational flexibility, and so on, during manufacturing of biologics. However, compared to its conventional counterparts based mainly on stainless steel, single use bioreactors are more susceptible to potential problems associated with compound leaching into the bioprocessing fluid. As a result, extractable profiling of the single-use system has become essential in the qualification of such systems for its use in drug manufacturing. The aim of this study is to evaluate the effectiveness of an extraction solvent system developed to study the extraction profile of single-use bioreactors in which aqueous-based systems are largely used. The results showed that with a non-targeted analytical approach, the extraction solvent allowed the generation and identification of an array of extractable compounds from four commercially available single-use bioreactors. Most of extractables are degradation products of polymer additives, among which was a compound that was later found to be highly detrimental to mammalian cell growth. PMID- 25691715 TI - Manufacturing of High-Concentration Monoclonal Antibody Formulations via Spray Drying-the Road to Manufacturing Scale. AB - Spray-dried monoclonal antibody (mAb) powders may offer applications more versatile than the freeze-dried cake, including preparing high-concentration formulations for subcutaneous administration. Published studies on this topic, however, are generally scarce. This study evaluates a pilot-scale spray dryer against a laboratory-scale dryer to spray-dry multiple mAbs in consideration of scale-up, impact on mAb stability, and feasibility of a high-concentration preparation. Under similar conditions, both dryers produced powders of similar properties-for example, water content, particle size and morphology, and mAb stability profile-despite a 4-fold faster output by the pilot-scale unit. All formulations containing arginine salt or a combination of arginine salt and trehalose were able to be spray-dried with high powder collection efficiency (>95%), but yield was adversely affected in formulations with high trehalose content due to powder sticking to the drying chamber. Spray-drying production output was dictated by the size of the dryer operated at an optimal liquid feed rate. Spray-dried powders could be reconstituted to high-viscosity liquids, >300 cP, substantially beyond what an ultrafiltration process can achieve. The molar ratio of trehalose to mAb needed to be reduced to 50:1 in consideration of isotonicity of the formulation with mAb concentration at 250 mg/mL. Even with this low level of sugar protection, long-term stability of spray-dried formulations remained superior to their liquid counterparts based on size variant and potency data. This study offers a commercially viable spray-drying process for biological bulk storage and an option for high-concentration mAb manufacturing. LAY ABSTRACT: This study evaluates a pilot-scale spray dryer against a laboratory-scale dryer to spray-dry multiple monoclonal antibodies (mAbs) from the perspective of scale-up, impact on mAb stability, and feasibility of a high-concentration preparation. The data demonstrated that there is no process limitation in solution viscosity when high-concentration mAb formulations are prepared from spray-dried powder reconstitution compared with concentration via the conventional ultrafiltration process. This study offers a commercially viable spray-drying process for biological bulk storage and a high-concentration mAb manufacturing option for subcutaneous administration. The outcomes of this study will benefit scientists and engineers who develop high-concentration mAb products by providing a viable manufacturing alternative. PMID- 25691716 TI - Scale-up of Sterilizing-grade Membrane Filters from Discs to Pleated Cartridges: Effects of Operating Parameters and Solution Properties. AB - For direct flow sterilizing-grade filtration, a linear scale-up between the performance of discs and pleated filter cartridges has traditionally been assumed. Linear scale-up assumes that the filtration performances, defined here as filter flux and capacity, scale linearly with the membrane area and remains independent of the selected device formats. However, experimental results show that the later assumption does not hold in all cases. In this article, we investigated the effect of solution properties and operating parameters on scale up with both fouling and non-fouling feeds. For non-fouling solutions, such as buffers, the flux ratio, defined as alpha, between pleated filter cartridges and disc filters range from 0.5 to 0.85. For complex fouling feeds, such as protein or cell culture media solutions, the ratio of initial flux between pleated filter cartridges and discs was the same as the flux ratio, alpha. For fouling solutions, the ratio of filtration capacity between pleated cartridges and discs, referred to as capacity ratio, beta, was variable. We found that beta was sensitive to the particle size distribution of the challenge solution and the mode of filtration operation (constant pressure or constant flux), whereas it was less sensitive to the magnitude of the operating pressure or flux and concentration of the fouling species. For most conditions tested, beta among pleated cartridges and discs was within +/-20% variation of unity. At the end, we present a modified standard model that accounts for both variations in flux ratio, alpha, as well as capacity ratios, beta, for estimating the requirement for membrane area at manufacturing scale with proteinacious fouling and non protein/non-fouling feeds. The data show that for cases where filtration is capacity controlled, flux ratios between the pleated filter and disc are not critical. For such cases, the use of a high-area laid-over pleated cartridge construction allows for reducing the number of 10 inch pleated filter cartridges required to process the batch volume. LAY ABSTRACT: Scale-up remains at the core of a process development. For direct flow sterilizing-grade filtration, a linear scale-up between the performance of discs and pleated filter cartridges has traditionally been assumed. Linear scale-up assumes that the filtration performances, defined here as filter flux and capacity, scale linearly with the membrane area and remains independent of the selected device formats. However, experimental results show that the later assumption does not hold in all cases. We investigated the effect of solution properties and operating parameters on scale-up from membrane disc to pleated filter cartridges. Typical values of flux and capacity ratios and the guidelines on scale-up of direct flow filters from bench-scale to manufacturing-scale are presented. Specifically, we found that the flux ratio for pleated filter and small-scale disc range from 0.5 to 0.85, and capacity ratio for most cases is within +/-20% variation of unity, with some exceptions. PMID- 25691717 TI - A strategy for the prevention of protein oxidation by drug product in polymer based syringes. AB - Recently, new and advanced ideas have been presented on the value of polymer based syringes for improved safety, better strength, reduced aggregation, and the prevention of drug degradation. In this report, our findings on drug degradation from protein oxidation will be presented and discussed. Commonly, dissolved oxygen is one of the factors for causing protein degradation. Due to the nature of higher gas permeability in polymer-based syringes, it was thought to be difficult to control the oxygen level during storage. However, this report demonstrates the appropriateness of combining the use of an oxygen absorber within the secondary packaging as a deoxygenated packaging system. In addition, this report suggests that another factor to enhance protein oxidization is related to radicals on the syringe barrel from sterilization by irradiation. We demonstrate that steam sterilization can minimize protein oxidization, as the protein filled in steam sterilized syringe is much more stable. In conclusion, the main oxidation pathway of a protein has been identified as dissolved oxygen and radical generation within a polymer container. Possible solutions are herewith presented for controlling oxidation by means of applying a deoxygenated packaging system as well as utilizing steam sterilization as a method of sterilization for prefillable polymer syringes. LAY ABSTRACT: There have been many presentations and discussions about the risks associated with glass prefilled syringes. Advanced ideas are being presented on the value of polymer based syringes for improved safety, better strength, reduced protein aggregation, and the prevention of drug degradation. Drug degradation based on protein oxidation is discussed in this report. Identification of the main factors causing this degradation and possible solutions available by using polymer-based syringes will be presented. The causes of protein oxidation have been identified as dissolved oxygen and radicals generated by the applied method of sterilization. The oxidation reaction created by dissolved oxygen within the drug product can be effectively inhibited by controlling the removal of the oxygen through the use of a deoxygenated packaging system. This packaging system can control the level or complete removal of oxygen from the primary container and the secondary packaging system. Protein oxidation induced by the formation of radicals from sterilization by irradiation is another critical aspect where it was thought that various sterilization methods were acceptable without loosing drug product quality. However, this report is first to demonstrate that gamma sterilized polymer-based syringes accelerated protein oxidation by radical generation; this effect can be prevented by means of steam sterilization. PMID- 25691718 TI - Implementation of a high-throughput ion chromatographic assay to assess glass degradation in drug product formulations. AB - The primary container for parenterals is usually composed of glass. Given the recent industry-wide spike in glass-related problems, assays capable of detecting glass degradation before glass-related particles are visible in solution have practical significance. A rapid, high-throughput ion chromatography method coupled with molybdate reaction is described here for detection and quantitation of silicic acid (soluble form of silica) in complex samples. The method involves ion exchange separation of the silicate anion at high pH followed by a post column derivatization step with sodium molybdate reagent. The resulting molybdo silicate complex is detected with high sensitivity in the visible wavelength range at 410 nm and correlates to the level of soluble silica in solution. This assay is high-throughput and amenable for implementation during the early phase of product development. The assay provides a direct measurement to assess potential incompatibility between the formulation and its glass container. The Si levels measured by this method showed a direct correlation to the vial surface morphology changes as monitored by differential interference contrast microscopy. LAY ABSTRACT: Recently, the pharmaceutical industry has been faced with glass quality challenges that have resulted in many products being recalled from the market. Monitoring levels of soluble silica in solution is critical because silica is the primary component of glass containers used in the pharmaceutical industry. Given this recent industry-wide increase in glass-related problems, assays capable of detecting glass degradation before glass-related particles are visible in solution have practical significance. A rapid assay to detect the soluble form of silica is presented here. The method presented will enable earlier detection of a formulation and container incompatibility instead of waiting until glass-related particles are visible in solution. PMID- 25691719 TI - Non-destructive vacuum decay method for pre-filled syringe closure integrity testing compared with dye ingress testing and high-voltage leak detection. AB - In reaction to the limitations of the traditional sterility test methods, in 2008, the U.S. Food and Drug Administration issued the guidance "Container and Closure System Integrity Testing in Lieu of Sterility Testing as a Component of the Stability Protocol for Sterile Products" encouraging sterile drug manufacturers to use properly validated physical methods, apart from conventional microbial challenge testing, to confirm container closure integrity as part of the stability protocol. The case study presented in this article investigated the capability of four container closure integrity testing methods to detect simulated defects of different sizes and types on glass syringes, prefilled both with drug product intended for parenteral administration and sterile water. The drug product was a flu vaccine (Agrippal, Novartis Vaccines, Siena, Italy). Vacuum decay, pharmacopoeial dye ingress test, Novartis specific dye ingress test, and high-voltage leak detection were, in succession, the methods involved in the comparative studies. The case study execution was preceded by the preparation of two independent sets of reference prefilled syringes, classified, respectively, as examples of conforming to closure integrity requirements (negative controls) and as defective (positive controls). Positive controls were, in turn, split in six groups, three of with holes laser-drilled through the prefilled syringe glass barrel, while the other three with capillary tubes embedded in the prefilled syringe plunger. These reference populations were then investigated by means of validated equipment used for container closure integrity testing of prefilled syringe commercial production; data were collected and analyzed to determine the detection rate and the percentage of false results. Results showed that the vacuum decay method had the highest performance in terms of detection sensitivity and also ensured the best reliability and repeatability of measurements. An innovative technical solution, preventing possible prefilled syringe plunger movement during container closure integrity testing execution, is presented as well. LAY ABSTRACT: The growing need to meet sterile drug products' regulatory, quality, and safety expectations has progressively driven new developments and improvements both in container closure integrity testing methods and in the respective equipment, over the last years. Indeed, container closure integrity testing establishes the container closure system capability to provide required protection to the drug product and to demonstrate maintenance of product sterility over its shelf life. This article describes the development of four container closure integrity testing approaches for the evaluation of glass prefilled syringe closure integrity, including two destructive (pharmacopoeial and Novartis specific dye ingress test) and two non-destructive (vacuum decay and high-voltage leak detection) methods. The important finding from the validation of comparative studies was that the vacuum decay method resulted in the most effective, reliable and repeatable detection of defective samples, whether the defect was exposed to sterile water, to drug product, or to air. Complete sets of known defects were created for this purpose (5 MUm, 10 MUm, 20 MUm certified leakages by laser drilled holes and capillary tubes). All investigations and studies were conducted at Bonfiglioli Engineering S.r.l. (Vigarano Pieve, Ferrara, Italy) and at Novartis Vaccines (Sovicille, Siena, Italy). PMID- 25691720 TI - Industry perspective on the medical risk of visible particles in injectable drug products. PMID- 25691721 TI - Proceedings of the 2013 Viral Clearance Symposium (Princeton, NJ). PMID- 25691722 TI - Viral clearance of traditional unit operations: virus-retentive filtration. PMID- 25691723 TI - Viral clearance using traditional, well-understood unit operations: session 1.2. Anion exchange chromatography; and session 1.3. Protein a chromatography. PMID- 25691724 TI - Viral Inactivation: Low pH and Detergent. PMID- 25691725 TI - Session 1.5: other viral clearance and inactivation approaches (multimodal chromatography, membrane chromatography, chemical precipitation). PMID- 25691726 TI - Session 2/3: integrated viral clearance strategy and case studies. PMID- 25691727 TI - Session 4: overall integrated viral clearance and adventitious agents strategy. PMID- 25691728 TI - 2013 viral clearance symposia - session 5. Conference summary: key discussion and outcomes, pending questions, and proposed experiments. PMID- 25691730 TI - Caffeine and Caffeic Acid Inhibit Growth and Modify Estrogen Receptor and Insulin like Growth Factor I Receptor Levels in Human Breast Cancer. AB - PURPOSE: Epidemiologic studies indicate that dietary factors, such as coffee, may influence breast cancer and modulate hormone receptor status. The purpose of this translational study was to investigate how coffee may affect breast cancer growth in relation to estrogen receptor-alpha (ER) status. EXPERIMENTAL DESIGN: The influence of coffee consumption on patient and tumor characteristics and disease free survival was assessed in a population-based cohort of 1,090 patients with invasive primary breast cancer in Sweden. Cellular and molecular effects by the coffee constituents caffeine and caffeic acid were evaluated in ER(+) (MCF-7) and ER(-) (MDA-MB-231) breast cancer cells. RESULTS: Moderate (2-4 cups/day) to high (>=5 cups/day) coffee intake was associated with smaller invasive primary tumors (Ptrend = 0.013) and lower proportion of ER(+) tumors (Ptrend = 0.018), compared with patients with low consumption (<=1 cup/day). Moderate to high consumption was associated with lower risk for breast cancer events in tamoxifen-treated patients with ER(+) tumors (adjusted HR, 0.51; 95% confidence interval, 0.26 0.97). Caffeine and caffeic acid suppressed the growth of ER(+) (P <= 0.01) and ER(-) (P <= 0.03) cells. Caffeine significantly reduced ER and cyclin D1 abundance in ER(+) cells. Caffeine also reduced the insulin-like growth factor-I receptor (IGFIR) and pAkt levels in both ER(+) and ER(-) cells. Together, these effects resulted in impaired cell-cycle progression and enhanced cell death. CONCLUSIONS: The clinical and experimental findings demonstrate various anticancer properties of caffeine and caffeic acid against both ER(+) and ER(-) breast cancer that may sensitize tumor cells to tamoxifen and reduce breast cancer growth. PMID- 25691731 TI - K562-Derived Whole-Cell Vaccine Enhances Antitumor Responses of CAR-Redirected Virus-Specific Cytotoxic T Lymphocytes In Vivo. AB - PURPOSE: Adoptive transfer of Epstein-Barr virus (EBV)-specific and cytomegalovirus (CMV)-specific cytotoxic T cells (CTL) genetically modified to express a chimeric antigen receptor (CAR) induces objective tumor responses in clinical trials. In vivo expansion and persistence of these cells are crucial to achieve sustained clinical responses. We aimed to develop an off-the-shelf whole cell vaccine to boost CAR-redirected virus-specific CTLs in vivo after adoptive transfer. As proof of principle, we validated our vaccine approach by boosting CMV-specific CTLs (CMV-CTLs) engineered with a CAR that targets the GD2 antigen. EXPERIMENTAL DESIGN: We generated the whole-cell vaccine by engineering the K562 cell line to express the CMV-pp65 protein and the immune stimulatory molecules CD40L and OX40L. Single-cell-derived clones were used to stimulate CMV-CTLs in vitro and in vivo in a xenograft model. We also assessed whether the in vivo boosting of CAR-redirected CMV-CTLs with the whole-cell vaccine enhances the antitumor responses. Finally, we addressed potential safety concerns by including the inducible safety switch caspase9 (iC9) gene in the whole-cell vaccine. RESULTS: We found that K562-expressing CMV-pp65, CD40L, and OX40L effectively stimulate CMV-specific responses in vitro by promoting antigen cross-presentation to professional antigen-presenting cells (APCs). Vaccination also enhances antitumor effects of CAR-redirected CMV-CTLs in xenograft tumor models. Activation of the iC9 gene successfully induces growth arrest of engineered K562 implanted in mice. CONCLUSIONS: Vaccination with a whole-cell vaccine obtained from K562 engineered to express CMV-pp65, CD40L, OX40L and iC9 can safely enhance the antitumor effects of CAR-redirected CMV-CTLs. PMID- 25691732 TI - The plant cell in the new age of scientific publishing. PMID- 25691733 TI - Genome-wide characterization of cis-acting DNA targets reveals the transcriptional regulatory framework of opaque2 in maize. AB - Opaque2 (O2) is a transcription factor that plays important roles during maize endosperm development. Mutation of the O2 gene improves the nutritional value of maize seeds but also confers pleiotropic effects that result in reduced agronomic quality. To reveal the transcriptional regulatory framework of O2, we studied the transcriptome of o2 mutants using RNA sequencing (RNA-Seq) and determined O2 DNA binding targets using chromatin immunoprecipitation coupled to high-throughput sequencing (ChIP-Seq). The RNA-Seq analysis revealed 1605 differentially expressed genes (DEGs) and 383 differentially expressed long, noncoding RNAs. The DEGs cover a wide range of functions related to nutrient reservoir activity, nitrogen metabolism, stress resistance, etc. ChIP-Seq analysis detected 1686 O2 DNA binding sites distributed over 1143 genes. Overlay of the RNA-Seq and ChIP Seq results revealed 35 O2-modulated target genes. We identified four O2 binding motifs; among them, TGACGTGG appears to be the most conserved and strongest. We confirmed that, except for the 16- and 18-kD zeins, O2 directly regulates expression of all other zeins. O2 directly regulates two transcription factors, genes linked to carbon and amino acid metabolism and abiotic stress resistance. We built a hierarchical regulatory model for O2 that provides an understanding of its pleiotropic biological effects. PMID- 25691734 TI - Ancient dynamin segments capture early stages of host-mitochondrial integration. AB - Eukaryotic cells use dynamins-mechano-chemical GTPases--to drive the division of endosymbiotic organelles. Here we probe early steps of mitochondrial and chloroplast endosymbiosis by tracing the evolution of dynamins. We develop a parsimony-based phylogenetic method for protein sequence reconstruction, with deep time resolution. Using this, we demonstrate that dynamins diversify through the punctuated transformation of sequence segments on the scale of secondary structural elements. We find examples of segments that have remained essentially unchanged from the 1.8-billion-y-old last eukaryotic common ancestor to the present day. Stitching these together, we reconstruct three ancestral dynamins: The first is nearly identical to the ubiquitous mitochondrial division dynamins of extant eukaryotes, the second is partially preserved in the myxovirus resistance--like dynamins of metazoans, and the third gives rise to the cytokinetic dynamins of amoebozoans and plants and to chloroplast division dynamins. The reconstructed sequences, combined with evolutionary models and published functional data, suggest that the ancestral mitochondrial division dynamin also mediated vesicle scission. This bifunctional protein duplicated into specialized mitochondrial and vesicle variants at least three independent times- in alveolates, green algae, and the ancestor of fungi and metazoans-accompanied by the loss of the ancient prokaryotic mitochondrial division protein FtsZ. Remarkably, many extant species that retain FtsZ also retain the predicted ancestral bifunctional dynamin. The mitochondrial division apparatus of such organisms, including amoebozoans, red algae, and stramenopiles, seems preserved in a near-primordial form. PMID- 25691735 TI - The fingerprint of climate trends on European crop yields. AB - Europe has experienced a stagnation of some crop yields since the early 1990s as well as statistically significant warming during the growing season. Although it has been argued that these two are causally connected, no previous studies have formally attributed long-term yield trends to a changing climate. Here, we present two statistical tests based on the distinctive spatial pattern of climate change impacts and adaptation, and explore their power under a range of parameter values. We show that statistical power for the identification of climate change impacts is high in many settings, but that power for identifying adaptation is almost always low. Applying these tests to European agriculture, we find evidence that long-term temperature and precipitation trends since 1989 have reduced continent-wide wheat and barley yields by 2.5% and 3.8%, respectively, and have slightly increased maize and sugar beet yields. These averages disguise large heterogeneity across the continent, with regions around the Mediterranean experiencing significant adverse impacts on most crops. This result means that climate trends can account for ~ 10% of the stagnation in European wheat and barley yields, with likely explanations for the remainder including changes in agriculture and environmental policies. PMID- 25691736 TI - Coding principles of the canonical cortical microcircuit in the avian brain. AB - Mammalian neocortex is characterized by a layered architecture and a common or "canonical" microcircuit governing information flow among layers. This microcircuit is thought to underlie the computations required for complex behavior. Despite the absence of a six-layered cortex, birds are capable of complex cognition and behavior. In addition, the avian auditory pallium is composed of adjacent information-processing regions with genetically identified neuron types and projections among regions comparable with those found in the neocortex. Here, we show that the avian auditory pallium exhibits the same information-processing principles that define the canonical cortical microcircuit, long thought to have evolved only in mammals. These results suggest that the canonical cortical microcircuit evolved in a common ancestor of mammals and birds and provide a physiological explanation for the evolution of neural processes that give rise to complex behavior in the absence of cortical lamination. PMID- 25691737 TI - Single-step fermentative production of the cholesterol-lowering drug pravastatin via reprogramming of Penicillium chrysogenum. AB - The cholesterol-lowering blockbuster drug pravastatin can be produced by stereoselective hydroxylation of the natural product compactin. We report here the metabolic reprogramming of the antibiotics producer Penicillium chrysogenum toward an industrial pravastatin production process. Following the successful introduction of the compactin pathway into the beta-lactam-negative P. chrysogenum DS50662, a new cytochrome P450 (P450 or CYP) from Amycolatopsis orientalis (CYP105AS1) was isolated to catalyze the final compactin hydroxylation step. Structural and biochemical characterization of the WT CYP105AS1 reveals that this CYP is an efficient compactin hydroxylase, but that predominant compactin binding modes lead mainly to the ineffective epimer 6-epi-pravastatin. To avoid costly fractionation of the epimer, the enzyme was evolved to invert stereoselectivity, producing the pharmacologically active pravastatin form. Crystal structures of the optimized mutant P450(Prava) bound to compactin demonstrate how the selected combination of mutations enhance compactin binding and enable positioning of the substrate for stereo-specific oxidation. Expression of P450(Prava) fused to a redox partner in compactin-producing P. chrysogenum yielded more than 6 g/L pravastatin at a pilot production scale, providing an effective new route to industrial scale production of an important drug. PMID- 25691738 TI - Increasing propensity to mind-wander with transcranial direct current stimulation. AB - Humans mind-wander quite intensely. Mind wandering is markedly different from other cognitive behaviors because it is spontaneous, self-generated, and inwardly directed (inner thoughts). However, can such an internal and intimate mental function also be modulated externally by means of brain stimulation? Addressing this question could also help identify the neural correlates of mind wandering in a causal manner, in contrast to the correlational methods used previously (primarily functional MRI). In our study, participants performed a monotonous task while we periodically sampled their thoughts to assess mind wandering. Concurrently, we applied transcranial direct current stimulation (tDCS). We found that stimulation of the frontal lobes [anode electrode at the left dorsolateral prefrontal cortex (DLPFC), cathode electrode at the right supraorbital area], but not of the occipital cortex or sham stimulation, increased the propensity to mind wander. These results demonstrate for the first time, to our knowledge, that mind wandering can be enhanced externally using brain stimulation, and that the frontal lobes play a causal role in mind-wandering behavior. These results also suggest that the executive control network associated with the DLPFC might be an integral part of mind-wandering neural machinery. PMID- 25691739 TI - Sugar-based amphiphilic nanoparticles arrest atherosclerosis in vivo. AB - Atherosclerosis, the build-up of occlusive, lipid-rich plaques in arterial walls, is a focal trigger of chronic coronary, intracranial, and peripheral arterial diseases, which together account for the leading causes of death worldwide. Although the directed treatment of atherosclerotic plaques remains elusive, macrophages are a natural target for new interventions because they are recruited to lipid-rich lesions, actively internalize modified lipids, and convert to foam cells with diseased phenotypes. In this work, we present a nanomedicine platform to counteract plaque development based on two building blocks: first, at the single macrophage level, sugar-based amphiphilic macromolecules (AMs) were designed to competitively block oxidized lipid uptake via scavenger receptors on macrophages; second, for sustained lesion-level intervention, AMs were fabricated into serum-stable core/shell nanoparticles (NPs) to rapidly associate with plaques and inhibit disease progression in vivo. An AM library was designed and fabricated into NP compositions that showed high binding and down-regulation of both MSR1 and CD36 scavenger receptors, yielding minimal accumulation of oxidized lipids. When intravenously administered to a mouse model of cardiovascular disease, these AM NPs showed a pronounced increase in lesion association compared with the control nanoparticles, causing a significant reduction in neointimal hyperplasia, lipid burden, cholesterol clefts, and overall plaque occlusion. Thus, synthetic macromolecules configured as NPs are not only effectively mobilized to lipid-rich lesions but can also be deployed to counteract atheroinflammatory vascular diseases, highlighting the promise of nanomedicines for hyperlipidemic and metabolic syndromes. PMID- 25691740 TI - Major diversification of voltage-gated K+ channels occurred in ancestral parahoxozoans. AB - We examined the origins and functional evolution of the Shaker and KCNQ families of voltage-gated K(+) channels to better understand how neuronal excitability evolved. In bilaterians, the Shaker family consists of four functionally distinct gene families (Shaker, Shab, Shal, and Shaw) that share a subunit structure consisting of a voltage-gated K(+) channel motif coupled to a cytoplasmic domain that mediates subfamily-exclusive assembly (T1). We traced the origin of this unique Shaker subunit structure to a common ancestor of ctenophores and parahoxozoans (cnidarians, bilaterians, and placozoans). Thus, the Shaker family is metazoan specific but is likely to have evolved in a basal metazoan. Phylogenetic analysis suggested that the Shaker subfamily could predate the divergence of ctenophores and parahoxozoans, but that the Shab, Shal, and Shaw subfamilies are parahoxozoan specific. In support of this, putative ctenophore Shaker subfamily channel subunits coassembled with cnidarian and mouse Shaker subunits, but not with cnidarian Shab, Shal, or Shaw subunits. The KCNQ family, which has a distinct subunit structure, also appears solely within the parahoxozoan lineage. Functional analysis indicated that the characteristic properties of Shaker, Shab, Shal, Shaw, and KCNQ currents evolved before the divergence of cnidarians and bilaterians. These results show that a major diversification of voltage-gated K(+) channels occurred in ancestral parahoxozoans and imply that many fundamental mechanisms for the regulation of action potential propagation evolved at this time. Our results further suggest that there are likely to be substantial differences in the regulation of neuronal excitability between ctenophores and parahoxozoans. PMID- 25691741 TI - Essential functions of primate frontopolar cortex in cognition. AB - Brodmann's area 10 is one of the largest cytoarchitecturally defined regions in the human cerebral cortex, occupying the most anterior part of the prefrontal cortex [frontopolar cortex (FPC)], and is believed to sit atop a prefrontal hierarchy. The crucial contributions that the FPC makes to cognition are unknown. Rodents do not possess such [corrected] a FPC, but primates do, and we report here the behavioral effects of circumscribed FPC lesions in nonhuman primates. FPC lesions selectively impaired rapid one-trial learning about unfamiliar objects and unfamiliar objects-in-scenes, and also impaired rapid learning about novel abstract rules. Object recognition memory, shifting between established abstract behavioral rules, and the simultaneous application of two distinct rules were unaffected by the FPC lesion. The distinctive pattern of impaired and spared performance across these seven behavioral tasks reveals that the FPC mediates exploration and rapid learning about the relative value of novel behavioral options, and shows that the crucial contributions made by the FPC to cognition differ markedly from the contributions of other primate prefrontal regions. PMID- 25691742 TI - Regulation and aggregation of intrinsically disordered peptides. AB - Intrinsically disordered proteins (IDPs) are a unique class of proteins that have no stable native structure, a feature that allows them to adopt a wide variety of extended and compact conformations that facilitate a large number of vital physiological functions. One of the most well-known IDPs is the microtubule associated tau protein, which regulates microtubule growth in the nervous system. However, dysfunctions in tau can lead to tau oligomerization, fibril formation, and neurodegenerative disease, including Alzheimer's disease. Using a combination of simulations and experiments, we explore the role of osmolytes in regulating the conformation and aggregation propensities of the R2/wt peptide, a fragment of tau containing the aggregating paired helical filament (PHF6*). We show that the osmolytes urea and trimethylamine N-oxide (TMAO) shift the population of IDP monomer structures, but that no new conformational ensembles emerge. Although urea halts aggregation, TMAO promotes the formation of compact oligomers (including helical oligomers) through a newly proposed mechanism of redistribution of water around the perimeter of the peptide. We put forth a "superposition of ensembles" hypothesis to rationalize the mechanism by which IDP structure and aggregation is regulated in the cell. PMID- 25691743 TI - Antisense long noncoding RNAs regulate var gene activation in the malaria parasite Plasmodium falciparum. AB - The virulence of Plasmodium falciparum, the causative agent of the deadliest form of human malaria, is attributed to its ability to evade human immunity through antigenic variation. These parasites alternate between expression of variable antigens, encoded by members of a multicopy gene family named var. Immune evasion through antigenic variation depends on tight regulation of var gene expression, ensuring that only a single var gene is expressed at a time while the rest of the family is maintained transcriptionally silent. Understanding how a single gene is chosen for activation is critical for understanding mutually exclusive expression but remains a mystery. Here, we show that antisense long noncoding RNAs (lncRNAs) initiating from var introns are associated with the single active var gene at the time in the cell cycle when the single var upstream promoter is active. We demonstrate that these antisense transcripts are incorporated into chromatin, and that expression of these antisense lncRNAs in trans triggers activation of a silent var gene in a sequence- and dose-dependent manner. On the other hand, interference with these lncRNAs using complement peptide nucleic acid molecules down-regulated the active var gene, erased the epigenetic memory, and induced expression switching. Altogether, our data provide evidence that these antisense lncRNAs play a key role in regulating var gene activation and mutually exclusive expression. PMID- 25691744 TI - Cell-specific proteomic analysis in Caenorhabditis elegans. AB - Proteomic analysis of rare cells in heterogeneous environments presents difficult challenges. Systematic methods are needed to enrich, identify, and quantify proteins expressed in specific cells in complex biological systems including multicellular plants and animals. Here, we have engineered a Caenorhabditis elegans phenylalanyl-tRNA synthetase capable of tagging proteins with the reactive noncanonical amino acid p-azido-L-phenylalanine. We achieved spatiotemporal selectivity in the labeling of C. elegans proteins by controlling expression of the mutant synthetase using cell-selective (body wall muscles, intestinal epithelial cells, neurons, and pharyngeal muscle) or state-selective (heat-shock) promoters in several transgenic lines. Tagged proteins are distinguished from the rest of the protein pool through bioorthogonal conjugation of the azide side chain to probes that permit visualization and isolation of labeled proteins. By coupling our methodology with stable-isotope labeling of amino acids in cell culture (SILAC), we successfully profiled proteins expressed in pharyngeal muscle cells, and in the process, identified proteins not previously known to be expressed in these cells. Our results show that tagging proteins with spatiotemporal selectivity can be achieved in C. elegans and illustrate a convenient and effective approach for unbiased discovery of proteins expressed in targeted subsets of cells. PMID- 25691745 TI - Rectifying RNA splicing errors in hereditary neurodegenerative disease. PMID- 25691746 TI - Balancing copy number in ribosomal DNA. PMID- 25691747 TI - Hybrid origins and the earliest stages of diploidization in the highly successful recent polyploid Capsella bursa-pastoris. AB - Whole-genome duplication (WGD) events have occurred repeatedly during flowering plant evolution, and there is growing evidence for predictable patterns of gene retention and loss following polyploidization. Despite these important insights, the rate and processes governing the earliest stages of diploidization remain poorly understood, and the relative importance of genetic drift, positive selection, and relaxed purifying selection in the process of gene degeneration and loss is unclear. Here, we conduct whole-genome resequencing in Capsella bursa pastoris, a recently formed tetraploid with one of the most widespread species distributions of any angiosperm. Whole-genome data provide strong support for recent hybrid origins of the tetraploid species within the past 100,000-300,000 y from two diploid progenitors in the Capsella genus. Major-effect inactivating mutations are frequent, but many were inherited from the parental species and show no evidence of being fixed by positive selection. Despite a lack of large scale gene loss, we observe a decrease in the efficacy of natural selection genome-wide due to the combined effects of demography, selfing, and genome redundancy from WGD. Our results suggest that the earliest stages of diploidization are associated with quantitative genome-wide decreases in the strength and efficacy of selection rather than rapid gene loss, and that nonfunctionalization can receive a "head start" through a legacy of deleterious variants and differential expression originating in parental diploid populations. PMID- 25691748 TI - Heavy-chain receptor editing unbound. PMID- 25691749 TI - Control of a hair bundle's mechanosensory function by its mechanical load. AB - Hair cells, the sensory receptors of the internal ear, subserve different functions in various receptor organs: they detect oscillatory stimuli in the auditory system, but transduce constant and step stimuli in the vestibular and lateral-line systems. We show that a hair cell's function can be controlled experimentally by adjusting its mechanical load. By making bundles from a single organ operate as any of four distinct types of signal detector, we demonstrate that altering only a few key parameters can fundamentally change a sensory cell's role. The motions of a single hair bundle can resemble those of a bundle from the amphibian vestibular system, the reptilian auditory system, or the mammalian auditory system, demonstrating an essential similarity of bundles across species and receptor organs. PMID- 25691751 TI - Correction for Takao and Miyakawa, Genomic responses in mouse models greatly mimic human inflammatory diseases. PMID- 25691750 TI - HDAC inhibition prevents white matter injury by modulating microglia/macrophage polarization through the GSK3beta/PTEN/Akt axis. AB - Severe traumatic brain injury (TBI) elicits destruction of both gray and white matter, which is exacerbated by secondary proinflammatory responses. Although white matter injury (WMI) is strongly correlated with poor neurological status, the maintenance of white matter integrity is poorly understood, and no current therapies protect both gray and white matter. One candidate approach that may fulfill this role is inhibition of class I/II histone deacetylases (HDACs). Here we demonstrate that the HDAC inhibitor Scriptaid protects white matter up to 35 d after TBI, as shown by reductions in abnormally dephosphorylated neurofilament protein, increases in myelin basic protein, anatomic preservation of myelinated axons, and improved nerve conduction. Furthermore, Scriptaid shifted microglia/macrophage polarization toward the protective M2 phenotype and mitigated inflammation. In primary cocultures of microglia and oligodendrocytes, Scriptaid increased expression of microglial glycogen synthase kinase 3 beta (GSK3beta), which phosphorylated and inactivated phosphatase and tensin homologue (PTEN), thereby enhancing phosphatidylinositide 3-kinases (PI3K)/Akt signaling and polarizing microglia toward M2. The increase in GSK3beta in microglia and their phenotypic switch to M2 was associated with increased preservation of neighboring oligodendrocytes. These findings are consistent with recent findings that microglial phenotypic switching modulates white matter repair and axonal remyelination and highlight a previously unexplored role for HDAC activity in this process. Furthermore, the functions of GSK3beta may be more subtle than previously thought, in that GSK3beta can modulate microglial functions via the PTEN/PI3K/Akt signaling pathway and preserve white matter homeostasis. Thus, inhibition of HDACs in microglia is a potential future therapy in TBI and other neurological conditions with white matter destruction. PMID- 25691752 TI - iASPP, a previously unidentified regulator of desmosomes, prevents arrhythmogenic right ventricular cardiomyopathy (ARVC)-induced sudden death. AB - Desmosomes are anchoring junctions that exist in cells that endure physical stress such as cardiac myocytes. The importance of desmosomes in maintaining the homeostasis of the myocardium is underscored by frequent mutations of desmosome components found in human patients and animal models. Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a phenotype caused by mutations in desmosomal components in ~ 50% of patients, however, the causes in the remaining 50% of patients still remain unknown. A deficiency of inhibitor of apoptosis stimulating protein of p53 (iASPP), an evolutionarily conserved inhibitor of p53, caused by spontaneous mutation recently has been associated with a lethal autosomal recessive cardiomyopathy in Poll Hereford calves and Wa3 mice. However, the molecular mechanisms that mediate this putative function of iASPP are completely unknown. Here, we show that iASPP is expressed at intercalated discs in human and mouse postmitotic cardiomyocytes. iASPP interacts with desmoplakin and desmin in cardiomyocytes to maintain the integrity of desmosomes and intermediate filament networks in vitro and in vivo. iASPP deficiency specifically induces right ventricular dilatation in mouse embryos at embryonic day 16.5. iASPP-deficient mice with exon 8 deletion (Ppp1r13l(Delta8/Delta8)) die of sudden cardiac death, displaying features of ARVC. Intercalated discs in cardiomyocytes from four of six human ARVC cases show reduced or loss of iASPP. ARVC-derived desmoplakin mutants DSP-1-V30M and DSP-1-S299R exhibit weaker binding to iASPP. These data demonstrate that by interacting with desmoplakin and desmin, iASPP is an important regulator of desmosomal function both in vitro and in vivo. This newly identified property of iASPP may provide new molecular insight into the pathogenesis of ARVC. PMID- 25691753 TI - RING finger protein 121 facilitates the degradation and membrane localization of voltage-gated sodium channels. AB - Following their synthesis in the endoplasmic reticulum (ER), voltage-gated sodium channels (NaV) are transported to the membranes of excitable cells, where they often cluster, such as at the axon initial segment of neurons. Although the mechanisms by which NaV channels form and maintain clusters have been extensively examined, the processes that govern their transport and degradation have received less attention. Our entry into the study of these processes began with the isolation of a new allele of the zebrafish mutant alligator, which we found to be caused by mutations in the gene encoding really interesting new gene (RING) finger protein 121 (RNF121), an E3-ubiquitin ligase present in the ER and cis Golgi compartments. Here we demonstrate that RNF121 facilitates two opposing fates of NaV channels: (i) ubiquitin-mediated proteasome degradation and (ii) membrane localization when coexpressed with auxiliary NaVbeta subunits. Collectively, these results indicate that RNF121 participates in the quality control of NaV channels during their synthesis and subsequent transport to the membrane. PMID- 25691754 TI - EF-hand protein Ca2+ buffers regulate Ca2+ influx and exocytosis in sensory hair cells. AB - EF-hand Ca(2+)-binding proteins are thought to shape the spatiotemporal properties of cellular Ca(2+) signaling and are prominently expressed in sensory hair cells in the ear. Here, we combined genetic disruption of parvalbumin-alpha, calbindin-D28k, and calretinin in mice with patch-clamp recording, in vivo physiology, and mathematical modeling to study their role in Ca(2+) signaling, exocytosis, and sound encoding at the synapses of inner hair cells (IHCs). IHCs lacking all three proteins showed excessive exocytosis during prolonged depolarizations, despite enhanced Ca(2+)-dependent inactivation of their Ca(2+) current. Exocytosis of readily releasable vesicles remained unchanged, in accordance with the estimated tight spatial coupling of Ca(2+) channels and release sites (effective "coupling distance" of 17 nm). Substitution experiments with synthetic Ca(2+) chelators indicated the presence of endogenous Ca(2+) buffers equivalent to 1 mM synthetic Ca(2+)-binding sites, approximately half of them with kinetics as fast as 1,2-Bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA). Synaptic sound encoding was largely unaltered, suggesting that excess exocytosis occurs extrasynaptically. We conclude that EF-hand Ca(2+) buffers regulate presynaptic IHC function for metabolically efficient sound coding. PMID- 25691755 TI - Effect of dietary energy and protein content on growth and carcass traits of Pekin ducks. AB - A study was conducted to determine the influence of dietary energy and protein concentrations on growth performance and carcass traits of Pekin ducks from 15 to 35 d of age. In experiment 1, 14-d-old ducks were randomly assigned to 3 dietary metabolizable energy (11.8, 12.8, and 13.8 MJ/kg) and 3 crude protein concentrations (15, 17, and 19%) in a 3*3 factorial arrangement (6 replicate pens; 66 ducks/pen). Carcass characteristics were evaluated on d 28, 32, and 35. In Experiment 2, 15-d-old ducks (6 replicate cages; 6 ducks/cage) were randomly allotted to the 9 diets that were remixed with 0.5% chromic oxide. Excreta were collected from d 17 to 19, and ileal digesta was collected on d 19 to determine AMEn and amino acid digestibility. In Experiment 1, there were interactions (P<0.05) between dietary metabolizable energy and crude protein (CP) on body weight (BW) gain and feed intake, wherein BW gain increased more to increasing dietary CP as dietary metabolizable energy increased. However, feed intake was only influenced by dietary crude protein at 11.8 MJ ME/kg and not 12.8 or 13.8 MJ/kg. As dietary CP increased from 15 to 19%, breast meat yield increased by 10.8% on d 35 (P<0.01). Conversely, increasing metabolizable energy from 11.8 to 13.8 MJ/kg increased dressing percentage, breast skin, and subcutaneous fat, but decreased breast meat yield (% but not weight) on d 35 (P<0.01). In Experiment 2, the determined AMEn for diets formulated to contain 11.8, 12.8, or 13.8 MJ ME/kg were 11.66, 12.68, and 13.75 MJ/kg, respectively; determined standardized ileal digestible Lys was 0.95, 1.00, and 1.21% for diets formulated to contain 15, 17, or 19% crude protein, respectively. The best body weight gain and feed conversion ratio was obtained when ducks were fed a high dietary AMEn (13.75 MJ/kg) and high CP (19%, 1.21% SID Lys). These results provide a framework for subsequent modeling of amino acid and energy inputs and the corresponding outputs of growth performance and carcass components. PMID- 25691756 TI - Consequences of different growth rates in broiler breeder and layer hens on embryogenesis, metabolism and metabolic rate: A review. AB - Intensive genetic selection of broiler breeders and layer hens for economically important production traits, which has been carried out for almost a century, resulted in considerable differences in the mechanisms of growth and development and, thus, in avian metabolism, both during embryogenesis and after hatching. Selection for meat production (broiler breeders) and eggs (layer hens) led to increased productivity but also brought about metabolic disorders. That intensive genetic selection of broiler breeders and layer hens is effective is seen, for example, in the differences in growth and development, metabolism of the yolk sac, hormones and lipids, gas exchange, and thermogenesis. Due to genetic proximity and different developmental mechanisms in broiler breeders and layer hens, avian embryos and chicks serve as excellent models for fundamental scientific research. This review paper discusses the consequences of different growth rates as a result of long-term genetic selection on embryonic development and metabolic rate of broilers and layers. The evidence presented herein indicates that it would be worth comparing these issues in a meta-analysis. PMID- 25691757 TI - Effect of coccidia challenge and natural betaine supplementation on performance, nutrient utilization, and intestinal lesion scores of broiler chickens fed suboptimal level of dietary methionine. AB - The aim of the present experiment was to examine the effect of coccidia challenge and natural betaine supplementation on performance, nutrient utilization, and intestinal lesion scores of broiler chickens fed suboptimal level of dietary methionine. The experimental design was a 2*2 factorial arrangement of treatments evaluating two levels of betaine supplementation (0 and 960 g betaine/t of feed) without or with coccidia challenge. Each treatment was fed to 8 cages of 8 male broilers (Ross 308) for 1 to 21d. On d 14, birds in the 2 challenged groups received mixed inocula of Eimeria species from a recent field isolate, containing approximately 180,000 E. acervulina, 6,000 E. maxima, and 18,000 E. tenella oocysts. At 21d, digesta from the terminal ileum was collected for the determination of dry matter, energy, nitrogen, amino acids, starch, fat, and ash digestibilities. Lesion scores in the different segments of the small intestine were also measured on d 21. Performance and nutrient digestibility data were analyzed by two-way ANOVA. Lesion score data were analyzed using Pearson chi square test to identify significant differences between treatments. Orthogonal polynomial contrasts were used to assess the significance of linear or quadratic models to describe the response in the dependent variable to total lesion scores. Coccidia challenge reduced (P<0.0001) the weight gain and feed intake, and increased (P<0.0001) the feed conversion ratio. Betaine supplementation had no effect (P>0.05) on the weight gain or feed intake, but lowered (P<0.05) the feed conversion ratio. No interaction (P>0.05) between coccidia challenge and betaine supplementation was observed for performance parameters. Betaine supplementation increased (P<0.05) the digestibility of dry matter, nitrogen, energy, fat, and amino acids only in birds challenged with coccidia as indicated by the significant interaction (P<0.0001) between betaine supplementation and coccidia challenge. The main effect of coccidia challenge reduced (P<0.05) starch digestibility. Betaine supplementation improved (P<0.05) starch digestibility regardless of the coccidia challenge. For each unit increase in the total lesion score, there was a linear (P<0.001) decrease in digestibility of mean amino acids, starch, and fat by 3.8, 3.4 and 16%, respectively. Increasing total lesion scores resulted in a quadratic (P<0.05) decrease in dry matter digestibility and ileal digestible energy. No lesions were found in the intestine or ceca of the unchallenged treatments. In the challenged treatments, betaine supplementation reduced (P<0.01) the lesion scores at the duodenum, lower jejunum, and total lesion scores compared to the treatment without supplements. In conclusion, coccidia challenge lowered the digestibility of energy and nutrients and increased the feed conversion ratio of broilers. However, betaine supplementation reduced the impact of coccidia challenge and positively affected nutrient digestibility and the feed conversion ratio. PMID- 25691758 TI - Effects of the in ovo injection of 25-hydroxycholecalciferol on the yolk and serum characteristics of male and female broiler embryos. AB - Serum concentrations of 25-hydroxycholecalciferol [25(OH)D3] in broiler embryos at 19 d of incubation:doi:have been shown to increase 3 times by the in ovo injection of 0.60 MUg 25(OH)D3 on 18 doi. In this trial, effects of the injection of 25(OH)D3 at 18 doi on the yolks and sera of male and female Ross*Ross 708 broiler embryos were assessed. On 18 doi, embryonated eggs that were set in a single stage incubator were assigned to 6 replicate trays within each of 2 injection treatment groups. Treatments included those injected with 100 MUL commercial diluent (control) and those injected with 0.60 MUg 25(OH)D3 in 100 MUL commercial diluent. On 19 doi, embryos and their yolk sacs were extracted for determination of sex, yolk weight, BW, serum CA and phosphorous concentrations, and yolk CA, phosphorous, moisture, dry matter, and lipid concentrations. The weight of female embryos with their attached yolk sacs as a percentage of set egg weight was greater than that of males (P=0.03). There were treatment*sex interactions for the weight of embryos with their attached yolk sacs relative to 19 doi egg weight (P=0.05) and for yolk CA concentration (P=0.004). In eggs that received 25(OH)D3, the weight of female embryos with their attached yolk sacs relative to 19 doi egg weight was higher than that of males (P=0.005), and percentage yolk CA was higher in control eggs containing female embryos in comparison to those containing males (P=0.007). An injection of 0.60 MUg 25(OH)D3 at 18 doi eliminated yolk CA differences associated with embryo sex, suggesting that 25(OH)D3 may influence sex-related differences in the rate of yolk CA absorption by broiler embryos and may be related to subsequent sex-related differences in posthatch bone strength. PMID- 25691759 TI - DNA methylation and histone modification patterns during the late embryonic and early postnatal development of chickens. AB - Early mammalian embryonic cells have been proven to be essential for embryonic development and the health of neonates. A series of epigenetic reprogramming events, including DNA methylation and histone modifications, occur during early embryonic development. However, epigenetic marks in late embryos and neonates are not well understood, especially in avian species. To investigate the epigenetic patterns of developing embryos and posthatched chicks, embryos at embryonic day 5 (E5), E8, E11, E14, E17, and E20 and newly hatched chicks on day of life 1 (D1), D7, D14, D21 were collected. The levels of global DNA methylation and histone H3 at lysine 9 residue (H3K9) modifications were measured in samples of liver, jejunum, and breast skeletal muscles by Western blotting and immunofluorescence staining. According to our data, decreased levels of proliferating cell nuclear antigen expression were found in the liver and a V-shaped pattern of proliferating cell nuclear antigen expression was found in the jejunum. The level of proliferating cell nuclear antigen in muscle was relatively stable. Caspase 3 expression gradually decreased over time in liver, was stable in the jejunum, and increased in muscle. Levels of DNA methylation and H3K9 acetylation decreased in liver over time, while the pattern was N-shaped in jejunal tissue and W-shaped in pectoral muscles, and these changes were accompanied by dynamic changes of DNA methyltransferases, histone acetyltransferases 1, and histone deacetylase 2. Moreover, dimethylation, trimethylation, and acetylation of H3K9 were expressed in a time- and tissue-dependent manner. After birth, epigenetic marks were relatively stable and found at lower levels. These results indicate that spatiotemporal specific epigenetic alterations could be critical for the late development of chick embryos and neonates. PMID- 25691760 TI - Kernohan's notch. PMID- 25691761 TI - Structural and dynamic properties that govern the stability of an engineered fibronectin type III domain. AB - Consensus protein design is a rapid and reliable technique for the improvement of protein stability, which relies on the use of homologous protein sequences. To enhance the stability of a fibronectin type III (FN3) domain, consensus design was employed using an alignment of 2123 sequences. The resulting FN3 domain, FN3con, has unprecedented stability, with a melting temperature >100 degrees C, a DeltaG(D-N) of 15.5 kcal mol(-1) and a greatly reduced unfolding rate compared with wild-type. To determine the underlying molecular basis for stability, an X ray crystal structure of FN3con was determined to 2.0 A and compared with other FN3 domains of varying stabilities. The structure of FN3con reveals significantly increased salt bridge interactions that are cooperatively networked, and a highly optimized hydrophobic core. Molecular dynamics simulations of FN3con and comparison structures show the cooperative power of electrostatic and hydrophobic networks in improving FN3con stability. Taken together, our data reveal that FN3con stability does not result from a single mechanism, but rather the combination of several features and the removal of non-conserved, unfavorable interactions. The large number of sequences employed in this study has most likely enhanced the robustness of the consensus design, which is now possible due to the increased sequence availability in the post-genomic era. These studies increase our knowledge of the molecular mechanisms that govern stability and demonstrate the rising potential for enhancing stability via the consensus method. PMID- 25691762 TI - Use of a genetically encoded hydrogen peroxide sensor for whole cell screening of enzyme activity. AB - We report the use of HyPer, a genetically encoded, fluorescent sensor that reacts with hydrogen peroxide (H2O2), in a novel screen to engineer enzymes for enhanced production of H2O2. We co-expressed HyPer with cytochrome P450 BM3 variants and, using HyPer's ratiometric signal, found variants that produce greater amounts of H2O2 than the wild-type enzyme through the leakage reaction. The screen avoids lysis procedures and the addition of reagents to assay intracellular contents. Less laborious screening procedures will be useful in engineering more powerful H2O2 generators as tools in quantitative redox biology, and increasing the utility of enzymes that produce H2O2 as a by-product alongside a valuable compound. PMID- 25691763 TI - Managing Asthma on the College Campus: Findings of a Texas Pilot Study. AB - BACKGROUND: Students attending institutions of higher education have the option of utilizing their student health center (SHC) for asthma management. However, a review of the available literature revealed no previous research as to how SHCs on college campuses in Texas manage students with asthma. This led to the following research questions; how are SHCs in Texas managing asthma for college students, and what are the SHC directors' attitudes and perceptions of the impact of asthma on their college campuses? METHODS: This descriptive pilot study randomly selected 20 colleges in Texas; 17 institutions agreed to participate. The inclusion criteria consisted of 4-y colleges accredited by the Southern Association of Colleges and Schools with an undergraduate student population of greater than 1,000 full-time students, excluding online colleges. Once identified, the director of each institution's SHC was contacted by telephone and invited to complete the Managing Asthma on College Campuses Survey instrument via telephone interview (n = 14) or e-mail (n = 3). Descriptive statistics were used to analyze quantitative data and common themes were noted for the qualitative data. RESULTS: Quantitative data obtained through the survey revealed 23.5% of SHCs provide individualized asthma action plans to students and 35% of SHCs stated they have an emergency action plan for asthma exacerbations. Respondents noted 2 major barriers for effective asthma management on campus: lack of understanding of chronic disease management and underuse of the SHC due to a lack of awareness of its existence. Perceived barriers to visiting the SHC included access issues, money, and students self-medicating with short-acting beta2 agonist inhalers and/or over-the-counter medications. CONCLUSIONS: The majority of directors were satisfied with asthma services provided to students; however, they felt more face-to-face asthma education was needed. PMID- 25691764 TI - Feasibility Study on Neurally Adjusted Ventilatory Assist in Noninvasive Ventilation After Cardiac Surgery in Infants. AB - BACKGROUND: Our objective was to evaluate the feasibility, the quality of synchronization, and the influence on respiratory parameters of the noninvasive neurally adjusted ventilatory assist (NIV-NAVA) mode in infants after cardiac bypass surgery. We conducted a prospective, randomized cross-over study in infants undergoing noninvasive ventilation (NIV) after cardiac surgery. METHODS: Subjects were 10 infants < 5 kg. After extubation, subjects underwent 2 consecutive ventilatory modes after randomization into groups. In the CPAP first group, the subjects were ventilated first in nasal CPAP-1 and then in NIV-NAVA-2 for 30 min in each mode. In the NIV-NAVA first group, periods were reversed. All children were ventilated using the same interface. RESULTS: The analysis of curves showed a synchronization rate of 99.3% for all respiratory cycles. The rate of pneumatic inspiratory trigger was 3.4%. Asynchronies were infrequent. Some typical respiratory patterns (continuous effort and discontinuous inspiration) were found at rates of 10.9% and 31.1%, respectively. The respiratory trends showed a lower maximum diaphragmatic electrical activity (EAdi(max)) in NIV-NAVA periods compared with CPAP periods (P < .001 in the beginning of periods). The breathing frequency decreased significantly during the nasal CPAP-2 and NIV-NAVA-1 periods (P < .05). The inspiratory pressure increased significantly during the NIV-NAVA-1 and NIV-NAVA-2 periods (P < .05), but there was no significant difference for each parameter when comparing Delta values between the beginning and the end of each period. The EAdi signal was easy to obtain in all subjects, and no major side effects were associated with the use of NIV-NAVA. CONCLUSIONS: NIV-NAVA allows good synchronization in bi-level NIV in infant cardiac subjects weighing < 5 kg. The analysis of respiratory parameters shows that NIV NAVA decreases the work of breathing more effectively than nasal CPAP. The study shows some typical respiratory patterns in infants. (ClinicalTrials.gov registration NCT01570933.). PMID- 25691765 TI - Variability in Mechanical Ventilation: What's All the Noise About? AB - Controlled mechanical ventilation is characterized by a fixed breathing frequency and tidal volume. Physiological and mathematical models have demonstrated the beneficial effects of varying tidal volume and/or inspiratory pressure during positive-pressure ventilation. The addition of noise (random changes) to a monotonous nonlinear biological system, such as the lung, induces stochastic resonance that contributes to the recruitment of collapsed alveoli and atelectatic lung segments. In this article, we review the mechanism of physiological pulmonary variability, the principles of noise and stochastic resonance, and the emerging understanding that there are beneficial effects of variability during mechanical ventilation. PMID- 25691766 TI - Understanding Attitudes, Beliefs, and Information Seeking Regarding Hookah Smoking in Parents of College Students: An Exploratory Qualitative Pilot Study. AB - BACKGROUND: Hookah smoking has become increasingly common among young adults in the United States. College students engage in hookah smoking due to the increased exposure and popularity of hookah bars surrounding college campuses. There is limited information on parental perceptions of college students' hookah smoking. METHODS: Forty-four telephone interviews were recorded and transcribed with parents of college students using a structured interview guide to explore perceptions, beliefs, behaviors, and information seeking regarding hookah smoking. The transcripts were coded and categorized using NVivo software, and emerging themes were uncovered. RESULTS: Parents were lacking in awareness and knowledge of hookah smoking and health consequences. They often equated hookah smoking with bong use from their own college experiences. Although negative effects were equated with cigarette smoking, some parents reported beneficial effects of hookah smoking. Some parents disapproved of their college students smoking hookah, whereas others felt it was important that they try new behaviors in moderation. The varying responses indicate that parents were not receiving consistent messages, if any, regarding hookah tobacco smoking. CONCLUSIONS: Informing parents of current novel risky behaviors such as hookah smoking is necessary as they are trusted sources of information for young adult children. Delivering information and educational messages to both students and their parents may be a worthy approach when developing campaigns to deter hookah smoking. There is a need to deter hookah smoking, as it remains a public health concern. PMID- 25691767 TI - The Dose-Response Relationship Between Body Mass Index and Mortality in Subjects Admitted to the ICU With and Without Mechanical Ventilation. AB - BACKGROUND: Obesity has been associated with increased mortality in the general population, whereas a paradoxical relationship between higher body mass index and lower mortality has been referred to as the obesity paradox in critically ill patients. However, it remains unknown whether a particular subgroup is most affected. The aim of the present study is to elucidate whether obesity is associated with lower mortality in the ICU population by comparing subjects with and without mechanical ventilation. METHODS: A total of 334,238 subjects from a nationwide database who were discharged between July 2010 and March 2012 and who were admitted to general ICUs during their hospitalization were included in this study. The primary outcome was in-hospital mortality. RESULTS: Of all subjects evaluated, 23.3% were started on mechanical ventilation within the first 2 d after ICU admission. Compared with the non-ventilated group, the ventilated group was more likely to have sepsis, pneumonia, or coma. The ventilated group underwent more procedures within the first 2 d after ICU admission compared with the non-ventilated group. A restricted cubic spline function showed lower mortality in subjects with a higher body mass index among the ventilated group, whereas mortality was increased with increasing body mass index in the non ventilated group. CONCLUSIONS: This study shows that a high body mass index is associated with low mortality in the mechanically ventilated group, whereas the non-ventilated group showed a reverse J-shaped association. There was a higher mortality rate in underweight subjects in both groups. PMID- 25691768 TI - Severe Re-expansion Pulmonary Edema Induced by One-Lung Ventilation. AB - We present 2 cases of severe re-expansion pulmonary edema (RPE) after one-lung ventilation (OLV) for thoracic surgery. A 32-y-old woman with multiple lung metastases developed severe RPE after OLV during lung resection surgery. A 37-y old man with infective endocarditis also developed severe RPE after OLV for mitral valve plasty with minimally invasive cardiac surgery. In both cases, results of a preoperative pulmonary function test and oxygenation were almost normal, and pleural effusion or pulmonary congestion was not detected in preoperative computed tomography; however, there was a possibility that subclinical lung injury existed before surgery. The levels of interleukin-8 and monocyte chemotactic protein-1, which are thought to play important roles in the development of lung injury, in bronchial secretions were extremely high after the onset of RPE. These results suggest that the pathogenesis of RPE shares, at least in part, a common pathophysiology of acute lung injury. PMID- 25691769 TI - Ultrasound assessment of response to intra-articular therapy in osteoarthritis of the knee. AB - OBJECTIVE: Assessment of the synovium in patients with knee OA is of great potential value for clinical trials. Ultrasonography could provide this but few data exist on its ability to assess synovial response to therapies. The aim of this study was to examine whether US can detect synovial response to IA corticosteroid (IACS) therapy and to explore associations between synovial characteristics and symptoms. METHODS: A total of 35 people with ACR radiographic knee OA were included, including those who required an injection of 80 mg of IA methylprednisolone. All participants completed a visual analogue scale for pain and underwent US of the knee at baseline, 1 and 4 weeks. Minimum clinically important improvement (MCII) in pain was >=20 mm. RESULTS: One week of data were available for 33 patients (19 received IACS and 14 others). Synovial thickness (ST) decreased in 16 IACS patients and 2 others [mean between-group difference 4.7 mm (95% CI 1.1, 8.2), P = 0.012]. Absolute reduction was not associated with absolute reduction in pain (r = 0.20, P = 0.289), but decreased ST was substantively associated with reduction in pain greater than or equal to the MCII (52.9% vs 23.1%, P = 0.098, phi = 0.30). The power Doppler score decreased in 13 IACS patients and 3 others {median change in IACS patients -1.0 [interquartile range (IQR) -5.0-0.0], others 0.0 [-0.3-1.3], P = 0.004}. Absolute changes in pain and power Doppler score were weakly associated (rho = 0.36, P = 0.049) and a decreased power Doppler score was associated with reduction in pain greater than or equal to the MCII (64.3% vs 18.8%, P = 0.011, phi = 0.46). CONCLUSION: Ultrasonography can detect short-term synovial response in knee OA. In particular, power Doppler score may be both responsive to and associated with pain, warranting further investigation. PMID- 25691771 TI - CCR 20th Anniversary commentary: stayin' alive-antiapoptotic proteins and breast cancer. AB - The control of cell death involves a complex interaction of multiple proteins. In a study published in the January 1, 2000, issue of Clinical Cancer Research, Tanaka and colleagues demonstrated that one of the proapoptotic proteins, survivin, was frequently expressed in breast cancer. In the subsequent years, effectors of apoptosis have translated into important prognostic indicators and potential therapeutic targets. PMID- 25691772 TI - Molecular pathways: trafficking of metabolic resources in the tumor microenvironment. AB - A model of tumor metabolism is proposed that describes how the complementary metabolic functions of the local stroma and the tumor cells contribute to cancer progression. Cancer cells alter the metabolism of cancer-associated fibroblasts to obtain lactate and amino acids, which are utilized for energy production, rapid growth, and resistance to chemotherapy drugs. Cancer cells use glutamine supplied by cancer-associated fibroblasts to replenish tricarboxylic acid cycle intermediates and as a nitrogen source for nucleotide synthesis. Moreover, adipocytes in the microenvironment attract cancer cells through the secretion of inflammatory cytokines and proteases. The cancer cells then induce metabolic changes in the adipocytes to acquire free fatty acids that are oxidized by cancer cells to generate energy for proliferation. Increasing knowledge about the metabolic symbiosis within the tumor has led to novel therapeutic strategies designed to restrict metabolic adaptation, including inhibiting lactate transporters and repurposing antidiabetic drugs (thiazolidinediones, metformin). PMID- 25691773 TI - Novel actions of next-generation taxanes benefit advanced stages of prostate cancer. AB - PURPOSE: To improve the outcomes of patients with castration-resistant prostate cancer (CRPC), there is an urgent need for more effective therapies and approaches that individualize specific treatments for patients with CRPC. These studies compared the novel taxane cabazitaxel with the previous generation docetaxel, and aimed to determine which tumors are most likely to respond. EXPERIMENTAL DESIGN: Cabazitaxel and docetaxel were compared via in vitro modeling to determine the molecular mechanism, biochemical and cell biologic impact, and cell proliferation, which was further assessed ex vivo in human tumor explants. Isogenic pairs of RB knockdown and control cells were interrogated in vitro and in xenograft tumors for cabazitaxel response. RESULTS: The data herein show that (i) cabazitaxel exerts stronger cytostatic and cytotoxic response compared with docetaxel, especially in CRPC; (ii) cabazitaxel induces aberrant mitosis, leading to pyknotic and multinucleated cells; (iii) taxanes do not act through the androgen receptor (AR); (iv) gene-expression profiling reveals distinct molecular actions for cabazitaxel; and (v) tumors that have progressed to castration resistance via loss of RB show enhanced sensitivity to cabazitaxel. CONCLUSIONS: Cabazitaxel not only induces improved cytostatic and cytotoxic effects, but also affects distinct molecular pathways, compared with docetaxel, which could underlie its efficacy after docetaxel treatment has failed in patients with CRPC. Finally, RB is identified as the first potential biomarker that could define the therapeutic response to taxanes in metastatic CRPC. This would suggest that loss of RB function induces sensitization to taxanes, which could benefit up to 50% of CRPC cases. PMID- 25691774 TI - pVHL/HIF-regulated CD70 expression is associated with infiltration of CD27+ lymphocytes and increased serum levels of soluble CD27 in clear cell renal cell carcinoma. AB - PURPOSE: CD70, a member of the TNF ligand superfamily, has been shown frequently overexpressed in clear cell renal cell carcinoma (ccRCC). The mechanisms of CD70's upregulation and its role in ccRCC are unknown. EXPERIMENTAL DESIGN: CD70 expression was immunohistochemically analyzed in 667 RCCs and RCC metastases. Von Hippel-Lindau gene (VHL) mutations, expression patterns of VHL protein (pVHL), hypoxia-inducible factor (HIF) alpha, and several HIF targets were studied in tissues and cell lines and correlated with CD70 overexpression. Gene promoter analysis was performed to confirm CD70 as HIF target gene. Consecutive tissue sections were immunostained to reveal the relation between CD70-expressing RCCs and tumor-infiltrating lymphocytes positive for the CD70 receptor (CD27). CD70 mediated release of soluble CD27 in RCC was assessed by coculture experiments and sera analysis of patients with RCC. RESULTS: Elevated CD70 expression was seen in 80% of primary tumors and metastases of ccRCC and correlated with dysregulation of the pVHL/HIF pathway. In vitro analyses demonstrated that CD70 upregulation is driven by HIF. Furthermore, CD27(+) lymphocytes preferentially infiltrate CD70 expressing ccRCCs. CD70-dependent release of soluble CD27 in cocultures may explain the high CD27 levels observed in sera of patients with CD70-expressing ccRCC. The combination of lymphocyte infiltration and CD70 expression in RCC was associated with worse patient outcome. CONCLUSION: Our findings demonstrate that in ccRCC, CD70 expression is regulated by HIF as a consequence of pVHL inactivation. Increased serum levels of CD27 suggest the existence of CD70 expressing ccRCC, thus representing a potential serum marker for patients suffering from this disease. PMID- 25691775 TI - Ang1 and Tie2 are predictive biomarkers for bevacizumab-letter. PMID- 25691776 TI - Correction: reduced p21WAF1/CIP1 via alteration of p53-DDX3 pathway is associated with poor relapse-free survival in early-stage human papillomavirus-associated lung cancer. PMID- 25691777 TI - Linking differences in action perception with differences in action execution. AB - Successful human social interactions depend upon the transmission of verbal and non-verbal signals from one individual to another. Non-verbal social communication is realized through our ability to read and understand information present in other people's actions. It has been proposed that employing the same motor programs, we use to execute an action when observing the same action underlies this action understanding. The main prediction of this framework is that action perception should be strongly correlated with parameters of action execution. Here, we demonstrate that subjects' sensitivity to observed movement speeds is dependent upon how quickly they themselves executed the observed action. This result is consistent with the motor theory of social cognition and suggests that failures in non-verbal social interactions between individuals may in part result from differences in how those individuals move. PMID- 25691778 TI - White matter microstructure in the executive network associated with aggression in healthy adolescents and young adults. AB - Predicting which individuals may engage in aggressive behavior is of interest in today's society; however, there is little data on the neural basis of aggression in healthy individuals. Here, we tested whether regional differences in white matter (WM) microstructure were associated with later reports of aggressive tendencies. We recontacted healthy young adults an average of 3 years after they underwent research MRI scans. Via electronic survey, we administered the Buss Perry Aggression Questionnaire. We divided aggression into Aggressive Thoughts (Anger and Hostility subscales) and Aggressive Acts (Verbal and Physical subscales) and used Tract-Based Spatial Statistics to test the relationship of those measures to WM microstructure. In 45 individuals age 15-30 at baseline, we observed significant relationships between Aggressive Acts and fractional anisotropy (FA) in a parietal region consistent with the superior longitudinal fasciculus (SLF). As the SLF has an established relationship to executive function, we performed an exploratory analysis in a subset of individuals with working memory data. Decreased FA in executive network regions, as well as working memory performance, were associated with later self-reported aggressive tendencies. This has implications for our healthy behavior understanding of as well as that of patient populations known to have executive dysfunction. PMID- 25691781 TI - Physicians and climate change policy: we are powerful agents of change. PMID- 25691782 TI - Drugged-driving: putting the brakes on pot use. PMID- 25691784 TI - The new ethics of Aboriginal health research. PMID- 25691785 TI - Peer review conflicts of interest surface at CIHR. PMID- 25691786 TI - Cognitive assessments in multicultural populations using the Rowland Universal Dementia Assessment Scale: a systematic review and meta-analysis. AB - BACKGROUND: Canada has a growing multinational immigrant population. Many commonly used cognitive assessment tools have known cultural biases and are difficult to use in ethnically diverse patient populations. The Rowland Universal Dementia Assessment Scale (RUDAS) is a cognitive assessment tool that was created for culturally and linguistically diverse populations. We performed a systematic review and meta-analysis to assess the psychometric characteristics of the RUDAS and to compare it with other available tools. METHODS: We identified studies that assessed the psychometric properties of the RUDAS compared with a reference standard for diagnosing dementia or compared the RUDAS to other cognitive assessment tools. Two independent reviewers screened the abstracts and full-text articles and reviewed bibliographies for further references. We extracted data using standardized forms and assessed studies for risk of bias. RESULTS: Our search resulted in 148 articles, from which 11 were included. The RUDAS was assessed in 1236 participants and was found to have a pooled sensitivity of 77.2% (95% confidence interval [CI] 67.4-84.5) and a pooled specificity of 85.9% (95% CI 74.8-92.6) yielding a positive likelihood ratio of 5.5 (95% CI 2.9-10.7) and a negative likelihood ratio of 0.27 (95% CI 0.17-0.40). A pooled estimate of the correlation between the RUDAS and the Mini-Mental State Examination (MMSE) was 0.77 (95% CI 0.72-0.81). Results of the RUDAS were less affected by language and education level than the MMSE. INTERPRETATION: The RUDAS is a brief and freely available cognitive assessment tool with reasonable psychometric characteristics that may be particularly useful in patients with diverse backgrounds. PMID- 25691787 TI - Canada's response to female genital mutilation: are we failing our girls? PMID- 25691788 TI - Tremor mimicking ventricular tachycardia. PMID- 25691789 TI - CIHR modifies virtual peer review amidst complaints. PMID- 25691790 TI - How to assess a survey report: a guide for readers and peer reviewers. PMID- 25691791 TI - A 37-year-old man with numbness in the hand. PMID- 25691792 TI - Red tape blocks care for Aboriginal children. PMID- 25691794 TI - Other consequences of reduced duty hours. PMID- 25691795 TI - Other consequences of reduced duty hours. The authors respond. PMID- 25691796 TI - Medical tourism dialogue needs a broader scope. PMID- 25691797 TI - Canada must help the wounded children of Gaza. PMID- 25691798 TI - Management of a 28-year-old with chest pain. PMID- 25691799 TI - Management of a 28-year-old with chest pain. The authors respond. PMID- 25691800 TI - Hepatitis C screening. PMID- 25691801 TI - Assembly of a Cost-Effective Anode Using Palladium Nanoparticles for Alkaline Fuel Cell Applications. AB - Nanotechnology allows the synthesis of nanoscale catalysts, which offer an efficient alternative for fuel cell applications. In this laboratory experiment, the student selects a cost-effective anode for fuel cells by comparing three different working electrodes. These are commercially available palladium (Pd) and glassy carbon (GC) electrodes, and a carbon paste (CP) electrode that is prepared by the students in the laboratory. The GC and CP were modified with palladium nanoparticles (PdNP) suspensions. The electrodes efficiencies were studied for ethanol oxidation in alkaline solution using cyclic voltammetry techniques. The ethanol oxidation currents obtained were used to determine the current density using the geometric and surface area of each electrode. Finally, students were able to choose the best electrode and relate catalytic activity to surface area for ethanol oxidation in alkaline solution by completing a critical analysis of the cyclic voltammetry results. With this activity, fundamental electrochemical concepts were reinforced. PMID- 25691802 TI - Laminar Tendon Composites with Enhanced Mechanical Properties. AB - PURPOSE: A strong isotropic material that is both biocompatible and biodegradable is desired for many biomedical applications, including rotator cuff repair, tendon and ligament repair, vascular grafting, among others. Recently, we developed a technique, called "bioskiving" to create novel 2D and 3D constructs from decellularized tendon, using a combination of mechanical sectioning, and layered stacking and rolling. The unidirectionally aligned collagen nanofibers (derived from sections of decellularized tendon) offer good mechanical properties to the constructs compared with those fabricated from reconstituted collagen. METHODS: In this paper, we studied the effect that several variables have on the mechanical properties of structures fabricated from tendon slices, including crosslinking density and the orientation in which the fibers are stacked. RESULTS: We observed that following stacking and crosslinking, the strength of the constructs is significantly improved, with crosslinked sections having an ultimate tens ile strength over 20 times greater than non-crosslinked samples, and a modulus nearly 50 times higher. The mechanism of the mechanical failure mode of the tendon constructs with or without crosslinking was also investigated. CONCLUSIONS: The strength and fiber organization, combined with the ability to introduce transversely isotropic mechanical properties makes the laminar tendon composites a biocompatiable material that may find future use in a number of biomedical and tissue engineering applications. PMID- 25691803 TI - Hopping Diffusion of Nanoparticles in Polymer Matrices. AB - We propose a hopping mechanism for diffusion of large nonsticky nanoparticles subjected to topological constraints in both unentangled and entangled polymer solids (networks and gels) and entangled polymer liquids (melts and solutions). Probe particles with size larger than the mesh size ax of unentangled polymer networks or tube diameter ae of entangled polymer liquids are trapped by the network or entanglement cells. At long time scales, however, these particles can diffuse by overcoming free energy barrier between neighboring confinement cells. The terminal particle diffusion coefficient dominated by this hopping diffusion is appreciable for particles with size moderately larger than the network mesh size ax or tube diameter ae . Much larger particles in polymer solids will be permanently trapped by local network cells, whereas they can still move in polymer liquids by waiting for entanglement cells to rearrange on the relaxation time scales of these liquids. Hopping diffusion in entangled polymer liquids and networks has a weaker dependence on particle size than that in unentangled networks as entanglements can slide along chains under polymer deformation. The proposed novel hopping model enables understanding the motion of large nanoparticles in polymeric nanocomposites and the transport of nano drug carriers in complex biological gels such as mucus. PMID- 25691804 TI - Teacher Distress and the Role of Experiential Avoidance. AB - Teachers' psychological wellbeing is important for teachers and students, but is highly stressful, particularly in special education. We examined the role of experiential avoidance (EA) in the wellbeing of 529 middle and elementary school teachers. EA involves the tendency to avoid thoughts, feelings, and other internal experiences even when doing so causes long-range consequences. Using a teacher-specific measure, we investigated its relationship to stress associated with student misbehavior and limited social support. We assessed EA's relationship to burnout and depression, finding EA significantly and moderately correlated with depression and all scales of Maslach's Burnout Inventory. Mediation analyses showed EA mediated the relationship between stress associated with student behavior and measures of wellbeing. We found 26.8% of teachers mildly, 8.9% moderately, and 2.8% moderately severely or severely depressed. This evidence concurs with studies showing the value of mindfulness-based interventions and points to the utility of implementing interventions aimed at decreasing EA in teachers. PMID- 25691805 TI - A divergent route to 9, 10-oxygenated tetrahydroprotoberberine and 8 oxoprotoberberine alkaloids: synthesis of (+/-)-isocorypalmine and oxypalmatine. AB - A new route which is germane to the synthesis of 9,10-oxygenated tetrahydroprotoberberines and 8-oxoprotoberberines is described. The route features the use of a diester (14) generated from reaction of dimethylmalonate with an aryl halide in the presence of n-butyllithium. The amide 17 prepared in subsequent steps is a versatile precursor for the synthesis of tetrahydroprotoberberine and 8-oxoprotoberberine scaffolds using standard high yielding reactions. In this manner, (+/-)-isocorypalmine and oxypalmatine have been synthesized in 23% and 22 % yields respectively. PMID- 25691806 TI - Correlation between sperm parameters and protein expression of antioxidative defense enzymes in seminal plasma: a pilot study. AB - BACKGROUND: Semen analysis is the cornerstone in the evaluation of male (in)fertility. However, there are men with normal semen tests but with impaired fertilizing ability, as well as fertile men with poor sperm characteristics. Thus, there is rising interest to find novel parameters that will help to predict and define the functional capacity of spermatozoa. METHODS: We examined whether there is a correlation between semen parameters (count, progressive motility, and morphology) and protein expression/activity of antioxidative defense enzymes in seminal plasma from 10 normospermic subjects. RESULTS: Sperm progressive motility was in positive correlation with seminal plasma protein expression of both superoxide dismutase (SOD) isoforms (MnSOD and CuZnSOD) and catalase. Also, positive correlation was observed between sperm count and MnSOD protein expression, as well as between sperm morphology and protein expression of catalase in seminal plasma. In contrast, protein expression of glutathione peroxidase was not in correlation with any sperm parameter, while its activity negatively correlated with sperm morphology and motility. CONCLUSIONS: These data suggest that evaluation of protein expression of antioxidative defense enzymes in seminal plasma might be of importance in the evaluation of male fertility status and that could be used as an additional biomarker along with classic semen analysis in assessment of semen quality. PMID- 25691807 TI - High CD133 expression in the nucleus and cytoplasm predicts poor prognosis in non small cell lung cancer. AB - OBJECTIVE: The aim of this study was to investigate the expression of Prominin-1 (CD133) in cancer cells and its potential value as a prognostic indicator of survival in patients with non-small cell lung cancer (NSCLC). METHODS: Cancerous tissues and matched normal tissues adjacent to the carcinoma from 239 NSCLC patients were obtained immediately after surgery. Immunohistochemistry of tissue microarrays was used to characterize the expression of CD133 in NSCLC and adjacent tissues. The correlation of CD133 expression with clinical characteristics and prognosis was determined by statistical analysis. RESULTS: CD133 protein expression levels in both the cytoplasm and nucleus were significantly higher in NSCLC tissues compared with corresponding peritumoral tissue (P < 0.05). CD133 expression in the nucleus of NSCLC cells was related to tumor diameter (P = 0.027), tumor differentiation (P < 0.001), and TNM stage (P = 0.007). Kaplan-Meier survival and Cox regression analyses revealed that high CD133 expression in the nucleus was an independent predictor of poor prognosis of NSCLC, as was high cytoplasmic CD133 expression (P < 0.001). CONCLUSION: Our findings provide the first evidence that high expression of CD133 in both the nucleus and cytoplasm is associated with poor prognosis in NSCLC. PMID- 25691808 TI - Deficits in endogenous adenosine formation by ecto-5'-nucleotidase/CD73 impair neuromuscular transmission and immune competence in experimental autoimmune myasthenia gravis. AB - AMP dephosphorylation via ecto-5'-nucleotidase/CD73 is the rate limiting step to generate extracellular adenosine (ADO) from released adenine nucleotides. ADO, via A2A receptors (A2ARs), is a potent modulator of neuromuscular and immunological responses. The pivotal role of ecto-5'-nucleotidase/CD73, in controlling extracellular ADO formation, prompted us to investigate its role in a rat model of experimental autoimmune myasthenia gravis (EAMG). Results show that CD4(+)CD25(+)FoxP3(+) regulatory T cells express lower amounts of ecto-5' nucleotidase/CD73 as compared to controls. Reduction of endogenous ADO formation might explain why proliferation of CD4(+) T cells failed upon blocking A2A receptors activation with ZM241385 or adenosine deaminase in EAMG animals. Deficits in ADO also contribute to neuromuscular transmission failure in EAMG rats. Rehabilitation of A2AR-mediated immune suppression and facilitation of transmitter release were observed by incubating the cells with the nucleoside precursor, AMP. These findings, together with the characteristic increase in serum adenosine deaminase activity of MG patients, strengthen our hypothesis that the adenosinergic pathway may be dysfunctional in EAMG. Given that endogenous ADO formation is balanced by ecto-5'-nucleotidase/CD73 activity and that A2ARs exert a dual role to restore use-dependent neurocompetence and immune suppression in myasthenics, we hypothesize that stimulation of the two mechanisms may have therapeutic potential in MG. PMID- 25691809 TI - Modulation of extracellular ATP content of mast cells and DRG neurons by irradiation: studies on underlying mechanism of low-level-laser therapy. AB - Low-level-laser therapy (LLLT) is an effective complementary treatment, especially for anti-inflammation and wound healing in which dermis or mucus mast cells (MCs) are involved. In periphery, MCs crosstalk with neurons via purinergic signals and participate in various physiological and pathophysiological processes. Whether extracellular ATP, an important purine in purinergic signaling, of MCs and neurons could be modulated by irradiation remains unknown. In this study, effects of red-laser irradiation on extracellular ATP content of MCs and dorsal root ganglia (DRG) neurons were investigated and underlying mechanisms were explored in vitro. Our results show that irradiation led to elevation of extracellular ATP level in the human mast cell line HMC-1 in a dose dependent manner, which was accompanied by elevation of intracellular ATP content, an indicator for ATP synthesis, together with [Ca(2+)]i elevation, a trigger signal for exocytotic ATP release. In contrast to MCs, irradiation attenuated the extracellular ATP content of neurons, which could be abolished by ARL 67156, a nonspecific ecto-ATPases inhibitor. Our results suggest that irradiation potentiates extracellular ATP of MCs by promoting ATP synthesis and release and attenuates extracellular ATP of neurons by upregulating ecto-ATPase activity. The opposite responses of these two cell types indicate complex mechanisms underlying LLLT. PMID- 25691810 TI - Xerostomia induced by radiotherapy: an overview of the physiopathology, clinical evidence, and management of the oral damage. AB - BACKGROUND: The irradiation of head and neck cancer (HNC) often causes damage to the salivary glands. The resulting salivary gland hypofunction and xerostomia seriously reduce the patient's quality of life. PURPOSE: To analyze the literature of actual management strategies for radiation-induced hypofunction and xerostomia in HNC patients. METHODS: MEDLINE/PubMed and the Cochrane Library databases were electronically evaluated for articles published from January 1, 1970, to June 30, 2013. Two reviewers independently screened and included papers according to the predefined selection criteria. RESULTS: Sixty-one articles met the inclusion criteria. The systematic review of the literature suggests that the most suitable methods for managing the clinical and pathophysiological consequences of HNC radiotherapy might be the pharmacological approach, for example, through the use of cholinergic agonists when residual secretory capacity is still present, and the use of salivary substitutes. In addition, a modified diet and the patient's motivation to enhance oral hygiene can lead to a significant improvement. CONCLUSION: Radiation-induced xerostomia could be considered a multifactorial disease. It could depend on the type of cancer treatment and the cumulative radiation dose to the gland tissue. A preventive approach and the correct treatment of the particular radiotherapeutic patient can help to improve the condition of xerostomia. PMID- 25691811 TI - Hedgehog signaling in cancer stem cells: a focus on hematological cancers. AB - The stem cell paradigm was first demonstrated in hematopoietic stem cells. Whilst classically it was cytokines and chemokines which were believed to control stem cell fate, more recently it has become apparent that the stem cell niche and highly conserved embryonic pathways play a key role in governing stem cell behavior. One of these pathways, the hedgehog signaling pathway, found in all organisms, is vitally important in embryogenesis, performing the function of patterning through early stages of development, and in adulthood, through the control of somatic stem cell numbers. In addition to these roles in health however, it has been found to be deregulated in a number of solid and hematological malignancies, components of the hedgehog pathway being associated with a poor prognosis. Further, these components represent viable therapeutic targets, with inhibition from a drug development perspective being readily achieved, making the hedgehog pathway an attractive potential therapeutic target. However, although the concept of cancer stem cells is well established, how these cells arise and the factors which influence their behavior are not yet fully understood. The role of the hedgehog signaling pathway and its potential as a therapeutic target in hematological malignancies is the focus of this review. PMID- 25691812 TI - Targeted treatment for chronic lymphocytic leukemia: clinical potential of obinutuzumab. AB - Introduction of targeted agents revolutionized the treatment of chronic lymphocytic leukemia (CLL) in the past decade. Addition of chimeric monoclonal anti-CD20 antibody rituximab to chemotherapy significantly improved efficacy including overall survival (OS) in untreated fit patients; humanized anti-CD52 antibody alemtuzumab and fully human anti-CD20 antibody ofatumumab lead to improvement in refractory disease. Novel small molecule inhibitors such as ibrutinib and idelalisib demonstrated excellent activity and were very recently licensed in relapsed/refractory CLL. Obinutuzumab (GA101) is the newest monoclonal antibody approved for the treatment of CLL. This novel, glycoengineered, type II humanized anti-CD20 antibody is characterized by enhanced antibody-dependent cellular cytotoxicity and direct induction of cell death compared to type I antibodies. Combination of obinutuzumab and chlorambucil yielded significantly better OS in comparison to chlorambucil monotherapy in untreated comorbid patients. These results led to approval of obinuzutumab for the treatment of CLL. Numerous clinical trials combining obinutuzumab with other cytotoxic drugs and novel small molecules are currently under way. This review focuses on the role of obinutuzumab in the treatment of CLL. PMID- 25691814 TI - Targeted treatments for multiple myeloma: specific role of carfilzomib. AB - Carfilzomib is a selective, irreversible proteasome inhibitor, initially approved in the US in 2012 as single-agent therapy for relapsed and refractory multiple myeloma. Numerous Phase II studies have evaluated carfilzomib in the relapsed and refractory as well as the newly diagnosed setting, and Phase III studies are entering their final analysis. Data continue to grow to support its use as both single-agent therapy and in combination with immunomodulatory and other novel agents. This review discusses the role of carfilzomib in the treatment of multiple myeloma. Its mechanism of action, pharmacokinetics, and role in clinical management will be reviewed. PMID- 25691813 TI - Asthma pharmacogenetics and the development of genetic profiles for personalized medicine. AB - Human genetics research will be critical to the development of genetic profiles for personalized or precision medicine in asthma. Genetic profiles will consist of gene variants that predict individual disease susceptibility and risk for progression, predict which pharmacologic therapies will result in a maximal therapeutic benefit, and predict whether a therapy will result in an adverse response and should be avoided in a given individual. Pharmacogenetic studies of the glucocorticoid, leukotriene, and beta2-adrenergic receptor pathways have focused on candidate genes within these pathways and, in addition to a small number of genome-wide association studies, have identified genetic loci associated with therapeutic responsiveness. This review summarizes these pharmacogenetic discoveries and the future of genetic profiles for personalized medicine in asthma. The benefit of a personalized, tailored approach to health care delivery is needed in the development of expensive biologic drugs directed at a specific biologic pathway. Prior pharmacogenetic discoveries, in combination with additional variants identified in future studies, will form the basis for future genetic profiles for personalized tailored approaches to maximize therapeutic benefit for an individual asthmatic while minimizing the risk for adverse events. PMID- 25691815 TI - Awareness regarding clinical application of pharmacogenetics among Japanese pharmacists. AB - Advances in pharmacogenetic analysis technology have accelerated the movement to incorporate pharmacogenetic analysis data into medicine. Therefore, pharmacists will soon have to provide guidance and raise pharmaceutical questions regarding prescriptions based on patient pharmacogenomic information. The objective of this study was to clarify Japanese pharmacists' awareness of pharmacogenetics. We conducted a postal questionnaire survey among 372 pharmacists belonging to Tsuruha Holdings. Available data were collected from 268 pharmacists (male [n=133], <40 years old [n=170], drugstore pharmacists [n=182]). Of the pharmacists, 19.0% of the population were aware of the Ethical Guidelines for Human Genome/ Gene Analysis Research in Japan, 31.0% of the population had heard either or both the terms "pharmacogenomics" and "pharmacogenetics", and 16.8% of the population were aware that health insurance covered pharmacogenomic tests performed before prescription in Japan. Only 0.4% indicated that they could raise pharmaceutical questions regarding prescriptions based on patients' pharmacogenomic information, and 61.2% of the population indicated a preference to undertake pharmacogenomic tests to predict the efficacy or adverse reactions of a drug. We found a need for actions to improve the awareness of pharmacists about pharmacogenetics and create an environment in which pharmacists are able to provide appropriate medical service based on pharmacogenomic information. PMID- 25691816 TI - Cancer stem cells in haematological malignancies. AB - At least several types of human haematological malignancies can now be seen as 'stem-cell diseases'. The best-studied in this context is acute myeloid leukaemia (AML). It has been shown that these diseases are driven by a pool of 'leukaemia stem cells (LSC)', which remain in the quiescent state, have the capacity to survive and self-renew, and are responsible for the recurrence of cancer after classical chemotherapy. It has been understood that LSC must be eliminated in order to cure patients suffering from haematological cancers. Recent advances in LSC research have allowed for description of LSC phenotype and identification of potential targets for anti-LSC therapies. This concise review summarises the current view on LSC biology and targeted approaches against LSC. PMID- 25691817 TI - Oncogenesis and induced pluripotency - commonalities of signalling pathways. AB - Rapid progress in the field of adult cells reprogramming back into a stem cell like fate revealed shared mechanisms of action with tumoural reprogramming. A hallmark of stem cells - self-renewal and differentiation potential - seems to be tightly interlaced with large proliferation capacity and cellular plasticity of cancer cells. In this review, we briefly summarise the core transcription factors critical to maintenance of ES cell signature and overexpressed in many types of cancer, as well as signalling pathways involved in both induced pluripotency and oncogenesis, with particular regard to the role of tumour suppressor p53. PMID- 25691818 TI - Molecular mechanisms of induced pluripotency. AB - Growing knowledge concerning transcriptional control of cellular pluripotency has led to the discovery that the fate of differentiated cells can be reversed, which has resulted in the generation, by means of genetic manipulation, of induced pluripotent stem cells. Overexpression of just four pluripotency-related transcription factors, namely Oct3/4, Sox2, Klf4, and c-Myc (Yamanaka factors, OKSM), in fibroblasts appears sufficient to produce this new cell type. Currently, we know that these factors induce several changes in genetic program of differentiated cells that can be divided in two general phases: the initial one is stochastic, and the subsequent one is highly hierarchical and organised. This review briefly discusses the molecular events leading to induction of pluripotency in response to forced presence of OKSM factors in somatic cells. We also discuss other reprogramming strategies used thus far as well as the advantages and disadvantages of laboratory approaches towards pluripotency induction in different cell types. PMID- 25691819 TI - Epigenetic mechanisms of induced pluripotency. AB - Reprogramming of somatic cells to induced pluripotent stem cells (iPSCs) requires profound alterations in the epigenetic landscape. During reprogramming, a change in chromatin structure resets the gene expression and stabilises self-renewal. Reprogramming is a highly inefficient process, in part due to multiple epigenetic barriers. Although many epigenetic factors have already been shown to affect self renewal and pluripotency in embryonic stem cells (ESCs), only a few of them have been examined in the context of dedifferentiation. In order to improve current protocols of iPSCs generation, it is essential to identify epigenetic drivers and blockages of somatic cell reprogramming. PMID- 25691820 TI - Hypoxia-shaped vascular niche for cancer stem cells. AB - The tumour microenvironment, long considered as determining cancer development, still offers research fields to define hallmarks of cancer. An early key-step, the "angiogenic switch", allows tumour growth. Pathologic angiogenesis is a cancer hallmark as it features results of tumour-specific properties that can be summarised as a response to hypoxia. The hypoxic state occurs when the tumour mass reaches a volume sufficient not to permit oxygen diffusion inside the tumour centre. Thus tumour cells turn on adaptation mechanisms to the low pO2 level, inducing biochemical responses in terms of cytokines/chemokines/receptors and consequently recruitment of specific cell types, as well as cell-selection inside the tumour. Moreover, these changes are orchestrated by the microRNA balance strongly reflecting the hypoxic milieu and mediating the cross-talk between endothelial and tumour cells. MicroRNAs control of the endothelial precursor vascular settings shapes the niche for selection of cancer stem cells. PMID- 25691821 TI - Biology of renal tumour cancer stem cells applied in medicine. AB - The present article highlights the diverse role of stem cells in normal kidney and renal cancer, with special emphasis on surface markers. Proteins such as CD105 and CD133 have been reported as being significant in clear cell renal cell carcinoma (ccRCC) cancer stem cells. The role of normal kidney progenitor cells and their surface markers is compared with the role of those surface markers in ccRCC. Subsequently, we state the current hypothesis about origin of tumour initiating cells along with their clinical and prognostic potential in RCC. Finally, we present future perspectives with respect to recent studies. PMID- 25691822 TI - Immunotargeting of cancer stem cells. AB - Cancer stem cells (CSCs) represent a distinctive population of tumour cells that control tumour initiation, progression, and maintenance. Their influence is great enough to risk the statement that successful therapeutic strategy must target CSCs in order to eradicate the disease. Because cancer stem cells are highly resistant to chemo- and radiotherapy, new tools to fight against cancer have to be developed. Expression of antigens such as ALDH, CD44, EpCAM, or CD133, which distinguish CSCs from normal cells, together with CSC immunogenicity and relatively low toxicity of immunotherapies, makes immune targeting of CSCs a promising approach for cancer treatment. This review will present immunotherapeutic approaches using dendritic cells, T cells, pluripotent stem cells, and monoclonal antibodies to target and eliminate CSCs. PMID- 25691823 TI - Selenium as a marker of cancer risk and of selection for control examinations in surveillance. AB - Publication is summarization of existing data being results of literature review and our experience on usefulness of selenium as a diagnostic marker selection for control examinations in surveillance and as a marker of patients with high risk of cancers. PMID- 25691824 TI - Viruses in cancer cell plasticity: the role of hepatitis C virus in hepatocellular carcinoma. AB - Viruses are considered as causative agents of a significant proportion of human cancers. While the very stringent criteria used for their classification probably lead to an underestimation, only six human viruses are currently classified as oncogenic. In this review we give a brief historical account of the discovery of oncogenic viruses and then analyse the mechanisms underlying the infectious causes of cancer. We discuss viral strategies that evolved to ensure virus propagation and spread can alter cellular homeostasis in a way that increases the probability of oncogenic transformation and acquisition of stem cell phenotype. We argue that a useful way of analysing the convergent characteristics of viral infection and cancer is to examine how viruses affect the so-called cancer hallmarks. This view of infectious origin of cancer is illustrated by examples from hepatitis C infection, which is associated with a high proportion of hepatocellular carcinoma. PMID- 25691825 TI - The Cancer Genome Atlas (TCGA): an immeasurable source of knowledge. AB - The Cancer Genome Atlas (TCGA) is a public funded project that aims to catalogue and discover major cancer-causing genomic alterations to create a comprehensive "atlas" of cancer genomic profiles. So far, TCGA researchers have analysed large cohorts of over 30 human tumours through large-scale genome sequencing and integrated multi-dimensional analyses. Studies of individual cancer types, as well as comprehensive pan-cancer analyses have extended current knowledge of tumorigenesis. A major goal of the project was to provide publicly available datasets to help improve diagnostic methods, treatment standards, and finally to prevent cancer. This review discusses the current status of TCGA Research Network structure, purpose, and achievements. PMID- 25691826 TI - Regulation of breast cancer stem cell features. AB - Cancer stem cells (CSCs) are rare, tumour-initiating cells that exhibit stem cell properties: capacity of self-renewal, pluripotency, highly tumorigenic potential, and resistance to therapy. Cancer stem cells have been characterised and isolated from many cancers, including breast cancer. Developmental pathways, such as the Wnt/beta-catenin, Notch/gamma-secretase/Jagged, Shh (sonic hedgehog), and BMP signalling pathways, which direct proliferation and differentiation of normal stem cells, have emerged as major signalling pathways that contribute to the self renewal of stem and/or progenitor cells in a variety of organs and cancers. Deregulation of these signalling pathways is frequently linked to an epithelial mesenchymal transition (EMT), and breast CSCs often possess properties of cells that have undergone the EMT process. Signalling networks mediated by microRNAs and EMT-inducing transcription factors tie the EMT process to regulatory networks that maintain "stemness". Recent studies have elucidated epigenetic mechanisms that control pluripotency and stemness, which allows an assessment on how embryonic and normal tissue stem cells are deregulated during cancerogenesis to give rise to CSCs. Epigenetic-based mechanisms are reversible, and the possibility of "resetting" the abnormal cancer epigenome by applying pharmacological compounds targeting epigenetic enzymes is a promising new therapeutic strategy. Chemoresistance of CSCs is frequently driven by various mechanisms, including aberrant expression/activity of ABC transporters, aldehyde dehydrogenase and anti-oncogenic proteins (i.e. BCL2, B-cell lymphoma-2), enhanced DNA damage response, activation of pro-survival signalling pathways, and epigenetic deregulations. Despite controversy surrounding the CSC hypothesis, there is substantial evidence for their role in cancer, and a number of drugs intended to specifically target CSCs have entered clinical trials. PMID- 25691827 TI - Computational characterisation of cancer molecular profiles derived using next generation sequencing. AB - Our current understanding of cancer genetics is grounded on the principle that cancer arises from a clone that has accumulated the requisite somatically acquired genetic aberrations, leading to the malignant transformation. It also results in aberrent of gene and protein expression. Next generation sequencing (NGS) or deep sequencing platforms are being used to create large catalogues of changes in copy numbers, mutations, structural variations, gene fusions, gene expression, and other types of information for cancer patients. However, inferring different types of biological changes from raw reads generated using the sequencing experiments is algorithmically and computationally challenging. In this article, we outline common steps for the quality control and processing of NGS data. We highlight the importance of accurate and application-specific alignment of these reads and the methodological steps and challenges in obtaining different types of information. We comment on the importance of integrating these data and building infrastructure to analyse it. We also provide exhaustive lists of available software to obtain information and point the readers to articles comparing software for deeper insight in specialised areas. We hope that the article will guide readers in choosing the right tools for analysing oncogenomic datasets. PMID- 25691829 TI - Multipolar Ewald methods, 1: theory, accuracy, and performance. AB - The Ewald, Particle Mesh Ewald (PME), and Fast Fourier-Poisson (FFP) methods are developed for systems composed of spherical multipole moment expansions. A unified set of equations is derived that takes advantage of a spherical tensor gradient operator formalism in both real space and reciprocal space to allow extension to arbitrary multipole order. The implementation of these methods into a novel linear-scaling modified "divide-and-conquer" (mDC) quantum mechanical force field is discussed. The evaluation times and relative force errors are compared between the three methods, as a function of multipole expansion order. Timings and errors are also compared within the context of the quantum mechanical force field, which encounters primary errors related to the quality of reproducing electrostatic forces for a given density matrix and secondary errors resulting from the propagation of the approximate electrostatics into the self consistent field procedure, which yields a converged, variational, but nonetheless approximate density matrix. Condensed-phase simulations of an mDC water model are performed with the multipolar PME method and compared to an electrostatic cutoff method, which is shown to artificially increase the density of water and heat of vaporization relative to full electrostatic treatment. PMID- 25691830 TI - Multipolar Ewald methods, 2: applications using a quantum mechanical force field. AB - A fully quantum mechanical force field (QMFF) based on a modified "divide-and conquer" (mDC) framework is applied to a series of molecular simulation applications, using a generalized Particle Mesh Ewald method extended to multipolar charge densities. Simulation results are presented for three example applications: liquid water, p-nitrophenylphosphate reactivity in solution, and crystalline N,N-dimethylglycine. Simulations of liquid water using a parametrized mDC model are compared to TIP3P and TIP4P/Ew water models and experiment. The mDC model is shown to be superior for cluster binding energies and generally comparable for bulk properties. Examination of the dissociative pathway for dephosphorylation of p-nitrophenylphosphate shows that the mDC method evaluated with the DFTB3/3OB and DFTB3/OPhyd semiempirical models bracket the experimental barrier, whereas DFTB2 and AM1/d-PhoT QM/MM simulations exhibit deficiencies in the barriers, the latter for which is related, in part, to the anomalous underestimation of the p-nitrophenylate leaving group pKa. Simulations of crystalline N,N-dimethylglycine are performed and the overall structure and atomic fluctuations are compared with the experiment and the general AMBER force field (GAFF). The QMFF, which was not parametrized for this application, was shown to be in better agreement with crystallographic data than GAFF. Our simulations highlight some of the application areas that may benefit from using new QMFFs, and they demonstrate progress toward the development of accurate QMFFs using the recently developed mDC framework. PMID- 25691831 TI - Efficient implementation of the pair atomic resolution of the identity approximation for exact exchange for hybrid and range- separated density functionals. AB - An efficient new molecular orbital (MO) basis algorithm is reported implementing the pair atomic resolution of the identity approximation (PARI) to evaluate the exact exchange contribution (K) to self-consistent field methods, such as hybrid and range-separated hybrid density functionals. The PARI approximation, in which atomic orbital (AO) basis function pairs are expanded using auxiliary basis functions centered only on their two respective atoms, was recently investigated by Merlot et al. [J. Comput. Chem. 2013, 34, 1486]. Our algorithm is significantly faster than quartic scaling RI-K, with an asymptotic exchange speedup for hybrid functionals of (1 + X/N), where N and X are the AO and auxiliary basis dimensions. The asymptotic speedup is 2 + 2X/N for range separated hybrids such as CAM-B3LYP, omegaB97X-D, and omegaB97X-V which include short- and long-range exact exchange. The observed speedup for exchange in omegaB97X-V for a C68 graphene fragment in the cc-pVTZ basis is 3.4 relative to RI-K. Like conventional RI-K, our method greatly outperforms conventional integral evaluation in large basis sets; a speedup of 19 is obtained in the cc pVQZ basis on a C54 graphene fragment. Negligible loss of accuracy relative to exact integral evaluation is demonstrated on databases of bonded and nonbonded interactions. We also demonstrate both analytically and numerically that the PARI K approximation is variationally stable. PMID- 25691832 TI - KECSA-Movable Type Implicit Solvation Model (KMTISM). AB - Computation of the solvation free energy for chemical and biological processes has long been of significant interest. The key challenges to effective solvation modeling center on the choice of potential function and configurational sampling. Herein, an energy sampling approach termed the "Movable Type" (MT) method, and a statistical energy function for solvation modeling, "Knowledge-based and Empirical Combined Scoring Algorithm" (KECSA) are developed and utilized to create an implicit solvation model: KECSA-Movable Type Implicit Solvation Model (KMTISM) suitable for the study of chemical and biological systems. KMTISM is an implicit solvation model, but the MT method performs energy sampling at the atom pairwise level. For a specific molecular system, the MT method collects energies from prebuilt databases for the requisite atom pairs at all relevant distance ranges, which by its very construction encodes all possible molecular configurations simultaneously. Unlike traditional statistical energy functions, KECSA converts structural statistical information into categorized atom pairwise interaction energies as a function of the radial distance instead of a mean force energy function. Within the implicit solvent model approximation, aqueous solvation free energies are then obtained from the NVT ensemble partition function generated by the MT method. Validation is performed against several subsets selected from the Minnesota Solvation Database v2012. Results are compared with several solvation free energy calculation methods, including a one to-one comparison against two commonly used classical implicit solvation models: MM-GBSA and MM-PBSA. Comparison against a quantum mechanics based polarizable continuum model is also discussed (Cramer and Truhlar's Solvation Model 12). PMID- 25691833 TI - Multilevel summation method for electrostatic force evaluation. AB - The multilevel summation method (MSM) offers an efficient algorithm utilizing convolution for evaluating long-range forces arising in molecular dynamics simulations. Shifting the balance of computation and communication, MSM provides key advantages over the ubiquitous particle-mesh Ewald (PME) method, offering better scaling on parallel computers and permitting more modeling flexibility, with support for periodic systems as does PME but also for semiperiodic and nonperiodic systems. The version of MSM available in the simulation program NAMD is described, and its performance and accuracy are compared with the PME method. The accuracy feasible for MSM in practical applications reproduces PME results for water property calculations of density, diffusion constant, dielectric constant, surface tension, radial distribution function, and distance-dependent Kirkwood factor, even though the numerical accuracy of PME is higher than that of MSM. Excellent agreement between MSM and PME is found also for interface potentials of air-water and membrane-water interfaces, where long-range Coulombic interactions are crucial. Applications demonstrate also the suitability of MSM for systems with semiperiodic and nonperiodic boundaries. For this purpose, simulations have been performed with periodic boundaries along directions parallel to a membrane surface but not along the surface normal, yielding membrane pore formation induced by an imbalance of charge across the membrane. Using a similar semiperiodic boundary condition, ion conduction through a graphene nanopore driven by an ion gradient has been simulated. Furthermore, proteins have been simulated inside a single spherical water droplet. Finally, parallel scalability results show the ability of MSM to outperform PME when scaling a system of modest size (less than 100 K atoms) to over a thousand processors, demonstrating the suitability of MSM for large-scale parallel simulation. PMID- 25691835 TI - Intestinal Research Is Now Registered in PubMed Central. PMID- 25691834 TI - Physics-based potentials for the coupling between backbone- and side-chain-local conformational states in the UNited RESidue (UNRES) force field for protein simulations. AB - The UNited RESidue (UNRES) model of polypeptide chains is a coarse-grained model in which each amino-acid residue is reduced to two interaction sites, namely, a united peptide group (p) located halfway between the two neighboring alpha-carbon atoms (Calphas), which serve only as geometrical points, and a united side chain (SC) attached to the respective Calpha. Owing to this simplification, millisecond molecular dynamics simulations of large systems can be performed. While UNRES predicts overall folds well, it reproduces the details of local chain conformation with lower accuracy. Recently, we implemented new knowledge-based torsional potentials (Krupa et al. J. Chem. Theory Comput. 2013, 9, 4620-4632) that depend on the virtual-bond dihedral angles involving side chains: Calpha...Calpha...Calpha...SC (tau(1)), SC...Calpha...Calpha...Calpha (tau(2)), and SC...Calpha...Calpha...SC (tau(3)) in the UNRES force field. These potentials resulted in significant improvement of the simulated structures, especially in the loop regions. In this work, we introduce the physics-based counterparts of these potentials, which we derived from the all-atom energy surfaces of terminally blocked amino-acid residues by Boltzmann integration over the angles lambda(1) and lambda(2) for rotation about the Calpha...Calpha virtual-bond angles and over the side-chain angles chi. The energy surfaces were, in turn, calculated by using the semiempirical AM1 method of molecular quantum mechanics. Entropy contribution was evaluated with use of the harmonic approximation from Hessian matrices. One-dimensional Fourier series in the respective virtual-bond dihedral angles were fitted to the calculated potentials, and these expressions have been implemented in the UNRES force field. Basic calibration of the UNRES force field with the new potentials was carried out with eight training proteins, by selecting the optimal weight of the new energy terms and reducing the weight of the regular torsional terms. The force field was subsequently benchmarked with a set of 22 proteins not used in the calibration. The new potentials result in a decrease of the root-mean-square deviation of the average conformation from the respective experimental structure by 0.86 A on average; however, improvement of up to 5 A was observed for some proteins. PMID- 25691836 TI - A clinical significance of assessing cytomegalovirus infection status in patients with ulcerative colitis. PMID- 25691837 TI - The positive influences of increasing age at diagnosis of inflammatory bowel disease on disease prognostication in asian perspective. PMID- 25691838 TI - Seminar Report From the 2014 Taiwan Society of Inflammatory Bowel Disease (TSIBD) Spring Forum (May 24th, 2014): Crohn's Disease Versus Intestinal Tuberculosis Infection. AB - Since Taiwan is an endemic area for tuberculosis (TB), differential diagnosis between the intestinal TB and Crohn's disease is an important issue. The steering committee of Taiwan Society of Inflammatory Bowel Disease (TSIBD) has arranged a seminar accordingly on May 24th, 2014 and the different point of views by gastroenterologist, radiologist, pathologist and infectious disease specialist were suggested to help the proper diagnosis and management of these two diseases. PMID- 25691839 TI - Intestinal permeability regulation by tight junction: implication on inflammatory bowel diseases. AB - Epithelial tight junctions (TJs) are the key structures regulating paracellular trafficking of macromolecules. The TJ is multi-protein complex that forms a selective permeable seal between adjacent epithelial cells and demarcates the boundary between apical and basolateral membrane domains. Disruption of the intestinal TJ barrier, followed by permeation of luminal noxious molecules, induces a perturbation of the mucosal immune system and inflammation, which can act as a trigger for the development of intestinal and systemic diseases. Inflammatory bowel disease (IBD) patients demonstrate increased intestinal paracellular permeability. Although it remains unclear whether barrier dysfunction precedes disease or results from active inflammation, increased intestinal TJ disruption is observed in IBD patients suggest that dysregulation of TJ barrier integrity may predispose or enhance IBD progression. Therefore, therapeutic target to restore the TJ barrier integrity may provide effective therapeutic and preventive approaches against IBD. This review discusses the molecular structure and regulation of intestinal TJs and the involvement of intestinal TJs in IBD pathogenesis. PMID- 25691840 TI - Intestinal stricture in Crohn's disease. AB - Crohn's disease (CD) is a disease with chronic inflammation of unknown etiology involving any part of the gastrointestinal tract. The incidence and prevalence of CD are increasing recently in Asia. Half of the CD patients will have intestinal complications, such as strictures or fistulas, within 20 years after diagnosis. Twenty-five percentage of CD patients have had at least one small bowel stricture and 10% have had at least one colonic stricture and lead to significant complications. Most of these patients will require at least one surgery during their lifetime. Early diagnosis and evaluation with adequate managements for the patients can prevent disability and mortality of these patient. Here, we reviewed the current incidence of CD with stricture, the etiology of stricture, and how to diagnose and manage the stricture. PMID- 25691841 TI - Computed tomography enterography and magnetic resonance enterography in the diagnosis of Crohn's disease. AB - Imaging of the small bowel is complicated by its length and its overlapping loops. Recently, however, the development of crosssectional imaging techniques, such as computed tomography enterography (CTE) and magnetic resonance enterography (MRE) has shifted fundamental paradigms in the diagnosis and management of patients with suspected or known Crohn's disease (CD). CTE and MRE are noninvasive imaging tests that involve the use of intraluminal oral and intravenous contrast agents to evaluate the small bowel. Here, we review recent advances in each cross-sectional imaging modality, their advantages and disadvantages, and their diagnostic performances in the evaluation of small bowel lesions in CD. PMID- 25691842 TI - Comparative analysis of gastrointestinal microbiota between normal and caudal related homeobox 2 (cdx2) transgenic mice. AB - BACKGROUND/AIMS: Caudal-related homeobox 2 (Cdx2) is expressed in the human intestinal metaplastic mucosa and induces intestinal metaplastic mucosa in the Cdx2 transgenic mouse stomach. Atrophic gastritis and intestinal metaplasia commonly lead to gastric achlorhydria, which predisposes the stomach to bacterial overgrowth. In the present study, we determined the differences in gut microbiota between normal and Cdx2 transgenic mice, using quantitative reverse transcription polymerase chain reaction (qRT-PCR). METHODS: Twelve normal (control) and 12 Cdx2 transgenic mice were sacrificed, and the gastric, jejunal, ileac, cecal and colonic mucosa, and feces were collected. To quantitate bacterial microbiota, we used real-time qRTPCR with 16S rRNA gene-targeted, species-specific primers. RESULTS: The total numbers of bacteria in the gastric, jejunal, ileac, cecal, and colonic mucosa of the Cdx2 transgenic mice were significantly higher than those of the normal mice. The Bacteroides fragilis group and also Prevotella were not detected in the stomach of the normal mice, although they were detected in the Cdx2 transgenic mice. Moreover, the Clostridium coccoides group, Clostridium leptum subgroup, Bacteroides fragilis group, and Prevotella were not detected in the jejunum or ileum of the normal mice, although they were detected in the Cdx2 transgenic mice. The fecal microbiota of the normal mice was similar to that of the Cdx2 transgenic mice. CONCLUSIONS: Our results showed the differences in composition of gut microbiota between normal and Cdx2 transgenic mice, which may be caused by the development of gastric achlorhydria and intestinal metaplasia in Cdx2 transgenic mice. PMID- 25691843 TI - Usefulness of the cytomegalovirus antigenemia assay in patients with ulcerative colitis. AB - BACKGROUND/AIMS: Patients with ulcerative colitis (UC) are at high risk for cytomegalovirus (CMV) reactivation. The usefulness of the CMV antigenemia assay in active UC patients has rarely been studied. We assessed whether the assay detects CMV colitis and predicts clinical outcomes in patients with UC. METHODS: We retrospectively reviewed the medical records of patients hospitalized for moderate-to-severe UC from 2003 to 2012. Positive CMV antigenemia was defined as >=1 pp65-positive cell per 2*10(5) polymorphonuclear neutrophils. CMV colitis was defined as the presence of inclusion bodies and/or positive immunohistochemistry in the colonic mucosa. The primary outcome was steroid refractoriness, defined as the absence of clinical improvement after intravenous high-dose steroid administration. RESULTS: A total of 43 patients were enrolled. CMV antigenemia was detected in 12 (27.9%) patients. Positive CMV antigenemia was significantly associated with CMV colitis (P =0.001). The sensitivity and specificity of positive CMV antigenemia for diagnosing CMV colitis were 66.7% and 87.1%, respectively. Steroid refractoriness was found in 11 of 12 (91.7%) and 12 of 31 (38.7%) patients with positive and negative CMV antigenemia, respectively (P =0.002). The independent predictors for steroid refractoriness were positive CMV antigenemia (adjusted odds ratio [OR], 7.73; 95% confidence interval [CI], 1.22 49.19; P =0.030) and a shorter duration from the diagnosis of UC (adjusted OR, 0.99; 95% CI, 0.98-0.99; P =0.025). CONCLUSIONS: The CMV antigenemia assay shows low sensitivity but high specificity for detecting CMV colitis and may predict steroid-refractory UC. Early rescue therapy might be considered in UC patients positive for CMV antigenemia. PMID- 25691844 TI - Old age at diagnosis is associated with favorable outcomes in korean patients with inflammatory bowel disease. AB - BACKGROUND/AIMS: Despite the rising incidence and prevalence of inflammatory bowel disease (IBD) in Asian populations, data regarding clinical characteristics of patients in Asia based on age at diagnosis are relatively sparse. The aim of this study was to compare clinical characteristics based on the age at diagnosis according to the Montreal Classification in Korean IBD patients. METHODS: We recruited consecutive patients with IBD at two tertiary hospitals and retrospectively reviewed their medical information. Patients were divided into three groups according to their age at diagnosis: youth (<17 years), young adult (17-40 years), and middle-old (>40 years). The main clinical characteristics for comparison were the achievement of a remission state at the last follow-up visit, cumulative rate of surgery, and cumulative use of immunomodulators and tumor necrosis factor-alpha (TNFalpha) blockers during the follow-up period. RESULTS: In total, 346 IBD patients were included (Crohn's disease [CD] 146 and ulcerative colitis 200; 36 youth, 202 young adult, and 113 middle-old). The middle-old group with CD was characterized by a predominance of uncomplicated behavior (P=0.013) and a lower frequency of perianal disease (P=0.009). The middle-old group was associated more with a less aggressive disease course than the younger group, as shown by more frequent remission (P=0.004), being less likely to undergo surgery (P<0.001), and lower cumulative use of immunomodulators and TNFalpha blockers (P<0.001). CONCLUSIONS: Age at diagnosis according to the Montreal Classification is an important prognostic factor for Korean IBD patients. PMID- 25691845 TI - Circulating ghrelin levels and obestatin/ghrelin ratio as a marker of activity in ulcerative colitis. AB - BACKGROUND/AIMS: Ghrelin levels are known to increase in patients with ulcerative colitis (UC), but serum obestatin levels in UC patients are not well elucidated. The aim of this study was to examine the relationship between serum ghrelin and obestatin levels and disease activity in UC patients. METHODS: The serum ghrelin and obestatin levels were measured in 21 UC patients (12 with active disease and 9 in remission) using enzyme-linked immunosorbent assay. The relationship between the circulating levels of these 2 hormones and disease activity was analyzed. The colonic mucosal mRNA expression of ghrelin and obestatin was measured by quantitative reverse transcription polymerase chain reaction. RESULTS: The mean serum ghrelin values were significantly higher in patients with active disease than in patients with remission (1370.6+/-404.3 vs. 783.5+/-235.3 pg/mL, P=0.001). Colonic mucosal mRNA expression of ghrelin was also significantly higher in patients with active disease than in patients in remission (0.805+/ 0.214 vs. 0.481+/-0.356, P=0.018). However, the mean serum obestatin levels and colonic mucosal mRNA expression of obestatin were not significantly different between both groups. The circulating obestatin/ghrelin ratio was significantly lower in patients with active UC than in patients in remission (0.32+/-0.08 vs. 0.58+/-0.20, P=0.001). CONCLUSIONS: The serum ghrelin levels and the obestatin/ghrelin ratio were related to the activity of UC, but serum obestatin was not related to activity of UC. The ghrelin levels and the obestatin/ghrelin ratio could serve as activity markers in patients with UC. PMID- 25691846 TI - Alcohol drinking increased the risk of advanced colorectal adenomas. AB - BACKGROUND/AIMS: Age, sex, gene and life style are modulating risks for colon cancer. Although alcohol intake may impact on colorectal adenoma, clear association has not been established yet. We aimed to investigate effects of alcohol consumption on the characteristics of colorectal adenoma. METHODS: Patients who underwent colonoscopic polypectomy of colorectal adenoma in the department of gastroenterology of Eulji hospital through 2005 to 2012, having both blood tests and ultrasound or abdominal CT examination were enrolled. The alcohol drinking patients were subdivided into normal or abnormal laboratory group, and alcoholic liver diseases group. RESULTS: 212 patients with colorectal adenoma were analyzed; advanced adenoma and multiple adenoma were found in 68 (32.0%) and 79 (37.2%) patients. When compared to the nondrinker group (120/212 patients), the alcohol drinker group (92/212 patients) represented significantly high odds ratios (ORs) for advanced adenoma (OR, 2.697; P=0.002), and multiple adenoma (OR, 1.929; P=0.039). Among alcohol drinker (92 patients), the ORs of advanced adenoma were 6.407 (P=0.003) in alcoholic liver diseases group (17 patients), 3.711 (P=0.002) in the alcohol drinker with abnormal lab (24 patients), and 2.184 (P=0.034), in the alcohol drinker with normal lab (51 patients) compared to nondrinker group. CONCLUSIONS: This study showed that alcohol drinking may influence on the development of advanced colorectal adenoma and multiplicity. Especially in the group with alcoholic liver diseases and with abnormal lab presented significantly higher ORs of advanced adenoma. PMID- 25691847 TI - Refractory Clostridium difficile Infection Cured With Fecal Microbiota Transplantation in Vancomycin-Resistant Enterococcus Colonized Patient. AB - The rates and severity of Clostridium difficile infections, including pseudomembranous colitis, have increased markedly. However, there are few effective treatments for refractory or recurrent C. difficile infections and the outcomes are poor. Fecal microbiota transplantation is becoming increasingly accepted as an effective and safe intervention in patients with recurrent disease, likely due to the restoration of a disrupted microbiome. Cure rates of >90% are being consistently reported from multiple centers. We cured a case of severe refractory C. difficile infection with fecal microbiota transplantation in a patient colonized by vancomycin-resistant enterococcus. PMID- 25691848 TI - Perianal Abscess and Proctitis by Klebsiella pneumoniae. AB - Klebsiella pneumoniae (K. pneumoniae) can at times cause invasive infections, especially in patients with diabetes mellitus and a history of alcohol abuse. A 61-year-old man with diabetes mellitus and a history of alcohol abuse presented with abdominal and anal pain for two weeks. After admission, he underwent sigmoidoscopy, which revealed multiple ulcerations with yellowish exudate in the rectum and sigmoid colon. The patient was treated with ciprofloxacin and metronidazole. After one week, follow up sigmoidoscopy was performed owing to sustained fever and diarrhea. The lesions were aggravated and seemed webbed in appearance because of damage to the rectal mucosa. Abdominal computed tomography and rectal magnetic resonance imaging were performed, and showed a perianal and perirectal abscess. The patient underwent laparoscopic sigmoid colostomy and perirectal abscess incision and drainage. Extended-spectrum beta-lactamase producing K. pneumoniae was identified in pus culture. The antibiotics were switched to ertapenem. He improved after surgery and was discharged. K. pneumoniae can cause rapid invasive infection in patients with diabetes and a history of alcohol abuse. We report the first rare case of proctitis and perianal abscess caused by invasive K. pneumoniae infection. PMID- 25691849 TI - Anaphylactic shock caused by ingestion of polyethylene glycol. AB - Colonoscopy is the current standard method for evaluation of the colon. The diagnostic accuracy and therapeutic safety of colonoscopy depend on the quality of colonic cleansing and preparation. Generally, all these preparations have been demonstrated to be safe for use in healthy individuals without significant comorbid conditions. Based on safety and efficacy concerns, polyethylene glycol (PEG) is most commonly utilized as a bowel preparation solution for colonoscopy. Adverse events in patients receiving PEG are mostly clinically non-significant. However, fatal adverse events rarely have been shown to occur in the few individuals who experience vomiting or aspiration. Anaphylactic shock associated with ingestion of PEG electrolyte solution is an extremely rare fatal complication, and reported mainly in Western countries. Here, we report the first case of anaphylactic shock following the ingestion of PEG solution in Korea. PMID- 25691850 TI - A patient with intermittent abdominal pain for three weeks. PMID- 25691851 TI - Questions about sedation protocols for double-balloon enteroscopy. PMID- 25691852 TI - Author's Reply. PMID- 25691853 TI - Development of a low-volume, highly sensitive microimmunoassay using computational fluid dynamics-driven multiobjective optimization. AB - Immunoassays are one of the most versatile and widely performed biochemical assays and, given their selectivity and specificity, are used in both clinical and research settings. However, the high cost of reagents and relatively large sample volumes constrain the integration of immunoassays into many applications. Scaling the assay down within microfluidic devices can alleviate issues associated with reagent and sample consumption. However, in many cases a new device is designed and empirically optimized for each specific analyte, a costly and time consuming approach. In this paper, we report the development of a microfluidic bead-based immunoassay which, using antibody coated microbeads, can potentially detect any analyte or combination of analytes for which antibody coated microbeads can be generated. We also developed a computational reaction model and optimization algorithm that can be used to optimize the device for any analyte. We applied this technique to develop a low volume IL-6 immunoassay with high sensitivity (358 fM, 10 pg/mL) and a large dynamic range (4 orders of magnitude). This device design and optimization technique can be used to design assays for any protein with an available antibody and can be used with a large number of applications including biomarker discovery, temporal in vitro studies using a reduced number of cells and reagents, and analysis of scarce biological samples in animal studies and clinical research settings. PMID- 25691854 TI - Do all roads lead to Rome? The role of neuro-immune interactions before birth in the programming of offspring obesity. AB - The functions of the nervous system can be powerfully modulated by the immune system. Although traditionally considered to be quite separate, neuro-immune interactions are increasingly recognized as critical for both normal and pathological nervous system function in the adult. However, a growing body of information supports a critical role for neuro-immune interactions before birth, particularly in the prenatal programming of later-life neurobehavioral disease risk. This review will focus on maternal obesity, as it represents an environment of pathological immune system function during pregnancy that elevates offspring neurobehavioral disease risk. We will first delineate the normal role of the immune system during pregnancy, including the role of the placenta as both a barrier and relayer of inflammatory information between the maternal and fetal environments. This will be followed by the current exciting findings of how immuno-modulatory molecules may elevate offspring risk of neurobehavioral disease by altering brain development and, consequently, later life function. Finally, by drawing parallels with pregnancy complications other than obesity, we will suggest that aberrant immune activation, irrespective of its origin, may lead to neuro-immune interactions that otherwise would not exist in the developing brain. These interactions could conceivably derail normal brain development and/or later life function, and thereby elevate risk for obesity and other neurobehavioral disorders later in the offspring's life. PMID- 25691855 TI - Contextual modulation of social and endocrine correlates of fitness: insights from the life history of a sex changing fish. AB - Steroid hormones are critical regulators of reproductive life history, and the steroid sensitive traits (morphology, behavior, physiology) associated with particular life history stages can have substantial fitness consequences for an organism. Hormones, behavior and fitness are reciprocally associated and can be used in an integrative fashion to understand how the environment impacts organismal function. To address the fitness component, we highlight the importance of using reliable proxies of reproductive success when studying proximate regulation of reproductive phenotypes. To understand the mechanisms by which the endocrine system regulates phenotype, we discuss the use of particular endocrine proxies and the need for appropriate functional interpretation of each. Lastly, in any experimental paradigm, the responses of animals vary based on the subtle differences in environmental and social context and this must also be considered. We explore these different levels of analyses by focusing on the fascinating life history transitions exhibited by the bi-directionally hermaphroditic fish, Lythrypnus dalli. Sex changing fish are excellent models for providing a deeper understanding of the fitness consequences associated with behavioral and endocrine variation. We close by proposing that local regulation of steroids is one potential mechanism that allows for the expression of novel phenotypes that can be characteristic of specific life history stages. A comparative species approach will facilitate progress in understanding the diversity of mechanisms underlying the contextual regulation of phenotypes and their associated fitness correlates. PMID- 25691856 TI - Neurogenic niches in the brain: help and hindrance of the barrier systems. AB - In the developing central nervous system, most neurogenesis occurs in the ventricular and subventricular proliferative zones. In the adult telencephalon, neurogenesis contracts to the subependyma zone and the dentate gyrus (subgranular zone) of the hippocampus. These restricted niches containing progenitor cells which divide to produce neurons or glia, depending on the intrinsic and environmental cues. Neurogenic niches are characterized by a comparatively high vascular density and, in many cases, interaction with the cerebrospinal fluid (CSF). Both the vasculature and the CSF represent a source of signaling molecules, which can be relatively rapidly modulated by external factors and circulated through the central nervous system. As the brain develops, there is vascular remodeling and a compartmentalization and dynamic modification of the ventricular surface which may be responsible for the change in the proliferative properties. This review will explore the relationship between progenitor cells and the developing vascular and ventricular space. In particular the signaling systems employed to control proliferation, and the consequence of abnormal vascular or ventricular development on growth of the telencephalon. It will also discuss the potential significance of the barriers at the vascular and ventricular junctions in the influence of the proliferative niches. PMID- 25691857 TI - Plasticity in the prefrontal cortex of adult rats. AB - We review the plastic changes of the prefrontal cortex of the rat in response to a wide range of experiences including sensory and motor experience, gonadal hormones, psychoactive drugs, learning tasks, stress, social experience, metaplastic experiences, and brain injury. Our focus is on synaptic changes (dendritic morphology and spine density) in pyramidal neurons and the relationship to behavioral changes. The most general conclusion we can reach is that the prefrontal cortex is extremely plastic and that the medial and orbital prefrontal regions frequently respond very differently to the same experience in the same brain and the rules that govern prefrontal plasticity appear to differ for those of other cortical regions. PMID- 25691858 TI - A use-dependent increase in release sites drives facilitation at calretinin deficient cerebellar parallel-fiber synapses. AB - Endogenous Ca(2+)-binding proteins affect synaptic transmitter release and short term plasticity (STP) by buffering presynaptic Ca(2+) signals. At parallel-fiber (PF)-to-Purkinje neuron (PN) synapses in the cerebellar cortex loss of calretinin (CR), the major buffer at PF terminals, results in increased presynaptic Ca(2+) transients and an almost doubling of the initial vesicular releases probability (p r). Surprisingly, however, it has been reported that loss of CR from PF synapses does not alter paired-pulse facilitation (PPF), while it affects presynaptic Ca(2+) signals as well as p r. Here, we addressed this puzzling observation by analyzing the frequency- and Ca(2+)-dependence of PPF at unitary PF-to-PN synapses of wild-type (WT) and CR-deficient (CR(-/-)) mice using paired recordings and computer simulations. Our analysis revealed that PPF in CR(-/-) is indeed smaller than in the WT, to a degree, however, that indicates that rapid vesicle replenishment and recruitment of additional release sites dominate the synaptic efficacy of the second response. These Ca(2+)-driven processes operate more effectively in the absence of CR, thereby, explaining the preservation of robust PPF in the mutants. PMID- 25691859 TI - Contribution of parvalbumin and somatostatin-expressing GABAergic neurons to slow oscillations and the balance in beta-gamma oscillations across cortical layers. AB - Cortical interneurons are classified into several subtypes that contribute to cortical oscillatory activity. Parvalbumin (PV)-expressing cells, a type of inhibitory interneuron, are involved in the gamma oscillations of local field potentials (LFPs). Under ketamine-xylazine anesthesia or sleep, mammalian cortical circuits exhibit slow oscillations in which the active-up state and silent-down state alternate at ~1 Hz. The up state is composed of various high frequency oscillations, including gamma oscillations. However, it is unclear how PV cells and somatostatin (SOM) cells contribute to the slow oscillations and the high-frequency oscillations nested in the up state. To address these questions, we used mice lacking glutamate decarboxylase 67, primarily in PV cells (PV-GAD67 mice) or in SOM cells (SOM-GAD67 mice). We then compared LFPs between PV-GAD67 mice and SOM-GAD67 mice. PV cells target the proximal regions of pyramidal cells, whereas SOM cells are dendrite-preferring interneurons. We found that the up state was shortened in duration in the PV-GAD67 mice, but tended to be longer in SOM-GAD67 mice. Firing rate tended to increase in PV-GAD67 mice, but tended to decrease in SOM-GAD67 mice. We also found that delta oscillations tended to increase in SOM-GAD67 mice, but tended to decrease in PV-GAD67 mice. Current source density and wavelet analyses were performed to determine the depth profiles of various high-frequency oscillations. High gamma and ripple (60-200 Hz) power decreased in the neocortical upper layers specifically in PV-GAD67 mice, but not in SOM-GAD67. In addition, beta power (15-30 Hz) increased in the deep layers, specifically in PV-GAD67 mice. These results suggest that PV cells play important roles in persistence of the up state and in the balance between gamma and beta bands across cortical layers, whereas SOM and PV cells may make an asymmetric contribution to regulate up-state and delta oscillations. PMID- 25691860 TI - Patterns of hypothalamic regionalization in amphibians and reptiles: common traits revealed by a genoarchitectonic approach. AB - Most studies in mammals and birds have demonstrated common patterns of hypothalamic development highlighted by the combination of developmental regulatory genes (genoarchitecture), supporting the notion of the hypothalamus as a component of the secondary prosencephalon, topologically rostral to the diencephalon. In our comparative analysis we have summarized the data on the expression patterns of different transcription factors and neuroactive substances, used as anatomical markers, in the developing hypothalamus of the amphibian Xenopus laevis and the juvenile turtle Pseudemys scripta. This analysis served to highlight the organization of the hypothalamus in the anamniote/amniotic transition. We have identified supraoptoparaventricular and the suprachiasmatic regions (SCs) in the alar part of the hypothalamus, and tuberal and mammillary regions in the basal hypothalamus. Shared features in the two species are: (1) The supraoptoparaventricular region (SPV) is defined by the expression of Otp and the lack of Nkx2.1/Isl1. It is subdivided into rostral, rich in Otp and Nkx2.2, and caudal, only Otp-positive, portions. (2) The suprachiasmatic area contains catecholaminergic cell groups and lacks Otp, and can be further divided into rostral (rich in Nkx2.1 and Nkx2.2) and a caudal (rich in Isl1 and devoid of Nkx2.1) portions. (3) Expression of Nkx2.1 and Isl1 define the tuberal hypothalamus and only the rostral portion expresses Otp. (4) Its caudal boundary is evident by the lack of Isl1 in the adjacent mammillary region, which expresses Nkx2.1 and Otp. Differences in the anamnio-amniote transition were noted since in the turtle, like in other amniotes, the boundary between the alar hypothalamus and the telencephalic preoptic area shows distinct Nkx2.2 and Otp expressions but not in the amphibian (anamniote), and the alar SPV is defined by the expression of Otp/Pax6, whereas in Xenopus only Otp is expressed. PMID- 25691861 TI - Visual homeostatic processing in V1: when probability meets dynamics. PMID- 25691862 TI - Chronic shifts in the length and phase of the light cycle increase intermittent alcohol drinking in C57BL/6J mice. AB - INTRODUCTION: Shift workers-e.g., health care professionals, truck drivers, and factory workers-are forced to maintain daily cycles at odds with their natural circadian rhythms and as a consequence need to frequently readjust these cycles. This shift work-induced circadian desynchrony (CD) is associated with increased sleep disorders and with alcohol abuse. Nonetheless, it has proven difficult to model CD-induced changes in alcohol consumption in mouse models, which is an important step toward identifying the mechanisms by which CD increases alcohol intake. This study examined whether frequent changes in the light cycle could increase free access alcohol intake in a mouse line that readily consumes alcohol. METHODS: Free access alcohol intake, water intake, and wheel-running activity patterns of male C57BL/6J mice were measured while the mice were maintained on a normal 12HR photoperiod for baseline data for 2 weeks. The mice were then exposed to an alternating photoperiod of 12 h and 18 h, with light onset advanced 8 h during the 18HR photoperiod. The photoperiods rotated every 3 days, for 21 days total. RESULTS: The repeated pattern of phase advances and delays, with a concurrent change in the length of the photoperiod, shifted mice to a pattern of intermittent alcohol drinking without altering water intake. Wheel running activity demonstrated that mice were unable to reset their behavioral clocks during CD, showing constant, low-level activity with no peak in activity at the start of the dark phase and greater activity during the morning light phase. CONCLUSION: It is possible to model CD effects on alcohol intake in C57BL/6J mice using a pattern of phase shifts and changes in the photoperiod. Using this model, we demonstrate that mice begin intermittent drinking during CD, and this increase in alcohol intake does not correlate with an increase in overall activity or in overall fluid intake. PMID- 25691863 TI - The cortisol response to exercise in young adults. PMID- 25691864 TI - Investigating reasoning with multiple integrated neuroscientific methods. PMID- 25691865 TI - High-Dimensional ICA Analysis Detects Within-Network Functional Connectivity Damage of Default-Mode and Sensory-Motor Networks in Alzheimer's Disease. AB - High-dimensional independent component analysis (ICA), compared to low dimensional ICA, allows to conduct a detailed parcellation of the resting-state networks. The purpose of this study was to give further insight into functional connectivity (FC) in Alzheimer's disease (AD) using high-dimensional ICA. For this reason, we performed both low- and high-dimensional ICA analyses of resting state fMRI data of 20 healthy controls and 21 patients with AD, focusing on the primarily altered default-mode network (DMN) and exploring the sensory-motor network. As expected, results obtained at low dimensionality were in line with previous literature. Moreover, high-dimensional results allowed us to observe either the presence of within-network disconnections and FC damage confined to some of the resting-state subnetworks. Due to the higher sensitivity of the high dimensional ICA analysis, our results suggest that high-dimensional decomposition in subnetworks is very promising to better localize FC alterations in AD and that FC damage is not confined to the DMN. PMID- 25691866 TI - Self-reported physical activity and objective aerobic fitness: differential associations with gray matter density in healthy aging. AB - Aerobic fitness (AF) and self-reported physical activity (srPA) do not represent the same construct. However, many exercise and brain aging studies interchangeably use AF and srPA measures, which may be problematic with regards to how these metrics are associated with brain outcomes, such as morphology. If AF and PA measures captured the same phenomena, regional brain volumes associated with these measures should directly overlap. This study employed the general linear model to examine the differential association between objectively-measured AF (treadmill assessment) and srPA (questionnaire) with gray matter density (GMd) in 29 cognitively unimpaired community-dwelling older adults using voxel based morphometry. The results show significant regional variance in terms of GMd when comparing AF and srPA as predictors. Higher AF was associated with greater GMd in the cerebellum only, while srPA displayed positive associations with GMd in occipito-temporal, left perisylvian, and frontal regions after correcting for age. Importantly, only AF level, and not srPA, modified the relationship between age and GMd, such that higher levels of AF were associated with increased GMd in older age, while decreased GMd was seen in those with lower AF as a function of age. These results support existing literature suggesting that both AF and PA exert beneficial effects on GMd, but only AF served as a buffer against age related GMd loss. Furthermore, these results highlight the need for use of objective PA measurement and comparability of tools across studies, since results vary dependent upon the measures used and whether these are objective or subjective in nature. PMID- 25691867 TI - Widespread increase of functional connectivity in Parkinson's disease with tremor: a resting-state FMRI study. AB - Parkinson's disease (PD) is a clinically heterogeneous disease in the symptomatology dominated by tremor, akinesia, or rigidity. Focusing on PD patients with tremor, this study investigated their discoordination patterns of spontaneous brain activity by combining voxel-wise centrality, seed-based functional connectivity, and network efficiency methods. Sixteen patients and 20 matched healthy controls (HCs) were recruited and underwent structural and resting-state functional MRI scan. Compared with the HCs, the patients exhibited increased centrality in the frontal, parietal, and occipital regions while decreased centrality in the cerebellum anterior lobe and thalamus. Seeded at these regions, a distributed network was further identified that encompassed cortical (default mode network, sensorimotor cortex, prefrontal and occipital areas) and subcortical (thalamus and basal ganglia) regions and the cerebellum and brainstem. Graph-based analyses of this network revealed increased information transformation efficiency in the patients. Moreover, the identified network correlated with clinical manifestations in the patients and could distinguish the patients from HCs. Morphometric analyses revealed decreased gray matter volume in multiple regions that largely accounted for the observed functional abnormalities. Together, these findings provide a comprehensive view of network disorganization in PD with tremor and have important implications for understanding neural substrates underlying this specific type of PD. PMID- 25691868 TI - Inhibition of histone deacetylase (HDAC) by 4-phenylbutyrate results in increased junctional conductance between rat corpora smooth muscle cells. AB - 4-phenylbutyrate (4-PB) has been shown to increase the protein content in a number of cells types. One such protein is Connexin43 (Cx43). We show here that 4 phenylbutyrate exposure results in significantly elevated cell to cell coupling, as determined by dual whole cell patch clamp. Incubation with 5 mM 4PB for 24 h or more nearly doubles junctional conductance. Interestingly, mRNA levels for Cx43 declined with exposure to 4-PB while western blot analysis revealed not significant change in protein levels. These data are most consistent with stabilization of the existing Cx43 pool or alterations in the number of functional channels within an existing pool of active and silent channels. These data represent a baseline for testing the efficacy of increased connexin mediated coupling in a variety of multicellular functions including erectile function. PMID- 25691869 TI - Ambiguities in dietary antioxidant supplementation compared to calcium channel blockers therapy. PMID- 25691870 TI - Ion channelopathies in human induced pluripotent stem cell derived cardiomyocytes: a dynamic clamp study with virtual IK1. AB - Human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) are widely used in studying basic mechanisms of cardiac arrhythmias that are caused by ion channelopathies. Unfortunately, the action potential profile of hiPSC-CMs-and consequently the profile of individual membrane currents active during that action potential-differs substantially from that of native human cardiomyocytes, largely due to almost negligible expression of the inward rectifier potassium current (IK1). In the present study, we attempted to "normalize" the action potential profile of our hiPSC-CMs by inserting a voltage dependent in silico IK1 into our hiPSC-CMs, using the dynamic clamp configuration of the patch clamp technique. Recordings were made from single hiPSC-CMs, using the perforated patch clamp technique at physiological temperature. We assessed three different models of IK1, with different degrees of inward rectification, and systematically varied the magnitude of the inserted IK1. Also, we modified the inserted IK1 in order to assess the effects of loss- and gain-of-function mutations in the KCNJ2 gene, which encodes the Kir2.1 protein that is primarily responsible for the IK1 channel in human ventricle. For our experiments, we selected spontaneously beating hiPSC-CMs, with negligible IK1 as demonstrated in separate voltage clamp experiments, which were paced at 1 Hz. Upon addition of in silico IK1 with a peak outward density of 4-6 pA/pF, these hiPSC-CMs showed a ventricular-like action potential morphology with a stable resting membrane potential near -80 mV and a maximum upstroke velocity >150 V/s (n = 9). Proarrhythmic action potential changes were observed upon injection of both loss-of-function and gain-of function IK1, as associated with Andersen-Tawil syndrome type 1 and short QT syndrome type 3, respectively (n = 6). We conclude that injection of in silico IK1 makes the hiPSC-CM a more reliable model for investigating mechanisms underlying cardiac arrhythmias. PMID- 25691871 TI - The regulation of muscle mass by endogenous glucocorticoids. AB - Glucocorticoids are highly conserved fundamental regulators of energy homeostasis. In response to stress in the form of perceived danger or acute inflammation, glucocorticoids are released from the adrenal gland, rapidly mobilizing energy from carbohydrate, fat and protein stores. In the case of inflammation, mobilized protein is critical for the rapid synthesis of acute phase reactants and an efficient immune response to infection. While adaptive in response to infection, chronic mobilization can lead to a profound depletion of energy stores. Skeletal muscle represents the major body store of protein, and can become substantially atrophied under conditions of chronic inflammation. Glucocorticoids elicit the atrophy of muscle by increasing the rate of protein degradation by the ubiquitin-proteasome system and autophagy lysosome system. Protein synthesis is also suppressed at the level of translational initiation, preventing the production of new myofibrillar protein. Glucocorticoids also antagonize the action of anabolic regulators such as insulin further exacerbating the loss of protein and muscle mass. The loss of muscle mass in the context of chronic disease is a key feature of cachexia and contributes substantially to morbidity and mortality. A growing body of evidence demonstrates that glucocorticoid signaling is a common mediator of wasting, irrespective of the underlying initiator or disease state. This review will highlight fundamental mechanisms of glucocorticoid signaling and detail the mechanisms of glucocorticoid-induced muscle atrophy. Additionally, the evidence for glucocorticoids as a driver of muscle wasting in numerous disease states will be discussed. Given the burden of wasting diseases and the nodal nature of glucocorticoid signaling, effective anti-glucocorticoid therapy would be a valuable clinical tool. Therefore, the progress and potential pitfalls in the development of glucocorticoid antagonists for muscle wasting will be discussed. PMID- 25691872 TI - Friend or foe? Carbon monoxide and the mitochondria. PMID- 25691873 TI - Self-control and the effects of movie alcohol portrayals on immediate alcohol consumption in male college students. AB - BACKGROUND: In movies, alcohol-related cues are frequently depicted and there is evidence for a link between movie alcohol cues and immediate alcohol consumption. Less is known about factors influencing immediate effects movie alcohol exposure on drinking. The exertion of self-control is thought to be important in avoiding or resisting certain temptations. AIMS: The aim of the present study was to assess the immediate effects of movie alcohol portrayals on drinking of male social drinkers and to assess the moderating role of self-control in this relation. It was hypothesized that participants would drink more when exposed to movie alcohol portrayals and that especially participants with low self-control would be affected by these portrayals. METHODS: A between-subjects design comparing two movie conditions (alcohol or no portrayal of alcohol) was used, in which 154 pairs of male friends (ages 18-30) watched a 1-h movie in a semi naturalistic living room setting. Their alcohol consumption while watching was examined. Participants completed a questionnaire assessing self-control as well as their self-reported weekly alcohol use. A multivariate regression analysis was conducted to test the effects of movie condition on alcohol comsumption. RESULTS: Self-control moderated the relation between movie condition and alcohol consumption. Assignment to the alcohol movie condition increased alcohol consumption during the movie for males with high self-control but not for males with low self-control. CONCLUSION: Viewing a movie with alcohol portrayals can lead to higher alcohol consumption in a specific sample of young men while watching a movie. PMID- 25691874 TI - The lived body in schizophrenia: transition from basic self-disorders to full blown psychosis. AB - This paper provides the results of a phenomenological study of patients with schizophrenia during their first psychiatric hospitalization. The study aims at clarify aspects related to the diagnosis of schizophrenia and to reach a greater understanding of the illness, with a view to contribute to prevention and psychotherapeutic intervention models. First, the paper offers a description of the patients' "disembodiment" manifested in acute phases of schizophrenia. Second, it presents a description of the subjective anomalies that may be considered as disorders of "ipseity" or of pre-reflexive self-awareness. Third, the description is extended to encompass secondary disturbances to processes of establishing consensual intersubjectivity that lead to difficulties in shared communication practices and a progressive withdrawal from the intersubjective world. The conclusion states that a structural element, a key part of the personal processes involved in schizophrenia, is the diminishment of self presence in experience, which manifests on both individual and social levels. PMID- 25691875 TI - Is strength of handedness reliable over repeated testing? An examination of typical development and autism spectrum disorder. AB - Despite a lack of agreement concerning the age at which adult-like patterns of handedness emerge, it is generally understood that hand preference presents early in life and development is variable. Young children (ages 3-5 years) are described as having weak hand preference; however, older children (ages 7-10 years) display stronger patterns. Here, strength of hand preference refers to reliable use of the preferred hand. In comparison to their typically developing (TD) peers, individuals with autism spectrum disorder (ASD) are described as having a weak hand preference. This study aimed to extend the literature to assess three measures of handedness (Waterloo Handedness Questionnaire - WHQ, Annett pegboard - AP, and WatHand Cabinet Test - WHCT) in two repeated sessions. The first research question aimed to delineate if the strength of hand use changes across testing sessions as a function of age in typical development. Right-handed children reported a reliable preference for the right hand on the WHQ, similar to adults. A marginally significant difference was revealed between 3- to 4- and 5- to 6-year-olds on the AP. This was attributed to weak lateralization in 3- to 4-year-olds, where the establishment of hand preference by age 6 leads to superior performance with the preferred hand in 5- to 6-year olds. Finally, for the WHCT, 3- to 4-year-olds had the highest bimanual score, indicating use of the same hand to lift the cabinet door and retrieve an object. It is likely that the task was not motorically complex enough to drive preferred hand selection for older participants. The second research question sought to determine if there is difference between (TD) children and children with ASD. No differences were revealed; however, children with ASD did display variable AP performance, providing partial support for previous literature. Findings will be discussed in light of relevant literature. PMID- 25691876 TI - Motivations for responses to ostracism. PMID- 25691877 TI - Adolescents' academic achievement and life satisfaction: the role of parents' education. AB - Drawing on the background of positive psychology, there has only recently been a focus on adolescents' life satisfaction (LS) in the context of education. Studies examining the relationship between adolescents' academic achievement and LS have shown conflicting results and the reasons are not fully understood. The present study investigated the role of parents' education as a potential moderator of the relationship between adolescents' academic achievement and LS. A sample of German high school students (N = 411) reported parents' educational attainment, as an indicator of family socio-economic status, and students' academic achievement was operationalized by grade point average in five subjects. Results indicated that only mothers' education functioned as a moderator of the relationship between academic achievement and students' LS. The association between academic achievement and LS was only found in the group of students whose mothers had achieved the same or a higher education (at least high school diploma) as their own children. Fathers' educational attainment, however, was not a significant moderator of the respective relationship. Directions for future research and the differential influences of fathers' and mothers' education are discussed with regard to potential underlying processes. PMID- 25691878 TI - Left-handers look before they leap: handedness influences reactivity to novel Tower of Hanoi tasks. AB - A sample of 203 task naive left- and right-handed participants were asked to complete a combination of the 3- and 4-disk Towers of Hanoi (ToH), manipulating novelty and complexity. Self-reported state anxiety and latency to respond (initiation time) were recorded before each ToH. Novelty had a major effect on initiation time, particularly for left-handers. Left-handers had a longer latency to start and this was significantly longer on the first trial. Irrespective of hand-preference, initiation time reduced on the second trial, however, this was greatest for left-handers. Condition of task did not systematically influence initiation time for right handers, but did for left-handers. State anxiety was influenced by task novelty and complexity in a more complicated way. During the first trial, there was a significant handedness * number of disks interaction with left-handers having significantly higher state anxiety levels before the 3 disk ToH. This suggests that the initial reaction to this task for left-handers was not simply due to perceived difficulty. On their second trial, participants completing a novel ToH had higher state anxiety scores than those completing a repeated version. Overall, left-handers had a larger reduction in their state anxiety across trials. Relating to this, the expected strong positive correlation between state and trait anxiety was absent for left-handed females in their first tower presentation, but appeared on their second. This was driven by low trait anxiety individuals showing a higher state anxiety response in the first (novel) trial, supporting the idea that left-handed females respond to novelty in a way that is not directly a consequence of their trait anxiety. A possible explanation may be stereotype threat influencing the behavior of left-handed females. PMID- 25691879 TI - Melancholia before the twentieth century: fear and sorrow or partial insanity? AB - Throughout the history of psychopathology, several meanings have been assigned to the term melancholia. The main ones were related to affective disorders (fear and sadness) and abnormal beliefs. At the time of Hippocrates melancholia was regarded mainly in its affective component. Since that time, and until the eighteenth century, authors and opinions have been divided, with both aspects (affective disorders and abnormal beliefs), being valued. Finally, in the eighteenth to nineteenth centuries, with Pinel at its peak, melancholia becomes exclusively a synonym of abnormal beliefs. At the turn of the nineteenth to the twentieth century, the affective component returns as the main aspect characterizing melancholia. PMID- 25691880 TI - Consequences of traumatic brain injury for human vergence dynamics. AB - PURPOSE: Traumatic brain injury involving loss of consciousness has focal effects in the human brainstem, suggesting that it may have particular consequences for eye movement control. This hypothesis was investigated by measurements of vergence eye movement parameters. METHODS: Disparity vergence eye movements were measured for a population of 123 normally sighted individuals, 26 of whom had suffered diffuse traumatic brain injury (dTBI) in the past, while the remainder served as controls. Vergence tracking responses were measured to sinusoidal disparity modulation of a random-dot field. Disparity vergence step responses were characterized in terms of their dynamic parameters separately for the convergence and divergence directions. RESULTS: The control group showed notable differences between convergence and divergence dynamics. The dTBI group showed significantly abnormal vergence behavior on many of the dynamic parameters. CONCLUSION: The results support the hypothesis that occult injury to the oculomotor control system is a common residual outcome of dTBI. PMID- 25691881 TI - Mechanism of action of acetazolamide and idiopathic intracranial hypertension. PMID- 25691882 TI - Characterization of a minimal pKW2124 replicon from Weissella cibaria KLC140 and its application for the construction of the Weissella expression vector pKUCm1. AB - A 2.1-kb plasmid was previously isolated from Weissella cibaria KLC140 in kimchi and cloned into pUC19 along with the slpA and gfp genes, resulting in an 8.6-kb pKWCSLGFP construct for use as a novel surface display vector. To reduce the size of the vector, the minimal replicon of pKW2124 was determined. The pKW2124 plasmid contains a putative origin of replication (ori), a potential ribosomal binding site (RBS), and the repA gene encoding a plasmid replication protein. To conduct the minimal replicon experiment, four different PCR products (MR1, ori+RBS+repA; MR2, RBS+repA; MR2', repA; MR3, fragment of repA) were obtained and cloned into pUC19 (pKUCm1, pKUCm2, pKUCm2', and pKUCm3, respectively) containing the chloramphenicol acetyltransferase (CAT) gene. These constructed vectors were electroporated into W. confusa ATCC 10881 with different transformation efficiencies of 1.5 * 10(5) CFU/MUg, 1.3 * 10(1) CFU/MUg, and no transformation, respectively, suggesting that the putative ori, RBS, and repA gene are essential for optimum plasmid replication. Subsequent segregational plasmid stability testing of pKUCm1 and pKUCm2 showed that the vector pKUCm1 is highly stable up to 100 generations but pKUCm2 was completely lost after 60 generations, suggesting that the putative ori may be important for plasmid stability in the host strain. In addition, a host range test of pKUCm1 revealed that it has a broad host range spectrum including Weissella, Lactococcus, Leuconostoc, and even Lactobacillus. To verify the application of pKUCm1, the beta-galactosidase gene and its promoter region from W. cibaria KSD1 were cloned in the vector, resulting in pKUGal. Expression of the beta-galactosidase gene was confirmed using blue-white screening after IPTG induction. The small and stable pKUGal vector will be useful for gene transfer, expression, and manipulation in the Weissella genome and in other lactic acid bacteria. PMID- 25691883 TI - Induction of the pro-inflammatory NF-kB-sensitive miRNA-146a by human neurotrophic viruses. PMID- 25691884 TI - Known Allergen Structures Predict Schistosoma mansoni IgE-Binding Antigens in Human Infection. AB - The IgE response has been associated with both allergic reactions and immunity to metazoan parasites. Recently, we hypothesized that all environmental allergens bear structural homology to IgE-binding antigens from metazoan parasites and that this homology defines the relatively small number of protein families containing allergenic targets. In this study, known allergen structures (Pfam domains) from major environmental allergen families were used to predict allergen-like (SmProfilin, SmVAL-6, SmLipocalin, SmHSP20, Sm triosephosphate isomerase, SmThioredoxin, Sm superoxide dismutase, SmCyclophilin, and Sm phosphoglycerate kinase) and non-allergen-like [Sm dynein light chain (SmDLC), SmAldolase SmAK, SmUbiquitin, and Sm14-3-3] proteins in Schistosoma mansoni. Recombinant antigens were produced in Escherichia coli and IgG1, IgG4, and IgE responses against them measured in a cohort of people (n = 222) infected with S. mansoni. All allergen like antigens were targeted by IgE responses in infected subjects, whilst IgE responses to the non-allergen-like antigens, SmAK, SmUbiquitin, and Sm14-3-3 were essentially absent being of both low prevalence and magnitude. Two new IgE binding Pfam domain families, not previously described in allergen family databases, were also found, with prevalent IgE responses against SmDLC (PF01221) and SmAldolase (PF00274). Finally, it was demonstrated that immunoregulatory serological processes typically associated with allergens also occurred in responses to allergen-like proteins in S. mansoni infections, including the production of IgG4 in people responding with IgE and the down-regulation of IgE in response to increased antigen exposure from S. mansoni eggs. This study establishes that structures of known allergens can be used to predict IgE responses against homologous parasite allergen-like molecules (parallergens) and that serological responses with IgE/IgG4 to parallergens mirror those seen against allergens, supporting our hypothesis that allergenicity is rooted in expression of certain protein domain families in metazoan parasites. PMID- 25691885 TI - Tryptophan-degrading enzymes in tumoral immune resistance. AB - Tryptophan is required for T lymphocyte effector functions. Its degradation is one of the mechanisms selected by tumors to resist immune destruction. Two enzymes, tryptophan-2,3-dioxygenase and indoleamine 2,3-dioxygenase 1, control tryptophan degradation through the kynurenine pathway. A third protein, indoleamine 2,3-dioxygenase 2, was identified more recently. All three enzymes were reported to be expressed in tumors, and are candidate targets for pharmacological inhibition aimed at restoring effective anti-tumoral immunity. In this review, we compare these three enzymes in terms of structure, activity, regulation, and expression in healthy and cancerous tissues, in order to appreciate their relevance to tumoral immune resistance. PMID- 25691886 TI - Lineage-specific evolution of Methylthioalkylmalate synthases (MAMs) involved in glucosinolates biosynthesis. AB - Methylthioalkylmalate synthases (MAMs) encoded by MAM genes are central to the diversification of the glucosinolates, which are important secondary metabolites in Brassicaceae species. However, the evolutionary pathway of MAM genes is poorly understood. We analyzed the phylogenetic and synteny relationships of MAM genes from 13 sequenced Brassicaceae species. Based on these analyses, we propose that the syntenic loci of MAM genes, which underwent frequent tandem duplications, divided into two independent lineage-specific evolution routes and were driven by positive selection after the divergence from Aethionema arabicum. In the lineage I species Capsella rubella, Camelina sativa, Arabidopsis lyrata, and A. thaliana, the MAM loci evolved three tandem genes encoding enzymes responsible for the biosynthesis of aliphatic glucosinolates with different carbon chain-lengths. In lineage II species, the MAM loci encode enzymes responsible for the biosynthesis of short-chain aliphatic glucosinolates. Our proposed model of the evolutionary pathway of MAM genes will be useful for understanding the specific function of these genes in Brassicaceae species. PMID- 25691887 TI - OsSDS is essential for DSB formation in rice meiosis. AB - SDS is a meiosis specific cyclin-like protein and required for DMC1 mediated double-strand break (DSB) repairing in Arabidopsis. Here, we found its rice homolog, OsSDS, is essential for meiotic DSB formation. The Ossds mutant is normal in vegetative growth but both male and female gametes are inviable. The Ossds meiocytes exhibit severe defects in homologous pairing and synapsis. No gammaH2AX immunosignals in Ossds meiocytes together with the suppression of chromosome fragmentation in Ossds-1 Osrad51c, both provide strong evidences that OsSDS is essential for meiotic DSB formation. Immunostaining investigations revealed that meiotic chromosome axes are normally formed but both SC installation and localization of recombination elements are failed in Ossds. We suspected that this cyclin protein has been differentiated pretty much between monocots and dicots on its function in meiosis. PMID- 25691888 TI - Photopolarization of Fucus zygotes is determined by time sensitive vectorial addition of environmental cues during axis amplification. AB - Fucoid zygotes have been extensively used to study cell polarization and asymmetrical cell division. Fertilized eggs are responsive to different environmental cues (e.g., light, gravity) for a long period before the polarity is fixed and the cells germinate accordingly. First, it is commonly believed that the direction and sense of the polarization vector are established simultaneously as indicated by the formation of an F-actin patch. Secondly, upon reorientation of the zygote, a new polar gradient is formed and it is assumed that the position of the future rhizoid pole is only influenced by the latter. Here we tested these two hypotheses investigating photopolarization in Fucus zygotes by reorienting zygotes 90 degrees relative to a unilateral light source at different time points during the first cell cycle. We conclude that fixation of direction and sense of the polarization vector is indeed established simultaneously. However, the experiments yielded a distribution of polarization axes that cannot be explained if only the last environmental cue is supposed to determine the polarization axis. We conclude that our observations, together with published findings, can only be explained by assuming imprinting of the different polarization vectors and their integration as a vectorial sum at the moment of axis fixation. This way cells will average different serially perceived cues resulting in a polarization vector representative of the dynamic intertidal environment, instead of betting exclusively on the perceived vector at the moment of axis fixation. PMID- 25691890 TI - Population genetic structure, linkage disequilibrium and effective population size of conserved and extensively raised village chicken populations of Southern Africa. AB - Extensively raised village chickens are considered a valuable source of biodiversity, with genetic variability developed over thousands of years that ought to be characterized and utilized. Surveys that can reveal a population's genetic structure and provide an insight into its demographic history will give valuable information that can be used to manage and conserve important indigenous animal genetic resources. This study reports population diversity and structure, linkage disequilibrium and effective population sizes of Southern African village chickens and conservation flocks from South Africa. DNA samples from 312 chickens from South African village and conservation flocks (n = 146), Malawi (n = 30) and Zimbabwe (n = 136) were genotyped using the Illumina iSelect chicken SNP60K BeadChip. Population genetic structure analysis distinguished the four conservation flocks from the village chicken populations. Of the four flocks, the Ovambo clustered closer to the village chickens particularly those sampled from South Africa. Clustering of the village chickens followed a geographic gradient whereby South African chickens were closer to those from Zimbabwe than to chickens from Malawi. Different conservation flocks seemed to have maintained different components of the ancestral genomes with a higher proportion of village chicken diversity found in the Ovambo population. Overall population LD averaged over chromosomes ranged from 0.03 +/- 0.07 to 0.58 +/- 0.41 and averaged 0.15 +/- 0.16. Higher LD, ranging from 0.29 to 0.36, was observed between SNP markers that were less than 10 kb apart in the conservation flocks. LD in the conservation flocks steadily decreased to 0.15 (PK) and 0.24 (VD) at SNP marker interval of 500 kb. Genomewide LD decay in the village chickens from Malawi, Zimbabwe and South Africa followed a similar trend as the conservation flocks although the mean LD values for the investigated SNP intervals were lower. The results suggest low effective population sizes particularly in the conservation flocks. The utility and limitations of the iselect chicken SNP60K in village chicken populations is discussed. PMID- 25691889 TI - Disorders of phospholipid metabolism: an emerging class of mitochondrial disease due to defects in nuclear genes. AB - The human nuclear and mitochondrial genomes co-exist within each cell. While the mitochondrial genome encodes for a limited number of proteins, transfer RNAs, and ribosomal RNAs, the vast majority of mitochondrial proteins are encoded in the nuclear genome. Of the multitude of mitochondrial disorders known to date, only a fifth are maternally inherited. The recent characterization of the mitochondrial proteome therefore serves as an important step toward delineating the nosology of a large spectrum of phenotypically heterogeneous diseases. Following the identification of the first nuclear gene defect to underlie a mitochondrial disorder, a plenitude of genetic variants that provoke mitochondrial pathophysiology have been molecularly elucidated and classified into six categories that impact: (1) oxidative phosphorylation (subunits and assembly factors); (2) mitochondrial DNA maintenance and expression; (3) mitochondrial protein import and assembly; (4) mitochondrial quality control (chaperones and proteases); (5) iron-sulfur cluster homeostasis; and (6) mitochondrial dynamics (fission and fusion). Here, we propose that an additional class of genetic variant be included in the classification schema to acknowledge the role of genetic defects in phospholipid biosynthesis, remodeling, and metabolism in mitochondrial pathophysiology. This seventh class includes a small but notable group of nuclear-encoded proteins whose dysfunction impacts normal mitochondrial phospholipid metabolism. The resulting human disorders present with a diverse array of pathologic consequences that reflect the variety of functions that phospholipids have in mitochondria and highlight the important role of proper membrane homeostasis in mitochondrial biology. PMID- 25691892 TI - Integrating food webs with metabolic networks: modeling contaminant degradation in marine ecosystems. PMID- 25691891 TI - How the cell cycle impacts chromatin architecture and influences cell fate. AB - Since the earliest observations of cells undergoing mitosis, it has been clear that there is an intimate relationship between the cell cycle and nuclear chromatin architecture. The nuclear envelope and chromatin undergo robust assembly and disassembly during the cell cycle, and transcriptional and post transcriptional regulation of histone biogenesis and chromatin modification is controlled in a cell cycle-dependent manner. Chromatin binding proteins and chromatin modifications in turn influence the expression of critical cell cycle regulators, the accessibility of origins for DNA replication, DNA repair, and cell fate. In this review we aim to provide an integrated discussion of how the cell cycle machinery impacts nuclear architecture and vice-versa. We highlight recent advances in understanding cell cycle-dependent histone biogenesis and histone modification deposition, how cell cycle regulators control histone modifier activities, the contribution of chromatin modifications to origin firing for DNA replication, and newly identified roles for nucleoporins in regulating cell cycle gene expression, gene expression memory and differentiation. We close with a discussion of how cell cycle status may impact chromatin to influence cell fate decisions, under normal contexts of differentiation as well as in instances of cell fate reprogramming. PMID- 25691894 TI - Genetic algorithm-based test data generation for multiple paths via individual sharing. AB - The application of genetic algorithms in automatically generating test data has aroused broad concerns and obtained delightful achievements in recent years. However, the efficiency of genetic algorithm-based test data generation for path testing needs to be further improved. In this paper, we establish a mathematical model of generating test data for multiple paths coverage. Then, a multipopulation genetic algorithm with individual sharing is presented to solve the established model. We not only analyzed the performance of the proposed method theoretically, but also applied it to various programs under test. The experimental results show that the proposed method can improve the efficiency of generating test data for many paths' coverage significantly. PMID- 25691893 TI - Neural Regulation of CNS Angiogenesis During Development. AB - Vertebrates have evolved a powerful vascular system that involves close interactions between blood vessels and target tissues. Vascular biology had been mostly focused on the study of blood vessels for decades, which has generated large bodies of knowledge on vascular cell development, function and pathology. We argue that the prime time has arrived for vascular research on vessel-tissue interactions, especially target tissue regulation of vessel development. The central nervous system (CNS) requires a highly efficient vascular system for oxygen and nutrient transport as well as waste disposal. Therefore, neurovascular interaction is an excellent entry point to understanding target tissue regulation of blood vessel development. In this review, we summarize signaling pathways that transmit information from neural cells to blood vessels during development and the mechanisms by which they regulate each step of CNS angiogenesis. We also review important mechanisms of neural regulation of blood-brain barrier establishment and maturation, highlighting different functions of neural progenitor cells and pericytes. Finally, we evaluate potential contribution of malfunctioning neurovascular signaling to the development of brain vascular diseases and discuss how neurovascular interactions could be involved in brain tumor angiogenesis. PMID- 25691895 TI - Log-linear model based behavior selection method for artificial fish swarm algorithm. AB - Artificial fish swarm algorithm (AFSA) is a population based optimization technique inspired by social behavior of fishes. In past several years, AFSA has been successfully applied in many research and application areas. The behavior of fishes has a crucial impact on the performance of AFSA, such as global exploration ability and convergence speed. How to construct and select behaviors of fishes are an important task. To solve these problems, an improved artificial fish swarm algorithm based on log-linear model is proposed and implemented in this paper. There are three main works. Firstly, we proposed a new behavior selection algorithm based on log-linear model which can enhance decision making ability of behavior selection. Secondly, adaptive movement behavior based on adaptive weight is presented, which can dynamically adjust according to the diversity of fishes. Finally, some new behaviors are defined and introduced into artificial fish swarm algorithm at the first time to improve global optimization capability. The experiments on high dimensional function optimization showed that the improved algorithm has more powerful global exploration ability and reasonable convergence speed compared with the standard artificial fish swarm algorithm. PMID- 25691896 TI - Self-adaptive prediction of cloud resource demands using ensemble model and subtractive-fuzzy clustering based fuzzy neural network. AB - In IaaS (infrastructure as a service) cloud environment, users are provisioned with virtual machines (VMs). To allocate resources for users dynamically and effectively, accurate resource demands predicting is essential. For this purpose, this paper proposes a self-adaptive prediction method using ensemble model and subtractive-fuzzy clustering based fuzzy neural network (ESFCFNN). We analyze the characters of user preferences and demands. Then the architecture of the prediction model is constructed. We adopt some base predictors to compose the ensemble model. Then the structure and learning algorithm of fuzzy neural network is researched. To obtain the number of fuzzy rules and the initial value of the premise and consequent parameters, this paper proposes the fuzzy c-means combined with subtractive clustering algorithm, that is, the subtractive-fuzzy clustering. Finally, we adopt different criteria to evaluate the proposed method. The experiment results show that the method is accurate and effective in predicting the resource demands. PMID- 25691897 TI - Upper gastrointestinal mucosal injury and symptoms in elderly low-dose aspirin users. AB - Background. We investigated the prevalence, symptoms, and QOL impact of esophageal (EI), gastric (GI), and duodenal mucosal injury (DI) individually between low-dose aspirin (LDA) users and nonusers to reveal the clinical features of LDA-related mucosal injury. Methods. Data were extracted from the records of subjects who underwent upper gastrointestinal endoscopy at our department between April 2008 and December 2013. Responses from 3162 elderly patients on Frequency Scale for Symptoms of GERD (FSSG) and SF-8 QOL questionnaires (SF-8) were analyzed. FSSG items were classified into total score (TS), reflux score (RS), and dyspepsia score (DS). The SF-8 questionnaire consisted of the physical component summary (PCS) and mental component summary (MCS). Results. Prevalence among LDA users and nonusers, respectively, was 9.6% and 10.0% (P = 0.83) for EI, 35.9% and 27.5% (P = 0.0027) for GI, 3.3% and 3.4% (P = 0.84) for DI, and 8.2% and 5.2% (P = 0.036) for mucosal injury in 2 or more organs. LDA users diagnosed with EI had significantly lower PCS, LDA users diagnosed with GI had significantly lower DS, and LDA users diagnosed with DI had significantly lower RS and significantly lower MCS. Conclusion. These results provide important clinical information indicating that symptom-based management is not appropriate in LDA users regarding upper gastrointestinal mucosal injury. PMID- 25691898 TI - The effect of intravenous iron treatment on quality of life in inflammatory bowel disease patients with nonanemic iron deficiency. AB - Background. Iron deficiency is the prevalent complication of inflammatory bowel disease (IBD). Herein, we investigated the effect of intravenous iron treatment on quality of life (QoL) in nonanemic and iron deficient IBD patients. Methods. Eighty-five IBD patients were recruited for this study. The patients were intravenously administered 500 mg iron sucrose in the first week of the study. Hematologic parameters and QoL were evaluated before to iron treatment and during the 12th week of treatment. The Inflammatory Bowel Disease Questionnaire (IBDQ) and the Short Form-36 (SF-36) Health Survey were used to assess QoL. Results. Prior to intravenous iron administration, the IBDQ, SF-36 Physical Component Summary (PCS) and Mental Component Summary (MCS) scores were 152.3 +/- 30.6, 46.7 +/- 7.3, and 45.7 +/- 9.8, respectively. In the 12th week of iron administration, those scores were 162.3 +/- 25.5 (P < 0.001), 49.3 +/- 6.4 (P < 0.001), and 47.6 +/- 8.9 (P = 0.024), respectively, which were all significantly different from the scores prior to iron administration. The mean changes in the IBDQ scores for ulcerative colitis and Crohn's disease were 8.7% and 3.0% (P = 0.029), were 6.4% and 4.7% (P = 0.562) for the SF-36 PCS, and were 4.6% and 3.2% (P = 0.482) for the SF-36 MCS, respectively. Conclusion. Intravenous iron treatment may improve QoL in nonanemic, but iron deficient, IBD patients. PMID- 25691899 TI - The Increased Expression of CCL20 and CCR6 in Rectal Mucosa Correlated to Severe Inflammation in Pediatric Ulcerative Colitis. AB - Background/Aims. The aim of this study is to clarify the differences of CCL20 and CCR6 expression, chemokine correlated to intestinal homeostasis, between pediatric and adult ulcerative colitis (UC) patients. Methods. Onehundred forty one patients who underwent proctocolectomy were divided to two groups including childhood-onset UC (CUC, <16 years old, n = 24) and adult-onset UC (AUC, ?16 years old, n = 117). A total of 141 formalin-fixed, paraffin-embedded tissue samples of rectum were obtained from these patients. Histological inflammation of rectum in resected specimen was evaluated by using Geboes histological assessment. In immunohistochemistry study, the CCL20 expression was evaluated by intensity and the stained area, and the CCR6 expression was evaluated by lymphocytes infiltration pattern. Results. CCL20 score and CCR6 positive lymphocytes infiltration pattern were statistically significantly correlated with histological inflammation severity of UC in all patients (P < 0.05). CCL20 and CCR6 expression in CUC were statistically significantly higher than that in AUC in all or pathologically severe cases (P < 0.05). Conclusions. CCL20 and CCR6 may play a significant role in local damage and pathological changes in UC especially pediatric patients. In the future, our understanding of the differences in CCL CCR6 interaction between adults and children may lead to the pathogenesis of IBD. PMID- 25691900 TI - Improving perinatal care in the rural regions worldwide by wireless enabled antepartum fetal monitoring: a demonstration project. AB - Background. Fetal and neonatal morbidity and mortality are significant problems in developing countries; remote maternal-fetal monitoring offers promise in addressing this challenge. The Gary and Mary West Health Institute and the Instituto Carlos Slim de la Salud conducted a demonstration project of wirelessly enabled antepartum maternal-fetal monitoring in the state of Yucatan, Mexico, to assess whether there were any fundamental barriers preventing deployment and use. Methods. Following informed consent, high-risk pregnant women at 27-29 weeks of gestation at the Chemax primary clinic participated in remote maternal-fetal monitoring. Study participants were randomized to receive either prototype wireless monitoring or standard-of-care. Feasibility was evaluated by assessing technical aspects of performance, adherence to monitoring appointments, and response to recommendations. Results. Data were collected from 153 high-risk pregnant indigenous Mayan women receiving either remote monitoring (n = 74) or usual standard-of-care (n = 79). Remote monitoring resulted in markedly increased adherence (94.3% versus 45.1%). Health outcomes were not statistically different in the two groups. Conclusions. Remote maternal-fetal monitoring is feasible in resource-constrained environments and can improve maternal compliance for monitoring sessions. Improvement in maternal-fetal health outcomes requires integration of such technology into sociocultural context and addressing logistical challenges of access to appropriate emergency services. PMID- 25691901 TI - Clinicopathological risk factors and biochemical predictors of safe discharge after total thyroidectomy and central compartment node dissection for thyroid cancer: a prospective study. AB - To determine the clinicopathological risk factors and reliable biochemical predictors of the development of hypocalcemic symptoms after total thyroidectomy on the basis of serum calcium and intact parathyroid hormone (PTH) levels measured 1 hour after surgery, a prospective study was performed on 817 patients who underwent a total thyroidectomy with central compartment node dissection (CCND) due to well-differentiated thyroid cancer. We evaluated the correlations between hypocalcemic symptom development and clinicopathological factors. And the predictability for hypocalcemic symptom development of intact PTH cut-offs (<10 pg/mL and <20 pg/mL, resp.) according to serum calcium level subgroup was analyzed. Female gender (P < 0.001) was the only independent risk factor for hypocalcemic symptom development in multivariate regression analysis. The negative predictive value (NPV) of intact PTH, signifying nondevelopment of hypocalcemic symptoms, was higher than the positive predictive value (PPV) which signified development of hypocalcemic symptoms. In addition, when we applied the different adoption of the intact PTH cut-off according to serum calcium level, we could obtain more increased NPVs. A female gender and the application of more specific cut-offs for intact PTH according to the serum calcium levels measured 1 hour after surgery may help the patients to be more safely discharged. PMID- 25691902 TI - Malocclusion in elementary school children in beirut: severity and related social/behavioral factors. AB - Aim. To assess severity of malocclusion in Lebanese elementary school children and the relationship between components of malocclusion and sociodemographic and behavioral factors. Methods. Dental screening was performed on 655 school children aged 6-11 from 2 public (PB) and 5 private (PV) schools in Beirut. A calibrated examiner recorded occlusion, overjet, overbite, posterior crossbite, midline diastema, and crowding. Another examiner determined the DMFT (Decayed/Missing/Filled Teeth) score. A questionnaire filled by the parents provided data on sociodemographic and behavioral factors. Multinomial, binomial, and multiple linear regressions tested the association of these factors with occlusal indices. Results. Malocclusion was more severe in PB students. Age and sucking habit were associated with various components of malocclusion. Crowding was more prevalent among males and significantly associated with the DMFT score. Income and educational level were significantly higher (P < 0.05) in PV pupils and deleterious habits were more frequent in PB children. Conclusions. Children of lower socioeconomic background had more severe malocclusions and poorer general dental health. Compared to Western and WHO norms, the findings prompt health policy suggestions to improve dental care of particularly public school children through regular screenings in schools, prevention methods when applicable, and cost effective practices through public and private enabling agencies. PMID- 25691903 TI - More than one disease process in chronic sinusitis based on mucin fragmentation patterns and amino Acid analysis. AB - Objective. To characterise fragmentation patterns and amino acid composition of MUC2 and MUC5AC in chronic sinusitis. Methods. Antigenic identity of purified sinus mucins was determined by ELISA. Fragmentation patterns of a MUC5AC rich sample mucin were analysed by Sepharose CL-2B gel chromatography. Samples, divided into one MUC2 rich and one MUC5AC rich group, were subjected to sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) and their amino acid contents were analysed. Results. Reduction, trypsin digestion, and papain digestion produced progressively smaller mucin species. On SDS-PAGE, digested MUC5AC rich mucin produced four distinct products. Amino acid analysis was characteristic of mucins with high serine, threonine, and proline contents and reduction and proteolysis increased relative proportions of these amino acids. MUC5AC rich mucins contained more protein than MUC2 rich mucins. Conclusion. Sinus mucin fragmentation produced mucin subunits and glycopeptide units of smaller molecular sizes which are likely to have lower viscoelastic properties. Applying this in vivo could alter mucus physical properties and biologic functions. Amino acid contents of MUC2 and MUC5AC mucins are different. This could be contributing to biological properties and functions of sinus mucins. These data suggest that there may be different pathological processes occurring at the cellular level on chronic sinusitis. PMID- 25691904 TI - Human adipose derived stem cells induced cell apoptosis and s phase arrest in bladder tumor. AB - The aim of this study was to determine the effect of human adipose derived stem cells (ADSCs) on the viability and apoptosis of human bladder cancer cells. EJ and T24 cells were cocultured with ADSCs or cultured with conditioned medium of ADSCs (ADSC-CM), respectively. The cell counting and colony formation assay showed ADSCs inhibited the proliferation of EJ and T24 cells. Cell viability assessment revealed that the secretions of ADSCs, in the form of conditioned medium, were able to decrease cancer cell viability. Wound-healing assay suggested ADSC-CM suppressed migration of T24 and EJ cells. Moreover, the results of the flow cytometry indicated that ADSC-CM was capable of inducing apoptosis of T24 cells and inducing S phase cell cycle arrest. Western blot revealed ADSC-CM increased the expression of cleaved caspase-3 and cleaved PARP, indicating that ADSC-CM induced apoptosis in a caspase-dependent way. PTEN/PI3K/Akt pathway and Bcl-2 family proteins were involved in the mechanism of this reaction. Our study indicated that ADSCs may provide a promising and practicable manner for bladder tumor therapy. PMID- 25691905 TI - Low oxygen tension enhances osteogenic potential of bone marrow-derived mesenchymal stem cells with osteonecrosis-related functional impairment. AB - Objective. Glucocorticoids can affect the function of bone marrow-derived mesenchymal stem cells (BMMSCs) adversely and merit the requirement for a strategy to correct this anomaly; we assessed the effect of low oxygen (2%) on BMMSCs from rabbits with osteonecrosis. Methods. Bone marrow-derived mesenchymal stem cells from normal rabbits and rabbits with osteonecrosis were divided into four groups: (1) normal-normoxia group, with normal BMMSCs cultured under 20% oxygen; (2) osteonecrosis-normoxia group, with BMMSCs from rabbits with osteonecrosis cultured under 20% oxygen; (3) osteonecrosis-low oxygen treated group, with BMMSCs from rabbits with osteonecrosis cultured under 2% oxygen; (4) normal-low oxygen treated group, with normal BMMSCs cultured under 2% oxygen. The proliferation, osteogenic, and adipogenic differentiation of MSCs and expression of stemness genes, osteogenic, and adipogenic differentiation markers were investigated. Results. Compared with BMMSCs from normal rabbits, those from osteonecrosis rabbits showed significantly reduced proliferation ability, repressed expression of stemness genes, decreased osteoblasts formation, and increased adipocytes formation, indicating an osteonecrosis-related impairment. Low oxygen (2%) treated BMMSCs from osteonecrosis rabbits showed not only increased proliferation and osteogenic potential but also decreased adipogenic potential. Conclusion. Low oxygen (2%) culture represents a novel strategy to augment BMMSC function affected by glucocorticoids and holds significance for future strategies to treat femoral head osteonecrosis. PMID- 25691906 TI - Effect of GuiXiong Xiaoyi Wan in Treatment of Endometriosis on Rats. AB - Objective. To evaluate the effect of GuiXiong Xiaoyi Wan (GXXYW) on the development of endometriosis in a rat model. Methods. Sprague-Dawley rats with surgically induced endometriosis were randomly treated with low-dose GXXYW, high dose GXXYW, or vehicle (negative control) for 28 days. Immunohistochemistry was used to assess cell proliferation in the lesions. The terminal deoxynucleotidyl transferase- (TdT-) mediated dUTP biotin nick end labelling (TUNEL) method was performed to analyse the apoptosis induced by GuiXiong Xiaoyi Wan. The percentages of CD3+ lymphocytes, CD4+ lymphocytes, and CD8+ lymphocytes in the spleens of the rats were evaluated using flow cytometric analysis. Results. Treatment with GXXYW significantly decreased the lesion size, inhibited cell proliferation, and induced apoptosis in endometriotic tissue. The spleens of GXXYW-treated rats also demonstrated a significant increase in the percentage of CD4+ lymphocytes and a significant decrease in the percentage of CD8+ lymphocytes. Conclusions. These results suggest that, in a rat model, GXXYW may be effective in the suppression of the growth of endometriosis, possibly through the inhibition of cell proliferation, the induction of apoptosis of endometriotic cells, and the regulation of the immune system. PMID- 25691907 TI - Topical Treatment with Xiaozheng Zhitong Paste (XZP) Alleviates Bone Destruction and Bone Cancer Pain in a Rat Model of Prostate Cancer-Induced Bone Pain by Modulating the RANKL/RANK/OPG Signaling. AB - To explore the effects and mechanisms of Xiaozheng Zhitong Paste (XZP) on bone cancer pain, Wistar rats were inoculated with vehicle or prostate cancer PC-3 into the tibia bone and treated topically with inert paste, XZP at 15.75, 31.5, or 63 g/kg twice per day for 21 days. Their bone structural damage, nociceptive behaviors, bone osteoclast and osteoblast activity, and the levels of OPG, RANL, RNAK, PTHrP, IGF-1, M-CSF, IL-8, and TNF-alpha were examined. In comparison with that in the placebo group, significantly reduced numbers of invaded cancer cells, decreased levels of bone damage and mechanical threshold and paw withdrawal latency, lower levels of serum TRACP5b, ICTP, PINP, and BAP, and less levels of bone osteoblast and osteoclast activity were detected in the XZP-treated rats (P<0.05). Moreover, significantly increased levels of bone OPG but significantly decreased levels of RANL, RNAK, PTHrP, IGF-1, M-CSF, IL-8, and TNF-alpha were detected in the XZP-treated rats (P<0.05 for all). Together, XZP treatment significantly mitigated the cancer-induced bone damage and bone osteoclast and osteoblast activity and alleviated prostate cancer-induced bone pain by modulating the RANKL/RANK/OPG pathway and bone cancer-related inflammation in rats. PMID- 25691908 TI - Hepatoprotective Effect of Terminalia chebula against t-BHP-Induced Acute Liver Injury in C57/BL6 Mice. AB - We aimed to identify the hepatoprotective effects of Terminalia chebula water extract (TCW) and its corresponding pharmacological actions using C57/BL6 mice model of tert-butylhydroperoxide-(t-BHP-) induced acute liver injury. Mice were orally administered with TCW (0, 50, 100, or 200 mg/kg) or gallic acid (100 mg/kg) for 5 days before t-BHP (2.5 mM/kg) injection. Liver enzymes, histopathology, oxidative stress parameters, antioxidant components, and inflammatory cytokines were examined 18 h after t-BHP injection. t-BHP injection caused dramatic elevation of serum AST, ALT, and LDH level, while TCW pretreatment notably attenuated these elevations. Inflammatory cytokines including TNF-alpha, IL-1beta, and IL-6 were notably increased in hepatic tissues, and then these were efficiently attenuated by TCW pretreatment. t-BHP injection notably increased malondialdehyde, total reactive oxygen species, and nitric oxide in the liver tissue, while it markedly dropped the antioxidant activities including total antioxidant capacity, total glutathione contents, glutathione peroxidase, superoxide dismutase, and catalase. TCW pretreatment remarkably ameliorated these alterations, and these effects were relevant to gene expressions. Histopathological examinations supported the above findings. Collectively, these findings well prove that TCW beneficially prevents acute and severe liver injury and clarify its corresponding mechanisms involved in the inhibition of oxidative stress and inflammatory cytokines. PMID- 25691909 TI - Biophysical and clinical research on acupuncture and moxibustion. PMID- 25691910 TI - Neuroprotective effect of gui zhi (ramulus cinnamomi) on ma huang- (herb ephedra ) induced toxicity in rats treated with a ma huang-gui zhi herb pair. AB - Herb Ephedra (Ma Huang in Chinese) and Ramulus Cinnamomi (Gui Zhi in Chinese) are traditional Chinese herbs, often used together to treat asthma, nose and lung congestion, and fever with anhidrosis. Due to the adverse effects of ephedrine, clinical use of Ma Huang is restricted. However, Gui Zhi extract has been reported to decrease spontaneous activity in rats and exert anti-inflammatory and neuroprotective effects. The present study explored the possible inhibitory effect of Gui Zhi on Ma Huang-induced neurotoxicity in rats when the two herbs were used in combination. All Ma Huang and Ma Huang-Gui Zhi herb pair extracts were prepared using methods of traditional Chinese medicine and were normalized based on the ephedrine content. Two-month-old male Sprague-Dawley rats (n = 6 rats/group) were administered Ma Huang or the Ma Huang-Gui Zhi herb pair extracts for 7 days (ephedrine = 48 mg/kg), and locomotor activity was measured. After 7 days, oxidative damage in the prefrontal cortex was measured. Gui Zhi decreased hyperactivity and sensitization produced by repeated Ma Huang administration and attenuated oxidative stress induced by Ma Huang. The results of this study demonstrate the neuroprotective potential of Gui Zhi in Ma Huang-induced hyperactivity and oxidative damage in the prefrontal cortex of rats when used in combination. PMID- 25691911 TI - Nonlinear Bayesian estimation of BOLD signal under non-Gaussian noise. AB - Modeling the blood oxygenation level dependent (BOLD) signal has been a subject of study for over a decade in the neuroimaging community. Inspired from fluid dynamics, the hemodynamic model provides a plausible yet convincing interpretation of the BOLD signal by amalgamating effects of dynamic physiological changes in blood oxygenation, cerebral blood flow and volume. The nonautonomous, nonlinear set of differential equations of the hemodynamic model constitutes the process model while the weighted nonlinear sum of the physiological variables forms the measurement model. Plagued by various noise sources, the time series fMRI measurement data is mostly assumed to be affected by additive Gaussian noise. Though more feasible, the assumption may cause the designed filter to perform poorly if made to work under non-Gaussian environment. In this paper, we present a data assimilation scheme that assumes additive non Gaussian noise, namely, the e-mixture noise, affecting the measurements. The proposed filter MAGSF and the celebrated EKF are put to test by performing joint optimal Bayesian filtering to estimate both the states and parameters governing the hemodynamic model under non-Gaussian environment. Analyses using both the synthetic and real data reveal superior performance of the MAGSF as compared to EKF. PMID- 25691912 TI - On better estimating and normalizing the relationship between clinical parameters: comparing respiratory modulations in the photoplethysmogram and blood pressure signal (DPOP versus PPV). AB - DPOP (DeltaPOP or Delta-POP) is a noninvasive parameter which measures the strength of respiratory modulations present in the pulse oximeter waveform. It has been proposed as a noninvasive alternative to pulse pressure variation (PPV) used in the prediction of the response to volume expansion in hypovolemic patients. We considered a number of simple techniques for better determining the underlying relationship between the two parameters. It was shown numerically that baseline-induced signal errors were asymmetric in nature, which corresponded to observation, and we proposed a method which combines a least-median-of-squares estimator with the requirement that the relationship passes through the origin (the LMSO method). We further developed a method of normalization of the parameters through rescaling DPOP using the inverse gradient of the linear fitted relationship. We propose that this normalization method (LMSO-N) is applicable to the matching of a wide range of clinical parameters. It is also generally applicable to the self-normalizing of parameters whose behaviour may change slightly due to algorithmic improvements. PMID- 25691913 TI - Clustering of reads with alignment-free measures and quality values. AB - BACKGROUND: The data volume generated by Next-Generation Sequencing (NGS) technologies is growing at a pace that is now challenging the storage and data processing capacities of modern computer systems. In this context an important aspect is the reduction of data complexity by collapsing redundant reads in a single cluster to improve the run time, memory requirements, and quality of post processing steps like assembly and error correction. Several alignment-free measures, based on k-mers counts, have been used to cluster reads. Quality scores produced by NGS platforms are fundamental for various analysis of NGS data like reads mapping and error detection. Moreover future-generation sequencing platforms will produce long reads but with a large number of erroneous bases (up to 15 %). RESULTS: In this scenario it will be fundamental to exploit quality value information within the alignment-free framework. To the best of our knowledge this is the first study that incorporates quality value information and k-mers counts, in the context of alignment-free measures, for the comparison of reads data. Based on this principles, in this paper we present a family of alignment-free measures called D (q) -type. A set of experiments on simulated and real reads data confirms that the new measures are superior to other classical alignment-free statistics, especially when erroneous reads are considered. Also results on de novo assembly and metagenomic reads classification show that the introduction of quality values improves over standard alignment-free measures. These statistics are implemented in a software called QCluster (http://www.dei.unipd.it/~ciompin/main/qcluster.html). PMID- 25691914 TI - An integrative approach for a network based meta-analysis of viral RNAi screens. AB - BACKGROUND: Big data is becoming ubiquitous in biology, and poses significant challenges in data analysis and interpretation. RNAi screening has become a workhorse of functional genomics, and has been applied, for example, to identify host factors involved in infection for a panel of different viruses. However, the analysis of data resulting from such screens is difficult, with often low overlap between hit lists, even when comparing screens targeting the same virus. This makes it a major challenge to select interesting candidates for further detailed, mechanistic experimental characterization. RESULTS: To address this problem we propose an integrative bioinformatics pipeline that allows for a network based meta-analysis of viral high-throughput RNAi screens. Initially, we collate a human protein interaction network from various public repositories, which is then subjected to unsupervised clustering to determine functional modules. Modules that are significantly enriched with host dependency factors (HDFs) and/or host restriction factors (HRFs) are then filtered based on network topology and semantic similarity measures. Modules passing all these criteria are finally interpreted for their biological significance using enrichment analysis, and interesting candidate genes can be selected from the modules. CONCLUSIONS: We apply our approach to seven screens targeting three different viruses, and compare results with other published meta-analyses of viral RNAi screens. We recover key hit genes, and identify additional candidates from the screens. While we demonstrate the application of the approach using viral RNAi data, the method is generally applicable to identify underlying mechanisms from hit lists derived from high-throughput experimental data, and to select a small number of most promising genes for further mechanistic studies. PMID- 25691915 TI - Comparison of impact and cost-effectiveness of rotavirus supplementary and routine immunization in a complex humanitarian emergency, Somali case study. AB - BACKGROUND: A humanitarian emergency involves a complete breakdown of authority that often disrupts routine health care delivery, including immunization. Diarrheal diseases are a principal cause of morbidity and mortality among children during humanitarian emergencies. The objective of this study was to assess if vaccination against rotavirus, the most common cause of severe diarrhea among children, either as an addition to routine immunization program (RI) or supplemental immunization activity (SIA) would be cost-effective during a humanitarian emergency to decrease diarrhea morbidity and mortality, using Somalia as a case study. METHODS: An impact and cost-effectiveness analysis was performed comparing no vaccine; two-dose rotavirus SIA and two-dose of RI for the 424,592 births in the 2012 Somali cohort. The main summary measure was the incremental cost per disability-adjusted life-year (DALY) averted. Univariate sensitivity analysis examined the extent to which the uncertainty in the variables affected estimates. RESULTS: If introduced in Somalia, a full-series rotavirus RI and SIA would save 908 and 359 lives, respectively, and save US$63,793 and US$25,246 in direct medical costs, respectively. The cost of a RI strategy would be US$309,458. Because of the high operational costs, a SIA strategy would cost US$715,713. US$5.30 per DALY would be averted for RI and US$37.62 per DALY averted for SIA. Variables that most substantially influenced the cost-effectiveness for both RI and SIA were vaccine program costs, mortality rate, and vaccine effectiveness against death. CONCLUSIONS: Based on our model, rotavirus vaccination appears to be a cost-effective intervention as either RI or SIA, as defined by the World Health Organization as one to three times the per capita Gross Domestic Product (Somalia $112 in 2011). RI would have greater health impact and is more cost effective than SIA, assuming feasibility of reaching the target population. However, given the lack of infrastructure, whether RI is realistic in this setting remains unanswered, and alternative approaches like SIA should be further examined. PMID- 25691916 TI - Assessing the experiences of intra-uterine device users in a long-term conflict setting: a qualitative study on the Thailand-Burma border. AB - BACKGROUND: In Burma, severe human rights violations, civil conflict, and the persecution of ethnic and linguistic minority populations has resulted in the displacement of millions of people, many of whom now reside as internally displaced populations (IDPs) in Eastern Burma or in Thailand as refugees or undocumented migrants. Use of the intra-uterine device (IUD), a non-user dependent and highly reliable method of long acting reversible contraception, has the potential to make a significant impact on reproductive health in this protracted conflict setting. OBJECTIVES: This qualitative study aimed to understand Burmese women's experiences with and perceptions of the IUD and identify avenues for improving contraceptive service delivery along the Thailand Burma border. METHODS: In the summer of 2013, we conducted in-person in-depth open-ended interviews with 31 women who obtained IUDs from a clinic along the border. We conducted a content and thematic analysis of these data using both a priori (pre-determined) and emergent codes and inductive techniques. RESULTS: Women's experiences with the IUD are overwhelmingly positive and the experiences of friends and family impact use of the device. Financial considerations and access to reproductive health facilities also shape the use of the IUD in this region. The IUD is rare along the Thailand-Burma border and misinformation about this method of contraception is pervasive. CONCLUSION: Our findings suggest that this modality of contraception is culturally acceptable and may be able to address structural barriers to reproductive health services along the Thailand Burma border. Ensuring that information provided by health care providers and among peer groups is evidence-based, a full range of contraceptive methods is available, and adoption of an IUD is affordable are priorities for expanding access to reproductive health services in this setting. PMID- 25691917 TI - A transcriptomic analysis of Neurospora crassa using five major crop residues and the novel role of the sporulation regulator rca-1 in lignocellulase production. AB - BACKGROUND: Crop residue is an abundant, low-cost plant biomass material available worldwide for use in the microbial production of enzymes, biofuels, and valuable chemicals. However, the diverse chemical composition and complex structure of crop residues are more challenging for efficient degradation by microbes than are homogeneous polysaccharides. In this study, the transcriptional responses of Neurospora crassa to various plant straws were analyzed using RNA Seq, and novel beneficial factors for biomass-induced enzyme production were evaluated. RESULTS: Comparative transcriptional profiling of N. crassa grown on five major crop straws of China (barley, corn, rice, soybean, and wheat straws) revealed a highly overlapping group of 430 genes, the biomass commonly induced core set (BICS). A large proportion of induced carbohydrate-active enzyme (CAZy) genes (82 out of 113) were also conserved across the five plant straws. Excluding 178 genes within the BICS that were also upregulated under no-carbon conditions, the remaining 252 genes were defined as the biomass regulon (BR). Interestingly, 88 genes were only induced by plant biomass and not by three individual polysaccharides (Avicel, xylan, and pectin); these were denoted as the biomass unique set (BUS). Deletion of one BUS gene, the transcriptional regulator rca-1, significantly improved lignocellulase production using plant biomass as the sole carbon source, possibly functioning via de-repression of the regulator clr-2. Thus, this result suggests that rca-1 is a potential engineering target for biorefineries, especially for plant biomass direct microbial conversion processes. CONCLUSIONS: Transcriptional profiling revealed a large core response to different sources of plant biomass in N. crassa. The sporulation regulator rca 1 was identified as beneficial for biomass-based enzyme production. PMID- 25691918 TI - An investigation of gene-gene interactions in dose-response studies with Bayesian nonparametrics. AB - BACKGROUND: Best practice for statistical methodology in cell-based dose-response studies has yet to be established. We examine the ability of MANOVA to detect trait-associated genetic loci in the presence of gene-gene interactions. We present a novel Bayesian nonparametric method designed to detect such interactions. RESULTS: MANOVA and the Bayesian nonparametric approach show good ability to detect trait-associated genetic variants under various possible genetic models. It is shown through several sets of analyses that this may be due to marginal effects being present, even if the underlying genetic model does not explicitly contain them. CONCLUSIONS: Understanding how genetic interactions affect drug response continues to be a critical goal. MANOVA and the novel Bayesian framework present a trade-off between computational complexity and model flexibility. PMID- 25691919 TI - Toxic lung injury in a patient addicted to "legal highs" - case study. AB - BACKGROUND: Toxic lung injury may manifest itself in many different ways, ranging from respiratory tract irritation and pulmonary edema in severe cases to constrictive bronchiolitis, being a more distant consequence. It is most often the result of accidental exposure to harmful substances at work, at home, or a consequence of industrial disaster. CASE REPORT: This article presents a case of toxic lung injury which occurred after inhalation of legal highs, the so-called "artificial hashish" and at first presented itself radiologically as interstitial pneumonia with pleural effusion and clinically as hypoxemic respiratory insufficiency. After treatment with high doses of steroids, it was histopathologically diagnosed as organizing pneumonia with lipid bodies. CONCLUSIONS: Due to the lack of pathognomonic radiological images for toxic lung injury, information on possible etiology of irritants is very important. As novel psychoactive substances appeared in Europe, they should be considered as the cause of toxic lung injury. PMID- 25691920 TI - Triaxial system in re-embolization for recanalization of pulmonary arteriovenous malformations. AB - BACKGROUND: Recanalization occurs occasionally, following coil embolization of pulmonary arteriovenous malformations (PAVM), and can lead to ischemic stroke; therefore re-embolization is important. A 1.9-Fr. no-taper microcatheter that can be inserted into a 2.7-Fr. microcatheter (named the triaxial system) has recently become available, and contributes to super-selective catheterization for small or tortuous vessels. The aim of this study was to evaluate the usefulness of re embolization for recanalization of PAVM using the triaxial system. MATERIAL/METHODS: Recanalization was diagnosed in 8 patients with 13 PAVMs between June 2011 and November 2012, and re-embolization was attempted with a conventional microcatheter at first in all 13 PAVMs. However, in three of them it failed with the conventional microcatheter, and then the system was exchanged to the triaxial system. Thus, re-embolization using the triaxial system was performed in 3 PAVMs of 3 female patients, with a median age of 63 years (range, 46-73 years). We assessed technical success, complications, and outcome. RESULTS: The disappearance of recanalization was confirmed by angiography in all re embolization procedures (technical success rate was 100%). Re-embolization was then successfully achieved inside the original coils, and no branch artery of normal lung tissue was embolized. There were no complications related with this procedure. The blood flow of recanalization was decreased in all cases in a follow-up of 27-33 months (median, 31). CONCLUSIONS: Triaxial system appears to be useful for recanalization of PAVM, especially in difficult cases with a conventional system. PMID- 25691921 TI - Integrative Analysis of "-Omics" Data Using Penalty Functions. AB - In the analysis of omics data, integrative analysis provides an effective way of pooling information across multiple datasets or multiple correlated responses, and can be more effective than single-dataset (response) analysis. Multiple families of integrative analysis methods have been proposed in the literature. The current review focuses on the penalization methods. Special attention is paid to sparse meta-analysis methods that pool summary statistics across datasets, and integrative analysis methods that pool raw data across datasets. We discuss their formulation and rationale. Beyond "standard" penalized selection, we also review contrasted penalization and Laplacian penalization which accommodate finer data structures. The computational aspects, including computational algorithms and tuning parameter selection, are examined. This review concludes with possible limitations and extensions. PMID- 25691923 TI - Repetitive sequences based on genotyping of Candida albicans isolates obtained from Iranian patients with human immunodeficiency virus. AB - OBJECTIVES: Candidiasis infection caused by Candida albicans has been known as a major problem in patients with immune disorders. The objective of this study was to genotype the C. albicans isolates obtained from oral cavity of patients with positive human immunodeficiency virus (HIV(+)) with or/and without oropharyngeal candidiasis (OPC). MATERIALS AND METHODS: A total of 100 C. albicans isolates from Iranian HIV(+)patients were genotyped using specific PCR primers of the 25S rDNA and RPS genes. RESULTS: The frequencies of genotypes A, B and C which were achieved using 25S rDNA , were 66, 24 and 10 percent, respectively. In addition, genotypes D and E were not found in this study. Each C. albicans genotype was further classified into four subtypes (types 2, 3, 2/3 and 3/4) by PCR amplification targeting RPS sequence. CONCLUSION: In general, genotype A3 constituted the majority of understudy clinical isolates obtained from oral cavity of Iranian HIV(+) patients. PMID- 25691922 TI - Human activated macrophages and hypoxia: a comprehensive review of the literature. AB - Macrophages accumulate in poorly vascularised and hypoxic sites including solid tumours, wounds and sites of infection and inflammation where they can be exposed to low levels of oxygen for long periods. Up to date, different studies have shown that a number of transcription factors are activated by hypoxia which in turn activate a broad array of mitogenic, pro-invasive, pro-angiogenic, and pro metastatic genes. On the other hand, macrophages respond to hypoxia by up regulating several genes which are chief factors in angiogenesis and tumorigenesis. Therefore, in this review article we focus mainly on the role of macrophages during inflammation and discuss their response to hypoxia by regulating a diverse array of transcription factors. We also review the existing literatures on hypoxia and its cellular and molecular mechanism which mediates macrophages activation. PMID- 25691924 TI - Dengue virus type-3 envelope protein domain III; expression and immunogenicity. AB - OBJECTIVES: Production of a recombinant and immunogenic antigen using dengue virus type-3 envelope protein is a key point in dengue vaccine development and diagnostic researches. The goals of this study were providing a recombinant protein from dengue virus type-3 envelope protein and evaluation of its immunogenicity in mice. MATERIALS AND METHODS: Multiple amino acid sequences of different isolates of dengue virus type-3, corresponding to the envelope protein domain III, were achieved from GenBank. Clustal V alignment tool was used to provide a consensus amino acid sequence. Nucleotide sequence of the coding gene was optimized using "Optimizer". The origami (DE3) strain of Escherichia coli was used as the host in order to express the protein. A commercial affinity chromatography method was used to purify the recombinant protein. Immunogenicity of the recombinant protein was evaluated in mice using ELISA, MTT and cytokine assays. RESULTS: A consensus amino acid sequence corresponding to the most important region of dengue virus type-3 envelope protein (domain III) was provided. A high concentration (>= 20 mg/L culture medium) of soluble recombinant antigen (EDIII3) was achieved. Immunized mice developed specific antibody responses against EDIII3 protein. The splenocytes from EDIII3-immunized mice showed a high proliferation rate in comparison with the negative control. In addition, the concentrations of two measured cytokines (IFN-gamma and IL-4) were increased markedly in immunized mice. CONCLUSION: The results showed that the expressed recombinant EDIII3 protein is an immunogenic antigen and can be applied to induce specific immune responses against dengue virus type-3. PMID- 25691925 TI - UV mutagenesis for the overproduction of xylanase from Bacillus mojavensis PTCC 1723 and optimization of the production condition. AB - OBJECTIVES: This study highlights xylanase overproduction from Bacillus mojavensis via UV mutagenesis and optimization of the production process. MATERIALS AND METHODS: Bacillus mojavenis PTCC 1723 underwent UV radiation. Mutants' primary screening was based on the enhanced Hollow Zone Diameter/ Colony Diameter Ration (H/C ratios) of the colonies in comparison with the wild strain on Xylan agar medium. Secondly, enzyme production of mutants was compared with parental strain. Optimization process using lignocellulolytic wastes was designed with Minitab software for the best overproducer mutant. RESULTS: H/C ratio of 3.1 was measured in mutant number 17 in comparison with the H/C ratio of the parental strain equal to 1.6. Selected mutant produced 330.56 IU/ml xylanase. It was 3.45 times more enzyme than the wild strain with 95.73 IU/ml xylanase. Optimization resulted 575 IU/ml xylanase, with wheat bran as the best carbon source, corn steep liquor as the best nitrogen source accompanied with natural bakery yeast powder, in a medium with pH 7, after 48 hr incubation at 37 degrees C, and the shaking rate of 230 rpm. Optimum xylanase activity was assayed at pH 7 and 40 degrees C. Enzyme stability pattern shows it retains 62% of its initial activity at pH 9 after 3 hr. It also maintains up to 66% and 59% of its initial activity after 1 hr of pre-incubation at 70 degrees C and 80 degrees C. CONCLUSION: Mutation and optimization caused 5.9 times more enzyme yield by mutant strain. Also this enzyme can be categorized as an alkali-tolerant and thermo-stable xylanase. PMID- 25691926 TI - An animal model study for bone repair with encapsulated differentiated osteoblasts from adipose-derived stem cells in alginate. AB - OBJECTIVES: Adipose derived stem cells (ADSCs) can be engineered to express bone specific markers. The aim of this study is to evaluate repairing tibia in animal model with differentiated osteoblasts from autologous ADSCs in alginate scaffold. MATERIALS AND METHODS: In this study, 6 canine's ADSCs were encapsulated in alginate and differentiated into osteoblasts. Alkaline phosphatase assay (ALP) and RT-PCR method were applied to confirm the osteogenic induction. Then, encapsulated differentiated cells (group 1) and cell-free alginate (group 2) implanted in defected part of dog's tibia for 4 and 8 weeks. Regenerated tissues and compressive strength of samples were evaluated by histological and Immunohistochemical (IHC) methods and Tensometer Universal Machine. RESULTS: Our results showed that ADSCs were differentiated into osteoblasts in vitro, and type I collagen and osteocalcin genes expression in differentiated osteoblasts was proved by RT-PCR. In group 2, ossification and thickness of trabecula were low compared to group 1, and in both groups woven bone was observed instead of control group's compact bone. Considering time, we found bone trabeculae regression and ossification reduction after 8 weeks compared with 4 weeks in group 2, but in group 1 bone formation was increased in 8 weeks. Presence of differentiated cells caused significantly more compressive strength in comparison with group 2 (P-value <=0.05). CONCLUSION: This research showed that engineering bone from differentiated adipose-derived stem cells, encapsulated in alginate can repair tibia defects. PMID- 25691927 TI - Proconvulsive effect of hydrochlorothiazide in an in vitro rat seizure model. AB - OBJECTIVES: Protective effects of diuretics, particularly of hydrochlorothiazide (HCT), for the development of epilepsy have been described in vivo. However, its mechanism of action is unknown. MATERIALS AND METHODS: Extracellular field potentials were recorded from the CA1- and CA3-subfields of the hippocampus of rats. Epileptiform discharges were induced by omission of Mg2+ from the artificial cerebrospinal fluid (ACSF). HCT was added to the ACSF at a concentration of 2 mmol/l, 0.2 mmol/l or 0.02 mmol/l. Frequency, amplitude and duration of the epileptiform discharges were evaluated. Long-term potentiation (LTP) was induced with and without the presence of HCT (n=6; 2 mmol/l). In addition, rats were injected with HCT (n=4) or saline (n=2), and the brain tissue was analyzed using HPLC. RESULTS: Application of 0.02, 0.2, and 2 mmol/l HCT accelerated the frequency of discharges by 50%, 91%, and 100%, respectively. The amplitude of burst discharges also increased by 9%, 54%, and 300%, and the duration of epileptiform discharges increased by 10%, 30% and 120%. All parameters returned close to the basal levels after 60min washout of the substance. HCT increased the electrical evoked potentials but did not affect the LTP in hippocampal tissues. There was no evidence of HCT in the rat brain after intraperitoneal injection. CONCLUSION: Exposure of hippocampal slices to HCT enhanced epileptiform activity in a dose-dependent manner. In addition, HCT does not seem to cross the blood brain barrier in rats. Thus, the anticonvulsive effect of HCT most likely is not through direct neuronal effect. PMID- 25691928 TI - Differences in growth promotion, drug response and intracellular protein trafficking of FLT3 mutants. AB - OBJECTIVES: Mutant forms FMS-like tyrosine kinase-3 (FLT3), are reported in 25% of childhood acute lymphoid leukemia (ALL) and 30% of acute myeloid leukemia (AML) patients. In this study, drug response, growth promoting, and protein trafficking of FLT3 wild-type was compared with two active mutants (Internal Tandem Duplication (ITD)) and D835Y. MATERIALS AND METHODS: FLT3 was expressed on factor-dependent cells (FDC-P1) using retroviral transduction. The inhibitory effects of CEP701, imatinib, dasatinib, PKC412 and sunitinib were studied on cell proliferation and FLT3 tyrosine phosphorylation. Total expression and proportion of intracellular and surface FLT3 was also determined. RESULTS: FDC-P1 cells became factor-independent after expression of human FLT3 mutants (ITD and D835Y). FDC-P1 cells expressing FLT3-ITD grow 3 to 4 times faster than those expressing FLT3-D835Y. FD-FLT3-ITD cells were three times more resistant to sunitinib than the FD-FLT3-WT cells. The Geo means for surface FLT3 expression in FD-FLT3-ITD and -D835Y were 65 and 70% less than the FD-FLT3-WT cells. About 40% of expressed FLT3 was detected as intracellular in FD-FLT3-D835Y cell compared to 4 and 4.5% in FD-FLT3-WT and -ITD cells. CONCLUSION: Retention of D835Y FLT3 mutant protein may cause altered signaling, endoplasmic reticulum stress and activation of apoptotic signaling pathways leading to lower proliferation rate in FD-FLT3-D835Y than the FLT3-WT and ITD mutant., these may also also contribute, along with the preferential affinity, to the increased sensitivity of D835Y of CEP701 and PKC412. Studying these genetic variations can help determining the prognosis and designing a therapeutic plan for the patients with FLT3 mutations. PMID- 25691929 TI - Expressions of CD11a, CD11b, and CD11c integrin proteins in rats with myocardial hypertrophy. AB - OBJECTIVES: To examine the expressions of CD11a, CD11b, and CD11c integrins in the myocardial tissues of rats with isoproterenol-induced myocardial hypertrophy. This study also provided morphological data to investigate the signal transduction mechanisms of myocardial hypertrophy and reverse it. MATERIALS AND METHODS: A myocardial hypertrophy model was established by subcutaneously injecting isoprenaline in healthy adult Sprague-Dawley rats. Myocardial tissues were obtained, embedded in conventional paraffin, sectioned, and stained with hematoxylin. Pathological changes in myocardial tissues were then observed. The expressions and distributions of CD11a, CD11b, and CD11c integrins were detected by immunohistochemistry. Changes in the mRNA expressions of CD11a, CD11b, and CD11c in the myocardial tissues of rats were detected by RT-PCR. Image analysis software was used to determine the expressions of CD11a, CD11b, and CD11c integrins quantitatively. RESULTS: Immunohistochemical results showed that the positive expressions of CD11a, CD11b, and CD11c integrins increased significantly in the experimental group compared with those in the control group. The mRNA expressions of CD11a, CD11b, and CD11c in the myocardial tissues of rats were consistent with the immunohistochemical results. CONCLUSION: The increase in the protein expressions of CD11a, CD11b, and CD11c integrins may have an important role in the occurrence and development of myocardial hypertrophy. PMID- 25691930 TI - Protection of rats from thioacetamide-induced hepatic fibrosis by the extracts of a traditional Uighur medicine Cichorium glandulosum. AB - OBJECTIVES: To clarify the protective effects of Cichorium glandulosum (CG) extracts on thioacetamide (TAA)-induced rat hepatic fibrosis. MATERIALS AND METHODS: The dry roots of CG were smashed and percolated with 95% ethanol, and the residual was prepared into petroleum ether extract (CG-V), ethyl acetate extract (CG-VI) and n-butyl alcohol extract (CG-VII). Thirty-six Wistar rats were randomly divided into a normal group, a model group, a CG-V group (15 mg/kg), a CG-VI group (3 mg/kg), a CG-VII group (6 mg/kg) and a positive drug group (silibinin capsule, 8 mg/kg). Organ indices and serum levels of glutamic oxaloacetic and glutamic-pyruvic transaminases of intragastrically administered rats were obtained. Expressions of FN, Smad3, IGFBPrP1 and TGF-beta1 genes were detected by Western Blot and immunohistochemical assays. Apoptosis was examined by TUNEL assay. RESULTS: Hepatic fibrosis of treatment groups was evidently mitigated. Expressions of FN, Smad3 and TGF-beta1 in administration groups were higher than those in normal group, and moreover were significantly higher in CG-V and CG-VII groups than those of model group. Apoptotic index of model group was significantly higher than that of normal group, but indices of CG-V and CG-VII groups were significantly lower than that of model group. Significantly more FN, Smad3 and IGFBPrP1 were expressed in treatment groups than those in normal group. CONCLUSION: CG extracts may function by altering TGF-beta/Smads signal transduction pathway. PMID- 25691931 TI - AKT family and miRNAs expression in IL-2 induced CD4(+)T cells. AB - OBJECTIVES: Study of non-coding RNAs is considerable to elucidate principal biological questions or design new therapeutic strategies. miRNAs are a group of non-coding RNAs that their functions in PI3K/AKT signaling and apoptosis pathways after T cell activation is not entirely clear. Herein, miRNAs expression and their putative targets in the mentioned pathways were studied in the activated CD4(+)T cells. MATERIALS AND METHODS: Herein, proliferation rate and IL-2 secretion were measured in treated and untreated cells by IL-2. Putative targets of up-regulated miRNAs were predicted by bioinformatics approaches in the apoptotic and PI3K/AKT signaling pathways. Then the expression of two putative targets was evaluated by quantitative RT-PCR. RESULTS: Proliferation rate of treated cells by IL-2 increased in a dose- and time- dependent manner. Naive and activated CD4(+)T cells induced by different dose of IL-2 secreted abundant amounts of IL-2. Also, in IL-2 un-induced cells (IL-2 depleted cells) after 3 days, decrease of proliferation has been shown. In silico analysis predicted putative targets of up-regulated miRNAs such as AKT1, AKT3 and apoptotic genes in the activated cells induced or un-induced by IL-2. Decrease of AKT3 was shown by Q-RT-PCR as a potential target of miRNAs overexpressed in IL-2 depleted cells. But there was no significant difference in AKT1 expression in two cell groups. CONCLUSION: Our analysis suggests that decrease of AKT3 was likely controlled via up-regulation of specific miRNAs in IL-2 depleted cells. Also it seems that miRNAs play role in induction of different apoptosis pathways in IL-2 induced and un-induced cells. PMID- 25691932 TI - Neuroprotective effects of crocin on the histopathological alterations following brain ischemia-reperfusion injury in rat. AB - OBJECTIVES: Some histopathological alterations take place in the ischemic regions following brain ischemia. Recent studies have demonstrated some neuroprotective roles of crocin in different models of experimental cerebral ischemia. Here, we investigated the probable neuroprotective effects of crocin on the brain infarction and histopathological changes after transient model of focal cerebral ischemia. MATERIALS AND METHODS: Experiment was performed in four groups of rats (each group; n=8), sham, control ischemia and ischemia treated rats. Transient focal cerebral ischemia was induced by 80 min middle cerebral artery occlusion (MCAO) followed by 24 hr reperfusion. Crocin, at doses 50 and 80 mg/kg, was injected at the beginning of ischemia (IP injection). Neurologic outcome (Neurological Deficit Score, NDS scale), infarct volume (TTC staining) and histological studies were assessed 24 hr after termination of MCAO. RESULTS: Treatment with crocin, at doses 50 and 80 mg/kg, significantly reduced the cortical infarct volume by 48% and 60%, and also decreased striatal infarct volume by 45% and75%, respectively. Crocin at two different doses significantly improved the NDS of ischemic rats. At histological evaluation, crocin, at dose 80 mg/kg more than 50 mg/kg, decreased the number of eosinophilic (prenecrotic) neurons and reduced the fiber demyelination and axonal damage in ischemic regions. CONCLUSION: Our findings indicated that crocin effectively reduces brain ischemia-induced injury and improves neurological outcomes. Crocin also is a potent neuroprotective factor that can be able to prevent histopathological alterations following brain ischemia. PMID- 25691933 TI - Comparison of random and aligned PCL nanofibrous electrospun scaffolds on cardiomyocyte differentiation of human adipose-derived stem cells. AB - OBJECTIVES: Cardiomyocytes have small potentials for renovation and proliferation in adult life. The most challenging goal in the field of cardiovascular tissue engineering is the creation of an engineered heart muscle. Tissue engineering with a combination of stem cells and nanofibrous scaffolds has attracted interest with regard to Cardiomyocyte creation applications. Human adipose-derived stem cells (ASCs) are good candidate for use in stem cell-based clinical therapies. They could be cultured and differentiated into several lineages such as cartilage, bone, muscle, neuronal cells, etc. MATERIALS AND METHODS: In the present study, human ASCs were cultured on random and aligned polycaprolactone (PCL) nanofibers. The capacity of random and aligned PCL nanofibrous scaffolds to support stem cells for the proliferation was studied by MTT assay. The cardiomyocyte phenotype was first identified by morphological studies and Immunocytochemistry (ICC) staining, and then confirmed with evaluation of specific cardiac related gene markers expression by real-time RT-PCR. RESULTS: The proliferation rate of ASCs on aligned nanofibrous PCL was significantly higher than random nanofibrous PCL. ICC and morphological studies results confirmed cardiomyocyte differentiation of ASCs on the nanofibrous scaffolds. In addition, the expression rate of cardiovascular related gene markers such as GATA 4, alpha-MHC and Myo-D was significantly increased in aligned nanofibrous PCL compared with random nanofibrous PCL. CONCLUSION: Our results show that the aligned PCL nanofibers are suitable physical properties as polymeric artificial scaffold in cardiovascular tissue engineering application. PMID- 25691934 TI - Role of Brg1 in progression of esophageal squamous cell carcinoma. AB - OBJECTIVES: Epigenetic regulation of gene expression can be carried out through chromatin remodeling enzymes such as SWI/SNF. Brg1 also known as SMARCA4 is a catalytic subunit of SWI/SNF, which is necessary for MMPs expression. Matrix metalloproteinases (MMPs) are known as important player enzymes during tumor progression and metastasis. Aberrant epigenetic modification of chromatin should be precisely clarified to reveal probable unknown pathways in ESCC progression. Probable role of Brg1 in ESCC tumorigenesis and metastasis was studied through the assessment of Brg1 mRNA expression in KYSE30, and further evaluation about the biology of Brg1 was performed through the Brg1 silencing. MATERIALS AND METHODS: Level of Brg1 mRNA expression in KYSE30 was compared to normal tissues using the real time polymerase chain reaction (PCR). Moreover, KYSE30 cells were transfected with Brg1-siRNA to silence the Brg1. RESULTS: Our results showed for the first time that Brg1 mRNA expression was increased in KYSE30 cell line (ESCC cell line) compared with normal esophageal tissue of ESCC patients. Rate of transfection in KYSE30 was also between 40 to 50%, using the pSilencer-Brg1shRNA (1:1 ratio). CONCLUSION: Our data indicated that chromatin remodeling machinery is a novel aspect in tumor biology of ESCC, and overexpression of Brg1 as an important member of SWI/SNF might be involved in the migration and invasion of ESCC tumoral cells. PMID- 25691935 TI - Wrestlers' immune cells produce higher interleukin-6 and lower interleukin-12 and interleukin-13 in response to in vitro mitogen activation. AB - OBJECTIVES: Although recent investigations have shown chronic inflammation and inflammation-associated diseases might be ameliorated by exercise; little is known about the relation between exercise training with anti/pro-inflammatory cytokines. MATERIALS AND METHODS: This cross sectional study was conducted to compare interleukin-4 (IL-4), IL-6, IL-10, IL-12, IL-13, interferon gamma (IFN gamma ) levels in serum, and their in vitro production by whole blood (WB) cells and by peripheral blood mononuclear cells (PBMCs) in response to mitogens lipopolysaccharide and phytohemagglutinin. Twelve elite wrestlers with history of three times per week exercise training for about 9.5 years, and thirteen healthy silent controls were recruited. To analysis the cytokines by enzyme linked immunosorbent assay (ELISA), the blood samples were taken 24 hr after the last training session from the wrestlers. RESULTS: Serum analysis for IL-4, IL-6, IL 10, IL-12, IL-13 and IFN-gamma indicated no statistical difference between the two groups. Meanwhile, 48 hr in vitro activation of WB and PBMCs by the mitogens revealed that IL-6 production was elevated in both WB and PBMCs. Whereas, IL-12 and IL-13 were decreased in supernatant of PBMCs and WB cells cultures, respectively. CONCLUSION: It seems that wrestling cause immune system cells to produce anti-inflammatory myokine IL-6 and decrease production of pro inflammatory cytokine IL-12 and IL-13. PMID- 25691936 TI - Feasibility assessment of in vitro chemoresponse assay on stereotactic biopsies of glioblastoma multiforms: a step towards personalized medicine. AB - OBJECTIVES: P In vitro chemosensitivity and resistance assays (CSRAs) are a promising tool for personalized treatment of glioblastoma multiform (GBM). These assays require a minimum of 1 to 2 g of tumor specimen for testing, but this amount is not always accessible. We aimed to assess the feasibility and validity of utilizing stereotactic biopsies of GBM in CSRAs. MATERIALS AND METHODS: Single cell suspension was prepared from 1 g weight explants of the established xenograft tumor of GBM. Also, primary culture was carried out on 35 mg weight specimens, as a surrogate for stereotactic biopsies. Then, chemoresponse profile of cells obtained by direct cell disaggregation and primary culture was determined using temozolomide and carmustine by clonogenic assay. RESULTS: There was no statistically significant difference in the cytotoxicity of temozolomide and carmustine between cells obtained from both methods. CONCLUSION: This work supports the feasibility of using stereotactic biopsies of GBM in CSRAs. PMID- 25691937 TI - New insight into the immunomodulatory mechanisms of Tretinoin in NMRI mice. AB - OBJECTIVES: Recent evidence have proposed that Tretinoin produced in the gut preferentially promote differentiation of FoxP3+Treg cells but inhibits Th17 lymphocytes, and this may be the main immunomdulatory mechanism of Tretinoin in vivo. This study was done to investigate the effects of Tretinoin in outbred white mice after challenge with sheep red blood cells (SRBC). MATERIALS AND METHODS: Twenty male NMRI-mice randomly allocated in two equal groups. Mice were treated with 1*10(9) SRBCs emulsified in CFA intraperitoneally twice with one weak interval. Animals were bled 5 days after last injection. Moreover, 48 hr before bleeding time, 1*10(9) SRBCs were injected into the left hind foot pad of mice. Tretinoin (25 mg/kg-every other day) were intraperitoneally injected into the treatment group from the beginning of the study and continued throughout the study. The levels of anti-SRBC antibody and the specific cellular immune responses were measured by microhemagglutination test and footpad thickness, respectively. Moreover, splenocytes were checked for proliferation rate, respiratory burst, cytokine production and FoxP3+Treg cells frequency. RESULTS: Tretinoin markedly alleviated cellular immunity and concurrently potentiated humoral immunity after mice challenge with SRBCs. Furthermore, aside from reducing NBT reduction and lymphocyte proliferation, Tretinoin markedly suppressed the secretion of interleukin-17 and conversely, increased the production of interleukin-10. However, the level of IFN-gamma and the frequency of FoxP3+Treg cells did not alter significantly. CONCLUSION: The in vivo immunomudlatoty effects of Tretinoin may be partly due to immune deviation from pro-inflammatory cytokine interleukin-17 to anti-inflammatory cytokine interleukin-10, but not absolutely depend on the expansion of FoxP3(+)Treg cells. PMID- 25691938 TI - Surface protein mutations in chronic hepatitis B patients who received hepatitis B vaccine therapy. AB - OBJECTIVE S: The aim of this study was to determine the correlation between vaccine therapy and appearance of mutations in hepatitis B surface antigen (HBsAg)-positive chronic hepatitis B virus (HBV) patients. MATERIALS AND METHODS: 16 patients received the HBV vaccine and another 16 individuals from the control group did not. The surface gene was amplified and directly sequenced from samples prior to vaccination and six months after the third dose. RESULTS: Only one patient lost HBsAg. 48 and 44 amino acid mutations were found before and after vaccine therapy in the vaccine group respectively, 51 of which (55.4%) occurred in immune epitopes: 5 were in B cell, 21 in T helper (Th), and 25 in cytotoxic T lymphocyte (CTL) epitopes. In the control group, 35 and 41 amino acid substitutions were found before and after therapy, respectively. 32 (42%) of 76 amino acid changes occurred within immune epitopes. There were no differences in age, gender, and duration of chronicity in both patient and control groups in terms of the frequency and the patterns of mutations. CONCLUSION: In chronic carriers who already had HBsAg variants selected by the host-immune response, any immune stimulation by the vaccine had no effect on the chronic state of these patients or selected any remarkable escape mutants. Newer strategies should be considered based on third generation or the use of DNA vaccines or new adjuvants. PMID- 25691939 TI - Molecular characterization of Aspergillus infections in an Iranian educational hospital using RAPD-PCR method. AB - OBJECTIVES: The nosocomial infections by Aspergillus species are associated with constructions and increased dust loads in hospital indoors. Our main object was to find the environmental sources of Aspergillus species causing hospital acquired infections. MATERIALS AND METHODS: The clinical and environmental samplings were performed during 18 months from spring 2010 to summer 2011 in Imam educational hospital, Urmia, Iran. A morphological diagnosis was performed including microscopic characterization of isolated aspergillus from cultured specimens and polymerase chain reaction - restriction fragment length polymorphism (PCR-RFLP) for the identification in the level of species. Random amplified polymorphic DNA - PCR RAPD-PCR using random primers for rDNA gene was performed to compare Aspergillus isolates of clinical cases with the relevant environmental sources. RESULTS: Use of RAPD method resulted various differential patterns, so that some Aspergillus isolates from the clinical and hospital indoor were completely matched (matched pairs) and some other Aspergillus isolates were not matched. In the case of matched pairs, Aspergillus niger and A. flavus isolated from broncoalveolar lavage and sinus discharge were relevant to those of air conditioner and walls surfaces, respectively. CONCLUSION: The hospital sources for the Aspergillus clinical isolates included air condition and walls. RAPD-PCR analysis can play a trivial role to find the hospital sources of Aspergillus clinical isolates. PMID- 25691940 TI - Alpha-1 antitrypsin, retinol binding protein and keratin 10 alterations in patients with psoriasis vulgaris, a proteomic approach. AB - OBJECTIVES: Psoriasis is an autoimmune disease that appears on the skin. Although psoriasis is clinically and histologically well characterized, its pathogenesis is unknown in detail. The aims of this study were to evaluate the proteome of psoriatic patients' sera and to compare them with those of normal healthy human to find valuable biomarkers. MATERIALS AND METHODS: In a case-control study, twenty cases of white patients with psoriasis vulgaris, 10 males and 10 females and sixteen healthy controls, 8 males and 8 females were enrolled in the study. The serum protein expression patterns obtained after depletion of albumin were compared by using two dimensional gel electrophoresis (2-DE) coupled to MALDI/TOF TOF to identify disease associated proteins. RESULTS: Differential expression of nine protein spots representing four unique proteins including alpha-1 antitrypsin, retinol binding protein, keratin 10 and an unknown protein (with pI 6.47 and molecular weight of 19941 Da), between psoriatic and healthy human serum were found. Furthermore, expression of four new alpha-1 antitrypsin isoforms with different molecular weight and isoelectric point were observed in psoriatic serums in this research for the first time. CONCLUSION: A unique proteomic profiling with abnormal expression of alpha-1 antitrypsin and presence of keratin 10 in sera of psoriasis patients were observed that may constitute new and useful findings of psoriasis and offer a clue to a better understanding of the inflammatory pathway. PMID- 25691941 TI - The mitochondrial DNA mutations associated with cardiac arrhythmia investigated in an LQTS family. AB - OBJECTIVES: As mitochondrial oxidative stress is probably entailed in ATP production, a candidate modifier factor for the long QT syndrome (LQTS) could be mitochondrial DNA (mtDNA). It has been notified that ion channels' activities in cardiomyocytes are sensitive to the ATP level. MATERIALS AND METHODS: The sample of the research was an Iranian family with LQTS for mutations by PCR-SSCP and DNA sequencing. The study searched about 40% of the entire mitochondrial genome in the family. RESULTS: Four novel mutations that lead to an amino acid substitution and two mutations in mitochondrial tRNA have been informed in this study. A Statistically significant correlation (r = 0.737) between QTc (ms) and the age of LQTS patients has been reported. CONCLUSION: The research data show that these mitochondrial mutations, in a family with LQTS, might be the responsible mitochondrial that defect and increase the gravity of LQTS. PMID- 25691942 TI - Plasma levels of leptin and visfatin in rheumatoid arthritis patients; is there any relationship with joint damage? AB - OBJECTIVE S: Rheumatoid arthritis (RA) is a chronic systemic inflammatory disorder, primarily targeting the synovium and articular cartilage that leads to joint damage. Recent reports have suggested the role of adipocytokines in mediating joint damage; however it still is a matter of debate. The purpose of this study was to evaluate the association between serum values of adiopocytokines (leptin, visfatin) and radiographic joint damage in patients with RA. MATERIALS AND METHODS: Fifty-four patients diagnosed with RA, based on Revised ACR Criteria 2010, with 1-5 year disease duration since diagnosis, were enrolled. Twenty-nine of patients had erosion in radiographic studies and 25patients had no erosion. Radiographic joint damages were defined according to Larsen Score. Additionally, serum levels of adipocytokines were measured and cross-sectional associations with radiographic damage were explored, adjusting for pertinent confounders. RESULTS: The serum level of visfatin were significantly higher in patients with radiographic joint damage compared with patients with no joint damage (P=0.013). This difference remained significant after adjustment for C-reactive protein levels (P=0.008), but not after adjustment for disease duration (P=0.247). The mean leptin serum levels were not different between these two groups (P=0.903). There was a positive correlation between leptin levels and BMI (r=0.494, P<0.001). However, after adjustment for BMI, leptin levels had no difference between two groups (P=0.508). CONCLUSION: This study revealed that visfatin levels were significantly higher in patients with radiographic joint damage dependently to disease duration. Therefore, it seems that adipocytokine may be a valuable factor in therapeutic targets in the future. PMID- 25691943 TI - Cloning and expression of the enzymatic region of Streptococcal hyaluronidase. AB - OBJECTIVES: Streptococcus pyogenes produces extracellular hyaluronidase enzyme. This enzyme is directly associated with the spread of the organism during infection. The objective of the present study was to clone and express the nucleotide sequence of the enzyme which is involved in hyaluronidase enzymatic activity. MATERIALS AND METHODS: The enzymatic region of hyaluronidase gene was detected by bioinformatics method. The PCR method was used to amplify enzymatic region of hyaluronidase gene from chromosomal DNA of Streptococcus pyogenes. The eluted product was cloned into the prokaryotic expression vector pET32a which was digested by BamHI and HindIII restriction endonuclease enzymes. The target protein was expressed in the Escherichia coli. The bacteria including pET32a-hylA (hylA is abbreviation of Streptococcus pyogenes hyaluronidase gene and hylA is abbreviation of Streptococcus pyogenes hyaluronidase protein) plasmids were induced by IPTG and analyzed by SDS-PAGE. The enzymatic evaluation and antigenicity was finally studied. RESULTS: Enzymes digestion analysis, sequencing results showed that the target gene (1296 base pair) was inserted correctly into the recombinant vector. The expressed protein (65 KDa) was purified successfully via affinity chromatography. Data also indicated that enzymatic region of hyaluronidase protein from Streptococcus pyogenes was recognized in all 5 patient's sera. CONCLUSION: In general, it is possible to produce the enzymatic regions of the Streptococcus pyogenes hyaluronidase in E. coli. The antigenic property of the produced protein is well retained. Considering the product's domestic demand and also low efficiency of production and pathogenicity of Streptococcus species, it is possible to produce it as recombinant product. PMID- 25691944 TI - Glucose concentration in culture medium affects mRNA expression of TRPV1 and CB1 receptors and changes capsaicin toxicity in PC12 cells. AB - OBJECTIVE S: Hyperglycemia is widely recognized as the underlying cause for some debilitating conditions in diabetic patients. The role of cannabinoid CB1 and vanilloid TRPV1 receptors and their endogenous agonists, endovanilloids, in diabetic neuropathy is shown in many studies. Here we have used PC12 cell line to investigate the possible influence of glucose concentration in culture medium on cytoprotective or toxic effects of a CB1 [WIN55 212-2 (WIN)], or TRPV1 [Capsaicin (CAS)] agonist. MATERIALS AND METHODS: Cell viability was tested using the MTT assay. We have also measured TRPV1 and CB1 transcripts by real time reverse transcription-polymerase chain reaction while cells were grown in low (5.5 mM) and high (50 mM) glucose concentrations. RESULTS: Real time PCR results indicated that high glucose medium increased (P<0.01) TRPV1 mRNA and decreased (P <0.001) that of CB1. Cell culture tests show that hyperglycemic cells are more vulnerable (Dose * Medium, F (3,63)=41.5, P<0.001) to the toxic effects of capsaicin compared to those grown in low glucose medium. CONCLUSION: These findings propose that hyperglycemic conditions may result in neuronal cell death because of inducing a counterbalance between cytotoxic TRPV1 and cytoprotective CB1 receptors. PMID- 25691945 TI - Synthesis and docking analysis of new heterocyclic system of tetrazolo[5',1':2,3][1,3,4]thiadiazepino [7,6-b]quinolines as aldose reductase inhibitors. AB - OBJECTIVES: In recent years, the chemistry of Tetrazolo[5',1':2,3][1,3,4]thiadiazepino [7,6-b] quinolines have received considerable attention owing to their synthetic and effective biological importance which exhibits a wide variety of biological activity. As the inhibitor of aldose reductase, the aforementioned compounds may have implication in preventing complications of diabetes. MATERIALS AND METHODS: A group of tetrazolo[5',1':2,3][1,3,4]thiadiazepino [7,6-b] quinoline derivatives were synthesized, and theoretically evaluated for their inhibitory potency against aldose reductase (ALR) via docking process. The docking calculation was done in Genetic Optimization for Ligand Docking (GOLD) 5.2 software using Genetic algorithm. RESULTS: Compounds 3a and 3f showed the best inhibitory potency by GOLD score value of 78.83 and 76.88 respectively. CONCLUSION: All of the best models formed strong hydrogen bonds with Trp 111 and Tyr 209 via tetrazole moiety. It was found that pi-pi interaction between Tyr 209, Trp 20 and His 110 side chain and quinolin moiety was one of the common factors in enzyme-inhibitor junction. It was found that both hydrogen bonding and hydrophobic interactions are important in the structure and function of biological molecules, especially for inhibition in a complex. PMID- 25691946 TI - Comparison of human adipose-derived stem cells and chondroitinase ABC transplantation on locomotor recovery in the contusion model of spinal cord injury in rats. AB - OBJECTIVES: Spinal cord injury (SCI) is one of the most serious clinical diseases and its treatment has been a subject of interest to researchers. There are two important therapeutic strategies in the treatment of SCI: replacing lost tissue cells through cells implantation and scar elimination. Therefore, in this study we used human adipose-derived stem cells (hADSCs) implantation and injection of Chondroitinase ABC. Aim of present study was to answer to this question: which one is more efficient for Improvement of locomotor recovery after SCI in rat? Transplantation of hADSCs or injection of ChABC. MATERIALS AND METHODS: The spinal cord of rats was injured by contusion using a weight-drop at the level of T8-9, the hADSCs and Chondroitinase ABC were infused in to the spinal cord tissue after injury. BBB test was performed and recorded for each animal weekly for 8 weeks. After the 8(th) weeks, Serial cross-sections were stained with cresyl violet and examined under a light microscope and area of cavity in the spinal cord was measured. RESULTS: At 8(th) weeks after injection, hADSCs and ChABC significantly promote locomotor function (P<0.01) and spinal cords of hADSCs and ChABC group had cavities much smaller than those of the control group (P<0.001). CONCLUSION: Results of the present study shows dealing with inappropriate neuro inhibitory environment and glial scar by ChABC have equal role compare to cell therapy (with hADSCs) for improving motor function after SCI and this result in adoption of proper therapeutic strategies for SCI intervention is important. PMID- 25691947 TI - The effects of co-administration of opium and morphine with nicotine during pregnancy on spatial learning and memory of adult male offspring rats. AB - OBJECTIVES: Smoking opium/cigarette is a global health concern. The aim of this study was to examine learning and memory of rat male offsprings whose mothers had been exposed to either opium or morphine with nicotine during pregnancy. MATERIALS AND METHODS: Wistar rats were used for the experiments. In the female rats, opium, morphine and nicotine dependencies were induced by daily injections of drug solution for 10 days before mating. Spatial memory was tested by Morris water maze test in male pups at the postnatal day 60. The duration that took until the rats found the platform in the maze and also their swimming speed were recorded. RESULTS: An increase in the platform finding duration was observed for the pups of dependent mothers in comparison with the control in the training trial (P<0.05). Prenatal exposure to opium/morphine and nicotine significantly decreased the time spent in the trigger zone to find the hidden platform (P<0.05) but had no significant effect on the swimming speed in the probe test. However, no significant difference was observed in the learning and memory behavior of offspring whose mothers received morphine, opium, nicotine or the co administration of either morphine or opium with nicotine. CONCLUSION: The present study showed that the opium, morphine and nicotine abuse and co-administration of opium/morphine with nicotine during pregnancy may cause deficits in spatial learning of male rat offspring. Based on our data, no synergistic effects of co drug administration were observed on learning and memory in male rat offspring. PMID- 25691948 TI - Green tea extract protects endothelial progenitor cells from oxidative insult through reduction of intracellular reactive oxygen species activity. AB - OBJECTIVES: Many studies have reported that tea consumption decreases cardiovascular risk, but the mechanisms remain unclear. Green tea is known to have potent antioxidant and free radical scavenging activities. This study aimed to investigate whether green tea extract (GTE) can protect endothelial progenitors cells (EPCs) against oxidative stress through antioxidant mechanisms. MATERIALS AND METHODS: Mononuclear cells (MNCs) were isolated from peripheral blood by density gradient centrifugation with Ficoll. The cells were then plated on fibronectin-coated culture dishes. After 7 days of culture, EPCs were characterized as adherent cells double positive for DiI-ac-LDL uptake and lectin binding. EPCs were further identified by assessing the expression of CD34/45, CD133, and KDR. EPCs were then treated with hydrogen peroxide (H2O2) at doses of 50, 100, 200 uM and incubated with or without GTE (25 ug/ml). The intracellular reactive oxygen species (ROS) levels were detected by flow cytometry using a 2',7'-dichlorofluorescein diacetate (DCF-DA) fluorescent probe. RESULTS: GTE ameliorated the cell viability of EPCs induced by H2O2 at doses of 50, 100, 200 uM for about 25.47, 22.52, and 11.96% higher than controls, respectively. GTE also decreased the intracellular ROS levels of EPCs induced by H2O2 at doses of 50, 100, 200 uM for about 84.24, 92.27, and 93.72% compared to controls, respectively. CONCLUSION: GTE improves cell viability by reducing the intracellular ROS accumulation in H2O2-induced EPCs. PMID- 25691949 TI - Effect of thoracic epidural blockade on hypoxia-induced pulmonary arterial hypertension in rats. AB - OBJECTIVES: The present study was aimed to investigate the influence of thoracic epidural blockade on hypoxia-induced pulmonary hypertension in rats. MATERIALS AND METHODS: Forty eight Wistar rats were randomly divided into 4 equal groups, named normoxia hypoxia hypoxia/ ropivacaine and hypoxia/saline. Animals were placed in a hypoxia chamber and instrumented with epidural catheters at the thoracic level. Rats were injected with saline or ropivacaine. Haemodynamic measurements included pulmonary artery pressure and right ventricular hypertrophy. Degree of pulmonary vascular remodeling was determined by Hematoxylin and Eosin (HE) staining. Serum cyclic GMP (cGMP) and TNF-alpha were measured using radioimmuno assay. Real-time PCR and western boltting were employed to examine the expression of cAMP responding-element binding protein (CREB). RESULTS: We found that the thoracic epidural blockade significantly decreased chronic hypoxia-induced pulmonary hypertension and vascular remodeling in rats. Ropivacaine-treated rats exhibited significantly lower mean pulmonary artery pressure (mPAP), ratio of right ventricular weight to left ventricular plus septal weight (RV/(LV+S)) and wall thickness of pulmonary artery compared with those of control rats. Hypoxia-induced increase in levels of serum cGMP and TNF-alpha was reversed by thoracic epidural blockade. Moreover, hypoxia increased expression of CREB at mRNA and protein levels which could be suppressed by thoracic epidural blockade. CONCLUSION: Thoracic epidural blockade reduced mPAP and serum level of TNF-alpha and increased cGMP. The treatment reversed upregulated expression of CREB at mRNA and protein production. PMID- 25691950 TI - Association of ADAM33 gene polymorphisms with allergic asthma. AB - OBJECTIVES: Asthma results from the interaction between genetic and environmental factors. ADAM33 gene on chromosome 20p13 is associated with asthma and airway hyperresponsiveness. MATERIALS AND METHODS: This is a case-control study, where four SNPs S1 (rs3918396), T1 (rs2280091), T2 (rs2280090), V4 (rs2787094) of ADAM33 gene have been assessed in patients with allergic asthma and normal controls (95 patients and 86 normal). Blood samples of these participants have been genotyped by PCR and the RFLP method. RESULTS: There was no association between asthmatic patients and polymorphisms of alleles, genotypes and haplotypes of the ADAM33 gene. When categorizing the asthmatic patients in severe, moderate and mild groups, associations in the subcategories of asthmatic patients were found. There were associations between polymorphisms of C allele of T1 SNP with severe asthmatic patients and G allele of V4 SNP with moderate asthmatics respectively (P=0.006, P=0.01). There was a significant association between sensitivity to mite and polymorphism of C allele of T1 SNP (P=0.02). Besides, there was a significant association between sensitivity to weeds and genotype GG of V4 SNP (P=0.05). CONCLUSION: Polymorphisms of ADAM33 gene might be associated with severe asthma and sensitivity to aeroallergens in northeast of Iran, but further studies are needed to determine the polymorphisms in this area and other regions of our country. PMID- 25691951 TI - Preparation and characterization of PLGA nanospheres loaded with inactivated influenza virus, CpG-ODN and Quillaja saponin. AB - OBJECTIVES: The purpose of this study was preparation and evaluation of PLGA nanospheres containing the influenza virus and different adjuvants, Quillaja saponin (QS) and CpG-ODN. MATERIALS AND METHODS: Nanospheres were prepared using the double emulsion-solvent evaporation method. The morphological and physicochemical properties were studied by scanning electron microscopy (SEM), determination of zeta potential, encapsulation efficiency and release profile. RESULTS: The particle size of formulations was less than 1000 nm, except for formulations containing antigen. The results were confirmed with SEM images. Encapsulation efficiency of antigen, QS and CpG ODN were 80%, 62% and 31%, respectively. The zeta potential of nanospheres was about -30 mV. The burst release was observed for all encapsulates and reached to about 48%, 44% and 35% within 90 min for antigen, CpG-ODN and Qs content, respectively. CONCLUSION: The formulations showed proper physicochemical properties. These nanospheres have good potential to be used as delivery systems/adjuvants for immunization against influenza. PMID- 25691952 TI - On the nose: genetic and evolutionary aspects of smell. PMID- 25691953 TI - Health economic comparison of SLIT allergen and SCIT allergoid immunotherapy in patients with seasonal grass-allergic rhinoconjunctivitis in Germany. AB - BACKGROUND: Allergoids are chemically modified allergen extracts administered to reduce allergenicity and to maintain immunogenicity. Oralair(r) (the 5-grass tablet) is a sublingual native grass allergen tablet for pre- and co-seasonal treatment. Based on a literature review, meta-analysis, and cost-effectiveness analysis the relative effects and costs of the 5-grass tablet versus a mix of subcutaneous allergoid compounds for grass pollen allergic rhinoconjunctivitis were assessed. METHODS: A Markov model with a time horizon of nine years was used to assess the costs and effects of three-year immunotherapy treatment. Relative efficacy expressed as standardized mean differences was estimated using an indirect comparison on symptom scores extracted from available clinical trials. The Rhinitis Symptom Utility Index (RSUI) was applied as a proxy to estimate utility values for symptom scores. Drug acquisition and other medical costs were derived from published sources as well as estimates for resource use, immunotherapy persistence, and occurrence of asthma. The analysis was executed from the German payer's perspective, which includes payments of the Statutory Health Insurance (SHI) and additional payments by insurants. Comprehensive deterministic and probabilistic sensitivity analyses and different scenarios were performed to test the uncertainty concerning the incremental model outcomes. RESULTS: The applied model predicted a cost-utility ratio of the 5-grass tablet versus a market mix of injectable allergoid products of ? 12,593 per QALY in the base case analysis. Predicted incremental costs and QALYs were ? 458 (95% confidence interval, CI: ? 220; ? 739) and 0.036 (95% CI: 0.002; 0.078), respectively. Compared to the allergoid mix the probability of the 5-grass tablet being the most cost-effective treatment option was predicted to be 76% at a willingness-to-pay threshold of ? 20,000. The results were most sensitive to changes in efficacy estimates, duration of the pollen season, and immunotherapy persistence rates. CONCLUSIONS: This analysis suggests the sublingual native 5 grass tablet to be cost-effective relative to a mix of subcutaneous allergoid compounds. The robustness of these statements has been confirmed in extensive sensitivity and scenario analyses. PMID- 25691954 TI - A general model of intra-annual tree growth using dendrometer bands. AB - Tree growth is an important indicator of forest health, productivity, and demography. Knowing precisely how trees' grow within a year, instead of across years, can lead to a finer understanding of the mechanisms that drive these larger patterns. The growing use of dendrometer bands in research forests has only rarely been used to measure growth at resolutions finer than yearly, but intra-annual growth patterns can be observed from dendrometer bands using precision digital calipers and weekly measurements. Here we present a workflow to help forest ecologists fit growth models to intra-annual measurements using standard optimization functions provided by the R platform. We explain our protocol, test uncertainty in parameter estimates with respect to sample sizes, extend the optimization protocol to estimate robust lower and upper annual diameter bounds, and discuss potential challenges to optimal fits. We offer R code to implement this workflow. We found that starting values and initial optimization routines are critical to fitting the best functional forms. After using a bounded, broad search method, a more focused search algorithm obtained consistent results. To estimate starting and ending annual diameters, we combined the growth function with early and late estimates of beginning and ending growth. Once we fit the functions, we present extension algorithms that estimate periodic reductions in growth, total growth, and present a method of controlling for the shifting allocation to girth during the growth season. We demonstrate that with these extensions, an analysis of growth response to weather (e.g., the water available to a tree) can be derived in a way that is comparable across trees, years, and sites. Thus, this approach, when applied across broader data sets, offers a pathway to build inference about the effects of seasonal weather on growth, size- and light-dependent patterns of growth, species-specific patterns, and phenology. PMID- 25691955 TI - Bryozoans are returning home: recolonization of freshwater ecosystems inferred from phylogenetic relationships. AB - Bryozoans are aquatic invertebrates that inhabit all types of aquatic ecosystems. They are small animals that form large colonies by asexual budding. Colonies can reach the size of several tens of centimeters, while individual units within a colony are the size of a few millimeters. Each individual within a colony works as a separate zooid and is genetically identical to each other individual within the same colony. Most freshwater species of bryozoans belong to the Phylactolaemata class, while several species that tolerate brackish water belong to the Gymnolaemata class. Tissue samples for this study were collected in the rivers of Adriatic and Danube basin and in the wetland areas in the continental part of Croatia (Europe). Freshwater and brackish taxons of bryozoans were genetically analyzed for the purpose of creating phylogenetic relationships between freshwater and brackish taxons of the Phylactolaemata and Gymnolaemata classes and determining the role of brackish species in colonizing freshwater and marine ecosystems. Phylogenetic relationships inferred on the genes for 18S rRNA, 28S rRNA, COI, and ITS2 region confirmed Phylactolaemata bryozoans as radix bryozoan group. Phylogenetic analysis proved Phylactolaemata bryozoan's close relations with taxons from Phoronida phylum as well as the separation of the Lophopodidae family from other families within the Plumatellida genus. Comparative analysis of existing knowledge about the phylogeny of bryozoans and the expansion of known evolutionary hypotheses is proposed with the model of settlement of marine and freshwater ecosystems by the bryozoans group during their evolutionary past. In this case study, brackish bryozoan taxons represent a link for this ecological phylogenetic hypothesis. Comparison of brackish bryozoan species Lophopus crystallinus and Conopeum seurati confirmed a dual colonization of freshwater ecosystems throughout evolution of this group of animals. PMID- 25691956 TI - Ecophysiological responses to different forest patch type of two codominant tree seedlings. AB - According to gap-phase dynamics theory, forests can be divided into four distinct patch types: gap patch (G), building patch (B), mature patch (M), and degeneration patch (D). Varying light conditions across patch types are one of the most important factors affecting the coexistence of vegetation. Mechanisms of coexistence can be understood through detailed knowledge of ecophysiological responses of codominant tree seedlings to patch types. The following study was conducted to determine ecophysiological responses of Cyclobalanopsis glauca (an evergreen broad-leaved species) and Bothrocaryum controversum (a deciduous broad leaved species) to four different patch types. During the gap-phase dynamics, light intensity and the magnitude of change in the four different patches followed the order of: G > B > D > M. Both species had the greatest photosynthetic capacity in the G patch. Dry leaf mass per area (LMA), Chlorophyll a + b concentration (Chl), carotenoids (Car), and nitrogen content per area (N a ) all responded to changes in light across patch type, but B. controversum showed greater sensitivity and changes than C. glauca. From G to M patch, the maximal quantum efficiency of PSII (F v /F m ) had a larger variation magnitude for B. controversum than for C. glauca. From G to M patch, B. controversum showed significant changes in gas exchange, while C. glauca showed only small changes. Ecophysiological trait partitioning of response to light in different patches provides a possible explanation of a coexistence mechanism. PMID- 25691957 TI - Challenging the paradigm of nitrogen cycling: no evidence of in situ resource partitioning by coexisting plant species in grasslands of contrasting fertility. AB - In monoculture, certain plant species are able to preferentially utilize different nitrogen (N) forms, both inorganic and organic, including amino acids and peptides, thus forming fundamental niches based on the chemical form of N. Results from field studies, however, are inconsistent: Some showing that coexisting plant species predominantly utilize inorganic N, while others reveal distinct interspecies preferences for different N forms. As a result, the extent to which hypothetical niches are realized in nature remains unclear. Here, we used in situ stable isotope tracer techniques to test the idea, in temperate grassland, that niche partitioning of N based on chemical form is related to plant productivity and the relative availability of organic and inorganic N. We also tested in situ whether grassland plants vary in their ability to compete for, and utilize peptides, which have recently been shown to act as an N source for plants in strongly N-limited ecosystems. We hypothesized that plants would preferentially use NO3 (-)-N and NH4 (+)-N over dissolved organic N in high productivity grassland where inorganic N availability is high. On the other hand, in low-productivity grasslands, where the availability of dissolved inorganic N is low, and soil availability of dissolved organic N is greater, we predicted that plants would preferentially use N from amino acids and peptides, prior to microbial mineralization. Turves from two well-characterized grasslands of contrasting productivity and soil N availability were injected, in situ, with mixtures of (15)N-labeled inorganic N (NO3 (-) and NH4 (+)) and (13)C(15)N labeled amino acid (l-alanine) and peptide (l-tri-alanine). In order to measure rapid assimilation of these N forms by soil microbes and plants, the uptake of these substrates was traced within 2.5 hours into the shoots of the most abundant plant species, as well as roots and the soil microbial biomass. We found that, contrary to our hypothesis, the majority of plant species across both grasslands took up most N in the form of NH4 (+), suggesting that inorganic N is their predominant N source. However, we did find that organic N was a source of N which could be utilized by plant species at both sites, and in the low-productivity grassland, plants were able to capture some tri-alanine-N directly. Although our findings did not support the hypothesis that differences in the availability of inorganic and organic N facilitate resource partitioning in grassland, they do support the emerging view that peptides represent a significant, but until now neglected, component of the terrestrial N cycle. PMID- 25691958 TI - Genetic analysis shows low levels of hybridization between African wildcats (Felis silvestris lybica) and domestic cats (F. s. catus) in South Africa. AB - Hybridization between domestic and wild animals is a major concern for biodiversity conservation, and as habitats become increasingly fragmented, conserving biodiversity at all levels, including genetic, becomes increasingly important. Except for tropical forests and true deserts, African wildcats occur across the African continent; however, almost no work has been carried out to assess its genetic status and extent of hybridization with domestic cats. For example, in South Africa it has been argued that the long-term viability of maintaining pure wildcat populations lies in large protected areas only, isolated from human populations. Two of the largest protected areas in Africa, the Kgalagadi Transfrontier and Kruger National Parks, as well as the size of South Africa and range of landscape uses, provide a model situation to assess how habitat fragmentation and heterogeneity influences the genetic purity of African wildcats. Using population genetic and home range data, we examined the genetic purity of African wildcats and their suspected hybrids across South Africa, including areas within and outside of protected areas. Overall, we found African wildcat populations to be genetically relatively pure, but instances of hybridization and a significant relationship between the genetic distinctiveness (purity) of wildcats and human population pressure were evident. The genetically purest African wildcats were found in the Kgalagadi Transfrontier Park, while samples from around Kruger National Park showed cause for concern, especially combined with the substantial human population density along the park's boundary. While African wildcat populations in South Africa generally appear to be genetically pure, with low levels of hybridization, our genetic data do suggest that protected areas may play an important role in maintaining genetic purity by reducing the likelihood of contact with domestic cats. We suggest that approaches such as corridors between protected areas are unlikely to remain effective for wildcat conservation, as the proximity to human settlements around these areas is projected to increase the wild/domestic animal interface. Thus, large, isolated protected areas will become increasingly important for wildcat conservation and efforts need to be made to prevent introduction of domestic cats into these areas. PMID- 25691959 TI - Demographic effects of extreme weather events: snow storms, breeding success, and population growth rate in a long-lived Antarctic seabird. AB - Weather extremes are one important element of ongoing climate change, but their impacts are poorly understood because they are, by definition, rare events. If the frequency and severity of extreme weather events increase, there is an urgent need to understand and predict the ecological consequences of such events. In this study, we aimed to quantify the effects of snow storms on nest survival in Antarctic petrels and assess whether snow storms are an important driver of annual breeding success and population growth rate. We used detailed data on daily individual nest survival in a year with frequent and heavy snow storms, and long term data on petrel productivity (i.e., number of chicks produced) at the colony level. Our results indicated that snow storms are an important determinant of nest survival and overall productivity. Snow storm events explained 30% of the daily nest survival within the 2011/2012 season and nearly 30% of the interannual variation in colony productivity in period 1985-2014. Snow storms are a key driver of Antarctic petrel breeding success, and potentially population dynamics. We also found state-dependent effects of snow storms and chicks in poor condition were more likely to die during a snow storm than chicks in good condition. This stresses the importance of considering interactions between individual heterogeneity and extreme weather events to understand both individual and population responses to climate change. PMID- 25691960 TI - Structure of trophic and mutualistic networks across broad environmental gradients. AB - This study aims to understand how inherent ecological network structures of nestedness and modularity vary over large geographic scales with implications for community stability. Bipartite networks from previous research from 68 locations globally were analyzed. Using a meta-analysis approach, we examine relationships between the structure of 22 trophic and 46 mutualistic bipartite networks in response to extensive gradients of temperature and precipitation. Network structures varied significantly across temperature gradients. Trophic networks showed decreasing modularity with increasing variation in temperature within years. Nestedness of mutualistic networks decreased with increasing temperature variability between years. Mean annual precipitation and variability of precipitation were not found to have significant influence on the structure of either trophic or mutualistic networks. By examining changes in ecological networks across large-scale abiotic gradients, this study identifies temperature variability as a potential environmental mediator of community stability. Understanding these relationships contributes to our ability to predict responses of biodiversity to climate change at the community level. PMID- 25691961 TI - Gene flow and population structure of a solitary top carnivore in a human dominated landscape. AB - While African leopard populations are considered to be continuous as demonstrated by their high genetic variation, the southernmost leopard population exists in the Eastern and Western Cape, South Africa, where anthropogenic activities may be affecting this population's structure. Little is known about the elusive, last free-roaming top predator in the region and this study is the first to report on leopard population structuring using nuclear DNA. By analyzing 14 microsatellite markers from 40 leopard tissue samples, we aimed to understand the populations' structure, genetic distance, and gene flow (Nm). Our results, based on spatially explicit analysis with Bayesian methods, indicate that leopards in the region exist in a fragmented population structure with lower than expected genetic diversity. Three population groups were identified, between which low to moderate levels of gene flow were observed (Nm 0.5 to 3.6). One subpopulation exhibited low genetic differentiation, suggesting a continuous population structure, while the remaining two appear to be less connected, with low emigration and immigration between these populations. Therefore, genetic barriers are present between the subpopulations, and while leopards in the study region may function as a metapopulation, anthropogenic activities threaten to decrease habitat and movement further. Our results indicate that the leopard population may become isolated within a few generations and suggest that management actions should aim to increase habitat connectivity and reduce human-carnivore conflict. Understanding genetic diversity and connectivity of populations has important conservation implications that can highlight management of priority populations to reverse the effects of human-caused extinctions. PMID- 25691962 TI - Rainfall during parental care reduces reproductive and survival components of fitness in a passerine bird. AB - Adverse weather conditions during parental care may have direct consequences for offspring production, but longer-term effects on juvenile and parental survival are less well known. We used long-term data on reproductive output, recruitment, and parental survival in northern wheatears (Oenanthe oenanthe) to investigate the effects of rainfall during parental care on fledging success, recruitment success (juvenile survival), and parental survival, and how these effects related to nestling age, breeding time, habitat quality, and parental nest visitation rates. While accounting for effects of temperature, fledging success was negatively related to rainfall (days > 10 mm) in the second half of the nestling period, with the magnitude of this effect being greater for breeding attempts early in the season. Recruitment success was, however, more sensitive to the number of rain days in the first half of the nestling period. Rainfall effects on parental survival differed between the sexes; males were more sensitive to rain during the nestling period than females. We demonstrate a probable mechanism driving the rainfall effects on reproductive output: Parental nest visitation rates decline with increasing amounts of daily rainfall, with this effect becoming stronger after consecutive rain days. Our study shows that rain during the nestling stage not only relates to fledging success but also has longer-term effects on recruitment and subsequent parental survival. Thus, if we want to understand or predict population responses to future climate change, we need to consider the potential impacts of changing rainfall patterns in addition to temperature, and how these will affect target species' vital rates. PMID- 25691963 TI - Using heterozygosity-fitness correlations to study inbreeding depression in an isolated population of white-tailed deer founded by few individuals. AB - A heterozygosity-fitness correlations (HFCs) may reflect inbreeding depression, but the extent to which they do so is debated. HFCs are particularly likely to occur after demographic disturbances such as population bottleneck or admixture. We here study HFC in an introduced and isolated ungulate population of white tailed deer Odocoileus virginianus in Finland founded in 1934 by four individuals. A total of 422 >= 1-year-old white-tailed deer were collected in the 2012 hunting season in southern Finland and genotyped for 14 microsatellite loci. We find significant identity disequilibrium as estimated by g 2. Heterozygosity was positively associated with size- and age-corrected body mass, but not with jaw size or (in males) antler score. Because of the relatively high identity disequilibrium, heterozygosity of the marker panel explained 51% of variation in inbreeding. Inbreeding explained approximately 4% of the variation in body mass and is thus a minor, although significant source of variation in body mass in this population. The study of HFC is attractive for game- and conservation oriented wildlife management because it presents an affordable and readily used approach for genetic monitoring that allowing identification of fitness costs associated with genetic substructuring in what may seem like a homogeneous population. PMID- 25691964 TI - Are the numbers adding up? Exploiting discrepancies among complementary population models. AB - Large carnivores are difficult to monitor because they tend to be sparsely distributed, sensitive to human activity, and associated with complex life histories. Consequently, understanding population trend and viability requires conservationists to cope with uncertainty and bias in population data. Joint analysis of combined data sets using multiple models (i.e., integrated population model) can improve inference about mechanisms (e.g., habitat heterogeneity and food distribution) affecting population dynamics. However, unobserved or unobservable processes can also introduce bias and can be difficult to quantify. We developed a Bayesian hierarchical modeling approach for inference on an integrated population model that reconciles annual population counts with recruitment and survival data (i.e., demographic processes). Our modeling framework is flexible and enables a realistic form of population dynamics by fitting separate density-dependent responses for each demographic process. Discrepancies estimated from shared parameters among different model components represent unobserved additions (i.e., recruitment or immigration) or removals (i.e., death or emigration) when annual population counts are reliable. In a case study of gray wolves in Wisconsin (1980-2011), concordant with policy changes, we estimated that a discrepancy of 0% (1980-1995), -2% (1996-2002), and 4% (2003 2011) in the annual mortality rate was needed to explain annual growth rate. Additional mortality in 2003-2011 may reflect density-dependent mechanisms, changes in illegal killing with shifts in wolf management, and nonindependent censoring in survival data. Integrated population models provide insights into unobserved or unobservable processes by quantifying discrepancies among data sets. Our modeling approach is generalizable to many population analysis needs and allows for identifying dynamic differences due to external drivers, such as management or policy changes. PMID- 25691965 TI - Wildfire risk for main vegetation units in a biodiversity hotspot: modeling approach in New Caledonia, South Pacific. AB - Wildfire has been recognized as one of the most ubiquitous disturbance agents to impact on natural environments. In this study, our main objective was to propose a modeling approach to investigate the potential impact of wildfire on biodiversity. The method is illustrated with an application example in New Caledonia where conservation and sustainable biodiversity management represent an important challenge. Firstly, a biodiversity loss index, including the diversity and the vulnerability indexes, was calculated for every vegetation unit in New Caledonia and mapped according to its distribution over the New Caledonian mainland. Then, based on spatially explicit fire behavior simulations (using the FLAMMAP software) and fire ignition probabilities, two original fire risk assessment approaches were proposed: a one-off event model and a multi-event burn probability model. The spatial distribution of fire risk across New Caledonia was similar for both indices with very small localized spots having high risk. The patterns relating to highest risk are all located around the remaining sclerophyll forest fragments and are representing 0.012% of the mainland surface. A small part of maquis and areas adjacent to dense humid forest on ultramafic substrates should also be monitored. Vegetation interfaces between secondary and primary units displayed high risk and should represent priority zones for fire effects mitigation. Low fire ignition probability in anthropogenic-free areas decreases drastically the risk. A one-off event associated risk allowed localizing of the most likely ignition areas with potential for extensive damage. Emergency actions could aim limiting specific fire spread known to have high impact or consist of on targeting high risk areas to limit one-off fire ignitions. Spatially explicit information on burning probability is necessary for setting strategic fire and fuel management planning. Both risk indices provide clues to preserve New Caledonia hot spot of biodiversity facing wildfires. PMID- 25691966 TI - Dynamic relationships between body size, species richness, abundance, and energy use in a shallow marine epibenthic faunal community. AB - We study the temporal variation in the empirical relationships among body size (S), species richness (R), and abundance (A) in a shallow marine epibenthic faunal community in Coliumo Bay, Chile. We also extend previous analyses by calculating individual energy use (E) and test whether its bivariate and trivariate relationships with S and R are in agreement with expectations derived from the energetic equivalence rule. Carnivorous and scavenger species representing over 95% of sample abundance and biomass were studied. For each individual, body size (g) was measured and E was estimated following published allometric relationships. Data for each sample were tabulated into exponential body size bins, comparing species-averaged values with individual-based estimates which allow species to potentially occupy multiple size classes. For individual based data, both the number of individuals and species across body size classes are fit by a Weibull function rather than by a power law scaling. Species richness is also a power law of the number of individuals. Energy use shows a piecewise scaling relationship with body size, with energetic equivalence holding true only for size classes above the modal abundance class. Species-based data showed either weak linear or no significant patterns, likely due to the decrease in the number of data points across body size classes. Hence, for individual based size spectra, the SRA relationship seems to be general despite seasonal forcing and strong disturbances in Coliumo Bay. The unimodal abundance distribution results in a piecewise energy scaling relationship, with small individuals showing a positive scaling and large individuals showing energetic equivalence. Hence, strict energetic equivalence should not be expected for unimodal abundance distributions. On the other hand, while species-based data do not show unimodal SRA relationships, energy use across body size classes did not show significant trends, supporting energetic equivalence. PMID- 25691967 TI - Outbreeding effects in an inbreeding insect, Cimex lectularius. AB - In some species, populations with few founding individuals can be resilient to extreme inbreeding. Inbreeding seems to be the norm in the common bed bug, Cimex lectularius, a flightless insect that, nevertheless, can reach large deme sizes and persist successfully. However, bed bugs can also be dispersed passively by humans, exposing inbred populations to gene flow from genetically distant populations. The introduction of genetic variation through this outbreeding could lead to increased fitness (heterosis) or be costly by causing a loss of local adaptation or exposing genetic incompatibility between populations (outbreeding depression). Here, we addressed how inbreeding within demes and outbreeding between distant populations impact fitness over two generations in this re emerging public health pest. We compared fitness traits of families that were inbred (mimicking reproduction following a founder event) or outbred (mimicking reproduction following a gene flow event). We found that outbreeding led to increased starvation resistance compared to inbred families, but this benefit was lost after two generations of outbreeding. No other fitness benefits of outbreeding were observed in either generation, including no differences in fecundity between the two treatments. Resilience to inbreeding is likely to result from the history of small founder events in the bed bug. Outbreeding benefits may only be detectable under stress and when heterozygosity is maximized without disruption of coadaptation. We discuss the consequences of these results both in terms of inbreeding and outbreeding in populations with genetic and spatial structuring, as well as for the recent resurgence of bed bug populations. PMID- 25691968 TI - Postglacial range shift and demographic expansion of the marine intertidal snail Batillaria attramentaria. AB - To address the impacts of past climate changes, particularly since the last glacial period, on the history of the distribution and demography of marine species, we investigated the evolutionary and demographic responses of the intertidal batillariid gastropod, Batillaria attramentaria, to these changes, using the snail as a model species in the northwest Pacific. We applied phylogeographic and divergence population genetic approaches to mitochondrial COI sequences from B. attramentaria. To cover much of its distributional range, 197 individuals collected throughout Korea and 507 publically available sequences (mostly from Japan) were used. Finally, a Bayesian skyline plot (BSP) method was applied to reconstruct the demographic history of this species. We found four differentiated geographic groups around Korea, confirming the presence of two distinct, geographically subdivided haplogroups on the Japanese coastlines along the bifurcated routes of the warm Tsushima and Kuroshio Currents. These two haplogroups were estimated to have begun to split approximately 400,000 years ago. Population divergence analysis supported the hypothesis that the Yellow Sea was populated by a northward range expansion of a small fraction of founders that split from a southern ancestral population since the last glacial maximum (LGM: 26,000-19,000 years ago), when the southern area became re-submerged. BSP analyses on six geographically and genetically defined groups in Korea and Japan consistently demonstrated that each group has exponentially increased approximately since the LGM. This study resolved the phylogeography of B. attramentaria as a series of events connected over space and time; while paleoceanographic conditions determining the connectivity of neighboring seas in East Asia are responsible for the vicariance of this species, the postglacial sea level rise and warming temperatures have played a crucial role in rapid range shifts and broad demographic expansions of its populations. PMID- 25691969 TI - Minor differences in body condition and immune status between avian influenza virus-infected and noninfected mallards: a sign of coevolution? AB - Wildlife pathogens can alter host fitness. Low pathogenic avian influenza virus (LPAIV) infection is thought to have negligible impacts on wild birds; however, effects of infection in free-living birds are largely unstudied. We investigated the extent to which LPAIV infection and shedding were associated with body condition and immune status in free-living mallards (Anas platyrhynchos), a partially migratory key LPAIV host species. We sampled mallards throughout the species' annual autumn LPAIV infection peak, and we classified individuals according to age, sex, and migratory strategy (based on stable hydrogen isotope analysis) when analyzing data on body mass and five indices of immune status. Body mass was similar for LPAIV-infected and noninfected birds. The degree of virus shedding from the cloaca and oropharynx was not associated with body mass. LPAIV infection and shedding were not associated with natural antibody (NAbs) and complement titers (first lines of defense against infections), concentrations of the acute phase protein haptoglobin (Hp), ratios of heterophils to lymphocytes (H:L ratio), and avian influenza virus (AIV)-specific antibody concentrations. NAbs titers were higher in LPAIV-infected males and local (i.e., short distance) migrants than in infected females and distant (i.e., long distance) migrants. Hp concentrations were higher in LPAIV-infected juveniles and females compared to infected adults and males. NAbs, complement, and Hp levels were lower in LPAIV infected mallards in early autumn. Our study demonstrates weak associations between infection with and shedding of LPAIV and the body condition and immune status of free-living mallards. These results may support the role of mallards as asymptomatic carriers of LPAIV and raise questions about possible coevolution between virus and host. PMID- 25691970 TI - All you can eat: is food supply unlimited in a colonially breeding bird? AB - Food availability is generally considered to determine breeding site selection and therefore plays an important role in hypotheses explaining the evolution of colony formation. Hypotheses trying to explain why birds join a colony usually assume that food is not limited, whereas those explaining variation in colony size suggest that food is under constraint. In this study, we investigate the composition and amount of food items not eaten by the nestlings and found in nest burrows of colonially nesting European bee-eaters (Merops apiaster). We aimed to determine whether this unconsumed food is an indicator of unlimited food supply, the result of mistakes during food transfer between parents and chicks or foraging selectivity of chicks. Therefore, we investigated the amount of dropped food for each nest in relation to reproductive performance and parameters reflecting parental quality. Our data suggest that parents carry more food to the nest than chicks can eat and, hence, food is not limited. This assumption is supported by the facts that there is a positive relationship between dropped food found in a nest and the number of fledglings, nestling age, and chick health condition and that the amount of dropped food is independent of colony size. There is variation in the amount of dropped food within colonies, suggesting that parent foraging efficiency may also be an important determinant. Pairs nesting in the center of a colony performed better than those nesting on the edge, which supports the assumption that quality differences between parents are important as well. However, dropped food cannot be used as an indicator of local food availability as (1) within-colony variation in dropped food is larger than between colony variation and, (2) the average amount of dropped food is not related to colony size. PMID- 25691971 TI - Host switching in a generalist parasitoid: contrasting transient and transgenerational costs associated with novel and original host species. AB - Parasitoids face challenges by switching between host species that influence survival and fitness, determine their role in structuring communities, influence species invasions, and affect their importance as biocontrol agents. In the generalist parasitoid, Venturia canescens (Gravenhorst) (Hymenoptera: Ichneumonidae), we investigated the costs in encapsulation, survival, and body size on juveniles when adult parasitoids switched from their original host, Plodia interpunctella (Hubner) (Lepidotera, Pyralidae) to a novel host, Ephestia kuehniella (Zeller) (Lepidoptera, Pyralidae), over multiple generations. Switching had an initial survival cost for juvenile parasitoids in the novel host, but increased survival occurred within two generations. Conversely, mortality in the original host increased. Body size, a proxy for fecundity, also increased with the number of generations in the novel host species, reflecting adaptation or maternal effects due to the larger size of the novel host, and therefore greater resources available to the developing parasitoid. Switching to a novel host appears to have initial costs for a parasitoid, even when the novel host may be better quality, but the costs rapidly diminish. We predict that the net cost of switching to a novel host for parasitoids will be complex and will depend on the initial reduction in fitness from parasitizing a novel host versus local adaptations against parasitoids in the original host. PMID- 25691972 TI - Value of information in natural resource management: technical developments and application to pink-footed geese. AB - The "value of information" (VOI) is a generic term for the increase in value resulting from better information to guide management, or alternatively, the value foregone under uncertainty about the impacts of management (Yokota and Thompson, Medical Decision Making 2004; 24: 287). The value of information can be characterized in terms of several metrics, including the expected value of perfect information and the expected value of partial information. We extend the technical framework for the value of information by further developing the relationship between value metrics for partial and perfect information and describing patterns of their performance. We use two different expressions for the expected value of partial information to highlight its relationship to the expected value of perfect information. We also develop the expected value of partial information for hierarchical uncertainties. We highlight patterns in the value of information for the Svalbard population of the pink-footed goose (Anser brachyrhynchus), a population that is subject to uncertainty in both reproduction and survival functions. The framework for valuing information is seen as having widespread potential in resource decision making, and serves as a motivation for resource monitoring, assessment, and collaboration. PMID- 25691973 TI - Social effects on foraging behavior and success depend on local environmental conditions. AB - In social groups, individuals' dominance rank, social bonds, and kinship with other group members have been shown to influence their foraging behavior. However, there is growing evidence that the particular effects of these social traits may also depend on local environmental conditions. We investigated this by comparing the foraging behavior of wild chacma baboons, Papio ursinus, under natural conditions and in a field experiment where food was spatially clumped. Data were collected from 55 animals across two troops over a 5-month period, including over 900 agonistic foraging interactions and over 600 food patch visits in each condition. In both conditions, low-ranked individuals received more agonism, but this only translated into reduced foraging performances for low ranked individuals in the high-competition experimental conditions. Our results suggest one possible reason for this pattern may be low-ranked individuals strategically investing social effort to negotiate foraging tolerance, but the rank-offsetting effect of this investment being overwhelmed in the higher competition experimental environment. Our results also suggest that individuals may use imbalances in their social bonds to negotiate tolerance from others under a wider range of environmental conditions, but utilize the overall strength of their social bonds in more extreme environments where feeding competition is more intense. These findings highlight that behavioral tactics such as the strategic investment of social effort may allow foragers to mitigate the costs of low rank, but that the effectiveness of these tactics is likely to be limited in certain environments. PMID- 25691974 TI - Modeling the two-locus architecture of divergent pollinator adaptation: how variation in SAD paralogs affects fitness and evolutionary divergence in sexually deceptive orchids. AB - Divergent selection by pollinators can bring about strong reproductive isolation via changes at few genes of large effect. This has recently been demonstrated in sexually deceptive orchids, where studies (1) quantified the strength of reproductive isolation in the field; (2) identified genes that appear to be causal for reproductive isolation; and (3) demonstrated selection by analysis of natural variation in gene sequence and expression. In a group of closely related Ophrys orchids, specific floral scent components, namely n-alkenes, are the key floral traits that control specific pollinator attraction by chemical mimicry of insect sex pheromones. The genetic basis of species-specific differences in alkene production mainly lies in two biosynthetic genes encoding stearoyl-acyl carrier protein desaturases (SAD) that are associated with floral scent variation and reproductive isolation between closely related species, and evolve under pollinator-mediated selection. However, the implications of this genetic architecture of key floral traits on the evolutionary processes of pollinator adaptation and speciation in this plant group remain unclear. Here, we expand on these recent findings to model scenarios of adaptive evolutionary change at SAD2 and SAD5, their effects on plant fitness (i.e., offspring number), and the dynamics of speciation. Our model suggests that the two-locus architecture of reproductive isolation allows for rapid sympatric speciation by pollinator shift; however, the likelihood of such pollinator-mediated speciation is asymmetric between the two orchid species O. sphegodes and O. exaltata due to different fitness effects of their predominant SAD2 and SAD5 alleles. Our study not only provides insight into pollinator adaptation and speciation mechanisms of sexually deceptive orchids but also demonstrates the power of applying a modeling approach to the study of pollinator-driven ecological speciation. PMID- 25691975 TI - Avian top predator and the landscape of fear: responses of mammalian mesopredators to risk imposed by the golden eagle. AB - Top predators may induce extensive cascading effects on lower trophic levels, for example, through intraguild predation (IGP). The impacts of both mammalian and avian top predators on species of the same class have been extensively studied, but the effects of the latter upon mammalian mesopredators are not yet as well known. We examined the impact of the predation risk imposed by a large avian predator, the golden eagle (Aquila chrysaetos, L.), on its potential mammalian mesopredator prey, the red fox (Vulpes vulpes, L.), and the pine marten (Martes martes, L.). The study combined 23 years of countrywide data from nesting records of eagles and wildlife track counts of mesopredators in Finland, northern Europe. The predation risk of the golden eagle was modeled as a function of territory density, density of fledglings produced, and distance to nearest active eagle territory, with the expectation that a high predation risk would reduce the abundances of smaller sized pine martens in particular. Red foxes appeared not to suffer from eagle predation, being in fact most numerous close to eagle nests and in areas with more eagle territories. This is likely due to similar prey preferences of the two predators and the larger size of foxes enabling them to escape eagle predation risk. Somewhat contrary to our prediction, the abundance of pine martens increased from low to intermediate territory density and at close proximity to eagle nests, possibly because of similar habitat preferences of martens and eagles. We found a slightly decreasing trend of marten abundance at high territory density, which could indicate that the response in marten populations is dependent on eagle density. However, more research is needed to better establish whether mesopredators are intimidated or predated by golden eagles, and whether such effects could in turn cascade to lower trophic levels, benefitting herbivorous species. PMID- 25691976 TI - Trade-off between thermal tolerance and insecticide resistance in Plutella xylostella. AB - Fitness costs associated with resistance to insecticides have been well documented, usually at normal temperature conditions, in many insect species. In this study, using chlorpyrifos-resistant homozygote (RR) and chlorpyrifos susceptible homozygote (SS) of resistance ace1 allele of Plutella xylostella (DBM), we confirmed firstly that high temperature experience in pupal stage influenced phenotype of wing venation in insecticide-resistant and insecticide susceptible Plutella xylostella, and SS DBM showed significantly higher thermal tolerance and lower damages of wing veins under heat stress than RR DBM. As compared to SS DBM, RR DBM displayed significantly lower AChE sensitivity to chlorpyrifos, higher basal GSTs activity and P450 production at 25 degrees C, but higher inhibitions on the enzyme activities and P450 production as well as reduced resistance to chlorpyrifos under heat stress. Furthermore, RR DBM displayed significantly higher basal expressions of hsp69s, hsp72s, hsp20,hsp90,Apaf-1, and caspase-7 at 25 degrees C, but lower induced expressions of hsps and higher induced expressions of Apaf-1,caspase-9, and caspase-7 under heat stress. These results suggest that fitness costs of chlorpyrifos resistance in DBM may partly attribute to excess consumption of energy caused by over production of detoxification enzymes and hsps when the proteins are less demanded at conducive environments but reduced expressions when they are highly demanded by the insects to combat environmental stresses, or to excess expressions of apoptotic genes under heat stress, which results in higher apoptosis. The evolutionary and ecological implications of these findings at global warming are discussed. PMID- 25691978 TI - Diversity patterns of ground beetles and understory vegetation in mature, secondary, and plantation forest regions of temperate northern China. AB - Plantation and secondary forests form increasingly important components of the global forest cover, but our current knowledge about their potential contribution to biodiversity conservation is limited. We surveyed understory plant and carabid species assemblages at three distinct regions in temperate northeastern China, dominated by mature forest (Changbaishan Nature Reserve, sampled in 2011 and 2012), secondary forest (Dongling Mountain, sampled in 2011 and 2012), and forest plantation habitats (Bashang Plateau, sampled in 2006 and 2007), respectively. The alpha-diversity of both taxonomic groups was highest in plantation forests of the Bashang Plateau. Beetle alpha-diversity was lowest, but plant and beetle species turnover peaked in the secondary forests of Dongling Mountain, while habitats in the Changbaishan Nature Reserve showed the lowest turnover rates for both taxa. Changbaishan Nature Reserve harbored the highest proportion of forest specialists. Our results suggest that in temperate regions of northern China, the protected larch plantation forest established over extensive areas might play a considerable role in maintaining a high biodiversity in relation to understory herbaceous plant species and carabid assemblages, which can be seen as indicators of forest disturbance. The high proportion of phytophagous carabids and the rarity of forest specialists reflect the relatively homogenous, immature status of the forest ecosystems on the Bashang Plateau. China's last remaining large old growth forests like the ones on Changbaishan represent stable, mature ecosystems which require particular conservation attention. PMID- 25691979 TI - Quantitative genetics of learning ability and resistance to stress in Drosophila melanogaster. AB - Even though laboratory evolution experiments have demonstrated genetic variation for learning ability, we know little about the underlying genetic architecture and genetic relationships with other ecologically relevant traits. With a full diallel cross among twelve inbred lines of Drosophila melanogaster originating from a natural population (0.75 < F < 0.93), we investigated the genetic architecture of olfactory learning ability and compared it to that for another behavioral trait (unconditional preference for odors), as well as three traits quantifying the ability to deal with environmental challenges: egg-to-adult survival and developmental rate on a low-quality food, and resistance to a bacterial pathogen. Substantial additive genetic variation was detected for each trait, highlighting their potential to evolve. Genetic effects contributed more than nongenetic parental effects to variation in traits measured at the adult stage: learning, odorant perception, and resistance to infection. In contrast, the two traits quantifying larval tolerance to low-quality food were more strongly affected by parental effects. We found no evidence for genetic correlations between traits, suggesting that these traits could evolve at least to some degree independently of one another. Finally, inbreeding adversely affected all traits. PMID- 25691980 TI - Biomarkers of animal health: integrating nutritional ecology, endocrine ecophysiology, ecoimmunology, and geospatial ecology. AB - Diverse biomarkers including stable isotope, hormonal, and ecoimmunological assays are powerful tools to assess animal condition. However, an integrative approach is necessary to provide the context essential to understanding how biomarkers reveal animal health in varied ecological conditions. A barrier to such integration is a general lack of awareness of how shared extraction methods from across fields can provide material from the same animal tissues for diverse biomarker assays. In addition, the use of shared methods for extracting differing tissue fractions can also provide biomarkers for how animal health varies across time. Specifically, no study has explicitly illustrated the depth and breadth of spacial and temporal information that can be derived from coupled biomarker assessments on two easily collected tissues: blood and feathers or hair. This study used integrated measures of glucocorticoids, stable isotopes, and parasite loads in the feathers and blood of fall-migrating Northern saw-whet owls (Aegolius acadicus) to illustrate the wealth of knowledge about animal health and ecology across both time and space. In feathers, we assayed deuterium (deltaD) isotope and corticosterone (CORT) profiles, while in blood we measured CORT and blood parasite levels. We found that while earlier migrating owls had elevated CORT levels relative to later migrating birds, there was also a disassociation between plasma and feather CORT, and blood parasite loads. These results demonstrate how these tissues integrate time periods from weeks to seasons and reflect energetic demands during differing life stages. Taken together, these findings illustrate the potential for integrating diverse biomarkers to assess interactions between environmental factors and animal health across varied time periods without the necessity of continually recapturing and tracking individuals. Combining biomarkers from diverse research fields into an integrated framework hold great promise for advancing our understanding of environmental effects on animal health. PMID- 25691981 TI - Evolutionary dynamics of ecological niche in three Rhinogobio fishes from the upper Yangtze River inferred from morphological traits. AB - In the past decades, it has been debated whether ecological niche should be conserved among closely related species (phylogenetic niche conservatism, PNC) or largely divergent (traditional ecological niche theory and ecological speciation) and whether niche specialist and generalist might remain in equilibrium or niche generalist could not appear. In this study, we employed morphological traits to describe ecological niche and test whether different niche dimensions exhibit disparate evolutionary patterns. We conducted our analysis on three Rhinogobio fish species (R. typus,R. cylindricus, and R. ventralis) from the upper Yangtze River, China. Among the 32 measured morphological traits except body length, PCA extracted the first four principal components with their loading scores >1.000. To find the PNC among species, Mantel tests were conducted with the Euclidean distances calculated from the four principal components (representing different niche dimensions) against the pairwise distances calculated from mitochondrial cytochrome b sequence variations. The results showed that the second and the third niche dimension, both related to swimming ability and behavior, exhibited phylogenetic conservatism. Further comparison on niche breadth among these three species revealed that the fourth dimension of R. typus showed the greatest width, indicating that this dimension exhibited niche generalism. In conclusion, our results suggested that different niche dimensions could show different evolutionary dynamic patterns: they may exhibit PNC or not, and some dimensions may evolve generalism. PMID- 25691982 TI - Estimating the spatial position of marine mammals based on digital camera recordings. AB - Estimating the spatial position of organisms is essential to quantify interactions between the organism and the characteristics of its surroundings, for example, predator-prey interactions, habitat selection, and social associations. Because marine mammals spend most of their time under water and may appear at the surface only briefly, determining their exact geographic location can be challenging. Here, we developed a photogrammetric method to accurately estimate the spatial position of marine mammals or birds at the sea surface. Digital recordings containing landscape features with known geographic coordinates can be used to estimate the distance and bearing of each sighting relative to the observation point. The method can correct for frame rotation, estimates pixel size based on the reference points, and can be applied to scenarios with and without a visible horizon. A set of R functions was written to process the images and obtain accurate geographic coordinates for each sighting. The method is applied to estimate the spatiotemporal fine-scale distribution of harbour porpoises in a tidal inlet. Video recordings of harbour porpoises were made from land, using a standard digital single-lens reflex (DSLR) camera, positioned at a height of 9.59 m above mean sea level. Porpoises were detected up to a distance of ?3136 m (mean 596 m), with a mean location error of 12 m. The method presented here allows for multiple detections of different individuals within a single video frame and for tracking movements of individuals based on repeated sightings. In comparison with traditional methods, this method only requires a digital camera to provide accurate location estimates. It especially has great potential in regions with ample data on local (a)biotic conditions, to help resolve functional mechanisms underlying habitat selection and other behaviors in marine mammals in coastal areas. PMID- 25691983 TI - Are we underestimating the genetic variances of dimorphic traits? AB - Populations often contain discrete classes or morphs (e.g., sexual dimorphisms, wing dimorphisms, trophic dimorphisms) characterized by distinct patterns of trait expression. In quantitative genetic analyses, the different morphs can be considered as different environments within which traits are expressed. Genetic variances and covariances can then be estimated independently for each morph or in a combined analysis. In the latter case, morphs can be considered as separate environments in a bivariate analysis or entered as fixed effects in a univariate analysis. Although a common approach, we demonstrate that the latter produces downwardly biased estimates of additive genetic variance and heritability unless the quantitative genetic architecture of the traits concerned is perfectly correlated between the morphs. This result is derived for four widely used quantitative genetic variance partitioning methods. Given that theory predicts the evolution of genotype-by-environment (morph) interactions as a consequence of selection favoring different trait combinations in each morph, we argue that perfect correlations between the genetic architectures of the different morphs are unlikely. A sampling of the recent literature indicates that the majority of researchers studying traits expressed in different morphs recognize this and do estimate morph-specific quantitative genetic architecture. However, ca. 16% of the studies in our sample utilized only univariate, fixed-effects models. We caution against this approach and recommend that it be used only if supported by evidence that the genetic architectures of the different morphs do not differ. PMID- 25691984 TI - Do mothers prefer helpers or smaller litters? Birth sex ratio and litter size adjustment in cotton-top tamarins (Saguinus oedipus). AB - Sex allocation theory has been a remarkably productive field in behavioral ecology with empirical evidence regularly supporting quantitative theoretical predictions. Across mammals in general and primates in particular, however, support for the various hypotheses has been more equivocal. Population-level sex ratio biases have often been interpreted as supportive, but evidence for small scale facultative adjustment has rarely been found. The helper repayment (HR) also named the local resource enhancement (LRE) hypothesis predicts that, in cooperatively breeding species, mothers invest more in the sex which assists with rearing future offspring and that this bias will be more pronounced in mothers who require extra assistance (i.e., due to inexperience or a lack of available alloparents). We tested these hypotheses in captive cotton-top tamarins (Saguinus oedipus) utilizing the international studbook and birth records obtained through a questionnaire from ISIS-registered institutions. Infant sex, litter size, mother's age, parity, and group composition (presence of nonreproductive subordinate males and females) were determined from these records. The HR hypothesis was supported over the entire population, which was significantly biased toward males (the "helpful" sex). We found little support for helper repayment at the individual level, as primiparous females and those in groups without alloparents did not exhibit more extreme tendencies to produce male infants. Primiparous females were, however, more likely to produce singleton litters. Singleton births were more likely to be male, which suggests that there may be an interaction between litter size adjustment and sex allocation. This may be interpreted as supportive of the HR hypothesis, but alternative explanations at both the proximate and ultimate levels are possible. These possibilities warrant further consideration when attempting to understand the ambiguous results of primate sex ratio studies so far. PMID- 25691985 TI - America's red gold: multiple lineages of cultivated cochineal in Mexico. AB - Cultivated cochineal (Dactylopius coccus) produces carminic acid, a valuable red dye used to color textiles, cosmetics, and food. Extant native D. coccus is largely restricted to two populations in the Mexican and the Andean highlands, although the insect's ultimate center of domestication remains unclear. Moreover, due to Mexican D. coccus cultivation's near demise during the 19th century, the genetic diversity of current cochineal stock is unknown. Through genomic sequencing, we identified two divergent D. coccus populations in highland Mexico: one unique to Mexico and another that was more closely related to extant Andean cochineal. Relic diversity is preserved in the crops of small-scale Mexican cochineal farmers. Conversely, larger-scale commercial producers are cultivating the Andean-like cochineal, which may reflect clandestine 20th century importation. PMID- 25691986 TI - How integrated are behavioral and endocrine stress response traits? A repeated measures approach to testing the stress-coping style model. AB - It is widely expected that physiological and behavioral stress responses will be integrated within divergent stress-coping styles (SCS) and that these may represent opposite ends of a continuously varying reactive-proactive axis. If such a model is valid, then stress response traits should be repeatable and physiological and behavioral responses should also change in an integrated manner along a major axis of among-individual variation. While there is some evidence of association between endocrine and behavioral stress response traits, few studies incorporate repeated observations of both. To test this model, we use a multivariate, repeated measures approach in a captive-bred population of Xiphophorus birchmanni. We quantify among-individual variation in behavioral stress response to an open field trial (OFT) with simulated predator attack (SPA) and measure waterborne steroid hormone levels (cortisol, 11-ketotestosterone) before and after exposure. Under the mild stress stimulus (OFT), (multivariate) behavioral variation among individuals was consistent with a strong axis of personality (shy-bold) or coping style (reactive-proactive) variation. However, behavioral responses to a moderate stressor (SPA) were less repeatable, and robust statistical support for repeatable endocrine state over the full sampling period was limited to 11-ketotestosterone. Although post hoc analysis suggested cortisol expression was repeatable over short time periods, qualitative relationships between behavior and glucocorticoid levels were counter to our a priori expectations. Thus, while our results clearly show among-individual differences in behavioral and endocrine traits associated with stress response, the correlation structure between these is not consistent with a simple proactive reactive axis of integrated stress-coping style. Additionally, the low repeatability of cortisol suggests caution is warranted if single observations (or indeed repeat measures over short sampling periods) of glucocorticoid traits are used in ecological or evolutionary studies focussed at the individual level. PMID- 25691987 TI - Adaptive plasticity and epigenetic variation in response to warming in an Alpine plant. AB - Environmentally induced phenotypic plasticity may be a critical component of response to changing environments. We examined local differentiation and adaptive phenotypic plasticity in response to elevated temperature in half-sib lines collected across an elevation gradient for the alpine herb, Wahlenbergia ceracea. Using Amplified Fragment Length Polymorphism (AFLP), we found low but significant genetic differentiation between low- and high-elevation seedlings, and seedlings originating from low elevations grew faster and showed stronger temperature responses (more plasticity) than those from medium and high elevations. Furthermore, plasticity was more often adaptive for plants of low-elevation origin and maladaptive for plants of high elevation. With methylation sensitive AFLP (MS-AFLP), we revealed an increase in epigenetic variation in response to temperature in low-elevation seedlings. Although we did not find significant direct correlations between MS-AFLP loci and phenotypes, our results demonstrate that adaptive plasticity in temperature response to warming varies over fine spatial scales and suggest the involvement of epigenetic mechanisms in this response. PMID- 25691988 TI - Assessing the phylogeographic history of the montane caddisfly Thremma gallicum using mitochondrial and restriction-site-associated DNA (RAD) markers. AB - Repeated Quaternary glaciations have significantly shaped the present distribution and diversity of several European species in aquatic and terrestrial habitats. To study the phylogeography of freshwater invertebrates, patterns of intraspecific variation have been examined primarily using mitochondrial DNA markers that may yield results unrepresentative of the true species history. Here, population genetic parameters were inferred for a montane aquatic caddisfly, Thremma gallicum, by sequencing a 658-bp fragment of the mitochondrial CO1 gene, and 12,514 nuclear RAD loci. T. gallicum has a highly disjunct distribution in southern and central Europe, with known populations in the Cantabrian Mountains, Pyrenees, Massif Central, and Black Forest. Both datasets represented rangewide sampling of T. gallicum. For the CO1 dataset, this included 352 specimens from 26 populations, and for the RAD dataset, 17 specimens from eight populations. We tested 20 competing phylogeographic scenarios using approximate Bayesian computation (ABC) and estimated genetic diversity patterns. Support for phylogeographic scenarios and diversity estimates differed between datasets with the RAD data favouring a southern origin of extant populations and indicating the Cantabrian Mountains and Massif Central populations to represent highly diverse populations as compared with the Pyrenees and Black Forest populations. The CO1 data supported a vicariance scenario (north-south) and yielded inconsistent diversity estimates. Permutation tests suggest that a few hundred polymorphic RAD SNPs are necessary for reliable parameter estimates. Our results highlight the potential of RAD and ABC-based hypothesis testing to complement phylogeographic studies on non-model species. PMID- 25691989 TI - Discordance between morphological and molecular species boundaries among Caribbean species of the reef sponge Callyspongia. AB - Sponges are among the most species-rich and ecologically important taxa on coral reefs, yet documenting their diversity is difficult due to the simplicity and plasticity of their morphological characters. Genetic attempts to identify species are hampered by the slow rate of mitochondrial sequence evolution characteristic of sponges and some other basal metazoans. Here we determine species boundaries of the Caribbean coral reef sponge genus Callyspongia using a multilocus, model-based approach. Based on sequence data from one mitochondrial (COI), one ribosomal (28S), and two single-copy nuclear protein-coding genes, we found evolutionarily distinct lineages were not concordant with current species designations in Callyspongia. While C. fallax,C. tenerrima, and C. plicifera were reciprocally monophyletic, four taxa with different morphologies (C. armigera,C. longissima,C. eschrichtii, and C. vaginalis) formed a monophyletic group and genetic distances among these taxa overlapped distances within them. A model based method of species delimitation supported collapsing these four into a single evolutionary lineage. Variation in spicule size among these four taxa was partitioned geographically, not by current species designations, indicating that in Callyspongia, these key taxonomic characters are poor indicators of genetic differentiation. Taken together, our results suggest a complex relationship between morphology and species boundaries in sponges. PMID- 25691990 TI - Naturally rare versus newly rare: demographic inferences on two timescales inform conservation of Galapagos giant tortoises. AB - Long-term population history can influence the genetic effects of recent bottlenecks. Therefore, for threatened or endangered species, an understanding of the past is relevant when formulating conservation strategies. Levels of variation at neutral markers have been useful for estimating local effective population sizes (N e ) and inferring whether population sizes increased or decreased over time. Furthermore, analyses of genotypic, allelic frequency, and phylogenetic information can potentially be used to separate historical from recent demographic changes. For 15 populations of Galapagos giant tortoises (Chelonoidis sp.), we used 12 microsatellite loci and DNA sequences from the mitochondrial control region and a nuclear intron, to reconstruct demographic history on shallow (past ?100 generations, ?2500 years) and deep (pre-Holocene, >10 thousand years ago) timescales. At the deep timescale, three populations showed strong signals of growth, but with different magnitudes and timing, indicating different underlying causes. Furthermore, estimated historical N e of populations across the archipelago showed no correlation with island age or size, underscoring the complexity of predicting demographic history a priori. At the shallow timescale, all populations carried some signature of a genetic bottleneck, and for 12 populations, point estimates of contemporary N e were very small (i.e., < 50). On the basis of the comparison of these genetic estimates with published census size data, N e generally represented ?0.16 of the census size. However, the variance in this ratio across populations was considerable. Overall, our data suggest that idiosyncratic and geographically localized forces shaped the demographic history of tortoise populations. Furthermore, from a conservation perspective, the separation of demographic events occurring on shallow versus deep timescales permits the identification of naturally rare versus newly rare populations; this distinction should facilitate prioritization of management action. PMID- 25691991 TI - Hierarchical analysis of genetic structure in the habitat-specialist Eastern Sand Darter (Ammocrypta pellucida). AB - Quantifying spatial genetic structure can reveal the relative influences of contemporary and historic factors underlying localized and regional patterns of genetic diversity and gene flow - important considerations for the development of effective conservation efforts. Using 10 polymorphic microsatellite loci, we characterize genetic variation among populations across the range of the Eastern Sand Darter (Ammocrypta pellucida), a small riverine percid that is highly dependent on sandy substrate microhabitats. We tested for fine scale, regional, and historic patterns of genetic structure. As expected, significant differentiation was detected among rivers within drainages and among drainages. At finer scales, an unexpected lack of within-river genetic structure among fragmented sandy microhabitats suggests that stratified dispersal resulting from unstable sand bar habitat degradation (natural and anthropogenic) may preclude substantial genetic differentiation within rivers. Among-drainage genetic structure indicates that postglacial (14 kya) drainage connectivity continues to influence contemporary genetic structure among Eastern Sand Darter populations in southern Ontario. These results provide an unexpected contrast to other benthic riverine fish in the Great Lakes drainage and suggest that habitat-specific fishes, such as the Eastern Sand Darter, can evolve dispersal strategies that overcome fragmented and temporally unstable habitats. PMID- 25691992 TI - Sexual segregation in North American elk: the role of density dependence. AB - We investigated how density-dependent processes and subsequent variation in nutritional condition of individuals influenced both timing and duration of sexual segregation and selection of resources. During 1999-2001, we experimentally created two population densities of North American elk (Cervus elaphus), a high-density population at 20 elk/km(2), and a low-density population at 4 elk/km(2) to test hypotheses relative to timing and duration of sexual segregation and variation in selection of resources. We used multi-response permutation procedures to investigate patterns of sexual segregation, and resource selection functions to document differences in selection of resources by individuals in high- and low-density populations during sexual segregation and aggregation. The duration of sexual segregation was 2 months longer in the high density population and likely was influenced by individuals in poorer nutritional condition, which corresponded with later conception and parturition, than at low density. Males and females in the high-density population overlapped in selection of resources to a greater extent than in the low-density population, probably resulting from density-dependent effects of increased intraspecific competition and lower availability of resources. PMID- 25691993 TI - Metabolic variation in natural populations of wild yeast. AB - Ecological diversification depends on the extent of genetic variation and on the pattern of covariation with respect to ecological opportunities. We investigated the pattern of utilization of carbon substrates in wild populations of budding yeast Saccharomyces paradoxus. All isolates grew well on a core diet of about 10 substrates, and most were also able to grow on a much larger ancillary diet comprising most of the 190 substrates we tested. There was substantial genetic variation within each population for some substrates. We found geographical variation of substrate use at continental, regional, and local scales. Isolates from Europe and North America could be distinguished on the basis of the pattern of yield across substrates. Two geographical races at the North American sites also differed in the pattern of substrate utilization. Substrate utilization patterns were also geographically correlated at local spatial scales. Pairwise genetic correlations between substrates were predominantly positive, reflecting overall variation in metabolic performance, but there was a consistent negative correlation between categories of substrates in two cases: between the core diet and the ancillary diet, and between pentose and hexose sugars. Such negative correlations in the utilization of substrate from different categories may indicate either intrinsic physiological trade-offs for the uptake and utilization of substrates from different categories, or the accumulation of conditionally neutral mutations. Divergence in substrate use accompanies genetic divergence at all spatial scales in S. paradoxus and may contribute to race formation and speciation. PMID- 25691994 TI - A hierarchical Bayesian model to estimate the unobservable predation rate on sawfly cocoons by small mammals. AB - Predation by small mammals has been reported as an important mortality factor for the cocoons of sawfly species. However, it is difficult to provide an accurate estimate of newly spun cocoons and subsequent predation rates by small mammals for several reasons. First, all larvae do not spin cocoons at the same time. Second, cocoons are exposed to small mammal predation immediately after being spun. Third, the cocoons of the current generation are indistinguishable from those of the previous generation. We developed a hierarchical Bayesian model to estimate these values from annual one-time soil sampling datasets. To apply this model to an actual data set, field surveys were conducted in eight stands of larch plantations in central Hokkaido (Japan) from 2009 to 2012. Ten 0.04-m(2) soil samples were annually collected from each site in mid-October. The abundance of unopened cocoons (I), cocoons emptied by small-mammal predation (M), and empty cocoons caused by something other than small-mammal predation (H) were determined. The abundance of newly spun cocoons, the predation rate by small mammals before and after cocoon sampling, and the annual rate of empty cocoons that remained were estimated. A posterior predictive check yielded Bayesian P values of 0.54, 0.48, and 0.07 for I, M, and H, respectively. Estimated predation rates showed a significant positive correlation with the number of trap captures of small mammals. Estimates of the number of newly spun cocoons had a significant positive correlation with defoliation intensity. These results indicate that our model showed an acceptable fit, with reasonable estimates. Our model is expected to be widely applicable to all hymenopteran and lepidopteran insects that spin cocoons in soil. PMID- 25691995 TI - Detecting a hierarchical genetic population structure: the case study of the Fire Salamander (Salamandra salamandra) in Northern Italy. AB - The multistep method here applied in studying the genetic structure of a low dispersal and philopatric species, such as the Fire Salamander Salamandra salamandra, was proved to be effective in identifying the hierarchical structure of populations living in broad-leaved forest ecosystems in Northern Italy. In this study, 477 salamander larvae, collected in 28 sampling populations (SPs) in the Prealpine and in the foothill areas of Northern Italy, were genotyped at 16 specie-specific microsatellites. SPs showed a significant overall genetic variation (Global F ST = 0.032, P < 0.001). The genetic population structure was assessed by using STRUCTURE 2.3.4. We found two main genetic groups, one represented by SPs inhabiting the Prealpine belt, which maintain connections with those of the Eastern foothill lowland (PEF), and a second group with the SPs of the Western foothill lowland (WF). The two groups were significantly distinct with a Global F ST of 0.010 (P < 0.001). While the first group showed a moderate structure, with only one divergent SP (Global F ST = 0.006, P < 0.001), the second group proved more structured being divided in four clusters (Global F ST = 0.017, P = 0.058). This genetic population structure should be due to the large conurbations and main roads that separate the WF group from the Prealpine belt and the Eastern foothill lowland. The adopted methods allowed the analysis of the genetic population structure of Fire Salamander from wide to local scale, identifying different degrees of genetic divergence of their populations derived from forest fragmentation induced by urban and infrastructure sprawl. PMID- 25691996 TI - No species is an island: testing the effects of biotic interactions on models of avian niche occupation. AB - Traditionally, the niche of a species is described as a hypothetical 3D space, constituted by well-known biotic interactions (e.g. predation, competition, trophic relationships, resource-consumer interactions, etc.) and various abiotic environmental factors. Species distribution models (SDMs), also called "niche models" and often used to predict wildlife distribution at landscape scale, are typically constructed using abiotic factors with biotic interactions generally been ignored. Here, we compared the goodness of fit of SDMs for red-backed shrike Lanius collurio in farmlands of Western Poland, using both the classical approach (modeled only on environmental variables) and the approach which included also other potentially associated bird species. The potential associations among species were derived from the relevant ecological literature and by a correlation matrix of occurrences. Our findings highlight the importance of including heterospecific interactions in improving our understanding of niche occupation for bird species. We suggest that suite of measures currently used to quantify realized species niches could be improved by also considering the occurrence of certain associated species. Then, an hypothetical "species 1" can use the occurrence of a successfully established individual of "species 2" as indicator or "trace" of the location of available suitable habitat to breed. We hypothesize this kind of biotic interaction as the "heterospecific trace effect" (HTE): an interaction based on the availability and use of "public information" provided by individuals from different species. Finally, we discuss about the incomes of biotic interactions for enhancing the predictive capacities on species distribution models. PMID- 25691997 TI - Integrated survival analysis using an event-time approach in a Bayesian framework. AB - Event-time or continuous-time statistical approaches have been applied throughout the biostatistical literature and have led to numerous scientific advances. However, these techniques have traditionally relied on knowing failure times. This has limited application of these analyses, particularly, within the ecological field where fates of marked animals may be unknown. To address these limitations, we developed an integrated approach within a Bayesian framework to estimate hazard rates in the face of unknown fates. We combine failure/survival times from individuals whose fates are known and times of which are interval censored with information from those whose fates are unknown, and model the process of detecting animals with unknown fates. This provides the foundation for our integrated model and permits necessary parameter estimation. We provide the Bayesian model, its derivation, and use simulation techniques to investigate the properties and performance of our approach under several scenarios. Lastly, we apply our estimation technique using a piece-wise constant hazard function to investigate the effects of year, age, chick size and sex, sex of the tending adult, and nesting habitat on mortality hazard rates of the endangered mountain plover (Charadrius montanus) chicks. Traditional models were inappropriate for this analysis because fates of some individual chicks were unknown due to failed radio transmitters. Simulations revealed biases of posterior mean estimates were minimal (<= 4.95%), and posterior distributions behaved as expected with RMSE of the estimates decreasing as sample sizes, detection probability, and survival increased. We determined mortality hazard rates for plover chicks were highest at <5 days old and were lower for chicks with larger birth weights and/or whose nest was within agricultural habitats. Based on its performance, our approach greatly expands the range of problems for which event-time analyses can be used by eliminating the need for having completely known fate data. PMID- 25691998 TI - Evolution of leaf warbler songs (Aves: Phylloscopidae). AB - Songs in passerine birds are important for territory defense and mating. Speciation rates in oscine passerines are so high, due to cultural evolution, that this bird lineage makes up half of the extant bird species. Leaf warblers are a speciose Old-World passerine family of limited morphological differentiation, so that songs are even more important for species delimitation. We took 16 sonographic traits from song recordings of 80 leaf warbler taxa and correlated them with 15 potentially explanatory variables, pairwise, and in linear models. Based on a well-resolved molecular phylogeny of the same taxa, all pairwise correlations were corrected for relatedness with phylogenetically independent contrasts and phylogenetic generalized linear models were used. We found a phylogenetic signal for most song traits, but a strong one only for the duration of the longest and of the shortest element, which are presumably inherited instead of learned. Body size of a leaf warbler species is a constraint on song frequencies independent of phylogeny. At least in this study, habitat density had only marginal impact on song features, which even disappeared through phylogenetic correction. Maybe most leaf warblers avoid the deterioration through sound propagation in dense vegetation by singing from exposed perches. Latitudinal (and longitudinal) extension of the breeding ranges was correlated with most song features, especially verse duration (longer polewards and westwards) and complexity (lower polewards). Climate niche or expansion history might explain these correlations. The number of different element types per verse decreases with elevation, possibly due to fewer resources and congeneric species at higher elevations. PMID- 25691999 TI - On the use of stable oxygen isotope (delta (18)O) measurements for tracking avian movements in North America. AB - Tracking migratory animals has benefitted using measurements of naturally occurring stable isotopes of hydrogen (delta (2)H) in keratinous tissues such as hair and feathers to link animal origins to continental patterns or isoscapes of delta (2)H in precipitation. However, for most taxa, much less information exists on the use of stable oxygen isotope ratios (delta (18)O) despite the fact that delta (2)H and delta (18)O are strongly linked in environmental waters through the meteoric relationship and the possibility of using both isotopes to infer greater information on origins and climatic conditions where tissues are grown. A fundamental requirement of using stable isotopes to assign individuals and populations to origins is the development of a rescaling function linking environmental food web signals to the tissue of interest and for birds, this has not been carried out. Here, we derived the relationship between H and O isotopes in known source feathers of 104 individuals representing 11 species of insectivorous passerines sampled across the strong precipitation isoscape of North America. We determined again a strong expected relationship between feather delta (2)H (delta (2)Hf) and long-term amount-weighted precipitation delta (2)H (delta (2)Hp; r (2) = 0.77), but the corresponding relationship between delta (18)Of and delta (18)Op was poor (r (2) = 0.32) for the same samples. This suggests that delta (2)H measurements are currently more useful for assignment of insectivorous songbirds to precipitation isoscapes but does not preclude other uses of the delta (18)Of data. Currently, mechanisms responsible for the decoupling of H and O isotopes in food webs is poorly known, and we advocate a much broader sampling of both isotopes in the same keratinous tissues across precipitation isotope gradients and across taxa to resolve this issue and to increase the power of using water isotopes to track migratory animals. PMID- 25692001 TI - Ecology and evolution. PMID- 25692000 TI - Limited sampling hampers "big data" estimation of species richness in a tropical biodiversity hotspot. AB - Macro-scale species richness studies often use museum specimens as their main source of information. However, such datasets are often strongly biased due to variation in sampling effort in space and time. These biases may strongly affect diversity estimates and may, thereby, obstruct solid inference on the underlying diversity drivers, as well as mislead conservation prioritization. In recent years, this has resulted in an increased focus on developing methods to correct for sampling bias. In this study, we use sample-size-correcting methods to examine patterns of tropical plant diversity in Ecuador, one of the most species rich and climatically heterogeneous biodiversity hotspots. Species richness estimates were calculated based on 205,735 georeferenced specimens of 15,788 species using the Margalef diversity index, the Chao estimator, the second-order Jackknife and Bootstrapping resampling methods, and Hill numbers and rarefaction. Species richness was heavily correlated with sampling effort, and only rarefaction was able to remove this effect, and we recommend this method for estimation of species richness with "big data" collections. PMID- 25685321 TI - Longevity of Atlantic Sharpnose Sharks Rhizoprionodon terraenovae and Blacknose Sharks Carcharhinus acronotus in the western North Atlantic Ocean based on tag recapture data and direct age estimates. AB - Longevity of Rhizoprionodon terraenovae and Carcharhinus acronotus in the western North Atlantic Ocean was examined using direct age estimates from vertebral sections and tag-recapture data. Time-at-liberty ranged from 7.7-14.0 years (mean =10.1) for R. terraenovae and 10.9-12.8 years (mean =11.9) for C. acronotus. Maximum estimated longevity was determined to be 19.8 years through tag-recapture data and 18.5 years from direct age estimates for R. terraenovae and 22.8 years through tag-recapture data and 20.5 years through direct age estimates for C. acronotus. These longevity estimates represent a large increase over previous estimates and may have significant effects on analyses that depend on longevity including lifetime fecundity, mortality rates, demographic analyses and stock assessments. PMID- 25685322 TI - ABS-Scan: In silico alanine scanning mutagenesis for binding site residues in protein-ligand complex. AB - Most physiological processes in living systems are fundamentally regulated by protein-ligand interactions. Understanding the process of ligand recognition by proteins is a vital activity in molecular biology and biochemistry. It is well known that the residues present at the binding site of the protein form pockets that provide a conducive environment for recognition of specific ligands. In many cases, the boundaries of these sites are not well defined. Here, we provide a web server to systematically evaluate important residues in the binding site of the protein that contribute towards the ligand recognition through in silico alanine scanning mutagenesis experiments. Each of the residues present at the binding site is computationally mutated to alanine. The ligand interaction energy is computed for each mutant and the corresponding DeltaDeltaG values are calculated by comparing it to the wild type protein, thus evaluating individual residue contributions towards ligand interaction. The server will thus provide a ranked list of residues to the user in order to obtain loss-of-function mutations. This web-tool can be freely accessed through the following address: http://proline.biochem.iisc.ernet.in/abscan/. PMID- 25685323 TI - Diversity of two-component systems: insights into the signal transduction mechanism by the Staphylococcus aureus two-component system GraSR. AB - The response to cationic antimicrobial peptides (CAMPs) in Staphylococcus aureus relies on a two-component system (TCS), GraSR, an auxiliary protein GraX and an ATP-binding cassette (ABC) transporter, VraF/G. To understand the signal transduction mechanism by GraSR, we investigated the kinase activity of the cytoplasmic domain of histidine kinase GraS and the interaction with its cognate response regulator GraR. We also investigated interactions among the auxiliary protein GraX, GraS/R and the ATPase protein of the ABC transporter, VraF. We found that GraS lacks autophosphorylation activity, unlike a similar histidine kinase, BceS, of Bacillus subtilis. In addition, the interaction between GraS and GraR is very weak in comparison to the stronger interaction observed between BceS and its conjugated response regulator, BceR, suggesting that CAMP signaling may not flow directly from GraS to GraR. We found that the auxiliary protein GraX interacts with VraF and GraR, and requires the histidine phosphotransfer and dimerization domain of GraS to interact with this protein. Further, VraF requires the GraS region that connects the membrane-bound domain with the cytoplasmic domain of this protein for interaction with GraS. The interactions of GraX with GraS/R and VraF indicate that GraX may serve as a scaffold to bring these proteins in close proximity to GraS, plausibly to facilitate activation of GraS to ultimately transduce the signal to GraR. PMID- 25692005 TI - Bioequivalence of Sandoz methylphenidate osmotic-controlled release tablet with Concerta(r) (Janssen-Cilag). AB - The aim was to assess the bioequivalence of Sandoz methylphenidate osmotic controlled release (OCR) tablets (Sandoz [Methylphenidate[ MPH OCR) with Concerta(r), a methylphenidate formulation indicated for the treatment of attention deficit/hyperactivity disorder (ADHD). Four open-label, randomized, single-dose, two-way crossover bioequivalence studies were conducted in healthy subjects: three fasting studies with 54-, 36- and 18-mg doses of methylphenidate, and one fed study with the 54-mg dose. The d- and l-threo-methylphenidate plasma levels were quantified using liquid chromatographic methods with tandem mass spectrometry (LC MS/MS). Bioequivalence of the formulations was accepted if the 90% geometric confidence intervals of the ratio of least-squares means of Sandoz MPH OCR to Concerta(r) of ln-transformed area under the curve (AUC0-t ) and C max were within the acceptance range of 80-125%. All studies met the bioequivalence criteria, and 90% geometric confidence intervals for AUC0-t and C max were within the predefined range. All plasma concentration time curves for Sandoz MPH OCR under fasting conditions showed a biphasic profile comparable with Concerta(r), confirmed by bioequivalence of the partial metrics AUC0-2h, AUC2-24 h, C max(0-2 h) and C max(2-24 h). Both products were well tolerated and no relevant differences in the safety profiles were observed. It was concluded that Sandoz MPH OCR is bioequivalent to Concerta(r) in terms of rate and extent of absorption when administered as a single dose of one extended-release tablet of 54, 36, or 18 mg under fasting conditions and at a dose of 54 mg under fed conditions. PMID- 25692006 TI - Cariprazine exerts antimanic properties and interferes with dopamine D2 receptor beta-arrestin interactions. AB - Activation of dopamine D2 receptors (D2R) modulates G protein/cAMP-dependent signaling and also engages Akt-GSK-3 signaling through D2R/beta-arrestin 2 scaffolding of Akt and PP2A. This G protein-independent pathway may be important in mediating the antimanic effects of mood stabilizers and antipsychotics. The mood stabilizer lithium influences behavior and Akt/GSK-3 signaling in mice and many antipsychotics have been shown to more potently antagonize the activity of the beta-arrestin-2 pathway relative to the G protein-dependent pathway. Cariprazine, an antipsychotic with potent D3R/D2R partial agonist activity and preferential binding to D3R, was investigated for its effects on the mediators of D2R pathways in vitro and its efficacy in animal models of mania. Effects on G protein-dependent activity were measured via inhibition of isoproterenol-induced cAMP production; effects on D2R/beta-arrestin 2 signaling were determined using bioluminescence resonance energy transfer (BRET). Cariprazine was tested in vivo for antimanic-like activity, using the ouabain-induced hyperactivity model in rats. Cariprazine was more potent than aripiprazole in inhibiting isoproterenol induced cAMP although both compounds showed similar maximum efficacy. In assays of D2R/beta-arrestin 2-dependent interactions, cariprazine showed very weak partial agonist activity, unless the levels of receptor kinase were increased; as an antagonist it showed similar potency to haloperidol and ~fivefold greater potency than aripiprazole. In an animal model of mania, cariprazine showed similar efficacy as lithium in attenuating the effects of ouabain-induced hyperactivity. In summary, the differential effects of cariprazine on D2R G protein and beta-arrestin 2 mediators of signal transduction pathways could contribute to its potent antimanic-like activity. PMID- 25692007 TI - A novel application of t-statistics to objectively assess the quality of IC50 fits for P-glycoprotein and other transporters. AB - Current USFDA and EMA guidance for drug transporter interactions is dependent on IC50 measurements as these are utilized in determining whether a clinical interaction study is warranted. It is therefore important not only to standardize transport inhibition assay systems but also to develop uniform statistical criteria with associated probability statements for generation of robust IC50 values, which can be easily adopted across the industry. The current work provides a quantitative examination of critical factors affecting the quality of IC50 fits for P-gp inhibition through simulations of perfect data with randomly added error as commonly observed in the large data set collected by the P-gp IC50 initiative. The types of errors simulated were (1) variability in replicate measures of transport activity; (2) transformations of error-contaminated transport activity data prior to IC50 fitting (such as performed when determining an IC50 for inhibition of P-gp based on efflux ratio); and (3) the lack of well defined "no inhibition" and "complete inhibition" plateaus. The effect of the algorithm used in fitting the inhibition curve (e.g., two or three parameter fits) was also investigated. These simulations provide strong quantitative support for the recommendations provided in Bentz et al. (2013) for the determination of IC50 values for P-gp and demonstrate the adverse effect of data transformation prior to fitting. Furthermore, the simulations validate uniform statistical criteria for robust IC50 fits in general, which can be easily implemented across the industry. A calibration of the t-statistic is provided through calculation of confidence intervals associated with the t-statistic. PMID- 25692008 TI - Cellular density-dependent down-regulation of EP4 prostanoid receptors via the up regulation of hypoxia-inducible factor-1alpha in HCA-7 human colon cancer cells. AB - Increases in prostaglandin E2 (PGE2) and cyclooxygenase-2 (COX-2) levels are features of colon cancer. Among the different E-type prostanoid receptor subtypes, EP4 receptors are considered to play a crucial role in carcinogenesis by, for example, inducing COX-2 when stimulated with PGE2. However, EP4 receptor levels and PGE2-induced cellular responses are inconsistent among the cellular conditions. Therefore, the connections responsible for the expression of EP4 receptors were investigated in the present study by focusing on cell density induced hypoxia-inducible factor-1alpha (HIF-1alpha). The expression of EP4 receptors was examined using immunoblot analysis, quantitative polymerase chain reaction, and reporter gene assays in HCA-7 human colon cancer cells with different cellular densities. The involvement of HIF-1alpha and its signaling pathways were also examined by immunoblot analysis, reporter gene assays, and with siRNA. We here demonstrated that EP4 receptors as well as EP4 receptor mediated COX-2 expression levels decreased with an increase in cellular density. In contrast, HIF-1alpha levels increased in a cellular density-dependent manner. The knockdown of HIF-1alpha by siRNA restored the expression of EP4 receptors and EP4 receptor-mediated COX-2 in cells at a high density. Thus, the cellular density-dependent increase observed in HIF-1alpha expression levels reduced the expression of COX-2 by decreasing EP4 receptor levels. This novel regulation mechanism for the expression of EP4 receptors by HIF-1alpha may provide an explanation for the inconsistent actions of PGE2. The expression levels of EP4 receptors may vary depending on cellular density, which may lead to the differential activation of their signaling pathways by PGE2. Thus, cellular density-dependent PGE2-mediated signaling may determine the fate/stage of cancer cells, i.e., the surrounding environments could define the fate/stage of malignancies associated with colon cancer. PMID- 25692011 TI - p-Cresyl sulfate, a uremic toxin, causes vascular endothelial and smooth muscle cell damages by inducing oxidative stress. AB - The major cause of death in patients with chronic kidney disease (CKD) is cardiovascular disease. Here, p-Cresyl sulfate (PCS), a uremic toxin, is considered to be a risk factor for cardiovascular disease in CKD. However, our understanding of the vascular toxicity induced by PCS and its mechanism is incomplete. The purpose of this study was to determine whether PCS enhances the production of reactive oxygen species (ROS) in vascular endothelial and smooth muscle cells, resulting in cytotoxicity. PCS exhibited pro-oxidant properties in human umbilical vein endothelial cells (HUVEC) and aortic smooth muscle cells (HASMC) by enhancing NADPH oxidase expression. PCS also up-regulates the mRNA levels and the protein secretion of monocyte chemotactic protein-1 (MCP-1) in HUVEC. In HASMC, PCS increased the mRNA levels of alkaline phosphatase (ALP), osteopontin (OPN), core-binding factor alpha 1, and ALP activity. The knockdown of Nox4, a subunit of NADPH oxidase, suppressed the cell toxicity induced by PCS. The vascular damage induced by PCS was largely suppressed in the presence of probenecid, an inhibitor of organic anion transporters (OAT). In PCS-overloaded 5/6-nephrectomized rats, plasma MCP-1 levels, OPN expression, and ALP activity of the aortic arch were increased, accompanied by the induction of Nox4 expression. Collectively, the vascular toxicity of PCS can be attributed to its intracellular accumulation via OAT, which results in an enhanced NADPH oxidase expression and increased ROS production. In conclusion, we found for the first time that PCS could play an important role in the development of cardiovascular disease by inducing vascular toxicity in the CKD condition. PMID- 25692009 TI - Characterization of the 5-HT2C receptor agonist lorcaserin on efficacy and safety measures in a rat model of diet-induced obesity. AB - The 5-HT2C receptor agonist lorcaserin (Belviq(r)) has been Food and Drug Administration (FDA) approved for the treatment of obesity. The present study is a back translational investigation into the effect of 28-day lorcaserin treatment in a diet-induced obesity (DIO) model using male, Sprague-Dawley rats. An assessment of drug effect on efficacy and multiple safety endpoints including cardiac function was undertaken. Lorcaserin (1-2 mg/kg SC b.i.d.) significantly reduced percentage body weight gain compared to vehicle-treated controls (VEH: 10.6 +/- 0.4%; LOR 1: 7.6 +/- 1.2%; LOR 2: 5.4 +/- 0.6%). Measurement of body composition using quantitative magnetic resonance (QMR) imaging indicated this change was due to the selective reduction in body fat mass. Modest effects on food intake were recorded. At the completion of the treatment phase, echocardiography revealed no evidence for valvulopathy, that is, no aortic or mitral valve regurgitation. The pharmacokinetics of the present treatment regimen was determined over a 7-day treatment period; plasma C min and C max were in the range 13-160 ng/mL (1 mg/kg b.i.d.) and 34-264 ng/mL (2 mg/kg b.i.d.) with no evidence for drug accumulation. In sum, these studies show an effect of lorcaserin in the DIO model, that in the context of the primary endpoint measure of % body weight change was similar to that reported clinically (i.e., 3.0-5.2% vs. 3.2%). The present studies highlight the translational value of obesity models such as DIO, and suggest that assuming consideration is paid to nonspecific drug effects such as malaise, the DIO model has reasonable forward translational value to help predict clinical outcomes of a new chemical entity. PMID- 25692012 TI - Common misconceptions about data analysis and statistics. AB - Ideally, any experienced investigator with the right tools should be able to reproduce a finding published in a peer-reviewed biomedical science journal. In fact, the reproducibility of a large percentage of published findings has been questioned. Undoubtedly, there are many reasons for this, but one reason may be that investigators fool themselves due to a poor understanding of statistical concepts. In particular, investigators often make these mistakes: (1) P-Hacking. This is when you reanalyze a data set in many different ways, or perhaps reanalyze with additional replicates, until you get the result you want. (2) Overemphasis on P values rather than on the actual size of the observed effect. (3) Overuse of statistical hypothesis testing, and being seduced by the word "significant". (4) Overreliance on standard errors, which are often misunderstood. PMID- 25692013 TI - Gene expression changes caused by the p38 MAPK inhibitor dilmapimod in COPD patients: analysis of blood and sputum samples from a randomized, placebo controlled clinical trial. AB - The p38 mitogen-activated protein kinase (MAPK) intracellular signaling pathway responds to a variety of extracellular stimuli, including cytokines, Toll-like receptor agonists, and components of cigarette smoke to influence the expression of proinflammatory mediators. Activation of p38 MAPK is increased within the lungs of chronic obstructive pulmonary disease (COPD) patients. In clinical trials, treatment of COPD patients with p38 MAPK inhibitors has been shown to reduce systemic inflammation plasma biomarkers C-reactive protein (CRP) and fibrinogen. As CRP and fibrinogen have been associated with poor clinical outcomes in COPD patients, such as mortality, exacerbation, and hospitalization, we analyzed gene expression data from COPD subjects treated with dilmapimod with the aim of understanding the effects of p38 MAPK inhibition on the inflammatory genome of immune cells within the systemic circulation. Whole blood and induced sputum samples were used to measure mRNA levels by gene array and PCR. Pathway and network analysis showed STAT1, MMP-9, CAV1, and IL-1beta as genes regulated by dilmapimod that could also influence fibrinogen levels, while only IL-1beta was identified as a gene regulated by dilmapimod that could influence CRP levels. This suggests that p38 MAPK inhibits specific inflammatory pathways, leading to to differential effects on CRP and fibrinogen levels in COPD patients. PMID- 25692014 TI - Advice on statistical analysis, and new journal guidance for experimental design and analysis. PMID- 25692015 TI - Pharmacological and pharmacokinetic properties of JNJ-40411813, a positive allosteric modulator of the mGlu2 receptor. AB - Compounds modulating metabotropic glutamate type 2 (mGlu2) receptor activity may have therapeutic benefits in treating psychiatric disorders like schizophrenia and anxiety. The pharmacological and pharmacokinetic properties of a novel mGlu2 receptor-positive allosteric modulator (PAM), 1-butyl-3-chloro-4-(4-phenyl-1 piperidinyl)-2(1H)-pyridinone (JNJ-40411813/ADX71149) are described here. JNJ 40411813 acts as a PAM at the cloned mGlu2 receptor: EC50 = 147 +/- 42 nmol/L in a [(35)S]GTPgammaS binding assay with human metabotropic glutamate type 2 (hmGlu2) CHO cells and EC50 = 64 +/- 29 nmol/L in a Ca(2+) mobilization assay with hmGlu2 G alpha16 cotransfected HEK293 cells. [(35)S]GTPgammaS autoradiography on rat brain slices confirmed PAM activity of JNJ-40411813 on native mGlu2 receptor. JNJ-40411813 displaced [(3)H]JNJ-40068782 and [(3)H]JNJ 46281222 (mGlu2 receptor PAMs), while it failed to displace [(3)H]LY341495 (a competitive mGlu2/3 receptor antagonist). In rats, JNJ-40411813 showed ex vivo mGlu2 receptor occupancy using [(3)H]JNJ-46281222 with ED50 of 16 mg/kg (p.o.). PK-PD modeling using the same radioligand resulted in an EC50 of 1032 ng/mL. While JNJ-40411813 demonstrated moderate affinity for human 5HT2A receptor in vitro (K b = 1.1 MUmol/L), higher than expected 5HT2A occupancy was observed in vivo (in rats, ED50 = 17 mg/kg p.o.) due to a metabolite. JNJ-40411813 dose dependently suppressed REM sleep (LAD, 3 mg/kg p.o.), and promoted and consolidated deep sleep. In fed rats, JNJ-40411813 (10 mg/kg p.o.) was rapidly absorbed (C max 938 ng/mL at 0.5 h) with an absolute oral bioavailability of 31%. Collectively, our data show that JNJ-40411813 is an interesting candidate to explore the therapeutic potential of mGlu2 PAMs, in in vivo rodents experiments as well as in clinical studies. PMID- 25692016 TI - Prediction of clinical pharmacokinetics of AMG 181, a human anti-alpha 4 beta 7 monoclonal antibody for treating inflammatory bowel diseases. AB - The purpose of this study was to predict a safe starting dose of AMG 181, a human anti-alpha 4 beta 7 antibody for treating inflammatory bowel diseases, based on cynomolgus monkey pharmacokinetic (PK) and pharmacodynamic (PD) data. A two compartment model with parallel linear and target-mediated drug disposition for AMG 181 PK in cynomolgus monkey was developed. The estimated parameters were allometrically scaled to predict human PK. An E max PD model was used to relate AMG 181 concentration and free alpha 4 beta 7 receptor data in cynomolgus monkey. AMG 181 clinical doses were selected based on observed exposures at the no adverse effect level of 80 mg.kg(-1) in monkeys, the predicted human exposures, and AMG 181 concentration expected to produce greater than 50% alpha 4 beta 7 receptor occupancy in humans. The predicted human AMG 181 clearance and central volume of distribution were 144 mL.day(-1) and 2900 mL, respectively. The estimated EC50 for free alpha 4 beta 7 receptor was 14 ng.mL(-1). At the 0.7 mg starting dose in humans, the predicted exposure margins were greater than 490,000 and AMG 181 concentrations were predicted to only briefly cover the free alpha 4 beta 7 receptor EC10. Predictions for both C max and AUC matched with those observed in the first-in-human study within the 7 mg subcutaneous to 420 mg intravenous dose range. The developed model aided in selection of a safe starting dose and a pharmacological relevant dose escalation strategy for testing of AMG 181 in humans. The clinically observed human AMG 181 PK data validated the modeling approach based on cynomolgus monkey data alone. PMID- 25692017 TI - Genetic variation in aryl N-acetyltransferase results in significant differences in the pharmacokinetic and safety profiles of amifampridine (3,4-diaminopyridine) phosphate. AB - The clinical use of amifampridine phosphate for neuromuscular junction disorders is increasing. The metabolism of amifampridine occurs via polymorphic aryl N acetyltransferase (NAT), yet its pharmacokinetic (PK) and safety profiles, as influenced by this enzyme system, have not been investigated. The objective of this study was to assess the effect of NAT phenotype and genotype on the PK and safety profiles of amifampridine in healthy volunteers (N = 26). A caffeine challenge test and NAT2 genotyping were used to delineate subjects into slow and fast acetylators for PK and tolerability assessment of single, escalating doses of amifampridine (up to 30 mg) and in multiple daily doses (20 mg QID) of amifampridine. The results showed that fast acetylator phenotypes displayed significantly lower C max, AUC, and shorter t 1/2 for amifampridine than slow acetylators. Plasma concentrations of the N-acetyl metabolite were approximately twofold higher in fast acetylators. Gender differences were not observed. Single doses of amifampridine demonstrated dose linear PKs. Amifampridine achieved steady state plasma levels within 1 day of dosing four times daily. No accumulation or time-dependent changes in amifampridine PK parameters occurred. Overall, slow acetylators reported 73 drug-related treatment-emergent adverse events versus 6 in fast acetylators. Variations in polymorphic NAT corresponding with fast and slow acetylator phenotypes significantly affects the PK and safety profiles of amifampridine. PMID- 25692018 TI - Muscarinic M1 receptor and cannabinoid CB1 receptor do not modulate paraoxon induced seizures. AB - One of the major signs of severe organophosphate poisoning is seizures. Previous studies have shown that both muscarinic agonist- and organophosphate-induced seizures require activation of muscarinic acetylcholine receptors in the central nervous system. Seizures induced by the muscarinic agonist pilocarpine require the M1 receptor and are modulated by cannabinoid CB1 receptors. In this study, we determined whether M1 and CB1 receptors also regulated seizures induced by the organophosphate paraoxon. We found no differences in seizures induced by paraoxon in wild-type (WT) and M1 knockout (KO) mice, indicating that in contrast to pilocarpine seizures, M1 receptors are not required for paraoxon seizures. Furthermore, we found that pilocarpine administration resulted in seizure independent activation of ERK in the hippocampus in a M1 receptor-dependent manner, while paraoxon did not induce seizure-independent activation of ERK in the mouse hippocampus. This shows that pilocarpine and paraoxon activated M1 receptors in the hippocampus to different extents. There were no differences in seizures induced by paraoxon in WT and CB1 KO mice, and neither CB1 agonist nor antagonist administration had significant effects on paraoxon seizures, indicating that, in contrast to pilocarpine seizures, paraoxon seizures are not modulated by CB1 receptors. These results demonstrate that there are fundamental molecular differences in the regulation of seizures induced by pilocarpine and paraoxon. PMID- 25692019 TI - Functional desensitization of the beta 2 adrenoceptor is not dependent on agonist efficacy. AB - Chronic treatment with beta 2 adrenoceptor agonists is recommended as a first line maintenance therapy for chronic obstructive pulmonary disease (COPD). However, a potential consequence of long-term treatment may be the loss of functional response (tachyphylaxis) over time. In this study, we have investigated the tendency of such agonists, with a range of efficacies, to develop functional desensitization to cAMP responses in primary human bronchial smooth muscle cells following prolonged agonist exposure. The data show that upon repeat exposure, all agonists produced functional desensitization to the same degree and rate. In addition, beta 2 adrenoceptor internalization and beta arrestin-2 recruitment were monitored using beta 2.eGFP visualization and the PathHunterTM beta-arrestin-2 assay, respectively. All agonists were capable of causing robust receptor internalization and beta-arrestin-2 recruitment, the rate of which was influenced by agonist efficacy, as measured in those assays. In summary, although a relationship exists between agonist efficacy and the rate of both receptor internalization and beta-arrestin-2 recruitment, there is no correlation between agonist efficacy and the rate or extent of functional desensitization. PMID- 25692020 TI - Oxytocin does not directly alter cardiac repolarization in rabbit or human cardiac myocytes. AB - Oxytocin, a nine amino acid peptide, is highly conserved in placental mammals, including humans. Oxytocin has a physiological role in parturition and parenteral administration of the synthetic peptide is used to induce labor and control postpartum hemorrhage. Endogenous levels of oxytocin before labor are ~20 pg/mL, but pharmacological administration of the peptide can achieve levels of 110 pg/mL (0.1 nmol/L) following intravenous administration. Cardiac arrhythmia and premature ventricular contractions have been associated with oxytocin administration in addition to QTc interval prolongation. In the conscious rabbit model, intravenous oxytocin produced QT and QTc prolongation. The mechanism of oxytocin-induced QTc prolongation is uncertain but could be the result of indirect changes in autonomic nervous tone, or a direct effect on the duration of cardiomyocyte repolarization. The purpose of this study was to examine the ability of oxytocin to alter cardiac repolarization directly. Two conventional models were used: QTc interval evaluation in the isolated rabbit heart (IRH) and assessment of action potential duration (APD) in human ventricular myocytes (HVM). Oxytocin did not prolong QTc intervals in IRH or APD in HVM when tested at suprapharmacological concentrations, for example, up to 1 MUmol/L. The results indicate that oxytocin has very low risk for eliciting QTc and APD prolongation directly, and infer that the QTc changes observed in vivo may be attributed to an indirect mechanism. PMID- 25692021 TI - 5-HT is a potent relaxant in rat superior mesenteric veins. AB - Serotonin (5-HT, 5-hydroxytryptamine) reduces blood pressure of the conscious rat when administered chronically (1 week). 5-HT does not directly relax isolated arteries, and microsphere experiments in 5-HT-infused rats suggested that 5-HT increased flow to the splanchnic bed. We hypothesized that 5-HT increased splanchnic flow because of direct venous relaxation; our focus was thus on the superior mesenteric vein (SMV) as an important vein in splanchnic circulation. Real-time RT-PCR, immunohistochemistry and Western analyses supported the predominant expression of the 5-HT2B and 5-HT7 receptor in the SMV. The SMV was mounted in tissue baths for measurement of isometric contraction. 5-HT caused a concentration-dependent relaxation of the endothelin-1 (ET-1)-contracted vein. The threshold of 5-HT-induced venous relaxation was significantly lower than for 5-HT-induced venous contraction (~2 vs. 700 nmol/L, respectively). A series of serotonergic agonists established in their use of receptor characterization was tested, and the following rank order of potency found for agonist-induced relaxation (receptor selectivity): 5-CT (5-HT1/5-HT7)>5-HT = LP-44 (5 HT7)>PNU109291 (5-HT1D) = BW723C86 (5-HT2B). 8-OH-DPAT (5-HT1A/7), CP93129 (5 HT1B), mCPBG (5-HT3/4), AS19 (5-HT7) and TCB-2 (5-HT2A) did not relax the isolated vein. Consistent with these findings, two different 5-HT7 receptor antagonists SB 269970 and LY215840 but not the 5-HT2B receptor antagonist LY272015 nor the nitric oxide synthase inhibitor LNNA abolished 5-CT-induced relaxation of the isolated SMV. 5-CT (1 MUg kg(-1) min(-1), sc) also reduced blood pressure over 7 days. These findings suggest that 5-HT directly relaxes the SMV primarily through activation of the 5-HT7 receptor. PMID- 25692022 TI - Components of the endocannabinoid and dopamine systems are dysregulated in Huntington's disease: analysis of publicly available microarray datasets. AB - The endocannabinoid system (ECS) and the dopaminergic system (DAS) are two major regulators of basal ganglia function. During Huntington's disease (HD) pathogenesis, the expression of genes in both the ECS and DAS is dysregulated. The purpose of this study was to determine the changes that were consistently observed in the ECS and DAS during HD progression in the central nervous system (CNS) and in the periphery in different models of HD and human HD tissue. To do this, we conducted a meta-analysis of differential gene expression in the ECS and DAS using publicly available microarray data. The consolidated data were summarized as observed changes in gene expression (OCGE) using a weighted sum for each gene. In addition, consolidated data were compared to previously published studies that were not available in the gene expression omnibus (GEO) database. The resulting data confirm gene expression changes observed using different approaches and provide novel insights into the consistency between changes observed in human tissue and various models, as well as disease stage- and tissue specific transcriptional dysregulation in HD. The major implication of the systems-wide data presented here is that therapeutic strategies targeting the ECS or DAS must consider the dynamic changes in gene expression over time and in different body areas, which occur during HD progression and the interconnectedness of the two systems. PMID- 25692023 TI - Varenicline enhances dopamine release facilitation more than nicotine after long term nicotine treatment and withdrawal. AB - An important factor contributing to the high relapse rates among smokers is nicotine withdrawal symptoms. Multiple studies suggest that decreased dopamine release in nucleus accumbens plays a key role in withdrawal. However, recent reports showed that long-term nicotine exposure itself also decreases accumbal dopamine release, suggesting that additional mechanisms are involved in withdrawal. Here, we used real-time cyclic voltammetry in brain slices containing the nucleus accumbens to further elucidate the changes in dopamine release linked to nicotine withdrawal. Rats received vehicle or nicotine via the drinking water for 2-3 months. Studies assessing the expression of somatic signs in vehicle treated, nicotine-treated, and 24-h nicotine withdrawn rats showed that nicotine withdrawal led to a significant increase in somatic signs. Subsequent voltammetry studies showed that long-term nicotine decreased single-pulse-stimulated dopamine release via an interaction at alpha6beta2* receptors. Nicotine withdrawal led to a partial recovery in alpha6beta2* receptor-mediated release. In addition, long term nicotine treatment alone increased dopamine release paired-pulse ratios and this was partially reversed with nicotine removal. We then evaluated the effect of bath-applied nicotine and varenicline on dopamine release. Nicotine and varenicline both decreased single-pulse-stimulated release in vehicle-treated, nicotine-treated, and nicotine withdrawn rats. However, bath-applied varenicline increased paired-pulse ratios to a greater extent than nicotine during long-term nicotine treatment and after its withdrawal. Altogether these data suggest that nicotine withdrawal is associated with a partial restoration of dopamine release measures to control levels and that varenicline's differential modulation of dopamine release may contribute to its mechanism of action. PMID- 25692024 TI - Active surveillance of visual impairment due to adverse drug reactions: findings from a national study in the United Kingdom. AB - As visual impairment (VI) due to adverse drug reactions (ADR) is rare in adults and children, there is an incomplete evidence base to inform guidance for screening and for counseling patients on the potential risks of medications. We report on suspected drugs and the eye conditions found in a national study of incidence of diagnosis of visual impairment due to suspected ADR. Case ascertainment was via the British Ophthalmological Surveillance Unit (BOSU), between March 2010 and February 2012, with follow-up after 6 months. CASE DEFINITION: any child or adult with bilateral or unilateral visual impairment due to a suspected ADR, using distance acuity worse than Snellen 6/18 (logMAR 0.48) in the better eye (bilateral) or affected eye (unilateral). Anonymized patient information on potential cases was provided by managing ophthalmologists, comprising visual status before and after suspected ADR, ophthalmic condition attributable to the ADR, preexisting eye disease and prescribed medications at the time of the ADR. Permanency and causality of the visual impairment were confirmed by the managing clinician, after 6 months, using the WHO Uppsala Monitoring Committee criteria. Over 2 years, 36 eligible cases were reported of whom 23 had permanent VI. While most cases were due to drugs known to have adverse side-effects, some were unanticipated sporadic cases. Visual impairment due to ADRs is rare. However, with for example, increasing polypharmacy in the elderly, monitoring of ocular ADRs, although challenging, is necessary. PMID- 25692025 TI - In vitro and in vivo pharmacological characterization of a neuropeptide S tetrabranched derivative. AB - The peptide welding technology (PWT) is a novel chemical strategy that allows the synthesis of multibranched peptides with high yield, purity, and reproducibility. With this approach, a tetrabranched derivative of neuropeptide S (NPS) has been synthesized and pharmacologically characterized. The in vitro activity of PWT1 NPS has been studied in a calcium mobilization assay. In vivo, PWT1-NPS has been investigated in the locomotor activity (LA) and recovery of the righting reflex (RR) tests. In calcium mobilization studies, PWT1-NPS behaved as full agonist at the mouse NPS receptor (NPSR) being threefold more potent than NPS. The selective NPSR antagonists [ (t) Bu-D-Gly(5)]NPS and SHA 68 displayed similar potency values against NPS and PWT1-NPS. In vivo, both NPS (1-100 pmol, i.c.v.) and PWT1 NPS (0.1-100 pmol, i.c.v.) stimulated mouse LA, with PWT1-NPS showing higher potency than NPS. In the RR assay, NPS (100 pmol, i.c.v.) was able to reduce the percentage of mice losing the RR after diazepam administration and their sleep time 5 min after the i.c.v. injection, but it was totally inactive 2 h after the injection. On the contrary, PWT1-NPS (30 pmol, i.c.v.), injected 2 h before diazepam, displayed wake-promoting effects. This PWT1-NPS stimulant effect was no longer evident in mice lacking the NPSR receptor. The PWT1 technology can be successfully applied to the NPS sequence. PWT1-NPS displayed in vitro a pharmacological profile similar to NPS. In vivo PWT1-NPS mimicked NPS effects showing higher potency and long-lasting action. PMID- 25692026 TI - Identification of trichlormethiazide as a Mdr1a/b gene expression enhancer via a dual secretion-based promoter assay. AB - Transporters of the ATP-binding cassette (ABC) family such as MDR1 play a pivotal role in persistence of brain homeostasis by contributing to the strict permeability properties of the blood-brain barrier. This barrier on one hand compromises treatment of central nervous system diseases by restricting access of drugs; on the other hand, an impaired or altered function of barrier building cells has been described in neurological disorders. The latter might contribute to increased vulnerability of the brain under pathological conditions or even enforce pathogenesis. Here, we present a novel approach for a systematic examination of drug impact on Mdr1 gene expression by establishing a dual reporter gene assay for the murine upstream core promoters of Mdr1a and b. We validated the time-resolved assay in comparison with single reporter gene constructs and applied it to analyze effects of a Food and Drug Administration (FDA)-approved drug library consisting of 627 substances. The chemo-preventive synthetic dithiolethione oltipraz was reidentified with our assay as an already known inducer of Mdr1 gene expression. Together with two newly characterized modifiers - gemcitabine and trichlormethiazide - we prove our findings in a blood brain barrier culture model as well as in wild-type and Mdr1 knockout mice. In sum, we could demonstrate that our dual reporter gene assay delivers results, which also persist in the living animal and consequently is applicable for further analysis and prediction of Mdr1 regulation in vivo. PMID- 25692027 TI - Preclinical evaluation of the antipsychotic potential of the mGlu2-positive allosteric modulator JNJ-40411813. AB - JNJ-40411813/ADX71149 (1-butyl-3-chloro-4-(4-phenylpiperidin-1-yl) pyridin-2(1H) one) is a positive allosteric modulator (PAM) of the mGlu2 receptor, which also displays 5-Hydroxytryptamine (5HT2A) antagonism after administration in rodents due to a rodent-specific metabolite. JNJ-40411813 was compared with the orthosteric mGlu2/3 agonist LY404039 (4-amino-2-thiabicyclo [3.1.0] hexane-4,6 dicarboxylic acid 2,2-dioxide), the selective mGlu2 PAM JNJ-42153605 (3 (cyclopropylmethyl)-7-(4-phenylpiperidin-1-yl)-8 (trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridine) and the 5HT2A antagonist ritanserin in rodent models for antipsychotic activity and potential side effects, attempting to differentiate between the various compounds and mechanisms of action. In mice, JNJ-40411813, JNJ-42153605, and LY404039 inhibited spontaneous locomotion and phencyclidine- and scopolamine-induced but not d amphetamine-induced hyperlocomotion; the 5HT2A antagonist ritanserin inhibited only spontaneous locomotion and phencyclidine-induced hyperlocomotion. As measured by 2-deoxyglucose uptake, all compounds reversed memantine-induced brain activation in mice. The two mGlu2 PAMs and LY404039, but not ritanserin, inhibited conditioned avoidance behavior in rats. Like ritanserin, the mGlu2 ligands antagonized 2,5-dimethoxy-4-methylamphetamine-induced head twitches in rats. LY404039 but not the mGlu2 PAMs impaired rotarod performance in rats and increased the acoustic startle response in mice. Our results show that although 5HT2A antagonism has effect in some models, mGlu2 receptor activation is sufficient for activity in several animal models of antipsychotic activity. The mGlu2 PAMs mimicked the in vivo pharmacodynamic effects observed with LY404039 except for effects on the rotarod and acoustic startle, suggesting that they produce a primary activity profile similar to that of the mGlu2/3 receptor agonist while they can be differentiated based on their secondary activity profile. The results are discussed in light of clinical data available for some of these molecules, in particular JNJ-40411813. PMID- 25692028 TI - Revision of instructions to authors for pharmacology research and perspectives: enhancing the quality and transparency of published work. PMID- 25692029 TI - Long-lasting oral analgesic effects of N-protected aminophosphinic dual ENKephalinase inhibitors (DENKIs) in peripherally controlled pain. AB - The peripheral endogenous opioid system is critically involved in neuropathic and inflammatory pain generation as suggested by the modulation of opioid receptors expression and enkephalins (ENKs) release observed in these painful conditions. Accordingly, an innovative approach in the treatment of these nocifensive events is to increase and maintain high local concentrations of extracellular pain evoked ENKs, by preventing their physiological enzymatic inactivation by two Zn metallopeptidases, the neutral endopeptidase (NEP, neprilysin, EC 3.4.24.11) and the neutral aminopeptidase (APN, EC 3.4.11.2). With this aim, new orally active dual ENKephalinase inhibitors (DENKIs) were designed as soluble prodrugs by introducing a N-terminal cleavable carbamate in the previously described aminophosphinic inhibitors. This induces long-lasting antinociceptive responses after oral administration, in various rodent models of inflammatory and neuropathic pain. These responses are mediated through stimulation of peripheral opioid receptors by DENKIs-protected ENKs as demonstrated by naloxone methiodide reversion. In all tested models, the most efficient prodrug 2a (PL265) was active, at least during 150-180 min, after single oral administration of 25-50 mg/kg in mice and of 100-200 mg/kg in rats. In models of neuropathic pain, both hyperalgesia and allodynia were markedly reduced. Interestingly, combination of inactive doses of 2a (PL265) and of the anti-epileptic drug gabapentin had synergistic effect on neuropathic pain. Pharmacokinetic studies of 2a (PL265) in rats show that the active drug is the only generated metabolite produced. These encouraging results have made 2a (PL265) a suitable candidate for clinical development. PMID- 25692030 TI - Prophylaxis in older Canadian adults with hemophilia A: lessons and more questions. AB - BACKGROUND: Although prophylaxis is a standard of care for young children in developed countries, known to reduce the severity of hemophilic arthropathy, older adults with existing arthropathy have not traditionally used prophylaxis. Recent studies have shown that adults with hemophilia A are increasingly adopting prophylaxis but the characteristics of this treatment in older adults are not well understood. This multicenter observational study was conducted to describe how secondary/tertiary prophylaxis is being used in older adults (>=40 years of age) in comparison to younger adults with severe hemophilia A. METHODS: Eligible adult (>=18 years of age) Canadian males with baseline FVIII:C <=2% from the participating centres were observed over a 2 year period. RESULTS: Of the 220 adult severe hemophilia patients enrolled, 70% (155/220) used prophylaxis during the observational period. Only 27% (60/220) are older adults with very few >60 years of age. A lower proportion of older adults use prophylaxis compared to younger adults (58% vs. 75%, p = 0.016), with most patients in both groups using continuous prophylaxis (92 and 94% respectively). When considering all treatment modalities together, younger subjects use more factor concentrate than older subjects (2437 u/kg/year vs. 1702 u/kg/year, p = 0.027); however, older subjects on prophylaxis use 3447 u/kg/year and had an ABR of 12 while those on demand use 560 u/kg/year and had an ABR of 13. CONCLUSION: A significant number of older adults use secondary/tertiary continuous prophylaxis in Canada, accounting for a significant fraction of factor concentrate utilization. PMID- 25692031 TI - An Updated Meta-Analysis: Risk Conferred by Glutathione S-Transferases (GSTM1 and GSTT1) Polymorphisms to Age-Related Cataract. AB - Purpose. To study the effects of glutathione S-transferase M1 (GSTM1) and T1 (GSTT1) polymorphisms on age-related cataract (ARC). Methods. After a systematic literature search, all relevant studies evaluating the association between GSTs polymorphisms and ARC were included. Results. Fifteen studies on GSTM1 and nine studies on GSTT1 were included in this meta-analysis. In the pooled analysis, a significant association between null genotype of GSTT1 and ARC was found (OR = 1.229, 95% CI = 1.057-1.429, and P = 0.007). In subgroup analysis, the association between cortical cataract (CC) and GSTM1 null genotype was statistically significant (OR = 0.713, 95% CI = 0.598-0.850, and P < 0.001). In addition, GSTM1 null genotype was significantly associated with ARC causing risk to individuals working indoors and not individuals working outdoors. The association between GSTT1 null genotype and risk of ARC was statistically significant in Asians (OR = 1.442, 95% CI = 1.137-1.830, and P = 0.003) but not in Caucasians. Conclusions. GSTM1 positive genotype is associated with increased risk of CC and loses the protective role in persons who work outdoors. Considering the ethnic variation, GSTT1 null genotype is found to be associated with increased risk of ARC in Asians but not in Caucasians. PMID- 25692032 TI - Evaluation of 24-Hour Arterial Stiffness Indices and Central Hemodynamics in Healthy Normotensive Subjects versus Treated or Untreated Hypertensive Patients: A Feasibility Study. AB - Objective. Central blood pressure (BP) and vascular indices estimated noninvasively over the 24 hours were compared between normotensive volunteers and hypertensive patients by a pulse wave analysis of ambulatory blood pressure recordings. Methods. Digitalized waveforms obtained during each brachial oscillometric BP measurement were stored in the device memory and analyzed by the validated Vasotens technology. Averages for the 24 hours and for the awake and asleep subperiods were computed. Results. 142 normotensives and 661 hypertensives were evaluated. 24-hour central BP, pulse wave velocity (PWV), and augmentation index (AI) were significantly higher in the hypertensive group than in the normotensive group (119.3 versus 105.6 mmHg for systolic BP, 75.6 versus 72.3 mmHg for diastolic BP, 10.3 versus 10.0 m/sec for aortic PWV, -9.7 versus -40.7% for peripheral AI, and 24.7 versus 11.0% for aortic AI), whereas reflected wave transit time (RWTT) was significantly lower in hypertensive patients (126.6 versus 139.0 ms). After adjusting for confounding factors a statistically significant between-group difference was still observed for central BP, RWTT, and peripheral AI. All estimates displayed a typical circadian rhythm. Conclusions. Noninvasive assessment of 24-hour arterial stiffness and central hemodynamics in daily life dynamic conditions may help in assessing the arterial function impairment in hypertensive patients. PMID- 25692033 TI - CYP17A1 and Blood Pressure Reactivity to Stress in Adolescence. AB - Adolescents who exhibit exaggerated blood pressure (BP) reactivity to physical and mental challenges are at increased risk of developing hypertension in adulthood. BP at rest and in response to challenges is higher in males than females, beginning in early adolescence. CYP17A1 is one of the well-established gene loci of adult hypertension. Here, we investigated whether this gene locus is associated with elevated BP at rest and in response to physical (active standing) and mental (math stress) challenges in adolescence. We studied 496 male and 532 female adolescents (age 12-18 years) who were recruited from a genetic founder population. Our results showed that the variant of CYP17A1 rs10786718 was associated with enhanced BP reactivity to the mental but not physical challenge and in males but not females. In males, BP increase in response to math stress was higher in major versus minor allele homozygotes by 7.6 mm Hg (P = 8.3 * 10( 6)). Resting BP was not associated with the CYP17A1 variant in either sex. These results suggest that, in adolescent males but not females, CYP17A1 enhances BP reactivity to mental stress. Whether this effect contributes to the higher prevalence of hypertension in males than females later in life remains to be determined. PMID- 25692034 TI - An efficient and improved methodology for the screening of industrially valuable xylano-pectino-cellulolytic microbes. AB - Xylano-pectino-cellulolytic enzymes are valuable enzymes of the industrial sector. In our earlier study, we have reported a novel and cost effective methodology for the qualitative screening of cellulase-free xylano-pectinolytic microorganisms by replacing the commercial, highly expensive substrates with agricultural residues, but the microorganisms with xylanolytic, pectinolytic, cellulolytic, xylano-pectinolytic, xylano-cellulolytic, pectino-cellulolytic, and xylano-pectino-cellulolytic potential were obtained. The probability of getting the desired combination was low, so efforts were made to further improve this cost effective methodology for obtaining the high yield of the microbes capable of producing desired combination of enzymes. By inclusion of multiple enrichment steps in sequence, using only practically low cost substrates and without any nutrient media till primary screening stage, this improved novel protocol for screening gave only the desired microorganisms with xylano-pectino-cellulolytic activity. Using this rapid, efficient, cost effective, and improved methodology, microbes with required combination of enzymes can be obtained and the probability of getting the desired microorganisms is cent percent. This is the first report presenting the methodology for the isolation of xylano-pectino-cellulolytic positive microorganisms at low cost and consuming less time. PMID- 25692035 TI - Nonselective mevalonate kinase inhibitor as a novel class of antibacterial agents. AB - Introduction. There are a few evidences about targeting isoprenoids biosynthesis pathway in bacteria for finding new antibiotics. This study was conducted to assess antibacterial effects of vanadyl sulfate (VS), one of the mevalonate kinase inhibitors to find a new target for killing bacteria. Materials and Methods. Antibacterial effect of VS alone and in combination with glycine or EDTA was assessed on Escherichia coli and Pseudomonas aeruginosa as Gram-negative and Staphylococcus aureus and Enterococcus faecalis as Gram-positive bacteria using serial dilution method and minimum inhibitory concentrations (MICs) identified. Result. MICs for S. aureus and E. coli were 4 and 8 mg/mL, respectively. VS could not affect the growth of two other bacteria. However, VS in combination with glycine not only inhibited the growth of E. faecalis and P. aeruginosa, but also reduced MICs for VS-sensitive bacteria (S. aureus and E. coli). EDTA could reduce MIC for E. coli and P. aeruginosa. Conclusion. VS could inhibit the growth of S. aurous and E. coli, and adding glycine or EDTA improved VS antibacterial activity presumably via instability of the cell wall and enhanced transport of VS through bacterial cell wall. Inhibition of the isoprenoid pathway might provide new tools to overcome bacterial resistance. PMID- 25692036 TI - Interleukin-16 gene polymorphisms are considerable host genetic factors for patients' susceptibility to chronic hepatitis B infection. AB - Host genetic background is known as an important factor in patients' susceptibility to infectious diseases such as viral hepatitis. The aim of this study was to determine the effect of genetic polymorphisms of interleukin-16 (IL 16) cytokine on susceptibility of hepatitis B virus (HBV) infected patients to develop chronic HBV infection. Genotyping was conducted using PCR followed by enzymatic digestion and RFLP (restriction fragment length polymorphism) analysis. We genotyped three single nucleotide polymorphisms (SNPs) in the Il-16 gene (rs11556218 T>G, rs4778889 T>C, and rs4072111 C>T) to test for relationship between variation at these loci and patients' susceptibility to chronic HBV infection. Allele frequency of Il-16 gene rs4072111 and rs11556218 was significantly different between chronic HBV patients and healthy blood donors. Genotype frequency of rs4778889 polymorphism of Il-16 gene was significantly different when chronic HBV patients and HBV clearance subjects were compared. Our results showed that Il-16 gene polymorphisms are considerable host genetic factors when we chase biomarkers for prognosis of HBV infected patients. PMID- 25692037 TI - Minimising unnecessary mastectomies in a predominantly Chinese community. AB - BACKGROUND: Recent data shows that the use of breast conservation treatment (BCT) for breast cancer may result in superior outcomes when compared with mastectomy. However, reported rates of BCT in predominantly Chinese populations are significantly lower than those reported in Western countries. Low BCT rates may now be a concern as they may translate into suboptimal outcomes. A study was undertaken to evaluate BCT rates in a cohort of predominantly Chinese women. METHODS: All patients who underwent surgery on the breast at the authors' healthcare facility between October 2008 and December 2011 were included in the study and outcomes of treatment were evaluated. RESULTS: A total of 171 patients were analysed. Two-thirds of the patients were of Chinese ethnicity. One hundred and fifty-six (85.9%) underwent BCT. Ninety-eight of 114 Chinese women (86%) underwent BCT. There was no difference in the proportion of women undergoing BCT based on ethnicity. After a median of 49 months of follow-up, three patients (1.8%) had local recurrence and 5 patients (2.9%) suffered distant metastasis. Four patients (2.3%) have died from their disease. CONCLUSION: BCT rates exceeding 80% in a predominantly Chinese population are possible with acceptable local and distant control rates, thereby minimising unnecessary mastectomies. PMID- 25692038 TI - Contralateral risk-reducing mastectomy: review of risk factors and risk-reducing strategies. AB - Rates of contralateral risk-reducing mastectomy have increased substantially over the last decade. Surgical oncologists are often in the frontline, dealing with requests for this procedure. This paper reviews the current evidence base regarding contralateral breast cancer, assesses the various risk-reducing strategies, and evaluates the cost-effectiveness of contralateral risk-reducing mastectomy. PMID- 25692039 TI - Role clarification processes for better integration of nurse practitioners into primary healthcare teams: a multiple-case study. AB - Role clarity is a crucial issue for effective interprofessional collaboration. Poorly defined roles can become a source of conflict in clinical teams and reduce the effectiveness of care and services delivered to the population. Our objective in this paper is to outline processes for clarifying professional roles when a new role is introduced into clinical teams, that of the primary healthcare nurse practitioner (PHCNP). To support our empirical analysis we used the Canadian National Interprofessional Competency Framework, which defines the essential components for role clarification among professionals. A qualitative multiple case study was conducted on six cases in which the PHCNP role was introduced into primary care teams. Data collection included 34 semistructured interviews with key informants involved in the implementation of the PHCNP role. Our results revealed that the best performing primary care teams were those that used a variety of organizational and individual strategies to carry out role clarification processes. From this study, we conclude that role clarification is both an organizational process to be developed and a competency that each member of the primary care team must mobilize to ensure effective interprofessional collaboration. PMID- 25692040 TI - In situ thrombosis of small pulmonary arteries in pulmonary hypertension developing after chemotherapy for malignancy. AB - A few reports have provided histopathological insight into pulmonary hypertension developing after antitumor chemotherapy. In general, plexogenic pulmonary arteriopathy is a commonly observed finding in patients with severe pulmonary hypertension. We herein report a novel pathological finding that may characterize the histopathological change occurring in patients with pulmonary hypertension after chemotherapy for malignancy. Lung biopsy or autopsy was performed in 7 patients with pulmonary hypertension that developed during or after chemotherapy between 2006 and 2013 to examine the pulmonary vascular changes or to determine the cause of death. Pathological findings included in situ thrombosis in the small pulmonary arteries in 4 of 7 patients. In 2 of 4 patients, pulmonary hypertension was controlled by anticoagulants and antithrombotic agents. One patient who had organized thrombi attained spontaneous remission with oxygen therapy. The other patient died of sudden cardiopulmonary arrest during chemotherapy. Autopsy showed complete occlusion of the peripheral small pulmonary arteries and veins by thrombi. These results demonstrate that in situ thrombosis in the small pulmonary arteries could cause pulmonary hypertension after chemotherapy. PMID- 25692041 TI - Chemical characteristics, synthetic methods, and biological potential of quinazoline and quinazolinone derivatives. AB - The heterocyclic fused rings quinazoline and quinazolinone have drawn a huge consideration owing to their expanded applications in the field of pharmaceutical chemistry. Quinazoline and quinazolinone are reported for their diversified biological activities and compounds with different substitutions bring together to knowledge of a target with understanding of the molecule types that might interact with the target receptors. Quinazolines and quinazolinones are considered as an important chemical for the synthesis of various physiological significance and pharmacological utilized molecules. Quinazolines and quinazolinone are a large class of biologically active compounds that exhibited broad spectrum of biological activities such as anti-HIV, anticancer, antifungal, antibacterial, antimutagenic, anticoccidial, anticonvulsant, anti-inflammatory, antidepressant, antimalarial, antioxidant, antileukemic, and antileishmanial activities and other activities. Being considered as advantaged scaffold, the alteration is made with different substituent. PMID- 25692042 TI - The Relationship between Intramuscular Adipose Tissue, Functional Mobility, and Strength in Postmenopausal Women with and without Type 2 Diabetes. AB - Objectives. To determine (1) whether intramuscular adipose tissue (IntraMAT) differs between women with and without type 2 diabetes and (2) the association between IntraMAT and mobility and strength. Methods. 59 women >= 65 years with and without type 2 diabetes were included. A 1-Tesla MRI was used to acquire images of the leg. Timed-up-and-go (TUG) and grip strength were measured. Regression was used to determine associations between the following: (1) type 2 diabetes and IntraMAT (covariates: age, ethnicity, BMI, waist : hip ratio, and energy expenditure), (2) IntraMAT and TUG (covariates: diabetes, age, BMI, and energy expenditure), and (3) IntraMAT and grip strength (covariates: diabetes, age, height, and lean mass). Results. Women with diabetes had more IntraMAT. After adjustment, IntraMAT was similar between groups (diabetes mean [SD] = 13.2 [1.4]%, controls 11.8 [1.3]%, P = 0.515). IntraMAT was related to TUG and grip strength, but the relationships became nonsignificant after adjustment for covariates (difference/percent IntraMAT [95% CI]: TUG = 0.041 seconds [-0.079 0.161], P = 0.498, grip strength = -0.144 kg [-0.335-0.066], P = 0.175). Conclusions. IntraMAT alone may not be a clinically important predictor of functional mobility and strength; however, whether losses in functional mobility and strength are promoted by IntraMAT accumulation should be explored. PMID- 25692043 TI - Mystery of hepatitis e virus: recent advances in its diagnosis and management. AB - Mysterious aspects of the long presumed to be well-known hepatitis E virus (HEV) have recently surfaced that distinguish it from other hepatotropic viruses. It is a cause of chronic hepatitis in immunosuppressed patients. It has human to human transmission through blood and mantains high seroprevalence in blood donors. HEV has also been found to occur more frequently in the West in those without a history of travel to endemic countries. It has varied extrahepatic manifestations and has multiple non-human reservoirs including pigs and rats. Considering these recent discoveries, it appears odd that HEV is not sought more frequently when working up acute and chronic hepatitis patients. The disease is particularly severe among pregnant women and has a high attack rate in young adults. What adds to its ambiguity is the absence of a well-established diagnostic criteria for its detection and that there is no specific antiviral drug for hepatitis E, except for isolated cases where ribavirin or pegylated interferon alpha has been used with occasional success. This review paper discusses the recent advances in the knowledge of the virus itself, its epidemiology, diagnostic approach and prevention, and the treatment options available. PMID- 25692044 TI - Radiofrequency Ablation of Typical Atrial Flutter via Right Jugular Vein due to Bilateral Obstructed Iliac Veins in a Patient with Dilated Cardiomyopathy. AB - Ablation of cavotricuspid isthmus (CTI) is the gold standard method in the treatment of isthmus dependent atrial flutter (AFl). Venous access was obtained usually via right or left femoral veins. In rare cases of obstruction of iliofemoral veins, ablation of CTI can be performed only through the superior approach. We present a 74-year-old woman of typical AFl and dilated cardiomyopathy that was ablated through the right jugular vein because of obstruction of the left and the right iliac veins. This is the first report of successful ablation of CTI in a patient with dilated cardiomyopathy via superior approach. PMID- 25692045 TI - Impella induced massive hemolysis: reemphasizing echocardiographic guidance for correct placement. AB - The Impella LP 2.5 (Abiomed, Danvers, MA) has been a tool of use for high risk coronary procedures and for cardiogenic shock. As with any invasive or intracardiac device, improper placement can result in disastrous complications. Hemolytic anemia secondary to Impella implantation is one of the documented complications. However, cases of severe hemolytic anemia are rare in the literature. Proven imaging modalities like ultrasound need to be used to guide proper placement. We present a case of device induced severe hemolysis due to Impella insertion and the need to use ultrasound guidance to avoid such an unnecessary complication. PMID- 25692046 TI - Aspiration thrombectomy in a patient with suprarenal inferior vena cava thrombosis. AB - DVT has rarely been observed in the inferior vena cava (IVC). Pulmonary embolism (PE), which can be life-threatening, often occurred in patients with IVC thrombosis. Therefore, an IVC filter is frequently used in those patients for the prevention of PE. A case of successful endovascular treatment of an IVC thrombus in a patient with relative contraindications to implantation of an IVC filter is presented. This case report shows that aspiration of thrombi caught in the removable IVC filter may be an alternative to surgery in high-risk patients with catheter-related suprarenal inferior vena cava thrombosis. PMID- 25692047 TI - Staphylococcal toxic shock syndrome caused by tampon use. AB - The authors report a case of near-fatal sepsis with multiorgan failure resulting from a Staphylococcal tampon-associated toxic shock syndrome, requiring a lengthy critical care admission. Successful treatment of this condition focuses on early identification, source control, and administration of antimicrobial agents. Intravenous immunoglobulin therapy used early may prevent widespread tissue necrosis. PMID- 25692048 TI - Untypical amlodipine-induced gingival hyperplasia. AB - Amlodipine is a third generation dihydropyridine calcium channel blocker that is frequently used in therapy of hypertension. Among many side effects, amlodipine has been found associated with gingival overgrowth (GO) which usually occurs within the first three months of starting therapy at a dose of 10 mg/day. However, there are very few reports on amlodipine-induced gingival overgrowth (AIGO) at a lower dose (5 mg/day) and only after short term administration. A 64 year-old male patient with hypertension, who received amlodipine (5 mg/day) for four years, sought medical attention at the Department of Periodontology and Oral Medicine, Institute of Dentistry, Banja Luka, Bosnia and Herzegovina. The patient complained of masticatory problems due to extensive maxillary GO along with pain, bleeding, and foul odor. The clinical and the histological evidences were consistent with AIGO. The first line treatment consisted of the amlodipine substitution (amlodipine was replaced with enalapril, 5 mg/day) and the scaling and root planning/SRP. At one-month follow-up, drug replacement and SRP resulted in some reduction of the inflammation and significant reduction of symptoms. Further, gingivectomy/gingivoplasty helped overcome the effect of these drugs. The possibility of AIGO should be considered for a lower dose, as well as a late presentation. PMID- 25692049 TI - Profound hypoglycemia with ecstasy intoxication. AB - Background. 3,4-Methylenedioxymethamphetamine (MDMA) or ecstasy is a synthetic drug that is commonly abused for its stimulant and euphoric effects. Adverse MDMA effects include hyperthermia, psychomotor agitation, hemodynamic compromise, renal failure, hyponatremia, and coma. However, endogenous hyperinsulinemia with severe persistent hypoglycemia has not been reported with MDMA use. Case Report. We report the case of a 29-year-old woman who remained severely hypoglycemic requiring continuous intravenous infusion of high-dose dextrose solutions for more than 24 hours after MDMA intoxication. Serum insulin and C-peptide levels confirmed marked endogenous hyperinsulinemia as the cause of the severe hypoglycemia. Why Should an Emergency Physician Be Aware of This? Immediate and frequent monitoring of blood glucose should be instituted in patients presenting with MDMA ingestion particularly if found to be initially hypoglycemic. Early recognition can help prevent the deleterious effects of untreated hypoglycemia that can add to the morbidity from MDMA use. Clinicians need to be aware of this side effect of MDMA so they can carefully monitor and treat it, especially in patients presenting with altered mental status. PMID- 25692050 TI - Central giant cell granuloma of posterior maxilla: first expression of primary hyperparathyroidism. AB - A case of 19-year-old male patient reported with the chief complaint of slowly growing diffuse painless swelling over the right part of the face from last 6 months. Intraoral examination revealed a swelling on right side of palate in relation to molar region with buccal cortical plate expansion. Radiographic examination (orthopantograph and 3DCT) showed large multilocular radiolucency in right maxilla with generalized loss of lamina dura. Incisional biopsy was done and specimen was sent for histopathological examination which showed multinucleated giant cells containing 15-30 nuclei. Based on clinical, radiological, and histopathological findings provisional diagnosis of central giant cell granuloma was made. Blood tests after histopathology demonstrated elevated serum calcium level and alkaline phosphatase level. Immunoassay of parathyroid hormone (PTH) level was found to be highly elevated. Radiographic examination of long bones like humerus and femur, mandible, and skull was also done which showed osteoclastic lesions. Considering the clinical, radiographic, histopathological, and blood investigation findings, final diagnosis of brown tumour of maxilla was made. The patient underwent partial parathyroidectomy under general anaesthesia to control primary hyperparathyroidism. Surgical removal of the bony lesion was done by curettage. The patient has been followed up for 1 year with no postoperative complications and the lesion healed uneventfully. PMID- 25692051 TI - Magnetic resonance enterography: the test of choice in diagnosing intestinal "zebras". AB - Small bowel tumors and other rare intestinal disorders are often exceedingly difficult to identify. Even cutting-edge technologies, such as push enteroscopy and capsule endoscopy, can fail to determine the cause of a patient's symptoms. At our institution magnetic resonance enterography (MRE) has become an increasingly reliable tool in the difficult-to-diagnose or difficult-to-monitor patient. In this retrospective case series, we discuss four patients with four rare intestinal disorders that were successfully diagnosed using MRE after failing to be diagnosed using more routine technologies, such as CT scans and flexible sigmoidoscopies. With the discussion of these four cases we demonstrate that MRE is a useful diagnostic modality in patients whose surveillance is difficult or to diagnose rare colorectal disease phenomena, colloquially referred to as "zebras." PMID- 25692052 TI - High-Risk Microgranular Acute Promyelocytic Leukemia with a Five-Way Complex Translocation Involving PML-RARA. AB - Acute promyelocytic leukemia (APL) is classically characterized by chromosomal translocation (15;17), resulting in the PML-RARA fusion protein leading to disease. Here, we present a case of a 50-year-old man who presented with signs and symptoms of acute leukemia with concern for APL. Therapy was immediately initiated with all-trans retinoic acid. The morphology of his leukemic blasts was consistent with the hypogranular variant of APL. Subsequent FISH and cytogenetic analysis revealed a unique translocation involving five chromosomal regions: 9q34, 17q21, 15q24, 12q13, and 15q26.1. Molecular testing demonstrated PML/RARA fusion transcripts. Treatment with conventional chemotherapy was added and he went into a complete remission. Given his elevated white blood cell count at presentation, intrathecal chemotherapy for central nervous system prophylaxis was also given. The patient remains on maintenance therapy and remains in remission. This is the first such report of a 5-way chromosomal translocation leading to APL. Similar to APL with chromosomal translocations other than classical t(15;17) which result in the typical PML-RARA fusion, our patient responded promptly to an ATRA-containing regimen and remains in complete remission. PMID- 25692053 TI - Successful Allogeneic Hematopoietic Stem Cell Transplantation of a Patient Suffering from Type II Congenital Dyserythropoietic Anemia A Rare Case Report from Western India. AB - The most frequent form of congenital dyserythropoiesis (CDA) is congenital dyserythropoietic anemia II (CDA II). CDA II is a rare genetic anemia in humans, inherited in an autosomally recessive mode, characterized by hepatosplenomegaly normocytic anemia and hemolytic jaundice. Patients are usually transfusion independent except in severe type. We are here reporting a case of severe transfusion-dependent type II congenital dyserythropoietic anemia in a 5-year-old patient who has undergone allogeneic hematopoietic stem cell transplantation (HSCT) at our bone marrow transplantation centre. Patient has had up until now more than 14 mL/kg/month of packed cell volume (PCV), which he required every 15 to 20 days to maintain his hemoglobin of 10 gm/dL and hematocrit of 30%. His pre HSCT serum ferritin was 1500 ng/mL and he was on iron chelating therapy. Donor was HLA identical sibling (younger brother). The preparative regimen used was busulfan, cyclophosphamide, and antithymocyte globulin (Thymoglobulin). Cyclosporine and short-term methotrexate were used for graft versus host disease (GVHD) prophylaxis. Engraftment of donor cells was quick and the posttransplant course was uneventful. The patient is presently alive and doing well and he has been transfusion-independent for the past 33 months after HSCT. PMID- 25692054 TI - Clostridium paraputrificum Bacteremia Associated with Colonic Necrosis in a Patient with AIDS. AB - Clostridium species are anaerobic Gram-positive rods that can cause a broad range of invasive infections in humans, including myonecrosis and bacteremia. Importantly, clostridial bacteremia is frequently associated with underlying medical conditions, such as colonic malignancy. Characterizing Clostridium spp. and understanding their associated clinical disease spectrum are paramount to provide optimal treatment, thereby decreasing morbidity and mortality especially in those with underlying debilitating comorbidities. Clostridium paraputrificum is an infrequently isolated Clostridium species and its clinical significance has not been well described. We herein report a case of bacteremia due to C. paraputrificum in a 65-year-old man with AIDS who developed acute colonic necrosis complicated by septic shock. We then review other cases of bacteremia associated with C. paraputrificum in the literature in addition to discussing the clinical significance of anaerobic bacteremia in general. To our knowledge, our report is the second case of C. paraputrificum bacteremia in a patient with AIDS. PMID- 25692055 TI - Pasteurella multocida Septicemia in a Patient with Cirrhosis: An Autopsy Report. AB - More people are keeping pets in their homes but may not be sufficiently aware of the potential danger from infections. We report an autopsy case of a 57-year-old man affected by cirrhosis. Septic shock with Pasteurella multocida pneumonia was the cause of his death. P. multocida was the source of infection via the respiratory tract and caused pneumonia. Cirrhosis is one of the risk factors for P. multocida infection. A detailed patient history about animal exposure should be obtained and a differential diagnosis of P. multocida infection must be kept in mind. PMID- 25692056 TI - Lemierre's Syndrome: Recognising a Typical Presentation of a Rare Condition. AB - Lemierre's syndrome is a rare complication following an acute oropharyngeal infection. The aetiological agent is typically anaerobic bacteria of the genus Fusobacterium. The syndrome is characterised by a primary oropharyngeal infection followed by metastatic spread and suppurative thrombophlebitis of the internal jugular vein. If left untreated, Lemierre's syndrome carries a mortality rate of over 90%. Whilst relatively common in the preantibiotic era, the number of cases of Lemierre's syndrome subsequently declined with the introduction of antibiotics. With the increase of antibiotic resistance and a greater reluctance to prescribe antibiotics for minor conditions such as tonsillitis, there are now concerns developing about the reemergence of the condition. This increasing prevalence in the face of an unfamiliarity of clinicians with the classical features of this "forgotten disease" may result in the misdiagnosis or delay in diagnosis of this potentially fatal illness. This case report illustrates the delay in diagnosis of probable Lemierre's syndrome in a 17-year-old female, its diagnosis, and successful treatment which included the use of anticoagulation therapy. Whilst there was a positive outcome, the case highlights the need for a suspicion of this rare condition when presented with distinctive signs and symptoms. PMID- 25692057 TI - Syringomyelia with Chiari I malformation presenting as hip charcot arthropathy: a case report and literature review. AB - Neuroarthropathy (neuropathic osteoarthropathy), also known as Charcot joint, is a condition characterized by a progressive articular surface destruction in the setting of impaired nociceptive and proprioceptive innervation of the involved joint. It is seen most commonly in the foot and ankle secondary to peripheral neuropathy associated with diabetes mellitus. Cases of hip (Charcot) neuroarthropathy are rare and almost exclusively reported in patients with neurosyphilis (tabes dorsalis). We report a case of a 36-year-old man who presented to the emergency department complaining of right hip pain. On physical examination, pain and thermal sensory deficits were noted in the upper torso with a cape-like distribution, as well as signs of an upper motor neuron lesion in the left upper and lower extremities. A magnetic resonance imaging study (MRI) of the right hip showed evidence of early articular surface destruction and periarticular edema consistent with hip Charcot arthropathy. An MRI of the spine revealed an Arnold-Chiari type I malformation with extensive syringohydromyelia of the cervical and thoracic spine. PMID- 25692058 TI - Angiosarcoma arising in a patient with a 10-year-old hemangioma. AB - The transformation of a benign hemangioma into a malignant angiosarcoma has been rarely reported, with only 11 cases reported in the literature. There have been no reports of malignant transformation of hemangioma into angiosarcoma in association with epithelioid hemangioendothelioma, to our knowledge. The existence of precursor malignancies in the tumorigenesis of sarcomas is still not clearly defined. We describe the case of a 40-year-old woman with a preceding history of a suspected hemangioma for ten years, who upon resection was found on histology to have evidence of a hemangioma with an associated area of epithelioid hemangioendothelioma as well as areas of overt high grade epithelioid angiosarcoma. These findings raise the possibility of the evolution of hemangioma to epithelioid hemangioendothelioma, and the latter to overt angiosarcoma. The patient was managed as having a high grade sarcoma with wide resection and radiation. She declined systemic adjuvant chemotherapy after a thorough discussion about the risks and benefits of chemotherapy, and she currently remains disease free one year after the surgery. PMID- 25692059 TI - Cryptococcus laurentii Diarrhea in a Neoplastic Patient. AB - We present a rare case of diarrhea and neutropenia caused by Cryptococcus laurentii (C. laurentii) infection in old patient with metastatic rectal cancer who underwent FOLFOX plus Cetuximab chemotherapy. C. laurentii is an extremely rare human pathogen. To the best of our knowledge, here, we report the first case of diarrhea and neutropenia caused by C. laurentii in a 74-year-old man with metastatic rectal cancer and hepatic metastases who underwent FOLFOX plus Cetuximab chemotherapy. PMID- 25692060 TI - Metastatic Extramammary Paget's Disease of Scrotum Responds Completely to Single Agent Trastuzumab in a Hemodialysis Patient: Case Report, Molecular Profiling and Brief Review of the Literature. AB - Extramammary Paget's disease (EMPD) is a rare cancer. Although EMPD is usually noninvasive and treated with local therapy, once metastatic the prognosis of EMPD is poor and treatment options are limited. We report a case of a complete response to single agent trastuzumab in a hemodialysis patient with metastatic Her2/neu overexpressed EMPD of the scrotum. Molecular profiling of his case as well as 12 other EMPD and 8 mammary Paget disease (MPD) cases was completed and revealed multiple biomarker aberrations. Overexpression of Her2 was frequently noted (30%-40%) in both EMPD and MPD patients and when present can be effectively treated with Her2 targeted agents. Trastuzumab therapy can be safely utilized in a hemodialysis patient. In addition, multiple protein overexpression and loss were seen in EMPD including PD-1, PD-L1, PTEN, and AR as well as PIK3CA mutation. These findings may lead to possible therapeutic interventions targeting these pathways in a disease with few effective treatment options. PMID- 25692061 TI - Nasal dermoplasty for recurrent polyps in a patient with churg-strauss syndrome. AB - Nasal dermoplasty for recurrent polyps (NDRP) is a new technique for the surgical treatment of this condition. Churg-Strauss syndrome is characterized by the presence of nasal polyps with a great tendency for relapse after surgical or pharmaceutical treatment. It is the first time that we use NDRP to treat nasal polyps in a patient with Churg-Strauss syndrome. The patient was a 33-year-old female suffering from Churg-Strauss syndrome having had multiple operations in the past for recurrent polyps. NDRP was performed on the left nostril only. The mucosa of the left nasal vault was replaced by a split-thickness skin graft (modified dermoplasty). On the right nostril, polyps were removed and the ostia of the paranasal sinuses were enlarged as in typical endoscopic sinus surgery. The skin graft had a successful take and eight months after the operation no polyps are detected on the left side while polyps have recurred on the right nasal cavity. Applying the technique to a single nostril has several advantages, namely, the reduction of the operational time and therefore the risks for the patient from a prolonged general anaesthetic and the ability to judge the efficacy of the technique on the same patient. PMID- 25692062 TI - Bilateral symmetrical herpes zoster in an immunocompetent 15-year-old adolescent boy. AB - Herpes zoster is uncommon in immunocompetent children. The bilateral symmetrical occurrence of herpes zoster lesions is extremely rare. We report a 15-year-old immunocompetent Chinese adolescent boy who developed bilateral symmetrical herpes zoster lesions. To our knowledge, the occurrence of bilateral symmetrical herpes zoster lesions in an immunocompetent individual has not been reported in the pediatric literature. PMID- 25692063 TI - A case of battery ingestion in a pediatric patient: what is its importance? AB - This is a case of a two-year-old boy who has been suffering from food regurgitation and frequent vomiting over the past seven months which were progressively worsening with time. He was initially diagnosed with gastroesophageal reflux disease and treated accordingly but responded only minimally. Investigations and interventional procedures including a chest X-ray showed a metallic round object in the upper esophagus consistent with a button battery which was removed via a thoracotomy after an esophagoscopy was not successful. This child would not have developed such serious complications and would not have required major surgery had the foreign body been identified and removed early on. PMID- 25692064 TI - Nonbacterial osteitis of the clavicle: longitudinal imaging series from initial diagnosis to clinical improvement. AB - Nonbacterial osteitis is a rare autoinflammatory disease. Often it is mistaken for a tumor or osteomyelitis. We present a case of a twelve-year-old girl referred to our hospital because of a lesion of the right clavicle. The differential diagnoses were sarcoma, osteitis, and Langerhans cell histiocytosis. After biopsy the diagnosis nonbacterial osteitis (NBO) was established. Treatment of choice is a nonsteroidal anti-inflammatory drug. This case report gives a complete follow-up of the disease, showing the pitfalls of the diagnosis. PMID- 25692065 TI - A new mutation in blau syndrome. AB - Blau syndrome is a rare, autosomal dominant, granulomatous autoinflammatory disease. The classic triad of the disease includes recurrent uveitis, granulomatous dermatitis, and symmetrical arthritis. Blau syndrome is related to mutations located at the 16q12.2-13 gene locus. To date, 11 NOD2 gene mutations causing Blau syndrome have been described. Here, we describe a 5-year-old male patient who presented with Blau syndrome associated with a novel sporadic gene mutation that has not been reported previously. PMID- 25692066 TI - Repeated Intra-Arterial Thrombectomy within 72 Hours in a Patient with a Clear Contraindication for Intravenous Thrombolysis. AB - Introduction. Treating patients with acute ischemic stroke, proximal arterial vessel occlusion, and absolute contraindication for administering intravenous recombinant tissue plasminogen activator (rtPA) poses a therapeutic challenge. Intra-arterial thrombectomy constitutes an alternative treatment option. Materials and Methods. We report a case of a 57-year-old patient with concomitant gastric adenocarcinoma, who received three intra-arterial thrombectomies in 72 hours due to repeated occlusion of the left medial cerebral artery (MCA). Findings. Intra-arterial recanalization of the left medial cerebral artery was performed three times with initially good success. However, two days later, the right medial cerebral artery became occluded. Owing to the overall poor prognosis at that time and knowing the wishes of the patient, we decided not to perform another intra-arterial recanalization procedure. Conclusion. To our knowledge, this is the first case illustrating the use of repeated intra-arterial recanalization in early reocclusion of intracranial vessels. PMID- 25692067 TI - Injecting drug users and their health seeking behavior: a cross-sectional study in dhaka, bangladesh. AB - Introduction and Aim. Injecting drug users (IDUs) are amongst the most vulnerable people to acquisition of HIV/AIDS. This study aims to collect information on IDUs and their health seeking behavior in Bangladesh. Design and Methods. A cross sectional study was conducted among 120 IDUs attending a drug rehabilitation center in Dhaka, Bangladesh. Data were collected on sociodemographics, drug use, health seeking behavior, knowledge of injecting drugs, and sexual behavior. Results. The mean +/- SD and median (IQR) age of the participants were 32.5 +/- 21.3 and 33 (27-38) years, respectively, with only 9.2% females. Injection buprenorphine was the drug of choice for 40% of participants, and 58% of the participants first started drug use with smoking cannabis. 73.3% of participants shared needles sometimes and 57.5% were willing to use the needle exchange programs. 60% of the participants had no knowledge about the diseases spread by injection. Condom use during the last intercourse with regular partners was 11.7% and with any partners 15.8%. Conclusion. IDUs in Bangladesh are a high-risk group for HIV/AIDS due to lack of knowledge and risky behaviors. Education and interventions specifically aimed at IDUs are needed, because traditional education may not reach IDUs or influence their behavior. PMID- 25692068 TI - Functional activation and effective connectivity differences in adolescent marijuana users performing a simulated gambling task. AB - Background. Adolescent marijuana use is associated with structural and functional differences in forebrain regions while performing memory and attention tasks. In the present study, we investigated neural processing in adolescent marijuana users experiencing rewards and losses. Fourteen adolescents with frequent marijuana use (>5 uses per week) and 14 nonuser controls performed a computer task where they were required to guess the outcome of a simulated coin flip while undergoing magnetic resonance imaging. Results. Across all participants, "Wins" and "Losses" were associated with activations including cingulate, middle frontal, superior frontal, and inferior frontal gyri and declive activations. Relative to controls, users had greater activity in the middle and inferior frontal gyri, caudate, and claustrum during "Wins" and greater activity in the anterior and posterior cingulate, middle frontal gyrus, insula, claustrum, and declive during "Losses." Effective connectivity analyses revealed similar overall network interactions among these regions for users and controls during both "Wins" and "Losses." However, users and controls had significantly different causal interactions for 10 out of 28 individual paths during the "Losses" condition. Conclusions. Collectively, these results indicate adolescent marijuana users have enhanced neural responses to simulated monetary rewards and losses and relatively subtle differences in effective connectivity. PMID- 25692069 TI - Cytokines Modulate the "Immune-Metabolism" Interactions during Behcet Disease: Effect on Arginine Metabolism. AB - Aim and Methods. In this study, we evaluated NOS and arginase activities and their regulation during Behcet disease, a systemic chronic inflammatory disorder with uncertain etiology. The peripheral blood mononuclear cells of 36 patients and 15 control samples (PBMC) were cultured in either RPMI 1640, MEM, or DMEM complemented with 10% of FBS and antibiotics. Cultures were performed with or without the control or patients plasma. Subsequent treatment contained anticytokines (IL-6, TGF-beta), a mitogenic effector (PHA), or NOS modulators (L NMMA, BH4). Culture supernatants were harvested after 24 h of incubation. NO and urea measurements were, respectively, performed by modified Griess and Berthelot methods. Results. Higher urea levels were found in patients' plasma compared to the control's (P < 0.05). NOS modulators induced inverted production profiles for NO and urea (P < 0.05). Their results differed depending on the clinical findings (P < 0.05). It was also found that cytokine neutralization induced different response profiles in patients as opposed to control cultures (P < 0.05). Conclusion. Our results suggest that arginases can compete with NOS2 for L arginine during Behcet disease. Both enzymes are regulated by environmental cytokines and substrate availability. Furthermore, it seems that NOS/arginase balance is dependent on clinical expression. PMID- 25692070 TI - Levetiracetam Ameliorates L-DOPA-Induced Dyskinesia in Hemiparkinsonian Rats Inducing Critical Molecular Changes in the Striatum. AB - L-DOPA-induced dyskinesias (LID) remain a major problem of long-term therapy of Parkinson's disease. Levetiracetam, a new antiepileptic drug, has been shown to reduce LID, but the mechanisms underlying its effects are unknown. In this study, we assessed the effect of levetiracetam on key mediators of LID in rats with 6 hydroxydopamine (6-OHDA) lesions. Following chronic administration of L-DOPA (12 mg/kg, twice daily for 14 days), rats developed abnormal involuntary movements (AIMs), but co-administration of levetiracetam (15, 30, and 60 mg/kg) with equivalent L-DOPA dosing significantly reduced AIMs scores in a dose dependent manner. The effects of levetiracetam were associated with changes in striatal expression of DeltaFosB, phosphorylated extracellular signal-regulated kinases 1 and 2 (p-ERK1/2), and phosphorylated cAMP-regulated phosphoprotein of 32 kDa (p DARPP-32). These data support that levetiracetam acts at multiple sites in the pathogenetic cascade of LID, and that further understanding of these actions of antiepileptics may contribute to developing new LID therapies. PMID- 25692071 TI - Solid-phase extraction strategies to surmount body fluid sample complexity in high-throughput mass spectrometry-based proteomics. AB - For large-scale and standardized applications in mass spectrometry- (MS-) based proteomics automation of each step is essential. Here we present high-throughput sample preparation solutions for balancing the speed of current MS-acquisitions and the time needed for analytical workup of body fluids. The discussed workflows reduce body fluid sample complexity and apply for both bottom-up proteomics experiments and top-down protein characterization approaches. Various sample preparation methods that involve solid-phase extraction (SPE) including affinity enrichment strategies have been automated. Obtained peptide and protein fractions can be mass analyzed by direct infusion into an electrospray ionization (ESI) source or by means of matrix-assisted laser desorption ionization (MALDI) without further need of time-consuming liquid chromatography (LC) separations. PMID- 25692072 TI - General analytical procedure for determination of acidity parameters of weak acids and bases. AB - The paper presents a new convenient, inexpensive, and reagent-saving general methodology for the determination of pK a values for components of the mixture of diverse chemical classes weak organic acids and bases in water solution, without the need to separate individual analytes. The data obtained from simple pH-metric microtitrations are numerically processed into reliable pK a values for each component of the mixture. Excellent agreement has been obtained between the determined pK a values and the reference literature data for compounds studied. PMID- 25692073 TI - Regularities of Anthocyanins Retention in RP HPLC for "Water-Acetonitrile Phosphoric Acid" Mobile Phases. AB - The influence of exchange of HCOOH (System 2) by phosphoric acid (System 1) for acidification of the "acetonitrile-water" mobile phases for reversed-phase HPLC of anthocyanins was investigated in the framework of relative retention analysis. The differences and similarities of anthocyanins separation were revealed. It has been shown that some common features of the quantitative relationships may be used for preliminary anthocyanins structure differentiation, according to the number of OH-groups in anthocyanidin backbone as well as to a number of saccharide molecules in glycoside radicals in position 3 of the anthocyanin without MS detection. PMID- 25692074 TI - STRUCTURAL AND FUNCTIONAL CONSEQUENCES OF CIRCULAR PERMUTATION ON THE ACTIVE SITE OF OLD YELLOW ENZYME. AB - Circular permutation of the NADPH-dependent oxidoreductase Old Yellow Enzyme from Saccharomyces pastorianus (OYE1) can significantly enhance the enzyme's catalytic performance. Termini relocation into four regions of the protein (sectors I-IV) near the active site has proven effective in altering enzyme function. To better understand the structural consequences and rationalize the observed functional gains in these OYE1 variants, we selected representatives from sectors I-III for further characterization by biophysical methods and X-ray crystallography. These investigations not only show trends in enzyme stability and quaternary structure as a function of termini location, but also provide a possible explanation for the catalytic gains in our top-performing OYE variant (new N-terminus at residue 303; sector III). Crystallographic analysis indicates that termini relocation into sector III affects the loop beta6 region (amino acid positions: 290-310) of OYE1 which forms a lid over the active site. Peptide backbone cleavage greatly enhances local flexibility, effectively converting the loop into a tether and consequently increasing the environmental exposure of the active site. Interestingly, such active site remodeling does not negatively impact the enzyme's activity and stereoselectivity, nor does it perturb the conformation of other key active site residues with the exception of Y375. These observations were confirmed in truncation experiments, deleting all residues of the loop beta6 region in our OYE variant. Intrigued by the finding that circular permutation leaves most of the key catalytic residues unchanged, we also tested OYE permutants for possible additive or synergistic effects of amino acid substitutions. Distinct functional changes in these OYE variants were detected upon mutations at W116, known in native OYE1 to cause inversion of diastereo selectivity for (S)-carvone reduction. Our findings demonstrate the contribution of loop beta6 toward determining the stereoselectivity of OYE1, an important insight for future OYE engineering efforts. PMID- 25692075 TI - Dermatopathology: An abridged compendium of words. A discussion of them and opinions about them. Part 7 (M-O). PMID- 25692076 TI - Dermatoscopic imaging of skin lesions by high school students: a cross-sectional pilot study. AB - BACKGROUND: The ability of novices to perform imaging of skin lesions is not well studied. OBJECTIVES: To determine the ability of 12th grade high school students without formal training to take clinical and dermatoscopic images of skin lesions on patient-actors. PATIENTS/METHODS: Nineteen participants were divided into 11 gender-specific groups of 1-2 students. Groups were provided written instructions and assessed in their ability to (a) identify 8 pre-specified skin lesions, (b) take overview clinical images, and (c) take contact, polarized dermatoscopic images. Groups captured the same images twice using two different cameras [Nikon TM 1 J1 / VEOS HD1 and a VEOS DS3 (Canfield Scientific, Inc.)]. The sequence of camera use was determined using block randomization. If students made visibly poor skin contact during dermatoscopic imaging using their first camera, study investigators provided verbal instructions to place the second camera directly onto the skin. Students completed anonymous surveys before and after the imaging activity. RESULTS: Students were proficient at identifying the correct pre specified skin lesions (86/88, 98%), capturing sufficient quality overview clinical images of the back and legs (41/42, 98%), and taking dermatoscopic images of the entire skin lesion (174/176, 99%). Regarding dermatoscopic image quality, 116 of 175 (66%) images were in focus. Out of focus images were attributed to poor skin contact. Groups that received feedback (n=4) were able to obtain a significantly higher proportion of in focus dermatoscopic images using their second camera compared to their first camera (16% to 72%, P<0.001). CONCLUSIONS: We identified several barriers that exist for participant-acquired dermatoscopic imaging. Instructions emphasizing the importance of skin contact are useful. Our results may help guide future patient-acquired teledermatoscopy efforts. PMID- 25692077 TI - Melanoma in situ colonizing basal cell carcinoma: a case report and review of the literature. AB - Colonization of basal cell carcinoma (BCC) by melanoma cells is a unique and uncommonly reported cutaneous entity. We describe a bluish nodule on the left forearm found during routine skin cancer surveillance examination with suspicious dermatoscopic findings including central-blue-white veil, sparse atypical dots, and a surrounding pink vascular blush with focal irregular tan-brown pigmentation at the periphery. Histopathology demonstrated a pigmented BCC with an overlying and adjacent melanoma in situ (MIS), as well as colonization of the BCC nodule by melanoma cells. We performed a review of the literature on the topic and discuss other presentations of cutaneous neoplasms composed of both BCC and melanoma, including collision, combined, and biphenotypic tumors. The prognostic and management challenges inherent to this distinctive neoplasm are summarized. PMID- 25692078 TI - Granuloma annulare and necrobiosis lipoidica with sequential occurrence in a patient: report and review of literature. AB - Granuloma annulare (GA) and necrobiosis lipoidica (NL) are granulomatous diseases of undetermined etiology. Rarely, both dermatoses have been reported to occur concomitantly in patients. GA and NL are characterized histologically by areas of necrobiosis of collagen. The two diseases share some common characteristics, which may suggest that these dermatoses could occur as a spectrum in some patients or possibly share a similar pathogenesis. We report on a 67-year-old Caucasian woman with a history of NL on the anterior shins that later developed lesions of GA on the breasts, trunk, and wrist. We also review the literature and discuss the characteristics of patients with concomitant GA and NL. PMID- 25692079 TI - The mythical concept and untoward consequences of a diagnosis of dysplastic nevus: an overdue tribute to A. Bernard Ackerman, MD. PMID- 25692080 TI - Microcystic adnexal carcinoma of the cheek-a case report with dermatoscopy and dermatopathology. AB - We present a case report of a microcystic adnexal carcinoma on the cheek of a 67 year-old man. Clinical, dermatoscopic and dermatopathologic images are presented. A search of the literature has not discovered any previously published dermatoscopy images of microcystic adenexal carcinoma. PMID- 25692081 TI - Hypopigmented atypical Spitzoid neoplasms (atypical Spitz nevi, atypical Spitz tumors, Spitzoid melanoma): a clinicopathological update. PMID- 25692082 TI - Incidental Merkel cell carcinoma in a cutaneous horn: a case report. AB - Merkel cell carcinoma (MCC) is a rare cutaneous neuroendocrine malignancy, which usually presents as an asymptomatic, rapidly growing, firm nodule on sun-damaged skin. We present a 93-year-old female who presented with a "cutaneous horn" on the face. On excision, histologic examination revealed a combined squamous cell carcinoma in situ with underlying MCC. Merkel cell polyomavirus immunohistochemistry was negative in this lesion. This case report highlights the significant association between MCC and squamous cell carcinoma and the uncommon clinical presentation of this combined tumor in the form of a cutaneous horn. PMID- 25692083 TI - An itching plaque. PMID- 25692084 TI - Evolving clonal nevus-case report with serial digital dermatoscopy and dermatopathology. AB - We present a case of a clonal nevus arising from a previously banal melanocytic nevus over a 15-month period on the central back of a 30-year-old woman in a primary care skin cancer practice in Melbourne, Australia. Clinical, dermatoscopic and dermatopathologic images are presented. A search of the literature has discovered no previously published dermatoscopy images of an evolving clonal nevus. PMID- 25692085 TI - Dermoscopic clues to diagnose acantholytic dyskeratosis. PMID- 25692086 TI - Dermatoscopic findings of atrophic dermatofibrosarcoma protuberans. AB - Dermatofibrosarcoma protuberans (DFSP) is an uncommon locally aggressive mesenchymal tumor with a high local recurrence rate. Atrophic DFSP is a rare variant of DFSP characterized by a non-protuberant lesion. We report on a 23-year old female, who presented with an atrophic, asymptomatic macule on the right side of her back 2 cm in diameter. Dermatoscopic examination revealed homogenous pigment network on a purplish erythematous background. The histopathological finding of the incisional biopsy material was consistent with DFSP. To our knowledge, this is the second case of atrophic DFSP discussing the dermatoscopic features of this relatively rare condition. PMID- 25692087 TI - Reticular telangiectatic erythema: case report and literature review. AB - BACKGROUND: Reticular telangiectatic erythema is a benign cutaneous reaction that may occur in patients who have received a subcutaneous implantable cardioverter defibrillator. Reticular telangiectatic erythema is characterized by asymptomatic telangiectasias, blanchable erythematous patches, or both overlying and/or adjacent to the subcutaneous implantable cardioverter-defibrillator. PURPOSE: We describe a man who developed reticular telangiectatic erythema after receiving a subcutaneous implantable cardioverter-defibrillator and review the salient features of this condition. We also summarize the conditions that can mimic reticular telangiectatic erythema. MATERIALS AND METHODS: The features of a man with reticular telangiectatic erythema are presented and the literature on reticular telangiectatic erythema is reviewed. RESULTS: Our patient developed reticular telangiectatic erythema within one month of subcutaneous implantable cardioverter-defibrillator insertion. The subcutaneous manifestations were asymptomatic. The patient concurred to have periodic clinical follow up and his condition will be monitored for any changes. CONCLUSION: Reticular telangiectatic erythema is a benign condition characterized by the development of erythema, telangiectasia, or both following insertion of a subcutaneous implantable cardioverter-defibrillator. Other subcutaneous implantable cardioverter defibrillator-related side effects, such as pressure dermatitis and contact dermatitis, can mimic the condition. Reticular telangiectatic erythema can also be observed following insertion of other devices or, rarely, in the absence of inserted devices. Local microcirculatory changes and subcutaneous implantable cardioverter-defibrillator-related obstruction of blood flow have been suggested as possible mechanisms of pathogenesis. The diagnosis can usually be established by clinical presentation. Therefore, patch testing can usually be omitted. Reticular telangiectatic erythema is typically asymptomatic and thus removal of the device is not required. PMID- 25692088 TI - A pigmented lesion with yellow-white globular-like structures. PMID- 25692089 TI - What is your diagnosis? A solitary purple papule on the arm-Answer. PMID- 25692090 TI - Multiple painful brownish plaques associated with local hyperhidrosis. AB - Eccrine angiomatous hamartoma is a rare hamartomatous lesion characterized by proliferation of eccrine glands and small blood vessels, and occasionally other elements. It generally arises congenitally or later in childhood, as solitary or multiple lesions on the distal extremities. Adult-onset multiple lesions are very rare. Herein we describe a 33-year-old male with symptomatic multiple eccrine angiomatous hamartoma lesions. PMID- 25692091 TI - The importance of early diagnosis and treatment of kaposiform hemangioendothelioma complicated by Kasabach-Merritt phenomenon. AB - Kaposiform hemangioendothelioma (KHE) is a locally aggressive vascular tumor that may be complicated by Kasabach-Merritt phenomenon (KMP), a profound thrombocytopenia resulting from platelet trapping within a vascular tumor, either KHE or tufted angioma (TA). Typical features also include low fibrinogen and elevated D-dimers. It is well known that KMP is not caused by infantile hemangiomas. Management of vascular tumors complicated by KMP is challenging, and it is common for referral centers to receive patients in critical medical condition after multimodality treatment failure of vascular anomalies. Our aim is to communicate the importance of early diagnosis and treatment of KHE associated with KMP. A full-term male newborn with KHE complicated by KMP is reported. Treatment with vincristine, aspirin and ticlopidine normalized the coagulation parameters within one week, requiring a total of six doses of vincristine, seven months of ticlopidine and 17 months of aspirin. Early diagnosis and treatment of KHE complicated by KMP may allow the administration of fewer doses of vincristine and avoid the use of corticosteroids. PMID- 25692092 TI - Quantitative sensory and motor measures detect change overtime and correlate with walking speed in individuals with multiple sclerosis. AB - BACKGROUND: Impairments of sensation, strength, and walking are common in multiple sclerosis (MS). The relationship among these abnormalities and how they change over time remains unclear. OBJECTIVE: To determine the extent that quantitative lower extremity sensory and motor measures detect abnormalities over time, relate to global disability, and to walking speed in individuals with MS. METHODS: This prospective, longitudinal analysis evaluated 136 MS subjects. Measures included measures of leg strength, sensation, the Expanded Disability Status Scale(EDSS) and timed 25-foot walk test (T25FW). Mixed effects regression models were used. RESULTS: Our cohort's mean age is 44.3+/-10.8 years (mean+/ SD), EDSS score range 0-7.5, 66% were females, and follow-up time was 2.1+/-1.2 years. Strength significantly changed over time; the RRMS group demonstrated the greatest changes in ADF (3.3 lbs/yr) while the PPMS group showed significant HF changes (-2.1 lbs/yr). Walking speed was affected most by HF, especially in the weakest individuals (HF<20 lbs); T25FW increased by 0.20 s for each 1 lb loss (p=0.001). Likewise T25FW changed by 0.19 s for each 1 lb change in ADF (p<0.01). CONCLUSION: Quantitative measures detected changes in sensation and strength over time, despite a stable respective functional systems scores of the EDSS. Quantitative measurement tools may improve the sensitivity of disability measures in MS and further investigation of these tools as outcomes in future clinical trials of rehabilitative and neuroreparative interventions is warranted. PMID- 25692093 TI - Individual, social and environmental correlates of physical activity in overweight and obese African American and Hispanic women: A structural equation model analysis. AB - OBJECTIVE: Ecologic frameworks account for multilevel factors related to physical activity (PA) and may be used to develop effective interventions for women. The purpose of this study was to examine the influence of individual, social and environmental factors on PA among African American and Hispanic women using structural equation modeling. METHOD: Overweight and obese women (N=164, 65.9% African American) completed a 7-day accelerometer protocol, a physical assessment, and questionnaires on body image, self-efficacy, motivational readiness, social support, home environment for physical activity and perceived environment. Trained assessors evaluated each participant's neighborhood and collected objective measures of physical activity resources and the pedestrian environment. Assessments were completed between 2006 and 2008. RESULTS: Structural model fit was acceptable (RMSEA=.030). Body composition and image was negatively associated with PA, and motivational readiness had an indirect effect on PA through body composition and image. PA resources and the pedestrian environment operated through the perceived environment to positively influence neighborhood cohesion, which was positively associated with body composition and image. CONCLUSION: PA is more heavily influenced by intrapersonal factors related to weight. Improving intrapersonal factors related to weight and perceptions of the environment may lead to increased PA in African American and Hispanic women. PMID- 25692095 TI - Tagged MRI based cardiac motion modeling and toxicity evaluation in breast cancer radiotherapy. PMID- 25692094 TI - Impairments that influence physical function among survivors of childhood cancer. AB - Children treated for cancer are at increased risk of developing chronic health conditions, some of which may manifest during or soon after treatment while others emerge many years after therapy. These health problems may limit physical performance and functional capacity, interfering with participation in work, social, and recreational activities. In this review, we discuss treatment-induced impairments in the endocrine, musculoskeletal, neurological, and cardiopulmonary systems and their influence on mobility and physical function. We found that cranial radiation at a young age was associated with broad range of chronic conditions including obesity, short stature, low bone mineral density and neuromotor impairments. Anthracyclines and chest radiation are associated with both short and long-term cardiotoxicity. Although numerous chronic conditions are documented among individuals treated for childhood cancer, the impact of these conditions on mobility and function are not well characterized, with most studies limited to survivors of acute lymphoblastic leukemia and brain tumors. Moving forward, further research assessing the impact of chronic conditions on participation in work and social activities is required. Moreover, interventions to prevent or ameliorate the loss of physical function among children treated for cancer are likely to become an important area of survivorship research. PMID- 25692096 TI - Endoplasmic reticulum stress, genome damage, and cancer. AB - Endoplasmic reticulum (ER) stress has been linked to many diseases, including cancer. A large body of work has focused on the activation of the ER stress response in cancer cells to facilitate their survival and tumor growth; however, there are some studies suggesting that the ER stress response can also mitigate cancer progression. Despite these contradictions, it is clear that the ER stress response is closely associated with cancer biology. The ER stress response classically encompasses activation of three separate pathways, which are collectively categorized the unfolded protein response (UPR). The UPR has been extensively studied in various cancers and appears to confer a selective advantage to tumor cells to facilitate their enhanced growth and resistance to anti-cancer agents. It has also been shown that ER stress induces chromatin changes, which can also facilitate cell survival. Chromatin remodeling has been linked with many cancers through repression of tumor suppressor and apoptosis genes. Interplay between the classic UPR and genome damage repair mechanisms may have important implications in the transformation process of normal cells into cancer cells. PMID- 25692097 TI - Calreticulin as cancer treatment adjuvant: combination with photodynamic therapy and photodynamic therapy-generated vaccines. AB - Calreticulin is recognized as one of the pivotal damage-associated molecular pattern molecules alerting the host of the presence of distressed cells. In this role, calreticulin becomes exposed on the surface of tumor cells treated by several types of cancer therapy including photodynamic therapy (PDT). The goal of the present study was to examine the potential of externally added calreticulin for augmenting antitumor effect mediated by PDT. Recombinant calreticulin was found to bind to mouse SCCVII tumor cells treated by PDT. Compared to the outcome with PDT alone, cure rates of SCCVII tumors grown in immunocompetent C3H/HeN mice were elevated when calreticulin (0.4 mg/mouse) was injected peritumorally immediately after PDT. Such therapeutic gain with PDT plus calreticulin combination was not obtained with SCCVII tumors growing in immunodeficient NOD scid mice. In PDT-vaccine protocol, where PDT-treated SCCVII cells are used for vaccination of SCCVII tumor-bearing mice, adding recombinant calreticulin to cells before their injection produced improved therapeutic effect. The expression of calreticulin gene was reduced in PDT-treated cells, while no changes were observed with the expression of this gene in tumor, liver, and spleen tissues in PDT-vaccine-treated mice. These findings reveal that externally added recombinant calreticulin can boost antitumor response elicited by PDT or PDT-generated vaccines, and can thus serve as an effective adjuvant for cancer treatment with PDT and probably other cancer cell stress-inducing modalities. PMID- 25692098 TI - The treatment of metastatic non-small cell lung cancer in a new era of personalized medicine. PMID- 25692099 TI - Orientia tsutsugamushi ankyrin repeat-containing protein family members are Type 1 secretion system substrates that traffic to the host cell endoplasmic reticulum. AB - Scrub typhus is an understudied, potentially fatal infection that threatens one billion persons in the Asia-Pacific region. How the causative obligate intracellular bacterium, Orientia tsutsugamushi, facilitates its intracellular survival and pathogenesis is poorly understood. Many intracellular bacterial pathogens utilize the Type 1 (T1SS) or Type 4 secretion system (T4SS) to translocate ankyrin repeat-containing proteins (Anks) that traffic to distinct subcellular locations and modulate host cell processes. The O. tsutsugamushi genome encodes one of the largest known bacterial Ank repertoires plus T1SS and T4SS components. Whether these potential virulence factors are expressed during infection, how the Anks are potentially secreted, and to where they localize in the host cell are not known. We determined that O. tsutsugamushi transcriptionally expresses 20 unique ank genes as well as genes for both T1SS and T4SS during infection of mammalian host cells. Examination of the Anks' C termini revealed that the majority of them resemble T1SS substrates. Escherichia coli expressing a functional T1SS was able to secrete chimeric hemolysin proteins bearing the C-termini of 19 of 20 O. tsutsugamushi Anks in an HlyBD-dependent manner. Thus, O. tsutsugamushi Anks C-termini are T1SS-compatible. Conversely, Coxiella burnetii could not secrete heterologously expressed Anks in a T4SS dependent manner. Analysis of the subcellular distribution patterns of 20 ectopically expressed Anks revealed that, while 6 remained cytosolic or trafficked to the nucleus, 14 localized to, and in some cases, altered the morphology of the endoplasmic reticulum. This study identifies O. tsutsugamushi Anks as T1SS substrates and indicates that many display a tropism for the host cell secretory pathway. PMID- 25692100 TI - Commensal E. coli Stx2 lysogens produce high levels of phages after spontaneous prophage induction. AB - Enterohemorrhagic E. coli (EHEC) is a food-borne pathogen that causes disease ranging from uncomplicated diarrhea to life-threatening hemolytic uremic syndrome (HUS) and nervous system complications. Shiga toxin 2 (Stx2) is the major virulence factor of EHEC and is critical for development of HUS. The genes encoding Stx2 are carried by lambdoid bacteriophages and the toxin production is tightly linked to the production of phages during lytic cycle. It has previously been suggested that commensal E. coli could amplify the production of Stx2-phages and contribute to the severity of disease. In this study we examined the susceptibility of commensal E. coli strains to the Stx2-converting phage phi734, isolated from a highly virulent EHEC O103:H25 (NIPH-11060424). Among 38 commensal E. coli strains from healthy children below 5 years, 15 were lysogenized by the phi734 phage, whereas lytic infection was not observed. Three of the commensal E. coli phi734 lysogens were tested for stability, and appeared stable and retained the phage for at least 10 cultural passages. When induced to enter lytic cycle by H2O2 treatment, 8 out of 13 commensal lysogens produced more phi734 phages than NIPH-11060424. Strikingly, five of them even spontaneously (non-induced) produced higher levels of phage than the H2O2 induced NIPH-11060424. An especially high frequency of HUS (60%) was seen among children infected by NIPH-11060424 during the outbreak in 2006. Based on our findings, a high Stx2 production by commensal E. coli lysogens cannot be ruled out as a contributor to the high frequency of HUS during this outbreak. PMID- 25692101 TI - Small vessel disease: not a small problem. PMID- 25692102 TI - Lacunar infarction and small vessel disease: pathology and pathophysiology. AB - Two major vascular pathologies underlie brain damage in patients with disease of small size penetrating brain arteries and arterioles; 1) thickening of the arterial media and 2) obstruction of the origins of penetrating arteries by parent artery intimal plaques. The media of these small vessels may be thickened by fibrinoid deposition and hypertrophy of smooth muscle and other connective tissue elements that accompanies degenerative changes in patients with hypertension and or diabetes or can contain foreign deposits as in amyloid angiopathy and genetically mediated conditions such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. These pathological changes lead to 2 different pathophysiologies: 1) brain ischemia in regions supplied by the affected arteries. The resultant lesions are deep small infarcts, most often involving the basal ganglia, pons, thalami and cerebral white matter. And 2) leakage of fluid causing edema and later gliosis in white matter tracts. The changes in the media and adventitia effect metalloproteinases and other substances within the matrix of the vessels and lead to abnormal blood/brain barriers in these small vessels. and chronic gliosis and atrophy of cerebral white matter. PMID- 25692103 TI - Genetics of cerebral small vessel disease. AB - Cerebral small vessel disease (SVD) is an important cause of stroke and cognitive impairment among the elderly and is a more frequent cause of stroke in Asia than in the US or Europe. Although traditional risk factors such as hypertension or diabetes mellitus are important in the development of cerebral SVD, the exact pathogenesis is still uncertain. Both, twin and family history studies suggest heritability of sporadic cerebral SVD, while the candidate gene study and the genome-wide association study (GWAS) are mainly used in genetic research. Robust associations between the candidate genes and occurrence of various features of sporadic cerebral SVD, such as lacunar infarction, intracerebral hemorrhage, or white matter hyperintensities, have not yet been elucidated. GWAS, a relatively new technique, overcomes several shortcomings of previous genetic techniques, enabling the detection of several important genetic loci associated with cerebral SVD. In addition to the more common, sporadic cerebral SVD, several single-gene disorders causing cerebral SVD have been identified. The number of reported cases is increasing as the clinical features become clear and diagnostic examinations are more readily available. These include cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy, COL4A1-related cerebral SVD, autosomal dominant retinal vasculopathy with cerebral leukodystrophy, and Fabry disease. These rare single gene disorders are expected to play a crucial role in our understanding of cerebral SVD pathogenesis by providing animal models for the identification of cellular, molecular, and biochemical changes underlying cerebral small vessel damage. PMID- 25692104 TI - Cerebral amyloid angiopathy: emerging concepts. AB - Cerebral amyloid angiopathy (CAA) involves cerebrovascular amyloid deposition and is classified into several types according to the amyloid protein involved. Of these, sporadic amyloid beta-protein (Abeta)-type CAA is most commonly found in older individuals and in patients with Alzheimer's disease (AD). Cerebrovascular Abeta deposits accompany functional and pathological changes in cerebral blood vessels (CAA-associated vasculopathies). CAA-associated vasculopathies lead to development of hemorrhagic lesions [lobar intracerebral macrohemorrhage, cortical microhemorrhage, and cortical superficial siderosis (cSS)/focal convexity subarachnoid hemorrhage (SAH)], ischemic lesions (cortical infarction and ischemic changes of the white matter), and encephalopathies that include subacute leukoencephalopathy caused by CAA-associated inflammation/angiitis. Thus, CAA is related to dementia, stroke, and encephalopathies. Recent advances in diagnostic procedures, particularly neuroimaging, have enabled us to establish a clinical diagnosis of CAA without brain biopsies. Sensitive magnetic resonance imaging (MRI) methods, such as gradient-echo T2(*) imaging and susceptibility-weighted imaging, are useful for detecting cortical microhemorrhages and cSS. Amyloid imaging with amyloid-binding positron emission tomography (PET) ligands, such as Pittsburgh Compound B, can detect CAA, although they cannot discriminate vascular from parenchymal amyloid deposits. In addition, cerebrospinal fluid markers may be useful, including levels of Abeta40 for CAA and anti-Abeta antibody for CAA related inflammation. Moreover, cSS is closely associated with transient focal neurological episodes (TFNE). CAA-related inflammation/angiitis shares pathophysiology with amyloid-related imaging abnormalities (ARIA) induced by Abeta immunotherapies in AD patients. This article reviews CAA and CAA-related disorders with respect to their epidemiology, pathology, pathophysiology, clinical features, biomarkers, diagnosis, treatment, risk factors, and future perspectives. PMID- 25692105 TI - Cerebral small vessel disease and chronic kidney disease. AB - Chronic kidney disease, defined by a decreased glomerular filtration rate or albuminuria, is recognized as a major global health burden, mainly because it is an established risk factor for cardiovascular and cerebrovascular diseases. The magnitude of the effect of chronic kidney disease on incident stroke seems to be higher in persons of Asian ethnicity. Since the kidney and brain share unique susceptibilities to vascular injury due to similar anatomical and functional features of small artery diseases, kidney impairment can be predictive of the presence and severity of cerebral small vessel diseases. Chronic kidney disease has been reported to be associated with silent brain infarcts, cerebral white matter lesions, and cerebral microbleeds, independently of vascular risk factors. In addition, chronic kidney disease affects cognitive function, partly via the high prevalence of cerebral small vessel diseases. Retinal artery disease also has an independent relationship with chronic kidney disease and cognitive impairment. Stroke experts are no longer allowed to be ignorant of chronic kidney disease. Close liaison between neurologists and nephrologists can improve the management of cerebral small vessel diseases in kidney patients. PMID- 25692106 TI - Case characteristics, hyperacute treatment, and outcome information from the clinical research center for stroke-fifth division registry in South Korea. AB - Characteristics of stroke cases, acute stroke care, and outcomes after stroke differ according to geographical and cultural background. To provide epidemiological and clinical data on stroke care in South Korea, we analyzed a prospective multicenter clinical stroke registry, the Clinical Research Center for Stroke-Fifth Division (CRCS-5). Patients were 58% male with a mean age of 67.2+/-12.9 years and median National Institutes of Health Stroke Scale score of 3 [1-8] points. Over the 6 years of operation, temporal trends were documented including increasing utilization of recanalization treatment with shorter onset to-arrival delay and decremental length of stay. Acute recanalization treatment was performed in 12.7% of cases with endovascular treatment utilized in 36%, but the proportion of endovascular recanalization varied across centers. Door-to-IV alteplase delay had a median of 45 [33-68] min. The rate of symptomatic hemorrhagic transformation (HT) was 7%, and that of any HT was 27% among recanalization-treated cases. Early neurological deterioration occurred in 15% of cases and were associated with longer length of stay and poorer 3-month outcomes. The proportion of mRS scores of 0-1 was 42% on discharge, 50% at 3 months, and 55% at 1 year after the index stroke. Recurrent stroke up to 1 year occurred in 4.5% of patients; the rate was higher among older individuals and those with neurologically severe deficits. The above findings will be compared with other Asian and US registry data in this article. PMID- 25692107 TI - Elevated calcium after acute ischemic stroke: association with a poor short-term outcome and long-term mortality. AB - BACKGROUND AND PURPOSE: An elevated intracellular calcium level is known to be a major initiator and activator of ischemic cell death pathway; however, in recent studies, elevated serum calcium levels have been associated with better clinical outcomes and smaller cerebral infarct volumes. The pathophysiological role played by calcium in ischemic stroke is largely unknown. METHODS: Acute stroke patients from a prospective stroke registry, consecutively admitted during October 2002 September 2008, were included. Significant associations between the modified Rankin scale distribution at discharge and serum calcium or albumin-corrected calcium were identified using ordinal logistic regression analysis. Cox proportional hazard models were used for survival analysis. RESULTS: Mean serum calcium and albumin-corrected calcium levels of the 1,915 participants on admission were 8.97+/-0.58 mg/dL and 9.07+/-0.49 mg/dL, respectively. Second [adjusted odds ratio 1.32 (95% confidence interval 1.07-1.61)] and third [1.24 (1.01-1.53)] tertiles of serum calcium level and the third [1.24 (1.01-1.53)] tertile of albumin-corrected calcium level were found to be independent risk factors for a poor discharge outcome. Significant relationships were observed with serum calcium [1.19 (1.03-1.38)] and albumin-corrected calcium [1.21(1.01 1.44)] as linear variables. However, only albumin-corrected calcium was associated with long-term mortality, third tertile [adjusted hazard ratio 1.40 (1.07-1.83)], and increase by 1 mg/dL [1.46 (1.16-1.84)]. CONCLUSIONS: Elevated albumin-corrected serum calcium levels are associated with a poorer short-term outcome and greater risk of long-term mortality after acute ischemic stroke. PMID- 25692108 TI - White matter hyperintensity in ischemic stroke patients: it may regress over time. AB - BACKGROUND AND PURPOSE: White matter hyperintensities (WMH) are frequently observed on MRI in ischemic stroke patients as well as in normal elderly individuals. Besides the progression of WMH, the regression of WMH has been rarely reported. Thus, we aimed to investigate how WMH change over time in patients with ischemic stroke, particularly focusing on regression. METHODS: We enrolled ischemic stroke patients who underwent brain MRI more than twice with at least a 6 month time-interval. Based on T2-weighted or FLAIR MRI, WMH were visually assessed, followed by semiautomatic volume measurement. Progression or regression of WMH change was defined when 0.25 cc increase or decrease was observed and it was also combined with visible change. A statistical analysis was performed on the pattern of WMH change over time and factors associated with change. RESULTS: A total of 100 patients were enrolled. Their age (mean+/-SD) was 67.5+/-11.8 years and 63 were male. The imaging time-interval (mean) was 28.0 months. WMH progressed in 27, regressed in 9 and progressed in distinctive regions and regressed in others in 5 patients. A multiple logistic regression model showed that age (odds ratio[OR] 2.51, 90% confidence interval[CI] 1.056 5.958), male gender (OR 2.957, 95% CI 1.051-9.037), large vessel disease (OR 1.955, 95% CI 1.171-3.366), and renal dysfunction (OR 2.900, 90% CI 1.045-8.046) were associated with progression. Regarding regression, no significant factor was found in the multivariate analysis. CONCLUSIONS: In 21.5% of ischemic stroke patients, regression of WMH was observed. WMH progression was observed in a third of ischemic stroke patients. PMID- 25692109 TI - Cerebral arterial calcification is an imaging prognostic marker for revascularization treatment of acute middle cerebral arterial occlusion. AB - BACKGROUND AND PURPOSE: To study the significance of intracranial artery calcification as a prognostic marker for acute ischemic stroke patients undergoing revascularization treatment after middle cerebral artery (MCA) trunk occlusion. METHODS: Patients with acute MCA trunk occlusion, who underwent intravenous and/or intra-arterial revascularization treatment, were enrolled. Intracranial artery calcification scores were calculated by counting calcified intracranial arteries among major seven arteries on computed tomographic angiography. Patients were divided into high (HCB; score >=3) or low calcification burden (LCB; score <3) groups. Demographic, imaging, and outcome data were compared, and whether HCB is a prognostic factor was evaluated. Grave prognosis was defined as modified Rankin Scale 5-6 for this study. RESULTS: Of 80 enrolled patients, the HCB group comprised 15 patients, who were older, and more commonly had diabetes than patients in the LCB group. Initial National Institutes of Health Stroke Scale (NIHSS) scores did not differ (HCB 13.3+/-2.7 vs. LCB 14.6+/-3.8) between groups. The final good reperfusion after revascularization treatment (thrombolysis in cerebral infarction score 2b-3, HCB 66.7% vs. LCB 69.2%) was similarly achieved in both groups. However, the HCB group had significantly higher NIHSS scores at discharge (16.0+/-12.3 vs. 7.9+/-8.3), and more frequent grave outcome at 3 months (57.1% vs. 22.0%) than the LCB group. HCB was proven as an independent predictor for grave outcome at 3 months when several confounding factors were adjusted (odds ratio 4.135, 95% confidence interval, 1.045-16.359, P=0.043). CONCLUSIONS: Intracranial HCB was associated with grave prognosis in patients who have undergone revascularization for acute MCA trunk occlusion. PMID- 25692110 TI - Impacts of rapid recanalization and collateral circulation on clinical outcome after intraarterial thrombolysis. AB - BACKGROUND AND PURPOSE: Rapid recanalization might improve clinical outcomes after intraarterial thrombolysis (IAT) for acute ischemic stroke patients with collateral circulation. We determined whether rapid recanalization and collateral circulation affect clinical outcomes after IAT. METHODS: We retrospectively evaluated the clinical and radiological data of 134 consecutive patients who underwent IAT for intracranial artery occlusion. The interval from symptom onset to recanalization after IAT (onset-to-recanalization time) as an estimate of the probability of good clinical outcome (modified Rankin scale 0-2) was calculated in patients with collateral circulation in the ischemic hemisphere, which was rated poor (0/1 American Society of Interventional and Therapeutic Neuroradiology criteria) or good (2-4). Changes in National Institute of Health Stroke Scale (NHISS) score before and after IAT and modified Rankins scale scores 3 months after discharge were compared with respect to onset-to-recanalization time. RESULTS: In patients with good collateral circulation, the estimated onset-to recanalization time for a 0.5 probability of a good clinical outcome was 347 minutes; with poor collateral circulation, it was 172 minutes for a 0.2 probability of good clinical outcome. Outcome analyses according to onset-to recanalization time showed patients recanalized <6 hours had lower NHISS scores (<4.5, 4.5-6, >6 hours of onset-to-recanalization time, and non-recanalization: 5.1, 6.9, 11.9, and 19.8, respectively) at discharge and higher percentages of good clinical outcome (69%, 66.7%, 21.9%, and 0%, respectively) 3 months after IAT. CONCLUSIONS: The time window to expect a high probability of a good clinical outcome after IAT is highly dependent on the collateral circulation. PMID- 25692111 TI - Acute stroke with concomitant acute myocardial infarction: will you thrombolyse? PMID- 25692112 TI - In vivo Image of Cerebral Amyloid Angiopathy in an Alzheimer's Disease Mouse Model. PMID- 25692113 TI - Aortic stiffness in patients with deep and lobar intracerebral hemorrhage: role of antihypertensive drugs and statins. PMID- 25692114 TI - Response: aortic stiffness in patients with deep and lobar intracerebral hemorrhage: role of antihypertensive drugs and statins. PMID- 25692115 TI - Effects of combination therapy of docetaxel with selenium on the human breast cancer cell lines MDA-MB-231 and MCF-7. AB - PURPOSE: The anticancer property and cytoprotective role of selenium in chemotherapy have been reported. However, the combination effects of selenium on chemotherapy for advanced breast cancer have not yet been clearly defined. The purpose of this study was to investigate the combined effects of selenium on chemotherapy using docetaxel on breast cancer cell lines. METHODS: Under adherent culture conditions, two breast cancer cell lines, MDA-MB-231 and MCF-7, were treated with docetaxel at 500pM and selenium at 100nM, 1uM, or 10uM. Changes in cell growth, cell cycle duration, and degree of apoptosis after 72 hours in each treated group were evaluated. RESULTS: In the MDA-MB-231 cells, the combination therapy group (docetaxel at 500pM plus selenium at 10uM) showed a significantly decreased percentage of cell growth (15% vs. 28%; P = 0.004), a significantly increased percentage of late apoptosis (63% vs. 26%; P = 0.001), and an increased cell cycle arrest in the G2/M phase (P = 0.001) compared with the solitary docetaxel therapy group. Isobologram analysis demonstrated the synergistic effect of the combination therapy in the MDA-MB-231 cells. However, in the MCF-7 cells, no significant differences in the percentage of cell growth apoptosis, the percentage of apoptosis, and the pattern of cell cycle arrest were noted between the combination therapy groups and the solitary docetaxel therapy group. CONCLUSION: Our in vitro study indicated that the combination of selenium with docetaxel inhibits cell proliferation through apoptosis and cell arrest in the G2/M phase in MDA-MB-231 breast cancer cells. PMID- 25692116 TI - Predictive factors of central lymph node metastasis in papillary thyroid carcinoma. AB - PURPOSE: The aim of this study was to evaluate the correlation between central lymph node (CLN) metastasis and clinicopathologic characteristics of papillary thyroid cancer (PTC). In addition, we investigated the incidence and risk factors for contralateral CLN metastasis in unilateral PTC. This study suggests the appropriate surgical extent for CLN dissection. METHODS: A prospective study of 500 patients with PTC who underwent total thyroidectomy and prophylactic bilateral CLN dissection was conducted. RESULTS: Of 500 patients, 255 had CLN metastases. The rate of CLN metastasis was considerably higher in cases of younger patients (<45 years old) (P < 0.001; odds ratio [OR], 2.357) and of a maximal tumor size greater than 1 cm (P < 0.001; OR, 3.165). Ipsilateral CLN metastasis was detected in 83.1% of cases (133/160) of unilateral PTC, only contralateral CLN metastases in 3.7% of cases (6/160), and bilateral CLN metastases in 13.1% of cases (21/160). The rate of contralateral CLN metastasis was considerably higher in cases of PTC with a large tumor size (>=1 cm) (P = 0.019; OR, 4.440) and with ipsilateral CLN metastasis (P = 0.047; OR, 2.613). CONCLUSION: Younger age (<45 years old) and maximal tumor size greater than 1 cm were independent risk factors for CLN metastasis. Maximal tumor size greater than 1 cm and presence of ipsilateral CLN macrometastasis were independent risk factors for contralateral CLN metastasis. Therefore, both CLN dissections should be considered for unilateral PTC with a maximal tumor size greater than 1 cm or presence of ipsilateral CLN macrometastasis. PMID- 25692117 TI - A comparative analysis of endoscopic thyroidectomy versus conventional thyroidectomy in clinically lymph node negative thyroid cancer. AB - PURPOSE: Differentiated thyroid cancer has a good prognosis and high incidence in young women. Since endoscopic techniques were first recorded in 1996, surgical indications of endoscopic thyroidectomy have broadened. Therefore, the aim of this study is to investigate the usefulness of endoscopic thyroidectomy in clinically lymph node negative (cN0) thyroid cancer patients, based on oncologic completeness and safety, considering cosmetic outcomes. METHODS: From July 2009 to June 2011, a total of 166 cases had undergone endoscopic thyroidectomy using the BABA (bilateral axillo-breast approach) method or conventional open thyroidectomy by one surgeon. Finally, excluding 72 patients, 94 patients with cN0 thyroid cancer were divided into two groups according to operative methods and analyzed to compare differences between the two methods retrospectively (endoscopic group, n = 49; conventional open group, n = 45). RESULTS: We practiced comparative analysis for clinicopathologic characteristics, surgical outcomes including postoperative complications, and recurred cases during follow up periods of each group. The results showed there was a tendency for patients, young, women rather than men, and having small size of thyroid cancer, to prefer endoscopic surgery to open surgery. Meanwhile, in postoperative complications, there were no statistically significant differences. During short follow-up periods, no recurrence or mortality case was observed. CONCLUSION: Endoscopic thyroidectomy is a feasible and safe method for the treatment of clinically lymph node negative (cN0) thyroid cancer. PMID- 25692118 TI - Astrocyte elevated gene-1 overexpression in hepatocellular carcinoma: an independent prognostic factor. AB - PURPOSE: Astrocyte elevated gene-1 (AEG-1) plays important roles in tumorigenesis such as proliferation, invasion, metastasis, angiogenesis, and chemoresistance. We examined the expression of AEG-1 in patients with hepatocellular carcinoma (HCC). METHODS: Eighty-five samples were collected from patients with HCC who underwent surgery and were histopathologically confirmed to have HCC. Two independent pathologists, experienced in evaluating immunohistochemistry and blinded to the clinical outcomes of the patients, reviewed all samples. They determined AEG-1 expression semiquantitatively by assessing the percentage of positively stained immunoreactive cells and staining intensity. Clinicopathological data were analyzed in association with prognosis. RESULTS: The association was estimated by univariate and multivariate analyses with Cox regression. Tumor size (hazard ratio [HR], 2.285; 95% confidence interval [CI], 1.175-4.447; P = 0.015), microvascular invasion (HR, 6.754; 95% CI, 1.631-27.965; P = 0.008), and AEG-1 expression (HR, 4.756; 95% CI, 1.697-13.329; P = 0.003) were independent prognostic factors for overall survival. Those for disease-free survival rate were tumor size (HR, 2.245; 95% CI, 1.282-3.933; P = 0.005) and AEG 1 expression (HR, 1.916; 95% CI, 1.035-3.545; P = 0.038). The cumulative 5-year survival and recurrence rates were 89.2% and 50.0% in the low-expressing group and 24.5% and 82.4% in the high-expressing group, respectively. CONCLUSION: The results suggest that AEG-1 overexpression could serve as a valuable prognostic marker in patients with HCC. PMID- 25692119 TI - Can intravenous patient-controlled analgesia be omitted in patients undergoing laparoscopic surgery for colorectal cancer? AB - PURPOSE: Opioid-based intravenous patient-controlled analgesia (IV-PCA) is a popular method of postoperative analgesia, but many patients suffer from PCA related complications. We hypothesized that PCA was not essential in patients undergoing major abdominal surgery by minimal invasive approach. METHODS: Between February 2013 and August 2013, 297 patients undergoing laparoscopic surgery for colorectal cancer were included in this retrospective comparative study. The PCA group received conventional opioid-based PCA postoperatively, and the non-PCA group received intravenous anti-inflammatory drugs (Tramadol) as necessary. Patients reported their postoperative pain using a subjective visual analogue scale (VAS). The PCA-related adverse effects and frequency of rescue analgesia were evaluated, and the recovery rates were measured. RESULTS: Patients in the PCA group experienced less postoperative pain on days 4 and 5 after surgery than those in the non-PCA group (mean [SD] VAS: day 4, 6.2 [0.3] vs. 7.0 [0.3], P = 0.010; and day 5, 5.1 [0.2] vs. 5.5 [0.2], P = 0.030, respectively). Fewer patients in the non-PCA group required additional parenteral analgesia (41 of 93 patients vs. 53 of 75 patients, respectively), and none in the non-PCA group required rescue PCA postoperatively. The incidence of postoperative nausea and vomiting was significantly higher in the non-PCA group than in the PCA group (P < 0.001). The mean (range) length of hospital stay was shorter in the non-PCA group (7.9 [6-10] days vs. 8.7 [7-16] days, respectively, P = 0.03). CONCLUSION: Our Results suggest that IV-PCA may not be necessary in selected patients those who underwent minimal invasive surgery for colorectal cancer. PMID- 25692120 TI - Effect of IL-18 binding protein on hepatic ischemia-reperfusion injury induced by infrarenal aortic occlusion. AB - PURPOSE: Severe local and systemic tissue damage called ischemia/reperfusion (IR) injury occurs during the period of reperfusion. Free oxygen radicals and proinflammatory cytokines are responsible for reperfusion injury. IL-18 binding protein (IL-18BP) is a natural inhibitor of IL-18. The balance between IL-18 and IL-18BP has an important role in the inflammatory setting. The present study aimed to investigate whether IL-18BP had a protective role in remote organ hepatic IR injury. METHODS: Wistar-Albino rats were divided into three groups that contained seven rats. Group I (sham): Laparotomy and infrarenal abdominal aorta (AA) dissection were done but no clamping was done. Group II (I/R): The infrarenal AA was clamped by atraumatic microvascular clamp for 30 minutes and then was exposed to 90 minutes of reperfusion. Group III (IR + IL-18BP): 75 ug/kg of IL-18BP in 0.9% saline (1 mL) was administered 30 minutes before infrarenal AA dissection and clamping; 30 minutes of ischemia was applied and then was exposed to 90 minutes of reperfusion. RESULTS: Serum AST, ALT, and LDH levels were remarkably higher in IR group and returned to normal levels in treatment group. The proinflammatory cytokine levels had decreased in treatment group, and was statistically significant compared with the IR group. Serum levels of total oxidant status and oxidative stress index decreased and levels of total antioxidant status increased by IL-18BP. CONCLUSION: This study suggested that IL 18BP has antioxidant, anti-inflammatory and hepatoprotective effects in cases of IR with infrarenal AA induced liver oxidative damage. PMID- 25692121 TI - Effect of donor-specific antibodies and panel reactive antibodies in living donor liver transplant recipients. AB - PURPOSE: Preformed circulating donor-specific antibodies (DSAs) immunologically challenge vascular endothelium and the bile duct. However, the liver is an immune tolerant organ and can avoid immunological challenges. This study was undertaken to analyze the effects of DSAs after adult living donor liver transplantation (LDLT). METHODS: We retrospectively reviewed 219 LDLT patients' records treated at our center. RESULTS: Of the 219 patients, 32 (14.6%) were DSA (+) and 187 (85.4%) were DSA (-). Class I DSAs were present in 18 patients, class II in seven patients, and both in seven patients. Seven patients (3.2%) showed DSA to HLA-A, four (1.8%) to HLA-B, seven (3.2%) to HLA-DR, and 14 (6.4%) to two or more HLAs. More DSAs were observed in female recipients than male recipients in the DSA (+) group. The DSA (+) group showed significantly higher levels of class I and II panel reactive antibody (PRA) than did the DSA (-) group. No significant intergroup differences were found between incidences of primary nonfunction, acute rejection, vascular complication, or biliary complication. There were no significant differences in graft survival rates between the two groups. However, the recipients with multiple DSAs tended to have more acute rejection episodes and events of biliary stricture and lower graft survival rates than did patients in the DSA (-) group. CONCLUSION: In LDLT, the presence of multiple DSAs and high PRA seemed to be associated with poor graft outcomes, although our results did not reach statistical significance. Large cohort studies are necessary to clarify the impact of DSA and PRA in LDLT. PMID- 25692122 TI - Transfusion free radical antegrade modular pancreaticosplenectomy of metastatic neuroendocrine tumor of the pancreas in Jehovah's Witness patient. AB - In a popular sense, Jehovah's Witnesses (JW) have their creeds, one of which is refusal of blood transfusion. Such refusal may impinge on their proper management, especially in critical situations. We present a case of successful bloodless multimodality therapy, which was performed for a JW. The patient was a 49-year-old woman and JW who had general weakness 7 days before admission. She was diagnosed with a pancreatic neuroendocrine tumor (PNET) with hepatic metastases. Transcatheter arterial chemoembolization and Sandostatin LAR injection were performed, and then she was given a transfusion-free Radical antegrade modular pancreatosplenectomy sequentially. We gave recombinant human erythropoietin and iron hydroxide sucrose complex daily for five days after surgery. She was discharged at postoperative day 12 without any surgical complications. Multimodality therapy is very important for optimal treatment of PNET. Along with intimate interdepartmental cooperation, careful patient selection and appropriate perioperative management could possibly enhance the surgical outcome. PMID- 25692123 TI - A rare nonincisional lateral abdominal wall hernia. AB - A 68-year-old woman presented a rare lateral abdominal wall hernia. Three month before admission to Chungbuk National University Hospital, she found a large protruding mass measuring 8 cm in diameter in the midaxillary line just below the costal margin upon heavy coughing. She had no history of abdominal trauma, infection, or operation previously. The mass was easily reduced manually or by position change to left lateral decubitus. CT scan showed a defect of the right transversus abdominis muscle and internal oblique muscle at the right flank with omental herniation. Its location is different from that of spigelian hernia or lumbar hernia. The peritoneal lining of the hernia sac was smooth and there was no evidence of inflammation or adhesion. The hernia was successfully repaired laparoscopically using Parietex composite mesh with an intraperitoneal onlay mesh technique. The patient was discharged uneventfully and did not show any evidence of recurrence at follow-up visits. PMID- 25692124 TI - Posterior triangle approach for lateral in-plane technique during hemodialysis catheter insertion via the internal jugular vein. AB - A recent widespread concept is that ultrasound-guided central venous catheter insertion is a mandatory method. Some techniques have been introduced for ultrasound-guided central venous catheterization. Among them, short-axis lateral in-plane technique is considered to be the most useful technique for internal jugular vein access. Therefore, we used this technique for the insertion of a large-bore cuffed tunneled dual-lumen catheter for hemodialysis. Additionally, a lesser number of catheter angulations may lead to good flow rates and catheter function; we recommend that skin puncture site in the neck at the posterior triangle is better than the Sedillot's triangle. Using this approach, we can reduce the possible complications of pinching and kinking of the catheter. PMID- 25692125 TI - Interaction between Positive End Expiratory Pressure and Cardiac Index. PMID- 25692126 TI - Can UPR integrate fasting and stem cell regeneration? PMID- 25692127 TI - Autologous fibrin glue as an encapsulating scaffold for delivery of retinal progenitor cells. AB - The retina is a highly sophisticated piece of the neural machinery that begins the translation of incoming light signals into meaningful visual information. Several degenerative diseases of the retina are characterized by photoreceptor loss and eventually lead to irreversible blindness. Regenerative medicine, using tissue engineering-based constructs to deliver progenitor cells or photoreceptors along with supporting carrier matrix is a promising approach for restoration of structure and function. Fresh fibrin glue (FG) produced by the CryoSeal((r))FS system in combination with mouse retinal progenitor cells (RPCs) were evaluated in this study. In vitro expanded RPCs isolated from postnatal mouse retina were encapsulated into FG and cultured in the presence of the protease inhibitor, tranexamic acid. Encapsulation of RPCs into FG did not show adverse effects on cell proliferation or cell survival. RPCs exhibited fibroblast-like morphology concomitantly with attachment to the encapsulating FG surface. They expressed alpha7 and beta3 integrin subunits that could mediate attachment to fibrin matrix via an RGD-independent mechanism. The three-dimensional environment and the attachment surface provided by FG was associated with a rapid down-regulation of the progenitor marker SOX2 and enhanced the expression of the differentiation markers cone-rod homeobox and recoverin. However, the in vitro culture conditions did not promote full differentiation into mature photoreceptors. Nevertheless, we have shown that autologous fibrin, when fabricated into a scaffold for RPCs for delivery to the retina, provides the cells with external cues that could potentially improve the differentiation events. Hence, transient encapsulation of RPCs into FG could be a valid and potential treatment strategy to promote retinal regeneration following degenerative diseases. However, further optimization is necessary to maximize the outcomes in terms of mature photoreceptors. PMID- 25692128 TI - Composite scaffold of poly(vinyl alcohol) and interfacial polyelectrolyte complexation fibers for controlled biomolecule delivery. AB - Controlled delivery of hydrophilic proteins is an important therapeutic strategy. However, widely used methods for protein delivery suffer from low incorporation efficiency and loss of bioactivity. The versatile interfacial polyelectrolyte complexation (IPC) fibers have the capacity for precise spatiotemporal release and protection of protein, growth factor, and cell bioactivity. Yet its weak mechanical properties limit its application and translation into a viable clinical solution. To overcome this limitation, IPC fibers can be incorporated into polymeric scaffolds such as the biocompatible poly(vinyl alcohol) hydrogel (PVA). Therefore, we explored the use of a composite scaffold of PVA and IPC fibers for controlled biomolecule release. We first observed that the permeability of biomolecules through PVA films were dependent on molecular weight. Next, IPC fibers were incorporated in between layers of PVA to produce PVA-IPC composite scaffolds with different IPC fiber orientation. The composite scaffold demonstrated excellent mechanical properties and efficient biomolecule incorporation. The rate of biomolecule release from PVA-IPC composite grafts exhibited dependence on molecular weight, with lysozyme showing near-linear release for 1 month. Angiogenic factors were also incorporated into the PVA-IPC grafts, as a potential biomedical application of the composite graft. While vascular endothelial growth factor only showed a maximum cumulative release of 3%, the smaller PEGylated-QK peptide showed maximum release of 33%. Notably, the released angiogenic biomolecules induced endothelial cell activity thus indicating retention of bioactivity. We also observed lack of significant macrophage response against PVA-IPC grafts in a rabbit model. Showing permeability, mechanical strength, precise temporal growth factor release, and bioinertness, PVA-IPC fibers composite scaffolds are excellent scaffolds for controlled biomolecule delivery in soft tissue engineering. PMID- 25692129 TI - Identification of Salt-Stress-Induced Genes from the RNA-Seq Data of Reaumuria trigyna Using Differential-Display Reverse Transcription PCR. AB - Next generation sequencing (NGS) technologies have been used to generate huge amounts of sequencing data from many organisms. However, the correct choice of candidate genes and prevention of false-positive results computed from digital gene expression (DGE) of RNA-seq data are vital when using these genetic resources. We indirectly identified 18 salt-stress-induced Reaumuria trigyna transcripts from the transcriptome sequencing data using differential-display reverse transcription PCR (DDRT-PCR) combined with local BLAST searches. Highly consistent with the DGE results, the quantitative real-time PCR expression patterns of these transcripts showed strong upregulation by salt stress, suggesting that these genes may play important roles in R. trigyna's survival under high-salt environments. The method presented here successfully identified responsive genes from the massive amount of RNA-seq data. Thus, we suggest that DDRT-PCR could be employed to mine NGS data in a wide range of applications in transcriptomic studies. In addition, the genes identified in the present study are promising candidates for further elucidation of the salt tolerance mechanisms in R. trigyna. PMID- 25692130 TI - Prevalence of gene rearrangements in Mexican children with acute lymphoblastic leukemia: a population study-report from the Mexican Interinstitutional Group for the identification of the causes of childhood leukemia. AB - Mexico has one of the highest incidences of childhood leukemia worldwide and significantly higher mortality rates for this disease compared with other countries. One possible cause is the high prevalence of gene rearrangements associated with the etiology or with a poor prognosis of childhood acute lymphoblastic leukemia (ALL). The aims of this multicenter study were to determine the prevalence of the four most common gene rearrangements [ETV6-RUNX1, TCF3-PBX1, BCR-ABL1, and MLL rearrangements] and to explore their relationship with mortality rates during the first year of treatment in ALL children from Mexico City. Patients were recruited from eight public hospitals during 2010 2012. A total of 282 bone marrow samples were obtained at each child's diagnosis for screening by conventional and multiplex reverse transcription polymerase chain reaction to determine the gene rearrangements. Gene rearrangements were detected in 50 (17.7%) patients. ETV6-RUNX1 was detected in 21 (7.4%) patients, TCF3-PBX1 in 20 (7.1%) patients, BCR-ABL1 in 5 (1.8%) patients, and MLL rearrangements in 4 (1.4%) patients. The earliest deaths occurred at months 1, 2, and 3 after diagnosis in patients with MLL, ETV6-RUNX1, and BCR-ABL1 gene rearrangements, respectively. Gene rearrangements could be related to the aggressiveness of leukemia observed in Mexican children. PMID- 25692131 TI - Protein complex discovery by interaction filtering from protein interaction networks using mutual rank coexpression and sequence similarity. AB - The evaluation of the biological networks is considered the essential key to understanding the complex biological systems. Meanwhile, the graph clustering algorithms are mostly used in the protein-protein interaction (PPI) network analysis. The complexes introduced by the clustering algorithms include noise proteins. The error rate of the noise proteins in the PPI network researches is about 40-90%. However, only 30-40% of the existing interactions in the PPI databases depend on the specific biological function. It is essential to eliminate the noise proteins and the interactions from the complexes created via clustering methods. We have introduced new methods of weighting interactions in protein clusters and the splicing of noise interactions and proteins-based interactions on their weights. The coexpression and the sequence similarity of each pair of proteins are considered the edge weight of the proteins in the network. The results showed that the edge filtering based on the amount of coexpression acts similar to the node filtering via graph-based characteristics. Regarding the removal of the noise edges, the edge filtering has a significant advantage over the graph-based method. The edge filtering based on the amount of sequence similarity has the ability to remove the noise proteins and the noise interactions. PMID- 25692132 TI - Medial calcar support and radiographic outcomes of plate fixation for proximal humeral fractures. AB - Plate fixation remains one of the most popular surgical procedures for treating proximal humeral fractures (PHFx); however, substantial rates of complications have been reported in the literature. The objectives of the study were to examine how medial calcar support (MCS) affects the radiographic outcomes and to determine the prognostic factors predicting treatment failure. We performed a retrospective cohort study of 89 adult patients who had PHFx and were treated with plate fixation at our institution in 2007-2011. The enrolled patients were separated into two groups according to disruption of medial calcar. Our results revealed an increased rate of poor radiographic outcomes in patients with disrupted medial calcar. Osteonecrosis of the humeral head and redisplacement were the two radiographic outcomes which had a positive causality with disruption of medial calcar (P = 0.008 and 0.050, resp.). Deficient medial calcar, inadequate reduction, diabetes mellitus, chronic kidney disease, and chronic liver disease were all significant predictors for the development of osteonecrosis in patients after PHFx surgery. Inadequate reduction was also a predictor for redisplacement. We confirmed that the restoration of medial calcar as well as comorbid conditions plays key roles in treatment of patients having PHFx with disrupted medial calcar. PMID- 25692133 TI - Functional relevance of coronary artery disease by cardiac magnetic resonance and cardiac computed tomography: myocardial perfusion and fractional flow reserve. AB - Coronary artery disease (CAD) is one of the leading causes of morbidity and mortality and it is responsible for an increasing resource burden. The identification of patients at high risk for adverse events is crucial to select those who will receive the greatest benefit from revascularization. To this aim, several non-invasive functional imaging modalities are usually used as gatekeeper to invasive coronary angiography, but the diagnostic yield of elective invasive coronary angiography remains unfortunately low. Stress myocardial perfusion imaging by cardiac magnetic resonance (stress-CMR) has emerged as an accurate technique for diagnosis and prognostic stratification of the patients with known or suspected CAD thanks to high spatial and temporal resolution, absence of ionizing radiation, and the multiparametric value including the assessment of cardiac anatomy, function, and viability. On the other side, cardiac computed tomography (CCT) has emerged as unique technique providing coronary arteries anatomy and more recently, due to the introduction of stress-CCT and noninvasive fractional flow reserve (FFR-CT), functional relevance of CAD in a single shot scan. The current review evaluates the technical aspects and clinical experience of stress-CMR and CCT in the evaluation of functional relevance of CAD discussing the strength and weakness of each approach. PMID- 25692134 TI - Lunasin inhibits cell proliferation via apoptosis and reduces the production of proinflammatory cytokines in cultured rheumatoid arthritis synovial fibroblasts. AB - Lunasin, a peptide with 43 amino acid residues and initially isolated and identified in soybean cotyledon, has gained extensive attention due to its anti inflammatory and anticancer properties. However, its treatment efficacy on rheumatoid arthritis (RA) and corresponding mechanisms have not been reported. Herein, the synovial fibroblasts harvested and isolated from patients with RA were treated with lunasin at various concentrations to examine the proliferation, apoptosis status, and corresponding cell cycle of cultured RA synovial fibroblasts. Meanwhile, the underlying mechanisms of lunasin for RA treatment are explored through Western blot, real-time PCR, ELISA, and luciferase reporter assays. Lunasin significantly inhibited the proliferation and induced the apoptosis of cultured RA synovial fibroblasts. In addition, lunasin reduced the production of interleukin-6 (IL-6), IL-8, and matrix metalloproteinase-3 (MMP-3) and suppressed the activation of NF-kappaB in cultured RA synovial fibroblasts but did not reveal obvious modulation on the secretion and gene expression of MMP 1. Therefore, lunasin will have promising potential as a novel nutritional supplement or drug candidate for RA due to its potency of suppressing synovial cell proliferation and decreasing the production of proinflammatory cytokines and MMPs in synovial cells. PMID- 25692135 TI - In vitro bactericidal activity of 4- and 5-chloro-2-hydroxy-N-[1-oxo-1 (phenylamino)alkan-2-yl]benzamides against MRSA. AB - A series of nine substituted 2-hydroxy-N-[1-oxo-1-(phenylamino)alkan-2 yl]benzamides was assessed as prospective bactericidal agents against three clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) and S. aureus ATCC 29213 as the reference and quality control strain. The minimum bactericidal concentration was determined by subculturing aliquots from MIC determination onto substance-free agar plates. The bactericidal kinetics of compounds 5-chloro-2-hydroxy-N-[(2S)-3-methyl-1-oxo-1-{[4 (trifluoromethyl)phenyl]amino}butan-2-yl]benzamide (1f), N-{(2S)-1-[(4 bromophenyl)amino]-3-methyl-1-oxobutan-2-yl}-4-chloro-2-hydroxybenzamide (1g), and 4-chloro-N-{(2S)-1-[(3,4-dichlorophenyl)amino]-3-methyl-1-oxobutan-2-yl}-2 hydroxybenzamide (1h) was established by time-kill assay with a final concentration of the compound equal to 1x, 2x, and 4x MIC; aliquots were removed at 0, 4, 6, 8, and 24 h time points. The most potent bactericidal agent was compound 1f exhibiting remarkable rapid concentration-dependent bactericidal effect even at 2x MIC at 4, 6, and 8 h (with a reduction in bacterial count ranging from 3.08 to 3.75 log10 CFU/mL) and at 4x MIC at 4, 6, 8, and 24 h (5.30 log10 CFU/mL reduction in bacterial count) after incubation against MRSA 63718. Reliable bactericidal effect against other strains was maintained at 4x MIC at 24 h. PMID- 25692136 TI - TLR4/NF-kappaB-responsive microRNAs and their potential target genes: a mouse model of skeletal muscle ischemia-reperfusion injury. AB - BACKGROUND: The aim of this study was to profile TLR4/NF-kappaB-responsive microRNAs (miRNAs) and their potential target genes in the skeletal muscles of mice following ischemia-reperfusion injury. METHODS: Thigh skeletal muscles of C57BL/6, Tlr4(-/-), and NF-kappaB(-/-) mice isolated based on femoral artery perfusion were subjected to ischemia for 2 h and reperfusion for 0 h, 4 h, 1 d, and 7 d. The muscle specimens were analyzed with miRNA arrays. Immunoprecipitation with an argonaute 2- (Ago2-) specific monoclonal antibody followed by whole genome microarray was performed to identify mRNA associated with the RNA-silencing machinery. The potential targets of each upregulated miRNA were identified by combined analysis involving the bioinformatics algorithm miRanda and whole genome expression. RESULTS: Three TLR4/NF-kappaB-responsive miRNAs (miR-15a, miR-744, and miR-1196) were significantly upregulated in the muscles following ischemia-reperfusion injury. The combined in silico and whole genome microarray approaches identified 5, 4, and 20 potential target genes for miR-15a, miR-744, and miR-1196, respectively. Among the 3 genes (Zbed4, Lrsam1, and Ddx21) regulated by at least 2 of the 3 upregulated miRNAs, Lrsam1 and Ddx21 are known to be associated with the innate immunity pathway. CONCLUSIONS: This study profiled TLR4/NF-kappaB-responsive miRNAs and their potential target genes in mouse skeletal muscle subjected to ischemia-reperfusion injury. PMID- 25692137 TI - Melanoma cells homing to the brain: an in vitro model. AB - We developed an in vitro contact through-feet blood brain barrier (BBB) model built using type IV collagen, rat astrocytes, and human umbilical vein endothelial cells (HUVECs) cocultured through Transwell porous polycarbonate membrane. The contact between astrocytes and HUVECs was demonstrated by electron microscopy: astrocytes endfeet pass through the 8.0 MUm pores inducing HUVECs to assume a cerebral phenotype. Using this model we evaluated transmigration of melanoma cells from two different patients (M1 and M2) selected among seven melanoma primary cultures. M2 cells showed a statistically significant higher capability to pass across the in vitro BBB model, compared to M1. Expression of adhesion molecules was evaluated by flow cytometry: a statistically significant increased expression of MCAM, alphavbeta3, and CD49b was detected in M1. PCR array data showed that M2 had a higher expression of several matrix metalloproteinase proteins (MMPs) compared to M1. Specifically, data suggest that MMP2 and MMP9 could be directly involved in BBB permeability and that brain invasion by melanoma cells could be related to the overexpression of many MMPs. Future studies will be necessary to deepen the mechanisms of central nervous system invasion. PMID- 25692138 TI - Epicardial adipose tissue reflects the presence of coronary artery disease: comparison with abdominal visceral adipose tissue. AB - Accumulation of visceral adipose tissue is associated with a risk of coronary artery disease (CAD). The aim of this study was to examine whether different types of adipose tissue depot may play differential roles in the progression of CAD. Consecutive 174 patients who underwent both computed tomography (CT) and echocardiography were analyzed. Cardiac and abdominal CT scans were performed to measure epicardial and abdominal visceral adipose tissue (EAT and abdominal VAT, resp.). Out of 174 patients, 109 and 113 patients, respectively, presented coronary calcification (CC) and coronary atheromatous plaque (CP). The EAT and abdominal VAT areas were larger in patients with CP compared to those without it. Interestingly, the EAT area was larger in patients with CC compared to those without CC, whereas no difference was observed in the abdominal VAT area between patients with CC and those without. Multivariable logistic regression analysis revealed that the presence of echocardiographic EAT was an independent predictor of CP and CC, but the abdominal VAT area was not. These results suggest that EAT and abdominal VAT may play differential pathological roles in CAD. Given the importance of CC and CP, we should consider the precise assessment of CAD when echocardiographic EAT is detected. PMID- 25692139 TI - Targeted next generation sequencing identifies novel mutations in RP1 as a relatively common cause of autosomal recessive rod-cone dystrophy. AB - We report ophthalmic and genetic findings in families with autosomal recessive rod-cone dystrophy (arRCD) and RP1 mutations. Detailed ophthalmic examination was performed in 242 sporadic and arRCD subjects. Genomic DNA was investigated using our customized next generation sequencing panel targeting up to 123 genes implicated in inherited retinal disorders. Stringent filtering coupled with Sanger sequencing and followed by cosegregation analysis was performed to confirm biallelism and the implication of the most likely disease causing variants. Sequencing identified 9 RP1 mutations in 7 index cases. Eight of the mutations were novel, and all cosegregated with severe arRCD phenotype, found associated with additional macular changes. Among the identified mutations, 4 belong to a region, previously associated with arRCD, and 5 others in a region previously associated with adRCD. Our prevalence studies showed that RP1 mutations account for up to 2.5% of arRCD. These results point out for the necessity of sequencing RP1 when genetically investigating sporadic and arRCD. It further highlights the interest of unbiased sequencing technique, which allows investigating the implication of the same gene in different modes of inheritance. Finally, it reports that different regions of RP1 can also lead to arRCD. PMID- 25692140 TI - Comparison of two reconstructive techniques in the surgical management of four level cervical spondylotic myelopathy. AB - To compare the clinical efficacy and radiological outcome of treating 4-level cervical spondylotic myelopathy (CSM) with either anterior cervical discectomy and fusion (ACDF) or "skip" corpectomy and fusion, 48 patients with 4-level CSM who had undergone ACDF or SCF at our hospital were analyzed retrospectively between January 2008 and June 2011. Twenty-seven patients received ACDF (Group A) and 21 patients received SCF. Japanese Orthopaedic Association (JOA) score, Neck Disability Index (NDI) score, and Cobb's angles of the fused segments and C2-7 segments were compared in the two groups. The minimum patient follow-up was 2 years. No significant differences between the groups were found in demographic and baseline disease characteristics, duration of surgery, or follow-up time. Our study demonstrates that there was no significant difference in the clinical efficacy of ACDF and SCF, but ACDF involves less intraoperative blood loss, better cervical spine alignment, and fewer postoperative complications than SCF. PMID- 25692141 TI - Cone dystrophy in patient with homozygous RP1L1 mutation. AB - The purpose of this study was to determine whether an autosomal recessive cone dystrophy was caused by a homozygous RP1L1 mutation. A family including one subject affected with cone dystrophy and four unaffected members without evidence of consanguinity underwent detailed ophthalmic evaluations. The ellipsoid and interdigitation zones on the spectral-domain optical coherence tomography images were disorganized in the proband. The proband had a reduced amplitude of cone and flicker full-field electroretinograms (ERGs). Focal macular ERGs and multifocal ERGs were severely reduced in the proband. A homozygous RP1L1 mutation (c.3628T>C, p.S1210P) was identified in the proband. Family members who were heterozygous for the p.S1210P mutation had normal visual acuity and normal results of clinical evaluations. To investigate other putative pathogenic variant(s), a next-generation sequencing (NGS) approach was applied to the proband. NGS identified missense changes in the heterozygous state of the PCDH15, RPGRIP1, and GPR98 genes. None of these variants cosegregated with the phenotype and were predicted to be benign reinforcing the putative pathogenicity of the RP1L1 homozygous mutation. The AO images showed a severe reduction of the cone density in the proband. Our findings indicate that a homozygous p.S1210P exchange in the RP1L1 gene can cause cone dystrophy. PMID- 25692142 TI - MRI-targeted biopsies versus systematic transrectal ultrasound guided biopsies for the diagnosis of localized prostate cancer in biopsy naive men. AB - INTRODUCTION: To compare, in the same cohort of men, the detection of clinically significant disease in standard (STD) cores versus multiparametric magnetic resonance imaging (mpMRI) targeted (TAR) cores. MATERIAL AND METHODS: A prospective study was conducted on 129 biopsy naive men with clinical suspicion of prostate cancer. These patients underwent prebiopsy mpMRI with STD systematic biopsies and TAR biopsies when lesions were found. The agreement between the TAR and the STD protocols was measured using Cohen's kappa coefficient. RESULTS: Cancer detection rate of MRI-targeted biopsy was 62.7%. TAR protocol demonstrated higher detection rate of clinically significant disease compared to STD protocol. The proportion of cores positive for clinically significant cancer in TAR cores was 28.9% versus 9.8% for STD cores (P < 0.001). The proportion of men with clinically significant cancer and the proportion of men with Gleason score 7 were higher with the TAR protocol than with the STD protocol (P = 0.003; P = 0.0008, resp.). CONCLUSION: mpMRI improved clinically significant prostate cancer detection rate compared to STD protocol alone with less tissue sampling and higher Gleason score. Further development in imaging as well as multicentre studies using the START recommendation is needed to elucidate the role of mpMRI targeted biopsy in the management of prostate cancer. PMID- 25692143 TI - Potential therapeutic benefit of combining gefitinib and tamoxifen for treating advanced lung adenocarcinoma. AB - INTRODUCTION: Epidermal growth factor receptor (EGFR) mutations are known as oncogene driver mutations and with EGFR mutations exhibit good response to the EGFR tyrosine kinase inhibitor Gefitinib. Some studies have shown that activation of estrogen and estrogen receptor alpha or beta (ERalpha/beta) promote adenocarcinoma. We evaluated the relationship between the two receptors and the potential therapeutic benefit with Gefitinib and Tamoxifen. METHODS: We assessed the association between EGFR mutations as well as ERalpha/beta expression/location and overall survival in a cohort of 55 patients with LAC from a single hospital. PC9 (EGFR exon 19 deletion mutant; Gefitinib-vulnerable cells) and A549 (EGFR wild type; Gefitinib-resistant cells) cancer cells were used to evaluate the in vitro therapeutic benefits of combining Gefitinib and Tamoxifen. RESULTS: We found that the cytosolic but not the nuclear expression of ERbeta was associated with better OS in LAC tumors but not associated with EGFR mutation. The in vitro study showed that combined Gefitinib and Tamoxifen resulted in increased apoptosis and cytosolic expression of ERbeta. In addition, combining both medications resulted in reduced cell growth and increased the cytotoxic effect of Gefitinib. CONCLUSION: Tamoxifen enhanced advanced LAC cytotoxic effect induced by Gefitinib by arresting ERbeta in cytosol. PMID- 25692144 TI - Development of a loop-mediated isothermal amplification assay for rapid detection of Trichosporon asahii in experimental and clinical samples. AB - Invasive trichosporonosis is a deep mycosis found mainly in immunocompromised hosts, and the major pathogen is Trichosporon asahii. We detected the species specific intergenic spacers (IGS) of rRNA gene of T. asahii using a loop-mediated isothermal amplification (LAMP) assay in 15 isolates with 3 different visualization methods, including SYBR green detection, gel electrophoresis, and turbidimetric methods. The LAMP assay displayed superior rapidity to other traditional methods in the detection time; that is, only 1 h was needed for detection and identification of the pathogen DNA. Furthermore, the detection limit of the LAMP assay was more sensitive than the PCR assay. We also successfully detect the presence of T. asahii in samples from experimentally infected mice and samples from patients with invasive trichosporonosis caused by T. asahii, suggesting that this method may become useful in clinical applications in the near future. PMID- 25692145 TI - Cardiac emergencies in neurosurgical patients. AB - Perioperative safety concerns are a major area of interest in recent years. Severe cardiac perturbation such as cardiac arrest is one of the most dreaded complications in the intraoperative period; however, little is known about the management of these events in the patients undergoing elective neurosurgery. This special group needs further attention, as it is often neither feasible nor appropriate to apply conventional advanced cardiac life support algorithms in patients undergoing neurosurgery. Factors such as neurosurgical procedure and positioning can also have a significant effect on the occurrence of cardiac arrest. Therefore, the aim of this paper is to describe the various causes and management of cardiac emergencies with special reference to cardiac arrest during elective neurosurgical procedures, including discussion of position-related factors and resuscitative considerations in these situations. This will help to formulate possible guidelines for management of such events. PMID- 25692146 TI - Comparison between the traditional and a rapid screening test for cryoimmunoglobulins detection. AB - OBJECTIVES: A new rapid, automatic, and sensitive screening test useful to detect cryoglobulins in serum samples is proposed. DESIGN AND METHODS: The increase of turbidity during the cryoglobulin aggregation was monitored spectrophotometrically in sera from 400 patients with clinical evidence of cryoglobulinemia related disorders and 100 controls. Results were correlated to those obtained by the traditional method. RESULTS: Kinetics of the aggregation curves were described by their maximum turbidity increase, lag time, and slope. Despite a partial correspondence between the traditional and the rapid test, patients with symptomatic cryoglobulinemia showed turbidity values significantly higher than the determined cutoff. Moreover, a functional classification of cryoglobulins is proposed. CONCLUSIONS: Due to its high reproducibility, operator independence, low cost, and results obtained within 2 hours, the rapid test can be used as a "real time" monitoring of cryoglobulinemia related diseases and for the evaluation of plasmapheresis efficacy. PMID- 25692147 TI - Phylogenetic groups of Escherichia coli strains from patients with urinary tract infection in Iran based on the new Clermont phylotyping method. AB - OBJECTIVES: In 2013, Clermont classified E. coli strains into eight phylogenetic groups using a new quadruplex PCR method. The aims of this study were to identify the phylogenetic groups of E. coli based on this method and to assess their antibiotic resistance patterns in Bushehr, Iran. METHODS: In this cross-sectional study, 140 E. coli isolates were subjected to phylogenetic typing by a quadruplex PCR method. Antimicrobial susceptibility testing was performed by disk diffusion method. RESULTS: Phylogenetic group B2 was most predominant (39.3%), followed by unknown (27.1%), E (9.3%), C and clade I (each 6.4%), B1 (5%), F and D (each 2.9%), and A (0.7%). The most common antibiotic resistance was related to amoxicillin (82.1%) and the least to meropenem (0.7%). 82.14% of isolates were multiple drug resistant (MDR). Antibiotic resistance was mainly detected in group B2 (50%). CONCLUSIONS: Our findings showed the high prevalence of MDR E. coli isolates with dominance of group B2. About 25% of E. coli isolates belong to the newly described phylogroups C, E, F, and clade I. Such studies need to be done also in other regions to provide greater understanding of the antibiotic resistance pattern and the prevalences of different phylogenetic groups. PMID- 25692148 TI - Portulaca oleracea L.: a review of phytochemistry and pharmacological effects. AB - Portulaca oleracea L., belonging to the Portulacaceae family, is commonly known as purslane in English and Ma-Chi-Xian in Chinese. It is a warm-climate, herbaceous succulent annual plant with a cosmopolitan distribution. It is eaten extensively as a potherb and added in soups and salads around the Mediterranean and tropical Asian countries and has been used as a folk medicine in many countries. Diverse compounds have been isolated from Portulaca oleracea, such as flavonoids, alkaloids, polysaccharides, fatty acids, terpenoids, sterols, proteins vitamins and minerals. Portulaca oleracea possesses a wide spectrum of pharmacological properties such as neuroprotective, antimicrobial, antidiabetic, antioxidant, anti-inflammatory, antiulcerogenic, and anticancer activities. However, few molecular mechanisms of action are known. This review provides a summary of phytochemistry and pharmacological effects of this plant. PMID- 25692149 TI - Regulation of DEAH/RHA helicases by G-patch proteins. AB - RNA helicases from the DEAH/RHA family are present in all the processes of RNA metabolism. The function of two helicases from this family, Prp2 and Prp43, is regulated by protein partners containing a G-patch domain. The G-patch is a glycine-rich domain discovered by sequence alignment, involved in protein-protein and protein-nucleic acid interaction. Although it has been shown to stimulate the helicase's enzymatic activities, the precise role of the G-patch domain remains unclear. The role of G-patch proteins in the regulation of Prp43 activity has been studied in the two biological processes in which it is involved: splicing and ribosome biogenesis. Depending on the pathway, the activity of Prp43 is modulated by different G-patch proteins. A particular feature of the structure of DEAH/RHA helicases revealed by the Prp43 structure is the OB-fold domain in C terminal part. The OB-fold has been shown to be a platform responsible for the interaction with G-patch proteins and RNA. Though there is still no structural data on the G-patch domain, in the current model, the interaction between the helicase, the G-patch protein, and RNA leads to a cooperative binding of RNA and conformational changes of the helicase. PMID- 25692150 TI - Early aging in Chernobyl clean-up workers: long-term study. AB - This paper represents data of long-term open prospective study. 312 male clean-up workers, who participated in elimination of the Chernobyl disaster consequences in 1986-87, were observed and examined in Moscow Research Institute of Psychiatry. The average age of patients was 57,0 +/- 6,8 years. All patients were diagnosed with psychoorganic syndrome, caused by combination of different factors, which led to early cerebrovascular pathology, which was confirmed by clinical, neuropsychological, and instrumental examination. Anamnesis and the level of social adaptation were also assayed. Clinical estimation was done with the use of specially developed Clinical Psychopathological Chart. All the symptoms were divided into 4 groups (asthenic, psychovegetative, dysthymic, and cognitive symptom-complexes). No pronounced signs of dementia were observed. The control group included 44 clean-up workers without mental disorders. Predomination of various exogenous factors before and after accident was noted. Therapy included different vasotropic remedies, as well as family therapy, art therapy, and cognitive training. The possibilities of the reverse development of symptoms were statistically proved. The results allow making a conclusion that these disorders could not be explained either by radiation effects or by PTSD but connected with cerebrovascular pathology. PMID- 25692151 TI - Lower extremity function following partial calcanectomy in high-risk limb salvage patients. AB - Partial calcanectomy (PC) is an established limb salvage procedure for treatment of deep heel ulceration with concomitant calcaneal osteomyelitis. The purpose of this study is to determine if a relationship exists between the amount of calcaneus removed during PC and the resulting lower extremity function and limb salvage outcomes. Consecutive PC patients were retrospectively divided into two cohorts defined by the amount of calcaneus resected before wound closure: patients in cohort 1 retained = 50% of calcaneus, while patients in cohort 2 underwent resection of >50% of the calcaneus. The Lower Extremity Function Scale (LEFS) was used to assess postoperative lower extremity function. The average amount of calcaneus resected was 13% +/- 9.2 (1-39%) and 74% +/- 19.5 (51-100) in cohorts 1 and 2, respectively (P < 0.0001). Below knee amputation was performed in 7 (28%) and 5 (29%) of subjects in cohorts 1 and 2, respectively (P = 1.0). The average LEFS score was 33.9 +/- 15.0 for subjects in cohort 1 and 36.2 +/- 19.9 for the subjects cohort 2 (P = 0.8257) which correlates to "moderate to quite a bit of difficulty." Our study suggests that regardless of the amount of calcaneus resected, PC provides a viable treatment option for high-risk patients with calcaneal osteomyelitis. PMID- 25692152 TI - Distal femoral osteotomy in genovalgum: internal fixation with blade plate versus casting. AB - BACKGROUND: To compare the results of two different ways of distal femoral osteotomy stabilization in patients suffering from genuvalgum: internal fixation with plate, and casting. METHODS: In a non-randomized prospective study, after distal femoral osteotomy with the zigzag method, patients were divided into two groups: long leg casting, and internal fixation with blade plate. For all patients, questionnaires were filled to obtain data. Information such as range of motion, tibiofemoral anatomical angle and complications were recorded. RESULTS: 38 knees with valgus deformity underwent distal femoral supracondylar osteotomy. (8 with plaster cast and 30 with internal fixation using a blade plate). Preoperative range of motion was 129+/-6 degrees and six months later it was 120+/-14 degrees . The preoperative tibiofemoral angle was 32+/-6 degrees ; postoperative tibiofemoral angles were 3+/-3 degrees , 6+/-2 degrees , and 7+/-3 degrees just after operation, six months, and two years later, respectively. Although this angle was greater among the group stabilized with a cast, this difference was not statistically significant. In postoperative complications, over-correction was found in five, recorvatom deformity in one, knee stiffness in three and superficial wound infection was recorded in three knees. CONCLUSIONS: There is no prominent difference in final range of motion and alignment whether fixation is done with casting or internal fixation. However, the complication rate seems higher in the casting method. PMID- 25692153 TI - Heterotopic Ossification around the Knee after Internal Fixation of a Complex Tibial Plateau Fracture Combined with the Use of Demineralized Bone Matrix (DBM): A Case Report. AB - Demineralized bone matrix has been successfully commercialized as an alternative bone graft material that not only can function as filler but also as an osteoinductive graft. Numerous studies have confirmed its beneficial use in clinical practice. Heterotopic ossification after internal fixation combined with the use of demineralized bone matrix has not been widely reported. In this paper we describe a 39 year old male who sustained a complex articular fracture that developed clinically significant heterotopic ossification after internal fixation with added demineralized bone matrix. Although we cannot be sure that there is a cause-and-effect relation between demineralized bone matrix and the excessive heterotopic ossification seen in our patient, it seems that some caution in using demineralised bone matrix in similar cases is warranted. Also, given the known inter- and intraproduct variability, the risks and benefits of these products should be carefully weighed. PMID- 25692154 TI - Bilateral neck femur fracture following a generalized seizure- a rare case report. AB - Hip fractures are one of the most common injuries which present to an orthopaedic surgeon. Most of these cases are unilateral .Bilateral simultaneous femur neck fracture is a rare occurrence. We report a case of a bilateral neck femur fracture in a 30 year male following a generalized tonic clonic seizure in view of its rarity and also to increase the awareness of such rare injuries. The patient was operated within 3 hours. At 5 months, the patient had good radiological and functional outcome. During a convulsion, there is a powerful and forceful contraction of muscles which may lead to fracture or dislocation. The incidence of fractures following a convulsion is 1.1%. A delay in diagnosis can lead to complications like avascular necrosis, osteoarthritis, non union, functional disability and legal consequences. All orthopaedic surgeons and emergency physicians should be aware of such uncommon injuries to ensure early diagnosis and treatment. PMID- 25692155 TI - Small Finger Metacarpal Shaft Wedged between Ring and Small Metacarpal Bases: a Report of 2 Cases. AB - We present two patients with a displaced fracture of the small finger metacarpal base, where the shaft of the small finger metacarpal was wedged between the bases of the ring and small finger metacarpals. The striking appearance on radiographs led to initial recommendations for surgery, but both patients preferred non operative treatment and did well in the short term without surgery. PMID- 25692156 TI - Bilateral Synovial Knee Chondromatosis in a Patient with Rheumatoid Arthritis: Case-report and Literature Review. AB - We presented a female patient with RA complaining of progressive pain, swelling, and crepitation of the knee joints that was diagnosed with bilateral synovial chondromatosis (SC) of both knees. Radiographies revealed characteristic findings of SC including multiple calcified multifaceted loose bodies within both knees. Removal of cartilaginous segments as well as total synovectomy was performed arthroscopically on the left side and via open surgery on the right side. Short term postoperative follow-up of our patient revealed improved knee function and resolution of all symptoms. PMID- 25692157 TI - Granular cell tumor presenting as a large leg mass. AB - Granular cell tumor is a rare benign neoplasm most commonly appears in the head and neck region, especially in the tongue, cheek mucosa, and palate. Occurrence in limbs is even rarer. These tumors account for approximately 0.5% of all soft tissue tumors. Granular cell tumor can also affect other organs including skin, breast, and lungs. Local recurrence and metastasis is potentially higher in malignant forms with poor prognosis in respect to the benign counterparts. The average diameter of the tumor is usually about 2-3 cm. We report a granular cell tumor in the leg with an unusual size. PMID- 25692158 TI - Bilateral simultaneous femoral neck and shafts fractures - a case report. AB - Simultaneous fractures of the femoral neck and shaft are not common injuries, though they cannot be considered rare. Herein, we report our experience with a patient with bilateral occurance of this injury. Up to the best of our knowkedge this is the first case reported in literature in which correct diagnosis was made initially. Both femurs were fixed using broad 4.5 mm dynamic compression plate and both necks were fixed using 6.5 mm cannulated screws. Femur fixation on one side was converted to retrograde nailing because of plate failure. Both neck fractures healed uneventfully. In spite of rarity of concomitant fractures of femoral neck and shaft, this injury must be approached carefully demanding especial attention and careful device selection. PMID- 25692159 TI - Primary Osteosarcoma of the Sternum: A case Report and Review of the Literature. AB - Osteosarcoma (osteogenic sarcoma: OS) is the most common primary malignant bone tumor of long bones, whereas primary osteosarcoma of chest wall, especially in sternum, is extremely rare. We report a 57-year-old man with an immobile slow growing mass located in the middle of the sternum. The patient had no significant pain or tenderness and the past medical history was not remarkable. CT-scan showed a large densely sclerotic sternal mass and MRI revealed an extensive central signal loss within the tumor because of necrosis. We performed a CT guided needle biopsy, but it was inconclusive. After an incisional biopsy, a high grade osteosarcoma of the sternum was diagnosed. The patient underwent subtotal sternal resection and reconstruction using synthetic mesh and bone cement followed by chemotherapy and external beam radiotherapy. After one year of follow up, the patient is back to normal life and is doing the daily activities without problem. By this time, focal recurrence or metastatic disease did not occur. PMID- 25692160 TI - Tranexamic Acid in total joint arthroplasty: efficacy and safety. PMID- 25692161 TI - Doctor Shoja-ad-Din Sheikholeslamzadeh and his Achievements. AB - Doctor Shoja-ad-Din Sheikholeslamzadeh (also known as Dr. Sheikh) (1931-2014) was an outstanding orthopedic surgeon. He is credited for the establishment of the Iranian Association of Rehabilitation, Shafa Yahyaian Hospital as an Orthopedic and Rehabilitation Center, the Social Welfare Organization, Iran's emergency dispatch center (115) and many other major projects that led to the upgrading of health care services in Iran. He also served as the Minister of Social Welfare and Minister of Health and Welfare before the Islamic revolution. The history of modern health care management and modern orthopedic surgery in Iran are indebted to the great leadership and executive abilities of Dr. Sheikh. PMID- 25692162 TI - Evidence-Based ACL Reconstruction. AB - There is controversy in the literature regarding a number of topics related to anterior cruciate ligament (ACL) reconstruction. The purpose of this article is to answer the following questions: 1) Bone-patellar tendon-bone reconstruction (BPTB-R) or hamstrimg reconstruction (H-R); 2) Double bundle or single bundle; 3) Allograft or authograft; 4) Early or late reconstruction; 5) Rate of return to sports after ACL reconstruction; 6) Rate of osteoarthritis after ACL reconstruction. A Cochrane Library and PubMed (MEDLINE) search of systematic reviews and meta-analysis related to ACL reconstruction was performed. The key words were: ACL reconstruction, systematic reviews and meta-analysis. The main criteria for selection were that the articles were systematic reviews and meta analyses focused on the aforementioned questions. Sixty-nine articles were found, but only 26 were selected and reviewed because they had a high grade (I-II) of evidence. BPTB-R was associated with better postoperative knee stability but with a higher rate of morbidity. However, the results of both procedures in terms of functional outcome in the long-term were similar. The double-bundle ACL reconstruction technique showed better outcomes in rotational laxity, although functional recovery was similar between single-bundle and double-bundle. Autograft yielded better results than allograft. There was no difference between early and delayed reconstruction. 82% of patients were able to return to some kind of sport participation. 28% of patients presented radiological signs of osteoarthritis with a follow-up of minimum 10 years. PMID- 25692163 TI - Surgical procedures of the elbow: a nationwide cross-sectional observational study in the United States. AB - BACKGROUND: Elbow surgery is shared by several subspecialties. We were curious about the most common elbow surgeries and their corresponding diagnoses in the United States. METHODS: We used the National Hospital Discharge Survey (NHDS) and the National Survey of Ambulatory Surgery (NSAS) data gathered in 2006-databases that together provide an estimate of all inpatient and ambulatory surgical care in the US. RESULTS: An estimated 150,000 elbow surgeries were performed in the US in 2006, 75% in an outpatient setting. The most frequent diagnosis treated operative was enthesopathy (e.g. lateral epicondylitis) and it was treated with several different procedures. More than three quarters of all elbow surgeries treated enthesopathy, cubital tunnel syndrome, or fracture (radial head in particular). Arthroscopy and arthroplasty accounted for less than 10% of all elbow surgeries. CONCLUSIONS: Elbow surgery in the United States primarily addresses enthesopathies such as tennis elbow, cubital tunnel syndrome, and trauma. It is notable that some of the most common elbow surgeries (those that address enthesopathy and radial head fracture) are some of the most variably utilized and debated. PMID- 25692164 TI - Giant cell tumor of tendon sheath. AB - BACKGROUND: Giant cell tumor of tendon sheath (GCTTS) is often thought of as a volar finger mass. We hypothesized that GCTTS are equally common on the dorsal and volar aspects of the hand. In addition, we hypothesized that there are no factors associated with the location (volar versus dorsal) and largest measured dimension of a GCTTS. METHODS: A total of 126 patients with a pathological diagnosis of a GCTTS of the hand or finger were reviewed. Basic demographic and GCTTS specific information was obtained. Bivariable analyses were used to assess predicting factors for location (volar or dorsal side) and largest measured diameter of a GCTTS. RESULTS: Seventy-two tumors (57%) were on the volar side of the hand, 47 (37%) were dorsal, 6 (4.8%) were both dorsal and volar, and one was midaxial (0.79%). The most common site of a GCTTS was the index finger (30%). There were no factors significantly associated with the location (volar or dorsal, n=119) of the GCTTS. There were also no factors significantly associated with a larger diameter of a GCTTS. CONCLUSIONS: A GCTTS was more frequently seen on the volar aspect of the hand. No significant factors associated with the location or an increased size of a GCTTS were found in this study. PMID- 25692165 TI - Better survival of total knee replacement in patients older than 70 years: a prospective study with 8 to 12 years follow-up. AB - BACKGROUND: Modern knee designs have popularized its use in younger patients due to its better performance. There remains uncertainty whether higher demands of these patients can affect implant survivorship. PURPOSE: To assess whether modern knee designs have provided similar results in patients younger than 70 years versus older patients. METHODS: We included 203 consecutive patients (236 knees) who underwent knee replacement for osteoarthritis with a mean follow-up of 11.4 years (range: 8.8 to 12). The mean age was 70 years (range: 31 to 85). Knee replacements were stratified into two groups: 109 were younger than 70 years and 127 were older than 70 years (70 years of age is the mandatory retirement age). RESULTS: There were no significant pre-operative differences between groups with regards to knee alignment, alpha or beta angles, knee score or function score. Fourteen implants were radiographically loose at last follow up visit. Groups were matched in terms of demographic data. We found that patients older than 70 years had significantly better mean survivorship at 12 years. (97% vs. 88%; P=0.010). Patients under 70 years presented with a higher rate of polyethylene wear which was further associated with radiolucent lines in the femur and tibia as well as the presence of osteolysis. There was also an association between migration and presence of osteolysis. CONCLUSIONS: Patients over 70 years old undergoing cemented total knee replacement for osteoarthritis showed better implant survivorship versus patients under 70 years old. PMID- 25692166 TI - Biomechanical Comparison Between Bashti Bone Plug Technique and Biodegradable Screw for Fixation of Grafts in Ligament surgery. AB - BACKGROUND: Ligament reconstruction is a common procedure in orthopedic surgery. Although several popular techniques are currently in use, new methods are proposed for secure fixation of the tendon graft into the bone tunnel. PURPOSES: We sought to introduce our new technique of Bashti bone plug for fixation of soft tissue graft in anterior cruciate ligament (ACL) reconstruction and to compare its biomechanical features with conventional absorbable interference screw technique in a bovine model. METHODS: Twenty pairs of bovine knees were harvested after death. Soft tissue was removed and the Achilles tendon was harvested to be used as an ACL graft. It was secured into the bone tunnel on the tibial side via two different methods: Bashti Bone Plug technique and conventional screw method. Biomechanical strength was measured using 200 N and 300 N cyclic loading on the graft. Pull out strength was also tested until the graft fails. RESULTS: No graft failure was observed after 200 N and 300 N cyclic loading in either fixation methods. When testing for pull out failure, 21 tendons (53%) were torn and 19 tendons (48%) slipped out. No fixation failure occurred, which did not reveal a significant difference between the bone plug or interference screw group (P=0.11). The mean pull out force until failure of the graft was 496+/-66 N in the screw group and 503+/-67 N in the bone plug group (P=0.76). CONCLUSIONS: Our suggested fixation technique of Bashti bone plug is a native, cheap, and feasible method that provides comparable biomechanical strength with interference screw when soft tissue fixation was attempted in bovine model. PMID- 25692167 TI - The results of biplanar distal femoral osteotomy; a case series study. AB - BACKGROUND: Distal femur wedge osteotomies for varus or valgus alignment of the lower extremity could be done in either uniplanar or biplanar fashion.Union time and stability of the osteotomy site has been considered important in this anatomic region. In this study, clinical and radiographic findings of biplane distal femur osteotomy were reported. METHODS: Clinical, functional, and radiological findings of eight patients (10 knees) underwent biplane distal femur osteotomy were evaluated. Visual analogue score (VAS) and Lysholm-Tegner knee score were used for the assessment of pain and function before and three months after surgery. RESULTS: In this study, eight patients were included. All patients were female. The mean age was 28+/-6.3. The mean pre-operative mechanical angle was 8.7+/-2.2 degrees and the post-operative angle was 1.4+/-0.53 degrees in patients with valgus alignment whileit was 7.0+/-1.0 degrees preoperatively and 0.66+/-1.2 degrees postoperatively in patients with varus alignment. The mean lateral distal femoral angle (LDFA) was 85+/-8.0 degrees before surgery and was 88+/-1.3 degrees after surgery. According to Lysholm-Tegner knee score, in the post-operative visit, six knees were good and four were excellent. The mean union time was 9.2+/-2.3 weeks. CONCLUSIONS: Biplane distal femur osteotomy is a reliable technique that creates larger surfaces and more stability at the osteotomy site with further rapid union. PMID- 25692168 TI - Stage IE Primary Bone Lymphoma:Limb Salvage for Local Recurrence. AB - BACKGROUND: Primary bone lymphoma or non-Hodgkin lymphoma of bone is a rare disease. There are only a few case series of stage IE of this condition in medical literature. The aim of this study is to determine the rate of survival for stage IE after combined modality treatment, the rate of local recurrence, and the results of limb salvage in cases of local recurrence. METHODS: We collected data from 61 patients with histologically confirmed PBL treated at the Musculoskeletal Oncology Department of our hospital from 2000 to 2010. Retrospective evaluation included demographics, symptoms, tumor locations, outcomes of surgical treatment for local recurrence and survival rates. RESULTS: All patients received Combined Modality Therapy. Overall,five year survival was 89% and five year disease free survival rate was 78%. Local recurrence occurred in 6 patients during follow up period, which was treated surgically by wide excision and reconstruction. The mean follow-up for the local recurrence group was 36(24-54) months and mortality rate in this group was 17%. CONCLUSIONS: Combined Modality Therapy for stage IE primary bone lymphomaresults in good survival rate. In case of local recurrence, wide excision and reconstruction improves the outcomes. PMID- 25692169 TI - Short Form-McGill Pain Questionnaire-2 (SF-MPQ-2): A Cross-Cultural Adaptation and Validation Study of the Persian Version in Patients with Knee Osteoarthritis. AB - BACKGROUND: We aimed to develop and validate the Persian version of Short Form McGill Pain Questionnaire-2 (SF-MPQ-2) in patients with knee osteoarthritis. METHODS: Translation and back translation was performed using Beaton's guideline. After a consensus has achieved on the Persian version of SF-MPQ-2, it was administered to 30 patients with knee osteoarthritis in a pilot study. Then, we enrolled 100 patients with knee osteoarthritis to fill the final SF-MPQ-2 as well as SF-36 and WOMAC questionnaires. Forty-three patients returned 3 days after the initial visit to fill the Persian SF-MPQ-2 for the second time. Construct validity was tested by Pearson's correlation coefficient between subscales of SF MPQ-2 and subscales of SF-36 and WOMAC. Internal consistency for total and subscales was calculated by Cronbach's alpha and reliability between test retest was performed using Intraclass correlation coefficient (ICC). RESULTS: ICC for subscales of SF-MPQ-2 ranged from 0.73 to 0.90. The ICC for total SF-MPQ-2 was 0.90. Cronbach's alpha for subscales was 0.65-0.74 at the first visit and 0.58 0.81 at the second visit. Cronbach's alpha for the total questionnaire was 0.88 and 0.91 at the first and second visit, respectively. Pearson's correlation coefficient was highly significant when comparing subscales specifically with WOMAC (r=-0.47 to -0.61; P<0.001). Interscale correlation between subscales of SF MPQ-2 was significant as well (r: 0.43-0.88, P<0.001). CONCLUSIONS: Persian SF MPQ-2 showed excellent reliability and good to excellent internal consistency throughout the questionnaire. It is a valid and reliable instrument for measuring the pain intensity and applicable in osteoarthritic pain assessment. PMID- 25692170 TI - Prediction of mortality in hip fracture patients: role of routine blood tests. AB - BACKGROUND: To assess the mortality predictive value of routine blood tests in patients with hip fracture. METHODS: In a retrospective descriptive study, medical records of 204 hip fractured patients with the age of 60 or older who were admitted to the Department of Orthopedics was considered regarding routine laboratory tests. Predictive values of these tests were assessed using receiver operating characteristic curve (ROC). RESULTS: The incidence of death due to hip fracture was 24%. The mortality rate was significantly increased with age > 65 (OR= 15). There was no significant difference between mortality in regards to gender. High plasma BUN (more than 20 mg/dl) and creatinine (more than 1.3 mg/dl) significantly increased the chance of mortality. [OR= 3.0 and OR=2.5 for BUN and creatinine, respectively]. Patients' mortality did not show any correlation with sodium and potassium plasma levels and blood hemoglobin. CONCLUSIONS: There is direct correlation between plasma levels of BUN and creatinine and 3-month mortality after hip fractures. Patients with high plasma levels of BUN were three times more likely to die than those with normal BUN. Also, patients with high plasma creatinine levels were 2.5 times more likely to die than those who had normal values. Mortality was also associated with increasing age but did not vary with gender. Patients aging more than 65 were 15 times more likely to die following a hip fracture than those with younger age. PMID- 25692171 TI - The Zarit Caregiver Burden Interview Short Form (ZBI-12) in spouses of Veterans with Chronic Spinal Cord Injury, Validity and Reliability of the Persian Version. AB - BACKGROUND: To test the psychometric properties of the Persian version of Zarit Burden Interview (ZBI-12) in the Iranian population. METHODS: After translating and cultural adaptation of the questionnaire into Persian, 100 caregiver spouses of Iran- Iraq war (1980-88) veterans with chronic spinal cord injury who live in the city of Mashhad, Iran, invited to participate in the study. The Persian version of ZBI-12 accompanied with the Persian SF-36 was completed by the caregivers to test validity of the Persian ZBI-12.A Pearson's correlation coefficient was calculated for validity testing. In order to assess reliability of the Persian ZBI-12, we administered the ZBI-12 randomly in 48 caregiver spouses again 3 days later. RESULTS: Generally, the internal consistency of the questionnaire was found to be strong (Cronbach's alpha 0.77). Intercorrelation matrix between the different domains of ZBI-12 at test-retest was 0.78. The results revealed that majority of questions the Persian ZBI_12 have a significant correlation to each other. In terms of validity, our results showed that there is significant correlations between some domains of the Persian version the Short Form Health Survey -36 with the Persian Zarit Burden Interview such as Q1 with Role Physical (P=0.03),General Health (P=0.034),Social Functional (0.037), Mental Health (0.023) and Q3 with Physical Function (P=0.001),Viltality (0.002), Socil Function (0.001). CONCLUSIONS: Our findings suggest that the Zarit Burden Interview Persian version is both a valid and reliable instrument for measuring the burden of caregivers of individuals with chronic spinal cord injury. PMID- 25692172 TI - Motor aphasia as a rare presentation of fat embolism syndrome; a case report. AB - Fat embolism syndrome is a clinical diagnosis, and diagnostic procedures are not specific. In every trauma patient, Fat embolism syndrome has to be considered as a possibility and supportive treatment should begin as soon as possible. The authors reported a rare case of Fat embolism syndrome whose only neurological symptom was motor aphasia. A young man sustained comminuted femoral shaft fracture following an accident presented dyspnea, motor aphasia and petechial rash. The Po2 and O2 Saturation were 53 and 91.1%. The body temperature was 38.5 degrees C. The hemoglobin decreased from 12.9 to 8.7 and platelet from 121000 to 84000 mg/dl. The pulse rate was 120 bpm. The CT scan and MRI were normal. Fat embolism syndrome was diagnosed according to both Gurd and Schonfeld criteria ruling out other possible causes. Patient recovered completely. Although rare, focal neurological symptoms and motor aphasia should be kept in mind as a part of diagnostic criteria. PMID- 25692173 TI - Chronic Osteomyelitis in the Femoral Midshaft Following Arthroscopic ACL Reconstruction. AB - A 25 year-old man presented with pain, swelling, and intermittent drainage from distal lateral aspect of his left knee three months after undergoing isolated ACL reconstruction with arthroscopic hamstring autograft and endobottom technique. His surgeon at that time tried to eliminate the pathology through arthroscopic wash out in two attempts. However, the pain, edema, and discharge recurred after a year of being symptom free. The patient underwent imaging assessment and anteroposterior and lateral radiographs demonstrated a sclerotic area beneath the femoral condoyle in femoral tunnel and a fusiform sclerotic area in the lateral aspect of femoral midshaft. Magnetic Resonance Imaging revealed necrotic tissue with bone edema consistent with the sclerotic area in radiographs indicating micro abscesses and osteomyelitis. A diagnosis of femoral chronic osteomyelitis was made and the patient underwent arthroscopic drainage and washout, followed by open surgery for diaphysial femoral osteomyelitis. Rehabilitation was started and after six months the patient returned to his work. PMID- 25692174 TI - Depression from childhood through adolescence: Risk mechanisms across multiple systems and levels of analysis. AB - This paper selectively reviews recent research, especially in the last two years (2012-2014) in preschool, child, and adolescent depression. In particular, attention is paid to developmental epidemiology as well as risk factors and processes that contribute to depression trajectories over time. Emphasis is placed on a developmental psychopathology perspective in which risks are instantiated across multiple systems and levels of analysis, including genetics, stress contexts and processes, biological stress mechanisms, temperament, emotion, reward, cognitive factors and processes, and interpersonal influences. These risks dynamically transact over time, as they emerge and stabilize into relatively trait-like vulnerabilities that confer risk for the increasing rates of depression observed in adolescence. Overall, this summary illustrates that considerable progress has been made recently in understanding the complex developmental processes contributing to depression. Finally, a few gaps are highlighted as opportunities for future research. PMID- 25692175 TI - Accredited translational medicine centre: Human renal fibrotic disease: Translational research at the Center for Cell Biology and Cancer Research (CCBCR), Albany Medical College, Albany, NY. PMID- 25692176 TI - The collaborative search by tag-based user profile in social media. AB - Recently, we have witnessed the popularity and proliferation of social media applications (e.g., Delicious, Flickr, and YouTube) in the web 2.0 era. The rapid growth of user-generated data results in the problem of information overload to users. Facing such a tremendous volume of data, it is a big challenge to assist the users to find their desired data. To attack this critical problem, we propose the collaborative search approach in this paper. The core idea is that similar users may have common interests so as to help users to find their demanded data. Similar research has been conducted on the user log analysis in web search. However, the rapid growth and change of user-generated data in social media require us to discover a brand-new approach to address the unsolved issues (e.g., how to profile users, how to measure the similar users, and how to depict user generated resources) rather than adopting existing method from web search. Therefore, we investigate various metrics to identify the similar users (user community). Moreover, we conduct the experiment on two real-life data sets by comparing the Collaborative method with the latest baselines. The empirical results show the effectiveness of the proposed approach and validate our observations. PMID- 25692177 TI - A novel one-pot and one-step microwave-assisted cyclization-methylation reaction of amino alcohols and acetylated derivatives with dimethyl carbonate and TBAC. AB - A simple and efficient microwave-assisted methodology for the synthesis of 4 substituted-3-methyl-1,3-oxazolidin-2-ones from amino alcohols catalyzed by a ionic liquid was developed. This novel one-pot and one-step cyclization methylation reaction represents an easier and faster method than any other reported protocols that can be used to obtain the desired products in good yields and high purity. Applying microwave irradiation at 130 degrees C in the presence of TBAC, dimethyl carbonate acts simultaneously as carbonylating and methylating agent and surprisingly promotes an in situ basic trans esterification when a N acetylated amino alcohol is used as starting material. Furthermore, dimethyl carbonate worked better than diethyl carbonate in performing this reaction. PMID- 25692178 TI - Simulation of contrast agent transport in arteries with multilayer arterial wall: impact of arterial transmural transport on the bolus delay and dispersion. AB - One assumption of DSC-MRI is that the injected contrast agent is kept totally intravascular and the arterial wall is impermeable to contrast agent. The assumption is unreal for such small contrast agent as Gd-DTPA can leak into the arterial wall. To investigate whether the unreal assumption is valid for the estimation of the delay and dispersion of the contrast agent bolus, we simulated flow and Gd-DTPA transport in a model with multilayer arterial wall and analyzed the bolus delay and dispersion qualified by mean vascular transit time (MVTT) and the variance of the vascular transport function. Factors that may affect Gd-DTPA transport hence the delay and dispersion were further investigated, such as integrity of endothelium and disturbed flow. The results revealed that arterial transmural transport would slightly affect MVTT and moderately increase the variance. In addition, although the integrity of endothelium can significantly affect the accumulation of contrast agent in the arterial wall, it had small effects on the bolus delay and dispersion. However, the disturbed flow would significantly increase both MVTT and the variance. In conclusion, arterial transmural transport may have a small effect on the bolus delay and dispersion when compared to the flow pattern in the artery. PMID- 25692179 TI - Twin-Schnorr: a security upgrade for the Schnorr identity-based identification scheme. AB - Most identity-based identification (IBI) schemes proposed in recent literature are built using pairing operations. This decreases efficiency due to the high operation costs of pairings. Furthermore, most of these IBI schemes are proven to be secure against impersonation under active and concurrent attacks using interactive assumptions such as the one-more RSA inversion assumption or the one more discrete logarithm assumption, translating to weaker security guarantees due to the interactive nature of these assumptions. The Schnorr-IBI scheme was first proposed through the Kurosawa-Heng transformation from the Schnorr signature. It remains one of the fastest yet most secure IBI schemes under impersonation against passive attacks due to its pairing-free design. However, when required to be secure against impersonators under active and concurrent attacks, it deteriorates greatly in terms of efficiency due to the protocol having to be repeated multiple times. In this paper, we upgrade the Schnorr-IBI scheme to be secure against impersonation under active and concurrent attacks using only the classical discrete logarithm assumption. This translates to a higher degree of security guarantee with only some minor increments in operational costs. Furthermore, because the scheme operates without pairings, it still retains its efficiency and superiority when compared to other pairing-based IBI schemes. PMID- 25692180 TI - Machine learning for medical applications. PMID- 25692181 TI - Editorial: systematic reviews: a stamp of approval for the "best available evidence"? PMID- 25692182 TI - A review of pathogenesis, diagnosis, treatment options, and differential diagnosis of odontogenic infections: a rather mundane pathology? AB - Odontogenic infections are common in the dental practice and their treatment should be a standard procedure for every dentist. For optimal management of septic intraoral problems, the practitioner must understand the underlying causes and etiologies of odontogenic infections. Therefore, the purpose of this article is to outline basic inflammatory processes involved in the development of odontogenic and intraoral infections including relevant pathogens, biochemical processes mediated by pro-inflammatory molecules, the basics of abscess formation, the host response, and the clinical appearance of intraoral septic processes. Furthermore, treatment modalities of odontogenic infections and associated lesions are discussed and a brief explanation of possible complications and their management is provided. PMID- 25692183 TI - FTIR imaging of structural changes in visceral and subcutaneous adiposity and brown to white adipocyte transdifferentiation. AB - Obesity is a heterogeneous disorder which increases risks for multiple metabolic diseases, such as type 2 diabetes. The current study aims to characterize and compare visceral and subcutaneous adipose tissues in terms of macromolecular content and investigate transdifferentiation between white and brown adipocytes. Regarding this aim, Fourier transform infrared (FTIR) microspectroscopy and uncoupling protein 1 (UCP1) immunohistological staining were used to investigate gonadal (visceral) and inguinal (subcutaneous) adipose tissues of male Berlin fat mice inbred (BFMI) lines, which are spontaneously obese. The results indicated a remarkable increase in the lipid/protein ratio, accompanied with a decrease of UCP1 protein content which might be due to the transdifferentiation of brown adipocytes to white adipocytes in obese groups. It has been widely reported that brown adipose tissue has a strong effect on fatty acid and glucose homeostasis and it could provide an opportunity for the therapy of obesity. When the amount of brown adipose tissue was decreased, lower unsaturation/saturation ratio, qualitatively longer hydrocarbon acyl chain length of lipids and higher amount of triglycerides were obtained in both adipose tissues of mice lines. The results also revealed that subcutaneous adipose tissue was more prone to obesity-induced structural changes than visceral adipose tissue, which could originate from it possessing a lower amount of brown adipose tissue. The current study clearly revealed the power of FTIR microspectroscopy in the precise determination of obesity-induced structural and functional changes in inguinal and gonadal adipose tissue of mice lines. PMID- 25692184 TI - Coupling a solid phase microextraction (SPME) probe with ambient MS for rapid enrichment and detection of phosphopeptides in biological samples. AB - In this study, we developed a probe-electrospray ionization method by coupling a SPME probe modified with nanosized TiO2 directly to nanoESI-MS for the phosphoproteome analysis, which demonstrated excellent selectivity and sensitivity for enrichment of phosphopeptides in complex biological samples. PMID- 25692185 TI - Transformers: the changing phases of low-dimensional vanadium oxide bronzes. AB - In this feature article, we explore the electronic and structural phase transformations of ternary vanadium oxides with the composition MxV2O5 where M is an intercalated cation. The periodic arrays of intercalated cations ordered along quasi-1D tunnels or layered between 2D sheets of the V2O5 framework induce partial reduction of the framework vanadium atoms giving rise to charge ordering patterns that are specific to the metal M and stoichiometry x. This periodic charge ordering makes these materials remarkably versatile platforms for studying electron correlation and underpins the manifestation of phenomena such as colossal metal-insulator transitions, quantized charge corrals, and superconductivity. We describe current mechanistic understanding of these emergent phenomena with a particular emphasis on the benefits derived from scaling these materials to nanostructured dimensions wherein precise ordering of cations can be obtained and phase relationships can be derived that are entirely inaccessible in the bulk. In particular, structural transformations induced by intercalation are dramatically accelerated due to the shorter diffusion path lengths at nanometer-sized dimensions, which cause a dramatic reduction of kinetic barriers to phase transformations and facilitate interconversion between the different frameworks. We conclude by summarizing numerous technological applications that have become feasible due to recent advances in controlling the structural chemistry and both electronic and structural phase transitions in these versatile frameworks. PMID- 25692186 TI - A three dimensional magnetically frustrated metal-organic framework via the vertices augmentation of underlying net. AB - In our efforts to fabricate magnetically frustrated materials, a feasible vertices augmentation method was successfully used to construct a 4-fold interpenetrating three dimensional metal-organic framework (MOF) with rare topology by linking [Fe3(MU3-O)(MU-O2CCH3)6](+) triangular moieties through the pure anti,anti acetate ligands. Strong antiferromagnetic interactions were found to exist between the neighboring Fe(III) ions without long-range magnetic ordering above 2.2 K, indicating the strong geometric spin frustration nature of this MOF. PMID- 25692187 TI - A reversible two-electron redox system involving a divalent lead species. AB - Reduction of THF-stabilized plumbacyclopentadienylidene with lithium afforded dilithioplumbole. On the other hand, oxidation of the dilithioplumbole provided the starting plumbacyclopentadienylidene. This is the unprecedented example of a reversible interconversion between group 14 M(II) and its dianionic species bearing organic substituents. PMID- 25692188 TI - A concise route to the highly-functionalized azetidine precursor: the enantioselective synthesis of penaresidin B. AB - An efficient and high-yielding synthesis of penaresidin B is disclosed herein. The concise 8-step synthesis of azetidine aldehyde was devised by incorporating our novel strategy for ready access to 3-amino-2,3-dideoxysugars via regio- and stereoselective tandem hydroamination/glycosylation of glycal as the key step. PMID- 25692189 TI - Selective hydroxylation of benzene derivatives and alkanes with hydrogen peroxide catalysed by a manganese complex incorporated into mesoporous silica-alumina. AB - Selective hydroxylation of benzene derivatives and alkanes to the corresponding phenol and alcohol derivatives with hydrogen peroxide was efficiently catalysed by a manganese tris(2-pyridylmethyl)amine (tpa) complex ([(tpa)Mn(II)](2+)) incorporated into mesoporous silica-alumina with highly acidic surfaces in contrast to the reactions in a homogeneous solution where [(tpa)Mn(II)](2+) was converted catalytically to a much less active bis(MU-oxo)dimanganese(III,IV) complex. PMID- 25692190 TI - Course of experimental infection of canine leishmaniosis: follow-up and utility of noninvasive diagnostic techniques. AB - This study compares the utility of a molecular diagnosis of experimental CanL on non-invasive samples (urine, conjunctival (CS), oral (OS) and vulvar (VS) swabs) with that of traditional invasive techniques during the course of infection. Eight dogs were experimen-tally infected with Leishmania infantum and followed monthly for 12 months to assess clinical, clinicopathological, immunological and parasitological variables. Active infection was produced in 100% of the dogs. The animals showed positive bone marrow (BM) cytologies and cultures, clinical signs, clinicopathological abnormalities and a high specific humoral immune response. The infection was detected at 90 days post-infection (p.i.) by real-time quantitative PCR (rtQ-PCR) on BM in all dogs and in blood in 2 dogs, while anti L. infantum antibody seroconversion occurred between Days 120 and 180 days p.i. The tissue with the highest L. infantum kDNA load, as detected by rtQ-PCR, was BM (range 381.5-70,000 parasites/ml at the study end), this sample type showing greater sensitivity than peripheral blood (PB). The vulvar swabs used here for the first time to quantify para-site loads in dogs revealed a greater load than oral and conjunctival swabs at one year p.i. Urine samples showed the lowest concentrations of L. infantum DNA (maximum: 8.57 par-asites/ml). Our results suggest that for the early detection of infection, adding to serology a test such as rtQ-PCR on OS or VS improves sensitivity and specificity. PMID- 25692191 TI - Risks for sleep-related deaths among infants differ by age group. PMID- 25692192 TI - Serious adverse events caused by vaccines are rare and need to be balanced against their protective benefits. PMID- 25692193 TI - Cochrane review examines use of intraprtum prophylactic antibiotics for prevention of neonatal group B strep colonization. PMID- 25692194 TI - Pregnant women use nonprofessional sources when seeking information about complementary and alternative practices. PMID- 25692195 TI - American College of Physicians recommends against screening pelvic examinations in asymptomatic adult nonpregnant women. PMID- 25692196 TI - Response: Understand your talents, accept your limitations. PMID- 25692197 TI - Obituary. Hu Tian-Sheng. PMID- 25692198 TI - Sudden onset diplopia in an elderly male patient: question. PMID- 25692199 TI - MicroRNA profiling of the bovine alveolar macrophage response to Mycobacterium bovis infection suggests pathogen survival is enhanced by microRNA regulation of endocytosis and lysosome trafficking. AB - Mycobacterium bovis, the causative agent of bovine tuberculosis, a major problem for global agriculture, spreads via an airborne route and is taken up by alveolar macrophages (AM) in the lung. Here, we describe the first next-generation sequencing (RNA-seq) approach to temporally profile miRNA expression in primary bovine AMs post-infection with M. bovis. One, six, and forty miRNAs were identified as significantly differentially expressed at 2, 24 and 48 h post infection, respectively. The differential expression of three miRNAs (bta-miR-142 5p, bta-miR-146a, and bta-miR-423-3p) was confirmed by RT-qPCR. Pathway analysis of the predicted mRNA targets of differentially expressed miRNAs suggests that these miRNAs preferentially target several pathways that are functionally relevant for mycobacterial pathogenesis, including endocytosis and lysosome trafficking, IL-1 signalling and the TGF-beta pathway. Over-expression studies using a bovine macrophage cell-line (Bomac) reveal the targeting of two key genes in the innate immune response to M. bovis, IL-1 receptor-associated kinase 1 (IRAK1) and TGF-beta receptor 2 (TGFBR2), by miR-146. Taken together, our study suggests that miRNAs play a key role in tuning the complex interplay between M. bovis survival strategies and the host immune response. PMID- 25692200 TI - Alexander R. Cools (1941-2013): in memoriam 'Lex of the basal ganglia'. PMID- 25692201 TI - Good clinical practice in trauma care research: considerations for inter hospital patient transfers. PMID- 25692202 TI - Obituary. Yukio Fukuyama, MD (1928-2014). PMID- 25692203 TI - "Coxsackievirus A6 associated hand, foot and mouth disease in adults: clinical presentation and review of the literature" [J. Clin. Virol. 60 (2014) 381-386]. PMID- 25692204 TI - Identification of essential outstanding questions for an adequate European laboratory response to Ebolavirus Zaire West Africa 2014. AB - On August 8 2014, the World Health Organization (WHO) declared the outbreak of Ebola Virus Disease (EVD) evolving in West Africa since December 2013, a Public Health Emergency of International Concern (PHEIC). It is expected that the outbreak of Ebolavirus Disease (EVD) in West Africa will lead to increased testing of individuals in Europe for EVD. The severity of the situation in West Africa warranted a critical appraisal of the laboratory preparedness and response for EVD, with a focus on information needs for laboratories involved in diagnostics of rare viral diseases associated with the European Network for the Diagnostics of "Imported" Viral Diseases", ENIVD. Essential knowledge and knowledge gaps for an adequate laboratory response focusing on virus properties, infection kinetics, tests specifics and field performances were identified. An inventory of the laboratory capacity for EVD diagnostics among ENIVD laboratories was made. PMID- 25692205 TI - Re: genotype and phenotype frequencies of paraoxonase 1 in fertile and infertile men--reply. PMID- 25692206 TI - Topoisomerase IIalpha as a prognostic factor in pituitary tumors. AB - INTRODUCTION: There is an ongoing search for markers of pituitary tumor proliferation and progression that could facilitate further treatment and patient monitoring. OBJECTIVES: We studied topoisomerase IIalpha (topo IIalpha) expression in different types of pituitary adenomas to evaluate its prognostic value. PATIENTS AND METHODS: In a retrospective study of 60 patients (mean age, 46.7 +/-17.6 y) who underwent pituitary tumor surgery, expression of topo IIalpha was assessed by immunohistochemistry and compared with histopathological tumor features, clinical symptoms, magnetic resonance imaging, and postoperative tumor recurrence or progression. RESULTS: Expression of topo IIalpha was observed in 44 of 60 pituitary adenomas (73%). The highest topo IIalpha index was observed in adrenocorticotropic hormone (ACTH)-secreting tumors (median, 1.13% [0.37-1.21]), followed by silent-ACTH tumors (0.94% [0.89-1.0]), and hormone immunonegative adenomas (0.8% [0.65-1.55]). There were no differences in topo IIalpha expression with respect to age or sex. Significant correlations were observed between the topo IIalpha index and tumor size, its invasiveness, abnormal ocular test results, and postoperative tumor recurrence. In patients with a topo IIalpha index exceeding 1%, we observed a 3.5-fold higher relative risk of tumor recurrence as compared with patients with a topo IIalpha index lower than 1% (95% confidence interval: 1.8-6.9; P <0.001). Patients with acromegaly who received somatostatin analogues before the surgery had a lower median topo IIalpha index compared with untreated patients (0%[0-0.22] vs. 0.71% [0.17-1.0]; P <0.05). CONCLUSIONS: In our study group, a topo IIalpha index exceeding 1% was a prognostic factor for tumor recurrence or progression, especially in patients with hormonally inactive adenomas, which facilitates patient selection for intensive postoperative treatment. Use of somatostatin analogues in acromegaly inhibits topo IIalpha expression, providing molecular evidence for the effectiveness of these analogues. PMID- 25692207 TI - Alteration of Airway Reactivity and Reduction of Ryanodine Receptor Expression by Cigarette Smoke in Mice. AB - Small airways are a major site of airflow limitation in chronic obstructive pulmonary disease (COPD). Despite the detrimental effects of long-term smoking in COPD, the effects of acute cigarette smoke (CS) exposure on small airway reactivity have not been fully elucidated. Balb/C mice were exposed to room air (sham) or CS for 4 days to cause airway inflammation. Changes in small airway lumen area in response to contractile agents were measured in lung slices in situ using phase-contrast microscopy. Separate slices were pharmacologically maintained at constant intracellular Ca(2+) using caffeine/ryanodine before contractile measurements. Gene and protein analysis of contractile signaling pathways were performed on separate lungs. Monophasic contraction to serotonin became biphasic after CS exposure, whereas contraction to methacholine was unaltered. This altered pattern of contraction was normalized by caffeine/ryanodine. Expression of contractile agonist-specific receptors was unaltered; however, all isoforms of the ryanodine receptor were down-regulated. This is the first study to show that acute CS exposure selectively alters small airway contraction to serotonin and down-regulates ryanodine receptors involved in maintaining Ca(2+) oscillations in airway smooth muscle. Understanding the contribution of ryanodine receptors to altered airway reactivity may inform the development of novel treatment strategies for COPD. PMID- 25692208 TI - "Platinum H": refining the H-Index to more realistically assess career trajectory and scientific publications. PMID- 25692209 TI - Influence of bone marrow-derived mesenchymal stem cells pre-implantation differentiation approach on periodontal regeneration in vivo. AB - AIM: The implantation of bone marrow-derived mesenchymal stem cells (MSCs) has previously been shown successful to achieve periodontal regeneration. However, the preferred pre-implantation differentiation strategy (e.g. maintenance of stemness, osteogenic or chondrogenic induction) to obtain optimal periodontal regeneration is still unknown. This in vivo study explored which differentiation approach is most suitable for periodontal regeneration. MATERIALS AND METHODS: Mesenchymal stem cells were obtained from Fischer rats and seeded onto poly(lactic-co-glycolic acid)/poly(E-caprolactone) electrospun scaffolds, and then pre-cultured under different in vitro conditions: (i) retention of multilineage differentiation potential; (ii) osteogenic differentiation approach; and (iii) chondrogenic differentiation approach. Subsequently, the cell-scaffold constructs were implanted into experimental periodontal defects of Fischer rats, with empty scaffolds as controls. After 6 weeks of implantation, histomorphometrical analyses were applied to evaluate the regenerated periodontal tissues. RESULTS: The chondrogenic differentiation approach showed regeneration of alveolar bone and ligament tissues. The retention of multilineage differentiation potential supported only ligament regeneration, while the osteogenic differentiation approach boosted alveolar bone regeneration. CONCLUSION: Chondrogenic differentiation of MSCs before implantation is a useful strategy for regeneration of alveolar bone and periodontal ligament, in the currently used rat model. PMID- 25692210 TI - Integrated control of emission reductions, energy-saving, and cost-benefit using a multi-objective optimization technique in the pulp and paper industry. AB - Reduction of water pollutant emissions and energy consumption is regarded as a key environmental objective for the pulp and paper industry. The paper develops a bottom-up model called the Industrial Water Pollutant Control and Technology Policy (IWPCTP) based on an industrial technology simulation system and multiconstraint technological optimization. Five policy scenarios covering the business as usual (BAU) scenario, the structural adjustment (SA) scenario, the cleaner technology promotion (CT) scenario, the end-treatment of pollutants (EOP) scenario, and the coupling measures (CM) scenario have been set to describe future policy measures related to the development of the pulp and paper industry from 2010-2020. The outcome of this study indicates that the energy saving amount under the CT scenario is the largest, while that under the SA scenario is the smallest. Under the CT scenario, savings by 2020 include 70 kt/year of chemical oxygen demand (COD) emission reductions and savings of 7443 kt of standard coal, 539.7 ton/year of ammonia nitrogen (NH4-N) emission reductions, and savings of 7444 kt of standard coal. Taking emission reductions, energy savings, and cost benefit into consideration, cleaner technologies like highly efficient pulp washing, dry and wet feedstock preparation, and horizontal continuous cooking, medium and high consistency pulping and wood dry feedstock preparation are recommended. PMID- 25692211 TI - Methods for the estimation of the National Institute for Health and Care Excellence cost-effectiveness threshold. AB - BACKGROUND: Cost-effectiveness analysis involves the comparison of the incremental cost-effectiveness ratio of a new technology, which is more costly than existing alternatives, with the cost-effectiveness threshold. This indicates whether or not the health expected to be gained from its use exceeds the health expected to be lost elsewhere as other health-care activities are displaced. The threshold therefore represents the additional cost that has to be imposed on the system to forgo 1 quality-adjusted life-year (QALY) of health through displacement. There are no empirical estimates of the cost-effectiveness threshold used by the National Institute for Health and Care Excellence. OBJECTIVES: (1) To provide a conceptual framework to define the cost effectiveness threshold and to provide the basis for its empirical estimation. (2) Using programme budgeting data for the English NHS, to estimate the relationship between changes in overall NHS expenditure and changes in mortality. (3) To extend this mortality measure of the health effects of a change in expenditure to life-years and to QALYs by estimating the quality-of-life (QoL) associated with effects on years of life and the additional direct impact on QoL itself. (4) To present the best estimate of the cost-effectiveness threshold for policy purposes. METHODS: Earlier econometric analysis estimated the relationship between differences in primary care trust (PCT) spending, across programme budget categories (PBCs), and associated disease-specific mortality. This research is extended in several ways including estimating the impact of marginal increases or decreases in overall NHS expenditure on spending in each of the 23 PBCs. Further stages of work link the econometrics to broader health effects in terms of QALYs. RESULTS: The most relevant 'central' threshold is estimated to be L12,936 per QALY (2008 expenditure, 2008-10 mortality). Uncertainty analysis indicates that the probability that the threshold is < L20,000 per QALY is 0.89 and the probability that it is < L30,000 per QALY is 0.97. Additional 'structural' uncertainty suggests, on balance, that the central or best estimate is, if anything, likely to be an overestimate. The health effects of changes in expenditure are greater when PCTs are under more financial pressure and are more likely to be disinvesting than investing. This indicates that the central estimate of the threshold is likely to be an overestimate for all technologies which impose net costs on the NHS and the appropriate threshold to apply should be lower for technologies which have a greater impact on NHS costs. LIMITATIONS: The central estimate is based on identifying a preferred analysis at each stage based on the analysis that made the best use of available information, whether or not the assumptions required appeared more reasonable than the other alternatives available, and which provided a more complete picture of the likely health effects of a change in expenditure. However, the limitation of currently available data means that there is substantial uncertainty associated with the estimate of the overall threshold. CONCLUSIONS: The methods go some way to providing an empirical estimate of the scale of opportunity costs the NHS faces when considering whether or not the health benefits associated with new technologies are greater than the health that is likely to be lost elsewhere in the NHS. Priorities for future research include estimating the threshold for subsequent waves of expenditure and outcome data, for example by utilising expenditure and outcomes available at the level of Clinical Commissioning Groups as well as additional data collected on QoL and updated estimates of incidence (by age and gender) and duration of disease. Nonetheless, the study also starts to make the other NHS patients, who ultimately bear the opportunity costs of such decisions, less abstract and more 'known' in social decisions. FUNDING: The National Institute for Health Research-Medical Research Council Methodology Research Programme. PMID- 25692213 TI - IMS-MS and IMS-IMS investigation of the structure and stability of dimethylamine sulfuric acid nanoclusters. AB - Recent studies of new particle formation events in the atmosphere suggest that nanoclusters (i.e, the species formed during the early stages of particle growth which are composed of 10(1)-10(3) molecules) may consist of amines and sulfuric acid. The physicochemical properties of sub-10 nm amine-sulfuric acid clusters are hence of interest. In this work, we measure the density, thermostability, and extent of water uptake of <8.5 nm effective diameter dimethylamine-sulfuric (DMAS) nanoclusters in the gas phase, produced via positive electrospray ionization. Specifically, we employ three systems to investigate DMAS properties: ion mobility spectrometry (IMS, with a parallel-plate differential mobility analyzer) is coupled with mass spectrometry to measure masses and collision cross sections for <100 kDa positively charged nanoclusters, two differential mobility analyzers in series (IMS-IMS) are used to examine thermostability, and finally a differential mobility analyzer coupled to an atmospheric pressure drift tube ion mobility spectrometer (also IMS-IMS) is used for water uptake measurements. IMS MS measurements reveal that dry DMAS nanoclusters have densities of ~1567 kg/m(3) near 300 K, independent of the ratio of dimethylamine to sulfuric acid originally present in the electrospray solution. IMS-IMS thermostability studies reveal that partial pressures of DMAS nanoclusters are dependent upon the electrospray solution concentration ratio, R = [H2SO4]/[(CH3)2NH]. Extrapolating measurements, we estimate that dry DMAS nanoclusters have surface vapor pressures of order 10( 4) Pa near 300 K, with the surface vapor pressure increasing with increasing values of R through most of the probed concentration range. This suggests that nanocluster surface vapor pressures are substantially enhanced by capillarity effects (the Kelvin effect). Meanwhile, IMS-IMS water uptake measurements show clearly that DMAS nanoclusters uptake water at relative humidities beyond 10% near 300 K, and that larger clusters uptake water to a larger extent. In total, our results suggest that dry DMAS nanoclusters (in the 5-8.5 nm size range in diameter) would not be stable under ambient conditions; however, DMAS nanoclusters would likely be hydrated in the ambient (in some cases above 20% water by mass), which could serve to reduce surface vapor pressures and stabilize them from dissociation. PMID- 25692212 TI - HPV vaccination for prevention of skin cancer. AB - Cutaneous papillomaviruses are associated with specific skin diseases, such as extensive wart formation and the development of non-melanoma skin cancer (NMSC), especially in immunosuppressed patients. Hence, clinical approaches are required that prevent such lesions. Licensed human papillomavirus (HPV) vaccines confer type-restricted protection against HPV types 6, 11, 16 and 18, responsible of 90% of genital warts and 70% of cervical cancers, respectively. However, they do not protect against less prevalent high-risk types or cutaneous HPVs. Over the past few years, several studies explored the potential of developing vaccines targeting cutaneous papillomaviruses. These vaccines showed to be immunogenic and prevent skin tumor formation in certain animal models. Furthermore, under conditions mimicking the ones found in the intended target population (i.e., immunosuppression and in the presence of an already established infection before vaccination), recent preclinical data shows that immunization can still be effective. Strategies are currently focused on finding vaccine formulations that can confer protection against a broad range of papillomavirus-associated diseases. The state-of-the-art of these approaches and the future directions in the field will be presented. PMID- 25692214 TI - Bronsted acid catalyzed asymmetric diels-alder reactions: stereoselective construction of spiro[tetrahydrocarbazole-3,3'-oxindole] framework. AB - The chiral phosphoric acid catalyzed asymmetric Diels-Alder reactions of 2 vinylindoles with methyleneindolinones have been established, which efficiently construct the spiro[tetrahydrocarbazole-3,3'-oxindole] architecture with one quaternary and three contiguous stereogenic centers in high yields (up to 99%) and excellent stereoselectivities (up to >95:5 dr, 97% ee). This reaction not only provides an efficient strategy to access enantioenriched spiro[tetrahydrocarbazole-3,3'-oxindoles] based on hydrogen-bonding activation mode but also supplies successful examples of catalytic asymmetric Diels-Alder reactions for constructing complex spiro-frameworks with optical purity. PMID- 25692215 TI - Measurement of the hydrodynamic radius of quantum dots by fluorescence correlation spectroscopy excluding blinking. AB - One of the most important properties of quantum dots (QDs) is their size. Their size will determine optical properties and in a colloidal medium their range of interaction. The most common techniques used to measure QD size are transmission electron microscopy (TEM) and X-ray diffraction. However, these techniques demand the sample to be dried and under a vacuum. This way any hydrodynamic information is excluded and the preparation process may alter even the size of the QDs. Fluorescence correlation spectroscopy (FCS) is an optical technique with single molecule sensitivity capable of extracting the hydrodynamic radius (HR) of the QDs. The main drawback of FCS is the blinking phenomenon that alters the correlation function implicating in a QD apparent size smaller than it really is. In this work, we developed a method to exclude blinking of the FCS and measured the HR of colloidal QDs. We compared our results with TEM images, and the HR obtained by FCS is higher than the radius measured by TEM. We attribute this difference to the cap layer of the QD that cannot be seen in the TEM images. PMID- 25692216 TI - Q fever through consumption of unpasteurised milk and milk products - a risk profile and exposure assessment. AB - Q fever is a zoonotic disease caused by the bacterium Coxiella burnetii which is endemic in cattle, sheep and goats in much of the world, including the United Kingdom (UK). There is some epidemiological evidence that a small proportion of cases in the developed world may arise from consumption of unpasteurised milk with less evidence for milk products such as cheese. Long maturation at low pH may give some inactivation in hard cheese, and viable C. burnetii are rarely detected in unpasteurised cheese compared to unpasteurised milk. Simulations presented here predict that the probability of exposure per person to one or more C. burnetii through the daily cumulative consumption of raw milk in the UK is 0.4203. For those positive exposures, the average level of exposure predicted is high at 1266 guinea pig intraperitoneal infectious dose 50% units (GP_IP_ID50 ) per person per day. However, in the absence of human dose-response data, the case is made that the GP_IP_ID50 unit represents a very low risk through the oral route. The available evidence suggests that the risks from C. burnetii through consumption of unpasteurised milk and milk products (including cheese) are not negligible but they are lower in comparison to transmission via inhalation of aerosols from parturient products and livestock contact. PMID- 25692217 TI - Shorter mothers have shorter pregnancies. AB - We assessed whether maternal height was associated with gestational age in a cohort of 294 children born at term. Increasing maternal height was associated with longer pregnancy duration (p = 0.002). Stratified analyses showed that the main effect on pregnancy length appears to occur among shorter mothers (<165 cm tall), whose pregnancies were ~0.6 and ~0.7 weeks shorter than pregnancies of mothers 165-170 cm (p = 0.0009) and >170 cm (p = 0.0002) tall, respectively. Further, children of shorter mothers were more likely to be born early term than those of average height (p = 0.021) and taller (p = 0.0003) mothers. Maternal stature is likely to be a contributing factor influencing long-term outcomes in the offspring via its effect on pregnancy length. PMID- 25692219 TI - Temperature management in the new year. PMID- 25692218 TI - Synchrony in serum antibody response to conserved proteins of Streptococcus pneumoniae in young children. AB - Conserved Streptococcus pneumoniae (Spn) proteins are currently under investigation as vaccine candidates. We recently identified a subset of children prone to frequent acute otitis media (AOM) that we refer to as stringently defined otitis prone (sOP). We investigated the synchrony of serum antibody responses against 5 Spn protein vaccine antigens, PhtD, LytB, PcpA, PhtE, and PlyD1 resulting from nasopharyngeal colonization and AOM in sOP children (49 observations) and non-otitis prone (NOP) children (771 observations). Changes in serum IgG and IgM were quantitated with ELISA. IgG antibody concentrations against PhtD, PcpA, and PlyD1 rose in synchrony in sOP and NOP children; that is, the proteins appeared equally and highly immunogenic in children at age 6 to 15 months and then leveled off in their rise at 15 to 25 months. In contrast, rises in concentrations to PhtE and LytB were significantly slower and had not peaked in children even at 25 months of age, consistent with lower immunogenicity. Serum IgM responses against PhtD and PlyD1 were in synchrony in children at age 6-25 months old. PcpA did not induce a significant increase of serum IgM response in children, suggesting that primary responses to PcpA occurred prior to children attaining age 6 months old. PhtD, PcpA, and Ply elicit a synchronous natural acquisition of serum antibody in young children suggesting that a trivalent Spn protein vaccine combining PhtD, PcpA, and PlyD1 would be less likely to display antigen competition when administered as a combination vaccine in young children. PMID- 25692220 TI - Clinical studies targeting stroke. PMID- 25692221 TI - Current advances in the use of therapeutic hypothermia. PMID- 25692222 TI - Clinical Q & A: translating therapeutic temperature management from theory to practice. PMID- 25692223 TI - Instrumental variable estimation in a survival context. AB - Bias due to unobserved confounding can seldom be ruled out with certainty when estimating the causal effect of a nonrandomized treatment. The instrumental variable (IV) design offers, under certain assumptions, the opportunity to tame confounding bias, without directly observing all confounders. The IV approach is very well developed in the context of linear regression and also for certain generalized linear models with a nonlinear link function. However, IV methods are not as well developed for regression analysis with a censored survival outcome. In this article, we develop the IV approach for regression analysis in a survival context, primarily under an additive hazards model, for which we describe 2 simple methods for estimating causal effects. The first method is a straightforward 2-stage regression approach analogous to 2-stage least squares commonly used for IV analysis in linear regression. In this approach, the fitted value from a first-stage regression of the exposure on the IV is entered in place of the exposure in the second-stage hazard model to recover a valid estimate of the treatment effect of interest. The second method is a so-called control function approach, which entails adding to the additive hazards outcome model, the residual from a first-stage regression of the exposure on the IV. Formal conditions are given justifying each strategy, and the methods are illustrated in a novel application to a Mendelian randomization study to evaluate the effect of diabetes on mortality using data from the Health and Retirement Study. We also establish that analogous strategies can also be used under a proportional hazards model specification, provided the outcome is rare over the entire follow-up. PMID- 25692224 TI - Happier, faster: Developmental changes in the effects of mood and novelty on responses. AB - Positive mood ameliorates several cognitive processes: It can enhance cognitive control, increase flexibility, and promote variety seeking in decision making. These effects of positive mood have been suggested to depend on frontostriatal dopamine, which is also associated with the detection of novelty. This suggests that positive mood could also affect novelty detection. In the present study, children and adults saw either a happy or a neutral movie to induce a positive or neutral mood. After that, they were shown novel and familiar images. On some trials a beep was presented over headphones either at the same time as the image or at a 200-ms stimulus onset asynchrony (SOA), and the task of the participant was to detect these auditory targets. Children were slower in responding than adults. Positive mood, however, speeded responses, especially in children, and induced facilitatory effects of novelty. These effects were consistent with increased arousal. Although effects of novelty were more consistent with an attentional response, in children who had watched a happy movie the novel images evoked a more liberal response criterion, suggestive of increased arousal. This suggests that mood and novelty may affect response behaviour stronger in children than in adults. PMID- 25692225 TI - Nano copper oxide-incorporated mesoporous carbon composite as multimode adsorbent for selective isolation of hemoglobin. AB - Assembly of nano-objects with tunable size, morphology and function into integrated nanostructures is critical for the development of a novel nanosystem in adsorption, sensing and drug/gene delivery. We demonstrate herein the fabrication of ordered mesoporous carbon by assembling uniform and highly dispersed copper-oxide (CuxOy) nanoparticles into the mesopores via evaporation of solvent from the mixture of triblock copolymer, carbon source and metal nitrate hydrate. The ordered 2D hexagonal mesoporous carbon composite possesses a large surface area of 580.8 cm(2)/g, a uniform pore size of 5.4 nm, a large pore volume of 0.64 cm(3)/g and a high metal content of 3.32 wt %. The mesoporous composite exhibits excellent adsorption selectivity and high adsorption capacity to hemoglobin (Hb) under the synergistic effect of hydrophobic and metal-affinity interactions as well as size exclusion. This facilitates multimode adsorption of hemoglobin fitting Langmuir adsorption model and offers an adsorption capacity of 1666.7 mg g(-1) for hemoglobin. The mesoporous composite is used for the isolation of hemoglobin from human whole blood with high purity. It demonstrates the potential of the copper-oxide nanoparticle-embedded mesoporous carbon composite in selective isolation/removal of specific protein species from biological sample matrixes. PMID- 25692226 TI - USP9X inhibition promotes radiation-induced apoptosis in non-small cell lung cancer cells expressing mid-to-high MCL1. AB - BACKGROUND AND PURPOSE: Radiotherapy (RT) is vital for the treatment of locally advanced non-small cell lung cancer (NSCLC), yet its delivery is limited by tolerances of adjacent organs. We sought therefore to identify and characterize gene targets whose inhibition may improve RT. MATERIALS AND METHODS: Whole genome pooled shRNA cytotoxicity screens were performed in A549 and NCI-H460 using a retroviral library of 74,705 sequences. Cells were propagated with or without daily radiation Monday-Friday. Radiosensitization by top differential dropout hits was assessed by clonogenic assays. Apoptosis was assessed using a caspase 3/7 cell-based activity assay and by annexin V-FITC and PI staining. MCL1 expression was assessed by qPCR and Western blotting. RESULTS: USP9X, a deubiquitinase, was a top hit among druggable gene products. WP1130, a small molecule USP9X inhibitor, showed synergistic cytotoxicity with IR. MCL1, an anti apoptotic protein deubiquitinated by USP9X, decreased with USP9X inhibition and IR. This was accompanied by increases in caspase 3/7 activity and apoptosis. In a panel of NSCLC lines, MCL1 and USP9X protein and gene expression levels were highly correlated. Lines showing high levels of MCL1 expression were the most sensitive to USP9X inhibition. CONCLUSIONS: These data support the use of MCL1 expression as a predictive biomarker for USP9X inhibitors in NSCLC therapy. PMID- 25692227 TI - Prion protein regulates glutathione metabolism and neural glutamate and cysteine uptake via excitatory amino acid transporter 3. AB - Prion protein (PrP) plays crucial roles in regulating antioxidant systems to improve cell defenses against cellular stress. Here, we show that the interactions of PrP with the excitatory amino acid transporter 3 (EAAT3), gamma glutamyl transpeptidase (gamma-GT), and multi-drug resistance protein 1 (MRP1) in astrocytes and the interaction between PrP and EAAT3 in neurons regulate the astroglial and neuronal metabolism of the antioxidant glutathione. Ablation of PrP in astrocytes and cerebellar neurons leads to dysregulation of EAAT3-mediated uptake of glutamate and cysteine, which are precursors for the synthesis of glutathione. In PrP-deficient astrocytes, levels of intracellular glutathione are increased, and under oxidative stress, levels of extracellular glutathione are increased, due to (i) increased glutathione release via MRP1 and (ii) reduced activity of the glutathione-degrading enzyme gamma-GT. In PrP-deficient cerebellar neurons, cell death is enhanced under oxidative stress and glutamate excitotoxicity, when compared to wild-type cerebellar neurons. These results indicate a functional interplay of PrP with EAAT3, MRP1 and gamma-GT in astrocytes and of PrP and EAAT3 in neurons, suggesting that these interactions play an important role in the metabolic cross-talk between astrocytes and neurons and in protection of neurons by astrocytes from oxidative and glutamate-induced cytotoxicity. Interactions of prion protein (PrP) with excitatory amino acid transporter 3 (EAAT3), gamma-glutamyl transpeptidase (GGT) and multi-drug resistance protein 1 (MRP1) regulate the astroglial and neuronal metabolism of glutathione (GSH) which protects cells against the cytotoxic oxidative stress. PrP controls the release of GSH from astrocytes via MRP1 and regulates the hydrolysis of extracellular GSH by GGT as well as the neuronal and astroglial glutamate and cysteine uptake via EAAT3. PMID- 25692228 TI - Discriminative modulation of the highest occupied molecular orbital energies of graphene and carbon nanotubes induced by charging. AB - The highest occupied molecular orbital (HOMO) energies of carbon nanotubes (CNTs) and graphene are crucial in fundamental and applied research of carbon nanomaterials, and so their modulation is desired. Our first-principles calculations reveal that the HOMO energies of CNTs and graphene can both be raised by negatively charging, and that the rate of increase of the HOMO energy of a CNT is much greater and faster than that of graphene with the same number of C atoms. This discriminative modulation holds true regardless of the number of C atoms and the CNT type, and so is universal. This work provides a new opportunity to develop all-carbon devices with CNTs and graphene as different functional elements. PMID- 25692229 TI - Griffith criterion for brittle fracture in graphene. AB - There are prevailing concerns with the critical dimensions when conventional theories break down. Here we find that the Griffith criterion remains valid for cracks down to 10 nm but overestimates the strength of shorter cracks. We observe the preferred crack extension along the zigzag edge in graphene, and explain this phenomenon by local strength-based failure rather than energy-based Griffith criterion. These results provide a mechanistic basis for reliable applications of graphene in miniaturized devices and nanocomposites. PMID- 25692230 TI - Regulation of gene expression through inefficient splicing of U12-type introns. AB - U12-type introns are a rare class of nuclear introns that are removed by a dedicated U12-dependent spliceosome and are thought to regulate the expression of their target genes owing through their slower splicing reaction. Recent genome wide studies on the splicing of U12-type introns are now providing new insights on the biological significance of this parallel splicing machinery. The new studies cover multiple different organisms and experimental systems, including human patient cells with mutations in the components of the minor spliceosome, zebrafish with similar mutations and various experimentally manipulated human cells and Arabidopsis plants. Here, we will discuss the potential implications of these studies on the understanding of the mechanism and regulation of the minor spliceosome, as well as their medical implications. PMID- 25692231 TI - RNA gymnastics in mammalian signal recognition particle assembly. AB - More than one third of the cellular proteome is destined for incorporation into cell membranes or export from the cell. In all domains of life, the signal recognition particle (SRP) delivers these proteins to the membrane and protein traffic falls apart without SRP logistics. With the aid of a topogenic transport signal, SRP retrieves its cargo right at the ribosome, from where they are sorted to the translocation channel. Mammalian SRP is a ribonucleoprotein complex consisting of an SRP RNA of 300 nucleotides and 6 proteins bound to it. Assembly occurs in a hierarchical manner mainly in the nucleolus and only SRP54, which recognizes the signal sequence and regulates the targeting process, is added as the last component in the cytosol. Here we present an update on recent insights in the structure, function and dynamics of SRP RNA in SRP assembly with focus on the S domain, and present SRP as an example for the complex biogenesis of a rather small ribonucleoprotein particle. PMID- 25692232 TI - Ribosome-associated ncRNAs: an emerging class of translation regulators. AB - Accumulating recent evidence identified the ribosome as binding target for numerous small and long non-protein-coding RNAs (ncRNAs) in various organisms of all 3 domains of life. Therefore it appears that ribosome-associated ncRNAs (rancRNAs) are a prevalent, yet poorly understood class of cellular transcripts. Since rancRNAs are associated with the arguable most central enzyme of the cell it seems plausible to propose a role in translation control. Indeed first experimental evidence on small rancRNAs has been presented, linking ribosome association with fine-tuning the rate of protein biosynthesis in a stress dependent manner. PMID- 25692233 TI - Ribonucleotide triggered DNA damage and RNA-DNA damage responses. AB - Research indicates that the transient contamination of DNA with ribonucleotides exceeds all other known types of DNA damage combined. The consequences of ribose incorporation into DNA, and the identity of protein factors operating in this RNA DNA realm to protect genomic integrity from RNA-triggered events are emerging. Left unrepaired, the presence of ribonucleotides in genomic DNA impacts cellular proliferation and is associated with chromosome instability, gross chromosomal rearrangements, mutagenesis, and production of previously unrecognized forms of ribonucleotide-triggered DNA damage. Here, we highlight recent findings on the nature and structure of DNA damage arising from ribonucleotides in DNA, and the identification of cellular factors acting in an RNA-DNA damage response (RDDR) to counter RNA-triggered DNA damage. PMID- 25692234 TI - The role of microRNAs in osteoclasts and osteoporosis. AB - Osteoclasts are the exclusive cells of bone resorption. Abnormally activating osteoclasts can lead to low bone mineral density, which will cause osteopenia, osteoporosis, and other bone disorders. To date, the mechanism of how osteoclast precursors differentiate into mature osteoclasts remains elusive. MicroRNAs (miRNAs) are novel regulatory factors that play an important role in numerous cellular processes, including cell differentiation and apoptosis, by post transcriptional regulation of genes. Recently, a number of studies have revealed that miRNAs participate in bone homeostasis, including osteoclastic bone resorption, which sheds light on the mechanisms underlying osteoclast differentiation. In this review, we highlight the miRNAs involved in regulating osteoclast differentiation and bone resorption, and their roles in osteoporosis. PMID- 25692235 TI - FMRP interacts with G-quadruplex structures in the 3'-UTR of its dendritic target Shank1 mRNA. AB - Fragile X syndrome (FXS), the most common cause of inherited intellectual disability, is caused by the loss of expression of the fragile X mental retardation protein (FMRP). FMRP, which regulates the transport and translation of specific mRNAs, uses its RGG box domain to bind mRNA targets that form G quadruplex structures. One of the FMRP in vivo targets, Shank1 mRNA, encodes the master scaffold proteins of the postsynaptic density (PSD) which regulate the size and shape of dendritic spines because of their capacity to interact with many different PSD components. Due to their effect on spine morphology, altered translational regulation of Shank1 transcripts may contribute to the FXS pathology. We hypothesized that the FMRP interactions with Shank1 mRNA are mediated by the recognition of the G quadruplex structure, which has not been previously demonstrated. In this study we used biophysical techniques to analyze the Shank1 mRNA 3'-UTR and its interactions with FMRP and its phosphorylated mimic FMRP S500D. We found that the Shank1 mRNA 3 ' -UTR adopts two very stable intramolecular G-quadruplexes which are bound specifically and with high affinity by FMRP both in vitro and in vivo. These results suggest a role of G-quadruplex RNA motif as a structural element in the common mechanism of FMRP regulation of its dendritic mRNA targets. PMID- 25692236 TI - Comprehensive analysis of human small RNA sequencing data provides insights into expression profiles and miRNA editing. AB - MicroRNAs (miRNAs) play key regulatory roles in various biological processes and diseases. A comprehensive analysis of large scale small RNA sequencing data (smRNA-seq) will be very helpful to explore tissue or disease specific miRNA markers and uncover miRNA variants. Here, we systematically analyzed 410 human smRNA-seq datasets, which samples are from 24 tissue/disease/cell lines. We tested the mapping strategies and found that it was necessary to make multiple round mappings with different mismatch parameters. miRNA expression profiles revealed that on average ~70% of known miRNAs were expressed at low level or not expressed (RPM < 1) in a sample and only ~9% of known miRNAs were relatively highly expressed (RPM > 100). About 30% known miRNAs were not expressed in all of our used samples. The miRNA expression profiles were compiled into an online database (HMED, http://bioinfo.life.hust.edu.cn/smallRNA/). Dozens of tissue/disease specific miRNAs, disease/control dysregulated miRNAs and miRNAs with arm switching events were discovered. Further, we identified some highly confident editing sites including 24 A-to-I sites and 23 C-to-U sites. About half of them were widespread miRNA editing sites in different tissues. We characterized that the 2 types of editing sites have different features with regard to location, editing level and frequency. Our analyses for expression profiles, specific miRNA markers, arm switching, and editing sites, may provide valuable information for further studies of miRNA function and biomarker finding. PMID- 25692237 TI - Characterization of binding of LARP6 to the 5' stem-loop of collagen mRNAs: implications for synthesis of type I collagen. AB - Type I collagen is composed of 2 polypeptides, alpha1(I) and alpha2(I), which fold into triple helix. Collagen alpha1(I) and alpha2(I) mRNAs have a conserved stem-loop structure in their 5' UTRs, the 5'SL. LARP6 binds the 5'SL to regulate type I collagen expression. We show that 5 nucleotides within the single stranded regions of 5'SL contribute to the high affinity of LARP6 binding. Mutation of individual nucleotides abolishes the binding in gel mobility shift assay. LARP6 binding to 5'SL of collagen alpha2(I) mRNA is more stable than the binding to 5'SL of alpha1(I) mRNA, although the equilibrium binding constants are similar. The more stable binding to alpha2(I) mRNA may favor synthesis of the heterotrimeric type I collagen. LARP6 needs 2 domains to contact 5'SL, the La domain and the RRM. T133 in the La domain is critical for folding of the protein, while loop 3 in the RRM is critical for binding 5'SL. Loop 3 is also involved in the interaction of LARP6 and protein translocation channel SEC61. This interaction is essential for type I collagen synthesis, because LARP6 mutant which binds 5'SL but which does not interact with SEC61, suppresses collagen synthesis in a dominant negative manner. We postulate that LARP6 directly targets collagen mRNAs to the SEC61 translocons to facilitate coordinated translation of the 2 collagen mRNAs. The unique sequences of LARP6 identified in this work may have evolved to enable its role in type I collagen biosynthesis. PMID- 25692238 TI - Characterization of the UGA-recoding and SECIS-binding activities of SECIS binding protein 2. AB - Selenium, a micronutrient, is primarily incorporated into human physiology as selenocysteine (Sec). The 25 Sec-containing proteins in humans are known as selenoproteins. Their synthesis depends on the translational recoding of the UGA stop codon to allow Sec insertion. This requires a stem-loop structure in the 3' untranslated region of eukaryotic mRNAs known as the Selenocysteine Insertion Sequence (SECIS). The SECIS is recognized by SECIS-binding protein 2 (SBP2) and this RNA:protein interaction is essential for UGA recoding to occur. Genetic mutations cause SBP2 deficiency in humans, resulting in a broad set of symptoms due to differential effects on individual selenoproteins. Progress on understanding the different phenotypes requires developing robust tools to investigate SBP2 structure and function. In this study we demonstrate that SBP2 protein produced by in vitro translation discriminates among SECIS elements in a competitive UGA recoding assay and has a much higher specific activity than bacterially expressed protein. We also show that a purified recombinant protein encompassing amino acids 517-777 of SBP2 binds to SECIS elements with high affinity and selectivity. The affinity of the SBP2:SECIS interaction correlated with the ability of a SECIS to compete for UGA recoding activity in vitro. The identification of a 250 amino acid sequence that mediates specific, selective SECIS-binding will facilitate future structural studies of the SBP2:SECIS complex. Finally, we identify an evolutionarily conserved core cysteine signature in SBP2 sequences from the vertebrate lineage. Mutation of multiple, but not single, cysteines impaired SECIS-binding but did not affect protein localization in cells. PMID- 25692239 TI - Splicing changes in SMA mouse motoneurons and SMN-depleted neuroblastoma cells: evidence for involvement of splicing regulatory proteins. AB - Spinal Muscular Atrophy (SMA) is caused by deletions or mutations in the Survival Motor Neuron 1 (SMN1) gene. The second gene copy, SMN2, produces some, but not enough, functional SMN protein. SMN is essential to assemble small nuclear ribonucleoproteins (snRNPs) that form the spliceosome. However, it is not clear whether SMA is caused by defects in this function that could lead to splicing changes in all tissues, or by the impairment of an additional, less well characterized, but motoneuron-specific SMN function. We addressed the first possibility by exon junction microarray analysis of motoneurons (MNs) isolated by laser capture microdissection from a severe SMA mouse model. This revealed changes in multiple U2-dependent splicing events. Moreover, splicing appeared to be more strongly affected in MNs than in other cells. By testing mutiple genes in a model of progressive SMN depletion in NB2a neuroblastoma cells, we obtained evidence that U2-dependent splicing changes occur earlier than U12-dependent ones. As several of these changes affect genes coding for splicing regulators, this may acerbate the splicing response induced by low SMN levels and induce secondary waves of splicing alterations. PMID- 25692240 TI - Positive correlation between ADAR expression and its targets suggests a complex regulation mediated by RNA editing in the human brain. AB - A-to-I RNA editing by adenosine deaminases acting on RNA is a post transcriptional modification that is crucial for normal life and development in vertebrates. RNA editing has been shown to be very abundant in the human transcriptome, specifically at the primate-specific Alu elements. The functional role of this wide-spread effect is still not clear; it is believed that editing of transcripts is a mechanism for their down-regulation via processes such as nuclear retention or RNA degradation. Here we combine 2 neural gene expression datasets with genome-level editing information to examine the relation between the expression of ADAR genes with the expression of their target genes. Specifically, we computed the spatial correlation across structures of post mortem human brains between ADAR and a large set of targets that were found to be edited in their Alu repeats. Surprisingly, we found that a large fraction of the edited genes are positively correlated with ADAR, opposing the assumption that editing would reduce expression. When considering the correlations between ADAR and its targets over development, 2 gene subsets emerge, positively correlated and negatively correlated with ADAR expression. Specifically, in embryonic time points, ADAR is positively correlated with many genes related to RNA processing and regulation of gene expression. These findings imply that the suggested mechanism of regulation of expression by editing is probably not a global one; ADAR expression does not have a genome wide effect reducing the expression of editing targets. It is possible, however, that RNA editing by ADAR in non-coding regions of the gene might be a part of a more complex expression regulation mechanism. PMID- 25692241 TI - Prospective multi-centre randomised trial comparing induction of labour with a double-balloon catheter versus dinoprostone. AB - This randomised controlled study compared the efficacy of double-balloon catheter versus vaginal prostaglandin E2 (dinoprostone) for induction of labour. In total, 825 pregnant women with cephalic presentation and an unfavourable cervix undergoing induction for conventional indications were randomised to double balloon or vaginal dinoprostone (3 mg) groups. There was a significantly higher failure rate for labour induction in the balloon group (relative risk: 1.25, 95% confidence interval [CI]: 1.02-1.49). Median induction time was 27.3 h in the balloon group and 29.8 h in the dinoprostone group (difference not significant). After 24 h, 55.3% had given birth in the balloon group versus 54.3% in the dinoprostone group. Additional oxytocin stimulation was used more often in the balloon (46%) compared with that in the dinoprostone (34%) (relative risk: 1.34 (95%CI 1.16 -1.54) group. Caesarean section rates and neonatal outcome were similar. Overall, the two methods for induction were comparable with regard to efficacy and safety. PMID- 25692242 TI - Optimal angulations for obtaining an en face view of each coronary aortic sinus and the interventricular septum: Correlative anatomy around the left ventricular outflow tract. AB - An optimal image intensifier angulation used for obtaining an en face view of a target structure is important in electrophysiologic procedures performed around each coronary aortic sinus (CAS). However, few studies have revealed the fluoroscopic anatomy of the target area. This study investigated the optimal angulation for each CAS and the interventricular septum (IVS). The study included 102 consecutive patients who underwent computed tomography coronary angiography. The optimal angle for each CAS was determined by rotating the volume-rendered image around the vertical axis. The angle formed between the anteroposterior axis and IVS was measured using the horizontal section. The frontal direction was defined as zero, positive, or negative if the en face view of the target CAS was obtained in the frontal view, left anterior oblique (LAO) direction, or right anterior oblique (RAO) direction, respectively. The optimal angles for the left, right, and non-CASs were 120.3 +/- 10.5 degrees , 4.8 +/- 16.3 degrees , and 110.0 +/- 13.8 degrees , respectively. The IVS angle was 42.6 +/- 8.5 degrees . Accordingly, the optimal image intensifier angulations for the left, right, and non-CASs and the IVS were estimated to be RAO 60 degrees , LAO 5 degrees , LAO 70 degrees , and RAO 50 degrees , respectively. The IVS angle was the most common independent predictor of the optimal angle for each CAS. Differences in the optimal angulations for each CAS and the IVS are demonstrated. The biplane angulation needs to be tailored according to the individual patients and target structures for electrophysiologic procedures. PMID- 25692244 TI - Architectural Implications for Spatial Object Association Algorithms. AB - Spatial object association, also referred to as crossmatch of spatial datasets, is the problem of identifying and comparing objects in two or more datasets based on their positions in a common spatial coordinate system. In this work, we evaluate two crossmatch algorithms that are used for astronomical sky surveys, on the following database system architecture configurations: (1) Netezza Performance Server(r), a parallel database system with active disk style processing capabilities, (2) MySQL Cluster, a high-throughput network database system, and (3) a hybrid configuration consisting of a collection of independent database system instances with data replication support. Our evaluation provides insights about how architectural characteristics of these systems affect the performance of the spatial crossmatch algorithms. We conducted our study using real use-case scenarios borrowed from a large-scale astronomy application known as the Large Synoptic Survey Telescope (LSST). PMID- 25692243 TI - Synthetic fluorescent probes for studying copper in biological systems. AB - The potent redox activity of copper is required for sustaining life. Mismanagement of its cellular pools, however, can result in oxidative stress and damage connected to aging, neurodegenerative diseases, and metabolic disorders. Therefore, copper homeostasis is tightly regulated by cells and tissues. Whereas copper and other transition metal ions are commonly thought of as static cofactors buried within protein active sites, emerging data points to the presence of additional loosely bound, labile pools that can participate in dynamic signalling pathways. Against this backdrop, we review advances in sensing labile copper pools and understanding their functions using synthetic fluorescent indicators. Following brief introductions to cellular copper homeostasis and considerations in sensor design, we survey available fluorescent copper probes and evaluate their properties in the context of their utility as effective biological screening tools. We emphasize the need for combined chemical and biological evaluation of these reagents, as well as the value of complementing probe data with other techniques for characterizing the different pools of metal ions in biological systems. This holistic approach will maximize the exciting opportunities for these and related chemical technologies in the study and discovery of novel biology of metals. PMID- 25692245 TI - Evaluation of graduate nursing students' information literacy self-efficacy and applied skills. AB - Maintaining evidence-based nursing practice requires information literacy (IL) skills that should be established prior to completing an undergraduate nursing degree. Based on Bandura's social cognitive theory, this cross-sectional descriptive correlational study assessed the perceived and applied IL skills of graduate nursing students from two family nurse practitioner (FNP) programs in the midwestern United States. Results showed that although the 26 newly admitted FNP students demonstrated a high level of confidence in their IL skills, the students did not perform well in the actual IL skills test. According to Bandura, the students' confidence in their IL knowledge should allow students to be engaged in course activities requiring IL skills. Nurse educators teaching in undergraduate or graduate programs are in key positions to incorporate IL experiences into class activities to allow for skill assessment and further practice. Further research is needed on nursing students' IL self-efficacy and performance. PMID- 25692246 TI - Trimethoprim-sulfamethoxazole (cotrimoxazole) desensitization in an HIV-infected 5-yr-old girl. PMID- 25692247 TI - Complementary relationships between traditional media and health apps among american college students. AB - OBJECTIVE: This study explored the potential relationships between existing media and health apps for health information among college students. PARTICIPANTS: This study collected and analyzed a total of 408 surveys from students of 7 universities across the United States. METHODS: In order to explore the research questions and test the hypotheses, quantitative data from the online survey were analyzed through hierarchical regression analyses. RESULTS: Results from the hierarchical regression analyses indicated that the perceived credibility of health information from traditional mass media was positively and significantly associated with college students' perception of health apps. However, there was no significant effect in regards to online media. CONCLUSIONS: This study's consideration of the relationships between existing media and health apps may guide health practitioners in their strategic approaches to improve the well being of college students. PMID- 25692248 TI - Evaluation of heart rate and blood pressure variability as indicators of physiological compensation to hemorrhage before shock. AB - Individual responses to hemorrhage vary, with varying periods of compensation before the development of shock. We characterized heart rate and blood pressure variability measures during hemorrhage of 25 mL/kgBody Weight for 15 min in conscious sheep (N = 7, 14 total hemorrhages) as markers of the transition from compensated to decompensated shock using the continuous wavelet transform. Heart rate-low frequency (HR-LF) and systolic blood pressure-low frequency (SBP-LF) indices were developed to represent the change in spectral power during hemorrhage as low-frequency (0.06 - 0.15 Hz) power divided by the sum of high (0.15 - 1.0 Hz)- and very low (0.02 - 0.06 Hz) frequency power. Heart rate rose from 96.3 (22.2) beats/min (mean [SD] across all trials) to a peak of 176.0 (25.4) beats/min occurring at a minimum time of 5.3 min to a maximum of 22.1 min (11.7 [1.6] min), depending on the trial, after the start of hemorrhage. During the HR-compensated response to hemorrhage, there was elevated HR-LF and SBP-LF in five of the seven animals. In these animals, HR-LF and SBP-LF dropped to below baseline levels around the time of the peak HR. The results from this conscious animal study suggest that HR and SBP low-frequency power rise during the compensation phase of the response to hemorrhage in conscious sheep. Use of variability monitoring could aid in describing an individual's current response to hemorrhage and anticipation of impending decompensation; however, individual differences in the response limit this potential. PMID- 25692249 TI - Safety of D-beta-Hydroxybutyrate and Melatonin for the Treatment of Hemorrhagic Shock With Polytrauma. AB - D-beta-hydroxybutyrate (BHB) and melatonin (M) treatment improves survival in animal models of hemorrhagic shock. Here, we evaluated the safety of BHB/M via 2 routes of administration in a porcine hemorrhagic shock/polytrauma model. Furthermore, we assessed BHB/M serum concentrations after intravenous and intraosseous infusion of different BHB/M doses in healthy pigs. Pigs underwent pulmonary contusion, liver injury, and hemorrhage. Injured animals were treated with an intravenous or intraosseous bolus of BHB/M or lactated Ringer's solution (LR), followed by 4 h of continuous infusion of the respective fluid (n = 12 per group). Pigs were resuscitated with LR (1 h) and then LR and shed blood (20 h). Physiological data and blood samples were analyzed throughout the experiment. In a second study, we infused healthy pigs intravenously or intraosseously with BHB/M at 3 different doses (n = 4 per group). There were no differences between groups in physiologic measurements (heart rate, mean arterial pressure, and cardiac output), organ function markers (alanine aminotransferase, aspartate aminotransferase, serum urea nitrogen, total creatinine kinase, and lactate dehydrogenase), or histopathology. The BHB/M-treated animals exhibited transient changes in blood Na, K, pH, and lactate. Differences in survival were not statistically significant. There was a trend toward decreased survival after intraosseous infusion, potentially related to lower circulating BHB and melatonin levels. Healthy pigs had higher drug serum concentrations after intravenous than after intraosseous infusion of BHB/M at the standard, but not the double dose. D beta-hydroxybutyrate /M in doses previously shown to be associated with improved survival is safe in a porcine hemorrhagic shock/polytrauma model. Intravenous infusion is the preferred route of administration at standard doses. PMID- 25692250 TI - Intrathoracic Pressure Regulation Improves Cerebral Perfusion and Cerebral Blood Flow in a Porcine Model of Brain Injury. AB - Brain injury is a leading cause of death and disability in children and adults in their most productive years. Use of intrathoracic pressure regulation (IPR) to generate negative intrathoracic pressure during the expiratory phase of positive pressure ventilation improves mean arterial pressure and 24-h survival in porcine models of hemorrhagic shock and cardiac arrest and has been demonstrated to decrease intracranial pressure (ICP) and cerebral perfusion pressure (CPP) in these models. Application of IPR for 240 min in a porcine model of intracranial hypertension (ICH) will increase CPP when compared with controls. Twenty-three female pigs were subjected to focal brain injury by insertion of an epidural Foley catheter inflated with 3 mL of saline. Animals were randomized to treatment for 240 min with IPR set to a negative expiratory phase pressure of -12 cmH2O or no IPR therapy. Intracranial pressure, mean arterial pressure, CPP, and cerebral blood flow (CBF) were evaluated. Intrathoracic pressure regulation significantly improved mean CPP and CBF. Specifically, mean CPP after 90, 120, 180, and 240 min of IPR use was 43.7 +/- 2.8 mmHg, 44.0 +/- 2.7 mmHg, 44.5 +/- 2.8 mmHg, and 43.1 +/- 1.9 mmHg, respectively; a significant increase from ICH study baseline (39.5 +/- 1.7 mmHg) compared with control animals in which mean CPP was 36.7 +/- 1.4 mmHg (ICH study baseline) and then 35.9 +/- 2.1 mmHg, 33.7 +/- 2.8 mmHg, 33.9 +/- 3.0 mmHg, and 36.0 +/- 2.7 mmHg at 90, 120, 180, and 240 min, respectively (P < 0.05 for all time points). Cerebral blood flow, as measured by an invasive CBF probe, increased in the IPR group (34 +/- 4 mL/100 g-min to 49 +/- 7 mL/100 g-min at 90 min) but not in controls (27 +/- 1 mL/100 g-min to 25 +/- 5 mL/100 g-min at 90 min) (P = 0.01). Arterial pH remained unchanged during the entire period of IPR compared with baseline values and control values. In this anesthetized pig model of ICH, treatment with IPR significantly improved CPP and CBF. This therapy may be of clinical value by noninvasively improving cerebral perfusion in states of compromised cerebral perfusion. PMID- 25692251 TI - Intrathoracic Pressure Regulation Augments Stroke Volume and Ventricular Function in Human Hemorrhage. AB - Obtaining intravenous (i.v.) access for fluid administration is a critical step in treating hemorrhage. However, expertise, supplies, and personnel to accomplish this task can be delayed or even absent in austere environments. An alternative approach that can "buy time" and improve circulation when i.v. fluids are absent is needed. Preclinical studies show that intrathoracic pressure regulation (ITPR) can increase perfusion in hypovolemia in the absence of i.v. fluid. We compared ITPR with placebo in humans undergoing a 15% hemorrhage under general anesthesia. Paired healthy volunteers (n = 7, aged 21 - 35 years) received either ITPR or placebo on different study days. Institutional review board informed consent was obtained. Subjects were anesthetized using propofol, intubated, and mechanically ventilated and hemorrhaged (10 mL/kg). Twenty minutes after hemorrhage, ITPR (-12 cm H2O vacuum) or placebo (device but no vacuum) was administered for another 60 min. Intravenous fluid was administered when systolic blood pressure was less than 85 mmHg. Hemodynamics, cardiac function by echocardiography, and volumetric data were compared. Data were expressed in Deltamean +/- SEM before and after ITPR/placebo intervention. There were no differences in mean arterial pressure (ITPR, 2.1 +/- 3 mmHg; placebo, -0.7 +/- 3 mmHg) or fluid infused (ITPR, 17.4 +/- 4 mL/kg; placebo, 18.6 +/- 5 mL/kg). Urinary output and plasma volume also were not significantly different. Intrathoracic pressure regulation augmented stroke volume (ITPR, 22 +/- 5 mL, placebo, 6 +/- 4 mL; P < 0.05), ejection fraction (ITPR, 4% +/- 1%; placebo, 0% +/- 1%), and diastolic function (DeltaE/e') (ITPR, 0.8 +/- 0.4 vs. placebo, +0.81 +/- 0.6; P < 0.05). Intrathoracic pressure regulation did not improve mean arterial pressure in healthy volunteers aged 21 to 35 years. However, ITPR augmented stroke volume, which could be caused by improved ventricular function. PMID- 25692252 TI - Effects of ghrelin on postresuscitation brain injury in a rat model of cardiac arrest. AB - Poor neurological outcome remains a major problem in patients with cardiac arrest. Ghrelin has been shown to be neuroprotective in models of neurologic injury in vitro and in vivo. This study was performed to assess the effects of ghrelin on postresuscitation brain injury in a rat model of cardiac arrest. Sprague-Dawley rats were subjected to 6-min cardiac arrest and resuscitated successfully. Either vehicle (saline) or ghrelin (80 MUg/kg) was injected blindly immediately after return of spontaneous circulation (ROSC). A tape removal test was performed to evaluate neurological function at 24, 48, and 72 h after ROSC. Then, brain tissues were harvested and coronal brain sections were analyzed by hematoxylin and eosin (HE) staining for neuronal viability and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining for apoptosis in hippocampal CA1 sectors. In additional groups, rats were sacrificed at 6 h after ROSC, and hippocampal tissues were collected for further analysis. We found that animals treated with ghrelin had improved neurological performances, reduced neuronal injury, and inhibited neuronal apoptosis compared with the vehicle group. Moreover, ghrelin treatment was associated with the following: (1) a decrease in caspase-3 up-regulation and an increased Bcl-2/Bax ratio, (2) a reduction in maleic dialdehyde content and an up-regulation in superoxide dismutase activity, and (3) an increase in uncoupling protein 2 (UCP 2) expression. Our results suggest that ghrelin treatment attenuated postresuscitation brain injury in rats, possibly via regulation of apoptosis, oxidative stress, and mitochondrial UCP-2 expression. Ghrelin may have therapeutic potential when administered after cardiac arrest and cardiopulmonary resuscitation. PMID- 25692254 TI - Development of a Nonhuman Primate (Rhesus Macaque) Model of Uncontrolled Traumatic Liver Hemorrhage. AB - Hemorrhage is the leading cause of potentially survivable trauma mortality, necessitating the development of improved therapeutic interventions. The objective of this study was to develop and characterize a reproducible clinically translatable nonhuman primate model of uncontrolled severe hemorrhage. Such a model is required to facilitate the development and meaningful evaluation of human-derived therapeutics. In Rhesus macaques, a laparoscopic left-lobe hepatectomy of 25% (n = 2), 50% (n = 4), or 60% (n = 6) was performed at T = 0 min, with no attempt at hemorrhage control until T = 120 min. A constant-rate infusion of normal saline was administered between T = 15 and 120 min to a total volume of 20 mL/kg. At T = 120 min, a laparotomy was performed to gain surgical hemostasis and quantify blood loss. Physiological parameters were recorded, and blood samples were collected at defined intervals until termination of the study at T = 480 min. Statistical analyses used Student t tests, with P < 0.05 considered statistically significant. Results are reported as mean +/- SEM. The calculated percent blood loss for the 25% hepatectomy group was negligible (2.3% +/- 0.2%), whereas the 50% and 60% hepatectomy groups exhibited 26.6% +/- 7.1% and 24.9% +/- 3.8% blood loss, respectively. At T = 5 min, blood pressure for the 25%, 50%, and 60% hepatectomy groups was reduced by 13.8%, 60.8%, and 63.2% from the respective baseline values (P < 0.05). In the 60% hepatectomy group, alterations in thromboelastometry parameters and systemic inflammatory markers were observed. The development of a translatable nonhuman primate model of uncontrolled hemorrhage is an ongoing process. This study demonstrates that 60% hepatectomy offers a significant reproducible injury applicable for the evaluation of human-derived therapeutics. PMID- 25692255 TI - Severe lymphopenia is associated with elevated plasma interleukin-15 levels and increased mortality during severe sepsis. AB - Sepsis-related mortality has been found increased in RAG-1 knockout mice. However, in patients admitted to medical intensive care units, it is unknown whether severe lymphocyte depletion at admission is associated with increased interleukin (IL)-7 and IL-15 levels in circulation, and increased mortality. We prospectively enrolled 92 patients who were admitted to medical intensive care units for severe sepsis or septic shock. At admission, 24 patients (26.1%) had severe lymphopenia, defined as lymphocyte counts of less than 0.5 * 10(3)/MUL. Severe lymphopenia was associated with significantly higher plasma levels of tumor necrosis factor alpha, IL-6, IL-8, and IL-10 and was also independently associated with 28-day mortality (adjusted hazard ratio, 3.532; 95% confidence interval, 1.482-8.416; P = 0.004). The levels of plasma IL-15, but not IL-7, were increased modestly in patients with severe lymphopenia compared with those without (median, 12.2 vs. 6.4 pg/mL; P = 0.005). The elevated plasma IL-15 levels were contrarily associated with significantly decreased B-cell lymphoma 2 mRNA expression in peripheral blood mononuclear cells. In conclusion, severe lymphopenia was associated with increased mortality in patients with severe sepsis. We found that patients with sepsis with severe lymphopenia had down regulated B-cell lymphoma 2 mRNA expression in peripheral blood mononuclear cells, despite increased plasma IL-15 concentrations. Whether IL-7 and IL-15 are insufficient in patients with severe lymphopenia during severe sepsis warrants further investigations. PMID- 25692256 TI - Hepatoprotective effect of casodex after trauma hemorrhage in a rodent model. AB - Casodex (bicalutamide), an androgen receptor antagonist, is used for the treatment of prostate cancer. Recent evidences show that Akt signaling pathway exerts organ-protective effects after injury. The aim of this study was to investigate whether Akt plays any role in the casodex-mediated attenuation of hepatic injury after trauma-hemorrhagic shock. Male Sprague-Dawley rats underwent trauma hemorrhage (mean blood pressure kept at approximately 35-40 mm Hg for 90 min), followed by fluid resuscitation. During resuscitation, a single dose of casodex (5 mg/kg, intravenous) with and without a phosphatidylinositol 3-kinase inhibitor wortmannin (1 mg/kg, intravenous), wortmannin or vehicle was administered. Plasma aspartate aminotransferase and alanine aminotransferase levels and various hepatic parameters were measured at 24 h after resuscitation. One-way analysis of variance and the Tukey test were used for statistical analysis. These results showed that trauma hemorrhage increased hepatic myeloperoxidase activity, interleukin 6 and intercellular adhesion molecule 1 levels, and plasma aspartate aminotransferase and alanine aminotransferase concentrations. In the trauma hemorrhage rats treated with casodex, these parameters were significantly improved. Casodex treatment also increased hepatic phospho-Akt expression compared with vehicle-treated trauma hemorrhaged rats. Coadministration of wortmannin with casodex abolished the casodex-induced advantageous effects on the aforementioned parameters and hepatic injury. Our results suggest that the protective effect of casodex administration on attenuation of hepatic injury after trauma hemorrhage, which is, at least in part, through Akt-dependent pathway. PMID- 25692257 TI - Impairment of the endothelial glycocalyx in cardiogenic shock and its prognostic relevance. AB - In cardiogenic shock (CS), pathophysiological changes include microcirculatory dysfunction, vascular leakage, and an increase in platelet and leukocyte adhesion to the endothelium, as well as endothelial activation and dysfunction. The endothelial glycocalyx has been recognized as a central modulator of these processes. Glycosaminoglycan heparan sulfate is a major component of the glycocalyx of endothelial cells, and syndecan-1 (S1) represents the most prevalent proteoglycan. The aim of the current study was to investigate circulating levels of the glycocalyx components in patients with infarct-related CS. In 184 patients with CS complicating acute myocardial infarction, blood samples were collected at admission and after one day. Intra-aortic balloon pumping was used in 94 patients (51%). Glycosaminoglycan heparan sulfate and S1 were measured using standard enzyme-linked immunosorbent assay kits. All-cause mortality at 30 days was used for outcome assessment. Levels of S1 decreased between days 1 and 2 (339 [interquartile range [QR], 109-852] vs. 220 [IQR, 57 606] ng/mL; P = 0.01). In contrast, glycosaminoglycan heparan sulfate increased over time (1.9 [IQR, 0.3-6.4] vs. 7.1 [IQR, 3.7-11.7] mg/mL; P < 0.001). Survivors at 30 days had lower admission S1 levels (P < 0.001). In multivariable analysis, S1 remained an independent predictor of 30-day mortality (odds ratio per MUg/mL, 2.2 [95% confidence interval, 1.30-3.58]; P = 0.003) together with serum lactate, age, and ejection fraction. Increased levels of S1 are an independent predictor of short-term mortality in patients with acute myocardial infarction and CS.ClinicalTrials.gov Identifier: NCT00491036. PMID- 25692259 TI - A Cohort Study of Pediatric Shock: Frequency of Corticosteriod Use and Association with Clinical Outcomes. AB - INTRODUCTION: Pediatric shock is associated with significant morbidity and limited evidence suggests treatment with corticosteroids. The objective of this study was to describe practice patterns and outcomes associated with corticosteroid use in children with shock. METHODS: We conducted a retrospective, cohort study in four pediatric intensive care units (PICU) in Canada. Patients aged newborn to 17 years admitted to PICU with shock between January 2010 and June 2011 were eligible. RESULTS: 364 patients were included. The frequency of hydrocortisone administration was 22.3% overall (95% CI: 18.0, 26.5) and 59.4% in patients who received at least 60 cc/kg of fluid and were on two or more vasoactive agents. Patients administered hydrocortisone had higher PRISM scores (19, IQR 11-24 versus 9, IQR 5-16; P < 0.0001), higher inotrope scores (15, IQR 10-25 versus 7.5, IQR 3.3-10.6, P < 0.0001) and were more likely to have received 60 cc/kg of fluid resuscitation (59.3% versus 33.6%, OR 2.88, 95% CI: 2.09, 3.96). In an adjusted analysis, patients who received hydrocortisone spent more time on vasoactive infusions (64 versus 34 hours, hazard ratio 0.72, 95% CI: 0.62, 0.84) and had a higher incidence of positive cultures between day 4 and day 28 post admission (24.7% versus 14.5%, OR 1.79, 95% CI: 1.58, 2.04). CONCLUSION: Hydrocortisone administration was associated with longer time on vasopressors and increased incidence of positive cultures even after correcting for illness severity. Caution should be exercised in administering hydrocortisone for shock until there is clear evidence for benefit in this patient population. PMID- 25692258 TI - Intestine immune homeostasis after alcohol and burn injury. AB - Traumatic injury remains one of the most prevalent reasons for patients to be hospitalized. Burn injury accounts for 40,000 hospitalizations in the United States annually, resulting in a large burden on both the health and economic system and costing millions of dollars every year. The complications associated with postburn care can quickly cause life-threatening conditions including sepsis and multiple organ dysfunction and failure. In addition, alcohol intoxication at the time of burn injury has been shown to exacerbate these problems. One of the biggest reasons for the onset of these complications is the global suppression of the host immune system and increased susceptibility to infection. It has been hypothesized that infections after burn and other traumatic injury may stem from pathogenic bacteria from within the host's gastrointestinal tract. The intestine is the major reservoir of bacteria within the host, and many studies have demonstrated perturbations of the intestinal barrier after burn injury. This article reviews the findings of these studies as they pertain to changes in the intestinal immune system after alcohol and burn injury. PMID- 25692260 TI - Improving the prediction of mortality and the need for life-saving interventions in trauma patients using standard vital signs with heart-rate variability and complexity. AB - The goal of this study was to determine the effectiveness of using traditional and new vital signs (heart rate variability and complexity [HRV, HRC]) for predicting mortality and the need for life-saving interventions (LSIs) in prehospital trauma patients. Our hypothesis was that statistical regression models using traditional and new vital signs would be superior in predictive performance over models using standard vital signs alone. This study involved 108 prehospital trauma patients transported from the point of injury via helicopter. Heart rate variability and HRC were calculated using criterion standard R-R interval sequences manually verified from the patients' electrocardiograms. Means and standard deviations for vital signs, HRV, HRC, and Glasgow coma scale (GCS) scores were obtained for nonsurvivors versus survivors and LSI versus non-LSI patient groups and then compared using Wilcoxon statistical tests. Receiver operating characteristic curves were also obtained to compare different regression models for predicting mortality and the need for LSIs. Seventeen patients (16%) died. Eighty-two patients (76%) received a total of 142 LSIs. Receiver-operating characteristic curves demonstrated better prediction of mortality and LSI needs using heart rate and HRC (area under the curve [AUC]; AUCs, 0.86 and 0.86) than using heart rate alone (AUCs, 0.79 and 0.57). Likewise, receiver-operating characteristic curves demonstrated better prediction using total GCS score and HRC (AUCs, 0.82 and 0.97) than using total GCS score (AUCs, 0.81 and 0.91). Similar results were obtained for heart rate and HRV (AUCs, 0.86 and 0.73). The major implication of this study was that traditional and new vital signs (HRV and HRC) should be used simultaneously to improve prediction of mortality and the need for LSIs in prehospital trauma patients during all echelons of trauma care. Improvements in the timely use and diagnostic accuracy of transportable vital signs monitors will require use of traditional and new vital signs from the trauma patient cohort. PMID- 25692261 TI - Gamma delta T cells regulate inflammatory cell infiltration of the lung after trauma-hemorrhage. AB - Trauma-hemorrhage (TH) promotes acute lung injury (ALI) and other pulmonary related complications in part through an exaggerated inflammatory response. Studies have implicated gammadelta T cells in the development of inflammatory complications after major injury; however, it is unknown whether gammadelta T cells play a role in the development of ALI after TH. To study this, C57BL/6 wild type (WT) and delta TCR mice were subjected to TH or sham treatment. Lung injury was clearly evident at 2 h after TH, as evidenced by increased lung permeability, myeloperoxidase levels, and proinflammatory cytokine/chemokine levels (interleukin-1beta [IL-1beta], IL-6, IL-10, keratinocyte chemokine, macrophage inflammatory protein 1alpha, macrophage inflammatory protein 1beta, and regulated upon activation normal T-cell expressed, secreted chemokine). Phenotypic analysis of lung cells showed an increase in T-cell numbers after TH. The vast majority of these cells were alphabeta T cells, irrespective of injury. Although gammadelta T cells were a small percentage of the total T-cell infiltrate, their numbers did increase after injury. In mice lacking gammadelta T cells (delta TCR mice), TH induced T-cell infiltration of the lung was markedly attenuated, whereas infiltration of other inflammatory cells was increased (i.e., monocytes, granulocytes, and myeloid-derived suppressor cells). In conclusion, these findings suggest that gammadelta T cells regulated the infiltration of the lung with inflammatory cells after injury. PMID- 25692262 TI - Hierarchical structural design for fracture resistance in the shell of the pteropod Clio pyramidata. AB - The thecosomes are a group of planktonic pteropods with thin, 1 mm-sized aragonitic shells, which are known to possess a unique helical microstructure consisting of interlocking nanofibres. Here we investigate the detailed hierarchical structural and mechanical design of the pteropod Clio pyramidata. We quantify and elucidate the macroscopic distribution of the helical structure over the entire shell (~1 mm), the structural characteristics of the helical assembly (~10-100 MUm), the anisotropic cross-sectional geometry of the fibrous building blocks (~0.5-10 MUm) and the heterogeneous distribution of intracrystalline organic inclusions within individual fibres (<0.5 MUm). A global fibre-like crystallographic texture is observed with local in-plane rotations. Microindentation and electron microscopy studies reveal that the helical organization of the fibrous building blocks effectively constrains mechanical damages through tortuous crack propagation. Uniaxial micropillar compression and cross-sectional transmission electron microscopy directly reveal that the interlocking fibrous building blocks further retard crack propagation at the nanometre scale. PMID- 25692263 TI - Fractalkine (CX3CL1): a biomarker reflecting symptomatic severity in patients with knee osteoarthritis. AB - BACKGROUND: Elevated serum and synovial fluid (SF) fractalkine (CX3CL1) levels have been detected in patients with knee osteoarthritis (OA). The current study was carried out to investigate the association between serum and SF fractalkine levels with symptomatic severity in patients with knee OA. METHOD: One hundred ninety-three patients with OA and 182 healthy controls were enrolled in this study. The symptomatic severity was assessed by the Western Ontario McMaster University Osteoarthritis scores. RESULTS: Fractalkine levels in SF and serum were both positively associated with self-reported greater pain and physical disability. CONCLUSIONS: Fractalkine in SF and serum may serve as a biomarker for reflecting symptomatic severity. Therapeutic interventions that target fractalkine signaling pathways to delay OA-related symptoms deserve further study. PMID- 25692264 TI - Considerably improved photovoltaic performance of carbon nanotube-based solar cells using metal oxide layers. AB - Carbon nanotube-based solar cells have been extensively studied from the perspective of potential application. Here we demonstrated a significant improvement of the carbon nanotube solar cells by the use of metal oxide layers for efficient carrier transport. The metal oxides also serve as an antireflection layer and an efficient carrier dopant, leading to a reduction in the loss of the incident solar light and an increase in the photocurrent, respectively. As a consequence, the photovoltaic performance of both p-single-walled carbon nanotube (SWNT)/n-Si and n-SWNT/p-Si heterojunction solar cells using MoOx and ZnO layers is improved, resulting in very high photovoltaic conversion efficiencies of 17.0 and 4.0%, respectively. These findings regarding the use of metal oxides as multifunctional layers suggest that metal oxide layers could improve the performance of various electronic devices based on carbon nanotubes. PMID- 25692266 TI - Controlling the morphology, composition and crystal structure in gold-seeded GaAs(1-x)Sb(x) nanowires. AB - While III-V binary nanowires are now well controlled and their growth mechanisms reasonably well understood, growing ternary nanowires, including controlling their morphology, composition and crystal structure remains a challenge. However, understanding and control of ternary alloys is of fundamental interest and critical to enable a new class of nanowire devices. Here, we report on the progress in understanding the complex growth behaviour of gold-seeded GaAs1-xSbx nanowires grown by metalorganic vapour phase epitaxy. The competition between As and Sb atoms for incorporation into the growing crystal leads to a tunability of the Sb content over a broad range (x varies from 0.09 to 0.6), solely by changing the AsH3 flow. In contrast, changing TMSb flow is more effective in affecting the morphology and crystal structure of the nanowires. Inclined faults are found in some of these nanowires and directly related to the kinking of the nanowires and controlled by TMSb flow. Combined with the observed sharp increase of wetting angle between the Au seed and nanowire, the formation of inclined faults are attributed to the Au seed being dislodged from the growth front to wet the sidewalls of the nanowires, and are related to the surfactant role of Sb. The insights provided by this study should benefit future device applications relying on taper- and twin-free ternary antimonide III-V nanowire alloys and their heterostructures. PMID- 25692267 TI - Evidence update on prevention of surgical site infection. AB - PURPOSE OF REVIEW: Surgical site infection (SSI) is a common healthcare associated infection and complicates up to 10-20% of operations with considerable strain on healthcare resources. Apart from the widely adopted use of appropriate hair removal, antibiotic prophylaxis, avoidance of hypothermia and perioperative glycaemic control to reduce SSIs, this review has considered new research and systematic reviews, and whether their findings should be included in guidelines. RECENT FINDINGS: The efficacy of preoperative bathing/showering, antibiotic prophylaxis for clean surgery and perioperative oxygen supplementation to reduce the risk of SSI is still in doubt. By contrast, the use of 2% chlorhexidine in alcohol skin preparation, postoperative negative pressure wound therapy and antiseptic surgical dressings do show promise. Antimicrobial sutures in independent meta-analyses were found to reduce the risk of SSI after all classes of surgery (except dirty) whereas the use of wound guards, or diathermy skin incision (compared with scalpel incision), did not. SUMMARY: The incidence of SSI after surgery is not falling. Based on this review of published trials and evidence-based systematic reviews some advances might be included into these care bundles. More research is needed together with improved compliance with care bundles. PMID- 25692268 TI - What is the best therapeutic approach to methicillin-resistant Staphylococcus aureus pneumonia? AB - PURPOSE OF REVIEW: The purpose of this review is to define what the best therapeutic approach is for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) pneumonia. RECENT FINDINGS: Although two meta-analyses reported conflicting findings, recent retrospective studies reported higher success rates in patients with MRSA pneumonia treated with linezolid when compared to vancomycin. Only registration trials are available for some anti-MRSA antibiotics, such as telavancin, ceftaroline, and ceftobiprole. Scarce information is available regarding the best therapeutic approach for MRSA community-acquired pneumonia. SUMMARY: Linezolid seems to be a better choice than vancomycin for the treatment of MRSA ventilator-associated pneumonia. It is still unclear whether this affirmation holds for other forms of MRSA pneumonia. Further research is needed to define whether newer antibiotics are better alternatives than currently recommended agents. PMID- 25692269 TI - New therapeutic options for noncystic fibrosis bronchiectasis. AB - PURPOSE OF REVIEW: Patients with noncystic fibrosis bronchiectasis (NCFB) share many of the respiratory symptoms of cystic fibrosis and often are provided therapies effective in cystic fibrosis, often without clear evidence of benefit. There are currently no approved therapies for NCFB, but in recent years, there has been increased interest in developing new therapies due to the increasing prevalence and perceived unmet needs. This review is meant to provide the most recent information to clinicians about currently available and pipeline therapies for NCFB. RECENT FINDINGS: Inhaled antibiotics may provide effective bacterial suppressive therapy with an acceptable safety profile in adults with NCFB, although evidence of improved outcomes is limited. Inhaled hyperosmolar agents such as hypertonic saline and mannitol are promising but study results have been mixed. Macrolide antibiotics have anti-inflammatory properties and, in several randomized controlled trials, demonstrated the benefit of chronic low-dose treatment. Other anti-inflammatory agents that have shown promising preliminary results include statins and neutrophil elastase inhibitors. SUMMARY: There is high-quality evidence supporting chronic low-dose macrolide therapy in patients with NCFB. There is limited evidence of benefit of other therapies, including inhaled antibiotics and pharmacologic agents to enhance mucus clearance. PMID- 25692270 TI - Rapid diagnostic tests for defining the cause of community-acquired pneumonia. AB - PURPOSE OF REVIEW: We review the potential new diagnostic tools for determining the cause of pneumonia in the setting of community-acquired infection after outlining the limitation of currently available tests. RECENT FINDINGS: A number of new tools are on the horizon with the potential to overcome the problems of existing tests. These tools include new nucleic acid amplification platforms, real-time computer-assisted microscopy, next-generation sequencing and high throughput mass spectrometry. All of these tests still face significant barriers before they can enter general clinical practice including cost, reliability and physician acceptance. SUMMARY: Although new platforms are exciting and do offer the promise of finally moving beyond our current very limited scope of microbiological tests, empiric therapy based on knowledge of local epidemiological data is likely to remain the standard of care until the hurdles of proven accuracy, physician acceptance and cost-effectiveness are successfully negotiated. PMID- 25692271 TI - How to choose the duration of antibiotic therapy in patients with pneumonia. AB - PURPOSE OF REVIEW: The appropriate duration of antimicrobial treatment in patients with pneumonia remains a matter of controversy. The purpose of this article is to review different approaches that have been used to determine the duration of antimicrobial therapy mainly driven either by the antibiotic chosen, isolated pathogen, host characteristics, or severity of the disease. RECENT FINDINGS: When considered individually, every approach has strengths and weaknesses. Targeting the duration of antibiotic therapy based on a single biomarker, such as procalcitonin, is a promising approach that showed a reduction in antibiotic exposure in different settings, diseases, and study populations. Furthermore, an individualized approach according to time to reach clinical stability takes into account all the previous cited factors and may be another feasible and effective strategy to determine the most appropriate duration of the antibiotic therapy in patients with pneumonia. SUMMARY: A shorter duration of antibiotic course based on response to treatment may be favorable in patients with pneumonia due to a potential reduction of adverse events and antibiotic resistance, the opportunity to enhance patients' compliance and to decrease healthcare costs. PMID- 25692272 TI - Antibiotic de-escalation in the ICU: how is it best done? AB - PURPOSE OF REVIEW: An antimicrobial policy consisting of the initial use of wide spectrum antimicrobials followed by a reassessment of treatment when culture results are available is termed de-escalation therapy. Our aim is to examine the safety and feasibility of antibiotic de-escalation in critically ill patients providing practical tips about how to accomplish this strategy in the critical care setting. RECENT FINDINGS: Numerous studies have assessed the rates of de escalation therapy (range from 10 to 60%) in patients with severe sepsis or ventilator-associated pneumonia as well as the factors associated with de escalation. De-escalation generally refers to a reduction in the spectrum of administered antibiotics through the discontinuation of antibiotics or switching to an agent with a narrower spectrum. Diverse studies have identified the adequacy of initial therapy as a factor independently associated with de escalation. Negative impact on different outcome measures has not been reported in the observational studies. Two randomized clinical trials have evaluated this strategy in patients with ventilator-associated pneumonia or severe sepsis. These trials alert us about the possibility that this strategy may be linked to a higher rate of reinfections but without an impact on mortality. SUMMARY: Antibiotic de-escalation is a well tolerated management strategy in critically ill patients but unfortunately is not widely adopted. PMID- 25692273 TI - Novel negative pressure wound therapy with instillation and the management of diabetic foot infections. AB - PURPOSE OF REVIEW: The use of negative pressure wound therapy with instillation (NPWTi) in complex or difficult-to-treat acute and chronic wounds has expanded rapidly since the introduction of commercially available NPWTi systems. We summarize the evidence related to NPWTi and particularly focus on the application of this technology in diabetic foot ulcers, diabetic foot infections and postoperative diabetic wounds. RECENT FINDINGS: The benefits of negative pressure wound therapy (NPWT) are well documented in the treatment of complex acute and chronic wounds, including noninfected postoperative diabetic wounds and diabetic foot ulcers. Combining intermittent wound irrigation with NPWT may offer additional benefits compared to NPWT alone, including further reduction of wound bed bioburden, increased granulation tissue formation and provision of wound irrigation in a sealed environment, thus preventing potential cross-contamination events. Recently, available evidence suggests that adjunctive NPWTi may be superior to standard NPWT in the management of diabetic infections following surgical debridement and may promote granulation tissue formation in slow-to-heal wounds. SUMMARY: Available evidence relating to the utilization of NPWTi in diabetic foot infections is promising but limited in quality, being derived mostly from case series or small retrospective or prospective studies. In order to confirm or refute the potential benefits of NPWTi in this patient cohort, well designed randomized controlled studies are required that compare NPWTi to NPWT or standard wound care methodologies. PMID- 25692274 TI - Alternative clinical indications for novel antibiotics licensed for skin and soft tissue infection? AB - PURPOSE OF REVIEW: A number of novel antibiotics in different classes have been registered and licensed in recent years for complicated skin and soft tissue infections or acute bacterial skin and skin structure infections. Many of these have activity against resistant gram-positive bacteria (linezolid, daptomycin, oritavancin, dalbavancin and tedizolid). In addition, two have gram-negative activity (ceftaroline and tigecycline). The licence for the clinical use of these agents is very narrow, but the clinical need is much broader. This is a personal opinion of the prospective clinical roles for these novel antibiotics. RECENT FINDINGS: All were found to be noninferior to standard comparators in registration trials. There are few data on their use in other clinical conditions outside the narrow confines of the registration trials. 'Off-label' use is likely to be more common than the licensed use, and data need to be collected on clinical and microbiological efficacy and adverse effects in real life. SUMMARY: There is now a wide range of antibiotics for treating complicated skin and soft tissue infections or acute bacterial skin and skin structure infections, and they all have a role in different clinical scenarios. Use in nonlicensed situations needs to be assessed. PMID- 25692275 TI - Trends in surgical site infections following orthopaedic surgery. AB - PURPOSE OF REVIEW: This review presents an update on recent findings relating to the prevention, control and epidemiology of infections following orthopaedic surgery. RECENT FINDINGS: Trends in population rates and characteristics of patients undergoing hip and knee replacement surgery, coupled with the reported excess infection risk in obese patients, emphasize the current and future impact of increasing population obesity on healthcare delivery. SUMMARY: Prevention of orthopaedic infection is dependent on elimination or optimal management of documented risk factors. Guidelines and quality standards play a key role in translating this evidence base into a framework of practices for the prevention of surgical site infections. Increasing levels of orthopaedic infection due to Enterobacteriaceae, coupled with an increasingly obese surgical population may necessitate a reassessment of antimicrobial prophylaxis strategies. PMID- 25692276 TI - Predictors of clinically significant postoperative events after open craniosynostosis surgery. AB - BACKGROUND: Craniosynostosis surgery is associated with clinically significant postoperative events requiring intensive care unit (ICU) admission. The authors investigate specific variables, which might influence the risk for these events, and thereby make recommendations regarding the need for postoperative ICU admission. METHODS: A retrospective review of 225 children undergoing open craniosynostosis repair at a single center during a 10-yr period is reported. The primary outcome measure was the incidence of predefined clinically relevant postoperative cardiorespiratory and hematological events requiring ICU admission. RESULTS: The incidences of postoperative cardiorespiratory and hematological events requiring ICU care were 14.7% (95% CI, 10.5 to 20.1%) and 29.7% (95% CI, 24.0 to 36.3%), respectively. Independent predictors of cardiorespiratory events were body weight less than 10 kg, American Society of Anesthesiologists physical status 3 or 4, intraoperative transfusion of greater than 60 ml/kg packed erythrocytes, and the occurrence of an intraoperative complication. The independent predictors of hematological events were body weight less than 10 kg, American Society of Anesthesiologists physical status 3 or 4, intraoperative transfusion of greater than 60 ml/kg packed erythrocytes, transfusion of hemostatic products (fresh-frozen plasma, platelets, and/or cryoprecipitate), and tranexamic acid not administered. CONCLUSIONS: Children undergoing craniosynostosis surgery are at increased risk for clinically significant postoperative events requiring ICU admission if they are less than 10 kg body weight, American Society of Anesthesiologists physical status 3 or 4, require intraoperative transfusion of greater than 60 ml/kg of packed erythrocytes, receive hemostatic blood products, or if they develop a significant intraoperative complication. Tranexamic acid administration was associated with fewer postoperative events. A predictive clinical algorithm for pediatric patients having major craniosynostosis surgery was developed and validated to risk stratify these patients. PMID- 25692277 TI - Sequence-selective DNA binding with cell-permeable oligoguanidinium-peptide conjugates. AB - Conjugation of a short peptide fragment from a bZIP protein to an oligoguanidinium tail results in a DNA-binding miniprotein that selectively interacts with composite sequences containing the peptide-binding site next to an A/T-rich tract. In addition to stabilizing the complex with the target DNA, the oligoguanidinium unit also endows the conjugate with cell internalization properties. PMID- 25692278 TI - Spontaneous Regression of an Infantile Scalp Tumor. Infantile myofibromatosis. PMID- 25692279 TI - Using a virtual patient in an advanced assessment course. AB - BACKGROUND: A virtual patient, Digital Clinical Experience (DCE), was incorporated into an advanced assessment course. METHOD: Students conducted systems-based physical examinations on the DCE, documenting findings using a standard history format and physical examination skills checklists. Faculty reviewed transcripts generated from the students' history and physical examination to evaluate the logical order and progression of the examination. RESULTS: The nine DCE modules were included as half of the 2-hour weekly laboratory requirement and counted as 17.5% of the course grade. Faculty customized specific components of individual modules, including instructions to students and model documentation, to align with course objectives and faculty preferences. DCE use permitted faculty to provide structured student practice and evaluate essential advanced assessment skills that have not been previously assessed for individual students due to excessive time and cost. CONCLUSION: The potential impact of integrating a virtual patient on students' history taking and physical examination skills in their clinical courses should be explored. PMID- 25692280 TI - Retraction: High uniformity and improved nonlinearity by embedding nanocrystals in selector-less resistive random access memory. PMID- 25692281 TI - Enveloped virus-like particles as vaccines against pathogenic arboviruses. AB - Arthropod-borne arboviruses form a continuous threat to human and animal health, but few arboviral vaccines are currently available. Advances in expression technology for complex, enveloped virus-like particles (eVLPs) create new opportunities to develop potent vaccines against pathogenic arboviruses. In this short review, I highlight the successes and challenges in eVLP production for members of the three major arbovirus families: Flaviviridae (e.g., dengue, West Nile, Japanese encephalitis); Bunyaviridae (e.g., Rift Valley fever); and Togaviridae (e.g., chikungunya). The results from pre-clinical testing will be discussed as well as specific constraints to the large-scale manufacture and purification of eVLPs, which are complex assemblies of membranes and viral glycoproteins. Insect cells emerge as ideal substrates for correct arboviral glycoprotein folding and posttranslational modification to yield high quality eVLPs. Furthermore, baculovirus expression in insect cell culture is scalable and has a proven safety record in industrial human and veterinary vaccine manufacturing. In conclusion, eVLPs produced in insect cells using modern biotechnology have a realistic potential to be used in novel vaccines against arboviral diseases. PMID- 25692282 TI - Development of a list of high-risk operations for patients 65 years and older. AB - IMPORTANCE: No consensus exists regarding the definition of high-risk surgery in older adults. An inclusive and precise definition of high-risk surgery may be useful for surgeons, patients, researchers, and hospitals. OBJECTIVE: To develop a list of high-risk operations. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study and modified Delphi procedure. The setting included all Pennsylvania acute care hospitals (Pennsylvania Health Care Cost Containment Council [PHC4] April 1, 2001, to December 31, 2007) and a nationally representative sample of US acute care hospitals (Nationwide Inpatient Sample [NIS], Healthcare Cost and Utilization Project, Agency for Healthcare Research and Quality January 1, 2001, to December 31, 2006). Patients included were those 65 years and older admitted to PHC4 hospitals and those 18 years and older admitted to NIS hospitals. We identified International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) procedure codes associated with at least 1% inpatient mortality in the PHC4. We used a modified Delphi procedure with 5 board-certified surgeons to further refine this list by excluding nonoperative procedures and operations that were unlikely to be the proximate cause of mortality and were instead a marker of critical illness (eg, tracheostomy). We then cross-validated this list of ICD-9-CM codes in the NIS. MAIN OUTCOMES AND MEASURES: Modified Delphi procedure consensus of at least 4 of 5 panelists and proportion agreement in the NIS. RESULTS: Among 4,739,522 admissions of patients 65 years and older in the PHC4, a total of 2,569,589 involved a procedure, encompassing 2853 unique procedures. Of 1130 procedures associated with a crude inpatient mortality of at least 1%, 264 achieved consensus as high-risk operations by the modified Delphi procedure. The observed inpatient mortality in the NIS was at least 1% for 227 of 264 procedures (86%) in patients 65 years and older. The pooled inpatient mortality for these identified high-risk procedures performed on patients 65 years and older was double the pooled inpatient mortality for correspondingly identified high-risk operations for patients younger than 65 years (6% vs 3%). CONCLUSIONS AND RELEVANCE: We developed a list of procedure codes to identify high-risk surgical procedures in claims data. This list of high-risk operations can be used to standardize the definition of high-risk surgery in quality and outcomes-based studies and to design targeted clinical interventions. PMID- 25692283 TI - APTEC: aptamer-tethered enzyme capture as a novel rapid diagnostic test for malaria. AB - We report the rapid diagnosis of malaria by aptamer-tethered enzyme capture (APTEC) whereby an aptamer captures biomarker Plasmodium falciparum lactate dehydrogenase (PfLDH) then activity is measured colorimetrically. The robust test was sensitive (limit of detection = 4.9 ng mL(-1)) and could reliably diagnose malaria in clinical blood samples. PMID- 25692284 TI - Multifocal endometriotic lesions associated with cancer are clonal and carry a high mutation burden. AB - Endometriosis is a significant risk factor for clear cell and endometrioid ovarian cancers and is often found contiguous with these cancers. Using whole genome shotgun sequencing of seven clear cell ovarian carcinomas (CCC) and targeted sequencing in synchronous endometriosis, we have investigated how this carcinoma may evolve from endometriosis. In every case we observed multiple tumour-associated somatic mutations in at least one concurrent endometriotic lesion. ARID1A and PIK3CA mutations appeared consistently in concurrent endometriosis when present in the primary CCC. In several cases, one or more endometriotic lesions carried the near-complete complement of somatic mutations present in the index CCC tumour. Ancestral mutations were detected in both tumour adjacent and -distant endometriotic lesions, regardless of any cytological atypia. These findings provide objective evidence that multifocal benign endometriotic lesions are clonally related and that CCCs arising in these patients progress from endometriotic lesions that may already carry sufficient cancer-associated mutations to be considered neoplasms themselves, albeit with low malignant potential. We speculate that genomically distinct classes of endometriosis exist and that ovarian endometriosis with high mutational burden represents one class at high risk for malignant transformation. PMID- 25692285 TI - Anti-Inflammatory Activity of Butein and Luteolin Through Suppression of NFkappaB Activation and Induction of Heme Oxygenase-1. AB - Butein and luteolin are members of the flavonoid family, which displays a variety of biological activities. In this study, we demonstrated that butein and luteolin exert anti-inflammatory activities in RAW264.7 macrophages by inducing heme oxygenase-1 (HO-1) expression. Butein and luteolin dose-dependently attenuated inducible nitric oxide synthase (iNOS) expression, leading to the suppression of iNOS-derived nitric oxide (NO) production. The inhibitory effect of butein on NO production was greater than that of luteolin. Consistent with this finding, butein also showed higher inhibitory effects on lipopolysaccharide (LPS)-induced translocation of nuclear factor kappaB (NFkappaB) and NFkappaB reporter gene activity in macrophages than luteolin. Furthermore, the expression of HO-1 was dose-dependently induced by butein and luteolin treatments in macrophages. Additionally, the anti-inflammatory activities of butein and luteolin involved the induction of HO-1 expression, as confirmed by the zinc protoporphyrin (ZnPP) treatment (HO-1 selective inhibitor) and HO-1 small interfering (si)RNA system. ZnPP-mediated downregulation and siRNA-mediated knockdown of HO-1 significantly abolished the inhibitory effects of butein and luteolin on the production of NO in LPS-induced macrophages. Consequently, butein and luteolin were shown to be effective HO-1 inducers capable of inhibiting macrophage-derived proinflammatory mechanisms. These findings indicate that butein and luteolin are potential therapeutic agents for the treatment of inflammatory diseases. PMID- 25692286 TI - High mobility group box 1 induced human lung myofibroblasts differentiation and enhanced migration by activation of MMP-9. AB - High mobility group box 1 (HMGB1) is a nuclear protein that involves the binding with DNA and influences chromatin regulation and transcription. HMGB1 is also a cytokine that can activate monocytes and neutrophils involved in inflammation. In this study, we investigated the role of HMGB1 on cellular activation using human fibroblast cell line WI-38. After treatment with 1, 10, and 100 ng/mL of HMGB1 for 24 h, we did not find obviously cytotoxicity and cellular proliferation of WI 38 cells by MTT and BrdU incorporation assay, respectively. However, we found that treatment with 10 and 100 ng/mL of HMGB1 induced the differentiation of lung fibroblasts into myofibroblasts and myofibroblasts showed higher migration ability through activation of matrix metalloproteinase (MMP)-9 activation. To delineate the mechanism underlying HMGB1-induced cellular migration, we examined HMGB1-induced mitogen activated protein kinases (MAPKs), including extracellular signal related kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 mitogen activated protein kinase (p38) phosphorylation, as well as nuclear factor (NF) kappaB nuclear translocation. Using specific inhibitors and shRNAs of protein kinases, we observed that repression of ERK, JNK, p38, and NF-kappaB all inhibited HMGB1-induced cellular differentiation, migration and MMP-9 activation in WI-38 cells. In addition, knocking down of RAGE but not TLR2 and TLR4 by shRNAs attenuated HMGB1-induced myofibroblast differentiation and migration. In conclusion, our study demonstrated that HMGB1 induced lung fibroblasts' differentiation into myofibroblasts and enhanced cell migration through induction of MMP-9 activation and the RAGE-MAPK and NF-kappaB interaction signaling pathways. Targeting HMGB1 might be a potential therapeutic approach for alleviation of airway remodeling seen in chronic airway inflammatory diseases. PMID- 25692287 TI - Crowdsourcing as a screening tool to detect clinical features of glaucomatous optic neuropathy from digital photography. AB - AIM: Crowdsourcing is the process of simplifying and outsourcing numerous tasks to many untrained individuals. Our aim was to assess the performance and repeatability of crowdsourcing in the classification of normal and glaucomatous discs from optic disc images. METHODS: Optic disc images (N = 127) with pre determined disease status were selected by consensus agreement from grading experts from a large cohort study. After reading brief illustrative instructions, we requested that knowledge workers (KWs) from a crowdsourcing platform (Amazon MTurk) classified each image as normal or abnormal. Each image was classified 20 times by different KWs. Two study designs were examined to assess the effect of varying KW experience and both study designs were conducted twice for consistency. Performance was assessed by comparing the sensitivity, specificity and area under the receiver operating characteristic curve (AUC). RESULTS: Overall, 2,540 classifications were received in under 24 hours at minimal cost. The sensitivity ranged between 83-88% across both trials and study designs, however the specificity was poor, ranging between 35-43%. In trial 1, the highest AUC (95%CI) was 0.64(0.62-0.66) and in trial 2 it was 0.63(0.61-0.65). There were no significant differences between study design or trials conducted. CONCLUSIONS: Crowdsourcing represents a cost-effective method of image analysis which demonstrates good repeatability and a high sensitivity. Optimisation of variables such as reward schemes, mode of image presentation, expanded response options and incorporation of training modules should be examined to determine their effect on the accuracy and reliability of this technique in retinal image analysis. PMID- 25692288 TI - Plant virus particles carrying tumour antigen activate TLR7 and Induce high levels of protective antibody. AB - Induction of potent antibody is the goal of many vaccines targeted against infections or cancer. Modern vaccine designs that use virus-like particles (VLP) have shown efficacy for prophylactic vaccination against virus-associated cancer in the clinic. Here we used plant viral particles (PVP), which are structurally analogous to VLP, coupled to a weak idiotypic (Id) tumour antigen, as a conjugate vaccine to induce antibody against a murine B-cell malignancy. The Id-PVP vaccine incorporates a natural adjuvant, the viral ssRNA, which acts via TLR7. It induced potent protective anti-Id antibody responses in an in vivo mouse model, superior to the "gold standard" Id vaccine, with prevalence of the IgG2a isotype. Combination with alum further increased antibody levels and maintained the IgG2a bias. Engagement of TLR7 in vivo was followed by secretion of IFN-alpha by plasmacytoid dendritic cells and by activation of splenic CD11chi conventional dendritic cells. The latter was apparent from up-regulation of co-stimulatory molecules and from secretion of a wide range of inflammatory cytokines and chemokines including the Th1-governing cytokine IL-12, in keeping with the IgG2a antibody isotype distribution. PVP conjugates are a novel cancer vaccine design, offering an attractive molecular form, similar to VLP, and providing T-cell help. In contrast to VLP, they also incorporate a safe "in-built" ssRNA adjuvant. PMID- 25692289 TI - Correction: thermodynamic system drift in protein evolution. PMID- 25692290 TI - Drinking citrus fruit juice inhibits vascular remodeling in cuff-induced vascular injury mouse model. AB - Citrus fruits are thought to have inhibitory effects on oxidative stress, thereby attenuating the onset and progression of cancer and cardiovascular disease; however, there are few reports assessing their effect on vascular remodeling. Here, we investigated the effect of drinking the juice of two different citrus fruits on vascular neointima formation using a cuff-induced vascular injury mouse model. Male C57BL6 mice were divided into five groups as follows: 1) Control (water) (C), 2) 10% Citrus unshiu (CU) juice (CU10), 3) 40% CU juice (CU40), 4) 10% Citrus iyo (CI) juice (CI10), and 5) 40% CI juice (CI40). After drinking them for 2 weeks from 8 weeks of age, cuff injury was induced by polyethylene cuff placement around the femoral artery. Neointima formation was significantly attenuated in CU40, CI10 and CI40 compared with C; however, no remarkable preventive effect was observed in CU10. The increases in levels of various inflammatory markers including cytokines such as monocyte chemotactic protein-1, interleukin-6 (IL-6), IL-1beta, and tumor necrosis factor-alpha in response to vascular injury did not differ significantly between C, CU10 and CI10. The increases in cell proliferation and superoxide anion production were markedly attenuated in CI10, but not in CU10 compared with C. The increase in phosphorylated ERK expression was markedly attenuated both in CU10 and CI10 without significant difference between CU10 and CI10. Accumulation of immune cells did not differ between CU10 and CI10. These results indicate that drinking citrus fruit juice attenuates vascular remodeling partly via a reduction of oxidative stress. Interestingly, the preventive efficacy on neointima formation was stronger in CI than in CU at least in part due to more prominent inhibitory effects on oxidative stress by CI. PMID- 25692291 TI - Differences in SOM decomposition and temperature sensitivity among soil aggregate size classes in a temperate grasslands. AB - The principle of enzyme kinetics suggests that the temperature sensitivity (Q10) of soil organic matter (SOM) decomposition is inversely related to organic carbon (C) quality, i.e., the C quality-temperature (CQT) hypothesis. We tested this hypothesis by performing laboratory incubation experiments with bulk soil, macroaggregates (MA, 250-2000 MUm), microaggregates (MI, 53-250 MUm), and mineral fractions (MF, <53 MUm) collected from an Inner Mongolian temperate grassland. The results showed that temperature and aggregate size significantly affected on SOM decomposition, with notable interactive effects (P<0.0001). For 2 weeks, the decomposition rates of bulk soil and soil aggregates increased with increasing incubation temperature in the following order: MA>MF>bulk soil >MI(P <0.05). The Q10 values were highest for MA, followed (in decreasing order) by bulk soil, MF, and MI. Similarly, the activation energies (Ea) for MA, bulk soil, MF, and MI were 48.47, 33.26, 27.01, and 23.18 KJ mol-1, respectively. The observed significant negative correlations between Q10 and C quality index in bulk soil and soil aggregates (P<0.05) suggested that the CQT hypothesis is applicable to soil aggregates. Cumulative C emission differed significantly among aggregate size classes (P <0.0001), with the largest values occurring in MA (1101 MUg g-1), followed by MF (976 MUg g-1) and MI (879 MUg g-1). These findings suggest that feedback from SOM decomposition in response to changing temperature is closely associated withsoil aggregation and highlights the complex responses of ecosystem C budgets to future warming scenarios. PMID- 25692292 TI - Hexon modification to improve the activity of oncolytic adenovirus vectors against neoplastic and stromal cells in pancreatic cancer. AB - Primary pancreatic carcinoma has an unfavourable prognosis and standard treatment strategies mostly fail in advanced cases. Virotherapy might overcome this resistance to current treatment modalities. However, data from clinical studies with oncolytic viruses, including replicating adenoviral (Ad) vectors, have shown only limited activity against pancreatic cancer and other carcinomas. Since pancreatic carcinomas have a complex tumor architecture and frequently a strong stromal compartment consisting of non-neoplastic cell types (mainly pancreatic stellate cells = hPSCs) and extracellular matrix, it is not surprising that Ad vectors replicating in neoplastic cells will likely fail to eradicate this aggressive tumor type. Because the TGFbeta receptor (TGFBR) is expressed on both neoplastic cells and hPSCs we inserted the TGFBR targeting peptide CKS17 into the hypervariable region 5 (HVR5) of the capsid protein hexon with the aim to generate a replicating Ad vector with improved activity in complex tumors. We demonstrated increased transduction of both pancreatic cancer cell lines and of hPSCs and enhanced cytotoxicity in co-cultures of both cell types. Surface plasmon resonance analysis demonstrated decreased binding of coagulation factor X to CKS17-modified Ad particles and in vivo biodistribution studies performed in mice indicated decreased transduction of hepatocytes. Thus, to increase activity of replicating Ad vectors we propose to relax tumor cell selectivity by genetic hexon-mediated targeting to the TGFBR (or other receptors present on both neoplastic and non-neoplastic cells within the tumor) to enable replication also in the stromal cell compartment of tumors, while abolishing hepatocyte transduction, and thereby increasing safety. PMID- 25692293 TI - Sequence variations and protein expression levels of the two immune evasion proteins Gpm1 and Pra1 influence virulence of clinical Candida albicans isolates. AB - Candida albicans, the important human fungal pathogen uses multiple evasion strategies to control, modulate and inhibit host complement and innate immune attack. Clinical C. albicans strains vary in pathogenicity and in serum resistance, in this work we analyzed sequence polymorphisms and variations in the expression levels of two central fungal complement evasion proteins, Gpm1 (phosphoglycerate mutase 1) and Pra1 (pH-regulated antigen 1) in thirteen clinical C. albicans isolates. Four nucleotide (nt) exchanges, all representing synonymous exchanges, were identified within the 747-nt long GPM1 gene. For the 900-nt long PRA1 gene, sixteen nucleotide exchanges were identified, which represented synonymous, as well as non-synonymous exchanges. All thirteen clinical isolates had a homozygous exchange (A to G) at position 73 of the PRA1 gene. Surface levels of Gpm1 varied by 8.2, and Pra1 levels by 3.3 fold in thirteen tested isolates and these differences influenced fungal immune fitness. The high Gpm1/Pra1 expressing candida strains bound the three human immune regulators more efficiently, than the low expression strains. The difference was 44% for Factor H binding, 51% for C4BP binding and 23% for plasminogen binding. This higher Gpm1/Pra1 expressing strains result in enhanced survival upon challenge with complement active, Factor H depleted human serum (difference 40%). In addition adhesion to and infection of human endothelial cells was increased (difference 60%), and C3b surface deposition was less effective (difference 27%). Thus, variable expression levels of central immune evasion protein influences immune fitness of the human fungal pathogen C. albicans and thus contribute to fungal virulence. PMID- 25692294 TI - Effect of implant vs. tissue reconstruction on cancer specific survival varies by axillary lymph node status in breast cancer patients. AB - BACKGROUND: To compare the breast cancer-specific survival (BCSS) between patients who underwent tissue or implant reconstruction after mastectomy. METHOD: We used the database from Surveillance, Epidemiology, and End Results (SEER) registries and compared the BCSS between patients who underwent tissue and implant reconstruction after mastectomy. Cox-regression models were fitted, adjusting for known clinicopathological features. The interaction between the reconstruction types (tissue/implant) and nodal status (N-stage) was investigated. RESULTS: A total of 6,426 patients with a median age of 50 years were included. With a median follow up of 100 months, the 10-year cumulative BCSS and non-BCSS were 85.1% and 95.4%, respectively. Patients who underwent tissue reconstruction had tumors with a higher T-stage, N-stage, and tumor grade and tended to be ER/PR-negative compared to those who received implant reconstruction. In univariate analysis, implant-reconstruction was associated with a 2.4% increase (P = 0.003) in the BCSS compared with tissue-reconstruction. After adjusting for significant risk factors of the BCSS (suggested by univariate analysis) and stratifying based on the N-stage, there was only an association between the reconstruction type and the BCSS for the N2-3 patients (10-year BCSS of implant vs. tissue-reconstruction: 68.7% and 59.0%, P = 0.004). The 10-year BCSS rates of implant vs. tissue-reconstruction were 91.7% and 91.8% in N0 patients (P>0.05) and 84.5% and 84.4% in N1 patients (P>0.05), respectively. CONCLUSIONS: The implant (vs. tissue) reconstruction after mastectomy was associated with an improved BCSS in N2-3 breast cancer patients but not in N0-1 patients. A well-designed, prospective study is needed to further confirm these findings. PMID- 25692295 TI - Selection by pollinators on floral traits in generalized Trollius ranunculoides (Ranunculaceae) along altitudinal gradients. AB - Abundance and visitation of pollinator assemblages tend to decrease with altitude, leading to an increase in pollen limitation. Thus increased competition for pollinators may generate stronger selection on attractive traits of flowers at high elevations and cause floral adaptive evolution. Few studies have related geographically variable selection from pollinators and intraspecific floral differentiation. We investigated the variation of Trollius ranunculoides flowers and its pollinators along an altitudinal gradient on the eastern Qinghai-Tibet Plateau, and measured phenotypic selection by pollinators on floral traits across populations. The results showed significant decline of visitation rate of bees along altitudinal gradients, while flies was unchanged. When fitness is estimated by the visitation rate rather than the seed number per plant, phenotypic selection on the sepal length and width shows a significant correlation between the selection strength and the altitude, with stronger selection at higher altitudes. However, significant decreases in the sepal length and width of T. ranunculoides along the altitudinal gradient did not correspond to stronger selection of pollinators. In contrast to the pollinator visitation, mean annual precipitation negatively affected the sepal length and width, and contributed more to geographical variation in measured floral traits than the visitation rate of pollinators. Therefore, the sepal size may have been influenced by conflicting selection pressures from biotic and abiotic selective agents. This study supports the hypothesis that lower pollinator availability at high altitude can intensify selection on flower attractive traits, but abiotic selection is preventing a response to selection from pollinators. PMID- 25692296 TI - Heat-attributable deaths between 1992 and 2009 in Seoul, South Korea. AB - BACKGROUND: Climate change may significantly affect human health. The possible effects of high ambient temperature must be better understood, particularly in terms of certain diseases' sensitivity to heat (as reflected in relative risks [RR]) and the consequent disease burden (number or fraction of cases attributable to high temperatures), in order to manage the threat. PURPOSE: This study investigated the number of deaths attributable to abnormally high ambient temperatures in Seoul, South Korea, for a wide range of diseases. METHOD: The relationship between mortality and daily maximum temperature using a generalized linear model was analyzed. The threshold temperature was defined as the 90th percentile of maximum daily temperatures. Deaths were classified according to ICD 10 codes, and for each disease, the RR and attributable fractions were determined. Using these fractions, the total number of deaths attributable to daily maximum temperatures above the threshold value, from 1992 to 2009, was calculated. Data analyses were conducted in 2012-2013. RESULTS: Heat-attributable deaths accounted for 3,177 of the 271,633 deaths from all causes. Neurological (RR 1.07; 95% CI, 1.04-1.11) and mental and behavioral disorders (RR 1.04; 95% CI, 1.01-1.07) had relatively high increases in the RR of mortality. The most heat-sensitive diseases (those with the highest RRs) were not the diseases that caused the largest number of deaths attributable to high temperatures. CONCLUSION: This study estimated RRs and deaths attributable to high ambient temperature for a wide variety of diseases. Prevention-related policies must account for both particular vulnerabilities (heat-sensitive diseases with high RRs) and the major causes of the heat mortality burden (common conditions less sensitive to high temperatures). PMID- 25692297 TI - Epithelial and stromal cell urokinase plasminogen activator receptor expression differentially correlates with survival in rectal cancer stages B and C patients. AB - Urokinase plasminogen activator receptor (uPAR) has been proposed as a potential prognostic factor for colorectal cancer (CRC) patient survival. However, CRC uPAR expression remains controversial, especially regarding cell types where uPAR is overexpressed (e.g., epithelium (uPARE) or stroma-associated cells (uPARS)) and associated prognostic relevance. In this study, two epitope-specific anti-uPAR monoclonal antibodies (MAbs) could discriminate expression of uPARE from uPARS and were used to examine this association with survival of stages B and C rectal cancer (RC) patients. Using immunohistochemistry, MAbs #3937 and R4 were used to discriminate uPARE from uPARS respectively in the central and invasive frontal regions of 170 stage B and 179 stage C RC specimens. Kaplan-Meier and Cox regression analyses were used to determine association with survival. uPAR expression occurred in both epithelial and stromal compartments with differential expression observed in many cases, indicating uPARE and uPARS have different cellular roles. In the central and invasive frontal regions, uPARE was adversely associated with overall stage B survival (HR = 1.9; p = 0.014 and HR = 1.5; p = 0.031, respectively) reproducing results from previous studies. uPARS at the invasive front was associated with longer stage C survival (HR = 0.6; p = 0.007), reflecting studies demonstrating that macrophage peritumoural accumulation is associated with longer survival. This study demonstrates that different uPAR epitopes should be considered as being expressed on different cell types during tumour progression and at different stages in RC. Understanding how uPARE and uPARS expression affects survival is anticipated to be a useful clinical prognostic marker of stages B and C RC. PMID- 25692298 TI - The European ruminants during the "Microbunodon Event" (MP28, Latest Oligocene): impact of climate changes and faunal event on the ruminant evolution. AB - The Earth already experienced numerous episodes of global warming and cooling. One of the latest impressive events of temperature rising was the Late Oligocene Warming that occurred around 25 Mya. An increase of the marine temperature of 2 to 4 degrees C has been observed in a short time interval. In Europe, this major climatic event can be correlated to the continental faunal turnover "Microbunodon Event". This event is marked by a huge faunal turnover (40% of the ungulate fauna during the first 500k years) and environmental changes. Drier conditions associated to the appearance of the seasonality lead to new environmental conditions dominated by wooded savannahs. This is correlated to a major arrival of Asiatic immigrants. Moreover, from a homogenous fauna during the main part of the Oligocene, local climatic variations between the European Western coast and the more central Europe could have provided faunal regionalism during the latest Oligocene and earliest Miocene. Considering the ruminants, this event is the major ever known for this group in Europe. A total renewal at the family level occurred. Thanks to a precise stratigraphic succession, major evolutionary elements are highlighted. Typical Oligocene species, mainly Tragulina, were adapted to wooded environments and were leaves/fruits eaters. They disappeared at the end of MP27 or the early MP28. This corresponds to the appearance of the Asiatic immigrants. The Tragulina (Lophiomerycidae, Bachitheriidae) and stem Pecora gave way to more derived stem and maybe crown Pecora (e.g. "Amphitragulus", Babameryx, Dremotherium). These newcomers were adapted to more open environments and mixed feeding. The disappearance of the Tragulina is probably linked to environmental and vegetation changes, and competition. They give way to more derived ruminants having a more efficient metabolism in drier conditions and a better assimilation of less energetic food. PMID- 25692299 TI - Noncanonical binding of BiP ATPase domain to Ire1 and Perk is dissociated by unfolded protein CH1 to initiate ER stress signaling. AB - The unfolded protein response (UPR) is an essential cell signaling system that detects the accumulation of misfolded proteins within the endoplasmic reticulum (ER) and initiates a cellular response in order to maintain homeostasis. How cells detect the accumulation of misfolded proteins remains unclear. In this study, we identify a noncanonical interaction between the ATPase domain of the ER chaperone BiP and the luminal domains of the UPR sensors Ire1 and Perk that dissociates when authentic ER unfolded protein CH1 binds to the canonical substrate binding domain of BiP. Unlike the interaction between chaperone and substrates, we found that the interaction between BiP and UPR sensors was unaffected by nucleotides. Thus, we discover that BiP is dual functional UPR sensor, sensing unfolded proteins by canonical binding to substrates and transducing this event to noncanonical, signaling interaction to Ire1 and Perk. Our observations implicate BiP as the key component for detecting ER stress and suggest an allosteric mechanism for UPR induction. PMID- 25692300 TI - A Genome-wide hybrid incompatibility landscape between Caenorhabditis briggsae and C. nigoni. AB - Systematic characterization of hybrid incompatibility (HI) between related species remains the key to understanding speciation. The genetic basis of HI has been intensively studied in Drosophila species, but remains largely unknown in other species, including nematodes, which is mainly due to the lack of a sister species with which C. elegans can mate and produce viable progeny. The recent discovery of a C. briggsae sister species, C. nigoni, has opened up the possibility of dissecting the genetic basis of HI in nematode species. However, the paucity of dominant and visible marker prevents the efficient mapping of HI loci between the two species. To elucidate the genetic basis of speciation in nematode species, we first generated 96 chromosomally integrated GFP markers in the C. briggsae genome and mapped them into the defined locations by PCR and Next Generation Sequencing (NGS). Aided by the marker, we backcrossed the GFP associated C. briggsae genomic fragments into C. nigoni for at least 15 generations and produced 111 independent introgressions. The introgression fragments cover most of the C. briggsae genome. We finally dissected the patterns of HI by scoring the embryonic lethality, larval arrest, sex ratio and male sterility for each introgression line, through which we identified pervasive HI loci and produced a genome-wide landscape of HI between the two nematode species, the first of its type for any non-Drosophila species. The HI data not only provided insights into the genetic basis of speciation, but also established a framework for the possible cloning of HI loci between the two nematode species. Furthermore, the data on hybrids confirmed Haldane's rule and suggested the presence of a large X effect in terms of fertility between the two species. Importantly, this work opens a new avenue for studying speciation genetics between nematode species and allows parallel comparison of the HI with that in Drosophila and other species. PMID- 25692301 TI - Synergistic antimicrobial activity of combinations of sanguinarine and EDTA with vancomycin against multidrug resistant bacteria. AB - A combination of antimicrobial drugs has a potential to overcome multidrug resistant pathogens. In our study we tested the combination of an antimicrobial DNA-intercalating alkaloid (sanguinarine), a chelator (EDTA) with a standard antibiotic (vancomycin), i.e. drugs, which differ in their mode of action. The antibacterial activities of individual substances and of two-drug and three-drug combinations were evaluated for 34 strains of Gram-positive and Gramnegative bacteria (among them 23 clinical isolates) which are not sensitive for vancomycin. MIC and MBC values were determined for each drug individually. Sanguinarine demonstrated a strong activity against all the strains; its activity was comparable to that of antibiotics (MIC = 0.5 - 128 ug/ml). Time kill pharmacokinetics were studied for different concentrations of sanguinarine. A sanguinarine concentration of 16 x MIC was bactericidal against both Gram positive and Gram-negative strains within 4 to 6 h of incubation. EDTA has only bacteriostatic activity against both Gram-positive and Gram-negative bacteria. As expected, vancomycin is active against Gram-positive bacteria (MIC = 0.125 - 16 ug/ml) but much weaker against Gram-negative bacteria (MIC = 4 - 128 ug/ml). Using the checkerboard design, two- and threedrug combinations were evaluated. Additive and synergistic effects were recorded for all sanguinarine + EDTA and sanguinarine + EDTA + vancomycin combinations against Gram-negative bacteria. Time kill assays indicated that only the combination of 1 x MIC sanguinarine + 1 x MIC EDTA + 1 x MIC vancomycin resulted in a synergistic interaction against MRSA. In the combination assays Gram-negative bacteria became sensitive for vancomycin. More experiments are needed to demonstrate that such a combination strategy also works under in vivo conditions and is clinically relevant. PMID- 25692302 TI - Which foods may be addictive? The roles of processing, fat content, and glycemic load. AB - OBJECTIVES: We propose that highly processed foods share pharmacokinetic properties (e.g. concentrated dose, rapid rate of absorption) with drugs of abuse, due to the addition of fat and/or refined carbohydrates and the rapid rate the refined carbohydrates are absorbed into the system, indicated by glycemic load (GL). The current study provides preliminary evidence for the foods and food attributes implicated in addictive-like eating. DESIGN: Cross-sectional. SETTING: University (Study One) and community (Study Two). PARTICIPANTS: 120 undergraduates participated in Study One and 384 participants recruited through Amazon MTurk participated in Study Two. MEASUREMENTS: In Study One, participants (n = 120) completed the Yale Food Addiction Scale (YFAS) followed by a forced choice task to indicate which foods, out of 35 foods varying in nutritional composition, were most associated with addictive-like eating behaviors. Using the same 35 foods, Study Two utilized hierarchical linear modeling to investigate which food attributes (e.g., fat grams) were related to addictive-like eating behavior (at level one) and explored the influence of individual differences for this association (at level two). RESULTS: In Study One, processed foods, higher in fat and GL, were most frequently associated with addictive-like eating behaviors. In Study Two, processing was a large, positive predictor for whether a food was associated with problematic, addictive-like eating behaviors. BMI and YFAS symptom count were small-to-moderate, positive predictors for this association. In a separate model, fat and GL were large, positive predictors of problematic food ratings. YFAS symptom count was a small, positive predictor of the relationship between GL and food ratings. CONCLUSION: The current study provides preliminary evidence that not all foods are equally implicated in addictive-like eating behavior, and highly processed foods, which may share characteristics with drugs of abuse (e.g. high dose, rapid rate of absorption) appear to be particularly associated with "food addiction." PMID- 25692304 TI - Trichosanthin benefits the treatment of caesarean scar pregnancies. AB - This retrospective study aimed to assess the efficacy of trichosanthin (TCS) in combination with or without uterine arteries embolisation (UAE), uterine curettage and sac aspiration for the treatment of caesarean scar pregnancies (CSPs). We enrolled 200 patients at 4-17 weeks' postmenstrual age with suspected CSP. CSP was diagnosed based on serum beta-human chorionic gonadotropin (beta hCG) level and transvaginal ultrasound. The patients were divided into TCS group and non-TCS group, who were treated with TCS and methotrexate, respectively, in combination with UAE and uterine curettage. TCS treatment had a success rate of 96.1% (50 of 52), similar to that in non-TCS group (98.6%, 146/148). Serum beta hCG levels on days 3, 5 and 7 in TCS group were significantly decreased. The complications were fever and pain, which were alleviated with symptomatic treatment. At follow-up, all 52 patients except one case with hysterectomy from TCS treatment group had resumed normal menstruation. In conclusion, TCS combined with bilateral UAE and uterine curettage is a safe and effective treatment for CSP, especially in patients with dangerously high serum beta-hCG levels. PMID- 25692303 TI - Quantitative proteomics reveals an altered cystic fibrosis in vitro bronchial epithelial secretome. AB - Alterations in epithelial secretions and mucociliary clearance contribute to chronic bacterial infection in cystic fibrosis (CF) lung disease, but whether CF lungs are unchanged in the absence of infection remains controversial. A proteomic comparison of airway secretions from subjects with CF and control subjects shows alterations in key biological processes, including immune response and proteolytic activity, but it is unclear if these are due to mutant CF transmembrane conductance regulator (CFTR) and/or chronic infection. We hypothesized that the CF lung apical secretome is altered under constitutive conditions in the absence of inflammatory cells and pathogens. To test this, we performed quantitative proteomics of in vitro apical secretions from air-liquid interface cultures of three life-extended CF (DeltaF508/DeltaF508) and three non CF human bronchial epithelial cells after labeling of CF cells by stable isotope labeling with amino acids in cell culture. Mass spectrometry analysis identified and quantitated 666 proteins across samples, of which 70 exhibited differential enrichment or depletion in CF secretions (+/-1.5-fold change; P < 0.05). The key molecular functions were innate immunity (24%), cytoskeleton/extracellular matrix organization (24%), and protease/antiprotease activity (17%). Oxidative proteins and classical complement pathway proteins that are altered in CF secretions in vivo were not altered in vitro. Specific differentially increased proteins-MUC5AC and MUC5B mucins, fibronectin, and matrix metalloproteinase-9-were validated by antibody-based assays. Overall, the in vitro CF secretome data are indicative of a constitutive airway epithelium with altered innate immunity, suggesting that downstream consequences of mutant CFTR set the stage for chronic inflammation and infection in CF airways. PMID- 25692305 TI - The relationship between lifestyle, occupational health, and work-related factors with presenteeism amongst general practitioners. AB - There is evidence that general practitioners (GPs) are more likely to exhibit sickness presenteeism than other health professional groups or other high-income earners and less likely to take sick leave. This study aims to examine the relationship between lifestyle, occupational health, and work-related factors with presenteeism amongst GPs. A cross-sectional study was conducted amongst GPs in 2011. Logistic regression was used to determine crude and adjusted odds ratios between lifestyle, occupational health, and work-related factors with presenteeism. Whilst adjusting for age and gender, exercising 1 to 3 times a week (odds ratio [OR] = 4.88), not having a good work-life balance (OR = 4.2), work related sleep problems (OR = 2.55), moderate psychological distress (OR = 3.94), and poor or fair health (OR = 6.22) were associated with presenteeism. Increased burnout and reduced job satisfaction and workability due to the physical demands of the job were also associated with presenteeism. In conclusion, presenteeism amongst GPs can be addressed by implementing interventions in relation to physical activity, stress reduction, and sleep hygiene and improving work-life balance and the physical demands of the job. PMID- 25692306 TI - A functional insertion/deletion polymorphism in the promoter region of the NFKB1 gene increases the risk of papillary thyroid carcinoma. AB - This study aimed to assess whether an insertion/deletion polymorphic variation rs28362491 in the NFKB1 promoter region was related to the risk of papillary thyroid carcinoma (PTC). Genomic DNA was extracted from the peripheral venous blood of 352 patients with PTC and 459 controls. The NFKB1 rs28362491 polymorphism was genotyped by using a polymerase chain reaction assay. We found that the frequency of the heterozygous genotype ATTG1/ATTG2 was significantly higher in the cases compared to the controls (odds ratios [OR]=1.44, 95% confidence intervals [CI]=1.05-1.96, p=0.02). Moreover, the frequency of ATTG1/ATTG2+ATTG1/ATTG1 genotypes was significantly elevated in the cases compared to the controls (OR=1.38, 95% CI=1.03-1.85, p=0.03). These findings suggest that the -94 insertion/deletion ATTG polymorphism in the NFKB1 promoter might be associated with an increased risk of PTC. PMID- 25692308 TI - Partial protection against 2009 pandemic influenza A (H1N1) of seasonal influenza vaccination and related regional factors: Updated systematic review and meta analyses. AB - This updated systematic review and meta-analyses aims to systematically evaluate the cross-protection of seasonal influenza vaccines against the 2009 pandemic A (H1N1) influenza infection, and investigate the potential effect of the influenza strains circulating previous to the pandemic on the association between vaccine receipt and pandemic infection. In addition, subgroup analysis was performed based on the study locations and previous circulating influenza viruses. Relevant articles in English and Chinese from 2009 to October 2013 were systematically searched, and 21 eligible studies were included. For case-control studies, an insignificant 20% reduced risk for pandemic influenza infection based on combined national data (OR = 0.80; 95%CI: 0.60, 1.05) was calculated for people receiving seasonal influenza vaccination. However, for RCTs, an insignificant increase in the risk of seasonal influenza vaccines was observed (RR = 1.27; 95% CI: 0.46, 3.53). For the subgroup analysis, a significant 35% cross-protection was observed in the subgroup where influenza A outbreaks were detected before the 2009 pandemic. Moreover, the results indicated that seasonal influenza vaccination may reduce the risk of influenza-like illnesses (ILIs) (RR = 0.91; 95% CI: 0.84, 0.99). Our findings partially support the hypothesis that seasonal vaccines may offer moderate cross-protection for adults against laboratory-confirmed pandemic influenza A (H1N1) infection and ILIs. Further immunological studies are needed to understand the mechanism underlying these findings. PMID- 25692307 TI - Inauhzin(c) inactivates c-Myc independently of p53. AB - Oncogene MYC is deregulated in many human cancers, especially in lymphoma. Previously, we showed that inauhzin (INZ) activates p53 and inhibits tumor growth. However, whether INZ could suppress cancer cell growth independently of p53 activity is still elusive. Here, we report that INZ(c), a second generation of INZ, suppresses c-Myc activity and thus inhibits growth of human lymphoma cells in a p53-independent manner. INZ(c) treatment decreased c-Myc expression at both mRNA and protein level, and suppressed c-Myc transcriptional activity in human Burkitt's lymphoma Raji cells with mutant p53. Also, we showed that overexpressing ectopic c-Myc rescues the inhibition of cell proliferation by INZ(c) in Raji cells, implicating c-Myc activity is targeted by INZ(c). Interestingly, the effect of INZ(c) on c-Myc expression was impaired by disrupting the targeting of c-Myc mRNA by miRNAs via knockdown of ribosomal protein (RP) L5, RPL11, or Ago2, a subunit of RISC complex, indicating that INZ(c) targets c-Myc via miRNA pathways. These results reveal a new mechanism that INZ PMID- 25692309 TI - Laparoscopic middle pancreatectomy: how do I do it? AB - BACKGROUND: Although laparoscopic surgery is now extensively used, laparoscopic middle pancreatectomy (LMP) has rarely been described. STUDY DESIGN AND METHODS: A 45-year-old woman was diagnosed with branch duct intraductal papillary mucinous neoplasia (IPMN) at the pancreatic neck, which was discovered after numerous attacks of acute pancreatitis. LMP was decided on for treatment. RESULTS: The patient underwent pure LMP with right to left dissection and one-layer pancreatogastric anastomosis. Surgery lasted 160 minutes, with 20 mL of blood loss. A frozen section showed negative margins on both sides. The postoperative course was uneventful with 15 days in the hospital. Histology confirmed the diagnosis of branch duct IPMN with moderate dysplasia and negative margins. The patient is symptom free 6 months after surgery. CONCLUSIONS: Our results and the data in the literature suggest that the laparoscopic approach is indicated for middle pancreatectomy because there are no technical or oncological contraindications and the outcome is similar to that with the open approach. PMID- 25692310 TI - One-Year Safety of Olodaterol Once Daily via Respimat(r) in Patients with GOLD 2 4 Chronic Obstructive Pulmonary Disease: Results of a Pre-Specified Pooled Analysis. AB - The novel long-acting beta2-agonist olodaterol demonstrated an acceptable safety profile in short-term phase II clinical studies. This analysis of four randomized, double-blind, placebo-controlled, parallel-group, phase III studies (1222.11, NCT00782210; 1222.12, NCT00782509; 1222.13, NCT00793624; 1222.14, NCT00796653) evaluated the long-term safety of olodaterol once daily (QD) in a large cohort of patients with moderate to very severe (Global initiative for chronic Obstructive Lung Disease 2-4) chronic obstructive pulmonary disease (COPD). The studies compared olodaterol (5 or 10 MUg) QD via Respimat(r), formoterol 12 MUg twice daily (BID) via Aerolizer(r) (1222.13 and 1222.14), and placebo for 48 weeks. Patients continued receiving background maintenance therapy, with ~60% receiving concomitant cardiovascular therapy and 25% having a history of concomitant cardiac disease. Pre-specified analyses of pooled data assessed the adverse events (AEs) and serious AEs in the whole population, and in subgroups with cardiac disease, along with in-depth electrocardiogram and Holter monitoring. In total, 3104 patients were included in the safety analysis: 876 received olodaterol 5 MUg, 883 received olodaterol 10 MUg, 885 received placebos, and 460 received formoterol 12 MUg BID. Overall incidence of on-treatment AEs (71.2%), serious AEs (16.1%), and deaths (1.7%) were balanced across treatment groups. Respiratory and cardiovascular AEs, including major adverse cardiac events, were reported at similar frequencies in placebo and active treatment groups. The safety profiles of both olodaterol 5 MUg (marketed and registered dose) and 10 MUg QD delivered via Respimat(r) are comparable to placebo and formoterol BID in this population, with no safety signals identified. PMID- 25692311 TI - Perceived Built Environment Characteristics of On-Campus and Off-Campus Neighborhoods Associated With Physical Activity of College Students. AB - OBJECTIVE: To identify differences in neighborhood environment and their association with physical activity (PA) levels of on-campus compared with off campus students. PARTICIPANTS: Participants were 822 undergraduate students at a mid-sized mid-Atlantic university. METHODS: Students completed the Neighborhood Environment Walkability Scale-Abbreviated and the International Physical Activity Questionnaire in October 2013. RESULTS: Lower residential density, traffic safety, and crime scores and higher land-use mix diversity, aesthetics, and lack of parking scores were reported among on-campus residents. On-campus residents reported higher levels of active transportation PA, leisure PA, and total PA. Land-use mix diversity, aesthetics, and lack of cul-de-sacs were associated with physical activity level. CONCLUSION: The on-campus and off-campus environments differ in ways that may impact the ability of undergraduate students to be physically active. Strategies to promote continued active transportation and leisure PA are discussed. PMID- 25692312 TI - Predictors of Recurrent Stroke in Patients with Ischemic Stroke: Comparison Study between Transesophageal Echocardiography and Cardiac CT. AB - PURPOSE: To investigate cardiac computed tomographic (CT) findings predictive of recurrent stroke in patients with ischemic stroke and determine the incremental risk stratification benefit of cardiac CT findings compared with transesophageal echocardiography (TEE) findings in patients with ischemic stroke. MATERIALS AND METHODS: This single-center prospective study protocol was approved by the institutional review boards, and written informed consent was obtained from all patients. Among 548 consecutive patients, 374 patients with ischemic stroke (254 men and 120 women, with a mean age of 63.1 years) who underwent TEE and cardiac CT were prospectively enrolled in this study. TEE and cardiac CT images were assessed for cardioembolic sources, including thrombus, tumor, spontaneous echo contrast, valvular vegetation, atrial septal aneurysm, patent foramen ovale, and aortic plaque. The primary end point was stroke recurrence. Prognostic factors were assessed with Cox univariate and multivariate analysis. The integrated area under the receiver operating characteristic curve was calculated to compare the prognostic abilities of CT and TEE parameters. RESULTS: During a median follow-up period of 433 days, there were a total of 28 recurrent stroke events. The TEE parameter of plaque complexity (hazard ratio, 13.512; 95% confidence interval: 3.668, 49.778; P < .001) and CT parameter of plaque complexity (hazard ratio, 32.538; 95% confidence interval: 7.544, 140.347; P < .001) were predictors of recurrent stroke. The time-dependent receiver operating characteristic curve analysis demonstrated no significant differences in prediction of recurrent stroke between TEE and CT parameters (integrated area under the receiver operating characteristic curve, 0.812 vs 0.840, respectively). CONCLUSION: Complex aortic plaque evaluated with cardiac CT and TEE was associated with an increased risk of stroke recurrence in patients with ischemic stroke. PMID- 25692313 TI - Social marketing to promote HPV vaccination in pre-teenage children: talk about a sexually transmitted infection. AB - A significant barrier to the delivery of HPV vaccine is reluctance by both healthcare providers and parents to vaccinate at age 11 or 12, which may be considered a young age. This barrier has been called "vaccine hesitancy" in recent research. In this commentary, we suggest using social marketing strategies to promote HPV vaccination at the recommended preteen ages. We emphasize a critical public health message of a sexually transmitted infection (STI) as preventable and vaccination against HPV as a way to protect against its consequences. The message tackles the issue of vaccine hesitancy head on, by saying that most people are at risk for HPV and there is a way to prevent HPV's serious consequences of cancer. Our approach to this conversation in the clinical setting is also to engage the preteen in a dialog with the parent and provider. We expect our emphasis on the risk of STI infection will not only lead to increased HPV vaccination at preteen ages but also lay important groundwork for clinical adoption of other STI vaccines in development (HIV, HSV, Chlamydia, and Gonorrhea) as well as begin conversations to promote sexual health. PMID- 25692314 TI - An investigation into the role of polymeric carriers on crystal growth within amorphous solid dispersion systems. AB - Using phase diagrams derived from Flory-Huggins theory, we defined the thermodynamic state of amorphous felodipine within three different polymeric carriers. Variation in the solubility and miscibility of felodipine within different polymeric materials (using F-H theory) has been identified and used to select the most suitable polymeric carriers for the production of amorphous drug polymer solid dispersions. With this information, amorphous felodipine solid dispersions were manufactured using three different polymeric materials (HPMCAS HF, Soluplus, and PVPK15) at predefined drug loadings, and the crystal growth rates of felodipine from these solid dispersions were investigated. Crystallization of amorphous felodipine was studied using Raman spectral imaging and polarized light microscopy. Using this data, we examined the correlation among several characteristics of solid dispersions to the crystal growth rate of felodipine. An exponential relationship was found to exist between drug loading and crystal growth rate. Moreover, crystal growth within all selected amorphous drug-polymer solid dispersion systems were viscosity dependent (eta(-xi)). The exponent, xi, was estimated to be 1.36 at a temperature of 80 degrees C. Values of xi exceeding 1 may indicate strong viscosity dependent crystal growth in the amorphous drug-polymer solid dispersion systems. We argue that the elevated exponent value (xi > 1) is a result of drug-polymer mixing which leads to a less fragile amorphous drug-polymer solid dispersion system. All systems investigated displayed an upper critical solution temperature, and the solid-liquid boundary was always higher than the spinodal decomposition curve. Furthermore, for PVP-FD amorphous dispersions at drug loadings exceeding 0.6 volume ratio, the mechanism of phase separation within the metastable zone was found to be driven by nucleation and growth rather than liquid-liquid separation. PMID- 25692315 TI - Impact of iron and folic acid supplementation on oxidative stress during pregnancy. AB - The aim of the study was to assess serum total antioxidant capacity (TAC) and the impact of supplements on oxidative stress (OS) during pregnancy. Fifty volunteer pregnant women (21-40 years old), in the 12 +/- 2 weeks' and 38 +/- 2 weeks' gestation of pregnancy (study group), and 25 non-pregnant healthy women (control group) were enrolled. All pregnant women were divided into two age groups (A1: < 35 years and A2: >= 35 years) and four groups according to supplementation (B1: iron, B2: folic acid, B3: both and B4: none). Antioxidant activity was assayed using the TAC kit (Cayman Chemical Co.). Level of statistical significance was p < 0.05. Serum TAC values in all pregnant women in the first trimester were significantly lower, as compared with those of the control group. Levels of TAC increased significantly in the third trimester of pregnancy, especially with folic acid or no supplementation. In conclusion, pregnancy is associated with OS, which is promoted by the administration of iron supplementation. PMID- 25692316 TI - Patchy particle packing under electric fields. AB - Colloidal particles equipped with two, three, or four negatively charged patches, which endow the particles with 2-fold, 3-fold, or tetrahedral symmetries, form 1D chains, 2D layers, and 3D packings when polarized by an AC electric field. Two patch particles, with two patches on opposite sides of the particle (2-fold symmetry) pack into the cmm plane group and 3D packings with I4mm space group symmetry, in contrast to uncharged spherical or ellipsoidal colloids that typically crystallize into a face-centered ABC layer packing. Three-patch particles (3-fold symmetry) form chains having a 21 screw axis symmetry, but these chains pair in a manner such that each individual chain has one-fold symmetry but the pair has 21 screw axis symmetry, in an arrangement that aligns the patches that would favor Coulombic interactions along the chain. Surprisingly, some chain pairs form unanticipated double-helix regions that result from mutual twisting of the chains about each other, illustrating a kind of polymorphism that may be associated with nucleation from short chain pairs. Larger 2D domains of the three-patch particles crystallize in the p6m plane group with alignment (with respect to the field) and packing densities that suggest random disorder in the domains, whereas four-patch particles form 2D domains in which close-packed rows are aligned with the field. PMID- 25692317 TI - Low contribution of PbO2-coated lead service lines to water lead contamination at the tap. AB - To determine if residential water sampling corroborates the expectation that formation of stable PbO2 coatings on lead service lines (LSLs) provides an effective lead release control strategy, lead profile sampling was evaluated for eight home kitchen taps in three U.S. cities with observed PbO2-coated LSLs (Newport, Rhode Island; Cincinnati and Oakwood, Ohio). After various water standing times, these LSLs typically released similar or lower peak lead levels (1 to 18 MUg/L) than the lead levels from the respective kitchen faucets (1 to 130 MUg/L), and frequently 50-80% lower than the lead levels typically reported from Pb(II)-coated LSLs in comparable published sampling studies. Prolonged stagnation (10-101 h) at the Cincinnati sites produced varying results. One site showed minimal (0-4 MUg/L) increase in lead release from the PbO2-coated LSL, and persistence of free chlorine residual. However, the other site showed up to a 3 fold increase proportional to standing time, with essentially full depletion of the chlorine residual. Overall, lead release was consistently much lower than that reported in studies of Pb(II)-coated LSL scales, suggesting that natural formation of PbO2 in LSLs is an effective lead "corrosion" control strategy. PMID- 25692318 TI - Tough coating proteins: subtle sequence variation modulates cohesion. AB - Mussel foot protein-1 (mfp-1) is an essential constituent of the protective cuticle covering all exposed portions of the byssus (plaque and the thread) that marine mussels use to attach to intertidal rocks. The reversible complexation of Fe(3+) by the 3,4-dihydroxyphenylalanine (Dopa) side chains in mfp-1 in Mytilus californianus cuticle is responsible for its high extensibility (120%) as well as its stiffness (2 GPa) due to the formation of sacrificial bonds that help to dissipate energy and avoid accumulation of stresses in the material. We have investigated the interactions between Fe(3+) and mfp-1 from two mussel species, M. californianus (Mc) and M. edulis (Me), using both surface sensitive and solution phase techniques. Our results show that although mfp-1 homologues from both species bind Fe(3+), mfp-1 (Mc) contains Dopa with two distinct Fe(3+) binding tendencies and prefers to form intramolecular complexes with Fe(3+). In contrast, mfp-1 (Me) is better adapted to intermolecular Fe(3+) binding by Dopa. Addition of Fe(3+) did not significantly increase the cohesion energy between the mfp-1 (Mc) films at pH 5.5. However, iron appears to stabilize the cohesive bridging of mfp-1 (Mc) films at the physiologically relevant pH of 7.5, where most other mfps lose their ability to adhere reversibly. Understanding the molecular mechanisms underpinning the capacity of M. californianus cuticle to withstand twice the strain of M. edulis cuticle is important for engineering of tunable strain tolerant composite coatings for biomedical applications. PMID- 25692319 TI - Devitrification properties of vapor-deposited ethylcyclohexane glasses and interpretation of the molecular mechanism for formation of vapor-deposited glasses. AB - We constructed an adiabatic calorimeter adapted for the preparation and in situ thermal characterization of vapor-deposited glasses and reported the investigation of the enthalpic states and dynamic properties of ethylcyclohexane (ECH) glasses prepared by vapor deposition in the temperature range of (0.71 0.96)Tg,liq; Tg,liq = (101 +/- 1) K is the calorimetric glass transition temperature of the bulk liquid. It was verified that the ECH glasses deposited at temperatures immediately below Tg,liq were characterized by lower enthalpies and higher devitrification temperatures (Tdev), as compared to the glass obtained by supercooling the bulk liquid. The deposition temperature (TD) expected to yield experimentally the entity with the highest Tdev and the lowest enthalpic state was estimated to be 0.93Tg,liq. A model potentially elucidating the fundamental mechanism of formation and devitrification for the glasses prepared via the physical vapor deposition method as a function of TD was proposed. The fundamental point is that the glass is formed by deposition in a molecule-by molecule fashion and the molecule deposited is frozen in a certain configuration determined by its being itself on the surface. For amorphous entities prepared at a TD much lower than Tg,liq, the surface molecule is frozen mostly as they are deposited. For the entity deposited at TD = 0.93Tg,liq in the case of ECH, the surface molecule is mobile immediately after the deposition to look for its stable configuration only on account of the intermolecular interactions with the molecules beneath and in the same surface layer as itself and freezes in a certain reasonably stable configuration; the molecules below the surface layer have already frozen in and get more stabilization energy through the additional interactions with the surface molecules. As a result, the intermolecular interaction of the molecules accumulated in such a way is stronger than that in the bulk liquid glass. It is argued that this is the fundamental reason why the glass formed immediately below Tg,liq has a lower enthalpy and a higher devitrification temperature than those of the liquid-cooled one. PMID- 25692320 TI - Metal-free oxidative functionalization of C(sp(3))-H bond adjacent to oxygen and radical addition to olefins. AB - A DTBP-promoted oxidative functionalization of a C(sp(3))-H bond adjacent to oxygen and intermolecular radical addition to olefins without use of any metal catalyst or photoredox catalysis is reported. The reaction has a wide scope of olefin, alcohol, and cycloether substrates, which provides an easy way for direct preparation of alpha,omega-amino alcohols. PMID- 25692321 TI - Development of a highly active electrocatalyst via ultrafine Pd nanoparticles dispersed on pristine graphene. AB - A unique synthesis was developed to immobilize Pd nanoparticles on pristine graphene (PG) sheets via a facile supercritical carbon dioxide route. Pristine graphene was obtained by sonication-assisted exfoliation of graphite in an organic solvent. Finely dispersed worm-like Pd nanoparticles are homogeneously deposited on the hydrophobic graphene surfaces. The combination of pristine graphene sheets and well-dispersed Pd nanoparticles provided large electrochemically active surface areas (ECSA) for both direct formic acid fuel cell (DFAFC) and methanol fuel cell (DMFC). The ECSA values are more than twice as large as those of reduced graphene oxide and carbon nanotube based counterparts or six times those of conventional XC-72 carbon black. Significant enhancements were also observed in the electrocatalytic activity and stability measurements. The excellent electrochemical property of Pd/PG is attributable to the well-preserved graphene structure that ensures electrical conductivity and stability of the composite. Its large surface area also allows for the deposition of small size and high dispersion of the Pd nanoparticles. This straightforward synthesis offers a new pathway for developing highly active electrocatalysts based on pristine graphene with fully optimized properties. PMID- 25692322 TI - Aminobenzofuran-fused rhodamine dyes with deep-red to near-infrared emission for biological applications. AB - Aminobenzofuran-fused rhodamine dyes (AFR dyes) containing an amino group were constructed by an efficient condensation based on 3-coumaranone derivatives. AFR dyes exhibited significantly improved properties, including deep-red and near infrared emissions, a large Stokes shift, good photostability, and wide pH stability. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium assay experiments show that these AFR dyes are biocompatible for their low cytotoxicity to both A549 and HeLa cells. Cell imaging data reveal that AFR1, AFR1E, and AFR2 are mainly located in the mitochondria, while AFR3 is a lysosome tracker. As far as we know, NIR AFR3 is the longest fluorescent rhodamine derivative containing the amino group. These amino group-containing AFR dyes hold great potential in fluorogenic detection, biomolecule labeling, and cell imaging. PMID- 25692323 TI - Excited-state proton transfer of weak photoacids adsorbed on biomaterials: 8 hydroxy-1,3,6-pyrenetrisulfonate on chitin and cellulose. AB - Time-resolved and steady-state florescence measurements were used to study the photoprotolytic process of an adsorbed photoacid on cellulose and chitin. For that purpose we used the 8-hydroxy-1,3,6-pyrenetrisulfonate (HPTS) photoacid which transfers a proton to water with a time constant of 100 ps, but is incapable of doing so in methanol or ethanol. We found that both biopolymers accept a proton from the electronically excited acidic ROH form of HPTS. The excited-state proton-transfer (ESPT) rate of HPTS adsorbed on chitin is greater than that on cellulose by a factor of 5. The ESPT on chitin also occurs in the presence of methanol or ethanol, but at a slower rate. The transferred protons can recombine efficiently with the conjugate excited base, the RO(-) form of HPTS. PMID- 25692324 TI - Na2RE2TeO4(BO3)2 (RE = Y, Dy-Lu): luminescent and structural studies on a series of mixed metal borotellurates. AB - The first examples of metal borotellurates, namely, Na2RE2TeO4(BO3)2 (RE = Y, Dy Lu) have been prepared by using solid-state reactions. They possess similar structures and crystallize in space group P21/c (No. 14). These compounds feature a novel [RE2TeO4(BO3)2](2-) 3D network structure composed of linear [TeO4(BO3)2](8-) anions interconnected by RE(3+) ions with the voids of the network filled by the Na(+) ions. They exhibit high thermal stability (higher than 800 degrees C). Results of magnetic measurements on Dy, Ho, and Er compounds indicate that they display weak antiferromagnetic interaction between RE(III) centers. Luminescent studies show that Na2Er2TeO4(BO3)2 has a strong emission at 1.562 MUm with a wide fwhm (70 nm) and moderate lifetime (0.18 ms), whereas Na2Yb2TeO4(BO3)2 has a strong NIR region emission around 1.02 MUm. Furthermore, UV-vis-NIR absorption spectra, infrared spectra, and DFT calculations for the Y compound as a representative were also accomplished. PMID- 25692325 TI - Immunomodulating properties of protein hydrolysates for application in cow's milk allergy. AB - Cow's milk proteins cause allergic symptoms in 2-3% of all infants. In these individuals, the tolerogenic state of the intestinal immune system is broken, which can lead to sensitization against antigens and eventually to allergic responses. Although a true treatment for food allergy is not available, symptoms can be avoided by providing the infants with hydrolyzed proteins. Hydrolyzed proteins are proteins that are enzymatically degraded. They lack typical allergenic IgE-binding epitopes but are also thought to play a pertinent role in other mechanisms inducing hypoallergenic effects. This review discusses the mechanisms and evidence for immunomodulating properties of cow's milk hydrolysates. Hydrolysates are found to strengthen the epithelial barrier, modulate T-cell differentiation, and decrease inflammation. Some studies suggest a role for hydrolysates in manipulating pathogen recognition receptors signaling as underlying mechanism. Peptides from hydrolysates have been shown to bind to TLR2 and TLR4 and influence cytokine production in epithelial cells and macrophages. Current insight suggests that hydrolysates may actively participate in modulating the immune responses in subjects with cow's milk allergy and those at risk to develop cow's milk allergy. However, more research is required to design effective and reproducible means to develop targeting strategies to modulate the immune response. PMID- 25692326 TI - Pharmacological interventions for those who have sexually offended or are at risk of offending. AB - BACKGROUND: Sexual offending is a serious social problem, a public health issue, and a major challenge for social policy. Victim surveys indicate high incidence and prevalence levels and it is accepted that there is a high proportion of hidden sexual victimisation. Surveys report high levels of psychiatric morbidity in survivors of sexual offences.Biological treatments of sex offenders include antilibidinal medication, comprising hormonal drugs that have a testosterone suppressing effect, and non-hormonal drugs that affect libido through other mechanisms. The three main classes of testosterone-suppressing drugs in current use are progestogens, antiandrogens, and gonadotropin-releasing hormone (GnRH) analogues. Medications that affect libido through other means include antipsychotics and serotonergic antidepressants (SSRIs). OBJECTIVES: To evaluate the effects of pharmacological interventions on target sexual behaviour for people who have been convicted or are at risk of sexual offending. SEARCH METHODS: We searched CENTRAL (2014, Issue 7), Ovid MEDLINE, EMBASE, and 15 other databases in July 2014. We also searched two trials registers and requested details of unidentified, unpublished, or ongoing studies from investigators and other experts. SELECTION CRITERIA: Prospective controlled trials of antilibidinal medications taken by individuals for the purpose of preventing sexual offences, where the comparator group received a placebo, no treatment, or 'standard care', including psychological treatment. DATA COLLECTION AND ANALYSIS: Pairs of authors, working independently, selected studies, extracted data, and assessed the risk of bias of included studies. We contacted study authors for additional information, including details of methods and outcome data. MAIN RESULTS: We included seven studies with a total of 138 participants, with data available for 123. Sample sizes ranged from 9 to 37. Judgements for categories of risk of bias varied: concerns were greatest regarding allocation concealment, blinding of outcome assessors, and incomplete outcome data (dropout rates in the five community-based studies ranged from 3% to 54% and results were usually analysed on a per protocol basis).Participant characteristics in the seven studies were heterogeneous, but the vast majority had convictions for sexual offences, ranging from exhibitionism to rape and child molestation.Six studies examined the effectiveness of three testosterone-suppressing drugs: cyproterone acetate (CPA), ethinyl oestradiol (EO), and medroxyprogesterone acetate (MPA); a seventh evaluated two antipsychotics (benperidol and chlorpromazine). Five studies were placebo-controlled; in two, MPA was administered as an adjunctive treatment to a psychological therapy (assertiveness training or imaginal desensitisation). Meta analysis was not possible due to heterogeneity of interventions, comparators, study designs, and other issues. The quality of the evidence overall was poor. In addition to methodological issues, much evidence was indirect. PRIMARY OUTCOME: recividism. Two studies reported recidivism rates formally. One trial of intramuscular MPA plus imaginal desensitisation (ID) found no reports of recividism at two-year follow-up for the intervention group (n = 10 versus one relapse within the group treated by ID alone). A three-armed trial of oral MPA, alone or in combination with psychological treatment, reported a 20% rate of recidivism amongst those in the combined treatment arm (n = 15) and 50% of those in the psychological treatment only group (n = 12). Notably, all those in the 'oral MPA only' arm of this study (n = 5) dropped out immediately, despite treatment being court mandated.Two studies did not report recidivism rates as they both took place in one secure psychiatric facility from which no participant was discharged during the study, whilst another three studies did not appear directly to measure recividism but rather abnormal sexual activity alone. SECONDARY OUTCOMES: The included studies report a variety of secondary outcomes. Results suggest that the frequency of self reported deviant sexual fantasies may be reduced by testosterone-suppressing drugs, but not the deviancy itself (three studies). Where measured, hormonal levels, particularly levels of testosterone, tended to correlate with measures of sexual activity and with anxiety (two studies). One study measured anxiety formally; one study measured anger or aggression. Adverse events: Six studies provided information on adverse events. No study tested the effects of testosterone-suppressing drugs beyond six to eight months and the cross-over design of some studies may obscure matters (given the 'rebound effect' of some hormonal treatments). Considerable weight gain was reported in two trials of oral MPA and CPA. Side effects of intramuscular MPA led to discontinuation in some participants after three to five injections (the nature of these side effects was not described). Notable increases in depression and excess salivation were reported in one trial of oral MPA. The most severe side effects (extra-pyramidal movement disorders and drowsiness) were reported in a trial of antipsychotic medication for the 12 participants in the study. No deaths or suicide attempts were reported in any study. The latter is important given the association between antilibidinal hormonal medication and mood changes. AUTHORS' CONCLUSIONS: We found only seven small trials (all published more than 20 years ago) that examined the effects of a limited number of drugs. Investigators reported issues around acceptance and adherence to treatment. We found no studies of the newer drugs currently in use, particularly SSRIs or GnRH analogues. Although there were some encouraging findings in this review, their limitations do not allow firm conclusions to be drawn regarding pharmacological intervention as an effective intervention for reducing sexual offending.The tolerability, even of the testosterone-suppressing drugs, was uncertain given that all studies were small (and therefore underpowered to assess adverse effects) and of limited duration, which is not consistent with current routine clinical practice. Further research is required before it is demonstrated that their administration reduces sexual recidivism and that tolerability is maintained.It is a concern that, despite treatment being mandated in many jurisdictions, evidence for the effectiveness of pharmacological interventions is so sparse and that no RCTs appear to have been published in two decades. New studies are therefore needed and should include trials with larger sample sizes, of longer duration, evaluating newer medications, and with results stratified according to category of sexual offenders. It is important that data are collected on the characteristics of those who refuse and those who drop out, as well as those who complete treatment. PMID- 25692327 TI - Surface-engineered graphene navigate divergent biological outcomes toward macrophages. AB - The "nano-bio" interface profoundly shapes the interaction between cells and nanomaterials and can even decide a cell's fate. As a nascent two-dimensional material, graphene has many unique attributes and is proposed to be a promising candidate for biomedical applications. Thus, for graphene-based applications, it is necessary to clarify how the graphene surface navigates biological outcomes when encountering "janitorial" cells (macrophages). For this purpose, we synthesized nanographene oxide (nGO) and engineered the surface with polyethylene glycol (PEG), bovine serum albumin (BSA), and poly(ether imide) (PEI). In contrast to pristine nGO, decoration with PEG and BSA hindered endocytosis and improved their benignancy toward macrophages. Contrarily, nGO-PEI commenced with favorable endocytosis but then suffered stagnation due to compromised macrophage viability. To unravel the underlying mechanisms regulating these diverse macrophage fates, we built a stepwise analysis. Compared to the others, nGO-PEI tended to interact electrostatically with mitochondria after their cellular internalization. Such an unexpected encounter disrupted the normal potential and integrity of mitochondria and then elicited an alteration in reactive oxygen species and cytochrome c. These responses further initiated the activation of the caspase family and ultimately dictated cells to undergo apoptosis. The advances described above will complement our knowledge of graphene functionality and serve to guide its application in biotechnological applications. PMID- 25692329 TI - Soft-tissue re-growth following fibre retention osseous resective surgery or osseous resective surgery: a multilevel analysis. AB - BACKGROUND: The aim of this study was to assess soft-tissue re-growth following Fibre Retention Osseous Resective Surgery (FibReORS) or Osseous Resective Surgery (ORS) over a 12-month healing period. MATERIAL AND METHODS: Thirty patients with chronic periodontitis showing persistent periodontal pockets at posterior natural teeth after cause-related therapy were enroled. Periodontal pockets were associated with infrabony defect <=3 mm; 15 patients were randomly assigned to FibReORS (test group) and 15 to ORS (control group). Measurements were performed by a blind and calibrated examiner. Soft-tissue rebound after flap suture was monitored by changes in gingival recession at 1-, 3-, 6-, and 12- month follow up. Multilevel analysis considering patient, site, and time levels was performed. RESULTS: Greater osseous resection during surgery and higher post surgical gingival recession was observed in the ORS group. The mean amount of soft-tissue rebound following surgery was 2.5 mm for ORS-treated sites and 2.2 mm for FibReORS-treated sites. Approximately 90% of the coronal re-growth was detectable after 6 months for both procedures. The interaction between ORS and time of observation showed a higher soft-tissue rebound after 12 months (p = 0.0233) for ORS-treated sites. CONCLUSIONS: Both procedures showed a similar coronal soft tissue re-growth with a significant higher recession reduction for ORS-treated sites. Significant clinical stability of the gingival margin is obtained 6 months after surgery for both procedures. PMID- 25692330 TI - Altered intrahepatic microcirculation of idiopathic portal hypertension in relation to glutamine synthetase expression. AB - AIM: Alteration in intrahepatic microcirculation of idiopathic portal hypertension (IPH) has been poorly understood. This study aimed to characterize altered intrahepatic microcirculation of IPH focusing on the expression pattern of glutamine synthetase (GS). METHODS: Immunohistochemical staining of GS was performed using liver sections of IPH (n = 28). Serial section analysis was performed to determine microcirculatory disturbances of IPH. RESULTS: Paraportal shunt vessels were observed in 20 cases of IPH, and they were divided into two types according to the GS staining pattern; hepatocytes surrounding the vessels were negative for GS (type 1) and positive for GS (type 2). All 20 cases had one or more type 1 vessels within a section, and 10 cases were further associated with type 2 vessels. The cases with type 2 vessels showed infrequent symptoms of esophageal varices. Regarding the GS staining as an indicator of hepatic veins, some type 2 vessels were supposed to represent portovenous shunts. Isolated arteries in hepatic parenchyma were present in 21 cases, and they were located around terminal hepatic venules in six cases, corresponding to centrizonal arteries. Broad hepatocellular GS staining in hyperplastic lesions was noted in five cases, whereas nodular regenerative hyperplasia lacked GS expression. CONCLUSION: GS immunostaining revealed microcirculatory disturbances of IPH that were associated with abnormalities in both venous and arterial vessels. PMID- 25692331 TI - Expression of the synaptic exocytosis-regulating molecule complexin 2 in taste buds and its participation in peripheral taste transduction. AB - Taste information from type III taste cells to gustatory neurons is thought to be transmitted via synapses. However, the molecular mechanisms underlying taste transduction through this pathway have not been fully elucidated. In this study, to identify molecules that participate in synaptic taste transduction, we investigated whether complexins (Cplxs), which play roles in regulating membrane fusion in synaptic vesicle exocytosis, were expressed in taste bud cells. Among four Cplx isoforms, strong expression of Cplx2 mRNA was detected in type III taste cells. To investigate the function of CPLX2 in taste transduction, we observed taste responses in CPLX2-knockout mice. When assessed with electrophysiological and behavioral assays, taste responses to some sour stimuli in CPLX2-knockout mice were significantly lower than those in wild-type mice. These results suggested that CPLX2 participated in synaptic taste transduction from type III taste cells to gustatory neurons. A part of taste information is thought to be transmitted via synapses. However, the molecular mechanisms have not been fully elucidated. To identify molecules that participate in synaptic taste transduction, we investigated complexins (Cplxs) expression in taste bud cells. Strong expression of Cplx2 mRNA was detected in taste bud cells. Furthermore, taste responses to some sour stimuli in CPLX2- knockout mice were significantly lower than those in wild-type mice. These suggested that CPLX2 participated in synaptic taste transduction. PMID- 25692332 TI - Neurocytoprotective Effects of Aliphatic Hydroxamates from Lovastatin, a Secondary Metabolite from Monascus-Fermented Red Mold Rice, in 6-Hydroxydopamine (6-OHDA)-Treated Nerve Growth Factor (NGF)-Differentiated PC12 Cells. AB - Lovastatin, a secondary metabolite isolated from Monascus-fermented red rice mold, has neuroprotective activity and permeates the blood-brain barrier. The aim of this study was to enhance the activity of lovastatin for potential use as a treatment for neuronal degeneration in Parkinson's disease. Six lovastatin derived compounds were semisynthesized and screened for neurocytoprotective activity against 6-hydroxydopamine (6-OHDA)-induced toxicity in human neuroblastoma PC12 cells. Four compounds, designated as 3a, 3d, 3e, and 3f, significantly enhanced cell viability. In particular, compound 3f showed excellent neurocytoprotective activity (97.0 +/- 2.7%). Annexin V-FITC and propidium iodide double staining and 4',6-diamidino-2-phenylindole staining indicated that compound 3f reduced 6-OHDA-induced apoptosis in PC12 cells. Compound 3f also reduced caspase-3, -8, and -9 activities, and intracellular calcium concentrations elevated by 6-OHDA in a concentration-dependent manner, without inhibiting reactive oxygen species generation. JC-1 staining indicated that compound 3f also stabilized mitochondrial membrane potential. Thus, compound 3f may be used as a neurocytoprotective agent. Future studies should investigate its potential application as a treatment for Parkinson's disease. PMID- 25692333 TI - Anti-inflammatory and antioxidant activities of the nonlipid (aqueous) components of sesame oil: potential use in atherosclerosis. AB - Dietary intervention to prevent inflammation and atherosclerosis has been a major focus in recent years. We previously reported that sesame oil (SO) was effective in inhibiting atherosclerosis in low-density lipoprotein-receptor negative mice. We also noted that the levels of many proinflammatory markers were lower in the SO-treated animals. In this study we tested whether the non-lipid, aqueous components associated with SO would have anti-inflammatory and antioxidant effects. Polymerase chain reaction array data indicated that sesame oil aqueous extract (SOAE) was effective in reducing lipopolysaccharide (LPS)-induced inflammation in RAW 264.7 macrophage cells. Expression of inflammatory cytokines such as interleukin (IL)-1alpha, IL-6, and tumor necrosis factor alpha (TNF alpha) was also analyzed independently in cells pretreated with SOAE followed by inflammatory assault. Effect of SOAE on TNF-alpha-induced MCP-1 and VCAM1 expression was also tested in human umbilical vein endothelial cells. We observed that SOAE significantly reduced inflammatory markers in both macrophages and endothelial cells in a concentration-dependent manner. SOAE was also effective in inhibiting LPS-induced TNF-alpha and IL-6 levels in vivo at different concentrations. We also noted that in the presence of SOAE, transcription and translocation of NF-kappaB was suppressed. SOAE was also effective in inhibiting oxidation of lipoproteins in vitro. These results suggest the presence of potent anti-inflammatory and antioxidant compounds in SOAE. Furthermore, SOAE differentially regulated expression of scavenger receptors and increased ATP binding cassette A1 (ABCA1) mRNA expression by activating liver X receptors (LXRs), suggesting additional effects on lipid metabolism. Thus, SOAE appears multipotent and may serve as a valuable nonpharmacological agent in atherosclerosis and other inflammatory diseases. PMID- 25692334 TI - High-efficiency type II cell-enhanced green fluorescent protein expression facilitates cellular identification, tracking, and isolation. AB - We have developed a transgenic mouse expressing enhanced green fluorescent protein (EGFP) in virtually all type II (TII) alveolar epithelial cells. The CBG mouse (SPC-BAC-EGFP) contains a bacterial artificial chromosome modified to express EGFP within the mouse surfactant protein (SP)-C gene 3' untranslated region. EGFP mRNA expression is limited to the lung. EGFP fluorescence is both limited to and exhibited by all cells expressing pro-SP-C; fluorescence is uniform throughout all lobes of the lung and does not change as mice age. EGFP(+) cells also express SP-B but do not express podoplanin, a type I (TI) cell marker. CBG mice show no evidence of lung disease with aging. In 3 hours, TII cells can be isolated in >99% purity from CBG mice by FACS; the yield of 3.7 +/- 0.6 * 10(6) cells represents approximately 25 to 60% of the TII cells in the lung. By FACS analysis, approximately 0.9% of TII cells are in mitosis in uninjured lungs; after bleomycin injury, 4.1% are in mitosis. Because EGFP fluorescence can be detected for >14 days in culture, at a time that SP-C mRNA expression is essentially nil, this line may be useful for tracking TII cells in culture and in vivo. When CBG mice are crossed to transgenic mice expressing rat podoplanin, TI and TII cells can be easily simultaneously identified and isolated. When bred to other strains of mice, EGFP expression can be used to identify TII cells without the need for immunostaining for SP-C. These mice should be useful in models of mouse pulmonary disease and in studies of TII cell biology, biochemistry, and genetics. PMID- 25692335 TI - Phyllodes tumour of vulva with prominent pseudoangiomatous stromal hyperplasia features: A case report and review of literature. PMID- 25692336 TI - Implementation and operational research: evaluating outcomes of patients lost to follow-up in a large comprehensive care treatment program in western Kenya. AB - BACKGROUND: Academic Model Providing Access To Healthcare (AMPATH) program provides comprehensive HIV care and treatment services. Approximately, 30% of patients have become lost to follow-up (LTFU). We sought to actively trace and identify outcomes for a sample of these patients. METHODS: LTFU was defined as missing a scheduled visit by >=3 months. A randomly selected sample of 17% of patients identified as LTFU between January 2009 and June 2011 was generated, with sample stratification on age, antiretroviral therapy (ART) status at last visit, and facility. Chart reviews were conducted followed by active tracing. Tracing was completed by trained HIV-positive outreach workers July 2011 to February 2012. Outcomes were compared between adults and children and by ART status. RESULTS: Of 14,811 LTFU patients, 2540 were randomly selected for tracing (2179 adults, 1071 on ART). The chart reviews indicated that 326 (12.8%) patients were not actually LTFU. Outcomes for 71% of sampled patients were determined including 85% of those physically traced. Of those with known outcomes, 21% had died, whereas 29% had disengaged from care for various reasons. The remaining patients had moved away (n = 458, 25%) or were still receiving HIV care (n = 443 total, 25%). CONCLUSIONS: Our findings demonstrate the feasibility of a large scale sampling-based approach. A significant proportion of patients were found not to be LTFU, and further, high numbers of patients who were LTFU could not be located. Over a quarter of patients disengaged from care for various reasons including access challenges and familial influences. PMID- 25692337 TI - Effects of a senior practicum course on nursing students' confidence in speaking up for patient safety. AB - As patient advocates, nurses are responsible for speaking up against unsafe practices. Nursing students must develop the confidence to speak up for patient safety so that they can hold themselves, as well as their peers and coworkers, accountable for patients' well-being. The purpose of this study was to examine the effects of a senior practicum course on confidence for speaking up for patient safety in nursing students. Confidence in speaking up for patient safety was measured with the Health Professional Education in Patient Safety Survey. The study showed a significant increase in nursing students' confidence after the senior practicum course, but there was no significant change in students' confidence in questioning someone of authority. PMID- 25692339 TI - Use of student clinical partner dyads as a teaching strategy to facilitate learning. AB - Collaborative learning has been used effectively in the classroom, but it is not well understood in the clinical setting. Student clinical partner (SCP) dyads were used as an intentional teaching method to foster teamwork, learning, and confidence. Students were assigned a patient and a student partner. SCP dyads were expected to provide complete care to their assigned patient, listen to report for their partner's patient, prioritize patient needs, participate in learning experiences for all assigned patients, and function as a team. Students (n = 26) compared their clinical rotation with SCP dyads to their clinical rotations without SCP dyads. The majority strongly agreed that SCP dyads had a positive impact on teamwork (74%), learning experiences (58%), and student clinical confidence (62%). Reflective journals stated that SCP dyads increased exposure to patient care activities, confidence in management, prioritization, teamwork, and time with the faculty. PMID- 25692338 TI - Tumor suppression by resistant maltodextrin, Fibersol-2. AB - Resistant maltodextrin Fibersol-2 is a soluble and fermentable dietary fiber that is Generally Recognized As Safe (GRAS) in the United States. We tested whether Fibersol-2 contains anti-tumor activity. Human colorectal cancer cell line, HCT116, and its isogenic cells were treated with FIbersol-2. Tumor growth and tumorigenesis were studied in vitro and in vivo. Apoptotic pathway and generation of reactive oxygen species (ROS) were investigated. We discovered that Fibersol-2 significantly inhibits tumor growth of HCT116 cells by inducing apoptosis. Fibersol-2 strongly induces mitochondrial ROS and Bax-dependent cleavage of caspase 3 and 9, which is shown by isogenic HCT116 variants. Fibersol-2 induces phosphorylation of Akt, mTOR in parental HCT116 cells, but not in HCT116 deficient for Bax or p53. It prevents growth of tumor xenograft without any apparent signs of toxicity in vivo. These results identify Fibersol-2 as a mechanism-based dietary supplement agent that could prevent colorectal cancer development. PMID- 25692340 TI - Role of microRNA-30c in lipid metabolism, adipogenesis, cardiac remodeling and cancer. AB - PURPOSE OF REVIEW: To summarize the role of the microRNA-30c (miR-30c) in lipid metabolism and adipogenesis, to address consequences associated with reduced expression in cancer and cardiac function, and to speculate benefits of overexpressing miR-30c in the treatment of hyperlipidemia, atherosclerosis, and cancer. RECENT FINDINGS: Overexpression of hepatic miR-30c curtails hyperlipidemia and atherosclerosis by decreasing lipid biosynthesis and lipoprotein secretion. miR-30c expression is significantly elevated during cellular adipogenesis and might play a pro-adipogenic role by up-regulating the expression of adipocyte markers and inducing lipid accumulation. miR-30c is downregulated in cardiac hypertrophy and ischemia, indicating that its expression might be essential for normal cardiac structure and function. Many studies have demonstrated that miR-30c is lower in cancer and its high expression impedes cancer progression by targeting genes involved in cell proliferation and invasion. SUMMARY: These studies highlight the important role miR-30c plays in lipid metabolism, adipogenesis, and cell proliferation and differentiation. Further, they point to pathologic outcomes associated with reduced expression in cancer and cardiac hypertrophy. Additionally, they suggest that increasing miR 30c expression in the liver and cancerous tissue might reduce hyperlipidemia and atherosclerosis, and cancer progression and metastasis, respectively. Studies are needed to evaluate the efficacy of miR-30c mimic in the treatment of these disorders. PMID- 25692341 TI - Glucokinase regulatory protein: complexity at the crossroads of triglyceride and glucose metabolism. AB - PURPOSE OF REVIEW: Glucokinase regulator (GCKR) encodes glucokinase regulatory protein (GKRP), a hepatocyte-specific inhibitor of the glucose-metabolizing enzyme glucokinase (GCK). Genome-wide association studies have identified a common coding variant within GCKR associated with multiple metabolic traits. This review focuses on recent insights into the critical role of GKRP in hepatic glucose metabolism that have stemmed from the study of human genetics. This knowledge has improved our understanding of glucose and lipid physiology and informed the development of targeted molecular therapeutics for diabetes. RECENT FINDINGS: Rare GCKR variants have effects on GKRP expression, localization, and activity. These variants are collectively associated with hypertriglyceridaemia but are not causal. Crystal structures of GKRP and the GCK-GKRP complex have been solved, providing greater insight into the molecular interactions between these proteins. Finally, small molecules have been identified that directly bind GKRP and reduce blood glucose levels in rodent models of diabetes. SUMMARY: GCKR variants across the allelic spectrum have effects on glucose and lipid homeostasis. Functional analysis has highlighted numerous molecular mechanisms for GKRP dysfunction. Hepatocyte-specific GCK activation via small molecule GKRP inhibition may be a new avenue for type 2 diabetes treatment, particularly considering evidence indicating GKRP loss-of-function alone does not cause hypertriglyceridaemia. PMID- 25692342 TI - Identifying functional noncoding variants from genome-wide association studies for cardiovascular disease and related traits. AB - PURPOSE OF REVIEW: Genome-wide association studies have identified many novel loci for cardiovascular disease and related traits. Attention is now shifting towards the analysis of these loci for causal variants, with a view to identify the novel mechanisms leading to disease. RECENT FINDINGS: This review focuses on the approaches to identify causal, noncoding variants for coronary artery disease, lipid traits and other cardiovascular risk factors. Fine-mapping studies are discussed, along with the novel statistical approaches to produce 'credible sets'. The use of combining genome-wide association study datasets with experimental methods such as expression quantitative trait loci and allele specific chromatin accessibility are explored, with recent examples discussed. Mapping long-range chromatin interactions and evolving genome-editing technologies such as clustered regularly interspaced short palindromic repeats combined with clustered regularly interspaced short palindromic repeats associated (Cas9) nuclease promise to aid considerably the search for causal variants. SUMMARY: Identification of causal variants for cardiovascular disease and related traits is still in the early stages, but with technologies evolving and increasingly relevant tissue samples undergoing analysis, there are favourable prospects that many new mechanisms for disease will be uncovered by the end of this decade. PMID- 25692343 TI - Gene-environment interaction in dyslipidemia. AB - PURPOSE OF REVIEW: Recent genome-wide association studies have identified numerous common genetic variants associated with plasma lipid traits and have provided new insights into the regulation of lipoprotein metabolism including the identification of novel biological processes. These findings add to a body of existing data on dietary and environmental factors affecting plasma lipids. Here we explore how interactions between genetic risk factors and other phenotypes may explain some of the missing heritability of plasma lipid traits. RECENT FINDINGS: Recent studies have identified true statistical interaction between several environmental and genetic risk factors and their effects on plasma lipid fractions. These include interactions between behaviors such as smoking or exercise as well as specific dietary nutrients and the effect size of specific genetic variants on plasma lipid traits risk and modifying effects of measures of adiposity on the cumulative impact of a number of common genetic variants on each of plasma triglycerides and HDL cholesterol. SUMMARY: Interactions between genetic risk factors and clinical phenotypes may account for some of the unexplained heritability of plasma lipid traits. Recent studies provide biological insight into specific genetic associations and may aid in the identification of dyslipidemic patients for whom specific lifestyle interventions are likely to be most effective. PMID- 25692344 TI - The immunity-diet-microbiota axis in the development of metabolic syndrome. AB - PURPOSE OF REVIEW: Recent evidence demonstrates that the gut-microbiota can be considered as one of the major factors causing metabolic and cardiovascular diseases. RECENT FINDINGS: Pattern recognition receptors as well as antimicrobial peptides are a key factor in controlling the intestinal microbiota composition. Deficiencies in these genes lead to changes in the composition of the gut microbiota, causing leakage of endotoxins into the circulation, and the development of low-grade chronic inflammation and insulin resistance. Dietary composition can also affect the microbiota: a diet rich in saturated fats allows the expansion of pathobionts that damage the intestinal epithelial cell layer and compromise its barrier function. In contrast, a diet high in fiber supports the microbiota to produce short-chain fatty acids, thereby promoting energy expenditure and protecting against inflammation and insulin resistance. SUMMARY: The interactions between the microbiota, innate immunity, and diet play an important role in controlling metabolic homeostasis. A properly functioning innate immune system, combined with a low-fat and high-fiber diet, is important in preventing dysbiosis and reducing the susceptibility to developing the metabolic syndrome and its associated cardiovascular diseases. PMID- 25692345 TI - Recent developments in genome and exome-wide analyses of plasma lipids. AB - PURPOSE OF REVIEW: Genome-wide association scans (GWAS) have identified over 100 human loci associated with variation in lipids. The identification of novel genes and variants that affect lipid levels is made possible by next-generation sequencing, rare variant discovery and analytic advances. The current status of the genetic basis of lipid traits will be presented. RECENT FINDINGS: Expansion of GWAS sample sizes for lipid traits has not substantially increased the proportion of trait variance explained by common genetic variants (less than 15% of trait variation captured). Although GWAS has discovered novel loci and pathways with putative biological function and impact on cardiovascular disease risk, discovery of the genes in these loci remains challenging. Exome sequencing promises to identify genes with protein-coding variants with a large impact on lipids, as shown for LDL-cholesterol levels associated with novel (PNPLA5) and known (LDLR, PCSK9, APOB) genes. SUMMARY: Current results have increased our understanding of the genetic architecture of lipids, expanding the range of effect and frequency for variants identified for lipid traits. Identification of novel lipid-associated gene variants, even if small in effect or rare in the population, could provide important novel drug targets and biological pathways for dyslipidemia. PMID- 25692346 TI - The life cycle of the low-density lipoprotein receptor: insights from cellular and in-vivo studies. AB - PURPOSE OF REVIEW: Long-term exposure to elevated concentrations of LDL cholesterol increases the risk of cardiovascular events. The main player in clearing LDL cholesterol is the LDL receptor (LDLR) trafficking pathway; however, our fundamental knowledge about the mechanisms regulating this pathway is still incomplete. RECENT FINDINGS: The LDLR pathway is very complex and involves multiple proteins. Endocytosis is regulated by two different adaptor proteins, that is, autosomal recessive hypercholesterolemia and Disabled-2. The proteolysis of the LDLR is regulated by inducible degrader of the LDLR and proprotein convertase subtilisin/kexin type 9. However, only a few proteins have been identified that provide insights into the endosomal sorting and recycling of the LDLR. SUMMARY: Since the discovery of LDLR, knowledge about its function has greatly expanded. As a result of its importance in maintaining homeostatic LDL levels, the LDLR pathway has emerged as a key therapeutic target to reduce circulating cholesterol. In order to be able to treat and diagnose individuals with hypercholesterolemia in the future, it is important to learn more about the LDLR trafficking pathway, as we still lack a full mechanistic understanding of how LDLR trafficking is controlled. PMID- 25692347 TI - Targeted next-generation sequencing in monogenic dyslipidemias. AB - PURPOSE OF REVIEW: To evaluate the potential clinical translation of high throughput next-generation sequencing (NGS) methods in diagnosis and management of dyslipidemia. RECENT FINDINGS: Recent NGS experiments indicate that most causative genes for monogenic dyslipidemias are already known. Thus, monogenic dyslipidemias can now be diagnosed using targeted NGS. Targeting of dyslipidemia genes can be achieved by either: designing custom reagents for a dyslipidemia specific NGS panel; or performing genome-wide NGS and focusing on genes of interest. Advantages of the former approach are lower cost and limited potential to detect incidental pathogenic variants unrelated to dyslipidemia. However, the latter approach is more flexible because masking criteria can be altered as knowledge advances, with no need for re-design of reagents or follow-up sequencing runs. Also, the cost of genome-wide analysis is decreasing and ethical concerns can likely be mitigated. DNA-based diagnosis is already part of the clinical diagnostic algorithms for familial hypercholesterolemia. Furthermore, DNA-based diagnosis is supplanting traditional biochemical methods to diagnose chylomicronemia caused by deficiency of lipoprotein lipase or its co-factors. SUMMARY: The increasing availability and decreasing cost of clinical NGS for dyslipidemia means that its potential benefits can now be evaluated on a larger scale. PMID- 25692348 TI - HDL re-examined. AB - PURPOSE OF REVIEW: To summarize the current evidence concerning the role of HDL-C and HDL-associated parameters in the risk for cardiovascular disease (CVD). RECENT FINDINGS: Numerous population studies have shown that plasma levels of HDL C are inversely associated with CVD risk; in patient care HDL-C levels are therefore widely implemented in risk estimation models. A number of antiatherogenic properties have been ascribed to the HDL particle, but the hypothesis that HDL is causally related to CVD has been seriously challenged by recent data obtained from both human genetic studies and clinical trials. The final word on HDL-C as a therapeutic target is pending, as a number of clinical endpoint trials specifically focusing on the effect(s) of HDL-C increasing agents are underway. Moreover, recent data show that HDL efflux capacity could hold independent predictive value for CVD events, which clearly highlights the potential need to focus on HDL functionality, rather than on HDL-C levels. SUMMARY: The dogmatic concept that HDL-C levels predict future CVD events is undisputed, but the role of HDL-C as a causal factor in atherosclerosis has been challenged by a number of different types of studies. In recent years, a paradigm shift toward 'HDL functionality' is apparent. Whether or not optimizing these markers of HDL functionality actually does reduce CVD risk requires formal testing in prospective controlled studies. PMID- 25692349 TI - Cognitive Behavioral Therapy as a Treatment for Electroconvulsive Therapy Phobia: Case Report and Review of Literature. AB - BACKGROUND: Electroconvulsive therapy (ECT) can raise feelings of fear and anxiety in our patients. No documented cases of phobia regarding ECT or its treatment were found in the literature. METHODS: We present a patient who developed anxiety regarding ECT that was severe enough to be classified as a phobia. She was successfully treated with cognitive behavioral therapy (CBT) for her phobia and was subsequently able to tolerate ECT. We conducted a literature review of ECT phobia, fear, and anxiety using MEDLINE, PsycINFO, and EMBASE. RESULTS: We outlined how CBT, in our specific case, was helpful in treating extreme and unrealistic fears concerning ECT. We could not find a case of phobia related to ECT in the literature; however, both qualitative and quantitative studies illustrate that ECT causes anxiety and fear. CONCLUSIONS: Although cases of ECT phobia are rare, feelings of fear and anxiety surrounding ECT are common. The experience of ECT is individualized for each patient, and CBT can be a successful treatment in those who have anxiety related to ECT. PMID- 25692350 TI - Immunogenicity and safety of purified chick-embryo cell rabies vaccine under Zagreb 2-1-1 or 5-dose Essen regimen in Chinese children 6 to 17 years old and adults over 50 years: a randomized open-label study. AB - The aim of this Phase IIIb, open-label, randomized study was to demonstrate the non-inferiority of immune responses and to assess the safety of a purified chick embryo cell rabies vaccine (PCECV) in healthy Chinese children (6 to 17 years) and older adults (>=51 years) following 2 alternative intramuscular (IM) simulated post-exposure prophylaxis (PEP) regimens: 4-dose Zagreb or 5-dose Essen regimen. Serum samples were collected prior to vaccination on Days 1 and 15 and on day 43 to assess immune response by rabies virus neutralizing antibody (RVNA) concentrations. Solicited adverse events (AEs) were recorded for up to 7 days following each vaccine dose, and unsolicited AEs throughout the entire study period. PCECV vaccination induced a strong immune response at Day 15, and the non inferiority in immune response of the Zagreb vs. the Essen regimen was demonstrated in children and older adults. At Day 15,100% of children (N = 224), and 99% of subjects >=51 years of age (N = 376) developed adequate RVNA concentrations (>=0.5 IU/mL); at Day 43 all subjects achieved RVNA concentrations >=0.5 IU/mL, for both PEP regimens. The well-known tolerability and safety profile of the PCECV was again observed in this study following either Zagreb or Essen regimens. Rabies PEP vaccination with PCECV following a Zagreb regimen induced immune responses non-inferior to those of the Essen regimen, and had a similar safety and tolerability profile to the Essen regimen in Chinese children, adolescents, and adults over 51 years. ClinicalTrials.gov identifier: NCT01680016. PMID- 25692351 TI - Role of QuantiFERON((r))-TB Gold In-Tube in tuberculosis contact investigation: experience in a tuberculosis unit. AB - BACKGROUND: Interferon-gamma release assays (IGRAs) are increasingly used for the diagnosis of latent tuberculosis infection (LTBI). Because of the lack of a gold standard for the diagnosis of LTBI, IGRAs are compared to the tuberculin skin test (TST) and yield conflicting results. We assessed the usefulness of an IGRA test, QuantiFERON((r))-TB Gold In-Tube (QFT-G-IT), for diagnosing LTBI compared with TST in the setting of a contact screening study. METHODS: A prospective comparison between the QFT-G-IT and the TST in TB contact subjects in a low TB burden area was conducted sequentially between January 2006 and December 2012. RESULTS: A moderate concordance between the two tests (kappa = 0.44 for TST cut off of 5 mm and kappa = 0.56 for TST cut-off of 15 mm) was found. A better agreement was shown in younger contacts and in non-vaccinated contacts when using a TST of 15 mm. Independent risk factors for a TST(+)/QFT-G-IT(-) discordance were history of BCG vaccination and age between 31 and 59 years. Discordance was also more frequent using a TST cut-off value of 5 mm. QFT-G-IT(+)/TST(-) was infrequent and was found in older contacts. CONCLUSIONS: Based on our data, we cannot recommend the use of QFT-G-IT as the only test to rule out LTBI, especially in older patients. PMID- 25692352 TI - Adrenal and hepatic aspergillosis in an immunocompetent patient. AB - Invasive aspergillosis, an infection most frequently induced by Aspergillus fumigatus and Aspergillus flavus, typically occurs in immunocompromised patients and is usually transmitted through inhalation of Aspergillus spores. As the lungs are by far the most common site involved in invasive aspergillosis and invasive aspergillosis in immunocompetent hosts is very rare, there have been a few case reports of extra-pulmonary, disseminated invasive aspergillosis in immunocompetent persons. Herein, we report a case of an adult, male, immunocompetent patient with disseminated invasive aspergillosis that successively spread from the right adrenal gland to the left hepatic lobe. The patient was successfully treated through surgical excisions of his adrenal and hepatic masses followed by voriconazole therapy. To our knowledge, this is the first case report of invasive aspergillosis affecting the adrenal glands. PMID- 25692353 TI - Evaluation of the Cobas TaqMan MTB test for detection of Mycobacterium tuberculosis complex. AB - BACKGROUND: The Cobas TaqMan MTB assay is used for rapid detection of the Mycobacterium tuberculosis complex (MTC) in clinical samples. It is only validated for respiratory samples, but is often requested by physicians for non respiratory specimens. The aim of this study was therefore to evaluate the performance of this assay in clinical praxis in a country with low prevalence of tuberculosis (TB). METHODS: The results from 2388 respiratory and 1005 non respiratory human specimens were analyzed by this real-time PCR technique. Using culture results as the gold standard, the sensitivity, specificity, positive predictive value (PPV), and negative predictive values (NPV) of the PCR results were calculated. RESULTS: For smear-positive respiratory specimens all the four values investigated were 100%. The number of smear-positive non-respiratory specimens was only eight, and all of these eight specimens reacted positively. Sensitivity was 51% for smear-negative respiratory specimens, and 47% for smear negative non-respiratory specimens. When all non-respiratory specimens were analyzed together the sensitivity was 51%. Specimens from 16 patients were PCR positive but culture-negative and these cases are discussed. In one case, TB DNA was still present in sputum 2 years after a successful treatment. CONCLUSION: The study shows that the Cobas TaqMan MTB assay performs well in smear-positive samples, while the sensitivities are unsatisfactory for both respiratory and non respiratory smear-negative specimens. Furthermore, the analyses emphasize that this assay cannot be used to evaluate treatment or contagiousness, or to detect relapses or screen for TB. PMID- 25692354 TI - Paradoxical reaction of tuberculous vertebral osteomyelitis: a case series. AB - Paradoxical reactions of tuberculosis (TB) in vertebral osteomyelitis are very rarely reported. We experienced four cases of severe paradoxical reactions in tuberculous vertebral osteomyelitis. Four cases of tuberculous vertebral osteomyelitis were confirmed by an acid-fast bacilli smear or culture. The patients were human immunodeficiency virus negative, and were all initially treated with isoniazid, ethambutol, rifampicin and pyrazinamide. Their symptoms improved with anti-TB drugs. However, after 2-12 weeks, their symptoms had recurred, and spinal magnetic resonance imaging at the time of readmission revealed an aggravation of vertebral osteomyelitis. Operations were carried out to relieve severe pain or spinal cord decompression. Through continued anti-TB drug therapy, all patients recovered without sequelae. PMID- 25692355 TI - Anastomotic Leakage After Low Anterior Resection for Rectal Cancer Is Different Between Minimally Invasive Surgery and Open Surgery. AB - OBJECTIVE: To review and compare clinical manifestations of and risk factors for anastomotic leakage (AL) after low anterior resection for rectal cancer between minimally invasive surgery (MIS) and open surgery (OS). BACKGROUND: MIS for rectal cancer has become popular, and its clinical course is different from OS. Many studies have reported on the risk factors and oncologic influence of AL. However, few have directly compared clinical manifestations and risk factors for AL between MIS and OS. METHODS: From January 2004 to December 2012, a total of 1704 consecutive patients who underwent elective low anterior resection with colorectal anastomosis for rectal cancer were eligible. The variables associated with short-term outcomes and risk factors were analyzed. RESULTS: The overall AL incidence was 6.4%. In the MIS-AL group, the time to diagnosis of AL and the time to second operation were shorter. A majority of the patients (77.8%) in the MIS AL group underwent second MIS operation, whereas none in the OS-AL group. The hospital stays after second MIS were shorter than those after second open operation. Multivariate analyses revealed that male sex, smoking and alcohol intake history, previous abdominal surgery, longer operation times, low-lying tumor, and using 2 or more staplers for distal rectal resection were independent risk factors in the MIS-AL group, whereas smoking and alcohol intake history, operation times, and blood loss were significant in the OS-AL group. CONCLUSIONS: The clinical manifestations of and risk factors for AL were different between MIS and OS. AL after MIS may be more influenced by factors related to technical difficulties. Close attention should be given to patients undergoing surgery with risk factors for AL. PMID- 25692356 TI - Reply to the Letter to the Editor: Addition of RAS Mutation Status May Strengthen the Predictive Model for Progression of Indeterminate Pulmonary Nodules. PMID- 25692358 TI - Development of an Enhanced Recovery After Surgery Guideline and Implementation Strategy Based on the Knowledge-to-action Cycle. AB - BACKGROUND: Enhanced Recovery After Surgery (ERAS) protocols have been shown to increase recovery, decrease complications, and reduce length of stay. However, they are difficult to implement. OBJECTIVE: To develop and implement an ERAS clinical practice guideline (CPG) at multiple hospitals. METHODS: A tailored strategy based on the Knowledge-to-action (KTA) cycle was used to develop and implement an ERAS CPG at 15 academic hospitals in Canada. This included an initial audit to identify gaps and interviews to assess barriers and enablers to implementation. Implementation included development of an ERAS guideline by a multidisciplinary group, communities of practice led by multidiscipline champions (surgeons, anesthesiologists, and nurses) both provincially and locally, educational tools, and clinical pathways as well as audit and feedback. RESULTS: The initial audit revealed there was greater than 75% compliance in only 2 of 18 CPG recommendations. Main themes identified by stakeholders were that the CPG must be based on best evidence, there must be increased communication and collaboration among perioperative team members, and patient education is essential. ERAS and Pain Management CPGs were developed by a multidisciplinary team and have been adopted at all hospitals. Preliminary data from more than 1000 patients show that the uptake of recommended interventions varies but despite this, mean length of stay has decreased with low readmission rates and adverse events. CONCLUSIONS: On the basis of short-term findings, our results suggest that a tailored implementation strategy based on the KTA cycle can be used to successfully implement an ERAS program at multiple sites. PMID- 25692360 TI - Natural History and Management of Blunt Traumatic Pseudoaneurysms of the Internal Carotid Artery: The Harborview Algorithm Based Off a 10-Year Experience. AB - OBJECTIVE: To define the natural history of, and treatment strategy for, blunt traumatic internal carotid artery (ICA) pseudoaneurysms. BACKGROUND: The natural history and management of traumatic ICA pseudoaneurysms is controversial. METHODS: We retrospectively identified all traumatic ICA pseudoaneurysms diagnosed on head/neck computed tomographic angiography at a high-volume trauma center over a 10-year period. Radiographic and clinical data were recorded, and a treatment algorithm was derived. RESULTS: Forty-three pseudoaneurysms were diagnosed in 39 patients. All patients were treated with daily aspirin unless contraindicated, and 82% underwent daily transcranial Doppler ultrasonography with embolic monitoring. A rate of 8 or more emboli per hour was predictive of embolic stroke (P = 0.0076). Acute ischemic or embolic stroke was seen in 7 patients (16%) with an overall mortality in this subpopulation of 42% (n = 3). Four patients (9%) underwent acute surgical treatment (parent vessel sacrifice and/or arterial bypass) for ongoing ischemia. Long-term radiographic and clinical follow-up was obtained for 36 surviving patients (mean = 8 months; range: 1 week 5 years), all of whom were maintained on daily aspirin. No delayed ischemic or embolic events were reported. For ICA pseudoaneurysms treated with aspirin and observation alone, 9 (28%) increased in size, 17 (53%) decreased or stabilized, and 6 (19%) resolved. Enlargement of 5 mm or more in maximal diameter underwent delayed endovascular treatment with a 100% obliteration rate and no complications. CONCLUSIONS: Traumatic ICA pseudoaneurysms are safely treated with daily aspirin, embolic monitoring, and radiographic surveillance. Acute stroke or hemorrhage, or delayed radiographic progression, are indications for endovascular or surgical treatment. PMID- 25692361 TI - A Novel Concept for Partial Liver Transplantation in Nonresectable Colorectal Liver Metastases: The RAPID Concept. AB - OBJECTIVE: Selected patients with nonresectable colorectal liver metastases benefit from liver transplantation and have acceptable 5-year survival rates. However, allocating full-sized grafts to this group of patients is difficult due to the scarcity of grafts. This could be improved by utilizing small partial grafts, which mandates effective strategies to overcome the problems regarding insufficient functional liver mass. METHODS: We have developed a protocol incorporating previously reported experiences from living donor transplantation and recent developments in liver surgery, facilitating transplantation of very small liver grafts. At the time of transplantation, segments 1 to 3 are resected in the recipient and orthotopically replaced by a segment 2 to 3 allograft. Portal inflow is modulated by redirecting the portal flow to the graft with concomitant focus on keeping the portal vein pressure below 20 mm Hg. A second stage hepatectomy is performed as soon as the graft has regenerated to a sufficient volume. RESULTS: A graft weighing 330 g was transplanted to a 50-year old man weighing 92 kg, and the portal vein to the right remnant liver was closed. The volume of the liver graft was doubled 2 weeks after the first procedure, and it increased further after the second procedure, with extended right hepatectomy performed at day 23 after transplantation. There were no signs of liver failure or small-for-size syndrome. CONCLUSIONS: The current protocol and ongoing study could represent a possible strategy to increase the availability of liver transplantation to patients with nonresectable liver tumors such as hepatocellular carcinoma and colorectal liver metastases. PMID- 25692363 TI - Guest editorial: High impact spinal surgery articles. PMID- 25692364 TI - The impact of standing regional cervical sagittal alignment on outcomes in posterior cervical fusion surgery. AB - BACKGROUND: Positive spinal regional and global sagittal malalignment has been repeatedly shown to correlate with pain and disability in thoracolumbar fusion. OBJECTIVE: To evaluate the relationship between regional cervical sagittal alignment and postoperative outcomes for patients receiving multilevel cervical posterior fusion. METHODS: From 2006 to 2010, 113 patients received multilevel posterior cervical fusion for cervical stenosis, myelopathy, and kyphosis. Radiographic measurements made at intermediate follow-up included the following: (1) C1-C2 lordosis, (2) C2-C7 lordosis, (3) C2-C7 sagittal vertical axis (C2-C7 SVA; distance between C2 plumb line and C7), (4) center of gravity of head SVA (CGH-C7 SVA), and (5) C1-C7 SVA. Health-related quality-of-life measures included neck disability index (NDI), visual analog pain scale, and SF-36 physical component scores. Pearson product-moment correlation coefficients were calculated between pairs of radiographic measures and health-related quality-of-life scores. RESULTS: Both C2-C7 SVA and CGH-C7 SVA negatively correlated with SF-36 physical component scores (r =-0.43, P< .001 and r =-0.36, P = .005, respectively). C2-C7 SVA positively correlated with NDI scores (r = 0.20, P = .036). C2-C7 SVA positively correlated with C1-C2 lordosis (r = 0.33, P = .001). For significant correlations between C2-C7 SVA and NDI scores, regression models predicted a threshold C2-C7 SVA value of approximately 40 mm, beyond which correlations were most significant. CONCLUSION: Our findings demonstrate that, similar to the thoracolumbar spine, the severity of disability increases with positive sagittal malalignment following surgical reconstruction. PMID- 25692365 TI - The craniovertebral junction area and the role of the ligaments and membranes. AB - Traumatic injuries of the craniovertebral junction (CVJ) area are common and frequently the outcome of motor vehicle accidents, falls, and diving accidents. To define and characterize CVJ traumatic injuries, some international classifications are currently in use, and they are thought and focused on junction bone fracture. However, recent data point out a major important role of the CVJ ligaments and membranes in traumatic injuries with a secondary function of the osseous structures. Emphasizing the correct role of the ligaments and membranes is extremely important for determining appropriate medical or surgical planning for patients and also to design new CVJ injury classifications. We reviewed every recent major publication on the ligaments and membranes of the CVJ area. We divided the information into sections concerning anatomy, embryology, biomechanics, trauma, and CVJ bone fractures. A role of the ligaments and membranes in the traumatic injuries of the CVJ area has often been recognized; but only recently, with the increase in the knowledge of the anatomic and biomechanical junction area, supported by neuroradiological tools (magnetic resonance imaging) and a more detailed traumatic injuries assessment, has the role of the ligaments and membranes been highlighted. Ligaments and membranes have a pivotal role in each junctional ability and are the key to orienting any medical or surgical indications in this unique area of the spine. PMID- 25692366 TI - The comprehensive anatomical spinal osteotomy classification. AB - BACKGROUND: Global sagittal malalignment is significantly correlated with health related quality-of-life scores in the setting of spinal deformity. In order to address rigid deformity patterns, the use of spinal osteotomies has seen a substantial increase. Unfortunately, variations of established techniques and hybrid combinations of osteotomies have made comparisons of outcomes difficult. OBJECTIVE: To propose a classification system of anatomically-based spinal osteotomies and provide a common language among spine specialists. METHODS: The proposed classification system is based on 6 anatomic grades of resection (1 through 6) corresponding to the extent of bone resection and increasing degree of destabilizing potential. In addition, a surgical approach modifier is added (posterior approach or combined anterior and posterior approaches). Reliability of the classification system was evaluated by an analysis of 16 clinical cases, rated 2 times by 8 different readers, and calculation of Fleiss kappa coefficients. RESULTS: Intraobserver reliability was classified as 'almost perfect'; Fleiss kappa coefficient averaged 0.96 (range, 0.92-1.0) for resection type and 0.90 (0.71-1.0) for the approach modifier. Results from the interobserver reliability for the classification were 0.96 for resection type and 0.88 for the approach modifier. CONCLUSION: This proposed anatomically based classification system provides a consistent description of the various osteotomies performed in spinal deformity correction surgery. The reliability study confirmed that the classification is simple and consistent. Further development of its use will provide a common frame for osteotomy assessment and permit comparative analysis of different treatments. PMID- 25692367 TI - Impact of tumor histology on resectability and neurological outcome in primary intramedullary spinal cord tumors: a single-center experience with 102 patients. AB - BACKGROUND: Surgical outcomes for intramedullary spinal cord tumors are affected by many variables including tumor histology and preoperative neurological function. OBJECTIVE: To analyze the impact of tumor histology on neurological outcome in primary intramedullary spinal cord tumors. METHODS: A retrospective review of 102 consecutive patients with intramedullary spinal cord tumors treated at a single institution between January 1998 and March 2009. RESULTS: Ependymomas were the most common tumors with 55 (53.9%), followed by 21 astrocytomas (20.6%), 12 hemangioblastomas (11.8%), and 14 miscellaneous tumors (13.7%). Gross total resection was achieved in 50 ependymomas (90.9%), 3 astrocytomas (14.3%), 11 hemangioblastomas (91.7%), and 12 miscellaneous tumors (85.7%). At a mean follow up of 41.8 months (range, 1-132 months), we observed recurrences in 4 ependymoma cases (7.3%), 10 astrocytoma cases (47.6%), 1 miscellaneous tumor case (7.1%), and no recurrence in hemangioblastoma cases. When analyzed by tumor location, there was no difference in neurological outcomes (P = .66). At the time of their last follow-up visit, 11 patients (20%) with an ependymoma improved, 38 (69%) remained the same, and 6 (10.9%) worsened. In patients with an astrocytoma, 1 (4.8%) improved, 10 (47.6%) remained the same, and 10 (47.6%) worsened. One patient (8.3%) with a hemangioblastoma improved and 11 (91.7%) remained the same. No patient with a hemangioblastoma worsened. In the miscellaneous tumor group, 2 (14.3%) improved, 10 (71.4%) remained the same, and 2 (14.3%) worsened. Preoperative neurological status (P = .02), tumor histology (P = .005), and extent of resection (P < .0001) were all predictive of functional neurological outcomes. CONCLUSION: Tumor histology is the most important predictor of neurological outcome after surgical resection because it predicts resectability and recurrence. PMID- 25692368 TI - Implications of spinopelvic alignment for the spine surgeon. AB - The relation of the pelvis to the spine has previously been overlooked as a contributor to sagittal balance. However, it is now recognized that spinopelvic alignment is important to maintain an energy-efficient posture in normal and disease states. The pelvis is characterized by an important anatomic landmark, the pelvic incidence (PI). The PI does not change after adolescence, and it directly influences pelvic alignment, including the parameters of pelvic tilt (PT) and sacral slope (SS) (PI = PT 1 SS), overall sagittal spinal balance, and lumbar lordosis. In the setting of an elevated PI, the spineadapts with increased lumbar lordosis. To prevent or limit sagittal imbalance, the spine may also compensate with increased PT or pelvic retroversion to attempt to maintain anupright posture. Abnormal spinopelvic parameters contribute to multiple spinal conditions including isthmic spondylolysis, degenerative spondylolisthesis, deformity, and impact outcome after spinal fusion. Sagittal balance, pelvic incidence, and all spinopelvic parameters are easily and reliably measured on standing, full-spine (lateral) radiographs, and it is essential to accurately assess and measure these sagittal values to understand their potential role in the disease process, and to promote spinopelvic balance at surgery. In this article, we provide a comprehensive review of the literature regarding the implications of abnormal spinopelvic parameters and discuss surgical strategies for correction of sagittal balance. Additionally, the authors rate and critique the quality of the literature cited in a systematic review approach to give the reader an estimate of the veracity of the conclusions reached from these reports. PMID- 25692369 TI - SPORT: Does incidental durotomy affect longterm outcomes in cases of spinal stenosis? AB - BACKGROUND: Incidental durotomy is a familiar encounter during surgery for lumbar spinal stenosis. The impact of durotomy on long-term outcomes remains a matter of debate. OBJECTIVE: To determine the impact of durotomy on the long-term outcomes of patients in the Spine Patient Outcomes Research Trial (SPORT). METHODS: The SPORT cohort participants with a confirmed diagnosis of spinal stenosis, without associated spondylolisthesis, undergoing standard, first-time, open decompressive laminectomy, with or without fusion, were followed up from baseline at 6 weeks, and 3, 6, and 12 months and yearly thereafter at 13 spine clinics in 11 US states. Patient data from this prospectively gathered database were reviewed. As of May 2009, the mean follow-up among all analyzed patients was 43.8 months. RESULTS: Four hundred nine patients underwent first-time open laminectomy with or without fusion. Thirty-seven of these patients (9%) had an incidental durotomy. No significant differences were observed with or without durotomy in age; sex; race; body mass index; the prevalence of smoking, diabetes mellitus, and hypertension; decompression level; number of levels decompressed; or whether an additional fusion was performed. The durotomy group had significantly increased operative duration, operative blood loss, and inpatient stay. There were, however, no differences in incidence of nerve root injury, mortality, additional surgeries, or primary outcomes (Short Form-36 Bodily Pain or Physical Function scores or Oswestry Disability Index) at yearly follow-ups to 4 years. CONCLUSIONS: Incidental durotomy during first-time lumbar laminectomy for spinal stenosis did not impact long-term outcomes in affected patients. PMID- 25692370 TI - Determination of the minimum improvement in pain, disability, and health state associated with cost-effectiveness: introduction of the concept of minimum cost effective difference. AB - BACKGROUND: Minimum clinical important difference (MCID) has been adopted as the smallest improvement in patient-reported outcome needed to achieve a level of improvement thought to be meaningful to patients. OBJECTIVE: To use a common MCID calculation method with a cost-utility threshold anchor to introduce the concept of minimum cost-effective difference (MCED). METHODS: Forty-five patients undergoing transforaminal lumbar interbody fusion for degenerative spondylolisthesis were included. Outcome questionnaires were administered before and 2 years after surgery. Total cost per quality-adjusted life-year (QALY) gained was calculated for each patient. MCED was determined from receiver operating characteristic curve analysis with a cost-effective anchor of < $50,000/QALY and < $75,000/QALY. MCID was determined with the health transition item as the anchor. RESULTS: Significant improvement was observed 2 years after transforaminal lumbar interbody fusion for all outcome measures. Mean total cost per QALY gained at 2 years was $42,854. MCED was greater than MCID for each outcome measure, meaning that a greater improvement was required to represent cost-effectiveness than a clinically meaningful improvement to patients. The area under the receiver-operating characteristic curve was consistently >= 0.70 with both cost-effective anchors, suggesting that outcome change scores were accurate predictors of cost-effectiveness. Mean cost per QALY gained was significantly lower for patients achieving compared with those not achieving an MCED in visual analog scale for leg pain ($43,560 vs $112,087), visual analog scale for back pain ($41,280 vs $129440), Oswestry Disability Index ($30,954 vs $121,750), and EuroQol 5D ($35800 vs $189412). CONCLUSION: MCED serves as the smallest improvement in an outcome instrument that is associated with a cost-effective response to surgery. With the use of cost-effective anchor of < $50,000/QALY, MCED after transforaminal lumbar interbody fusion was 4 points for visual analog scale for low back pain, 3 points for visual analog scale for leg pain, 22 points for Oswestry Disability Index, and 0.31 QALYs for EuroQol 5D. PMID- 25692371 TI - Pharmacological therapy for acute spinal cord injury. PMID- 25692372 TI - Recollection and familiarity components of recognition: effect of side of mesio temporal damage. AB - We investigated the memory performance of three patients with unilateral mesio temporal lobe damage with the aim of evaluating the roles of the left and right hemispheres in recollection and familiarity. Consistent with the "Material Specificity Hypothesis", the right brain-damaged individual was selectively poor on recollection and familiarity tests for faces. Conversely, left-lesioned patients were severely deficient in recollection and familiarity of verbal material but mildly deficient on visual-spatial tests. This partially unexpected finding is interpreted in light of the ability of humans to verbally recode almost any material, thus giving rise to left-hemisphere effects for nominally nonverbal stimuli. PMID- 25692373 TI - Older Adult Self-Efficacy Study of Mobile Phone Diabetes Management. AB - The purpose of this study was to evaluate participant self-efficacy and use of a mobile phone diabetes health intervention for older adults during a 4-week period. Participants included seven adults (mean age, 70.3 years) with type 2 diabetes cared for by community-based primary care physicians. Participants entered blood glucose data into a mobile phone and personalized patient Internet Web portal. Based on blood glucose values, participants received automatic messages and educational information to self-manage their diabetes. Study measures included prior mobile phone/Internet use, the Stanford Self-Efficacy for Diabetes Scale, the Stanford Energy/Fatigue Scale, the Short Form-36, the Patient Health Questionnaire-9 (depression), the Patient Reported Diabetes Symptom Scale, the Diabetes Stages of Change measure, and a summary of mobile system use. Participants had high self-efficacy and high readiness and confidence in their ability to monitor changes to control their diabetes. Participants demonstrated ability to use the mobile intervention and communicate with diabetes educators. PMID- 25692374 TI - Epidural analgesia during labour - maternal understanding and experience - informed consent. AB - Women obtain information on epidural analgesia from various sources. For epidural for pain relief in labour this is provided by the anaesthetist as part of the consenting process. There is much discussion about the inadequacy of this consenting process; we report on women's knowledge, experience and recall of this process at a regional hospital with a 24-h epidural service. Fifty-four women were interviewed within 72 h of a vaginal birth. 91% of the women had acquired information from friends, relatives and antenatal classes. Lack of recall of benefits of epidural analgesia accounted for 26 (38%) and 25 (26%) of the responses, respectively. Similarly in terms of amount of pain relief they could expect, 13 (21%) could not remember and 13 (21%) thought that it may not work. We suggest use of varying methods of disseminating information and wider utilisation of anaesthetists in the antenatal educational programmes. PMID- 25692375 TI - PRECICE intramedullary limb lengthening system. AB - The PRECICE((r)) Intramedullary Limb Lengthening System (Ellipse Technologies Inc., CA, USA) is a remotely controlled, magnetically driven, implantable limb lengthening intramedullary nail system. It has both CE mark and US FDA clearance for its first- (2011) and second-generation (2013) implants. It is indicated for the treatment of limb length discrepancy and short stature. It has been used worldwide in over 1000 cases. Its reported and published results in over 250 cases has been excellent with less pain and lower complication rates than with external fixation methods or previous implantable nail systems. PMID- 25692376 TI - Fine-tuning vitamin E-containing telodendrimers for efficient delivery of gambogic acid in colon cancer treatment. AB - Certain natural products such as gambogic acid (GA) exhibit potent antitumor effects. Unfortunately, administration of these natural products is limited by their poor solubility in conventional pharmaceutical solvents. In this study, a series of telodendrimers, composed of linear polyethylene glycol (PEG)-blocking dendritic oligomer of cholic acid (CA) and vitamin E (VE), have been designed with architectures optimized for efficient delivery of GA and other natural anticancer compounds. Two of the telodendrimers with segregated CA and VE domains self-assembled into stable cylindrical and/or spherical nanoparticles (NPs) after being loaded with GA as observed under transmission electron microscopy (TEM), which correlated with the dynamic light scattering (DLS) analysis of sub-30 nm particle sizes. A very high GA loading capacity (3:10 drug/polymer w/w) and sustained drug release were achieved with the optimized telodendrimers. These novel nanoformulations of GA were found to exhibit similar in vitro cytotoxic activity against colon cancer cells as the free drug. Near-infrared fluorescence small animal imaging revealed preferential accumulation of GA-loaded NPs into tumor tissue. The optimized nanoformulation of GA achieved superior antitumor efficacy compared to GA-Cremophor EL formulation at equivalent doses in HT-29 human colon cancer xenograft mouse models. Given the mild adverse effects associated with this natural compound and the enhanced anticancer effects via tumor targeted telodendrimer delivery, the optimized GA nanoformulation is a promising alternative to the traditional chemotherapy in colon cancer treatment. PMID- 25692377 TI - Predictors of weight loss after laparoscopic gastric plication: a prospective study. AB - INTRODUCTION: Laparoscopic gastric plication (LGP) is a bariatric procedure for the treatment of morbid obesity that has recently increased in popularity. Herein, the predictors of weight loss following LGP are investigated. PATIENTS AND METHODS: This prospective study was performed on cases performed by a single surgeon between 2000 and 2011. The association between nine independent variables and ideal weight loss (percentage of excess weight loss [%EWL] >=80%) at 24 months postoperatively was assessed in 330 patients who underwent LGP. The studied variables were as follows: age at surgery, gender, preoperative body mass index, preoperative comorbidities, marital status (single versus married), employment status (employed versus unemployed), family support in helping the patient to engage in physical activities and continue on a healthy diet (never/a little versus sometimes/a lot), the experience of pain or gastroesophageal reflux during or after eating (yes or no), and participation in support groups following LGP (yes or no). RESULTS: Ideal weight loss (%EWL >=80%) was achieved in 60 patients, and %EWL <80% (suboptimal weight loss) occurred in 270 patients. Being single, female, and of younger age and participation in group meetings were significantly associated with experiencing ideal weight loss at 24 months, postoperatively. However, no significant difference was observed between the two groups in terms of preoperative body mass index, comorbidities, employment, a relative being a coworker, and the experience of pain or gastroesophageal reflux after eating. CONCLUSIONS: This study identified predictor factors positively associated with ideal weight loss. These results would aid surgeons in better patient selection and identification of patients requiring more careful follow up. In addition, it provides patients with more realistic assessment of potential outcome of the procedure. PMID- 25692378 TI - Trivalent influenza vaccine-induced antibody response to circulating influenza a (H3N2) viruses in 2010/11 and 2011/12 seasons. AB - To evaluate antibody response induced by trivalent inactivated influenza vaccine (TIV) against circulating influenza A (H3N2) strains in healthy adults during the 2010/11 and 2011/12 seasons, a hemagglutination-inhibition (HI) assay was utilized to calculate geometric mean antibody titer (GMT), seroprotection rate (post vaccination HI titers of >=1 :40), and seroresponse rate (4-fold increase in antibody level). In the 2010/11 season, GMT increased 1.8- to 2.0-fold following the first dose of TIV against 3 circulating strains and 2.2-fold following the second compared to before vaccination. The seroresponse rate ranged from 22% to 26% following the first dose of TIV and from 31% to 33% following the second (n = 54 ). The seroprotection rate increased from a range of 6% to 13% to a range of 26% to 33% following the first dose of TIV and to a range of 37% to 42% following the second (n = 54 ). In the 2011/12 season, GMT increased 1.4-fold against A/Osaka/110/2011 and 1.8-fold against A/Osaka/5/2012. For A/Osaka/110/2011, the seroresponse rate was 29%, and the seroprotection rate increased from 26% to 55% following vaccination (n = 31 ). For A/Osaka/5/2012, the seroresponse rate was 26%, and the seroprotection rate increased from 68% to 84% following vaccination (n = 31 ). HI assays with reference antisera demonstrated that the strains in the 2011/12 season were antigenically distinct from vaccine strain (A/Victoria/210/2009). In conclusion, the vaccination increased the seroprotection rate against circulating H3N2 strains in the 2010/11 and 2011/12 seasons. Vaccination of TIV might have potential to induce reactive antibodies against antigenically distinct circulating H3N2 viruses. PMID- 25692379 TI - Maternal attachment and mind-mindedness: the role of emotional specificity. AB - We explored the relation between maternal mind-mindedness (i.e., a mother's tendency to verbally refer to her infant's mental world through use of infant directed mental state terms) and maternal attachment. Mothers (N = 76), classified prenatally as Autonomous, Dismissing, Preoccupied, and Unresolved using the Adult Attachment Interview (AAI), simulated speaking to their 6-month old infants in positive and negative emotion contexts. Mothers' utterances were coded for frequency of use of emotion and cognition-related mind-minded terms. Results indicated a significant negative relation between coherence of mind scores on the AAI and emotion mind-mindedness in the positive emotion context. When differences between insecure attachment categories and mind-mindedness were explored, results indicated that mothers with Preoccupied attachments were significantly more likely to use emotion-related terms than mothers with Dismissing attachments and that these differences were most pronounced in the negative emotion context. A similar pattern was found for mothers with Unresolved attachments compared to those with organized (Autonomous, Dismissing, Preoccupied) attachment classifications, however use of emotion mind-minded terms did not differ by emotional context. Future research directions highlighting the importance of exploring the unique contribution of Preoccupied, Dismissing and Unresolved attachment and emotional context in the exploration of mind-mindedness are discussed. PMID- 25692380 TI - Weight and weight-related behaviors among 2-year college students. AB - OBJECTIVES AND PARTICIPANTS: The purpose of this article is to describe weight indicators and weight-related behaviors of students enrolled in 2-year colleges, including sex differences. METHODS: During Fall 2011 and Spring 2012, 441 students from 3 Minnesota community colleges enrolled in the Choosing Healthy Options in College Environments and Settings (CHOICES) Study and completed baseline assessments. Participants completed a baseline survey evaluating eating and activity patterns, sleep, and stress and measures of height, weight, waist circumference, and body fat. RESULTS: Participants were primarily female (68%), white (73%), with a mean age of 22.8 years, and 66.2% reporting an annual income < $12,000. Almost half (47%) were overweight or obese. Young males appeared to engage the most in risky health behaviors and had higher levels of overweight or obesity, compared with young females. CONCLUSIONS: Findings confirm the need for innovative interventions targeting this understudied and underserved young adult population. PMID- 25692381 TI - Folding or misfolding: the choice of beta-hairpin. AB - Proteins fold through complex inter-residue interactions which are mutually supportive and cooperatively lead to thermodynamically favorable native structures. Competing (misfolded) structures, however, could exist, which might affect the thermodynamic and kinetic properties of folded structure. Running long time REMD simulations on two beta-structured polypeptides, the present study identifies the folded and (less populated) competing misfolded states of beta hairpins. Of particular interest is a one-residue shifted misfolded state which has been often seen in previous reports. The folding and misfolding pathways are then energetically characterized by free energy landscape analysis, indicating that the folding and misfolding of beta-hairpin are parallel pathways and a protein's selection of following which pathway is a consequence of the competition between the formation of alterable turn configurations and cross strand hydrophobic interactions. Proteins possessing high percentage of hydrophobic residues introduce strong cross-strand hydrophobic interactions which stabilize the native structural elements in the folding pathway, leading to low possibility of misfolding. The present study provides novel insights into the origin of sequence-dependent beta-hairpin misfolding "hidden" behind experimentally detectable beta-hairpin folding, suggesting the direction for the structure design of beta-structured protein. PMID- 25692382 TI - Positive-Themed Suicide Prevention Messages Delivered by Adolescent Peer Leaders: Proximal Impact on Classmates' Coping Attitudes and Perceptions of Adult Support. AB - Developing science-based communication guidance and positive-themed messages for suicide prevention are important priorities. Drawing on social learning and elaboration likelihood models, we designed and tested two positive-focused presentations by high school peer leaders delivered in the context of a suicide prevention program (Sources of Strength). Thirty-six classrooms in four schools (N = 706 students) were randomized to (1) peer leader modeling of healthy coping, (2) peer leader modeling plus audience involvement to identify trusted adults, or (3) control condition. Students' attitudes and norms were assessed by immediate post-only assessments. Exposure to either presentation enhanced positive coping attitudes and perceptions of adult support. Students who reported suicide ideation in the past 12 months benefited more than nonsuicidal students. Beyond modeling alone, audience involvement modestly enhanced expectations of adult support, congruent with the elaboration likelihood model. Positive peer modeling is a promising alternative to communications focused on negative consequences and directives and may enhance social-interpersonal factors linked to reduced suicidal behaviors. PMID- 25692383 TI - Mapping functional group free energy patterns at protein occluded sites: nuclear receptors and G-protein coupled receptors. AB - Occluded ligand-binding pockets (LBP) such as those found in nuclear receptors (NR) and G-protein coupled receptors (GPCR) represent a significant opportunity and challenge for computer-aided drug design. To determine free energies maps of functional groups of these LBPs, a Grand-Canonical Monte Carlo/Molecular Dynamics (GCMC/MD) strategy is combined with the Site Identification by Ligand Competitive Saturation (SILCS) methodology. SILCS-GCMC/MD is shown to map functional group affinity patterns that recapitulate locations of functional groups across diverse classes of ligands in the LBPs of the androgen (AR) and peroxisome proliferator activated-gamma (PPARgamma) NRs and the metabotropic glutamate (mGluR) and beta2 adreneric (beta2AR) GPCRs. Inclusion of protein flexibility identifies regions of the binding pockets not accessible in crystal conformations and allows for better quantitative estimates of relative ligand binding affinities in all the proteins tested. Differences in functional group requirements of the active and inactive states of the beta2AR LBP were used in virtual screening to identify high efficacy agonists targeting beta2AR in Airway Smooth Muscle (ASM) cells. Seven of the 15 selected ligands were found to effect ASM relaxation representing a 46% hit rate. Hence, the method will be of use for the rational design of ligands in the context of chemical biology and the development of therapeutic agents. PMID- 25692384 TI - Clinical and Histologic Analysis of the Efficacy of Topical Rapamycin Therapy Against Hypomelanotic Macules in Tuberous Sclerosis Complex. AB - IMPORTANCE: Tuberous sclerosis complex (TSC) is an autosomal dominant disorder leading to the aberrant activation of the mammalian target of rapamycin complex 1. Although the efficacy of mammalian target of rapamycin complex 1 inhibitors against tumors in patients with TSC, including facial angiofibroma, has been well investigated, their efficacy against hypomelanotic macules in patients with TSC is unknown. OBJECTIVES: To evaluate objectively the efficacy of topical rapamycin treatment of hypomelanotic macules in patients with TSC and to elucidate the mechanisms of how rapamycin improves the macules. DESIGN, SETTING, AND PARTICIPANTS: We performed a prospective, baseline-controlled trial of 6 patients with TSC and hypomelanotic macules in non-sun-exposed and sun-exposed skin at the Department of Dermatology, Osaka University, from August 4, 2011, through September 27, 2012. Rapamycin gel, 0.2%, was applied to the lesions twice a day for 12 weeks. Histologic examinations and blood tests were conducted at the start and completion of treatment. Blood rapamycin levels were analyzed at completion. EXPOSURES: Topical rapamycin treatment for hypomelanotic macules. MAIN OUTCOMES AND MEASURES: Objective evaluation of rapamycin treatment of hypomelanotic macules in TSC with delta-L (L indicates the brightness of the color) levels on spectrophotometry at the start and completion (12 weeks) of treatment and at 4 and 12 weeks after discontinuation of treatment (16 and 24 weeks, respectively). RESULTS: Improvement of hypomelanotic macules (in delta-L values) was significant at 12 weeks (mean [SD], 2.501 [1.694]; P < .05), 16 weeks (1.956 [1.567]; P < .01), and 24 weeks (1.836 [1.638]; P < .001). Although efficacy tended to be prominent in sun-exposed skin, we did not observe significant differences (in delta-L values) between sun-exposed and non-sun-exposed skin at 12 weeks (mean [SD], 1.859 [0.629] and 3.142 [2.221], respectively), 16 weeks ( 1.372 [0.660] and 2.539 [2.037], respectively), and 24 weeks (1.201 [0.821] and 2.471 [2.064], respectively). No adverse events were observed, and rapamycin was not detected in the blood of any patient. Electron microscopic analysis of hypomelanotic macules revealed that topical rapamycin treatment significantly improved the uniformity of the melanosome numbers in the TSC melanocytes (pretreatment macules: mean [SD], 25.71 [21.90] [range, 5-63]; posttreatment macules: 42.43 [3.60] [range, 38 49]; P < .001). Moreover, rapamycin treatment induced the recovery of melanosomes in TSC-knocked-down melanocytes from depleted amounts (mean [SD], 16.43 [11.84]) to normal levels (42.83 [14.39]; P < .001). CONCLUSIONS AND RELEVANCE: Topical rapamycin treatment was effective and safe against hypomelanotic macules arising from TSC. This efficacy of rapamycin was corroborated as stemming from the improvement of impaired melanogenesis in TSC melanocytes. PMID- 25692386 TI - Unprecedented pseudo-ortho and ortho metallation of [2.2]paracyclophanes--a methyl group matters. AB - The first example of a pseudo-ortho metallation on [2.2]paracyclophane is presented, giving easy access to enantiopure compounds of this type. By slight modification of the directing group, metallation of the ortho- and C2-positions is possible. The mechanism was further investigated by means of density functional theory (DFT) calculations. PMID- 25692387 TI - Enhanced survival of mice infused with bone marrow-derived as compared with adipose-derived mesenchymal stem cells. AB - AIM: Less invasive therapies using mesenchymal stem cells (MSC) are being developed to treat patients with severe liver cirrhosis. MSC constitute a promising cell source for regenerative therapy and are frequently isolated from bone marrow (BMSC) or adipose tissue (ASC). Therefore, this study assessed the characteristics of these two cell types and their safety for cell infusion. METHODS: In vitro, exhaustive genetic analysis was performed using human (h)BMSC and hASC. Subsequently, the expression of mRNA and protein was evaluated. In vivo, mouse (m)BMSC or mASC was infused into serial mice via the peripheral vein, and 24-h survival rate, prothrombin time and cause of death were analyzed. RESULTS: On polymerase chain reaction, western blotting, enzyme-linked immunoassay and fluorescence-activated cell sorting, tissue factor was found to be expressed at higher levels in hASC than in hBMSC. Prothrombin time in mice infused with mASC (>120 s) was markedly longer than that of untreated mice (6.5 +/- 1.7 s) and that of mice infused with BMSC (6.7 +/- 0.8 s) (P < 0.001), indicating that pro-coagulation activity was potently enhanced after ASC infusion. The 24-h survival rates in the mASC- and mBMSC-infused groups were 46.4% (13/28) and 95.5% (21/22), respectively; in the former, the rate decreased with increasing number of infused mASC. This cell number-dependent effect was not observed with mBMSC. A histopathological analysis of mice that died immediately following mASC infusion revealed multiple thrombi in the blood vessels of the lungs. CONCLUSION: These results indicate that BMSC are a superior and safer cell source for regenerative therapy. PMID- 25692385 TI - Design, synthesis, and characterization of graphene-nanoparticle hybrid materials for bioapplications. PMID- 25692388 TI - Base-promoted transannulation of heterocyclic enamines and 2,3-epoxypropan-1 ones: regio- and stereoselective synthesis of fused pyridines and pyrroles. AB - Base-promoted transannulation of heterocyclic enamines and 2,3-epoxypropan-1-ones has been successfully achieved, providing a new access to structurally diverse fused pyridines and pyrroles with excellent regio- and stereoselectivity. Treatment with N-aryl 4-aminofuran-2(5H)-ones and 2,3-epoxypropan-1-ones under microwave heating resulted in functional furo[3,2-b]pyridines in good yields. The N-aryl 4-aminopyrrol-2(5H)-ones bearing an electron-withdrawing group engaged in the reaction afforded pyrrolo[3,2-b]pyridines, whereas their counterparts with an electron-neutral or an electron-donating group underwent a different reaction pathway to form pyrrolo[3,2-b]pyrroles through C-C bond cleavage. PMID- 25692389 TI - Mussel-inspired new approach for polymerization and cross-linking of peptides and proteins containing tyrosines by Fremy's salt oxidation. AB - Our objective was to develop a method mimicking the natural process of coherence in marine mollusks, by direct chemical conversion of protein tyrosine residues to DOPA-o-quinones, which consequently generates polymerization and cross-linking. Fremy's salt, (ON(SO3K)2, was used to convert tyrosine residues in peptides and proteins to reactive o-quinones. The conversion of tyrosines to DOPA-o-quinones, and their ability to polymerize or cross-link, was tested on tyramine, peptides, and proteins. The peptides tested were as follows: biotin-PEG4-tyramine (PEG-BT), and two decapeptides (identical to the repeating units comprising the mussel's adhesive protein). The proteins tested were as follows: bovine pancreatic ribonuclease A (RNase), lysozyme, IgG, avidin, and streptavidin. The oxidized peptides and proteins were all shown to incorporate oxygen atoms and undergo polymerization and cross-linking, depending on the availability of nucleophiles, mostly lysine amino groups of proteins. All the peptides and the noninteracting proteins such as RNase and lysozyme underwent homopolymerization upon Fremy's salt oxidation. When Fremy's salt oxidaized PEG-BT was mixed with the above proteins, it did not react with any of these proteins because PEG-BT underwent fast self-polymerization. Conversely, streptavidin or avidin cross-linked with PEG-BT after preincubation, thus showing that biorecognition is a prerequisite for cross-linking. Polymerization and cross-linking also occurred, following Fremy's salt oxidation of interacting proteins such as avidin and strepavidin with biotinyilated lysozyme or biotinylated RNase. This indicates that only proteins in very close proximity readily cross-link and polymerize via tyrosine residues. Attempts to convert DOPA-quinone to DOPA by reduction with sodium dithionite (Na2S2O4), was successful as far as small peptides were used. Fremy's salt oxidation can serve as an easy and useful tool to polymerize and cross-link proteins, for fabrication of biomaterials and to study protein-protein interactions. PMID- 25692390 TI - Assimilation efficiency of PBDE congeners in Chinook salmon. AB - Polybrominated diphenyl ether (PBDE) flame retardants are environmental contaminants that can accumulate in biota. PBDE accumulation in an organism depends on exposure, assimilation efficiency, and elimination/metabolism. Net assimilation efficiency represents the fraction of the contaminant that is retained in the organism after exposure. In the present study, congener-specific estimates of net PBDE assimilation efficiencies were calculated from dietary exposures of juvenile Chinook salmon. The fish were exposed to one to eight PBDE congeners up to 1500 ng total PBDEs/g food. Mean assimilation efficiencies varied from 0.32 to 0.50 for BDE congeners 28, 47, 99, 100, 153, and 154. The assimilation efficiency of BDE49 was significantly greater than 100%, suggesting biotransformation from higher brominated congeners. Whole body concentrations of BDE49 significantly increased with both exposure to increasing concentrations of BDE99 and decreasing fish lipid levels, implying lipid-influenced debromination of BDE99 to BDE49. Excluding BDE49, PBDE assimilation efficiency was not significantly related to the numbers of congeners in the diets, or congener hydrophobicity, but was greater in foods with higher lipid levels. Estimates of PBDE assimilation efficiency can be used in bioaccumulation models to assess threats from PBDE exposure to Chinook salmon health and recovery efforts, as well as to their predators. PMID- 25692391 TI - Prospective evaluation of treatment of open fractures: effect of time to irrigation and debridement. AB - IMPORTANCE: The standard practice of irrigation and debridement (I&D) of open fractures within 6 hours of injury remains controversial. OBJECTIVE: To prospectively evaluate the effect of the time from injury to the initial I&D on infectious complications. DESIGN, SETTING, AND PARTICIPANTS: A total of 315 patients who were admitted to a level 1 trauma center with open extremity fractures from September 22, 2008, through June 21, 2011, were enrolled in a prospective observational study and followed up for 1 year after discharge (mean [SD] age, 33.9 [16.3] years; 79% were male; and 78.4% were due to blunt trauma). Demographics, mechanism of injury, time to I&D, operative intervention, and incidence of local infectious complications were documented. Patients were stratified into 4 groups based on the time of I&D (<6 hours, 7-12 hours, 13-18 hours, and 19-24 hours after injury). Univariate and multivariable analysis were used to determine the effect of time to I&D on outcomes. MAIN OUTCOMES AND MEASURES: Development of local infectious complications at early (<30 days) or late (>30 days and <1 year) intervals from admission. RESULTS: The most frequently injured site was the lower extremity (70.2%), and 47.9% of all injuries were Gustilo classification type III. There was no difference in fracture location, degree of contamination, or antibiotic use between groups. All patients underwent I&D within 24 hours. Overall, 14 patients (4.4%) developed early wound infections, while 10 (3.2%) developed late wound infections (after 30 days). The infection rate was not statistically different on univariate (<6 hours, 4.7%; 7-12 hours, 7.5%; 13-18 hours, 3.1%; and 19-24 hours, 3.6%; P = .65) or multivariable analysis (<6-hour group [reference], P = .65; 7- to 12-hour group adjusted odds ratio [AOR] [95% CI], 2.1 [0.4-10.2], P = .37; 13- to 18-hour group AOR [95% CI], 0.8 [0.1-4.5], P = .81; 19- to 24-hour group AOR [95% CI], 1.1 [0.2-6.2], P = .90). Time to I&D did not affect the rate of nonunion, hardware failure, length of stay, or mortality. CONCLUSIONS AND RELEVANCE: In this prospective analysis, time to I&D did not affect the development of local infectious complications provided it was performed within 24 hours of arrival. PMID- 25692392 TI - In situ visualization of metallurgical reactions in nanoscale Cu/Sn diffusion couples. AB - The Cu-Sn metallurgical soldering reaction in two-segmented Cu-Sn nanowires is studied by in situ transmission electron microscopy. By varying the relative lengths of Cu and Sn segments, we show that the metallurgical reaction results in a Cu-Sn solid solution for small Sn/Cu length ratio while Cu-Sn intermetallic compounds (IMCs) for larger Sn/Cu length ratios. Upon heating the nanowires to ~500 degrees C, two phase transformation pathways occur, eta-Cu6Sn5 -> epsilon Cu3Sn -> delta-Cu41Sn11 for nanowires with a long Cu segment and eta-Cu6Sn5 -> epsilon-Cu3Sn -> gamma-Cu3Sn with a short Cu segment. The evolution of Kirkendall voids in the nanowires demonstrates that Cu diffuses faster than Sn in IMCs. Void growth results in the nanowire breakage that shuts off the inter-diffusion of Cu and Sn and thus leads to changes in the phase transformation pathway in the IMCs. PMID- 25692393 TI - Impact of oral immunotherapy on quality of life in egg-allergic children. PMID- 25692395 TI - 2,2- and 2,6-Diarylpiperidines by aryl migration within lithiated urea derivatives of tetrahydropyridines. AB - 2-Aryltetrahydropyridines formed by anionic cyclization or ring-closing metathesis were converted to their N'-aryl urea derivatives. Depending on the position of the unsaturation within the tetrahydropyridine ring, metalation by deprotonative lithiation or carbolithiation led to migration of the N'-aryl substituent to the 2- or 6-position via intramolecular nucleophilic attack of a benzylic organolithium on the aryl ring. The products are a range of 2,2-, 2,2,3 , and 2,6-polysubstituted piperidine derivatives. Related chemistry was observed in pyrroline homologues. PMID- 25692396 TI - Ir(2-phenylpyridine)2(benzene-1,2-dithiolate) anion as a diastereoselective metalloligand and nucleophile: stereoelectronic effect, spectroscopy, and computational study of the methylated and aurated complexes and their oxygenation products. AB - The anionic complex [Ir(2-phenylpyridine)2(benzene-1,2-dithiolate)](-) ([IrSS]( )) is a nucleophile and metalloligand that reacts with methyl iodide and AuPR3(+) (R = Ph or Et) to form S-methylated complexes (thiother-thiolate and dithiother complexes) and S-aurated complexes, respectively. The reactions are completely diastereselective, producing only the enantiomers LambdaS and DeltaR or LambdaSS and DeltaRR. The diastereoselectivity is stereoelectronically controlled by the orientation of the highest occupied molecular orbital (HOMO) of [IrSS](-) arising from filled dpi-ppi antibonding interactions, and the chirality of the iridium ion. Methylation or auration removes the high-energy lone pair of the thiolate S atom, leading to low-lying HOMOs composed mainly of the Ir d-orbital and the 2 phenylpyridine pi (ppypi) orbital. The methylated and aurated complexes can be oxidized by H2O2 or peracid to give sulfinate-thiother, disulfoxide, and sulfinate-sulfoxide complexes, and the oxygenation further stabilizes the HOMO. All the complexes are luminescent, and their electronic spectra are interpreted with the aid of time-dependent density functional theory calculations. The thiother-thiolate complex exhibits ligand(S)-to-ligand(pi* of ppy)-charge transfer/metal-to-ligand-charge-transfer absorption (LLCT/MLCT) and a relatively low-energy (3)LLCT/MLCT emission, while the other complexes display (3)pipi*/MLCT emissions. PMID- 25692397 TI - A new O3-type layered oxide cathode with high energy/power density for rechargeable Na batteries. AB - A new O3-Na(0.78)Li(0.18)Ni(0.25)Mn(0.583)O(w) is prepared as the cathode material for Na-ion batteries, delivering exceptionally high energy density and superior rate performance. The single-slope voltage profile and ex situ synchrotron X-ray diffraction data demonstrate that no phase transformation happens through a wide range of sodium concentrations (up to 0.8 Na removed). Ni(2+)/Ni(4+) is suggested to be the main redox center. Further optimization could be realized by tuning the combination and the ratio of transition metals. PMID- 25692398 TI - Tellurium: a maverick among the chalcogens. AB - The scant attention paid to tellurium in both inorganic and organic chemistry textbooks may reflect, in part, the very low natural abundance of the element. Such treatments commonly imply that the structures and reactivities of tellurium compounds can be extrapolated from the behaviour of their lighter chalcogen analogues (sulfur and selenium). In fact, recent findings and well-established observations clearly illustrate that this assumption is not valid. The emerging importance of the unique properties of tellurium compounds is apparent from the variety of their known and potential applications in both inorganic and organic chemistry, as well as materials science. With reference to selected contemporary examples, this Tutorial Review examines the fundamental concepts that are essential for an understanding of the unique features of tellurium chemistry with an emphasis on hypervalency, three-centre bonding, secondary bonding interactions, sigma and pi-bond energies (multiply bonded compounds), and Lewis acid behaviour. PMID- 25692399 TI - 15.7% Efficient 10-MUm-thick crystalline silicon solar cells using periodic nanostructures. AB - Only ten micrometer thick crystalline silicon solar cells deliver a short-circuit current of 34.5 mA cm(-2) and power conversion efficiency of 15.7%. The record performance for a crystalline silicon solar cell of such thinness is enabled by an advanced light-trapping design incorporating a 2D inverted pyramid photonic crystal and a rear dielectric/reflector stack. PMID- 25692400 TI - Protective Effects of Quercetin Against HgCl2-Induced Nephrotoxicity in Sprague Dawley Rats. AB - Mercury is a well-known environmental pollutant that can cause nephropathic diseases, including acute kidney injury (AKI). Although quercetin (QC), a natural flavonoid, has been reported to have medicinal properties, its potential protective effects against mercury-induced AKI have not been evaluated. In this study, the protective effect of QC against mercury-induced AKI was investigated using biochemical parameters, new protein-based urinary biomarkers, and a histopathological approach. A 250 mg/kg dose of QC was administered orally to Sprague-Dawley male rats for 3 days before administration of mercury chloride (HgCl2). All animals were sacrificed at 24 h after HgCl2 treatment, and biomarkers associated with nephrotoxicity were measured. Our data showed that QC absolutely prevented HgCl2-induced AKI, as indicated by biochemical parameters such as blood urea nitrogen (BUN) and serum creatinine (sCr). In particular, QC markedly decreased the accumulation of Hg in the kidney. Urinary excretion of protein-based biomarkers, including clusterin, kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), monocyte chemoattractant protein-1 (MCP-1), tissue inhibitor of metalloproteinases 1 (TIMP-1), and vascular endothelial growth factor (VEGF) in response to HgCl2 administration were significantly decreased by QC pretreatment relative to that in the HgCl2 treated group. Furthermore, urinary excretion of metallothionein and Hg were significantly elevated by QC pretreatment. Histopathological examination indicated that QC protected against HgCl2-induced proximal tubular damage in the kidney. A TUNEL assay indicated that QC pretreatment significantly reduced apoptotic cell death in the kidney. The administration of QC provided significant protective effects against mercury-induced AKI. PMID- 25692401 TI - Electrospun fibrous mats with conjugated tetraphenylethylene and mannose for sensitive turn-on fluorescent sensing of Escherichia coli. AB - A rapid and sensitive detection of microbes in water and biological fluids is a key requirement in water and food safety, environmental monitoring, and clinical diagnosis and treatment. In the current study, electrospun polystyrene-co-maleic anhydride (PSMA) fibers with conjugated mannose and tetraphenylethylene (TPE) were developed for Escherichia coli (E. coli) detection, taking advantage of the high grafting capabilities of ultrafine fibers and the highly porous structure of the fibrous mat to entrap bacterial cells. The specific binding between mannose grafts on PSMA fibers and FimH proteins from the fimbriae of E. coli led to an efficient "turn-on" profile of TPE due to the aggregation-induced emission (AIE) effect. Poly(ethylene glycol) diamine was used as hydrophilic tethers to increase the conformational mobility of mannose grafts, indicating a more sensitive change in the fluorescence intensity against bacteria concentrations, a lower fluorescence background of fibers without bacteria incubation, and a sufficient space for bacteria binding, compared with the use of hexamethylenediamine or poly(ethylene imine) as spacers for mannose grafting. The addition of bovine serum albumin, glucose, or both of them into bacteria suspensions showed no significant changes in the fluorescence intensity of fibrous mats, indicating the anti-interference capability against these proteins and saccharides. An equation was drafted of the fluorescence intensities of fibrous mats against E. coli concentrations ranging from 10(2) to 10(5) CFU/mL. The test strip format was established on mannose-conjugated PSMA fibers after exposure to E. coli of different concentrations, providing a potential tool with a visual sensitivity of bacteria concentrations as low as 10(2) CFU/mL in a matter of minutes. This strategy may offer a capacity to be expanded to exploit electrospun fibrous mats and other carbohydrate-cell interactions for bioanalysis and biosensing of pathogenic bacteria. PMID- 25692402 TI - Induction of STAT3-Dependent CXCL5 Expression and Neutrophil Recruitment by Oncostatin-M during Pneumonia. AB - Acute bacterial pneumonia is a significant public health concern worldwide. Understanding the signals coordinating lung innate immunity may foster the development of therapeutics that limit tissue damage and promote host defense. We have previously shown that lung messenger RNA expression of the IL-6 family cytokine oncostatin-M (OSM) is significantly elevated in response to bacterial stimuli. However, its physiological significance during pneumonia is unknown. Here we demonstrate that OSM is rapidly increased in the airspaces of mice after pulmonary infection with Escherichia coli. Neutralization of OSM caused a substantial decrease in airspace neutrophils and macrophages. OSM blockade also caused a marked reduction in lung chemokine (C-X-C motif) ligand (CXCL) 5 expression, whereas other closely related neutrophil chemokines, CXCL1 and CXCL2, were unaffected. Intratracheal administration of recombinant OSM was sufficient to recapitulate the effect on CXCL5 induction, associated with robust activation of the signal transducer and activator of transcription 3 (STAT3) transcription factor. Cell sorting revealed that OSM effects were specific to lung epithelial cells, including a positive feedback loop in which OSM may facilitate expression of its own receptor. Finally, in vitro studies demonstrated that STAT3 was required for maximal OSM-induced CXCL5 expression. These studies demonstrate a novel role for OSM during pneumonia as an important signal to epithelial cells for chemokine induction mediating neutrophil recruitment. PMID- 25692403 TI - Cognitive behavioural therapy for anxiety disorders in children and adolescents. AB - BACKGROUND: A previous Cochrane review (James 2005) showed that cognitive behavioural therapy (CBT) was effective in treating childhood anxiety disorders; however, questions remain regarding (1) the relative efficacy of CBT versus non CBT active treatments; (2) the relative efficacy of CBT versus medication and the combination of CBT and medication versus placebo; and (3) the long-term effects of CBT. OBJECTIVES: To examine (1) whether CBT is an effective treatment for childhood and adolescent anxiety disorders in comparison with (a) wait-list controls; (b) active non-CBT treatments (i.e. psychological placebo, bibliotherapy and treatment as usual (TAU)); and (c) medication and the combination of medication and CBT versus placebo; and (2) the long-term effects of CBT. SEARCH METHODS: Searches for this review included the Cochrane Central Register of Controlled Trials (CENTRAL) and the Cochrane Depression, Anxiety and Neurosis Group Register, which consists of relevant randomised controlled trials from the bibliographic databases-The Cochrane Library (1970 to July 2012), EMBASE, (1970 to July 2012) MEDLINE (1970 to July 2012) and PsycINFO (1970 to July 2012). SELECTION CRITERIA: All randomised controlled trials (RCTs) of CBT versus waiting list, active control conditions, TAU or medication were reviewed. All participants must have met the criteria of the Diagnostic and Statistical Manual (DSM) or the International Classification of Diseases (ICD) for an anxiety diagnosis, excluding simple phobia, obsessive-compulsive disorder, post-traumatic stress disorder and elective mutism. DATA COLLECTION AND ANALYSIS: The methodological quality of included trials was assessed by three reviewers independently. For the dichotomous outcome of remission of anxiety diagnosis, the odds ratio (OR) with 95% confidence interval (CI) based on the random-effects model, with pooling of data via the inverse variance method of weighting, was used. Significance was set at P < 0.05. Continuous data on each child's anxiety symptoms were pooled using the standardised mean difference (SMD). MAIN RESULTS: Forty-one studies consisting of 1806 participants were included in the analyses. The studies involved children and adolescents with anxiety of mild to moderate severity in university and community clinics and school settings. For the primary outcome of remission of any anxiety diagnosis for CBT versus waiting list controls, intention-to-treat (ITT) analyses with 26 studies and 1350 participants showed an OR of 7.85 (95% CI 5.31 to 11.60, Z = 10.26, P < 0.0001), but with evidence of moderate heterogeneity (P = 0.04, I2 = 33%). The number needed to treat (NNT) was 6.0 (95% CI 7.5 to 4.6). No difference in outcome was noted between individual, group and family/parental formats. ITT analyses revealed that CBT was no more effective than non-CBT active control treatments (six studies, 426 participants) or TAU in reducing anxiety diagnoses (two studies, 88 participants). The few controlled follow-up studies (n = 4) indicate that treatment gains in the remission of anxiety diagnosis are not statistically significant. AUTHORS' CONCLUSIONS: Cognitive behavioural therapy is an effective treatment for childhood and adolescent anxiety disorders; however, the evidence suggesting that CBT is more effective than active controls or TAU or medication at follow-up, is limited and inconclusive. PMID- 25692404 TI - Is lateral localisation of placenta a risk factor for adverse perinatal outcomes? AB - The aim of this study was to evaluate the relationship between placental localisation and perinatal outcomes. This study was performed in a tertiary centre hospital by retrospectively analysing the medical records of patients who were followed up and underwent delivery in the same hospital. The patients were divided into two groups according to the placental locations (central and lateral) in their routine sonographic findings between the 18 and 24 weeks' gestation. Out of 1,057 patients, 87.4% (n = 919) had centrally located placentas and 12.6% (n = 133) had laterally located placentas. Preeclampsia was found to be significantly higher in the lateral placental location group (4.5% vs. 1.6%; p = 0.027). There was a significant correlation with foetal growth restriction (FGR), preterm birth rates, low Apgar scores and need for neonatal intensive care unit in the lateral placental location group (p < 0.05). The pregnant women with laterally located placentas should be followed up promptly with special care for the risk of preeclampsia and FGR, and poor neonatal outcomes. PMID- 25692405 TI - Whole-exome DNA sequence analysis of Brca2- and Trp53-deficient mouse mammary gland tumours. AB - Germline mutations in the tumour suppressor BRCA2 predispose to breast, ovarian and a number of other human cancers. Brca2-deficient mouse models are used for preclinical studies but the pattern of genomic alterations in these tumours has not yet been described in detail. We have performed whole-exome DNA sequencing analysis of mouse mammary tumours from Blg-Cre Brca2(f/f) Trp53(f/f) animals, a model of BRCA2-deficient human cancer. We also used the sequencing data to estimate DNA copy number alterations in these tumours and identified a recurrent copy number gain in Met, which has been found amplified in other mouse mammary cancer models. Through a comparative genomic analysis, we identified several mouse Blg-Cre Brca2(f/f) Trp53(f/f) mammary tumour somatic mutations in genes that are also mutated in human cancer, but few of these genes have been found frequently mutated in human breast cancer. A more detailed analysis of these somatic mutations revealed a set of genes that are mutated in human BRCA2 mutant breast and ovarian tumours and that are also mutated in mouse Brca2-null, Trp53 null mammary tumours. Finally, a DNA deletion surrounded by microhomology signature found in human BRCA1/2-deficient cancers was not common in the genome of these mouse tumours. Although a useful model, there are some differences in the genomic landscape of tumours arising in Blg-Cre Brca2(f/f) Trp53(f/f) mice compared to human BRCA-mutated breast cancers. Therefore, this needs to be taken into account in the use of this model. PMID- 25692406 TI - Solar irradiance changes and photobiological effects at earth's surface following astrophysical ionizing radiation events. AB - Astrophysical ionizing radiation events have been recognized as a potential threat to life on Earth, primarily through depletion of stratospheric ozone and subsequent increase in surface-level solar ultraviolet radiation. Simulations of the atmospheric effects of a variety of events (such as supernovae, gamma-ray bursts, and solar proton events) have been previously published, along with estimates of biological damage at Earth's surface. In this work, we employed the Tropospheric Ultraviolet and Visible (TUV) radiative transfer model to expand and improve calculations of surface-level irradiance and biological impacts following an ionizing radiation event. We considered changes in surface-level UVB, UVA, and photosynthetically active radiation (visible light) for clear-sky conditions and fixed aerosol parameter values. We also considered a wide range of biological effects on organisms ranging from humans to phytoplankton. We found that past work overestimated UVB irradiance but that relative estimates for increase in exposure to DNA-damaging radiation are still similar to our improved calculations. We also found that the intensity of biologically damaging radiation varies widely with organism and specific impact considered; these results have implications for biosphere-level damage following astrophysical ionizing radiation events. When considering changes in surface-level visible light irradiance, we found that, contrary to previous assumptions, a decrease in irradiance is only present for a short time in very limited geographical areas; instead we found a net increase for most of the modeled time-space region. This result has implications for proposed climate changes associated with ionizing radiation events. PMID- 25692407 TI - Protection from cyanide-induced brain injury by the Nrf2 transcriptional activator carnosic acid. AB - Cyanide is a life-threatening, bioterrorist agent, preventing cellular respiration by inhibiting cytochrome c oxidase, resulting in cardiopulmonary failure, hypoxic brain injury, and death within minutes. However, even after treatment with various antidotes to protect cytochrome oxidase, cyanide intoxication in humans can induce a delayed-onset neurological syndrome that includes symptoms of Parkinsonism. Additional mechanisms are thought to underlie cyanide-induced neuronal damage, including generation of reactive oxygen species. This may account for the fact that antioxidants prevent some aspects of cyanide induced neuronal damage. Here, as a potential preemptive countermeasure against a bioterrorist attack with cyanide, we tested the CNS protective effect of carnosic acid (CA), a pro-electrophilic compound found in the herb rosemary. CA crosses the blood-brain barrier to up-regulate endogenous antioxidant enzymes via activation of the Nrf2 transcriptional pathway. We demonstrate that CA exerts neuroprotective effects on cyanide-induced brain damage in cultured rodent and human-induced pluripotent stem cell-derived neurons in vitro, and in vivo in various brain areas of a non-Swiss albino mouse model of cyanide poisoning that simulates damage observed in the human brain. Cyanide, a potential bioterrorist agent, can produce a chronic delayed-onset neurological syndrome that includes symptoms of Parkinsonism. Here, cyanide poisoning treated with the proelectrophillic compound carnosic acid, results in reduced neuronal cell death in both in vitro and in vivo models through activation of the Nrf2/ARE transcriptional pathway. Carnosic acid is therefore a potential treatment for the toxic central nervous system (CNS) effects of cyanide poisoning. ARE, antioxidant responsive element; Nrf2 (NFE2L2, Nuclear factor (erythroid-derived 2)-like 2). PMID- 25692408 TI - PI3K-independent mTOR activation promotes lapatinib resistance and IAP expression that can be effectively reversed by mTOR and Hsp90 inhibition. AB - Although HER2 targeted therapies have substantially improved outcomes in HER2 overexpressing (HER2+) breast cancer, resistance to these therapies remains a clinical challenge. To better understand the mechanisms of resistance to lapatinib, a HER2 and EGFR dual kinase inhibitor, we treated HER2+ breast cancer cells with lapatinib for an extended period to generate a lapatinib-resistant (LapR) cell line model and examined cancer-promoting signaling activation in LapR cells. We found that LapR cells possess enhanced mTOR activation, which was independent of PI3K and other known mTOR activators. Lapatinib resistance could be reversed by mTOR kinase inhibition. Intriguingly, LapR cells had constitutive cytosolic cytochrome C, indicating that LapR cells suppress lapatinib-induced apoptosis downstream of cytochrome C release from mitochondria into the cytosol rather than by preventing its release into the cytosol. Consistent with this notion, LapR cells possessed increased levels of 2 of the inhibitors of apoptosis (IAPs), survivin and c-IAP-2, which are reported to block caspase activation downstream of cytosolic cytochrome C release. Further, treatment with the mTOR kinase inhibitor AZD8055 or the Hsp90 inhibitor 17-AAG reversed expression of IAPs and overcame lapatinib resistance in LapR cells. Together, these data suggest that suppression of apoptosis downstream of cytosolic cytochrome C release, possibly through increased expression of IAPs or other caspase suppressing proteins, may promote lapatinib resistance. Further, PI3K is thought to be the main driver of lapatinib resistance, but our findings indicate that PI3K inhibitors may be ineffective in some lapatinib-resistant HER2+ breast cancers with PI3K-independent activation of mTOR kinase, which may instead benefit from mTOR or Hsp90 inhibitors. PMID- 25692409 TI - Improving students' safety practice behaviors through a simulation-based learning experience. AB - This study evaluated 175 senior-level undergraduate nursing students' perceptions and comfort level regarding safety principles and practices before and after participating in a safety-focused clinical simulation-based experience during their nursing leadership course. The Healthcare Professionals Patient Safety Assessment (HPPSA) was used to measure students' perceptions and comfort level regarding patient safety practices. Respondents rated their level of agreement about statements related to errors and safety in health care, their comfort level in reporting and disclosing an error, and whether they had seen, disclosed, or reported an error. The t test for the HPPSA Part 2 was statistically significant (n = 153, t = 2.78, p = 0.006) with mean pretest and posttest scores of 16.95 (SD = 3.44) and 17.69 (SD = 3.25), respectively. The findings suggest simulation is a teaching strategy that may contribute to increasing undergraduate nursing students' comfort with reporting or investigating errors. PMID- 25692410 TI - Genetic screening and diagnosis in epilepsy? AB - PURPOSE OF REVIEW: Genetic discovery has been extremely rapid over the last year, with many new discoveries illuminating novel mechanisms and pathways. In particular, the application of whole exome and whole genome sequencing has identified many new genetic causes of the epilepsies. As such methods become increasingly available, it will be critical for practicing neurologists to be acquainted with them. This review surveys some important developments over the last year. RECENT FINDINGS: The range of tests available to the clinician is wide, and likely soon to be dominated by whole exome and whole genome sequencing. Both whole exome and whole genome sequencing have usually proven to be more powerful than most existing tests. Many new genes have been implicated in the epilepsies, with emerging evidence of the involvement of particular multigene pathways. SUMMARY: For the practicing clinician, it will be important to appreciate progress in the field, and to prepare for the application of novel genetic testing in clinical practice, as genetic data are likely to contribute importantly for many people with epilepsy. PMID- 25692411 TI - Less is more: novel less-invasive surgical techniques for mesial temporal lobe epilepsy that minimize cognitive impairment. AB - PURPOSE OF REVIEW: New minimally invasive techniques are becoming available to treat focal-onset epilepsy. The open surgical treatment of mesial temporal lobe epilepsy (MTLE), although associated with high rates of seizure freedom, is confounded by adverse impacts on neurocognitive function. This review covers new techniques being explored for surgical treatment of MTLE that in early studies have been achieving high seizure-free rates with preservation of memory and other functions referable to the mesial and lateral temporal regions. RECENT FINDINGS: Multiple subpial transections of the hippocampus, and stereotactic approaches including radiofrequency ablation and laser interstitial thermal therapy have achieved rates of seizure freedom comparable to open resection but with fewer neurocognitive adverse effects. Electrical neuromodulation approaches, including responsive neurostimulation, direct hippocampal stimulation, and thalamic deep brain stimulation preserve cognitive function and achieve significant seizure suppression, but have not yet achieved high seizure-free rates. SUMMARY: With the recent success in minimally invasive approaches with respect to seizure freedom and preservation of neurocognitive functions, it is predicted that fewer patients will be receiving 'classic' open resections for MTLE such as temporal lobectomy. These new approaches also promise to decrease discomfort, time away from work, and healthcare utilization. PMID- 25692412 TI - Reappraisal of corpus callosotomy. AB - PURPOSE OF REVIEW: Corpus callosotomy is a palliative surgical treatment modality that has gone in and out of favor. The purpose of this review is to summarize the studies of callosotomy in the past years as a treatment for severe drug-resistant epilepsy with traumatizing drop attacks, mostly in children and also in some adults. The aim is also to discuss knowledge gaps and suggest how these could be addressed. RECENT FINDINGS: Lately, a number of callosotomy series, mostly retrospective and single center, have included 289 operated patients. A few series have included nonoperated controls; one prospective long-term series is national and population based. Seizure outcome is shown to be comparable to that earlier reported, with best effect against drop attacks. There is no consensus on whether anterior or complete callosotomy is to be preferred. In a meta-analysis of callosotomy versus vagal nerve stimulation, callosotomy led to better seizure outcome. Diffusion tensor imaging may be a promising tool to analyze the completeness of the procedure. SUMMARY: Callosotomy remains an effective palliative procedure. Many unresolved issues, such as prognostic indicators, nonseizure-related outcomes, whether to choose anterior or complete callosotomy, and outcomes and adverse effects in adults, need to be studied in prospective, preferably multicenter studies. PMID- 25692413 TI - The one year effects of three doses of hepatitis B vaccine as a booster in anti HBs-negative children 11-15 years after primary immunization; China, 2009-2011. AB - The aim of this study was to evaluate hepatitis B surface antibody (anti-HBs) levels one year after hepatitis B booster vaccination in anti-HBs-negative (<10 mIU/mL) children 11-15 y after primary vaccination. Anti-HBs titers were examined in 235 children who were negative for hepatitis B surface antigen (HBsAg), anti HBs, and hepatitis B core antibody (anti-HBc). The children were then divided into 3 groups based on their anti-HBs levels pre-booster: Group I, <0 .1 mIU/mL; Group II, 0.1 to <1 .0 mIU/mL; and Group III, 1.0 to <10 .0 mIU/mL. They were vaccinated with 3 doses of hepatitis B vaccine (0-1-6 month, 20 ug), and anti-HBs levels were measured. One month after the first dose, the anti-HBs positive rates (>= 10 mIU/mL) in Groups I-III were 56.14%, 83.61% and 100%. One month after the third dose, the anti-HBs-positive rates in Groups I-III were 96.49%, 98.36% and 100%. One year after the third dose, the anti-HBs-positive rates in Groups I-III were 73.68%, 75.41% and 98.29%, respectively. Protective levels declined more rapidly for those with lower titers. Children with pre-booster anti-HBs titers of 1-9.9 mIU/mL might not need any booster dose, and the children with pre-booster titers of 0.1-0.9 and <0 .1 mIU/mL might need more than one dose booster vaccination. PMID- 25692414 TI - Sixteen years of the Roche Organ Transplantation Research Foundation. PMID- 25692417 TI - Intramuscular atypical lipomatous tumor/well-differentiated liposarcoma of the pectoralis major masquerading as a breast tumor: management and review of the literature. AB - Atypical lipomatous tumor (ALT)/well-differentiated liposarcoma (WDL) of the pectoralis major muscle is an exceedingly rare clinical entity. We describe here a case of intramuscular ALT/WDL of the pectoralis major muscle in a female patient who presented with clinical manifestations of a rapidly growing breast tumor. Diagnostic evaluation and management of the patient are discussed along with a review of the relevant literature. We conclude that although the clinical examination may be inconclusive, the mammogram and especially the magnetic resonance imaging scan can precisely delineate the anatomic location and extent of the ALT/WDL of the pectoralis major muscle, thus allowing a correct preoperative diagnosis and adequate preoperative surgical planning. Complete resection is the treatment of choice for ALT/WDL. Long-term follow-up, however, remains mandatory because of the risk of local recurrence or delayed dedifferentiation. PMID- 25692415 TI - CEACAM1 induces B-cell survival and is essential for protective antiviral antibody production. AB - B cells are essential for antiviral immune defence because they produce neutralizing antibodies, present antigen and maintain the lymphoid architecture. Here we show that intrinsic signalling of CEACAM1 is essential for generating efficient B-cell responses. Although CEACAM1 exerts limited influence on the proliferation of B cells, expression of CEACAM1 induces survival of proliferating B cells via the BTK/Syk/NF-kappaB-axis. The absence of this signalling cascade in naive Ceacam1(-/-) mice limits the survival of B cells. During systemic infection with cytopathic vesicular stomatitis virus, Ceacam1(-/-) mice can barely induce neutralizing antibody responses and die early after infection. We find, therefore, that CEACAM1 is a crucial regulator of B-cell survival, influencing B cell numbers and protective antiviral antibody responses. PMID- 25692418 TI - Elevated platelet count as predictor of recurrence in rectal cancer patients undergoing preoperative chemoradiotherapy followed by surgery. AB - The impact of systemic inflammatory response (SIR) on prognostic and predictive outcome in rectal cancer after neoadjuvant chemoradiotherapy (CRT) has not been fully investigated. This retrospective study enrolled 89 patients with locally advanced rectal cancer who underwent neoadjuvant CRT and for whom platelet (PLT) counts and SIR status [neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratio (PLR)] were available. Both clinical values of PLT and SIR status in rectal cancer patients were investigated. Elevated PLT, NLR, PLR, and pathologic TNM stage III [ypN(+)] were associated with significantly poor overall survival (OS). Elevated PLT, NLR, and ypN(+) were shown to independently predict OS. Elevated PLT and ypN(+) significantly predicted poor disease-free survival (DFS). Elevated PLT was identified as the only independent predictor of DFS. PLT counts are a promising pre-CRT biomarker for predicting recurrence and poor prognosis in rectal cancer. PMID- 25692419 TI - Preoperative assessment of vascular anatomy by multidetector computed tomography before laparoscopic colectomy for transverse colon cancer: report of a case. AB - Although the safety of laparoscopic surgery for colon cancer has been reported in many randomized controlled trials, concerns about the difficulty of surgery for transverse colon cancer has not been fully resolved, mainly because of the variation in the vascular anatomy of mesenteric vessels, which leads to difficulty in determining the optimal operative procedure and the extent of lymph node dissection. We present the case of a patient with transverse colon cancer who underwent laparoscopic surgery after preoperative assessment using a combination of endoscopic clipping and three-dimensional computed tomography angiography (3DCTA). A 68-year-old man was diagnosed with transverse colon cancer, and laparoscopic surgery has been planned. 3DCTA showed right-middle and left-middle colic arteries arising independently from the superior mesenteric artery. The relationship between the clip and vessels showed that the right middle colic artery was the feeding artery of the tumor. Operative findings were consistent with 3DCTA findings, and transverse colectomy with lymph node dissection was successfully performed. PMID- 25692420 TI - High Expression of DARPP-32 in Colorectal Cancer Is Associated With Liver Metastases and Predicts Survival for Dukes A and B Patients: Results of a Pilot Study. AB - The purpose of this study was to investigate prognostic significance of Dopamine and cAMP-Regulated neuronal Phosphoprotein 32 (DARPP-32) expression in primary colorectal cancer. The study material consisted of clinical and histopathological data of 100 patients operated for colorectal cancer between 1994 and 1997. For immunohistochemical analysis, specific rabbit antibodies for DARPP-32 were used and the percentage of stained tumor cells was calculated under gross magnification (400 times) on a sample of 500 tumor cells. DARPP-32 expression in the primary tumor was significantly greater in patients with distant metastases compared to patients with no distant metastases (p=0.002). In multivariate regression analysis, DARPP-32 expression in the primary tumor was a significant predictor of distant metastases. With a cut-off point of 76.5%, DARPP-32 expression in the primary tumor significantly influenced both overall and disease free survival, especially for Dukes A and B patients (p=0.037). The results of this study indicate that DARPP-32 may be a potential marker of worse prognosis and a valuable tool for managing further adjuvant treatment in patients with stages Dukes A and B colorectal cancer. PMID- 25692421 TI - Pneumatosis cystoides intestinalis: an unusual cause of intestinal ischemia and pneumoperitoneum. AB - Pneumatosis cystoides intestinalis (PCI), with an unknown etiology, is an uncommon disease characterized by the presence of multiple gas-filled cysts within the submucosa or subserosa of the intestinal wall. Intestinal obstruction and/or perforation are relatively uncommon complications associated with PCI. The patients are often prone to misdiagnosis or mistreatment. The diagnosis of PCI is based on plain radiography or endoscopy. Multidetector computed tomography (MDCT) provides data on other intra-abdominal pathologies. Therefore, it is an important modality for the diagnosis of PCI. We present a case of PCI in a 58-year-old man affected by peritoneal free air with multidetector computed tomography imaging findings. We performed the plain film of the abdomen, and MDCT studies that showed numerous, diffuse, bubble-like intramural gas collections into the jejunum, ileum, and colon walls at the left-upper quadrant of the abdomen. MDCT findings were confirmed by surgical exploration. PMID- 25692422 TI - Results of surgery in general surgical patients receiving warfarin: retrospective analysis of 61 patients. AB - The aim of this study is to investigate postoperative complications, mortality rates, and to determine the factors affecting mortality on the patients receiving warfarin therapy preoperatively, as well as comparing the results obtained from emergency and elective surgeries. Surgical outcomes of 61 patients on long-term oral anticoagulation with warfarin who underwent surgery in our center were retrospectively reviewed over an 8-year period. Thirty-three (54.1%) patients were female, with a mean age of 53 years. Mitral valve replacement (62.3%) was the most frequent indication for chronic anticoagulation therapy. Twelve out of 61 (19.2%) patients underwent emergency surgery; 59 (96.7%) operations were classified as major surgery. We did not observe any thromboembolic events on patients receiving our bridging therapy protocol. Cardiopulmonary dysfunction (CPD; 19.7%) and hemorrhage (16.4%) were the most encountered postoperative complications. Presence of CPD, bleeding, endocarditis, and mortality were statistically significant for emergency surgeries when compared with the results obtained from elective surgeries. There were 5 (8.2%) deaths observed during follow-up. It was found that advanced age, prolonged duration of operations, and presence of CPD had a statistically significant effect on mortality (P < 0.05). The patients receiving oral anticoagulant had high postoperative complication and mortality rates. This case was more evident in emergency surgeries. It is recommendable that as mortality is more apparent in the patients who undergo emergency surgeries-being older, having long duration of operations as well as CPD. Therefore during the postoperative follow-up process, the patients should be closely monitored. PMID- 25692423 TI - What we know about management of traumatic abdominal wall hernia: review of the literature and case report. AB - Traumatic abdominal wall hernia (TAWH) is an uncommon form of hernia caused by blunt traumatic disruption of the abdominal wall musculature/fascia and abdominal organ herniation. Diagnosis of TAWH is challenging and requires a high level of suspicion. This form of hernia seems to be underrepresented in the English language medical literature. There is currently no consensus on the optimal management for TAWH. In this article, we discuss the management of a 36-year-old motorcycle driver who was involved in a road traffic accident. On evaluation at our trauma center, he was found to have TAWH. Diagnostic criteria, imaging modalities and different management options for TAWH will be discussed. PMID- 25692424 TI - Lactate levels in bowel strangulation with experimental animal model. AB - Bowel strangulation is a common disease and often requires an urgent operation. Our previous report showed that lactate concentration in the blood is a good predictive marker for emergency. However, the alteration in lactate levels during the course of bowel strangulation remains unclear. We have investigated the progressive increase of lactate after induction of bowel strangulation with animal experiments. Thirty-six mice were randomly divided into 6 groups: 0, 8, 16, 24, 48, and 72 hours after operation. Under anesthesia, laparotomy was performed and a 5-cm segment of terminal ileum with the mesenteric artery and veins was ligated to create a strangulation obstruction. After operation, the arterial blood was collected and lactate concentration and pH were measured using a blood gas analyzer. Lactate concentration in the 8-hour group was markedly increased, while pH decreased significantly (P < 0.05). Lactate concentrations were kept at a high level from 8 to 72 hours after operation. The time lag between strangulation and an increase of lactate is 8 hours. Our study is the first report of a bowel strangulation mouse model. Therefore, it would be possible to find a more specific marker of bowel strangulation using our experimental model. PMID- 25692425 TI - Totally laparoscopic repair of an ileal and uterine iatrogenic perforation secondary to endometrial curettage. AB - Small bowel perforation is a unique, serious complication during endometrial biopsy. The authors report a case of a double uterine-ileal perforation totally managed by primary laparoscopic repair. A 63-year-old female was admitted with acute abdomen 2 days after an endometrial curettage. Abdominal X-ray shows signs of pneumoperitoneum. Emergency diagnostic laparoscopy was performed and a uterine ileal perforation was identified. Repair was accomplished by a totally laparoscopic intracorporeally suturing of the 2 breaches. Postoperative course showed only a delayed ileus and the patient was discharged after 5 days with no complications. When acute abdomen arises following uterine biopsy, a potential iatrogenic intestinal laceration always has to be ruled out. Laparoscopic approach is a quick and safe technique in these cases. Totally laparoscopic primary closure of the iatrogenic ileal laceration may be accomplished with low morbidity. PMID- 25692426 TI - The reliability of fine-needle aspiration biopsy in terms of malignancy in patients with Hashimoto thyroiditis. AB - The aim of this study was to analyze the presence of malignancy in patients with Hashimoto's thyroiditis and to investigate the reliability of preoperative fine needle aspiration biopsy (FNAB). The retrospective study included 44 patients who were operated on for nodular goiter between December 2010 and October 2011. The patients underwent thyroidectomy following a cytologic analysis plus FNAB. Hashimoto's thyroiditis was confirmed on histopathology in all patients. FNAB results were defined as benign in 14 (31.8%), suspicion for malignancy in 17 (38.6%), malignant in 9 (20.5%), and inadequate in 4 (9.1%). Following the thyroidectomy, presence of papillary thyroid carcinoma and follicular variant of papillary thyroid carcinoma were detected in 10 patients (22.7%) and 1 (2.3%) patient, respectively. The FNAB results were interpreted in terms of malignancy, which revealed the sensitivity as 80%; specificity, 40%; false positives, 69.2%; false negatives, 14.3%; positive predictive value, 31.8%; negative predictive value, 85.7%; and diagnostic accuracy, 50%. The coexistence of Hashimoto's thyroiditis with papillary thyroid carcinoma is quite common. The FNAB results for such cases are hard to evaluate, and they are likely to increase the number of false positives. PMID- 25692427 TI - Gangrenous cholecystitis: mortality and risk factors. AB - As a serious complication of cholelithiasis, gangrenous cholecystitis presents greater mortality than noncomplicated cholecystitis. The aim of this study was to specify the risk factors on mortality. 107 consecutive patients who underwent surgery due to gangrenous cholecystitis between January 1997 and October 2011 were investigated retrospectively. The study included 60 (56.1%) females and 47 (43.9%) males, with a mean age of 60.7 +/- 16.4 (21-88) years. Cardiovascular diseases were the most frequently accompanying medical issues (24.3%). Thirty-six complications (33.6%) developed in 29 patients, and surgical site infection was proven as the most common. Longer delay time prior to hospital admission, low white blood cell count, presence of diabetes mellitus, higher blood levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase and total bilirubin, pericholecystic fluid in abdominal ultrasonography, and conversion from laparoscopic surgery to open surgery were identified as risk factors affecting mortality (P < 0.001, P = 0.001, P = 0.044, P = 0.005, P = 0.049, P = 0.009, P = 0.022, P = 0.011, and P = 0.004, respectively). Longer delay time prior to hospital admission and low white blood cell count were determined as independent risk factors affecting mortality. PMID- 25692428 TI - Common bile duct exploration in an elderly Asian population. AB - Common bile duct exploration (CBDE) is an accepted treatment for choledocholithiasis. This procedure is not well studied in the elderly population. Here we evaluate the results of CBDE in elderly patients (>70 years) and compare the open (group A) with the laparoscopic group (group B). A retrospective review was performed of elderly patients with proven common bile duct (CBD) stones who underwent CBDE from January 2005 to December 2009. There were 55 patients in group A and 33 patients in group B. Mean age was 77.6 years (70-91 years). Both groups had similar demographics, liver function tests, and stone size-12 mm (range, 5-28 mm). Patients who had empyema (n = 9), acute cholecystitis (n = 15), and those who had had emergency surgery (n = 28) were more likely to be in group A (P < 0.05). The mean length of stay for group A was 11.7 +/- 7.3 days; for group B, 5.2 +/- 6.3 days; the complication rate was higher in group A (group A, 38.2%; group B, 8.5%; P = 0.072). The overall complication and mortality rate was 29.5% and 3.4%, respectively. CBDE can be performed safely in the elderly with accepted morbidity and mortality. The laparoscopic approach is feasible and safe in elective setting even in the elderly. PMID- 25692429 TI - Impact of Glissonean pedicle approach for centrally located hepatocellular carcinoma in mongolia. AB - Approaches to surgical resection of centrally located HCC remain controversial. Traditionally, hemi- or extended hepatectomy is suggested. However, it carries a high risk of postoperative complications in patients with cirrhosis. An alternative approach is Glissonean pedicle transection method. This study was conducted to assess the surgical and survival outcomes associated with central liver resection using the Glissonean pedicle transection. Sixty-nine patients with centrally located HCC were studied retrospectively. They were divided into conventional approach group with hemi- or extended hepatectomy, and Glissonean approach group with multisegmental central liver resection using the Glissonean pedicle transection. Glissonean pedicle transection method has comparable or superior surgical and survival outcomes to conventional hemi- or extended hepatectomy with regard to intraoperative bleeding, complications, hospital stay, and postoperative mortality and survival outcomes in patients with centrally located HCC. The 1-, 3-, and 5-year overall survival rates of the conventional approach group were 74%, 64%, and 55% respectively. For the Glissonean approach group, the 1 and 3-year overall survival rates were 86% and 61%, respectively. Glissonean pedicle transection method is a safe and effective surgical procedure in patients with centrally located HCC. PMID- 25692430 TI - No mortality or pancreatic fistula after full-thickness suture pancreaticogastrostomy in 39 patients who underwent pancreaticoduodenectomy. AB - Pancreaticoduodenectomy is considered the standard operation for periampullary tumors. Despite major advances in pancreatic surgery, pancreatic fistula is still an important cause of morbidity and mortality after pancreaticoduodenectomy. Meticulous surgical technique and proper reconstruction of the pancreas are essential to prevent pancreatic fistula. Pancreaticogastrostomy is a safe method for reconstruction of the pancreas after pancreaticoduodenectomy. Regardless of pancreatic texture or duct diameter, the reconstruction is performed by passing full-thickness sutures through both the anterior and posterior sides of the pancreas. In this study, we report 39 cases of reconstruction with pancreaticogastrostomy after pancreaticoduodenectomy without mortality or pancreatic fistula. PMID- 25692431 TI - A resected case of intraductal tubulopapillary neoplasm of the pancreas: report of a case. AB - The patient was a 61-year-old male who was referred to our hospital after dilatation of the main pancreatic duct was detected by screening ultrasonography. Computed tomography revealed a protruding lesion measuring 15 mm in diameter within the main pancreatic duct in the head of the pancreas, and magnetic resonance cholangiopancreatography revealed interruption of the duct at the tumor site. We performed pancreaticoduodenectomy under a suspected diagnosis of invasive ductal carcinoma. Gross examination of the resected specimen showed that the tumor invaginated into the main pancreatic duct, and no mucin was found. Histological examination revealed proliferation of high-grade dysplastic cells in a tubulopapillary growth pattern. Immunohistochemically, cytokeratin 7 expression was detected, but not trypsin expression. Based on these morphological features, we diagnosed the tumor as intraductal tubulopapillary neoplasm (ITPN). We report the case with bibliographic consideration, together with a review of intraductal neoplasms of the pancreas encountered at our institution. PMID- 25692432 TI - Radical Resection of a Primarily Unresectable Pancreatic Cancer After Neoadjuvant Chemotherapy Using Gemcitabine, TS-1, and Nafamostat Mesilate; Report of a Case. AB - A 58-year-old male visited his primary physician for epigastric and back pain. Abdominal-enhanced computed tomography (CT) revealed a hypovascular pancreatic tumor measuring 17 * 11 mm in the uncinate process of the pancreas extending into the superior mesenteric plexus for greater than 180 degrees . With a diagnosis of unresectable pancreatic cancer, the patient received gemcitabine and TS-1 with arterial infusion of nafamostat mesilate. After 3 courses of chemotherapy, enhanced CT revealed a decrease in size of the pancreatic tumor with no lymph node and distant metastasis and improved invasion of the superior mesenteric plexus down to 120 degrees . The patient underwent R0 pancreaticoduodenectomy. The patient made a satisfactory recovery without complications and was discharged on postoperative day 10. We herein report the first curative resected case of a primarily unresectable pancreatic cancer after neoadjuvant chemotherapy using gemcitabine, TS-1, and nafamostat mesilate. PMID- 25692433 TI - The prone position during surgery and its complications: a systematic review and evidence-based guidelines. AB - Surgery in the prone position is often a necessity when access to posterior anatomic structures is required. However, many complications are known to be associated with this type of surgery, as physiologic changes occur with increased pressure to anterior structures. While several studies have discussed postoperative vision loss, much fewer studies with lower levels of evidence have addressed other complications. A systematic literature review was conducted using 2 different databases, and 53 papers were regarded as appropriate for inclusion. Qualitative and quantitative analysis was performed. Thirteen complications were identified. Postoperative vision loss and cardiovascular complications, including hypovolemia and cardiac arrest, had the most number of studies and highest level of evidence. Careful planning for optimal positioning, padding, timing, as well as increased vigilance are evidence-based recommendations where operative prone positioning is required. PMID- 25692434 TI - Evaluation of Demographic and Clinical Characteristics of Patients who Attempted Suicide by Self-Inflicted Burn Using Catalyzer. AB - Our aim was to assess demographic and clinical characteristics of patients treated at our units who attempted suicide by self-incineration, and to compare the results of burns with or without catalyzer use. Twenty patients who attempted suicide by self-incineration were examined in terms of clinical and demographic characteristics. Average age of the study population was 35 years (range 13-85 years). Average percentage of total body surface area burn was 53% (9%-100%). Six (30%) patients used gasoline and 5 (25%) used paint thinner in order to catalyze burning. Of these 11 patients who used a catalyzer, 5 (45.4%) had inhalation injury and 7 (63.6%) died. Among 9 patients who did not use any catalyzer, 1 (11.1%) had inhalation injury and 4 (44.4%) died. In general, inhalation injury was diagnosed in 6 patients (30%) while 11 (55%) patients died. A high morbidity and mortality rate was found in patients who used a catalyzer. PMID- 25692435 TI - Hereditary gingivo-alveolar hyperplasia: a report of two siblings. AB - Gingival hyperplasia is characterized by fibrotic gingival overgrowth. The lesion may bury all the crown of the teeth and lead to impairment in masticatory functions and aesthetic disfigurement. This inherited disease is considered rare. We presented two cases of gingival hyperplasia in two siblings: an 11-year-old girl and an 8-year-old boy, whose mother had also suffered from the disease. The two siblings presented with generalized gingival overgrowth involving the maxillary and mandibular arches and covering almost all of the teeth. We performed surgery to reduce the excessive gingivo-alveolar tissue and disclosed most of the teeth. The patients showed functional and aesthetic improvement. The last follow-up through a phone call, which was conducted 12 months after the surgery, revealed no recurrent hyperplasia. PMID- 25692436 TI - Anterolateral intermuscular approach for type A2 intertrochanteric fractures: a cadaveric study. AB - This cadaveric study was designed to clarify the anatomic basis of using an anterolateral intermuscular approach to repair type A2 intertrochanteric fractures (ITF). The conventional lateral approach to surgery that is used for ITF has several disadvantages that can result in both intraoperative and postoperative complications, especially for type A2 ITF. Previous studies have suggested using minimally-invasive total hip arthroplasty (THA) with an anterolateral approach. The legs of 10 formalin-fixed Asian cadavers were dissected, simulating an anterolateral surgical approach. The distances from the superior gluteal nerve and the lateral femoral circumflex artery branches to the lateral protrusive point of the greater trochanter were measured. The anterolateral intermuscular approach provided excellent exposure of the GT, the lesser trochanter and the femoral neck. The gluteus medius branch of the ascending branch of the lateral femoral circumflex artery (GMB-LFCA) and the most inferior branch of the superior gluteal nerve (MIB-SGN) were found to cross the spatium intermusculare between the gluteus medius and the tensor fasciae latae. The distance from the GMB-LFCA, in the intermuscular plane, to the lateral protrusive point of the GT was (4.04 +/- 1.00 cm, range 2.96-6.62 cm); and the distance from the MIB-SGN to the lateral protrusive point of the GT was (5.47 +/- 1.61 cm, range 3.68-9.56 cm). The anterolateral intermuscular approach is relatively safe, provides excellent exposure, and causes less soft-tissue damage than the traditional approach, and it represents a promising new method to surgically treat type A2 ITF. PMID- 25692437 TI - A cadaveric study on sacroiliac joint injection. AB - The scope of this study was to explore the possibility as well as the feasibility of sacroiliac joint injection following simple X-ray clip location. For the cadaveric study, 10 fixed sacroiliac joint (SIJ) sectional specimens, 4 dried cadaveric pelvises and 21 embalmed adult cadaveric pelvises were dissected, followed by an injection of contrast agent into the joint. The irrigation of the agent was observed through CT scanning. For the radiologic study, 188 CT scans of ankylosing spondylitis patients (143 male, 45 female) were collected from 2010 to 2012, in Nanfang Hospital. What was measured was (1) Distance between the posterior midline and sagittal synovium; (2) Length of the sagittal synovium; (3) Distance between the midpoint of the sagittal synovium and posterior superior iliac spine; and (4) Distance between the superficial skin vertical to the sagittal synovium point were measured. For the practice-based study: 20 patients (17 males and 3 females) with early ankylosing spondylitis, from Nanfang Hospital affiliated with Southern Medical University were recruited, and sacroiliac joint unguided injections were done on the basis of the cadaveric and radiologic study. Only the inferior 1/3(rd) portion parallel to the posterior midline could be injected into since the superior 2/3(rd) portion were filled with interosseous ligaments. Thirteen of the 20 patients received successful injections as identified by CT scan using the contrast agent. Sacroiliac joint injection following simple X-ray clip location is possible and feasible if the operation is performed by trained physicians familiar with the sacroiliac joint and its surrounding anatomic structures. PMID- 25692438 TI - Anatomic study of individualized and improved pedicle screw implantation in the lower cervical spine. AB - The objective of this study was to explore a safe, reliable, and effective method for pedicle screw implantation in the lower cervical spine. Recently, a number of studies have shown that cervical pedicle screw fixation is better than roadside steel plate after cervical screw internal fixation within the scope of its indications. However, the difficulty of the former surgery technology is relatively higher and it is much easier to cause many complications. Therefore, domestic and foreign scholars have been positively exploring safer, easier operations and cheaper methods of pedicle screw implantation in the lower cervical spine. The lower cervical spine areas (C3-C7) of 7 adult cadavers were carried out with computed tomography (CT) scans of 1-mm slices. The entry point, angle, and length of the screws were determined by the measurement of CT images in a picture archiving and communication system. The pedicle screws were implanted with the technique of improved Abumi pedicle screw placement in the lab. The accuracy of the screws was evaluated by the Andrew CT classification criteria of pedicle screw position and gross observation after the experiment. A total of 66 screws were implanted in the lower cervical spine, and 90.9% of the screws inserted were found to be in an optimal position. The method of individualized and improved pedicle screw implantation in the lower cervical spine is relatively safe and reliable, which can be considered to be used in the clinic. PMID- 25692439 TI - Acute cervical epidural hematoma, screw pullout, and esophageal perforation after anterior cervical corpectomy surgery: report of a case. AB - To report a series of complications related to anterior cervical surgery in the same patient. There have been many reports of complications related to anterior cervical surgeries. These include cervical hematoma, instrumentation extrusion, or esophageal injury after anterior cervical decompression. However, there have been no reports of all these complications occurring in 1 patient. This is our report of a patient who experienced all 3 of these complications. The patient was a 73-year-old man suffering from cervical spondylotic myelopathy who was treated with C5 anterior cervical corpectomy and fusion with titanium mesh and bone graft. The patient successively experienced cervical hematoma, screw pullout, and esophageal perforation, and was treated accordingly. Although the patient suffered a series of complications after anterior cervical corpectomy, all the complications were treated successfully. It serves as a caution that a first complication such as hematoma in anterior cervical corpectomy with fusion should be given enough attention to prevent further complications. PMID- 25692440 TI - A review on the safety of one-stage circumferential ring constriction release. AB - The study was undertaken to investigate the use of one-stage circumferential ring constriction release with Z-plasties regarding the safety, aesthetic appearance, and limb function. A thorough review was conducted on all English publications in PubMed during the period of 2001 through 2011. Titles and abstracts were identified using online search engine from National Library of Medicine's PubMed database under the keywords "limb constriction ring," "limb constriction band," "amniotic band," "annular constriction," and "circumferential constriction." We used Boolean operator and field of title. Evaluation was done to search indications, timing of the first surgical intervention, time interval between surgeries, patients' gender, anatomic location of the ring, wound healing problems, and scar quality. Fourteen publications met the criteria. There were 17 patients with 25 ring constrictions in total. Sixteen ring constrictions (64%) were circumferential; nine (36%) were semi-circumferential. Mean age of 14 patients treated with one-stage release was 4.8 years. Six articles mentioned about normal development of postoperative limb function. Mean age of three patients treated with staged release was 10.5 months. Two articles mentioned regained distal muscle function postoperatively. It is confirmed that surgeons may continue the practice to release circumferential CRS in one stage. PMID- 25692441 TI - The role and validity of surgical simulation. AB - In the last three decades, simulation has become a key tool in the training of doctors and the maintenance of patient safety. Simulation offers an immersive, realistic way of learning technical skills. Recent changes to the training schemes in many surgical specialities mean that the hours spent working between senior house officer and consultant have been reduced. This, combined with other pressures (such as reduced operating hours), means that surgery has moved away from its traditional apprenticeship model and toward a competency-based one. Simulation can be a standardized and safe method for training and assessing surgeons. Use of simulation for training has become significant alongside the development of laparoscopic techniques, and evidence suggests that skills obtained in simulation are applicable in real clinical scenarios. Simulation allows trainees to make mistakes, to ask the "what if?" questions, and to learn and reflect on such situations without risking patient safety. Virtual reality simulators have been used to allow experts to plan complicated operations and assess perioperative risks. Most recently, fully immersive simulations, such as those with whole theater teams involved, and patient-centered simulations allow development of other key skills aside from purely technical ones. Use of simulation in isolation from traditional teaching methods will furnish the surgeon in training with skills, but the best time and place to use such skills comes only with experience. In this article we examine the role of simulation in surgical training and its impact in the context of reduced training time. PMID- 25692442 TI - Surgical management of perforated gastrointestinal posttransplantation lymphoproliferative disorder after heart transplantation. AB - Posttransplantation lymphoproliferative disorder (PTLD) is a relatively rare and life-threatening complication after organ transplantation. From 1999 to 2012, 45 adult patients underwent heart transplantation at our hospital. Two of the patients developed PTLD after transplantation and required emergency surgery due to intestinal perforation. These cases were informative regarding the adequate surgical management of such cases. Both cases revealed Epstein-Barr virus-related PTLD. The optimal treatment of PTLD remains controversial, and PTLD with gastrointestinal perforation could be critical because the patients are already debilitated and immunocompromised after transplantation. Therefore, the nonspecific abdominal symptoms can be diagnostic for PTLD, and proper surgical intervention should be performed immediately. We present these two suggestive and rare cases in regard to the management of perforation with PTLD and a review of literature. PMID- 25692443 TI - Granular cell tumor of the esophagus with elevated preoperative serum carbohydrate antigen 19-9: a case report. AB - A 59-year-old Japanese man was admitted to our hospital for treatment of a submucosal tumor of the esophagus detected by upper gastrointestinal endoscopy and computed tomography (CT). Endoscopic examination revealed a submucosal tumor in the esophagus 35 cm from the incisor teeth. Biopsy of the lesions identified granular cell tumor. CT indicated a projecting and slightly enhanced homogenous mass measuring 2.0 * 1.5 cm in the esophagus below the tracheal bifurcation. Serum tumor marker studies revealed elevated carbohydrate antigen (CA) 19-9. Therefore, the tumor was considered to have malignant potential, and surgical resection was performed. The final pathologic diagnosis was a benign granular cell tumor, positive for S-100 protein. The patient was doing well with normal CA 19-9 levels and no recurrence more than 5 years after surgery. To the best of our knowledge, this is the first report of a granular cell tumor with elevated serum CA 19-9. PMID- 25692444 TI - Strict Selection Criteria During Surgical Training Ensures Good Outcomes in Laparoscopic Omental Patch Repair (LOPR) for Perforated Peptic Ulcer (PPU). AB - Application of minimal access surgery in acute care surgery is limited due to various reasons. Laparoscopic omental patch repair (LOPR) for perforated peptic ulcer (PPU) surgery is safe and feasible but not widely implemented. We report our early experience of LOPR with emphasis on strict selection criteria. This is a descriptive study of all patients operated on for PPU at academic university affiliated institutes from December 2010 to February 2012. All the patients who were operated on for LOPR were included as the study population and their records were studied. Perioperative outcomes, Boey score, Mannheim Peritonitis Index (MPI), and physiologic and operative severity scores for enumeration of mortality and morbidity (POSSUM) scores were calculated. All the data were tabulated in a Microsoft Excel spreadsheet and analyzed using Stata Version 8.x. (StataCorp, College Station, TX, USA). Fourteen patients had LOPR out of a total of 45 patients operated for the PPU. Mean age was 46 years (range 22-87 years). Twelve patients (86%) had a Boey score of 0 and all patients had MPI < 21 (mean MPI = 14). The predicted POSSUM morbidity and mortality were 36% and 7%, respectively. Mean ulcer size was 5 mm (range 2-10 mm), mean operating time was 100 minutes (range 70-123 minutes) and mean length of hospital stay was 4 days (range 3-6 days). There was no morbidity or mortality pertaining to LOPR. LOPR should be offered by acute care surgical teams when local expertise is available. This can optimize patient outcomes when strict selection criteria are applied. PMID- 25692445 TI - Renal endometriosis tends to be misdiagnosed as renal tumor: a rare case report. AB - Renal endometriosis is a rare disease for which the mechanisms of pathogenesis are still unclear. As such, early diagnosis and an appropriate treatment are often delayed because of the tendency to be misdiagnosed as a renal tumor. In October 2013 we performed a radical nephrectomy for a 37-year-old woman with renal endometriosis who was preoperatively misdiagnosed as having a right renal tumor. Avoiding the misdiagnosis of renal endometriosis requires a detailed case history, especially regarding whether the cyclicity of lumbodorsal pain and hematuria correlates with patients' menstrual cycles. Imaging examinations are commonly helpful for localization, whereas relieving symptoms with drugs to create a hypoestrogenic state is useful for clinical diagnosis. However, a final diagnosis for renal endometriosis still must depend on histopathologic examination. PMID- 25692446 TI - Manual Replacement of Double J Stent Without Fluoroscopy (Double j stent replacement). AB - It is not always possible to replace a ureteric stent with a new one due to the fact that tumoral effect increases in ureter with time. We present our experience of manual replacement of double J stent without fluoroscopy. The data from 23 female patients who underwent double J stent replacement with a total of 110 times was retrospectively analyzed. The steps of technique are as follows: take out distal end of the double J stent through urethra to external urethral meatus cystoscopically, insert a 0.035-inch guide wire through double J stent to the renal pelvis or intra pelvicaliceal system, take out old double J stent over guide wire, slide new stent over guide wire and at external meatus level take out guide wire while gently sliding distal end of double J stent over guide wire into urethra. The mean age was 58.39 +/- 9.21 years. Cervical, endometrial, and ovarian cancer were diagnosed in 16, 4, and 3 patients respectively. The mean follow-up and indwelling period were 13.8 +/- 5.2, 3.8 +/- 0.6 months, respectively. Increased pelvicaliceal dilatation, serum creatinine level, or renal parenchymal loss was not observed. Replacement of double J stents with this technique is easy and can be used successfully in distal ureteral obstructions. PMID- 25692447 TI - Exploring masculinity and marginalization of male undergraduate nursing students' experience of belonging during clinical experiences. AB - Aggressive recruitment strategies used in Canadian undergraduate nursing programs have enjoyed only moderate success, given that male students represent a small percentage of the student population. To determine whether there were gender differences in their sense of belonging, undergraduate nursing students (n = 462) in southern Alberta were surveyed using the Belongingness Scale-Clinical Placement Experience questionnaire. No significant gender differences were found on two of the subscales. However, male students demonstrated significantly lower scores on the efficacy subscale (p = 0.02). This finding suggests that some men experience feelings of marginalization and discrimination. Nurse educators and students are encouraged to explore their worldviews related to gendered performances and teaching practices that create bias. Practice environments are encouraged to deinstitutionalize policies and procedures that accentuate femininities of care. Finally, men entering into the nursing profession are encouraged to reflect on how their gender performance may facilitate or detract from their feelings of belonging. PMID- 25692448 TI - Tetrahedrally coordinated carbonates in Earth's lower mantle. AB - Carbonates are the main species that bring carbon deep into our planet through subduction. They are an important rock-forming mineral group, fundamentally distinct from silicates in the Earth's crust in that carbon binds to three oxygen atoms, while silicon is bonded to four oxygens. Here we present experimental evidence that under the sufficiently high pressures and high temperatures existing in the lower mantle, ferromagnesian carbonates transform to a phase with tetrahedrally coordinated carbons. Above 80 GPa, in situ synchrotron infrared experiments show the unequivocal spectroscopic signature of the high-pressure phase of (Mg,Fe)CO3. Using ab-initio calculations, we assign the new infrared signature to C-O bands associated with tetrahedrally coordinated carbon with asymmetric C-O bonds. Tetrahedrally coordinated carbonates are expected to exhibit substantially different reactivity than low-pressure threefold coordinated carbonates, as well as different chemical properties in the liquid state. Hence, this may have significant implications for carbon reservoirs and fluxes, and the global geodynamic carbon cycle. PMID- 25692449 TI - Evaluation of Choroidal Thickness in Ankylosing Spondylitis Using Optical Coherence Tomography. PMID- 25692450 TI - Upregulation of Sestrin2 expression protects against macrophage apoptosis induced by oxidized low-density lipoprotein. AB - Sestrin2 is involved in a different cellular response to stress conditions. However, the function of Sestrin2 in the cardiovascular system remains unknown. In the present study, we tested whether Sestrin2 has a beneficial effect on macrophage cell apoptosis induced by oxidized low-density lipoprotein (oxLDL). We found that oxLDL induces expression of Sestrin2 in RAW264.7 cells in a time dependent and dose-dependent manner. We also found that knockdown of Sestrin2 using small RNA interference promotes cell apoptosis and reactive oxygen species production induced by oxLDL. In addition, our results show that the c-Jun NH(2) terminal kinase (JNK)/c-Jun pathway is activated by oxLDL. Inhibiting the activity of the JNK pathway abolishes the increase of Sestrin2 induced by oxLDL. These findings suggest that the inductive effect of Sestrin2 is mediated by the JNK/c-Jun pathway. Our results indicate that the induction of Sestrin2 acts as a compensatory response to oxLDL for survival, implying that stimulating expression of Sestrin2 might be an effective pharmacological target for the treatment of lipid-related cardiovascular diseases. PMID- 25692451 TI - Systematic review of uterus-preserving treatment modalities for abnormally invasive placenta. AB - This is a systematic review for evaluating failure rates (secondary hysterectomy or maternal mortality) and success rates (subsequent menstruation or pregnancy) following radiological or conservative surgical interventions for abnormally invasive placenta (AIP). Twelve cohort studies and 8 case series or case reports were included. The cumulative outcomes showed success rates of 159/177 (89.8) for arterial embolisation, a secondary hysterectomy in 20/177 (11.3%), a subsequent menstruation in 74/85 (87.1%) and a subsequent pregnancy in 3/10 (30%). Artery occlusion balloon presented a success rate of 33/42 (78.6%), and a secondary hysterectomy presented that of 8/42 (19%). Uterus-preserving surgery showed a success rate of 48/76 (63.2), a secondary hysterectomy in 23/76 (30%), maternal mortality in 2/54 (3.7%), a subsequent menstruation in 20/37 (81.1%) and a subsequent pregnancy in 21/27 (77.8%). This review indicates that different uterine-sparing radiological and surgical techniques may be effective in managing AIP in select patients. PMID- 25692452 TI - A Comparative Analysis of Bupivacaine and Ropivacaine Effects on Human Cardiac SCN5A Channels. AB - BACKGROUND: Intoxication with local anesthetics may induce cardiac arrhythmias by interaction with ion channels. Ropivacaine has been introduced into clinical anesthesia as a safer alternative to bupivacaine, which is associated with a relatively high risk of cardiac arrhythmias. Diverging safety profiles may result from differences in the mode of interaction with cardiac Na(+) channels. We conducted this study to test this hypothesis and to provide experimental basis for the ongoing discussion regarding the cardiotoxic profiles of these local anesthetics. METHODS: The influence of bupivacaine and ropivacaine on the electrophysiological properties of Na(+) channels was investigated in human embryonic kidney-293 cells stably transfected with SCN5A channels cloned from the human heart using the patch-clamp technique in the outside-out configuration. RESULTS: Open-channel block of SCN5A channels was concentration dependent, with bupivacaine being approximately 4.5-fold more potent than ropivacaine (IC50 = 69.5 +/- 8.2 MUM vs IC50 = 322.2 +/- 29.9 MUM). Both drugs influenced the voltage dependency of channel activation and steady-state inactivation by shifting the membrane potential of half-maximal activation/inactivation toward somewhat more negative membrane potentials. In their inactivated state, SCN5A channels were slightly more sensitive toward bupivacaine than toward ropivacaine (IC50 = 2.18 +/- 0.16 MUM vs IC50 = 2.73 +/- 0.27 MUM). Blockade of inactivated channels developed in a concentration-dependent manner, with comparable time constants for both drugs, whereas recovery from block was approximately 2-fold faster for ropivacaine than for bupivacaine. CONCLUSIONS: Human cardiac Na(+) channels show state-dependent inhibition by ropivacaine, and the mode of interaction is comparable to that of bupivacaine. Therefore, modest differences in cardiotoxicity between these local anesthetic drugs are compatible with subtle differences in their interaction with human cardiac Na(+) channels. PMID- 25692453 TI - Analysis of remifentanil with liquid chromatography-tandem mass spectrometry and an extensive stability investigation in EDTA whole blood and acidified EDTA plasma. AB - BACKGROUND: Remifentanil is a MU-opioid receptor agonist that was developed as a synthetic opioid for use in anesthesia and intensive care medicine. Remifentanil is rapidly metabolized in both blood and tissues, which results in a very short duration of action. Even after blood sampling, remifentanil is unstable in whole blood and plasma through endogenous esterases and chemical hydrolysis. The instability of remifentanil in these matrices makes sample collection and processing a critical phase in the bioanalysis of remifentanil. METHODS: We have developed a fast and simple sample preparation method using protein precipitation followed by liquid chromatography-tandem mass spectrometry analysis. To improve the stability of remifentanil, citric acid, ascorbic acid, and formic acid were investigated for acidification of EDTA plasma. The stability of remifentanil was investigated in stock solution, EDTA whole blood, EDTA plasma, and acidified EDTA plasma at ambient temperature, 4 degrees C, 0 degrees C, and at -20 degrees C. RESULTS: The analytical method was fully validated based on the Food and Drug Administration guidelines for bioanalytical method validation with a large linear range of 0.20 to 250 ng/mL remifentanil in EDTA plasma acidified with formic acid. The stability results of remifentanil in EDTA tubes, containing whole blood placed in ice water, showed a decrease of approximately 2% in 2 hours. EDTA plasma acidified with citric acid, formic acid, and ascorbic acid showed 0.5%, 4.2%, and 7.2% remifentanil degradation, respectively, after 19 hours at ambient temperature. Formic acid was chosen because of its volatility and thus liquid chromatography-tandem mass spectrometry compatibility. The use of formic acid added to EDTA plasma improved the stability of remifentanil, which was stable for 2 days at ambient temperature, 14 days at 4 degrees C, and 103 days at -20 degrees C. CONCLUSIONS: The analytical method we developed uses a simple protein precipitation and maximal throughput by a 2-point calibration curve and short run times of 2.6 minutes. Best sample stability is obtained by placing tubes containing EDTA whole blood in ice water directly after sampling, followed by centrifugation and transfer of the EDTA plasma to tubes with formic acid. The stability of remifentanil in EDTA plasma was significantly improved by the addition of 1.5 MUL formic acid per milliliter of EDTA plasma. This analytical method and sample pretreatment are suitable for remifentanil pharmacokinetic studies. PMID- 25692454 TI - A review of technology-based interventions to maintain weight loss. AB - BACKGROUND: For many decades, healthcare providers and researchers have developed weight-loss interventions to help people achieve weight loss. Unfortunately, it is typical for people to lose weight quickly during the intervention period but then slowly regain weight until they return to their approximate baseline. Technology-based maintenance interventions are among the newest approaches to long-term weight loss. Several advantages make technology helpful for maintaining weight loss. The purpose of this article was to review and critique the randomized controlled trials of technology-based weight-loss maintenance interventions (WLMIs) for adults. MATERIALS AND METHODS: A systematic search through electronic databases and a manual citation search were conducted. Limited numbers of controlled trials published since 2000 that included randomization, and technology-based WLMIs were identified. RESULTS: The characteristics of the eight studies were diverse. The average score of study design quality was moderate. The results of the effectiveness of technology-based WLMIs were mixed. Technology-based WLMIs are more likely to be effective than usual care but not more effective than personal contact. CONCLUSIONS: Based on the review, guidelines were established for the selection and potential success of technology based WLMIs. The effectiveness of technology-based maintenance interventions for weight loss varied, and potential strategies and approaches are discussed to improve their effectiveness. Further studies are needed to better evaluate and refine the efficacy of technology-based WLMIs. PMID- 25692455 TI - Parents' decision-making about the human papillomavirus vaccine for their daughters: I. Quantitative results. AB - Vaccination against the human papillomavirus (HPV) is an effective primary prevention measure for HPV-related diseases. For children and young adolescents, the uptake of the vaccine is contingent on parental consent. This study sought to identify key differences between parents who obtain (acceptors) and parents who refuse (non-acceptors) the HPV vaccine for their daughters. In the context of a free, universal, school-based HPV vaccination program in Quebec, 774 parents of 9 10 year-old girls completed and returned a questionnaire by mail. The questionnaire was based on the theoretical constructs of the Health Belief Model (HBM), along with constructs from other theoretical frameworks. Of the 774 parents, 88.2% reported their daughter having received the HPV vaccine. Perceived susceptibility of daughters to HPV infection, perceived benefits of the vaccine, perceived barriers (including safety of the vaccine), and cues to action significantly distinguished between parents whose daughters had received the HPV vaccine and those whose daughters had not. Other significant factors associated with daughter vaccine uptake were parents' general vaccination attitudes, anticipated regret, adherence to other routinely recommended vaccines, social norms, and positive media influence. The results of this study identify a number of important correlates related to parents' decisions to accept or refuse the HPV vaccine uptake for their daughters. Future work may benefit from targeting such factors and incorporating other health behavior theories in the design of effective HPV vaccine uptake interventions. PMID- 25692456 TI - Interfacial assembly of lipopeptide surfactants on octyltrimethoxysilane-modified silica surface. AB - The adsorption of a series of cationic lipopeptide surfactants, C14Kn (where C14 denotes the myristic acyl chain and Kn represents n number of lysine residues) at the hydrophobic solid/water interface has been studied using spectroscopic ellipsometry (SE) and neutron reflection (NR). The hydrophobic C8 surface was prepared by grafting a monolayer of octyltrimethoxysilane on the silicon surface. SE was used to follow the dynamic adsorption from these lipopeptide surfactants and the amount was found to undergo a fast increase within the first 2-3 min, followed by a much slower process tending to equilibration in the subsequent 15 20 min. Lipopetide surfactants with n = 1-4 showed similar dynamic features, indicating that the interaction between the acyl chain and the C8 surface is the main driving force for adsorption. The saturation adsorption amount of C14Kn at the C8/water interface was found to be inversely related to the increasing number of Lys residues in the head group due to the increase of steric hindrance and electrostatic repulsion between the head groups. Solution concentration had a significant effect on the initial adsorption rate, similar to the feature observed from nonionic surfactants CmEn. The structure of the adsorbed layers was studied by NR in conjunction with isotopic contrasts. The layer formed by the head groups of C14K1 was 10 A thick, and those formed by C14K2, C14K3 and C14K4 head groups were all about 13 A thick. In contrast, the thicknesses of the layers formed by hydrophobic tails of C14K1, C14K2 C14K3, and C14K4 were found to be 17, 13, 10, and 10 A, respectively, resulting in the steady increase of area per molecule at the interface from 29 +/- 2 A(2) for C14K1 to 65 +/- 2 A(2) for C14K4. Thus, with an increase in the head group length, the molecules in the adsorbed layer tended to lie down upon adsorption. PMID- 25692457 TI - Impact of the adoption of tobacco-free campus policies on student enrollment at colleges and universities, North Carolina, 2001-2010. AB - OBJECTIVE: College and university administrators have expressed concern that adoption of tobacco-free policies may reduce applications and enrollment. This study examines adoption and implementation of 100% tobacco-free campus policies by institutions of higher education on applications and enrollment. PARTICIPANTS: North Carolina private colleges and universities and public community colleges. Analysis was conducted in 2011. METHODS: Student enrollment and application data were analyzed by campus type to determine (a) if there was a difference in student applications and enrollment before and after policy implementation, and (b) if there was a difference in student applications and enrollment for campuses with versus without a policy. RESULTS: No significant differences were found in student enrollment or applications when comparing years prior to and following policy implementation or when comparing with institutions without 100% tobacco free campus policies. CONCLUSIONS: The authors found no evidence that 100% tobacco-free policy adoption had an impact on student enrollment or applications. PMID- 25692458 TI - Hardness of oxynitride glasses: topological origin. AB - Oxynitride glasses are mixed-anion systems, in which the 2-fold coordinated oxygen atoms have been partially substituted by 3-fold coordinated nitrogen atoms. This so-called nitridation process introduces additional bonds and thereby constrains and compacts the glass network and consequently alters the glass hardness. To explore how and why hardness varies with the degree of nitridation, we have derived a topological model of oxynitride glass hardness using temperature-dependent constraint theory, by which the scaling of glass hardness with nitrogen content can be predicted. A linear model has been derived based on the assumption that the substitution of oxygen atoms with nitrogen atoms is responsible for the hardness increase due to the increase in the number (n) of bond-bending and bond-angular constraints. It turns out that the model agrees with the experimental observation, i.e., an approximate positive linear trend of the hardness change with nitrogen content is observed for a wide range of glass compositions. The topological model may thus be useful for designing new oxynitride glass compositions with targeted hardness values. PMID- 25692459 TI - Association Between Malignancy and Topical Use of Pimecrolimus. AB - IMPORTANCE: A black box warning describes a potential risk of malignancy associated with topical use of pimecrolimus to treat atopic dermatitis due to its similarity to oral calcineurin inhibitors used in solid-organ transplantation and spontaneous reporting of malignancies, including lymphomas and cutaneous malignancies. OBJECTIVE: To evaluate the risk of malignancy in a postmarketing study of children exposed to pimecrolimus. DESIGN, SETTING, AND PARTICIPANTS: A longitudinal cohort study among a nationwide ongoing long-term cohort of children enrolled in the Pediatric Eczema Elective Registry (PEER) who had a history of atopic dermatitis and pimecrolimus use with data available up through May 2014. MAIN OUTCOMES AND MEASURES: Reports of malignancy among those in the PEER compared with expected rates from the Surveillance, Epidemiology, and End Results (SEER) program. RESULTS: Overall, 7457 children were enrolled in the PEER, for a total of 26,792 person-years. Children used a mean (SD) of 793 (1356) g of pimecrolimus when enrolled in the study. As of May 2014, five malignancies had been reported. These include 2 leukemias, 1 osteosarcoma, and 2 lymphomas. No skin cancers were reported. The standardized incidence ratio for all malignancies (primary outcome) based on the age-standardized SEER population was 1.2 (95% CI, 0.5-2.8). As secondary analyses, the standardized incidence ratios (based on 2 cases for each) were 2.9 (95% CI, 0.7-11.7) for lymphoma and 2.0 (95% CI, 0.5 8.2) for leukemia. None of these findings were statistically significant. CONCLUSIONS AND RELEVANCE: Based on more than 25,000 person-years of follow-up, it seems unlikely that topical pimecrolimus as it was used in the PEER cohort to treat atopic dermatitis is associated with an increased risk of malignancy. PMID- 25692460 TI - Construction of stable polymeric vesicles based on azobenzene and beta cyclodextrin grafted poly(glycerol methacrylate)s for potential applications in colon-specific drug delivery. AB - Polymeric vesicles constructed from cyclodextrin- and azobenzene-grafted poly(glycidyl methacrylate)s showed excellent stability owing to the multiple host-guest complexation. Upon culturing in Na2S2O4-contained buffer solution, cargo-loaded vesicles disassembled, for potential applications in colon-specific drug delivery. PMID- 25692461 TI - Enantioselective assembly of spirocyclic oxindole-dihydropyranones through NHC catalyzed cascade reaction of isatins with N-hydroxybenzotriazole esters of alpha,beta-unsaturated carboxylic acid. AB - An NHC-catalyzed formal [4 + 2] reaction of isatins with N-hydroxybenzotriazole ester of alpha,beta-unsaturated carboxylic acids bearing gamma-H to construct spirocyclic oxindole-dihydropyranones featuring a chiral tetrasubstituted carbon stereogenic center was developed. The high enantioselectivity, the ready availability of the raw materials, the facile assembly, and the potential biological significance of the final products make this protocol an attractive alternative for the synthesis of spirocyclic heterocycles. PMID- 25692462 TI - Multivalent site-specific phage modification enhances the binding affinity of receptor ligands. AB - High-throughput screening of combinatorial chemical libraries is a powerful approach for identifying targeted molecules. The display of combinatorial peptide libraries on the surface of bacteriophages offers a rapid, economical way to screen billions of peptides for specific binding properties and has impacted fields ranging from cancer to vaccine development. As a modification to this approach, we have previously created a system that enables site-specific insertion of selenocysteine (Sec) residues into peptides displayed pentavalently on M13 phage as pIII coat protein fusions. In this study, we show the utility of selectively derivatizing these Sec residues through the primary amine of small molecules that target a G protein-coupled receptor, the adenosine A1 receptor, leaving the other coat proteins, including the major coat protein pVIII, unmodified. We further demonstrate that modified Sec-phage with multivalent bound agonist binds to cells and elicits downstream signaling with orders of magnitude greater potency than that of unconjugated agonist. Our results provide proof of concept of a system that can create hybrid small molecule-containing peptide libraries and open up new possibilities for phage-drug therapies. PMID- 25692463 TI - Macrophage migration inhibitory factor (MIF) and its receptors - interactions and suitability as biomarkers. PMID- 25692464 TI - Bioacessibility of PAHs in fuel soot assessed by an in vitro digestive model: effect of including an absorptive sink. AB - Polycyclic aromatic hydrocarbons (PAHs) associated with soot or black carbon can enter the human digestive tract by unintentional ingestion of soil or other particles. This study investigated the bioaccessibility of 11 PAHs in a composite fuel soot sample using an in vitro digestive model that included silicone sheet as an absorptive sink during the small intestinal digestion stage. The sheet was meant to simulate the passive transfer of PAHs in lumen fluid across the small intestinal epithelium, which was postulated to promote desorption of labile PAHs from the soot by steepening the soot-fluid concentration gradient. We show that the presence of silicone sheet during a 4 h default digestion time significantly increased the apparent bioaccessible fraction (Bapp, %), defined as the sum in the sheet and digestive fluid relative to the total PAH determined. The ability to increase Bapp for most PAHs leveled off above a sheet-to-soot ratio of 2.0 g per 50 mg, indicating that the sheet is an effective absorptive sink and promotes desorption in the mentioned way. Enhancement of Bapp by the sheet correlated positively with the octanol-water partition coefficient (Kow), even though the partition coefficient of PAH between sheet and digestive fluid (which contains bile acid micelles) correlated negatively with Kow. It was hypothesized that PAHs initially in the soot exist in labile and nonlabile states. The fraction of labile PAH still sorbed to the soot residue after digestion, and the maximum possible (limiting) bioaccessibility (Blim) could be estimated by varying the sheet-to-soot ratio. We show conclusively that the increase in bioccessibility due to the presence of the sheet is accounted for by a corresponding decrease in fraction of labile PAH still sorbed to the soot. The Blim ranged from 30.8 to 62.4%, independent of molecular size. The nonlabile fraction of individual PAHs (69.2-37.6% in this case) is therefore large and needs to be taken into account in risk assessment. PMID- 25692465 TI - UDP-glucuronosyltransferase 1A determinates intracellular accumulation and anti cancer effect of beta-lapachone in human colon cancer cells. AB - beta-lapachone (beta-lap), an NAD(P)H: quinone oxidoreductase 1 (NQO1) targeting antitumor drug candidate in phase II clinical trials, is metabolically eliminated via NQO1 mediated quinone reduction and subsequent UDP-glucuronosyltransferases (UGTs) catalyzed glucuronidation. This study intends to explore the inner link between the cellular glucuronidation and pharmacokinetics of beta-lap and its apoptotic effect in human colon cancer cells. HT29 cells S9 fractions exhibited high glucuronidation activity towards beta-lap, which can be inhibited by UGT1A9 competitive inhibitor propofol. UGT1A siRNA treated HT29 cells S9 fractions displayed an apparent low glucuronidation activity. Intracellular accumulation of beta-lap in HCT116 cells was much higher than that in HT29 cells, correlated with the absence of UGT1A in HCT116 cells. The cytotoxic and apoptotic effect of beta lap in HT29 cells were much lower than that in HCT116 cells; moreover, beta-lap triggered activation of SIRT1-FOXO1 apoptotic pathway was observed in HCT116 cells but not in HT29 cells. Pretreatment of HT29 cells with UGT1A siRNA or propofol significantly decreased beta-lap's cytotoxic and apoptotic effects, due to the repression of glucuronidation and the resultant intracellular accumulation. In conclusion, UGT1A is an important determinant, via switching NQO1-triggered redox cycle to metabolic elimination, in the intracellular accumulation of beta-lap and thereafter its cytotoxicity in human colon cancer cells. Together with our previous works, we propose that UGTs determined cellular pharmacokinetics is an important determinant in the apoptotic effects of NQO1 targeting substrates serving as chemotherapeutic drugs. PMID- 25692466 TI - Using dental enamel wrinkling to define sauropod tooth morphotypes from the Canadon Asfalto Formation, Patagonia, Argentina. AB - The early Middle Jurassic is regarded as the period when sauropods diversified and became major components of the terrestrial ecosystems. Not many sites yield sauropod material of this time; however, both cranial and postcranial material of eusauropods have been found in the Canadon Asfalto Formation (latest Early Jurassic-early Middle Jurassic) in Central Patagonia (Argentina), which may help to shed light on the early evolution of eusauropods. These eusauropod remains include teeth associated with cranial and mandibular material as well as isolated teeth found at different localities. In this study, an assemblage of sauropod teeth from the Canadon Asfalto Formation found in four different localities in the area of Cerro Condor (Chubut, Argentina) is used as a mean of assessing sauropod species diversity at these sites. By using dental enamel wrinkling, primarily based on the shape and orientation of grooves and crests of this wrinkling, we define and describe three different morphotypes. With the exception of one taxon, for which no cranial material is currently known, these morphotypes match the local eusauropod diversity as assessed based on postcranial material. Morphotype I is tentatively assigned to Patagosaurus, whereas morphotypes II and III correspond to new taxa, which are also distinguished by associated postcranial material. This study thus shows that enamel wrinkling can be used as a tool in assessing sauropod diversity. PMID- 25692467 TI - The effect of life history on retroviral genome invasions. AB - Endogenous retroviruses (ERV), or the remnants of past retroviral infections that are no longer active, are found in the genomes of most vertebrates, typically constituting approximately 10% of the genome. In some vertebrates, particularly in shorter-lived species like rodents, it is not unusual to find active endogenous retroviruses. In longer-lived species, including humans where substantial effort has been invested in searching for active ERVs, it is unusual to find them; to date none have been found in humans. Presumably the chance of detecting an active ERV infection is a function of the length of an ERV epidemic. Intuitively, given that ERVs or signatures of past ERV infections are passed from parents to offspring, we might expect to detect more active ERVs in species with longer generation times, as it should take more years for an infection to run its course in longer than in shorter lived species. This means the observation of more active ERV infections in shorter compared to longer-lived species is paradoxical. We explore this paradox using a modeling approach to investigate factors that influence ERV epidemic length. Our simple epidemiological model may explain why we find evidence of active ERV infections in shorter rather than longer-lived species. PMID- 25692468 TI - "A cigarette a day keeps the goodies away": smokers show automatic approach tendencies for smoking--but not for food-related stimuli. AB - Smoking leads to the development of automatic tendencies that promote approach behavior toward smoking-related stimuli which in turn may maintain addictive behavior. The present study examined whether automatic approach tendencies toward smoking-related stimuli can be measured by using an adapted version of the Approach-Avoidance Task (AAT). Given that progression of addictive behavior has been associated with a decreased reactivity of the brain reward system for stimuli signaling natural rewards, we also used the AAT to measure approach behavior toward natural rewarding stimuli in smokers. During the AAT, 92 smokers and 51 non-smokers viewed smoking-related vs. non-smoking-related pictures and pictures of natural rewards (i.e. highly palatable food) vs. neutral pictures. They were instructed to ignore image content and to respond to picture orientation by either pulling or pushing a joystick. Within-group comparisons revealed that smokers showed an automatic approach bias exclusively for smoking related pictures. Contrary to our expectations, there was no difference in smokers' and non-smokers' approach bias for nicotine-related stimuli, indicating that non-smokers also showed approach tendencies for this picture category. Yet, in contrast to non-smokers, smokers did not show an approach bias for food related pictures. Moreover, self-reported smoking attitude could not predict approach-avoidance behavior toward nicotine-related pictures in smokers or non smokers. Our findings indicate that the AAT is suited for measuring smoking related approach tendencies in smokers. Furthermore, we provide evidence for a diminished approach tendency toward food-related stimuli in smokers, suggesting a decreased sensitivity to natural rewards in the course of nicotine addiction. Our results indicate that in contrast to similar studies conducted in alcohol, cannabis and heroin users, the AAT might only be partially suited for measuring smoking-related approach tendencies in smokers. Nevertheless, our findings are of special importance for current etiological models and smoking cessation programs aimed at modifying nicotine-related approach tendencies in the context of a nicotine addiction. PMID- 25692469 TI - Findings from integrated behavioral and biologic survey among males who inject drugs (MWID) - Vietnam, 2009-2010: evidence of the need for an integrated response to HIV, hepatitis B virus, and hepatitis C virus. AB - INTRODUCTION: Given the overlapping modes of transmission of HIV, hepatitis B virus (HBV), and hepatitis C virus (HCV), understanding the burden and relationship of these infections is critical for an effective response. Representative data on these infections among males who inject drugs (MWID), the key high-risk population for HIV in Vietnam, are currently lacking. METHODS: Data and stored specimens from Vietnam's 2009-2010 Integrated Biologic and Behavioral Survey, a cross-sectional study among high-risk populations, were used for this analysis. Plasma samples were tested for HIV, HBV, and HCV using commercial assays. A questionnaire was administered to provide demographic, behavior, and service-uptake information. Provincial-level analyses were conducted to profile MWID enrollees and to provide estimates on the prevalence of HIV, HBV, and HCV infection. RESULTS: Among 3010 MWID sampled across 10 provinces, the median (range) HIV prevalence was 28.1% (1.0%-55.5%). Median prevalence for current HBV infection (HBsAg+) was 14.1% (11.7%-28.0%), for previous exposure to HBV (total anti-HBc+) was 71.4% (49.9%-83.1%), and for current or past HCV infection (HCV Ag/Ab+) was 53.8% (10.9%-80.8%). In adjusted analysis, HBsAg+ (aOR: 2.09, 1.01 4.34) and HCV Ag/Ab+ (aOR: 19.58, 13.07-29.33) status were significantly associated with HIV infection; the association with total anti-HBc+ approached significance (aOR: 1.29, 0.99-1.68). CONCLUSION: The prevalence and association between HIV, HBV, and HCV are high among MWID in Vietnam. These findings indicate the need for integrated policies and practice that for the surveillance, prevention, screening, and treatment of both HIV and viral hepatitis among MWID in Vietnam. PMID- 25692470 TI - Human papillomavirus vaccine uptake among individuals with systemic inflammatory diseases. AB - OBJECTIVES: The human papillomavirus (HPV) vaccine is safe and efficacious in patients with systemic inflammatory diseases (SID) who have higher rates of persistent HPV infection. We compared HPV vaccine uptake among SID and non-SID patients. METHODS: Using a U.S. insurance claims database (2006-2012), we identified individuals 9-26 years with >=2 SID diagnosis codes >=7 days apart with >=12 months of continuous enrollment prior to the second code (index date). We matched SID patients by age, sex and index date to randomly selected non-SID subjects and selected those with >=24 months of post-index date continuous follow up. We also identified a non-SID subcohort with >=1 diagnosis code for asthma. We defined initiation as >=1 HPV vaccination claim after 2007, and completion as 3 claims. We used multivariable logistic regression to assess uptake in females 11 26 years comparing SID, non-SID and asthma cohorts, adjusting for demographics, region, comorbidities, and healthcare utilization. RESULTS: We identified 5,642 patients 9-26 years with SID and 20,643 without. The mean age was 18.1 years (SD 4.9). We identified 1,083 patients with asthma; the mean age was 17.2 (SD 5.1). Among females, 20.6% with SID, 23.1% without SID and 22.9% with asthma, received >=1 HPV vaccine. In our adjusted models, the odds of receipt of >=1 vaccine was 0.87 times lower in SID (95% CI 0.77-0.98) compared to non-SID and did not differ for 3 vaccines (OR 1.03, 95% CI 0.83-1.26). The odds of initiation and completion were not statistically different between SID and non-SID asthma cohorts. CONCLUSIONS: In this nationwide cohort, HPV vaccine uptake was extremely low. Despite the heightened risk of persistent HPV infection among those with SID, no increase in HPV vaccine uptake was observed. Public health efforts to promote HPV vaccination overall are needed, and may be particularly beneficial for those at higher risk. PMID- 25692471 TI - So far away, yet so close: strong genetic structure in Homonota uruguayensis (Squamata, Phyllodactylidae), a species with restricted geographic distribution in the Brazilian and Uruguayan Pampas. AB - The Pampas is a biologically rich South American biome, but is poorly represented in phylogeographic studies. While the Pleistocene glacial cycles may have affected the evolutionary history of species distributed in forested biomes, little is known about their effects on the habitats that remained stable through glacial cycles. The South American Pampas have been covered by grasslands during both glacial and interglacial periods and therefore represent an interesting system to test whether the genetic structure in such environments is less pronounced. In this study, we sampled Pampean populations of Homonota uruguayensis from Southern Brazil and Uruguay to assess the tempo and mode of population divergence, using both morphological measurements and molecular markers. Our results indicate that, in spite of its narrow geographic distribution, populations of H. uruguayensis show high levels of genetic structure. We found four major well-supported mtDNA clades with strong geographic associations. Estimates of their divergence times fell between 3.16 and 1.82 million years before the present. Populations from the central portion of the species distribution, on the border between Uruguay and Brazil, have high genetic diversity and may have undergone a population expansion approximately 250,000 years before the present. The high degree of genetic structure is reflected in the analyses of morphological characters, and most individuals could be correctly assigned to their parental population based on morphology alone. Finally, we discuss the biogeographic and conservation implications of these findings. PMID- 25692472 TI - miRNA expression in control and FSHD fetal human muscle biopsies. AB - BACKGROUND: Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant disorder and is one of the most common forms of muscular dystrophy. We have recently shown that some hallmarks of FSHD are already expressed in fetal FSHD biopsies, thus opening a new field of investigation for mechanisms leading to FSHD. As microRNAs (miRNAs) play an important role in myogenesis and muscle disorders, in this study we compared miRNAs expression levels during normal and FSHD muscle development. METHODS: Muscle biopsies were obtained from quadriceps of both healthy control and FSHD1 fetuses with ages ranging from 14 to 33 weeks of development. miRNA expression profiles were analyzed using TaqMan Human MicroRNA Arrays. RESULTS: During human skeletal muscle development, in control muscle biopsies we observed changes for 4 miRNAs potentially involved in secondary muscle fiber formation and 5 miRNAs potentially involved in fiber maturation. When we compared the miRNA profiles obtained from control and FSHD biopsies, we did not observe any differences in the muscle specific miRNAs. However, we identified 8 miRNAs exclusively expressed in FSHD1 samples (miR-330, miR-331-5p, miR-34a, miR-380-3p, miR-516b, miR-582-5p, miR-517* and miR-625) which could represent new biomarkers for this disease. Their putative targets are mainly involved in muscle development and morphogenesis. Interestingly, these FSHD1 specific miRNAs do not target the genes previously described to be involved in FSHD. CONCLUSIONS: This work provides new candidate mechanisms potentially involved in the onset of FSHD pathology. Whether these FSHD specific miRNAs cause deregulations during fetal development, or protect against the appearance of the FSHD phenotype until the second decade of life still needs to be investigated. PMID- 25692474 TI - Portal flow modulation in auxiliary partial orthotopic liver transplantation. AB - APOLT is a suitable technique of liver transplantation in patients with ALF and some types of MLD. Portal venous steal is a problem with this procedure that leads to graft dysfunction and failure. Modulation of the portal flow to the graft and native liver can help in preventing this problem. We discuss the pathophysiology of this complication, review available literature regarding its management, and describe our results using the technique of graded hemiportal banding to achieve adequate perfusion for the graft and native liver. PMID- 25692473 TI - Tonic 5nM DA stabilizes neuronal output by enabling bidirectional activity dependent regulation of the hyperpolarization activated current via PKA and calcineurin. AB - Volume transmission results in phasic and tonic modulatory signals. The actions of tonic dopamine (DA) at type 1 DA receptors (D1Rs) are largely undefined. Here we show that tonic 5nM DA acts at D1Rs to stabilize neuronal output over minutes by enabling activity-dependent regulation of the hyperpolarization activated current (I h). In the presence but not absence of 5nM DA, I h maximal conductance (G max) was adjusted according to changes in slow wave activity in order to maintain spike timing. Our study on the lateral pyloric neuron (LP), which undergoes rhythmic oscillations in membrane potential with depolarized plateaus, demonstrated that incremental, bi-directional changes in plateau duration produced corresponding alterations in LP I hG max when preparations were superfused with saline containing 5nM DA. However, when preparations were superfused with saline alone there was no linear correlation between LP I hGmax and duty cycle. Thus, tonic nM DA modulated the capacity for activity to modulate LP I h G max; this exemplifies metamodulation (modulation of modulation). Pretreatment with the Ca2+-chelator, BAPTA, or the specific PKA inhibitor, PKI, prevented all changes in LP I h in 5nM DA. Calcineurin inhibitors blocked activity-dependent changes enabled by DA and revealed a PKA-mediated, activity independent enhancement of LP I hG max. These data suggested that tonic 5nM DA produced two simultaneous, PKA-dependent effects: a direct increase in LP I h G max and a priming event that permitted calcineurin regulation of LP I h. The latter produced graded reductions in LP I hG max with increasing duty cycles. We also demonstrated that this metamodulation preserved the timing of LP's first spike when network output was perturbed with bath-applied 4AP. In sum, 5nM DA permits slow wave activity to provide feedback that maintains spike timing, suggesting that one function of low-level, tonic modulation is to stabilize specific features of a dynamic output. PMID- 25692476 TI - Tertiary amine-catalyzed (4 + 2) annulations of delta-acetoxy allenoates: synthesis of multisubstituted 4H-pyran and 4H-chromene. AB - The DABCO-catalyzed divergent (4 + 2) annulations of delta-acetoxy allenoates 1 are reported. The chemical behavior of 1 under DABCO catalyst was found to be substrate dependent. Allenoate 1 with an aromatic group at deltaC preferentially reacted with salicylaldehyde derivative 2, delivering 4H-chromenes 3. On the other hand, allenoates 1 with an alkyl group at deltaC readily underwent (4 + 2) annulations with oxo diene 4 to afford 4H-pyrans 5. PMID- 25692475 TI - Fatty acid synthase cooperates with glyoxalase 1 to protect against sugar toxicity. AB - Fatty acid (FA) metabolism is deregulated in several human diseases including metabolic syndrome, type 2 diabetes and cancers. Therefore, FA-metabolic enzymes are potential targets for drug therapy, although the consequence of these treatments must be precisely evaluated at the organismal and cellular levels. In healthy organism, synthesis of triacylglycerols (TAGs)-composed of three FA units esterified to a glycerol backbone-is increased in response to dietary sugar. Saturation in the storage and synthesis capacity of TAGs is associated with type 2 diabetes progression. Sugar toxicity likely depends on advanced-glycation-end products (AGEs) that form through covalent bounding between amine groups and carbonyl groups of sugar or their derivatives alpha-oxoaldehydes. Methylglyoxal (MG) is a highly reactive alpha-oxoaldehyde that is derived from glycolysis through a non-enzymatic reaction. Glyoxalase 1 (Glo1) works to neutralize MG, reducing its deleterious effects. Here, we have used the power of Drosophila genetics to generate Fatty acid synthase (FASN) mutants, allowing us to investigate the consequence of this deficiency upon sugar-supplemented diets. We found that FASN mutants are lethal but can be rescued by an appropriate lipid diet. Rescued animals do not exhibit insulin resistance, are dramatically sensitive to dietary sugar and accumulate AGEs. We show that FASN and Glo1 cooperate at systemic and cell-autonomous levels to protect against sugar toxicity. We observed that the size of FASN mutant cells decreases as dietary sucrose increases. Genetic interactions at the cell-autonomous level, where glycolytic enzymes or Glo1 were manipulated in FASN mutant cells, revealed that this sugar-dependent size reduction is a direct consequence of MG-derived-AGE accumulation. In summary, our findings indicate that FASN is dispensable for cell growth if extracellular lipids are available. In contrast, FA-synthesis appears to be required to limit a cell-autonomous accumulation of MG-derived-AGEs, supporting the notion that MG is the most deleterious alpha-oxoaldehyde at the intracellular level. PMID- 25692478 TI - Microwave-assisted synthesis of water-soluble, fluorescent gold nanoclusters capped with small organic molecules and a revealing fluorescence and X-ray absorption study. AB - Colourless solutions of blue light-emitting, water-soluble gold nanoclusters (AuNC) were synthesized from gold colloids under microwave irradiation using small organic molecules as ligands. Stabilized by 1,3,5-triaza-7 phosphaadamantane (TPA) or L-glutamine (GLU), fluorescence quantum yields up to 5% were obtained. AuNC are considered to be very promising for biological labelling, optoelectronic devices and light-emitting materials but the structure property relationships have still not been fully clarified. To expand the knowledge about the AuNC apart from their fluorescent properties they were studied by X-ray absorption spectroscopy elucidating the oxidation state of the nanoclusters' gold atoms. Based on curve fitting of the XANES spectra in comparison to several gold references, optically transparent fluorescent AuNC are predicted to be ligand-stabilized Au5(+) species. Additionally, their near edge structure compared with analogous results of polynuclear clusters known from the literature discloses an increasing intensity of the feature close to the absorption edge with decreasing cluster size. As a result, a linear relationship between the cluster size and the X-ray absorption coefficient can be established for the first time. PMID- 25692479 TI - One-year follow-up of titanium/zirconium alloy X commercially pure titanium narrow-diameter implants placed in the molar region of the mandible: a randomized controlled trial. AB - OBJECTIVE: To analyze marginal bone loss (MBL) and clinical parameters around narrow-diameter implants (NDIs - 3.3 mm) made of titanium/zirconium alloy (TiZr) in comparison with commercially pure titanium (cpTi) installed in the molar region of the mandible after 1 year in function. MATERIALS AND METHODS: Ten patients participated in the study. A TiZr and a cpTi NDI were randomly installed in contralateral molar sites of the mandible of each patient in a split-mouth design. Eight weeks after healing, all metal-ceramic single crowns were adapted to the implants and patients were enrolled in a plaque control program. MBL at the mesial and distal aspects of the implants were evaluated by comparing periapical radiographs taken immediately after prosthesis installation (T1) and 1 year after loading (T2). Clinical probing depth, bleeding on probing, suppuration, visible plaque and implant mobility were evaluated to determine implant success and survival rates. RESULTS: Mean MBL at the interproximal aspects of TiZr implant sites was 0.32 +/- 0.27 mm, while at cpTi implant sites mean MBL was 0.35 +/- 0.24 mm (P = 0.60). Both TiZr and cpTi NDIs presented 100% implant survival and success rates, with no significant differences in the clinical parameters studied (P > 0.05). CONCLUSION: TiZr and cpTi NDIs presented similar outcomes after 1 year in function in the molar region of the mandible. The results suggest that TiZr and cpTi NDIs may be equally used to support single crowns in the posterior area of the mouth. However, further studies with longer follow-up periods are necessary to confirm these findings. PMID- 25692480 TI - Amygdala-hippocampal volume and the phenotypic heterogeneity of posttraumatic stress disorder: a cross-sectional study. PMID- 25692481 TI - Aggregation in amphiphilic macrocycle-substituted Gd(3+) DOTA-type chelates is affected by the regiochemistry of substitution. AB - Gd(3+) chelates of macrocyclic bifunctional chelators (BFCs) can differentiate into two regioisomers: corner and side. These isomers afford different orientations of chelate relative to conjugate. These differences alter the self assembly, tumbling, and effectiveness as magnetic resonance imaging contrast agents of the two biphenyl conjugate isomers. PMID- 25692486 TI - Decoloration rates of a photomerocyanine dye as a visual probe into hydrogen bonding interactions. AB - We have developed a visual marker for the investigation of hydrogen bonding (HB) effects. The decoloration rate of a photochromic dye that incorporates a latent intra-molecular HB feature can be linked to the HB character of the media. Kinetic and thermodynamic parameters of this simple decoloration approach for HB sensing are investigated both experimentally and by high level theoretical studies. This principle has been applied for the detection of changes in the HB character of stationary and fluidic systems. A major finding is the observation of a shear-related perturbation of the balance between intra- and inter-molecular HB within a dynamic thin film. PMID- 25692487 TI - Metal-organic framework based mixed matrix membranes: a solution for highly efficient CO2 capture? AB - The field of metal-organic framework based mixed matrix membranes (M(4)s) is critically reviewed, with special emphasis on their application in CO2 capture during energy generation. After introducing the most relevant parameters affecting membrane performance, we define targets in terms of selectivity and productivity based on existing literature on process design for pre- and post combustion CO2 capture. Subsequently, the state of the art in M(4)s is reviewed against these targets. Because final application of these membranes will only be possible if thin separation layers can be produced, the latest advances in the manufacture of M(4) hollow fibers are discussed. Finally, the recent efforts in understanding the separation performance of these complex composite materials and future research directions are outlined. PMID- 25692488 TI - Molecular bases of catalysis and ADP-ribose preference of human Mn2+-dependent ADP-ribose/CDP-alcohol diphosphatase and conversion by mutagenesis to a preferential cyclic ADP-ribose phosphohydrolase. AB - Among metallo-dependent phosphatases, ADP-ribose/CDP-alcohol diphosphatases form a protein family (ADPRibase-Mn-like) mainly restricted, in eukaryotes, to vertebrates and plants, with preferential expression, at least in rodents, in immune cells. Rat and zebrafish ADPRibase-Mn, the only biochemically studied, are phosphohydrolases of ADP-ribose and, somewhat less efficiently, of CDP-alcohols and 2',3'-cAMP. Furthermore, the rat but not the zebrafish enzyme displays a unique phosphohydrolytic activity on cyclic ADP-ribose. The molecular basis of such specificity is unknown. Human ADPRibase-Mn showed similar activities, including cyclic ADP-ribose phosphohydrolase, which seems thus common to mammalian ADPRibase-Mn. Substrate docking on a homology model of human ADPRibase Mn suggested possible interactions of ADP-ribose with seven residues located, with one exception (Cys253), either within the metallo-dependent phosphatases signature (Gln27, Asn110, His111), or in unique structural regions of the ADPRibase-Mn family: s2s3 (Phe37 and Arg43) and h7h8 (Phe210), around the active site entrance. Mutants were constructed, and kinetic parameters for ADP-ribose, CDP-choline, 2',3'-cAMP and cyclic ADP-ribose were determined. Phe37 was needed for ADP-ribose preference without catalytic effect, as indicated by the increased ADP-ribose Km and unchanged kcat of F37A-ADPRibase-Mn, while the Km values for the other substrates were little affected. Arg43 was essential for catalysis as indicated by the drastic efficiency loss shown by R43A-ADPRibase-Mn. Unexpectedly, Cys253 was hindering for cADPR phosphohydrolase, as indicated by the specific tenfold gain of efficiency of C253A-ADPRibase-Mn with cyclic ADP ribose. This allowed the design of a triple mutant (F37A+L196F+C253A) for which cyclic ADP-ribose was the best substrate, with a catalytic efficiency of 3.5'104 M-1s-1 versus 4'103 M-1s-1 of the wild type. PMID- 25692489 TI - A limitation of Hartmann-Shack system in measuring wavefront aberrations for patients received laser refractive surgery. AB - PURPOSE: To explore the relationship between ablation parameters of myopic laser surgery and measurement area of wavefront aberration (WA) with Hartmann-Shack wavefront sensor. METHODS: 58 subjects undergone myopic laser surgeries and 74 uncorrected myopic subjects were enrolled in this experiment. The laser ablation parameters were obtained from surgical records, which included spherical error (Rx), depth, and optical zone (OZ) of ablation. The measured area of WA was tested by the WASCA, and the real pupil size was tested by Pentacam. The corneal eccentricity (E value) and curvature was also measured with the Pentacam. All the measurements were performed under mydriatic condition. RESULTS: For uncorrected myopic eyes, the measured area of WA was similar with the real pupil size. But for the corrected eyes, the measured area of WA was smaller than the real pupil size with a mean difference of 0.66 +/- 0.54 mm for moderate myopia (t = 6.45, p < 0.0001) and 1.76 +/- 0.55 mm for high myopia (t = 18.92, p < 0.0001), but not for mild myopia. The Rx (t = -3.20, p = 0.0017), OZ (t = 64.4, p < 0.0001) and postoperative corneal E value (t = 2.52, p = 0.017) were the independent factors of measured area of WA. Measured area of WA = -0.81*Rx + 1.13*OZ + 0.49*postoperative corneal E value (r2 = 0.997). CONCLUSIONS: The WASCA has a limitation in measuring wavefront aberration over the whole pupil area when it's used for patients received myopic laser surgery. The measured area is smaller than the real pupil size and depends linearly on ablation depth, optical zone and corneal eccentricity. PMID- 25692490 TI - Incidence and overall survival of malignant ameloblastoma. AB - BACKGROUND: Malignant ameloblastoma, comprising metastasizing ameloblastoma and ameloblastic carcinoma, represents 1.6-2.2% of all odontogenic tumors. Due to its rare nature, malignant ameloblastoma has only been reported in the literature in small case series or case reports. Using the Surveillance, Epidemiology and End Results (SEER) database, we have performed a population-based study to determine the incidence rate and the absolute survival of malignant ameloblastoma. METHOD: Using the International Classification of Diseases for Oncology (ICD-O) codes 9310/3 and 9270/3, data from the SEER database were used to calculate the incidence rate and absolute survival rate of population with malignant ameloblastoma. RESULTS: The overall incidence rate of malignant ameloblastoma was 1.79 per 10 million person/year. The incidence rate was higher in males than females and also higher in black versus white population. The median overall survival was 17.6 years from the time of diagnosis and increasing age was associated with a statistically significant poorer survival. CONCLUSIONS: To our best knowledge, we report the largest population-based series of malignant ameloblastoma. The incidence rate was 1.79 per 10 million person/year and the overall survival was 17.6 years. PMID- 25692491 TI - An attempt to target anxiety sensitivity via cognitive bias modification. AB - Our goals in the present study were to test an adaptation of a Cognitive Bias Modification program to reduce anxiety sensitivity, and to evaluate the causal relationships between interpretation bias of physiological cues, anxiety sensitivity, and anxiety and avoidance associated with interoceptive exposures. Participants with elevated anxiety sensitivity who endorsed having a panic attack or limited symptom attack were randomly assigned to either an Interpretation Modification Program (IMP; n = 33) or a Control (n = 32) condition. During interpretation modification training (via the Word Sentence Association Paradigm), participants read short sentences describing ambiguous panic-relevant physiological and cognitive symptoms and were trained to endorse benign interpretations and reject threatening interpretations associated with these cues. Compared to the Control condition, IMP training successfully increased endorsements of benign interpretations and decreased endorsements of threatening interpretations at visit 2. Although self-reported anxiety sensitivity decreased from pre-selection to visit 1 and from visit 1 to visit 2, the reduction was not larger for the experimental versus control condition. Further, participants in IMP (vs. Control) training did not experience less anxiety and avoidance associated with interoceptive exposures. In fact, there was some evidence that those in the Control condition experienced less avoidance following training. Potential explanations for the null findings, including problems with the benign panic-relevant stimuli and limitations with the control condition, are discussed. PMID- 25692492 TI - Photon upconversion lithography: patterning of biomaterials using near-infrared light. AB - Photon upconversion lithography is demonstrated for the patterning of proteins using near-infrared light. Proteins and an upconverting-nanoparticle-decorated substrate are linked via blue-light-cleavable Ru complexes. The substrate is irradiated using near-infrared light with a photomask. In the exposed areas, upconverting nanoparticles convert the near-infrared light into blue light, which induces cleavage of the Ru complexes and release of the proteins. PMID- 25692493 TI - Computer simulations suggest a key role of membranous nanodomains in biliary lipid secretion. AB - The bile fluid contains various lipids that are secreted at the canalicular membrane of hepatocytes. As the secretion mechanism is still a matter of debate and a direct experimental observation of the secretion process is not possible so far, we used a mathematical model to simulate the extraction of the major bile lipids cholesterol, phosphatidylcholine and sphingomyelin from the outer leaflet of the canalicular membrane. Lipid diffusion was modeled as random movement on a triangular lattice governed by next-neighbor interaction energies. Phase separation in liquid-ordered and liquid-disordered domains was modeled by assigning two alternative ordering states to each lipid species and minimization of next-neighbor ordering energies. Parameterization of the model was performed such that experimentally determined diffusion rates and phases in ternary lipid mixtures of model membranes were correctly recapitulated. The model describes the spontaneous formation of nanodomains in the external leaflet of the canalicular membrane in a time window between 0.1 ms to 10 ms at varying lipid proportions. The extraction of lipid patches from the bile salt soluble nanodomain into the bile reproduced observed biliary phospholipid compositions for a physiological membrane composition. Comparing the outcome of model simulations with available experimental observations clearly favors the extraction of tiny membrane patches composed of about 100-400 lipids as the likely mechanism of biliary lipid secretion. PMID- 25692494 TI - Apoptosis Induction by Ocimum sanctum Extract in LNCaP Prostate Cancer Cells. AB - Tulsi (Ocimum sanctum Linn), commonly known as "holy basil," has been used for the treatment of a wide range of ailments in many parts of the world. This study focuses on apoptosis-inducing ability of tulsi extract on prostate cancer cells. For this purpose LNCaP prostate cancer cells were treated with different concentrations of 70% ethanolic extract of tulsi (EET) and then the cytotoxicity was determined after 24 and 48 h. After treatment with EET externalization of phosphatidyl serine (PS) from the inner membrane to outer leaflet of the plasma membrane was clearly evidenced by the results obtained from both flow cytometry analysis with Annexin V-FITC and pSIVA-IANBD binding fluorescence microscopy assay. Depolarization of the mitochondrial membrane potential was also evidenced by the presence of 5,5',6,6'-tetrachlolo-1,1',3,3'-tetraethyl benzimedazolyl carbocyanine iodide (JC-1) monomeric form in the EET-treated cells that emitted the green fluorescence when compared with the control cells that emitted the red fluorescence due to aggregation of JC-1. Furthermore, the level of poly (ADP ribose) polymerase (PARP) cleavage and Bcl-2 were determined using western blot analysis. When compared to the control cells the level of cleaved PARP was found to be higher with a concomitant decrease in the Bcl-2 level after 24 h of treatment of cells with EET. In addition, treatment with EET significantly elevated the activities of caspase-9 and caspase-3 in LNCaP cells compared with the control. Also, after 48 h of treatment all doses used in this study showed clear fragments of DNA, which is one of the hallmarks of apoptosis. Taken together, our findings suggest that, EET can effectively induce apoptosis in LNCaP cells via activation of caspase-9 and caspase-3 that can eventually lead to DNA fragmentation and cell death. PMID- 25692495 TI - Population-based Incidence of Pulmonary Nontuberculous Mycobacterial Disease in Oregon 2007 to 2012. AB - RATIONALE: Pulmonary nontuberculous mycobacteria (NTM) disease is a chronic, nonreportable illness, making it difficult to monitor. Although recent studies suggest an increasing prevalence of NTM disease in the United States, the incidence and temporal trends are unknown. OBJECTIVES: To describe incident cases and calculate the incidence and temporal trends of pulmonary NTM disease in Oregon. METHODS: We contacted all laboratories performing mycobacterial cultures on Oregon residents and collected demographic and specimen information for patients with NTM isolated during 2007 to 2012. We defined a case of pulmonary NTM disease using the 2007 American Thoracic Society/Infectious Disease Society of America microbiologic criteria. We used similar state-wide mycobacterial laboratory data from 2005 to 2006 to exclude prevalent cases from our calculations. We calculated annual pulmonary NTM disease incidence within Oregon during 2007 to 2012, described cases demographically and microbiologically, and evaluated incidence trends over time using a Poisson model. MEASUREMENTS AND MAIN RESULTS: We identified 1,146 incident pulmonary NTM cases in Oregon residents from 2007 to 2012. The median age was 69 years (range, 0.9-97 yr). Cases were more likely female (56%), but among patients less than 60 years old, disease was more common in male subjects (54%). Most (86%) were Mycobacterium avium/intracellulare cases; 68 (6%) were Mycobacterium abscessus/chelonae cases. Although not statistically significant, incidence increased from 4.8/100,000 in 2007 to 5.6/100,000 in 2012 (P for trend, 0.21). Incidence increased with age, to more than 25/100,000 in patients 80 years of age or older. CONCLUSIONS: This is the first population-based estimate of pulmonary NTM disease incidence in a region within the United States. In Oregon, disease incidence rose slightly during 2007 to 2012, and although more common in female individuals overall, disease was more common among male individuals less than 60 years of age. PMID- 25692496 TI - Dual-emissive nanohybrid for ratiometric luminescence and lifetime imaging of intracellular hydrogen sulfide. AB - We design a nanohybrid for the detection of hydrogen sulfide (H2S) based on mesoporous silica nanoparticles (MSNs). A phosphorescent iridium(III) complex and a specific H2S-sensitive merocyanine derivative are embedded into the nanohybrid. It exhibits a unique dual emission that is ascribed to the iridium(III) complex and the merocyanine derivative, respectively. Upon addition of sodium hydrogen sulfide (NaHS), the emission from the merocyanine derivative is quenched, while the emission from the iridium(III) complex is almost unchanged, which enables the ratiometric detection of H2S. Additionally, the nanohybrid has a long luminescence lifetime and displays a significant change in luminescence lifetime in response to H2S. Intracellular detection of H2S is performed via ratiometric imaging and photoluminescence lifetime imaging microscopy. Compared with the intensity-based method, the lifetime-based detection is independent of the probe concentration and can efficiently distinguish the signals of the probe from the autofluorescence in complex biological samples. PMID- 25692497 TI - Correction: Fluorescent sensors reporting the activity of ammonium transceptors in live cells. PMID- 25692499 TI - Wide-range controllable n-doping of molybdenum disulfide (MoS2) through thermal and optical activation. AB - Despite growing interest in doping two-dimensional (2D) transition metal dichalcogenides (TMDs) for future layered semiconductor devices, controllability is currently limited to only heavy doping (degenerate regime). This causes 2D materials to act as metallic layers, and an ion implantation technique with precise doping controllability is not available for these materials (e.g., MoS2, MoSe2, WS2, WSe2, graphene). Since adjustment of the electrical and optical properties of 2D materials is possible within a light (nondegenerate) doping regime, a wide-range doping capability including nondegenerate and degenerate regimes is a critical aspect of the design and fabrication of 2D TMD-based electronic and optoelectronic devices. Here, we demonstrate a wide-range controllable n-doping method on a 2D TMD material (exfoliated trilayer and bulk MoS2) with the assistance of a phosphorus silicate glass (PSG) insulating layer, which has the broadest doping range among the results reported to date (between 3.6 * 10(10) and 8.3 * 10(12) cm(-2)) and is also applicable to other 2D semiconductors. This is achieved through (1) a three-step process consisting of, first, dopant out-diffusion between 700 and 900 degrees C, second, thermal activation at 500 degrees C, and, third, optical activation above 5 MUW steps and (2) weight percentage adjustment of P atoms in PSG (2 and 5 wt %). We anticipate our widely controllable n-doping method to be a starting point for the successful integration of future layered semiconductor devices. PMID- 25692500 TI - Dietary fat and breast cancer mortality: A systematic review and meta-analysis. AB - BACKGROUND: The influence of dietary fat upon breast cancer mortality remains largely understudied despite extensive investigation into its influence upon breast cancer risk. OBJECTIVE: To conduct meta-analyses of studies to clarify the association between dietary fat and breast cancer mortality. DESIGN: MEDLINE and EMBASE were searched for relevant articles published up to March 2012. Risk of all-cause or breast-cancer-specific death was evaluated by combining multivariable adjusted estimates comparing highest versus lowest categories of intake; and per 20 g increase in intake of total and/or saturated fat (g/day) using random-effects meta-analyses. RESULTS: Fifteen prospective cohort studies investigating total fat and/or saturated fat intake (g/day) and breast cancer mortality were included. There was no difference in risk of breast-cancer specific death (n = 6; HR = 1.14; 95% CI: 0.86, 1.52; p = 0.34) or all-cause death (n = 4; HR = 1.73; 95% CI: 0.82, 3.66; p = 0.15) for women in the highest versus lowest category of total fat intake. Breast-cancer-specific death (n = 4; HR = 1.51; 95% CI: 1.09, 2.09; p < 0.01) was higher for women in the highest versus lowest category of saturated fat intake. CONCLUSIONS: These meta-analyses have shown that saturated fat intake negatively impacts upon breast cancer survival. PMID- 25692501 TI - Squamous cell carcinoma arising in a mature cystic teratoma exposed through a colo-ovarian fistula. PMID- 25692502 TI - TRIAD VI: how well do emergency physicians understand Physicians Orders for Life Sustaining Treatment (POLST) forms? AB - BACKGROUND: Physician Orders for Life-Sustaining Treatment (POLST) documents are active medical orders to be followed with intention to bridge treatment across health care systems. We hypothesized that these forms can be confusing and jeopardize patient safety. OBJECTIVES: The aim of this study was to determine whether POLST documents are confusing in the emergency department setting and how confusion impacts the provision or withholding of lifesaving interventions. METHODS: Members of the Pennsylvania chapter of the American College of Emergency Physicians were surveyed between September and October 2013. Respondents were to determine code status and treatment decisions in scenarios of critically ill patients with POLST documents who emergently arrest. Combinations of resuscitations (do not resuscitate [DNR], cardiopulmonary resuscitation) and levels of treatment (full, limited, comfort measures) were represented. Responses were summarized as percentages and analyzed by subgroup using the Fisher exact test. P = 0.05 was considered significant. We defined confusion in response as absence of consensus (supermajority of 95%). RESULTS: Our response rate was 26% (223/855). For scenarios specifying DNR and either full or limited treatment, most chose DNR (59%-84%) and 25% to 75% chose resuscitation. When the POLST specified DNR with comfort measures, 90% selected DNR and withheld resuscitation. When cardiopulmonary resuscitation/full treatment was presented, 95% selected "full code" and resuscitation. Physician age and experience significantly affected response rates; prior POLST education had no impact. In most scenarios depicted, responses reflected confusion over its interpretation. CONCLUSIONS: Significant confusion exists among members of the Pennsylvania chapter of the American College of Emergency Physicians regarding the use of POLST in critically ill patients. This confusion poses risk to patient safety. Additional training and/or safeguards are needed to allow patient choice as well as protect their safety. PMID- 25692503 TI - TRIAD VII: do prehospital providers understand Physician Orders for Life Sustaining Treatment documents? AB - BACKGROUND: Physician Orders for Life-Sustaining Treatment (POLST) documents are medical orders intended to honor patient choice in the hospital and prehospital settings. We hypothesized that prehospital personnel will find these forms confusing. OBJECTIVES: The aim of this study was to determine whether POLST documents accord consensus in determining code status and treatment decisions among emergency medical services providers on the basis of an Internet survey. Consensus in this context reflects content clarity. METHODS: A statewide survey of Pennsylvania emergency medical technicians and paramedics was conducted from October 2013 to January 2014. Respondents supplied code status and treatment decisions for scenarios involving critically ill patients who present with POLST documents and then develop cardiac arrest. The gamut of combinations of resuscitations (do not resuscitate [DNR], cardiopulmonary resuscitation) and treatment (full, limited, comfort measures) was represented. Subgroup analysis was done using the Fisher exact test with a Bonferroni-corrected P = 0.017 as significant. We defined consensus as a supermajority of 95%. RESULTS: Response to the survey was 18.4% (1069/5800). For scenarios specifying DNR and full or limited treatment, most chose DNR (59%-84%) and 25% to 75% chose resuscitation. With DNR and comfort measures specified, approximately 85% selected DNR and withheld resuscitation. When cardiopulmonary resuscitation/full treatment was presented, 95% selected "full code" and resuscitation. Respondent age significantly affected response rates (P <= 0.004); prior POLST education had no impact. For most scenarios, responses failed to attain consensus, suggesting confusion in interpretation of the form. CONCLUSIONS: In the Pennsylvania prehospital setting, POLST documents can be confusing, presenting a risk to patient safety. Additional research, standardized education, training, and/or safeguards are required to facilitate patient choice and protect safety. PMID- 25692504 TI - Dysregulation of inter-photoreceptor retinoid-binding protein (IRBP) after induced Muller cell disruption. AB - Reduced expression of a ~150 kDa protein was unexpectedly observed while investigating Norrin protein in a transgenic murine model in which Muller cells can be selectively and inducibly disrupted. Isolation of this unknown protein via ion exchange and hydrophobic interaction chromatography followed by Tandem mass spectrometry identified it as Inter-photoreceptor retinoid-binding protein (IRBP). Significantly reduced IRBP mRNA expression was observed at the early and late stages after Muller cell disruption. IRBP protein expression was also consistently reduced to 5.7% of the control level as early as 1 week after Muller cell disruption. This down-regulation of IRBP was accompanied by focal hyperfluorescent dots and cytotoxic N-retinylidene-N-retinylethanolamine (A2E) accumulation. In vitro treatment of cone photoreceptor cell lines with conditioned medium collected from stressed Muller cells suggested that Muller cells regulated photoreceptors expression of IRBP via secreted factor(s). In vivo studies suggested that one of these secreted factors was tumour necrosis factor alpha (TNFalpha). These findings suggest that dysregulation of IRBP expression caused by Muller cell dysfunction may be an important early event in photoreceptor degeneration in some retinal diseases. This study reports down regulation of inter-photoreceptor retinoid-binding protein (IRBP) in photoreceptors and retinoid cycle derangement after Muller cell disruption in a transgenic mouse model. The findings indicate that Muller cells communicate with photoreceptors in response to stress by secreting soluble protein factor(s). We propose that down-regulation of IRBP may represent an early and novel pathogenic mechanism in degenerative retinal diseases. PMID- 25692505 TI - Does advanced operative obstetrics still have a place in contemporary practice? AB - PURPOSE OF REVIEW: This article reviews recent significant contributions to the literature concerning advanced operative obstetric procedures used for rotational vaginal deliveries and their alternative, primary caesarean section. RECENT FINDINGS: Rising caesarean section rates are a global concern. Caesarean section in the second stage of labour is associated with high rates of maternal and fetal morbidity. Rotational vaginal deliveries may reduce the caesarean section rate without additional adverse effects on maternal and fetal outcomes. A recent national trainees' survey highlighted that training in the management of operative birth in the second stage of labour, especially when there is malposition of the fetal head, is a priority. SUMMARY: There is a need for evidence-based guidelines, including standardized documentation of these advanced procedures. Training strategies for junior practitioners to acquire these skills and for experienced practitioners to maintain and disseminate their skills should be prioritized. The safety of rotational delivery methods versus primary caesarean section is likely to prove difficult to assess directly, in the context of a randomized controlled trial, but may be approximated via a national prospective audit. PMID- 25692506 TI - What contributes to disparities in the preterm birth rate in European countries? AB - PURPOSE OF REVIEW: In countries with comparable levels of development and healthcare systems, preterm birth rates vary markedly--a range from 5 to 10% among live births in Europe. This review seeks to identify the most likely sources of heterogeneity in preterm birth rates, which could explain differences between European countries. RECENT FINDINGS: Multiple risk factors impact on preterm birth. Recent studies reported on measurement issues, population characteristics, reproductive health policies as well as medical practices, including those related to subfertility treatments and indicated deliveries, which affect preterm birth rates and trends in high-income countries. We showed wide variation in population characteristics, including multiple pregnancies, maternal age, BMI, smoking, and percentage of migrants in European countries. SUMMARY: Many potentially modifiable population factors (BMI, smoking, and environmental exposures) as well as health system factors (practices related to indicated preterm deliveries) play a role in determining preterm birth risk. More knowledge about how these factors contribute to low and stable preterm birth rates in some countries is needed for shaping future policy. It is also important to clarify the potential contribution of artifactual differences owing to measurement. PMID- 25692507 TI - Parents' decision-making about the human papillomavirus vaccine for their daughters: II. Qualitative results. AB - The goal of the study was to examine the reasons given by parents who accepted or refused the HPV vaccine for their daughters in the context of a free provincial school-based vaccination program. A random sample of parents of 9-10 y old girls completed a mail-in questionnaire. Parents' responses to 2 open-ended questions were assessed using content analysis. Coding themes were derived from the Health Belief Model. 806 parents returned and answered the relevant items. 88% of these parents decided to vaccinate their daughter. The primary reasons for parents' acceptance was the perceived benefits (e.g., health protection, cancer/HPV prevention) and cues to action (e.g., physician recommendation, trusting the school vaccine program). Reasons for parental refusal included barriers (e.g., fear of side effects) and low susceptibility (e.g., their daughter is not at risk). Both groups of parents had unanswered questions, doubts and often inaccurate information. This study provides unique insight into parents' perspectives concerning the decision making process for their daughter. There appears to be a need for accurate and complete information to assure informed HPV vaccine decision-making by parents and to increase HPV vaccine uptake. PMID- 25692508 TI - Lead excretion in spanish children with autism spectrum disorder. AB - Among epigenetic factors leading to increased prevalence of juvenile neuropsychiatric disorders, including autism spectrum disorder, exposure to metals, such as lead (Pb) have led to conflicting results. The aim of the present study was to determine the levels of Pb in the urine of children with autism spectrum disorder (ASD) compared with typically developing children (TD) age- and sex-matched, and to analyze any association between core symptoms of ASD, special diets, supplements intake or prescription drugs and the concentration of Pb. The study was performed in a group of children with ASD (n = 35, average age 7.4 +/- 0.5 years) and TD (n = 34, average age 7.7 +/- 0.9 years). Measurement of lead in urine was performed by atomic absorption spectrometry; symptoms of ASD were analyzed by diagnostic and statistical manual of mental disorders (DMS-IV) using the questionnary ADI-R. Careful clinical evaluation was also undertaken and statistical analysis was done taking into account any possible confounding factor. PMID- 25692510 TI - Bilateral diaphragmatic paralysis due to cervical chiropractic manipulation. AB - Neck pain from cervical spinal disease is a common problem with significant disability, and chiropractic manipulation has emerged as one of the leading forms of alternative treatment for such spinal symptoms. However, more experience with these forms of treatment has revealed associated complications that are far from benign. Complications range from mild symptoms, such as local neck tenderness or stiffness, to more severe injuries involving the spinal cord, peripheral nerve roots, and arteries within the neck. Phrenic nerve injury causing diaphragmatic palsy is a rare complication of cervical chiropractic manipulation. We report a case of bilateral diaphragmatic paralysis in a healthy gentleman who underwent cervical manipulation. Physicians must be aware of this complication and should be cautious when recommending spinal manipulation for the treatment of neck pain, especially in the presence of preexisting degenerative disease of the cervical spine. PMID- 25692509 TI - Dendritic cells induce Th2-mediated airway inflammatory responses to house dust mite via DNA-dependent protein kinase. AB - DNA-dependent protein kinase (DNA-PK) mediates double-stranded DNA break repair, V(D)J recombination and immunoglobulin class switch recombination, as well as innate immune and pro-inflammatory responses. However, there is limited information regarding the role of DNA-PK in adaptive immunity mediated by dendritic cells (DCs), which are the primary antigen-presenting cells in allergic asthma. Here we show that house dust mite induces DNA-PK phosphorylation, which is a marker of DNA-PK activation, in DCs via the generation of intracellular reactive oxygen species. We also demonstrate that pharmacological inhibition of DNA-PK, as well as the specific deletion of DNA-PK in DCs, attenuates the induction of allergic sensitization and Th2 immunity via a mechanism that involves the impaired presentation of mite antigens. Furthermore, pharmacological inhibition of DNA-PK following antigen priming similarly reduces the manifestations of mite-induced airway disease. Collectively, these findings suggest that DNA-PK may be a potential target for treatment of allergic asthma. PMID- 25692511 TI - Perfusion imaging in the 3-hour time window predicts a tPA-associated hemorrhage in acute ischemic stroke. AB - Perfusion imaging is being evaluated in acute ischemic stroke patients to identify those who may benefit from reperfusion therapies beyond the standard thrombolytic time window but limited data are available on its utility in patients presenting within the standard thrombolytic time window. We report a case of a patient presenting within the 3-hour time window where computerized tomographic perfusion imaging before intravenous thrombolysis identified a large volume of severely ischemic tissue and where intravenous tissue plasminogen activator administration subsequently resulted in a fatal intracerebral hemorrhage. Whether perfusion imaging can predict an increased risk of tissue plasminogen activator-associated symptomatic hemorrhage in patients presenting within the standard thrombolytic time window requires further study. PMID- 25692512 TI - Fluctuating Cotard syndrome in a patient with advanced Parkinson disease. AB - INTRODUCTION: Nonmotor fluctuations of psychiatric symptoms in patients suffering from Parkinson disease (PD) represent a very disabling condition, which may seriously interfere with the quality of life of patients and caregivers. In this regard, these disturbances are present with a higher frequency in advanced PD patients with associated motor complications and can appear both in "on" and in "off" period. Here we report on a case of fluctuating Cotard syndrome clearly related to "wearing-off" deterioration and responsive to levodopa treatment in a patient affected by advanced PD. CASE REPORT: A 76-year-old woman presented with a 13-year history of PD. Her caregivers reported that, in the last 2 months, she has developed a sudden onset of nihilistic delusion (Cotard syndrome), mainly during the "wearing-off" condition and associated with end of dose dyskinesias and akathisia.As Cotard syndrome clearly improved with the administration of levodopa, the patient was successfully treated changing the levodopa schedule with the shortening of intervals between levodopa intakes in small doses. CONCLUSIONS: Both the appearance of the Cotard syndrome in this patient during the "off" state and the subsequent improvement of psychotic symptoms after levodopa administration strongly suggest an important correlation with the dopaminergic dysregulation.This finding suggests that dopaminergic deficit might play a key factor in the development of Cotard syndrome. PMID- 25692513 TI - Primary granulomatous angiitis of the central nervous system with amyloid angiopathy: a case report and literature review. AB - Primary angiitis of the central nervous system is a rare idiopathic inflammation of vessels. We report on a 75-year-old male with primary angiitis of the central nervous system and cerebral amyloid angiopathy. He presented with subacute onset of progressive decline in cognitive functions, followed by confusion and coma. Initial brain magnetic resonance imaging favored meningoencephalitis. There was no improvement after treatment with antibiotics. Final diagnosis was proven by brain biopsy. Corticosteroids were given, but without significant improvement. This case is reported because of its rarity and its clinical presentation. PMID- 25692514 TI - Contraversive ocular tilt reaction after the lateral medullary infarction. AB - INTRODUCTION: The triad of ocular tilt reaction (OTR) is conjugated ocular torsion, skewed deviation, and head tilt. A lesion involving below the inferior pons develops ipsiversive OTR, whereas a lesion above the inferior pons leads to contraversive OTR. A lateral medullary infarction usually causes ipsiversive OTR. This is the first report of contraversive OTR following the lateral medullary infarction. CASE REPORT: A 58-year-old woman was admitted due to sudden-onset vertigo and gait disturbance. A neurological examination revealed OTR to the left side (left head tilt, leftward ocular torsion, and skew deviation). Lateropulsion to the right and dysmetria on the right arm and leg were present. Diffusion weighted MRI revealed an acute infarction of the right lateral medulla and the posterolateral pons. The patient slowly improved and can walk without sway after 1 week. Neither head tilt nor ataxia was observed after 3 months. CONCLUSIONS: Lateral medullary lesion typically results in ipsilateral OTR. Contraversive OTR of our patient might be derived from the disruption of the cerebellovestibular inhibitory pathway by the lesion in the juxtarestiform body in the lateral medulla. PMID- 25692515 TI - Profuse unilateral hyperhidrosis induced by urinary retention in a stroke patient. AB - INTRODUCTION: The diagnosis of urinary retention in stroke patients is challenging because their symptoms may be subtle, or go unnoticed. Furthermore, patients suffering from aphasia or impaired cognition often have difficulties communicating urination problems, leading to their urinary retention being overlooked. CASE REPORT: We report a 53-year-old man with bilateral pontine hemorrhage resulting in incomplete locked-in syndrome. During the patient's hospital course, he developed 3 episodes of rapid onset of profuse unilateral hyperhidrosis. All 3 episodes were found to be induced by an overly distended bladder and each time the unilateral hyperhidrosis resolved promptly after bladder drainage. CONCLUSIONS: This case provides the first description of unilateral hyperhidrosis as a manifestation of urinary retention in a stroke patient. It is important for clinicians to recognize this condition so that appropriate management can be implemented in time to prevent potential detrusor injury and renal impairment caused by bladder overdistension. PMID- 25692516 TI - Interictal regional delta slowing in cerebral sinus vein thrombosis. AB - The electroencephalographic finding of regional delta activity should alert to the possibility of an underlying structural abnormality of the brain as a cause. A 5-year-old boy, who presented with severe headache and focal seizures, had normal neurological examination and brain CT findings. The initial electroencephalograph showed focal delta activity. An emergent brain MRI disclosed a thrombosis of the left sigmoid sinus and jugular vein, but no parenchymal lesions. The regional delta activity can presumably serve as a marker for brain tissue damage in cerebral sinus vein thrombosis, and sometimes, even to add information to that gained from imaging studies. PMID- 25692517 TI - Physical activity level and future risk of mild cognitive impairment or dementia: a critically appraised topic. AB - BACKGROUND: The relationships between physical activity, cognition, and development of neurodegenerative diseases represent an area of intense research interest. Meta-analyses and prospective cohort studies show that greater levels of physical activity are associated with lower dementia risk. Most studies, however, depend on self-report data that are subject to recall and other biases. Obtaining objective and quantitative physical activity data could strengthen observational study validity. OBJECTIVE: To examine the association between objectively measured daytime activity and mild cognitive impairment (MCI) or Alzheimer disease (AD). METHODS: The objective was addressed through the development of a structured, critically appraised topic. We incorporated a clinical scenario, background information, a structured question, literature search strategy, critical appraisal, results, evidence summary, commentary, and bottom line conclusions. Participants included consultant and resident neurologists, clinical epidemiologists, a medical librarian, and behavioral neurology and neuropsychiatry content experts. RESULTS: We selected a prospective, single-center cohort study of 716 cognitively normal elderly participants followed for 3.5 years. Greater levels of physical activity, as measured using wrist actigraphy, were associated with a lower risk of incident MCI or AD (hazard ratio, 0.477; 95% confidence interval, 0.273-0.832). CONCLUSIONS: Objective measurement confirms that greater levels of physical activity are associated with decreased risk of a future diagnosis of MCI or AD. Further studies are needed to confirm the temporal association of exercise and future cognitive health and understand the relevant underlying biological mechanisms. PMID- 25692518 TI - Gains and development of undergraduate nursing students during a 2-year community service program. AB - Service-learning has long been regarded as a teaching strategy that promotes student learning while simultaneously contributing to the community. This article reports the service-learning experience of undergraduate nursing students who participated in a project with two nongovernmental organizations that enabled students to visit disadvantaged older adults on a regular basis. Fifty-two students were recruited to join the study. A content analysis of their reflective journals regarding their service-learning experience was performed. The texts were compared on the basis of their differences and similarities, sorted into categories, and then abstracted into themes. Four themes were identified: "I have learned a lot," "I have changed over time," "My perception of older people has changed," and "I have learned through experience." The students gained valuable experience from this project during a 2-year period. The main learning outcome was improved communication skills. The experience also promoted students' personal growth and professional development. PMID- 25692519 TI - Host genetic determinants of microbiota-dependent nutrition revealed by genome wide analysis of Drosophila melanogaster. AB - Animals bear communities of gut microorganisms with substantial effects on animal nutrition, but the host genetic basis of these effects is unknown. Here we use Drosophila to demonstrate substantial among-genotype variation in the effects of eliminating the gut microbiota on five host nutritional indices (weight, protein, lipid, glucose and glycogen contents); this includes variation in both the magnitude and direction of microbiota-dependent effects. Genome-wide association studies to identify the genetic basis of the microbiota-dependent variation reveal polymorphisms in largely non-overlapping sets of genes associated with variation in the nutritional traits, including strong representation of conserved genes functioning in signalling. Key genes identified by the GWA study are validated by loss-of-function mutations that altered microbiota-dependent nutritional effects. We conclude that the microbiota interacts with the animal at multiple points in the signalling and regulatory networks that determine animal nutrition. These interactions with the microbiota are probably conserved across animals, including humans. PMID- 25692521 TI - Cost-utility analysis of an adjunctive recombinant activated factor VIIa for on demand treatment of bleeding episodes in dengue haemorrhagic fever. AB - The present study aimed to assess the cost-utility analysis of using an adjunctive recombinant activated factor VIIa (rFVIIa) in children for controlling life-threatening bleeding in dengue haemorrhagic fever (DHF)/dengue shock syndrome (DSS). We constructed a decision-tree model, comparing a standard care and the use of an additional adjuvant rFVIIa for controlling life-threatening bleeding in children with DHF/DSS. Cost and utility benefit were estimated from the societal perspective. The outcome measure was cost per quality-adjusted life years (QALYs). Overall, treatment with adjuvant rFVIIa gained QALYs, but the total cost was higher. The incremental cost-utility ratio for the introduction of adjuvant rFVIIa was $4241.27 per additional QALY. Sensitivity analyses showed the utility value assigned for calculation of QALY was the most sensitive parameter. We concluded that despite high cost, there is a role for rFVIIa in the treatment of life-threatening bleeding in patients with DHF/DSS. PMID- 25692522 TI - Deep venous thrombosis in a patient presenting with severe left inguinal and hip pain: a case report. AB - Deep venous thrombosis (DVT) is a disease presenting with thrombosis and obstruction of its branches and interruption of blood flow of lower extremities. Pain, severe discomfort and swelling are the most frequent symptoms of DVT and the most life-threatening manifestation is pulmonary embolism. Herein an otherwise healthy, 27-year-old male patient presented with severe left inguinal and hip pain due to the DVT of proximal left lower extremity is presented. We assume that DVT should be kept in mind in patients presenting with musculoskeletal system pain, as it may cause life-threatening complications such as pulmonary thromboembolism. PMID- 25692523 TI - Blood coagulation and metabolic profiles in middle-aged male and female ob/ob mice. AB - Obese and diabetic states in humans are associated with an increased incidence of thrombotic diseases caused by various coagulation abnormalities. Genetically obese ob/ob mice produce metabolic abnormalities similar to those associated with type 2 diabetes. However, little is known about their coagulation features or sex differences. The present study aimed to determine the effects of obese and diabetic complications on blood coagulation and vascular diseases by exploring correlations between blood coagulation and metabolic profiles in middle-aged male and female ob/ob mice. Plasma levels of plasminogen activator inhibitor 1 (PAI-1) were significantly increased, whereas those that of platelet factor-4 (PF-4) was slightly, but significantly increased in male and female ob/ob mice compared with lean counterparts. Prothrombin time (PT) was significantly shortened in female ob/ob mice and activated partial thrombin time (APTT) significantly differed between male and female ob/ob mice. Plasma levels of antithrombin (AT) were significantly increased in male and female ob/ob mice. None of the other coagulation and fibrinolytic factors examined significantly differed between ob/ob mice and lean counterparts. On the contrary, factors such as body weight and cholesterol levels significantly differed between ob/ob and lean mice, whereas glucose, fructosamine and insulin levels significantly differed only in one sex of each strain. These results provided fundamental information about blood coagulation and metabolic features for exploring the function of altered blood coagulation states in ob/ob mice. PMID- 25692524 TI - Steps to diagnosis of a case of surreptitious intake of one of the newer direct oral anticoagulants: a case report and literature review. AB - Little is known about the effects of newer oral anticoagulants on various coagulation factors. When presented with a case of intentional or suspected overdose with an abnormal coagulation profile, it is imperative to have a working diagnostic algorithm to narrow the cause to a specific drug or drug class. This may become more crucial and time sensitive when dealing with a case of acute hemorrhage. Here we discuss the first reported case of what appears to be a surreptitious intake of newer oral anticoagulants and the steps leading to the diagnosis. PMID- 25692525 TI - Cerebral sinus venous thrombosis: clinical and pathogenetic perspectives from Tuscany. AB - Cerebral sinus venous thrombosis (CSVT) is a rare condition representing the 0.5 1% of all stroke cases which can have serious consequences. Early diagnosis and complete screening for acquired or inherited risk factors is crucial for decreasing morbidity and mortality. We have investigated clinical and aetiological factors in an Italian cohort of 43 patients with cerebral sinus venous thrombosis. Common presentation complaints were headache (81.4%), focal signs (20.9%), vomiting (11.6%) and seizures (6.9%). Acquired or inherited conditions were observed in more than 80% of cases. The commonest aetiological factors were contraceptives (74.1% of women), congenital thrombophilia (34.9%), infections and dysthyroidism (16.3%), hyperhomocysteinemia (9.3%), migraine (11.6%), cranial trauma (9.3%) and chronic myeloproliferative diseases (11.6%). Outcome was favourable in more than 80% of patients. Early diagnosis and anticoagulant treatment may decrease mortality and/or morbidity rates related with CVST in these patients. Thrombophilic abnormalities, either inherited or acquired, are worthy to be widely investigated. PMID- 25692526 TI - The Concept of Prosthetically Guided Maxillofacial and Implant Surgery for Maxillary Reconstruction. PMID- 25692527 TI - Global Coronary Artery Plaque Area is Associated with Myocardial Hypoperfusion in Women with Non-ST Elevation Myocardial Infarction. AB - BACKGROUND: Women with non-ST elevation myocardial infarction (NSTEMI) have similar extent of myocardial ischemia but less obstructive coronary artery disease (CAD) than their male counterparts. We tested the impact of global coronary artery plaque area and artery tortuosity on myocardial perfusion in NSTEMI patients. METHODS: Coronary artery plaque area was determined by quantitative angiography in 108 patients (32% women) with NSTEMI. Myocardial perfusion was assessed by contrast echocardiography in the 17 individual left ventricular segments. Artery tortuosity was defined as >=3 curves >45 degrees in a main coronary artery. RESULTS: Age, prevalence of hypertension, and diabetes did not differ between sexes (all nonsignificant). Women had lower prevalence of >=50% coronary artery stenosis (74% vs. 91%, p<0.05), while global coronary plaque area (35+/-22 vs. 43+/-21mm(2)) and the number of segments with hypoperfusion (6.9+/-3.7 vs. 7.2+/-3.4) did not differ between sexes (both p>0.07). In multivariate analysis, larger coronary artery plaque area was associated with a 35% higher risk for having severe myocardial hypoperfusion (odds ratio 1.35 [95% confidence interval 1.01-1.80], p<0.05) in the total study population, while no association between artery tortuosity and myocardial ischemia was found. Similar results were obtained in separate analysis among women and men. CONCLUSION: In women and men with NSTEMI, the global coronary artery plaque area was an important determinant of the severity of myocardial hypoperfusion at rest independent of presence of significant coronary stenoses. These findings may expand current understanding of NSTEMI in patients with nonobstructive CAD. PMID- 25692529 TI - Labetalol for hypertension in pregnancy. AB - INTRODUCTION: Labetalol is one of the most commonly used antihypertensive medications for the treatment of hypertension during pregnancy, an increasingly common and leading cause of maternal mortality and morbidity worldwide. AREAS COVERED: The literature reviewed included the 2014 Canadian national pregnancy hypertension guideline and its references. The additional published literature was retrieved through searches of Medline, CINAHL, and The Cochrane Library using appropriate controlled vocabulary (e.g., pregnancy, hypertension, pre-eclampsia, pregnancy toxemias) and key words (e.g., diagnosis, evaluation, classification, prediction, prevention, prognosis, treatment, and postpartum follow-up).Results were restricted to systematic reviews, randomized controlled trials, controlled clinical trials, and observational studies published in French or English, Jan Mar/14. The unpublished literature was identified by searching websites of health technology assessment and health technology-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. We evaluated the impact of interventions on substantive clinical outcomes for mothers and babies. EXPERT OPINION: Labetalol is a reasonable choice for treatment of severe or non-severe hypertension in pregnancy. However, we should continue our search for other therapeutic options. PMID- 25692531 TI - A neighborhood-centered clinical project: improving diabetes and cardiovascular outcomes in Hispanic women. AB - Neighborhood-centered disease prevention programs have become a growing means of introducing baccalaureate nursing students to health care systems. This article reports diabetes and cardiovascular clinical outcomes and health behavior changes made following a 2-year baccalaureate community/public health clinical project and partnership with an urban Hispanic neighborhood. This pilot study used a pretest-posttest design without comparators. The healthy lifestyle consisted of health coaching, physical activity, and lifestyle modification. Thirty-eight women completed the 12-week program. Results revealed significant reductions in diabetes and cardiovascular total risk scores, glycated hemoglobin, body mass index, and physical activity (alpha = 0.05). Students gained learning opportunities in research and public health competencies, while providing clinical practice, research, and scholarship opportunities for nurse educators. Insights from these programs can help faculty, students, and communities identify new approaches that are consistent with the National Prevention Strategy and the Patient Protection and Affordable Care Act to improve diabetes and cardiovascular outcomes among Hispanic women. PMID- 25692532 TI - Management of pulmonary exacerbations in cystic fibrosis: still an unmet medical need in clinical practice. AB - Pulmonary exacerbation (PEx) is a hallmark of cystic fibrosis. Although several criteria have been proposed for the definition of PEx, no consensus has yet been reached. Very often, many PEx cases go unreported. A standardized and validated definition is needed to reduce variability in clinical practice. The pathophysiology of recurrent episodes remains unclear, and both onset and risk are multifactorial. PEx leads to increased healthcare costs, impaired quality of life and a cycle in which PEx causes loss of lung function, which predisposes to further episodes. The number of episodes affects survival. Although early diagnosis and aggressive treatment are highly recommended, measures to prevent the emergence of new PEx are even more important. In particular, inhaled antibiotics administered under new treatment schedules could play a key role in preventing exacerbations and thus delay decline in lung function and reduce mortality. The primary objective is zero exacerbations. PMID- 25692533 TI - Liposome-encapsulated CpG enhances antitumor activity accompanying the changing of lymphocyte populations in tumor via intratumoral administration. AB - Although oligodeoxynucleotides containing CpG motifs (CpG-ODN) are potent immune stimulators, the use of natural CpG-ODN--phosphodiester-backbone CpG--has been limited due to its instability by nuclease in vivo. The aim of this study is to investigate the anticancer efficiency of CpG-ODN capsulated using liposome, which enhances the stability of CpG-ODN. We formulated lipoplex, encapsulated natural CpG-ODN from Mycobacterium bovis with liposome, and tested its immune stimulatory activity in vitro and in vivo. The lipoplex induced a systemic innate immune response in vivo and stimulated dendritic cells, but not macrophages, to stimulate proinflammatory cytokines such as tumor necrosis factor alpha and interleukin-6 in vitro. As expected, the lipoplex effectively mediated the prolonged cancer-therapeutic activity against B16 melanoma, which was dependent on natural killer and CD8(+) T cells. The therapeutic activity was observed after only intratumoral administration of lipoplex among several treatment routes. Intratumoral treatment of lipoplex significantly increased the populations of natural killer and CD8(+) T cells and reduced regulatory CD4(+) T cell recruitment, which was correlated with expression profiles of chemokines (CCL1, CCL3, CXCL1, CXCL10, and CCL22). The antitumor therapeutic effect of lipoplex was dependent on the altered lymphocyte population that might be developed by the profile of intratumoral chemokine expression. PMID- 25692534 TI - Molecular modeling and in-silico engineering of Cardamom mosaic virus coat protein for the presentation of immunogenic epitopes of Leptospira LipL32. AB - Expression of Cardamom mosaic virus (CdMV) coat protein (CP) in E. coli forms virus-like particles. In this study, the structure of CdMV CP was predicted and used as a platform to display epitopes of the most abundant surface-associated protein, LipL32 of Leptospira at C, N, and both the termini of CdMV CP. In silico, we have mapped sequential and conformational B-cell epitopes from the crystal structure of LipL32 of Leptospira interrogans serovar Copenhageni str. Fiocruz L1-130 using IEDB Elipro, ABCpred, BCPRED, and VaxiJen servers. Our results show that the epitopes displayed at the N-terminus of CdMV CP are promising vaccine candidates as compared to those displayed at the C-terminus or at both the termini. LipL32 epitopes, EP2, EP3, EP4, and EP6 are found to be promising B-cell epitopes for vaccine development. Based on the type of amino acids, length, surface accessibility, and docking energy with CdMV CP model, the order of antigenicity of the LipL32 epitopes was found to be EP4 > EP3 > EP2 > EP6. PMID- 25692536 TI - A Systematic Review and Meta-analysis of the Acceptability and Effectiveness of University Smoke-Free Policies. AB - OBJECTIVE: Systematically review studies of support for, and effectiveness of, university campuses' smoke-free policies. PARTICIPANTS/METHODS: A search was carried out for studies in English related to campus smoking bans through June 2013. Eligible studies had outcomes for student or faculty attitudes, or measures of smoking prevalence or secondhand smoke (SHS) exposure. RESULTS: Nineteen eligible studies were identified, 18 from the United States and 1 from the United Kingdom. A meta-analysis found 58.94% (95% confidence interval [CI] [52.35%, 65.53%]) of students (12 studies) and 68.39% (95% CI [65.12%, 71.67%]) of faculty (7 studies) supported smoke-free policies. Both studies measuring student smoking prevalence indicated a postban reduction (16.5% to 12.8% after 1 year [p < .001] and 9.5% to 7.0% [p = .036] after 3 years). Only 5% of UK universities were smoke free compared with 25% of US universities. CONCLUSIONS: A majority of students and faculty support smoke-free campus policies, which may reduce smoking and SHS exposure. PMID- 25692535 TI - Advances in aluminum hydroxide-based adjuvant research and its mechanism. AB - In the past few decades, hundreds of materials have been tried as adjuvant; however, only aluminum-based adjuvants continue to be used widely in the world. Aluminum hydroxide, aluminum phosphate and alum constitute the main forms of aluminum used as adjuvants. Among these, aluminum hydroxide is the most commonly used chemical as adjuvant. In spite of its wide spread use, surprisingly, the mechanism of how aluminum hydroxide-based adjuvants exert their beneficial effects is still not fully understood. Current explanations for the mode of action of aluminum hydroxide-based adjuvants include, among others, the repository effect, pro-phagocytic effect, and activation of the pro-inflammatory NLRP3 pathway. These collectively galvanize innate as well as acquired immune responses and activate the complement system. Factors that have a profound influence on responses evoked by aluminum hydroxide-based adjuvant applications include adsorption rate, strength of the adsorption, size and uniformity of aluminum hydroxide particles, dosage of adjuvant, and the nature of antigens. Although vaccines containing aluminum hydroxide-based adjuvants are beneficial, sometimes they cause adverse reactions. Further, these vaccines cannot be stored frozen. Until recently, aluminum hydroxide-based adjuvants were known to preferentially prime Th2-type immune responses. However, results of more recent studies show that depending on the vaccination route, aluminum hydroxide-based adjuvants can enhance both Th1 as well as Th2 cellular responses. Advances in systems biology have opened up new avenues for studying mechanisms of aluminum hydroxide-based adjuvants. These will assist in scaling new frontiers in aluminum hydroxide-based adjuvant research that include improvement of formulations, use of nanoparticles of aluminum hydroxide and development of composite adjuvants. PMID- 25692537 TI - Reactive conformation of the active site in the hairpin ribozyme achieved by molecular dynamics simulations with epsilon/zeta force field reparametrizations. AB - X-ray crystallography can provide important insights into the structure of RNA enzymes (ribozymes). However, the details of a ribozyme's active site architecture are often altered by the inactivating chemical modifications necessary to inhibit self-cleavage. Molecular dynamics (MD) simulations are able to complement crystallographic data and model the conformation of the ribozyme's active site in its native form. However, the performance of MD simulations is driven by the quality of the force field used. Force fields are primarily parametrized and tested for a description of canonical structures and thus may be less accurate for noncanonical RNA elements, including ribozyme catalytic cores. Here, we show that our recent reparametrization of epsilon/zeta torsions significantly improves the description of the hairpin ribozyme's scissile phosphate conformational behavior. In addition, we find that an imbalance in the force field description of the nonbonded interactions of the ribose 2'-OH contributes to the conformational behavior observed for the scissile phosphate in the presence of a deprotonated G8(-). On the basis of the new force field, we obtain a reactive conformation for the hairpin ribozyme active site that is consistent with the most recent mechanistic and structural data. PMID- 25692538 TI - Peer review pitfalls. PMID- 25692539 TI - Antibacterial photodynamic therapy with 808-nm laser and indocyanine green on abrasion wound models. AB - Infections with pathogens could cause serious health problems, such as septicemia and subsequent death. Some of these deaths are caused by nosocomial, chronic, or burn-related wound infections. Photodynamic therapy (PDT) can be useful for the treatment of these infections. Our aim was to investigate the antibacterial effect of indocyanine green (ICG) and 808-nm laser on a rat abrasion wound model infected with the multidrug resistant Staphylococcus aureus strain. Abrasion wounds were infected with a multidrug resistant clinical isolate of S. aureus. ICG concentrations of 500, 1000, and 2000 MUg/ml were applied with a 450 J/cm2 energy dose. Temperature change was monitored by a thermocouple system. The remaining bacterial burden was determined by the serial dilution method after each application. Wounds were observed for 11 days posttreatment. The recovery process was assessed macroscopically. Tissue samples were also examined histologically by hematoxylin-eosin staining. Around a 90% reduction in bacterial burden was observed after applications. In positive control groups (ICG-only and laser-only groups), there was no significant reduction. The applied energy dose did not cause any thermal damage to the target tissue or host environment. Results showed that ICG together with a 808-nm laser might be a promising antibacterial method to eliminate infections in animals and accelerate the wound healing process. PMID- 25692540 TI - Planar-chiral building blocks for metal-organic frameworks. AB - The first example of a planar-chiral building block being used for chiral metal organic frameworks (MOFs) is presented. The porous MOF structure combined with the chiral properties of the planar linker allows a selective adsorption, demonstrated for a nonpolar terpene limonene in thin surface-mounted MOF films. PMID- 25692543 TI - Probe molecule (PrM) approach in adverse outcome pathway (AOP) based high throughput screening (HTS): in vivo discovery for developing in vitro target methods. AB - Efficient and accurate adverse outcome pathway (AOP) based high-throughput screening (HTS) methods use a systems biology based approach to computationally model in vitro cellular and molecular data for rapid chemical prioritization; however, not all HTS assays are grounded by relevant in vivo exposure data. The challenge is to develop HTS assays with unambiguous quantitative links between in vitro responses and corresponding in vivo effects, which is complicated by metabolically insufficient systems, in vitro to in vivo extrapolation (IVIVE), cross-species comparisons, and other inherent issues correlating IVIVE findings. This article introduces the concept of ultrasensitive gas phase probe molecules (PrMs) to help bridge the current HTS assay IVIVE gap. The PrM concept assesses metabolic pathways that have already been well-defined from intact human or mammalian models. Specifically, the idea is to introduce a gas phase probe molecule into a system, observe normal steady state, add chemicals of interest, and quantitatively measure (from headspace gas) effects on PrM metabolism that can be directly linked back to a well-defined and corresponding in vivo effect. As an example, we developed the pharmacokinetic (PK) parameters and differential equations to estimate methyl tertiary butyl ether (MTBE) metabolism to tertiary butyl alcohol (TBA) via cytochrome (CYP) 2A6 in the liver from human empirical data. Because MTBE metabolic pathways are well characterized from in vivo data, we can use it as a PrM to explore direct and indirect chemical effects on CYP pathways. The PrM concept could be easily applied to in vitro and alternative models of disease and phenotype, and even test for volatile chemicals while avoiding liquid handling robotics. Furthermore, a PrM can be designed for any chemical with known empirical human exposure data and used to assess chemicals for which no information exists. Herein, we propose an elegant gas phase probe molecule-based approach to in vitro toxicity testing. PMID- 25692544 TI - Kinetic resolution of alpha-methylene-beta-hydroxy esters catalyzed by acyl transfer catalyst An-PIQ. AB - A highly efficient nonenzymatic kinetic resolution of a series of structurally diverse racemic alpha-methylene-beta-hydroxy esters utilizing the acyl transfer catalyst An-PIQ and propionic anhydride is reported. This procedure provides recovered alcohols with extremely high ee's (up to >99%) in reasonable conversions and excellent selectivity factors (S up to 108). Several synthetically important substrates were resolved in gram-scale reactions, and highly optically pure alpha-methylene-beta-hydroxy esters were obtained with excellent S values and good yields. PMID- 25692545 TI - Haemoconcentration of residual cardiopulmonary bypass blood using Hemosep (r): a randomised controlled trial. AB - Cardiac surgery and cardiopulmonary bypass are associated with haemodilution, activation of haemostasis and blood transfusion. We undertook a randomised controlled trial that included 53 patients in order to compare autotransfusion of residual cardiopulmonary bypass blood with residual blood concentrated using the novel Hemosep((r)) device. There was no difference in patients' mean (SD) haemoglobin concentration after autotransfusion of unprocessed blood compared with Hemosep; 103.5 (10.2) g.l(-1) vs 106.2 (12.4) g.l(-1), respectively, p = 0.40. The mean (SD) change in haemoglobin concentration after autotransfusion was 5.9 (5.3) g.l(-1) in the control group compared with 4.9 (6.3) g.l(-1) in the Hemosep group, p = 0.545. Adjusted for baseline haemoglobin concentrations, the estimated mean (95% CI) difference in change in haemoglobin concentration (control vs Hemosep) was 0.57 (-2.65 to 3.79) g.l(-1), p = 0.72. This was despite Hemosep's reducing the weight of the blood from a mean (SD) of 778.7 (243.0) g to 607.3 (248.2) g, p < 0.001. The haemoglobin concentration in the processed blood increased from a mean (SD) of 87.0 (15.1) g.l(-1) to 103.7 (17.4) g.l(-1), p < 0.001. We conclude that Hemosep is capable of haemoconcentration when employed to process residual cardiopulmonary bypass blood, but that this is insufficient to increase patient haemoglobin. PMID- 25692546 TI - In silico analysis of the interaction of avian aryl hydrocarbon receptors and dioxins to decipher isoform-, ligand-, and species-specific activations. AB - The aryl hydrocarbon receptor (AHR) mediates toxic responses to 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) and other dioxin-like compounds (DLCs). Avian species possess multiple AHR isoforms (AHR1, AHR1beta, and AHR2) that exhibit species- and isoform-specific responses to ligands. To account for the ligand preference in terms of the structural features of avian AHRs, we generated in silico homology models of the ligand-binding domain of avian AHRs based on holo human HIF-2alpha (PDB entry 3H7W ). Molecular docking simulations of TCDD and other DLCs with avian AHR1s and AHR2s using ASEDock indicated that the interaction energy increased with the number of substituted chlorine atoms in congeners, supporting AHR transactivation potencies and World Health Organization TCDD toxic equivalency factors of congeners. The potential interaction energies of an endogenous AHR ligand, 6-formylindolo [3,2-b] carbazole (FICZ) to avian AHRs were lower than those of TCDD, which was supported by a greater potency of FICZ for in vitro AHR-mediated transactivation than TCDD. The molecular dynamics simulation revealed that mean square displacements in Ile324 and Ser380 of TCDD bound AHR1 of the chicken, the most sensitive species to TCDD, were smaller than those in other avian AHR1s, suggesting that the dynamic stability of these amino acid residues contribute to TCDD preference. For avian AHR2, the corresponding residues (Val/Ser or Val/Ala type) were not responsible for differential TCDD sensitivity. Application of the three-dimensional reference interaction site model showed that the stabilization of TCDD binding to avian AHRs may be due to the solvation effect depending on the characteristics of two amino acids corresponding to Ile324 and Ser380 in chicken AHR1. This study demonstrates that in silico simulations of AHRs and ligands could be used to predict isoform-, ligand-, and species-specific interactions. PMID- 25692547 TI - Comparison of drought stress response and gene expression between a GM maize variety and a near-isogenic non-GM variety. AB - Maize MON810, grown and commercialised worldwide, is the only cultivated GM event in the EU. Maize MON810, variety DKC6575, and the corresponding near-isogenic line Tietar were studied in different growth conditions, to compare their behaviour in response to drought. Main photosynthetic parameters were significantly affected by drought stress in both GM and non-GM varieties to a similar extent. Though DKC6575 (GM) had a greater sensitivity in the early phase of stress response as compared with Tietar (non-GM), after six days of stress they behaved similarly, and both varieties recovered from stress damage. Profiling gene expression in water deficit regimes and in a generalised drought stress condition showed an up-regulation of many stress-responsive genes, but a greater number of differentially expressed genes was observed in Tietar, with genes belonging to transcription factor families and genes encoding heat shock proteins, late embryogenesis abundant proteins and detoxification enzymes. Since induction of these genes have been indicated from the literature as typical of stress responses, their activation in Tietar rather than in DKC6575 may be reminiscent of a more efficient response to drought. DKC6575 was also analysed for the expression of the transgene CryIAb (encoding the delta-endotoxin insecticidal protein) in water deficit conditions. In all the experiments, the CryIAb transcript was not influenced by drought stress, but was expressed at a constant level. This suggests that though possessing a different pattern of sensitivity to stress, the GM variety maintains the same expression level for the transgene. PMID- 25692548 TI - Cathepsin K knockout alleviates aging-induced cardiac dysfunction. AB - Aging is a major risk factor for cardiovascular disease. It has previously been shown that protein levels of cathepsin K, a lysosomal cysteine protease, are elevated in the failing heart and that genetic ablation of cathepsin K protects against pressure overload-induced cardiac hypertrophy and contractile dysfunction. Here we test the hypothesis that cathepsin K knockout alleviates age dependent decline in cardiac function. Cardiac geometry, contractile function, intracellular Ca(2+) properties, and cardiomyocyte apoptosis were evaluated using echocardiography, fura-2 technique, immunohistochemistry, Western blot and TUNEL staining, respectively. Aged (24-month-old) mice exhibited significant cardiac remodeling (enlarged chamber size, wall thickness, myocyte cross-sectional area, and fibrosis), decreased cardiac contractility, prolonged relengthening along with compromised intracellular Ca(2+) release compared to young (6-month-old) mice, which were attenuated in the cathepsin K knockout mice. Cellular markers of senescence, including cardiac lipofuscin, p21 and p16, were lower in the aged cathepsin K knockout mice compared to their wild-type counterpart. Mechanistically, cathepsin K knockout mice attenuated an age-induced increase in cardiomyocyte apoptosis and nuclear translocation of mitochondrial apoptosis inducing factor (AIF). In cultured H9c2 cells, doxorubicin stimulated premature senescence and apoptosis. Silencing of cathepsin K blocked the doxorubicin induced translocation of AIF from the mitochondria to the nuclei. Collectively, these results suggest that cathepsin K knockout attenuates age-related decline in cardiac function via suppressing caspase-dependent and caspase-independent apoptosis. PMID- 25692549 TI - Probiotics (Lactobacillus rhamnosus R0011 and acidophilus R0052) reduce the expression of toll-like receptor 4 in mice with alcoholic liver disease. AB - OBJECTIVE: The role of lipopolysaccharide (LPS) and toll-like receptor 4 (TLR 4) in the pathogenesis of alcoholic liver disease (ALD) has been widely established. We evaluated the biological effects of probiotics (Lactobacillus rhamnosus R0011 and acidophilus R0052), KRG (Korea red ginseng), and urushiol (Rhus verniciflua Stokes) on ALD, including their effects on normal and high-fat diet in mice. METHODS: One hundred C57BL/6 mice were classified into normal (N) and high-fat diet (H) groups. Each group was divided into 5 sub-groups: control, alcohol, alcohol+probiotics, alcohol+KRG, and alcohol+urushiol. A liver function test, histology, electron-microscopy, interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha, IL-6, and IL-10, and TLR 4 were evaluated and compared. RESULTS: In the N group, probiotics, KRG, and urushiol significantly reduced levels of TNF alpha (12.3+/-5.1, 13.4+/-3.9, and 12.1+/-4.3 vs. 27.9+/-15.2 pg/mL) and IL-1beta (108.4+/-39.4, 75.0+/-51.0, and 101.1+/-26.8 vs. 162.4+/-37.5 pg/mL), which were increased by alcohol. Alcohol-induced TLR 4 expression was reduced by probiotics and urushiol (0.7+/-0.2, and 0.8+/-0.1 vs. 1.0+/-0.3, p<0.001). In the H group, IL-10 was significantly increased by probiotics and KRG, compared with alcohol (25.3+/-15.6 and 20.4+/-6.2 vs. 7.6+/-5.6 pg/mL) and TLR 4 expression was reduced by probiotics (0.8+/-0.2 vs. 1.0+/-0.3, p = 0.007). CONCLUSIONS: Alcohol-induced TLR 4 expression was down-regulated by probiotics in the normal and high-fat diet groups. Probiotics, KRG, and urushiol might be effective in the treatment of ALD by regulating the gut-liver axis. PMID- 25692550 TI - P2Y2R deficiency attenuates experimental autoimmune uveitis development. AB - We aimed to study the role of the nucleotide receptor P2Y2R in the development of experimental autoimmune uveitis (EAU). EAU was induced in P2Y2+/+ and P2Y2-/- mice by immunization with IRBP peptide or by adoptive transfer of in vitro restimulated semi-purified IRBP-specific enriched T lymphocytes from spleens and lymph nodes isolated from native C57Bl/6 or P2Y2+/+ and P2Y2-/- immunized mice. Clinical and histological scores were used to grade disease severity. Splenocytes and lymph node cell phenotypes were analyzed using flow cytometry. Semi-purified lymphocytes and MACS-purified CD4+ T lymphocytes from P2Y2+/+ and P2Y2-/- immunized mice were tested for proliferation and cytokine secretion. Our data show that clinical and histological scores were significantly decreased in IRBP immunized P2Y2-/- mice as in P2Y2-/- mice adoptively transfered with enriched T lymphocytes from C57Bl/6 IRBP-immunized mice. In parallel, naive C57Bl/6 mice adoptively transferred with T lymphocytes from P2Y2-/- IRBP-immunized mice also showed significantly less disease. No differences in term of spleen and lymph node cell recruitment or phenotype appeared between P2Y2-/- and P2Y2+/+ immunized mice. However, once restimulated in vitro with IRBP, P2Y2-/- T cells proliferate less and secrete less cytokines than the P2Y2+/+ one. We further found that antigen-presenting cells of P2Y2-/- immunized mice were responsible for this proliferation defect. Together our data show that P2Y2-/- mice are less susceptible to mount an autoimmune response against IRBP. Those results are in accordance with the danger model, which makes a link between autoreactive lymphocyte activation, cell migration and the release of danger signals such as extracellular nucleotides. PMID- 25692551 TI - Disclosing bias in bisulfite assay: MethPrimers underestimate high DNA methylation. AB - Discordant results obtained in bisulfite assays using MethPrimers (PCR primers designed using MethPrimer software or assuming that non-CpGs cytosines are non methylated) versus primers insensitive to cytosine methylation lead us to hypothesize a technical bias. We therefore used the two kinds of primers to study different experimental models and methylation statuses. We demonstrated that MethPrimers negatively select hypermethylated DNA sequences in the PCR step of the bisulfite assay, resulting in CpG methylation underestimation and non-CpG methylation masking, failing to evidence differential methylation statuses. We also describe the characteristics of "Methylation-Insensitive Primers" (MIPs), having degenerated bases (G/A) to cope with the uncertain C/U conversion. As CpG and non-CpG DNA methylation patterns are largely variable depending on the species, developmental stage, tissue and cell type, a variable extent of the bias is expected. The more the methylome is methylated, the greater is the extent of the bias, with a prevalent effect of non-CpG methylation. These findings suggest a revision of several DNA methylation patterns so far documented and also point out the necessity of applying unbiased analyses to the increasing number of epigenomic studies. PMID- 25692552 TI - A click approach to novel D-ring-substituted 16alpha-triazolylestrone derivatives and characterization of their antiproliferative properties. AB - A simple and efficient synthesis of novel, D-ring substituted estrone derivatives containing a 16alpha-triazolyl moiety is described. Two epimeric azido alcohols (16alpha-azido-17alpha-hydroxy and 16alpha-azido-17beta-hydroxy) of estra 1,3,5(10)-triene-3-methyl ether were prepared, followed by copper(I)-catalyzed azide-alkyne cycloaddition with various terminal alkynes. The steroidal triazoles were obtained in high yields and their activities against three human cancer cell lines (HeLa, MCF7 and A431) were screened. The most effective analogs were submitted to additional experiments in order to characterize their antiproliferative properties. As evidenced by flow cytometry, the selected steroids induced a disturbance in the HeLa cell cycle in a concentration- and exposure-dependent manner, through an increase of the hypodiploid population (subG1) and a cell cycle arrest in the G2/M phase. A noncancerous human fibroblast cell line (MRC5) was used to determine the selectivities of these compounds. Fluorescent microscopy after Hoechst 33258 - propidium iodide (HOPI) double staining revealed nuclear condensation and disturbed cell membrane integrity. The enhanced activities of caspase-3 and caspase-9 without activation of caspase-8 in the treated cells indicated the activation of the intrinsic pathway of apoptosis. The levels of cell cycle regulators (CDK1, cyclin B1/B2 and cdc25B) were decreased and the ratio Bax/Bcl-2 was increased 24 h after the treatment of HeLa cells (determined at an mRNA level by means of an RT-PCR technique). Under the same conditions, two agents elicited substantially increased degrees of phosphorylation of stathmin, as evidenced by Western blotting. The presented results demonstrate that these steroids can be regarded as appropriate structural scaffolds for the design and synthesis of further steroid analogs as innovative drug candidates with good efficacy. PMID- 25692553 TI - Solvent-vapor-assisted dewetting of prepatterned thin polymer films: control of morphology, order, and pattern miniaturization. AB - Ultrathin (<100 nm) unstable polymer films exposed to a solvent vapor dewet by the growth of surface instability, the wavelength (lambda) of which depends on the film thickness (h(f)). While the dewetting of a flat polymer thin film results in random structures, we show that the dewetting of a prepatterned film results in myriad ordered mesoscale morphologies under specific conditions. Such a film undergoes rupture over the thinnest parts when the initial local thickness of these zones (h(rm)) is lower than a limiting thickness h(lim) ~ 10 nm. Additionally, the width of the pattern grooves (l(s)) must be wider than lambda(s) corresponding to a flat film having a thickness of h(rm) for pattern directed dewetting to take place over surface-tension-induced flattening. We first present an experimentally obtained morphology phase diagram that captures the conditions where a transition from surface-tension-induced flattening to pattern-directed-rupture takes place. Subsequently, we show the versatility of this technique in achieving a variety of aligned mesopatterns starting from a prepatterned film with simple grating geometry. The morphology of the evolving patterns depends on several parameters such as the initial film thickness (h(f)), prepattern amplitude (h(st)), duration of solvent vapor exposure (SVE), and wettability of the stamp used for patterning. Periodic rupture of the film at regular intervals imposes directionality on the evolving patterns, resulting in isolated long threads/cylindrical ridges of polymers, which subsequently disintegrate into an aligned array of droplets due to Rayleigh-Plateau instability under specific conditions. Other patterns such as a double periodic array of droplets and an array of holes are also possible to obtain. The evolution can be interrupted at any intermediate stage by terminating the solvent vapor annealing, allowing the creation of pattern morphology on demand. The created patterns are significantly miniaturized in size as compared to features obtained from dewetting a flat film with the same hf. PMID- 25692554 TI - Photocatalyzed site-selective C-H to C-C conversion of aliphatic nitriles. AB - beta- or gamma-Site-selective C-H alkylation of aliphatic nitriles has been achieved using a decatungstate salt as the photocatalyst. The observed site selectivity was justified by a radical polar effect in transition states for hydrogen abstraction. PMID- 25692556 TI - Use of short implants (6 mm) in a single-tooth replacement: a 5-year follow-up prospective randomized controlled multicenter clinical study. AB - OBJECTIVE: To evaluate prospectively clinical and radiographic outcomes of 6- or 10 mm-long implants with moderately rough surface (SLA((r)) ) loaded within 7 weeks from installation and supporting single crowns in the posterior regions in the course of 5 years of loading. MATERIAL AND METHODS: Sixty implants with a moderately rough surface, 30 tests (6 mm long, 4.1 mm in diameter) and 30 controls (10 mm long, 4.1 mm in diameter), were placed in posterior regions in 45 patients. After 6 weeks, impressions were taken and the implants were restored with a single fixed prosthesis made with gold-palladium alloy and porcelain. Survival rate and marginal bone loss were evaluated yearly. The clinical crown/implant ratio was calculated. RESULTS: During the follow-up period, five implants, four tests and one control, were lost. Of the four test implants, one was lost before loading, two between the 2nd and the 3rd years, and one during the 4th year of the follow-up period. The control implant was lost during the first year of function. Consequently, after 5 years of follow-up, a survival rate of 86.7% and 96.7% was observed at the test and control sites, respectively. CONCLUSION: The results of this study showed that 6-mm-long implants supporting single crowns loaded within 7 weeks from installation lose a small amount of marginal bone during 5 years of functional loading, similar to that of 10-mm-long implants. However, a higher degree of implant loss was recorded at the short implants, probably due to the fracturing of the surrounding bone. PMID- 25692557 TI - Molecular description of eye defects in the zebrafish Pax6b mutant, sunrise, reveals a Pax6b-dependent genetic network in the developing anterior chamber. AB - The cornea is a central component of the camera eye of vertebrates and even slight corneal disturbances severely affect vision. The transcription factor PAX6 is required for normal eye development, namely the proper separation of the lens from the developing cornea and the formation of the iris and anterior chamber. Human PAX6 mutations are associated with severe ocular disorders such as aniridia, Peters anomaly and chronic limbal stem cell insufficiency. To develop the zebrafish as a model for corneal disease, we first performed transcriptome and in situ expression analysis to identify marker genes to characterise the cornea in normal and pathological conditions. We show that, at 7 days post fertilisation (dpf), the zebrafish cornea expresses the majority of marker genes (67/84 tested genes) found also expressed in the cornea of juvenile and adult stages. We also characterised homozygous pax6b mutants. Mutant embryos have a thick cornea, iris hypoplasia, a shallow anterior chamber and a small lens. Ultrastructure analysis revealed a disrupted corneal endothelium. pax6b mutants show loss of corneal epithelial gene expression including regulatory genes (sox3, tfap2a, foxc1a and pitx2). In contrast, several genes (pitx2, ctnnb2, dcn and fabp7a) were ectopically expressed in the malformed corneal endothelium. Lack of pax6b function leads to severe disturbance of the corneal gene regulatory programme. PMID- 25692558 TI - The problem with competencies in global health education. AB - The demand for global health educational opportunities among students and trainees in high-income countries (HICs) has led to a proliferation of available global health programs. In keeping with the drive towards competency-based medical education, many of these programs have been defining their own global health competencies. Developing such competencies presents several unique challenges, including (1) a failure to take sufficient account of local contexts coupled with a lack of inclusiveness in developing these competencies, (2) the disjunction between the learning approaches of "individualism" in HICs and the relative "collectivism" of most host countries, and (3) shortcomings associated with assessing competencies in resource-limited settings. To meet these challenges, the author recommends reenvisioning the approach to competencies in global health using fresh metaphors, innovative modes of assessment, and the creation of more appropriate competency domains. PMID- 25692559 TI - Sounding off on social media: the ethics of patient storytelling in the modern era. AB - Use of social networking programs like Facebook and Twitter, which enable the public sharing of diverse content over the Internet, has risen dramatically in recent years. Although health professionals have faced consequences for clearly unethical online behavior, a relatively unexamined practice among medical students is the disclosure of patient care stories on social media in a manner that is technically compliant with the Health Insurance Portability and Accountability Act, yet is ethically questionable. In this Perspective, the authors review three such cases in which students do not specifically reveal a patient's identity but share details of a personal nature, motivated by a variety of intentions (e.g., a desire to reflect on a meaningful experience, reaching out for social support in the event of a patient's death). Using ethical principles and professional policy recommendations, they discuss aspects of these postings that are potentially problematic. Consequences include the possibility of undermining public trust in the profession, inadvertently identifying patients, and violating expectations of privacy. The authors recommend that medical schools explicitly address these issues across the preclinical and clinical curricula and emphasize that patient-related postings on social media may carry inherent risks both to patients and to the profession. PMID- 25692560 TI - Faculty Vitality-Surviving the Challenges Facing Academic Health Centers: A National Survey of Medical Faculty. AB - PURPOSE: Faculty with high vitality are essential to the missions of academic health centers (AHCs). Because little is known about how to measure or enhance faculty vitality, the authors assessed current faculty vitality and identified its predictors. METHOD: In a stratified random sample of 26 nationally representative U.S. AHCs, the authors surveyed 4,578 full-time faculty during 2007-2009. The validated survey measured detailed faculty perceptions of their professional experiences and organizational culture. Vitality was measured with a previously evaluated five-item scale. RESULTS: Of the faculty invited, 2,381 (52%) responded, with 2,218 eligible for analysis. Respondents included 512 (23%) underrepresented in medicine minority (URMM) faculty and 1,172 (53%) women. In a multivariable model including individual- and AHC-level factors, the strongest predictors of vitality were faculty members' perceptions of four dimensions of AHC culture: Relationships/inclusion, Values alignment, Work-life integration, and Institutional support (all P < .001). Weaker predictors were faculty age, institution type (public/private), and the AHC's National Institutes of Health funding rank (all P <= .03). Half of the respondents scored high on vitality, whereas 25% had low, or suboptimal, scores. Holding perceptions of culture constant, neither female nor URMM faculty had vitality scores that were different on average from male or nonminority faculty. CONCLUSIONS: A large percentage of faculty lack the vitality essential to meeting the AHC missions of discovery, education, and patient care. Enhancing faculty vitality, and AHC resilience, requires more attention to strengthening relationships, improving the misalignment between faculty and institutional values, and improving work-life integration. PMID- 25692561 TI - The passion and the peril: storytelling in medicine. AB - Medical caregivers are always telling stories because stories provide meaning to much of their working lives. Although there is surely an element of shock value in the stories that medical professionals choose to share, the compulsion to tell a story is largely motivated by the profound emotions kindled by the clinical experience. This impulse needs to be recognized by the profession, even nurtured. However, as Wells and colleagues highlight in this issue, social media adds a new twist to storytelling. Exponential amplification combined with lack of space for nuance is a toxic brew. This needs to be explicitly emphasized with medical trainees. Although privacy rules already exist, the meaning of professionalism is to cleave to the spirit of the law, not just the letter of the law. Caregivers' primary duty is toward patients, not to writing careers or to online following. Consent should be obtained wherever possible. Identifying characteristics must be changed. Any story that might be damaging, hurtful, or embarrassing to a patient does not belong in the public sphere. Nevertheless, those in medicine need to recognize that the impulse to tell a story is innate in the human race, especially so in the caregiving professions. Experienced caregivers need to help students understand that stories provide depth and meaning to medicine but, when broadcast inappropriately, can cause harm. PMID- 25692562 TI - New Century Scholars: A Mentorship Program to Increase Workforce Diversity in Academic Pediatrics. AB - This article describes a program aimed to increase workforce diversity and underrepresented minority (URM) representation in academic pediatric medicine. The New Century Scholars (NCScholars) program is a core program in the Academic Pediatric Association, the largest national organization for academic pediatric generalists. The program selects URM pediatric (or medicine-pediatrics) residents who are interested in academic careers and provides each NCScholar with a junior and senior mentor, as well as travel grants to the Pediatric Academic Societies annual meeting where activities specific to the program are held, and provides ongoing mentorship and career counseling support.The authors discuss the origination, operation, and changes to the program over the first 10 years of its existence, as well as outcome data for the participants in the program. To date, 60 of the 63 NCScholars have finished residency and/or have made postresidency plans, and 38 of these URM pediatricians (63%) have entered academic careers. The authors suggest that this type of mentorship program for URM pediatric trainees can be used as a model for other specialties and medical organizations. PMID- 25692563 TI - Sexual and gender minority identity disclosure during undergraduate medical education: "in the closet" in medical school. AB - PURPOSE: To assess identity disclosure among sexual and gender minority (SGM) students pursuing undergraduate medical training in the United States and Canada. METHOD: From 2009 to 2010, a survey was made available to all medical students enrolled in the 176 MD- and DO-granting medical schools in the United States and Canada. Respondents were asked about their sexual and gender identity, whether they were "out" (i.e., had publicly disclosed their identity), and, if they were not, their reasons for concealing their identity. The authors used a mixed methods approach and analyzed quantitative and qualitative survey data. RESULTS: Of 5,812 completed responses (of 101,473 eligible respondents; response rate 5.7%), 920 (15.8%) students from 152 (of 176; 86.4%) institutions identified as SGMs. Of the 912 sexual minorities, 269 (29.5%) concealed their sexual identity in medical school. Factors associated with sexual identity concealment included sexual minority identity other than lesbian or gay, male gender, East Asian race, and medical school enrollment in the South or Central regions of North America. The most common reasons for concealing one's sexual identity were "nobody's business" (165/269; 61.3%), fear of discrimination in medical school (117/269; 43.5%), and social or cultural norms (110/269; 40.9%). Of the 35 gender minorities, 21 (60.0%) concealed their gender identity, citing fear of discrimination in medical school (9/21; 42.9%) and lack of support (9/21; 42.9%). CONCLUSIONS: SGM students continue to conceal their identity during undergraduate medical training. Medical institutions should adopt targeted policies and programs to better support these individuals. PMID- 25692564 TI - H4octapa: highly stable complexation of lanthanide(III) ions and copper(II). AB - The acyclic ligand octapa(4-) (H4octapa = 6,6'-((ethane-1,2 diylbis((carboxymethyl)azanediyl))bis(methylene))dipicolinic acid) forms stable complexes with the Ln(3+) ions in aqueous solution. The stability constants determined for the complexes with La(3+), Gd(3+), and Lu(3+) using relaxometric methods are log KLaL = 20.13(7), log KGdL = 20.23(4), and log KLuL = 20.49(5) (I = 0.15 M NaCl). High stability constants were also determined for the complexes formed with divalent metal ions such as Zn(2+) and Cu(2+) (log KZnL = 18.91(3) and log KCuL = 22.08(2)). UV-visible and NMR spectroscopic studies and density functional theory (DFT) calculations point to hexadentate binding of the ligand to Zn(2+) and Cu(2+), the donor atoms of the acetate groups of the ligand remaining uncoordinated. The complexes formed with the Ln(3+) ions are nine coordinated thanks to the octadentate binding of the ligand and the presence of a coordinated water molecule. The stability constants of the complexes formed with the Ln(3+) ions do not change significantly across the lanthanide series. A DFT investigation shows that this is the result of a subtle balance between the increased binding energies across the 4f period, which contribute to an increasing complex stability, and the parallel increase of the absolute values of the hydration free energies of the Ln(3+) ions. In the case of the [Ln(octapa)(H2O)](-) complexes the interaction between the amine nitrogen atoms of the ligand and the Ln(3+) ions is weakened along the lanthanide series, and therefore the increased electrostatic interaction does not overcome the increasing hydration energies. A detailed kinetic study of the dissociation of the [Gd(octapa)(H2O)](-) complex in the presence of Cu(2+) shows that the metal assisted pathway is the main responsible for complex dissociation at pH 7.4 and physiological [Cu(2+)] concentration (1 MUM). PMID- 25692565 TI - Disrupted effective connectivity of cortical systems supporting attention and interoception in melancholia. AB - IMPORTANCE: Patients with melancholia report a distinct and intrusive dysphoric state during internally generated thought. Melancholia has long been considered to have a strong biological component, but evidence for its specific neurobiological origins is limited. The distinct neurocognitive, psychomotor, and mood disturbances observed in melancholia do, however, suggest aberrant coordination of frontal-subcortical circuitry, which may best be captured through analysis of complex brain networks. OBJECTIVE: To investigate the effective connectivity between spontaneous (resting-state) brain networks in melancholia, focusing on networks underlying attention and interoception. DESIGN, SETTING, AND PARTICIPANTS: We performed a cross-sectional, observational, resting-state functional magnetic resonance imaging study of 16 participants with melancholia, 16 with nonmelancholic depression, and 16 individuals serving as controls at a hospital-based research institute between August 30, 2010, and June 27, 2012. We identified 5 canonical resting-state networks (default mode, executive control, left and right frontoparietal attention, and bilateral anterior insula) and inferred spontaneous interactions among these networks using dynamic causal modeling. MAIN OUTCOMES AND MEASURES: Graph theoretic measures of brain connectivity, namely, in-degree and out-degree of each network and edge connectivity, between regions composed our principal between-group contrasts. RESULTS: Melancholia was characterized by a pervasive disconnection involving anterior insula and attentional networks compared with participants in the control (Mann-Whitney, 189.00; z = 2.38; P = .02) and nonmelancholic depressive (Mann-Whitney, 203.00; z = 2.93; P = .004) groups. Decreased effective connectivity between the right frontoparietal and insula networks was present in participants with melancholic depression compared with those with nonmelancholic depression (chi2 = 8.13; P = .004). Reduced effective connectivity between the insula and executive networks was found in individuals with melancholia compared with healthy controls (chi2 = 8.96; P = .003). CONCLUSIONS AND RELEVANCE: We observed reduced effective connectivity in resting-state functional magnetic resonance imaging between key networks involved in attention and interoception in melancholia. We propose that these abnormalities underlie the impoverished variety and affective quality of internally generated thought in this disorder. PMID- 25692566 TI - Catalytic amounts of CBr4 mediated dehydrogenative coupling of isochromans with aromatic ketones. AB - In the presence of catalytic amounts of CBr4 (a metal-free mediator), an unexpected oxidative dehydrogenative coupling of isochromans with ketones occurred to construct new C(sp(3))-C(sp(3)) bonds. The reactions were performed under simple solvent-free aerobic conditions. PMID- 25692567 TI - Clinical significance of cerebral microbleeds locations in CADASIL with R544C NOTCH3 mutation. AB - BACKGROUND AND PURPOSE: Although cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common single gene disorder of cerebral small blood vessels caused by NOTCH3 mutations, little has been described about the variation in the clinical findings between its underlying types of mutations. In particular, the presence of cerebral microbleeds (CMBs) has been an increasingly recognized magnetic resonance imaging finding in CADASIL, but their clinical significance is not clear. The purpose of this study is to assess whether CMBs are associated with symptomatic stroke in the CADASIL patients with R544C mutation and to compare the cerebral distribution of CMBs between CADASIL patients with and without symptomatic stroke. METHODS: This is a cohort study of patients who were diagnosed with genotype-confirmed R544C-mutation CADASIL. Primary neurologic symptoms were recorded. Symptomatic strokes were defined as transient ischemic attack, ischemic strokes and hemorrhagic strokes. CMBs were defined as focal areas of round signal loss on T2* weighted gradient echo planar images with a diameter of less than 10 mm. The locations of CMBs were divided into lobar, basal ganglia, thalamus, brain stem and cerebellum. Multiple logistic regressions were performed to identify the epidemiologic or vascular risk factors associated with symptomatic stroke in patients with CADASIL. RESULTS: Among total of 51 subjects in this cohort, CMBs were present in 20 of 32 patients (64.5%) in the symptomatic stroke-group and in 8 of 19 patients (42.1%) in the non-stroke group (p = 0.16). CMBs were observed more frequently in the basal ganglia (p<0.001) and the cerebellum (p<0.018) in the symptomatic stoke group compared to the non-stroke group. The mean number of CMBs was significantly higher in the symptomatic stroke group (15.4+/-18.0 lesions per patients with CMBs) versus those without symptomatic stroke (3.3+/ 3.0 lesions per patients with CMBs) (p = 0.003). Hypertension was an independent risk factor for symptomatic stroke in CADASIL (p = 0.014). It was independently associated with CMBs locations as basal ganglia (p = 0.016), thalamus (p = 0.010), brainstem (p = 0.044), and cerebellum (p = 0.049). However, It was not independently associated with CMBs on lobar lesion (p = 0.152). CONCLUSIONS: In this study hypertension was an independent predictor of CMBs presence in specific brain locations, as well as symptomatic stroke in the CADASIL patients. The distribution and burden of CMBs might be a clinically useful marker for the risk of symptomatic stroke. However, further prospective studies on the relationship between CMBs distribution and symptomatic stroke are required in order to support these preliminary findings. PMID- 25692568 TI - Adherence and uptake of artemisinin-based combination treatments for uncomplicated malaria: a qualitative study in northern Ghana. AB - BACKGROUND: Based on the recommendations of the World Health Organization in 2004, Ghana changed her antimalarial drug policy from mono-therapy to Artemisinin based Combination Therapy (ACTs). The country is currently using three first line drugs artesunate-amodiaquine, artemether-lumefantrine and dihydroartemisinin piperaquine for the treatment of uncomplicated malaria. Despite this policy, little or no qualitative studies have been conducted to establish the factors influencing adherence to the new treatment for malaria. This study explored factors influencing adherence to the use of ACTs in northern Ghana. METHODS: This was a qualitative study comprising forty (40) in-depth interviews with patients with malaria who visited selected public and private health facilities and received ACTs. Systematic sampling technique was used to select participants who were given ACTs for the interviews. Nvivo 9 software was used to code the data into themes for further analysis. RESULTS: The study revealed very important differences in knowledge about ACTs. As expected, the less or illiterates could not mention the type of ACT they would prefer to use for treating their malaria. The educated ones had a good knowledge on ACTs and preferred artemether lumefantrinee in treating their malaria. The reason was that the drug was good and it had minimal or no side effects. Individual attitudes toward the use of medications and the side effects associated with the use of these ACTs were found to be the main factors affecting adherence to the use of ACTs. Perceived cure of illness after the initial dose greatly affected adherence. Other factors such as forgetfulness and lack of information also influenced patient adherence to ACTs use. CONCLUSION: Individual knowledge, attitudes and behaviors greatly influence patients' adherence to ACTs use. Since ACTs take a number of days to complete, continuous education by health professionals could improve on adherence to ACTs use by patients with malaria. PMID- 25692569 TI - Development of a markerless deletion system for the fish-pathogenic bacterium Flavobacterium psychrophilum. AB - Flavobacterium psychrophilum is a Gram-negative fish pathogen that causes important economic losses in aquaculture worldwide. Although the genome of this bacterium has been determined, the function and relative importance of genes in relation to virulence remain to be established. To investigate their respective contribution to the bacterial pathogenesis, effective tools for gene inactivation are required. In the present study, a markerless gene deletion system has been successfully developed for the first time in this bacterium. Using this method, the F. psychrophilum fcpB gene, encoding a predicted cysteine protease homologous to Streptococcus pyogenes streptopain, was deleted. The developed system involved the construction of a conjugative plasmid that harbors the flanking sequences of the fcpB gene and an I-SceI meganuclease restriction site. Once this plasmid was integrated in the genome by homologous recombination, the merodiploid was resolved by the introduction of a plasmid expressing I-SceI under the control of the fpp2 F. psychrophilum inducible promoter. The resulting deleted fcpB mutant presented a decrease in extracellular proteolytic activity compared to the parental strain. However, there were not significant differences between their LD50 in an intramuscularly challenged rainbow trout infection model. The mutagenesis approach developed in this work represents an improvement over the gene inactivation tools existing hitherto for this "fastidious" bacterium. Unlike transposon mutagenesis and gene disruption, gene markerless deletion has less potential for polar effects and allows the mutation of virtually any non essential gene or gene clusters. PMID- 25692570 TI - An integrative multi-scale analysis of the dynamic DNA methylation landscape in aging. AB - Recent studies have demonstrated that the DNA methylome changes with age. This epigenetic drift may have deep implications for cellular differentiation and disease development. However, it remains unclear how much of this drift is functional or caused by underlying changes in cell subtype composition. Moreover, no study has yet comprehensively explored epigenetic drift at different genomic length scales and in relation to regulatory elements. Here we conduct an in-depth analysis of epigenetic drift in blood tissue. We demonstrate that most of the age associated drift is independent of the increase in the granulocyte to lymphocyte ratio that accompanies aging and that enrichment of age-hypermethylated CpG islands increases upon adjustment for cellular composition. We further find that drift has only a minimal impact on in-cis gene expression, acting primarily to stabilize pre-existing baseline expression levels. By studying epigenetic drift at different genomic length scales, we demonstrate the existence of mega-base scale age-associated hypomethylated blocks, covering approximately 14% of the human genome, and which exhibit preferential hypomethylation in age-matched cancer tissue. Importantly, we demonstrate the feasibility of integrating Illumina 450k DNA methylation with ENCODE data to identify transcription factors with key roles in cellular development and aging. Specifically, we identify REST and regulatory factors of the histone methyltransferase MLL complex, whose function may be disrupted in aging. In summary, most of the epigenetic drift seen in blood is independent of changes in blood cell type composition, and exhibits patterns at different genomic length scales reminiscent of those seen in cancer. Integration of Illumina 450k with appropriate ENCODE data may represent a fruitful approach to identify transcription factors with key roles in aging and disease. PMID- 25692571 TI - Redirection of genetically engineered CAR-T cells using bifunctional small molecules. AB - Chimeric antigen receptor (CAR)-engineered T cells (CAR-Ts) provide a potent antitumor response and have become a promising treatment option for cancer. However, despite their efficacy, CAR-T cells are associated with significant safety challenges related to the inability to control their activation and expansion and terminate their response. Herein, we demonstrate that a bifunctional small molecule "switch" consisting of folate conjugated to fluorescein isothiocyanate (folate-FITC) can redirect and regulate FITC-specific CAR-T cell activity toward folate receptor (FR)-overexpressing tumor cells. This system was shown to be highly cytotoxic to FR-positive cells with no activity against FR-negative cells, demonstrating the specificity of redirection by folate FITC. Anti-FITC-CAR-T cell activation and proliferation was strictly dependent on the presence of both folate-FITC and FR-positive cells and was dose titratable with folate-FITC switch. This novel treatment paradigm may ultimately lead to increased safety for CAR-T cell immunotherapy. PMID- 25692572 TI - Conductive fiber-based ultrasensitive textile pressure sensor for wearable electronics. AB - A flexible and sensitive textile-based pressure sensor is developed using highly conductive fibers coated with dielectric rubber materials. The pressure sensor exhibits superior sensitivity, very fast response time, and high stability, compared with previous textile-based pressure sensors. By using a weaving method, the pressure sensor can be applied to make smart gloves and clothes that can control machines wirelessly as human-machine interfaces. PMID- 25692573 TI - X-box binding protein 1 (XBP-1) enhances colorectal cancer cell invasion. AB - In this study, we investigated the role of X-box binding protein 1 (XBP-1) and vascular endothelial growth factor receptor-2 (VEGF-R2) signalling in colorectal cancer (CRC) cells invasion by evaluating their extent of activation in CRC tissues and cell lines using immunohistochemistry, western blotting, and invasion assays. Results showed that XBP-1 is expressed at high levels in metastatic and poorly differentiated tissue samples, whereas it appeared relatively low in moderately and well-differentiated tissue samples compared to those in normal colon tissue. The XBP-1 immunoreactivity score (IRS) was positively associated with increasing tumour invasion. In vitro studies showed that overexpression of XBP-1 promoted cancer cell invasion, which was suppressed by inhibition of XBP-1 using small interfering RNA molecules (siRNA). Inhibition of XBP-1 expression significantly decreased levels of VEGF-R2.In conclusion, XBP-1 might be regarded as a novel predictive biomarker in CRC invasion and metastasis. PMID- 25692574 TI - Gender differences in the risk factors for endothelial dysfunction in Chinese hypertensive patients: homocysteine is an independent risk factor in females. AB - OBJECTIVES: Endothelial dysfunction plays a key role in the pathogenesis of cardiovascular disease. However, the gender-related differences in risk factors for endothelial dysfunction are controversial. We investigated the gender differences in the risk factor profiles for endothelial dysfunction in Chinese hypertensive patients. METHODS: Vascular endothelial functions in 213 hypertensive patients were measured by digital reactive hyperemia peripheral arterial tonometry (RH-PAT). Peripheral blood samples were collected, and the self-reported smoking and alcohol consumption status, age, body mass index, heart rate, blood pressure and drug administrations were recorded. RESULTS: RH-PAT indexes were attenuated in both male and female hypertensive patients [1.60 (1.38 2.02) vs. 1.63 (1.44-1.98)]. Multivariate logistic regression analysis identified plasma creatinine (p < 0.001), total cholesterol (p = 0.001), homocysteine (p = 0.002) and smoking (p < 0.001) as the independent factors correlated with gender (male). Multivariate linear regression analysis further identified homocysteine as the factor that is significantly and independently correlated with the decrease in the RH-PAT indexes in female patients (odds ratio: -0.166, 95% confidence interval: -0.292 to -0.040, p = 0.01). However, none of these four factors were correlated with the RH-PAT indexes in male patients. CONCLUSIONS: There are gender-related differences in the risk factors for endothelial dysfunction in Chinese hypertensive patients. Homocysteine is an independent factor for endothelial dysfunction in female hypertensive patients. PMID- 25692575 TI - A qualitative study of patient motivation to adhere to combination antiretroviral therapy in South Africa. AB - Taken as prescribed, that is, with high adherence, combination antiretroviral therapy (ART) has changed HIV infection and disease from being a sure predictor of death to a manageable chronic illness. Adherence, however, is difficult to achieve and maintain. The CAPRISA 058 study was conducted between 2007 and 2009 to test the efficacy of individualized motivational counselling to enhance ART adherence in South Africa. As part of the overall trial, a qualitative sub-study was conducted, including 30 individual interviews and four focus group discussions with patients in the first 9 months of ART initiation. Data were inductively analyzed, using thematic analysis, to identify themes central to ART adherence in this context. Four themes emerged that characterize the participants' experiences and high motivation to adhere to ART. Participants in this study were highly motivated to adhere, as they acknowledged that ART was 'life-giving', in the face of a large amount of morbidity and mortality. They were further supported by techniques of routine remembering, and highlighted the importance of good social support and access to supportive healthcare workers, to their continued success in negotiating their treatment. Participants in the current study told us that their adherence motivation is enhanced by free accessible care, approachable and supportive healthcare workers, broad social acceptance of ART, and past first-hand experiences with AIDS-related co-morbidity and mortality. Programs that include specific attention to these aspects of care will likely be successful in the long term. PMID- 25692576 TI - Transfection system of amino-functionalized calcium phosphate nanoparticles: in vitro efficacy, biodegradability, and immunogenicity study. AB - Many methods have been developed in order to use calcium phosphate (CaP) for delivering nucleotides into living cells. Surface functionalization of CaP nanoparticles (CaP NPs) with N-(2-aminoethyl)-3-aminopropyltrimethoxysilane was shown recently to achieve dispersed NPs with a positive surface charge, capable of transfection (Chem. Mater. 2013, 25 (18), 3667). In this study, different crystal structures of amino-modified CaP NPs (brushite and hydroxyapatite) were investigated for their interaction in cell culture systems in more detail. Qualitative (confocal laser scanning microscopy) and quantitative (flow cytometry) transfection experiments with two cell lines showed the higher transfection efficacy of brushite versus hydroxyapatite. The transfection also revealed a cell type dependency. HEK293 cells were easier to transfect compared to A549 cells. This result was supported by the cytotoxicity results. A549 cells showed a higher degree of tolerance toward the CaP NPs. Further, the impact of the surface modification on the interaction with macrophages and complement as two important components of the innate immune system were considered. The amine surface functionalization had an effect of decreasing the release of proinflammatory cytokines. The complement interaction investigated by a C3a complement activation assay did show no significant differences between CaP NPs without or with amine modification and overall weak interaction. Finally, the degradation of CaP NPs in biological media was studied with respect to the two crystal structures and at acidic and neutral pH. Both amino-modified CaP NPs disintegrate within days at neutral pH, with a notable faster disintegration of brushite NPs at acidic pH. In summary, the fair transfection capability of this amino functionalized CaP NPs together with the excellent biocompatibility, biodegradability, and low immunogenicity make them interesting candidates for further evaluation. PMID- 25692577 TI - Why do cryptic species tend not to co-occur? A case study on two cryptic pairs of butterflies. AB - As cryptic diversity is being discovered, mostly thanks to advances in molecular techniques, it is becoming evident that many of these taxa display parapatric distributions in mainland and that they rarely coexist on islands. Genetic landscapes, haplotype networks and ecological niche modeling analyses were performed for two pairs of non-sister cryptic butterfly species, Aricia agestis A. cramera and Polyommatus icarus-P. celina (Lycaenidae), to specifically assess non-coexistence on western Mediterranean islands, and to test potential causes producing such chequered distribution patterns. We show that the morphologically and ecologically equivalent pairs of species do not coexist on any of the studied islands, although nearly all islands are colonized by one of them. According to our models, the cryptic pairs displayed marked climatic preferences and 'precipitation during the driest quarter' was recovered as the most important climatic determinant. However, neither dispersal capacity, nor climatic or ecological factors fully explain the observed distributions across particular sea straits, and the existence of species interactions resulting in mutual exclusion is suggested as a necessary hypothesis. Given that the studied species are habitat generalists, feeding on virtually unlimited resources, we propose that reproductive interference, together with climatic preferences, sustain density dependent mechanisms like "founder takes all" and impede coexistence on islands. Chequered distributions among cryptic taxa, both sister and non-sister, are common in butterflies, suggesting that the phenomenon revealed here could be important in determining biodiversity patterns. PMID- 25692578 TI - HuD interacts with Bdnf mRNA and is essential for activity-induced BDNF synthesis in dendrites. AB - Highly specific activity-dependent neuronal responses are necessary for modulating synapses to facilitate learning and memory. We present evidence linking a number of important processes involved in regulating synaptic plasticity, suggesting a mechanistic pathway whereby activity-dependent signaling, likely through protein kinase C (PKC)-mediated phosphorylation of HuD, can relieve basal repression of Bdnf mRNA translation in dendrites, allowing for increased TrkB signaling and synaptic remodeling. We demonstrate that the neuronal ELAV family of RNA binding proteins associates in vivo with several Bdnf mRNA isoforms present in the adult brain in an activity-dependent manner, and that one member, HuD, interacts directly with sequences in the long Bdnf 3' untranslated region (3'UTR) and co-localizes with Bdnf mRNA in dendrites of hippocampal neurons. Activation of PKC leads to increased dendritic translation of mRNAs containing the long Bdnf 3'UTR, a process that is dependent on the presence of HuD and its phosphorylation at threonine residues 149 and/or 165. Thus, we found a direct effect of HuD on regulating translation of dendritic Bdnf mRNAs to mediate local and activity-dependent increases in dendritic BDNF synthesis. PMID- 25692579 TI - Three-dimensional forces for two-dimensional motion. PMID- 25692580 TI - Stepping between membrane microdomains. PMID- 25692581 TI - Chromosome, cell cycle, and entropy. PMID- 25692582 TI - Quantifying protein diffusion and capture on filaments. AB - The functional relevance of regulating proteins is often limited to specific binding sites such as the ends of microtubules or actin-filaments. A localization of proteins on these functional sites is of great importance. We present a quantitative theory for a diffusion and capture process, where proteins diffuse on a filament and stop diffusing when reaching the filament's end. It is found that end-association after one-dimensional diffusion is the main source for tip localization of such proteins. As a consequence, diffusion and capture is highly efficient in enhancing the reaction velocity of enzymatic reactions, where proteins and filament ends are to each other as enzyme and substrate. We show that the reaction velocity can effectively be described within a Michaelis-Menten framework. Together, one-dimensional diffusion and capture beats the (three dimensional) Smoluchowski diffusion limit for the rate of protein association to filament ends. PMID- 25692583 TI - Lipid headgroups modulate membrane insertion of pHLIP peptide. AB - The pH low insertion peptide (pHLIP) is an important tool for drug delivery and visualization of acidic tissues produced by various maladies, including cancer, inflammation, and ischemia. Numerous studies indicate that pHLIP exists in three states: unfolded and soluble in water at neutral pH (State I), unfolded and bound to the surface of a phosphatidylcholine membrane at neutral pH (State II), and inserted across the membrane as an alpha-helix at low pH (State III). Here we report how changes in lipid composition modulate this insertion scheme. First, the presence of either anionic lipids, cholesterol, or phosphoethanolamine eliminates membrane binding at neutral pH (State II). Second, the apparent pKa for the insertion transition (State I -> State III) is increased with increasing content of anionic lipids, suggesting that electrostatic interactions in the interfacial region modulate protonation of acidic residues of pHLIP responsible for transbilayer insertion. These findings indicate a possibility for triggering protonation-coupled conformational switching in proteins at membrane interfaces through changes in lipid composition. PMID- 25692584 TI - Minimalistic predictor of protein binding energy: contribution of solvation factor to protein binding. AB - It has long been known that solvation plays an important role in protein-protein interactions. Here, we use a minimalistic solvation-based model for predicting protein binding energy to estimate quantitatively the contribution of the solvation factor in protein binding. The factor is described by a simple linear combination of buried surface areas according to amino-acid types. Even without structural optimization, our minimalistic model demonstrates a predictive power comparable to more complex methods, making the proposed approach the basis for high throughput applications. Application of the model to a proteomic database shows that receptor-substrate complexes involved in signaling have lower affinities than enzyme-inhibitor and antibody-antigen complexes, and they differ by chemical compositions on interfaces. Also, we found that protein complexes with components that come from the same genes generally have lower affinities than complexes formed by proteins from different genes, but in this case the difference originates from different interface areas. The model was implemented in the software PYTHON, and the source code can be found on the Shakhnovich group webpage: http://faculty.chemistry.harvard.edu/shakhnovich/software. PMID- 25692585 TI - Quantitative analysis and modeling probe polarity establishment in C. elegans embryos. AB - Cell polarity underlies many aspects of metazoan development and homeostasis, and relies notably on a set of PAR proteins located at the cell cortex. How these proteins interact in space and time remains incompletely understood. We performed a quantitative assessment of polarity establishment in one-cell stage Caenorhabditis elegans embryos by combining time-lapse microscopy and image analysis. We used our extensive data set to challenge and further specify an extant mathematical model. Using likelihood-based calibration, we uncovered that cooperativity is required for both anterior and posterior PAR complexes. Moreover, we analyzed the dependence of polarity establishment on changes in size or temperature. The observed robustness of PAR domain dimensions in embryos of different sizes is in agreement with a model incorporating fixed protein concentrations and variations in embryo surface/volume ratio. In addition, we quantified the dynamics of polarity establishment over most of the viable temperatures range of C. elegans. Modeling of these data suggests that diffusion of PAR proteins is the process most affected by temperature changes, although cortical flows appear unaffected. Overall, our quantitative analytical framework provides insights into the dynamics of polarity establishment in a developing system. PMID- 25692586 TI - Simulating the entropic collapse of coarse-grained chromosomes. AB - Depletion forces play a role in the compaction and decompaction of chromosomal material in simple cells, but it has remained debatable whether they are sufficient to account for chromosomal collapse. We present coarse-grained molecular dynamics simulations, which reveal that depletion-induced attraction is sufficient to cause the collapse of a flexible chain of large structural monomers immersed in a bath of smaller depletants. These simulations use an explicit coarse-grained computational model that treats both the supercoiled DNA structural monomers and the smaller protein crowding agents as combinatorial, truncated Lennard-Jones spheres. By presenting a simple theoretical model, we quantitatively cast the action of depletants on supercoiled bacterial DNA as an effective solvent quality. The rapid collapse of the simulated flexible chromosome at the predicted volume fraction of depletants is a continuous phase transition. Additional physical effects to such simple chromosome models, such as enthalpic interactions between structural monomers or chain rigidity, are required if the collapse is to be a first-order phase transition. PMID- 25692587 TI - Three-dimensional balance of cortical tension and axial contractility enables fast amoeboid migration. AB - Fast amoeboid migration requires cells to apply mechanical forces on their surroundings via transient adhesions. However, the role these forces play in controlling cell migration speed remains largely unknown. We used three dimensional force microscopy to measure the three-dimensional forces exerted by chemotaxing Dictyostelium cells, and examined wild-type cells as well as mutants with defects in contractility, internal F-actin crosslinking, and cortical integrity. We showed that cells pull on their substrate adhesions using two distinct, yet interconnected mechanisms: axial actomyosin contractility and cortical tension. We found that the migration speed increases when axial contractility overcomes cortical tension to produce the cell shape changes needed for locomotion. We demonstrated that the three-dimensional pulling forces generated by both mechanisms are internally balanced by an increase in cytoplasmic pressure that allows cells to push on their substrate without adhering to it, and which may be relevant for amoeboid migration in complex three dimensional environments. PMID- 25692588 TI - Bud-neck scaffolding as a possible driving force in ESCRT-induced membrane budding. AB - Membrane budding is essential for processes such as protein sorting and transport. Recent experimental results with ESCRT proteins reveal a novel budding mechanism, with proteins emerging in bud necks but separated from the entire bud surface. Using an elastic model, we show that ESCRT protein shapes are sufficient to spontaneously create experimentally observed structures, with protein-membrane interactions leading to protein scaffolds in bud-neck regions. Furthermore, the model reproduces experimentally observed budding directions and bud sizes. Finally, our results reveal that membrane-mediated sorting has the capability of creating structures more complicated than previously assumed. PMID- 25692589 TI - Low pH modulates the macroorganization and thermal stability of PSII supercomplexes in grana membranes. AB - Protonation of the lumen-exposed residues of some photosynthetic complexes in the grana membranes occurs under conditions of high light intensity and triggers a major photoprotection mechanism known as energy dependent nonphotochemical quenching. We have studied the role of protonation in the structural reorganization and thermal stability of isolated grana membranes. The macroorganization of granal membrane fragments in protonated and partly deprotonated state has been mapped by means of atomic force microscopy. The protonation of the photosynthetic complexes has been found to induce large-scale structural remodeling of grana membranes-formation of extensive domains of the major light-harvesting complex of photosystem II and clustering of trimmed photosystem II supercomplexes, thinning of the membrane, and reduction of its size. These events are accompanied by pronounced thermal destabilization of the photosynthetic complexes, as evidenced by circular dichroism spectroscopy and differential scanning calorimetry. Our data reveal a detailed nanoscopic picture of the initial steps of nonphotochemical quenching. PMID- 25692590 TI - In situ determination of structure and fluctuations of coexisting fluid membrane domains. AB - Biophysical understanding of membrane domains requires accurate knowledge of their structural details and elasticity. We report on a global small angle x-ray scattering data analysis technique for coexisting liquid-ordered (Lo) and liquid disordered (Ld) domains in fully hydrated multilamellar vesicles. This enabled their detailed analysis for differences in membrane thickness, area per lipid, hydrocarbon chain length, and bending fluctuation as demonstrated for two ternary mixtures (DOPC/DSPC/CHOL and DOPC/DPPC/CHOL) at different cholesterol concentrations. Lo domains were found to be ~10 A thicker, and laterally up to 20 A(2)/lipid more condensed than Ld domains. Their bending fluctuations were also reduced by ~65%. Increase of cholesterol concentration caused significant changes in structural properties of Ld, while its influence on Lo properties was marginal. We further observed that temperature-induced melting of Lo domains is associated with a diffusion of cholesterol to Ld domains and controlled by Lo/Ld thickness differences. PMID- 25692591 TI - Histones cause aggregation and fusion of lipid vesicles containing phosphatidylinositol-4-phosphate. AB - In a previous article, we demonstrated that histones (H1 or histone octamers) interact with negatively charged bilayers and induce extensive aggregation of vesicles containing phosphatidylinositol-4-phosphate (PIP) and, to a lesser extent, vesicles containing phosphatidylinositol (PI). Here, we found that vesicles containing PIP, but not those containing PI, can undergo fusion induced by histones. Fusion was demonstrated through the observation of intervesicular mixing of total lipids and inner monolayer lipids, and by ultrastructural and confocal microscopy studies. Moreover, in both PI- and PIP-containing vesicles, histones caused permeabilization and release of vesicular aqueous contents, but the leakage mechanism was different (all-or-none for PI and graded release for PIP vesicles). These results indicate that histones could play a role in the remodeling of the nuclear envelope that takes place during the mitotic cycle. PMID- 25692592 TI - Torque generation by axonemal outer-arm dynein. AB - Outer-arm dynein is the main engine providing the motive force in cilia. Using three-dimensional tracking microscopy, we found that contrary to previous reports Tetrahymena ciliary three-headed outer-arm dynein (alphabetagamma) as well as proteolytically generated two-headed (betagamma) and one-headed (alpha) subparticles showed clockwise rotation of each sliding microtubule around its longitudinal axis in microtubule corkscrewing assays. By measuring the rotational pitch as a function of ATP concentration, we also found that the microtubule corkscrewing pitch is independent of ATP concentration, except at low ATP concentrations where the pitch generated by both three-headed alphabetagamma and one-headed alpha exhibited significantly longer pitch. In contrast, the pitch driven by two-headed betagamma did not display this sensitivity. In the assays on lawns containing mixtures of alpha and betagamma at various ratios, the corkscrewing pitch increased dramatically in a nonlinear fashion as the ratio of alpha in the mixture increased. Even small proportions of alpha-subparticle could significantly increase the corkscrewing pitch of the mixture. Our data show that torque generation does not require the three-headed outer-arm dynein (alphabetagamma) but is an intrinsic property of the subparticles of axonemal dyneins and also suggest that each subparticle may have distinct mechanical properties. PMID- 25692593 TI - Comparison of three ionic liquid-tolerant cellulases by molecular dynamics. AB - We have employed molecular dynamics to investigate the differences in ionic liquid tolerance among three distinct family 5 cellulases from Trichoderma viride, Thermogata maritima, and Pyrococcus horikoshii. Simulations of the three cellulases were conducted at a range of temperatures in various binary mixtures of the ionic liquid 1-ethyl-3-methyl-imidazolium acetate with water. Our analysis demonstrates that the effects of ionic liquids on the enzymes vary in each individual case from local structural disturbances to loss of much of one of the enzyme's secondary structure. Enzymes with more negatively charged surfaces tend to resist destabilization by ionic liquids. Specific and unique structural changes in the enzymes are induced by the presence of ionic liquids. Disruption of the secondary structure, changes in dynamical motion, and local changes in the binding pocket are observed in less tolerant enzymes. Ionic-liquid-induced denaturation of one of the enzymes is indicated over the 500 ns timescale. In contrast, the most tolerant cellulase behaves similarly in water and in ionic liquid-containing mixtures. Unlike the heuristic approaches that attempt to predict enzyme stability using macroscopic properties, molecular dynamics allows us to predict specific atomic-level structural and dynamical changes in an enzyme's behavior induced by ionic liquids and other mixed solvents. Using these insights, we propose specific experimentally testable hypotheses regarding the origin of activity loss for each of the systems investigated in this study. PMID- 25692594 TI - Pulse dipolar ESR of doubly labeled mini TAR DNA and its annealing to mini TAR RNA. AB - Pulse dipolar electron-spin resonance in the form of double electron electron resonance was applied to strategically placed, site-specifically attached pairs of nitroxide spin labels to monitor changes in the mini TAR DNA stem-loop structure brought on by the HIV-1 nucleocapsid protein NCp7. The biophysical structural evidence was at Angstrom-level resolution under solution conditions not amenable to crystallography or NMR. In the absence of complementary TAR RNA, double labels located in both the upper and the lower stem of mini TAR DNA showed in the presence of NCp7 a broadened distance distribution between the points of attachment, and there was evidence for several conformers. Next, when equimolar amounts of mini TAR DNA and complementary mini TAR RNA were present, NCp7 enhanced the annealing of their stem-loop structures to form duplex DNA-RNA. When duplex TAR DNA-TAR RNA formed, double labels initially located 27.5 A apart at the 3'- and 5'-termini of the 27-base mini TAR DNA relocated to opposite ends of a 27 bp RNA-DNA duplex with 76.5 A between labels, a distance which was consistent with the distance between the two labels in a thermally annealed 27-bp TAR DNA-TAR RNA duplex. Different sets of double labels initially located 26-27 A apart in the mini TAR DNA upper stem, appropriately altered their interlabel distance to ~35 A when a 27 bp TAR DNA-TAR RNA duplex formed, where the formation was caused either through NCp7-induced annealing or by thermal annealing. In summary, clear structural evidence was obtained for the fraying and destabilization brought on by NCp7 in its biochemical function as an annealing agent and for the detailed structural change from stem-loop to duplex RNA-DNA when complementary RNA was present. PMID- 25692595 TI - Human adenosine A2A receptor binds calmodulin with high affinity in a calcium dependent manner. AB - Understanding how ligands bind to G-protein-coupled receptors and how binding changes receptor structure to affect signaling is critical for developing a complete picture of the signal transduction process. The adenosine A2A receptor (A2AR) is a particularly interesting example, as it has an exceptionally long intracellular carboxyl terminus, which is predicted to be mainly disordered. Experimental data on the structure of the A2AR C-terminus is lacking, because published structures of A2AR do not include the C-terminus. Calmodulin has been reported to bind to the A2AR C-terminus, with a possible binding site on helix 8, next to the membrane. The biological meaning of the interaction as well as its calcium dependence, thermodynamic parameters, and organization of the proteins in the complex are unclear. Here, we characterized the structure of the A2AR C terminus and the A2AR C-terminus-calmodulin complex using different biophysical methods, including native gel and analytical gel filtration, isothermal titration calorimetry, NMR spectroscopy, and small-angle X-ray scattering. We found that the C-terminus is disordered and flexible, and it binds with high affinity (Kd = 98 nM) to calmodulin without major conformational changes in the domain. Calmodulin binds to helix 8 of the A2AR in a calcium-dependent manner that can displace binding of A2AR to lipid vesicles. We also predicted and classified putative calmodulin-binding sites in a larger group of G-protein-coupled receptors. PMID- 25692596 TI - Promiscuous binding of Karyopherinbeta1 modulates FG nucleoporin barrier function and expedites NTF2 transport kinetics. AB - The transport channel of nuclear pore complexes (NPCs) contains a high density of intrinsically disordered proteins that are rich in phenylalanine-glycine (FG) repeat motifs (FG Nups). The FG Nups interact promiscuously with various nuclear transport receptors (NTRs), such as karyopherins (Kaps), that mediate the trafficking of nucleocytoplasmic cargoes while also generating a selectively permeable barrier against other macromolecules. Although the binding of NTRs to FG Nups increases molecular crowding in the NPC transport channel, it is unclear how this impacts FG Nup barrier function or the movement of other molecules, such as the Ran importer NTF2. Here, we use surface plasmon resonance to evaluate FG Nup conformation, binding equilibria, and interaction kinetics associated with the multivalent binding of NTF2 and karyopherinbeta1 (Kapbeta1) to Nsp1p molecular brushes. NTF2 and Kapbeta1 show different long- and short-lived binding characteristics that emerge from varying degrees of molecular retention and FG repeat binding avidity within the Nsp1p brush. Physiological concentrations of NTF2 produce a collapse of Nsp1p brushes, whereas Kapbeta1 binding generates brush extension. However, the presence of prebound Kapbeta1 inhibits Nsp1p brush collapse during NTF2 binding, which is dominated by weak, short-lived interactions that derive from steric hindrance and diminished avidity with Nsp1p. This suggests that binding promiscuity confers kinetic advantages to NTF2 by expediting its facilitated diffusion and reinforces the proposal that Kapbeta1 contributes to the integral barrier function of the NPC. PMID- 25692597 TI - Quantifying the entropy of binding for water molecules in protein cavities by computing correlations. AB - Protein structural analysis demonstrates that water molecules are commonly found in the internal cavities of proteins. Analysis of experimental data on the entropies of inorganic crystals suggests that the entropic cost of transferring such a water molecule to a protein cavity will not typically be greater than 7.0 cal/mol/K per water molecule, corresponding to a contribution of approximately +2.0 kcal/mol to the free energy. In this study, we employ the statistical mechanical method of inhomogeneous fluid solvation theory to quantify the enthalpic and entropic contributions of individual water molecules in 19 protein cavities across five different proteins. We utilize information theory to develop a rigorous estimate of the total two-particle entropy, yielding a complete framework to calculate hydration free energies. We show that predictions from inhomogeneous fluid solvation theory are in excellent agreement with predictions from free energy perturbation (FEP) and that these predictions are consistent with experimental estimates. However, the results suggest that water molecules in protein cavities containing charged residues may be subject to entropy changes that contribute more than +2.0 kcal/mol to the free energy. In all cases, these unfavorable entropy changes are predicted to be dominated by highly favorable enthalpy changes. These findings are relevant to the study of bridging water molecules at protein-protein interfaces as well as in complexes with cognate ligands and small-molecule inhibitors. PMID- 25692598 TI - Structural transitions and interactions in the early stages of human glucagon amyloid fibrillation. AB - A mechanistic understanding of the intermolecular interactions and structural changes during fibrillation is crucial for the design of safe and efficacious glucagon formulations. Amide hydrogen/deuterium exchange with mass spectrometric analysis was used to identify the interactions and amino acids involved in the initial stages of glucagon fibril formation at acidic pH. Kinetic measurements from intrinsic and thioflavin T fluorescence showed sigmoidal behavior. Secondary structural measurement of fibrillating glucagon using far-UV circular dichroism spectroscopy showed changes in structure from random coil -> alpha-helix -> beta sheet, with increase in alpha-helix content during the lag phase followed by increase in beta-sheet content during the growth phase. Hydrogen/deuterium exchange with mass spectrometric analysis of fibrillating glucagon suggested that C-terminal residues 22-29 are involved in interactions during the lag phase, during which N-terminal residues 1-6 showed no changes. Molecular dynamics simulations of glucagon fragments showed C-terminal to C-terminal interactions with greater alpha-helix content for the 20-29 fragment, with hydrophobic and aromatic residues (Phe-22, Trp-25, Val-23, and Met-27) predominantly involved. Overall, the study shows that glucagon interactions during the early phase of fibrillation are mediated through C-terminal residues, which facilitate the formation of alpha-helix-rich oligomers, which further undergo structural rearrangement and elongation to form beta-sheet-rich mature fibrils. PMID- 25692599 TI - Single-molecule imaging at high fluorophore concentrations by local activation of dye. AB - Single-molecule fluorescence microscopy is a powerful tool for observing biomolecular interactions with high spatial and temporal resolution. Detecting fluorescent signals from individual labeled proteins above high levels of background fluorescence remains challenging, however. For this reason, the concentrations of labeled proteins in in vitro assays are often kept low compared to their in vivo concentrations. Here, we present a new fluorescence imaging technique by which single fluorescent molecules can be observed in real time at high, physiologically relevant concentrations. The technique requires a protein and its macromolecular substrate to be labeled each with a different fluorophore. Making use of short-distance energy-transfer mechanisms, only the fluorescence from those proteins that bind to their substrate is activated. This approach is demonstrated by labeling a DNA substrate with an intercalating stain, exciting the stain, and using energy transfer from the stain to activate the fluorescence of only those labeled DNA-binding proteins bound to the DNA. Such an experimental design allowed us to observe the sequence-independent interaction of Cy5-labeled interferon-inducible protein 16 with DNA and the sliding via one-dimensional diffusion of Cy5-labeled adenovirus protease on DNA in the presence of a background of hundreds of nanomolar Cy5 fluorophore. PMID- 25692600 TI - An equilibrium model for the combined effect of macromolecular crowding and surface adsorption on the formation of linear protein fibrils. AB - The formation of linear protein fibrils has previously been shown to be enhanced by volume exclusion or crowding in the presence of a high concentration of chemically inert protein or polymer, and by adsorption to membrane surfaces. An equilibrium mesoscopic model for the combined effect of both crowding and adsorption upon the fibrillation of a dilute tracer protein is presented. The model exhibits behavior that differs qualitatively from that observed in the presence of crowding or adsorption alone. The model predicts that in a crowded solution, at critical values of the volume fraction of crowder or intrinsic energy of the tracer-wall interaction, the tracer protein will undergo an extremely cooperative transition-approaching a step function-from existence as a slightly self-associated species in solution to existence as a highly self associated and completely adsorbed species. Criteria for a valid experimental test of these predictions are presented. PMID- 25692601 TI - Effects of macromolecular crowding on the structure of a protein complex: a small angle scattering study of superoxide dismutase. AB - Macromolecular crowding can alter the structure and function of biological macromolecules. We used small-angle scattering to measure the effects of macromolecular crowding on the size of a protein complex, SOD (superoxide dismutase). Crowding was induced using 400 MW PEG (polyethylene glycol),TEG (triethylene glycol), alpha-MG (methyl-alpha-glucoside), and TMAO (trimethylamine n-oxide). Parallel small-angle neutron scattering and small-angle x-ray scattering allowed us to unambiguously attribute apparent changes in radius of gyration to changes in the structure of SOD. For a 40% PEG solution, we find that the volume of SOD was reduced by 9%. Considering the osmotic pressure due to PEG, this deformation corresponds to a highly compressible structure. Small-angle x ray scattering done in the presence of TEG suggests that for further deformation beyond a 9% decrease in volume-the resistance to deformation may increase dramatically. PMID- 25692602 TI - A novel explanation for observed CaMKII dynamics in dendritic spines with added EGTA or BAPTA. AB - We present a simplified reaction network in a single well-mixed volume that captures the general features of CaMKII dynamics observed during both synaptic input and spine depolarization. Our model can also account for the greater-than control CaMKII activation observed with added EGTA during depolarization. Calcium input currents are modeled after experimental observations, and existing models of calmodulin and CaMKII autophosphorylation are used. After calibration against CaMKII activation data in the absence of chelators, CaMKII activation dynamics due to synaptic input via n-methyl-d-aspartate receptors are qualitatively accounted for in the presence of the chelators EGTA and BAPTA without additional adjustments to the model. To account for CaMKII activation dynamics during spine depolarization with added EGTA or BAPTA, the model invokes the modulation of CaV2.3 (R-type) voltage-dependent calcium channel (VDCC) currents observed in the presence of EGTA or BAPTA. To our knowledge, this is a novel explanation for the increased CaMKII activation seen in dendritic spines with added EGTA, and suggests that differential modulation of VDCCs by EGTA and BAPTA offers an alternative or complementary explanation for other experimental results in which addition of EGTA or BAPTA produces different effects. Our results also show that a simplified reaction network in a single, well-mixed compartment is sufficient to account for the general features of observed CaMKII dynamics. PMID- 25692603 TI - Phosphatase specificity and pathway insulation in signaling networks. AB - Phosphatases play an important role in cellular signaling networks by regulating the phosphorylation state of proteins. Phosphatases are classically considered to be promiscuous, acting on tens to hundreds of different substrates. We recently demonstrated that a shared phosphatase can couple the responses of two proteins to incoming signals, even if those two substrates are from otherwise isolated areas of the network. This finding raises a potential paradox: if phosphatases are indeed highly promiscuous, how do cells insulate themselves against unwanted crosstalk? Here, we use mathematical models to explore three possible insulation mechanisms. One approach involves evolving phosphatase KM values that are large enough to prevent saturation by the phosphatase's substrates. Although this is an effective method for generating isolation, the phosphatase becomes a highly inefficient enzyme, which prevents the system from achieving switch-like responses and can result in slow response kinetics. We also explore the idea that substrate degradation can serve as an effective phosphatase. Assuming that degradation is unsaturatable, this mechanism could insulate substrates from crosstalk, but it would also preclude ultrasensitive responses and would require very high substrate turnover to achieve rapid dephosphorylation kinetics. Finally, we show that adaptor subunits, such as those found on phosphatases like PP2A, can provide effective insulation against phosphatase crosstalk, but only if their binding to substrates is uncoupled from their binding to the catalytic core. Analysis of the interaction network of PP2A's adaptor domains reveals that although its adaptors may isolate subsets of targets from one another, there is still a strong potential for phosphatase crosstalk within those subsets. Understanding how phosphatase crosstalk and the insulation mechanisms described here impact the function and evolution of signaling networks represents a major challenge for experimental and computational systems biology. PMID- 25692604 TI - Quantifying environmental limiting factors on tree cover using geospatial data. AB - Environmental limiting factors (ELFs) are the thresholds that determine the maximum or minimum biological response for a given suite of environmental conditions. We asked the following questions: 1) Can we detect ELFs on percent tree cover across the eastern slopes of the Lake Tahoe Basin, NV? 2) How are the ELFs distributed spatially? 3) To what extent are unmeasured environmental factors limiting tree cover? ELFs are difficult to quantify as they require significant sample sizes. We addressed this by using geospatial data over a relatively large spatial extent, where the wall-to-wall sampling ensures the inclusion of rare data points which define the minimum or maximum response to environmental factors. We tested mean temperature, minimum temperature, potential evapotranspiration (PET) and PET minus precipitation (PET-P) as potential limiting factors on percent tree cover. We found that the study area showed system-wide limitations on tree cover, and each of the factors showed evidence of being limiting on tree cover. However, only 1.2% of the total area appeared to be limited by the four (4) environmental factors, suggesting other unmeasured factors are limiting much of the tree cover in the study area. Where sites were near their theoretical maximum, non-forest sites (tree cover < 25%) were primarily limited by cold mean temperatures, open-canopy forest sites (tree cover between 25% and 60%) were primarily limited by evaporative demand, and closed canopy forests were not limited by any particular environmental factor. The detection of ELFs is necessary in order to fully understand the width of limitations that species experience within their geographic range. PMID- 25692605 TI - Magnetic microrods as a tool for microrheology. AB - Dynamics of superparamagnetic rods in crossed constant and alternating magnetic fields as a function of field frequency are studied and it is shown that above the critical value of the amplitude of the alternating field the rod oscillates around the direction of the alternating field. The fit of the experimentally measured time dependence of the mean orientation angle of the rod allows one to determine the ratio of magnetic and viscous torques which act on the rod. The protocol of microrheological measurements consists of recording the dynamics of the orientation of the rod when the magnetic field is applied at an angle to the rod and observing its relaxation due to the accumulated elastic energy after the field is switched off. The microrheological data obtained are in reasonable agreement with the macrorheological measurements. PMID- 25692606 TI - Ibuprofen for the treatment of patent ductus arteriosus in preterm or low birth weight (or both) infants. AB - BACKGROUND: Indomethacin is used as standard therapy to close a patent ductus arteriosus (PDA) but is associated with reduced blood flow to several organs. Ibuprofen, another cyclo-oxygenase inhibitor, may be as effective as indomethacin with fewer adverse effects. OBJECTIVES: To determine the effectiveness and safety of ibuprofen compared with indomethacin, other cyclo-oxygenase inhibitor, placebo or no intervention for closing a patent ductus arteriosus in preterm, low birth weight, or preterm and low birth weight infants. SEARCH METHODS: We searched The Cochrane Library, MEDLINE, EMBASE, Clincialtrials.gov, Controlled-trials.com, and www.abstracts2view.com/pas in May 2014. SELECTION CRITERIA: Randomised or quasi randomised controlled trials of ibuprofen for the treatment of a PDA in newborn infants. DATA COLLECTION AND ANALYSIS: Data collection and analysis conformed to the methods of the Cochrane Neonatal Review Group. MAIN RESULTS: We included 33 studies enrolling 2190 infants.Two studies compared intravenous (iv) ibuprofen versus placebo (270 infants). In one study (134 infants) ibuprofen reduced the incidence of failure to close a PDA (risk ratio (RR) 0.71, 95% confidence interval (CI) 0.51 to 0.99; risk difference (RD) -0.18, 95% CI -0.35 to -0.01; number needed to treat for an additional beneficial outcome (NNTB) 6, 95% CI 3 to 100). In one study (136 infants), ibuprofen reduced the composite outcome of infant mortality, infants who dropped out, or infants who required rescue treatment (RR 0.58, 95% CI 0.38 to 0.89; RD -0.22, 95% CI -0.38 to -0.06; NNTB 5, 95% CI 3 to 17). One study (64 infants) compared oral ibuprofen with placebo and noted a significant reduction in failure to close a PDA (RR 0.26, 95% CI 0.11 to 0.62; RD -0.44, 95% CI -0.65 to -0.23; NNTB 2, 95% CI 2 to 4).Twenty-one studies (1102 infants) reported failure rates for PDA closure with ibuprofen (oral or iv) compared with indomethacin (oral or iv). There was no significant difference between the groups (typical RR 1.00, 95% CI 0.84 to 1.20; I(2) = 0%; typical RD 0.00, 95% CI -0.05 to 0.05; I(2) = 0%). The risk of developing necrotising enterocolitis (NEC) was reduced for ibuprofen (16 studies, 948 infants; typical RR 0.64, 95% CI 0.45 to 0.93; typical RD -0.05, 95% CI -0.08 to -0.01; NNTB 20, 95% CI 13 to 100; I(2) = 0% for both RR and RD). The duration of ventilatory support was reduced with ibuprofen (oral or iv) compared with iv or oral indomethacin (six studies, 471 infants; mean difference (MD) -2.4 days, 95% CI 3.7 to -1.0; I(2) = 19%).Eight studies (272 infants) reported on failure rates for PDA closure in a subgroup of the above studies comparing oral ibuprofen with indomethacin (oral or iv). There was no significant difference between the groups (typical RR 0.96, 95% CI 0.73 to 1.27; typical RD -0.01, 95% CI -0.12 to 0.09). The risk of NEC was reduced with oral ibuprofen compared with indomethacin (oral or iv) (seven studies, 249 infants; typical RR 0.41, 95% CI 0.23 to 0.73; typical RD -0.13, 95% CI -0.22 to -0.05; NNTB 8, 95% CI 5 to 20; I(2) = 0% for both RR and RD). There was a decreased risk of failure to close a PDA with oral ibuprofen compared with iv ibuprofen (four studies, 304 infants; typical RR 0.41, 95% CI 0.27 to 0.64; typical RD -0.21, 95% CI -0.31 to -0.12; NNTB 5, 95% CI 3 to 8). Transient renal insufficiency was less common in infants who received ibuprofen compared with indomethacin. High dose versus standard dose of iv ibuprofen, early versus expectant administration of iv ibuprofen, echocardiographically guided iv ibuprofen treatment vs. standard iv ibuprofen treatment and continuous infusion of ibuprofen vs. intermittent boluses of ibuprofen and long-term follow-up were studied in too few trials to draw any conclusions. AUTHORS' CONCLUSIONS: Ibuprofen is as effective as indomethacin in closing a PDA and currently appears to be the drug of choice. Ibuprofen reduces the risk of NEC and transient renal insufficiency. Oro-gastric administration of ibuprofen appears as effective as iv administration. To make further recommendations, studies are needed to assess the effectiveness of high-dose versus standard-dose ibuprofen, early versus expectant administration of ibuprofen, echocardiographically guided versus standard iv ibuprofen, and continuous infusion versus intermittent boluses of ibuprofen. Studies are lacking evaluating the effect of ibuprofen on longer-term outcomes in infants with PDA. PMID- 25692607 TI - A unified model of shoot tropism in plants: photo-, gravi- and Propio-ception. AB - Land plants rely mainly on gravitropism and phototropism to control their posture and spatial orientation. In natural conditions, these two major tropisms act concurrently to create a photogravitropic equilibrium in the responsive organ. Recently, a parsimonious model was developed that accurately predicted the complete gravitropic and proprioceptive control over the movement of different organs in different species in response to gravitational stimuli. Here we show that the framework of this unifying graviproprioceptive model can be readily extended to include phototropism. The interaction between gravitropism and phototropism results in an alignment of the apical part of the organ toward a photogravitropic set-point angle. This angle is determined by a combination of the two directional stimuli, gravity and light, weighted by the ratio between the gravi- and photo-sensitivities of the plant organ. In the model, two dimensionless numbers, the graviproprioceptive number B and the photograviceptive number M, control the dynamics and the shapes of the movement. The extended model agrees well with two sets of detailed quantitative data on photogravitropic equilibrium in oat coleoptiles. It is demonstrated that the influence of light intensity I can be included in the model in a power-law-dependent relationship M(I). The numbers B and M and the related photograviceptive number D are all quantitative genetic traits that can be measured in a straightforward manner, opening the way to the phenotyping of molecular and mechanical aspects of shoot tropism. PMID- 25692608 TI - The Efficacy and Safety of Evekeo, Racemic Amphetamine Sulfate, for Treatment of Attention-Deficit/Hyperactivity Disorder Symptoms: A Multicenter, Dose-Optimized, Double-Blind, Randomized, Placebo-Controlled Crossover Laboratory Classroom Study. AB - OBJECTIVE: The study goal was to determine the efficacy and safety of an optimal dose of Evekeo, racemic amphetamine sulfate, 1:1 d-amphetamine and l-amphetamine (R-AMPH), compared to placebo in treating children with attention deficit/hyperactivity disorder (ADHD) in a laboratory classroom setting. METHODS: A total of 107 children ages 6-12 years were enrolled in this multicenter, dose optimized, randomized, double-blind, placebo-controlled crossover study. After 8 weeks of open-label dose optimization, 97 subjects were randomized to 2 weeks of double-blind treatment in the sequence of R-AMPH followed by placebo (n=47) or placebo followed by R-AMPH (n=50). Efficacy measures included the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) Rating Scale and Permanent Product Measure of Performance (PERMP) administered predose and at 0.75, 2, 4, 6, 8, and 10 hours postdose on 2 laboratory classroom days. Safety assessments included physical examination, chemistry, hematology, vital signs, and treatment-emergent adverse events (TEAEs). RESULTS: Compared to placebo, a single daily dose of R AMPH significantly improved SKAMP-Combined scores (p<0.0001) at each time point tested throughout the laboratory classroom days, with effect onset 45 minutes postdose and extending through 10 hours. R-AMPH significantly improved PERMP number of problems attempted and correct (p<0.0001) throughout the laboratory classroom days. During the twice-daily dose-optimization open-label phase, improvements were observed with R-AMPH in scores of the ADHD-Rating Scale IV and Clinical Global Impressions Severity and Improvement Scales. TEAEs and changes in vital signs associated with R-AMPH were generally mild and not unexpected. The most common TEAEs in the open-label phase were decreased appetite (27.6%), upper abdominal pain (14.3%), irritability (14.3%), and headache (13.3%). CONCLUSIONS: Compared to placebo, R-AMPH was effective in treating children aged 6-12 years with ADHD, beginning at 45 minutes and continuing through 10 hours postdose, and was well tolerated. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01986062. https://clinicaltrials.gov/ct2/show/NCT01986062. PMID- 25692609 TI - How should I treat a complex critical left main bifurcation lesion in a patient with poor left ventricular function, an occluded dominant right coronary artery and severe peripheral vascular disease? PMID- 25692610 TI - One-year clinical outcomes of the STENTYS Self-Apposing coronary stent in patients presenting with ST-segment elevation myocardial infarction: results from the APPOSITION III registry. AB - AIMS: The aim of APPOSITION III was to evaluate the feasibility and performance of the STENTYS Self-Apposing stent (STENTYS S.A., Paris, France) in the setting of primary percutaneous coronary intervention (PCI). METHODS AND RESULTS: APPOSITION III was an international, prospective, multicentre registry. The study population consisted of 965 patients. The rate of the primary endpoint major adverse cardiac events (MACE), defined as the composite of cardiac death, recurrent target vessel myocardial infarction (TV-MI), and clinically driven target lesion revascularisation (CD-TLR), at one year was 9.3%. One-year cardiac death rate was 2.0%, TV-MI rate was 1.3%, CD-TLR rate was 7.4% and definite/probable stent thrombosis (ST) rate was 3.5% (definite ST 2.8%). An interim safety analysis of in-hospital outcomes in the first 400 patients showed higher event rates if post-dilation was not performed, and post-dilations became highly recommended in the remaining cohort. Patients undergoing post-dilation eventually showed a numerically lower one-year MACE rate (8.4% vs. 11.3%, p=0.137). One-year TV-MI (0.8% vs. 2.5%, p=0.027) and definite ST (1.9% vs. 5.0%, p=0.010) rates were significantly lower if post-dilation was performed, with the divergence occurring at <30 days. CONCLUSIONS: The use of the STENTYS Self Apposing stent in the setting of primary PCI was feasible and associated with acceptable cardiovascular event rates which improved when post-dilation was performed. PMID- 25692611 TI - Paclitaxel-coated balloon catheter compared with drug-eluting stent for drug eluting stent restenosis in routine clinical practice. AB - AIMS: The aim of this study was to compare the efficacy between paclitaxel-coated balloon (PCB) and drug-eluting stent (DES) implantation for the treatment of DES restenosis in complex situations. METHODS AND RESULTS: Data of patients who received revascularisation for DES restenosis between 2004 and 2011 were collected. A total of 683 patients with 777 lesions were analysed in this study (306 lesions treated by PCB, 471 lesions by DES). The use of PCB or DES was at the discretion of the operator. Angiographic outcomes at six to eight months and clinical outcomes at 12-month follow-up were compared between groups. The primary outcome was binary restenosis. Cox regression analysis with propensity score adjustment suggested that there were no significant differences between the two groups with respect to binary restenosis, target lesion revascularisation (TLR), and major adverse cardiac events. As for the angiographic endpoints, subgroup analysis was performed for several parameters. There was a significant trend favouring PCB with respect to binary restenosis and TLR in non-focal type lesions and bifurcation lesions. CONCLUSIONS: Angiographic and clinical outcomes in the PCB group were similar to those in the repeat DES group. PCB seemed to offer more favourable results in non-focal type lesions and bifurcation lesions. PMID- 25692612 TI - Optical coherence tomography appraisal of residual thrombus burden in patients with ST-segment elevation myocardial infarction undergoing intraprocedural versus post-stenting prolonged bivalirudin infusion. Rationale and design of the MATRIX (Minimizing Adverse Haemorrhagic Events by TRansradial Access Site and angioX) OCT substudy. AB - AIMS: Residual thrombus accumulation around stent struts has been observed after the end of primary PCI and may represent a risk factor for acute stent thrombosis. The aim of this study is to test whether a strategy of prolonged bivalirudin infusion may reduce thrombosis of stent struts as compared to an intraprocedural only administration in subjects undergoing primary PCI. METHODS AND RESULTS: One hundred and sixty patients will be selected from the MATRIX (Minimizing Adverse Haemorrhagic Events by TRansradial Access Site and angioX) study with all the following inclusion criteria: a) STEMI patients undergoing primary PCI with stent implantation, b) randomisation to standard or prolonged bivalirudin treatment arm, and c) at least one critical (>70%) stenosis of non infarct-related coronary vessels suitable for staged PCI. Optical coherence tomography (OCT) of the infarct-related artery will be performed at the end of primary PCI and at the time of staged PCI which will be performed three to five days after the index procedure. The percentage difference in minimal flow area and in the number of stent cross-sections with a thrombotic area >5% will be measured at the end of primary PCI and at the time of staged PCI. CONCLUSIONS: The MATRIX OCT substudy will establish whether prolonging the infusion of bivalirudin after the end of primary PCI may reduce the amount of residual thrombotic material on stent struts. The effect of the long-infusion strategy on clinical outcome will be elucidated by the MATRIX study. PMID- 25692613 TI - Use of a temporary inferior vena cava filter during pregnancy in patients with thromboembolic events. AB - There are circumstances in the management of thromboembolic events during pregnancy when anticoagulant therapy is either contraindicated or not advisable, such as when pulmonary embolism (PE) or deep venous thrombosis is diagnosed close to term, given the risk of bleeding during delivery. In these cases, the thromboembolic risk can be controlled using temporary inferior vena cava filters (T-IVCFs). We present the case of a pregnant woman with thrombophilia who remained at rest for eight weeks due to an amniotic prolapse and for whom the placement of a T-IVCF was decided at 32 weeks' gestation after anticoagulant therapy had failed. An emergency caesarean section was performed at 33 weeks' gestation due to placental abruption following the spontaneous onset of preterm labour. The risk of bleeding during delivery when high doses of heparin are used, and the risk of PE when the heparin dose is decreased, needs to be evaluated versus the risks related to T-IVCF placement procedure and, as such, a review of the published experience in this field is warranted. We have concluded that T IVCFs can be a safe alternative treatment for pregnant women in whom anticoagulation therapy is either contraindicated or not advisable. PMID- 25692614 TI - Can technique used for gastrostomy tube placement reduce the risk of gastrostomy site metastasis in head and neck cancer patients? PMID- 25692615 TI - Development of the family symptom inventory: a psychosocial screener for children with hematology/oncology conditions. AB - A growing body of literature has begun to underscore the importance of integrating family-based comprehensive psychological screening into standard medical care for children with oncology and hematology conditions. There are no known family-based measures designed to screen for clinically significant emotional and behavioral concerns in pediatric oncology and hematology patients. The aim of this study was to develop and evaluate the Family Symptom Inventory (FSI), a brief screener of patient and family member psychological symptoms. The FSI also screens for common comorbid physical symptoms (pain and sleep disturbance) and is designed for use at any point during treatment and follow-up. A total of 488 caregivers completed the FSI during regular hematology/oncology visits for 193 cancer, 219 sickle cell disease, and 76 hematology pediatric patients. Exploratory factor analysis, confirmatory factor analysis, and tests of reliability and preliminary validity were conducted. Exploratory factor analysis suggested a 34-item, 4-factor solution, which was confirmed in an independent sample using confirmatory factor analysis (factor loadings=0.49 to 0.88). The FSI demonstrated good internal reliability (alpha's=0.86 to 0.92) and good preliminary validity. Regular psychosocial screening throughout the course of treatment and follow-up may lead to improved quality of care for children with oncology and hematology conditions. PMID- 25692616 TI - Epstein-barr virus-associated extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT Lymphoma) arising in the parotid gland of a child with ataxia telangiectasia. AB - Hematologic malignancies, in particular T-cell lymphomas/leukemias, are prevalent in patients with ataxia telangiectasia (AT), with most reported cases being clinically aggressive and high grade. Epstein-Barr virus (EBV) is often associated with lymphoid proliferations/neoplasms arising in immunodeficient patients. Reports of low-grade B-cell neoplasms in the ataxia telangiectasia population are extremely rare. Here, we describe a case of EBV-associated extranodal marginal zone lymphoma (mucosa-associated lymphoid tissue lymphoma) of the parotid gland in a 16-year-old boy with AT. In addition, we review the literature of hematologic malignancies in the AT population as well as the occurrence of EBV in mucosa-associated lymphoid tissue lymphoma. PMID- 25692617 TI - Crosstalk between Wnt/beta-catenin and Hedgehog/Gli signaling pathways in colon cancer and implications for therapy. AB - Wnt/beta-catenin and Hedgehog/Gli signalings play key roles in multiple biogenesis such as embryonic development and tissue homeostasis. Dysregulations of these 2 pathways are frequently found in most cancers, particularly in colon cancer. Their crosstalk has been increasingly appreciated as an important mechanism in regulating colon cancer progression. Our studies into the link between Wnt/beta-catenin and Hedgehog/Gli signalings in colon cancer revealed several possible crosstalk points and suggested potential therapeutic strategies for colon cancer. PMID- 25692618 TI - Structural studies reveal thalidomide's mechanism of action and clinical effects: crystal clear or clearly complexed? AB - Another piece of the thalidomide puzzle is unraveled through structural studies of thalidomide and its derivatives bound to its protein target cereblon. Two recent studies published in Nature (Fischer et al.) and Nature Structural & Molecular Biology (Chamberlain et al.) have shed light on the drug's mechanisms of action and its complex biological effects. PMID- 25692619 TI - Therapeutic approach guided by genetic alteration: use of MTOR inhibitor in renal medullary carcinoma with loss of PTEN expression. AB - Renal Medullary Cancer (RMC) is a rare and aggressive type of renal cell cancer that presents predominantly in patients with sickle cell hemoglobinopathies, and is typically metastatic at the time of presentation. Although platinum based chemotherapeutic regimens have recently emerged as the best option for producing a clinically significant response as reported in various case series, the response is far from satisfactory, as most RMC patients still succumb to their disease within a year of diagnosis. There is currently no standard of care for treatment of this disease. We report, to our knowledge, the first case of RMC where in molecular characterization of the tumor was used to guide therapy. In our patient, molecular analysis identified a decreased expression of Ribonucleotide Reductase M1(RRM1) and phosphatase and tensin homolog (PTEN). Based on these results of PTEN deficiency, we started our patient on everolimus (an MTOR inhibitor) maintenance after treating him with an induction chemotherapy regimen of Paclitaxel-Cisplatin-Gemcitabine (PCG). His tumor responded to induction therapy and he went into complete remission and remained in remission for 7 months. He is now alive about 14 months from his diagnosis and is asymptomatic with minimal disease. The rarity of RMC makes it very difficult to do any meaningful clinical trials in this group of patients. The overall prognosis for RMC remains very poor and knowledge about driver mutations may help in guiding therapy to improve survival in this select group of patients, where there is dearth of available therapies. PMID- 25692620 TI - The preclinical evaluation of the dual mTORC1/2 inhibitor INK-128 as a potential anti-colorectal cancer agent. AB - The colorectal cancer is the leading contributor of cancer-related mortality. Mammalian target of rapamycin (mTOR), existing in 2 complexes (mTORC1/2), is frequently dysregulated and constitutively activated in colorectal cancers. It represents an important drug target. Here we found that INK-128, the novel ATP competitive kinase inhibitor of mTOR, blocked both mTORC1 and mTORC2 activation in colorectal cancer cells (both primary and transformed cells). The immunoprecipitation results showed that the assembly of mTORC1 (mTOR-Raptor association) and mTORC2 (mTOR-Rictor-Sin1 association) was also disrupted by INK 128. INK-128 inhibited colorectal cancer cell growth and survival, and induced both apoptotic and non-apoptotic cancer cell death. Further, INK-128 showed no effect on Erk/MAPK activation, while MEK/Erk inhibition by MEK-162 enhanced INK 128-induced cytotoxicity in colorectal cancer cells. Meanwhile, INK-128 downregulated Fascin1 (FSCN1)/E-Cadherin expressions and inhibited HT-29 cell in vitro migration. In vivo, daily INK-128 oral administration inhibited HT-29 xenograft growth in mice, which was further enhanced by MEK-162 administration. Finally, we found that INK-128 sensitized 5-fluorouracil-(5-FU)-mediated anti-HT 29 activity in vivo and in vitro. Thus, our preclinical studies strongly suggest that INK-128 might be investigated for colorectal cancer treatment in clinical trials. PMID- 25692621 TI - Interplay between VEGF-A and cMET signaling in human vestibular schwannomas and schwann cells. AB - Vestibular schwannoma (VS), the fourth most common intracranial tumor, arises from the Schwann cells of the vestibular nerve. Although several pathways have been independently implicated in VS pathobiology, interactions among these pathways have not been explored in depth. We have investigated the potential cross-talk between hepatocyte growth factor (HGF) and vascular endothelial growth factor-A (VEGF-A) in human VS, an interaction that has been described in other physiological and pathological cell types. We affirmed previous findings that VEGF-A signaling is aberrantly upregulated in VS, and established that expression of HGF and its receptor cMET is also significantly higher in sporadic VS than in healthy nerves. In primary human VS and Schwann cell cultures, we found that VEGF A and HGF signaling pathways modulate each other. siRNAs targeting cMET decreased both cMET and VEGF-A protein levels, and siRNAs targeting VEGF-A reduced cMET expression. Additionally, siRNA-mediated knockdown of VEGF-A or cMET and pharmacologic inhibition of cMET decreased cellular proliferation in primary human VS cultures. Our data suggest cross-talk between these 2 prominent pathways in VS and highlight the HGF/cMET pathway as an additional important therapeutic target in VS. PMID- 25692622 TI - A new vaccine escape mutant of hepatitis B virus causes occult infection. AB - There is growing public concern regarding assay sensitivity to HBsAg mutants in clinical diagnosis and vaccine escape. The aim of this study is to introduce a new HBsAg mutant strain. The serum samples were those of patient X at the age of 3 months and 3 years respectively, and of her mother immediately before parturition, which were used to amplify the HBsAg-coding DNA fragments by PCR. The HBsAg DNA sequences were translated into their corresponding amino acid sequences and then aligned in pubmed with nucleotide blast. The sequencing data of S coding regions shows that patient X has been infected by a new HBV variant with an A to C substitution at nt431, resulting in an Asp(GAC)to Ala(GCC) substitution at aa144 of major protein; CC to AA substitution at nt359 and nt360, resulting in an Pro(CCC) to Gln(CAA) substitution at aa120 of pre "a" epitope; A to G substitution at nt491, resulting in an Glu(GAG) to Gly(GGG) substitution at aa164 of post "a" epitope. Three new mutations (S171F, S174N and Q181R) at the antigenic epitopes of HBV presented by HLA class I molecules are found. The HBV mutant strain causes vaccine escape and occult infection. PMID- 25692623 TI - Transoral robotic surgery for laryngeal cancer. AB - PURPOSE OF REVIEW: Transoral robotic surgery (TORS) has seen substantial surge since its introduction in around 2007. Although initially described for cancer of the oropharynx, advances in robotic instrumentation and endoscopy have allowed for application of TORS toward laryngeal cancer. This review discusses the recent published experience of TORS for laryngeal cancer. RECENT FINDINGS: TORS supraglottic laryngectomy continues to be the most frequent application of robotic surgery for laryngeal cancer. A number of case series have described the positive experience with TORS supraglottic laryngectomy with both oncologic and functional outcomes rivaling alternative therapy options. TORS total laryngectomy also continues to be applied in selective cases for laryngeal cancer. The objectives of TORS total laryngectomy is to reduce the size of the resultant pharyngotomy and to limit the lateral exposure of the cervical vessels. Although limited in numbers, TORS total laryngectomy appears to be a technique of increasing application. TORS approach for primary glottic cancer has also been described in limited case series. Although the majority of patients demonstrated positive outcomes following TORS glottic cordectomy, this technique may still require additional advancement of robotic technology before widespread application is seen. SUMMARY: A TORS approach for laryngeal cancer is increasing in application and utility. The major surgical procedures described to date include supraglottic laryngectomy, total laryngectomy, and glottic cordectomy with promising results. PMID- 25692624 TI - Role of hemithyroidectomy in differentiated thyroid cancer. AB - PURPOSE OF REVIEW: The incidence of differentiated thyroid cancer (DTC), especially among small tumors, is increasing worldwide, despite the fact that the mortality rate from thyroid cancer remains stable. Total thyroidectomy with or without radioiodine therapy is actually the standard treatment. In the last 2 decades, several studies have shown that lobectomy could be an alternative to total thyroidectomy in low-risk DTC without compromising overall survival. The aim of this article was to assess the role of conservative surgery (hemithyroidectomy) in DTC reviewing the literature data. RECENT FINDINGS: Recent advances in diagnostic techniques allow treatment to be tailored to patients' needs. The latest consensus guidelines suggest that patients with high-risk tumors should undergo total thyroidectomy, whereas patients with small, low-risk, node-negative DTC may be candidates for conservative surgery. Careful risk evaluation and stratification makes it possible to individualize treatment, avoid overtreatment and guarantee a good long-term prognosis with low recurrence risk. Excellent prognosis of DTC would require large sample sizes and long-term follow up for prospective trials comparing the outcomes of total thyroidectomy vs. lobectomy; however, there are several remarkable retrospective studies. SUMMARY: Based on current clinical data, a conservative surgery might be appropriate for patients with low-risk DTC. PMID- 25692625 TI - Management of the neck in maxillary sinus carcinomas. AB - PURPOSE OF REVIEW: To discuss and review the role for elective treatment of the neck in maxillary squamous cell carcinoma. Improvements in survival have been seen because of improved local therapies and control; therefore, the treatment of the neck has become a topic of debate. RECENT FINDINGS: The risk of occult metastases in neck nodes is higher for T3-4 tumors. The rate of nodal relapse in the N0 neck without elective treatment is 8-15%. With elective irradiation the nodal relapse rate decreases. However, most nodal relapses are accompanied by local failure or distant disease. Local failure remains the most common site of failure and cause of death in this patient population. SUMMARY: Treatment failure occurs overall in 62% of all patients, with local recurrence by far the most common site of treatment failure, which is rarely amenable to salvage therapy. Therefore, elective neck irradiation is not routinely indicated in the clinically N0 neck; those that recur only in the neck can be surgically salvaged more than 50% of the time. PMID- 25692626 TI - Gastrostomy in head and neck cancer: current literature, controversies and research. AB - PURPOSE OF REVIEW: This article explores the literature on the role of gastrostomy tube feeding use in the management of head and neck cancer, with special attention to its indications, timing of insertion, advantages, complications and quality of life issues. RECENT FINDINGS: The current guidelines in place across different countries and two ongoing randomized controlled trials are discussed in detail, and placed in the context of current evidence. SUMMARY: There remains a lack of consensus about when and which enteral feeding routes (gastrostomy or nasogastric tube) should be used and controversy about the long term effects on swallowing function as well as quality of life for patients. Local guidelines should be used or generated to guide practice or patients enrolled into existing trials until higher level evidence is generated. PMID- 25692627 TI - Recent advances in surgical management of parapharyngeal space tumors. AB - PURPOSE OF REVIEW: To summarize nuances in the surgical management of parapharyngeal space (PPS) tumors aimed to reduce postoperative sequelae without affecting oncologic outcomes. RECENT FINDINGS: The contemporary trend in surgery of PPS tumors is to develop minimally invasive approaches that allow tumor resection without the need for mandibulotomy or lateral skull base approaches. This can be obtained by refining well established surgical routes like the transcervical, improving those with limited applications like the transoral, and developing novel corridors like the transnasal (or the transoral/transvestibular). Therefore, careful surgical planning is mandatory in order to tailor treatment according to the patient and characteristics of the tumor, in view of a wide and heterogeneous choice of techniques (to be employed alone or in combination). SUMMARY: Technical refinements of transcervical and transoral approaches may lead to reduction in the rate of mandibulotomy performed for benign PPS tumors. This is also true when considering the possibility of combined approaches that provide excellent exposure and management of the upper PPS up to the skull base. PMID- 25692628 TI - Scapular tip free flap in head and neck reconstruction. AB - PURPOSE OF REVIEW: This article revises the present literature on the scapular tip free flap in head and neck reconstruction. RECENT FINDINGS: Scapular tip flap has been recently proposed as a good option for reconstruction of multiple areas of the head and neck including maxilla, mandible, scalp, and larynx. SUMMARY: This flap offers unique advantages such as the long pedicle, the possibility of harvesting chimeric flaps with multiple components, the reliability of the anatomy, and the good amount of bone that can be included in the flap. For these reasons, it is particularly useful in elderly patients or in reconstruction of those defects that require independent flap paddles, in particular for maxillary and mandibular reconstructions. PMID- 25692629 TI - Primary surgery versus (chemo)radiotherapy in oropharyngeal cancer: the radiation oncologist's and medical oncologist's perspectives. AB - PURPOSE OF REVIEW: Radiotherapy is the traditional treatment for oropharyngeal cancer (OPC) because of its ability to preserve anatomic form and function compared with other conventional curative options. Recently, transoral robotic surgery (TORS) and transoral laser microsurgery (TLM) have emerged prominently for T1-T2 OPC. This review summarizes the recent literature pertaining to OPC outcomes following primary TORS/TLM versus primary radiotherapy with or without chemotherapy and addresses controversies surrounding indications for adjuvant treatment following TORS/TLM. RECENT FINDINGS: Articles regarding OPC outcomes after primary TORS/TLM or radiotherapy/chemoradiotherapy published over the past 12 months were identified. TORS/TLM studies reported encouraging oncologic and functional outcomes. Primary radiotherapy alone showed exemplary results for a similar group of patients. However, comparisons of outcomes between these two primary modalities rely on historical data vulnerable to selection bias, even in a matched cohort study. The majority of cases treated with TORS/TLM also received adjuvant treatment. Soft tissue necrosis complicating this approach has also been reported. Controversies exist regarding the definition of resection margin status, prognostic value of extracapsular spread in human papillomavirus-related OPC and indications for adjuvant treatment following TORS/TLM. SUMMARY: TORS/TLM is an attractive approach for selected T1-T2 OPC, but its role should be refined based on a high level of evidence. PMID- 25692630 TI - Contemporary management of clival chordomas. AB - PURPOSE OF REVIEW: Clival chordomas are rare malignant tumors associated with a poor prognosis. In this article, we review the current literature to identify a variety of strategies that provide guidelines toward the optimal management for this aggressive tumor. RECENT FINDINGS: Molecular disease, particularly, the development of characterized chordoma cell lines, has become one of the new cornerstones for the histological diagnosis of chordomas and for the development of effective chemotherapeutic agents against this tumor. Brachyury, a transcription factor in notochord development, seems to provide an excellent diagnostic marker for chordoma and may also prove to be a valuable target for chordoma therapy. Aggressive cytoreductive surgery aiming for gross total resection with maintenance of key neurovascular structures, followed by proton beam or hadron radiation, provides the best local recurrence and overall survival rates. SUMMARY: Clival chordomas are locally aggressive tumors that are challenging to treat because of their unique biology, proximity to key neurovascular structures and poor prognosis. Currently, chordomas are optimally managed with aggressive surgery, whilst preserving key structures, and postoperative radiation in a multidisciplinary setting with an experienced team. The advancement of molecular techniques offers exciting future diagnostic and therapeutic options in the management of chordomas. PMID- 25692631 TI - Primary malignant parotid epithelial neoplasm: nodal metastases and management. AB - PURPOSE OF REVIEW: This article presents a summary of the recent publications on the diagnosis and management of primary malignant parotid epithelial neoplasm, with special emphasis on evaluation and treatment of nodal metastases. RECENT FINDINGS: Pathologists are challenged with making a diagnosis, classification and grading of salivary gland cancers. The unpredictable behaviour of this disease has been documented by clinicians reporting aggressiveness and variations in disease patterns within a single-cancer subgroup. Surgeons have identified a high incidence of occult nodal disease both at the primary site and the neck, which has frequently been understaged both clinically and on imaging in the presurgical workup. SUMMARY: The significance of a high incidence of occult nodal disease both at the primary site and the neck is that a more aggressive therapeutic strategy must be directed/advised by the multidisciplinary clinical team, to the disease located in the head and neck, thus improving likely cure, preventing local and distant disease failure. PMID- 25692632 TI - Transoral robotic surgery for oropharyngeal squamous cell carcinoma. AB - PURPOSE OF REVIEW: This article reviews recent information on outcomes, indications, techniques, and cost of transoral robotic surgery (TORS) for oropharyngeal squamous cell carcinoma (OPSCC). New information on comparisons between TORS, conventional surgery techniques, and chemoradiation is also highlighted. RECENT FINDINGS: Consistent with prior reports, recent studies show excellent oncologic and functional outcomes with TORS for OPSCC. As surgeon experience with this relatively new technique has increased, outcomes continue to improve and complications are rare. TORS may also have a role in management of carcinoma of unknown primary site. Compared with other treatment modalities, TORS for OPSCC may result in similar oncologic outcomes, improved functional outcomes, and decreased cost. SUMMARY: TORS for OPSCC results in excellent functional and oncologic outcomes. Randomized clinical trials are needed to compare TORS with adjuvant therapy to definitive chemoradiation and will determine whether adjuvant therapy and associated morbidity can be decreased without compromising survival. PMID- 25692633 TI - A cnidarian homologue of an insect gustatory receptor functions in developmental body patterning. AB - Insect gustatory and odorant receptors (GRs and ORs) form a superfamily of novel transmembrane proteins, which are expressed in chemosensory neurons that detect environmental stimuli. Here we identify homologues of GRs (Gustatory receptor like (Grl) genes) in genomes across Protostomia, Deuterostomia and non-Bilateria. Surprisingly, two Grls in the cnidarian Nematostella vectensis, NvecGrl1 and NvecGrl2, are expressed early in development, in the blastula and gastrula, but not at later stages when a putative chemosensory organ forms. NvecGrl1 transcripts are detected around the aboral pole, considered the equivalent to the head-forming region of Bilateria. Morpholino-mediated knockdown of NvecGrl1 causes developmental patterning defects of this region, leading to animals lacking the apical sensory organ. A deuterostome Grl from the sea urchin Strongylocentrotus purpuratus displays similar patterns of developmental expression. These results reveal an early evolutionary origin of the insect chemosensory receptor family and raise the possibility that their ancestral role was in embryonic development. PMID- 25692634 TI - Treatment of abdominal cellulite and circumference reduction with radiofrequency and dynamic muscle activation. AB - BACKGROUND: Cellulite is a frequent skin condition for which treatment remains a challenge. A wide variety of treatments are available but most procedures offer suboptimal clinical effect and/or delayed therapeutic outcome. Only few therapeutic options have proven efficacy in the treatment of cellulite. OBJECTIVE: To determine the efficacy and the safety profiles of radiofrequency and dynamic muscle activation technology in treatment of abdominal cellulite and circumference reduction. METHODS: Twenty-five females with abdominal cellulite received 6 weekly radiofrequency and dynamic muscle activation treatments. Treatment areas included the abdomen and both sides of flanks. Subjects were evaluated using standardized photographs, and measurements of body weight and abdominal circumference at baseline, before every treatment visit, and 1 week and four weeks after the final treatment. Subcutaneous tissue thickness was recorded by ultrasound at baseline and 4 weeks after completion of treatment protocol. Physicians' evaluation and patient's satisfaction of clinical improvement were also measured. RESULTS: All subjects completed the treatment protocol and attended every follow-up visits. There was significant abdominal circumference reduction of 2.96 and 2.52 cm at 1-, and 4-week follow-up visits (p < 0.05), respectively. At four weeks after the last treatment, the average circumferential reduction was sustained. Most of the patients were rated to have 25-49% improvement at 5th treatment, and 1- and 4-week follow-up visits. Ninety-two percent of the patients were satisfied with the treatment outcome. CONCLUSIONS: Radiofrequency provided beneficial effects on the reduction of abdomen and cellulite appearance. The benefit of muscle activation is yet to be determined. PMID- 25692635 TI - If you can't measure it... PMID- 25692636 TI - Advancing nursing education through partnerships. PMID- 25692637 TI - Five rules for scheduling 12-hour night shifts. PMID- 25692638 TI - Measures that matter. PMID- 25692639 TI - The urgent need for innovation in I.V. smart pumps. PMID- 25692640 TI - Making an impact: can a training program for leaders improve HCAHPS scores? PMID- 25692642 TI - Metrics for nurse managers. PMID- 25692643 TI - What prevents interprofessional care? PMID- 25692644 TI - Exemplary leadership: how style and culture predict organizational outcomes. PMID- 25692645 TI - Tips for interim nurse leader success. PMID- 25692646 TI - Help for a unit-based council. PMID- 25692647 TI - NEDD4 controls intestinal stem cell homeostasis by regulating the Hippo signalling pathway. AB - The Hippo pathway plays crucial roles in regulating organ size and stem cell homeostasis. Although the signalling cascade of the core Hippo kinases is relatively well understood, little is known about the mechanisms that modulate the activity of the Hippo pathway. Here, we report identification of NEDD4, a HECT-type E3 ubiquitin ligase, as a regulatory component of the Hippo pathway. We demonstrate that NEDD4 ubiquitylates and destabilizes WW45 and LATS kinase, both of which are required for active Hippo signalling. Interestingly, MST1 protects WW45, but not LATS2, against NEDD4. We also provide evidence indicating that NEDD4 inactivation at high cell density is a prerequisite for the elevated Hippo activity linked to contact inhibition. Moreover, NEDD4 promotes intestinal stem cell renewal in Drosophila by suppressing Hippo signalling. Collectively, we present a regulatory mechanism by which NEDD4 controls the Hippo pathway leading to coordinated cell proliferation and apoptosis. PMID- 25692648 TI - Impact of change to a concept-based baccalaureate nursing curriculum on student and program outcomes. AB - The purpose of this study was to compare selected baccalaureate program outcomes for a traditional, specialty-based curriculum (TC) to a concept-based curriculum (CBC). Outcomes included NCLEX-RN licensure pass rates, graduation rates, national assessment of critical thinking, and program satisfaction. Student self efficacy for performing nursing activities also was measured to assess the impact of the curriculum change on student confidence. The sample included 240 students enrolled in the two curricula during the last semester of the two baccalaureate nursing curricula. The TC sample (n = 104) included three cohort graduating classes, and the CBC sample (n = 136) included two cohort graduating classes. Findings indicated few differences on outcomes between the two curricula. Lack of a negative impact on program outcomes observed in this study may encourage other nursing colleges to implement newer curriculum models. Further study is needed on ways to evaluate the impact of curriculum change. PMID- 25692649 TI - Photomodulation of proliferation and differentiation of stem cells by the visible and infrared light. AB - OBJECTIVE: The aim of this article is to review experimental studies of visible and infrared light irradiation of human and animal stem cells (SCs) in vitro and in vivo to assess photobiomodulation effects on their proliferation and differentiation. BACKGROUND DATA: The clinical application of light irradiation remains controversial, primarily because of the complexity of the rational choice of irradiation parameters. In laboratories, the theoretical justification underlying the choice of irradiation parameters also remains a challenge. METHODS: A systematic review was completed of original research articles that investigated the effects of light irradiation on human and animal SCs in vitro and in vivo (to June 2014). Relevant articles were sourced from PubMed and MEDLINE((r)). The search terms were laser (light) therapy (irradiation), stem cells, and phototherapy, stem cells. RESULTS: The analysis revealed the importance of cell type when choosing the cell irradiation parameters. The influence of wavelength on the SC proliferation rate seemed to be nonsignificant. The high values of increased proliferation or differentiation were obtained using high power density, low energy density, and short exposure time. SC exposure to light without inducers did not lead to their differentiation. The maximum differentiation was achieved using irradiation parameters different from the ones needed to achieve the maximum proliferation of the same cells. CONCLUSIONS: Increased power density and reduced energy density were needed to increase the SC response. Based on the analysis, we have presented a graph of the cell response to generalized photostimulus, and introduced the concepts of "photostress" and "photoshock" to describe the stages of this response. PMID- 25692650 TI - Great expectations: pregnancy after bariatric surgery. PMID- 25692652 TI - Atelocollagen-mediated intravenous siRNA delivery specific to tumor tissues orthotopically xenografted in prostates of nude mice and its anticancer effects. AB - Successful short interfering RNA (siRNA)-based therapy for cancers depends on functional siRNA delivery specific to tumors. In our previous report, we have shown systemic siRNA delivery specific to human prostate cancer cell line PC-3 subcutaneous tumors in nude mice by atelocollagen, a collagen derivative, for formulating a complex with siRNA. We used an siRNA for human Bcl-xL as a model target. In the present study, we examined the antitumor effect on PC-3 orthotopic tumors in nude mice, as these tumors resemble the human clinical situation. The systemic intravenous administration of the complex (siRNA, 50 MUg/shot) significantly reduced Bcl-xL expression and induced apoptosis in the tumors, and suppressed their growth. Liver metastasis was also inhibited in the orthotopic model. We successfully showed tumor-specific accumulation of the siRNA by Cy3 labeled siRNA and the direct quantification of the siRNA via reverse-phase high performance liquid chromatography. The tumor-specific delivery was achieved by the enhanced permeability and retention effect, which is characteristic of macromolecular drugs. The high expression of vascular endothelial growth factor-A in the tumors provided adequate conditions to promote the permeability in the tumors, and to finally form the enhanced permeability and retention effect. In conclusion, our siRNA delivery is specific to the PC-3 orthotopic tumors in nude mice, and is practically feasible to treat tumors. PMID- 25692653 TI - High occurrence of extended-spectrum beta-lactamase-producing Salmonella in broiler carcasses from poultry slaughterhouses in South Korea. AB - The emergence of antibiotic-resistant foodborne Salmonella has become a major public health problem. Consumption of undercooked poultry contaminated with Salmonella can induce food poisoning in humans. In this study, we investigated the occurrence and antibiotic resistance patterns of Salmonella spp. isolated from 120 chicken carcasses produced in 6 poultry slaughterhouses in South Korea. A total of 11 samples (9.2%) were found contaminated with Salmonella: 5 isolates were serotyped as Salmonella Bellevue strain (slaughterhouse C) and 6 isolates were serotyped as Salmonella Enteritidis strain (slaughterhouse E). Salmonella Bellevue isolates were resistant to five antibiotics (ampicillin, chloramphenicol, nalidixic acid, tetracycline, and trimethoprim/sulfamethoxazole), while Salmonella Enteritidis isolates were resistant to nine antibiotics (ampicillin, cefotaxime, ceftazidime, cefazolin, cephalothin, amikacin, nalidixic acid, streptomycin, and tetracycline). All cephalosporin-resistant Salmonella Enteritidis isolates exhibited the extended spectrum beta-lactamase (ESBL) phenotype and carried the gene encoding CTX-M-15, the most prevalent ESBL enzyme worldwide. Based on molecular subtyping performed using the automated rep-polymerase chain reaction (PCR) system (DiversiLab), the isolates showing >= 95 similarity in their rep-PCR banding patterns were classified into 5 pulsotypes. Given that cephalosporins are the drugs of choice for invasive Salmonella infections, the high incidence of ESBL-producing strains in chicken should emphasize the necessity of regular monitoring of the occurrence of antibiotic-resistant ESBL-positive Salmonella strains in poultry meat. PMID- 25692654 TI - An outstanding catalyst for the oxygen-mediated oxidation of arylcarbinols, arylmethylene and arylacetylene compounds. AB - A convenient and sustainable protocol for the aerobic oxidation of benzyl alcohols to carbonyl compounds, based on the use of 1,2,4-triazole-type ligands and nickel(II) bromide, is described. This combination leads to the formation of an exceedingly active, enzyme-like system that allows for other oxidative processes, such as benzylic C-H oxidation and oxygen-mediated cleavage of C-C triple bond, a pioneering procedure for transformation of alkynes into carboxylic acids. PMID- 25692655 TI - Study of the interaction between DNP and DIDS with human hemoglobin as binary and ternary systems: spectroscopic and molecular modeling investigation. AB - The combination of several drugs is necessary, especially during long-term therapy. A competitive binding of the drugs can cause a decrease in the amount of drugs actually bound to the protein and increase the biologically active fraction of the drug. Here, the interaction between 4,4'-Diisothiocyano-2,2' stilbenedisulfonic acid (DIDS) and 2,4-Dinitrophenol (DNP) with Hemoglobin (Hb) was investigated by different spectroscopic and molecular modeling techniques. Fluorescence analysis was used to estimate the effect of the DIDS and DNP on Hb as well as to define the binding properties of binary and ternary complexes. The distance r between donor and acceptor was obtained by the FRET and found to be 2.25 and 2.13 nm for DIDS and DNP in binary and 2.08 and 2.07 nm for (Hb-DNP) DIDS and (Hb-DIDS) DNP complexes in ternary systems, respectively. Time-resolved fluorescence spectroscopy confirmed static quenching for Hb in the presence of DIDS and DNP in both systems. Furthermore, an increase in ellipticity values of Hb upon interaction with DIDS and DNP showed secondary structural changes of protein that determine to disrupt of hydrogen bonds and electrostatic interactions. Our results showed that the Hb destabilize in the presence of DIDS and DNP. Molecular modeling of the possible binding sites of DIDS and DNP in binary and ternary systems in Hb confirmed the experimental results. PMID- 25692656 TI - Safety and immunogenicity of single dose live attenuated varicella vaccine (VR 795 Oka strain) in healthy Indian children: a randomized controlled study. AB - Varicella, an acute viral systemic infection that may cause lifelong latent infection with the potential for causing clinical reactivation, may be prevented by immunization. The present study was an open label, randomized, controlled, phase III, multicentre trial, conducted to evaluate and compare the safety, tolerability and immunogenicity of a freeze dried live attenuated Oka strain Varicella Vaccine (VR 795 Oka strain) with Varilrix (Oka-RIT strain) in children. A total of 268 healthy Indian children aged 12 months to 12 y with baseline VZV IgG antibody (<100 mIU/ mL) were enrolled, and 256 children completed the study. The extent of rise of VZV IgG antibody titer assessed as 3-fold and 4-fold rise from baseline was found to be significantly higher (89.1% and 85.2%) in the test group as compared to control group (73.4% and 61.7%). The post-vaccination GMT of the test group was significantly higher (112.5 mIU/mL) as compared with the control group (67.8 mIU/mL) (P < 0.001). The seroconversion rate considering the 5 gp ELISA units/ml equivalent to 10mIU/ml were similar in the control (96.5%) and the test (98.3%) groups. The adverse events were not different in the control and test groups (P > 0.05). The test live attenuated vaccine was found to be highly immunogenic, safe and comparable to Varilrix used in control arm. PMID- 25692657 TI - Biocompatible PEDOT:Nafion composite electrode coatings for selective detection of neurotransmitters in vivo. AB - A Nafion and poly(3,4-ethylenedioxythiophene) (PEDOT) containing composite polymer has been electropolymerized on carbon-fiber microelectrodes with the goal of creating a mechanically stable, robust, and controllable electrode coating that increases the selectivity and sensitivity of in vivo electrochemical measurements. The coating is deposited on carbon-fiber microelectrodes by applying a triangle waveform from +1.5 V to -0.8 V and back in a dilute solution of ethylenedioxythiophene (EDOT) and Nafion in acetonitrile. Scanning electron microscopy demonstrated that the coating is uniform and ~100 nm thick. Energy dispersive X-ray spectroscopy demonstrated that both sulfur and fluorine are present in the coating, indicating the incorporation of PEDOT (poly(3,4 ethylenedioxythiophene) and Nafion. Two types of PEDOT:Nafion coated electrodes were then analyzed electrochemically. PEDOT:Nafion-coated electrodes made using 200 MUM EDOT exhibit a 10-90 response time of 0.46 +/- 0.09 s versus 0.45 +/- 0.11 s for an uncoated fiber in response to a 1.0 MUM bolus of dopamine. The electrodes coated using a higher EDOT concentration (400 MUM) are slower with a 10-90 response time of 0.84 +/- 0.19 s, but display increased sensitivity to dopamine, at 46 +/- 13 nA/MUM, compared to 26 +/- 6 nA/MUM for the electrodes coated in 200 MUM EDOT and 13 +/- 2 nA/MUM for an uncoated fiber. PEDOT:Nafion coated electrodes were lowered into the nucleus accumbens of a rat, and both spontaneous and electrically evoked dopamine release were measured. In addition to improvements in sensitivity and selectivity, the coating dramatically reduces acute in vivo biofouling. PMID- 25692658 TI - Native fluorescence spectroscopy of blood plasma of rats with experimental diabetes: identifying fingerprints of glucose-related metabolic pathways. AB - We present the results of a native fluorescence spectroscopy study of blood plasma of rats with experimental diabetes. It was shown that the fluorescence emission band shape at 320 nm excitation is the most indicative of hyperglycemia in the blood plasma samples. We provide the interpretation of this fact based on the changes in reduced nicotinamide adenine dinucleotide phosphate concentration due to glucose-related metabolic pathways and protein fluorescent cross-linking formation following nonenzymatic glycation. PMID- 25692659 TI - Application of chemometrics and cheminformatics in antimalarial drug research. PMID- 25692660 TI - Systematic and deliberate orientation and instruction for dedicated education unit staff. AB - On the basis of increasing complexity of the health care environment and recommended changes in how nurses are educated to meet these challenges, the University of Nevada Las Vegas, School of Nursing established an academic practice partnership with Summerlin Hospital Medical Center to develop a dedicated education unit (DEU). When the DEU model was implemented, variables that were not discussed in the literature needed to be addressed. One such challenge was how to impart pedagogy related to clinical teaching to the DEU nursing staff who would be acting as clinical dedicated unit instructors (CDIs). Of chief concern was the evaluation and monitoring of the quality of CDI-student interactions to ensure optimal student learning outcomes. This article addresses the development of a deliberate, systematic approach to the orientation and continued education of CDIs in the DEU. This information will assist other nursing programs as they begin to implement DEUs. PMID- 25692661 TI - Mental Health Treatment Barriers Among Racial/Ethnic Minority Versus White Young Adults 6 Months After Intake at a College Counseling Center. AB - OBJECTIVE: This study examined mental health treatment barriers following intake at a counseling center among racially/ethnically diverse college students. METHODS: College students (N = 122) seen for intake at a college counseling center in 2012-2013 completed self-reports of depressive symptoms, suicidal ideation, and mental health treatment barriers 6 months later. RESULTS: Racial/ethnic minority students less often reported previous mental health treatment and treatment after being seen at the counseling center, compared with white students. They also endorsed more treatment barriers--most commonly, financial concerns and lack of time--and more often endorsed stigma-related concerns. Treatment barriers were associated with not following through with counseling center recommendations and with greater depressive symptom severity but not with suicidal ideation during follow-up. CONCLUSIONS: Improving mental health treatment seeking among racial/ethnic minority college students should involve decreasing treatment barriers, improving access to affordable options, providing flexible scheduling or time-limited options, and decreasing stigma. PMID- 25692662 TI - chi-Shaped bis(areno)-1,4-dihydropyrrolo[3,2-b]pyrroles generated by oxidative aromatic coupling. AB - A synthesis of dihydropyrrolo[3,2-b]pyrroles fused with two peripheral arenes or heterocyclic units has been realized through the concise route. These nearly planar compounds were prepared starting from assembling the central core via condensation of 2-aryl or 2-heteroarylbenzaldehydes with aromatic amines and diacetyl, followed by double intramolecular oxidative aromatic coupling. This two step procedure afforded the desired products in overall yields of 5-36%, and it tolerates structural diversity of starting materials. All the final dyes exhibit strong blue fluorescence in solution. PMID- 25692663 TI - Back-extrapolating a land use regression model for estimating past exposures to traffic-related air pollution. AB - Land use regression (LUR) models rely on air pollutant measurements for their development, and are therefore limited to recent periods where such measurements are available. Here we propose an approach to overcome this gap and calculate LUR models several decades before measurements were available. We first developed a LUR model for NOx using annual averages of NOx at all available air quality monitoring sites in Israel between 1991 and 2011 with time as one of the independent variables. We then reconstructed historical spatial data (e.g., road network) from historical topographic maps to apply the model's prediction to each year from 1961 to 2011. The model's predictions were then validated against independent estimates about the national annual NOx emissions from on-road vehicles in a top-down approach. The model's cross validated R2 was 0.74, and the correlation between the model's annual averages and the national annual NOx emissions between 1965 and 2011 was 0.75. Information about the road network and population are persistent predictors in many LUR models. The use of available historical data about these predictors to resolve the spatial variability of air pollutants together with complementary national estimates on the change in pollution levels over time enable historical reconstruction of exposures. PMID- 25692664 TI - Enantioselective synthesis of cis-fused cyclooctanoids via rhodium(I)-catalyzed [4 + 2 + 2] cycloadditions. AB - Catalytic multicomponent [m + n + o]-type cycloadditions offer efficient, atom economical routes to diverse complex carbocycles. Recently, such transformations have emerged as unique strategies for medium ring carbocycle synthesis. Despite the important developments in this area, however, highly enantioselective [m + n + o]-type processes accessing medium ring carbocycles have yet to be developed. Herein, a rhodium-catalyzed [4 + 2 + 2] cycloaddition of allenedienes with allenes enabling the direct stereoselective synthesis of cis-fused cyclooctanoids is reported. These cycloadditions are successful with a diverse range of pi components and demonstrate the potential for high levels of enantioselectivity in a [4 + 2 + 2] process. PMID- 25692665 TI - Kinetics of silver nanoparticle deposition at PAH monolayers: reference QCM results. AB - The deposition kinetics of silver nanoparticles on Au/SiO2 /PAH substrate was studied under in situ conditions using the QCM method and the ex situ SEM imaging. Because of low dissipation, the Sauerbrey equation was used for calculating the mass per unit area (coverage). Measurements were done for various bulk suspension concentrations, flow rates, and ionic strengths. It was shown that particle deposition for the low coverage regime is governed by the bulk mass transfer step that results in a linear increase of the coverage with the time. A comparison of QCM and SEM results showed that the hydration of the silver monolayers was negligible. This allowed one to derive a universal kinetic equation that describes the mass transfer rates in the cell as a function of the bulk concentration, flow rate, and diffusion coefficient. Measurements were also performed for longer times and for various ionic strengths where the deposition kinetics and the maximum coverage of particles were determined. The experimental data confirmed a significant increase in the maximum coverage with ionic strength. This was interpreted as due to the decreasing range of the electrostatic interactions among deposited particles. These results were adequately interpreted in terms of the extended random sequential adsorption (eRSA) model. Additionally, it was shown that the QCM data matched the ex situ SEM results, indicating that the monolayer hydration was also negligible for higher coverage range. These results derived for the model silver nanoparticle system can be exploited as reference data for the interpretation of protein adsorption kinetics where the dry mass is needed in order to assess the extent of hydration. PMID- 25692666 TI - Aromaticity of metallabenzenes and related compounds. AB - The concept of aromaticity was initially introduced in chemistry to account for the stability, reactivity, molecular structures, and other properties of many unsaturated organic compounds. Despite that, it has been extended to other species with mobile electrons including saturated systems, transition structures, and even inorganic molecules. In this review, we focus on the aromaticity of a particular family of organometallic compounds known as metallabenzenes, which are characterized by the formal replacement of a CH group in benzene by an isolobal transition metal fragment. In addition, aromaticity of related compounds such as heterometallabenzenes is considered as well. To this end, we shall describe herein the insight gained by the available experimental data as well as by the application of the state-of-the-art computational methods developed as descriptors for aromaticity together with a critical evaluation of their performance to quantitatively estimate the strength of aromaticity of these systems. PMID- 25692667 TI - Sclerotic rings in mosasaurs (Squamata: Mosasauridae): structures and taxonomic diversity. AB - Mosasaurs (Squamata: Mosasauridae) were a highly diverse, globally distributed group of aquatic lizards in the Late Cretaceous (98-66 million years ago) that exhibited a high degree of adaptation to life in water. To date, despite their rich fossil record, the anatomy of complete mosasaur sclerotic rings, embedded in the sclera of the eyeball, has not been thoroughly investigated. We here describe and compare sclerotic rings of four mosasaur genera, Tylosaurus, Platecarpus, Clidastes, and Mosasaurus, for the first time. Two specimens of Tylosaurus and Platecarpus share an exact scleral ossicle arrangement, excepting the missing portion in the specimen of Platecarpus. Furthermore, the exact arrangement and the total count of 14 ossicles per ring are shared between Tylosaurus and numerous living terrestrial lizard taxa, pertaining to both Iguania and Scleroglossa. In contrast, two species of Mosasaurus share the identical count of 12 ossicles and the arrangement with each other, while no living lizard taxa share exactly the same arrangement. Such a mosaic distribution of these traits both among squamates globally and among obligatorily aquatic mosasaurs specifically suggests that neither the ossicle count nor their arrangement played major roles in the aquatic adaptation in mosasaur eyes. All the mosasaur sclerotic rings examined consistently exhibit aperture eccentricity and the scleral ossicles with gently convex outer side. Hitherto unknown to any squamate taxa, one specimen of Platecarpus unexpectedly shows a raised, concentric band of roughened surface on the inner surface of the sclerotic ring. It is possible that one or both of these latter features may have related to adaptation towards aquatic vision in mosasaurs, but further quantitative study of extant reptilian clades containing both terrestrial and aquatic taxa is critical and necessary in order to understand possible adaptive significances of such osteological features. PMID- 25692668 TI - Peri-substituted phosphorus-tellurium systems-an experimental and theoretical investigation of the P...Te through-space interaction. AB - A series of peri-substituted phosphorus-tellurium systems R'Te-Acenap-PR2 (R' = Ph, p-An, Nap, Mes, Tip; Acenap = acenaphthene-5,6-diyl (-C12H8); R = (i)Pr, Ph) exhibiting large "through-space" spin-spin coupling constants and the "onset" of three-center four-electron type interactions is presented. The influence of the substituents at the phosphorus and tellurium atoms as well as their behavior upon oxidation (with S, Se) or metal-coordination (Pt, Au) is discussed using NMR spectroscopy, single-crystal X-ray diffraction, and advanced density functional theory studies including NBO, AIM, and ELI-D analyses. PMID- 25692669 TI - Familial clustering of tic disorders and obsessive-compulsive disorder. AB - IMPORTANCE: Tourette syndrome/chronic tic disorder (TS/CT) and obsessive compulsive disorder (OCD) overlap in their phenomenological features and often co occur in affected individuals and families. Understanding how these disorders cluster in families provides important clinical information and is an important step in understanding the causes of these disorders. OBJECTIVE: To determine familial recurrence for TS/CT and OCD using a national epidemiologic sample. DESIGN, SETTING, AND PARTICIPANTS: We performed a population-based study of national health registries in Denmark, including all individuals (n = 1 741 271) born in Denmark from January 1, 1980, through December 31, 2007, and followed up through December 31, 2013. We identified those with TS/CT and/or OCD. MAIN OUTCOMES AND MEASURES: The prevalence of TS/CT and OCD and relative recurrence risk (RRR) for TS/CT or OCD among individuals with an oldest sibling or a parent diagnosed as having TS/CT or OCD compared with individuals without an affected oldest sibling or an affected parent. RESULTS: In this sample, 5596 individuals were diagnosed as having TS/CT; 6191, OCD; and 412, both disorders. The overall cohort prevalence of TS/CT was 0.42% (95% CI, 0.41%-0.43%) and of OCD, 0.84% (95% CI, 0.81%-0.87%). The mean sibling recurrence risk for TS/CT across all birth years was 9.88% (95% CI, 8.02%-12.16%) and for OCD, 4.01% (95% CI, 2.78%-5.76%). The sibling RRR for TS/CT was 18.63 (95% CI, 15.34-22.63). In contrast, the sibling RRR for OCD was 4.89 (95% CI, 3.45-6.93). The parent-offspring RRR for TS/CT was 61.02 (95% CI, 44.43-83.82), whereas the parent-offspring RRR for OCD was 6.25 (95% CI, 4.82-8.11). The sibling and parent-offspring cross-disorder risks were also significant, ranging from 3.20 (95% CI, 2.22-4.62) to 10.27 (95% CI, 5.17-20.39). CONCLUSIONS AND RELEVANCE: Tourette syndrome/CT and OCD cluster in families. The familial aggregation of TS/CT is profound and substantially higher than the familial aggregation for OCD. The recurrence risk estimates provide an important clinical framework for identifying individuals at risk and provide insights into the causes of these disorders. PMID- 25692670 TI - Comparative phenotypic and genotypic characterization of Salmonella spp. in pig farms and slaughterhouses in two provinces in northern Thailand. AB - Salmonella spp. are an important group of bacterial zoonotic pathogens which can cause acute food-borne diseases in humans. Pork products are the main source of salmonellosis, but the origins and transmission routes of the disease have not been clearly determined. The purpose of this study was to characterize Salmonella spp. isolated in pig production lines both from pig farms and from slaughterhouses in Chiang Mai and Lamphun provinces in northern Thailand. The study focuses on the association among serotypes, antimicrobial resistance patterns and Pulse Field Gel Electrophoresis (PFGE) patterns to investigate possible sources of infection and to provide information which could help strengthen salmonellosis control programs in the region. A total of 86 strains of Salmonella comprising five majority serotypes were identified. Antibiotic resistance to tetracycline was found to be the most prevalent (82.56%) followed by ampicillin (81.40%) and streptomycin (63.95%). Seven clusters and 28 fingerprint-patterns generated by PFGE were identified among strains recovered from various locations and at different times, providing information on associations among the strains as well as evidence of the existence of persistent strains in some areas. Study results suggest that Salmonella control programs should be implemented at slaughterhouse production lines, including surveillance to insure good hygiene practices, in addition to regular monitoring of large populations of farm animals. PMID- 25692671 TI - Estimation of potentially toxic elements contamination in anthropogenic soils on a brown coal mining dumpsite by reflectance spectroscopy: a case study. AB - In order to monitor Potentially Toxic Elements (PTEs) in anthropogenic soils on brown coal mining dumpsites, a large number of samples and cumbersome, time consuming laboratory measurements are required. Due to its rapidity, convenience and accuracy, reflectance spectroscopy within the Visible-Near Infrared (Vis-NIR) region has been used to predict soil constituents. This study evaluated the suitability of Vis-NIR (350-2500 nm) reflectance spectroscopy for predicting PTEs concentration, using samples collected on large brown coal mining dumpsites in the Czech Republic. Partial Least Square Regression (PLSR) and Support Vector Machine Regression (SVMR) with cross-validation were used to relate PTEs data to the reflectance spectral data by applying different preprocessing strategies. According to the criteria of minimal Root Mean Square Error of Prediction of Cross Validation (RMSEPcv) and maximal coefficient of determination (R2cv) and Residual Prediction Deviation (RPD), the SVMR models with the first derivative pretreatment provided the most accurate prediction for As (R2cv) = 0.89, RMSEPcv = 1.89, RPD = 2.63). Less accurate, but acceptable prediction for screening purposes for Cd and Cu (0.66 ? R2cv) ? 0.81, RMSEPcv = 0.0.8 and 4.08 respectively, 2.0 ? RPD ? 2.5) were obtained. The PLSR model for predicting Mn (R2cv) = 0.44, RMSEPcv = 116.43, RPD = 1.45) presented an inadequate model. Overall, SVMR models for the Vis-NIR spectra could be used indirectly for an accurate assessment of PTEs' concentrations. PMID- 25692672 TI - A non-aggregated and tumour-associated macrophage-targeted photosensitiser for photodynamic therapy: a novel zinc(II) phthalocyanine containing octa sulphonates. AB - A novel zinc(II) phthalocyanine bearing octa-sulphonates has been prepared, which is non-aggregated in water, highly photoactive and low dark-toxic. More interestingly, it exhibits specific affinity to macrophages via the scavenger receptor-A, and can selectively accumulate in tumour sites. PMID- 25692673 TI - Interacting agricultural pests and their effect on crop yield: application of a Bayesian decision theory approach to the joint management of Bromus tectorum and Cephus cinctus. AB - Worldwide, the landscape homogeneity of extensive monocultures that characterizes conventional agriculture has resulted in the development of specialized and interacting multitrophic pest complexes. While integrated pest management emphasizes the need to consider the ecological context where multiple species coexist, management recommendations are often based on single-species tactics. This approach may not provide satisfactory solutions when confronted with the complex interactions occurring between organisms at the same or different trophic levels. Replacement of the single-species management model with more sophisticated, multi-species programs requires an understanding of the direct and indirect interactions occurring between the crop and all categories of pests. We evaluated a modeling framework to make multi-pest management decisions taking into account direct and indirect interactions among species belonging to different trophic levels. We adopted a Bayesian decision theory approach in combination with path analysis to evaluate interactions between Bromus tectorum (downy brome, cheatgrass) and Cephus cinctus (wheat stem sawfly) in wheat (Triticum aestivum) systems. We assessed their joint responses to weed management tactics, seeding rates, and cultivar tolerance to insect stem boring or competition. Our results indicated that C. cinctus oviposition behavior varied as a function of B. tectorum pressure. Crop responses were more readily explained by the joint effects of management tactics on both categories of pests and their interactions than just by the direct impact of any particular management scheme on yield. In accordance, a C. cinctus tolerant variety should be planted at a low seeding rate under high insect pressure. However as B. tectorum levels increase, the C. cinctus tolerant variety should be replaced by a competitive and drought tolerant cultivar at high seeding rates despite C. cinctus infestation. This study exemplifies the necessity of accounting for direct and indirect biological interactions occurring within agroecosystems and propagating this information from the statistical analysis stage to the management stage. PMID- 25692674 TI - Mind the gap: genetic manipulation of basicranial growth within synchondroses modulates calvarial and facial shape in mice through epigenetic interactions. AB - Phenotypic integration patterns in the mammalian skull have long been a focus of intense interest as a result of their suspected influence on the trajectory of hominid evolution. Here we test the hypothesis that perturbation of cartilage growth, which directly affects only the chondrocranium during development, will produce coordinated shape changes in the adult calvarium and face regardless of mechanism. Using two murine models of cartilage undergrowth that target two very different mechanisms, we show that strong reduction in cartilage growth produces a short, wide, and more flexed cranial base. This in turn produces a short, wide face in both models. Cranial base and face are already correlated early in ontogeny, and the relationship between these modules gains structure through postnatal growth and development. These results provide further evidence that there exist physical interactions between developing parts of the phenotype that produce variation at a distance from the actual locus upon which a particular selective pressure is acting. Phenotypic changes observed over the course of evolution may not all require adaptationist explanations; rather, it is likely that a substantial portion of observed phenotypic variation over the history of a clade is not directly adaptive but rather a secondary consequence of some local response to selection. PMID- 25692675 TI - Patterns of leaf biochemical and structural properties of cerrado life forms: implications for remote sensing. AB - AIM: The general goal of this study is to investigate and analyze patterns of ecophysiological leaf traits and spectral response among life forms (trees, shrubs and lianas) in the Cerrado ecosystem. In this study, we first tested whether life forms are discriminated through leaf level functional traits. We then explored the correlation between leaf-level plant functional traits and spectral reflectance. LOCATION: Serra do Cipo National Park, Minas Gerais, Brazil. METHODS: Six ecophysiological leaf traits were selected to best characterize differences between life forms in the woody plant community of the Cerrado. Results were compared to spectral vegetation indices to determine if plant groups provide means to separate leaf spectral responses. RESULTS: Values obtained from leaf traits were similar to results reported from other tropical dry sites. Trees and shrubs significantly differed from lianas in terms of the percentage of leaf water content and Specific Leaf Area. Spectral indices were insufficient to capture the differences of these key traits between groups, though indices were still adequately correlated to overall trait variation. CONCLUSION: The importance of life forms as biochemical and structurally distinctive groups is a significant finding for future remote sensing studies of vegetation, especially in arid and semi-arid environments. The traits we found as indicative of these groups (SLA and water content) are good candidates for spectral characterization. Future studies need to use the full wavelength (400 nm 2500 nm) in order to capture the potential response of these traits. The ecological linkage to water balance and life strategies encourages these traits as starting points for modeling plant communities using hyperspectral remote sensing. PMID- 25692676 TI - The notch signaling regulates CD105 expression, osteogenic differentiation and immunomodulation of human umbilical cord mesenchymal stem cells. AB - Mesenchymal stem cells (MSCs) are a group of multipotent cells with key properties of multi-lineage differentiation, expressing a set of relatively specific surface markers and unique immunomodulatory functions. IDO1, a catabolic enzyme of tryptophan, represents a critical molecule mediating immunomodulatory functions of MSCs. However, the signaling pathways involved in regulating these key properties still remain elusive. To investigate the involvement of Notch signaling as well as other potential signaling pathway(s) in regulating these critical properties of MSCs, we treated human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) with gamma-secreatase inhibitor I (GSI-I), which inhibits both Notch signaling and ubiquitin-proteasome activities. It was shown that the GSI-I treatment resulted in apoptosis, reduced expression of surface markers CD73, CD90 and CD105, reduced osteogenic differentiation, and reduction of the hUC-MSCs-mediated suppression of Th1 lymphocyte proliferation and the IFN-gamma induced IDO1 expression. Through distinguishing the effects of GSI-I between Notch inhibition and proteasome inhibition, it was further observed that, whereas both Notch inhibition and proteasome inhibition were attributable to the reduced CD105 expression and osteogenic differentiation, but not to the induced apoptosis. However, Notch inhibition, but not proteasome inhibition, only contributed to the significant effect of GSI-I on Th1 proliferation probably through reducing IDO1 promoter activity. In conclusion, the Notch signaling may represent a very important cell signaling capable of regulating multiple critical properties, especially the immunomodulatory functions of MSCs. PMID- 25692677 TI - Eight-membered ring-containing jadomycins: implications for non-enzymatic natural products biosynthesis. AB - Jadomycin Oct (1) was isolated from Streptomyces venezuelae ISP5230 and characterized as a structurally unique eight-membered l-ornithine ring-containing jadomycin. The structure was elucidated through the semisynthetic derivatization of starting material via chemoselective acylation of the l-ornithine alpha-amino group using activated succinimidyl esters. Incorporation of 5-aminovaleric acid led to jadomycin AVA, a second eight-membered ring-containing jadomycin. These natural products illustrate the structural diversity permissible from a non enzymatic step within a biosynthetic pathway and exemplifies the potential for discovery of novel scaffolds. PMID- 25692678 TI - Thiofluorographene-hydrophilic graphene derivative with semiconducting and genosensing properties. AB - We present the first example of covalent chemistry on fluorographene, enabling the attachment of -SH groups through nucleophilic substitution of fluorine in a polar solvent. The resulting thiographene-like, 2D derivative is hydrophilic with semiconducting properties and bandgap between 1 and 2 eV depending on F/SH ratio. Thiofluorographene is applied in DNA biosensing by electrochemical impedance spectroscopy. PMID- 25692679 TI - Pelvic organ prolapse is associated with alteration of sphingosine-1 phosphate/Rho-kinase signalling pathway in human vaginal wall. AB - Pelvic organ prolapse (POP) is a debilitating condition of unknown aetiology affecting > 50% of women over 40 years of age. In POP patients, the vaginal walls are weakened allowing descent of pelvic organs through the vagina. We sought to determine if sphingosine-1-phosphate (S1P) signalling, which regulates smooth muscle contractility and apoptosis via the RhoA/Rho-kinase (ROK) pathway, is altered in the vagina of women with POP. Utilising anterior vaginal wall specimens, we provide novel demonstration of the S1P pathway in this organ. Additionally, comparing specimens from women having pelvic reconstructive surgery for POP and control subjects, we reveal increases in mRNA expression of the three major mammalian S1P receptors (S1P1-S1P3), and RhoA and the ROK isoforms: ROKalpha and ROKbeta in POP patients, which correlates with a decrease in elastic fibre assembly pathway constituents. Taken together, our data suggest the S1P/ROK pathway as a novel area for future POP research and potential therapeutic development. PMID- 25692681 TI - CHOPER filters enable rare mutation detection in complex mutagenesis populations by next-generation sequencing. AB - Next-generation sequencing (NGS) has revolutionized genetics and enabled the accurate identification of many genetic variants across many genomes. However, detection of biologically important low-frequency variants within genetically heterogeneous populations remains challenging, because they are difficult to distinguish from intrinsic NGS sequencing error rates. Approaches to overcome these limitations are essential to detect rare mutations in large cohorts, virus or microbial populations, mitochondria heteroplasmy, and other heterogeneous mixtures such as tumors. Modifications in library preparation can overcome some of these limitations, but are experimentally challenging and restricted to skilled biologists. This paper describes a novel quality filtering and base pruning pipeline, called Complex Heterogeneous Overlapped Paired-End Reads (CHOPER), designed to detect sequence variants in a complex population with high sequence similarity derived from All-Codon-Scanning (ACS) mutagenesis. A novel fast alignment algorithm, designed for the specified application, has O(n) time complexity. CHOPER was applied to a p53 cancer mutant reactivation study derived from ACS mutagenesis. Relative to error filtering based on Phred quality scores, CHOPER improved accuracy by about 13% while discarding only half as many bases. These results are a step toward extending the power of NGS to the analysis of genetically heterogeneous populations. PMID- 25692682 TI - Differential mRNA expression and glucocorticoid-mediated regulation of TRPM6 and TRPM7 in the heart and kidney throughout murine pregnancy and development. AB - The transient receptor potential (TRP) channels TRPM6 and TRPM7 are critically involved in maintaining whole body and cellular Mg2+ homeostasis and ensuring the normal function of organs such as the heart and kidney. However, we do not know how the expression of TRPM6 and TPRM7 in these organs changes throughout fetal development and adult life, and whether this expression can be hormonally regulated. This study determined the ontogeny of TRPM6 and TRPM7 mRNA expression from mid-gestation through to adulthood in the mouse. In a second series of experiments, we examined how maternal administration of the glucocorticoids corticosterone and dexamethasone between embryonic days 12.5-15 affected TRPM6 and TRPM7 channel mRNA expression in the mother and fetus. Whilst renal TRPM7 expression was relatively constant throughout development, renal TRPM6 expression was markedly upregulated after birth. In contrast, cardiac TRPM7 expression was 2 4 fold higher in the fetus than in the adult. Surprisingly, TRPM6 expression was detected in the fetal heart (qPCR and in situ hybridization). Glucocorticoid administration during gestation increased fetal cardiac expression of both channels without affecting renal expression. In contrast, in the dam renal TRPM6 and TRPM7 expression was increased by glucocorticoids with no change in the cardiac channel expression. These data suggest that TRPM6 and TRPM7 channels are important in organogenesis, and that elevated maternal glucocorticoid levels can alter the expression of these channels. This suggests that perturbations in hormonal regulatory systems during pregnancy may adversely impact upon normal fetal development, at least in part by altering expression of TRPM channels. PMID- 25692683 TI - Clinician attitudes toward CDC interim pre-exposure prophylaxis (PrEP) guidance and operationalizing PrEP for adolescents. AB - Prior to issuing formal HIV pre-exposure prophylaxis (PrEP) clinical practice guidelines in 2014, the US Centers for Disease Control and Prevention (CDC) had released interim guidance for oral PrEP use among adults. Because oral PrEP may be used off-label for youth and may soon be indicated for minor adolescents, we examined the potential adoption of the interim guidance among clinicians who care for HIV-infected and at-risk youth. Individual, semi-structured interviews were conducted with 15 US clinicians who were recruited through an adolescent HIV research network. The theory-driven interview guide, consisting primarily of open ended questions, assessed demographics, familiarity with the guidance, attitudes toward the guidance, and attitudes toward the use of the guidance for adult and adolescent patients. Transcripts were analyzed using framework analysis. Most clinicians (11/15) reported that the guidance was compatible with their practice, although several reported that some aspects, particularly frequency of follow-up visits, needed to be tailored to meet their patients' needs. We found variability in clinician reported characteristics of appropriate PrEP candidates (e.g., youth with substance use and mental health issues were noted to be both suitable and unsuitable PrEP candidates) and PrEP use in serodiscordant couples (e.g., whether PrEP would be recommended to a patient whose HIV-infected partner is virally suppressed). Clinician reported steps for initiation, monitoring, and discontinuing PrEP were largely consistent with the guidance. The observed variability in clinician practice with regard to oral PrEP may be reduced through interventions to educate clinicians about the content and rationale for guideline recommendations. PMID- 25692685 TI - Origin of the accumulation layer at the InN/a-In2O3 interface. AB - We perform first-principles Density Functional Theory calculations for the amorphous In2O3/InN (1100) heterostructure. Our results suggest that the interface between InN and its native amorphous oxide is a type "I" interface as observed in X-ray photoemission spectroscopy data for the same materials in the crystalline form. The microscopic analysis of the system reveals the presence of peculiar structural features localized at the interface, such as the formation of N-O bonds and the existence of N dangling bonds, that are responsible for donor states. These findings shed light on the origin of the electron accumulation layer occurring at the interface in spontaneously oxidized InN nanowires, recently associated with the observed increase in conductivity for such systems. PMID- 25692684 TI - Regulators of autophagosome formation in Drosophila muscles. AB - Given the diversity of autophagy targets and regulation, it is important to characterize autophagy in various cell types and conditions. We used a primary myocyte cell culture system to assay the role of putative autophagy regulators in the specific context of skeletal muscle. By treating the cultures with rapamycin (Rap) and chloroquine (CQ) we induced an autophagic response, fully suppressible by knockdown of core ATG genes. We screened D. melanogaster orthologs of a previously reported mammalian autophagy protein-protein interaction network, identifying several proteins required for autophagosome formation in muscle cells, including orthologs of the Rab regulators RabGap1 and Rab3Gap1. The screen also highlighted the critical roles of the proteasome and glycogen metabolism in regulating autophagy. Specifically, sustained proteasome inhibition inhibited autophagosome formation both in primary culture and larval skeletal muscle, even though autophagy normally acts to suppress ubiquitin aggregate formation in these tissues. In addition, analyses of glycogen metabolic genes in both primary cultured and larval muscles indicated that glycogen storage enhances the autophagic response to starvation, an important insight given the link between glycogen storage disorders, autophagy, and muscle function. PMID- 25692686 TI - Factitious lymphedema of the arm: case report and review of publications. AB - The aim of this study was to report a case of factitious lymphedema of the arm and related lymphoscintigraphic aspects. The case of a 36-year-old patient is reported who started to present with pain, in the 3rd finger of the right hand three years prior to this report, which she associated with her work. Joint effusion was identified and treated using a splint that restricted blood flow leading to edema of the distal third of the forearm. Since then the patient was treated however her condition worsened resulting in edema of the entire arm. Subsequently she was referred to our service. A physical examination identified a restrictive band in the axillary region of the arm that delimited the edema. Volumetry and lymphoscintigraphic examinations of the limb were performed. The lymphoscintigraphy demonstrated acceleration of the flow in the affected limb and dermal reflux. Clinical treatment with removal of the restriction allowed a rapid reduction in the volume of the limb. PMID- 25692687 TI - Early rehabilitation treatment in newborns with congenital muscular torticollis. AB - BACKGROUND: Congenital Muscular Torticollis (CMT) is the most common form of torticollis in infants; on clinical presentation it is classified into 3 types: 1) postural torticollis, with postural deformity only in the neck; 2) muscular torticollis, where neck deformity is associated with muscle tightness and restricted passive range of motion (ROM); and 3) sternomastoid tumor or pseudotumor, with a fibrotic, sternocleido-mastoid muscle mass and passive ROM limitations. AIM: The aim of this study was to evaluate the physical therapy outcome of infants with CMT treated either by parents using a home exercise program, or by a physical therapist. DESIGN: Longitudinal study. SETTING: Outpatients with CMT at our Department of Physical Medicine and Rehabilitation. POPULATION: Fifty consecutive newborns with CMT, referred by the primary pediatrician: METHODS: In our study, 50 infants with CMT were evaluated and treated either by a physical therapist or by parents using a home program. RESULTS: Sixteen females (32%) and 34 males (68%), aged 10.2 weeks (SD 6.66); 23 of the infants (46%) presented with more severe articular limitations than the others (P=0.002) and were therefore prescribed outpatient treatment by a physical therapist; the remaining 27 less severe cases (54%) were prescribed a home therapy program. 49 infants achieved full resolution after an average of 81.06 days (SD 64.05) of rehabilitation treatment. The group of patients who were treated at home achieved resolution more quickly (72.8 vs. 91.1 days), although statistical significance was not reached. CONCLUSIONS: Infants with CMT who were treated early, either at home or in the outpatient clinic, completely recovered normal neck movement in a short time. It is important not to discharge patients until they have achieved full resolution of CMT symptoms to exclude the minimal risk of relapse. CLINICAL REHABILITATION IMPACT: This study demonstrates the importance of early treatment in cases of congenital muscular torticollis. PMID- 25692688 TI - Feasibility of using the International Classification of Functioning, Disability and Health Core Set for evaluation of fall-related risk factors in acute rehabilitation settings. AB - BACKGROUND: Previously, we reported the use of an International Classification of Functioning (ICF) core set that can provide a holistic framework for evaluating the risk factors of falls; however, data on the feasibility of applying this core set are lacking. AIM: To investigate the feasibility of applying the fall-related ICF risk-factor core set in the case of patients in an acute-rehabilitation setting. DESIGN: A cross-sectional and descriptive correlational design. SETTING: Acute-rehabilitation ward. POPULATION: A total of 273 patients who experienced fall at acute-rehabilitation ward. METHODS: The data on falls were collected from the hospital's Nursing Information System (NIS) and the fall-reporting system (Adverse Event Reporting System, AERS) between 2010 and 2013. The relationship of both systems to the fall-related ICF core set was analyzed to assess the feasibility of their clinical application. We evaluated the feasibility of using the fall-related ICF risk-factor core set by using the frequency and the percentage of the fall patients in of the listed categories. RESULTS: The fall related ICF risk-factor core set category b735 (muscle tone functions) exhibited a high feasibility (85.95%) for clinical application, and the category b730 (muscle power functions) covered 77.11% of the patients. The feasibility of application of the category d410 (change basic body position) was also high in the case of all fall patients (81.69%). CONCLUSIONS: In the acute-rehabilitation setting, the feasibility of application of the fall-related ICF risk-factor core set is high. CLINICAL REHABILITATION IMPACT: The fall-related ICF risk-factor core set can help multidisciplinary teams develop fall-prevention strategies in acute rehabilitation wards. PMID- 25692689 TI - A de novo transcriptome and valid reference genes for quantitative real-time PCR in Colaphellus bowringi. AB - BACKGROUND: The cabbage beetle Colaphellus bowringi Baly is a serious insect pest of crucifers and undergoes reproductive diapause in soil. An understanding of the molecular mechanisms of diapause regulation, insecticide resistance, and other physiological processes is helpful for developing new management strategies for this beetle. However, the lack of genomic information and valid reference genes limits knowledge on the molecular bases of these physiological processes in this species. RESULTS: Using Illumina sequencing, we obtained more than 57 million sequence reads derived from C. bowringi, which were assembled into 39,390 unique sequences. A Clusters of Orthologous Groups classification was obtained for 9,048 of these sequences, covering 25 categories, and 16,951 were assigned to 255 Kyoto Encyclopedia of Genes and Genomes pathways. Eleven candidate reference gene sequences from the transcriptome were then identified through reverse transcriptase polymerase chain reaction. Among these candidate genes, EF1alpha, ACT1, and RPL19 proved to be the most stable reference genes for different reverse transcriptase quantitative polymerase chain reaction experiments in C. bowringi. Conversely, aTUB and GAPDH were the least stable reference genes. CONCLUSION: The abundant putative C. bowringi transcript sequences reported enrich the genomic resources of this beetle. Importantly, the larger number of gene sequences and valid reference genes provide a valuable platform for future gene expression studies, especially with regard to exploring the molecular mechanisms of different physiological processes in this species. PMID- 25692690 TI - Performance of social network sensors during Hurricane Sandy. AB - Information flow during catastrophic events is a critical aspect of disaster management. Modern communication platforms, in particular online social networks, provide an opportunity to study such flow and derive early-warning sensors, thus improving emergency preparedness and response. Performance of the social networks sensor method, based on topological and behavioral properties derived from the "friendship paradox", is studied here for over 50 million Twitter messages posted before, during, and after Hurricane Sandy. We find that differences in users' network centrality effectively translate into moderate awareness advantage (up to 26 hours); and that geo-location of users within or outside of the hurricane affected area plays a significant role in determining the scale of such an advantage. Emotional response appears to be universal regardless of the position in the network topology, and displays characteristic, easily detectable patterns, opening a possibility to implement a simple "sentiment sensing" technique that can detect and locate disasters. PMID- 25692691 TI - Essential role of the C-terminal helical domain in active site formation of selenoprotein MsrA from Clostridium oremlandii. AB - We previously determined the crystal structures of 1-Cys type selenoprotein MsrA from Clostridium oremlandii (CoMsrA). The overall structure of CoMsrA is unusual, consisting of two domains, the N-terminal catalytic domain and the C-terminal distinct helical domain which is absent from other known MsrA structures. Deletion of the helical domain almost completely abolishes the catalytic activity of CoMsrA. In this study, we determined the crystal structure of the helical domain-deleted (DeltaH-domain) form of CoMsrA at a resolution of 1.76 A. The monomer structure is composed of the central rolled mixed beta-sheet surrounded by alpha-helices. However, there are significant conformational changes in the N- and C-termini and loop regions of the DeltaH-domain protein relative to the catalytic domain structure of full-length CoMsrA. The active site structure in the DeltaH-domain protein completely collapses, thereby causing loss of catalytic activity of the protein. Interestingly, dimer structures are observed in the crystal formed by N-terminus swapping between two molecules. The DeltaH-domain protein primarily exists as a dimer in solution, whereas the full-length CoMsrA exists as a monomer. Collectively, this study provides insight into the structural basis of the essential role of the helical domain of CoMsrA in its catalysis. PMID- 25692692 TI - Low rates of both lipid-lowering therapy use and achievement of low-density lipoprotein cholesterol targets in individuals at high-risk for cardiovascular disease across Europe. AB - AIMS: To analyse the treatment and control of dyslipidaemia in patients at high and very high cardiovascular risk being treated for the primary prevention of cardiovascular disease (CVD) in Europe. METHODS AND RESULTS: Data were assessed from the European Study on Cardiovascular Risk Prevention and Management in Usual Daily Practice (EURIKA, ClinicalTrials.gov identifier: NCT00882336), which included a randomly sampled population of primary CVD prevention patients from 12 European countries (n = 7641). Patients' 10-year risk of CVD-related mortality was calculated using the Systematic Coronary Risk Evaluation (SCORE) algorithm, identifying 5019 patients at high cardiovascular risk (SCORE >=5% and/or receiving lipid-lowering therapy), and 2970 patients at very high cardiovascular risk (SCORE >=10% or with diabetes mellitus). Among high-risk individuals, 65.3% were receiving lipid-lowering therapy, and 61.3% of treated patients had uncontrolled low-density lipoprotein cholesterol (LDL-C) levels (>=2.5 mmol/L). For very-high-risk patients (uncontrolled LDL-C levels defined as >=1.8 mmol/L) these figures were 49.5% and 82.9%, respectively. Excess 10-year risk of CVD related mortality (according to SCORE) attributable to lack of control of dyslipidaemia was estimated to be 0.72% and 1.61% among high-risk and very-high risk patients, respectively. Among high-risk individuals with uncontrolled LDL-C levels, only 8.7% were receiving a high-intensity statin (atorvastatin >=40 mg/day or rosuvastatin >=20 mg/day). Among very-high-risk patients, this figure was 8.4%. CONCLUSIONS: There is a considerable opportunity for improvement in rates of lipid-lowering therapy use and achievement of lipid-level targets in high-risk and very-high-risk patients being treated for primary CVD prevention in Europe. PMID- 25692693 TI - Ezh2 lines up the chromatin in T regulatory cells. AB - Epigenetic modulation is critical for regulating the development and function of T cells. In this issue of Immunity, DuPage et al. (2015) show that the chromatin modifying enzyme Ezh2 induced by CD28 costimulation is essential for regulatory T (Treg) cell maintenance during activation and differentiation. PMID- 25692694 TI - The importance of cooperation: partnerless NFAT induces T cell exhaustion. AB - Downstream of costimulatory pathways, complexes of transcription factors NFAT and AP-1 promote effector T cell differentiation. In this issue of Immunity, Martinez et al. report that monomeric NFAT binding in the absence of a transcriptional partner induces a gene expression program involved in T cell exhaustion. PMID- 25692695 TI - Why worms watch their hemidesmosomes and why you should, too. AB - Hemidesmosomes are cellular attachment structures of great importance to the epidermis. In this issue of Immunity, Zhang et al. (2015) have discovered that in addition to having structural functions, invertebrate and human hemidesmosomes are actively monitored by the cell as a novel mechanism for detecting pathogenic infection. PMID- 25692696 TI - An oral commensal associates with disease: chicken, egg, or red herring? AB - Fusobacterium nucleatum might be the cause or consequence of disease in many tissues in and outside the mouth. In this issue of Immunity, Gur et al. (2015) suggest a new mechanism by which this oral commensal might help cancer cells escape host immunity. PMID- 25692697 TI - Mushrooming insights into skin dendritic cell physiology. AB - Mechanisms responsible for protective immunity against epicutaneous Candida infections are incompletely characterized. In this issue of Immunity, Kashem et al. demonstrate that different Candida life forms engage selected skin dendritic cell subsets in distinct compartments, resulting in qualitatively different immune responses. PMID- 25692698 TI - Immune complexes: not just an innocent bystander in chronic viral infection. AB - Understanding of how persistent viral infection impacts humoral immunity is incomplete. In this issue of Immunity, Wieland et al. (2015) and Yamada et al. (2015) find that high amounts of IgG-antigen complexes formed during chronic lymphocytic choriomeningitis infection can interfere with Fcgamma-receptor mediated effector activities, potentially contributing to immune dysfunction. PMID- 25692699 TI - Emerging functions of amphiregulin in orchestrating immunity, inflammation, and tissue repair. AB - Type 2 inflammatory responses can be elicited by diverse stimuli, including toxins, venoms, allergens, and infectious agents, and play critical roles in resistance and tolerance associated with infection, wound healing, tissue repair, and tumor development. Emerging data suggest that in addition to characteristic type 2-associated cytokines, the epidermal growth factor (EGF)-like molecule Amphiregulin (AREG) might be a critical component of type 2-mediated resistance and tolerance. Notably, numerous studies demonstrate that in addition to the established role of epithelial- and mesenchymal-derived AREG, multiple leukocyte populations including mast cells, basophils, group 2 innate lymphoid cells (ILC2s), and a subset of tissue-resident regulatory CD4(+) T cells can express AREG. In this review, we discuss recent advances in our understanding of the AREG EGF receptor pathway and its involvement in infection and inflammation and propose a model for the function of this pathway in the context of resistance and tissue tolerance. PMID- 25692700 TI - ICOS coreceptor signaling inactivates the transcription factor FOXO1 to promote Tfh cell differentiation. AB - T follicular helper (Tfh) cells are essential in the induction of high-affinity, class-switched antibodies. The differentiation of Tfh cells is a multi-step process that depends upon the co-receptor ICOS and the activation of phosphoinositide-3 kinase leading to the expression of key Tfh cell genes. We report that ICOS signaling inactivates the transcription factor FOXO1, and a Foxo1 genetic deletion allowed for generation of Tfh cells with reduced dependence on ICOS ligand. Conversely, enforced nuclear localization of FOXO1 inhibited Tfh cell development even though ICOS was overexpressed. FOXO1 regulated Tfh cell differentiation through a broad program of gene expression exemplified by its negative regulation of Bcl6. Final differentiation to germinal center Tfh cells (GC-Tfh) was instead FOXO1 dependent as the Foxo1(-/-) GC-Tfh cell population was substantially reduced. We propose that ICOS signaling transiently inactivates FOXO1 to initiate a Tfh cell contingency that is completed in a FOXO1-dependent manner. PMID- 25692701 TI - The transcription factor KLF2 restrains CD4+ T follicular helper cell differentiation. AB - T follicular helper (Tfh) cells are essential for efficient B cell responses, yet the factors that regulate differentiation of this CD4(+) T cell subset are incompletely understood. Here we found that the KLF2 transcription factor serves to restrain Tfh cell generation. Induced KLF2 deficiency in activated CD4(+) T cells led to increased Tfh cell generation and B cell priming, whereas KLF2 overexpression prevented Tfh cell production. KLF2 promotes expression of the trafficking receptor S1PR1, and S1PR1 downregulation is essential for efficient Tfh cell production. However, KLF2 also induced expression of the transcription factor Blimp-1, which repressed transcription factor Bcl-6 and thereby impaired Tfh cell differentiation. Furthermore, KLF2 induced expression of the transcription factors T-bet and GATA3 and enhanced Th1 differentiation. Hence, our data indicate KLF2 is pivotal for coordinating CD4(+) T cell differentiation through two distinct and complementary mechanisms: via control of T cell localization and by regulation of lineage-defining transcription factors. PMID- 25692702 TI - The ectoenzyme E-NPP3 negatively regulates ATP-dependent chronic allergic responses by basophils and mast cells. AB - Crosslinking of the immunoglobulin receptor FcepsilonRI activates basophils and mast cells to induce immediate and chronic allergic inflammation. However, it remains unclear how the chronic allergic inflammation is regulated. Here, we showed that ecto-nucleotide pyrophosphatase-phosphodiesterase 3 (E-NPP3), also known as CD203c, rapidly induced by FcepsilonRI crosslinking, negatively regulated chronic allergic inflammation. Basophil and mast cell numbers increased in Enpp3(-/-) mice with augmented serum ATP concentrations. Enpp3(-/-) mice were highly sensitive to chronic allergic pathologies, which was reduced by ATP blockade. FcepsilonRI crosslinking induced ATP secretion from basophils and mast cells, and ATP activated both cells. ATP clearance was impaired in Enpp3(-/-) cells. Enpp3(-/-)P2rx7(-/-) mice showed decreased responses to FcepsilonRI crosslinking. Thus, ATP released by FcepsilonRI crosslinking stimulates basophils and mast cells for further activation causing allergic inflammation. E-NPP3 decreases ATP concentration and suppresses basophil and mast cell activity. PMID- 25692703 TI - The interleukin-33-p38 kinase axis confers memory T helper 2 cell pathogenicity in the airway. AB - Memory CD4(+) T helper (Th) cells provide long-term protection against pathogens and are essential for the development of vaccines; however, some antigen-specific memory Th cells also drive immune-related pathology, including asthma. The mechanisms regulating the pathogenicity of memory Th cells remain poorly understood. We found that interleukin-33 (IL-33)-ST2 signals selectively licensed memory Th2 cells to induce allergic airway inflammation via production of IL-5 and that the p38 MAP kinase pathway was a central downstream target of IL-33-ST2 in memory Th2 cells. In addition, we found that IL-33 induced upregulation of IL 5 by memory CD4(+) T cells isolated from nasal polyps of patients with eosinophilic chronic rhinosinusitis. Thus, IL-33-ST2-p38 signaling appears to directly instruct pathogenic memory Th2 cells to produce IL-5 and induce eosinophilic inflammation. PMID- 25692704 TI - Structural damage in the C. elegans epidermis causes release of STA-2 and induction of an innate immune response. AB - The epidermis constantly encounters invasions that disrupt its architecture, yet whether the epidermal immune system utilizes damaged structures as danger signals to activate self-defense is unclear. Here, we used a C. elegans epidermis model in which skin-penetrating infection or injury activates immune defense and antimicrobial peptide (AMP) production. By systemically disrupting each architectural component, we found that only disturbance of the apical hemidesmosomes triggered an immune response and robust AMP expression. The epidermis recognized structural damage through hemidesmosomes associated with a STAT-like protein, whose disruption led to detachment of STA-2 molecules from hemidesmosomes and transcription of AMPs. This machinery enabled the epidermis to bypass certain signaling amplification and directly trigger AMP production when subjected to extensive architectural damage. Together, our findings uncover an evolutionarily conserved mechanism for the epithelial barriers to detect danger and activate immune defense. PMID- 25692705 TI - DNA damage primes the type I interferon system via the cytosolic DNA sensor STING to promote anti-microbial innate immunity. AB - Dysfunction in Ataxia-telangiectasia mutated (ATM), a central component of the DNA repair machinery, results in Ataxia Telangiectasia (AT), a cancer-prone disease with a variety of inflammatory manifestations. By analyzing AT patient samples and Atm(-/-) mice, we found that unrepaired DNA lesions induce type I interferons (IFNs), resulting in enhanced anti-viral and anti-bacterial responses in Atm(-/-) mice. Priming of the type I interferon system by DNA damage involved release of DNA into the cytoplasm where it activated the cytosolic DNA sensing STING-mediated pathway, which in turn enhanced responses to innate stimuli by activating the expression of Toll-like receptors, RIG-I-like receptors, cytoplasmic DNA sensors, and their downstream signaling partners. This study provides a potential explanation for the inflammatory phenotype of AT patients and establishes damaged DNA as a cell intrinsic danger signal that primes the innate immune system for a rapid and amplified response to microbial and environmental threats. PMID- 25692706 TI - [(Li(0.8)Fe(0.2))OH]FeS and the ferromagnetic superconductors [(Li(0.8)Fe(0.2))OH]Fe(S(1-x)Se(x)) (0 < x <= 1). AB - Superconductivity up to 43 K and magnetic ordering coexist in the iron chalcogenides [(Li(0.8)Fe(0.2))OH]Fe(S(1-x)Se(x)) (0 < x <= 1). Substitution of sulphur for selenium gradually suppresses superconductivity while the ferromagnetic signature persists up to non-superconducting [(Li(0.8)Fe(0.2))OH]FeS. PMID- 25692707 TI - Correspondence between maternal determination of child fullness and young children's self-determined fullness level: results from a standardized laboratory protocol. AB - BACKGROUND: This study examined maternal understanding and acceptance of young children's ability to self-assess fullness using a mixed-methods approach. METHODS: Twenty low-income mothers of 5- to 7-year-olds participated in this semistructured laboratory study. After consumption of a buffet dinner meal, mothers were asked to indicate their perception of their child's fullness level, and children were also asked to self-assess their fullness level. RESULTS: Five of the 20 mothers in the study were initially correct in their assessment of their child's level of fullness. Half of the incorrect mothers were willing to change their rating when informed that the child's fullness rating was different than her own. CONCLUSIONS: Semistructured interview results provide suggestive evidence that some mothers believe they understand their child's fullness level better than their children. Given that mothers have the potential to override children's ability to self-regulate eating behavior, teaching mothers to understand and appreciate young children's ability to self-regulate eating is an important area for intervention. PMID- 25692710 TI - Personality in sanctuary-housed chimpanzees: A comparative approach of psychobiological and penta-factorial human models. AB - We evaluate a sanctuary chimpanzee sample (N = 11) using two adapted human assessment instruments: the Five-Factor Model (FFM) and Eysenck's Psychoticism Extraversion-Neuroticism (PEN) model. The former has been widely used in studies of animal personality, whereas the latter has never been used to assess chimpanzees. We asked familiar keepers and scientists (N = 28) to rate 38 (FFM) and 12 (PEN) personality items. The personality surveys showed reliability in all of the items for both instruments. These were then analyzed in a principal component analysis and a regularized exploratory factor analysis, which revealed four and three components, respectively. The results indicate that both questionnaires show a clear factor structure, with characteristic factors not just for the species, but also for the sample type. However, due to its brevity, the PEN may be more suitable for assessing personality in a sanctuary, where employees do not have much time to devote to the evaluation process. In summary, both models are sensitive enough to evaluate the personality of a group of chimpanzees housed in a sanctuary. PMID- 25692711 TI - Recurrent cellular leiomyoma 10 years after total abdominal hysterectomy. PMID- 25692712 TI - Asset Decommissioning Risk Metrics for Floating Structures in the Gulf of Mexico. AB - Public companies in the United States are required to report standardized values of their proved reserves and asset retirement obligations on an annual basis. When compared, these two measures provide an aggregate indicator of corporate decommissioning risk but, because of their consolidated nature, cannot readily be decomposed at a more granular level. The purpose of this article is to introduce a decommissioning risk metric defined in terms of the ratio of the expected value of an asset's reserves to its expected cost of decommissioning. Asset decommissioning risk (ADR) is more difficult to compute than a consolidated corporate risk measure, but can be used to quantify the decommissioning risk of structures and to perform regional comparisons, and also provides market signals of future decommissioning activity. We formalize two risk metrics for decommissioning and apply the ADR metric to the deepwater Gulf of Mexico (GOM) floater inventory. Deepwater oil and gas structures are expensive to construct, and at the end of their useful life, will be expensive to decommission. The value of proved reserves for the 42 floating structures in the GOM circa January 2013 is estimated to range between $37 and $80 billion for future oil prices between 60 and 120 $/bbl, which is about 10 to 20 times greater than the estimated $4.3 billion to decommission the inventory. Eni's Allegheny and MC Offshore's Jolliet tension leg platforms have ADR metrics less than one and are approaching the end of their useful life. Application of the proposed metrics in the regulatory review of supplemental bonding requirements in the U.S. Outer Continental Shelf is suggested to complement the current suite of financial metrics employed. PMID- 25692713 TI - Electromechanical reshaping of ex vivo porcine trachea. AB - OBJECTIVES: The trachea is a composite cartilaginous structure particularly prone to various forms of convexities. Electromechanical reshaping (EMR) is an emerging technique used to reshape cartilaginous tissues by applying electric current in tandem with imposed mechanical deformation to achieve shape change. In this study, EMR was used to reshape tracheal cartilage rings to demonstrate the feasibility of this technology as a potentially minimally invasive procedure to alter tracheal structure. STUDY DESIGN: Controlled laboratory study using ex vivo porcine tracheae. METHODS: The natural concavity of each porcine tracheal ring was reversed around a cork mandrel. Two pairs of electrodes were inserted along the long axis of the tracheal ring and placed 1.5 millimeters from the midline. Current was applied over a range of voltages (3 volts [V], 4V, and 5V) for either 2 or 3 minutes. The degree of EMR-induced reshaping was quantified from photographs using digital techniques. Confocal imaging with fluorescent live and dead assays was conducted to determine viability of the tissue after EMR. RESULTS: Specimens that underwent EMR for 2 or 3 minutes at 4V or 5V were observed to have undergone significant (P < .05) reshaping relative to the control. Viability results demonstrated that EMR reshaping occurs at the expense of tissue injury, although the extent of injury is modest relative to conventional techniques. CONCLUSION: EMR reshapes tracheal cartilage rings as a function of voltage and application time. It has potential as a minimally invasive and cost-efficient endoscopic technology to treat pathologic tracheal convexities. Given our findings, consideration of EMR for use in larger ex vivo tracheal segments and animal studies is now plausible. PMID- 25692714 TI - The roles of post-translational modifications in the context of protein interaction networks. AB - Among other effects, post-translational modifications (PTMs) have been shown to exert their function via the modulation of protein-protein interactions. For twelve different main PTM-types and associated subtypes and across 9 diverse species, we investigated whether particular PTM-types are associated with proteins with specific and possibly "strategic" placements in the network of all protein interactions by determining informative network-theoretic properties. Proteins undergoing a PTM were observed to engage in more interactions and positioned in more central locations than non-PTM proteins. Among the twelve considered PTM-types, phosphorylated proteins were identified most consistently as being situated in central network locations and with the broadest interaction spectrum to proteins carrying other PTM-types, while glycosylated proteins are preferentially located at the network periphery. For the human interactome, proteins undergoing sumoylation or proteolytic cleavage were found with the most characteristic network properties. PTM-type-specific protein interaction network (PIN) properties can be rationalized with regard to the function of the respective PTM-carrying proteins. For example, glycosylation sites were found enriched in proteins with plasma membrane localizations and transporter or receptor activity, which generally have fewer interacting partners. The involvement in disease processes of human proteins undergoing PTMs was also found associated with characteristic PIN properties. By integrating global protein interaction networks and specific PTMs, our study offers a novel approach to unraveling the role of PTMs in cellular processes. PMID- 25692715 TI - Spatiotemporal mapping of PKA activity using biosensors. PMID- 25692716 TI - Multiplex CRISPR/Cas9-based genome editing for correction of dystrophin mutations that cause Duchenne muscular dystrophy. AB - The CRISPR/Cas9 genome-editing platform is a promising technology to correct the genetic basis of hereditary diseases. The versatility, efficiency and multiplexing capabilities of the CRISPR/Cas9 system enable a variety of otherwise challenging gene correction strategies. Here, we use the CRISPR/Cas9 system to restore the expression of the dystrophin gene in cells carrying dystrophin mutations that cause Duchenne muscular dystrophy (DMD). We design single or multiplexed sgRNAs to restore the dystrophin reading frame by targeting the mutational hotspot at exons 45-55 and introducing shifts within exons or deleting one or more exons. Following gene editing in DMD patient myoblasts, dystrophin expression is restored in vitro. Human dystrophin is also detected in vivo after transplantation of genetically corrected patient cells into immunodeficient mice. Importantly, the unique multiplex gene-editing capabilities of the CRISPR/Cas9 system facilitate the generation of a single large deletion that can correct up to 62% of DMD mutations. PMID- 25692717 TI - School-based HPV immunization of young adolescents: effects of two brief health interventions. AB - Adolescent immunization rates for human papillomavirus (HPV) are low and interventions within school-based health centers (SBHCs) may increase HPV uptake and series completion. We examined the effect of a parent health message intervention on HPV vaccination intent, first dose uptake and series completion among adolescents who received care at SBHCs. Via computer-assisted telephone interviews (CATI), 445 parents of young adolescents were randomly assigned to 2 two-level interventions using a 2 * 2 design (rhetorical question (RQ) or no-RQ and one-sided or two-sided message). The RQ intervention involved asking the parent a question they were likely to endorse (e.g., "Do you want to protect your daughter from cervical cancer?") with the expectation that they would then behave in a manner consistent with their endorsement (i.e., agree to vaccinate). For the one-sided message, parents were given information that emphasized the safety and effectiveness of HPV vaccine, whereas the two-sided message acknowledged that some parents might have concerns about the vaccine, followed by reassurance regarding the safety and effectiveness. At CATI conclusion, parents indicated intentions to have their adolescents vaccinated. Parents who endorsed any intent were sent a consent form to return and all adolescents with signed returned consents were vaccinated at SBHCs. Medical records were reviewed for uptake/completion. Parents were 87% female; adolescents were 66% male and racially/ethnically diverse. 42.5% of parents indicated some intention to immunize, 51.4% were unsure, and 6.1% were not interested. 34% (n = 151) of adolescents received their first dose with series completion rates of 67% (n = 101). The RQ component of the intervention increased intention to vaccinate (RR = 1.45; 95%CI 1.16,1.81), but not first dose uptake or series completion. The 1 sided and 2-sided messages had no effect. This brief, RQ health intervention enhanced intent, but did not impact vaccination rates, likely due to the time delay between the intervention and consent form receipt. PMID- 25692718 TI - Investigating general practitioner engagement with pharmacists in Home Medicines Review. AB - The Home Medicines Review (HMR) involves a home visit from an accredited HMR pharmacist to review a patient's medicines, and a report to the patient's general practitioner (GP) with recommendations for improving medicine management. Notwithstanding evidence supporting the benefits of medicines review, broad uptake by GPs in Australia remains low. We developed the 10-item Home Medicines Review Inventory (HMRI) to assess GP attitudes and behaviours regarding the HMR and modelled factors associated with the frequency of GP engagement with HMRs. Four items assessing frequency of behaviours and six items assessing attitudes related to HMR were answered by 180 GPs in a national GP survey. The HMRI's psychometric properties were examined with exploratory factor analysis (EFA), Rasch analysis, and correlations with related instruments. Structural equation modelling was used to evaluate factors associated with HMR-related behaviours. EFA and Rasch analysis generally supported the current format of the instrument. Attitudes to HMR, gender, previous positive experiences with pharmacists, a system for working together, and participation in joint education activities predicted frequency of HMR-related behaviours. Although GPs' attitudes to HMR were generally positive, HMR-related behaviours tended to occur with low frequency. This instrument may be used to investigate why HMR uptake has thus far been low and also help identify opportunities for building interprofessional communication and trust between GPs and pharmacists. PMID- 25692719 TI - An interprofessional education Russian cultural competence course: Implementation and follow-up perspectives. AB - Health sciences educators are faced with creating meaningful, effective and satisfying experiences in interprofessional education (IPE) and cultural competence (CC) required of both students and professionals in practice. This study evaluated the experience and attitudes of the participants in a course combining IPE and CC. A novel, interprofessional course in the Russian language and culture was developed and delivered to a group of medical, nursing, and pharmacy students. One year after the completion of the course, an anonymous, online survey was sent to the participants. Attitudes, comfort, self-efficacy in working with other cultures/healthcare professionals, and comparison of the course to other IPE activities were assessed. The survey suggested that the course was a satisfying and effective combination of IPE and CC in a pre professional health educational setting. Further work could be undertaken to evaluate the experiences of similar activities in the professional and continuing education arenas. PMID- 25692720 TI - A Systematic Review of Resistance Training Versus Endurance Training in COPD. AB - PURPOSE: Endurance training (ET) as part of pulmonary rehabilitation in patients with chronic obstructive pulmonary disease (COPD) has been shown to improve exercise capacity and health-related quality of life, but dyspnea limits the exercise intensity. Therefore, resistance training (RT), which may cause less dyspnea, could be an alternative. The purpose of this review was to formulate evidence-based recommendations on the use of RT in pulmonary rehabilitation of patients with COPD. Our primary outcomes were health-related quality of life, activities of daily living, dyspnea, possible harm, and total mortality. Our secondary outcomes were walking distance, lean body mass, muscle strength, and exercise capacity. METHODS: We identified randomized controlled trials through a systematic multidatabase search. One author checked titles and abstracts for relevance using broad inclusion criteria, whereas 2 authors independently checked the full-text articles for eligibility. Two authors independently extracted data and assessed the risk of bias and quality of evidence. Meta-analyses were performed when deemed feasible based on the quality and amount of data. RESULTS: We included 8 randomized controlled trials (328 participants). On the basis of moderate- to very low-quality evidence, we found no clinically important difference between RT and ET. We did not find sufficient data for a meta-analysis of total mortality, adverse events, dyspnea, or lean body mass. CONCLUSIONS: We found that in patients with COPD, RT seems to induce the same beneficial effects as ET. Therefore, we recommend that RT should be considered according to patient preferences when designing a pulmonary rehabilitation program for patients with COPD. PMID- 25692721 TI - Identification of candidates for observation. AB - PURPOSE OF REVIEW: The clinical value of active surveillance may still be limited due to acceptance and considerable misclassification rates, and inadequate follow up criteria. This review focuses on the most recent developments in the use of active surveillance and patient-specific factors that may be used to identify patients suitable for this strategy. RECENT FINDINGS: The number of patients diagnosed with low-risk prostate cancer has risen. Active surveillance acceptance rates are increasing, but still limited and varying importantly (2-49%). Misclassification is inevitable in all currently used protocols, although most of these patients still have relatively favorable-risk prostate cancer. African American race, obese, and older-aged patients show more unfavorable intermediate results in an active surveillance situation. These are unlikely to be explained by the small differences in preoperative characteristics only. Psychological profiling may also be added to the selection process. Most studies report intermediate endpoints only. SUMMARY: Patient-specific factors may be incorporated when identifying patients for active surveillance. This does not imply that active surveillance is not justified in specific groups, but may suggest the need for an intensified and personalized selection, instead of a one size-fits-all approach. PMID- 25692722 TI - Aligning evidence and practice: future research needs to increase utilization of active surveillance for favorable risk prostate cancer. AB - PURPOSE OF REVIEW: The prolonged natural history of prostate cancers detected through prostate-specific antigen-based testing has resulted in many men today undergoing treatment for prostate cancer that will not improve health outcomes. Active surveillance is an underutilized approach to reducing overtreatment of favorable risk prostate cancer. This review outlines the areas for future research that could improve the uptake of active surveillance as a management option. RECENT FINDINGS: The reasons for limited uptake of active surveillance for favorable risk prostate cancer are multifactorial and complex. The variability in management of favorable risk disease among older men can be attributed to a greater extent to the individual physician rather than tumor and patient characteristics. Increased uptake of active surveillance will depend on improved risk stratification at diagnosis, surveillance protocol standardization, and patient decision support that accounts for individual patient preferences. SUMMARY: The disconnect between evidence and practice with respect to management of favorable risk prostate cancer has resulted in overtreatment. Active surveillance as a management option for favorable risk disease may become more acceptable to patients and physicians as research needs are met. PMID- 25692723 TI - Observational studies and the natural history of screen-detected prostate cancer. AB - PURPOSE OF REVIEW: To review the recent observational studies and clinical trials that guide our understanding of the natural history of screen-detected prostate cancer. RECENT FINDINGS: Data from observational studies and clinical trials have been updated during the past year. The most important include the Scandinavian Prostate Cancer Group 4 study and the European Randomized Study of Prostate Cancer Screening. SUMMARY: Both retrospective population-based analyses and prospective randomized trials show that men who harbor low-volume low-grade prostate cancers have less than 6% risk of disease progression within a decade of diagnosis. For the men who pursue active surveillance prostate cancer mortality remains under 1% after a median follow-up of 6.8 years. Up to one-third of men abandon active surveillance protocols because of either prostate-specific antigen or biopsy progression. Around 10% abandon active surveillance because of anxiety. Researchers are actively exploring new imaging modalities and genetic markers to identify men whose prostate cancers are likely to progress. For now, patients with newly diagnosed prostate cancer must carefully weigh the threat posed by their disease against the possible benefits and harms associated with intervention. For some, active surveillance will be an appropriate choice. PMID- 25692724 TI - Patient and disease factors affecting the choice and adherence to active surveillance. AB - PURPOSE OF REVIEW: Treatment decisions for low-risk prostate cancer are arguably some of the most challenging in oncology. Active surveillance has emerged as an important option for many men with tumors estimated to have a low metastatic potential. Multiple complex patient and physician factors affect the recommendation, selection, and adherence to active surveillance. While baseline clinical criteria are used to identify candidates for this approach, it is important to identify and understand other forces that may influence the management of prostate cancer with active surveillance. RECENT FINDINGS: Patient perceptions and acceptance of active surveillance have improved over time. Treatment decisions for prostate cancer are strongly associated with physician recommendations, and a high-quality relationship between the patient and his healthcare system is critical to successful active surveillance. Patient understanding of prostate cancer and consistency of information received from separate physicians can affect a decision to pursue active surveillance. Psychological symptoms, most notably regarding anxiety and distress, can affect adherence to active surveillance over time. In general, anxiety for men on active surveillance is low, and lifestyle interventions and self-management strategies may be helpful for increasing quality of life and limiting abandonment of active surveillance in the absence of disease progression. SUMMARY: Multiple factors may affect the decision for and adherence to active surveillance for prostate cancer. It is important for both physicians and patients to be aware of these issues and work towards individualized approaches and interventions as needed to increase adoption of active surveillance in the future. PMID- 25692725 TI - Unique features of mutations revealed by sequentially reprogrammed induced pluripotent stem cells. AB - Although viable mice can be generated from induced pluripotent stem cells (iPSCs), the impact of accumulated mutations on the developmental potential of the resulting iPSCs remains to be determined. Here, we demonstrate that all-iPSC mice generated through tetraploid blastocysts complementation can tolerate the accumulation of somatic mutations for up to six generations using a Tet-on inducible reprogramming system. But, the viability of the all-iPS mice decreased with increasing generations. A whole-genome sequencing survey revealed that thousands of single-nucleotide variations (SNVs), including 44 non-synonymous ones, accumulated throughout the sequential reprogramming process. Subsequent analysis provides evidence that these accumulated SNVs account for the gradual reduction in viability of the resultant all-iPSC mice. Unexpectedly, our present reprogramming system revealed that pluripotent stem cells are heterogeneous in terms of possessing a set of copy-number alterations (CNAs). These CNAs are unique for pluripotent cells and subsequently disappear in the differentiating progenies. PMID- 25692726 TI - S-equol: a potential nonhormonal agent for menopause-related symptom relief. AB - Many women suffering from vasomotor symptoms (VMS) are now seeking nonpharmaceutical treatments for symptom relief. Recently, S-equol, an intestinal bacterial metabolite of the soybean isoflavone daidzein has received attention for its ability to alleviate VMS and provide other important health benefits to menopausal women. S-equol is found in very few foods and only in traces. About 50% of Asians and 25% of non-Asians host the intestinal bacteria that convert daidzein into S-equol. Clinical trials that evaluated the efficacy of an S-equol containing product found that VMS were alleviated but these trials were limited in scope and primarily involved Japanese women for whom hot flashes are a minor complaint. The only trial in the United States evaluating hot flashes found symptoms were significantly reduced by S-equol, but the study lacked a placebo group, although it did include a positive control. The daily dose of S-equol used in most trials was 10 mg, and because the half-life of S-equol is 7-10 hours, to maximize efficacy, it was taken twice daily. Subanalysis of epidemiologic studies suggests that equol producers are more likely to benefit from soyfood consumption than nonproducers with respect to both cardiovascular disease and osteoporosis, although the data are inconsistent. The limited safety data for S-equol do not suggest cause for concern, especially with regard to its effects on breast and endometrial tissue. Further studies are needed before definitive conclusions of its effectiveness for VMS can be made, but the preliminary evidence warrants clinicians discussing the potential of S-equol for the alleviation of VMS with patients. PMID- 25692727 TI - Controlling dental enamel-cavity ablation depth with optimized stepping parameters along the focal plane normal using a three axis, numerically controlled picosecond laser. AB - OBJECTIVE: The purpose of this study was to establish a depth-control method in enamel-cavity ablation by optimizing the timing of the focal-plane-normal stepping and the single-step size of a three axis, numerically controlled picosecond laser. BACKGROUND DATA: Although it has been proposed that picosecond lasers may be used to ablate dental hard tissue, the viability of such a depth control method in enamel-cavity ablation remains uncertain. METHODS: Forty-two enamel slices with approximately level surfaces were prepared and subjected to two-dimensional ablation by a picosecond laser. The additive-pulse layer, n, was set to 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70. A three-dimensional microscope was then used to measure the ablation depth, d, to obtain a quantitative function relating n and d. Six enamel slices were then subjected to three dimensional ablation to produce 10 cavities, respectively, with additive pulse layer and single-step size set to corresponding values. The difference between the theoretical and measured values was calculated for both the cavity depth and the ablation depth of a single step. These were used to determine minimum-difference values for both the additive-pulse layer (n) and single-step size (d). RESULTS: When the additive-pulse layer and the single-step size were set 5 and 45, respectively, the depth error had a minimum of 2.25 MUm, and 450 MUm deep enamel cavities were produced. CONCLUSIONS: When performing three dimensional ablating of enamel with a picosecond laser, adjusting the timing of the focal-plane-normal stepping and the single-step size allows for the control of ablation-depth error to the order of micrometers. PMID- 25692728 TI - Use of laser therapy in the healing process: a literature review. AB - OBJECTIVE: The purpose of this work was to conduct a literature search on the use of laser therapy in the tissue repair process, addressing different lasers and parameters used by the authors. METHODS: We conducted a literature review of electronic databases to search for articles that investigate the effects of laser therapy on wound healing in rats, mice, and humans with specific diseases, published from January 2008 to March 2013. RESULTS: In the 31 articles selected, the most frequently used type of laser was gallium-aluminium-arsenium (GaAIAs) in male rats. We noted that the protocol for laser application differed from author to author, making it difficult to compare results regarding the choice of parameters and treatment protocol. CONCLUSIONS: Laser therapy had a positive effect on the healing process of cutaneous lesions in rats, which was not observed in humans. PMID- 25692730 TI - Correction. PMID- 25692731 TI - Educational Outcomes for Orphan Girls in Rural Zimbabwe: Effects of a School Support Intervention. AB - Educational achievement has important implications for the health and well-being of young women in sub-Saharan Africa. The authors assessed the effects of providing school support on educational outcomes of orphan girls in rural Zimbabwe. Data were from a randomized controlled trial offering the intervention group comprehensive schooling support and controls no treatment initially and then fees only. Results indicated comprehensive support reduced school dropout and absence but did not improve test scores. Providing support to orphan girls is promising for addressing World Health Organization Millennium Development Goals, but further research is needed about contextual factors affecting girls' school participation and learning. PMID- 25692732 TI - Neuropsychological and behavioral correlates of impulsiveness in veterans with and without mild traumatic brain injury. AB - INTRODUCTION: Previous research has identified a relation between impulsiveness and substance use, as well as performance on certain tests of executive functioning. However, no prior research has investigated these relations in Operation Enduring Freedom, Operation Iraqi Freedom, or Operation New Dawn (OEF/OIF/OND) veterans with and without a history of mild traumatic brain injury (mTBI). METHOD: The present study utilized a sample of 127 veterans (55 controls, 72 mTBI). Relations among health behaviors, cognition, and domain scores (attentional, motor, and nonplanning impulsiveness) of the Barratt Impulsiveness Scale-11 (BIS-11) were examined using regression analyses. RESULTS: Nonplanning impulsiveness was associated with higher Alcohol Use Disorders Identification Test (AUDIT) score. Attentional and motor impulsiveness were not associated with performance on any measures of behavior or cognition. The relationship between nonplanning impulsiveness and alcohol misuse was not influenced by history of mTBI. CONCLUSIONS: These results partially support previous findings and indicate that an association between impulsiveness and problematic behaviors exists in OEF/OIF/OND veterans, regardless of TBI history. PMID- 25692733 TI - Plasmon resonance tuning using DNA origami actuation. AB - A strategy for an innovative, continuous and reversible LSPR tuning using DNA origami actuation to modulate the nanometric separation of two gold nanoparticles has been developed. The actuation mechanism is based on DNA hybridization, in particular three different DNA sequences were shown to induce resonance shift of up to 6 nm. PMID- 25692734 TI - Inhibition of adhesion of intestinal pathogens (Escherichia coli, Vibrio cholerae, Campylobacter jejuni, and Salmonella Typhimurium) by common oligosaccharides. AB - Inhibition of the binding of pathogenic adhesins to host glycans by suitable oligosaccharides forms the basis of antiadhesion therapies. Experiments were carried out to study the inhibition capability of oligosaccharides on the adhesion of four microorganisms (Escherichia coli, Vibrio cholerae, Campylobacter jejuni, and Salmonella Typhimurium) to HT-29 cells. Results showed that, in the absence of oligosaccharides, all of the four pathogens efficiently adhered to the cells. Cell adhesion with different bacteria was inhibited by distinct oligosaccharides (e.g., the adhesion number relative to control of V. cholerae could be significantly decreased by pectin oligosaccharide and chitooligosaccharide to about 16.1% and 18.9%, respectively). Saturation studies showed that the extent of antiadhesive effect for most of the suitable carbohydrates was dependent on their concentration. The observations from the study suggest that various carbohydrates may have antiadhesive activity and may be useful in future therapeutic study. PMID- 25692735 TI - Patients treated for hematologic malignancies: affected sexuality and health related quality of life. AB - BACKGROUND: Sexuality in relation to health-related quality of life (HRQoL) is studied mostly with younger patients as participants who have undergone bone marrow transplantation and concerns fertility and/or sexual function. However, patients with hematologic malignancies such as diffuse large B-cell lymphoma, chronic lymphocytic leukemia, or acute myeloid leukemia most often are above their fifties and are treated with chemotherapy or chemoimmunotherapy. OBJECTIVE: The aim was to examine how sexuality and HRQoL were affected in patients with hematologic malignancies at baseline compared with 1 month after chemotherapy or chemoimmunotherapy. METHODS: Data were collected twice with a longitudinal design using the Sexual Adjustment Questionnaire and the European Organization for Research and Treatment of Cancer Quality of Life questionnaire. RESULTS: Thirty two patients responded. The importance of sexuality, sexual desire, and sexual ability decreased 1 month after treatment and distressing symptoms such as feelings of tiredness occurred more frequently compared with baseline. At the same time, improvement in global health status/quality of life as well as affected functions in HRQoL was reported. CONCLUSION: The findings are of significance for nurses in cancer care as these highlight that sexuality and HRQoL need to be considered also in older patients with hematologic malignancies when fertility issues are of less importance. IMPLICATION FOR PRACTICE: To meet these patients' needs regarding sexuality and HRQoL, the care must provide greater consistency and continuity. One way is to organize the care in a patient centered way where patients continuously meet a nurse guided by the idea of holistic individual nursing care throughout the care trajectory. PMID- 25692736 TI - Self-management for adult patients with cancer: an integrative review. AB - BACKGROUND: Individuals with cancer are surviving long term, categorizing cancer as a chronic condition, and with it, numerous healthcare challenges. Symptoms, in particular, can be burdensome and occur from prediagnosis through many years after treatment. Symptom severity is inversely associated with functional status and quality of life. OBJECTIVE: Management of these millions of survivors of cancer in a stressed healthcare system necessitates effective self-care strategies. The purpose of this integrative review is to evaluate intervention studies led by nurse principal investigators for self-care management in patients with cancer. METHODS: PubMed, CINAHL (Cumulative Index to Nursing and Allied health Literature), and the Cochrane Database were searched from January 2000 through August 2012. Search terms included "symptom management and cancer," "self management and cancer," and "self-care and cancer." All articles for consideration included intervention studies with a nurse as the primary principal investigator. RESULTS: Forty-six articles were included yielding 3 intervention areas of educational and/or counseling sessions, exercise, and complementary and alternative therapies. Outcomes were predominately symptom focused and often included functional status and quality of life. Few studies had objective measures. Overarching themes were mitigation, but not prevention or elimination of symptoms, and improved quality of life related to functional status. No one intervention was superior to another for any given outcome. CONCLUSIONS: Current interventions that direct patients in self-care management of symptoms and associated challenges with cancer/survivorship are helpful, but incomplete. No one intervention can be recommended over another. IMPLICATIONS FOR PRACTICE: Guiding patients with cancer in self-care management is important for overall functional status and quality of life. Further investigation and tailored interventions are warranted. PMID- 25692737 TI - Eukaryotic tRNA paradox. AB - tRNAs are widely believed to segregate into two classes, I and II. Computational analysis of eukaryotic tRNA entries in Genomic tRNA Database, however, leads to new, albeit paradoxical, presence of more than a thousand class-I tRNAs with uncharacteristic long variable arms (V-arms), like in class-II. Out of 62,202 tRNAs from 69 eukaryotes, as many as 1431 class-I tRNAs have these novel extended V-arms, and we refer to them as paradoxical tRNAs (pxtRNAs). A great majority of these 1431 pxtRNA genes are located in intergenic regions, about 18% embedded in introns of genes or ESTs, and just one in 3'UTR. A check on the conservations of 2D and 3D base pairs for each position of these pxtRNAs reveals a few variations, but they seem to have almost all the known features (already known identity and conserved elements of tRNA). Analyses of the A-Box and B-Box of these pxtRNA genes in eukaryotes display salient deviations from the previously annotated conserved features of the standard promoters, whereas the transcription termination signals are just canonical and non-canonical runs of thymidine, similar to the ones in standard tRNA genes. There is just one such pxtRNA(ProAGG) gene in the entire human genome, and the availability of data allows epigenetic analysis of this human pxtRNA(ProAGG) in three different cell lines, H1 hESC, K562, and NHEK, to assess the level of its expression. Histone acetylation and methylation of this lone pxtRNA(ProAGG) gene in human differ from that of the nine standard human tRNA(ProAGG) genes. The V-arm nucleotide sequences and their secondary structures in pxtRNA differ from that of class-II tRNA. Considering these differences, hypotheses of alternative splicing, non-canonical intron and gene transfer are examined to partially improve the Cove scores of these pxtRNAs and to critically question their antecedence and novelty. PMID- 25692738 TI - Feasibility and efficacy of outpatient therapy with intermediate dose cytarabine, fludarabine and idarubicin for patients with acute myeloid leukaemia aged 70 or older. AB - OBJECTIVES: A multicentre prospective non-randomised study of de novo acute myeloid leukaemia (AML) in patients aged >=70 yr was designed to reduce toxicity and achieve acceptable complete remission (CR) rates. METHODS: The outpatient treatment included induction with oral fludarabine, subcutaneous cytarabine and subcutaneous filgrastim (FAG). The patients received more induction cycles according to the response achieved. If there was no response to induction with FAG, the following induction cycle included oral idarubicin, subcutaneous cytarabine and subcutaneous filgrastim (IAG). Patients achieving CR received one intensification (FAG on response to previous FAG or alternatively IAG) and one consolidation cycle (IAG). RESULTS: Thirty patients were enrolled from April 2004 to June 2007. The median age was 73 yr (range 70-77). Fifteen patients (50%) achieved CR. The 2-yr DFS was 29% (95% CI, 5-47%), and the 2-yr OS was 23% (95% CI, 12-35%). Twenty-five of 69 cycles (36%) were managed on a completely outpatient basis. The median hospital stay per cycle was 10 d (95% CI, 3-25). CONCLUSIONS: This study demonstrates the tolerability and efficacy of a semi intensive treatment in elderly de novo patients with AML managed on an outpatient basis, without substantial toxicity. PMID- 25692739 TI - Using SBAR to promote clinical judgment in undergraduate nursing students. AB - The purpose of this study was to describe how students identify and interpret multiple embedded clinical cues in a case study, and then reflect these using SBAR (Situation, Background, Assessment, and Recommendation). Using Tanner's model of clinical judgment, a descriptive design was used to examine SBAR assignments completed by second-semester nursing students (n = 80). The majority of students (n = 62, 77.5%) in the study were unable to successfully follow all of the clinical judgment phases of the model: noticing, interpreting, responding, and reflecting. Although SBAR is an important tool for communicating clinical information, gaps exist between noticing and interpreting clinical cues, and forming an appropriate course of action. PMID- 25692740 TI - Influenza vaccine response profiles are affected by vaccine preparation and preexisting immunity, but not HIV infection. AB - Vaccines dramatically reduce infection-related morbidity and mortality. Determining factors that modulate the host response is key to rational vaccine design and demands unsupervised analysis. To longitudinally resolve influenza specific humoral immune response dynamics we constructed vaccine response profiles of influenza A- and B-specific IgM and IgG levels from 42 healthy and 31 HIV infected influenza-vaccinated individuals. Pre-vaccination antibody levels and levels at 3 predefined time points after vaccination were included in each profile. We performed hierarchical clustering on these profiles to study the extent to which HIV infection associated immune dysfunction, adaptive immune factors (pre-existing influenza-specific antibodies, T cell responses), an innate immune factor (Mannose Binding Lectin, MBL), demographic characteristics (gender, age), or the vaccine preparation (split vs. virosomal) impacted the immune response to influenza vaccination. Hierarchical clustering associated vaccine preparation and pre-existing IgG levels with the profiles of healthy individuals. In contrast to previous in vitro and animal data, MBL levels had no impact on the adaptive vaccine response. Importantly, while HIV infected subjects with low CD4 T cell counts showed a reduced magnitude of their vaccine response, their response profiles were indistinguishable from those of healthy controls, suggesting quantitative but not qualitative deficits. Unsupervised profile-based analysis ranks factors impacting the vaccine-response by relative importance, with substantial implications for comparing, designing and improving vaccine preparations and strategies. Profile similarity between HIV infected and HIV negative individuals suggests merely quantitative differences in the vaccine response in these individuals, offering a rationale for boosting strategies in the HIV infected population. PMID- 25692741 TI - Detection of S-nitroso compounds by use of midinfrared cavity ring-down spectroscopy. AB - S-Nitroso compounds have received much attention in biological research. In addition to their role as nitric oxide donors, there is growing evidence that these compounds are involved in signaling processes in biological systems. Determination of S-nitrosylated proteins is of great importance for fundamental biological research and medical applications. The most common method to assay biological S-nitroso compounds is to chemically or photochemically reduce SNO functional groups to release nitric oxide, which is then entrained in an inert gas stream and detected, usually through chemiluminescence. We report a method of S-nitroso compound detection using cavity ring-down measurements of gaseous NO absorbance at 5.2 MUm. The proposed method, in contrast to the chemiluminescence based approach, can be used to distinguish isotopic forms of NO. We demonstrated sensitivity down to ~2 pmol of S(14)NO groups and ~5 pmol of S(15)NO groups for S nitroso compounds in aqueous solutions. The wide dynamic range of cavity ring down detection allows the measurement of S-nitroso compound levels from pico- to nanomole amounts. PMID- 25692742 TI - Post-stroke epilepsy in Polish paediatric patients. AB - AIM: The aim of this study was to characterize a group of children with early and late remote seizures, which occurred after arterial ischaemic stroke (AIS), and to find predictors of post-stroke seizures. METHOD: The study group, recruited in the Department of Neuropediatrics (Medical University of Silesia, Katowice, Poland), comprised 78 individuals (range 1-18y) who had suffered a stroke: 13 participants had early seizures, occurring up to 7 days after AIS, seven participants had late remote seizures, occurring more than 7 days after AIS, and 58 participants had no seizures. RESULTS: Post-stroke epilepsy occurred in 10 patients having post-stroke seizures. Participants affected by late remote seizures were younger, on average, than participants unaffected by seizures. The frequencies of total anterior circulation infarct (TACI) stroke subtype and focal cerebral arteriopathy (FCA) were significantly higher in the late seizure subgroup than in the subgroup without seizures (71% vs 26%, p=0.014, OR 7.17, and 100% vs 51%, p=0.015 respectively). Multivariable Cox analysis showed that age at time of stroke (p=0.027), FCA (p=0.010), and the number of infarct foci (p<0.001) were significant predictors of post-stroke seizures. INTERPRETATION: Age at time of stroke, presence of FCA, and number of infarct foci are predictors of post stroke seizures in Polish paediatric patients. PMID- 25692743 TI - Brief Behavioral Interventions for Symptoms of Depression and Insomnia in University Primary Care. AB - OBJECTIVE: To describe how behavioral activation (BA) for depression and stimulus control (SC) for insomnia can be modified to a brief format for use in a university primary care setting, and to evaluate preliminarily their effectiveness in reducing symptoms of depression and insomnia, respectively, using data collected in routine clinical care. PARTICIPANTS/METHODS: Chart review data were obtained for 11 patients treated between August 2009 and December 2010 with 1 session of brief BA for depression and 17 patients treated with 1 session of brief SC for insomnia. RESULTS: At 2-week follow-up, patients reported significant decreases in symptoms of depression on the Patient Health Questionnaire-9, t(10) = 3.95, p < .05, and insomnia on the Insomnia Severity Index, t(16) = 5.43, p < .05, respectively. CONCLUSIONS: This case report provides preliminary evidence of the external validity of brief BA and SC after they were adapted for use within university primary care. PMID- 25692747 TI - The negative charge of the membrane has opposite effects on the membrane entry and exit of pH-low insertion peptide. AB - The pH-low insertion peptide (pHLIP) targets acidic diseases such as cancer. The acidity of the environment causes key aspartic acids in pHLIP to become protonated, causing the peptide to insert into membranes. Here we investigate how the negative charge of the membrane influences how pHLIP enters and exits the lipid bilayer. We found that electrostatic repulsion affected differently the membrane entry and exit of pHLIP for negatively charged membranes. As a consequence, a large hysteresis was observed. We propose this is not a consequence of structural changes but results from local changes in the environment of aspartic acids, shifting their pK values. PMID- 25692748 TI - Online teaching: "are you there, and do you care?". AB - Much of nursing education is moving online, and faculty must learn to deliver content and communicate differently. A hybrid model of concept development provided insight into faculty's perceptions and expressions of online caring presence. Phase one of concept development revealed many related concepts. Phase two involved (a) six qualitative interviews with doctoral-prepared nursing faculty who taught 100% online, and (b) Watson's Ten Caritas Processes were revised for application in online nursing education and used as a guide for course review. Four themes emerged from the interview data: (a) online teaching experiences, (b) similarities and differences between online and face-to-face teaching, (c) online presence, and (d) online caring presence. Course review suggested that faculty promoted helping-trusting-caring relationships and addressed individual learning needs. Phase three integrated findings from phases one and two; a comprehensive definition of online caring presence was developed. Recommendations regarding technology and communication skill acquisition and Caritas Process application are suggested. PMID- 25692749 TI - Trojan-horse mechanism in the cellular uptake of silver nanoparticles verified by direct intra- and extracellular silver speciation analysis. AB - The so-called "Trojan-horse" mechanism, in which nanoparticles are internalized within cells and then release high levels of toxic ions, has been proposed as a behavior in the cellular uptake of Ag nanoparticles (AgNPs). While several reports claim to have proved this mechanism by measuring AgNPs and Ag ions (I) in cells, it cannot be fully proven without examining those two components in both intra- and extracellular media. In our study, we found that even though cells take up AgNPs similarly to (microglia (BV-2)) or more rapidly than (astrocyte (ALT)) Ag (I), the ratio of AgNPs to total Ag (AgNPs+Ag (I)) in both cells was lower than that in outside media. It could be explained that H2O2, a major intracellular reactive oxygen species (ROS), reacts with AgNPs to form more Ag (I). Moreover, the major speciation of Ag (I) in cells was Ag(cysteine) and Ag(cysteine)2, indicating the possible binding of monomer cysteine or vital thiol proteins/peptides to Ag ions. Evidence we found indicates that the Trojan-horse mechanism really exists. PMID- 25692750 TI - [Assessment of the spiritual needs of patients in palliative care]. AB - The appraisal and the right diagnostics of all needs and problems of patients, including the spiritual needs, are unavoidable for increase of the quality of the all-embracing nursing care. In the case of satisfying of the needs of the patients, it is important to have view the person as a unity of thebody and the soul. Identification and satisfying of the spiritual needs are not uncomplicated; moreover, spirituality does not have a target--ed and clear definition. In the palliative care, the solution and saturation of spiritual needs have a great priority, and it can be the key aspect of psychological activity. Also, medical experts are becoming aware of the meaning of spirituality as the part of psychological contentment more and more. Smaller importance is attached to measurement of spiritual needs, and in many medical institutions ends at the case history with the questions: "Are you a believer?", "Do you have any spiritual needs?". Spirituality and religion are very personal matters of every human. Many patients turn to religion to find answers to difficult questions while others find support through the spiritual beliefs outside the scope of organized religion. Mistaking of meanings of the spirituality and religionism can lead to many misunderstandings. The basic condition for the right diagnostics and satisfaction of spiritual needs are the definition of the used terms and using of standardized measurement devices in the clinical praxis. The target of summarizing study was to define the term of spirituality, to describe a lot of measurement devices these are suitable for the evaluation of human spiritual needs. For methodology for acquiring of the results of research works that are concerned with the questions of spiritual needs in case of the incurable patients, the following databases were used (2005-2013): EBSCO, Bibliographia Medica Cechoslovaca, Google Scholar, Solen - www.solen.cz, Profese on-line as the source of the data. The choice of studies were as follows the systematic overview, the summarizing essay, the qualitative and quantitative study. PMID- 25692751 TI - [Dental abnormalities after treatment for childhood cancer]. AB - Childhood cancer therapy often increases the risk of dental complications, such as tooth and roots agenesis, microdontia, abnormal development of tooth enamel, increased risk of cavity and other abnormalities. In a comparison with other late adverse effects of chemotherapy, radiotherapy and hematopoietic stem cell transplantion, a relative small number of clinical stud-ies observing patients for more than two years after completion of anticancer treatment was published. In this article, we review the incidence of dental abnormalities caused by commonly used anticancer treatment modalities as well as discuss their risk factors. Early identification of high-risk patients, early detection and management of dental abnormalities and better education of patients or their guardians, may have an impact on quality of life of cancer survivors. PMID- 25692752 TI - [Management of patients with castration-resistant metastatic prostate cancer]. AB - Prostate cancer belongs to the most common malignant tumors in males. Almost in all patients in advanced stage, disease progression occurs despite of castration therapy. Initial treatment of metastatic disease is androgen deprivation therapy. In the case of castration-resistant disease development in asymptomatic patients, it is a combination of abiraterone acetate plus prednisone and in symptomatic patients docetaxel with prednisone are considered gold standards at the present time. The aim of therapy must be assurance of adequate quality of life, pain reduction and survival improvement. The paper presents an overview of current castration-resistant metastatic prostate cancer treatment. PMID- 25692753 TI - Estimating cancer incidence, prevalence, and the number of cancer patients treated with antitumor therapy in 2015 and 2020 - analysis of the Czech National Cancer Registry. AB - BACKGROUND: Cancer burden in the Czech population ranks among the highest worldwide, which introduces a strong need for a prospective modelling of cancer incidence and prevalence rates. Moreover, a prediction of number of cancer patients requiring active antitumor therapy is also an important issue. This paper presents the stage-specific predictions of cancer incidence and prevalence, and the stage- and region-specific patients requiring active antitumor therapy for the most common cancer diagnoses in the Czech Republic for years 2015 and 2020. The stage-specific estimates are also presented with regard to the treatment phase as newly diagnosed patients, patients treated for non-terminal recurrence, and patients treated for terminal recurrence. PATIENTS AND METHODS: Data of the Czech National Cancer Registry from 1977 to 2011 has been used for the analysis, omitting the records of patients diagnosed as death certificate only or at autopsy. In total, 1,777,775 incidences have been considered for the estimation using a statistical model utilizing solely the population-based cancer registry data. All estimates have been calculated with respect to the changing demographic structure of the Czech population and the clinical stage at diagnosis. RESULTS: Considering year 2011 as the baseline, we predict 89%, 15%, 31% and 32% increase in prostate, colorectal, female breast and lung cancer incidence, respectively, in 2020 resulting in 13,153, 9,368, 8,695, and 8,604 newly dia-g--nosed cancer patients in that year, respectively. Regarding cancer prevalence in 2020, the estimated increase is 140%, 40%, 51%, and 17% for prostate, colorectal, female breast and lung cancer, respectively, meaning that more than 100,000 prevalent female breast cancer patients as well as more than 100,000 prevalent prostate cancer patients are expected in the Czech Republic. The estimated numbers of patients requiring active antitumor therapy for prostate, colorectal, female breast and lung cancer in the Czech Republic in 2020 are 23,652, 14,006, 14,759 and 8,272; respectively. CONCLUSIONS: The analysis documents a serious increase in cancer incidence and prevalence in the Czech Republic in years 2015 and 2020 when compared to the situation in 2011. Regarding the estimated numbers of patients requiring active antitumor therapy, the model confirms a continuous increase that must be accounted for in the future planning of health care in the Czech Republic. PMID- 25692754 TI - A new approach in DCE MRI data analysis for differentiating benign and malignant breast lesions. AB - BACKGROUND: Dynamic contrast enhanced MRI (DCE MRI) is able to reflect changes in vascularity, vessel permeability and extracellular diffusion space of tissues. The goal of this study was to investigate the use of DCE MRI to differentiate benign and malignant breast lesions. PATIENTS AND METHODS: From a database, five patients with malignant and five patients with benign lesions were randomly chosen. All patients underwent measurement in a 3T MR scanner using a breast coil. A series of T1-weighted MRI were performed using an intravenously delivered contrast agent. Then, 17 postcontrast sets were acquired within a timeframe of 13 seconds. All DCE MRI data were evaluated using the JIM image analysis package. We observed changes in signal intensity over the acquisition time - curves of dynamic contrast enhancement. CONCLUSION: We investigated parts of the curves with the largest increase in signal intensity during the timeframe. For further comparison, we used values of the highest signal intensity increases between the timeframes. Analysis of these results led to the proposal that the threshold between benign and malignant lesion had a relative value of 100. Furthermore, there was a significant difference between these two types of lesions. PMID- 25692755 TI - [The possibility of the serum concentration of osteocalcin determination in lung cancer patients with suspected bone metastases]. AB - AIM: The aim of this study was to compare serum levels of biochemical markers of bone metabolism - osteocalcin (OC) in correlation with bone metastases found during whole-body bone scintigraphy in patients with lung cancer. MATERIAL AND METHODS: The serum levels of OC as a bone formation marker were determined in 60 patients (46 male, 14 female, mean age 66.65, range 50-84 years) with lung cancer (51 non-small-cell lung cancers - NSCLC and nine small-cell lung cancers - SCLC) and correlated with the presence of bone metastases detected by whole-body bone scintigraphy (hybrid system SPECT/CT: BrightView XCT, Philips Healthcare). Whole body bone scintigraphy results were compared with OC for each patient with lung cancer and for person from control group of 10 persons (two males, eight females, mean age 52.3, range 34-67 years) with-out malignant disease. RESULTS: By whole body bone scintigraphy, bone metastases were found in 15 cases (25%), probably in 11 cases (18.33%) and 34 patients (56.67%) were without bone metastases out of 60 patients with lung cancer. The serum levels of OC were above reference range in five cases (8.33%) only with NSCLC and below reference range in 12 cases (20%) - in 10 cases in patients with NSCLC and in two cases in patients with SCLC. In control group of 10 persons, serum level of OC was below reference range only in one case. CONCLUSION: The serum concentrations of osteocalcin were not correlated with findings performed bywhole-body bone scintigraphy in patients with lung cancer. Osteocalcin serum levels determination probably does not have diagnostic importance in lung cancer patients with suspected bone metastases. PMID- 25692756 TI - Sarcomatoid carcinoma of the lung - a case report. AB - BACKGROUND: Sarcomatoid carcinoma (SARC) of the lung is a very rare and aggressive type of nonsmall cell lung cancer. It belongs to a group of poorly differentiated carcinomas with partial sarcomatoid differentiation or with a direct sarcoma component. Characteristic findings include a large tumor with an invasive tendency, early recurrence and systemic metastases. CASE: The authors present a case of SARC in the 77-year-old patient. Preoperative staging confirmed sarcomatoid carcinoma of the lower lobe of the left lung without generalization on PET/CT. However, an infiltration of more than 2/3 of the diaphragm was ascertained. A resection was performed - a left lower lobectomy with resection of the diaphragm and its replacement by a muscle flap made from the latissimus dorsi muscle with vascular pedicle. Histological findings confirmed the dia gnosis of sarcomatoid (pleomorphic) carcinoma pT3N0M0. The patient underwent adjuvant chemotherapy; recurrence and systemic dissemination of the disease occurred after 20 months; the patient died 21 months after the surgery. PMID- 25692757 TI - The role of modifying molecular chains in the formation of organized molecular films of organo-modified nanodiamond: construction of a highly ordered low defect particle layer and evaluation of desorption behavior of organic chains. AB - The role of organo-modifying molecular chains in the formation of molecular films of organo-modified nanodiamond is discussed herein based on interfacial chemical particle integration of organo-modified nanodiamond having a particle size of 5 nm. The surface of nanodiamond is known to be covered with a nanolayer of adsorbed water. This water nanolayer was exploited for organo-modification of nanodiamond with long-chain fatty acids via adsorption, leading to nanodispersion of nanodiamond in general organic solvents as a mimic of solvency. The organo modified nanodiamond dispersed "solution" was used as a spreading solution for depositing a mono-"particle" layer on the water surface, and a Langmuir particle layer was integrated at the air/water interface. Multi-"particle" layers were then formed via the Langmuir-Blodgett technique and were subjected to fine structural analysis. The effect of organo-modification enabled integration and multilayer formation of inorganic nanoparticles due to enhancement of the van der Waals interactions between the chains. That is to say, the "encounter" between the organo-modifying chain and the inorganic particles led to solubilization of the inorganic particles and enhanced interactions between the particles, which can be regarded as imparting new function to the organic molecules. The morphology of the single-particle layer was maintained after removal of the organic region of the composite via the baking process, whereas the regularity of the layered period was disordered. Thus, the organic chains are essential as modifiers for maintenance of the layered structure. PMID- 25692758 TI - Conformational analysis of triphenylphosphine ligands in stereogenic monometallic complexes: tools for predicting the preferred configuration of the triphenylphosphine rotor. AB - The extension of our simple model for predicting the propeller configuration of a triphenylphosphine ligand co-ordinated to achiral metal centres to include stereogenic metal systems is described. By considering nadir energy planes (NEP's) and a series of rigid-body calculations, a model has been developed to reliably predict the configuration of the triphenylphosphine rotor of stereogenic metal complexes. For complexes of the form [M(eta(5)-C5H5)(PPh3)(L(1))(L(2))], where it is assumed that L(1) is larger than L(2), the configuration of the triphenylphosphine rotor may be predicted by viewing a Newman projection along the L(1)-M bond. In the orientation where the PPh3 unit is pointing vertically downwards and the orthogonal L(2) ligand is pointing to the right [i.e., an (RM) configured complex, assuming that L(2) is ranked higher priority than L(1)], the conformation of L(1) can be expected to place the most sterically demanding substituent in the top-right quadrant. In cases where ligand L(1) still presents a steric incursion towards the PPh3 ligand (any part of L(1) other than H proximal to the PPh3 in the approximate zone -30 degrees to +60 degrees from the M-P bond) an (M)-configured rotor is expected, and when this interaction is not present a (P)-configured propeller is predicted. Without exception, these rules are consistent with all empirical data (>140 known crystal structures). PMID- 25692759 TI - Mixed valency in quadruple hydrogen-bonded dimers of bis(biimidazolate)dirhodium complexes. AB - Dirhodium complexes with biimidazole (H2bim) ligands [Rh2(O2CR)2(H2bim)2Cl2] (R = Bu ([1Cl2]), Pr ([2Cl2])), [Rh2(O2CBu)2(H2bim)2](PF6)2 ([1](PF6)2), [Rh2(O2CBu)2(H2bim)2(PPh3)2](PF6)2 ([1(PPh3)2](PF6)2), and [Rh2(O2CPr)2(H2bim)2(PPh3)2]Cl2 ([2(PPh3)2]Cl2) have been synthesized. Deprotonation of the biimidazole complexes afforded the quadruply hydrogen-bonded dimers of the biimidazolate complexes [Rh2(O2CR)2(Hbim)2(PPh3)2]2 (R = Bu ([1'(PPh3)2]2) and Pr ([2'(PPh3)2]2)). Complementary hydrogen bonds between the Hbim(-) ligands are not coplanar because the Hbim(-) ions in one dirhodium complex are not parallel (the dihedral angle between them is ca. 15 degrees ). A cyclic voltammogram of [1'(PPh3)2]2 shows two sets of two consecutive oxidation waves in CH2Cl2. The one-electron-oxidized species of [1'(PPh3)2]2 showed no intervalence charge-transfer band in the electronic spectrum and an axially symmetrical ESR spectrum with hyperfine structure because of two phosphorus atoms. These observations show that the odd electron is localized in a sigma(Rh Rh) orbital on one dirhodium unit. Theoretical calculations indicate that an oxidized complex [Rh2(O2CMe)2(bim)2(PMe3)2](-) hydrogen bonded with a biimidazole complex [Rh2(O2CMe)2(H2bim)2(PMe3)2](2+) was a stable mixed-valence complex. PMID- 25692760 TI - A Somatic p.G45E GJB2 Mutation Causing Porokeratotic Eccrine Ostial and Dermal Duct Nevus. AB - IMPORTANCE: Recent data demonstrated somatic mutations in GJB2 that were present in affected porokeratotic eccrine ostial and dermal duct nevus (PEODDN) tissue but absent in unaffected skin. Recognizing that PEODDN lesions can also appear in individuals with keratitis-ichthyosis-deafness syndrome and finding somatic mutations in their cohort, the authors concluded that somatic GJB2 mutation may cause PEODDN. By using whole-exome sequencing, we show that somatic GJB2 mutation alone is sufficient to cause PEODDN. OBSERVATIONS: We performed whole-exome sequencing of paired blood and affected tissue samples isolated from a PEODDN lesion of a primary school-aged female patient with bands of hyperkeratotic affected skin on the upper and lower extremities and trunk, and identified a single, protein-damaging p.Gly45Glu GJB2 mutation present in tissue samples but not in blood samples. CONCLUSION AND RELEVANCE: Our results prove that somatic GJB2 mutation is sufficient to cause PEODDN. Dominantly inherited GJB2 mutations, including the p.Gly45Glu found in our case, have been shown to cause the severe multisystem disorder keratitis-ichthyosis-deafness syndrome. GJB2 encodes connexin 26, a gap junction protein, which permits intercellular ion and macromolecule flux. Individuals with somatic mosaicism are at risk for transmitting systemic disease to their offspring, and all individuals with PEODDN lesions should be counseled regarding the risk of having a child with keratitis ichthyosis-deafness syndrome. PMID- 25692761 TI - Global positioning system derived performance measures are responsive indicators of physical activity, disease and the success of clinical treatments in domestic dogs. AB - OBJECTIVE: To assess the use of Global Positioning System receiver (GPS) derived performance measures for differentiating between: 1) different outdoor activities in healthy dogs; 2) healthy dogs and those with osteoarthritis; 3) osteoarthritic dogs before and after treatment with non-steroidal anti-inflammatory analgesia. DESIGN: Prospective study. ANIMALS: Ten healthy dogs and seven dogs with osteoarthritis of the elbow joint (OA dogs). PROCEDURE: Healthy dogs were walked on a standard route on-lead, off-lead and subjected to playing activity (chasing a ball) whilst wearing a GPS collar. Each dog was walked for five consecutive days. Dogs with OA were subjected to a single off-lead walk whilst wearing a GPS collar, and then administered oral Carprofen analgesia daily for two weeks. OA dogs were then subjected to the same walk, again wearing a GPS collar. RESULTS: GPS derived measures of physical performance could differentiate between on-lead activity, off-lead activity and playing activity in healthy dogs, and between healthy dogs and OA dogs. Variation in the performance measures analysed was greater between individual dogs than for individual dogs on different days. Performance measures could differentiate healthy dogs from OA dogs. OA Dogs treated with Carprofen analgesia showed improvements in their physical performance, which returned to values indistinguishable from those of healthy dogs on nearly all the measures assessed. CONCLUSIONS AND CLINICAL RELEVANCE: GPS derived measures of physical performance in dogs are objective, easy to quantify, and can be used to gauge the effects of disease and success of clinical treatments. Specific stimuli can be used to modulate physical performance beyond the self-governed boundaries that dogs will naturally express when allowed to exercise freely without stimulation. PMID- 25692762 TI - Exploring the interaction of SV2A with racetams using homology modelling, molecular dynamics and site-directed mutagenesis. AB - The putative Major Facilitator Superfamily (MFS) transporter, SV2A, is the target for levetiracetam (LEV), which is a successful anti-epileptic drug. Furthermore, SV2A knock out mice display a severe seizure phenotype and die after a few weeks. Despite this, the mode of action of LEV is not known at the molecular level. It would be extremely desirable to understand this more fully in order to aid the design of improved anti-epileptic compounds. Since there is no structure for SV2A, homology modelling can provide insight into the ligand-binding site. However, it is not a trivial process to build such models, since SV2A has low sequence identity to those MFS transporters whose structures are known. A further level of complexity is added by the fact that it is not known which conformational state of the receptor LEV binds to, as multiple conformational states have been inferred by tomography and ligand binding assays or indeed, if binding is exclusive to a single state. Here, we explore models of both the inward and outward facing conformational states of SV2A (according to the alternating access mechanism for MFS transporters). We use a sequence conservation analysis to help guide the homology modelling process and generate the models, which we assess further with Molecular Dynamics (MD). By comparing the MD results in conjunction with docking and simulation of a LEV-analogue used in radioligand binding assays, we were able to suggest further residues that line the binding pocket. These were confirmed experimentally. In particular, mutation of D670 leads to a complete loss of binding. The results shed light on the way LEV analogues may interact with SV2A and may help with the on-going design of improved anti-epileptic compounds. PMID- 25692763 TI - Expression of focal adhesion kinase in mouse cumulus-oocyte complexes, and effect of phosphorylation at Tyr397 on cumulus expansion. AB - We investigated the expression of focal adhesion kinase (FAK) in mouse cumulus oocyte complexes (COCs), as well as the role of FAK phosphorylation at Tyr397 during oocyte maturation. The effect of inhibiting FAK phosphorylation at Tyr397 during in vitro maturation (IVM) on subsequent fertilization and preimplantation embryo development was also examined. Western blotting analyses revealed that total and Tyr397-phosphorylated FAK were expressed in vivo in both cumulus cells and oocytes. Immunocytochemical studies localized this kinase throughout the cytoplasm of cumulus cells and oocytes; in particular, Tyr397-phosphorylated FAK tended to accumulate in regions where cumulus cells contact each other. Interestingly, the in vivo level of Tyr397 phosphorylation in cumulus cells was significantly lower after compared to before cumulus expansion. Addition of FAK inhibitor 14, which specifically blocks phosphorylation at Tyr397, stimulated oocyte meiotic maturation and cumulus expansion during IVM in the absence of follicle-stimulating hormone (FSH). Reverse-transcriptase PCR showed that the mRNA expression of hyaluronan synthase 2 (Has2), a marker of cumulus expansion, was significantly induced in cumulus cells. Subsequent in vitro fertilization and culture showed that more oocytes developed to the blastocyst stage when they were treated with FAK inhibitor 14 during IVM, although the blastocyst total cell number was lower than in oocytes stimulated with FSH. These results indicate that FAK is involved in the maturation of COCs; specifically, phosphorylation at Tyr397 may regulate cumulus expansion via the expression of Has2 mRNA in cumulus cells, which could affect the developmental competence of oocytes. PMID- 25692764 TI - Traditional risk factors are more relevant than HIV-specific ones for carotid intima-media thickness (cIMT) in a Brazilian cohort of HIV-infected patients. AB - BACKGROUND: Combination antiretroviral therapy (cART) had a dramatic impact on the mortality profile in human immunodeficiency virus (HIV) infected individuals and increased their life-expectancy. Conditions associated with the aging process have been diagnosed more frequently among HIV-infected patients, particularly, cardiovascular diseases. METHODS: Patients followed in the Instituto de Pesquisa Clinica Evandro Chagas (IPEC) prospective cohort in Rio de Janeiro were submitted to the general procedures from the Brazilian Longitudinal Study of Adult Health, comprising several anthropometric, laboratory and imaging data. Carotid intima media thickness (cIMT) was measured by ultrasonography, following the Mannheim protocol. Linear regression and proportional odds models were used to compare groups and covariables in respect to cIMT. The best model was chosen with the adaptive lasso procedure. RESULTS: A valid cIMT exam was available for 591 patients. Median cIMT was significantly larger for men than women (0.56mm vs. 0.53mm; p = 0.002; overall = 0.54mm). In univariable linear regression analysis, both traditional risk factors for cardiovascular diseases (CVD) and HIV-specific characteristics were significantly associated with cIMT values, but the best multivariable model chosen included only traditional characteristics. Hypertension presented the strongest association with higher cIMT terciles (OR = 2.51; 95%CI = 1.69-3.73), followed by current smoking (OR = 1,82; 95%CI = 1.19 2.79), family history of acute myocardial infarction or stroke (OR = 1.60; 95%CI = 1.10-2.32) and age (OR per year = 1.12; 95%CI = 1.10-1.14). CONCLUSIONS: Our results show that traditional cardiovascular disease (CVD) risk factors are the major players in determining increased cIMT among HIV infected patients in Brazil. This finding reinforces the need for thorough assessment of those risk factors in these patients to guarantee the incidence of CVD events remain under control. PMID- 25692765 TI - Dental ontogeny in pliocene and early pleistocene hominins. AB - Until recently, our understanding of the evolution of human growth and development derived from studies of fossil juveniles that employed extant populations for both age determination and comparison. This circular approach has led to considerable debate about the human-like and ape-like affinities of fossil hominins. Teeth are invaluable for understanding maturation as age at death can be directly assessed from dental microstructure, and dental development has been shown to correlate with life history across primates broadly. We employ non destructive synchrotron imaging to characterize incremental development, molar emergence, and age at death in more than 20 Australopithecus anamensis, Australopithecus africanus, Paranthropus robustus and South African early Homo juveniles. Long-period line periodicities range from at least 6-12 days (possibly 5-13 days), and do not support the hypothesis that australopiths have lower mean values than extant or fossil Homo. Crown formation times of australopith and early Homo postcanine teeth fall below or at the low end of extant human values; Paranthropus robustus dentitions have the shortest formation times. Pliocene and early Pleistocene hominins show remarkable variation, and previous reports of age at death that employ a narrow range of estimated long-period line periodicities, cuspal enamel thicknesses, or initiation ages are likely to be in error. New chronological ages for SK 62 and StW 151 are several months younger than previous histological estimates, while Sts 24 is more than one year older. Extant human standards overestimate age at death in hominins predating Homo sapiens, and should not be applied to other fossil taxa. We urge caution when inferring life history as aspects of dental development in Pliocene and early Pleistocene fossils are distinct from modern humans and African apes, and recent work has challenged the predictive power of primate-wide associations between hominoid first molar emergence and certain life history variables. PMID- 25692766 TI - Is there relationship between social support, psychological distress, mood disorders and emesis gravidarum? AB - OBJECTIVE: Emesis Gravidarum (EG) is common medical condition in pregnancy with significant negatively effects on daily social life, physical and psychological health. In this study, relationship of social support, psychological distress and mood disorders on EG were investigated. METHODS: The pregnant women with mild EG were accepted as control group and moderate and severe EG were accepted as patient group. All patients completed sociodemographic data collection form, Pregnancy-Unique Quantification of Emesis and Nausea scale (PUQE-24), Symptom Check List questionnaire (SCL-90 R), Spielberger state-trait anxiety inventory (STAI), Beck depression inventory (BDI) and Multidimensional Scale of Perceived Social Support (MSPSS). STAI, BDI, MSPSS and GSI (global symptom index) scores of the patients and control groups were compared. RESULTS: Statistically significant differences were found between the patients and control group on STAI score, BDI score and GSI scores. No statistically significant were found between the patients and control group on MSPSS score. CONCLUSION: Social support does not prevent patients from EG. But, there is a clear relationship between EG and psychological distress. Thus, psychiatric evaluation should be done in patients with EG. Obstetricians should encourage their patients to have psychiatric support. Further studies on relationship of psychosocial factors and EG are needed. PMID- 25692767 TI - Awareness, treatment, and control of diabetes in Bangladesh: a nationwide population-based study. AB - OBJECTIVES: To examine awareness, treatment, and control of diabetes mellitus among the adult population in Bangladesh. METHODS: The study used data from the 2011 nationally representative Bangladesh Demographic and Health Survey (BDHS). The BDHS sample is comprised of 7,786 adults aged 35 years or older. The primary outcome variables were fasting blood glucose, diagnosis, treatment, and control of diabetes. Multilevel logistic regression models were used to identify the risk factors for diabetes awareness. RESULTS: Overall, age-standardized prevalence of diabetes was 9.2%. Among subjects with diabetes, 41.2% were aware of their condition, 36.9% were treated, and 14.2% controlled their condition. A significant inequality in diabetes management was found from poor to wealthy households: 18.2% to 63.2% (awareness), 15.8% to 56.6% (treatment), and 8.2% to 18.4% (control). Multilevel models suggested that participants who had a lower education and lower economic condition were less likely to be aware of their diabetes. Poor management was observed among non-educated, low-income groups, and those who lived in the northwestern region. CONCLUSIONS: Diabetes has become a national health concern in Bangladesh; however, treatment and control are quite low. Improving detection, awareness, and treatment strategies is urgently needed to prevent the growing burden associated with diabetes. PMID- 25692768 TI - Molecular evidence for an old world origin of Galapagos and Caribbean band-winged grasshoppers (Acrididae: Oedipodinae: Sphingonotus). AB - Patterns of colonization and diversification on islands provide valuable insights into evolutionary processes. Due to their unique geographic position and well known history, the Galapagos Islands are an important model system for evolutionary studies. Here we investigate the evolutionary history of a winged grasshopper genus to infer its origin and pattern of colonization in the Galapagos archipelago. The grasshopper genus Sphingonotus has radiated extensively in the Palaearctic and many species are endemic to islands. In the New World, the genus is largely replaced by the genus Trimerotropis. Oddly, in the Caribbean and on the Galapagos archipelago, two species of Sphingonotus are found, which has led to the suggestion that these might be the result of anthropogenic translocations from Europe. Here, we test this hypothesis using mitochondrial and nuclear DNA sequences from a broad sample of Sphingonotini and Trimerotropini species from the Old World and New World. The genetic data show two distinct genetic clusters representing the New World Trimerotropini and the Old World Sphingonotini. However, the Sphingonotus species from Galapagos and the Caribbean split basally within the Old World Sphingonotini lineage. The Galapagos and Caribbean species appear to be related to Old World taxa, but are not the result of recent anthropogenic translocations as revealed by divergence time estimates. Distinct genetic lineages occur on the four investigated Galapagos Islands, with deep splits among them compared to their relatives from the Palaearctic. A scenario of a past wider distribution of Sphingonotus in the New World with subsequent extinction on the mainland and replacement by Trimerotropis might explain the disjunct distribution. PMID- 25692769 TI - A prospective study of interactions between a case management program and retention in care on HIV suppression in Taiwan, 2008-2012. PMID- 25692772 TI - The intermolecular NOE is strongly influenced by dynamics. AB - The intermolecular NOE in NMR spectroscopy is analyzed theoretically via computer simulation. Our test case is the homonuclear NOE between hydrogens in the ionic liquid 1-ethyl-3-methylimidazolium trifluoromethanesulfonate. A coarse-grained model of this system is developed and simulated in a 3 microseconds molecular dynamics run, subsequently used for analysis. Our findings are the following: Spin pair specific dynamics has a strong influence on the spectrum. As a consequence, structural information cannot be read off directly. Instead, different contributions to the signals must be disentangled before one can gain information about structure. We show that the extent of signal distortion through dynamics correlates with the spins' distance to their respective molecular centers of mass. Since we deal with pair distributions of spins, the extracted structure does not represent average distances between two spins but the sum of the influence of surrounding spins. In fact, we find that this influence is long ranged. Our data explicitly shows that the usual 1/r(6) dependence is replaced by a distance dependence between 1/r(3) and 1/r. However, structural information consists of a spin pair specific short-ranged contribution and a uniform long ranged contribution. The transition from specific to uniform is sensitive to the behavior of the underlying pair distribution functions. PMID- 25692771 TI - Combinations of beta-lactam or aminoglycoside antibiotics with plectasin are synergistic against methicillin-sensitive and methicillin-resistant Staphylococcus aureus. AB - Bacterial infections remain the leading killer worldwide which is worsened by the continuous emergence of antibiotic resistance. In particular, methicillin sensitive (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA) are prevalent and the latter can be difficult to treat. The traditional strategy of novel therapeutic drug development inevitably leads to emergence of resistant strains, rendering the new drugs ineffective. Therefore, rejuvenating the therapeutic potentials of existing antibiotics offers an attractive novel strategy. Plectasin, a defensin antimicrobial peptide, potentiates the activities of other antibiotics such as beta-lactams, aminoglycosides and glycopeptides against MSSA and MRSA. We performed in vitro and in vivo investigations to test against genetically diverse clinical isolates of MSSA (n = 101) and MRSA (n = 115). Minimum inhibitory concentrations (MIC) were determined by the broth microdilution method. The effects of combining plectasin with beta-lactams, aminoglycosides and glycopeptides were examined using the chequerboard method and time kill curves. A murine neutropenic thigh model and a murine peritoneal infection model were used to test the effect of combination in vivo. Determined by factional inhibitory concentration index (FICI), plectasin in combination with aminoglycosides (gentamicin, neomycin or amikacin) displayed synergistic effects in 76-78% of MSSA and MRSA. A similar synergistic response was observed when plectasin was combined with beta-lactams (penicillin, amoxicillin or flucloxacillin) in 87-89% of MSSA and MRSA. Interestingly, no such interaction was observed when plectasin was paired with vancomycin. Time kill analysis also demonstrated significant synergistic activities when plectasin was combined with amoxicillin, gentamicin or neomycin. In the murine models, plectasin at doses as low as 8 mg/kg augmented the activities of amoxicillin and gentamicin in successful treatment of MSSA and MRSA infections. We demonstrated that plectasin strongly rejuvenates the therapeutic potencies of existing antibiotics in vitro and in vivo. This is a novel strategy that can have major clinical implications in our fight against bacterial infections. PMID- 25692773 TI - Use of ultrafast time-resolved spectroscopy to demonstrate the effect of annealing on the performance of P3HT:PCBM solar cells. AB - The organic solar cells of heterojunction system, ITO/PEDOT:PSS/P3HT:PCBM/Al, with a thermal annealing after deposition of Al exhibit better performance than those with an annealing process before deposition of Al. In this study, ultrafast time-resolved spectroscopy is employed to reveal the underlying mechanism of annealing effects on the performance of P3HT:PCBM solar cell devices. The analyses of all decomposed relaxation processes show that the postannealed devices exhibit an increase in charge transfer, in the number of separated polarons and a reduction in the amount of recombination between excited carriers. Moreover, the longer lifetime for the excited carriers in postannealed devices indicates it is more likely to be dissociated into photocarriers and result in a larger value for photocurrent, which demonstrates the physical mechanism for increased device performance. PMID- 25692774 TI - The psychological aspects in sexually transmitted infections. AB - BACKGROUND: Over the last years the number of sexually transmitted diseases has greatly increased. This can be attributed mainly to less rigidity in the gender role and to the ever growing sexual liberalization. Sexuality today as in the past, represents an important and complex dimension of the human being. With respect to the psychological area many authors think that there are specific personality traits that to a higher extent compared to others might push individuals to carry out inconsiderate behavior among which there has been found a higher risk of sexually transmitted diseases (STD). In the present paper preliminary data of a research carried out provides information about sexual habits among patients of the IST of Florence. METHODS: A sample of 344 individuals, from 15 to over 70-year-old, Italians and strangers, has been asked to fill up a self-administered questionnaire. RESULTS: Through these data the psychological aspects at the base of sexual habits in our reference sample are highlighted even more clearly. Through the analysis of these data it will be possible to get a larger number of information that can be used for the building of psychological support experiences that take into account the individual differences among patients one finds through consultations and support. CONCLUSIONS: The psychological support is very important for a lot of patients who belong to the center and show inappropriate sexual behavior and exposed to risky sexual behavior. PMID- 25692775 TI - Multiple sclerosis following anti-tumor necrosis factor-alpha therapy for psoriasis: first case in Italy? AB - The use of tumor necrosis factor alpha (TNF-alpha) antagonists has greatly improved clinical management of psoriasis and other inflammatory diseases, but acute and chronic adverse reactions, including demyelination, are becoming increasingly recognized. We reported a case of multiple sclerosis in a 48-year old Italian man with plaque psoriasis treated with etanercept. Through a literature review, we found a total of 35 psoriatic patients, including our case, in whom a demyelinating disease developed in course of TNF-alpha antagonists therapy. Since neurological disorders are rarely associated with the use of anti TNF-alpha therapy in psoriatic patients, but have severe side effects, physicians should screen patients before starting therapy, excluding a positive anamnesis for demyelinating disease; if patients receiving anti-TNF-alpha drugs develop new or unusual neurological symptoms, the anti-TNF-alpha should be stopped and patients should be properly examined. Furthermore, therapies for demyelinating diseases that could exacerbate psoriasis manifestations should be carefully avoided. PMID- 25692776 TI - Efficacy of propranolol for cutaneous hemangiomas in premature children. AB - BACKGROUND: The purpose of the present study is to evaluate the efficacy and safety of propranolol for problematic infantile hemangiomas (IH), showing our experience on 24 children, with special focus on premature infants. METHODS: A retrospective observational study considered 24 patients who were given oral propranolol for the treatment of "problematic" IH. A multidisciplinary team, composed of a dermatologist, a pediatrician, a pediatric cardiologist, and a neonatologist, took part in the indication for propranolol and follow-up on all the patients. Propranolol was administered orally at the starting dose of 0.5-1 mg/kg/die and was gradually increased to the target dose of 2 mg/kg/die. A clinical gravity score, based on color, major diameter, thickness and texture was calculated for each IH, giving a numeric score before (t0) and after (tf) propranolol therapy. Improvement rate was evaluated in terms of score percentage difference between t0 and tf. RESULTS: All of the IH except one (96%), showed a variable grade of improvement, with a median score improvement of 69.1%. Median initial score in premature and term infants did not show any significant difference (P=0.38). Otherwise the two subgroups showed a significant difference in final scores: medium percentage improvement in premature and term infants, was respectively 80.9% and 49.6% (P<0.01). No significant side effects were reported during the treatment period. CONCLUSIONS: As pointed out in our study, IH in premature children showed a significantly better response to propranolol treatment. PMID- 25692777 TI - Resveratrol inhibits enterovirus 71 replication and pro-inflammatory cytokine secretion in rhabdosarcoma cells through blocking IKKs/NF-kappaB signaling pathway. AB - Polydatin and resveratrol, as major active components in Polygonum cuspidatum, have anti-inflammatory, antioxidant and antitumor functions. However, the effect and mechanism of polydatin and resveratrol on enterovirus 71 (EV71) have not been reported. In this study, resveratrol revealed strong antiviral activity on EV71, while polydatin had weak effect. Neither polydatin nor resveratrol exhibited influence on viral attachment. Resveratrol could effectively inhibit the synthesis of EV71/VP1 and the phosphorylation of IKKalpha, IKKbeta, IKKgamma, IKBalpha, NF-kappaB p50 and NF-kappaB p65, respectively. Meanwhile, the remarkably increased secretion of IL-6 and TNF-alpha in EV71-infected rhabdosarcoma (RD) cells could be blocked by resveratrol. These results demonstrated that resveratrol inhibited EV71 replication and cytokine secretion in EV71-infected RD cells through blocking IKKs/NF-kappaB signaling pathway. Thus, resveratrol may have potent antiviral effect on EV71 infection. PMID- 25692778 TI - Reduction-responsive dithiomaleimide-based nanomedicine with high drug loading and FRET-indicated drug release. AB - Dithiomaleimide-based camptothecin-containing nanoparticles are designed to have exceptionally high drug loading and are capable of reduction-responsive, FRET indicated drug release. PMID- 25692779 TI - Surfactant lipidomics in healthy children and childhood interstitial lung disease. AB - BACKGROUND: Lipids account for the majority of pulmonary surfactant, which is essential for normal breathing. We asked if interstitial lung diseases (ILD) in children may disrupt alveolar surfactant and give clues for disease categorization. METHODS: Comprehensive lipidomics profiles of broncho-alveolar lavage fluid were generated in 115 children by electrospray ionization tandem mass spectrometry (ESI-MS/MS). Two reference populations were compared to a broad range of children with ILD. RESULTS: Class and species composition in healthy children did not differ from that in children with ILD related to diffuse developmental disorders, chronic tachypnoe of infancy, ILD related to lung vessels and the heart, and ILD related to reactive lymphoid lesions. As groups, ILDs related to the alveolar surfactant region, ILD related to unclear respiratory distress syndrome in the mature neonate, or in part ILD related to growth abnormalities reflecting deficient alveolarisation, had significant alterations of some surfactant specific phospholipids. Additionally, lipids derived from inflammatory processes were identified and differentiated. In children with ABCA3-deficiency from two ILD causing mutations saturated and monounsaturated phosphatidylcholine species with 30 and 32 carbons and almost all phosphatidylglycerol species were severely reduced. In other alveolar disorders lipidomic profiles may be of less diagnostic value, but nevertheless may substantiate lack of significant involvement of mechanisms related to surfactant lipid metabolism. CONCLUSIONS: Lipidomic profiling may identify specific forms of ILD in children with surfactant alterations and characterized the molecular species pattern likely to be transported by ABCA3 in vivo. PMID- 25692780 TI - Divorce and eating behaviors: a 5-day within-subject study of preadolescent obesity risk. AB - BACKGROUND: Obesity rates have more than doubled among children and have tripled among adolescents since the 1980s, and currently more than one third of children and adolescents are overweight or obese. Parental divorce is a time of family upheaval, yet little is known about the family processes that link family structure and obesity. METHODS: The current study gathered a 5-day eating behavior questionnaire from 37 preadolescents (mean=10.26 years; standard deviation=1.32; 32.4% female) and one parent to explore whether marital status was linked to obesity risk behaviors (i.e., high consumption of sugar-sweetened beverages (SSBs), low consumption of produce, skipping breakfast, and eating dinners away from the home) and whether family context (e.g., parent time spent with child, parental acceptance, and family routines) mediated that link. RESULTS: Results showed that preadolescents in divorced families consumed more SSBs than preadolescents in married families, and there was a trend for less frequent breakfast consumption among preadolescents in the divorced families. Of the three family context variables, only family routines explained the link between family structure and obesity risk. CONCLUSIONS: This study highlights the importance of family processes during divorce to understand the etiology and prevalence of child and adolescent obesity. PMID- 25692781 TI - Can an intensive diet and exercise program prevent knee pain among overweight adults at high risk? AB - OBJECTIVE: It is unclear whether an intensive program of weight loss combined with exercise prevents the onset of knee pain among those at high risk. We examined whether an intensive lifestyle intervention (ILI) prevents incident knee pain compared with a diabetes mellitus support and education (DSE) comparison group among overweight adults with diabetes mellitus. METHODS: We conducted a secondary analysis of the Action for Health in Diabetes (Look AHEAD) study, which is a randomized intervention trial of adults who were obese and had type 2 diabetes mellitus starting in 2001. We studied a subcohort of 2,889 subjects who reported no knee pain at baseline but were at high risk due to obesity. Risk ratios (RRs) were calculated to examine the association of ILI versus DSE with incident knee pain at year 1 and year 4. All analyses were adjusted for potential confounders. RESULTS: Age, sex, and body mass index were similar among ILI and DSE participants with no knee pain at baseline. At year 1, ILI participants were 15% less likely to develop knee pain compared with DSE participants (RR 0.85, 95% confidence interval 0.74-0.98). At year 4, this difference decreased to 5% and was no longer statistically significant. CONCLUSION: An ILI of diet and exercise may prevent the development of knee pain among those at high risk in the short term. Health care providers may consider recommending diet and exercise as a means to prevent the development of knee pain among those at high risk. PMID- 25692782 TI - Laparoscopic management of a leiomyoma of the round ligament. PMID- 25692783 TI - Regulation of Leishmania (L.) amazonensis protein expression by host T cell dependent responses: differential expression of oligopeptidase B, tryparedoxin peroxidase and HSP70 isoforms in amastigotes isolated from BALB/c and BALB/c nude mice. AB - Leishmaniasis is an important disease that affects 12 million people in 88 countries, with 2 million new cases every year. Leishmania amazonensis is an important agent in Brazil, leading to clinical forms varying from localized (LCL) to diffuse cutaneous leishmaniasis (DCL). One interesting issue rarely analyzed is how host immune response affects Leishmania phenotype and virulence. Aiming to study the effect of host immune system on Leishmania proteins we compared proteomes of amastigotes isolated from BALB/c and BALB/c nude mice. The athymic nude mice may resemble patients with diffuse cutaneous leishmaniasis, considered T-cell hyposensitive or anergic to Leishmania's antigens. This work is the first to compare modifications in amastigotes' proteomes driven by host immune response. Among the 44 differentially expressed spots, there were proteins related to oxidative/nitrosative stress and proteases. Some correspond to known Leishmania virulence factors such as OPB and tryparedoxin peroxidase. Specific isoforms of these two proteins were increased in parasites from nude mice, suggesting that T cells probably restrain their posttranslational modifications in BALB/c mice. On the other hand, an isoform of HSP70 was increased in amastigotes from BALB/c mice. We believe our study may allow identification of potential virulence factors and ways of regulating their expression. PMID- 25692784 TI - Low dose CT screening for lung cancer: moving into the clinical arena. PMID- 25692785 TI - Application of risk prediction models to lung cancer screening: a review. AB - Globally, lung cancer is the leading cause of cancer death and is a major public health problem. Because lung cancer is usually diagnosed at an advanced stage, survival is generally poor. In recent decades, clinical advances have not led to marked improvements in outcomes. A recent advance of importance arose when the National Lung Screening Trial (NLST) findings indicated that low-dose computed tomography screening of high-risk individuals can lead to a lung cancer mortality reduction of 20%. NLST identified high-risk individuals using the following criteria: age 55 to 74 years; >=30 pack-years of smoking; and number of years since smoking cessation <=15 years. Medical screening is most effective when applied to high-risk individuals. The NLST criteria for high risk were practical for enrolling individuals into a clinical trial but are not optimal for risk estimation. Lung cancer risk prediction models are expected to be superior. Indeed, recently, 3 studies have provided quantitative evidence that selection of individuals for lung screening on the basis of estimates from high-quality risk prediction models is superior to using NLST criteria or similar criteria, such as the United States Preventive Services Task Force (USPSTF) criteria. Compared with NLST/USPSTF criteria, selection of individuals for screening using high-quality risk models should lead to fewer individuals being screened, more cancers being detected, and fewer false positives. More lives will be saved with greater cost effectiveness. In this paper, we review methodological background for prediction modeling, existing lung cancer risk prediction models and some of their findings, and current issues in lung cancer risk prediction modeling and discuss future research. PMID- 25692786 TI - Rough-legged buzzards, Arctic foxes and red foxes in a tundra ecosystem without rodents. AB - Small rodents with multi-annual population cycles strongly influence the dynamics of food webs, and in particular predator-prey interactions, across most of the tundra biome. Rodents are however absent from some arctic islands, and studies on performance of arctic predators under such circumstances may be very instructive since rodent cycles have been predicted to collapse in a warming Arctic. Here we document for the first time how three normally rodent-dependent predator species rough-legged buzzard, arctic fox and red fox - perform in a low-arctic ecosystem with no rodents. During six years (in 2006-2008 and 2011-2013) we studied diet and breeding performance of these predators in the rodent-free Kolguev Island in Arctic Russia. The rough-legged buzzards, previously known to be a small rodent specialist, have only during the last two decades become established on Kolguev Island. The buzzards successfully breed on the island at stable low density, but with high productivity based on goslings and willow ptarmigan as their main prey altogether representing a novel ecological situation for this species. Breeding density of arctic fox varied from year to year, but with stable productivity based on mainly geese as prey. The density dynamic of the arctic fox appeared to be correlated with the date of spring arrival of the geese. Red foxes breed regularly on the island but in very low numbers that appear to have been unchanged over a long period - a situation that resemble what has been recently documented from Arctic America. Our study suggests that the three predators found breeding on Kolguev Island possess capacities for shifting to changing circumstances in low-arctic ecosystem as long as other small - medium sized terrestrial herbivores are present in good numbers. PMID- 25692787 TI - Using ecological momentary assessment to investigate short-term variations in sexual functioning in a sample of peri-menopausal women from Iran. AB - The investigation of short-term changes in female sexual functioning has received little attention so far. The aims of the study were to gain empirical knowledge on within-subject and within- and across-variable fluctuations in women's sexual functioning over time. More specifically, to investigate the stability of women's self-reported sexual functioning and the moderating effects of contextual and interpersonal factors. A convenience sample of 206 women, recruited across eight Health care Clinics in Rasht, Iran. Ecological momentary assessment was used to examine fluctuations of sexual functioning over a six week period. A shortened version of the Female Sexual Function Index (FSFI) was applied to assess sexual functioning. Self-constructed questions were included to assess relationship satisfaction, partner's sexual performance and stress levels. Mixed linear two level model analyses revealed a link between orgasm and relationship satisfaction (Beta = 0.125, P = 0.074) with this link varying significantly between women. Analyses further revealed a significant negative association between stress and all six domains of women's sexual functioning. Women not only reported differing levels of stress over the course of the assessment period, but further differed from each other in how much stress they experienced and how much this influenced their sexual response. Orgasm and sexual satisfaction were both significantly associated with all other domains of sexual function (P<0.001). And finally, a link between partner performance and all domains of women's sexual functioning (P<0.001) could be detected. Except for lubrication (P = 0.717), relationship satisfaction had a significant effect on all domains of the sexual response (P<0.001). Overall, our findings support the new group of criteria introduced in the DSM-5, called "associated features" such as partner factors and relationship factors. Consideration of these criteria is important and necessary for clinicians when diagnosing FSD. PMID- 25692788 TI - Direct but no transgenerational effects of decitabine and vorinostat on male fertility. AB - Establishment and maintenance of the correct epigenetic code is essential for a plethora of physiological pathways and disturbed epigenetic patterns can provoke severe consequences, e.g. tumour formation. In recent years, epigenetic drugs altering the epigenome of tumours actively have been developed for anti-cancer therapies. However, such drugs could potentially also affect other physiological pathways and systems in which intact epigenetic patterns are essential. Amongst those, male fertility is one of the most prominent. Consequently, we addressed possible direct effects of two epigenetic drugs, decitabine and vorinostat, on both, the male germ line and fertility. In addition, we checked for putative transgenerational epigenetic effects on the germ line of subsequent generations (F1-F3). Parental adult male C57Bl/6 mice were treated with either decitabine or vorinostat and analysed as well as three subsequent untreated generations derived from these males. Treatment directly affected several reproductive parameters as testis (decitabine & vorinostat) and epididymis weight, size of accessory sex glands (vorinostat), the height of the seminiferous epithelium and sperm concentration and morphology (decitabine). Furthermore, after decitabine administration, DNA methylation of a number of loci was altered in sperm. However, when analysing fertility of treated mice (fertilisation, litter size and sex ratio), no major effect of the selected epigenetic drugs on male fertility was detected. In subsequent generations (F1-F3 generations) only subtle changes on reproductive organs, sperm parameters and DNA methylation but no overall effect on fertility was observed. Consequently, in mice, decitabine and vorinostat neither affected male fertility per se nor caused marked transgenerational effects. We therefore suggest that both drugs do not induce major adverse effects-in terms of male fertility and transgenerational epigenetic inheritance-when used in anti-cancer-therapies. PMID- 25692789 TI - Randomized double-blind trial comparing the cosmetic outcome of cutting diathermy versus scalpel for skin incisions. AB - BACKGROUND: Controversy exists about whether cutting diathermy for skin incisions leads to a cosmetically inferior scar. Cosmetic outcomes were compared between skin incisions created with cutting diathermy versus scalpel. Wound infection rates and postoperative incisional pain were also compared. METHODS: This was a randomized double-blind trial comparing cutting diathermy and scalpel in patients undergoing bowel resection. Scar cosmesis was assessed at 6 months after surgery by a plastic surgeon and a research associate using the Vancouver Scar Scale (VSS) and the Patient and Observer Scar Assessment Scale (POSAS). Patients also used POSAS to self-evaluate their scars. Wound infections within 30 days were recorded, and incision pain scores were measured on the first 5 days after operation. RESULTS: A total of 66 patients were randomized to cutting diathermy (31) or scalpel (35). At 6 months, there was no significant difference between the diathermy and scalpel groups in mean(s.d.) VSS scores (4.9(2.6) versus 5.0(1.9); P = 0.837), mean POSAS total scores (19.2(8.0) versus 20.0(7.4); P = 0.684) or subjective POSAS total scores (20.2(12.1) versus 21.3(10.4); P = 0.725). Neither were there significant differences in wound infection rates between the groups (5 of 30 versus 5 of 32; P = 1.000). Pain scores on day 1 after operation were significantly lower in the diathermy group (mean 1.68 versus 3.13; P = 0.018), but were not significantly different on days 2-5. CONCLUSION: Cutting diathermy is a cosmetically acceptable technique for abdominal skin incisions. There is no increased risk of wound infection, and diathermy may convey benefit in terms of early postoperative wound pain. REGISTRATION NUMBER: NCT01496404 ( http://www.clinicaltrials.gov). PMID- 25692790 TI - Frequency spectrum method-based stress analysis for oil pipelines in earthquake disaster areas. AB - When a long distance oil pipeline crosses an earthquake disaster area, inertial force and strong ground motion can cause the pipeline stress to exceed the failure limit, resulting in bending and deformation failure. To date, researchers have performed limited safety analyses of oil pipelines in earthquake disaster areas that include stress analysis. Therefore, using the spectrum method and theory of one-dimensional beam units, CAESAR II is used to perform a dynamic earthquake analysis for an oil pipeline in the XX earthquake disaster area. This software is used to determine if the displacement and stress of the pipeline meet the standards when subjected to a strong earthquake. After performing the numerical analysis, the primary seismic action axial, longitudinal and horizontal displacement directions and the critical section of the pipeline can be located. Feasible project enhancement suggestions based on the analysis results are proposed. The designer is able to utilize this stress analysis method to perform an ultimate design for an oil pipeline in earthquake disaster areas; therefore, improving the safe operation of the pipeline. PMID- 25692791 TI - Endocrine care of transpeople part I. A review of cross-sex hormonal treatments, outcomes and adverse effects in transmen. AB - Gender dysphoria (GD) is characterized by discomfort with the assigned or birth gender and the urge to live as a member of the desired sex. The goal of medical and surgical treatment is to improve the well-being and quality of life of transpeople. The acquisition of phenotypic features of the desired gender requires the use of cross-sex hormonal therapy (CHT). Adult transmen are treated with testosterone to induce virilization. In adolescents with severe and persistent GD, consideration can be given to arresting puberty at Tanner Stage II and if dysphoria persists, CHT is generally started after 16 years of age. Currently available short- and long-term safety studies suggest that CHT is reasonably safe in transmen. Monitoring of transmen should be more frequent during the first year of cross-sex hormone administration reducing to once or twice per year thereafter. Long-term monitoring after sex reassignment surgery (SRS) includes annual check-ups as are carried out for natal hypogonadal men. In elderly transmen, special attention should be paid to haematocrit in particular. Screening for breast and cervical cancer should be continued in transmen not undergoing SRS. PMID- 25692792 TI - Comparative study on the immunogenicity and safety of a purified chick embryo cell rabies vaccine (PCECV) administered according to two different simulated post exposure intramuscular regimens (Zagreb versus Essen). AB - Despite availability of effective rabies vaccines, India has the highest global mortality rate for rabies. Low socio-economic communities are most affected due to lack of awareness of the disease and poor compliance to post-exposure prophylactic regimens. Currently, the only approved intramuscular regimen for post-exposure prophylaxis (PEP) against rabies in India is the Essen regimen, which consists of 5 injections administered over 5 separate days in a period of one month. The high number of doses and clinical visits, however, are major reasons for non-compliance, and thus a shorter regimen would be beneficial. In a simulated PEP trial in healthy, adult subjects, this study evaluated whether purified chick embryo cell vaccine (PCECV), administered according to the WHO recommended 4-dose/3 visit Zagreb vaccination regimen is of equal immunogenicity and safety as the standard Essen regimen in Indian subjects. Two hundred and 50 healthy adults were enrolled and randomized into a Zagreb or Essen group, each receiving PCECV according to their respective regimen. Blood samples were collected on Days 0, 7, 14 and 42 and analyzed using the rapid fluorescent focus inhibition test (RFFIT). By Day 14, all subjects across both groups attained rabies virus neutralizing antibody (RVNA) concentrations of >= 0.5IU/ml. The Zagreb regimen was then demonstrated to be immunologically non-inferior to the Essen regimen by Day 14, which was the primary endpoint of the study. No safety issues were noted and the occurrence of adverse events was similar in both groups (17% and 15%, respectively). NCT01365494. CTRI No.: CTRI/2011/07/001857. PMID- 25692793 TI - Generation of embryonic stem cells from mouse adipose-tissue derived cells via somatic cell nuclear transfer. AB - Somatic cells can be reprogrammed into embryonic stem cells (ESCs) by nuclear transfer (NT-ESCs), or into induced pluripotent stem cells (iPSCs) by the "Yamanaka method." However, recent studies have indicated that mouse and human iPSCs are prone to epigenetic and transcriptional aberrations, and that NT-ESCs correspond more closely to ESCs derived from in vitro fertilized embryos than iPSCs. In addition, the procedure of NT-ESCs does not involve gene modification. Demonstration of generation of NT-ESCs using an easily-accessible source of adult cell types would be very important. Adipose tissue is a source of readily accessible donor cells and can be isolated from both males and females at different ages. Here we report that NT-ESCs can be generated from adipose tissue derived cells (ADCs). At morphological, mRNA and protein levels, these NT-ESCs show classic ESC colonies, exhibit alkaline phosphatase (AP) activity, and display normal diploid karyotypes. Importantly, these cells express pluripotent markers including Oct4, Sox2, Nanog and SSEA-1. Furthermore, they can differentiate in vivo into various types of cells from 3 germinal layers by teratoma formation assays. This study demonstrates for the first time that ESCs can be generated from the adipose tissue by somatic cell nuclear transfer (SCNT) and suggests that ADCs can be a new donor-cell type for potential therapeutic cloning. PMID- 25692794 TI - Cracking-assisted photolithography for mixed-scale patterning and nanofluidic applications. AB - Cracks are observed in many environments, including walls, dried wood and even the Earth's crust, and are often thought of as an unavoidable, unwanted phenomenon. Recent research advances have demonstrated the the ability to use cracks to produce various micro and nanoscale patterns. However, patterns are usually limited by the chosen substrate material and the applied tensile stresses. Here we describe an innovative cracking-assisted nanofabrication technique that relies only on a standard photolithography process. This novel technique produces well-controlled nanopatterns in any desired shape and in a variety of geometric dimensions, over large areas and with a high throughput. In addition, we show that mixed-scale patterns fabricated using the 'crack photolithography' technique can be used as master moulds for replicating numerous nanofluidic devices via soft lithography, which to the best of our knowledge is a technique that has not been reported in previous studies on materials' mechanical failure, including cracking. PMID- 25692795 TI - Novel STAMBP mutation and additional findings in an Arabic family. AB - Microcephaly-capillary malformation syndrome (MIC-CAP syndrome) is a newly recognized autosomal recessive congenital neurocutaneous central nervous system disorder characterized by severe microcephaly, early-onset seizures, profound psychomotor disability, and multiple cutaneous capillary lesions. In addition, affected patients have variable dysmorphic facial features and hypoplastic distal phalanges. It is distinctively caused by mutations in a newly characterized gene, STAMBP, encoding the deubiquitinating (DUB) isopeptidase that has a key role in cell surface receptor-mediated endocytosis and sorting. Herein, we describe an Arab family of two siblings with classic features of MIC-CAP syndrome that harbor a novel predicted splice mutation in STAMBP, which additionally display previously unreported findings of congenital hypothyroidism and alopecia areata. PMID- 25692796 TI - Cleaning Effectiveness of Three NiTi Rotary Instruments: A Focus on Biomaterial Properties. AB - Nickel-titanium (NiTi) instruments are commonly used for shaping the root canal system in endodontic practice. They are more flexible and have better cutting efficiency than conventional stainless steel files. The superelasticity of NiTi rotary files allows the clinicians to produce the desirable tapered root canal form with a reduced tendency to canal transportation and instrument fracture. HyFlex CM instruments are new NiTi rotary instruments with shape memory produced by an innovative methodology (patent pending) that uses a complex heating and cooling treatment that controls the material's memory. The aim of the present study was to compare the cleaning efficacy of two conventional (Mtwo, Revo-S) Ni Ti rotary instruments with HyFlex CM. 30 single-rooted freshly extracted teeth were divided into three groups. Root canals were shaped with three NiTi instruments (Mtwo, Revo-S and HyFlex CM) using 5.25% NaOCl and 17% EDTA solutions. Specimens were fractured longitudinally and prepared for SEM analysis at standard magnification of 1000*. The presence/absence of debris smear layer and the presence/absence of smear layer at coronal, middle, and apical third of each canal were evaluated using a 5-step scale for scores. Numeric data were analyzed using Kruskall-Wallis and Mann-Whitney U statistical tests and significance was predetermined at P < 0.05. This study revealed significant differences among the various groups. Despite some minor differences, all instruments removed smear layer and debris produced during instrumentation. HyFlex CM seem to be not so effective in promoting cleanliness of root canal walls and in removing smear layer from dentine if compared to Mtwo and Revo-S. PMID- 25692797 TI - Offering financial incentives to increase adherence to antipsychotic medication: the clinician experience. AB - Financial incentives for medication adherence in patients with psychotic disorders are controversial. It is not yet known whether fears expressed by clinicians are borne out in reality. We aimed to explore community mental health clinicians' experiences of the consequences of giving patients with psychotic disorders a financial incentive to take their depot medication. We implemented descriptive and thematic analyses of semistructured interviews with the clinicians of patients assigned to receive incentives within a randomized controlled trial. Fifty-nine clinicians were interviewed with regard to the effect of the incentives on 73 of the 78 patients allocated to receive incentives in the trial. Most commonly, the clinicians reported benefits for clinical management including improved adherence, contact, patient monitoring, communication, and trust (n = 52). Positive effects on symptoms, insight, or social functioning were reported for some (n = 33). Less commonly, problems for patient management were reported (n = 19) such as monetarization of the therapeutic relationship or negative consequences for the patient (n = 15) such as increased drug and alcohol use. Where requests for increased money occurred, they were rapidly resolved. It seems that, in most cases, the clinicians found that using incentives led to benefits for patient management and for patient health. However, in 33% of cases, some adverse effects were reported. It remains unclear whether certain clinical characteristics are associated with increased risk for adverse effects of financial incentives. The likelihood of benefit versus the smaller risk for adverse effects should be weighed up when deciding whether to offer incentives to individual patients. PMID- 25692798 TI - Dendritic geometry shapes neuronal cAMP signalling to the nucleus. AB - Neurons have complex dendritic trees, receiving numerous inputs at various distances from the cell body. Yet the rules of molecular signal propagation from dendrites to nuclei are unknown. DARPP-32 is a phosphorylation-regulated signalling hub in striatal output neurons. We combine diffusion-reaction modelling and live imaging to investigate cAMP-activated DARPP-32 signalling to the nucleus. The model predicts maximal effects on the nucleus of cAMP production in secondary dendrites, due to segmental decrease of dendrite diameter. Variations in branching, perikaryon size or spines have less pronounced effects. Biosensor kinase activity measurement following cAMP or dopamine uncaging confirms these predictions. Histone 3 phosphorylation, regulated by this pathway, is best stimulated by cAMP released in secondary-like dendrites. Thus, unexpectedly, the efficacy of diffusion-based signalling from dendrites to nucleus is not inversely proportional to the distance. We suggest a general mechanism by which dendritic geometry counterbalances the effect of dendritic distance for signalling to the nucleus. PMID- 25692799 TI - Intratympanic Steroid Treatments May Improve Hearing via Ion Homeostasis Alterations and Not Immune Suppression. AB - HYPOTHESIS: The inner ear (IE) endothelium is capable of responding to therapeutic steroids by altering the local expression of cytokine and ion homeostasis genes that impact inflammation and fluid regulation. BACKGROUND: Glucocorticoids are often given transtympanically for hearing disorders because of their anti-inflammatory effects, but their direct impact on IE ion homeostasis and cytokine gene expression has not been studied. METHODS: The middle ears of Balb/c mice were transtympanically injected with 5 MUL of phosphate-buffered saline, prednisolone (Pred), or dexamethasone (Dex). Untreated mice were used as controls. Mice were euthanized at 6, 24, and 72 hours; the cochleas were harvested; and total RNA was isolated from the IE tissues. Expression of eight cytokine genes and 24 ion homeostasis genes was analyzed with quantitative real time reverse transcription polymerase chain reaction. RESULTS: Phosphate-buffered saline caused upregulation of inflammatory cytokine genes that peaked at 6 hours. Surprisingly, Pred and Dex also caused upregulation of most cytokine genes. Interestingly, ion homeostasis genes were predominantly upregulated with Dex and Pred, with Pred having a larger effect. CONCLUSION: In the murine model, intratympanic steroids caused an initial upregulation of inflammatory cytokine genes in the IE, as well as predominant upregulation of ion homeostasis genes. These findings suggest that glucocorticoids do not suppress IE inflammation but rather cause an initial inflammatory response in the IE. Thus, inflammatory gene suppression is not a likely mechanism for their hearing restorative effects. On the other hand, these steroids have a significant mineralocorticoid function, as demonstrated by increased function of ion homeostasis genes, implicating their ionic and fluid regulatory properties as a mechanism for their therapeutic effects. PMID- 25692800 TI - High prevalence of rectal gonorrhea and Chlamydia infection in women attending a sexually transmitted disease clinic. AB - BACKGROUND: Testing women for urogenital Neisseria gonorrhoeae (GC) and Chlamydia trachomatis (CT) is common in sexually transmitted disease (STD) clinics. However, women may not be routinely tested for rectal GC/CT. This may lead to missed infections in women reporting anal intercourse (AI). METHODS: This was a retrospective review of all women who underwent rectal GC/CT testing from August 2012 to June 2013 at an STD clinic in Columbus, Ohio. All women who reported AI in the last year had a rectal swab collected for GC/CT nucleic acid amplification testing (n=331). Using log-binomial regression models, we computed unadjusted and adjusted associations for demographic and behavioral factors associated with rectal GC/CT infection. RESULTS: Participants (n=331) were 47% African-American, with median age of 29 years. Prevalence of rectal GC was 6%, rectal CT was 13%, and either rectal infection was 19%. Prevalence of urogenital GC and CT was 7% and 13% respectively. Among women with rectal GC, 14% tested negative for urogenital GC. Similarly, 14% of women with rectal CT tested negative for urogenital CT. In unadjusted analyses, there was increased rectal GC prevalence among women reporting sex in the last year with an injection drug user, with a person exchanging sex for drugs or money, with anonymous partners, and while intoxicated/high on alcohol or illicit drugs. After multivariable adjustment, no significant associations persisted, but a trend of increased rectal GC prevalence was observed for women <26 years of age (p=0.06) and those reporting sex while intoxicated/high on alcohol or drugs (p=0.05). For rectal CT, only age <26 years was associated with prevalent infection in unadjusted models; this association strengthened after multivariable adjustment (prevalence ratio: 6.03; 95% confidence interval: 2.29-15.90). CONCLUSION: Nearly one in five women who reported AI in the last year had rectal GC or CT infection. Urogenital testing alone would have missed 14% of rectal infections. Standardized guidelines would increase rectal GC/CT testing in women and help detect missed infections. PMID- 25692801 TI - Heterogeneous CD8+ T cell migration in the lymph node in the absence of inflammation revealed by quantitative migration analysis. AB - The three-dimensional positions of immune cells can be tracked in live tissues precisely as a function of time using two-photon microscopy. However, standard methods of analysis used in the field and experimental artifacts can bias interpretations and obscure important aspects of cell migration such as directional migration and non-Brownian walk statistics. Therefore, methods were developed for minimizing drift artifacts, identifying directional and anisotropic (asymmetric) migration, and classifying cell migration statistics. These methods were applied to describe the migration statistics of CD8+ T cells in uninflamed lymph nodes. Contrary to current models, CD8+ T cell statistics are not well described by a straightforward persistent random walk model. Instead, a model in which one population of cells moves via Brownian-like motion and another population follows variable persistent random walks with noise reproduces multiple statistical measures of CD8+ T cell migration in the lymph node in the absence of inflammation. PMID- 25692802 TI - Breast cancer survivorship--intersecting gendered discourses in a 5-year follow up study. AB - In this article the authors present a follow-up study of women's interview narratives about life 5 to 7 years after a breast cancer operation. The women had taken part in a study during the 6-month postoperation period. Art therapy contributed to well-being, including strengthening personal boundaries. In the new study, interview analysis informed by critical discursive psychology indicated three problematic discourses that the women still struggled with several years after the operation: the female survivor, the "good woman," and individual responsibility. We concluded that many women with a history of breast cancer need support several years after their medical treatment is finished. PMID- 25692803 TI - Mentalizing ability in patients with prefrontal cortex damage. AB - INTRODUCTION: Mentalizing ability is the issue in the social cognition of patients with brain injury that has received the most attention. The present study investigated mentalization ability in patients with prefrontal cortex damage. The aims of this study were to investigate: (a) whether patients with prefrontal cortex damage are impaired in mentalizing ability, including theory of mind (ToM) and empathy; (b) whether patients with ventromedial prefrontal cortex damage are impaired in different aspects of ToM; (c) whether patients with ventromedial prefrontal cortex damage are impaired in different aspects of empathy; and (d) whether impairment of mentalizing ability in patients with prefrontal cortex damage can be explained by executive dysfunction. METHOD: Mini Mental State Examination (MMSE), Matrix Reasoning subtest, working memory, executive function, theory of mind, and empathy assessments were conducted on eight patients with ventromedial prefrontal cortex damage, 15 patients with dorsolateral prefrontal cortex damage, and 19 normal comparisons matched for level of education and intelligence. RESULTS: The results showed that performance on affective and nonverbal theory of mind was significantly lower in patients with dorsolateral prefrontal cortex damage than in the comparison group. Performance on personal distress items of empathy was significantly lower in the ventromedial prefrontal cortex damage group than in the dorsolateral prefrontal cortex damage group. In addition, further multiple regression analysis showed that affective theory of mind could be explained by the Wisconsin Card Sorting Test-Modified (WCST-M), with an explained variance of up to 44%. CONCLUSION: The present study suggests that the impairment of mentalizing ability in patients with prefrontal cortex damage is partially the result of executive dysfunction. PMID- 25692804 TI - Creation of high mobility two-dimensional electron gases via strain induced polarization at an otherwise nonpolar complex oxide interface. AB - The discovery of two-dimensional electron gases (2DEGs) in SrTiO3-based heterostructures provides new opportunities for nanoelectronics. Herein, we create a new type of oxide 2DEG by the epitaxial-strain-induced polarization at an otherwise nonpolar perovskite-type interface of CaZrO3/SrTiO3. Remarkably, this heterointerface is atomically sharp and exhibits a high electron mobility exceeding 60,000 cm(2) V(-1) s(-1) at low temperatures. The 2DEG carrier density exhibits a critical dependence on the film thickness, in good agreement with the polarization induced 2DEG scheme. PMID- 25692805 TI - Diarrhoea in the critically ill. AB - PURPOSE OF REVIEW: To summarize existing evidence on definition, epidemiology, mechanisms, risk factors, consequences, outcome and management of diarrhoea in the critically ill. RECENT FINDINGS: In health, diarrhoea is defined as the passage of three or more loose or liquid stools per day. In the critically ill, the diagnosis is yet to be formalized and reported prevalence of diarrhoea varies according to the definition used. Recent studies estimate the prevalence between 14 and 21% and describe risk factors for diarrhoea in critically ill patients. The precipitant of diarrhoea always needs to be identified, as targeted therapies are important for several causes. Although the majority of patients with diarrhoea require only supportive care, it is always essential to exclude, or confirm and treat infectious diarrhoea. There is little evidence to support delaying or withdrawing provision of enteral nutrition in patients with diarrhoea, and we recommend continuing enteral nutrition whenever possible. However, the consequences of diarrhoea - hypovolaemia, electrolyte disturbances, malnutrition, skin lesions and contamination of wounds - should be avoided or at least recognized promptly. SUMMARY: A definition of diarrhoea and a practical approach to identify the precipitant and to manage diarrhoea in critically ill patients are proposed. PMID- 25692806 TI - Rationale for lumbar drains in aneurysmal subarachnoid hemorrhage. AB - PURPOSE OF REVIEW: The amount of blood in the basal cisterns is predictive for the final outcome after aneurysmal subarachnoid hemorrhage (SAH) and clinical problems such as delayed cerebral ischemia and angiographic vasospasm. A lumbar drainage presents an additional, physiologically appealing treatment. In contrast to an external ventricular drain, stasis of clots is thought to be prevented and clearance of the basal cisterns accelerated. In theory, patients with higher clinical grades and dense layers of subarachnoid blood should benefit most. RECENT FINDINGS: A positive signal but so far no conclusive evidence for lumbar drains in SAH is available from retrospective data. Two large series exist, one after clipping and one after endovascular coiling of the aneurysm leading to the index hemorrhage. The only high-quality large prospective trial failed to prove a better neurologic outcome at 6 months, but investigated predominantly good grade patients with less severe hemorrhage. Further data from another phase III trial is still pending. A concern on the safety of lumbar drains is not supported. SUMMARY: At present, no definite conclusions and recommendations on lumbar drains in patients after aneurysmal SAH are warranted. PMID- 25692807 TI - Liver transplantation in the context of organ shortage: toward extension and restriction of indications considering recent clinical data and ethical framework. AB - PURPOSE OF REVIEW: The scarcity of liver grafts requires to optimize the results of transplantation. Extensions and alternatives of liver transplantation have to be regularly evaluated. RECENT FINDINGS: Acute-on-chronic liver failure and severe alcoholic hepatitis may represent potential extensions of transplant indications. In these diseases, selected patients could obtain a significant benefit from liver transplantation, whereas long-term outcomes and global impact on waiting lists remain to be evaluated prospectively. Alternatives to transplantation may be represented by recent progress in the management of hepatitis C and the treatment of hepatocellular carcinoma. In hepatitis C, new drug combinations may improve the disease control, reducing the progression to cirrhosis and also the risk of post-transplant reinfection allowing to anticipate a future decrease in the indications for transplantation and retransplantation in these patients. In hepatocellular carcinoma, thanks to improvements in operative techniques and better identification of prognostic factors of cancer recurrency, surgical resection or radiofrequency destruction could appear now as true alternatives to transplant in highly selected patients. SUMMARY: Before implementation of these potential changes into decisional algorithms for listing and organ allocation, their consequences, either for patient's individual benefit or for global transplant outcomes, should be closely evaluated using objective long-term end points and taking into account the ethical recommendations for organ transplantation. PMID- 25692808 TI - Acute, nonvariceal upper gastrointestinal bleeding. AB - PURPOSE OF REVIEW: Acute, nonvariceal upper gastrointestinal bleeding (UGIB) is a common medical emergency encountered worldwide. Despite medical and technological advances, it remains associated with significant morbidity and mortality. RECENT FINDINGS: Rapid patient assessment and management are paramount. When indicated, upper endoscopy in patients presenting with acute UGIB is effective for both diagnosis of the bleeding site and provision of endoscopic hemostasis. Endoscopic hemostasis significantly reduces rebleeding rates, blood transfusion requirements, length of hospital stay, surgery, and mortality. Furthermore, early upper endoscopy, defined as being performed within 24 h of patient presentation, improves patient outcomes. SUMMARY: A structured approach to the patient with acute UGIB that includes early hemodynamic resuscitation and stabilization, preendoscopic risk stratification using validated instruments, pharmacologic and endoscopic intervention, and postendoscopy therapy is important to optimize patient outcome and assure efficient use of medical resources. PMID- 25692809 TI - Prediction of rumen degradability parameters of a wide range of forages and non forages by NIRS. AB - Kinetics of nutrient degradation in the rumen is an important component of feed evaluation systems for ruminants. The in situ technique is commonly used to obtain such dynamic parameters, but it requires cannulated animals and incubations last several days limiting its application in practice. On the other hand, feed industry relies strongly on NIRS to predict chemical composition of feeds and it has been used to predict nutrient degradability parameters. However, most of these studies were feedstuff specific, predicting degradability parameters of a particular feedstuff or category of feedstuffs, mainly forages or compound feeds and not grains and byproducts. Our objective was to evaluate the potential of NIRS to predict degradability parameters and effective degradation utilizing a wide range of feedstuffs commonly used in ruminant nutrition. A database of 809 feedstuffs was created. Feedstuffs were grouped as forages (FF; n=256), non-forages (NF; n=539) and of animal origin (n=14). In situ degradability data for dry matter (DM; n=665), CP (n=682) and NDF (n=100) were collected. Degradability was described in terms of washable fraction (a), slowly degradable fraction (b) and its rate of degradation (c). All samples were scanned from 1100 to 2500 nm using an NIRSystems 5000 scanning in reflectance mode. Calibrations were developed for all samples (ALL), FF and NF. Equations were validated with an external validation set of 20% of total samples. NIRS equations to predict the effective degradability and fractions a and b of DM, CP and NDF could be evaluated from being adequate for screening (r(2)>0.77; ratio of performance to deviation (RPD)=2.0 to 2.9) to suitable for quantitative purposes (r(2)>0.84; RPD=3.1 to 4.7), and some predictions were improved by group separation reducing the standard error of prediction. Similarly, the rate of degradation of CP (CP(c)) and DM (DM(c)) was predicted for screening purposes (RPD?2 and 2.5 for CP(c) and DM(c), respectively). However, the rate of degradation of NDF was not predicted accurately (NDF(c) : r(2)<0.75; RDP<2). PMID- 25692810 TI - Vernal Keratoconjunctivitis and immune-mediated diseases: One unique way to symptom control? PMID- 25692813 TI - Disposal capacity for spent fuel in China is not ready yet for the nuclear power boom. PMID- 25692814 TI - Statistical methods for handling unwanted variation in metabolomics data. AB - Metabolomics experiments are inevitably subject to a component of unwanted variation, due to factors such as batch effects, long runs of samples, and confounding biological variation. Although the removal of this unwanted variation is a vital step in the analysis of metabolomics data, it is considered a gray area in which there is a recognized need to develop a better understanding of the procedures and statistical methods required to achieve statistically relevant optimal biological outcomes. In this paper, we discuss the causes of unwanted variation in metabolomics experiments, review commonly used metabolomics approaches for handling this unwanted variation, and present a statistical approach for the removal of unwanted variation to obtain normalized metabolomics data. The advantages and performance of the approach relative to several widely used metabolomics normalization approaches are illustrated through two metabolomics studies, and recommendations are provided for choosing and assessing the most suitable normalization method for a given metabolomics experiment. Software for the approach is made freely available. PMID- 25692815 TI - Sesamol reduces the atherogenicity of electronegative L5 LDL in vivo and in vitro. AB - Highly electronegative low-density lipoprotein (LDL) L5 induces endothelial cell (EC) apoptosis, which leads to the development of atherosclerosis. We examined the effects of sesamol (1), a natural organic component of sesame oil, on plasma L5 levels and atherosclerosis development in a rodent model and on the L5-induced apoptosis of ECs. Syrian hamsters, which have an LDL profile similar to that of humans, were fed a normal chow diet (control), a high-fat diet (HFD), or a HFD supplemented with the administration of 50 or 100 mg/kg of 1 via oral gavage (HFD+1) for 16 weeks (n = 8 per group). Hamsters in the HFD+1 groups had reduced plasma L5 levels when compared with the HFD group. Oil Red O staining showed that atherosclerotic lesion size was markedly reduced in the aortic arch of hamsters in the HFD+1 groups when compared with that in the HFD group. In human aortic ECs, 0.3-3 MUM 1 blocked L5-induced apoptosis in a dose-dependent manner. Further mechanistic studies showed that 1 inhibited the L5-induced lectin-like oxidized LDL receptor-1 (LOX-1)-dependent phosphorylation of p38 MAPK and activation of caspase-3 and increased phosphorylation of eNOS and Akt. Our findings suggest that sesamol (1) protects against atherosclerosis by reducing L5-induced atherogenicity. PMID- 25692816 TI - Delayed school entry and academic performance: a natural experiment. AB - AIM: Recent reports suggest that delayed school entry (DSE) may be beneficial for children with developmental delays. However, studies of the effects of DSE are inconclusive. This study investigated the effects of DSE versus age-appropriate school entry (ASE) on children's academic achievement and attention in middle childhood. METHOD: In total, 999 children (492 females, 507 males; 472 born preterm) were studied as part of a prospective population-based longitudinal study in Germany. Using a natural experimental design, propensity score matching was applied to create two matched groups who differed only in terms of DSE versus ASE. Teacher ratings of achievement in mathematics, reading, writing, and attention were obtained in Year 1, and standardized tests were administered at 8 years of age. RESULTS: There was no evidence of a difference in the odds of DSE versus ASE children being rated as above average by teachers in Year 1. In contrast, the standardized mean test scores for DSE children were lower than ASE children's mean scores in all domains (mathematics: B=-0.28 [-0.51 to -0.06)], reading: B=-0.39 [-0.65 to -0.14], writing: B=-0.90 [-1.07 to -0.74], and attention: B=-0.58 [-0.79 to -0.36]). INTERPRETATION: DSE did not affect teacher rated academic performance. However, missing 1 year of learning opportunities was associated with poorer average performance in standardized tests at 8 years of age. Future research is needed to determine the long-term effect of DSE on academic achievement. PMID- 25692817 TI - Pilot testing a cognitive-behavioral protocol on psychosocial predictors of exercise, nutrition, weight, and body satisfaction changes in a college-level health-related fitness course. AB - OBJECTIVE: Small-scale pilot testing of supplementing a required college health related fitness course with a cognitive-behavioral exercise-support protocol (The Coach Approach). PARTICIPANTS: Three classes were randomly assigned to Usual processes (n = 32), Coach Approach-supplemented: Mid-size Groups (n = 32), and Coach Approach-supplemented: Small Groups (n = 34) conditions. METHODS: Repeated measures analyses of variance (ANOVAs) assessed overall and between-class changes in the behavioral/physiological factors of exercise, fruit/vegetable intake, and body mass index (BMI); and the psychosocial factors of self-regulation, exercise self-efficacy, mood, and body satisfaction. Dependent t tests evaluated within class changes. Multiple regression analyses tested prediction of exercise by changes in self-regulation, self-efficacy, and mood. RESULTS: Significant improvements in self-regulation and fruit/vegetable intake were found in all classes. The Coach Approach-supplemented classes demonstrated significant increases in exercise. Significant improvements in BMI, self-efficacy, and body satisfaction were found in only The Coach Approach-supplemented: Small Groups class. Psychosocial changes predicted increased exercise. Self-regulation was the strongest contributor. CONCLUSIONS: Overall, results were positive and warrant more comprehensive testing. PMID- 25692820 TI - Error in text. PMID- 25692821 TI - Error in byline and author contributions. PMID- 25692822 TI - Errors in figure labels. PMID- 25692823 TI - Spontaneous calcification process in primary renal cells from a medullary sponge kidney patient harbouring a GDNF mutation. AB - Medullary nephrocalcinosis is a hallmark of medullary sponge kidney (MSK). We had the opportunity to study a spontaneous calcification process in vitro by utilizing the renal cells of a patient with MSK who was heterozygous for the c. 27 + 18G>A variant in the GDNF gene encoding glial cell-derived neurotrophic factor. The cells were obtained by collagenase digestion of papillary tissues from the MSK patient and from two patients who had no MSK or nephrocalcinosis. These cells were typed by immunocytochemistry, and the presence of mineral deposits was studied using von Kossa staining, scanning electron microscopy analysis and an ALP assay. Osteoblastic lineage markers were studied using immunocytochemistry and RT-PCR. Staminality markers were also analysed using flow cytometry, magnetic cell separation technology, immunocytochemistry and RT-PCR. Starting from p2, MSK and control cells formed nodules with a behaviour similar to that of calcifying pericytes; however, Ca2PO4 was only found in the MSK cultures. The MSK cells had morphologies and immunophenotypes resembling those of pericytes or stromal stem cells and were positive for vimentin, ZO1, alphaSMA and CD146. In addition, the MSK cells expressed osteocalcin and osteonectin, indicating an osteoblast-like phenotype. In contrast to the control cells, GDNF was down-regulated in the MSK cells. Stable GDNF knockdown was established in the HK2 cell line and was found to promote Ca2PO4 deposition when the cells were incubated with calcifying medium by regulating the osteonectin/osteopontin ratio in favour of osteonectin. Our data indicate that the human papilla may be a perivascular niche in which pericyte/stromal-like cells can undergo osteogenic differentiation under particular conditions and suggest that GDNF down-regulation may have influenced the observed phenomenon. PMID- 25692824 TI - Cooperative learning using simulation to achieve mastery of nasogastric tube insertion. AB - Traditionally, psychomotor skills training for nursing students involves didactic instruction followed by procedural review and practice with a task trainer, manikin, or classmates. This article describes a novel method of teaching psychomotor skills to associate degree and baccalaureate nursing students, Cooperative Learning Simulation Skills Training (CLSST), in the context of nasogastric tube insertion using a deliberate practice-to-mastery learning model. Student dyads served as operator and student learner. Automatic scoring was recorded in the debriefing log. Student pairs alternated roles until they achieved mastery, after which they were assessed individually. Median checklist scores of 100% were achieved by students in both programs after one practice session and through evaluation. Students and faculty provided positive feedback regarding this educational innovation. CLSST in a deliberate practice-to-mastery learning paradigm offers a novel way to teach psychomotor skills in nursing curricula and decreases the instructor-to-student ratio. PMID- 25692825 TI - Robust sensor for extended autonomous measurements of surface ocean dissolved inorganic carbon. AB - Ocean carbon monitoring efforts have increased dramatically in the past few decades in response to the need for better marine carbon cycle characterization. Autonomous pH and carbon dioxide (CO2) sensors capable of yearlong deployments are now commercially available; however, due to their strong covariance, this is the least desirable pair of carbonate system parameters to measure for high quality, in situ, carbon-cycle studies. To expand the number of tools available for autonomous carbonate system observations, we have developed a robust surface ocean dissolved inorganic carbon (DIC) sensor capable of extended (>year) field deployments with a laboratory determined uncertainty of +/-5 MUmol kg(-1). Results from the first two field tests of this prototype sensor indicate that measurements of DIC are ~90% more accurate than estimates of DIC calculated from contemporaneous and collocated measurements of pH and CO2. The improved accuracy from directly measuring DIC gives rise to new opportunities for quantitative, autonomous carbon-cycle studies. PMID- 25692826 TI - Hard carbon originated from polyvinyl chloride nanofibers as high-performance anode material for Na-ion battery. AB - Two types of hard carbon materials were synthesized through direct pyrolysis of commercial polyvinyl chloride (PVC) particles and pyrolysis of PVC nanofibers at 600-800 degrees C, respectively, where the nanofibers were prepared by an electrospinning PVC precursors method. These as-prepared hard carbon samples were used as anode materials for Na-ion batteries. The hard carbon obtained from PVC nanofibers achieved a high reversible capacity of 271 mAh/g and an initial Coulombic efficiency of 69.9%, which were much superior to the one from commercial PVC, namely, a reversible capacity of 206 mAh/g and an initial Coulombic efficiency of 60.9%. In addition, the hard carbon originated from the PVC nanofibers exhibited good cycling stability and rate performance: the initial discharge capacities were 389, 228, 194, 178, 147 mAh/g at the current density of 12, 24, 60, 120, and 240 mA/g, respectively, retaining 211 mAh/g after 150 cycles. Such excellent cycle performance, high reversible capacity, and good rate capability enabled this hard carbon to be a promising candidate as anode material for Na-ion battery application. PMID- 25692827 TI - Amyloid nanospheres from polyglutamine rich peptides: assemblage through an intermolecular salt bridge interaction. AB - We have shown the conversion of an amyloid fiber forming nucleation pathway of polyglutamine (polyGln) to a non-nucleated pathway, generating nanospherical amyloid particles. This is achieved by engineering an intermolecular salt bridge interaction between the positively charged lysine and the negatively charged glutamate residues, in two polyGln rich peptides. The mechanism of their formation is characterized by chromatography, infrared, fluorescence and imaging methods. PMID- 25692828 TI - [Anticoagulant therapy in secondary prevention of coronary events]. AB - Secondary prevention of atherothrombotic events is the domain of antiplatelet therapy and according to present risk is used one drug strategy or combination of acetylsalicylic acid with ADP receptor blockers. The importance of the combination of dual antiplatelet therapy together with xabans or dabigatran was investigated in 6 clinical trials. Only one of them (ATLAS ACS 2-TIMI 51) indicated that treatment with small dose of rivaroxaban (2 * 2.5 mg) may be added to dual strategy of acetylsalicylic acid and clopidogrel. The risk of major bleeding event is increased and net clinical benefit is only about 0.5 % per year. Dual therapy with aspirin and prasugrel or tikagrelor is beneficial. In the second part of the review is discussed higher incidence of myocardial infarction in controlled group in the trial comparing treatment of dabigatran with warfarin. This relationship has not been resolved, however, in patients with higher risk of coronary events and indication of anticoagulant treatment with direct oral anticoagulants it is recommended to choose from xabans (apixaban and rivaroxaban). PMID- 25692829 TI - [Anaemia and iron deficiency in clinical practice:from cardiology to gastroenterology and beyond]. AB - Anaemia is one of the most common diseases. Worldwide affects up to 25% of the population. Anaemia with iron deficiency (Fe) is the leading one. It is not surprising that iron deficiency mainly affects women. Generally, anaemia is one of the major problems in every department of internal medicine. There is no ambition to provide a comprehensive review of the diagnosis and treatment of anaemia. The aim is to point out the common (but sometimes neglected) facts from daily practice in internal department and on the other hand, to highlight the news in the treatment focusing on parenteral Fe.The importance of anaemia at the department of internal medicine. Mentioned above, anaemia is very frequent in internal medicine. Especially, it is anaemia of Fe deficiency and anaemia of chronic disease. Mostly elderly and polymorbid patients (often with one dominant, sometimes cryptogenic disease) suffer from anaemia. I am concern about the fact that anaemia is often seen only as a sign of other disease and usually is not the target of diagnostic and therapeutic efforts.Diagnosis and treatment. The internal department physician is responsible for patient care, but cooperates with haematologist in case of severe anaemia in diagnostic and therapeutic process. Basic examination contains analysis of Fe, ferritin, transferrin, circulating serum transferrin receptors or other parameters. Of course, the focus in iron deficiency anaemia is on its possible loss or in case of chronic disease anaemia on primary disease.Notes to Fe treatment. If the patient has iron deficiency the Fe treatment is often indicated (after finding the cause). Iron is administered orally in most cases. There are several situations when parenteral Fe is not only preferable, but also represents the only therapeutic option. Currently, the best evidence for the positive effects is observed in parenterally administered Fe ferric carboxymaltose, Ferinject.Parenteral administration of Fe in gastroenterology. Gastorenterology is a common field for the use of Fe administration. The losses in the GIT are frequent as well as malabsorption of Fe in several gastrointestinal diseases. A typical example may be inflammatory bowel disease, especially Crohn's disease. Not only case reports demonstrate the positive effect of ferric carboxymaltose in Crohn's disease.Parenteral administration of Fe in cardiology. Recently published work (multicentric randomized controlled double-blinde trial) CONFIRM HF have proved that administration of ferric carboxymaltose in heart failure patients have improved their functional ability, NYHA stratification and quality of life. The pilot studies performed before resulted positively and CONFIRM HF only confirmed their conclusions.Quality of life - neglected parameter. Conclusions of CONFIRM HF introduce the improved quality of life as one of the main result. Unfortunately, it is a parameter (subjective, difficult to objectify) which doesn't have such importance as endpoint - indicator of intervention trials. It is shown that treatment of anaemia is important in chronic fatigue (especially women) and affects quality of life. Improvement in symptoms of fatigue has been demonstrated after administration of 1000 mg of ferric carboxymaltose. Fe treatment improves quality of life in anaemic oncology patients as well. PMID- 25692830 TI - [Embolic ischemic strokes]. AB - Treatment of acute phase of ischemic stroke is aimed to limit the amount of damage using reperfusion strategy and subsequently administration of treatment providing pharmacological secondary prevention of recurrence. The early aetiology diagnosis of stroke is crucial for effective secondary prevention as the highest risk of recurrence is within few weeks after stroke. Exclusion of cardiac and vascular source of embolism by imaging methods is an important part in management of patients with ischemic stroke. These embolic sources are categorized as high risk and states are associated with moderate or unclear risk. PMID- 25692831 TI - [Past and present issues of the pulmonary circulation in the General University Hospital in Prague]. AB - The development of right heart catheterization is closely connected not only with its pioneer Werner Forssmann but also with the University Hospital in Prague. Shortly after Forssmann's pioneering performance of catheterization, Dr. Otto Klein measured cardiac output using the Fick's principle in 11 patients in University Hospital. In the 60s and 70s of last century, there was established an research group represented by Severin Daum, Frantisek Boudik, Vlastimil Jezek, Alois Ourednik and Zdenek Suso at 2nd Internal Clinic of General Cardiopulmonary Hospital. After 1999, the issue of pulmonary hypertension has been re-emerged by Professor Michal Aschermann and this had significant clinical implications. The highly specialized centre for pulmonary arterial hypertension (PAH) was found at the clinic and in Cardio Centre of General University Hospital it has been initiated a successful program of pulmonary endarterectomy in chronic thromboembolic pulmonary hypertension (CTEPH) since 2004. Surgical treatment is also provided to patients from Slovakia. The number of patients, wide range of therapy and its results, including the excellent results of surgical treatment situates the centre among the most important centres in Europe dealing with pulmonary hypertension. PMID- 25692832 TI - [Catheter ablation of focus triggering ventricular fibrillation in patients with structural heart disease]. AB - First experiences with ablation of focus triggering ventricular fibrillation were reported in isolated cases of idiopathic ventricular fibrillation. Later, there were described the options in management of an electrical instability triggered by ectopic activity in patients after myocardial infarction. In both cases it was shown that the sources of extrasystoles originate almost exclusively from conducting system of chambers. Subsequently, isolated cases were also reported in other structural diseases. It is important that the urgent catheter ablation is able to remove focus which triggers electric instability. In many cases it is a lifesaving procedure. This review summarizes the current knowledge of the catheter ablation of focus triggering ventricular fibrillation with structural heart disease. PMID- 25692833 TI - [Current status of intravascular ultrasound in interventional cardiology]. AB - Although intravascular ultrasound has been used for decades, its common application in catheterization centres during coronary interventions is very rare and merely reaches few percents. The reason is the lack of randomized trials of its use and often few experiences in evaluation of ultrasound findings. Data based on meta-analysis of observational studies clearly demonstrated the positive effect on the most important parameters for the treatment of patients with ischemic heart disease, such as mortality and incidence of myocardial infarction after coronary interventions. Therefore, according to the latest guidelines for myocardial revascularization of the European Society of Cardiology is level of recommendation in category IIa for the use of intravascular ultrasound. IVUS continues to be an important part of new investigation methods which try to better describe coronary atherosclerosis. Particularly, it is the method NIRS (near-infrared spectroscopy) and other new methods of evaluating the composition and mechanical properties of plaque. These facts suggest that IVUS maintains its contribution in time of optical coherence tomography (OCT) and the emphasis put on the functional assessment of coronary stenoses.Key words: coronary atherosclerosis - intravascular ultrasound - percutaneous coronary intervention. PMID- 25692834 TI - [Obesity and heart]. AB - Cardiovascular complications of obesity are traditionally considered an important complication of obesity. Obesity itself is probably not direct cause of atherosclerosis or coronary heart disease. This may occur indirectly in metabolic complications of obesity, especially diabetes and metabolic syndrome. However, thrombogenicity potential of obesity contributes to embolism and atherosclerosis development. In cardiology is well-known a phenomenon of obesity paradox when obese patients have better prognosis than thin. This is the case of heart failure and some other cardiovascular diseases. Recently, a new concept has emerged of myokines - hormones from muscle tissue that have extensive protective effects on organism and probably on heart. Whether heart is a source of myokines is uncertain. However, undoubted importance has epicardial and pericardial fatty tissue. The epicardial fatty tissue has mainly protective effects on myocardium. This fatty tissue may produce factors of inflammation affecting the myocardium. Relationship between amount of epicardial fatty tissue and coronary heart disease is rather pathogenic. Currently, it is certain that obesity brings more metabolic and cancer complications than cardiovascular and accurate contribution to pathogenic or protective character of fatty tissue in cardiology requires further research. Nevertheless, the conclusion is that adipose tissue of organism and around the heart may be in some circumstances beneficial. PMID- 25692835 TI - [Carotid artery stenting - history, trends and innovations]. AB - Surgical carotid endarterectomy is traditionally considered the standard approach for the treatment of atherosclerotic carotid artery disease based on its long history of favorable outcomes. Many of the patients could, however, be offered carotid artery stenting (CAS), which has over time evolved into an elaborate method. With proper selection of patients, CAS provides comparable long-term outcomes and very low risk of periprocedural complication. This article summarises the current knowledge, trends and innovations in CAS. PMID- 25692836 TI - [Do natriuretic peptides have a new chance in treatment of heart failure?]. AB - The effect of natriuretic peptides on cardiovascular and renal system offers a potential benefit in therapy of hypertension and heart failure; however the current results of clinical trials are not encouraging. Synthetic B natriuretic peptide has demonstrated short-term hemodynamic improvement in patients, but in terms of renal function and long-term prognosis the effect was questionable. Nevertheless, new hope is ularitid a dual inhibitor of neprilysin and ARB: LCZ 696, the ongoing clinical studies and previous data from pilot studies appear promising. PMID- 25692837 TI - [Renal denervation in patients with resistant hypertension: is it still possible to resuscitate?]. AB - Transcatheter renal denervation (RDN) has been markedly applied and developed in clinical practice in past five years and not only for patients with resistant hypertension. The issue that more than 50% patients with so-called resistant hypertension are in fact patients without adherence to this type of mediation has not been resolved in RDN trials till now. The study Symplicity HTN-3 showed no differences in blood pressure change between the patients with RDN and group of patients after false procedure who continued in their drug therapy. Future of RDN is more than questionable and there is a need to return to animal studies that will verify the real effectiveness of RDN, subsequently, will redefine population of patients indicated for RDN and confirm the applicability of newly developed techniques. PMID- 25692838 TI - [Modern treatment of acute ischemic stroke]. AB - Acute ischemic stroke is a frequent cause of death and disability. Therepautic scepticism persists both among doctors and lay people. However, modern reperfusion therapy improved outcomes of acute stroke patients - at least of those presenting early after symptom onset. This review presents multidisciplinary approach to acute stroke - cooperation of neurologists, cardiologists and radiologists. Both reperfusion strategies are discussed: catheter-based thrombectomy and thrombolysis. PMID- 25692839 TI - [Percutaneous approach for treating mitral regurgitation with mitral clip (MitraClip)]. AB - Mitral regurgitation (MR) is the second most commonly encountered valvular lesion and it has been positively correlated with the subsequent development of heart failure and death. MitraClip therapy is a new percutaneous approach for treating mitral regurgitation which involves mechanical edge-to-edge coaptation of the mitral leaflets that is analogous to the surgical Alfieri technique. Indication for MitraClip in patients with severe degenerative or functional mitral regurgitation is based on clinical symptoms (NYHA II-IV) and specific anatomic criteria including a primary central regurgitant jet associated with the A2/P2 segments, in functional MR a coaptation length 2 mm, a coaptation depth 11 mm, in degenerative MR a flail gap <10 mm, and a flail width < 15 mm. Key exclusion criteria included LVEF 25%, LV end-systolic dimension > 55 mm, mitral valve orifice area < 4 cm2, recent myocardial infarction or endocarditis. The safety profile of the procedure appears to be excellent. Acute outcomes are favourable, and mid-term durability (up to 2 years) is reasonable. Patients who are older, at higher risk for surgical therapy, or with functional mitral regurgitation (FMR) and depressed ejection fractions will constitute the initial target population for MitraClip therapy. Since FMR is primarily a ventricular problem, it remains to be seen whether a leaflet intervention will have durable efficacy. PMID- 25692840 TI - [IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (studie IMPROVE-IT)]. AB - BACKGROUND: The IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) is evaluating the potential benefit for reduction in major cardiovascular (CV) events from the addition of ezetimibe versus placebo to 40 mg/d of simvastatin therapy in patients who present with acute coronary syndromes and have low-density lipoprotein cholesterol (LDL-C) 125 mg/dl. METHODS: Randomized double blind clinical trial in patients with acute coronary syndrome and low cholesterol level. The simvastatin monotherapy arms LDL-C target was < 70 mg/dl, the comparison arm was simvastatin + ezetimibe. Ezetimibe was assumed to further lower LDL-C by 15 mg/dl and produce an estimated ~ 8 % to 9 % treatment effect. The primary composite end point was CV death, nonfatal myocardial infarction (MI), nonfatal stroke, rehospitalization for unstable angina (UA), and coronary revascularization ( 30 days postrandomization). The targeted number of events was 5,250. RESULTS: 18,144 patients were enroled with either ST segment elevation MI (STEMI, n = 5,192) or UA/non-ST segment elevation MI (UA/NSTEMI, n = 12,952) from October 2005 to July 2010. Primary endpoint occured in 2 742 patients (34.7 %) treated with simvastatin in monotherapy and in 2 572 patients (32.7 %) (p = 0.016) treated with combination. Compared to patients with coronary heart disease given the drug simvastatin plus a placebo, those given both simvastatin and the non-statin drug, ezetimibe, had a 6.4 % lower combined risk of subsequent heart attack, stroke, cardiovascular death, rehospitalization for unstable angina and procedures to restore blood flow to the heart. Heart attacks alone were reduced by 13 %, and non-fatal stroke by 20 %. Deaths from cardiovascular disease were statistically the same in both groups. Patients were followed an average of approximately six years, and some as long as 8.5 years. Approximately 2 patients out of every 100 patients treated for 7 years avoided a heart attack or stroke [Number Needed to Treat (NNT) = 50/7 years]. CONCLUSIONS: The study has shown a claer benefit from combination treatment with simvastatin and ezetimibe in patients with acute coronary syndrome and low LDL-C. PMID- 25692841 TI - [Will the new SGLT2 inhibitor empagliflozin help us reduce the risk of hypoglycemia?]. AB - The treatment of patients with type 2 diabetes is typically accompanied by hypoglycemia, if insulin or derivatives of sulfonylurea are used within the treatment. Apart from the fact that hypoglycemias are the major obstacle to achieving the desirable compensation of diabetes, hypoglycemia also has a number of serious clinical consequences. A long term serious hypoglycemia may lead to a sudden death, heart attack or irreversible brain damage. Clinically significant are also the light or asymptomatic hypoglycemias which in a considerably negative way affect the patient's quality of life. The use of modern technologies in continuous monitoring of glycemias has shown that the occurrence of asymptomatic hypoglycemias is much higher than we anticipated and that they largely involve nocturnal hypoglycemia. Hypoglycemia is associated with an increased level of depression, anxiety, dissatisfaction with the treatment and with a greater number of physician office visits. Nocturnal hypoglycemia has a negative impact on the quality of sleep, it may impair cognitive functions and performance efficiency next day. The prevention of hypoglycemia is therefore one of the basic goals of diabetes treatment and the low risk of hypoglycemia is among the main requirements that we place on the newly developed antidiabetic drugs. The negligible risk of hypoglycemia, which is comparable to placebo both in monotherapy and in most combinations with the antidiabetic drugs available today, is evidenced by the data from the studies undertaken with empagliflozin. It shows that the low risk of hypoglycemia is one of the benefits of gliflozins, the new group of medications with a unique mechanism of effect which has quite recently appeared on our market. PMID- 25692842 TI - Expanding Haitian nurse educators' skills: a graduate course for current faculty. AB - Nursing faculty members in developing countries often teach large class sizes, with limited technology available. They face economic constraints and have few opportunities for professional development. A graduate course for Haitian nursing faculty was designed with the aim of addressing these challenges. Nurse educators in similar countries were queried about their challenges and effective strategies. Techniques and equipment currently used in Haiti were discussed and evaluated. The course focused on identifying methods to teach large classes effectively at low cost with minimal technology. Haitian faculty members were able to effectively demonstrate these new techniques as participants during the course. A survey conducted 1 year after course completion established that the Haitian faculty members had implemented new techniques in their classes, improving the quality of nursing education. Strategies taught may be effective in other developing countries where similar challenges exist. PMID- 25692843 TI - Molecular and cellular glyco-science - part I. PMID- 25692844 TI - The tobacco lectin, prototype of the family of Nictaba-related proteins. AB - In the last decade, a new class of low abundant plant l ectins was identified. These proteins are expressed after exposure of the plant to different stress factors and changing environmental conditions, and therefore are referred to as "inducible" lectins. Interestingly, these lectins accumulate in the nucleocytoplasmic compartment of plant cells. At present at least six carbohydrate recognition domains have been identified within the group of nucleocytoplasmic plant lectins. This review will focus on a group of proteins that show homology to the Nicotiana tabacum (tobacco) agglutinin or Nictaba. The tobacco lectin is a 38 kDa nucleocytoplasmic protein which is only expressed upon treatment with jasmonate-related compounds or after insect herbivory. The lectin exhibits specificity towards GlcNAc, but also reacts with N-glycan structures. Extensive searches revealed that Nictaba-related sequences are widespread in the plant kingdom. Analyses of the different transcriptome databases showed that the Nictaba domain is often part of chimeric proteins comprising one or more Nictaba domain(s) fused to unrelated N- and C-terminal domains with (un)known function. At present only few proteins of these Nictaba-related proteins have been studied and characterized for their biological properties and physiological role. Despite the sequence similarity and the conserved amino acids constituting the binding site, the Nictaba domain has a promiscuous carbohydrate binding site capable of interacting with different carbohydrate motifs, suggesting that subtle changes in the vicinity of the binding site can alter its sugar specificity. PMID- 25692845 TI - Galactose-specific seed lectins from Cucurbitaceae. AB - Lectins, the carbohydrate binding proteins have been studied extensively in view of their ubiquitous nature and wide-ranging applications. As they were originally found in plant seed extracts, much of the work on them was focused on plant seed lectins, especially those from legume seeds whereas much less attention was paid to the lectins from other plant families. During the last two decades many studies have been reported on lectins from the seeds of Cucurbitaceae species. The main focus of the present review is to provide an overview of the current knowledge on these proteins, especially with regard to their physico-chemical characterization, interaction with carbohydrates and hydrophobic ligands, 3 dimensional structure and similarity to type-II ribosome inactivating proteins. The future outlook of research on these galactose-specific proteins is also briefly considered. PMID- 25692847 TI - Lysosomal enzymes and their receptors in invertebrates: an evolutionary perspective. AB - Lysosomal biogenesis is an important process in eukaryotic cells to maintain cellular homeostasis. The key components that are involved in the biogenesis such as the lysosomal enzymes, their modifications and the mannose 6-phosphate receptors have been well studied and their evolutionary conservation across mammalian and non-mammalian vertebrates is clearly established. Invertebrate lysosomal biogenesis pathway on the other hand is not well studied. Although, details on mannose 6-phosphate receptors and enzymes involved in lysosomal enzyme modifications were reported earlier, a clear cut pathway has not been established. Recent research on the invertebrate species involving biogenesis of lysosomal enzymes suggests a possible conserved pathway in invertebrates. This review presents certain observations based on these processes that include biochemical, immunological and functional studies. Major conclusions include conservation of MPR-dependent pathway in higher invertebrates and recent evidence suggests that MPR-independent pathway might have been more prominent among lower invertebrates. The possible components of MPR-independent pathway that may play a role in lysosomal enzyme targeting are also discussed here. PMID- 25692846 TI - Glucosidase II and MRH-domain containing proteins in the secretory pathway. AB - N-glycosylation in the endoplasmic reticulum (ER) consists of the transfer of a preassembled glycan conserved among species (Glc3Man9GlcNAc2) from a lipid donor to a consensus sequence within a nascent protein that is entering the ER. The protein-linked glycans are then processed by glycosidases and glycosyltransferases in the ER producing specific structures that serve as signalling molecules for the fate of the folding glycoprotein: to stay in the ER during the folding process, to be retrotranslocated to the cytosol for proteasomal degradation if irreversibly misfolded, or to pursue transit through the secretory pathway as a mature glycoprotein. In the ER, each glycan signalling structure is recognized by a specific lectin. A domain similar to that of the mannose 6-phosphate receptors (MPRs) has been identified in several proteins of the secretory pathway. These include the beta subunit of glucosidase II (GII), a key enzyme in the early processing of the transferred glycan that removes middle and innermost glucoses and is involved in quality control of glycoprotein folding in the ER (QC), the lectins OS-9 and XTP3-B, proteins involved in the delivery of ER misfolded proteins to degradation (ERAD), the gamma subunit of the Golgi GlcNAc-1-phosphotransferase, an enzyme involved in generating the mannose 6 phosphate (M6P) signal for sorting acidic hydrolases to lysosomes, and finally the MPRs that deliver those hydrolytic enzymes to the lysosome. Each of the MRH containing proteins recognizes a different signalling N-glycan structure. Three dimensional structures of some of the MRH domains have been solved, providing the basis to understand recognition mechanisms. PMID- 25692848 TI - Sweet on Hedgehogs: regulatory roles of heparan sulfate proteoglycans in Hedgehog dependent cell proliferation and differentiation. AB - Morphogens exert their effects over long distances, typically by spreading from cell to cell to activate signal transduction in surrounding tissues in concentration-dependent manner. One example of a morphogen is the signaling molecule Hedgehog (Hh), which controls growth and patterning during development and has also been implicated in the progression of numerous cancers. To this end, accessory mechanisms that release, transport, and receive Hhs are required to elicit temporally and spatially specific responses in cells and tissues. The Hh spreading mechanism is especially intriguing, because all Hhs are released from the producing cells despite being synthesized as dually lipidated, membrane tethered molecules. In addition to this cellular association, Hhs bind strongly to extracellular heparan sulfate proteoglycans (HSPGs), which is expected to further reduce their spreading. Paradoxically, several lines of evidence suggest that Hh gradient formation actually requires HSPG expression, and that HSPGs act as both positive and negative regulators of Hh function. This article reviews the multiple roles that HSPGs play in Hh morphogen function, and discusses their congruity with proposed mechanisms of Hh solubilization, transport, and signal reception in vertebrate and invertebrate tissues. PMID- 25692849 TI - Heparan sulphate as a regulator of leukocyte recruitment in inflammation. AB - A key event in inflammatory disease is the transendothelial recruitment of leukocytes from the circulation to the site of inflammation. Intense research in the past decades indicates that the polyanionic carbohydrate heparan sulphate (HS) modulates multiple steps in the leukocyte recruitment cascade. Leukocyte recruitment is initiated by endothelial cell activation and presentation of chemokines to rolling leukocytes, which, via integrin activation, results in adhesion and diapedesis through the vessel wall. Heparan sulfate proteoglycans (HSPGs) immobilize the chemokines on the luminal endothelial cells, rendering them more robust against mechanical or hydrodynamic perturbations. During inflammation, endothelial HSPGs serve as ligands to L-selectin on leukocytes, transport chemokines in a basolateral to apical direction across the endothelium, and present chemokines at the luminal surface of the endothelium to circulating cells. HSPGs also promote chemokine oligomerization, which influences chemokine receptor signaling. Furthermore, proteoglycans of the syndecan family are involved in modulating integrin-mediated tight adhesion of leukocytes to the endothelium. Creation of a chemokine gradient by a localized chemokine release influences the speed of leukocyte recruitment from the blood to the tissue by attracting crawling neutrophils to optimal sites for transmigration. The directionality of intraluminal crawling is thought to be influenced by both mechanotactic and haptotactic signals, which are modulated by HS-dependent signaling processes. Finally, diapedesis is influenced by HS regarding transendothelial chemokine gradient formation and integrin- CAM interactions, and further enhanced by heparanase-mediated degradation of the endothelial basement membrane. Overall, the multifunctional role of HS in inflammation marks it as a potential target of glycan-centered therapeutic approaches. PMID- 25692850 TI - Contribution of university departments of rural health to rural health research: An analysis of outputs. AB - OBJECTIVE: To assess the research contribution of eleven University Departments of Rural Health (UDRH) which were established as a rural health workforce program in the late 1990s through analysis of peer-reviewed journal output. DESIGN AND SETTINGS: Descriptive study based on validated publications from publication output reported in annual key performance indicator (KPI) reports to the Commonwealth Department of Health, Australia. MAIN OUTCOME MEASURES: In addition to counts and the type of publications, articles were examined to assess fields of research, evidence of research collaboration, and potential for influencing policy. Funding acknowledgement was examined to provide insight into funding sources and research consultancies. RESULTS: Of the 182 peer-reviewed articles, UDRH staff members were the first and corresponding author for 45% (n = 82); most (69%, n = 126) were original research. Most publications examined included Australian data only (80%, n = 101). Over half (56%; n = 102) of the articles addressed rural health issues; Aboriginal health was the main subject in 14% (n = 26). Thirty-three articles (18%) discussed the policy implications of the research and only half (51%, n = 93) of the articles listed sources of funding. Number of authors per article ranged from 1-19, with a mean of 5 (SD = 3.2) authors per article, two-thirds of articles included authors from 2-5 universities/organisations but only 5% of articles included an author from more than one UDRH. CONCLUSIONS: Staff from UDRHs are regularly publishing peer reviewed articles, and research productivity demonstrated cooperation with external partners. Better collaboration between UDRH staff and others may help increase the quality and value of Australian rural health research. PMID- 25692851 TI - Dynamic modeling of the Ganga river system: impacts of future climate and socio economic change on flows and nitrogen fluxes in India and Bangladesh. AB - This study investigates the potential impacts of future climate and socio economic change on the flow and nitrogen fluxes of the Ganga river system. This is the first basin scale water quality study for the Ganga considering climate change at 25 km resolution together with socio-economic scenarios. The revised dynamic, process-based INCA model was used to simulate hydrology and water quality within the complex multi-branched river basins. All climate realizations utilized in the study predict increases in temperature and rainfall by the 2050s with significant increase by the 2090s. These changes generate associated increases in monsoon flows and increased availability of water for groundwater recharge and irrigation, but also more frequent flooding. Decreased concentrations of nitrate and ammonia are expected due to increased dilution. Different future socio-economic scenarios were found to have a significant impact on water quality at the downstream end of the Ganga. A less sustainable future resulted in a deterioration of water quality due to the pressures from higher population growth, land use change, increased sewage treatment discharges, enhanced atmospheric nitrogen deposition, and water abstraction. However, water quality was found to improve under a more sustainable strategy as envisaged in the Ganga clean-up plan. PMID- 25692852 TI - Large-scale plasma patterning of transparent graphene electrode on flexible substrates. AB - Graphene, a two-dimensional carbon material, has attracted significant interest for applications in flexible electronics as an alternative transparent electrode to indium tin oxide. However, it still remains a challenge to develop a simple, reproducible, and controllable fabrication technique for producing homogeneous large-scale graphene films and creating uniform patterns with desired shapes at defined positions. Here, we present a simple route to scalable fabrication of flexible transparent graphene electrodes using an oxygen plasma etching technique in a capacitively coupled plasma (CCP) system. Ascorbic acid-assisted chemical reduction enables the large-scale production of graphene with solution-based processability. Oxygen plasma in the CCP system facilitates the reproducible patterning of graphene electrodes, which allows controllable feature sizes and shapes on flexible plastic substrates. The resulting graphene electrode exhibits a high conductivity of 80 S cm(-1) and a transparency of 76% and retains excellent flexibility upon hard bending at an angle of +/-175 degrees and after repeated bending cycles. A simple LED circuit integrated on the patterned graphene film demonstrates the feasibility of graphene electrodes for use in flexible transparent electrodes. PMID- 25692853 TI - Efficacy of Rapamycin in Tuberous Sclerosis-Associated Hypopigmented Macules: Back to the Future. PMID- 25692854 TI - Curcumin conjugated with PLGA potentiates sustainability, anti-proliferative activity and apoptosis in human colon carcinoma cells. AB - Curcumin, an ingredient of turmeric, exhibits a variety of biological activities such as anti-inflammatory, anti-atherosclerotic, anti-proliferative, anti oxidant, anti-cancer and anti-metastatic. It is a highly pleiotropic molecule that inhibits cell proliferation and induces apoptosis in cancer cells. Despite its imperative biological activities, chemical instability, photo-instability and poor bioavailability limits its utilization as an effective therapeutic agent. Therefore, enhancing the bioavailability of curcumin may improve its therapeutic index for clinical setting. In the present study, we have conjugated curcumin with a biodegradable polymer Poly (D, L-lactic-co-glycolic acid) and evaluated its apoptotic potential in human colon carcinoma cells (HCT 116). The results show that curcumin-PLGA conjugate efficiently inhibits cell proliferation and cell survival in human colon carcinoma cells as compared to native curcumin. Additionally, curcumin conjugated with PLGA shows improved cellular uptake and exhibits controlled release at physiological pH as compared to native curcumin. The curcumin-PLGA conjugate efficiently activates the cascade of caspases and promotes intrinsic apoptotic signaling. Thus, the results suggest that conjugation potentiates the sustainability, anti-proliferative and apoptotic activity of curcumin. This approach could be a promising strategy to improve the therapeutic index of cancer therapy. PMID- 25692855 TI - Newborn hypoxia/anoxia inhibits cardiomyocyte proliferation and decreases cardiomyocyte endowment in the developing heart: role of endothelin-1. AB - In the developing heart, cardiomyocytes undergo terminal differentiation during a critical window around birth. Hypoxia is a major stress to preterm infants, yet its effect on the development and maturation of the heart remains unknown. We tested the hypothesis in a rat model that newborn anoxia accelerates cardiomyocyte terminal differentiation and results in reduced cardiomyocyte endowment in the developing heart via an endothelin-1-dependent mechanism. Newborn rats were exposed to anoxia twice daily from postnatal day 1 to 3, and hearts were isolated and studied at postnatal day 4 (P4), 7 (P7), and 14 (P14). Anoxia significantly increased HIF-1alpha protein expression and pre-proET-1 mRNA abundance in P4 neonatal hearts. Cardiomyocyte proliferation was significantly decreased by anoxia in P4 and P7, resulting in a significant reduction of cardiomyocyte number per heart weight in the P14 neonates. Furthermore, the expression of cyclin D2 was significantly decreased due to anoxia, while p27 expression was increased. Anoxia has no significant effect on cardiomyocyte binucleation or myocyte size. Consistently, prenatal hypoxia significantly decreased cardiomyocyte proliferation but had no effect on binucleation in the fetal heart. Newborn administration of PD156707, an ETA-receptor antagonist, significantly increased cardiomyocyte proliferation at P4 and cell size at P7, resulting in an increase in the heart to body weight ratio in P7 neonates. In addition, PD156707 abrogated the anoxia-mediated effects. The results suggest that hypoxia and anoxia via activation of endothelin-1 at the critical window of heart development inhibits cardiomyocyte proliferation and decreases myocyte endowment in the developing heart, which may negatively impact cardiac function later in life. PMID- 25692856 TI - Can plateletcrit, an underestimated platelet parameter, be related with preterm labour? AB - OBJECTIVE: Noninvasive and simple markers are needed for the prediction of preterm delivery in women at risk for preterm labour. The aim of this study was to determine the value of platelet indices in the prediction of preterm delivery. DESIGN: A retrospective study. SETTING: Routine antenatal care in Zonguldak Bulent Ecevit University between 2008 and 2011. SAMPLE: Ninety patients who delivered between 28 and 37 weeks of gestational age and 128 patients who delivered at term. METHODS: Plateletcrit and other haematological markers, cervical dilatation and effacement, and the neutrophil-to-lymphocyte ratio as an inflammation marker. MAIN OUTCOME MEASURE: The role of platelet indices in predicting the preterm delivery. RESULTS: The platelet count, plateletcrit, white blood cell count, red cell distribution width, and neutrophil count were significantly higher in the preterm delivery group. Receiver operating characteristic curve analysis showed that the plateletcrit cut-off value for predicting spontaneous preterm labour was 0.201%, with a sensitivity of 95.6% and specificity of 87.5%; the cut-off value for the platelet count was 234 ? 103/mm3 with a sensitivity of 81.0% and specificity of 71.0%. CONCLUSION: Plateletcrit is a low-cost, widely available, and noninvasive marker that might be used for the prediction of preterm delivery in patients with a history of preterm labour. PMID- 25692857 TI - Virtual electrophysiological study of atrial fibrillation in fibrotic remodeling. AB - Research has indicated that atrial fibrillation (AF) ablation failure is related to the presence of atrial fibrosis. However it remains unclear whether this information can be successfully used in predicting the optimal ablation targets for AF termination. We aimed to provide a proof-of-concept that patient-specific virtual electrophysiological study that combines i) atrial structure and fibrosis distribution from clinical MRI and ii) modeling of atrial electrophysiology, could be used to predict: (1) how fibrosis distribution determines the locations from which paced beats degrade into AF; (2) the dynamic behavior of persistent AF rotors; and (3) the optimal ablation targets in each patient. Four MRI-based patient-specific models of fibrotic left atria were generated, ranging in fibrosis amount. Virtual electrophysiological studies were performed in these models, and where AF was inducible, the dynamics of AF were used to determine the ablation locations that render AF non-inducible. In 2 of the 4 models patient specific models AF was induced; in these models the distance between a given pacing location and the closest fibrotic region determined whether AF was inducible from that particular location, with only the mid-range distances resulting in arrhythmia. Phase singularities of persistent rotors were found to move within restricted regions of tissue, which were independent of the pacing location from which AF was induced. Electrophysiological sensitivity analysis demonstrated that these regions changed little with variations in electrophysiological parameters. Patient-specific distribution of fibrosis was thus found to be a critical component of AF initiation and maintenance. When the restricted regions encompassing the meander of the persistent phase singularities were modeled as ablation lesions, AF could no longer be induced. The study demonstrates that a patient-specific modeling approach to identify non-invasively AF ablation targets prior to the clinical procedure is feasible. PMID- 25692858 TI - Assessment of P wave duration and P wave dispersion in high level football referees. AB - BACKGROUND: P wave dispersion and P wave maximal duration reflect the activation of atrial muscle and is influenced by the mass of the excited tissue. It may reflect atrial remodelling, most likely atrial fibrosis. The purpose of this study was to measure P wave duration and P wave dispersion in the high level football referees. METHODS: We recruited 104 elite and national referees with a training history of many years. The control group was made of 32 healthy sedentary subjects. The difference between P maximum and P minimum durations was defined as P wave dispersion. Echocardiographic parameters such as left atrial diameter were assessed with a Vivid 3 cardiovascular ultrasound system [3S sector probe (1.5-3.6 MHz), GE]. RESULTS: P wave maximum duration, P wave dispersion, left ventricle posterior wall thickness, inter-ventricular septum thickness and left atrial diameter were increased in the football referees as compared with healthy sedentary subjects. There were significant correlations of P wave dispersion with left atrial diameter and left ventricle posterior wall thickness CONCLUSIONS: P wave maximum duration, P wave dispersion and left atrial diameter were increased in the football referees. Also, there was a significant correlation between P wave dispersion and left atrial diameter. PMID- 25692859 TI - Short-term results of a 5-week comprehensive cardiac rehabilitation program after first-time myocardial infarction. AB - BACKGROUND: A prospective single-center interventional cohort study was conducted to evaluate the effects of a 5-week comprehensive cardiac rehabilitation program on terms exercise capacity, quality of life, echocardiographic findings and autonomic modulation after first-time myocardial infarction. METHODS: We studied 37 consecutive post-myocardial infartion patients (mean age 66 years). All patients began a 5-week cardiac rehabilitation supervised training. The exercise program consisted of 40 minutes of training, three times a week, on a cycle ergometer at 60-80% of the maximal heart rate. At baseline and after training program we analyzed: the distance walked after the Six-Minutes Walking Test (6MWT); quality of life (QoL) assesed using the Psychological General Well-Being Inventory (PGWBI) questionnaire; echocardiographic finding and autonomic balance assesed heart rate variability (HRV). RESULTS: We observed statistically significant improvement in exercise capacity (from 423+/-94 to 496+/-13 m; P<0.05). Also we observed statistically significant improvements in the many PGWBI dimensions; particularly, anxiety +5.8% (from 18.11+/-5.2 to 19.12+/-4.4); depression +6.0% (from 12.00+/-3.0 to 12.73+/-2.4); positive well-being +6% (from 11.55+/-3.5 to 12.23+/-4.0); general health +10.3% (from 9.48+/-3.5 to 10.46+/ 2.87); vitality +6.8% (from 12.96+/-4.2 to 13.85+/-4.2). Finally, we observed changes in HRV indices after training program: RR (from 903+/-169 ms to 952+/-163 ms; P<0.05), pNN50% (from 4.74+/-4.89 to 6.23+/-5.53; P<0.05), in time-domain; LF (from 274+/-169 to 362+/-233 ms2; P<0,05); HF (from 214+/-154 to 314+/-194 ms2; P<0.05) and LF/HF (from 1.53+/-0.54 to 1.24+/-0.47; P<0.05) in frequency-domain. CONCLUSIONS: The study suggest that a cardiac rehabilitation program in postmyocardial infarction improves exercise capacity, QoL and autonomic modulation. PMID- 25692860 TI - The feasibility of exercise videogames for cardiovascular risk reduction among adults: a pilot for "Wii heart fitness". AB - BACKGROUND: More than 30% of the U.S. population is prehypertensive, and the recommended treatment of lifestyle modification includes increased physical activity. Exercise videogames (EVG) are widely marketed to Americans as a means of increasing fitness. This study aimed to examine EVG among a sample of prehypertensive adults, to determine (1) feasibility and acceptability of EVG for physical activity, and (2) assess changes in (1) estimates of cardiovascular fitness and risk indices, and psychosocial constructs. METHODS: Participants with prehypertension completed a 12-week program including; 36, 1-hour sessions; supervised EVG program using Nintendo Wii platform and games. Assessments were at baseline and 13 weeks. Paired t-tests were conducted. RESULTS: Fourteen adults (84% female; mean age=53 years; 93% Caucasian; 87% employed) completed the study. The study retention rate was 74% and all participants reported satisfaction and enjoyment in the intervention and using the Wii for exercise. Despite the small sample size, significant improvements were seen in: physical activity minutes (P<0.01), peak heart rate (P=0.02), resting systolic blood pressure (P=0.02), and hip circumference (P=0.03). Significant improvements were also seen in the 36 item short-form survey (SF-36) as for general health (P=0.05), role limitations due to emotional problems (P=0.04), and vitality (P=0.01). CONCLUSIONS: Findings support that an EVG program is feasible, acceptable, and promising in promoting benefit to cardiovascular fitness and psychosocial health. These data provide pilot data for the necessary randomized clinical trials to examine efficacy and sustainability of EVG for adult engagement in physical activity for cardiovascular health promotion. PMID- 25692861 TI - Physical effects of a reconditioning programme in a group of chronic fatigue syndrome patients. AB - AIM: Physical exercise can be part of treatment in patients with chronic fatigue syndrome (CFS), where the aim would be to improve strength and endurance through increasing physical exercise (intensity and time) without aggravating symptomatology. The present study examines the effectiveness of a reconditioning programme (focusing on strength, endurance, balance and propioception) for achieving maximum functional capacity according to the clinical status of CFS patients. METHODS: Sixty-eight patients with CFS were randomly assigned to two groups: a control group (CG) comprising 22 patients and an active group (AG) of 46 patients, the latter being invited to take part in a functional reconditioning programme based on 12 weeks of laboratory training followed by a further 12-week home training period. Functional assessments were as follows: before (I) and after (II) the laboratory training and after (III) the home training. RESULTS: In the AG, 22 patients (67%) completed the intervention (laboratory) stage and 20 finished the whole protocol (61%). Patients in the AG showed improved static and dynamic balance, as well as significantly greater maximum strength (F=7.059, p<0.05). Differences in resistance strength were also observed, with the AG showing a 19.9% improvement between functional assessments I and II (p=0.04). We don't found changes in the CG. CONCLUSION: A physical exercise programme of this kind might offer CFS patients the opportunity to improve their strength, balance and quality of life, there being only a very small risk of relapse and none of the adverse effects of other treatments. PMID- 25692862 TI - Differing cytokine responses by ethnic groups to a bout of exercise-induced muscle damage: a preliminary report. AB - BACKGROUND: Strenuous exercise has been shown to alter immune and inflammatory responses potentially predisposing athletes to infection and injury. Ethnic disparities have been demonstrated in athletic performance and in the way individuals respond to exercise as well as in the predisposition towards certain diseases however, the information relating to immune and inflammatory responses to exercise between ethnic groups is still limited. The aim of this study was to investigate whether serum cytokine levels respond differently to eccentrically biased exercise in African and Caucasian males. METHODS: Seven black and 8 white males (18-22 years), active but untrained, participated in the study. Participants performed a 60-minute downhill run on a treadmill (gradient -13.5%) at a speed eliciting 75% of their VO2peak on a level grade. Venipunctures were performed before, immediately after and then at 3, 6, 9, 12, 24 hours, and 1, 2 and 3 weeks afterwards. The following serum cytokine concentrations were quantified using the Bio-Plex suspension array system: IL-4, IL-6, IL-10, IL-1ra, IL-12p70, IFNgamma, IL-7, IL-8, MCP-1, MIP-1beta, eotaxin, IP-10, IL-1beta, TNFalpha, GM-CSF, G-CSF, FGF basic and VEGF. RESULTS: Significant differences between the two groups were evident from 6 hours postexercise onwards with the African runners maintaining significantly higher relative cytokine concentrations. IL-6 serum concentrations of the African runners, for example, ranged from 8% to 55.1% higher than that of the Caucasian runners from 6 hours to 2 weeks postexercise (P<0.05). CONCLUSIONS: The study demonstrated that the cytokine response to a bout of downhill running differs between African and Caucasian runners indicating that ethnicity may play a role in exercise-induced immune and inflammatory responses. PMID- 25692863 TI - Symmetry considerations for the targeted assembly of entropically stabilized colloidal crystals via Voronoi particles. AB - The relationship between colloidal building blocks and their assemblies is an active field of research. As a strategy for targeting novel crystal structures, we examine the use of Voronoi particles, which are hard, space-filling particles in the shape of Voronoi cells of a target structure. Although Voronoi particles stabilize their target structure in the limit of high pressure by construction, the thermodynamic assembly of the same structure at moderate pressure, close to the onset of crystallization, is not guaranteed. Indeed, we find that a more symmetric crystal is often preferred due to additional entropic contributions arising from configurational or occupational degeneracy. We characterize the assembly behavior of the Voronoi particles in terms of the symmetries of the building blocks as well as the symmetries of crystal structures and demonstrate how controlling the degeneracies through a modification of particle shape and field-directed assembly can significantly improve the assembly propensity. PMID- 25692865 TI - Out of the Black Sea: phylogeography of the invasive killer shrimp Dikerogammarus villosus across Europe. AB - The amphipod Dikerogammarus villosus has colonized most of the European main inland water bodies in less than 20 years, having deteriorating effect on the local benthic communities. Our aim was to reveal the species phylogeography in the native Black Sea area, to define the source populations for the colonization routes in continental Europe and for the newly established UK populations. We tested for the loss of genetic diversity between source and invasive populations as well as along invasion route. We tested also for isolation by distance. Thirty three native and invasive populations were genotyped for mtDNA (COI, 16S) and seven polymorphic nuclear microsatellites to assess cryptic diversity (presence of deeply divergent lineages), historical demography, level of diversity within lineage (e.g., number of alleles), and population structure. A wide range of methods was used, including minimum spanning network, molecular clock, Bayesian clustering and Mantel test. Our results identified that sea level and salinity changes during Pleistocene impacted the species phylogeography in the Black Sea native region with four differentiated populations inhabiting, respectively, the Dnieper, Dniester, Danube deltas and Durungol liman. The invasion of continental Europe is associated with two sources, i.e., the Danube and Dnieper deltas, which gave origin to two independent invasion routes (Western and Eastern) for which no loss of diversity and no isolation by distance were observed. The UK population has originated in the Western Route and, despite very recent colonization, no drastic loss of diversity was observed. The results show that the invasion of the killer shrimp is not associated with the costs of loosing genetic diversity, which may contribute to the success of this invader in the newly colonized areas. Additionally, while it has not yet occurred, it might be expected that future interbreeding between the genetically diversified populations from two independent invasion routes will potentially even enhance this success. PMID- 25692866 TI - Raising kids, in a cultural blind spot. PMID- 25692867 TI - Sociodemographic and geographic predictors of quality of care in United States patients with end-stage renal disease due to lupus nephritis. AB - OBJECTIVE: To describe end-stage renal disease (ESRD) quality of care (receipt of pre-ESRD nephrology care, access to kidney transplantation, and placement of permanent vascular access for dialysis) in US patients with ESRD due to lupus nephritis (LN-ESRD) and to examine whether quality measures differ by patient sociodemographic characteristics or US region. METHODS: National surveillance data on patients in the US in whom treatment for LN-ESRD was initiated between July 2005 and September 2011 (n = 6,594) were analyzed. Odds ratios (ORs) and hazard ratios (HRs) with 95% confidence intervals (95% CIs) were determined for each quality measure, according to sociodemographic factors and US region. RESULTS: Overall, 71% of the patients received nephrology care prior to ESRD. Black and Hispanic patients were less likely than white patients to receive pre ESRD care (OR 0.73 [95% CI 0.63-0.85] and OR 0.73 [95% CI 0.60-0.88], respectively) and to be placed on the kidney transplant waitlist within the first year after the start of ESRD (HR 0.78 [95% CI 0.68-0.91] and HR 0.82 [95% CI 0.68 0.98], respectively). Those with Medicaid (HR 0.51 [95% CI 0.44-0.58]) or no insurance (HR 0.36 [95% CI 0.29-0.44]) were less likely than those with private insurance to be placed on the waitlist. Only 24% had a permanent vascular access, and placement was even less likely among the uninsured (OR 0.62 [95% CI 0.49 0.79]). ESRD quality-of-care measures varied 2-3-fold across regions of the US, with patients in the Northeast and Northwest generally having higher probabilities of adequate care. CONCLUSION: LN-ESRD patients have suboptimal ESRD care, particularly with regard to placement of dialysis vascular access. Minority race/ethnicity and lack of private insurance are associated with inadequate ESRD care. Further studies are warranted to examine multilevel barriers to, and develop targeted interventions to improve delivery of, care among patients with LN-ESRD. PMID- 25692868 TI - Prevalence and predictors of low bone mineral density and fragility fractures among HIV-infected patients at one Italian center after universal DXA screening: sensitivity and specificity of current guidelines on bone mineral density management. AB - Low bone mineral density (BMD) is frequent in HIV infection regardless of the use of antiretroviral therapy (ART). Uncertainties remain, however, as to when in HIV infection BMD screening should be performed. We designed a prospective study to estimate the efficacy of universal BMD screening by dual-energy X-ray absorptiometry (DXA). Since April 2009 through March 2011, HIV patients attending our Center were offered femoral/lumbar DXA to screen BMD. Low BMD for chronological age, that is significant osteopenia, was defined as a Z-score <= 2.0 at femur and lumbar spine. Nontraumatic bone fractures (NTBFs) were evaluated. The final sample included 163 patients. A Z-score <= -2.0 at any site was observed in 19.6% of cases: among these, 18.8% had no indication to DXA using current Italian HIV guidelines for BMD screening. A lower femoral Z-score was independently associated with lower BMI, AIDS diagnosis, HCV co-infection, antiretroviral treatment, and NTBFs; a lower lumbar Z-score with age, BMI, Nadir CD4 T-cell counts, and NTBFs. Prevalence of NTBFs was 27.0%, predictors being male gender, HCV co-infection, and lower femoral Z-scores. Our results suggest that measuring BMD by DXA in all HIV patients regardless of any further specification may help retrieving one-fifth of patients with early BMD disorders not identified using current criteria for selective screening of BMD. PMID- 25692869 TI - Mechanism of enhanced Bombyx mori nucleopolyhedrovirus-resistance by titanium dioxide nanoparticles in silkworm. AB - The infection of Bombyx mori nucleopolyhedrovirus (BmNPV) in silkworms is often lethal. It is difficult to prevent, and its lethality is correlated with both viral particle characteristics and silkworm strains. Low doses of titanium dioxide nanoparticles (TiO2 NPs) can promote silkworm growth and improve its resistance to organophosphate pesticides. In this study, TiO2 NPs' effect on BmNPV resistance was investigated by analyzing the characteristics of BmNPV proliferation and transcriptional differences in silkworm midgut and the transcriptional changes of immunity related genes after feeding with TiO2 NPs. We found that low doses of TiO2 NPs improved the resistance of silkworm against BmNPV by 14.88-fold, with the mortalities of the experimental group and control group being 0.56% and 8.33% at 144 h, respectively. The proliferation of BmNPV in the midgut was significantly increased 72 h after infection in both experimental and control groups; the control group reached the peak at 120 h, while the experimental group took 24 more hours to reach the maximal value that was 12.63 times lower than the control, indicating that TiO2 NPs can inhibit BmNPV proliferation in the midgut. Consistently, the expression of the BmNPV-resistant gene Bmlipase-1 had the same increase pattern as the proliferation changes. Immune signaling pathway analysis revealed that TiO2 NPs inhibited the proliferation of silkworm BmNPV to reduce the activation levels of janus kinase/signal transducer and activator of transcription (JAK/STAT) and phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway, while promoting the expression of Bmakt to improve the immunity. Overall, our results demonstrate that TiO2 NPs increase silkworm resistance against BmNPV by inhibiting virus proliferation and improving immunity in silkworms. PMID- 25692870 TI - Monoclonal antibodies directed to fucoidan preparations from brown algae. AB - Cell walls of the brown algae contain a diverse range of polysaccharides with useful bioactivities. The precise structures of the sulfated fucan/fucoidan group of polysaccharides and their roles in generating cell wall architectures and cell properties are not known in detail. Four rat monoclonal antibodies, BAM1 to BAM4, directed to sulfated fucan preparations, have been generated and used to dissect the heterogeneity of brown algal cell wall polysaccharides. BAM1 and BAM4, respectively, bind to a non-sulfated epitope and a sulfated epitope present in the sulfated fucan preparations. BAM2 and BAM3 identified additional distinct epitopes present in the fucoidan preparations. All four epitopes, not yet fully characterised, occur widely within the major brown algal taxonomic groups and show divergent distribution patterns in tissues. The analysis of cell wall extractions and fluorescence imaging reveal differences in the occurrence of the BAM1 to BAM4 epitopes in various tissues of Fucus vesiculosus. In Ectocarpus subulatus, a species closely related to the brown algal model Ectocarpus siliculosus, the BAM4 sulfated epitope was modulated in relation to salinity levels. This new set of monoclonal antibodies will be useful for the dissection of the highly complex and yet poorly resolved sulfated polysaccharides in the brown algae in relation to their ecological and economic significance. PMID- 25692871 TI - A cell-permeable fluorescent polymeric thermometer for intracellular temperature mapping in mammalian cell lines. AB - Changes in intracellular temperatures reflect the activity of the cell. Thus, the tool to measure intracellular temperatures could provide valuable information about cellular status. We previously reported a method to analyze the intracellular temperature distribution using a fluorescent polymeric thermometer (FPT) in combination with fluorescence lifetime imaging microscopy (FLIM). Intracellular delivery of the FPT used in the previous study required microinjection. We now report a novel FPT that is cell permeable and highly photostable, and we describe the application of this FPT to the imaging of intracellular temperature distributions in various types of mammalian cell lines. This cell-permeable FPT displayed a temperature resolution of 0.05 degrees C to 0.54 degrees C within the range from 28 degrees C to 38 degrees C in HeLa cell extracts. Using our optimized protocol, this cell-permeable FPT spontaneously diffused into HeLa cells within 10 min of incubation and exhibited minimal toxicity over several hours of observation. FLIM analysis confirmed a temperature difference between the nucleus and the cytoplasm and heat production near the mitochondria, which were also detected previously using the microinjected FPT. We also showed that this cell-permeable FPT protocol can be applied to other mammalian cell lines, COS7 and NIH/3T3 cells. Thus, this cell-permeable FPT represents a promising tool to study cellular states and functions with respect to temperature. PMID- 25692872 TI - Patient compliance with postnatal thromboprophylaxis: An observational study. AB - Prescription of postnatal thromboprophylaxis has increased with the Royal College of Obstetricians and Gynaecologists and the National Institute for Health and Care Excellence guidance. Our study of postnatal women meeting the criteria for thromboprophylaxis aimed to ascertain compliance with low-molecular-weight heparin and barriers to completion of a full course. Women were recruited from the antenatal clinic or postnatal wards. Those who agreed were contacted by telephone 14 days after delivery and asked about their compliance with and experience of thromboprophylaxis. 111 women were followed up. We found reported compliance with postnatal thromboprophylaxis to be high (83% taking the full course); most women self-injected (54%) but a significant number relied on family members (39%). Most would be prepared to take the course in a future pregnancy (94%); however, some felt that they needed more information. Reported compliance with postnatal thromboprophylaxis is high. This may be down to the motivation of the new mother, appropriate information giving and access to health care professionals for advice. PMID- 25692873 TI - Song trait similarity in great tits varies with social structure. AB - For many animals, long-range signalling is essential to maintain contact with conspecifics. In territorial species, individuals often have to balance signalling towards unfamiliar potential competitors (to solely broadcast territory ownership) with signalling towards familiar immediate neighbours (to also maintain so-called "dear enemy" relations). Hence, to understand how signals evolve due to these multilevel relationships, it is important to understand how general signal traits vary in relation to the overall social environment. For many territorial songbirds dawn is a key signalling period, with several neighbouring individuals singing simultaneously without immediate conflict. In this study we tested whether sharing a territory boundary, rather than spatial proximity, is related to similarity in dawn song traits between territorial great tits (Parus major) in a wild personality-typed population. We collected a large dataset of automatized dawn song recordings from 72 unique male great tits, during the fertile period of their mate, and compared specific song traits between neighbours and non-neighbours. We show here that both song rate and start time of dawn song were repeatable song traits. Moreover, neighbours were significantly more dissimilar in song rate compared to non-neighbours, while there was no effect of proximity on song rate similarity. Additionally, similarity in start time of dawn song was unrelated to sharing a territory boundary, but birds were significantly more similar in start time of dawn song when they were breeding in close proximity of each other. We suggest that the dissimilarity in dawn song rate between neighbours is either the result of neighbouring great tits actively avoiding similar song rates to possibly prevent interference, or a passive consequence of territory settlement preferences relative to the types of neighbours. Neighbourhood structuring is therefore likely to be a relevant selection pressure shaping variation in territorial birdsong. PMID- 25692874 TI - Aromatase inhibitors for prevention of breast cancer in postmenopausal women: a narrative review. AB - OBJECTIVE: The increasing incidence of breast cancer (BC) worldwide has resulted in widespread interest in primary prevention therapies. A number of large randomized trials have shown that selective estrogen receptor modulators can reduce the relative risk for BC by 30% to 40% in high-risk women. In early-stage BC, aromatase inhibitors (AIs) showed a 35% relative reduction in the risk of contralateral BCs compared with tamoxifen. In this narrative review, we discuss the role of AIs in the primary prevention of BC and novel research on combination hormone therapy-medical therapy for the primary prevention of BC. METHODS: Using PubMed/Medline, we comprehensively searched for studies of BC primary prevention using AIs, including studies of novel methods of prevention using combination hormone therapy-BC prevention. RESULTS: Two large multicenter, prospective, randomized, placebo-controlled trials have evaluated AIs--anastrozole (International Breast Cancer Intervention Study II) and exemestane (Mammary Prevention 3)--for BC risk reduction in women at increased risk for BC, which we summarize. We identified five studies (three completed and two ongoing) of combination AI-hormone therapy that are undergoing investigation for BC risk reduction. CONCLUSIONS: AIs are effective at BC risk reduction, although long term follow-up data are required to assess whether this risk reduction will result in reduced mortality. Combination hormone therapy-AI for BC risk reduction is experimental and warrants further investigation. PMID- 25692875 TI - What should women expect after stopping hormone therapy? PMID- 25692876 TI - The menstrual cycle's SWAN song. PMID- 25692877 TI - Compounded bioidentical hormone therapy: identifying use trends and knowledge gaps among US women. AB - OBJECTIVE: Two surveys (Harris and Rose surveys) were conducted to quantify the use of compounded hormone therapy (CHT; or bioidentical hormone therapy) among perimenopausal and postmenopausal women in the United States, to assess women's knowledge of CHT versus Food and Drug Administration (FDA)-approved hormone therapy, and to gather information on menopausal experience. METHODS: The Harris survey was administered to 801 women aged 45 to 60 years who had experienced at least one menopausal symptom. The Rose survey was administered to 2,044 women aged 40 years or older who were ever users of hormone therapy. Women were queried about menopausal symptoms, hormone therapy use, and knowledge of CHT. Findings from the Rose survey were extrapolated using US Census Bureau data and prescription claims for FDA-approved hormone therapy to estimate the prevalence of CHT use. RESULTS: According to extrapolations using Rose data, up to 2.5 million US women aged 40 years or older may use CHT annually, accounting for 28% to 68% of hormone therapy prescriptions. Harris data showed that 86% of women surveyed were unaware that CHT products are not FDA-approved. The Rose survey asked a subset of 1,771 women whether their hormone therapy had been personalized based on hormone levels; 21% (378) answered "yes" whereas 27% (476) did not know. In both surveys, most hormone therapy users stated that their physician had recommended the treatment. CONCLUSIONS: We estimate that 1 million to 2.5 million US women aged 40 years or older use CHT. The data suggest that many women are unaware that compounded hormones have not been evaluated or approved by the FDA. Providers have an educational opportunity to ensure that women considering hormone therapy understand the risks and benefits of inadequately regulated CHT. PMID- 25692878 TI - Money talks: untreated hot flashes cost women, the workplace, and society. PMID- 25692879 TI - Information following a diagnosis of congenital heart defect: experiences among parents to prenatally diagnosed children. AB - BACKGROUND: Prenatal screening of pregnant women in Sweden has improved the detection of major congenital heart defects (CHD). The aim was to explore parental experiences and need for information following a prenatal diagnosis of CHD. METHODS: Semi-structured interviews conducted with six fathers and five mothers to seven prenatally diagnosed children. Data were analyzed through content analysis. RESULTS: Three themes and 9 categories emerged. Theme 1, Grasping the facts today while reflecting on the future, containing five categories: Difficulties sorting out information when in emotional chaos; Respectful information regarding termination of pregnancy; Early information is crucial; Understanding the facts regarding the anomaly; Preparing for the future. Theme 2, Personal contact with medical specialists who give honest and trustworthy information is valued, containing two categories: Trust in information received from medical specialists and Truth and honesty is valued. Theme 3, An overwhelming amount of information on the Internet, containing two categories: Difficulties in finding relevant information and Easy to focus on cases with a poor outcome when searching the Internet. CONCLUSION: Early and honest information in line with individual preferences is crucial to support the decisional process regarding whether to continue or terminate the pregnancy. The use of illustrations is recommended, as a complement to oral information, as it increases comprehension and satisfaction with obtained information. Furthermore, the overwhelming amount of information on the Internet calls for compilation of easily accessible and reliable information sources via the Internet. PMID- 25692880 TI - Characterization of a recombinant humanized anti-cocaine monoclonal antibody and its Fab fragment. AB - Variations of post-translational modifications are important for stability and in vivo behavior of therapeutic antibodies. A recombinant humanized anti-cocaine monoclonal antibody (h2E2) was characterized for heterogeneity of N-linked glycosylation and disulfide bonds. In addition, charge heterogeneity, which is partially due to the presence or absence of C-terminal lysine on the heavy chains, was examined. For cocaine overdose therapy, Fab fragments may be therapeutic, and thus, a simplified method of generation, purification, and characterization of the Fab fragment generated by Endoproteinase Lys-C digestion was devised. Both the intact h2E2 antibody and purified Fab fragments were analyzed for their affinities for cocaine and 2 of its metabolites, benzoylecgonine and cocaethylene, by fluorescence quenching of intrinsic antibody tyrosine and tryptophan fluorescence resulting from binding of these drugs. Binding constants obtained from fluorescence quenching measurements are in agreement with recently published radioligand and ELISA binding assays. The dissociation constants determined for the h2E2 monoclonal and its Fab fragment are approximately 1, 5, and 20 nM for cocaethylene, cocaine, and benzoylecgonine, respectively. Tryptophan fluorescence quenching (emission at 330 nm) was measured after either excitation of tyrosine and tryptophan (280 nm) or selective excitation of tryptophan alone (295 nm). More accurate binding constants are obtained using tryptophan selective excitation at 295 nm, likely due to interfering absorption of cocaine and metabolites at 280 nm. These quenching results are consistent with multiple tryptophan and tyrosine residues in or near the predicted binding location of cocaine in a previously published 3-D model of this antibody's variable region. PMID- 25692881 TI - International validation of a risk score for complications and reinterventions after endovascular aneurysm repair. AB - BACKGROUND: Lifelong surveillance is considered mandatory after endovascular repair (EVAR) of abdominal aortic aneurysms to detect endograft complications and prevent aneurysm rupture. Current protocols are not cost-effective or clinically effective. The international validity of the St George's Vascular Institute (SGVI) score for EVAR complications was examined. METHODS: The ENGAGE registry recruited patients undergoing EVAR at 79 centres in 30 countries. Reinterventions and endograft complications were recorded for up to 3 years after surgery. Preoperative aneurysm morphology was extracted from the registry database, and used to predict whether patients would be at low or high risk of complications after EVAR based on the SGVI score. Kaplan-Meier analysis was used to compare the incidence of endograft complications and reinterventions in patients predicted to be at low risk compared with those predicted to be at high risk. RESULTS: Some 1207 patients underwent EVAR, with follow-up of up to 3 years. The SGVI score accurately discriminated freedom from reinterventions (90.5 versus 79.3 per cent in low- versus high-risk patients; P < 0.001), freedom from endograft complications (77.9 versus 69.6 per cent in low- versus high-risk patients; P = 0.012), and freedom from a composite outcome measure of reinterventions or endograft complications (75.0 versus 66.1 per cent in low- versus high-risk patients; P = 0.006) during mid-term follow-up. CONCLUSION: This study has provided international validation of a morphological risk score that predicts mid term reinterventions and endograft complications. The results may enable risk stratified surveillance after EVAR. PMID- 25692882 TI - Endocrine care of transpeople part II. A review of cross-sex hormonal treatments, outcomes and adverse effects in transwomen. AB - The treatment of transwomen relies on the combined administration of anti androgens or GnRH analogues to suppress androgen production and thereby reduce male phenotypic characteristics together with oestrogens to develop female characteristics. In transwomen, synthetic oestrogens such as ethinyl oestradiol, as well as conjugated equine oestrogens (CEE), should be avoided to minimize thromboembolic risks especially in older transwomen and in those with risk factors. Currently, available short- and long-term safety studies suggest that cross-sex hormonal therapy (CHT) can be considered safe in transwomen improving the well-being and quality of life of these individuals. Long-term monitoring should aim to decrease cardiovascular risks and should include prostate and breast cancer screenings. PMID- 25692883 TI - The spatiotemporal expansion of human rabies and its probable explanation in mainland China, 2004-2013. AB - BACKGROUND: Human rabies is a significant public health concern in mainland China. However, the neglect of rabies expansion and scarce analyses of the dynamics have made the spatiotemporal spread pattern of human rabies and its determinants being poorly understood. METHODS: We collected geographic locations and timeline of reported human rabies cases, rabies sequences and socioeconomic variables for the years 2004-2013, and integrated multidisciplinary approaches, including epidemiological characterization, hotspots identification, risk factors analysis and phylogeographic inference, to explore the spread pattern of human rabies in mainland China during the last decade. RESULTS: The results show that human rabies distribution and hotspots were expanding from southeastern regions to north or west regions, which could be associated with the evolution of the virus, especially the clade I-G. A Panel Poisson Regression analysis reveals that human rabies incidences had significant correlation with the education level, GDP per capita, temperature at one-month lag and canine rabies outbreak at two-month lag. CONCLUSIONS: The reduction in the overall human rabies incidence was accompanied by a westward and northward expansion of the circulating region in mainland China. Higher risk of human rabies was associated with lower level of education and economic status. New clades of rabies, especial Clade I-G, played an important role in recent spread. Our findings provide valuable information for rabies control and prevention in the future. PMID- 25692884 TI - Relevance of simultaneous mono-ubiquitinations of multiple units of PCNA homo trimers in DNA damage tolerance. AB - DNA damage tolerance (DDT) pathways, including translesion synthesis (TLS) and additional unknown mechanisms, enable recovery from replication arrest at DNA lesions. DDT pathways are regulated by post-translational modifications of proliferating cell nuclear antigen (PCNA) at its K164 residue. In particular, mono-ubiquitination by the ubiquitin ligase RAD18 is crucial for Poleta-mediated TLS. Although the importance of modifications of PCNA to DDT pathways is well known, the relevance of its homo-trimer form, in which three K164 residues are present in a single ring, remains to be elucidated. Here, we show that multiple units of a PCNA homo-trimer are simultaneously mono-ubiquitinated in vitro and in vivo. RAD18 catalyzed sequential mono-ubiquitinations of multiple units of a PCNA homo-trimer in a reconstituted system. Exogenous PCNA formed hetero-trimers with endogenous PCNA in WI38VA13 cell transformants. When K164R-mutated PCNA was expressed in these cells at levels that depleted endogenous PCNA homo-trimers, multiple modifications of PCNA complexes were reduced and the cells showed defects in DDT after UV irradiation. Notably, ectopic expression of mutant PCNA increased the UV sensitivities of Poleta-proficient, Poleta-deficient, and REV1 depleted cells, suggesting the disruption of a DDT pathway distinct from the Poleta- and REV1-mediated pathways. These results suggest that simultaneous modifications of multiple units of a PCNA homo-trimer are required for a certain DDT pathway in human cells. PMID- 25692885 TI - Decoding multiple sound categories in the human temporal cortex using high resolution fMRI. AB - Perception of sound categories is an important aspect of auditory perception. The extent to which the brain's representation of sound categories is encoded in specialized subregions or distributed across the auditory cortex remains unclear. Recent studies using multivariate pattern analysis (MVPA) of brain activations have provided important insights into how the brain decodes perceptual information. In the large existing literature on brain decoding using MVPA methods, relatively few studies have been conducted on multi-class categorization in the auditory domain. Here, we investigated the representation and processing of auditory categories within the human temporal cortex using high resolution fMRI and MVPA methods. More importantly, we considered decoding multiple sound categories simultaneously through multi-class support vector machine-recursive feature elimination (MSVM-RFE) as our MVPA tool. Results show that for all classifications the model MSVM-RFE was able to learn the functional relation between the multiple sound categories and the corresponding evoked spatial patterns and classify the unlabeled sound-evoked patterns significantly above chance. This indicates the feasibility of decoding multiple sound categories not only within but across subjects. However, the across-subject variation affects classification performance more than the within-subject variation, as the across subject analysis has significantly lower classification accuracies. Sound category-selective brain maps were identified based on multi-class classification and revealed distributed patterns of brain activity in the superior temporal gyrus and the middle temporal gyrus. This is in accordance with previous studies, indicating that information in the spatially distributed patterns may reflect a more abstract perceptual level of representation of sound categories. Further, we show that the across-subject classification performance can be significantly improved by averaging the fMRI images over items, because the irrelevant variations between different items of the same sound category are reduced and in turn the proportion of signals relevant to sound categorization increases. PMID- 25692886 TI - Solomonseal polysaccharide and sulfated Codonopsis pilosula polysaccharide synergistically resist Newcastle disease virus. AB - Five combinations of three ratios (PS9-sPS1, PS7-sPS3 and PS6-sPS4) were prepared with polysaccharide (PS) and sulfated polysaccharide (sPS). The antiviral activities of these compounds were subsequently compared in vitro using the MTT assay, observation of the virus structure and immunofluorescence. The results demonstrated that SP9-sCP1, CP7-sCA3, EP7-sAP3, CA9-sEP1 and EP7-sCA3 presented higher activities, and SP9-sCP1 displayed the highest virus inhibition rate and clearly killed the virus and inhibited viral antigen expression. In an in vivo test, 28-day-old chickens were challenged with Newcastle disease virus (NDV) and were administered the five drug combinations. On day 14 after the challenge, the morbidity, mortality and cure rate in each group were calculated. The results indicated that SP9-sCP1 presented the lowest morbidity and mortality and the highest cure rate. These results indicate that Solomonseal polysaccharide and sulfated Codonopsis pilosula polysaccharide synergistically resist NDV. Moreover, SP9-sCP1 had the highest efficacy and may be used as a new antiviral drug. PMID- 25692887 TI - Identification of the fourth duplication of upstream IHH regulatory elements, in a family with craniosynostosis Philadelphia type, helps to define the phenotypic characterization of these regulatory elements. PMID- 25692888 TI - Experimental diagenesis of organo-mineral structures formed by microaerophilic Fe(II)-oxidizing bacteria. AB - Twisted stalks are organo-mineral structures produced by some microaerophilic Fe(II)-oxidizing bacteria at O2 concentrations as low as 3 MUM. The presence of these structures in rocks having experienced a diagenetic history could indicate microbial Fe(II)-oxidizing activity as well as localized abundance of oxygen at the time of sediment deposition. Here we use spectroscopy and analytical microscopy to evaluate if--and what kind of--transformations occur in twisted stalks through experimental diagenesis. Unique mineral textures appear on stalks as temperature and pressure conditions increase. Haematite and magnetite form from ferrihydrite at 170 degrees C-120 MPa. Yet the twisted morphology of the stalks, and the organic matrix, mainly composed of long-chain saturated aliphatic compounds, are preserved at 250 degrees C-140 MPa. Our results suggest that iron minerals might play a role in maintaining the structural and chemical integrity of stalks under diagenetic conditions and provide spectroscopic signatures for the search of ancient life in the rock record. PMID- 25692889 TI - Development and blind clinical validation of a microRNA based predictor of response to treatment with R-CHO(E)P in DLBCL. AB - MicroRNAs (miRNA) are a group of short noncoding RNAs that regulate gene expression at the posttranscriptional level. It has been shown that microRNAs are independent predictors of outcome in patients with diffuse large B-cell lymphoma (DLBCL) treated with the drug combination R-CHOP. Based on the measured growth inhibition of 60 human cancer cell lines (NCI60) in the presence of doxorubicine, cyclophosphamide, vincristine and etoposide as well as the baseline microRNA expression of the 60 cell lines, a microRNA based response predictor to CHOP was developed. The response predictor consisting of 20 microRNAs was blindly validated in a cohort of 116 de novo DLBCL patients treated with R-CHOP or R CHOEP as first line treatment. The predicted sensitivity based on diagnostic FFPE samples matched the clinical response, with decreasing sensitivity in poor responders (P = 0.03). When the International Prognostic Index (IPI) was included in the prediction analysis, the separation between responders and non-responders improved (P = 0.001). Thirteen patients developed relapse, and five patients predicted sensitive to their second and third line treatment survived a median 1194 days, while eight patients predicted not sensitive to their second and third line treatment survived a median 187 days (90% CI: 485 days versus 227 days). Among the latter group it was predicted that four would have been sensitive to another second line treatment than the one they received. The predictions were almost the same when diagnostic biopsies were used as when relapse biopsies were used. These preliminary findings warrant testing in a larger cohort of relapse patients to confirm whether the miRNA based predictor can select the optimal second line treatment and increase survival. PMID- 25692890 TI - Oral propranolol for parotid infantile hemangiomas. AB - The aim of our study was to assess the efficacy and safety of oral propranolol for the treatment of parotid infantile hemangiomas. Between October 2009 and January 2013, propranolol was given orally to 30 infants with proliferating hemangiomas at a dose of 1.0 to 1.5 mg/kg per day in our department. The patients included 12 male infants and 18 female infants, aged between 2 and 13 months, with a median of 5.9 months. The lesions were located in the parotid region and measured from 1.5 cm * 2 cm * 0.5 cm to 6 cm * 8 cm * 3 cm in volume. Oral propranolol was administered once daily for a mean duration of 22.7 weeks (range, 14-32 wk). Follow-up times were from 1 to 10 months (median, 6.4 mo). Changes in the color and size of the tumor were recorded using hemisphere measurements and digital photographs. The treatment results were scored according to a 4-point scale. Overall response was graded scale 4 (excellent) in 18 patients, scale 3 (good) in 11 patients, scale 2 (moderate) in 1 patient, and scale 1 (poor) in none. No major collateral effects and rebounds were observed in any of the patients. Oral propranolol was a well-tolerated and effective treatment with mild adverse effects for parotid infantile hemangiomas. PMID- 25692891 TI - Severe meningeal calcification in a Crouzon patient carrying a mutant C342W FGFR2. AB - Crouzon is an autosomal dominant craniosynostosis syndrome caused by mutation in the fibroblast growth factor receptor (FGFR)-2 gene. Recent findings from animal studies imply a critical role for FGFs in the regulation of mineralization. Here, we presented a 5-year-old girl with severe meningeal calcification. Subsequently, we analyzed FGFR2 mutation and identified a mutation of Cys342Tyr. The findings suggest that abnormal calcification was atypical phenotype of Crouzon patients with Cys342Tyr mutation in FGFR2. PMID- 25692892 TI - Comparison of multi-space infections of the head and neck in the elderly and non elderly people, part II: the influencing factors of the outcomes. AB - OBJECTIVE: This study aims to identify significant predictors of 3 outcomes in the aged patients and non-elderly with multi-space infections of the head and neck: the number of incisions, the length of hospital stay, and complications. PATIENTS AND METHODS: A retrospective study was conducted on 242 patients receiving treatment for severe multi-space infections of the head and neck region. Study variables were categorized as demographics, clinical parameters, and laboratory values. The outcome variables were the number of incisions, length of hospital stay, and complications. Multivariate linear and logistic regression techniques were used to measure associations between study variables and the outcome variables. Statistical analyses of the results between groups were performed using the Student t test and chi. RESULTS: Multivariate analyses, controlling for confounding variables, indicated that the number of spaces affected was a predictor of the number of incisions and complications in the elderly group. In the non-elderly group, the number of spaces affected was a predictor of the number of incisions and length of hospital stay. Admission blood glucose level and admission white blood cell count were the predictors of complications in the non-elderly. CONCLUSION: This study identifies different study variables as predictors of outcomes in treating multi-space infections of the head and neck in the elderly and non-elderly group. The number of spaces affected is the most important predictor. PMID- 25692893 TI - Management of carotid body tumor and pseudoaneurysm after blunt dissection. AB - BACKGROUND: Surgical treatment of carotid body tumors remains challenging, and this study evaluated the outcomes of carotid body tumor and pseudoaneurysm after blunt dissection of the tumors. METHODS: Six cases were classified as Shamblin groups I, II, and III (1, 1, and 4 cases, respectively). Tumor size ranged from 2 * 3 to 5 * 6 (median, 3.7 * 4.7) cm. Two patients underwent blunt dissection of the carotid body tumor, two underwent blunt dissection and ligation of the external carotid artery of the carotid body tumor, and two patients had common carotid artery-internal carotid artery artificial vascular reconstruction. RESULTS: No perioperative mortality or stroke occurred. The mean blood loss was 455 (range, 250-650) mL. Two patients had pseudoaneurysm or vocal cord paralysis postoperatively and recovered with stent graft implantation and medical treatment, respectively. The patients were followed for 6 to 17 (mean, 11) months, with no recurrence observed. CONCLUSION: Surgical treatment of a carotid body tumor is acceptably safe and effective according to Shamblin classification. Pseudoaneurysm can occur after blunt dissection of the tumor and can be treated with a stent graft. PMID- 25692894 TI - Transparotid approach in the treatment of intracapsular condylar fracture. AB - PURPOSE: Open reduction and internal fixation of intracapsular condylar fractures is a great challenge due to the confined access. This study aims to explore the feasibility of transparotid approach in the treatment of intracapsular condylar fractures. PATIENTS AND METHODS: Eight patients with intracapsular condylar fractures were enrolled in this study. A minimized preauricular incision and transparotid access was used. Blunt dissection was performed perpendicularly to the condyle. The reduction and fixation of intracapsular condylar fractures were performed. After confirming that the fracture was fixed rigidly, the articular disc was repositioned. RESULTS: Using this incision, the condylar head and fracture stump were exposed perpendicularly. No extensive incision was needed and minimal invasion was realized. Postoperative CT scan showed that the condyle had been repositioned and fixed in the normal position. Occlusal disturbance, restriction of mouth opening, and lateral deviation were not found in the follow up. CONCLUSIONS: Transparotid approach gave an optimal view of the bony field, which allowed surgeons to work perpendicularly to the fracture, and facilitated the reduction of medially displaced proximal stumps. It was regarded as an ideal and valuable alternative in this potentially complicated procedure. PMID- 25692895 TI - Anatomical study of posterior clinoid process (PCP) and its clinical meanings. AB - PURPOSE: The aim of this study is to provide a new and comprehensive anatomic study of the posterior clinoid process (PCP) as well as data for PCP location to guide the surgeons in endoscopic surgery. MATERIALS AND METHODS: Computed tomography angiography images of 120 PCPs and structures around them in adults were reviewed. The measurement was on coronal, sagittal, and axial planes after multiplanar reconstruction. The length, width, and thickness were accessed for the best understanding of the feature of PCP. The distance from the base of the PCP and the middle lowest point of the sellar floor was measured to find the position of the PCP during the transphenoid approach. RESULT: PCP varies in width and thickness in different portions of it and is closely related to the internal carotid artery and posterior communicating artery, which makes it an important landmark during surgery. CONCLUSION: The shape of PCP is various, and the analysis of its relationship to the important structures around it is of great value. In addition, the preoperative radiological evaluation plays a major role in patients considered for endoscopic sinus surgery. Detailed preoperative analysis of the anatomy of the sphenoid sinus and its boundaries is crucial in facilitating entry to the pituitary fossa and reducing intraoperative complications. PMID- 25692896 TI - Strategy to minimize oral mucosal tear and lip injury in facial contouring and orthognathic surgery. PMID- 25692897 TI - Reconstruction of full-thickness lower eyelid defect using superficial temporal artery island flap combined with auricular cartilage graft. AB - Full-thickness lower eyelid defect is one of common surgical diseases, which may lead to exposure keratopathy, corneal ulceration, and blindness. The aim of this study was to investigate the effect of superficial temporal artery island flap combined with auricular cartilage graft on the repair of full-thickness lower eyelid defect.In this study, the reconstructions in 6 patients who had unilateral full-thickness lower eyelid defects due to ocular traumas or surgical resections of malignant tumors were carried out. The island flap of the frontal branch of superficial temporal artery reconstructed the outer layer and the total lower lid was supported with the plane of an auricular cartilage strip, offering a proper contour and physical strength to maintain a normal eyelid height. The follow-up time ranged from 6 to 24 months. No major complications including partial or total flap necrosis, signs of infection, venous congestion, and hematoma were seen in any of the patients, and all cases have been reconstructed well both aesthetically and functionally, showing esthetic eyelid contour, good color, and texture match.Superficial temporal artery island flap combined with auricular cartilage graft is a useful method functionally and cosmetically for the reconstructions of full-thickness lower eyelid defects because of its advantages including rich vascularity based on superficial temporal artery, wide pedicle rotational arc, which could be transferred throughout the face region, good eyelid contour with color and texture match, limited donor-site scar, and minimal postoperative morbidity. PMID- 25692898 TI - A correlational study of serum alkaline phosphatase level and developmental mandibular laterognathism. AB - The abnormal cartilage/bone metabolism in unilateral condyle may be a direct factor that contributes to developmental mandibular laterognathism. However, although many molecules have been demonstrated to play crucial roles in the development of temporomandibular joints, the exact molecular mechanisms that lead to the disrupted condylar cartilage/bone development were greatly unknown. In this retrospective study, our findings revealed that serum alkaline phosphatase (ALP) level in adult patients with developmental mandibular laterognathism was lower than that in control subjects, and the serum ALP levels continue to reduce in adult patients (>20 years old). Although the exact relationship between the lower serum ALP level and developmental mandibular laterognathism is unclear, the findings further support the opinion that the condylar growth may sustain for a long time in the affected condyle in patients with developmental mandibular laterognathism and offer an alternative choice to use total serum ALP activity as a possible biomarker to assess condylar growth activity in patients with developmental mandibular laterognathism. PMID- 25692899 TI - Total endoscopic versus conventional open thyroidectomy for papillary thyroid microcarcinoma. AB - BACKGROUND: The objective of this study was to conduct a meta-analysis to assess the safety and efficacy of total endoscopic thyroidectomy (TET) versus conventional open thyroidectomy (COT) for papillary thyroid microcarcinoma with regard to short-term clinical outcomes. METHODS: MEDLINE, EMBASE, Science Citation Index Expanded, and the Cochrane Central Register of Controlled Trials in the Cochrane Library between January 1996 and July 2014 were searched to identify relevant comparative studies. Pooled weighted mean differences (WMD) or odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using either fixed or random-effects models. The perioperative outcomes were evaluated. RESULTS: Five eligible nonrandomized studies were included, involving 1004 patients: 475 were TET and 529 were COT. Meta-analysis results revealed that TET group had a significantly longer operative time (WMD, 48.15; 95% CI, 27.54-68.75; P < 0.00001), compared with the COT group. While analyzing the number of removed lymph nodes, 4 studies were included. The TET group had a less number of removed lymph nodes (WMD, -0.68; 95% CI, -1.20 to -0.15; P = 0.01). There were no significant differences in terms of hospital stay, transient recurrent laryngeal nerve palsy, permanent recurrent laryngeal nerve palsy, transient hypocalcemia, and permanent hypocalcemia. CONCLUSIONS: Total endoscopic thyroidectomy appears to be a much feasible safe surgical procedure for papillary thyroid microcarcinoma in selected patients. PMID- 25692900 TI - Preauricular fibrolipoma presenting as upper parotid tumor. PMID- 25692901 TI - Bypass of the maxillary artery to proximal middle cerebral artery. AB - OBJECTIVE: The objective of this work was to explore the feasibility of bypass between the maxillary artery (MA) and proximity of middle cerebral artery (MCA). METHODS: Ten fixed and perfused adult cadaver heads were dissected bilaterally, 20 sides in total. The superficial temporal artery and its 2 branches were dissected, and outer diameters were measured. The MA and its branch were exposed as well as deep temporal artery; outer diameter of MA was measured. The lengths between the external carotid artery, internal carotid artery, maxillary artery, and proximal middle cerebral artery were measured. Ten healthy adults as targets (20 sides), inner diameter and blood flow dynamic parameters of the common carotid artery, external carotid artery, internal carotid artery, maxillary artery, superficial temporal artery, and its 2 branches were done with ultrasound examination. RESULTS: The mean outer diameter of MA (2.60 +/- 0.20 mm) was larger than that of the temporal artery trunk (1.70 +/- 0.30 mm). The mean lengths of graft vessels between the internal carotid artery, external carotid artery, and the bifurcation section of MCA (171.00 +/- 2.70 and 162.40 +/- 2.60 mm) were longer than the mean lengths of graft vessels between MA and MCA bifurcation section (61.70 +/- 1.50 mm). In adults, the mean blood flow of the second part of MA (62.70 +/- 13.30 mL/min) was more than that of the 2 branches of the superficial temporal artery (15.90 +/- 3.70 mL/min and 17.70 +/- 4.10 ml/min). CONCLUSION: Bypass between the maxillary artery and proximity of middle cerebral artery is feasible. It is a kind of effective high flow bypass with which the graft vessel is shorter and straighter than the bypass between internal carotid artery or external carotid artery and proximity of middle cerebral artery. PMID- 25692902 TI - Medical management, costs, and consequences of Alzheimer's disease in Germany: an analysis of health claims data. AB - OBJECTIVE: The main objective of this analysis was to assess the medical and economic differences between patients with and without diagnosed Alzheimer's Disease (AD). Analysis included co-morbidities, patterns of drug use, and clinical course, as well as the magnitude of these differences attributable to AD. METHODS: This evaluation is based on retrospective analyses of anonymized claims data from 2005-2008 provided by a large German Statutory Health Insurance (SHI). Cross-sectional analyses were performed with the following data: demographics, number of hospitalizations, number of in-patient days, number of ambulatory physician visits, number of drugs used, total number of defined daily doses (DDD) of prescribed drugs, and costs. A propensity score model was used to assess costs attributable to AD. RESULTS: Patients with AD caused substantially higher costs from the perspective of a SHI. The differences in long-term care costs explained 70-75% of the total cost difference, with being responsible for about half of the total costs in AD patients. Comparing matched AD patients with controls resulted in 2.2-2.4-fold higher costs in the cross-sectional analysis, ?7413-?9207 for AD patients vs ?3378-?3850 for controls. The propensity score model resulted in a difference of ?3771 attributable to AD. These costs are mainly caused by differences in hospitalization and long-term care costs. CONCLUSION: This analysis is one of the largest health economic studies of AD in Germany. The limitations of this study include the fact that reported diagnosis couldn't be validated and disease severity was not taken into account. Despite these methodological constraints, it can be concluded that AD is a substantial cost driver from the SHI payer perspective in Germany. PMID- 25692903 TI - The Adaptive Immune System of Haloferax volcanii. AB - To fight off invading genetic elements, prokaryotes have developed an elaborate defence system that is both adaptable and heritable-the CRISPR-Cas system (CRISPR is short for: clustered regularly interspaced short palindromic repeats and Cas: CRISPR associated). Comprised of proteins and multiple small RNAs, this prokaryotic defence system is present in 90% of archaeal and 40% of bacterial species, and enables foreign intruders to be eliminated in a sequence-specific manner. There are three major types (I-III) and at least 14 subtypes of this system, with only some of the subtypes having been analysed in detail, and many aspects of the defence reaction remaining to be elucidated. Few archaeal examples have so far been analysed. Here we summarize the characteristics of the CRISPR Cas system of Haloferax volcanii, an extremely halophilic archaeon originally isolated from the Dead Sea. It carries a single CRISPR-Cas system of type I-B, with a Cascade like complex composed of Cas proteins Cas5, Cas6b and Cas7. Cas6b is essential for CRISPR RNA (crRNA) maturation but is otherwise not required for the defence reaction. A systematic search revealed that six protospacer adjacent motif (PAM) sequences are recognised by the Haloferax defence system. For successful invader recognition, a non-contiguous seed sequence of 10 base-pairs between the crRNA and the invader is required. PMID- 25692904 TI - A prokaryotic twist on argonaute function. AB - Argonaute proteins can be found in all three domains of life. In eukaryotic organisms, Argonaute is, as the functional core of the RNA-silencing machinery, critically involved in the regulation of gene expression. Despite the mechanistic and structural similarities between archaeal, bacterial and eukaryotic Argonaute proteins, the biological function of bacterial and archaeal Argonautes has remained elusive. This review discusses new findings in the field that shed light on the structure and function of Argonaute. We especially focus on archaeal Argonautes when discussing the details of the structural and dynamic features in Argonaute that promote substrate recognition and cleavage, thereby revealing differences and similarities in Argonaute biology. PMID- 25692905 TI - Volcanogenic fluvial-lacustrine environments in iceland and their utility for identifying past habitability on Mars. AB - The search for once-habitable locations on Mars is increasingly focused on environments dominated by fluvial and lacustrine processes, such as those investigated by the Mars Science Laboratory Curiosity rover. The availability of liquid water coupled with the potential longevity of such systems renders these localities prime targets for the future exploration of Martian biosignatures. Fluvial-lacustrine environments associated with basaltic volcanism are highly relevant to Mars, but their terrestrial counterparts have been largely overlooked as a field analogue. Such environments are common in Iceland, where basaltic volcanism interacts with glacial ice and surface snow to produce large volumes of meltwater within an otherwise cold and dry environment. This meltwater can be stored to create subglacial, englacial, and proglacial lakes, or be released as catastrophic floods and proglacial fluvial systems. Sedimentary deposits produced by the resulting fluvial-lacustrine activity are extensive, with lithologies dominated by basaltic minerals, low-temperature alteration assemblages (e.g., smectite clays, calcite), and amorphous, poorly crystalline phases (basaltic glass, palagonite, nanophase iron oxides). This paper reviews examples of these environments, including their sedimentary deposits and microbiology, within the context of utilising these localities for future Mars analogue studies and instrument testing. PMID- 25692906 TI - Regulation of Genes Involved in Heterocyst Differentiation in the Cyanobacterium Anabaena sp. Strain PCC 7120 by a Group 2 Sigma Factor SigC. AB - The filamentous cyanobacterium Anabaena sp. strain PCC 7120 differentiates specialized cells for nitrogen fixation called heterocysts upon limitation of combined nitrogen in the medium. During heterocyst differentiation, expression of approximately 500 genes is upregulated with spatiotemporal regulation. In the present study, we investigated the functions of sigma factors of RNA polymerase in the regulation of heterocyst differentiation. The transcript levels of sigC, sigE, and sigG were increased during heterocyst differentiation, while expression of sigJ was downregulated. We carried out DNA microarray analysis to identify genes regulated by SigC, SigE, and SigG. It was indicated that SigC regulated the expression of genes involved in heterocyst differentiation and functions. Moreover, genes regulated by SigC partially overlapped with those regulated by SigE, and deficiency of SigC was likely to be compensated by SigE. PMID- 25692907 TI - Release of nitrous oxide and dinitrogen from a transition bog under drained and rewetted conditions due to denitrification: results from a [15N]nitrate-bromide double-tracer study. AB - Denitrification is well known being the most important nitrate-consuming process in water-logged peat soils, whereby the intermediate compound nitrous oxide (N(2)O) and the end product dinitrogen (N(2)) are ultimately released. The present study was aimed at evaluating the release of these gases (due to denitrification) from a nutrient-poor transition bog ecosystem under drained and three differently rewetted conditions at the field scale using a (15)N-tracer approach ([(15)N]nitrate application, 30 kg N ha(-1)) and a common closed-chamber technique. The drained site is characterized by a constant water table (WT) of 30 cm (here referred to as D30), while rewetted sites represent a constant WT of 15 cm, a constant WT of 0 cm (i.e. waterlogged), and an initial WT of 0 cm (which decreased slightly during the experiment), respectively, (here referred to as R15, R0, and R0(d), respectively). The highest N(2)O emissions were observed at D30 (291 ug N(2)O-N m(-2) h(-1)) as well as at R0d (665 ug N(2)O-N m(-2) h(-1)). At the rewetted peat sites with a constant WT (i.e. R15 and R0), considerably lower N2O emissions were observed (maximal 37 ug N(2)O-N m(-2) h(-1)). Concerning N(2) only at the initially water-logged peat site R0d considerable release rates (up to 3110 ug N(2)-N m(-2) h(-1)) were observed, while under drained conditions (D30) no N(2) emission and under rewetted conditions with a constant WT (R15 and R0) significantly lower N(2) release rates (maximal 668 ug N(2)-N m(-2) h(-1)) could be detected. In addition, it has been found that natural WT fluctuations at rewetted peat sites, in particular a rapid drop down of the WT, can induce high emission rates for both N(2)O and N(2). PMID- 25692908 TI - Small-molecule inhibitors targeting INK4 protein p18(INK4C) enhance ex vivo expansion of haematopoietic stem cells. AB - Among cyclin-dependent kinase inhibitors that control the G1 phase in cell cycle, only p18 and p27 can negatively regulate haematopoietic stem cell (HSC) self renewal. In this manuscript, we demonstrate that p18 protein is a more potent inhibitor of HSC self-renewal than p27 in mouse models and its deficiency promoted HSC expansion in long-term culture. Single-cell analysis indicated that deleting p18 gene favoured self-renewing division of HSC in vitro. Based on the structure of p18 protein and in-silico screening, we further identified novel smallmolecule inhibitors that can specifically block the activity of p18 protein. Our selected lead compounds were able to expand functional HSCs in a short-term culture. Thus, these putative small-molecule inhibitors for p18 protein are valuable for further dissecting the signalling pathways of stem cell self-renewal and may help develop more effective chemical agents for therapeutic expansion of HSC. PMID- 25692909 TI - Statistical mechanics provides novel insights into microtubule stability and mechanism of shrinkage. AB - Microtubules are nano-machines that grow and shrink stochastically, making use of the coupling between chemical kinetics and mechanics of its constituent protofilaments (PFs). We investigate the stability and shrinkage of microtubules taking into account inter-protofilament interactions and bending interactions of intrinsically curved PFs. Computing the free energy as a function of PF tip position, we show that the competition between curvature energy, inter-PF interaction energy and entropy leads to a rich landscape with a series of minima that repeat over a length-scale determined by the intrinsic curvature. Computing Langevin dynamics of the tip through the landscape and accounting for depolymerization, we calculate the average unzippering and shrinkage velocities of GDP protofilaments and compare them with the experimentally known results. Our analysis predicts that the strength of the inter-PF interaction (E(s)(m)) has to be comparable to the strength of the curvature energy (E(b)(m)) such that E(s)(m) - E(b)(m) ~ 1kBT, and questions the prevalent notion that unzippering results from the domination of bending energy of curved GDP PFs. Our work demonstrates how the shape of the free energy landscape is crucial in explaining the mechanism of MT shrinkage where the unzippered PFs will fluctuate in a set of partially peeled off states and subunit dissociation will reduce the length. PMID- 25692910 TI - Sustaining mammography screening among the medically underserved: a follow-up evaluation. AB - BACKGROUND: Our previous three-arm comparative effectiveness intervention in community clinic patients who were not up-to-date with screening resulted in mammography rates over 50% in all arms. OBJECTIVE: Our aim was to evaluate the effectiveness and cost-effectiveness of the three interventions on improving biennial screening rates among eligible patients. METHODS: A three-arm quasi experimental evaluation was conducted in eight community clinics from 2008 to 2011. Screening efforts included (1) enhanced care: Participants received an in person recommendation from a research assistant (RA) in year 1, and clinics followed usual clinic protocol for scheduling screening mammograms; (2) education intervention: Participants received education and in-person recommendation from an RA in year 1, and clinics followed usual clinic protocol for scheduling mammograms; or (3) nurse support: A nurse manager provided in-person education and recommendation, scheduled mammograms, and followed up with phone support. In all arms, mammography was offered at no cost to uninsured patients. RESULTS: Of 624 eligible women, biennial mammography within 24-30 months of their previous test was performed for 11.0% of women in the enhanced-care arm, 7.1% in the education- intervention arm, and 48.0% in the nurse-support arm (p<0.0001). The incremental cost was $1,232 per additional woman undergoing screening with nurse support vs. enhanced care and $1,092 with nurse support vs. education. CONCLUSIONS: Biennial mammography screening rates were improved by providing nurse support but not with enhanced care or education. However, this approach was not cost-effective. PMID- 25692911 TI - Mechanical properties and defect sensitivity of diamond nanothreads. AB - One of the newest carbon allotropes synthesized are diamond nanothreads. Using molecular dynamics, we determine the stiffness (850 GPa), strength (26.4 nN), extension (14.9%), and bending rigidity (5.35 * 10(-28) N.m(2)). The 1D nature of the nanothread results in a tenacity of 4.1 * 10(7) N.m/kg, exceeding nanotubes and graphene. As the thread consists of repeating Stone-Wales defects, through steered molecular dynamics (SMD), we explore the effect of defect density on the strength, stiffness, and extension of the system. PMID- 25692912 TI - #BlackLivesMatter--a challenge to the medical and public health communities. PMID- 25692913 TI - Bias, black lives, and academic medicine. PMID- 25692914 TI - Treatment choice for diabetic macular edema. PMID- 25692916 TI - Monoclonal antibodies specific to human Delta42PD1: A novel immunoregulator potentially involved in HIV-1 and tumor pathogenesis. AB - We recently reported the identification of Delta42PD1, a novel alternatively spliced isoform of human PD1 that induces the production of pro-inflammatory cytokines from human peripheral blood mononuclear cells and enhances HIV-specific CD8(+) T cell immunity in mice when engineered in a fusion DNA vaccine. The detailed functional study of Delta42PD1, however, has been hampered due to the lack of a specific monoclonal antibody (mAb). In this study, we generated 2 high affinity mAbs, clones CH34 (IgG2b) and CH101 (IgG1), from Delta42PD1-immunized mice. They recognize distinct domains of Delta42PD1 as determined by a yeast surface-displaying assay and ELISA. Moreover, they recognize native Delta42PD1 specifically, but not PD1, on cell surfaces by both flow cytometry and immunohistochemical assays. Delta42PD1 appeared to be expressed constitutively on healthy human CD14(+) monocytes, but its level of expression was down-regulated significantly during chronic HIV-1 infection. Since the level of Delta42PD1 expression on CD14(+) monocytes was negatively correlated with the CD4 count of untreated patients in a cross-sectional study, Delta42PD1 may play a role in HIV 1 pathogenesis. Lastly, when examining Delta42PD1 expression in human esophageal squamous-cell carcinoma tissues, we found high-level expression of Delta42PD1 on a subset of tumor-infiltrating T cells. Our study, therefore, resulted in 2 Delta42PD1-specific mAbs that can be used to further investigate Delta42PD1, a novel immune regulatory protein implicated in HIV-1 and tumor pathogenesis as well as other immune diseases. PMID- 25692917 TI - Ultrasensitive detection of microRNA through rolling circle amplification on a DNA tetrahedron decorated electrode. AB - MicroRNAs are a class of evolutionally conserved, small noncoding RNAs involved in the regulation of gene expression and affect a variety of biological processes including cellular differentiation, immunological response, tumor development, and so on. Recently, microRNAs have been identified as promising disease biomarkers. In this work, we have fabricated a novel electrochemical method for ultrasensitive detection of microRNA. Generally, a DNA tetrahedron decorated gold electrode is employed as the recognition interface. Then, hybridizations between DNA tetrahedron, microRNA, and primer probe initiate rolling circle amplification (RCA) on the electrode surface. Silver nanoparticles attached to the RCA products provide significant electrochemical signals and a limit of detection as low as 50 aM is achieved. Moreover, homology microRNA family members with only one or two mismatches can be successfully distinguished. Therefore, this proposed method reveals great advancements toward improved disease diagnosis and prognosis. PMID- 25692918 TI - High-density lipoprotein cholesterol: origins and the path ahead. AB - PURPOSE OF REVIEW: We provide a historical perspective of how high-density lipoprotein (HDL) cholesterol became a clinical standard, the evidence in favor of HDL function as a more appropriate indication of HDL's antiatherogenic nature, and the options ahead. RECENT FINDINGS: Recent studies have demonstrated a strong relationship between the cholesterol efflux capacity of plasma and prevalent cardiovascular disease (CVD) and CVD event risk, indicating the utility of HDL function as a diagnostic/prognostic of CVD. SUMMARY: We will present how HDL cholesterol came to be the standard proxy of HDL function, the key observations that drew its clinical relevance into question, and the pros and cons of commercially available approaches to measuring HDL function. PMID- 25692919 TI - Editorial: diabetes and the endocrine pancreas I. PMID- 25692920 TI - Rodent versus human insulitis: why the huge disconnect? AB - PURPOSE OF REVIEW: The purpose of this article is to summarize recent developments in the histopathology of recent-onset type 1 diabetes. RECENT FINDINGS: Insulitis is considered to be the defining lesion in young type 1 diabetic patients, and insight into its pathogenic mechanism is crucial for the development of effective new therapies. The present overview highlights some recent developments including an international consensus guideline for the diagnosis of insulitis in type 1 diabetic patients, immunophenotyping of the insulitic lesions, evidence for a heterogeneity of the disease process and a discussion on the differences and similarities between insulitis in patients and in rodent models of the disease. SUMMARY: We have reviewed recent data, published over the last year, on the nature and mechanism of insulitis in both patients and the nonobese diabetic mouse model. PMID- 25692921 TI - Medications for weight loss. AB - PURPOSE OF REVIEW: Overweight and obesity together with their comorbidities have become increasingly prevalent worldwide. The need for well tolerated, effective interventions has become increasingly urgent. Here we review the pharmacology, benefits, and risks of Western and Chinese medications used for weight loss. RECENT FINDINGS: Lifestyle interventions for weight loss are efficacious, but have had limited long-term durability. Bariatric surgery is very effective for weight loss and reversal of type 2 diabetes mellitus (T2DM), but it is invasive and not consistently durable in all patients. Recent studies show that newer Western pharmaceuticals and some traditional Chinese medications may be effective for appropriate patients in need of weight loss. SUMMARY: New Western medications, notably lorcaserin, phentermine/topiramate, naltrexone/bupropion, and liraglutide, are more effective and possibly safer than older medications but have important side-effects. Chinese herbal medicines may have efficacy similar to that of older Western medications and with few side-effects, but data are limited. We suggest that for appropriate patients, in particular those with or at high risk for T2DM, the judicious use of these medications with lifestyle modification is justified. This may be particularly true in Asia where T2DM develops at a low BMI, though more data are needed to support this concept. PMID- 25692922 TI - An update on the role of bariatric surgery in diabetes management. AB - PURPOSE OF REVIEW: To review the current state of knowledge on the effects of weight loss (bariatric) surgical procedures in individuals with type 2 diabetes. RECENT FINDINGS: Observational and randomized studies provide robust data on the efficacy of bariatric surgery for weight loss and improvement in hyperglycemia. Follow-up information up to 20 years is now available. Surgery offers similar benefits in individuals with BMI 30-35, compared with those with higher BMI. There is a better understanding of the role of gut hormones and nonhormonal factors on weight loss and glucose metabolism. Preoperative factors that predict favorable surgical outcomes have been identified. SUMMARY: Of commonly performed procedures, adjustable gastric banding has the lowest efficacy for weight loss and diabetes remission and a higher complication rate. Roux-en-Y gastric bypass and sleeve gastrectomy are comparable in terms of efficacy and complications. Remission rates for diabetes range between 40 and 80%; randomized trials show slightly lower remission rates compared with observational studies. At 20 years, approximately 50% of remitters have relapse of diabetes. Complex gut hormonal changes, caloric restriction, and other intestinal factors form the basis for metabolic effects of surgery. Better preoperative beta-cell function is the strongest predictor for remission. Long-term follow-up data is still sparse. PMID- 25692923 TI - Noncoding RNAs in beta cell biology. AB - PURPOSE OF REVIEW: The identification and characterization of essential islet transcription factors have improved our understanding of beta cell development, provided insights into many of the cellular dysfunctions related to diabetes, and facilitated the successful generation of beta cells from alternative cell sources. Recently, noncoding RNAs have emerged as a novel set of molecules that may represent missing components of the known islet regulatory pathways. The purpose of this article is to highlight studies that have implicated noncoding RNAs as important regulators of pancreas cell development and beta cell function. RECENT FINDINGS: Disruption of essential components of the microRNA processing machinery, in addition to misregulation of individual microRNAs, has revealed the importance of microRNAs in pancreas development and beta cell function. Furthermore, over 1000 islet-specific long noncoding RNAs have been identified in mouse and human islets, suggesting that this class of noncoding molecules will also play important functional roles in the beta cell. SUMMARY: The analysis of noncoding RNAs in the pancreas will provide important new insights into pancreatic regulatory processes that will improve our ability to understand and treat diabetes, and may facilitate the generation of replacement beta cells from alternative cell sources. PMID- 25692924 TI - Apolipoprotein C-III: a potent modulator of hypertriglyceridemia and cardiovascular disease. AB - PURPOSE OF REVIEW: The purpose of this article is to summarize the recent epidemiological, basic science, and pharmaceutical research linking apolipoprotein C-III (apoC-III) with the development and treatment of cardiovascular disease (CVD). RECENT FINDINGS: ApoC-III is an important emerging target linking hypertriglyceridemia with CVD. ApoC-III is a potent modulator of many established CVD risk factors, and is found on chylomicrons, very-low density lipoprotein, low-density lipoprotein, and high-density lipoprotein particles. Recent studies show that in humans, apoC-III levels are an independent risk factor for CVD, and its presence on lipoproteins may promote their atherogenicity. This year, two large-scale epidemiological studies have linked mutations in apoC-III with increased incidence of CVD and hypertriglyceridemia. ApoC-III raises plasma triglycerides through inhibition of lipoprotein lipase, stimulation of very-low density lipoprotein secretion, and is a novel factor in modulating intestinal triglyceride trafficking. ApoC-III also stimulates inflammatory processes in the vasculature and the pancreas. The combination of raising plasma triglycerides and independently stimulating inflammatory processes makes apoC-III a valuable target for reducing the residual CVD risk in patients already on statin therapy, or for whom triglycerides are poorly controlled. Clinical trials on apoC-III antisense oligonucleotides are in progress. SUMMARY: ApoC-III is a potent direct modulator of established CVD risk factors: plasma triglycerides and inflammation. Recent findings show that changes in apoC-III levels are directly associated with changes in cardiovascular risk and the atherogenicity of the lipoproteins on which apoC-III resides. Emerging roles of apoC-III include a role in directing the atherogenicity of high-density lipoprotein, intestinal dietary triglyceride trafficking, and modulating pancreatic beta-cell survival. The combination of these roles makes apoC-III an important therapeutic target for the management and prevention of CVD. PMID- 25692925 TI - Polyunsaturated fatty acid-phospholipid remodeling and inflammation. AB - PURPOSE OF REVIEW: To highlight some of the recent advances related to the control of polyunsaturated fatty acid (PUFA) incorporation and remodeling in membrane glycerophospholipids in inflammatory cells. RECENT FINDINGS: Several enzymes have recently been identified that are associated with the control of PUFA incorporation and remodeling into membrane phospholipids and their release. The functional roles of the different enzyme isotypes in the control of PUFA availability for lipid mediator biosynthesis and cell signaling are only now being established. The expression of specific acyl-CoA synthetase, lysophospholipid acyltransferase and phospholipase A2 isotypes has recently been shown to have an impact on membrane PUFA content, on the production of lipid mediators and on inflammation. SUMMARY: A better understanding of the complex processes associated with the control PUFA remodeling in membrane phospholipids may lead to the discovery of new therapeutic targets for the treatment of inflammatory diseases. PMID- 25692927 TI - Progress of artificial pancreas devices towards clinical use: the first outpatient studies. AB - PURPOSE OF REVIEW: This article describes recent progress in the automated control of glycemia in type 1 diabetes with artificial pancreas devices that combine continuous glucose monitoring with automated decision-making and insulin delivery. RECENT FINDINGS: After a gestation period of closely supervised feasibility studies in research centers, the last 2 years have seen publication of studies testing these devices in outpatient environments, and many more such studies are ongoing. The most basic form of automation, suspension of insulin delivery for actual or predicted hypoglycemia, has been shown to be effective and well tolerated, and a first-generation device has actually reached the market. Artificial pancreas devices that actively dose insulin fall into two categories, those that dose insulin alone and those that also use glucagon to prevent and treat hypoglycemia (bihormonal artificial pancreas). Initial outpatient clinical trials have shown that both strategies can improve glycemic management in comparison with patient-controlled insulin pump therapy, but only the bihormonal strategy has been tested without restrictions on exercise. SUMMARY: Artificial pancreas technology has the potential to reduce acute and chronic complications of diabetes and mitigate the burden of diabetes self-management. Successful outpatient studies bring these technologies one step closer to availability for patients. PMID- 25692926 TI - PCSK9 inhibition to reduce cardiovascular disease risk: recent findings from the biology of PCSK9. AB - PURPOSE OF REVIEW: Review novel insights into the biology of proprotein convertase subtilisin/kexin 9 (PCSK9) that may explain the extreme efficiency of PCSK9 inhibition and the unexpected metabolic effects resulting from PCSK9 monoclonal antibody therapy, and may identify additional patients as target of therapy. RECENT FINDINGS: For over 20 years, the practical knowledge of cholesterol metabolism has centered around cellular mechanisms, and around the idea that statin therapy is the essential step to control metabolic abnormalities for cardiovascular risk management. This view has been embraced by the recent AHA/ACC guidelines, but is being challenged by recent studies including nonstatin medications and by the development of a new class of cholesterol-lowering agents that seems destined to early US Food and Drug Administration approval. The discovery of PCSK9 - a circulating protein that regulates hepatic low-density lipoprotein (LDL) receptor and serum LDL cholesterol levels - has led to a race for its therapeutic inhibition. Recent findings on PCSK9 regulation and pleiotropic effects will help identify additional patient groups likely to benefit from the inhibitory therapy and unravel the full potential of PCSK9 inhibition therapy. SUMMARY: Injectable human monoclonal antibodies to block the interaction between PCSK9 and LDL receptor are demonstrating extraordinary efficacy (LDL reductions of up to 70%) and almost the absence of any side effects. A more moderate effect is seen on other lipoprotein parameters, with the exception of lipoprotein(a) levels. We describe mechanisms that can explain the effect on lipoprotein(a), predict a potential effect on postprandial triglyderides, and suggest a new category of patients for anti-PCSK9 therapy. PMID- 25692928 TI - Managing the Risk of Occupational Allergy in the Enzyme Detergent Industry. AB - Enzyme proteins have potential to cause occupational allergy/asthma. Consequently, as users of enzymes in formulated products, detergents manufacturers have implemented a number of control measures to ensure that the hazard does not translate into health effects in the workforce. To that end, trade associations have developed best practice guidelines which emphasize occupational hygiene and medical monitoring as part of an effective risk management strategy. The need for businesses to recognize the utility of this guidance is reinforced by reports where factories which have failed to follow good industrial hygiene practices have given rise to incidences of occupational allergy. In this article, an overview is provided of how the industry guidelines are actually implemented in practice and what experience is to be derived therefrom. Both medical surveillance and air monitoring practices associated with the implementation of industry guidelines at approximately 100 manufacturing facilities are examined. The data show that by using the approaches described for the limitation of exposure, for the provision of good occupational hygiene and for the active monitoring of health, the respiratory allergenic risk associated with enzyme proteins can be successfully managed. This therefore represents an approach that could be recommended to other industries contemplating working with enzymes. PMID- 25692929 TI - Long-lasting non-IgE-mediated gastrointestinal cow's milk allergy in infants with Down syndrome. PMID- 25692930 TI - Neural correlates of childhood language disorder: a systematic review. AB - AIM: The neurobiological contributions of childhood language disorder are not well understood. Yet there is increasing evidence that language disorder is associated with differences in brain structure and/or function in core language regions. A key hypothesis has been that children with language disorder do not show the same degree of leftward asymmetry of these regions as observed in typically developing children. We aimed to systematically review structural and functional magnetic resonance imaging (fMRI) studies to examine brain commonalities and differences between children with language disorder and typically developing controls; and differences in leftward asymmetry between these groups. METHOD: A systematic review was conducted using MeSH terms synonymous with childhood language disorder and brain MRI methods. The search identified 1443 papers, and 18 articles met the criteria and were appraised for level and quality of evidence. RESULTS: Atypical brain structure and function was reported within traditionally recognized language regions across studies, including the inferior frontal gyrus, posterior superior temporal gyrus, and caudate nucleus. The direction of difference (e.g. increased/decreased) was variable, however, likely because of differences in language disorder groups examined and magnetic resonance data acquisition and analysis approaches. As regards asymmetry, there was some evidence of reduction of the anticipated structural and functional leftward asymmetry in frontal language regions in language disorder groups. INTERPRETATION: Mounting evidence suggests that children with language disorder have atypical brain structure and function within neural regions integral to language. There is limited support for the hypothesis that children with language disorder show a reduction of leftward structural and/or functional asymmetry in frontal language regions. Interpretation is limited, however, by a high degree of variability in language disorder assessment and phenotype, and in magnetic resonance methodologies. A large-scale magnetic resonance study of brain structure and function is required in a well-defined language disorder population cohort, with replication, to provide confirmatory data on the neural correlates of childhood language disorder. PMID- 25692931 TI - The Impact of Work and Volunteer Hours on the Health of Undergraduate Students. AB - OBJECTIVE: To examine the impact of work and volunteer hours on 4 health issues among undergraduate college students. PARTICIPANTS: Full-time undergraduate students (N = 70,068) enrolled at 129 institutions who participated in the Spring 2011 American College Health Association-National College Health Assessment II survey. METHODS: Multiple linear regression and binary logistic regression were used to examine work and volunteer hour impact on depression, feelings of being overwhelmed, sleep, and physical activity. RESULTS: The impact of work and volunteer hours was inconsistent among the health outcomes. Increased work hours tended to negatively affect sleep and increase feelings of being overwhelmed. Students who volunteered were more likely to meet physical activity guidelines, and those who volunteered 1 to 9 hours per week reported less depression. CONCLUSIONS: College health professionals should consider integrating discussion of students' employment and volunteering and their intersection with health outcomes into clinical visits, programming, and other services. PMID- 25692915 TI - Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. AB - BACKGROUND: The relative efficacy and safety of intravitreous aflibercept, bevacizumab, and ranibizumab in the treatment of diabetic macular edema are unknown. METHODS: At 89 clinical sites, we randomly assigned 660 adults (mean age, 61+/-10 years) with diabetic macular edema involving the macular center to receive intravitreous aflibercept at a dose of 2.0 mg (224 participants), bevacizumab at a dose of 1.25 mg (218 participants), or ranibizumab at a dose of 0.3 mg (218 participants). The study drugs were administered as often as every 4 weeks, according to a protocol-specified algorithm. The primary outcome was the mean change in visual acuity at 1 year. RESULTS: From baseline to 1 year, the mean visual-acuity letter score (range, 0 to 100, with higher scores indicating better visual acuity; a score of 85 is approximately 20/20) improved by 13.3 with aflibercept, by 9.7 with bevacizumab, and by 11.2 with ranibizumab. Although the improvement was greater with aflibercept than with the other two drugs (P<0.001 for aflibercept vs. bevacizumab and P=0.03 for aflibercept vs. ranibizumab), it was not clinically meaningful, because the difference was driven by the eyes with worse visual acuity at baseline (P<0.001 for interaction). When the initial visual-acuity letter score was 78 to 69 (equivalent to approximately 20/32 to 20/40) (51% of participants), the mean improvement was 8.0 with aflibercept, 7.5 with bevacizumab, and 8.3 with ranibizumab (P>0.50 for each pairwise comparison). When the initial letter score was less than 69 (approximately 20/50 or worse), the mean improvement was 18.9 with aflibercept, 11.8 with bevacizumab, and 14.2 with ranibizumab (P<0.001 for aflibercept vs. bevacizumab, P=0.003 for aflibercept vs. ranibizumab, and P=0.21 for ranibizumab vs. bevacizumab). There were no significant differences among the study groups in the rates of serious adverse events (P=0.40), hospitalization (P=0.51), death (P=0.72), or major cardiovascular events (P=0.56). CONCLUSIONS: Intravitreous aflibercept, bevacizumab, or ranibizumab improved vision in eyes with center-involved diabetic macular edema, but the relative effect depended on baseline visual acuity. When the initial visual-acuity loss was mild, there were no apparent differences, on average, among study groups. At worse levels of initial visual acuity, aflibercept was more effective at improving vision. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01627249.). PMID- 25692932 TI - In vitro human metabolism of the flame retardant resorcinol bis(diphenylphosphate) (RDP). AB - Resorcinol bis(diphenylphosphate) (RDP) is widely used as a flame retardant in electrical/electronic products and constitutes a suitable alternative to decabrominated diphenyl ether. Due to its toxicity and its recently reported ubiquity in electronics and house dust, there are increasing concerns about human exposure to this emerging contaminant. With the aim of identifying human-specific biomarkers, the in vitro metabolism of RDP and its oligomers was investigated using human liver microsomes and human liver cytosol. Mono- and dihydroxy metabolites, together with glucuronidated and sulfated metabolites, were detected. Regarding RDP oligomers, only a hydroxy-metabolite of the dimer could be detected. RDP and its oligomers were also readily hydrolyzed, giving rise to a variety of compounds, such as diphenyl phosphate, para-hydroxy-triphenyl phosphate, and para-hydroxy RDP, which were further metabolized. These degradation products or impurities are possibly of environmental importance in future studies. PMID- 25692933 TI - A comparative study of layered transition metal oxide cathodes for application in sodium-ion battery. AB - Herein, we report a study on P-type layered sodium transition metal-based oxides with a general formula of NaxMO2 (M = Ni, Fe, Mn). We synthesize the materials via coprecipitation followed by annealing in air and rinsing with water, and we examine the electrodes as cathodes for sodium-ion batteries using a propylene carbonate-based electrolyte. We fully investigate the effect of the Ni-to-Fe ratio, annealing temperature, and sodium content on the electrochemical performances of the electrodes. The impact of these parameters on the structural and electrochemical properties of the materials is revealed by X-ray diffraction, scanning electron microscopy, and cyclic voltammetry, respectively. The suitability of this class of P-type materials for sodium battery application is finally demonstrated by cycling tests revealing an excellent electrochemical performance in terms of delivered capacity (i.e., about 200 mAh g(-1)) and charge discharge efficiency (approaching 100%). PMID- 25692934 TI - In reply. PMID- 25692935 TI - Regarding the effect of cured tuberculosis disease on longevity. PMID- 25692936 TI - Dual infection with pulmonary tuberculosis and Lophomonas blattarum in India. PMID- 25692937 TI - Cavitary tuberculosis and tracheal stenosis simulating granulomatosis with polyangiitis. PMID- 25692938 TI - Stillbirth and infant mortality in Aboriginal communities in Quebec. AB - BACKGROUND: Infant mortality and stillbirth rates among Aboriginal people are higher than in the rest of Canada, but little is known on the perinatal health status of First Nations people living on reserves. This study examines stillbirth and infant mortality rates among Aboriginal people in Quebec, notably, First Nations people living on reserves, and compares these rates with those of the province's non-Aboriginal population. DATA AND METHODS: Data on live births and stillbirths in Quebec from 1989 to 2008 were extracted from Statistics Canada's Infant Birth-Death Linked File. Postal codes were used to identify births and stillbirths on First Nations reserves, in the Cree and Naskapi communities (not on reserves), and in Inuit communities. Associations between type of community and mortality were measured using logistic regression models. RESULTS: Aboriginal people had a higher stillbirth rate than non-Aboriginal people in Quebec, but this difference was not significant after adjusting for socio-demographic characteristics (mothers' age and education, community size and isolation). Neonatal mortality was also higher among the Inuit. Post-neonatal mortality was higher among Aboriginal people, and was unrelated to differences in the mothers' age and education or to community size and isolation. Adjusted odds ratios (95% confidence intervals) for post-neonatal mortality on reserves, in the Cree and Naskapi communities, and in Inuit communities were, respectively, 1.57 (1.16 - 2.12), 3.01 (2.14 - 4.24) and 4.29 (3.09 - 5.97). INTERPRETATION: Stillbirth and infant mortality are higher among Aboriginal people than non-Aboriginal people in Quebec. The differences in post-neonatal mortality are particularly pronounced. PMID- 25692939 TI - Developing a non-categorical measure of child health using administrative data. AB - BACKGROUND: Few studies have examined the potential of linked administrative data for research on child health. This analysis describes the application of a non categorical survey-based tool, the Children with Special Health Care Needs (CSHCN) Screener, to administrative data. DATA AND METHODS: Five Screener items were applied to linked administrative health data from Population Data British Columbia. Hospital admissions and demographic and community characteristics for a cohort of children aged 6 to 10 in 2006 were examined to validate the use of these items. RESULTS: Overall, 17.5% of children were identified as CSHCN. An estimated 14% of children used more medical care and 5.2% had more functional limitations than is usual for children of the same age; 3.3% were prescribed long term medication; 1.9% needed/received treatment or counselling; and 0.1% needed/received special therapy. Boys were more likely than girls to be identified as CSHCN. INTERPRETATION: With some limitations, the CSHCN Screener can be applied to Canadian administrative health data. PMID- 25692940 TI - Cognitive load, emotion, and performance in high-fidelity simulation among beginning nursing students: a pilot study. AB - Establishing the impact of the high-fidelity simulation environment on student performance, as well as identifying factors that could predict learning, would refine simulation outcome expectations among educators. The purpose of this quasi experimental pilot study was to explore the impact of simulation on emotion and cognitive load among beginning nursing students. Forty baccalaureate nursing students participated in teaching simulations, rated their emotional state and cognitive load, and completed evaluation simulations. Two principal components of emotion were identified representing the pleasant activation and pleasant deactivation components of affect. Mean rating of cognitive load following simulation was high. Linear regression identiffed slight but statistically nonsignificant positive associations between principal components of emotion and cognitive load. Logistic regression identified a negative but statistically nonsignificant effect of cognitive load on assessment performance. Among lower ability students, a more pronounced effect of cognitive load on assessment performance was observed; this also was statistically non-significant. PMID- 25692942 TI - Spatio-temporal correlations in aqueous systems: computational studies of static and dynamic heterogeneity by 2D-IR spectroscopy. AB - Local heterogeneity is ubiquitous in natural aqueous systems. It can be caused locally by external biomolecular subsystems like proteins, DNA, micelles and reverse micelles, nanoscopic materials etc., but can also be intrinsic to the thermodynamic nature of the aqueous solution itself (like binary mixtures or at the gas-liquid interface). The altered dynamics of water in the presence of such diverse surfaces has attracted considerable attention in recent years. As these interfaces are quite narrow, only a few molecular layers thick, they are hard to study by conventional methods. The recent development of two dimensional infra red (2D-IR) spectroscopy allows us to estimate length and time scales of such dynamics fairly accurately. In this work, we present a series of interesting studies employing two dimensional infra-red spectroscopy (2D-IR) to investigate (i) the heterogeneous dynamics of water inside reverse micelles of varying sizes, (ii) supercritical water near the Widom line that is known to exhibit pronounced density fluctuations and also study (iii) the collective and local polarization fluctuation of water molecules in the presence of several different proteins. The spatio-temporal correlation of confined water molecules inside reverse micelles of varying sizes is well captured through the spectral diffusion of corresponding 2D-IR spectra. In the case of supercritical water also, we observe a strong signature of dynamic heterogeneity from the elongated nature of the 2D-IR spectra. In this case the relaxation is ultrafast. We find remarkable agreement between the different tools employed to study the relaxation of density heterogeneity. For aqueous protein solutions, we find that the calculated dielectric constant of the respective systems unanimously shows a noticeable increment compared to that of neat water. However, the 'effective' dielectric constant for successive layers shows significant variation, with the layer adjacent to the protein having a much lower value. Relaxation is also slowest at the surface. We find that the dielectric constant achieves the bulk value at distances more than 3 nm from the surface of the protein. PMID- 25692941 TI - Serum apolipoprotein A-I and large high-density lipoprotein particles are positively correlated with FEV1 in atopic asthma. AB - RATIONALE: Although lipids, apolipoproteins, and lipoprotein particles are important modulators of inflammation, varying relationships exist between these parameters and asthma. OBJECTIVES: To determine whether serum lipids and apolipoproteins correlate with the severity of airflow obstruction in subjects with atopy and asthma. METHODS: Serum samples were obtained from 154 atopic and nonatopic subjects without asthma, and 159 subjects with atopy and asthma. Serum lipid and lipoprotein levels were quantified using standard diagnostic assays and nuclear magnetic resonance (NMR) spectroscopy. Airflow obstruction was assessed by FEV1% predicted. MEASUREMENTS AND MAIN RESULTS: Serum lipid levels correlated with FEV1 only in the subjects with atopy and asthma. Serum levels of high density lipoprotein (HDL) cholesterol and apolipoprotein A-I (apoA-I) were positively correlated with FEV1 in subjects with atopy and asthma, whereas a negative correlation existed between FEV1 and serum levels of triglycerides, low density lipoprotein (LDL) cholesterol, apolipoprotein B (apoB), and the apoB/apoA I ratio. NMR spectroscopy identified a positive correlation between FEV1 and HDLNMR particle size, as well as the concentrations of large HDLNMR particles and total IDLNMR (intermediate-density lipoprotein) particles in subjects with atopy and asthma. In contrast, LDLNMR particle size and concentrations of LDLNMR and VLDLNMR (very-low-density lipoprotein) particles were negatively correlated with FEV1 in subjects with atopy and asthma. CONCLUSIONS: In subjects with atopy and asthma, serum levels of apoA-I and large HDLNMR particles are positively correlated with FEV1, whereas serum triglycerides, LDL cholesterol, and apoB are associated with more severe airflow obstruction. These results may facilitate future studies to assess whether apoA-I and large HDLNMR particles can reduce airflow obstruction and disease severity in asthma. PMID- 25692943 TI - The potential of antagonistic fungi for control of Fusarium graminearum and Fusarium crookwellense varies depending on the experimental approach. AB - AIMS: To investigate the potential of fungal antagonists to control Fusarium head blight (FHB) causing pathogens (Fusarium graminearum and F. crookwellense) with two different experimental approaches. METHODS AND RESULTS: Using two in vitro tests, Clonostachys rosea, Cladosporium cladosporioides and 10 Trichoderma strains were screened. In a co-culture assay, all Trichoderma strains significantly reduced the colony area of F. graminearum and F. crookwellense by 45-93%, whereas C. rosea and C. cladosporioides were not effective. In another assay, all antagonists from a chosen subset reduced the number of perithecia and ascospores on wheat straw by 88-100% when inoculated before the pathogen. Only C. rosea, a weak antagonist in the co-culture assay, was effective when inoculated after the pathogen, reducing perithecia and ascospore production by 73 and 100%, respectively. CONCLUSIONS: For screening antagonists and to avoid sorting out highly effective strains, it is crucial to consider different experimental approaches since the efficacy might differ substantially depending on the incubation conditions. By using two distinct experimental set-ups, we identified promising biological control agents. SIGNIFICANCE AND IMPACT OF THE STUDY: FHB is one of the most devastating fungal cereal diseases worldwide. As the pathogen overwinters on crop residues, application of antagonists on residues of the previous crop during harvest could be a promising approach to efficiently control FHB in cereals as an essential part of an integrated disease management. PMID- 25692944 TI - A Reassuring Rejoinder Against Malignant Influences of Topical Calcineurin Use in Children. PMID- 25692945 TI - Integration of deliberate practice and peer mentoring to enhance students' mastery and retention of essential skills. AB - Faculty in a 4-year baccalaureate nursing program were concerned with students' failure to retain the patient care skills of vital signs, breath sounds, and heart sounds learned in freshman and sophomore courses and consequent inability to transfer these high-frequency skills into the clinical setting. Because nursing is a practice profession, new graduates must be prepared to demonstrate specific competencies that are designed to improve practice. To address faculty concerns, support more positive learning outcomes, and engage in evidence-based nursing education, faculty developed and implemented an assignment that incorporated deliberate practice and peer mentoring into a sophomore course on the essentials of nursing practice. The purpose of this article is to describe the rationale, development and implementation, and feedback for a deliberate practice and peer mentoring assignment designed to enhance skill mastery and retention. PMID- 25692947 TI - Molecular and cellular glyco-science--Part II. PMID- 25692946 TI - Zebrin II / aldolase C expression in the cerebellum of the western diamondback rattlesnake (Crotalus atrox). AB - Aldolase C, also known as Zebrin II (ZII), is a glycolytic enzyme that is expressed in cerebellar Purkinje cells of the vertebrate cerebellum. In both mammals and birds, ZII is expressed heterogeneously, such that there are sagittal stripes of Purkinje cells with high ZII expression (ZII+), alternating with stripes of Purkinje cells with little or no expression (ZII-). The patterns of ZII+ and ZII- stripes in the cerebellum of birds and mammals are strikingly similar, suggesting that it may have first evolved in the stem reptiles. In this study, we examined the expression of ZII in the cerebellum of the western diamondback rattlesnake (Crotalus atrox). In contrast to birds and mammals, the cerebellum of the rattlesnake is much smaller and simpler, consisting of a small, unfoliated dome of cells. A pattern of alternating ZII+ and ZII- sagittal stripes cells was not observed: rather all Purkinje cells were ZII+. This suggests that ZII stripes have either been lost in snakes or that they evolved convergently in birds and mammals. PMID- 25692948 TI - Polysaccharide-protein nanoassemblies: novel soft materials for biomedical and biotechnological applications. AB - Polysaccharide and proteins are the major constituent building blocks of biological systems and often occur as highly organized macromolecular architectures (e.g. the capsid of viruses). Both can occur in the same or in different biological physiological environment interacting in specific or non specific ways. When isolated and purified, these macromolecules can harness self assembled (SA) soft nanomaterials by non-covalent electrostatic complexation. Although polysaccharide-protein electrostatic SA systems of this type have been studied for more than two decades, the possibility to design materials with enhanced biological function and improved technological advantages over those based on synthetic or inorganic components, has only started to be recognized and is yet to be fully realized. In this review we address two main type of SA polysaccharide-protein systems, namely, those based on chitosan-protein and those based on polyanionic polysaccharide (pectin, hyaluronic acid or alginate) - protein ones. The physical properties of chitosan- and polyanion-based SA nanocomplexes with oppositely charged proteins depend on the composition and conditions as reviewed here with reference to some specific systems. PMID- 25692949 TI - Proteins for breaking barriers in lignocellulosic bioethanol production. AB - Reduction in fossil fuel consumption by using alternate sources of energy is a major challenge facing mankind in the coming decades. Bioethanol production using lignocellulosic biomass is the most viable option for addressing this challenge. Industrial bioconversion of lignocellulosic biomass, though possible now, is not economically viable due to presence of barriers that escalate the cost of production. As cellulose and hemicellulose are the major constituents of terrestrial biomass, which is available in massive quantities, hydrolysis of cellulose and hemicellulose by the microorganisms are the most prominent biochemical processes happening in the earth. Microorganisms possess different categories of proteins associated with different stages of bioethanol production and a number of them are already found and characterized. Many more of these proteins need to be identified which suit the specificities needed for the bioethanol production process. Discovery of proteins with novel specificities and application of genetic engineering technologies to harvest the synergies existing between them with the aim to develop consolidated bioprocess is the major direction of research in the future. In this review, we discuss the different categories of proteins used for bioethanol production in the context of breaking the barriers existing for the economically feasible lignocellulosic bioethanol production. PMID- 25692950 TI - Amyloidogenicity of p53: a hidden link between protein misfolding and cancer. AB - Pathogenic aggregation is closely associated with various protein misfolding diseases such as type 2 diabetes mellitus and Alzheimer's disease. Amyloidogenic proteins that have a propensity to assemble into amyloid oligomers and fibrils form the aggregates. The tumor suppressor p53, a transcription factor that regulates the cell cycle and apoptosis, is also amyloidogenic. In tumor models, both wild type and mutant p53 proteins show aggregation kinetics and morphology similar to those of classical amyloidogenic proteins, such as beta-amyloid peptide and alpha- synuclein. Wild type p53 loses its anticancer activity when it aggregates, while p53 mutants with enhanced amyloidogenicity show accelerated aggregation. So far, amyloidogenic p53 mutations have been implicated in more than ten different types of cancer, suggesting a connection between p53 aggregation and cancer. Therefore, inhibition of both inherent and mutation induced p53 aggregation may stabilize p53 in a functional conformation and provide a novel approach to cancer prevention and treatment. Here, we summarize recent findings on carcinogenic aggregation of wild type p53 and its clinical mutants, structure-dependent amyloidogenesis of p53, and several promising strategies based on inhibition of p53 aggregation are also discussed. PMID- 25692951 TI - Proline-rich peptides: multifunctional bioactive molecules as new potential therapeutic drugs. AB - Proline-rich peptides (PRPs) include a large and heterogeneous group of small medium sized peptides characterized by the presence of proline residues often constituting peculiar sequences. This feature confers them a typical structure that determines the various biological functions endowed by these molecules. In particular the left-handed-polyproline-II helix is essential for the expression of the antimicrobial, immunomodulatory, antioxidant properties and to finely modulate protein-protein interactions, thus playing crucial roles in many cell signal transduction pathways. These peptides are widely diffuse in the animal kingdom and in humans, where they are present in many tissues and biological fluids. This review highlights the most relevant biological properties of these peptides, focusing on the potential therapeutic role that the PRPs may play as a promising source of new peptidebased novel drugs. PMID- 25692952 TI - The molecular basis for the post-translational addition of amino acids by L/F transferase in the N-end rule pathway. AB - The N-end rule pathway is a conserved targeted proteolytic process observed in organisms ranging from eubacteria to mammals. The N-end rule relates the metabolic stability of a protein to its N-terminal amino acid residue. The identity of the N-terminal amino acid residue is a primary degradation signal, often referred to as an N-degron, which is recognized by the components of the N end rule when it is a destabilizing N-terminus. N-degrons may be exposed by non processive proteolytic cleavages or by post-translational modifications. One modification is the post-translational addition of amino acids to the N-termini of proteins, a reaction catalyzed by aminoacyl-tRNA protein transferases. The aminoacyl-tRNA protein transferase in eubacteria like Escherichia coli is L/F transferase. Recent investigations have reported unexpected observations regarding the L/F transferase catalytic mechanism and its mechanisms of substrate recognition. Additionally, recent proteome-wide identification of putative in vivo substrates facilitates hypothesis into the yet elusive biological functions of the prokaryotic N-end rule pathway. Here we summarize the recent findings on the molecular mechanisms of catalysis and substrate recognition by the E. coli L/F transferase in the prokaryotic N-end rule pathway. PMID- 25692953 TI - Congruence of microsatellite and mitochondrial DNA variation in acrobat ants (Crematogaster subgenus Decacrema, Formicidae: Myrmicinae) inhabiting Macaranga (Euphorbiaceae) myrmecophytes. AB - A previously reported mitochondrial DNA (mtDNA) phylogeny of Crematogaster (subgenus Decacrema) ants inhabiting Macaranga myrmecophytes indicated that the partners diversified synchronously and their specific association has been maintained for 20 million years. However, the mtDNA clades did not exactly match morphological species, probably owing to introgressive hybridization among younger species. In this study, we determined the congruence between nuclear simple sequence repeat (SSR, also called microsatellite) genotyping and mtDNA phylogeny to confirm the suitability of the mtDNA phylogeny for inferring the evolutionary history of Decacrema ants. Analyses of ant samples from Lambir Hills National park, northeastern Borneo, showed overall congruence between the SSR and mtDNA groupings, indicating that mtDNA markers are useful for delimiting species, at least at the local level. We also found overall high host-plant specificity of the SSR genotypes of Decacrema ants, consistent with the specificity based on the mtDNA phylogeny. Further, we detected cryptic genetic assemblages exhibiting high specificity toward particular plant species within a single mtDNA clade. This finding, which may be evidence for rapid ecological and genetic differentiation following a host shift, is a new insight into the previously suggested long-term codiversification of Decacrema ants and Macaranga plants. PMID- 25692954 TI - Inflammation and hypoxia linked to renal injury by CCAAT/enhancer-binding protein delta. AB - Tubulointerstitial hypoxia plays a critical role in the pathogenesis of kidney injury, and hypoxia-inducible factor (HIF)-1 is a master regulator of cellular adaptation to hypoxia. Aside from oxygen molecules, factors that modify HIF-1 expression and functional operation remain obscure. Therefore, we sought to identify novel HIF-1-regulating genes in kidney. A short-hairpin RNA library consisting of 150 hypoxia-inducible genes was derived from a microarray analysis of the rat renal artery stenosis model screened for the effect on HIF-1 response. We report that CCAAT/enhancer-binding protein delta (CEBPD), a transcription factor and inflammatory response gene, is a novel HIF-1 regulator in kidney. CEBPD was induced in the nuclei of tubular epithelial cells in both acute and chronic hypoxic kidneys. In turn, CEBPD induction augmented HIF-1alpha expression and its transcriptional activity. Mechanistically, CEBPD directly bound to the HIF-1alpha promoter and enhanced its transcription. Notably, CEBPD was rapidly induced by inflammatory cytokines, such as IL-1beta in a nuclear factor-kappaB dependent manner, which not only increased HIF-1alpha expression during hypoxia, but was also indispensable for the non-hypoxic induction of HIF-1alpha. Thus our study provides novel insight into HIF-1 regulation in tubular epithelial cells and offers a potential hypoxia and inflammation link relevant in both acute and chronic kidney diseases. PMID- 25692955 TI - Differential expression and regulation of Klotho by paricalcitol in the kidney, parathyroid, and aorta of uremic rats. AB - Klotho plays an important role in the pathogenesis of cardiovascular disease in chronic kidney disease (CKD). Klotho is highly expressed in the kidney and parathyroid glands, but its presence in the vasculature is debated. Renal Klotho is decreased in CKD, but the effect of uremia on Klotho in other tissues is not defined. The effect of vitamin D receptor activator therapy in CKD on the expression of Klotho in various tissues is also in debate. In uremic rats (surgical 5/6th nephrectomy model), we compared 3 months of treatment with and without paricalcitol on Klotho immunostaining in the kidney, parathyroid glands, and aorta. With uremia, Klotho was unchanged in the parathyroid, significantly decreased in the kidney (66%) and the intimal-medial area of the aorta (69%), and significantly increased in the adventitial area of the aorta (67%) compared with controls. Paricalcitol prevented the decrease of Klotho in the kidney, increased expression in the parathyroid (31%), had no effect in the aortic media, but blunted the increase of Klotho in the aortic adventitia. We propose that fibroblasts are responsible for the expression of Klotho in the adventitia. In hyperplastic human parathyroid tissue from uremic patients, Klotho was higher in oxyphil compared with chief cells. Thus, under our conditions of moderate CKD and mild-to-moderate hyperphosphatemia in rats, the differential expression of Klotho and its regulation by paricalcitol in uremia is tissue-dependent. PMID- 25692956 TI - Microparticles: markers and mediators of sepsis-induced microvascular dysfunction, immunosuppression, and AKI. AB - Sepsis is a severe and complex syndrome that lacks effective prevention or therapeutics. The effects of sepsis on the microvasculature have become an attractive area for possible new targets and therapeutics. Microparticles (MPs) are cell membrane-derived particles that can promote coagulation, inflammation, and angiogenesis, and they can participate in cell-to-cell communication. MPs retain cell membrane and cytoplasmic constituents of their parental cells, including two procoagulants: phosphatidylserine and tissue factor. We highlight the role of microparticles released by endothelial and circulating cells after sepsis-induced microvascular injury, and we discuss possible mechanisms by which microparticles can contribute to endothelial dysfunction, immunosuppression, and multiorgan dysfunction--including sepsis-AKI. Once viewed as cellular byproducts, microparticles are emerging as a new class of markers and mediators in the pathogenesis of sepsis. PMID- 25692957 TI - High estimated pulmonary artery systolic pressure predicts adverse cardiovascular outcomes in stage 2-4 chronic kidney disease. AB - High estimated pulmonary artery systolic pressure (ePASP) is an established risk factor for mortality and cardiovascular (CV) events in the general population. High ePASP predicts mortality in dialysis patients but such a relationship has not been tested in patients with early CKD. Here we estimated the prevalence and the risk factors of high ePASP in 468 patients with CKD stage 2-4 and determined its prognostic power for a combined end point including cardiovascular death, acute heart failure, coronary artery disease, and cerebrovascular and peripheral artery events. High ePASP (35 mm Hg and above) was present in 108 CKD patients. In a multivariate logistic regression model adjusted for age, diabetes, hemoglobin, left atrial volume (LAV/BSA), left ventricular mass (LVM/BSA), and history of CV disease, age (OR, 1.06; 95% CI, 12 1.04-1.09) and LAV/BSA (OR, 1.05; 95% CI, 1.03-1.07) were the sole significant independent predictors of high ePASP. Elevated ePASP predicted a significantly high risk for the combined cardiovascular end point both in unadjusted analyses (HR, 2.70; 95% CI, 1.68 4.32) and in analyses adjusting for age, eGFR, hemoglobin, LAV/BSA, LVM/BSA, and the presence of diabetes and CV disease (HR, 1.75; 95% CI, 1.05-2.91). High ePASP is relatively common in patients with stage 2-4 CKD and predicts adverse CV outcomes independent of established classical and CKD-specific risk factors. Whether high ePASP is a modifiable risk factor in patients with CKD remains to be determined in randomized clinical trials. PMID- 25692958 TI - Prenatal diagnosis of a bilateral arterial duct associated with trisomy 18. PMID- 25692959 TI - Early knee osteoarthritis is evident one year following anterior cruciate ligament reconstruction: a magnetic resonance imaging evaluation. AB - OBJECTIVE: To determine the prevalence and factors associated with knee osteoarthritis (OA) defined by magnetic resonance imaging (MRI) and specific OA features on MRI 1 year after anterior cruciate ligament reconstruction (ACLR). METHODS: Isotropic 3.0T MRI scans were obtained for 111 participants (71 men; mean +/- SD age 30 +/- 8 years) 1 year after ACLR as well as for 20 age-, sex-, and activity level-matched uninjured controls. The MRI OA Knee Score was used to score specific OA features. MRI-defined tibiofemoral and patellofemoral OA was evaluated based on published criteria. Logistic regression identified factors associated with MRI-defined OA and specific OA features after ACLR. RESULTS: Following ACLR, medial and lateral tibiofemoral OA on MRI was observed in 7 participants (6%) and 12 participants (11%), respectively, while 19 participants (17%) had patellofemoral OA on MRI. The femoral trochlea was the region most affected by bone marrow lesions (19% of participants), cartilage lesions (31% of participants), and osteophytes (37% of participants). Meniscectomy at the time of ACLR (odds ratio 6.8 [95% confidence interval 2.0-23.3]) and body mass index (BMI) >25 kg/m(2) (odds ratio 3.0 [95% confidence interval 1.3-6.9]) predicted MRI-defined tibiofemoral OA and osteophytes, respectively. Men had higher odds of patellofemoral osteophytes (odds ratio 6.3 [95% confidence interval 2.4-16.2]). No uninjured controls had tibiofemoral or patellofemoral OA on MRI, and specific OA features were uncommon. CONCLUSION: OA 1 year following ACLR was more common than previously recognized, while being absent in uninjured control knees. The patellofemoral compartment seems to be at particular risk for early OA after ACLR, especially in men. The association with meniscectomy and BMI demonstrates the construct validity of MRI criteria. PMID- 25692960 TI - UV-emitting upconversion-based TiO2 photosensitizing nanoplatform: near-infrared light mediated in vivo photodynamic therapy via mitochondria-involved apoptosis pathway. AB - Photodynamic therapy (PDT) is a promising antitumor treatment that is based on the photosensitizers that inhibit cancer cells by yielding reactive oxygen species (ROS) after irradiation of light with specific wavelengths. As a potential photosensitizer, titanium dioxide (TiO2) exhibits minimal dark cytotoxicity and excellent ultraviolet (UV) light triggered cytotoxicity, but is challenged by the limited tissue penetration of UV light. Herein, a novel near infrared (NIR) light activated photosensitizer for PDT based on TiO2-coated upconversion nanoparticle (UCNP) core/shell nanocomposites (UCNPs@TiO2 NCs) is designed. NaYF4:Yb(3+),Tm(3+)@NaGdF4:Yb(3+) core/shell UCNPs can efficiently convert NIR light to UV emission that matches well with the absorption of TiO2 shells. The UCNPs@TiO2 NCs endocytosed by cancer cells are able to generate intracellular ROS under NIR irradiation, decreasing the mitochondrial membrane potential to release cytochrome c into the cytosol and then activating caspase 3 to induce cancer cell apoptosis. NIR light triggered PDT of tumor-bearing mice with UCNPs@TiO2 as photosensitizers can suppress tumor growth efficiently due to the better tissue penetration than UV irradiation. On the basis of the evidence of in vitro and in vivo results, UCNPs@TiO2 NCs could serve as an effective photosensitizer for NIR light mediated PDT in antitumor therapy. PMID- 25692961 TI - Characterization of the dystrophin-glycoprotein complex in airway smooth muscle: role of delta-sarcoglycan in airway responsiveness. AB - The dystrophin-glycoprotein complex (DGC) is an integral part of caveolae microdomains, and its interaction with caveolin-1 is essential for the phenotype and functional properties of airway smooth muscle (ASM). The sarcoglycan complex provides stability to the dystroglycan complex, but its role in ASM contraction and lung physiology in not understood. We tested whether delta-sarcoglycan (delta SG), through its interaction with the DGC, is a determinant of ASM contraction ex vivo and airway mechanics in vivo. We measured methacholine (MCh)-induced isometric contraction and airway mechanics in delta-SG KO and wild-type mice. Last, we performed immunoblotting and transmission electron microscopy to assess DGC protein expression and the ultrastructural features of tracheal smooth muscle. Our results reveal an age-dependent reduction in the MCh-induced tracheal isometric force and significant reduction in airway resistance at high concentrations of MCh (50.0 mg/mL) in delta-SG KO mice. The changes in contraction and lung function correlated with decreased caveolin-1 and beta dystroglycan abundance, as well as an age-dependent loss of caveolae in the cell membrane of tracheal smooth muscle in delta-SG KO mice. Collectively, these results confirm and extend understanding of a functional role for the DGC in the contractile properties of ASM and demonstrate that this results in altered lung function in vivo. PMID- 25692962 TI - Growth assessment of hepatic venous malformations. PMID- 25692963 TI - Structural basis of substrate specificity and regiochemistry in the MycF/TylF family of sugar O-methyltransferases. AB - Sugar moieties in natural products are frequently modified by O-methylation. In the biosynthesis of the macrolide antibiotic mycinamicin, methylation of a 6' deoxyallose substituent occurs in a stepwise manner first at the 2'- and then the 3'-hydroxyl groups to produce the mycinose moiety in the final product. The timing and placement of the O-methylations impact final stage C-H functionalization reactions mediated by the P450 monooxygenase MycG. The structural basis of pathway ordering and substrate specificity is unknown. A series of crystal structures of MycF, the 3'-O-methyltransferase, including the free enzyme and complexes with S-adenosyl homocysteine (SAH), substrate, product, and unnatural substrates, show that SAM binding induces substantial ordering that creates the binding site for the natural substrate, and a bound metal ion positions the substrate for catalysis. A single amino acid substitution relaxed the 2'-methoxy specificity but retained regiospecificity. The engineered variant produced a new mycinamicin analog, demonstrating the utility of structural information to facilitate bioengineering approaches for the chemoenzymatic synthesis of complex small molecules containing modified sugars. Using the MycF substrate complex and the modeled substrate complex of a 4'-specific homologue, active site residues were identified that correlate with the 3' or 4' specificity of MycF family members and define the protein and substrate features that direct the regiochemistry of methyltransfer. This classification scheme will be useful in the annotation of new secondary metabolite pathways that utilize this family of enzymes. PMID- 25692964 TI - Effects of testicular histopathology on sperm retrieval rates and ICSI results in non-obstructive azoospermia. AB - Non-obstructive azoospermia (NOA) is characterised by absence of sperm in the ejaculate. Significant relationship between the pattern of the testis histopathology of NOA and successful sperm retrieval rate is well known. In this study, we assess efficacy of testicular histopathology on sperm retrieval rates and intracytoplasmic sperm injection results after microdissection testicular sperm extraction in cases of non-obstructive azoospermia. It is a retrospective analysis of 111 NOA patients who have histopathological confirmation. According to histopathological findings, the patients were divided into three groups: Sertoli-cell-only syndrome (SCOS), maturation arrest (MA) and hypospermatogenesis. Sperm retrieval rate was significantly higher in hypospermatogenesis group compared with that in SCOS and MA groups. In terms of fertilisation and clinical pregnancy rates, there was no significant difference between the groups. As a result, compared with MA and SCOS, hypospermatogenesis has higher sperm retrieval rates. Our study revealed that once successful sperm retrieval is achieved, fertilisation and clinical pregnancy rates are similar in NOA patients. PMID- 25692965 TI - A versatile approach to obtain a high-purity semiconducting single-walled carbon nanotube dispersion with conjugated polymers. AB - High-purity semiconducting single-walled carbon nanotubes (s-SWCNTs) are urgently needed in the development of beyond-silicon nanoelectronics. The utility of conjugated polymers to assist in the sorting of s-SWCNTs has attracted immense attention due to the simplicity of the sorting process and the high selectivity of conjugated polymers for s-SWCNTs. Rather than developing new types of conjugated polymers, this work provides a versatile and facile route for the sorting of s-SWCNTs with improved purity which is far beyond the sensitivity of a spectrometer. PMID- 25692966 TI - Exercise, antioxidants, and the risk for pneumonia. PMID- 25692967 TI - Response. PMID- 25692968 TI - Functional outcome of autologous anorectal transplantation in an experimental model. AB - BACKGROUND: Although anorectal transplantation is a challenging procedure, it is a promising option for patients who have completely lost anorectal function or in whom it failed to develop, as in congenital malformations. The paucity of animal models with which to test functional outcomes was addressed in this study of anorectal manometry in rats. METHODS: Wistar rats were assigned randomly to four groups: orthotopic anorectal transplantation, heterotopic transplantation, sham operation, or normal control. Bodyweight and anal pressure were measured immediately before and after operation, and on postoperative days 7 and 14. ANOVA and Tukey's test were used to compare results for bodyweight, anal manometry and length of procedure. RESULTS: Immediately after the procedure, mean(s.d.) anal pressure in the orthotopic group (n = 13) dropped from 31.4(13.1) to 1.6(13.1) cmH2 O (P < 0.001 versus both sham operation (n = 13) and normal control (n = 15)), with partial recovery on postoperative day 7 (14.9(13.9) cmH2 O) (P = 0.009 versus normal control) and complete recovery on day 14 (23.7(12.2) cmH2 O). Heterotopic rats (n = 14) demonstrated partial functional recovery: mean(s.d.) anal pressure was 26.9(10.9) cmH2 O before operation and 8.6(6.8) cmH2 O on postoperative day 14 (P < 0.001 versus both sham and normal control). CONCLUSION: Orthotopic anorectal transplantation may result in better functional outcomes than heterotopic procedures. Surgical relevance Patients with a permanent colostomy have limited continence. Treatment options are available, but anorectal transplantation may offer hope. Some experimental studies have been conducted, but available data are currently insufficient to translate into a clinical option. This paper details functional outcomes in a rat model of anorectal autotransplantation. It represents a step in the translational research that may lead to restoration of anorectal function in patients who have lost or have failed to develop it. PMID- 25692969 TI - Seasonal alterations in host range and fidelity in the polyphagous mirid bug, Apolygus lucorum (Heteroptera: Miridae). AB - In herbivorous insects, host plant switching is commonly observed and plays an important role in their annual life cycle. However, much remains to be learned about seasonal host switching of various pestiferous arthropods under natural conditions. From 2006 until 2012, we assessed Apolygus lucorum (Meyer-Dur) host plant use in successive spring, summer and winter seasons at one single location (Langfang, China). Data were used to quantify changes in host plant breadth and host fidelity between seasons. Host fidelity of A. lucorum differed between seasons, with 87.9% of spring hosts also used in the summer and 36.1% of summer hosts used in winter. In contrast, as little as 25.6% host plant species were shared between winter and spring. Annual herbaceous plants are most often used for overwintering, while perennial woody plants are relatively important for initial population build-up in the spring. Our study contributes to an improved understanding of evolutionary interactions between A. lucorum and its host plants and lays the groundwork for the design of population management strategies for this important pest in myriad crops. PMID- 25692970 TI - ISCOMATRIXTM adjuvant reduces mucosal tolerance for effective pulmonary vaccination against influenza. AB - While most pathogens infect via mucosal surfaces, most current vaccines are delivered by injection. This situation remains despite awareness of the potential benefits of mucosal delivery for inducing protection against mucosa-infecting pathogens. A major obstacle to the development of such vaccines is the paucity of safe and effective adjuvants that induce mucosal responses in non-rodents. Previously we demonstrated in sheep the potency of pulmonary-delivered influenza ISCOMATRIXTM vaccine, which induces both mucosal and systemic immunity, even with low antigen doses. In the current study, lung pre-exposure to influenza antigen alone significantly reduced the immune response to subsequent pulmonary-delivered influenza ISCOMATRIXTM vaccine. A single dose of influenza antigen, delivered to the lung without exogenous adjuvant, upregulated IL-10 expression in bronchoalveolar lavage cells and FOXP3 expression in lung tissue, suggestive of induction of a regulatory T cell (Treg) response. However, this effect was inhibited by addition of ISCOMATRIXTM adjuvant. Moreover, effective pulmonary immunization with influenza ISCOMATRIXTM vaccine was associated with a depletion of Treg markers within lung tissues. Lung exposure to influenza antigen induced a localized mucosal tolerance that reduced the efficacy of subsequent influenza ISCOMATRIXTM vaccination. An important role of ISCOMATRIXTM adjuvant in pulmonary vaccination appears to be the depletion of Treg in lung tissues. Pulmonary vaccination remains capable of inducing a strong immune response against mucosal pathogens, but likely requires an adjuvant to overcome mucosal tolerance. ISCOMATRIXTM appears to have considerable potential as a mucosal adjuvant for use in humans, a major unmet need in mucosal vaccine development. PMID- 25692971 TI - Nest etiquette--where ants go when nature calls. AB - Sanitary behaviour is an important, but seldom studied, aspect of social living. Social insects have developed several strategies for dealing with waste and faecal matter, including dumping waste outside the nest and forming specialised waste-storage chambers. In some cases waste material and faeces are put to use, either as a construction material or as a long-lasting signal, suggesting that faeces and waste may not always be dangerous. Here we examine a previously undescribed behaviour in ants - the formation of well-defined faecal patches. Lasius niger ants were housed in plaster nests and provided with coloured sucrose solution. After two months, 1-4 well defined dark patches, the colour of the sucrose solution, formed within each of the plaster nests. These patches never contained other waste material such as uneaten food items, or nestmate corpses. Such waste was collected in waste piles outside the nest. The coloured patches were thus distinct from previously described 'kitchen middens' in ants, and are best described as 'toilets'. Why faeces is not removed with other waste materials is unclear. The presence of the toilets inside the nest suggests that they may not be an important source of pathogens, and may have a beneficial role. PMID- 25692972 TI - Molecular assessment of mating strategies in a population of Atlantic spotted dolphins. AB - Similar to other small cetacean species, Atlantic spotted dolphins (Stenella frontalis) have been the object of concentrated behavioral study. Although mating and courtship behaviors occur often and the social structure of the population is well-studied, the genetic mating system of the species is unknown. To assess the genetic mating system, we genotyped females and their progeny at ten microsatellite loci. Genotype analysis provided estimates of the minimum number of male sires necessary to account for the allelic diversity observed among the progeny. Using the estimates of male sires, we determined whether females mated with the same or different males during independent estrus events. Using Gerud2.0, a minimum of two males was necessary to account for the genetic variation seen among progeny arrays of all tested females. ML-Relate assigned the most likely relationship between offspring pairs; half or full sibling. Relationship analysis supported the conservative male estimates of Gerud2.0 but in some cases, half or full sibling relationships between offspring could not be fully resolved. Integrating the results from Gerud2.0, ML-Relate with previous observational and paternity data, we constructed two-, three-, and four-male pedigree models for each genotyped female. Because increased genetic diversity of offspring may explain multi-male mating, we assessed the internal genetic relatedness of each offspring's genotype to determine whether parent pairs of offspring were closely related. We found varying levels of internal relatedness ranging from unrelated to closely related (range -0.136-0.321). Because there are several hypothesized explanations for multi-male mating, we assessed our data to determine the most plausible explanation for multi-male mating in our study system. Our study indicated females may benefit from mating with multiple males by passing genes for long-term viability to their young. PMID- 25692973 TI - The association between serum dehydroepiandrosterone Sulphate (DHEA-S) level and bone mineral density in Korean men. AB - CONTEXT: Many lines of evidence indicate that dehydroepiandrosterone (DHEA) plays a distinct role in bone metabolism and that its sulphated form (DHEA-S), which is easily measured in blood, may be a potential biomarker of osteoporosis-related phenotypes. However, most previous epidemiologic studies focused on postmenopausal women and reported conflicting results. OBJECTIVE: We aimed to investigate the association between the serum DHEA-S level and bone mass in men. DESIGN AND METHODS: This large cross-sectional study included 1089 healthy Korean men who participated in a routine health screening examination. Bone mineral density (BMD) at the lumbar spine, total femur, femur neck, and trochanter and serum DHEA-S level were obtained in all subjects. RESULTS: After adjustment for age, body mass index, lifestyle factors and serum levels of calcium, phosphorus, testosterone, 25-OH-vitamin D3 and cortisol, higher serum DHEA-S concentrations were associated with higher BMD values at all skeletal sites. Consistently, compared to the subjects in the highest DHEA-S quartile (Q4), those in the lowest DHEA-S quartile (Q1) showed significantly lower BMD values. Multiple logistic regression analyses revealed that the odds ratios for the risk of lower BMD (T score <-1) increased in a dose-dependent manner across decreasing DHEA-S quartiles and the odds for the risk of lower BMD were 2.59-fold higher in Q1 than in Q4. CONCLUSION: These findings support previous evidences that DHEA-S has favourable effects on bone mass in men and suggest that a low serum DHEA-S level may be a potential risk factor for male osteoporosis. PMID- 25692974 TI - Inactivated human rotavirus vaccine induces heterotypic antibody response: correction and development of IgG avidity assay. AB - To improve lower efficacy among infants in low income countries and the safety (e.g., rare but severe intussusception) of live oral rotavirus vaccines, we have developed CDC-9 strain with G1P[8] specificity as a candidate inactivated rotavirus vaccine (IRV). This IRV of 3 doses elicits high titers of IgG, neutralizing activity to homotypic and heterotypic human strains and IgG avidity in guinea pigs, thus is a promising alternative to enhance global immunization against rotavirus in children. PMID- 25692975 TI - Defined TLR3-specific adjuvant that induces NK and CTL activation without significant cytokine production in vivo. AB - Ligand stimulation of the Toll-like receptors (TLRs) triggers innate immune response, cytokine production and cellular immune activation in dendritic cells. However, most TLR ligands are microbial constituents, which cause inflammation and toxicity. Toxic response could be reduced for secure immunotherapy through the use of chemically synthesized ligands with defined functions. Here we create an RNA ligand for TLR3 with no ability to activate the RIG-I/MDA5 pathway. This TLR3 ligand is a chimeric molecule consisting of phosphorothioate ODN-guided dsRNA (sODN-dsRNA), which elicits far less cytokine production than poly(I:C) in vitro and in vivo. The activation of TLR3/TICAM-1 pathway by sODN-dsRNA effectively induces natural killer and cytotoxic T cells in tumour-loaded mice, thereby establishing antitumour immunity. Systemic cytokinemia does not occur following subcutaneous or even intraperitoneal administration of sODN-dsRNA, indicating that TICAM-1 signalling with minute local cytokines sufficiently activate dendritic cells to prime tumoricidal effectors in vivo. PMID- 25692976 TI - Modulation of Huh7.5 spheroid formation and functionality using modified PEG based hydrogels of different stiffness. AB - Physical cues, such as cell microenvironment stiffness, are known to be important factors in modulating cellular behaviors such as differentiation, viability, and proliferation. Apart from being able to trigger these effects, mechanical stiffness tuning is a very convenient approach that could be implemented readily into smart scaffold designs. In this study, fibrinogen-modified poly(ethylene glycol)-diacrylate (PEG-DA) based hydrogels with tunable mechanical properties were synthesized and applied to control the spheroid formation and liver-like function of encapsulated Huh7.5 cells in an engineered, three-dimensional liver tissue model. By controlling hydrogel stiffness (0.1-6 kPa) as a cue for mechanotransduction representing different stiffness of a normal liver and a diseased cirrhotic liver, spheroids ranging from 50 to 200 MUm were formed over a three week time-span. Hydrogels with better compliance (i.e. lower stiffness) promoted formation of larger spheroids. The highest rates of cell proliferation, albumin secretion, and CYP450 expression were all observed for spheroids in less stiff hydrogels like a normal liver in a healthy state. We also identified that the hydrogel modification by incorporation of PEGylated-fibrinogen within the hydrogel matrix enhanced cell survival and functionality possibly owing to more binding of autocrine fibronectin. Taken together, our findings establish guidelines to control the formation of Huh7.5 cell spheroids in modified PEGDA based hydrogels. These spheroids may serve as models for applications such as screening of pharmacological drug candidates. PMID- 25692977 TI - Functional compartmentalization of the human superficial masseter muscle. AB - Some muscles have demonstrated a differential recruitment of their motor units in relation to their location and the nature of the motor task performed; this involves functional compartmentalization. There is little evidence that demonstrates the presence of a compartmentalization of the superficial masseter muscle during biting. The aim of this study was to describe the topographic distribution of the activity of the superficial masseter (SM) muscle's motor units using high-density surface electromyography (EMGs) at different bite force levels. Twenty healthy natural dentate participants (men: 4; women: 16; age 20+/ 2 years; mass: 60+/-12 kg, height: 163+/-7 cm) were selected from 316 volunteers and included in this study. Using a gnathodynamometer, bites from 20 to 100% maximum voluntary bite force (MVBF) were randomly requested. Using a two dimensional grid (four columns, six electrodes) located on the dominant SM, EMGs in the anterior, middle-anterior, middle-posterior and posterior portions were simultaneously recorded. In bite ranges from 20 to 60% MVBF, the EMG activity was higher in the anterior than in the posterior portion (p-value = 0.001).The center of mass of the EMG activity was displaced towards the posterior part when bite force increased (p-value = 0.001). The topographic distribution of EMGs was more homogeneous at high levels of MVBF (p-value = 0.001). The results of this study show that the superficial masseter is organized into three functional compartments: an anterior, a middle and a posterior compartment. However, this compartmentalization is only seen at low levels of bite force (20-60% MVBF). PMID- 25692978 TI - Utilisation of intensive foraging zones by female Australian fur seals. AB - Within a heterogeneous environment, animals must efficiently locate and utilise foraging patches. One way animals can achieve this is by increasing residency times in areas where foraging success is highest (area-restricted search). For air-breathing diving predators, increased patch residency times can be achieved by altering both surface movements and diving patterns. The current study aimed to spatially identify the areas where female Australian fur seals allocated the most foraging effort, while simultaneously determining the behavioural changes that occur when they increase their foraging intensity. To achieve this, foraging behaviour was successfully recorded with a FastLoc GPS logger and dive behaviour recorder from 29 individual females provisioning pups. Females travelled an average of 118 +/- 50 km from their colony during foraging trips that lasted 7.3 +/- 3.4 days. Comparison of two methods for calculating foraging intensity (first passage time and first-passage time modified to include diving behaviour) determined that, due to extended surface intervals where individuals did not travel, inclusion of diving behaviour into foraging analyses was important for this species. Foraging intensity 'hot spots' were found to exist in a mosaic of patches within the Bass Basin, primarily to the south-west of the colony. However, the composition of benthic habitat being targeted remains unclear. When increasing their foraging intensity, individuals tended to perform dives around 148 s or greater, with descent/ascent rates of approximately 1.9 m*s-1 or greater and reduced postdive durations. This suggests individuals were maximising their time within the benthic foraging zone. Furthermore, individuals increased tortuosity and decreased travel speeds while at the surface to maximise their time within a foraging location. These results suggest Australian fur seals will modify both surface movements and diving behaviour to maximise their time within a foraging patch. PMID- 25692979 TI - Effect of season and high ambient temperature on activity levels and patterns of grizzly bears (Ursus arctos). AB - Understanding factors that influence daily and annual activity patterns of a species provides insights to challenges facing individuals, particularly when climate shifts, and thus is important in conservation. Using GPS collars with dual-axis motion sensors that recorded the number of switches every 5 minutes we tested the hypotheses: 1. Grizzly bears (Ursus arctos) increase daily activity levels and active bout lengths when they forage on berries, the major high-energy food in this ecosystem, and 2. Grizzly bears become less active and more nocturnal when ambient temperature exceeds 20 degrees C. We found support for hypothesis 1 with both male and female bears being active from 0.7 to 2.8 h longer in the berry season than in other seasons. Our prediction under hypothesis 2 was not supported. When bears foraged on berries on a dry, open mountainside, there was no relationship between daily maximum temperature (which varied from 20.4 to 40.1 degrees C) and the total amount of time bears were active, and no difference in activity levels during day or night between warm (20.4-27.3 degrees C) and hot (27.9-40.1 degrees C) days. Our results highlight the strong influence that food acquisition has on activity levels and patterns of grizzly bears and is a challenge to the heat dissipation limitation theory. PMID- 25692980 TI - Yacon-Based Product in the Modulation of Intestinal Constipation. AB - This study aimed to assess the effects of a yacon-based product (YBP) on constipation in adults, including the elderly. Forty-eight individuals were recruited and divided into equal intervention groups named the test and control groups. The YBP (test) and the control (maltodextrin) were dissolved in commercial orange juice. The volunteers for the YBP/test group consumed, on a daily basis, orange juice containing 10 g fructooligosaccharide (FOS)/inulin per day. The control group consumed, on a daily basis, orange juice containing 25 g of maltodextrin. The study had a span of 30 days. We evaluated the participants' frequency of evacuation, consistency of the feces, constipation score, abdominal symptoms (flatulence, pain, and abdominal strain), and effects upon the microbiota, pH, lactate, and short-chain fatty acids (SCFAs) of the feces. The study showed an increased number of evacuations after the consumption of the YBP as well as an improvement in the consistency of the feces and a reduction in the constipation score. After 30 days of intervention, the group that consumed the YBP showed higher counts of Bifidobacterium, lower Clostridium and enterobacteria counts, and lower fecal pH. In relation to SCFAs, no significant change was found after the intervention. However, the lactate concentration was higher in the test group when compared to the post-treatment control group. The YBP was effective in improving constipation symptoms; not only was its functional characteristic in reducing constipation symptoms evident but it also demonstrated usefulness as a potential therapy. PMID- 25692981 TI - Isotope hydrology and baseflow geochemistry in natural and human-altered watersheds in the Inland Pacific Northwest, USA. AB - This study presents a stable isotope hydrology and geochemical analysis in the inland Pacific Northwest (PNW) of the USA. Isotope ratios were used to estimate mean transit times (MTTs) in natural and human-altered watersheds using the FLOWPC program. Isotope ratios in precipitation resulted in a regional meteoric water line of delta(2)H = 7.42.delta(18)O + 0.88 (n = 316; r(2) = 0.97). Isotope compositions exhibited a strong temperature-dependent seasonality. Despite this seasonal variation, the stream delta(18)O variation was small. A significant regression (tau = 0.11D(-1.09); r(2) = 0.83) between baseflow MTTs and the damping ratio was found. Baseflow MTTs ranged from 0.4 to 0.6 years (human altered), 0.7 to 1.7 years (mining-altered), and 0.7 to 3.2 years (forested). Greater MTTs were represented by more homogenous aqueous chemistry whereas smaller MTTs resulted in more dynamic compositions. The isotope and geochemical data presented provide a baseline for future hydrological modelling in the inland PNW. PMID- 25692982 TI - Functional and molecular evidence for Kv7 channel subtypes in human detrusor from patients with and without bladder outflow obstruction. AB - The aim of the study was to investigate whether Kv7 channels and their ancillary beta-subunits, KCNE, are functionally expressed in the human urinary bladder. Kv7 channels were examined at the molecular level and by functional studies using RT qPCR and myography, respectively. We found mRNA expression of KCNQ1, KCNQ3-KCNQ5 and KCNE1-5 in the human urinary bladder from patients with normal bladder function (n = 7) and in patients with bladder outflow obstruction (n = 3). Interestingly, a 3.4-fold up-regulation of KCNQ1 was observed in the latter. The Kv7 channel subtype selective modulators, ML277 (activator of Kv7.1 channels, 10 MUM) and ML213 (activator of Kv7.2, Kv7.4, Kv7.4/7.5 and Kv7.5 channels, 10 MUM), reduced the tone of 1 MUM carbachol pre-constricted bladder strips. XE991 (blocker of Kv7.1-7.5 channels, 10 MUM) had opposing effects as it increased contractions achieved with 20 mM KPSS. Furthermore, we investigated if there is interplay between Kv7 channels and beta-adrenoceptors. Using cumulative additions of isoprenaline (beta-adrenoceptor agonist) and forskolin (adenylyl cyclase activator) in combination with the Kv7 channel activator and blocker, retigabine and XE991, we did not find interplay between Kv7 channels and beta-adrenoceptors in the human urinary bladder. The performed gene expression analysis combined with the organ bath studies imply that compounds that activate Kv7 channels could be useful for treatment of overactive bladder syndrome. PMID- 25692983 TI - Diverse virulent pneumophages infect Streptococcus mitis. AB - Streptococcus mitis has emerged as one of the leading causes of bacterial endocarditis and is related to Streptococcus pneumoniae. Antibiotic resistance has also increased among strains of S. mitis and S. pneumoniae. Phages are being reinvestigated as alternatives to antibiotics for managing infections. In this study, the two virulent phages Cp-1 (Podoviridae) and Dp-1 (Siphoviridae), previously isolated from S. pneumoniae, were found to also infect S. mitis. Microbiological assays showed that both pneumophages could not only replicate in S. mitis but also produced more visible plaques on this host. However, the burst size and phage adsorption data were lower in S. mitis as compared to S. pneumoniae. A comparison of the genomes of each phage grown on both hosts produced identical nucleotide sequences, confirming that the same phages infect both bacterial species. We also discovered that the genomic sequence of podophage Cp-1 of the Felix d'Herelle collection is different than the previously reported sequence and thus renamed SOCP. PMID- 25692984 TI - MethylC-seq library preparation for base-resolution whole-genome bisulfite sequencing. AB - Current high-throughput DNA sequencing technologies enable acquisition of billions of data points through which myriad biological processes can be interrogated, including genetic variation, chromatin structure, gene expression patterns, small RNAs and protein-DNA interactions. Here we describe the MethylC sequencing (MethylC-seq) library preparation method, a 2-d protocol that enables the genome-wide identification of cytosine DNA methylation states at single-base resolution. The technique involves fragmentation of genomic DNA followed by adapter ligation, bisulfite conversion and limited amplification using adapter specific PCR primers in preparation for sequencing. To date, this protocol has been successfully applied to genomic DNA isolated from primary cell culture, sorted cells and fresh tissue from over a thousand plant and animal samples. PMID- 25692986 TI - Predictive and prognostic value of metabolic tumor volume (MTV) in patients with laryngeal carcinoma treated by radiotherapy (RT) / concurrent chemoradiotherapy (CCRT). AB - PURPOSE: To evaluate the predictive and prognostic value of pretreatment metabolic tumor volume (MTV) in patients with treated by radiotherapy (RT) or concurrent chemoradiotherapy (CCRT). METHODS: We reviewed the records of 118 patients with newly diagnosed laryngeal carcinoma, who had been treated by RT or CCRT. Pretreatment positron emission tomography (PET) was performed, and MTV values were obtained by contouring margins of standardized uptake value. Clinical factors and MTV were analyzed for their association with survival. RESULTS: Patients with residual disease showed a significantly higher MTV than those with a complete response (CR) after primary treatment. Univariate analysis showed that the patients with a high MTV had a significantly lower disease-free survival (DFS) (p < 0.001). Subsite (p = 0.010), T-stage (p < 0.001), nodal metastasis (p < 0.001) and clinical stage (p < 0.001) also correlated significantly with DFS. In the multivariate analysis, MTV and clinical stage were both found to be independent prognostic factors for DFS (p = 0.001, p = 0.034, respectively). The 3-year DFS for patients with a high MTV were significantly poorer than those with a low MTV (p < 0.001). CONCLUSIONS: MTV of the primary tumor is a significant prognostic factor for DFS in patients with laryngeal carcinoma treated by RT or CCRT. The results imply that MTV could be an important factor when planning treatment and follow-up for patients with laryngeal carcinoma. PMID- 25692985 TI - Supercooling preservation and transplantation of the rat liver. AB - The current standard for liver preservation involves cooling of the organ on ice (0-4 degrees C). Although it is successful for shorter durations, this method of preservation does not allow long-term storage of the liver. The gradual loss of hepatic viability during preservation puts pressure on organ sharing and allocation, may limit the use of suboptimal grafts and necessitates rushed transplantation to achieve desirable post-transplantation outcomes. In an attempt to improve and prolong liver viability during storage, alternative preservation methods are under investigation. For instance, ex vivo machine perfusion systems aim to sustain and even improve viability by supporting hepatic function at warm temperatures, rather than simply slowing down deterioration by cooling. Here we describe a novel subzero preservation technique that combines ex vivo machine perfusion with cryoprotectants to facilitate long-term supercooled preservation. The technique improves the preservation of rat livers to prolong storage times as much as threefold, which is validated by successful long-term recipient survival after orthotopic transplantation. This protocol describes how to load rat livers with cryoprotectants to prevent both intracellular and extracellular ice formation and to protect against hypothermic injury. Cryoprotectants are loaded ex vivo using subnormothermic machine perfusion (SNMP), after which livers can be cooled to -6 degrees C without freezing and kept viable for up to 96 h. Cooling to a supercooled state is controlled, followed by 3 h of SNMP recovery and orthotopic liver transplantation. PMID- 25692987 TI - Chimeric flap and free-style puzzle flap for extended coverage of the foot and ankle. PMID- 25692988 TI - Reply: The thin gluteal artery perforator free flap to resurface the posterior aspect of the leg and foot. PMID- 25692989 TI - Reply: High-dose-rate brachytherapy for the treatment of recalcitrant keloids: a unique effective treatment protocol. PMID- 25692990 TI - Explantation following nipple-sparing mastectomy: the Goldilocks approach to traditional breast reconstruction. PMID- 25692992 TI - Breast autoaugmentation: an enduring myth. PMID- 25692993 TI - Clinically significant fatigue: prevalence and associated factors in an international sample of adults with multiple sclerosis recruited via the internet. AB - BACKGROUND: Fatigue contributes a significant burden of disease for people with multiple sclerosis (PwMS). Modifiable lifestyle factors have been recognized as having a role in a range of morbidity outcomes in PwMS. There is significant potential to prevent and treat fatigue in PwMS by addressing modifiable risk factors. OBJECTIVES: To explore the associations between clinically significant fatigue and demographic factors, clinical factors (health-related quality of life, disability and relapse rate) and modifiable lifestyle, disease-modifying drugs (DMD) and supplement use in a large international sample of PwMS. METHODS: PwMS were recruited to the study via Web 2.0 platforms and completed a comprehensive survey measuring demographic, lifestyle and clinical characteristics, including health-related quality of life, disability, and relapse rate. RESULTS: Of 2469 participants with confirmed MS, 2138 (86.6%) completed a validated measure of clinically significant fatigue, the Fatigue Severity Scale. Participants were predominantly female from English speaking countries, with relatively high levels of education, and due to recruitment methods may have been highly pro-active about engaging in lifestyle management and self-help. Approximately two thirds of our sample (1402/2138; 65.6% (95% CI 63.7-67.7)) screened positive for clinically significant fatigue. Bivariate associations were present between clinically significant fatigue and several demographic, clinical, lifestyle, and medication variables. After controlling for level of disability and a range of stable socio-demographic variables, we found increased odds of fatigue associated with obesity, DMD use, poor diet, and reduced odds of fatigue with exercise, fish consumption, moderate alcohol use, and supplementation with vitamin D and flaxseed oil. CONCLUSION: This study supports strong and significant associations between clinically significant fatigue and modifiable lifestyle factors. Longitudinal follow-up of this sample may help clarify the contribution of reverse causation to our findings. Further research is required to explore these associations including randomized controlled trials of lifestyle interventions that may alleviate fatigue. PMID- 25692995 TI - Compressive straining of bilayer phosphorene leads to extraordinary electron mobility at a new conduction band edge. AB - By means of hybrid DFT calculations and the deformation potential approximation, we show that bilayer phosphorene under slight compression perpendicular to its surface exhibits extraordinary room temperature electron mobility of order 7 * 10(4) cm(2) V(-1) s(-1). This is approximately 2 orders of magnitude higher than is widely reported for ground state phosphorenes and is the result of the emergence of a new conduction band minimum that is decoupled from the in-plane acoustic phonons that dominate carrier scattering. PMID- 25692994 TI - Inhibition of the growth of Bacillus subtilis DSM10 by a newly discovered antibacterial protein from the soil metagenome. AB - A functional metagenomics based approach exploiting the microbiota of suppressive soils from an organic field site has succeeded in the identification of a clone with the ability to inhibit the growth of Bacillus subtilis DSM10. Sequencing of the fosmid identified a putative beta-lactamase-like gene abgT. Transposon mutagenesis of the abgT gene resulted in a loss in ability to inhibit the growth of B. subtilis DSM10. Further analysis of the deduced amino acid sequence of AbgT revealed moderate homology to esterases, suggesting that the protein may possess hydrolytic activity. Weak lipolytic activity was detected; however the clone did not appear to produce any beta-lactamase activity. Phylogenetic analysis revealed the protein is a member of the family VIII group of lipase/esterases and clusters with a number of proteins of metagenomic origin. The abgT gene was sub-cloned into a protein expression vector and when introduced into the abgT transposon mutant clones restored the ability of the clones to inhibit the growth of B. subtilis DSM10, clearly indicating that the abgT gene is involved in the antibacterial activity. While the precise role of this protein has yet to fully elucidated, it may be involved in the generation of free fatty acid with antibacterial properties. Thus functional metagenomic approaches continue to provide a significant resource for the discovery of novel functional proteins and it is clear that hydrolytic enzymes, such as AbgT, may be a potential source for the development of future antimicrobial therapies. PMID- 25692997 TI - Correction: In Silico Repositioning-Chemogenomics Strategy Identifies New Drugs with Potential Activity against Multiple Life Stages of Schistosoma mansoni. PMID- 25692996 TI - Resting-state temporal synchronization networks emerge from connectivity topology and heterogeneity. AB - Spatial patterns of coherent activity across different brain areas have been identified during the resting-state fluctuations of the brain. However, recent studies indicate that resting-state activity is not stationary, but shows complex temporal dynamics. We were interested in the spatiotemporal dynamics of the phase interactions among resting-state fMRI BOLD signals from human subjects. We found that the global phase synchrony of the BOLD signals evolves on a characteristic ultra-slow (<0.01Hz) time scale, and that its temporal variations reflect the transient formation and dissolution of multiple communities of synchronized brain regions. Synchronized communities reoccurred intermittently in time and across scanning sessions. We found that the synchronization communities relate to previously defined functional networks known to be engaged in sensory-motor or cognitive function, called resting-state networks (RSNs), including the default mode network, the somato-motor network, the visual network, the auditory network, the cognitive control networks, the self-referential network, and combinations of these and other RSNs. We studied the mechanism originating the observed spatiotemporal synchronization dynamics by using a network model of phase oscillators connected through the brain's anatomical connectivity estimated using diffusion imaging human data. The model consistently approximates the temporal and spatial synchronization patterns of the empirical data, and reveals that multiple clusters that transiently synchronize and desynchronize emerge from the complex topology of anatomical connections, provided that oscillators are heterogeneous. PMID- 25692998 TI - Change IS Possible: Reducing High-Risk Drinking Using a Collaborative Improvement Model. AB - OBJECTIVE: To describe the adoption of public health and improvement methodologies to address college students' high-risk drinking behaviors and to aid in prevention efforts. PARTICIPANTS: Members of 32 colleges and universities, content experts, and staff members of the National College Health Improvement Program (NCHIP). METHODS: A 2-year learning collaborative developed by NCHIP trained individuals from 32 different college and universities in using the Plan Do-Study-Act cycle as a method to create and implement initiatives aimed at reducing students' high-risk drinking behaviors and related harms. RESULTS: Participants experienced success ranging from noteworthy increases in type and amount of interventions directed at reducing high-risk drinking, to creating collaboratives across campus, the local community, and stakeholders. Challenges related to data collection and creating lasting cultural change remain. CONCLUSIONS: The use of quality improvement methodologies and creation of a national collaborative successfully effected meaningful change in high-risk drinking behaviors on college campuses. PMID- 25693000 TI - Food consumption and risk of childhood asthma. AB - BACKGROUND: The consumption of foods rich in n-3 polyunsaturated fatty acids has been proposed to protect against childhood asthma. This study explores the association of food consumption (including cow's milk (CM)-free diet) in early life and the risk of atopic and non-atopic asthma. METHODS: Food intake of 182 children with asthma and 728 matched controls was measured using 3-day food records, within the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) Nutrition Study cohort. The diagnoses of food allergies came both from the written questionnaire and from the registers of the Social Insurance Institution. Conditional logistic regression with generalized estimating equations framework was used in the analyses. RESULTS: The diagnosis of cow's milk allergy (CMA) led to multiple dietary restrictions still evident at 4 yr of age. Even after adjusting for CMA, higher consumption of CM products was inversely associated with the risk of atopic asthma and higher consumption of breast milk and oats inversely with the risk of non-atopic asthma. Early consumption of fish was associated with a decreased risk of all asthma. CONCLUSIONS: Dietary intake in early life combined with atopy history has a clear impact on the risk of developing asthma. Our results indicate that CM restriction due to CMA significantly increases and mediates the association between food consumption and childhood asthma risk. PMID- 25692999 TI - Modify or die?--RNA modification defects in metazoans. AB - Chemical RNA modifications are present in all kingdoms of life and many of these post-transcriptional modifications are conserved throughout evolution. However, most of the research has been performed on single cell organisms, whereas little is known about how RNA modifications contribute to the development of metazoans. In recent years, the identification of RNA modification genes in genome wide association studies (GWAS) has sparked new interest in previously neglected genes. In this review, we summarize recent findings that connect RNA modification defects and phenotypes in higher eukaryotes. Furthermore, we discuss the implications of aberrant tRNA modification in various human diseases including metabolic defects, mitochondrial dysfunctions, neurological disorders, and cancer. As the molecular mechanisms of these diseases are being elucidated, we will gain first insights into the functions of RNA modifications in higher eukaryotes and finally understand their roles during development. PMID- 25693001 TI - Influenza-Induced Priming and Leak of Human Lung Microvascular Endothelium upon Exposure to Staphylococcus aureus. AB - A major cause of death after influenza virus infection is lung injury due to a bacterial superinfection, yet the mechanism is unknown. Death has been attributed to virus-induced immunosuppression and bacterial overgrowth, but this hypothesis is based on data from the preantibiotic era and animal models that omit antimicrobial therapy. Because of diagnostic uncertainty, most patients with influenza receive antibiotics, making bacterial overgrowth unlikely. Respiratory failure after superinfection presents as acute respiratory distress syndrome, a disorder characterized by lung microvascular leak and edema. The objective of this study was to determine whether the influenza virus sensitizes the lung endothelium to leak upon exposure to circulating bacterial-derived molecular patterns from Staphylococcus aureus. In vitro as well as in vivo models of influenza followed by S. aureus superinfection were used. Molecular mechanisms were explored using molecular biology, knockout mice, and human autopsy specimens. Influenza virus infection sensitized human lung endothelium to leak when challenged with S. aureus, even at low doses of influenza and even when the pathogens were given days apart. Influenza virus increased endothelial expression of TNFR1 both in vitro and in intact lungs, a finding corroborated by human autopsy specimens of patients with influenza. Leak was recapitulated with protein A, a TNFR1 ligand, and sequential infection caused protein A-dependent loss of IkappaB, cleavage of caspases 8 and 3, and lung endothelial apoptosis. Mice infected sequentially with influenza virus and S. aureus developed significantly increased lung edema that was protein A and TNFR1 dependent. Influenza virus primes the lung endothelium to leak, predisposing patients to acute respiratory distress syndrome upon exposure to S. aureus. PMID- 25693002 TI - Transitioning through college with diabetes: themes found in online forums. AB - OBJECTIVE: Content analysis of Internet-based diabetes forum text was used to examine the experiences encountered by students with diabetes transitioning into and through college. PARTICIPANTS: Forum posts (N = 238) regarding attending college with diabetes were collected and analyzed. METHODS: Thematic coding was used to identify prominent topics, followed by analysis of theme distribution across college transitional stages. Three students with diabetes were recruited to review results and corroborate findings. RESULTS: Twenty thematic categories were identified. Preparation for college involved efforts to move toward autonomous diabetes management. Transitioning in was marked by adjusting to a college lifestyle, then working to manage issues such as busy schedules and alcohol use as continuing students, and turning attention toward future career options and finances while transitioning out. CONCLUSIONS: As they move into and through college, students with diabetes negotiate developmental and diabetes specific tasks within an environment that presents unique logistical, lifestyle, and psychological challenges. PMID- 25693003 TI - Achieving high dielectric constant and low loss property in a dipolar glass polymer containing strongly dipolar and small-sized sulfone groups. AB - In this report, a dipolar glass polymer, poly(2-(methylsulfonyl)ethyl methacrylate) (PMSEMA), was synthesized by free radical polymerization of the corresponding methacrylate monomer. Due to the large dipole moment (4.25 D) and small size of the side-chain sulfone groups, PMSEMA exhibited a strong gamma transition at a temperature as low as -110 degrees C at 1 Hz, about 220 degrees C below its glass transition temperature around 109 degrees C. Because of this strong gamma dipole relaxation, the glassy PMSEMA sample exhibited a high dielectric constant of 11.4 and a low dissipation factor (tan delta) of 0.02 at 25 degrees C and 1 Hz. From an electric displacement-electric field (D-E) loop study, PMSEMA demonstrated a high discharge energy density of 4.54 J/cm(3) at 283 MV/m, nearly 3 times that of an analogue polymer, poly(methyl methacrylate) (PMMA). However, the hysteresis loss was only 1/3-1/2 of that for PMMA. This study suggests that dipolar glass polymers with large dipole moments and small sized dipolar side groups are promising candidates for high energy density and low loss dielectric applications. PMID- 25693004 TI - A randomized, double blind, placebo-controlled, multicenter phase II trial of Allisartan Isoproxil in essential hypertensive population at low-medium risk. AB - BACKGROUND: Angiotensin II receptor blockers (ARBs) is a well-tolerated class of antihypertensive agents, exhibiting effective antihypertensive and cardiovascular protective function. The objective of the study was to examine the efficacy and safety of Allisartan Isoproxil, a newly developed, selective, nonpeptide blocker of the angiotensin II type 1 receptor (AT1R), in essential hypertensive patients at low-medium risk. METHODS AND FINDINGS: A Phase II prospective, randomized, double-blind, placebo-controlled, multicenter trial comparing Allisartan Isoproxil 240mg versus placebo was conducted in essential hypertensive patients at low-medium risk at 8 sites in China. After a 2-week placebo baseline period, 275 patients received once-daily treatment with Allisartan Isoproxil 240mg or placebo randomly for 8 weeks. Systolic/diastolic blood pressure (SBP/DBP) was measured at week 2, 4 and 8. By the end of treatment, mean reductions from baseline of SBP and DBP in Allisartan Isoproxil and placebo groups were 14.5/10.4 and 8.3/7.7 mmHg, respectively (P<0.01). The rate of effective blood pressure control in Allisartan Isoproxil group was significantly higher than in placebo group at week 4 (61.3% vs 50.0%, P<0.05) and week 8 (67.2% vs 48.6%, P<0.01). In terms of safety and tolerability, there were no report of death and serious adverse event (SAE) in all subjects. There was no difference of frequency between two groups in adverse event (AE) and adverse drug reaction (ADR) (P>0.05). No one withdraw because of an ADR in two groups. 124 patients received additional 56 weeks treatment with Allisartan Isoproxil and 84 of them completed the study. The rate of effective BP control kept up to 80% since week 24. No significant clinical change was observed and ADRs were generally mild or moderate during the long-term study. CONCLUSIONS/SIGNIFICANCE: Allisartan Isoproxil 240mg was effective and safe for essential hypertension patients at low-medium risk. TRIAL REGISTRATION: http://www.chictr.org/cn/ ChiCTR-TRC-10000886. PMID- 25693005 TI - Gallbladder cancer in Chile: what have we learned? AB - PURPOSE OF REVIEW: Gallbladder cancer (GBC) should be considered an orphan disease in oncology and represent a unique carcinogenetic model. This review will analyse some of the current aspects of GBC. RECENT FINDINGS: Chile has the highest incidence and mortality of GBC in the world. Most patients are diagnosed in advanced stages with few treatment options. During the last two decades, little progress has been made in early diagnosis and treatment. At the molecular level, recent access to next-generation sequencing and other techniques for detecting the mutations of multiple genes have made advances in this area. SUMMARY: The use of therapies targeted according to the detection of specific molecular alterations is in the early stages of evaluation and could represent a significant advance in the treatment of a large number of patients from developing countries. PMID- 25693006 TI - Genetics of Opisthorchis viverrini-related cholangiocarcinoma. AB - PURPOSE OF REVIEW: We review the genetic, epigenetic and transcriptional landscape of liver fluke (Opisthorchis viverrini, Ov)-related cholangiocarcinoma (CCA). Its distinct alterations, as compared with non-Ov-related CCA may help shed light on its underlying molecular mechanisms. RECENT FINDINGS: Recent whole exome and targeted sequencing not only confirmed frequent mutations in known CCA related genes including TP53 (44%), KRAS (16.7%) and SMAD4 (16.7%), but also revealed mutations in novel CCA-related genes associated with chromatin remodeling [BAP1 (2.8%), ARID1A (17.6%), MLL3 (13%) and IDH1/2 (2.8%)], WNT signaling [RNF43 (9.3%) and PEG3 (5.6%)] and KRAS/G protein signaling [GNAS (9.3%) and ROBO2 (9.3%)]. Interestingly, there is a significant difference in the frequency of mutated genes between Ov-related CCA and non-Ov-related CCA, such as p53 and IDH1/2, reflecting the impact of cause on pathogenesis. Altered DNA methylation and transcriptional profiles associated with xenobiotic metabolism and pro-inflammatory responses were also found in Ov-related CCA. SUMMARY: Liver fluke-induced chronic inflammation plays a crucial role in cholangiocarcinogenesis, resulting in distinct signatures of genetic, epigenetic and transcriptional alterations. These alterations, when contrasted with non-Ov related CCA, indicate a unique pathogenic process in Ov-related CCA and may have potential clinical implications on diagnostics, therapeutics and prevention. PMID- 25693007 TI - Yaws eradication--a goal finally within reach. PMID- 25693008 TI - Healthcare.gov 3.0--behavioral economics and insurance exchanges. PMID- 25693009 TI - Patients in context--EHR capture of social and behavioral determinants of health. PMID- 25693010 TI - Mass treatment with single-dose azithromycin for yaws. AB - BACKGROUND: Mass treatment with azithromycin is a central component of the new World Health Organization (WHO) strategy to eradicate yaws. Empirical data on the effectiveness of the strategy are required as a prerequisite for worldwide implementation of the plan. METHODS: We performed repeated clinical surveys for active yaws, serologic surveys for latent yaws, and molecular analyses to determine the cause of skin ulcers and identify macrolide-resistant mutations before and 6 and 12 months after mass treatment with azithromycin on a Papua New Guinean island on which yaws was endemic. Primary-outcome indicators were the prevalence of serologically confirmed active infectious yaws in the entire population and the prevalence of latent yaws with high-titer seroreactivity in a subgroup of children 1 to 15 years of age. RESULTS: At baseline, 13,302 of 16,092 residents (82.7%) received one oral dose of azithromycin. The prevalence of active infectious yaws was reduced from 2.4% before mass treatment to 0.3% at 12 months (difference, 2.1 percentage points; P<0.001). The prevalence of high-titer latent yaws among children was reduced from 18.3% to 6.5% (difference, 11.8 percentage points; P<0.001) with a near-absence of high-titer seroreactivity in children 1 to 5 years of age. Adverse events identified within 1 week after administration of the medication occurred in approximately 17% of the participants, included nausea, diarrhea, and vomiting, and were mild in severity. No evidence of emergence of resistance to macrolides against Treponema pallidum subspecies pertenue was seen. CONCLUSIONS: The prevalence of active and latent yaws infection fell rapidly and substantially 12 months after high-coverage mass treatment with azithromycin, with the reduction perhaps aided by subsequent activities to identify and treat new cases of yaws. Our results support the WHO strategy for the eradication of yaws. (Funded by Newcrest Mining and International SOS; YESA-13 ClinicalTrials.gov number, NCT01955252.). PMID- 25693011 TI - A 9-valent HPV vaccine against infection and intraepithelial neoplasia in women. AB - BACKGROUND: The investigational 9-valent viruslike particle vaccine against human papillomavirus (HPV) includes the HPV types in the quadrivalent HPV (qHPV) vaccine (6, 11, 16, and 18) and five additional oncogenic types (31, 33, 45, 52, and 58). Here we present the results of a study of the efficacy and immunogenicity of the 9vHPV vaccine in women 16 to 26 years of age. METHODS: We performed a randomized, international, double-blind, phase 2b-3 study of the 9vHPV vaccine in 14,215 women. Participants received the 9vHPV vaccine or the qHPV vaccine in a series of three intramuscular injections on day 1 and at months 2 and 6. Serum was collected for analysis of antibody responses. Swabs of labial, vulvar, perineal, perianal, endocervical, and ectocervical tissue were obtained and used for HPV DNA testing, and liquid-based cytologic testing (Papanicolaou testing) was performed regularly. Tissue obtained by means of biopsy or as part of definitive therapy (including a loop electrosurgical excision procedure and conization) was tested for HPV. RESULTS: The rate of high-grade cervical, vulvar, or vaginal disease irrespective of HPV type (i.e., disease caused by HPV types included in the 9vHPV vaccine and those not included) in the modified intention to-treat population (which included participants with and those without prevalent infection or disease) was 14.0 per 1000 person-years in both vaccine groups. The rate of high-grade cervical, vulvar, or vaginal disease related to HPV-31, 33, 45, 52, and 58 in a prespecified per-protocol efficacy population (susceptible population) was 0.1 per 1000 person-years in the 9vHPV group and 1.6 per 1000 person-years in the qHPV group (efficacy of the 9vHPV vaccine, 96.7%; 95% confidence interval, 80.9 to 99.8). Antibody responses to HPV-6, 11, 16, and 18 were noninferior to those generated by the qHPV vaccine. Adverse events related to injection site were more common in the 9vHPV group than in the qHPV group. CONCLUSIONS: The 9vHPV vaccine prevented infection and disease related to HPV-31, 33, 45, 52, and 58 in a susceptible population and generated an antibody response to HPV-6, 11, 16, and 18 that was noninferior to that generated by the qHPV vaccine. The 9vHPV vaccine did not prevent infection and disease related to HPV types beyond the nine types covered by the vaccine. (Funded by Merck; ClinicalTrials.gov number, NCT00543543). PMID- 25693013 TI - A randomized, controlled trial of oral propranolol in infantile hemangioma. AB - BACKGROUND: Oral propranolol has been used to treat complicated infantile hemangiomas, although data from randomized, controlled trials to inform its use are limited. METHODS: We performed a multicenter, randomized, double-blind, adaptive, phase 2-3 trial assessing the efficacy and safety of a pediatric specific oral propranolol solution in infants 1 to 5 months of age with proliferating infantile hemangioma requiring systemic therapy. Infants were randomly assigned to receive placebo or one of four propranolol regimens (1 or 3 mg of propranolol base per kilogram of body weight per day for 3 or 6 months). A preplanned interim analysis was conducted to identify the regimen to study for the final efficacy analysis. The primary end point was success (complete or nearly complete resolution of the target hemangioma) or failure of trial treatment at week 24, as assessed by independent, centralized, blinded evaluations of standardized photographs. RESULTS: Of 460 infants who underwent randomization, 456 received treatment. On the basis of an interim analysis of the first 188 patients who completed 24 weeks of trial treatment, the regimen of 3 mg of propranolol per kilogram per day for 6 months was selected for the final efficacy analysis. The frequency of successful treatment was higher with this regimen than with placebo (60% vs. 4%, P<0.001). A total of 88% of patients who received the selected propranolol regimen showed improvement by week 5, versus 5% of patients who received placebo. A total of 10% of patients in whom treatment with propranolol was successful required systemic retreatment during follow-up. Known adverse events associated with propranolol (hypoglycemia, hypotension, bradycardia, and bronchospasm) occurred infrequently, with no significant difference in frequency between the placebo group and the groups receiving propranolol. CONCLUSIONS: This trial showed that propranolol was effective at a dose of 3 mg per kilogram per day for 6 months in the treatment of infantile hemangioma. (Funded by Pierre Fabre Dermatologie; ClinicalTrials.gov number, NCT01056341.). PMID- 25693012 TI - Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. AB - BACKGROUND: In patients with metastatic breast cancer that is positive for human epidermal growth factor receptor 2 (HER2), progression-free survival was significantly improved after first-line therapy with pertuzumab, trastuzumab, and docetaxel, as compared with placebo, trastuzumab, and docetaxel. Overall survival was significantly improved with pertuzumab in an interim analysis without the median being reached. We report final prespecified overall survival results with a median follow-up of 50 months. METHODS: We randomly assigned patients with metastatic breast cancer who had not received previous chemotherapy or anti-HER2 therapy for their metastatic disease to receive the pertuzumab combination or the placebo combination. The secondary end points of overall survival, investigator assessed progression-free survival, independently assessed duration of response, and safety are reported. Sensitivity analyses were adjusted for patients who crossed over from placebo to pertuzumab after the interim analysis. RESULTS: The median overall survival was 56.5 months (95% confidence interval [CI], 49.3 to not reached) in the group receiving the pertuzumab combination, as compared with 40.8 months (95% CI, 35.8 to 48.3) in the group receiving the placebo combination (hazard ratio favoring the pertuzumab group, 0.68; 95% CI, 0.56 to 0.84; P<0.001), a difference of 15.7 months. This analysis was not adjusted for crossover to the pertuzumab group and is therefore conservative. Results of sensitivity analyses after adjustment for crossover were consistent. Median progression-free survival as assessed by investigators improved by 6.3 months in the pertuzumab group (hazard ratio, 0.68; 95% CI, 0.58 to 0.80). Pertuzumab extended the median duration of response by 7.7 months, as independently assessed. Most adverse events occurred during the administration of docetaxel in the two groups, with long-term cardiac safety maintained. CONCLUSIONS: In patients with HER2-positive metastatic breast cancer, the addition of pertuzumab to trastuzumab and docetaxel, as compared with the addition of placebo, significantly improved the median overall survival to 56.5 months and extended the results of previous analyses showing the efficacy of this drug combination. (Funded by F. Hoffmann-La Roche and Genentech; CLEOPATRA ClinicalTrials.gov number, NCT00567190.). PMID- 25693014 TI - Driving pressure and survival in the acute respiratory distress syndrome. AB - BACKGROUND: Mechanical-ventilation strategies that use lower end-inspiratory (plateau) airway pressures, lower tidal volumes (VT), and higher positive end expiratory pressures (PEEPs) can improve survival in patients with the acute respiratory distress syndrome (ARDS), but the relative importance of each of these components is uncertain. Because respiratory-system compliance (CRS) is strongly related to the volume of aerated remaining functional lung during disease (termed functional lung size), we hypothesized that driving pressure (DeltaP=VT/CRS), in which VT is intrinsically normalized to functional lung size (instead of predicted lung size in healthy persons), would be an index more strongly associated with survival than VT or PEEP in patients who are not actively breathing. METHODS: Using a statistical tool known as multilevel mediation analysis to analyze individual data from 3562 patients with ARDS enrolled in nine previously reported randomized trials, we examined DeltaP as an independent variable associated with survival. In the mediation analysis, we estimated the isolated effects of changes in DeltaP resulting from randomized ventilator settings while minimizing confounding due to the baseline severity of lung disease. RESULTS: Among ventilation variables, DeltaP was most strongly associated with survival. A 1-SD increment in DeltaP (approximately 7 cm of water) was associated with increased mortality (relative risk, 1.41; 95% confidence interval [CI], 1.31 to 1.51; P<0.001), even in patients receiving "protective" plateau pressures and VT (relative risk, 1.36; 95% CI, 1.17 to 1.58; P<0.001). Individual changes in VT or PEEP after randomization were not independently associated with survival; they were associated only if they were among the changes that led to reductions in DeltaP (mediation effects of DeltaP, P=0.004 and P=0.001, respectively). CONCLUSIONS: We found that DeltaP was the ventilation variable that best stratified risk. Decreases in DeltaP owing to changes in ventilator settings were strongly associated with increased survival. (Funded by Fundacao de Amparo e Pesquisa do Estado de Sao Paulo and others.). PMID- 25693015 TI - Clinical practice. Groin hernias in adults. PMID- 25693016 TI - Images in clinical medicine. Myxedema. PMID- 25693017 TI - Case records of the Massachusetts General Hospital. Case 6-2015. A 16-year-old boy with coughing spells. PMID- 25693018 TI - HPV "coverage". PMID- 25693019 TI - Driving pressure and respiratory mechanics in ARDS. PMID- 25693020 TI - A double-edged sword against type 1 diabetes. PMID- 25693021 TI - First-line crizotinib in ALK-positive lung cancer. PMID- 25693022 TI - First-line crizotinib in ALK-positive lung cancer. PMID- 25693023 TI - First-line crizotinib in ALK-positive lung cancer. PMID- 25693024 TI - Genetic basis for clinical response to CTLA-4 blockade. PMID- 25693025 TI - Genetic basis for clinical response to CTLA-4 blockade. PMID- 25693026 TI - Sensor technology in assessments of clinical skill. PMID- 25693027 TI - Conduct disorder and callous-unemotional traits in youth. PMID- 25693028 TI - Conduct disorder and callous-unemotional traits in youth. PMID- 25693029 TI - Viremic relapse after HIV-1 remission in a perinatally infected child. PMID- 25693030 TI - Videos in clinical medicine. Electrocardiographic monitoring in adults. PMID- 25693031 TI - Images in clinical medicine. Contagious ecthyma. PMID- 25693032 TI - Correction to "effective delivery of siRNA into cancer cells and tumors using well-defined biodegradable cationic star polymers". PMID- 25693033 TI - Joining time-resolved thermometry and magnetic-induced heating in a single nanoparticle unveils intriguing thermal properties. AB - Whereas efficient and sensitive nanoheaters and nanothermometers are demanding tools in modern bio- and nanomedicine, joining both features in a single nanoparticle still remains a real challenge, despite the recent progress achieved, most of it within the last year. Here we demonstrate a successful realization of this challenge. The heating is magnetically induced, the temperature readout is optical, and the ratiometric thermometric probes are dual emissive Eu(3+)/Tb(3+) lanthanide complexes. The low thermometer heat capacitance (0.021.K(-1)) and heater/thermometer resistance (1 K.W(-1)), the high temperature sensitivity (5.8%.K(-1) at 296 K) and uncertainty (0.5 K), the physiological working temperature range (295-315 K), the readout reproducibility (>99.5%), and the fast time response (0.250 s) make the heater/thermometer nanoplatform proposed here unique. Cells were incubated with the nanoparticles, and fluorescence microscopy permits the mapping of the intracellular local temperature using the pixel-by-pixel ratio of the Eu(3+)/Tb(3+) intensities. Time resolved thermometry under an ac magnetic field evidences the failure of using macroscopic thermal parameters to describe heat diffusion at the nanoscale. PMID- 25693034 TI - New stereoacuity test using a 3-dimensional display system in children. AB - The previously developed 3-dimensional (3D) display stereoacuity tests were validated only at distance. We developed a new stereoacuity test using a 3D display that works both at near and distance and evaluated its validity in children with and without strabismus. Sixty children (age range, 6 to 18 years) with variable ranges of stereoacuity were included. Side-by-side randot images of 4 different simple objects (star, circle, rectangle, and triangle) with a wide range of crossed horizontal disparities (3000 to 20 arcsec) were randomly displayed on a 3D monitor with MATLAB (Matworks, Inc., Natick, MA, USA) and were presented to subjects wearing shutter glasses at 0.5 m and 3 m. The 3D image was located in front of (conventional) or behind (proposed) the background image on the 3D monitor. The results with the new 3D stereotest (conventional and proposed) were compared with those of the near and distance Randot stereotests. At near, the Bland-Altman plots of the conventional and proposed 3D stereotest did not show significant difference, both of which were poorer than the Randot test. At distance, the results of the proposed 3D stereotest were similar to the Randot test, but the conventional 3D stereotest results were better than those of the other two tests. The results of the proposed 3D stereotest and Randot stereotest were identical in 83.3% at near and 88.3% at distance. More than 95% of subjects showed concordance within 2 grades between the 2 tests at both near and distance. In conclusion, the newly proposed 3D stereotest shows good concordance with the Randot stereotests in children with and without strabismus. PMID- 25693035 TI - Effects of visual fidelity on curve negotiation, gaze behaviour and simulator discomfort. AB - Technological developments have led to increased visual fidelity of driving simulators. However, simplified visuals have potential advantages, such as improved experimental control, reduced simulator discomfort and increased generalisability of results. In this driving simulator study, we evaluated the effects of visual fidelity on driving performance, gaze behaviour and subjective discomfort ratings. Twenty-four participants drove a track with 90 degrees corners in (1) a high fidelity, textured environment, (2) a medium fidelity, non textured environment without scenery objects and (3) a low-fidelity monochrome environment that only showed lane markers. The high fidelity level resulted in higher steering activity on straight road segments, higher driving speeds and higher gaze variance than the lower fidelity levels. No differences were found between the two lower fidelity levels. In conclusion, textures and objects were found to affect steering activity and driving performance; however, gaze behaviour during curve negotiation and self-reported simulator discomfort were unaffected. PRACTITIONER SUMMARY: In a driving simulator study, three levels of visual fidelity were evaluated. The results indicate that the highest fidelity level, characterised by a textured environment, resulted in higher steering activity, higher driving speeds and higher variance of horizontal gaze than the two lower fidelity levels without textures. PMID- 25693036 TI - Editorial: biomarkers of osteoarthritis (guest editor: guangju zhai). PMID- 25693037 TI - Outlines of the biochemistry of osteoarthritis. AB - Osteoarthritis (OA) is a complex, age dependent disease in which various factors, including metabolic changes, are all major contributors to its onset and progression. Anatomically, OA embraces the whole joint, i.e. articular cartilage, subchondral bone alterations and joint-lining synovial membrane. Correspondingly, OA development involves elaborate interactions of cartilaginous tissue metabolism and maintenance, osteogenesis, mineralization and inflammation of the synovial membrane. Identification of the molecular pathways and individual factors involved in OA etiology, understanding of mechanisms of their action and interaction are necessary conditions for developing the accurate diagnostic and prognostic tools and for providing OA patients effective treatment. There is a major progress in understanding of the molecular mechanisms of OA appearance and progression, which are pointing out to the network of biochemical factors important for normal functioning of the joints and changes leading to OA. The present review summarizes the data on the efficacy of the relevant biochemical factors affecting all the components of the joint and that could be therefore useful targets in treatment of OA. However, despite the dramatic growth of the knowledge concerning the biochemistry of OA and discovery of a number of useful biomarkers the real breakthrough in this area is still not achieved. PMID- 25693038 TI - Identification of early knee osteoarthritis - a new horizon. AB - Knee osteoarthritis (OA) is a common and significant cause of disability. Until recently, the major investigation to help establish a diagnosis of knee OA was the joint radiograph. This imaging modality offers only a two-dimensional image of a three-dimensional structure, and can only crudely identify major joint abnormalities at the later stage of disease. Moreover, joint radiographs cannot fully characterise subtle changes in intra and extraarticular structures, such as cartilage and bone marrow abnormalities that are now considered to be part of a whole-organ disease process. The recent advent of Magnetic Resonance Imaging (MRI) has enabled a three-dimensional assessment of the entire joint, thus providing new insights into the natural history of joint arthropathies. It is likely that morphological changes in articular structures caused by the OA process have their origins in the apparently healthy asymptomatic knee joint. MRI has therefore enabled the opportunity to better examine and understand pre clinical and very subtle early aberrations in joint morphology, prior to the onset of radiographic disease. This discussion seeks to explore knee OA as a disease entity that can be recognised before any radiographic change. This may pose new, yet exciting challenges for the identification and classification of disease, and provide a better understand of the pathogenesis of knee OA. PMID- 25693039 TI - Genetic markers of osteoarthritis. AB - Osteoarthritis (OA) is a chronic arthropathy, in which cartilage loss, osteophyte formation, and subchondral bone sclerosis lead to pain, disability, and a reduction in quality of life. OA is a multifactorial disease and OA cases are affected by both genetics and environment to varying degrees. Strong familial aggregation and heritabilities have been reported for OA at the hip, knee, hand and spine. Candidate gene studies and genome-wide linkage studies have identified genes in the bone morphogenetic pathway (e.g. GDF5), the thyroid regulation pathway (DIO2), apoptotic pathways as involved in genetic risk of large joint OA. Genome wide association studies have reported structural genes (COL6A4/DVWA), inflammation related genes (PTGS2/PLA2G4A) and a locus on chr 7q22 associated with knee OA and a gene involved transcriptional regulation (A2BP1) to be associated with hand OA. During the coming years, as additional genetic and functional studies further define the genetic architecture of OA and the underlying molecular mechanisms, additional targets for novel therapies and improved diagnostic and prognostic tests will be identified. PMID- 25693040 TI - Imaging biomarkers of spine osteoarthritis. AB - While there is an acknowledged need for biomarkers to progress arthritis research, imaging biomarkers for the spine have lagged behind those for peripheral joint osteoarthritis. Progress has been slow for a number of reasons. First and perhaps most importantly, there is currently no international agreement on definition of spine osteoarthritis (OA), either histologically or on imaging. Secondly, spine OA comprises two main pathologies, and debate continues as to whether they are separate entities or linked: degenerative disc disease and facet joint arthritis. Imaging those neighbouring joints is not straightforward and usually requires separate imaging investigations. Thirdly, it is only just becoming clear to what extent changes on imaging are associated with the main clinical problem - back pain. To compound the problem, the organisation of clinical services usually means that different specialties tend to focus on different anatomical areas, so a combined approach is not commonly adopted. Systematic evaluation of facet joints in epidemiological study is still in its infancy. Regardless of these hurdles, we have attempted in this review to summarise the state of play of imaging biomarkers in the spine with the emphasis on degenerative disc disease. MR imaging clearly leads the way and there exists a variety of specialist techniques such as T1rho and which may offer spine research imaging biomarkers in the future. PMID- 25693041 TI - Editorial [Hot Topic: Systemic Sclerosis: Recent Developments are Promising (Guest Editors: Lazaros I. Sakkas and Ian C. Chikanza)]. PMID- 25693042 TI - T-cells and B-cells in systemic sclerosis. AB - Systemic sclerosis (SSc) is characterized by activation of fibroblasts with extensive deposition of collagen, by small vessel vasculopathy with fibrointimal proliferation, and activation of the immune system, with hyper-gamma- globulinaemia and autoantibodies. Twin studies have shown that genetic factors play a minor role in SSc development. Serum autoantibodies and skin lymphocytic infiltrates and small vessel damage occur very early before the appearance of skin fibrosis. T cells can cause fibrosis and vasculopathy through cell-cell contact and cytokines. They produce TH2 cytokines (IL-4, IL13) and TH17 cytokines (IL-17), which are profibrotic. TH2 cells in experimental models also induce pulmonary arterial hypertension. Genetically engineered TGFbeta expression in pig arteries causes fibrointimal proliferation. T cells in skin lesions exhibit oligoclonality that persists over time, which indicates an antigen-driven T cell activation, but the antigen(s) responsible are not known. There are known environmental factors that can elicit an immune response and cause a SSc-like disease. T cells also provide help for B cells. B cells can contribute to fibrosis and vasculopathy through cytokines and autoantibodies. Autoantibodies can activate endothelial cells and fibroblasts to a profibrotic phenotype. Finally, treatments directed against T cells and B cells show promising effects in SSc. PMID- 25693043 TI - Role of growth factors in the pathogenesis of tissue fibrosis in systemic sclerosis. AB - The most severe clinical and pathologic manifestations of systemic sclerosis (SSc) are the result of a fibrotic process characterized by the excessive and often progressive deposition of collagen and other connective tissue macromolecules in skin and numerous internal organs. The mechanisms involved in the initiation and progression of the remarkable fibrotic process in SSc remain largely unknown. Extensive recent studies have indicated that a variety of polypeptide growth factors play a crucial role in this process. The most commonly implicated growth factors include transforming growth factor beta (TGF-beta), connective tissue growth factor (CTGF), platelet derived growth factor (PDGF), and vascular endothelial growth factor (VEGF). Here, the experimental evidence supporting the participation of various growth factors in the pathogenesis of the fibrotic process in SSc and the molecular mechanisms involved will be reviewed. PMID- 25693044 TI - Systemic sclerosis: clinical manifestations. AB - Systemic sclerosis (SSc) is a severe autoimmune disease that involves skin and internal organs. Clinical manifestations of SSc are very heterogeneous and derive from microvascular, inflammatory and fibrotic tissue changes. Besides the skin, lung, gastrointestinal tract, heart and kidneys are mainly affected. Over the last years, a progress in the treatment was made, especially in the field of renal involvement and pulmonary hypertension, but prognosis of the disease remains still bad. More efforts are needed to improve the management of organ impairment by early detection and prompt treatment, in order to prevent the development of severe complications. PMID- 25693045 TI - Promising anti-fibrotic approaches for future treatment of systemic sclerosis. AB - In the last years, several key-pathways for the aberrant activation of fibroblasts in SSc have been identified in pre-clinical studies. This review summarizes recently identified molecular targets for novel anti-fibrotic approaches in systemic sclerosis (SSc) and other fibrotic disorders. We will focus on pathways that can be targeted by drugs that are either already approved for other indications or that are currently evaluated in clinical trials. PMID- 25693046 TI - Growth assessment of hepatic venous malformations-reply. PMID- 25693047 TI - Natural products mediating ecological interactions in Antarctic benthic communities: a mini-review of the known molecules. AB - Out of the many bioactive compounds described from the oceans, only a small fraction have been studied for their ecological significance. Similarly, most chemically mediated interactions are not well understood, because the molecules involved remain unrevealed. In Antarctica, this gap in knowledge is even more acute in comparison to tropical or temperate regions, even though polar organisms are also prolific producers of chemical defenses, and pharmacologically relevant products are being reported from the Southern Ocean. The extreme and unique marine environments surrounding Antarctica along with the numerous unusual interactions taking place in benthic communities are expected to select for novel functional secondary metabolites. There is an urgent need to comprehend the evolutionary role of marine derived substances in general, and particularly at the Poles, since molecules of keystone significance are vital in species survival, and therefore, in structuring the communities. Here we provide a mini review on the identified marine natural products proven to have an ecological function in Antarctic ecosystems. This report recapitulates some of the bibliography from original Antarctic reviews, and updates the new literature in the field from 2009 to the present. PMID- 25693048 TI - Evaluation of eluents for the recovery of an enveloped virus from hands by whole hand sampling. AB - AIMS: The objective of this research is to evaluate eluents for recovery of an enveloped bacteriophage, Phi6, using whole-hand sampling. METHODS AND RESULTS: Virus was applied to the hands of volunteers and sampled by the glove juice method with 1.5% beef extract (BE), phosphate buffered saline (PBS), 0.01 and 0.1% Tween 80, tryptic soy broth (TSB) and 9% NaCl. Each volunteer underwent multiple rounds application and hand sampling. Mean log10 virus loss across trials was 2.6 for BE, 2.8 for PBS, 2.4 for TSB, 3.8 for NaCl, 3.0 for 0.1% Tween 80, and 2.9 for 0.01% Tween 80. Within each volunteer, there was a decline in viral loss from the first to last trial. CONCLUSIONS: These eluents can recover Phi6 from hands with approx. 2-3 log10 loss, comparable to recoveries previously reported for influenza. Protein and detergent-based eluents may have similar recoveries, but recovery may still vary across repeated sampling. SIGNIFICANCE AND IMPACT OF THE STUDY: Based on current work, protein-based eluents such as beef extract can maximize recovery of enveloped viruses during hand sampling, providing methods for evaluating survival and transmission of enveloped viruses on hands. Further exploration is needed of the effect of repeated sampling on recovery from whole-hand sampling. PMID- 25693049 TI - Theoretical investigations on Rh(III)-catalyzed cross-dehydrogenative aryl-aryl coupling via C-H bond activation. AB - The reaction mechanism of Rh(III)-catalyzed cross-dehydrogenative aryl-aryl coupling between benzamides and haloarenes was investigated through detailed density functional theoretical (DFT) studies in terms of regioselectivity and deuterium kinetic isotope effects (KIEs). Three possible routes including one PivO(-)-assisted reaction route and two non-PivO(-)-assisted reaction routes have been studied. The calculated results refute the proposed mechanism (without PivO( )-assisted process) in the experimental paper and demonstrate that the PivO(-) assisted reaction mechanism is the most favored. Meanwhile, the calculation revealed that the PivO(-) anion plays a crucial role as a proton acceptor in the C-H bond activation, especially when the second C-H activation of haloarenearene proceeds via a S(E)3 mechanism. The S(E)3 mechanism is presented for the Rh(III) catalyzed aryl-aryl reaction for the first time. Our mechanism is evaluated by the calculations of the para-/meta-regioselectivity and KIEs. And it is found that the second activation process is the rate-determining step of the whole catalytic cycle. All these calculated properties agree well with the experiment and Glorius's proposal that the Rh(III)-catalyzed cross-dehydrogenative C-C coupling reaction proceeds by dual C-H activations. Our theoretical studies suggest that the Rh(III) complex catalyst strongly affects the mechanisms of the second C-H activation step and thus this work might provide insight into the design of new catalytic systems. PMID- 25693050 TI - An augmented SMS intervention to improve access to antenatal CD4 testing and ART initiation in HIV-infected pregnant women: a cluster randomized trial. AB - BACKGROUND: Less than one-third of HIV-infected pregnant women eligible for combination antiretroviral therapy (ART) globally initiate treatment prior to delivery, with lack of access to timely CD4 results being a principal barrier. We evaluated the effectiveness of an SMS-based intervention to improve access to timely antenatal ART. METHODS: We conducted a stepped-wedge cluster randomized trial of a low-cost programmatic intervention in 20 antenatal clinics in Gaborone, Botswana. From July 2011-April 2012, 2 clinics were randomly selected every 4 weeks to receive an ongoing clinic-based educational intervention to improve CD4 collection and to receive CD4 results via an automated SMS platform with active patient tracing. CD4 testing before 26 weeks gestation and ART initiation before 30 weeks gestation were assessed. RESULTS: Three-hundred-sixty six ART-naive women were included, 189 registering for antenatal care under Intervention and 177 under Usual Care periods. Of CD4-eligible women, 100 (59.2%) women under Intervention and 79 (50.6%) women under Usual Care completed CD4 phlebotomy before 26 weeks gestation, adjusted odds ratio (aOR, adjusted for time that a clinic initiated Intervention) 0.87 (95% confidence interval [CI]0.47 1.63, P = 0.67). The SMS-based platform reduced time to clinic receipt of CD4 test result from median of 16 to 6 days (P<0.001), was appreciated by clinic staff, and was associated with reduced operational cost. However, rates of ART initiation remained low, with 56 (36.4%) women registering under Intervention versus 37 (24.2%) women under Usual Care initiating ART prior to 30 weeks gestation, aOR 1.06 (95%CI 0.53-2.13, P = 0.87). CONCLUSIONS: The augmented SMS based intervention delivered CD4 results more rapidly and efficiently, and this type of SMS-based results delivery platform may be useful for a variety of tests and settings. However, the intervention did not appear to improve access to timely antenatal CD4 testing or ART initiation, as obstacles other than CD4 impeded ART initiation during pregnancy. PMID- 25693051 TI - Location of the appendix at the third trimester of pregnancy: A new approach to old dilemma. AB - The aim of this study was to determine the location of the appendix at the third trimester of pregnancy as there are conflicting results in literature. Distances from the base of the appendix were measured intra-operatively to the anterior iliac spine (A), symphysis pubis (B) and the xyphoid process (C). The same measurements were taken from McBurney's point on the abdominal wall (A1, B1 and C1). In the allocated 21 pregnant and 18 non-pregnant women, distance A and B were 10.3 +/- 0.9 cm and 18.3 +/- 3.2 cm in pregnant and 6.7 +/- 0.9 cm and 13.2 +/- 0.9 cm in non-pregnant women (p < 0.001), respectively. Distance C was shorter in pregnant women (14.7 +/- 2.5 cm vs. 23.8 +/- 1.9, p < 0.001). Conversely, distance C1 was longer in pregnant women (30.3 +/- 3.0 vs. 24.8 +/- 5.1 cm, p = 0.004). This study provides evidence that the appendix moves cranially late in the course of the pregnancy. Therefore, McBurney's point cannot be used as a reference point to localise the appendix at the third trimester of pregnancy. PMID- 25693052 TI - Behavioural Difficulties That Co-occur With Specific Word Reading Difficulties: A UK Population-Based Cohort Study. AB - This study aimed to examine the association between specific word reading difficulties (SWRD) identified at age 7 years using a discrepancy approach and subsequent dimensional measures of behavioural difficulties reported by teachers and parents at age 11 years. Behavioural problems were assessed using the Strengths and Difficulties Questionnaire. Secondary analysis of a UK representative population-based sample of children (n = 12,631) was conducted using linear regression models. There were 284 children (2.2%) identified with SWRD at age 7 years. Children with SWRD had significantly higher scores on all measures of behavioural difficulties in unadjusted analysis. SWRD was associated with elevated behavioural difficulties at age 11 years according to parent report, and with greater emotional problems, hyperactivity and conduct issues according to teachers, even after having controlled for baseline difficulties. These results were replicated for children with low reading attainment, but no cognitive ability discrepancy. Categories of special educational need into which children with SWRD were classed at school were varied. Given high rates of co occurring behavioural difficulties, assessment that identifies each individual child's specific functional, rather than categorical, difficulties is likely to be the most effective way of providing classroom support. PMID- 25693053 TI - Probing the structure-relaxivity relationship of bis-hydrated Gd(DOTAla) derivatives. AB - Two structural isomers of the heptadentate chelator DO3Ala were synthesized, with carboxymethyl groups at either the 1,4- or 1,7-positions of the cyclen macrocycle. To interrogate the relaxivity under different rotatational dynamics regimes, the pendant primary amine was coupled to ibuprofen to enable binding to serum albumin. These chelators 6a and 6b form bis(aqua) ternary complexes with Gd(III) or Tb(III) as estimated from relaxivity measurements or luminescence lifetime measurements in water. The relaxivity of [Gd(6a)(H2O)2] and [Gd(6b)(H2O)2] was measured in the presence and absence of coordinating anions prevalent in vivo such as phosphate, lactate, and bicarbonate and compared with data attained for the q = 2 complex [Gd(DO3A)(H2O)2]. We found that relaxivity was reduced through formation of ternary complexes with lactate and bicarbonate, albeit to a lesser degree then the relaxivity of Gd(DO3A). In the presence of 100 fold excess phosphate, relaxivity was slightly increased and typical for q = 2 complexes of this size (8.3 mM(-1) s(-1) and 9.5 mM(-1) s(-1), respectively, at 37 degrees C, 60 MHz). Relaxivity for the complexes in the presence of HSA corresponded well to relaxivity obtained for complexes with reduced access for inner-sphere water (13.5 and 12.7 mM(-1) s(-1) at 37 degrees C, 60 MHz). Mean water residency time at 37 degrees C was determined using temperature-dependent (17)O-T2 measurements at 11.7 T and calculated to be (310)tauM = 23 +/- 1 ns for both structural isomers. Kinetic inertness under forcing conditions (pH 3, competing DTPA ligand) was found to be comparable to [Gd(DO3A)(H2O)]. Overall, we found that the replacement of one of the acetate arms of DO3A with an amino propionate arm does not significantly alter the relaxometric and kinetic inertness properties of the corresponding Gd complexes; however, it does provide access to easily functionalizable q = 2 derivatives. PMID- 25693054 TI - Microglia and neuroprotection. AB - Microglia were first identified over a century ago, but our knowledge about their ontogeny and functions has significantly expanded only recently. Microglia colonize the central nervous system (CNS) in utero and play essential roles in brain development. Once neural development is completed, microglia function as the resident innate immune cells of the CNS by surveying their microenvironment and becoming activated when the CNS is challenged by infection, injury, or disease. Despite the traditional view of microglia as being destructive in neurological diseases, recent studies have shown that microglia maintain CNS homeostasis and protect the CNS under various pathological conditions. Microglia can be prophylactically activated by modeling infection with systemic lipopolysaccharide injections and these activated microglia can protect the brain from traumatic injury through modulation of neuronal synapses. Microglia can also protect the CNS by promoting neurogenesis, clearing debris, and suppressing inflammation in diseases such as stroke, autism, and Alzheimer's. Microglia are the resident innate immune cells of the CNS. Despite the traditional view of microglia as being destructive in neurological diseases, recent studies have shown that they maintain tissue homeostasis and protect the CNS under various pathological conditions. They achieve so by clearing debris, promoting neurogenesis, suppressing inflammation and stripping inhibitory synapses. This review summarizes recent advances of our understanding on the multi-dimensional neuroprotective roles of microglia. PMID- 25693055 TI - Treatment of systemic necrotizing vasculitides in patients aged sixty-five years or older: results of a multicenter, open-label, randomized controlled trial of corticosteroid and cyclophosphamide-based induction therapy. AB - OBJECTIVE: To investigate a new therapeutic strategy, with rapid corticosteroid dose tapering and limited cyclophosphamide (CYC) exposure, for older patients with systemic necrotizing vasculitides (SNVs; polyarteritis nodosa [PAN], granulomatosis with polyangiitis [Wegnener's] [GPA], microscopic polyangiitis [MPA], or eosinophilic GPA [Churg-Strauss] [EGPA]). METHODS: A multicenter, open label, randomized controlled trial comprising patients >=65 years old and newly diagnosed as having SNV was conducted. The experimental treatment consisted of corticosteroids for ~9 months and a maximum of six 500-mg fixed-dose intravenous (IV) CYC pulses, every 2-3 weeks, then maintenance azathioprine or methotrexate. The control treatment included ~26 months of corticosteroids for all patients, combined with 500 mg/m(2) IV CYC pulses, every 2-3 weeks until remission, then maintenance for all patients with GPA or MPA and for those with EGPA or PAN with a Five-Factors Score (FFS) of >=1. Randomization used a 1:1 ratio computer generated list and was performed centrally with sealed opaque envelopes. The primary outcome measure was >=1 serious adverse event (SAE) occurring within 3 years of followup. Secondary outcome measures included remission and relapse rates. RESULTS: Among the 108 patients randomized, 4 were excluded (early consent withdrawal or protocol violation). Mean +/- SD age at diagnosis was 75.2 +/- 6.3 years. Analysis at 3 years included 53 patients (21 GPA, 21 MPA, 8 EGPA, and 3 PAN) in the experimental arm and 51 patients (15 GPA, 23 MPA, 6 EGPA, and 7 PAN) in the conventional arm. In total, 32 (60%) versus 40 (78%) had >=1 SAE (P = 0.04), most frequently infections; 6 (11%) versus 7 (14%) failed to achieve remission (P = 0.71); 9 (17%) versus 12 (24%) died (P = 0.41); and 20 (44%) of 45 versus 12 (29%) of 41 survivors in remission experienced a relapse (P = 0.15). CONCLUSION: For older SNV patients, an induction regimen limiting corticosteroid exposure and with fixed low-dose IV CYC pulses reduces SAEs in comparison to conventional therapy, and does not affect the remission rate. Three-year relapse rates remain high for both arms. PMID- 25693056 TI - Estimating the effect of intimate partner violence on women's use of contraception: a systematic review and meta-analysis. AB - BACKGROUND: Intimate partner violence (IPV) is an important global public health problem. While there is a growing literature on the association between IPV and women's reproductive health (RH) outcomes, most studies are cross-sectional-which weakens inference about the causal effect of IPV on women's RH. This systematic review synthesizes existing evidence from the strongest study designs to estimate the impact of IPV on women's use of contraception. METHODS: We searched 11 electronic databases from January of 1980 to 3 December 2013 and reviewed reference lists from systematic reviews for studies examining IPV and contraceptive use. To be able to infer causality, we limited our review to studies that had longitudinal measures of either IPV or women's use of contraception. RESULTS: Of the 1,574 articles identified by the search, we included 179 articles in the full text review and extracted data from 12 studies that met our inclusion criteria. We limited the meta-analysis to seven studies that could be classified as subject to low or moderate levels of bias. Women's experience of IPV was associated with a significant reduction in the odds of using contraception (n = 14,866; OR: 0.47; 95% CI: 0.25, 0.85; I2 = 92%; 95% CII2: 87%, 96%). Restricting to studies that measured the effect of IPV on women's use of partner dependent contraceptive methods was associated with a reduction in the heterogeneity of the overall estimate. In the three studies that examined women's likelihood of using male condoms with their partners, experience of IPV was associated with a significant decrease in condom use (OR: 0.48; 95% CIOR: 0.32, 0.72; I2 = 51%; 95% CII2: 0%, 86%). CONCLUSIONS: IPV is associated with a reduction in women's use of contraception; women who experience IPV are less likely to report using condoms with their male partners. Family planning and HIV prevention programs should consider women's experiences of IPV. PMID- 25693057 TI - Angiotensin II type 1 receptor autoantibody as a novel regulator of aldosterone independent of preeclampsia. AB - BACKGROUND: Preeclamptic women and their infants have significant morbidity and mortality worldwide. Abnormal aldosterone signaling is involved in the pathogenesis of preeclampsia, and the presence of agonistic autoantibodies against the angiotensin II type 1 receptor (AT1-AA) during disease has been observed. The role of AT1-AA in aldosterone generation with or without disease and the long-term impact of AT1-AA circulation in blood remain unclear. METHOD: We therefore assessed circulating AT1-AA and aldosterone levels in 76 patients with preeclampsia (35 severe and 41 mild), 26 patients with gestational hypertension, and 50 normotensive healthy pregnant women. RESULTS: First, the correlation of AT1-AA levels was confirmed for preeclamptic patients. We report here that all AT1-AA-positive hypertensive pregnant women exhibited decreased aldosterone levels, and early-onset preeclampsia patients with high proteinuria showed an inverse correlation of aldosterone levels with AT1-AA. To study this effect in more detail, we confirmed that AT1-AA decreased aldosterone levels in pregnant rats and then demonstrated that aldosterone levels decreased in response to the chronic administration of AT1-AA into nonpregnant rats. CONCLUSION: These results suggested that AT1-AA regulates levels of aldosterone, which was tested with cell culture studies, revealing that activation of AT1 receptors by AT1-AA directly led to abnormal aldosterone generation in a time and dose-dependent manner. We present here a mechanism for regulation of aldosterone production: AT1 AA activates AT1 receptors on adrenocortical cells independent of pregnancy, in a time and dose-dependent manner. PMID- 25693058 TI - Blood pressure is associated with the presence and severity of nonalcoholic fatty liver disease across the spectrum of cardiometabolic risk. AB - OBJECTIVES: To determine the relationship between clinically relevant blood pressure (BP) groups and nonalcoholic fatty liver disease (NAFLD) presence and severity especially in the milieu of other metabolic risk factors. PATIENTS AND METHODS: From a Brazilian cohort of 5362 healthy middle-aged men and women who presented for yearly physical examination and testing, the cross-sectional relationship between BP categories and NAFLD was assessed. BP groups were categorized as normal, prehypertension (PHT), and hypertension (HTN) according to the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure classification. NAFLD was ultrasound diagnosed, excluding persons with alcohol consumption more than 20 g/day. NAFLD severity was estimated using the Fibrosis-4 (FIB-4) risk score. RESULTS: The prevalence of NAFLD was 36.2%. Participants with NAFLD were older (mean 46 vs. 42 years, P < 0.001) and had elevated BMI (mean 29.0 vs. 24.7 kg/m, P < 0.001). The prevalence of NAFLD among persons with normal BP, PHT, and HTN was 16.5, 37.5, and 59.3%, respectively. In multivariate analyses, PHT and HTN were associated with elevated odds of NAFLD (PHT-adjusted odds ratio 1.3, 95% confidence interval 1.1, 1.6; HTN-adjusted odds ratio 1.8, 95% confidence interval 1.4-2.3) compared with normal BP. Among nonobese hypertensive patients, BP control (BP < 140/90 mmHg) was independently associated with 40% lower odds of prevalent NAFLD. Compared with hypertensive patients, both normotensive individuals and prehypertensive patients were more likely to have a low fibrosis risk (FIB-4 >= 1.3). CONCLUSION: Prevalent NAFLD may be seen early in the development of hypertension, even in the absence of other metabolic risk factors. Controlling BP among nonobese hypertensive patients may be beneficial in preventing or limiting NAFLD. PMID- 25693061 TI - From the pathophysiological to the epidemiological approach to hypertension research. PMID- 25693059 TI - Association of major dietary patterns and blood pressure longitudinal change in Bangladesh. AB - BACKGROUND: Observational studies and clinical trials have shown associations of diet and high blood pressure (BP). However, prospective studies on the association between dietary patterns and longitudinal BP change are lacking, especially in low-income populations. METHOD: We evaluated the association of dietary patterns and food groups with longitudinal change of BP in 10 389 participants in the Health Effects of Arsenic Longitudinal Study, with a median of 6.7 years of follow-up. Dietary information was obtained through a previously validated food-frequency questionnaire. BP was measured at baseline and at each biennial follow-up using the same method. RESULT: Each standard deviation (SD) increase for the 'gourd vegetable' dietary pattern score was related to a slower annual change of 0.08, 0.04, and 0.05 mmHg in SBP, DBP, or pulse pressure, respectively. Each SD increase in the 'balanced' dietary pattern score was related to a decreasing annual change of 0.06 mmHg (P = 0.012) and 0.08 mmHg in SBP and pulse pressure (P < 0.001). On the contrary, one SD increase in 'western' dietary pattern score was related to a greater annual increase of 0.07 (P = 0.005) and 0.05 mmHg in SBP and pulse pressure (P = 0.013). Higher intake of fruits and vegetables was associated with a slower rate of change in annual SBP and pulse pressure, whereas higher meat intake was related to a more rapid increase in annual pulse pressure. CONCLUSION: The findings suggest that dietary patterns play a significant role in the rate of BP change over time in a low income population. PMID- 25693060 TI - Longitudinal changes in cortical thinning associated with hypertension. AB - BACKGROUND: Cross-sectional studies of the association between hypertension (HTN) and brain atrophy have shown reductions in prefrontal, temporal, and hippocampal volumes, and have identified thinner cortices across the cortical mantle. METHOD: In the current study, we followed 96 participants enrolled in the Baltimore Longitudinal Study of Aging over a mean interval of 8 years (mean age at baseline = 68.7) and compared those who are hypertensive (n = 49) throughout the study with those who are normotensive (n = 47). RESULTS: Hypertensive individuals show an increased rate of thinning compared with normotensive individuals in several regions, including the frontomarginal gyrus in the left hemisphere, and the superior temporal, fusiform, and lateral orbitofrontal cortex in the right hemisphere. We also investigated the effects of midlife blood pressure (BP), intervisit variability in BP prior to imaging, and duration of HTN on areas that show subsequent differences in the rates of cortical thinning between groups. We found that higher midlife BP and longer durations of HTN predicted a higher rate of thinning in the right superior temporal gyrus. We also found that greater variability in SBP but not DBP predicted a higher rate of thinning in the right superior temporal gyrus, frontomarginal gyrus, and occipital pole. CONCLUSION: These findings demonstrate that hypertensive individuals show increased rates of thinning compared with normotensive individuals and suggest intervisit BP variability and midlife BP contribute to these longitudinal differences. PMID- 25693062 TI - Caramel color in soft drinks and exposure to 4-methylimidazole: a quantitative risk assessment. AB - Caramel color is added to many widely-consumed beverages as a colorant. Consumers of these beverages can be exposed to 4-methylimidazole (4-MEI), a potential carcinogen formed during its manufacture. California's Proposition 65 law requires that beverages containing 4-MEI concentrations corresponding to exposures that pose excess cancer risks > 1 case per 100,000 exposed persons (29 MUg 4-MEI/day) carry warning labels. Using ultrahigh-performance liquid chromatography-tandem mass spectrometry, we assessed 4-MEI concentrations in 12 beverages purchased in California and a geographically distant metropolitan area (New York) in which warning labels are not required. In addition, we characterized beverage consumption by age and race/ethnicity (using weighted means calculated from logistic regressions) and assessed 4-MEI exposure and resulting cancer risks and US population cancer burdens attributable to beverage consumption. Data on beverage consumption were obtained from the National Health and Nutrition Examination Survey, dose-response data for 4-MEI were obtained from the California Environmental Protection Agency Office of Environmental Health Hazards Assessment, and data on population characteristics were obtained from the U.S. Census Bureau. Of the 12 beverages, Malta Goya had the highest 4-MEI concentration (915.8 to 963.3MUg/L), lifetime average daily dose (LADD - 8.04x10 3 mg/kgBW-day), lifetime excess cancer risk (1.93x10-4) and burden (5,011 cancer cases in the U.S. population over 70 years); Coca-Cola had the lowest value of each (4-MEI: 9.5 to 11.7MUg/L; LADD: 1.01x10-4 mg/kgBW-day; risk: 1.92x10-6; and burden: 76 cases). 4-MEI concentrations varied considerably by soda and state/area of purchase, but were generally consistent across lots of the same beverage purchased in the same state/area. Routine consumption of certain beverages can result in 4-MEI exposures > 29 MUg/day. State regulatory standards appear to have been effective in reducing exposure to carcinogens in some beverages. Federal regulation of 4-MEI in caramel color may be appropriate. PMID- 25693063 TI - gamma-Secretase Mutation in an African American Family With Hidradenitis Suppurativa. PMID- 25693064 TI - Synthesis of [3-N-(11) C-methyl]temozolomide via in situ activation of 3-N hydroxymethyl temozolomide and alkylation with [(11) C]methyl iodide. AB - Temozolomide is a chemotherapeutic drug that is mainly used in the treatment of primary glioblastoma multiforme and recurrent high-grade glioma. Here, we report an efficient good manufacturing practice compliant method for the synthesis of [3 N-(11) C-methyl]temozolomide from 3-N-hydroxymethyl temozolomide that cleaves off formaldehyde in situ and becomes activated towards alkylation with [(11) C]methyl iodide. The labelling method was developed for an on-going patient study in which the predictive value of [3-N-(11) C-methyl]temozolomide and positron emission tomography on the outcome of temozolomide treatment is being investigated. The precursor was reacted with [(11) C]methyl iodide in the presence of 1,8 diazabicyclo[5.4.0]undec-7-ene in acetonitrile, heated at stepwise increasing temperature. Purification by semipreparative HPLC with pharmaceutical grade eluent and filtration gave approximately 10 mL sterile product solution ready for injection containing 1.55 +/- 0.38 GBq (n = 5), the specific activity was 88 +/- 25 GBq/umol and the radiochemical purity was 98.5 +/- 1.9%. (13) C-NMR spectroscopy confirmed the labelled position after colabelling with (11) C and (13) C. PMID- 25693065 TI - Characterizing protein modifications by reactive metabolites using magnetic bead bioreactors and LC-MS/MS. AB - We report here label-free metabolite-protein adduct detection and identification employing magnetic beads coated with metabolic enzymes as bioreactors to generate metabolites and possible metabolite-protein adducts for analysis by liquid chromatography-tandem mass spectrometry. PMID- 25693066 TI - Large-scale geographic variation in distribution and abundance of Australian deep water kelp forests. AB - Despite the significance of marine habitat-forming organisms, little is known about their large-scale distribution and abundance in deeper waters, where they are difficult to access. Such information is necessary to develop sound conservation and management strategies. Kelps are main habitat-formers in temperate reefs worldwide; however, these habitats are highly sensitive to environmental change. The kelp Ecklonia radiate is the major habitat-forming organism on subtidal reefs in temperate Australia. Here, we provide large-scale ecological data encompassing the latitudinal distribution along the continent of these kelp forests, which is a necessary first step towards quantitative inferences about the effects of climatic change and other stressors on these valuable habitats. We used the Autonomous Underwater Vehicle (AUV) facility of Australia's Integrated Marine Observing System (IMOS) to survey 157,000 m2 of seabed, of which ca 13,000 m2 were used to quantify kelp covers at multiple spatial scales (10-100 m to 100-1,000 km) and depths (15-60 m) across several regions ca 2-6 degrees latitude apart along the East and West coast of Australia. We investigated the large-scale geographic variation in distribution and abundance of deep-water kelp (>15 m depth) and their relationships with physical variables. Kelp cover generally increased with latitude despite great variability at smaller spatial scales. Maximum depth of kelp occurrence was 40-50 m. Kelp latitudinal distribution along the continent was most strongly related to water temperature and substratum availability. This extensive survey data, coupled with ongoing AUV missions, will allow for the detection of long-term shifts in the distribution and abundance of habitat-forming kelp and the organisms they support on a continental scale, and provide information necessary for successful implementation and management of conservation reserves. PMID- 25693067 TI - To kill, stay or flee: the effects of lions and landscape factors on habitat and kill site selection of cheetahs in South Africa. AB - Understanding how animals utilize available space is important for their conservation, as it provides insight into the ecological needs of the species, including those related to habitat, prey and inter and intraspecific interactions. We used 28 months of radio telemetry data and information from 200 kill locations to assess habitat selection at the 3rd order (selection of habitats within home ranges) and 4th order (selection of kill sites within the habitats used) of a reintroduced population of cheetahs Acinonyx jubatus in Phinda Private Game Reserve, South Africa. Along with landscape characteristics, we investigated if lion Panthera leo presence affected habitat selection of cheetahs. Our results indicated that cheetah habitat selection was driven by a trade-off between resource acquisition and lion avoidance, and the balance of this trade-off varied with scale: more open habitats with high prey densities were positively selected within home ranges, whereas more closed habitats with low prey densities were positively selected for kill sites. We also showed that habitat selection, feeding ecology, and avoidance of lions differed depending on the sex and reproductive status of cheetahs. The results highlight the importance of scale when investigating a species' habitat selection. We conclude that the adaptability of cheetahs, together with the habitat heterogeneity found within Phinda, explained their success in this small fenced reserve. The results provide information for the conservation and management of this threatened species, especially with regards to reintroduction efforts in South Africa. PMID- 25693068 TI - Technology and teaching innovations in nursing education: engaging the student. PMID- 25693069 TI - Critical-thinking challenge games and teaching outside of the box. PMID- 25693070 TI - Simulation gone wild: SIM OUT. PMID- 25693071 TI - Letter to the editor and response: guidelines for response to student requests for academic consideration: support versus enabling. PMID- 25693072 TI - Response from authors. PMID- 25693073 TI - Incorporating quality and safety education in nursing into nursing curriculum via implementation of student-led pediatric health and safety fair. PMID- 25693075 TI - Using high-fidelity simulation as a learning strategy in an undergraduate intensive care course. AB - Using high-fidelity simulations to facilitate student learning is an uncommon practice in Turkish nursing programs. The aim of the present study was to understand students' perceptions of the use of simulation in nursing courses. Subjects included 36 senior nursing students taking an intensive care course. This study revealed that high-fidelity simulation is an ideal method of promoting learning by helping students transfer theory into practice, build confidence and teamwork, and raise professional awareness. PMID- 25693076 TI - Diagnostic value of multiple tumor markers for patients with esophageal carcinoma. AB - BACKGROUND: Various studies assessing the diagnostic value of serum tumor markers in patients with esophageal cancer remain controversial. This study aims to comprehensively and quantitatively summarize the potential diagnostic value of 5 serum tumour markers in esophageal cancer. METHODS: We systematically searched PubMed, Embase, Chinese National Knowledge Infrastructure (CNKI) and Chinese Biomedical Database (CBM), through February 28, 2013, without language restriction. Studies were assessed for quality using QUADAS (quality assessment of studies of diagnostic accuracy). The positive likelihood ratio (PLR) and negative likelihood ratio (NLR) were pooled separately and compared with overall accuracy measures using diagnostic odds ratios (DORs) and symmetric summary receiver operating characteristic (SROC) curves. RESULTS: Of 4391 studies initially identified, 44 eligible studies including five tumor markers met the inclusion criteria for the meta-analysis, while meta-analysis could not be conducted for 12 other tumor markers. Approximately 79.55% (35/44) of the included studies were of relatively high quality (QUADAS score>=7). The summary estimates of the positive likelihood ratio (PLR), negative likelihood ratio (NLR) and diagnostic odds ratio (DOR) for diagnosing EC were as follows: CEA, 5.94/0.76/9.26; Cyfra21-1, 12.110.59/22.27; p53 antibody, 6.71/0.75/9.60; SCC-Ag, 7.66/0.68/12.41; and VEGF-C, 0.74/0.37/8.12. The estimated summary receiver operating characteristic curves showed that the performance of all five tumor markers was reasonable. CONCLUSIONS: The current evidence suggests that CEA, Cyfra21-1, p53, SCC-Ag and VEGF-C have a potential diagnostic value for esophageal carcinoma. PMID- 25693077 TI - The perils of straying from protocol: sampling bias and interviewer effects. AB - Fidelity to research protocol is critical. In a contingent valuation study in an informal urban settlement in Nairobi, Kenya, participants responded differently to the three trained interviewers. Interviewer effects were present during the survey pilot, then magnified at the start of the main survey after a seemingly slight adaptation of the survey sampling protocol allowed interviewers to speak with the "closest neighbor" in the event that no one was home at a selected household. This slight degree of interviewer choice led to inferred sampling bias. Multinomial logistic regression and post-estimation tests revealed that the three interviewers' samples differed significantly from one another according to six demographic characteristics. The two female interviewers were 2.8 and 7.7 times less likely to talk with respondents of low socio-economic status than the male interviewer. Systematic error renders it impossible to determine which of the survey responses might be "correct." This experience demonstrates why researchers must take care to strictly follow sampling protocols, consistently train interviewers, and monitor responses by interview to ensure similarity between interviewers' groups and produce unbiased estimates of the parameters of interest. PMID- 25693078 TI - Tractography of the spider monkey (Ateles geoffroyi) corpus callosum using diffusion tensor magnetic resonance imaging. AB - The objective of this research was to describe the organization, connectivity and microstructure of the corpus callosum of the spider monkey (Ateles geoffroyi). Non-invasive magnetic resonance imaging and diffusion-tensor imaging were obtained from three subjects using a 3T Philips scanner. We hypothesized that the arrangement of fibers in spider monkeys would be similar to that observed in other non-human primates. A repeated measure (n = 3) of fractional anisotropy values was obtained of each subject and for each callosal subdivision. Measurements of the diffusion properties of corpus callosum fibers exhibited a similar pattern to those reported in the literature for humans and chimpanzees. No statistical difference was reached when comparing this parameter between the different CC regions (p = 0.066). The highest fractional anisotropy values corresponded to regions projecting from the corpus callosum to the posterior cortical association areas, premotor and supplementary motor cortices. The lowest fractional anisotropy corresponded to projections to motor and sensory cortical areas. Analyses indicated that approximately 57% of the fibers projects to the frontal cortex and 43% to the post-central cortex. While this study had a small sample size, the results provided important information concerning the organization of the corpus callosum in spider monkeys. PMID- 25693079 TI - Molecular pathology of colorectal cancer. AB - Colorectal cancer (CRC) is one of the most intensively studied cancer types, partly because of its high prevalence but also because of the existence of its precursor lesions, tubular or villous adenomas, and more recently (sessile) serrated adenomas, which can be detected endoscopically and removed. The morphological steps in the adenoma-carcinoma sequence have been elucidated at a molecular level, which has been facilitated by identification of the genes responsible for familial intestinal cancer. However, apart from early detection of familial forms of CRC and its use in genetic counseling, until recently such detailed molecular knowledge has had little impact on clinical management of the disease. This has dramatically changed in the last decade. With drugs specifically targeting the epidermal growth factor receptor (EGFR) having been shown effective in CRC, mechanisms responsible for resistance have been explored. The finding that KRAS mutated cancers do not respond to anti-EGFR treatment has had a profound impact on clinical management and on molecular diagnostics of CRC. Additional genetic tests for mutations in NRAS, BRAF and PIK3CA contribute to determining who to treat, and others will follow. New therapies effective in patients with advanced CRC are under investigation. Remaining burning questions for optimal management are which patients will relapse after resection of the primary tumor and which patients will respond to the standard 5FU-oxaliplatin adjuvant treatment regimen. Predictive tests to address these issues are eagerly awaited. New classifications of CRC, based on molecular parameters, are emerging, and we will be confronted with new subtypes of CRC, for which the definition is based on combinations of gene expression patterns, chromosomal alterations, gene mutations and epigenetic characteristics. This will be instrumental in designing new approaches for therapy but will also be translated into molecular diagnostics. Both will contribute to improved clinical management of CRC. PMID- 25693080 TI - Lack of healing reaction in the cancer wound. AB - Surgical wounds in cancer patients have a relatively high dehiscence rate. Although cancer resections are performed so as to include macroscopically non involved tissues, some cancer cells can be present in the line of transection or surrounding tissues (R1 and R2 resections). The local healing process may facilitate proliferation of these localized cancer cells, and the high cytokine concentration within the healing wound may also attract cancer cells from distant sites to migrate into the wound area. The question arises how the tumor environment influences the wound healing process. The aim of the study was to monitor and compare, using immunohistochemical methods, the healing process of an incision wound performed through a metastatic liver tumor of colon cancer with the healing of a normal liver incision wound. The experiments were carried out on a CC531 colon cancer rat model. We observed impaired healing of cancer wounds at all stages of wound healing. Significantly fewer mononuclear cells infiltrated the cancer than the normal liver wounds. There were no significant differences in the phenotypes of infiltrating mononuclear cells. BrdU incorporation showed rapid proliferation of cancer but not infiltrating cells or fibroblasts in the cancer wounds. We observed no connective tissue formation and poor collagen deposition in cancer wounds. Additionally, cancer wounds were significantly deprived of newly formed vessels. We confirmed that the impaired migration and proliferation of inflammatory cells in cancer wounds and poor scar tissue formation contribute to impaired healing of cancer 'contaminated' wounds. PMID- 25693081 TI - Is there a place for practical chemoprevention of colorectal cancer in light of COX-2 heterogeneity? AB - COX-2 overexpression is widely recognized as an accidental and relatively important factor in the progress of colon neoplasia, but the practical significance of it has not yet been defined. As such, the purposes of the study were: an analysis of the changes of COX-2 expression within colon adenomas in the dependence of progress of dysplastic level within colon adenomas, the analysis of COX-2 expression in cryptal and superficial parts of polyp and, additionally, the analysis of the COX-2 heterogeneity between colon adenomas. One hundred and four cases with completely resected adenomas with high-grade epithelial dysplasia were included in the research. Each polyp had persistent low-grade dysplasia and normal colon mucosa at the base as an internal control. Immunohistochemical analysis with monoclonal COX-2 antibody was performed. Regression of COX-2 expression in high-grade colon intraepithelial lesions (HGCoIN) compared with low grade colon intraepithelial lesions (LGCoIN) (p = 0.00001) was observed. No correlation between stromal COX-2 expression and either LGCoIN or HGCoIN was found (p > 0.05). The next important observation was a difference in superficial and cryptal COX-2 expression (p < 0.001) and the evident heterogeneity of COX-2 expression among adenomas at LGCoIN as well HGCoIN foci (p < 0.01). The regression of COX-2 expression in high-grade parts of adenomas which we described may result in a reduction of the role of chemoprevention by the use of NSAIDs. PMID- 25693082 TI - Topoisomerase 2alpha status in invasive breast carcinoma - comparison of its clinical value according to immunohistochemical and fluorescence in situ hybridization methods of evaluation. AB - The main purpose of the study was to compare topoisomerase 2alpha (TOP2A) status in invasive breast carcinomas to the outcome of a therapy containing neoadjuvant treatment with anthracyclines (a combination chemotherapy treatment for breast cancer, namely AC [cyclophosphamide, doxorubicin]). To achieve these goals we created a method of evaluation with criteria based on two methods used in the present study (immunohistochemical [IHC] and fluorescence in situ hybridization [FISH]). The threshold for positive immunohistochemically evaluated status was set for all cases with: nuclear stain intensity score 3+ in 10% or more nuclei and nuclear stain intensity score 2+ in 50% or more nuclei. Our results suggest that TOP2A status may be used as a predictive factor for patient selection for protocols which include anthracyclines as one of the chemotherapeutics. Both methods, IHC and FISH, are suitable for implementation for diagnostic purposes, but IHC positive status measured according to the criteria presented above is the best predictor of longer disease-free survival (DFS) according to our study. Immunohistochemical also gave satisfactory results in all analyzed cases in comparison to only 60% of cases analyzed by FISH. PMID- 25693083 TI - Expression of stem cell marker CD44 in prostate cancer biopsies predicts cancer grade in radical prostatectomy specimens. AB - Cancer stem cells play an important role in development and progression of many cancer types including prostate adenocarcinoma. We used a stem cell marker CD44 to evaluate the prevalence of prostate cancer stem cells in prostate biopsies and in matched radical prostatectomy specimens. We tested both types of specimen for the existence of a correlation between the immunohistochemical expression of CD44 and Gleason grade, pathological stage (pT) according to TNM, patient age and preoperative plasma PSA levels in 52 patients. We found a positive correlation between the expression of CD44 in cancer cells from prostate biopsies and in matched radical prostatectomy specimens. We also observed that higher level of CD44 expression in cancer cells correlated with lower Gleason score, both in prostate biopsies and in radical prostatectomies. To the best of our knowledge we showed for the first time, that the level of CD44 expression in prostate biopsies correlates with that observed in matched radical prostatectomy specimens. Since the level of CD44 expression was shown to predict a response to anti cancer therapy in several types of human tumors, CD44 assessment might support a clinical decision making process in prostate cancer patients. PMID- 25693084 TI - Diagnostic significance of TIMP-1 level in serum and its immunohistochemical expression in colorectal cancer patients. AB - Tissue inhibitor of metalloproteinase-1 (TIMP-1) inhibits the ability of cancer cells to metastasize, but it can also stimulate cancer development. The aim of this study was to assess the level of TIMP-1 in serum and its expression in patients with colorectal cancer (CRC). The study group consisted of 43 patients diagnosed with colorectal cancer and 24 healthy volunteers. The level of TIMP-1 was assessed by the ELISA method while the expression of this protein was performed immunohistochemically. The concentration of TIMP-1 in the sera of colorectal cancer patients was significantly higher than in the healthy control group (p = 0.004). Higher level of TIMP-1 in the sera correlated with female gender (p = 0.045), tumor location in colon (p = 0.016), poorly differentiated tumor (p = 0.034) and higher platelet count in whole blood (p < 0.004). A positive reaction of the protein in cancer cells was observed in 31 cases and was found to correlate negatively with its reaction in peritumoral stroma (p < 0.001). According to this study, TIMP-1 protein may play an important role in cancer development. The assessment of this molecule in serum and tissue can be useful at the time of diagnosis and can help us to understand the nature of colorectal pathogenesis. PMID- 25693085 TI - Comparison of pathological staging and grading of urothelial bladder carcinoma in post-transurethral resection and post-radical cystectomy specimens. AB - Staging and grading of bladder cancer have a substantial impact on patients' prognosis. However, due to the relatively low quality and quantity of specimens from transurethral resection (TUR), initial histopathological examination may not be fully reliable. The aim of this study was to assess the repeatability of staging and grading in post-TUR and post-radical cystectomy (RC) specimens. Staging and grading in TUR and RC specimens were compared in a group of 181 consecutive patients. All microscopic examinations were performed by dedicated uropathologists. Median time from TUR to RC was 45 days. Additionally, an attempt to identify potential clinical variables influencing the risk of discrepancies was made. In post-RC specimens, the disease was down-staged in 13.8% and up staged in 54.6% of patients (K = -0.03, p < 0.02). Muscle-invasive bladder cancer was diagnosed in 67.6% of patients initially staged as T1. Cancer was down-graded in 10.3% and up-graded in 17.9% of patients (K = 0.44, p < 0.02). Early onset of disease, female sex and time interval from transurethral resection of bladder tumor (TURBT) to RC had no effect on incidence of discrepancies. Pathological post-TUR examination is not predictive for the final stage of cancer. The incidence of under- or overgrading of bladder cancer is significant, and efforts should be made to reduce it. PMID- 25693086 TI - The relationship of TP53 and GRIN2B gene polymorphisms with risk of occurrence and progression of primary open-angle glaucoma in a Polish population. AB - INTRODUCTION: Glaucoma is characterized by optic neuropathy of the retinal ganglion cells (RGCs). Retinal ganglian cell death may be mediated by apoptosis. TP53 is involved in this process. It can also be found that excitotoxicity contributes to apoptosis by excess stimulation of glutamate receptors. The aim of this study was to evaluate the relationship of the TP53 (rs1042522) and GRIN2B (rs3764028) gene polymorphisms with risk of occurrence of primary open-angle glaucoma (POAG). MATERIAL AND METHODS: The study population consisted of 186 patients and 188 healthy subjects. Genomic DNA was extracted from peripheral blood. Analysis of the gene polymorphisms was performed using PCR-RFLP. RESULTS: Comparison of the distributions of genotypes and alleles of the rs1042522 and rs3764028 polymorphisms showed no statistically significant differences between POAG patients and controls (p > 0.05). There was a statistically significant association of the rs1042522 polymorphism with progression of POAG depending on the retinal nerve fiber layer (p = 0.019). However, no significant differences between rs3764028 polymorphism and clinical parameters of POAG were observed (p > 0.05). CONCLUSIONS: The TP53 Arg72Pro and GRIN2B -421C/A gene polymorphisms were not associated with risk of occurrence of POAG in the Polish population. However, the Arg72Pro polymorphism of the TP53 gene may be related to progression of POAG. PMID- 25693087 TI - Mercury-induced nephrotic syndrome: a case report and review of the literature. AB - A 42-year-old man was admitted to the Nephrology Department because of nephrotic syndrome. Eight months prior to admission he attempted suicide by intravenous self-injection of 2.5 ml of elemental mercury. Renal biopsy was performed. Light microscopy findings showed normal glomeruli and injury of proximal tubular cells. Immunofluorescence was negative, and electron microscopy study revealed diffuse effacement of podocyte foot processes and vacuolization of podocyte cytoplasm. Minimal change disease was diagnosed. The patient was treated with 2,3 dimercaptopropane-1-sulfonate, for mercury detoxification, and steroids. In one year follow-up the 24-h urine protein excretion decreased from 30 gamma to 0.186 g, and the renal function remain normal. The presented case indicates that mercury intoxication should be mentioned as a cause of secondary minimal change disease. PMID- 25693088 TI - Huge alveolar soft part sarcoma of the retroperitoneum - case report. AB - Alveolar soft part sarcoma (ASPS) is a rare type of neoplasm, typically occurring in adolescents and young adults. Because of the rarity of this disease, there is no standard treatment plan. Chemotherapy and radiotherapy are not effective in this type of malignancy. Surgical excision is considered to be the treatment of choice. We report a case of a young woman with a painless mass in her left lower abdomen. Ultrasonography and CT scan revealed a large (21 cm) hard tumor occupying the left retroperitoneal space, which was surgically excised in our surgery department. The pathological diagnosis was ASPS. PMID- 25693089 TI - Extrauterine decidual reaction associated with pregnancy. AB - A case of pregnancy associated extrauterine decidual reaction of great omentum in a 25 year old woman, incidentally discovered during microscopic examination is described with a short review of literature. PMID- 25693091 TI - Mouse model to clarify ovarian clear-cell carcinoma. PMID- 25693092 TI - Chicks go left for less, right for more. PMID- 25693094 TI - A spinal neural circuit keeps mice moving. PMID- 25693095 TI - Using the whole plant to treat malaria. PMID- 25693097 TI - Neuroscience 2014. PMID- 25693098 TI - Blue-bloods of the sea. PMID- 25693099 TI - Interpreting guidance on significant changes. PMID- 25693100 TI - Response to protocol review scenario: Consequences of flawed IACUC policies. PMID- 25693101 TI - Response to protocol review scenario: A word from OLAW. PMID- 25693102 TI - Response to protocol review scenario: One wrong, one right. PMID- 25693103 TI - Response to protocol review scenario: Administrator actions appropriate. PMID- 25693104 TI - A systematic process for physical examination in preclinical research. PMID- 25693106 TI - Deep subconjunctival injection of gentamicin for the treatment of bacterial conjunctivitis in macaques (Macaca mulatta and Macaca fascicularis). AB - Infectious conjunctivitis occurs in a number of domestic and laboratory animal species and is usually treated topically with eye drops or eye ointments, which must be administered several times a day and sometimes for a prolonged period of time. In aggressive nonhuman primates or other large laboratory animal species, this may require the use of anesthesia or physical restraint before each treatment, which can be stressful to the animals and demanding for personnel. The authors describe a technique for administering deep subconjunctival injections of an antibiotic to laboratory macaques for the treatment of conjunctivitis. Three cases of recurrent conjunctivitis in macaques that responded poorly to other treatment approaches were effectively treated using this technique. This approach is recommended for the treatment of conjunctivitis in macaques and other large animal species. PMID- 25693107 TI - Imaging technologies and basic considerations for welfare of laboratory rodents. AB - Imaging technologies are regularly used in biomedical research to study processes in living animals in a noninvasive manner. But imaging procedures can affect animal physiology, and the need to anesthetize animals for imaging entails potential health risks. In addition, certain imaging modalities require the use of ionizing radiation or the administration of contrast agents or imaging biomarkers, which also have consequences for animal physiology. Finally, procedures associated with imaging, such as animal preparation (e.g., fasting, premedication) and blood sampling, can also affect physiology and animal welfare. Here, the authors review the imaging modalities commonly used for rodents in biomedical research and their associated considerations for animal welfare. PMID- 25693108 TI - Nalbuphine, a non-controlled opioid analgesic, and its potential use in research mice. AB - Nalbuphine is an inexpensive, non-controlled, opioid analgesic that has been in clinical use for decades. A kappa opioid receptor agonist and mu opioid receptor antagonist, nalbuphine causes fewer adverse effects than other opioid analgesics. The author reviews the characteristics of nalbuphine, analyzes studies of nalbuphine in mice and explores the potential use of nalbuphine to treat pain in research mice. In analgesiometric studies in mice, nalbuphine ameliorates both somatic and visceral pain. Nalbuphine seems to have a broad range of safe doses for subcutaneous administration in mice. Unlike non-steroidal anti-inflammatory drugs, nalbuphine does not antagonize prostaglandins or impede labor in mice. Although additional study is needed before clinical use can be recommended, evidence presented here suggests that nalbuphine might be an effective analgesic for dystocia (or difficult birth) and other painful conditions in research mice. PMID- 25693109 TI - Just go to training! PMID- 25693110 TI - The Beagle Freedom Deception Project. PMID- 25693111 TI - Value of a multifaceted career. PMID- 25693112 TI - Comparison of demographics, professional outcomes, and career satisfaction in accelerated and traditional baccalaureate nursing graduates. AB - This cross-sectional study examined accelerated second-degree (n = 117) and traditional (n = 71) baccalaureate nursing (BSN) graduates from a large, private, urban university in the mid-Atlantic United States regarding demographics, professional outcomes, and career satisfaction using an electronic survey. Results showed a statistically significant difference in two professional development variables: plans to return for an advanced nursing degree and membership in nursing professional organizations. There was no statistically significant difference in career satisfaction between accelerated second-degree and traditional BSN graduates. These findings indicated that both accelerated second-degree and traditional BSN graduates, despite matriculation in different nursing curricular models, have similar professional outcomes and career satisfaction. PMID- 25693113 TI - Addressing the primary care workforce: a study of nurse practitioner students' plans after graduation. AB - Primary care is a growing area, and nurse practitioners (NPs) hold promise for meeting the need for additional providers. This article reports on the future plans of more than 300 primary care NP students in family, adult, and adult gerontology programs. The sample was obtained through NP faculty, and data were collected via an online survey. Results indicated that although these students chose primary care, only 48% anticipated working in primary care; 26% planned to practice in rural areas, and 16% planned to work in an inner city. Reasons cited as important for pursuing a primary care position included the long-term patient relationship, faculty and preceptor mentors from the NP program, and clinical experiences as a student. Implications include providing more intensive faculty mentoring to increase the number of individuals seeking primary care positions after graduation and help with future career planning to meet personal career and nursing profession needs. PMID- 25693114 TI - A control systems approach to quantify wall shear stress normalization by flow mediated dilation in the brachial artery. AB - Flow-mediated dilation is aimed at normalization of local wall shear stress under varying blood flow conditions. Blood flow velocity and vessel diameter are continuous and opposing influences that modulate wall shear stress. We derived an index FMDv to quantify wall shear stress normalization performance by flow mediated dilation in the brachial artery. In 22 fasting presumed healthy men, we first assessed intra- and inter-session reproducibilities of two indices pFMDv and mFMDv, which consider the relative peak and relative mean hyperemic change in flow velocity, respectively. Second, utilizing oral glucose loading, we evaluated the tracking performance of both FMDv indices, in comparison with existing indices [i.e., the relative peak diameter increase (%FMD), the peak to baseline diameter ratio (Dpeak/Dbase), and the relative peak diameter increase normalized to the full area under the curve of blood flow velocity with hyperemia (FMD/shearAUC) or with area integrated to peak hyperemia (FMD/shearAUC_peak)]. Inter-session and intra-session reproducibilities for pFMDv, mFMDv and %FMD were comparable (intra-class correlation coefficients within 0.521-0.677 range). Both pFMDv and mFMDv showed more clearly a reduction after glucose loading (reduction of ~45%, p<=0.001) than the other indices (% given are relative reductions): %FMD (~11%, p>=0.074); Dpeak/Dbase (~11%, p>=0.074); FMD/shearAUC_peak (~20%, p>=0.016) and FMD/shearAUC (~38%, p<=0.038). Further analysis indicated that wall shear stress normalization under normal (fasting) conditions is already far from ideal (FMDv << 1), which (therefore) does not materially change with glucose loading. Our approach might be useful in intervention studies to detect intrinsic changes in shear stress normalization performance in conduit arteries. PMID- 25693115 TI - Association between air pollution and suicide in South Korea: a nationwide study. AB - Suggestive associations of suicide with air pollutant concentrations have been reported. Recognizing regional and temporal variability of pollutant concentrations and of suicide, we undertook a detailed meta-analysis of completed suicides in relation to 5 major pollutants over 6 years in the 16 administrative regions of the Republic of Korea, while also controlling for other established influences on suicide rates. Of the 5 major pollutants examined, ozone concentrations had a powerful association with suicide rate, extending back to 4 weeks. Over the range of 2 standard deviations (SD) around the annual mean ozone concentration, the adjusted suicide rate increased by an estimated 7.8% of the annual mean rate. Particulate matter pollution also had a significant effect, strongest with a 4-week lag, equivalent to 3.6% of the annual mean rate over the same 2 SD range that approximated the half of annual observed range. These results strongly suggest deleterious effects of ozone and particulate matter pollution on the major public health problem of suicide. PMID- 25693116 TI - Double tryptophan exciton probe to gauge proximal side chains in proteins: augmentation at low temperature. AB - The circular dichroic (CD) exciton couplet between tryptophans and/or tyrosines offers the potential to probe distances within 10 A in proteins. The exciton effect has been used with native chromophores in critical positions in a few proteins. Here, site-directed mutagenesis created double tryptophan probes for key sites of a protein (tear lipocalin). For tear lipocalin, the crystal and solution structures are concordant in both apo- and holo-forms. Double tryptophan substitutions were performed at sites that could probe conformation and were likely within 10 A. Far-UV CD spectra of double Trp mutants were performed with controls that had noninteracting substituted tryptophans. Low temperature (77 K) was tested for augmentation of the exciton signal. Exciton coupling appeared with tryptophan substitutions at positions within loop A-B (28 and 31, 33), between loop A-B (28) and strand G (103 and 105), as well as between the strands B (35) and C (56). The CD exciton couplet signals were amplified 3-5-fold at 77 K. The results were concordant with close distances in crystal and solution structures. The exciton couplets had functional significance and correctly assigned the holo conformation. The methodology creates an effective probe to identify proximal amino acids in a variety of motifs. PMID- 25693117 TI - Effect of Growth hormone replacement therapy on soluble Klotho in patients with Growth hormone deficiency. PMID- 25693123 TI - Orchestrating transcription with the Pol II CTD. PMID- 25693118 TI - RIPK3 promotes cell death and NLRP3 inflammasome activation in the absence of MLKL. AB - RIPK3 and its substrate MLKL are essential for necroptosis, a lytic cell death proposed to cause inflammation via the release of intracellular molecules. Whether and how RIPK3 might drive inflammation in a manner independent of MLKL and cell lysis remains unclear. Here we show that following LPS treatment, or LPS induced necroptosis, the TLR adaptor protein TRIF and inhibitor of apoptosis proteins (IAPs: X-linked IAP, cellular IAP1 and IAP2) regulate RIPK3 and MLKL ubiquitylation. Hence, when IAPs are absent, LPS triggers RIPK3 to activate caspase-8, promoting apoptosis and NLRP3-caspase-1 activation, independent of RIPK3 kinase activity and MLKL. In contrast, in the absence of both IAPs and caspase-8, RIPK3 kinase activity and MLKL are essential for TLR-induced NLRP3 activation. Consistent with in vitro experiments, interleukin-1 (IL-1)-dependent autoantibody-mediated arthritis is exacerbated in mice lacking IAPs, and is reduced by deletion of RIPK3, but not MLKL. Therefore RIPK3 can promote NLRP3 inflammasome and IL-1beta inflammatory responses independent of MLKL and necroptotic cell death. PMID- 25693125 TI - Transcription: a mitochondrial switch between transcription and replication. PMID- 25693126 TI - Structural basis of transcription initiation by RNA polymerase II. AB - Transcription of eukaryotic protein-coding genes commences with the assembly of a conserved initiation complex, which consists of RNA polymerase II (Pol II) and the general transcription factors, at promoter DNA. After two decades of research, the structural basis of transcription initiation is emerging. Crystal structures of many components of the initiation complex have been resolved, and structural information on Pol II complexes with general transcription factors has recently been obtained. Although mechanistic details await elucidation, available data outline how Pol II cooperates with the general transcription factors to bind to and open promoter DNA, and how Pol II directs RNA synthesis and escapes from the promoter. PMID- 25693130 TI - Getting up to speed with transcription elongation by RNA polymerase II. AB - Recent advances in sequencing techniques that measure nascent transcripts and that reveal the positioning of RNA polymerase II (Pol II) have shown that the pausing of Pol II in promoter-proximal regions and its release to initiate a phase of productive elongation are key steps in transcription regulation. Moreover, after the release of Pol II from the promoter-proximal region, elongation rates are highly dynamic throughout the transcription of a gene, and vary on a gene-by-gene basis. Interestingly, Pol II elongation rates affect co transcriptional processes such as splicing, termination and genome stability. Increasing numbers of factors and regulatory mechanisms have been associated with the steps of transcription elongation by Pol II, revealing that elongation is a highly complex process. Elongation is thus now recognized as a key phase in the regulation of transcription by Pol II. PMID- 25693134 TI - Metabolism: Transcriptionally activating brown fat. PMID- 25693131 TI - The Mediator complex: a central integrator of transcription. AB - The RNA polymerase II (Pol II) enzyme transcribes all protein-coding and most non coding RNA genes and is globally regulated by Mediator - a large, conformationally flexible protein complex with a variable subunit composition (for example, a four-subunit cyclin-dependent kinase 8 module can reversibly associate with it). These biochemical characteristics are fundamentally important for Mediator's ability to control various processes that are important for transcription, including the organization of chromatin architecture and the regulation of Pol II pre-initiation, initiation, re-initiation, pausing and elongation. Although Mediator exists in all eukaryotes, a variety of Mediator functions seem to be specific to metazoans, which is indicative of more diverse regulatory requirements. PMID- 25693135 TI - Improved lower bounds of DNA tags based on a modified genetic algorithm. AB - The well-known massively parallel sequencing method is efficient and it can obtain sequence data from multiple individual samples. In order to ensure that sequencing, replication, and oligonucleotide synthesis errors do not result in tags (or barcodes) that are unrecoverable or confused, the tag sequences should be abundant and sufficiently different. Recently, many design methods have been proposed for correcting errors in data using error-correcting codes. The existing tag sets contain small tag sequences, so we used a modified genetic algorithm to improve the lower bound of the tag sets in this study. Compared with previous research, our algorithm is effective for designing sets of DNA tags. Moreover, the GC content determined by existing methods includes an imprecise range. Thus, we improved the GC content determination method to obtain tag sets that control the GC content in a more precise range. Finally, previous studies have only considered perfect self-complementarity. Thus, we considered the crossover between different tags and introduced an improved constraint into the design of tag sets. PMID- 25693136 TI - Bisphenol a promotes cell survival following oxidative DNA damage in mouse fibroblasts. AB - Bisphenol A (BPA) is a biologically active industrial chemical used in production of consumer products. BPA has become a target of intense public scrutiny following concerns about its association with human diseases such as obesity, diabetes, reproductive disorders, and cancer. Recent studies link BPA with the generation of reactive oxygen species, and base excision repair (BER) is responsible for removing oxidatively induced DNA lesions. Yet, the relationship between BPA and BER has yet to be examined. Further, the ubiquitous nature of BPA allows continuous exposure of the human genome concurrent with the normal endogenous and exogenous insults to the genome, and this co-exposure may impact the DNA damage response and repair. To determine the effect of BPA exposure on base excision repair of oxidatively induced DNA damage, cells compromised in double-strand break repair were treated with BPA alone or co-exposed with either potassium bromate (KBrO3) or laser irradiation as oxidative damaging agents. In experiments with KBrO3, co-treatment with BPA partially reversed the KBrO3 induced cytotoxicity observed in these cells, and this was coincident with an increase in guanine base lesions in genomic DNA. The improvement in cell survival and the increase in oxidatively induced DNA base lesions were reminiscent of previous results with alkyl adenine DNA glycosylase-deficient cells, suggesting that BPA may prevent initiation of repair of oxidized base lesions. With laser irradiation-induced DNA damage, treatment with BPA suppressed DNA repair as revealed by several indicators. These results are consistent with the hypothesis that BPA can induce a suppression of oxidized base lesion DNA repair by the base excision repair pathway. PMID- 25693137 TI - Determination of the minimum initial intrathecal dose of isobaric 0.5% bupivacaine for the surgical repair of a proximal femoral fracture: A prospective, observational trial. AB - BACKGROUND: Femoral neck fractures usually require operative fixation. Spinal anaesthesia is the preferred technique for many anaesthetists, although single shot spinal anaesthesia may have severe haemodynamic side-effects. OBJECTIVE: To determine the initial minimum intrathecal dose of 0.5% isobaric bupivacaine required in order to achieve surgical anaesthesia within 15 min. DESIGN: Prospective controlled trial using the Dixon and Massey up-and-down method. SETTING: Patients awaiting surgery for proximal femoral fractures at Cork University Hospital were recruited between September 2012 and December 2012. PATIENTS: With institutional ethics approval and having obtained written informed consent from each, American Society of Anesthesiologists' physical status I to III patients aged more than 60 years were recruited. Twenty-three patients were recruited to the study, of which 22 were managed as per protocol. One patient was excluded because of the inability to insert an intrathecal catheter. INTERVENTION: A 22-guage spinal catheter was inserted between the L3 and L5 vertebral levels. An initial dose of 1 ml 0.5% isobaric bupivacaine was arbitrarily chosen as a starting point. The dose in subsequent patients was determined by the outcome of the preceding spinal block and adjusted by 0.1 ml until data on six independent pairs of patients with successful block/failed block were acquired. MAIN OUTCOME MEASURES: The minimum effective local anaesthetic dose of intrathecal 0.5% isobaric bupivacaine to achieve surgical anaesthesia was defined as the primary outcome. RESULTS: The minimum effective local anaesthetic dose of 0.5% bupivacaine was 0.24 ml (95% confidence interval 0.18 to 0.68). CONCLUSION: Our findings may influence clinicians' initial dose selection for spinal anaesthesia when a spinal catheter is used. The dose may be less than previously thought. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT01680120. PMID- 25693138 TI - Intraoperative temperature monitoring with zero heat flux technology (3M SpotOn sensor) in comparison with sublingual and nasopharyngeal temperature: An observational study. AB - BACKGROUND: Perioperative hypothermia is common in patients undergoing general anaesthesia and is associated with important adverse events. The 'gold standard' for monitoring body core temperature - the pulmonary artery catheter - is invasive and unsuitable for most patients. For routine clinical practice, other sites and methods of temperature monitoring are commonly used. OBJECTIVE: The aim of this study was to evaluate a new temperature sensor (3M SpotOn) using the 'zero heat flux' method attached to the forehead, and compare it to sublingual and nasopharyngeal sensors in terms of correlation, accuracy and precision. DESIGN: An observational study. SETTING: University Medical Center Schleswig Holstein, Campus Kiel, Germany from October 2013 to January 2014. PATIENTS: One hundred and twenty patients scheduled for elective gynaecological or trauma surgery undergoing general anaesthesia were enrolled into this study. Data of 83 patients were finally analysed. Patients with unexpected blood loss, haemodynamic instability determined by the need for continuous norepinephrine infusion and/or need for postoperative ventilation were excluded from this study. INTERVENTION: Temperature monitoring was established after induction of anaesthesia with sublingual and nasopharyngeal probes, and the SpotOn sensor. MAIN OUTCOME MEASURES: Body temperature was measured 15, 45 and 75 min after induction of anaesthesia from sublingual and nasopharyngeal probes and the 3M SpotOn sensor at precisely the same moment. RESULTS: Analysis of 83 data sets revealed that 3M SpotOn temperatures were almost identical with nasopharyngeal temperatures (mean difference 0.07 degrees C; P = 0.1424) and slightly lower than sublingual temperatures by 0.35 degrees C (P < 0.0001). Coefficients of determination (r) for both methods were between 0.87 (SpotOn vs. nasopharyngeal measurement) and 0.77 (SpotOn vs. sublingual measurement). Bland-Altman analysis revealed a bias (SD) between 0.07 degrees C (0.21) (SpotOn vs. nasopharyngeal) and -0.35 degrees C (0.29) (SpotOn vs. sublingual measurement). CONCLUSION: With respect to correlation, accuracy and precision, the 3M SpotOn sensor provides a good measurement of body temperature in comparison to the nasopharyngeal probe and an acceptable measurement in comparison with sublingual thermometry. It is adequate for clinical use. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT02031159. PMID- 25693139 TI - Regional anaesthesia in neonates, infants and children: an educational review. AB - Prophylactic analgesia with local anaesthesia is widely used in children and has a good safety record. Performing regional blocks in anaesthetised children is a safe and generally accepted practice. When compared with adults, lower concentrations of local anaesthetics are sufficient in children; the onset of a block occurs more rapidly but the duration is usually shorter. Local anaesthetics have a greater volume of distribution, a lower clearance and a higher free (non protein-bound) fraction. The recommended maximum dose has to be calculated for every individual. Peripheral blocks provide analgesia restricted to the site of surgery, and some of them have a very long duration of action. Abdominal wall blocks, such as transverse abdominis plane or ilio-inguinal nerve block, should be performed with the aid of ultrasound. Caudal anaesthesia is the single most important technique. Ropivacaine 0.2% or levobupivacaine 0.125 to 0.175% at roughly 1 ml kg-1 is adequate for most indications. Clonidine and morphine can be used to prolong the duration of analgesia. Ultrasound is not essential for performing caudal blocks, but it may be helpful in case of anomalies suspected at palpation and for teaching purposes. The use of paediatric epidural catheters will probably decline in the future because of the potential complications. PMID- 25693140 TI - One day on duty: Recreating an emergency department for medical students. PMID- 25693141 TI - Microcapsules for Enhanced Cargo Retention and Diversity. AB - Prevention of undesired leakage of encapsulated materials prior to triggered release presents a technological challenge for the practical application of microcapsule technologies in agriculture, drug delivery, and cosmetics. A microfluidic approach is reported to fabricate perfluoropolyether (PFPE)-based microcapsules with a high core-shell ratio that show enhanced retention of encapsulated actives. For the PFPE capsules, less than 2% leakage of encapsulated model compounds, including Allura Red and CaCl2 , over a four week trial period is observed. In addition, PFPE capsules allow cargo diversity by the fabrication of capsules with either a water-in-oil emulsion or an organic solvent as core. Capsules with a toluene-based core begin a sustained release of hydrophobic model encapsulants immediately upon immersion in an organic continuous phase. The major contribution on the release kinetics stems from the toluene in the core. Furthermore, degradable silica particles are incorporated to confer porosity and functionality to the otherwise chemically inert PFPE-based polymer shell. These results demonstrate the capability of PFPE capsules with large core-shell ratios to retain diverse sets of cargo for extended periods and make them valuable for controlled release applications that require a low residual footprint of the shell material. PMID- 25693142 TI - Macrophages and regulation of erythropoiesis. AB - PURPOSE OF REVIEW: The nature and function of macrophages at the center of erythroblastic islands is not fully understood. This review discusses novel findings on the phenotypic and molecular characterization of erythroblastic island macrophages, and their role in regulating normal and pathological erythropoiesis. RECENT FINDINGS: The phenotype to prospectively isolate erythroblastic island macrophages from mouse bone marrow has been identified. In vivo depletion of erythroblastic island macrophages causes blockade of erythroblast maturation and delays erythropoietic recovery following chemical insults. The cytokine granulocyte colony-stimulating factor arrests medullary erythropoiesis by depleting erythroblastic island macrophages from the bone marrow. In-vivo ablation of macrophages improves anemia associated with beta thalassemia and reduces red blood cell counts in the mouse model of polycythemia vera. The role of cell adhesion molecules regulating interactions between erythroblastic island macrophages and erythroblasts has been clarified, and mechanisms of pyrenocyte engulfment by erythroblastic island macrophages have been demonstrated to involve Mer tyrosine kinase receptor. SUMMARY: Prospective isolation of mouse erythroblastic island macrophages together with new genetic mouse models to specifically target erythroblastic island macrophages will enable molecular studies to better define their role in controlling erythroblast maturation. These studies have revealed the key role of erythroblastic island macrophages in regulating normal erythropoiesis and could be interesting targets to treat beta-thalassemia or polycythemia vera. PMID- 25693143 TI - Taxonomic and environmental variation of metabolite profiles in marine dinoflagellates of the genus symbiodinium. AB - Microorganisms in terrestrial and marine ecosystems are essential to environmental sustainability. In the marine environment, invertebrates often depend on metabolic cooperation with their endosymbionts. Coral reefs, one of the most important marine ecosystems, are based on the symbiosis between a broad diversity of dinoflagellates of the genus Symbiodinium and a wide phyletic diversity of hosts (i.e., cnidarian, molluscan, poriferan). This diversity is reflected in the ecology and physiology of the symbionts, yet the underlying biochemical mechanisms are still poorly understood. We examined metabolite profiles of four cultured species of Symbiodinium known to form viable symbioses with reef-building corals, S. microadriaticum (cp-type A194), S. minutum (cp-type B184), S. psygmophilum (cp-type B224) and S. trenchii (cp-type D206). Metabolite profiles were shown to differ among Symbiodinium species and were found to be affected by their physiological response to growth in different temperatures and light regimes. A combined Random Forests and Bayesian analysis revealed that the four Symbiodinium species examined primarily differed in their production of sterols and sugars, including a C29 stanol and the two sterols C28Delta5 and C28Delta5,22, as well as differences in metabolite abundances of a hexose and inositol. Inositol levels were also strongly affected by changes in temperature across all Symbiodinium species. Our results offer a detailed view of the metabolite profile characteristic of marine symbiotic dinoflagellates of the genus Symbiodinium, and identify patterns of metabolites related to several growth conditions. PMID- 25693144 TI - Application of metabolomics in drug resistant breast cancer research. AB - The metabolic profiles of breast cancer cells are different from normal mammary epithelial cells. Breast cancer cells that gain resistance to therapeutic interventions can reprogram their endogenous metabolism in order to adapt and proliferate despite high oxidative stress and hypoxic conditions. Drug resistance in breast cancer, regardless of subgroups, is a major clinical setback. Although recent advances in genomics and proteomics research has given us a glimpse into the heterogeneity that exists even within subgroups, the ability to precisely predict a tumor's response to therapy remains elusive. Metabolomics as a quantitative, high through put technology offers promise towards devising new strategies to establish predictive, diagnostic and prognostic markers of breast cancer. Along with other "omics" technologies that include genomics, transcriptomics, and proteomics, metabolomics fits into the puzzle of a comprehensive systems biology approach to understand drug resistance in breast cancer. In this review, we highlight the challenges facing successful therapeutic treatment of breast cancer and the innovative approaches that metabolomics offers to better understand drug resistance in cancer. PMID- 25693146 TI - Parting thoughts on medical education research and education for primary care. PMID- 25693145 TI - Systemic delivery of microRNA-101 potently inhibits hepatocellular carcinoma in vivo by repressing multiple targets. AB - Targeted therapy based on adjustment of microRNA (miRNA)s activity takes great promise due to the ability of these small RNAs to modulate cellular behavior. However, the efficacy of miR-101 replacement therapy to hepatocellular carcinoma (HCC) remains unclear. In the current study, we first observed that plasma levels of miR-101 were significantly lower in distant metastatic HCC patients than in HCCs without distant metastasis, and down-regulation of plasma miR-101 predicted a worse disease-free survival (DFS, P<0.05). In an animal model of HCC, we demonstrated that systemic delivery of lentivirus-mediated miR-101 abrogated HCC growth in the liver, intrahepatic metastasis and distant metastasis to the lung and to the mediastinum, resulting in a dramatic suppression of HCC development and metastasis in mice without toxicity and extending life expectancy. Furthermore, enforced overexpression of miR-101 in HCC cells not only decreased EZH2, COX2 and STMN1, but also directly down-regulated a novel target ROCK2, inhibited Rho/Rac GTPase activation, and blocked HCC cells epithelial-mesenchymal transition (EMT) and angiogenesis, inducing a strong abrogation of HCC tumorigenesis and aggressiveness both in vitro and in vivo. These results provide proof-of-concept support for systemic delivery of lentivirus-mediated miR-101 as a powerful anti-HCC therapeutic modality by repressing multiple molecular targets. PMID- 25693147 TI - Educating for complexity and professional judgement: whither the role of practice based research? PMID- 25693148 TI - Facilitating research in postgraduate medical education. PMID- 25693149 TI - Primary care education research - time to raise our game? PMID- 25693150 TI - Impact of rating demands on rater-based assessments of clinical competence. AB - PURPOSE: Many assessment practices used in primary care rely upon judgements provided by individuals observing trainees or colleagues. Despite there being many reasons to view these observations as cognitively complex, the extent to which fallibility in judgement reflects mental workload has not been examined experimentally. The objective of this study was to evaluate the impact of increasing rating demands on rater-based assessments of clinical competence. METHODS: Participants were randomly assigned to one of four conditions (in a 2*2 factorial design) and asked to rate three pre-recorded unscripted clinical encounters illustrating three levels of performance (high, medium, low). We looked at the effect on participants of having a larger (seven) or smaller (two) number of dimensions to rate, and/or distracting them with extraneous tasks (attending to patient status and the activity of additional individuals observable on video). Outcome measures included number of dimension-relevant behaviours identified, ability to differentiate between levels of performance, and inter-rater reliability. RESULTS: Using the two dimensions common to both groups, ANOVA revealed a significant effect of the number of dimensions included in the scale on the number of relevant behaviours identified: participants in the 2D group identified more features than those in the 7D group. Both groups were able to differentiate between levels of performance, but post hoc analyses revealed significance on all pairwise comparisons in the 2D group and not in the 7D group. Inter-rater reliability increased from 0.45 in the 7D group to 0.70 when participants were required to consider only two dimensions. By contrast, the distractions had little effect. CONCLUSIONS: The results of this study provide preliminary evidence that requiring raters to consider a greater number of dimensions can decrease (a) the number of dimension-relevant behaviours identified, (b) the capacity to differentiate between levels of performance, and (c) inter-rater reliability. PMID- 25693151 TI - Rating clinical competency - what can we realistically ask of our assessors? PMID- 25693152 TI - What do you do when you don't know what to do? GP associates in training (AiT) and their experiences of uncertainty. AB - Although study courses for AiTs commonly include sessions on the clinical evidence base and the consultation skills needed to manage uncertainty, there is little published about understanding AiTs' experiences of uncertainty and the coping strategies they currently use. This study explored in AiT focus groups the question 'what do you do when you don't know what to do?' Thematic analysis revealed that uncertainly was a common and difficult experience, occurring in a variety of clinical circumstances. We were able to identify both functional and dysfunctional strategies that trainees use in dealing with uncertainty. The resulting classification of uncertainty into the areas of analysing, negotiating, networking and team-working has implications for training, which are discussed. PMID- 25693153 TI - Does experience in general practice influence the clinical thinking of foundation trainees? AB - The aim of this exploratory study was to capture and identify changes in clinical thinking amongst foundation trainees after a four-month attachment in general practice, and to develop a means of analysing the data collected to inform understanding about how clinical thinking develops and changes for a trainee - the learner - in the context of clinical experience. We use the term 'clinical thinking' consistently throughout our paper to refer to the trainees' general thinking about a case, and do so in the same way as other academics. Through the innovative use of Mind Maps, we have sought to demonstrate whether there was a significant change in the themes and key features contained in maps drawn by foundation year 2 trainees before and after an attachment in general practice, and to locate the nature of the change if present. Being able to identify such change is potentially valuable as it can assist in revealing a trainee's learning needs and shape future learning. PMID- 25693154 TI - The GP retainer scheme: report of a national survey. AB - The current context of organisational change and new working patterns, together with the high cost of medical training, mean it is of vital importance that the NHS retains its trained workforce. The GP retainer scheme supports doctors who for reasons of personal circumstance are restricted in their ability to compete for employment in medicine, and aims to facilitate the retention of their skills and confidence. This national study evaluates the experiences and views of current and past GP retainers and provides a rigorous assessment of the retainer scheme. It is a mixed method study: an online questionnaire was completed by 318 current and ex-retainers across the UK; follow-up telephone interviews were conducted with 30 respondents. The study finds that the GP retainer scheme is effective in retaining GPs through times of transition and provides evidence to support the continuing funding of the scheme across the UK. The scheme is beneficial for doctors who also have a role in caring for young children and is also highly valued by a minority of GP retainers who are using it to return to work after illness, or to practice in a more limited role, due to chronic illness or disability. This study found variations in the implementation of the educational entitlement which is fundamental to the scheme. A minority of retainers experienced problems with the implementation of the scheme and recommendations are made for improvements. PMID- 25693155 TI - Teaching tips. PMID- 25693156 TI - A GP trainer's toolbox - an e-learning resource for general practice trainers. PMID- 25693157 TI - Supporting newly qualified GPs: an evolving educational programme in Dorset. PMID- 25693158 TI - Run simulation in your workplace. AB - Effective simulation does not require a hightech simulation suite. Bringing simulation into the workplace allows learners to practice with their own colleagues using local equipment, at low cost and on a more regular basis. PMID- 25693159 TI - Dementia and primary care: views of future general practitioners. PMID- 25693160 TI - Development and validation of 4 different rat models of uncontrolled hemorrhage. AB - IMPORTANCE: Hemorrhage is the leading cause of death in military trauma and second leading cause of death in civilian trauma. Although many well-established animal models of hemorrhage exist in the trauma and anticoagulant literature, few focus on directly quantitating blood loss. OBJECTIVE: To establish and validate a reproducible rodent model of uncontrolled hemorrhage to serve as the foundation for developing therapies for noncompressible torso trauma. DESIGN, SETTINGS, AND SUBJECTS: We developed and evaluated 4 different hemorrhage models using male Sprague-Dawley rats (6 rats/model), aged 10 to 14 weeks and weighing 330 to 460 g, at the Department of Surgery, Northwestern University. INTERVENTIONS: We used tail-cut (4 cm), liver punch biopsy (12 mm), liver laceration (3.0 * 1.5 cm), and spleen transection models. All animals underwent invasive hemodynamic monitoring. MAIN OUTCOMES AND MEASURES: Blood loss, expressed as a percentage of total blood volume (TBV), mean arterial pressure, and heart rate, which were recorded at 2- to 5-minute intervals. RESULTS: The tail-cut model resulted in a mean (SD) TBV loss of 15.4% (6.0%) with hemodynamics consistent with class I hemorrhagic shock. The liver punch biopsy model resulted in a mean (SD) TBV loss of 16.7% (3.3%) with hemodynamics consistent with class I hemorrhagic shock. The liver laceration model resulted in a mean (SD) TBV loss of 19.8% (3.0%) with hemodynamics consistent with class II hemorrhagic shock. The spleen transection model resulted in the greatest blood loss (P < .01), with a mean (SD) TBV loss of 27.9% (3.4%) and hemodynamics consistent with class II hemorrhagic shock. The liver laceration and punch biopsy models resulted in most of the blood loss within the first 2 minutes, whereas the spleen transection and tail-cut models resulted in a steady loss during 10 minutes. The liver laceration and spleen transection models resulted in the greatest degree of hemodynamic instability (mean [SD] arterial pressure decreases of 25 [1] and 41 [11] mm Hg, respectively). One-hour survival was 100% in all 4 models. CONCLUSIONS AND RELEVANCE: We established and validated the reproducibility of 4 different rat models of uncontrolled hemorrhage. These models provide a foundation to design novel nonsurgical therapies to control hemorrhage, and the different degrees of hemorrhagic shock produced from these models allow for flexibility in experimental design. PMID- 25693161 TI - A high-throughput cidality screen for Mycobacterium tuberculosis. AB - Exposure to Mycobacterium tuberculosis (Mtb) aerosols is a major threat to tuberculosis (TB) researchers, even in bio-safety level-3 (BSL-3) facilities. Automation and high-throughput screens (HTS) in BSL3 facilities are essential for minimizing manual aerosol-generating interventions and facilitating TB research. In the present study, we report the development and validation of a high throughput, 24-well 'spot-assay' for selecting bactericidal compounds against Mtb. The bactericidal screen concept was first validated in the fast-growing surrogate Mycobacterium smegmatis (Msm) and subsequently confirmed in Mtb using the following reference anti-tubercular drugs: rifampicin, isoniazid, ofloxacin and ethambutol (RIOE, acting on different targets). The potential use of the spot assay to select bactericidal compounds from a large library was confirmed by screening on Mtb, with parallel plating by the conventional gold standard method (correlation, r2 = 0.808). An automated spot-assay further enabled an MBC90 determination on resistant and sensitive Mtb clinical isolates. The implementation of the spot-assay in kinetic screens to enumerate residual Mtb after either genetic silencing (anti-sense RNA, AS-RNA) or chemical inhibition corroborated its ability to detect cidality. This relatively simple, economical and quantitative HTS considerably minimized the bio-hazard risk and enabled the selection of novel vulnerable Mtb targets and mycobactericidal compounds. Thus, spot-assays have great potential to impact the TB drug discovery process. PMID- 25693162 TI - Bovine milk proteome in the first 9 days: protein interactions in maturation of the immune and digestive system of the newborn. AB - In order to better understand the milk proteome and its changes from colostrum to mature milk, samples taken at seven time points in the first 9 days from 4 individual cows were analyzed using proteomic techniques. Both the similarity in changes from day 0 to day 9 in the quantitative milk proteome, and the differences in specific protein abundance, were observed among four cows. One third of the quantified proteins showed a significant decrease in concentration over the first 9 days after calving, especially in the immune proteins (as much as 40 fold). Three relative high abundant enzymes (XDH, LPL, and RNASE1) and cell division and proliferation protein (CREG1) may be involved in the maturation of the gastro-intestinal tract. In addition, high correlations between proteins involved in complement and blood coagulation cascades illustrates the complex nature of biological interrelationships between milk proteins. The linear decrease of protease inhibitors and proteins involved in innate and adaptive immune system implies a protective role for protease inhibitor against degradation. In conclusion, the results found in this study not only improve our understanding of the role of colostrum in both host defense and development of the newborn calf but also provides guidance for the improvement of infant formula through better understanding of the complex interactions between milk proteins. PMID- 25693163 TI - Schwann cells contribute to neurodegeneration in transthyretin amyloidosis. AB - Familial amyloidotic polyneuropathy (FAP) is one of the transthyretin (TTR) amyloidoses characterized by extracellular amyloid deposits and peripheral nerve involvement. Recently, we found significant expression of the TTR gene in Schwann cells of the peripheral nervous system. We hypothesized that local expression of variant TTR in Schwann cells may contribute to neurodegeneration in FAP. Schwann cells derived from the dorsal root ganglia (DRG) of transgenic mice expressing variant human TTR in a mouse null background were cultured long term to obtain spontaneously immortalized cell lines. We established an immortalized Schwann cell line, TgS1, derived from the transgenic mice. TgS1 cells synthesized variant TTR and secreted it into the medium. As sensory neuropathy usually arises early in FAP, we examined the effect of the conditioned medium derived from TgS1 cells on neurite outgrowth from DRG sensory neurons. Conditioned medium derived from TgS1 cells inhibited neurite outgrowth from the sensory neurons. TTR deposition in the DRG of aged transgenic mice was investigated by immunohistochemistry. TTR aggregates were observed in the cytoplasm of Schwann cells and satellite cells. Proteasome inhibition induced TTR aggregates as aggresomes in TgS1 cells. In conclusion, local variant TTR gene expression in Schwann cells might trigger neurodegeneration in FAP. We established a spontaneously immortalized Schwann cell line derived from familial amyloidotic polyneuropathy transgenic mice. Conditioned medium from the cells contained variant transthyretin (TTR), and inhibited neurite outgrowth of neurons. TTR aggregates were observed in the Schwann cells and satellite cells of aged mice. Proteasome inhibition induced TTR aggregates as aggresomes in the cultured cells. These results support the hypothesis that Schwann cells contribute to neurodegeneration in familial amyloidotic polyneuropathy (FAP). PMID- 25693164 TI - Investigating the associations of self-rated health: heart rate variability is more strongly associated than inflammatory and other frequently used biomarkers in a cross sectional occupational sample. AB - The present study aimed to investigate the possible mechanisms linking a single item measure of global self-rated health (SRH) with morbidity by comparing the association strengths between SRH with markers of autonomic nervous system (ANS) function, inflammation, blood glucose and blood lipids. Cross-sectional comprehensive health-check data of 3947 working adults (age 42+/-11) was used to calculate logistic regressions, partial correlations and compare correlation strength using Olkins Z. Adjusted logistic regression models showed a negative association between SRH (higher values indicating worse health) and measures of heart rate variability (HRV). Glycemic markers were positively associated with poor SRH. No adjusted association was found with inflammatory markers, BP or lipids. In both unadjusted and adjusted linear models Pearson's correlation strength was significantly higher between SRH with HRV measures compared to SRH with other biomarkers. This is the first study investigating the association of ANS function and SRH. We showed that a global measure of SRH is associated with HRV, and that all measures of ANS function were significantly more strongly associated with SRH than any other biomarker. The current study supports the hypothesis that the extent of brain-body communication, as indexed by HRV, is associated with self-rated health. PMID- 25693165 TI - Moulage: the decaying art of dermatology. PMID- 25693166 TI - Synthesis of deuterium-labelled isotopomer of deferasirox. AB - A d4 -labeled isotopomer of deferasirox was synthesized as internal standard for use in a LC/mass spectroscopy (MS)/MS method developed for the simultaneous quantitative determination of deferasirox in human serum. d4 -deferasirox was synthesized from d8 -toluene. PMID- 25693167 TI - Iron-catalyzed tandem cyclization of olefinic dicarbonyl compounds with benzylic Csp(3)-H bonds for the synthesis of dihydrofurans. AB - A novel iron-catalyzed radical cyclization of olefinic dicarbonyl compounds with benzyl hydrocarbons has been developed. This protocol provides ready access to a variety of dihydrofurans containing a quaternary carbon center in moderate to good yields. Furthermore, this reaction could also be further expanded to other types of substrates containing unactivated Csp(3)-H bonds, such as ethers and alkanes. PMID- 25693168 TI - Chemical composition and biological activities of trans-Himalayan alga Spirogyra porticalis (Muell.) Cleve. AB - The freshwater alga Spirogyra porticalis (Muell.) Cleve, a filamentous charophyte, collected from the Indian trans-Himalayan cold desert, was identified on the basis of morpho-anatomical characters. Extracts of this alga were made using solvents of varying polarity viz. n-hexane, acetonitrile, methanol and water. The antioxidant capacities and phenolic profile of the extracts were estimated. The methanol extract showing highest antioxidant capacity and rich phenolic attributes was further investigated and phytochemical profiling was conducted by gas chromatography-mass spectrometry (GC/MS) hyphenated technique. The cytotoxic activity of methanol extract was evaluated on human hepatocellular carcinoma HepG2 and colon carcinoma RKO cell lines. The anti-hypoxic effect of methanol extract of the alga was tested on in vivo animal system to confirm its potential to ameliorate oxidative stress. The antioxidant assays viz. ferric reducing antioxidant power (FRAP), 2,2'-azinobis-(3-ethylbenzothiazoline-6 sulfonic acid) diammonium salt (ABTS), 1,1-diphenyl-2-picrylhydrazyl (DPPH) and nitric oxide (NO) radical scavenging capacities, beta-carotene-linoleic acid bleaching property and lipid peroxidation exhibited analogous results, wherein the algal extracts showed significantly high antioxidant potential. The extracts were also found to possess high content of total proanthocyanidin, flavonoid and polyphenol. GC/MS analysis revealed the presence of thirteen chemotypes in the methanol extract representing different phytochemical groups like fatty acid esters, sterols, unsaturated alcohols, alkynes etc. with substantial phyto pharmaceutical importance. The methanol extract was observed to possess anticancer activity as revealed from studies on HepG2 and RKO cell lines. In the present study, S. porticalis methanol extract also provided protection from hypoxia-induced oxidative stress and accelerated the onset of adaptative changes in rats during exposure to hypobaric hypoxia. The bioactive phytochemicals present in this trans-Himalayan alga are of enormous interest and can be utilized sustainably for discovery of novel drugs against oxidative stress. PMID- 25693169 TI - The psychedelic state induced by ayahuasca modulates the activity and connectivity of the default mode network. AB - The experiences induced by psychedelics share a wide variety of subjective features, related to the complex changes in perception and cognition induced by this class of drugs. A remarkable increase in introspection is at the core of these altered states of consciousness. Self-oriented mental activity has been consistently linked to the Default Mode Network (DMN), a set of brain regions more active during rest than during the execution of a goal-directed task. Here we used fMRI technique to inspect the DMN during the psychedelic state induced by Ayahuasca in ten experienced subjects. Ayahuasca is a potion traditionally used by Amazonian Amerindians composed by a mixture of compounds that increase monoaminergic transmission. In particular, we examined whether Ayahuasca changes the activity and connectivity of the DMN and the connection between the DMN and the task-positive network (TPN). Ayahuasca caused a significant decrease in activity through most parts of the DMN, including its most consistent hubs: the Posterior Cingulate Cortex (PCC)/Precuneus and the medial Prefrontal Cortex (mPFC). Functional connectivity within the PCC/Precuneus decreased after Ayahuasca intake. No significant change was observed in the DMN-TPN orthogonality. Altogether, our results support the notion that the altered state of consciousness induced by Ayahuasca, like those induced by psilocybin (another serotonergic psychedelic), meditation and sleep, is linked to the modulation of the activity and the connectivity of the DMN. PMID- 25693170 TI - Prior individual training and self-organized queuing during group emergency escape of mice from water pool. AB - We study the impact of prior individual training during group emergency evacuation using mice that escape from an enclosed water pool to a dry platform via any of two possible exits. Experimenting with mice avoids serious ethical and legal issues that arise when dealing with unwitting human participants while minimizing concerns regarding the reliability of results obtained from simulated experiments using 'actors'. First, mice were trained separately and their individual escape times measured over several trials. Mice learned quickly to swim towards an exit-they achieved their fastest escape times within the first four trials. The trained mice were then placed together in the pool and allowed to escape. No two mice were permitted in the pool beforehand and only one could pass through an exit opening at any given time. At first trial, groups of trained mice escaped seven and five times faster than their corresponding control groups of untrained mice at pool occupancy rate rho of 11.9% and 4%, respectively. Faster evacuation happened because trained mice: (a) had better recognition of the available pool space and took shorter escape routes to an exit, (b) were less likely to form arches that blocked an exit opening, and (c) utilized the two exits efficiently without preference. Trained groups achieved continuous egress without an apparent leader-coordinator (self-organized queuing)-a collective behavior not experienced during individual training. Queuing was unobserved in untrained groups where mice were prone to wall seeking, aimless swimming and/or blind copying that produced circuitous escape routes, biased exit use and clogging. The experiments also reveal that faster and less costly group training at rho = 4%, yielded an average individual escape time that is comparable with individualized training. However, group training in a more crowded pool (rho = 11.9%) produced a longer average individual escape time. PMID- 25693171 TI - Forensic medical examinations conducted on complainants of sexual assault in the Forensic Medicine Institute, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, between 2006 and 2013. AB - A total of 46 cases of alleged sexual assault were analysed from the years 2006 2013 where forensic medical examinations were conducted. The material was compared with data from literature. All the victims were female. In 9 cases (20%) a sexual assault by sexual touching was alleged, 67% of complainants (31 cases) had alleged non-consensual sexual intercourse, 6 complainants (13%) had no recollection of events. Genital area injuries were reported in 26% of sexual assault victims. Injuries of other parts of the body were found in 73% of victims. None of the subjects were positive for severe injuries such as fractures, wounds, and head trauma with loss of consciousness. The majority of complainants (29 cases, 63%) were examined within 24 hours after the incident and 6 examinees (13%) were assessed between 24 and 48 hours after the alleged sexual assault. Eleven forensic medical examinations (24%) were conducted after the lapse of more than 48 hours since the alleged incident. Twenty nine complainants admitted that they had washed their genital area after the sexual assault. Forensic swabs were taken during all forensic medical examinations. PMID- 25693172 TI - Endogenous infection and hospital's civil liability - a case study. AB - The subject matter of this publication is the legal assessment of endogenous infection - the specific type of hospital infections. The main aim of the publication is to answer the question of whether medical and legal grounds exist for civil liability for endogenous infections and for treating those infections as cases of medical malpractice or medical events. The research method adopted is a case study. The authors have analysed a civil lawsuit for compensation instituted by an infected patient against a Polish hospital, adjudicated in 2013. The main conclusion of the publication is to postulate distinguishing medical malpractice from complications resulting from the reactions of the human body to treatment. The authors argue that endogenous infections should be treated as the latter-mentioned of these two cases. PMID- 25693173 TI - Lethal poisoning with theophylline in the form of rectally administered tablets. AB - The paper discusses the case of death of a 56-year-old man who died in a municipal hospital from which his body was taken to the Chair and Department of Forensic Medicine, Jagiellonian University Medical College, Krakow. The man was said to have been found unconscious by accidental passers-by. While being transported to the hospital's emergency department, he suffered an attack of convulsions and went into cardiac arrest. He was subsequently successfully resuscitated. A physical examination performed at the hospital revealed the presence of multiple, only slightly dissolved tablets in the man's rectum. The patient died on the 25th day of hospitalization. A toxicological analysis showed a toxic concentration of theophylline (25 mg/l) in the man's blood. Theophylline was identified as the main ingredient of the tablets. The cause of death was thus given as theophylline poisoning. The reported case is unusual in that the poisoning occurred as a result of overdosing on an oral drug which was administered by the victim rectally, and in that the chosen substance currently is not very commonly used in medicine, and does not cause symptoms of intoxication. PMID- 25693174 TI - Determination of cocaine and benzoylecgonine in nails by liquid chromatography electrospray ionization-tandem mass spectrometry. AB - Nails and hair are a biological matrix which can be analyzed to confirm the use of a xenobiotic even several months after intake. Results of nail analysis can be used, for example, as evidence in civil and criminal law cases in which a history of drug use can influence the court's decision. The paper presents results of analysis of a nail sample taken from a man who was suspected of trafficking cocaine. The suspect pleaded guilty to the possession of the drug for his own use because, as he claimed, he was addicted to cocaine. A nail sample was taken. Detection and quantification were carried out using liquid chromatography-mass spectrometry (LC-ESI-MS). The concentration of cocaine in nails was found to be 47 ng/mg, and benzoylecgonine - 14 ng/mg. PMID- 25693175 TI - A new dimension of the forensic DNA expertise - the need for training experts and expertise recipients. AB - Forensic genetics is a rapidly developing discipline. Nowadays, human genetic identification relies on the application of complex solutions ensuring high sensitivity and resistance to the inhibition and degradation of biological traces, and revealing maximum information which has relevance for the justice system. However, recent improvements in forensic DNA identification testing are associated with problems including secondary transfer, DNA mixtures and incompleteness of DNA profiles, which were formerly less significant. It also seems that the potential of the national DNA database in Poland has not been fully developed, and it is necessary to implement an appropriate information policy in order to improve it. Novel methods that can be applied at the level of investigation include analysis of biogeographic ancestry, prediction of visible traits, and estimation of human chronological age. Moreover, next-generation sequencing has a potential to entirely replace capillary electrophoresis in forensic genetics. Further works are necessary to ensure a proper implementation of uniform standards of data interpretation and evaluation of DNA evidence in forensic genetics. In order to maintain proper standards of forensic DNA assessment, continuous training of DNA experts and appropriate information policy for recipients of DNA assessments are required. PMID- 25693176 TI - Space use variation in co-occurring sister species: response to environmental variation or competition? AB - Coexistence often involves niche differentiation either as the result of environmental divergence, or in response to competition. Disentangling the causes of such divergence requires that environmental variation across space is taken into account, which is rarely done in empirical studies. We address the role of environmental variation versus competition in coexistence between two rodent species: Rhabdomys bechuanae (bechuanae) and Rhabdomys dilectus dilectus (dilectus) comparing their habitat preference and home range (HR) size in areas with similar climates, where their distributions abut (allopatry) or overlap (sympatry). Using Outlying Mean Index analyses, we test whether habitat characteristics of the species deviate significantly from a random sample of available habitats. In allopatry, results suggest habitat selection: dilectus preferring grasslands with little bare soil while bechuanae occurring in open shrublands. In sympatry, shrubland type habitats dominate and differences are less marked, yet dilectus selects habitats with more cover than bechuanae. Interestingly, bechuanae shows larger HRs than dilectus, and both species display larger HRs in sympatry. Further, HR overlaps between species are lower than expected. We discuss our results in light of data on the phylogeography of the genus and propose that evolution in allopatry resulted in adaptation leading to different habitat preferences, even at their distribution margins, a divergence expected to facilitate coexistence. However, since sympatry occurs in sites where environmental characteristics do not allow complete species separation, competition may explain reduced inter-species overlap and character displacement in HR size. This study reveals that both environmental variation and competition may shape species coexistence. PMID- 25693177 TI - Learning among nursing faculty: insights from a participatory action research project about teaching international students. AB - It is imperative that nursing education addresses the issues arising from globalization. The adjustment challenges faced by international nursing students globally highlight the need to understand how nursing faculty experience and teach nursing classes with a mix of domestic and foreign students. This article reports on a participatory action research (PAR) study to examine and enhance the scholarly teaching of international nursing students. The overarching research question for this PAR was: How did participation in a PAR study contribute to shared learning and professional development of nursing faculty teaching international students? Five major themes were identified across the PAR: creating sharing spaces, recognizing and respecting diversity, developing and acknowledging teaching capabilities, utilizing precious time, and valuing the research. In summary, PAR was a useful approach to engage faculty in research by providing a process and a space to address concerns about the teaching and learning of international students. PMID- 25693178 TI - Heat stress-induced disruption of endothelial barrier function is via PAR1 signaling and suppressed by Xuebijing injection. AB - Increased vascular permeability leading to acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) is central to the pathogenesis of heatstroke. Protease-activated receptor 1 (PAR1), the receptor for thrombin, plays a key role in disruption of endothelial barrier function in response to extracellular stimuli. However, the role of PAR1 in heat stress-induced endothelial hyper-permeability is unknown. In this study, we measured PAR1 protein expression in heat-stressed human umbilical venous endothelial cells (HUVECs), investigated the influences of PAR1 on endothelial permeability, F actin rearrangement, and moesin phosphorylation by inhibiting PAR1 with its siRNA, neutralizing antibody (anti-PAR1), specific inhibitor(RWJ56110), and Xuebijing injection (XBJ), a traditional Chinese medicine used for sepsis treatment, and evaluated the role of PAR1 in heatstroke-related ALI/ARDS in mice by suppressing PAR1 with RWJ56110, anti-PAR1and XBJ. We found that heat stress induced PAR1 protein expression 2h after heat stress in endothelial cells, caused the release of endothelial matrix metalloprotease 1, an activator of PAR1, after 60 or 120 min of heat stimulation, as well as promoted endothelial hyper permeability and F-actin rearrangement, which were inhibited by suppressing PAR1 with RWJ56110, anti-PAR1 and siRNA. PAR1 mediated moesin phosphorylation, which caused F-actin rearrangement and disruption of endothelial barrier function. To corroborate findings from in vitro experiments, we found that RWJ56110 and the anti-PAR1 significantly decreased lung edema, pulmonary microvascular permeability, protein exudation, and leukocytes infiltrations in heatstroke mice. Additionally, XBJ was found to suppress PAR1-moesin signal pathway and confer protective effects on maintaining endothelial barrier function both in vitro and in vivo heat-stressed model, similar to those observed above with the inhibition of PAR1. These results suggest that PAR1 is a potential therapeutic target in heatstroke. PMID- 25693179 TI - Perceived empathy of service providers mediates the association between perceived discrimination and behavioral intention to take up HIV antibody testing again among men who have sex with men. AB - HIV antibody testing is a key measure of HIV prevention for men who have sex with men (MSM). The World Health Organization recommends sexually active and at-risk MSM to take up HIV antibody testing regularly. This study aimed to investigate the prevalence of behavioral intention to take up HIV antibody testing in the next six months among Hong Kong MSM who were ever-testers. An anonymous cross sectional survey recruited 326 MSM who had taken up HIV antibody testing from gay friendly venues and internet in Hong Kong. Of the participants, 40.8% had had unprotected anal intercourse with regular or non-regular male sex partners in the last six months; they were at risk of HIV transmission despite experience in HIV antibody testing. Only 37.2% showed a strong intention to take up HIV antibody testing again in the next six months. Adjusted analysis showed that both perceived discrimination toward Hong Kong MSM (AOR = .60, 95% CI: .36-.98) and the CARE Measure assessing perceived empathy of service providers (AOR = 1.05, 95% CI: 1.02-1.08) were significantly associated with intention for retesting. Perceived discrimination, however, became statistically non-significant (AOR = .68, 95% CI: .41-1.14), when both CARE Measure and perceived discrimination entered into the adjusted model. It is warranted to increase HIV retesting rate by removing perceived discrimination and reducing the negative effect of perceived discrimination through enhancement of empathy of service providers. PMID- 25693180 TI - Hydrodynamic phonon transport in suspended graphene. AB - Recent studies of thermal transport in nanomaterials have demonstrated the breakdown of Fourier's law through observations of ballistic transport. Despite its unique features, another instance of the breakdown of Fourier's law, hydrodynamic phonon transport, has drawn less attention because it has been observed only at extremely low temperatures and narrow temperature ranges in bulk materials. Here, we predict on the basis of first-principles calculations that the hydrodynamic phonon transport can occur in suspended graphene at significantly higher temperatures and wider temperature ranges than in bulk materials. The hydrodynamic transport is demonstrated through drift motion of phonons, phonon Poiseuille flow and second sound. The significant hydrodynamic phonon transport in graphene is associated with graphene's two-dimensional features. This work opens a new avenue for understanding and manipulating heat flow in two-dimensional materials. PMID- 25693181 TI - Identification and characteristics of microRNAs from army worm, Spodoptera frugiperda cell line Sf21. AB - microRNAs play important regulatory role in all intrinsic cellular functions. Amongst lepidopteran insects, miRNAs from only Bombyx mori have been studied extensively with a little focus on Spodoptera sp. In the present study, we identified a total of 226 miRNAs from Spodoptera frugiperda cell line Sf21. Of the total, 116 miRNAs were well conserved within other insects, like B. mori, Drosophila melanogaster and Tribolium castenum while the remaining 110 miRNAs were identified as novel based on comparative analysis with the insect miRNA data set. Landscape distribution analysis based on Sf21 genome assembly revealed clustering of few novel miRNAs. A total of 5 miRNA clusters were identified and the largest one encodes 5 miRNA genes. In addition, 12 miRNAs were validated using northern blot analysis and putative functional role assignment for 6 Sf miRNAs was investigated by examining their relative abundance at different developmental stages of Spodoptera litura and body parts of 6th instar larvae. Further, we identified a total of 809 potential target genes with GO terms for selected miRNAs, involved in different metabolic and signalling pathways of the insect. The newly identified miRNAs greatly enrich the repertoire of insect miRNAs and analysis of expression profiles reveal their involvement at various steps of biochemical pathways of the army worm. PMID- 25693182 TI - Cardiac telocytes and fibroblasts in primary culture: different morphologies and immunophenotypes. AB - Telocytes (TCs) are a peculiar type of interstitial cells with very long prolongations termed telopodes. TCs have previously been identified in different anatomic structures of the heart, and have also been isolated and cultured from heart tissues in vitro. TCs and fibroblasts, both located in the interstitial spaces of the heart, have different morphologies and functionality. However, other than microscopic observation, a reliable means to make differential diagnosis of cardiac TCs from fibroblasts remains unclear. In the present study, we isolated and cultured cardiac TCs and fibroblasts from heart tissues, and observed their different morphological features and immunophenotypes in primary culture. Morphologically, TCs had extremely long and thin telopodes with moniliform aspect, stretched away from cell bodies, while cell processes of fibroblasts were short, thick and cone shaped. Furthermore, cardiac TCs were positive for CD34/c-kit, CD34/vimentin, and CD34/PDGFR-beta, while fibroblasts were only vimentin and PDGFR-beta positive. In addition, TCs were also different from pericytes as TCs were CD34 positive and alpha-SMA weak positive while pericytes were CD34 negative but alpha-SMA positive. Besides that, we also showed cardiac TCs were homogenously positive for mesenchymal marker CD29 but negative for hematopoietic marker CD45, indicating that TCs could be a source of cardiac mesenchymal cells. The differences in morphological features and immunophenotypes between TCs and fibroblasts will provide more compelling evidence to differentiate cardiac TCs from fibroblasts. PMID- 25693183 TI - Exact solutions of linear reaction-diffusion processes on a uniformly growing domain: criteria for successful colonization. AB - Many processes during embryonic development involve transport and reaction of molecules, or transport and proliferation of cells, within growing tissues. Mathematical models of such processes usually take the form of a reaction diffusion partial differential equation (PDE) on a growing domain. Previous analyses of such models have mainly involved solving the PDEs numerically. Here, we present a framework for calculating the exact solution of a linear reaction diffusion PDE on a growing domain. We derive an exact solution for a general class of one-dimensional linear reaction-diffusion process on 0 6,000 kgs per GMA of fresh game meat annually from hunting operators. To assess hunting industry compliance, we also compared the amount of meat expected as per the lease agreements versus observed amounts of meat provisioned from three GMAs during 2007-2009. In seven of eight annual comparisons of these GMAs, provisioning of meat exceeded what was required in the lease agreements. Provisioning occurred throughout the hunting season and peaked during the end of the dry season (September-October) coincident with when rural Zambians are most likely to encounter food shortages. We extrapolated our results across all GMAs and estimated 129,771 kgs of fresh game meat provisioned annually by the sport hunting industry to rural communities in Zambia at an approximate value for the meat alone of >US$600,000 exclusive of distribution costs. During the hunting moratorium (2013-2014), this supply of meat has halted, likely adversely affecting rural communities previously reliant on this food source. Proposed alternatives to sport hunting should consider protein provisioning in addition to other benefits (e.g., employment, community pledges, anti-poaching funds) that rural Zambian communities receive from the sport hunting industry. PMID- 25693192 TI - Elevated background noise in adult attention deficit hyperactivity disorder is associated with inattention. AB - BACKGROUND: Inattention and distractibility are core symptoms of attention deficit hyperactivity disorder (ADHD). Still the neuronal organization is largely unknown. Previously we studied the electrophysiological activity of a distinct neuronal network-the retina-and found no change in stimulus-driven neural activity in patients with ADHD. However there is growing evidence for an elevated non stimulus-driven neural activity, or neuronal background noise, as underlying pathophysiological correlate. To further examine the biological bases that might underlie ADHD and problems with inattention, we performed a new analysis to test the hypothesis of an elevated background noise as underlying neuronal correlate for ADHD and problems with inattention in humans. A direct measure of background noise in patients with ADHD has not been described yet. METHODS: The retinal background noise was assessed based on pattern electroretinogram (PERG) data in 20 unmedicated ADHD patients and 20 healthy controls. The PERG is an electrophysiological measure for retinal ganglion cell function. ADHD severity was assessed by interview and questionnaire. RESULTS: Noise amplitude was significantly higher (138%) in patients with ADHD compared to the control group (p = 0.0047). Noise amplitude correlated significantly with psychometric measures for ADHD (CAARS) especially inattention (r = 0.44, p = 0.004). CONCLUSIONS: The data provide evidence that an elevated background noise is associated with symptoms of inattention in ADHD and support the use of therapeutic interventions that reduce noise and distraction in patients with ADHD. PMID- 25693193 TI - Genetic etiology of renal agenesis: fine mapping of Renag1 and identification of Kit as the candidate functional gene. AB - Congenital anomalies of the kidney and urogenital tract (CAKUT) occur in approximately 0.5% of live births and represent the most frequent cause of end stage renal disease in neonates and children. The genetic basis of CAKUT is not well defined. To understand more fully the genetic basis of one type of CAKUT, unilateral renal agenesis (URA), we are studying inbred ACI rats, which spontaneously exhibit URA and associated urogenital anomalies at an incidence of approximately 10%. URA is inherited as an incompletely dominant trait with incomplete penetrance in crosses between ACI and Brown Norway (BN) rats and a single responsible genetic locus, designated Renag1, was previously mapped to rat chromosome 14 (RNO14). The goals of this study were to fine map Renag1, identify the causal genetic variant responsible for URA, confirm that the Renag1 variant is the sole determinant of URA in the ACI rat, and define the embryologic basis of URA in this rat model. Data presented herein localize Renag1 to a 379 kilobase (kb) interval that contains a single protein coding gene, Kit (v-kit Hardy Zukerman 4 feline sarcoma viral oncogene homolog); identify an endogenous retrovirus-derived long terminal repeat located within Kit intron 1 as the probable causal variant; demonstrate aberrant development of the nephric duct in the anticipated number of ACI rat embryos; and demonstrate expression of Kit and Kit ligand (Kitlg) in the nephric duct. Congenic rats that harbor ACI alleles at Renag1 on the BN genetic background exhibit the same spectrum of urogenital anomalies as ACI rats, indicating that Renag1 is necessary and sufficient to elicit URA and associated urogenital anomalies. These data reveal the first genetic link between Kit and URA and illustrate the value of the ACI rat as a model for defining the mechanisms and cell types in which Kit functions during urogenital development. PMID- 25693194 TI - Temporal and spatial transcriptional fingerprints by antipsychotic or propsychotic drugs in mouse brain. AB - Various types of antipsychotics have been developed for the treatment of schizophrenia since the accidental discovery of the antipsychotic activity of chlorpromazine. Although all clinically effective antipsychotic agents have common properties to interact with the dopamine D2 receptor (D2R) activation, their precise mechanisms of action remain elusive. Antipsychotics are well known to induce transcriptional changes of immediate early genes (IEGs), raising the possibility that gene expressions play an essential role to improve psychiatric symptoms. Here, we report that while different classes of antipsychotics have complex pharmacological profiles against D2R, they share common transcriptome fingerprint (TFP) profile of IEGs in the murine brain in vivo by quantitative real-time PCR (qPCR). Our data showed that various types of antipsychotics with a profound interaction of D2R including haloperidol (antagonist), olanzapine (antagonist), and aripiprazole (partial agonist) all share common spatial TFPs closely homologous to those of D2R antagonist sulpiride, and elicited greater transcriptional responses in the striatum than in the nucleus accumbens. Meanwhile, D2R agonist quinpirole and propsychotic NMDA antagonists such as MK 801 and phencyclidine (PCP) exhibited the contrasting TFP profiles. Clozapine and propsychotic drug methamphetamine (MAP) displayed peculiar TFPs that reflect their unique pharmacological property. Our results suggest that transcriptional responses are conserved across various types of antipsychotics clinically effective in positive symptoms of schizophrenia and also show that temporal and spatial TFPs may reflect the pharmacological features of the drugs. Thus, we propose that a TFP approach is beneficial to evaluate novel drug candidates for antipsychotic development. PMID- 25693195 TI - Expression and functional role of orphan receptor GPR158 in prostate cancer growth and progression. AB - Prostate cancer (PCa) is the second-leading cause of cancer-related mortality, after lung cancer, in men from developed countries. In its early stages, primary tumor growth is dependent on androgens, thus generally can be controlled by androgen deprivation therapy (ADT). Eventually however, the disease progresses to castration-resistant prostate cancer (CRPC), a lethal form in need of more effective treatments. G-protein coupled receptors (GPCRs) comprise a large clan of cell surface proteins that have been implicated as therapeutic targets in PCa growth and progression. The findings reported here provide intriguing evidence of a role for the newly characterized glutamate family member GPR158 in PCa growth and progression. We found that GPR158 promotes PCa cell proliferation independent of androgen receptor (AR) functionality and that this requires its localization in the nucleus of the cell. This suggests that GPR158 acts by mechanisms different from other GPCRs. GPR158 expression is stimulated by androgens and GPR158 stimulates AR expression, implying a potential to sensitize tumors to low androgen conditions during ADT via a positive feedback loop. Further, we found GPR158 expression correlates with a neuroendocrine (NE) differentiation phenotype and promotes anchorage-independent colony formation implying a role for GPR158 in therapeutic progression and tumor formation. GPR158 expression was increased at the invading front of prostate tumors that formed in the genetically defined conditional Pten knockout mouse model, and co-localized with elevated AR expression in the cell nucleus. Kaplan-Meier analysis on a dataset from the Memorial Sloan Kettering cancer genome portal showed that increased GPR158 expression in tumors is associated with lower disease-free survival. Our findings strongly suggest that pharmaceuticals targeting GPR158 activities could represent a novel and innovative approach to the prevention and management of CRPC. PMID- 25693196 TI - Validation of cross-genotype neutralization by hepatitis B virus-specific monoclonal antibodies by in vitro and in vivo infection. AB - Vaccines based on hepatitis B virus (HBV) genotype A have been used worldwide for immunoprophylaxis and are thought to prevent infections by non-A HBV strains effectively, whereas, vaccines generated from genotype C have been used in several Asian countries, including Japan and Korea, where HBV genotype C is prevalent. However, acute hepatitis B caused by HBV genotype A infection has been increasing in Japan and little is known about the efficacy of immunization with genotype C-based vaccines against non-C infection. We have isolated human monoclonal antibodies (mAbs) from individuals who were immunized with the genotype C-based vaccine. In this study, the efficacies of these two mAbs, HB0116 and HB0478, were analyzed using in vivo and in vitro models of HBV infection. Intravenous inoculation of HBV genotype C into chimeric mice with human hepatocytes resulted in the establishment of HBV infection after five weeks, whereas preincubation of the inocula with HB0116 or HB0478 protected chimeric mice from genotype C infection completely. Interestingly, both HB0116 and HB0478 were found to block completely genotype A infection. Moreover, infection by a genotype C strain with an immune escape substitution of amino acid 145 in the hepatitis B surface protein was also completely inhibited by incubation with HB0478. Finally, in vitro analysis of dose dependency revealed that the amounts of HB0478 required for complete protection against genotype C and genotype A infection were 5.5 mIU and 55 mIU, respectively. These results suggested that genotype C-based vaccines have ability to induce cross-genotype immunity against HBV infection. PMID- 25693197 TI - The transfection of BDNF to dopamine neurons potentiates the effect of dopamine D3 receptor agonist recovering the striatal innervation, dendritic spines and motor behavior in an aged rat model of Parkinson's disease. AB - The progressive degeneration of the dopamine neurons of the pars compacta of substantia nigra and the consequent loss of the dopamine innervation of the striatum leads to the impairment of motor behavior in Parkinson's disease. Accordingly, an efficient therapy of the disease should protect and regenerate the dopamine neurons of the substantia nigra and the dopamine innervation of the striatum. Nigral neurons express Brain Derived Neurotropic Factor (BDNF) and dopamine D3 receptors, both of which protect the dopamine neurons. The chronic activation of dopamine D3 receptors by their agonists, in addition, restores, in part, the dopamine innervation of the striatum. Here we explored whether the over expression of BDNF by dopamine neurons potentiates the effect of the activation of D3 receptors restoring nigrostriatal innervation. Twelve-month old Wistar rats were unilaterally injected with 6-hydroxydopamine into the striatum. Five months later, rats were treated with the D3 agonist 7-hydroxy-N,N-di-n-propy1-2 aminotetralin (7-OH-DPAT) administered i.p. during 41/2 months via osmotic pumps and the BDNF gene transfection into nigral cells using the neurotensin-polyplex nanovector (a non-viral transfection) that selectively transfect the dopamine neurons via the high-affinity neurotensin receptor expressed by these neurons. Two months after the withdrawal of 7-OH-DPAT when rats were aged (24 months old), immunohistochemistry assays were made. The over-expression of BDNF in rats receiving the D3 agonist normalized gait and motor coordination; in addition, it eliminated the muscle rigidity produced by the loss of dopamine. The recovery of motor behavior was associated with the recovery of the nigral neurons, the dopamine innervation of the striatum and of the number of dendritic spines of the striatal neurons. Thus, the over-expression of BDNF in dopamine neurons associated with the chronic activation of the D3 receptors appears to be a promising strategy for restoring dopamine neurons in Parkinson's disease. PMID- 25693198 TI - Increased classical endoplasmic reticulum stress is sufficient to reduce chondrocyte proliferation rate in the growth plate and decrease bone growth. AB - Mutations in genes encoding cartilage oligomeric matrix protein and matrilin-3 cause a spectrum of chondrodysplasias called multiple epiphyseal dysplasia (MED) and pseudoachondroplasia (PSACH). The majority of these diseases feature classical endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) as a result of misfolding of the mutant protein. However, the importance and the pathological contribution of ER stress in the disease pathogenesis are unknown. The aim of this study was to investigate the generic role of ER stress and the UPR in the pathogenesis of these diseases. A transgenic mouse line (ColIITgcog) was generated using the collagen II promoter to drive expression of an ER stress-inducing protein (Tgcog) in chondrocytes. The skeletal and histological phenotypes of these ColIITgcog mice were characterised. The expression and intracellular retention of Tgcog induced ER stress and activated the UPR as characterised by increased BiP expression, phosphorylation of eIF2alpha and spliced Xbp1. ColIITgcog mice exhibited decreased long bone growth and decreased chondrocyte proliferation rate. However, there was no disruption of chondrocyte morphology or growth plate architecture and perturbations in apoptosis were not apparent. Our data demonstrate that the targeted induction of ER stress in chondrocytes was sufficient to reduce the rate of bone growth, a key clinical feature associated with MED and PSACH, in the absence of any growth plate dysplasia. This study establishes that classical ER stress is a pathogenic factor that contributes to the disease mechanism of MED and PSACH. However, not all the pathological features of MED and PSACH were recapitulated, suggesting that a combination of intra- and extra-cellular factors are likely to be responsible for the disease pathology as a whole. PMID- 25693199 TI - Microstructural white matter tissue characteristics are modulated by homocysteine: a diffusion tensor imaging study. AB - Homocysteine level can lead to adverse effects on the brain white matter through endothelial dysfunction, microstructural inflammation, and neurotoxin effects. Despite previously observed associations between elevated homocysteine and macroscopic structural brain changes, it is still unknown whether microstructural associations of homocysteine on brain tissue properties can be observed in healthy subjects with routine MRI. To this end, we investigated potential relationships between homocysteine levels and microstructural measures computed with diffusion tensor imaging (DTI) in a cohort of 338 healthy participants. Significant positive correlations were observed between homocysteine levels and diffusivity measures in the bilateral temporal WM, the brainstem, and the bilateral cerebellar peduncle. This is the first study demonstrating that DTI is sufficiently sensitive to relate microstructural WM properties to homocysteine levels in healthy subjects. PMID- 25693200 TI - Multi locus variable-number tandem repeat (MLVA) typing tools improved the surveillance of Salmonella enteritidis: a 6 years retrospective study. AB - Surveillance of Salmonella enterica subsp. enterica serovar Enteritidis is generally considered to benefit from molecular techniques like multiple-locus variable-number of tandem repeats analysis (MLVA), which allow early detection and confinement of outbreaks. Here, a surveillance study, including phage typing, antimicrobial susceptibility testing and MLVA on 1,535 S. Enteritidis isolates collected between 2007 and 2012, was used to evaluate the added value of MLVA for public health surveillance in Belgium. Phage types PT4, PT8, PT21, PT1, PT6, PT14b, PT28 and PT13 dominate the Belgian S. Enteritidis population. The isolates of S. Enteritidis were most frequently susceptible to all antibiotics tested. 172 different MLVA profiles were detected, of which 9 frequent profiles included 67.2% of the S. Enteritidis population. During a serial passage experiment on selected isolates to investigate the in vitro stability of the 5 MLVA loci, no variations over time were observed indicating that the MLVA profiles were stable. The MLVA profile of isolates originating from different outbreaks in the Democratic Republic of the Congo (DRC) between 2010 and 2011 were distinct from any of the MLVA profiles found in Belgian isolates throughout the six year observational period and demonstrates that MLVA improves public health surveillance of S. Enteritidis. However, MLVA should be complemented with other subtyping methods when investigating outbreaks is caused by the most common MLVA profile. PMID- 25693201 TI - A rolling circle replication mechanism produces multimeric lariats of mitochondrial DNA in Caenorhabditis elegans. AB - Mitochondrial DNA (mtDNA) encodes respiratory complex subunits essential to almost all eukaryotes; hence respiratory competence requires faithful duplication of this molecule. However, the mechanism(s) of its synthesis remain hotly debated. Here we have developed Caenorhabditis elegans as a convenient animal model for the study of metazoan mtDNA synthesis. We demonstrate that C. elegans mtDNA replicates exclusively by a phage-like mechanism, in which multimeric molecules are synthesized from a circular template. In contrast to previous mammalian studies, we found that mtDNA synthesis in the C. elegans gonad produces branched-circular lariat structures with multimeric DNA tails; we were able to detect multimers up to four mtDNA genome unit lengths. Further, we did not detect elongation from a displacement-loop or analogue of 7S DNA, suggesting a clear difference from human mtDNA in regard to the site(s) of replication initiation. We also identified cruciform mtDNA species that are sensitive to cleavage by the resolvase RusA; we suggest these four-way junctions may have a role in concatemer to-monomer resolution. Overall these results indicate that mtDNA synthesis in C. elegans does not conform to any previously documented metazoan mtDNA replication mechanism, but instead are strongly suggestive of rolling circle replication, as employed by bacteriophages. As several components of the metazoan mitochondrial DNA replisome are likely phage-derived, these findings raise the possibility that the rolling circle mtDNA replication mechanism may be ancestral among metazoans. PMID- 25693202 TI - Inhibited Wnt signaling causes age-dependent abnormalities in the bone matrix mineralization in the Apert syndrome FGFR2(S252W/+) mice. AB - Apert syndrome (AS) is a type of autosomal dominant disease characterized by premature fusion of the cranial sutures, severe syndactyly, and other abnormalities in internal organs. Approximately 70% of AS cases are caused by a single mutation, S252W, in fibroblast growth factor receptor 2 (FGFR2). Two groups have generated FGFR2 knock-in mice Fgfr2S252W/+ that exhibit features of AS. During the present study of AS using the Fgfr2S252W/+ mouse model, an age related phenotype of bone homeostasis was discovered. The long bone mass was lower in 2 month old mutant mice than in age-matched controls but higher in 5 month old mutant mice. This unusual phenotype suggested that bone marrow-derived mesenchymal stem cells (BMSCs), which are vital to maintain bone homeostasis, might be involved. BMSCs were isolated from Fgfr2S252W/+ mice and found that S252W mutation could impair osteogenic differentiation BMSCs but enhance mineralization of more mature osteoblasts. A microarray analysis revealed that Wnt pathway inhibitors SRFP1/2/4 were up-regulated in mutant BMSCs. This work provides evidence to show that the Wnt/beta-catenin pathway is inhibited in both mutant BMSCs and osteoblasts, and differentiation defects of these cells can be ameliorated by Wnt3a treatment. The present study suggested that the bone abnormalities caused by deregulation of Wnt pathway may underlie the symptoms of AS. PMID- 25693203 TI - Direct binding of retromer to human papillomavirus type 16 minor capsid protein L2 mediates endosome exit during viral infection. AB - Trafficking of human papillomaviruses to the Golgi apparatus during virus entry requires retromer, an endosomal coat protein complex that mediates the vesicular transport of cellular transmembrane proteins from the endosome to the Golgi apparatus or the plasma membrane. Here we show that the HPV16 L2 minor capsid protein is a retromer cargo, even though L2 is not a transmembrane protein. We show that direct binding of retromer to a conserved sequence in the carboxy terminus of L2 is required for exit of L2 from the early endosome and delivery to the trans-Golgi network during virus entry. This binding site is different from known retromer binding motifs and can be replaced by a sorting signal from a cellular retromer cargo. Thus, HPV16 is an unconventional particulate retromer cargo, and retromer binding initiates retrograde transport of viral components from the endosome to the trans-Golgi network during virus entry. We propose that the carboxy-terminal segment of L2 protein protrudes through the endosomal membrane and is accessed by retromer in the cytoplasm. PMID- 25693205 TI - [Structure of postoperative infectious complications while hip replacement operations and osteosynthesis of long bones]. AB - In this article, there are given data of 1523 case histories for detection of postoperative infectious complications. Among them 653 cases were hip replacement surgeries and 870 cases were osteosynthesis of long bones. All of these operations were performed in department of traumatology in 2010-2014 years. With use of descriptive epidemiological method of research, for both types of surgical interventions were detected: most often reasons and indications for surgical treatment, prevalence of patients gender and age, incidence of early and late (both deep and superficial) postoperative infectious complications of surgical site, and also forms and incidence of common inflammatory diseases and statistically significant risk factors of there appearance. PMID- 25693204 TI - In-silico identification and functional validation of allele-dependent AR enhancers. AB - Androgen Receptor (AR) and Estrogen Receptors (ERs) are key nuclear receptors that can cooperate in orchestrating gene expression programs in multiple tissues and diseases, targeting binding elements in promoters and distant enhancers. We report the unbiased identification of enhancer elements bound by AR and ER-alpha whose activity can be allele-specific depending on the status of nearby Single Nucleotide Polymorphisms (SNP). ENCODE data were computationally mined to nominate genomic loci with: (i) chromatin signature of enhancer activity from activation histone marks, (ii) binding evidence by AR and ER-alpha, (iii) presence of a SNP. Forty-one loci were identified and two, on 1q21.3 and 13q34, selected for characterization by gene reporter, Chromatin immunoprecipitation (ChIP) and RT-qPCR assays in breast (MCF7) and prostate (PC-3) cancer-derived cell lines. We observed allele-specific enhancer activity, responsiveness to ligand-bound AR, and potentially influence on the transcription of closely located genes (RAB20, ING1, ARHGEF7, ADAM15). The 1q21.3 variant, rs2242193, showed impact on AR binding in MCF7 cells that are heterozygous for the SNP. Our unbiased genome-wide search proved to be an efficient methodology to discover new functional polymorphic regulatory regions (PRR) potentially acting as risk modifiers in hormone-driven cancers and overall nominated SNPs in PRR across 136 transcription factors. PMID- 25693206 TI - [The clinical significance of pvuii polymorphism estradiol receptor alpha gene to improve diagnosis of proliferative forms of benign breast dysplasia]. AB - The aim - to determine the role of single nucleotide polymorphism PvuII of the gene EsRalpha as an indicator of proliferative activity in benign breast dysplasia (BBD) and its effect on receptor status of breast tissue for expression EsRalpha. Defined genotype PvuII polymorphism EsRalpha, the expression level in remote EsRalpha among patients with BBD. For these patients, and morphological parameters samples are divided into groups and compared. It is shown that there is a connection between the PvuII-gene polymorphism EsRalpha with the degree of proliferation (chi2=43,142; p<0,0001) and the expression level EsRalpha (chi2=51,041; p<0,0001) in breast tissue at BBD in patients with homozygous (C/C) polymorphism PvuII of the gene EsRalpha. Addition to the standard morphological study justified immunohistochemical study with the definition of the expression level of EsRalpha due to the fact that the increase in the level of expression associated with an increase in cell proliferation in tumors with BBD (chi2=7,370; p=0,007). An algorithm for the diagnosis of proliferative forms BBD. PMID- 25693207 TI - [Risk-factors for development of suppurative-inflamatory infections in puerperas]. AB - In this article there are shown data of epidemiolgycal analysis of parturition cases (analysis is performed with use of descriptive and evaluative method) for detection of potential risk factors for development of suppurative-inflamatory infections in puerperas. Study was performed in obstetric hospital of the " Imedis Clinica" within 2014 year. 3248 parturition cases were analysed, among them 2373 (73,06% cases of physiological birth and 875 (26,99%) caesarium operation cases. From all cases were detected only 296 (9,211%) cases complicated with basic forms of suppurative-inflamatory infections. Also was performed analysis of post-parturation complications, dependet on anamnesys of pregnants. As a result it was detected, that most significant risk factors for devolpment of suppurative-inflamatory infections in puerperas with physiological birth were genitourinay inflamatory diseases while pregnancy, prolonged (more than 6 hours) parturition period. In cases with caesarian operation, such factors, apart from operation itself, were genitourinary inflamatory diseases while pregnancy, prolonged (more than 5 hours) waterless period, tribal activities before operation, tribal activities more than 5 hours, operation duration longer than 30 minutes and huge haemorage while surgery. PMID- 25693208 TI - [Gynecology operations combined with hernioplasty]. AB - Hernioplasty is one of the most widespread planned simultaneous operations in practice of obstetrics and gynecology. Rising trend of such interventions has been steadily increasing in these latter days. We have conducted 64 gynecology operations combined with hernioplasty. 5 operations were conducted in an expedited manner; 59 interventions were planned. Age of our patients ranged from 24 to 57. Duration of the surgical interventions was 129 minutes as average; duration of hospital stay days - 4+/-2 days, which didn't extend terms of stay at the stationary of the patients with separately conducted operations. Expressed pain syndrome was assessed with the amount of the used analgesics. Tension free hernioplasty by using reticulated polypropylene implants, on simultaneous operations, including hernioplasty combined with the gynecological components, gives good functional results and esthetic effect, excluding possibility of serious complications in the postoperative period. PMID- 25693209 TI - Ovarian reserve in the women of late reproductive age after conservative treatment of polycystic ovary syndrome in adolescence. AB - The aim of the present study was to assess of the ovarian reserve of the women of late reproductive age after the conservative treatment of polycystic ovary syndrome in adolescence. A total of 67 women of late reproductive age with confirmed primary PCOS in adolescence and 70 age-matched controls were included in the study. The patients with PCOS underwent clinical investigation and conservative treatment with antiandrogens and oral contraceptive pills (OCPs) between 1984 and 1990y. and at the time of original diagnosis they were 13-18 years. The patients were collected via analysis of histories at primary diagnosis of PCOS in adolescence and at the time of the follow-up investigation of reproductive hormones was conducted. Data were compared between the study and control groups. After conservative treatment PCOS patients had higher levels of anti-Mullerian hormone and greater number of antral follicles than controls (r<0.01 and r<0.05, respectively). Our data suggest that PCOS patients who underwent conservative treatment with OCPs in adolescence have the better ovarian reserve in late reproductive age compared with age-matched controls. PMID- 25693210 TI - Diagnostic features of polycystic ovary syndrome in adolescents (review). AB - The problem of Polycystic Ovary Syndrome (PCOS) is of a special importance due to its connection with not only medical but with psychosocial factors. PCOS is the most common endocrine cause of anovulatory infertility. It is a major factor for the metabolic syndrome, cardiovascular disease, type 2 diabetes mellitus (T2DM). Clinical symptoms of PCOS such as acne, hirsutism, obesity, alopecia represent psychological problem, especially for the adolescents. Many women who have PCOS have the onset of symptoms during adolescence. Early diagnosis and treatment of PCOS are important for preventing of the above mentioned long-term consequences associated with this condition. Adolescent patients often have diagnostic problems because the features of normal puberty are similar with symptoms of PCOS. This article reviews the diagnostic and differential diagnostic characteristics of PCOS in adolescents. In conclusion, consensus statement in adolescent patients is still awaiting. Our data suggest that it may be prudent to define adolescent PCOS according to the Carmina modified Rotterdam criteria. The increase rate of metabolic syndrome in adolescents with PCOS emphasize the importance of regular screening due to the high cardiometabolic disorders risk. PMID- 25693211 TI - The maxillary second molar - anatomical variations (case report). AB - To be acquainted with dental anatomical specificity is of great importance for dental endodontic treatment algorithm. The subject of present publication is 2 clinical cases of upper second molars, detailed characterization of, which is considered very important for enrichment of anatomical knowledge about dental anatomical variations. In one case, the reason for admission to the clinic of a 38-year-old woman was complains as of esthetic character as well as functional misbalance (disturbance of chewing function due to the damage of orthopedic construction). The patient indicated to the existence of coronary defects of large size aesthetic discomforts, damage and discolouration of old orthopedic construction (denture) in maxillary right molar area. According to the data obtained after clinical and visiographical examinations, chronic periodontitis of 17 teeth was identified as a result of incomplete endodontic treatment. According to the data obtained after clinical and visiographical examinations, the diagnosis of chronic periodontitis of 17 teeth was identified, tooth 17 with 2 roots and 2 canals. In the second clinical case, the reason for admission to the clinic of a 39-year-old woman was severe pain in the upper right molar area. The patient indicated to the caries on the tooth 17. After completion of proper survey clinical and visiographical examinations, acute pulpitis (K04.00) - with three roots and 4 canals was diagnosed. In both cases after the proper examinations and agreement with the patients a treatment plan envisaging: 17 teeth endodontic treatment, filling of caries defects and their preparation on one hand for orthopedic construction (denture) and on the other hand for restoration of anatomical integrity by light-cured composite, was scheduled. The present study is designed to prevent complications of endodontic treatment of the second molar, to optimize diagnosis and treatment algorithm, once again proving reliable information indicating to the individuality of treatment tactics. PMID- 25693212 TI - [Implication of laparoscopy in diagnostics of genital tb among women through cytohistological testing of bioptic specimen]. AB - Diagnostics of genital TB among women is a serious challenge because of the absence of specific clinical manifestation and difficulty to obtain material for bacteriological verification of the pathogen. All the cases with ascites and masses in pelvic cavity must undergo thorough testing to exclude tuberculosis. The present article describes 14 suspect cases of genital TB, where along with the mandatory clinical diagnostic studies (including PCR of ascites and bacteriological testing for TB, also on carcinoma of CA-125 ovary) they have conducted laparoscopy, with further cytological and bacteriological testing of bioptic sample. This method allowed us to diagnose genital and abdominal tuberculosis among women in 85,7% of cases through cytologic and histologic testing and to exclude ovarian carcinoma. Effectiveness of laparoscopy has been confirmed in diagnostics of genital and abdominal TB. PMID- 25693213 TI - [Clinical course of acute coronary syndrome in dependence on containing of homozystein and S677T methylenetetrahydrofolate reductase gene polymorphism]. AB - Nowadays to a numerous factors of IHD development risks hyperhomocysteinemia (HHc), C-reactive protein, fibrogen, as well as genetic disorders are relating. With development of IHD and its complications associated methylentetrahudrofolate reductase gene mutation of S677T polymorphism. The purpose of the investigation was studying the connection between acute coronary syndrome severity (ACS) in dependence on plasma homocysteine containing and genotype by S677T polymorphism MTHFR gene. Examined: 161 patients with ACS and 87 almost healthy people. Identification of 4th exon allelic polymorphism MTHFR S677T gene (rs1801133) was conducted with method of polymerase chain reaction, the investigation of homocysteine containing with immunoenzymated method. The statistic analyze was performed with using of SPSS - 17 programme. According to results of study patients with ACS of homozygote by minor allele T S677T MTHFR gene polymorphism by main allele C and heterozygote were associated with high homocysteine containing in plasma. While frequencies of T/T genotype was reliably higher in patients with ACS with segment ST elevation and complicated course compare with patients with ACS with segment ST elevation and non-complicated course and ACS without climbs of segment ST. Also, statistically reliable difference in genotypes distribution by C677T MTHFR gene polymorphism in dependence on homocysteine plasma level and clinical course of ACS severity were established. PMID- 25693214 TI - Dermatoscopic features of pigmented and non-pigmented basal cell carcinoma. AB - Basal cell carcinoma (BCC) is one of the most common malignant tumors, which accounts for about 75% of all skin cancers, its early diagnosis is crucial for proper treatment. In recent years, an increasingly important role in the early and differential diagnosis of skin tumors plays dermatoscopy, making possible to improve the diagnosis of pigmented and nonpigmented skin lesions, especially in the early stages of development. The aim of this work is to study the dermatoscopic criteria for pigmented and nonpigmented BCC using the algorithm of H. Kittler. Were studied 78 cases of different clinical types of BCC, diagnosis was based on clinical and dermatoscopic picture with further confirmation by cytology. The obtained data show that for pigmented BCC are characteristic five major signs of dermatoscopy - lines, dots, clods, circles and pseudopodia, whereas for non-pigmented form - pattern of blood vessels and, as an additional feature, structureless areas. Further studies are needed to evaluate specific dermoscopic hallmarks regarding different categories of BCC and sensitivity of these dermatoscopic features. PMID- 25693215 TI - [The method of estimation of endothelium functional condition in patients with essential arterial hypertension in combination with diabetes mellitus type 2]. AB - The method of estimation of endothelium-dependent vasodilatation (EDVD) of the brachial artery has been elaborated to the patients with essential arterial hypertension stage II in combination with diabetes mellitus type 2 using the method of multivariate regression analysis as an alternative to the reactive hyperemia test using high-resolution ultrasound. The method allows estimating of EDVD of the brachial artery on the basis of five traditional parameters of ultrasound diagnostics without special equipment. This simplifies the diagnosis, significantly reduces its duration and might have widespread use in the primary diagnosis. PMID- 25693216 TI - [New markers of progression of chronic heart failure in patients with myocardial infarction, type 2 diabetes and obesity]. AB - Currently identified a large number of biomarkers that are closely linked with the development of chronic heart failure, some of which are clusterin and fractalkine. Accordingly, the purpose of our study was - to evaluate the role of clusterin and fractalkine in progression of chronic heart failure in patients with postinfarction cardiosclerosis, type 2 diabetes and obesity. We investigated 71 patients with postinfarction cardiosclerosis, type 2 diabetes and obesity. All patients with postinfarction cardiosclerosis, diabetes and obesity were divided into groups according to the functional class of chronic heart failure (CHF). It was found that an increase the level of fractalkine and reduced clusterin leads due to the development of systolic dysfunction and heart failure progression in patients with postinfarction cardiosclerosis, type 2 diabetes and obesity. Fractalkine and clusterin play an important role in progression of the heart failure in patients with postinfarction cardiosclerosis, type 2 diabetes and obesity, and this gives them the right to be considered indicators of the severity of CHF. PMID- 25693217 TI - [Atrial fibrillation after mitral valve replacement]. AB - Atrial fibrillation at patients with mitral valve disease is a common complication, both before and after surgery. The analysis of factors associated with the risk of atrial fibrillation in patients with mitral valvular disease was perfomed. It has been established that the conduct of surgery in patients with mitral valve contributes not only to improve the clinical course of the disease, but also the restoration of sinus rhythm. PMID- 25693218 TI - [Nonspecific ulcerative colitis in combination with rheumatoid arthritis (case report)]. AB - The rheumatoid arthritis in the structure of rheumatological diseases occupies about 10% and is one of the most widespread inflammatory diseases of joints. The joint damage often meeting by the nonspecific ulcerative colitis, but combination of rheumatoid arthritis with nonspecific ulcerative colitis is rare. In this article described a case of the nonspecific ulcerative colitis associated with rheumatoid arthritis, in which arthritis occurred 8 years before the onset of nonspecific ulcerative colitis. PMID- 25693219 TI - Ige-mediated food allergy - current problems and future perspectives (review). AB - The incidence and prevalence of FA have changed over time, and many studies have indeed suggested a true rise in prevalence over the past 10-20 years. Recent studies showed that prevalence of self-reported food allergy is 17, 3%, versus challenged confirmed - 0.9%. The majority of allergic reactions to foods, particularly in children, are suggested to be caused primarily by eight foods, namely cow's milk, egg, wheat, soy, peanut, tree nuts, fish, and shellfish. Clinical symptoms of FA include skin, gastrointestinal and systemic reaction anaphylaxis that might be life-threatening and cause fatal reaction. Diagnosis of food allergy is based on SPT, sIgE measurements, component resolved diagnostics (CRD) and double-blind placebo-controlled food challenge (DBPCFC) tests. The primary therapy for food allergy is strict avoidance of the causal foods. Patients should be provided an emergency action plan, including how to administer an epinephrine autoinjector. It is recommended that all infants be exclusively breast-fed, without maternal diet restriction of allergens, until 4 to 6 months of age. Recent studies have shown that oral immunotherapy (OIT) can induce desensitization and modulate allergen-specific immune responses. Further work to evaluate the long-term effectiveness and safety of this therapy is ongoing and needed before they are used in the main-stream care of children or adults with food allergy. PMID- 25693220 TI - Blood pressure patterns in urban and rural children and adolescents of the Kakheti region (East Georgia). AB - Research was conducted in urban and rural areas of the city Telavi in 2012-2013. 493 public school pupils aged 6-18 were studied (267-urban resident, 226-rural resident). Results are grouped separately for all (13) aging clusters. This indicator is compared to each other by sex and living area (urban/rural) and received results are then grouped for 3 aging groups: I - early childhood 6-8 years of age n=136 (boys - 71, girls - 65; II - middle childhood 9 - 11 years of age n=147 (boys - 82, girls - 65) and III - adolescence 12-18 years of age n=213 (boys - 98, girls - 115). Measurements were taken on the right arm, three times with 3 minutes intervals. Both rural and urban area resident children's (boys, girls) SAP/DAP was evaluated. Data was processed statistically by "ANOVA". To determine correlation between different study groups, parametric and nonparametric methods were used.Significance was determined with 95% of variability. Results of the comparison of systolic and diastolic blood pressure for boys and girls living in rural and urban areas demonstrated: There seems to be no significant difference between boys and girls living in urban and rural areas. The biggest difference was identified in: 1) Boys in Aging Group I - SAP rural pupil boys averagely is 5.7 mm/Hg higher compared to urban resident boys; 2) For girls in Aging Group III of rural residents, SAP is averagely 3mm/Hg higher compared to same group of urban residents. Same difference was identified in girls considering DAP data.This may be due to several reasons, such as: 1) village inhabitants are more physically active. 2) BMI of the residents living in the rural areas is lower compeard to the residents living in the citie. Our findings are in line with the results obtained in Iraq and Russia. PMID- 25693221 TI - [Possible mechanism of hyperemia in the skin caused by non-painful mechanical pressure]. AB - It is believed that hyperemia in the skin, resulting from applied weak mechanical pressure delays the development of ischemia, and that it is a defensive neurovascular reaction against the local pressure, which can be considered as a critical point in terms of prevention of ischemia and, respectively, the risk for development of bedsores. Taking into account that nitric oxide can be released from autonomic nerves and make a significant contribution to the functioning of the mechanism of neurogenic vasodilation in different tissues, and the fact that the same role can also play the calcitonin gene-related peptide, the aim of this study was to clarify the role of each of these factors in the development of local hyperemia caused by non-painful, mechanical pressure on the skin. In experiments on white rats with a quantitative measurement of the intensity of skin blood flow, it was confirmed that in case of non-painful pressure acting on the skin, two-phase reaction of local blood flow appears - at first there is an increase in its level, and then an exponential decrease with stabilization at a level below the initial one. Analysis of received data allow to make conclusion that in relization of this phenomenon the role of trigger element belongs to nitric oxide, and the role of the executing unit - to calcitonin gene-related peptide. The effectiveness of this combined mechanism is limited by development of dominance of pressor-induced mechanical compression of cutaneous vessels over its vasodilator effect. PMID- 25693222 TI - [Computed tomographic evaluation of the healing of experimental defect of a long bone of the skeleton after implantation into its cavity osteoplastic material "Cerabone(r)"]. AB - Described in the literature properties of osteoplastic material "Cerabone(r)" have been obtained from studies in the maxilla and cancellous bone. The lack of data on the impact of "Cerabone(r)" on the dynamics of the healing of defects of compact substance of the long bones of the skeleton dictates the need for such studies. Implantation of osteoplastic material "Cerabone (r)" was performed into the defect of rat femoral shaft followed by computer-tomographic analysis of its healing. Starting from the 30th day until the end of the experiment (120th day) there were found faint signs of rarefaction in the distal part adjacent to the defect of parent bone, with no signs of bone resorption in its proximal part. There was identified an extremely high density of the implantation site "Cerabone(r)", no visible radiographic evidence of resorption of osteoplastic material and ensuring by the latter the stability of volume of the defect in cortical bone at all stages of the experiment. PMID- 25693223 TI - [The influence of extracorporeal laser radiation on structural indices of erythrocytes]. AB - Object of the research was to study the diffractometric indices of erythrocytes, while 1 ml of the blood of the experimental animals was irradiated extracorporally by helium-neon laser. For this purpose 1 ml blood was taken from normal weight, (1200 gr) grown up shinshila rabbits, that we divided into 7 groups and irradiated with 10 vat helium-neon laser during 0.5-1 minutes. After irradiation blood was injected back to the organism of rabbits. After 2-6 hours from irradiation blood was taken from veins, to study by electronic microscope and later to be processed by diffractometric analysis method. The examinations testify that after extracorporeal irradiation diffractometric characteristics of erythrocytes' membranes are lower than after general irradiation, which indicates to the different energetic possibilities of laser. The extracorporeal irradiation, performed by laser and input of radiated blood back to organism is considered to be a shock therapy from the side of erythrocytes, which promote the defense function of the organism itself. The base for the shock therapy should be important factors such as homeostasis, compensative-adaptive mechanisms and so on. Exactly this above mentioned should be manifested after the sensitized cells are led back to the body (1 ml of blood) and with their existence they should promote display of the defense mechanisms. PMID- 25693224 TI - [Effect glutargin in blinding function of serum albumin and other indicators of functional state of liver in acute toxic alcoholic hepatitis]. AB - Acute toxic alcoholic hepatitis continue to be relevant problem of modern medicine as a result of a significant spread of alcoholism in Ukraine and world. Aim - to explore the effect glutargin in blinding function of serum albumin and other indicators of functional state of liver in acute alcoholic toxic hepatitis in experiments on white rats. All animals were divided into four groups. The first (control group) consisted of 20 healthy intact animals, second - 17 rats with acute toxic alcoholic hepatitis, which was taken out of the experiment on the second day of its commencement, the third - 16 animals with similarly modeled pathology, which was taken out on the seventh day from the beginning of the experiment, fourth - 20 animals with acute toxic alcoholic hepatitis, which underwent correction of 4.0% solution glutargin during seven days. Shown, that blinding function of serum albumin, reduced in conditions studied pathology, take place pronounced biochemical signs of liver parenchyma. Under the influence of glutargin studied parameters significantly improved. In acute toxic alcoholic hepatitis significantly disturbing protein-synthetic liver function, occur phenomena cytolysis, suppressed blinding function of serum albumin with maximum expression on the second day of the experiment and with signs of recovery on the seventh day. Under the influence of glutargin upgraded indicators of blinding function of serum albumin: total protein, aminotransferase, alkaline phosphatase, total bilirubin. The activity of serum aspartate aminotransferase normalized and reached the level of control. PMID- 25693225 TI - An overview of ethnic and gender differences in pain sensation. AB - Increasing amounts of clinical and experimental evidence show differences in pain responses between different ethnic groups. At the same time, the experience of pain is characterized by immense inter-individual and group variability with one likely contributing factor being ethnicity. Synergistically, pain and ethnicity are multidimensional, malleable and shaped by culture. Although there is no consensus regarding the underlying mechanisms, ethnic group differences inevitably reflect a holistic influence of biological, psychological and socio cultural factors. Numerous studies, investigating a wide variety of painful conditions, have also suggested gender differences in pain perception. Particularly, epidemiologic and clinical findings clearly demonstrate that women are at increased risk for chronic pain and some data suggest that women may experience more severe clinical pain. Studies of experimentally induced pain have produced a very consistent pattern of results, with women exhibiting greater pain sensitivity, enhanced pain facilitation and reduced pain inhibition compared with men, though the magnitude of these sex differences varies across studies. PMID- 25693255 TI - [ Key point in exposing the inter-lobular pulmonary artery]. PMID- 25693246 TI - Mobile technology and its use in clinical nursing education: a literature review. AB - Nursing students face a variety of challenges to learning in clinical practice, from the theory-practice gap, to a lack of clinical supervision and the ad hoc nature of learning in clinical environments. Mobile technology is proposed as one way to address these challenges. This article comprehensively summarizes and critically reviews the available literature on mobile technology used in undergraduate clinical nursing education. It identifies the lack of clear definitions and theory in the current body of evidence; the variety of mobile devices and applications used; the benefits of mobile platforms in nursing education; and the complexity of sociotechnical factors, such as the cost, usability, portability, and quality of mobile tools, that affect their use in undergraduate clinical nursing education. Implications for nursing education and practice are outlined, and recommendations for future research are discussed. PMID- 25693256 TI - A year of records, resignations and respect. PMID- 25693257 TI - Advance care planning: a matter of time. PMID- 25693258 TI - Perceptions about bridge programs for PAs. PMID- 25693259 TI - The new FSAs are not so flexible anymore. PMID- 25693260 TI - Sleep problems in older adults. Serious health consequences can result from inadequate rest. PMID- 25693261 TI - CRP & cardiovascular disease. Measuring C-reactive protein can help assess a patient's CVD risk. PMID- 25693262 TI - Acetaminophen & children. Why have pediatric dosage guidelines changed, and what does it mean in practice? PMID- 25693263 TI - Wegener's granulomatosis. A patient with a rare vasculitis presents diagnostic challenges. PMID- 25693264 TI - OTC treatment for osteoarthritis. Can over-the-counter joint pain supplements delay the progression of OA?. PMID- 25693265 TI - Rising forces. PMID- 25693266 TI - Tips for keeping waiting patients patient. PMID- 25693267 TI - Risk management's 10 commandments. PMID- 25693268 TI - HCPCS: getting paid for 'other' services. PMID- 25693269 TI - National Salary Report 2010. Inching forward with mixed results. PMID- 25693270 TI - Parasomnias. Common sleep disorders in children and adults. PMID- 25693271 TI - Anticoagulation therapy. Stay alert to potential complications. PMID- 25693272 TI - Fibromyxoma during labor. A rare tumor in an unusual location in a woman about to deliver. PMID- 25693273 TI - Charcot Neuroarthropathy. Recognize and refer quickly to prevent foot amputation. PMID- 25693274 TI - Pediatric psoriasis. Treat the psychosocial effects along with the physical ones. PMID- 25693275 TI - Continuous glucose monitors. A GPS for blood sugar control? PMID- 25693276 TI - Bet on success at IMPACT. PMID- 25693277 TI - Working with recruiters: what's the real deal? PMID- 25693278 TI - NPs and PAs must be immunization advocates. PMID- 25693279 TI - New job, new town: is re-lo right for you? PMID- 25693280 TI - Acute bronchitis in the convenient care setting. PMID- 25693281 TI - Severe persistent asthma in adults. The rise of omalizumab. PMID- 25693282 TI - The big squeeze. An overview of thoracic outlet syndrome. PMID- 25693283 TI - Hot in here? Coping with hot flashes in menopause. . PMID- 25693284 TI - Carbohydrate counting. A vital tool for blood sugar control. PMID- 25693285 TI - From hypertension to heart failure. Develop an exit strategy. PMID- 25693286 TI - Insulin omission for weight loss. The dangers of diabulimia. PMID- 25693287 TI - Sudden cardiac death in young athletes. Toward better assessment of risk factors. PMID- 25693288 TI - Black cohosh. An alternative approach to HRT for menopause. PMID- 25693289 TI - Celiac disease. Furor in the small intestine. PMID- 25693290 TI - [Perceptual image dissimilarity--a novel metric for objective assessment of image quality in computed tomography with iterative reconstruction]. AB - An iterative reconstruction (IR) technique in computed tomography (CT) is expected to play an important role in reducing the radiation dose while preserving both spatial resolution and contrast-to-noise ratio. However, images obtained by using the IR technique are known to have different visual appearances from those obtained by using the traditional filtered back-projection (FBP) reconstruction. This appearance is often figuratively described as "blocky," but it has not been objectively characterized further. In this paper, we propose a novel image quality metric, called "perceptual image dissimilarity" (PID), to characterize the visual dissimilarity between FBP and IR images. The PID was formulated as a grayscale transformation and subsequent structural similarity (SSIM)-based image quality measurement. The PID metric was validated using phantom images with three different modules. Sixty datasets, each consisting of an IR image and its corresponding noise-level-equivalent FBP image, were visually assigned "subjective dissimilarity scores" on a five level scale by six observers. The data sets were then quantitatively analyzed using both the PID and the traditional mean squared error (MSE) metrics. Our results show that the PID is highly consistent with the subjective dissimilarity score and thus delivers superior performance, whereas the MSE fails to quantify the observers' visual perception. PMID- 25693291 TI - [Topics of radiation biology for cancer treatment]. AB - Recent advances in the field of radiation therapy (RT) have considerably improved treatment outcomes of various cancers. It is related to not only the technological progress in medical physics but also the analytical progress in radiation biological effectiveness. However, the treatment results of RT, especially in advanced cancer, are still insufficient, therefore it is necessary to establish a safety and more effective method for treating cancer. Understanding the radiation biology is essential to appreciate the effect of RT. Hence, we review the controversial point of RT for radiation biology and introduce the results of basic research. PMID- 25693292 TI - [Smart choice between two DNA double-strand break repair mechanisms]. AB - DNA double-strand break (DSB) is considered most deleterious among radiation induced DNA damages and most relevant to the biological effects of radiation. In eukaryotic cells, DSB is repaired mainly through two pathways: non-homologous end joining (NHEJ) and homologous recombination (HR). These repair pathways seem to play complementary roles. NHEJ is considered less accurate than HR, but HR is available only in late S and G2 phases in vertebrates. Recent studies elucidated how cells choose one from these two pathways depending on the circumstance: cell cycle phase, complexity of DNA damage and chromatin structure. PMID- 25693293 TI - [Mechanism of oxygen effect for photon and heavy-ion beams]. AB - The oxygen effect was observed as 1912 by Swartz. The ratio of doses administered under hypoxic to oxic conditions needed to achieve the same biological effect is called the oxygen enhancement ratio (OER). For low-LET radiation, such as photon radiation, the OER at high doses has a value of between 2.5 and 3, and the OER has a smaller value of about 2.5 or less at lower doses. The oxygen effect is large and important in the case of low-LET radiations. Radio-chemical reactions are generally believed to be the fundamental mechanisms underlying oxygen effects. Oxygen fixes the damage produced by free radical. In the absence of oxygen, damage produced by the indirect action may be repaired. The OER has been determined for a wide variety of chemical and biologic systems with different endpoints. For high-LET radiation such as heavy-ions, oxygen effect is very small. The oxygen-in-the-track hypothesis proposed to account for this effect, suggests that cells exposed to high-LET radiation exhibit an oxygenated microenvironment around the particle track, even when they are irradiated under anoxic conditions. PMID- 25693294 TI - [Significance of radiation-induced bystander effects in radiation therapy]. AB - Since 1994, a Phase I/II clinical study and radiotherapy have carried out using carbon-ion beams produced with the Heavy Ion Medical Accelerator in Chiba (HIMAC) at National Institute of Radiological Sciences. Now we constructed the new treatment facility for the advanced carbon-ion therapy at HIMAC applying a 3D fast spot scanning system with pencil beams. In the field of fundamental biological studies for high-LET heavy ions, there are some reports regarding bystander effects after exposure to alpha particles derived from 238Pu or He-ion microbeams. However, only limited sets of studies have examined bystander effects after exposure to different ion species heavier than helium, such as carbon ions. We have been investigating bystander cellular responses in both normal human and human tumor cells irradiated with the HIMAC carbon ions. Bystander cell-killing effect was observed in the cells harboring wild-type P53 gene, but not in the P53 mutated cells. Moreover, observed bystander effect was suppressed by treating with a specific inhibitor of gap-junction mediated cell-cell communication. There is clear evidence that the carbon-ion irradiation enables the enhanced cell killing in cells with wild-type P53 gene via gap-junction mediated bystander effect. PMID- 25693295 TI - [Risk of second cancer after radiation therapy]. AB - This review describes the secondary cancer after radiotherapy. Secondary cancer is a great concern for cancer survivors, especially for childhood cancer survivors not only because of their intrinsic high susceptibility to radiation but also because of successful achievement of longer survival. Recent advance of molecular biology reveals unique genomic changes, which distinguish radiation induced tumors from spontaneous or chemically induced tumors. PMID- 25693296 TI - The state of the art of sensory substitution. PMID- 25693297 TI - Is there a future for sensory substitution outside academic laboratories? AB - Sensory substitution devices (SSDs) have been developed with the ultimate purpose of supporting sensory deprived individuals in their daily activities. However, more than forty years after their first appearance in the scientific literature, SSDs still remain more common in research laboratories than in the daily life of people with sensory deprivation. Here, we seek to identify the reasons behind the limited diffusion of SSDs among the blind community by discussing the ergonomic, neurocognitive and psychosocial issues potentially associated with the use of these systems. We stress that these issues should be considered together when developing future devices or improving existing ones. We provide some examples of how to achieve this by adopting a multidisciplinary and participatory approach. These efforts would contribute not solely to address fundamental theoretical research questions, but also to better understand the everyday needs of blind people and eventually promote the use of SSDs outside laboratories. PMID- 25693298 TI - The skin as a medium for sensory substitution. AB - The last 50 years or so has seen great optimism concerning the potential of sensory substitution and augmentation devices to enhance the lives of those with (or even those without) some form of sensory loss (in practice, this has typically meant those who are blind or suffering from low vision). One commonly discussed solution for those individuals who are blind has been to use one of a range of tactile-visual sensory substitution systems that represent objects captured by a camera as outline images on the skin surface in real-time (what Loomis, Klatzky and Giudice, 2012, term general-purpose sensory substitution devices). However, despite the fact that touch, like vision, initially codes information spatiotopically, I would like to argue that a number of fundamental perceptual, attentional, and cognitive limitations constraining the processing of tactile information mean that the skin surface is unlikely ever to provide such general-purpose sensory substitution capabilities. At present, there is little evidence to suggest that the extensive cortical plasticity that has been demonstrated in those who have lost (or never had) a sense can do much to overcome the limitations associated with trying to perceive high rates of spatiotemporally varying information presented via the skin surface (no matter whether that surface be the back, stomach, forehead, or tongue). Instead, the use of the skin will likely be restricted to various special-purpose devices that enable specific activities such as navigation, the control of locomotion, pattern perception, etc. PMID- 25693299 TI - Sensory substitution for balance control using a vestibular-to-tactile device. AB - Postural control is essential for most activities of daily living. The impairment of this function can be extremely disabling. This work was stimulated by the testimony of a bilateral partial foot amputee who describes his difficulty in maintaining balance while washing his hair in the shower. We postulated that if the postural control system could not rely on accurate and reliable somatosensory inputs from the foot and ankle, as is probably the case following bilateral foot amputation due to the loss of the foot afferents and efferents, the weight of visual and vestibular cues would increase. We therefore assessed if a vestibular to-tactile sensory substitution device could compensate for this impairment. Two separate experiments were conducted. Experiment 1: The effect of a vestibular-to tongue tactile biofeedback balance system on the postural stability of this amputee was tested (on a force platform) and compared with a non-amputated, matched control group. The results showed that use of the biofeedback reduced centre of foot (CoP) displacement in all subjects but more spectacularly in the amputee. Experiment 2: The effect of the biofeedback was tested in 16 young healthy adults following a protocol of ankle muscle fatigue (known to alter ankle neuromuscular function and to perturb the control of bipedal posture). The results showed a significant decrease in CoP displacement compared with the control, non-biofeedback condition and a significantly greater effect of the biofeedback in the fatigue than the non-fatigue condition. Taken together, the results of these two studies suggest that an individual with double partial foot amputation was able to improve his balance control thanks to the use of a vestibular-to-tongue tactile biofeedback balance system and that young healthy individuals were able to take advantage of it to reduce the postural destabilisation induced by plantar-flexor muscle fatigue. Further studies are however necessary to confirm this in larger numbers of impaired persons as well as to assess the effectiveness in dynamic situations. PMID- 25693300 TI - Visual objects in the auditory system in sensory substitution: how much information do we need? AB - Sensory substitution devices such as The vOICe convert visual imagery into auditory soundscapes and can provide a basic 'visual' percept to those with visual impairment. However, it is not known whether technical or perceptual limits dominate the practical efficacy of such systems. By manipulating the resolution of sonified images and asking naive sighted participants to identify visual objects through a six-alternative forced-choice procedure (6AFC) we demonstrate a 'ceiling effect' at 8 x 8 pixels, in both visual and tactile conditions, that is well below the theoretical limits of the technology. We discuss our results in the context of auditory neural limits on the representation of 'auditory' objects in a cortical hierarchy and how perceptual training may be used to circumvent these limitations. PMID- 25693301 TI - Touch-screen technology for the dynamic display of -2D spatial information without vision: promise and progress. AB - Many developers wish to capitalize on touch-screen technology for developing aids for the blind, particularly by incorporating vibrotactile stimulation to convey patterns on their surfaces, which otherwise are featureless. Our belief is that they will need to take into account basic research on haptic perception in designing these graphics interfaces. We point out constraints and limitations in haptic processing that affect the use of these devices. We also suggest ways to use sound to augment basic information from touch, and we include evaluation data from users of a touch-screen device with vibrotactile and auditory feedback that we have been developing, called a vibro-audio interface. PMID- 25693302 TI - The effect of extended sensory range via the EyeCane sensory substitution device on the characteristics of visionless virtual navigation. AB - Mobility training programs for helping the blind navigate through unknown places with a White-Cane significantly improve their mobility. However, what is the effect of new assistive technologies, offering more information to the blind user, on the underlying premises of these programs such as navigation patterns? We developed the virtual-EyeCane, a minimalistic sensory substitution device translating single-point-distance into auditory cues identical to the EyeCane's in the real world. We compared performance in virtual environments when using the virtual-EyeCane, a virtual-White-Cane, no device and visual navigation. We show that the characteristics of virtual-EyeCane navigation differ from navigation with a virtual-White-Cane or no device, and that virtual-EyeCane users complete more levels successfully, taking shorter paths and with less collisions than these groups, and we demonstrate the relative similarity of virtual-EyeCane and visual navigation patterns. This suggests that additional distance information indeed changes navigation patterns from virtual-White-Cane use, and brings them closer to visual navigation. PMID- 25693303 TI - Making sense of the chemical senses. AB - We review our recent behavioural and imaging studies testing the consequences of congenital blindness on the chemical senses in comparison with the condition of anosmia. We found that congenitally blind (CB) subjects have increased sensitivity for orthonasal odorants and recruit their visually deprived occipital cortex to process orthonasal olfactory stimuli. In sharp contrast, CB perform less well than sighted controls in taste and retronasal olfaction, i.e. when processing chemicals inside the mouth. Interestingly, CB do not recruit their occipital cortex to process taste stimuli. In contrast to these findings in blindness, congenital anosmia is associated with lower taste and trigeminal sensitivity, accompanied by weaker activations within the 'flavour network' upon exposure to such stimuli. We conclude that functional adaptations to congenital anosmia or blindness are quite distinct, such that CB can train their exteroceptive chemical senses and recruit normally visual cortical areas to process chemical information from the surrounding environment. PMID- 25693304 TI - The process of distal attribution illuminated through studies of sensory substitution. AB - When we interact with objects in our environment, as a general rule we are not aware of the proximal stimulation they provide, but we directly experience the external object. This process of assigning an external cause is known as distal attribution. It is extremely difficult to measure how distal attribution emerges because it arises so early in life and appears to be automatic. Sensory substitution systems give us the possibility to measure the process as it occurs online. With these devices, objects in our environment produce novel proximal stimulation patterns and individuals have to establish the link between the proximal stimulation and the distal object. This review disentangles the contributing factors that allow the nervous system to assign a distal cause, thereby creating the experience of an external world. In particular, it highlights the role of the assumption of a stable world, the role of movement, and finally that of calibration. From the existing sensory substitution literature it appears that distal attribution breaks down when one of these principles is violated and as such the review provides an important piece to the puzzle of distal attribution. PMID- 25693305 TI - Evidence-based management of Kawasaki disease in the emergency department. AB - Kawasaki disease, also known as mucocutaneous lymph node syndrome, was first described in Japan in 1967. It is currently the leading cause of acquired heart disease in children in the United States. Untreated Kawasaki disease may lead to the formation of coronary artery aneurysms and sudden cardiac death in children. This vasculitis presents with fever for >= 5 days, plus a combination of key criteria. Because each of the symptoms commonly occurs in other childhood illnesses, the disease can be difficult to diagnose, especially in children who present with an incomplete form of the disease. At this time, the etiology of the disease remains unknown, and there is no single diagnostic test to confirm the diagnosis. This issue reviews the presentation, diagnostic criteria, and management of Kawasaki disease in the emergency department. Emergency clinicians should consider Kawasaki disease as a diagnosis in pediatric patients presenting with prolonged fever, as prompt evaluation and management can significantly decrease the risk of serious cardiac sequelae. PMID- 25693306 TI - Integrative approach to diagnosis of genital human papillomaviruses (HPV) infection of female. AB - Human papillomavirus (HPV) is a virus from the papillomavirus family that is capable of infecting humans. Some types of HPVs cause warts, while others can lead to cancers of the cervix, vulva, vagina, penis, oropharynx and anus. High risk human papillomavirus (hr HPV) has been detected in almost all cervical squamous cell carcinomas and adenocarcinomas. All patients examined by colposcopy. Cervical swab is routinely done and patients are screened with both HPV DNA by Real Time Polimerase Chain Reaction (RT PCR) testing and Pap testing. Pictures obtained by colposcopy were examined by indirect Bi-Digital O-Ring Test (BDORT) by using reference control substance (RCS): HPV 16, HPV 18, and Integrin alpha5 beta1. BDORT was developed by Prof. Omura Y. of New York and received U.S. patent in 1993. For detection of HPV DNA we used RT PCR and standard Qiagen method which detect 18 types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 6, 11, 42, 43, 44) of HPV from smear. From 63 patients where is BDORT indicated presence of HPV, in 49 patients (77.8%) RT PCR confirmed presence of HPV. From 63 patients in 54 patients (85.7%), we detected, by colposcopic exam, some kind of lesions associated with HPV infection. Results obtained by RT PCR: one type (1/18) of DNA HPV in 25 patients (51.02%), 2 types (2/18) in 15 patients (30.61%) and 3 types (3/18) in 9 patients (18.37%). Although BDORT results usually have higher sensitivity and detection rate is much higher, it can be used together with RT PCR in detection of HPV and cervical lesions associated with HPV infection. PMID- 25693307 TI - 3,5,11 needles: looking for the perfect number of needles--a randomized and controlled study. AB - Acupuncture has been successfully used in myofascial pain syndromes. However, the number of needles used, i.e. the "dose" of acupuncture stimulation, to obtain the best antinociceptive efficacy, is still a matter of debate. The question was addressed comparing the clinical efficacy of 3 different therapeutic schemes, mainly characterized by different numbers of needles used on 90 patients affected by a painful cervical myofascial syndrome. Patients were divided into 3 groups; the first group of 30 patients was treated with 11 needles, the second group of 30 patients was treated with 5 needles and the third group of 30 patients was treated with 3 needles. Each group underwent eight cycles of somatic acupuncture. In each session and in each group, all needles were stimulated until the pain tolerance threshold was reached; "pain tolerance is the amount of pain a person can handle without breaking down, either physically or emotionally". Pain intensity was evaluated before therapy, immediately after, and at 1 and 3 months follow-up by means of both the Mc Gill Pain Questionnaire and the Visual Analogue Scale (VAS). Pain and the repercussion of pain on the patient's quality of life (DOPE- Descriptors Of Pain Effects) were also measured using a test we developed, administered at each session. In all groups, needles were inserted superficially, except for the two most painful trigger points that were deeply inserted. All groups, independently from the number of needles used, obtained a good and significant therapeutic effect without clinically relevant differences among groups. For this pathology and patients of this kind, the number of needles, 3 or 5 or 11, seems not to be an important variable in determining the therapeutic effect. PMID- 25693308 TI - The beneficial effect of electro-acupuncture given at PC6 (Neiguan-point) by the increase in cardiac transient outward K+ current channel which depends on the gene and protein expressions in artificially induced myocardial ischemia rats. AB - This study explored the mechanism of electro-acupuncture (EA) at PC6 to improve the heart function by regulating the cardiac transient outward potassium current (= Ito) channel in myocardial ischemia (MI). Kv1.4 is the main component of the slow Ito (Ito.s) channel. Kv4.2 and Kv4.3 are the main components of the fast Ito (Ito.f) channel. KChIP2 is a compound protein of Ito channel. In this experiment, MI was induced by injecting isoproterenol in rats, and the gene and protein expressions of Kv1.4, Kv4.2, Kv4.3 and KChIP2 were lower [The gene and protein decreased (42.8 +/- 4.3)% and (37.2 +/- 4.7)% respectively.] than the control rats significantly (p < 0.05). After MI induction, the MI rats were divided into three groups, including PC6, LU7 (Lieque-point) and Non-acupoint group which were acupunctured at once a day for 7 days respectively. After EA at PC6 and LU7, the gene and protein expressions showed obvious increased [EA at PC6: the gene and protein increased (50.24 +/- 5.4)% and (39.14 +/- 5.3)% respectively. EA at LU7: the gene and protein increased (24.6 +/- 2.8)% and (22.04 +/- 5.5)% respectively] and they are all higher than MI rats significantly (p < 0.05). EA at PC6 and LU7 showed the same variation, and the effects of EA at PC6 and LU7 were better than Non-acupuncture-point (p < 0.05). The effects of EA at PC6 were significantly better [The gene and protein increased (19.74 +/- 2.7)% and (14.14 +/- 4.4)% respectively] than LU7 (p < 0.05). PC6 is an acupoint of the pericardium meridian, and the pericardium meridian which corresponds to adrenal gland according to Omura Y's research, can affect the heart function directly LU7 belong to the lung meridian, and the lung plays an important factor in blood circulation according to TCM. So PC6 is more effective than LU7 on heart function regulation. The results suggested that PC6 showed the target effect of meridian specificity on regulating the Kv channel in MI. PMID- 25693309 TI - The impact of acupuncture treatment on nitric oxide (NO) in migraine patients. AB - The purpose of this study is to contribute to efforts to understand the pathophysiology of migraine and create an alternative perspective for prophylaxis and treatment of migraine attacks. Acupuncture treatment was applied to the 22 volunteer migraine patients. The acupuncture treatment consists of 5 sessions with 2 sessions per week. Blood samples have been collected before performing acupuncture, after the 1st session and after the 5th session of the acupuncture. And for the control group blood samples were collected only once. In our study the mean serum NO levels in healthy people were (3.58 +/- 0.53) while patients with migraine group were (5.55 +/- 0.70) respectively. Serum NO levels were 55% higher in migraine group compared to the control group. The NO concentration also decreased after 5th session (30%) (p < 0.05). After the 1st sessions NO level decreased 4.86% in the migraine group. After the 5th session NO level decreased 30.63% in the migraine group. After the 5th session NO level decreased 27.08% compared to 1st session in the migraine group. After the 1st session of acupuncture treatment, level of NO in migraine group were 4.86% and it is reduced but statistically not significant. After the 5th acupuncture treatment serum NO levels were reduced to (3.85 +/- 0.62) 30.63% in migraine group and were statistically lower (p < 0.05). After the 5th session NO level decreased 27.08% compared to 1st session in the migraine group. In this study, acupuncture treatment is appeared to be effective by lowering the levels of serum NO and acupuncture has cumulative effects. Although there are earlier studies showing the effect of NO in migraine, this has been the 1st study in this field, which shows the effect of acupuncture on NO in migraine patients. PMID- 25693310 TI - Sacred Cursing:In Memoriam, Dannie Abse (1923-2014). PMID- 25693311 TI - Guest Editors' Introduction: On the limits of disciplinarity: literature, medicine, religion. PMID- 25693313 TI - Conversing with some chickadees: cautious acts of ontological translation. PMID- 25693312 TI - Medical eros: caregivers, loss, and an ethics of waiting. PMID- 25693314 TI - "All Apollo's arts": divine cures, Afro-Caribbean knowledge, and healing poetry in the British West Indies. PMID- 25693315 TI - When the doctor is a gardener: Victoria Sweet, Hildegard of Bingen, and the genres of physician-writers. PMID- 25693316 TI - Forged by fire: Margery Kempe's account of postnatal psychosis. PMID- 25693317 TI - Maternity, midwifery, and ministers: the Puritan origins of American obstetrics. PMID- 25693318 TI - The resurrection and the knife: Protestant cadavers and the rise of American medicine. PMID- 25693319 TI - Quacks, nostrums, and miraculous cures: narratives of medical modernity in the nineteenth-century United States. PMID- 25693320 TI - Sin vs. science? Rethinking venereal disease in turn-of-the-century America. PMID- 25693321 TI - Commentary: storytelling and the construction of reality. PMID- 25693322 TI - South Carolina Health Coordinating Council. PMID- 25693323 TI - [Secretome of the adult liver fluke Opisthorchis felineus]. AB - The opisthorchiasis caused by Opisthorchis felineus, the Siberian liver fluke remains a serious public health problem in Russia and Eastern Europe. Proteomic identification of the proteins in the excretory-secretory products (ESPs) released by O. felineus is an important key for the investigation of host parasite interactions and understanding the mechanisms involved in parasite survival within the host. In the ESP of O. felineus we have identified 37 proteins using high-resolution proteomics approach (LTQ-FT-ICR mass spectrometer). The O. felineus secretes either excretes a complex mixture of proteins including: glycolytic enzymes (enolase, aldolase, fructose-1 ,6 bisphosphatase and other); detoxification proteins (4 isoform of glutathione S transferases, Cu/Zn superoxide dismutase, thioredoxin peroxidase, thioredoxin); cytoskeletal proteins (beta tubulin and paramyosin); a number of proteases (cathepsin F, B1, leucin aminopeptidase 2); protease inhibitors (putative cys1 protein, leukocyte elastase inhibitor), binding proteins (ferritin, myoglobin, FABP) and other. In the O. felineus ESP we also identified Of-HDM protein belonging to a novel family "helminth defence molecules" (HDMs). The O. felineus proteins identified in this study provide necessary information for the further investigation of molecular mechanisms of opisthorchiasis pathogenesis and some of them would be of interest as potential antigens for vaccine and immunodiagnostics development and as potential new anthelmintic drug targets. PMID- 25693324 TI - Identification of species Leucochloridium paradoxum and L. perturbatum (Trematoda) based on rDNA sequences. AB - The full nucleotide sequences of DNA ribosome cluster of Leucochloridium paradoxum Carus, 1835 and L. perturbatum Pojmanska, 1967 were obtained. rDNA was extracted from 40 isolates of Leucochloridium sp. and analyzed using specific primers. The intraspecific genetically identity of morphologically detected L. paradoxum and L. perturbatum sporocysts was proven. A noticeable interspecific divergence between L. paradoxum and L. perturbatum was indicated. Using rDNA genotyping a case of double infection of snail Succinea sp. with L. paradoxum and L. perturbatum sporocysts was detected. PMID- 25693325 TI - [The evaluation of snail host-trematode parasite trophic relationships using stable isotope analysis]. AB - Stable isotope ratios of carbon (13C/12C, delta13C) and nitrogen (15N/14N, delta15N) in snail-host tissue (the foot and hepatopancreas) and trematode parasites on two stages of their life cycle were analyzed. Trophic structure in co-occurring trematode larvae was examined in the following species: five species of cercariae (Echinoparyphium recurvatum, Hypodereum conoideum, Plagiorchis mutationis, Diplostomum chromatophorum and D. volvens) and two species of metacercariae (Cotylurus cornutus and Echinoparyphium recurvatum) within two closely related snail hosts Lymnaea stagnalis and L. tumida using stable isotope analyses. Snail and parasite sampling was conducted in a riverine portion of the Kargat River of the Lake Chany basin, in the south of Western Siberia (54 degrees 37'76"N, 78 degrees 13'07" E), in August 2009. Four out of five studied cercariae species were depleted in 15N as well as in 13C relatively to snail hosts tissues (foot and hepatopancreas), supporting our previously published data for Plagiorchis mutationis and Echinoparyphium recurvatum cercariae. Such fractionation of cercariae is untypical of the commonly observed relationship between consumers and their food. D. chromatophorum cercariae had demonstrated an insufficient enrichment in delta15N volume in relation to the hepatopancreas. Both two species of metacercariae (C. cornutus and E. recurvatum) showed a significant enrichment in delta15N volume relatively to the host tissue consumed (fractionation values ranging from 1.5 to 4 per thousand depending on the species). The differences in delta15N and delta13C volume between cercariae and metacercariae observed in this study illustrate the complexity of the host- parasite trophic relationships. Such isotopic differences between cercariae and metacercariae can probably be explained by selective consumption of specific amino acids or lipids or by changes in metabolism associated with the life cycle of the parasite. The present study represents the first comparative analysis of trophic relationships between the host and the endoparasite at different life cycle stages. It demonstrates the potency of the stable isotope analyses for understanding trophic relationships in multispecies parasite communities. PMID- 25693326 TI - [On morphogenesis of metacestodes from the family Schistotaeniidae (Cyclophyllidea) by the example of euascocercus Schistotaenia srivastavai Raush, 1970]. AB - Morphogenesis of the true ascocercus (euascocercus or euascocysticercoid) was studied in Schistotaenia srivastavai, a relatively rare parasite of the Red necked Grebe Podiceps griseigena, and of intermediate hosts, damselfy and dragonfly larvae, in the Okhotsk-Kolyma region. Stages of postembryonic development were reconstructed by the material from spontaneously infected dragonflies' larvae, which corresponded to the published data on the development of metacestodes from the genus Tatria s. l. studied by Mrazek (1927) and Rees (1973). The euascocercus is the most widespread morphological modification of ascocysticercoids among Schistotaeniidae. According to Gulyaev (1989) and our data, the species of the family (the genus Mircia) have also a polycephalic modification of the ascocercus, or the multicercus. It represents a maternal individual that is filled with numerous small filial cysticercoids during the postembryonic development. These cysticercoids are formed of individual buds in the outer wall; later on, they are gemmated into the primary cavity of the maternal individual. Consequently, each daughter individual possesses its own single-layer exocyst, homological to the inner layer of the two-layered exocyst of the other ascocerci. Supposedly, exocyst's outer layer of monocephalic ascocerci is homologous to the outer wall of multicercus' maternal individual. Finally, diagnostic features of the third modification of ascocerci, namely megalocercus, described in the uniquely large metacestode Dioecocestus asper, corresponds to the characteristic of the metacestode Schistotaenia tenuicirrus, studied by Boertje (1975). S. tenuicirrus differs from D. asper in the spiral configuration formed on the entire surface of the endocyst (in D. asper, only on its dorsal side), and in a low number of proglottids in the larval strobile (D. asper possesses a multisegmental strobile). The reason, why so large protective envelopes (exo- and endocysts) develop in S. tenuicirrus with relatively small size of prospective body, remains unclear. Thus, life cycles of Schistotaeniidae represent all three modifications of the ascocerci: the true ascocercus (Shistotaenia, Tatria, Ryjikovilepis, Joyeuxilepis), the multicercus (genus Mircia), and the megalocercus (S. tenuicirrus). PMID- 25693327 TI - [Infestation rates of the main commercial fish species with larvae of contracaecum osculatum (Rudolphi, 1802) (Nematoda: Anisakidae) in Russian waters of the SoutH Baltic in 2000-2012]. AB - The infestation dynamic of the sprat (Sprattus sprattus balticus), the Baltic herring (Clupea harengus membras), and the Baltic cod (Gadus morhua callaris) with nematodes Contracaecum osculatum 1 (Anisakidae) from Russian waters of the South Baltic were studied in 2000-2012. Peculiarities of larval growth in different hosts were analyzed. A total of 6233 fish specimens were investigated, including 1420, 3867, and 946 specimens of sprat, herring, and cod, respectively. The prevalence and mean intensity indices of sprat, herring, and cod constituted 1.27 +/- 1 0.3% and 1.0, 1.4 +/- 0.19% and 1.13 +/- 0.38, and 11.63 +/- 1.04% and 5.62 +/- 8.00, respectively. The increasing of infection indices was observed in recent years. It was associated with the increase in the number of grey seals, definitive hosts of C. osculatum in the Baltic Sea. The growth of helminthes larvae in sprats, Baltic herrings, and cods was revealed. The important role of the sprat in the cod infestation with C. osculatum and in the transmission of this parasite was demonstrated for the first time. PMID- 25693328 TI - [Differences in the infestation rate of young cyprinid fishes (Cypriniformes) by metacercaria of Posthodiplostomum Cuticola (Digenea, Diplostomatidae) in river and lake systems of the Lake Chany basin (Western Siberia)]. AB - A total of 12 fish species were studied for the invasion of P. cuticola (Nordmann, 1832) metacercariae in the Chany Lake estuaries, river and lake systems during different periods of water level. All infected individuals were represented by juveniles of the family Cyprinidae, except for adults of the dace Leuciscus leuciscus. (L.). Under an average water level (2010) the highest rate of fish invasion was revealed in the estuary zone, where the prevalence of infection (PI) constituted 37.5%, 13.4%, and 5.9% for the gudgeon Gobio gobio, the roach Rutilus rutilus (L.), and the dace L. leuciscus (L.), respectively. An infested carp Cyprinus carpio L. (Heckel) (PI - 13.5%) was recorded in the lower Kargat River, and the goldfish Carassius auratus (L.) (PI - 3.2%), in the lake system. Mean intensity of infection (MI) constituted 1.3, 1.4, 2.5, 2.6, and 1.0 in gudgeon, roach, dace, carp, and bream (Abramis brama L.), respectively. During dry season (2011) with high water salinity only two fish species were infected with P. cuticola metacercariae, the goldfish (PI - 7.9%) and the roach (PI - 1.5%). No correlation between PI and fish density was revealed. It is assumed that the high degree of water salinity is a limiting factor regulating the efficiency of cercariae transition from the first intermediate host (Planorbis planorbis (L.)) to the second one (Pisces, Cyprinidae). PMID- 25693329 TI - [Age-related dynamics of roach infection rate with Ligula intestinalis (Cestoda: Ligulidae) plerocercoids and probability of its usage for the calculation of host death rate]. AB - Results of special parasitological dissections of roach samples from catches with the same fishing gear and at the same station (Monakhovo Cove, Chivyrkui Bay of the Lake Baikal) and at the same time in different years (1998-2002) are given. Stability of age-related dynamics of roach infection rate with Ligula intestinalisis in different years with the maximum of prevalence and mean abundance in fish of 3+ age, and the following sharp decrease in these rates in elder age groups, was revealed. Basing on prevalence decreasing of a single roach generation, the rate of fish mortality during its growth from age group 3+ to 4+ was estimated as 15.9-20.7%. PMID- 25693330 TI - [Proposal for making guidelines of regional anesthesia in patients under anticoagulation therapy or antiplatelet therapy]. PMID- 25693331 TI - [Lower thoracic epidural analgesia improves postoperative analgesia following vaginal total hysterectomy]. AB - BACKGROUND: In our hospital, lumbar epidural analgesia had been used for postoperative analgesia following vaginal total hysterectomy (VTH). But some patients experienced severe abdominal pain or numbness of the legs. Therefore we planned a randomized prospective study to compare lower thoracic epidural analgesia and lumbar epidural analgesia following VTH. METHODS: Fifty patients were allocated to two groups: those who received lower thoracic epidural analgesia(T group)and the other who received lumbar epidural analgesia (L group). Both groupsreceived the same continuous epidural analgesia using fentanyl and ropivacaine after the operation. RESULTS: The T group required significantly lower frequency of analgesic agents compared with that of the L group (2.5+/-1.9 times vs. 1.2+/-1.1 times, P< 0.05). Fewer patients in the T group had felt numbness in their legs compared to the L group (8% vs. 55%, P<0.05). CONCLUSIONS: Lower thoracic epidural analgesia is more effective to provide postoperative analgesic effect following VTH compared with lumbar epidural analgesia. PMID- 25693332 TI - [Efficacy and safety of sugammadex (Org 25969) in reversing moderate neuromuscular block induced by rocuronium or vecuronium in Japanese patients]. AB - BACKGROUND: Efficacy and safety of sugammadex in reversing neuromuscular block induced by rocuronium or vecuronium were investgated in Japanese patients. METHODS: We studied 98 Japanese patients undergoing surgery requiring general anesthesia. Patients were allocated randomly to receive intubation dose of rocuronium or vecuronium. During surgery, patients received additional doses of rocuronium or vecuronium for maintenance of moderate block. At T2 reappearance sugammadex 0-4.0 mg . kg-1 was administered. The neuromuscular block was monitored with acceleromyography using TOF stimuli. Sevoflurane was administered to all treatment groups after intubation. RESULTS: For the rocuronium-induced neuromuscular block, the mean recovery time of the T4/T1 ratio to 0.9 decreased from 82.1 min in the placebo group to 1.8 min in the 4.0 mg . kg-1 sugammadex group. For the vecuronium-induced neuromuscular block, it decreased from 83.2 min in the placebo group to 2.1 min in the sugammadex 4.0 mg . kg-1 group. Plasma concentrations of sugammadex were approximately dose proportional over the dose range of 0.5 to 4.0 mg . kg-1 and independent of the neuromuscular blocking agents used. No clinical evidence of recurarization or residual curarization was observed. CONCLUSIONS: The efficacy and safety of sugammadex were confirmed in Japanese surgical patients. PMID- 25693333 TI - [Efficacy and safety of sugammadex (Org 25969) in reversing deep neuromuscular block induced by rocuronium or vecuronium in Japanese patients]. AB - BACKGROUND: Efficacy and safety of sugammadex in reversing neuromuscular block induced by rocuronium or vecuronium were investgated in Japanese patients. METHODS: We studied 99 Japanese patients undergoing surgery requiring general anesthesia. Patients were allocated randomly to receive intubation dose of rocuronium or vecuronium. During surgery, patients received additional dose of rocuronium or vecuronium for maintenance of deep block. At 1-2 PTC, 0.5-8.0 mg . kg-1 of sugammadex was administered. The neuromuscular block was monitored with acceleromyography using TOF stimuli. Sevoflurane was administered to all treatment groups after intubation. RESULTS: For the rocuronium-induced neuromuscular block, the mean recovery time of the T4/T1 ratio to 0.9 decreased from 66.9 min in the sugammadex 0.5 mg kg-1 group to 1.3 min in the sugammadex 8.0 mg kg-1 group. For the vecuronium-induced neuromuscular block it decreased from 79.5 min in the sugammadex 0.5 mg . kg-1 group to 2.9 min in the sugammadex 8.0 mg . kg-1 group. No clinical evidence of recurarization or residual curarization was observed. CONCLUSIONS: The efficacy and safety of sugammadex were confirmed in Japanese surgical patients for reversal from deep block. PMID- 25693334 TI - [Analgesic efficacy of transversus abdominis plane block after open abdominal aortic aneurysm surgery]. AB - BACKGROUND: Ultrasound (US)-guided transversus abdominis plane (TAP) block is widely-spread analgesic technique for the patients undergoing abdominal surgery and can be provided safely for the patients receiving anticoagulation therapy. We conducted a retrospective comparative trial of analgesic efficacy between the patient who received US-guided TAP block with postoperative continuous iv fentanyl infusion (group T) and those who received epidural analgesia (group E). METHODS: Twenty three patients who had undergone abdominal aortic replacement were analyzed retrospectively. The number of patients in group T was 12, and those in group E was 11. The postoperative first ambulation day, the postoperative first oral feeding day, the length of hospital stay, the use of rescue analgesic medication, and the incidence of postoperative nausea and vomiting (PONV) were compared between the two groups. P<0.05 was considered significant RESULTS: There were no significant differences in baseline characteristics between the two groups. There were no significant differences in postoperative first ambulation day (P=0.97), the postoperative first oral feeding day (P=0.46), the length of hospital stay (P= 0.32), the number of times of rescue analgesic medication (P=0.55), and the incidence of PONV between the two groups. CONCLUSIONS: US-guided TAP block is a useful option as analgesic technique for patients undergoing abdominal aortic replacement PMID- 25693335 TI - [Postoperative numerical rating scale in patients undergoing gynecological laparotomy under general anesthesia combined with either single epidural injection or transverses abdominis plane block]. AB - BACKGROUND: After the operation, early postoperative ambulation has been recommended for thromboprophylaxis. As more anticoagulant drugs have become available, hemorrhagic complication of epidural anesthesia is the focus of attention. Recently, the spread of ultrasound-guided nerve block has improved the efficacy of the transversus abdominis plane block Therefore, we compared transversus abdominis plane block with epidural anesthesia regarding postoperative numerical scale in patients undergoing gynecological surgery. METHODS: Doses of administrated narcotics during anesthesia, frequencies of administration of analgesics and vomiting up to 24 hours postoperatively, and numerical rating scale (NRS) at the first and 18th postoperative hours were retrospectively surveyed in patients undergoing gynecological laparotomy. Anesthesia was maintained with sevoflurane combined with either single epidural injection of 6-12 ml of 0.375- 0.75% lopivacaine with 2-4 mg of morphine in 16 patients (Epi group) or ultrasound-guided transverses bilateral abdominis plane block (TAPB) using 20 ml of 0.375% lopivacaine, respectively, in 16 patients (TAP group). RESULTS: No significant differences were found in age, height, weight, ASA-physical status, volume of intraoperative blood loss and surgical time. Both the total administrated doses of remifentanil and fentanyl during anesthesia in TAP group were significantly larger than those in Epi group. Number of postoperative vomiting was larger in Epi group. However, NRS at the postoperative first and 18th hours showed no significant differences between the two groups. The technique of ultrasound-guided TAPB is relatively easy compared with that of epidural injection and TAPB has an advantage in availability in patients receiving anticoagulant therapy. CONCLUSIONS: No significant difference in postoperative NRS between two groups in this survey suggests that TAPB in combination with appropriate postoperative pain service is useful in patients contraindicated to epidural puncture. PMID- 25693336 TI - [Ultrasound assessment of gastric content in cesarean delivery patients: an observational study]. AB - BACKGROUND: The aim of this observational study is to examine the benefit of ultrasound assessment of gastric content in cesarean delivery (CD) patients. METHODS: Thirty-nine patients scheduled for CD were assigned to a scheduled CD group and to an emergency group. Before CD, gastric ultrasonography examinations to calculate CSA (cross sectional area) of gastric antrum were performed to determine if gastric content was residual, and patients in the emergency group were asked what and when they had eaten. They were classified as full stomach when CSA was 2.5 cm2 or more and the sonographic characteristics of the antrum showed mixture with high echogenic particles. RESULTS: Eight patients were assigned to a scheduled CD group and thirty-one patients to an emergency group, respectively. None of the scheduled CD group should be CSA of 2.5 cm2 or more and eight of the emergency group should be 2.5 cm2 or more, including 3 patients with or without labor showing residual gastric contents after more than 10 hours of ingestion. CONCLUSIONS : There are some CD patients with the high risk of aspiration with or without labor even 10 hours after the last ingestion. PMID- 25693337 TI - [Anesthetic management of a pneumothorax patient with complete situs inversus]. AB - We experienced a case of pneumothorax in a patient with complete situs inversus. A 30-year-old man was scheduled for partial resection of the left lung under video assisted thoracic surgery. He had asymptomatic complete situs inversus. We advanced a bronchial blocker easily into the left (anatomically right) main bronchus under fiberoptic guidance. One lung ventilation during the operation was performed successfully. The chest X-ray after the surgery showed an atelectasis of the left upper lobe. After endotracheal suction, we extubated him and noticed improvement of atelectasis. There are several ways of one lung ventilation in patients with situs inversus. To use a bronchial blocker is one of the effective choices. However, in some cases, it is necessary to consider using a double-lumen tube depending on the case considering the anatomical structure and the characteristics of the procedure. PMID- 25693338 TI - [Cardioversion for paroxysmal supraventricular tachycardia during lung surgery in a patient with concealed Wolff-Parkinson-White syndrome]. AB - We report a case of paroxysmal supraventricular tachycardia (PSVT) that occurred during video-assisted thoracoscopic (VATS) lobectomy in a patient with concealed Wolff-Parkinson-White (WPW) syndrome. A 59-year-old man with lung cancer was scheduled for VATS lobectomy under general anesthesia. After inserting a thoracic epidural catheter, general anesthesia was induced with intravenous administration of propofol. Anesthesia was maintained with inhalation of desfurane in an air/oxygen mixture and intravenous infusion of remifentanil. Recurrent PSVT occurred three times, and the last episode of PSVT continued for 50 minutes regardless of administration of antiarrhythmic drugs. Synchronized electric shock via adhesive electrode pads on the patient's chest successfully converted PSVT back to normal sinus rhythm. The remaining course and postoperative period were uneventful. An electrophysiological study performed after hospital discharge detected concealed WPW syndrome, which had contributed to the development of atrioventricular reciprocating tachycardia. Concealed WPW syndrome is a rare, but critical complication that could possibly cause lethal atrial tachyarrhythmias during the perioperative period. In the present case, cardioversion using adhesive electrode pads briefly terminated PSVT in a patient with concealed WPW syndrome. PMID- 25693339 TI - [Anesthetic management for laparoscopic pheochromocytoma resection in a patient with cardiac dysfunction under dynamic monitoring]. AB - A 51-year-old women with cardiac dysfunction due to catecholamine-induced cardiomyopathy underwent laparoscopic adrenalectomy for pheochromocytoma. Her preoperative cardiac status was New York Heart Association (NYHA) class IIand left ventricular ejection fraction (LVEF) was 45%. In her anesthetic management, we used FloTrac(r) system and monitored arterial pressure-based cardiac output (APCO) and stroke volume variation (SVV) continuously as the indicator of intraoperative hemodynamics. Although her hemodynamics fluctuated highly during manipulation of the tumor and after ligation of adrenal vein intraoperatively, we could manage them rapidly by adjusting administration of vasodilator or pressor agents and appropriate volume expansion under monitoring APCO and SVV. The operation was completed successfully and postoperative course was almost uneventful. As laparoscopic pheochromocytoma resection is accomplished in a brief period with less surgical invasion compared with laparotomy, it may be possible to manage hemodynamics of the patient with cardiac dysfunction properly under dynamic monitoring using FloTrac(r) system. PMID- 25693340 TI - [Perioperative management of an obese patient complicated with sleep apnea syndrome (SAS) undergoing awake craniotomy]. AB - Both obesity (BMI over 30) and SAS are risks for Supper airway maintenance. We report an obese patient (BMI 33.5) with SAS who underwent awake craniotomy. Weight reduction was instructed 1 month before the operation, and the patient lost enough weight to use intraoperative MRI. Under general anesthesia, surgical pads containing 2% lidocaine with adrenaline were inserted into the nasal cavities. The patient's airway S was secured by i-gel(r) until dura was opened. A nasal airway was then inserted to confirm the upper airway patency and anesthetics were terminated The patient regained consciousness and started respiration. The i-gel(r) was removed. The nasal airway was changed to an RAE tracheal tube ; the tube was fixed above the vocal cords under bronchofiberscopic observation. Continuous positive airway pressure (CPAP) via RAE tube was started. Neither coughing nor epistaxis was observed.The RAE tube prevented glossoptosis and did not disturb speech mapping. Emergent endotracheal intubation was easily managed because the tube was close to the glottis. The RAE tube was removed and nasal CP AP was applied overnight Carefully prepared CP AP support via nasal RAE tube was practical in keeping upper airway patency for an obese patient complicated with SAS undergoing awake craniotomy. PMID- 25693341 TI - [Case of urgent surgical cricothyrotomy in CICV situation during induction of anesthesia for hemostasis after tonsillectomy]. AB - A 38-year-old man (BMI 31) underwent bilateral tonsillectomy for sleep apnea syndrome under general anesthesia without any airway difficulty. On the fifth post-operative day excessive bleeding occurred suddenly. Emergency tracheostomy was planned, not under local anesthesia but general anesthesia in the presence of otolaryngologists for urgent tracheostomy, since the patient could not lie in the supine position. Tracheal intubation was tried using rapid sequence technique. However, excessive bleeding in the oral cavity did not allow successful direct laryngoscopy, resulting in CICV situation. When CICV situation was con- firmed associated with SpO2 91%, surgical cricothyrotomy was started by otolaryngologists. SpO2 decreased to 13% associated with heart rate of 38 beats . min-1 immediately before restoration of ventilation and oxygenation. After hemostasis, he showed uneventful post-operative course. On the occasion of airway management for excessive laryngopharyngeal bleeding, emergency surgical crycothyrotomy should be performed immediately before the fall of oxygen tension, if rapid sequence tracheal intubation had failed. PMID- 25693342 TI - [Air-Q(r) intubating laryngeal airway as a conduit for tracheal intubation in a patient with Apert syndrome: a case report]. AB - We present a case of an 18-year-old male who underwent strabismus operation under general anesthesia. In his childhood, tracheostomy had been performed for the repair of cleft lip and palate. His Mallampati classification was IV and preoperative endoscopic examination revealed megaloglossia and severe airway narrowing. For possible difficult airway, intubating laryngeal airway (air-Q(r), size 2.5) was used for tracheal intubation. Following insertion of air-Q(r), trachea was intubated via air-Q(r) guided with fiberscope. The patient was ventilated via tracheal tube with the air-Q(r) remaining in place during the operation. air-Q(r) can be effectively utilized for airway management for an adult Apert syndrome patient PMID- 25693343 TI - [Intraoperative acute airway obstruction due to the damage of a reinforced endotracheal tube in thyroidectomy]. AB - A 55-year-old woman was scheduled for left thyroidectomy. Anesthesia was induced without problems and maintained without nitrous oxide. Sixteen minutes after the start of the procedure, airway pressures and endtidal carbon dioxide concentration increased suddenly. An attempt to pass a suction catheter down the endotracheal tube was unsuccessful. A protuberance was found in the reinforced endotracheal tube. After reintubation with a new reinforced endotracheal tube, ventilation was improved immediately. The rest of the procedure was done uneventfully. Similar phenomenon was reported in the reuse of endotracheal tube and the use of nitrous oxide. In our case, airway obstruction was caused by the pinhole that was created in a manufacturing process. We have to keep in mind that endotracheal tube itself may be out of order if other causes have been excluded. PMID- 25693344 TI - [Successful anesthetic management of laparoscopic rectopexy using rocuronium and sugammadex in a patient with Becker muscular dystrophy]. AB - A 70-year-old man with Becker muscular dystrophy (BMD) underwent laparoscopic rectopexy under general anesthesia. For anesthetic induction, we administered total 0.6 mg . kg-1 of rocuronium with titration. Eight minutes later, train-of four (TOF) count reached to 0 and the patient was intubated smoothly. One hundred and five minutes later, TOF ratio recovered to 100% and we administered rocuronium 10 mg additionally. Surgery was finished without any problems 95 minutes after thereafter. TOF ratio was 45% and we administered sugammadex 3 mg . kg-1, reversing neuromuscular blockade to TOF ratio 100% within 1.5 minute. The patient awoke clearly and respiratory condition was good. He was extubated without remaining neuromuscular blockade. Postoperative course was stable and there was no serious adverse effect on his muscular function intra- and post operatively. In conclusion, rocuronium and sugammadex can be used safely and effectively in general anesthetic management for patients with muscular dystrophy. However, as the onset times and durations of these agents can be longer, we should administer these agents with titration carefully under periodic neuromuscular monitoring. PMID- 25693345 TI - [Desflurane anesthesia without muscle relaxant for a patient with myasthenia gravis undergoing laparoscopic high anterior resection: a case report]. AB - Myasthenia gravis (MG) is an autoimmune disease affecting neuromuscular junction, which is characterized by fluctuating muscle weakness and abnormal fatigability. The use of muscle relaxants is major concern in anesthetic management for patients with MG. Muscle relaxant is a practical tool to assure immobilization during surgery under general anesthesia Anesthetic management without muscle relaxants for patients with MG is challenging, because it is difficult to assure immobilization. However, pharmacological effects of muscle relaxants can be prolonged in patients with MG, resulting in the increased incidence of postoperative respiratory support. We, here, describe an anesthetic management of an 82-year-old man with MG undergoing laparoscopic surgery. Anesthesia was induced with propofol and remifentanil Desflurane was administered via a face mask, and the patient was manually ventilated for 10 min, and the trachea was intubated safely without muscle relaxants. Anesthesia was maintained with desflurane and remifentanil. We did not administer muscle relaxants to the patient during surgery. Throughout laparoscopic procedures, no movements of the patient were observed, and there were no problems concerning the laparoscopic view of the operation filed. The surgery was uneventful. The patient emerged from anesthesia smoothly, and was extubated safely. The postoperative course of the patient was also uneventful. PMID- 25693346 TI - [Excision of a superior vena cava aneurysm with venous malformations in the face, neck and mouth]. AB - Aneurysm of the superior vena cava is a very rare disease, and there have been few reports of such cases. We report a case of superior vena cava aneurysm excision with venous malformations in the face, neck and mouth. The aneurysm was excised after performing sclerosing therapy for multiple hemangiomas over a period of about one year. PMID- 25693347 TI - [Anesthetic management of a pregnant woman with brain tumor]. AB - A 35-year-old parturient, 35 weeks pregnant, pre- sented with intracranial tumor with increased intracra- nial pressure. She underwent emergency cesarean section under general anesthesia, followed by craniotomy. The intraoperative and postoperative courses were uneventful. The occurrence of brain tumors during pregnancy is very rare; meanwhile pregnancy may aggravate the natural history of an intracranial tumor, and may even unmask previously unknown diagnosis. The decision to proceed with cesarean section and neurosurgery depends on the site, size, type of tumor, neurological signs and symptoms, age of the fetus, and the patient's wishes. Therefore, close communication between the neurologist, neurosurgeon, anesthesiologist, obstetrician and the patient is very important. PMID- 25693348 TI - [Perioperative management of off-pump CABG for a 93-year-old man]. AB - In recent years, the aging population has been growing, and the operative techniques and anesthetic methods have advanced. With these developments and medical support, the number of operations on very elderly patients has been increasing. We report the perioperative management of off-pump CABG for a 93-year old man. When the heart was displaced during the operation, hypotension was induced and a marked reduction of his bispectral index (BIS) to "1" appeared. During the perioperative period, the patient developed delirium that was difficult to manage, but he was discharged from the hospital without any complications on POD 21. As part of the perioperative management, intraoperative cerebral circulatory management with attention to cerebral perfusion and prevention of postoperative delirium is crucial. PMID- 25693349 TI - [Continuous hemodiafiltration during graft repair for a ruptured thoracoabdominal aortic aneurysm was useful in a patient with chronic renal failure]. AB - A 74-year-old man with ruptured thoracoabdominal aortic aneurysm was scheduled for open surgical repair under partial cardiopulmonary bypass. He had a history of diabetes mellitus and a concomitant renal dysfunction, requiring regular intermittent hemodialysis. To maintain electrolytes, acid base as well as water balance within adequate ranges, we planned to use continuous hemodiafiltration (CHDF) during the surgery because there was a high incidence of bolus transfusion to deal with massive bleeding in these surgeries. We increased fluid removal speed of ultrafiltration when blood components had to be infused rapidly. With these considerations, the patient did not develop fluid overload, hyperkalemia, or aggravation of acidosis. We did not administer anticoagulants into CHDF circuit because activated coagulation time was prolonged probably due to massive bleeding prior to the surgery. Heparin was administered just before the partial car diopulmonary bypass. There was no evidence for thromboembolic complications due to CHDF use. In conclusion, we successfully managed electrolytes as well as acid base balance, and hydration of a patient with chronic renal failure by using CHDF during open graft repair of ruptured thoracoabdominal aortic aneurysm. PMID- 25693350 TI - [Suspected case of postoperative malignant hyperthermia treated with dantrolene one week after neurosurgery]. AB - We report the case of a 16-year-old man who presented with hyperthermia (>40 degrees C), an elevated creatine kinase level (>64,000 IU . l-1), and myoglobinuria one week after undergoing two successive neurosurgeries for a brain hemorrhage under sevoflurane anesthesia. After having been diagnosed with suspicious atypical postoperative malignant hyperthermia, he was treated with dantrolene and his symptoms disappeared on the day of dantrolene administration. Central hyperthermia is defined as hyperthermia associated with thermoregulatory dysfunction after brainstem injury. Postoperative malignant hyperthermia can sometimes be difficult to distinguish from central hyperthermia, especially after neurosurgery. We could not eliminate the possibility of central hyperthermia as a cause of hyperthermia in the present patient If marked postoperative hyperthermia must be addressed immediately and managed appropriately in neurosurgical patients and dantrolene having few serious side effects, we were able to control his symptoms immediately after the infusion of dantrolene. Therefore, the administration of dantrolene should be considered when treating unidentified postoperative hyperthermia after a neurosurgical procedure. PMID- 25693351 TI - [Anesthetic management for abdominoperineal resection of the rectum in a patient with superior vena cava syndrome]. AB - Since superior vena cava syndrome (SVCs) causes ntracranial hypertension and edema of the upper respiratory tract close attention should be paid to brain circulatory dysfunction and obstruction of the upper airway. A male patient with SVCs and complete obstruction of the bilateral internal jugular veins was scheduled for abdominoperineal resection of the rectum under general anesthesia To evaluate the brain circuation, we monitored the external jugular venous pressure and regional saturation of oxygen (rSO) by INVOS(r) in the cerebral frontal cortex. If the external ugular venous pressure would rise above 20 mmHg, we planned to change the horizontal supine position to a head up position and then remove blood from the external jugular vein. Fortunately, since the external jugular venous pressure was maintained within 20 mmHg, and since no great decreases in rSO2 occurred during surgery, we did not change the patient's position or remove blood from the patient. The surgical procedure was completed uneventfully, and pharyngoarngeal edema was not seen. He did not show any neurological deficits after surgery. From experience of khis patient, we concluded that monitoring of external cigular venous pressure and rSO2 is useful for anesthetic management in patints with SVCs. PMID- 25693352 TI - [Visualization of the airway using ultrasound]. PMID- 25693353 TI - [Visualization of the airway using ultrasound - author's reply]. PMID- 25693354 TI - [Delayed discharge from the intensive care unit]. AB - BACKGROUND: Delayed discharge from ICU to the general ward can exert an adverse effect. We researched whether patients are discharged smoothly from our ICU to the general ward. METHODS: We defined that patients were eligible for discharge if they are without administration of catecholamine, being assisted by mechanical ventilation and having blood purification therapy. RESULTS: Average time from actual discharge to the time patient was considered eligible for discharge was fifteen hours. This study was retrospective. CONCLUSIONS: We need to investigate further the reasons why delayed discharge occurred. It is im portant that patients are discharged from the ICU to the general ward properly. Delayed discharge can delay the recovery and expose the patient to multi-resistant microorganisms. We studied whether patients are discharged smoothly from the ICU to the general ward. PMID- 25693355 TI - [Measurement of external pressure of peroneal nerve tract coming in contact with lithotomy leg holders using pressure distribution measurement system BIG-MAT(r)]. AB - We investigated external pressure on peroneal nerve tract coming in contact with two kinds of leg holders using pressure distribution measurement system BIG- MAT(r) (Nitta Corp., Osaka) in the lithotomy position Peak contact (active) pressure at the left fibular head region coming in contact with knee-crutch-type leg holder M(r) (Takara Belmont Corp., Osaka), which supports the left popliteal fossa, was 78.0 +/- 26.4 mmHg. On the other hand, peak contact pressure at the left lateral lower leg region coming in contact with boot-support-type leg holder Bel Flex(r) (Takara Belmont Corp., Osaka), which supports the left lower leg and foot was 26.3+/-7.9 mmHg. These results suggest that use of knee-crutch-type leg holder is more likely to induce common peroneal nerve palsy at the fibular head region, but use of boot-support-type leg holder dose not easily induce superficial peroneal nerve palsy at the lateral lower leg region, because capillary blood pressure is known to be 32 mmHg. Safer holders for positioning will be developed to prevent nerve palsy based on the analysis of chronological change in external pressure using BIG-MAT(r) system during anesthesia. PMID- 25693356 TI - [President's message: familial hypercholesterolemia]. PMID- 25693357 TI - [Editorial. Familial hypercholesterolemia]. PMID- 25693358 TI - [Familial hypercholesterolemia: epidemiology, genetics, diagnosis, and screening]. AB - Familial hypercholesterolaemia (FH) is an autosomal dominant genetic disorder characterized by el- evated plasma levels of low-density lipoprotein-cholesterol (LDL-C) and increased risk of premature coronary heart disease. There are two types of FH, namely homozygous and heterozygous FH. FH is most commonly (85%) attributable to mutations in the LDL receptor (LDL-R) gene. Other rare causes are the mutations of genes encoding apolipoprotein B (Apo B), pro-protein convertase subtilisin/ kexin type 9 (PCSK9) and LDL adaptor protein 1 (LDLRAP 1). FH is both underdiagnosed and undertreated, particu- larly among children. Approximately 20% of patients are diagnosed and, of those, only a small minority receive ap- propriate treatment. The risk of premature coronary heart disease (CHD) is elevated about 20-fold in untreated FH patients. Early diagnosis of FH enables prompt treatment and prevention of consequent morbidity and mortality from premature CHD. There is no single internationally accepted set of criteria for the clinical diagnosis of FH. The most commonly used are the US (Make Early Diagnosis to Prevent Early Death) MEDPED, the UK (Simon Broome), and the Dutch Lipid Clinic sets of criteria that have been statistically and genetically validated. For early diagnosis and prevention of CVD, testing lipid levels in all first-degree relatives of diagnosed FH patients is necessary. Genetic screening for FH is generally not needed for diagnosis or clinical management, but may be useful when the diagnosis is uncertain. PMID- 25693359 TI - [Heterozygous familial hypercholesterolemia]. AB - Heterozygous familial hypercholesterolemia (HeFH) is an autosomal co-dominant inherited disease associated with increased risk of early cardiovascular disease. Plasma low-density lipoprotein concentrations of the affected individuals are 2 to 3 times higher than the normal population. The prevalence of the HeFH is 1/500 and only 20% of the cases are diagnosed. A minority of the diagnosed patients (16%) are able to reach treatment. Early identification of the patients with HeFH enables exact treatment and prevention of the premature coronary artery disease. So, screening of the relatives of the index cases is essential. HeFH is diagnosed by the use of clinical criteria like family history, physical examination, and cholesterol levels. Mutation analysis may provide an accurate diagnosis in suspicious cases. Treatment strategies mostly aim to provide a reduction of low density cholesterol levels of >50% from baseline. First-line treatment is statins. However, most of the patients with HeFH do not achieve target cholesterol levels with maximum tolerated doses of statins. Combinations of statins with ezetimibe, niacin or bile acid sequestrants have limited value. New classes of drugs for the treatment of hypercholesterolemia include microsomal triglyceride transfer protein inhibitors, apolipoprotein B synthesis inhibitors, and pro-protein convertase subtilisin/kexin 9 inhibitors. This review aims to discuss the updated information regarding the diagnosis and treatment of HeFH. PMID- 25693360 TI - [Homozygous familial hypercholesterolemia]. AB - Familiar hypercholesterolemia (FH) is genetic disease characterized with extremely high levels of cholesterol leading to cholesterol deposition in skin and tissues and premature atherosclerosis due to defective LDL receptors. In homozygous individuals (HoFH) premature cardiovascular (CV) events and aortic stenosis could develop at very early ages due to the exposure of the vessels including aorta to high lipid levels since birth. Patients with HoFH do not respond to conventional antilipid agents including statins due to defective LDL receptors. Therefore,LDL apheresis is still the only choice of treatment in HoFH. However, in order to prevent both the development of CV events and aortic stenosis, regular apheresis should be initiated before the age of 10 years. With the knowledge of the 21.2% consanguineous marriages in Turkey, it could be suggested that the prevalence of FH is high in our country. However, the frequency of HoFH in Turkey is not known and there is limited data on prognosis in long term studies. This limited data denotes an extremely high mortality and morbidity in patients with HoFH. The main problem in these patients is late diagnosis leading to a delayed treatment. However, early diagnosis is the key factor for the prevention of premature atherosclerosis and for ensuring long-term survival in HoFH. Moreover, FH is a genetic disease that could be easily diagnosed with a detailed family history, physical examination, and assessment of lipid levels. In order to commence early diagnosis and early treatment, awareness of the physicians should be increased. Particularly raising the awareness among primary care physicians regarding high cholesterol levels in children and adolescents would be a substantial step. Public should realize that FH is a common disease with high mortality, and that the harms of high cholesterol begin in childhood. In order to achieve all these goals, National policy for the diagnosis and management of AH is warranted. PMID- 25693361 TI - [LDL apheresis in the treatment of familial hypercholesterolemia]. AB - Low density lipoprotein (LDL) apheresis is one of the main therapeutic models for homozygous and severe heterozygous form of the familial hypercholesterolemia patients. Anti-atherogenic, anti-thrombogenic and anti-inflammatory effects of apheresis has positive effects on prevention of cardiovascular disease by improving of the tissue perfusion. Blood LDL cholesterol levels, response to medical therapy, presence or severity of the coronary heart disease are the main determinants of the apheresis indications. Except bleeding tendency and heparin sensitivity, there are no contraindications. In parallel with low body weight, pediatric practice could be more risky; however, there is also a 3.5-year-old apheresis application without problems. The first successful plasmapherisis for the removal of LDL cholesterol in circulation was performed in 1975. Plasmapheresis, today, is only emergency treatment model in cases of life threatening hyperchylomicronemia. New apheresis techniques have rather high selectivity for atherogenic lipoproteins containing apolipoprotein-B100. If existing apheresis technique has low effectiveness (acute decrease of LDL cholesterol <60%), primarily calculated plasma or blood treatment volumes could be increased and then technique could be switched to other one. Early identification of the affected patients and aggressive LDL apheresis treatment significantly reduce the burden of cardiovascular disease in children and adult patients with homozygous or severe heterozygous familial hypercholesterolemia. PMID- 25693362 TI - [Homozygous familial hypercholesterolemia]. AB - Familial hypercholesterolemia (FH) is caused by genetic deficiency of LDL receptors leading to extremely high cholesterol levels and atherosclerosis at early ages. For the prevention of early atherosclerotic cardiovascular events, effective reduction of LDL-cholesterol is necessary from the early ages. However, particularly in homozygous patients, it's almost impossible to achieve target LDL cholesterol levels with antilipid agents including statin agents, due to the severe LDL receptor dysfunction. LDL apheresis is an effective treatment modality in severe AH patients. However, the invasive, chronic time consuming nature of this treatment decreases the compliance of these patients. Moreover, atherosclerosis progress in 25% of the patients undergoing regular and effective apheresis even though since early ages. Clinical data also indicate that there is still an unmet medical need for new effective treatments for AH patients. This review will address new therapeutic strategies targeting Apolipoprotein (Apo) B including MTTP inhibitor Lomitapideand oligonucleotide Mipomersen. As both agents are targeted against ApoB, they are expected to be effective even in receptor negative homozygous AH patients. PMID- 25693363 TI - [Proprotein convertase subtilisin/kexin type 9 (PCSK9) and inhibitors]. AB - Hypercholesterolemia is a major risk factor for atherosclerosis. Low-density lipoprotein cholesterol (LDL-C) lowering drugs reduce cardiovascular morbidity and mortality. However, many individuals treated with statins do not achieve their target levels of LDL-C. So, there is great need for new drugs to reduce cholesterol in those patients who have not achieved target levels with statins as well as those who are statin intolerant. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a novel agent, which plays an important role in the regulation of cholesterol metabolism. It increases degradation of the low-density lipoprotein receptor, modulates cholesterol metabolism, and transport. This review will address new therapeutic strategies targeting PCSK9, including monoclonal antibodies, small interfering RNAs, and other small molecule inhibitors. PMID- 25693364 TI - [Development of a two stage virtual impactor for stationary source PM10 and PM2.5 sampling]. AB - China does not have a national standard method for stationary source PM10 and PM2.5 sampling. Current commercial PM10/PM2.5 samplers have some limitations when used in China. In this study, we developed a two stage virtual impactor for sampling PM10/PM2.5 from stationary source. Its performance was evaluated using laboratory generated aerosol. Its collection efficiency curve satisfies the requirement of ISO 7708:1995 for PM10/PM2.5 samplers. The diameter of this cylindrical virtual impactor is 74 mm, smaller than the diameter of the sampling port in most stationary sources in China. Both filter papers and filter thimbles can be used with this impactor which makes it suitable for both low and high dust concentration sampling. The ratio of the minor flowrate to the total flowrate influences the cutoff size (D50) of the virtual impactor. Reducing this ratio will lead to an increase in D50. The distance from the bottom of the accelerating nozzle to the top of the collecting nozzle should be greater than 1.5-2.0 times the diameter of the accelerating nozzle. PMID- 25693365 TI - [Characteristics and the impact factors of acid rain in Fuzhou and Xiamen 1992 2012]. AB - Based on the observed acid rain data, synoptic situations and mass concentrations of atmospheric pollutants data from 1992 to 2012, the temporal variation characteristics and the impact factors of acid rain were analyzed in Fuzhou and Xiamen. The results showed that acid rain and non-acid rain accounted for 38.1% and 61.9% respectively in Fuzhou, 40.6% and 59.4% respectively in Xiamen. The annual average pH was 4.1-5.5 in Fuzhou. Acid rain pollution alleviated after 2007 in Fuzhou, and alleviated after 2006 in Xiamen. Acid rain was more serious in winter and spring than in summer and autumn. Precipitation intensity could affect the acidity of rain. Acid rain was observed more serious in southeast, southwest, west and northwest wind in Fuzhou, and more serious in northeast, southwest, west and northwest wind in Xiamen. Acid rain was most severe under the condition of transformed surface cold high, while most light under the conditions of typhoon (intertropical convergence zone) and outside of typhoon (intertropical convergence zone). There was a negative correlation between the mass concentrations of atmospheric pollutants, such as SO2, NO2, PM10, and the pH of rain in Fuzhou. PMID- 25693366 TI - [Concentration distribution of metal elements in atmospheric aerosol under different weather conditions in Qingdao Coastal Region]. AB - To know the influence of different weather conditions on the concentration of metal elements in aerosols in the coastal region, total suspended particles (TSP) samples were collected from April to May 2012, and August 2012 to March 2013 in the Qingdao coastal region, and common trace metals were analyzed by using Inductively Coupled Plasma-Mass Spectrometry (ICP-MS) and Inductively Coupled Plasma-Atomic Emission Spectrometry (ICP-AES). The results showed that Al, Ca, Fe, Na, K and Mg were the dominant metal elements in TSP, and the sum of the six elements accounted for 94.2% of the sum of all metals. TSP and metal elements had significant monthly variations, Fe, Al, K, Ca, Mg, Zn, Ba, Mn, Ti, Sr and Li had the highest concentration in November and January, while Be, Sc, Co, Ni and Cr showed the highest value in January. Na had the highest concentration in August, November and February, and the lowest in December. Pb had the highest concentration in January and February, and the lowest in August and December. Enrichment factors indicated that Be, Co, Al, Ca, Fe, K, Mg, Mn, Sr and Ti were mainly affected by natural sources; Li, Cr, Ni, Zn, Ba and Na were affected by natural sources and part of anthropogenic sources; Pb was mainly from anthropogenic sources. Different weather conditions had great impact on TSP and metal elements concentrations, all the measured metals had the highest concentrations in smog except Ti. Compared with the sunny day, the concentration of atmospheric particulate Ti decreased, while the other elements increased by 1 to 4 times in smog. Li, Be, Cr, Ni, Al, Fe, Mg and Mn had little variation in concentration in foggy day, and the concentration of Pb and Na increased considerably. The concentration of Co, Ca and Ti reduced obviously in fog. Except for Cr, Co and Ti, the other elements increased by 1 to 3 times in haze. Most of the elements had the minimal enrichment factors in sunny day, while the other had the maximal enrichment factor in foggy day. Enrichment factors of Ni, Zn, Ba, K, Na, Pb and Sr varied in the order of sunny day < haze day < smog day the newly cultivated sandy croplands > the old oasis croplands. The loss of N leaching was closely correlated to the silt + caly content in the 0-100 cm soil depth. The groundwater NO(3-)-N concentration varied from 1.01 to 5.17 mg . L(-1), with a mean value of 2.65 mg . L(-1) and from 6.6 to 29.5 mg . L(-1), with an average of 20.8 mg . L(-1) in the area of old oasis croplands and the newly cultivated croplands, respectively. The averaged groundwater NO(3-)-N concentration in the area of newly cultivated sandy croplands during the period of May and October, 2013 was 26.5 mg . L(-1), which was increased by 9.5 mg . L(-1) in comparison with the same period of 2012. There was a clear increasing trend in groundwater NO(3-)-N concentration in the sand-fixing zone outside oasis. The textural characteristics of soil unsaturated zone in the shallow groundwater distribution area was the key determining factor for controlling soil NO(3-)-N leaching and groundwater nitrate pollution. The newly cultivated sandy croplands were the nitrate vulnerable zones and high-risk areas of groundwater nitrate pollution. The implementation of cultivation pattern and irrigation and fertilization management that could effectively reduce groundwater NO(3-)-N pollution should be considered in the development of ecological agriculture. PMID- 25693371 TI - [Health assessment of river ecosystem in Haihe River Basin, China]. AB - With the development of economy, the health of river ecosystem is severely threatened because of the increasing effects of human activities on river ecosystem. In this paper, the authors assessed the river ecosystem health in aspects of chemical integrity and biological integrity, using the criterion in water quality, nutrient, and benthic macroinvertebrates of 73 samples in Haihe River Basin. The research showed that the health condition of river ecosystem in Haihe River Basin was bad overall since the health situation of 72. 6% of the samples was "extremely bad". At the same time, the health situation in Haihe River Basin exhibited obvious regional gathering effect. We also found that the river water quality was closely related to human activities, and the eutrophication trend of water body was evident in Haihe River Basin. The biodiversity of the benthic animal was low and lack of clean species in the basin. The indicators such as ammonia nitrogen, total nitrogen and total phosphorus were the key factors that affected the river ecosystem health in Haihe River Basin, so the government should start to curb the deterioration of river ecosystem health by controlling these nutrients indicators. For river ecosystem health assessment, the multi-factors comprehensive evaluation method was superior to single-factor method. PMID- 25693372 TI - [Analysis on the variation characteristics of iron and manganese concentration and its genesis in Changtan Reservoir in Taizhou, Zhejiang Province]. AB - Changtan Reservoir in Taizhou City Zhejiang Province and its inflow rivers were surveyed in January and from April to December in 2013. Based on those data and the water quality monitoring data in Changtan Reservoir collected in previous years, the change characteristics of iron and manganese concentrations in source water reservoir were investigated. Furthermore, the causes of water pollution by iron and manganese were discussed based on the variation of water temperature, dissolved oxygen (DO) in reservoir with water depth. The results showed that the seasonal variation characteristics of iron and the manganese concentrations in reservoir were much in evidence. Their concentrations were high from June to August and the highest values over the years at the outlet of Changtan Reservoir were 2.38 mg . L(-1) and 1.24 mg . L(-1), respectively. The iron and the manganese concentrations exceeded the Surface Water Environment Quality Standard (GB 383822002) of 0.3 mg . L(-1) and 0.1 mg . L(-1) from May to October. And in 2013, their highest values in the reservoir outlet exceeded the standard by 5. 6 times and 12. 4 times, respectively. The maxima of iron and manganese concentrations in the major rivers were 0.89 mg . L(-1) and 0.56 mg . L(-1), which were lower than those in the reservoir outlet. The comprehensive analysis result indicated that the exogenous pollution was not the major source of iron and manganese in the reservoir. The iron and manganese concentration at the bottom of the reservoir reached the maximum in July, 2.42 mg . L(-1) and 1.20 mg . L(-1), respectively. The typical vertical distribution of temperature, DO and iron and manganese concentrations in the reservoir in summer showed that seasonal anoxic environment caused by the thermal stratification led to the release of iron manganese from the deposits. The endogenous pollution caused by thermal stratification effect was the direct cause for the high iron and manganese concentrations in water. To control iron and manganese pollution in drinking water resource reservoir, efficient and direct in situ water quality improvement and repair technology should be developed. PMID- 25693373 TI - [Spatiotemporal characteristics of nitrogen and phosphorus in a mountainous urban lake]. AB - Longjing Lake in Chongqing Expo Garden is a typical representative of mountainous urban lake. Based on water quality monitoring of Longjing Lake, spatiotemporal characteristics of nitrogen and phosphorus and their relations were analyzed, combined with natural and human factors considered. The results indicated that annual average concentrations of TN and TP in overall lake were (1.42 +/- 0.46) mg . L(-1) and (0.09 +/- 0.03) mg . L(-1), nitrogen and phosphorus concentrations fluctuated seasonally which were lower during the flooding season than those during the dry season. Nitrogen and phosphorus concentration in main water area, open water areas and bay areas of Longjing Lake were distributed with temporal and spatial heterogeneity by different regional influencing factors. The seasonal variation of the main water area was basically consistent with overall lake. Two open water areas respectively connected the main water area with the upstream region, bay areas. TN and TP concentrations were gradually reduced along the flow direction. Upstream water quality and surrounding park functional layout impacted nitrogen and phosphorus nutrient concentrations of open water areas. Nutrient concentrations of typical bay areas were higher than those of main water area and open water areas. The mean mass fraction of PN/TN and PP/TP accounted for a large proportion (51.7% and 72.8%) during the flooding season, while NO(3-)-N/TN and SRP/TP accounted for more (42.0% and 59.4%) during the dry season. The mass fraction of ammonia nitrogen and dissolved organic nitrogen in total nitrogen were relatively stable. The annual mean of N/P ratio was 18.429 +/- 7.883; the period of nitrogen limitation was 5.3% while was 21.2% for phosphorus limitation. PMID- 25693374 TI - [Formation of geochemistry in underground river under rainfall conditions: an examule for underground river at Xueyu Cave, Chongqing]. AB - Through the monitoring of geochemical indexes in underground river of Xueyu Cave in Chongqing under rainfall conditions, we found that all indexes responded quickly to rainfall, and there was a correlation among them. Each index was analyzed with the principal component analysis, three main components were extracted which can represent 82.761% of the information to reflect the formation of geochemistry in underground river under rainfall conditions. The results showed that the contribution rates of soil leaching represented as increased concentration of total Fe, total Mn, and Al3+, and dilution effect represented as reduced concentration of K+, Na+ and Sr2+ to the change of geochemical characteristics were 41.718%, which should be paid more attentions for its great damage to karst soil and safety of drinking water. Karst water dissolution of dolomite and recharge area of agricultural activities, caverns were 29.958%, as for karst water on limestone dissolution represented, as increased concentration of Ca2+ the contribution rate was 11.084%. PMID- 25693375 TI - [Contamination and ecological risk assessment of polycyclic aromatic hydrocarbons in water and in Karst underground river catchment]. AB - Water samples in Laolongdong underground river catchment were collected to determine the concentration, compositional profiles, and evaluate ecological risk of 16 priority polycyclic aromatic hydrocarbons (PAHs). PAHs were measured by GC/MS. The total concentrations of 16 PAH ranged from 81.5-8019 ng . L(-1) in underground river, 288.7-15,200 ng . L(-1) in karst springs, and 128.4-2,442 ng . L(-1) in surface water. Affected by waste water from Huangjueya town, concentrations of PAHs in underground river were higher than those in surface water and waste water from sinkhole. The PAHs profiles were dominated by 3 ring PAHs. There were differences of monthly variations of PAHs contents in the water, due to waste water, season and different characteristics of PAH. Surface water and waste water from sinkhole played an important role on contamination in the river. The levels of ecological risk were generally moderately polluted and heavily polluted according to all detected PAH compounds in the water. PMID- 25693376 TI - [Pollution characteristics and ecological risk of polybrominated diphenyl ethers (PBDEs) in river sediments from an electrical equipment dismantling area]. AB - Polybrominated diphenyl ethers (PBDEs) were determined in sediments collected from a river which through an electrical equipment dismantling area. The results showed that concentrations of PBDEs ranged from 101 to 20,400 ng . g(-1) with an average of 3,700 ng . g(-1), and BDE209 was the most dominant homologue accounted for more than 94% of all detected homologues. The concentration of PBDEs was higher in the middle of river than that in upstream and downstream and the average concentration in downstream was higher than the upstream, with a peak of concentration in the area near by dismantling industrial park. PBDEs pollution in this region is relatively serious compared with other regions. It was estimated that 0.39 t PBDEs (including 0.36 t BDE209) was discharged into the river as a result of dismantling industrial activities in last 40 years. A preliminary ecological risk assessment for PBDEs in sediments was conducted by hazard quotient method, the results showed that the OctaBDEs and DecaBDEs were in a low ecological risk, while the PentaBDEs was in a particularly high risk and could cause great harm to the environment. PMID- 25693377 TI - [Ecological risk assessment of heavy metals in surface sediments in the southern and central Haihe River Basin]. AB - Several heavy metals, including Cu, Zn, Cr, Ni, Pb, and Cd, were investigated at 80 sampling sites in the southern and central areas of Haihe River Basin. The spatial patterns and potential anthropogenic impacts of heavy metals were evaluated by several methods, such as the potential ecological risk index and enrichment factors (EFs). Results showed that, (1) The concentrations of heavy metals in the sediments were higher than the background values in most sites except for Cr, Ni. The concentration of Cd was 2.64 times higher than its background value. Based on the potential ecological risk index for single heavy metal, Cd in river sediments showed a high potential ecological risk while the other elements showed a slight potential ecological risk at most sampling sites. Generally, the decreasing order of the heavy metals was Cd > Cu > Pb > Ni > Cr > Zn. (2) The concentration of heavy metals in surface sediment varied in different regions. The concentration of heavy metals and the potential ecological risks were higher in the Ziya river (RI = 155. 64) and Daqing river (RI = 111.84) than those in the other rivers. For example, slight pollution of heavy metals was found in the Tuhai, Majia river (RI = 69. 54) and Heilonggang river (RI = 84. 50) due to a relatively low level of industrialization. (3) Cd, Pb, Zn, Cr were positively correlated with each other and might be derived from similar sources. The increasing order of anthropogenic impacts on heavy metals was Ni < Cr < Cu < Zn < Pb < Cd according to the calculated EFs. The anthropogenic impacts differed in different rivers. For example, strong impacts were found in the Ziya, Daqing, Yongding and Zhangwei rivers whereas weak impacts were showed in Tuhai, Majia and Heilonggang rivers. PMID- 25693378 TI - [Distribution characteristics of COD and DO and its influencing factors in the Daliaohe Estuary]. AB - The concentrations of COD and DO were measured in the Daliaohe Estuary in April, July and November of 2010, and their distribution characteristics and influencing factors were discussed. The results showed that the concentrations of COD were 12.10, 4.42 and 4.38 mg . L(-1) in April, July and November of 2010, respectively. They were mainly influenced by rainfall, runoff and municipal sewage. COD values decreased with the increasing DO from the inner of Daliaohe Estuary to adjacent waters. Spatial distribution of COD was mainly controlled by agriculture and urban sewage and tides. The concentrations of DO were 8.46, 4.23 and 10.30 mg . L(-1) in April, July and November of 2010, respectively, and were mainly influenced by temperature and oxygen consumption of organic matter. Hypoxic zone was found in the low-salinity area in summer, which was mainly controlled by excessive emission of organic matter and nutrients in Yingkou, tidal effects and long residence time of water in the estuary. PMID- 25693379 TI - [Seasonal variation in the absorption and fluorescence characteristics of CDOM in downstream of Liaohe River]. AB - Chromophoric dissolved organic matter (CDOM), which is an important part of dissolved organic matter (DOM), is considered as the largest storage of dissolved organic carbon in the aquatic environment. Liaohe River is the seventh largest river in China with annual runoff of 1.48 billion m3. As a result, studying on CDOM of Liaohe River is very important in estimating the organic carbon flux into sea. Seasonal optical characteristics of CDOM in the downstream of Liaohe River were investigated using absorbance spectroscopy and fluorescence excitation emission matrices (EEMs). CDOM absorption coefficient at 355 nm [aCDOM (355)] in spring was lower than that in autumn and winter while low molecular weight substances were found in autumn and high molecular weight substances in spring based on the absorption coefficient and absorption slope (S) of CDOM. Samples in different seasons all exhibited fairly strong protein-like fluorophore (fluorophore B and fluorophore T) in the EEMs but the values showed apparent temporal variations. Based on the analysis of the relationships between different fluorophores, strong correlations (R2 > 0. 9) were observed between fluorophore A and C in spring, fluorophore B and T in autumn and winter, which illustrated that they had similar CDOM originalsources. However, a weak relationship (R2 = 0.21) was found between fluorophore B and T in spring, demonstrating the complexity and diversity of CDOM sources. Starting from autumn to winter and the subsequent spring, humic-like fluorophores exhibited enhanced fluorescent intensity, which could be ascribed to exogenous input. Furthermore, linear relationship between aCDOM (355) and Fn (355) in different seasons was examined in the study, and the strongest relationship was obtained in winter (R2 = 0.75), followed by autumn (R2 = 0.48) and spring (R2 = 0.01). This study indicated that fluorophore B in autumn and winter (R = 0.66; R = 0.89) as well as humic-like fluorophores (A and C, R = 0.74; R = 0.82) in spring were the main contributors to the CDOM optical characteristics. PMID- 25693380 TI - [Nitrogen uptake and denitrification study on the joint treatment of aquatic vegetation and immobilized nitrogen cycling bacteria in Taihu Lake]. AB - Undisturbed sediment cores were collected from Meiliang Bay, Taihu Lake. Immobilized nitrogen cycling bacteria (INCB), Elodea nuttallii were added to four groups of restoration incubation chambers respectively to explore the nitrogen removal mechanism in different restoration treatments. uN tracer and isotope pairing technique were used to determine the rates of plant uptake and denitrification in different treatments. The results showed that denitrification rates were significantly different among the treatments, while cores with addition of both INCB and Elodea nuttallii achieved the highest denitrification rate of 99.35 MUmol . (m2 . h)( -1) and plant uptake rate of 36.55 MUg . (m2 . h) -1. Elodea nuttallii in the cores could assimilate nitrate itself and enhance coupled nitrification- denitrification. Compared with plant uptake, denitrification was the main pathway of nitrogen removal. The results also showed that the combination of Elodea nuttallii and INCB could promote benthic nitrogen removal and purification of water body. PMID- 25693381 TI - [Actinobacteria and their odor-producing capacities in a surface water in Shanghai]. AB - The odor in raw water is one of the main sources of odor in drinking water. The occurrence of actinobacteria and their odor producing capacities in a reservoir in.Shanghai were investigated. Gauze's medium and membrane filtration were used for actinobacteria isolation. Through combined methods of 16S rRNA sequencing, colony and hyphae morphology, carbon source utilization, physiological and biochemical characteristics, 40 strains of actinobacteria were identified from the reservoir. Results showed that there were 38 Streptomyces, an Aeromicrobium and a Pseudonocardia. Liquid culture medium and the real reservoir water were used to test the odor producing capacity of these 40 strains of actinobacteria, and headspace solid phase microextraction (HS-SPME) and high resolution gas chromatography mass spectroscopy (GC/MS) were used to analyze the odor compounds 2-methylisoborneol (2-MIB) and geosmin (GSM) in the fermentation liquor. The test results showed that, the odor-producing capacities of these actinobacteria in different fermentation media showed different variation trends, even within the genera Streptomyces. The odor-producing capacity of actinobacteria in the liquid culture medium could not represent their states in the reservoir water or their actual odor contribution to the aquatic environment. PMID- 25693382 TI - [Laboratory evaluation of remediation of nitrobenzene contaminated aquifer by using groundwater circulation well]. AB - A two-dimension simulated sand box was set up to investigate the influencing factors, such as the initial groundwater level, aeration rate and the initial groundwater rate, that affect groundwater circulation well (GCW) by determining the intensity of groundwater circulation which was characterized by the variation of groundwater level before and after aeration. The optimal operating parameters were used to remediate nitrobenzene contaminated aquifer. The results demonstrated that: GCW could be well operated under the conditions of 45 cm groundwater level, 0.7 m3 . h(-1) aeration rate. The effects of groundwater velocity less than 1.0 m . d(-1) could be ignored. The lateral mobility rate of nitrobenzene was faster than that of longitudinal. The average concentration of nitrobenzene was 246.97 mg . L(-1) on day 50 of leakage. During the remediation of circulation well, an efficient organics remediation region was gradually formed around the circulation well. The organics in this region was removed preferentially, and the concentration decreased continuously. Besides the efficient remediation region, there was a transient region, where the concentration of organics was influenced by the combined effects of adsorption/desorption and migration potential of organics. During the whole remediation process, the concentration of nitrobenzene went through three stages described as rapid removal, slow removal. After 14h aeration, the nitrobenzene average concentration was reduced to 71.19 mg L(-1). The residual nitrobenzene was distributed in regions far away from GCW. Therefore, nitrobenzene contaminated aquifer could be well remediated by GCW, and there were optimal operation conditions and appropriate remediation time which guaranteed the best remediation effect. PMID- 25693383 TI - [Sorption characteristics of tea waste modified by hydrated ferric oxide toward Pb(II) in water]. AB - Hydrated ferric oxide was successfully impregnated onto tea waste by precipitation to obtain a new sorbent named HFO-TW, the adsorption characteristics of which toward Pb(II) in aqueous solution was investigated by evaluating the effects of pH value, contact time, coexisting ion, temperature, and initial concentration of Pb(II). The Pb(II) sorption onto HFO-TW was pH- dependent, and the higher pH value was more helpful for Pb(II) adsorption onto HFO-TW in the pH range of 2.5-7. Lead sorption speed was quick and could reach equilibrium within 100 min, and the kinetics curve could be fitted well by both pseudo-first and pseudo-second models. The related coefficient was 98.8%. HFO-TW exhibited highly selective lead retention and the adsorption capacity of Pb(II) onto HFO-TW was declined by only 12.1 mg . g(-1) and 8.1 mg . g(-1) in the presence of competing Ca(II), Mg(II) at 50 times of the target ion. In addition, Pb(II) sorption onto HFO-TW could be described satisfactorily by Langmuir model, and the maximal sorption capacity calculated by Langmuir equation was 89.43 mg . g(-1), which was much higher than the unmodified tea waste and other bio sorbents. All the results validated that HFO-TW was a promising sorbent for removal of lead from waters. PMID- 25693384 TI - [Effects of UV radiation on the aggregation performance of small molecular organic acids]. AB - This study systematically investigated the effects of UV radiation on the aggregation of small molecular aliphatic carboxylic acids and phenolic acids by jar test. Experimental results show that solution pH has little effect on the coagulation of small molecular aliphatic carboxylic acids including citric acid, oxalic acid, tartaric acid, and succinic acid. For the solutions pretreated with UV light, the removal rates of the selected aliphatic carboxylic acids in coagulation are higher than that without UV radiation. Further study shows that photochemical reactions occur during UV radiation which decreases the negative charge in aliphatic carboxylic acids, and thereby increases their aggregation properties. Different from aliphatic carboxylic acids, phenol, salicylic acid, and benzoic acid have poor coagulation properties, and UV radiation does not have notable effects on their aggregation in the coagulation process. The coagulation performance of tannic acid is better than the other phenolic acids. At pH = 6, its removal rate is above 90%, which may be contributed to the aliphatic carboxylic acid structure in its molecular. Meanwhile, the large molecular of tannic acid is also easier to be adsorbed by the hydrolysis products of PAC1. PMID- 25693385 TI - [UV photolysis of propranolol in aqueous solution: mechanism and toxicity of photoproducts]. AB - This paper studied the phtodegradation behavior, mechanism and security of propranolol (PRO) in water under ultraviolet irradiation using the high pressure mercury lamp. The photodegradation mechanism was verified by reactive oxygen species (ROS) quenching method, and the photoproducts security was evaluated by luminescent bacteria toxicity test. The results showed that the rate of photolysis (k) of PRO decreased with increasing initial concentration, and showed a significant negative correlation (r2 > 0.95). The increasing k value was also accompanied with higher pH of the solution, and the k values were 0.0953-0.267 min(-1) under pH 5-9. ROS quenching experiments showed that the PRO UV photolysis process included a triplet PRO (3PRO*) direct photolysis participation, and self sensitized photolysis participation caused by hydroxyl radical (.OH) and singlet oxygen (1O2). Direct photolysis rate was greater than the rate of self-sensitized photolysis. The result of 1O2 steady concentration measured by FFA as the probe was consistent with the quenching method. The toxicity evaluation illustrated the formation of some intermediate photoproducts, which were more toxic than PRO. PMID- 25693386 TI - [Photo-catalytical degradation of diphenylarsinic acid by TiO2 (P25)]. AB - Diphenylarsinic acid (DPAA) is the major contaminant in environment polluted by abandoned chemical weapons. DPAA poses high risks to biota but remediation methods for this contaminant are rare. Previous research showed DPAA could be degraded within a short time by TiO2 (P25). Here the kinetics of DPAA degradation catalyzed by P25 was studied. Results showed the photo-catalytical degradation of DPAA by P25 consisted of two processes: adsorption and photo-reaction. The whole reaction could be fitted by Langmuir-Hinshelwood kinetics. Variation in pH and ionic strength caused change in adsorption of DPAA onto the TiO2 catalyst, which led to the change of reaction rate, showing a decreasing trend with the decreasing adsorption amount of DPAA. Dissolved oxygen promoted the catalytical degradation of DPAA by TiO2, and the hydroxyl free radical played the most important role in the photodegradation of DPAA, which was testified through quenching experiments with free radical scanvengers. PMID- 25693387 TI - [Effect of carbon/nitrogen ratio on short-cut nitrification and denitrification of polyurethane biofilm reactor]. AB - The short-cut nitrification and denitrification process of a polyurethane biofilm reactor was studied at four different carbon to nitrogen ratios (C/N ratios) (C/N =15:1, 10:1, 5:1 and 1.8:1) with focus on reactor performance and microbial community composition. Results showed that when the influent carbon/nitrogen ratio decreased from 15 to 10, 5 and 1.8, the nitrite accumulation rate was increased from 56.1% to 62.3%, 72.3% and 83.2% after 100 d operation. System achieved the optimal removal efficiency at an influent carbon/nitrogen ratio of 10 with 99.1% of ammonia removal and 91.0% of total nitrogen removal. Simultaneous nitrification and denitrification occurred in the polyurethane biofilm system at different influent carbon/nitrogen ratio. As the influent carbon/nitrogen ratio decreased from 15 to 10, 5 and 1.8, the efficiency of simultaneous nitrification and denitrification was gradually reduced. The microbial biofilm analysis indicated that the microbial diversity of biofilm with an influent carbon/nitrogen ratio of 15 was significantly higher than that in other conditions. The predominant ammonia oxidizing bacteria and nitrite oxidizing bacteria were Nitrosospira sp. and Nitrospira sp., respectively, and the predominant denitrifying bacteria were Pseudomonas sp. PMID- 25693388 TI - [Distribution and removal of anaerobic antibiotic resistant bacteria during mesophilic anaerobic digestion of sewage sludge]. AB - Sewage sludge is one of the major sources that releasing antibiotic resistant bacteria (ARB) and antibiotic resistant genes (ARG) into the environment since it contains large amount of ARB, but there is little information about the fate of the anaerobic ARB in the anaerobic digestion of sewage sludge. Therefore, the distribution, removal and seasonal changes of tetracycline and beta-lactam antibiotics resistant bacteria in the mesophilic egg-shaped digesters of a municipal wastewater treatment plant were investigated for one year in this study. Results showed that there were higher amounts of ARB and higher resistance rate of beta-lactam antibiotics than that of tetracycline antibiotics in the sewage sludge. All ARB could be significantly reduced during the mesophilic anaerobic digestion process by 1.48-1.64 log unit (P < 0.05). Notably, the ampicillin and cephalothin resistance rates were significantly increased after anaerobic digestion by 12.0% and 14.3%, respectively (P < 0.05). The distribution of ARB in the sewage sludge had seasonal change characteristics. Except for chlorotetracycline resistant bacteria, there were more ARB in the sewage sludge in cold season than in warm season (P < 0.05). PMID- 25693389 TI - [Spatial distribution and risk assessment of insecticides in surface soil from a rapidly urbanizing region]. AB - To examine the distribution patterns of organic contaminants in rapidly urbanizing regions, the levels and spatial distributions of 19 overlooked insecticides, i. e., phenyl-pyrazole class (fipronil), chlordane, endosulfan, nonachlor, hexachlorobenzene, heptachlor, dieldrin, aldrin, endrin, methoxychlor and their metabolites, were examined in 229 soil samples collected from the Pearl River Delta (PRD) and surrounding areas. The results indicated that higher insecticide levels distributed in the central PRD, while lower levels congested in the surrounding areas. The similar spatial patterns between the levels of insecticides and economic prosperity or population density demonstrated that social-economic factors may have dictated the spatial patterns of insecticides. In addition, the changing of land-use types during urbanization processes, e.g., historical plowlands have been converted into residential landscapes, resulted in high concentrations of banned insecticides in metropolis of the central PRD. Source diagnostics indicated that new inputs of technical chlordane products existed in the PRD and surrounding areas. Fipronil was degraded into fipronil sulfone and fipronil sulfide in most soil samples because of its low half-life in soil. Finally, a risk assessment of 19 insecticides in soil for human health suggested that six samples collected from the major administrative districts with dense population had potential cancer or non-cancer risk to human health. Therefore, these overlooked insecticides should be concerned in future environmental research. PMID- 25693390 TI - [Field measurement of soil mercury emission in a Masson pine forest in Tieshanping, Chongqing in Southwestern China]. AB - To investigate soil mercury emission characteristics in areas with high atmospheric mercury concentration, the soil-air exchanging flux of gaseous elemental mercury (Hg0) was measured for four seasons from September 2012 to July 2013 in a Masson pine forest of Tieshanping, Chongqing in Southwestern China using a dynamic flux chamber and a LUMEX RA-915+ mercury analyzer. The effects of ambient air mercury concentration and environmental factors, such as radiation intensity, air temperature, air humidity, soil temperature, and soil water content, on exchanging flux were also studied. Results showed that there was obvious seasonal variation of the Hg0 exchanging flux, with the highest value of 35.3 ng . (m2 . d)(-1) in the summer and very low values in other seasons, even negative in spring and winter. In addition to radiation intensity and air/soil temperature, ambient air mercury concentration was an important impacting factor, which was negatively correlated with the Hg0 exchanging flux, with the equilibrium concentration at 5.61 ng . m(-3). The total soil emission of Hg0 was estimated to be 2.65 MUg . (m2 . a)(-1), which was much lower than that in similar forests in cleaner areas. High ambient air Hg0 concentration in Tieshanping was the main reason for the difference. PMID- 25693391 TI - [Chlorine speciation and concentration in cultivated soil in the northeastern China studied by X-ray absorption near edge structure]. AB - A procedure has been proposed to determine chlorine speciation and concentration in soil with X-ray absorption near edge structure (XANES), and this method was applied to study the cultivated soil (bog, dark brown and black cultivated soil) in the Northeastern China. Qualitative analysis was carried out by least-squares fitting of sample spectra with standard spectra of three model compounds (NaCl, 3 chloropropionic acid, chlorophenol red). Linear correlation between the absolute fluorescence intensity of a series of NaCl standards and the Cl concentration was used as quantification standard for measuring the total Cl concentration in samples. The detection limits,relative standard deviation (RSD), recoveries were 2 mg . kg(-1), 0%-5% and 77%-133%, respectively. The average concentration of total Cl was 19 mg . kg(-1). The average relative content was as high as 61% of organochlorine with the concentration of 1-2 times as high as the concentration of inorganic chloride. The distribution trend of the total Cl, inorganic chloride and organic chlorine in different types of soil was: bog arable soil > dark brown soil > black soil. In conclusion, XANES is a reliable method to nondestructively characterize the speciation and concentration of chlorine in soil, which would provide some basic data for the future study of the chlorine's biogeochemical transformations. PMID- 25693392 TI - [Soil organic carbon storage changes with land reclamation under vegetation reconstruction on opencast coal mine dump]. AB - Vegetation reconstruction was an effective solution to reclaim the opencast coal mine dump which was formed in the process of mining. To understand the impact of the vegetation reconstruction patterns' on the mine soil organic carbon (SOC) storage was essential for selecting the methods of vegetation restoration and also important for accurately estimating the potential of the soil carbon sequestration. The study area was on the Heidaigou opencast coal mine, which was 15 years reclaimed coal mine dump in Zhungeer, Inner Mongolia autonomous region, we selected 5 vegetation reconstruction patterns (natural recovery land, grassland, bush land, mixed woodland of arbor and bush, arbor land), and 16 vegetation types, 408 soil samples (0-100 m), to study the effect of the vegetation reconstruction patterns on the SOC storage. The results were showed as follows: (1) on the reclaimed coal mine dump, the vegetation reconstruction patterns significantly affected the SOC content and its distribution in the soil profile (P < 0.05). The surface 0-10 cm SOC content was grassland > shrub land > arbor forest > mixed forest of arbor and shrub > natural recovery land, in which the grassland, shrub land and arbor forest were about 2.2, 1.3, and 1.3 times of natural recovery land (2.14 g . kg(-1)) respectively. The total nitrogen (TN) showed the similar trends. (2) Among the vegetation types, Medicago sativa had the highest surface SOC content (5.71 g . kg(-1)) and TN content (0.49 g . kg( 1)), that were 171.3% and 166.7% higher than the natural recovery land, and two times of Hippophae rhamnoides, Amorpha fruticosa + Pinus tabulaeformis and Robinia pseudoacacia. (3) The effect of vegetation types on SOC mainly concentrated in the 0-20 cm depth, and the effect on TN accounted for 40 cm. (4) For the SOC storage, the order was original landform area > reclaimed dump > new dump and grassland > woodland (including arbor and shrub land). After 15 years revegetation, the soil carbon storage of the grassland, shrub land and arbor land were increased by 15.47 t . hm(-2), 6.93 t . hm(-2) and 6.95 t . hm(-2) respectively in the 100 cm depth, which were equivalent to 2/3, 1/2 and 1/2 of the original landform levels. The results showed a great ability of carbon sequestration. PMID- 25693393 TI - [Effect of sulfur on the species of Fe and As under redox condition in paddy soil]. AB - Redox conditions of the polluted paddy soil with exogenous As were simulated by redox reaction apparatus after flowing N2 and O2 applied with different forms of inorganic sulfur(CK-S0, elemental sulfur-S1 and sulfate-S2). Results showed that redox potential (Eh) was about -100 - -200 mV and the pH 7.0-8.0 and the pe + pH 4-7 in soil solution when flowed N2, and Eh about 200 mV and the pH 6.5-7.5 and pe + pH 9-12 when continuously flowed O2. Concentrations of the dissolved Fe in soil solution were in 1.2-1.6 mg x L(-1) either flowed N2 or O2, and the order of Fe concentrations was AsS0 treatment > AsS1 treatment > AsS2 treatment. Amounts of soil Fe oxide by HCl extraction from different treatments were 5 g . kg(-1) lower than the original soil [(21.4 +/- 0.3) g . kg(-1)] when flowed N2, and it was in favor of the transformation of crystal Fe into amorphous iron and Fe2+. Activity of Fe oxides from different treatments increased comparing to that of the original soil (46. 8%), and the order of activity of Fe oxides was AsS2 treatment (49.4%) < AsS1 treatment (60%). Fe2+ in solution and FeS were oxidized into Fe3+, and hydrolysis of Fe3+ was produced into Fe(OH)3 precipitation when flowed O2. It increased the contents of acid-soluble and crystal Fe oxide, and the order of activity of Fe oxides was AsS1 (41.2%) treatment > AsS2 (36.1%) treatment. Concentrations of As in soil solution were in the order of AsS0 [(1.13 +/- 0.04) mg . L(-1)] > AsS1 [(0.89 +/- 0.01) mg L(- 1)] > AsS2 [ (0.77 +/- 0.04 )mg . L(-1)] when flowed N2 and was AsS1 [(0.77 +/- 0.01) mg . L(-1)] > AsS0 [(0.20 +/- 0.09 ) mg . L(-1)] > AsS2 [(0.09 +/- 0.01) mg . L(-1)] when flowed O2. The proportions of arsenic fractions followed the order of the residual phases (34.9%-41.4%) ~ specifically-sorbed (37.4%-39.5%) > well-crystallized hydrous oxides of Fe/Mn (23.3%-25.6%) > non-specifically sorbed (2.4%-3.3%) > amorphous hydrous oxides of Fe/Mn (0.5%-0.8%) when flowed N2, and was the residual phases (30.8%-39.3%) specifically-sorbed (30.3%-34.7%) > well-crystallized hydrous oxides of Fe/Mn (26.0%-28.7%) > amorphous hydrous oxides of Fe/Mn (9.3%-10.7%) > non-specifically sorbed (0.5%-1.6%) when flowed O2. Arsenic from amorphous hydrous oxides of Fe/Mn raised about 9% by flowing O2 than by flowing N2. This could be the effect of the aging amorphous Fe/Mn on the transformation of As, and the increased activity of iron oxide under reducing conditions and enhanced mobility of Arsenic. Elemental surfer system could increase mobility of arsenic more than sulfate system which may decrease degree of activity of iron oxide. PMID- 25693394 TI - [Response of ectomycorrhizal fungi to aluminum stress and low potassium soil]. AB - Soil acidification, aluminum (Al3+) toxicity and nutrient deficiency could be some of the most important reasons for the decline and death of forests in tropical and subtropical areas. Ectomycorrhizal fungi for Al3+ resistance and nutrient mobilization are beneficial for preventing forests against Al3+ toxicity and increasing forest productivity. Therefore, Suillus luteus (SI 13), Pisolithus tinctorius (Pt 715) and Suillus subluteus (Ss 00) were grown in liquid culture medium with soil as the sole K source under Al3+ stress to study the fungal growth, organic acid and proton efflux, and potassium (K) unitization. The result indicated that the fungal growth, organic acid and proton efflux, and nutrient uptake, including nitrogen (N), phosphorus (P) and potassium (K), were regulated by Al3+ concentration in culture solutions. They increased with increasing Al3+ at low concentration and after reaching a peak, they started to decrease. Fungal strain with high resistance to Al3+ also showed higher Al3+ concentration at the peak than those with low ability. Al3+ concentration at the peak of fungal biomass and N uptake by Pt 715 was four folds or twice of Ss 00 and SI 13, respectively. The uptake of P and K and efflux of organic acids and protons by Pt 715 were also higher than Ss 00 and Sl 13. All three fungal strains could utilize structural K in soil minerals and the utilization rate reached 2.10% for Pt 715, 1.43% for Ss 00 and 1.17% for Sl 13, respectively, which could be related to the types and amount of organic acids and protons. PMID- 25693395 TI - [Long-term manure application induced shift of diversity and abundance of antibiotic resistance genes in paddy soil]. AB - To investigate the effect of long-term manure application on the profiles of antibiotic resistance genes (ARGs) in paddy soil, the abundance of ARGs targeted by 295 primers sets were measured by using high-throughput quantitative PCR technique. A total of 107 types of ARGs were detected in long-term manured paddy soil, which is significantly higher than that in control paddy soil (P < 0.05). PCA analysis and UPGMA cluster demonstrated that long-term manure application significantly changed the ARGs diversity and abundance in paddy soils. There were 49 types antibiotic resistance genes were enriched significantly in paddy soil applied with manure (P < 0.05), especially the mexF, which belongs to quinolones chloramphenicol resistance genes, increased 1791-fold compared with paddy soil of no manure application. Our results showed that long-term application of manure in paddy soil resulted in the shift of abundance and diversity of ARGs, high throughput quantitative PCR could be a powerful tool concerning the environmental ARGs dimensions. PMID- 25693396 TI - [Effect of phosphate and organic acid addition on passivation of simulated Pb contaminated soil and the stability of the product]. AB - Organic acids can improve the phosphorus availability, influence the immobilization of heavy metals in soil, and has very complicated function in phosphorus activation and heavy metal passivation. This research took simulated Pb contaminated soil as material, phosphate and citric acid as remediation matter, adopted BCR continuous extraction, 0.01 mol . L(-1) CaCl2 and toxicity characteristic leaching procedure (TCLP) to evaluate the remediation effect. Besides, malic acid and NaNO3 were taken as desorption reagents to discuss the stability of the phosphorus-citric acid-Pb system. The results showed that: in the absence of citric acid, the amount of acid extracted Pb decreased along with the increase of P concentration; when the P concentration was 100 and 400 mg . kg(-1), acid extractable Pb increased with the increasing of citric acid concentration. However, residual Pb changed in the opposite direction from acid extractable Pb. The phenomenon showed that P improved the bioavailability of Pb, while citric acid had the opposite effect. With a certain organic acid concentration, extractable Pb contents extracted by 0.01 mol . L(-1) CaCl2 and TCLP both decreased with the increasing P concentration, therefore, P had immobilization effect on Pb in contaminated soil. But at a fixed P concentration, extractable Pb contents by 0.01 mol . L(-1) CaCl2 and TCLP changed in the opposite trend with the increasing citric acid concentration. The desorption rate of Pb in soil increased with the increasing malic acid concentration, the decreasing pH and the increasing ionic strength. The desorption extent of Pb in soil with P only was lower than that with both P and citric acid. But the stability of Pb passivated by the former was higher. PMID- 25693397 TI - [Bioremediation of chromium (VI) contaminated site by reduction and microbial stabilization of chromium]. AB - Chromium (VI) contaminated soil samples were collected from a chemical plant in Suzhou. Firstly, the reduced soil was prepared by adding reagent (Stone-sulfure reagent) into polluted soil to transfer most chromium (VI) into chromium (III), then a nutrient solution was introduced into the reduced soil, and the stabilized soil was obtained after 60 days culturing. The chromium (VI) content of the three kinds of soil was analyzed. The results showed that the chromium (VI) content in toxicity characteristic leaching liquid (TCLL) dropped by 96. 8% (from 8.26 mg . L(-1) to 0.26 mg . L(-1)), and the total chromium content dropped by 95.7% (from 14.66 mg . L(-1) to 0.63 mg . L(-1)) after bioremediation in 5% nutrient solution. Additionally, the durability of chromium stabilization was tested by potassium permanganate oxidation and sterilization of microbe-treated soil. After oxidation, the chromium (VI) content in TCLL of the reduced soil was increased from 8.26 mg . L(-1) to 14.68 mg . L(-1). However, the content after bioremediation was decreased to 2.68 mg . L(-1). The results of sterilization demonstrated that the death of microbe had no significant effect on the stabilization of chromium. Consequently, the research in this paper demonstrated the feasibility of bioremediation of chromium (VI) polluted soil through reduction followed by stabilization/soilidification, and provided a technique with low cost but high efficiency. PMID- 25693398 TI - [Effect of thermal enhanced soil vapor extraction on benzene removal in different soil textures]. AB - Experiments were carried out to investigate the effect of thermal enhanced soil vapor extraction (SVE) on benzene removal from sand, loam and clay and the mechanism. Compared to the routine control treatment, the benzene removal rates were improved by 13. 1% and 12. 3% and the remediation periods were reduced by 75% and 14%, from sand and loam respectively using thermal enhanced SVE. Thermal enhancement decreased the moisture content and increased the soil permeability of clay. On the surface of clay particles, absorption peaks of carboxyl and ethyl disappeared and the content of soil organic substances decreased significantly. Compared to the conventional SVE, the benzene removal rate was improved by 34% in clay soil treated by thermal enhanced SVE. For sand and loam, thermal enhancement could increase the removal rate by promoting the diffusion of benzene in the soil and achieve substantial removal of pollutants in a relatively short period of time. For clay, it could enhance the effect of SVE by reducing the absorption capacity between soil particle surface and contaminant and improving the performance of the gas diffusion in soil by decreasing the moisture content and increasing the soil permeability. PMID- 25693399 TI - [Effects of elevated O3 concentration on nitrogen in greening tree species in southern China]. AB - Numerous studies have indicated that rising ozone (O3) in the troposphere significantly decreased the photosynthesis and the activity of Rubisco enzyme. So it can be inferred that the N uptake and distribution within the plants could be affected by elevated O3. In this study, ten greening woody species, widely distributed in subtropical China, were exposed to charcoal-filtered air (CF, less than 20 nL . L(-1)) and elevated O3 (E-O3, mean concentration of 150 nL . L(-1)) in open top chambers. The results showed that E-O3 significantly reduced the leaves biomass in Liquidamba formosana by 20.9%, the stem biomass in Liriodendron chinense by 21.4%, the root biomass in L. formosana and L. chinense by 24.2% and 32.5%, respectively. E-O3 significantly affected the N concentration in the stem but not those in leaves and root. The N uptakes in the whole tree (Nlu), the leaves and the root were significantly affected by E-O3. Compared to CF, E-O3 significantly reduced the Nlu in L. chinense by 28.4% and Schima superba by 22.7% but significantly increased the Nlu in Neolitsea sericea by 15.5%. Elevated O3 concentration had no significant influence on N distribution within the plants across the selected 10 tree species. PMID- 25693400 TI - [Effects of nitrogen application on soil greenhouse gas fluxes in Eucalyptus plantations with different soil organic carbon content]. AB - The effects of nitrogen fertilization or nitrogen deposition on soil greenhouse gases fluxes has been well studied, while little has been piloted about the effects of nitrogen application on soil greenhouse gas fluxes and its discrepancy with different soil organic carbon content. In our study, we conducted field control experiment in a young Eucalyptus plantation in Southeast China. We compared the effects of 4 levels of nitrogen fertilization (Control: 0 kg . hm( 2); Low N: 84.2 kg . hm(-2); Medium N: 166.8 kg . hm(-2); High N: 333.7 kg . hm( 2)) on soil GHGs fluxes from 2 sites (LC and HC) with significantly different soil organic carbon (SOC) content (P < 0.05). The results showed: (1) Fertilization had significant priming effect on CO2 and N2O emission fluxes. One month after fertilization, both CO2 and N2O had the flux peak and decreased gradually, and the difference among the treatments disappeared at the end of the growing season. However, fertilization had no significant effect on CH4 oxidation between the 2 sites. (2) Fertilization and SOC were two crucial factors that had significant effects on CO2 and N2O emission. Fertilization had a significant positive effect on CO2 and N2O emission fluxes (P < 0.001). CH4 oxidation rates decreased with the increasing N addition, but there was no statistical difference (P > 0.05). The CO2 and N2O emission fluxes were significantly higher in HC than those in LC (P < 0.01). (3) Fertilization and SOC had great interactive effect on CO2 and N2O emission (P < 0.05). Compared with fluxes in LC, the fluxes in HC were much more sensitive to N input: low N could remarkably stimulate the CO2 and N2O emission. In conclusion, the effects of nitrogen fertilization on soil GHGs fluxes were not only in connection with the intensify of nitrogen, but also closely tied to the SOC content. When we assess the effects of nitrogen on soil GHGs fluxes, the difference induced by SOC should not be ignored. PMID- 25693401 TI - [Ozone effects on soil microbial community of rice investigated by 13C isotope labeling]. AB - This study was initiated to explore the effects of dynamic ozone (O3) exposure on soil microbial biomass and phospholipid fatty acids (PLFAs) under potted rice. A pulse-chase labeling experiment was designed to expose potted rice with 13CO2 for 6 h after one and two months, the rice were fumigated by elevated O3 concentration with an 8 h mean of 110 nL . L(-1) (O3). The allocation of the assimilated 13C to soil microorganisms was estimated by analyzing the 13C profile of microbial phospholipid fatty acids (PLFAs). After one month O3 exposure, the soil microbial biomass carbon was not affected, while the 13C-microbial biomass was significantly decreased with elevated O3. Both the total and 13C microbial biomass carbon was remarkably lower than that of control treatment after two months O3 exposure. Principal components analysis of 13C-PLFA data showed that elevated O3 significantly changed soil microbial structure after two month exposures, while there was no difference of 13C-PLFA structure between control and elevated O3 treatments after one month exposure. Deltadelta13C per hundred thousand of individual PLFA was significantly affected by O3 after both one and two month exposures. Only did ozone change the relative abundance of individual 13C-PLFA (13C%) of bacterial fatty acids after one month exposure, while after two month exposures, the 13C% of fungal and actinomycetic fatty acids were markedly changed by elevated O3. PMID- 25693402 TI - [Enhanced aerobic degradation of low chlorinated biphenyls by constructing surfactants Burkholderia xenovorans LB400 based system]. AB - It has been proposed that the increasing of water solubility of PCBs can enhance the biodegradation efficiency. The biodegradation system of PCBs by Burkholderia xenovorans LB400 in the presence of different surfactants, namely TX-100, Tween 80, RL crude and HPCD were established to investigate the effect of surfactants on the biodegradation of hydrophobic organic compounds. The results indicated that the water solubility ratios of PCB5 and PCB31 were 54.7%-100%, 59.8%-100%; 10.5%-40.8%, 6.8%-31.6%; 10.3%-19.9%, 3.3%-11.6% and 19.5%-34.2%, 4.2%-10.7%, which were accordingly enhanced by TX-100 (CMC = 194 mg . L(-1)), Tween 80 (CMC =13.1 mg . L(-1)), and RL crude (CMC = 50 mg . L(-1)) with concentrations of 1-7 CMC, respectively and HPCD with concentrations of 500-1,500 mg . L(-1). Moreover, the growth inhibition ratio of B. xenovorans LB400 was 30.3%-45.8% with TX-100 concentration of 1-7 CMC, while it was 10.0%-15.4% for Tween 80 with concentration of 0.1-1 CMC; RL crude could boost the growth of strain LB400 as substrate while HPCD exerted no impact on it. The addition of surfactants can improve the biodegradation ratios of PCB31 (5 mg . L(-1)) by 23.7%-65.5% for TX 100, 14.6%-44.3% for Tween 80, 9.6%- 27.2% for RL crude and 15.3%-20.7% for HPCD depending on the surfactant concentrations, while it had minor effects on the biodegradation ratios of PCB5 (10 mg . L(-1)). It is concluded that the promoting effects of surfactant on PCBs biodegradation are mainly due to the increased concentrations of PCBs-surfactant micelles in aqueous solution and when TX-100 and Tween 80 concentrations are set as 1 and 7 CMC, the biodegradation ratios of PCB31 can achieve 100% and 81.7% , while the growth inhibition ratios of B. xenovorans LB400 are 30.3% and 5.4%, respectively. PMID- 25693403 TI - [Identification of a high ammonia nitrogen tolerant and heterotrophic nitrification-aerobic denitrification bacterial strain TN-14 and its nitrogen removal capabilities]. AB - A new strain of high ammonia nitrogen tolerant and heterotrophic nitrification aerobic denitrification bacterium TN-14 was isolated from the environment. Its physiological and biochemical characteristics and molecular identification, performences of heterotrophic nitrification-aerobic, the abilities of resistance to ammonia nitrogen as well as the decontamination abilities were studied, respectively. It was preliminary identified as Acinetobacter sp. according to its physiological and biochemical characteristics and molecular identification results. In heterotrophic nitrification system, the ammonia nitrogen and total nitrogen removal rate of the bacterial strain TN-14 could reach 97.13% and 93.53% within 24 h. In nitrates denitrification system, the nitrate concentration could decline from 94.24 mg . L(-1) to 39.32 mg . L(-1) within 24 h, where the removal rate was 58.28% and the denitrification rate was 2.28 mg . (L . h)(-1); In nitrite denitrification systems, the initial concentration of nitrite could be declined from 97.78 mg . L(-1) to 21.30 mg x L(-1), with a nitrite nitrogen removal rate of 78.22%, and a denitrification rate of 2.55 mg . (L. h)(-1). Meanwhile, strain TN-14 had the capability of flocculant production, and the flocculating rate could reach 94.74% when its fermentation liquid was used to treat 0.4% kaolin suspension. Strain TN-14 could grow at an ammonia nitrogen concentration as high as 1200 mg . L(-1). In the aspect of actual piggery wastewater treatment by strain TN-14, the removal rate of COD, ammonia nitrogen, TN and TP cloud reached 85.30%, 65.72%, 64.86% and 79.41%, respectively. Strain TN-14 has a good application prospect in biological treatment of real high- ammonia wastewater. PMID- 25693404 TI - [Isolation and identification of electrochemically active microorganism from micro-aerobic environment]. AB - Extracellular electron transfer of electrochemically active microorganism plays vital role in biogeochemical cycling of metals and carbon and in biosynthesis of bioenergy. Compared to anaerobic anode, micro-aerobic anode captures more energy from microbial fuel cell. However, most of previous researches focused on functioning bacteria in anaerobic anode, functioning bacteria in micro-aerobic anode was rarely studied. Herein, we used the traditional aerobic screening technology to isolate functioning bacteria from a micro-aerobic anode. Three pure cultures Aeromonas sp. WS-XY2, Citrobacter sp. WS-XY3 and Bacterium strain WS-XY4 were obtained. WS-XY2 and WS-XY3 were belonged to Proteobacteria, whereas WS-XY4 was possibly a new species. Cyclic voltammetry and chronoamperometry analysis demonstrated all of them showed the electrochemical activity by direct extracellular electron transfer, and micro-aerobic anode could select bacteria that have similar electrochemical activity to proliferate on the anode. We further conclude that functioning bacteria in micro-aerobic anode are more efficient than that of anaerobic anode may be the reason that micro-aerobic anode has better performance than anaerobic anode. Therefore, a thorough study of functioning bacteria in micro-aerobic anode will significantly promote the energy recovery from microbial fuel cell. PMID- 25693405 TI - [Characteristics of microbial community structure during isolation of electrical active bacteria]. AB - To investigate the effect of selective culturing on microorganisms and functional role of electrical active bacteria in biofilm, some exoelectrogens were isolated from microbial fuel cell (MFC) anodic biofilm using Hungate roll-tube technique with iron oxide as indicator. At the same time, the dynamics of the microbial community structure was monitored during the pure culture isolation. The results show that maximum voltages of MFCs feeding with lactic acid, acetic acid and steroid wastewater are 0.57, 0.60 and 0.40 V respectively. The dominant bacteria isolated from seed sludge and anodic films feeding with acetate and lactate belong to phylum Proteobacteria; while steroid wastewater contains relative high diversity of bacteria, i. e. Proteobacteria, Firmicutes and Bacteroidetes. After enriching and culturing, two bacteria were consequently obtained, which shared the highest similarity with Enterobacter ludwigii and Citrobacter freundii respectively. When inoculated in MFC with lactic acid as the substrate, they produced maximum voltage of 0.10 and 0.17 V individually. This study shows that electrical active bacteria can be isolated from the MFC anodic biofilm using anaerobic gradient dilution culture techniques with iron oxide as indicator. Microbial community structure presents markedly shifting during the bacteria isolation owing to its selectivity. PMID- 25693406 TI - [Predicting copper toxicity to Hypophthalmichthys molitrix and Ctenopharyngodon idellus based on biotic ligand model]. AB - A series of 96 h copper acute toxicity experiments were conducted with Ctenopharyngodon idellus and Hypophthalmichthys molitrix under different concentrations of DOC [rho(DOC) 0.05, 0.5, 1, 2, 4 mg . L(-1)]. Higher DOC resulted in a reduction of toxicity, which was in line with the concepts of the biotic ligand model (BLM). It was concluded that the mean absolute deviation (MAD) of LC50 with Ctenopharyngodon idellus and Hypophthalmichthys molitrix was 591.2, 157.14 MUg . L(-1) and 728.18, 91.24 MUg x L(-1), respectively, by the prediction of copper BLM developed for Fathead minnow and Rainbow trout. Based on speciation analysis of biotic ligand model, it was shown that LA50 values of Ctenopharyngodon idellus and Hypophthalmichthys molitrix were 10.960 and 3.978 nmol . g(-1), respectively. Then the MAD values became 280.52 and 92.25 MUg . L( 1) for Ctenopharyngodon idellus and Hypophthalmichthys molitrix using the normalized LA50. Finally by searching toxicity data in literature, the MAD values on Ctenopharyngodon idellus and Hypophthalmichthys molitrix were 252.37 and 50.26 MUg . L(-1), successively. This result verified that the toxicity prediction based on biotic ligand model was practical. PMID- 25693407 TI - [Macrozoobenthos community structure and water quality evaluation of Tian'e Zhou Oxbows]. AB - A quarterly investigation of the macrozoobenthos community in Tian'e Zhou Yangtze Oxbows was conducted during January 2011 to October 2011. And water quality was assessed based on the benthic macroinvertebrate community structure. It shows that, a total of 30 macrozoobenthos species were found, among which, Insecta (14 species) , Mollusca (6 species), Oligochaeta (8 species) and others (2 species) accounted for 46.67%, 20.00%, 26.67%, and 6.67% of the total, respectively. The dominant species were Clinotanypus, Cryptochironomus digitatus, Limnodrilus claparedeianus, and Limnodrilus hoffmeisteri. The average annual density and biomass of macrozoobenthos were 558.37 ind . m(-2), and 14.03 g . m(-2), respectively. The density of macrozoobenthos was highest in the winter and lowest in the spring, the biomass was highest in the autumn and lowest in the spring. In ten sampling points, No. 8 had the highest density, 1986.00 ind . m(-2), No. 7 had the highest biomass, 50.22 g . m(-2), and No. 6 had the lowest density and biomass, 98.00 ind . m(-2) and 0.85 g . m(-2). The evaluation with Shannon-Wiener diversity index (H'), Margalef richness index (d), Family-level biotic index (FBI), and integrated pollution index (BI) indicated that the overall water quality of the Tian'e Zhou Oxbow was moderate-heavy pollution (III-IV). As compared to that in 2003-2004 (II), the water quality of Tian'e Zhou Oxbow was somewhat decreased. PMID- 25693408 TI - [Species selection methods in deriving water quality criteria for aquatic life]. AB - The Mann-Whitney U test method was used to analyze the species sensitivity to ammonia toxicity. And based on the analysis, the relationship between species selection method and WQC deriving method was studied by using toxicology, biological taxonomy and sampling-inference theory. Results showed that vertebrate species, especially the Actinopterygii, accounted for the vast majority in the toxicity test species. And the species composition of toxicity test species was inconsistent with the species composition of the ecosystem. Sensitivity to ammonia toxicity among different taxa varied significantly for most species except some species in individual taxa, especially the less sensitive species. The variable coefficient of interspecies decreased with the reduction of biological classification level. To a certain extent, it showed that the species sensitivities in the same taxa to toxicant were more similar than those in different taxa. According to sampling-inference theory, the WQC for aquatic life deriving method belonged to the design-based inference. And taxonomic groups could be used as auxiliary variables to conduct a stratifactory sampling for species selection in WQC deriving which could improve the sampling efficiency and precision. PMID- 25693409 TI - [Correlations between HBCD and thyroid hormone concentrations in human serum from production source area]. AB - The levels of hexabromocyclododecane (HBCD) in human serum from the HBCD production source region were detected by UPLC-ESI-MS/MS. The concentrations (lipid weight) of ? HBCD in 80 serum samples ranged from not detectable to 2702.5 ng . g(-1). The mean and median values were 104.9 ng . g(-1) and 5.9 ng . g(-1), respectively. The most abundant HBCD isomer in 42 samples was gamma-HBCD, while alpha-HBCD was the most abundant isomer in the other 26 serum samples. There was no significant difference in ? HBCD concentration among different age and gender. In this study, the thyroid hormone abnormality rate in the 80 residents was up to 33%. The thyroid hormone abnormality rate of the residents whose serum HBCD was detected was significantly higher than those without HBCD in serum. Since the local residents were highly exposed to HBCD, the probability of thyroid abnormality might be significantly increased. PMID- 25693410 TI - [Preparation of cobalt oxide mesoporous metallic oxide-clay composites and their catalytic performance in the oxidation of benzene]. AB - Laponite clays composited with alumina, ceria and zirconia etc. were prepared using polyoxocations or simple metal ions as precursors, and then cobalt oxide was loaded onto them to obtain the catalysts. The results showed that compared with laponite clays, the as-prepared laponite had wide range of pore size distribution and increased pore volume. The pore volumes of laponite clays composited with alumina and ceria were more than 0.75 cm3 . g(-1). N2 isotherm type was maintained after Co3O4 loading, however, the N2 adsorption decreased with the increase of Co3 O4 loading, indicating the decrease of pore volume, which was caused by the blockage of metallic oxide/clay composites support. Furthermore, dispersion and catalytic performance of the catalysts were significantly influenced by the composited metallic elements. It was shown that according to the diffraction peak half-width of 311 crystal facet and scherrer equation, when the Co loading was 21.3% at laponite clays composited with Fe, Zr, Ce, Al, the average sizes of Co3O4 were 17.2, 16.0, 16.5 and 18.0 nm, respectively. Alumina composited clay with 21.3% Co loading showed high catalytic activity, the complete conversion temperature of benzene was 350 degrees C. Among metallic oxide/laponite composites, the ZrO composited laponite with 21.3% Co loading exhibited the best catalytic performance, which could completely convert benzene at 310 degrees C. PMID- 25693411 TI - [Catalytic degradation of naphthalene by CuO (-CeO2)/Al2O3]. AB - Three catalysts CuO/Al2O3, CeO2/Al2O3 and CuO-CeO2/Al2O3 were prepared by the impregnation method. The textural and structural properties of the synthesized catalysts were characterized by N2 adsorption/desorption, SEM and XRD, and the effect of active ingredients, flow rate and reaction temperature on catalytic degradation of naphthalene (NaP) were investigated in fixed-bed reactor. The experimental results show that the prepared 18% CeO2/Al2O3 has a low catalytic activity of NaP. Nevertheless, both 18% CuO/Al2O3 and 9% CuO-9% CeO2/Al2O3 exhibit high catalytic activity whose removal efficiencies at 300 degrees C can reach 91% and 89%, respectively. Besides, compared with CuO/Al2O3, CuO-CeO2/Al2O3 possesses a higher low-temperature activity. Furthermore, the variation of flow rates has little effect on the performance of two catalysts. PMID- 25693412 TI - [Toxicity tests and their application in safety assessment of water quality]. AB - The safety of water quality has important impacts not only on the health of ecological system, but also on the survival and development of human beings. The conventional assessment methods for water quality based on the concentration limits are not reliable. The toxicity tests can vividly reflect the whole adverse biological effects of multiple chemicals in water body, which has been regarded as a necessary supplement for conventional water quality assessment methods based on physicochemical parameters. Considering the chemical pollutants usually have various adverse biological effects, the ecotoxicity testing methods, including lethality, genotoxicity, endocrine disrupting effects, were classified according to the different toxicity types. Then, the potential applications of toxicity testing methods and corresponding evaluation indices in evaluating the toxicity characteristics of ambient water samples were discussed. Particularly, the safety assessment methods for water quality based on the toxicity tests, including potential toxicology, toxicity unit classification system, potential ecotoxic effect probe, and safety assessment of water quality based on toxicity test battery, were summarized. This paper not only systematically reviewed the progress of toxicity tests and their application in safety assessment of water quality, but also provided the scientific basis for the further development in the future. PMID- 25693413 TI - [Assessment on the COD discharge status of municipal wastewater treatment plant in a city of China]. AB - Based on the statistical theory, the paper collected routine monitoring data for 3 years of 11 municipal wastewater treatment plants with secondary treatment or enhanced secondary treatment in a northern city in China, and analysis of the discharge concentration distribution of COD showed a Delta-lognormal distribution. On this basis, referring to the formulation methods of water pollutant discharge limits used in the USA, the paper studied and assessed the discharge status of COD of the municipal wastewater treatment plants in the city, including the daily maximum and the monthly average discharge status, and came to the conclusion that the daily maximum discharge status met the first grade A class discharge standard (50 mg . L(-1)) required by the Discharge Standard of Pollutants for Municipal Wastewater Treatment Plant (GB 18918-2002). Meanwhile, the assessment conclusion was obtained for the monthly average discharge status, and the conclusions were discussed. The assessment method and the conclusions in this paper might provide reference for formulation and revision of water discharge standards. PMID- 25693414 TI - [Assessment of ecological environment benefits of reclaimed water reuse in Beijing]. AB - With the rapid development of the social economy and the sustained growth of population, China is facing increasingly serious water problems, and reclaimed water utilization has become an effective measure to solve water shortage problem and to control further deterioration of the ecological environment. Reclaimed water utilization can not only save a lot of fresh water, but also reduce the environmental impact of wastewater discharge, and thus has great ecological environmental benefits, including resource, environmental and human health benefits and so on. This study used the opportunity cost method to construct an evaluation system for ecological environmental benefits of reclaimed water utilization, and Beijing was taken as an example to conduct an estimation of ecological environmental benefits of reclaimed water utilization. Research results indicated that the reclaimed water utilization in Beijing had considerable environmental benefits for Y 1.2 billion in 2010, in which replacement of fresh water accounted for the largest share. The benefits of environmental improvement and groundwater recharge were large, while the other benefits were small or negative. The ecological environment benefits of reclaimed water utilization in Beijing was about 1.8 times that of its direct economic benefits, showing that reclaimed water utilization was in accordance with sustainable development. Related methods and results will provide scientific basis to promote the development of reclaimed water utilization in our country. PMID- 25693415 TI - [Construction of index system for early warning of persistent organic pollutants (POPs) pollution incidents in China]. AB - Early warning of pollution incidents caused by persistent organic pollutants (POPs) is urgently needed for China in the circumstances of serious POPs pollution and in increasing demand for improvement in chemical risk management. Given different categories of POPs and pollution incidents, the index system for early warning of POPs pollution accidents was built based on lifecycle theory and POPs formation mechanisms. It will be helpful for decision makers to enhance the early warning management of POPs pollution incidents in China. The index system for early warning includes two parts, early warning and mechanism for system operation. The indices include risk source indicators, warning indicators and warning level indicators. To ensure the effective implementation of this system, the mechanisms for response and policy guarantee were also formulated. These mechanisms contain dynamic inventory management and periodical assessment of risk sources, timely and effective report of warning conditions, as well as coordination and cooperation among the relevant departments. PMID- 25693416 TI - [Environmental damages assessment: establishment of system framework in China]. AB - Health injury, properties compensation and ecological and environmental destruction caused by environmental pollutions have become the focuses of the government, the public and the society at present in China. The experiences of developed countries have revealed that the environmental damage assessment system must be established through development of environmental damage assessment legislations, technologies and funding guarantee system suitable for the nation's conditions based on the specific environmental situation and main issues. China has some experience in marine ecological environment, fishery resources damage assessment, forest resources damage assessment and remediation management of contaminated sites; however, the managing function of environmental damage assessment is assigned to different governmental departments. There are also shortcomings such as few cases of environmental public compensation, insufficient environmental privacy determination and compensation, etc. Based on the methods of materials and information collections, questionnaires, visiting environmental court and government sectors, interviews to assessment organizations and professionals, launching practical assessments to related cases and participating in environmental public lawsuits, the situation of environmental pollution damages in China was analyzed, the related legislation and management mechanism were reviewed, the corresponding assessment organizations regarding environmental damages were sort out, and the funding sources of environmental damage assessment were explored. Aiming at the main issues in Chinese environmental damage management, a standard and unified system for environmental damage assessment based on current managing and technological systems is important to improve the practical work in determination, assessment and compensation of environmental pollution damage in China, and to further explore the feasible environmental damage quantitative management. PMID- 25693417 TI - Role of visual and non-visual cues in constructing a rotation-invariant representation of heading in parietal cortex. AB - As we navigate through the world, eye and head movements add rotational velocity patterns to the retinal image. When such rotations accompany observer translation, the rotational velocity patterns must be discounted to accurately perceive heading. The conventional view holds that this computation requires efference copies of self-generated eye/head movements. Here we demonstrate that the brain implements an alternative solution in which retinal velocity patterns are themselves used to dissociate translations from rotations. These results reveal a novel role for visual cues in achieving a rotation-invariant representation of heading in the macaque ventral intraparietal area. Specifically, we show that the visual system utilizes both local motion parallax cues and global perspective distortions to estimate heading in the presence of rotations. These findings further suggest that the brain is capable of performing complex computations to infer eye movements and discount their sensory consequences based solely on visual cues. PMID- 25693419 TI - FRAT-up, a Web-based fall-risk assessment tool for elderly people living in the community. AB - BACKGROUND: About 30% of people over 65 are subject to at least one unintentional fall a year. Fall prevention protocols and interventions can decrease the number of falls. To be effective, a prevention strategy requires a prior step to evaluate the fall risk of the subjects. Despite extensive research, existing assessment tools for fall risk have been insufficient for predicting falls. OBJECTIVE: The goal of this study is to present a novel web-based fall-risk assessment tool (FRAT-up) and to evaluate its accuracy in predicting falls, within a context of community-dwelling persons aged 65 and up. METHODS: FRAT-up is based on the assumption that a subject's fall risk is given by the contribution of their exposure to each of the known fall-risk factors. Many scientific studies have investigated the relationship between falls and risk factors. The majority of these studies adopted statistical approaches, usually providing quantitative information such as odds ratios. FRAT-up exploits these numerical results to compute how each single factor contributes to the overall fall risk. FRAT-up is based on a formal ontology that enlists a number of known risk factors, together with quantitative findings in terms of odds ratios. From such information, an automatic algorithm generates a rule-based probabilistic logic program, that is, a set of rules for each risk factor. The rule-based program takes the health profile of the subject (in terms of exposure to the risk factors) and computes the fall risk. A Web-based interface allows users to input health profiles and to visualize the risk assessment for the given subject. FRAT up has been evaluated on the InCHIANTI Study dataset, a representative population based study of older persons living in the Chianti area (Tuscany, Italy). We compared reported falls with predicted ones and computed performance indicators. RESULTS: The obtained area under curve of the receiver operating characteristic was 0.642 (95% CI 0.614-0.669), while the Brier score was 0.174. The Hosmer Lemeshow test indicated statistical significance of miscalibration. CONCLUSIONS: FRAT-up is a web-based tool for evaluating the fall risk of people aged 65 or up living in the community. Validation results of fall risks computed by FRAT-up show that its performance is comparable to externally validated state-of-the-art tools. A prototype is freely available through a web-based interface. TRIAL REGISTRATION: ClinicalTrials.gov NCT01331512 (The InChianti Follow-Up Study); http://clinicaltrials.gov/show/NCT01331512 (Archived by WebCite at http://www.webcitation.org/6UDrrRuaR). PMID- 25693420 TI - Current applications of PET imaging of sex hormone receptors with a fluorinated analogue of estradiol or of testosterone. AB - Currently, the most frequent approach in the oncologic applications of positron emission tomography (PET) is detecting the hypermetabolic activity of the cancer tissue. A more specific approach, which may be complementary, is detecting the overexpression of receptors. In this review article, we aim to evaluate the results that are currently available for PET imaging of the sex hormone receptors in clinical oncology. The indication of PET and now PET/CT has been more disputed in breast carcinoma than in many other primary cancers (e.g., lung, head and neck, colorectal, lymphoma). 18F-fluorodeoxyglucose (FDG), the glucose analogue for PET imaging, has a limited sensitivity to detect the primary breast tumors in case of lobular or in situ forms or small sized tumors localised on systematic mammography, and to identify minimal node invasion in the axilla. Using 16alpha [18F]fluoro-17beta-estradiol (FES), a fluorinated estradiol analogue, PET is able to detect the over-expression of the oestrogen receptor (ER) in lesions, at a whole-body level. FES and FDG appear complementary for a better diagnostic performance in staging locally advanced breast cancer or restaging recurrent or metastatic breast cancer. Another potential indication is predicting the response to starting or resuming hormone therapy in patients with metastatic breast cancer, in relation with the ER status of all lesions revealed by FES PET. In two retrospective studies, FDG PET was also able to predict the response to hormone therapy, on basis of a metabolic flare, observed either after 7-10 days of treatment or during an estradiol challenge. A prospective comparison of those approaches is warranted. One study reported predicting response to neoadjuvant chemotherapy thanks to a low value of FES SUV(max) or FES/FDG SUV(max) ratio. The presence of ER in uterine tumors, including the benign ones, in ovarian cancers or even in meningiomas, may have therapeutic consequences and FES PET could have a clinical utility in those settings; only initial results are available. The indication of PET and PET/CT has been even more disputed in prostate carcinoma, due to the lack of significant FDG uptake in most cases, at least before the castration-resistant stage. Using FDHT, a fluorinated testosterone analogue, PET is able to detect the over-expression of the androgen receptor (AR) in lesions, at a whole-body level. At least partly due to the rather large number of alternative tracers that are in development or even routinely available in some countries, few FDHT studies have been published until now. From absorbed dose values previously published for FES by the team of University of Washington School of Medicine at Seattle, and for FDHT by the teams of Memorial Sloan Kettering Cancer Center at New York and of Washington University at St. Louis, we applied the coefficients of ICRP publication 103 and calculated an effective dose per unit of injected activity of 0.023 mSv/MBq for FES and 0.018 mSv/MBq for FDHT. The radiation exposure is of the same order of magnitude as with FDG. PMID- 25693418 TI - The stress-responsive kinases MAPKAPK2/MAPKAPK3 activate starvation-induced autophagy through Beclin 1 phosphorylation. AB - Autophagy is a fundamental adaptive response to amino acid starvation orchestrated by conserved gene products, the autophagy (ATG) proteins. However, the cellular cues that activate the function of ATG proteins during amino acid starvation are incompletely understood. Here we show that two related stress responsive kinases, members of the p38 mitogen-activated protein kinase (MAPK) signaling pathway MAPKAPK2 (MK2) and MAPKAPK3 (MK3), positively regulate starvation-induced autophagy by phosphorylating an essential ATG protein, Beclin 1, at serine 90, and that this phosphorylation site is essential for the tumor suppressor function of Beclin 1. Moreover, MK2/MK3-dependent Beclin 1 phosphorylation (and starvation-induced autophagy) is blocked in vitro and in vivo by BCL2, a negative regulator of Beclin 1. Together, these findings reveal MK2/MK3 as crucial stress-responsive kinases that promote autophagy through Beclin 1 S90 phosphorylation, and identify the blockade of MK2/3-dependent Beclin 1 S90 phosphorylation as a mechanism by which BCL2 inhibits the autophagy function of Beclin 1. PMID- 25693421 TI - New approaches for imaging and therapy of solid cancer. AB - Radionuclide therapy is a systemic treatment that aims to deliver cytotoxic radiation to cancer cells. Due to their properties, antibodies have been considered as suitable agent for the delivery of therapeutic radioisotopes, radioimmunotherapy (RIT). This article gives an overview of new approaches for imaging and therapy of solid cancer with particular attention to strategies to enhance treatment success. Examples of increased antibody uptake by targeting stromal constituent of tumor microenvironment such as fibronectin (FN) an important tumor-associated angiogenesis targeting agent, with specifically designed antibody format will be provided. Strategies oriented to identify patients most likely to benefit from RIT including identification of radiosensitivity profiles, in vivo target identification by teragnostic approach and better prediction of dosimetric estimates would be presents. Combination regimens such as with chemo-radiotherapy and immunotherapy would be also discussed as an approach to enhance RIT success. PMID- 25693422 TI - Predictors of HIV enacted stigma among Chilean women. AB - AIMS AND OBJECTIVES: To investigate if socio-demographic factors, religiosity, HIV-related knowledge, Marianismo, history of having been tested for HIV, knowing someone who died of AIDS and HIV risk perception were predictive factors to HIV enacted stigma predictors among Chilean women. BACKGROUND: HIV infection is the number one cause of death among women during their reproductive years. In Chile, studies with people living with HIV demonstrate the existence of HIV-related stigma. However, limited evidence is available about the underlying causes of HIV enacted stigma that results in stigmatisation and discrimination. DESIGN: The current cross-sectional study is a secondary analysis of data collected to assess the impact of an HIV prevention intervention (Mano a Mano-Mujer) designed for Chilean women. A quasi-experimental design was used in the original study. METHODS: This study was conducted in two communities in Santiago, Chile. The sample for this study consisted of 496 Chileans between ages 18-49. Descriptive statistics and multiple regression were used for the analysis. RESULTS: Participants in the study reported high levels (77.8%) of HIV enacted stigma. Higher levels of HIV-related knowledge were associated with lower levels of HIV enacted stigma. Women with higher education had lower levels of HIV enacted stigma than women with elementary education. In addition, greater levels of marianismo (cultural belief that women should be passive, faithful, and devoted to family) were associated with higher HIV enacted stigma scores. CONCLUSIONS: The findings reflected the presence of HIV enacted stigma among Chilean women. Identifying the significant predictors of HIV enacted stigma can help the nursing community to design HIV prevention interventions that include the reduction in HIV enacted stigma. HIV evidence-based prevention interventions should incorporate contents related to stigma to contribute to prevent HIV enacted stigma at individual and community levels in accordance with the bioecological model. RELEVANCE TO CLINICAL PRACTICE: The results of this study could serve to develop HIV prevention interventions that target the reduction in HIV enacted stigma. PMID- 25693423 TI - Antecolic reconstruction is a predictor of the occurrence of roux stasis syndrome after distal gastrectomy. AB - BACKGROUND: Roux-en-Y reconstruction after distal gastrectomy can result in delayed gastric emptying, called Roux stasis syndrome (RSS). The cause of RSS has not been completely identified. This study retrospectively investigated the development of RSS. METHODS: Between April 2008 and March 2014, we performed 138 procedures with distal gastrectomy using Roux-en-Y reconstruction. The development of RSS was analyzed and examined for correlations with the length of the operation, amount of blood loss, and surgical procedure. RESULTS: RSS was observed in 16 of the 138 patients. There were no relationships between the length of the operation or amount of blood loss and the development of RSS according to the Mann-Whitney U test. There were also no significant differences in the development of RSS between the patients treated with laparotomy and laparoscopic surgery, end-to-side, side-to-side, or end-to-end anastomosis or isoperistaltic or antiperistaltic anastomosis, as determined using the chi-square test. However, the development of RSS tended to lower in the patients who underwent laparoscopic surgery, side-to-side anastomosis, and isoperistaltic anastomosis. In addition, there was a significant difference between the patients who received antecolic and retrocolic reconstruction (p=0.005). CONCLUSIONS: Our findings suggest that antecolic reconstruction correlates with a lower likelihood of developing RSS. PMID- 25693424 TI - Survival benefit of surgical treatment for liver metastases from gastric cancer. AB - BACKGROUND AND OBJECTIVES: Indications for the resection of liver metastases from gastric cancers (GLM) remain controversial, and few previous studies have reported subsequent surgical outcomes. Thus, the present retrospective study was designed to clarify the benefits of surgical treatment and identify prognostic factors. METHODS: Outcomes of 47 patients with or without hepatectomy for GLM were retrospectively compared. RESULTS: A total of 22 patients received surgical treatment for GLM, and overall 1-, 3-, and 5-year survival rates were 86, 26, and 26 %, respectively, and the median survival time (MST) was 22 months. Among 25 patients who did not receive hepatic surgical treatment, the overall survival rates were 24, 8.0, and 4.0 % at 1-, 3-, and 5-years, respectively, with an MST of 7 months. A significant difference was observed between patients with and without the liver surgical treatment (P < 0.001). Univariate and multivariate analyses of recipients of surgery, only the number of liver metastases (solitary or multiple) was significantly predictive of survival (HR = 0.26, P = 0.029) following hepatic resection for GLM. CONCLUSIONS: Surgical treatment of GLM should be considered when complete excision including the primary tumor appears to be possible, particularly in cases of solitary hepatic metastases. PMID- 25693425 TI - The importance of connexin hemichannels during chondroprogenitor cell differentiation in hydrogel versus microtissue culture models. AB - Appropriate selection of scaffold architecture is a key challenge in cartilage tissue engineering. Gap junction-mediated intercellular contacts play important roles in precartilage condensation of mesenchymal cells. However, scaffold architecture could potentially restrict cell-cell communication and differentiation. This is particularly important when choosing the appropriate culture platform as well as scaffold-based strategy for clinical translation, that is, hydrogel or microtissues, for investigating differentiation of chondroprogenitor cells in cartilage tissue engineering. We, therefore, studied the influence of gap junction-mediated cell-cell communication on chondrogenesis of bone marrow-derived mesenchymal stromal cells (BM-MSCs) and articular chondrocytes. Expanded human chondrocytes and BM-MSCs were either (re-) differentiated in micromass cell pellets or encapsulated as isolated cells in alginate hydrogels. Samples were treated with and without the gap junction inhibitor 18-alpha glycyrrhetinic acid (18alphaGCA). DNA and glycosaminoglycan (GAG) content and gene expression levels (collagen I/II/X, aggrecan, and connexin 43) were quantified at various time points. Protein localization was determined using immunofluorescence, and adenosine-5'-triphosphate (ATP) was measured in conditioned media. While GAG/DNA was higher in alginate compared with pellets for chondrocytes, there were no differences in chondrogenic gene expression between culture models. Gap junction blocking reduced collagen II and extracellular ATP in all chondrocyte cultures and in BM-MSC hydrogels. However, differentiation capacity was not abolished completely by 18alphaGCA. Connexin 43 levels were high throughout chondrocyte cultures and peaked only later during BM-MSC differentiation, consistent with the delayed response of BM-MSCs to 18alphaGCA. Alginate hydrogels and microtissues are equally suited culture platforms for the chondrogenic (re-)differentiation of expanded human articular chondrocytes and BM MSCs. Therefore, reducing direct cell-cell contacts does not affect in vitro chondrogenesis. However, blocking gap junctions compromises cell differentiation, pointing to a prominent role for hemichannel function in this process. Therefore, scaffold design strategies that promote an increasing distance between single chondroprogenitor cells do not restrict their differentiation potential in tissue engineered constructs. PMID- 25693426 TI - Optimization of Chlorella vulgaris and bioflocculant-producing bacteria co culture: enhancing microalgae harvesting and lipid content. AB - Microalgae are a sustainable bioresource, and the biofuel they produce is widely considered to be an alternative to limited natural fuel resources. However, microalgae harvesting is a bottleneck in the development of technology. Axenic Chlorella vulgaris microalgae exhibit poor harvesting, as expressed by a flocculation efficiency of 0.2%. This work optimized the co-culture conditions of C. vulgaris and bioflocculant-producing bacteria in synthetic wastewater using response surface methodology (RSM), thus aiming to enhance C. vulgaris harvesting and lipid content. Three significant process variables- inoculation ratio of bacteria and microalgae, initial glucose concentration, and co-culture time- were proposed in the RSM model. F-values (3.98/8.46) and R(2) values (0.7817/0.8711) both indicated a reasonable prediction by the RSM model. The results showed that C. vulgaris harvesting efficiency reached 45.0-50.0%, and the lipid content was over 21.0% when co-cultured with bioflocculant-producing bacteria under the optimized culture conditions of inoculation ratio of bacteria and microalgae of 0.20-0.25, initial glucose concentration of <1.5 kg m(-3) and co-culture time of 9-14 days. This work provided new insights into microalgae harvesting and cost effective microalgal bioproducts, and confirmed the promising prospect of introducing bioflocculant-producing bacteria into microalgae bioenergy production. SIGNIFICANCE AND IMPACT OF THE STUDY: This work optimized the co culture conditions of microalgae (C. vulgaris) and bioflocculant-producing bacteria (F2, Rhizobium radiobacter) in synthetic wastewater using response surface methodology, aiming to enhance C. vulgaris harvesting and lipid produced content. Bioflocculant-producing microbes are environmentally friendly functional materials. They avoid the negative effects of traditional chemical flocculants. This work provided new insights into microalgae harvesting and cost-effective production of microalgal bioproducts, and confirmed the promising prospect of introducing bioflocculant-producing bacteria into microalgae bioenergy production. PMID- 25693427 TI - Adaptation of physiological cross-sectional area and serial number of sarcomeres after tendon transfer of rat muscle. AB - Tendon transfer surgery to a new extensor insertion was performed for musculus flexor carpi ulnaris (FCU) of young adult rats, after which animals were allowed to recover. Mechanical properties and adaptive effects on body mass, bone growth, serial number of sarcomeres, and muscle physiological cross-sectional area were studied. Between the transfer and control groups, no differences were found for body mass and forearm length growth. In contrast, transferred muscles had a 19% smaller physiological cross-sectional area and 25% fewer sarcomeres in series within its muscle fibers than control muscles, i.e., a deficit in muscle belly growth is present. Our present results confirm our the length of previous work showing a limited capability of changing the adapted transferred FCU muscle belly, as the muscle-tendon complex is stretched, so that most of the acute FCU length change must originate from the tendon. This should most likely be attributed to surgery-related additional and/or altered connective tissue linkages at the muscle-tendon boundary. The substantially increased FCU tendon length found, after recovery from surgery and adaptation to the conditions of the transferred position, is likely to be related to such enhanced stretching of the FCU tendon. PMID- 25693428 TI - Neonatal resuscitation in Vietnam: a national survey of a middle-income country. AB - AIM: Interventions that improve neonatal resuscitation are critical if we are to reduce perinatal mortality. We evaluated the consistency of resuscitation practices, and adherence to the international guidelines for neonatal resuscitation, in a large representative sample of hospitals in Vietnam. METHODS: A questionnaire was sent to 187 public central, provincial and district hospitals, representing the three levels of public hospital-based maternity services in Vietnam. RESULTS: The overall response rate was 85.7% (160/187 hospitals), and the response rate was 100%, 90.3% and 81.7% for central, provincial and district hospitals, respectively. There were 620 300 births in the surveyed hospitals during the year 2011, representing almost half of all inpatient births in Vietnam. Neonatal resuscitation was provided by obstetricians and, or, midwives at all levels. Half of the hospitals did not follow recommendations for delaying cord clamping. The majority of the hospitals did not have a wall thermometer in the delivery room (80.5%) and did not monitor neonatal temperature after birth (64.1%). A large proportion of hospitals (39.9%) used 100% oxygen to initiate resuscitation and only central hospitals avoided this practice. CONCLUSION: Our survey identified significant variations in resuscitation practices between central, provincial and district hospitals and limited adherence to international recommendations. PMID- 25693429 TI - Investigation of prototypal MOFs consisting of polyhedral cages with accessible Lewis-acid sites for quinoline synthesis. AB - A series of prototypal metal-organic frameworks (MOFs) consisting of polyhedral cages with accessible Lewis-acid sites, have been systematically investigated for Friedlander annulation reaction, a straightforward approach to synthesizing quinoline and its derivatives. Amongst them MMCF-2 demonstrates significantly enhanced catalytic activity compared with the benchmark MOFs, HKUST-1 and MOF 505, as a result of a high-density of accessible Cu(II) Lewis acid sites and large window size in the cuboctahedral cage-based nanoreactor of MMCF-2. PMID- 25693430 TI - [Autologous hematopoietic cell transplantation in patients with multiple myeloma. Experience in 53 patients]. AB - BACKGROUND: Autologous hematopoietic cell transplantation (THA) in patients with multiple myeloma and amyloidosis is the standard of care to promote disease free survival and quality of life. AIM: To report our experience with THA in patients with multiple myeloma. MATERIAL AND METHODS: Retrospective review of the hematopoietic cell transplantation database of a hospital of a Medical School. Forty seven patients with multiple myeloma and six with amyloid light chain amyloidosis were identified. Clinical and demographic data were obtained from the records. RESULTS: The overall five year survival of patients was 55%. Transplant related or non-relapse mortality occurred in 7%. We found no differences in outcomes among patients younger or older than 50 years. CONCLUSIONS: Our data supports that THA can be done in our country with similar results to those obtained in international transplantation centers. Chronological age should not be a limitation to offer this therapy to patients with multiple myeloma and amyloidosis. PMID- 25693431 TI - [Changes in cerebral blood flow velocity in supine and sitting position in patients with aneurysmal subarachnoid hemorrhage]. AB - BACKGROUND: Early mobilization in intensive care units (ICU) provides respiratory, neurological and cardiovascular benefits in hospitalized patients. However, the orthostatic effects of changing from a supine to a sitting position may interfere with cerebral hemodynamics of patients with aneurysmal subarachnoid hemorrhage (aSAH). AIM: To describe the changes in mean cerebral blood flow velocity (MCBFV) in supine and sitting position, in adult patients with aSAH, with asymptomatic vasospasm (AVS) or without vasospasm (VS) at a neurosurgical ICU. MATERIAL AND METHODS: Descriptive case series study in 21 patients with aSAH, both with and without VS. They were positioned in a supine 30 degrees position and then seated at the edge of bed for six minutes. MCBFV was measured by transcranial Doppler (TCD), and hemodynamic variables in both positions were registered. After this basal assessment and for 21 days after the episode of SAH, patients were seated once a day and signs of VS were recorded. RESULTS: No significant changes in MCBFV or hemodynamic variables were detected during position changes, except for an increase in heart rate in the sitting position. No patient with AVS at the onset, had symptomatic VS during the 21 days of follow up when patients were seated. Among patients with a normal MCBFV at baseline, five patients (24%) had VS at a mean of three days after the first time that they were seated on the edge of bed. CONCLUSIONS: Sitting patients at the edge of the bed is a safe mobilization alternative for patients who suffered aSAH who did not have VS or had AVS. PMID- 25693432 TI - [Serum anti endomysial and anti transglutaminase antibodies in patients with connective tissue diseases]. AB - BACKGROUND: The detection of anti-transglutaminase IgA (tTG) and anti-endomysial (EMA) is used for screening of celiac disease (CD) with a sensitivity and specificity of 90 and 99% respectively. There is an association between CD and connective tissue diseases (CTD). AIM: To report the frequency of IgA tTG and EMA in patients with a definite diagnosis of CTD and inflammatory arthropathies (IA). MATERIAL AND METHODS: One hundred forty nine patients, aged 19 to 86 years (133 females) with CTD and IA were studied. tTG were determined by ELISA and EMA by indirect immunofluorescence. RESULTS: Eight participants had at least one positive antibody (5.4%, confidence intervals (CI) = 1.8-9), six had both (4.0% CI = 0.9-7.2) and two had only tTG positive. An intestinal biopsy was performed in four of these participants, finding a marked villous atrophy in three and partial atrophy in one. CONCLUSIONS: Five percent of this group of patients with CTD or IA had positive antibodies for CD. PMID- 25693433 TI - [Alcohol consumption among traveling Chilean older people]. AB - BACKGROUND: Problems associated with alcohol consumption are prevalent in Chile, but little is known about the situation in the elderly. AIM: To perform a screening to detect alcohol-related problems and risks in the Chilean older people who travel. MATERIAL AND METHODS: The Alcohol Use Disorders Identification Test (AUDIT) questionnaire was answered by 1,076 travelers aged 60 to 93 years (66% females), who participated in trips organized by the Chilean National Tourism Service (SERNATUR). RESULTS: Seventy six percent of respondents acknowledged to have ingested an alcoholic drink during the last month. The average AUDIT score was of 2.2 +/- 2.6. Only 3.7% of the sample had a score equal or higher than eight, considered as risky use. Within this last group, 60% had symptoms of alcohol dependence. A higher alcohol consumption was associated with male gender (p < 0.01), being younger than 75 years of age (p < 0.01), having a medium-low economic income (p < 0.01) and having a higher education level (p = 0.03). There was no significant association with the respondents' occupation. CONCLUSIONS: In this sample of Chilean traveling older people, there was a high prevalence of alcohol consumption, and nearly 4% of respondents had alcohol related problems. PMID- 25693434 TI - [Effects of neonatal nutritional status on the risk for metabolic syndrome in Chilean obese children]. AB - BACKGROUND: Neonatal malnutrition defined by birth weight (BW) is a risk factor for obesity and cardio-metabolic diseases in adults. Neonatal ponderal index (NPI) may have better diagnostic value than BW to establish nutritional status. AIM: To determine the effect of neonatal nutritional status, established by the three NPI curves available in Chile, on the risk of Metabolic Syndrome (MS) in obese school children. MATERIAL AND METHODS: A nested case/control study in a sample of 410 obese school children aged 10 to 16 years (57% males) was performed. The dichotomous response variable was the presence of MS defined as International Diabetes Federation (IDF) or Cook's criteria. The exposure variable was having NPI < percentile (p) 10. RESULTS: The frequency of MS was 36 and 39% according to the IDF and Cook criteria, respectively. The proportion of children with neonatal malnutrition exceeded 20%. A significantly increased risk for MS was only found when PNI was defined according to Lagos's Table and MS was defined using IDF criteria. Having a PNI > p90, however, showed a trend towards a reduced risk of MS, which only reached significance using Lagos's Table and Cook's Criteria. CONCLUSIONS: Neonatal malnutrition defined by NPI is common in obese school children. The condition of neonatal under nutrition defined as PNI < p10 may be a risk factor for developing MS. Instead, having a NPI > p90 could be protective. PMID- 25693435 TI - [Changes in the consumption of dairy products, sugary drinks and processed juices in the Chilean population]. AB - BACKGROUND: Nowadays, Chilean population tends to replace or eat a lower amount of food with health protective properties and a higher proportion of unhealthy foodstuff. AIM: To describe and compare the intake of dairy products, sugary drinks and processed juices among Chileans. MATERIAL AND METHODS: An analysis of data compiled from the Survey on Household Budget and Expenses carried out by the Chilean National Institute of Statistics (INE), using a representative sample of households. The sample was surveyed between 1987 and 2007. The analysis was performed for all households surveyed and for households belonging to the second (highest incomes) and fifth quintile (lowest incomes). The Chilean Food Guide and the international recommendations of the Institute of Medicine of the United States and the American Heart Association (in the case of sugars) were used as reference. RESULTS: Even though the intake of dairy products increased during the period of the survey, it was lower than the intake of sugary drinks and juices, which increased. Also, calcium recommendations were not covered. On the other hand, the intake of added sugars increased to figures over current recommendations. CONCLUSIONS: The intake of dairy products and calcium is below the recommended amounts established by international organisms, and added sugars intake is greater than the advisable levels recommended by international organisms. PMID- 25693436 TI - [Contribution of Chilean research to the formulation of national clinical guidelines]. AB - BACKGROUND: In Chile, 80 diseases were included in a health care system called Health Care Guarantees (GES) and clinical guidelines were elaborated for their management. AIM: To assess the scientific background of guidelines and if they were based on research financed by the Chilean National Commission for Science and Technology. MATERIAL AND METHODS: The references of the 82 guidelines developed for 80 diseases were reviewed, registering their number, authors, country of origin and funding source. RESULTS: The guidelines had a total of 6,604 references. Of these, only 185 were Chilean (2.8%) and five (0.08%) originated from research financed by the National Commission for Science and Technology. CONCLUSIONS: The contribution of research funded by national agencies to the formulation of clinical guidelines is minimal. PMID- 25693437 TI - [Adaptation and validation of checklists to detect medication prescription and dispensing errors]. AB - BACKGROUND: Adverse effects of medications are an important source of morbidity. Prescription and dispensing errors are an important cause of these adverse effects. AIM: To adapt and validate two checklists, one to measure errors in handwritten prescriptions and other to detected errors in the medication dispensing process of hospital pharmacies for outpatient care. MATERIAL AND METHODS: The study was conducted in three stages. First, checklists for medication errors developed elsewhere were adapted. Afterwards, the checklists were reviewed by experts. Finally, the inter and intra-observer reliability of each checklist was assessed, testing them in 32 occasions by two independent observers. RESULTS: The checklists for medication prescription and dispensing were composed by 12 and seven items, respectively. They were corrected according to experts' opinions. The intraclass correlations of the results of each tester were 0.68 and 0.82 for the prescription and dispensing error checklists, respectively. CONCLUSIONS: The developed checklists for the detection of errors in prescription and dispensing of medications are reliable en can be applied in future studies. PMID- 25693438 TI - [Effects of alpha lipoic acid and pirfenidone on liver cells antioxidant modulation against oxidative damage]. AB - BACKGROUND: Liver fibrogenic processes are related to cellular redox state. Glutathione (GSH) is the major cellular antioxidant. GSH induced activation could be related to antifibrogenic effects. AIM: To explore the association between the antifibrogenic effect and pro-antioxidant mechanisms of alpha-lipoic acid (ALA) and pirfenidone (PFD). MATERIAL AND METHODS: HepG2 cells and primary HSC cultures were exposed to menadione 0.1 MUM (MEN) as oxidative stress inducer and treated to ALA (5 mM) or PFD (10 MUM, 100 MUM y 1000 MUM). RESULTS: In HSC, PFD decreased cell proliferation and the expression of COL1A1, TGF-beta1, TIMP1, IL6, TNFalpha and MCP1 induced by MEN. Furthermore it was confirmed that ALA and PFD activate diverse antioxidants mediators, however MEN decreases this response. Then, MEN, ALA and PFD induce an antioxidant response, the first one as a response to injury and the latter two as pro-antioxidant inducers. Therefore, when cells are exposed to oxidative stress, endogenous systems activate a battery of mediators that increase the antioxidant potential. When these cells are treated with ALA and PFD, de novo formation of protective genes decreases since previous elicited protection induced in response to injury, enhance ALA and PFD effects. CONCLUSION: Regardless of the route of action, ALA and PFD induce the biosynthesis of antioxidants mediators which is associated with modulation of fibrogenic processes. PMID- 25693439 TI - [Causal relationship between the use of gadolinium based contrast media and nephrogenic systemic fibrosis]. AB - Nephrogenic systemic fibrosis (NSF) is a severe iatrogenic disease that affect patients with impaired renal function exposed to gadolinium-based contrast agents. Clinically, symptoms develop within days or weeks after the exposure and mimic a scleromyxedema. The causal relationship between use of gadolinium-based contrast agents and NSF led to develop clinical guidelines aiming to limit the use of this contrast medium in high risk patients. These guidelines decreased the incidence of NSF in the last years. Unfortunately there is no specific treatment for NSF yet. Thus, strict adherence to current guidelines is key to prevent new cases. Renal dysfunction is increasingly common in our population. Therefore, practicing physicians should be aware of this potential complication of the use of gadolinium based contrast media. PMID- 25693440 TI - [Use of hyperbaric oxygenation for wound management]. AB - Hyperbaric oxygenation consists in exposing patients to increased gas pressures while inhaling pure oxygen. It involves the use of hyperbaric chambers that can double or triple gas pressure inside them. Hyperbaric oxygenation may be useful in different clinical situations, but mostly for the treatment of decompression syndrome. In the last decades, it has been used for the management of different kinds of wounds. Hyperbaric oxygenation not only increases the delivery of oxygen to damaged tissues, but also stimulates angiogenesis, collagen synthesis, stem cell migration and local immune response. Clinical trials that have addressed the use of hyperbaric oxygenation are difficult to compare due to their heterogeneity in terms of experimental design, kind of injuries involved and assessment of outcome. Even though, most studies support the concept that hyperbaric oxygenation accelerates the healing process. PMID- 25693441 TI - [Management of the potential organ donor]. AB - Solid organ transplantation is limited by donor availability. The loss of brain function produces hemodynamic, respiratory, hormonal and metabolic changes that lead to hypotension and organ dysfunction. Management of a potential donor is similar to any critically ill patient. Cardiovascular stability and protective ventilatory support must be pursued, aimed at minimizing the local and systemic inflammatory response that is triggered by brain death. There is no consensus on protocols for hormonal supplementation. The administration of vasopressin analogues and steroids may be beneficial under certain conditions. Appropriate medical management helps to optimize the function of different organs prior to transplantation. This may increase the number of harvested organs and improve their functional outcome in the recipient. PMID- 25693442 TI - [Nutrient intake of Chilean older people according to body mass index]. AB - BACKGROUND: An adequate consumption of micro and macro nutrients is essential to maintain an adequate health among older people. AIM: To compare the consumption of micro- and macronutrients in older people from three Chilean cities, according to their nutritional status. MATERIAL AND METHODS: Body mass index (BMI) was assessed and a food consumption tendency survey was applied to 976 non-disabled older people, living in the community. Thinness was defined as a BMI < 23 kg/m2. RESULTS: Twenty percent of females and 17% of males had a BMI < 23 kg/m2. Participants with a higher BMI had a greater intake of micro- and macronutrients. In females, micronutrient intake was adequate among those with higher BMI, although mean intake of calcium and vitamin B-12 were below recommendations. In males, iron, zinc, calcium, magnesium, vitamin A, vitamin B6, vitamin B12 and pantothenic acid intake were below recommendation. CONCLUSIONS: Thin older adults, regardless of sex, had a lower intake of calories and micro- and macronutrients. Additionally, an overall low consumption of zinc, calcium, magnesium and vitamin B12 was detected. PMID- 25693443 TI - [Cutaneous involvement in multiple myeloma. Report of one case]. AB - Cutaneous involvement in multiple myeloma (MM) is extremely rare. It may correspond to plasmocytomas, secondary amyloidosis, paraneoplastic syndromes or drug reactions. We report a 75-year-old female with skin lesions, corresponding to extramedullary plasmacytomas (EPs), as a manifestation of MM progression. Most EPs appear in the upper airway and gastrointestinal tract, but have also been described in the genitourinary tract, lung, kidney, thyroid and in 2% of cases, in the skin. Cutaneous lesions are generally associated with terminal stages of the disease and a poor prognosis. PMID- 25693444 TI - [Meningitis-retention syndrome. Report of one case]. AB - The Meningitis-Retention Syndrome associates aseptic meningitis and neurogenic bladder, with a vesical dysfunction that outlasts meningitis widely. Urodynamic assessment shows a detrusor palsy with normal function of the external sphincter. We report a 24-year-old male admitted for headache, fever, myalgias and acute urinary retention, which was diagnosed as a urinary tract infection. Worsening of symptoms and slight meningeal signs prompted for a lumbar puncture that yielded a cerebrospinal fluid with 94 lymphocytes, in which etiological evaluation was inconclusive. Meningeal syndrome and myalgia subsided by the fifth day, while urinary retention persisted. A magnetic resonance imaging of the brain and spinal cord done at the fifth day, showed high intensity signals in basal ganglia and central spinal cord, not altered by contrast. These images disappeared in the imaging control performed two months later. Bladder dysfunction lasted at least until the second month of follow up. PMID- 25693445 TI - [Manuel Nunez Butron, M.D.: a world pioneer of Primary Medical Care]. PMID- 25693447 TI - SUSCEPTIBILITY ARTIFACTS ON T2*-WEIGHTED MAGNETIC RESONANCE IMAGING OF THE CANINE AND FELINE SPINE. AB - The T2*-weighted gradient recalled echo sequence is a sensitive means to detect blood degradation products. While not a routine sequence in magnetic resonance imaging of the spine in small animals, it can provide additional valuable information in select cases. The goal of this retrospective, cross-sectional study was to describe findings when acquiring this sequence during magnetic resonance imaging examination of the spine in small animals. The University of Tennessee's veterinary radiology database was searched for dogs and cats that underwent magnetic resonance imaging for suspect spinal disease in which a T2* weighted gradient recalled echo sequence was acquired and susceptibility artifact was identified. The following information was recorded: signalment, clinical signs, location and appearance of susceptibility artifact, and final diagnosis. Thirty-nine cases were included in the study. Extradural susceptibility artifacts were observed in cases of intervertebral disc herniation with or without associated hemorrhage (n = 28), extradural hemorrhage associated with spinal trauma (n = 2), hemophilia (n = 1), and in a cystic extradural mass (n = 1). Remaining lesions displaying susceptibility artifact were intramedullary and included presumptive acute noncompressive nucleus pulposus extrusion (n = 2), hematoma (n = 1), hemangiosarcoma metastasis (n = 1), intramedullary disc extrusion (n = 1), presumptive meningomyelitis (n = 1), and a mass of undetermined etiology (n = 1). Inclusion of a T2*-weighted gradient recalled echo sequence may be helpful in spinal magnetic resonance imaging when standard imaging sequences are ambiguous or intramedullary lesions are observed. PMID- 25693446 TI - The biology of Plasmodium vivax explored through genomics. AB - Malaria is a mosquito-borne disease caused by the Plasmodium parasite. Of the four Plasmodium species that routinely cause human malaria, Plasmodium vivax is the most widespread species outside Africa, causing ~18.9 million cases in 2012. P. vivax cannot be cultured continuously in vitro, which severely hampers research in nonendemic and endemic countries alike. Consequently, whole-genome sequencing has become an effective means to interrogate the biology of the P. vivax parasite. Our comparative genomic analysis of five P. vivax reference genomes and several whole-genome sequences of the closely related monkey malaria species P. cynomolgi has revealed an extraordinary level of genetic diversity and enabled characterization of novel multigene families and important single-copy genes. The generation of whole-genome sequences from multiple clinical isolates is also driving forward knowledge concerning the biology and evolution of the species. Understanding the biology of P. vivax is crucial to develop potential antimalarial drugs and vaccines and to achieve the goal of eliminating malaria. PMID- 25693448 TI - Measuring diaphragm thickness with ultrasound in mechanically ventilated patients: feasibility, reproducibility and validity. AB - PURPOSE: Ultrasound measurements of diaphragm thickness (T di) and thickening (TFdi) may be useful to monitor diaphragm activity and detect diaphragm atrophy in mechanically ventilated patients. We aimed to establish the reproducibility of measurements in ventilated patients and determine whether passive inflation by the ventilator might cause thickening apart from inspiratory effort. METHODS: Five observers measured T di and TFdi in 96 mechanically ventilated patients. The probe site was marked in 66 of the 96 patients. TFdi was measured at peak and end inspiration (airway occluded and diaphragm relaxed) in nine healthy volunteers inhaling to varying lung volumes. The association with diaphragm electrical activity was quantified. RESULTS: Right hemidiaphragm thickness was obtained on 95 % of attempts; left hemidiaphragm measurements could not be obtained consistently. Right hemidiaphragm thickness measurements were highly reproducible (mean +/- SD 2.4 +/- 0.8 mm, repeatability coefficient 0.2 mm, reproducibility coefficient 0.4 mm), particularly after marking the location of the probe. TFdi measurements were only moderately reproducible (median 11 %, IQR 3-17 %, repeatability coefficient 17 %, reproducibility coefficient 16 %). TFdi and diaphragm electrical activity were positively correlated, r2 = 0.32, p < 0.01). At inspiratory volumes below 50 % of inspiratory capacity, passive inflation did not cause diaphragm thickening. TFdi was considerably lower in patients on either partially assisted or controlled ventilation compared to healthy subjects (median 11 vs. 35 %, p < 0.001). CONCLUSIONS: Ultrasound measurements of right hemidiaphragm thickness are feasible and highly reproducible in ventilated patients. At clinically relevant inspiratory volumes, diaphragm thickening reflects muscular contraction and not passive inflation. This technique can be reliably employed to monitor diaphragm thickness, activity, and function during mechanical ventilation. PMID- 25693449 TI - Asynchronies during mechanical ventilation are associated with mortality. AB - PURPOSE: This study aimed to assess the prevalence and time course of asynchronies during mechanical ventilation (MV). METHODS: Prospective, noninterventional observational study of 50 patients admitted to intensive care unit (ICU) beds equipped with Better CareTM software throughout MV. The software distinguished ventilatory modes and detected ineffective inspiratory efforts during expiration (IEE), double-triggering, aborted inspirations, and short and prolonged cycling to compute the asynchrony index (AI) for each hour. We analyzed 7,027 h of MV comprising 8,731,981 breaths. RESULTS: Asynchronies were detected in all patients and in all ventilator modes. The median AI was 3.41 % [IQR 1.95 5.77]; the most common asynchrony overall and in each mode was IEE [2.38 % (IQR 1.36-3.61)]. Asynchronies were less frequent from 12 pm to 6 am [1.69 % (IQR 0.47 4.78)]. In the hours where more than 90 % of breaths were machine-triggered, the median AI decreased, but asynchronies were still present. When we compared patients with AI > 10 vs AI <= 10 %, we found similar reintubation and tracheostomy rates but higher ICU and hospital mortality and a trend toward longer duration of MV in patients with an AI above the cutoff. CONCLUSIONS: Asynchronies are common throughout MV, occurring in all MV modes, and more frequently during the daytime. Further studies should determine whether asynchronies are a marker for or a cause of mortality. PMID- 25693450 TI - Solvatochromic shifts of Br2 and I2 in water cages of type 512, 51262, 51263, and 51264. AB - Despite the relatively small size of molecular bromine and iodine, the physicochemical behavior in different solvents is not yet fully understood, in particular when excited-state properties are sought. In this work, we investigate isolated halogen molecules trapped in clathrate hydrate cages. Relativistic supermolecular calculations reveal that the environment shift to the excitation energies of the (nondegenerate) states 3Piu and 1Piu lie within a spread of 0.05 eV, respectively, suggesting that environment shifts can be estimated with scalar relativistic treatments. As even scalar-relativistic calculations are problematic for excited-state calculations for clathrates with growing size and basis sets, we have applied the subsystem-based scheme frozen-density embedding, which avoids a supermolecular treatment. This allows for the calculation of excited states for extended clusters with coupled-cluster methods and basis sets of triple-zeta quality with additional diffuse functions mandatory for excited-state properties, as well as a facile treatment at scalar-relativistic exact two-component level of theory for the heavy atoms bromine and iodine. This simple approach yields scalar relativistic estimates for solvatochromic shifts introduced by the clathrate cages. PMID- 25693451 TI - Performance of low cost scalable air-cathode microbial fuel cell made from clayware separator using multiple electrodes. AB - Performance of scalable air-cathode microbial fuel cell (MFC) of 26 L volume, made from clayware cylinder with multiple electrodes, was evaluated. When electrodes were connected in parallel with 100 Omega resistance (R ext), power of 11.46 mW was produced which was 4.48 and 3.73 times higher than individual electrode pair and series connection, respectively. Coulombic efficiency of 5.10 +/- 0.13% and chemical oxygen demand (COD) removal of 78.8 +/- 5.52% was observed at R ext of 3 Omega. Performance under different organic loading rates (OLRs) varying from 0.75 to 6.0 g CODL(-1)d(-1) revealed power of 17.85 mW (47.28 mA current) at OLR of 3.0 g CODL(-1)d(-1). Internal resistance (R int) of 5.2 Omega observed is among the least value reported in literature. Long term operational stability (14 months) demonstrates the technical viability of clayware MFC for practical applications and potential benefits towards wastewater treatment and electricity recovery. PMID- 25693452 TI - Role of probiotic Lactobacillus fermentum KKL1 in the preparation of a rice based fermented beverage. AB - A dominant lactic acid bacteria, Lactobacillus fermentum KKL1 was isolated from an Indian rice based fermented beverage and its fermentative behavior on rice was evaluated. The isolate grown well in rice and decreased the pH, with an increase of total titratable acidity on account of high yield in lactic acid and acetic acid. The production of alpha-amylase and glucoamylase by the strain reached plateau on 1st and 2nd day of fermentation respectively. The accumulation of malto-oligosaccharides of different degrees of polymerization was also found highest on 4th day. Besides, phytase activity along with accumulation of free minerals also unremittingly increased throughout the fermentation. The fermented materials showed free radical scavenging activity against DPPH radicals. In-vitro characteristics revealed the suitability of the isolate as probiotic organism. The above profiling revealed that probiotic L. fermentum KKL1 have the significant impact in preparation of rice beer and improves its functional characteristics. PMID- 25693453 TI - Identification of arrhythmogenic right ventricular cardiomyopathy-causing gene mutations in young sudden unexpected death autopsy cases. AB - Arrhythmogenic right ventricular cardiomyopathy (ARVC) results in an increased risk of sudden death. We sought mutations of desmoglein-2 (DSG2), desmoplakin (DSP), and plakophilin-2 (PKP2) in 15 cases of sudden death whose causes of death could not be determined at autopsy. In three victims, mutations were identified in DSP. Two of these mutations were novel; one had previously been reported in a patient with ARVC that had been diagnosed clinically. Histological findings were not typical of ARVC; however, it was notable that these mutations were present in three of 15 cases, a relatively high proportion. The causal relationship between the mutations and ARVC is unclear, but the mutations might have been associated with faulty desmosomal proteins resulting in fatal arrhythmia. Combining information gathered by the traditional means of gross and histological examination with postmortem genetic analysis of young victims would assist in identifying their cause of death. PMID- 25693454 TI - Response to: speculations on the pathophysiology of Takotsubo syndrome. PMID- 25693455 TI - Comparison of streamlined liner of the pharynx airway (SLIPA TM) and laryngeal mask airway: a systematic review and meta-analysis. AB - We performed a systematic review to compare the efficacy and safety of the streamlined liner of the pharynx airway and laryngeal mask airway used in adults during general anaesthesia. We included 14 studies with studies with 1273 patients in total. There was no evidence of a difference between the two devices in insertion success rate on the first attempt (13 studies, 1143 patients), insertion time (seven studies, 576 patients), ease of insertion (five studies, 466 patients), oropharyngeal leak pressure (eight studies, 771 patients) and the quality of the fibreoptic view of the larynx through the device (three studies, 281 patients). The relative risk (95% CI) of bloodstaining of the device (nine studies, 859 patients) was 2.09 (1.46-3.00) for the streamlined liner of the pharynx airway compared with the laryngeal mask airway. Other adverse events were comparable. Subgroup analysis suggested that the insertion by novice users might be faster and more successful with the streamlined liner of the pharynx airway than the laryngeal mask airway; however, this was from only two studies and 186 patients. The method of size selection of the streamlined liner of the pharynx airway device might also affect the speed of insertion: choosing according to the width of the patient's thyroid cartilage, rather than height, may produce better results. PMID- 25693456 TI - A new species of Drepanocephalus Dietz, 1909 (Digenea: Echinostomatidae) from the double-crested cormorant Phalacrocorax auritus (Lesson) (Aves: Phalacrocoracidae) in North America. AB - Drepanocephalus auritus n. sp. is described based on specimens from the double crested cormorant Phalacrocorax auritus (Lesson) in North America. The new species differs from its congeners in its very narrow, elongate body, long uterine field and widely separated testes. Sequences of the nuclear rRNA gene cluster, spanning the 3' end of the nuclear ribosomal 18S rRNA gene, internal transcribed spacer region (ITS1+5.8S gene+ITS2) and partial 28S gene (2,345 bp), were identical in specimens collected from North Dakota, Minnesota and Mississippi, USA. Sequences of the 651 bp long fragment of the mitochondrial cox1 gene exhibited very low intraspecific variability (< 1%). Comparisons of the newly-generated sequences with those available in the GenBank indicate that the sequences from North America published under the name D. spathans Dietz, 1909 in fact represent D. auritus n. sp. PMID- 25693457 TI - Anomalomermis ephemerophagis n. g., n. sp. (Nematoda: Mermithidae) parasitic in the mayfly Ephemerella maculata Traver (Ephermeroptera: Ephermerellidae) in California, USA. AB - A new nematode, Anomalomermis ephemerophagis n. g., n. sp. (Nematoda: Mermithidae) is described from the mayfly Ephemerella maculata Traver (Ephermeroptera: Ephermerellidae) in California. The new species is characterised by six cephalic papillae and four additional disk papillae located on the head between the cephalic papillae and stoma. Additional diagnostic characters are: a terminal mouth opening; absence of X-fibers in the cuticle of both postparasitic juveniles and adults; paired, curved, medium-sized spicules; a straight barrow shaped vagina and large eggs. Two infectious agents were present in some specimens. This is the first description of an adult nematode from a mayfly. PMID- 25693458 TI - Breinlia (Breinlia) jittapalapongi n. sp. (Nematoda: Filarioidea) from the Asian house rat Rattus tanezumi Temminck in Lao PDR. AB - A new species of filarioid nematode of the genus Breinlia Yorke & Maplestone, 1926 (Nematoda: Filarioidea) is described from rodents in Lao PDR and according to its morphology, is placed in the subgenus Breinlia. Breinlia (Breinlia) jittapalapongi n. sp. occurs in the Asian house rat (Rattus tanezumi Temminck) and the Sikkim rat (Rattus andamanensis Blyth) and is reported from two localities (Luang Prabang and Champasak). The new species can be distinguished from all other congeners, which are mostly distributed in Australasia (twenty-two species), South East Asia (four species) and India (two species), by the following characters of the males: shape and size of gubernaculum, length of spicules, pattern of cloacal papillae and presence of sclerotised ring in the buccal capsule. This is the fifth species of Breinlia described from South East Asia. PMID- 25693459 TI - A new species of Bothriocephalus Rudolphi, 1808 (Eucestoda: Bothriocephalidea) from the channel bull blenny Cottoperca gobio (Gunther) (Perciformes: Bovichtidae) on the Patagonian shelf off Argentina. AB - Bothriocephalus timii n. sp. is the first tapeworm species reported from a bovichtid fish. The new species was commonly found (prevalence 85%) in the intestine of Cottoperca gobio (Gunther) collected on the Patagonian shelf off Argentina. It is characterised by a strobila with segments and proglottides usually longer than wide, having posterolateral wing-like expansions with a medial notch on both the dorsal and ventral surfaces; a scolex with an apical disk; elongate bothria opening posteriorly, with laterally and longitudinally extended convex lappets; testes 42-185 in number, in one layer, arranged in two lateral continuous bands along the strobila; an elongate cirrus-sac, situated obliquely, with the proximal part curved anteriolaterally; and an ovary which is usually butterfly-shaped. The new species is morphologically similar to B. bengalensis Devi, 1975 from Carangoides plagiotaeniata Bleeker, B. branchiostegi Yamaguti, 1952 from Branchiostegus japonicus Houttuyn, B. carangis Yamaguti, 1968 from C. ferdau Forsskal and B. gadellus Blend & Dronen, 2003 from Gadella imberbis (Vaillant) based on the presence of posterolateral wing-like expansions with a medial notch on dorsal and ventral surfaces of segments and proglottides along the strobila. Bothriocephalus timii n. sp. differs from B. bengalensis, B. branchiostegi and B. carangis in the absence of a vaginal sphincter and from B. gadellus in the number of testes and the size of scolex. Unpublished molecular data suggest that B. timii is most closely related to B. australis Kuchta, Scholz & Justine, 2009 from Platycephalus spp. and B. scorpii (Muller, 1776) from Myoxocephalus scorpius (Linnaeus). The genus Indobothrium Sedova & Gulyaev, 2009 is herein considered a junior synonym of Bothriocephalus Rudolphi, 1808. PMID- 25693460 TI - A review of larval Chyzeria Canestrini, 1897 (Acari: Parasitengonina: Chyzeriidae). AB - Type-material for all larvae of species of Chyzeria Canestrini, 1897 (Prostigmata: Chyzerioidea: Chyzeriidae) was examined, diagnoses are presented and a key to species provided. The genus Chyzeria is divided in two species groups, onychia and hirsti, according to morphological and host preference differences. In addition, two new species of Chyzeria are described from specimens parasitising paropsine beetles (Coleoptera: Chrysomelidae): Chyzeria southcotti n. sp. from five species of Paropsini in northern New South Wales, and Chyzeria grandis n. sp. from Paropsisterna agricola (Chapuis) in Victoria and Trachymela sp. in Tasmania. The larvae of Chyzeria derricki Southcott, 1982 are reported from Anostostoma australasiae (Gray) (Orthoptera: Stenopelmatidae) in southeast Queensland, and larvae of Chyzeria flindersi Southcott, 1982 are reported from P. agricola from Tasmania. PMID- 25693461 TI - Pigmentation patterns are useful for species identification of third-stage larvae of gnathiids (Crustacea: Isopoda) parasitising coastal elasmobranchs in southern Japan. AB - Previous studies from southern Japan reported larval stages of eight gnathiid isopod species parasitising coastal elasmobranchs. Since gnathiid larvae of these different species closely resembled each other, it was necessary to obtain specimens of free-living adult males for identification to the species level. This was achieved by allowing larvae of the final stage to moult into adult males. From these males, specimens of a species new to science were discovered and described here as Gnathia rufescens n. sp. The main differentiating characteristics of G. rufescens n. sp. are: (i) the apex of pleotelson is oval shaped; (ii) the dorsal sulcus is wide in the posterior part; and (iii) the article 3 of the pylopod is not reduced in the male. Additionally, this paper summarises the specific pigmentation patterns of third-stage larvae of the new species and eight previously described species. Furthermore, host records and host use by the gnathiids were summarised based on data from 158 hosts and over 4,500 gnathiid samples; these are discussed with a focus on host-specificity of the nine gnathiid species studied. PMID- 25693462 TI - Four new species of the genus Diolcogaster Ashmead, 1900 (Hymenoptera: Braconidae: Microgastrinae) from South East Asia with a key to the Indian species. AB - Four new species of the genus Diolcogaster Ashmead, 1900 (Hymenoptera: Braconidae: Microgastrinae) are described and illustrated: Diolcogaster andamanensis n. sp. from the Andaman Islands, and D. duocolor n. sp., D. longistria n. sp. and D. solitarium n. sp. from mainland India. The solitary larval parasitoid D. solitarium was reared from Gatesclarkeana sp. (Lepidoptera: Tortricidae). A new combination, Diolcogaster tomentosae (Wilkinson, 1930) n. comb., is proposed for the Indian species Protomicroplitis tomentosae (Wilkinson, 1930) along with its redescription and documentation of the gregarious cocoons associated with the pyralid (Epipaschiinae) host feeding on Terminalia cattappa L. PMID- 25693463 TI - A new species of Isospora Schneider, 1881 (Apicomplexa: Eimeriidae) infecting the intestine of the Mediterranean house gecko Hemidactylus turcicus Linnaeus (Reptilia: Gekkonidae). AB - A new species of Isospora Schneider, 1881 was discovered in the Mediterranean house gecko, Hemidactylus turcicus (Linnaeus) in Saudi Arabia. Both exogenous (sporulated oocysts) and endogenous developmental stages (meronts, gamonts) were studied and measured. Sporulated oocysts are spheroidal to slightly subspheroidal, 17-22 (18) um wide, with a smooth, bi-layered oocyst wall; micropyle, polar granule and oocyst residuum are all absent. Sporocysts are ovoidal, 9-11 * 6-8 (10 * 7) um, with both Stieda and sub-Stieda bodies, a dispersed granular sporocyst residuum, and four sporozoites. Endogenous stages develop extranuclearly in the cytoplasm of epithelial cells of the small intestine. Early uninucleate meronts are spheroidal, c.3-5 (4) um wide. Multinucleated meronts are subspheroidal, 11-15 * 9-12 (13 * 10) um, but mature meront and merozoites were not seen. Mature microgamonts, with up to 60 microgametes, are spheroidal, 11-15 (13) um; macrogamonts are subspheroidal, with a prominent central nucleus, and measured 11-14 * 7-10 (12 * 8) um. PMID- 25693465 TI - The AJT report. PMID- 25693464 TI - Electronic structure calculations of ESR parameters of melanin units. AB - Melanins represent an important class of natural pigments present in plants and animals that are currently considered to be promising materials for applications in optic and electronic devices. Despite their interesting properties, some of the basic features of melanins are not satisfactorily understood, including the origin of their intrinsic paramagnetism. A number of experiments have been performed to investigate the electron spin resonance (ESR) response of melanin derivatives, but until now, there has been no consensus regarding the real structure of the paramagnetic centers involved. In this work, we have employed electronic structure calculations to evaluate the ESR parameters of distinct melanin monomers and dimers in order to identify the possible structures associated with unpaired spins in this biopolymer. The g-factors and hyperfine constants of the cationic, anionic and radicalar structures were investigated. The results confirm the existence of at least two distinct paramagnetic centers in melanin structure, identifying the chemical species associated with them and their roles in electrical conductivity. PMID- 25693467 TI - Fee-for-value and wRVU-based physician productivity-an emerging paradox. PMID- 25693468 TI - Share 35: a liver in time saves lives? PMID- 25693469 TI - Firmly tilting the balance of clinical transplant immunity toward tolerance. PMID- 25693470 TI - Rotavirus in organ transplantation: drug-virus-host interactions. AB - Although rotavirus is usually recognized as the most common etiology of diarrhea in young children, it can in fact cause severe diseases in organ transplantation recipients irrespective of pediatric or adult patients. This comprehensive literature analysis revealed 200 cases of rotavirus infection with 8 related deaths in the setting of organ transplantation been recorded. Based on published cohort studies, an average incidence of 3% (187 infections out of 6176 organ recipients) was estimated. Rotavirus infection often causes severe gastroenteritis complications and occasionally contributes to acute cellular rejection in these patients. Immunosuppressive agents, universally used after organ transplantation to prevent organ rejection, conceivably play an important role in such a severe pathogenesis. Interestingly, rotavirus can in turn affect the absorption and metabolism of particular immunosuppressive medications via several distinct mechanisms. Even though rotaviral enteritis is self-limiting in general, infected transplantation patients are usually treated with intensive care, rehydration and replacement of nutrition, as well as applying preventive strategies. This article aims to properly assess the clinical impact of rotavirus infection in the setting of organ transplantation and to disseminate the interactions among the virus, host and immunosuppressive medications. PMID- 25693471 TI - The putative role of mast cells in lung transplantation. AB - Mast cells (MCs) were primarily recognized as effector cells of allergy. These cells are acting predominantly at the interface between the host and the external environment, such as skin, gastrointestinal and the respiratory tract. Only recently, MCs have gained increased recognition as cells of functional plasticity with immune-regulatory properties that influence both the innate and the adaptive immune response in inflammatory disorders, cancer and transplantation. Through the secretion of both proinflammatory and antiinflammatory mediators, MCs can either ameliorate or deteriorate the course and outcome in lung transplantation. Recent research from other models recognized the immune-protective activity of MCs including its role as an important source of IL-10 and TGF-beta for the modulation of alloreactive T cell responses or assistance in Treg activity. This paper summarizes the current understanding of MCs in lung transplantation and discusses MC-mediated immune-mechanisms by which the outcome of the engrafted organ is modulated. PMID- 25693472 TI - Compensating the transplant professional: time for a model change. AB - Compensation models for physicians are currently based primarily on the work relative value unit (wRVU) that rewards productivity by work volume. The value based payment structure soon to be ushered in by the Centers for Medicare and Medicaid Services rewards clinical quality and outcomes. This has prompted changes in wRVU value for certain services that will result in reduced payment for specialty procedures such as transplantation. To maintain a stable and competent workforce and achieve alignment between clinical activity, growth imperatives, and cost effectiveness, compensation of transplant physicians must evolve toward a matrix of measures beyond the procedure-based activity. This personal viewpoint proposes a redesign of transplant physician compensation plans to include the "virtual RVU" to recognize and reward meaningful clinical integration defined as hospital-physician commitment to specified and measurable metrics for current non-RVU-producing activities. Transplantation has been a leader in public outcomes reporting and is well suited to meet the challenges ahead that can only be overcome with a tight collaboration and alignment between surgeons, other physicians, support staff, and their respective institution and leadership. PMID- 25693473 TI - Alginate encapsulant incorporating CXCL12 supports long-term allo- and xenoislet transplantation without systemic immune suppression. AB - Islet transplantation represents a potentially curative approach for individuals with Type I Diabetes. The requirement for systemic immune suppression to control immune-mediated rejection of transplanted islets and the limited human islet supply represent significant roadblocks to progress for this approach. Islet microencapsulation in alginate offers limited protection in the absence of systemic immunosuppression, but does not support long-term islet survival. The chemokine, CXCL12, can repel effector T cells while recruiting immune-suppressive regulatory T cells (Tregs) to an anatomic site while providing a prosurvival signal for beta-cells. We proposed that coating or encapsulating donor islets with CXCL12 would induce local immune-isolation and protect and support the function of an allo- or xenograft without systemic immune suppression. This study investigated the effect of alginate microcapsules incorporating CXCL12 on islet function. Islet transplantation was performed in murine models of insulin dependent diabetes. Coating of islets with CXCL12 or microencapsulation of islets with alginate incorporating the chemokine, resulted in long-term allo- and xenoislet survival and function, as well as a selective increase in intragraft Tregs. These data support the use of CXCL12 as a coating or a component of an alginate encapsulant to induce sustained local immune-isolation for allo- or xenoislet transplantation without systemic immunosuppression. PMID- 25693474 TI - Early changes in liver distribution following implementation of Share 35. AB - In June 2013, a change to the liver waitlist priority algorithm was implemented. Under Share 35, regional candidates with MELD >= 35 receive higher priority than local candidates with MELD < 35. We compared liver distribution and mortality in the first 12 months of Share 35 to an equivalent time period before. Under Share 35, new listings with MELD >= 35 increased slightly from 752 (9.2% of listings) to 820 (9.7%, p = 0.3), but the proportion of deceased-donor liver transplants (DDLTs) allocated to recipients with MELD >= 35 increased from 23.1% to 30.1% (p < 0.001). The proportion of regional shares increased from 18.9% to 30.4% (p < 0.001). Sharing of exports was less clustered among a handful of centers (Gini coefficient decreased from 0.49 to 0.34), but there was no evidence of change in CIT (p = 0.8). Total adult DDLT volume increased from 4133 to 4369, and adjusted odds of discard decreased by 14% (p = 0.03). Waitlist mortality decreased by 30% among patients with baseline MELD > 30 (SHR = 0.70, p < 0.001) with no change for patients with lower baseline MELD (p = 0.9). Posttransplant length-of-stay (p = 0.2) and posttransplant mortality (p = 0.9) remained unchanged. In the first 12 months, Share 35 was associated with more transplants, fewer discards, and lower waitlist mortality, but not at the expense of CIT or early posttransplant outcomes. PMID- 25693475 TI - Chimerism, graft survival, and withdrawal of immunosuppressive drugs in HLA matched and mismatched patients after living donor kidney and hematopoietic cell transplantation. AB - Thirty-eight HLA matched and mismatched patients given combined living donor kidney and enriched CD34(+) hematopoietic cell transplants were enrolled in tolerance protocols using posttransplant conditioning with total lymphoid irradiation and anti-thymocyte globulin. Persistent chimerism for at least 6 months was associated with successful complete withdrawal of immunosuppressive drugs in 16 of 22 matched patients without rejection episodes or kidney disease recurrence with up to 5 years follow up thereafter. One patient is in the midst of withdrawal and five are on maintenance drugs. Persistent mixed chimerism was achieved in some haplotype matched patients for at least 12 months by increasing the dose of T cells and CD34(+) cells infused as compared to matched recipients in a dose escalation study. Success of drug withdrawal in chimeric mismatched patients remains to be determined. None of the 38 patients had kidney graft loss or graft versus host disease with up to 14 years of observation. In conclusion, complete immunosuppressive drug withdrawal could be achieved thus far with the tolerance induction regimen in HLA matched patients with uniform long-term graft survival in all patients. PMID- 25693477 TI - An unusual case of ischemic nephropathy. PMID- 25693478 TI - Effect of HCV, HIV and coinfection in kidney transplant recipients: mate kidney analyses: the role of diabetes. PMID- 25693479 TI - Response: effect of HCV monoinfection and HIV coinfection in kidney transplant recipients-the role of diabetes. PMID- 25693480 TI - Effect of HCV/HIV coinfection versus HCV monoinfection in kidney transplant recipients. PMID- 25693482 TI - [Risk stratification of sudden cardiac death in dilated cardiomyopathy. Programmed ventricular stimulation]. AB - There is a strong correlation between clinical presentation and results of the electrophysiological study (EPS) in patients with dilated cardiomyopathy. Patients with spontaneous ventricular tachycardia (VT) or syncope often have inducible VT in contrast to patients who have no history of arrhythmias or syncope. Therefore, the EPS is rather not useful for risk stratification but for planning of an adjuvant antiarrhythmic or ablation therapy. This is also true for patients with frequent ventricular extrasystole or nonsustained VT in whom VT may aggravate heart failure. An EP study may still be useful to differentiate between syncope of bradycardic or tachycardic origin. PMID- 25693483 TI - [Microvolt T-wave alternans. Ischemic vs. nonischemic dilated cardiomyopathy]. AB - The use of implantable cardioverter defibrillators (ICD) for primary preventive therapy of sudden arrhythmogenic death has become a mainstay in selected patients with systolic congestive heart failure, particularly in the setting of ischemic and nonischemic cardiomyopathy (Moss et al., N Engl J Med 346:877-883, 2002; Bardy et al., N Engl J Med 352:225-237, 2005). However, more accurate identification of high-risk patients is desirable in order to avoid unnecessary ICD implants. Since currently available risk stratification methods have limited predictive accuracy, development of new techniques is important in order to noninvasively assess arrhythmogenic risk in patients prone to sudden death.Microvolt level T-wave alternans (mTWA) has recently been proposed to assess abnormalities in ventricular repolarization favoring the occurrence of reentrant arrhythmias (Adam et al., J Electrocardiol 17:209-218, 1984; Pastore et al., Circulation 99:1385-1394, 1999). In 1994, a preliminary clinical study by Rosenbaum et al. convincingly demonstrated that mTWA is closely related to arrhythmia induction in the electrophysiology laboratory as well as to the occurrence of spontaneous ventricular tachyarrhythmias during follow-up (Rosenbaum et al., N Engl J Med 330:235-241,1994). More recently, a number of clinical studies have examined its clinical applicability in ischemic and nonischemic cardiomyopathy. PMID- 25693486 TI - An evaluation of the residual toxicity and chemistry of a sodium hydroxide-based ballast water treatment system for freshwater ships. AB - Nonnative organisms in the ballast water of freshwater ships must be killed to prevent the spread of invasive species. The ideal ballast water treatment system (BWTS) would kill 100% of ballast water organisms with minimal residual toxicity to organisms in receiving waters. In the present study, the residual toxicity and chemistry of a BWTS was evaluated. Sodium hydroxide was added to elevate pH to >11.5 to kill ballast water organisms, then reduced to pH <9 by sparging with wet scrubbed diesel exhaust (the source of CO2 ). Cladocerans (Ceriodaphnia dubia), amphipods (Hyalella azteca), and fathead minnows (Pimephales promelas) were exposed for 2 d to BWTS water under an air atmosphere (pH drifted to >=9) or a 2.5% CO2 atmosphere (pH 7.5-8.2), then transferred to control water for 5 d to assess potential delayed toxicity. Chemical concentrations in the BWTS water met vessel discharge guidelines with the exception of concentrations of copper. There was little to no residual toxicity to cladocerans or fish, but the BWTS water was toxic to amphipods. Maintaining a neutral pH and diluting BWTS water by 50% eliminated toxicity to the amphipods. The toxicity of BWTS water would likely be minimal because of rapid dilution in the receiving water, with subsurface release likely preventing pH rise. This BWTS has the potential to become a viable method for treating ballast water released into freshwater systems. PMID- 25693485 TI - Multidrug-resistant tuberculosis in Europe, 2010-2011. AB - Drug-resistant Mycobacterium tuberculosis is challenging elimination of tuberculosis (TB). We evaluated risk factors for TB and levels of second-line drug resistance in M. tuberculosis in patients in Europe with multidrug-resistant (MDR) TB. A total of 380 patients with MDR TB and 376 patients with non-MDR TB were enrolled at 23 centers in 16 countries in Europe during 2010-2011. A total of 52.4% of MDR TB patients had never been treated for TB, which suggests primary transmission of MDR M. tuberculosis. At initiation of treatment for MDR TB, 59.7% of M. tuberculosis strains tested were resistant to pyrazinamide, 51.1% were resistant to >=1 second-line drug, 26.6% were resistant to second-line injectable drugs, 17.6% were resistant to fluoroquinolones, and 6.8% were extensively drug resistant. Previous treatment for TB was the strongest risk factor for MDR TB. High levels of primary transmission and advanced resistance to second-line drugs characterize MDR TB cases in Europe. PMID- 25693487 TI - Mixed Effects Modeling Using Stochastic Differential Equations: Illustrated by Pharmacokinetic Data of Nicotinic Acid in Obese Zucker Rats. AB - Inclusion of stochastic differential equations in mixed effects models provides means to quantify and distinguish three sources of variability in data. In addition to the two commonly encountered sources, measurement error and interindividual variability, we also consider uncertainty in the dynamical model itself. To this end, we extend the ordinary differential equation setting used in nonlinear mixed effects models to include stochastic differential equations. The approximate population likelihood is derived using the first-order conditional estimation with interaction method and extended Kalman filtering. To illustrate the application of the stochastic differential mixed effects model, two pharmacokinetic models are considered. First, we use a stochastic one compartmental model with first-order input and nonlinear elimination to generate synthetic data in a simulated study. We show that by using the proposed method, the three sources of variability can be successfully separated. If the stochastic part is neglected, the parameter estimates become biased, and the measurement error variance is significantly overestimated. Second, we consider an extension to a stochastic pharmacokinetic model in a preclinical study of nicotinic acid kinetics in obese Zucker rats. The parameter estimates are compared between a deterministic and a stochastic NiAc disposition model, respectively. Discrepancies between model predictions and observations, previously described as measurement noise only, are now separated into a comparatively lower level of measurement noise and a significant uncertainty in model dynamics. These examples demonstrate that stochastic differential mixed effects models are useful tools for identifying incomplete or inaccurate model dynamics and for reducing potential bias in parameter estimates due to such model deficiencies. PMID- 25693488 TI - Emerging Insights for Translational Pharmacokinetic and Pharmacokinetic Pharmacodynamic Studies: Towards Prediction of Nose-to-Brain Transport in Humans. AB - To investigate the potential added value of intranasal drug administration, preclinical studies to date have typically used the area under the curve (AUC) in brain tissue or cerebrospinal fluid (CSF) compared to plasma following intranasal and intravenous administration to calculate measures of extent like drug targeting efficiencies (%DTE) and nose-to-brain transport percentages (%DTP). However, CSF does not necessarily provide direct information on the target site concentrations, while total brain concentrations are not specific to that end either as non-specific binding is not explicitly considered. Moreover, to predict nose-to-brain transport in humans, the use of descriptive analysis of preclinical data does not suffice. Therefore, nose-to-brain research should be performed translationally and focus on preclinical studies to obtain specific information on absorption from the nose, and distinguish between the different transport routes to the brain (absorption directly from the nose to the brain, absorption from the nose into the systemic circulation, and distribution between the systemic circulation and the brain), in terms of extent as well as rate. This can be accomplished by the use of unbound concentrations obtained from plasma and brain, with subsequent advanced mathematical modeling. To that end, brain extracellular fluid (ECF) is a preferred sampling site as it represents most closely the site of action for many targets. Furthermore, differences in nose characteristics between preclinical species and humans should be considered. Finally, pharmacodynamic measurements that can be obtained in both animals and humans should be included to further improve the prediction of the pharmacokinetic-pharmacodynamic relationship of intranasally administered CNS drugs in humans. PMID- 25693489 TI - Comparison of Nonlinear Mixed Effects Models and Noncompartmental Approaches in Detecting Pharmacogenetic Covariates. AB - Genetic data is now collected in many clinical trials, especially in population pharmacokinetic studies. There is no consensus on methods to test the association between pharmacokinetics and genetic covariates. We performed a simulation study inspired by real clinical trials, using the pharmacokinetics (PK) of a compound under development having a nonlinear bioavailability along with genotypes for 176 single nucleotide polymorphisms (SNPs). Scenarios included 78 subjects extensively sampled (16 observations per subject) to simulate a phase I study, or 384 subjects with the same rich design. Under the alternative hypothesis (H1), six SNPs were drawn randomly to affect the log-clearance under an additive linear model. For each scenario, 200 PK data sets were simulated under the null hypothesis (no gene effect) and H1. We compared 16 combinations of four association tests, a stepwise procedure and three penalised regressions (ridge regression, Lasso, HyperLasso), applied to four pharmacokinetic phenotypes, two observed concentrations, area under the curve estimated by noncompartmental analysis and model-based clearance. The different combinations were compared in terms of true and false positives and probability to detect the genetic effects. In presence of nonlinearity and/or variability in bioavailability, model-based phenotype allowed a higher probability to detect the SNPs than other phenotypes. In a realistic setting with a limited number of subjects, all methods showed a low ability to detect genetic effects. Ridge regression had the best probability to detect SNPs, but also a higher number of false positives. No association test showed a much higher power than the others. PMID- 25693490 TI - Fetal Microchimerism in Cancer Protection and Promotion: Current Understanding in Dogs and the Implications for Human Health. AB - Fetal microchimerism is the co-existence of small numbers of cells from genetically distinct individuals living within a mother's body following pregnancy. During pregnancy, bi-directional exchange of cells occurs resulting in maternal microchimerism and even sibling microchimerism in offspring. The presence of fetal microchimerism has been identified with lower frequency in patients with cancers such as breast and lymphoma and with higher frequency in patients with colon cancer and autoimmune diseases. Microchimeric cells have been identified in healing and healed tissues as well as normal and tumor tissues. This has led to the hypothesis that fetal microchimerism may play a protective role in some cancers and may provoke other cancers or autoimmune disease. The long periods of risk for these diseases make it a challenge to prospectively study this phenomenon in human populations. Dogs get similar cancers as humans, share our homes and environmental exposures, and live compressed life-spans, allowing easier prospective study of disease development. This review describes the current state of understanding of fetal microchimerism in humans and dogs and highlights the similarities of the common cancers mammary carcinoma, lymphoma, and colon cancer between the two species. Study of fetal microchimerism in dogs might hold the key to characterization of the type and function of microchimeric cells and their role in health and disease. Such an understanding could then be applied to preventing and treating disease in humans. PMID- 25693492 TI - Natural allelic diversity in OsDREB1F gene in the Indian wild rice germplasm led to ascertain its association with drought tolerance. AB - KEY MESSAGE: Three coding SNPs and one haplotype identified in the OsDREB1F gene have potential to be associated with drought tolerance in rice. Drought is a serious constraint to rice production worldwide, that can be addressed by deployment of drought tolerant genes. OsDREB1F, one of the most potent drought tolerance transcription activator genes, was re-sequenced for allele mining and association study in a set of 136 wild rice accessions and four cultivated rice. This analysis led to identify 22 SNPs with eight haplotypes based on allelic variations in the accessions used. The nucleotide variation-based neutrality tests suggested that the OsDREB1F gene has been subjected to purifying selection in the studied set of rice germplasm. Six different OsDREB1F protein variants were identified on the basis of translated amino acid residues amongst the orthologues. Five protein variants were truncated due to deletions in coding region and found susceptible to drought stress. Association study revealed that three coding SNPs of this gene were significantly associated with drought tolerance. One OsDREB1F variant in the activation domain of OsDREB1F gene which led to conversion of aspartate amino acid to glutamate was found to be associated with drought tolerance. Three-dimensional homology modeling assisted to understand the functional significance of this identified potential allele for drought tolerance in rice. The natural allelic variants mined in the OsDREB1F gene can be further used in translational genomics for improving the water use efficiency in rice. PMID- 25693493 TI - Molecular characterization of a transcriptionally active Ty1/copia-like retrotransposon in Gossypium. AB - KEY MESSAGE: A transcriptionally active Ty1/copia -like retrotransposon was identified in the genome of Gossypium barbadense. The different heat activation of this element was observed in two tetraploid cotton species. Most retrotransposons from plants are transcriptionally silent, or activated under certain conditions. Only a small portion of elements are transcriptionally active under regular condition. A long terminal repeat (LTR) retrotransposon was isolated from the cultivated Sea Island cotton (H7124) genome during the investigation of the function of a homeodomain leucine zipper gene (HD1) in trichome growth. Insertion of this element in HD1 gene of At sub-genome was related to the trichomeless stem in Gossypium barbadense. The element, named as GBRE-1, had all features of a typical Ty1/copia retrotransposon and possessed high similarity to the members of ONSEN retrotransposon family. It was 4997 bp long, comprising a single 4110 bp open reading frame, which encoded 1369 amino acids including the conserved domains of gag and pol. The expression of GBRE-1 was detected under regular condition in G. barbadense and G. hirsutum, and its expression level was increased under heat-stress condition in G. hirsutum. Besides, its expression pattern was similar to that of the ONSEN retrotransposon. Abundant cis-regulatory motifs related to stress-response and transcriptional regulation were found in the LTR sequence. These results suggested that GBRE-1 was a transcriptionally active retrotransposon in Gossypium. To our knowledge, this is the first report of the isolation of a complete Ty1/copia-type retrotransposon with present-day transcriptional activity in cotton. PMID- 25693494 TI - Involvement of secondary messengers and small organic molecules in auxin perception and signaling. AB - Auxin is a major phytohormone involved in most aspects of plant growth and development. Generally, auxin is perceived by three distinct receptors: TRANSPORT INHIBITOR RESISTANT1-Auxin/INDOLE ACETIC ACID, S-Phase Kinase-Associated Protein 2A and AUXIN-BINDING PROTEIN1. The auxin perception is regulated by a variety of secondary messenger molecules, including nitric oxide, reactive oxygen species, calcium, cyclic GMP, cyclic AMP, inositol triphosphate, diacylglycerol and by physiological pH. In addition, some small organic molecules, including inositol hexakisphosphate, yokonolide B, p-chlorophenoxyisobutyric acid, toyocamycin and terfestatin A, are involved in auxin signaling. In this review, we summarize and discuss the recent progress in understanding the functions of these secondary messengers and small organic molecules, which are now thoroughly demonstrated to be pervasive and important in auxin perception and signal transduction. PMID- 25693496 TI - [Pulmonary manifestations of connective tissue diseases]. AB - Systemic autoimmune diseases are responsible for about 25% of all deaths due to interstitial lung disease; therefore, an early identification of patients with pulmonary manifestation changes the management. Detection, differential diagnostic classification and staging of the pneumological pattern of findings are largely based on high-resolution computed tomography (HR-CT). The main differential diagnostic challenges are interstitial manifestations which present with radiological-histopathological phenotypes of interstitial pneumonia. The most common form of interstitial pulmonary reaction form of connective tissue diseases is the nonspecific interstitial pneumonia (NSIP) pattern. In rheumatoid arthritis, a usual interstitial pneumonia (UIP) pattern is dominant. Uncharacteristic reactions of airways and pleura can be the leading symptom or present as accompanying findings. A serious complication is pulmonary hypertension. Drug-induced lung lesions can present with similar HR-CT morphology as connective tissue diseases and can only be differentiated in the temporal and clinical context. PMID- 25693495 TI - Advances in the understanding of cuticular waxes in Arabidopsis thaliana and crop species. AB - The aerial parts of plants are covered with a cuticle, a hydrophobic layer consisting of cutin polyester and cuticular waxes that protects them from various environmental stresses. Cuticular waxes mainly comprise very long chain fatty acids and their derivatives such as aldehydes, alkanes, secondary alcohols, ketones, primary alcohols, and wax esters that are also important raw materials for the production of lubricants, adhesives, cosmetics, and biofuels. The major function of cuticular waxes is to control non-stomatal water loss and gas exchange. In recent years, the in planta roles of many genes involved in cuticular wax biosynthesis have been characterized not only from model organisms like Arabidopsis thaliana and saltwater cress (Eutrema salsugineum), but also crop plants including maize, rice, wheat, tomato, petunia, Medicago sativa, Medicago truncatula, rapeseed, and Camelina sativa through genetic, biochemical, molecular, genomic, and cell biological approaches. In this review, we discuss recent advances in the understanding of the biological functions of genes involved in cuticular wax biosynthesis, transport, and regulation of wax deposition from Arabidopsis and crop species, provide information on cuticular wax amounts and composition in various organs of nine representative plant species, and suggest the important issues that need to be investigated in this field of study. PMID- 25693497 TI - Accuracy of single-tooth restorations based on intraoral digital and conventional impressions in patients. AB - OBJECTIVES: The purpose of this clinical study was to compare the marginal fit of dental crowns based on three different intraoral digital and one conventional impression methods. METHODS: Forty-nine teeth of altogether 24 patients were prepared to be treated with full-coverage restorations. Digital impressions were made using three intraoral scanners: Sirona CEREC AC Omnicam (OCam), Heraeus Cara TRIOS and 3M Lava True Definition (TDef). Furthermore, a gypsum model based on a conventional impression (EXA'lence, GC, Tokyo, Japan) was scanned with a standard laboratory scanner (3Shape D700). Based on the dataset obtained, four zirconia copings per tooth were produced. The marginal fit of the copings in the patient's mouth was assessed employing a replica technique. RESULTS: Overall, seven measurement copings did not fit and, therefore, could not be assessed. The marginal gap was 88 MUm (68-136 MUm) [median/interquartile range] for the TDef, 112 MUm (94-149 MUm) for the Cara TRIOS, 113 MUm (81-157 MUm) for the laboratory scanner and 149 MUm (114-218 MUm) for the OCam. There was a statistically significant difference between the OCam and the other groups (p < 0.05). CONCLUSION: Within the limitations of this study, it can be concluded that zirconia copings based on intraoral scans and a laboratory scans of a conventional model are comparable to one another with regard to their marginal fit. CLINICAL RELEVANCE: Regarding the results of this study, the digital intraoral impression can be considered as an alternative to a conventional impression with a consecutive digital workflow when the finish line is clearly visible and it is possible to keep it dry. PMID- 25693498 TI - Stress enhances the sensitivity of Salmonella enterica serovar Typhimurium to bacteriocins. AB - AIMS: The aim of this study was to evaluate the potential application of bacteriocins against Gram-negative bacteria when associated with others food preservation methods. METHODS AND RESULTS: Salmonella was subjected to heat, cold, acid and chemical (with ethylenediaminetetracetate and trisodium phosphate) stresses. Then, the cells were recovered and subjected to treatment with bacteriocins (500 AU ml(-1) ) for 6 h. Heat and cold stress were those that promoted more sensitization to bactericidal activity of nisin. Under the same conditions, bovicin HC5 acted more rapidly than nisin reducing the number of viable cells to undetectable levels after 20 min of treatment. Similar results with use of nisin only were observed after 6 h of treatment. CONCLUSIONS: Stress conditions used in food industry, such as temperature and pH, and use of chelating agents or membrane disruptors, sensitized Salmonella Typhimurium cells to bacteriocins produced by lactic acid bacteria, such as nisin and bovicin HC5. SIGNIFICANCE AND IMPACT OF THE STUDY: Food preservation methods sensitized Gram negative bacteria to bacteriocins activity, which demonstrate the potential of nisin and bovicin HC5 to inhibit the growth of Salmonella. PMID- 25693499 TI - Target-based whole-cell screening by 1H NMR spectroscopy. AB - An NMR-based approach marries the two traditional screening technologies (phenotypic and target-based screening) to find compounds inhibiting a specific enzymatic reaction in bacterial cells. Building on a previous study in which it was demonstrated that hydrolytic decomposition of meropenem in living Escherichia coli cells carrying New Delhi metallo-beta-lactamase subclass 1 (NDM-1) can be monitored in real time by NMR spectroscopy, we designed a cell-based NMR screening platform. A strong NDM-1 inhibitor was identified with cellular IC50 of 0.51 MUM, which is over 300-fold more potent than captopril, a known NDM-1 inhibitor. This new screening approach has great potential to be applied to targets in other cell types, such as mammalian cells, and to targets that are only stable or functionally competent in the cellular environment. PMID- 25693500 TI - Cycloartane Glycosides from the Roots of Cimicifuga foetida with Wnt Signaling Pathway Inhibitory Activity. AB - Four new 9,19-cycloartane triterpenoids, cimilactone E (1), cimilactone F (2), 2' O-(E)-butenoyl-23-epi-26-deoxyactein (3), and 2',12beta-O-diacetylcimiracemonol-3 O-beta-d-xylopyranoside (4), together with four known constituents (5-8) were isolated from the roots of Cimicifuga foetida. The new structures were elucidated by extensive spectroscopic analysis. In addition, compounds 7 and 8 showed significant Wnt signaling pathway inhibitory activity, with IC50 values of 3.33 and 13.34 MUM, respectively, using the luciferase reporter gene assay. PMID- 25693501 TI - The role of the detergent micelle in preserving the structure of membrane proteins in the gas phase. AB - Despite the growing importance of the mass spectrometry of membrane proteins, it is not known how their transfer from solution into vacuum affects their stability and structure. To address this we have carried out a systematic investigation of ten membrane proteins solubilized in different detergents and used mass spectrometry to gain physicochemical insight into the mechanism of their ionization and desolvation. We show that the chemical properties of the detergents mediate the charge state, both during ionization and detergent removal. Using ion mobility mass spectrometry, we monitor the conformations of membrane proteins and show how the surface charge density dictates the stability of folded states. We conclude that the gas-phase stability of membrane proteins is increased when a greater proportion of their surface is lipophilic and is consequently protected by the physical presence of the micelle. PMID- 25693502 TI - Fabrication of condensate microdrop self-propelling porous films of cerium oxide nanoparticles on copper surfaces. AB - Condensate microdrop self-propelling (CMDSP) surfaces have attracted intensive interest. However, it is still challenging to form metal-based CMDSP surfaces. We design and fabricate a type of copper-based CMDSP porous nanoparticle film. An electrodeposition method based on control over the preferential crystal growth of isotropic nanoparticles and synergistic utilization of tiny hydrogen bubbles as pore-making templates is adopted for the in situ growth of cerium oxide porous nanoparticle films on copper surfaces. After characterizing their microscopic morphology, crystal structure and surface chemistry, we explore their CMDSP properties. The nanostructure can realize the efficient ejection of condensate microdrops with sizes below 50 MUm. PMID- 25693504 TI - The temporal relationship between change in symptoms of prolonged grief and posttraumatic stress following old age spousal bereavement. AB - BACKGROUND: High levels of prolonged grief symptoms (PGS) and posttraumatic stress symptoms (PTS) are relatively common following bereavement. The two types of bereavement complications share some but not all of the same features. Little research has studied which of the two precedes the other following the death of a loved one. The purpose of this study was to examine the temporal relationship between change in PGS and PTS during the first 4 years following old age spousal loss. METHODS: Participants were 237 Danes (40% male; mean age = 73 years, SD = 4.4; range 65-81) who during the year of 2006 lost their spouse. Participants completed self-report questionnaires at 6 months (n = 237), 13 months (n = 198), 18 months (n = 192), and 48 months (n = 213) post loss. Main outcome measures were Inventory of Complicated Grief-Revised and the Harvard Trauma Questionnaire. RESULTS: Lower level mediation analyses were performed. Results indicated that PGS mediated 83% of the relationship between time and PTS, whereas PTS only mediated 17% of the relationship between time and PGS. These results suggest that changes in PGS mediated changes in PTS following spousal bereavement to a greater extent than vice versa. CONCLUSIONS: The findings in the present study indicate that changes in PGS may precede and potentially directly impact changes in PTS following bereavement. This tentative conclusion points to the potential value of targeting PGS in psychological interventions at an early point in the long-term perspective following old age spousal bereavement. PMID- 25693505 TI - Energetic, structural and electronic properties of metal vacancies in strained AlN/GaN interfaces. AB - AlN/GaN heterostructures have been studied using density-functional pseudopotential calculations yielding the formation energies of metal vacancies under the influence of local interfacial strains, the associated charge distribution and the energies of vacancy-induced electronic states. Interfaces are built normal to the polar <0 0 0 1> direction of the wurtzite structure by joining two single crystals of AlN and GaN that are a few atomic layers thick; thus, periodic boundary conditions generate two distinct heterophase interfaces. We show that the formation energy of vacancies is a function of their distance from the interfaces: the vacancy-interface interaction is found repulsive or attractive, depending on the type of the interface. When the interaction is attractive, the vacancy formation energy decreases with increasing the associated electric charge, and hence the equilibrium vacancy concentration at the interface is greater. This finding can reveal the well-known morphological differences existing between the two types of investigated interfaces. Moreover, we found that the electric charge is strongly localized around the Ga vacancy, while in the case of Al vacancies is almost uniformly distributed throughout the AlN/GaN heterostructure. Crucially, for the applications of heterostructures, metal vacancies introduce deep states in the calculated bandgap at energy levels from 0.5 to 1 eV above the valence band maximum (VBM). It is, therefore, predicted that vacancies could initiate 'green luminescence' i.e. light emission in the energy range of 2.5 eV stemming from electronic transitions between these extra levels, and the conduction band, or energy levels, due to shallow donors. PMID- 25693506 TI - Inorganic nanovehicle for potential targeted drug delivery to tumor cells, tumor optical imaging. AB - In this work, an inorganic multifunctional nanovehicle was tailored as a carrier to deliver anticancer drug for tumor optical imaging and therapy. The nanovehicle could be used as a dually targeted drug nanovehicle by bonded magnetical (passive) and folic acid (active) targeting capabilities. In addition, it was developed using rhodamine 6G (R6G) as a fluorescence reagent, and an alpha zirconium phosphate nanoplatform (Zr(HPO4)2.H2O, abbreviated as alpha-ZrP) as the anticancer drug nanovehicle. The novel drug-release system was designed and fabricated by intercalation of alpha-ZrP with magnetic Fe3O4 nanoparticles and anticancer drug 5-fluorouracil (5-FU), followed by reacting with a folate acid chitosan-rhodamine6G (FA-CHI-R6G) complex, and then alpha-ZrP intercalated with Fe3O4 nanoparticles and 5-fluorouracil (5-FU) was successfully encapsulated into chitosan (CHI). The resultant multifunctional drug delivery system was characterized by scanning electron microscopy, X-ray diffraction, energy dispersive X-ray analysis, photoluminescence spectra, magnetometry, fluorescence microscopy imaging studies and other characterization methods. Simultaneously, the drug release in vitro on the obtained nanocomposites that exhibited a sustained release behavior was carried out in buffer solution at 37 degrees C, which demonstrated clearly that the nanocomposites shown a sustained release behavior. Meanwhile, cell culture experiments also indicated that the drug release system had the potential to be used as an dually targeted drug nanovehicle into the tumor cells. PMID- 25693508 TI - "Missing perikymata"--fact or fiction? A study on chimpanzee (Pan troglodytes verus) canines. AB - Recently, a lower than expected number of perikymata between repetitive furrow type hypoplastic defects has been reported in chimpanzee canines from the Fongoli site, Senegal (Skinner and Pruetz: Am J Phys Anthropol 149 (2012) 468-482). Based on an observation in a localized enamel fracture surface of a canine of a chimpanzee from the Tai Forest (Ivory Coast), these authors inferred that a nonemergence of striae of Retzius could be the cause for the "missing perikymata" phenomenon in the Fongoli chimpanzees. To check this inference, we analyzed the structure of outer enamel in three chimpanzee canines. The teeth were studied using light-microscopic and scanning-electron microscopic techniques. Our analysis of the specimen upon which Skinner and Pruetz (Am J Phys Anthropol 149 (2012) 468-482) had made their original observation does not support their hypothesis. We demonstrate that the enamel morphology described by them is not caused by a nonemergence of striae of Retzius but can be attributed to structural variations in outer enamel that result in a differential fracture behavior. Although rejecting the presumed existence of nonemergent striae of Retzius, our study provided evidence that, in furrow-type hypoplastic defects, a pronounced tapering of Retzius increments can occur, with the striae of Retzius forming acute angles with the outer enamel surface. We suggest that in such cases the outcrop of some striae of Retzius is essentially unobservable at the enamel surface, causing too low perikymata counts. The pronounced tapering of Retzius increments in outer enamel presumably reflects a mild to moderate disturbance of the function of late secretory ameloblasts. PMID- 25693509 TI - A macro perspective for client-centred practice in curricula: Critique and teaching methods. AB - BACKGROUND: Client-centred practice is often eclipsed by social, economic, and political inequities. Ignoring these realities obstructs clients' goal attainment. OBJECTIVES: The author advocates for the integration of a macro perspective inclusive of participation barriers and supports in occupational therapy curricula and seeks to motivate educators to adopt teaching approaches that develop students' abilities to address the complexities of client-centred practice. METHOD: This article integrates a critical analysis of the literature on client-centred practice with reflexivity on disability studies and autoethnography. FINDINGS: Educational standards require students to learn about the social, economic, and political contexts that impact on client-centred practice and the need for advocacy to enable participation. Theoretical support of a macro perspective for client-centred practice is strongly evident in the literature. Information on methods for teaching students how to actualize these concepts in practice is scant. Thus, strategies to inform the integration of a macro perspective into curricula and concrete activities to develop students' competencies for empowered client-centred practice are required. CONCLUSION: Educators have an ethical responsibility to critique their pedagogy to determine whether they are adequately preparing students for client-centred practice. The focus must move from teaching a micro perspective of client-centred practice to a macro perspective that enables occupational justice and empowerment. PMID- 25693507 TI - Molecular epidemiology of noroviruses associated with sporadic gastroenteritis in children in Novosibirsk, Russia, 2003-2012. AB - Noroviruses (NoVs) are an important cause of acute gastroenteritis worldwide. To monitor the molecular epidemiology of NoVs genogroup II (GII) in Novosibirsk, Russia, a total of 10,198 stool samples from young children hospitalized with acute gastroenteritis and two asymptomatic comparison groups were collected from 2003 to 2012. All samples were screened for the presence of NoV GII, rotavirus, and astrovirus by RT-PCR. The prevalence of NoV in gastroenteritis cases was 13.1%, varying from 7.1% to 21.3% in different seasons. Rotavirus and/or astrovirus were detectable in 25% of the NoV-positive samples. NoV was detected throughout the year with a seasonal increase during winter months. Based on sequence analysis of regions D and/or C within the VP1 gene, 892 identified NoV strains were divided into nine genotypes-GII.3 (51%), GII.4 (44%), GII.6 (2%), as well as GII.1, GII.2, GII.5, GII.7, GII.16, and GII.21 (totally, 3%). The prevalence of NoV in the comparison groups was considerably lower (~2.5%); only GII.4 (n = 6), GII.21 (n = 2) and GII.1 (n = 1) genotypes were revealed. Based on phylogenetic analysis of the ORF1/ORF2 junction region sequences, GII.P21/GII.3 recombinant and GII.P4/GII.4 were prevalent genotypes (totally, 93%) and their ratio changed every season. The median age of children with NoV infection was 6.6 months (range, <1-35 months), but it was different depending on NoV genotype. Children infected with the NoV GII.3 were younger (median 6.2 months) than GII.4 positive patients (median 9.1 months). This is the first long-term systematic study of NoV molecular epidemiology in Russia. PMID- 25693510 TI - Mesenchymal Wnt/beta-Catenin Signaling Controls Epithelial Stem Cell Homeostasis in Teeth by Inhibiting the Antiapoptotic Effect of Fgf10. AB - Continuous growth of rodent incisors relies on epithelial stem cells (SCs) located in the SC niche called labial cervical loop (LaCL). Here, we found a population of apoptotic cells residing in a specific location of the LaCL in mouse incisor. Activated Caspase 3 and Caspase 9, expressed in this location colocalized in part with Lgr5 in putative SCs. The addition of Caspase inhibitors to incisors ex vivo resulted in concentration dependent thickening of LaCL. To examine the role of Wnt signaling in regulation of apoptosis, we exposed the LaCL of postnatal day 2 (P2) mouse incisor ex vivo to BIO, a known activator of Wnt/beta-catenin signaling. This resulted in marked thinning of LaCL as well as enhanced apoptosis. We found that Wnt/beta-catenin signaling was intensely induced by BIO in the mesenchyme surrounding the LaCL, but, unexpectedly, no beta catenin activity was detected in the LaCL epithelium either before or after BIO treatment. We discovered that the expression of Fgf10, an essential growth factor for incisor epithelial SCs, was dramatically downregulated in the mesenchyme around BIO-treated LaCL, and that exogenous Fgf10 could rescue the thinning of the LaCL caused by BIO. We conclude that the homeostasis of the epithelial SC population in the mouse incisor depends on a proper rate of apoptosis and that this apoptosis is controlled by signals from the mesenchyme surrounding the LaCL. Fgf10 is a key mesenchymal signal limiting apoptosis of incisor epithelial SCs and its expression is negatively regulated by Wnt/beta-catenin. Stem Cells 2015;33:1670-1681. PMID- 25693511 TI - Surgical antibiotic prophylaxis in children: adherence to indication, choice of agent, timing, and duration. AB - PURPOSE: Surgical antibiotic prophylaxis (SAP) in children is poorly characterized. We investigated SAP for children undergoing elective surgical procedures. METHODS: We prospectively investigated elective surgical procedures performed in children <18 years, from November 2012 to February 2013, in three tertiary-care children's hospitals in Italy. Data were derived from clinical records. Antibiotics were considered prophylactic if given by parenteral route during the same day of the procedure. SAP indication was defined according to international guidelines. Whenever SAP was indicated, it was defined appropriate if antibiotic choice was different from third-/fourth-generation cephalosporins, carbapenems, or piperacillin/tazobactam; timing of first dose was within 60 min before incision; and duration of administration was <=24 h. Multivariable logistic regression model was used to assess independent predictors of adherence to SAP administration, for procedures with SAP indication performed in all hospitals. RESULTS: Data on 765 procedures were collected. SAP was administered in 81% of 206 procedures with SAP indication and in 18% of 559 procedures with no indication. Type of procedure and hospital were significantly associated with adherence of administration to SAP indication. In the 206 procedures where SAP was indicated, overall appropriateness of antibiotic choice, timing, and duration was 8%. CONCLUSIONS: The SAP rate observed in procedures with SAP indication and the appropriateness of drug choice, timing, and duration are reasons of concern. Quality improvement interventions for implementing SAP recommendations in children are strongly needed, and their impact should be evaluated at hospital level. PMID- 25693512 TI - Nonradiative Auger recombination in semiconductor nanocrystals. AB - We calculate the rate of nonradiative Auger recombination in negatively charged CdSe nanocrystals (NCs). The rate is nonmonotonic, strongly oscillating with NC size, and sensitive to the NC surface. The oscillations result in nonexponential decay of carriers in NC ensembles. Using a standard single-exponential approximation of the decay dynamics, we determine the apparent size dependence of the Auger rate in an ensemble and derive CdSe surface parameters consistent with the experimental dependence on size. PMID- 25693513 TI - Optimized distance-dependent atom-pair-based potential DOOP for protein structure prediction. AB - The DOcking decoy-based Optimized Potential (DOOP) energy function for protein structure prediction is based on empirical distance-dependent atom-pair interactions. To optimize the atom-pair interactions, native protein structures are decomposed into polypeptide chain segments that correspond to structural motives involving complete secondary structure elements. They constitute near native ligand-receptor systems (or just pairs). Thus, a total of 8609 ligand receptor systems were prepared from 954 selected proteins. For each of these hypothetical ligand-receptor systems, 1000 evenly sampled docking decoys with 0 10 A interface root-mean-square-deviation (iRMSD) were generated with a method used before for protein-protein docking. A neural network-based optimization method was applied to derive the optimized energy parameters using these decoys so that the energy function mimics the funnel-like energy landscape for the interaction between these hypothetical ligand-receptor systems. Thus, our method hierarchically models the overall funnel-like energy landscape of native protein structures. The resulting energy function was tested on several commonly used decoy sets for native protein structure recognition and compared with other statistical potentials. In combination with a torsion potential term which describes the local conformational preference, the atom-pair-based potential outperforms other reported statistical energy functions in correct ranking of native protein structures for a variety of decoy sets. This is especially the case for the most challenging ROSETTA decoy set, although it does not take into account side chain orientation-dependence explicitly. The DOOP energy function for protein structure prediction, the underlying database of protein structures with hypothetical ligand-receptor systems and their decoys are freely available at http://agknapp.chemie.fu-berlin.de/doop/. PMID- 25693514 TI - Id3 induces an Elk-1-caspase-8-dependent apoptotic pathway in squamous carcinoma cells. AB - Inhibitor of differentiation/DNA-binding (Id) proteins are helix-loop-helix (HLH) transcription factors. The Id protein family (Id1-Id4) mediates tissue homeostasis by regulating cellular processes including differentiation, proliferation, and apoptosis. Ids typically function as dominant negative HLH proteins, which bind other HLH proteins and sequester them away from DNA promoter regions. Previously, we have found that Id3 induced apoptosis in immortalized human keratinocytes upon UVB exposure, consistent with its role as a tumor suppressor. To investigate the role of Id3 in malignant squamous cell carcinoma (SCC) cells (A431), a tetracycline-regulated inducible system was used to induce Id3 in cell culture and mouse xenograft models. We found that upon Id3 induction, there was a decrease in cell number under low serum conditions, as well as in soft agar. Microarray, RT-PCR, immunoblot, siRNA, and inhibitor studies revealed that Id3 induced expression of Elk-1, an E-twenty-six (ETS)-domain transcription factor, inducing procaspase-8 expression and activation. Id3 deletion mutants revealed that 80 C-terminal amino acids, including the HLH, are important for Id3 induced apoptosis. In a mouse xenograft model, Id3 induction decreased tumor size by 30%. Using immunofluorescent analysis, we determined that the tumor size decrease was also mediated through apoptosis. Furthermore, we show that Id3 synergizes with 5-FU and cisplatin therapies for nonmelanoma skin cancer cells. Our studies have shown a molecular mechanism by which Id3 induces apoptosis in SCC, and this information can potentially be used to develop new treatments for SCC patients. PMID- 25693515 TI - Natural variance in salt tolerance and induction of starch accumulation in duckweeds. AB - MAIN CONCLUSION: Ten of 34 tested duckweed clones showed relatively higher salt tolerance. Salinity stress induced high level of starch accumulation in these clones, making them potential feedstock candidates for biofuel production. Duckweeds are promising as a new generation of crop plants that requires minimal input while providing fast biomass production. Two important traits of interest that can impact on the economic viability of this system are their sensitivity to salt and the starch content of the harvested duckweed. We have surveyed 33 strains of duckweed selected from across all 5 genera and amongst 13 species to quantify the natural variance of these traits. We found that there are large ranges of intraspecific variations in salt tolerance, while all species examined accumulated more starch in response to the initial stages of salt stress. However, the magnitude of the change in starch content varied widely between strains. Our results suggest that specific duckweed clones can be cultivated under relatively saline conditions, while increasing salt in the medium before harvesting could be used to increase starch in duckweed biomass for bioethanol production. PMID- 25693516 TI - Atrial autonomic denervation for the treatment of long-standing symptomatic sinus bradycardia in non-elderly patients. AB - PURPOSE: Multiple lead and generator replacement and related complications often complicate the decision of pacemaker implantation in non-elderly patients with symptomatic bradycardia. This study sought to investigate the efficacy and safety of atrial autonomic denervation for treating the symptomatic long-standing sinus bradycardia (SB) in non-elderly patients. METHODS AND RESULTS: Eleven non-elderly patients (mean age, 45.9 +/- 10.9 years; eight men) with a long history of SB (106.2 +/- 43.7 months; range, 60-189) were enrolled. Five atrial ganglionated plexies (GPs), identified by anatomic distribution and high-frequency stimulation, were targeted and ablated. The end point was elimination of the vagal response at ablation sites. The symptoms of SB and Holter were followed up at 3 days, 6, and 12 months and, thereafter, over a period of 18 months. Six patients were under 50 years old (group I) and 5 patients were between 50 and 60 years old (group II). There were 3.1 +/- 0.7 GPs with positive vagal response and 11.3 +/- 2.7 ablation sites in each patient. During the 18.4 +/- 6.2 (range, 12 25) months of follow-up, all patients reported significant symptom improvement with a significant decrease of the SB-related symptoms score. The total heartbeats, mean, and minimum heart rate significantly increased that persisted for 12 months. Compared with patients in group II, those in group I had more increases in total heartbeats and mean heart rate (HR). CONCLUSION: Atrial autonomic denervation increases sinus rate and improves symptoms in non-elderly patients with symptomatic long-standing SB, thus, potentially serving as an alternative to pacemaker implantation. PMID- 25693518 TI - O(6) -methylguanine DNA methyltransferase repairs platinum-DNA adducts following cisplatin treatment and predicts prognoses of nasopharyngeal carcinoma. AB - Cisplatin (CDDP) is an important anti-cancer drug commonly used in various human cancers, including nasopharyngeal carcinoma (NPC). How to overcome the drug resistance of CDDP provides opportunities to improve clinical outcomes of NPC. O(6) -methylguanine-DNA methyltransferase (MGMT) has been well-characterized to be a therapeutic determinant of O(6) -alkylguanine alkylating drugs. However, the underlying mechanism and clinical relevance between MGMT and CDDP remain poorly defined in NPC. In this study, we showed that MGMT-proficient cells were highly resistant to the cytotoxic effects of CDDP as compared to MGMT-deficient cells. Further studies showed that the platinum level of DNA after CDDP exposure was significantly lower in MGMT-proficient cells than in MGMT-deficient cells. Host cell reactivation assay revealed that MGMT protected NPC cells from CDDP-induced DNA damage by enhancing DNA repair capacity. Importantly, we demonstrated for the first time that MGMT protein directly bound to CDDP-induced DNA damages. Subsequently, CDDP-bound MGMT protein became ubiquitinated and was degraded through ubiquitin-mediated proteasome system. We further analyzed the relationship between MGMT expression and clinical survivals in a cohort of 83 NPC patients. NPC patients who received CDDP-based concurrent chemoradiotherapy (CCRT), with high MGMT expression level, exhibited shorter progression-free survival (PFS; p = 0.022) and overall survival (OS; p = 0.015), than patients with low MGMT expression level. Furthermore, high MGMT expression level remained to be an independent prognostic factor for worse PFS (p = 0.01, hazard ratio 2.23) and OS (p = 0.018, hazard ratio 2.14). Our findings suggest that MGMT protein is important to determine the efficacy of CDDP in NPC. PMID- 25693519 TI - Biomimetic wall-shaped hierarchical microstructure for gecko-like attachment. AB - Most biological hairy adhesive systems involved in locomotion rely on spatula shaped terminal elements, whose operation has been actively studied during the last decade. However, though functional principles underlying their amazing performance are now well understood, due to technical difficulties in manufacturing the complex structure of hierarchical spatulate systems, a biomimetic surface structure featuring true shear-induced dynamic attachment still remains elusive. To try bridging this gap, a novel method of manufacturing gecko-like attachment surfaces is devised based on a laser-micromachining technology. This method overcomes the inherent disadvantages of photolithography techniques and opens wide perspectives for future production of gecko-like attachment systems. Advanced smart-performance surfaces featuring thin-film-based hierarchical shear-activated elements are fabricated and found capable of generating friction force of several tens of times the contact load, which makes a significant step forward towards a true gecko-like adhesive. PMID- 25693517 TI - Tumour growth of colorectal rat liver metastases is inhibited by hepatic arterial infusion of the mTOR-inhibitor temsirolimus after portal branch ligation. AB - Portal branch ligation (PBL) can be performed before major hepatic resection of colorectal liver metastases (mCRC) to increase the remnant liver mass. However, PBL may also stimulate mCRC growth through hepatic arterial hyperperfusion and growth factor release. Herein, we studied whether hepatic arterial infusion (HAI) of the mTOR-inhibitor temsirolimus (Tem) is capable of inhibiting the growth of colorectal liver metastases after PBL. WAG/Rij rats were randomized to four groups (n=6 each) and underwent subcapsular implantation of 5*10(5) CC531 cells into the left liver lobe. The animals of two groups underwent simultaneous PBL of the tumour bearing liver lobe. Ten days later animals underwent a HAI either of temsirolimus (Tem and PBL Tem) or saline solution (Sham and PBL Sham). Tumour size was analyzed at days 10 and 13 using three-dimensional ultrasound. In Sham controls tumour volume increased by 43%. After PBL Sham tumour volume increased by 52%. In contrast, in animals undergoing HAI of temsirolimus the tumour growth was not only completely inhibited, but tumour volume was found decreased, irrespective of PBL. After HAI of temsirolimus immunohistochemistry revealed an increased cleaved caspase-3 activity, indicating stimulation of apoptotic cell death. In parallel temsirolimus treatment was associated with a significant reduction of PECAM-1 positive cells within the tumour tissue, implying a reduced tumour vascularisation. HAI of temsirolimus is capable of inhibiting the growth of CC531 colorectal rat liver metastases also after PBL. PMID- 25693522 TI - Beyond the genome. PMID- 25693523 TI - Nature journals offer double-blind review. PMID- 25693524 TI - The idea factory. PMID- 25693525 TI - Europe needs fresh focus on big-science projects. PMID- 25693538 TI - Saudi Arabia opens top-notch laser lab. PMID- 25693539 TI - Cybercrime fight targets user error. PMID- 25693540 TI - Young scientists lead the way on fresh ideas. PMID- 25693541 TI - Language origin debate rekindled. PMID- 25693543 TI - Radical energy ideas secure private funds. PMID- 25693542 TI - Scientists seek 'Homo chippiens'. PMID- 25693544 TI - Sex redefined. PMID- 25693545 TI - Museums: The endangered dead. PMID- 25693546 TI - Corruption: Good governance powers innovation. PMID- 25693551 TI - Physics theory: 'Simple' or 'elegant' criteria are not valid. PMID- 25693552 TI - Natural history: Rescue Eastern Europe's collections. PMID- 25693553 TI - Plant genetics: Czech centre marks Mendel anniversary. PMID- 25693554 TI - Illegal trade: Tweak Chinese law to end ivory demand. PMID- 25693555 TI - Drug discovery: Early antibiotic from a cranberry bog. PMID- 25693556 TI - Vernon B. Mountcastle (1918-2015). PMID- 25693557 TI - Astrophysics: A lithium-rich stellar explosion. PMID- 25693558 TI - Evolution: Finches sequenced. PMID- 25693560 TI - Climate science: The future of coastal ocean upwelling. PMID- 25693561 TI - Presenting the epigenome roadmap. PMID- 25693562 TI - Epigenomics: Roadmap for regulation. PMID- 25693564 TI - Chromatin architecture reorganization during stem cell differentiation. AB - Higher-order chromatin structure is emerging as an important regulator of gene expression. Although dynamic chromatin structures have been identified in the genome, the full scope of chromatin dynamics during mammalian development and lineage specification remains to be determined. By mapping genome-wide chromatin interactions in human embryonic stem (ES) cells and four human ES-cell-derived lineages, we uncover extensive chromatin reorganization during lineage specification. We observe that although self-associating chromatin domains are stable during differentiation, chromatin interactions both within and between domains change in a striking manner, altering 36% of active and inactive chromosomal compartments throughout the genome. By integrating chromatin interaction maps with haplotype-resolved epigenome and transcriptome data sets, we find widespread allelic bias in gene expression correlated with allele-biased chromatin states of linked promoters and distal enhancers. Our results therefore provide a global view of chromatin dynamics and a resource for studying long range control of gene expression in distinct human cell lineages. PMID- 25693565 TI - Transcription factor binding dynamics during human ES cell differentiation. AB - Pluripotent stem cells provide a powerful system to dissect the underlying molecular dynamics that regulate cell fate changes during mammalian development. Here we report the integrative analysis of genome-wide binding data for 38 transcription factors with extensive epigenome and transcriptional data across the differentiation of human embryonic stem cells to the three germ layers. We describe core regulatory dynamics and show the lineage-specific behaviour of selected factors. In addition to the orchestrated remodelling of the chromatin landscape, we find that the binding of several transcription factors is strongly associated with specific loss of DNA methylation in one germ layer, and in many cases a reciprocal gain in the other layers. Taken together, our work shows context-dependent rewiring of transcription factor binding, downstream signalling effectors, and the epigenome during human embryonic stem cell differentiation. PMID- 25693566 TI - Integrative analysis of haplotype-resolved epigenomes across human tissues. AB - Allelic differences between the two homologous chromosomes can affect the propensity of inheritance in humans; however, the extent of such differences in the human genome has yet to be fully explored. Here we delineate allelic chromatin modifications and transcriptomes among a broad set of human tissues, enabled by a chromosome-spanning haplotype reconstruction strategy. The resulting large collection of haplotype-resolved epigenomic maps reveals extensive allelic biases in both chromatin state and transcription, which show considerable variation across tissues and between individuals, and allow us to investigate cis regulatory relationships between genes and their control sequences. Analyses of histone modification maps also uncover intriguing characteristics of cis regulatory elements and tissue-restricted activities of repetitive elements. The rich data sets described here will enhance our understanding of the mechanisms by which cis-regulatory elements control gene expression programs. PMID- 25693563 TI - Integrative analysis of 111 reference human epigenomes. AB - The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation and human disease. PMID- 25693567 TI - Cell-of-origin chromatin organization shapes the mutational landscape of cancer. AB - Cancer is a disease potentiated by mutations in somatic cells. Cancer mutations are not distributed uniformly along the human genome. Instead, different human genomic regions vary by up to fivefold in the local density of cancer somatic mutations, posing a fundamental problem for statistical methods used in cancer genomics. Epigenomic organization has been proposed as a major determinant of the cancer mutational landscape. However, both somatic mutagenesis and epigenomic features are highly cell-type-specific. We investigated the distribution of mutations in multiple independent samples of diverse cancer types and compared them to cell-type-specific epigenomic features. Here we show that chromatin accessibility and modification, together with replication timing, explain up to 86% of the variance in mutation rates along cancer genomes. The best predictors of local somatic mutation density are epigenomic features derived from the most likely cell type of origin of the corresponding malignancy. Moreover, we find that cell-of-origin chromatin features are much stronger determinants of cancer mutation profiles than chromatin features of matched cancer cell lines. Furthermore, we show that the cell type of origin of a cancer can be accurately determined based on the distribution of mutations along its genome. Thus, the DNA sequence of a cancer genome encompasses a wealth of information about the identity and epigenomic features of its cell of origin. PMID- 25693568 TI - Conserved epigenomic signals in mice and humans reveal immune basis of Alzheimer's disease. AB - Alzheimer's disease (AD) is a severe age-related neurodegenerative disorder characterized by accumulation of amyloid-beta plaques and neurofibrillary tangles, synaptic and neuronal loss, and cognitive decline. Several genes have been implicated in AD, but chromatin state alterations during neurodegeneration remain uncharacterized. Here we profile transcriptional and chromatin state dynamics across early and late pathology in the hippocampus of an inducible mouse model of AD-like neurodegeneration. We find a coordinated downregulation of synaptic plasticity genes and regulatory regions, and upregulation of immune response genes and regulatory regions, which are targeted by factors that belong to the ETS family of transcriptional regulators, including PU.1. Human regions orthologous to increasing-level enhancers show immune-cell-specific enhancer signatures as well as immune cell expression quantitative trait loci, while decreasing-level enhancer orthologues show fetal-brain-specific enhancer activity. Notably, AD-associated genetic variants are specifically enriched in increasing-level enhancer orthologues, implicating immune processes in AD predisposition. Indeed, increasing enhancers overlap known AD loci lacking protein-altering variants, and implicate additional loci that do not reach genome wide significance. Our results reveal new insights into the mechanisms of neurodegeneration and establish the mouse as a useful model for functional studies of AD regulatory regions. PMID- 25693569 TI - Explosive lithium production in the classical nova V339 Del (Nova Delphini 2013). AB - The origin of lithium (Li) and its production process have long been uncertain. Li could be produced by Big Bang nucleosynthesis, interactions of energetic cosmic rays with interstellar matter, evolved low-mass stars, novae, and supernova explosions. Chemical evolution models and observed stellar Li abundances suggest that at least half the Li may have been produced in red giants, asymptotic giant branch (AGB) stars, and novae. No direct evidence, however, for the supply of Li from evolved stellar objects to the Galactic medium has hitherto been found. Here we report the detection of highly blue-shifted resonance lines of the singly ionized radioactive isotope of beryllium, (7)Be, in the near-ultraviolet spectra of the classical nova V339 Del (Nova Delphini 2013) 38 to 48 days after the explosion. (7)Be decays to form (7)Li within a short time (half-life of 53.22 days). The (7)Be was created during the nova explosion via the alpha-capture reaction (3)He(alpha,gamma)(7)Be (ref. 5). This result supports the theoretical prediction that a significant amount of (7)Li is produced in classical nova explosions. PMID- 25693571 TI - Intensification and spatial homogenization of coastal upwelling under climate change. AB - The timing and strength of wind-driven coastal upwelling along the eastern margins of major ocean basins regulate the productivity of critical fisheries and marine ecosystems by bringing deep and nutrient-rich waters to the sunlit surface, where photosynthesis can occur. How coastal upwelling regimes might change in a warming climate is therefore a question of vital importance. Although enhanced land-ocean differential heating due to greenhouse warming has been proposed to intensify coastal upwelling by strengthening alongshore winds, analyses of observations and previous climate models have provided little consensus on historical and projected trends in coastal upwelling. Here we show that there are strong and consistent changes in the timing, intensity and spatial heterogeneity of coastal upwelling in response to future warming in most Eastern Boundary Upwelling Systems (EBUSs). An ensemble of climate models shows that by the end of the twenty-first century the upwelling season will start earlier, end later and become more intense at high but not low latitudes. This projected increase in upwelling intensity and duration at high latitudes will result in a substantial reduction of the existing latitudinal variation in coastal upwelling. These patterns are consistent across three of the four EBUSs (Canary, Benguela and Humboldt, but not California). The lack of upwelling intensification and greater uncertainty associated with the California EBUS may reflect regional controls associated with the atmospheric response to climate change. Given the strong linkages between upwelling and marine ecosystems, the projected changes in the intensity, timing and spatial structure of coastal upwelling may influence the geographical distribution of marine biodiversity. PMID- 25693570 TI - Direct observation of bond formation in solution with femtosecond X-ray scattering. AB - The making and breaking of atomic bonds are essential processes in chemical reactions. Although the ultrafast dynamics of bond breaking have been studied intensively using time-resolved techniques, it is very difficult to study the structural dynamics of bond making, mainly because of its bimolecular nature. It is especially difficult to initiate and follow diffusion-limited bond formation in solution with ultrahigh time resolution. Here we use femtosecond time-resolved X-ray solution scattering to visualize the formation of a gold trimer complex, [Au(CN)2(-)]3 in real time without the limitation imposed by slow diffusion. This photoexcited gold trimer, which has weakly bound gold atoms in the ground state, undergoes a sequence of structural changes, and our experiments probe the dynamics of individual reaction steps, including covalent bond formation, the bent-to-linear transition, bond contraction and tetramer formation with a time resolution of ~500 femtoseconds. We also determined the three-dimensional structures of reaction intermediates with sub-angstrom spatial resolution. This work demonstrates that it is possible to track in detail and in real time the structural changes that occur during a chemical reaction in solution using X-ray free-electron lasers and advanced analysis of time-resolved solution scattering data. PMID- 25693572 TI - Cytometry: Measure for measure. PMID- 25693574 TI - Soft tissue myoepithelial carcinoma with rhabdoid-like features and EWSR1 rearrangement: Fine needle aspiration cytology with histologic correlation. AB - A new case of soft tissue myoepithelial carcinoma (MEC) with rhabdoid-like differentiation is presented including cytologic, histopathologic, immunohistochemical, and molecular biologic features. A 45-year-old woman was admitted to the Hospital with nodular mass involving the lower part of the abdominal wall. Fine-needle aspiration cytology showed a round cell tumor with abundant cytoplasm in the myxoid background. The nuclei were uniform, round to ovoid, with finely distributed chromatin, nucleoli, and pale, vacuolated, or eosinophilic cytoplasm with rhabdoid-like appearance resembling a soft tissue malignant rhabdoid tumor. The surgically removed tumor was poorly demarcated, yellow, soft, and myxoid. The histopathology revealed sheets of poorly differentiated round malignant cells with focal myxoid stroma and rhabdoid-like morphology. Immunohistochemistry showed positivity for CK (AE1/AE3), EMA, S100, vimentin, CD99, and SMA; however desmin, CD34, and gliofibrilar acid protein (GFAP) were negative. Tumor cells revealed loss of INI1 expression. The EWSR1 gene rearrangement was detected by fluorescence in situ hybridization (FISH), but molecular biology failed to detect EWSR1/ETS, EWSR1/NR4A3, EWSR1/DDIT3, EWSR1/ATF1, EWSR1-POU5F1, EWSR1/ZNF444, EWSR1-PBX1 gene fusions. The final diagnosis was soft tissue malignant myoepithelioma with rhabdoid changes and EWSR1 gene rearrangement. The differential diagnosis included soft tissue malignant rhabdoid tumor, cellular extraskeletal myxoid chondrosarcoma, proximal epithelioid sarcoma, and other soft tissue tumor with EWSR1 rearrangement. To our knowledge, this is the first case of MEC with rhabdoid features and description of fine-needle aspiration cytology. PMID- 25693575 TI - Experimental and computational insights into carbon dioxide fixation by RZnOH species. AB - Organozinc hydroxides, RZnOH, possessing the proton-reactive alkylzinc group and the CO2 -reactive Zn-OH group, represent an intriguing group of organometallic precursors for the synthesis of novel zinc carbonates. Comprehensive experimental and computational investigations on 1) solution and solid-state behavior of tBuZnOH (1) species in the presence of Lewis bases, namely, THF and 4 methylpyridine; 2) step-by-step sequence of the reaction between 1 and CO2; and 3) the effect of a donor ligand and/or an excess of tBu2Zn as an external proton acceptor on the reaction course are reported. DFT calculations for the insertion of carbon dioxide into the dinuclear alkylzinc hydroxide 12 are fully consistent with (1)H NMR spectroscopy studies and indicate that this process is a multistep reaction, in which the insertion of CO2 seems to be the rate-determining step. Moreover, DFT studies show that the mechanism of the rearrangement between key intermediates, that is, the primary alkylzinc bicarbonate with a proximal position of hydrogen and the secondary alkylzinc bicarbonate with a distal position of hydrogen, most likely proceeds through internal rotation of the dinuclear bicarbonate. PMID- 25693576 TI - Tuberculous meningitis: advances in diagnosis and treatment. AB - INTRODUCTION: Tuberculous meningitis (TBM) is the most severe form of infection caused by Mycobacterium tuberculosis, causing death or disability in more than half of those affected. The aim of this review is to examine recent advances in our understanding of TBM, focussing on the diagnosis and treatment of this devastating condition. SOURCES OF DATA: Papers on TBM published between 1891 and 2014 and indexed in the NCBI Pubmed. The following search terms were used: TBM, diagnosis, treatment and outcome. AREAS OF AGREEMENT: The diagnosis of TBM remains difficult as its presentation is non-specific and may mimic other causes of chronic meningoencephalitis. Rapid recognition of TBM is crucial, however, as delays in initiating treatment are associated with poor outcome. The laboratory diagnosis of TBM is hampered by the low sensitivity of cerebrospinal fluid microscopy and the slow growth of M. tuberculosis in conventional culture systems. The current therapy of TBM is based on the treatment of pulmonary tuberculosis, which may not be ideal. The combination of TBM and HIV infection poses additional management challenges because of the need to treat both infections and the complications associated with them. AREAS OF CONTROVERSY: The pathogenesis of TBM remains incompletely understood limiting the development of interventions to improve outcome. The optimal therapy of TBM has not been established in clinical trials, and increasing antimicrobial resistance threatens successful treatment of this condition. The use of adjunctive anti-inflammatory agents remains controversial, and their mechanism of action remains incompletely understood. The role of surgical intervention is uncertain and may not be available in areas where TBM is common. GROWING POINTS: Laboratory methods to improve the rapid diagnosis of TBM are urgently required. Clinical trials of examining the use of high-dose rifampicin and/or fluoroquinolones are likely to report in the near future. AREAS TIMELY FOR DEVELOPING RESEARCH: The use of biomarkers to improve the rapid diagnosis of TBM warrants further investigation. The role of novel antituberculosis drugs, such as bedaquiline and PA-824, in the treatment of TBM remains to be explored. Human genetic polymorphisms may explain the heterogeneity of response to anti-inflammatory therapies and could potentially be used to tailor therapy. PMID- 25693577 TI - Effectiveness of Music Listening in Patients With Total Knee Replacement During CPM Rehabilitation. AB - AIM: This study investigated the effects of music listening on the anxiety, heart rate variability (HRV), and joint range of motion (ROM) of patients undergoing continuous passive motion (CPM) after total knee replacement surgery. METHOD: An experimental design was used. Participants in the experimental group (n = 49) listened to music from 10 min before receiving CPM until the end of the session (25 min in total) on the first and second day following surgery, whereas participants in the control group (n = 42) did not listen to music but rested quietly in bed starting 10 min before and throughout CPM. RESULTS: Compared with the control group, the experimental group exhibited significantly lower anxiety levels (p < .05) and increased CPM angles (p < .05) during treatment and increased active flexion ROM (p < .05) upon discharge. The low-frequency (LF)/high-frequency (HF) power ratio, normalized LF HRV, and normalized HF HRV of the two groups differed significantly, indicating that the patients in the experimental group had greater parasympathetic activity compared with those in the control group. CONCLUSION: Music listening can effectively reduce patient anxiety and enhance the ROM of their joints during postoperative rehabilitation. Health-care practitioners should consider including music listening as a routine practice for postoperative rehabilitation following orthopedic surgery. PMID- 25693578 TI - CQC produces guidance on using hidden cameras to identify abuse. PMID- 25693579 TI - Comparing the spelling and reading abilities of students with cochlear implants and students with typical hearing. AB - The purpose of this study was to determine whether students with and without hearing loss (HL) differed in their spelling abilities and, specifically, in the underlying linguistic awareness skills that support spelling ability. Furthermore, we examined whether there were differences between the two groups in the relationship between reading and spelling. We assessed the spelling, word level reading, and reading comprehension skills of nine students with cochlear implants and nine students with typical hearing who were matched for reading age. The students' spellings were analyzed to determine whether the misspellings were due to errors with phonemic awareness, orthographic pattern or morphological awareness, or poor mental graphemic representations. The students with HL demonstrated markedly less advanced spelling abilities than the students with typical hearing. For the students with HL, the misspellings were primarily due to deficiencies in orthographic pattern and morphological awareness. Correlations between measures of spelling and both real word reading and reading comprehension were lower for the students with HL. With additional investigations using a similar approach to spelling analysis that captures the underlying causes for spelling errors, researchers will better understand the linguistic awareness abilities that students with HL bring to the task of reading and spelling. PMID- 25693580 TI - Neuroimaging of HIV-associated cryptococcal meningitis: comparison of magnetic resonance imaging findings in patients with and without immune reconstitution. AB - To determine the frequency, imaging characteristics, neuroanatomical distribution and dynamics of magnetic resonance imaging findings in HIV-associated cryptococcal meningitis in immunocompromised patients we compared patients without antiretroviral therapy with patients undergoing immune reconstitution. Neuroimaging and clinical data of 21 consecutive patients presenting to a German HIV centre in a 10-year period between 2005 and 2014 were reviewed. We identified eight patients with magnetic resonance imaging findings related to cryptococcal disease: five patients without antiretroviral therapy and three patients receiving effective antiretroviral therapy resulting in immune reconstitution. The pattern of magnetic resonance imaging manifestations was different in the two groups. In patients not on antiretroviral therapy, pseudocysts (n = 3) and lacunar ischaemic lesions (n = 2) were detected. Contrast-enhancing focal leptomeningeal and/or parenchymal lesions were found in all patients under immune reconstitution (n = 3). Magnetic resonance imaging lesions suggestive of leptomeningitis or meningoencephalitis were detected in all patients with a recurrence of cryptococcal meningitis under immune reconstitution, which differs from the classical magnetic resonance imaging findings in patients without antiretroviral therapy. In antiretroviral therapy-treated patients with past medical history of cryptococcal meningitis, detection of contrast-enhancing focal meningeal and/or parenchymal lesions should prompt further investigations for a recurrence of cryptococcal meningitis under immune reconstitution. PMID- 25693581 TI - A multispecialty pediatric neurovascular conference: a model for interdisciplinary management of complex disease. AB - INTRODUCTION: In 2013, our institution established a multidisciplinary pediatric neurovascular conference for coordination of care. Here, we review our initial experience. METHODS: Clinical and demographic data were obtained from medical records for patients presented to the pediatric neurovascular conference from April 2013 to July 2014. Patient descriptive characteristics were described by mean and standard deviation for continuous measures and by number and percent for categorical measures. Patients were secondarily stratified by lesion/disease type, and descriptive statistics were used to measure demographic and clinical variables. RESULTS: The pediatric neurovascular conference met 26 times in the study period. Overall, 75 children were presented to the conference over a 15 month period. The mean age was 9.8 (standard deviation, 6.3) years. There were 42 (56%) male patients. These 75 children were presented a total of 112 times. There were 28 (37%) patients with history of stroke. Complex vascular lesions were the most frequently discussed entity; of 62 children (83%) with a diagnosed vascular lesion, brain arteriovenous malformation (29%), cavernous malformation (15%), and moyamoya (11%) were most common. Most discussions were for review of imaging (35%), treatment plan formulation (27%), the need for additional imaging (25%), or diagnosis (13%). Standardized care protocols for arteriovenous malformation and moyamoya were developed. CONCLUSION: A multidisciplinary conference among a diverse group of providers guides complex care decisions, helps standardize care protocols, promotes provider collaboration, and supports continuity of care in pediatric neurovascular disease. PMID- 25693582 TI - Post-traumatic epilepsy in children-experience from a tertiary referral center. AB - BACKGROUND: Post-traumatic epilepsy after a traumatic brain injury occurs in 10% 20% of children. Unfortunately, a biomarker that could provide prognostic information about both post-traumatic epilepsy and cognitive development is lacking. In this first of a series of studies, we have reviewed and analyzed clinical variables in children following traumatic brain injury to understand the epidemiologic and clinical characteristics of post-traumatic epilepsy in our urban population. METHODS: We performed a retrospective electronic chart review of patients who had suffered traumatic brain injury and subsequently evaluated at Children's Hospital of Michigan from 2002 to 2012. Various epidemiologic and clinical variables were analyzed. RESULTS: Patients who had severe traumatic brain injury and post-traumatic epilepsy had an abnormal acute head computed tomography. These patients had increased number of different seizure types, increased risk of intractability of epilepsy, and were on multiple antiepileptic drugs. Hypomotor seizure was the most common seizure type in these patients. There was a high prevalence of patients who suffered nonaccidental trauma, all of whom had severe traumatic brain injury. CONCLUSIONS: This study demonstrates a need for biomarkers in children following traumatic brain injury to reliably evaluate the risk of post-traumatic epilepsy. PMID- 25693583 TI - Delayed finger tapping and cognitive responses in preterm-born male teenagers with mild spastic diplegia. AB - BACKGROUND: Information on fine motor and basic cognitive functions in spastic diplegia is sparse in the literature. The aim of this study was to investigate index finger's tapping speed and cognitive functions in categorization and old/new recognition of pictures in patients with mild spastic diplegia. METHODS: Fifteen preterm-born male teenagers with mild spastic diplegia and 15 healthy male teenagers participated in this study. Finger-tapping tests and cognitive tests were performed on all participants. Outcomes were compared between the two groups. RESULTS: In the finger-tapping tests, the tapping speed was significantly slower in patients than in controls. In the tests of tapping one key persistently and tapping two keys alternately, the reaction time gaps between the left and right digits were larger in patients than in controls. In the categorization tests, the accuracies and reaction times for animal/plant and girl face pictures, but not for boy face pictures, were significantly worse in patients than in controls. In the recognition tests, the accuracies for old/new, animal/plant, and boy/girl face pictures were significantly lower in patients than in controls. The reaction times for old/new, animal/plant, and new face pictures, but not for old face pictures, were significantly longer in patients compared with controls. CONCLUSIONS: Our results demonstrate delayed finger tapping and cognitive responses in preterm-born male teenagers with mild spastic diplegia. Our experimental paradigm is sensitive for the study of fine motor and cognitive functions between patients and healthy controls. PMID- 25693584 TI - The McMaster Pediatric Migraine Questionnaire: a prospective validation study. AB - OBJECTIVE: Migraine affects approximately 4%-11% of elementary school children; yet reaching a diagnosis in this age group can be challenging. The goal of this study was to develop a screening migraine questionnaire that could be easily implemented by a general pediatrician and validate its use in diagnosing migraine in children 5-12 years old. METHODS: A questionnaire, the McMaster Migraine Tool, was developed using the International Classification of Headache Disorders-II criteria for migraine. The validity of the questionnaire was assessed by comparing the diagnosis based on the results of the questionnaire compared with the diagnosis made by a pediatric neurologist. RESULTS: The questionnaire was used to assess a cohort of 69 children referred to the Pediatric Neurology Clinic for headache. The sensitivity and specificity of the McMaster Migraine Tool were determined to be 84% and 69%, respectively. Families graded its ease of use to be 9 of 10 (10 being easy to use). CONCLUSION: The McMaster Migraine Tool may be useful in diagnosing migraine in 5-12-year-old children, as it is readily completed and regarded as easy to use. Application of this tool could lead to expedited diagnosis and management of migraine. PMID- 25693585 TI - 8q13.1-q13.2 deletion associated with inferior cerebellar vermian hypoplasia and digital anomalies: a new syndrome? AB - BACKGROUND: Cerebellar vermis hypoplasia has been associated with a large number of chromosomal abnormalities and metabolic disorders, with few candidate genes clearly linked to isolated cerebellar vermis hypoplasia. PATIENT DESCRIPTION: We describe on a 12-year-old boy with inferior vermian hypoplasia associated with a novel de novo microdeletion. He presented with intellectual, speech and language impairment, unilateral facial nerve weakness, marked constipation, and bilateral hand and foot anomalies that were not consistent with any previously described syndrome. His hand features were digital reductions similar to those seen in 4q34 deletion syndrome, known as the "tale of the nail" sign. Cranial magnetic resonance imaging demonstrated isolated inferior cerebellar vermis hypoplasia. RESULTS: A de novo 1.4 Mb interstitial deletion was identified at 8q13.1-q13.2 on chromosomal microarray. This copy number variant involves 18 human genome reference sequence genes, with 11 Mendelian Inheritance in Man genes. Homozygous mutations in one of these genes (CSPP1) has recently been recently described as causing Joubert syndrome. CONCLUSION: We propose that the constellation of clinical features in this child represents a novel microdeletion syndrome and hypothesize that CSPP1 or other genes within the deleted region contribute to the cerebellar development. PMID- 25693586 TI - Bilateral paramedian thalamic syndrome after infection. AB - BACKGROUND: Although bilateral paramedian thalamic infarctions occur more frequently in adults than in children, they are rare entities at any age. The syndrome is thought to result from occlusion of the artery of Percheron, which arises as a common trunk from one of the posterior cerebral arteries to supply both paramedian thalamic regions. We describe two children with acute ischemic infarction involving both paramedian thalami developing after infection. PATIENTS: The first patient developed mutism with ataxia after chicken pox infection. The second child developed headache, somnolence, agitation, and speech dysfunction following an upper respiratory tract infection. Bilateral thalamic lesions were documented on magnetic resonance imaging of both children. CONCLUSION: Bilateral infarctions of the paramedian thalamus may result in severe illness and impairment. Common clinical manifestations include disorientation, confusion, hypersomnolence, deep coma and "coma vigil," or akinetic mutism (awake unresponsiveness), as well as severe memory impairment. PMID- 25693587 TI - Pott's puffy tumor. PMID- 25693588 TI - Acute behavioral abnormality in an adolescent: absence status. PMID- 25693590 TI - Mechanisms and Therapeutic Strategies for Major Neurological Disorders: Current Advances and Future Perspectives. PMID- 25693591 TI - Editorial: Switching to biological agents in autoimmune and autoinflammatory disorders: current targets and therapy. PMID- 25693589 TI - Prevalence and prognosis of Alzheimer's disease at the mild cognitive impairment stage. AB - Three sets of research criteria are available for diagnosis of Alzheimer's disease in subjects with mild cognitive impairment: the International Working Group-1, International Working Group-2, and National Institute of Aging-Alzheimer Association criteria. We compared the prevalence and prognosis of Alzheimer's disease at the mild cognitive impairment stage according to these criteria. Subjects with mild cognitive impairment (n = 1607), 766 of whom had both amyloid and neuronal injury markers, were recruited from 13 cohorts. We used cognitive test performance and available biomarkers to classify subjects as prodromal Alzheimer's disease according to International Working Group-1 and International Working Group-2 criteria and in the high Alzheimer's disease likelihood group, conflicting biomarker groups (isolated amyloid pathology or suspected non Alzheimer pathophysiology), and low Alzheimer's disease likelihood group according to the National Institute of Ageing-Alzheimer Association criteria. Outcome measures were the proportion of subjects with Alzheimer's disease at the mild cognitive impairment stage and progression to Alzheimer's disease-type dementia. We performed survival analyses using Cox proportional hazards models. According to the International Working Group-1 criteria, 850 (53%) subjects had prodromal Alzheimer's disease. Their 3-year progression rate to Alzheimer's disease-type dementia was 50% compared to 21% for subjects without prodromal Alzheimer's disease. According to the International Working Group-2 criteria, 308 (40%) subjects had prodromal Alzheimer's disease. Their 3-year progression rate to Alzheimer's disease-type dementia was 61% compared to 22% for subjects without prodromal Alzheimer's disease. According to the National Institute of Ageing Alzheimer Association criteria, 353 (46%) subjects were in the high Alzheimer's disease likelihood group, 49 (6%) in the isolated amyloid pathology group, 220 (29%) in the suspected non-Alzheimer pathophysiology group, and 144 (19%) in the low Alzheimer's disease likelihood group. The 3-year progression rate to Alzheimer's disease-type dementia was 59% in the high Alzheimer's disease likelihood group, 22% in the isolated amyloid pathology group, 24% in the suspected non-Alzheimer pathophysiology group, and 5% in the low Alzheimer's disease likelihood group. Our findings support the use of the proposed research criteria to identify Alzheimer's disease at the mild cognitive impairment stage. In clinical settings, the use of both amyloid and neuronal injury markers as proposed by the National Institute of Ageing-Alzheimer Association criteria offers the most accurate prognosis. For clinical trials, selection of subjects in the National Institute of Ageing-Alzheimer Association high Alzheimer's disease likelihood group or the International Working Group-2 prodromal Alzheimer's disease group could be considered. PMID- 25693592 TI - Sonic Hedgehog pathway is upregulated in adamantinomatous craniopharyngiomas. AB - OBJECTIVES: Pituitary stem cells play a role in the oncogenesis of human adamantinomatous craniopharyngiomas (aCPs). We hypothesized that crosstalk between the Wnt/beta-catenin and Sonic Hedgehog (SHH) pathways, both of which are important in normal pituitary development, would contribute to the pathogenesis of aCPs. DESIGN: To explore the mRNA and protein expression of components of the SHH signaling pathway in aCPs and their relationship with the identification of CTNNB1/beta-catenin mutations and patients outcomes. PATIENTS AND METHODS: In 18 aCP samples, CTNNB1 was sequenced, and the mRNA expression levels of SHH pathway members (SHH, PTCH1, SMO, GLI1, GLI2, GLI3, and SUFU) and SMO, GLI1, GLI3, SUFU, beta-catenin, and Ki67 proteins were evaluated by quantitative real-time PCR and immunohistochemistry respectively. Anterior normal pituitaries were used as controls. Associations between molecular findings and clinical data were analyzed. RESULTS: The aCPs presented higher mRNA expression of SHH (+400-fold change (FC); P<0.01), GLI1 (+102-FC; P<0.001), and GLI3 (+5.1-FC; P<0.01) than normal anterior pituitaries. Longer disease-free survival was associated with low SMO and SUFU mRNA expression (P<0.01 and P=0.02 respectively). CTNNB1/beta catenin mutations were found in 47% of the samples. aCPs with identified mutations presented with higher mRNA expression of SMO and GLI1 (+4.3-FC; P=0.02 and +10.2-FC; P=0.03 respectively). SMO, GLI1, GLI3, and SUFU staining was found in 85, 67, 93, and 64% of the samples respectively. Strong GLI1 and GLI3 staining was detected in palisade cells, which also labeled Ki67, a marker of cell proliferation. CONCLUSIONS: The upregulation of SHH signaling occurs in aCPs. Thus, activation of Wnt/beta-catenin and SHH pathways, both of which are important in pituitary embryogenesis, appears to contribute to the pathogenesis of aCP. PMID- 25693593 TI - Self dialysis and video consultations feature in report on innovative care. PMID- 25693594 TI - Biopsychosocial care for chronic back pain. PMID- 25693595 TI - Design and Multi-Country Validation of Text Messages for an mHealth Intervention for Primary Prevention of Progression to Hypertension in Latin America. AB - BACKGROUND: Mobile health (mHealth) has been posited to contribute to the reduction in health gaps and has shown fast and widespread growth in developing countries. This growth demands understanding of, and preparedness for, local cultural contexts. OBJECTIVE: To describe the design and validation of text messages (short message service, SMS) that will be used for an mHealth behavioral change intervention to prevent hypertension in three Latin American countries: Argentina, Guatemala, and Peru. METHODS: An initial set of 64 SMS text messages were designed to promote healthy lifestyles among individuals in different stages of behavior change, addressing four key domains: salt and sodium intake, fruit and vegetable intake, consumption of high fat and sugar foods, and physical activity. The 64 SMS text messages were organized into nine subsets for field validation. In each country 36 people were recruited, half of them being male. Of the participants, 4 per country evaluated each subset of SMS text messages, which contained between 6 and 8 SMS text messages regarding different key domains and stages of change. The understanding and appeal of each SMS text message was assessed using a 7-item questionnaire. The understanding and appeal ratings were used to reach a final set of 56 SMS text messages. RESULTS: Overall, each of the 64 SMS text messages received a total of 12 evaluations (4 per country). The majority of evaluations-742 out of a total of 767 (96.7%) valid responses revealed an adequate understanding of the key idea contained in the SMS text message. On a scale from 1 to 10, the average appeal score was 8.7 points, with a range of 4 to 10 points. Based on their low scores, 8 SMS text messages per country were discarded. Once the final set of 56 SMS text messages was established, and based on feedback obtained in the field, wording and content of some SMS text messages were improved. Of the final set, 9, 8, and 16 of the SMS text messages were improved based on participant evaluations from Argentina, Guatemala, and Peru, respectively. Most SMS text messages selected for the final set (49/56, 88%) were the same in all countries, except for small wording differences. CONCLUSIONS: The final set of SMS text messages produced had very high rates of understanding and appeal in three different Latin American countries. This study highlights the importance of developing and validating a package of simple, preventative SMS text messages, grounded in evidence and theory, across three different Latin American countries with active engagement of end users. PMID- 25693596 TI - Cardiovascular effects, body composition, quality of life and pain after a Zumba fitness program in Italian overweight women. AB - BACKGROUND: The aim of this paper was to investigate the cardiovascular effects, body composition, quality of life and pain after a 12-week Zumba fitness program in a group of overweight women through an observational study, community physical activity program involving twenty-seven overweight women (38.9+/-9.7 years). METHODS: Cardiometabolic profile, body composition, quality of life and pain were assessed after a 12-week Zumba fitness program. RESULTS: Significant improvements in body weight and BMI (71.5 vs. 74.2 kg, 28.02 vs. 29.1 kg/m2), in circumferences (arm: 27.9 vs. 30.3, waist: 80.1 vs. 83.9, hip: 102 vs. 107.4 cm), in fat and muscular mass (25.2 vs. 26.9, 34.4 vs. 27.2 kg), in intracellular (19 vs. 17.5 kg), and in extracellular water (14.9 vs. 16.8 kg) were recorded. A decrease in blood pressure was observed (118.3/69.4 vs. 125/75.5 mmHg). Cardiovascular response to the maximal exercise test showed a decrease in heart rate and in systolic blood pressure with an increase of work (118.9 vs. 116.7 watt). SF-36 showed variations in physical functioning (99.4 vs. 92.8) and in the limitation on the emotional role (88.9 vs. 66.6). With regards the Brief Pain Inventory-SF, a decrease in pain severity and pain interference score was seen (0.5 vs. 1.6, 0.06 vs. 0.5). CONCLUSIONS: Results demonstrate that Zumba fitness can be an effective way to obtain beneficial health effects and that it can also be recommended for overweight women. PMID- 25693597 TI - Hyaluronan suppresses mechanical stress-induced expression of catabolic enzymes by human chondrocytes via inhibition of IL-1beta production and subsequent NF kappaB activation. AB - OBJECTIVE: To investigate the inhibitory effect of hyaluronan (HA) on mechanical stress- induced expression of a disintegrin and metalloproteinase with thrombospondin type 1 motifs (ADAMTS)-4, -5 and matrix metalloproteinase (MMP)-13 by human chondrocytes. MATERIALS AND METHODS: Normal human articular chondrocytes were pre-incubated with or without 1.0 mg/mL HA (2700 kDa) for 12 h at 37 degrees C in stretch chambers, then they were exposed to uni-axial cyclic tensile strain (CTS, 0.5 Hz, 10% elongation). The expression of ADAMTS-4, -5, and MMP-13 were analyzed by real-time polymerase chain reaction and Immunocytochemistry. The concentration of IL-1beta in the supernatant was measured using enzyme-linked immunosorbent assay (ELISA). The nuclear translocation of runt-related transcription factor 2 (RUNX-2) and nuclear factor-kappaB (NF-kappaB) was examined by ELISA and immunocytochemistry, and phosphorylation of NF-kappaB was examined by western blotting. RESULTS: HA inhibited mRNA expression of ADAMTS-4, 5, and MMP13 after 24 h CTS via inhibition of IL-1beta secretion and NF-kappaB activation. However, HA failed to inhibit CTS-induced RUNX-2 expression and subsequent expression of ADAMTS-5 and MMP-13 1 h after CTS. CONCLUSIONS: Our results demonstrated that HA significantly suppressed mechanical stress-induced expression of catabolic proteases by inhibition of the NF-kappaB-IL-1beta pathway, but did not suppress mechanical stress-induced RUNX-2 signaling. PMID- 25693598 TI - Dealing with the unknown: reducing the proportion of unvalidated treatments offered to children. PMID- 25693599 TI - A gas-filled appendix on a plain X-ray of the abdomen in a preterm neonate. PMID- 25693600 TI - A large-scale measurement, analysis and modelling of electromagnetic radiation levels in the vicinity of GSM/UMTS base stations in an urban area. AB - The present study analyses the electric field radiating from the GSM/UMTS base stations located in central Malatya, a densely populated urban area in Turkey. The authors have conducted both instant and continuous measurements of high frequency electromagnetic fields throughout their research by using non-ionising radiation-monitoring networks. Over 15,000 instant and 13,000,000 continuous measurements were taken throughout the process. The authors have found that the normal electric field radiation can increase ~25% during daytime, depending on mobile communication traffic. The authors' research work has also demonstrated the fact that the electric field intensity values can be modelled for each hour, day or week with the results obtained from continuous measurements. The authors have developed an estimation model based on these values, including mobile communication traffic (Erlang) values obtained from mobile phone base stations and the temperature and humidity values in the environment. The authors believe that their proposed artificial neural network model and multivariable least squares regression analysis will help predict the electric field intensity in an environment in advance. PMID- 25693601 TI - Natural radionuclides in cigarette tobacco from Serbian market and effective dose estimate from smoke inhalation. AB - The activity concentrations of natural radionuclides ((40)K, (210)Pb, (210)Po, (226)Ra and (228)Ra) in 17 most frequently used cigarette brands in Serbia and corresponding effective doses due to smoke inhalation are presented. The mean annual effective doses for (210)Pb and (210)Po were estimated to be 47.3 and 724 uSv y(-1) for (210)Pb and (210)Po, respectively. Serbia currently has the highest smoking rate in the world. The results of this study indicate the high contribution of the annual effective dose due to smoke inhalation to the total inhalation dose from natural radionuclides. The more effective implementation of actions for reducing smoking prevalence in Serbia is highly needed. PMID- 25693602 TI - Anemia and Transfusion in Critical Care: Physiology and Management. AB - OBJECTIVE: The objective of this report is to review the physiology and management of anemia in critical care. Selected publications on physiology and transfusion related to anemia and critical care, including the modern randomized trials of conservative versus liberal transfusion policy, were used. Anemia is compensated and tolerated in most critically ill patients as long as oxygen delivery is at least twice oxygen consumption. There are risks to blood transfusion which can be minimized by blood banking practice. The availability of cultured red cells may allow correction of anemia without significant risk. The benefit of transfusion in anemia must be weighted against the risk in any specific patient. CONCLUSION AND RECOMMENDATION: In a criticially ill patient, anemia should be managed to avoid oxygen supply dependency (oxygen delivery less than twice comsumption) and to maintain moderate oxygen delivery reserve (DO2/VO2 > 3). PMID- 25693603 TI - Authors' Response. PMID- 25693605 TI - A proposed method for retrospective eye dose assessments for the purposes of resolving cataract compensation claims. AB - The 2011 International Commission on Radiological Protection (ICRP) statement on tissue reactions suggested a significant reduction in the threshold dose for radiation induced cataracts. This, combined with the potential for a long delay between exposure and cataract diagnosis, may result in an increased requirement to evaluate eye dose from past exposures in order to settle current compensation claims. This article highlights how compensation claims relating to radiation exposure are assessed within the UK legal system and suggests that in vivo Electro Paramagnetic Resonance (EPR) dosimetry of teeth has utility for the retrospective quantification of radiation doses to the eye. It was identified that in vivo EPR in its current form may be sufficiently sensitive to support cataract compensation claims, although further work is required to enable appropriate dose conversion coefficients to be quantified. PMID- 25693606 TI - Reliability assessment for pulse wave measurement using artificial pulse generator. AB - This study aimed to assess intrinsic reliabilities of devices for pulse wave measurement (PWM). An artificial pulse generator system was constructed to create a periodic pulse wave. The stability of the periodic output was tested by the DP103 pressure transducer. The pulse generator system was then used to evaluate the TD01C system. Test-re-test and inter-device reliability assessments were conducted on the TD01C system. First, 11 harmonic components of the pulse wave were calculated using Fourier series analysis. For each harmonic component, coefficient of variation (CV), intra-class correlation coefficient (ICC) and Bland-Altman plot were used to determine the degree of reliability of the TD01C system. In addition, device exclusion criteria were pre-specified to improve consistency of devices. The artificial pulse generator system was stable to evaluate intrinsic reliabilities of devices for PWM (ICCs > 0.95, p < 0.001). TD01C was reliable for repeated measurements (ICCs of test-re-test reliability > 0.95, p < 0.001; CVs all < 3%). Device exclusion criteria successfully excluded the device with defect; therefore, the criteria reduced inter-device CVs of harmonics and improved consistency of the selected devices for all harmonic components. This study confirmed the feasibility of intrinsic reliability assessment of devices for PWM using an artificial pulse generator system. Moreover, potential novel findings on the assessment combined with device exclusion criteria could be a useful method to select the measuring devices and to evaluate the qualities of them in PWM. PMID- 25693604 TI - Risk factors for death from invasive pneumococcal disease, Europe, 2010. AB - We studied the possible association between patient age and sex, clinical presentation, Streptococcus pneumoniae serotype, antimicrobial resistance, and death in invasive pneumococcal disease cases reported by 17 European countries during 2010. The study sample comprised 2,921 patients, of whom 56.8% were men and 38.2% were >65 years of age. Meningitis occurred in 18.5% of cases. Death was reported in 264 (9.0%) cases. Older age, meningitis, and nonsusceptibility to penicillin were significantly associated with death. Non-pneumococcal conjugate vaccine (PCV) serotypes among children <5 years of age and 7-valent PCV serotypes among persons 5-64 years of age were associated with increased risk for death; among adults >65 years of age, risk did not differ by serotype. These findings highlight differences in case-fatality rates between serotypes and age; thus, continued epidemiologic surveillance across all ages is crucial to monitor the long-term effects of PCVs. PMID- 25693607 TI - A PE_PGRS33 protein of Mycobacterium tuberculosis: an ideal target for future tuberculosis vaccine design. AB - It is known that cellular immune response is relevant to fight against tuberculosis (TB); hence, identification of mycobacterial antigens that induce a protective immune cellular response is of great interest, especially for the development of effective TB vaccines. Genomic data have an impact on the identification of potential antigens as new vaccine targets. In this review, we summarize the current knowledge about the advances in new TB vaccine designs as well as the features reported for the pro-glu_polymorphic GC-rich sequence (PE_PGRS33) protein, considering this molecule as a prototype of the PE_PGRS family to better understand the biological function of this protein family that could be considered an ideal target for future vaccine design. PMID- 25693608 TI - Enhanced functional integration of human photoreceptor precursors into human and rodent retina in an ex vivo retinal explant model system. AB - Retinal disease is the major cause of irreversible blindness in developed countries. Transplantation of photoreceptor precursor cells (PPCs) derived from human embryonic stem cells (hESCs) is a promising and widely applicable approach for the treatment of these blinding conditions. Previously, it has been shown that after transplantation into the degenerating retina, the percentage of PPCs that undergo functional integration is low. The factors that inhibit PPC engraftment remain largely unknown, in part, because so many adverse factors could be at play during in vivo experiments. To advance our knowledge in overcoming potential adverse effects and optimize PPC transplantation, we have developed a novel ex vivo system. Harvested neural retina was placed directly on top of cultured retinal pigment epithelial (RPE) cells from a number of different sources. To mimic PPC transplantation into the subretinal space, hESC-derived PPCs were inserted between the retinal explant and underlying RPE. Explants cocultured with hESC-derived RPE maintained normal gross morphology and viability for up to 2 weeks, whereas the explants cultured on ARPE19 and RPE-J failed by 7 days. Furthermore, the proportion of PPCs expressing ribbon synapse-specific proteins BASSOON and RIBEYE was significantly higher when cocultured with hESC derived RPE (20% and 10%, respectively), than when cocultured with ARPE19 (only 6% and 2%, respectively). In the presence of the synaptogenic factor thrombospondin-1 (TSP-1), the proportion of BASSOON-positive and RIBEYE-positive PPCs cocultured with hESC-derived RPE increased to ~30% and 15%, respectively. These data demonstrate the utility of an ex vivo model system to define factors, such as TSP-1, which could influence integration efficiency in future in vivo experiments in models of retinal degeneration. PMID- 25693609 TI - Randomised clinical trial: the 5-HT4 agonist revexepride in patients with gastro oesophageal reflux disease who have persistent symptoms despite PPI therapy. AB - BACKGROUND: A substantial proportion of patients with gastro-oesophageal reflux disease (GERD) have only a partial response to proton pump inhibitor (PPI) therapy. Prokinetic drugs may improve reflux symptoms by enhancing oesophageal motility and gastric emptying. AIM: To evaluate the effect of revexepride, a novel prokinetic 5-hydroxytryptamine type 4 (5-HT4 ) receptor agonist, compared with placebo, in patients with GERD who have a partial response to PPIs. METHODS: A phase 2b, double-blind, parallel-group study was conducted, in which patients were randomised to one of three revexepride treatment groups (0.1, 0.5 and 2.0 mg three times daily) or placebo (1:1:1:1 ratio). Daily e-diary data captured patients' symptoms over an 8-week treatment period. The primary efficacy outcome was the weekly percentage of regurgitation-free days in the second half of the study (weeks 5-8). RESULTS: In total, 480 patients were randomised and 477 received treatment (mean age 47.9 years; 61% women). The mean percentage of regurgitation-free days increased from baseline (range, 15.0-18.8%) to week 8 (62.3-70.5%) in all four study arms; however, there were no statistically significant differences in this change between placebo and the three treatment arms. No dose-dependent relationship in treatment effect was observed for any of the study endpoints. The incidence of treatment-emergent adverse events (TEAEs) was revexepride dose-dependent. Only one serious TEAE occurred and none resulted in death. CONCLUSIONS: Revexepride was no more effective than placebo in controlling regurgitation in patients with GERD symptoms partially responsive to PPIs. Revexepride was well tolerated. ClinicalTrials.gov Identifier: NCT01472939. PMID- 25693610 TI - Impact of the Mobile HealthPROMISE Platform on the Quality of Care and Quality of Life in Patients With Inflammatory Bowel Disease: Study Protocol of a Pragmatic Randomized Controlled Trial. AB - BACKGROUND: Inflammatory bowel disease (IBD) is a chronic condition of the bowel that affects over 1 million people in the United States. The recurring nature of disease makes IBD patients ideal candidates for patient-engaged care that is centered on enhanced self-management and improved doctor-patient communication. In IBD, optimal approaches to management vary for patients with different phenotypes and extent of disease and past surgical history. Hence, a single quality metric cannot define a heterogeneous disease such as IBD, unlike hypertension and diabetes. A more comprehensive assessment may be provided by complementing traditional quality metrics with measures of the patient's quality of life (QOL) through an application like HealthPROMISE. OBJECTIVE: The objective of this pragmatic randomized controlled trial is to determine the impact of the HealthPROMISE app in improving outcomes (quality of care [QOC], QOL, patient adherence, disease control, and resource utilization) as compared to a patient education app. Our hypothesis is that a patient-centric self-monitoring and collaborative decision support platform will lead to sustainable improvement in overall QOL for IBD patients. METHODS: Participants will be recruited during face to-face visits and randomized to either an interventional (ie, HealthPROMISE) or control (ie, education app). Patients in the HealthPROMISE arm will be able to update their information and receive disease summary, quality metrics, and a graph showing the trend of QOL (SIBDQ) scores and resource utilization over time. Providers will use the data for collaborative decision making and quality improvement interventions at the point of care. Patients in the control arm will enter data at baseline, during office visits, and at the end of the study but will not receive any decision support (trend of QOL, alert, or dashboard views). RESULTS: Enrollment in the trial will be starting in first quarter of 2015. It is intended that up to 300 patients with IBD will be recruited into the study (with 1:1 allocation ratio). The primary endpoint is number of quality indicators met in HealthPROMISE versus control arm. Secondary endpoints include decrease in number of emergency visits due to IBD, decrease in number of hospitalization due to IBD, change in generic QOL score from baseline, proportion of patients in each group who meet all eligible outpatient quality metrics, and proportion of patients in disease control in each group. In addition, we plan to conduct protocol analysis of intervention patients with adequate HealthPROMISE utilization (more than 6 log-ins with data entry from week 0 through week 52) achieving above mentioned primary and secondary endpoints. CONCLUSIONS: HealthPROMISE is a unique cloud-based patient-reported outcome (PRO) and decision support tool that empowers both patients and providers. Patients track their QOL and symptoms, and providers can use the visual data in real time (integrated with electronic health records [EHRs]) to provide better care to their entire patient population. Using pragmatic trial design, we hope to show that IBD patients who participate in their own care and share in decision making have appreciably improved outcomes when compared to patients who do not. TRIAL REGISTRATION: ClinicalTrials.gov NCT02322307; https://clinicaltrials.gov/ct2/show/NCT02322307 (Archived by WebCite at http://www.webcitation.org/6W8PoYThr). PMID- 25693611 TI - Cytochrome P450 CYP4DE1 and CYP6CW3v2 contribute to ethiprole resistance in Laodelphax striatellus (Fallen). AB - Laodelphax striatellus Fallen (Hemiptera: Delphacidae), a destructive pest of rice, has developed high resistance to multiple insecticides, threatening the success of pest management programmes. The present study investigated ethiprole resistance mechanisms in a field population that is highly resistant to ethiprole. That population was used to establish a laboratory population that was subjected to further selection to produce a resistant strain. Target genes were cloned and compared between the resistant and the susceptible strains, the role of detoxification enzymes was examined, and the relative expression levels of 71 detoxification enzyme genes were tested using quantitative real time (RT)-PCR. The laboratory selection enhanced the resistance from 107-fold to 180-fold. The Rdl-type target site mutation seldom occurred in the resistant strain and is unlikely to represent the major mechanism underlying the observed resistance. Of the three important detoxification enzymes, only P450 monooxygenase was found to be associated with ethiprole resistance. Moreover, two genes, CYP4DE1 and CYP6CW3v2, were found to be overexpressed in the resistant strain. Furthermore, gene-silencing via a double-stranded RNA feeding test was carried out, and the results showed that the mRNA levels of CYP4DE1 and CYP6CW3v2 were reduced in the resistant strain, whereas ethiprole susceptibility was increased. These results suggest that CYP4DE1 and CYP6CW3v2 play an important role in ethiprole resistance in L. striatellus. PMID- 25693612 TI - [Utility of Pneumonia Severity Index in hospitalized patients with pneumonia in intensive respiratory care units]. AB - INTRODUCTION: The aim of this study was to evaluate the prognostic value of Pneumonia Severity Index (PSI) for prediction of 30-day mortality in patients admitted to intensive care unit (ICU) for community-acquired pneumonia (CAP). In patients with CAP, comorbidities, complications, and physical, laboratory, radiological and microbiological findings were evaluated relative to their prognosis. PATIENT AND METHODS: In the study, 197 patients with CAP, hospitalised at ICU of Department of Respiratory Medicine, University Hospital Olomouc between 2008 and 2012, were enrolled. Risk factors according to PSI were assessed in all patients. RESULTS: In the studied cohort of patients with CAP, mean values of PSI were 115.4 +/- SD 30.4 points. Overall, 29 patients (14.7 %) deceased. When comparing deceased and survived patients, statistically significant differences were found in PSI (mean +/- SD: 137.4 +/- 26.1 vs 111.7 +/- 29.6 points, p < 0.0001), age (mean +/- SD: 76.3 +/- 12.9 vs 65.5 +/- 14.7 years, p < 0.0001), incidence of heart diseases (86.2 % vs 67.3 %, p = 0.04) and ischaemic heart disease (58.6 % vs 38.7 %, p = 0.04). Assessment of physical and laboratory findings showed that deceased patients had significantly increased incidence of tachycardia above 90/min (51.7 % vs 27.4 %, p = 0.01), tachypnoe above 30/min (37.9 % vs 13.7 %, p = 0.001) and acidosis with pH < 7.35 (27.6 % vs 8.9 %, p = 0.004) comparing to survived patients. No significant correlation between PSI and the length of hospitalisation in survived patients was observed. In patients with Staphylococcus sp. and Klebsiella pneumoniae infection, longer hospitalisation period was observed. Comparison of other parameters such as comorbidities, physical and laboratory findings, and pathogens showed no significant differences when comparing deceased to survived patients. CONCLUSION: Our study showed that PSI represents an important predictor of 30-day mortality in patients with CAP at ICU, but does not correlate neither with the length of hospitalisation nor with particular pathogens. Independent negative prognostic factors in CAP were age, incidence of heart diseases (most importantly ischaemic heart disease), tachycardia, tachypnoe and acidosis. Staphylococcus sp. and Klebsiella pneumoniae infection led to longer hospitalisation period. All these factors point out the need for increased care in CAP patients. PMID- 25693613 TI - [POET2 registry: Comparison of annual direct medical costs of treating type 2 diabetes after addition of insulin NPH or insulin glargine to oral antidiabetic therapy in the Czech Republic]. AB - INTRODUCTION: Poor glycemic control and the resulting development of complications of type 2 diabetes (DM2T) increase treatment costs. If adequate glycemic control cannot be achieved by lifestyle modifications and oral antidiabetic (OAD) therapy, initiation of insulin therapy is recommended. Cost effectiveness of basal insulins of the type NPH or glargine in combination with OAD for the treatment of DM2T was examined in a number of pharmacoeconomic studies. However, none of these studies were conducted in the Czech Republic. Therefore, the aim of the project POET2 was to compare annual direct medical costs of treating DM2T after addition of insulin NPH or glargine to OAD therapy in a clinical practice setting in the Czech Republic. METHODOLOGY: Data collected from 1967 patients who met the criteria for inclusion into the non-interventional prospective registry POET2 (DM2T, ongoing OAD therapy, glycated hemoglobin HbA1c > 6 % IFCC) and who were observed for 12 months following the start of insulin therapy (glargine: n = 1061 vs NPH: n = 906) were analysed. Costs of treatment were analysed from the perspective of health insurance companies and included costs of medication, medical devices and medical procedures. RESULTS: In both treatment groups a reduction of HbA1c (glargine group: by 1.77 % IFCC vs NPH group: by 1.73 % IFCC) and fasting plasma glucose (glargine group: by 3.67 mmol/l vs NPH group: by 3.63 mmol/l) was observed. Insulin glargine therapy was associated with the incidence of a significantly lower number of documented symptomatic hypoglycemic events (glargine group: 0.840 events per patient and year of treatment vs. NPH group: 1.053 events per patient and year of treatment; p < 0.05). Overall annual direct medical costs associated with the initiation of basal insulin treatment were higher on average by 2547.07 CZK among patients treated with insulin glargine (glargine group: 12173.09 +/- 4169.44 CZK vs NPH group: 9626.02 +/- 3432.79 CZK; p < 0.001) due to higher costs of medication (glargine group: 7992.97 +/- 4001.81 CZK vs NPH group: 3784.2 +/- 3181.48 CZK; p < 0.001). By contrast, costs of medical devices (glargine group: 2332.08 +/- 917.84 CZK vs NPH group: 3893.95 +/- 989.79 CZK; p < 0.001) and medical procedures (glargine group: 1848.04 +/- 684.89 CZK vs NPH group: 1947.87 +/- 685.43 CZK; p < 0.001) were lower among patients treated with insulin glargine. CONCLUSION: Addition of basal insulin to OAD therapy was an efficacious therapeutic intervention for the treatment of DM2T in a clinical practice setting in the Czech Republic. Overall annual direct medical costs were higher among patients treated with insulin glargine than among patients treated with insulin NPH. However, costs of medical devices and medical procedures were lower in the insulin glargine group. In addition, incidence of hypoglycemia was significantly lower among patients treated with insulin glargine. PMID- 25693614 TI - [Therapeutic monitoring of amikacin and gentamicin in routine clinical practice]. AB - Aminoglycosides constitute one of the oldest classes of antimicrobials. Despite their relative toxicity, mainly nephrotoxicity and ototoxicity, aminoglycosides are valuable in current clinical practice. They are bactericidal agents with activity against aerobic gram-negative infections and against gram-positive cocci when added to a cell wall active antimicrobial-based regimen (e.g. betalactams). Aminoglycosides have a concentration-dependent bactericidal effect and a long post antibiotic effect. There is accumulating evidence to show that large, single, daily doses (or more correctly, extended interval dosing) of aminoglycosides is associated with less nephrotoxicity and ototoxicity and comparable, if not superior clinical outcomes than the same total dose administered in small, multiple doses. The efficacy and toxicity of aminoglycosides show a strong direct positive relationship with blood drug concentrations. A key strategy in minimizing toxicity and optimizing therapy is therapeutic drug monitoring. Key words: aminoglycosides - amikacin - gentamicin - therapeutic monitoring. PMID- 25693615 TI - [Association between asymptomatic hyperuricaemia and metabolic syndrome in the adolescents]. AB - In humans, uric acid represents a biologically active end-product of purine nucleotides. Several studies in children and adolescents documented an association between hyperuricaemia and the components metabolic syndrome. High intake of fructose-sweetened beverages might increase uricaemia, since fructose is the only saccharide which metabolism results in the formation of uric acid. Current knowledge does not allow distinguishing whether hyperuricaemia is causally related to the components of metabolic syndrome, or rather represents a marker of an enhanced risk, and poor outcome. No guidelines exist whether or not to treat asymptomatic hyperuricaemia in the adolescents. Randomized controlled prospective clinical studies are needed to elucidate whether uric acid-lowering management would beneficially affect the prevalence of metabolic syndrome, and the incidence of cardiovascular disease. PMID- 25693616 TI - [Research of relations among sleep disorders, obstructive sleep apnoea, hypertension onset and hypertensive treatment - current or long-term trend?]. AB - This paper is discussing recent findings about links between obstructive sleep apnea syndrome and arterial hypertension. It describes diagnostic approaches and also therapy of patients. It is describing options of pharmacological treatment and the influence of continuous positive airway pressure therapy on blood pressure level. PMID- 25693617 TI - [Tachycardia-induced cardiomyopathy]. AB - Cardiomyopathy is a heterogeneous group of diseases of heart muscle accompanied with impaired cardiac function. Tachycardia-induced cardiomyopathy (TIC) is caused by prolonged tachycardia leading to dilatation and systolic dysfunction with clinical manifestation of heart failure. This state is reversible after normalization of heart rate. The diagnosis is usually made retrospectively after normalization of heart rate and recovery of left ventricular function (LVF). More than 100 years after the first documented case (described in 1913 in a young patient with atrial fibrillation and symptoms of heart failure [25]) is still limited knowledge of pathophysiological mechanisms. The most common arrhythmias responsible for the TIC include atrial fibrillation [1,2], atrial flutter [3], incessant supraventricular tachycardia [4], ventricular tachycardia (VT) [5] and frequent ventricular extrasystoles (VES) [6]. TIC detection and therapeutic intervention is crucial considering potential reversibility of tachycardia. Current options of treatment involve drug therapy and surgical or catheter ablation. PMID- 25693618 TI - [The role of the assessment of heavy/light chain pairs of immunoglobulin in monoclonal gammopathies]. AB - The aim of the paper is to inform about the contribution of novel, highly sensitive analytic technique for the assessment of serum immunoglobulins (Hevylite), enabling separate quantitative assessment of heavy/light chain pairs of immunoglobulin (HLC), i. e. the monoclonal ("involved") and polyclonal ("noninvolved") isotype including their ratio (HLC-r) in monoclonal gammopathies. We particularly target the characteristics of this technique, the compari-son of its clinical contribution with standard methods used in the diagnostics, course and the detection of relapse and progression of the disease, as well as the stratification, assessment of therapeutic outcome and prognosis in monoclonal gammopathy of undetermined significance, multiple myeloma, Waldenstrom's macroglobulinemia, systemic AL-amyloidosis and some non-Hodgkin lymphomas. Present results show that in comparison with existing routinely used techniques the Hevylite method enriches clinical practice with the assessment of serum levels of "uninvolved" Ig. It enables the evaluation of the depth of "immunoparesis", and the determination of HLC-r index that is needful for the stratification of MM into "risk cohorts". It also contributes to prognostic assessment and improvement of the evaluation of the depth of therapeutic response. In MGUS individuals the HLC-r index provides information about the risk of malignant transformation. We await the results of ongoing validation studies that are expected to provide specific indications for Hevylite technique for MG in routine practice. PMID- 25693619 TI - [Acute and chronic aortic diseases of the thoracic and abdominal aorta of the adult - 2014 AS SMC Guidelines on the classification and diagnosis of aortic diseases]. AB - In addition to organovascular arterial ischemic diseases (cardiovascular, vasculovascular, neurovascular, extre-mitovascular, renovascular, genitovascular, bronchopulmovascular, mesenteriovascular, osteoarthromusculovascular, dermovascular, oculovascular, otovascular, stomatovascular etc.), aortic diseases contribute to the wide spectrum of arterial diseases: aortic aneurysms (AA), acute aortic syndromes (AAS) including aortic dissection (AD), intramural haematoma (IMH), penetrating atherosclerotic ulcer (PAU) and traumatic aortic injury (TAI), pseudoaneurysm, aortic rupture, atherosclerosis, vasculitis as well as genetic diseases (e.g. Turner syndrome, Marfan syndrome, Ehlers-Danlos syndrome) and congenital abnormalities including the coarctation of the aorta (CoA). Similarly to other arterial diseases, aortic diseases may be diagnosed after a long period of subclinical development or they may have an acute presentation. Acute aortic syndrome is often the first sign of the disease, which needs rapid diagnosis and decisionmaking to reduce the extremely poor prognosis. Key clinical-etiology-anatomy-patophysiology (CEAP) diagnostic aspects of aortic diseases are discussed in this document (project Vessels). PMID- 25693620 TI - [Distribution of values of glycated haemoglobin in a population with type 2 diabetes: a project Valetudo]. AB - Currently, there are no available data on distribution of the values of glycated haemoglobin in patients with type 2 diabetes in the Czech Republic. More frequent, efficacy and early application of new antidiabetic agents is limited by indication criterion which restricts the payment of this therapy for patients with poorly compensated diabetes defined by threshold value of 60 mmol/mol (6% IFCC). The study Valetudo analyzed distribution of glycated haemoglobin values in the random population of patients with type 2 diabetes and showed that within the critical range from 43 mmol/mol to 80 mmol/mol is the average frequency of patients from the whole population of 1.88%/1 mmol/mol glycated haemoglobin. Interpretation of data from cross-sectional studies is very difficult as they involve patients before treatment (possibly before the intensification of therapy) and also patients successfully treated.Key words: diabetes mellitus type 2 - distribution of HbA1c - glycated haemoglobin - HbA1c - Valetudo project. PMID- 25693621 TI - Interface controlled oxidation states in layered cobalt oxide nanoislands on gold. AB - Layered cobalt oxides have been shown to be highly active catalysts for the oxygen evolution reaction (OER; half of the catalytic "water splitting" reaction), particularly when promoted with gold. However, the surface chemistry of cobalt oxides and in particular the nature of the synergistic effect of gold contact are only understood on a rudimentary level, which at present prevents further exploration. We have synthesized a model system of flat, layered cobalt oxide nanoislands supported on a single crystal gold (111) substrate. By using a combination of atom-resolved scanning tunneling microscopy, X-ray photoelectron and absorption spectroscopies and density functional theory calculations, we provide a detailed analysis of the relationship between the atomic-scale structure of the nanoislands, Co oxidation states and substrate induced charge transfer effects in response to the synthesis oxygen pressure. We reveal that conversion from Co(2+) to Co(3+) can occur by a facile incorporation of oxygen at the interface between the nanoisland and gold, changing the islands from a Co-O bilayer to an O-Co-O trilayer. The O-Co-O trilayer islands have the structure of a single layer of beta-CoOOH, proposed to be the active phase for the OER, making this system a valuable model in understanding of the active sites for OER. The Co oxides adopt related island morphologies without significant structural reorganization, and our results directly demonstrate that nanosized Co oxide islands have a much higher structural flexibility than could be predicted from bulk properties. Furthermore, it is clear that the gold/nanoparticle interface has a profound effect on the structure of the nanoislands, suggesting a possible promotion mechanism. PMID- 25693622 TI - Intrapulmonary shunts and their clinical implications for the echocardiographer. PMID- 25693623 TI - Embryology and anatomy of intrapulmonary shunts. AB - Pulmonary vascular shunting poses a major clinical risk. In this brief overview, we discuss the morphological aspects of shunting vessels in the lung, their development, and the regulation of their patency. PMID- 25693624 TI - Clinical consideration for techniques to detect and quantify blood flow through intrapulmonary arteriovenous anastomoses: lessons from physiological studies. AB - Intrapulmonary arteriovenous anastomoses (IPAVA) are large diameter (>50 MUm) vascular conduits, present in >95% of healthy humans. Because IPAVA are large diameter pathways that allow blood flow to bypass the pulmonary capillary network, blood flow through IPAVA (QIPAVA) can permit the transpulmonary passage of particles larger than pulmonary capillaries. IPAVA have been known to exist for over 50 years, but their physiological and clinical significance are still being established; although, currently suggested roles for QIPAVA include allowing emboli to reach the systemic circulation and providing a source of shunt. Studying QIPAVA is an important area of research and as the suggested roles become better established, detecting and quantifying QIPAVA may become significantly more important in the clinic. Several techniques that can be used to quantify and/or detect QIPAVA in animals, ex vivo human/animal lungs, and intact healthy humans; microspheres, radiolabeled macroaggregated albumin particles, and saline contrast echocardiography, are reviewed with limitations and advantages to each. The current body of literature using these techniques to study QIPAVA in animals, ex vivo lungs, and healthy humans has established conditions when QIPAVA is present, such as during exercise or with arterial hypoxemia and conditions when QIPAVA is absent, such as at rest or during exercise breathing 100% O2 . Many of these physiological studies have direct application to patient populations and we discuss each of these findings in the context of their potential to influence the clinical utility, and interpretation, of the results from these techniques highlighted in this review. PMID- 25693625 TI - Intrapulmonary shunt and SCUBA diving: another risk factor? AB - Laboratory and field investigations have demonstrated that intrapulmonary arteriovenous anastomoses (IPAVA) may provide an additional means for venous gas emboli (VGE) to cross over to the arterial circulation due to their larger diameter compared to pulmonary microcirculation. Once thought to be the primary cause of decompression sickness (DCS), it has been demonstrated that, even in large quantities, their presence does not always result in injury. Normally, VGE are trapped in the site of gas exchange in the lungs and eliminated via diffusion. When VGE crossover takes place in arterial circulation, they have the potential to cause more harm as they are redistributed to the brain, spinal column, and other sensitive tissues. The patent foramen ovale (PFO) was once thought to be the only risk factor for an increase in arterialization; however, IPAVAs represent another pathway for this crossover to occur. The opening of IPAVAs is associated with exercise and hypoxic gas mixtures, both of which divers may encounter. The goal of this review is to describe how IPAVAs may impact diving physiology, specifically during decompression, and what this means for the individual diver as well as the future of commercial and recreational diving. Future research must continue on the relationship between IPAVAs and the environmental and physiological circumstances that lead to their opening and closing, as well as how they may contribute to diving injuries such as DCS. PMID- 25693626 TI - Identification and management of atypical hemolytic uremic syndrome immediately post-heart transplantation. AB - Atypical hemolytic uremic syndrome (aHUS) is a serious hematologic disorder with high mortality if left untreated. A comprehensive literature review revealed only two cases of aHUS post-heart transplantation. In both cases the disease developed after induction of calcineurin inhibitor therapy. We report a case of immediate post-heart transplantation aHUS, manifested before the induction of, and therefore not associated with, calcineurin inhibitors. PMID- 25693627 TI - Quadriceps neural alterations in anterior cruciate ligament reconstructed patients: A 6-month longitudinal investigation. AB - The purpose of this investigation was to evaluate differences in quadriceps corticospinal excitability, spinal-reflexive excitability, strength, and voluntary activation before, 2 weeks post and 6 months post-anterior cruciate ligament reconstruction (ACLr). This longitudinal, case-control investigation examined 20 patients scheduled for ACLr (11 females, 9 males; age: 20.9 +/- 4.4 years; height:172.4 +/- 7.5 cm; weight:76.2 +/- 11.8 kg) and 20 healthy controls (11 females, 9 males; age:21.7 +/- 3.7 years; height: 173.7 +/- 9.9 cm; weight: 76.1 +/- 19.7 kg). Maximal voluntary isometric contractions (MVIC), central activation ratio (CAR), normalized Hoffmann spinal reflexes, active motor threshold (AMT), and normalized motor-evoked potential (MEP) amplitudes at 120% of AMT were measured in the quadriceps muscle at the specific time points. ACLr patients demonstrated bilateral reductions in spinal-reflexive excitability compared with controls before surgery (P = 0.02) and 2 weeks post-surgery (P <= 0.001). ACLr patients demonstrated higher AMT at 6 months post-surgery (P <= 0.001) in both limbs. No MEP differences were detected. Quadriceps MVIC and CAR were lower in both limbs of the ACLr group before surgery and 6 months post surgery (P <= 0.05) compared with controls. Diminished excitability of spinal reflexive and corticospinal pathways are present at different times following ACLr and occur in combination with clinical deficits in quadriceps strength and activation. Early rehabilitation strategies targeting spinal-reflexive excitability may help improve postoperative outcomes, while later-stage rehabilitation may benefit from therapeutic techniques aimed at improving corticospinal excitability. PMID- 25693628 TI - Work-related skin diseases in Norway may be underreported: data from 2000 to 2013. PMID- 25693629 TI - Prevalence and patterns of alcohol use in pregnancy in remote Western Australian communities: The Lililwan Project. AB - INTRODUCTION AND AIMS: Alcohol use in pregnancy is thought to be common in remote Australian communities, but no population-based data are available. Aboriginal leaders in remote Western Australia invited researchers to determine the prevalence and patterns of alcohol use in pregnancy within their communities. DESIGN AND METHODS: A population-based survey of caregivers of all children born in 2002/2003 and living in the Fitzroy Valley in 2010/2011 (n = 134). Alcohol use risk was categorised using the Alcohol Use Disorders Identification Test consumption subset (AUDIT-C) tool. Birth and child outcomes were determined by interview, medical record review and physical examination. RESULTS: 127/134 (95%) eligible caregivers participated: 78% were birth mothers, 95% were Aboriginal and 55% reported alcohol use in index pregnancies; 88% reported first trimester drinking and 53% drinking in all trimesters. AUDIT-C scores were calculated for 115/127 women, of whom 60 (52%) reported alcohol use in pregnancy. Of the 60 women who drank (AUDIT-C score >= 1), 12% drank daily/almost daily, 33% drank 2-3 times per week; 71% drank >= 10 standard drinks on a typical occasion; 95% drank at risky or high-risk levels (AUDIT-C score >= 4). Mean AUDIT-C score was 8.5 +/- 2.3 (range 2-12). The most common drinking pattern was consumption of >= 10 standard drinks either 2-4 times per month (27%) or 2-3 times per week (27%). DISCUSSION AND CONCLUSIONS: High-risk alcohol use in pregnancy is common in remote, predominantly Aboriginal communities in north western Australia. Prevention strategies to reduce prenatal alcohol use are urgently needed. PMID- 25693630 TI - A Taphonomic Study Exploring the Differences in Decomposition Rate and Manner between Frozen and Never Frozen Domestic Pigs (Sus scrofa). AB - This research examined differences in decomposition rate and manner of domestic pig subjects (Sus scrofa) in never frozen (control) and previously frozen (experimental) research conditions. Eight control and experimental subjects were placed in an identical outdoor research environment. Daily quantitative and qualitative measurements were collected: abdominal circumference, total body score (TBS), temperature, photographs, descriptive decomposition stages, and visual observations. Field necropsies were performed at accumulated degree days (ADD) between 50 and 300 (Celsius). Paired samples t-tests of ADD to TBS >3.0, TBS >9.5, and TBS >16.0 indicate the rate of decomposition of experimental subjects was significantly slower than controls at both TBS >3 and >9.5 (p = 0.003 and p = 0.002, respectively). A suite of qualitative indicators of predecomposition freezing is also reported. The differences between experimental and control subjects suggest previously frozen subjects should not be used in taphonomic research, as results do not accurately reflect the "normal" taphonomic condition. PMID- 25693631 TI - p120-Catenin modulating nuclear factor-kappaB activation is partially RhoA/ROCKdependent in scratch injury. AB - p120-catenin (p120) is known as a cadherin-associated protein that participates in tumor metastasis and invasion, as well as an anti-inflammatory mediator. Recently, its anti-inflammatory role is drawing increasing attention, but the regulatory mechanisms are still unknown. Here, we report that p120 modulated inflammatory responses partially depends on RhoA/ROCK pathway in scratch-induced injury in human bronchial epithelial cells (BECs). For the first time, we found that p120 was significantly reduced in BECs after scratching, which could induce interleukin-8 (IL-8) production through nuclear factor-kappaB (NF-kappaB) activation accompanied with IkappaBalpha phosphorylation. Over-expression of p120 3A could inhibit NF-kappaB activation and IL-8 mRNA expression and protein synthesis after scratching, while p120 knockdown by small interfering RNA could promote NF-kappaB activation and IL-8 mRNA expression and protein synthesis after scratching. Furthermore, we found that RhoA was the binding partner of p120 in BECs. Although total RhoA and p120-binded RhoA remained unchanged, the RhoA activity was increased after scratching. Chemical blockade of RhoA/ROCK signaling (Y27632) inhibited scratch-induced nuclear translocation of NF-kappaB p65. Over expression of p120 3A attenuated scratch-induced RhoA activation, whereas silence of p120 significantly elevated scratch-induced RhoA activation in BCEs. Conclusively, these results indicate an anti-inflammatory effect of p120 in bronchial epithelial cells through its modulation of NF-kappaB signaling depending on RhoA/ROCK pathway. PMID- 25693632 TI - Evaluating noninvasive genetic sampling techniques to estimate large carnivore abundance. AB - Monitoring large carnivores is difficult because of intrinsically low densities and can be dangerous if physical capture is required. Noninvasive genetic sampling (NGS) is a safe and cost-effective alternative to physical capture. We evaluated the utility of two NGS methods (scat detection dogs and hair sampling) to obtain genetic samples for abundance estimation of coyotes, black bears and Canada lynx in three areas of Newfoundland, Canada. We calculated abundance estimates using program capwire, compared sampling costs, and the cost/sample for each method relative to species and study site, and performed simulations to determine the sampling intensity necessary to achieve abundance estimates with coefficients of variation (CV) of <10%. Scat sampling was effective for both coyotes and bears and hair snags effectively sampled bears in two of three study sites. Rub pads were ineffective in sampling coyotes and lynx. The precision of abundance estimates was dependent upon the number of captures/individual. Our simulations suggested that ~3.4 captures/individual will result in a < 10% CV for abundance estimates when populations are small (23-39), but fewer captures/individual may be sufficient for larger populations. We found scat sampling was more cost-effective for sampling multiple species, but suggest that hair sampling may be less expensive at study sites with limited road access for bears. Given the dependence of sampling scheme on species and study site, the optimal sampling scheme is likely to be study-specific warranting pilot studies in most circumstances. PMID- 25693633 TI - Mycoplasma pneumoniae and Chlamydia spp. infection in community-acquired pneumonia, Germany, 2011-2012. AB - Mycoplasma pneumoniae and Chlamydia spp., which are associated with community acquired pneumonia (CAP), are difficult to propagate, and can cause clinically indistinguishable disease patterns. During 2011-2012, we used molecular methods to test adult patients in Germany with confirmed CAP for infection with these 2 pathogens. Overall, 12.3% (96/783) of samples were positive for M. pneumoniae and 3.9% (31/794) were positive for Chlamydia spp.; C. psittaci (2.1%) was detected more frequently than C. pneumoniae (1.4%). M. pneumoniae P1 type 1 predominated, and levels of macrolide resistance were low (3.1%). Quarterly rates of M. pneumoniae-positive samples ranged from 1.5% to 27.3%, showing a strong epidemic peak for these infections, but of Chlamydia spp. detection was consistent throughout the year. M. pneumoniae-positive patients were younger and more frequently female, had fewer co-occurring conditions, and experienced milder disease than did patients who tested negative. Clinicians should be aware of the epidemiology of these pathogens in CAP. PMID- 25693634 TI - CD11c(+) macrophages and levels of TNF-alpha and MMP-3 are increased in synovial and adipose tissues of osteoarthritic mice with hyperlipidaemia. AB - To understand more clearly the link between osteoarthritis and hyperlipidaemia, we investigated the inflammatory macrophage subsets and macrophage-regulated matrix metalloprotease-3 (MMP-3) and A disintegrin and metalloprotease with thrombospondin motifs-4 (ADAMTS4) in synovial (ST) and adipose tissues (AT) of osteoarthritic mice with hyperlipidaemia (STR/Ort). CD11c(+) F4/80(+) CD11b(+) macrophage populations in the ST and AT of 9-month-old STR/Ort and C57BL/6J mice were characterized and compared by flow cytometry and real-time polymerase chain reaction (PCR) analyses. Expression of tumour necrosis factor (TNF)-alpha, MMP-3 and ADAMTS4, and the response of these factors to anionic liposomal clodronate induced-macrophage depletion were also evaluated by real-time PCR. Expression of TNF-alpha in CD11c(+) cells, which were isolated by magnetic beads, was compared to CD11c(-) cells. In addition, the effect of TNF-alpha on cultured synovial fibroblasts and adipocytes was investigated. CD11c(+) F4/80(+) CD11b(+) macrophages were increased in ST and AT of STR/Ort mice. The CD11c(+) cell fraction highly expressed TNF-alpha. Expression of TNF-alpha and MMP3 was increased in ST and AT, and was decreased upon macrophage depletion. TNF-alpha treatment of cultured synovial fibroblasts and adipocytes markedly up-regulated MMP-3. CD11c(+) F4/80(+) CD11b(+) macrophages were identified as a common inflammatory subset in the AT and ST of STR/Ort mice with hyperlipidaemia. The induction of inflammation in AT and ST may be part of a common mechanism that regulates MMP3 expression through TNF-alpha. Our findings suggest that increased numbers of CD11c(+) macrophages and elevated levels of TNF-alpha and MMP-3 in AT and ST may explain the relationship between hyperlipidaemia and OA. PMID- 25693635 TI - Influence of connection type on the biomechanical behavior of distal extension mandibular removable partial dentures supported by implants and natural teeth. AB - Few studies are performed to evaluate the influence of connection type on the stress distribution of distal extension mandibular removable partial dentures (RPDs) supported by both implants and natural teeth. In this study, five three dimensional finite element models were prepared to simulate mandibular bilateral partially edentulous arches. Four were RPDs supported by both implants and natural teeth, and the other one was RPDs supported only by natural teeth. The maximum equivalent (EQV) stress values of bone around implants, the abutments, and the mucosa displacements of the related supporting structures were measured. It was found that a non-rigid telescopic coping was more favorable to protect the implant than a rigid telescopic coping. Compared with other connection types, the easy resilient attachment (ERA) system seemed to be effective to associate implant without complications. However, the results obtained in the present study should be cautiously interpreted in the clinic. PMID- 25693636 TI - Letter to the editor: response to my letter by Geoff Vaughan and Malcolm Grimston. PMID- 25693637 TI - Effect of 3,4-dihydroxyacetophenone on endothelial dysfunction in obese rats. AB - CONTEXT: 3,4-Dihydroxyacetophenone (DHAP) has been reported to possess cardiovascular pharmacological effects. OBJECTIVE: This study was designed to determine whether DHAP could improve endothelial function in obese rats. MATERIALS AND METHODS: Wistar rats were randomly divided into control, obesity, and DHAP groups and fed a normal, high-fat, and high-fat plus DHAP (10 mg kg(-1) d(-1)) diet, respectively, for 8 weeks. Endothelial-dependent vasodilatation was assessed. Endothelial nitric oxide synthase (eNOS) activity and nitric oxide (NO) production in endothelial cells were determined. Nuclear transcription factor kappa B (NF-kappaB) expression and superoxide production in aorta were evaluated. RESULTS: DHAP treatment significantly decreased plasma triglycerides (0.94 +/- 0.31 mmol/l versus 1.36 +/- 0.29 mmol/l, p < 0.05) and free fatty acids (0.53 +/- 0.15 mmol/l versus 0.99 +/- 0.24 mmol/l, p < 0.05), reduced serum tumor necrosis factor alpha (35.56 +/- 9.28 pg/ml versus 68.3 +/- 10.24 pg/ml, p < 0.05) and malondialdehyde (2.94 +/- 0.58 pg/ml versus 6.45 +/- 0.70 pg/ml, p < 0.05), and increased serum adiponectin levels (164.5 +/- 34.5 MUg/l versus 84.5 +/- 20.4 MUg/l, p < 0.05). DHAP enhanced endothelial-dependent vasodilatation and improved endothelial function in obese rats (p < 0.05). eNOS activity and NO production in endothelial cells significantly decreased and NF-kappaB activation and superoxide production in aorta significantly increased in obese rats compared with the control group (p < 0.05). However, DHAP treatment significantly up-regulated the eNOS-NO pathway and decreased NF-kappaB activation and superoxide production (p < 0.05). CONCLUSION: DHAP improved endothelial function in obese rats. This beneficial effect may be associated with up-regulation of the eNOS-NO pathway by improving lipid metabolism and reducing oxidative stress and inflammation activity. PMID- 25693638 TI - EGF-coated nano-dendriplexes for tumor-targeted nucleic acid delivery in vivo. AB - The clinical success of therapeutic DNA is still hindered due to the lack of effective delivery carriers. Here, we designed a tumor-targeted gene nano delivery system based on EGFR targeting strategy. Epidermal growth factor (EGF) was introduced to nano-complexes of PAMAM dendrimer and DNA via electrostatic interactions to form self-assembled PAMAM/DNA/EGF nano-complexes. The properties of self-assembled complexes were characterized by gel retardation assay and particle size and zeta potential analysis. Meanwhile, the toxicity of EGF dendriplexes was evaluated by the MTT assay, which indicated that the complexes exhibited decreased cytotoxicity with the incorporation of EGF. We labeled polyamidoamine (PAMAM) dendrimers with FITC or a near-infrared (NIR) dye Lss670 and tested the cellular uptake in vitro and biodistribution in xenograft mouse tumor models. As compared to dendriplexes, the ternary EGF-dendriplexes showed a significantly higher cellular uptake into HepG2 cells due to the specific binding between EGF and EGF receptor (EGFR) over expressed on HepG2 cells, which resulted in the enhanced gene transfection efficiency. The biodistribution of EGF dendriplexes in vivo was monitored with in vivo imaging technique, which indicated that EGF-dendriplexes enhanced EGFR-positive tumor-targeted biodistribution. These findings indicate that this novel nano-vector realized efficiently tumor-targeting gene delivery and high efficient gene expression in vivo, and it may possess a potential targeting gene delivery system in cancer therapy. PMID- 25693639 TI - Development of an anti-microbial peptide-mediated liposomal delivery system: a novel approach towards pH-responsive anti-microbial peptides. AB - On one hand, the application of anti-microbial peptides (AMPs) in the construction of AMPs-mediated drug delivery system has not yet been fully exploited; on the other hand, its non-selectivity in vivo has also limited its clinical application. In this work, we chose one pH-responsive peptide, [D]-H6L9, and functionalized it onto the surface of liposomes (D-Lip). The protonation of histidines in the sequence of [D]-H6L9 under pH 6.3 could switch the surface charge of D-Lip from negative (under pH 7.4) to positive (under pH 6.3), and the cellular uptake and tumor spheroids uptake were increased accordingly. Lysosome co-localization assay suggested that there was only little overlap of D-Lip with lysosomes in 12 h, which indicated that D-Lip could escape lysosomes effectively. In vivo biodistribution assay on C26 tumor-bearing BALB/C mice showed that DiR labeled D-Lip could reach tumors as much as PEG-Lip, and both tumor slices and quantitative measurement of dispersed cells of in vivo tumors by flow cytometry demonstrated that D-Lip could be taken up by tumors more efficiently. Therefore, we have established an anti-microbial peptide-mediated liposomal delivery system for tumor delivery. PMID- 25693640 TI - A photo-responsive peptide- and asparagine-glycine-arginine (NGR) peptide mediated liposomal delivery system. AB - The conjugation of tunable peptides or materials with nanocarriers represents a promising approach for drug delivery to tumor cells. In this study, we report the development of a novel liposomal carrier system that exploits the cell surface binding synergism between photo-sensitive peptides (PSPs) and targeting ligands. The positive charges of the lysine residues on the cell-penetrating peptides (CPPs) were temporarily caged by the photolabile-protective groups (PG), thereby forming a PSP. Furthermore, this PSP enhances specific uptake into cancer cells after rapidly uncaging the PG via near-infrared (NIR) light illumination. In the circulatory system, the cell penetrability of PSP was hindered. In contrast, the asparagine-glycine-arginine (NGR) peptide moieties, selectively bind to CD13 positive tumors, were attached to the nanocarrier to facilitate the active accumulation of this liposomal carrier in tumor tissue. The dual-modified liposomes (PSP/NGR-L) were prepared by emulsification method, and the concentrations of DSPE-PEG2000-psCPP and DSPE-PEG5000-NGR in the liposomes were chosen to be 4% and 1% (molar ratio), respectively. The mean particle size of the PSP/NGR-L was about 95 nm, and the drug entrapment efficiency was more than 90%. Cellular uptake results demonstrated that the proposed PSP/NGR-L had an enhancement of cancer cell recognition and specific uptake. Furthermore, the PSP/NGR-L demonstrated a stronger antitumor efficacy in the HT-1080 tumor model in nude mice with the aid of NIR illumination. PMID- 25693641 TI - Novel pH-sensitive hydrogels for 5-aminosalicylic acid colon targeting delivery: in vivo study with ulcerative colitis targeting therapy in mice. AB - Current guidelines recommend patients with active and mild-to-moderate ulcerative colitis (UC), who have received initial therapy with 5-aminosalicylic acid (5 ASA). In this study, a novel drug delivery vehicle achieved by pH-sensitive hydrogels was applied to 5-ASA. In our previous work, a novel P(CE-MAA-MEG) pH sensitive hydrogel was successfully synthesized by the heat-initiated free radical polymerization method. The aim of this study is to investigate its site specific delivering of drugs to the colon and evaluate its colon-targeting characteristic in vivo. 5-ASA was chosen as a model drug and successfully loaded in the hydrogel. In vitro investigations were carried out to evaluate its release process. Above all, animal treatment results reveal an obvious effect on the UC healing. Therefore, all results suggested that the developed 5-ASA-P(CE-MAA-MEG) hydrogel (5-ASA-GEL) as a colon-targeting vector might have a great potential application in the UC therapy. PMID- 25693642 TI - In vitro and in vivo study of Baicalin-loaded mixed micelles for oral delivery. AB - The aim of this work was to research the potential functions and the mechanism of absorption of the baicalin (BC)-loaded micelle system that contained Pluronic P123 copolymer (P123) and sodium taurocholate (ST) as carrier materials via oral delivery. Based on the numerous advantages of oral administration, such as cost effectiveness, flexible and accommodated dosing regimen, and improved compliance for patients, the ST-P123-MMs system would be evaluated as oral delivery vehicle of BC. In this study, X-ray powder diffractometer analysis confirmed the phase change of BC after being incorporated in mixed micelles. The release study in simulated gastric fluid/simulated intestinal fluid exhibited that BC-loaded ST P123-MMs presented a sustained drug release behavior. Compared with coumarin-6 solution, higher cellar uptake efficiency was achieved for coumarin-6 loaded ST P123-MMs towards Caco-2 cell lines. The in situ perfusion test in rat indicated that the absorption of BC-loaded ST-P123-MMs in intestinal tract was stronger than BC solution. After oral administration, the Cmax and AUC of BC-loaded ST P123-MMs were 1.77 times and 1.54 times as high as those of BC suspension in rat, respectively. Promisingly, the formulated BC exhibited a prolonged circulation time with the oral bioavailability increased to 1.54-fold compared with the control group. These results all suggested that P123 and ST mixed micelles could serve as a promising approach to oral administration of BC. PMID- 25693643 TI - Differential effects of the extracellular microenvironment on human embryonic stem cell differentiation into keratinocytes and their subsequent replicative life span. AB - Culture microenvironment plays a critical role in the propagation and differentiation of human embryonic stem cells (hESCs) and their differentiated progenies. Although high efficiency of hESC differentiation to keratinocytes (hESC-Kert) has been achieved, little is known regarding the effects of early culture microenvironment and pertinent extracellular matrix (ECM) interactions during epidermal commitment on subsequent proliferative capacity of hESC-Kert. The aim of this study is to evaluate the effects of the different ECM microenvironments during hESC differentiation on subsequent replicative life span of hESC-Kert. In doing so, H1-hESCs were differentiated to keratinocytes (H1 Kert) in two differentiation systems. The first system employed autologous fibroblast feeder support, in which keratinocytes (H1-Kert(ACC)) were derived by coculture of hESCs with hESC-derived fibroblasts (H1-ebFs). The second system employed a novel decellularized matrix from H1-ebFs to create a dermoepidermal junction-like (DEJ) matrix. H1-Kert(AFF) were derived by differentiation of hESCs on the feeder-free system employing the DEJ matrix. Our study indicated that the feeder-free system with the use of DEJ matrix was more efficient in differentiation of hESCs toward epidermal progenitors. However, the feeder-free system was not sufficient to support the subsequent replicative capacity of differentiated keratinocytes. Of note, H1-Kert(AFF) showed limited replicative capacity with reduced telomere length and early cellular senescence. We further showed that the lack of cell-cell interactions during epidermal commitment led to heightened production of TGF-beta1 by hESC-Kert during extended culture, which in turn was responsible for resulting in the limited replicative life span with cellular senescence of hESC-Kert derived under the feeder-free culture system. This study highlights for the first time the importance of the culture microenvironment and cell-ECM interactions during differentiation of hESCs on subsequent replicative life span and cellular senescence of the differentiated keratinocytes, with implications for use of these cells for applications in tissue engineering and regenerative medicine. PMID- 25693644 TI - AAP President's Address. PMID- 25693645 TI - Sixteen years of the roche organ transplantation research foundation. PMID- 25693646 TI - Understanding suicide among older adults: a review of psychological and sociological theories of suicide. AB - OBJECTIVES: Older adults die by suicide at a higher rate than any other age group in nearly every country globally. Suicide among older adults has been an intractable clinical and epidemiological problem for decades, due in part to an incomplete understanding of the causes of suicide, as well as imprecision in the prediction and prevention of suicidal thoughts and behaviors in later life. Theory-driven investigations hold promise in addressing these gaps by systematically identifying testable, and thus falsifiable, mechanisms that may better explain this phenomenon and also point to specific interventions. METHOD: In this article, we comprehensively review key extant psychological and sociological theories of suicide and discuss each theory's applicability to the understanding and prevention of suicide among older adults. RESULTS: Despite a modest number of theories of suicide, few have undergone extensive empirical investigation and scrutiny, and even fewer have been applied specifically to older adults. CONCLUSION: To advance the science and contribute findings with a measurable clinical and public health impact, future research in this area, from conceptual to applied, must draw from and integrate theory. PMID- 25693647 TI - A mini review on central nervous system potential of isatin derivatives. AB - Isatin is a heterocyclic moiety which can be used for the synthesis of a large variety of heterocyclic compounds such as quinolines, indoles and as raw material for medicinal important drugs. This review gives an overview of the advances of isatin for the synthesis of various heterocyclic compounds and shows the various biological potentials such as anticonvulsant, sedative, hypnotic, monoamine oxidase inhibitors, antianxiety, antipsychoactives activity etc. Isatin derivatives displayed as potent anticonvulsant potential in a large variety of preclinical anticonvulsant models. Present review article is an attempt to compile the various central nervous system potential of synthesized isatin analogs which will serve as a valuable source of information for the researchers working in this field. PMID- 25693648 TI - Systematic review: Whipple's disease (Tropheryma whipplei infection) and its unmasking by tumour necrosis factor inhibitors. AB - BACKGROUND: The classical form of Whipple's disease (WD), clinically characterised by arthropathy, diarrhoea and weight loss, is rare. Recently, other more frequent forms of Tropheryma whipplei infection have been recognised. The clinical spectrum includes an acute, self-limiting disease in children, localised forms affecting cardiac valves or the central nervous system without intestinal symptoms, and asymptomatic carriage of T. whipplei which is found in around 4% of Europeans. Genomic analysis has shown that T. whipplei represents a host dependent or opportunistic bacterium. It has been reported that the clinical course of T. whipplei infection may be influenced by medical immunosuppression. AIM: To identify associations between immunomodulatory treatment and the clinical course of T. whipplei infection. METHODS: A PubMed literature search was performed and 19 studies reporting on immunosuppression, particularly therapy with tumour necrosis factor inhibitors (TNFI) prior to the diagnosis in 41 patients with Whipple?s disease, were evaluated. RESULTS: As arthritis may precede the diagnosis of WD by many years, a relevant percentage (up to 50% in some reports) of patients are treated with immunomodulatory drugs or with TNFI. Many publications report on a complicated Whipple?s disease course or T. whipplei endocarditis following medical immunosuppression, particularly after TNFI. Standard diagnostic tests such as periodic acid-Schiff stain used to diagnose Whipple?s disease often fail in patients who are pre-treated by TNFI. CONCLUSIONS: In cases of doubt, Whipple?s disease should be excluded before therapy with TNFI. The fact that immunosuppressive therapy contributes to the progression of T. whipplei infection expands our pathogenetic view of this clinical entity. PMID- 25693649 TI - Molecular interactions and immune responses between Maize fine streak virus and the leafhopper vector Graminella nigrifrons through differential expression and RNA interference. AB - Graminella nigrifrons is the only known vector for Maize fine streak virus (MFSV). In this study, we used real-time quantitative PCR to compare the expression profiles of transcripts that putatively function in the insect immune response: four peptidoglycan recognition proteins (PGRP-SB1, -SD, -LC and LB), Toll, spaetzle, defensin, Dicer-2 (Dcr-2), Argonaut-2 (Ago-2) and Arsenic resistance protein 2 (Ars-2). Except for PGRP-LB and defensin, transcripts involved in humoral pathways were significantly suppressed in G. nigrifrons fed on MFSV-infected maize. The abundance of three RNA interference (RNAi) pathway transcripts (Dcr-2, Ago-2, Ars-2) was significantly lower in nontransmitting relative to transmitting G. nigrifrons. Injection with double-stranded RNA (dsRNA) encoding segments of the PGRP-LC and Dcr-2 transcripts effectively reduced transcript levels by 90 and 75% over 14 and 22 days, respectively. MFSV acquisition and transmission were not significantly affected by injection of either dsRNA. Knock-down of PGRP-LC resulted in significant mortality (greater than 90%) at 27 days postinjection, and resulted in more abnormal moults relative to those injected with Dcr-2 or control dsRNA. The use of RNAi to silence G. nigrifrons transcripts will facilitate the study of gene function and pathogen transmission, and may provide approaches for developing novel targets of RNAi based pest control. PMID- 25693650 TI - Variation in Inpatient Consultation Among Older Adults in the United States. AB - BACKGROUND: Differences among hospitals in the use of inpatient consultation may contribute to variation in outcomes and costs for hospitalized patients, but basic epidemiologic data on consultations nationally are lacking. OBJECTIVE: The purpose of the study was to identify physician, hospital, and geographic factors that explain variation in rates of inpatient consultation. DESIGN: This was a retrospective observational study. SETTING AND PARTICIPANTS: This work included 3,118,080 admissions of Medicare patients to 4,501 U.S. hospitals in 2009 and 2010. MAIN MEASURES: The primary outcome measured was number of consultations conducted during the hospitalization, summarized at the hospital level as the number of consultations per 1,000 Medicare admissions, or "consultation density." KEY RESULTS: Consultations occurred 2.6 times per admission on average. Among non critical access hospitals, use of consultation varied 3.6-fold across quintiles of hospitals (933 versus 3,390 consultations per 1,000 admissions, lowest versus highest quintiles, p < 0.001). Sicker patients received greater intensity of consultation (rate ratio [RR] 1.18, 95% CI 1.17-1.18 for patients admitted to ICU; and RR 1.19, 95% CI 1.18-1.20 for patients who died). However, even after controlling for patient-level factors, hospital characteristics also predicted differences in rates of consultation. For example, hospital size (large versus small, RR 1.31, 95% CI 1.25-1.37), rural location (rural versus urban, RR 0.78, CI 95% 0.76-0.80), ownership status (public versus not-for-profit, RR 0.94, 95% CI 0.91-0.97), and geographic quadrant (Northeast versus West, RR 1.17, 95% CI 1.12-1.21) all influenced the intensity of consultation use. CONCLUSIONS: Hospitals exhibit marked variation in the number of consultations per admission in ways not fully explained by patient characteristics. Hospital "consultation density" may constitute an important focus for monitoring resource use for hospitals or health systems. PMID- 25693651 TI - Association of Care Practices with Suicide Attempts in US Veterans Prescribed Opioid Medications for Chronic Pain Management. AB - IMPORTANCE: Patients receiving opioid therapy are at elevated risk of attempting suicide. Guidelines recommend practices to mitigate risk, but it is not known whether these are effective. OBJECTIVE: Our aim was to examine associations between the receipt of guideline-recommended care for opioid therapy and risk of suicide attempt. DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective analysis of administrative data for all Veteran patients prescribed any short acting opioids on a chronic basis or any long-acting opioids from the Veterans Health Administration during fiscal year 2010. MAIN OUTCOMES AND MEASURES: Multivariate, mixed-effects logistic regression analyses were conducted to define the associations between the risk of suicide attempt and receipt of guideline recommended care at the individual level and rates of use of recommended care at the facility level, while accounting for patient risk factors. RESULTS: At the individual level, having a mood disorder was highly associated with suicide attempts (odds ratios [ORs] = 3.5, 3.9; 95% confidence intervals [CIs] = 3.3-3.9, 3.3-4.6 for chronic short-acting and long-acting groups, respectively). At the facility level, patients on opioid therapy within the facilities ordering more drug screens were associated with decreased risk of suicide attempt (ORs = 0.2, 0.3; CIs = 0.1-0.3, 0.2-0.6 for chronic short-acting and long-acting groups, respectively). In addition, patients on long-acting opioid therapy within the facilities providing more follow-up after new prescriptions were associated with decreased risk of suicide attempt (OR = 0.2, CI = 0.0-0.7), and patients on long acting opioid therapy within the facilities having higher sedative co prescription rates were associated with increased risk of suicide attempt (OR = 20.3, CI = 1.1-382.2). CONCLUSIONS AND RELEVANCE: Encouraging facilities to make more consistent use of drug screening, provide follow-up within 4 weeks for patients initiating new opioid prescriptions, and avoid sedative co-prescription in combination with long-acting opioids may help prevent suicide attempts. Some clinicians may selectively employ guideline-recommended practices with at-risk patients. PMID- 25693652 TI - Tolerability of High-Volume Subcutaneous Injections of a Viscous Placebo Buffer: A Randomized, Crossover Study in Healthy Subjects. AB - Monoclonal antibody biotherapeutics are often administered by subcutaneous (SC) injection. Due to dose requirements and formulation limitations, SC injections >1 mL are often required. We used a viscous placebo buffer (5 cP), characteristic of a high-concentration antibody formulation, to investigate the effect of dose volume and injection rate on the tolerability of higher-volume SC injections. In this randomized, crossover, single-center study, 48 healthy adults received one 1.2-mL bolus injection over 5 s and three 3.5-mL injections over 1, 4, and 10 min in different abdominal quadrants, with each injection separated by approximately 2 h. The primary objective was to compare pain scores associated with the injections, immediately after administration and 1 h later, using a 100-mm visual analog scale (VAS). Secondary objectives included assessment of adverse events, including injection site reactions and swelling. Mean age was 38.4 (11.6) years and 20 subjects (42%) were female. Lowest mean VAS score was for the 10-min (6.83 mm) and highest for the 1-min injection (19.13 mm). One hour after administration, mean VAS scores were <3.5 mm for all injections. Swelling was similar among the three 3.5-mL injections. After needle removal, leakage occurred following 14 (29%) 1.2-mL injections, eight (17%) 4-min injections, five (10%) 1 min injections, and four (8%) 10-min injections. Fifteen subjects (31%) experienced an adverse event, none of which was serious, fatal, or led to study discontinuation. All injection durations were well tolerated, suggesting a single large-volume SC injection of a biotherapeutic agent could be used instead of multiple injections. PMID- 25693653 TI - A general route toward complete room temperature processing of printed and high performance oxide electronics. AB - Critical prerequisites for solution-processed/printed field-effect transistors (FETs) and logics are excellent electrical performance including high charge carrier mobility, reliability, high environmental stability and low/preferably room temperature processing. Oxide semiconductors can often fulfill all the above criteria, sometimes even with better promise than their organic counterparts, except for their high process temperature requirement. The need for high annealing/curing temperatures renders oxide FETs rather incompatible to inexpensive, flexible substrates, which are commonly used for high-throughput and roll-to-roll additive manufacturing techniques, such as printing. To overcome this serious limitation, here we demonstrate an alternative approach that enables completely room-temperature processing of printed oxide FETs with device mobility as large as 12.5 cm(2)/(V s). The key aspect of the present concept is a chemically controlled curing process of the printed nanoparticle ink that provides surprisingly dense thin films and excellent interparticle electrical contacts. In order to demonstrate the versatility of this approach, both n-type (In2O3) and p-type (Cu2O) oxide semiconductor nanoparticle dispersions are prepared to fabricate, inkjet printed and completely room temperature processed, all-oxide complementary metal oxide semiconductor (CMOS) invertors that can display significant signal gain (~18) at a supply voltage of only 1.5 V. PMID- 25693654 TI - Surgical management of recurrent upper vaginal prolapse following sacral colpopexy. AB - INTRODUCTION AND HYPOTHESIS: As sacral colpopexy (SC) is increasingly utilised in the surgical management of apical prolapse, we will undoubtedly be asked to manage recurrent prolapse after SC. We present a four-step technique of performing a repeated laparoscopic sacral colpopexy (LSC) for the surgical management of recurrent upper vaginal prolapse after SC surgery. METHODS: Between July 2012 and July 2013 women presenting with symptomatic post-SC vault prolapse were prospectively evaluated. Peri-operative morbidity and short-term complications were recorded. Surgical outcomes were objectively assessed utilising the Pelvic Organ Prolapse Quantification (POP-Q) system, the Australian Pelvic Floor Questionnaire (APFQ) and the Patient Global Impression of Improvement (PGI-I). RESULTS: Five women underwent LSC. Extensive adhesiolysis was required in three patients and the dissection was characterised by marked fibrosis. The mesh remained attached to the sacrum and had limited contact with the anterior vagina and vault in all cases. At a mean follow-up of 8.5 months all women had resolution of the awareness of prolapse, less than stage 2 prolapse on examination and high levels of satisfaction on PGI-I. CONCLUSIONS: While the repeat LSC is feasible, safe and effective, adhesions and marked fibrosis make this a challenging intervention. Further evaluation is required. PMID- 25693655 TI - Creating a gold standard surgical device: scientific discoveries leading to TVT and beyond: Ulf Ulmsten Memorial Lecture 2014. AB - INTRODUCTION AND HYPOTHESIS: The discovery of tension-free vaginal tape (TVT) began in 1986 with two unrelated observations: pressure applied unilaterally at the midurethra controlled urine loss on coughing; implanted Teflon tape caused a collagenous tissue reaction. METHODS AND RESULTS: In 1987, Mersilene tape was implanted retropubically in 13 large dogs, with the aim of creating an artificial collagenous pubourethral neoligament. Extensive testing showed that the operation was safe and effective. In 1988-1989, human testing was carried out (n = 30). Mersilene tape cured 100 % of stress and mixed incontinence with a sling in situ; however, there was simultaneous recurrence of the two symptoms in 50 % on sling removal. X-rays showed no elevation of the bladder neck. In 1990-1993, collaboration with Ulf Ulmsten took place: a permanently implanted tape was required. Polypropylene was the ideal material. In 2003, the neoligament principle was applied as an adjustable "micro" sling to the arcus tendineus fasciae pelvis (ATFP), cardinal, uterosacral ligaments, and perineal body for cure of cystocele, rectocele, and apical prolapse. It was found that symptoms such as urgency, nocturia, chronic pelvic pain, obstructive defecation syndrome (ODS), and fecal incontinence were frequently cured or improved. CONCLUSIONS: The lecture concluded with advice to younger members. Without new paradigms, there are no randomized controlled trials, no meta-analyses, Cochrane. Indeed, no progress. Be open to new concepts. Read Kuhn's "The Structure of Scientific Revolutions" to understand the discovery process. Examine the relationship among symptoms, ATFP, cardinal, uterosacral ligaments, and the perineal body. This is the next paradigm. Don't disregard anomalies. Pursue them. They are the pathway to discovery. Innovation is born from challenge, not conformity. Persist, even when meeting resistance. Resistance is a sign that your discovery is important. PMID- 25693656 TI - Unravelling the complex genetic background of atopic dermatitis: from genetic association results towards novel therapeutic strategies. AB - Atopic dermatitis (AD) is a chronic inflammatory skin disease arising from complex interaction between genetic and environmental factors. As the starting point of the so-called "atopic march", e.g. the progression towards allergic asthma in some but not all affected children, AD has come into focus for potential disease-modifying strategies. To elucidate the genetic factors influencing AD development, linkage, association as well as genome-wide association studies have been performed over the last two decades. The results suggest that besides variation in immune-mediated pathways, an intact skin barrier function plays a key role in AD development. Mutations in the gene encoding filaggrin, a major structural protein in the epidermis, have been consistently associated with AD, especially the early-onset persistent form of disease, and are regarded as the most significant known risk factor for AD development to date. Additionally, variation in some other genes involved in skin integrity and barrier function have shown association with AD. However, the known genetic risk factors can only explain a small part of the heritability at the moment. Whole-exome or whole-genome sequencing studies have not been reported yet, but will probably soon evaluate the influence of rare variations for AD development. Additionally, large multi-centre studies comprehensively incorporating gene-gene and gene-environment interactions as well as epigenetic mechanisms might further elucidate the genetic factors underlying AD pathogenesis and, thus, open the way for a more individualized treatment in the future. PMID- 25693657 TI - The co-operative performance of a hydrated salt assisted sponge like P(VDF-HFP) piezoelectric generator: an effective piezoelectric based energy harvester. AB - We have prepared hydrated salt filler assisted sponge like P(VDF-HFP) micro porous electroactive films to fabricate a high performance flexible piezoelectric generator (FPG). These FPGs deliver up to 8 V of open circuit voltage under external stress and also generate enough power to turn on at least fifteen commercial blue light emitting diodes (LEDs) instantly. Furthermore, capacitors have been successfully charged by repeated finger touches indicating the potential of the FPGs to be used as self-powered devices where different types of mechanical vibrations can be applied. The high performance of FPGs might be attributed to the co-operative contribution from the porous electret structure and electroactive nature of the P(VDF-HFP) film, as they also enhance the dielectric permittivity. This approach is simple, cost-effective, and well-suited for large-scale fabrication of high-performance FPGs. PMID- 25693658 TI - Neurodevelopmental effects of fetal antiepileptic drug exposure. AB - Many studies investigating cognitive outcomes in children of women with epilepsy report an increased risk of mental impairment. Verbal scores on neuropsychometric measures may be selectively more involved. While a variety of factors contribute to the cognitive problems of children of women with epilepsy, antiepileptic drugs (AEDs) appear to play a major role. The mechanisms by which AEDs affect neurodevelopmental outcomes remain poorly defined. Animal models suggest that AED induced apoptosis, altered neurotransmitter environment, and impaired synaptogenesis are some of the mechanisms responsible for cognitive and behavioral teratogenesis. AEDs that are known to induce apoptosis, such as valproate, appear to affect children's neurodevelopment in a more severe fashion. Fetal valproate exposure has dose-dependent associations with reduced cognitive abilities across a range of domains, and these appear to persist at least until the age of 6. Some studies have shown neurodevelopmental deficiencies associated with the use of phenobarbital and possibly phenytoin. So far, most of the investigations available suggest that fetal exposures to lamotrigine or levetiracetam are safer with regard to cognition when compared with other AEDs. Studies on carbamazepine show contradictory results, but most information available suggests that major poor cognitive outcomes should not be attributed to this medication. Overall, children exposed to polytherapy prenatally appear to have worse cognitive and behavioral outcomes compared with children exposed to monotherapy, and with the unexposed. There is an increase risk of neurodevelopmental deficits when polytherapy involves the use of valproate versus other agents. PMID- 25693659 TI - Ergostatrien-3beta-ol from Antrodia camphorata inhibits diabetes and hyperlipidemia in high-fat-diet treated mice via regulation of hepatic related genes, glucose transporter 4, and AMP-activated protein kinase phosphorylation. AB - This study was designed to explore the effects and mechanism of ergostatrien 3beta-ol (EK100) from the submerged whole broth of Antrodia camphorata on diabetes and dyslipidemia in high fat diet (HFD)-fed mice for 12 weeks. The C57BL/6J mouse fed with a high fat diet (HFD) could induce insulin resistance and hyperlipidemia. After 8 week of induction, mice were receiving EK100 (at three dosages) or fenofibrate (Feno) or rosiglitazone (Rosi) or vehicle by oral gavage 4 weeks afterward. HFD-fed mice display increased blood glucose, glycated hemoglobin (HbA1c), total cholesterol (TC), triglyceride (TG), insulin, and leptin levels. These blood markers were significantly lower in EK100-treated mice, and finally ameliorated insulin resistance. EK100 treatment exhibited reduced hepatic ballooning degeneration and size of visceral adipocytes. Glucose transporter 4 (GLUT4) proteins and phosphorylation of Akt in skeletal muscle were significantly increased in EK100- and Rosi-treated mice. EK100, Feno, and Rosi treatment led to significant increases in phosphorylation of AMP-activated protein kinase (phospho-AMPK) protein in both skeletal muscle and liver. Moreover, EK100 caused a decrease in hepatic expressions of phosphenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6 Pase), and decreased glucose production. EK100 lowered blood TG level by inhibition of hepatic fatty acid synthesis by dampening sterol response element binding protein-1c (SREBP-1c) but increasing expression of peroxisome proliferator activated receptor alpha (PPARalpha). Moreover, EK100-treated mice reduced blood TC levels by decreased hepatic expressions of SREBP2, which plays a major role in the regulation of cholesterol synthesis. EK100 increased high-density lipoprotein cholesterol (HDL C) concentrations by increasing expressions of apolipoprotein A-I (apo A-I) in liver tissue. Our findings manifest that EK100 may have therapeutic potential in treating type 2 diabetes associated with hyperlipidemia in HFD-fed mice by regulation of GLUT4, PEPCK, G6 Pase, SREBP1c, SREBP2, apo A-I, and AMPK phosphorylation. PMID- 25693660 TI - Quantifying the erosion of natural darkness in the global protected area system. AB - The nighttime light environment of much of the earth has been transformed by the introduction of electric lighting. This impact continues to spread with growth in the human population and extent of urbanization. This has profound consequences for organismal physiology and behavior and affects abundances and distributions of species, community structure, and likely ecosystem functions and processes. Protected areas play key roles in buffering biodiversity from a wide range of anthropogenic pressures. We used a calibration of a global satellite data set of nighttime lights to determine how well they are fulfilling this role with regard to artificial nighttime lighting. Globally, areas that are protected tend to be darker at night than those that are not, and, with the exception of Europe, recent regional declines in the proportion of the area that is protected and remains dark have been small. However, much of these effects result from the major contribution to overall protected area coverage by the small proportion of individual protected areas that are very large. Thus, in Europe and North America high proportions of individual protected areas (>17%) have exhibited high levels of nighttime lighting in all recent years, and in several regions (Europe, Asia, South and Central America) high proportions of protected areas (32-42%) have had recent significant increases in nighttime lighting. Limiting and reversing the erosion of nighttime darkness in protected areas will require routine consideration of nighttime conditions when designating and establishing new protected areas; establishment of appropriate buffer zones around protected areas where lighting is prohibited; and landscape level reductions in artificial nighttime lighting, which is being called for in general to reduce energy use and economic costs. PMID- 25693661 TI - Molecular imaging of prostate cancer: translating molecular biology approaches into the clinical realm. AB - The epidemiology of prostate cancer has dramatically changed since the introduction of prostate-specific antigen (PSA) screening in the 1980's. Most prostate cancers today are detected at early stages of the disease and are considered 'indolent'; however, some patients' prostate cancers demonstrate a more aggressive behaviour which leads to rapid progression and death. Increasing understanding of the biology underlying the heterogeneity that characterises this disease has led to a continuously evolving role of imaging in the management of prostate cancer. Functional and metabolic imaging techniques are gaining importance as the impact on the therapeutic paradigm has shifted from structural tumour detection alone to distinguishing patients with indolent tumours that can be managed conservatively (e.g., by active surveillance) from patients with more aggressive tumours that may require definitive treatment with surgery or radiation. In this review, we discuss advanced imaging techniques that allow direct visualisation of molecular interactions relevant to prostate cancer and their potential for translation to the clinical setting in the near future. The potential use of imaging to follow molecular events during drug therapy as well as the use of imaging agents for therapeutic purposes will also be discussed. KEY POINTS: * Advanced imaging techniques allow direct visualisation of molecular interactions in prostate cancer. * MRI/PET, optical and Cerenkov imaging facilitate the translation of molecular biology. * Multiple compounds targeting PSMA expression are currently undergoing clinical translation. * Other targets (e.g., PSA, prostate-stem cell antigen, GRPR) are in development. PMID- 25693662 TI - Visceral artery aneurysms: Incidence, management, and outcome analysis in a tertiary care center over one decade. AB - OBJECTIVES: To evaluate the incidence, management, and outcome of visceral artery aneurysms (VAA) over one decade. METHODS: 233 patients with 253 VAA were analyzed according to location, diameter, aneurysm type, aetiology, rupture, management, and outcome. RESULTS: VAA were localized at the splenic artery, coeliac trunk, renal artery, hepatic artery, superior mesenteric artery, and other locations. The aetiology was degenerative, iatrogenic after medical procedures, connective tissue disease, and others. The rate of rupture was much higher in pseudoaneurysms than true aneurysms (76.3% vs.3.1%). Fifty-nine VAA were treated by intervention (n = 45) or surgery (n = 14). Interventions included embolization with coils or glue, covered stents, or combinations of these. Thirty-five cases with ruptured VAA were treated on an emergency basis. There was no difference in size between ruptured and non-ruptured VAA. After interventional treatment, the 30-day mortality was 6.7% in ruptured VAA compared to no mortality in non ruptured cases. Follow-up included CT and/or MRI after a mean period of 18.0 +/- 26.8 months. The current status of the patient was obtained by a structured telephone survey. CONCLUSIONS: Pseudoaneurysms of visceral arteries have a high risk for rupture. Aneurysm size seems to be no reliable predictor for rupture. Interventional treatment is safe and effective for management of VAA. KEY POINTS: * Diagnosis of visceral artery aneurysms is increasing due to CT and MRI. * Diameter of visceral arterial aneurysms is no reliable predictor for rupture. * False aneurysms/pseudoaneurysms and symptomatic cases need emergency treatment. * Interventional treatment is safe and effective. PMID- 25693663 TI - Automated attenuation-based tube voltage selection for body CTA: Performance evaluation of 192-slice dual-source CT. AB - OBJECTIVE: To assess radiation dose and image quality in body CT-angiography (CTA) with automated attenuation-based tube voltage selection (ATVS) on a 192 slice dual-source CT (DSCT). METHODS: Forty patients (69.5 +/- 9.6 years) who had undergone body CTA with ATVS (ref.kVp 100, ref.mAs 90) using a 2x192-slice CT in single-source mode were retrospectively included. All patients had undergone prior CTA with a 2x128-slice CT and ATVS with identical imaging and contrast media protocols, serving for comparison. Images were reconstructed with iterative reconstruction at similar strength levels. Radiation dose was determined. Image quality was assessed semi-quantitatively (1:excellent, 5:non-diagnostic), aortic attenuation, noise and CNR were determined. RESULTS: As compared to 128-slice DSCT, 192-slice DSCT selected tube voltages were lower in 30 patients (75 %), higher in 3 (7.5 %), and similar in 7 patients (17.5 %). CTDIvol was lower with 192-slice DSCT (4.7 +/- 1.9 mGy vs. 5.8 +/- 2.1 mGy; p < 0.001). Subjective image quality, mean aortic attenuation (342 +/- 67HU vs. 268 +/- 67HU) and CNR (9.8 +/- 2.5 vs. 8.2 +/- 2.9) were higher with 192-slice DSCT (all p < 0.01), all datasets being diagnostic. CONCLUSION: Our study suggests that ATVS of 192-slice DSCT for body CTA is associated with an improved image quality and further radiation dose reduction of 19 % compared to 128-slice DSCT. KEY POINTS: * 192-slice DSCT allows imaging from 70 kVp to 150 kVp at 10 kVp increments. * 192-slice DSCT allows for radiation-dose reduction in body-CTA with ATVS. * Subjective and objective image quality increase compared to 128-slice DSCT. PMID- 25693664 TI - Noninvasive detection of cardiac amyloidosis using delayed enhanced MDCT: a pilot study. AB - OBJECTIVES: To evaluate myocardial enhancement of patients with cardiac amyloidosis (CA) using computed tomography (CT). METHODS: Thirteen patients with CA and 11 control patients were examined with first-pass and delayed CT acquisition. A qualitative and quantitative analysis of images was performed. Myocardial attenuation, myocardial signal-to-noise ratio (SNRmyoc), blood pool SNR (SNRblood), contrast-to-noise ratio between blood pool and myocardium (CNRblood-myoc) and relative attenuation index (RAI) defined as variation of myocardial attenuation between delayed and first-pass acquisitions were calculated. RESULTS: Two false negative cases (15 %) and three false positive cases (27 %) were detected on qualitative analysis. SNRmyoc of patients with CA was significantly (p < 0.05) lower on first-pass (4.08 +/- 1.9) and higher on delayed acquisition (7.10 +/- 2.7) than control patients (6.1 +/- 2.2 and 5.03 +/ 1.8, respectively). Myocardial attenuation was higher in CA (121 +/- 39 HU) than control patients (81 +/- 17 HU) on delayed acquisition. CNRblood-myoc was significantly (p < 0.05) lower in CA (1.51 +/- 0.7) than control patients (2.85 +/- 1.2) on delayed acquisition. The RAI was significantly (p < 0.05) higher in CA (0.12 +/- 0.25) than in control patients (-0.56 +/- 0.21). CONCLUSION: Dual phase MDCT can detect abnormal myocardial enhancement in patients with CA. KEY POINTS: * CT can detect abnormal first-pass and delayed enhancement in cardiac amyloidosis. * Measurement of relative myocardial enhancement between acquisitions helps to detect cardiac amyloidosis. * CT may provide useful data to diagnose cardiac amyloidosis. PMID- 25693665 TI - Santorinicele: secretin-enhanced magnetic resonance cholangiopancreatography findings before and after minor papilla sphincterotomy. AB - OBJECTIVES: To evaluate secretin-enhanced MRCP (S-MRCP) findings of patients with pancreas divisum and Santorinicele, before and after minor papilla sphincterotomy. METHODS: S-MRCP examinations of 519 patients with suspected pancreatic disease were included. Size of the main pancreatic duct, presence and calibre of Santorinicele were evaluated. Duodenal filling was assessed on dynamic images. After sphincterotomy the same parameters and the clinical findings were re-evaluated. RESULTS: Pancreas divisum was depicted in 55/519 patients (11 %) by MRCP and an additional 26/519 by S-MRCP (total 81/519, 16 %). Santorinicele was detected in 7/81 patients (8.6 %) with pancreas divisum by MRCP and an additional 20/81 by S-MRCP (total 27/81, 33 %). Dorsal duct in patients with Santorinicele was significantly larger in the head compared with patients with only pancreas divisum (p < 0.01), in basal conditions (average 2.4 versus 1.9 mm) and after secretin administration (average 3.0 versus 2.4 mm). Duodenal filling was impaired in 11/27 patients (41 %) with Santorinicele. After sphincterotomy significant reduction in size of Santorinicele (-33 %) and dorsal duct (-17 %), increase of pancreatic juice and symptoms improvement were observed. CONCLUSION: Secretin administration increases the accuracy of MRCP in detecting Santorinicele and demonstrates the impaired duodenal filling. S-MRCP is useful to assess results of sphincterotomy. KEY POINTS: * Secretin-enhanced MRCP gives anatomical and functional information on pancreatic outflow dynamics. * Santorinicele is a cystic dilatation of the termination of the Santorini duct. * S-MRCP images are the most useful to recognize the presence of Santorinicele. * Minor papilla sphincterotomy during ERCP is indicated in patients with Santorinicele. PMID- 25693666 TI - Evaluation of whole body Ultralow-Dose CT for the assessment of ventriculoperitoneal shunt complications: an experimental ex-vivo study in a swine model. AB - OBJECTIVE: To evaluate the suitability of whole body Ultralow-dose CT (ULD-CT) as a diagnostic tool for the evaluation of ventriculoperitoneal shunt (VP-shunt) complications with special regards to radiation dose and image quality. METHODS: Fourteen VP-shunts were implanted in 7 swine cadavers (weight: 55-70 kg). Twenty two mechanical complications (extracranial and extraperitoneal malpositioning, breakages, disconnections) were induced in nine VP-shunts. Ten ULD-CT scans with different parameters (tube voltage: 80, 100, 120 kV; tube current: 20 or 50 mAs; Pitch (P): 1 or 1.5) were acquired; the combination of 120 kV and 50 mAs was omitted. Radiation dose estimation, blinded readings, and quantitative and qualitative assessment of the CT-data were performed. RESULTS: Effective radiation doses varied between 0.44 +/- 0.06 and 2.55 +/- 0.35 mSv. ULD-CT protocols provided a mean sensitivity (i.e., correctly detected shunt complications) of 98.2 %. Unnoticed or incorrectly identified complications did not exceed one complication (4.5 %) in any ULD-CT protocol. Diagnostic confidence was sufficient for all ULD-CT protocols except for protocols with 80 kV and 20 mAs. CONCLUSIONS: ULD-CT allows accurate detection of VP-shunt complications at radiation doses similar or lower than reported for a radiographic shunt series. At the tested radiation dose levels, ULD-CT thus provides an alternative to a radiographic shunt series. KEY POINTS: * Ultralow-dose CT accurately detects Ventriculoperitoneal Shunt complications. * Radiation dosage is similar or lower than reported for a radiographic shunt series. * Ultralow-dose CT potentially shortens the diagnostic process when shunt complications are suspected. PMID- 25693667 TI - Evaluation of several FDG PET parameters for prediction of soft tissue tumour grade at primary diagnosis and recurrence. AB - OBJECTIVES: This study evaluates the diagnostic accuracy of SUV-based parameters derived from [(18) F]-2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) in order to optimize non-invasive prediction of soft tissue tumour (STT) grade. METHODS: One hundred and twenty-nine lesions from 123 patients who underwent FDG-PET for primary staging (n = 79) or assessment of recurrence (n = 44) of STT were analyzed retrospectively. Histopathology was the reference standard for tumour grading. Absolute values and tumour-to-liver ratios of several standardized uptake value (SUV) parameters were correlated with tumour grading. RESULTS: At primary diagnosis SUVmax, SUVpeak, SUVmax/SUVliver and SUVpeak/SUVliver showed good correlation with tumour grade. SUVpeak (area under the receiver-operating-characteristic, AUC-ROC: 0.82) and SUVpeak/SUVliver (AUC ROC: 0.82) separated best between low grade (WHO intermediate, grade 1 sarcoma, and low risk gastrointestinal stromal tumours, GISTs) and high grade (grade 2/3 sarcoma and intermediate/high risk GISTs) lesions: optimal threshold for SUVpeak/SUVliver was 2.4, which resulted in a sensitivity of 79 % and a specificity of 81 %. At disease recurrence, the AUC-ROC was <0.75 for each parameter. CONCLUSIONS: A tumour SUVpeak of at least 2.4 fold mean liver uptake predicts high grade histopathology with good diagnostic accuracy at primary staging. At disease recurrence, FDG-PET does not reliably separate high and low grade lesions. KEY POINTS: * Several SUV parameters accurately predict soft tissue sarcoma grade at primary diagnosis. * Tumour-to-liver ratios are of comparable value to absolute SUV parameters. * SUV peak /SUV liver >2.4 had 79 % sensitivity and 81 % specificity for high grade lesions. * At recurrence, FDG PET does not reliably indicate high grade sarcomas. PMID- 25693668 TI - Caveat of measuring perfusion indexes using intravoxel incoherent motion magnetic resonance imaging in the human brain. AB - OBJECTIVES: To numerically and experimentally investigate the robustness of intravoxel incoherent motion (IVIM) magnetic resonance imaging in measuring perfusion indexes in the human brain. METHODS: Eighteen healthy volunteers were imaged on a 3 T clinical system. Data of IVIM imaging (12 b-values ranging from 0 to 1000 s/mm(2), 12 repetitions) were fitted with a bi-exponential model to extract blood volume fraction (f) and pseudo-diffusion coefficient (D*). The robustness of measurement was assessed by bootstrapping. Dynamic susceptibility contrast (DSC) imaging and arterial spin-labelling (ASL) imaging were performed for cross-modal comparison. Numerical simulations were performed to assess the accuracy and precision of f and D* estimates at varied signal-to-noise ratio (SNRb1000). RESULTS: Based on our experimental setting (SNRb1000 ~ 30), the average error/variability is ~5 %/25 % for f and ~100 %/30 % for D* in gray matter, and ~10 %/50 % for f and ~300 %/60 % for D* in white matter. Correlation was found between f and DSC-derived cerebral blood volume in gray matter (r = 0.29 - 0.48 across subjects, p < 10(-5)), but not in white matter. No correlation was found between f-D* product and ASL-derived cerebral blood flow. CONCLUSIONS: f may provide noninvasive measurement of cerebral blood volume, particularly in gray matter. D* has limited robustness and should be interpreted with caution. KEY POINTS: * A minimum SNR b1000 of 30 is recommended for reliable IVIM imaging. * f may provide noninvasive measurement of cerebral blood volume. * f correlates with CBV DSC in gray matter. * There is no correlation between fD* and CBF ASL . * D* has limited robustness and should be interpreted with caution. PMID- 25693669 TI - Prognostic value of tumor shrinkage versus fragmentation following radiochemotherapy and surgery for rectal cancer. AB - Most patients with rectal cancer receive neoadjuvant radiochemotherapy (RCT), causing a variable decrease in tumor mass. We evaluated the prognostic impact of pathologic parameters reflecting tumor response to RCT, either directly or indirectly. Seventy-six rectal cancer patients receiving neoadjuvant RCT between 2006 and 2009 were included. We studied the association between disease-free survival (DFS) and the "classical" clinicopathologic features as well as tumor deposits, circumferential resection margin (CRM), Dworak regression grade, and tumor and nodal downstaging. Patients with tumor downstaging had a longer DFS (p = 0.05), indicating a more favorable prognosis when regression was accompanied by a decrease in tumor infiltrative depth, referred to as tumor shrinkage. Moreover, tumor downstaging was significantly associated with larger CRM and nodal downstaging (p = 0.02), suggesting that shrinkage of the primary tumor was associated with a decreased nodal tumor load. Higher Dworak grade did not correlate with tumor downstaging, nor with higher CRM or prolonged DFS. This implies that tumor mass decrease was sometimes due to fragmentation rather than shrinkage of the primary tumor. Lastly, the presence of tumor deposits was clearly associated with reduced DFS (p = 0.01). Assessment of tumor shrinkage after RCT via tumor downstaging and CRM is a good way of predicting DFS in rectal cancer, and shrinkage of the primary tumor is associated with a decreased nodal tumor load. Assessing regression based on the amount of tumor in relation to stromal fibrosis does not accurately discern tumor fragmentation from tumor shrinkage, which is most likely the reason why Dworak grade had less prognostic relevance. PMID- 25693670 TI - Chilli leaf curl virus infection highlights the differential expression of genes involved in protein homeostasis and defense in resistant chilli plants. AB - Geminiviruses have evolved with tremendous potential of recombination and possess the ability to manipulate several cellular processes of hosts. Chilli leaf curl virus (ChiLCV) is a monopartite Begomovirus (family Geminiviridae) which has emerged as a serious threat to chilli production worldwide. To date, development of resistant chilli varieties through conventional plant breeding techniques remains the major antiviral strategy. To explore the potential resistance factors in Capsicum annuum var. Punjab Lal, we performed a transcriptome analysis in ChiLCV-infected plants by exploiting the advantage of sensitivity and efficiency of suppression subtractive hybridization (SSH). Out of 480 clones screened, 231 unique expressed sequence tags (ESTs) involved in different cellular and physiological processes were identified. An interactome network of ChiLCV responsive differentially expressed genes revealed an array of proteins involved in key cellular processes including transcription, replication, photosynthesis, and defense. A comparative study of gene expression between resistant and susceptible chilli plants revealed upregulation of several defense-related genes such as nucleotide-binding site leucine-rich repeat (NBS-LRR) domain containing protein, lipid transfer protein, thionin, polyphenol oxidase, and other proteins like ATP/ADP transporter in the ChiLCV-resistant variety. Taken together, the present study provides novel insights into the transcriptomics of ChiLCV resistant chilli plants. PMID- 25693671 TI - A GH57 4-alpha-glucanotransferase of hyperthermophilic origin with potential for alkyl glycoside production. AB - 4-alpha-Glucanotransferase (GTase) enzymes (EC 2.4.1.25) modulate the size of alpha-glucans by cleaving and reforming alpha-1,4 glycosidic bonds in alpha glucans, an essential process in starch and glycogen metabolism in plants and microorganisms. The glycoside hydrolase family 57 enzyme (GTase57) studied in the current work catalyzes both disproportionation and cyclization reactions. Amylose was converted into cyclic amylose (with a minimum size of 17 glucose monomers) as well as to a spectrum of maltodextrins, but in contrast to glycoside hydrolase family 13 cyclodextrin glucanotransferases (CGTases), no production of cyclodextrins (C6-C8) was observed. GTase57 also effectively produced alkyl glycosides with long alpha-glucan chains from dodecyl-beta-D-maltoside and starch, demonstrating the potential of the enzyme to produce novel variants of surfactants. Importantly, the GTase57 has excellent thermostability with a maximal activity at 95 degrees C and an activity half-life of 150 min at 90 degrees C which is highly advantageous in this manufacturing process suggesting that enzymes from this relatively uncharacterized family, GH57, can be powerful biocatalysts for the production of large head group glucosides from soluble starch. PMID- 25693672 TI - Acinetobacter species as model microorganisms in environmental microbiology: current state and perspectives. AB - Acinetobacter occupies an important position in nature because of its ubiquitous presence in diverse environments such as soils, fresh water, oceans, sediments, and contaminated sites. Versatile metabolic characteristics allow species of this genus to catabolize a wide range of natural compounds, implying active participation in the nutrient cycle in the ecosystem. On the other hand, multi drug-resistant Acinetobacter baumannii causing nosocomial infections with high mortality has been raising serious concerns in medicine. Due to the ecological and clinical importance of the genus, Acinetobacter was proposed as a model microorganism for environmental microbiological studies, pathogenicity tests, and industrial production of chemicals. For these reasons, Acinetobacter has attracted significant attention in scientific and biotechnological fields, but only limited research areas such as natural transformation and aromatic compound degradation have been intensively investigated, while important physiological characteristics including quorum sensing, motility, and stress response have been neglected. The aim of this review is to summarize the recent achievements in Acinetobacter research with a special focus on strain DR1 and to compare the similarities and differences between species or other genera. Research areas that require more attention in future research are also suggested. PMID- 25693673 TI - Erratum to: deciphering the role of coumarin as a novel quorum sensing inhibitor suppressing virulence phenotypes in bacterial pathogens. PMID- 25693675 TI - Staphylococcal biofilm formation on the surface of three different calcium phosphate bone grafts: a qualitative and quantitative in vivo analysis. AB - Differences in physico-chemical characteristics of bone grafts to fill bone defects have been demonstrated to influence in vitro bacterial biofilm formation. Aim of the study was to investigate in vivo staphylococcal biofilm formation on different calcium phosphate bone substitutes. A foreign-body guinea-pig infection model was used. Teflon cages prefilled with beta-tricalcium phosphate, calcium deficient hydroxyapatite, or dicalcium phosphate (DCP) scaffold were implanted subcutaneously. Scaffolds were infected with 2 * 10(3) colony-forming unit of Staphylococcus aureus (two strains) or S. epidermidis and explanted after 3, 24 or 72 h of biofilm formation. Quantitative and qualitative biofilm analysis was performed by sonication followed by viable counts, and microcalorimetry, respectively. Independently of the material, S. aureus formed increasing amounts of biofilm on the surface of all scaffolds over time as determined by both methods. For S. epidermidis, the biofilm amount decreased over time, and no biofilm was detected by microcalorimetry on the DCP scaffolds after 72 h of infection. However, when using a higher S. epidermidis inoculum, increasing amounts of biofilm were formed on all scaffolds as determined by microcalorimetry. No significant variation in staphylococcal in vivo biofilm formation was observed between the different materials tested. This study highlights the importance of in vivo studies, in addition to in vitro studies, when investigating biofilm formation of bone grafts. PMID- 25693676 TI - Silver-containing antimicrobial membrane based on chitosan-TPP hydrogel for the treatment of wounds. AB - Treatment of non-healing wounds represents hitherto a severe dilemma because of their failure to heal caused by repeated tissue insults, bacteria contamination and altered physiological condition. This leads to face huge costs for the healthcare worldwide. To this end, the development of innovative biomaterials capable of preventing bacterial infection, of draining exudates and of favoring wound healing is very challenging. In this study, we exploit a novel technique based on the slow diffusion of tripolyphosphate for the preparation of macroscopic chitosan hydrogels to obtain soft pliable membranes which include antimicrobial silver nanoparticles (AgNPs) stabilized by a lactose-modified chitosan (Chitlac). UV-Vis and TEM analyses demonstrated the time stability and the uniform distribution of AgNPs in the gelling mixture, while swelling studies indicated the hydrophilic behavior of membrane. A thorough investigation on bactericidal properties of the material pointed out the synergistic activity of chitosan and AgNPs to reduce the growth of S. aureus, E. coli, S. epidermidis, P. aeruginosa strains and to break apart mature biofilms. Finally, biocompatibility assays on keratinocytes and fibroblasts did not prove any harmful effects on the viability of cells. This novel technique enables the production of bioactive membranes with great potential for the treatment of non-healing wounds. PMID- 25693677 TI - Antibacterial and non-cytotoxic effect of nanocomposites based in polyethylene and copper nanoparticles. AB - In this study, an antibacterial, but not cytotoxic nanomaterial based on polyethylene and copper nanoparticles was prepared by in situ polymerization. PE CuNps nanocomposites against Escherichia coli, completely suppressed the number of live bacteria after 12 h incubation compared to neat PE. TEM images showed that nanocomposites damage the plasma membrane of the bacteria, revealing a bacteriolytic effect. Toxic effects of copper nanoparticles on viability of neuroblastoma line cell also was evaluated, revealing a non cytotoxic effect for the doses used, showing that this nanocomposite is a ideal material for medical devices. PMID- 25693679 TI - Correlates in the Endorsement of Psychotic Symptoms and Services Use: Findings from the Collaborative Psychiatric Epidemiology Surveys. AB - Endorsement of psychotic symptoms serves as an indicator of significant health issues and interpersonal distress. Seeking services is the ultimate recourse for many individuals, yet few studies have assessed the help-seeking process in a nationally representative sample. This study, guided by Lewis-Fernandez et al.'s (J Nerv Ment Dis 197(5):337-347, 2009) analyses, examined the association of lifetime endorsement of psychotic symptoms with demographic, clinical and support system variables and types of services received. Based on nationally weighted epidemiological data, 11.6 % of adults reported one or more psychotic symptoms. Psychotic symptoms were associated with poor physical and mental health, specifically depressive, anxiety, and substance use disorders. Respondents were more likely to receive services from both informal and mental health providers and were more likely to be hospitalized than those not endorsing psychotic symptoms. Study findings inform community efforts to develop comprehensive services for individuals experiencing psychotic symptoms. PMID- 25693678 TI - Privileged frameworks from snake venom. AB - Venom as a form of chemical prey capture is a key innovation that has underpinned the explosive radiation of the advanced snakes (Caenophidia). Small venom proteins are often rich in disulfide bonds thus facilitating stable molecular scaffolds that present key functional residues on the protein surface. New toxin types are initially developed through the venom gland over-expression of normal body proteins, their subsequent gene duplication and diversification that leads to neofunctionalisation as random mutations modify their structure and function. This process has led to preferentially selected (privileged) cysteine-rich scaffolds that enable the snake to build arrays of toxins many of which may lead to therapeutic products and research tools. This review focuses on cysteine-rich small proteins and peptides found in snake venoms spanning natriuretic peptides to phospholipase enzymes, while highlighting their three-dimensional structures and biological functions as well as their potential as therapeutic agents or research tools. PMID- 25693680 TI - Effects of Fluoride on DNA Damage and Caspase-Mediated Apoptosis in the Liver of Rats. AB - Fluoride compounds are abundant and widely distributed in the environment at a variety of concentrations. Further, fluoride induces toxic effects in target organs such as the liver. In this study, we investigated liver histopathology, DNA damage, apoptosis, and the mRNA and protein expressions of caspase-3 and -9 in the rat livers by administering varying concentrations of fluoride (0, 50, 100, 200 mg/L ) for 120 days. The results showed fluoride-induced morphological changes and significantly increased apoptosis and DNA damage in rats exposed to fluoride, especially in response to higher doses. The immunohistochemical and qRT PCR results indicated that caspase-3, caspase-9 protein positive expression and mRNA relative expression enhanced with increasing NaF concentration. In summary, our findings suggest that chronic exposure to fluoride causes damages to liver histopathology and leads to liver apoptosis through caspase-mediated pathways. PMID- 25693682 TI - [Researcher of the month]. PMID- 25693681 TI - Lead, Arsenic, and Manganese Metal Mixture Exposures: Focus on Biomarkers of Effect. AB - The increasing exposure of human populations to excessive levels of metals continues to represent a matter of public health concern. Several biomarkers have been studied and proposed for the detection of adverse health effects induced by lead (Pb), arsenic (As), and manganese (Mn); however, these studies have relied on exposures to each single metal, which fails to replicate real-life exposure scenarios. These three metals are commonly detected in different environmental, occupational, and food contexts and they share common neurotoxic effects, which are progressive and once clinically apparent may be irreversible. Thus, chronic exposure to low levels of a mixture of these metals may represent an additive risk of toxicity. Building upon their shared mechanisms of toxicity, such as oxidative stress, interference with neurotransmitters, and effects on the hematopoietic system, we address putative biomarkers, which may assist in assessing the onset of neurological diseases associated with exposure to this metal mixture. PMID- 25693683 TI - Quantitative Evaluation of an Instrument to Identify Chronic Pain in HIV-Infected Individuals. AB - A method to rapidly identify the presence of chronic pain would enhance the care of HIV-infected individuals, but such an instrument has not been assessed in this population to date. We assessed the construct validity of the two-question Brief Chronic Pain Questionnaire (BCPQ) in HIV-infected patients by assessing the association between BCPQ responses and known correlates of chronic pain. Participants in the University of Alabama Center for AIDS Research Network of Integrated Clinical Systems cohort completed the BCPQ, along with the EuroQOL to assess physical function, the PHQ-9 to assess depression, and the PHQ-anxiety module to assess anxiety. Among 100 participants, 25% were female, the mean age was 45 (SD 12), 63% were African American, 27% were publicly insured, the median CD4(+) T cell count was 572 cells/mm(3) (IQR 307-788), and 82% had an undetectable viral load. Participants with chronic pain were more likely to have impaired mobility (43% vs. 12%, p=0.001), difficulty with usual activities (47% vs. 12%, p<0.001), lower overall health state (70 vs. 84, p=0.002), pain today (80% vs. 27%, p<0.001), depression (30% vs. 15%, p=0.10), and anxiety (43% vs. 10%, p<0.001) than those without chronic pain. This study provides preliminary evidence for the BCPQ as a brief questionnaire to identify the presence of chronic pain in HIV care settings. PMID- 25693684 TI - Quality of life, anxiety, depression and obsessive-compulsive tendencies in patients with chronic hand eczema. AB - BACKGROUND: Chronic hand eczema is a common dermatological disorder of multifactorial aetiology. It affects physical, material, social and psychological aspects of life, thereby impairing health-related quality of life. OBJECTIVES: The aim of the present study was to assess quality of life, anxiety, depression and obsessive-compulsive tendencies in patients with chronic hand eczema. MATERIALS AND METHODS: Seventy-one patients with chronic hand eczema were included in the study. Quality of life was evaluated according to the Dermatology Life Quality Index (DLQI). Patients were also assessed for anxiety and depression with the Hospital Anxiety and Depression Scale (HADS), and for compulsive behaviour with the Leyton Trait Scale. RESULTS: The DLQI score was 11.11 +/- 1.81 in patients with chronic hand eczema. Scores on the Leyton Trait Scale were significantly higher than those of healthy controls (p < 0.027). As concerns the HADS-Anxiety subscale, patients with hand dermatitis had statistically significantly higher scores than those of volunteers (p = 0.002). In contrast, no statistically significant difference was found between the two groups with regard to the HADS-Depression subscale score and total HADS score. CONCLUSION: Hand eczema treatment should address the severity of skin lesions as well as the psychological impact of hand eczema. PMID- 25693685 TI - Brain-bladder control network: the unsolved 21st century urological mystery. AB - A review of functional brain imaging studies of bladder control in participants with normal control and pathological conditions. In the normal condition, bladder and urethral afferents received in the periaqueductal gray relay the information to the insula, the anterior cingulate cortex and the prefrontal cortex. During the storage phase, these superior regions control the pontine micturition center to inhibit voiding. In overactive bladder patients, brain responses are different. Cortical responses become exaggerated, especially in the anterior cingulate cortex and the supplementary motor area. That is what presumably evokes the "urgency". The supplementary motor area is activated during contraction of the pelvic floor muscles, and provides protection against incontinence. We believe that functional brain imaging studies are promising not only for the understanding of bladder dysfunction, but also as an aid to the development of therapeutic options for chronic disorders. PMID- 25693686 TI - Effects of azidothymidine on protein kinase C activity and expression in erythroleukemic cell K562 and acute lymphoblastic leukemia cell HSB-2. AB - Azidothymidine (AZT) is one of the anti-retroviral drugs currently used for the treatment of HIV-infected patients. Several other effects of the drug have been studied in vitro, such as the alterations of some enzymes, the inhibition of cell proliferation, and the increase of transferrin receptor expression. In this study, we investigated the alterations of protein kinase C (PKC) activity, PKCalpha and PKCbetaII expressions and plasmatic membrane fluidity induced by AZT in two cancer cell lines, human chronic myeloid (K562) and human acute lymphoblastic (HSB-2) leukemia cells, respectively. The results showed that both PKC activity and membrane fluidity in HSB-2 cells increased after 24 h of drug incubation. PKCalpha expression in HSB-2 cells decreased after 48 h of AZT exposure, when the cell growth also decreased. However, in K562 cells, the PKCalpha and PKCbetaII expressions enhanced in the presence of the drug when the growth was inhibited. The results indicate that AZT is less effective in inhibiting the growth of acute lymphoblastic HSB-2 leukemia cells than inhibiting that of chronic myeloid K562 cells. In fact, after 24 h exposure, the HSB-2 cell growth decreased less than K562 cell growth. PMID- 25693687 TI - Epidemiology of human Mycobacterium bovis disease, California, USA, 2003-2011. AB - We conducted a retrospective review of California tuberculosis (TB) registry and genotyping data to evaluate trends, analyze epidemiologic differences between adult and child case-patients with Mycobacterium bovis disease, and identify risk factors for M. bovis disease. The percentage of TB cases attributable to M. bovis increased from 3.4% (80/2,384) in 2003 to 5.4% (98/1,808) in 2011 (p = 0.002). All (6/6) child case-patients with M. bovis disease during 2010-2011 had >1 parent/guardian who was born in Mexico, compared with 38% (22/58) of child case patients with M. tuberculosis disease (p = 0.005). Multivariate analysis of TB case-patients showed Hispanic ethnicity, extrapulmonary disease, diabetes, and immunosuppressive conditions, excluding HIV co-infection, were independently associated with M. bovis disease. Prevention efforts should focus on Hispanic binational families and adults with immunosuppressive conditions. Collection of additional risk factors in the national TB surveillance system and expansion of whole-genome sequencing should be considered. PMID- 25693688 TI - Parkinson's patients' executive profile and goals they set for improvement: Why is cognitive rehabilitation not common practice? AB - Impairments in executive functions (EF) are the core cognitive impairment in patients with Parkinson's disease (PD). Surprisingly, cognitive rehabilitation is not routinely offered to patients with PD. However, in patients with acquired brain injury (ABI), cognitive rehabilitation, in particular strategic executive training, is common practice and has been shown to be effective. In this study, we determined whether PD patients have different needs and aims with regard to strategic executive training than ABI patients, and whether possible differences might be a reason for not offering this kind of cognitive rehabilitation programme to patients with PD. Patients' needs and aims were operationalised by individually set goals, which were classified into domains of EF and daily life. In addition, patients with PD and ABI were compared on their cognitive, in particular EF, profile. Overall, PD patients' goals and cognitive profile were similar to those of patients with ABI. Therefore, based on the findings of this study, there is no reason to assume that strategic executive training cannot be part of standard therapy in PD. However, when strategic executive training is applied in clinical practice, disease-specific characteristics need to be taken into account. PMID- 25693689 TI - Thymic alterations induced by partial hepatectomy: Upregulation of glycoprotein 96, CD91 and TLR2 and generation of regulatory T cells. AB - Glycoprotein 96 (gp96) is an endoplasmic reticulum (ER)-resident heat shock protein. It controls the folding of nascent membrane-spanning and secretory proteins, participates in stress-induced unfolded protein response (UPR) and in pathways leading to proteolysis of damaged proteins through ER-associated degradation pathways and chaperone-mediated autophagy. In addition, gp96 controls the steroid biosynthesis and Ca2+ homeostasis and participates in insulin IGF/signaling pathways. Besides, owing to its peptide chaperone capacity and ability to interact with antigen-presenting cells, gp96 has been implicated in priming of innate and adaptive immunity. In an attempt to visualize the intensity of ER-stress in thymus and possible participation of gp96 in generation of auto reactive T cell clones that were detected in regenerating liver, in this study we investigated the dynamics of gp96 expression in partially hepatectomized (pHx) and sham Hx mice. Simultaneously, we detected the thymic expression of receptors responsible for endocytosis of gp96-chaperoned peptides (CD91) and intracellular activation of ER-stress pathways (TLR2), as well as the expression of TGF-beta and the distribution of CD4+CD25+FoxP3+ cells. The data have shown that both pHx and sham Hx induced an accelerated apoptosis and hypoplasia in thymus. Partial Hx induced, however, a higher expression of gp96, the translocation of the CD91, TLR2 and TGF-beta immunostaining from medulla to cortex and an appearance of Treg cells. The data show that pHx triggers in thymus the ER-stress and UPR response and suggest that gp96 participates in the generation of natural Treg cells, which might be involved in the control of liver regeneration in the periphery. PMID- 25693690 TI - Toxicological findings in fatal motor vehicle collisions in ontario, Canada: a one-year study. AB - Drug-impaired driving is a complex area of forensic toxicology due in part to limited data concerning the type of drugs involved and the concentrations detected. This study analyzed toxicological findings in drivers from fatal motor vehicle collisions (FMVCs) in Ontario, Canada, over a one-year period using a standardized protocol. Of the 229 cases included in the study, 56% were positive for alcohol and/or drugs. After alcohol, cannabis was the most frequently encountered substance (27%), followed by benzodiazepines (17%) and antidepressants (17%). There were differences in drugs detected by age but no marked difference in drugs detected between single and multiple FMVC's. Not all drugs detected were considered impairing either due to drug type, concentration or case history. The findings indicate the importance of comprehensive drug testing in FMVCs and highlight the need to consider a variety of factors, in addition to drug type and concentration, when assessing the role of drugs in driving impairment. PMID- 25693691 TI - Catalytic asymmetric inverse-electron-demand oxa-Diels-Alder reaction of in situ generated ortho-quinone methides with 3-methyl-2-vinylindoles. AB - The first catalytic asymmetric inverse-electron-demand (IED) oxa-Diels-Alder reaction of ortho-quinone methides, generated in situ from ortho-hydroxybenzyl alcohols, has been established. By selecting 3-methyl-2-vinylindoles as a class of competent dienophiles, this approach provides an efficient strategy to construct an enantioenriched chroman framework with three adjacent stereogenic centers in high yields and excellent stereoselectivities (up to 99 % yield, >95:5 d.r., 99.5:0.5 e.r.). The utilization of ortho-hydroxybenzyl alcohols as precursors of dienes and 3-methyl-2-vinylindoles as dienophiles, as well as the hydrogen-bonding activation mode of the substrates met the challenges of a catalytic asymmetric IED oxa-Diels-Alder reaction. PMID- 25693692 TI - Mitogenome metadata: current trends and proposed standards. AB - Mitogenome metadata are descriptive terms about the sequence, and its specimen description that allow both to be digitally discoverable and interoperable. Here, we review a sampling of mitogenome metadata published in the journal Mitochondrial DNA between 2005 and 2014. Specifically, we have focused on a subset of metadata fields that are available for GenBank records, and specified by the Genomics Standards Consortium (GSC) and other biodiversity metadata standards; and we assessed their presence across three main categories: collection, biological and taxonomic information. To do this we reviewed 146 mitogenome manuscripts, and their associated GenBank records, and scored them for 13 metadata fields. We also explored the potential for mitogenome misidentification using their sequence diversity, and taxonomic metadata on the Barcode of Life Datasystems (BOLD). For this, we focused on all Lepidoptera and Perciformes mitogenomes included in the review, along with additional mitogenome sequence data mined from Genbank. Overall, we found that none of 146 mitogenome projects provided all the metadata we looked for; and only 17 projects provided at least one category of metadata across the three main categories. Comparisons using mtDNA sequences from BOLD, suggest that some mitogenomes may be misidentified. Lastly, we appreciate the research potential of mitogenomes announced through this journal; and we conclude with a suggestion of 13 metadata fields, available on GenBank, that if provided in a mitogenomes's GenBank record, would increase their research value. PMID- 25693693 TI - High-altitude adaptation of Tibetan chicken from MT-COI and ATP-6 perspective. AB - The problem of hypoxia adaptation in high altitudes is an unsolved brainteaser in the field of life sciences. As one of the best chicken breeds with adaptability to highland environment, the Tibetan chicken, is genetically different from lowland chicken breeds. In order to gain a better understanding of the mechanism of hypoxic adaptability in high altitude, in the present study, we focused on the MT-COI together with ATP-6 gene to explore the regulatory mechanisms for hypoxia adaptability in Tibet chicken. Here, we sequenced MT-COI of 29 Tibetan chickens and 30 Chinese domestic chickens and ATP-6 gene of 28 Tibetan chickens and 29 Chinese domestic chickens. In MT-COI gene, 9 single nucleotide polymorphisms (SNPs) were detected though none of these was a missense mutation, confirming the fact that MT-COI gene is a largely conservative sequence. In ATP-6 gene, 6 single nucleotide polymorphisms (SNPs) were detected and we found a missense mutation (m.9441G > A) in the ATP-6 gene of Tibetan chicken resulting in an amino acid substitution. Due to the critical role of ATP-6 gene in the proton translocation and energy metabolism, we speculated the possibility of this mutation playing an important role in easier energy conversion and metabolism in Tibetan chickens than Chinese domestic chickens so as to better adapt to the harsh environment of the high-altitude areas. The Median-joining profile also suggested that haplotype Ha2 has the ancestral position to the other haplotypes and has significant relationship with high-altitude adaptation in ATP-6 gene. Therefore, we considered that the polymorphism (m.9441G > A) in the ATP-6 gene may affect the specific functions of ATP-6 enzyme relating to high-altitude adaptation of Tibetan chicken and MT-COI gene is a largely conservative sequence. PMID- 25693694 TI - The complete mitogenome of the bluespotted ribbontail ray Taeniura lymma (Forsskal, 1775) (Elasmobranchii: Myliobatiformes: Dasyatidae). AB - The complete mitogenome of the ray Taeniura lymma was recovered from genome skimming using the HiSeq sequencing system. The T. lymma mitogenome has 17,652 base pairs (59.13% A + T content) made up of 13 protein-coding genes, 2 ribosomal subunit genes, 22 transfer RNAs and a 1906 bp non-coding AT-rich region. This mitogenome sequence is the second for a ray from Australian waters, the first for the genus Taeniura and the ninth for the family Dasyatidae. PMID- 25693695 TI - Population genetic diversity of sesarmid crab (Perisesarma bidens) in China based on mitochondrial DNA. AB - The population genetic diversity of Perisesarma bidens in China was investigated using 627 bp fragment of mtDNA COI gene sequence. A total of 186 individuals were collected from ten localities over most of the species' range and 31 different haplotypes were obtained. The most frequent haplotype was Hap2, which was shared in all ten localities (132 individuals), whereas most haplotypes were rare and existed in only one or two individuals. Haplotype diversity (h) and nucleotide diversity (pi) ranged from 0.338 to 0.731 and from 0.00058 to 0.00278, respectively, which represented a moderate level of haplotype diversity and a low level of nucleotide diversity. The genetic distance ranged from 0.0006 to 0.0028 within populations and from 0.0006 to 0.0023 between populations. An analysis of molecular variance and conventional population statistics (FST) revealed a low level of genetic differentiation among ten populations (FST = -0.00439, p > 0.05), indicating that no significant population genetic structure existed in populations from the East China Sea and South China Sea. Both mismatch distribution and neutrality tests implied a recent population expansion event for the sesarmid crab species in the late Pleistocene. PMID- 25693696 TI - The complete mitochondrial genome of Coilia grayii (Clupeiformes: Engraulidae). AB - In this study, the complete mitochondrial genome (mitogenome) sequence of Coilia grayii has been determined by long polymerase chain reaction and primer walking methods. The mitogenome is a circular molecule of 16,851 bp in length and contains 37 mitochondrial genes including 13 protein-coding genes, 2 ribosomal RNA (rRNA), 22 transfer RNAs (tRNAs) and a control region as other bony fishes. Within the control region, we identified the termination-associated sequence domain (TAS), the central conserved sequence block domains (CSB-F, CSB-E and CSB D), and the conserved sequence block domains (CSB-1, CSB-2 and CSB-3). PMID- 25693697 TI - The complete mitochondrial genome of European wild boar, Sus scrofa scrofa. AB - In this study, we report the complete mitochondrial genome sequence of the European wild boar, Sus scrofa scrofa for the first time. The genome is found to be 16,770 bp in length and has a base composition of A (34.63%), G (13.38%), C (26.21%), and T (25.78%), indicating that the percentage of A + T (60.41%) was higher than G + C (39.59%). Similar to other pigs, it contains a typically conserved structure including 13 protein-coding genes, 22 transfer RNA genes, 2 ribosomal RNA genes, and 1 control region (D-loop). Most of the genes were located on the H-strand except for the ND6 gene and eight tRNA genes. The complete mitochondrial genome sequence provided here would add a new genetic resource and new study on the evolution of the genus Sus. PMID- 25693698 TI - Complete mitochondrial genome of the Spadenose shark Scoliodon laticaudus (Carcharhiniformes: Carcharhinidae). AB - The complete mitochondrial genome of the Spadenose shark Scoliodon laticaudus has been determined for the first time in this study. It was 16,695 bp in length and consisted of 37 genes with typical gene order in vertebrate mitogenome. The nucleotide base content of S. laticaudus mitogenome was 31.5% A, 23.7% C, 13.2% G and 31.6% T. Two start codons (GTG and ATG) and three stop codons (AGA, TAG and TAA/T) were used in the protein-coding genes. The 22 tRNAs ranged from 67 bp (tRNA-Cys and tRNA-Ser2) to 75 bp (tRNA-Leu1) in length. The tRNA-Ser2 could not be folded into typical cloverleaf secondary structure by lacking the dihydrouridine (DHC) arm stem. PMID- 25693699 TI - Complete mitochondrial genome of a wild Alashan Red Deer (Cervus elaphus alxaicus). AB - The complete mitochondrial genome of a wild red deer from Helan Mountain, China was sequenced and annotated newly. The total length of the mitochondrial genome is 16,428 bp, with a base composition of 33.3% A, 28.8% T, 24.4% C and 13.5% G, and it contains 12S rRNA gene, 16S rRNA gene, 22 tRNA genes, 13 protein-coding genes and 1 control region. PMID- 25693700 TI - The complete mitochondrial genome of Hemiculterella sauvagei (Teleostei, Cyprinidae, Hemiculterella). AB - Hemiculterella sauvagei, a Chinese minnow endemic to the upper Yangtze River, is an important part of the aquatic ecosystem and plays a vital ecological role in maintaining aquatic biodiversity. In this study, we provide the first mitochondrial genome of H. sauvagei. The complete mitochondrial genome of H. sauvagei is 16618 bp in length, containing 13 protein-coding genes, two rRNA genes (12 S and 16 S rRNA), 22 tRNA genes and a non-coding control region (D loop). The gene nucleotide composition of H. sauvagei is A = 29.9%, T = 27.0%, C = 17.4% and G = 25.6%, with a slight AT bias of 56.9%. The complete mitochondrial genome of H. sauvagei would be useful for further studies on genetic diversity and molecular phylogenetic relationship of the subfamily Cultrinae. PMID- 25693701 TI - The mitochondrial tRNA(Gln) T4353C mutation may not be associated with essential hypertension in Han Chinese population. AB - We reported here the possible role of a mitochondrial tRNA mutation: T4353C in clinical expression of essential hypertension in Chinese population. The human mammalian mitochondrial tRNA database was used to analyze the conservation index of this mutation between different species. Moreover, phylogenetic analysis showed that the T4353C mutation belonged to human mitochondrial haplogroup HV, a West Eurasian haplogroup found throughout Western Asia and Eastern European but was infrequent in China. In addition, structural prediction of the T4353C mutation indicated that this transition did not alter the secondary structure of tRNA(Gln). Together, our data indicated that the T4353C mutation occurred infrequent and may not be associated with essential hypertension in Han Chinese population. PMID- 25693702 TI - Corrigendum. PMID- 25693703 TI - The complete mitogenome of the freshwater fairy shrimp Streptocephalus sirindhornae (Crustacea: Anostraca: Streptocephalidae). AB - In this study, we amplified, sequenced and analyzed the complete mitogenome of the freshwater fairy shrimp Streptocephalus sirindhornae (Crustacea: Anostraca: Streptocephalidae). The full-length of the S. sirindhornae mitogenome is a circular molecule of 16,887 bp in size with an A + T content of 64.5%. It has the largest putative control region (2794 bp) with the lowest A + T content (62.6%) for all determined branchiopod mitogenomes. The genome consisted of 37 genes that are involved in the respiration chain as well as the mitochondrial translation system. The S. sirindhornae mitogenome exhibits an identical gene arrangement as the Artemia pattern, which shows translocation and inversion of two transfer-RNA genes compared to the pancrustacean ancestral pattern. This is by far the first determined mitogenome of a freshwater fairy shrimp. The results of our study will provide significant data for reconstructing the consensus Branchiopoda tree of life. PMID- 25693704 TI - Characterization of the complete mitochondrial genome of the treehopper Darthula hardwickii (Hemiptera: Aetalionidae). AB - The complete sequence of the mitochondrial genome of the treehopper Darthula hardwickii is presented. The circular genome is 15,359 bp long with 37 genes and 77.4% A + T content. Twenty-three genes are located on the J-strand, the remaining being oriented on the N-strand. Gene order is identical to that of the typical arrangement of other treehoppers. This genome is highly economized with 66 overlapped nucleotides between neighboring genes in 16 locations. All protein coding genes initiate with ATN codons. All of the 22 tRNAs, ranging from 60 to 73 bp, have the clover-leaf structure, except the dihydrouridine (DHU) arm of tRNA(Ser (AGN)) and tRNA(Arg) forms a simple loop as seen in many other metazoans. The sizes of the large and small ribosomal RNA genes are 1198 and 737 bp, respectively. The control region is 1081 bp in length with 83.72% A + T content. The complete mitogenome sequence of D. hardwickii could provide fundamental data for the phylogenetic studies of the Aetalionidae and Membracoidea and the Hemiptera as well. PMID- 25693705 TI - The complete mitogenome sequence of Pseudohynobius jinfo (Urodela: Hynobiidae). AB - The complete mitogenome sequence of Pseudohynobius jinfo, which is endemic to China, is sequenced in the present study. The genome was 16,393 bp in length, including 13 typical vertebrate protein-coding genes, 2 rRNA genes, 22 tRNA genes, and 1 non-coding control region. Except for ND6 and eight tRNA genes, all other mitochondrial genes were encoded on the heavy strand. The gene order and composition of P. jinfo was similar to that of the most Hynobiidae. Seven genes (ND1, ND2, COII, COIII, ND3, ND4 and Cytb) had an incomplete stop codon. Base composition of the genome was A (33.6%), T (31.8%), C (20.6%) and G (14.1%) with an A + T-rich feature (65.4%) as that of other vertebrate mitochondrial genomes. There was a long non-coding region (126 bp) between tRNA-Thr and tRNA-Pro genes. PMID- 25693706 TI - Complete mitochondrial genome of the Yellow-bellied Tit Parus venustulus (Passeriformes, Paridae). AB - The circular mitochondrial genome of Yellow-bellied Tit Parus venustulus is 16,778 bp in length, containing 13 protein-coding genes (PCGs), 2 ribosomal RNA genes, 22 transfer RNA (tRNA) genes, and a putative control region. All of the genes are encoded on the H-strand, except for one PCG (nad6) gene and eight tRNA genes (tRNA(Gln), tRNA(Ala), tRNA(Asn), tRNA(Cys), tRNA(Tyr), tRNA(Ser)(UCN), tRNA(Pro) and tRNA(Glu)). All of these PCGs are initiated with ATG, except for cox1, which began with GTG, while stopped by six types of stop codons. All tRNA genes have the potential to fold into typical clover-leaf structure, with exception of the tRNA(Ser)(AGY) which lacks the DHU stem. PMID- 25693707 TI - The complete mitogenome of the Australian freshwater shrimp Paratya australiensis Kemp, 1917 (Crustacea: Decapoda: Atyidae). AB - The mitochondrial genome sequence of the Australian freshwater shrimp, Paratya australiensis, is presented, which is the fourth for genera of the superfamily Atyoidea and the first atyid from the southern hemisphere. The base composition of the P. australiensis, mitogenome is 33.55% for T, 18.24% for C, 35.16% for A, and 13.06% for G, with an AT bias of 71.58%. It has a mitogenome of 15,990 base pairs comprised of 13 protein-coding, 2 ribosomal subunit and 22 transfer RNAs genes and a non-coding AT-rich region. The mitogenome gene order for the species is typical for atyid shrimps, which conform to the primitive pan crustacean model. PMID- 25693708 TI - The complete mitogenome of the rock pool prawn Palaemon serenus (Heller, 1862) (Crustacea: Decapoda: Palaemonidae). AB - The mitochondrial genome of the rock pool prawn (Palaemon serenus), is sequenced, making it the third for genera of the family Palaemonidae and the first for the genus Palaemon. The mitogenome is 15,967 base pairs in length and comprises 13 protein-coding genes, 2 ribosomal subunit genes, 22 transfer RNAs and a non coding AT-rich region. The P. serenus mitogenome has an AT bias of 58.97% and a base composition of 29.79% for T, 24.14% for C, 29.18% for A, and 16.89% for G. The mitogenome gene order of P. serenus is identical to Exopalaemon carinicauda. PMID- 25693709 TI - The complete nucleotide sequence of the mitochondrial genome of the Asian longhorn beetle, Anoplophora glabripennis (Coleoptera: Cerambycidae). AB - The complete mitochondrial genome of Anoplophora glabripennis has been investigated and analyzed. The genome is a circular molecule of 15,774 bp, containing 13 protein-coding genes (PCGs), 2 rRNA genes, 22 tRNA genes, and an A + T-rich region. The nucleotide composition of the A.glabripennis mitogenome is strongly biased toward A + T nucleotides (78.30%). Nine protein-coding genes and 14 tRNA genes are encoded on the H strand, and the other 4 protein-coding genes and 8 tRNA genes are encoded on the L strand. The arrangement of genes is identical to all know longhorn beetles mitochondrial genomes. PMID- 25693710 TI - The complete mitochondrial genomes of Cynomys leucurus and C. ludovicianus (Rodentia: Sciuridae). AB - The mitochondrial genomes of the white - tailed praire dog Cynomys leucurus and black-tailed prairie dog C. ludovicianus (Rodentia: Sciuridae) are circular molecules of 16,454 bp and 16,466 bp in length, respectively, containing 37 genes as in other Rodentia species. The A + T content of the overall base composition of the H-strand is 63.0% and 62.6% for C. leucurus and C. ludovicianus, respectively. The control region of the C. leucurus and C. ludovicianus mt genome is 1012 bp in length, and the A + T content of this region is 63.5% and 62.0%, respectively. Nucleotide sequence divergence of the mt genome (p distance) between C. leucurus and C. ludovicianus was 4.0%. PMID- 25693711 TI - The complete mitochondrial genome of the confused flour beetle Tribolium confusum (Coleoptera: Tenebrionidae). AB - Flour beetles of the genus Tribolium are economically important as destructive cosmopolitan pests of stored flour, corn, peanuts, and other dried agricultural products. The confused flour beetle Tribolium confusum Jacquelin du Val (1868) is one of the most important pest species of flour beetle. Here we sequenced and characterized the complete mitochondrial genome of T. confusum, the entire sequence is 15,813 bp in size with 72.8% AT content. It consists of 13 protein coding genes (PCGs), 22 transfer RNA (tRNA), 2 ribosomal RNA (rRNA) genes and one major non-coding AT-rich region. The mitogenome of T. confusum exhibits a gene arrangement and content identical to the most common type in insects. All PCGs are start with a typical ATN initiation codon, except for the cox1, which use AAC as its start codon instead of ATN. Ten genes use standard complete termination codon (six TAA, three TAG), whereas the cox2, cox3, nad4 and nad5 genes end with single T. Except for trnS1 ((AGN)), all tRNA genes display typical secondary cloverleaf structures as those of other insects. The sizes of the large and small ribosomal RNA genes are 1277 and 773 bp, respectively. The AT content of the AT rich region is 79.5%. The 5 bp conserved motif TACTA was found in the intergenic region between trnS2 ((UCN)) and nad1. PMID- 25693712 TI - Changes in the Mitogenome Announcement manuscript category. PMID- 25693713 TI - Characteristics of the mitochondrial genome of four native goats in China (Capra hircus). AB - Here, we describe the complete mitochondrial genome sequences of Jining Gray goat, Fushun black goat, Youzhou black-skin goat, and Hechuan white goat. The mitogenome of those four goats consisted of 16,640 nt, consisting of 13 protein coding genes, 22 transfer RNA (tRNA) genes, 2 ribosomal RNA (rRNA) genes and a control region. As in other mammals, most mitochondrial genes are encoded on the heavy strand, except for ND6 and eight tRNA genes, which are encoded on the light strand. The complete mitogenome of these four local breeds of Chinese native goats could provide an important data to further breed improvement and animal genetics resource conservation in China. PMID- 25693714 TI - The complete mitochondrial genome for an epilepsy model of rat WAG/Rij strain (Rattus norvegicus). AB - Epilepsy is recurrent spontaneous seizures resulting from abnormal synchronized activity of neurons in the brain. Rodent models contributed significantly for the study of this disease. We sequenced the complete mitochondrial genome of an epilepsy model of rat WAG/Rij strain for the first time. The total length of the mitogenome was 16,310 bp and contains 159 SNPs compared with the Rattus norvegicus strain BN/SsNHsdMCW reference sequence. PMID- 25693715 TI - Next-generation sequencing yields the complete mitochondrial genome of the flathead mullet, Mugil cephalus cryptic species in East Australia (Teleostei: Mugilidae). AB - In this study, the complete mitogenome sequence of a cryptic species from East Australia (Mugil sp. H) belonging to the worldwide Mugil cephalus species complex (Teleostei: Mugilidae) has been sequenced by next-generation sequencing method. The assembled mitogenome, consisting of 16,845 bp, had the typical vertebrate mitochondrial gene arrangement, including 13 protein-coding genes, 22 transfer RNAs, 2 ribosomal RNAs genes and a non-coding control region of D-loop. D-loop consists of 1067 bp length, and is located between tRNA-Pro and tRNA-Phe. The overall base composition of East Australia M. cephalus is 28.4% for A, 29.3% for C, 15.4% for G and 26.9% for T. The complete mitogenome may provide essential and important DNA molecular data for further phylogenetic and evolutionary analysis for flathead mullet species complex. PMID- 25693716 TI - Complete mitochondrial genome of Chinese icefish Neosalanx tangkahkeiis (Salmoniformes, Salangidae): comparison reveals Neosalanx taihuensis not a valid name. AB - The complete mitochondrial genome of Neosalanx tangkahkeiis was determined to be 16,550 bp in length with (A+T) content of 49.7%, and it consists of 13 protein coding genes, 22 tRNAs, 2 ribosomal RNAs, and a control region. The gene composition and the structural arrangement of the N. tangkahkeiis complete mtDNA were identical to most of other vertebrates. The sequence comparison showed that mitogenome of N. tangkahkeiis had a 99.9% of similarity with so-called N. taihuensis, indicating they are the same species and N. taihuensis is not a valid name. PMID- 25693717 TI - Mitochondrial genome of a spontaneous multiple myeloma bone cancer model mouse C57BL/KaLwRij strain. AB - We sequenced the complete mitochondrial genome of a multiple myeloma bone cancer model mouse C57BL/KaLwRij strain for the first time. The total length of the mitogenome was 16,297 bp, with 13 protein-coding genes, 2 ribosomal RNA genes, 22 transfer RNA genes. This mitochondrial genome sequence contains 127 SNPs compared with the house mouse reference sequence. PMID- 25693718 TI - Complete mitochondrial genome of Cacopsylla coccinae (Hemiptera: Psyllidae). AB - In this study, the first complete mitochondrial genome (mitogenome) sequence of Cacopsylla coccinae was determined by long PCR and primer walking methods. The complete mitochondrial genome is 14,832 bp in length and contains 13 protein coding genes, 2 ribosomal RNA genes, 22 transfer RNA genes as well as a control region. The overall base composition of the genome is A (38.16%), T (33.88%), C (17.95%) and G (10.01%). Stop codon was incomplete for coxII gene and ND1 gene. The gene overlaps were suggested between 13 pairs of the contiguous genes in C. coccinae. The mitogenome would contribute to resolving phylogenetic position and interrelationships of Cacopsylla. PMID- 25693719 TI - Deregulated tyrosine-phenylalanine metabolism in pulmonary tuberculosis patients. AB - Metabolic profiling of biofluids from tuberculosis (TB) patients would help us in understanding the disease pathophysiology and may also be useful for the development of novel diagnostics and host-directed therapy. In this pilot study we have compared the urine metabolic profiles of two groups of subjects having similar TB symptoms and categorized as active TB (ATB, n = 21) and non-TB (NTB, n = 21) based on GeneXpert test results. Silylation, gas chromatography mass spectrometry, and standard chemometric methods were employed to identify the important molecules and deregulated metabolic pathways. Eleven active TB patients were followed up on longitudinally for comparative urine metabolic profiling with healthy controls (n = 11). A set of 42 features qualified to have a variable importance parameter score of > 1.5 of a partial least-squares discriminate analysis model and fold change of > 1.5 at p value < 0.05 between ATB and NTB. Using these variables, a receiver operating characteristics curve was plotted and the area under the curve was calculated to be 0.85 (95% CI: 0.72-0.96). Several of these variables that represent norepinephrine, gentisic acid, 4-hydroxybenzoic acid, hydroquinone, and 4-hydroxyhippuric acid are part of the tyrosine phenylalanine metabolic pathway. In the longitudinal study we observed a treatment-dependent trend in the urine metabolome of follow-up samples, and subjects declared as clinically cured showed similar metabolic profile as those of asymptomatic healthy subjects. The deregulated tyrosine-phenylalanine axis reveals a potential target for diagnostics and intervention in TB. PMID- 25693720 TI - Development of a Microsphere-based Immunoassay for Serological Detection of African Horse Sickness Virus and Comparison with Other Diagnostic Techniques. AB - African horse sickness (AHS) is a viral disease that causes high morbidity and mortality rates in susceptible Equidae and therefore significant economic losses. More rapid, sensitive and specific assays are required by diagnostic laboratories to support effective surveillance programmes. A novel microsphere-based immunoassay (Luminex assay) in which beads are coated with recombinant AHS virus (AHSV) structural protein 7 (VP7) has been developed for serological detection of antibodies against VP7 of any AHSV serotype. The performance of this assay was compared with that of a commercial enzyme-linked immunosorbent assay (ELISA) and commercial lateral flow assay (LFA) on a large panel of serum samples from uninfected horses (n = 92), from a reference library of all AHSV serotypes (n = 9), on samples from horses experimentally infected with AHSV (n = 114), and on samples from West African horses suspected of having AHS (n = 85). The Luminex assay gave the same negative results as ELISA when used to test the samples from uninfected horses. Both assays detected antibodies to all nine AHSV serotypes. In contrast, the Luminex assay detected a higher rate of anti-VP7 positivity in the West African field samples than did ELISA or LFA. The Luminex assay detected anti VP7 positivity in experimentally infected horses at 7 days post-infection, compared to 13 days for ELISA. This novel immunoassay provides a platform for developing multiplex assays, in which the presence of antibodies against multiple ASHV antigens can be detected simultaneously. This would be useful for serotyping or for differentiating infected from vaccinated animals. PMID- 25693721 TI - T1 process and dynamics in glass-forming hard-sphere liquids. AB - To study the relationship between dynamics and structure in a glass-forming liquid, we introduce a purely geometric criterion for locally mobile particles in a dense hard-sphere fluid: namely, "T1-active" particles, which can gain or lose at least one Voronoi neighbor by moving within their free volume with other particles fixed. We obtain geometrical and dynamical properties for monodisperse hard-sphere fluids with 0.40 < phi < 0.64 using a "crystal-avoiding" MD simulation that effectively suppresses crystallization without altering the dynamics. We find that the fraction of T1-active particles vanishes at random close packing, while the percolation threshold of T1-inactive particles is essentially identical to the commonly identified hard-sphere glass transition, phig ~ 0.585. PMID- 25693722 TI - Impact of hepatic arterial hemodynamics in predicting early hepatic arterial thrombosis in pediatric recipients younger than three yr after living donor liver transplantation. AB - We used Doppler US to evaluate the changes in hepatic arterial hemodynamics that occur following LDLT in pediatric recipients, with a view to assessing the utility of these parameters in predicting early HAT. A retrospective review of 144 pediatric recipients (73 males, 71 females) who underwent routine Doppler US in the first week after LDLT was undertaken, and changes in hepatic arterial hemodynamics were assessed. The HARI and HAPSV were compared in patients with early HAT (defined as occurring in the first postoperative week) and a control group, and the utility of these parameters in predicting early HAT after LDLT was determined. A total of 11 pediatric recipients experienced early HAT, being diagnosed on average four and a half days after LDLT. HARI and HAPSV values were significantly different between the early HAT group and controls. HARI values <0.6 on the day before the onset of early HAT were able to predict HAT development with a sensitivity of 81.8% and specificity of 95.2%. This provides evidence for routine Doppler US examination in these patients and supports consideration of more intensive anticoagulation in these high-risk patients. PMID- 25693723 TI - Reference Ranges in [(99m)Tc]Mercaptoacetyltriglycerine Renography: Comparison of a Semi-automated (Xeleris, GE) and Manual (Picker, Odyssey) Processing Software. AB - PURPOSE: The purpose of the study was to define reference ranges for quantitative parameters in [(99m)Tc]mercaptoacetyltriglycerine ([(99m)Tc]MAG3) renography to assist interpretation in a semi-automated (Xeleris, GE) compared to a manual (Picker, Odyssey) software package. PROCEDURES: Forty-eight subjects approved for renal donation were evaluated with [(99m)Tc]MAG3 renography using both the Xeleris and the Picker software. RESULTS: Reference ranges for the two software were comparable regarding the relative function of the two kidneys (the split function, SF) and the residual activities (RA). The time to peak whole-kidney activities (T max whole-kidney) was more dependent on the type of software. Using Bland-Altman limits, we found good and acceptable agreement between the two methods. CONCLUSIONS: We found good correlation between renography results using the Xeleris and Picker software packages. However, software-specific reference ranges are needed. PMID- 25693724 TI - Anaplastic large cell lymphoma of the chest wall with cytoplasmic globules and variability in nuclear morphology including a teddy bear-shaped nucleus. PMID- 25693725 TI - Squamous cell carcinoma and pilonidal cyst disease. AB - AIM: Squamous cell carcinoma developed on a chronic pilonidal cyst. CASE REPORT: Authors describe the case of a squamous cell carcinoma developed on a chronic pilonidal cyst in a 63- years-old patient with a 43 years history of recurrent pilonidal sinus disease. RESULTS: The patient underwent incisional biopsy, staging with total body CT and, finally, radical surgery. After 30 months there were no evidence of recurrence. DISCUSSION: Pilonidal sinus disease is a common disease that affects especially male subjects, obese and with excess of body hair. The complications that arise most frequently are cellulitis, abscess formation and developments of recurrences. Malignant transformation appears rather rare and is reported in the literature with a percentage that goes from 0.02% to 0.1%. CONCLUSIONS: Authors recommend accurate inspection of the pilonidal area in all chronic and longstanding inflammatory lesions and possibly practice incisional biopsies to exclude malignant degeneration. PMID- 25693726 TI - NIPT-based screening for Down syndrome and beyond: what do pregnant women think? AB - OBJECTIVE: The aim of the study is to study pregnant women's views on noninvasive prenatal testing (NIPT) for Down syndrome and the potential to test for a broader range of conditions. METHODS: An online questionnaire available on the Dutch pregnancy fair website was completed by 381 pregnant women. RESULTS: Of the women, 51% expressed interest in having NIPT, including 33% of women who had declined first-trimester screening. The majority (73%) thought that the uptake of screening would increase with NIPT. Most women agreed that testing for life threatening (89%), severe physical (79%), or severe mental (76%) disorders should be offered. A minority (29%) felt that prenatal screening should also be offered for late-onset disorders. Most (41%) preferred to have a free choice from a list of disorders, 31% preferred a 'closed offer', and 26% preferred choosing between packages of disorders. Although most women (76%) thought that screening for a broad range of conditions would avoid much suffering, 39% feared that it would confront couples with choices, the implications of which would be difficult to grasp. CONCLUSION: The results suggest that the uptake of screening will increase with NIPT. If NIPT will be offered for a broad range of conditions, it is crucial to find a way that facilitates rather than undermines well-informed decision making. PMID- 25693727 TI - Association between height and thyroid cancer risk: a meta-analysis of prospective cohort studies. AB - While several epidemiological studies have investigated the relationship between height and risk for thyroid cancer, the results were inconsistent. In the present study, a systematic review and meta-analysis of prospective cohort studies was conducted to assess the impact of height on thyroid cancer risk. Online databases were searched up to December 30, 2014, for prospective cohort studies on the association between height and thyroid cancer risk. Pooled relative risks (RRs) and 95% confidence intervals (CIs) were calculated using a random-effects model of meta-analysis. In all, 11 articles were included in this meta-analysis, including 15 prospective cohort studies, containing 6,695,593 participants and 7,062 cases of thyroid cancer. By comparing the highest versus the lowest categories of height, we reported that risk of thyroid cancer was increased with height in both men (summary RR = 1.40, 95%CI 1.09-1.78, p = 0.008) and women (summary RR = 1.54, 95%CI 1.30-1.83, p < 0.001). The summary RR of thyroid cancer per 5-cm increase in height was 1.16 (95%CI 1.09-1.23, p < 0.001). The results were similar among men (per 5-cm increase RR = 1.13, 95%CI 1.03-1.23, p = 0.011) and women (per 5-cm increase RR = 1.18, 95%CI 1.10-1.27, p < 0.001). No obvious risk of publication bias was observed. Our meta-analysis provides strong evidence for a dose-response relationship between height and risk of thyroid cancer in both men and women. PMID- 25693728 TI - ABORTED GAMETOPHYTE 1 is required for gametogenesis in Arabidopsis. AB - In flowering plants, the male and female gametogenesis is a crucial step of sexual reproduction. Although many genes have been identified as being involved in the gametogenesis process, the genetic mechanisms underlying gametogenesis remains poorly understood. We reported here characterization of the gene, ABORTED GAMETOPHYTE 1 (AOG1) that is newly identified as essential for gametogenesis in Arabidopsis thaliana. AOG1 is expressed predominantly in reproductive tissues including the developing pollen grains and ovules. The AOG1 protein shares no significant amino acid sequence similarity with other documented proteins and is located mainly in nuclei of the cells. Mutation in AOG1 caused degeneration of pollen at the uninucleate microspore stage and severe defect in embryo sacs, leading to a significant reduction in male and female fertility. Furthermore, the molecular analyses showed that the aog1 mutant significantly affected the expression of several genes, which are required for gametogenesis. Our results suggest that AOG1 plays important roles in gametogenesis at the stage prior to pollen mitosis I (PMI) in Arabidopsis, possibly through collaboration with other genes. PMID- 25693730 TI - Hypomagnesaemia and its potential impact on thiamine utilisation in patients with alcohol misuse at the Alice Springs Hospital. AB - INTRODUCTION AND AIMS: Alcohol rapidly reduces thiamine among alcohol-dependent individuals. Poor diet and alcohol's impact on absorption, storage, activation and excretion of thiamine are thought to be the mechanisms. Previous literature identifies magnesium as an important cofactor in thiamine utilisation, which might also be compromised in alcohol dependent patients. The aim was to describe the thiamine status and clinical profile for a sample of heavy alcohol users entering the Alice Springs Hospital in the Northern Territory of Australia and to examine the relationship between thiamine deficiency, magnesium deficiency and cognitive functioning. DESIGN AND METHODS: Cross-sectional study examining thiamine pyrophosphate (TPP) and magnesium concentrations for a sample of 62 males and 43 females (N = 105; n = 88 Aboriginal, n = 13 non-Indigenous). Cognition was assessed using the Rowland Universal Dementia Assessment Scale. RESULTS: TPP concentrations were within or above the reference range. Aboriginal patients had significantly lower TPP than non-Indigenous patients. A marginally significant difference was found between individuals with thiamine supplementation recorded within the previous 20 days compared with those without. Mean serum magnesium was in the low normal range with magnesium deficiency (i.e. <0.80 mmol L(-1)) present in 48% of those tested. Serum magnesium (but not TPP) concentrations correlated positively with cognitive test scores. DISCUSSION AND CONCLUSIONS: Despite increased exposure to risk factors for Wernicke Korsakoff Syndrome, no patient had TPP concentrations below the reference range. High patient readmission and aggressive thiamine treatment policies may explain this finding. However, low magnesium may be prevalent and could contribute to impaired thiamine utilisation. PMID- 25693729 TI - Pancreatic cancer and FOLFIRINOX: a new era and new questions. AB - FOLFIRINOX (FFX) was introduced to clinical practice in 2010 following publication of the PRODIGE 4/ACCORD 11 study, which compared this novel regimen to gemcitabine in metastatic pancreatic cancer. Median overall survival, progression-free survival, and objective responses were all superior with FFX and there was improved time to definitive deterioration in quality of life. Despite initial concerns over toxicity, there has been rapid uptake of this regimen, both revolutionizing management and opening the door to innovative research. As experience with FFX has accrued, many questions have arisen including the management of toxicities, the impact of frequent modifications, the optimal number of cycles, integration with other regimens and modalities, interpretation of radiologic and serologic response, utility of molecular signatures, and potential benefit in unique clinical settings such as pre- and postsurgery. This review will closely examine these issues, not only to summarize current knowledge but also to fuel scientific debate. PMID- 25693731 TI - 24-HOUR ACTIVITY RHYTHM AND SLEEP DISTURBANCES IN DEPRESSION AND ANXIETY: A POPULATION-BASED STUDY OF MIDDLE-AGED AND OLDER PERSONS. AB - BACKGROUND: Disturbed circadian rhythms have been associated with depression and anxiety, but it is unclear if disturbances in the 24-hr activity rhythm and sleep are independently and specifically related to these disorders. METHODS: In 1,714 middle-aged and elderly participants of the Rotterdam Study, we collected actigraphy recordings of at least 96 hr (138 +/- 14 hr, mean +/- standard deviation). Activity rhythms were quantified calculating the fragmentation of the rhythm, stability of the rhythm over days, and timing of the rhythm. Total sleep time, sleep onset latency, and wake after sleep onset were also estimated with actigraphy. Depressive symptoms were assessed with the Center for Epidemiologic Studies Depression scale, persons with clinically relevant depressive symptoms were interviewed to diagnose DSM-IV-depressive disorder. Anxiety disorders were determined with the Munich version of the Composite International Diagnostic Interview. RESULTS: More fragmented rhythms were associated with clinically relevant depressive symptoms (odds ratio (OR): 1.27, 95% confidence interval (CI): 1.04;1.54) and anxiety disorders (OR: 1.39, 95% CI: 1.14;1.70) after covariate adjustment. Less stable rhythms, longer sleep onset latency, and more wake after sleep onset were related to clinically relevant depressive symptoms or anxiety disorders only if not adjusted for covariates and other activity rhythm and sleep indicators. CONCLUSIONS: Our study in middle-aged and elderly persons suggests that fragmentation of the 24-hr activity rhythm is associated with depression and anxiety. Moreover, this association also largely accounts for the effect of disturbed sleep on these psychiatric disorders. PMID- 25693732 TI - Interleukin-1 family cytokines and their regulatory proteins in normal pregnancy and pre-eclampsia. AB - Maternal systemic inflammation is a feature of pre-eclampsia, a condition in pregnancy characterized by hypertension and proteinuria. Pre-eclampsia is caused by the placenta; many placental factors contribute to the syndrome's progression, and proinflammatory cytokines have been identified previously as one such mediator. The interleukin (IL)-1 family of cytokines are key regulators of the inflammatory network, and two naturally occurring regulatory molecules for IL-1 family cytokines, IL-1RA and sST2, have been found previously to be elevated in maternal blood from women with pre-eclampsia. Here we investigate more recently identified IL-1 family cytokines and regulatory molecules, IL-1RAcP, IL-37, IL 18BP, IL-36alpha/beta/gamma/Ra and IL-38 in pre-eclampsia. Pregnant women have more circulating IL-18BP and IL-36Ra than non-pregnant women, and sIL-1RAcP is elevated from women with pre-eclampsia compared to normal pregnancies. The placenta expresses all the molecules, and IL-37 and IL-18BP are up-regulated significantly in pre-eclampsia placentas compared to those from normal pregnancies. Together, these changes contribute to the required inhibition of maternal systemic cytotoxic immunity in normal pregnancy; however, in pre eclampsia the same profile is not seen. Interestingly, the increased circulating levels of sIL-1RAcP and increased placental IL-18BP and IL-37, the latter of which we show to be induced by hypoxic damage to the placenta, are all factors which are anti-inflammatory. While the placenta is often held responsible for the damage and clinical symptoms of pre-eclampsia by the research community, here we show that the pre-eclampsia placenta is also trying to prevent inflammatory damage to the mother. PMID- 25693733 TI - The sulfated polysaccharide fucoidan rescues senescence of endothelial colony forming cells for ischemic repair. AB - The efficacy of cell therapy using endothelial colony-forming cells (ECFCs) in the treatment of ischemia is limited by the replicative senescence of isolated ECFCs in vitro. Such senescence must therefore be overcome in order for such cell therapies to be clinically applicable. This study aimed to investigate the potential of sulfated polysaccharide fucoidan to rescue ECFCs from cellular senescence and to improve in vivo vascular repair by ECFCs. Fucoidan preconditioning of senescent ECFCs was shown by flow cytometry to restore the expression of functional ECFC surface markers (CD34, c-Kit, VEGFR2, and CXCR4) and stimulate the in vitro tube formation capacity of ECFCs. Fucoidan also promoted the expression of cell cycle-associated proteins (cyclin E, Cdk2, cyclin D1, and Cdk4) in senescent ECFCs, significantly reversed cellular senescence, and increased the proliferation of ECFCs via the FAK, Akt, and ERK signaling pathways. Fucoidan was found to enhance the survival, proliferation, incorporation, and endothelial differentiation of senescent ECFCs transplanted in ischemic tissues in a murine hind limb ischemia model. Moreover, ECFC-induced functional recovery and limb salvage were markedly improved by fucoidan pretreatment of ECFCs. To our knowledge, the findings of our study are the first to demonstrate that fucoidan enhances the neovasculogenic potential of ECFCs by rescuing them from replicative cellular senescence. Pretreatment of ECFCs with fucoidan may thus provide a novel strategy for the application of senescent stem cells to therapeutic neovascularization. PMID- 25693734 TI - Heterogeneous catalysis. AB - A heterogeneous catalyst is a functional material that continually creates active sites with its reactants under reaction conditions. These sites change the rates of chemical reactions of the reactants localized on them without changing the thermodynamic equilibrium between the materials. PMID- 25693736 TI - Commentary: golden years and a bright future for biochemical education. PMID- 25693735 TI - Investigation of the role of the calvin cycle and C1 metabolism during HCHO metabolism in gaseous HCHO-treated petunia under light and dark conditions using 13C-NMR. AB - INTRODUCTION: It has been shown that formaldehyde (HCHO) absorbed by plants can be assimilated through the Calvin cycle or C1 metabolism. Our previous study indicated that Petunia hybrida could effectively eliminate HCHO from HCHO polluted air. OBJECTIVE: To understand the roles of C1 metabolism and the Calvin cycle during HCHO metabolism and detoxification in petunia plants treated with gaseous H(13)CHO under light and dark conditions. METHODS: Aseptically grown petunia plants were treated with gaseous H(13)CHO under dark and light conditions. The metabolites generated from HCHO detoxification in petunia were investigated using (13)C-NMR. RESULTS: [2-(13)C]glycine (Gly) was generated via C1 metabolism and [U-(13)C]glucose (Gluc) was produced through the Calvin cycle simultaneously in petunia treated with low-level gaseous H(13)CHO under light conditions. Generation of [2-(13)C]Gly decreased whereas [U-(13) C]Gluc and [U (13)C]fructose (Fruc) production increased greatly under high-level gaseous H(13)CHO stress in the light. In contrast, [U-(13)C]Gluc and [U-(13)C] Fruc production decreased greatly and [2-(13)C]Gly generation increased significantly under low-level and high-level gaseous H(13)CHO stress in the dark. CONCLUSION: C1 metabolism and the Calvin cycle contributed differently to HCHO metabolism and detoxification in gaseous H(13CHO-treated petunia plants. As the level of gaseous HCHO increased, the role of C1 metabolism decreased and the role of the Calvin cycle increased under light conditions. However, opposite changes were observed in petunia plants under dark conditions. PMID- 25693737 TI - Comparative analysis of the L, M, and S RNA segments of Crimean-Congo haemorrhagic fever virus isolates from southern Africa. AB - Crimean-Congo haemorrhagic fever virus (CCHFV) is a member of the Bunyaviridae family with a tripartite, negative sense RNA genome. This study used predictive software to analyse the L (large), M (medium), and S (small) segments of 14 southern African CCHFV isolates. The OTU-like cysteine protease domain and the RdRp domain of the L segment are highly conserved among southern African CCHFV isolates. The M segment encodes the structural glycoproteins, GN and GC, and the non-structural glycoproteins which are post-translationally cleaved at highly conserved furin and subtilase SKI-1 cleavage sites. All of the sites previously identified were shown to be conserved among southern African CCHFV isolates. The heavily O-glycosylated N-terminal variable mucin-like domain of the M segment shows the highest sequence variability of the CCHFV proteins. Five transmembrane domains are predicted in the M segment polyprotein resulting in three regions internal to and three regions external to the membrane across the G(N), NS(M) and G(C) glycoproteins. The corroboration of conserved genome domains and sequence identity among geographically diverse isolates may assist in the identification of protein function and pathogenic mechanisms, as well as the identification of potential targets for antiviral therapy and vaccine design. As detailed functional studies are lacking for many of the CCHFV proteins, identification of functional domains by prediction of protein structure, and identification of amino acid level similarity to functionally characterised proteins of related viruses or viruses with similar pathogenic mechanisms are a necessary step for selection of areas for further study. PMID- 25693738 TI - Dermal exposure of Eisenia andrei earthworms: Effects of heavy metals on metallothionein and phytochelatin synthase gene expressions in coelomocytes. AB - Parameters such as total number of coelomocytes, riboflavin content in coelomocytes, expression of genes implied in metal homeostasis, and detoxification mechanisms can be used as biomarkers to assess the impact of metals on annelids. Defense biomarkers (detoxification gene expressions and coelomocyte parameters) were investigated in the ecotoxicologically important species Eisenia andrei following in vivo exposure to 5 different metals (zinc, copper, nickel, lead, and cadmium) at known concentrations. Coelomocyte numbers and riboflavin content were not affected by metallic exposure, but metal-specific gene expression variations were evidenced. PMID- 25693739 TI - Cell-based therapy by implanted human bone marrow-derived mononuclear cells improved bone healing of large bone defects in rats. AB - QUESTION/AIM: Cell-based therapy by cultivated stem cells (mesenchymal stem cells [MSC] and endothelial progenitor cells [EPC]) in a large-sized bone defect has already shown improved vascularization and new bone formation. However, these methods are clinically afflicted with disadvantages. Another heterogeneous bone marrow cell population, the so-called human bone marrow-derived mononuclear cells (BMC), has nevertheless been used clinically and showed improved vascularization in ischemic limbs or in the myocardium. For clinical use, a certified process has been established; thus, BMC were isolated from bone marrow aspirate by density gradient centrifugation, washed, cleaned, and given back to patients within several hours. This investigation tested the ability of human BMC seeded on beta tricalcium phosphate (beta-TCP) and placed into a large bone defect in rats to improve the bone healing process in vivo. METHODS: Human EPC were isolated from buffy coat, and MSC or BMC, respectively, were isolated from bone marrow aspirate by density gradient centrifugation. 1.0*10(6) cells were loaded onto 750 MUL beta TCP (0.7-1.4 mm). Large femoral defects (6 mm) in athymic rats were created surgically and stabilized with an internal fixateur. The remaining defects were filled with beta-TCP granules alone (group 1), beta-TCP+EPC/MSC (group 2), or beta-TCP+BMC (group 3). After 8 weeks, histomorphometric analysis (new bone formation), radiological microcomputer tomography analysis (bony bridging), and biomechanical testing (three-point bending) were achieved. Moreover, a tumorigenicity study was performed to evaluate the safety of BMC implantation after 26 weeks. For statistical analysis, the Kruskal-Wallis test was used. RESULTS: Eight weeks after implantation of EPC/MSC or BMC, respectively, we detected a more significant new bone formation compared to control. In group 2 and 3, bony bridging of the defect was seen. In the control group, more chondrocytes and osteoid were detected. In the BMC and EPC/MSC group, respectively, less chondrocytes and a significantly more advanced bone formation were observed. The biomechanical stability of the bone regenerate was significantly enhanced if BMC and EPC/MSC, respectively, were implanted compared to control. Moreover, no tumor formation was detected either macroscopically or histologically after 26 weeks of BMC implantation. DISCUSSION: Implanted BMC suggest that a heterogeneous cell population may provide a powerful cellular therapeutic strategy for bone healing in a large bone defect in humans. PMID- 25693740 TI - Finite element analysis of the transfer of sound in the myringosclerotic ear. AB - This work presents a biomechanical study of myringosclerosis (MS), an abnormal condition of the ear that produces calcification of the lamina propria of the eardrum. The study researched the transfer of sound to the stapes depending on the localization, dimension and calcification degree of the MS plaques. Results were obtained using a validated finite element model of the ear. The mechanical properties of the lamina propria were modified, in order to model MS plaques, using the rule of mixtures for particle composites considering that the plaques are made of hydroxyapatite particles in a matrix of connective tissue. Results show that the localization and dimension of the plaques are a factor of higher importance than calcification for loss of hearing through MS. The mobility of the stapes decreased with the presence of larger plaques and also when the tympanic annulus and the area of the handle of the malleus were involved. PMID- 25693741 TI - Effects of saliva on early post-tooth extraction tissue repair in rats. AB - The aim of the present study was to perform a biochemical, histological, and histomorphometrical evaluation of the mechanisms involved in tissue repair in rats subjected to submandibulectomy-induced hyposialia, 24, 48, and 72 hours of post-tooth extraction. We studied the correlation between the lack of submandibular saliva and the modulation of inflammatory mediators involved in tissue repair, such as prostaglandin E2 , nitric oxide (NO), and tumor necrosis factor alpha (TNF-alpha). Rats with hyposialia showed a delay in socket healing, slow replacement of the clot with granulation tissue, and fewer cells and collagen fibers, concomitant with a longer inflammatory process, as compared to controls. The lack of saliva induced by submandibulectomy modified the levels of prostaglandin E2 , NO, and TNF-alpha, and tissue response in the early stages of wound healing compared to controls, and could thus determine alterations in later osteogenic response. Our results allow concluding that hyposialia modulates the parameters of inflammation studied here, and that it is essential for optimal healing. Therefore, these findings provide evidence for the importance of submandibular saliva to final bone socket healing. PMID- 25693743 TI - Silver phosphate/graphitic carbon nitride as an efficient photocatalytic tandem system for oxygen evolution. AB - Herein, we show the facile synthesis of an efficient silver phosphate/graphitic carbon nitride (Ag3 PO4 /g-C3 N4 ) photocatalyst for oxygen production and pollutant degradation by using electrostatically driven assembly and ion-exchange processes. The composite materials demonstrate a sheet-like C3 N4 structure, decorated with different Ag3 PO4 particles sizes. Detailed analysis of the reactions mechanism by electron-spin resonance and radical-capture agents strongly imply the formation of an in situ Z-scheme by the evolution of small silver nanoparticles in the interface of the materials under illumination. The Ag nanoparticles improve charge separation within the composite material by acting as a storage and recombination center for electrons and holes from Ag3 PO4 and C3 N4 , respectively. In addition, the photostability of Ag3 PO4 is enhanced relative to that of the bulk materials, which results in a stabilized heterojunction. We believe that this work provides new insight into the operation mechanism of composite photocatalysts for water splitting and opens the possibility for advanced photocatalysis based on the higher oxidation power of Ag3 PO4 . PMID- 25693744 TI - Dietary phenolics against colorectal cancer--From promising preclinical results to poor translation into clinical trials: Pitfalls and future needs. AB - Colorectal cancer (CRC) remains a major cause of cancer death worldwide. Over 70% of CRC cases are sporadic and related to lifestyle. Epidemiological studies inversely correlate CRC incidence with the intake of fruits and vegetables but not with their phenolic content. Preclinical studies using in vitro (cell lines) and animal models of CRC have reported anticancer effects for dietary phenolics through the regulation of different markers and signaling pathways. Herein, we review and contrast the evidence between preclinical studies and clinical trials (patients with CRC or at risk, familial adenopolyposis or aberrant crypt foci) investigating the protective effects of curcumin, resveratrol, isoflavones, green tea extracts (epigallocatechin gallate), black raspberry powder (anthocyanins and ellagitannins), bilberry extract (anthocyanins), ginger extracts (gingerol derivatives), and pomegranate extracts (ellagitannins and ellagic acid). To date, curcumin is the most promising polyphenol as possible future adjuvant in CRC management. Overall, the clinical evidence of dietary phenolics against CRC is still weak and the amounts needed to exert some effects largely exceed common dietary doses. We discuss here the possible reasons behind the gap between preclinical and clinical research (inconsistence of results, lack of clinical endpoints, etc.), and provide an outlook and a roadmap to approach this topic. PMID- 25693745 TI - Mechanisms for the influence of citrus rootstocks on fruit size. AB - To obtain insight into potential mechanisms underlying the influence of rootstock on fruit size, we performed a comparative analysis of 'Shatangju' mandarin grafted onto two rootstocks. The results demonstrated that trees grafted onto Canton lemon produced larger fruits through an enhancement of cell expansion in the ripening period. The difference in fruit size may be due to greater auxin levels in fruits from trees on Canton lemon, and different auxin levels may be produced by parent trees as the result of AUX1 upregulation. Rootstocks also modulate auxin signaling by affecting the transcription of several auxin response factor genes. There were higher abscisic acid concentrations in fruits of 'Shatangju'/Trifoliate orange, resulting in an inhibition of fruit growth and cell expansion through suppression of the synthesis of growth promoting hormones. Furthermore, expansins may be involved in the regulation of final fruit size by influencing cell expansion. Multiple pathways likely exist in citrus rootstocks that regulate fruit size. PMID- 25693746 TI - Hypnotics and mortality--partial confounding by disease, substance abuse and socioeconomic factors? AB - PURPOSE: The aim of this Cohort study of 10 527 Danish men was to investigate the extent to which the association between hypnotics and mortality is confounded by several markers of disease and living conditions. METHODS: Exposure was purchases of hypnotics 1995-1999 ("low users" (150 or less defined daily dose (DDD)) or "high users" (151 or more DDD)). Follow-up for all-cause mortality was from 1 Jan 2000 to 19 June 2010. Cox proportional hazard models were used to study the association. Covariates were entered one at a time and simultaneously. Results were reported using hazard ratio (HR) and 95% confidence intervals (CI). RESULTS: When covariates were entered one at a time, the changes in HR estimates showed that psychiatric disease, socioeconomic position and substance abuse reduced the excess risk by 17-36% in the low user group and by 45-52% in the high user group. Somatic disease, intelligence score and cohabitation reduced the excess risk by 2 11% in the low user group and 8-24% in the high user group. When adjusting for all covariates, the HR was reduced to 1.22 95% CI (0.97-1.54) in the low user group and 1.43 95% CI (1.11-1.85) in the high user group. CONCLUSIONS: The results of this study point at psychiatric disease, substance abuse and socioeconomic position as potential confounding factors partly explaining the association between use of hypnotics and all-cause mortality. PMID- 25693747 TI - Basophil infiltration in eosinophilic oesophagitis and proton pump inhibitor responsive oesophageal eosinophilia. AB - BACKGROUND: The features of proton pump inhibitor-responsive oesophageal eosinophilia (PPI-REE) are similar to those of eosinophilic oesophagitis (EoE), but PPI-REE demonstrates symptomatic and histological responses to PPI therapy. Several studies have shown that basophils play a crucial role in the pathogenesis of allergic diseases. AIM: To identify and compare basophil infiltration in the oesophageal epithelium in patients with EoE, PPI-REE, gastroesophageal reflux disease (GERD) and normal oesophagus (controls). METHODS: Biopsy specimens from 43 patients, including 12 with EoE, 11 with PPI-REE, 10 with GERD and 10 normal oesophagus, were analysed. Immunohistochemistry was performed to quantify the number of basophils and mast cells in the oesophageal epithelium. Double immunofluorescence staining for thymic stromal lymphopoietin (TSLP) and basophils was performed. Patients with EoE were treated with swallowed fluticasone. RESULTS: There were no differences in clinical, endoscopic or histological features between patients with EoE and PPI-REE. There were more basophils and mast cells in patients with EoE and PPI-REE than in patients with GERD and control subjects. Basophil infiltration of the oesophageal epithelium in patients with EoE was higher than that in patients with PPI-REE (3.6 +/- 2.8 per high power field vs. 1.2 +/- 0.9 per high power field respectively; P = 0.02); however, there was no significant difference in mast cell infiltration between the two groups. TSLP was highly expressed in the oesophageal epithelium in areas infiltrated by basophils. Steroid therapy significantly decreased intraepithelial basophils in patients with EoE. CONCLUSION: Basophils may play an important role in the pathogenesis of eosinophilic oesophagitis. PMID- 25693748 TI - A Comparison of the J-1 Visa Waiver and Loan Repayment Programs in the Recruitment and Retention of Physicians in Rural Nebraska. AB - PURPOSE: There is a dearth of literature evaluating the effectiveness of programs aimed at recruiting and retaining physicians in rural Nebraska. Taking advantage of the Nebraska Health Professional Tracking System, this study attempts to comparatively assess the effectiveness of the J-1 visa waiver and state loan repayment programs in the recruitment and retention of physicians in rural Nebraska. METHODS: A mixed methods approach was used. We tracked 240 physicians who enrolled in the J-1 visa waiver and state loan repayment programs between 1996 and 2012 until 2013. In addition, key informant interviews were conducted to obtain perspectives on the recruitment and retention of physicians in rural Nebraska through the 2 programs. FINDINGS: Results from multilevel survival regression analysis indicated that physicians enrolled in the J-1 visa waiver program were more likely to leave rural Nebraska when compared with those enrolled in the state loan repayment program. Participants in the qualitative study, however, cautioned against declaring one program as superior over the other, given that the 2 programs addressed different needs for different communities. In addition, results suggested that fostering the integration of physicians and their families into rural communities might be a way of enhancing retention, regardless of program. CONCLUSION: The findings from this study highlight the complexity of recruitment and retention issues in rural Nebraska and suggest the need for more holistic and family-centered approaches to addressing these issues. PMID- 25693750 TI - Erratum to: Brain-derived neurotrophic factor is produced by skeletal muscle cells in response to contraction and enhances fat oxidation via activation of AMP activated protein kinase. PMID- 25693749 TI - Vitamin D status in men with psoriatic arthritis: a case-control study. AB - We determined hypovitaminosis D prevalence in men with psoriatic arthritis. This is a cross-sectional, analyst blinded, age- and sex-matched, case-control study. Men with psoriatic arthritis have significantly lower 25-hydroxyvitamin D levels. Men with psoriatic arthritis are at increased odds of suffering from hypovitaminosis D. INTRODUCTION: Skeletal manifestations as a result of abrupted bone metabolism may be predominant in psoriatic arthritis (PsA). Vitamin D plays a vital role in maintenance of skeletal health and is known to modulate the immune system in various autoimmune diseases including PsA. The aim of the present study was to determine the prevalence of hypovitaminosis D in a treatment naive, de novo psoriatic arthritis male cohort in a cross-sectional, analyst blinded, age- and sex-matched, case-control study. METHODS: 25 hydroxyvitamin D (25OHD), parathyroid (PTH), osteocalcin (OC) and C-terminal telopeptides of type I collagen (CTx) levels, and lumbar spine and femoral neck bone mineral density were compared between 53 PsA and controls. RESULTS: The prevalence of hypovitaminosis D (25 hydroxyvitamin D (25OHD) levels <75 nmol/L) was 81 and 57 % in the PsA and control groups, respectively. Compared to the healthy controls, 25OHD (67.2 (12-137) nmol/L vs. 51.9 (15-95) nmol/L; p = 0.001) was significantly lower, and osteocalcin (13.6 (5-33) MUg/L vs. 18.2 (6-35) MUg/L; p = 0.003) and C terminal telopeptides of type-I collagen (0.20 (0.01-0.71) MUg/L vs. 0.28 (0.06 0.69) MUg/L; p = 0.008) were significantly higher in the PsA group. A significant association was found between hypovitaminosis D and PsA; the odds for patients with PsA of having hypovitaminosis D was 3.297 (95 % confidence interval 1.372 to 7.922). CONCLUSION: The results of this study suggest that men with PsA have significantly lower 25-hydroxyvitamin D levels, and furthermore, men with PsA are at statistically significant increased odds of suffering from hypovitaminosis D. PMID- 25693753 TI - Consistent prediction of streaming potential in non-Newtonian fluids: the effect of solvent rheology and confinement on ionic conductivity. AB - By considering an ion moving inside an imaginary sphere filled with a power-law fluid, we bring out the implications of the fluid rheology and the influence of the proximity of the other ions towards evaluating the conduction current in an ionic solution. We show that the variation of the conductivity as a function of the ionic concentration is both qualitatively and quantitatively similar to that predicted by the Kohlrausch law. We then utilize this consideration for estimating streaming potentials developed across narrow fluidic confinements as a consequence of the transport of ions in a convective medium constituting a power law fluid. These estimates turn out to be in sharp contrast to the classical estimates of streaming potential for non-Newtonian fluids, in which the effect of rheology of the solvent is merely considered to affect the advection current, disregarding its contributions to the conduction current. Our results have potential implications of devising a new paradigm of consistent estimation of streaming potentials for non-Newtonian fluids, with combined considerations of the confinement effect and fluid rheology in the theoretical calculations. PMID- 25693751 TI - Diabetes risk and amino acid profiles: cross-sectional and prospective analyses of ethnicity, amino acids and diabetes in a South Asian and European cohort from the SABRE (Southall And Brent REvisited) Study. AB - AIMS/HYPOTHESIS: South Asian individuals have an increased risk of diabetes compared with Europeans that is unexplained by obesity and traditional or established metabolic measures. Circulating amino acids (AAs) may provide additional explanatory insights. In a unique cohort of European and South Asian men, we compared cross-sectional associations between AAs, metabolic and obesity traits, and longitudinal associations with incident diabetes. METHODS: Nuclear magnetic spectroscopy was used to measure the baseline (1988-1991) levels of nine AAs in serum samples from a British population-based cohort of 1,279 European and 1,007 South Asian non-diabetic men aged 40-69 years. Follow-up was complete for 19 years in 801 European and 643 South Asian participants. RESULTS: The serum concentrations of isoleucine, phenylalanine, tyrosine and alanine were significantly higher in South Asian men, while cross-sectional correlations of AAs with glycaemia and insulin resistance were similar in the two ethnic groups. However, most AAs were less strongly correlated with measures of obesity in the South Asian participants. Diabetes developed in 227 (35%) South Asian and 113 (14%) European men. Stronger adverse associations were observed between branched chain and aromatic AAs and incident diabetes in South Asian men. Tyrosine was a particularly strong predictor of incident diabetes in South Asian individuals, even after adjustment for metabolic risk factors, including obesity and insulin resistance (adjusted OR for a 1 SD increment, 1.47, 95% CI 1.17,1.85, p = 0.001) compared with Europeans (OR 1.10, 0.87, 1.39, p = 0.4; p = 0.045 for ethnicity * tyrosine interaction). CONCLUSIONS/INTERPRETATION: Branched chain and aromatic AAs, particularly tyrosine, may be a focus for identifying novel aetiological mechanisms and potential treatment targets for diabetes in South Asian populations and may contribute to their excess risk of diabetes. PMID- 25693754 TI - Electromyography of crural and pedal muscles in tufted capuchin monkeys (Sapajus apella): Implications for hallucal grasping behavior and first metatarsal morphology in euprimates. AB - A hypertrophied peroneal process of the hallucal metatarsal, as seen in prosimians, has been linked to a powerful hallucal grasp via the contraction of the peroneus longus (PL) muscle causing adduction of the big toe. Electromyography (EMG) studies of lemurs and lorises, however, have concluded that PL is not substantially recruited during small branch locomotion when powerful hallucal grasping is needed most, and have suggested that there is no link between PL activity and peroneal process size. If this is correct, then we should also observe no change in PL activity when strong hallucal grasping is required in anthropoids because they have a relatively smaller peroneal process for PL to act on. This study addresses this hypothesis by evaluating EMG of crural and pedal muscles in capuchins (Sapajus apella) walking on substrates of different diameters. During locomotion on the narrow substrate (3.1 cm) that should elicit a strong hallucal grasp, we observed an intense increased recruitment of adductor hallucis, but only sustained, rather than markedly increased, PL activity. This indicates that PL is not involved in powerful hallucal grasping in capuchins, and confirms similar findings previously documented in prosimians. We continue to reject the hypothesis that a large peroneal process is an adaptation for powerful grasping and further argue that its morphology may not be related to PL's ability to adduct the hallux at all. In addition, the morphology of the peroneal process should not be used to assess hallucal grasping performance in fossils. PMID- 25693755 TI - Unexpected self-sorting self-assembly formation of a [4:4] sulfate:ligand cage from a preorganized tripodal urea ligand. AB - The design and synthesis of tripodal ligands 1-3 based upon the N-methyl-1,3,5 benzenetricarboxamide platform appended with three aryl urea arms is reported. This ligand platform gives rise to highly preorganized structures and is ideally suited for binding SO4 (2-) and H2 PO4 (-) ions through multiple hydrogen-bonding interactions. The solid-state crystal structures of 1-3 with SO4 (2-) show the encapsulation of a single anion within a cage structure, whereas the crystal structure of 1 with H2 PO4 (-) showed that two anions are encapsulated. We further demonstrate that ligand 4, based on the same platform but consisting of two bis-urea moieties and a single ammonium moiety, also recognizes SO4 (2-) to form a self-assembled capsule with [4:4] SO4 (2-) :4 stoichiometry in which the anions are clustered within a cavity formed by the four ligands. This is the first example of a self-sorting self-assembled capsule where four tetrahedrally arranged SO4 (2-) ions are embedded within a hydrophobic cavity. PMID- 25693756 TI - Lower bone mineral density in Somali women living in Sweden compared with African Americans. AB - Vitamin D deficiency can lead to osteomalacia. Bone mineral density was lower in Somali women, living in Sweden, in relation to both the American and the African American reference populations. The majority, 73 %, had vitamin D deficiency, and supplementation should be considered to prevent from osteomalacia, osteoporosis and future fractures. PURPOSE: Low vitamin D can lead to osteomalacia. The hypothesis was that bone mineral density (BMD) in Somali women living in Sweden was lower in comparison with different ethnic reference populations. METHODS: Women from Somalia, n = 67, median age 35.8 years (range 18 to 56), latitude 0-10 degrees North living in Gothenburg, Sweden, latitude 57 degrees North, >2 years were studied. All wore traditional Islamic clothing and had skin photo type V. BMD was recorded as the Z-score and compared with white American and African American women, respectively, using standard data from the dual energy X-ray absorptiometry (DXA) manufacturer (Lunar Prodigy enCORETM, GE Healthcare, LU44663). A fasting blood test was drawn for analysis of serum 25(OH)D. RESULTS: The median Z-score compared with the American white population was -0.9 SD of the lumbar spine (p < 0.00001), 0.1 SD of the left hip and 0.0 SD of the right hip (ns). The median Z-score compared with the African-American population was -1.6 SD of the lumbar spine (p < 0.00001), -0.9 SD of the left hip and -0.9 SD of the right hip (p < 0.001). The majority, 73 %, had vitamin D deficiency, serum 25(OH)D <25 nmol/l (<10 ng/ml). BMD did not correlate to vitamin D levels or to the number of years in Sweden. One wrist fracture was reported. CONCLUSIONS: BMD was lower in these fairly young immigrant women from Somalia, living in Sweden, in relation to both the American and the African-American reference populations. Vitamin D supplementation should be considered to prevent from osteomalacia, osteoporosis and future fractures. PMID- 25693758 TI - Serum levels of leptin and IP-10 in preeclampsia compared to controls. AB - PURPOSE: Preeclampsia (PE) is a pregnancy-specific syndrome with a complex, yet elusive, etiology. The production of a variety of factors probably implicated in diverse pathways may trigger endothelial dysfunction leading to PE pathogenesis. The aim of the present study was to investigate and compare the concentrations of leptin and interferon-gamma-inducible protein-10 (IP-10), factors characterized by inflammatory, immunomodulatory and angiogenic activities, and to evaluate their possible interaction in women with normotensive pregnancy and PE. METHODS: The study was carried out on a total of 58 pregnant women, 29 women with PE and 29 controls. Serum leptin and IP-10 levels were determined by enzyme-linked immunosorbent assay. RESULTS: Serum leptin levels were significantly increased in women with PE compared to controls and this difference was stronger in women with severe PE (p < 0.001). Although IP-10 serum concentrations were elevated in our preeclamptic women, this difference was not statistically significant. No correlation was found between leptin and IP-10. CONCLUSIONS: The results of the present study support a significant role of leptin in PE; however, this association was independent from serum IP-10 levels, suggesting that there is no crucial interplay between these two proteins in PE. PMID- 25693757 TI - Chronic pruritus in the elderly: pathophysiology, diagnosis and management. AB - Chronic itch in the elderly is a common problem, with a significant impact on quality of life and sleep in elderly patients. Chronic itch may be attributable to several causes, including dry skin, immunosenescence and neural degeneration. Itch may also be caused by skin diseases, such as seborrhoeic dermatitis and stasis dermatitis; systemic conditions, such as end-stage renal disease and diabetes; and psychogenic conditions, such as depression and anxiety. The use of polypharmacy may also cause itch, with or without a rash. Specifically, thiazides and calcium channel blockers have been known to cause itch in elderly patients. Management should be tailored according to the underlying dermatological or systemic aetiology of itch. Topical treatment is the mainstay of therapy, providing special emphasis on skin hydration and barrier repair. In addition, topical and oral medications that target the nervous system and reduce neuronal hypersensitization, such as gabapentin and selective antidepressants, have a role in treating patients with severe chronic itch. Furthermore, management must account for changes in metabolism and pharmacokinetics of drugs in the aging population in order to prevent the occurrence of adverse effects. PMID- 25693759 TI - Assessment of serum angiotensin-converting enzyme in patients with epithelial ovarian cancer. AB - BACKGROUND AND AIMS: Clinicopathologic and molecular studies have provided new insights and understanding on the pathological events during ovarian carcinogenesis. Moreover, angiotensin II-enhanced tumor cell invasion via type 1 angiotensin II receptor in ovarian cancer cell lines was recently demonstrated. It has been suggested that renin-angiotensin system (RAS) activity increases in diseases involving the female reproductive system. In the present study, we aimed to analyze the possible relationship between the levels of circulating angiotensin-converting enzyme (ACE), an important molecule of RAS, and ovarian cancer (OC). MATERIALS AND METHODS: This study was conducted in 41 epithelial OC patients (mean age 56.1 +/- 10.2 years) and 19 healthy controls (mean age 53.4 +/ 13.1 years). Clinical and laboratory features are summarized. Serum ACE and Ca 125 levels were measured using commercially available laboratory kits. RESULTS: Serum ACE levels of epithelial OC patients and controls were 30.58 +/- 13.37 and 14.15 +/- 3.67, respectively. Serum ACE levels were significantly elevated in epithelial OC patients in comparison to healthy controls. Ca-125 levels of epithelial OC patients were also significantly elevated in epithelial OC patients. No correlation was observed between ACE levels and Ca-125 levels. In epithelial OC patients, serum ACE levels did not differ according to stages and pathologic subtypes of the patients. CONCLUSION: Our results showed that serum ACE levels were increased in OC patients. Being an important component of RAS, circulating ACE might be associated with ongoing pathobiologic events in ovarian carcinogenesis. Therefore, targeting the RAS pathway could provide a future treatment strategy for this cancer type. PMID- 25693760 TI - Mechanosensitive membrane probes. AB - This article assembles pertinent insights behind the concept of planarizable push pull probes. As a response to the planarization of their polarized ground state, a red shift of their excitation maximum is expected to report on either the disorder, the tension, or the potential of biomembranes. The combination of chromophore planarization and polarization contributes to various, usually more complex processes in nature. Examples include the color change of crabs or lobsters during cooking or the chemistry of vision, particularly color vision. The summary of lessons from nature is followed by an overview of mechanosensitive organic materials. Although often twisted and sometimes also polarized, their change of color under pressure usually originates from changes in their crystal packing. Intriguing exceptions include the planarization of several elegantly twisted phenylethynyl oligomers and polymers. Also mechanosensitive probes in plastics usually respond to stretching by disassembly. True ground-state planarization in response to molecular recognition is best exemplified with the binding of thoughtfully twisted cationic polythiophenes to single- and double stranded oligonucleotides. Molecular rotors, en vogue as viscosity sensors in cells, operate by deplanarization of the first excited state. Pertinent recent examples are described, focusing on lambda-ratiometry and intracellular targeting. Complementary to planarization of the ground state with twisted push pull probes, molecular rotors report on environmental changes with quenching or shifts in emission rather than absorption. The labeling of mechanosensitive channels is discussed as a bioengineering approach to bypass the challenge to create molecular mechanosensitivity and use biological systems instead to sense membrane tension. With planarizable push-pull probes, this challenge is met not with twistome screening, but with "fluorescent flippers," a new concept to insert large and bright monomers into oligomeric probes to really feel the environment and also shine when twisted out of conjugation. PMID- 25693761 TI - FDG PET/CT for bone and soft-tissue biopsy. PMID- 25693762 TI - Metabolic phenotyping by liquid chromatography-mass spectrometry to study human health and disease. PMID- 25693763 TI - Platelet serotonin modulates immune functions. AB - This short review addresses immune functions of platelet serotonin. Platelets transport serotonin at a high concentration in dense granules and release it upon activation. Besides haemostatic, vasotonic and developmental modulation, serotonin also influences a variety of immune functions (mediated by different serotonin receptors). First, platelet serotonergic effects are directed against invading pathogens via activation and proliferation of lymphocytes, modulation of cytokine release, and recruitment of neutrophils to sites of acute inflammation by induction of selectin expression on endothelial cells. Second, serotonin levels are elevated in autoimmune diseases, such as asthma or rheumatoid arthritis, and during tissue regeneration after ischemia of myocardium or brain. Specific antagonism of serotonin receptors appears to improve survival after myocardial infarction or sepsis and to attenuate asthmatic attacks in animal models. It will be of great clinical relevance if these findings can be translated into human applications. In conclusion, targeting immune modulatory effects of platelet serotonin may provide novel therapeutic options for common health problems. PMID- 25693764 TI - Genotoxic evaluation of bupivacaine and levobupivacaine in the Drosophila wing spot test. AB - Bupivacaine and levobupivacaine are amino amide local anesthetics commonly used in medical practice. Although bupivacaine consists of a racemic mixture of S (-) bupivacaine and R (+)-bupivacaine enantiomers, levobupivacaine is comprised of pure S (-)-bupivacaine. It has been known that levobupivacaine is preferable to bupivacaine since it may cause cardiovascular and nervous system toxicity. For determining genotoxicity of these anesthetics, we used the wing somatic mutation and recombination test in Drosophila melanogaster. Three-day-old trans heterozygous larvae were treated with bupivacaine and levobupivacaine. Analysis of the standard crosses indicated that bupivacaine and levobupivacaine did not exhibit mutagenic or recombinogenic activity until toxic doses have been reached at the larval stage. When we examined bupivacaine and levobupivacaine in the HB cross, bupivacaine did not exhibit any genotoxicity at high concentrations (500 ug/mL), but levobupivacaine did exert genotoxicity at high concentrations (1000 ug/mL)-depending on the substantial recombinogenic effect. PMID- 25693765 TI - Outcomes from treating bile acid malabsorption using a multidisciplinary approach. AB - BACKGROUND & AIM: Despite bile acid malabsorption affecting >1 % of the population, the outcomes of treatment are largely unreported. This study evaluated the effectiveness of a structured intervention for this condition. METHOD: This was a retrospective evaluation of prospectively recorded patient reported outcome measures in a consecutive cohort of patients diagnosed with bile acid malabsorption seen in a cancer centre gastroenterology clinic. Every patient completed a 7-day food diary, a gastrointestinal symptom rating scale questionnaire and Bristol stool chart before the first clinic appointment and the symptom questionnaire and Bristol stool chart before all subsequent appointments. Patients who reported any episodes of type 6 or 7 stool were referred for a (75)Selenium (Se) homocholic acid taurine scan. Abnormal gastrointestinal symptoms were investigated and treated systematically using a peer reviewed management algorithm. RESULTS: Between 2011 and 2013, 136 men, 146 women, median age 66 years (range 19-89) underwent a scan. 143 (51 %) had 7-day isotope retention of <=20 %. 105 (73 %) had previously undergone pelvic radiotherapy and 67 (47 %) GI surgery. 123 (86 %) were treated with low-fat diets, 79 (55 %) with a bile acid sequestrant, 73 (51 %) both. On discharge, 100 (70 %) patients reported an overall symptom improvement (mean -4.2 points, p < 0.0001). In patients who had only bile acid malabsorption and no other gastrointestinal diagnoses, 77 % (41/53) reported a mean improvement of -5.4 points (p < 0.0005). Patients reported a clinically significant improvement in urgency, faecal incontinence, wind, nocturnal defaecation, tiredness, abdominal pain, bloating, and steatorrhoea, (p = <0.0005). Stool frequency was reduced and stool consistency was improved. CONCLUSION: In this large cohort of complex patients, bile acid malabsorption is common and a multidisciplinary approach to managing gastrointestinal symptoms is effective. PMID- 25693766 TI - Letter to the editor: we do not agree with Mr Skelcher's view of things. PMID- 25693767 TI - IL-33/ST2 involves the immunopathology of ocular toxoplasmosis in murine model. AB - Ocular toxoplasmosis (OT) is the major cause of infective uveitis. Since the eye is a special organ protected by immune privilege, its immune response is different from general organs with Toxoplasma gondii infection. Here, we used Kunming outbred mice to establish OT by intravitreal injection of T. gondii RH strain tachyzoites, IL-33 expression in the eyes was localized by immunostaining, the levels of interleukin (IL)-33 and ST2 (IL-33 receptor) and T-helper (Th)1 and Th2-associated cytokines in the eye and cervical lymph nodes (CLNs) of infected mice were measured, and their correlations were analyzed. Our results showed that the pathologies of the eye and CLN tissues and the IL-33 positive cells in the eye tissues of ocular T. gondii-infected mice were all increased at days 2, 6, and 9 postinfection (p.i.), accompanied with significantly increased transcript levels of IL-33, ST2, IL-1beta, IFN-gamma, IL-12p40, IL-10, and IL-13 in both the eyes and CLNs, and increased IL-4 expressions in the eyes of T. gondii-infected mice. There were significant correlations between the levels of IFN-gamma and ST2, IL-4 and ST2, and IL-13 and ST2 in the eye tissues (P < 0.001), significant correlations between the levels of IFN-gamma and ST2 (P < 0.001) as well as between IL-13 and ST2 (P < 0.05) in the CLNs, and significant correlations between the levels of IL-1beta and IL-33 in the eyes (P < 0.05) and between IL 1beta and IL-33/ST2 in the CLNs (P < 0.001 and P < 0.01, respectively). Our data indicated that IL-33/ST2 may involve the regulation of ocular immunopathology induced by T. gondii infection. PMID- 25693768 TI - The bioactive acidic serine- and aspartate-rich motif peptide. AB - The organic component of the bone matrix comprises 40% dry weight of bone. The organic component is mostly composed of type I collagen and small amounts of non collagenous proteins (NCPs) (10-15% of the total bone protein content). The small integrin-binding ligand N-linked glycoprotein (SIBLING) family, a NCP, is considered to play a key role in bone mineralization. SIBLING family of proteins share common structural features and includes the arginine-glycine-aspartic acid (RGD) motif and acidic serine- and aspartic acid-rich motif (ASARM). Clinical manifestations of gene mutations and/or genetically modified mice indicate that SIBLINGs play diverse roles in bone and extraskeletal tissues. ASARM peptides might not be primary responsible for the functional diversity of SIBLINGs, but this motif is suggested to be a key domain of SIBLINGs. However, the exact function of ASARM peptides is poorly understood. In this article, we discuss the considerable progress made in understanding the role of ASARM as a bioactive peptide. PMID- 25693769 TI - Progression and regression of cervical pap test lesions in an urban AIDS clinic in the combined antiretroviral therapy era: a longitudinal, retrospective study. AB - Our objective was to evaluate the progression and regression of cervical dysplasia in human immunodeficiency virus (HIV)-positive women during the late antiretroviral era. Risk factors as well as outcomes after treatment of cancerous or precancerous lesions were examined. This is a longitudinal retrospective review of cervical Pap tests performed on HIV-infected women with an intact cervix between 2004 and 2011. Subjects needed over two Pap tests for at least 2 years of follow-up. Progression was defined as those who developed a squamous intraepithelial lesion (SIL), atypical glandular cells (AGC), had low-grade SIL (LSIL) followed by atypical squamous cells-cannot exclude high-grade SIL (ASC-H) or high-grade SIL (HSIL), or cancer. Regression was defined as an initial SIL with two or more subsequent normal Pap tests. Persistence was defined as having an SIL without progression or regression. High-risk human papillomavirus (HPV) testing started in 2006 on atypical squamous cells of undetermined significance (ASCUS) Pap tests. AGC at enrollment were excluded from progression analysis. Of 1,445 screened, 383 patients had over two Pap tests for a 2-year period. Of those, 309 had an intact cervix. The median age was 40 years and CD4+ cell count was 277 cells/mL. Four had AGC at enrollment. A quarter had persistently normal Pap tests, 64 (31%) regressed, and 50 (24%) progressed. Four developed cancer. The only risk factor associated with progression was CD4 count. In those with treated lesions, 24 (59%) had negative Pap tests at the end of follow-up. More studies are needed to evaluate follow-up strategies of LSIL patients, potentially combined with HPV testing. Guidelines for HIV-seropositive women who are in care, have improved CD4, and have persistently negative Pap tests could likely lengthen the follow-up interval. PMID- 25693770 TI - Estimating the burden of recurrent events in the presence of competing risks: the method of mean cumulative count. AB - Cumulative incidence has been widely used to estimate the cumulative probability of developing an event of interest by a given time, in the presence of competing risks. When it is of interest to measure the total burden of recurrent events in a population, however, the cumulative incidence method is not appropriate because it considers only the first occurrence of the event of interest for each individual in the analysis: Subsequent occurrences are not included. Here, we discuss a straightforward and intuitive method termed "mean cumulative count," which reflects a summarization of all events that occur in the population by a given time, not just the first event for each subject. We explore the mathematical relationship between mean cumulative count and cumulative incidence. Detailed calculation of mean cumulative count is described by using a simple hypothetical example, and the computation code with an illustrative example is provided. Using follow-up data from January 1975 to August 2009 collected in the Childhood Cancer Survivor Study, we show applications of mean cumulative count and cumulative incidence for the outcome of subsequent neoplasms to demonstrate different but complementary information obtained from the 2 approaches and the specific utility of the former. PMID- 25693771 TI - Becofsky et al. respond to "Misclassifying fitness and depression". PMID- 25693772 TI - Oxidative balance scores and risk of incident colorectal cancer in a US prospective cohort study. AB - Although oxidative stress is implicated in colorectal carcinogenesis, human studies on associations of individual prooxidants and antioxidants with colorectal cancer (CRC) have been inconclusive. We incorporated individual environmental factors known to affect oxidative stress into 4 oxidative balance scores (OBS) and investigated their associations with CRC in the Cancer Prevention Study II Nutrition Cohort. During 1999-2009, a total of 1,109 incident CRC cases were identified among 80,063 participants in the Nutrition Cohort who had completed detailed questionnaires. Four OBS with different weighting methods (equal weights, literature review-based, a posteriori data-based, and weights based on Bayesian analysis) were created by combining 16 dietary and nondietary lifestyle factors. Higher values for all 4 OBS, representing more antioxidant exposures than prooxidant exposures, were associated with 41%-53% lower risks of CRC; for example, the relative risk for the highest OBS quartile versus the lowest in the Bayesian analysis was 0.50 (95% confidence interval: 0.41, 0.61). The associations were more modest when OBS was restricted to either dietary or nondietary components. These results, obtained using comprehensive summary measures of oxidative balance-especially considering the similarity of the findings derived using the different weighting methods-support the hypothesis that a predominance of antioxidant lifestyle exposures (both dietary and nondietary) over prooxidant lifestyle exposures reduces risk of CRC. PMID- 25693773 TI - Invited commentary: Fitness and fatness-causes of depression or of misclassification? AB - Parsing the relative contributions of fitness and fatness to various disease states has long interested investigators, despite their almost certainly intertwined causal relationships. In this issue of the Journal, Becofsky et al. ( examined these constructs in relation to depressive symptoms assessed using the Center for Epidemiologic Studies Depression Scale, a widely used and well validated instrument that ascertains several domains related to depression. The authors found stronger and more consistent associations of elevated depressive symptoms with objectively measured fitness than with any measure of fatness. These analyses highlight a serious concern in analyses of risk factors for complex clinical constructs--the likelihood of differential misclassification with respect to the risk factors of interest in scales with multiple, wide ranging domains. In this interesting example, the multi-item Center for Epidemiologic Studies Depression Scale, which validly captures the multiple domains of depression, contains measures of psychomotor retardation that could easily reflect fitness itself. Because an instrument's validity is uncertain if selected items are removed and gold-standard measures of complex clinical constructs are rarely truly gold, options to remedy this problem in most epidemiologic studies are few. Nonetheless, their analysis illustrates the particular caution needed when examining exposures that plausibly relate to misclassification in multidimensional outcomes of interest. PMID- 25693774 TI - The association between objectively measured sedentary behavior and red blood cell distribution width in a national sample of US adults. PMID- 25693775 TI - A prospective study of fitness, fatness, and depressive symptoms. AB - Being overweight or obese might be a risk factor for developing depression. It is also possible that low cardiorespiratory fitness, rather than overweight or obesity, is the better predictor of depressive symptom onset. Adults in the Aerobics Center Longitudinal Study (Dallas, Texas) underwent fitness and fatness assessments between 1979 and 1998 and later completed a questionnaire about depressive symptoms in 1990, 1995, or 1999. Separate logistic regression models were used to test the associations between 3 fatness measures (body mass index, waist circumference, and percentage of body fat) and the onset of depressive symptoms. Analyses were repeated using fitness as the predictor variable. Additional analyses were performed to study the joint association of fatness and fitness with the onset of depressive symptoms. After controlling for fitness, no measure of fatness was associated with the onset of depressive symptoms. In joint analyses, low fitness was more strongly associated with the onset of elevated depressive symptoms than was fatness, regardless of the measure of fatness used. Overall, results from the present study suggest that low fitness is more strongly associated with the onset of elevated depressive symptoms than is fatness. To reduce the risk of developing depression, individuals should be encouraged to improve their fitness regardless of body fatness. PMID- 25693776 TI - Practical guidance for conducting mediation analysis with multiple mediators using inverse odds ratio weighting. AB - Despite the recent flourishing of mediation analysis techniques, many modern approaches are difficult to implement or applicable to only a restricted range of regression models. This report provides practical guidance for implementing a new technique utilizing inverse odds ratio weighting (IORW) to estimate natural direct and indirect effects for mediation analyses. IORW takes advantage of the odds ratio's invariance property and condenses information on the odds ratio for the relationship between the exposure (treatment) and multiple mediators, conditional on covariates, by regressing exposure on mediators and covariates. The inverse of the covariate-adjusted exposure-mediator odds ratio association is used to weight the primary analytical regression of the outcome on treatment. The treatment coefficient in such a weighted regression estimates the natural direct effect of treatment on the outcome, and indirect effects are identified by subtracting direct effects from total effects. Weighting renders treatment and mediators independent, thereby deactivating indirect pathways of the mediators. This new mediation technique accommodates multiple discrete or continuous mediators. IORW is easily implemented and is appropriate for any standard regression model, including quantile regression and survival analysis. An empirical example is given using data from the Moving to Opportunity (1994-2002) experiment, testing whether neighborhood context mediated the effects of a housing voucher program on obesity. Relevant Stata code (StataCorp LP, College Station, Texas) is provided. PMID- 25693778 TI - [Complication management after interventions on thoracic organs : deep sternal wound infections]. AB - With an incidence rate of 0.5-4 % and a mortality of up to 50 %, deep sternal wound infections are a rare but devastating complication after median sternotomy for cardiac surgery. Currently, no standard operating procedures exist. Long-term drainage with continuous lavage or negative pressure wound therapy should be used to condition the wound. After restabilization of the sternum and primary closure, the infection often reoccurs presenting deep cavities with an open, unstable thorax and an uncovered mediastinum. This article gives an overview of the different options for deep sternal wound infections in plastic reconstructive surgery. The key point for successful treatment is still the extent of debridement. Primary coverage with a pedicled flap can be made only if the wound debridement was performed radically enough. In the clinic of the author, in which over 120 patients with deep sternal wound infections were treated in 2.5 years, latissimus dorsi muscle flaps have been established as the gold standard. PMID- 25693777 TI - Long-term exposure to air pollution and type 2 diabetes mellitus in a multiethnic cohort. AB - Although air pollution has been suggested as a possible risk factor for type 2 diabetes mellitus (DM), results from existing epidemiologic studies have been inconsistent. We investigated the associations of prevalence and incidence of DM with long-term exposure to air pollution as estimated using annual average concentrations of particulate matter with an aerodynamic diameter of 2.5 MUm or less (PM2.5) and nitrogen oxides at baseline (2000) in the Multi-Ethnic Study of Atherosclerosis. All participants were aged 45-84 years at baseline and were recruited from 6 US sites. There were 5,839 participants included in the study of prevalent DM and 5,135 participants without DM at baseline in whom we studied incident DM. After adjustment for potential confounders, we found significant associations of prevalent DM with PM2.5 (odds ratio (OR) = 1.09, 95% confidence interval (CI): 1.00, 1.17) and nitrogen oxides (OR = 1.18, 95% CI: 1.01, 1.38) per each interquartile-range increase (2.43 ug/m(3) and 47.1 ppb, respectively). Larger but nonsignificant associations were observed after further adjustment for study site (for PM2.5, OR = 1.16, 95% CI: 0.94, 1.42; for nitrogen oxides, OR = 1.29, 95% CI: 0.94, 1.76). No air pollution measures were significantly associated with incident DM over the course of the 9-year follow-up period. Results were partly consistent with a link between long-term exposure to air pollution and the risk of type 2 DM. Additional studies with a longer follow-up time and a greater range of air pollution exposures, including high levels, are warranted to evaluate the hypothesized association. PMID- 25693779 TI - [Special surgical complications in chronic inflammatory bowel diseases]. AB - After colorectal and anorectal interventions for chronic inflammatory bowel diseases, specific complications can occur.In Crohn's disease these complications mainly occur after proctocolectomy. Pelvic sepsis can be prevented by omentoplasty with fixation inside the pelvis. A persisting sepsis of the sacral cavity can be treated primarily by dissection of the anal sphincter which ensures better drainage. In cases of chronic sacral sepsis, transposition of the gracilis muscle is a further effective option. Early recurrence of a transsphincteric anal fistula should be treated by reinsertion of a silicon seton drainage.Complications after restorative proctocolectomy are frequent and manifold (35%). The main acute complications are anastomotic leakage and pelvic sepsis. Therapy consists of transperineal drainage of the abscess with simultaneous transanal drainage. Late complications due to technical and septic reasons are still a relevant problem even 36 years after introduction of this operative technique. A consistent approach with detailed diagnostic and surgical therapy results in a 75% rescue rate of ileoanal pouches. PMID- 25693780 TI - [Aortofemoral vascular graft infections and their prevention]. AB - Vascular prosthesis infections are potentially severe adverse events following vascular reconstruction. They are often associated with a high morbidity and mortality, especially in the aortofemoral region. The present article outlines the diagnosis, prevention and treatment of vascular graft infections in a clinical setting. The clinical presentation, inflammatory markers, microbiological work-up and imaging studies can contribute to diagnosing a prosthesis infection. Regarding the bacterial spectrum involved in the etiology of prosthesis infections, single organism infections (monoinfections) have become less significant over the past years, whereas infections with multiple organisms now constitute the most abundant microbiological constellation. Also, infections with resistant bacterial strains have been increasing in number over the past years and deserve special consideration. It remains unclear whether both aspects are due to a true epidemiological change or are the result of advanced molecular microbiological diagnostic methods. While during the past decades perioperative antibiotic prophylaxis was regarded as the most important measure for preventing prosthesis infections in vascular surgery, other primary preventive hygiene strategies have been increasingly explored and grouped together in the sense of preventive bundles. In most cases of deep postoperative infections involving a prosthetic device in the aortofemoral region, explantation of the prosthesis will be required. In situ and extra-anatomical reconstructions are often performed in such cases and the decision process to develop an optimal treatment plan must consider several individual factors. In select patients, palliative preservation of the prosthesis despite surrounding infection (i.e. graft salvage) and best conservative management in combination with local surgical measures, such as incision and drainage and vacuum therapy, deserve consideration as a treatment option for patients with a high surgical risk. PMID- 25693782 TI - Regional spread of Ebola virus, West Africa, 2014. AB - To explain the spread of the 2014 Ebola epidemic in West Africa, and thus help with response planning, we analyzed publicly available data. We found that the risk for infection in an area can be predicted by case counts, population data, and distances between affected and nonaffected areas. PMID- 25693781 TI - Rates and Correlates of Unemployment Across Four Common Chronic Pain Diagnostic Categories. AB - PURPOSE: To examine rates and correlates of unemployment across distinct common chronic pain diagnoses. METHODS: Data were analyzed from a sample of 2,382 patients with chronic pain in the Quebec Pain Registry (QPR). Patients were grouped into the following diagnostic categories based on their primary pain diagnosis recorded in the QPR: musculoskeletal pain; myofascial pain; neuropathic pain, and visceral pain. Analyses were performed to examine the associations between pain diagnosis, patient demographics, pain intensity, depressive symptoms, and unemployment status. RESULTS: Pain diagnosis, age, marital status, education, pain intensity, and depressive symptoms were each significant unique predictors of unemployment status in a hierarchical logistic regression analysis; the addition of depressive symptoms in this model contributed to the greatest increment of model fit. CONCLUSIONS: Depressive symptoms are associated with unemployment across a number of common chronic pain conditions, even when controlling for other factors that are associated with unemployment in these patients. Depressive symptoms, as a modifiable factor, may thus be an important target of intervention for unemployed patients with chronic pain. PMID- 25693783 TI - Improvement of scalp and nail lesions with ixekizumab in a phase 2 trial in patients with chronic plaque psoriasis. AB - BACKGROUND: Scalp and nail psoriasis have a major impact on quality of life and are traditionally resistant to therapy. Ixekizumab is a monoclonal antibody that targets IL-17A, a key cytokine in psoriasis pathogenesis. OBJECTIVE: Changes in nail and scalp psoriasis associated with ixekizumab treatment were evaluated in a post hoc analysis of a phase 2 study comprising a 20-week randomized, placebo controlled (RCT) period and 48 weeks of an open-label extension (OLE) period. METHODS: There were 142 patients with moderate-to-severe plaque psoriasis at baseline of the RCT. Patients were randomized to receive placebo, 10, 25, 75 or 150 mg of ixekizumab injected subcutaneously at weeks 0, 2, 4, 8, 12 and 16. In the OLE, all patients received 120 mg ixekizumab every 4 weeks. Nail Psoriasis Severity Index (NAPSI) and Psoriasis Scalp Severity Index (PSSI) were used to evaluate nail and scalp psoriasis respectively. Fifty-eight (41.0%) patients had nail psoriasis (NAPSI > 0) and 105 (74.0%) had scalp psoriasis (PSSI > 0) at baseline; these cases were evaluated for the present analyses. RESULTS: At RCT week 20, patients with scalp psoriasis in the 25-, 75- and 150-mg groups had significant mean change and percent improvement from baseline PSSI of -16.3 (75.3%; P = 0.001), -11.6 (83.7%; P = 0.001) and -18.2 (82.2%; P < 0.001) respectively compared to -6.0 (18.8%) in placebo. Patients with nail psoriasis in the 75- and 150-mg groups had significant improvements from baseline NAPSI of 26.3 (63.8%; P = 0.003) and -23.1 (52.6%; P = 0.009) respectively compared to 0.4 (-1.7%) in placebo. By OLE week 48, 78.0% of patients with scalp psoriasis and 51.0% of patients with nail psoriasis experienced complete resolution of lesions (PSSI = 0 or NAPSI = 0). CONCLUSIONS: Ixekizumab monotherapy improved scalp psoriasis quickly with maintenance of clinical response and complete resolution of plaques in the majority of patients. Additionally, over 50.0% of patients with nail psoriasis experienced complete resolution of nail lesions by OLE week 48. PMID- 25693784 TI - Cycloparaphenylene-based ionic donor-acceptor supramolecule: isolation and characterization of Li+@C60?[10]CPP. AB - The first cycloparaphenylene (CPP)-based ionic donor-acceptor supramolecule Li(+)@C60?[10]CPP?X(-) has been synthesized. X-ray crystallography not only confirmed the molecular structure of Li(+)@C60?[10]CPP?X(-) but also uncovered the formation of a unique ionic crystal. The strong charge-transfer interaction between [10]CPP and Li(+)@C60, which was confirmed by electrochemical measurement and spectroscopic analyses, caused significant delocalization of the positive charge across the entire complex. PMID- 25693785 TI - Discovery and in vitro and in vivo profiles of N-ethyl-N-[2-[3-(5-fluoro-2 pyridinyl)-1H-pyrazol-1-yl]ethyl]-2-(2H-1,2,3-triazol-2-yl)-benzamide as a novel class of dual orexin receptor antagonist. AB - Orexins play an important role in sleep/wake regulation, and orexin receptor antagonists are a focus of novel therapy for the treatment of insomnia. We identified 27e (TASP0428980) as a potent dual orexin receptor antagonist through the systematic modification of our original designed lead A. We demonstrated the potent sleep-promoting effects of 27e at ip dose of 3mg/kg in a rat polysomnogram study. 27e exhibited relatively short half-life profiles in rats and dogs. Furthermore, accumulating evidence regarding ADME profiles indicates that the predicted human half-life of 27e should be 1.2-1.4h. These data indicated that 27e has a short-acting hypnotic property, suggesting that 27e might be useful for treating primary insomnia while exhibiting a low risk of next-day residual somnolence. Thus, 27e and its related compounds should be further evaluated to enable advancement to clinical trials. PMID- 25693786 TI - Bis-3-chloropiperidines containing bridging lysine linkers: Influence of side chain structure on DNA alkylating activity. AB - A series of bis-3-chloropiperidines containing lysine linkers was synthesised as DNA alkylating model compounds by using a bidirectional synthetic strategy. These novel piperidine mustard based agents have been evaluated for their alkylating properties towards nucleic acids and were shown to alkylate and cleave DNA with strong preference for guanine residues. Our studies reveal that the introduction of aromatic groups in the side chain of the lysine linker has an impact on DNA alkylating activity. Analysis by ESI mass spectrometry enabled the verification of the reactive aziridinium ion formation. Overall, the results confirm our recently proposed reaction mechanism of bis-3-chloropiperidines. PMID- 25693787 TI - 6,7-Dihydrobenzo[f]benzo[4,5]imidazo[1,2-d][1,4]oxazepine derivatives as selective inhibitors of PI3Kalpha. AB - Twenty eight 6,7-dihydrobenzo[f]benzo[4,5]imidazo[1,2-d][1,4]oxazepine derivatives were synthesized and evaluated their biological activities as PI3K inhibitors. Biological evaluation against four human tumor cell lines revealed that most target compounds showed impressively better antiproliferative activities than that of LY294002. Among these compounds, compound 25 exhibited the most potent and selective activity for PI3Kalpha, with the IC50 value of 0.016MUM, an approximately 30-fold increase in comparison with LY294002, it also has an increased potency of approximately 11-fold for PI3Kbeta. It indicated the potential of developing 6,7-dihydrobenzo[f]benzo[4,5]imidazo[1,2-d][1,4]oxazepine derivatives as the new PI3Kalpha selective inhibitors for tumor treatment. PMID- 25693788 TI - Radiating low back pain in general practice: incidence, prevalence, diagnosis, and long-term clinical course of illness. AB - OBJECTIVE: The aim of this study was to calculate the incidence and prevalence of radiating low back pain, to explore the long-term clinical course of radiating low back pain including the influence of radiculopathy (in a subsample of the study population) and non-radiating low back pain thereon, and to describe general practitioners' (GPs') treatment strategies for radiating low back pain. DESIGN: A historic prospective cohort study. SETTING: Dutch general practice. SUBJECTS: Patients over 18 years of age with a first episode of radiating low back pain, registered by the ICPC code L86. MAIN OUTCOME MEASURES: Incidence and prevalence, clinical course of illness, initial diagnoses established by the GPs, and treatment strategies. RESULTS: Mean incidence was 9.4 and mean prevalence was 17.2 per 1000 person years. In total, 390 patients had 1193 contacts with their GPs; 50% had only one contact with their GP. Consultation rates were higher in patients with a history of non-radiating low back pain and in patients with a diagnosis of radiculopathy in the first five years. In this study's subsample of 103 patients, L86 episodes represented radiculopathy in 50% of cases. Medication was prescribed to 64% of patients, mostly NSAIDs. Some 53% of patients were referred, mainly to physiotherapists and neurologists; 9% of patients underwent surgery. CONCLUSION: Watchful waiting seems to be sufficient general practice care in most cases of radiating low back pain. Further research should be focused on clarifying the relationship between radicular radiating low back pain, non radicular radiating low back pain, and non-radiating low back pain. PMID- 25693789 TI - A therapeutic approach to assessing legal capacity in Australia. AB - Australia lacks a satisfactory, national paradigm for assessing legal capacity in the context of testamentary, enduring power of attorney and advance care directive documents. Capacity assessments are currently conducted on an ad hoc basis by legal and/or medical professionals. The reliability of the assessment process is subject to the skill set and mutual understanding of the legal and/or medical professional conducting the assessment. There is a growth in the prevalence of diseases such as dementia. Such diseases impact upon cognition which increasingly necessitates collaboration between the legal and medical professions when assessing the effect of mentally disabling conditions upon legal capacity. Miscommunication and lack of understanding between legal and medical professionals involved could impede the development of a satisfactory paradigm. This article will discuss legal capacity assessment in Australia and how to strengthen the relationship between legal and medical professionals involved in capacity assessments. The development of a national paradigm would promote consistency and transparency of process, helping to improve the professional relationship and maximising the principles of autonomy, participation and dignity. PMID- 25693790 TI - Effect of high-dose phytase supplementation in broilers from 22 to 42 days post hatch given diets severely limited in available phosphorus. AB - 1. Two trials were conducted from 22 to 42 d post-hatch to evaluate the effectiveness of high concentrations of supplemental phytase in maize-soya bean meal-based diets severely limited in available phosphorus (P). Growth performance, plasma P and tibia ash (TA) were measured. 2. Each trial used 220 21 d-old male broilers in 20 pens with 11 birds per pen. Dietary treatments included a positive control [PC, 4.3 g/kg nonphytate P (NPP)], negative control [NC, 2.3 g/kg NPP (Trial 1) or 1.4 g/kg NPP (Trial 2)] and NC plus 1000, 2000 or 4000 phytase U/kg of the diet. 3. Birds fed on the PC diet had higher average daily gain (ADG), gain to feed ratio (G:F), plasma P (Trials 1 and 2) and TA (Trial 2) than those fed on the NC. 4. In Trial 1, ADG and G:F values of the NC plus 1000, 2000 or 4000 phytase U/kg reached those of the PC. Plasma P values of the NC plus 2000 or 4000 phytase U/kg reached that of the PC. Although TA values of the NC, NC + 1000 or NC + 2000 reached that of the PC, TA of the NC + 4000 was more than that of the PC. 5. In Trial 2, ADG and G:F values of the NC plus 4000 phytase U/kg reached those of the PC; nevertheless, plasma P values of the NC diets did not come up to that of the PC. While TA values of the NC, NC + 1000 or NC + 2000 did not reach that of the PC, TA of the NC + 4000 was greater than that of the PC. 6. Results of this study showed that, in the diets with 2.3 and 1.4 g/kg NPP, respectively, 1000 and 4000 phytase U/kg can be sufficient to obtain a comparable performance in broilers to those given diets adequate in available P. PMID- 25693792 TI - Medical education in Singapore. AB - Allopathic medical education in Singapore extends for more than a century from its simple beginnings. In recent times, changes have been rapid, both in undergraduate and postgraduate specialty medical training. Over the last decade, undergraduate medical education has increased from a single to three medical schools and the postgraduate training has expanded further by incorporating the Accreditation Council for Graduate Medical Education International framework. With these changes, the curricula, assessment systems, as well as teaching and learning approaches, with the use of technology-enhanced learning and program evaluation processes have expanded, largely based on best evidence medical education. To support these initiatives and the recent rapid expansion, most training institutions have incorporated faculty development programs, such as the Centre for Medical Education at the National University of Singapore. PMID- 25693791 TI - Primaquine or other 8-aminoquinoline for reducing Plasmodium falciparum transmission. AB - BACKGROUND: Mosquitoes become infected with Plasmodium when they ingest gametocyte-stage parasites from an infected person's blood. Plasmodium falciparum gametocytes are sensitive to 8-aminoquinolines (8AQ), and consequently these drugs could prevent parasite transmission from infected people to mosquitoes and reduce the incidence of malaria. However, when used in this way, these drugs will not directly benefit the individual.In 2010, the World Health Organization (WHO) recommended a single dose of primaquine (PQ) at 0.75 mg/kg alongside treatment for P. falciparum malaria to reduce transmission in areas approaching malaria elimination. In 2013, the WHO revised this to 0.25 mg/kg to reduce risk of harms in people with G6PD deficiency. OBJECTIVES: To assess the effects of PQ (or an alternative 8AQ) given alongside treatment for P. falciparum malaria on malaria transmission and on the occurrence of adverse events. SEARCH METHODS: We searched the following databases up to 5 January 2015: the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL), published in The Cochrane Library (Issue 1, 2015); MEDLINE (1966 to 5 January 2015); EMBASE (1980 to 5 January 2015); LILACS (1982 to 5 January 2015); metaRegister of Controlled Trials (mRCT); and the WHO trials search portal using 'malaria*', 'falciparum', 'primaquine', 8-aminoquinoline and eight individual 8AQ drug names as search terms. In addition, we searched conference proceedings and reference lists of included studies, and contacted researchers and organizations. SELECTION CRITERIA: Randomized controlled trials (RCTs) or quasi-RCTs in children or adults, comparing PQ (or alternative 8AQ) as a single dose or short course alongside treatment for P. falciparum malaria, with the same malaria treatment given without PQ/8AQ. DATA COLLECTION AND ANALYSIS: Two review authors independently screened all abstracts, applied inclusion criteria and extracted data. We sought evidence of an impact on transmission (community incidence), infectiousness (mosquitoes infected from humans) and potential infectiousness (gametocyte measures). We calculated the area under the curve (AUC) for gametocyte density over time for comparisons for which data were available. We sought data on haematological and other adverse effects, asexual parasite clearance time and recrudescence. We stratified the analysis by artemisinin and non-artemisinin treatments; and by PQ dose (low < 0.4 mg/kg; medium >= 0.4 to < 0.6 mg/kg; high >= 0.6 mg/kg). We used the GRADE approach to assess evidence quality. MAIN RESULTS: We included 17 RCTs and one quasi-RCT. Eight trials tested for G6PD status: six then excluded participants with G6PD deficiency, one included only those with G6PD deficiency, and one included all irrespective of status. The remaining 10 trials either did not report on whether they tested (eight trials), or reported that they did not test (two trials).Nine trials included study arms with artemisinin-based treatments and eleven included study arms with non-artemisinin-based treatments.Only one trial evaluated PQ given as a single dose of less than 0.4 mg/kg. PQ with artemisinin-based treatments: No trials evaluated effects on malaria transmission directly (incidence, prevalence or entomological inoculation rate) and none evaluated infectiousness to mosquitoes. For potential infectiousness, the proportion of people with detectable gametocytaemia on day eight was reduced by around two-thirds with the high dose PQ category (RR 0.29, 95% confidence interval (CI) 0.22 to 0.37; seven trials, 1380 participants, high quality evidence) and the medium dose PQ category (RR 0.30, 95% CI 0.16 to 0.56; one trial, 219 participants, moderate quality evidence). For the low dose category, the effect size was smaller and the 95% CIs include the possibility of no effect (dose: 0.1 mg/kg: RR 0.67, 95% CI 0.44 to 1.02; one trial, 223 participants, low quality evidence). Reductions in log(10)AUC estimates for gametocytaemia on days 1 to 43 with medium and high doses ranged from 24.3% to 87.5%. For haemolysis, one trial reported percent change in mean haemoglobin against baseline and did not detect a difference between the two arms (very low quality evidence). PQ with non-artemisinin treatments: No trials assessed effects on malaria transmission directly. Two small trials from the same laboratory in China evaluated infectiousness to mosquitoes, and reported that infectivity was eliminated on day 8 in 15/15 patients receiving high dose PQ compared to 1/15 in the control group (low quality evidence). For potential infectiousness, the proportion of people with detectable gametocytaemia on day 8 was reduced by three-fifths with high dose PQ category (RR 0.39, 95% CI 0.25 to 0.62; four trials, 186 participants, high quality evidence), and by around two-fifths with medium dose category (RR 0.60, 95% CI 0.49 to 0.75; one trial, 216 participants, high quality evidence), with no trial in the low dose PQ category reporting this outcome. Reduction in log(10)AUC for gametocytaemia days 1 to 43 were 24.3% and 27.1% for two arms in one trial giving medium dose PQ. No trials systematically sought evidence of haemolysis.Two trials evaluated the 8AQ bulaquine, and suggest the effects may be greater than PQ, but the small number of participants (N = 112) preclude a definite conclusion. AUTHORS' CONCLUSIONS: In individual patients, PQ added to malaria treatments reduces gametocyte prevalence, but this is based on trials using doses of more than 0.4 mg/kg. Whether this translates into preventing people transmitting malaria to mosquitoes has rarely been tested in controlled trials, but there appeared to be a strong reduction in infectiousness in the two small studies that evaluated this. No included trials evaluated whether this policy has an impact on community malaria transmission.For the currently recommended low dose regimen, there is currently little direct evidence to be confident that the effect of reduction in gametocyte prevalence is preserved, or that it is safe in people with G6PD deficiency. PMID- 25693793 TI - Development, implementation, and evaluation of an integrated multidisciplinary Objective Structured Clinical Examination (OSCE) in primary health care settings within limited resources. AB - BACKGROUND: In ordinary circumstances, objective structured clinical examination (OSCE) is a resource-intensive assessment method. In case of developing and implementing multidisciplinary OSCE, there is no doubt that the cost will be greater. AIM: Through this study a research project was conducted to develop, implement and evaluate a multidisciplinary OSCE model within limited resources. METHODS: This research project went through the steps of blueprinting, station writing, resources reallocation, implementation and finally evaluation. RESULTS: The developed model was implemented in the Primary Health Care (PHC) program which is one of the pillars of the Community-Based undergraduate curriculum of the Faculty of Medicine, Suez Canal University (FOM-SCU). Data for evaluation of the implemented OSCE model were derived from two resources. First, feedback of the students and assessors through self-administered questionnaires was obtained. Second, evaluation of the OSCE psychometrics was done. The deliverables of this research project included a set of validated integrated multi-disciplinary and low cost OSCE stations with an estimated reliability index of 0.6. CONCLUSION: After having this experience, we have a critical mass of faculty members trained on blueprinting and station writing and a group of trained assessors, facilitators and role players. Also there is a state of awareness among students on how to proceed in this type of OSCE which renders future implementation more feasible. PMID- 25693794 TI - Sequencing learning experiences to engage different level learners in the workplace: An interview study with excellent clinical teachers. AB - PURPOSE: Learning in the clinical workplace can appear to rely on opportunistic teaching. The cognitive apprenticeship model describes assigning tasks based on learner rather than just workplace needs. This study aimed to determine how excellent clinical teachers select clinical learning experiences to support the workplace participation and development of different level learners. METHODS: Using a constructivist grounded theory approach, we conducted semi-structured interviews with medical school faculty identified as excellent clinical teachers teaching multiple levels of learners. We explored their approach to teach different level learners and their perceived role in promoting learner development. We performed thematic analysis of the interview transcripts using open and axial coding. RESULTS: We interviewed 19 clinical teachers and identified three themes related to their teaching approach: sequencing of learning experiences, selection of learning activities and teacher responsibilities. All teachers used sequencing as a teaching strategy by varying content, complexity and expectations by learner level. The teachers initially selected learning activities based on learner level and adjusted for individual competencies over time. They identified teacher responsibilities for learner education and patient safety, and used sequencing to promote both. CONCLUSIONS: Excellent clinical teachers described strategies for matching available learning opportunities to learners' developmental levels to safely engage learners and improve learning in the clinical workplace. PMID- 25693795 TI - The impact of the educational environment on career choice and attitudes toward psychiatry. AB - BACKGROUND: The educational environment may influence students' attitudes towards medical specialties, which in turn can affect specialty career choices. The present study sought to establish if perceptions of the educational environment in a psychiatry rotation influenced attitudinal changes towards psychiatry in medical students and impacts decisions about psychiatry as a career choice. METHODS: The modified Attitudes to Psychiatry Scale, Dundee Ready Educational Environment Measure, and questions specific to career choice in psychiatry were administered to 100 undergraduates in a psychiatry rotation. RESULTS: Significant improvements in attitudes toward psychiatry were highly correlated with the educational environment, particularly when it was perceived as providing inspiration and enabling students to recognize the merits of psychiatry and the effectiveness of treatment. However, there was a worsening trend in the stigma to psychiatry in the posting, and only the positive attitudinal change (but not educational environment) influenced a career choice in psychiatry. CONCLUSIONS: While the educational environment contributes towards positive attitudinal changes in a specialty rotation, stigma of psychiatry continues to be a limiting factor, which is, unfortunately, not clearly addressed in the curriculum. The findings support the urgent need for interventions in this area. PMID- 25693796 TI - Academic outcomes of a community-based longitudinal integrated clerkships program. AB - BACKGROUND: Longitudinal integrated clerkships (LICs) receive recognition internationally as effective, innovative alternatives to traditional block rotations (TBRs) in undergraduate medical education. No studies of LICs in the USA have assessed how students perform on all the standardized exams. AIM: To compare performance on standardized tests of students in the first four years of LICs at the University of North Carolina School of Medicine-Asheville (UNC SOM Asheville) with students from UNC SOM's Chapel Hill main campus in TBRs. METHODS: LIC and TBR students' previous academic performance was considered using Medical College Admissions Test (MCAT) and United States Medical Licensing Examination (USMLE) Step 1 scores. Step 1 exam tests students' pre-clinical, basic science knowledge. Outcome measures included all eight standardized National Board of Medical Examiners (NBME) Subject Shelf Examinations and USMLE Step 2 Clinical Knowledge (CK) examinations, which are used widely in the US to assess students' progress and as prerequisites to eventual licensure. TBR students were selected using propensity scores to match LIC students. Groups were also compared on the required core clinical conditions documented, and on residency specialty choice. RESULTS: Asheville LIC students earned higher scores on the Step 2 CK examination and the six shelf examinations linked to longitudinal clerkships than the matched TBR students (Step 2 CK exam, Family Medicine and Ambulatory Medicine shelf exams reached statistical significance). LIC students logged greater percentages of core conditions than TBR students and more often chose primary care residencies. CONCLUSIONS: UNC School of Medicine medical students participating in a longitudinal integrated curriculum in a community setting outperformed fellow students who completed a more TBR curriculum within the school's academic medical center. Differences were found in performance on standard tests of clinical knowledge (six NBME exams and Step 2 CK exam), documented breadth of clinical experiences, and likelihood of choosing primary care residency programs. PMID- 25693797 TI - DYn-2 Based Identification of Arabidopsis Sulfenomes. AB - Identifying the sulfenylation state of stressed cells is emerging as a strategic approach for the detection of key reactive oxygen species signaling proteins. Here, we optimized an in vivo trapping method for cysteine sulfenic acids in hydrogen peroxide (H2O2) stressed plant cells using a dimedone based DYn-2 probe. We demonstrated that DYn-2 specifically detects sulfenylation events in an H2O2 dose- and time-dependent way. With mass spectrometry, we identified 226 sulfenylated proteins after H2O2 treatment of Arabidopsis cells, residing in the cytoplasm (123); plastid (68); mitochondria (14); nucleus (10); endoplasmic reticulum, Golgi and plasma membrane (7) and peroxisomes (4). Of these, 123 sulfenylated proteins have never been reported before to undergo cysteine oxidative post-translational modifications in plants. All in all, with this DYn-2 approach, we have identified new sulfenylated proteins, and gave a first glance on the locations of the sulfenomes of Arabidopsis thaliana. PMID- 25693798 TI - Rapid Phosphoproteomic Effects of Abscisic Acid (ABA) on Wild-Type and ABA Receptor-Deficient A. thaliana Mutants. AB - Abscisic acid (ABA)1 is a plant hormone that controls many aspects of plant growth, including seed germination, stomatal aperture size, and cellular drought response. ABA interacts with a unique family of 14 receptor proteins. This interaction leads to the activation of a family of protein kinases, SnRK2s, which in turn phosphorylate substrates involved in many cellular processes. The family of receptors appears functionally redundant. To observe a measurable phenotype, four of the fourteen receptors have to be mutated to create a multilocus loss-of function quadruple receptor (QR) mutant, which is much less sensitive to ABA than wild-type (WT) plants. Given these phenotypes, we asked whether or not a difference in ABA response between the WT and QR backgrounds would manifest on a phosphorylation level as well. We tested WT and QR mutant ABA response using isotope-assisted quantitative phosphoproteomics to determine what ABA-induced phosphorylation changes occur in WT plants within 5 min of ABA treatment and how that phosphorylation pattern is altered in the QR mutant. We found multiple ABA induced phosphorylation changes that occur within 5 min of treatment, including three SnRK2 autophosphorylation events and phosphorylation on SnRK2 substrates. The majority of robust ABA-dependent phosphorylation changes observed were partially diminished in the QR mutant, whereas many smaller ABA-dependent phosphorylation changes observed in the WT were not responsive to ABA in the mutant. A single phosphorylation event was increased in response to ABA treatment in both the WT and QR mutant. A portion of the discovery data was validated using selected reaction monitoring-based targeted measurements on a triple quadrupole mass spectrometer. These data suggest that different subsets of phosphorylation events depend upon different subsets of the ABA receptor family to occur. Altogether, these data expand our understanding of the model by which the family of ABA receptors directs rapid phosphoproteomic changes. PMID- 25693799 TI - Large-Scale Interlaboratory Study to Develop, Analytically Validate and Apply Highly Multiplexed, Quantitative Peptide Assays to Measure Cancer-Relevant Proteins in Plasma. AB - There is an increasing need in biology and clinical medicine to robustly and reliably measure tens to hundreds of peptides and proteins in clinical and biological samples with high sensitivity, specificity, reproducibility, and repeatability. Previously, we demonstrated that LC-MRM-MS with isotope dilution has suitable performance for quantitative measurements of small numbers of relatively abundant proteins in human plasma and that the resulting assays can be transferred across laboratories while maintaining high reproducibility and quantitative precision. Here, we significantly extend that earlier work, demonstrating that 11 laboratories using 14 LC-MS systems can develop, determine analytical figures of merit, and apply highly multiplexed MRM-MS assays targeting 125 peptides derived from 27 cancer-relevant proteins and seven control proteins to precisely and reproducibly measure the analytes in human plasma. To ensure consistent generation of high quality data, we incorporated a system suitability protocol (SSP) into our experimental design. The SSP enabled real-time monitoring of LC-MRM-MS performance during assay development and implementation, facilitating early detection and correction of chromatographic and instrumental problems. Low to subnanogram/ml sensitivity for proteins in plasma was achieved by one-step immunoaffinity depletion of 14 abundant plasma proteins prior to analysis. Median intra- and interlaboratory reproducibility was <20%, sufficient for most biological studies and candidate protein biomarker verification. Digestion recovery of peptides was assessed and quantitative accuracy improved using heavy-isotope-labeled versions of the proteins as internal standards. Using the highly multiplexed assay, participating laboratories were able to precisely and reproducibly determine the levels of a series of analytes in blinded samples used to simulate an interlaboratory clinical study of patient samples. Our study further establishes that LC-MRM-MS using stable isotope dilution, with appropriate attention to analytical validation and appropriate quality control measures, enables sensitive, specific, reproducible, and quantitative measurements of proteins and peptides in complex biological matrices such as plasma. PMID- 25693800 TI - Antiandrogens act as selective androgen receptor modulators at the proteome level in prostate cancer cells. AB - Current therapies for prostate cancer include antiandrogens, inhibitory ligands of the androgen receptor, which repress androgen-stimulated growth. These include the selective androgen receptor modulators cyproterone acetate and hydroxyflutamide and the complete antagonist bicalutamide. Their activity is partly dictated by the presence of androgen receptor mutations, which are commonly detected in patients who relapse while receiving antiandrogens, i.e. in castrate-resistant prostate cancer. To characterize the early proteomic response to these antiandrogens we used the LNCaP prostate cancer cell line, which harbors the androgen receptor mutation most commonly detected in castrate-resistant tumors (T877A), analyzing alterations in the proteome, and comparing these to the effect of these therapeutics upon androgen receptor activity and cell proliferation. The majority are regulated post-transcriptionally, possibly via nongenomic androgen receptor signaling. Differences detected between the exposure groups demonstrate subtle changes in the biological response to each specific ligand, suggesting a spectrum of agonistic and antagonistic effects dependent on the ligand used. Analysis of the crystal structures of the AR in the presence of cyproterone acetate, hydroxyflutamide, and DHT identified important differences in the orientation of key residues located in the AF-2 and BF-3 protein interaction surfaces. This further implies that although there is commonality in the growth responses between androgens and those antiandrogens that stimulate growth in the presence of a mutation, there may also be influential differences in the growth pathways stimulated by the different ligands. This therefore has implications for prostate cancer treatment because tumors may respond differently dependent upon which mutation is present and which ligand is activating growth, also for the design of selective androgen receptor modulators, which aim to elicit differential proteomic responses dependent upon cellular context. PMID- 25693801 TI - Protein Methionine Sulfoxide Dynamics in Arabidopsis thaliana under Oxidative Stress. AB - Reactive oxygen species such as hydrogen peroxide can modify proteins via direct oxidation of their sulfur-containing amino acids, cysteine and methionine. Methionine oxidation, studied here, is a reversible posttranslational modification that is emerging as a mechanism by which proteins perceive oxidative stress and function in redox signaling. Identification of proteins with oxidized methionines is the first prerequisite toward understanding the functional effect of methionine oxidation on proteins and the biological processes in which they are involved. Here, we describe a proteome-wide study of in vivo protein-bound methionine oxidation in plants upon oxidative stress using Arabidopsis thaliana catalase 2 knock-out plants as a model system. We identified over 500 sites of oxidation in about 400 proteins and quantified the differences in oxidation between wild-type and catalase 2 knock-out plants. We show that the activity of two plant-specific glutathione S-transferases, GSTF9 and GSTT23, is significantly reduced upon oxidation. And, by sampling over time, we mapped the dynamics of methionine oxidation and gained new insights into this complex and dynamic landscape of a part of the plant proteome that is sculpted by oxidative stress. PMID- 25693802 TI - Quantitative phosphoproteomics analysis reveals a key role of insulin growth factor 1 receptor (IGF1R) tyrosine kinase in human sperm capacitation. AB - One of the most important changes during sperm capacitation is the enhancement of tyrosine phosphorylation. However, the mechanisms of protein tyrosine phosphorylation during sperm capacitation are not well studied. We used label free quantitative phosphoproteomics to investigate the overall phosphorylation events during sperm capacitation in humans and identified 231 sites with increased phosphorylation levels. Motif analysis using the NetworKIN algorithm revealed that the activity of tyrosine phosphorylation kinases insulin growth factor 1 receptor (IGF1R)/insulin receptor is significantly enriched among the up regulated phosphorylation substrates during capacitation. Western blotting further confirmed inhibition of IGF1R with inhibitors GSK1904529A and NVP-AEW541, which inhibited the increase in tyrosine phosphorylation levels during sperm capacitation. Additionally, sperm hyperactivated motility was also inhibited by GSK1904529A and NVP-AEW541 but could be up-regulated by insulin growth factor 1, the ligand of IGF1R. Thus, the IGF1R-mediated tyrosine phosphorylation pathway may play important roles in the regulation of sperm capacitation in humans and could be a target for improvement in sperm functions in infertile men. PMID- 25693803 TI - Discovery of predictive biomarkers for litter size in boar spermatozoa. AB - Conventional semen analysis has been used for prognosis and diagnosis of male fertility. Although this tool is essential for providing initial quantitative information about semen, it remains a subject of debate. Therefore, development of new methods for the prognosis and diagnosis of male fertility should be seriously considered for animal species of economic importance as well as for humans. In the present study, we applied a comprehensive proteomic approach to identify global protein biomarkers in boar spermatozoa in order to increase the precision of male fertility prognoses and diagnoses. We determined that l-amino acid oxidase, mitochondrial malate dehydrogenase 2, NAD (MDH2), cytosolic 5' nucleotidase 1B, lysozyme-like protein 4, and calmodulin (CALM) were significantly and abundantly expressed in high-litter size spermatozoa. We also found that equatorin, spermadhesin AWN, triosephosphate isomerase (TPI), Ras related protein Rab-2A (RAB2A), spermadhesin AQN-3, and NADH dehydrogenase [ubiquinone] iron-sulfur protein 2 (NDUFS2) were significantly and abundantly expressed in low-litter size spermatozoa (>3-fold). Moreover, RAB2A, TPI, and NDUFS2 were negatively correlated with litter size, whereas CALM and MDH2 were positively correlated. This study provides novel biomarkers for the prediction of male fertility. To the best of our knowledge, this is the first work that shows significantly increased litter size using male fertility biomarkers in a field trial. Moreover, these protein markers may provide new developmental tools for the selection of superior sires as well as for the prognosis and diagnosis of male fertility. PMID- 25693805 TI - NHS doctors' interests in private practice should be declared. PMID- 25693804 TI - Interactions of the Antiviral Factor Interferon Gamma-Inducible Protein 16 (IFI16) Mediate Immune Signaling and Herpes Simplex Virus-1 Immunosuppression. AB - The interferon-inducible protein IFI16 has emerged as a critical antiviral factor and sensor of viral DNA. IFI16 binds nuclear viral DNA, triggering expression of antiviral cytokines during infection with herpesviruses. The knowledge of the mechanisms and protein interactions through which IFI16 exerts its antiviral functions remains limited. Here, we provide the first characterization of endogenous IFI16 interactions following infection with the prominent human pathogen herpes simplex virus 1 (HSV-1). By integrating proteomics and virology approaches, we identified and validated IFI16 interactions with both viral and host proteins that are involved in HSV-1 immunosuppressive mechanisms and host antiviral responses. We discover that during early HSV-1 infection, IFI16 is recruited to sub-nuclear puncta and subsequently targeted for degradation. We observed that the HSV-1 E3 ubiquitin ligase ICP0 is necessary, but not sufficient, for the proteasom e-mediated degradation of IFI16 following infection. We substantiate that this ICP0-mediated mechanism suppresses IFI16 dependent immune responses. Utilizing an HSV-1 strain that lacks ICP0 ubiquitin ligase activity provided a system for studying IFI16-dependent cytokine responses to HSV-1, as IFI16 levels were maintained throughout infection. We next defined temporal IFI16 interactions during this immune signaling response. We discovered and validated interactions with the viral protein ICP8 and cellular ND10 nuclear body components, sites at which HSV-1 DNA is present during infection. These interactions may be critical for IFI16 to bind to nuclear viral DNA. Altogether, our results provide critical insights into both viral inhibition of IFI16 and interactions that can contribute to IFI16 antiviral functions. PMID- 25693806 TI - Fluorographane (C1H(x)F(1-x-delta))n: synthesis and properties. AB - Fluorographane (C1HxF1-x-delta)n was obtained from graphene by hydrogenation via the Birch reaction with consequent fluorination of the resulting graphane. Fluorographane exhibits fast heterogeneous electron transfer rates and hydrophobicity, which increase with increasing fluorination. PMID- 25693807 TI - RCGP nutrition group aims at helping GPs talk to patients about weight issues. PMID- 25693808 TI - Phenothiazine-derived antipsychotic drugs inhibit dynamin and clathrin-mediated endocytosis. AB - Chlorpromazine is a phenothiazine-derived antipsychotic drug (APD) that inhibits clathrin-mediated endocytosis (CME) in cells by an unknown mechanism. We examined whether its action and that of other APDs might be mediated by the GTPase activity of dynamin. Eight of eight phenothiazine-derived APDs inhibited dynamin I (dynI) in the 2-12 um range, the most potent being trifluoperazine (IC50 2.6 +/ 0.7 um). They also inhibited dynamin II (dynII) at similar concentrations. Typical and atypical APDs not based on the phenothiazine scaffold were 8- to 10 fold less potent (haloperidol and clozapine) or were inactive (droperidol, olanzapine and risperidone). Kinetic analysis showed that phenothiazine-derived APDs were lipid competitive, while haloperidol was uncompetitive with lipid. Accordingly, phenothiazine-derived APDs inhibited dynI GTPase activity stimulated by lipids but not by various SH3 domains. All dynamin-active APDs also inhibited transferrin (Tfn) CME in cells at related potencies. Structure-activity relationships (SAR) revealed dynamin inhibition to be conferred by a substituent group containing a terminal tertiary amino group at the N2 position. Chlorpromazine was previously proposed to target AP-2 recruitment in the formation of clathrin-coated vesicles (CCV). However, neither chlorpromazine nor thioridazine affected AP-2 interaction with amphiphysin or clathrin. Super resolution microscopy revealed that chlorpromazine blocks neither clathrin recruitment by AP-2, nor AP-2 recruitment, showing that CME inhibition occurs downstream of CCV formation. Overall, potent dynamin inhibition is a shared characteristic of phenothiazine-derived APDs, but not other typical or atypical APDs, and the data indicate that dynamin is their likely in-cell target in endocytosis. PMID- 25693809 TI - Relationship between preventable hospital deaths and other measures of safety: an exploratory study. PMID- 25693810 TI - Antidepressant use and risk of suicide and attempted suicide or self harm in people aged 20 to 64: cohort study using a primary care database. AB - OBJECTIVE: To assess the associations between different antidepressant treatments and the rates of suicide and attempted suicide or self harm in people with depression. DESIGN: Cohort study. SETTING: Patients registered with UK general practices contributing data to the QResearch database. PARTICIPANTS: 238,963 patients aged 20 to 64 years with a first diagnosis of depression between 1 January 2000 and 31 July 2011, followed up until 1 August 2012. EXPOSURES: Antidepressant class (tricyclic and related antidepressants, selective serotonin reuptake inhibitors, other antidepressants), dose, and duration of use, and commonly prescribed individual antidepressant drugs. Cox proportional hazards models were used to calculate hazard ratios adjusting for potential confounding variables. MAIN OUTCOME MEASURES: Suicide and attempted suicide or self harm during follow-up. RESULTS: During follow-up, 87.7% (n = 209,476) of the cohort received one or more prescriptions for antidepressants. The median duration of treatment was 221 days (interquartile range 79-590 days). During the first five years of follow-up 198 cases of suicide and 5243 cases of attempted suicide or self harm occurred. The difference in suicide rates during periods of treatment with tricyclic and related antidepressants compared with selective serotonin reuptake inhibitors was not significant (adjusted hazard ratio 0.84, 95% confidence interval 0.47 to 1.50), but the suicide rate was significantly increased during periods of treatment with other antidepressants (2.64, 1.74 to 3.99). The hazard ratio for suicide was significantly increased for mirtazapine compared with citalopram (3.70, 2.00 to 6.84). Absolute risks of suicide over one year ranged from 0.02% for amitriptyline to 0.19% for mirtazapine. There was no significant difference in the rate of attempted suicide or self harm with tricyclic antidepressants (0.96, 0.87 to 1.08) compared with selective serotonin reuptake inhibitors, but the rate of attempted suicide or self harm was significantly higher for other antidepressants (1.80, 1.61 to 2.00). The adjusted hazard ratios for attempted suicide or self harm were significantly increased for three of the most commonly prescribed drugs compared with citalopram: venlafaxine (1.85, 1.61 to 2.13), trazodone (1.73, 1.26 to 2.37), and mirtazapine (1.70, 1.44 to 2.02), and significantly reduced for amitriptyline (0.71, 0.59 to 0.85). The absolute risks of attempted suicide or self harm over one year ranged from 1.02% for amitriptyline to 2.96% for venlafaxine. Rates were highest in the first 28 days after starting treatment and remained increased in the first 28 days after stopping treatment. CONCLUSION: Rates of suicide and attempted suicide or self harm were similar during periods of treatment with selective serotonin reuptake inhibitors and tricyclic and related antidepressants. Mirtazapine, venlafaxine, and trazodone were associated with the highest rates of suicide and attempted suicide or self harm, but the number of suicide events was small leading to imprecise estimates. As this is an observational study the findings may reflect indication biases and residual confounding from severity of depression and differing characteristics of patients prescribed these drugs. The increased rates in the first 28 days of starting and stopping antidepressants emphasise the need for careful monitoring of patients during these periods. PMID- 25693811 TI - Pedometers for older people can increase physical activity, research shows. PMID- 25693812 TI - An unusual shunt from the pulmonary artery to the left atrial appendage. PMID- 25693813 TI - Maximizing computational tools for successful drug discovery. AB - Drug discovery is an iterative cycle of identifying promising hits followed by lead optimization via bioisosteric replacements. In the search for compounds affording good bioactivity, equal importance should also be placed on achieving those with favorable pharmacokinetic properties. Thus, the balance and realization of both key properties is an intricate problem that requires great caution. In this editorial, the authors explore the available computational tools in the context of the extant of big data that has borne out via advents of the Omics revolution. As such, the selection of appropriate computational tools for analyzing the vast number of chemical libraries, target proteins and interactomes is the first step toward maximizing the chance for success. However, in order to realize this, it is also necessary to have a solid foundation on the big concepts of drug discovery as well as knowing which tools are available in order to give drug discovery scientists the best opportunity. PMID- 25693814 TI - Prevalence and determinants of cognitive impairment in patients with chronic kidney disease: a cross-sectional study in Benin City, Nigeria. AB - BACKGROUND: Chronic kidney disease (CKD) has become a public health concern and may be complicated by cognitive impairment (CI) contributing significantly to morbidity and poor prognosis. This hospital-based study aimed at determining the prevalence and the determinants of CI among CKD patients in Nigeria. MATERIALS AND METHODS: A total of 190 CKD patients and a 100 healthy control subjects completed this cross-sectional study. Sociodemographic data and history of common clinical features of CKD were obtained with the use of interviewer administered semi-structured questionnaires. The six-item cognitive impairment test was used for assessment of cognitive function of patients and controls. RESULTS: The prevalence of CI in Stages 3, 4, and 5 CKD patients were 24.0%, 41.6%, and 46.2%, respectively with overall prevalence of 35.3% while only 6.0% of controls had CI (P = 0.03). The most potent determinants of CI were low hematocrit (odds ratio [OR] =3.50), low serum bicarbonate levels (OR = 2.20), and high serum urea (OR = 2.11). CONCLUSION: CKD is associated with significant CI in Nigerian patients especially with progressive deterioration in renal function. There is a need for regular evaluation of CKD patients for cognitive deficits. PMID- 25693815 TI - Neuroimaging of young adults with stroke in Ilorin Nigeria. AB - BACKGROUND: Stroke in young adults is relatively uncommon. Computed tomography (CT) and magnetic resonance imaging (MRI) are the most valuable tools for the diagnosis of stroke. Recent data on stroke in young adults in Nigeria is sparse. The aim of this study is to document the imaging pattern in young patients aged 15-45 years with suspected cerebrovascular accidents (CVA) in the Nigerian environment. MATERIALS AND METHODS: This was a retrospective study of 69 patients aged 15-45 years, with clinical diagnosis of stroke, referred for neuro-imaging, from October 2008 to November 2013. All patients with the clinical diagnosis of stroke within this age group were recruited into the study. Images were obtained from a four slice channel general electric CT machine and a 0.2 Tesla Siemens Magnetom Concerto MRI scanner. RESULTS: A total of 69 patients (44 males and 25 females) were studied. Sixty out of 69 (87.0%) patients were accurately diagnosed with CVA, with 9 (13.0) cases of misdiagnoses. A total of 21 (35%) out of the 60 cases confirmed on imaging had intracerebral hemorrhage (ICH), 10 (16.7%) had subarachnoid hemorrhage (SAH) and 29 (48.3%) had cerebral infarct (CI). Hypertension was the common risk factor for all stroke subtypes. The most common location for ICH, was the basal ganglia in 8 (38.8%), while the commonest pattern for CI, was lacunar infarct in the basal ganglia (51.7%). CONCLUSION: The incidence of hemorrhagic CVA (ICH and SAH combined) was slightly higher than ischemic CVA in this study. Lacunar infarcts in the basal ganglia and also ICH in the basal ganglia were the most common patterns, both are strongly linked to hypertension. A diagnostic protocol of stroke in young adults, to include neuroimaging and other ancillary investigations is advocated for stroke in young adults as some of the etiologies are treatable. PMID- 25693816 TI - Development of a time-trend model for analyzing and predicting case-pattern of Lassa fever epidemics in Liberia, 2013-2017. AB - OBJECTIVE: The objective was to develop a case-pattern model for Lassa fever (LF) among humans and derive predictors of time-trend point distribution of LF cases in Liberia in view of the prevailing under-reporting and public health challenge posed by the disease in the country. MATERIALS AND METHODS: A retrospective 5 years data of LF distribution countrywide among humans were used to train a time trend model of the disease in Liberia. A time-trend quadratic model was selected due to its goodness-of-fit (R2 = 0.89, and P < 0.05) and best performance compared to linear and exponential models. Parameter predictors were run on least square method to predict LF cases for a prospective 5 years period, covering 2013 2017. RESULTS: The two-stage predictive model of LF case-pattern between 2013 and 2017 was characterized by a prospective decline within the South-coast County of Grand Bassa over the forecast period and an upward case-trend within the Northern County of Nimba. Case specific exponential increase was predicted for the first 2 years (2013-2014) with a geometric increase over the next 3 years (2015-2017) in Nimba County. CONCLUSION: This paper describes a translational application of the space-time distribution pattern of LF epidemics, 2008-2012 reported in Liberia, on which a predictive model was developed. We proposed a computationally feasible two-stage space-time permutation approach to estimate the time-trend parameters and conduct predictive inference on LF in Liberia. PMID- 25693817 TI - A 3 year audit of adult epilepsy care in a Nigerian tertiary hospital (2011 2013). AB - BACKGROUND: Epilepsy audit provides positive feedback to physicians that could assist in improving the quality of health care services provided for patients. This study was carried out to evaluate care given to people with epilepsy with the aim of determining potentials for improvement. MATERIALS AND METHODS: Medical records of patients with uncomplicated epilepsy who have attended the neurology clinic at the University of Ilorin Teaching Hospital for not less 12 months between years 2011and 2013 were reviewed. RESULTS: A total of 125 patients were as evaluated; of which 64 (51%) were males and 61 (49%) were females. Their median age was 26 (21-40) years and median seizure duration of 9 (4-15) years. Close to 65% of the patients were below 30 years of age. Most patients (68%) were referred by general practitioners/family physicians. Generalized epilepsy was the predominant seizure type seen in 73 (58%) patients. Majority of patients (76%) were on antiepileptic drug (AED) monotherapy, and 28 (22%) were on two AEDs combination. Eighty-one patients (64%) used carbamazepine either singly (63%) or in combination (18%) at an average dose of 600 mg/day. The two other common AEDs used were: Sodium valproate (45%) and phenobarbitone (9%). Fifty-one patients (41%) had good seizure control (no seizure in preceding 1 year), 34 (27%) had partial control (<12 attacks/year) and 41 (36%) had poor control (>1 attack/month). Overall, 66 patients (48%) had their medication changed between 2 and 3 times in the course of treatment, and the most common reason was poor seizure control. Twenty-one (21%) did not comply with the use of given AED. CONCLUSIONS: Less than half of our patients had good epilepsy control. To improve on drug compliance attending physicians need to prescribe more of the relatively cheaper AED like the phenobarbitone and to optimize drug dosage before switching to another. PMID- 25693818 TI - Sleep disturbances among patients with epilepsy in Nigeria. AB - BACKGROUND: There is a complex inter-relationship between sleep disorders and epilepsy, and there are few studies in Nigeria on sleep disorders in epilepsy. This study was carried out to determine the prevalence, pattern and predictors of sleep disturbances among persons with epilepsy (PWE). MATERIALS AND METHODS: This was a multi-center, cross-sectional study of 124 PWE in Nigeria. A questionnaire was used to collect data on social and demographic variables, epilepsy- related variables and sleep disturbances in PWE. Exclusion criteria were mental retardation, and use of sedative drugs. The data was analyzed using Statistical Package for Social Sciences version 11.0 and P < 0.05 was considered as significant. RESULTS: There were 77 males and 47 females with a mean age of 33.4 +/- 13.1 years. The mean age of seizure onset was 23.7 +/- 14.6 years, while the mean duration of epilepsy was 9.5 +/- 9.4 years. The commonest type of epilepsy was secondarily generalized tonic-clonic seizures (62%). The prevalence of sleep disorders in PWE was 82%. Parasomnias occurred in 46%, followed by obstructive sleep apnea in 23%, insomnia (19%) excessive daytime sleepiness (EDS) (17%), and restless leg syndrome (11%). None of the socio-demographic or epilepsy- related variables was predictive of EDS or parasomnias in PWE (P > 0.05). CONCLUSION: There is a high frequency of sleep disorders among PWE. Clinicians should screen PWE for sleep disturbances. PMID- 25693819 TI - Nonglaucomatous optic atrophy in Benin City. AB - CONTEXT: Optic atrophy is a clinical sign and not a disease. The etiology of optic atrophy is diverse, some of which may be life threatening. PATIENTS AND METHODS: A retrospective review of the medical records of all adult patients aged 16 years and above with nonglaucomatous optic atrophy at the eye clinic of the University of Benin Teaching Hospital over a 4-year period was conducted. RESULTS: One hundred and four patients had nonglaucomatous optic atrophy. There were 58 males and 46 females with a male:female of 1.3:1. Their ages ranged from 16 to 83 years with a mean age of 49.2 +/- 17.74 years. Majority (75%) of the patients were in the age range of 31-70 years. One hundred and fifty-seven eyes were affected with bilateral involvement in 53 patients. The etiology was unknown in 47 (45.2%) patients. Choriodoretinal disease 24 (23.1%), trauma 14 (13.5%), toxic-nutritional 8 (7.7%) and compressive lesions 5 (4.8%) were the most common among the known etiologies. CONCLUSION: Optic atrophy is the end result of injury to the anterior visual pathway from a myriad of disease processes. A broad knowledge of the etiology of optic atrophy is needed to make a diagnosis . PMID- 25693820 TI - Pattern of injuries seen during an insurgency: a 5-year review of 1339 cases from Nigeria. AB - BACKGROUND: When there is an insurgency, the use of force in the form of weaponry, is employed. This may lead to the total breakdown of law and order, resulting in destruction of life and property. Health workers may be killed or captured, and, health facilities destroyed or stretched beyond their functional capacity. This is a report of experience with injuries seen in a tertiary hospital in north eastern Nigeria, under an insurgency situation. MATERIALS AND METHODS: After obtaining clearance from the medical Ethics Committee of UMTH, we reviewed the case files of all patients treated for injuries sustained as a result of the Boko Haram insurgency from January 2009 to December 2013. Those brought in dead, were not included in the study. RESULTS: We reviewed the case files, theatre notes, admission and discharge registers of 1339 cases. 1223 (91.3%) of the victims were males, while 116 (8.7%) were females. Gunshot wounds accounted for 1229 (91.8%) of the injuries, bomb blast 90 (6.7%), others 15 (1.1%) knife (Cut throat) 4 (0.3%) and road traffic accident 1 (0.01%). Casualties were made up of civilians 1144 (85.4%), the joint task force (a force made up of the Military, Police, Customs and Immigration, against the insurgents) 117 (8.7%), and insurgents 22 (1.6%). The ages of the patients ranged from 1 to 80 years, peaking at the 21-40 age brackets (796 or 59.4%). The extremities were most affected, 734 (54.8%), followed by the torso 423 (31.6%), multiple injuries 93 (6.9%) and head and neck 89 (6.6%). 1226 (91.6%) of the victims survived while 113 (8.4%) died from their injuries. This followed massive blood loss from injuries to the torso 69 (61.1%) multiple injuries 15 (13.3) and extremities 6 (5.3%). Others causes were fatal injuries to the head and neck 22 (19.5%) and 90% burns following bomb blast 1 (0.9%). CONCLUSION: Injuries resulting from insurgency will continue to be a problem in many developing countries because their health facilities in terms of personnel and materials are ill prepared for such a situation . PMID- 25693821 TI - The challenges of healthcare delivery in conflict zones. PMID- 25693822 TI - Mapping of Lassa fever cases in post-conflict Liberia, 2008-2012: a descriptive and categorical analysis of age, gender and seasonal pattern. PMID- 25693823 TI - Intramuscular cysticercosis. PMID- 25693824 TI - The reliability of thyroid nodule ultrasound features and size to predict malignancy in fine needle aspiration specimens: Practical utility for the evaluating pathologist. AB - BACKGROUND: The prognostic impact of ultrasound features of thyroid nodules is debated. We explore the correlation between nodule size, echogenicity on US, and malignancy. METHODS: We performed a retrospective review of thyroid nodules undergoing ultrasound guided FNA (US-FNA) at our institution between 01/2008 05/2013. RESULTS: In all, 2,403 nodules from 2,293 patients (age range 14-91, mean 54, median 56, M: F-1:3.2) underwent US-FNA. 766 nodules were resected, 337 were malignant (size range 0.4-8.7 cm, median 2 cm, mean 2.37 cm,) and 429 were benign (size range 0.5-9.7 cm, median 2.5 cm, mean 2.79 cm). The malignant diagnoses included: classical variant of PTC 77 (size range 0.5-5.5 cm, mean 1.5 cm), follicular variant of PTC 209 (size range 0.14-7.5 cm, mean 2.1 cm), tall cell variant of PTC 7 (size range 0.5-2.4 cm, mean1.4 cm), poorly differentiated carcinoma 5 (size range 5-8.7 cm, mean 6.42 cm), follicular carcinoma 27 (size range 0.5-7 cm, mean 3.03 cm), and oncocytic follicular carcinoma 9 cases (size range 1.4-7.2 cm, mean 3.2 cm). Of the malignant nodules with echogenicity reported on US, 93 were hypoechoic, 26 hyperechoic, 20 isoechoic, and 76 heteroechoic; increased vascularity on US was seen in 69/337 (20%). On US, 105 benign nodules were reported as hypoechoic, 35 hyperechoic, 43 isoechoic, and 100 as heterogeneous; increased vascularity on US was seen in 88/429 (20%). CONCLUSIONS: A malignant diagnosis was more common in thyroid nodules <=1.0 cm. No differences were noted in the US-features of benign and malignant thyroid nodules. PMID- 25693825 TI - Effects of lowering the alcohol minimum purchasing age on weekend hospitalised assaults of young Maori in New Zealand. AB - INTRODUCTION AND AIMS: We examine the association between reducing the alcohol minimum purchasing age from 20 to 18 years in December 1999 and rates of weekend assault hospitalisation among young Maori in the following 12 years. Our previous work showed deleterious effects for young people overall. In keeping with Treaty of Waitangi principles, we sought to determine whether the policy was similarly detrimental for Maori. DESIGN AND METHODS: We used Poisson regression to examine data from 1995 to 2011 on Maori hospitalised on Friday-Sunday following assault, separately by gender among 15- to 17-year-olds and 18- to 19-year-olds, versus 20 to 21-year-olds as a control for changes in economic and environmental factors. RESULTS: There was no evidence to suggest weekend assault hospitalisations increased significantly more among 15- to 17-year-old or 18- to 19-year-old Maori males in the post-change periods (incidence rate ratios varied between 0.83 and 1.13; P values >0.25) compared with increases observed in 20- to 21-year-old Maori males. For Maori females, estimates were more variable, but overall, there was no evidence of the hypothesised effect (incidence rate ratios between 0.60 and 1.09; P values >0.07). DISCUSSION AND CONCLUSIONS: Overall, we find no evidence that lowering the minimum alcohol purchasing age increased weekend hospitalised assaults among young Maori. Inferences are compromised by lack of statistical power which underlines the importance of planning for evaluation of important policies well before they are implemented, particularly with a view to meeting obligations to Maori arising from the Treaty of Waitangi. PMID- 25693826 TI - The connection of cytoskeletal network with plasma membrane and the cell wall. AB - The cell wall provides external support of the plant cells, while the cytoskeletons including the microtubules and the actin filaments constitute an internal framework. The cytoskeletons contribute to the cell wall biosynthesis by spatially and temporarily regulating the transportation and deposition of cell wall components. This tight control is achieved by the dynamic behavior of the cytoskeletons, but also through the tethering of these structures to the plasma membrane. This tethering may also extend beyond the plasma membrane and impact on the cell wall, possibly in the form of a feedback loop. In this review, we discuss the linking components between the cytoskeletons and the plasma membrane, and/or the cell wall. We also discuss the prospective roles of these components in cell wall biosynthesis and modifications, and aim to provide a platform for further studies in this field. PMID- 25693827 TI - Degradation of organic ultraviolet filter diethylamino hydroxybenzoyl hexyl benzoate in aqueous solution by UV/H2O2. AB - Steady-state and transient-state photolysis experiments were conducted to investigate the degradation of organic ultraviolet filter diethylamino hydroxybenzoyl hexyl benzoate (DHHB) in the aqueous solution by UV/H2O2. Results showed that the obvious degradation of DHHB was not observed under UV irradiation (lambda = 254 nm), and the DHHB degradation was conducted due to the oxidation by hydroxyl radical (HO.). While the H2O2 concentration was between 0.05 and 0.10 mol L(-1), the highest DHHB degradation efficiency was obtained. The lower solution pH favored the transformation of DHHB, and the coexisting Cl(-) and NO3( ) ions slightly enhanced the conversion. The degradation of DHHB by HO. followed a pseudo-first-order kinetic model with different initial DHHB concentrations. By intermediate products during DHHB oxidation and laser flash photolysis spectra analysis, a primary degradation pathway was proposed. PMID- 25693828 TI - Effects of flow speed and circulation interval on water quality and zooplankton in a pond-ditch circulation system. AB - A pond-ditch circulation system (PDCS) shows great promises for ecological restoration of rural contaminated water in southern China. In this study, the optimal flow speed, circulation interval, and their combination for the system were investigated for higher pollutant removal efficiency and lower costs in three separate experiments: I, II, and III, respectively. In each experiment, there are three PDCSs (S1, S2, and S3) with different water circulation speeds or circulation intervals, respectively. The results demonstrated that in experiment I, total nitrogen (TN) removal rates, species numbers, and diversity indexes of zooplankton in S1 with a flow speed of 3.6 L/h were significantly higher than those in S2 (7.2 L/h) and S3 (10.2 L/h), respectively. Similarly, in experiment II, S3 circulating every other 4 h had significantly higher TN reduction rates, species numbers, and diversity indexes than S1 and S2 circulating every other 1 and 2 h, respectively. In experiment III, water qualities in S1 (circulation of 3.6 L/h + interval of 4 h) were better than those in S2 (7.2 L/h + 4 h) and S3 (10.2 L/h + 6 h), respectively. Together, circulation at every other 4 h (3.6 L/h) is probably the optimal operating condition for the PDCS in remediating rural contaminated water. PMID- 25693829 TI - Nitrite accumulation during denitrification depends on the carbon quality and quantity in wastewater treatment with biofilters. AB - This study aims to understand the mechanisms of nitrite appearance during wastewater denitrification by biofilters, focusing on the role of the carbon source. Experiments were carried out at lab-scale (batch tests) and full-scale plant (Parisian plant, capacities of 240,000 m(3) day(-1)). Results showed that the nature of the carbon source affects nitrite accumulation rates. This accumulation is low, 0.05 to 0.10 g N-NO2(-) per g N-NO3(-) eliminated, for alcohols such as methanol, ethanol, or glycerol. The utilization of glycerol leads to fungal development causing clogging of the biofilters. This fungal growth and consequent clogging exclude this carbon source, with little nitrite accumulation, as carbon source for denitrification. Whatever the carbon source, the C/N ratio in the biofilter plays a major role in the appearance of residual nitrite; an optimal C/N ratio from 3.0 to 3.2 allows a complete denitrification without any nitrite accumulation. PMID- 25693830 TI - Effects of copper on reserve mobilization in embryo of Phaseolus vulgaris L. AB - The present research reports a biochemical and micro-submicroscopic analysis of copper effect on reserve mobilization during germination of Phaseolus vulgaris L. var. soisson nain hatif seeds. Dry embryonic cells are rich in protein bodies and little starch grains. In Cu-treated embryos copper inhibited 50% of albumin and globulin mobilization after 72 h imbibition. The severe alterations in treated embryo cells, observed by electron microscope, were probably the cause of the inability to utilize the amino acids freed by protein mobilization and so possibly the cause of the inhibition of P. vulgaris embryonic axis elongation. PMID- 25693831 TI - The Cultural Meaning of Cardiac Illness and Self-Care Among Lebanese Patients With Coronary Artery Disease. AB - BACKGROUND: Cardiac disease is the leading cause of death in Lebanon, accounting for 22% to 26% of total deaths in the country. A thorough understanding of perceptions of cardiac illness and related self-care management is critical to the development of secondary prevention programs that are specific to the Lebanese culture. PURPOSE: To explore the cultural perceptions of cardiac illness and the associated meaning of self-care among Lebanese patients. DESIGN: Using a qualitative descriptive method, semistructured interviews were conducted with a purposive sample of 15 Lebanese cardiac patients recruited from a medical center in Beirut, Lebanon. FINDINGS: The qualitative descriptive analysis yielded one overarching and two other themes describing perceptions of cardiac illness and self-care within the Lebanese cultural context. The overarching cultural theme was, "Lebanese cardiac patients were unfamiliar with the term concept and meaning of self-care." Lebanese cardiac patients thanked God and accepted their fate (Theme I). The participants considered their cardiac incident a life or death warning (Theme II). IMPLICATIONS FOR PRACTICE: Health care providers need to consider patients' cultural perception of illness while planning and evaluating cardiac self-care programs. PMID- 25693832 TI - Molecular architecture requirements for polymer-grafted lignin superplasticizers. AB - Superplasticizers are a class of anionic polymer dispersants used to inhibit aggregation in hydraulic cement, lowering the yield stress of cement pastes to improve workability and reduce water requirements. The plant-derived biopolymer lignin is commonly used as a low-cost/low-performance plasticizer, but attempts to improve its effects on cement rheology through copolymerization with synthetic monomers have not led to significant improvements. Here we demonstrate that kraft lignin can form the basis for high-performance superplasticizers in hydraulic cement, but the molecular architecture must be based on a lignin core with a synthetic-polymer corona that can be produced via controlled radical polymerization. Using slump tests of ordinary Portland cement pastes, we show that polyacrylamide-grafted lignin prepared via reversible addition-fragmentation chain transfer polymerization can reduce the yield stress of cement paste to similar levels as a leading commercial polycarboxylate ether superplasticizer at concentrations ten-fold lower, although the lignin material produced via controlled radical polymerization does not appear to reduce the dynamic viscosity of cement paste as effectively as the polycarboxylate superplasticizer, despite having a similar affinity for the individual mineral components of ordinary Portland cement. In contrast, polyacrylamide copolymerized with a methacrylated kraft lignin via conventional free radical polymerization having a similar overall composition did not reduce the yield stress or the viscosity of cement pastes. While further work is required to elucidate the mechanism of this effect, these results indicate that controlling the architecture of polymer-grafted lignin can significantly enhance its performance as a superplasticizer for cement. PMID- 25693833 TI - Integrative oncology - strong science is needed for better patient care. PMID- 25693834 TI - DNMT3A in haematological malignancies. AB - DNA methylation patterns are disrupted in various malignancies, suggesting a role in the development of cancer, but genetic aberrations directly linking the DNA methylation machinery to malignancies were rarely observed, so this association remained largely correlative. Recently, however, mutations in the gene encoding DNA methyltransferase 3A (DNMT3A) were reported in patients with acute myeloid leukaemia (AML), and subsequently in patients with various other haematological malignancies, pointing to DNMT3A as a critically important new tumour suppressor. Here, we review the clinical findings related to DNMT3A, tie these data to insights from basic science studies conducted over the past 20 years and present a roadmap for future research that should advance the agenda for new therapeutic strategies. PMID- 25693835 TI - Integrative oncology - strong science is needed for better patient care. PMID- 25693837 TI - Fetal sex and maternal risk of gestational diabetes mellitus: the impact of having a boy. AB - OBJECTIVE: Retrospective analyses of perinatal databases have raised the intriguing possibility of an increased risk of gestational diabetes mellitus (GDM) in women carrying a male fetus, but it has been unclear if this was a spurious association. We thus sought to evaluate the relationship between fetal sex and maternal glucose metabolism in a well-characterized cohort of women reflecting the full spectrum of gestational glucose tolerance from normal to mildly abnormal to GDM. RESEARCH DESIGN AND METHODS: A total of 1,074 pregnant women underwent metabolic characterization, including oral glucose tolerance test (OGTT), at mean 29.5 weeks' gestation. The prevalence of GDM, its pathophysiologic determinants (beta-cell function and insulin sensitivity/resistance), and its clinical risk factors were compared between women carrying a female fetus (n = 534) and those carrying a male fetus (n = 540). RESULTS: Women carrying a male fetus had lower mean adjusted beta-cell function (insulinogenic index divided by HOMA of insulin resistance: 9.4 vs. 10.5, P = 0.007) and higher mean adjusted blood glucose at 30 min (P = 0.025), 1 h (P = 0.004), and 2 h (P = 0.02) during the OGTT, as compared with those carrying a female fetus. Furthermore, women carrying a male fetus had higher odds of developing GDM (odds ratio 1.39 [95% CI 1.01-1.90]). Indeed, male fetus further increased the relative risk of GDM conferred by the classic risk factors of maternal age >35 years and nonwhite ethnicity by 47 and 51%, respectively. CONCLUSIONS: Male fetus is associated with poorer beta-cell function, higher postprandial glycemia, and an increased risk of GDM in the mother. Thus, fetal sex potentially may influence maternal glucose metabolism in pregnancy. PMID- 25693836 TI - Topoisomerase-mediated chromosomal break repair: an emerging player in many games. AB - The mammalian genome is constantly challenged by exogenous and endogenous threats. Although much is known about the mechanisms that maintain DNA and RNA integrity, we know surprisingly little about the mechanisms that underpin the pathology and tissue specificity of many disorders caused by defective responses to DNA or RNA damage. Of the different types of endogenous damage, protein-linked DNA breaks (PDBs) are emerging as an important player in cancer development and therapy. PDBs can arise during the abortive activity of DNA topoisomerases, a class of enzymes that modulate DNA topology during several chromosomal transactions, such as gene transcription and DNA replication, recombination and repair. In this Review, we discuss the mechanisms underpinning topoisomerase induced PDB formation and repair with a focus on their role during gene transcription and the development of tissue-specific cancers. PMID- 25693838 TI - Targeting ASCT2-mediated glutamine uptake blocks prostate cancer growth and tumour development. AB - Glutamine is conditionally essential in cancer cells, being utilized as a carbon and nitrogen source for macromolecule production, as well as for anaplerotic reactions fuelling the tricarboxylic acid (TCA) cycle. In this study, we demonstrated that the glutamine transporter ASCT2 (SLC1A5) is highly expressed in prostate cancer patient samples. Using LNCaP and PC-3 prostate cancer cell lines, we showed that chemical or shRNA-mediated inhibition of ASCT2 function in vitro decreases glutamine uptake, cell cycle progression through E2F transcription factors, mTORC1 pathway activation and cell growth. Chemical inhibition also reduces basal oxygen consumption and fatty acid synthesis, showing that downstream metabolic function is reliant on ASCT2-mediated glutamine uptake. Furthermore, shRNA knockdown of ASCT2 in PC-3 cell xenografts significantly inhibits tumour growth and metastasis in vivo, associated with the down regulation of E2F cell cycle pathway proteins. In conclusion, ASCT2-mediated glutamine uptake is essential for multiple pathways regulating the cell cycle and cell growth, and is therefore a putative therapeutic target in prostate cancer. PMID- 25693839 TI - Rapid method for the quantification of hydroquinone concentration: chemiluminescent analysis. AB - Topical hydroquinone serves as a skin whitener and is usually available in cosmetics or on prescription based on the hydroquinone concentration. Quantification of hydroquinone content therefore becomes an important issue in topical agents. High-performance liquid chromatography (HPLC) is the commonest method for determining hydroquinone content in topical agents, but this method is time-consuming and uses many solvents that can become an environmental issue. We report a rapid method for quantifying hydroquinone content by chemiluminescent analysis. Hydroquinone induces the production of hydrogen peroxide in the presence of basic compounds. Hydrogen peroxide induced by hydroquinone oxidized light-emitting materials such as lucigenin, resulted in the production of ultra weak chemiluminescence that was detected by a chemiluminescence analyzer. The intensity of the chemiluminescence was found to be proportional to the hydroquinone concentration. We suggest that the rapid (measurement time, 60 s) and virtually solvent-free (solvent volume, <2 mL) chemiluminescent method described here for quantifying hydroquinone content may be an alternative to HPLC analysis. PMID- 25693840 TI - Integrin alpha6beta1 Expressed in ESCs Instructs the Differentiation to Endothelial Cells. AB - Adhesion of embryonic stem cells (ESCs) to the extracellular matrix may influence differentiation potential and cell fate decisions. Here, we investigated the inductive role of binding of integrin alpha6beta1 expressed in mouse (m)ESCs to laminin-1 (LN1) in mediating the differentiation of ESCs to endothelial cells (ECs). We observed that alpha6beta1 binding to LN1 was required for differentiation to ECs. alpha6beta1 functioned by recruiting the adaptor tetraspanin protein CD151, which activated FAK and Akt signaling and mediated the EC lineage-specifying transcription factor Er71. In contrast, association of the ESC-expressed alpha3beta1, another highly expressed LN1 binding integrin, with CD151, prevented alpha6beta1-mediated differentiation. CD151 thus functioned as a bifurcation router to direct ESCs toward ECs when alpha6beta1 associated with CD151, or prevented transition to ECs when alpha3beta1 associated with CD151. These observations were recapitulated in mice in which alpha6 integrin or CD151 knockdown reduced the expression of Er71-regulated angiogenesis genes and development of blood vessels. Thus, interaction of alpha6beta1 in ESCs with LN1 activates alpha6beta1/CD151 signaling which programs ESCs toward the EC lineage fate. PMID- 25693841 TI - Aquatic environmental risk assessment for human use of the old antibiotic sulfamethoxazole in Europe. AB - Sulfamethoxazole (SMX) is an old sulfonamide antibiotic that was launched first in combination with trimethoprim in 1969 by F.Hoffmann-La Roche. Although sales figures for SMX have been declining over the past 20 yr, the compound is still widely used; moreover, many measured environmental concentrations (MECs) are available from Europe, the United States, Asia, Australia, and Africa. To assess aquatic risks of SMX in Europe, the exposure of European surface waters was predicted based on actual sales figures from IMS Health, incorporating environmental fate data on one side, and based on collated MECs representing more than 5500 single measurements in Europe on the other. Environmental effects were assessed using chronic and subchronic ecotoxicity data for 16 groups of aquatic organisms, from periphyton communities to cyanobacteria, algae, higher plants, various invertebrates, and vertebrates. Predicted no-effect concentrations (PNECs) were derived using both deterministic and probabilistic methodology. The predicted environmental concentration (PEC)/PNEC and MEC/PNEC comparisons overall showed no appreciable risk, except in a low incidence (<0.55%) of cases in which exceptionally high MECs led to MEC/PNEC risk characterization ratios greater than 1. The PNECs derived in the present study can be used to extend aquatic environmental risk assessment for SMX to other continents. No risk appears for indirect human exposure to SMX via the environment. PMID- 25693842 TI - Characterization of patients referred for non-specific intellectual disability testing: the importance of autosomal genes for diagnosis. AB - Genetic testing for non-specific intellectual disability (ID) presents challenges in daily clinical practice. Historically, the focus of the genetic elucidation of non-specific ID has been on genes on the X chromosome, and recent research has brought attention to the growing contribution of autosomal genes. In addition, next-generation sequencing (NGS) has greatly improved the ability to simultaneously analyze multiple genetic loci, making large panel testing a practical approach to testing for non-specific ID. We performed NGS analysis of a total of 90 genes implicated in non-specific ID. The 90 genes included 56 X linked genes and 34 autosomal genes. Pathogenic variants were identified in 11 of 52 (21%) patient samples. Nine of the eleven cases harbored mutations in autosomal genes including AP4B1, STXB1, SYNGAP1, TCF4 and UBE3A. Our mutation positive cases provide further evidence supporting the prevalence of autosomal mutations in patients referred for non-specific ID testing and the utility of their inclusion in multi-gene panel analysis. PMID- 25693843 TI - High glycemic index and glycemic load are associated with moderately increased cancer risk. AB - SCOPE: To obtain an up-to-date quantification of the association between dietary glycemic index (GI) and glycemic load (GL) and the risk of cancer. METHODS AND RESULTS: We conducted a systematic review and meta-analysis of observational studies updated to January 2015. Summary relative risks (RRs) were derived using random effects models. Seventy-five reports were evaluated in the systematic review (147,090 cases), and 72 were included in the meta-analyses by cancer site. Considering hormone-related cancers, summary RRs comparing the highest versus the lowest GI and GL intake were, respectively, 1.05 and 1.07 for breast, 1.13 and 1.17 for endometrial, 1.11 and 1.19 for ovarian, and 1.06 and 1.04 for prostate cancers. Considering digestive-tract cancers, summary RRs for GI and GL were, respectively, 1.46 and 1.25 for esophageal (squamous cell carcinoma), 1.17 and 1.10 for stomach, 1.16 (significant) and 1.10 for colorectal, 1.11 and 1.14 for liver, and 1.10 and 1.01 for pancreatic cancers. In most of these meta-analyses, significant heterogeneity among studies was observed. In subgroup analyses, case control studies and studies from Europe tended to estimate higher RRs. CONCLUSION: High-GI and high-GL diets are related to moderately increased risk of cancer at several common sites. PMID- 25693844 TI - MBL2 polymorphisms in women with atypical squamous cells of undetermined significance. AB - Infection with high risk Human papillomavirus (HPV) is the main known cause of cervical cancer. HPV induces different grades of lesions: among them, Atypical squamous cells of undetermined significance are abnormal lesions that could evolve in pre-cancer lesions or spontaneously regress. The mannose binding lectin (MBL) is an innate immunity serum protein also found in cervico-vaginal mucosa, whose expression is known to be affected by polymorphisms in exon 1 and promoter of the MBL2 gene. In the present study the possible association between MBL2 functional polymorphisms and susceptibility to develop atypical squamous cells of undetermined significance was investigated in a group of women from North-East of Italy, stratified for HPV infection status. The MBL2 D and O alleles and the deficient producer combined genotypes, responsible for low MBL production, were more represented among atypical squamous cells of undetermined significance positive women than healthy controls and the results were confirmed when only HPV negative samples were considered. These results suggest a possible involvement of MBL2 functional polymorphisms in atypical squamous cells of undetermined significance susceptibility. PMID- 25693845 TI - Protease-Sensitive Inhibitory Activity of Cell-free Supernatant of Lactobacillus crispatus 156 Synergizes with Ciprofloxacin, Moxifloxacin and Streptomycin Against Pseudomonas aeruginosa: An In Vitro Study. AB - Ciprofloxacin and streptomycin are frequently prescribed for the treatment of medical conditions originating due to infection by Pseudomonas aeruginosa. However, fluoroquinolone administration has been linked to the outgrowth of Clostridium difficile pathogen, especially in immunocompromised patients. Secondly, frequent administration of antibiotics may lead to development of resistance in the pathogens. Thus, there is a need to explore innovative adjunct therapies to lower the therapeutic doses of the antibiotics. Herein, we evaluated the synergism, if any, between conventional antibiotics and the cell-free supernatant (CFS) of vaginal Lactobacillus crispatus 156 against P. aeruginosa MTCC 741. L. crispatus 156 was isolated from the human vaginal tract, and its CFS had broad-spectrum antimicrobial activity against various Gram-positive and Gram negative pathogens, including P. aeruginosa. The inhibitory substance present in the CFS completely lost its activity after treatment with proteinases and was resistant to temperatures up to 80 degrees C and pH ranging from 2 to 6. The cumulative production of the inhibitory substance in CFS was studied, and it showed that the secretion of the inhibitory substance was initiated in middle log phase of growth and peaked in late log phase. Further, CFS synergized the activities of ciprofloxacin, moxifloxacin, and streptomycin as evaluated in terms of checkerboard titrations. It lowered the minimum inhibitory concentration (MIC) of ciprofloxacin by almost 30 times and MIC of both moxifloxacin and streptomycin by 8 times. Interestingly, pepsin treatment of CFS caused the complete abrogation of its synergistic effect with all the three antibiotics. Thus, from the study, it can be concluded that probiotic-based alternative therapeutic regimen can be designed for the treatment of P. aeruginosa infections. PMID- 25693846 TI - Comparative genomic analysis of seven Mycoplasma hyosynoviae strains. AB - Infection with Mycoplasma hyosynoviae can result in debilitating arthritis in pigs, particularly those aged 10 weeks or older. Strategies for controlling this pathogen are becoming increasingly important due to the rise in the number of cases of arthritis that have been attributed to infection in recent years. In order to begin to develop interventions to prevent arthritis caused by M. hyosynoviae, more information regarding the specific proteins and potential virulence factors that its genome encodes was needed. However, the genome of this emerging swine pathogen had not been sequenced previously. In this report, we present a comparative analysis of the genomes of seven strains of M. hyosynoviae isolated from different locations in North America during the years 2010 to 2013. We identified several putative virulence factors that may contribute to the ability of this pathogen to adhere to host cells. Additionally, we discovered several prophage genes present within the genomes of three strains that show significant similarity to MAV1, a phage isolated from the related species, M. arthritidis. We also identified CRISPR-Cas and type III restriction and modification systems present in two strains that may contribute to their ability to defend against phage infection. PMID- 25693847 TI - Regioselective Pd-catalyzed methoxycarbonylation of alkenes using both paraformaldehyde and methanol as CO surrogates. AB - In recent years, considerable effort has focused on the development of novel carbonylative transformations using CO surrogates. Consequently, toxic CO gas can be replaced by more convenient inorganic or organic carbonyl compounds. Herein, the first regioselective methoxycarbonylation of alkenes with paraformaldehyde and methanol as CO substitutes is reported. This new procedure is applicable to a series of alkenes in the presence of a palladium catalyst under relatively mild conditions and is highly atom efficient. PMID- 25693848 TI - Narratives, memorable cases and metaphors of night nursing: findings from an interpretative phenomenological study. AB - The aim of the study was to explore the experiences of night nurses. An interpretative phenomenological study was undertaken, and 35 nurses working in Italian medical, surgical and intensive care units were purposely recruited. Data were gathered in 2010 by semi-structured interviews, collecting nurses' narratives, memorable cases and metaphors, aimed at summarising the essence of work as a nurse during the night. The experience of night nursing is based on four interconnected themes: (i) working in a state of alert, (ii) growing by expanding autonomy and responsibility, (iii) assuring sensitive surveillance and (iv) experiencing deep intimacy. Memorable episodes were polarised along (i) expected/unexpected events; (ii) positive/negative epilogues; and (iii) life/death issues. Many of the emergent metaphors described working during the night as being in the middle of a space where an apparent calm scene takes place, but unpredictable factors may suddenly change the order of events and the outcomes, creating chaos. Working during the night alerts nurses, who increase autonomy, expanding their role and assuming more responsibility with respect to that assumed during daily shifts. The nurses' clinical reasoning is based on data they carefully listen to, and on the meaning that nurses give time by time to different noises and silence. While in the past a sense of companionships was reported, a loneliness or a 'neutral' experience concerning the relationships with colleagues seems to prevail during night nursing. Working night shifts is a complex task, and specific training must be assured to students/novices. PMID- 25693849 TI - Discriminating Lamiophlomis rotata According to Geographical Origin by (1)H-NMR Spectroscopy and Multivariate Analysis. AB - INTRODUCTION: Lamiophlomis rotata (Duyiwei) is a folk herbal medicine that traditionally has been used in China as a hemostatic agent. Raw plant materials used for medicinal products from different geographical regions are often inconsistent in chemical composition. Metabolic fingerprinting provides a new approach for distinguishing the geographical origins of L. rotata. OBJECTIVE: To identify metabolites that contribute to the different geographical regions of L. rotata samples. METHODS: Lamiophlomis rotata metabolomics were performed by (1)H nuclear magnetic resonance (NMR) spectroscopy and multivariate statistical analyses. The L. rotata metabolic profile was prepared for NMR measurements using methanol-d4 solvent. Principal component analysis (PCA) and hierarchical cluster analysis (HCA) were applied to analyse the L. rotata (1)H-NMR spectroscopy data. RESULTS: Nine iridoid glycosides, one flavonoid and three phenylpropanoid glycosides were detected in L. rotata by (1)H-NMR spectroscopy. (1)H-NMR measurements and multivariate analysis were used to successfully discriminate samples from three different locations. CONCLUSION: The NMR-based analysis of L. rotata is a more comprehensive approach than traditional chromatographic methods. Simple sample preparation, rapidity and reproducibility of are additional advantages of NMR analysis. PMID- 25693850 TI - Vigorous physical activity and carotid distensibility in young and mid-aged adults. AB - Although physical activity (PA) improves arterial distensibility, it is unclear which type of activity is most beneficial. We aimed to examine the association of different types of PA with carotid distensibility (CD) and the mechanisms involved. Data included 4503 Australians and Finns aged 26-45 years. Physical activity was measured by pedometers and was self-reported. CD was measured using ultrasound. Other measurements included resting heart rate (RHR), cardiorespiratory fitness (CRF), blood pressure, biomarkers and anthropometry. Steps/day were correlated with RHR (Australian men r = -0.10, women r = - 0.14; Finnish men r = -0.15, women r = -0.11; P<0.01), CRF and biochemical markers, but not with CD. Self-reported vigorous leisure-time activity was more strongly correlated with RHR (Australian men r = -0.23, women r = -0.19; Finnish men r = 0.20, women r = -0.13; P < 0.001) and CRF, and was correlated with CD (Australian men r = 0.07; Finnish men r = 0.07, women r = 0.08; P < 0.05). This relationship of vigorous leisure-time activity with CD was mediated by RHR independently of potential confounders. In summary, vigorous leisure-time PA but not total or less intensive PA was associated with arterial distensibility in young to mid-aged adults. Promotion of vigorous PA is therefore recommended among this population. RHR was a key intermediary factor explaining the relationship between vigorous PA and arterial distensibility. PMID- 25693851 TI - Accurate quantitative measurements of brachial artery cross-sectional vascular area and vascular volume elastic modulus using automated oscillometric measurements: comparison with brachial artery ultrasound. AB - Increasing vascular diameter and attenuated vascular elasticity may be reliable markers for atherosclerotic risk assessment. However, previous measurements have been complex, operator-dependent or invasive. Recently, we developed a new automated oscillometric method to measure a brachial artery's estimated area (eA) and volume elastic modulus (V(E)). The aim of this study was to investigate the reliability of new automated oscillometric measurement of eA and V(E). Rest eA and V(E) were measured using the recently developed automated detector with the oscillometric method. eA was estimated using pressure/volume curves and V(E) was defined as follows (V(E)=Delta pressure/ (100 * Delta area/area) mm Hg/%). Sixteen volunteers (age 35.2+/-13.1 years) underwent the oscillometric measurements and brachial ultrasound at rest and under nitroglycerin (NTG) administration. Oscillometric measurement was performed twice on different days. The rest eA correlated with ultrasound-measured brachial artery area (r=0.77, P<0.001). Rest eA and VE measurement showed good reproducibility (eA: intraclass correlation coefficient (ICC)=0.88, V(E): ICC=0.78). Under NTG stress, eA was significantly increased (12.3+/-3.0 vs. 17.1+/-4.6 mm(2), P<0.001), and this was similar to the case with ultrasound evaluation (4.46+/-0.72 vs. 4.73+/-0.75 mm, P<0.001). V(E) was also decreased (0.81+/-0.16 vs. 0.65+/-0.11 mm Hg/%, P<0.001) after NTG. Cross-sectional vascular area calculated using this automated oscillometric measurement correlated with ultrasound measurement and showed good reproducibility. Therefore, this is a reliable approach and this modality may have practical application to automatically assess muscular artery diameter and elasticity in clinical or epidemiological settings. PMID- 25693852 TI - Iron restriction inhibits renal injury in aldosterone/salt-induced hypertensive mice. AB - Excess iron is associated with the pathogenesis of several renal diseases. Aldosterone is reported to have deleterious effects on the kidney, but there have been no reports of the role of iron in aldosterone/salt-induced renal injury. Therefore, we investigated the effects of dietary iron restriction on the development of hypertension and renal injury in aldosterone/salt-induced hypertensive mice. Ten-week-old male C57BL/6J mice were uninephrectomized and infused with aldosterone for four weeks. These were divided into two groups: one fed a high-salt diet (Aldo) and the other fed a high-salt with iron-restricted diet (Aldo-IR). Vehicle-infused mice without a uninephrectomy were also divided into two groups: one fed a normal diet (control) and the other fed an iron restricted diet (IR) for 4 weeks. As compared with control and IR mice, Aldo mice showed an increase in both systolic blood pressure and urinary albumin/creatinine ratio, but these increases were reduced in the Aldo-IR group. In addition, renal histology revealed that Aldo mice exhibited glomerulosclerosis and tubulointerstitial fibrosis, whereas these changes were attenuated in Aldo-IR mice. Expression of intracellular iron transport protein transferrin receptor 1 was increased in the renal tubules of Aldo mice compared with control mice. Dietary iron restriction attenuated the development of hypertension and renal injury in aldosterone/salt-induced hypertensive mice. PMID- 25693853 TI - Outcomes of 83 fetuses exposed to angiotensin receptor blockers during the second or third trimesters: a literature review. AB - This literature review was conducted to provide better counsel to pregnant women who erroneously took angiotensin receptor blockers (ARBs) during the second and/or third trimesters regarding infant outcomes. Information was available on 83 fetuses in 34 literature reports, including one that we encountered recently. Fourteen pregnancies were terminated, and six were unknown regarding status of amniotic fluid volume (AFV). Fifty-eight and five fetuses did and did not show oligohydramnios, respectively, after being exposed to ARBs. Of the 58 fetuses that presented with oligohydramnios, 57 were exposed to ARBs at gestational week (GW) ? 20, and 19 exhibited resolution of oligohydramnios 1-6 weeks after cessation of ARBs. The 24 mothers without oligohydramnios at delivery ceased taking ARBs earlier (GW of 26.8 +/- 5.1 vs. 31.8 +/- 4.0, respectively, P = 0.000) and had longer duration of gestation after cessation of ARBs (8.4 +/- 5.2 vs. 0.7 +/- 2.3 weeks, respectively, P = 0.000). The mothers without oligohydramnios also had better outcomes in terms of favorable infant outcomes (63% (15/24) vs. 15% (6/39), respectively, P = 0.000) and infant mortality rates (13% (3/24) vs. 56% (22/39), respectively, P = 0.001) than the 39 with oligohydramnios. Thus, a favorable outcome may be feasible if the fetuses are not indicated for prompt delivery at presentation and exhibit normal AFV or resolution of oligohydramnios after cessation of ARBs. Although the prevalence rate of oligohydramnios was high in this study, it may have been due to publication bias. A prospective study suggested a lower prevalence rate than that reported in the present study. PMID- 25693854 TI - Association between renal iron accumulation and renal interstitial fibrosis in a rat model of chronic kidney disease. AB - Iron accumulation is associated with the pathophysiology of chronic kidney disease (CKD). Renal fibrosis is a final common feature that contributes to the progression of CKD; however, little is known about the association between renal iron accumulation and renal interstitial fibrosis in CKD. Here we investigate the effects of iron chelation on renal interstitial fibrosis in a rat model of CKD. CKD was induced by 5/6 nephrectomy in Sprague-Dawley rats. At 8 weeks after operation, 5/6 nephrectomized rats were administered an oral iron chelator, deferasirox (DFX), in chow for 8 weeks. Other CKD rats were given a normal diet. Sham-operative rats given a normal diet served as a control. CKD rats exhibited hypertension, glomerulosclerosis and renal interstitial fibrosis. Iron chelation with DFX did not change hypertension and glomerulosclerosis; however, renal interstitial fibrosis was attenuated in CKD rats. Consistent with these findings, renal gene expression of collagen type III and transforming growth factor-beta was increased in CKD rats compared with the controls, while iron chelation suppressed these increments. In addition, a decrease in vimentin along an increase in E-cadherin in renal gene expression was observed in CKD rats with iron chelation. CKD rats also showed increased CD68-positive cells in the kidney, whereas its increase was attenuated by iron deprivation. Similarly, increased renal gene expression of CD68, tumor necrosis factor-alpha and monocyte chemoattractant protein-1 was suppressed in CKD rats with iron chelation. Renal iron accumulation seems to be associated with renal interstitial fibrosis in a rat model of CKD. PMID- 25693855 TI - Central blood pressure estimation by using N-point moving average method in the brachial pulse wave. AB - Recently, a method of estimating the central systolic blood pressure (C-SBP) using an N-point moving average method in the radial or brachial artery waveform has been reported. Then, we investigated the relationship between the C-SBP estimated from the brachial artery pressure waveform using the N-point moving average method and the C-SBP measured invasively using a catheter. C-SBP using a N/6 moving average method from the scaled right brachial artery pressure waveforms using VaSera VS-1500 was calculated. This estimated C-SBP was compared with the invasively measured C-SBP within a few minutes. In 41 patients who underwent cardiac catheterization (mean age: 65 years), invasively measured C-SBP was significantly lower than right cuff-based brachial BP (138.2 +/- 26.3 vs 141.0 +/- 24.9 mm Hg, difference -2.78 +/- 1.36 mm Hg, P = 0.048). The cuff-based SBP was significantly higher than invasive measured C-SBP in subjects with younger than 60 years old. However, the estimated C-SBP using a N/6 moving average method from the scaled right brachial artery pressure waveforms and the invasively measured C-SBP did not significantly differ (137.8 +/- 24.2 vs 138.2 +/- 26.3 mm Hg, difference -0.49 +/- 1.39, P = 0.73). N/6-point moving average method using the non-invasively acquired brachial artery waveform calibrated by the cuff-based brachial SBP was an accurate, convenient and useful method for estimating C-SBP. Thus, C-SBP can be estimated simply by applying a regular arm cuff, which is greatly feasible in the practical medicine. PMID- 25693856 TI - Environmental origins of hypertension: phylogeny, ontogeny and epigenetics. AB - Hypertension and renal parenchymal disease are intricately linked. Primary renal parenchymal disease can impact on sodium and volume regulation and lead to hypertension, while arterial hypertension can induce renal parenchymal injury and precipitate renal dysfunction. The examination for clues to the environmental origins of renal disease and hypertension necessitates an approach that integrates epidemiology, clinical medicine, developmental biology, environmental science and epigenetics, such that the manner in which genes and the environment interact can be better understood to pave the way for innovative management paradigms with regards to prevention, diagnosis and treatment. This review summarizes the extant literature and provides cogent arguments for the need to evaluate chronic adult onset disease models such as hypertension and renal disease from the modern perspective that takes into account prenatal exposures, the intrauterine environment and development, postnatal growth and transgenerational epigenetic modifications with their attendant future disease risk from the individual to the population level. PMID- 25693857 TI - Glucose and the risk of hypertension in first-degree relatives of patients with type 2 diabetes. AB - To test the hypothesis that plasma glucose (PG) levels is associated with the incidence of hypertension (HT) in nondiabetic and non-hypertensive first-degree relatives (FDR) of people with type 2 diabetes (T2D). A total of 1089 FDR without diabetes and/or HT of consecutive patients with T2D 30-70 years old were examined and followed for a mean (s.d.) of 6.9 (1.7) years for HT incidence. At baseline and through follow-up, participants underwent a standard 75 gm 2-h oral glucose tolerance test. HT was defined according to the criteria of the Seventh Report of Joint National Committee. We used Cox proportional hazard models to estimate hazard ratio for incident HT and plotted a receiver operating characteristic curve to assess discrimination. The PG levels at baseline were associated with incidence of HT, independently of age, gender, obesity and high cholesterol, high density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, education and systolic blood pressure. Those with impaired glucose tolerance were 54% (hazard ratio 1.54; 95% confidence interval (CI) 1.33, 1.77) more likely to develop HT than those with normal glucose tolerance. Those with impaired fasting glucose were also 23% (hazard ratio 1.23; 95% CI 1.01, 1.50) more likely to develop HT. High PG levels were consistently associated with incident HT. PMID- 25693858 TI - Continuous infusion of angiotensin II modulates hypertrophic differentiation and apoptosis of chondrocytes in cartilage formation in a fracture model mouse. AB - Although components of the renin-angiotensin system (RAS) are reported to be expressed in cultured chondrocytes and cartilage, little is known about the precise function of Angiotensin II (Ang II) in chondrocytes. In this study, we employed a rib fracture model mouse to investigate the effect of Ang II on chondrocytes. Ang II type 1 receptor (AT1R) was expressed in chondrocytes in the growth plate of mouse tibia. Continuous infusion of Ang II to rib-fractured mice resulted in a significant increase in the volume of cartilage, suggesting Ang II induced hypertrophic differentiation of chondrocytes. It was also confirmed by a significant increase in the mRNA expression of Sox9 and runt-related transcription factor 2 (Runx2), which are genes related to chondrocyte differentiation, and type X collagen, matrix metalloproteinase (MMP)-13 and Indian hedgehog (Ihh), which are hypertrophic chondrocyte-specific molecular markers. Chondrocyte hypertrophy with upregulation of these genes was attenuated by administration of olmesartan, an AT1R blocker, but not by hydralazine. Moreover, Ang II infusion significantly suppressed apoptosis of chondrocytes, accompanied by significant induction of mRNA expression of bcl-2 and bcl-xL. Olmesartan, but not hydralazine, significantly attenuated the reduction of apoptotic cells and the increase in anti-apoptotic genes induced by Ang II infusion. Overall, the present study demonstrated that Ang II promoted hypertrophic differentiation of chondrocytes and reduced apoptosis of hypertrophic chondrocytes independently of high blood pressure. The present data indicate the role of Ang II in cartilage, and might provide a new concept for treatment of cartilage diseases. PMID- 25693859 TI - Safety and efficacy of LCZ696, a first-in-class angiotensin receptor neprilysin inhibitor, in Japanese patients with hypertension and renal dysfunction. AB - This 8-week, multi-center, open-label study assessed the safety and efficacy of LCZ696, a first-in-class angiotensin receptor neprilysin inhibitor, in Japanese patients with hypertension and renal dysfunction. Patients (n=32) with mean sitting systolic blood pressure (msSBP) ?140 mm Hg (after a 2-5-week washout of previous antihypertensive medications) and estimated glomerular filtration rate (eGFR) ?15 and <60 ml min(-1) 1.73 m(-2) received LCZ696 100 mg with an optional titration to 200 and 400 mg in a sequential manner starting from Week 2 in patients with inadequate BP control (msSBP ?130 mm Hg and mean sitting diastolic blood pressure (msDBP) ?80 mm Hg) and without safety concerns. Safety was assessed by monitoring and recording all adverse events (AEs) and change in potassium and creatinine. Efficacy was assessed as change from baseline in msSBP/msDBP. The mean baseline BP was 151.6/86.9 mm Hg, urinary albumin/creatinine ratio (UACR) geometric mean was 7.3 mg mmol(-1) and eGFR was ?30 and <60 in 25 (78.1%) patients and was ?15 and <30 in 7 (21.9%) patients. Fourteen (43.8%) patients reported at least one AE, which were mild in severity. No severe AEs or deaths were reported. There were no clinically meaningful changes in creatinine, potassium, blood urea nitrogen and eGFR. The geometric mean reduction in UACR was 15.1%, and the mean reduction in msSBP and msDBP was 20.5+/-11.3 and 8.3+/-6.3 mm Hg, respectively, from baseline to Week 8 end point. LCZ696 was generally safe and well tolerated and showed effective BP reduction in Japanese patients with hypertension and renal dysfunction without a decline in renal function. PMID- 25693860 TI - Characterisation of the metabolites of an antibacterial endophyte Botryodiplodia theobromae Pat. of Dracaena draco L. by LC-MS/MS. AB - Botryodiplodia theobromae Pat. belongs to the endophytic fungi that live within the tissues of medicinal plants and produce bioactive natural products. The endophyte was isolated from the leaves of Dracaena draco L. The LC-MS-based metabolite fingerprinting of the ethyl acetate extract of B. theobromae with antibacterial activity led to the identification of 13 metabolites pertaining to various classes: dipeptides (maculosin and L,L-cyclo(leucylprolyl), alkaloid (norharman), coumarin and isocoumarins (bergapten, meranzin and monocerin), sesquiterpene (dihydrocumambrin A), aldehyde (formyl indanone), fatty alcohol (halaminol A) and fatty acid amide (palmitoleamide, palmitamide, capsi-amide and oleamide). This study reports for the first time, the LC-MS and LC-MS/MS identification of 13 known bioactive metabolites from the antibacterial ethyl acetate extract of B.theobromae isolated from the leaves of D. draco L. PMID- 25693861 TI - Aetiological stratification as a conceptual framework for gene-by-environment interaction research in psychiatry. AB - It has been argued that gene-by-environment interactions (G * E) research is unlikely to progress knowledge about psychiatric disorders, in contrast to genome wide association (GWA) studies. However, G * E approaches are not alternatives for gene-hunting but a way to identify genetic and biological mechanisms within subgroups of patients exposed to a similar aetiological (environmental) factor via a process of 'aetiological stratification'. This is important as diagnostic categories targeted by GWA studies are inherently heterogeneous and lack biological validity. Aetiological stratification builds on examining possible phenotypic and/or molecular specificity associated with exposure to the environmental factor across multiple potentially relevant disorders, combined with efforts to identify an underlying biological substrate. G * E hypotheses within this framework investigate (1) which genes influence the degree to which individuals develop identified biological alterations that link environmental exposure to specific phenotypic and/or molecular characteristics within or across psychiatric disorders and (2) which genes are implicated in determining the development of psychopathology once this biological alteration has been brought about. As gene-hunting is not a goal in itself, the examination of pathway and/or polygenic risk scores may be more informative than the examination of individual markers, at the same time reducing multiple testing and the associated risk of spurious findings. PMID- 25693862 TI - Neurovascular distribution within the abdominal head of the pectoralis major muscle: Application to breast and flap surgery. AB - The abdominal head of the pectoralis major (AHPM) is important in cosmetic and flap surgeries. Few studies have reported on its neurovascular entry points and distribution patterns. We aimed to determine the entry points and distribution patterns of the neurovascular structures within the AHPM. Thirty-two hemithoraxes were dissected, and the distribution patterns of the neurovascular structures were classified into several categories. The neurovascular entry points were measured at the horizontal line passing through the jugular notch (x-axis) and the midclavicular line (y-axis). The AHPM was innervated by the communication branches of the medial pectoral nerve (MPN) and the lateral pectoral nerve (LPN) in 78.1% of the specimens and of the MPN without the communication branches in 21.9%. All the LPNs had communication branches, which could be classified as independent in 46.9% of the samples, with the MPN in 21.9%, and with the LPN in 9.3%. The blood supply of the AHPM was composed of branches from the lateral thoracic artery (LTA) in 62.5% of the specimens, the thoracoacromial artery (TA) in 15.6%, and the LTA with the TA in 21.9%. The mean distance of the entry point was 6.3 cm +/- 1.3 cm lateral to the y-axis, 8.1 cm +/- 3.3 cm below the x-axis in the nerves, 6.5 cm +/- 1.2 cm lateral to the y-axis, and 8.6 cm +/- 3.0 cm below the x-axis in the arteries. This study defined the average neurovascular entry point and distribution pattern in detail using standard lines to enable the AHPM to be better understood. PMID- 25693863 TI - Bird predation selects for wing shape and coloration in a damselfly. AB - Wing shape is related to flight performance, which is expected to be under selection for improving flight behaviours such as predator avoidance. Moreover, wing conspicuousness, usually involved in sexual selection processes, is also relevant in terms of predation risk. In this study, we examined how predation by a passerine bird, the white wagtail Motacilla alba, selects wing shape and wing colour patch size in males of the banded demoiselle Calopteryx splendens. The wing colour patch is intra- and intersexually selected in the study species. In a field study, we compared wings of live damselflies to wings of predated damselflies which are always discarded after predation. Based on aerodynamic theory and a previous study on wing shape of territorial tactics in damselflies, we predicted an overall short and broad wing, with a concave front margin shape to be selected by predation. This shape would be expected to improve escaping ability. Moreover, we predicted that wing patch size should be negatively selected by predation. We found that selection operated differently on fore- and hindwings. In contrast to our predictions, predation favoured a slender general forewing shape. However, the predicted wing shape was favoured in hindwings. We also found selection favouring a narrower wing colour patch. Our results suggest different roles of fore- and hindwings in flight, as previously suggested for Calopteryx damselflies and shown for butterflies and moths. Forewings would be more involved in sustained flight and hindwings in flight manoeuvrability. Our results differ somehow from a recently published work in the same study system, but using another population, suggesting that selection can fluctuate across space, despite the simplicity of this predator-prey system. PMID- 25693865 TI - Key factors of susceptibility to anti-tuberculosis drug-induced hepatotoxicity. AB - Anti-tuberculosis drug-induced hepatotoxicity (ATDH) is one of the leading adverse drug reactions during the course of tuberculosis treatment and poses a considerable challenge to clinicians and researchers. Previous studies have revealed the important contribution of drug metabolism and transporter enzymes to the complexity of ATDH. The emerging roles of immune response and oxidative stress resulting from reactive metabolite in the development of ATDH have also gained attention recently. Both non-genetic and genetic factors can have a significant impact on the susceptibility to ATDH, consequently altering the risk of hepatotoxicity in susceptible individuals. Non-genetic risk factors associated with ATDH include host factors, environment factors and drug-related factors. Genetic factors contributing to the susceptibility of ATDH involve genetic variations in bioactivation/toxification pathways via the cytochrome P450 enzymes (phase I), detoxification reactions by N-acetyl transferase 2, glutathione S transferase and uridine diphosphate glucuronosyltransferase (phase II) and hepatic transport (phase III), together with immunological factors and antioxidant response. Better understanding of these factors may help to predict and prevent the occurrence of ATDH and develop more effective treatments. This review focuses on the mechanisms of ATDH and the key factors of susceptibility associated with drug metabolism, hepatic transport, immune response and oxidative stress. PMID- 25693864 TI - Diquat causes caspase-independent cell death in SH-SY5Y cells by production of ROS independently of mitochondria. AB - Evidence indicates that Parkinson's disease (PD), in addition to having a genetic aetiology, has an environmental component that contributes to disease onset and progression. The exact nature of any environmental agent contributing to PD is unknown in most cases. Given its similarity to paraquat, an agrochemical removed from registration in the EU for its suspected potential to cause PD, we have investigated the in vitro capacity of the related herbicide Diquat to cause PD like cell death. Diquat showed greater toxicity towards SH-SY5Y neuroblastoma cells and human midbrain neural cells than paraquat and also MPTP, which was independent of dopamine transporter-mediated uptake. Diquat caused cell death independently of caspase activation, potentially via RIP1 kinase, with only a minor contribution from apoptosis, which was accompanied by enhanced reactive oxygen species production in the absence of major inhibition of complex I of the mitochondrial respiratory chain. No changes in alpha-synuclein expression were observed following 24-h or 4-week exposure. Diquat may, therefore, kill neural tissue by programmed necrosis rather than apoptosis, reflecting the pathological changes seen following high-level exposure, although its ability to promote PD is unclear. PMID- 25693866 TI - A virtual reality-based method of decreasing transmission time of visual feedback for a tele-operative robotic catheter operating system. AB - BACKGROUND: An Internet-based tele-operative robotic catheter operating system was designed for vascular interventional surgery, to afford unskilled surgeons the opportunity to learn basic catheter/guidewire skills, while allowing experienced physicians to perform surgeries cooperatively. Remote surgical procedures, limited by variable transmission times for visual feedback, have been associated with deterioration in operability and vascular wall damage during surgery. METHODS: At the patient's location, the catheter shape/position was detected in real time and converted into three-dimensional coordinates in a world coordinate system. At the operation location, the catheter shape was reconstructed in a virtual-reality environment, based on the coordinates received. The data volume reduction significantly reduced visual feedback transmission times. RESULTS: Remote transmission experiments, conducted over inter-country distances, demonstrated the improved performance of the proposed prototype. The maximum error for the catheter shape reconstruction was 0.93 mm and the transmission time was reduced considerably. CONCLUSIONS: The results were positive and demonstrate the feasibility of remote surgery using conventional network infrastructures. PMID- 25693867 TI - Effects of Knowledge on Attitude Formation and Change Toward Genetically Modified Foods. AB - In three waves, this study investigates the impact of risk and benefit knowledge on attitude formation toward genetically modified (GM) foods as well as the moderating effect of knowledge level on attitude change caused by receiving information. The data in Wave 1 (N = 561) demonstrate that both benefit and risk knowledge either directly contribute to attitude formation or indirectly affect attitudes through the mediating roles of benefit and risk perceptions. Overall, benefit and risk knowledge affect consumer attitudes positively and negatively, respectively. In Wave 2, 486 participants from Wave 1 were provided with information about GM foods, and their attitudes were assessed. Three weeks later, 433 of these participants again reported their attitudes. The results indicate that compared with the benefit and mixed information, risk information has a greater and longer lasting impact on attitude change, which results in lower acceptance of GM foods. Furthermore, risk information more strongly influences participants with a higher knowledge level. The moderating effect of knowledge on attitude change may result from these participants' better understanding of and greater trust in the information. These findings highlight the important role of knowledge in attitude formation and attitude change toward GM foods as well as the necessity of considering the determinants of attitude formation in attitude change studies. PMID- 25693868 TI - Following the compositional changes of fresh grape skin cell walls during the fermentation process in the presence and absence of maceration enzymes. AB - Cell wall profiling technologies were used to follow compositional changes that occurred in the skins of grape berries (from two different ripeness levels) during fermentation and enzyme maceration. Multivariate data analysis showed that the fermentation process yielded cell walls enriched in hemicellulose components because pectin was solubilized (and removed) with a reduction as well as exposure of cell wall proteins usually embedded within the cell wall structure. The addition of enzymes caused even more depectination, and the enzymes unravelled the cell walls enabling better access to, and extraction of, all cell wall polymers. Overripe grapes had cell walls that were extensively hydrolyzed and depolymerized, probably by natural grape-tissue-ripening enzymes, and this enhanced the impact that the maceration enzymes had on the cell wall monosaccharide profile. The combination of the techniques that were used is an effective direct measurement of the hydrolysis actions of maceration enzymes on the cell walls of grape berry skin. PMID- 25693869 TI - The Impact of Near-Universal Insurance Coverage on Breast and Cervical Cancer Screening: Evidence from Massachusetts. AB - This paper investigates the effect of expansion to near-universal health insurance coverage in Massachusetts on breast and cervical cancer screening. We use data from 2002 to 2010 to compare changes in receipt of mammograms and Pap tests in Massachusetts relative to other New England states. We also consider the effect specifically among low-income women. We find positive effects of Massachusetts health reform on cancer screening, suggesting a 4 to 5% increase in mammograms and 6 to 7% increase in Pap tests annually. Increases in both breast and cervical cancer screening are larger 3 years after the implementation of reform than in the year immediately following, suggesting that there may be an adjustment or learning period. Low-income women experience greater increases in breast and cervical cancer screening than the overall population; among women with household income less than 250% of the federal poverty level, mammograms increase by approximately 8% and Pap tests by 9%. Overall, Massachusetts health reform appears to have increased breast and cervical cancer screening, particularly among low-income women. Our results suggest that reform was successful in promoting preventive care among targeted populations. PMID- 25693870 TI - Italian normative data for the Battery for Visuospatial Abilities (TERADIC). AB - Battery for Visuospatial Abilities (BVA, known in Italy as TeRaDiC) has been developed to analyse putative basic skills involved in drawing and to plan and monitor outcomes after rehabilitation of visuoconstructional disorders. It encompasses eight tasks assessing both simple "perceptual" abilities, such as line length and line orientation judgments and complex "representational" abilities, such as mental rotation. The aim of present study was to provide normative values for BVA collected in a wide sample of healthy Italian subjects. Three hundred seventeen healthy Italian subjects (173 women and 144 men) of different age classes (age range, 40-95 years) and education level (from primary to university), with a normal score on Mini Mental State Examination, completed BVA/TeRaDiC. Multiple linear regression analysis revealed that age and education significantly influenced performance on most tests of the BVA/TeRaDiC; only line length judgment was not affected by educational level. Gender significantly affected line orientation judgment and mental rotation, with an advantage for males in both tests. From the derived linear equations, a correction grid for adjusting BVA/TeRaDiC raw scores was built. Using a non-parametric technique, inferential cut-off scores were determined and equivalent scores computed. The present study provided Italian normative data for the BVA/TeRaDiC useful for both clinical and research purposes. PMID- 25693871 TI - Effects of slow repetitive transcranial magnetic stimulation in patients with corticobasal syndrome. AB - Corticobasal syndrome is characterized by asymmetric cortical sensorimotor dysfunction and parkinsonism; an altered cortical excitability has been reported. We explored with transcranial magnetic stimulation the motor cortical excitability in corticobasal syndrome, and the effects of slow repetitive transcranial magnetic stimulation. With transcranial magnetic stimulation, we studied two corticobasal syndrome patients. We determined bilaterally from the first dorsal interosseous muscle: relaxed threshold, and contralateral and ipsilateral silent period. We also evaluated the contralateral silent period after active/sham slow repetitive transcranial magnetic stimulation on the most affected side. At T0 the silent period was bilaterally short. On the most affected side, active slow repetitive transcranial magnetic stimulation induced a short lasting prolongation of the contralateral silent period. In corticobasal syndrome, transcranial magnetic stimulation showed a reduction cortical inhibitory phenomenon potentially reversed transiently by slow repetitive transcranial magnetic stimulation. PMID- 25693872 TI - Probing the nature of upconversion nanocrystals: instrumentation matters. AB - Probing the nature of nanocrystalline materials such as the surface state, crystal structure, morphology, composition, optical and magnetic characteristics is a crucial step in understanding their chemical and physical performance and in exploring their potential applications. Upconversion nanocrystals have recently attracted remarkable interest due to their unique nonlinear optical properties capable of converting incident near-infrared photons to visible and even ultraviolet emissions. These optical nanomaterials also hold great promise for a broad range of applications spanning from biolabeling to optoelectronic devices. In this review, we overview the instrumentation techniques commonly utilized for the characterization of upconversion nanocrystals. A considerable emphasis is placed on the analytical tools for probing the optical properties of the luminescent nanocrystals. The advantages and limitations of each analytical technique are compared in an effort to provide a general guideline, allowing optimal conditions to be employed for the characterization of such nanocrystals. Parallel efforts are devoted to new strategies that utilize a combination of advanced emerging tools to characterize such nanosized phosphors. PMID- 25693873 TI - Quantification of neocortical ratios in stem primates. AB - Extant euprimates (=crown primates) have a characteristically expanded neocortical region of the brain relative to that of other mammals, but the timing of that expansion in their evolutionary history is poorly resolved. Examination of anatomical landmarks on fossil endocasts of Eocene euprimates suggests that significant neocortical expansion relative to contemporaneous mammals was already underway. Here, we provide quantitative estimates of neocorticalization in stem primates (plesiadapiforms) relevant to the question of whether relative neocortical expansion was uniquely characteristic of the crown primate radiation. Ratios of neocortex to endocast surface areas were calculated for plesiadapiforms using measurements from virtual endocasts of the paromomyid Ignacius graybullianus (early Eocene, Wyoming) and the microsyopid Microsyops annectens (middle Eocene, Wyoming). These data are similar to a published estimate for the plesiadapid, Plesiadapis tricuspidens, but contrast with those calculated for early Tertiary euprimates in being within the 95% confidence intervals for archaic mammals generally. Interpretation of these values is complicated by the paucity of sampled endocasts for older stem primates and euarchontogliran outgroups, as well as by a combination of effects related to temporal trends, allometry, and taxon-unique specializations. Regardless, these results are consistent with the hypothesis that a shift in brain organization occurred in the first euprimates, likely in association with elaborations to the visual system. PMID- 25693874 TI - [Ocular lymphoma: diagnosis and therapy]. PMID- 25693875 TI - [Lymphoma of the ocular adnexa]. AB - BACKGROUND: Lymphomas of the ocular adnexa are heterogeneous and demonstrate a wide range of clinical, histological, immunohistochemical and molecular genetic characteristics. AIM: The aim of this article is to give an overview of the interdisciplinary diagnostics and individually adapted lymphoma subtype-based therapy. DIAGNOSTICS: Depending on the lymphoma localisation, i.e. whether in the eyelid, the conjunctiva or in the orbit, a photograph or a radiological scan is required to record the tumor extent. Visual function is more likely to be impacted when the lymphoma arises in the posterior orbit, close to the optic nerve and imaging diagnostics are therefore necessary. Histological investigations are essential for confirming the lymphoma diagnosis and give information about the particular subtype, which in turn will determine subsequent patient management, Clinical staging investigations for determining the systemic extent of the lymphoma manifestation (e.g. imaging, blood analyses as well as bone marrow biopsy) are mandatory. THERAPY: External beam radiation, local and systemic chemotherapy or in some cases antibiotics are treatment options after surgical excision in isolated ocular adnexal lymphoma. The TNM classification of the American Joint Committee on Cancer or the Ann Arbor staging system, as well as the guidelines of the German Society of Hematology and Medical Oncology are all tools to aid the choice of the appropriate individually adapted therapy for systemic disease, which includes psycho-oncological care. PMID- 25693876 TI - [Diagnostics and treatment of choroidal lymphoma]. AB - Choroidal lymphoma is a rare disease and can be classified into primary and secondary choroidal lymphomas. Primary choroidal lymphoma is a low-grade extranodal marginal zone B-cell lymphoma and secondary choroidal lymphomas present ocular manifestations of disseminated systemic lymphomas. Typical clinical features of choroidal lymphoma are multifocal, yellow-whitish choroidal infiltrates. The vitreous body is usually clear and cell-free. Choroidal lymphoma has a tendency to extend through the sclera. In contrast to primary choroidal lymphoma, which is more often unilateral, does not show signs of anterior segment involvement and has a slow progression, secondary choroidal lymphoma is more often bilateral, has a rapidly progressive course with anterior segment and vitreous involvement and belongs to the high-grade lymphomas. The definitive diagnosis of choroidal lymphoma can only be confirmed by histopathological examination of biopsy tissue. The choroidal biopsy is the gold standard in the diagnostics of choroidal lymphoma. To date, no standardized treatment for choroidal lymphoma has been established. The treatment modalities include external beam radiotherapy, immunotherapy with rituximab and chemotherapy. The prognosis for survival of primary choroidal lymphoma is usually good. The prognosis of secondary choroidal lymphoma depends on the malignancy grade of systemic lymphoma. PMID- 25693877 TI - Iron-catalyzed asymmetric hydrosilylation of 1,1-disubstituted alkenes. AB - The highly regio- and enantioselective iron-catalyzed anti-Markovnikov hydrosilylation of 1,1-disubstituted aryl alkenes was developed using iminopyridine oxazoline ligands to afford chiral organosilanes. Additional derivatization of these products lead to chiral organosilanols, cyclic silanes, phenol derivatives, and 3-substituted 2,3-dihydrobenzofurans. PMID- 25693878 TI - Carbon dots (C-dots) from cow manure with impressive subcellular selectivity tuned by simple chemical modification. AB - Improved cellular selectivity for nucleoli staining was achieved by simple chemical modification of carbon dots (C-dots) synthesized from waste carbon sources such as cow manure (or from glucose). The C-dots were characterized and functionalized (amine-passivated) with ethylenediamine, affording amide bonds that resulted in bright green fluorescence. The new modified C-dots were successfully applied as selective live-cell fluorescence imaging probes with impressive subcellular selectivity and the ability to selectively stain nucleoli in breast cancer cell lineages (MCF-7). The C-dots were also tested in four other cellular models and showed the same cellular selection in live-cell imaging experiments. PMID- 25693879 TI - Cost of acute stroke care for patients with atrial fibrillation compared with those in sinus rhythm. AB - BACKGROUND: Atrial fibrillation (AF) is a major risk factor for stroke. Cost effectiveness studies of anticoagulants for stroke prevention in AF rarely utilise AF-stroke-specific cost data in their analyses, as data are limited. Data that exist do not account for AF found on prolonged cardiac monitoring after stroke, further underestimating the clinical and economic burden of AF-stroke. OBJECTIVE: Our objective was to investigate differences in direct medical costs of acute stroke care among patients with and without AF. METHODS: Data were prospectively collected from 213 consecutive patients with confirmed stroke (196 ischaemic [IS], 17 intracranial haemorrhage [ICH]), admitted to a UK district general hospital between November 2011 and October 2012. Sociodemographic, clinical and cardiac monitoring characteristics were recorded, and resource use was calculated using a 'bottom-up' approach. Univariate and multivariate stepwise regressions were performed to identify predictors of direct cost. RESULTS: Among patients with IS, 73 had AF (37%). These patients were older, experienced greater stroke severity, lengths of hospitalisation, inpatient mortality and discharge to institutionalised care than those without AF. Mean acute care costs for the year 2012 were L6,978 (standard deviation [SD] 6,769, range 510-36,952). Mean (SD) costs were significantly higher for patients with AF than for those without (L9,083 [7,381] vs. L5,729 [6,071], p = <0.001). AF independently predicted acute care cost along with history of heart failure and stroke severity. The adjusted independent effect of having AF on costs was an additional L2,173 (95% confidence interval 91-4,254; p = 0.041). Costs for patients with an ICH did not differ according to cardiac rhythm. CONCLUSION: Direct medical costs of acute stroke care for patients with AF may be 50% greater than for patients without. Economic studies should take this into account to ensure the benefits of anticoagulants are not underestimated. PMID- 25693880 TI - The Archiv fur Ohrenheilkunde (Archive of Otology): a structural analysis of the first 50 years (1864-1914). AB - In 1864, Anton von Troltsch in Wurzburg, Hermann Schwartze in Halle/Saale, and Adam Politzer in Vienna founded the Archiv fur Ohrenheilkunde (Archive of Otology), the ancestor of the European Archives of Oto-Rhino-Laryngology and Head and Neck. It was the world's first journal solely devoted to otology, and thus to otorhinolaryngology. The aim of this study was to analyse the structure of this journal and its contents during the first 50 years of its publication, until it definitively became an otorhinolaryngological journal in 1915. A total of 2,271 articles were registered during this time. They were classified according to content topic, article type, and the number of figures and graphs that they contained. Almost three-quarters of the articles were related to purely otological topics, as implied by the journal's title. Until the turn of the twentieth century, the majority of the articles were original papers or case reports. The number of original papers declined over the decades in favour of case reports. One-third of each volume usually consisted of a vast variety of items, such as congress announcements, conference proceedings, and book reviews. The journal also maintained a wide variety of scientific and current social and political subjects. Otological reviews and conference proceedings were key landmarks of the journal. All of these various papers provided an overview of the historical organisation and development of otology between 1864 and 1914. At that time, the Archiv fur Ohrenheilkunde was a leading national and international journal. PMID- 25693881 TI - Orderly arranged fluorescence dyes as a highly efficient chemiluminescence resonance energy transfer probe for peroxynitrite. AB - Chemiluminescence (CL) probes for reactive oxygen species (ROS) are commonly based on a redox reaction between a CL reagent and ROS, leading to poor selectivity toward a specific ROS. The energy-matching rules in the chemiluminescence resonance energy transfer (CRET) process between a specific ROS donor and a suitable fluorescence dye acceptor is a promising method for the selective detection of ROS. Nevertheless, higher concentrations of fluorescence dyes can lead to the intractable aggregation-caused quenching effect, decreasing the CRET efficiency. In this report, we fabricated an orderly arranged structure of calcein-sodium dodecyl sulfate (SDS) molecules to improve the CRET efficiency between ONOOH* donor and calcein acceptor. Such orderly arranged calcein-SDS composites can distinguish peroxynitrite (ONOO(-)) from a variety of other ROS owing to the energy matching in the CRET process between ONOOH* donor and calcein acceptor. Under the optimal experimental conditions, ONOO(-) could be assayed in the range of 1.0-20.0 MUM, and the detection limit for ONOO(-) [signal-to-noise ratio (S/N) = 3] was 0.3 MUM. The proposed strategy has been successfully applied in both detecting ONOO(-) in cancer mouse plasma samples and monitoring the generation of ONOO(-) from 3-morpholinosydnonimine (SIN-1). Recoveries from cancer mouse plasma samples were in the range of 96-105%. The success of this work provides a unique opportunity to develop a CL tool to monitor ONOO(-) with high selectivity in a specific manner. Improvement of selectivity and sensitivity of CL probes holds great promise as a strategy for developing a wide range of probes for various ROS by tuning the types of fluorescence dyes. PMID- 25693882 TI - Cementless femoral revision in patients with a previous cemented prosthesis. AB - PURPOSE: The aim of this study was to evaluate the effectiveness associated with the use of the cementless femoral revision in patients with a previous cemented prosthesis. METHODS: This study reviewed 92 revision femoral stem performed by a single senior surgeon between January 2006 and December 2012 at our institution. All patients complained of unbearable pain before operation, of which 19 cases had extensively porous-coated revision in Paprosky type I or II femoral defects and 73 had modular tapered revision in type IIIA or IIIB defects. All patients had clinical and radiographic follow-up for an average of 3.9 years (range two to seven years), with a mean age of 62.5 years (range 46-86 years) at surgery. RESULTS: There was no re-revision for loosening. Complications included delayed wound healing in two (2.2 %) patients, dislocation in four (4.3 %), intra operative femoral fracture in 11 (12.0 %), and periprosthetic fracture postoperatively in three (3.3 %).The average Harris hip scores (HHS) increased from 38.1 (range 20-70) pre-operatively to 82.5 (range 40-95), and the average visual analog scores (VAS) decreased from 8 .3 (range 4-10) pre-operatively to 1.5 (range 0-5) at final follow-up. Radiographic results including stress shielding, subsidence of the stems, bone ingrowth and prosthesis loosening showed that prostheses were stably fixed postoperatively. CONCLUSION: This supported that cementless fixation, with the use of extensively porous-coated stems or modular tapered stems, was efficient in patients with a previous failed cemented stem. PMID- 25693883 TI - Open unstable metaphyseo-diaphyseal fractures of the tibia in adolescents: treatment by flexible intramedullary nails augmented by external fixator. AB - INTRODUCTION: The treatment of open and unstable metaphyseo-diaphyseal fractures of the tibia in adolescents is challenging. It is important to choose a fixation method that can maintain alignment, allow wound care and not violate the growth plate. The aim of this work was to evaluate the efficacy of using flexible intramedullary nails (FIN) augmented by external fixator (EF) in the management of such fractures. PATIENTS AND METHODS: A total of 26 males, with a mean age of 14.08 years and average body weight of 49.8 kg, presented with open metaphyseo diaphyseal tibial fractures. All cases were treated using FIN augmented by mono lateral EF. The fractures were located at the upper third in 17 cases and at the lower third in nine cases. The fracture pattern was spiral in eight cases, oblique in seven and multi-fragmentary in 11. The results were evaluated according to the scoring system for femoral TENs. RESULTS: All fractures united primarily after an average eight to 12 weeks with no evident angular deformity or limb-length discrepancy. None of the cases required cast immobilization or revision procedure. Twenty patients had excellent results, six patients showed good results and none had poor results. Fracture characteristics as well as patients' characteristics had no statistically significant effect (p > 0.005) on the final end results. CONCLUSIONS: The use of FIN augmented by EF is a good alternative in the management of open metaphyseo-diaphyseal tibial fractures in adolescents. This fixation provides more stability, allows easy access to the wound and early patients' ambulation. PMID- 25693884 TI - Postoperative change in the length and extrusion of the medial meniscus after anterior cruciate ligament reconstruction. AB - PURPOSE: The medial meniscus is a secondary stabilizer of anterior tibial translation in anterior cruciate ligament (ACL)-deficient knees. ACL reconstruction effectively restores an increased anterior tibial translation in the ACL-deficient knee. However, knee osteoarthritis sometimes develops in ACL reconstructed patients during a long-term follow-up period. We hypothesized that the medial meniscal position would be different between the ACL-deficient and reconstructed knees. The aim of this study was to investigate pre-operative and postoperative location of the medial meniscus in patients who underwent ACL reconstruction. METHODS: ACL-reconstructed knees (28 knees) and normal knees (27 knees) were investigated. Medial tibial plateau length (MTPL) and medial tibial plateau width (MTPW) were determined using radiographic images. Magnetic resonance imaging (MRI)-based medial meniscal length (MML), medial meniscal width (MMW), and medial meniscal extrusion (MME) were measured. Postoperative change in the MML, MMW, and MME were evaluated and compared with those in normal knees. RESULTS: No significant differences between the ACL-deficient (pre-operative) and normal groups were noted. The ACL-reconstructed (postoperative) group showed an increase in the MML, in the percentage of the MML (%MML = 100 MML/MTPL), and in the MME. Significant differences between postoperative and normal groups were observed in the MML, %MML, and MME. MMW and MMW percentage (100 MMW/MTPW) were similar in all groups. CONCLUSIONS: The anteroposterior length and radial extrusion of the medial meniscus increased after ACL reconstruction. Transposition of the medial meniscus may be a possible cause of developing further degenerative knee joint disorders after ACL reconstruction. PMID- 25693885 TI - The oncolytic virus, pelareorep, as a novel anticancer agent: a review. AB - Pelareorep (REOLYSIN(r)) is an investigational new drug, a proprietary formulation consisting of a live, replication-competent, naturally occurring Reovirus Type 3 Dearing strain. Through several preclinical studies it was determined that reovirus can exhibit profound cytotoxic effects on cancer cells predominantly with an activated RAS-signalling pathway. Moreover, it was discovered that reoviruses can "hitchhike" on peripheral blood mononuclear cells and dendritic cells, thereby evading neutralizing antibodies of the host immune system. Cell carriage, targeted delivery, triggering host immune response and other inherent characteristics of the reovirus led to its further advancement into cancer therapy. When injected into Sprague-Dawley rats, the viral routes of clearance, predominantly through the spleen and liver, remained consistent with earlier studies. Toxicology findings were considered incidental and not associated with pelareorep when tested in animal models. Pelareorep demonstrated a high level of homogeneity at the amino acid level and genetic stability when compared to the master and working virus banks. The drug is manufactured in a 100 L bioreactor after which it is purified and formulated for use in pre-clinical, clinical and research studies. Over the past few decades, we have witnessed a paradigm shift from conventional therapy to the conceivable use of oncolytic viruses for the treatment of cancer. This review will detail pre-clinical evidence of anticancer activity of pelareorep that has led to extensive clinical development. Several Phase I-II clinical trials have been completed or are ongoing in cancer patients on a broad spectrum of solid tumors and hematologic malignancies. PMID- 25693886 TI - Phase-I dose finding and pharmacokinetic study of the novel hydrophilic camptothecin ST-1968 (namitecan) in patients with solid tumors. AB - PURPOSE: This is a first-in-human, phase I, dose-escalation study to determine the maximum tolerated dose (MTD) of intravenous, flat-dosed ST-1968 (namitecan), a new hydrophilic camptothecan derivative. METHODS: Namitecan was administered intravenously over 2 h on day 1 and day 8 every 21 days (D1-D8-Q21D), starting at a flat dose of 2.5 mg, and increased according to a 3 + 3 cohort design. Due to frequent skipping of day 8 dosing for cytopenias, the study was expanded to test namitecan dosing on day 1 every 21 days (D1-Q21) at a starting dose of 17.5 mg. Major dose-limiting toxicity (DLT) was defined as grade (G) 4 neutropenia persisting >5 days, febrile neutropenia, G3 thrombocytopenia or G2 non hematological toxicity. RESULTS: Thirty-four patients were included into the D1 D8-Q21D group (2.5, 5, 10, 15, 17.5, 20 mg dosing cohorts), 29 patients into the D1-21D group (17.5, 20, 23, 27, 30 mg dosing cohorts). Neutropenia was the DLT in both groups, with 15 mg being defined as the recommended dose (RD) for the D1-D8 Q21D group, and 23 mg for the D1-Q21D group. Non-hematological toxicity was negligible. One patient with endometrial cancer in the D1-D8-Q21D group and one patient with cholangiocellular carcinoma in the D1-Q21D group experienced a partial remission. Namitecan exhibited fully dose-proportional pharmacokinetics. CONCLUSIONS: This study demonstrates clinical safety, favourable pharmacokinetics and preliminary antitumor activity of the novel hydrophilic camptothecin analogue namitecan in patients with heavily pretreated solid malignancies, when given either on a 2 out of 3 weeks or 3-weekly regimen. PMID- 25693887 TI - Recent dramatic evolution of the Journal of Gastroenterology (JG): a note from current Editorial Director and former Editor-in-Chief of JG. PMID- 25693888 TI - Hyaluronic acid-fabricated nanogold delivery of the inhibitor of apoptosis protein-2 siRNAs inhibits benzo[a]pyrene-induced oncogenic properties of lung cancer A549 cells. AB - Benzo[a]pyrene (BaP), a component of cooking oil fumes (COF), promotes lung cancer cell proliferation and survival via the induction of inhibitor of apoptosis protein-2 (IAP-2) proteins. Thus knockdown of IAP-2 would be a promising way to battle against lung cancer caused by COF. Functionalized gold nanoparticle (AuNP) is an effective delivery system for bio-active materials. Here, biocompatible hyaluronic acid (HA) was fabricated into nanoparticles to increase the target specificity by binding to CD44-over-expressed cancer cells. IAP-2-specific small-interfering RNA (siRNAs) or fluorescein isothiocyanate (FITC) were then incorporated into AuNP-HA. Conjugation of IAP-2 siRNA into AuNPs HA was verified by the UV-vis spectrometer and Fourier transform infrared spectrometer. Further studies showed that AuNP-HA/FITC were effectively taken up by A549 cells through CD44-mediated endocytosis. Incubation of BaP-challenged cells with AuNP-HA-IAP-2 siRNAs silenced the expression of IAP-2, decreased cell proliferation and triggered pronounced cell apoptosis by the decrease in Bcl-2 protein and the increase in Bax protein as well as the active form of caspases-3. The BaP-elicited cell migration and enzymatic activity of the secreted matrix metalloproteinase-2 were also substantially suppressed by treatment with AuNP-HA IAP-2 siRNAs. These results indicated that IAP-2 siRNAs can be efficiently delivered into A549 cells by functionalized AuNP-HA to repress the IAP-2 expression and BaP-induced oncogenic events, suggesting the potential therapeutic application of IAP-2 siRNA or other siRNA-conjugated AuNP-HA composites to COF induced lung cancer and other gene-caused diseases in the future. PMID- 25693889 TI - Optimizing the glutamatergic challenge model for psychosis, using S+ -ketamine to induce psychomimetic symptoms in healthy volunteers. AB - The psychomimetic effects that occur after acute administration of ketamine can constitute a model of psychosis and antipsychotic drug action. However, the optimal dose/concentration has not been established and there is a large variety in outcome measures. In this study, 36 healthy volunteers (21 males and 15 females) received infusions of S(+)-ketamine or placebo to achieve pseudo-steady state concentrations of 180 and 360 ng/mL during two hours. The target of 360 ng/mL induced increasingly more intensive effects than expected, and the targets were subsequently reduced to 120 and 240 ng/mL, which were considered tolerable. There was a clear, concentration-dependent psychomimetic effect as shown on all subscales of the positive and negative syndrome scale (e.g. positive subscale +43.7%, 95%CI 34.4-53.7%, p < 0.0001 for 120 ng/mL and +70.5%, 95%CI 59.0-82.8%, p < 0.0001 for 240 ng/mL) and different visual analogue scales. The startle reflex was inhibited (prepulse inhibition) by both main target concentrations to a similar extent, suggesting a maximum effect. Ketamine was found to constitute a robust model for induction of psychomimetic symptoms and the optimal concentration range for a drug interaction study would be between 100 and 200 ng/mL. PMID- 25693890 TI - Effects of glucose administration on category exclusion recognition. AB - Previous research has produced discrepant findings as to whether glucose administration effects lead to enhanced recollection or arise only under dual task conditions. The aim of the present research was to address these issues by firstly employing an alternative cognitively demanding paradigm that has been linked to hippocampal function, i.e. the Process Dissociation Procedure (PDP). A second aim was to use this paradigm to explore whether glucose affects qualitative aspects of memory function. To achieve these aims, the PDP task was administered to participants who had either consumed a glucose (25 g) or aspartame-sweetened control drink. Results demonstrated glucose facilitation effects only under difficult task conditions and with no such effect emerging for the process of recollection. The present results support the contention that the beneficial effects of glucose arise under hippocampally driven, cognitively demanding task conditions, and that this effect enhances quantitative but not qualitative aspects of recognition memory. PMID- 25693891 TI - Hyperfibrinolysis during liver transplantation is associated with bleeding. PMID- 25693892 TI - Pediatric Neurocritical Care: A Short Survey of Current Perceptions and Practices. AB - BACKGROUND: Although attention to neurologic injuries and illnesses in pediatric critical care is not new, a sub-specialized field of pediatric neurocritical care has only recently been recognized. Pediatric neurocritical care is an emerging area of clinical and investigative focus. Little is known about the prevalence of specialized pediatric neurocritical care services nor about perceptions regarding how it is impacting medical practice. This survey sought to capture perceptions about an emerging area of specialized pediatric neurocritical care among practitioners in intersecting disciplines, including pediatric intensivists, pediatric neurologits and pediatric neurosurgeons. METHODS: A web-based survey was distributed via email to members of relevant professional societies and groups. Survey responses were analyzed using descriptive statistics. Differences in responses between groups of respondents were analyzed using Chi-squared analysis where appropriate. MAIN RESULTS: Specialized clinical PNCC programs were not uncommon among the survey respondents with 20% currently having a PNCC service at their institution. Despite familiarity with this area of sub specialization among the survey respondents, the survey did not find consensus regarding its value. Overall, 46% of respondents believed that a specialized clinical PNCC service improves the quality of care of critically ill children. Support for PNCC sub-specialization was more common among pediatric neurologists and pediatric neurosurgeons than pediatric intensivists. This survey found support across specialties for creating PNCC training pathways for both pediatric intensivists and pediatric neurologists with an interest in this specialized field. CONCLUSIONS: PNCC programs are not uncommon; however, there is not clear agreement on the optimal role or benefit of this area of practice sub specialization. A broader dialog should be undertaken regarding the emerging practice of pediatric neurocritical care, the potential benefits and drawbacks of this partitioning of neurology and critical care medicine practice, economic and other practical factors, the organization of clinical support services, and the formalization of training and certification pathways for sub-specialization. PMID- 25693893 TI - Cooling Activity is Associated with Neurological Outcome in Patients with Severe Cerebrovascular Disease Undergoing Endovascular Temperature Control. AB - BACKGROUND: Neuroprotection through targeted temperature management is currently investigated in patients with severe brain injury in multiple trials. Feedback devices have been shown to precisely reach and maintain target temperature by constantly adjusting cooling activity. We analyzed the association between cooling activity expressed as cool bath temperatures and functional neurological outcome. METHODS: Data were retrospectively analyzed from a prospective randomized trial on controlled prophylactic normothermia (i.e., 36.5 degrees C) in patients with severe cerebrovascular disease. Body core temperature of patients who had been randomized to the endovascular group, was controlled using an endovascular cooling device. Cool bath temperature was analyzed over a period of 168 h. Functional neurological outcome was evaluated at 180 days using the modified Rankin Scale. RESULTS: 51 of 102 patients included were randomized to the endovascular group. Cool bath temperature data were available from 47/51 patients. Patients with lower cool bath temperatures reflecting high cooling activity had a more favorable neurological outcome at 180 days (mRS 0-2) than patients with low cooling activity (p < 0.05). We did not find a significant correlation between cool bath temperature and inflammatory markers. CONCLUSION: High cooling activity of an endovascular feedback device is associated with favorable outcome in patients with severe cerebrovascular disease. PMID- 25693894 TI - Tissue underlying the intestinal epithelium elicits proliferation of intestinal stem cells following cytotoxic damage. AB - The goals of this study were to document the proliferative response of intestinal stem cells (ISCs) during regeneration after damage from doxorubicin (DXR), and to characterize the signals responsible for ISC activation. To this end, jejuni from DXR-treated mice were harvested for histology, assessment of ISC numbers and proliferation by flow cytometry, crypt culture, and RNA analyses. Histology showed that crypt depth and width were increased 4 days after DXR. At this time point, flow cytometry on tissue collected 1 h after EdU administration revealed increased numbers of CD24(lo)UEA(-) ISCs and increased percentage of ISCs cycling. In culture, crypts harvested from DXR-treated mice were equally proliferative as those of control mice. Addition of subepithelial intestinal tissue (SET) collected 4 days after DXR elicited increased budding (1.4 +/- 0.3 vs. 5.1 +/- 1.0 buds per enteroid). Microarray analysis of SET collected 4 days after DXR revealed 1030 differentially expressed transcripts. Cross-comparison of Gene Ontology terms considered relevant to ISC activation pointed to 10 candidate genes. Of these, the epidermal growth factor (EGF) family member amphiregulin and the BMP antagonist chordin-like 2 were chosen for further study. In crypt culture, amphiregulin alone did not elicit significant budding, but amphiregulin in combination with BMP antagonism showed marked synergism (yielding 6.3 +/- 0.5 buds per enteroid). These data suggest a critical role for underlying tissue in regulating ISC behavior after damage, and point to synergism between amphiregulin and chordin-like 2 as factors which may account for activation of ISCs in the regenerative phase. PMID- 25693895 TI - A Sertoli cell-specific connexin43 knockout leads to altered interstitial connexin expression and increased Leydig cell numbers. AB - The Sertoli cell (SC)-specific knockout (KO) of connexin43 (Cx43) results in spermatogenic arrest at the level of spermatogonia and/or SC-only syndrome. Histology of the interstitial compartment suggests Leydig cell (LC) hyperplasia. Our aim has been to investigate possible effects of the SC-specific KO of Cx43 (SCCx43KO) on interstitial LC. We therefore counted LC via the optical dissector method (per microliter of testicular tissue and per testis) and found LC to be significantly increased in SCCx43KO(-/-) compared with wild-type mice. Semiquantitative western blot together with Cx43 and 3beta-hydroxysteroid dehydrogenase immunohistochemistry showed that Cx43 protein was significantly reduced and barely detectable in LC in adult SCCx43KO(-/-) mice. This reduction of Cx43 protein was accompanied by a reduction of Cx43 mRNA as analyzed by laser assisted microdissection of interstitial cells and subsequent quantitative real time polymerase chain reaction (PCR). Interestingly, Cx45, another recently detected connexin in LC, was also downregulated. Preliminary qualitative data of LC differentiation markers (Thb2, Hsd3b6) and a steroidogenic marker (Hsd17b3) obtained by reverse transcription plus PCR revealed no obvious differences. Thus, the loss of Cx43 in SC also provokes the downregulation of connexins in interstitial LC at the transcriptional and translational levels. Moreover, SCCx43KO leads to alterations in LC numbers. Despite these alterations, steroidogenesis seems not to be impaired. Further studies, including ultrastructural analysis of the tissue as well as quantitative examination of additional LC markers and testosterone, and functional in vitro experiments, should provide more information about LC differentiation and function in SCCx43KO(-/-) mice. PMID- 25693897 TI - Psychophysiological response and energy balance during a 14-h ultraendurance mountain running event. AB - Many studies have researched the psychophysiological response and energy balance of athletes in numerous ultraendurance probes, but none has investigated an ultraendurance mountain running event. The current study aims to analyze changes in blood lactate concentration, rating of perceived exertion, heart rate, heart rate variability, and energy balance after the performance of an ultraendurance mountain running event. The parameters in the 6 participants who finished the event were analyzed (age, 30.8 +/- 3.1 years; height, 176.2 +/- 8.6 cm; body mass, 69.2 +/- 3.7 kg). The race covered 54 km, with 6441 m of altitude change, 3556 m downhill and 2885 m uphill. The athletes completed together the race in 14 h and 6 min. After the ultraendurance event, the athletes presented a negative energy balance of 4732 kcal, a blood lactate concentration of 2.8 +/- 0.3 mmol/L, a heart rate mean/heart rate maximum ratio of 0.64, a heart rate mean of 111.4 +/ 5.9 beats/min, a decrease in vagal modulation, and an increase in sympathetic modulation, and recorded 19.5 +/- 1.5 points on the 6-20 rating of perceived exertion scale. The event was a stressful stimulus for the athletes despite the low intensity measured by blood lactate concentration and heart rate. The results obtained may be used by coaches as a reference parameter of heart rate, heart rate variability, rating of perceived exertion, and lactate concentration to develop specific training programs. In addition, the energy balance data obtained in this research may improve nutritional intake strategies. PMID- 25693896 TI - Desmosome regulation and signaling in disease. AB - Desmosomes are cell-cell adhesive organelles with a well-known role in forming strong intercellular adhesion during embryogenesis and in adult tissues subject to mechanical stress, such as the heart and skin. More recently, desmosome components have also emerged as cell signaling regulators. Loss of expression or interference with the function of desmosome molecules results in diseases of the heart and skin and contributes to cancer progression. However, the underlying molecular mechanisms that result in inherited and acquired disorders remain poorly understood. To address this question, researchers are directing their studies towards determining the functions that occur inside and outside of the junctions and the extent to which functions are adhesion-dependent or independent. This review focuses on recent discoveries that provide insights into the role of desmosomes and desmosome components in cell signaling and disease; wherever possible, we address molecular functions within and outside of the adhesive structure. PMID- 25693898 TI - Effect of a prior bout of preconditioning exercise on muscle damage from downhill walking. AB - This study investigated whether reduced-duration downhill walking (DW) would confer a protective effect against muscle damage induced by a subsequent bout of longer duration DW performed 1 week or 4 weeks later. Healthy young adults were allocated to a control or one of the preconditioning exercise (PRE-1wk or PRE 4wk) groups (10 men and 4 women per group). PRE-1wk and PRE-4wk groups performed 20-min DW (-28% slope, 5 km/h, 10% body mass added to a backpack) 1 week and 4 weeks before 40-min DW, respectively, and the control group performed 40-min DW only. Maximal voluntary contraction (MVC) knee extension torque, plasma creatine kinase (CK) activity, and muscle soreness (100-mm visual analog scale) were measured before, immediately after, and 24, 48, and 72 h after DW, and the changes in these variables were compared among groups. The control group showed symptoms of muscle damage (e.g., prolonged decrease in MVC: -14% +/- 10% at 48 h post-DW) after 40-min DW. Changes in all variables after 40-min DW of PRE-1wk and PRE-4wk groups were 54%-61% smaller (P < 0.05) than the control group, without significant differences between PRE-1wk and PRE-4wk groups for MVC and plasma CK activity. Importantly, changes after the preconditioning exercise (20-min DW) were 67%-69% smaller (P < 0.05) than those after the 40-min DW of the control group. These findings suggest that 20-min DW resulting in minor muscle damage conferred a protective effect against subsequent 40-min DW, and its effect could last for more than 4 weeks. PMID- 25693899 TI - Relationships between VO2 and blood lactate responses after all-out running exercise. AB - To verify the effects of training status and blood lactate concentration (BLC) responses on the early excess postexercise oxygen consumption (EPOC), 8 sprinters, 7 endurance runners, and 7 untrained subjects performed an incremental test to determine maximal oxygen uptake and a 1-min all-out test to determine BLC and oxygen uptake recovery curves. BLC kinetics was evaluated to assess the quantity of lactate accumulated during exercise (QlaA), lactate removal ability (k2), and quantity of lactate removed from 0 to 10 min postexercise (QlaR). Oxygen uptake off-kinetics was evaluated to assess the decay time constants (tau1 and tau2); moreover, EPOC was measured during the first 10 min after exercise. While sprinters had 98%-100% and 94%-100% likelihood of having the highest EPOC and decay time constants, endurance runners had 98%-100% and 95%-100% likelihood of having the lowest EPOC and decay time constants. EPOC was correlated with QlaA (r = 0.74) and QlaR (r = 0.61). tau1 and tau2 were correlated with maximal oxygen uptake (r > -0.57), k2 (r > -0.48), and QlaR relative to QlaA (r > -0.60). Our findings indicate that oxygen uptake recovery is associated with fast lactate removal and aerobic training. Furthermore, the metabolites derived from anaerobic energy production seem to induce a greater EPOC after all-out exercise. PMID- 25693902 TI - [Interventional strategies in hypertension management]. AB - A number of invasive treatment approaches have become established in the management of severe treatment-resistant hypertension in recent years, including renal denervation and baroreceptor activation therapy. Both methods achieve their antihypertensive effect by influencing the autonomic nervous system. Renal denervation in particular has stimulated considerable interest, since it is simple to perform and initial studies have yielded highly promising results. However, enthusiasm has waned significantly since the initial euphoria. This is due to the fact that the first randomized placebo-controlled double-blind study showed the method to have no significant effect on blood pressure. This experience illustrates the importance of conducting double-blind studies. On the other hand, these results should not lead to renal denervation being shelved. On the contrary, it is worth attempting to improve the treatment and develop criteria to identify which patients it is likely to benefit. Although experience with baroreceptor activation therapy is significantly more limited, similar conclusions can be drawn on it, despite the fact that-in contrast to renal denervation-it achieved a blood pressure reduction of around 10 mmHg in a double blind study. A potential novel treatment approach lies in creating an arteriovenous shunt between the iliac artery and vein, which has a particularly marked effect on diastolic blood pressure by reducing peripheral resistance. Therapy using brain stimulation of areas in the brainstem region responsible for blood pressure regulation is still at an experimental stage. PMID- 25693903 TI - [Cystic fibrosis and associated complications]. AB - Cystic fibrosis (CF) is an autosomal recessive inherited metabolic disease. The mutation is located on the long arm of chromosome 7. Due to a defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, chloride ion transport is reduced across the cell membrane. As a result, the disease can be described as an exocrinopathy. In all organs with exocrine glands, disorders occur in association with the defective chloride transport. The main impact of this defect is manifested in the lungs. Therefore, the most common cause of death is pulmonary disease with respiratory insufficiency due to recurrent infections. Unfortunately, a cure for the disease is still not available. However, new therapies that may affect the CFTR mutation more specifically give new hope for better therapeutic options in the future. The long-term goal of therapy is to develop a causal therapy for all six different mutation classes and thus for about 2000 mutations. PMID- 25693904 TI - Residue depletion of ampicillin in eggs. AB - A residue depletion study of ampicillin (AMP) was performed after oral dosing (60.0 mg/kg and 120.0 mg/kg body weight once a day for 5 days) to laying hens, through the use of reversed-phase high-performance liquid chromatography with fluorescence detection (RP-HPLC-FLD) to achieve detection of ampicillin residue in eggs. Limit of detection was 0.5 ng/g, and limit of quantitation was 1.2 ng/g for ampicillin. Extraction recoveries of ampicillin from samples fortified at 5.0 125.0 ng/g levels ranged from 77.5% to 84.6% in albumen, 77.9% to 87.5% in yolk, and 77.9% to 88.6% in whole egg, with coefficients of variation <= 9.3%. The maximum concentrations of ampicillin in albumen, yolk, and whole egg were detected at 1, 2, and 1 day after the last administration of ampicillin, respectively. Ampicillin was not detectable in albumen at day 9 of withdrawal time, at day 10 and 11 in yolk, and day 9 and 11 in whole egg at each of those 2 dose levels. The theoretical withdrawal time of AMP in whole egg was 6.730 and 7.296 days for 60 and 120 mg/kg oral dosage, respectively. This method also proved to be suitable as a rapid and reliable method for the determination of ampicillin in other poultry eggs. PMID- 25693905 TI - Expression and immunolocalisation of follicle-stimulating hormone receptors in gonads of newborn and adult female horses. AB - In mares, FSH and its receptor (FSHR) are essential for ovarian function. The objective of the present study was to analyse FSHR gene expression at the mRNA and protein levels in ovarian tissue from newborn and adult horses. Expression of mRNA was analysed by reverse transcription polymerase chain reaction, whereas FSHR protein was visualised by immunohistochemistry (IHC), immunofluorescence labelling (IF) and western blot. FSHR mRNA was detected in ovarian follicles and luteal tissue from adult mares, as well as in the ovaries of neonates. Follicular growth up to 4mm in diameter was already present in neonates. Using IHC and IF, FSHR protein was detected in granulosa cells, cumulus cells and inconsistently in oocytes, independent of the animal's age or the stage of folliculogenesis. A lower FSHR expression was observed in theca cells in comparison to granulosa cells. FSHR was abundant in the ovarian stroma cells of neonates but not of adults. Luteal cells stained positive for FSHR independent of the stage of corpus luteum development. The presence of FSHR protein in various cell populations of the ovary was confirmed by western blot. In conclusion, FSHR is present in horse ovaries consistently from birth onwards and expression remains constant during the oestrous cycle. PMID- 25693906 TI - Corticotrophin-releasing hormone (CRH) expression in the dermoid component of ovarian teratomas. PMID- 25693908 TI - Establishing the impact of temporary tissue expanders on electron and photon beam dose distributions. AB - PURPOSE: This study investigates the effects of temporary tissue expanders (TTEs) on the dose distributions in breast cancer radiotherapy treatments under a variety of conditions. METHODS: Using EBT2 radiochromic film, both electron and photon beam dose distribution measurements were made for different phantoms, and beam geometries. This was done to establish a more comprehensive understanding of the implant's perturbation effects under a wider variety of conditions. RESULTS: The magnetic disk present in a tissue expander causes a dose reduction of approximately 20% in a photon tangent treatment and 56% in electron boost fields immediately downstream of the implant. The effects of the silicon elastomer are also much more apparent in an electron beam than a photon beam. CONCLUSIONS: Evidently, each component of the TTE attenuates the radiation beam to different degrees. This study has demonstrated that the accuracy of photon and electron treatments of post-mastectomy patients is influenced by the presence of a tissue expander for various beam orientations. The impact of TTEs on dose distributions establishes the importance of an accurately modelled high-density implant in the treatment planning system for post-mastectomy patients. PMID- 25693909 TI - Reproducibility of the incremental shuttle walk test for women with morbid obesity. AB - OBJECTIVE: The incremental shuttle walk test (ISWT) is a valuable tool for the assessment of functional capacity. However, few studies have used the ISWT in individuals with obesity or have determined its reproducibility in this population. PURPOSE: The aim of the present study was to evaluate the reproducibility of the ISWT in women with morbid obesity. METHODS: Twenty-three women with a body mass index >40 kg/m(2) (mean age: 39.1 +/- 7.7) performed the ISWT twice on the same day. RESULTS: The mean distance traveled was 313.3 +/- 100.2 m on the first test and 322.5 +/- 98.9 on the second test, with no significant difference between tests. The intraclass correlation coefficient (0.91) indicated excellent reproducibility. Reliability determined through Bland Altman analysis revealed a small mean difference between tests (-9.2 m). CONCLUSION: The practice of repeating the ISWT appears to be unnecessary for women with morbid obesity, as demonstrated by the excellent reproducibility of the test. PMID- 25693910 TI - Hydrazide macrocycles as effective transmembrane channels for ammonium. AB - Three shape-persistent aromatic hydrazide macrocycles that bear phenylalanine tripeptide chains have been synthesized. These macrocycles can insert into lipid bilayers to form single-molecular ion channels which exhibit a high NH4(+)/K(+) selectivity. PMID- 25693911 TI - Attachment style impacts behavior and early oculomotor response to positive, but not negative, pictures. AB - The present study investigated whether oculomotor behavior is influenced by attachment styles. The Relationship Scales Questionnaire was used to assess attachment styles of forty-eight voluntary university students and to classify them into attachment groups (secure, preoccupied, fearful, and dismissing). Eye tracking was recorded while participants engaged in a 3-seconds free visual exploration of stimuli presenting either a positive or a negative picture together with a neutral picture, all depicting social interactions. The task consisted in identifying whether the two pictures depicted the same emotion. Results showed that the processing of negative pictures was impermeable to attachment style, while the processing of positive pictures was significantly influenced by individual differences in insecure attachment. The groups highly avoidant regarding to attachment (dismissing and fearful) showed reduced accuracy, suggesting a higher threshold for recognizing positive emotions compared to the secure group. The groups with higher attachment anxiety (preoccupied and fearful) showed differences in automatic capture of attention, in particular an increased delay preceding the first fixation to a picture of positive emotional valence. Despite lenient statistical thresholds induced by the limited sample size of some groups (p < 0.05 uncorrected for multiple comparisons), the current findings suggest that the processing of positive emotions is affected by attachment styles. These results are discussed within a broader evolutionary framework. PMID- 25693912 TI - Consumer understanding and use of health claims: the case of functional foods. AB - As widely acknowledged functional foods (FFs) may contribute to improve human health due to the presence of specific components useful for their protective action against several diseases. However it is essential that consumers are able to comprehend and assess the properties of FFs health claims play a central role in helping consumers to select among food alternatives, beyond providing protection against unsupported or misleading statements about foods properties. At the same time health claims are the main marketing tool that the food industry could use to differentiate FFs from other products. Clearly, massive investments in research and development are necessary to enter the FF market segment, together with the possibility to protect innovation through patents. Current paper aims to examine factors influencing consumer understanding and use of food health claims on FFs, as well as providing several indications for developers, marketers and policy makers. After a brief review of the literature the results of a quantitative survey conducted online on 650 Italian consumers are presented. Results show that consumer use and understanding of health claims on FFs depend on different variables such as socio-demographic characteristics, knowledge and confidence with nutrition information but also wording and variables related specifically to the product. Furthermore, different segments with a diverse degree of use and understanding of health claims have been identified. Therefore, to boost market growth, more efforts are needed by policy makers and marketers to provide better information on nutrition and health aspects of FF using an approach capable to ensure truthful, significant and clear information. Finally some recent patents related to the FFs market with specific regard to components and/or functionality investigated in the current paper are reviewed. PMID- 25693913 TI - Microbial adhesion capacity. Influence of shear and temperature stress. AB - Environmental parameters dictate the conditions for both biofilm formation and deconstruction. The aim of this study is to analyse the impact of hydrodynamic and thermodynamic effects on bacterial detachment. Escherichia coli grown on two stainless steel metal surfaces with different roughness (brushed with roughness of 0.05 MUm and electropolished with roughness of 0.29 MUm) are exposed to laminar and turbulent (shower) flows of phosphate buffered saline media at temperatures of 8, 20 and 37 degrees C. Results show that the turbulent flow removes significantly more bacterial cells than laminar flow (p <0.05) on both materials. This indicates that the shear force determines the rate of detached bacteria. It is also observed that detachment of cells is more efficient on brushed than on electropolished contact surfaces because on the latter surface, fewer cells were attached before exposure. Moreover, we demonstrate that the temperature of the washing agent has an impact on bacterial detachment. At the same flow conditions, the exposure to higher temperature results in greater detachment rate. PMID- 25693914 TI - Atomic force microscopy characterization of palmitoylceramide and cholesterol effects on phospholipid bilayers: a topographic and nanomechanical study. AB - Supported planar bilayers (SPBs) on mica substrates have been studied at 23 degrees C under atomic force microscopy (AFM)-based surface topography and force spectroscopy with two main objectives: (i) to characterize palmitoylceramide (pCer)-induced gel (Lbeta) domains in binary mixtures with either its sphingolipid relative palmitoylsphingomyelin (pSM) or the glycerophospholipid dipalmitoylphosphorylcholine (DPPC) and (ii) to evaluate effects of incorporating cholesterol (Chol) into the previous mixtures in terms of Cer and Chol cooperation for the generation of lamellar gel (Lbeta) phases of ternary composition. Binary phospholipid/pCer mixtures at XpCer < 0.33 promote the generation of laterally segregated micron-sized pCer-rich domains. Their analysis at different phospholipid/pCer ratios, by means of domain thickness, roughness, and mechanical resistance to tip piercing, reveals unvarying AFM-derived features over increasing pCer concentrations. These results suggest that the domains grow in size with increasing pCer concentrations while keeping a constant phospholipid/pCer stoichiometry. Moreover, the data show important differences between pCer interactions with pSM or DPPC. Gel domains generated in pSM/pCer bilayers are thinner than the pSM-rich surrounding phase, while the opposite is observed in DPPC/pCer mixtures. Furthermore, a higher breakthrough force is observed for pSM/pCer as compared to DPPC/pCer domains, which can be associated with the preferential pCer interaction with its sphingolipid relative pSM. Cholesterol incorporation into both binary mixtures at a high Chol and pCer ratio abolishes any phospholipid/pCer binary domains. Bilayers with properties different from any of the pure or binary samples are observed instead. The data support no displacement of Chol by pCer or vice versa under these conditions, but rather a preferential interaction between the two hydrophobic lipids. PMID- 25693915 TI - The influence of pre- and posterror responses on measures of intraindividual variability in younger and older adults. AB - The current study examined the effects of responses on error-adjacent trials (i.e., those immediately preceding or following errors) on age differences in measures of intraindividual variability and the shape of response time (RT) distributions on a two-back task. Removing error-adjacent responses reduced variability as measured by the coefficient of variation, but did so similarly for younger and older adults. However, older adults' standard deviations (SDs) were less than those of younger adults with comparable RTs, raising questions regarding the validity of the coefficient of variation. An ex-Gaussian analysis revealed that removing the RTs on error-adjacent trials reduced the length of the tails of distributions and the skewness of the distributions. These properties were reduced more for older adults than for younger adults. These results indicate that the influence of error-adjacent trials should be considered when analyzing intraindividual variability and the shape of RT distributions to test theories of cognitive aging. PMID- 25693916 TI - Association of Hemostatic Gene Polymorphisms With Early-Onset Ischemic Heart Disease in Egyptian Patients. AB - The association between hereditary thrombophilia and venous thrombosis is well established but controversial data exist with respect to arterial thrombosis. We performed a pilot study on 31 patients with acute myocardial infarction (AMI), 21 patients with unstable angina (UA), and 20 healthy volunteers to investigate the role of various hemostatic gene polymorphisms in young Egyptian patients, who survived their first ischemic heart disease (IHD). Thrombophilic gene polymorphisms were tested using multiplex polymerase chain reaction and reverse hybridization technique. We showed an increased risk of AMI with factor V (FV) Leiden and prothrombin G20210A heterozygosity. The increased risks of UA was associated with GA and A allele of fibrinogen beta-455G->A polymorphism. Conversely, factor XIII (FXIII) Val34Leu GT and T allele were protective in the UA group. Nevertheless, the prevalence of FV H1299R, plasminogen activator inhibitor 1 4G/5G, glycoprotein IIIa C1565T, 5,10-methylenetetrahydrofolate reductase C677T, and A1298C mutations did not differ between patients with IHD and controls. The data have clinical implications regarding screening and thromboprophylaxis in high-risk individuals younger than 40 years. PMID- 25693917 TI - Cerebral Thrombotic Complications Related to l-Asparaginase Treatment for Acute Lymphoblastic Leukemia: Retrospective Review of 10 Cases. AB - l-Asparaginase is a potent antileukemia agent and an essential part of treatment protocols for acute lymphoblastic leukemia. However, toxicity limits dose escalation, especially in adults. This includes a significant risk of thrombosis, which remains an important source of avoidable morbidity and mortality. Here, we provide a detailed report of 10 cases of cerebral thrombotic complications that occurred over a 5-year period at 4 large tertiary referral hospitals. To our knowledge, this is the first report of this type in the published literature. PMID- 25693918 TI - Serum Apelin 13 Levels in Patients With Pulmonary Embolism. AB - INTRODUCTION AND AIM: Expression and peptide immunoreactivity of apelin messenger RNA have been described in a variety of tissues, including gastrointestinal tract, adipose tissue, brain, kidney, liver, cardiovascular system, and lungs. This study aimed to investigate the possible involvement of the endogenous apelin in the pathophysiological events that occur in patients with pulmonary embolism (PE). MATERIALS AND METHODS: In total, 53 patients with PE and 35 healthy volunteers were included the study. This cross-sectional study was conducted at a tertiary care university hospital and among patients diagnosed as having PE. The control group consisted of healthy volunteers who applied to hospital for a routine checkup examination. Serum apelin 13 levels were measured in both the groups and their results were compared. RESULTS: The median ages were 57 and 53 years, and female-male ratios were 30/23 and 20/15, in the PE and control groups, respectively. The mean serum apelin 13 levels were found to be significantly higher in the PE group (76.94 +/- 10.70 ng/mL) than in the control group (50.01 +/- 7.13 ng/mL; P < .001). CONCLUSION: This study demonstrated that apelin 13 levels are elevated in patients with PE. These results suggest that apelin may be a novel biomarker and a potential therapeutic target in patients with acute PE in the future. PMID- 25693919 TI - Chiral recognition of Arg based on label-free PET nanochannel. AB - Herein, we design a label-free PET nanochannel for enantioselective recognition of Arg by adding bovine serum albumin (BSA) as chiral selector. This method does not require modification on the channel surface and has applicability for fabricating other chiral sensors. PMID- 25693920 TI - Reducing Operating Room Costs Through Real-Time Cost Information Feedback: A Pilot Study. AB - PURPOSE: To create a protocol for providing real-time operating room (OR) cost feedback to surgeons. We hypothesize that this protocol will reduce costs in a responsible way without sacrificing quality of care. METHODS: All OR costs were obtained and recorded for robot-assisted partial nephrectomy and laparoscopic donor nephrectomy. Before the beginning of this project, costs pertaining to the 20 most recent cases were analyzed. Items were identified from previous cases as modifiable for replacement or omission. Timely feedback of total OR costs and cost of each item used was provided to the surgeon after each case, and costs were analyzed. RESULTS: A cost analysis of the robot-assisted partial nephrectomy before the washout period indicates expenditures of $5243.04 per case. Ten recommended modifiable items were found to have an average per case cost of $1229.33 representing 23.4% of the total cost. A postwashout period cost analysis found the total OR cost decreased by $899.67 (17.2%) because of changes directly related to the modifiable items. Therefore, 73.2% of the possible identified savings was realized. The same stepwise approach was applied to laparoscopic donor nephrectomies. The average total cost per case before the washout period was $3530.05 with $457.54 attributed to modifiable items. After the washout period, modifiable items costs were reduced by $289.73 (8.0%). No complications occurred in the donor nephrectomy cases while one postoperative complication occurred in the partial nephrectomy group. CONCLUSION: Providing surgeons with feedback related to OR costs may lead to a change in surgeon behavior and decreased overall costs. Further studies are needed to show equivalence in patient outcomes. PMID- 25693921 TI - A case report of a pulmonary metastasis of a polymorphous low-grade adenocarcinoma. PMID- 25693922 TI - Health-care professionals' attitudes across different hospital departments regarding alcohol-related presentations. AB - INTRODUCTION AND AIMS: Attitudes to individuals presenting with alcohol-related issues are important in developing therapeutic relationships and applying alcohol related interventions. This study explores staff attitudes to these individuals across a range of roles and departments. DESIGN AND METHODS: Data were gathered from 204 staff in the Southern Health and Social Care Trust in Northern Ireland. Regression models were used to predict attitudes as measured by the Short Alcohol and Alcohol Problems Perception Questionnaire (SAAPPQ). RESULTS: Two hundred and four people participated in the study. The sample comprised doctors, nurses, allied health professionals and other staff who had face-to-face contact with patients. Staff worked in accident and emergency (A&E), medical, surgical, addiction or psychiatry departments. Staff working in addiction and psychiatry departments had significantly higher levels of role adequacy compared with those in A&E. Staff in addictions also demonstrated higher levels of role legitimacy, motivation and role satisfaction than those in A&E. Doctors had higher role adequacy and role legitimacy than nursing staff. DISCUSSION AND CONCLUSIONS: There are critical differences in staff attitudes to patients presenting with alcohol-related issues in a range of hospital settings; training and working in a specialist setting have a significant positive influence on staff attitudes. This suggests that further training and support would positively enhance the attitudes of staff in a variety of professional roles and across a range of hospital settings in the management of patients presenting with alcohol-related difficulties. [Iqbal N, McCambridge O, Edgar L, Young C, Shorter GW. Health-care professionals' attitudes across different hospital departments regarding alcohol related presentations. Drug Alcohol Rev 2015;34:487-94]. PMID- 25693923 TI - Effect of aged bone marrow microenvironment on mesenchymal stem cell migration. AB - Mesenchymal stem cells (MSCs) are known to have many notable features, especially their multiple differentiation ability and immunoregulatory capacity. MSCs are important stem cells in the bone marrow (BM), and their characteristics are affected by the BM microenvironment. However, effects of the BM microenvironment on the properties of MSCs are not well understood. In this study, we found that BM from aged mice decreased MSC colony formation. Flow cytometry data showed that the proportion of B220(+) cells in BM from aged mice was significantly lower than that in BM from young mice, while the proportion of CD11b(+), CD3(+), Gr-1(+), or F4/80(+) cells are on the contrary. CD11b(+), B220(+), and Ter119(+) cells from aged mice were not the subsets that decreased MSC colony formation. We further demonstrated that both BM from aged mice and young mice exhibited similar effects on the proliferation of murine MSC cell line C3H10T1/2. However, when cocultured with BM from aged mice, C3H10T1/2 showed slower migration ability. In addition, we found that phosphorylation of JNK (c-Jun N-terminal kinases) in C3H10T1/2 cocultured with BM from aged mice was lower than that in C3H10T1/2 cocultured with BM from young mice. Collectively, our data revealed that BM from aged mice could decrease the migration of MSCs from their niche through regulating the JNK pathway. PMID- 25693924 TI - Age-related expression of Neurexin1 and Neuroligin3 is correlated with presynaptic density in the cerebral cortex and hippocampus of male mice. AB - Neurexin1 (Nrxn1) and Neuroligin3 (Nlgn3) are cell adhesion proteins, which play an important role in synaptic plasticity that declines with advancing age. However, the expression of these proteins during aging has not been analyzed. In the present study, we have examined the age-related changes in the expression of these proteins in cerebral cortex and hippocampus of 10-, 30-, 50-, and 80-week old male mice. Reverse transcriptase polymerase chain reaction (RT-PCR) analysis indicated that messenger RNA (mRNA) level of Nrxn1 and Nlgn3 significantly increased from 10 to 30 weeks and then decreased at 50 weeks in both the regions. However, in 80-week-old mice, Nrxn1 and Nlgn3 were further downregulated in cerebral cortex while Nrxn1 was downregulated and Nlgn3 was upregulated in hippocampus. These findings were corroborated by immunoblotting and immunofluorescence results. When the expression of Nrxn1 and Nlgn3 was correlated with presynaptic density marker synaptophysin, it was found that synaptophysin protein expression in cerebral cortex was high at 10 weeks and decreased gradually up to 80 weeks, whereas in hippocampus, it decreased until 50 weeks and then increased remarkably at 80 weeks. Furthermore, Pearson's correlation analysis showed that synaptophysin had a strong relation with Nrxn1 and Nlgn3 in cerebral cortex and with Nlgn3 in hippocampus. Thus, these findings showed that Nrxn1 and Nlgn3 are differentially expressed in cerebral cortex and hippocampus which might be responsible for alterations in synaptic plasticity during aging. PMID- 25693925 TI - Construction and validation of a detailed kinetic model of glycolysis in Plasmodium falciparum. AB - The enzymes in the Embden-Meyerhof-Parnas pathway of Plasmodium falciparum trophozoites were kinetically characterized and their integrated activities analyzed in a mathematical model. For validation of the model, we compared model predictions for steady-state fluxes and metabolite concentrations of the hexose phosphates with experimental values for intact parasites. The model, which is completely based on kinetic parameters that were measured for the individual enzymes, gives an accurate prediction of the steady-state fluxes and intermediate concentrations. This is the first detailed kinetic model for glucose metabolism in P. falciparum, one of the most prolific malaria-causing protozoa, and the high predictive power of the model makes it a strong tool for future drug target identification studies. The modelling workflow is transparent and reproducible, and completely documented in the SEEK platform, where all experimental data and model files are available for download. DATABASE: The mathematical models described in the present study have been submitted to the JWS Online Cellular Systems Modelling Database (http://jjj.bio.vu.nl/database/penkler). The investigation and complete experimental data set is available on SEEK (10.15490/seek.1. INVESTIGATION: 56). PMID- 25693926 TI - Updates in colorectal cancer stem cell research. AB - Colorectal cancer (CRC) is one of the world most common malignant tumors, also is the main disease, which cause tumor-associated death. Surgery and chemotherapy are the most used treatment of CRC. Recent research reported that, cancer stem cells (CSCs) are considered as the origin of tumor genesis, development, metastasis and recurrence in theory. At present, it has been proved that, CSCs existed in many tumors including CRC. In this review, we summary the identification of CSCs according to the cell surface markers, and the development of drugs that target colorectal cancer stem cells. PMID- 25693927 TI - Recent advances of histone modification in gastric cancer. AB - Epigenetics play important roles during development progress of tumor. The histone modifications are the most important constituted field. Recently, accumulating research focused on exploring the roles of those modifications in regulating tumorigenesis. Moreover, the dysregulation of histone modifications is supposed to have vital clinical significance. Numerous histone modifications have the potential to be prognostic biomarkers, monitoring response of therapy, early diagnostic markers. Herein, we review the recent advances of histone modifications involving development of gastric cancer. PMID- 25693928 TI - High levels of D-dimer correlated with disease status and poor prognosis of inoperable metastatic colorectal cancer patients treated with bevacizumab. AB - PURPOSE: To assess the levels of D-dimer baseline levels in inoperable metastatic colorectal cancer (mCRC) patients treated with bevacizumab and its relationship with prognosis. MATERIALS AND METHODS: From June 1, 2011 to December 31, 2013, a total of 121 patients with mCRC received beacizumab combined with chemotherapy and 74 of them were included in the present study. A nonparametric statistical test was performed to analyze the relationship between plasma D-dimer levels and clinical pathological factors. The Cox proportional model was used to analyze the effects of D-dimer on progression-free survival (PFS) time and overall survival (OS). RESULTS: Of the 74 cases, 40 were men and 34 women (aged 31-74 years), with a median age of 55.5 years. The median of PFS and OS were 6.3 and 17.8 months respectively. High levels of baseline plasma D-dimer were correlated with high scoring of Eastern Cooperative Oncology Group-Performance Status (P = 0.001), IV phase of disease at the first visit (P = 0.001), unremoval primary focal (P = 0.006), the number of metastatic organs >= 2 (P = 0.034), abdominal cavity effusion (P = 0.004) and no history of adjuvant chemotherapy (P = 0.003). It was found by single factor analysis that plasma baseline D-dimer levels >= 1.9 MUg/mL were closely related with a short PFS (hazard ratio [HR] 2.14, 95% confidence interval [CI] 1.04-4.40, P = 0.038) and OS (HR 5.22, 95% CI 2.05-13.28, P = 0.001). After adjustment for other factors, plasma baseline D-dimer levels >= 1.9 MUg/mL were still closely correlated with a short OS (HR 3.52, 95% CI 1.28-9.67, P = 0.015). CONCLUSION: High levels of plasma baseline D-dimer correlated with high tumor load, advanced disease status and poor prognosis of inoperable mCRC patients treated with bevacizumab. However, clinical research on a much larger cohort of patients will be required to verify these findings. PMID- 25693929 TI - MicroRNA-146a rs2910164 G/C polymorphism and gastrointestinal cancer susceptibility: a meta-analysis based on East Asian population. AB - OBJECTIVE: The relationship between microRNA (miR-146a) rs2910164G/C polymorphism and gastrointestinal cancer susceptibility is not consistent with each other of the published articles. The aim of this meta-analysis was to acquire a more precise effect of the association between the miR-146a rs2910164 G/C polymorphism and gastrointestinal cancer. MATERIALS AND METHODS: Through searching of the MedLine, Embase, China National Knowledge Infrastructure, and Wanfang databases. Case-control or cohort studies about the relationship between miR-146a rs2910164 G/C polymorphism and gastrointestinal cancer susceptibility were screened and included in this meta-analysis. Quantitative data synthesis was conducted for the associations of miR-146a rs2910164 G/C polymorphism and gastrointestinal cancer risk by statistical software STATA-11.0. RESULTS: Ten studies including 6473 gastrointestinal cancer patients and 7923 controls were identified and included in this meta-analysis. For recessive genetic model (CC vs. CG + GG), people with CG or GG is associated with the susceptibility of gastrointestinal cancer compared with genotype of CC (R = 0.73, 5% confidence interval [CI]: 0.55-0.97, [P = 0.03]); But for dominant model (CC + CG vs. GG) and homozygous model (CC vs. GG), no association of the miR-146a rs2910164G/C polymorphism and gastrointestinal cancer susceptibility were found (dominant: Odds ratio [OR] =0.94, 95% CI: 0.82-1.03, [P = 0.37]; homozygous: OR = 0.85, 95% CI: 0.71-1.03, [P = 0.10]). Sub-group analysis, for homozygous model, people with GG genotype had increased risk of developing colorectal cancer (OR = 0.77, 95% CI: 0.64-0.93, [P = 0.008]). CONCLUSION: No significant association between miR-146a rs2910164G/C polymorphism and gastrointestinal cancer susceptibility was found in this meta-analysis. But for homozygous model, people with GG genotype may have increased risk of developing colorectal cancer. PMID- 25693930 TI - Metastatic brain tumors from small-cell esophageal cancer: clinical characteristics and outcome. AB - AIMS: Few studies have examined the clinical characteristics of patients with brain metastases from small-cell esophageal cancer. In this study, we review the clinical characteristics and outcomes in patients with brain metastases from small-cell esophageal cancer. PATIENTS AND METHODS: From August 2002 to August 2012, consecutive patients diagnosed with brain metastases from small-cell esophageal cancer and treated with radiotherapy were enrolled. Clinical features, diagnostic findings, and survival were analyzed. RESULTS: Six patients treated with brain radiotherapy were identified. The median age was 64 (range 61-74) years. All patients had neurological impairments. Three patients had supra- and infra-tentorial metastases, and three patients had cerebrum metastases. Brain metastases were detected when esophageal cancer was initially diagnosed in two patients. In three patients, magnetic resonance imaging findings after radiotherapy confirmed a significant response to treatment. The median overall survival was 6.0 months. During the same period, 43 patients with squamous cell carcinoma and seven patients with adenocarcinoma who had brain metastases were identified. Survival periods for squamous cell carcinoma and adenocarcinoma patients who had brain metastases were 5.5 months and 4.2 months, respectively. There was no significant difference in overall survival according to the histological type. CONCLUSIONS: Brain metastases from small-cell esophageal cancer tend to spread to the cerebellum and impair patients' quality-of-life. Brain radiotherapy had a positive effect in this case series; however, overall survival remains short. PMID- 25693931 TI - Endo-laparoscopic rendezvous approach for pericardia with gastric posterior wall of gastrointestinal stromal tumor: analysis of 52 consecutive cases. AB - BACKGROUND: Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor in the gastrointestinal tract and most frequently developed in the stomach, and surgical therapy is limited on removal of the tumor lesion. The aim of this study was to investigate the clinical values of endo-laparoscopic rendezvous approach for pericardial GISTs within gastric posterior wall. MATERIALS AND METHODS: Surgical outcome and clinical data of 52 patients with pericardial GISTs within gastric posterior wall treated at Tianjin Peoples' Hospital from January 2004 to October 2013 were analyzed. Endo-laparoscopic rendezvous approach was used as an operative procedure for tumor resection ranged from 10 to 50 mm. Endoscopic ultrasound, computed tomography and microscopic findings all certified the gastric spindle type GIST locating in the submucosa to muscle proper. RESULTS: Endo-laparoscopic rendezvous approach was attempted in 52 patients (male/female: 31/21) with median age of 51 years (25-71 years). The median operating time was 80 min (range: 40-120 min) and median intra-operative blood loss was 26 ml (range: 10-50 ml). The median hospital stay was 5 days (range: 4-6 days), while the median tumor size was 25 mm (range: 7-50 mm). All operative margins were clear. There were no recurrences or metastases of all patients in a median follow-up of 24 months (range: 6-36 months). CONCLUSIONS: Endo laparoscopic rendezvous approach is considered to represent the next revolution in surgery. The new technique is reliable and effective in clinical application, due to the advantages of accurate and quick localization for pericardial GIST within gastric posterior wall. PMID- 25693932 TI - Association between Helicobacter pylori infection and colorectal neoplasm risk: a meta-analysis based on East Asian population. AB - OBJECTIVE: The association between Helicobacter pylori (HP) infection and colorectal neoplasm risk was not clear. The aim of this study was to evaluate whether HP infection can increase the risk of developing colorectal neoplasm by meta-analysis. MATERIALS AND METHODS: A detailed literature search was performed on Medline, PubMed, Web of Science, and China National Knowledge Infrastructure for related research publications written in English and/or Chinese. The relevant case-control or cohort studies reporting an association between HP infection and colorectal neoplasm risk were screened and included in this meta-analysis. The association between HP infection and colorectal neoplasm risk was expressed by odds ratio (OR) and its 95% confidence interval (CI). The heterogeneity among the included articles was assessed by I 2 test, and the pooled OR was calculated by fixed effect model in case of no significant heterogeneity otherwise random effect model was employed. All the statistical analyses were done by STATA-11.0 and MetaAnalyst Beta 3.13 software. RESULTS: Finally, a total of 2081 colorectal neoplasm patients and 5598 healthy controls from nine eligible studies were included in this meta-analysis. The pooled OR for the association between HP infection and colorectal neoplasm risk was 0.18 with its 95% CI of 0.99-1.40, (P > 0.05). We further divided the colorectal neoplasm into the hyperplastic polyps, adenomas and colorectal cancer sub-groups according to colorectal neoplasm types. The pooled ORs and their 95% CIs were OR Hyperplastic_polyps = 0.72, 95% CI: 0.44 1.18, (P > 0.05), OR Adenomas = 1.83, 95% CI: 1.35-2.51, (P < 0.01), OR Colorectal_cancer = 1.08, 95% CI: 0.89-1.68 (P > 0.05). For different region sub groups, the pooled ORs and 95% CIs were OR South_Korea = 1.18, 95% CI: 0.84-1.66, (P > 0.05), OR China = 0.78, 95% CI: 0.53-1.13, (P > 0.05), OR Taiwan = 1.06, 95% CI: 0.69-1.62, (P > 0.05), OR Japan = 1.33, 95% CI: 1.07-1.65, (P < 0.05) for South Korea, China main land, Taiwan and Japanese. CONCLUSION: In general, no statistical association between HP infection and colorectal neoplasm risk was found in this meta-analysis. But, HP infection may increase the risk of developing colorectal adenomas. PMID- 25693933 TI - Concurrent involved-field radiotherapy and XELOX in gastric cancer patients with postoperative oligometastatic recurrence. AB - PURPOSE: The aim of this study was to retrospectively observe gastric adenocarcinoma patients with postoperative oligometastatic recurrence and investigated the effects of concurrent involved-field radiotherapy (RT) and XELOX on progression-free survival (PFS). PATIENTS AND METHODS: From 2008 to 2011, 246 patients underwent curative resection of gastric carcinoma was enrolled. A retrospective review was performed on 34 patients with distant recurrence. Among them, 19 patients were oligometastases patients, where 13 patients received involved-field RT with a dose of 40-60 Gy by an intensity-modulated RT technique and concurrent XELOX chemotherapy, four patients were treated with XELOX chemotherapy alone (oxaliplatin 130 mg/m2, capecitabine 1000 mg/m2, twice daily, 3 week each cycle), and two patients with only brain metastasis were not included in the analysis. RESULTS: The median PFS was 11 months in the 13 oligometastatic patients who received concurrent involved-field RT and XELOX. The oligometastatic patients receiving concurrent radiochemotherapy trended toward a better median PFS when compared with those receiving chemotherapy alone. CONCLUSIONS: For patients with postoperative oligometastatic recurrence, concurrent involved-field RT and XELOX showed better responses and was a choice for first-line treatment. PMID- 25693934 TI - Is the incidence of postoperative anastomotic leakage different between laparoscopic and open total mesorectal excision in patients with rectal cancer? A meta-analysis based on randomized controlled trials and controlled clinical trials. AB - OBJECTIVE: The purpose of this meta-analysis was to assess whether the incidence of postoperative anastomotic leakage (PAL) was different between laparoscopic and open total mesorectal excision (TME) in patients with rectal cancer. MATERIALS AND METHODS: The PubMed, Medline, Cochrane Library, Wanfang and China National Knowledge Infrastructure databases were searched for selecting the randomized controlled trials (RCTs) and controlled clinical trials (CCT) on the incidence of PAL between laparoscopic and open TME for rectal cancer. The incidence rate of PAL was extracted from each of the individual study and pooled by the STATA-11.0 statistical software. RESULTS: Six RCTs and 19 CCTs were included in this meta analysis. The pooled results indicated that no statistical difference of PAL rate was found between aparoscopic and open TME in patients with rectal cancer (odds ratio [OR] =0.81, 95% confidence interval [CI]: 0.61-1.07, [P > 0.05]); The sub group analysis when pooling the RCTs and CCTs respectively also indicated that there was no statistical difference of PAL rate between the laparoscopic and open TME (OR = 0.70, 95% CI: 0.35-1.39, [P > 0.05] for RCTs and OR = 0.84, 95% CI: 0.61-1.14, [P > 0.05]). CONCLUSION: Based on present studies, laparoscopic TME does not increase the risk of PAL. PMID- 25693935 TI - Clinical analysis of gastroenteropancreatic neuroendocrine tumor with liver metastasis, compared with primary hepatic neuroendocrine tumor. AB - OBJECTIVE: The objective was to study the clinicopathologic features, grading, treatment protocols, and prognostic of gastroenteropancreatic neuroendocrine tumor (NET) with liver metastasis and primary hepatic NET. MATERIALS AND METHODS: The clinical data of 34 patients with hepatic NET were retrospectively reviewed. According to the primary tumor location and 2010 World Health Organization classification, the cases were categorized to analyze the clinicopathologic features, treatment condition, and prognostic factors. RESULTS: There was a marked male predominance either in gastroenteropancreatic NET liver metastasis group or primary group. Primary hepatic NET is mostly single nodule located in the right lobe of liver, and the metastatic hepatic NET is mostly from pancreas with multiple nodules and metastasizes to both lobes of the liver, with a high degree of malignancy and poor prognosis. There are 17 cases (50%) of NET and 17 cases (50%) of neuroendocrine carcinoma (NEC) in all the 34 patients of this study. The mitotic figure and Ki-67 proliferation index are both higher in NEC group than in NET group, which indicated highly malignancy of the NEC. The 5-year disease-free survival (DFS) rates for primary group and metastatic group were 30% and 40%, respectively (P > 0.05), while the 5-year survival rates were 35% and 66%, respectively (P > 0.05). Different tumor grade was found closely associated with 5-year DFS (P < 0.05) and overall survival (OS) (P < 0.05) in both groups. Furthermore, we found 5-year DFS of patients with primary site of the tumor located in the gastrointestinal tract was much lower than that located in pancreas (P < 0.05), while the 5-year OS showed no significant differences between two groups (P > 0.05). CONCLUSIONS: Surgery is an effective method for the treatment of hepatic NET; tumor grading is an important determinant factor of prognosis. PMID- 25693936 TI - Submucosal tunneling endoscopic resection for the treatment of rectal submucosal tumors originating from the muscular propria layer. AB - OBJECTIVE: The objective was to evaluate the clinical value of submucosal tunneling endoscopic resection (STER) for the treatment of submucosal tumors (SMTs) originating from the muscular propria (MP) in the rectum. PATIENTS AND METHODS: The clinicopathological data of 12 cases with rectal SMTs originating from the MP layer performed STER in our center from January 2012 to June 2014 were analyzed retrospectively. RESULTS: Three males and nine females (M/F, 1/3) were studied in this series. The median age of the patients was 53.5 (range, 41 84) years. The tumors located 5-10 cm from the anal verge. En bloc STER was performed successfully in all of the 12 cases. The median size of resected specimens was 1.4 cm (range 1.0-3.0 cm). The median procedure time was 49.5 min (range 40-70 min). Three patients developed low fever after the operation and were all recovered after receiving intravenous antibiotics. One of these three cases developed mucosa perforation, which was closed immediately with metal clips. One patient developed subcutaneous emphysema in one lower limb, which disappeared with conservative treatments 2 weeks after the STER procedure. The median hospital stays were 3.1 (range 2-8) days. Postoperative pathological outcomes revealed schwannoma in 3 cases, leiomyoma in 2 cases, stromal tumor in 5 cases, and proliferation of collagen fibers nodular degeneration in 2 cases. No lesion residual or recurrence was found during postoperative follow-up of 4-33 months. CONCLUSION: STER is a feasible, safe, and effective method for treating SMTs originating from the MP layer in the rectum. PMID- 25693937 TI - The diagnostic value of DNA hypermethylation in stool for colorectal cancer: a meta-analysis. AB - OBJECTIVE: We performed this meta-analysis to document the diagnostic performance of DNA hypermethylation in stool for colorectal cancer (CRC). MATERIALS AND METHODS: Relevant studies that reported the diagnostic performance of stool DNA hypermethylation in CRC and healthy control were searched and extracted from electronic databases. After careful evaluation of the included articles, the numbers of true positive, false positive, false negative and true negative cases identified by stool DNA hypermethylation were extracted and pooled for diagnostic sensitivity, specificity, positive likely hood ratio, negative likely hood ratio, diagnostic odds ratio and the summary receiver operating characteristic (SROC) curve. All the statistical analysis was done by MetaDiSc1.4 and STATA-11.0 software. RESULTS: Thirty diagnostic trails including 1,629 CRC patients and 1,531 controls were included in this meta-analysis according to the inclusion and exclusion criteria. The overall diagnostic value of DNA hypermethylation in stool for CRC was: Pooled sensitivity, 0.71 (0.69-0.73); pooled specificity, 0.92 (0.90 0.93); pooled positive likely hood ratio, 7.59 (5.83-9389); pooled negative likely hood ratio, 0.33 (0.27-0.42); pooled diagnostic odds ratio, 27.78 (19.94 38.72) and area under the SROC curve was 0.93 (0.91-0.95). CONCLUSION: These results indicate a great diagnostic potential for DNA hypermethylation as a reliable marker in stool for CRC. PMID- 25693938 TI - The relationship between P16 gene promoter methylation and gastric cancer: a meta analysis based on Chinese patients. AB - OBJECTIVE: To evaluate the P16 gene promoter methylation rate in gastric cancer tissue and healthy controls. And further assess the clinical value of P16 gene promoter methylation as a biomarker for gastric cancer diagnosis. MATERIALS AND METHODS: Four databases, Medline, VIP, CNKI, WANFANG were searched to find the diagnostic trials about P16 gene promoter methylation in gastric cancer and healthy control. The pooled sensitivity, specificity, positive likelihood ratio (+LR), negative likelihood ratio (-LR) and the receiver operating characteristic curve (ROC) were calculated by Meta-DiSc1.4 (http://www.hrc.es/investigacion/metadisc.html) software. RESULTS: Nine studies involving 487 gastric cancer patients and 271 healthy controls were included in this meta-analysis. The median methylation rate for gastric cancer group was 43.3% with its range of 28.3-64.4%. And the median methylation rate for healthy control group was 0.0% with its range of 0.0-13.3%. The methylation rate in gastric cancer was statistical higher than in the healthy control (P < 0.05). The pooled sensitivity, specificity, +LR, -LR and the area under the ROC curve were 0.44 (95% confidence interval [CI]: 0.40-0.49), 0.97 (95% CI: 0.95-0.99), 13.11 (95% CI: 4.02-42.63), 0.58 (95% CI: 0.49-0.70), 23.62 (95% CI: 6.90-80.90) and 0.44, respectively. CONCLUSION: Our meta-analysis indicates that P16 gene promoter methylation array is a useful method for diagnosis of gastric cancer with relatively low sensitivity and very high specificity. PMID- 25693939 TI - Neuroimaging and clinical characteristics of brain metastases from esophageal carcinoma in Chinese patients. AB - OBJECTIVE: The objective was to describe the magnetic resonance imaging (MRI) and clinical characteristics of brain metastases from esophageal carcinoma diagnosed in patients from the Zhejiang Province of China, in order to provide a useful reference for the future diagnosis and treatment of similar patients. MATERIALS AND METHODS: Medical data were obtained for 31 patients who received treatment for brain metastases from esophageal carcinoma at the Zhejiang Provincial Cancer Hospital between January 1998 and July 2013. For this retrospective analysis, the primary tumors were pathologically confirmed. In addition, 6 cases had both pathologic records of brain metastasis events and complete MRI records available. Survival follow-up data were also obtained. RESULTS: Thirty-one patients (30 males, 1 female) with a total of 62 tumors were diagnosed with squamous cell carcinoma (n = 26), adenocarcinoma (n = 3), and small cell carcinoma (n = 2). While most patients complained of movement disturbance (51.6%) and headaches (32.3%), MRI characterized tumors with cystic elements (80.6%), tumors with thin cyst walls and enhancement (59.7%), and tumors with a peripheral edema zone <2 cm in diameter (59.7%). Moreover, a major radiological indicator for prognosis was a shift of midline. CONCLUSION: Most of the patients with brain metastases from esophageal carcinoma were male. Furthermore, many of the T1-weighted MRI images detected thin wall, enhanced single or multiple cystic lesions with an edema zone <2 cm in diameter. These imaging characteristics may represent this type of brain metastasis. PMID- 25693940 TI - Plasma interleukin 17 in the diagnosis of hepatocellular carcinoma: a retrospective study of 39 cases. AB - OBJECTIVE: The purpose of this retrospective study was to evaluate the diagnosis efficacy of plasma interleukin 17 (IL-17) for hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Thirty-nine patients with confirmed HCC and 41 healthy controls were retrospectively analyzed in this study. The serum level of IL-17 was tested by enzyme-linked immunosorbent assay. And the plasma level of carcino embryonic antigen (CEA) and alpha fetoprotein (AFP) were arrayed by radioimmunoassay. The plasma level of IL-17, CEA and AFP between HCC and healthy control group were compared. And the diagnostic sensitivity and specificity for IL-17, CEA and AFP in patients with HCC was calculated using the GraphPad Prism 5.0 software. RESULTS: The plasma level of IL-17, CEA and AFP were 2.88 +/- 1.75 (ng/L), 2.99 +/- 2.12 (MUg/L) and 6.91 +/- 4.56 (mg/L) in healthy control group and 5.57 +/- 1.59 (ng/L), 8.31 +/- 5.40 (MUg/L) and 190.50 +/- 79.08 (mg/L) in HCC group. Plasma level of IL-17, CEA and AFP in HCC group was statistical higher than in healthy control group (all P < 0.05). For plasma IL-17, the diagnostic sensitivity and specificity were 74.36% and 75.61% at the cut-off value of 4.23 (ng/L) with the area under the receiver operating characteristic (ROC) curve of 0.86; For plasma CEA, the diagnostic sensitivity and specificity were 69.23% and 70.73% at the cut-off value of 4.14 (MUg/L) with the area under the ROC curve of 0.80; For plasma AFP, he diagnostic sensitivity and specificity were 100.00% and 65.85% at the cut-off value of 10.25 (mg/L) with the area under the ROC curve of 0.96. CONCLUSION: Plasma IL-17 was significant elevated in patients with HCC compared to healthy control group which could be a potential biomarker for diagnosis of HCC. PMID- 25693941 TI - The diagnostic value of serum carcino-embryonic antigen, alpha fetoprotein and carbohydrate antigen 19-9 for colorectal cancer. AB - OBJECTIVE: The aim of this study is to investigate whether or not serum carcino embryonic antigen (CEA), alpha fetoprotein (AFP) and carbohydrate antigen 19-9 (CA19-9) can be used as potential biomarkers for colorectal cancer (CRC) diagnosis. MATERIALS AND METHODS: Forty-six patients with pathology or cytology confirmed CRC and 36 cases with non-malignant colorectal disease (NMCD) were included in this retrospective study. The serum level of CEA, AFP and CA19-9 were arrayed and recorded for the two groups. The diagnosis sensitivity, specificity and area under the receiver-operating characteristic (ROC) curve for serum CEA, AFP and CA19-9 were calculated by the STATA-10.0 software. RESULTS: We found that serum CEA, AFP and CA19-9 level in CRC patients were significantly higher than in NMCDs cases (all P < 0.05). The diagnosis sensitivity of CRC for CEA, AFP and CA19-9 were 80.43%, 73.91% and 69.57%; the diagnosis specificity of CRC for CEA, AFP and CA19-9 were 75.00%, 69.44% and 61.11%. The areas under the ROC curves for CEA, AFP and CA19-9, were 0.88, 0.78 and 0.77 respectively. CONCLUSION: These findings suggest that serum CEA, AFP and CA19-9 may be a useful biomarker for diagnosis of colorectal carcinoma against NMCD. PMID- 25693942 TI - A systematic review and meta-analysis of runt-related transcription factor 3 gene promoter hypermethylation and risk of gastric cancer. AB - OBJECTIVE: To evaluate the association between runt-related transcription factor 3 (RUNX3) gene promoter hypermethylation and gastric cancer risk by meta analysis. MATERIALS AND METHODS: By searching Medline, EMBASE, Ovid, China National Knowledge Infrastructure and Wanfang databases, the open published articles reporting the relationship between RUNX3 gene promoter hypermethylation, and gastric carcinoma risk, were screened. The aggregated odds ratio of RUNX3 gene promoter hypermethylation in cancerous sample of gastric cancer patients compared to normal gastric tissue of gastric cancer patients was pooled by statistic software STATA-11.0. RESULTS: Sixteen studies include 2631 samples were finally included in this meta-analysis. The aggregated results indicated that the hypermethylation rate in cancerous tissue was much higher than that in normal tissue (55.1% vs. 26.5%, P < 0.05). And the pooled results showed that the RUNX3 gene promoter methylation odds in tumor tissue in gastric cancer patients compared to normal gastric tissue was 5.47 (95% confidence interval: 3.34-8.96). CONCLUSION: RUNX3 gene promoter hypermethylation rate was much higher in tumor tissue than that in normal gastric tissue in the patient with gastric cancer. PMID- 25693943 TI - Clinical analysis of acute lung injury after esophagectomy. AB - OBJECTIVE: Acute lung injury (ALI) is one of the most severe postoperative complications after esophagectomy for esophageal cancer patients. In order to clarify the mechanism of ALI, we, therefore, studied the operative course of a group of patients who underwent elective esophagectomy. MATERIALS AND METHODS: We retrospectively analyzed 75 patients underwent an esophagectomy and reconstruction for thoracic esophageal cancer. RESULTS: No statistically significant differences were observed between the two groups regarding their clinical backgrounds, such as their age, smoking index, preoperative pulmonary function, the location of the main tumor, and the tumor nodes metastasis stage. Operative time is thus considered to be a significant factor. The odds ratio (OR) of ALI in cases whose preoperative pulmonary function was 6.70 in comparison to the abnormal preoperative pulmonary functions. The OR for more intraoperative bleeding (>1000 g) was 0.83, compared with a lesser intraoperative bleeding although the difference was not statistically significant (P = 0.076). Anastomotic leakage occurred in four patients (44%) in Group I while it only occurred in two patient (6%) among the 33 Group II patients (P = 0.011). CONCLUSION: Greater surgical stress, such as a longer operative time, is thus considered to be associated with the first attack of ALI. The adverse events developing in the extrathoracic site, such as necrosis and local infection around anastomosis may, therefore, be the second attack. Furthermore, ALI may cause not only systemic inflammatory response syndrome but also other complications such as anastomotic leakage. PMID- 25693944 TI - Diagnostic value of endorectal ultrasonography for rectal carcinoma: a meta analysis. AB - OBJECTIVE: The aim of this meta-analysis was to evaluate the diagnosis efficacy of endorectal ultrasonography (ERUS) for rectal carcinoma. MATERIALS AND METHODS: We searched all the published articles about ERUS in evaluation of rectal carcinoma in the electronic databases. The pooled diagnosis sensitivity, specificity, diagnosis odds ratio, a positive likelihood ratio, negative likelihood ratio, and area under the receiver operating characteristic (ROC) were calculated by MetaDiSc-1.4 software. RESULTS: Fourteen studies with 1583 subjects meeting the inclusion criteria were recruited in this meta-analysis. For tumor invasion evaluated by ERUS, the pooled diagnosis sensitivity, specificity, diagnosis odds ratio, positive likelihood ratio, negative likelihood ratio and area under the ROC were 0.95 (0.92-0.97), 0.80 (0.71-0.86), 62.88 (9.30-425.33), 3.66 (2.48-5.39), 0.07 (0.01-0.40), and 0.86; for lymph node involvement evaluated by EU, the pooled diagnosis sensitivity, specificity, diagnosis odds ratio, positive likelihood ratio, negative likelihood ratio and area under the ROC were 0.58 (0.53-0.63), 0.80 (0.77-0.84), 5.93 (4.07-8.63), 2.85 (2.30-3.52), 0.54 (0.46-0.63) and 0.78. CONCLUSION: ERUS was a good method for the assessment of invasion of rectal tumors and lymph node involvement. PMID- 25693945 TI - Stretching self-entangled DNA molecules in elongational fields. AB - We present experiments of self-entangled DNA molecules stretching under a planar elongational field, and their stretching dynamics are compared to identical molecules without entanglements. Self-entangled molecules stretch in a stage-wise fashion, persisting in an "arrested" state for decades of strain prior to rapidly stretching, slowing down the stretching dynamics by an order of magnitude compared to unentangled molecules. Self-entangled molecules are shown to proceed through a transient state where one or two ends of the molecule are protruding from an entangled, knotted core. This phenomenon sharply contrasts with the wide array of transient configurations shown here and by others for stretching polymers without entanglements. The rate at which self-entangled molecules stretch through this transient state is demonstrably slower than unentangled molecules, providing the first direct experimental evidence of a topological friction. These experimental observations are shown to be qualitatively and semi quantitatively reproduced by a dumbbell model with two fitting parameters, the values of which are reasonable in light of previous experiments of knotted DNA. PMID- 25693946 TI - Effects of sucrose and benzyl alcohol on GCSF conformational dynamics revealed by hydrogen deuterium exchange mass spectrometry. AB - Protein stability, one of the major concerns for therapeutic protein development, can be optimized during process development by evaluating multiple formulation conditions. This can be a costly and lengthy procedure where different excipients and storage conditions are tested for their impact on protein stability. A better understanding of the effects of different formulation conditions at the molecular level will provide information on the local interactions within the protein leading to a more rational design of stable and efficacious formulations. In this study, we examined the roles of the excipients, sucrose and benzyl alcohol, on the conformational dynamics of recombinant human granulocyte colony stimulating factor using hydrogen/deuterium exchange coupled with mass spectrometry (HDX-MS). Under physiological pH and temperature, sucrose globally protects the whole molecule from deuterium uptake, whereas benzyl alcohol induces increased deuterium uptake of the regions within the alpha-helical bundle, with even larger extent. The HDX experiments described were incorporated a set of internal peptides (Zhang et al., 2012. Anal Chem 84:4942-4949) to monitor the differences in intrinsic exchange rates in different formulations. In addition, we discussed the feasibility of implementing HDX-MS with these peptide probes in protein formulation development. PMID- 25693947 TI - Can physicians conceive of performing euthanasia in case of psychiatric disease, dementia or being tired of living? AB - BACKGROUND: Euthanasia and physician-assisted suicide (EAS) in patients with psychiatric disease, dementia or patients who are tired of living (without severe morbidity) is highly controversial. Although such cases can fall under the Dutch Euthanasia Act, Dutch physicians seem reluctant to perform EAS, and it is not clear whether or not physicians reject the possibility of EAS in these cases. AIM: To determine whether physicians can conceive of granting requests for EAS in patients with cancer, another physical disease, psychiatric disease, dementia or patients who are tired of living, and to evaluate whether physician characteristics are associated with conceivability. A cross-sectional study (survey) was conducted among 2269 Dutch general practitioners, elderly care physicians and clinical specialists. RESULTS: The response rate was 64% (n=1456). Most physicians found it conceivable that they would grant a request for EAS in a patient with cancer or another physical disease (85% and 82%). Less than half of the physicians found this conceivable in patients with psychiatric disease (34%), early-stage dementia (40%), advanced dementia (29-33%) or tired of living (27%). General practitioners were most likely to find it conceivable that they would perform EAS. CONCLUSIONS: This study shows that a minority of Dutch physicians find it conceivable that they would grant a request for EAS from a patient with psychiatric disease, dementia or a patient who is tired of living. For physicians who find EAS inconceivable in these cases, legal arguments and personal moral objections both probably play a role. PMID- 25693948 TI - Adipogenic Differentiation of hMSCs is Mediated by Recruitment of IGF-1r Onto the Primary Cilium Associated With Cilia Elongation. AB - Primary cilia are single non-motile organelles that provide a highly regulated compartment into which specific proteins are trafficked as a critical part of various signaling pathways. The absence of primary cilia has been shown to prevent differentiation of human mesenchymal stem cells (hMSCs). Changes in primary cilia length are crucial for regulating signaling events; however it is not known how alterations in cilia structure relate to differentiation. This study tested the hypothesis that changes in primary cilia structure are required for stem cell differentiation. hMSCs expressed primary cilia that were labeled with acetylated alpha tubulin and visualized by confocal microscopy. Chemically induced differentiation resulted in lineage specific changes in cilia length and prevalence which were independent of cell cycle. In particular, adipogenic differentiation resulted in cilia elongation associated with the presence of dexamethasone, while insulin had an inhibitory effect on cilia length. Over a 7 day time course, adipogenic differentiation media resulted in cilia elongation within 2 days followed by increased nuclear PPARgamma levels; an early marker of adipogenesis. Cilia elongation was associated with increased trafficking of insulin-like growth factor-1 receptor beta (IGF-1Rbeta) into the cilium. This was reversed on inhibition of elongation by IFT-88 siRNA transfection, which also decreased nuclear PPARgamma. This is the first study to show that adipogenic differentiation requires primary cilia elongation associated with the recruitment of IGF-1Rbeta onto the cilium. This study may lead to the development of cilia targeted therapies for controlling adipogenic differentiation and associated conditions such as obesity. PMID- 25693949 TI - Luminescence properties of green-emitting Ca2MgSi2O7:Eu2+ phosphor by a solid state reaction method. AB - A europium (Eu)-doped di-calcium magnesium di-silicate phosphor, Ca2MgSi2O7 :Eu(2+) , was prepared using a solid-state reaction method. The phase structure, particle size, surface morphology, elemental analysis, different stretching mode and luminescence properties were analyzed by X-ray diffraction (XRD), transmission electron microscopy (TEM), field emission scanning electron microscopy (FESEM) with energy dispersive X-ray spectroscopy (EDX), Fourier transform infrared (FTIR) spectroscopy, photoluminescence (PL) and mechanoluminescence (ML). The phase structure of Ca2MgSi2O7:Eu(2+) was an akermanite-type structure, which belongs to the tetragonal crystallography with space group P421 m; this structure is a member of the melilite group and forms a layered compound. The surface of the prepared phosphor was not found to be uniform and particle distribution was in the nanometer range. EDX and FTIR confirm the components of Eu(2+)-doped Ca2MgSi2O7 phosphor. Under UV excitation, the main emission peak appeared at 530 nm, belonging to the broad emission ascribed to the 4f(6) 5d(1) -> 4f(7) transition of Eu(2+). The ML intensity of the prepared phosphor increased linearly with increasing impact velocity. A CIE color chromaticity diagram and ML spectrum confirmed that the prepared Ca2MgSi2O7:Eu(2+) phosphor would emit green color and the ML spectrum was similar to that of PL, which indicated that ML is emitted from the same center of Eu(2+) ions. PMID- 25693950 TI - Communicating the risk of violent and offending behavior: review and introduction to this special issue. AB - How to communicate risk of recidivism in correctional and forensic contexts has been a subject of scholarly discussion for two decades. This emerging literature, however, is sparse compared with studies on the assessment of risk for violent and offending behavior. In this special issue of Behavioral Sciences and the Law, we have gathered together empirical and review papers exemplifying promising directions and methodologies. We begin with a review of the state of the field, and lessons that can be drawn from research into medical risk assessment and risk communication, finding that many of the same principles apply to the forensic context. How risks are framed, and how numerate assessors are, affects how risk information is understood and applied. We discuss the existing research bearing on these issues, as well as the conceptual, practical, empirical, and legal implications of communicating risk using numerical or categorical risk terms. Along with the seven articles in this volume, we suggest directions for future research on measuring and communicating change, understanding and managing the statistical literacy of those who use and communicate risk assessments, and developing a theoretical framework for forensic risk communication research. We hope this volume will help integrate and invigorate research into forensic risk communication. PMID- 25693951 TI - The use of risk and need factors in forensic mental health decision-making and the role of gender and index offense severity. AB - Canadian legislation makes Review Boards (RBs) responsible for rendering dispositions for individuals found Not Criminally Responsible on account of Mental Disorder (NCRMD) after considering public safety, the mental condition of the accused, and his/her potential for community reintegration. We reviewed 6,743 RB hearings for 1,794 individuals found NCRMD in the three largest Canadian provinces to investigate whether items from two empirically supported risk assessment measures, the Historical Clinical Risk Management-20 and the Violence Risk Appraisal Guide, were considered. Less than half the items were included in expert reports or in RBs' reasons for dispositions, and consideration of these items differed according to gender and index offense severity of the accused. These items included evidence-based risk factors and/or legally specified criteria: mental health, treatment, and criminal history. These results illustrate the gap between research on risk factors and the integration of this evidence into practice. In particular, we recommend the implementation of structured measures to reduce the potential for clinicians to be unduly influenced by gender and offense severity. PMID- 25693952 TI - Preventative detention decisions: reliance on expert assessments and evidence of partisan allegiance within the Canadian context. AB - The purpose of this study was to examine judges' written reasons for sentencing in preventative detention hearings and the expert risk assessment reports presented, to determine the level of reliance placed on expert risk assessment reports and to examine the presence of partisan allegiance within the Canadian context. Results demonstrated that judges' decisions were consistent with expert assessments in terms of risk, treatment amenability, and risk management. Experts' ratings of treatment amenability and risk management were also significant predictors of the designation outcome, indicating that judges rely on this information in making their final decision. Finally, there was evidence of partisan allegiance, with prosecution-retained Psychopathy Checklist-Revised scores being significantly higher than defense-retained experts' scores. The results have implications for the development of consistent guidelines for the communication of risk, treatment amenability, and management information. PMID- 25693953 TI - Evaluation and applications of the clinically significant change method with the Violence Risk Scale-Sexual Offender version: implications for risk-change communication. AB - We examined the use of the clinically significant change (CSC) method with the Violence Risk Scale-Sexual Offender version (VRS-SO), and its implications for risk communication, in a combined sample of 945 treated sexual offenders from three international settings, followed up for a minimum 5 years post-release. The reliable change (RC) index was used to identify thresholds of clinically meaningful change and to create four CSC groups (already okay, recovered, improved, unchanged) based on VRS-SO dynamic scores and amount of change made. Outcome analyses demonstrated important CSC-group differences in 5-year rates of sexual and violent recidivism. However, when baseline risk was controlled via Cox regression survival analysis, the pattern and magnitude of CSC-group differences in sexual and violent recidivism changed to suggest that observed variation in recidivism base rates could be at least partly explained by pre-existing group differences in risk level. Implications for communication of risk-change information and applications to clinical practice are discussed. PMID- 25693954 TI - Evidence for risk estimate precision: implications for individual risk communication. AB - Actuarial risk assessment instruments using well-established predictor variables measured at the individual level (e.g., age, criminal history, psychopathy) discriminate well between recidivists and non-recidivists across diverse samples. Data indicating the relative risk of recidivism can inform policy decisions about allocating resources according to risk within a correctional system, consistent with the first of the risk-need-responsivity (RNR) principles. Evidence for the precision of absolute risk as applied to an individual based on scores from many samples, however, has proven challenging. In this paper, we present a study examining the association of actuarial risk estimate precision with sample size using the Post Conviction Risk Assessment (PCRA; Lowenkamp et al., 2013), in samples of up to 26,642 offenders. Results indicate that the precision of individual estimates can be demonstrated with sufficient sample size. We believe that the implications of absolute risk for the communication of an individual offender's risks have been poorly understood. We argue that the purpose of individual-level risk communication is to ensure the effective application of policy, which requires matching a new case to aggregate data. We illustrate how an offender's risk might thus be communicated, and conclude that this function is distinct from management of an individual's criminogenic needs and identification of effective and suitable treatments. PMID- 25693955 TI - Progress in violence risk assessment and communication: hypothesis versus evidence. AB - We draw a distinction between hypothesis and evidence with respect to the assessment and communication of the risk of violent recidivism. We suggest that some authorities in the field have proposed quite valid and reasonable hypotheses with respect to several issues. Among these are the following: that accuracy will be improved by the adjustment or moderation of numerical scores based on clinical opinions about rare risk factors or other considerations pertaining to the applicability to the case at hand; that there is something fundamentally distinct about protective factors so that they are not merely the obverse of risk factors, such that optimal accuracy cannot be achieved without consideration of such protective factors; and that assessment of dynamic factors is required for optimal accuracy and furthermore interventions aimed at such dynamic factors can be expected to cause reductions in violence risk. We suggest here that, while these are generally reasonable hypotheses, they have been inappropriately presented to practitioners as empirically supported facts, and that practitioners' assessment and communication about violence risk run beyond that supported by the available evidence as a result. We further suggest that this represents harm, especially in impeding scientific progress. Nothing here justifies stasis or simply surrendering to authoritarian custody with somatic treatment. Theoretically motivated and clearly articulated assessment and intervention should be provided for offenders, but in a manner that moves the field more firmly from hypotheses to evidence. PMID- 25693956 TI - Grant T. Harris (1950-2014). AB - This obituary of Dr. Grant Harris describes his life and the outstanding contributions he made to the field of correctional and forensic psychology. PMID- 25693957 TI - Punishing repeat offenders in the Netherlands: balancing between incapacitation and treatment. AB - In the Netherlands, punishing repeat offenders is not a foregone conclusion. After a decades-long search for an appropriate punishment, repeat offenders are currently punished by means of a custodial security measure. A custodial security measure is additional incarceration often beyond the original penalty. This new penal measure can be imposed for a maximum of 2 years, and is designed to ensure public safety and reduce recidivism by way of incapacitation. However, given the fact that nearly every repeat offender suffers from severe comorbid problems (e.g., a mental illness and substance abuse disorder), judges tend to consider these objectives from a long-term perspective by insisting on as much treatment during detention as possible. Consequently, the punishment for repeat offenders balances between incapacitation and treatment. While some have argued that the current Dutch sentencing scheme represents a new way of sentencing, this article demonstrates that the reliance on the sometimes dichotomous goals of punishment and rehabilitation is characteristic not only of the current type of repeat offender punishment, but of all previous types as well. PMID- 25693958 TI - Professional Standards Authority accredited registers for people who work in health and care occupations that are not regulated. PMID- 25693959 TI - Royal college calls on hospitals to tackle emergency department "exit block" to hospital beds. PMID- 25693960 TI - Measuring neuroplasticity in children using brain stimulation. PMID- 25693961 TI - Corticosteroids reduce treatment failure in severe community acquired pneumonia, trial shows. PMID- 25693962 TI - Control of stem-cell behavior by fine tuning the supramolecular assemblies of low molecular-weight gelators. AB - Controlling the behavior of stem cells through the supramolecular architecture of the extracellular matrix remains an important challenge in the culture of stem cells. Herein, we report on a new generation of low-molecular-weight gelators (LMWG) for the culture of isolated stem cells. The bola-amphiphile structures derived from nucleolipids feature unique rheological and biological properties suitable for tissue engineering applications. The bola-amphiphile-based hydrogel scaffold exhibits the following essential properties: it is nontoxic, easy to handle, injectable, and features a biocompatible rheology. The reported glycosyl nucleoside bola-amphiphiles (GNBA) are the first examples of LMWG that allow the culture of isolated stem cells in a gel matrix. The results (TEM observations and rheology) suggest that the supramolecular organizations of the matrix play a role in the behavior of stem cells in 3D environments. PMID- 25693963 TI - Procedures for treating precancerous cervical cancer do not reduce fertility, study shows. PMID- 25693964 TI - A novel fragile X syndrome mutation reveals a conserved role for the carboxy terminus in FMRP localization and function. AB - Loss of function of the FMR1 gene leads to fragile X syndrome (FXS), the most common form of intellectual disability. The loss of FMR1 function is usually caused by epigenetic silencing of the FMR1 promoter leading to expansion and subsequent methylation of a CGG repeat in the 5' untranslated region. Very few coding sequence variations have been experimentally characterized and shown to be causal to the disease. Here, we describe a novel FMR1 mutation and reveal an unexpected nuclear export function for the C-terminus of FMRP. We screened a cohort of patients with typical FXS symptoms who tested negative for CGG repeat expansion in the FMR1 locus. In one patient, we identified a guanine insertion in FMR1 exon 15. This mutation alters the open reading frame creating a short novel C-terminal sequence, followed by a stop codon. We find that this novel peptide encodes a functional nuclear localization signal (NLS) targeting the patient FMRP to the nucleolus in human cells. We also reveal an evolutionarily conserved nuclear export function associated with the endogenous C-terminus of FMRP. In vivo analyses in Drosophila demonstrate that a patient-mimetic mutation alters the localization and function of Dfmrp in neurons, leading to neomorphic neuronal phenotypes. PMID- 25693965 TI - Three-phase hollow-fiber microextraction combined with ion-pair high-performance liquid chromatography for the simultaneous determination of five components of compound alpha-ketoacid tablets in human urine. AB - The determination of alpha-ketoacid concentration is demanded to evaluate the absorption and metabolic behavior of compound alpha-ketoacid tablets taken by chronic kidney disease patients. To eliminate the interference of endogenous substance of urine and enrich the analytes, a three-phase hollow-fiber liquid phase microextraction combined with ion-pair high-performance liquid chromatography method was established for the determination of d,l-alpha hydroxymethionine calcium, d,l-alpha-ketoisoleucine calcium, alpha-ketovaline calcium, alpha-ketoleucine calcium, and alpha-ketophenylalanine calcium of compound alpha-ketoacid tablets in human urine samples. The extraction parameters, such as organic solvent, pH of donor phase and acceptor phase, stirring rate, and extraction time were optimized. Under the optimal conditions, the obtained enrichment factors were up to 11-, 110-, 198-, 202-, and 50-fold, respectively. The calibration curves for these analytes were linear over the range of 0.1-10 mg/L for alpha-ketovaline calcium, d,l-alpha-ketoisoleucine calcium, and alpha-ketoleucine calcium, 0.5-10 mg/L for d,l-alpha hydroxymethionine calcium, and alpha-ketophenylalanine calcium with r > 0.99. The relative standard deviations (n = 5) were less than 6.27% and the LODs were 100.7, 10.0, 5.8, 7.8, and 8.6 MUg/L (based on S/N = 3), respectively. Good recoveries from spiked urine samples (92-118%) were obtained. The proposed method demonstrated excellent sample clean-up and analytes enrichment to determine the five components in human urine. PMID- 25693966 TI - Molecular basis for the recognition of cyclic-di-AMP by PstA, a PII-like signal transduction protein. AB - Cyclic-di-AMP (c-di-AMP) is a broadly conserved bacterial second messenger that is of importance in bacterial physiology. The molecular receptors mediating the cellular responses to the c-di-AMP signal are just beginning to be discovered. PstA is a previously uncharacterized PII -like protein which has been identified as a c-di-AMP receptor. PstA is widely distributed and conserved among Gram positive bacteria in the phylum Firmicutes. Here, we report the biochemical, structural, and functional characterization of PstA from Listeria monocytogenes. We have determined the crystal structures of PstA in the c-di-AMP-bound and apo forms at 1.6 and 2.9 A resolution, respectively, which provide the molecular basis for its specific recognition of c-di-AMP. PstA forms a homotrimer structure that has overall similarity to the PII protein family which binds ATP. However, PstA is markedly different from PII proteins in the loop regions, and these structural differences mediate the specific recognition of their respective nucleotide ligand. The residues composing the c-di-AMP binding pocket are conserved, suggesting that c-di-AMP recognition by PstA is of functional importance. Disruption of pstA in L. monocytogenes affected c-di-AMP-mediated alterations in bacterial growth and lysis. Overall, we have defined the PstA family as a conserved and specific c-di-AMP receptor in bacteria. PMID- 25693967 TI - Serious cardiac complications in coronary spasm provocation tests using acetylcholine or ergonovine: analysis of 21 512 patients from the diagnosis procedure combination database in Japan. AB - BACKGROUND: Previous studies on complications with coronary spasm provocation tests were based on small sample sizes or were limited to high-volume centers. The risk of provocation tests using acetylcholine (ACH) or ergonovine (ER) remains to be fully examined by a large-scale multicenter study. HYPOTHESIS: ACH provocation tests are associated with a higher rate of serious cardiac complications than ER tests. METHODS: Using the Diagnosis Procedure Combination database in Japan, we identified patients aged >=20 years who underwent a pharmacological provocation test during coronary angiography. We assessed the composite outcome of cardiac complications requiring urgent procedures (defibrillation, chest compression, intra-aortic balloon pumping, or extracorporeal membrane oxygenation) or death on the day of the provocation test, and compared the outcome between ACH and ER tests. RESULTS: Of 21 512 eligible patients in 602 hospitals, 10 628 (49.4%) underwent an ACH test and 10 884 (50.6%) underwent an ER test. The composite outcome occurred in 141 (0.7%) patients. The ACH group was significantly more likely to have the composite outcome than the ER group (0.9% vs 0.4%, P < 0.001). The propensity-score analyses showed consistent results (propensity score-matched, 0.9% vs 0.4%, P = 0.003; inverse probability-weighted, 0.8% vs 0.4%, P < 0.001). In a multivariable logistic regression analysis, ACH tests were significantly associated with a higher rate of the composite outcome than ER tests (odds ratio: 1.75, 95% confidence interval: 1.13-2.69, P = 0.011). CONCLUSIONS: This retrospective cohort study suggested that ACH tests were associated with a higher rate of cardiac complications than ER tests. PMID- 25693968 TI - Dianions as Formal Oxidants: Synthesis and Characterization of Aromatic Dilithionickeloles from 1,4-Dilithio-1,3-butadienes and [Ni(cod)2]. AB - Organolithium compounds can behave as reductants but never as oxidants in redox reactions. Reported herein is that 1,4-dilithio-1,3-butadienes reacted with [Ni(cod)2] (cod = 1,5-cyclooctadiene) to deliver dilithionickeloles. Single crystal X-ray structural analysis revealed a coplanar structure of dilithionickeloles with an averaging of bond lengths. XPS data confirmed the oxidation state of Ni in dilithionickeloles was Ni(2+). (7)Li NMR spectra of dilithionickeloles and theoretical calculations revealed a considerable aromatic character. In this redox reaction, the dilithio dianionic compounds behaved as formal oxidants, thus oxidizing Ni(0) into Ni(2+). These results demonstrated that organolithium compounds with pi-conjugation could be used as oxidants and could continue to accept extra electrons. PMID- 25693969 TI - Cerebral responses to puncturing at different acupoints for treating meal-related functional dyspepsia. AB - BACKGROUND: To investigate the similarities and differences in cerebral responses to puncturing at different acupoints for treating meal-related functional dyspepsia (FD). METHODS: Twenty right-handed FD patients were enrolled and randomized divided into two groups. Each patient received 20 sessions' electro acupuncture treatment. The acupoints used in Group A were four acupoints on the Stomach Meridian, and the acupoints used in Group B were four acupoints on the Gallbladder Meridian. PET-CT scans were performed before and after acupuncture treatment to record the changes of cerebral glycometabolism. KEY RESULTS: After treatment, the dyspepsia symptoms and the quality of life (QOL) of the patients in each group were significantly improved (p < 0.05) and there was insignificant difference in efficacy between the two groups (p > 0.05). In Group A, deactivation in brainstem, bilateral anterior cingulate cortex (ACC) and cerebellum, left superior medial frontal gyrus, orbital frontal cortex (OFC), and thalamus, etc., and activation in bilateral middle cingulate cortex (MCC), precuneus and lingual gyrus, etc. were observed. In Group B, deactivation in brainstem, bilateral thalamus, putamen, ACC, postterior cingulate cortex, hippocampus and cerebellum, etc., and activation in bilateral MCC, precuneus, left OFC, etc. were observed (p < 0.05, Family-wise error corrected). CONCLUSIONS & INFERENCES: Different acupoints have similar clinical efficacy but relatively different cerebral responses. The influence on the sensory transduction regions (brainstem and thalamus) and visceral modulation regions might be the common mechanism of different acupoints treating for FD, and the modulation on some emotion/cognition-related areas (e.g., prefrontal cortex) is the potential difference between the different acupoints. PMID- 25693970 TI - Quantitative Determination of Secoiridoids and Phenylpropanoids in Different Extracts of Ligustrum Vulgare L. Leaves by a Validated HPTLC-Photodensitometry Method. AB - INTRODUCTION: The genus Ligustrum (Oleaceae) is distributed in Europe and Asia (south China and Korea), where it is used to prevent hypertension, sore throats, inflammation and diabetes. The main groups of compounds in extracts of Ligustrum vulgare are biologically active secoiridoids and phenylpropanoids. OBJECTIVES: The aim of the study was primarily the development and validation of a HPTLC photodensitometry method for separation and determination of secoiridoids (oleacein, oleuropein) and phenylpropanoids (echinacoside) in different extracts prepared from leaves of L. vulgare. A secondary issue was the quantitative screening of oleacein, oleuropein and echinacoside in extracts from leaves collected at different stages of plant growth (from May to September). METHODS: A HPTLC-photodensitometry method was developed and validated for quantification of oleuropein, oleacein and echinacoside in plant extracts (aqueous and ethanolic extract, decoction, infusion). Silica gel was used as the stationary phase and dichloromethane:methanol:formic acid:water (80:25:1.5:4, v/v/v/v) as the mobile phase. RESULTS: The HPTLC-photodensitometry method developed for quantification of oleacein, oleuropein and echinacoside was specific, accurate and precise. The presence of oleacein was detected in aqueous extracts, whereas oleuropein was present, in particular, in ethanolic extracts, decoctions and infusions. Echinacoside was detected in all the extracts prepared. The content of secoiridoids was variable from May to September, whereas the amount of echinacoside increased in this term. CONCLUSION: The developed and validated HPTLC-photodensitometry method allowed performing fast screening of quantitative profiles of oleacein, oleuropein and echinacoside in preparations of privet leaves. PMID- 25693971 TI - The association between plasma visfatin levels and ED. AB - Visfatin was initially proposed as a clinical marker of atherosclerosis, endothelial dysfunction and vascular damage, with a potential prognostic value. It has been shown that endothelial dysfunction has an important role in ED. We aimed to determine the levels of visfatin in ED patients and characterize the relationship between visfatin levels and ED. This case-control study was conducted between October 2010 and August 2012, and 41 severe ED patients (group 1) and 36 healthy controls (group 2) were involved. Fasting visfatin level was measured with enzyme-linked immunosorbent assay method. The groups were compared in terms of some clinical (height, weight and body mass index) and biochemical parameters (glucose, triglycerides, cholesterol, low-density lipoprotein and high density lipoprotein). No statistically significant difference in the visfatin levels was found between the patients and the controls (17, 5+/-14.4, 14, 9+/-7 and 9, respectively, P=0.399). No difference in the other clinical and biochemical parameters was observed between the two groups. No significant difference in the serum visfatin levels of ED patients compared with healthy patients was noticed. Further studies are needed to confirm the effect of visfatin on cardiometabolic diseases and ED, indeed. PMID- 25693972 TI - Supramolecular assembly of achiral alkynylplatinum(II) complexes and carboxylic beta-1,3-glucan into different helical handedness stabilized by Pt???Pt and/or pi pi interactions. AB - Two-component ensembles of alkynylplatinum(II) terpyridine (tpy) complexes and carboxylic beta-1,3-glucan (CurCOOH) have been investigated by using spectroscopic and microscopic techniques, as well as time-dependent UV/Vis absorption and circular dichroism (CD) experiments. Microscopic images of [Pt(tpy){C=CC6 H4 (CH2 NMe3 -4)}](OTf)2 (1) have revealed spherical nanostructures, whereas helical fibrous structures of different lengths, depending on the concentration of complex 1 and CurCOOH, were observed. The helical assemblies have been found to show low-energy metal-metal-to-ligand charge transfer (MMLCT) absorption and triplet MMLCT ((3) MMLCT) emission, which are indicative of Pt???Pt and/or pi-pi interactions between the complex 1 molecules. Interestingly, the ensemble has been demonstrated to show different handedness and even a change in handedness over time under different experimental conditions. Low temperatures, low concentrations of CurCOOH, high concentrations of complex 1, or successive addition of CurCOOH into complex 1 solution favor the formation of right-handed helical assemblies, whereas high temperatures, high concentrations of CurCOOH, low concentrations of complex 1, or single-batch addition of CurCOOH into complex 1 solution result in a fast chiroptical inversion of the ensemble solution, giving rise to the left-handed helical assemblies as the dominant species. The results have been rationalized by considering the competing kinetically and thermodynamically controlled assembly elongation of the ensemble, which leads to the formation of right-handed and left handed helical assemblies, respectively. The change in the handedness of the ensemble has been demonstrated to stem from the formation of two-component assemblies with supramolecular interactions, in contrast to the template- induced chiral amplification commonly observed in other systems. PMID- 25693973 TI - Anti-inflammatory effect of garlic 14-kDa protein on LPS-stimulated-J774A.1 macrophages. AB - CONTEXT: Garlic 14-kDa protein is purified from garlic (Allium sativum L.) which is used in traditional medicine and exerts various immunomodulatory activities. OBJECTIVE: The present study investigated the suppressive effect of garlic 14-kDa protein on LPS-induced expression of pro-inflammatory mediators and underlying mechanism in inflammatory macrophages. MATERIALS AND METHODS: J774A.1 macrophages were treated with 14-kDa protein (5-30 MUg/ml) with/without LPS (1 MUg/ml) and the production of inflammatory mediators such as prostaglandin E2 (PGE2), TNF alpha, and IL-1beta released were measured using ELISA. Nitric oxide (NO) production was determined using the Griess method. The anti-inflammatory activity of 14-kDa protein was examined by measuring inducible nitric oxide synthase and cyclooxygenase-2 proteins using western blot. The expression of nuclear NF-kappaB p65 subunit was assessed by western blot. RESULTS: Garlic 14-kDa protein significantly inhibited the excessive production of NO, PGE, TNF-alpha, and IL 1beta in lipopolysaccharide (LPS)-activated J774A.1 macrophages in a concentration-related manner without cytotoxic effect. Western blot analysis demonstrated that garlic 14-kDa protein suppressed corresponding inducible NO synthase expression and activated cyclooxygenase-2 protein expression. The inhibitory effect was mediated partly by a reduction in the activity and expression of transcription factor NF-kappaB protein. CONCLUSION: Our results suggested, for the first time, garlic 14-kDa protein exhibits anti-inflammatory properties in macrophages possibly by suppressing the inflammatory mediators via the inhibition of transcription factor NF-kappaB signaling pathway. The traditional use of garlic as anti-inflammatory remedy could be ascribed partly to 14-kDa protein content. This protein might be a useful candidate for controlling inflammatory diseases and further investigations in vivo. PMID- 25693974 TI - Sertoli cell as a model in male reproductive toxicology: Advantages and disadvantages. AB - Pressure towards population aging in the demographic pyramid is not only due to sociological/personal choices but also due to subfertility or infertility. There are several chemicals and mixtures that impair male fertility. While experimental animal models are crucial to identify compounds that affect male fertility, it is essential to use reliable in vitro models to determine cellular targets and intracellular pathways that mediate chemical toxicity in the male reproductive system. In this review, we focused on the somatic Sertoli cell (SC) that, within the testis, is a major target for hormonal signaling and provides physical and nutritional support to developing germ cells. The different outcomes possible in each type of study: in vivo versus in vitro (either in primary or immortalized cell cultures) are analyzed. Herein, we intend to clarify the unique features that render SCs as excellent candidates for a robust in vitro model to study the deleterious effects of chemicals on male reproductive health. The sensitivity of SCs to toxicants/pharmaceuticals is discussed and, based on the literature reviewed we propose the in vitro study of SC physiology as a model to disclose deleterious effects of substances to male fertility. PMID- 25693975 TI - Ovarian Hormones Regulate SP-D Expression in the Mouse Uterus During Estrous Cycle and Early Pregnancy. AB - PROBLEM: Differential expression of SP-D in the cycling human and mouse endometrium suggests its regulation by ovarian hormones. METHOD OF STUDY: SP-D expression in the mouse uterus was analyzed across the estrous cycle and during early pregnancy. Effect of exogenous ovarian hormones on the uterine expression of SP-D was analyzed. RESULTS: SP-D expression varied across the estrous cycle and peaked in the estrous phase. SP-D transcript levels increased by fourfold in the uteri of estrogen-treated mice while co-administration of estrogen and progesterone enhanced SP-D levels by ninefold. However, treatment with progesterone alone significantly downregulated SP-D expression. Diethylstilbestrol enhanced SP-D transcript levels in the uteri of immature mice by 10-fold. During pregnancy, SP-D levels declined rapidly from 0.5 dpc to 6.5 dpc. In silico analysis predicted the presence of two potential ERE and 1 PRE in the mouse SP-D gene promoter region. CONCLUSION: Estrogen positively regulates expression of SP-D in the mouse uterus. Progesterone, along with estrogen synergizes SP-D expression, however, when administered alone results in negative regulation. PMID- 25693976 TI - Perihematoma edema: a potential translational target in intracerebral hemorrhage? PMID- 25693977 TI - 4-Hydroxy-2-nonenal attenuates beta2-adrenoceptor-mediated vasodilation of rat retinal arterioles. AB - 4-Hydroxy-2-nonenal (4-HNE) is a major reactive aldehyde formed by lipid peroxidation, and it plays an important role in the pathogenesis of several vascular diseases, including diabetes mellitus. In this study, we examined the effects of 4-HNE on the vasodilatory mechanisms of rat retinal arterioles. The retinal vasodilator responses were assessed by measuring the diameter of retinal arterioles in the fundus images. Intravitreal injection of 4-HNE significantly prevented the vasodilation of retinal arterioles induced by the beta2 adrenoceptor agonist salbutamol but not the nitric oxide donor (+/-)-(E)-4-ethyl 2-[(E)-hydroxyimino]-5-nitro-3-hexenamide (NOR3). Iberiotoxin, an inhibitor of large-conductance KCa (BKCa) channels, significantly reduced the salbutamol induced vasodilation of retinal arterioles. The vasodilator effect of BMS-191011, a BKCa channel opener, on retinal arterioles was significantly attenuated by 4 HNE. These results suggest that 4-HNE attenuates retinal vasodilator responses to beta2-adrenoceptor agonists through the impairment of the BKCa pathway. The direct effect of 4-HNE on retinal blood vessels may, therefore, contribute to the retinal vascular dysfunction observed in patients with diabetes mellitus. PMID- 25693978 TI - Investigation of therapeutic potential and molecular mechanism of vitamin P and digoxin in I/R-induced myocardial infarction in rat. AB - Ischemic-reperfusion (I/R) is a major event in the pathogenesis of ischemic heart disease that leads to higher rate of mortality. The study has been designed to investigate the therapeutic potential and molecular mechanism of vitamin P and digoxin in I/R-induced myocardial infarction in isolated rat heart preparation by using Langendorff apparatus. The animals were treated with vitamin P (50 and 100 mg/kg; p.o.) and digoxin (500 MUg/kg) for 5 consecutive days. Digoxin served as a positive control in the present study. On the sixth day, the heart was harvested and induced to 30 min of global ischemia followed by 120 min of reperfusion using Langendorff apparatus. The coronary effluent was collected at different time intervals (i.e. basal, 1, 15, 30, 45, 60 and 120 min.) for the assessment of myocardial contractility function. In addition, creatine kinase-M and B subunits (CK-MB), lactate dehydrogenase (LDH1) and Na(+)-K(+)-ATPase activity along with oxidative tissue biomarkers (i.e. thio-barbituric acid reactive substances (TBARS) and reduced glutathione (GSH)) changes were estimated. The I/R of myocardium produced decrease in coronary flow rate; increase in CK-MB, LDH1 and Na(+)-K(+)-ATPase activity along with increase in TBARS and decrease in GSH levels as compared to normal group. The treatment with vitamin P (100 mg/kg) and digoxin (500 MUg/kg) have produced a significant (p < 0.05) ameliorative effect against I/R induced above functional, metabolic and tissue biomarkers changes. Vitamin P has an ameliorative potential against I/R induced myocardial functional changes. It may be due to its free radical scavenging and anti-infarct property via inhibition of Na(+)-K(+)-ATPase activity. Therefore, it can be used as a potential therapeutic medicine for the management of cardiovascular disorders. PMID- 25693980 TI - On autonomy in student-run clinics. PMID- 25693981 TI - Continuing professional development: a burden lacking educational outcomes or a marker of professionalism? PMID- 25693982 TI - Dyad training: effective, efficient and transferable. What are we waiting for? PMID- 25693983 TI - Examining our hidden curricula: powerful, visible, gendered and discriminatory. PMID- 25693984 TI - When I say... response process validity. PMID- 25693985 TI - Learning in student-run clinics: a systematic review. AB - CONTEXT: Student-run clinics (SRCs) have existed for many years and may provide the most realistic setting for context-based learning and legitimate early clinical experiences with responsibility for patient care. We reviewed the literature on student outcomes of participation in SRCs. METHODS: A systematic literature review was performed using the PubMed, EMBASE, PsycINFO and ERIC databases. Included articles were reviewed for conclusions and outcomes; study quality was assessed using the Medical Education Research Study Quality Instrument (MERSQI). RESULTS: A total of 42 articles met the inclusion criteria and were included in the quantitative synthesis. The effects of participation on students' attitudes were mainly positive: students valued the SRC experience. Data on the effects of SRC participation on students' skills and knowledge were based mainly on expert opinions and student surveys. Students reported improved skills and indicated that they had acquired knowledge they were unlikely to have gained elsewhere in the curriculum. The quality of specific aspects of care delivered by students was comparable with that of regular care. CONCLUSIONS: The suggestion that students should be trained as medical professionals with responsibility for patient care early in the curriculum is attractive. In an SRC this responsibility is central. Students valued the early training opportunity in SRCs and liked participating. However, little is known about the effect of SRC participation on students' skills and knowledge. The quality of care provided by students seemed adequate. Further research is needed to assess the effect of SRC participation on students' skills, knowledge and behaviour. PMID- 25693986 TI - The effect of continuing professional development on public complaints: a case control study. AB - OBJECTIVES: This study aimed to investigate the relationship between participation in different types of continuing professional development (CPD), and incidences and types of public complaint against physicians. METHODS: Cases included physicians against whom complaints were made by members of the public to the medical regulatory body in Ontario, Canada, the College of Physicians and Surgeons of Ontario (CPSO), during 2008 and 2009. The control cohort included physicians against whom no complaints were documented during the same period. We focused on complaints related to physician communication, quality of care and professionalism. The CPD data included all Royal College of Physicians and Surgeons of Canada (RCPSC) and College of Family Physicians of Canada (CFPC) CPD programme activities reported by the case and control physicians. Multivariate logistic regression models were used to determine if the independent variable, reported participation in CPD, was associated with the dependent variable, the complaints-related status of the physician in the year following reported CPD activities. RESULTS: A total of 2792 physicians were included in the study. There was a significant relationship between participation in CPD, type of CPD and type of complaint received. Analysis indicated that physicians who reported overall participation in CPD activities were significantly less likely (odds ratio 0.604; p = 0.028) to receive quality of care-related complaints than those who did not report participating in CPD. Additionally, participation in group-based CPD was less likely (OR 0.681; p = 0.041) to result in quality of care-related complaints. CONCLUSIONS: The findings demonstrate a positive relationship between participation in the national CPD programmes of the CFPC and RCPSC, and lower numbers of public complaints received by the CPSO. As certification bodies and regulators alike are increasingly mandating CPD, they are encouraged to continually evaluate the effectiveness of their programmes to maximise programme impact on physician performance at the population level. PMID- 25693987 TI - Evaluating the impact of high- and low-fidelity instruction in the development of auscultation skills. AB - CONTEXT: A principal justification for the use of high-fidelity (HF) simulation is that, because it is closer to reality, students will be more motivated to learn and, consequently, will be better able to transfer their learning to real patients. However, the increased authenticity is accompanied by greater complexity, which may reduce learning, and variability in the presentation of a condition on an HF simulator is typically restricted. OBJECTIVES: This study was conducted to explore the effectiveness of HF and low-fidelity (LF) simulation for learning within the clinical education and practice domains of cardiac and respiratory auscultation and physical assessment skills. METHODS: Senior-level nursing students were randomised to HF and LF instruction groups or to a control group. Primary outcome measures included LF (digital sounds on a computer) and HF (human patient simulator) auscultation tests of cardiac and respiratory sounds, as well as observer-rated performances in simulated clinical scenarios. RESULTS: On the LF auscultation test, the LF group consistently demonstrated performance comparable or superior to that of the HF group, and both were superior to the performance of the control group. For both HF outcome measures, there was no significant difference in performance between the HF and LF instruction groups. CONCLUSIONS: The results from this study suggest that highly contextualised learning environments may not be uniformly advantageous for instruction and may lead to ineffective learning by increasing extraneous cognitive load in novice learners. PMID- 25693988 TI - The effect of dyad versus individual simulation-based ultrasound training on skills transfer. AB - CONTEXT: Dyad practice may be as effective as individual practice during clinical skills training, improve students' confidence, and reduce costs of training. However, there is little evidence that dyad training is non-inferior to single student practice in terms of skills transfer. OBJECTIVES: This study was conducted to compare the effectiveness of simulation-based ultrasound training in pairs (dyad practice) with that of training alone (single-student practice) on skills transfer. METHODS: In a non-inferiority trial, 30 ultrasound novices were randomised to dyad (n = 16) or single-student (n = 14) practice. All participants completed a 2-hour training programme on a transvaginal ultrasound simulator. Participants in the dyad group practised together and took turns as the active practitioner, whereas participants in the single group practised alone. Performance improvements were evaluated through pre-, post- and transfer tests. The transfer test involved the assessment of a transvaginal ultrasound scan by one of two clinicians using the Objective Structured Assessment of Ultrasound Skills (OSAUS). RESULTS: Thirty participants completed the simulation-based training and 24 of these completed the transfer test. Dyad training was found to be non-inferior to single-student training: transfer test OSAUS scores were significantly higher than the pre-specified non-inferiority margin (delta score 7.8%, 95% confidence interval -3.8-19.6%; p = 0.04). More dyad (71.4%) than single (30.0%) trainees achieved OSAUS scores above a pre-established pass/fail level in the transfer test (p = 0.05). There were significant differences in performance scores before and after training in both groups (pre- versus post test, p < 0.01) with large effect sizes (Cohen's d = 3.85) and no significant interactions between training type and performance (p = 0.59). The dyad group demonstrated higher training efficiency in terms of simulator score per number of attempts compared with the single-student group (p = 0.03). CONCLUSION: Dyad practice improves the efficiency of simulation-based training and is non-inferior to individual practice in terms of skills transfer. PMID- 25693989 TI - Reading between the lines: faculty interpretations of narrative evaluation comments. AB - OBJECTIVES: Narrative comments are used routinely in many forms of rater-based assessment. Interpretation can be difficult as a result of idiosyncratic writing styles and disconnects between literal and intended meanings. Our purpose was to explore how faculty attendings interpret and make sense of the narrative comments on residents' in-training evaluation reports (ITERs) and to determine the language cues that appear to be influential in generating and justifying their interpretations. METHODS: A group of 24 internal medicine (IM) faculty attendings each categorised a subgroup of postgraduate year 1 (PGY1) and PGY2 IM residents based solely on ITER comments. They were then interviewed to determine how they had made their judgements. Constant comparative techniques from constructivist grounded theory were used to analyse the interviews and develop a framework to help in understanding how ITER language was interpreted. RESULTS: The overarching theme of 'reading between the lines' explained how participants read and interpreted ITER comments. Scanning for 'flags' was part of this strategy. Participants also described specific factors that shaped their judgements, including: consistency of comments; competency domain; specificity; quantity, and context (evaluator identity, rotation type and timing). There were several perceived purposes of ITER comments, including feedback to the resident, summative assessment and other more socially complex objectives. CONCLUSIONS: Participants made inferences based on what they thought evaluators intended by their comments and seemed to share an understanding of a 'hidden code'. Participants' ability to 'read between the lines' explains how comments can be effectively used to categorise and rank-order residents. However, it also suggests a mechanism whereby variable interpretations can arise. Our findings suggest that current assumptions about the purpose, value and effectiveness of ITER comments may be incomplete. Linguistic pragmatics and politeness theories may shed light on why such an implicit code might evolve and be maintained in clinical evaluation. PMID- 25693990 TI - Grades in formative workplace-based assessment: a study of what works for whom and why. AB - CONTEXT: Grades are commonly used in formative workplace-based assessment (WBA) in medical education and training, but may draw attention away from feedback about the task. A dilemma arises because the self-regulatory focus of a trainee must include self-awareness relative to agreed standards, which implies grading. OBJECTIVES: In this study we aimed to understand the meaning which medical students construct from WBA feedback with and without grades, and what influences this. METHODS: Year 3 students were invited to take part in a randomised crossover study in which each student served as his or her own control. Each student undertook one WBA with and one without grades, and then chose whether or not to be given grades in a third WBA. These preferences were explored in semi structured interviews. A realist approach to analysis was used to gain understanding of student preferences and the impact of feedback with and without grades. RESULTS: Of 83 students who were given feedback with and without grades, 65 (78%) then chose to have feedback with grades and 18 (22%) without grades in their third WBA. A total of 24 students were interviewed. Students described how grades locate their performance and calibrate their self-assessment. For some, low grades focused attention and effort. Satisfactory and high grades enhanced self-efficacy. CONCLUSIONS: Grades are concrete, powerful and blunt, can be harmful and need to be explained to help students create helpful meaning from them. Low grades risk reducing self-efficacy in some and may encourage others to focus on proving their ability rather than on improvement. A metaphor of the semi permeable membrane is introduced to elucidate how students reduced potential negative effects and enhanced the positive effects of feedback with grades by selective filtering and pumping. This study illuminates the complexity of the processing of feedback by its recipients, and informs the use of grading in the provision of more effective, tailored feedback. PMID- 25693991 TI - Learning about gender on campus: an analysis of the hidden curriculum for medical students. AB - CONTEXT: Gender sensitivity is a crucial factor in the provision of quality health care. This paper explores acquired gendered values and attitudes among medical students through an analysis of the hidden curriculum that exists within formal medical classes and informal learning. METHODS: Discourse analysis was adopted as the research method. Data were collected from the Bulletin Board System (BBS), which represented an essential communication platform among students in Taiwan before the era of Facebook. The study examined 197 gender related postings on the BBS boards of nine of 11 universities with a medical department in Taiwan, over a period of 10 years from 2000 to 2010. RESULTS: The five distinctive characteristics of the hidden curriculum were as follows: (i) gendered stereotypes of physiological knowledge; (ii) biased treatment of women; (iii) stereotyped gender-based division of labour; (iv) sexual harassment and a hostile environment, and (v) ridiculing of lesbian, gay, bisexual and transgender (LGBT) people. Both teachers and students co-produced a heterosexual masculine culture and sexism, including 'benevolent sexism' and 'hostile sexism'. As a result, the self-esteem and learning opportunities of female and LGBT students have been eroded. CONCLUSIONS: The paper explores gender dynamics in the context of a hidden curriculum in which heterosexual masculinity and stereotyped sexism are prevalent as norms. Both teachers and students, whether through formal medical classes or informal extracurricular interactive activities, are noted to contribute to the consolidation of such norms. The study tentatively suggests three strategies for integrating gender into medical education: (i) by separating physiological knowledge from gender stereotyping in teaching; (ii) by highlighting the importance of gender sensitivity in the language used within and outside the classroom by teachers and students, and (iii) by broadening the horizons of both teachers and students by recounting examples of the lived experiences of those who have been excluded and discriminated against, particularly members of LGBT and other minorities. PMID- 25693992 TI - Learning to care for older patients: hospitals and nursing homes as learning environments. AB - CONTEXT: A significant challenge facing health care is the ageing of the population, which calls for a major response in medical education. Most clinical learning takes place within hospitals, but nursing homes may also represent suitable learning environments in which students can gain competencies in geriatric medicine. OBJECTIVES: This study explores what students perceive as the main learning outcomes of a geriatric medicine clerkship in a hospital or a nursing home, and explicitly addresses factors that may stimulate or hamper the learning process. METHODS: This qualitative study falls within a constructivist paradigm: it draws on socio-cultural learning theory and is guided by the principles of constructivist grounded theory. There were two phases of data collection. Firstly, a maximum variation sample of 68 students completed a worksheet, giving brief written answers on questions regarding their geriatric medicine clerkships. Secondly, focus group discussions were conducted with 19 purposively sampled students. We used template analysis, iteratively cycling between data collection and analysis, using a constant comparative process. RESULTS: Students described a broad range of learning outcomes and formative experiences that were largely distinct from their learning in previous clerkships with regard to specific geriatric knowledge, deliberate decision making, end-of life care, interprofessional collaboration and communication. According to students, the nursing home differed from the hospital in three aspects: interprofessional collaboration was more prominent; the lower resources available in nursing homes stimulated students to be creative, and students reported having greater autonomy in nursing homes compared with the more extensive educational guidance provided in hospitals. CONCLUSIONS: In both hospitals and nursing homes, students not only learn to care for older patients, but also describe various broader learning outcomes necessary to become good doctors. The results of our study, in particular the specific benefits and challenges associated with learning in the nursing home, may further inform the implementation of geriatric medicine clerkships in hospitals and nursing homes. PMID- 25693993 TI - Is involvement in medical education becoming a 'tick-box' exercise for junior doctors? PMID- 25693994 TI - When innovation was young. PMID- 25693995 TI - Countercurrent extraction of soluble sugars from almond hulls and assessment of the bioenergy potential. AB - Almond hulls contain considerable proportions (37% by dry weight) of water soluble, fermentable sugars (sucrose, glucose, and fructose), which can be extracted for industrial purposes. The maximum optimal solids loading was determined to be 20% for sugar extraction, and the addition of 0.5% (w/v) pectinase aided in maintaining a sufficient free water volume for sugar recovery. A laboratory countercurrent extraction experiment utilizing a 1 h steep followed by three extraction (wash) stages produced a high-concentration (131 g/L fermentable sugar) syrup. Overall, sugar recovery efficiency was 88%. The inner stage washing efficiencies were compatible with solution equilibrium calculations, indicating that efficiency was high. The concentrated sugar syrup was fermented to ethanol at high efficiency (86% conversion), and ethanol concentrations in the broth were 7.4% (v/v). Thin stillage contained 233 g SCOD/L, which was converted to biomethane at an efficiency of 90% with a biomethane potential of 297 mL/g SCODdestroyed. Overall, results suggested that a minima of 49 gal (185 L) ethanol and 75 m(3) methane/t hulls (dry whole hull basis) are achievable. PMID- 25693996 TI - Chloroquine analogues in drug discovery: new directions of uses, mechanisms of actions and toxic manifestations from malaria to multifarious diseases. AB - Antimalarial drugs (e.g. chloroquine and its close structural analogues) were developed primarily to treat malaria; however, they are beneficial for many dermatological, immunological, rheumatological and severe infectious diseases, for which they are used mostly today. Chloroquine and hydroxychloroquine, two of the most fascinating drugs developed in the last 50 years, are increasingly recognized for their effectiveness in myriad non-malarial diseases. In advanced research, chloroquine and hydroxychloroquine have been shown to have various immunomodulatory and immunosuppressive effects, and currently have established roles in the management of rheumatic diseases, lupus erythematosus (different forms) and skin diseases, and in the treatment of different forms of cancer. Recently, chloroquine analogues have also been found to have metabolic, cardiovascular, antithrombotic and antineoplastic effects. This review is concerned with the lysosomotropic, anti-inflammatory and immunomodulatory mechanisms of chloroquine, hydroxychloroquine, quinacrine and related analogues, and the current evidence for both their beneficial effects and potential adverse manifestations in various diseases. PMID- 25693997 TI - A Phase I study to assess the safety, tolerability and pharmacokinetic profile of boceprevir and sildenafil when dosed separately and together, in healthy male volunteers. AB - OBJECTIVES: Boceprevir is a first-generation direct-acting antiviral licensed for the treatment of hepatitis C infection. Sildenafil is an oral therapy for erectile dysfunction. As boceprevir is a potent inhibitor of CYP3A4, potential pharmacokinetic interactions may occur when it is coadministered with sildenafil. The aim of this study was to assess the pharmacokinetic profile of sildenafil and boceprevir when dosed separately and together in healthy volunteers. METHODS: Thirteen male subjects completed the following study procedures: phase 1 (Day 0), a single dose of 25 mg of sildenafil was administered; washout period (Days 1-9); phase 2 (Days 10-15), 800 mg of boceprevir three times a day was administered; and phase 3 (Day 16), 800 mg of boceprevir and 25 mg of sildenafil were administered. All drugs were administered in the fed state. Intensive pharmacokinetic sampling was undertaken on Days 0, 15 and 16. Differences in the pharmacokinetic parameters of sildenafil, N-desmethyl-sildenafil and boceprevir between phase 3 and the earlier phases were evaluated by changes in the geometric mean ratios (GMRs). RESULTS: All the drugs were well tolerated with no safety concerns arising. In the presence of boceprevir (phase 3 versus phase 1), the GMR for the plasma Cmax and the AUC24 for sildenafil increased by 1.9-fold (95% CI 1.5-2.4) and 2.7-fold (95% CI 2.1-3.4), respectively, whereas a reduction in the Cmax of N-desmethyl-sildenafil was observed (GMR 0.5, 95% CI 0.4-0.7). No significant changes in boceprevir exposure were observed between phases 3 and 2. CONCLUSIONS: Exposure of sildenafil is increased in the presence of boceprevir. A dose adjustment of sildenafil is therefore necessary. An initial dose of 25 mg of sildenafil is suggested. PMID- 25693998 TI - Better Off Alone Than With a Smoker: The Influence of Partner's Smoking Behavior in Later Life. AB - OBJECTIVES: We examine how the likelihood of smoking cessation among smokers and patterns of adherence to smoking cessation differ by partnership status, partnership changes, and partners' smoking behavior. The data are a nationally representative sample of smokers in middle and older age from the Health and Retirement Study (1992-2010). METHOD: We use multivariate logistic regression models to analyze the likelihood of smoking cessation among smokers and then estimate adherence to smoking cessation using discrete-time event history models. RESULTS: Those partnered with smokers and those whose partners relapse into smoking are much less likely than the unpartnered to quit smoking and adhere to smoking cessation. Respondents partnered with non-smokers and those whose partners quit smoking are more likely to quit smoking than the unpartnered. Those recently widowed, divorced, and repartnered have similar smoking changes to the consistently unpartnered. DISCUSSION: Being partnered does not always mean healthier behavior changes. Rather, the association between partnership status and smoking changes depends greatly on the health behavior changes of the partner. The partnership context at the time of smoking cessation sets the stage for longer term patterns of adherence, shaping health in older age. PMID- 25693999 TI - Intact Semantic Priming of Critical Lures in Alzheimer's Disease: Implications for False Memory. AB - OBJECTIVES: The present study examines the question of the activation of the critical lure (CL) in Alzheimer's patients with a Deese-Roediger-McDermott (DRM) like task. More precisely, older adults and Alzheimer's patients performed a lexical decision task in which they were asked to categorize strings of letters as words or nonwords. Contrary to the DRM paradigm in which the activation of the CL is inferred from its production at recall, such a lexical decision task does not require the joint use of intentional recovery strategies and source monitoring processes that are known to be particularly impaired in Alzheimer's patients. The performance at the lexical decision therefore reflects the activation of the CL without contamination from such strategic processes. METHOD: Twenty-nine older adults and 25 Alzheimer's patients performed a lexical decision task with DRM lists intermixed with neutral words and nonwords. RESULTS: Analysis indicated that older adults as well as Alzheimer's patients showed shorter lexical decision latencies for CLs than for other types of words. DISCUSSION: Contrary to the existing literature, our results suggest that the activation of the CL is preserved in Alzheimer's patients at mild to moderate stages of the disease. PMID- 25694000 TI - The Impact of Hospital Acquisition of Physician Practices on Referral Patterns. AB - Multiple parties influence the choice of facility for hospital-based inpatient and outpatient services. The patient is the central figure, but their choice of facility is guided by their physician and influenced by hospital characteristics. This study estimated changes in referral patterns for inpatient admissions and outpatient diagnostic imaging associated with changes in ownership of three multispecialty clinic systems headquartered in Minneapolis-St. Paul, MN. These clinic systems were acquired by two hospital-owned integrated delivery systems (IDSs) in 2007, increasing the probability that hospital preferences influenced physician guidance on facility choice. We used a longitudinal dataset that allowed us to predict changes in referral patterns, controlling for health plan enrollee, coverage, and clinic system characteristics. The results are an important empirical contribution to the literature examining the impact of hospital ownership on location of service. When this change in ownership forged new relationships, there was a significant reduction in the use of facilities historically selected for inpatient admissions and outpatient imaging and an increase in the use of the acquiring IDS's facilities. These changes were weaker in the IDS acquiring two clinic systems, suggesting that management of multiple acquisitions simultaneously may impact the ability of the IDS to build strong referral relationships. PMID- 25694003 TI - What's wrong with the practice of medicine today? PMID- 25694002 TI - Regulation of RNA metabolism is important for in vitro dedifferentiation of plant cells. AB - The characteristic high regenerative ability of plants has been exploited to develop in vitro plant regeneration techniques, which are usually initiated by an in vitro dedifferentiation step induced by artificial phytohormone treatment. Recent advances in plant molecular biological and genetic technologies have revealed the importance of the regulation of RNA metabolism, including the control of rRNA biosynthesis, pre-mRNA splicing, and miRNA-based RNA decay, in successful in vitro dedifferentiation. This review provides a brief overview of current knowledge of the roles of RNA metabolism in the dedifferentiation of plant cells in vitro. In addition, the possibility that plant-specific aspects of RNA metabolism regulation are linked closely to their high regenerative ability is discussed. PMID- 25694001 TI - Reprogramming of plant cells induced by 6b oncoproteins from the plant pathogen Agrobacterium. AB - Reprogramming of plant cells is an event characterized by dedifferentiation, reacquisition of totipotency, and enhanced cell proliferation, and is typically observed during formation of the callus, which is dependent on plant hormones. The callus-like cell mass, called a crown gall tumor, is induced at the sites of infection by Agrobacterium species through the expression of hormone-synthesizing genes encoded in the T-DNA region, which probably involves a similar reprogramming process. One of the T-DNA genes, 6b, can also by itself induce reprogramming of differentiated cells to generate tumors and is therefore recognized as an oncogene acting in plant cells. The 6b genes belong to a group of Agrobacterium T-DNA genes, which include rolB, rolC, and orf13. These genes encode proteins with weakly conserved sequences and may be derived from a common evolutionary origin. Most of these members can modify plant growth and morphogenesis in various ways, in most cases without affecting the levels of plant hormones. Recent studies have suggested that the molecular function of 6b might be to modify the patterns of transcription in the host nuclei, particularly by directly targeting the host transcription factors or by changing the epigenetic status of the host chromatin through intrinsic histone chaperone activity. In light of the recent findings on zygotic resetting of nucleosomal histone variants in Arabidopsis thaliana, one attractive idea is that acquisition of totipotency might be facilitated by global changes of epigenetic status, which might be induced by replacement of histone variants in the zygote after fertilization and in differentiated cells upon stimulation by plant hormones as well as by expression of the 6b gene. PMID- 25694004 TI - Legends in urology. PMID- 25694005 TI - Calcification of the vas deferens and seminal vesicles: a review. AB - INTRODUCTION: Calcification of the vas deferens and seminal vesicles is a rare condition of unknown incidence. It has been described in association with diabetes, hyperparathyroidism and genitourinary tuberculosis, amongst other conditions. Little is known about the clinical significance and management of this condition. We review the literature in an effort to find answers about an entity that is frequently appreciated as an incidental finding. MATERIALS AND METHODS: An electronic database search was performed (Medline) using the key words: vas deferens; seminal vesicles; calcification, alone or in combination. Articles were selected according to relevance and quality of evidence. RESULTS: The search included published manuscripts between 1960 and 2012. A total of 17 relevant publications were identified. The majority were written in the English language and mostly consisted of case presentations and reports of radiologic findings. CONCLUSION: Calcification of the vas deferens and seminal vesicles is a rare condition. However, it may be implicated in male factor infertility and symptoms from the urogenital tract. Treatment should be directed towards the underlying cause on an individual basis. It is unknown whether control of the primary process has any effects on the histopathological appearance of the ducts and/or their improvement of function. PMID- 25694006 TI - A systematic review of expanded prostate cancer index composite (EPIC) quality of life after surgery or radiation treatment. AB - INTRODUCTION: The Expanded Prostate Cancer Index Composite (EPIC) is a validated and widely adopted instrument that measures patient quality of life. This study aims to describe and compare patient quality of life in the bowel, urinary, and sexual domains across different prostate cancer treatments. MATERIALS AND METHODS: A systematic review of English articles published prior to 2012 was conducted. Peer reviewed articles reporting longitudinal EPIC data in a statistically analyzable form with clearly defined time points were included. Articles were assessed by content experts to ensure optimal treatment quality. Screening of studies and extraction of data were completed using a predefined data abstraction tool. Data on bowel, urinary, and sexual domains were documented. Scores in each domain range from a low of 0 to a high of 100. RESULTS: Twenty-six articles, representing 8302 patients, were included. All treatments were associated with short term or long term reductions in urinary, bowel, and sexual domains. Surgery patients had better post-treatment bowel quality of life; however, average declines were small regardless of treatment. Post-treatment urinary incontinence scores were lower for surgery patients; while radiation patients had worse urinary irritation. Average urinary bother and function were similar between treatment groups at 18 months post-treatment. Surgery patients had better baseline sexual function. A greater decline in sexual function was observed in surgery patients compared to radiation patients. CONCLUSIONS: Prostate cancer treatments have different impacts on patient quality of life and function. The magnitude of difference between treatment-related adverse effects may be important to patients when choosing therapy. PMID- 25694007 TI - Surgical complications associated with robotic urologic procedures in elderly patients. AB - INTRODUCTION: Urologic malignancies are often diagnosed at an older age, and are increasingly managed utilizing robotic-assisted surgical techniques. As such, we assessed and compared peri-postoperative complication rates following robotic urologic surgery in elderly and younger patients. MATERIALS AND METHODS: A retrospective analysis of IRB-approved databases and electronic medical records identified patients who underwent robotic-assisted urologic surgery between December 2003-September 2013. Patients were grouped according to surgical procedure (partial nephrectomy, radical cystectomy, radical prostatectomy) and age at surgery (<= 74 or >= 75 years old). Associations between age, comorbidities, Charlson comorbidity index (CCI), and patient outcomes were evaluated within each surgery type. RESULTS: 97.5% and 2.5% of patients were <= 74 or >= 75 years old, respectively. Cystectomies, partial nephrectomies and prostatectomies accounted for 3.5%, 9.5% and 87.1% of surgeries, respectively. Within cystectomy, nephrectomy and prostatectomy groups, 24.4%, 12.5% and 0.6% patients were >= 75 years old. Within each surgical type, elderly patients had significantly elevated CCI scores. Length of stay was significantly prolonged in elderly patients undergoing partial nephrectomy or prostatectomy. In elderly cystectomy, partial nephrectomy and prostatectomy patients, 36.7%, 14.3% and 5.9% suffered >= 1 Clavien grade 3-5 complication, respectively. Major complications were not significantly different between age groups. A qualitatively similar pattern was observed regarding Clavien grade 1-2 complications. CONCLUSIONS: The risks of robotic-assisted urologic surgery in elderly patients are not significantly elevated compared to younger patients. PMID- 25694008 TI - Low intensity extracorporeal shockwave therapy for erectile dysfunction: a study in an Indian population. AB - INTRODUCTION: Erectile dysfunction (ED) has been shown to be associated with a number of physical conditions and affects not only physical but also psychosocial health. Currently oral, on-demand phosphodiesterase type 5 inhibitors (PDE5i) are preferred first line treatment. Though effective, these drugs have limitations and are associated with significant non-compliance, side effects and do not reverse the underlying pathology. Non-invasive low intensity shockwave therapy (LISWT) has been shown to significantly improve erectile function in men previously PDE5i dependent. We describe our experience and results with this therapy in an Indian population of men with ED. This study assessed the efficacy of low intensity extracorporeal shockwave therapy (LI-ESWT) on Indian men with organic ED who had previously responded to PDE5i. MATERIALS AND METHODS: All the patients underwent a 1 month PDE5i washout period. Men were randomized to receive either 12 sessions of LI-ESWT (n = 95) or placebo/sham therapy (n = 40). Before the first treatment, erectile function and penile hemodynamics were assessed to substantiate a vascular etiology for the ED. Outcomes were assessed using Erection Hardness Score (EHS), International Index of Erectile Function-Erectile Function Domain (IIEF-EF domain) and Clinical Global Impression of Change (CGIC) scores at 1, 3, 6, 9 and 12 months post-treatment. RESULTS: We found a significant increase in the EHS and IIEF-EF Domain scores from visit 1 to follow up 5 (12 months) in the treated group compared to the placebo group. By 1 month after treatment there were highly significant differences between the LI-ESWT and placebo groups (p < 0.0001). Out of 60 men in the LI-ESWT group who completed the study, 47 (78%) men at FU1 and 43 (71%) at FU5 who were initially unable to achieve spontaneous erections hard enough for penetration (EHS <= 2) were able to do so (EHS >= 3) compared to none in the placebo group. The treatment was well tolerated and none of the men experienced treatment related discomfort or reported any adverse effects from the treatment. CONCLUSIONS: In this double blind, placebo-controlled study, LI-ESWT demonstrated a positive long term clinical effect with improvement in erectile function of Indian men with vasculogenic ED who were prior responders to PDE5i therapy. The efficacy and tolerability of this treatment, coupled with its long term benefits and rehabilitative characteristics, make it an attractive new therapeutic option for men with vasculogenic erectile dysfunction. PMID- 25694009 TI - Phenotype, symptom severity and treatment in a 'cured' cohort of chronic pelvic pain syndrome patients. AB - INTRODUCTION: To identify a cohort of chronic pelvic pain syndrome (CPPS) patients who considered their symptoms completely resolved and analyze their demographics, clinical phenotype, treatments and NIH-Chronic Prostatitis Symptom Index (CPSI) scores. MATERIALS AND METHODS: We identified 35 CPPS patients who at the follow up, reported their symptoms completely resolved ('cured'). Demographics, UPOINT phenotypes, treatments, and CPSI scores were examined. We also compared these variables to a database of 220 previously evaluated CPPS patients. RESULTS: Patients ranged in age from 19 to 72 years. Median follow up was 12 months. Mean change in CPSI sub scores before and after therapy were pain 9.7 +/- 3.8 to 2.7 +/- 2.9, urinary 4.0 +/- 2.8 to 1.1 +/- 1.2, QoL 8.1 +/- 2.7 to 2.3 +/- 2.5, and total 21.8 +/- 6.6 to 6.2 +/- 1.0 (all p < 0.0001). Only 9 (26%) patients reported a total score of 0. Comparing this 'cured' group to a previously published cohort of phenotyped CPPS patients, the 'cured' group had lower starting total and pain CPSI scores (21.8 versus 25.0 p = 0.007; 9.7 versus 11.5 p = 0.006 respectively). CONCLUSIONS: Many men with CPPS can reach a subjective cure, however, the majority do not reach a CPSI score of 0. This group of "cured" patients is similar to our typical tertiary referral cohort in terms of age and phenotype but differs in having slightly lower pre-treatment CPSI scores. PMID- 25694010 TI - Renal calculi: trends in the utilization of shockwave lithotripsy and ureteroscopy. AB - INTRODUCTION: To assess trends in the usage of extracorporeal shockwave lithotripsy (SWL) and ureteroscopy (URS) in the treatment of renal calculi. MATERIALS AND METHODS: An analysis of the 5% Medicare Public Use Files (years 2001, 2004, 2007 and 2010) was performed to evaluate changes in the use of SWL and URS to treat renal calculi. Patients were identified using ICD-9 (cm) and CPT codes. Statistical analyses, including the Fisher, ?2 tests, and multivariate logistic regression analysis were performed using SAS 9.3 (SAS Institute Inc., Cary, NC, USA) and SPSS v20 (IBM Corp., Armonk, NY, USA). RESULTS: The absolute number of patients diagnosed with (+85.1%) and treated for (+31.5%) kidney calculi increased from 2001 to 2010. The ratio of diagnosed/treated patients declined from 15.2% in 2001 to 10.8% in 2010. Whites (OR = 1.27, p < 0.0001), patients in the South (OR = 1.16, p < 0.0001) and those <= 84 years of age were more likely to be treated. The utilization of SWL (84.7%) was greater than URS (15.3%), but the utilization of URS increased over time from 8.4% in 2001 to 20.6% of cases by 2010 (p < 0.0001). Treatment via URS was more likely in women (OR = 1.28, p < 0.0001), in patients living outside the South (OR = 1.29-1.45, p <= 0.006) and in later years of the study (OR = 2.87, p < 0.0001). CONCLUSIONS: Treatment patterns for renal calculi changed from 2001 to 2010. The usage of URS increased at the cost of SWL. Multiple sociodemographic factors correlated with the likelihood of being treated surgically as well as the choice of the surgical approach. PMID- 25694011 TI - Prospective phase I study on testicular castration induced by radiation treatment. AB - INTRODUCTION: Surgery and luteinizing hormone-releasing hormone (LHRH) analogs are standard androgen deprivation treatments (ADT) for patients with advanced prostate cancer. We performed a phase I study to explore if irradiation to the testes could be used as an alternative to ADT. MATERIALS AND METHODS: All patients had advanced prostate cancer with normal testosterone levels before treatment and indication for long term castration. Treatment started with one LHRH analog injection (to induce a fast drop of testosterone) followed by irradiation to the whole scrotum. Two fractionation regimens were tested: 17 Gy in 2 fractions, and 24 Gy in 3 fractions. Hormonal blood evaluation was performed before and every 3 months after radiotherapy. Toxicity was evaluated at each visit by the CTCv3 scoring system. This was an IRB approved prospective study. RESULTS: The first three patients received 17 Gy in 2 fractions. None of them developed acute or late skin toxicity and none became castrated, keeping normal levels of testosterone during the time they were followed at 11, 24 and 36 months post-radiotherapy. Another four patients received 24 Gy in 3 fractions. Two developed grade 1 temporary acute dermatitis and, again, none of them became castrated during follow up of 11-36 months. CONCLUSIONS: Prospective studies assessing the effect of the Leydig cells after direct irradiation to the testes are rare. The two radiotherapy regimens used in this study were well tolerated, but not capable of causing castration after 11-36 months of follow up. It is not yet clear whether radiation treatment can effectively induce castration in men. PMID- 25694012 TI - Risk factors associated with 30 day hospital readmission following partial nephrectomy. AB - INTRODUCTION: To assess risk factors for unplanned readmission following open and minimally invasive partial nephrectomy (PN). MATERIALS AND METHODS: From the National Surgical Quality Improvement Program database, patients with renal malignancy undergoing PN in 2011 or 2012 were reviewed. Using multivariable logistic regression, we identified variables associated with 30 day hospital readmission. RESULTS: Of the 2124 patients identified who underwent PN, 1253 (59%) were minimally invasive PN (MIPN) and 871 (41%) open PN (OPN). There were no differences in preoperative comorbidities between MIPN and OPN patients. The rate of unplanned hospital readmission for the entire cohort was 5%, which varied from 7% for OPN to 4% for MIPN. Seven percent of OPN and 2% of MIPN patients developed a Clavien grade III-V complication. For OPN, developing an in-hospital Clavien grade III-V complication was associated with a 6-fold increase in the odds of requiring subsequent readmission (95% CI 2.22-14.47, p < 0.001). For MIPN, an in-hospital Clavien grade III-V complication was associated with nearly 16 times increased odds of unplanned readmission (95% CI 6.08-41.65, p<0.001) and history of chronic anticoagulation was associated with a five times increased odds of unplanned readmission (95% CI 1.44-18.25, p = 0.012). Finally, operative time for MIPN was associated with increased odds of readmission (OR 1.08, 95% CI 1.04-1.16, p < 0.001). Patient comorbidities and ASA score were not associated with unplanned readmission for OPN or MIPN. CONCLUSIONS: Patients developing high grade complications are at increased risk of subsequent unplanned readmission. These patients who develop significant in-hospital complications may benefit from increased post-discharge contact with healthcare providers and from preoperative counseling regarding their risk of unplanned readmission. PMID- 25694013 TI - Hospital readmission following urologic surgery. PMID- 25694014 TI - The burden of overtreatment: comparison of toxicity between single and combined modality radiation therapy among low risk prostate cancer patients. AB - INTRODUCTION: To compare radiation related toxicities among men with low risk prostate cancer treated with single or multimodal radiation therapy. MATERIALS AND METHODS: The SEER-Medicare linked database was used to assess the relationship between treatment type and toxicity among men with low risk prostate cancer treated with brachytherapy (BT), external beam radiation therapy (EBRT), or combined therapy between 2004 and 2007. Inverse probability of treatment weighting was utilized to minimize selection bias and control for confounding. Multivariate logistic regression models were used to explore the relationship between treatment and outcomes. RESULTS: Overall 1915 (43.9%), 1893 (43.4%), and 555 (12.7%) patients were treated with EBRT, BT, and combined therapy, respectively. In univariate analyses, combined modality radiation was more toxic than BT alone for GU incontinence (56.76% versus 49.08%), GU obstruction (21.26% versus 19.70%), and erectile dysfunction (22.52% versus 22.24%) (p < 0.01, all comparisons). Compared to EBRT alone, combined modality radiation was more toxic for GI bleeding (7.21% versus 6.21%), GU incontinence (56.76% versus 29.24%), GU obstruction (21.26% versus 14.15%), and erectile dysfunction (22.52% versus 15.35%) (p < 0.01, all comparisons). Among the most frequent radiation toxicity events, the probability of treatment associated toxicity was highest for patients receiving combined modality treatment and lowest for the group treated with EBRT. After multivariate adjustment, EBRT alone demonstrated protective effects against GU obstruction (OR 0.56 [CI 0.50-0.63]), GI bleeding (OR 0.57 [CI 0.48-0.67]), GU incontinence (OR 0.39 [CI 0.36-0.43]), and erectile dysfunction (OR 0.68 [CI 0.61 0.76]) when compared to combined therapy. CONCLUSIONS: The use of combined modality radiation therapy in low risk prostate cancer patients is discordant with clinical guidelines and associated with a significantly increased burden of associated toxicity when compared to EBRT monotherapy. Prudent patient selection and judicious use of combined therapy among men with low risk prostate cancer represents a targetable area to reduce the burden of overtreatment. PMID- 25694015 TI - Histologic upgrading in patients eligible for active surveillance on saturation biopsy. AB - INTRODUCTION: We evaluated the risk of histologic upgrading and upstaging in patients who met strict active surveillance (AS) criteria on saturation biopsy and elected to undergo radical prostatectomy. MATERIALS AND METHODS: A retrospective review was conducted of 362 consecutive, individual patients who underwent transrectal ultrasound guided saturation biopsy (32 cores) between 2006 and 2013. Thirty-one patients (9%) were eligible for AS based on Hopkins criteria for very low risk (VLR): stage T1c, prostate-specific antigen (PSA) density <= 0.15 ng/mL2, Gleason <= 6, <= 2 cores and <= 50% core. Twenty patients (64%) elected radical prostatectomy, 2 (7%) elected radiation treatment and 9 (29%) elected AS (n = 9, 29%). Radical prostatectomy results were used to evaluate for upgrading and upstaging. RESULTS: Patient and saturation biopsy characteristics were similar amongst radical prostatectomy, radiation and AS patients. Mean age was 63 years (range 50-75) and 27 patients (87%) had a prior negative biopsy. Median time to prostatectomy was 3 months (range 1-46). Upgrading (Gleason >= 7) was identified in 40% (n = 8) of patients: Gleason 3+4 (n = 7) and Gleason 4+3 (n = 1). Upstaging (>= T3) was not identified. Mean follow up was 47 months (range 11-99) for all patients. No patient developed biochemical recurrence or required salvage treatment. CONCLUSIONS: Despite increased prostate sampling, patients who met strict AS criteria on saturation biopsy were at high risk for Gleason upgrading, but fortunately at low risk for upstaging and biochemical recurrence. Patients contemplating AS based on saturation biopsy results should be counseled appropriately. MRI-TRUS fusion biopsy may be an alternative to saturation biopsy until proven otherwise. PMID- 25694016 TI - Urologic and endovascular repair of a uretero-iliac artery fistula. AB - Patients with a uretero-iliac artery fistula (UIAF) are at an elevated risk of life-threatening hemorrhage. Identification and treatment of the fistula may be challenging, and requires the combined expertise of a urologist and endovascular specialist. This manuscript provides a list of equipment needed and describes our technique for diagnosing and treating a UIAF. PMID- 25694017 TI - Robot-assisted radical nephrectomy with inferior vena cava tumor thrombectomy: technique and initial outcomes. AB - INTRODUCTION: To describe our technique for robot-assisted radical nephrectomy (RARN) with inferior vena cava (IVC) tumor thrombectomy and to present initial results for our first two patients. MATERIALS AND METHODS: Two patients with renal masses with infrahepatic IVC extension underwent RARN with IVC tumor thrombectomy using a four-arm configuration. Both cases were right-sided tumors. Vascular control was obtained with complete cross-clamping of the vena cava with robotic bulldog clamps. Intraoperative ultrasound was used to delineate extent of tumor extension. Specimens were removed en-bloc, and the IVC was closed with 2 layers of 4-0 Prolene. The specimen is extracted through a lower midline incision. RESULTS: Two robotic IVC thrombectomies were successfully completed. There were no conversions, intraoperative or postoperative complications. Median operative time was 243 minutes with a median estimated blood loss of 150 mL. Both patients were able to ambulate independently free of intravenous opioids on postoperate day 1. Median length of stay was 4.5 (range 3-6) days. Final pathology revealed clear cell RCC in both cases with negative surgical margins. CONCLUSIONS: Robotic technology may facilitate RN and IVC thrombectomy in the well selected patient and appears to be a safe and feasible approach. PMID- 25694018 TI - Delivery of a massive urinary stone from an augmented bladder using obstetrical forceps. AB - A 48-year-old man presented for evaluation of an expanding abdominal mass. Twenty years earlier, he had developed Fournier's gangrene requiring extensive debridement. He underwent augmentation cystoplasty with a catheterizable stoma due to a proximal urethral stricture. Fifteen years later, he was found to have a 14 cm x 18 cm bladder augment calculus. Simpson obstetric forceps were passed into the augment to deliver a 1110 gram stone with minimal devitalization of the colonic augmentation tissue. This is the first report of stone management with obstetric forceps in an augmented bladder. The specimen itself is among the largest stones ever reported. PMID- 25694019 TI - Ureteral obstruction following partial nephrectomy: can it be caused by fibrin glue? AB - Fibrin sealants are widely used during partial nephrectomy, however reports regarding the potential complications associated with their use are limited. We present the case of a 67-year-old male who developed delayed ureteral obstruction without hydronephrosis following partial nephrectomy in a solitary kidney. We hypothesize that the obstruction and absence of hydronephrosis were caused by extrinsic compression and subsequent inflammation due to the fibrin glue. Our report underscores the importance of a high index of suspicion for obstruction when acute kidney injury occurs following partial nephrectomy when fibrin glue is used, even in the absence of collecting system dilatation. PMID- 25694020 TI - A biological approach to assembling tissue modules through endothelial capillary network formation. AB - To create functional tissues having complex structures, bottom-up approaches to assembling small tissue modules into larger constructs have been emerging. Most of these approaches are based on chemical reactions or physical interactions at the interface between tissue modules. Here we report a biological assembly approach to integrate small tissue modules through endothelial capillary network formation. When adjacent tissue modules contain appropriate extracellular matrix materials and cell types that support robust endothelial capillary network formation, capillary tubules form and grow across the interface, resulting in assembly of the modules into a single, larger construct. It was shown that capillary networks formed in modules of dense fibrin gels seeded with human umbilical vein endothelial cells (HUVECs) and mesenchymal stem cells (MSCs); adjacent modules were firmly assembled into an integrated construct having a strain to failure of 117 +/- 26%, a tensile strength of 2208 +/- 83 Pa and a Young's modulus of 2548 +/- 574 Pa. Under the same culture conditions, capillary networks were absent in modules of dense fibrin gels seeded with either HUVECs or MSCs alone; adjacent modules disconnected even when handled gently. This biological assembly approach eliminates the need for chemical reactions or physical interactions and their associated limitations. In addition, the integrated constructs are prevascularized, and therefore this bottom-up assembly approach may also help address the issue of vascularization, another key challenge in tissue engineering. PMID- 25694022 TI - The future of industrial bioprocessing: batch or continuous? PMID- 25694023 TI - Developing principles for predicting ionic liquid effects on reaction outcome. The importance of the anion in controlling microscopic interactions. AB - A series of ionic liquids containing anions of differing coordination strength were investigated as solvents for the condensation reaction of an alkyl amine and an aromatic aldehyde. As predicted, the rate constant of the process was found to increase with the proportion of the ionic liquid in the reaction mixture. Temperature-dependent kinetic analyses demonstrated that by varying the ability of the anion to interact with the cation the magnitude of both the enthalpy and entropy of activation could be controlled in a predictable manner, with the activation parameters being linearly dependent on the ionic liquid basicity. Interestingly, the unexpected trend in the rate constants observed when altering the anion of the ionic liquid highlighted the presence of more subtle secondary microscopic interactions involving the anion, further emphasizing the fragility of the enthalpy - entropy balance. PMID- 25694021 TI - Family and friendship informal support networks and social anxiety disorder among African Americans and Black Caribbeans. AB - BACKGROUND: This study explores relationships between Social Anxiety Disorder (SAD) and quality and frequency of involvement with family and friends. METHODS: Data are from a nationally representative sample of African American and Black Caribbean adults (n = 5191), the National Survey of American Life. SAD was assessed using the DSM-IV World Mental Health Composite International Diagnostic Interview. RESULTS: Findings indicated that among both populations, close supportive ties with family members and friends are protective against meeting criteria for SAD. Negative interactions with family (e.g., conflicts), however, are a risk factor for SAD among both African Americans and Black Caribbeans. For African Americans, an interaction indicates that the relationship between negative interaction and social anxiety is much stronger among African Americans who are not emotionally close to their families. For Caribbean Blacks, an interaction suggests that the odds of meeting criteria for SAD were higher among Black Caribbeans who had high negative interaction with family as well as low levels of friendship closeness. LIMITATIONS: The cross-sectional nature of the study does not allow for causal attributions for findings. CONCLUSIONS: This study demonstrates that SAD may impact black ethnic subgroups differently, which has important implications for understanding the nature, etiology, and treatment of this disorder. PMID- 25694024 TI - Impact of preoperative laboratory investigation and blood cross-match on clinical management of pediatric neurosurgical patients. AB - PURPOSE: Studies in the adult literature suggest that preoperative laboratory investigations and cross-match are performed unnecessarily and rarely lead to changes in clinical management. The purposes of this study were the following: (1) to explore whether preoperative laboratory investigations in neurosurgical children alter clinical management and (2) to determine the utilization of cross matched blood perioperatively in elective pediatric neurosurgical cases. METHODS: We reviewed pediatric patient charts for elective neurosurgery procedures (June 2010-June 2014) at out institution. Variables collected include preoperative complete blood count (CBC), electrolytes, coagulation, group and screen, and cross-match. A goal of the review was to identify instances of altered clinical management, as a consequence of preoperative blood work. The number of cross matched blood units transfused perioperatively was also determined. RESULTS: Four hundred seventy-seven electively scheduled pediatric neurosurgical patients were reviewed. Preoperative CBC was done on 294, and 39.8 % had at least one laboratory abnormality. Electrolytes (84 patients) and coagulation panels (241 patients) were abnormal in 23.8 and 24.5 %, respectively. The preoperative investigations led to a change in clinical management in three patients, two of which were associated with significant past medical history. Group and screen test was performed in 62.5 % of patients and 57.9 % had their blood cross matched. Perioperative blood transfusions (71 % of these patients were under 3 years of age) were received by 3.6 % of patients (17/477). The cross-match to transfusion ratio was 16. CONCLUSION: This study suggests that the results of preoperative laboratory exams have limited value, apart from cases with oncology and complex preexisting conditions. Additionally, cross-matching might be excessively conducted in elective pediatric neurosurgical cases. PMID- 25694025 TI - Radiation therapy after subtotal resection of pediatric grade II/III spinal ependymomas: what is the evidence? PMID- 25694026 TI - Multichannel conductance of folded single-molecule wires aided by through-space conjugation. AB - Deciphering charge transport through multichannel pathways in single-molecule junctions is of high importance to construct nanoscale electronic devices and deepen insight into biological redox processes. Herein, we report two tailor-made folded single-molecule wires featuring intramolecular pi-pi stacking interactions. The scanning tunneling microscope (STM) based break-junction technique and theoretical calculations show that through-bond and through-space conjugations are integrated into one single-molecule wire, allowing for two simultaneous conducting channels in a single-molecule junction. These folded molecules with stable pi-pi stacking interaction offer conceptual advances in single-molecule multichannel conductance, and are perfect models for conductance studies in biological systems, organic thin films, and pi-stacked columnar aggregates. PMID- 25694027 TI - Match running performance during fixture congestion in elite soccer: research issues and future directions. AB - It has been proposed that match congestion in elite soccer results in residual fatigue and underperformance in ensuing competition due to insufficient recovery time. In this article, matters relating to match congestion and running performance in elite soccer competition are discussed. We suggest a need to determine the extent to which elite players are, in reality, exposed to periods of match congestion and hence to potential declines in performance. Despite evidence of exercise-induced muscle damage combined with a decline in physical performance up to 72 h post-match, research using time-motion analyses suggests that running performance represented by distances covered is unaffected over periods of match congestion. We recommend analysis of alternative movement variables including accelerations, decelerations and turns that are taxing metabolically and contribute greatly to muscle damage. Moreover, a holistic approach combining subjective ratings with biochemical, hormonal and immunological responses to exercise would be pertinent, especially in players frequently exposed to match congestion. Contemporary practitioners typically implement various post-match recovery treatments during dense schedules in an attempt to accelerate recovery and ensure that subsequent running performance is not unduly affected. However, empirical evidence to support their efficacy in maintaining running performance is lacking and we recommend controlled intervention studies using match simulations in an attempt to verify their effectiveness. These points are critically addressed using findings from the current scientific literature, while gaps in the current body of knowledge and future directions for research are highlighted. PMID- 25694028 TI - Proximity ligation assays of protein and RNA interactions in the male-specific lethal complex on Drosophila melanogaster polytene chromosomes. AB - In Drosophila, the male-specific lethal (MSL) complex specifically targets the male X chromosome and participates in a twofold increase in expression output leading to functional dosage compensation. The complex includes five proteins and two non-coding RNAs (ncRNAs). A number of additional associated factors have also been identified. However, the components' roles and interactions have not been fully elucidated. The in situ proximity ligation assay (PLA) provides a sensitive means to determine whether proteins and other factors have bound to chromosomes in close proximity to each other, and thus may interact. Thus, we modified, tested, and applied the assay to probe interactions of MSL complex components on polytene chromosomes. We show that in situ PLA can detect and map both protein protein and protein-ncRNA interactions on polytene chromosomes at high resolution. We further show that all five protein components of the MSL complex are in close proximity to each other, and the ncRNAs roX1 and roX2 bind the complex in close proximity to MLE. Our results also indicate that JIL1, a histone H3 Ser10 kinase enriched on the male X chromosome, interacts with MSL1 and MSL2, but not MSL3 of the MSL complex. In addition, we corroborate proposed interactions of the MSL complex with both CLAMP and TopoII. PMID- 25694029 TI - Rational designed bipolar, conjugated polymer-DNA composite beacon for the sensitive detection of proteins and ions. AB - Nature owns remarkable capabilities in sensing target molecules, while the artificial biosensor lags far behind nature. Inspired by nature, we devise a new sensing platform that can specifically bind the molecules and synchronously initiate a specific signal response. We rationally designed a type of bipolar probe that is comprised of a hydrophilic DNA part and a hydrophobic conjugated polymer (CP) unit. In aqueous solution, they can form micelles with a hydrophobic CP core and a hydrophilic DNA shell. The aggregation-caused quenching suppresses the fluorescence of CP. Adding telomerase, the hydropathical profile of the bipolar probes is drastically regulated that results in the collapse of micelles and liberates fluorescence simultaneously. The probe has been used in both mimic systems and real urine samples (38 samples). We achieve sensitive and specific detection of telomerase and obtain clearly classification for normal people and cancer patients. It can also be used in a signal off sensor that is used to detect mercury ions. PMID- 25694030 TI - Immobilization and continuous recycling of photoredox catalysts in ionic liquids for applications in batch reactions and flow systems: catalytic alkene isomerization by using visible light. AB - A catalytic (E)- to (Z)-isomerization of olefins using a photoredox catalyst under mild reaction conditions is presented. A variety of (Z)-alkenes can be prepared in the presence of visible light. A new reaction system allows an easy and efficient scale-up, as well as a continuous flow process in which the photocatalyst is immobilized in an ionic liquid and continuously recycled by simple phase separation. PMID- 25694031 TI - A neighborhood statistics model for predicting stream pathogen indicator levels. AB - Because elevated levels of water-borne Escherichia coli in streams are a leading cause of water quality impairments in the U.S., water-quality managers need tools for predicting aqueous E. coli levels. Presently, E. coli levels may be predicted using complex mechanistic models that have a high degree of unchecked uncertainty or simpler statistical models. To assess spatio-temporal patterns of instream E. coli levels, herein we measured E. coli, a pathogen indicator, at 16 sites (at four different times) within the Squaw Creek watershed, Iowa, and subsequently, the Markov Random Field model was exploited to develop a neighborhood statistics model for predicting instream E. coli levels. Two observed covariates, local water temperature (degrees Celsius) and mean cross-sectional depth (meters), were used as inputs to the model. Predictions of E. coli levels in the water column were compared with independent observational data collected from 16 in-stream locations. The results revealed that spatio-temporal averages of predicted and observed E. coli levels were extremely close. Approximately 66 % of individual predicted E. coli concentrations were within a factor of 2 of the observed values. In only one event, the difference between prediction and observation was beyond one order of magnitude. The mean of all predicted values at 16 locations was approximately 1 % higher than the mean of the observed values. The approach presented here will be useful while assessing instream contaminations such as pathogen/pathogen indicator levels at the watershed scale. PMID- 25694032 TI - Electrochemical determination of hydrazine using a ZrO2 nanoparticles-modified carbon paste electrode. AB - In the present paper, the use of a carbon paste electrode modified by 3-(4'-amino 3'-hydroxy-biphenyl-4-yl)-acrylic acid (3,4'AA) and ZrO2 nanoparticles prepared by a simple and rapid method was described. The heterogeneous electron transfer properties of (3,4'AA) coupled to ZrO2 nanoparticles at the carbon paste electrode were investigated using cyclic voltammetry, chronoamperometry, and square wave voltammetry in aqueous buffer solutions. Under the optimized conditions, the square wave voltammetric peak currents of hydrazine increased linearly with hydrazine concentrations in the range of 2.5 * 10(-8) to 5.0 * 10( 5) M, and detection limit of 14 nM was obtained for hydrazine. Finally, this modified electrode was used for the determination of hydrazine in water samples, using standard addition method. PMID- 25694033 TI - Residue, dissipation, and safety evaluation of pyridalyl nanoformulation in Okra (Abelmoschus esculentus [L] Moench). AB - A comparative study on residues and rate of dissipation of a new nanoformulation of pyridalyl and commercial pyridalyl was carried out on okra under net house and field conditions. Okra crop was sprayed with commercial and nanoformulation of pyridalyl at recommended (75 g a. i./ha) and double the recommended dose (150 g a. i./ha) at the time of fruiting. Quantitation of residues of pyridalyl in okra was done by ultra high performance liquid chromatography over a period of 15 days, and recovery of the method ranged from 79 to 87 %. The half life calculated from the dissipation pattern of pyridalyl on okra for commercial and developed nanoformulation proved that residues of nanopyridalyl did not persist much longer than that of conventional formulation in net house as well as in field trials. The risk quotient value of pyridalyl in okra was significantly lower than 1, implying its negligible risk to the humans. PMID- 25694034 TI - Tuning of ZnO 1D nanostructures by atomic layer deposition and electrospinning for optical gas sensor applications. AB - We explored for the first time the ability of a three-dimensional polyacrylonitrile/ZnO material-prepared by a combination of electrospinning and atomic layer deposition (ALD) as a new material with a large surface area-to enhance the performance of optical sensors for volatile organic compound (VOC) detection. The photoluminescence (PL) peak intensity of these one-dimensional nanostructures has been enhanced by a factor of 2000 compared to a flat Si substrate. In addition, a phase transition of the ZnO ALD coating from amorphous to crystalline has been observed due to the properties of a polyacrylonitrile nanofiber template: surface strain, roughness, and an increased number of nucleation sites in comparison with a flat Si substrate. The greatly improved PL performance of these nanostructured surfaces could produce exciting materials for implantation in VOC optical sensor applications. PMID- 25694035 TI - Restoration of riparian areas following the removal of cattle in the northwestern great basin. AB - We assessed the effects of the elimination of livestock in riparian systems at Hart Mountain National Antelope Refuge in southeastern Oregon, 23 years after the removal of cattle grazing, using 64 photos taken before grazing was removed compared with later retake photos. Two methods were used for this assessment: (1) a qualitative visual method comparing seven cover types and processes and (2) a new quantitative method of inserting digital line transects into photos. Results indicated that channel widths and eroding banks decreased in 64 and 73% of sites, respectively. We found a 90% decrease in the amount of bare soil (P < 0.001) and a 63% decrease in exposed channel (P < 0.001) as well as a significant increase in the cover of grasses/sedges/forbs (15% increase, P = 0.037), rushes (389% increase, P = 0.014), and willow (388% increase, P < 0.001). We also assessed the accuracy of the new method of inserting digital line transects into photo pairs. An overall accuracy of 91% (kappa 83%) suggests that digital line transects can be a useful tool for quantifying vegetation cover from photos. Our results indicate that the removal of cattle can result in dramatic changes in riparian vegetation, even in semi-arid landscapes and without replanting or other active restoration efforts. PMID- 25694036 TI - Host and habitat filtering in seedling root-associated fungal communities: taxonomic and functional diversity are altered in 'novel' soils. AB - Climatic and land use changes have significant consequences for the distribution of tree species, both through natural dispersal processes and following management prescriptions. Responses to these changes will be expressed most strongly in seedlings near current species range boundaries. In northern temperate forest ecosystems, where changes are already being observed, ectomycorrhizal fungi contribute significantly to successful tree establishment. We hypothesised that communities of fungal symbionts might therefore play a role in facilitating, or limiting, host seedling range expansion. To test this hypothesis, ectomycorrhizal communities of interior Douglas-fir and interior lodgepole pine seedlings were analysed in a common greenhouse environment following growth in five soils collected along an ecosystem gradient. Currently, Douglas-fir's natural distribution encompasses three of the five soils, whereas lodgepole pine's extends much further north. Host filtering was evident amongst the 29 fungal species encountered: 7 were shared, 9 exclusive to Douglas-fir and 13 exclusive to lodgepole pine. Seedlings of both host species formed symbioses with each soil fungal community, thus Douglas-fir did so even where those soils came from outside its current distribution. However, these latter communities displayed significant taxonomic and functional differences to those found within the host distribution, indicative of habitat filtering. In contrast, lodgepole pine fungal communities displayed high functional similarity across the soil gradient. Taxonomic and/or functional shifts in Douglas-fir fungal communities may prove ecologically significant during the predicted northward migration of this species; especially in combination with changes in climate and management operations, such as seed transfer across geographical regions for forestry purposes. PMID- 25694037 TI - Menaquinone-7 supplementation improves arterial stiffness in healthy postmenopausal women. A double-blind randomised clinical trial. AB - Observational data suggest a link between menaquinone (MK, vitamin K2) intake and cardiovascular (CV) health. However, MK intervention trials with vascular endpoints are lacking. We investigated long-term effects of MK-7 (180 ug MenaQ7/day) supplementation on arterial stiffness in a double-blind, placebo controlled trial. Healthy postmenopausal women (n=244) received either placebo (n=124) or MK-7 (n=120) for three years. Indices of local carotid stiffness (intima-media thickness IMT, Diameter end-diastole and Distension) were measured by echotracking. Regional aortic stiffness (carotid-femoral and carotid-radial Pulse Wave Velocity, cfPWV and crPWV, respectively) was measured using mechanotransducers. Circulating desphospho-uncarboxylated matrix Gla-protein (dp ucMGP) as well as acute phase markers Interleukin-6 (IL-6), high-sensitive C reactive protein (hsCRP), tumour necrosis factor-alpha (TNF-alpha) and markers for endothelial dysfunction Vascular Cell Adhesion Molecule (VCAM), E-selectin, and Advanced Glycation Endproducts (AGEs) were measured. At baseline dp-ucMGP was associated with IMT, Diameter, cfPWV and with the mean z-scores of acute phase markers (APMscore) and of markers for endothelial dysfunction (EDFscore). After three year MK-7 supplementation cfPWV and the Stiffness Index betasignificantly decreased in the total group, whereas distension, compliance, distensibility, Young's Modulus, and the local carotid PWV (cPWV) improved in women having a baseline Stiffness Index beta above the median of 10.8. MK-7 decreased dp-ucMGP by 50 % compared to placebo, but did not influence the markers for acute phase and endothelial dysfunction. In conclusion, long-term use of MK-7 supplements improves arterial stiffness in healthy postmenopausal women, especially in women having a high arterial stiffness. PMID- 25694038 TI - Oxidative lipidomics coming of age: advances in analysis of oxidized phospholipids in physiology and pathology. AB - SIGNIFICANCE: Oxidized phospholipids are now well recognized as markers of biological oxidative stress and bioactive molecules with both pro-inflammatory and anti-inflammatory effects. While analytical methods continue to be developed for studies of generic lipid oxidation, mass spectrometry (MS) has underpinned the advances in knowledge of specific oxidized phospholipids by allowing their identification and characterization, and it is responsible for the expansion of oxidative lipidomics. RECENT ADVANCES: Studies of oxidized phospholipids in biological samples, from both animal models and clinical samples, have been facilitated by the recent improvements in MS, especially targeted routines that depend on the fragmentation pattern of the parent molecular ion and improved resolution and mass accuracy. MS can be used to identify selectively individual compounds or groups of compounds with common features, which greatly improves the sensitivity and specificity of detection. Application of these methods has enabled important advances in understanding the mechanisms of inflammatory diseases such as atherosclerosis, steatohepatitis, leprosy, and cystic fibrosis, and it offers potential for developing biomarkers of molecular aspects of the diseases. CRITICAL ISSUES AND FUTURE DIRECTIONS: The future in this field will depend on development of improved MS technologies, such as ion mobility, novel enrichment methods and databases, and software for data analysis, owing to the very large amount of data generated in these experiments. Imaging of oxidized phospholipids in tissue MS is an additional exciting direction emerging that can be expected to advance understanding of physiology and disease. PMID- 25694039 TI - Inhibition of uPAR-TGFbeta crosstalk blocks MSC-dependent EMT in melanoma cells. AB - The capacity of cancer cells to undergo epithelial-to-mesenchymal transition (EMT) is now considered a hallmark of tumor progression, and it is known that interactions between cancer cells and mesenchymal stem cells (MSCs) of tumor microenvironment may promote this program. Herein, we demonstrate that MSC conditioned medium (MSC-CM) is a potent inducer of EMT in melanoma cells. The EMT profile acquired by MSC-CM-exposed melanoma cells is characterized by an enhanced level of mesenchymal markers, including TGFbeta/TGFbeta-receptors system upregulation, by increased invasiveness and uPAR expression, and in vivo tumor growth. Silencing TGFbeta in MSC is found to abrogate ability of MSC to promote EMT characteristics in melanoma cells, together with uPAR expression, and this finding is strengthened using an antagonist peptide of TGFbetaRIII, the so-called P17. Finally, we demonstrate that the uPAR antisense oligonucleotide (uPAR aODN) may inhibit EMT of melanoma cells either stimulated by exogenous TGFbeta or MSC CM. Thus, uPAR upregulation in melanoma cells exposed to MSC-medium drives TGFbeta-mediated EMT. On the whole, TGFbeta/uPAR dangerous liaison in cancer cell/MSC interactions may disclose a new strategy to abrogate melanoma progression. KEY MESSAGE: Mesenchymal stem cell (MSC)-conditioned medium induces EMT-like profile in melanoma. MSC-derived TGFbeta promotes uPAR and TGFbeta/TGFbeta-receptor upregulation in melanoma. TGFbeta gene silencing in MSCs downregulates uPAR expression and EMT in melanoma. uPAR downregulation prevents MSC-induced EMT-like profile in melanoma cells. Inhibition of the dangerous TGFbeta/uPAR relationship might abrogate melanoma progression. PMID- 25694040 TI - Environmental harshness shapes life-history variation in an Australian temporary pool breeding frog: a skeletochronological approach. AB - For many amphibians, high temperatures and limited precipitation are crucial habitat characteristics that limit species ranges and modulate life-history characteristics. Although knowledge of the ability of amphibians to cope with such environmental harshness is particularly relevant in the light of ongoing environmental change, relatively little is known about natural variation in age, maturation and associated life-history traits across species' ranges. We used the analysis of growth rings in bones to investigate the link between environmental harshness and life-history traits, including age and body size distribution, in specimens from 20 populations of the Australian bleating froglet, Crinia pseudinsignifera. Despite the short lifespan of the species, bone slides revealed geographic variation in average age, body size and reproductive investment linked to variation in temperature and rainfall. We found no difference in age at maturation in different climatic harshness regimes. Frogs from harsher environments invested less in their first reproductive event but grew older than their counterparts in more benign environments, thereby allowing for more reproductive events and buffering them against the increased chance of reproductive failure in the harsher environments. For individual frogs, climatic harshness experienced during an individual's life promoted larger body size. Overall, these results illustrate how bone structure analyses from preserved specimens allow both the testing of ecogeographic hypotheses and the assessment of the adaptive potential of species in the light of environmental change. PMID- 25694041 TI - Photosynthetic capacity of tropical montane tree species in relation to leaf nutrients, successional strategy and growth temperature. AB - Photosynthetic capacity of tree leaves is typically positively related to nutrient content and little affected by changes in growth temperature. These relationships are, however, often poorly supported for tropical trees, for which interspecific differences may be more strongly controlled by within-leaf nutrient allocation than by absolute leaf nutrient content, and little is known regarding photosynthetic acclimation to temperature. To explore the influence of leaf nutrient status, successional strategy and growth temperature on the photosynthetic capacity of tropical trees, we collected data on photosynthetic, chemical and morphological leaf traits of ten tree species in Rwanda. Seven species were studied in a forest plantation at mid-altitude (~1,700 m), whereas six species were studied in a cooler montane rainforest at higher altitude (~2,500 m). Three species were common to both sites, and, in the montane rainforest, three pioneer species and three climax species were investigated. Across species, interspecific variation in photosynthetic capacity was not related to leaf nutrient content. Instead, this variation was related to differences in within-leaf nitrogen allocation, with a tradeoff between investments into compounds related to photosynthetic capacity (higher in pioneer species) versus light-harvesting compounds (higher in climax species). Photosynthetic capacity was significantly lower at the warmer site at 1,700 m altitude. We conclude that (1) within-leaf nutrient allocation is more important than leaf nutrient content per se in controlling interspecific variation in photosynthetic capacity among tree species in tropical Rwanda, and that (2) tropical montane rainforest species exhibit decreased photosynthetic capacity when grown in a warmer environment. PMID- 25694042 TI - Modeling rates of life form cover change in burned and unburned alpine heathland subject to experimental warming. AB - Elevated global temperatures are expected to alter vegetation dynamics by interacting with physiological processes, biotic relationships and disturbance regimes. However, few studies have explicitly modeled the effects of these interactions on rates of vegetation change, despite such information being critical to forecasting temporal patterns in vegetation dynamics. In this study, we build and parameterize rate-change models for three dominant alpine life forms using data from a 7-year warming experiment. These models allowed us to examine how the interactions between experimental warming, the abundance of bare ground (a measure of past disturbance) and neighboring life forms (a measure of life form interaction) affect rates of cover change in alpine shrubs, graminoids and forbs. We show that experimental warming altered rates of life form cover change by reducing the negative effects of neighboring life forms and positive effects of bare ground. Furthermore, we show that our models can predict the observed direction and rate of life form cover change at burned and unburned long-term monitoring sites. Model simulations revealed that warming in unburned vegetation is expected to result in increased forb and shrub cover and decreased graminoid cover. In contrast, in burned vegetation, warming is predicted to slow post-fire regeneration in both graminoids and forbs and facilitate rapid expansion in shrub cover. These findings illustrate the applicability of modeling rates of vegetation change using experimental data. Our results also highlight the need to account for both disturbance and the abundance of other life forms when examining and forecasting vegetation dynamics under climatic change. PMID- 25694043 TI - Commentary: Parental care and the proximate links between maternal effects and offspring fitness. AB - Maternal effects influence the phenotype of offspring through non-genetic mechanisms, and thus are important components of individual life-histories and act as drivers of and/or constraints on phenotypic evolution. A maternal effect common in egg-laying vertebrates is provisioning of the yolk with carotenoids, organic pigments that often color sexual ornaments and are hypothesized to play positive and substantial physiological roles. In a recent study, yolks of great tit (Parus major) eggs were directly supplemented with carotenoids, and the effects on offspring fitness proxies measured (Marri and Richner in Oecologia 176:371-377, 2014a). Nestlings from supplemented broods were heavier early in development and more likely to fledge, but otherwise equivalent to control nestlings. The authors consider in detail the potential physiological mechanisms that might underlie this result, and here I expand on their Discussion by considering a non-exclusive explanation: that parents provided higher quality care to broods that received supplemental carotenoids. I discuss the general non independence of pre- and post-hatching/parturition maternal effects when parents care for offspring, and then briefly review evidence that carotenoids specifically are tied to the intensity of avian begging displays. Finally, I detail how inclusive fitness opportunities and constraints shape the adaptive landscape in which maternal effects operate, highlighting both theoretical and applied concerns surrounding questions about the adaptiveness of maternal effects. PMID- 25694044 TI - Urbanized birds have superior establishment success in novel environments. AB - Many animals have adapted to the proximity of humans and thereby gained an advantage in a world increasingly affected by human activity. Numerous organisms have invaded novel areas and thereby increased their range. Here, we hypothesize that an ability to thrive in urban habitats is a key innovation that facilitates successful establishment and invasion. We test this hypothesis by relating the probability of establishment by birds on oceanic islands to the difference in breeding population density between urban and nearby rural habitats as a measure of urbanization in the ancestral range. This measure was the single-most important predictor of establishment success and the only statistically significant one, with additional effects of sexual dichromatism, number of releases and release effort, showing that the ability to cope with human proximity is a central component of successful establishment. Because most invasions occur as a consequence of human-assisted establishment, the ability to cope with human proximity will often be of central importance for successful establishment. PMID- 25694045 TI - Mechanical characterization of cervical squamous carcinoma cells by atomic force microscopy at nanoscale. AB - To investigate the nanoscale mechanical properties of exfoliated cervical epithelial cells from patients to further reveal the pathogenesis of cervical cancer and help early diagnose. Exfoliated cells were collected from nine patients with chronic cervicitis or CIN1(control group), 30 patients with CIN2-3 (CIN 2-3 group), and 13 patients with cervical cancer (cervical cancer group). Stiffness of the cells was determined by atomic force microscope (AFM). Expression of P16INK4A was studied by immunocytochemistry. Environmental scanning electron microscopy was performed to observe the surface microtopography of the exfoliated cells. Young's modulus was measured for cells exfoliated from control and patients with CIN 2-3 and cervical cancer by AFM. The results showed that with increasing cervical lesions, the Young's modulus of the exfoliated cervical cells increased (P < 0.05). The modulus of the exfoliated cells was significantly decreased in the three patients 1 year after the surgery compared with the value before the surgery. Expression of P16INK4A in the exfoliated cells had not been statistically significant. Squamous cells from cervical cancer group had dense and disordered microvilli without clear microridges compare to other groups. The Young's modulus is increased from the control group, to CIN2-3 and cervical cancer groups, suggesting that the stiffness of cervical epithelial cells increases gradually with increasing cervical lesions. The changes in the mechanical properties of the exfoliated cells occur earlier than the changes in cell morphology. Therefore, analysis of mechanical properties of the exfoliated cells may be used to aid early diagnosis of the cancer. PMID- 25694046 TI - Preoperative chemoradiotherapy with 5-fluorouracil and oxaliplatin for locally advanced rectal cancer: long-term results of a phase II trial. AB - The aim of this study was to report long-term results of patients with locally advanced rectal cancer treated by neoadjuvant chemoradiotherapy with fluorouracil, leucovorin, and oxaliplatin. From February 2002 to November 2006, a total of 58 patients with locally advanced rectal cancer were recruited. Secondary endpoints included the cumulative incidence of local and distant recurrences, disease-free survival, and overall survival. The median follow-up time was 138 months (109-151 months). The cumulative incidence of local recurrence at 10 years was 12.1%. The cumulative incidence of distant recurrence at 10 years was 53.4%. The overall survival in the intention-to-treat population was 39.5% at 10 years. Disease-free survival in the intention-to-treat population was 41.8% at 10 years. Univariate analysis revealed that pathologic complete response was associated with local recurrence, distant recurrence, disease-free survival, and overall survival (p < .05). Distant recurrence remains the predominant pattern of failure for patients with locally advanced rectal cancer after preoperative chemoradiotherapy and total mesorectal excision. Pathologic complete response is an independent prognostic factor for locally advanced rectal cancer after preoperative chemoradiotherapy. PMID- 25694047 TI - Effect of baicalin-copper on the induction of apoptosis in human hepatoblastoma cancer HepG2 cells. AB - The medical properties of baicalin have been well known for many years. However, the discovery that baicalin in the presence of metal ions is more effective than baicalin alone changed the course of drug research. The present study was designed to investigate the effect and possible mechanism of apoptosis induced by baicalin-copper in a human hepatoblastoma cancer cell line (HepG2) and in vivo. This study demonstrated that baicalin-copper suppresses the proliferation of HepG2 cells in a dose-dependent manner. Intraperitoneal injection of baicalin copper resulted in a significant decrease in tumor growth in xenografts in nude mice. Acridine orange staining and flow cytometry analysis demonstrated that baicalin-copper induced apoptosis in HepG2 cells and caused cells to arrest in G2 M phase of the cell cycle. Furthermore, baicalin-copper treatment significantly increased the Bax/Bcl-2 ratio and p38 levels, as well as decreased the expression of caspase-3, p-PI3K, p-Akt and p-mTOR (P < 0.01). All of the evidences above indicate that baicalin-copper induces apoptosis in HepG2 cells by down-regulating the PI3K/Akt/mTOR signaling pathway. PMID- 25694048 TI - Syllable transposition effects in korean word recognition. AB - Research on the impact of letter transpositions in visual word recognition has yielded important clues about the nature of orthographic representations. This study investigated the impact of syllable transpositions on the recognition of Korean multisyllabic words. Results showed that rejection latencies in visual lexical decision for syllable-transposed Korean nonwords were delayed as compared with matched Korean nonwords without syllable transpositions. These findings bolster the case that the syllable provides an important functional unit in Korean word recognition, and suggest a degree of position invariance in syllable representations. PMID- 25694049 TI - Pharmacokinetic/pharmacodynamic relationship of marbofloxacin against Aeromonas hydrophila in Chinese soft-shelled turtles (Trionyx sinensis). AB - The single-dose disposition kinetics of the antibiotic marbofloxacin were determined in Chinese soft-shelled turtles (n = 10) after oral and intramuscular (i.m.) dose of 10 mg/kg bodyweight. The in vitro and ex vivo activities of marbofloxacin in serum against a pathogenic strain of Aeromonas hydrophila were determined. A concentration-dependent antimicrobial activity of marbofloxacin was confirmed for levels lower than 4 * MIC. For in vivo PK data, values of AUC: minimum inhibitory concentration (MIC) ratio for serum were 1166.6 and 782.4 h, respectively, after i.m. and oral dosing of marbofloxacin against a pathogenic strain of A. hydrophila (MIC = 0.05 MUg/mL). The ex vivo growth inhibition data after oral dosing were fitted to the inhibitory sigmoid Emax equation to provide the values of AUC/MIC required to produce bacteriostasis, bactericidal activity and elimination of bacteria. The respective values were 23.79, 36.35 and 126.46 h. It is proposed that these findings might be used with MIC50 or MIC90 data to provide a rational approach to the design of dosage schedules, which optimize efficacy in respect of bacteriological as well as clinical cures. PMID- 25694050 TI - Identification of a new diterpene biosynthetic gene cluster that produces O methylkolavelool in Herpetosiphon aurantiacus. AB - Diterpenoids are usually found in plants and fungi, but are rare in bacteria. We have previously reported new diterpenes, named tuberculosinol and isotuberculosinol, which are generated from the Mycobacterium tuberculosis gene products Rv3377c and Rv3378c. No homologous gene was found at that time, but we recently found highly homologous proteins in the Herpetosiphon aurantiacus ATCC 23779 genome. Haur_2145 was a class II diterpene cyclase responsible for the conversion of geranylgeranyl diphosphate into kolavenyl diphosphate. Haur_2146, homologous to Rv3378c, synthesized (+)-kolavelool through the nucleophilic addition of a water molecule to the incipient cation formed after the diphosphate moiety was released. Haur_2147 afforded (+)-O-methylkolavelool from (+) kolavelool, so this enzyme was an O-methyltransferase. This new diterpene was indeed detected in H. aurantiacus cells. This is the first report of the identification of a (+)-O-methylkolavelool biosynthetic gene cluster. PMID- 25694051 TI - Skin biopsy leading to diagnosis of diffuse intravascular B-cell lymphoma presenting as a fever of unknown origin. PMID- 25694052 TI - Prevalence of self-reported stomach symptoms after consuming milk among indigenous Sami and non-Sami in Northern- and Mid-Norway - the SAMINOR study. AB - OBJECTIVE: The main purpose of this work was to identify the prevalence of self reported stomach symptoms after consuming milk among Sami and non-Sami adults. STUDY DESIGN: A cross-sectional population-based study (the SAMINOR study). Data were collected by self-administrated questionnaires. METHOD: SAMINOR is a population-based study of health and living conditions conducted in 24 municipalities in Northern Norway during 2003 and 2004. The present study included 15,546 individuals aged between 36 and 79, whose ethnicity was categorized as Sami (33.4%), Kven (7.3%) and Norwegian majority population (57.2%). RESULTS: Sami respondents had a higher prevalence of self-reported stomach symptoms after consuming milk than the Norwegian majority population. The reporting was highest among Sami females (27.1%). Consumption of milk and dairy products (yoghurt and cheese) was high among all the ethnic groups. However, significantly more Sami than non-Sami never (or rarely) consume milk or cheese, and individuals who reported stomach symptoms after consuming milk had an significant lower intake of dairy products than those not reporting stomach symptoms after consuming dairy products. Sami reported general abdominal pain more often than the majority population. The adjusted models show a significant effect of Sami ethnicity in both men and women on self-reported stomach symptoms after consuming milk. In females, the odds ratio (OR)=1.77 (p=0.001) and in males OR=1.64 (p=0.001). CONCLUSION: Our study shows that the Sami population reported more stomach symptoms after consuming milk, suggesting a higher prevalence of milk intolerance among the Sami population than the Norwegian majority population. PMID- 25694054 TI - Ovariectomy-Induced Osteopenia Influences the Middle and Late Periods of Bone Healing in a Mouse Femoral Osteotomy Model. AB - OBJECTIVE: It is known that bone healing is delayed in the presence of osteoporosis in humans. However, due to the complexities of the healing of osteoporotic fractures, animal models may be more appropriate for studying the effects of osteoporosis in more detail and for testing drugs on the fracture repair process. The purpose of this study was to investigate the influence of ovariectomy-induced osteopenia in bone healing in an open femoral osteotomy model, and to test the feasibility of this model for evaluating the healing process under osteopenic conditions. METHODS: Ovariectomized (OVX) mouse models were employed to assess the effects of osteopenia on fracture healing, A mid shaft femur osteotomy model was also established 3 weeks after ovariectomy as an osteopenic fracture group (OVX group). Femurs were then harvested at 2 weeks and 6 weeks after fracture for X-ray radiography, micro-computed tomography (micro CT), histology, and biomechanical analysis. A sham-operated group (sham group) was used for comparison. RESULTS: The OVX mice had significantly lower bone volume density (BVF), volumetric bone mineral density (vBMD), and tissue mineral density (TMD) in the fracture calluses at 6 weeks (p<0.05), and similar trend was observed in 2 weeks. Additionally, larger calluses in OVX animals were observed via micro-CT and X-ray, but these did not result in better healing outcomes, as determined by biomechanical test at 6 weeks. Histological images of the healing fractures in the OVX mice found hastening of broken end resorption and delay of hard callus remodeling. The impaired biomechanical measurements in the OVX group (p<0.05) were consistent with micro-CT measurements and radiographic scoring, which also indicated delay in fracture healing of the OVX group. CONCLUSIONS: This study provided evidence that ovariectomy-induced osteopenia impair the middle and late bone healing process. These data also supported the validity of the mouse femoral osteotomy model in evaluating the process of bone healing under osteopenic conditions. PMID- 25694055 TI - Antimicrobial resistance surveillance of flomoxef in China. AB - The aim of this study was to investigate the susceptibility of flomoxef against clinical isolates collected from China and understand the trend of antimicrobial resistance. A total of 2955 pathogenic strains isolated from 18 tertiary hospitals in 18 cities of China over the period from July 2011 to June 2012 were studied. And the susceptibility tests were performed using agar dilution method recommended by CLSI in central laboratory. Flomoxef showed good potency against Enterobacteriaceae with susceptibility rate 85%-100%. The susceptibility rates of flomoxef against Staphylococcus spp. isolates were 63.9%-92.2%; 98.8% of MSSA and 88.2% of MSSE were susceptible to this drug. For other tested bacteria including Moraxella catarrhalis, Haemophilus spp., and Streptococcus spp. (except Viridans group streptococci) flomoxef showed good potency with susceptibility rate more than 95%. All these results strongly suggest that flomoxef is a potent antibacterial agent against major pathogens in China. PMID- 25694057 TI - Correction: A new, cheap, and productive FeP anode material for sodium-ion batteries. PMID- 25694056 TI - Effect of angiotensin II receptor blockers, candesartan, on osteoprotegerin level in hypertensive patients: Link between bone and RAAS. AB - INTRODUCTION: The renin-angiotensin-aldosterone system (RAAS) has recently been considered as a possible link between bone and vascular disease. The present study was designed to determine the effect of the angiotensin II receptor blocker candesartan on circulating osteoprotegerin (OPG) in hypertensive patients with multiple cardiovascular risk factors. MATERIAL AND METHODS: A total of 69 hypertensive patients were randomized to two groups: Group 1 included patients treated with oral candesartan in doses of 16 mg to 32 mg per day in addition to routine standard of care (routine care + ARB), and Group 2 included patients who received routine standard of care other than ARBs or ACEIs, with no change to their treatment (routine care). Patients were evaluated for lipid profile, HbA1C, insulin, C-peptide, CRP, aldosterone, renin, homeostasis model assessment-insulin resistance (HOMA-IR) and OPG. RESULTS: Baseline OPG levels did not differ significantly by treatment group. Post-treatment serum OPG levels were marginally lower in Group1 compared with Group 2; however, this decrease did not reach statistical significance (p = 0.077). CONCLUSIONS: In the present study, treatment with the ARB candesartan had no significant effect on circulating OPG levels in hypertensive patients with multiple cardiovascular risk factors. To the best of our knowledge, the present study is the first to estimate an effect of candesartan on bone remodeling marker such as OPG. PMID- 25694058 TI - The innate and adaptive response to mosquito saliva and Plasmodium sporozoites in the skin. AB - A malaria infection begins when an infected mosquito takes a blood meal and inoculates parasites into the skin of its mammalian host. The parasite then has to exit the skin and escape the immune cells that protect the body from infection and alert the system to intruding pathogens. It has become apparent that this earliest stage of infection is amenable to vaccine interventions. Here, we discuss how the innate and adaptive host response to both mosquito saliva and the parasite may interfere with the infection, as well as possible mechanisms the parasite might use to circumvent the host defense. PMID- 25694059 TI - Electrostatic and aromatic interaction-directed supramolecular self-assembly of a designed Fmoc-tripeptide into helical nanoribbons. AB - Supramolecular self-assembly offers an efficient pathway for creating macroscopically chiral structures in biology and materials science. Here, a new peptide consisting of an N-(9-fluorenylmethoxycarbonyl) headgroup connected to an aromatic phenylalanine-tryptophan dipeptide and terminated with zwitterionic lysine (Fmoc-FWK) and its cationic form (Fmoc-FWK-NH2) were designed for self assembly into chiral structures. It was found that the Fmoc-FWK peptide self assembled into left-handed helical nanoribbons at pH 11.2-11.8, whereas it formed nanofibers at pH 5 and 12 and large flat ribbons composed of many nanofibers in the pH range of 6-11. However, only nanofibers were observed in the cases of Fmoc FWK-NH2 at different values. A series of structural characterizations based on CD, FTIR, UV-vis and fluorescence spectroscopy reveal that the electrostatic and aromatic interactions and the associated hydrogen bonding direct the self assembly into various structures. The enhanced pi-pi stacking and hydrogen bonding were found in the helical nanoribbons. This difference in intermolecular interactions should be derived from the ionization of carboxyl and amino groups from lysine residues at different pH values. Furthermore, we performed molecular dynamics simulations to gain insight into the assembly mechanisms. The results imply that a relatively rigid molecular conformation and the strong intramolecular aromatic interaction between Trp and Fmoc groups favor chiral self assembly. This study is the first attempt to design a Fmoc-tripeptide for the fabrication of helical structures with macroscopic chirality, which provides a successful example and allows us to create new peptide-based chiral assembly systems. PMID- 25694060 TI - Imeglimin increases glucose-dependent insulin secretion and improves beta-cell function in patients with type 2 diabetes. AB - AIMS: To assess the glucose-stimulated insulin secretion effect of imeglimin in patients with type 2 diabetes. METHODS: We conducted a double-blind, randomized, placebo-controlled study in 33 patients with type 2 diabetes [glycated haemoglobin 6.8 +/- 0.1% (51 mmol/mol)], who were drug-naive or withdrawn from their previous metformin monotherapy for 2 weeks and received imeglimin 1500 mg twice daily or placebo for 1 week. Glucose-stimulated insulin secretion was assessed using a hyperglycaemic clamp. The primary endpoint was insulin secretion as defined by total insulin response [incremental area under the curve (iAUC)0-45 min ] and insulin secretion rate (ISR) calculated from C-peptide deconvolution. beta-cell glucose sensitivity at steady state (second phase: 25-45 min), hepatic insulin extraction and insulin clearance were also calculated. RESULTS: Imeglimin treatment for 7 days raised the insulin secretory response to glucose by +112% (iAUC0-45 , p = 0.035), first-phase ISR by +110% (p = 0.034) and second-phase ISR by +29% (p = 0.031). Imeglimin improved beta-cell glucose sensitivity by +36% (p = 0.034) and tended to decrease hepatic insulin extraction (-13%; p = 0.056). Imeglimin did not affect glucagon secretion. CONCLUSIONS: In patients with type 2 diabetes, imeglimin improves beta-cell function, which may contribute to the glucose-lowering effect observed with imeglimin in clinical trials. PMID- 25694061 TI - Horizon scan of nanomedicinal products. AB - AIM: A horizon scan of nanomedicinal product on the market or undergoing clinical investigation by analyzing the current nanomedicinal landscape. MATERIALS & METHODS: The horizon scan includes a search of literature, clinical trial registries and the internet. RESULTS: This horizon scan yielded 175 nanomedicinal products. Most products were intended for cancer treatment, followed by infectious diseases. Polymer conjugates, liposomes and protein nanoparticles were the most used structures for nanomedicinal products. CONCLUSIONS: This paper provides an overview of nanomedicinal products on the market or undergoing clinical investigation, their application areas and specific properties. PMID- 25694062 TI - CEA-targeted nanoparticles allow specific in vivo fluorescent imaging of colorectal cancer models. AB - Fluorescent imaging of colorectal tumor cells would improve tumor localization and allow intra-operative staging, facilitating stratification of surgical resections thereby improving patient outcomes. We aimed to develop and test fluorescent nanoparticles capable of allowing this in vivo. Dye-doped silica nanoparticles were synthesized. Anti-CEA (carcinoembryonic antigen) or control IgGs were conjugated to nanoparticles using various chemical strategies. Binding of CEA-targeted or control nanoparticles to colorectal cancer cells was quantified in vitro, and in vivo after systemic-delivery to murine xenografts. CEA-targeted, polyamidoamine dendrimer-conjugated, nanoparticles, but not control nanoparticles, allowed strong tumor-specific imaging. We are the first to demonstrate live, specific, in vivo imaging of colorectal cancer cells using antibody-targeted fluorescent nanoparticles. These nanoparticles have potential to allow intra-operative fluorescent visualization of tumor cells. PMID- 25694063 TI - An unusual large abdominal malakoplakia following trauma: Diagnosed on FNAC. AB - Malakoplakia is a rare chronic granulomatous inflammatory disease, related to immune deficiency and impaired bactericidal macrophage activity. Common sites of involvement include urinary bladder and kidney followed by gastrointestinal tract. We present an unusual case of abdominal malakoplakia diagnosed preoperatively on ultrasound-guided fine-needle aspiration cytology (FNAC). It presented as a large locally aggressive mass with extensive involvement of multiple bowel loops in an 18-year-old boy following blunt trauma to the abdomen. The demonstration of calcified laminated intracytoplasmic Michaelis-Gutman bodies in histiocytes is a reliable diagnostic feature of malakoplakia on FNAC smears, which can guide an appropriate medical management. PMID- 25694064 TI - Alpha-glucosidase inhibitory and antiplasmodial properties of terpenoids from the leaves of Buddleja saligna Willd. AB - In our continuing search for biologically active natural product(s) of plant origin, Buddleja saligna, a South African medicinal plant, was screened in line with its traditional use for antidiabetic (yeast alpha glucosidase inhibitory) and antiplasmodial (against a chloroquine sensitive strain of Plasmodium falciparum (NF54)) activities. The hexane fraction showed the most promising activity with regards to its antidiabetic (IC(50) = 260 +/- 0.112 ug/ml) and antiplasmodial (IC(50) = 8.5 +/- 1.6 ug/ml) activities. Using activity guided fractionation three known terpenoids (betulonic acid, betulone and spinasterol) were isolated from this species for the first time. The compounds displayed varying levels of biological activities (antidiabetic: 27.31 ug/ml >= IC(50) >= 5.6 ug/ml; antiplasmodial: 14 ug/ml >= IC(50) >= 2 ug/ml) with very minimal toxicity. PMID- 25694065 TI - Kinetic characterization of 4,4'-biphenylsulfonamides as selective non-zinc binding MMP inhibitors. AB - We describe the characterisation of a series of 4,4'-biphenylsulfonamides as selective inhibitors of matrix metalloproteases MMP-2 and -13, two enzymes involved in cell invasion and angiogenesis. Double-inhibitor studies in the presence of acetohydroxamic acid show that these molecules do not bind the catalytic zinc. Moreover, two of the characterised inhibitors (11 and 19) act as non-competitive inhibitors, whereas the para-methyl ester derivative 13 behaves as a competitive inhibitor. This finding suggests that this class of molecules binds to a catalytic subsite, possibly the S1'-pocket. Moreover, since these compounds also act as inhibitors of carbonic anhydrases (CAs), another family of enzymes involved in cell invasion, they could be potentially useful as CA/MMP dual target inhibitors with increased efficacy as anticancer agents. PMID- 25694066 TI - A theory of change for positive developmental approaches to improving outcomes among emerging adults with serious mental health conditions. AB - Recent evidence attests to the shortcomings of typical services for improving outcomes among emerging adults with serious mental health conditions (SMHCs). Researchers and providers have responded by developing new programs and interventions for meeting the unique needs of these young people. A significant number of these programs and interventions can be described as taking a positive developmental approach, which is informed by a combination of theoretical sources, including theories of positive development, self-determination, ecological systems, and social capital. To date, however, there has been no comprehensive theoretical statement describing how or why positive change should occur as a result of using a positive developmental approach when intervening with this population. The goal of this article is to propose a general model that "backfills" a theory behind what appears to be an effective and increasingly popular approach to improving outcomes among emerging adults with SMHCs. PMID- 25694067 TI - Introduction to the Special Issue: Empirically-based Interventions for Emerging Adults with Serious Mental Health Conditions. PMID- 25694068 TI - Dietary flaxseed independently lowers circulating cholesterol and lowers it beyond the effects of cholesterol-lowering medications alone in patients with peripheral artery disease. AB - BACKGROUND: Dietary flaxseed lowers cholesterol in healthy subjects with mild biomarkers of cardiovascular disease (CVD). OBJECTIVE: The aim was to investigate the effects of dietary flaxseed on plasma cholesterol in a patient population with clinically significant CVD and in those administered cholesterol-lowering medications (CLMs), primarily statins. METHODS: This double-blind, randomized, placebo-controlled trial examined the effects of a diet supplemented for 12 mo with foods that contained either 30 g of milled flaxseed [milled flaxseed treatment (FX) group; n = 58] or 30 g of whole wheat [placebo (PL) group; n = 52] in a patient population with peripheral artery disease (PAD). Plasma lipids were measured at 0, 1, 6, and 12 mo. RESULTS: Dietary flaxseed in PAD patients resulted in a 15% reduction in circulating LDL cholesterol as early as 1 mo into the trial (P = 0.05). The concentration in the FX group (2.1 +/- 0.10 mmol/L) tended to be less than in the PL group (2.5 +/- 0.2 mmol/L) at 6 mo (P = 0.12), but not at 12 mo (P = 0.33). Total cholesterol also tended to be lower in the FX group than in the PL group at 1 mo (11%, P = 0.05) and 6 mo (11%, P = 0.07), but not at 12 mo (P = 0.24). In a subgroup of patients taking flaxseed and CLM (n = 36), LDL-cholesterol concentrations were lowered by 8.5% +/- 3.0% compared with baseline after 12 mo. This differed from the PL + CLM subgroup (n = 26), which increased by 3.0% +/- 4.4% (P = 0.030) to a final concentration of 2.2 +/- 0.1 mmol/L. CONCLUSIONS: Milled flaxseed lowers total and LDL cholesterol in patients with PAD and has additional LDL-cholesterol-lowering capabilities when used in conjunction with CLMs. This trial was registered at clinicaltrials.gov as NCT00781950. PMID- 25694069 TI - The effectiveness of prophylactic attachment of adhesive defibrillation pads in adult living donor liver transplantation. AB - BACKGROUND: The aim of current study is to present the effectiveness of prophylactic attachment of adhesive defibrillation electrode pads in adult living donor liver transplantation. MATERIAL AND METHODS: We divided 487 adult living donor liver transplantation patients into 2 Eras according to the history of without (Era 1) and with (Era 2) pre-attachment of adhesive defibrillation pads. The incidences of intraoperative cardiac events requiring cardioversion or defibrillation, its management, and outcome between Era 1 and 2 were compared. RESULTS: Two cases out of 124 patients (1.6%) in Era 1 had cardiac arrest. The closed chest cardiac massage in 1 cardiac arrest in Era 1 required trans diaphragmatic open-chest cardiac massage followed by internal cardiac defibrillation due to difficulty in performing external defibrillation. Both patients of Era 1 had in-hospital mortality. Four patients of Era 2 (n=363) received electrical treatment (1.01%); 2 had paroxysmal tachycardia requiring cardio-version and the other 2 had ventricular fibrillation requiring closed chest cardiac massage and external defibrillation. All 4 patients in Era 2 regained sinus rhythm after electrical treatment, tolerated the subsequent operation well, and had 100% survival to date. CONCLUSIONS: Our results show that prophylactic attachment of adhesive defibrillation pads allows the immediate performance of cardioversion, conventional closed-chest CPR, and defibrillation if indicated without any delay and without interference with the sterility of the operation field. Our preliminary result is clear and encouraging. PMID- 25694070 TI - Review of Theoretical Prediction Models for Organic Extract Metabolites, Effect of Drying Temperature on Smooth Muscle Relaxing Activity Induced by Organic Extracts Specially Cecropia Obtusifolia Portal and Web Server Predictors of Drug Protein Interaction. AB - Cecropia obtusifolia bertol is medicinal specie used in the treatment of diabetes mellitus and hypertension and it has scientific studies that support the traditional use. However, it is required to understand the influence of drying temperature on the yield and pharmacological activity. Drying rate, extraction efficiency, changes in the UV-Vis spectrum and estimating chlorophylls were stimulated with the increasing temperature. Finally, relaxant activity of vascular smooth muscle is increased by 70oC and reducing ability by the method of CARF increases with temperature. Analytical studies are required to identify changes in the metabolic content and those that ensure the safety and efficacy for human consumption. In this sense, bioinformatic studies may be helpful. Studies such as QSAR can help us to study these metabolites derived from natural products. MIND-BETS model and NL MIND-BETS model to predict DPIs was introduced using MARCH-INSIDE (MI) software to calculate structural parameters for drugs and enzymes respectively. We firstly revised the state-of-art on the design with review of previous works with hypertension activity based on theoretical studies. A study, evaluating the effect of drying temperature of leaves of C. obtusifolia on the relaxing of vascular smooth muscle, antioxidant activity and the presence of chlorophylls, with a focus on Cecropia metabolites. Last, we carried out QSAR studies using MIND-BEST and NL MIND-BEST web servers in order to understand the essential metabolites structural requirement for binding with receptors for FDA proteins. PMID- 25694072 TI - Multitarget network strategies to influence memory and forgetting: the Ras/MAPK pathway as a novel option. AB - The Ras/mitogen activated protein kinase (MAPK) pathway has key importance in development, cell differentiation and senescence, tumorigenesis, learning and memory. The clinical manifestations associated with this highly conserved pathway are called RASopathies. Phenotypic features are diverse and overlapping, but cognitive impairment is a common symptom. Here, we propose an approach based on molecular networks that link learning, memory and forgetting to the RASopathies and various neurodegenerative and neurodevelopmental diseases such as Alzheimer's disease, Parkinson's disease and autism spectrum disorders. We demonstrate the cross-talks of the molecular pathways in RASopathies and memory and the role of compartmentalization in these processes. The approved drugs are also overviewed, and C. elegans is proposed as a viable model system for experimental exploration and compound target prediction.n. PMID- 25694071 TI - Multiscale modelling of relationships between protein classes and drug behavior across all diseases using the CANDO platform. AB - We have examined the effect of eight different protein classes (channels, GPCRs, kinases, ligases, nuclear receptors, proteases, phosphatases, transporters) on the benchmarking performance of the CANDO drug discovery and repurposing platform (http://protinfo.org/cando). The first version of the CANDO platform utilizes a matrix of predicted interactions between 48278 proteins and 3733 human ingestible compounds (including FDA approved drugs and supplements) that map to 2030 indications/diseases using a hierarchical chem and bio-informatic fragment based docking with dynamics protocol (> one billion predicted interactions considered). The platform uses similarity of compound-proteome interaction signatures as indicative of similar functional behavior and benchmarking accuracy is calculated across 1439 indications/diseases with more than one approved drug. The CANDO platform yields a significant correlation (0.99, p-value < 0.0001) between the number of proteins considered and benchmarking accuracy obtained indicating the importance of multitargeting for drug discovery. Average benchmarking accuracies range from 6.2 % to 7.6 % for the eight classes when the top 10 ranked compounds are considered, in contrast to a range of 5.5 % to 11.7 % obtained for the comparison/control sets consisting of 10, 100, 1000, and 10000 single best performing proteins. These results are generally two orders of magnitude better than the average accuracy of 0.2% obtained when randomly generated (fully scrambled) matrices are used. Different indications perform well when different classes are used but the best accuracies (up to 11.7% for the top 10 ranked compounds) are achieved when a combination of classes are used containing the broadest distribution of protein folds. Our results illustrate the utility of the CANDO approach and the consideration of different protein classes for devising indication specific protocols for drug repurposing as well as drug discovery. PMID- 25694073 TI - Network based approach to drug discovery: a mini review. AB - With the rapid development of high-throughput genomic technologies and the accumulation of genome-wide datasets for human disease, it has been shown that using only reductionistic principles has been difficult to capture the complex biological networks and design rational medication. However, the emerging paradigm of "network based methodology" proposes to harness the power of networks to uncover relationships between various data types of interest for drug discovery. Recent advances include networks that encompass relationships between drugs, disease-related genes, therapeutic targets and diseases. It is shown how network techniques can help in the investigation of the mechanism of action of existing drugs, new molecules, or to identify novel disease genes and targets. We review how these different types of network analysis approaches facilitate drug discovery and their associated challenges. Some representative examples are reviewed to show that network analysis is a powerful, integrated, computational and experimental approach to improve the drug discovery process. PMID- 25694074 TI - In silico assessment of the acute toxicity of chemicals: recent advances and new model for multitasking prediction of toxic effect. AB - The assessment of acute toxicity is one of the most important stages to ensure the safety of chemicals with potential applications in pharmaceutical sciences, biomedical research, or any other industrial branch. A huge and indiscriminate number of toxicity assays have been carried out on laboratory animals. In this sense, computational approaches involving models based on quantitative-structure activity/toxicity relationships (QSAR/QSTR) can help to rationalize time and financial costs. Here, we discuss the most significant advances in the last 6 years focused on the use of QSAR/QSTR models to predict acute toxicity of drugs/chemicals in laboratory animals, employing large and heterogeneous datasets. The advantages and drawbacks of the different QSAR/QSTR models are analyzed. As a contribution to the field, we introduce the first multitasking (mtk) QSTR model for simultaneous prediction of acute toxicity of compounds by considering different routes of administration, diverse breeds of laboratory animals, and the reliability of the experimental conditions. The mtk-QSTR model was based on artificial neural networks (ANN), allowing the classification of compounds as toxic or non-toxic. This model correctly classified more than 94% of the 1646 cases present in the whole dataset, and its applicability was demonstrated by performing predictions of different chemicals such as drugs, dietary supplements, and molecules which could serve as nanocarriers for drug delivery. The predictions given by the mtk-QSTR model are in very good agreement with the experimental results. PMID- 25694075 TI - Role of moving average analysis for development of multi-target (Q)SAR models. AB - In modern drug discovery era, multi target- quantitative structure activity relationship [mt- (Q)SAR] approaches have emerged as novel and powerful alternatives in the field of in-silico drug design so as to facilitate the discovery of new chemical entities with multiple biological activities. Amongst various machine learning approaches, moving average analysis (MAA) has frequently exhibited high accuracy of prediction of diverse biological activities against different biological targets and experimental conditions. Role of MAA in developing (Q)SAR models for prediction of single/dual or multi target activity has been briefly reviewed in the present article. Subsequently, MAA was successfully utilized for developing mt-(Q)SAR models for simultaneous prediction of anti-Plasmodium falciparum and anti-Trypanosoma brucei rhodesiense activities of benzyl phenyl ether derivatives. The statistical significance of models was assessed through intercorrelation analysis, sensitivity, specificity and Matthew's correlation coefficient. Proposed MAA based models were also validated using test set. High predictability of the order of 80% to 95% amalgamated with safety (indicated by high value of selectivity index) of proposed mt-(Q)SAR models justifies use of MAA in developing models in order to obtain more realistic and accurate results for prediction of anti-protozal activity against multiple targets. Active ranges of the proposed models can play a significant role in the development of novel, potent, versatile and safe anti-protozoal drugs with improved profile in terms of both anti-Plasmodium falciparum and anti Trypanosoma brucei rhodesiense activities. PMID- 25694076 TI - Development of HuperTacrines as non-toxic, cholinesterase inhibitors for the potential treatment of Alzheimer's disease. AB - This paper describes our preliminary results on the ADMET, synthesis, biochemical evaluation, and molecular modeling of racemic HuperTacrines (HT), new hybrids resulting from the juxtaposition of huperzine A and tacrine for the potential treatment of Alzheimer's disease (AD). The synthesis of these HT was executed by Friedlander-type reactions of 2-amino-6-oxo-1,6-dihydropyridine-3-carbonitriles, or 7-amino-2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridine- 8-carbonitriles, with cyclohexanone. In the biochemical evaluation, initial and particular attention was devoted to test their toxicity on human hepatoma cells, followed by the in vitro inhibition of human cholinesterases (hAChE, and hBuChE), and the kinetics/mechanism of the inhibition of the most potent HT; simultaneous molecular modeling on the best HT provided the key binding interactions with the human cholinesterases. >From these analyses, (+/-)-5-amino-3-methyl- 3,4,6,7,8,9 hexahydrobenzo[b][1,8]naphthyridin-2(1H)-one (HT1) and (+/-)-5-amino-3-(2,6 dichlorophenyl)-3,4,6,7,8,9- hexahydrobenzo[b][1,8]naphthyridin-2(1H)-one (HT3) have emerged as characterized by extremely low liver toxicity reversible mixed type, selective hAChE and, quite selective irreversible hBuChEIs, respectively, showing also good druglike properties for AD-targeted drugs. PMID- 25694077 TI - Benzo- and thienobenzo- diazepines: multi-target drugs for CNS disorders. AB - Benzodiazepines (BZ or BZD) are a class of gabaminergic psychoactive chemicals used in hypnotics, sedation, in the treatment of anxiety, and in other CNS disorders. These drugs include alprazolam (Xanax), diazepam (Valium), clonazepam (Klonopin), and others. There are two distinct types of pharmacological binding sites for benzodiazepines in the brain (BZ1 and BZ2), these sites are on GABA-A receptors, and are classified as short, intermediate, or long-acting. From the thienobenzodiazepine class (TBZ), Olanzapine (2-methyl-4-(4-methyl-l-piperazinyl) 10H-thieno[2,3-b][1,5]benzodiazepine) (Zyprexa) was used as an example to demonstrate the antagonism of this class of compounds for multiples receptors including: dopamine D1-D5, alpha-adrenoreceptor, histamine H1, muscarinic M1-M5 and 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3 and 5-HT6 receptors. Olanzapine is an atypical antipsychotic agent, structurally related to clozapine, and extensively used for the treatment of schizophrenia, bipolar disorder-associated mania, and the behavioral symptoms of Alzheimer's disease. The functional blockade of these multiple receptors contributes to the wide range of its pharmacologic and therapeutic activities, having relatively few side effects when compared to other antipsychotics agents. Thienobenzodiazepines (such as Olanzapine) are characterized as multi- receptor- targeted- acting- agents. This mini-review discusses these 2 drug classes that act on the central nervous system, the main active compounds used, and the various receptors with which they interact. In addition, we propose 12 olanzapine analogues, and generated Random Forest models, from a data set obtained from the ChEMBL database, to classify the structures as active or inactive against 5 dopamine receptors (D1, D2, D3, D4, D5 and D6), and dopamine transporter. PMID- 25694078 TI - Mutagenicity: QSAR - quasi-QSAR - nano-QSAR. AB - Mutagenic potential of biphenyl-4-amines and multi-walled carbon nanotubes (MWCNTs) have been modeled by optimal descriptors. The optimal descriptors are calculated with the Monte Carlo method by means of the CORAL software (http://www.insilico.eu/coral). The optimal descriptor is a translator of eclectic data into prediction of various endpoints in general and into the prediction of the mutagenic potential (TA100) in particular. So-called, quasi SMILES are suggested as representation of various circumstances which can influence the endpoint. The correlation weights of various circumstances are the basis of the approach. The statistical characteristics of models for the mutagenic potential (decimal logarithm of TA100) for the external invisible validation sets are the following (i) in the case of biphenyl-4- amines: n=7-11; r(2)=0.649+/-0.046; s=0.211+/-0.029; and (ii) in the case of MWCNTs: n=6, r(2)=0.804+/-0.107; s=0.048+/-0.01. PMID- 25694079 TI - Multi-target drug discovery in medicinal chemistry: current status and future perspectives. PMID- 25694080 TI - EDITORIAL (Thematic Issue: Ectonucleotidases as Novel Drug Targets: Recent Advances in Therapeutic Applications). PMID- 25694081 TI - Ecto-nucleotidase inhibitors: recent developments in drug discovery. AB - Ecto-nucleotidases are nucleotide metabolizing enzymes that are divided into four different families; nucleoside triphosphate diphosphohydrolases (NTPDases), ecto 5'-nucleotidase (ecto-5'-NT), nucleotide pyrophosphatase/phosphodiesterases (NPPs), and alkaline phosphatases (APs). These enzymes are responsible for the hydrolysis of nucleotidases (nucleoside 5'-triphosphates, 5'-diphosphates and 5' monophosphates). Ecto-nucleotidases modulate P1- and P2-receptor-mediated signaling. Alterations in extracellular nucleotide and adenosine level can increase or decrease P1 and P2 activity. Potent and selective ligands for certain ectonucleotidase are important as pharmacological tools to investigate the (patho)physiological roles of these enzymes. Furthermore, such ligands are required to study their potential as novel drugs, e.g., as immunomodulatory agents, for the treatment of cancer, cardiovascular or central nervous system disorders. Hence, this review aims to provide an overview of ecto-nucleotidases inhibitors developed so far. PMID- 25694082 TI - Is Ecto-nucleoside Triphosphate Diphosphohydrolase (NTPDase)-based Therapy of Central Nervous System Disorders Possible? AB - Extracellular nucleotides and nucleosides are signalling molecules acting in all tissues and organs, including the central nervous system (CNS). A wide variety of effects, exerted by ecto-purines, requires that their levels, and ATP in particular, must be precisely controlled. Under physiological conditions, concentration of ecto-purines is regulated by a complex cascade of ecto-enzymes, including ecto-NTPDases (nucleoside triphosphate diphosphohydrolases), ecto-NPPs (nucleotide pyrophosphohydrolases/phosphodiesterases), ectoalkaline phosphatases, and ecto-5'nucleotidase. Adenylate kinase, transferring the phosphate moiety between nucleotides, also plays a role in controlling ecto-purines concentration. Disturbances in the elements of purinergic pathway within the CNS underlie the induction and amplification of many neurological pathologies. ATP released in bulk from the cells, and not degraded by less efficient or dysfunctional ecto nucleotidases, triggers excitotoxic damage and neuro-inflammation in the brain tissue. High ATP concentration activating specific receptors has been shown to be involved in various disorders throughout CNS, including brain injury and ischemia, neuro-inflammation, epilepsy as well as neuropathic pain and migraine. Taking the above mentioned influence of ATP into consideration, the modulation of ecto-NTPDase activity or its site-targeted delivery seems a good therapeutic method. The availability of effective brain-targeted drug-delivery system is one of the most significant challenges facing potential NTPDase-based treatment of CNS disorders. The application of genetically engineered stem cells as carrier vehicles offers a promising strategy for the efficient delivery of the enzyme to CNS tissues. PMID- 25694083 TI - Inhibition of alkaline phosphatase: an emerging new drug target. AB - Alkaline phosphatase (AP, EC 3.1.3.1.) is a metalloenzyme that belongs to a family of ectonucleotidases. The other members of ectonucleotidase family are ecto-nucleoside triphosphate diphosphohydrolases (E-NTPDases), ecto-nucleotide pyrophosphatase/phosphodiesterases (E-NPPs) and ecto-5'-nucleotidase (e5'NT). These ectonucleotidases are responsible for hydrolyzing extracellular nucleotides to nucleosides including adenosine. Many of these extracellular nucleotides and adenosine are important signaling molecules that act on their respective receptors (adenosine activated P1 receptor; nucleotide activated P2 receptor, each having many sub-types) and are therefore responsible for triggering cellular responses that lead to important physiological and immunological changes. A dedicated, concerted cohort of ectonucleotidases is responsible for controlling the availability of these extracellular signaling molecules at their respective receptors. Inhibitors of these ectonucleotidases provide the means by which these cellular processes can be modulated. This mini review has been written in the wake of mounting evidence of potential therapeutic benefits associated with inhibition of alkaline phosphatases and aims to provide prolific leads to design more potent and selective AP inhibitors. PMID- 25694084 TI - Structural and Modeling Studies on ecto-5'-nucleotidase Aiding in Inhibitor Design. AB - Ecto-5'-nucleotidase (e5NT) hydrolyzes extracellular nucleotides and contributes to purinergic signaling. e5NT is implicated in a variety of pathological states including immunological diseases and cancer and represents an emerging drug target. Herein, we review structural and computational studies that have helped to better understand ligand binding characteristics and mechanistic features of the enzyme and led to the identification of new classes of e5NT inhibitors. PMID- 25694085 TI - Effect of Sodium Arsenite on Mouse Skin Carcinogenesis. AB - Arsenic is carcinogenic in human beings, and environmental exposure to arsenic is a public health issue that affects large populations worldwide. Thus, studies are needed to determine the mode of action of arsenic and prevent harmful effects arising from arsenic intake. The present study assessed the influence of sodium arsenite (As(3+)) on potentially carcinogenic processes that are either pre existing or concomitant with chronic intake of water containing As(3+). Experiments using SenCar mice were designed to evaluate the effect of chronic administration of As(3+) (2, 20, or 200 mg of As(3+)/L) in drinking water that overlapped to varying degrees with a 2-stage carcinogenesis protocol carried out over 9 months. The results showed a time-dependent pattern. During early stages of carcinogenesis (6-12 weeks), animals exposed to As(3+) and the carcinogenesis protocol showed increased numbers of tumors compared to control animals. During late carcinogenesis (16-30 weeks), the number of tumors stabilized to below control values, but the tumors showed increased malignancy. These findings indicate that the outcomes of the 2-stage skin carcinogenesis protocol are modified by the presence of arsenite in drinking water, which increases the rate of carcinoma development. PMID- 25694086 TI - Practical Applications of in Vivo and ex Vivo MRI in Toxicologic Pathology Using a Novel High-performance Compact MRI System. AB - Magnetic resonance imaging (MRI) is widely used in preclinical research and drug development and is a powerful noninvasive method for assessment of phenotypes and therapeutic efficacy in murine models of disease. In vivo MRI provides an opportunity for longitudinal evaluation of tissue changes and phenotypic expression in experimental animal models. Ex vivo MRI of fixed samples permits a thorough examination of multiple digital slices while leaving the specimen intact for subsequent conventional hematoxylin and eosin (H&E) histology. With the advent of new compact MRI systems that are designed to operate in most conventional labs without the cost, complexity, and infrastructure needs of conventional MRI systems, the possibility of MRI becoming a practical modality is now viable. The purpose of this study was to investigate the capabilities of a new compact, high-performance MRI platform (M2TM; Aspect Imaging, Israel) as it relates to preclinical toxicology studies. This overview will provide examples of major organ system pathologies with an emphasis on how compact MRI can serve as an important adjunct to conventional pathology by nondestructively providing 3 dimensional (3-D) digital data sets, detailed morphological insights, and quantitative information. Comparative data using compact MRI for both in vivo and ex vivo are provided as well as validation using conventional H&E. PMID- 25694087 TI - Effects of Chronic Ochratoxin A Exposure on p53 Heterozygous and p53 Homozygous Mice. AB - Exposure to the mycotoxin ochratoxin A (OTA) causes nephropathy in domestic animals and rodents and renal tumors in rodents and poultry. Humans are exposed to OTA by consuming foods made with contaminated cereal grains and other commodities. Management of human health risks due to OTA exposure depends, in part, on establishing a mode of action (MOA) for OTA carcinogenesis. To further investigate OTA's MOA, p53 heterozygous (p53+/-) and p53 homozygous (p53+/+) mice were exposed to OTA in diet for 26 weeks. The former are susceptible to tumorigenesis upon chronic exposure to genotoxic carcinogens. OTA-induced renal damage but no tumors were observed in either strain, indicating that p53 heterozygosity conferred little additional sensitivity to OTA. Renal changes included dose-dependent increases in cellular proliferation, apoptosis, karyomegaly, and tubular degeneration in proximal tubules, which were consistent with ochratoxicosis. The lowest observed effect level for renal changes in p53+/- and p53+/+ mice was 200 MUg OTA/kg bw/day. Based on the lack of tumors and the severity of renal and body weight changes at a maximum tolerated dose, the results were interpreted as suggestive of a primarily nongenotoxic (epigenetic) MOA for OTA carcinogenesis in this mouse model. PMID- 25694088 TI - Characterization of Periodic Acid-Schiff-Positive Granular Deposits in the Hippocampus of SJL/J Mice. AB - Periodic acid-Schiff (PAS)-positive granular deposits in the hippocampus have been reported previously in certain inbred mouse strains such as C57BL/6 and the senescent-accelerated mouse prone-8. Here, we report for the first time that similar PAS-positive granules age dependently occur in SJL/J mice, a mouse strain, for instance, used for central nervous system disease research. Moreover, similar granules stained intensely positive with a polyclonal antibody directed against p75 neurotrophin receptor (p75(NTR)). Granular deposits were absent in young mice and developed with aging in CA1 and CA2 regions of the hippocampus. Interestingly, granules significantly diminished in SJL/J mice previously treated with cuprizone, a copper chelator, which is a useful model for toxic demyelination. The presented data support the idea that granules might be the result of an imbalance of redox-active metals and/or a dysregulation of complementary mechanisms that regulate their homeostasis in astrocyte-neuron coupling, respectively. It remains to be determined whether the unsuspected immunoreactivity for p75(NTR) represents a false-positive reaction or whether p75(NTR) is crucially involved in the pathogenesis of age-related hippocampal granular deposits in mice. PMID- 25694089 TI - Inhibition against growth of glioblastoma multiforme in vitro using etoposide loaded solid lipid nanoparticles with p-aminophenyl-alpha-D-manno-pyranoside and folic acid. AB - Solid lipid nanoparticles (SLNs) grafted with p-aminophenyl-alpha-D-manno pyranoside (APMP) and folic acid (FA) (APMP-FA-SLNs) were applied to encapsulate 4'-demethylepipodophyllotoxin 9-(4,6-O-ethylidene-beta-D-glucopyranoside) (etoposide) (ETP) for promoting the antiproliferation of malignant glioblastoma multiforme. ETP-loaded APMP-FA-SLNs (APMP-FA-ETP-SLNs) were used to penetrate the blood-brain barrier (BBB) and retard the propagation of U87MG cells. An incorporation of APMP and FA increased the particle size, the cytotoxicity to U87MG cells, and the permeability coefficient for propidium iodide and ETP across the BBB. In addition, an increase in the APMP and FA concentration reduced the zeta potential, the grafting efficiency of APMP and FA, the dissolution rate of ETP, and the transendothelial electrical resistance. Immunochemical staining images evidenced that APMP-FA-ETP-SLNs could infiltrate the BBB via glucose transporter 1 and recognize U87MG cells via folate receptor. APMP-FA-ETP-SLNs can be an effective pharmacotherapeutic formulation in targeting delivery to the brain and in inhibitory efficacy against tumorous cells for cancer therapy. PMID- 25694090 TI - [Ebola virus disease]. AB - Ebola is one of the most virulent zoonotic RNA viruses causing in humans haemorrhagic fever with fatality ratio reaching 90%. During the outbreak of 2014 the number of deaths exceeded 8.000. The "imported" cases reported in Western Europe and USA highlighted the extreme risk of Ebola virus spreading outside the African countries. Thus, haemorrhagic fever outbreak is an international epidemiological problem, also due to the lack of approved prevention and therapeutic strategies. The editorial review article briefly summarizes current knowledge on Ebola virus disease epidemiology, etiology, pathogenesis, clinical presentation, diagnosis as well as possible prevention and treatment. PMID- 25694091 TI - The determinants of spread of Ebola virus disease - an evidence from the past outbreak experiences. AB - The paper summarizes available evidence regarding the determinants of spread of Ebola virus disease, including health care and community related risk factors. It was observed that the level of uncertainty for the estimations is relatively high which may hinder to make some predictions for the future evolution of EVD outbreak. The natural history of EVD has shown that the disease may pose a problem to developed countries and may present a thread to individuals. Although observed modes of transmission mainly include direct contact and contaminated staff, high case fatality ratio and frequent contacts among individuals in developed countries are among determinants which may lead to the development of the EVD outbreak. PMID- 25694092 TI - The evolution of Ebola virus disease outbreaks. AB - The paper presents general information regarding descriptive epidemiology of Ebola virus disease (EVD) outbreaks. Some observations have shown the decrease in case fatality ratio after several generations of patient-to-patient passage. An increase in the frequency of EVD outbreaks across decades was also noticed. The knowledge about the past outbreaks may provide crucial information about the evolution of EVD epidemic, which may be useful for future preventions. PMID- 25694093 TI - Ebola virus disease control in Poland - are we ready for fight? AB - Despite very low risk assessment, Polish authorities should be prepared for imported EVD cases and be ready to protect public against the spread of Ebolavirus (EBOV). There is the consistent system of infectious diseases surveillance and control in entire country, regulated by law. In Poland the Public Sanitary Inspection has jurisdiction over infectious diseases surveillance. A reporting system functions at three levels. The entire spectrum of viral hemorrhagic fevers is included in the list of 59th notifiable diseases and causative organisms. EVD is regarded as sever, often fatal communicable disease that should be notify promptly. According to Polish legislation EVD cases would be obligatorily isolated in hospital ward. Each potential contact of EVD case should be individually assessed for risk of exposure and categorized for staying under mandatory quarantine or under active monitoring. The governor of each Polish province has established the Epidemic Active Plan and indicated the place for quarantine if needed. The Ministry of Health established the procedures of management of EVD suspected cases and persons in risk to be infected with EBOV in outpatient care. There are prepared separate procedures for dispatcher of emergency medical service, GP's, hospital emergency departments and airports. There are 10 hospitals with division of infectious diseases, with high level isolation units, ready for EVD patient's admission. There is one reference laboratory in Poland in National Institute of Public Health, which performed tests for EBOV detection. The hospitals and outpatient care services and sanitary inspection were evaluated on possession the appropriate PPE for medical staff, in case of direct contact with EVD patient would be needed. Regardless, very law risk for Poland to be affected by EVD outbreak our country is sufficiently prepared for fighting with EBOV infection. PMID- 25694094 TI - Ebola haemorrhagic fever virus: pathogenesis, immune responses, potential prevention. AB - Ebola zoonotic RNA filovirus represents human most virulent and lethal pathogens, which induces acute hemorrhagic fever and death within few days in a range of 60 90% of symptomatic individuals. Last outbreak in 2014 in West Africa caused panic that Ebola epidemic can be spread to other continents. Number of deaths in late December reached almost 8,000 individuals out of more than 20,000 symptomatic patients. It seems that only a coordinated international response could counteract the further spread of Ebola. Major innate immunity mechanisms against Ebola are associated with the production of interferons, that are inhibited by viral proteins. Activation of host NK cells was recognized as a leading immune function responsible for recovery of infected people. Uncontrolled cell infection by Ebola leads to an impairment of immunity with cytokine storm, coagulopathy, systemic bleeding, multi-organ failure and death. Tested prevention strategies to induce antiviral immunity include: i. recombinant virus formulations (vaccines); ii. cocktail of monoclonal antibodies (serotherapy); iii. alternative RNA interference-based antiviral methods. Maintaining the highest standards of aseptic and antiseptic precautions is equally important. Present brief review summarizes a current knowledge concerning pathogenesis of Ebola hemorrhagic disease and the virus interaction with the immune system and discusses recent advances in prevention of Ebola infection by vaccination and serotherapy. PMID- 25694095 TI - Ebola virus disease - pathogenesis, clinical presentation and management. AB - On March 2014 the WHO notified the outbreak of Ebola virus disease (EVD) in Guinea, and infection quickly spread to another West African countries including Sierra Leone, Liberia and Nigeria. Current outbreak is the largest in the history, since discovery of the virus in 1976. Imported cases and infection among healthcare workers in Europe and United States have elucidated necessity of better education of medical staff. Clinicians must be familiar with clinical picture of EVD, differential diagnosis and therapeutic approach, as rapid diagnosis and prompt introduction of supportive therapy can have a significant impact on the survival. PMID- 25694096 TI - General introduction into the Ebola virus biology and disease. AB - Epidemic of Ebola hemorrhagic fever which appeared in the countries of West Africa in 2014, is the largest outbreak which occurred so far. The virus causing this epidemic, Zaire Ebolavirus (ZEBOV), along with four other species of Ebolaviruses is classified to the genus Ebolavirus in the family Filoviridae. ZEBOV is one of the most virulent pathogens among the viral haemorrhagic fevers, and case fatality rates up to 90% have been reported. Mortality is the result of multi-organ failure and severe bleeding complications. The aim of this review is to present the general characteristics of the virus and its biological properties, pathogenicity and epidemiology, with a focus on laboratory methods used in the diagnosis of these infections. PMID- 25694097 TI - Pharmacotherapy of Ebola hemorrhagic fever: a brief review of current status and future perspectives. AB - The 2014 outbreak clearly showed that Ebola viruses (EBOV) remain a substantial threat for public health. The mainstay of management of patients with Ebola disease is isolation of patients and use of strict barrier nursing procedures; the present treatment strategies are mainly symptomatic and supportive (fluid resuscitation, antypyretics, antidiarrheal drugs). Currently, there is no approved therapy for Ebola hemorrhagic fever (EHF), however several advanced treatment options were tested in animal models (on non-human primates or rodents). They include use of both symptomatic (e.g. use of tissue factor inhibitors - rhNAPc2, rhAPC - to abolish coagulopathy) and specific antiviral approaches: e.g. monoclonal anti EBOV antibodies (ZMapp, MB-003), phosphorodiamidate morpholino oligomers (PMOs), liposomes containing siRNA (LNP siRNA:TKM-Ebola) and small molecule inhibitors (e.g. BCX4430, favipiravir). The scope of this article is to briefly review the most promising therapeutics for EHF, based on the data coming from rare clinical reports, studies on animals and results from in vitro models. PMID- 25694098 TI - Brain vascular pericytes following ischemia have multipotential stem cell activity to differentiate into neural and vascular lineage cells. AB - Brain vascular pericytes (PCs) are a key component of the blood-brain barrier (BBB)/neurovascular unit, along with neural and endothelial cells. Besides their crucial role in maintaining the BBB, increasing evidence shows that PCs have multipotential stem cell activity. However, their multipotency has not been considered in the pathological brain, such as after an ischemic stroke. Here, we examined whether brain vascular PCs following ischemia (iPCs) have multipotential stem cell activity and differentiate into neural and vascular lineage cells to reconstruct the BBB/neurovascular unit. Using PCs extracted from ischemic regions (iPCs) from mouse brains and human brain PCs cultured under oxygen/glucose deprivation, we show that PCs developed stemness presumably through reprogramming. The iPCs revealed a complex phenotype of angioblasts, in addition to their original mesenchymal properties, and multidifferentiated into cells from both a neural and vascular lineage. These data indicate that under ischemic/hypoxic conditions, PCs can acquire multipotential stem cell activity and can differentiate into major components of the BBB/neurovascular unit. Thus, these findings support the novel concept that iPCs can contribute to both neurogenesis and vasculogenesis at the site of brain injuries. PMID- 25694099 TI - MELDEQ : An alternative Model for End-Stage Liver Disease score for patients with hepatocellular carcinoma. AB - Multiple studies have demonstrated an advantage for hepatocellular carcinoma (HCC) patients under the current liver allocation system, such that the United Network for Organ Sharing (UNOS) recently voted in support of a proposal to delay granting Model for End-Stage Liver Disease (MELD) exception points to all HCC patients for 6 months, independently of a candidate's native MELD score or alpha fetoprotein (AFP) level. We obtained UNOS data on adult patients who were added to the wait list between January 22, 2005 and September 30, 2009, and we explored the relationship between HCC, MELD, AFP, and other factors that contribute to not only dropout on the wait list but posttransplant survival as well. The aim was to establish an equivalent Model for End-Stage Liver Disease (MELDEQ ) score for HCC patients that would reduce the disparity in access to transplantation between HCC and non-HCC patients. We determined risk groups for HCC patients with dropout hazards equivalent to those of non-HCC patients, and we evaluated projections for HCC wait-list dropout/transplantation probabilities on the basis of the MELDEQ prioritization scheme. Projections indicate that lower risk HCC patients (MELDEQ <= 18) would have dropout probabilities similar to those of non-HCC patients in the same MELD score range, whereas dropout probabilities for higher risk HCC patients would actually be improved. The posttransplant survival of all HCC risk groups is lower than that of their non-HCC counterparts, with 1-year survival of 0.77 (95% CI, 0.70-0.85) for MELDEQ scores >= 31. These results suggest that HCC patients with a combination of a low biochemical MELD score and a low AFP level (MELDEQ <= 15) would receive a marked advantage in comparison with patients with chemical MELD scores in a similar range and that a delay of 6 months for listing may be appropriate. In contrast, patients with MELDEQ scores > 15 would likely be adversely affected by a universal 6-month delay in listing. PMID- 25694100 TI - Deciphering Genome Environment Wide Interactions Using Exposed Subjects Only. AB - The recent successes of genome-wide association studies (GWAS) have renewed interest in genome environment wide interaction studies (GEWIS) to discover genetic factors that modulate penetrance of environmental exposures to human diseases. Indeed, gene-environment interactions (G * E), which have not been emphasized in the GWAS era, could be a source contributing to the missing heritability, a major bottleneck limiting continuing GWAS successes. In this manuscript, we describe a design and analytic strategy to focus on G * E using only exposed subjects, dubbed as e-GEWIS. Operationally, an e-GEWIS analysis is equivalent to a GWAS analysis on exposed subjects only, and it has actually been used in some earlier GWAS without being explicitly identified as such. Through both analytics and simulations, e-GEWIS has been shown better efficiency than the usual cross-product-based analysis of G * E interaction with both cases and controls (cc-GEWIS), and they have comparable efficiency to case-only analysis of G * E (c-GEWIS), with potentially smaller sample sizes. The formalization of e GEWIS here provides a theoretical basis to legitimize this framework for routine investigation of G * E, for more efficient G * E study designs, and for improvement of reproducibility in replicating GEWIS findings. As an illustration, we apply e-GEWIS to a lung cancer GWAS data set to perform a GEWIS, focusing on gene and smoking interaction. The e-GEWIS analysis successfully uncovered positive genetic associations on chromosome 15 among current smokers, suggesting a gene-smoking interaction. Although this signal was detected earlier, the current finding here serves as a positive control in support of this e-GEWIS strategy. PMID- 25694101 TI - Bronsted acid catalyzed alpha'-functionalization of silylenol ethers with indoles. AB - A new method which enables carbon-carbon bond formation at the alpha'-position of silylenol ethers by using catalytic amounts of pyridinium triflate is reported. This chemistry successfully produces, structurally challenging, highly substituted indole-containing silylenol ethers in excellent yields with complete regiocontrol, presumably through silyloxyallyl cation intermediates. Despite the use of Bronsted acid, the silylenol ether moiety does not undergo protodesilylation, thus underscoring the very mild reaction conditions. PMID- 25694102 TI - Survival with cerebral palsy over five decades in western Sweden. AB - AIM: The life expectancy of individuals with cerebral palsy (CP) is often reduced compared with the general population. Long-term survival with CP is rarely reported. The aim of this study was to investigate survival and the causes of death in relation to CP type and motor and accompanying impairments documented in the CP register of western Sweden over five decades. METHOD: All individuals born between 1959 and 2002 were included in the study. CP was classified according to Hagberg and the Surveillance of Cerebral Palsy in Europe (SCPE). Motor and accompanying impairments were documented. Causes of death were derived from the National Board of Health and Welfare, and population data were obtained from Statistics Sweden. Log-rank tests with Kaplan-Meier plots were used for statistical analyses. RESULTS: Of the 1856 individuals (1033 males, 823 females) with CP included in the study, 180 (9.6%) had died by 31 December 2009. Tetraplegia, dyskinetic CP, severe cognitive impairment, and epilepsy were associated with decreased survival rates. At Gross Motor Function Classification System (GMFCS) level V, survival rates among individuals with spastic CP were lower than among those with dyskinetic CP. However, compared with the general population, there was an elevated death rate among individuals with CP for all age groups and CP types. At all ages, females with CP had a larger excess risk of death than males. Respiratory failure caused 53% of deaths. For individuals with hemiplegia, as in the general population, 20% of deaths were accidental. INTERPRETATION: Survival rates are influenced by CP type but there is an elevated risk of death for individuals with any type of CP, compared with those without CP. PMID- 25694103 TI - Role of a 12-lead electrocardiogram in the diagnosis of cardiac tamponade as diagnosed by transthoracic echocardiography in patients with malignant pericardial effusion. AB - BACKGROUND: Few studies have looked at the utility of the 12-lead electrocardiogram (ECG) in diagnosing cardiac tamponade in malignant pericardial effusion (PE). The aim of this study was to determine the sensitivity (Se), specificity (Sp), positive predictive value (PPV), and negative predictive value (NPV) of 12-lead ECG in diagnosing cardiac tamponade in PE. HYPOTHESIS: Abnormalities on a 12 lead ECG can be used to diagnose or exclude cardiac tamponade in patients with malignant PE. METHODS: Using echocardiography as the gold standard for diagnosis of cardiac tamponade, we determined the Se, Sp, PPV, and NPV for individual and combinations of the 3 ECG abnormalities (low-voltage complexes, electrical alternans, and sinus tachycardia). RESULTS: For PEs of all sizes, the Se, Sp, PPV, and NPV for detecting cardiac tamponade were: low-voltage complexes (56%, 74%, 81%, 46%), electrical alternans (23%, 98%, 95%, 39%), and sinus tachycardia (76%, 60%, 79%, 56%), respectively. Presence of all 3 and any of the 3 ECG abnormalities had a Se, Sp, PPV, and NPV of 8%, 100%, 100%, 36% and 89%, 47%, 77%, 69%, respectively, for cardiac tamponade. The odds ratios for cardiac tamponade in PE were 3.7 (95% confidence interval [CI]: 1.65-8.30) for low-voltage complexes, 12.3 (95% CI: 1.58-95.17) for electrical alternans, and 4.9 (95% CI: 2.22-10.80) for sinus tachycardia. Presence of any of 3 ECG abnormalities had an odds ratio of 7.3 (95% CI: 2.9-18.1) for cardiac tamponade. CONCLUSIONS: In malignant PE, combination of ECG abnormalities can supplement clinical examination in the diagnosis of echocardiographic cardiac tamponade. Due to its low NPV, 12-lead ECG cannot be used as a screening tool to exclude cardiac tamponade with malignant PE. PMID- 25694104 TI - New factors and signaling pathways for developmental regulation. PMID- 25694105 TI - Regulation of Cellular Response Pattern to Phosphorus Ion is a New Target for the Design of Tissue-Engineered Blood Vessel. AB - Regulation of cellular response pattern to phosphorus ion (PI) is a new target for the design of tissue-engineered materials. Changing cellular response pattern to high PI can maintain monocyte/macrophage survival in TEBV and the signal of increasing PI can be converted by klotho to the adenosine signals through the regulation of energy metabolism in monocytes/macrophages. PMID- 25694106 TI - Systematic review and meta-analysis of Japanese familial Alzheimer's disease and FTDP-17. AB - Mutations in APP, PSEN1 and PSEN2 as the genetic causes of familial Alzheimer's disease (FAD) have been found in various ethnic populations. A substantial number of FAD pedigrees with mutations have been reported in the Japanese population; however, it remains unclear whether the genetic and clinical features of FAD in the Japanese population differ from those in other populations. To address this issue, we conducted a systematic review and meta-analysis of Japanese FAD and frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) by literature search. Using this analysis, we identified 39 different PSEN1 mutations in 140 patients, 5 APP mutations in 35 patients and 16 MAPT mutations in 84 patients. There was no PSEN2 mutation among Japanese patients. The age at onset in Japanese FAD patients with PSEN1 mutations was significantly younger than that in patients with APP mutations. Kaplan-Meier analysis revealed that patients with MAPT mutations showed a shorter survival than patients with PSEN1 or APP mutations. Patients with mutations in different genes exhibit characteristic clinical presentations, suggesting that mutations in causative genes may modify the clinical presentations. By collecting and cataloging genetic and clinical information on Japanese FAD and FTDP-17, we developed an original database designated as Japanese Familial Alzheimer's Disease Database, which is accessible at http://alzdb.bri.niigata-u.ac.jp/. PMID- 25694107 TI - A case of autism spectrum disorder arising from a de novo missense mutation in POGZ. AB - Autism spectrum disorder (ASD) is a clinically heterogeneous psychiatric disorder with various genetic backgrounds. Here, we report a novel mutation in the pogo transposable element-derived protein with zinc finger domain gene (POGZ) identified by trio-based whole exome sequencing. To date, a total of seven de novo POGZ mutations in ASD have been reported. POGZ contains a total of five functional domains, and this study reports the first de novo missense mutation in the centromere protein B-like DNA-binding domain. POGZ is highly expressed in the human fetal brain and is involved in mitosis and the regulation of neuronal proliferation. Therefore its loss-of-function or pathogenic missense mutations are likely to be causative of ASD. PMID- 25694108 TI - Conceptual quantum chemical analysis of bonding and noncovalent interactions in the formation of frustrated Lewis pairs. AB - The contributions of covalent and noncovalent interactions to the formation of classical adducts of bulky Lewis acids and bases and frustrated Lewis pairs (FLPs) were scrutinized by using various conceptual quantum chemical techniques. Significantly negative complexation energies were calculated for fourteen investigated Lewis pairs containing bases and acids with substituents of various sizes. A Ziegler-Rauk-type energy decomposition analysis confirmed that two types of Lewis pairs can be distinguished on the basis of the nature of the primary interactions between reactants; dative-bond formation and concomitant charge transfer from the Lewis base to the acid is the dominant and most stabilizing factor in the formation of Lewis acid-base adducts, whereas weak interactions are the main thermodynamic driving force (>50 %) for FLPs. Moreover, the ease and extent of structural deformation of the monomers appears to be a key component in the formation of the former type of Lewis pairs. A Natural Orbital for Chemical Valence (NOCV) analysis, which was used to visualize and quantify the charge transfer between the base and the acid, clearly showed the importance and lack of this type of interaction for adducts and FLPs, respectively. The Noncovalent Interaction (NCI) method revealed several kinds of weak interactions between the acid and base components, such as dispersion, pi-pi stacking, C-H???pi interaction, weak hydrogen bonding, halogen bonding, and weak acid-base interactions, whereas the Quantum Theory of Atoms in Molecules (QTAIM) provided further conceptual insight into strong acid-base interactions. PMID- 25694109 TI - Superdomains in the protein structure hierarchy: The case of PTP-C2. AB - Superdomain is uniquely defined in this work as a conserved combination of different globular domains in different proteins. The amino acid sequences of 25 structurally and functionally diverse proteins from fungi, plants, and animals have been analyzed in a test of the superdomain hypothesis. Each of the proteins contains a protein tyrosine phosphatase (PTP) domain followed by a C2 domain. Four novel conserved sequence motifs have been identified, one in the PTP domain and three in the C2 domain. All contribute to the PTP-C2 domain interface in PTEN, a tumor suppressor, and all are more conserved than the PTP signature motif, HCX3 (K/R)XR, in the 25 sequences. We show that PTP-C2 was formed prior to the fungi, plant, and animal kingdom divergence. A superdomain as defined here does not fit the usual protein structure classification system. The demonstrated existence of one superdomain suggests the existence of others. PMID- 25694110 TI - Divorce among physicians and other healthcare professionals in the United States: analysis of census survey data. AB - OBJECTIVES: To estimate the prevalence and incidence of divorce among US physicians compared with other healthcare professionals, lawyers, and non healthcare professionals, and to analyze factors associated with divorce among physicians. DESIGN: Retrospective analysis of nationally representative surveys conducted by the US census, 2008-13. SETTING: United States. PARTICIPANTS: 48,881 physicians, 10,086 dentists, 13,883 pharmacists, 159,044 nurses, 18,920 healthcare executives, 59,284 lawyers, and 6,339,310 other non-healthcare professionals. MAIN OUTCOME MEASURES: Logistic models of divorce adjusted for age, sex, race, annual income, weekly hours worked, number of years since marriage, calendar year, and state of residence. Divorce outcomes included whether an individual had ever been divorced (divorce prevalence) or became divorced in the past year (divorce incidence). RESULTS: After adjustment for covariates, the probability of being ever divorced (or divorce prevalence) among physicians evaluated at the mean value of other covariates was 24.3% (95% confidence interval 23.8% to 24.8%); dentists, 25.2% (24.1% to 26.3%); pharmacists, 22.9% (22.0% to 23.8%); nurses, 33.0% (32.6% to 33.3%); healthcare executives, 30.9% (30.1% to 31.8%); lawyers, 26.9% (26.4% to 27.4%); and other non-healthcare professionals, 35.0% (34.9% to 35.1%). Similarly, physicians were less likely than those in most other occupations to divorce in the past year. In multivariable analysis among physicians, divorce prevalence was greater among women (odds ratio 1.51, 95% confidence interval 1.40 to 1.63). In analyses stratified by physician sex, greater weekly work hours were associated with increased divorce prevalence only for female physicians. CONCLUSIONS: Divorce among physicians is less common than among non-healthcare workers and several health professions. Female physicians have a substantially higher prevalence of divorce than male physicians, which may be partly attributable to a differential effect of hours worked on divorce. PMID- 25694112 TI - Including partners in trials of financial incentives for smoking cessation in pregnancy. PMID- 25694111 TI - Multidisciplinary biopsychosocial rehabilitation for chronic low back pain: Cochrane systematic review and meta-analysis. AB - OBJECTIVE: To assess the long term effects of multidisciplinary biopsychosocial rehabilitation for patients with chronic low back pain. DESIGN: Systematic review and random effects meta-analysis of randomised controlled trials. DATA SOURCES: Electronic searches of Cochrane Back Review Group Trials Register, CENTRAL, Medline, Embase, PsycINFO, and CINAHL databases up to February 2014, supplemented by hand searching of reference lists and forward citation tracking of included trials. STUDY SELECTION CRITERIA: Trials published in full; participants with low back pain for more than three months; multidisciplinary rehabilitation involved a physical component and one or both of a psychological component or a social or work targeted component; multidisciplinary rehabilitation was delivered by healthcare professionals from at least two different professional backgrounds; multidisciplinary rehabilitation was compared with a non- multidisciplinary intervention. RESULTS: Forty one trials included a total of 6858 participants with a mean duration of pain of more than one year who often had failed previous treatment. Sixteen trials provided moderate quality evidence that multidisciplinary rehabilitation decreased pain (standardised mean difference 0.21, 95% confidence interval 0.04 to 0.37; equivalent to 0.5 points in a 10 point pain scale) and disability (0.23, 0.06 to 0.40; equivalent to 1.5 points in a 24 point Roland-Morris index) compared with usual care. Nineteen trials provided low quality evidence that multidisciplinary rehabilitation decreased pain (standardised mean difference 0.51, -0.01 to 1.04) and disability (0.68, 0.16 to 1.19) compared with physical treatments, but significant statistical heterogeneity across trials was present. Eight trials provided moderate quality evidence that multidisciplinary rehabilitation improves the odds of being at work one year after intervention (odds ratio 1.87, 95% confidence interval 1.39 to 2.53) compared with physical treatments. Seven trials provided moderate quality evidence that multidisciplinary rehabilitation does not improve the odds of being at work (odds ratio 1.04, 0.73 to 1.47) compared with usual care. Two trials that compared multidisciplinary rehabilitation with surgery found little difference in outcomes and an increased risk of adverse events with surgery. CONCLUSIONS: Multidisciplinary biopsychosocial rehabilitation interventions were more effective than usual care (moderate quality evidence) and physical treatments (low quality evidence) in decreasing pain and disability in people with chronic low back pain. For work outcomes, multidisciplinary rehabilitation seems to be more effective than physical treatment but not more effective than usual care. PMID- 25694113 TI - Asymmetric ruthenium-catalyzed hydrogenation of 2,6-disubstituted 1,5 naphthyridines: access to chiral 1,5-diaza-cis-decalins. AB - The first asymmetric hydrogenation (AH) of 2,6-disubstituted and 2,3,6 trisubstituted 1,5-naphthyridines, catalyzed by chiral cationic ruthenium diamine complexes, has been developed. A wide range of 1,5-naphthyridine derivatives were efficiently hydrogenated to give 1,2,3,4-tetrahydro-1,5-naphthyridines with up to 99 % ee and full conversions. This facile and green protocol is applicable to the scaled-up synthesis of optically pure 1,5-diaza-cis-decalins, which have been used as rigid chelating diamine ligands for asymmetric synthesis. PMID- 25694114 TI - "How can I help you hear?" The transforming power of six little words. PMID- 25694115 TI - The arterial circle of the brain, its branches and connections in selected representatives of the Antilopinae. AB - The arterial circle of the brain, that is, the circle of Willis, and its branches in ruminants have been chiefly described in farm animals and only in selected wild species. In view of the deficit of information about this vascular region in numerous other species of the Ruminantia, the arteries of the encephalic base were analyzed in five antelope species representing different genera of the Bovidae, Antilopinae. Specimens of the following species were examined: springbuck (Antidorcas marsupialis), blackbuck (Antilope cervicapra), dik-dik (Madoqua kirkii), saiga (Saiga tatarica), and oribi (Ourebia ourebi). Post autopsy material received from domestic zoological gardens was used to inject the bilateral common carotid arteries with a stained acetone solution of vinyl superchloride. When the material was polymerized, the specimens were macerated enzymatically. The process resulted in casts of arteries of the head and encephalic base on a skeletal scaffold. The investigations revealed that the bilateral components of the arterial circle of the brain, that is, the rostral cerebral artery and caudal communicating artery, arose from the division of the intracranial segment of the internal carotid artery, which emerges from the rostral epidural rete mirabile. The extracranial segment of the internal carotid artery was obliterated. In consequence of this process, the blood reaches the brain chiefly from the maxillary artery. The research proved that the arteries of the encephalic base in the Antilopinae are most similar to the vessels described in antelopes of Tragelaphus, Taurotragus, and Boselaphus genera and small domestic ruminants. However, they are different from the arterial pattern of the encephalic base in bovines and other species classified as the Bovini. PMID- 25694116 TI - Stella preserves maternal chromosome integrity by inhibiting 5hmC-induced gammaH2AX accumulation. AB - In the mouse zygote, Stella/PGC7 protects 5-methylcytosine (5mC) of the maternal genome from Tet3-mediated oxidation to 5-hydroxymethylcytosine (5hmC). Although ablation of Stella causes early embryonic lethality, the underlying molecular mechanisms remain unknown. In this study, we report impaired DNA replication and abnormal chromosome segregation (ACS) of maternal chromosomes in Stella-null embryos. In addition, phosphorylation of H2AX (gammaH2AX), which has been reported to inhibit DNA replication, accumulates in the maternal chromatin of Stella-null zygotes in a Tet3-dependent manner. Cell culture assays verified that ectopic appearance of 5hmC induces abnormal accumulation of gammaH2AX and subsequent growth retardation. Thus, Stella protects maternal chromosomes from aberrant epigenetic modifications to ensure early embryogenesis. PMID- 25694117 TI - Cardiovascular afferents cause the release of 5-HT in the nucleus tractus solitarii; this release is regulated by the low- (PMAT) not the high-affinity transporter (SERT). AB - The nucleus tractus solitarii (NTS) integrates inputs from cardiovascular afferents and thus is crucial for cardiovascular homeostasis. These afferents primarily release glutamate, although 5-HT has also been shown to play a role in their actions. Using fast-cyclic voltammetry, an increase in 5-HT concentrations (range 12-50 nm) could be detected in the NTS in anaesthetized rats in response to electrical stimulation of the vagus and activation of cardiopulmonary, chemo- and baroreceptor reflexes. This 5-HT signal was not potentiated by the serotonin transporter (SERT) or the noradrenaline transporter (NET) inhibitors citalopram and desipramine (1 mg kg(-1) ). However, decynium-22 (600 MUg kg(-1) ), an organic cation 3 transporter (OCT3)/plasma membrane monoamine transporter (PMAT) inhibitor, increased the 5-HT signal by 111 +/- 21% from 29 +/- 10 nm. The effectiveness of these inhibitors was tested against the removal time of 5-HT and noradrenaline applied by microinjection to the NTS. Citalopram and decynium-22 attenuated the removal of 5-HT but not noradrenaline, whereas desipramine had the reverse action. The OCT3 inhibitor corticosterone (10 mg kg(-1) ) had no effect. Blockade of glutamate receptors with topical kynurenate (10-50 nm) reduced the vagally evoked 5-HT signal by 50%, indicating that this release was from at least two sources. It is concluded that vagally evoked 5-HT release is under the regulation of the high-capacity, low-affinity transporter PMAT, not the low capacity, high-affinity transporter SERT. This is the first demonstration that PMAT may be playing a physiological role in the regulation of 5-HT transmission and this could indicate that 5-HT is acting, in part, as a volume transmitter within the NTS. PMID- 25694118 TI - Development and validation of a generic liquid chromatographic method for the simultaneous determination of five commonly used antimalarial drugs: Application to pharmaceutical formulations and human plasma. AB - A simple, sensitive, and rapid liquid chromatographic method was developed and validated using diode array detection for the determination of five commonly used antimalarial drugs in pharmaceutical formulations and in human plasma. Chromatographic separation of antimalarial drugs and internal standard (ibuprofen) was achieved on a C18 column with a mobile phase composed of 10 mM dipotassium orthophosphate at pH 3.0, methanol, and acetonitrile in a ratio of 20:38:42 v/v, at a flow rate of 1 mL/min. The analytes were monitored at 220 nm and separated in ?10 min. The method was validated for linearity, accuracy, precision, limit of quantification, and robustness. Both intra- and interday precisions (in terms of %RSD) were lower than 3% and accuracy ranged from 98.1 to 104.5%. Extraction recoveries were >=96% in plasma. The limits of quantitation for artemether, lumefantrine, pyrimethamine, sulfadoxine, and mefloquine were 0.3, 0.03, 0.06, 0.15, and 0.15 MUg/mL in human plasma. Stability under various conditions was also investigated. The method was successfully applied for quantification of antimalarial drugs in marketed formulations and in spiked human plasma. The method can be employed for routine QC purposes and in pharmacokinetic investigations. PMID- 25694119 TI - Paradoxal Inflammatory Effects of Anti-Inflammatory Mediators in Fetal Origin Cells. PMID- 25694120 TI - Withdrawn: Stem Cell Transplant from Unrelated Donor in Patients with Severe Aplastic Anemia: Indications, Donor Selection, Conditioning, GVHD Prophylaxis. AB - Withdrawn by the publisher. PMID- 25694121 TI - MicroRNAs in Breast Cancer: One More Turn in Regulation. AB - MicroRNAs (miRNAs) are small non-coding RNA molecules that critically regulate the expression of genes. MiRNAs are involved in physiological cellular processes; however, their deregulation has been associated with several pathologies, including cancer. In human breast cancer, differently expressed levels of miRNAs have been identified from those in normal breast tissues. Moreover, several miRNAs have been correlated with pathological phenotype, cancer subtype and therapy response in breast cancer. The resistance to therapy is increasingly a problem in patient management, and miRNAs are emerging as novel therapeutic targets and potential predictive biomarkers for treatment. This review provides an overview of the current situation of miRNAs in breast cancer, focusing on their involvement in resistance and the circulating miRNA. The mechanisms of therapeutic resistance regulated by miRNAs, such as the regulation of receptors, the modification of enzymes of drug metabolism, the inhibition of cell cycle control or pro-apoptotic proteins, the alteration of histone activity and the regulation of DNA repair machinery among others, are discussed for breast cancer clinical subtypes. Additionally, in this review, we summarize the recent knowledge that has established miRNA detection in peripheral body fluids as a suitable biomarker. We review the detection of miRNA in liquid biopsies and its implications for the diagnosis and monitoring of breast cancer. This new generation of cancer biomarkers may lead to a significant improvement in patient management. PMID- 25694122 TI - Steps and Routes of HCV Infection: The Great Promise of New Anti-Viral Targets. AB - A major breakthrough in understanding the steps and signalling that drives the HCV to reach a full life-cycle has been achieved by in vitro models that have facilitated elevated virus production, resulting in the discovery of pathways and factors involved in virus entry, translation and replication. The HCV enters host cells through binding of its envelope glycoproteins to cell receptors, followed by clathrin-mediated endocytosis and fusion with cell membranes, leading to virus uncoating and cell entry. This chain of events is mediated by sequential involvement of different co-receptors, for example, SR-B1, CD81 and the tight junction proteins- claudin and occludin. HCV RNA replication and translation are coupled processes, requiring cooperation of replicase, helicase and other viral proteins with cell-regulatory factors. Virion packaging and release are highly targetable steps, although they require greater in-depth investigation. The HCV immune response appears to be fairly ineffective, and neutralizing antibodies that inhibit E2-CD81 binding are unable to resolve infection. HCV-transmission through cell-to-cell contact has been implicated in the evolution of chronic infection. In particular, CD81-dependency and the role of other co-factors involved in entry in cell-to-cell infection, as well as virus escape from host neutralization still require confirmation. To highlight viral and cell mechanisms implicated in HCV-infection, we review here some of the major discoveries that have been made, from virus entry to its release from infected cells, in understanding the HCV host-cell interplay, which may help in defining new molecular targets to provide therapeutic antiviral strategies. PMID- 25694125 TI - Skewed mutational spectrum of RET proto-oncogene Exon10 in Iranian patients with medullary thyroid carcinoma. AB - Thyroid cancer is the most common endocrine malignant tumor. Medullary thyroid carcinoma (MTC) is an aggressive tumor arising from calcitonin-producing parafollicular cells. MTC has autosomal dominant inheritance and accounts for 5 10 % of all thyroid cancers. It occurs in hereditary (25 %, hMTC) and sporadic (75 %, sMTC) forms. Gain-of-function mutations in the REarranged during transfection (RET) proto-oncogene have been identified in 98 % of hMTC and 50 % of sMTC. The aim of this investigation was to identify mutation(s) in the much conserved RET exon10 in Iranian MTC patients. We started screening patients with MTC for RET in 2001. This study included 347 individuals (154 with sMTC, 38 with FMTC, 8 with multiple endocrine neoplasia type 2A [MEN2A], 3 with MEN2B, and 3 with pheochromocytoma; 207 index cases and 140 relatives). Germline mutation screening of RET exon10 was performed with PCR-DNA sequencing. A total of 14 missense mutations (10 mutations in men and 4 in women) were identified in cysteine codons 611, 618, and 620 (exon10) in 11 patients and three first-degree relatives as follows: four C611Y (three with FMTC and one relative), one C618R (FMTC), one C618S (sMTC), one C620G (sMTC), four C620R (one with FMTC and three with sMTC), and three C620F (one with FMTC and two relatives). In the present study, six different mutations were identified in exon10 of RET in 14 patients with sMTC and FMTC that were restricted to codons 611, 618, and 620, but not in codon 609. This data showed a skewed pattern of RET exon10 mutation compared to other populations. No mutation was found for MEN2A, MEN2B, and pheochromocytoma in exon10 in this population. In the most common mutations in exon10, the FMTC and sMTC patients were C611Y and C620R, respectively. PMID- 25694124 TI - Core principles of bacterial autoinducer systems. AB - SUMMARY: Autoinduction (AI), the response to self-produced chemical signals, is widespread in the bacterial world. This process controls vastly different target functions, such as luminescence, nutrient acquisition, and biofilm formation, in different ways and integrates additional environmental and physiological cues. This diversity raises questions about unifying principles that underlie all AI systems. Here, we suggest that such core principles exist. We argue that the general purpose of AI systems is the homeostatic control of costly cooperative behaviors, including, but not limited to, secreted public goods. First, costly behaviors require preassessment of their efficiency by cheaper AI signals, which we encapsulate in a hybrid "push-pull" model. The "push" factors cell density, diffusion, and spatial clustering determine when a behavior becomes effective. The relative importance of each factor depends on each species' individual ecological context and life history. In turn, "pull" factors, often stress cues that reduce the activation threshold, determine the cellular demand for the target behavior. Second, control is homeostatic because AI systems, either themselves or through accessory mechanisms, not only initiate but also maintain the efficiency of target behaviors. Third, AI-controlled behaviors, even seemingly noncooperative ones, are generally cooperative in nature, when interpreted in the appropriate ecological context. The escape of individual cells from biofilms, for example, may be viewed as an altruistic behavior that increases the fitness of the resident population by reducing starvation stress. The framework proposed here helps appropriately categorize AI-controlled behaviors and allows for a deeper understanding of their ecological and evolutionary functions. PMID- 25694123 TI - Archaeal extrachromosomal genetic elements. AB - SUMMARY: Research on archaeal extrachromosomal genetic elements (ECEs) has progressed rapidly in the past decade. To date, over 60 archaeal viruses and 60 plasmids have been isolated. These archaeal viruses exhibit an exceptional diversity in morphology, with a wide array of shapes, such as spindles, rods, filaments, spheres, head-tails, bottles, and droplets, and some of these new viruses have been classified into one order, 10 families, and 16 genera. Investigation of model archaeal viruses has yielded important insights into mechanisms underlining various steps in the viral life cycle, including infection, DNA replication and transcription, and virion egression. Many of these mechanisms are unprecedented for any known bacterial or eukaryal viruses. Studies of plasmids isolated from different archaeal hosts have also revealed a striking diversity in gene content and innovation in replication strategies. Highly divergent replication proteins are identified in both viral and plasmid genomes. Genomic studies of archaeal ECEs have revealed a modular sequence structure in which modules of DNA sequence are exchangeable within, as well as among, plasmid families and probably also between viruses and plasmids. In particular, it has been suggested that ECE-host interactions have shaped the coevolution of ECEs and their archaeal hosts. Furthermore, archaeal hosts have developed defense systems, including the innate restriction-modification (R-M) system and the adaptive CRISPR (clustered regularly interspaced short palindromic repeats) system, to restrict invasive plasmids and viruses. Together, these interactions permit a delicate balance between ECEs and their hosts, which is vitally important for maintaining an innovative gene reservoir carried by ECEs. In conclusion, while research on archaeal ECEs has just started to unravel the molecular biology of these genetic entities and their interactions with archaeal hosts, it is expected to accelerate in the next decade. PMID- 25694126 TI - Thermo-chemotherapy Induced miR-218 upregulation inhibits the invasion of gastric cancer via targeting Gli2 and E-cadherin. AB - Thermo-chemotherapy has been proven to reduce the invasion capability of cancer cells. However, the molecular mechanism underlying this anti-invasion effect is still unclear. In this study, the role of thermo-chemotherapy in the inhibition of tumor invasion was studied. The results demonstrated that expression of miR 218 was downregulated in gastric cancer tissues, which had a positive correlation with tumor invasion and metastasis. In vitro thermo-chemotherapy increased miR 218 expression in SGC7901 cells and inhibited both proliferation and invasion of cancer cells. Gli2 was identified as a downstream target of miR-218, and its expression was negatively regulated by miR-218. The thermo-chemotherapy induced miR-218 upregulation was also accompanied by increasing of E-cadherin expression. In conclusion, the present study indicates that thermo-chemotherapy can effectively decrease the invasion capability of cancer cells and increase cell cell adhesion. miR-218 and its downstream target Gli2, as well as E-cadherin, participate in the anti-invasion process. PMID- 25694128 TI - What factors promote resilience and protect against burnout in first-year pediatric and medicine-pediatric residents? AB - Burnout has high costs for pediatricians and their patients. There is increasing interest in educational interventions to promote resilience and minimize burnout among pediatric trainees. This study tested a conceptual model of factors that might promote resilience and protect against burnout, and which could serve as targets for addressing burnout in pediatric residents. Questionnaires were administered in a cross-sectional survey of (n = 45) first-year pediatric and medicine-pediatric residents. A minority (40%) of residents met one or more criteria for burnout. Physician empathy and emotional intelligence were not significantly correlated with burnout or resilience. Self-compassion and mindfulness were positively associated with resilience and inversely associated with burnout. Thus many residents in this sample endorsed burnout; mindfulness and self-compassion were associated with resilience and may promote resilience and protect against burnout in these trainees. Future studies should explore the impact of training in mindfulness and self-compassion in pediatric trainees. PMID- 25694129 TI - New bioactive chromanes from Litchi chinensis. AB - Seven new delta-tocotrienols, designated litchtocotrienols A-G (1-7), together with one glorious macrocyclic analogue, macrolitchtocotrienol A (8), and one new meroditerpene chromane, cyclolitchtocotrienol A (9), were isolated from the leaves of Litchi chinensis. Their structures were mainly determined by extensive spectroscopic analysis, and their biological activities were evaluated by cytotoxicity against human gastric adenocarcinoma cell lines (AGS, ATCC CRL-1739) and hepatoma carcinoma cell line (HepG2 2.2.1.5). The structure-activity relationship of the isolated compounds was also discussed. PMID- 25694130 TI - Evaluation of the first maxillary molar post-extraction socket as a model for dental implant osseointegration research. AB - OBJECTIVES: Published information regarding the use of rat jawbones for dental implant osseointegration research is limited and often inconsistent. This study assessed the suitability and feasibility of placing dental implants into the rat maxilla and to establish parameters to be used for dental implant research using this model. MATERIALS AND METHODS: Forty-two customized titanium implants (2 * 3 mm) were placed bilaterally in the maxillary first molar area of 21 Sprague Dawley rats. Every animal received two implants. The animals were subsequently sacrificed at days 3, 7, 14, 28 and 56 post-surgery. Resin-embedded sections of the implant and surrounding maxilla were prepared for histological and histomorphometric analyses. RESULTS: The mesial root of the first molar in the rat maxilla was the optimal site to place the implant. Although the most apical 2 3 threads of the implant penetrated into the sinus cavity, 2 mm of the remaining implant was embedded in the bone. New bone formation at day 7 around the implant increased further at day 14, as measured by the percentage of bone-to-implant contact (%BIC) and new bone area (%BA) in the implant thread chambers (55.1 +/- 8.9% and 63.7 +/- 7.7%, respectively). There was a further significant increase between day 14 and 28 (P < 0.05), however, no significant differences were found between day 28 and 56 in either %BIC or %BA. CONCLUSIONS: The mesial root socket of the first molar in the rat maxilla is a useful model for dental implant research. Osseointegration following implant placement as measured by BIC plateaued after 28 days. The recommended implant dimensions are 1.5 mm in diameter and 2 mm in length. PMID- 25694131 TI - Saccharin-based MU-oxo imidoiodane: a readily available and highly reactive reagent for electrophilic amination. AB - Three new saccharin-based hypervalent iodine compounds were prepared by the reaction of saccharine with (diacetoxyiodo)arenes or acetoxybenziodoxole. Structures of these new imidoiodanes were established by X-ray crystallography. The saccharin-based MU-oxo-bridged imidoiodane readily reacts with silyl enol ethers under mild conditions to give the corresponding alpha-aminated carbonyl compounds in moderate yields. PMID- 25694132 TI - Efficient acetone-butanol-ethanol production (ABE) by Clostridium acetobutylicum XY16 immobilized on chemically modified sugarcane bagasse. AB - Sugarcane bagasse was chemically modified by polyethylenimine (PEI) and glutaraldehyde (GA) and then used as a support to immobilize Clostridium acetobutylicum XY16 in the process of butanol production. Compared with batch fermentation using unmodified sugarcane bagasse, 22.3 g/L total solvents were produced by cells immobilized on 4 g/L PEI treated sugarcane bagasse with high solvent productivity of 0.62 g/(L h) and glucose consumption rate of 1.67 g/(L h). Improvement of 14, 43, and 37 % in total solvent titer, solvent productivity and glucose consumption rate was observed, respectively. Enhanced solvent production of 25.14 g/L was obtained when using a high concentration of glucose of 80 g/L. Continuous fermentation was studied using PEI/GA modified sugarcane bagasse as immobilization support with a range of dilution which rates from 0.2 to 2.5 to find an optimal condition. The maximum solvent productivity of 11.32 g/(L h) was obtained at a high dilution rate of 2.0 h(-1). PMID- 25694133 TI - PAI-1 modulates cell migration in a LRP1-dependent manner via beta-catenin and ERK1/2. AB - Plasminogen activator inhibitor-1 (PAI-1) is the major and most specific acting urokinase (uPA) and tissue plasminogen activator (tPA) inhibitor. Apart from its function in the fibrinolytic system, PAI-1 was also found to contribute to processes like tissue remodelling, angiogenesis, and tumour progression. However, the role of PAI-1 in those processes remains largely controversial with respect to the influence of PAI-1 on cell signalling pathways. Although PAI-1 does not possess its own cellular receptor, it can be bound to low-density lipoprotein receptor-related protein 1 (LRP1) which was proposed to modulate the beta-catenin pathway. Therefore, we used wild-type mouse embryonic fibroblasts (MEFs), and MEFs deficient of LRP1 to study PAI-1 as modulator of the beta-catenin pathway. We found that PAI-1 influences MEF proliferation and motility in a LRP1-dependent manner and that beta-catenin is important for that response. In addition, expression of beta-catenin and beta-catenin-dependent transcriptional activity were induced by PAI-1 in wild type MEFs, but not in LRP1-deficient cells. Moreover, PAI-1-induced ERK1/2 activation was more prominent in the LRP1 deficient cells and interestingly knockdown of beta-catenin abolished this effect. Together, the data of the current study show that PAI-1 can promote cell migration via LRP1-dependent activation of the beta-catenin and ERK1/2 MAPK pathway which may be important in stage-specific treatment of human diseases associated with high PAI-1 levels. PMID- 25694134 TI - Treatment of ocular motor palsies. AB - OPINION STATEMENT: The management of ocular motor palsies first requires careful determination of the etiology. Possibilities include ischemia, inflammation, infection, trauma, compression, or congenital. Prognosis for recovery varies greatly between etiologies; hence, determination of the underlying process is crucial in the short- and long-term management of these patients. Naturally, our ultimate goal is to improve visual function as much as possible. A guiding principle in the initial management of ocular motor palsies is to improve patient comfort and visual function by eliminating diplopia in primary position while clinically observing the patient for improvement or stability. Offering a definitive treatment which creates the largest possible zone of binocular single vision in primary and reading positions can be undertaken once stability has been demonstrated. In the initial phase after an acute ocular motor palsy has occurred, occlusion of an eye can be used to eliminate diplopia. Options include a patch or applying translucent or satin tape to one of the lenses which prevents diplopia but still lets light through. Alternatively, prismatic correction placed on or ground into spectacles may improve function and restore binocularity in patients with temporary or permanent ocular deviations. This is generally effective for patients with up to 20 to 25 prism diopters (PD) of horizontal misalignment and 10 to 15 PD of vertical. Once a stable misalignment has been demonstrated (several months), a variety of surgical options exist. Use of adjustable sutures, improved suture materials, and surgical techniques has expanded the role and scope of surgery for these patients. Planning the surgical approach is based on residual extraocular muscle function, careful measurements, and assessment of patient expectations. PMID- 25694135 TI - New perspectives on proton pumping in cellular respiration. PMID- 25694136 TI - Schistosomal appendicitis with portal hypertension. PMID- 25694137 TI - A simple tool to evaluate common disorders: validation of a "proctological symptom scale". AB - PURPOSE: Proctological symptomatology is of little complexity and therefore appears particularly suitable for comparative evaluation by visual scales. We devised a "proctological symptom scale" (PSS) with separate scales for four cardinal proctological symptoms: pain, itching/irritation, discharge/moisture, and bleeding. The objective of this study was to evaluate the PSS among proctological patients and non-proctological controls. METHODS: This was a single center non-interventional observational study on 229 proctological patients and 133 controls. The main outcome measures investigated were age- and sex-stratified comparison of the non-proctological cohort and the controls, effect of therapeutic intervention on scale values in a subset of patients with haemorrhoidal disease, and sensitivity of the PSS to detect therapeutic failure in this subset of patients. RESULTS: The PSS was found to significantly differentiate between proctological patients and controls. Gender and age had no significant influence on PSS values in the proctological cohort. The intervention (one session of rubber band ligation in patients with haemorrhoidal disease) was reflected by a significantly improved overall PSS. In 16 cases within this group, the PSS got worse. A case-by-case follow-up of these patients showed that 14 of the 16 patients ended up with surgery (or with the advice to have surgery). CONCLUSIONS: The PSS reliably differentiates proctological patients from non proctological controls. Following intervention, the PSS reliably differentiated therapeutic success from failure. We find the PSS to be a simple and useful tool in our clinical routine since it provides an easily obtainable and reproducible basis for the visit-by-visit assessment of proctological patients. The PSS may also be suitable for studies to measure and compare symptomatic improvement and success of different therapies in proctology. PMID- 25694138 TI - Anterior sphincteroplasty for fecal incontinence: predicting incontinence relapse. AB - PURPOSE: This study was designed to evaluate the efficiency of anterior sphincteroplasty in preventing fecal incontinence relapsing in 85 female patients. METHODS: This observational study followed individuals for up to 10 years after intervention. Fecal incontinence relapse was analyzed using Generalized Linear Models and Kaplan-Meier tables. Bias due to informative censoring and missing data were assessed. Two postoperative cutoff Wexner scores (4 and 8) were used to classify individuals into continent or incontinent, and their model implications were examined. RESULTS: The hazard of relapsing appeared constant over time. This led to exponential time-to-relapse functions, and a linear increase of cumulative hazard over time. Predicted median relapsing time was 33 years, and overall risk 0.09 +/- 0.03, when using a cutoff Wexner score of 8 (moderate), and 5 years, overall risk 0.45 +/- 0.05, when using a cutoff of 4 (mild). There was a potential underestimation in parameters (bias) due to informative censoring, i.e., individual with better prognoses were more likely to drop out before relapsing compared to those with worse prognoses. Thus, true relapsing times may be longer than our current estimates. CONCLUSIONS: The predictive model can be used in practice for individual prognosis after intervention, based on preoperative Wexner scores. The effect of anterior sphincteroplasty on fecal incontinence does not seem to deteriorate over time. A consensus Wexner cutoff is necessary to compare data and interventions. PMID- 25694139 TI - Vascular anatomy of the small intestine-a comparative anatomic study on humans and pigs. AB - BACKGROUND: Porcine models are well established for studying intestinal anastomotic healing. In this study, we aimed to clarify the anatomic differences between human and porcine small intestines. Additionally, we investigated the influences of longitudinal and circular sutures on human small intestine perfusion. METHODS: Intestines were obtained from human cadavers (n = 8; small intestine, n = 51) and from pigs (n = 10; small intestine, n = 60). Vascularization was visualized with mennige gelatin perfusion and high-resolution mammography. Endothelial cell density was analyzed with immunohistochemistry and factor VIII antibodies. We also investigated the influence of suture techniques (circular anastomoses, n = 19; longitudinal sutures, n = 15) on vascular perfusion. RESULTS: Only human samples showed branching of mesenteric vessels. Compared to the pig, human vessels showed closer connections at the entrance to the bowel wall (p = 0.045) and higher numbers of intramural anastomoses (p < 0.001). Porcine main vessels formed in multifilament-like vessel bundles and displayed few intramural vessel anastomoses. Circular anastomoses induced a circular perfusion defect at the bowel wall; longitudinal anastomoses induced significantly smaller perfusion defects (p < 0.001). Both species showed higher vascular density in the jejunum than in the ileum (p < 0.001). Human samples showed similar vascular density within the jejunum (p = 0.583) and higher density in the ileum (p < 0.001) compared to pig samples. CONCLUSION: The results showed significant differences between human and porcine intestines. The porcine model remains the standard for studies on anastomotic healing because it is currently the only viable model for studying anastomosis and wound healing. Nevertheless, scientific interpretations must consider the anatomic differences between humans and porcine intestines. PMID- 25694141 TI - Tim-3 expression in tumour-associated macrophages: a new player in HCC progression. PMID- 25694140 TI - High-resolution analysis of central nervous system expression patterns in zebrafish Gal4 enhancer-trap lines. AB - BACKGROUND: The application of the Gal4/UAS system to enhancer and gene trapping screens in zebrafish has greatly increased the ability to label and manipulate cell populations in multiple tissues, including the central nervous system (CNS). However the ability to select existing lines for specific applications has been limited by the lack of detailed expression analysis. RESULTS: We describe a Gal4 enhancer trap screen in which we used advanced image analysis, including three dimensional confocal reconstructions and documentation of expression patterns at multiple developmental time points. In all, we have created and annotated 98 lines exhibiting a wide range of expression patterns, most of which include CNS expression. Expression was also observed in nonneural tissues such as muscle, skin epithelium, vasculature, and neural crest derivatives. All lines and data are publicly available from the Zebrafish International Research Center (ZIRC) from the Zebrafish Model Organism Database (ZFIN). CONCLUSIONS: Our detailed documentation of expression patterns, combined with the public availability of images and fish lines, provides a valuable resource for researchers wishing to study CNS development and function in zebrafish. Our data also suggest that many existing enhancer trap lines may have previously uncharacterized expression in multiple tissues and cell types. PMID- 25694142 TI - Claudins and barrier dysfunction in intestinal inflammation: cause or consequence? PMID- 25694143 TI - Reference materials for chemical analysis. PMID- 25694145 TI - Negative chemical ionization gas chromatography coupled to hybrid quadrupole time of-flight mass spectrometry and automated accurate mass data processing for determination of pesticides in fruit and vegetables. AB - Gas chromatography coupled to high resolution hybrid quadrupole time-of-flight mass spectrometry (GC-QTOF MS), operating in negative chemical ionization (NCI) mode and combining full scan with MSMS experiments using accurate mass analysis, has been explored for the automated determination of pesticide residues in fruit and vegetables. Seventy compounds were included in this approach where 50 % of them are not approved by the EU legislation. A global 76 % of the analytes could be identified at 1 MUg kg(-1). Recovery studies were developed at three concentration levels (1, 5, and 10 MUg kg(-1)). Seventy-seven percent of the detected pesticides at the lowest level yielded recoveries within the 70 %-120 % range, whereas 94 % could be quantified at 5 MUg kg(-1), and the 100 % were determined at 10 MUg kg(-1). Good repeatability, expressed as relative standard deviation (RSD <20 %), was obtained for all compounds. The main drawback of the method was the limited dynamic range that was observed for some analytes that can be overcome either diluting the sample or lowering the injection volume. A home made database was developed and applied to an automatic accurate mass data processing. Measured mass accuracies of the generated ions were mainly less than 5 ppm for at least one diagnostic ion. When only one ion was obtained in the single-stage NCI-MS, a representative product ion from MSMS experiments was used as identification criterion. A total of 30 real samples were analyzed and 67 % of the samples were positive for 12 different pesticides in the range 1.0-1321.3 MUg kg(-1). PMID- 25694144 TI - Label-free detection and identification of protein ligands captured by receptors in a polymerized planar lipid bilayer using MALDI-TOF MS. AB - Matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) coupled with affinity capture is a well-established method to extract biological analytes from complex samples followed by label-free detection and identification. Many bioanalytes of interest bind to membrane-associated receptors; however, the matrices and high-vacuum conditions inherent to MALDI-TOF MS make it largely incompatible with the use of artificial lipid membranes with incorporated receptors as platforms for detection of captured proteins and peptides. Here we show that cross-linking polymerization of a planar supported lipid bilayer (PSLB) provides the stability needed for MALDI-TOF MS analysis of proteins captured by receptors embedded in the membrane. PSLBs composed of poly(bis-sorbylphosphatidylcholine) (poly(bis-SorbPC)) and doped with the ganglioside receptors GM1 and GD1a were used for affinity capture of the B subunits of cholera toxin, heat-labile enterotoxin, and pertussis toxin. The three toxins were captured simultaneously, then detected and identified by MS on the basis of differences in their molecular weights. Poly(bis-SorbPC) PSLBs are inherently resistant to nonspecific protein adsorption, which allowed selective toxin detection to be achieved in complex matrices (bovine serum and shrimp extract). Using GM1-cholera toxin subunit B as a model receptor-ligand pair, we estimated the minimal detectable concentration of toxin to be 4 nM. On-plate tryptic digestion of bound cholera toxin subunit B followed by MS/MS analysis of digested peptides was performed successfully, demonstrating the feasibility of using the PSLB-based affinity capture platform for identification of unknown, membrane-associated proteins. Overall, this work demonstrates that combining a poly(lipid) affinity capture platform with MALDI-TOF MS detection is a viable approach for capture and proteomic characterization of membrane-associated proteins in a label-free manner. PMID- 25694146 TI - Dietary uptake of omega-3 fatty acids in mouse tissue studied by time-of-flight secondary ion mass spectrometry (TOF-SIMS). AB - Dietary intake of omega-3 fatty acids is associated with considerable health benefits, including the prevention of metabolic disorders such as cardiovascular disease and type 2 diabetes. Furthermore, incorporation of the main omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), at the systemic level has been found to be more efficient when these fatty acids are supplied in the form of marine phospholipids compared to triglycerides. In this work, the uptake of omega-3 fatty acids and their incorporation in specific lipids were studied in adipose, skeletal muscle, and liver tissues of mice given high-fat diets with or without omega-3 supplements in the form of phospholipids or triglycerides using time-of-flight secondary ion mass spectrometry (TOF-SIMS). The results demonstrate significant uptake of EPA and DHA, and the incorporation of these fatty acids in specific lipid molecules, in all three tissue types in response to the dietary omega-3 supplements. Moreover, the results indicate reduced concentrations of arachidonic acid (AA) and depletion of lipids containing AA in tissue samples from mice given supplementary omega-3, as compared to the control mice. The effect on the lipid composition, in particular the DHA uptake and AA depletion, was found to be significantly stronger when the omega-3 supplement was supplied in the form of phospholipids, as compared to triglycerides. TOF-SIMS was found to be a useful technique for screening the lipid composition and simultaneously obtaining the spatial distributions of various lipid classes on tissue surfaces. PMID- 25694147 TI - A fully automated method for simultaneous determination of aflatoxins and ochratoxin A in dried fruits by pressurized liquid extraction and online solid phase extraction cleanup coupled to ultra-high-pressure liquid chromatography tandem mass spectrometry. AB - According to current demands and future perspectives in food safety, this study reports a fast and fully automated analytical method for the simultaneous analysis of the mycotoxins with high toxicity and wide spread, aflatoxins (AFs) and ochratoxin A (OTA) in dried fruits, a high-risk foodstuff. The method is based on pressurized liquid extraction (PLE), with aqueous methanol (30%) at 110 degrees C, of the slurried dried fruit and online solid-phase extraction (online SPE) cleanup of the PLE extracts with a C18 cartridge. The purified sample was directly analysed by ultra-high-pressure liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) for sensitive and selective determination of AFs and OTA. The proposed analytical procedure was validated for different dried fruits (vine fruit, fig and apricot), providing method detection and quantification limits much lower than the AFs and OTA maximum levels imposed by EU regulation in dried fruit for direct human consumption. Also, recoveries (83-103%) and repeatability (RSD < 8, n = 3) meet the performance criteria required by EU regulation for the determination of the levels of mycotoxins in foodstuffs. The main advantage of the proposed method is full automation of the whole analytical procedure that reduces the time and cost of the analysis, sample manipulation and solvent consumption, enabling high-throughput analysis and highly accurate and precise results. PMID- 25694148 TI - Continuous comprehensive two-dimensional liquid chromatography-electrospray ionization mass spectrometry of complex lipidomic samples. AB - A new continuous comprehensive two-dimensional liquid chromatography-electrospray ionization mass spectrometry method has been developed for the lipidomic characterization of complex biological samples. The reversed-phase ultra-high performance liquid chromatography with a C18 column (150 mm * 1 mm, 1.7 MUm) used in the first dimension makes the separation of numerous lipid species differing in their hydrophobic part of the molecule, mainly fatty acyl chain lengths and the number and positions of double bonds, possible. Coeluted lipid species in the first dimension are resolved by the fast hydrophilic interaction liquid chromatography separation (50 mm * 3 mm, 2.7 MUm, core-shell particles) of lipid classes according to their different polarities in the second dimension. Retention times in both dimensions, accurate m/z values, and tandem mass spectra provide high confidence in the identification of lipid species. The retention behavior of individual lipids in reversed-phase mode follows the equivalent carbon number pattern, which provides an additional tool for unambiguous identification. This analytical method is applied for the lipidomic characterization of total lipid extracts of human plasma and porcine brain samples, which resulted in the identification of 143 lipid species from four lipid categories and ten lipid classes. PMID- 25694149 TI - A review of biosensing techniques for detection of trace carcinogen contamination in food products. AB - Carcinogen contaminations in the food chain, for example heavy metal ions, pesticides, acrylamide, and mycotoxins, have caused serious health problems. A major objective of food-safety research is the identification and prevention of exposure to these carcinogens, because of their impossible-to-reverse tumorigenic effects. However, carcinogen detection is difficult because of their trace-level presence in food. Thus, reliable and accurate separation and determination methods are essential to protect food safety and human health. This paper summarizes the state of the art in separation and determination methods for analyzing carcinogen contamination, especially the advances in biosensing methods. Furthermore, the application of promising technology including nanomaterials, imprinted polymers, and microdevices is detailed. Challenges and perspectives are also discussed. PMID- 25694150 TI - Evaluation of the benefits and risks of introducing Ebola community care centers, Sierra Leone. AB - In some parts of western Africa, Ebola treatment centers (ETCs) have reached capacity. Unless capacity is rapidly scaled up, the chance to avoid a generalized Ebola epidemic will soon diminish. The World Health Organization and partners are considering additional Ebola patient care options, including community care centers (CCCs), small, lightly staffed units that could be used to isolate patients outside the home and get them into care sooner than otherwise possible. Using a transmission model, we evaluated the benefits and risks of introducing CCCs into Sierra Leone's Western Area, where most ETCs are at capacity. We found that use of CCCs could lead to a decline in cases, even if virus transmission occurs between CCC patients and the community. However, to prevent CCC amplification of the epidemic, the risk of Ebola virus-negative persons being exposed to virus within CCCs would have to be offset by a reduction in community transmission resulting from CCC use. PMID- 25694151 TI - Esophagectomy for end-stage achalasia. AB - Achalasia is a disease for which treatments are palliative in nature. Success of therapy is judged by a number of metrics, the most important being relief of symptoms, such as dysphagia and regurgitation. Patients often compensate for symptoms though a variety of dietary and lifestyle modifications, making symptomatic assessment of therapeutic outcome unreliable. Given this fact, and the progressive nature of the condition if left inadequately treated, patients not infrequently present with the disabling manifestations of end-stage disease for which esophagectomy is the best option. In appropriately selected patients, and when performed in experienced centers, esophagectomy with foregut reconstruction can be undertaken successfully with acceptable rates of morbidity and mortality, as well as a good long-term symptomatic outcome, in cases of end stage achalasia. PMID- 25694152 TI - Clinical manifestation of Fuchs uveitis syndrome in childhood. AB - PURPOSE: The aim of this study was to describe clinical signs and complications of Fuchs uveitis syndrome (FUS) with onset in childhood. METHODS: Ophthalmologic findings and complications in patients with FUS becoming manifest before the age of 16 years were analyzed in a retrospective study at a tertiary referral uveitis center. Inclusion criteria were the presence of pathognomonic FUS findings at any time point and exclusion of any systemic immune-mediated or infectious disease. RESULTS: A total of 23 patients (male = 16, female = 7) with juvenile FUS (unilateral n = 20, bilateral n = 3 patients) were included in the study. Mean ages at uveitis and FUS diagnosis were 12.0 +/- 4.2 and 22.7 +/- 10.7 years, respectively. In six patients, inflammation was noted at age <= 7 years. The following inflammatory signs were observed in a total of 26 eyes: <= 1+ anterior chamber cell grade (n = 26), vitreous cells (n = 24), fine keratic precipitates (KPs; n = 23), stellate KPs (n = 11), mutton-fat KPs (n = 23), diffuse (n = 24) or inferior (n = 8) distribution of KPs, Koeppe nodules (n = 10), and iris heterochromia (n = 14). A representative subgroup of patients (n = 5) is shown who presented with non-specific clinical signs in the beginning and in whom typical FUS signs became manifest only at a later stage. Secondary complications such as cataract (n = 19), ocular hypertension (n = 3), or glaucomatous disc damage (n = 2) were found after a mean uveitis duration of 11.6, 19.5, and 20.3 years, respectively. CONCLUSION: FUS may begin in early childhood, and the characteristic findings may not be present at onset of disease. The diagnosis is often delayed for years, occasionally with the consequence of overtreatment with anti-inflammatory drugs. PMID- 25694153 TI - Posterior scleral reinforcement combined with patching therapy for pre-school children with unilateral high myopia. AB - PURPOSE: Our purpose was to investigate the effect of posterior scleral reinforcement (PSR) combined with patching therapy for pre-school children with unilateral high myopia. METHODS: A total of 32 pre-school children with unilateral high myopia were recruited. They were randomly divided into the PSR and control group, each of which had 16 patients. The patients in the PSR group underwent the simplified PSR surgery followed by rigid gas permeable contact lens wear and traditional patching therapy, while the patients in the control group were only prescribed contact lens wear and patching. Patients were reviewed and the axial length, refraction, best-corrected visual acuity, and stereoscopic vision were respectively examined postoperatively at yearly intervals for three years. RESULTS: The best-corrected visual acuity was significantly higher in the PSR group than that in the control group at any study visit. A statistically significant difference in axial length was found between the PSR group (27.38 +/- 1.30 mm) and the control group (28.29 +/- 0.74 mm) at the postoperative three year (p = 0.03) time point. There was a statistical difference in refractive error between the PSR group (-13.13 +/- 2.55 D) and the control group (-15.42 +/- 1.83 D) at 3-year follow-up. No significant difference was found between the two groups with respect to the stereoscopic vision by the end of follow-up at 3 years (p =0.103). CONCLUSIONS: PSR combined with the patching therapy has the potential to arrest the progression of high myopia and to help the treatment for amblyopia. PMID- 25694154 TI - The geometry relaxation and intersystem crossing of quaterthiophene studied by femtosecond spectroscopy. AB - Quaterthiophene is used as a fluorescent marker for biological applications, but the intrinsic excited state dynamics for its high triplet-formation yield are still under debate due to the complexity of the molecule structure and the undetermined energy level order. In this work, ultrafast geometry relaxation and intersystem crossing of quaterthiophene in 1,4-dioxane are studied by femtosecond time-resolved spectroscopy combined with quantum calculations. Transient absorption spectra at a pump wavelength of 400 nm are completely recorded up to the delay time of 1 ns. The kinetic traces of excited state absorption indicate that geometry relaxation occurs on the S1 potential energy surface with a time constant of ~70 ps. Two triplet-triplet absorption bands centered at 563 nm and 600 nm show a direct dynamical conversion. The intersystem crossing is determined to be ~398 ps. The high triplet yield is measured as ~0.7 via the efficient intersystem crossing. On the basis of quantum chemical calculations, a general mechanism is proposed to describe the geometry relaxation and intersystem crossing processes. PMID- 25694155 TI - Cobalt-catalyzed negishi cross-coupling reactions of (hetero)arylzinc reagents with primary and secondary alkyl bromides and iodides. AB - We report a cobalt-catalyzed cross-coupling of di(hetero)arylzinc reagents with primary and secondary alkyl iodides or bromides using THF-soluble CoCl2 ?2 LiCl and TMEDA as a ligand, which leads to the corresponding alkylated products in up to 88 % yield. A range of functional groups (e.g. COOR, CN, CF3 , F) are tolerated in these substitution reactions. Remarkably, we do not observe rearrangement of secondary alkyl iodides to unbranched products. Additionally, the use of cyclic TBS-protected iodohydrins leads to trans-2-arylcyclohexanol derivatives in excellent diastereoselectivities (up to d.r.=99:1). PMID- 25694156 TI - Spodoptera frugiperda (Lepidoptera: Noctuidae) host-plant variants: two host strains or two distinct species? AB - The moth Spodoptera frugiperda is a well-known pest of crops throughout the Americas, which consists of two strains adapted to different host-plants: the first feeds preferentially on corn, cotton and sorghum whereas the second is more associated with rice and several pasture grasses. Though morphologically indistinguishable, they exhibit differences in their mating behavior, pheromone compositions, and show development variability according to the host-plant. Though the latter suggest that both strains are different species, this issue is still highly controversial because hybrids naturally occur in the wild, not to mention the discrepancies among published results concerning mating success between the two strains. In order to clarify the status of the two host-plant strains of S. frugiperda, we analyze features that possibly reflect the level of post-zygotic isolation: (1) first generation (F1) hybrid lethality and sterility; (2) patterns of meiotic segregation of hybrids in reciprocal second generation (F2), as compared to the meiosis of the two parental strains. We found a significant reduction of mating success in F1 in one direction of the cross and a high level of microsatellite markers showing transmission ratio distortion in the F2 progeny. Our results support the existence of post-zygotic reproductive isolation between the two laboratory strains and are in accordance with the marked level of genetic differentiation that was recovered between individuals of the two strains collected from the field. Altogether these results provide additional evidence in favor of a sibling species status for the two strains. PMID- 25694157 TI - The molecular basis of antifolate resistance in Plasmodium falciparum: looking beyond point mutations. AB - Drugs that target the folate-synthesis pathway have a long history of effectiveness against a variety of pathogens. As antimalarials, the antifolates were safe and well tolerated, but resistance emerged quickly and has persisted even with decreased drug pressure. The primary determinants of resistance in Plasmodium falciparum are well-described point mutations in the enzymes dihydropteroate synthase and dihydrofolate reductase targeted by the combination sulfadoxine-pyrimethamine. Recent work has highlighted the contributions of additional parasite adaptation to antifolate resistance. In fact, the evolution of antifolate-resistant parasites is multifaceted and complex. Gene amplification of the first enzyme in the parasite folate synthesis pathway, GTP-cyclohydrolase, is strongly associated with resistant parasites and potentially contributes to persistence of resistant parasites. Further understanding of how parasites adjust flux through the folate pathway is important to the further development of alternative agents targeting this crucial synthesis pathway. PMID- 25694158 TI - NMR assignments for the insertion domain of bacteriophage CUS-3 coat protein. AB - CUS-3 is a P22-like tailed dsDNA bacteriophage that infects Escherichia coli serotype K1. The CUS-3 coat protein, which forms the icosahedral capsid, has a conserved HK97-fold but with a non-conserved accessory domain known as the insertion domain (I-domain). Sequence alignment of the coat proteins from CUS-3 and P22 shows higher sequence similarity for the I-domains (35 %) than for the HK97-cores, suggesting the I-domains play important functional roles. The I domain of the P22 coat protein, which has an NMR structure comprised of a six stranded beta-barrel, has been shown to govern the assembly, stability and size of the resulting capsid particles. Here, we report the (1)H, (15)N, and (13)C assignments for the I-domain from the coat protein of bacteriophage CUS-3. The secondary structure and dynamics of the CUS-3 I-domain, predicted from the assigned NMR chemical shifts, agree with those of the P22 I-domain, suggesting the CUS-3 and P22 I-domains may have similar structures and functions in capsid assembly. PMID- 25694159 TI - Dyad content is reduced in cardiac myocytes of mice with impaired calmodulin regulation of RyR2. AB - In cardiac muscle, calmodulin (CaM) regulates the activity of several membrane proteins involved in Ca(2+) homeostasis (CaV1.2; RyR2, SERCA2, PMCA). Three engineered amino acid substitutions in the CaM binding site of the cardiac ryanodine receptor (RyR2) in mice (Ryr2 (ADA/ADA) ) strongly affect cardiac function, with impaired CaM inhibition of RyR2, reduced SR Ca(2+) sequestration, and early cardiac hypertrophy and death (Yamaguchi et al., J Clin Invest 117:1344 1353, 2007). We have examined the ultrastructure and RyR2 immunolocalization in WT and Ryr2 (ADA/ADA) hearts at ~10 days after birth. The myocytes show only minor evidence of structural damage: some increase in intermyofibrillar space, with occasional areas of irregular SR disposition and an increase in frequency of smaller myofibrils, despite an increase of about 15 % in average myocyte cross sectional area. Z line streaming, a sign of myofibrillar stress, is limited and fairly rare. Immunolabeling with an anti-RyR2 antibody shows that RyR-positive foci located at the level of the Z lines are less frequent in mutant hearts. A dramatic decrease in the frequency and size of dyads, accompanied by a decrease in occupancy of the gap by RyR2, but without obvious alterations in location and general structure is a notable ultrastructural feature. The data suggest that the uneven distribution of dyads or calcium release sites within the cells resulting from an overall reduction in RyR2 content may contribute to the poor cardiac performance and early death of Ryr2 (ADA/ADA) mice. An unusual fragmentation of mitochondria, perhaps related to imbalances in free cytoplasmic calcium levels, accompanies these changes. PMID- 25694160 TI - Slow motor units in female rat soleus are slower and weaker than their male counterparts. AB - The aim of the study was to investigate sex-related differences in contractile properties, parameters of action potentials, and mechanisms of force regulation of motor units in the rat soleus muscle, which is a frequent experimental model in animal research. It was revealed that the mean mass of the muscle in males was bigger than in females, by approximately 80%. However, the relation of the muscle mass to the body mass was not significantly different. These results correspond to approximately twice as much tetanic force per motor unit in male rats, and higher maximal contractile output, reflected by the force-time area per stimulus pulse. On the other hand, no differences were observed with respect to twitch forces of motor units. Thus the twitch-to-tetanus ratio was significantly higher in females. Additionally, the contraction and the half-relaxation times were significantly longer in female motor units, which might be due to differences in muscle architecture. The force-frequency curve in males was shifted rightwards with respect to females, indicating that the same relative level of tetanic force could be achieved at considerably lower stimulation frequency in females. The analysis of motor unit action potentials revealed about four times higher amplitudes in male rats, whereas the time parameters of action potentials were similar. The motor units in male and female rat soleus are considerably different and these observations should be taken in the consideration in various experiments on the muscle. PMID- 25694161 TI - Safety of percutaneous vertebroplasty for the treatment of metastatic spinal tumors in patients with posterior wall defects. AB - PURPOSE: To assess the clinical effect of percutaneous vertebroplasty (PVP) in the treatment of metastatic spinal tumors in patients with posterior wall defect. METHODS: The treated vertebrae bodies were divided into four groups: group A, non posterior vertebral wall defect; group B, posterior vertebral wall with cribriform defects; group C, posterior vertebral wall with local fragmentation defects; group D, posterior vertebral wall with severe defects. The injected volume of bone cement, visual analogue scale (VAS) score, Karnofsky Performance Scale (KPS), cement leakage and survival were analyzed. RESULTS: The injected volume of bone cement for group A was significantly higher than posterior wall defect group (including group B, C, and D). No significant differences about the injected volume of bone cement among the posterior wall defect groups. The incidence of bone cement leakage for group A was not significantly different as compared to posterior vertebral wall defect group. However, there were significant differences with respect to the incidence of bone cement leakage among the posterior wall defect groups. In four groups the postoperative VAS pain scores and KPS were statistical different as comparison to the preoperative values. No statistical difference with respect to the VAS pain scores and KPS was observed at any time point between the non-posterior wall defect group and posterior wall defect group. CONCLUSION: PVP can be an effective treatment for metastatic spinal tumors in patients with posterior wall deficiency; however, care should be taken to control the distribution of the bone cement due to the relatively high risk of cement leakage. PMID- 25694162 TI - Liver concentrations of copper, zinc, iron and molybdenum in sheep and goats from northern Greece, determined by energy-dispersive X-ray fluorescence spectrometry. AB - Energy-dispersive X-Ray fluorescence spectrometry was used to determine the concentrations of copper (Cu), zinc, iron and molybdenum in the liver of 76 sheep and goats from the regions of Macedonia-Thrace, northern Greece. In general, metal concentrations were in the adequate range, with one main exception of Cu deficiency observed in all of the examined goat liver samples and Cu-toxicity found in 4 % of the sheep liver samples. One-way analysis of variance was carried out to determine significant differences among means depending on animal species, sex and age. Pearson correlation analysis was used to explore correlations between metal concentrations. The results obtained in the present study are discussed in the framework of diagnostic ranges, suggested for classifying the metal status of sheep and goats, and are compared with liver metal concentrations reported world-wide. PMID- 25694163 TI - Predominance and sources of alkane and fatty acid biomarkers in the surface sediments of Chitrapuzha River (South India). AB - Surface sediment samples were collected from Chitrapuzha (Cochin) estuarine system to identify the natural and anthropogenic origin of organic matter. The distribution and sources of organic matter were assessed with the help of fatty acid and alkane biomarkers. Fatty acids ranging from C12 to C28 were identified and C16:0 was the most abundant fatty acid, which contributed between 23.5 % and 52.4 % to total fatty acids. The low levels of polyunsaturated fatty acids indicate the effective bacterial recycling of algal fatty acids during the whole settling and depositing process. Aliphatic hydrocarbons ranging from C12 to C33 were identified and the total concentration ranged from 7876 to 43,357 ng g(-1). The presence of unresolved complex mixtures and lower pristane to phytane ratios indicates the petroleum contamination in the study area. PMID- 25694164 TI - Is there one measure-of-fit that fits all? A taxonomy and review of measures-of fit for risk-equalization models. AB - This study provides a taxonomy of measures-of-fit that have been used for evaluating risk-equalization models since 2000 and discusses important properties of these measures, including variations in analytic method. It is important to consider the properties of measures-of-fit and variations in analytic method, because they influence the outcomes of evaluations that eventually serve as a basis for policymaking. Analysis of 81 eligible studies resulted in the identification of 71 unique measures that were divided into 3 categories based on treatment of the prediction error: measured based on squared errors, untransformed errors, and absolute errors. We conclude that no single measure-of fit is best across situations. The choice of a measure depends on preferences about the treatment of the prediction error and the analytic method. If the objective is measuring financial incentives for risk selection, the only adequate evaluation method is to assess the predictive performance for non-random groups. PMID- 25694165 TI - Incorporation of magnesium ions into photo-crosslinked alginate hydrogel enhanced cell adhesion ability. AB - Photo-crosslinked alginate hydrogel attracts wide interest in tissue engineering because of its excellent controllability and stability. However, its highly hydrophilic property makes cell adhesion difficult. Plenty of studies have confirmed that magnesium ions (Mg(2+) ) can efficiently improve the attachment of osteoblasts. In this study, for the first time, we fabricated a durable, crosslinked, alginate hydrogel with a dual-crosslinking network. Photo crosslinked alginate hydrogel was chosen as the basic backbone, and various amounts of Mg(2+) were incorporated into the hydrogel through ionic crosslinking. The results showed that the physicochemical properties of the hydrogels, including surface structure, composition, swelling ratio, ion release and elastic modulus, could be well tuned by controlling the amount of Mg(2+) incorporated. In addition, a certain amount of Mg(2+) significantly improved the attachment and spread of osteoblasts on the hydrogels. These characteristics make Mg(2+) incorporated photo-crosslinked alginate hydrogel a promising scaffold for bone tissue engineering. PMID- 25694166 TI - Morphology dependent field emission of acid-spun carbon nanotube fibers. AB - Acid spun carbon nanotube (CNT) fibers were investigated for their field emission properties and performance was determined to be dependent on fiber morphology. The fibers were fabricated by wet-spinning of pre-made CNTs. Fiber morphology was controlled by a fabrication method and processing conditions, as well as purity, size, and type of the CNT starting material. The internal fiber structure consisted of CNT fibrils held together by van der Waals forces. Alignment and packing density of the CNTs affects the fiber's electrical and thermal conductivity. Fibers with similar diameters and differing morphology were compared, and those composed of the most densely packed and well aligned CNTs were the best field emitters as exhibited by a lower turn-on voltage and a larger field enhancement factor. Fibers with higher electrical and thermal conductivity demonstrated higher maximum current before failure and longer lifetimes. A stable emission current at 3 mA was obtained for 10 h at a field strength of <1 V MUm( 1). This stable high current operation makes these CNT fibers excellent candidates for use as low voltage electron sources for vacuum electronic devices. PMID- 25694167 TI - Improving Radiology Report Quality by Rapidly Notifying Radiologist of Report Errors. AB - Radiology report errors occur for many reasons including the use of pre-filled report templates, wrong-word substitution, nonsensical phrases, and missing words. Reports may also contain clinical errors that are not specific to the speech recognition including wrong laterality and gender-specific discrepancies. Our goal was to create a custom algorithm to detect potential gender and laterality mismatch errors and to notify the interpreting radiologists for rapid correction. A JavaScript algorithm was devised to flag gender and laterality mismatch errors by searching the text of the report for keywords and comparing them to parameters within the study's HL7 metadata (i.e., procedure type, patient sex). The error detection algorithm was retrospectively applied to 82,353 reports 4 months prior to its development and then prospectively to 309,304 reports 15 months after implementation. Flagged reports were reviewed individually by two radiologists for a true gender or laterality error and to determine if the errors were ultimately corrected. There was significant improvement in the number of flagged reports (pre, 198/82,353 [0.24%]; post, 628/309,304 [0.20%]; P = 0.04) and reports containing confirmed gender or laterality errors (pre, 116/82,353 [0.014%]; post, 285/309,304 [0.09%]; P < 0.0001) after implementing our error notification system. The number of flagged reports containing an error that were ultimately corrected improved dramatically after implementing the notification system (pre, 17/116 [15%]; post, 239/285 [84%]; P < 0.0001). We developed a successful automated tool for detecting and notifying radiologists of potential gender and laterality errors, allowing for rapid report correction and reducing the overall rate of report errors. PMID- 25694168 TI - Environmentally friendly transistors and circuits on paper. AB - We created environmentally friendly low-voltage, ion-modulated transistors (IMTs) that can be fabricated successfully on a paper substrate. A range of ionic liquids (ILs) based on choline chloride (ChoCl) were used as the electrolytic layer in the IMTs. Different organic compounds were mixed with ChoCl to create solution-processable deep eutectic mixtures that are liquid or semiliquid at room temperature. In the final, solid version of the IMT, the ILs are also solidified by using a commercial binder to create printable transistor structures The semiconductor layer in the IMT is also substituted with a blend of the original semiconductor and a biodegradable polymer insulator. This reduces the amount of expensive and potentially harmful semiconductor used, and it also provides increased transistor performance, especially increasing the device switching speed. These environmentally friendly IMTs are then used to create ring oscillators, logic gates, and memories on paper. PMID- 25694170 TI - Fast delocalization leads to robust long-range excitonic transfer in a large quantum chlorosome model. AB - Chlorosomes are efficient light-harvesting antennas containing up to hundreds of thousands of bacteriochlorophyll molecules. With massively parallel computer hardware, we use a nonperturbative stochastic Schrodinger equation, while including an atomistically derived spectral density, to study excitonic energy transfer in a realistically sized chlorosome model. We find that fast short-range delocalization leads to robust long-range transfer due to the antennae's concentric-roll structure. Additionally, we discover anomalous behavior arising from different initial conditions, and outline general considerations for simulating excitonic systems on the nanometer to micrometer scale. PMID- 25694169 TI - Autophagy attenuates noise-induced hearing loss by reducing oxidative stress. AB - AIMS: Reactive oxygen species play a dual role in mediating both cell stress and defense pathways. Here, we used pharmacological manipulations and siRNA silencing to investigate the relationship between autophagy and oxidative stress under conditions of noise-induced temporary, permanent, and severe permanent auditory threshold shifts (temporary threshold shift [TTS], permanent threshold shift [PTS], and severe PTS [sPTS], respectively) in adult CBA/J mice. RESULTS: Levels of oxidative stress markers (4-hydroxynonenal [4-HNE] and 3-nitrotyrosine [3-NT]) increased in outer hair cells (OHCs) in a noise-dose-dependent manner, whereas levels of the autophagy marker microtubule-associated protein light chain 3 B (LC3B) were sharply elevated after TTS but rose only slightly in response to PTS and were unaltered by sPTS noise. Furthermore, green fluorescent protein (GFP) intensity increased in GFP-LC3 mice after TTS-noise exposure. Treatment with rapamycin, an autophagy activator, significantly increased LC3B expression, while diminishing 4-HNE and 3-NT levels, reducing noise-induced hair cell loss, and, subsequently, noise-induced hearing loss (NIHL). In contrast, treatment with either the autophagy inhibitor 3-methyladenine (3MA) or LC3B siRNA reduced LC3B expression, increased 3-NT and 4-HNE levels, and exacerbated TTS to PTS. INNOVATION: This study demonstrates a relationship between oxidative stress and autophagy in OHCs and reveals that autophagy is an intrinsic cellular process that protects against NIHL by attenuating oxidative stress. CONCLUSIONS: The results suggest that the lower levels of oxidative stress incurred by TTS-noise exposure induce autophagy, which promotes OHC survival. However, excessive oxidative stress under sPTS-noise conditions overwhelms the beneficial potential of autophagy in OHCs and leads to OHC death and NIHL. PMID- 25694171 TI - Evaluation of the tear film instability in children with allergic diseases. AB - CONTEXT: The presence of dry eye syndrome (DES) in ocular allergic diseases was evaluated in several studies. Despite this, little exists about the tear film instability in atopic children including patients with allergic rhinitis (AR), allergic conjunctivitis (AC) and asthma. This is a study which presents intriguing findings regarding the relationship of tear film instability with clinical aspects in atopic children. OBJECTIVE: To determine the tear film instability in children with AR, AC and asthma. MATERIALS AND METHODS: One hundred and thirty-five consecutive children with AR, AC and asthma as study group and 45 children without any systemic and ocular abnormality as control group were included in the study. Skin prick tests, measurement of tear film breakup time (TFBUT), serum immunoglobulin E and eosinophil counts were performed in all patients. Also four subgroups of patients were designated as AR group (Group I), AC group (Group II), asthma group (Group III) and control group (Group IV). RESULTS: Socio-demographic characteristics were similar except for family atopy between the groups (p > 0.05). The mean TFBUT was significantly lower in the study group (15.5 +/- 4.4 s) than the control group (18.4 +/- 2.9 s; p = 0.000). Also, there was no significant differences in the percentage of the patients who has TFBUT<10 s (p = 0.066). In logistic regression analysis, atopy was found to be the determinant of lower TFBUT (OR = 16.33, 95%; CI = 1.17 to 228.05, p = 0.03). CONCLUSION: The presence of tear film instability was higher in children with AC, AR and asthma. This finding should be taken in consideration in atopic children. PMID- 25694172 TI - Acute and long-term ocular effects of acrolein vapor on the eyes and potential therapies. AB - Acrolein is an important agent in chemical ocular burns. With regard to the results of the study reported by Dachir et al.; we discuss the particular role of acrolein in chemical warfare and the beneficial effects of proanthocyanidins on the acrolein-induced ocular injuries. PMID- 25694174 TI - The new allele HLA-DPB1*363:01 identified by sequence-based typing in a donor from the Chinese Marrow Donor Program. AB - The new allele HLA-DPB1*363:01 most closely resembles DPB1*92:01, differing at a single position 191 (exon 2, codon 35). PMID- 25694175 TI - Critical factors about feedback: 'They told me what I did wrong; but didn't give me any feedback'. PMID- 25694176 TI - Embedding Research in Undergraduate Learning Opportunities. AB - As a means of promoting scholarship, faculty are increasingly including undergraduate nursing students as team members in faculty-led research projects. Research involvement is a high-impact educational practice that enhances student engagement and retention rates and enables the reflection and integration of learning. The purpose of this article is to describe the benefits and innovative ways of directly involving undergraduate nursing students in faculty-guided research projects. Case examples from four non-research-intensive nursing programs are presented to illustrate the benefits of undergraduate student research involvement to students, faculty, their communities, as well as the nursing profession. Student assistance in all phases of the research process, ranging from research question generation, literature reviews, methods development, and data collection and analysis, to presentations and manuscript publication, motivates and helps faculty progress with their research programs. Benefits also include the creation of effective learning experiences that build nursing knowledge and potentially contribute to community health. PMID- 25694177 TI - Symptom Representation and Treatment-Seeking Prior to Diagnosis of Atrial Fibrillation. AB - Early treatment-seeking for symptoms of atrial fibrillation (AF) is critical to avert AF-related stroke and heart failure, but early treatment is hindered if symptoms are not accurately interpreted. The purpose of this research was to describe symptom representation and treatment-seeking responses prior to diagnosis of AF. For this descriptive study, 150 participants were surveyed to describe the type and temporality of symptoms, perceptions regarding the cause, seriousness, controllability of symptoms, and responses to symptoms prior to diagnosis. Participants' mean age was 66.5 years, and 51% were female. Participants perceived symptoms as having nondisease-based causes, as not very serious, and as amenable to self-management. The majority took a wait and see response with 69% waiting more than 1 week after symptom onset to seek treatment. Lack of recognition of the seriousness of symptoms of AF and delayed treatment put patients at risk of poorer outcomes. PMID- 25694178 TI - Role of ultrasound in the diagnosis and treatment of nonalcoholic fatty liver disease and its complications. AB - We review the role of liver ultrasonography (US) and related techniques as non invasive tools in predicting metabolic derangements, liver histology, portal hypertension and cardiovascular risk as well as allowing early diagnosis and management of hepatocellular carcinoma in patients with nonalcoholic fatty liver disease. In this setting, US detects fatty changes as low as >=20% and hepatic steatosis identified ultrasonographically, in its turn, closely mirrors coronary and carotid atherosclerosis burden. Semi-quantitative US indices (to exclude nonalcoholic steatohepatitis) and sonoelastography (to quantify fibrosis) help in predicting liver histology and selecting patients to submit to liver biopsy. Surveillance for hepatocellular carcinoma conducted through biannual US is mandatory and US has a role in guiding locoregional treatment and in evaluating the efficacy of treatment. High-intensity focused ultrasound can be delivered with precision resulting in coagulative necrosis of hepatocellular carcinoma without puncturing the liver. Costs and inconveniences have so far hampered its diffusion. PMID- 25694179 TI - Why I had to resign from my general practice. PMID- 25694180 TI - High potency cannabis is associated with tripled risk of psychosis, study indicates. PMID- 25694181 TI - Pyrene-based dyad and triad leading to a reversible chemical and redox optical and magnetic switch. AB - Two new pyrene-polychlorotriphenylmethyl (PTM) dyads and triads have been synthesized and characterized by optical, magnetic, and electrochemical methods. The interplay between the different electronic states of the PTM moiety in the dyads and triads and the optical and magnetic properties of the molecules have been studied. The electronic spectra of the radicals 5(.) and 6(.) show the intramolecular charge-transfer transition at around 700 nm due to the acceptor character of the PTM radical. In the diamagnetic protonated derivatives 3 and 4 the fluorescence due to the pyrene is maintained, whereas in the radicals 5(.) and 6(.) and the corresponding anions 5(-) and 6(-) there is a clear quenching of the fluorescence, which is more efficient in the case of radicals. The redox activity of PTM radicals that are easily reduced to the corresponding carbanion has been exploited to fabricate electrochemical switches with optical and magnetic response. PMID- 25694182 TI - Doctors' financial interests should be declared to avoid any impression of impropriety. PMID- 25694183 TI - Getting sedentary people moving through active travel. PMID- 25694184 TI - Pocket-sized ultrasound - a new tool for heart-failure nurses in daily clinical practice? PMID- 25694185 TI - GABA circuitry, cells and molecular regulation in schizophrenia: life in the graveyard. PMID- 25694187 TI - Chest pain, dyspnoea and hypotension in a 61-year-old woman. PMID- 25694186 TI - Retinal microvessels reflect familial vulnerability to psychotic symptoms: A comparison of twins discordant for psychotic symptoms and controls. AB - Mounting evidence suggests that individuals with schizophrenia have an underlying vulnerability to cardiovascular disease, and a recent study suggested that this vulnerability might be reflected in the retinal microvasculature. The purpose of this study was to test the hypothesis that the retinal microvessels reflect familial vulnerability to psychotic symptoms. Participants were 531 adolescent and young adult twins who took part in the Brisbane Longitudinal Twin Study and the Twins Eye Study in Tasmania. The twins had photographs taken of their retina when they were adolescents or young adults (M age=20.6 years), and retinal vessel diameter was assessed using computer software. The twins completed an assessment of psychosis symptoms approximately six years later. We compared retinal venular diameters of individuals with one or more symptoms of psychosis (n=45), their unaffected co-twins (n=24), and controls (n=462). Individuals with one or more symptoms of psychosis had wider venules (standardized mean=0.29) than controls (standardized mean=-0.04; p=.03), and unaffected co-twins had venular diameters that were intermediate (standardized mean=0.13) between the two groups, suggesting that wide venules may represent a proxy marker of familial vulnerability to psychosis symptoms. Consistent with previous work, there were no differences in arteriolar diameter between individuals with and without symptoms of psychosis. Findings suggest that wide retinal venules may serve as a proxy marker of familial liability to psychosis symptoms. The pathophysiological mechanisms linking psychosis and cardiovascular disease may be operative from early in life, possibly at the level of the microvasculature. PMID- 25694188 TI - Pancreatic amyloidoma associated with elevated CA19-9: A case diagnosed by endoscopic ultrasound-guided fine-needle aspiration biopsy. PMID- 25694189 TI - The impact of hypertension as a road to heart failure with preserved ejection fraction: diagnostic value of two-dimensional speckle tracking echocardiography for the early impairment of left atrial-left ventricular-arterial coupling. AB - Heart failure with preserved ejection fraction (HFPEF) is a syndrome that frequently occurs in older people and patients with cardiovascular risk factors, particularly hypertension. This syndrome is not a specific disease process, whereas is associated with high morbidity and mortality in patients with heart failure with reduced ejection fraction (HFREF) as well. Therefore, a "one size fits all" diagnosis strategy is unlikely to operate for patients with HFPEF. Assessment of left atrial (LA)-left ventricular (LV)-arterial coupling seems to have a clinical impact on hypertensive patients, because HF signs and symptoms have been found to be significantly related to inappropriate LA-LV interaction during diastole and LV-arterial interaction during systole. Two-dimensional speckle tracking echocardiography (2DSTE) is a new tool that may have a role in earlier detecting the impaired LA, LV, and arterial function in asymptomatic patients. This review explored the impact of LA-LV-arterial coupling in understanding the pathophysiology of hypertension as a road to HFPEF, and the possibilities of clinical application by using 2DSTE. PMID- 25694190 TI - Neonatal hypertension: an underdiagnosed condition, a review article. AB - Advances in neonatology and intensive monitoring has increased our ability to identify and measure blood pressure in sick premature and term infants and this has contributed to an increased awareness of hypertension in the NICU. A few recent studies done by Zubrow and others have offered many new information on blood pressure values over the first month after birth and on other many intrinsic and extrinsic factors that can cause effects on the blood pressure in the neonatal period. There are no definite cut off for labelling hypertension in newborn period and also doubts are there on the pharmacological treatment. This is a field in neonatology which is least studied hence requires further inquiry. This review article will cover several aspects of neonatal hypertension like definition, normotensive data, etiology, clinical characteristics, diagnostic modalities, treatment choices and long term effect of these newborns. PMID- 25694191 TI - Catheter-related atrial thrombus: tip of the iceberg? AB - Although guidelines recommend catheters as a last resort for establishing a vascular access in patients undergoing dialysis, they continue to be used widely for this purpose. Catheter-related atrial thrombus (CRAT) is rarely reported in this group of patients, and it can lead to serious complications. The aim of this study was to determine the incidence of CRAT in patients undergoing hemodialysis with permanent-tunneled catheters. A total of 50 patients undergoing hemodialysis with permanent catheters were included in this study. The diagnosis of CRAT was based on transthoracic echocardiography findings. Thrombus was present in nine patients (18%) and related to the tip of the catheter in all cases. Except for one patient with two foci of thrombus, all patients had a single focus. There were no significant associations between the development of thrombus and the duration of catheter use or the location of the catheter. Furthermore, catheter related atrial thrombus did not appear to have a significant effect on mortality. The asymptomatic character of CRAT can be responsible for the low reporting rates, and its exact role in increased mortality and morbidity related with catheter use remains unknown. While planning management strategies, information on different options for vascular access routes and possible catheter-related complications should be provided to all patients who will undergo dialysis, together with a discussion involving other replacement alternatives for end-stage renal disease. PMID- 25694194 TI - Concise review: humanized models of tumor immunology in the 21st century: convergence of cancer research and tissue engineering. AB - Despite positive testing in animal studies, more than 80% of novel drug candidates fail to proof their efficacy when tested in humans. This is primarily due to the use of preclinical models that are not able to recapitulate the physiological or pathological processes in humans. Hence, one of the key challenges in the field of translational medicine is to "make the model organism mouse more human." To get answers to questions that would be prognostic of outcomes in human medicine, the mouse's genome can be altered in order to create a more permissive host that allows the engraftment of human cell systems. It has been shown in the past that these strategies can improve our understanding of tumor immunology. However, the translational benefits of these platforms have still to be proven. In the 21st century, several research groups and consortia around the world take up the challenge to improve our understanding of how to humanize the animal's genetic code, its cells and, based on tissue engineering principles, its extracellular microenvironment, its tissues, or entire organs with the ultimate goal to foster the translation of new therapeutic strategies from bench to bedside. This article provides an overview of the state of the art of humanized models of tumor immunology and highlights future developments in the field such as the application of tissue engineering and regenerative medicine strategies to further enhance humanized murine model systems. PMID- 25694195 TI - Nigel Edwards: Best contribution to medicine--not becoming a doctor. PMID- 25694197 TI - Politicians vie to support access to talking therapies on NHS. PMID- 25694196 TI - Porous hyaluronic acid hydrogels for localized nonviral DNA delivery in a diabetic wound healing model. AB - The treatment of impaired wounds requires the use of biomaterials that can provide mechanical and biological queues to the surrounding environment to promote angiogenesis, granulation tissue formation, and wound closure. Porous hydrogels show promotion of angiogenesis, even in the absence of proangiogenic factors. It is hypothesized that the added delivery of nonviral DNA encoding for proangiogenic growth factors can further enhance this effect. Here, 100 and 60 MUm porous and nonporous (n-pore) hyaluronic acid-MMP hydrogels with encapsulated reporter (pGFPluc) or proangiogenic (pVEGF) plasmids are used to investigate scaffold-mediated gene delivery for local gene therapy in a diabetic wound healing mouse model. Porous hydrogels allow for significantly faster wound closure compared with n-pore hydrogels, which do not degrade and essentially provide a mechanical barrier to closure. Interestingly, the delivery of pDNA/PEI polyplexes positively promotes granulation tissue formation even when the DNA does not encode for an angiogenic protein. And although transfected cells are present throughout the granulation tissue surrounding, all hydrogels at 2 weeks, pVEGF delivery does not further enhance the angiogenic response. Despite this, the presence of transfected cells shows promise for the use of polyplex-loaded porous hydrogels for local gene delivery in the treatment of diabetic wounds. PMID- 25694198 TI - Doctors can depart from guidelines in patients' best interests. PMID- 25694199 TI - Divergent solid-phase synthesis of natural product-inspired bipartite cyclodepsipeptides: total synthesis of seragamide A. AB - Macrocyclic natural products (NPs) and analogues thereof often show high affinity, selectivity, and metabolic stability, and methods for the synthesis of NP-like macrocycle collections are of major current interest. We report an efficient solid-phase/cyclorelease method for the synthesis of a collection of macrocyclic depsipeptides with bipartite peptide/polyketide structure inspired by the very potent F-actin stabilizing depsipeptides of the jasplakinolide/geodiamolide class. The method includes the assembly of an acyclic precursor chain on a polymeric carrier, terminated by olefins that constitute complementary fragments of the polyketide section and cyclization by means of a relay-ring-closing metathesis (RRCM). The method was validated in the first total synthesis of the actin-stabilizing cyclodepsipeptide seragamide A and the synthesis of a collection of structurally diverse bipartite depsipeptides. PMID- 25694200 TI - Effects of sleep deprivation on action potential and transient outward potassium current in ventricular myocytes in rats. AB - BACKGROUND: Sleep deprivation contributes to the development and recurrence of ventricular arrhythmias. However, the electrophysiological changes in ventricular myocytes in sleep deprivation are still unknown. MATERIAL AND METHODS: Sleep deprivation was induced by modified multiple platform technique. Fifty rats were assigned to control and sleep deprivation 1, 3, 5, and 7 days groups, and single ventricular myocytes were enzymatically dissociated from rat hearts. Action potential duration (APD) and transient outward current (Ito) were recorded using whole-cell patch clamp technique. RESULTS: Compared with the control group, the phases of APD of ventricular myocytes in 3, 5, and 7 days groups were prolonged and APD at 20% and 50% level of repolarization (APD20 and APD50) was significantly elongated (The APD20 values of control, 1, 3, 5, and 7 days groups: 5.66+/-0.16 ms, 5.77+/-0.20 ms, 8.28+/-0.30 ms, 11.56+/-0.32 ms, 13.24+/-0.56 ms. The APD50 values: 50.66+/-2.16 ms, 52.77+/-3.20 ms, 65.28+/-5.30 ms, 83.56+/-7.32 ms, 89.24+/-5.56 ms. P<0.01, n=18). The current densities of Ito significantly decreased. The current density-voltage (I-V) curve of Ito was vitally suppressed downward. The steady-state inactivation curve and steady-state activation curve of Ito were shifted to left and right, respectively, in sleep deprivation rats. The inactivation recovery time of Ito was markedly retarded and the time of closed-state inactivation was markedly accelerated in 3, 5, and 7 days groups. CONCLUSIONS: APD of ventricular myocytes in sleep deprivation rats was significantly prolonged, which could be attributed to decreased activation and accelerated inactivation of Ito. PMID- 25694201 TI - Men and women from the STRIDE clinical trial: An assessment of stimulant abstinence symptom severity at residential treatment entry. AB - BACKGROUND AND OBJECTIVES: Gender-specific factors associated with stimulant abstinence severity were examined in a stimulant abusing or dependent residential treatment sample (N = 302). METHOD: Bivariate statistics tested gender differences in stimulant abstinence symptoms, measured by participant-reported experiences of early withdrawal. Multivariate linear regression examined gender and other predictors of stimulant abstinence symptom severity. RESULTS: Women compared to men reported greater stimulant abstinence symptom severity. Anxiety disorders and individual anxiety-related abstinence symptoms accounted for this difference. African American race/ethnicity was predictive of lower stimulant abstinence severity. DISCUSSION AND CONCLUSIONS: Women were more sensitive to anxiety-related stimulant withdrawal symptoms. SCIENTIFIC SIGNIFICANCE: Clinics that address anxiety-related abstinence symptoms, which more commonly occur in women, may improve treatment outcome. PMID- 25694202 TI - US guideline may drop cholesterol limits but keep link between dietary saturated fats and trans fats and heart disease. PMID- 25694203 TI - Solid-state 17O NMR spectroscopy of paramagnetic coordination compounds. AB - High-quality solid-state (17)O (I=5/2) NMR spectra can be successfully obtained for paramagnetic coordination compounds in which oxygen atoms are directly bonded to the paramagnetic metal centers. For complexes containing V(III) (S=1), Cu(II) (S=1/2), and Mn(III) (S=2) metal centers, the (17)O isotropic paramagnetic shifts were found to span a range of more than 10,000 ppm. In several cases, high resolution (17)O NMR spectra were recorded under very fast magic-angle spinning (MAS) conditions at 21.1 T. Quantum-chemical computations using density functional theory (DFT) qualitatively reproduced the experimental (17)O hyperfine shift tensors. PMID- 25694204 TI - Lung function profiles and aerobic capacity of adult cigarette and hookah smokers after 12 weeks intermittent training. AB - INTRODUCTION: Pulmonary function is compromised in most smokers. Yet it is unknown whether exercise training improves pulmonary function and aerobic capacity in cigarette and hookah smokers and whether these smokers respond in a similar way as do non-smokers. AIM: To evaluate the effects of an interval exercise training program on pulmonary function and aerobic capacity in cigarette and hookah smokers. METHODS: Twelve cigarette smokers, 10 hookah smokers, and 11 non-smokers participated in our exercise program. All subjects performed 30 min of interval exercise (2 min of work followed by 1 min of rest) three times a week for 12 weeks at an intensity estimated at 70% of the subject's maximum aerobic capacity (VO2max). Pulmonary function was measured using spirometry, and maximum aerobic capacity was assessed by maximal exercise testing on a treadmill before the beginning and at the end of the exercise training program. RESULTS: As expected, prior to the exercise intervention, the cigarette and hookah smokers had significantly lower pulmonary function than the non-smokers. The 12-week exercise training program did not significantly affect lung function as assessed by spirometry in the non-smoker group. However, it significantly increased both forced expiratory volume in 1 second and peak expiratory flow (PEF) in the cigarette smoker group, and PEF in the hookah smoker group. Our training program had its most notable impact on the cardiopulmonary system of smokers. In the non smoker and cigarette smoker groups, the training program significantly improved VO2max (4.4 and 4.7%, respectively), v VO2max (6.7 and 5.6%, respectively), and the recovery index (7.9 and 10.5%, respectively). CONCLUSIONS: After 12 weeks of interval training program, the increase of VO2max and the decrease of recovery index and resting heart rate in the smoking subjects indicated better exercise tolerance. Although the intermittent training program altered pulmonary function only partially, both aerobic capacity and life quality were improved. Intermittent training should be advised in the clinical setting for subjects with adverse health behaviors. PMID- 25694205 TI - Research Ethics Education in the STEM Disciplines: The Promises and Challenges of a Gaming Approach. AB - While education in ethics and the responsible conduct of research (RCR) is widely acknowledged as an essential component of graduate education, particularly in the STEM disciplines (science, technology, engineering, and math), little consensus exists on how best to accomplish this goal. Recent years have witnessed a turn toward the use of games in this context. Drawing from two NSF-funded grants (one completed and one on-going), this paper takes a critical look at the use of games in ethics and RCR education. It does so by: (a) setting the development of research and engineering ethics games in wider historical and theoretical contexts, which highlights their promise to solve important pedagogical problems; (b) reporting on some initial results from our own efforts to develop a game; and (c) reflecting on the challenges that arise in using games for ethics education. In our discussion of the challenges, we draw out lessons to improve this nascent approach to ethics education in the STEM disciplines . PMID- 25694206 TI - Disaster nursing skills, knowledge and attitudes required in earthquake relief: Implications for nursing education. AB - BACKGROUND: Globally, nurses becoming more aware of getting better prepared for disaster relief, but in China, disaster nursing knowledge, courses and research are still limited. INTRODUCTION: China has long been prone to disasters, but disaster nursing education and training is in its infancy. AIM: This study explored the skills, knowledge and attitudes required by registered nurses from across China who worked in the aftermath of three large earthquakes to try to determine future disaster nursing education requirements. METHOD: The Questionnaire of Nurses' Disaster Nursing Skills at Earthquake Sites, assessing nursing skills, knowledge and attitudes, was distributed to 139 registered nurses in 38 hospitals in 13 provinces across China who had worked in one or more earthquake disaster zones. Descriptive statistics were used for quantitative data, and content analysis for qualitative data. RESULTS: Eighty-nine questionnaires were returned, a response rate of 68.3%. No respondent had ever received specific disaster nursing training prior to their post-earthquake nursing. Skills most often used by respondents were haemostasis bandaging, fixation, manual handling, observation and monitoring, debridement and dressing, and mass casualty transportation. Respondents identified that the most important groups of skills required were cardiopulmonary resuscitation; haemostasis, bandaging, fixation, and manual handling; and emergency management. They emphasized the need for psychological care of victims as well as that of fellow health workers. CONCLUSION: No respondent had ever received disaster nursing training prior to engagement at the earthquake disaster sites. All believed that there were important gaps in their knowledge and skills, and supported disaster nursing courses in the future. IMPLICATIONS FOR NURSING AND HEALTH POLICY: China urgently needs to develop disaster nursing courses, with the support of nurse leaders, educationalists and government, to implement training using an all hazards approach in accordance with international best practice and trainees' background clinical experience and knowledge. PMID- 25694207 TI - 'Early' and 'late' timing for renal replacement therapy in acute kidney injury after cardiac surgery: a prospective, interventional, controlled, single-centre trial. AB - OBJECTIVES: Acute kidney injury after cardiac surgery (CS-AKI) is strongly associated with in-hospital mortality and morbidity. We aimed to investigate whether 'early' or 'late' initiation of renal replacement therapy (RRT) in patients with CS-AKI is associated with a survival benefit or more favourable outcomes. METHODS: All patients who had undergone cardiac surgery at 'Ospedali Riuniti' of Ancona from July 2011 to February 2013 were prospectively enrolled and divided into two treatment groups: the 'early' approach was used during the first 10 months, and the 'late' approach during the next 10 months. 'Early' RRT was started after 6 h of urine output less than 0.5 ml/kg/h, whereas in the 'late' group, therapy started on the basis of persistent (>12 h) oliguria. A total of 1658 patients were enrolled in the trial. The primary outcome was operative mortality, and the secondary outcomes were length of intensive care unit and hospital stay. RESULTS: The total number of patients treated with RRT was 59 (3.6%): 46 (5.5%) in the 'early' group and 13 (1.6%) in the 'late' group (P < 0.0001). Although RRT was significantly less utilized in the 'late' group, no significant difference in the primary and secondary outcomes was found, but a trend towards a better outcome in the 'late' group was observed. Furthermore, we found a significant difference in mortality between the two approaches in the subgroups of patients with preoperative renal dysfunction and in patients suffering from CS-AKI with a clear advantage of the late strategy. CONCLUSIONS: Our results do not support the use of early RRT in CS-AKI. CLINICAL TRIAL REGISTRATION: This trial is registered in the clinicaltrial.gov registry: NCT01961999. PMID- 25694208 TI - Children have a reduced maximal voluntary activation level of the adductor pollicis muscle compared to adults. AB - PURPOSE: The role of nervous factors in the muscle strength difference between children and adults is debated, and the level of physical activity may confound this comparison. The purpose of this study was thus to compare, between children and adults, the maximal voluntary activation level (MVA) of the adductor pollicis (AP) muscle, which is weakly influenced by the level of physical activity. METHODS: Thirteen boys (11.6 +/- 0.1 years) and eight men (25.6 +/- 1.5 years) were involved in this study. Neuromuscular function assessment included the evaluation of maximal voluntary contraction (MVC) force and of the MVA from peripheral magnetic stimulations of the ulnar nerve. The cross-sectional area of the AP muscle was determined with ultrasonography and used to calculate the specific force. A theoretical value of specific force, extrapolated for a full MVA, was finally computed (specific force@100 % MVA). RESULTS: MVC force (66.8 +/ 6.2 vs. 111.0 +/- 4.5 N, respectively; P < 0.001) and MVA (85.0 +/- 2.7 vs. 94.8 +/- 1.4 %, respectively; P < 0.05) were significantly lower in children compared to adults. The specific force was lower in children compared to adults (46.8 +/- 3.6 vs. 56.9 +/- 2.5 N/cm(2), respectively; P < 0.05), but the specific force@100 % MVA did not differ between groups. CONCLUSION: The results suggest that on an untrained muscle such as the AP muscle, the reduced ability of children to voluntarily activate their muscle could partly account for the difference of muscle strength between children and adults. PMID- 25694209 TI - The influence of estradiol on muscle damage and leg strength after intense eccentric exercise. AB - PURPOSE: To examine the influence of estradiol on muscle damage and leg strength after intense eccentric exercise. METHODS: Eight men (MEN), eight normally menstruating women (WomenNM), and eight women using oral contraceptives (WomenOC) participated in this study. Subjects performed 240 maximal-effort bilateral eccentric contractions of the quadriceps muscle groups designed to elicit exercise-induced muscle damage (EiMD). Serum creatine kinase (CK), myoglobin (Mb), and fatty acid-binding protein (FABP) concentrations were measured before (pre-) EiMD, as well as 0, 6, 24, and 48 h post-EiMD. Peak isometric quadriceps torque (i.e., leg strength) was measured pre-EiMD, as well as 24 and 48 h post EiMD. RESULTS: The increases in CK, Mb, and FABP concentrations from pre- to post EiMD were greater in MEN (10-fold, 15-fold, and fourfold, respectively) and WomenOC (sevenfold, 11-fold, and ninefold) compared with WomenNM (five-, six-, and threefold; p < 0.05). The decline in leg strength was about 10 % pre- to 24 h post-EiMD in all groups and decreased a further 10-15 % by 48 h post-EiMD in the MEN and WomenOC only. CONCLUSION: Our findings suggest an important role of estradiol in blunting the muscle damage response to intense eccentric exercise and preserving muscle function after EiMD. PMID- 25694210 TI - Role of FODMAPs in Patients With Irritable Bowel Syndrome. AB - Irritable bowel syndrome (IBS) is a condition characterized by abdominal pain, bloating, flatus, and altered bowel habits. The role of dietary components in inducing IBS symptoms is difficult to explore. To date, foods are not considered a cause but rather symptom-triggering factors. Particular interest has been given to the so-called FODMAPs (fermentable oligo-, di-, and monosaccharides and polyols). We aimed to summarize the evidence from the most common approaches to manage suspected food intolerance in IBS, with a particular interest in the role of FODMAPs and the effects of a low FODMAP diet. We reviewed literature, consulting PubMed and Medline by using the search terms FODMAP(s), fructose, lactose, fructans, galactans, polyols (sorbitol, mannitol, maltitol, xylitol, erythritol, polydextrose, and isomalt), irritable bowel syndrome, and functional gastrointestinal symptoms. FODMAP-restricted diets have been used for a long time to manage patients with IBS. The innovation in the so-called FODMAP concept is that a global restriction should have a more consistent effect than a limited one in preventing abdominal distension. Even though all the potential low FODMAP diets provide good relief of symptoms in many patients, there is just a little relief in others. Several studies highlight the role of low FODMAP diets to improve symptoms in patients with IBS. The evidence on this dietary approach supports the hypothesis that a low FODMAP diet should be the first dietary approach. However, many points remain to be clarified, including the evaluation of possibly significant nutrition concerns. PMID- 25694211 TI - Association of angiotensin-converting enzyme gene polymorphism with schizophrenia and depressive symptom severity in a Chinese population. AB - BACKGROUND: Depressive symptoms are frequently observed in schizophrenia patients. Angiotensin-converting enzyme (ACE), a key enzyme of renin-angiotensin system, can catalyze the degradation of neuropeptides and modulate dopaminergic and serotonergic neurotransmission. Previous studies have revealed the association of the ACE gene insertion/deletion polymorphism with depressive disorder and its treatment response but not with the depressive symptoms in schizophrenia. OBJECTIVE: The aim of this study is to examine whether this polymorphism was associated with susceptibility to schizophrenia and with its psychopathological symptoms, especially depressive symptoms in a Han Chinese population. METHODS: This polymorphism was genotyped in 382 chronic patients and 538 healthy controls. Psychopathology was characterised using the positive and negative syndrome scale. RESULTS: The allelic and genotypic frequencies of this polymorphism significantly differed between patients and controls (both p < 0.001). A significant difference in the positive and negative syndrome scale depressive symptom score was observed among the three genotypes (p < 0.03), with higher score in patients with insertion/insertion (I/I) than with deletion/deletion (D/D) genotypes (p < 0.05). Furthermore, there was a significant linear correlation between the number of I alleles and the depressive symptom score (p < 0.05). CONCLUSIONS: The ACE gene insertion/deletion polymorphism may play a role in susceptibility to schizophrenia and also in its depressive symptom severity in a Han Chinese population. PMID- 25694212 TI - Analysis of ethyl glucuronide and ethyl sulfate using aqueous normal-phase chromatography with mass spectrometry. AB - The use of aqueous normal-phase chromatography is explored as a possible format for the analysis of the forensically significant compounds ethyl glucuronide and ethyl sulfate. Standard solutions of the two compounds are used to verify the retention capabilities of two stationary phases (diamond hydride and undecanoic acid). These results are then compared to data obtained on hair extracts to determine if any matrix effects exist with respect to both retention and peak shape. The undecanoic stationary phase is used for the establishment of calibration curves for quantitative analysis. These curves are utilized to determine the concentration of ethyl glucuronide in several hair samples tested. PMID- 25694213 TI - HLA-A*02:541, a novel variant of HLA-A*02, discovered in a Taiwanese unrelated hematopoietic stem cell donor. AB - Two nucleotide changes at residue 524 and residue 527 of HLA-A*02:07:01 results in a novel allele, HLA-A*02:541. PMID- 25694214 TI - Platelet adhesion to podoplanin under flow is mediated by the receptor CLEC-2 and stabilised by Src/Syk-dependent platelet signalling. AB - Platelet-specific deletion of CLEC-2, which signals through Src and Syk kinases, or global deletion of its ligand podoplanin results in blood-filled lymphatics during mouse development. Platelet-specific Syk deficiency phenocopies this defect, indicating that platelet activation is required for lymphatic development. In the present study, we investigated whether CLEC-2-podoplanin interactions could support platelet arrest from blood flow and whether platelet signalling is required for stable platelet adhesion to lymphatic endothelial cells (LECs) and recombinant podoplanin under flow. Perfusion of human or mouse blood over human LEC monolayers led to platelet adhesion and aggregation. Following alphaIIbbeta3 blockade, individual platelets still adhered. Platelet binding occurred at venous but not arterial shear rates. There was no adhesion using CLEC-2-deficient blood or to vascular endothelial cells (which lack podoplanin). Perfusion of human blood over human Fc-podoplanin (hFcPDPN) in the presence of monoclonal antibody IV.3 to block FcgammaRIIA receptors led to platelet arrest at similar shear rates to those used on LECs. Src and Syk inhibitors significantly reduced global adhesion of human or mouse platelets to LECs and hFcPDPN. A similar result was seen using Syk-deficient mouse platelets. Reduced platelet adhesion was due to a decrease in the stability of binding. In conclusion, our data reveal that CLEC-2 is an adhesive receptor that supports platelet arrest to podoplanin under venous shear. Src/Syk-dependent signalling stabilises platelet adhesion to podoplanin, providing a possible molecular mechanism contributing to the lymphatic defects of Syk-deficient mice. PMID- 25694216 TI - A superamphiphobic coating with an ammonia-triggered transition to superhydrophilic and superoleophobic for oil-water separation. AB - Superhydrophilic and superoleophobic materials are very attractive for efficient and cost-effective oil-water separation, but also very challenging to prepare. Reported herein is a new superamphiphobic coating that turns superhydrophilic and superoleophobic upon ammonia exposure. The coating is prepared from a mixture of silica nanoparticles and heptadecafluorononanoic acid-modified TiO2 sol by a facile dip-coating method. Commonly used materials, including polyester fabric and polyurethane sponge, modified with this coating show unusual capabilities for controllable filtration of an oil-water mixture and selective removal of water from bulk oil. We anticipate that this novel coating may lead to the development of advanced oil-water separation techniques. PMID- 25694215 TI - Brain systems underlying encounter expectancy bias in spider phobia. AB - Spider-phobic individuals are characterized by exaggerated expectancies to be faced with spiders (so-called encounter expectancy bias). Whereas phobic responses have been linked to brain systems mediating fear, little is known about how the recruitment of these systems relates to exaggerated expectancies of threat. We used fMRI to examine spider-phobic and control participants while they imagined visiting different locations in a forest after having received background information about the likelihood of encountering different animals (spiders, snakes, and birds) at these locations. Critically, imagined encounter expectancies modulated brain responses differently in phobics as compared with controls. Phobics displayed stronger negative modulation of activity in the lateral prefrontal cortex, precuneus, and visual cortex by encounter expectancies for spiders, relative to snakes or birds (within-participants analysis); these effects were not seen in controls. Between-participants correlation analyses within the phobic group further corroborated the hypothesis that these phobia specific modulations may underlie irrationality in encounter expectancies (deviations of encounter expectancies from objective background information) in spider phobia; the greater the negative modulation a phobic participant displayed in the lateral prefrontal cortex, precuneus, and visual cortex, the stronger was her bias in encounter expectancies for spiders. Interestingly, irrationality in expectancies reflected in frontal areas relied on right rather than left hemispheric deactivations. Our data accord with the idea that expectancy biases in spider phobia may reflect deficiencies in cognitive control and contextual integration that are mediated by right frontal and parietal areas. PMID- 25694217 TI - Effects of sitagliptin on counter-regulatory and incretin hormones during acute hypoglycaemia in patients with type 1 diabetes: a randomized double-blind placebo controlled crossover study. AB - AIMS: To assess whether the dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin affects glucagon and other counter-regulatory hormone responses to hypoglycaemia in patients with type 1 diabetes. METHODS: We conducted a single-centre, randomized, double-blind, placebo-controlled, three-period crossover study. We studied 16 male patients with type 1 diabetes aged 18-52 years, with a diabetes duration of 5-20 years and intact hypoglycaemia awareness. Participants received sitagliptin (100 mg/day) or placebo for 6 weeks and attended the hospital for three acute hypoglycaemia studies (at baseline, after sitagliptin treatment and after placebo). The primary outcome was differences between the three hypoglycaemia study days with respect to plasma glucagon responses from the initialization phase of the hypoglycaemia intervention to 40 min after onset of the autonomic reaction. RESULTS: Sitagliptin treatment significantly increased active levels of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1. No significant differences were observed for glucagon or adrenergic counter-regulatory responses during the three hypoglycaemia studies. Growth hormone concentration at 40 min after occurrence of autonomic reaction was significantly lower after sitagliptin treatment [median (IQR) 23 (0.2-211.0) mEq/l] compared with placebo [median (IQR) 90 (8.8-180) mEq/l; p = 0.008]. CONCLUSIONS: Sitagliptin does not affect glucagon or adrenergic counter regulatory responses in patients with type 1 diabetes, but attenuates the growth hormone response during late hypoglycaemia. PMID- 25694218 TI - A region-matching method for pulse transit time estimation: potential for improving the accuracy in determining carotid femoral pulse wave velocity. AB - Carotid femoral pulse wave velocity (cfPWV) is the 'gold standard' for assessment of arterial stiffness. The reliability of cfPWV measurement depends on the estimation of pulse transit time (PTT). This study aimed to validate a region matching method for determining PTT and cfPWV against the existing 'foot-to-foot' methods. A cohort of 81 subjects (33 males and 48 females) aged 25-80 (45.1+/ 15.7 years) were studied. PTTs were estimated by the region matching and 'foot-to foot' methods ('diastole minimum', 'maximum first derivative', 'maximum second derivative' and 'tangent intersection' methods) with manual identification as the reference method and were subsequently used to calculate cfPWV. In a subgroup of 30 individuals, the measurements were repeated after 1 h. There were excellent correlations between cfPWV obtained by the reference method and all the estimated methods (r>0.9, P<0.001 for all), except the diastole minimum method (r=0.793, P<0.001). The region-matching method yielded cfPWV with a better accuracy (mean difference=-0.161 m s(-1), limits of agreement: -0.79 to 0.46 m s(-1)) and repeatability (mean difference=-0.228 m s(-1), intraclass correlation coefficient=0.957) comparing with the 'foot-to-foot' methods. These results demonstrate that the proposed region-matching method is more accurate and suitable for PTT estimation and cfPWV measurement. PMID- 25694219 TI - The Freiburg sport therapy program for eating disordered outpatients: a pilot study. AB - PURPOSE: Many patients with anorexia or bulimia nervosa use physical activity as a method to influence weight and shape and/or exercise in a compulsive manner. This form of exercising is associated with a more severe illness and higher relapse rates. In a proof-of-concept study, effects of a newly developed sport therapy program aiming to reduce unhealthy exercising were assessed. METHODS: Thirty-six patients with eating disorders took part in four group terms of the program, each lasting 3 months. They were compared to a matched control group. Main outcome criterion was a reduction in the total score of the commitment to exercise scale (CES). RESULTS: In the completer analysis, we found statistically significant reductions in the CES total score over time (time * group; p = 0.003) and significant improvements in overall eating psychopathology and quality of life (pre -> post). The dropout rate was high (34 %), mainly due to external reasons (time schedule, etc.). CONCLUSIONS: Findings point to specific effects of a newly developed outpatient sport therapy program for eating disorders. Detailed assessments of patients before assigning them to the program will be necessary to reduce dropout rates. The next step has to be a randomized controlled study. PMID- 25694220 TI - Comparison of optical properties of chromophoric dissolved organic matter (CDOM) in alpine lakes above or below the tree line: insights into sources of CDOM. AB - Here we investigated absorption and fluorescence properties of chromophoric dissolved organic matter (CDOM) in 15 alpine lakes located below or above the tree line to determine its source and composition. The results indicate that the concentrations of CDOM in below-tree-line lakes are significantly higher than in above-tree-line lakes, as evidenced from the absorption coefficients of a250 and a365. The intensities of the protein-like and humic-like fluorescence in below tree-line lakes are higher than in above-tree-line lakes as well. Three fluorescent components were identified using parallel factor analysis (PARAFAC) modelling. Component 1 is probably associated with biological degradation of terrestrial humic component. The terrestrial humic-like component 2 is only found in below-tree-line lakes. The protein-like or phenolic component 3 is dominant in above-tree-line lakes, which is probably more derived from autochthonous origin. In this study, (1) higher a250/a365 and S275-295 values indicate smaller molecular weights of CDOM in above-tree-line lakes than in below-tree-line lakes, and smaller molecular weights at the surface than at 2.0 m depth; (2) SUVA254 and FI255 results provide evidence of lower percent aromaticity of CDOM in above-tree line lakes; and (3) FI310 and FI370 suggest a strong allochthonous origin at the surface in below-tree-line lakes, and more contribution from autochthonous biological and aquatic bacterial origin in above-tree-line lakes. PMID- 25694221 TI - Endoscopy of gastropods: A novel view of the mantle cavities and gills of the keyhole limpet Diodora aspera and the abalone Haliotis rufescens. AB - The gills, or ctenidia, of marine gastropods serve as the sites for respiratory gas exchange. Cilia on the surface provide the pump that moves water through the mantle cavity and enhance diffusion. Because the gills are housed inside the shell, it is difficult to view them while they are functioning. Published images of gills show contracted, fragile structures that are distorted by the processes of dissection and preservation. Members of the families Fissurellidae (keyhole limpets) and Haliotidae (abalone) have openings in their shells through which water enters and/or exits. I inserted an endoscope connected to a video camera into the openings of the shells of living, non-anaesthetized individuals of the fissurellid Diodora aspera and the haliotid Haliotis rufescens. In both species, the dorsal afferent branchial vessel of the afferent gill axis appeared large and inflated, as did the leaflets that extended from either side of the axis. In D. aspera, the leaflets appeared to fill the mantle cavity and responded to touch, particles, and dye in the water by contracting quickly and slowly re-extending. In contrast, the gills of H. rufescens did not noticeably respond to disturbance. On the other hand, these gills showed a regular pattern of pleats that had not been described in the extensive anatomical literature of these common and economically significant animals. These results provide a novel view of the gastropod mantle cavity as a dynamic space filled by the gills, which divide the mantle cavity into distinct incurrent and excurrent chambers and produce a laminar flow of water through the cavity. PMID- 25694222 TI - Synthesis, characterization, and unique catalytic activities of a fluorinated nickel enolate. AB - We have synthesized a new nickel enolate [(PhCOCF2)Ni(dcpe)][FB(C6F5)3] featuring fluorine atoms on the enolate moiety via B(C6F5)3-promoted C-F bond activation of alpha,alpha,alpha-trifluoroacetophenone. X-ray diffraction study of [(PhCOCF2)Ni(dcpe)][FB(C6F5)3] revealed that the complex had adopted an eta(3) oxallyl coordination mode in the crystal lattice. The reaction of (t)BuNC with [(PhCOCF2)Ni(dcpe)][FB(C6F5)3] resulted in the coordination of isocyanide to the nickel center to form a C-bound enolate complex. The reactions of [(PhCOCF2)Ni(dcpe)][FB(C6F5)3] with aldehydes gave insertion products quantitatively which were fully characterized by NMR spectroscopy. Furthermore, we established unique catalytic applications for [(PhCOCF2)Ni(dcpe)][FB(C6F5)3] toward a Tishchenko reaction, along with a highly selective crossed esterification of alpha,alpha,alpha-trifluoroacetophenones with aldehydes. PMID- 25694223 TI - Assessing the geographic coverage and spatial clustering of illicit drug users recruited through respondent-driven sampling in New York City. AB - We assess the geographic coverage and spatial clustering of drug users recruited through respondent-driven sampling (RDS) and discuss the potential for biased RDS prevalence estimates. Illicit drug users aged 18-40 were recruited through RDS (N = 401) and targeted street outreach (TSO) (N = 210) in New York City. Using the Google Maps APITM, we calculated travel distances and times using public transportation between each participant's recruitment location and the study office and between RDS recruiter-recruit pairs. We used K function analysis to evaluate and compare spatial clustering of (1) RDS vs. TSO respondents and (2) RDS seeds vs. RDS peer recruits. All participant recruitment locations clustered around the study office; however, RDS participants were significantly more likely to be recruited within walking distance of the study office than TSO participants. The TSO sample was also less spatially clustered than the RDS sample, which likely reflects (1) the van's ability to increase the sample's geographic heterogeneity and (2) that more TSO than RDS participants were enrolled on the van. Among RDS participants, individuals recruited spatially proximal peers, geographic coverage did not increase as recruitment waves progressed, and peer recruits were not less spatially clustered than seeds. Using a mobile van to recruit participants had a greater impact on the geographic coverage and spatial dependence of the TSO than the RDS sample. Future studies should consider and evaluate the impact of the recruitment approach on the geographic/spatial representativeness of the sample and how spatial biases, including the preferential recruitment of proximal peers, could impact the precision and accuracy of estimates. PMID- 25694224 TI - Partner Incarceration and African-American Women's Sexual Relationships and Risk: A Longitudinal Qualitative Study. AB - Racialized mass incarceration is associated with racial/ethnic disparities in HIV and other sexually transmitted infections (STIs) in the US. The purpose of this longitudinal qualitative study was to learn about the processes through which partner incarceration affects African-American women's sexual risk. Four waves of in-depth qualitative interviews were conducted in 2010-2011 with 30 women in Atlanta, Georgia (US) who had recently incarcerated partners. Approximately half the sample misused substances at baseline. Transcripts were analyzed using grounded theory. For over half the sample (N = 19), partner incarceration resulted in destitution, and half of this group (N = 9) developed new partnerships to secure shelter or food; most misused substances. Other women (N = 9) initiated casual relationships to meet emotional or sexual needs. When considered with past research, these findings suggest that reducing incarceration rates among African-American men may reduce HIV/STIs among African-American women, particularly among substance-misusing women, as might rapidly linking women with recently incarcerated partners to housing and economic support and drug treatment. PMID- 25694225 TI - Engineering of ribozymes with useful activities in the ancient RNA world. AB - Evidence has been growing that an RNA world existed before DNA- and protein-based life. In this regard, a longstanding research goal has been to develop functional RNAs capable of catalyzing numerous chemical reactions. Much effort has been undertaken in finding RNA enzymes that catalyze the replication of RNA molecules, including the enzymes themselves. This, however, is far from being resolved. Apart from replication, other functionalities that contribute to higher genetic complexity and extended functional space are of high relevance to RNA-world scenarios. We have engineered a variety of hairpin ribozyme descendants possessing activity for RNA recombination, circularization, and oligomerization. Furthermore, we have developed ribozymes that can be regulated by external cofactors such as flavine mononucleotide (FMN), and we have designed a system for RNA-catalyzed RNA aminoacylation as a possible path toward a transition from the RNA world to modern life. PMID- 25694226 TI - Mortality and readmission rates in patients hospitalized for acute decompensated heart failure: a comparison between cardiology and general-medicine service outcomes in an underserved population. AB - BACKGROUND: With recent legislation imposing penalties on hospitals for above average 30-day all-cause readmissions for patients with acute decompensated heart failure (ADHF), there is concern these penalties will more heavily impact hospitals serving socioeconomically vulnerable and underserved populations. HYPOTHESIS: Patients with ADHF and low socioeconomic status have better postdischarge mortality and readmission outcomes when cardiologists are involved in their in-hospital care. METHODS: We retrospectively searched the electronic medical record for patients hospitalized for ADHF from 2001 to 2010 in 3 urban hospitals within a large university-based health system. These patients were divided into 2 groups based on whether a cardiologist was involved in their care or not. Measured outcomes were 30- and 60-day postdischarge mortality and readmission rates. RESULTS: Out of the 7516 ADHF patients, 1434 patients were seen by a cardiologist (19%). These patients had lower 60-day mortality (5.4% vs 7.0%; hazard ratio [HR]: 0.70, 95% confidence interval [CI]: 0.52-0.96, P = 0.034) and lower 30- and 60-day readmission rates (16.7% vs 20.6%; HR: 0.76, 95% CI: 0.66-0.89, P = 0.002, and 26.1% vs 30.2%; HR: 0.81, 95% CI: 0.72-0.92, P = 0.003, respectively). There was no significant difference in the in-hospital mortality between the 2 groups. Compared with other races, whites with systolic HF have marginally lower HF-related readmission rates when treated by cardiologists. CONCLUSIONS: In this cohort of ADHF patients from the Bronx, New York, involvement of a cardiologist resulted in improved short-term mortality and readmission outcomes compared with treatment by general internal medicine. PMID- 25694227 TI - Evaluation of beta-blocker gel and effect of dosing volume for topical delivery. AB - Although topical administration of beta-blockers is desired because of the improved therapeutic efficacy and reduced systemic adverse effects compared with systemic administration in the treatment of infantile hemangioma, the permeation of beta-blockers across skin under finite dose conditions has not been systematically studied and an effective topical beta-blocker formulation for skin application is not available. The present study evaluated the permeation of beta blockers propranolol, betaxolol, and timolol across human epidermal membrane (HEM) from a topical gel in Franz diffusion cells in vitro under various dosing conditions. The effects of occlusion and dosing volume on percutaneous absorption of beta-blockers from the gel were studied. The permeation data were compared with those of finite dose diffusion theory. The results showed that skin permeation of beta-blockers generally could be enhanced two to three times by skin occlusion. The cumulative amounts of beta-blockers permeated across HEM increased with increasing dosing volume. An adequate fit was obtained between the theoretical curve and experimental permeation data, indicating that the experimental results of the gel are consistent with finite dose diffusion theory. In conclusion, the findings suggest the feasibility of using topical gels of beta blockers for infantile hemangioma treatment and topical application with skin occlusion is preferred. PMID- 25694228 TI - Evaluation of fibroblast attachment in root conditioning with Er, Cr:YSGG laser versus EDTA: a SEM study. AB - The regeneration of periodontal support is a main concern in periodontal therapy. This study aims to investigate the efficacy of Er, Cr:YSGG laser and EDTA based conditioning in attachment of fibroblast on root surfaces. This in vitro study was conducted on 81 root plates (6 mm * 4 mm * 1 mm) prepared from 27 single rooted human mature teeth. The samples were divided into three groups: (1) Er, Cr: YSGG laser conditioning with a G6 tip (2.78 um, 0.75 W, pulse duration of 140 us, repetition rate of 20 Hz) for 5-7 s; (2) EDTA conditioning (17%, pH: 8) for 1 min; and (3) the control group which were exposed neither to EDTA nor laser. The viability and proliferation rates assessments were performed using MTT assay on days 3 and 5. In addition, the level of cell attachment was studied using scanning electron microscopy. The data indicated Er, Cr:YSGG conditioning increased cell viability by lapse of time (from days 3-5), with significantly better cell attachment compared to the other groups on days 3 and 5 (P < 0.05). In addition, increasing cell attachment in the EDTA conditioning group compared with the control group was statistically significant on day 5 but not on day 3 (P < 0.05). In conclusion, Er, Cr:YSGG laser conditioning can promote enhance fibroblast attachment on dentinal root surfaces more than EDTA. PMID- 25694229 TI - pH responsiveness of fibrous assemblies of repeat-sequence amphipathic alpha helix polypeptides. AB - We reported previously that our designed polypeptide alpha3 (21 residues), which has three repeats of a seven-amino-acid sequence (LETLAKA)3, forms not only an amphipathic alpha-helix structure but also long fibrous assemblies in aqueous solution. To address the relationship between the electrical states of the polypeptide and its alpha-helix and fibrous assembly formation, we characterized mutated polypeptides in which charged amino acid residues of alpha3 were replaced with Ser. We prepared the following polypeptides: 2Salpha3 (LSTLAKA)3, in which all Glu residues were replaced with Ser residues; 6Salpha3 (LETLASA)3, in which all Lys residues were replaced with Ser; and 2S6Salpha3 (LSTLASA)3; in which all Glu and Lys residues were replaced with Ser. In 0.1M KCl, 2Salpha3 formed an alpha-helix under basic conditions and 6Salpha3 formed an alpha-helix under acid conditions. In 1M KCl, they both formed alpha-helices under a wide pH range. In addition, 2Salpha3 and 6Salpha3 formed fibrous assemblies under the same buffer conditions in which they formed alpha-helices. alpha-Helix and fibrous assembly formation by these polypeptides was reversible in a pH-dependent manner. In contrast, 2S6Salpha3 formed an alpha-helix under basic conditions in 1M KCl. Taken together, these findings reveal that the charge states of the charged amino acid residues and the charge state of the Leu residue located at the terminus play an important role in alpha-helix formation. PMID- 25694230 TI - Efficient Cu-catalyzed atom transfer radical addition reactions of fluoroalkylsulfonyl chlorides with electron-deficient alkenes induced by visible light. AB - Fluoroalkylsulfonyl chlorides, R(f)SO2Cl, in which R(f)=CF3, C4F9, CF2H, CH2F, and CH2CF3, are used as a source of fluorinated radicals to add fluoroalkyl groups to electron-deficient, unsaturated carbonyl compounds. Photochemical conditions, using Cu mediation, are used to produce the respective alpha-chloro beta-fluoroalkylcarbonyl products in excellent yields through an atom transfer radical addition (ATRA) process. Facile nucleophilic replacement of the alpha chloro substituent is shown to lead to further diverse functionalization of the products. PMID- 25694231 TI - Advance and stagnation in the treatment of patients with lymphoma and myeloma: Analysis using population-based cancer registry data in Japan from 1993 to 2006. AB - There have been significant advances in the treatment of patients with lymphoma and myeloma. Although the improvements in survival outcome have been clearly addressed by clinical trials, these studies includes patients who are otherwise healthy and would be eligible for trials that the actual improvement in survival in the general patient population over time is yet to be elucidated. Therefore, we reviewed the cancer-registry data of patients with lymphoma and myeloma in Japan from 1993 to 2006 and estimated relative survival (adjusted for competing causes of death in same-age members of the general population) according to three periods of diagnosis (1993-1997, 1998-2002 and 2003-2006). We also estimated conditional 5-year relative survival (5-year survival rate of patients who have survived 5 years). A total of 26,141 patients were reviewed and analyzed. Relative survival improved in Hodgkin lymphoma (HL, N = 853, +20% improvement), diffuse large B-cell lymphoma (DLBCL, N = 4,919, +14% improvement) and follicular lymphoma (FL, N = 1,333, +13% improvement). In contrast, we found no significant improvement in survival since 1993 in peripheral T-cell lymphoma (PTCL, N = 667, +4% improvement), adult T-cell leukemia/lymphoma (ATLL, N = 2,166, -5% improvement) or multiple myeloma (MM, N = 4,914, -2% improvement). Conditional 5 year survival of HL, DLBCL, FL, PTCL, ATLL and MM was 88, 87, 79, 63, 53 and 45%, respectively. Relative survival of patients with HL, DLBCL and FL significantly improved from 1993 to 2006 in Japan; in contrast, no improvement was seen in other diseases, suggesting unmet need of novel treatment strategies. PMID- 25694232 TI - Regulation of longitudinal esophageal motility in the house musk shrew (Suncus murinus). AB - Suncus murinus (house musk shrew; suncus) is a species of insectivore that has an ability to vomit. Although longitudinal movement of the esophagus would be related to the emetic response, regulatory mechanisms for the suncus esophageal motility are unclear. Therefore, the aim of the present study was to clarify components that regulate esophageal motility in the suncus. An isolated segment of the suncus esophagus was placed in an organ bath, and longitudinal mechanical responses were recorded using a force transducer. Electrical stimulation of the vagus trunk evoked a biphasic contractile response. The first phase of the contractile response was blocked by alpha-bungarotoxin, a blocker of nicotinic acetylcholine receptors on striated muscle cells, whereas the second one was blocked by atropine, a blocker of muscarinic acetylcholine receptors on smooth muscle cells. Next, we investigated whether mast cells are involved in motor functions of the suncus esophagus. Application of a mast cell stimulator, compound 48/80, elicited contractile responses, which was resistant to tetrodotoxin. Exogenous application of serotonin and histamine induced contractile responses. The mast cell activation-mediated contraction was abolished by double desensitization by serotonin and histamine and pre-treatment with indomethacin, a cyclooxygenase inhibitor. The findings show that cholinergic and non-cholinergic transmitters induce longitudinal contraction in the suncus esophagus, which might contribute to esophageal shortening during emesis. Cholinergic transmitters are derived from vagal efferents, and non-cholinergic transmitters, which are thought to be serotonin, histamine and prostaglandins, are released from mast cells. PMID- 25694234 TI - Interfacial nanobubbles on atomically flat substrates with different hydrophobicities. AB - The dependence of the morphology of interfacial nanobubbles on atomically flat substrates with different wettability ranges was investigated by using PeakForce quantitative nanomechanics. Interfacial nanobubbles were formed and imaged on silicon nitride (Si3N4), mica, and highly ordered pyrolytic graphite (HOPG) substrates that were partly covered by reduced graphene oxide (rGO). The contact angles and sizes of those nanobubbles were measured under the same conditions. Nanobubbles with the same lateral width exhibited different heights on the different substrates, with the order Si3N4~mica>rGO>HOPG, which is consistent with the trend of the hydrophobicity of the substrates. PMID- 25694233 TI - Developments in intervertebral disc disease research: pathophysiology, mechanobiology, and therapeutics. AB - Low back pain is a leading cause of disability worldwide and the second most common cause of physician visits. There are many causes of back pain, and among them, disc herniation and intervertebral disc degeneration are the most common diagnoses and targets for intervention. Currently, clinical treatment outcomes are not strongly correlated with diagnoses, emphasizing the importance for characterizing more completely the mechanisms of degeneration and their relationships with symptoms. This review covers recent studies elucidating cellular and molecular changes associated with disc mechanobiology, as it relates to degeneration and regeneration. Specifically, we review findings on the biochemical changes in disc diseases, including cytokines, chemokines, and proteases; advancements in disc disease diagnostics using imaging modalities; updates on studies examining the response of the intervertebral disc to injury; and recent developments in repair strategies, including cell-based repair, biomaterials, and tissue engineering. Findings on the effects of the omega-6 fatty acid, linoleic acid, on nucleus pulposus tissue engineering are presented. Studies described in this review provide greater insights into the pathogenesis of disc degeneration and may define new paradigms for early or differential diagnostics of degeneration using new techniques such as systemic biomarkers. In addition, research on the mechanobiology of disease enriches the development of therapeutics for disc repair, with potential to diminish pain and disability associated with disc degeneration. PMID- 25694235 TI - A survey on signals and systems in ambulatory blood pressure monitoring using pulse transit time. AB - Blood pressure monitoring based on pulse transit or arrival time has been the focus of much research in order to design ambulatory blood pressure monitors. The accuracy of these monitors is limited by several challenges, such as acquisition and processing of physiological signals as well as changes in vascular tone and the pre-ejection period. In this work, a literature survey covering recent developments is presented in order to identify gaps in the literature. The findings of the literature are classified according to three aspects. These are the calibration of pulse transit/arrival times to blood pressure, acquisition and processing of physiological signals and finally, the design of fully integrated blood pressure measurement systems. Alternative technologies as well as locations for the measurement of the pulse wave signal should be investigated in order to improve the accuracy during calibration. Furthermore, the integration and validation of monitoring systems needs to be improved in current ambulatory blood pressure monitors. PMID- 25694237 TI - [Bulgarian rheumatology in the twentieth century : German-Bulgarian collegiality]. PMID- 25694236 TI - Sitagliptin protects proliferation of neural progenitor cells in diabetic mice. AB - Sitagliptin (SIT) is a dipeptidyl peptidase-4 (DPP-4) inhibitor that enhances the effects of incretin hormones, such as Glucose-dependent Insulinotropic Peptide (also known as Gastric Inhibitory Polypeptide, GIP) and Glucagon-Like Peptide 1 (GLP-1). We have now evaluated the effect of SIT on proliferation of neural progenitors in diabetic mice. A condition resembling the non-obese type 2 diabetes mellitus (D2) was achieved by a combination of streptozotocin and nicotinamide (NA-STZ), whereas a type 1-like disease (D1) was provoked by STZ without NA. Non-diabetic mice received vehicle injections. Cell proliferation was estimated by bromodeoxyuridine (BrdU) incorporation in two different regions of the subventricular zone (SVZ), the largest reserve of neural stem cells in the adult brain. SIT treatment did not modify the high fasting blood glucose (BG) levels and intraperitoneal glucose tolerance test (IPGTT) of D1 mice. By contrast, in D2 mice, SIT treatment significantly reduced BG and IPGTT. Both D1 and D2 mice showed a substantial reduction of BrdU labeling in the SVZ. Remarkably, SIT treatment improved BrdU labeling in both conditions. Our findings suggest that SIT would protect proliferation of neural progenitor cells even in the presence of non-controlled diabetic alterations. PMID- 25694238 TI - Comparison of self-rated health and activity limitation as predictors of short term mortality in the older population. PMID- 25694240 TI - Real-time heterogeneous protein-protein interaction between alphaA-crystallin N terminal mutants and alphaB-crystallin using quartz crystal microbalance (QCM). AB - The lens transparency depends on higher concentration of lens proteins and their interactions. alpha-Crystallin is one of the predominant lens proteins, responsible for proper structural and functional architecture of the lens microenvironment, and any alteration of which results in cataract formation. The R12C, R21L, R49C and R54C are the most significant and prevalent alphaA crystallin congenital cataract-causing mutants worldwide. Protein-protein interaction, crucial for lens proper structure and function, was posited to be lost due to point mutation and the elucidation of which could shed light on the molecular basis of cataract. In this conjuncture, we report quartz crystal microbalance (QCM) as a warranted technique for real-time analysis of protein protein interaction between the N-terminal mutants of alphaA-crystallin and alphaB-crystallin. The biophysical characteristics of the mutated proteins were determined by size-exclusion HPLC, far-UV circular dichroism and fluorescence studies. Far-UV circular dichroism spectral analysis displayed slight modifications in beta-sheet of R54C mutant. Altered intrinsic tryptophan fluorescence and decreased bis-ANS fluorescence were observed in all the N terminal mutations revealing the tertiary structural changes and decreased exposure of surface hydrophobicity. An emphatic fall in the chaperone activity was observed in the N-terminal mutants, R12C, R21L and R54C. QCM analysis revealed the occurrence of strong heterogeneous interaction between alphaA crystallin and alphaB-crystallin. Nevertheless, decreased interactions were observed with the N-terminal mutants. In summary, the present study concludes that the loss of interactions between alphaA-crystallin N-terminal mutants and alphaB-crystallin signifies quaternary structural alterations due to mutation in the arginine residues. PMID- 25694241 TI - Does the adolescent patellar tendon respond to 5 days of cumulative load during a volleyball tournament? AB - Patellar tendinopathy (jumper's knee) has a high prevalence in jumping athletes. Excessive load on the patellar tendon through high volumes of training and competition is an important risk factor. Structural changes in the tendon are related to a higher risk of developing patellar tendinopathy. The critical tendon load that affects tendon structure is unknown. The aim of this study was to investigate patellar tendon structure on each day of a 5-day volleyball tournament in an adolescent population (16-18 years). The right patellar tendon of 41 players in the Australian Volleyball Schools Cup was scanned with ultrasound tissue characterization (UTC) on every day of the tournament (Monday to Friday). UTC can quantify structure of a tendon into four echo types based on the stability of the echo pattern. Generalized estimating equations (GEE) were used to test for change of echo type I and II over the tournament days. Participants played between eight and nine matches during the tournament. GEE analysis showed no significant change of echo type percentages of echo type I (Wald chi-square = 4.603, d.f. = 4, P = 0.331) and echo type II (Wald chi-square = 6.070, d.f. = 4, P = 0.194) over time. This study shows that patellar tendon structure of 16-18-year-old volleyball players is not affected during 5 days of cumulative loading during a volleyball tournament. PMID- 25694242 TI - Kruppel-like factor 1 mutations and expression of hemoglobins F and A2 in homozygous hemoglobin E syndrome. AB - The basis for variability of hemoglobin (Hb) F in homozygous Hb E disease is not well understood. We have examined multiple mutations of the Kruppel-like factor 1 (KLF1) gene; an erythroid specific transcription factor and determined their associations with Hbs F and A2 expression in homozygous Hb E. Four KLF1 mutations including G176AfsX179, T334R, R238H, and -154 (C-T) were screened using specific PCR assays on 461 subjects with homozygous Hb E and 100 normal controls. None of these four mutations were observed in 100 normal controls. Among 461 subjects with homozygous Hb E, 306 had high (>=5 %) and 155 had low (<5 %) Hb F. DNA analysis identified the KLF1 mutations in 35 cases of the former group with high Hb F, including the G176AfsX179 mutation (17/306 = 5.6 %), T334R mutation (9/306 = 2.9 %), -154 (C-T) mutation (7/306 = 2.3 %), and R328H mutation (2/306 = 0.7 %). Only two subjects in the latter group with low Hb F carried the G176AfsX179 and -154 (C-T) mutations. Significant higher Hb A2 level was observed in those of homozygous Hb E with the G176AfsX179 mutation as compared to those without KLF1 mutations. These results indicate that KLF1 is among the genetic factors associated with increased Hbs F and A2, and in combination with other factors could explain the variabilities of these Hb expression in Hb E syndrome. PMID- 25694243 TI - The differential effect of low- versus high-frequency random noise stimulation in the treatment of tinnitus. AB - Tinnitus is the sensation of a ringing, buzzing, roaring or hissing sound in the absence of an external sound. As tinnitus has been related to hyperactivity and synaptic plasticity changes in the central auditory system, invasive and noninvasive neuromodulation methods have been used to interfere with this underlying mechanism to reduce tinnitus loudness and distress. Recently, transcranial random noise stimulation applied over the auditory cortex induced a more pronounced effect on tinnitus loudness than transcranial direct current and alternating current stimulation. We performed tRNS over the temporoparietal cortex in 154 patients with non-pulsatile tinnitus. A total of 119 patients received low-frequency tRNS (lf-tRNS), 19 high-frequency tRNS (hf-tRNS) and 16 whole frequency spectrum tRNS (wf-tRNS). The effect was evaluated by using the numeric rating scale loudness and distress pre- and post-stimulation. This study revealed a significant reduction in tinnitus loudness when lf-tRNS and hf-tRNS were applied as well as a reduction in tinnitus-related distress with lf-tRNS. Moreover, we observed a significantly more pronounced reduction in loudness and distress in pure tone (PT) tinnitus compared to narrow band noise (NBN) tinnitus when hf-tRNS was applied, a difference that could not be obtained with lf-tRNS. Based on these results, tRNS might be a promising treatment option for non pulsatile tinnitus; however, we cannot yet provide a clear mechanistic explanation for the different results obtained with different types of stimulation, i.e., lf-tRNS, hf-tRNS and wf-tRNS, or with different types of tinnitus, i.e., PT and NBN tinnitus. PMID- 25694244 TI - Passive perceptual learning versus active searching in a novel stimuli vigilance task. AB - A criticism of laboratory vigilance or sustained attention research is the employment of static monotonous tasks with repetitive targets as opposed to the use of dynamic tasks with novel target stimuli. Unfortunately dynamic tasks employing novel stimuli may result in the mixture of two cognitive processes: active sustained attention search and passive perceptual learning. Moreover, the relative engagement of these two processes may depend on individual differences. In the present study, we examined this by having participants perform a dynamic auditory vigilance task with rare novel targets. In addition, some participants performed this task while also performing a secondary motor tracking task, a dual task scenario. In the dual-task scenario, participants who failed to accurately detect the first target stimuli showed improvements in their tracking performance with time-on-task, suggesting reserves of attention. This improvement in tracking performance was not evident for those who accurately detected the first target stimuli, as their attention was likely actively engaged (searching). In addition, participants in the dual-task scenario who accurately detected the first target stimuli reported high workload and increased post-task tense arousal, results characteristic of participants performing static vigilance tasks. These results indicate the possibility that in a dynamic vigilance task with novel target stimuli participants may diverge in how they approach the task. Some participants will actively monitor the display for targets (search), whereas others will passively learn the target stimuli. Thus, these tasks may pose significant challenges to researchers who wish to examine vigilance in isolation from perceptual learning. PMID- 25694245 TI - Beyond the SNARC effect: distance-number mapping occurs in the peripersonal space. AB - Estimating distance of objects relative to one's body is important for interaction with the environment. Given that distance is an interval of magnitude describing space, distance and the commonly used estimations of magnitude, i.e., numbers, may share a common representation system (the ATOM theory, Walsh in Trends Cogn Sci 7(11):483-488, 2003). The current study systematically examined the association between distance and number representations on both the sagittal and transverse axes on the transverse plane in the peripersonal space. Participants in Experiment 1 judged the parity of digits by pressing one of two buttons (both were in front of participants): One was near the body and the other away from it. We found that near responses were faster when paired with smaller numbers and far responses with larger numbers. When one button was set in front and the other in back in Experiment 2, no mapping was found. In Experiment 3, when both buttons were on the right side aligned with the transverse axis, small near and large-far mapping were found. However, no such effect was found on the left side. These results suggest that numbers are mapped onto the whole transverse plane of the peripersonal space, not only a left-right oriented number line. PMID- 25694246 TI - Active Surveillance for Adverse Events Within 90 Days: The Standard for Reporting Surgical Outcomes After Pancreatectomy. AB - BACKGROUND: The rate of adverse events after pancreatectomy is widely reported as a measure of surgical quality. However, morbidity data are routinely acquired retrospectively and often are reported at 30 days. The authors hypothesized that morbidity after pancreatectomy is therefore underreported. They sought to compare rates of adverse events calculated at multiple time points after pancreatectomy. METHODS: The authors instituted an active surveillance system to detect, categorize, and grade the severity of all adverse events after pancreatectomy, using the modified Accordion system and International Study Group of Pancreatic Surgery definitions. All patients and clinical events were monitored directly for at least 90 days after surgery. RESULTS: Of 315 consecutively monitored patients, 239 (76 %) experienced 500 unique adverse events. The absolute number of unique adverse events increased by 32 % between index discharge and 90 days and by 10 % between 30 and 90 days. The number of severe adverse events increased by 96 % between discharge and 90 days and by 29 % between 30 and 90 days. In this study, 16 % of the patients experienced at least one severe adverse event within the index hospitalization, 24 % within 30 postoperative days, and 29 % within 90 days. Among the 80 readmissions that occurred within 90 days, 28 (35 %) occurred later than 30 days after pancreatectomy. CONCLUSIONS: Approximately one-third of severe adverse events and readmissions are reported more than 30 days after surgery. All adverse events that occur within 90 days of surgery must be identified and reported for accurate characterization of the morbidity associated with pancreatectomy. PMID- 25694247 TI - An investigation into the origin of the biased agonism associated with the urotensin II receptor activation. AB - The urotensin II receptor (UTR) has long been studied mainly for its involvement in the cardiovascular homeostasis both in health and disease state. Two endogenous ligands activate UTR, i.e. urotensin II (U-II) and urotensin II related peptide (URP). Extensive expression of the two ligands uncovers the diversified pathophysiological effects mediated by the urotensinergic system such as cardiovascular disorders, smooth muscle cell proliferation, renal disease, diabetes, and tumour growth. As newly reported, U-II and URP have distinct effects on transcriptional activity, cell proliferation, and myocardial contractile activities supporting the idea that U-II and URP interact with UTR in a distinct manner (biased agonism). To shed light on the origin of the divergent activities of the two endogenous ligands, we performed a conformational study on URP by solution NMR in sodium dodecyl sulfate micelle solution and compared the obtained NMR structure of URP with that of hU-II previously determined. Finally, we undertook docking studies between URP, hU-II, and an UT receptor model. PMID- 25694248 TI - Nanomicroarray and multiplex next-generation sequencing for simultaneous identification and characterization of influenza viruses. AB - Conventional methods for detection and discrimination of influenza viruses are time consuming and labor intensive. We developed a diagnostic platform for simultaneous identification and characterization of influenza viruses that uses a combination of nanomicroarray for screening and multiplex next-generation sequencing (NGS) assays for laboratory confirmation. The nanomicroarray was developed to target hemagglutinin, neuraminidase, and matrix genes to identify influenza A and B viruses. PCR amplicons synthesized by using an adapted universal primer for all 8 gene segments of 9 influenza A subtypes were detected in the nanomicroarray and confirmed by the NGS assays. This platform can simultaneously detect and differentiate multiple influenza A subtypes in a single sample. Use of these methods as part of a new diagnostic algorithm for detection and confirmation of influenza infections may provide ongoing public health benefits by assisting with future epidemiologic studies and improving preparedness for potential influenza pandemics. PMID- 25694249 TI - Boron-doped, carbon-coated SnO2/graphene nanosheets for enhanced lithium storage. AB - Heteroatom doping is an effective method to adjust the electrochemical behavior of carbonaceous materials. In this work, boron-doped, carbon-coated SnO2 /graphene hybrids (BCTGs) were fabricated by hydrothermal carbonization of sucrose in the presence of SnO2/graphene nanosheets and phenylboronic acid or boric acid as dopant source and subsequent thermal treatment. Owing to their unique 2D core-shell architecture and B-doped carbon shells, BCTGs have enhanced conductivity and extra active sites for lithium storage. With phenylboronic acid as B source, the resulting hybrid shows outstanding electrochemical performance as the anode in lithium-ion batteries with a highly stable capacity of 1165 mA h g(-1) at 0.1 A g(-1) after 360 cycles and an excellent rate capability of 600 mA h g(-1) at 3.2 A g(-1), and thus outperforms most of the previously reported SnO2 based anode materials. PMID- 25694250 TI - [Cancer and family: tasks and stress of relatives]. AB - BACKGROUND: Relatives are the primary and existential resource of cancer patients, while at the same time experiencing substantial distress themselves. OBJECTIVES: This article presents a description of tasks, roles and distress factors, the prevalence of psychosocial distress, description of risk factors in families contributing to dysfunctional coping, options and empirical evidence for the efficacy of psychosocial support. METHODS: Evaluation of registry data, analysis of case reports, discussion of basic research findings, meta-analyses and expert judgments. RESULTS: Psychosocial distress in relatives of cancer patients is comparable to the degree of distress experienced by the patients and is sometimes even higher. Distress in relatives is still underrecognized, underreported and undertreated. Hostile interaction patterns, low emotional expression and high conflict tendencies impair coping with cancer and its treatment. Psychosocial support for the family of cancer patients improves coping behavior and the quality of life both in relatives and patients. CONCLUSION: Professional and lay caregivers need to adopt a social perspective on cancer whereby participation and inclusion of relatives in the treatment, acknowledgment of their engagement and recognition of their distress is beneficial for both patients and their relatives. Screening for psychosocial distress in relatives is recommended, attention should be drawn to psychosocial support services and utilization should be encouraged. PMID- 25694251 TI - [Do new oral therapies show advantages in the basal therapy of multiple sclerosis? Pro]. PMID- 25694252 TI - [Do new oral therapies show advantages in the basal therapy of multiple sclerosis? Con]. PMID- 25694253 TI - Multiparameter-based bioassay of 2-(4-chlorophenyl)-4-(4-methoxyphenyl) quinazoline, a newly-synthesized quinazoline derivative, toward Microcystis aeruginosa HAB5100 (cyanobacteria). AB - Quinazoline derivatives have wide biological activities and therapeutic properties, implying their potential for development and application on a large scale. In the present study, 2-(4-chlorophenyl)-4-(4-methoxyphenyl) quinazoline (CMQ), was selected to examine its effect on unicellular cyanobacteria, Microcystis aeruginosa by evaluating growth, physiological and molecular responses. Growth was inhibited by CMQ, with a 96 h EC50 of 1.93 +/- 0.19 mg L( 1). The up-regulated expression of prx was shown, reflecting that oxidative stress might be a toxic factor of CMQ. At higher concentrations of CMQ, the quantum yields of Y(II) and Y(NPQ) in photosystem II decreased seriously and Y(NO) increased sharply, and psbA gene encoding for D1 protein was over expressed. These results demonstrated that high concentrations of CMQ had different inhibitory targets associated with photosystem electron transport and with sites beyond the electron transport chain, leading to severe toxicity. PMID- 25694254 TI - Characterization and risk assessment of polychlorinated biphenyls in city park soils of Xi'an, China. AB - Polychlorinated biphenyl (PCB) concentrations in surface soil samples (0-10 cm) from 23 city parks (8 urban and 15 suburban) from Xi'an, China were presented. The average concentration of Sigma7 PCBs among all the sites was 1.68 ng g(-1) dry weight. High detection frequency (100 %) of PCB 28 and PCB 52 suggested wide occurrence of PCB contaminations in Xi'an. Among these PCBs, PCB 28, 52 and 153 were the most dominant compounds (14.9 %, 39.3 % and 9.5 % of the Sigma7 PCBs on average, respectively). "Urban fractionation effect" was found in Xi'An. In other words, PCB concentrations were higher in the urban city park soils than those in suburban park soils. The PCB contamination in Xi'an city park soils were at a low level based on the Dutch guideline. However, dioxin-like PCB congeners were detected from 12 parks, which indicated further investigation was urgently required in future. Furthermore, total PCB concentrations were used to evaluate the cancer risk via ingestion, dermal and inhalation and the results showed that the total cancer risk was at the very low level in this area. PMID- 25694255 TI - Balancing my disease: women's perspectives of living with inflammatory bowel disease. AB - AIMS AND OBJECTIVES: The purpose of this research was to examine the lived experiences of women with inflammatory bowel disease, by specifically exploring their management of their illness after diagnosis. BACKGROUND: Inflammatory bowel disease is a chronic autoimmune disease that has no known cause or cure. It is composed of two types of conditions: Crohn's disease and Ulcerative Colitis which have similar signs and symptoms, but have distinct physiological properties. Currently, Canada has the highest reported prevalence and incidence rates of inflammatory bowel disease in the world (Molodecky et al. 2012). Despite these increasing rates, there is a lack of knowledge and understanding of the burdens associated with inflammatory bowel disease, in particular from the participant's perspective. DESIGN & METHODS: Heuristic phenomenology was the theoretical orientation used for this study. Eight women (aged 30-50 years) with inflammatory bowel disease who resided in Southern Ontario were recruited. Each participant completed background questionnaires and a one-on-one semi-structured interview. RESULTS: Several salient themes were identified; however, this paper will solely focus on one theme, balancing my disease. To achieve balance, the women described changing dietary behaviours, adjusting daily routines and managing symptoms through medications. These modifications were described as being important in controlling inflammatory bowel disease symptomatology on a day-to-day basis. CONCLUSION: There are many triggers for inflammatory bowel disease symptomatology. As such, the means in which those with inflammatory bowel disease manage their conditions varies. Participants discussed using a combination of strategies to control their condition. RELEVANCE TO CLINICAL PRACTICE: This information is important for patients living with inflammatory bowel disease, their support people, and healthcare professionals to identify various key strategies to improve the quality of life and well-being of those affected by inflammatory bowel disease. Furthermore, this research provided a voice to women diagnosed with inflammatory bowel disease by allowing them to openly convey their experiences of living with inflammatory bowel disease. PMID- 25694256 TI - Persistent systemic monocyte and neutrophil activation in neonatal encephalopathy. AB - AIM: Circulating immune cell activation is associated with worse outcome in adult and animal models of brain injury. Our aim was to profile the systemic inflammatory response over the first week of life in infants at risk of neonatal encephalopathy and correlate early neutrophil and monocyte endotoxin and activation responses with outcome. METHODS: Prospective observational study in a tertiary referral university hospital including 22 infants requiring resuscitation at birth who had serial (five time points) neutrophil and monocyte CD11b (marker of cell adhesion) (intracellular Reactive oxygen intermediates) ROI (cell activation), and Toll-like receptor (endotoxin recognition) before and after endotoxin stimulation ex vivo compared to neonatal controls. RESULTS: All neonates requiring resuscitation at delivery (n = 122 samples) had higher neutrophil and monocyte CD11b and TLR-4 expressions compared with adults and neonatal controls. Neonates with abnormal neuroimaging and/or severe neonatal encephalopathy had increased CD11b, ROI and TLR-4. Increased PMN TLR-4 expression was associated with increased mortality in infants with neonatal encephalopathy (NE). CONCLUSION: Innate immune dysregulation in the first week of life is associated with severity of outcome in neonatal brain injury in this cohort and may be amenable to immunomodulation. PMID- 25694257 TI - Comparing vaginal misoprostol versus Foley catheter plus vaginal isosorbide mononitrate for labor induction. AB - OBJECTIVE(S): To compare the effectiveness and safety of intra-cervical Foley catheter combined with intra-vaginal isosorbide mononitrate (IMN) versus intra vaginal misoprostol for cervical ripening and labor induction in pregnant women with unripe cervices. METHODS: Open-labeled randomized controlled trial in Cairo university hospital, Cairo, Egypt during 2012-2014. Three hundred and ninety-five pregnant women at term or post-term with an indication for labor induction and unripe cervix were included in the study. The subjects were randomly divided into two groups. Vaginal misoprostol was used in group 1 (n = 197) and intra-cervical Foley catheter plus vaginal IMN in group 2 (n = 198). Our main outcome measure was cesarean section rate. RESULTS: Among the 395 included patients there were significantly lower duration of induction of labor (p < 0.001) in group 1with lower cesarean section rates [22.8% in group 1versus 33.3% in group 2; RR 0.7 (0.6-0.9), (p = 0.020)]. Whereas the uterine hyperstimulation (p < 0.001) was significantly higher in group 1. There were no significant differences between both groups as regard patients' demographic characteristics. CONCLUSIONS(S): Vaginal misoprostol is more effective but less safe than Foley catheter combined with vaginal IMN for induction of labor in term and post-term pregnancy. PMID- 25694258 TI - Breastfeeding initiation rates among immigrant women in central Italy between 2006 and 2011. AB - OBJECTIVE: This study was aimed at evaluating differences in breastfeeding initiation rates by maternal place of birth among women giving birth in one of 14 hospitals in Lazio, Italy, between 2006 and 2011. METHODS: The data on 14 hospitals for this study were taken from a survey on healthy newborns carried out during the month of October each year. It collected information on maternal characteristics and infant feeding during the hospital stay. The exposure variable was maternal place of birth. The outcome variable was infant feeding during hospital stay classified as exclusive breastfeeding, predominant breastfeeding (PBF), complementary feeding or formula feeding. Both a descriptive analysis and a logistic regression on infant feeding (exclusive/PBF versus partial or non-breastfeeding) by maternal place of birth were carried out. The logistic regression model was adjusted for confounding factors. A random effect model was used to take into account the correlation of data among the hospitals. RESULTS: Among the 6505 mothers included in this study, 18.7% were born in non industrialized countries. Overall, 64.9% of mothers exclusively breastfed their babies, with lower prevalence among Asiatic mothers. The logistic model confirmed that breastfeeding was lower among infants born to Asian mothers (OR: 0.52; 95% CI: 0.35-0.77) compared with other groups, taking into account the effect of the other variables included in this model. Intracluster correlation was equal to 26%, showing that the hospital's model of care is a strong predictor of the initiation of breastfeeding. CONCLUSIONS: These data are useful for targeting disadvantaged groups when promoting breastfeeding. PMID- 25694259 TI - 0-7-21 hypofractionated palliative radiotherapy: an effective treatment for advanced head and neck cancers. AB - OBJECTIVE: We report our experience in providing palliative radiotherapy (RT) to patients with head and neck cancers (HNCs). Our hypofractionated regimen, "0-7 21", treats patients with 24 Gy in three fractions. METHODS: Patients, disease and response data were retrieved for candidates of 0-7-21 from 2005 to 2012. Primary end points included symptom and tumour size responses to RT based on response evaluation criteria in solid tumours (RECIST) guidelines. Secondary end points included progression-free survival (PFS) within the irradiated field, overall survival (OS) and symptomatic PFS (SPFS), calculated using Kaplan-Meier method and adverse events. Cox proportional hazards regression and logistic regression were used to investigate for prognostic factors. RESULTS: A total of 110 patients were included. Among the patients, 40% and 31% had complete response for symptoms and tumour size, respectively; 42% and 50% had partial response for symptoms and tumour size, respectively; and 15% had stability of symptoms and tumour size. Median 6-month OS was 51%, and PFS within the irradiated field was 39%. Planning target volume was predictive of OS (p < 0.001), PFS (p < 0.001) and SPFS (p < 0.005), while higher TNM stage was associated with poorer tumour response (p = 0.02). CONCLUSION: 0-7-21 is an effective and well-tolerated palliative RT regimen for patients with HNC. There was excellent symptom and local control with acceptable toxicity profile in these patients. ADVANCES IN KNOWLEDGE: This is the first study to describe the outcomes of 0-7-21 in treating advanced HNCs. The positive results suggest that 0-7-21 provides excellent palliation with minimal toxicity, with significantly less on-treatment time than current published palliative RT regimen. PMID- 25694260 TI - A new method of measuring the stiffness of corpus cavernosum penis with ShearWaveTM Elastography. AB - OBJECTIVE: To evaluate the feasibility of measuring the stiffness of corpus cavernosum penis (CCP) with ShearWaveTM Elastography (SWE; SuperSonic Imagine, Aix-en-Provence, France). METHODS: 40 healthy volunteers with ages ranging from 19 to 81 years (mean, 36 years; standard deviation, 17 years) were selected in this study. The ultrafast ultrasound device Aixplorer((r)) (SuperSonic Imagine) was used for the research and the probe selected was SuperLinearTM SL15-4 (SuperSonic Imagine). The shear wave stiffness (SWS) of CCP was measured using SWE images. The measurement indexes of SWS included (1) SWS of CCP measured in the transverse section (SWS-T), (2) SWS of CCP measured in the longitudinal section (SWS-L) and (3) mean of SWS-T and SWS-L (SWS-M). The interval between hormone test and SWE examination of each subject was less than 7 days. The paired t-test was used to analyse the differences between SWS-T and SWS-L. The Pearson correlation was used to analyse the correlation of SWS of CCP with age as well as with sex hormone levels. RESULTS: There was no significant difference between SWS T and SWS-L (p > 0.05). SWS (SWS-T, SWS-L, SWS-M) was negatively correlated with age and oestradiol value, and SWS (SWS-T, SWS-L, SWS-M) was positively correlated with testosterone value. CONCLUSION: SWE could serve as a new non-invasive method of evaluating the stiffness of CCP. ADVANCES IN KNOWLEDGE: It is the first time that we have discussed the feasibility of measuring the stiffness of CCP with SWE and analysed the correlation of SWS of CCP with age as well as with sex hormone levels. PMID- 25694261 TI - Contemporary and emerging strategies for eliminating human African trypanosomiasis due to Trypanosoma brucei gambiense: review. AB - OBJECTIVES: To review current and emerging tools for Gambiense HAT control and elimination, and propose strategies that integrate these tools with epidemiological evidence. METHODS: We reviewed the scientific literature to identify contemporary and emerging tools and strategies for controlling and eliminating Gambiense HAT. Through an iterative process involving key stakeholders, we then developed comprehensive scenarios leading to elimination, considering both established and new tools for diagnosis, case treatment and vector control. RESULTS: Core components of all scenarios include detecting and treating cases with established or emerging techniques. Relatively more intensive scenarios incorporate vector control. New tools considered include tiny targets for tsetse fly control, use of rapid diagnostic tests and oral treatment with fexinidazole or oxaboroles. Scenarios consider the time when critical new tools are expected to become ready for deployment by national control programmes. Based on a review of the latest epidemiological data, we estimate the various interventions to cover 1,380,600 km(2) and 56,986,000 people. CONCLUSIONS: A number of new tools will fill critical gaps in the current armamentarium for diagnosing and treating Gambiense HAT. Deploying these tools in endemic areas will facilitate the comprehensive and sustainable control of the disease considerably and contribute to the ultimate goal of elimination. PMID- 25694262 TI - Lipid-Conjugation of Endogenous Neuropeptides: Improved Biotherapy against Human Pancreatic Cancer. AB - Neuropeptides are small neuronal signaling molecules that act as neuromodulators for a variety of neural functions including analgesia, reproduction, social behavior, learning, and memory. One of the endogenous neuropeptides-Met Enkephalin (Met-Enk), has been shown to display an inhibitory effect on cell proliferation and differentiation. Here, a novel lipid-modification approach is shown to create a small library of neuropeptides that will allow increased bioavailability and plasma stability after systemic administration. It is demonstrated, on an experimental model of human pancreatic adenocarcinoma, that lipid conjugation of Met-Enk enhances its tumor suppression efficacy compared to its nonlipidated counterparts, both in vitro and in vivo. More strikingly, the in vivo studies show that a combination therapy with a reduced concentration of Gemcitabine has suppressed the tumor growth considerably even three weeks after the last treatment. PMID- 25694263 TI - Probing the interaction of distamycin A with S100beta: the "unexpected" ability of S100beta to bind to DNA-binding ligands. AB - DNA-minor-groove-binding ligands are potent antineoplastic molecules. The antibiotic distamycin A is the prototype of one class of these DNA-interfering molecules that have been largely used in vitro. The affinity of distamycin A for DNA is well known, and the structural details of the complexes with some B-DNA and G-quadruplex-forming DNA sequences have been already elucidated. Here, we show that distamycin A binds S100beta, a protein involved in the regulation of several cellular processes. The reported affinity of distamycin A for the calcium(II)-loaded S100beta reinforces the idea that some biological activities of the DNA-minor-groove-binding ligands arise from the binding to cellular proteins. PMID- 25694264 TI - Formal asymmetric catalytic thiolation with a bifunctional catalyst at a water oil interface: synthesis of benzyl thiols. AB - The enantioselective conjugated addition of tritylthiol to in situ generated ortho-quinone methides (o-QMs) is catalyzed by an acid-base bifunctional squaramide organocatalyst. The transformation proceeds with high yield (up to 99 %) and stereoselectivity (up to 97:3 e.r.) using water as solvent under mild conditions. The catalyst system provides a new strategy for the synthesis of optically active benzyl mercaptans. Control experiments suggested that o-QMs are generated by the tertiary amine moiety of the squaramide organocatalyst and that the water-oil biphase is crucial for achieving high reactivity and stereoselectivity. PMID- 25694265 TI - Racial disparities in laryngeal cancer treatment and outcome: A population-based analysis of 24,069 patients. AB - OBJECTIVES: To determine the impact of race on laryngeal preservation strategies and overall survival (OS) for laryngeal squamous cell carcinoma (SCC). STUDY DESIGN: Retrospective, national cancer database analysis. METHODS: Data were extracted from the Surveillance, Epidemiology, and End Results database. Chi square test, Kaplan-Meier method, and Cox regression models were employed in SPSS 20.0 (Armonk, NY: IBM Corp.) for data analyses. RESULTS: A total of 24,069 patients with laryngeal SCC were identified. Of these, 18,166 (75.5%) patients were white, 3,475 (14.4%) were black, 1,608 (6.7%) were Hispanic, and 820 (3.4%) were Asian. Compared with other races, black patients were more likely to be diagnosed at a younger age (P < 0.001), undergo lymph node dissection (P < 0.001), have nodal metastasis (P < 0.001), be with advanced stage disease (P < 0.001), and be unmarried (P < 0.001). Black patients with T1 to T2 and T3 disease were more likely to undergo total laryngectomy as compared with white patients (T1-2: 8.2% vs. 4.3%; P < 0.001; T3: 28.4% vs. 24.3%; P = 0.023). For patients with T4 disease, however, rates of primary radiotherapy among black patients were higher (40.5% vs. 35.7%; P = 0.015). The 5-year OS for white, black, Hispanic, and Asian patients were 60.6%, 52.7%, 59.5% and 65.7% (P < 0.001). This significant 5-year OS difference by race persisted regardless of age, gender, year of diagnosis, primary treatment, nodal status, or tumor grade. On multivariate analysis, race remained an independent prognostic factor for OS. CONCLUSIONS: Race is an independent prognostic factor for OS. Further studies are warranted to evaluate causes for racial disparities and discrepancies in OS and laryngeal preservation strategies. PMID- 25694266 TI - Preoperative Opioid Misuse is Associated With Increased Morbidity and Mortality After Elective Orthopaedic Surgery. AB - BACKGROUND: Many patients having discretionary orthopaedic surgery take opioids daily, either with a prescription or illicitly, however little is known regarding the prevalence and effect of high-risk opioid use (eg, abuse, dependence) in the perioperative orthopaedic setting. QUESTIONS/PURPOSES: We sought (1) to determine the prevalence of opioid abuse and dependence in patients undergoing major elective orthopaedic surgery; (2) to characterize the relationship of opioid abuse and dependence with in-hospital postoperative mortality and adverse events, failure to rescue, prolonged length of stay, and nonroutine disposition; and (3) to identify factors associated with high-risk opioid use. METHODS: We used coding data collected in discharge records from the Nationwide Inpatient Sample (2002 2011). We analyzed changes with time in the prevalence of opioid abuse and dependence on admission. Finally, we used multivariate regression modeling to measure the association of opioid abuse and dependence with in-hospital postoperative mortality, morbidity, and resource utilization, and to identify factors associated with high-risk opioid use. RESULTS: The prevalence of opioid abuse and dependence increased from 0.095% in 2002 to 0.24% in 2011, an increase of 152% (p < 0.001). Opioid abuse and dependence were associated with increased inpatient mortality (odds ratio [OR], 3.7; 95% CI, 2.7-5.1) and aggregate morbidity (OR, 2.3 l; 95% CI, 2.2-2.4), including induced mental disorder (OR, 5.9; 95% CI, 5.4-6.3), respiratory failure (OR, 3.1; 95% CI, 2.7-3.6), surgical site infection (OR, 2.5; 95% CI, 2.0-3.0), mechanical ventilation (OR, 2.3; 95% CI, 2.0-2.5), pneumonia (OR, 2.1; 95% CI, 1.8-2.3), myocardial infarction (OR, 1.9; 95% CI, 1.3-2.6), and postoperative ileus or other gastrointestinal events (OR, 1.4; 95% CI, 1.3-1.6) (p < 0.001 for all listed entities). Abuse and dependence also were associated with increased risk for prolonged hospital length of stay (OR, 2.5; 95% CI, 2.4-2.5), nonroutine discharge (OR, 2.2; 95% CI, 2.2 2.3), and failure to rescue (OR, 2.0; 95% CI, 1.4-2.8). High-risk opioid users were more likely to be younger, male, nonwhite, Medicaid-insured patients with mental health and substance use disorders, and to be undergoing spine surgery. Hospital-related characteristics included urban setting, geographic location in the Northeast or West, and serving as a teaching facility. CONCLUSION: Opioid abuse and dependence are increasing rapidly among orthopaedic surgical inpatients and are associated with considerable postoperative morbidity and mortality and resource utilization. We recommend that orthopaedic surgeons screen patients carefully for opioid misuse preoperatively, help patients who are using opioids inappropriately to discontinue them before scheduling elective surgery, decline to perform elective surgery in patients who misuse opioids, and closely monitor patients who are habituated to opioids at the time they undergo surgery. LEVEL OF EVIDENCE: Level III, prognostic study. PMID- 25694267 TI - Incidence of Low Back Pain After Lumbar Discectomy for Herniated Disc and Its Effect on Patient-reported Outcomes. AB - BACKGROUND: Long-term postdiscectomy degenerative disc disease and low back pain is a well-recognized disorder; however, its patient-centered characterization and quantification are lacking. QUESTIONS/PURPOSES: We performed a systematic literature review and prospective longitudinal study to determine the frequency of recurrent back pain after discectomy and quantify its effect on patient reported outcomes (PROs). METHODS: A MEDLINE search was performed to identify studies reporting on the frequency of recurrent back pain, same-level recurrent disc herniation, and reoperation after primary lumbar discectomy. After excluding studies that did not report the percentage of patients with persistent back or leg pain more than 6 months after discectomy or did not report the rate of same level recurrent herniation, 90 studies, which in aggregate had evaluated 21,180 patients, were included in the systematic review portion of this study. For the longitudinal study, all patients undergoing primary lumbar discectomy between October 2010 and March 2013 were enrolled into our prospective spine registry. One hundred fifteen patients were more than 12 months out from surgery, 103 (90%) of whom were available for 1-year outcomes assessment. PROs were prospectively assessed at baseline, 3 months, 1 year, and 2 years. The threshold of deterioration used to classify recurrent back pain was the minimum clinically important difference in back pain (Numeric Rating Scale Back Pain [NRS-BP]) or Disability (Oswestry Disability Index [ODI]), which were 2.5 of 10 points and 20 of 100 points, respectively. RESULTS SYSTEMATIC REVIEW: The proportion of patients reporting short-term (6-24 months) and long-term (> 24 months) recurrent back pain ranged from 3% to 34% and 5% to 36%, respectively. The 2-year incidence of recurrent disc herniation ranged from 0% to 23% and the frequency of reoperation ranged from 0% to 13%. PROSPECTIVE STUDY: At 1-year and 2-year followup, 22% and 26% patients reported worsening of low back pain (NRS: 5.3 +/- 2.5 versus 2.7 +/- 2.8, p < 0.001) or disability (ODI%: 32 +/- 18 versus 21 +/- 18, p < 0.001) compared with 3 months. CONCLUSIONS: In a systematic literature review and prospective outcomes study, the frequency of same-level disc herniation requiring reoperation was 6%. Two-year recurrent low back pain may occur in 15% to 25% of patients depending on the level of recurrent pain considered clinically important, and this leads to worse PROs at 1 and 2 years postoperatively. PMID- 25694268 TI - Letter to the editor: minimally invasive surgical approaches in the management of tuberculosis of the thoracic and lumbar spine. PMID- 25694269 TI - Letter to the editor: infrapatellar saphenous neuralgia after TKA can be improved with ultrasound-guided local treatments. PMID- 25694270 TI - Comparison between echocardiographic and non-ECG-gated CT measurements in dogs. AB - The aim of this study was to compare echocardiographic measurements with non-ECG gated contrast-enhanced cardiac CT measurements in dogs. Fifty-seven dogs were included in the study. The following echocardiographic parameters were measured: M-mode interventricular septum in diastole and systole, left ventricular internal diameter in diastole and systole, left ventricular free wall in diastole and systole, 2D left atrial maximal diameter, 2D left atrium to aorta ratio in diastole, 2D aortic annulus in systole and 2D pulmonary annulus in diastole and systole. CT measurements were obtained from multiplanar reconstruction images, replicating the imaging planes used for 2D measurements on echocardiography. It was not possible to discriminate between systole and diastole. The results showed moderate Lin's concordance correlation coefficients between the left ventricular internal diameter in systole (0.77), the aortic annuli (0.84) and the pulmonary annuli in diastole (0.78) and systole (0.80). Low coefficients were obtained between the other parameters. Bland-Altman plots for the parameters with highest concordance correlation coefficients were calculated. They suggested equivalence between the measurements of the aortic annuli. Equivalence was not seen between the remaining echocardiographic and CT measurements. Therefore, non-ECG-gated CT is not a reliable way of quantitatively assessing cardiac size. PMID- 25694271 TI - Management of thyroid nodules incidentally discovered on MIBI scanning for primary hyperparathyroidism. AB - INTRODUCTION: Parathyroid sestamibi scan is routinely performed before parathyroid surgery. A large number of thyroid cancers take up 99mTc-sestamibi (MIBI). Since 2001, thyroid nodules discovered on sestamibi, nodules >2 cm, and/or with suspicious criteria were resected. The aim of this study was to evaluate the results of this policy. METHODS: All patients operated on for hyperparathyroidism, with a MIBI and cervical ultrasonography (US) with a thyroid resection for nodule, were retrospectively included. RESULTS: From 2001 to 2013, 685 patients were operated on for hyperparathyroidism. Some 137 (85 % females) had both preoperative MIBI and cervical US and a thyroid resection. The mean age was 63.2 +/- 12.8 years. Sixty-three patients had a total thyroidectomy and 74 a lobectomy. Thirty-six patients had a thyroid cancer. The median size of cancers was 6.5 mm (0.3-22 mm), and 23 (16.7 %) patients had microcarcinoma. Among the 137 patients, 44 (32 %) had a MIBI+ nodule including 22 cancers. Sixty-one percent of malignant nodules were MIBI+ (22/36). The median size of MIBI+ cancers was 15 mm (9-22 mm) versus 2 mm (0.3-17 mm) for MIBI- cancers (p = 0.03). Twenty two percent of benign nodules were MIBI+ (22/101). Finally, the sensitivity, specificity, positive predictive value, and negative predictive value of MIBI were 61, 78, 50, and 85 %, respectively. CONCLUSION: Thyroid nodules incidentally discovered on MIBI in hyperparathyroidism patients should be resected. PMID- 25694272 TI - Hibiscus sabdariffa leaf polyphenolic extract induces human melanoma cell death, apoptosis, and autophagy. AB - Melanoma is the least common but most fatal form of skin cancer. Previous studies have indicated that an aqueous extract of Hibiscus sabdariffa leaves possess hypoglycemic, hypolipidemic, and antioxidant effects. In this study, we want to investigate the anticancer activity of Hibiscus leaf polyphenolic (HLP) extract in melanoma cells. First, HLP was exhibited to be rich in epicatechin gallate (ECG) and other polyphenols. Apoptotic and autophagic activities of HLP and ECG were further evaluated by DAPI stain, cell-cycle analysis, and acidic vascular organelle (AVO) stain. Our results revealed that both HLP and ECG induced the caspases cleavages, Bcl-2 family proteins regulation, and Fas/FasL activation in A375 cells. In addition, we also revealed that the cells presented AVO-positive after HLP treatments. HLP could increase the expressions of autophagy-related proteins autophagy-related gene 5 (ATG5), Beclin1, and light chain 3-II (LC3-II), and induce autophagic cell death in A375 cells. These data indicated that the anticancer effect of HLP, partly contributed by ECG, in A375 cells. HLP potentially could be developed as an antimelanoma agent. PMID- 25694273 TI - Relationship between regional cerebral blood flow and neuropsychiatric symptoms in dementia with Lewy bodies. AB - OBJECTIVE: This aim of this study was to examine the mechanisms underlying the neuropsychiatric symptoms in dementia with Lewy bodies by investigating regional cerebral blood flow. METHODS: Participants were 27 patients who fulfilled the diagnostic criteria for probable dementia with Lewy bodies. All subjects underwent single-photon emission computed tomography scans using technetium-99 m hexamethylpropyleneamine oxime. Neuropsychiatric symptoms were evaluated by neuropsychiatric inventory. Multiple regression analyses using neuropsychiatric inventory and voxel-based analyses of covariance of the regional cerebral blood flow images between subjects with or without each neuropsychiatric symptom were performed. Additionally, similar voxel-based analyses of covariance between subjects with each neuropsychiatric symptom and normal subjects were performed. RESULTS: There were no significant correlations in any psychiatric symptoms in multiple regression analyses. All subjects had hallucination but none had euphoria. We analyzed eight neuropsychiatric symptom scores with the exception of hallucination and euphoria using voxel-based analyses of covariance. Significant differences of regional cerebral blood flow were shown in groups with agitation, disinhibition, and irritability. Subjects with agitation showed hypoperfusion in the parietal lobule, the precuneus, and the angular gyrus, and hyperperfusion in the fusiform gyrus, the lingual gyrus, and the thalamus. Subjects with disinhibition showed hypoperfusion in the left frontal gyrus. Subjects with irritability showed hyperperfusion in the right frontal gyrus. There were no significant differences in regional cerebral blood flow between subjects with any neuropsychiatric symptoms and normal subjects. CONCLUSION: This study reveals that dysfunction of specific brain regions is associated with various neuropsychiatric symptoms in dementia with Lewy bodies. PMID- 25694274 TI - Differentiation between traumatic tap and aneurysmal subarachnoid hemorrhage: prospective cohort study. AB - OBJECTIVES: To describe the findings in cerebrospinal fluid from patients with acute headache that could distinguish subarachnoid hemorrhage from the effects of a traumatic lumbar puncture. DESIGN: A substudy of a prospective multicenter cohort study. SETTING: 12 Canadian academic emergency departments, from November 2000 to December 2009. PARTICIPANTS: Alert patients aged over 15 with an acute non-traumatic headache who underwent lumbar puncture to rule out subarachnoid hemorrhage. MAIN OUTCOME MEASURE: Aneurysmal subarachnoid hemorrhage requiring intervention or resulting in death. RESULTS: Of the 1739 patients enrolled, 641 (36.9%) had abnormal results on cerebrospinal fluid analysis with >1 * 10(6)/L red blood cells in the final tube of cerebrospinal fluid and/or xanthochromia in one or more tubes. There were 15 (0.9%) patients with aneurysmal subarachnoid hemorrhage based on abnormal results of a lumbar puncture. The presence of fewer than 2000 * 10(6)/L red blood cells in addition to no xanthochromia excluded the diagnosis of aneurysmal subarachnoid hemorrhage, with a sensitivity of 100% (95% confidence interval 74.7% to 100%) and specificity of 91.2% (88.6% to 93.3%). CONCLUSION: No xanthochromia and red blood cell count <2000 * 10(6)/L reasonably excludes the diagnosis of aneurysmal subarachnoid hemorrhage. Most patients with acute headache who meet this cut off will need no further investigations and aneurysmal subarachnoid hemorrhage can be excluded as a cause of their headache. PMID- 25694275 TI - Looking for efficient G-quadruplex ligands: evidence for selective stabilizing properties and telomere damage by drug-like molecules. AB - There is currently significant interest in the development of G-quadruplex interactive compounds, given the relationship between the ability to stabilize these non-canonical DNA structures and anticancer activity. In this study, a set of biophysical assays was applied to evaluate the binding of six drug-like ligands to DNA G-quadruplexes with different folding topologies. Interestingly, two of the investigated ligands showed selective G-quadruplex-stabilizing properties and biological activity. These compounds may represent useful leads for the development of more potent and selective ligands. PMID- 25694276 TI - The General Medical Council responds to the special report in The BMJ on regulating doctors' financial and commercial interests. PMID- 25694277 TI - Identification of a novel HLA-A*02:06:14 allele by polymerase chain reaction sequence-based typing in a Chinese bone marrow donor. AB - HLA*02:06:14 differs from HLA-A*02:06:01 by a single nucleotide substitution G > A at position 246. PMID- 25694278 TI - The mother of CSI in a nutshell. PMID- 25694279 TI - [Assessment of hidden curriculum components by medical students]. AB - BACKGROUND: Hidden curriculum refers to the unwritten, unofficial, and often unintended lessons, values, and perspectives that students learn at the university, which influences the acquisition of professional skills. AIM: To analyze the perception about the influence of the hidden curriculum in the education of medical students at the Universidad de Concepcion, Chile. MATERIAL AND METHODS: Qualitative investigation with case study approach. Seventeen graduated medical students were selected by probability sampling. A semi structured interview was used to collect the information and a content analysis was applied. RESULTS: Forty seven percent of participants recognized having fulfilled their academic expectations. As favorable factors for academic achievement the students underlined clinical practice, access to patients and to clinical fields. As negative factors, they identified the lack of commitment, educational support and over-specialization of their mentors. CONCLUSIONS: The results show the strengths and weaknesses of the educational environment of undergraduated medical students. This information should be used to modify teaching environments. PMID- 25694280 TI - [Long term results of mitral balloon valvuloplasty]. AB - BACKGROUND: Mitral balloon valvuloplasty (MBV) is the therapy of choice for the treatment of symptomatic mitral stenosis with suitable anatomy. Although its short and mid-term results are favorable, there is a paucity of information about long-term follow-up. AIM: To assess the late results of MBV. MATERIAL AND METHODS: A cohort of 225 patients aged 8 to 20 years who were subjected to a MBV from 1989 to 2001, was studied. All variables at the time of the procedure, short and long-term results and major events during follow-up (new mitral intervention and mortality) were recorded. Uni and multivariate analysis were used to assess prognosis. RESULTS: The mean follow-up lapse was 13.5 years (range 8 to 20 years). During this period, 88 patients (39.1%) remained event-free and in acceptable functional capacity. Eight percent died, 8% required a second MBV and 43.5% required a surgical mitral valve replacement. A post-procedural area equal or greater to 1.9 cm2 was associated with a greater likelihood of free-event survival (log rank test: p = 0.02/Cox proportional regression model: coefficient 0.54, p = 0.04). CONCLUSIONS: MBV is effective, although there is a high chance of new interventions in the long-term follow-up. A larger post-procedure mitral area is associated with a better prognosis. PMID- 25694281 TI - [Association of quality of life perception with sleeping patterns in Chilean older people]. AB - BACKGROUND: An adequate sleeping pattern recovers physical and mental wellbeing and improves mood. AIM: To determine the association between quality of life and quantity of sleep in older people living in Santiago and Vina del Mar, Chile. MATERIAL AND METHODS: The Spanish versions of the Health Promoting Lifestyles survey and the Pittsburgh Sleep Quality Index were answered by 975 non-disabled participants aged 70.7 +/- 7.4 years (61% females). RESULTS: Older adults who slept < 7.0 or > 8.5 hours (h) per night were at higher risk of having lower quality of life scores for all sub-domains, compared with those that slept 7.0 to 8.5 h per night. CONCLUSIONS: A normal sleep pattern in older adults is associated with a better quality of life perception. PMID- 25694282 TI - [Prevalence of psychiatric disorders among teenage offenders]. AB - BACKGROUND: There has been a significant number of adolescents admitted to National Youth Service of Chile (SENAME) detention centers in recent years, specifically since the promulgation of a law reform on juveniles' penal responsibility for people aged 14 to 18 years (2006). AIM: To determine the prevalence of psychiatric disorders in adolescent male offenders aged between 14 and 17 years. MATERIAL AND METHODS: The Mini International Neuropsychiatric Interview for Kids and Adolescents (MINI-KID) was applied to 489 adolescents admitted to detention centers, to determine the presence of psychiatric disorders. (Hypo) maniac episodes, eating disorders, pervasive developmental disorders, tic disorders, and psychotic disorders were excluded. Furthermore, for purposes of analysis, 23 cases that used a substance of abuse or had signs of consumption the day of the interview were excluded. RESULTS: Eighty six percent of respondents had at least one psychiatric disorder. The most common were substance use disorders (76%). Among these, marijuana dependence disorder had the higher frequency (51%). Disruptive behavior disorders had also a high prevalence (38%), followed by anxiety disorders (27%), attention deficit and hyperactivity disorder (26%), and affective disorders (21%). CONCLUSIONS: There is a high prevalence of psychiatric morbidity among teenage offenders which could undermine rehabilitation. PMID- 25694283 TI - [Vitamin D levels in older healthy Chilean adults and their association with functional performance]. AB - BACKGROUND: People over 60 years old are at risk of Vitamin D deficiency, which can affect functional performance, since this vitamin is involved in muscle function and protein synthesis. AIM: To measure 25OH vitamin D levels in healthy older people from Santiago de Chile, and evaluate their relationship with functional performance. SUBJECTS AND METHODS: Healthy subjects aged 60 years or more and living in the community were invited to participate. People with chronic diseases, cognitive impairment, physical disability, smokers and those consuming more than three medications per day were excluded. Hand grip and gait speed were measured and a blood sample was obtained to measure 25OH vitamin D by radioimmunoanalysis. RESULTS: One hundred and four participants aged 60 to 98 years (55% females) were studied. Mean vitamin D levels were 17.3 +/- 6.1 ng/mL. Females had lower levels than males (15.6 +/- 5.8 and 19.2 +/- 6.0 ng/mL respectively p < 0.01). Eighty three percent of females and 55.3% of males had values below 20 ng/mL (the cutoff point for deficiency). Only 3.5% of females and 8.5% of males had values of 30 ng/ml or higher. There was a significant correlation between vitamin D levels, gait speed and grip strength (r = 0.32 and 0.34 respectively, p < 0.01), especially in women over 74 years. CONCLUSIONS: Vitamin D deficiency is almost universal in healthy adults over 60 years living in Santiago de Chile, especially in women. This deficiency is associated with a deranged functional performance and is a potentially modifiable risk factor for disability. PMID- 25694284 TI - [Correlation between aPTT and antifactor Xa to determine therapeutic ranges for unfractionated heparin]. AB - BACKGROUND: The therapeutic range (TR) of activated partial thromboplastin time (aPTT) for unfractionated heparin (UFH) dosing was established in the 1970 decade. Since then aPTT determination has changed. Current TR may be sub or supra therapeutic depending on the reagents of the test, and therefore, responsible for complications of therapy. AIM: To establish the TR for UFH dosing in our institution using antifactor Xa analysis as reference standard. MATERIAL AND METHODS: After obtaining an informed consent, 43 blood samples were obtained for aPTT determination and antifactor Xa assay in 23 patients treated with intravenous UFH. Samples were processed at Emergency and Hemostasis Labs. We excluded patients receiving other anticoagulants, with thrombophilia, pregnancy or liver disease. RESULTS: Mean aPTT values in the Hemostasis and Emergency labs were 57.1 +/- 18.9 and 56.6 +/- 18.3 seconds, respectively (p = 0.77). The squared correlation coefficients between aPTT and antifactor Xa at hemostasis and emergency labs were R2 0.5 and 0.45 respectively, p < 0.001. Using a linear regression analysis, therapeutic aPTT range values in our laboratory were established between 50 and 80 seconds, corresponding to antifactor Xa values of 0.3 to 0.7 IU/mL. CONCLUSIONS: According to current recommendations, validation of aPTT determination with reference techniques should be done in every institution. PMID- 25694285 TI - [Nutritional status and postoperative complications in patients with digestive cancer]. AB - BACKGROUND: Risk of malnutrition is elevated among oncologic patients, and this increases postoperative morbidity and mortality. AIM: To study the association between nutritional status and postoperative outcomes in a group of patients with gastrointestinal cancers. PATIENTS AND METHODS: We studied 129 patients with diagnosis of digestive cancer, previous to potentially curative surgery. Nutritional status was evaluated through anthropometric measures, Subjective Global Assessment (SGA), dietary intake recalls and routine biochemical parameters. Functional performance was assessed by the Karnofsky index (KI). Cancer stage was classified according to TNM4. During the postoperative period, complications, length of stay at the critical care ward and duration of hospitalization were registered. Thirty days after discharge, patients were contacted, and the appearance of new complications was listed. RESULTS: According to SGA 14.7% of patients were classified as well nourished (A), 57.3% as moderately undernourished or at risk of malnutrition (B) and 27.9% as severely malnourished (C). The incidence of total complications was 25.5%. Nutritional status was not associated with cancer stage. The frequency of complications among patients classified as A, B and C were 5.5, 25.3 and 37.1% respectively (p = 0.03). CONCLUSIONS: We detected a high frequency of malnutrition in this group of patients. Overall the frequency of postoperative complications was low, however malnourished patients exhibited a higher rate of surgical complications. PMID- 25694286 TI - [KRAS gene somatic mutations in Chilean patients with colorectal cancer]. AB - BACKGROUND: The molecular testing of KRAS mutation status in metastatic colorectal cancer patients is mandatory to identify patients eligible for anti epidermal growth factor receptor monoclonal antibody therapy. AIM: To report the frequency of KRAS gene mutations in Chilean patients with colorectal cancer (CRC). MATERIAL AND METHODS: A cohort of 262 Chilean patients with CRC aged 26 to 90 years (53% males), was studied. KRAS mutation status was analyzed by real-time polymerase chain reaction and correlated with clinicopathological data. RESULTS: Ninety-eight patients (37%) were positive for KRAS mutations. G12D was the most common mutation with a frequency of 36.7%, followed by G12V (25.5%), G13D (17.3%), G12A (7.1%), G12C (6.1%), G12S (5.1%) and G12R (2%). The frequency of the mutation in left, right colon and rectal tumors was 37.8, 32.6 and 44.9%, respectively. Among tumors with mutations, 86.7% were well or moderately differentiated tumors and the rest were poorly differentiated. No significant associations between KRAS gene mutations and other clinicopathological features of the tumor were observed. CONCLUSIONS: The frequencies of KRAS mutations reported in this study are similar to frequencies reported for European and North American populations, lower than in a Spanish study and higher than in a Peruvian study. PMID- 25694287 TI - [Psychometric properties of the quality of life questionnaire health related KIDSCREEN-27 in Chilean adolescents]. AB - BACKGROUND: KIDSCREEN-52, which assesses health related quality of life in adolescents, has been adapted and validated in Chile showing excellent psychometric properties. There is a shorter version of the instrument, whose psychometric properties must be assessed. AIM: To evaluate the psychometric properties of the instrument KIDSCREEN-27 in Chilean adolescents. MATERIAL AND METHODS: A secondary analysis of the database obtained for the adaptation and validation of KIDSCREEN-52. RESULTS: The reliability, calculated through Cronbach?s alpha, for the entire instrument (five dimensions) was 0.89. For physical well-being, psychological well-being, autonomy and relationship with parents and peer social support dimensions, scores were higher than 0.75 while for school environment, the score was 0.69. The confirmatory factor analysis showed that the indices obtained to assess the goodness of fit in this study were a chi2 (314) = 10521.4, a Root Mean Square Error of Approximation = 0.064 and a Comparative Fit index = 0.96. KIDSCREEN-27 scores were higher among men in the physical well-being, psychological well-being, autonomy and relationship with parents dimensions and among women in social support and peers and school environment dimensions. Scores were higher in younger age groups. CONCLUSIONS: The Chilean version of KIDSCREEN-27 instrument has adequate reliability and validity. PMID- 25694288 TI - [Relationship between self-directed learning with learning styles and strategies in medical students]. AB - BACKGROUND: Self-directed learning (SDL) skills are particularly important in medical education, considering that physicians should be able to regulate their own learning experiences. AIM: To evaluate the relationship between learning styles and strategies and self-directed learning in medical students. MATERIAL AND METHODS: One hundred ninety nine first year medical students (120 males) participated in the study. Preparation for Independent Learning (EPAI) scale was used to assess self-direction. Schmeck learning strategies scale and Honey and Alonso (CHAEA) scales were used to evaluate learning styles and strategies. RESULTS: Theoretical learning style and deep processing learning strategy had positive correlations with self-direct learning. CONCLUSIONS: Medical students with theoretical styles and low retention of facts are those with greater ability to self-direct their learning. Further studies are required to determine the relationship between learning styles and strategies with SDL in medical students. The acquired knowledge will allow the adjustment of teaching strategies to encourage SDL. PMID- 25694289 TI - [Identification of risk factors for congenital malformations]. AB - BACKGROUND: The relative importance of congenital malformations as a cause of death in the first year of life is increasing along with the control of preventable causes of perinatal mortality. AIM: To identify risk factors for congenital malformations. PATIENTS AND METHODS: Retrospective case-control study of births registered in the database of The Latin American Collaborative Study of Congenital Malformations (ECLAMC), in the period 2001-2010. RESULTS: Birth weight and gestational age were significantly lower in cases than controls, behaving as risk factors and associated with a greater severity of congenital malformations. The risk and severity of congenital malformations increased along with mother's age. Fetal growth retardation, a history of congenital malformations in the family, physical factors and acute illnesses of the mother in the first trimester of pregnancy were also significant risk factors for congenital malformations and their severity. The educational level of the mother was a protective factor for congenital malformations and their severity. CONCLUSIONS: Variables previously identified as risk factors for congenital malformations, were significantly related with the occurrence of congenital malformations and their severity. PMID- 25694290 TI - [Prevalence of obesity among Chilean women in childbearing ages]. AB - BACKGROUND: Women in childbearing ages (WCBA) represent a strategic intervention group to reverse the global trend of increasing obesity. AIM: To conduct a review of studies reporting obesity prevalence in WCBA in Chile in the last 25 years. MATERIAL AND METHODS: To describe obesity prevalence, we used three approaches, namely qualitative review of studies describing obesity prevalence in WCBA and a comparative study of the prevalence of obesity, overweight, abdominal and morbid obesity in WCBA from 2003 and 2009-10 National Health Surveys (ENS). Finally, nutrition status trends of pregnant women in the period 1987-2013 were plotted. RESULTS: According to ENS, obesity prevalence exceeded 20% and excess weight 50%, both in 2003 and 2009-10 surveys. We found seven population studies, being difficult to compare them due to the heterogeneity of obesity definitions, design, and populations. Population studies showed that the prevalence of obesity increases along with age. The higher prevalence of obesity in WCBA aged 20 to 43 years was found in the city of San Carlos in 2007 (35.5%). The lowest was found in female university students, ranging from 0% to 5.9%. Obesity in pregnant women increased from 12.9% to 32.2% in the period 1987-2004 and from 20.3% to 26.3% in the period 2005-2013. CONCLUSIONS: There is a high and increasing prevalence of obesity among women in childbearing age, whether pregnant or not-pregnant. PMID- 25694291 TI - [A glossary for discussion about abortion]. AB - Abortion and its diverse possible legal regulations is one of the major and toughest social controversies. This debate is even more problematic due to biases, prejudgments, different ideologies, beliefs, religious doctrines and political pressures. Chile has recently begun a new national discussion with an evident confusion, both in juridical and clinical terminology, which makes very difficult to achieve the necessary plural debate for a social and political consensus. The authors structured an academic collaborative project to create a glossary as a contribution for a discussion based on clearly defined notions about the different terms used in the abortion debate. Twenty-two concepts were selected and their definitions were reviewed and discussed by more than 50 different specialists. The final version of this glossary in Spanish language is presented. PMID- 25694292 TI - [Diego Rivera: a great master and a didactic and discerning medical historian]. AB - Diego Rivera is one of the artistic giants of the 20th century. His many original creations included landscapes, portraits and large murals created in both Mexico and the United States. Rivera ventured into many styles-cubism, naturalism and narrative realism-with great success. Rivera's murals build on those of the Renaissance, pre-historic and colonial civilizations of Mexico. Biological and medical topics and their history form an important concern in Rivera's work, present in many of his murals in a highly informative and creative manner. His two History of Cardiology murals present an original and comprehensive account of the developments of this medical specialty from pre-historic to modern times. His History of Medicine in Mexico (The people demands health) mural is a creatively and vigorously fashioned and highly dynamic and synthetic vision of the relationships between pre-historic and modern medicine in Mexico and its social foundations. Medical topics such as vaccines and vaccination, embryology and surgery are inventively and accurately presented in the large mural, Detroit Industry. The trigger and impetus for the concern of Rivera for these topics of life and death, and the exceedingly ground-breaking way he presents them, appear to stem from his rational materialism, his concern for collective wellbeing, his belief in progress through scientific developments and political action and his commitment to understand Mexican and American history. PMID- 25694293 TI - [Cardiac magnetic resonance in arrhythmogenic right ventricular dysplasia: report of two cases]. AB - Arrhythmogenic right ventricular dysplasia is an inherited condition characterized by replacement of normal myocardium by fatty or fibro-fatty tissue, which mainly affects the right ventricle. The most frequent form of presentation is ventricular tachycardia or sudden death, whose origin is considered to be a product of fibrous or fatty infiltration of the myocardium. This structural damage can be detected by cardiac magnetic resonance imaging (MR). We report two patients with ventricular tachycardia due to arrhythmogenic right ventricular dysplasia. A 49 year-old female with a history of ventricular tachycardia. EKG showed epsilon waves and a prolonged QTc. Echocardiogram showed right ventricular dilatation and dysfunction. MR showed right ventricular fatty infiltration. An implantable cardioverter-defibrillator was installed to the patient. A 37 year old male was admitted for recurrent syncope. On admission a ventricular tachycardia was detected. An echocardiogram showed right ventricular dilatation and dysfunction. MR showed a large zone of fibrosis in the right ventricle. An implantable cardioverter-defibrillator was also installed. PMID- 25694294 TI - [Bilateral renal vein thrombosis and acute renal failure due to inferior vena cava filter thrombosis. Report of one case]. AB - Bilateral renal vein thrombosis is an unusual etiology of acute renal failure and usually is associated with nephrotic syndrome. We report a 77-year-old man, consulting in the emergency room for anuria that appeared 24 hours after a syncope. The patient was carrier of an inferior vena cava filter prophylactically installed 17 months earlier and was not receiving anticoagulation. Serum creatinine on admission was 5.45 mg/dl and blood urea nitrogen was 54 mg/dl. Computed tomography and Doppler ultrasonography showed an extensive thrombosis of inferior vena cava and both renal veins. Heparin therapy was started with a rapid recovery of renal function and diuresis. PMID- 25694295 TI - [Pulmonary artery sarcoma mimicking a Hughes Stovin syndrome. Report of one case]. AB - Pulmonary artery sarcoma is an uncommon entity with high mortality. Its clinical presentation is usually indistinguishable from pulmonary embolism, which leads to a significant delay in diagnosis. Hughes-Stovin syndrome is characterized by venous thrombosis and aneurysms of the pulmonary or bronchial artery. We report a 59 year-old female with a history of recurrent pulmonary embolism. In the last thromboembolic episode a pulmonary artery aneurysm was found on a CT scan. The patient was operated performing a left inferior lobectomy. The patient died five days after surgery and the pathological examination of the surgical piece revealed a pulmonary artery sarcoma. PMID- 25694296 TI - [Purple urine bag syndrome: report of one case]. AB - Purple urine bag syndrome is an uncommon but particularly striking phenomenon observed in people with urinary catheters and co-existent urinary tract infections. A chemical reaction between plastic and certain bacterial enzymes results in an intense purple urine color. We report a 72 year-old male with a cystostomy. A purple coloration of his urinary drainage bag and tubing was noted in the context of a urinary tract infection caused by Citrobacter freundii. PMID- 25694297 TI - [Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT): a diagnostic challenge]. PMID- 25694298 TI - [Undergraduate medical research: what is going on in Chile?]. PMID- 25694299 TI - Exploring diradical chemistry: a carbon-centered radical may act as either an anion or electrophile through an orbital isomer. AB - Diradical intermediates, formed by thermolysis of alkynylcyclobutenones, can display radical, anion, or electrophilic character because of the existence of an orbital isomer with zwitterionic and cyclohexatrienone character. Our realization that water, alcohols, and certain substituents can induce the switch provides new opportunities in synthesis. For example, it can be used to shut down radical pathways and to give access to aryl carbonates and tetrasubstituted quinones. PMID- 25694300 TI - Glucose-lowering effect and glycaemic variability of insulin glargine, insulin detemir and insulin lispro protamine in people with type 1 diabetes. AB - AIM: To compare, using a continuous glucose monitoring (CGM) system, the effect on glycaemic variability of insulin glargine, detemir and lispro protamine. METHODS: A total of 49 white people with type 1 diabetes, not well controlled by three times daily insulin lispro, taken for at least 2 months before study and on a stable dose, were enrolled. The study participants were randomized to add insulin glargine, detemir or lispro protamine, once daily, in the evening. We used a CGM system, the iPro Digital Recorder (Medtronic MiniMed, Northridge, CA, USA) for 1 week. Glycaemic control was assessed according to mean blood glucose values, the area under the glucose curve above 3.9 mmol/l (AUC(>3.9)) or above 10.0 mmol/l (AUC(>10.0)), and the percentage of time spent with glucose values >3.9 or >10.0 mmol/l. Intraday glycaemic variability was assessed using standard deviation (s.d.) values, the mean amplitude of glycaemic excursions and continuous overlapping of net glycaemic action. Day-to-day glycaemic variability was assessed using the mean of daily differences. RESULTS: The s.d. was found to be significantly lower with insulin lispro protamine and glargine compared with insulin detemir. AUC(>3.9) was higher and AUC(>10.0) was lower with insulin lispro protamine and glargine compared with detemir. The mean amplitude of glycaemic excursions and continuous overlapping net glycaemic action values were lower with insulin lispro protamine and glargine compared with detemir. In addition, the mean of daily differences was significantly lower with insulin lispro protamine and glargine compared with detemir. Fewer hypoglycaemic events were recorded during the night-time with insulin lispro protamine compared with glargine and detemir. CONCLUSIONS: The results suggest that insulin lispro protamine and glargine are more effective than detemir in reducing glycaemic variability and improving glycaemic control in people with type 1 diabetes. Insulin lispro protamine seems to lead to fewer hypoglycaemic events than other insulin regimens. PMID- 25694301 TI - On framing the research question and choosing the appropriate research design. AB - Clinical epidemiology is the science of human disease investigation with a focus on diagnosis, prognosis, and treatment. The generation of a reasonable question requires definition of patients, interventions, controls, and outcomes. The goal of research design is to minimize error, to ensure adequate samples, to measure input and output variables appropriately, to consider external and internal validities, to limit bias, and to address clinical as well as statistical relevance. The hierarchy of evidence for clinical decision-making places randomized controlled trials (RCT) or systematic review of good quality RCTs at the top of the evidence pyramid. Prognostic and etiologic questions are best addressed with longitudinal cohort studies. PMID- 25694302 TI - Research ethics for clinical researchers. AB - This chapter describes the history of the development of modern research ethics. The governance of research ethics is discussed and varies according to geographical location. However, the guidelines used for research ethics review are very similar across a wide variety of jurisdictions. The paramount importance of protecting the privacy and confidentiality of research participants is discussed at length. Particular emphasis is placed on the process of informed consent, and step-by-step practical guidelines are described. The issue of research in vulnerable populations is touched upon and guidelines are provided. Practical advice is provided for researchers to guide their interactions with research ethics boards. Issues related to scientific misconduct and research fraud are not dealt with in this paper. PMID- 25694303 TI - Definitions of bias in clinical research. AB - In this chapter a catalog of the various types of bias that can affect the validity of clinical epidemiologic studies is presented. The biases can be grouped into those associated with selection of subjects, misclassification or misinformation, and finally confounding. Definitions are provided for each type of bias listed. PMID- 25694304 TI - Longitudinal studies 1: Determination of risk. AB - Longitudinal or observational study designs are important methodologies to investigate potential associations that may not be amenable to randomized controlled trials. In many cases they may be performed using existing data and are often cost-effective ways of addressing important questions. The major disadvantage of observational studies is the potential for bias. The absence of randomization means that one can never be certain that unknown confounders are present, and specific studies designs have their own inherent forms of bias. Careful study design may minimize bias. Establishing casual association based on observational methods requires due consideration of the quality of the individual study and knowledge of their limitations. PMID- 25694305 TI - Longitudinal studies 2: Modeling data using multivariate analysis. AB - Statistical models are used to study the relationship between exposure and disease while accounting for the potential role of other factors impact upon outcomes. This adjustment is useful to obtain unbiased estimates of true effects or to predict future outcomes. Statistical models include a systematic and an error component. The systematic component explains the variability of the response variable as a function of the predictors and is summarized in the effect estimates (model coefficients). The error element of the model represents the variability in the data unexplained by the model and is used to build measures of precisions around the point estimates (Confidence Intervals). PMID- 25694306 TI - Longitudinal studies 3: Data modeling using standard regression models and extensions. AB - In longitudinal studies the relationship between exposure and disease can be measured once or multiple times while participants are monitored over time. Traditional regression techniques are used to model outcome data when each epidemiological unit is observed once. These models include generalized linear models for quantitative continuous, discrete, or qualitative outcome responses, and models for time-to-event data. When data come from the same subjects or group of subjects, observations are not independent and the underlying correlation needs to be addressed in the analysis. In these circumstances extended models are necessary to handle complexities related to clustered data, and repeated measurements of time-varying predictors and/or outcomes. PMID- 25694307 TI - Longitudinal studies 4: Matching strategies to evaluate risk. AB - Matching is a strategy that can be used to control for confounding at the design stage of observational studies that examine exposure-outcome relationships. In case-control studies, matching can be used to generate subsamples of case and control units that are similar with respect to one or more confounders. In cohort studies, matching can balance confounder(s) so that they are the same in exposed and unexposed groups. Matching methods have been extended to include multivariable approaches, the most common being propensity score matching in observation studies of interventions. This chapter describes the major principles of matching applied to case-control, cohort, and propensity score studies. Matched study designs provide several advantages for controlling confounding in observational studies; however, they remain vulnerable to residual confounding and can even introduce bias when implemented incorrectly. PMID- 25694308 TI - Longitudinal studies 5: Development of risk prediction models for patients with chronic disease. AB - Chronic diseases are now the major cause of ill health in both developed and developing countries. Chronic diseases evolve, over decades, from an early reversible phase, to a late stage of irreversible organ damage. Importantly, the trajectory of individual patients with a chronic disease is highly variable. This uncertainty causes substantial stress and difficulty for patients, care providers and health systems. Clinical risk prediction models address this uncertainty by incorporating multiple variables to more precisely estimate the risk of adverse events for an individual patient. In the current chapter, we describe the general approach to developing a risk prediction model. We then illustrate how these methods were applied in the development and validation of the Kidney Failure Risk Equation (KFRE), which accurately predicts the risk of kidney failure in patients with Chronic Kidney Disease Stages 3-5. PMID- 25694309 TI - Randomized controlled trials 1: Design. AB - Today's clinical practice relies on the application of well-designed clinical research, the gold standard test of an intervention being the randomized controlled trial. Principles of the randomized control trial include emphasis on the principal research question, randomization, blinding; definitions of outcome measures, of inclusion and exclusion criteria, and of comorbid and confounding factors; enrolling an adequate sample size; planning data management and analysis; preventing challenges to trial integrity such as drop-out, drop-in, and bias. The application of pretrial planning is stressed to ensure the proper application of epidemiological principles resulting in clinical studies that are feasible and generalizable. In addition, funding strategies and trial team composition are discussed. PMID- 25694310 TI - Randomized controlled trials 2: Analysis. AB - When analyzing the results of a trial the primary outcome variable must be kept in clear focus. In the analysis plan consideration must be given to comparing the characteristics of the subjects, taking account of differences in these characteristics, intention to treat analysis, interim analyses and stopping rules, mortality comparisons, composite outcomes, research design including run in periods, factorial, stratified, and crossover designs, number needed to treat, power issues, multivariate modeling, and hypothesis-generating analyses. PMID- 25694311 TI - Randomized controlled trials 3: Measurement and analysis of patient-reported outcomes. AB - The study of patient-reported outcomes, now common in clinical research, had its origins in social and scientific developments during the latter twentieth century. Patient-reported outcomes comprise functional and health status, health related quality of life, and quality of life. The terms overlap and are used inconsistently, and these reports of experience should be distinguished from expressions of preference regarding health states. Regulatory standards from the USA and European Union provide some guidance regarding reporting of patient reported outcomes. The determination that measurement of patient-reported outcomes is important depends in part on the balance between subjective and objective outcomes of the health problem under study. Instrument selection depends to a large extent on practical considerations. A number of instruments can be identified that are frequently used in particular clinical situations. The domain coverage of commonly used generic short forms varies substantially. Individualized measurement of quality of life is possible, but resource intensive. Focus groups are useful, not only for scale development but also to confirm the appropriateness of existing instruments. Under classical test theory, validity and reliability are the critical characteristics of tests. Under item response theory, validity remains central, but the focus moves from the reliability of scales to the relative levels of traits in individuals and items' relative difficulty. Plans for clinical studies should include an explicit model of the relationship of patient-reported outcomes to other parameters, as well as definition of the magnitude of difference in patient-reported outcomes that will be considered important. It is particularly important to minimize missing patient reported outcome data; to a limited extent, a variety of statistical techniques can mitigate the consequences of missing data. PMID- 25694312 TI - Randomized controlled trials 4: Biomarkers and surrogate outcomes. AB - Biomarkers are defined as anatomic, physiologic, biochemical, molecular, or genetic parameters associated with the presence, absence, or severity of a disease process. As such, biomarkers may be useful as prognostic and diagnostic tests. Establishing the utility of a given biomarker as a prognostic or diagnostic test requires the conduct of carefully designed cohort studies in which the biomarker and the outcome of interest are measured independently. The design and analysis of such studies is discussed. Surrogate outcomes in clinical trials consist of events or biomarkers intended to reflect important clinical outcomes. Surrogate outcomes may offer advantages in providing statistically robust estimates of treatment effects with smaller sample sizes. However, to be useful, surrogate outcomes have to be validated to ensure that the effect of therapy on them truly reflects the effect of therapy on the important clinical outcomes of interest. PMID- 25694313 TI - Randomized controlled trials 5: Determining the sample size and power for clinical trials and cohort studies. AB - Performing well-powered randomized controlled trials is of fundamental importance in clinical research. The goal of sample size calculations is to assure that statistical power is acceptable while maintaining a small probability of a type I error. This chapter overviews the fundamentals of sample size calculation for standard types of outcomes for two-group studies. It considers (1) the problems of determining the size of the treatment effect that the studies will be designed to detect, (2) the modifications to sample size calculations to account for loss to follow-up and nonadherence, (3) the options when initial calculations indicate that the feasible sample size is insufficient to provide adequate power, and (4) the implication of using multiple primary endpoints. Sample size estimates for longitudinal cohort studies must take account of confounding by baseline factors. PMID- 25694314 TI - Randomized controlled trials 6: On contamination and estimating the actual treatment effect. AB - The intention-to-treat analysis is the gold standard for evaluating efficacy in a randomized controlled trial. However, when non-adherence to randomized treatments is high, the actual treatment effect may be underestimated. The impact of drop out from the intervention group or drop-in to the control group may be controlled by trial design, increasing the sample size, effective study execution, and a prespecified analytical plan to take contamination into account. These analyses may include censoring at time of co-interventions associated with stopping treatment, lag censoring which allows an additional period after discontinuation of study treatment to account for residual treatment effects, inverse probability of censoring weights (IPCW), accelerated failure time models, and contamination adjusted intent-to-treat analysis. These methods are particularly useful in assessing the "prescribed efficacy" of the study treatment, which can aid clinical decision-making. PMID- 25694315 TI - Randomized controlled trials 7: Analysis and interpretation of quality-of-life scores. AB - Quality-of-life (QoL) outcomes are important elements of randomized controlled trials. The instruments for measurement of QoL vary but usually multiple comparisons are possible, a concern that can be offset by prespecifying the outcomes of interest. Missing data may threaten the validity of QoL assessments in trials. Therefore familiarity with the strategies used to account for missing data is necessary. Measures that incorporate both survival and QoL are helpful for treatment decisions. The definition of minimal clinically important differences in QoL scores is important and often derived using inadequate methods. PMID- 25694316 TI - Randomized controlled trials: planning, monitoring, and execution. AB - Large integrated multidisciplinary teams have become recognized as an efficient means by which to drive innovation and discovery in clinical research. This chapter describes how to plan, budget and fund these large studies and execute the studies with well-designed governance and monitoring protocols in place, to efficiently manage the large, often dispersed teams involved. Sources of funding are identified, budget development, justification, reporting, financial governance and accountability are described, in addition to the creation and management of the multidisciplinary team that will implement the research plan. PMID- 25694317 TI - Evaluation of diagnostic tests. AB - As technology advances, diagnostic tests continue to improve, and each year we are presented with new alternatives to standard procedures. Given the plethora of diagnostic alternatives, diagnostic tests must be evaluated to determine their place in the diagnostic armamentarium. The first step involves determining the accuracy of the test, including the sensitivity and specificity, positive and negative predictive values, likelihood ratios for positive and negative tests, and receiver operating characteristic (ROC) curves. The role of the test in a diagnostic pathway has then to be determined, following which the effect on patient outcome should be examined. PMID- 25694318 TI - Qualitative research in clinical epidemiology. AB - This chapter has been written to specifically address the usefulness of qualitative research for the practice of clinical epidemiology. The methods of grounded theory to facilitate understanding of human behavior and construction of monitoring scales for use in quantitative studies are discussed. In end-stage renal disease patients receiving long-term hemodialysis, a qualitative study used grounded theory to generate a multilayered classification system, which culminated in a substantive theory on living with end-stage renal disease and hemodialysis. The qualitative data base was re-visited for the purpose of scale development and led to the Patient Perception of Hemodialysis Scale (PPHS). The quantitative study confirmed that the PPHS was psychometrically valid and reliable and supported the major premises of the substantive theory. PMID- 25694319 TI - Health economics in clinical research. AB - The pressure for health care systems to provide more resource intensive health care and newer, more costly, therapies is significant, despite limited health care budgets. As such, demonstration that a new therapy is effective is no longer sufficient to ensure that it is funded within publicly funded health care systems. The impact of a therapy on health care costs is also an important consideration for decision-makers who must allocate scarce resources. The clinical benefits and costs of a new therapy can be estimated simultaneously using economic evaluation, the strengths and limitations of which are discussed herein. In addition, this chapter includes discussion of the important economic outcomes that can be collected within a clinical trial (alongside the clinical outcome data) enabling consideration of the impact of the therapy on overall resource use, thus enabling performance of an economic evaluation, if the therapy is shown to be effective. PMID- 25694320 TI - Clinical genetic research 1: Bias. AB - Clinical epidemiological research in genetic diseases entails assessment of phenotypes, the burden and etiology of disease, and the efficacy of preventive measures or treatments in populations. In all areas, the main focus is to describe the relationship between exposure and outcome and to determine one of the following: prevalence, incidence, cause, prognosis, or effect of treatment. The accuracy of these conclusions is determined by the validity of the study. Validity is determined by addressing potential biases and possible confounders that may be responsible for the observed association. Therefore, it is important to understand the types of bias that exist and also to be able to assess their impact on the magnitude and direction of the observed effect. The following chapter reviews the epidemiological concepts of selection bias, information bias, and confounding and discusses ways in which these sources of bias can be minimized. PMID- 25694321 TI - Clinical genetic research 2: Genetic epidemiology of complex phenotypes. AB - Genetic factors play a substantive role in the susceptibility to common diseases. Due to recent and rapid advancements in characterization of genetic variants and large-scale genotyping platforms, multiple genes and genetic variants have now been identified for common, complex diseases. The most efficient method for gene identification at present appears to be large-scale association-based studies, which integrate genetic and epidemiological principles. As the strategy for gene identification studies has shifted towards genetic association-based methods rather than traditional linkage analysis, epidemiological methods are increasingly being integrated into genetic investigations. Consequently, the disciplines of genetics and epidemiology, which historically have functioned separately, have been integrated into a discipline referred to as genetic epidemiology. In this chapter, we review methods for establishing the genetic burden of complex genetic disease, followed by methods for gene and/or genetic variant identification and when appropriate we highlight the epidemiological issues that guide these methods. PMID- 25694322 TI - Clinical genetic research 3: Genetics ELSI (Ethical, Legal, and Social Issues) research. AB - ELSI (Ethical, Legal, and Social Issues) is a widely used acronym in the bioethics literature that encompasses a broad range of research areas involved in examining the various impacts of science and technology on society. In Canada, GE3LS (Genetics, Ethical, Economic, Environmental, Legal, Social issues) is the term used to describe ELSI studies. It is intentionally more expansive in that GE3LS explicitly brings economic and environmental issues under its purview. ELSI/GE3LS research has become increasingly important in recent years as there has been a greater emphasis on "translational research" that moves genomics from the bench to the clinic. The purpose of this chapter is to outline a range of ELSI-related work that might be conducted as part of a large scale genetics or genomics research project, and to provide some practical insights on how a scientific research team might incorporate a strong and effective ELSI program within its broader research mandate. We begin by describing the historical context of ELSI research and the development of GE3LS research in the Canadian context. We then illustrate how some ELSI research might unfold by outlining a variety of research questions and the various methodologies that might be employed in addressing them in an area of ELSI research that is encompassed under the term "public engagement." We conclude with some practical pointers about how to build an effective ELSI/GE3LS team and focus within a broader scientific research program. PMID- 25694323 TI - Evidence-based decision-making 1: Critical appraisal. AB - This chapter provides an introduction to the concept of Evidence-based Medicine (EBM) including its history, rooted in Canada and its important role in modern medicine. The chapter both defines EBM and explains the process of conducting EBM. It includes a discussion of the hierarchy of evidence that exists with reference to common methods used to assess the levels of quality inherent in study designs. The focus of the chapter is on how to critically appraise the medical literature, as one step in the EBM process. Critical appraisal requires an understanding of the strengths and weaknesses of study design and how these in turn impact the validity and applicability of research findings. Strong critical appraisal skills are critical to evidence-based decision-making. PMID- 25694324 TI - Evidence-based decision-making 2: Systematic reviews and meta-analysis. AB - The number of studies published in the biomedical literature has dramatically increased over the last few decades. This massive proliferation of literature makes clinical medicine increasingly complex, and information from multiple studies is often needed to inform a particular clinical decision. However, available studies often vary in their design, methodological quality, populations studied and may define the research question of interest quite differently, which can make it challenging to synthesize their conclusions. In addition, since even highly cited trials may be challenged over time, clinical decision-making requires ongoing reconciliation of studies which provide different answers to the same question. Because it is often impractical for readers to track down and review all the primary studies, systematic reviews and meta-analyses are an important source of evidence on the diagnosis, prognosis, and treatment of any given disease. This chapter summarizes methods for conducting and reading systematic reviews and meta-analyses, as well as describing potential advantages and disadvantages of these publications. PMID- 25694325 TI - Evidence-based decision-making 3: Health technology assessment. AB - This chapter begins with a brief introduction to health technology assessment (HTA). HTA is concerned with the systematic evaluation of the consequences of the adoption and use of new health technologies and improving the evidence on existing technologies. The objective of mainstream HTA is to support evidence based decision- and policy-making that encourage the uptake of efficient and effective health care technologies. This chapter provides a basic framework for conducting an HTA as well as some fundamental concepts and challenges in assessing health technologies. A case study of the assessment of drug eluting stents in Ontario is presented to illustrate the HTA process. Whether HTA is beneficial-supporting timely access to needed technologies-or detrimental depends on three critical issues: when the assessment is performed; how it is performed; and how the findings are used. PMID- 25694326 TI - Evidence-based decision-making 4: Development and limitations of clinical practice guidelines. AB - Clinical practice guidelines are systematically developed statements to assist practitioners and patients reach appropriate health care decisions. If developed properly, clinical practice guidelines assimilate and translate an abundance of evidence published on a daily basis into practice recommendations and, in doing so, reduce the use of unnecessary or harmful interventions, and facilitate the treatment of patients to achieve maximum benefit and minimum risk at an acceptable cost. Traditionally, clinical practice guidelines were consensus-based statements, often riddled with expert opinion. It is now recognized that clinical practice guidelines should be developed according to a transparent process involving principles of bias minimization and systematic evidence retrieval and review, with a focus on patient-relevant outcomes. The process for the development, implementation, and evaluation of clinical practice guidelines is reviewed in this chapter. PMID- 25694327 TI - Evidence-based decision-making 5: Translational research. AB - The delay in turning research into practice for the benefit of patient care has been compared to a "leaky pipeline." In the early 2000s, this delay raised concerns among governmental agencies and other sponsors of health services in many countries. Facilitating the translation of basic and clinical research into clinical practice through evidence-based decision-making and improving population health is now a major goal of health research investment agencies. Translational research or knowledge translation has emerged to bridge the gaps between basic and clinical research, and between clinical research and clinical practice. Various frameworks and definitions of translational research are presented. We present an example of an Integrated Knowledge Translation Team in Bariatric Care, and explain how an integrated knowledge translation (iKT) approach was created at the program's inception. This led to evidence-based decision-making and subsequent practice change in one area of the health care system. Real-world successes and challenges in moving research to practice are discussed. PMID- 25694328 TI - Evidence-based decision-making 6: Utilization of administrative databases for health services research. AB - Health-care systems require reliable information on which to base health-care planning and make decisions, as well as to evaluate their policy impact. Administrative data provide important information about health services use, expenditures, clinical outcomes, and may be used to assess quality of care. With increased digitalization and accessibility of administrative databases, these data are more readily available for health service research purposes, aiding evidence-based decision-making. This chapter discusses the utility of administrative data for population-based studies of health and health care. PMID- 25694329 TI - Evidence-based decision-making 7: Knowledge translation. AB - There is a significant gap between what is known and what is implemented by key stakeholders in practice (the evidence to practice gap). The primary purpose of knowledge translation is to address this gap, bridging evidence to clinical practice. The knowledge to action cycle is one framework for knowledge translation that integrates policy-makers throughout the research cycle. The knowledge to action cycle begins with the identification of a problem (usually a gap in care provision). After identification of the problem, knowledge creation is undertaken, depicted at the center of the cycle as a funnel. Knowledge inquiry is at the wide end of the funnel, and moving down the funnel, the primary data is synthesized into knowledge products in the form of educational materials, guidelines, decision aids, or clinical pathways. The remaining components of the knowledge to action cycle refer to the action of applying the knowledge that has been created. This includes adapting knowledge to local context, assessing barriers to knowledge use, selecting, tailoring implementing interventions, monitoring knowledge use, evaluating outcomes, and sustaining knowledge use. Each of these steps is connected by bidirectional arrows and ideally involves healthcare decision-makers and key stakeholders at each transition. PMID- 25694330 TI - Evidence-based decision-making 8: Health policy, a primer for researchers. AB - There is a growing expectation that research will be used to inform decision making. It is important for researchers to understand how health policy is developed and the different ways they can influence the development of policy. Public policy is developed to resolve identified problems. Health policy is a subset of public policy and is typically concerned with issues related to the health of populations either from a service delivery perspective or from a broader public health and social determinants of health perspective. The policy planning algorithm is well established and follows the basic decision-making framework: assessment, planning, implementation, and evaluation. A variety of government and nongovernment stakeholders engage in complex debates to identify and resolve policy issues. In this chapter we explore how researchers can use their research to influence the development of health policy. Knowledge translation strategies focused on communicating research to policy-makers require considerable thought and planning. PMID- 25694331 TI - How to treat a Piraha: medical ethics and cultural difference. PMID- 25694332 TI - [6]-Gingerol Affects Glucose Metabolism by Dual Regulation via the AMPKalpha2 Mediated AS160-Rab5 Pathway and AMPK-Mediated Insulin Sensitizing Effects. AB - [6]-Gingerol has been used to control diabetes and dyslipidemia; however, its metabolic role is poorly understood. In this study, [6]-gingerol increased adenosine monophosphate (AMP)-activated protein kinase (AMPK) phosphorylation in mouse skeletal muscle C2C12 cells. Stimulation of glucose uptake by [6]-gingerol was dependent on AMPKalpha2. Moreover, both Inhibition and knockdown of AMPKalpha2 blocked [6]-gingerol-induced glucose uptake. [6]-Gingerol significantly decreased the activity of protein phosphatase 2A (PP2A). Inhibition of PP2A activity with okadaic acid enhanced the phosphorylation of AMPKalpha2. Moreover, the interaction between AMPKalpha2 and PP2A was increased by [6] gingerol, suggesting that PP2A mediates the effect of [6]-gingerol on AMPK phosphorylation. In addition, [6]-gingerol increased the phosphorylation of Akt substrate 160 (AS160), which is a Rab GTPase-activating protein. Inhibition of AMPKalpha2 blocked [6]-gingerol-induced AS160 phosphorylation. [6]-gingerol increased the Rab5, and AMPKalpha2 knockdown blocked [6]-gingerol-induced expression of Rab5, indicating AMPK play as an upstream of Rab5. It also increased glucose transporter 4 (GLUT4) mRNA and protein expression and stimulated GLUT4 translocation. Furthermore, insulin-mediated glucose uptake and Akt phosphorylation were further potentiated by [6]-gingerol treatment. This potentiation was not observed in the presence of AMPK inhibitor compound C. In summary, our results suggest that [6]-gingerol plays an important role in glucose metabolism via the AMPKalpha2-mediated AS160-Rab5 pathway and through potentiation of insulin-mediated glucose regulation. PMID- 25694333 TI - Intergenerational transmission of attachment in abused and neglected mothers: the role of trauma-specific reflective functioning. AB - There are still important gaps in our knowledge regarding the intergenerational transmission of attachment from mother to child, especially in mothers with childhood histories of abuse and neglect (CA&N). This study examined the contributions of reflective function concerning general attachment relationships, and specifically concerning trauma, as well as those of maternal attachment states of mind to the prediction of infant attachment disorganization in a sample of mothers with CA&N and their infants, using a 20-month follow-up design. Attachment and reflective functioning were assessed during pregnancy with the Adult Attachment Interview. Infant attachment was evaluated with the Strange Situation Procedure. The majority (83%) of infants of abused and neglected mothers were classified as insecure, and a significant proportion (44%) manifested attachment disorganization. There was a strong concordance between mother and child attachment, indicative of intergenerational transmission of attachment in parents with CA&N and their infants. Both unresolved trauma and trauma-specific reflective function made significant contributions to explaining variance in infant attachment disorganization. The findings of this study highlight the importance of trauma-specific mentalization in the intergenerational transmission of attachment by mothers with a history of childhood maltreatment, and provide new evidence of the importance of the absence of mentalization regarding trauma for infant attachment. PMID- 25694334 TI - Native mass spectrometry and ion mobility characterization of trastuzumab emtansine, a lysine-linked antibody drug conjugate. AB - Antibody-drug conjugates (ADCs) are biochemotherapeutics consisting of a cytotoxic chemical drug linked covalently to a monoclonal antibody. Two main classes of ADCs, namely cysteine and lysine conjugates, are currently available on the market or involved in clinical trials. The complex structure and heterogeneity of ADCs makes their biophysical characterization challenging. For cysteine conjugates, hydrophobic interaction chromatography is the gold standard technique for studying drug distribution, the naked antibody content, and the average drug to antibody ratio (DAR). For lysine ADC conjugates on the other hand, which are not amenable to hydrophobic interaction chromatography because of their higher heterogeneity, denaturing mass spectrometry (MS) and UV/Vis spectroscopy are the most powerful approaches. We report here the use of native MS and ion mobility (IM-MS) for the characterization of trastuzumab emtansine (T DM1, Kadcyla((r))). This lysine conjugate is currently being considered for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer, and combines the anti-HER2 antibody trastuzumab (Herceptin((r))), with the cytotoxic microtubule-inhibiting maytansine derivative, DM1. We show that native MS combined with high-resolution measurements and/or charge reduction is beneficial in terms of the accurate values it provides of the average DAR and the drug load profiles. The use of spectral deconvolution is discussed in detail. We report furthermore the use of native IM-MS to directly determine DAR distribution profiles and average DAR values, as well as a molecular modeling investigation of positional isomers in T-DM1. PMID- 25694335 TI - Brief report: isogenic induced pluripotent stem cell lines from an adult with mosaic down syndrome model accelerated neuronal ageing and neurodegeneration. AB - Trisomy 21 (T21), Down Syndrome (DS) is the most common genetic cause of dementia and intellectual disability. Modeling DS is beginning to yield pharmaceutical therapeutic interventions for amelioration of intellectual disability, which are currently being tested in clinical trials. DS is also a unique genetic system for investigation of pathological and protective mechanisms for accelerated ageing, neurodegeneration, dementia, cancer, and other important common diseases. New drugs could be identified and disease mechanisms better understood by establishment of well-controlled cell model systems. We have developed a first nonintegration-reprogrammed isogenic human induced pluripotent stem cell (iPSC) model of DS by reprogramming the skin fibroblasts from an adult individual with constitutional mosaicism for DS and separately cloning multiple isogenic T21 and euploid (D21) iPSC lines. Our model shows a very low number of reprogramming rearrangements as assessed by a high-resolution whole genome CGH-array hybridization, and it reproduces several cellular pathologies seen in primary human DS cells, as assessed by automated high-content microscopic analysis. Early differentiation shows an imbalance of the lineage-specific stem/progenitor cell compartments: T21 causes slower proliferation of neural and faster expansion of hematopoietic lineage. T21 iPSC-derived neurons show increased production of amyloid peptide-containing material, a decrease in mitochondrial membrane potential, and an increased number and abnormal appearance of mitochondria. Finally, T21-derived neurons show significantly higher number of DNA double strand breaks than isogenic D21 controls. Our fully isogenic system therefore opens possibilities for modeling mechanisms of developmental, accelerated ageing, and neurodegenerative pathologies caused by T21. PMID- 25694336 TI - Hidden unilateral aplasia of the frontal sinus: a radioanatomic study. AB - BACKGROUND: Hidden unilateral frontal sinus aplasia is the absence of 1 frontal sinus with increased pneumatization of contralateral sinus toward the aplastic side. It may give the false impression of the presence of 2 separate frontal sinuses, creating potential for complications during the surgery. The aim of this study was to evaluate the prevalence and morphology of this anatomical variation using multiplanar reconstruction of computed tomography (CT) results. METHODS: A total of 305 CT examinations were analyzed. Hidden unilateral frontal sinus aplasia was defined as lack of pneumatization of 1 frontal sinus beyond the level of the orbital roof, with increased pneumatization of the contralateral sinus, extending to the sagittal plane, crossing the lamina papyracea on the side of the aplastic sinus. RESULTS: Eleven patients (3.6%) with hidden unilateral frontal sinus aplasia were identified, 5 on the left and 6 on the right side, in 5 female and 6 male patients. Twenty-four (7.8%) patients with "regular" frontal sinus aplasia (without hyperplastic contralateral frontal sinus) were found, 4 with bilateral aplasia and 20 with unilateral aplasia. CONCLUSION: Hidden unilateral aplasia of the frontal sinus is a relatively uncommon anatomical variation. Its presence should be considered during routine preoperative CT evaluation because it poses the risk of intraoperative complications. PMID- 25694337 TI - Phosphine-catalyzed remote beta-C-H functionalization of amines triggered by trifluoromethylation of alkenes: one-pot synthesis of bistrifluoromethylated enamides and oxazoles. AB - An unprecedented phosphine-catalyzed remote beta-C?H functionalization of amine derivatives triggered by trifluoromethylation of an alkene with Togni's reagent was disclosed. This reaction proceeded through the highly selective and concomitant activation of an unactivated alkene and the beta-C sp 3?H bond of an amine derivative, providing bistrifluoromethylated enamides in excellent yields with good regio-, chemo-, and stereoselectivity. Furthermore, the newly developed one-pot protocol provides a facile and step-economical access to valuable trisubstituted 5-(trifluoromethyl)oxazoles. Mechanistic studies showed that this reaction may initiate with a novel phosphine-catalyzed radical trifluoromethylation of unactivated alkene via a phosphorus radical cation. PMID- 25694338 TI - Interventional radiology for critical hemorrhage in obstetrics: Japanese Society of Interventional Radiology (JSIR) procedural guidelines. AB - There has been an increasing demand for interventional radiology (IR) procedures for the treatment of severe postpartum hemorrhage (PPH) (also called critical hemorrhage in obstetrics). The Japanese Society of Interventional Radiology Guideline Committee developed the practical guidelines for IR procedures for severe PPH using evidence-based methodology. This article aimed to describe the rationale for developing these guidelines and to provide the answers for clinical questions about IR procedures consisting of current available evidence and the consensus among experts. PMID- 25694339 TI - CT-guided aspiration and steroid injection of symptomatic paralabral cysts of the hip. AB - PURPOSE: The objective of this article is to present the clinical use of aspiration and steroid injection under CT guidance for symptomatic paralabral cysts of the hip. MATERIALS AND METHODS: Four cases of symptomatic paralabral cysts of the hip were treated with aspiration and steroid injection after MR examinations had been performed. The imaging characteristics of the cysts, including the location, size, extracapsular extension, and associated labral tears, were evaluated. Under CT guidance, an 18-gauge spinal needle punctured the cyst, and aspiration was performed using local anesthesia. After irrigation with 50 % diluted iodine contrast material, steroid alone or a mixture of steroid and 1 % lidocaine was injected into the cyst. CT images during and after the procedure, procedural reports, and medical records were reviewed for analysis. RESULTS: Three cysts were located in the anteroinferior region, while one cyst was located in the posterior region. At the 1-month follow-up, symptom improvement had been achieved in all four patients. However, in the patient who had the largest cyst with extracapsular extension, symptoms recurred after 5 months, and the patient underwent surgery. CONCLUSION: CT-guided aspiration and steroid injection were feasible for the treatment of symptomatic paralabral cysts of the hip. During the procedures, all four cysts collapsed. PMID- 25694340 TI - Penicillin is the drug of choice to treat all stages of syphilis despite a paucity of clinical trials data for the treatment of some stages, pregnant women and HIV-infected people. PMID- 25694341 TI - Evidence is weak to support hepatocellular carcinoma screening in chronic liver disease. PMID- 25694342 TI - Confronting as autonomy promotion: Speaking up against discrimination and psychological well-being in racial minorities. AB - Few studies have considered confrontation in the context of coping with discriminatory experiences. These studies test for the first time whether confronting racial discrimination is associated with greater psychological well being and physical health through the promotion of autonomy. In two separate samples of racial minorities who had experienced racial discrimination, confrontation was associated with greater psychological well-being, and this relationship was mediated by autonomy promotion. These findings did not extend to physical health symptoms. These studies provide preliminary evidence that confrontation may aid in the process of regaining autonomy after experiencing discrimination and therefore promote well-being. PMID- 25694343 TI - Predictors of suicidality in bariatric surgery candidates. AB - Risk for suicidality (current or past suicidal ideation or attempt) increases after bariatric surgery; however, there is a paucity of research investigating suicidality predictors in this population. This study involved a retrospective chart review of individuals seeking psychological clearance for bariatric surgery. In total, 32 participants (15.8%) were classified as reporting suicidality. These participants endorsed greater depressive symptomatology and hopelessness, and hopelessness and mood disorder diagnosis each uniquely predicted whether or not a patient was classified as reporting suicidality. The findings within suggest that increased attention to the relationship among these variables may improve methods for identification of high-risk patients. Implications for clinical practiced are discussed. PMID- 25694344 TI - The role of narcissism in health-risk and health-protective behaviors. AB - This study examined the role of narcissism in health-risk and health-protective behaviors in a sample of 365 undergraduate students. Regression analyses were used to test the influence of narcissism on health behaviors. Narcissism was positively predictive of alcohol use, marijuana use, and risky driving behaviors, and it was associated with an increased likelihood of consistently having a healthy eating pattern. Narcissism was also positively predictive of physical activity. Results are discussed with reference to the potential short-term and long-term health implications and the need for future research on the factors involved in the relationship between narcissism and health behaviors. PMID- 25694345 TI - Multiple myeloma: Updates for pharmacists in the treatment of relapsed and refractory disease. AB - There have been a number of recent advances in the treatment of patients with relapsed and refractory multiple myeloma. However, despite additional FDA approved therapies including carfilzomib and pomalidomide as well as clinical trials investigating new combinations of existing treatments, multiple myeloma remains an incurable disease. New therapies currently in the drug development pipeline for relapsed and refractory disease include additional proteasome inhibitors (oprozomib, marizomib, ixazomib), histone deacetylase inhibitors (panobinostat, ricolinostat, quisinostat), monoclonal antibodies (daratumumab, elotuzumab, SAR650984), Bruton's tyrosine kinase inhibitors (ibrutinib), a selective inhibitor of nuclear export, and others. This review will focus on these newly developing therapies as well as the ever expanding role of the pharmacist in supportive care for patients with relapsed and refractory multiple myeloma. PMID- 25694346 TI - Ipilimumab may increase the severity of cutenaous toxicity related to radiotherapy. AB - Ipilimumab, monoclonal antibody against cytotoxic T-lymphocyte antigen-4 and, radiotherapy are commonly used to treat unresectable and metastatic melanoma. As a result of upregulation of immune system with ipilimumab, many immune-related adverse effects, such as dermatitis, colitis, hepatitis, and hypophysitis, have been previously reported in literature. Typically, these effects are treated with high-dose steroids and mostly heal up. Here, we report a case who was receiving radiotherapy due to metastatic malignant melanoma with atypical generalized rash, which was enlarged with concurrent ipilimumab treatment. PMID- 25694347 TI - Granulomas and giant cells in hypersensitivity pneumonitis. AB - Hypersensitivity pneumonitis (HP) is an immunologically mediated form of diffuse lung disease, with histopathologic features that include cellular bronchiolitis, interstitial pneumonia, poorly formed granulomas, isolated multinucleated giant cells (MNGCs), organizing pneumonia, and interstitial fibrosis. This study describes the clinical and histopathologic findings in a retrospective series of 40 consecutive patients diagnosed with HP at the Mayo Clinic in Rochester, MN, between 1997 and 2011. Because the literature indicates that granulomas and MNGCs are located in the interstitium, particular attention was given to their distribution. Of the 40 patients, 33 underwent surgical lung biopsy and 7 underwent lung transplantation. Thirty-eight (95%) patients had interstitial pneumonia; 37 (93%), cellular bronchiolitis; 32 (80%), nonnecrotizing granulomas; 31 (78%), isolated MNGCs; 34 (85%) organizing pneumonia, and 31 (78%); interstitial fibrosis. In 27 cases, the granulomas were within airspaces; and in 26, they were interstitial. In 25 cases, MNGCs were within airspaces; and in 24, they were interstitial. In 3 (8%) cases, both granulomas and MNGCs were seen only within airspaces. Interstitial fibrosis was centrilobular in 22 cases, resembled usual interstitial pneumonia in 18 cases, and resembled nonspecific interstitial pneumonia in 11 cases. The "classic triad" of bronchiolitis, interstitial pneumonia, and granulomas was seen in 29 (73%) cases and was most frequent in biopsy than explant specimens (P = .004). This study confirms that granulomas and MNGCs are not confined to the pulmonary interstitium in HP. PMID- 25694348 TI - Escalating chronic kidney diseases of multi-factorial origin (CKD-mfo) in Sri Lanka: causes, solutions, and recommendations-update and responses. PMID- 25694349 TI - A silver-free, reflective substrate electrode for electron extraction in top illuminated organic photovoltaics. AB - The choice of metals suitable as the reflective substrate electrode for top illuminated organic photovoltaics (OPVs) is extremely limited. Herein, we report a novel substrate electrode for this class of OPV architecture based on an Al | Cu | AlOx triple-layer structure, which offers a reflectivity comparable to that of Al over the wavelength range 400-900 nm, a work function suitable for efficient electron extraction in OPVs and high stability towards oxidation. In addition to demonstrating the advantage of this composite electrode over Al in model top-illuminated OPVs, we also present the results of a photoelectron spectroscopy study, which show that an oxidised 0.8 nm Al layer deposited by thermal evaporation onto an Al | Cu reflective substrate electrode is sufficient to block oxidation of the underlying Cu by air or during deposition of a ZnO1-x electron-transport layer. This is remarkable given that the self-limiting oxide thickness on Al metal is greater than 2 nm. PMID- 25694350 TI - A dose-response study of vitamin D3 supplementation in healthy Chinese: a 5-arm randomized, placebo-controlled trial. AB - PURPOSE: To determine the dose-response of vitamin D3 supplementation on serum 25 hydroxyvitamin D [25(OH)D] among Chinese adults. METHODS: In this 5-arm, randomized, double-blinded controlled trial, 76 healthy participants were assigned to orally administrate 0, 400, 800, 1200 or 2000 IU/d of vitamin D3 for 16 weeks. Serum 25(OH)D, parathyroid hormone, calcium, biomarkers of liver and renal function were measured at multiple time points. RESULTS: The mean (SD) serum 25(OH)D at baseline was 31.6 (8.7) nmol/L, and the dose-response relationship was curvilinear with a plateau around 6 weeks for all doses. At week 16, 25(OH)D was increased by 6.0 (6.5), 21.7 (15.8), 26.3 (12.6), 32.0 (12.8) and 36.3 (26.0) nmol/L for 0, 400, 800, 1200 and 2000 IU/d (all P <= 0.002), corresponding to approximately 19, 53, 67, 77 and 80 % of reversion of vitamin D deficiency, respectively. Daily intake of 800 IU vitamin D3 reached a targeted 25(OH)D >= 30 nmol/L in at least 97.5 % of Chinese, but not a targeted 25(OH)D >= 50 nmol/L even with 2000 IU/d. Change of 25(OH)D was inversely associated with change of PTH concentration (r = -0.39, P < 0.001) after controlling for age and sex. No between-group differences were observed in terms of the change in serum calcium, alanine transaminase, aspartate aminotransferase, gamma glutamyltransferase and creatinine (P >= 0.22). CONCLUSIONS: Supplementation with 400, 800, 1200 or 2000 IU/d vitamin D could improve the vitamin D deficiency with various degrees. Whether 2000 IU/d vitamin D3 would generate a better result without side effect requires more studies with larger samples in future. PMID- 25694351 TI - Circulating CUDR, LSINCT-5 and PTENP1 long noncoding RNAs in sera distinguish patients with gastric cancer from healthy controls. AB - The examination of circulating nucleic acids (CNAs) is an emerging noninvasive diagnostic technique. However, it is unclear if serum long noncoding RNAs (lncRNAs) represent a novel marker to detect gastric cancer (GC). In this study, we measured 39 candidate cancer-associated lncRNAs by reverse transcription and quantitative polymerase chain reaction (RT-qPCR) in sera from 110 patients with GC, 106 age- and sex-matched healthy subjects and 15 patients with gastric peptic ulcer, markers were validated and assessed by RT-qPCR. The correlation of the expression levels of the candidate serum lncRNAs with clinical parameters of GC patients was performed. A three-lncRNA signature, including CUDR, LSINCT-5 and PTENP1, was identified that may be potential diagnostic marker for GC. The areas under the receiver operating characteristic (ROC) curve for this serum three lncRNA signature were 0.920 and 0.829 for the two sets of serum samples. Moreover, a risk model for the serum three-lncRNA signature demonstrated that healthy samples can be distinguished from early GC samples. Three-lncRNA signature in serum was identified as diagnostic marker for GC. This work may facilitate the detection of GC and serve as the basis for further studies of the clinical value of serum lncRNAs in maintaining surveillance and forecasting prognosis. PMID- 25694352 TI - Tumor-specific mutations in low-frequency genes affect their functional properties. AB - Causal genetic changes in oligodendrogliomas (OD) with 1p/19q co-deletion include mutations in IDH1, IDH2, CIC, FUBP1, TERT promoter and NOTCH1. However, it is generally assumed that more somatic mutations are required for tumorigenesis. This study aimed to establish whether genes mutated at low frequency can be involved in OD initiation and/or progression. We performed whole-genome sequencing on three anaplastic ODs with 1p/19q co-deletion. To estimate mutation frequency, we performed targeted resequencing on an additional 39 ODs. Whole genome sequencing identified a total of 55 coding mutations (range 8-32 mutations per tumor), including known abnormalities in IDH1, IDH2, CIC and FUBP1. We also identified mutations in genes, most of which were previously not implicated in ODs. Targeted resequencing on 39 additional ODs confirmed that these genes are mutated at low frequency. Most of the mutations identified were predicted to have a deleterious functional effect. Functional analysis on a subset of these genes (e.g. NTN4 and MAGEH1) showed that the mutation affects the subcellular localization of the protein (n = 2/12). In addition, HOG cells stably expressing mutant GDI1 or XPO7 showed altered cell proliferation compared to those expressing wildtype constructs. Similarly, HOG cells expressing mutant SASH3 or GDI1 showed altered migration. The significantly higher rate of predicted deleterious mutations, the changes in subcellular localization and the effects on proliferation and/or migration indicate that many of these genes functionally may contribute to gliomagenesis and/or progression. These low-frequency genes and their affected pathways may provide new treatment targets for this tumor type. PMID- 25694354 TI - Treatment of anxiety during pregnancy: room to grow. PMID- 25694355 TI - Cost-effectiveness of prophylactic granulocyte colony-stimulating factor for febrile neutropenia in breast cancer patients receiving FEC-D. AB - 5-fluorouracil, epirubicin, cyclophosphamide -> docetaxel (FEC-D) has been associated with higher-than-expected rates of febrile neutropenia (FN) that meet the current guideline threshold of 20 % for primary prophylaxis (PP) with granulocyte colony-stimulating factor (G-CSF). We examined the cost-effectiveness of FEC-D with varying strategies of G-CSF prophylaxis from the perspective of the public payer in Ontario, Canada. A state-transition model was developed to compare three strategies: FEC-D with secondary prophylaxis (SP) only, PP starting with the first cycle of D, and PP starting with the first cycle of FEC. Analysis was conducted for a hypothetical cohort of 50-year-old early-stage breast cancer patients undergoing adjuvant chemotherapy, at a 10-year horizon. Results were expressed in quality-adjusted life-years (QALYs) and 2013 Canadian dollars. Costs and benefits were discounted at 5 %. Event rates, costs, and utilities were derived from the literature. One-way and probabilistic sensitivity analyses were conducted. Using filgrastim, the incremental cost-effectiveness ratios (ICERs) for starting PP with the first cycle of D and starting PP with the first cycle of FEC, compared to using SP only, were $57,886/QALY and $116,186/QALY, respectively. With pegfilgrastim, the ICERs for the same strategies were $90,735/QALY and $149,483/QALY. Compared to using filgrastim SP only, starting PP with D had a 24 % chance of being cost-effective at a willingness-to-pay (WTP) threshold of $50,000/QALY, and a 99 % chance at a WTP threshold of $100,000/QALY. Results were sensitive to FN-related parameters, such as the risk of FN per cycle with D and the associated mortality, but were robust to uncertainty in parameters related to breast cancer, such as the utilities and hazard of relapse. FEC-D with PP starting with the first cycle of D is most likely to be cost-effective, especially with increased risk of FN and mortality from FN. PMID- 25694356 TI - The interaction mechanism between lipopeptide (daptomycin) and polyamidoamine (PAMAM) dendrimers. AB - The interaction mechanism of lipopeptide antibiotic daptomycin and polyamidoamine (PAMAM) dendrimers was studied using fluorescence spectroscopy. The fluorescence changes observed are associated with daptomycin-dendrimer interactions. The binding isotherms were constructed by plotting the fluorescence difference at 460 nm from kynurenine (Kyn-13) of daptomycin in the presence and absence of dendrimer. A one-site and two-site binding model were quantitatively generated to estimate binding capacity and affinity constants from the isotherms. The shape of the binding isotherm and the dependence of the estimated capacity constants on dendrimer sizes and solvent pH values provide meaningful insight into the mechanism of interactions. A one-site binding model adequately describes the binding isotherm obtained under a variety of experimental conditions with dendrimers of various sizes in the optimal binding pH region 3.5 to 4.5. Comparing the pH-dependent binding capacity with the ionization profiles of daptomycin and dendrimer, the ionized aspartic acid residue (Asp-9) of daptomycin primarily interact with PAMAM cationic surface amine. PMID- 25694357 TI - Diversity of yeast and mold species from a variety of cheese types. AB - To generate a comprehensive profile of viable fungi (yeasts and molds) on cheese as it is purchased by consumers, 44 types of cheese were obtained from a local grocery store from 1 to 4 times each (depending on availability) and sampled. Pure cultures were obtained and identified by DNA sequence of the ITS region, as well as growth characteristics and colony morphology. The yeast Debaryomyces hansenii was the most abundant fungus, present in 79 % of all cheeses and 63 % of all samples. Penicillium roqueforti was the most common mold, isolated from a variety of cheeses in addition to the blue cheeses. Eighteen other fungal species were isolated, ten from only one sample each. Most fungi isolated have been documented from dairy products; a few raise potential food safety concerns (i.e. Aspergillus flavus, isolated from a single sample and capable of producing aflatoxins; and Candida parapsilosis, an emerging human pathogen isolated from three cheeses). With the exception of D. hansenii (present in most cheese) and P. roqueforti (a necessary component of blue cheese), no strong correlation was observed between cheese type, manufacturer, or sampling time with the yeast or mold species composition. PMID- 25694358 TI - Reliability of vertebral fractures assessment (VFA) in children with osteogenesis imperfecta. AB - The aim of this study is to evaluate the diagnostic accuracy of vertebral fractures assessment (VFA) in comparison with conventional radiography in identifying vertebral fractures in children and adolescents affected by OI. On 58 patients (33 males, 25 females; age range 1-18 years; 41 children and 17 adolescents) with osteogenesis imperfecta (OI type I, n = 44, OI type III, n = 4; OI type IV, n = 10), lateral spine images by radiographs and by dual-energy X-ray absorptiometry (DXA) were acquired. For vertebral fracture diagnosis, plain radiographs were used as "gold standard" and VFA and morphometric X-ray absorptiometry (MXA) were performed. The visualized vertebrae were 738 (97.9%) by radiographs and 685 (90.9%) by DXA of a total of 754 vertebrae from T4 to L4. VFA and MXA identified, respectively, 129 (74%) and 116 (66%) of the 175 vertebral fractures detected by radiographs. Radiographs identified 36 patients with vertebral fractures, VFA 35 and MXA 41 (6 false positives). On a per vertebra basis, radiographs and VFA had elevated agreement (93.9%; k score 0.81, 95% CI 0.76-0.86), that resulted slightly lower for MXA (90.6%; k score 0.72, 95% CI 0.65-0.78). VFA and MXA demonstrated high sensitivity (95.6 and 94.1 %, respectively) while specificity was 100% for VFA and 90.6% for MXA on a per patient basis; the agreement was excellent for VFA (98.3%; k score 0.96, 95% CI 0.89-1.03) and good for MXA (87.9%; k score 0.73, 95% CI 0.55-0.91). The diagnostic performance parameters resulted better for VFA (sensitivity 95.6%; specificity 100%; PPV 100%; NPV 97.2%), than for MXA (sensitivity 94.1%; specificity 85.4%; PPV 72.7%; NPV 97.2%). The results of our study demonstrate the reliability of VFA for diagnosis of vertebral fractures in children with OI suggesting its use as a more safe and practical alternative to conventional radiography. PMID- 25694359 TI - Deteriorating effect on bone metabolism and microstructure by passive cigarette smoking through dual actions on osteoblast and osteoclast. AB - There is no clear evidence to show the direct causal relationship between passive cigarette smoking and osteoporosis. Furthermore, the underlying mechanism is unknown. The objective of this study is to demonstrate the effects of long-term passive cigarette smoking on bone metabolism and microstructure by a mouse model and cell culture systems. BALB/c mice were exposed to 2 or 4 % cigarette smoke for 14 weeks. The bone turnover biochemical markers in urine and serum and also the bone micro-architecture by micro-CT were compared with the control group exposed to normal ambient air. In the cell culture experiments, mouse MC3T3-E1 and RAW264.7 cell lines to be employed as osteoblast and osteoclast, respectively, were treated with the sera obtained from 4 % smoking or control mice. Their actions on cell viability, differentiation, and function on these bone cells were assessed. The urinary mineral and deoxypyridinoline (DPD) levels, and also the serum alkaline phosphatase activity, were significantly higher in the 4 % smoking group when compared with the control group, indicating an elevated bone metabolism after cigarette smoking. In addition, femoral osteopenic condition was observed in the 4 % smoking group, as shown by the decrease of relative bone volume and trabecular thickness. In isolated cell studies, osteoblast differentiation and bone formation were inhibited while osteoclast differentiation was increased. The current mouse smoking model and the isolated cell studies demonstrate that passive cigarette smoke could induce osteopenia by exerting a direct detrimental effect on bone cells differentiation and further on bone remodeling process. PMID- 25694360 TI - Dickkopf-1 and sclerostin serum levels in patients with systemic mastocytosis. AB - Bone involvement, mainly osteoporosis but also osteosclerosis, is frequent in patients with indolent systemic mastocytosis (ISM). The recent characterization of the canonical Wnt/beta-catenin pathway in the regulation of bone remodeling provided important insights for our understanding of the pathophysiology of a number of conditions. The regulation of Wnt pathway in bone is predominantly driven by the production of receptor inhibitors such as Dickkopf-1 (DKK1) and sclerostin (SOST). This study aimed to explore if the various bone involvements in patients with ISM might be explained by variations in serum levels of DKK1 and SOST. This is a cross-sectional study in an adult ISM cohort (13 men and 13 women with diagnosed ISM) and fifty-two healthy sex and age-matched controls. Early morning, fasting and venous sampling was obtained in all subjects. The main outcome measures were serum bone-specific alkaline phosphatase (bALP), C-terminal telopeptides of type I collagene (CTX), DKK1, SOST, parathyroid hormone (PTH), bone mineral density, and prevalent vertebral fractures. Mean DKK1 serum levels were about two-folds higher in patients, than in controls (65,0 +/- 43.3 vs. 33.1 +/- 19.4 pmol/L, respectively; p < 0.001), irrespective of the presence of osteoporotic or diffuse osteosclerotic bone involvement. DKK1 serum levels were positively correlated with PTH and both CTX and bALP. Mean SOST serum levels were not significantly different in patients versus controls, and we did not observe any significant correlation between SOST and any available clinical or laboratory parameters, with the only exception of a positive correlation with age. In conclusion, in our study, we observed that DKK1, but not SOST, serum levels significantly increased in ISM patients with various bone involvements, and correlated with PTH and bone turnover markers. Our results suggest that the Wnt/beta-catenin pathway is not primarily involved in the pathophysiology of the array of bone involvement in ISM. PMID- 25694361 TI - Development of a cyclosporin-A-induced immune tolerant rat model to test marrow allograft cell type effects on bone repair. AB - Bone repair is an important concept in tissue engineering, and the ability to repair bone in hypotrophic conditions such as that of irradiated bone, represents a challenge for this field. Previous studies have shown that a combination of bone marrow and (BCP) was effective to repair irradiated bone. However, the origin and role played by each cell type in bone healing still remains unclear. In order to track the grafted cells, the development of an animal model that is immunotolerant to an allograft of bone marrow would be useful. Furthermore, because the immune system interacts with bone turnover, it is of critical importance to demonstrate that immunosuppressive drugs do not interfere with bone repair. After a preliminary study of immunotolerance, cyclosporin-A was chosen to be used in immunosuppressive therapy. Ten rats were included to observe qualitative and quantitative bone repair 8 days and 6 weeks after the creation of bone defects. The defects were filled with an allograft of bone marrow alone or in association with BCP under immunosuppressive treatment (cyclosporin-A). The results showed that there was no significant interaction of cyclosporin-A with osseous regeneration. The use of this new immunotolerant rat model of bone marrow allograft in future studies will provide insight on how the cells within the bone marrow graft contribute to bone healing, especially in irradiated conditions. PMID- 25694362 TI - Argan oil reduces, in rats, the high fat diet-induced metabolic effects of obesity. AB - BACKGROUND AND AIM: Obesity is a multi-factorial disorder which is of worldwide concern. In addition to calorie control, some specific dietary components might help resolving some of the complication of obesity, by providing antioxidant and anti-inflammatory activities. We investigated the effect of argan oil supplementation on plasma lipid profile and oxidant-antioxidant status of rats with high-fat diet (HFD)-induced obesity compared with rats fed a normal diet (ND). METHODS AND RESULTS: We used an animal model of high fat diet-induced obesity to study the metabolic effects of argan oil and we measured several markers lipid and redox statuses. Consumption of a high-fat diet led to an increase in serum total cholesterol (TC), LDL-cholesterol (LDL-C), and triacylglycerols (TAG) concentrations; however, argan oil blunted the increases of TC, LDL-C and TG, glucose, and insulin. Plasma total antioxidant capacity, erythrocyte catalase and superoxide dismutase activities were lower, whereas plasma hydroperoxide, thiobarbituric acid-reacting substances, and susceptibility of LDL to copper-induced oxidation were higher in obese rats compared with normal rats. Administration of argan oil ameliorated all these indices of redox status. CONCLUSIONS: Proper diet and lifestyle should be foremost implemented to reduce the lipoprotein metabolism and oxidant/antioxidant status alterations brought about by obesity. In addition, argan oil reduces the metabolic effects of obesity and its use might be promoted within the context of a balanced diet. PMID- 25694363 TI - Brief Report: The Role of Task Support in the Spatial and Temporal Source Memory of Adults with Autism Spectrum Disorder. AB - Adults with autism spectrum disorder (ASD) show intact recognition (supported procedure) but impaired recall (unsupported procedure) of incidentally-encoded context. Because this has not been demonstrated for temporal source, we compared the temporal and spatial source memory of adults with ASD and verbally matched typical adults. Because of difficulties with temporal processing in ASD, we predicted ASD adults would benefit from test support for location but not temporal occurrence of studied words. We found similar levels of recognition and source memory for both groups but there was a greater effect of support on memory for location source in the ASD group. The lack of an effect of support for temporal source may simply reflect a difficulty in operationalising temporal cues. PMID- 25694364 TI - Computer-Assisted Face Processing Instruction Improves Emotion Recognition, Mentalizing, and Social Skills in Students with ASD. AB - This study examined the extent to which a computer-based social skills intervention called FaceSay was associated with improvements in affect recognition, mentalizing, and social skills of school-aged children with Autism Spectrum Disorder (ASD). FaceSay offers students simulated practice with eye gaze, joint attention, and facial recognition skills. This randomized control trial included school-aged children meeting educational criteria for autism (N = 31). Results demonstrated that participants who received the intervention improved their affect recognition and mentalizing skills, as well as their social skills. These findings suggest that, by targeting face-processing skills, computer-based interventions may produce changes in broader cognitive and social skills domains in a cost- and time-efficient manner. PMID- 25694365 TI - Self-assembled discrete molecules for sensing nitroaromatics. AB - Efficient sensing of trace amount nitroaromatic (NAC) explosives has become a major research focus in recent time due to concerns over national security as well as their role as environment pollutants. NO2 -containing electron-deficient aromatic compounds, such as picric acid (PA), trinitrotoluene (TNT), and dinitrotoluene (DNT), are the common constituents of many commercially available chemical explosives. In this article, we have summarized our recent developments on the rational design of electron-rich self-assembled discrete molecular sensors and their efficacy in sensing nitroaromatics both in solution as well as in vapor phase. Several pi-electron-rich fluorescent metallacycles (squares, rectangles, and tweezers/pincers) and metallacages (trigonal and tetragonal prisms) have been synthesized by means of metal-ligand coordination-bonding interactions, with enough internal space to accommodate electron-deficient nitroaromatics at the molecular level by multiple supramolecular interactions. Such interactions subsequently result in the detectable fluorescence quenching of sensors even in the presence of trace quantities of nitroaromatics. The fascinating sensing characteristics of molecular architectures discussed in this article may enable future development of improved sensors for nitroaromatic explosives. PMID- 25694366 TI - [Dynamic versus static cement spacer in periprosthetic knee infection: A meta analysis]. AB - BACKGROUND: The standard of care for treatment of periprosthetic joint infection (PJI) after total knee arthroplasty (TKA) is two-stage revision arthroplasty. The cement spacer in the interim period can be classified as either a static/non articulating spacers (e.g., traditionally simple cement blocks) or a mobile/articulating spacer. OBJECTIVES: The goal of the present meta-analysis is to analyze the outcomes with regard to infection control between dynamic and static knee spacers in the treatment of infected TKA with a minimum 3-year follow up. MATERIALS AND METHODS: We systematically reviewed the literature for potentially relevant articles addressing two-stage revision of an infected TKA using the MEDLINE computerized literature databases. Only 25 articles studies with a minimum follow-up examination of 36 months met the inclusion criteria and were analyzed with regard to infection control after reimplantation between static (318 cases) and dynamic group (700 cases). RESULTS: At latest follow-up, the eradication rate in the dynamic group was 89.7% (range 63-100%; SD 9.1) and in the static group 84.8% (range 67-92.4%; SD 7.8; p = 0.32). We are unable to comment on the Hospital for Special Surgery (HSS) Score and complication rates between static and dynamic spacers because the majority of the studies did not report on this. CONCLUSION: The data show that there are no differences regarding infection control between static and dynamic spacers in the treatment of infected TKA. PMID- 25694367 TI - A look into amyloid formation by transthyretin: aggregation pathway and a novel kinetic model. AB - The aggregation of proteins into insoluble amyloid fibrils is the hallmark of many, highly debilitating, human pathologies such as Alzheimer's or Parkinson's disease. Transthyretin (TTR) is a homotetrameric protein implicated in several amyloidoses like Senile Systemic Amyloidosis (SSA), Familial Amyloid Polyneuropathy (FAP), Familial Amyloid Cardiomyopathy (FAC), and the rare Central Nervous System selective Amyloidosis (CNSA). In this work, we have investigated the kinetics of TTR aggregation into amyloid fibrils produced by the addition of NaCl to acid-unfolded TTR monomers and we propose a mathematically simple kinetic mechanism to analyse the aggregation kinetics of TTR. We have conducted circular dichroism, intrinsic tryptophan fluorescence and thioflavin-T emission experiments to follow the conformational changes accompanying amyloid formation at different TTR concentrations. Kinetic traces were adjusted to a two-step model with the first step being second-order and the second being unimolecular. The molecular species present in the pathway of TTR oligomerization were characterized by size exclusion chromatography coupled to multi-angle light scattering and by transmission electron microscopy. The results show the transient accumulation of oligomers composed of 6 to 10 monomers in agreement with reports suggesting that these oligomers may be the causative agent of cell toxicity. The results obtained may prove to be useful in understanding the mode of action of different compounds in preventing fibril formation and, therefore, in designing new drugs against TTR amyloidosis. PMID- 25694368 TI - Primary malignant melanoma of the urethra detected by urine cytology in a male patient. PMID- 25694369 TI - A covalent approach for site-specific RNA labeling in Mammalian cells. AB - Advances in RNA research and RNA nanotechnology depend on the ability to manipulate and probe RNA with high precision through chemical approaches, both in vitro and in mammalian cells. However, covalent RNA labeling methods with scope and versatility comparable to those of current protein labeling strategies are underdeveloped. A method is reported for the site- and sequence-specific covalent labeling of RNAs in mammalian cells by using tRNA(Ile2) -agmatidine synthetase (Tias) and click chemistry. The crystal structure of Tias in complex with an azide-bearing agmatine analogue was solved to unravel the structural basis for Tias/substrate recognition. The unique RNA sequence specificity and plastic Tias/substrate recognition enable the site-specific transfer of azide/alkyne groups to an RNA molecule of interest in vitro and in mammalian cells. Subsequent click chemistry reactions facilitate the versatile labeling, functionalization, and visualization of target RNA. PMID- 25694370 TI - Direct interactions in the recognition between the environmental estrogen bisphenol AF and human serum albumin. AB - Bisphenol AF (BPAF) was used as a model compound to investigate the binding mechanism between the endocrine disrupting compound and human serum albumin (HSA) using multispectroscopic techniques and molecular modeling method at the protein level. The results indicated that BPAF was indeed bound to HSA and located in the hydrophobic pocket of HSA on subdomain IIA through hydrogen bond and van der Waals interactions. The fluorescence quenching data showed that the binding of BPAF and HSA quenched the intrinsic fluorescence of HSA, and the static quenching constants were acquired. PMID- 25694371 TI - The effectiveness of lumbar extensor training: local stabilization or dynamic strengthening exercises. A review of literature. AB - BACKGROUND: Deconditioning of the lumbar extensor musculature (lumbar erector spinae and multifidus) is a risk factor for low back injury and pain. The article presents various aspects of scientific reports which confirm the effectiveness of lumbar extensor exercises. MATERIAL AND METHODS: The articles to be reviewed were extracted from the MedLine and PubMed data - bases. The following key words were used as search terms: lumbar multifidus muscle exercises, low back global exercise, motor control exercise in chronic low back pain, low back stabilization exercise. RESULTS: A number of prior investigations have described lumbar multifidus atrophy and replacement by fat after low back injury. Restoration of the tonic activity of the multifidus muscle is an essential condition in regaining health and spine functions. On the other hand, conditioning and strengthening exercises are considered valuable in effectively 'pre-habilitating' and reducing injury risk for athletes. CONCLUSIONS: 1. The lumbar low load specific stabilization exercises would be more efficient than muscle strengthening in the improvement of chronic low back pain. 2. Conditioning and strengthening exercises are considered valuable in effectively 'pre-habilitating' and reducing injury risk for athletes. PMID- 25694372 TI - Capitellar fractures in children. AB - BACKGROUND: Capitellar fractures are extremely rare. The Polish literature does not provide any reports on the treatment of these fractures. The aim of this paper is to present our treatment results and to compare them with reports from other authors. MATERIAL AND METHODS: We investigated a group of 9 patients aged 7 17 years (mean age 14 years). One patient (11%) had sustained a non-displaced fracture, while 8 (89%) had sustained fractures with more than 2 mm displacement. According to the type of fracture, one patient was treated conservatively and the others underwent surgical treatment. In the children who were operated on, the humeral capitulum was fixed with a bioabsorbable pin in one patient and with K wires in seven patients. Objective elbow function was evaluated using the Mayo Elbow Score (MES). Subjective elbow function was evaluated by patients on the basis of the Oxford Elbow Score (OES). CONCLUSIONS: 1. Non-displaced capitellar fractures should be treated conservatively. 2. Fractures with more than 2 mm displacement should be reduced surgically with percutaneous fixation with K wires. PMID- 25694373 TI - Influence of neurophysiological hippotherapy on the transference of the centre of gravity among children with cerebral palsy. AB - BACKGROUND: The aim of the study was to present the influence of neurophysiological hippotherapy on the transference of the centre of gravity (COG) among children with cerebral palsy (CP). MATERIAL AND METHODS: The study involved 19 children aged 4-13 years suffering from CP who demonstrated an asymmetric (A/P) model of compensation. Body balance was studied with the Cosmogamma Balance Platform. An examination on this platform was performed before and after a session of neurophysiological hippotherapy. In order to compare the correlations and differences between the examinations, the results were analysed using Student's T-test for dependent samples at p <= 0.05 as the level of statistical significance and descriptive statistics were calculated. RESULTS: The mean value of the body's centre of gravity in the frontal plane (COG X) was 18.33 (mm) during the first examination, changing by 21.84 (mm) after neurophysiological hippotherapy towards deloading of the antigravity lower limb (p <= 0.0001). The other stabilographic parameters increased; however, only the change in average speed of antero - posterior COG oscillation was statistically significant (p = 0.0354). CONCLUSION: 1. One session of neurophysiological hippotherapy induced statistically significant changes in the position of the centre of gravity in the body in the frontal plane and the average speed of COG oscillation in the sagittal plane among CP children demonstrating an asymmetric model of compensation (A/P). PMID- 25694374 TI - Exposure of the surgeon's hands to radiation during hand surgery procedures. AB - BACKGROUND: The objective of the study was to assess the time of exposure of the surgeon's hands to radiation and calculate of the equivalent dose absorbed during surgery of hand and wrist fractures with C-arm fluoroscope guidance. MATERIAL AND METHODS: The necessary data specified by the objective of the study were acquired from operations of 287 patients with fractures of fingers, metacarpals, wrist bones and distal radius. 218 operations (78%) were percutaneous procedures and 60 (22%) were performed by open method. Data on the time of exposure and dose of radiation were acquired from the display of the fluoroscope, where they were automatically generated. These data were assigned to the individual patient, type of fracture, method of surgery and the operating surgeon. RESULTS: Fixations of distal radial fractures required longer times of radiation exposure (mean 61 sec.) than fractures of the wrist/metacarpals and fingers (38 and 32 sec., respectively), which was associated with absorption of significantly higher equivalent doses. Fixations of distal radial fractures by open method were associated with statistically significantly higher equivalent doses (0.41 mSv) than percutaneous procedures (0.3 mSv). Fixations of wrist and metacarpal bone fractures by open method were associated with lower equivalent doses (0.34 mSv) than percutaneous procedures (0.37 mSv),but the difference was not significant. Fixations of finger fractures by open method were associated with lower equivalent doses (0.13 mSv) than percutaneous procedures (0.24 mSv), the difference being statistically non-significant. Statistically significant differences in exposure time and equivalent doses were noted between 4 surgeons participating in the study, but no definitive relationship was found between these parameters and surgeons' employment time. CONCLUSIONS: 1. Hand surgery procedures under fluoroscopic guidance are associated with mild exposure of the surgeons' hands to radiation. 2. The equivalent dose was related to the type of fracture, operative technique and - to some degree - to the time of employment of the surgeon. PMID- 25694375 TI - Utility of craniosacral therapy in treatment of patients with non-specific low back pain. Preliminary report. AB - BACKGROUND: Non-specific low back pain is an increasingly common musculoskeletal ailment. The aim of this study was to examine the utility of craniosacral therapy techniques in the treatment of patients with lumbosacral spine overload and to compare its effectiveness to that of trigger point therapy, which is a recognised therapeutic approach. MATERIAL AND METHODS: The study enrolled 55 randomly selected patients (aged 24-47 years) with low back pain due to overload. Other causes of this condition in the patients were ruled out. The participants were again randomly assigned to two groups: patients treated with craniosacral therapy (G-CST) and patients treated with trigger point therapy (G-TPT). Multiple aspects of the effectiveness of both therapies were evaluated with the use of: an analogue scale for pain (VAS) and a modified Laitinen questionnaire, the Schober test and surface electromyography of the multifidus muscle. The statistical analysis of the outcomes was based on the basic statistics, the Mann-Whitney U test and Wilcoxon's signed rank test. The statistical significance level was set at p<=0.05. RESULTS: Both groups demonstrated a significant reduction of pain measured with the VAS scale and the Laitinen questionnaire. Moreover, the resting bioelectric activity of the multifidus muscle decreased significantly in the G CST group. The groups did not differ significantly with regard to the study parameters. CONCLUSIONS: 1. Craniosacral therapy and trigger point therapy may effectively reduce the intensity and frequency of pain in patients with non specific low back pain. 2. Craniosacral therapy, unlike trigger point therapy, reduces the resting tension of the multifidus muscle in patients with non specific lumbosacral pain. The mechanism of these changes requires further research. 3. Craniosacral therapy and trigger point therapy may be clinically effective in the treatment of patients with non-specific lumbosacral spine pain. 4. The present findings represent a basis for conducting further and prospective studies of larger and randomized samples. PMID- 25694376 TI - Problems of patients with degenerative disease of the spine and their guality of life. AB - BACKGROUND: The aim of the study was to investigate health problems in patients with degenerative disease of the spine (the main reason for deterioration of physical fitness) and to determine the need for health education. MATERIAL AND METHODS: The study involved 50 people. A diagnostic survey with an ad hoc questionnaire was used. Quality of life was assessed with the WHOQOL-BREF questionnaire. The HAQ-DI indicator of disability was used to assess the respondents' health status. RESULTS: Biological problems in the respondents included pain (60%). Psychological problems included a sense of inferiority (54%) and feeling lonely (24%). The most frequent difficulties in fulfilling social roles were problems associated with low social and occupational activity (56%). The patients assessed their health as significantly worse (p = 0.006) than the quality of their lives. The quality of life was the highest (67.9 points) in the social sphere, and the lowest (60.9 points) in the psychological sphere. CONCLUSIONS: 1. The main health problems reported by the study participants were cervical and lumbar spinal pain experienced during prolonged physical activity in the course of daily living activities. 2. The quality of life decreases with increasing difficulty in performing daily activities. 3. It is important to strengthen patients' belief that physical activity, including physiotherapy, has a positive impact on physical fitness and the ability to perform daily activities. 4. An important aim of the therapeutic team is to support and motivate patients to cope with difficult situations and function in society. PMID- 25694377 TI - Treatment of subtalar calcanean fractures using trans-osseous limited lateral approach. AB - BACKGROUND: Calcaneal fractures are the most common fractures of the tarsal bones. The majority of these fractures are produced by axial force like a fall from a height. Controversy still exists on the best line of treatment. This study is to evaluate the results of trans-osseous limited lateral approach as a minimally invasive surgical treatment of the displaced intra-articular calcaneal fractures. MATERIAL AND METHODS: The study included forty two patients (46 feet) with displaced intra-articular calcaneal fractures admitted to El-Hadra University Hospital. They were treated by trans-osseous open reduction of subtalar joint and internal fixation by k-wires consuming the trans-osseous limited lateral approach. Out of 42 patients, 36 pateints (85.7%) were males. RESULTS: Using calcaneal fracture scoring system, the mean score was 67.55+17.35. Satisfactory results were found in 26 patients (61.9%), while 16 patients (38.1%) had unsatisfactory results. There was significant relationship between classification of the fracture and the final results (the more the grade of the fracture, the worse the final score) (x 2 =5.914, p=0.05). The value of calcaneal angles were significantly improved after surgery including bohler angle (p=0.0001), gissane angle (p=0.0001), calcaneal pitch angle (p=0.001) and calcaneofibular space (p=0.0021). CONCLUSIONS: 1. Trans-osseous limited lateral approach is an effective method for management of intra articular calcaneal fractures. 2. Anatomical reduction for intra articular calcaneal fractures is essential. 3. Functional outcome of intra articular calcaneal fractures depends upon the initial damage of the articular cartilage. 4. There is a need for multi center prospective randomized study for accurate assessment of the results of operative management of intra articular calcaneal fractures involving pre and post-operative CT for assessment of reduction and using a rational scoring system and a long period of follow up. PMID- 25694378 TI - Midterm functional outcome after operative management of midfoot injuries. AB - Background. Injuries of the midfoot are often missed and therefore underestimated. Early diagnosis and treatment are crucial for the final outcome. The primary aim of this study was to assess the pattern and results of early operative management of mid-foot injuries after a midterm follow up. Material and methods. This study was conducted on 25 patients (19 Males, 6 Females ) with mean age of 34.6 years (range 18-60 years) with mid-foot fracture dislocations who were admitted consecutively at our centre from May 2008 through November 2010. 25 patients fulfilling our inclusion criteria with mid-foot fracture dislocations were included in this study. Mechanism of injury, its pattern and results of operative management of midfoot injuries were assessed after acute management of these fractures on urgent basis. Evaluation of results was done by AOFAS Score. Results. Most common mode of injury was indirect trauma due to fall (n=12) followed by road traffic accident (n=9). Males (n=19) outnumbered females (n=6). The pattern of injuries requiring operative treatment as per our criteria were Lisfranc fracture dislocations (n=22) and navicular fractures (n=3). The mean follow up was 3.2 years and mean AOFAS score at 3.2 years was 78.36, with most patients losing points to pain and decreased recreational function. Conclusion. The Lisfranc fracture dislocations are the most common injuries around midfoot requiring operative treatment, and we believe that operative treatment considerably improves functional outcome in these injuries. PMID- 25694379 TI - Symptoms of depression in elderly patients with osteoarticular diseases undergoing hospital rehabilitation. AB - BACKGROUND: To evaluate the impact of hospital rehabilitation on depression among patients with osteo articular diseases. MATERIAL AND METHODS: An ad hoc questionnaire designed by the authors were the Beck scale and Laitinen scale administered to 50 hospitalized patients with osteoarticular diseases before and after rehabilitation. RESULTS: Symptoms of depression were found in 16 of the 50 patients (32%) on admission to the hospital compared to 8 (16%) after completing rehabilitation (Chi 2 = 4.08, p = 0.0433). The differences in the Beck scale for each of the respondents before and after physiotherapy were statistically significant (p <0.0001). We found a correlation between the occurrence of depression, and the presence of co-morbidities before and after rehabilitation (r = 0.29, r = 0.34). Before (r = 0.36, p = 0.0094) and after rehabilitation (r = 0.64, p <0.0001), symptoms of depression correlated with pain severity. 49 patients (98%), including all 16 with depression, complained of pain. Rehabilitation produced a reduction in pain frequency (p <0.0001), intensity (p <0.0001), medi cation use (p <0.0001) and movement limitation (p = 0.0004). CONCLUSIONS: 1. Patient age, osteoarticular diseases and comorbidities correlated positively with symptoms of depression. 2. Hospital-based rehabilitation of patients with osteoarticular diseases had a significant impact on reducing the incidence and severity of pain and reducing the consumption of analgesics. 3. Hospital rehabilitation helps eliminate or reduce the severity of symptoms of depression and markedly improves patients' daily functioning. PMID- 25694380 TI - Intramedullary stabilization and over-nail lengthening as two-stage treatment of femoral nonunion with shortening. Case study. AB - Nonunion is one of the most serious complications of long bone fractures. It may be accompanied by a shortening of the segment. The authors describe the case of a 21-year-old woman with a post-traumatic nonunion with shortening of the femur. Treatment was divided into two stages: first, a previously placed nail was removed and new intramedullary stabilization was carried out while bone defects were filled with a bone graft substitute and platelet rich plasma was administered. After the nonunion had healed, the femur was lengthened over an external fixator and an intramedullary nail, resulting in equality of limb length. After eight years of follow-up, the lower limbs remain equal with a properly aligned long axis of the lower limb operated on and a full range of motion in the joints. The treatment strategy described in our article may be an alternative to one-stage surgery if the patient does not consent to it or in the presence of contraindications, but it is associated with a longer treatment time and necessity of additional surgeries. PMID- 25694381 TI - Lymphorrhoea as an early complication after decompression of C5 and C6 roots through scalenotomy. Successful treatment with VATS preceded by conservative treatment. AB - Lymphorrhoea is a rare complication after orthopaedic surgeries. This paper presents a case of a patient who demonstrated cervical lymphorrhoea as an early complication of scalenotomy. The lymphorrhoea was success - fully stopped through VATS closure of the thoracic duct following initial ineffective conservative treatment. PMID- 25694382 TI - [In Process Citation]. PMID- 25694383 TI - Initiation of GnRH agonist treatment on 3-5 days postoperatively in endometriosis patients: a randomized controlled trial. AB - Seventy patients with stage III or IV endometriosis were randomly assigned to 2 groups after conservative surgery. Group O (n = 35) received 3 cycles of a 28-day gonadotropin-releasing hormone agonist (GnRH-a) treatment (goserelin, 3.6 mg) starting 3-5 days postoperatively. Group M (n = 35) received the same treatment starting on days 1-5 of menstruation. Groups were further subdivided according to add-back treatment. Pre- and posttreated levels of estradiol (E2 ), follicle stimulating hormone (FSH), and luteinizing hormone (LH) and visual analog scale (VAS), Kupperman menopausal index (KMI), and bone mineral density (BMD) scores were recorded. The incidence of uterine bleeding was assessed. In both groups, serum levels of E2 , FSH, and LH and VAS scores decreased significantly after treatment. Spotting was the most frequent bleeding pattern. During cycle 1, the bleeding time in group M was much longer that than that in group O (P =.001), and the bleeding rate in group M was significantly higher than that in group O (P =.024, RR = 1.185). In patients with stage III or IV endometriosis, the efficacy of GnRH-a initiated 3-5 days postoperatively was equivalent to that of GnRH-a initiated on days 1-5 of menstruation. Female patients who initiated GnRH-a treatment 3-5 days postoperatively experienced less uterine bleeding during the first cycle of treatment. PMID- 25694384 TI - Opposing orientations of the anti-psychotic drug trifluoperazine selected by alternate conformations of M144 in calmodulin. AB - The anti-psychotic drug trifluoperazine (TFP) is an antagonist observed to bind to calcium-saturated calmodulin ((Ca(2+) )4 -CaM) at ratios of 1:1 (1CTR), 2:1 (1A29), and 4:1 (1LIN). Each structure contains one TFP bound in the hydrophobic cleft of the C-domain of CaM. However, the orientation of the trifluoromethyl (CF3 ) moiety differs among them: it is buried in the C-domain cleft of 1A29 and 1LIN, but protrudes from 1CTR. We report a 2.0 A resolution crystallographic structure (4RJD) of TFP bound to the (Ca(2+) )-saturated C-domain of CaM (CaMC ). The asymmetric unit contains two molecules of (Ca(2+) )2 -CaMC . Chain backbones were nearly identical, but the orientation of TFP in the cleft of Chain A matched 1A29/1LIN, while TFP bound to Chain B matched 1CTR. This was accommodated by a flip of the M144 sidechain and small changes in sidechains of M109 and M145. Docking simulations suggested that the rotamer conformation of M144 determined the orientation of TFP within the cleft of (Ca(2+) )2 -CaMC . Chains A and B show that the open cleft of (Ca(2+) )2 -CaMC is promiscuous in accepting TFP in reversed directions under the same crystallization conditions. Observing multiple orientations of an antagonist bound to a single protein highlights the challenge of designing highly specific pharmaceuticals, and may have importance for QSAR of other CF3 -containing drugs such as fluoxetine (anti-depressant) or efavirenz (reverse transcriptase inhibitor). This study emphasizes that a single structure of a complex represents an energetically accessible state, but does not necessarily show the full range of energetically equivalent states. PMID- 25694385 TI - Selective inhibitors of glutathione transferase P1 with trioxane structure as anticancer agents. AB - The response to chemotherapy in cancer patients is frequently compromised by drug resistance. Although chemoresistance is a multifactorial phenomenon, many studies have demonstrated that altered drug metabolism through the expression of phase II conjugating enzymes, including glutathione transferases (GSTs), in tumor cells can be directly correlated with resistance against a wide range of marketed anticancer drugs. In particular, overexpression of glutathione transferase P1 (GSTP1) appears to be a factor for poor prognosis during cancer therapy. Former and ongoing clinical trials have confirmed GSTP1 inhibition as a principle for antitumor therapy. A new series of 1,2,4-trioxane GSTP1 inhibitors were designed via a type II photooxygenation route of allylic alcohols followed by acid catalyzed peroxyacetalization with aldehydes. A set of novel inhibitors exhibit low micromolar to high nanomolar inhibition of GSTP1, revealing preliminary SAR for further lead optimization. Importantly, high selectivity over another two human GST classes (GSTA1 and GSTM2) has been achieved. The trioxane GSTP1 inhibitors may therefore serve as a basis for the development of novel drug candidates in overcoming chemoresistance. PMID- 25694387 TI - Hybrid fibers made of molybdenum disulfide, reduced graphene oxide, and multi walled carbon nanotubes for solid-state, flexible, asymmetric supercapacitors. AB - One of challenges existing in fiber-based supercapacitors is how to achieve high energy density without compromising their rate stability. Owing to their unique physical, electronic, and electrochemical properties, two-dimensional (2D) nanomaterials, e.g., molybdenum disulfide (MoS2 ) and graphene, have attracted increasing research interest and been utilized as electrode materials in energy related applications. Herein, by incorporating MoS2 and reduced graphene oxide (rGO) nanosheets into a well-aligned multi-walled carbon nanotube (MWCNT) sheet followed by twisting, MoS2 -rGO/MWCNT and rGO/MWCNT fibers are fabricated, which can be used as the anode and cathode, respectively, for solid-state, flexible, asymmetric supercapacitors. This fiber-based asymmetric supercapacitor can operate in a wide potential window of 1.4 V with high Coulombic efficiency, good rate and cycling stability, and improved energy density. PMID- 25694388 TI - Undifferentiated State Induced by Rb-p53 Double Inactivation in Mouse Thyroid Neuroendocrine Cells and Embryonic Fibroblasts. AB - Retinoblastoma tumor suppressor protein (RB) is inactivated more frequently during tumor progression than during tumor initiation. However, its exact role in controlling the malignant features associated with tumor progression is poorly understood. We established in vivo and in vitro models to investigate the undifferentiated state induced by Rb inactivation. Rb heterozygous mice develop well-differentiated thyroid medullary carcinoma. We found that additional deletion of Trp53, without change in lineage, converted these Rb-deficient tumors to a poorly differentiated type associated with higher self-renewal activity. Freshly prepared mouse embryonic fibroblasts (MEFs) of Rb(-/-) ; Trp53(-/-) background formed stem cell-like spheres that expressed significant levels of embryonic genes despite of lacking the ability to form colonies on soft agar or tumors in immune-deficient mice. This suggested that Rb-p53 double inactivation resulted in an undifferentiated status but without carcinogenic conversion. We next established Rb(-/-) ; N-ras(-/-) MEFs that harbored a spontaneous carcinogenic mutation in Trp53. These cells (RN6), in an Rb-dependent manner, efficiently generated spheres that expressed very high levels of embryonic genes, and appeared to be carcinogenic. We then screened an FDA-approved drug library to search for agents that suppressed the spherogenic activity of RN6 cells. Data revealed that RN6 cells were sensitive to specific agents including ones those are effective against cancer stem cells. Taken together, all these findings suggest that the genetic interaction between Rb and p53 is a critical determinant of the undifferentiated state in normal and tumor cells. PMID- 25694389 TI - Gels based on anion recognition between triurea receptor and phosphate anion. AB - Anion recognition between the triurea receptor and phosphate anion is demonstrated as the cross-linkage to build supramolecular polymer gels for the first time. A novel multi-block copolymer (3) is designed to have functional triurea groups as cross-linking units along the polymer main chain. By virtue of anion coordination between the triurea receptor and phosphate anion with a binding mode of 2:1, supramolecular polymer gels are then prepared based on anion recognition using 3 as the building block. PMID- 25694390 TI - Identification of chronic rhinosinusitis phenotypes using cluster analysis. AB - BACKGROUND: Current clinical classifications of chronic rhinosinusitis (CRS) have been largely defined based upon preconceived notions of factors thought to be important, such as polyp or eosinophil status. Unfortunately, these classification systems have little correlation with symptom severity or treatment outcomes. Unsupervised clustering can be used to identify phenotypic subgroups of CRS patients, describe clinical differences in these clusters and define simple algorithms for classification. METHODS: A multi-institutional, prospective study of 382 patients with CRS who had failed initial medical therapy completed the Sino-Nasal Outcome Test (SNOT-22), Rhinosinusitis Disability Index (RSDI), Medical Outcomes Study Short Form-12 (SF-12), Pittsburgh Sleep Quality Index (PSQI), and Patient Health Questionnaire (PHQ-2). Objective measures of CRS severity included Brief Smell Identification Test (B-SIT), CT, and endoscopy scoring. All variables were reduced and unsupervised hierarchical clustering was performed. After clusters were defined, variations in medication usage were analyzed. Discriminant analysis was performed to develop a simplified, clinically useful algorithm for clustering. RESULTS: Clustering was largely determined by age, severity of patient reported outcome measures, depression, and fibromyalgia. CT and endoscopy varied somewhat among clusters. Traditional clinical measures, including polyp/atopic status, prior surgery, B-SIT and asthma, did not vary among clusters. A simplified algorithm based upon productivity loss, SNOT-22 score, and age predicted clustering with 89% accuracy. Medication usage among clusters did vary significantly. CONCLUSION: A simplified algorithm based upon hierarchical clustering is able to classify CRS patients and predict medication usage. Further studies are warranted to determine if such clustering predicts treatment outcomes. PMID- 25694391 TI - Free-standing gold-nanoparticle monolayer film fabricated by protein self assembly of alpha-synuclein. AB - Free-standing nanoparticle films are of great importance for developing future nano-electronic devices. We introduce a protein-based fabrication strategy of free-standing nanoparticle monolayer films. alpha-Synuclein, an amyloidogenic protein, was utilized to yield a tightly packed gold-nanoparticle monolayer film interconnected by protein beta-sheet interactions. Owing to the stable protein protein interaction, the film was successfully expanded to a 4-inch diameter sheet, which has not been achieved with any other free-standing nanoparticle monolayers. The film was flexible in solution, so it formed a conformal contact, surrounding even microspheres. Additionally, the monolayer film was readily patterned at micrometer-scale and thus unprecedented double-component nanoparticle films were fabricated. Therefore, the free-floating gold nanoparticle monolayer sheets with these properties could make the film useful for the development of bio-integrated nano-devices and high-performance sensors. PMID- 25694392 TI - Bonding and singlet-triplet gap of silicon trimer: effects of protonation and attachment of alkali metal cations. AB - We revisit the singlet-triplet energy gap (DeltaE(ST)) of silicon trimer and evaluate the gaps of its derivatives by attachment of a cation (H(+), Li(+), Na(+), and K(+)) using the wavefunction-based methods including the composite G4, coupled-cluster theory CCSD(T)/CBS, CCSDT and CCSDTQ, and CASSCF/CASPT2 (for Si3) computations. Both (1)A1 and (3)A2' states of Si3 are determined to be degenerate. An intersystem crossing between both states appears to be possible at a point having an apex bond angle of around alpha = 68 +/- 2 degrees which is 16 +/- 4 kJ/mol above the ground state. The proton, Li(+) and Na(+) cations tend to favor the low-spin state, whereas the K(+) cation favors the high-spin state. However, they do not modify significantly the DeltaE(ST). The proton affinity of silicon trimer is determined as PA(Si3) = 830 +/- 4 kJ/mol at 298 K. The metal cation affinities are also predicted to be LiCA(Si3) = 108 +/- 8 kJ/mol, NaCA(Si3) = 79 +/- 8 kJ/mol and KCA(Si3) = 44 +/- 8 kJ/mol. The chemical bonding is probed using the electron localization function, and ring current analyses show that the singlet three-membered ring Si3 is, at most, nonaromatic. Attachment of the proton and Li(+) cation renders it anti-aromatic. PMID- 25694393 TI - Ethical codes on drug promotion in UK and Sweden are too weak, say researchers. PMID- 25694394 TI - Reserving mental health detention for conditions that can be treated. PMID- 25694395 TI - Vitamin D Control of Hematopoietic Cell Differentiation and Leukemia. AB - It is now well known that in the mammalian body vitamin D is converted by successive hydroxylations to 1,25-dihydroxyvitamin D (1,25D), a steroid-like hormone with pleiotropic properties. These include important contributions to the control of cell proliferation, survival and differentiation, as well as the regulation of immune responses in disease. Here, we present recent advances in current understanding of the role of 1,25D in myelopoiesis and lymphopoiesis, and the potential of 1,25D and analogs (vitamin D derivatives; VDDs) for the control of hematopoietic malignancies. The reasons for the unimpressive results of most clinical studies of the therapeutic effects of VDDs in leukemia and related diseases may include the lack of a precise rationale for the conduct of these studies. Further, clinical trials to date have generally used extremely heterogeneous patient populations and, in many cases, small numbers of patients, generally without controls. Although low calcemic VDDs have been used and combined with agents that can increase the leukemia cell killing or differentiation effects in acute leukemias, the sequencing of agents used for combination therapy should to be more clearly delineated. Most importantly, it is recommended that in future clinical trials the rationale for the basis of the enhancing action of drug combinations should be clearly articulated and the effects on anticancer immunity should also be evaluated. PMID- 25694396 TI - A hammock flap: A modified backflip flap for the surgical correction of cicatricial entropion. PMID- 25694397 TI - Re: 'Enhanced recovery after surgery in microvascular breast reconstruction'. PMID- 25694398 TI - Modulatory effects of adiponectin on the polarization of tumor-associated macrophages. AB - The plasticity of macrophages with selective functional phenotypes partially arises in respective to their microenvironment. Tumor-associated macrophages (TAMs) may promote disease progression with tumor specific manner. Here we report that in pediatric malignant soft-tissue tumors, the presence of TAMs and expression of adiponectin (APN) are heterogeneous. Both APN and TAMs had high expression in rhabdomyosarcoma, especially in the malignant subtype, alveolar rhabdomyosarcoma. To investigate the mode of action of APN on TAM activation, a murine MN/MCA1 sarcoma model was used. The Results revealed that exogenous APN had no effect on MN/MCA1 proliferation but tumor size was markedly reduced in apn(-/-) mice versus WT controls. The accumulation of TAMs in apn(-/-) mice was also reduced which correlated to downregulated serum levels of MCP-1. Likewise, TAMs in apn(-/-) mice exhibited a M1-like phenotype, characterized by increase in MHC II(high) population and M1 phenotypic markers, such as iNOS gene and serum TNF-alpha accompanied by a decrease in M2 markers, namely YM1 gene and serum IL 10. In addition, APN deficiency increased the number of CD4(+) T cells, CD8(+) T cells and NK cells in tumors and reduced tumor metastasis. The altered phenotype of TAMs in apn(-/-) mice was associated with a marked decrease in phospho-p38 and treatment with a p38 MAPK inhibitor significantly reduced tumor size and increased MHC II expression on TAMs in WT mice, implying p38 MAPK signaling pathway may contribute to APN-mediated TAM polarization. Collectively, our findings suggest that APN may have a potential role in regulating soft tissue sarcoma growth. PMID- 25694399 TI - Canadian paper retreats after vaccine story sparks furor. PMID- 25694400 TI - Governors' association backs expanded primary care role for pharmacists. PMID- 25694401 TI - California strengthens antimicrobial stewardship mandate for hospitals. PMID- 25694403 TI - Medicare's star ratings bring opportunity for pharmacists. PMID- 25694404 TI - Summaries of safety labeling changes approved by FDA-Boxed Warnings Highlights October-December 2014. PMID- 25694405 TI - Outcomes related to postsurgical opioids. PMID- 25694406 TI - Outcomes related to postsurgical opioids--reply. PMID- 25694407 TI - Need for pediatric antimicrobial stewardship. PMID- 25694408 TI - Pharmacy students' experience with a capstone project. PMID- 25694409 TI - Management of heart failure patients through integrative medical group visits. PMID- 25694410 TI - Carfilzomib: a second-generation proteasome inhibitor for the treatment of multiple myeloma. AB - PURPOSE: The pharmacology, clinical efficacy, safety, cost, dosage and administration, and place in therapy of carfilzomib for the treatment of multiple myeloma (MM) are reviewed. SUMMARY: Proteasome inhibition in MM has become a cornerstone in treatment regimens. Carfilzomib, a second-generation proteasome inhibitor, has demonstrated efficacy in patients with relapsed or refractory disease who have received at least two prior therapies including bortezomib and an immunomodulatory agent. Carfilzomib is an irreversible inhibitor and binds to a different site than bortezomib on the proteasome. A Phase II study evaluated 266 heavily pretreated patients with relapsed or refractory MM who had received at least two prior therapies, including bortezomib and either thalidomide or lenalidomide. The overall response rate was 23.7%, with a median duration of response of 7.8 months. The median overall survival time was 15.6 months. Carfilzomib has a similar adverse-effect profile to bortezomib, including anemia, thrombocytopenia, fatigue, dyspnea, and nausea; however, it does not result in the development or worsening of peripheral neuropathy. Carfilzomib is infused intravenously over 2-10 minutes for 2 consecutive days every week for three out of four weeks, with a 12-day rest period. Dosing is based on the patient's actual body surface area. Carfilzomib is available in 60-mg vials for single infusion. The total cost for a year of therapy is approximately $155,852. CONCLUSION: Carfilzomib, a second-generation proteasome inhibitor that irreversibly inhibits the 26S proteasome, has shown efficacy in clinical studies of patients with relapsed or refractory MM, though the drug's role in the management of MM is not yet clear. PMID- 25694411 TI - Dapagliflozin: a new sodium-glucose cotransporter 2 inhibitor for treatment of type 2 diabetes. AB - PURPOSE: The pharmacologic properties and clinical efficacy of dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes, are reviewed. SUMMARY: Dapagliflozin (Farxiga, AstraZeneca) is a selective SGLT2 inhibitor approved as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. Dapagliflozin lowers blood glucose independent of insulin secretion and action by inhibiting renal reabsorption of glucose, thus promoting increased urinary excretion of glucose. Dapagliflozin has been shown to improve glycemic parameters in patients with type 2 diabetes when used as monotherapy or in combination with metformin, glimepiride, pioglitazone, sitagliptin, or insulin. Dapagliflozin treatment is associated with weight reduction, it has a low intrinsic propensity to cause hypoglycemia, and it may offer the advantage of a complementary mechanism of action when added to other therapies. During Phase III clinical trials, dapagliflozin was generally well tolerated, with an overall frequency of adverse events similar to that reported with placebo use. However, increased rates of genital and, in some trials, urinary tract infections have been reported in dapagliflozin-treated groups relative to placebo groups. Pooled data from clinical trials indicated an imbalance in bladder cancer cases between dapagliflozin-treated and placebo groups; however, most cases were diagnosed within one year of exposure. Ongoing research is expected to further delineate the effects of dapagliflozin on bladder cancer risk and cardiovascular safety measures. CONCLUSION: Dapagliflozin, an SGLT2 inhibitor, offers a novel treatment option for type 2 diabetes that is independent of insulin secretion or action. PMID- 25694412 TI - Alternative schedules of levothyroxine administration. AB - PURPOSE: Published evidence on bedtime versus prebreakfast administration of levothyroxine is reviewed. SUMMARY: Because levothyroxine absorption has been shown to increase when the drug is administered to patients in a fasted state, the standard recommendation is that levothyroxine be taken one half to one hour prior to breakfast and at least four hours before or after potentially interacting drugs. However, compliance with this recommendation may be problematic for patients with unpredictable or variable schedules. A literature search identified four published studies of bedtime levothyroxine dosing. Two of the studies demonstrated a significant decrease in levels of thyroid-stimulating hormone (TSH) with levothyroxine administration at bedtime versus 30 minutes before breakfast, one study showed an increase in TSH when levothyroxine was taken at bedtime versus one hour before breakfast, and one study found no significant differences in TSH levels or other thyroid function monitoring limitations with bedtime versus standard dosing in subjects naive to levothyroxine therapy. The inconsistent study findings may be attributable to a number of variables, including dietary differences among the study populations, the use of potentially interacting supplements in one study, and variable intervals between levothyroxine administration and food intake. Neither dosing method correlated with substantial changes in assessments of quality of life or symptom severity; in two of the studies, patients indicated a preference for bedtime levothyroxine administration. CONCLUSION: Based on the available literature, bedtime administration of levothyroxine is an option for patients with hypothyroidism who want to avoid taking their medication with food. PMID- 25694413 TI - Comparison of rehospitalization rates and associated costs among patients with schizophrenia receiving paliperidone palmitate or oral antipsychotics. AB - PURPOSE: Comparative data on rehospitalization patterns and associated institutional costs after inpatient treatment with paliperidone palmitate or oral antipsychotic therapy are reported. METHODS: A retrospective cohort study was conducted using discharge and billing records from a large hospital database. Selected clinical and cost outcomes were compared in a cohort of adult patients who received the long-acting antipsychotic paliperidone palmitate during a schizophrenia-related index hospital stay and a cohort of patients who received oral antipsychotic therapy during their index admission. Inverse probability-of treatment weights based on propensity scores were used to reduce confounding. Rates of all-cause and schizophrenia-related rehospitalization and emergency room (ER) use in the two cohorts over periods of up to 12 months were analyzed using a multivariate Cox proportional hazard model. Institutional costs for the evaluated postdischarge events were compared via multivariate linear regression analysis. RESULTS: In the first 12 months after index hospital discharge, the risk of all cause rehospitalization and ER use was significantly lower in the paliperidone palmitate cohort than in the oral antipsychotic cohort (hazard ratio, 0.61; 95% confidence interval [CI], 0.59-0.63; p < 0.0001); institutional costs during the first 6 months after discharge were significantly lower in the paliperidone palmitate cohort than in the comparator group (adjusted mean monthly cost difference -$404; 95% CI, -$781 to -$148; p < 0.0001). CONCLUSION: The use of paliperidone palmitate therapy during patients' index hospital admission for schizophrenia was associated with a reduced risk of hospital readmission or ER use and lower postdischarge institutional costs. PMID- 25694414 TI - Compatibility of cefepime and vancomycin during simulated Y-site administration of prolonged infusion. AB - PURPOSE: The physical and chemical compatibility of cefepime and vancomycin at concentrations typically used in prolonged-infusion cefepime infusions was assessed. METHODS: Samples from a typical Y-site configuration of standard infusion vancomycin and prolonged-infusion cefepime were collected at various time points during the simulated 4-hour infusion. Samples were analyzed by visual inspection, spectrophotometry, and high-performance liquid chromatography (HPLC). Infusion antibiotics were reconstituted in pairwise combinations of 0.9% sodium chloride injection and 5% dextrose injection to determine the effects of solvent selection on stability. Infusion simulations were performed in triplicate without light protection under fluorescent lighting at room temperature (22.5 degrees C). Experimental replicates were not run simultaneously but on sequential days due to the considerable time (~12 hours) required to analyze samples obtained from a single infusion simulation and the known time-dependent instability of reconstituted cefepime beyond 24 hours. Physical stability was assessed visually for evidence of particulate formation, haze, precipitation, color change, and gas evolution. Samples were also assessed spectrophotometrically at 600 nm at the time of collection and 24 hours after collection. RESULTS: Cefepime was compatible with vancomycin at the concentrations tested. The solvent selected (0.9% sodium chloride or 5% dextrose) to reconstitute either antibiotic had no impact on compatibility. Solutions were indistinguishable from positive and negative controls (heat-degraded cefepime and freshly reconstituted cefepime, respectively) at all time points assessed in terms of visual clarity, spectrophotometric absorbance, and HPLC recovery. CONCLUSION: Cefepime and vancomycin were physically and chemically compatible during simulated Y-site administration of prolonged-infusion cefepime. PMID- 25694415 TI - In-use physicochemical and microbiological stability of biological parenteral products. PMID- 25694416 TI - Decision support at the point of prescribing to increase formulary adherence. AB - PURPOSE: Study results demonstrating the effectiveness of order-entry clinical decision support (CDS) alerts as a tool for enforcing therapeutic interchange are presented. METHODS: A retrospective observational study was conducted at an academic medical center to evaluate formulary nonadherence before and after implementation of a fully electronic medical record with computerized prescriber order-entry (CPOE) technology configured to display therapeutic interchange alerts immediately on entry of orders for nonformulary agents. Formulary nonadherence (defined as the proportion of pharmacist-verified nonformulary orders to total verified orders) within eight medication classes was assessed during a six-month baseline period and two consecutive six-month periods after implementation. RESULTS: In the 12 months after implementation of the therapeutic interchange alerts, the overall rate of formulary nonadherence decreased by 65%, from 3.5% at baseline to 1.2% during the second 6-month postintervention period (p < 0.001). The total number of verified nonformulary orders decreased from 300 at baseline to 102 during the second postintervention period. The largest decreases in formulary nonadherence were observed in the intranasal steroid drug class (the rate of nonadherent orders declined by a total of 12 percentage points) and the nonbarbiturate sedatives and hypnotics class (a 5-point decline), with significant 6- and 12-month declines also documented in four of the remaining six drug classes. CONCLUSION: The incorporation of hard-stop CDS alerts into the CPOE system improved the overall rate of prescriber adherence to institutional therapeutic interchange protocols. PMID- 25694417 TI - Lapatinib versus lapatinib plus capecitabine as second-line treatment in human epidermal growth factor receptor 2-amplified metastatic gastro-oesophageal cancer: a randomised phase II trial of the Arbeitsgemeinschaft Internistische Onkologie. AB - INTRODUCTION: Human epidermal growth factor receptor 2 (HER2) amplification is present in a subgroup of gastroo-esophageal cancers (GCs). HER2 inhibition with trastuzumab has shown to improve outcomes in advanced disease. Lapatinib ditosylate (LAP), a dual anti-epidermal growth factor receptor (EGFR) and anti HER2 tyrosine kinase inhibitor with preclinical activity against GC, has been approved in HER2-positive breast cancer. We aimed to study the activity of LAP in HER2-amplified GC. MATERIALS AND METHODS: Patients (pts) with HER2-positive (gene amplification or increased copy numbers based on predefined criteria) advanced GC were randomly allocated 1:1 to receive LAP 1250mg per day 1-21 plus capecitabine (CAP) 2000mg/m(2) on days 1-14 of a 21-day cycle or LAP 1500mg monotherapy day 1 21 after having failed on a platinum-based first-line therapy. HER2 status was assessed centrally. The primary end-point was the objective response rate (ORR) as assessed by the investigator using Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1). We aimed to include 38 pts per arm to show an interesting response rate of ?20% in either of the two arms. RESULTS: 37 pts were enrolled (18 to LAP+CAP, 19 to LAP). Pts had received a median of three prior treatment lines. 12 pts in the LAP+CAP group (67%) and 12 pts in the LAP group (63%) had received prior trastuzumab. Only two pts (11.1%; 95% confidence interval (CI): 1.37-34.7), both in the LAP+CAP arm, achieved an objective response. The study was closed prematurely for futility. Median time to progression was 42 (95% CI: 38-61) days in the LAP group and 83 (95% CI: 42-86) days in the LAP+CAP group. Other secondary efficacy end-points (progression-free and overall survival) were comparable in the two treatment groups. Rates of diarrhoea were higher with LAP+CAP (61%; 95% CI: 35-83) compared to 26% (95% CI 9 51) with LAP mono, whereas other adverse events were mostly similar between the groups (18 [100%] versus 17 [90%]). DISCUSSION: Lapatinib showed insufficient activity in HER2-amplified pretreated advanced GC. The safety profile of LAP or LAP+CAP was as expected with some more toxicity in the combination arm. (ClinicalTrials.gov Identifier, NCT01145404). PMID- 25694418 TI - A geospatial analysis of the relationship between neighbourhood socioeconomic status and adult severe injury in Greater Vancouver. AB - BACKGROUND: Every year, injuries cost the Canadian healthcare system billions of dollars and result in thousands of emergency room visits, hospitalisations and deaths. The purpose of this study was to explore the relationship between neighbourhood socioeconomic status (NSES) and the rates of all-cause, unintentional and intentional severe injury in Greater Vancouver adults. A second objective was to determine whether the identified associations were spatially consistent or non-stationary. METHODS: Severe injury cases occurring between 2001 and 2006 were identified using the British Columbia's Coroner's Service records and the British Columbia Trauma Registry, and mapped by census dissemination areas using a geographical information system. Descriptive statistics and exploratory spatial data analysis methods were used to gain a better understanding of the data sets and to explore the relationship between the rates of severe injury and two measures of NSES (social and material deprivation). Ordinary least squares and geographically weighted regression were used to model these relationships at the global and local levels. RESULTS: Inverse relationships were identified between both measures of NSES and the rates of severe injury with the strongest associations located in Greater Vancouver's most socioeconomically deprived neighbourhoods. Social deprivation was found to have a slightly stronger relationship with the rates of severe injury than material deprivation. CONCLUSIONS: Results of this study suggest that policies and programmes aimed at reducing the burden of severe injury in Greater Vancouver should take into account social and material deprivation, and should target the most socioeconomically deprived neighbourhoods in Greater Vancouver. PMID- 25694419 TI - Morphological changes in vascular and circulating blood cells following exposure to detergent sclerosants. AB - OBJECTIVES: To investigate morphological changes in vascular and circulating blood cells following exposure to detergent sclerosants sodium tetradecyl sulfate and polidocanol. METHODS: Samples of whole blood, isolated leukocytes, platelets, endothelial cells, and fibroblasts were incubated with varying concentrations of sclerosants. Whole blood smears were stained with Giemsa and examined by light and bright field microscopy. Phalloidin and Hoechst stains were used to analyze cytoplasmic and nuclear morphology by fluorescence microscopy. Endothelial cell and fibroblasts were analyzed by live cell imaging. RESULTS: Higher concentrations of sclerosants induced cell lysis. Morphological changes in intact cells were observed at sublytic concentrations of detergents. Low concentration sodium tetradecyl sulfate induced erythrocyte acanthocytosis and macrocytosis, while polidocanol induced Rouleaux formation and increased the population of target cells and stomatocytes. Leukocytes showed swelling, blebbing, vacuolation, and nuclear degradation following exposure to sodium tetradecyl sulfate, while polidocanol induced pseudopodia formation, chromatin condensation, and fragmentation. Platelets exhibited pseudopodia with sodium tetradecyl sulfate and a "fried egg" appearance with polidocanol. Exposure to sodium tetradecyl sulfate resulted in size shrinkage in both endothelial cell and fibroblasts, while endothelial cell developed distinct spindle morphology. Polidocanol induced cytoplasmic microfilament bundles in both endothelial cell and fibroblasts. Patchy chromatin condensation was observed following exposure of fibroblasts to either agent. CONCLUSION: Detergent sclerosants are biologically active at sublytic concentrations. The observed morphological changes are consistent with cell activation, apoptosis, and oncosis. The cellular response is concentration dependent, cell-specific, and sclerosant specific. PMID- 25694420 TI - Force dependence of energy barriers in atomic friction and single-molecule force spectroscopy: critique of a critical scaling relation. AB - Friction force microscopy and single-molecule force spectroscopy are experimental methods to explore multistable energy landscapes by means of a controlled reduction of the energy barriers between adjacent potential minima. This affects the system's interstate transition rates proportional to e(-DeltaE(f)/kBT), with DeltaE(f) being the barrier height, k(B)T the thermal energy, and f the elastic force applied. It is often assumed that, at large forces, the barrier height scales as (f(c) - f)(3/2), where f(c) is the critical force, at which the barrier vanishes. We show that, for the elastic forces produced by a pulling device of finite stiffness kappa, this scaling relation is actually incorrect. Rather, the barrier is a double-valued function of force of the form E(f) ? (kappa/kappa(c) +/-?1 - f/f(0))(3), where f(0) is the maximal force that the system potential can generate, and the characteristic stiffness kappa(c) is not necessarily much larger than kappa. In particular, for finite kappa, the barrier vanishes at a certain force f(kappa) < f(0), but, in view of the double-valuedness of DeltaE(f), the maximal force f0 can still be reached. We derive the relation between the most probable force at the moment of transition, fm, and the pulling velocity, v. The usually assumed scaling f(m) ? (ln v)(2/3) is recovered as the kappa -> 0 limit of our more general result, but becomes increasingly worse as kappa grows. We introduce a new data analysis method that allows one to quantitatively characterize the system potential and evaluate the stiffness of the pulling device, kappa, which is usually not known beforehand. We demonstrate the feasibility of our method by analyzing the results of a numerical experiment based on the standard Prandtl-Tomlinson model of nanoscale friction. PMID- 25694421 TI - A Virtual Academic Unit--the first 10 years. PMID- 25694422 TI - The management of neonatal respiratory distress syndrome in preterm infants (European Consensus Guidelines--2013 update). PMID- 25694423 TI - Inhibition of AMP Kinase by the Protein Phosphatase 2A Heterotrimer, PP2APpp2r2d. AB - AMP kinase is a heterotrimeric serine/threonine protein kinase that regulates a number of metabolic processes, including lipid biosynthesis and metabolism. AMP kinase activity is regulated by phosphorylation, and the kinases involved have been uncovered. The particular phosphatases counteracting these kinases remain elusive. Here we discovered that the protein phosphatase 2A heterotrimer, PP2A(Ppp2r2d), regulates the phosphorylation state of AMP kinase by dephosphorylating Thr-172, a residue that activates kinase activity when phosphorylated. Co-immunoprecipitation and co-localization studies indicated that PP2A(Ppp2r2d) directly interacted with AMP kinase. PP2A(Ppp2r2d) dephosphorylated Thr-172 in rat aortic and human vascular smooth muscle cells. A positive correlation existed between decreased phosphorylation, decreased acetyl-CoA carboxylase Acc1 phosphorylation, and sterol response element-binding protein 1c dependent gene expression. PP2A(Ppp2r2d) protein expression was up-regulated in the aortas of mice fed a high fat diet, and the increased expression correlated with increased blood lipid levels. Finally, we found that the aortas of mice fed a high fat diet had decreased AMP kinase Thr-172 phosphorylation, and contained an Ampk-PP2A(Ppp2r2d) complex. Thus, PP2A(Ppp2r2d) may antagonize the aortic AMP kinase activity necessary for maintaining normal aortic lipid metabolism. Inhibiting PP2A(Ppp2r2d) or activating AMP kinase represents a potential pharmacological treatment for many lipid-related diseases. PMID- 25694424 TI - Formation of disulfide bridges drives oligomerization, membrane pore formation, and translocation of fibroblast growth factor 2 to cell surfaces. AB - Fibroblast growth factor 2 (FGF2) is a key signaling molecule in tumor-induced angiogenesis. FGF2 is secreted by an unconventional secretory mechanism that involves phosphatidylinositol 4,5-bisphosphate-dependent insertion of FGF2 oligomers into the plasma membrane. This process is regulated by Tec kinase mediated tyrosine phosphorylation of FGF2. Molecular interactions driving FGF2 monomers into membrane-inserted FGF2 oligomers are unknown. Here we identify two surface cysteines that are critical for efficient unconventional secretion of FGF2. They represent unique features of FGF2 as they are absent from all signal peptide-containing members of the FGF protein family. We show that phosphatidylinositol 4,5-bisphosphate-dependent FGF2 oligomerization concomitant with the generation of membrane pores depends on FGF2 surface cysteines as either chemical alkylation or substitution with alanines impairs these processes. We further demonstrate that the FGF2 variant forms lacking the two surface cysteines are not secreted from cells. These findings were corroborated by experiments redirecting a signal-peptide-containing FGF family member from the endoplasmic reticulum/Golgi-dependent secretory pathway into the unconventional secretory pathway of FGF2. Cis elements known to be required for unconventional secretion of FGF2, including the two surface cysteines, were transplanted into a variant form of FGF4 without signal peptide. The resulting FGF4/2 hybrid protein was secreted by unconventional means. We propose that the formation of disulfide bridges drives membrane insertion of FGF2 oligomers as intermediates in unconventional secretion of FGF2. PMID- 25694425 TI - Structure of Escherichia coli dGTP triphosphohydrolase: a hexameric enzyme with DNA effector molecules. AB - The Escherichia coli dgt gene encodes a dGTP triphosphohydrolase whose detailed role still remains to be determined. Deletion of dgt creates a mutator phenotype, indicating that the dGTPase has a fidelity role, possibly by affecting the cellular dNTP pool. In the present study, we have investigated the structure of the Dgt protein at 3.1-A resolution. One of the obtained structures revealed a protein hexamer that contained two molecules of single-stranded DNA. The presence of DNA caused significant conformational changes in the enzyme, including in the catalytic site of the enzyme. Dgt preparations lacking DNA were able to bind single-stranded DNA with high affinity (Kd ~ 50 nM). DNA binding positively affected the activity of the enzyme: dGTPase activity displayed sigmoidal (cooperative) behavior without DNA but hyperbolic (Michaelis-Menten) kinetics in its presence, consistent with a specific lowering of the apparent Km for dGTP. A mutant Dgt enzyme was also created containing residue changes in the DNA binding cleft. This mutant enzyme, whereas still active, was incapable of DNA binding and could no longer be stimulated by addition of DNA. We also created an E. coli strain containing the mutant dgt gene on the chromosome replacing the wild-type gene. The mutant also displayed a mutator phenotype. Our results provide insight into the allosteric regulation of the enzyme and support a physiologically important role of DNA binding. PMID- 25694426 TI - Peroxisomal Pex3 activates selective autophagy of peroxisomes via interaction with the pexophagy receptor Atg30. AB - Pexophagy is a process that selectively degrades peroxisomes by autophagy. The Pichia pastoris pexophagy receptor Atg30 is recruited to peroxisomes under peroxisome proliferation conditions. During pexophagy, Atg30 undergoes phosphorylation, a prerequisite for its interactions with the autophagy scaffold protein Atg11 and the ubiquitin-like protein Atg8. Atg30 is subsequently shuttled to the vacuole along with the targeted peroxisome for degradation. Here, we defined the binding site for Atg30 on the peroxisomal membrane protein Pex3 and uncovered a role for Pex3 in the activation of Atg30 via phosphorylation and in the recruitment of Atg11 to the receptor protein complex. Pex3 is classically a docking protein for other proteins that affect peroxisome biogenesis, division, and segregation. We conclude that Pex3 has a role beyond simple docking of Atg30 and that its interaction with Atg30 regulates pexophagy in the yeast P. pastoris. PMID- 25694427 TI - Structure-function analyses of the small GTPase Rab35 and its effector protein centaurin-beta2/ACAP2 during neurite outgrowth of PC12 cells. AB - The small GTPase Rab35 is a molecular switch for membrane trafficking that regulates a variety of cellular events. We previously showed that Rab35 promotes neurite outgrowth of nerve growth factor-stimulated PC12 cells through interaction with centaurin-beta2 (also called ACAP2). Centaurin-beta2 is the only Rab35-binding protein reported thus far that exclusively recognizes Rab35 and does not recognize any of the other 59 Rabs identified in mammals, but the molecular basis for the exclusive specificity of centaurin-beta2 for Rab35 has remained completely unknown. In this study, we performed deletion and mutation analyses and succeeded in identifying the residues of Rab35 and centaurin-beta2 that are crucial for formation of a Rab35.centaurin-beta2 complex. We found that two threonine residues (Thr-76 and Thr-81) in the switch II region of Rab35 are responsible for binding centaurin-beta2 and that the same residues are dispensable for Rab35 recognition by other Rab35-binding proteins. We also determined the minimal Rab35-binding site of centaurin-beta2 and identified two asparagine residues (Asn-610 and Asn-691) in the Rab35-binding site as key residues for its specific Rab35 recognition. We further showed by knockdown rescue approaches that neither a centaurin-beta2 binding-deficient Rab35(T76S/T81A) mutant nor a Rab35 binding-deficient centaurin beta2(N610A/N691A) mutant supported neurite outgrowth of PC12 cells, thereby demonstrating the functional significance of the Rab35/centaurin-beta2 interaction during neurite outgrowth of PC12 cells. PMID- 25694428 TI - Contributions of unique intracellular domains to switchlike biosensing by Toll like receptor 4. AB - Toll-like receptors (TLRs) mediate immune recognition of both microbial infections and tissue damage. Aberrant TLR signaling promotes disease; thus, understanding the regulation of TLR signaling is of medical relevance. Although downstream mediators of TLR signaling have been identified, the detailed mechanism by which ligand binding-mediated dimerization induces downstream signaling remains poorly understood. Here, we investigate this question for TLR4, which mediates responsiveness to bacterial LPS and drives inflammatory disease. TLR4 exhibits structural and functional features that are unique among TLRs, including responsiveness to a wide variety of ligands. However, the connection between these structural features and the regulation of signaling is not clear. Here, we investigated how the unique intracellular structures of TLR4 contribute to receptor signaling. Key conclusions include the following. 1) The unique intracellular linker of TLR4 is important for achieving LPS-inducible signaling via Toll/IL-1 receptor (TIR) domain-containing adapter-inducing interferon-beta (TRIF) but less so for signaling via myeloid differentiation primary response 88 (MyD88). 2) Membrane-bound TLR4 TIR domains were sufficient to induce signaling. However, introducing long, flexible intracellular linkers neither induced constitutive signaling nor ablated LPS-inducible signaling. Thus, the initiation of TLR4 signaling is regulated by a mechanism that does not require tight geometric constraints. Together, these observations necessitate refining the model of TLR4 signal initiation. We hypothesize that TLR4 may interact with an inhibitory partner in the absence of ligand, via both TIR and extracellular domains of TLR4. In this speculative model, ligand binding induces dissociation of the inhibitory partner, triggering spontaneous, switchlike TIR domain homodimerization to initiate downstream signaling. PMID- 25694429 TI - Guanine nucleotide exchange factor alphaPIX leads to activation of the Rac 1 GTPase/glycogen phosphorylase pathway in interleukin (IL)-2-stimulated T cells. AB - Recently, we have reported that the active form of Rac 1 GTPase binds to the glycogen phosphorylase muscle isoform (PYGM) and modulates its enzymatic activity leading to T cell proliferation. In the lymphoid system, Rac 1 and in general other small GTPases of the Rho family participate in the signaling cascades that are activated after engagement of the T cell antigen receptor. However, little is known about the IL-2-dependent Rac 1 activator molecules. For the first time, a signaling pathway leading to the activation of Rac 1/PYGM in response to IL-2 stimulated T cell proliferation is described. More specifically, alphaPIX, a known guanine nucleotide exchange factor for the small GTPases of the Rho family, preferentially Rac 1, mediates PYGM activation in Kit 225 T cells stimulated with IL-2. Using directed mutagenesis, phosphorylation of alphaPIX Rho-GEF serines 225 and 488 is required for activation of the Rac 1/PYGM pathway. IL-2-stimulated serine phosphorylation was corroborated in Kit 225 T cells cultures. A parallel pharmacological and genetic approach identified PKCtheta as the serine/threonine kinase responsible for alphaPIX serine phosphorylation. The phosphorylated state of alphaPIX was required to activate first Rac 1 and subsequently PYGM. These results demonstrate that the IL-2 receptor activation, among other early events, leads to activation of PKCtheta. To activate Rac 1 and consequently PYGM, PKCtheta phosphorylates alphaPIX in T cells. The biological significance of this PKCtheta/alphaPIX/Rac 1 GTPase/PYGM signaling pathway seems to be the control of different cellular responses such as migration and proliferation. PMID- 25694430 TI - Alternative splicing generates a novel truncated Cav1.2 channel in neonatal rat heart. AB - L-type Cav1.2 Ca(2+) channel undergoes extensive alternative splicing, generating functionally different channels. Alternatively spliced Cav1.2 Ca(2+) channels have been found to be expressed in a tissue-specific manner or under pathological conditions. To provide a more comprehensive understanding of alternative splicing in Cav1.2 channel, we systematically investigated the splicing patterns in the neonatal and adult rat hearts. The neonatal heart expresses a novel 104-bp exon 33L at the IVS3-4 linker that is generated by the use of an alternative acceptor site. Inclusion of exon 33L causes frameshift and C-terminal truncation. Whole cell electrophysiological recordings of Cav1.233L channels expressed in HEK 293 cells did not detect any current. However, when co-expressed with wild type Cav1.2 channels, Cav1.233L channels reduced the current density and altered the electrophysiological properties of the wild type Cav1.2 channels. Interestingly, the truncated 3.5-domain Cav1.233L channels also yielded a dominant negative effect on Cav1.3 channels, but not on Cav3.2 channels, suggesting that Cavbeta subunits is required for Cav1.233L regulation. A biochemical study provided evidence that Cav1.233L channels enhanced protein degradation of wild type channels via the ubiquitin-proteasome system. Although the physiological significance of the Cav1.233L channels in neonatal heart is still unknown, our report demonstrates the ability of this novel truncated channel to modulate the activity of the functional Cav1.2 channels. Moreover, the human Cav1.2 channel also contains exon 33L that is developmentally regulated in heart. Unexpectedly, human exon 33L has a one-nucleotide insertion that allowed in-frame translation of a full Cav1.2 channel. An electrophysiological study showed that human Cav1.233L channel is a functional channel but conducts Ca(2+) ions at a much lower level. PMID- 25694431 TI - Influence of oxidized purine processing on strand directionality of mismatch repair. AB - Replicative DNA polymerases are high fidelity enzymes that misincorporate nucleotides into nascent DNA with a frequency lower than [1/10(5)], and this precision is improved to about [1/10(7)] by their proofreading activity. Because this fidelity is insufficient to replicate most genomes without error, nature evolved postreplicative mismatch repair (MMR), which improves the fidelity of DNA replication by up to 3 orders of magnitude through correcting biosynthetic errors that escaped proofreading. MMR must be able to recognize non-Watson-Crick base pairs and excise the misincorporated nucleotides from the nascent DNA strand, which carries by definition the erroneous genetic information. In eukaryotes, MMR is believed to be directed to the nascent strand by preexisting discontinuities such as gaps between Okazaki fragments in the lagging strand or breaks in the leading strand generated by the mismatch-activated endonuclease of the MutL homologs PMS1 in yeast and PMS2 in vertebrates. We recently demonstrated that the eukaryotic MMR machinery can make use also of strand breaks arising during excision of uracils or ribonucleotides from DNA. We now show that intermediates of MutY homolog-dependent excision of adenines mispaired with 8-oxoguanine (G(O)) also act as MMR initiation sites in extracts of human cells or Xenopus laevis eggs. Unexpectedly, G(O)/C pairs were not processed in these extracts and failed to affect MMR directionality, but extracts supplemented with exogenous 8 oxoguanine DNA glycosylase (OGG1) did so. Because OGG1-mediated excision of G(O) might misdirect MMR to the template strand, our findings suggest that OGG1 activity might be inhibited during MMR. PMID- 25694432 TI - The interaction of protein-tyrosine phosphatase alpha (PTPalpha) and RACK1 protein enables insulin-like growth factor 1 (IGF-1)-stimulated Abl-dependent and -independent tyrosine phosphorylation of PTPalpha. AB - Protein tyrosine phosphatase alpha (PTPalpha) promotes integrin-stimulated cell migration in part through the role of Src-phosphorylated PTPalpha-Tyr(P)-789 in recruiting and localizing p130Cas to focal adhesions. The growth factor IGF-1 also stimulates PTPalpha-Tyr-789 phosphorylation to positively regulate cell movement. This is in contrast to integrin-induced PTPalpha phosphorylation, that induced by IGF-1 can occur in cells lacking Src family kinases (SFKs), indicating that an unknown kinase distinct from SFKs can target PTPalpha. We show that this IGF-1-stimulated tyrosine kinase is Abl. We found that PTPalpha binds to the scaffold protein RACK1 and that RACK1 coordinates the IGF-1 receptor, PTPalpha, and Abl in a complex to enable IGF-1-stimulated and Abl-dependent PTPalpha-Tyr 789 phosphorylation. In cells expressing SFKs, IGF-1-stimulated phosphorylation of PTPalpha is mediated by RACK1 but is Abl-independent. Furthermore, expressing the SFKs Src and Fyn in SFK-deficient cells switches IGF-1-induced PTPalpha phosphorylation to occur in an Abl-independent manner, suggesting that SFK activity dominantly regulates IGF-1/IGF-1 receptor signaling to PTPalpha. RACK1 is a molecular scaffold that integrates growth factor and integrin signaling, and our identification of PTPalpha as a RACK1 binding protein suggests that RACK1 may coordinate PTPalpha-Tyr-789 phosphorylation in these signaling networks to promote cell migration. PMID- 25694433 TI - Direct interactions with the integrin beta1 cytoplasmic tail activate the Abl2/Arg kinase. AB - Integrins are heterodimeric alpha/beta extracellular matrix adhesion receptors that couple physically to the actin cytoskeleton and regulate kinase signaling pathways to control cytoskeletal remodeling and adhesion complex formation and disassembly. beta1 integrins signal through the Abl2/Arg (Abl-related gene) nonreceptor tyrosine kinase to control fibroblast cell motility, neuronal dendrite morphogenesis and stability, and cancer cell invasiveness, but the molecular mechanisms by which integrin beta1 activates Arg are unknown. We report here that the Arg kinase domain interacts directly with a lysine-rich membrane proximal segment in the integrin beta1 cytoplasmic tail, that Arg phosphorylates the membrane-proximal Tyr-783 in the beta1 tail, and that the Arg Src homology domain then engages this phosphorylated region in the tail. We show that these interactions mediate direct binding between integrin beta1 and Arg in vitro and in cells and activate Arg kinase activity. These findings provide a model for understanding how beta1-containing integrins interact with and activate Abl family kinases. PMID- 25694434 TI - The transcription factor Mesp1 interacts with cAMP-responsive element binding protein 1 (Creb1) and coactivates Ets variant 2 (Etv2) gene expression. AB - Mesoderm posterior 1 (Mesp1) is well recognized for its role in cardiac development, although it is expressed broadly in mesodermal lineages. We have previously demonstrated important roles for Mesp1 and Ets variant 2 (Etv2) during lineage specification, but their relationship has not been defined. This study reveals that Mesp1 binds to the proximal promoter and transactivates Etv2 gene expression via the CRE motif. We also demonstrate the protein-protein interaction between Mesp1 and cAMP-responsive element binding protein 1 (Creb1) in vitro and in vivo. Utilizing transgenesis, lineage tracing, flow cytometry, and immunostaining technologies, we define the lineage relationship between Mesp1- and Etv2-expressing cell populations. We observe that the majority of Etv2 EYFP(+) cells are derived from Mesp1-Cre(+) cells in both the embryo and yolk sac. Furthermore, we observe that the conditional deletion of Etv2, using a Mesp1 Cre transgenic strategy, results in vascular and hematopoietic defects similar to those observed in the global deletion of Etv2 and that it has embryonic lethality by embryonic day 9.5. In summary, our study supports the hypothesis that Mesp1 is a direct upstream transactivator of Etv2 during embryogenesis and that Creb1 is an important cofactor of Mesp1 in the transcriptional regulation of Etv2 gene expression. PMID- 25694435 TI - Kruppel-like factor 2 represses transcription of the telomerase catalytic subunit human telomerase reverse transcriptase (hTERT) in human T cells. AB - In normal human T cells, telomerase activity is strictly regulated. T cells are thought to express telomerase to avoid replicative senescence, unlike most normal somatic cells with definite replicative lifespan. T cells in blood and tissues are usually in a state of quiescence without expression of the limiting catalytic subunit of telomerase, human telomerase reverse transcriptase (hTERT). In contrast to activation, repression of hTERT transcription has not been studied well. Our previous studies have found an hTERT promoter element with repressive function. Here we identified KLF2, which represses hTERT transcription by binding to the putative promoter element. KLF2 and hTERT exhibited reciprocal mRNA expression patterns in primary human T cells. In activated T cells, KLF2 binding to the hTERT promoter was eliminated, relieving the repression of hTERT transcription found in resting T cells. Our results suggest that KLF2 is involved in strict repression of hTERT expression through binding to the promoter in primary human T cells. PMID- 25694436 TI - Epidermolysis Bullosa Pruriginosa: Case Series and Review of the Literature. AB - Epidermolysis bullosa (EB) pruriginosa is a rare clinical subtype of dystrophic epidermolysis bullosa (DEB) that is characterized by intense pruritus resulting in hypertrophic, lichenified, prurigo-like plaques and nodules secondary to scratching. The variability in the age of onset, rarity of intact bullae, histologic ambiguities, and close resemblance to other conditions such as acquired inflammatory dermatoses may make diagnosis difficult for this unusual condition, for which fewer than 100 cases have been documented. In this report, we describe 3 cases of EB pruriginosa and review the current literature. PMID- 25694437 TI - The association between skin autofluorescence and vascular complications in Chinese patients with diabetic foot ulcer: an observational study done in Shanghai. AB - The tissue accumulation of advanced glycation end products (AGEs) can be noninvasively assessed as skin autofluorescence (SAF) by the AGE Reader(TM) device. We aimed to detect the association between SAF and diabetes-associated vascular complications in diabetic foot ulcer (DFU) patients engaged in this study. This cross-sectional survey consisted of 118 consecutive hospitalized diabetic foot patients. The diabetic microvascular (retinopathy, nephropathy, and neuropathy) and macrovascular referring to coronary heart disease (CHD), cerebrovascular disease (CVD), or peripheral artery disease (PAD) complications were evaluated, and then they were divided into different subgroups based on the assessment of vascular complications. As seen from the results, the mean SAF value was 2.8 +/- 0.2 AU. SAF was significantly associated with diabetes duration and blood urea nitrogen (R(2) = 62.8%; P < .01). Moreover, in logistic regression analysis, SAF was significantly associated with retinopathy (odds ratio [OR] = 40.11), nephropathy (OR = 8.44), CHD (OR = 44.31), CVD (OR = 80.73), and PAD (OR = 5.98 * 10(9)). In conclusion, SAF, reflecting tissue accumulation of AGEs, is independently associated with the presence of vascular complications in DFU patients. PMID- 25694438 TI - A molecular survey concerning the origin of Cyperus esculentus (Cyperaceae, Poales): two sides of the same coin (weed vs. crop). AB - BACKGROUND AND AIMS: Cyperus esculentus is widespread in tropical and temperate zones and is also present in cooler regions. It is used as a crop plant, but it also occurs in the wild and as a weed. As a consequence of its ecological plasticity, C. esculentus has remarkable variability, with several morphotypes. Four wild-type varieties are presently recognized, in addition to the cultivated form. This study investigates the phylogenetic position and biogeography of C. esculentus with the objective of contributing new data to increase the understanding of its evolutionary history. METHODS: Genealogical relationships among genotypes were inferred by using plastid DNA haplotype and nuclear ribosomal (nr) DNA ribotype sequences for 70 specimens either collected in the field or obtained from herbaria. Statistical dispersal-vicariance (S-DIVA) and Bayesian binary method (BBM) analyses were used to reconstruct the possible ancestral ranges of C. esculentus. In order to determine the age of C. esculentus, a time-measured phylogenetic analysis was performed. KEY RESULTS: Considerable variation between the chosen nuclear and plastid markers was detected (27 ribotypes vs. six haplotypes). No geographical structure was displayed among the haplotypes, but information on the dispersal pattern may be deduced. Two types of ribotypes were detected in nrDNA, with an evident geographical segregation into an Old World group and a polymorphic New World group. Both S-DIVA and BBM analyses suggested a biogeographical history in which dispersal from the African region has been crucial in shaping the current distribution pattern of C. esculentus. The most recent common ancestor between C. esculentus races has an age of 5.1 million years (95 % highest posterior density 2.5-10.2). CONCLUSIONS: The molecular analysis provides novel insights into the evolutionary history of C. esculentus. The results have various taxonomic and phylogenetic implications, including a hypothesis on the origin and phylogeography of this species, which probably originated in the late Cenozoic in Africa, and reached the Americas repeatedly, independently of Columbian exchanges. PMID- 25694440 TI - Correction. PMID- 25694439 TI - The chirality dependent spin filter design in the graphene-like junction. AB - We investigate the chirality-dependent spin transport in a graphene-like topological insulator (TI) TI/n junction, where a perpendicular magnetic field or an off-resonant circularly- polarized light field is applied to the normal (n) region. It is found that the coupling between the helical edge states of the TI and chiral edge states from the magnetic/light field results in a perfect spin filtering effect and only one spin species can tunnel through the junction interface. The origin is ascribed to the chirality-conservation requirement, since the two spin species have the opposite chiralities in the TI region and in the n region both of them have the same chiralities. For a TI/n superlattice structure, the spin filtering effect is enhanced and even survives in a fairly strong disorder environment. PMID- 25694441 TI - Correction. PMID- 25694442 TI - Anticipatory control through associative learning of subliminal relations: invisible may be better than visible. AB - We showed that anticipatory cognitive control could be unconsciously instantiated through subliminal cues that predicted enhanced future control needs. In task switching experiments, one of three subliminal cues preceded each trial. Participants had no conscious experience or knowledge of these cues, but their performance was significantly improved on switch trials after cues that predicted task switches (but not particular tasks). This utilization of subliminal information was flexible and adapted to a change in cues predicting task switches and occurred only when switch trials were difficult and effortful. When cues were consciously visible, participants were unable to discern their relevance and could not use them to enhance switch performance. Our results show that unconscious cognition can implicitly use subliminal information in a goal directed manner for anticipatory control, and they also suggest that subliminal representations may be more conducive to certain forms of associative learning. PMID- 25694443 TI - Mass spectrometric analysis of unknown haemoglobin fractions identified by high performance liquid chromatography in an antenatal screening programme. AB - AIMS: The majority of haematology laboratories use automated high-performance liquid chromatography (HPLC) as a primary method in the screening of samples for haemoglobin variants and thalassaemia. HPLC detects adducted fractions, such as HbA1C and other peaks of unknown significance. The National Health Service (NHS) Sickle and Thalassaemia Screening Programme does not mandate further assessment of these unknown peaks, but their presence may cause concern or precipitate detailed investigations. Mass spectrometry (MS) is being increasingly used in NHS Laboratories and is an effective method of characterising variant haemoglobins. METHOD: Antenatal blood samples accepted for NHS Sickle and Thalassaemia Screening Programme from 2005 to 2013 were assessed. Those samples with unidentified peaks on HPLC were further analysed by Liquid chromatography tandem MS (LCMSMS). RESULTS: 58,493 samples were processed. 966 (1.6%) significant haemoglobinopathies were identified. 68 patients (0.11%) were found to have unidentified peaks on HPLC. alpha chain variants: two were hyperunstable alpha variants, Hb Adana and Hb H/Constant Spring. The patient with HbH/Constant Spring required transfusion during pregnancy. Other abnormalities include 24 unstable alpha chain variants of minimal clinical significance and 17 alpha chain variants of no clinical significance. The frequency of beta chain abnormalities was lower, with 10 patients having an insignificant beta chain variant, 4 mildly unstable beta chain variants (2 of whom had increased oxygen affinity) and 4 with variants associated with increased oxygen affinity. CONCLUSIONS: The prevalence of unidentified variants on automated HPLC within our population is 0.1%. LCMSMS is an effective technique to assist in the characterisation of unknown haemoglobin variants. alpha chain variants of limited clinical significance were the most commonly detected abnormality. PMID- 25694444 TI - Combined treatment strategies for microtubule stabilizing agent-resistant tumors. AB - BACKGROUND: Resistance to microtubule-stabilizing agents is a major hurdle for successful cancer therapy. We investigated combined treatment of microtubule stabilizing agents (MSAs) with inhibitors of angiogenesis to overcome MSA resistance. METHODS: Treatment regimens of clinically relevant MSAs (patupilone and paclitaxel) and antiangiogenic agents (everolimus and bevacizumab) were investigated in genetically defined MSA-resistant lung (A549EpoB40) and colon adenocarcinoma (SW480) tumor xenografts in nude mice (CD1-Foxn1, ICRnu; 5-14 per group). Tumor growth delays were calculated by Kaplan-Meier analysis with Holm-Sidak tests. All statistical tests were two-sided. RESULTS: Inhibition of mTOR-kinase by everolimus only minimally reduced the proliferative activity of beta tubulin-mutated lung adenocarcinoma cells alone and in combination with the MSA patupilone, but everolimus inhibited expression and secretion of vascular endothelial growth factor (VEGF) from these cells. mTOR-kinase inhibition strongly sensitized tumor xenografts derived from these otherwise MSA-resistant tumor cells to patupilone. Tumors treated with the combined modality of everolimus and patupilone had statistically significantly reduced tumor volume and stronger tumor growth delay (16.2 +/- 1.01 days) than control- (7.7 +/- 0.3 days, P = .004), patupilone- (10 +/- 0.97 days, P = .009), and everolimus-treated (10.6 +/- 1.4 days, P = .014) tumors. A combined treatment modality with bevacizumab also resensitized this MSA-refractory tumor model to patupilone. Treatment combination also strongly reduced microvessel density, corroborating the relevance of VEGF targeting for the known antivasculature-directed potency of MSA alone in MSA-sensitive tumor models. Resensitization to MSAs was also probed in P glycoprotein-overexpressing SW480-derived tumor xenografts. Different bevacizumab regimens also sensitized this otherwise-resistant tumor model to clinically relevant MSA paclitaxel. CONCLUSIONS: A treatment combination of MSAs with antiangiogenic agents is potent to overcome tumor cell-linked MSA resistance and should be considered as strategy for MSA-refractory tumor entities. PMID- 25694445 TI - The microtubule cross-linker Feo controls the midzone stability, motor composition, and elongation of the anaphase B spindle in Drosophila embryos. AB - Chromosome segregation during anaphase depends on chromosome-to-pole motility and pole-to-pole separation. We propose that in Drosophila embryos, the latter process (anaphase B) depends on a persistent kinesin-5-generated interpolar (ip) microtubule (MT) sliding filament mechanism that "engages" to push apart the spindle poles when poleward flux is turned off. Here we investigated the contribution of the midzonal, antiparallel MT-cross-linking nonmotor MAP, Feo, to this "slide-and-flux-or-elongate" mechanism. Whereas Feo homologues in other systems enhance the midzone localization of the MT-MT cross-linking motors kinesin-4, -5 and -6, the midzone localization of these motors is respectively enhanced, reduced, and unaffected by Feo. Strikingly, kinesin-5 localizes all along ipMTs of the anaphase B spindle in the presence of Feo, including at the midzone, but the antibody-induced dissociation of Feo increases kinesin-5 association with the midzone, which becomes abnormally narrow, leading to impaired anaphase B and incomplete chromosome segregation. Thus, although Feo and kinesin-5 both preferentially cross-link MTs into antiparallel polarity patterns, kinesin-5 cannot substitute for loss of Feo function. We propose that Feo controls the organization, stability, and motor composition of antiparallel ipMTs at the midzone, thereby facilitating the kinesin-5-driven sliding filament mechanism underlying proper anaphase B spindle elongation and chromosome segregation. PMID- 25694446 TI - PKCiota interacts with Rab14 and modulates epithelial barrier function through regulation of claudin-2 levels. AB - PKCiota is essential for the establishment of epithelial polarity and the normal assembly of tight junctions. We find that PKCiota knockdown does not compromise the steady-state distribution of most tight junction proteins but results in increased transepithelial resistance (TER) and decreased paracellular permeability. Analysis of the levels of tight junction components demonstrates that claudin-2 protein levels are decreased. However, other tight junction proteins, such as claudin-1, ZO-1, and occludin, are unchanged. Incubation with an aPKC pseudosubstrate recapitulates the phenotype of PKCiota knockdown, including increased TER and decreased levels of claudin-2. In addition, overexpression of PKCiota results in increased claudin-2 levels. ELISA and coimmunoprecipitation show that the TGN/endosomal small GTPase Rab14 and PKCiota interact directly. Immunolabeling shows that PKCiota and Rab14 colocalize in both intracellular puncta and at the plasma membrane and that Rab14 expression is required for normal PKCiota distribution in cysts in 3D culture. We showed previously that knockdown of Rab14 results in increased TER and decreased claudin 2. Our results suggest that Rab14 and aPKC interact to regulate trafficking of claudin-2 out of the lysosome-directed pathway. PMID- 25694447 TI - Drosophila CLIP-190 and mammalian CLIP-170 display reduced microtubule plus end association in the nervous system. AB - Axons act like cables, electrically wiring the nervous system. Polar bundles of microtubules (MTs) form their backbones and drive their growth. Plus end-tracking proteins (+TIPs) regulate MT growth dynamics and directionality at their plus ends. However, current knowledge about +TIP functions, mostly derived from work in vitro and in nonneuronal cells, may not necessarily apply to the very different context of axonal MTs. For example, the CLIP family of +TIPs are known MT polymerization promoters in nonneuronal cells. However, we show here that neither Drosophila CLIP-190 nor mammalian CLIP-170 is a prominent MT plus end tracker in neurons, which we propose is due to low plus end affinity of the CAP Gly domain-containing N-terminus and intramolecular inhibition through the C terminus. Instead, both CLIP-190 and CLIP-170 form F-actin-dependent patches in growth cones, mediated by binding of the coiled-coil domain to myosin-VI. Because our loss-of-function analyses in vivo and in culture failed to reveal axonal roles for CLIP-190, even in double-mutant combinations with four other +TIPs, we propose that CLIP-190 and -170 are not essential axon extension regulators. Our findings demonstrate that +TIP functions known from nonneuronal cells do not necessarily apply to the regulation of the very distinct MT networks in axons. PMID- 25694448 TI - Distinct self-interaction domains promote Multi Sex Combs accumulation in and formation of the Drosophila histone locus body. AB - Nuclear bodies (NBs) are structures that concentrate proteins, RNAs, and ribonucleoproteins that perform functions essential to gene expression. How NBs assemble is not well understood. We studied the Drosophila histone locus body (HLB), a NB that concentrates factors required for histone mRNA biosynthesis at the replication-dependent histone gene locus. We coupled biochemical analysis with confocal imaging of both fixed and live tissues to demonstrate that the Drosophila Multi Sex Combs (Mxc) protein contains multiple domains necessary for HLB assembly. An important feature of this assembly process is the self interaction of Mxc via two conserved N-terminal domains: a LisH domain and a novel self-interaction facilitator (SIF) domain immediately downstream of the LisH domain. Molecular modeling suggests that the LisH and SIF domains directly interact, and mutation of either the LisH or the SIF domain severely impairs Mxc function in vivo, resulting in reduced histone mRNA accumulation. A region of Mxc between amino acids 721 and 1481 is also necessary for HLB assembly independent of the LisH and SIF domains. Finally, the C-terminal 195 amino acids of Mxc are required for recruiting FLASH, an essential histone mRNA-processing factor, to the HLB. We conclude that multiple domains of the Mxc protein promote HLB assembly in order to concentrate factors required for histone mRNA biosynthesis. PMID- 25694449 TI - Cytoplasmic hGle1A regulates stress granules by modulation of translation. AB - When eukaryotic cells respond to stress, gene expression pathways change to selectively export and translate subsets of mRNAs. Translationally repressed mRNAs accumulate in cytoplasmic foci known as stress granules (SGs). SGs are in dynamic equilibrium with the translational machinery, but mechanisms controlling this are unclear. Gle1 is required for DEAD-box protein function during mRNA export and translation. We document that human Gle1 (hGle1) is a critical regulator of translation during stress. hGle1 is recruited to SGs, and hGLE1 small interfering RNA-mediated knockdown perturbs SG assembly, resulting in increased numbers of smaller SGs. The rate of SG disassembly is also delayed. Furthermore, SG hGle1-depletion defects correlate with translation perturbations, and the hGle1 role in SGs is independent of mRNA export. Interestingly, we observe isoform-specific roles for hGle1 in which SG function requires hGle1A, whereas mRNA export requires hGle1B. We find that the SG defects in hGle1 depleted cells are rescued by puromycin or DDX3 expression. Together with recent links of hGLE1 mutations in amyotrophic lateral sclerosis patients, these results uncover a paradigm for hGle1A modulating the balance between translation and SGs during stress and disease. PMID- 25694450 TI - Control of lipid organization and actin assembly during clathrin-mediated endocytosis by the cytoplasmic tail of the rhomboid protein Rbd2. AB - Clathrin-mediated endocytosis (CME) is facilitated by a precisely regulated burst of actin assembly. PtdIns(4,5)P2 is an important signaling lipid with conserved roles in CME and actin assembly regulation. Rhomboid family multipass transmembrane proteins regulate diverse cellular processes; however, rhomboid mediated CME regulation has not been described. We report that yeast lacking the rhomboid protein Rbd2 exhibit accelerated endocytic-site dynamics and premature actin assembly during CME through a PtdIns(4,5)P2-dependent mechanism. Combined genetic and biochemical studies showed that the cytoplasmic tail of Rbd2 binds directly to PtdIns(4,5)P2 and is sufficient for Rbd2's role in actin regulation. Analysis of an Rbd2 mutant with diminished PtdIns(4,5)P2-binding capacity indicates that this interaction is necessary for the temporal regulation of actin assembly during CME. The cytoplasmic tail of Rbd2 appears to modulate PtdIns(4,5)P2 distribution on the cell cortex. The syndapin-like F-BAR protein Bzz1 functions in a pathway with Rbd2 to control the timing of type 1 myosin recruitment and actin polymerization onset during CME. This work reveals that the previously unstudied rhomboid protein Rbd2 functions in vivo at the nexus of three highly conserved processes: lipid regulation, endocytic regulation, and cytoskeletal function. PMID- 25694451 TI - Specific interaction with the nuclear transporter importin alpha2 can modulate paraspeckle protein 1 delivery to nuclear paraspeckles. AB - Importin (IMP) superfamily members mediate regulated nucleocytoplasmic transport, which is central to key cellular processes. Although individual IMPalpha proteins exhibit dynamic synthesis and subcellular localization during cellular differentiation, including during spermatogenesis, little is known of how this affects cell fate. To investigate how IMPalphas control cellular development, we conducted a yeast two-hybrid screen for IMPalpha2 cargoes in embryonic day 12.5 mouse testis, a site of peak IMPalpha2 expression coincident with germ-line masculization. We identified paraspeckle protein 1 (PSPC1), the original defining component of nuclear paraspeckles, as an IMPalpha2-binding partner. PSPC1 IMPalpha2 binding in testis was confirmed in immunoprecipitations and pull downs, and an enzyme-linked immunosorbent assay-based assay demonstrated direct, high affinity PSPC1 binding to either IMPalpha2/IMPbeta1 or IMPalpha6/IMPbeta1. Coexpression of full-length PSPC1 and IMPalpha2 in HeLa cells yielded increased PSPC1 localization in nuclear paraspeckles. High-throughput image analysis of >3500 cells indicated IMPalpha2 levels can directly determine PSPC1-positive nuclear speckle numbers and size; a transport-deficient IMPalpha2 isoform or small interfering RNA knockdown of IMPalpha2 each reduced endogenous PSPC1 accumulation in speckles. This first validation of an IMPalpha2 nuclear import cargo in fetal testis provides novel evidence that PSPC1 delivery to paraspeckles, and consequently paraspeckle function, may be controlled by modulated synthesis of specific IMPs. PMID- 25694452 TI - MiR-1188 at the imprinted Dlk1-Dio3 domain acts as a tumor suppressor in hepatoma cells. AB - The aberrant expression of microRNAs (miRNAs) has frequently been reported in cancer studies; miRNAs play roles in development, progression, metastasis, and prognosis. Recent studies indicate that the miRNAs within the Dlk1-Dio3 genomic region are involved in the development of liver cancer, but the role of miR-1188 in hepatocellular carcinoma (HCC) and the pathway by which it exerts its function remain largely unknown. Here we demonstrate that miR-1188 is significantly down regulated in mouse hepatoma cells compared with normal liver tissues. Enhanced miR-1188 suppresses cell proliferation, migration, and invasion in vitro and inhibits the tumor growth of HCC cells in vivo. Moreover, overexpressed miR-1188 promotes apoptosis, enhances caspase-3 activity, and also up-regulates the expression of Bax and p53. MiR-1188 directly targets and negatively regulates Bcl 2 and Sp1. Silencing of Bcl-2 and Sp1 exactly copies the proapoptotic and anti invasive effects of miR-1188, respectively. The expression of apoptosis- and invasion-related genes, such as Vegfa, Fgfr1, and Rprd1b, decreases after enhancement of miR-1188, as determined by gene expression profiling analysis. Taken together, our results highlight an important role for miR-1188 as a tumor suppressor in hepatoma cells and imply its potential role in cancer therapy. PMID- 25694453 TI - The CSC proteins FAP61 and FAP251 build the basal substructures of radial spoke 3 in cilia. AB - Dynein motors and regulatory complexes repeat every 96 nm along the length of motile cilia. Each repeat contains three radial spokes, RS1, RS2, and RS3, which transduct signals between the central microtubules and dynein arms. Each radial spoke has a distinct structure, but little is known about the mechanisms of assembly and function of the individual radial spokes. In Chlamydomonas, calmodulin and spoke-associated complex (CSC) is composed of FAP61, FAP91, and FAP251 and has been linked to the base of RS2 and RS3. We show that in Tetrahymena, loss of either FAP61 or FAP251 reduces cell swimming and affects the ciliary waveform and that RS3 is either missing or incomplete, whereas RS1 and RS2 are unaffected. Specifically, FAP251-null cilia lack an arch-like density at the RS3 base, whereas FAP61-null cilia lack an adjacent portion of the RS3 stem region. This suggests that the CSC proteins are crucial for stable and functional assembly of RS3 and that RS3 and the CSC are important for ciliary motility. PMID- 25694454 TI - A novel UGGT1 and p97-dependent checkpoint for native ectodomains with ionizable intramembrane residue. AB - Only native polypeptides are released from the endoplasmic reticulum (ER) to be transported at the site of activity. Persistently misfolded proteins are retained and eventually selected for ER-associated degradation (ERAD). The paradox of a structure-based protein quality control is that functional polypeptides may be destroyed if they are architecturally unfit. This has health-threatening implications, as shown by the numerous "loss-of-function" proteopathies, but also offers chances to intervene pharmacologically to promote bypassing of the quality control inspection and export of the mutant, yet functional protein. Here we challenged the ER of human cells with four modular glycopolypeptides designed to alert luminal and membrane protein quality checkpoints. Our analysis reveals the unexpected collaboration of the cytosolic AAA-ATPase p97 and the luminal quality control factor UDP-glucose:glycoprotein glucosyltransferase (UGGT1) in a novel, BiP- and CNX-independent checkpoint. This prevents Golgi transport of a chimera with a native ectodomain that passes the luminal quality control scrutiny but displays an intramembrane defect. Given that human proteopathies may result from impaired transport of functional polypeptides with minor structural defects, identification of quality checkpoints and treatments to bypass them as shown here upon silencing or pharmacologic inhibition of UGGT1 or p97 may have important clinical implications. PMID- 25694455 TI - Mitotic entry in the presence of DNA damage is a widespread property of aneuploidy in yeast. AB - Genetic instability is a hallmark of aneuploidy in budding and fission yeast. All aneuploid yeast strains analyzed to date harbor elevated levels of Rad52-GFP foci, a sign of DNA damage. Here we investigate how continuously elevated levels of DNA damage affect aneuploid cells. We show that Rad52-GFP foci form during S phase, consistent with the observation that DNA replication initiation and elongation are impaired in some aneuploid yeast strains. We furthermore find that although DNA damage is low in aneuploid cells, it nevertheless has dramatic consequences. Many aneuploid yeast strains adapt to DNA damage and undergo mitosis despite the presence of unrepaired DNA leading to cell death. Wild-type cells exposed to low levels of DNA damage exhibit a similar phenotype, indicating that adaptation to low levels of unrepaired DNA is a general property of the cell's response to DNA damage. Our results indicate that by causing low levels of DNA damage, whole-chromosome aneuploidies lead to DNA breaks that persist into mitosis. Such breaks provide the substrate for translocations and deletions that are a hallmark of cancer. PMID- 25694456 TI - A cohort study of influences, health outcomes and costs of patients' health seeking behaviour for minor ailments from primary and emergency care settings. AB - OBJECTIVES: To compare health-related and cost-related outcomes of consultations for symptoms suggestive of minor ailments in emergency departments (EDs), general practices and community pharmacies. DESIGN: Observational study; prospective cohort design. SETTING: EDs (n=2), general practices (n=6) and community pharmacies (n=10) in a mix of rural/urban and deprived/affluent areas across North East Scotland and East Anglia. Participants Adults (>=18 years) presenting between 09:00 and 18:00 (Monday-Friday) in general practices and 09:00-18:00 (Monday-Saturday) in pharmacies and EDs with >=1 of the following: musculoskeletal pain; eye discomfort; gastrointestinal disturbance; or upper respiratory tract-related symptoms. INTERVENTIONS: Participants completed three questionnaires: baseline (prior to index consultation); satisfaction with index consultation and follow-up (2 weeks after index consultation). MAIN OUTCOME MEASURES: Symptom resolution, quality of life, costs, satisfaction and influences on care-seeking behaviour. RESULTS: 377 patients participated, recruited from EDs (81), general practices (162) and community pharmacies (134). The 2-week response rate was 70% (264/377). Symptom resolution was similar across all three settings: ED (37.3%), general practice (35.7%) and pharmacy (44.3%). Mean overall costs per consultation were significantly lower for pharmacy (L29.30 (95% CI L21.60 to L37.00)) compared with general practice (L82.34 (95% CI L63.10 to L101.58)) and ED (L147.09 (95% CI L125.32 to L168.85)). Satisfaction varied across settings and by measure used. Compared with pharmacy and general practice use, ED use was significantly (p<0.001) associated with first episode and short duration of symptom(s), as well as higher levels of perceived seriousness and urgency for seeking care. Convenience of location was the most common reason for choice of consultation setting. CONCLUSIONS: These results suggest similar health-related outcomes and substantially lower costs with pharmacy consultations for minor ailments. Effective strategies are now needed to shift demand for minor ailment management away from EDs and general practices to the community pharmacy setting. PMID- 25694457 TI - Bibliometrics of NIHR HTA monographs and their related journal articles. AB - OBJECTIVES: A bibliometric analysis of the UK National Institute for Health Research (NIHR) Health Technology Assessment (HTA) monographs and their related journal articles by: (1) exploring the differences in citations to the HTA monographs in Google Scholar (GS), Scopus and Web of Science (WoS), and (2) comparing Scopus citations to the monographs with their related journal articles. SETTING: A study of 111 HTA monographs published in 2010 and 2011, and their external journal articles. MAIN OUTCOME MEASURES: Citations to the monographs in GS, Scopus and WoS, and to their external journal articles in Scopus. RESULTS: The number of citations varied among the three databases, with GS having the highest and WoS the lowest; however, the citation-based rankings among the databases were highly correlated. Overall, 56% of monographs had a related publication, with the highest proportion for primary research (76%) and lowest for evidence syntheses (43%). There was a large variation in how the monographs were cited, compared to journal articles, resulting in more frequent problems, with unlinked citations in Scopus and WoS. When comparing differences in the number of citations between monograph publications with their related journal articles from the same project, we found that monographs received more citations than their journal articles for evidence syntheses and methodology projects; by contrast, journal articles related to primary research monographs were more highly cited than their monograph. CONCLUSIONS: The numbers of citations to the HTA monographs differed considerably between the databases, but were highly correlated. When a HTA monograph had a journal article from the same study, there were more citations to the journal article for primary research, but more to the monographs for evidence syntheses. Citations to the related journal articles were more reliably recorded than citations to the HTA monographs. PMID- 25694458 TI - Comparable mRNA expression of inflammatory markers but lower claudin-1 mRNA levels in foreskin tissue of HSV-2 seropositive versus seronegative asymptomatic Kenyan young men. AB - OBJECTIVES: Skin biopsies from local sites of herpes simplex virus 2 (HSV-2) induced ulcers can show infiltrates of inflammatory cells several months after macroscopic healing. We hypothesise that foreskin tissue samples of asymptomatic HSV-2 seropositive men had remaining signs of inflammation at the molecular level. Even in the absence of clinical lesions, genital inflammation may contribute to increased HIV susceptibility on sexual exposure to the virus. SETTING: Foreskin tissue samples were collected from men undergoing elective circumcision in Kisumu, Kenya. PARTICIPANTS: The foreskin tissue samples (n=86) were stratified into study groups based on HSV-2 serology and assessed for mRNA expression of inflammatory markers. Markers of interest were further assessed by immunohistochemical staining within the tissue samples. RESULTS: The two study groups had comparable levels of all molecular markers (CD3, CD4, CD8, CD69, CCR5, HLA-DR, Langerin, DC-SIGN, Mannose Receptor 1, IL-1, IL-6, TNF-alpha, beta7, IgA, IFN-alpha, CCL5, E-cadherin, ZO-1 and occludin), except for lower mRNA levels of the epithelial junction protein claudin-1 in the HSV-2 seropositive group (p=0.008). Although mRNA levels of claudin-1 were lower in HSV-2 seropositive individuals, the corresponding protein could be visualised in the foreskin epithelium of all samples tested. CONCLUSIONS: Whereas no general inflammation was demonstrated in the foreskin of asymptomatic HSV-2 seropositive individuals, a decreased expression of claudin-1 indicates a less robust genital epithelial barrier. An intact epithelial barrier is essential for blocking mucosal entry of genital infections, including HIV. PMID- 25694459 TI - Do guidelines offer implementation advice to target users? A systematic review of guideline applicability. AB - OBJECTIVE: Providers and patients are most likely to use and benefit from guidelines accompanied by implementation support. Guidelines published in 2007 and earlier assessed with the Appraisal of Guidelines, Research and Evaluation (AGREE) instrument scored poorly for applicability, which reflects the inclusion of implementation instructions or tools. The purpose of this study was to examine the applicability of guidelines published in 2008 or later and identify factors associated with applicability. DESIGN: Systematic review of studies that used AGREE to assess guidelines published in 2008 or later. DATA SOURCES: MEDLINE and EMBASE were searched from 2008 to July 2014, and the reference lists of eligible items. Two individuals independently screened results for English language studies that reviewed guidelines using AGREE and reported all domain scores, and extracted data. Descriptive statistics were calculated across all domains. Multilevel regression analysis with a mixed effects model identified factors associated with applicability. RESULTS: Of 245 search results, 53 were retrieved as potentially relevant and 20 studies were eligible for review. The mean and median domain scores for applicability across 137 guidelines published in 2008 or later were 43.6% and 42.0% (IQR 21.8-63.0%), respectively. Applicability scored lower than all other domains, and did not markedly improve compared with guidelines published in 2007 or earlier. Country (UK) and type of developer (disease-specific foundation, non-profit healthcare system) appeared to be associated with applicability when assessed with AGREE II (not original AGREE). CONCLUSIONS: Despite increasing recognition of the need for implementation tools, guidelines continue to lack such resources. To improve healthcare delivery and associated outcomes, further research is needed to establish the type of implementation tools needed and desired by healthcare providers and consumers, and methods for developing high-quality tools. PMID- 25694460 TI - National survey of physicians to determine the effect of unconditional incentives on response rates of physician postal surveys. AB - OBJECTIVES: Physicians are a commonly targeted group in health research surveys, but their response rates are often relatively low. The goal of this paper was to evaluate the effect of unconditional incentives in the form of a coffee card on physician postal survey response rates. DESIGN: Following 13 key informant interviews and eight cognitive interviews a survey questionnaire was developed. PARTICIPANTS: A random sample of 534 physicians, stratified by physician group (geriatricians, family physicians, emergency physicians) was selected from a national medical directory. SETTING: Using computer generated random numbers; half of the physicians in each stratum were allocated to receive a coffee card to a popular national coffee chain together with the first survey mailout. INTERVENTIONS: The intervention was a $10 Tim Hortons gift card given to half of the physicians who were randomly allocated to receive the incentive. RESULTS: 265 (57.0%) physicians completed the survey. The response rate was significantly higher in the group allocated to receive the incentive (62.7% vs 51.3% in the control group; p=0.01). CONCLUSIONS: Our results indicate that an unconditional incentive in the form of a coffee gift card can substantially improve physician response rates. Future research can look at the effect of varying amounts of cash on the gift cards on response rates. PMID- 25694461 TI - A tool for prediction of risk of rehospitalisation and mortality in the hospitalised elderly: secondary analysis of clinical trial data. AB - OBJECTIVES: To construct and internally validate a risk score, the '80+ score', for revisits to hospital and mortality for older patients, incorporating aspects of pharmacotherapy. Our secondary aim was to compare the discriminatory ability of the score with that of three validated tools for measuring inappropriate prescribing: Screening Tool of Older Person's Prescriptions (STOPP), Screening Tool to Alert doctors to Right Treatment (START) and Medication Appropriateness Index (MAI). SETTING: Two acute internal medicine wards at Uppsala University hospital. Patient data were used from a randomised controlled trial investigating the effects of a comprehensive clinical pharmacist intervention. PARTICIPANTS: Data from 368 patients, aged 80 years and older, admitted to one of the study wards. PRIMARY OUTCOME MEASURE: Time to rehospitalisation or death during the year after discharge from hospital. Candidate variables were selected among a large number of clinical and drug-specific variables. After a selection process, a score for risk estimation was constructed. The 80+ score was internally validated, and the discriminatory ability of the score and of STOPP, START and MAI was assessed using C-statistics. RESULTS: Seven variables were selected. Impaired renal function, pulmonary disease, malignant disease, living in a nursing home, being prescribed an opioid or being prescribed a drug for peptic ulcer or gastroesophageal reflux disease were associated with an increased risk, while being prescribed an antidepressant drug (tricyclic antidepressants not included) was linked to a lower risk of the outcome. These variables made up the components of the 80+ score. The C-statistics were 0.71 (80+), 0.57 (STOPP), 0.54 (START) and 0.63 (MAI). CONCLUSIONS: We developed and internally validated a score for prediction of risk of rehospitalisation and mortality in hospitalised older people. The score discriminated risk better than available tools for inappropriate prescribing. Pending external validation, this score can aid in clinical identification of high-risk patients and targeting of interventions. PMID- 25694462 TI - Should patients on vitamin K antagonists be treated differently? PMID- 25694463 TI - Brachial pulse pressure in heart failure: simple to measure but complex to interpret. PMID- 25694465 TI - Massive Soft Tissue Neurofibroma (Elephantiasis Neuromatosa): Case Report and Review of Literature. AB - The authors review the literature on massive soft tissue neurofibroma. The methods included a review of 71 reports (PubMed search 1929-2012) with a total of 91 massive soft tissue neurofibroma patients and illustration of clinical and radiological progression of massive soft tissue neurofibroma on a patient with neurofibromatosis type 1. The mean age at initial examination was 21 years. Tumor onset was mostly in childhood years. The commonest affected body segment was the lower extremity (46%), followed by head/neck (30%). Surgical management was pursued in the majority of cases (79%). Bleeding was a common complication (25%). Recurrence was described in 12%; multiple resections cases were described. Malignant transformation occurred in 5%. Although massive soft tissue neurofibroma may be present early in life, massive tumor overgrowth may take years. Predicting disease progression and/or benefit of surgical intervention early in the disease course is challenging. Recurrence and malignant transformation are possible. Massive soft tissue neurofibroma does not respond to chemotherapy or radiotherapy and is associated with life-threatening surgical complications. PMID- 25694464 TI - Statin-associated muscle symptoms: impact on statin therapy-European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management. AB - Statin-associated muscle symptoms (SAMS) are one of the principal reasons for statin non-adherence and/or discontinuation, contributing to adverse cardiovascular outcomes. This European Atherosclerosis Society (EAS) Consensus Panel overviews current understanding of the pathophysiology of statin-associated myopathy, and provides guidance for diagnosis and management of SAMS. Statin associated myopathy, with significant elevation of serum creatine kinase (CK), is a rare but serious side effect of statins, affecting 1 per 1000 to 1 per 10 000 people on standard statin doses. Statin-associated muscle symptoms cover a broader range of clinical presentations, usually with normal or minimally elevated CK levels, with a prevalence of 7-29% in registries and observational studies. Preclinical studies show that statins decrease mitochondrial function, attenuate energy production, and alter muscle protein degradation, thereby providing a potential link between statins and muscle symptoms; controlled mechanistic and genetic studies in humans are necessary to further understanding. The Panel proposes to identify SAMS by symptoms typical of statin myalgia (i.e. muscle pain or aching) and their temporal association with discontinuation and response to repetitive statin re-challenge. In people with SAMS, the Panel recommends the use of a maximally tolerated statin dose combined with non-statin lipid-lowering therapies to attain recommended low-density lipoprotein cholesterol targets. The Panel recommends a structured work-up to identify individuals with clinically relevant SAMS generally to at least three different statins, so that they can be offered therapeutic regimens to satisfactorily address their cardiovascular risk. Further research into the underlying pathophysiological mechanisms may offer future therapeutic potential. PMID- 25694466 TI - Complexity of the Hereditary Motor and Sensory Neuropathies: Clinical and Cellular Characterization of the MPZ p.D90E Mutation. AB - Early-onset hereditary motor and sensory neuropathies are rare diseases representing a broad clinical and genetic spectrum. Without a notable familial history, the clinical diagnosis is complicated because acquired causes of peripheral neuropathy, such as inflammatory neuropathies, neuropathies with toxic causes, and nutritional deficiencies, must be considered. We examined the clinical, electrophysiological, and pathologic manifestations of a boy with an initial diagnosis of chronic inflammatory demyelinating polyneuropathy. The progression of the disease despite treatment led to a suspicion of hereditary motor and sensory neuropathy. Genetic testing revealed the presence of the MPZ p.D90E mutation in heterozygosis. To clarify the pathogenicity of this mutation and achieve a conclusive diagnosis, we investigated the MPZ p.D90E mutation through in silico and cellular approaches. This study broadens the clinical phenotype of hereditary motor and sensory neuropathy due to MPZ mutation and emphasises the difficulty of achieving an accurate genetic diagnosis in a sporadic patient to provide an appropriate pharmacologic treatment. PMID- 25694467 TI - Facial Expression in Response to Smell and Taste Stimuli in Small and Appropriate for Gestational Age Newborns. AB - Small for gestational age newborns can later suffer from eating difficulties and slow growth. Nutritional preferences can be influenced by changes in sensory perception of smell and taste. To determine whether these could be detected at birth, the authors examined the different recognition pattern of smell and taste in small for gestational age newborns compared to appropriate for gestational age controls, as expressed by gusto-facial and naso-facial reflexes. The authors performed video analysis of facial expressions of 10 small for gestational age and 12 control newborns exposed to various tastes and smells. No difference in the facial recognition patterns for taste or smell was demonstrated between small for gestational age and controls, except for perception of distilled water. Newborns show recognizable patterns of facial expression in response to taste and smell stimuli. Perception of taste and smell in small for gestational age newborns is not different from controls, as measured by the method of facial recognition. PMID- 25694468 TI - Current Understanding of the Role of Complement in IgA Nephropathy. AB - Complement activation has a role in the pathogenesis of IgA nephropathy, an autoimmune disease mediated by pathogenic immune complexes consisting of galactose-deficient IgA1 bound by antiglycan antibodies. Of three complement activation pathways, the alternative and lectin pathways are involved in IgA nephropathy. IgA1 can activate both pathways in vitro, and pathway components are present in the mesangial immunodeposits, including properdin and factor H in the alternative pathway and mannan-binding lectin, mannan-binding lectin-associated serine proteases 1 and 2, and C4d in the lectin pathway. Genome-wide association studies identified deletion of complement factor H-related genes 1 and 3 as protective against the disease. Because the corresponding gene products compete with factor H in the regulation of the alternative pathway, it has been hypothesized that the absence of these genes could lead to more potent inhibition of complement by factor H. Complement activation can take place directly on IgA1 containing immune complexes in circulation and/or after their deposition in the mesangium. Notably, complement factors and their fragments may serve as biomarkers of IgA nephropathy in serum, urine, or renal tissue. A better understanding of the role of complement in IgA nephropathy may provide potential targets and rationale for development of complement-targeting therapy of the disease. PMID- 25694469 TI - DMP1-derived peptides promote remineralization of human dentin. AB - Remineralization of dentin during dental caries is of considerable clinical interest. Dentin matrix protein 1 (DMP1) is a non-collagenous calcium-binding protein that plays a critical role in biomineralization. In the present study, we tested if peptides derived from DMP1 can be used for dentin remineralization. Peptide pA (pA, MW = 1.726 kDa) and peptide pB (pB, MW = 2.185), containing common collagen-binding domains and unique calcium-binding domains, were synthesized by solid-phase chemistry. An extreme caries lesion scenario was created by collagenase digestion, and the biomineral-nucleating potential of these peptides was ascertained when coated on collagenase-treated dentin matrix and control, native human dentin matrix under physiological levels of calcium and phosphate. Scanning electron microscopy analysis suggests that peptide pB was an effective nucleator when compared with pA. However, a 1:4 ratio of pA to pB was determined to be ideal for dentin remineralization, based on hydroxyapatite (HA) morphology and calcium/phosphorus ratios. Interestingly, HA was nucleated on collagenase-challenged dentin with as little as 20 min of 1:4 peptide incubation. Electron diffraction confirmed the presence of large HA crystals that produced a diffraction pattern indicative of a rod-like crystal structure. These findings suggest that DMP1-derived peptides may be useful to modulate mineral deposition and subsequent formation of HA when exposed to physiological concentrations of calcium and phosphate. PMID- 25694470 TI - Neurocognitive development and behaviour in school-aged children after surgery for univentricular or biventricular congenital heart disease. AB - OBJECTIVES: To assess the long-term neuropsychological and behavioural profile of school-aged children who were treated for univentricular heart (UVH) conditions or biventricular heart defect (BiVH) in infancy in a cross-sectional study design. METHODS: Sixty-three patients, 17 UVH (13 males, 4 females) and 46 BiVH (19 males, 27 females), were assessed at a mean age of 9.1 years (2.2 years) with an intelligence and neuropsychological test battery. Results were compared between subgroups (UVH, BiVH and a healthy control group). Associations between cognitive outcome, medical and socio-demographic factors were explored. Parents completed the Child Behavior Checklist (CBCL). RESULTS: Mean intelligence and neuropsychological scores were found within normal ranges for all diagnostic groups. Significant differences between UVH patients and controls emerged on auditory sustained and alternating attention, fine motor skills, visuospatial information processing, and to a lesser extent, memory performance. Parents of UVH patients reported more externalizing problems and school problems. Patient groups did not differ on neuropsychological outcome measures, nor on behavioural problems as rated by parents. CONCLUSIONS: After Fontan completion, patients at school age display intelligence scores within normal population-based ranges. However, they were found at risk for subtle shortcomings in attention, fine motor skills, visuospatial information processing and externalizing behaviour problems. Considerations pertaining to neurobehavioural outcome in school-aged children are discussed. PMID- 25694471 TI - Safety and feasibility of a novel adjustable mitral annuloplasty ring: a multicentre European experience. AB - OBJECTIVES: Recurrent mitral regurgitation is a significant problem after mitral valve repair in patients with functional valve disease. We report the safety and feasibility of a novel adjustable mitral annuloplasty device that permits downsizing of the anterior-posterior diameter late after initial surgery. METHODS: In this multicentre, non-randomized, observational register, patients with moderate or severe mitral regurgitation undergoing surgical mitral valve repair with the MiCardia EnCorSQTM Mitral Valve Repair system were evaluated. Patient characteristics, operative specifications and results as well as postoperative follow-up were collected for all five centres. RESULTS: Ninety-four patients with a median age of 71 (64-75) years (EuroSCORE II 6.7 +/- 6.3; 66% male, 48% ischaemic MR, 37% dilated cardiomyopathy and 15% degenerative disease) were included. Operative mortality was 1% and the 1-year survival was 93%. Ring adjustment was attempted in 12 patients at a mean interval of 9 +/- 6 months after surgery. In three of these attempts, a technical failure occurred. In 1 patient, mitral regurgitation was reduced two grades, in 2 patients mitral regurgitation was reduced one grade and in 6 patients, mitral regurgitation did not change significantly. The mean grade of mitral regurgitation changed from 2.9 +/- 0.9 to 2.1 +/- 0.7 (P = 0.02). Five patients were reoperated after 11 +/- 9 months (Ring dehiscence: 2; failed adjustment: 3). CONCLUSION: We conclude that this device may provide an additional treatment option in patients with functional mitral regurgitation, who are at risk for reoperation due to recurrent mitral regurgitation. Clinical results in this complex disease were ambiguous and patient selection seems to be a crucial step for this device. Further trials are required to estimate the clinical value of this therapeutic concept. PMID- 25694472 TI - Efficacy of mechanical postconditioning following warm, global ischaemia depends on circulating fatty acid levels in an isolated, working rat heart model?. AB - OBJECTIVES: The number of heart transplantations is limited by donor organ availability. Donation after circulatory determination of death (DCDD) could significantly improve graft availability; however, organs undergo warm ischaemia followed by reperfusion, leading to tissue damage. Laboratory studies suggest that mechanical postconditioning [(MPC); brief, intermittent periods of ischaemia at the onset of reperfusion] can limit reperfusion injury; however, clinical translation has been disappointing. We hypothesized that MPC-induced cardioprotection depends on fatty acid levels at reperfusion. METHODS: Experiments were performed with an isolated rat heart model of DCDD. Hearts of male Wistar rats (n = 42) underwent working-mode perfusion for 20 min (baseline), 27 min of global ischaemia and 60 min reperfusion with or without MPC (two cycles of 30 s reperfusion/30 s ischaemia) in the presence or absence of high fat [(HF); 1.2 mM palmitate]. Haemodynamic parameters, necrosis factors and oxygen consumption (O2C) were assessed. Recovery rate was calculated as the value at 60 min reperfusion expressed as a percentage of the mean baseline value. The Kruskal Wallis test was used to provide an overview of differences between experimental groups, and pairwise comparisons were performed to compare specific time points of interest for parameters with significant overall results. RESULTS: Percent recovery of left ventricular (LV) work [developed pressure (DP)-heart rate product] at 60 min reperfusion was higher in hearts reperfused without fat versus with fat (58 +/- 8 vs 23 +/- 26%, P < 0.01) in the absence of MPC. In the absence of fat, MPC did not affect post-ischaemic haemodynamic recovery. Among the hearts reperfused with HF, two significantly different subgroups emerged according to recovery of LV work: low recovery (LoR) and high recovery (HiR) subgroups. At 60 min reperfusion, recovery was increased with MPC versus no MPC for LV work (79 +/ 6 vs 55 +/- 7, respectively; P < 0.05) in HiR subgroups and for DP (40 +/- 27 vs 4 +/- 2%), dP/dtmax (37 +/- 24 vs 5 +/- 3%) and dP/dtmin (33 +/- 21 vs 5 +/- 4%; P < 0.01 for all) in LoR subgroups. CONCLUSIONS: Effects of MPC depend on energy substrate availability; MPC increased recovery of LV work in the presence, but not in the absence, of HF. Controlled reperfusion may be useful for therapeutic strategies aimed at improving post-ischaemic recovery of cardiac DCDD grafts, and ultimately in increasing donor heart availability. PMID- 25694473 TI - Cost prediction following traumatic brain injury: model development and validation. AB - OBJECTIVE: The ability to predict costs following a traumatic brain injury (TBI) would assist in planning treatment and support services by healthcare providers, insurers and other agencies. The objective of the current study was to develop predictive models of hospital, medical, paramedical, and long-term care (LTC) costs for the first 10 years following a TBI. METHODS: The sample comprised 798 participants with TBI, the majority of whom were male and aged between 15 and 34 at time of injury. Costing information was obtained for hospital, medical, paramedical, and LTC costs up to 10 years postinjury. Demographic and injury severity variables were collected at the time of admission to the rehabilitation hospital. RESULTS: Duration of PTA was the most important single predictor for each cost type. The final models predicted 44% of hospital costs, 26% of medical costs, 23% of paramedical costs, and 34% of LTC costs. Greater costs were incurred, depending on cost type, for individuals with longer PTA duration, obtaining a limb or chest injury, a lower GCS score, older age at injury, not being married or defacto prior to injury, living in metropolitan areas, and those reporting premorbid excessive or problem alcohol use. CONCLUSIONS: This study has provided a comprehensive analysis of factors predicting various types of costs following TBI, with the combination of injury-related and demographic variables predicting 23-44% of costs. PTA duration was the strongest predictor across all cost categories. These factors may be used for the planning and case management of individuals following TBI. PMID- 25694474 TI - Destruction of paranodal architecture in inflammatory neuropathy with anti contactin-1 autoantibodies. AB - OBJECTIVE: Autoantibodies against paranodal proteins have been described in patients with inflammatory neuropathies, but their association with pathology of nodes of Ranvier is unclear. We describe the clinical phenotype and histopathological changes of paranodal architecture of patients with autoantibodies against contactin-1, identified from a cohort with chronic inflammatory demyelinating polyradiculoneuropathy (n=53) and Guillain-Barre syndrome (n=21). METHODS: We used ELISA to detect autoantibodies against contactin-1. Specificity of the autoantibodies was confirmed by immunoblot assay, binding to contactin-1-transfected human embryonic kidney cells, binding to paranodes of murine teased fibres and preabsorption experiments. Paranodal pathology was investigated by immunofluorescence labelling of dermal myelinated fibres. RESULTS: High reactivity to contactin-1 by ELISA was found in four patients with chronic inflammatory demyelinating polyradiculoneuropathy and in none of the patients with Guillain-Barre syndrome, which was confirmed by cell binding assays in all four patients. The four patients presented with a typical clinical picture, namely acute onset of disease and severe motor symptoms, with three patients manifesting action tremor. Immunofluorescence-labelling of paranodal proteins of dermal myelinated fibres revealed disruption of paranodal architecture. Semithin sections showed axonal damage but no classical signs of demyelination. INTERPRETATION: We conclude that anti-contactin-1-related neuropathy constitutes a presumably autoantibody-mediated form of inflammatory neuropathy with distinct clinical symptoms and disruption of paranodal architecture as a pathological correlate. Anti-contactin-1-associated neuropathy does not meet morphological criteria of demyelinating neuropathy and therefore, might rather be termed a 'paranodopathy' rather than a subtype of demyelinating inflammatory neuropathy. PMID- 25694475 TI - Neurological picture: Sunderland's median nerve fascicular anatomy revisited by ultrasound. PMID- 25694476 TI - Characterization of an orthovoltage biological irradiator used for radiobiological research. AB - Orthovoltage irradiators are routinely used to irradiate specimens and small animals in biological research. There are several reports on the characteristics of these units for small field irradiations. However, there is limited knowledge about use of these units for large fields, which are essential for emerging large field irregular shape irradiations, namely total marrow irradiation used as a conditioning regimen for hematological malignancies. This work describes characterization of a self-contained Orthovoltage biological irradiator for large fields using measurements and Monte Carlo simulations that could be used to compute the dose for in vivo or in vitro studies for large-field irradiation using this or a similar unit. Percentage depth dose, profiles, scatter factors, and half-value layers were measured and analyzed. A Monte Carlo model of the unit was created and used to generate depth dose and profiles, as well as scatter factors. An ion chamber array was also used for profile measurements of flatness and symmetry. The output was determined according to AAPM Task Group 61 guidelines. The depth dose measurements compare well with published data for similar beams. The Monte Carlo-generated depth dose and profiles match our measured doses to within 2%. Scatter factor measurements indicate gradual variation of these factors with field size. Dose rate measured by placing the ion chamber atop the unit's steel plate or solid water indicate enhanced readings of 5 to 28% compared with those measured in air. The stability of output over a 5 year period is within 2% of the 5-year average. PMID- 25694477 TI - Sorting out the paracrine kidney. PMID- 25694478 TI - Mitochondrial dysfunction confers albumin-induced NLRP3 inflammasome activation and renal tubular injury. AB - Proteinuria is involved in the development of tubular lesions and in the progressive loss of renal function in chronic kidney diseases via uncertain mechanisms. Growing evidence suggests a pathogenic role of mitochondrial dysfunction in chronic kidney diseases. Therefore, the present study aimed to define the roles of mitochondria in proteinuria-induced renal tubular injury and their underlying mechanisms. Using the albumin-overload mouse model, we observed severe tubular structure damage and striking tubular cell apoptosis. Furthermore, tubular epithelial cells displayed a loss of E-cadherin expression and gained expression of alpha-smooth muscle actin and vimentin, indicating a cellular phenotypic alteration. Strikingly, these albumin overload-induced abnormalities were robustly blocked by a mitochondrial SOD2 mimic, Mn(III) tetrakis (4-benzoic acid)porphyrin chloride (MnTBAP). In agreement with these results, we observed a marked change in mitochondrial morphology accompanied by mitochondrial cytochrome c release and a copy number reduction of mitochondrial DNA. These alterations were largely reversed by MnTBAP, suggesting a key role for mitochondria-derived oxidative stress in mediating the albumin effect on mitochondrial dysfunction and subsequent tubular injury. Moreover, the NOD-like receptor family, pyrin domain containing 3 (NLRP3)/caspase-1/cytokine cascade was activated in the kidney by albumin overload and was entirely abolished by MnTBAP. In albumin-treated mouse proximal tubular cells, albumin directly induced ROS production, mitochondrial dysfunction, NLRP3/caspase-1/cytokine cascade activation, cell apoptosis, and cellular phenotypic transition. Similar to our in vivo results, treatment with either MnTBAP or cyclosporin A, a mitochondrial permeability transition pore inhibitor, remarkably attenuated these abnormalities in cells. Taken together, these novel findings demonstrate a potential role for the mitochondrial dysfunction/NLRP3 inflammasome axis in the pathogenesis of proteinuria-induced renal tubular injury. PMID- 25694479 TI - A mathematical model of rat proximal tubule and loop of Henle. AB - Proximal tubule and loop of Henle function are coupled, with proximal transport determining loop fluid composition, and loop transport modulating glomerular filtration via tubuloglomerular feedback (TGF). To examine this interaction, we begin with published models of the superficial rat proximal convoluted tubule (PCT; including flow-dependent transport in a compliant tubule), and the rat thick ascending Henle limb (AHL). Transport parameters for this PCT are scaled down to represent the proximal straight tubule (PST), which is connected to the thick AHL via a short descending limb. Transport parameters for superficial PCT and PST are scaled up for a juxtamedullary nephron, and connected to AHL via outer and inner medullary descending limbs, and inner medullary thin AHL. Medullary interstitial solute concentrations are specified. End-AHL hydrostatic pressure is determined by distal nephron flow resistance, and the TGF signal is represented as a linear function of end-AHL cytosolic Cl concentration. These two distal conditions required iterative solution of the model. Model calculations capture inner medullary countercurrent flux of urea, and also suggest the presence of an outer medullary countercurrent flux of ammonia, with reabsorption in AHL and secretion in PST. For a realistically strong TGF signal, there is the expected homeostatic impact on distal flows, and in addition, a homeostatic effect on proximal tubule pressure. The model glycosuria threshold is compatible with rat data, and predicted glucose excretion with selective 1Na(+):1glucose cotransporter (SGLT2) inhibition comports with observations in the mouse. Model calculations suggest that enhanced proximal tubule Na(+) reabsorption during hyperglycemia is sufficient to activate TGF and contribute to diabetic hyperfiltration. PMID- 25694480 TI - A mathematical model of the rat nephron: glucose transport. AB - Mathematical models of the proximal tubule (PT), loop of Henle (LOH), and distal nephron have been combined to simulate transport by rat renal tubules. The ensemble is composed of 24,000 superficial (SF) nephrons and 12,000 juxtamedullary (JM) nephrons in 5 classes (according to LOH length); all coalesce into 7,200 connecting tubules (CNT). Medullary interstitial solute concentrations are specified. The model equations require that each nephron glomerular filtration rate (GFR) satisfies a tubuloglomerular feedback (TGF) relationship, and each initial hydrostatic pressure yields a common CNT pressure; that common CNT pressure is determined from an overall distal hydraulic resistance to flow. By virtue of the greater GFR for JM nephrons, fluid delivery to SF and JM tubules is comparable. Glucose reabsorption is restricted to the PT, cotransported with one Na in the convoluted tubule (SGLT2), and two Na in the straight tubule (SGLT1). Increasing ambient glucose from 5 to 10 mM increases proximal Na reabsorption and decreases distal delivery. This is mitigated by a TGF-mediated increase in GFR, and may thus be an etiology for TGF-mediated glomerular hyperfiltration. With SGLT2 inhibition by 95%, the model predicts that under normoglycemic conditions about 60% of filtered glucose will still be reabsorbed, so that profound glycosuria is not to be expected. Compared with glucose-driven osmotic diuresis, SGLT2 inhibition provokes greater natriuresis. When hyperglycemia is superimposed on SGLT2 inhibition, the model suggests that natriuresis may be severe, reflecting synergy of a proximal diuretic and osmotic diuresis. In sum, the model captures TGF-mediated diabetic hyperfiltration and predicts glomerular protection with SGLT2 inhibition. PMID- 25694481 TI - Higher filtration fraction in formerly early-onset preeclamptic women without comorbidity. AB - Formerly preeclamptic women have an increased risk for developing end-stage renal disease, which has been attributed to altered renal hemodynamics and abnormalities in the renin-angiotensin-aldosterone system. Whether this is due to preeclampsia itself or to comorbid conditions is unknown. Renal hemodynamics and responsiveness to ANG II during low Na(+) intake (7 days, 50 mmol Na(+)/24 h) and high Na(+) (HS) intake (7 days, 200 mmol Na(+)/24 h) were studied in 18 healthy normotensive formerly early-onset preeclamptic women (fPE women) and 18 healthy control subjects (fHP women), all selected for absence of comorbidity. At the end of each diet, renal hemodynamics and blood pressure were measured before and during graded ANG II infusion. Both HS intake and former preeclampsia increased filtration fraction (FF) without an interaction between the two. FF was highest during HS intake in fPE women [0.31 +/- 0.12 vs. 0.29 +/- 0.11 in fHP women, generalized estimating equation analysis (body mass index corrected), P = 0.03]. The renal response to ANG II infusion was not different between groups. In conclusion, fPE women have a higher FF compared with fHP women. As this was observed in the absence of comorbidity, preeclampsia itself might exert long-term effects on renal hemodynamics. However, we cannot exclude the presence of prepregnancy alterations in renal function, which, in itself, lead to an increased risk for preeclampsia. In experimental studies, an elevated FF has been shown to play a pathogenic role in the development of hypertension and renal damage. Future studies, however, should evaluate whether the subtle differences in renal hemodynamics after preeclampsia contribute to the increased long-term renal risk after preeclampsia. PMID- 25694482 TI - Spinal stimulation of the upper lumbar spinal cord modulates urethral sphincter activity in rats after spinal cord injury. AB - After spinal cord injury (SCI), the neurogenic bladder is observed to develop asynchronous bladder and external urethral sphincter (EUS) contractions in a condition known as detrusor-sphincter dyssnergia (DSD). Activation of the EUS spinal controlling center located at the upper lumbar spinal cord may contribute to reduce EUS dyssynergic contractions and decrease urethral resistance during voiding. However, this mechanism has not been well studied. This study aimed at evaluating the effects of epidural stimulation (EpS) over the spinal EUS controlling center (L3) in combination with a serotonergic receptor agonist on EUS relaxation in naive rats and chronic (6-8 wk) T8 SCI rats. Cystometrogram and EUS electromyography (EMG) were obtained before and after the intravenous administration of 5HT-1A receptor agonist and antagonist. The latency, duration, frequency, amplitude, and area under curve of EpS-evoked EUS EMG responses were analyzed. EpS on L3 evoked an inhibition of EUS tonic contraction and an excitation of EUS intermittent bursting/relaxation correlating with urine expulsion in intact rats. Combined with a 5HT-1A receptor agonist, EpS on L3 evoked a similar effect in chronic T8 SCI rats to reduce urethral contraction (resistance). This study examined the effect of facilitating the EUS spinal controlling center to switch between urine storage and voiding phases by using EpS and a serotonergic receptor agonist. This novel approach of applying EpS on the EUS controlling center modulates EUS contraction and relaxation as well as reduces urethral resistance during voiding in chronic SCI rats with DSD. PMID- 25694483 TI - The swan-neck lesion: proximal tubular adaptation to oxidative stress in nephropathic cystinosis. AB - Cystinosis is an inherited disorder resulting from a mutation in the CTNS gene, causing progressive proximal tubular cell flattening, the so-called swan-neck lesion (SNL), and eventual renal failure. To determine the role of oxidative stress in cystinosis, histologic sections of kidneys from C57BL/6 Ctns(-/-) and wild-type mice were examined by immunohistochemistry and morphometry from 1 wk to 20 mo of age. Additional mice were treated from 1 to 6 mo with vehicle or mitoquinone (MitoQ), an antioxidant targeted to mitochondria. The leading edge of the SNL lost mitochondria and superoxide production, and became surrounded by a thickened tubular basement membrane. Progression of the SNL as determined by staining with lectin from Lotus tetragonolobus accelerated after 3 mo, but was delayed by treatment with MitoQ (38 +/- 4% vs. 28 +/- 1%, P < 0.01). Through 9 mo, glomeruli had retained renin staining and intact macula densa, whereas SNL expressed transgelin, an actin-binding protein, but neither kidney injury molecule-1 (KIM-1) nor cell death was observed. After 9 mo, clusters of proximal tubules exhibited localized oxidative stress (4-hydroxynonenal binding), expressed KIM-1, and underwent apoptosis, leading to the formation of atubular glomeruli and accumulation of interstitial collagen. We conclude that nephron integrity is initially maintained in the Ctns(-/-) mouse by adaptive flattening of cells of the SNL through loss of mitochondria, upregulation of transgelin, and thickened basement membrane. This adaptation ultimately fails in adulthood, with proximal tubular disruption, formation of atubular glomeruli, and renal failure. Antioxidant treatment targeted to mitochondria delays initiation of the SNL, and may provide therapeutic benefit in children with cystinosis. PMID- 25694484 TI - Disruption of the cytochrome P-450 1B1 gene exacerbates renal dysfunction and damage associated with angiotensin II-induced hypertension in female mice. AB - Recently, we demonstrated in female mice that protection against ANG II-induced hypertension and associated cardiovascular changes depend on cytochrome P-450 (CYP)1B1. The present study was conducted to determine if Cyp1b1 gene disruption ameliorates renal dysfunction and organ damage associated with ANG II-induced hypertension in female mice. ANG II (700 ng.kg(-1).min(-1)) infused by miniosmotic pumps for 2 wk in female Cyp1b1(+/+) mice did not alter water consumption, urine output, Na(+) excretion, osmolality, or protein excretion. However, in Cyp1b1(-/-) mice, ANG II infusion significantly increased (P < 0.05) water intake (5.50 +/- 0.42 ml/24 h with vehicle vs. 8.80 +/- 0.60 ml/24 h with ANG II), urine output (1.44 +/- 0.37 ml/24 h with vehicle vs. 4.30 +/- 0.37 ml/24 h with ANG II), and urinary Na(+) excretion (0.031 +/- 0.016 mmol/24 h with vehicle vs. 0.099 +/- 0.010 mmol/24 h with ANG II), decreased osmolality (2,630 +/- 79 mosM/kg with vehicle vs. 1,280 +/- 205 mosM/kg with ANG II), and caused proteinuria (2.60 +/- 0.30 mg/24 h with vehicle vs. 6.96 +/- 0.55 mg/24 h with ANG II). Infusion of ANG II caused renal fibrosis, as indicated by an accumulation of renal interstitial alpha-smooth muscle actin, collagen, and transforming growth factor-beta in Cyp1b1(-/-) but not Cyp1b1(+/+) mice. ANG II also increased renal production of ROS and urinary excretion of thiobarburic acid reactive substances and reduced the activity of antioxidants and urinary excretion of nitrite/nitrate and the 17beta-estradiol metabolite 2 methoxyestradiol in Cyp1b1(-/-) but not Cyp1b1(+/+) mice. These data suggest that Cyp1b1 plays a critical role in female mice in protecting against renal dysfunction and end-organ damage associated with ANG II-induced hypertension, in preventing oxidative stress, and in increasing activity of antioxidant systems, most likely via generation of 2-methoxyestradiol from 17beta-estradiol. PMID- 25694486 TI - In this issue of Occupational Medicine. PMID- 25694485 TI - Aliskiren restores renal AQP2 expression during unilateral ureteral obstruction by inhibiting the inflammasome. AB - Ureteral obstruction is associated with reduced expression of renal aquaporins (AQPs), urinary concentrating defects, and an enhanced inflammatory response, in which the renin-angiotensin system (RAS) may play an important role. We evaluated whether RAS blockade by a direct renin inhibitor, aliskiren, would prevent the decreased renal protein expression of AQPs in a unilateral ureteral obstruction (UUO) model and what potential mechanisms may be involved. UUO was performed for 3 days (3UUO) and 7 days (7UUO) in C57BL/6 mice with or without aliskiren injection. In 3UUO and 7UUO mice, aliskiren abolished the reduction of AQP2 protein expression but not AQP1, AQP3, and AQP4. mRNA levels of renal AQP2 and vasopressin type 2 receptor were decreased in obstructed kidneys of 7UUO mice, which were prevented by aliskiren treatment. Aliskiren treatment was also associated with a reduced inflammatory response in obstructed kidneys of UUO mice. Aliskiren significantly decreased mRNA levels of several proinflammatory factors, such as transforming growth factor-beta and tumor necrosis factor-alpha, seen in obstructed kidneys of UUO mice. Interestingly, mRNA and protein levels of the NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome components apoptosis-associated speck-like protein containing a caspase recruitment domain, caspase-1, and IL-1beta were dramatically increased in obstructed kidneys of 7UUO mice, which were significantly suppressed by aliskiren. In primary cultured inner medullary collecting duct cells, IL-1beta significantly decreased AQP2 expression. In conclusions, RAS blockade with the direct renin inhibitor aliskiren increased water channel AQP2 expression in obstructed kidneys of UUO mice, at least partially by preventing NLRP3 inflammasome activation in association with ureteral obstruction. PMID- 25694487 TI - Medically unexplained symptoms. PMID- 25694488 TI - Stephen Adam, The Gas Worker c.1878. PMID- 25694489 TI - Systematic review: plantar fasciitis and prolonged weight bearing. AB - BACKGROUND: Plantar fasciitis (PF) is one of the most common causes of foot pain. Work can involve factors that may predispose to foot pain. AIMS: To systematically review the evidence of the association between weight bearing (walking or standing) and PF among workers. METHODS: Literature search of relevant indexing databases from inception to May 2012, grey literature, websites of relevant organizations and reference lists for all identified articles. Two reviewers independently selected studies for full review, assessed methodological quality and graded evidence. Findings were summarized qualitatively. RESULTS: Four studies were included; all were assessed as high or unclear risk of bias. Three studies were case-control studies; two used clinic populations and one used volunteers. The other study was cross-sectional involving the workforce of an assembly plant. A number of associations between PF and risk factors were identified including sex, obesity, foot biomechanics and job factors (e.g. job tenure). Two case-control studies and the cross-sectional study found an association with weight bearing, but the assessment of weight bearing varied (e.g. time on feet, time walking or standing). There was low-quality evidence to confirm a causal relationship (Royal College of General Practitioners (RCGP) * grade). CONCLUSIONS: This systematic review found low-quality evidence of an association between PF and weight-bearing tasks such as walking and standing on hard surfaces. The only occupations specifically identified as having higher risk were those associated with the engine assembly plant. Further research is required to fully determine the association between weight bearing and PF. PMID- 25694490 TI - A multidisciplinary clinic for occupational disease. PMID- 25694491 TI - A practical demonstration of Boyle's Law. PMID- 25694492 TI - Jaw ache--an occupational hazard? PMID- 25694493 TI - Mental health of UK Armed Forces medical personnel post-deployment. AB - BACKGROUND: The mental health effects of deployment vary widely, and personnel in both combat and combat support roles, including medical personnel, may be adversely affected. AIMS: To compare the mental health of deployed UK military medical staff in both forward and rear locations and to compare these two groups with other deployed military personnel. METHODS: Participants were medics who had deployed to Iraq or Afghanistan and provided information about their deployed role, experiences during and on return from deployment and demographic and military factors. Health outcomes included common mental health problems (using 12-item General Health Questionnaire), post-traumatic stress disorder (PTSD, using 17-item Post-Traumatic Stress Disorder Checklist-Civilian Version), multiple physical symptoms and alcohol use (using 10-item Alcohol Use Disorders Identification Test). RESULTS: The sample comprised 321 medical personnel. The response rate was 56%. The mental health outcomes for forward located medics (FMs) were no different than those for rear located medics (RLMs). When comparing FMs and RLMs against all other military roles, a small but significant increase in PTSD symptoms in FMs was found. FMs were more likely to rate their work while deployed as being above their skills and experience, report exposure to more combat experiences and report a more challenging homecoming experience than RLMs. CONCLUSIONS: These results suggest that while the overall rates of self-reported mental health disorders were similar in FMs and RLMs, FMs reported more PTSD symptoms than all other roles, which may have been related to working in more hostile environments in more challenging roles while deployed and their experiences on returning home. PMID- 25694494 TI - Engineered nanoparticles at the workplace: current knowledge about workers' risk. PMID- 25694495 TI - Alcohol's harm to others' well-being and health: a comparison between Chile and Australia. AB - AIMS: To assess the degree to which relationships with heavy drinkers affect health and well-being of the Chilean population, and how this compares with previously published analyses of an Australian sample in order to establish intercultural differences in the effects of others' heavy drinking. METHOD: Data are from a face-to-face survey of 1500 Chileans. Respondents were asked to identify people in their lives who were heavy drinkers. Information on respondents' well-being and health was collected using the Personal Well-Being Index and the EuroQol Group 5-Dimension Self-Report Questionnaire score (EQ-5D) index. Sociodemographic information was also gathered. Bivariate and multivariate analyses were performed to determine whether heavy drinkers in the respondents' lives (both living in or out of their household) were related to health and well being. Results were contrasted with those for Australia reported by Livingston et al. [in (2010) Impact of heavy drinkers on others' health and well-being. J Stud Alcohol Drugs 71: , 778-785]. RESULTS: Heavy drinkers inside the household negatively affect the health and well-being of Chileans. Heavy drinkers outside the household have a negative but smaller effect on their health and well-being. This contrasts with Australia where most of the harm seems to arise from heavy drinkers identified outside the household. CONCLUSIONS: In both countries, health and well-being are affected by others' heavy drinking. The particular structure of harm may vary across cultures: in Chile, heavy drinkers identified inside the household are the most harmful, whereas in Australia those identified outside the household are the most harmful. This should have an impact on the policy design. PMID- 25694496 TI - Soft tissue sarcoma, non-Hodgkin's lymphoma and chronic lymphocytic leukaemia in workers exposed to phenoxy herbicides: extended follow-up of a UK cohort. AB - OBJECTIVES: To provide further information on the possible carcinogenicity of phenoxy herbicides, and in particular their relationship to soft tissue sarcoma (STS), non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukaemia (CLL). METHODS: We extended follow-up to December 2012 for 8036 men employed at five factories in the UK which had manufactured phenoxy herbicides, or in a contract spraying business. Mortality was compared with that for England and Wales by the person-years method. Nested case-control analyses compared men with incident or fatal STS (n=15) or NHL/CLL (n=74) and matched controls (up to 10 per case). RESULTS: 4093 men had died, including 2303 since the last follow-up. Mortality from all causes and all cancers was close to expectation, but an excess of deaths from NHL was observed among men who had worked for >=1 year in jobs with more than background exposure to phenoxy herbicides (19 deaths, SMR 1.85, 95% CI 1.12 to 2.89). Four deaths from STS occurred among men potentially exposed above background (3.3 expected). In the nested case-control analyses, there were no significantly elevated risks or consistent trends across categories of potential exposure for either STS or NHL/CLL. Among men who had worked for >=1 year in potentially exposed jobs, the highest OR (for STS) was only 1.30 (95% CI 0.30 to 5.62). CONCLUSIONS: Our findings are consistent with the current balance of epidemiological evidence. If phenoxy herbicides pose a hazard of either STS or NHL, then any absolute increase in risk is likely to be small. PMID- 25694497 TI - Towards evidence-based emergency medicine: best BETs from the Manchester Royal Infirmary. BET 1: role of vinegar in Irukandji syndrome. AB - A shortcut review was carried out to establish whether dousing areas of contact with vinegar could relieve the symptoms of Irukandji syndrome. Four studies were directly relevant to the question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these papers are tabulated. The clinical bottom line is there is a lack of evidence for effectiveness and the latest local guidelines should be followed. PMID- 25694499 TI - Towards evidence-based emergency medicine: best BETs from the Manchester Royal Infirmary. BET 2: In patients presenting with an exacerbation of COPD can a normal venous blood gas pCO2 rule out arterial hypercarbia? AB - A shortcut review was carried out to establish whether a normal partial pressure of carbon dioxide (pCO2) on a venous blood sample could be used to rule out hypercarbia. Eleven studies were directly relevant to the question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these papers are tabulated. The clinical bottom line is that a normal venous pCO2 effectively rules out arterial hypercarbia. PMID- 25694500 TI - Re: McFarlane, W. R., et al: clinical and functional outcomes after 2 years in the early detection and intervention for the prevention of psychosis multisite effectiveness trial. Schizophr Bull. 2015 Jan;41(1):30-43. PMID- 25694506 TI - Siderophore cooperation of the bacterium Pseudomonas fluorescens in soil. AB - While social interactions play an important role for the evolution of bacterial siderophore production in vitro, the extent to which siderophore production is a social trait in natural populations is less clear. Here, we demonstrate that siderophores act as public goods in a natural physical environment of Pseudomonas fluorescens: soil-based compost. We show that monocultures of siderophore producers grow better than non-producers in soil, but non-producers can exploit others' siderophores, as shown by non-producers' ability to invade populations of producers when rare. Despite this rare advantage, non-producers were unable to outcompete producers, suggesting that producers and non-producers may stably coexist in soil. Such coexistence is predicted to arise from the spatial structure associated with soil, and this is supported by increased fitness of non producers when grown in a shaken soil-water mix. Our results suggest that both producers and non-producers should be observed in soil, as has been observed in marine environments and in clinical populations. PMID- 25694507 TI - The revival of a so-called rotten fish: the ontogeny of the Devonian acanthodian Triazeugacanthus. AB - Since its original description as a chordate, the Late Devonian Scaumenella mesacanthi has been interpreted alternately as a prochordate, a larval ostracoderm and an immature acanthodian. For the past 30 years, these minute specimens were generally considered as decayed acanthodians, most of them belonging to Triazeugacanthus affinis. Among the abundant material of 'Scaumenella', we identified a size series of 188 specimens of Triazeugacanthus based on otolith characteristics. Despite taphonomic alteration, we describe proportional growth and progressive appearance of skeletal elements through size increase. Three ontogenetic stages are identified based on squamation extent, ossification completion and allometric growth. We demonstrate that what has been interpreted previously as various degrees of decomposition corresponds to ontogenetic changes. PMID- 25694508 TI - Walking the tightrope: Using quantitative Doppler echocardiography to optimize ventricular filling pressures in patients hospitalized for acute heart failure. AB - Acutely decompensated heart failure (HF), one of the most common reasons for hospitalization, places an intense economic pressure on the health care system and adversely affects outcome of HF patients. Due to lack of reliable clinical tools to assess and monitor hemodynamics, accurate judgment on cardiac preload remains a challenge and complicates current inpatient HF management. In this review, we discuss the emerging role of real-time quantitative Doppler echocardiography (DE) in identifying inappropriate cardiac preload, monitoring volume status during the management, and improving quality of care in patients with acute HF. We illustrate the utilization of DE in common clinical scenarios, propose stepwise algorithms to effectively utilize serial quantitative DE in the bedside care, and discuss obstacles and prospects of quantitative DE utilization in HF management. These efforts will further prompt the development of multi center prospective studies to define and validate the specific roles of quantitative DE in reducing hospitalization time and improving outcome of HF patients. PMID- 25694509 TI - Association of serial high sensitivity troponin T with onset of atrial fibrillation in ST elevation myocardial infarction patients undergoing primary percutaneous coronary intervention. AB - AIMS: Previous reports claimed that high sensitivity troponin T (HsTnT) is not associated with atrial fibrillation (AF) in the setting of acute ST-elevation myocardial infarction (STEMI) and primary percutaneous coronary intervention. However, the association of serial HsTnT levels and new-onset AF is unknown. We therefore assessed the temporal association between HsTnT levels and post infarction AF. METHODS AND RESULTS: 830 patients enrolled in On-TIME II were included. HsTnT was assessed at baseline, and 24h and 72 h after admission for STEMI. New-onset AF episodes were divided into three subgroups: AF during the first 24h of admission, AF 24-72 h after admission and AF >72 h after admission. ROC analysis and binary logistic regression were performed. Mean age was 62 +/- 12 years and 76% were male. Seventy-three patients developed new-onset AF: 41 patients developed AF during the first 24h of admission, 14 patients developed AF 24-72 h after admission and 18 patients developed AF >72 h after admission. HsTnT at baseline was associated with new-onset AF (area under curve (AUC) 0.596, p=0.008), but not with AF during the first 24h of admission (AUC: 0.539, p=0.414). HsTnT after 24h (AUC 0.792, p=0.001) and after 72 h (AUC: 0.884, p<0.001) were associated with AF 24-72 h and >72 h after admission. HsTnT after 24h and 72 h were stronger predictors of AF compared with HsTnT at baseline. In regression analysis, age (odds ratio 1.056, p<0.001), Killip Class >1 (odds ratio: 2.694, p=0.010) and HsTnT after 24h (odds ratio: 1.012, p=0.017) and after 72 h (odds ratio: 1.035, p<0.001) showed the strongest association with post infarction AF. CONCLUSION: Serial HsTnT plasma levels are associated with post infarction, new-onset AF. PMID- 25694510 TI - Germline and somatic SDHx alterations in apparently sporadic differentiated thyroid cancer. AB - Along with breast and endometrial cancers, thyroid cancer is a major component cancer in Cowden syndrome (CS). Germline variants in SDHB/C/D (SDHx) genes account for subsets of CS/CS-like cases, conferring a higher risk of breast and thyroid cancers over those with only germline PTEN mutations. To investigate whether SDHx alterations at both germline and somatic levels occur in apparently sporadic breast cancer and differentiated thyroid cancer (DTC), we analyzed SDHx genes in the following four groups: i) 48 individuals with sporadic invasive breast adenocarcinoma for germline mutation; ii) 48 (expanded to 241) DTC for germline mutation; iii) 37 pairs DTC tumor-normal tissues for germline and somatic mutation and mRNA expression levels; and iv) data from 476 patients in the Cancer Genome Atlas thyroid carcinoma dataset for validation. No germline SDHx variant was found in a pilot series of 48 breast cancer cases. As germline SDHx variants were found in our pilot of 48 thyroid cancer cases, we expanded to three series of DTC comprising a total 754 cases, and found 48 (6%) with germline SDHx variants (P<0.001 compared with 0/350 controls). In 513 tumors, we found 27 (5%) with large somatic duplications within chromosome 1 encompassing SDHC. Both papillary and follicular thyroid tumors showed consistent loss of SDHC/D gene expression (P<0.001), which is associated with earlier disease onset and higher pathological-TNM stage. Therefore, we conclude that both germline and somatic SDHx mutations/variants occur in sporadic DTC but are very rare in sporadic breast cancer, and overall loss of SDHx gene expression is a signature of DTC. PMID- 25694511 TI - Highly specific role of the insulin receptor in breast cancer progression. AB - Accumulating evidence from clinical trials indicates that specific targeting of the IGF1 receptor (IGF1R) is not efficient as an anti-breast cancer treatment. One possible reason is that the mitogenic signals from the insulin receptor (IR) can be processed independently or as compensation to inhibition of the IGF1R. In this study, we highlight the role of the IR in mediating breast tumor progression in both WT mice and a hyperinsulinemic MKR mouse model by induction of Ir (Insr) or Igf1r knockdown (KD) in the mammary carcinoma Mvt-1 cell line. By using the specific IR antagonist-S961, we demonstrated that Igf1r-KD induces elevated responses by the IR to IGF1. On the other hand, Ir-KD cells generated significantly smaller tumors in the mammary fat pads of both WT and MKR mice, as opposed to control cells, whereas the Igf1r-KD cells did not. The tumorigenic effects of insulin on the Mvt-1 cells were also demonstrated using microarray analysis, which indicates alteration of genes and signaling pathways involved in proliferation, the cell cycle, and apoptosis following insulin stimulation. In addition, the correlation between IR and the potential prognostic marker for aggressive breast cancer, CD24, was examined in the Ir-KD cells. Fluorescence activated cell sorting (FACS) analysis revealed more than 60% reduction in CD24 expression in the Ir-KD cells when compared with the control cells. Our results also indicate that CD24-expressing cells can restore, at least in part, the tumorigenic capacity of Ir-KD cells. Taken together, our results highlight the mitogenic role of the IR in mammary tumor progression with a direct link to CD24 expression. PMID- 25694512 TI - bHLH proteins involved in Drosophila neurogenesis are mutually regulated at the level of stability. AB - Proneural bHLH activators are expressed in all neuroectodermal regions prefiguring events of central and peripheral neurogenesis. Drosophila Sc is a prototypical proneural activator that heterodimerizes with the E-protein Daughterless (Da) and is antagonized by, among others, the E(spl) repressors. We determined parameters that regulate Sc stability in Drosophila S2 cells. We found that Sc is a very labile phosphoprotein and its turnover takes place via at least three proteasome-dependent mechanisms. (i) When Sc is in excess of Da, its degradation is promoted via its transactivation domain (TAD). (ii) In a DNA-bound Da/Sc heterodimer, Sc degradation is promoted via an SPTSS phosphorylation motif and the AD1 TAD of Da; Da is spared in the process. (iii) When E(spl)m7 is expressed, it complexes with Sc or Da/Sc and promotes their degradation in a manner that requires the corepressor Groucho and the Sc SPTSS motif. Da/Sc reciprocally promotes E(spl)m7 degradation. Since E(spl)m7 is a direct target of Notch, the mutual destabilization of Sc and E(spl) may contribute in part to the highly conserved anti-neural activity of Notch. Sc variants lacking the SPTSS motif are dramatically stabilized and are hyperactive in transgenic flies. Our results propose a novel mechanism of regulation of neurogenesis, involving the stability of key players in the process. PMID- 25694513 TI - A novel endonuclease that may be responsible for damaged DNA base repair in Pyrococcus furiosus. AB - DNA is constantly damaged by endogenous and environmental influences. Deaminated adenine (hypoxanthine) tends to pair with cytosine and leads to the A:T->G:C transition mutation during DNA replication. Endonuclease V (EndoV) hydrolyzes the second phosphodiester bond 3' from deoxyinosine in the DNA strand, and was considered to be responsible for hypoxanthine excision repair. However, the downstream pathway after EndoV cleavage remained unclear. The activity to cleave the phosphodiester bond 5' from deoxyinosine was detected in a Pyrococcus furiosus cell extract. The protein encoded by PF1551, obtained from the mass spectrometry analysis of the purified fraction, exhibited the corresponding cleavage activity. A putative homolog from Thermococcus kodakarensis (TK0887) showed the same activity. Further biochemical analyses revealed that the purified PF1551 and TK0887 proteins recognize uracil, xanthine and the AP site, in addition to hypoxanthine. We named this endonuclease Endonuclease Q (EndoQ), as it may be involved in damaged base repair in the Thermococcals of Archaea. PMID- 25694515 TI - The Association of Elevated HDL Levels With Carotid Atherosclerosis in Middle Aged Women With Untreated Essential Hypertension. AB - High-density lipoprotein cholesterol (HDL-C), a negative risk factor, is positively associated with a decreased risk of coronary heart disease. We investigated the association between high HDL-C levels and target organ damage (TOD) in never treated women with hypertension. We measured HDL-C levels in 117 women followed by estimation of TODs, that is, pulse wave velocity, microalbuminuria, left ventricular mass index, coronary flow reserve, and carotid intima-media thickness (cIMT). Women were divided into 2 groups (HDLH and HDLL), regarding HDL-C quartiles (upper quartile vs the first 3 lower quartiles). In HDLH group : HDL >=70 mg/dL), cIMT was nonindependently, negatively related to HDL-C (rho = -.42, P < .05). Using receiver -operating characteristic curve (ROC) analysis in the HDLH group, we concluded that the cutoff value of HDL >=76.5 mg/dL moderately predicted the absence of carotid atherosclerosis (area under the curve: 0.77, P = .02; confidence interval: 0.57-0.97; sensitivity 73% and specificity 67%). Increased HDL-C may predict the absence of carotid atherosclerosis in middle-age women with untreated essential hypertension and consequently contribute to total cardiovascular risk estimation and treatment planning. PMID- 25694514 TI - In plants, decapping prevents RDR6-dependent production of small interfering RNAs from endogenous mRNAs. AB - Cytoplasmic degradation of endogenous RNAs is an integral part of RNA quality control (RQC) and often relies on the removal of the 5' cap structure and their subsequent 5' to 3' degradation in cytoplasmic processing (P-)bodies. In parallel, many eukaryotes degrade exogenous and selected endogenous RNAs through post-transcriptional gene silencing (PTGS). In plants, PTGS depends on small interfering (si)RNAs produced after the conversion of single-stranded RNAs to double-stranded RNAs by the cellular RNA-dependent RNA polymerase 6 (RDR6) in cytoplasmic siRNA-bodies. PTGS and RQC compete for transgene-derived RNAs, but it is unknown whether this competition also occurs for endogenous transcripts. We show that the lethality of decapping mutants is suppressed by impairing RDR6 activity. We establish that upon decapping impairment hundreds of endogenous mRNAs give rise to a new class of rqc-siRNAs, that over-accumulate when RQC processes are impaired, a subset of which depending on RDR6 for their production. We observe that P- and siRNA-bodies often are dynamically juxtaposed, potentially allowing for cross-talk of the two machineries. Our results suggest that the decapping of endogenous RNA limits their entry into the PTGS pathway. We anticipate that the rqc-siRNAs identified in decapping mutants represent a subset of a larger ensemble of endogenous siRNAs. PMID- 25694516 TI - Clinical Characteristics of Patients on Hemodialysis With Peripheral Arterial Disease. AB - Patients on hemodialysis (HD; n = 210) were examined for peripheral arterial disease (PAD) using ankle-brachial index (ABI) and toe-brachial index (TBI). The prevalence of PAD was 38.1%. Among patients with PAD, 87.5% were newly diagnosed with PAD, 42.5% were diagnosed with TBI <0.6 despite ABI >= 0.9, and 68.7% had no lower limb symptoms. In patients with PAD, the prevalence rate of cerebrovascular disease was 36.3%, coronary artery disease was 42.5%, spinal stenosis was 33.2%, and vertebral fracture 15.0% and was significantly higher than those of the non PAD patients. Low high-density lipoprotein cholesterol was the most important biomarker among patients with PAD. PAD has been underdiagnosed and untreated in patients on HD because most patients do not have symptoms that could be due to diabetic neuropathy or have insufficient daily activity to experience exertional leg symptoms. Screening for PAD using the ABI and TBI increased diagnostic efficiency in patients on HD and may lead to effective early treatments, including pharmacotherapy, revascularization therapy, and exercise rehabilitation to avoid the worst possible scenario such as lower limb amputation, cardiovascular event, and death. PMID- 25694517 TI - Genomic and epidemiological characteristics provide new insights into the phylogeographical and spatiotemporal spread of porcine epidemic diarrhea virus in Asia. AB - Porcine epidemic diarrhea has become pandemic in the Asian pig-breeding industry, causing significant economic loss. In the present study, 11 complete genomes of porcine epidemic diarrhea virus (PEDV) field isolates from China were determined and analyzed. Frequently occurring mutations were observed, which suggested that full understanding of the genomic and epidemiological characteristics is critical in the fight against PEDV epidemics. Comparative analysis of 49 available genomes clustered the PEDV strains into pandemic (PX) and classical (CX) groups and identified four hypervariable regions (V1 to V4). Further study indicated key roles for the spike (S) gene and the V2 region in distinguishing between the PX and CX groups and for studying genetic evolution. Genotyping and phylogeny-based geographical dissection based on 219 S genes revealed the complexity and severity of PEDV epidemics in Asia. Many subgroups have formed, with a wide array of mutations in different countries, leading to the outbreak of PEDV in Asia. Spatiotemporal reconstruction based on the analysis suggested that the pandemic group strains originated from South Korea and then extended into Japan, Thailand, and China. However, the novel pandemic strains in South Korea that appeared after 2013 may have originated from a Chinese variant. Thus, the serious PED epidemics in China and South Korea in recent years were caused by the complex subgroups of PEDV. The data in this study have important implications for understanding the ongoing PEDV outbreaks in Asia and will guide future efforts to effectively prevent and control PEDV. PMID- 25694518 TI - Gene expression profiling of Burkholderia cenocepacia at the time of cepacia syndrome: loss of motility as a marker of poor prognosis? AB - Cepacia syndrome (CS) is a fatal septic condition that develops in approximately 20% of cystic fibrosis (CF) patients chronically infected with the Burkholderia cepacia complex (Bcc). The most common causative agent is Burkholderia cenocepacia, a clinically dominant Bcc species that contains the globally distributed epidemic strain sequence type 32 (ST32). Using microarrays, we compared the transcriptomes of ST32 isolates from the bloodstream at the time of CS with their sputum counterparts recovered 1 to 2 months prior to the development of CS. Global gene expression profiles of blood isolates revealed greater activities of the virulence genes involved in the type III secretion system, the bacterial exopolysaccharide cepacian, and quorum sensing, while reduced expression was demonstrated for flagellar genes. Furthermore, a nonmotile phenotype (as evaluated by a swimming motility assay) was identified in blood isolates from 6 out of 8 patients with CS; this phenotype was traceable to 24 months prior to the onset of CS. Loss of motility was not observed in any of the 89 ST32 isolates recovered over the course of chronic infection from 17 patients without CS. In conclusion, the gene expression of Bcc bacteria disseminated during CS has been elucidated for the first time. This study demonstrated marked differences at the transcriptome level between isogenic ST32 isolates that are attributable to the stage and site of infection. The finding of a nonmotile B. cenocepacia isolate may serve as a warning sign for the development of CS in the near future. PMID- 25694519 TI - Glycoprotein-based enzyme-linked immunosorbent assays for serodiagnosis of infectious laryngotracheitis. AB - For detection of infectious laryngotracheitis virus (ILTV) antibody, glycoprotein B-, C-, and D-based enzyme-linked immunosorbent assays (B-, C-, and D-ELISAs, respectively) were developed. The B- and D-ELISAs showed enhanced detection of anti-ILTV antibodies in infected chickens compared to that of the commercial ELISA. Furthermore, the D-ELISA was efficient in detecting seroconversion with vectored vaccine, using recombinant Newcastle disease virus (rNDV) expressing glycoprotein D (gD) as the vaccine vector. PMID- 25694520 TI - Disseminated rhinovirus C8 infection with infectious virus in blood and fatal outcome in a child with repeated episodes of bronchiolitis. AB - We report a fatal case of acute lower respiratory tract disease with human rhinovirus C (HRV-C) as the unique cause in a 19-month-old girl with a history of repeated episodes of bronchiolitis. HRV-C type 8 nucleic acids were observed in respiratory, stool, and cerebrospinal fluid samples, and infectious virions were isolated from patient serum after inoculation onto reconstituted airway epithelia. PMID- 25694521 TI - Single-molecule arrays for ultrasensitive detection of host immune response to dengue virus infection. AB - Dengue virus serotype 2-positive plasma was applied to two indirect single molecule arrays (Simoas) for the detection of anti-dengue virus IgG and IgM. The Simoas were 1,000 and 10,000 times more sensitive than enzyme-linked immunosorbent assays (ELISAs) for the detection of IgG and IgM, respectively. Using Simoas, serology may be used for the detection of dengue virus infection in the acute phase. PMID- 25694522 TI - Matrix-assisted laser desorption ionization-time of flight mass spectrometry meropenem hydrolysis assay with NH4HCO3, a reliable tool for direct detection of carbapenemase activity. AB - A comparison of a matrix-assisted laser desorption ionization-time of flight mass spectrometric (MALDI-TOF MS) meropenem hydrolysis assay with the Carba NP test showed that both methods exhibited low sensitivity (approximately 76%), mainly due to the false-negative results obtained with OXA-48-type producers. The addition of NH4HCO3 to the reaction buffer for the MALDI-TOF MS assay dramatically improved its sensitivity (98%). Automatic interpretation of the MALDI-TOF MS assay, using the MBT STAR-BL software, generally agreed with the results obtained after manual analysis. For the Carba NP test, spectrophotometric analysis found six additional carbapenemase producers. PMID- 25694523 TI - Efficient isolation of Swine influenza viruses by age-targeted specimen collection. AB - The control of swine influenza virus (SIV) infection is paramount for increasing the productivity of pig farming and minimizing the threat of pandemic outbreaks. Thus, SIV surveillance should be conducted by region and on a regular basis. Here, we established a microneutralization assay specific for SIV seroprevalence surveillance by using reporter gene-expressing recombinant influenza viruses. Growth-based SIV seroprevalence revealed that most sows and piglets were positive for neutralizing antibodies against influenza viruses. In contrast, the 90-day old growing pigs exhibited limited neutralizing activity in their sera, suggesting that this particular age of population is most susceptible to SIV infection and thus is an ideal age group for SIV isolation. From nasal swab specimens of healthy pigs in this age population, we were able to isolate SIVs at a higher incidence (5.3%) than those of previous reports. Nucleotide sequencing and phylogenetic analysis of the hemagglutinin (HA) genes revealed that the isolated SIVs have circulated and evolved in pigs but not have been recently introduced from humans, implying that a large number of SIV lineages may remain "undiscovered" in the global porcine populations. We propose that the 90-day-old growing pig-targeted nasal swab collection presented in this study facilitates global SIV surveillance and contributes to the detection and control of SIV infection. PMID- 25694524 TI - Challenges in antigenic characterization of circulating influenza A(H3N2) viruses during the 2011-2012 influenza season: an ongoing problem? AB - Genetic and antigenic characterization of 37 representative influenza A(H3N2) virus strains isolated in Greece during the 2011-2012 winter season was performed to evaluate matching of the viruses with the seasonal influenza vaccine strain A/Perth/16/2009. Hemagglutinin gene sequence analysis revealed that all Greek strains clustered within the Victoria/208 genetic clade. Furthermore, substitutions in the antigenic and glycosylation sites suggested potential antigenic drift. Our hemagglutination inhibition (HI) analysis showed that the Greek viruses were Perth/16-like; however, these viruses were characterized as Victoria/208-like when tested at the United Kingdom WHO Collaborating Centre (CC) with HI assays performed in the presence of oseltamivir, a finding consistent with the genetic characterization data. Variability in the HI test performance experienced by other European laboratories indicated that antigenic analysis of the A(H3N2) virus has limitations and, until its standardization, national influenza reference laboratories should include genetic characterization results for selection of representative viruses for detailed antigenic analysis by the WHO CCs. PMID- 25694525 TI - Presence of virulent Newcastle disease virus in vaccinated chickens in farms in Pakistan. AB - One year after a virulent Newcastle disease virus (vNDV) outbreak in Pakistan, the causative strain was present in vaccinated chickens of multiple farms despite the existence of high-average NDV-specific antibody titers (>4.75 log2). The data suggest a possible role of vaccinated birds as reservoirs of vNDV. PMID- 25694526 TI - Analysis of a local HIV-1 epidemic in portugal highlights established transmission of non-B and non-G subtypes. AB - The existing data support Portugal as the western European country with the highest HIV-1 subtype diversity. However, detailed phylogenetic studies of Portuguese HIV-1 epidemics are still scarce. Thus, our main goal was to analyze the phylodynamics of a local HIV-1 infection in the Portuguese region of Minho. Molecular epidemiological analysis was applied to data from 289 HIV-1-infected individuals followed at the reference hospital of the province of Minho, Portugal, at which isolated viruses had been sequenced between 2000 and 2012. Viruses of the G (29.1%) and B (27.0%) subtypes were the most frequent, followed by recombinant forms (17.6%) and the C (14.5%), F1 (7.3%), and A1 (4.2%) subtypes. Multinomial logistic regression revealed that the odds of being infected with the A1 and F1 subtypes increased over the years compared with those with B, G, or C subtypes or recombinant viruses. As expected, polyphyletic patterns suggesting multiple and old introductions of the B and G subtypes were found. However, transmission clusters of non-B and non-G viruses among native individuals were also found, with the dates of the most recent common ancestor estimated to be in the early 2000s. Our study supports that the HIV-1 subtype diversity in the Portuguese region of Minho is high and has been increasing in a manner that is apparently driven by factors other than immigration and international travel. Infections with A1 and F1 viruses in the region of Minho are becoming established and are mainly found in sexually transmitted clusters, reinforcing the need for more efficacious control measures targeting this infection route. PMID- 25694527 TI - Impact of revised cefepime CLSI breakpoints on Escherichia coli and Klebsiella pneumoniae susceptibility and potential impact if applied to Pseudomonas aeruginosa. AB - The CLSI reduced the cefepime Enterobacteriaceae susceptibility breakpoint and introduced the susceptible-dose-dependent (S-DD) category. In this study, MICs were determined for a Gram-negative collection to assess the impact of this change. For Enterobacteriaceae, this resulted in <2% reduction in susceptibility, with 1% being S-DD. If applied to Pseudomonas aeruginosa, the % susceptibility (%S) dropped from 77% to 43%, with 34% being S-DD. The new breakpoints did little to the Enterobacteriaceae %S, but for P. aeruginosa, a profound reduction was seen in %S. The recognition of a S-DD response to cefepime should alert clinicians to the possible need for higher doses. PMID- 25694528 TI - Contribution of neonatal amniotic fluid testing to diagnosis of congenital toxoplasmosis. AB - We evaluated the molecular diagnosis of congenital toxoplasmosis (CT) on neonatal amniotic fluid samples from 488 mother-child pairs. Maternal infection during pregnancy was diagnosed and dated or could not be ruled out. Forty-six cases of CT were defined according to the European Research Network on CT classification system and case definitions. Neonatal amniotic fluid testing had an overall sensitivity of 54% (95% confidence interval [95% CI], 39 to 69%) and a specificity of 100% (95% CI, 99 to 100%). Its sensitivity was 33% (95% CI, 13 to 59%) when antenatal diagnosis was positive and 68% (95% CI, 48 to 84%) when antenatal diagnosis was negative or lacking. This difference in sensitivity may have been due to treatment of antenatally diagnosed cases. Relative to postnatal serology, neonatal amniotic fluid testing allowed an earlier diagnosis to be made in 26% of the cases (95% CI, 9 to 51%). PMID- 25694529 TI - Comparative evaluation of three commercial quantitative cytomegalovirus standards by use of digital and real-time PCR. AB - The recent development of the 1st WHO International Standard for human cytomegalovirus (CMV) and the introduction of commercially produced secondary standards have raised hopes of improved agreement among laboratories performing quantitative PCR for CMV. However, data to evaluate the trueness and uniformity of secondary standards and the consistency of results achieved when these materials are run on various assays are lacking. Three concentrations of each of the three commercially prepared secondary CMV standards were tested in quadruplicate by three real-time and two digital PCR methods. The mean results were compared in a pairwise fashion with nominal values provided by each manufacturer. The agreement of results among all methods for each sample and for like concentrations of each standard was also assessed. The relationship between the nominal values of standards and the measured values varied, depending upon the assay used and the manufacturer of the standards, with the degree of bias ranging from +0.6 to -1.0 log10 IU/ml. The mean digital PCR result differed significantly among the secondary standards, as did the results of the real-time PCRs, particularly when plotted against nominal log10 IU values. Commercially available quantitative secondary CMV standards produce variable results when tested by different real-time and digital PCR assays, with various magnitudes of bias compared to nominal values. These findings suggest that the use of such materials may not achieve the intended uniformity among laboratories measuring CMV viral load, as envisioned by adaptation of the WHO standard. PMID- 25694530 TI - Systematic serological testing for hepatitis E virus in kidney transplant recipients. AB - Hepatitis E virus (HEV) genotype 3 is endemic in Europe and hyperendemic in southern France. Recent reports of a high prevalence of HEV RNA in blood donations and in culinary specialties from this geographical area confirmed the endemicity of HEV and sources of viral transmission in this geographical area. HEV causes acute and chronic hepatitis in solid organ transplant recipients. Since March 2012, we have implemented systematic HEV serological testing in our cohort of kidney transplant recipients (KTRs) in Marseille in southeastern France. The aim of our study was to assess HEV exposure in this cohort between March 2012 and May 2014. During these 27 months, we found that 39% of the patients who underwent kidney transplantation had an anti-HEV IgG response using a sensitive microplate enzyme immunoassay. This seroprevalence was approximately 43% at both 1 and 8 years after, using the same assay. In addition, systematic HEV serological testing detected 6 cases of HEV infection among 578 KTRs (1%) during the 27 months of the study, with 5 at an acute stage and 1 at a chronic stage. In conclusion, continuous HEV monitoring in this population is useful for better understanding the epidemiology of HEV in France, because these patients are a well-monitored population. Moreover, HEV monitoring in KTRs is clinically relevant because HEV represents a clinical threat in these patients. Nevertheless, HEV serological testing may be more fruitful for identifying HEV infections when performed in cases of biological liver abnormalities than when performed systematically. PMID- 25694531 TI - Identification and expression of Babesia ovis secreted antigen 1 and evaluation of its diagnostic potential in an enzyme-linked immunosorbent assay. AB - In order to identify immunoreactive proteins that are usable for the immunological diagnosis of Babesia ovis infections, a phage lambda cDNA expression library was constructed and screened using parasite-specific immune serum. Immunoscreening resulted in the identification of a full-length cDNA clone encoding a secreted protein designated Babesia ovis secreted antigen 1 (BoSA1). The full-length BoSA1 cDNA contained a 1,137-bp open reading frame that encoded a protein of 378 amino acids, with a signal peptide and 2 internal repeat domains. The theoretical molecular mass of the mature protein was 42.5 kDa. Recombinant BoSA1 (rBoSA1) protein was expressed in Escherichia coli strain DH5alpha cells as a glutathione S-transferase (GST) fusion protein and was purified by affinity chromatography. Purified rBoSA1 was tested for reactivity with sera from animals experimentally or naturally infected with B. ovis, in an indirect enzyme-linked immunosorbent assay (ELISA). The results showed that specific antibodies against rBoSA1 were detectable on days 7 and 8 of the experimental infection and were maintained during the sampling period. Additionally, 38 field sera taken from sheep naturally infected with B. ovis gave strong positive reactions in the ELISA between day 20 and day 30 of treatment. As a result, the identified recombinant BoSA1 protein seems to be a promising diagnostic antigen that is usable for the development of serological assays for the diagnosis of ovine babesiosis. This is the first report on the molecular cloning, expression, and potential use of a recombinant antigen for the diagnosis of ovine babesiosis. PMID- 25694532 TI - First human case of fatal Halicephalobus gingivalis meningoencephalitis in Australia. AB - Halicephalobus gingivalis (previously Micronema deletrix) is a free-living nematode known to cause opportunistic infections, mainly in horses. Human infections are very rare, but all cases described to date involved fatal meningoencephalitis. Here we report the first case of H. gingivalis infection in an Australian human patient, confirmed by nematode morphology and sequencing of ribosomal DNA. The implications of this case are discussed, particularly, the need to evaluate real-time PCR as a diagnostic tool. PMID- 25694533 TI - A new real-time reverse transcription-PCR assay for detection of human enterovirus 68 in respiratory samples. AB - A global reemergence of human enterovirus 68 (EV-D68) associated with severe respiratory illness occurred in 2014. We developed and validated an EV-D68 specific real-time reverse transcription-PCR (RT-PCR) for the detection of EV-D68 in respiratory samples. The rapid diagnosis of EV-D68 may contribute to better management of EV-D68 infections. PMID- 25694534 TI - The efficacy of recombinant human soluble thrombomodulin for the treatment of shiga toxin-associated hemolytic uremic syndrome model mice. AB - BACKGROUND: Recombinant human soluble thrombomodulin (rhTM) is a promising therapeutic natural anticoagulant that is comparable to antithrombin, tissue factor pathway inhibitor and activated protein C. In order to clarify the efficacy of rhTM for the treatment of typical hemolytic uremic syndrome (t-HUS), we examined changes in renal damage in t-HUS mice treated with rhTM or vehicle alone. METHODS: We used severe and moderate t-HUS mice injected with shiga toxin (Stx) and lipopolysaccharide (LPS). The severe t-HUS mice were divided into two subgroups [an rhTM subgroup (Group A) and a saline subgroup (Group B)] along with the moderate t-HUS mice [an rhTM subgroup (Group C) and a saline subgroup (Group D)]. Groups E and F were healthy mice treated with rhTM or saline, respectively. RESULTS: All mice in Group B died at 80-90 h post-administration of Stx2 and LPS whereas all mice in Group A remained alive. Loss of body weight, serum creatinine level, endothelial injury and mesangiolysis scores at 24 h after administration in the t-HUS mice treated with rhTM were lower than those in t-HUS mice treated with saline. The levels of hemoglobin at 6 h and platelet counts at 24 h after administration in Group A were higher than those in Group B. Serum interleukin (IL)-6, IL-1beta and tumor necrotic factor (TNF)-alpha levels at 24 h after administration in Group A were lower than those in Group B. Serum C5b-9 levels at 24 h after the administration and serum fibrinogen degradation product (FDP) at 72 h after the administration of Stx2 and LPS were lower in Group A than in Group B. CONCLUSIONS: These results indicate that rhTM might afford an efficacious treatment for t-HUS model mice via the inhibition of further thrombin formation and amelioration of hypercoagulant status. PMID- 25694535 TI - Improved prognosis in Norwegian patients with glomerulonephritis associated with anti-neutrophil cytoplasmic antibodies. AB - BACKGROUND: Glomerulonephritis associated with anti-neutrophil cytoplasmic antibodies (ANCA) is associated with increased mortality and a high risk of end stage renal disease (ESRD). Here, we investigated whether the prognosis has improved over the last 25 years. METHODS: Patients were identified in the Norwegian Kidney Biopsy Registry. We included all patients with pauci-immune crescentic glomerulonephritis and a positive ANCA test from 1988 to 2012. Deaths and ESRD in the cohort were identified through record linkage with the Norwegian Population Registry (deaths) and the Norwegian Renal Registry (ESRD). Outcomes of patients diagnosed in 1988-2002 were compared with outcomes of patients diagnosed in 2003-12. RESULTS: A cohort of 455 patients with ANCA-associated glomerulonephritis was identified. The mean follow-up was 6.0 years (range, 0.0 23.4). During the study period, 165 (36%) patients died and 124 (27%) progressed to ESRD. Compared with patients diagnosed in 1988-2002, those diagnosed in 2003 12 had higher mean initial estimated glomerular filtration rates (37 versus 27 mL/min/1.73 m(2)) and lower risk of ESRD (1-year risk: 13 versus 19%; 10-year risk: 26 versus 37%). The composite endpoint, ESRD or death within 0-1 year after diagnosis, was reduced from 34 to 25%. In patients over 60 years old, 1-year mortality fell from 33 to 20%. CONCLUSIONS: In Norwegian patients with ANCA associated glomerulonephritis, prognosis was significantly better in 2003-12 compared with 1988-2002. This improvement was probably partly due to a shorter diagnostic delay, and better therapeutic management in older patients. PMID- 25694536 TI - Recurrence of paroxysmal atrial fibrillation after pulmonary vein isolation: is repeat pulmonary vein isolation enough? A prospective, randomized trial. AB - AIMS: In patients with paroxysmal atrial fibrillation (pAF), pulmonary vein isolation (PVI) has become an accepted treatment option with single procedure success rates of 60-80%. A repeat ablation is performed in ~30% of patients because of arrhythmia recurrence. The strategy for this repeat procedure is not defined. METHODS AND RESULTS: Patients with pAF recurrence after PVI were prospectively randomized and underwent a second ablation procedure with either PVI of all reconnected veins or PVI with an additional left atrial anterior line. Follow-up in our arrhythmia clinic was every 3 months up to 12 months including 7 day Holter monitoring. A total of 77 patients (mean age 63 +/- 9 years, 69% males) were included in the analysis. A repeat PVI was performed in 41 patients, PVI + anterior line in 36 patients. After a follow-up of 12 months, 26 of 41 (63%) patients after repeat PVI and 18 of 36 (50%) patients with PVI + anterior line were in stable sinus rhythm off antiarrhythmic medication (P = 0.26). In most patients (12 of 15 patients with PVI and 14 of 18 patients with PVI + anterior line) with an arrhythmia recurrence after the second procedure, the recurring arrhythmia was paroxysmal AF. In 2 of 15 patients of the PVI group and in 4 of 18 patients of the PVI + anterior line group atypical flutter was the reoccurring arrhythmia (P = NS). CONCLUSION: In this prospective randomized trial, patients with a recurrence of paroxysmal AF had no better outcome after repeat PVI + one left atrial line compared with patients with repeat PVI only. PMID- 25694537 TI - Drug persistence with rivaroxaban therapy in atrial fibrillation patients-results from the Dresden non-interventional oral anticoagulation registry. AB - AIMS: Worldwide, rivaroxaban is increasingly used for stroke prevention in atrial fibrillation (SPAF) but little is known about the rates of or reasons for rivaroxaban discontinuations in daily care. Using data from a prospective, non interventional oral anticoagulation (NOAC) registry, we analysed rivaroxaban treatment persistence. METHODS AND RESULTS: Persistence with rivaroxaban in SPAF was assessed in an ongoing, prospective, non-interventional registry of >2600 NOAC patients from daily care using the Kaplan-Meier time-to-first-event analysis. Reasons for and management of rivaroxaban discontinuation were assessed. Potential baseline risk factors for treatment discontinuation were evaluated using Cox regression analysis. Between October 2011 and April 2014, 1204 rivaroxaban SPAF patients were enrolled [39.3% switched from vitamin K antagonists (VKAs) and 60.7% newly treated patients]. Of these, 223 patients (18.5%) stopped rivaroxaban during follow-up (median 544 days), which translates into a discontinuation rate of 13.6 (95% CI 11.8-15.4) per 100 patient-years. Most common reasons for treatment discontinuations were bleeding complications (30% of all discontinuations), followed by other side-effects (24.2%) and diagnosis of stable sinus rhythm (9.9%). A history of chronic heart failure (HR 1.43; 95% CI 1.09-1.87; P = 0.009) or diabetes (HR 1.39; 95% CI 1.06-1.82; P = 0.018) were the only statistically significant baseline risk factors for rivaroxaban discontinuation. After discontinuation of rivaroxaban, patients received antiplatelet therapy (31.8%), VKA (24.2%), another NOAC (18.4%), heparin (9.9%), or nothing (15.7%). CONCLUSION: Our data indicate that overall persistence with rivaroxaban therapy is high, with a discontinuation rate of ~15% in the first year of treatment and few additional discontinuations thereafter. PMID- 25694538 TI - Non-vitamin K antagonist oral anticoagulants: considerations on once- vs. twice daily regimens and their potential impact on medication adherence. AB - Suboptimal medication adherence is a widespread problem in ambulatory care of chronic diseases, with deviations in either direction from the prescribed dosing regimen. For the non-vitamin K antagonist oral anticoagulants (NOACs), such deviations occur and can lead to bleeding or clotting, as suboptimal adherence involves temporary periods of either overdosing or underdosing. In this expert review, we discuss: (a) the proper definition of adherence in terms of its three elements: initiation, implementation, and discontinuation; (b) how adherence is reliably and accurately measured and (c) successfully enhanced, to achieve and maintain safe and effective levels of NOAC-based anticoagulation. We also discuss the comparative effects of prescribing the same total daily dose, given either once-daily or as half-strength twice-daily doses. Because NOACs have plasma half lives of ~12 h, the twice-daily dosing regimen is less prone than the once-daily dosing regimen to hazardously high peaks or hazardously low troughs in anticoagulant concentrations and associated actions. As in other fields of oral drug treatment, the continuity of drug action is greater with twice-daily than with once-daily dosing, despite the fact that a few more doses are skipped with twice-daily than with once-daily dosing. This paradox is explained by the disproportionately greater impact on drug action of skipping a once-daily than a twice-daily dose. Integration of these principles into real-world medication management is the next step in the improvement of oral anticoagulation. PMID- 25694539 TI - Extreme strength observed in limpet teeth. AB - The teeth of limpets exploit distinctive composite nanostructures consisting of high volume fractions of reinforcing goethite nanofibres within a softer protein phase to provide mechanical integrity when rasping over rock surfaces during feeding. The tensile strength of discrete volumes of limpet tooth material measured using in situ atomic force microscopy was found to range from 3.0 to 6.5 GPa and was independent of sample size. These observations highlight an absolute material tensile strength that is the highest recorded for a biological material, outperforming the high strength of spider silk currently considered to be the strongest natural material, and approaching values comparable to those of the strongest man-made fibres. This considerable tensile strength of limpet teeth is attributed to a high mineral volume fraction of reinforcing goethite nanofibres with diameters below a defect-controlled critical size, suggesting that natural design in limpet teeth is optimized towards theoretical strength limits. PMID- 25694540 TI - Transitional flow in aneurysms and the computation of haemodynamic parameters. AB - Haemodynamic forces appear to play an influential role in the evolution of aneurysms. This has led to numerous studies, usually based on computational fluid dynamics. Their focus is predominantly on the wall shear stress (WSS) and associated derived parameters, attempting to find correlations between particular patterns of haemodynamic indices and regions subjected to disease formation and progression. The indices are generally determined by integration of flow properties over a single cardiac cycle. In this study, we illustrate that in some cases the transitional flow in aneurysms can lead to significantly different WSS distributions in consecutive cardiac cycles. Accurate determination of time averaged haemodynamic indices may thus require simulation of a large number of cycles, which contrasts with the common approach to determine parameters using data from a single cycle. To demonstrate the role of transitional flow, two exemplary cases are considered: flow in an abdominal aortic aneurysm and in an intracranial aneurysm. The key differences that are observed between these cases are explained in terms of the integral timescale of the transitional flows in comparison with the cardiac cycle duration: for relatively small geometries, transients will decay before the next cardiac cycle. In larger geometries, transients are still present when the systolic phase produces new instabilities. These residual fluctuations serve as random initial conditions and thus seed different flow patterns in each cycle. To judge whether statistics are converged, the derived indices from at least two successive cardiac cycles should be compared. PMID- 25694541 TI - Spectroscopic analysis of myoglobin and cytochrome c dynamics in isolated cardiomyocytes during hypoxia and reoxygenation. AB - Raman microspectroscopy was applied to monitor the intracellular redox state of myoglobin and cytochrome c from isolated adult rat cardiomyocytes during hypoxia and reoxygenation. The nitrite reductase activity of myoglobin leads to the production of nitric oxide in cells under hypoxic conditions, which is linked to the inhibition of mitochondrial respiration. In this work, the subsequent reoxygenation of cells after hypoxia is shown to lead to increased levels of oxygen-bound myoglobin relative to the initial levels observed under normoxic conditions. Increased levels of reduced cytochrome c in ex vivo cells are also observed during hypoxia and reoxygenation by Raman microspectroscopy. The cellular response to reoxygenation differed dramatically depending on the method used in the preceding step to create hypoxic conditions in the cell suspension, where a chemical agent, sodium dithionite, leads to reduction of cytochromes in addition to removal of dissolved oxygen, and bubbling-N2 gas leads to displacement of dissolved oxygen only. These results have an impact on the assessment of experimental simulations of hypoxia in cells. The spectroscopic technique employed in this work will be used in the future as an analytical method to monitor the effects of varying levels of oxygen and nutrients supplied to cardiomyocytes during either the preconditioning of cells or the reperfusion of ischaemic tissue. PMID- 25694542 TI - Scaling and universality in the human voice. AB - Speech is a distinctive complex feature of human capabilities. In order to understand the physics underlying speech production, in this work, we empirically analyse the statistics of large human speech datasets ranging several languages. We first show that during speech, the energy is unevenly released and power-law distributed, reporting a universal robust Gutenberg-Richter-like law in speech. We further show that such 'earthquakes in speech' show temporal correlations, as the interevent statistics are again power-law distributed. As this feature takes place in the intraphoneme range, we conjecture that the process responsible for this complex phenomenon is not cognitive, but it resides in the physiological (mechanical) mechanisms of speech production. Moreover, we show that these waiting time distributions are scale invariant under a renormalization group transformation, suggesting that the process of speech generation is indeed operating close to a critical point. These results are put in contrast with current paradigms in speech processing, which point towards low dimensional deterministic chaos as the origin of nonlinear traits in speech fluctuations. As these latter fluctuations are indeed the aspects that humanize synthetic speech, these findings may have an impact in future speech synthesis technologies. Results are robust and independent of the communication language or the number of speakers, pointing towards a universal pattern and yet another hint of complexity in human speech. PMID- 25694543 TI - Sources of variability in cytosolic calcium transients triggered by stimulation of homogeneous uro-epithelial cell monolayers. AB - Epithelial tissue structure is the emergent outcome of the interactions between large numbers of individual cells. Experimental cell biology offers an important tool to unravel these complex interactions, but current methods of analysis tend to be limited to mean field approaches or representation by selected subsets of cells. This may result in bias towards cells that respond in a particular way and/or neglect local, context-specific cell responses. Here, an automated algorithm was applied to examine in detail the individual calcium transients evoked in genetically homogeneous, but asynchronous populations of cultured non immortalized normal human urothelial cells when subjected to either the global application of an external agonist or a localized scratch wound. The recorded calcium transients were classified automatically according to a set of defined metrics and distinct sub-populations of cells that responded in qualitatively different ways were observed. The nature of this variability in the homogeneous cell population was apportioned to two sources: intrinsic variation in individual cell responses and extrinsic variability due to context-specific factors of the environment, such as spatial heterogeneity. Statistically significant variation in the features of the calcium transients evoked by scratch wounding according to proximity to the wound edge was identified. The manifestation of distinct sub populations of cells is considered central to the coordination of population level response resulting in wound closure. PMID- 25694544 TI - Membrane blebbing as a recovery manoeuvre in site-specific sonoporation mediated by targeted microbubbles. AB - Site-specific perforation of the plasma membrane can be achieved through ultrasound-triggered cavitation of a single microbubble positioned adjacent to the cell. However, for this perforation approach (sonoporation), the recovery manoeuvres invoked by the cell are unknown. Here, we report new findings on how membrane blebbing can be a recovery manoeuvre that may take place in sonoporation episodes whose pores are of micrometres in diameter. Each sonoporation site was created using a protocol involving single-shot ultrasound exposure (frequency: 1 MHz; pulse length: 30 cycles; peak negative pressure: 0.45 MPa) which triggered inertial cavitation of a single targeted microbubble (diameter: 1-5 um). Over this process, live confocal microscopy was conducted in situ to monitor membrane dynamics, model drug uptake kinetics and cytoplasmic calcium ion (Ca(2+)) distribution. Results show that blebbing would occur at a recovering sonoporation site after its resealing, and it may emerge elsewhere along the membrane periphery. The bleb size was correlated with the pre-exposure microbubble diameter, and 99% of blebbing cases at sonoporation sites were inflicted by microbubbles larger than 1.5 um diameter (analysed over 124 sonoporation episodes). Blebs were not observed at irreversible sonoporation sites or when sonoporation site repair was inhibited via extracellular Ca(2+) chelation. Functionally, the bleb volume was found to serve as a buffer compartment to accommodate the cytoplasmic Ca(2+) excess brought about by Ca(2+) influx during sonoporation. These findings suggest that membrane blebbing would help sonoporated cells restore homeostasis. PMID- 25694545 TI - Regional ejection fraction and regional area strain for left ventricular function assessment in male patients after first-time myocardial infarction. AB - In this work, we present a method to assess left ventricle (LV) regional function from cardiac magnetic resonance (CMR) imaging based on the regional ejection fraction (REF) and regional area strain (RAS). CMR scans were performed for 30 patients after first-time myocardial infarction (MI) and nine age- and sex matched healthy volunteers. The CMR images were processed to reconstruct three dimensional LV geometry, and the REF and RAS in a 16-segment model were computed using our proposed methodology. The method of computing the REF was tested and shown to be robust against variation in user input. Furthermore, analysis of data was feasible in all patients and healthy volunteers without any exclusions. The REF correlated well with the RAS in a nonlinear manner (quadratic fit-R(2) = 0.88). In patients after first-time MI, the REF and RAS were significantly reduced across all 16 segments (REF: p < 0.05; RAS: p < 0.01). Moreover, the REF and RAS significantly decreased with the extent of transmural scar obtained from late gadolinium-enhanced CMR images. In addition, we show that the REF and RAS can be used to identify regions with compromised function in the patients with preserved global ejection fraction with reasonable accuracy (more than 78%). These preliminary results confirmed the validity of our approach for accurate analysis of LV regional function. Our approach potentially offers physicians new insights into the local characteristics of the myocardial mechanics after a MI. PMID- 25694546 TI - The RED domain of Paired is specifically required for Drosophila accessory gland maturation. AB - The evolutionarily conserved paired domain consists of the N-terminal PAI and the C-terminal RED domains, each containing a helix-turn-helix motif capable of binding DNA. Despite its conserved sequence, the physiological functions of the RED domain remain elusive. Here, we constructed a prd transgene expressing a truncated Paired (Prd) protein without the RED domain, and examined its rescue ability in prd mutants. We found that the RED domain is specifically required for the expression of Acp26Aa and sex peptide in male accessory glands, and the induction of female post-mating response. Our data thus identified an important physiological function for the evolutionarily conserved RED domain. PMID- 25694547 TI - Epigenetic variation and environmental change. AB - Environmental conditions can change the activity of plant genes via epigenetic effects that alter the competence of genetic information to be expressed. This may provide a powerful strategy for plants to adapt to environmental change. However, as epigenetic changes do not modify DNA sequences and are therefore reversible, only those epi-mutations that are transmitted through the germline can be expected to contribute to a long-term adaptive response. The major challenge for the investigation of epigenetic adaptation theories is therefore to identify genomic loci that undergo epigenetic changes in response to environmental conditions, which alter their expression in a heritable way and which improve the plant's ability to adapt to the inducing conditions. This review focuses on the role of DNA methylation as a prominent epigenetic mark that controls chromatin conformation, and on its potential in mediating expression changes in response to environmental signals. PMID- 25694548 TI - The cadmium-tolerant pea (Pisum sativum L.) mutant SGECdt is more sensitive to mercury: assessing plant water relations. AB - Heavy metals have multiple effects on plant growth and physiology, including perturbation of plant water status. These effects were assessed by exposing the unique Cd-tolerant and Cd-accumulating pea (Pisum sativum L.) mutant SGECd(t) and its wild-type (WT) line SGE to either cadmium (1, 4 MUM CdCl2) or mercury (0.5, 1, 2 MUM HgCl2) in hydroponic culture for 12 days. When exposed to Cd, SGECd(t) accumulated more Cd in roots, xylem sap, and shoot, and had considerably more biomass than WT plants. WT plants lost circa 0.2 MPa turgor when grown in 4 MUM CdCl2, despite massive decreases in whole-plant transpiration rate and stomatal conductance. In contrast, root Hg accumulation was similar in both genotypes, but WT plants accumulated more Hg in leaves and had a higher stomatal conductance, and root and shoot biomass compared with SGECd(t). Shoot excision resulted in greater root-pressure induced xylem exudation of SGECd(t) in the absence of Cd or Hg and following Cd exposure, whereas the opposite response or no genotypic differences occurred following Hg exposure. Exposing plants that had not been treated with metal to 50 MUM CdCl2 for 1h increased root xylem exudation of WT, whereas 50 MUM HgCl2 inhibited and eliminated genotypic differences in root xylem exudation, suggesting differences between WT and SGECd(t) plants in aquaporin function. Thus, root water transport might be involved in mechanisms of increased tolerance and accumulation of Cd in the SGECd(t) mutant. However, the lack of cross-tolerance to Cd and Hg stress in the mutant indicates metal-specific mechanisms related to plant adaptation. PMID- 25694549 TI - The Capsicum annuum class IV chitinase ChitIV interacts with receptor-like cytoplasmic protein kinase PIK1 to accelerate PIK1-triggered cell death and defence responses. AB - The pepper receptor-like cytoplasmic protein kinase, CaPIK1, which mediates signalling of plant cell death and defence responses was previously identified. Here, the identification of a class IV chitinase, CaChitIV, from pepper plants (Capsicum annuum), which interacts with CaPIK1 and promotes CaPIK1-triggered cell death and defence responses, is reported. CaChitIV contains a signal peptide, chitin-binding domain, and glycol hydrolase domain. CaChitIV expression was up regulated by Xanthomonas campestris pv. vesicatoria (Xcv) infection. Notably, avirulent Xcv infection rapidly induced CaChitIV expression in pepper leaves. Bimolecular fluorescence complementation and co-immunoprecipitation revealed that CaPIK1 interacts with CaChitIV in planta, and that the CaPIK1-CaChitIV complex is localized mainly in the cytoplasm and plasma membrane. CaChitIV is also localized in the endoplasmic reticulum. Transient co-expression of CaChitIV with CaPIK1 enhanced CaPIK1-triggered cell death response and reactive oxygen species (ROS) and nitric oxide (NO) bursts. Co-silencing of both CaChitIV and CaPIK1 in pepper plants conferred enhanced susceptibility to Xcv infection, which was accompanied by a reduced induction of cell death response, ROS and NO bursts, and defence response genes. Ectopic expression of CaPIK1 in Arabidopsis enhanced basal resistance to Hyaloperonospora arabidopsidis infection. Together, the results suggest that CaChitIV positively regulates CaPIK1-triggered cell death and defence responses through its interaction with CaPIK1. PMID- 25694550 TI - Inducible HSP70 is critical in preventing the aggregation and enhancing the processing of PMP22. AB - Chaperones, also called heat shock proteins (HSPs), transiently interact with proteins to aid their folding, trafficking, and degradation, thereby directly influencing the transport of newly synthesized molecules. Induction of chaperones provides a potential therapeutic approach for protein misfolding disorders, such as peripheral myelin protein 22 (PMP22)-associated peripheral neuropathies. Cytosolic aggregates of PMP22, linked with a demyelinating Schwann cell phenotype, result in suppression of proteasome activity and activation of proteostatic mechanisms, including the heat shock pathway. Although the beneficial effects of chaperones in preventing the aggregation and improving the trafficking of PMP22 have been repeatedly observed, the requirement for HSP70 in events remains elusive. In this study, we show that activation of the chaperone pathway in fibroblasts from PMP22 duplication-associated Charcot-Marie-Tooth disease type 1A patient with an FDA-approved small molecule increases HSP70 expression and attenuates proteasome dysfunction. Using cells from an HSP70.1/3( /-) (inducible HSP70) mouse model, we demonstrate that under proteotoxic stress, this chaperone is critical in preventing the aggregation of PMP22, and this effect is aided by macroautophagy. When examined at steady-state, HSP70 appears to play a minor role in the trafficking of wild-type-PMP22, while it is crucial for preventing the buildup of the aggregation-prone Trembler-J-PMP22. HSP70 aids the processing of Trembler-J-PMP22 through the Golgi and its delivery to lysosomes via Rab7-positive vesicles. Together, these results demonstrate a key role for inducible HSP70 in aiding the processing and hindering the accumulation of misfolded PMP22, which in turn alleviates proteotoxicity within the cells. PMID- 25694551 TI - Nutrition facts in multiple sclerosis. AB - The question whether dietary habits and lifestyle have influence on the course of multiple sclerosis (MS) is still a matter of debate, and at present, MS therapy is not associated with any information on diet and lifestyle. Here we show that dietary factors and lifestyle may exacerbate or ameliorate MS symptoms by modulating the inflammatory status of the disease both in relapsing-remitting MS and in primary-progressive MS. This is achieved by controlling both the metabolic and inflammatory pathways in the human cell and the composition of commensal gut microbiota. What increases inflammation are hypercaloric Western-style diets, characterized by high salt, animal fat, red meat, sugar-sweetened drinks, fried food, low fiber, and lack of physical exercise. The persistence of this type of diet upregulates the metabolism of human cells toward biosynthetic pathways including those of proinflammatory molecules and also leads to a dysbiotic gut microbiota, alteration of intestinal immunity, and low-grade systemic inflammation. Conversely, exercise and low-calorie diets based on the assumption of vegetables, fruit, legumes, fish, prebiotics, and probiotics act on nuclear receptors and enzymes that upregulate oxidative metabolism, downregulate the synthesis of proinflammatory molecules, and restore or maintain a healthy symbiotic gut microbiota. Now that we know the molecular mechanisms by which dietary factors and exercise affect the inflammatory status in MS, we can expect that a nutritional intervention with anti-inflammatory food and dietary supplements can alleviate possible side effects of immune-modulatory drugs and the symptoms of chronic fatigue syndrome and thus favor patient wellness. PMID- 25694552 TI - Control of human PLP1 expression through transcriptional regulatory elements and alternatively spliced exons in intron 1. AB - Although the myelin proteolipid protein gene (PLP1) encodes the most abundant protein in central nervous system (CNS) myelin, not much is known about the mechanisms that govern expression of the human gene (hPLP1). Much more is known about the processes that regulate Plp1 gene expression in rodents. From studies with Plp1-lacZ transgenic mice, it was determined that the first intron of mouse Plp1 (mPlp1) is required to attain high levels of expression in brain, concurrent with the active myelination period. Other studies have suggested that within mPlp1 intron 1 (>8 kb) lie several regions with enhancer-like activity. To test whether these sequences (and possibly others) in hPLP1 intron 1 are functional, deletion-transfection analysis was performed with hPLP1-lacZ constructs that contain various portions of the intron, or lack it altogether. Results presented here demonstrate the importance of hPLP1 intron 1 in achieving maximal levels of expression in the immortalized oligodendroglial cell line, Oli-neu. Deletion analysis indicates that the intron contains multiple positive regulatory elements which are active in Oli-neu cells. Some of these elements appear to be functionally conserved between human and mouse, while others are not. Furthermore, our studies demonstrate that multiple splice variants can be formed due to inclusion of extra (supplementary) exons from what is classically thought of as hPLP1 intron 1. Thus, splicing of these novel exons (which are not recognized as such in mPlp1 due to lack of conserved splice sites) must utilize factors common to both human and mouse since Oli-neu cells are of mouse origin. PMID- 25694553 TI - Myelin abnormalities in the optic and sciatic nerves in mice with GM1 gangliosidosis. AB - GM1-gangliosidosis is a glycosphingolipid lysosomal storage disease involving accumulation of GM1 and its asialo form (GA1) primarily in the brain. Thin-layer chromatography and X-ray diffraction were used to analyze the lipid content/composition and the myelin structure of the optic and sciatic nerves from 7- and 10-month old beta-galactosidase (beta-gal) +/? and beta-gal -/- mice, a model of GM1gangliosidosis. Optic nerve weight was lower in the beta-gal -/- mice than in unaffected beta-gal +/? mice, but no difference was seen in sciatic nerve weight. The levels of GM1 and GA1 were significantly increased in both the optic nerve and sciatic nerve of the beta-gal -/- mice. The content of myelin-enriched cerebrosides, sulfatides, and plasmalogen ethanolamines was significantly lower in optic nerve of beta-gal -/- mice than in beta-gal +/? mice; however, cholesteryl esters were enriched in the beta-gal -/- mice. No major abnormalities in these lipids were detected in the sciatic nerve of the beta-gal -/- mice. The abnormalities in GM1 and myelin lipids in optic nerve of beta-gal -/- mice correlated with a reduction in the relative amount of myelin and periodicity in fresh nerve. By contrast, the relative amount of myelin and periodicity in the sciatic nerves from control and beta-gal -/- mice were indistinguishable, suggesting minimal pathological involvement in sciatic nerve. Our results indicate that the greater neurochemical pathology observed in the optic nerve than in the sciatic nerve of beta-gal -/- mice is likely due to the greater glycolipid storage in optic nerve. PMID- 25694554 TI - A single-nucleotide polymorphism in serine-threonine kinase 11, the gene encoding liver kinase B1, is a risk factor for multiple sclerosis. AB - We identified a family in which five siblings were diagnosed with multiple sclerosis (MS) or clinically isolated syndrome. Several women in the maternal lineage have comorbidities typically associated with Peutz Jeghers Syndrome, a rare autosomal-dominant disease caused by mutations in the serine-threonine kinase 11 (STK11) gene, which encodes liver kinase B1. Sequence analysis of DNA from one sibling identified a single-nucleotide polymorphism (SNP) within STK11 intron 5. This SNP (dbSNP ID: rs9282860) was identified by TaqMan polymerase chain reaction (PCR) assays in DNA samples available from two other siblings. Further screening was carried out in samples from 654 relapsing-remitting MS patients, 100 primary progressive MS patients, and 661 controls. The STK11-SNP has increased frequency in all female patients versus controls (odds ratio = 1.66, 95% CI = 1.05, 2.64, p = .032). The STK11-SNP was not associated with disease duration or onset; however, it was significantly associated with reduced severity (assessed by MS severity scores), with the lowest scores in patients who also harbored the HLA-DRB1*1501 allele. In vitro studies showed that peripheral blood mononuclear cells from members of the family were more sensitive to the mitochondrial inhibitor metformin than cells from MS patients with the major STK11 allele. The increased association of SNP rs9282860 in women with MS defines this variant as a genetic risk factor. The lower disease severity observed in the context of HLA-DRB1*1501 combined with limited in vitro studies raises the provocative possibility that cells harboring the STK11-SNP could be targeted by drugs which increase metabolic stress. PMID- 25694555 TI - Percutaneous emergency airway access; prevention, preparation, technique and training. PMID- 25694556 TI - Low intraoperative tidal volume ventilation with minimal PEEP and postoperative morbidity and mortality. PMID- 25694557 TI - Low tidal volumes during intraoperative ventilation: Beneficial or Harmful? PMID- 25694558 TI - Reply from the authors. PMID- 25694559 TI - Limited benefit of prophylactic continuous positive airway pressure following lung resection surgery. PMID- 25694560 TI - Reply from the authors. PMID- 25694561 TI - Reply from the authors. PMID- 25694562 TI - Comparing anaesthesiologist's muscular activity and workload during GlideScope vs Macintosh laryngoscopy. Is it really comparable? PMID- 25694563 TI - Propofol EC50: an effect of luteal phase core temperature differences? PMID- 25694564 TI - Could opioid sparing, rather than a direct non-steroidal anti-inflammatory drug effect, be responsible for improved survival after conservative breast surgery? PMID- 25694565 TI - Reply from the authors. PMID- 25694566 TI - An additional mechanism of visual loss. PMID- 25694567 TI - Simulation-based training in anaesthesia: have we been training non-technical skills? PMID- 25694568 TI - Reply from the authors. PMID- 25694569 TI - Pre-ictal bispectral index values; are they accurate? PMID- 25694570 TI - Reliability of bispectral index analysis in patients undergoing Caesarean section. PMID- 25694571 TI - Avoiding awareness in Caesarean sections under general anaesthesia. PMID- 25694572 TI - Isolated forearm movement does not equate to awareness. PMID- 25694573 TI - The IFT (isolated forearm technique) and consciousness. PMID- 25694574 TI - Does fasting time alter fluid responsiveness after induction of anaesthesia? PMID- 25694581 TI - Clarification. PMID- 25694583 TI - Friendships in preschool children with autism spectrum disorder: What holds them back, child characteristics or teacher behavior? AB - Children begin to show preferences for specific playmates as early as the first 2 years of life. Children with autism spectrum disorder have difficulty making friends, even in elementary and middle school. However, very little is known about earlier friendships in children with autism such as preschool friendships. This study examined friendships in preschool children with autism and explored how joint attention contributes to these friendships in mainstream settings. A secondary aim was to determine the extent to which teachers used strategies to facilitate friendship development. The participants were 31 mainstreamed preschool children (ages 2-5 years) with autism spectrum disorder. School observations were conducted individually to capture participants' interactions with peers and adults during free play. The results indicated that 20% of the participants had friendships at school. Children with friends were more likely than children without friends to be jointly engaged with their peers during free play, and they used higher joint attention skills. Teachers used few friendship facilitating strategies, and more often used behavioral management strategies within the classrooms. Future studies may want to examine the effects of early interventions and/or teacher training on the development of friendships in preschool children with autism spectrum disorder within the school setting. PMID- 25694584 TI - Support for community-based research. PMID- 25694585 TI - Regarding Mandell and Lecavalier's editorial "should we believe the Centers for Disease Control and Prevention's autism spectrum disorders prevalence estimates" and subsequent exchange with Durkin et al. PMID- 25694586 TI - Plugged in: Electronics use in youth and young adults with autism spectrum disorder. AB - Although electronic technology currently plays an integral role for most youth, there are growing concerns of its excessive and compulsive use. This study documents patterns and impact of electronics use in individuals with autism spectrum disorder compared to typically developing peers. Participants included 172 parents of typically developing individuals and 139 parents of individuals with an autism spectrum disorder diagnosis, ranging in age from 6 to 21 years. Parents completed an online survey of demographics and the frequency, duration, and problematic patterns of electronics use in their youth and young adults. Individuals with autism spectrum disorder were reported to use certain electronics more often in the last month and on an average day, and had greater compulsive Internet and video game use than individuals without autism spectrum disorder. Across both samples, males used video games more often than females. Compared to parents of individuals without autism spectrum disorder, parents of individuals with autism spectrum disorder were significantly more likely to report that electronics use was currently having a negative impact. The implications of problematic electronics use for individuals with autism spectrum disorder are discussed. PMID- 25694587 TI - Lack of collagen VIII reduces fibrosis and promotes early mortality and cardiac dilatation in pressure overload in mice. AB - AIMS: In pressure overload, left ventricular (LV) dilatation is a key step in transition to heart failure (HF). We recently found that collagen VIII (colVIII), a non-fibrillar collagen and extracellular matrix constituent, was reduced in hearts of mice with HF and correlated to degree of dilatation. A reduction in colVIII might be involved in LV dilatation, and we here examined the role of reduced colVIII in pressure overload-induced remodelling using colVIII knock-out (col8KO) mice. METHODS AND RESULTS: Col8KO mice exhibited increased mortality 3-9 days after aortic banding (AB) and increased LV dilatation from day one after AB, compared with wild type (WT). LV dilatation remained increased over 56 days. Forty-eight hours after AB, LV expression of main structural collagens (I and III) was three-fold increased in WT mice, but these collagens were unaltered in the LV of col8KO mice together with reduced expression of the pro-fibrotic cytokine TGF-beta, SMAD2 signalling, and the myofibroblast markers Pxn, alpha SMA, and SM22. Six weeks after AB, LV collagen mRNA expression and protein were increased in col8KO mice, although less pronounced than in WT. In vitro, neonatal cardiac fibroblasts from col8KO mice showed lower expression of TGF-beta, Pxn, alpha-SMA, and SM22 and reduced migratory ability possibly due to increased RhoA activity and reduced MMP2 expression. Stimulation with recombinant colVIIIalpha1 increased TGF-beta expression and fibroblast migration. CONCLUSION: Lack of colVIII reduces myofibroblast differentiation and fibrosis and promotes early mortality and LV dilatation in response to pressure overload in mice. PMID- 25694588 TI - Ischaemic preconditioning preferentially increases protein S-nitrosylation in subsarcolemmal mitochondria. AB - Nitric oxide (NO) and protein S-nitrosylation (SNO) have been shown to play important roles in ischaemic preconditioning (IPC)-induced acute cardioprotection. The majority of proteins that show increased SNO following IPC are localized to the mitochondria, and our recent studies suggest that caveolae transduce acute NO/SNO cardioprotective signalling in IPC hearts. Due to the close association between subsarcolemmal mitochondria (SSM) and the sarcolemma/caveolae, we tested the hypothesis that SSM, rather than the interfibrillar mitochondria (IFM), are major targets for NO/SNO signalling derived from caveolae-associated eNOS. Following either control perfusion or IPC, SSM and IFM were isolated from Langendorff perfused mouse hearts, and SNO was analysed using a modified biotin switch method with fluorescent maleimide fluors. In perfusion control hearts, the SNO content was higher in SSM compared with IFM (1.33 +/- 0.19, ratio of SNO content Perf-SSM vs. Perf-IFM), and following IPC SNO content significantly increased preferentially in SSM, but not in IFM (1.72 +/- 0.17 and 1.07 +/- 0.04, ratio of SNO content IPC-SSM vs. Perf-IFM, and IPC IFM vs. Perf-IFM, respectively). Consistent with these findings, eNOS, caveolin 3, and connexin-43 were detected in SSM, but not in IFM, and IPC resulted in a further significant increase in eNOS/caveolin-3 levels in SSM. Interestingly, we did not observe an IPC-induced increase in SNO or eNOS/caveolin-3 in SSM isolated from caveolin-3(-/-) mouse hearts, which could not be protected with IPC. In conclusion, these results suggest that SSM may be the preferential target of sarcolemmal signalling-derived post-translational protein modification (caveolae derived eNOS/NO/SNO), thus providing an important role in IPC-induced cardioprotection. PMID- 25694589 TI - Maturation of human herpesvirus 6A glycoprotein O requires coexpression of glycoprotein H and glycoprotein L. AB - Glycoprotein O (gO) is conserved among betaherpesviruses, but little is known about the maturation process of gO in human herpesvirus 6 (HHV-6). We found that HHV-6 gO maturation was accompanied by cleavage of its carboxyl terminus and required coexpression of gH and gL, which promoted the export of gO out of the endoplasmic reticulum (ER). Finally, we also found that gO was not required for HHV-6A growth in T cells. PMID- 25694590 TI - The laminin receptor is a cellular attachment receptor for classical Swine Fever virus. AB - Classical swine fever virus (CSFV) is the causative agent of classical swine fever (CSF), a highly contagious, economically important viral disease in many countries. The E(rns) and E2 envelope glycoproteins are responsible for the binding to and entry into the host cell by CSFV. To date, only one cellular receptor, heparan sulfate (HS), has been identified as being involved in CSFV attachment. HS is also present on the surface of various cells that are nonpermissive to CSFV. Hence, there must be another receptor(s) that has been unidentified to date. In this study, we used a set of small interfering RNAs (siRNAs) against a number of porcine cell membrane protein genes to screen cellular proteins involved in CSFV infection. This approach resulted in the identification of several proteins, and of these, the laminin receptor (LamR) has been demonstrated to be a cellular receptor for several viruses. Confocal analysis showed that LamR is colocalized with CSFV virions on the membrane, and a coimmunoprecipitation assay indicated that LamR interacts with the CSFV E(rns) protein. In inhibition assays, anti-LamR antibodies, soluble laminin, or LamR protein significantly inhibited CSFV infection in a dose-dependent manner. Transduction of PK-15 cells with a recombinant lentivirus expressing LamR yielded higher viral titers. Moreover, an attachment assay demonstrated that LamR functions during virus attachment. We also demonstrate that LamR acts as an alternative attachment receptor, especially in SK6 cells. These results indicate that LamR is a cellular attachment receptor for CSFV. IMPORTANCE: Classical swine fever virus (CSFV) is the causative agent of classical swine fever (CSF), an economically important viral disease affecting the pig industry in many countries. To date, only heparan sulfate (HS) has been identified to be an attachment receptor for CSFV. Here, using RNA interference screening with small interfering RNAs (siRNAs) against a number of porcine membrane protein genes, we identified the laminin receptor (LamR) to be another attachment receptor. We demonstrate the involvement of LamR together with HS in virus attachment, and we elucidate the relationship between LamR and HS. LamR also serves as an attachment receptor for many viral pathogens, including dengue virus, a fatal human flavivirus. The study will help to enhance our understanding of the life cycle of flaviviruses and the development of antiviral strategies for flaviviruses. PMID- 25694591 TI - Expression of the novel hepatitis C virus core+1/ARF protein in the context of JFH1-based replicons. AB - Hepatitis C virus contains a second open reading frame within the core gene, designated core+1/ARF. Here we demonstrate for the first time expression of core+1/ARF protein in the context of a bicistronic JFH1-based replicon and report the production of two isoforms, core+1/L (long) and core+1/S (short), with different kinetics. PMID- 25694592 TI - Peptides designed to spatially depict the Epstein-Barr virus major virion glycoprotein gp350 neutralization epitope elicit antibodies that block virus neutralizing antibody 72A1 interaction with the native gp350 molecule. AB - Epstein-Barr virus (EBV) is the etiologic agent of infectious mononucleosis and the root cause of B-cell lymphoproliferative disease in individuals with a weakened immune system, as well as a principal cofactor in nasopharyngeal carcinoma, various lymphomas, and other cancers. The EBV major virion surface glycoprotein gp350 is viewed as the best vaccine candidate to prevent infectious mononucleosis in healthy EBV-naive persons and EBV-related cancers in at-risk individuals. Previous epitope mapping of gp350 revealed only one dominant neutralizing epitope, which has been shown to be the target of the monoclonal antibody 72A1. Computer modeling of the 72A1 antibody interaction with the gp350 amino terminus was used to identify gp350 amino acids that could form strong ionic, electrostatic, or hydrogen bonds with the 72A1 antibody. Peptide DDRTTLQLAQNPVYIPETYPYIKWDN (designated peptide 2) and peptide GSAKPGNGSYFASVKTEMLGNEID (designated peptide 3) were designed to spatially represent the gp350 amino acids predicted to interact with the 72A1 antibody paratope. Peptide 2 bound to the 72A1 antibody and blocked 72A1 antibody recognition of the native gp350 molecule. Peptide 2 and peptide 3 were recognized by human IgG and shown to elicit murine antibodies that could target gp350 and block its recognition by the 72A1 antibody. This work provides a structural mapping of the interaction between the EBV-neutralizing antibody 72A1 and the major virion surface protein gp350. gp350 mimetic peptides that spatially depict the EBV-neutralizing epitope would be useful as a vaccine to focus the immune system exclusively to this important virus epitope. IMPORTANCE: The production of virus-neutralizing antibodies targeting the Epstein-Barr virus (EBV) major surface glycoprotein gp350 is important for the prevention of infectious mononucleosis and EBV-related cancers. The data presented here provide the first in silico map of the gp350 interaction with a virus-blocking monoclonal antibody. Immunization with gp350 peptides identified by in silico mapping generated antibodies that cross-react with the EBV gp350 molecule and block recognition of the gp350 molecule by a virus-neutralizing antibody. Through its ability to focus the immune system exclusively on the gp350 sequence important for viral entry, these peptides may form the basis of an EBV vaccine candidate. This strategy would sidestep the production of other irrelevant gp350 antibodies that divert the immune system from generating a protective antiviral response or that impede access to the virus-blocking epitope by protective antibodies. PMID- 25694593 TI - Broad-spectrum inhibitors against 3C-like proteases of feline coronaviruses and feline caliciviruses. AB - Feline infectious peritonitis and virulent, systemic calicivirus infection are caused by certain types of feline coronaviruses (FCoVs) and feline caliciviruses (FCVs), respectively, and are important infectious diseases with high fatality rates in members of the Felidae family. While FCoV and FCV belong to two distinct virus families, the Coronaviridae and the Caliciviridae, respectively, they share a dependence on viral 3C-like protease (3CLpro) for their replication. Since 3CLpro is functionally and structurally conserved among these viruses and essential for viral replication, 3CLpro is considered a potential target for the design of antiviral drugs with broad-spectrum activities against these distinct and highly important viral infections. However, small-molecule inhibitors against the 3CLpro enzymes of FCoV and FCV have not been previously identified. In this study, derivatives of peptidyl compounds targeting 3CLpro were synthesized and evaluated for their activities against FCoV and FCV. The structures of compounds that showed potent dual antiviral activities with a wide margin of safety were identified and are discussed. Furthermore, the in vivo efficacy of 3CLpro inhibitors was evaluated using a mouse model of coronavirus infection. Intraperitoneal administration of two 3CLpro inhibitors in mice infected with murine hepatitis virus A59, a hepatotropic coronavirus, resulted in significant reductions in virus titers and pathological lesions in the liver compared to the findings for the controls. These results suggest that the series of 3CLpro inhibitors described here may have the potential to be further developed as therapeutic agents against these important viruses in domestic and wild cats. This study provides important insights into the structure and function relationships of 3CLpro for the design of antiviral drugs with broader antiviral activities. IMPORTANCE: Feline infectious peritonitis virus (FIPV) is the leading cause of death in young cats, and virulent, systemic feline calicivirus (vs-FCV) causes a highly fatal disease in cats for which no preventive or therapeutic measure is available. The genomes of these distinct viruses, which belong to different virus families, encode a structurally and functionally conserved 3C like protease (3CLpro) which is a potential target for broad-spectrum antiviral drug development. However, no studies have previously reported a structural platform for the design of antiviral drugs with activities against these viruses or on the efficacy of 3CLpro inhibitors against coronavirus infection in experimental animals. In this study, we explored the structure-activity relationships of the derivatives of 3CLpro inhibitors and identified inhibitors with potent dual activities against these viruses. In addition, the efficacy of the 3CLpro inhibitors was demonstrated in mice infected with a murine coronavirus. Overall, our study provides the first insight into a structural platform for anti-FIPV and anti-FCV drug development. PMID- 25694594 TI - Murine coronavirus ubiquitin-like domain is important for papain-like protease stability and viral pathogenesis. AB - Ubiquitin-like domains (Ubls) now are recognized as common elements adjacent to viral and cellular proteases; however, their function is unclear. Structural studies of the papain-like protease (PLP) domains of coronaviruses (CoVs) revealed an adjacent Ubl domain in severe acute respiratory syndrome CoV, Middle East respiratory syndrome CoV, and the murine CoV, mouse hepatitis virus (MHV). Here, we tested the effect of altering the Ubl adjacent to PLP2 of MHV on enzyme activity, viral replication, and pathogenesis. Using deletion and substitution approaches, we identified sites within the Ubl domain, residues 785 to 787 of nonstructural protein 3, which negatively affect protease activity, and valine residues 785 and 787, which negatively affect deubiquitinating activity. Using reverse genetics, we engineered Ubl mutant viruses and found that AM2 (V787S) and AM3 (V785S) viruses replicate efficiently at 37 degrees C but generate smaller plaques than wild-type (WT) virus, and AM2 is defective for replication at higher temperatures. To evaluate the effect of the mutation on protease activity, we purified WT and Ubl mutant PLP2 and found that the proteases exhibit similar specific activities at 25 degrees C. However, the thermal stability of the Ubl mutant PLP2 was significantly reduced at 30 degrees C, thereby reducing the total enzymatic activity. To determine if the destabilizing mutation affects viral pathogenesis, we infected C57BL/6 mice with WT or AM2 virus and found that the mutant virus is highly attenuated, yet it replicates sufficiently to elicit protective immunity. These studies revealed that modulating the Ubl domain adjacent to the PLP reduces protease stability and viral pathogenesis, revealing a novel approach to coronavirus attenuation. IMPORTANCE: Introducing mutations into a protein or virus can have either direct or indirect effects on function. We asked if changes in the Ubl domain, a conserved domain adjacent to the coronavirus papain-like protease, altered the viral protease activity or affected viral replication or pathogenesis. Our studies using purified wild-type and Ubl mutant proteases revealed that mutations in the viral Ubl domain destabilize and inactivate the adjacent viral protease. Furthermore, we show that a CoV encoding the mutant Ubl domain is unable to replicate at high temperature or cause lethal disease in mice. Our results identify the coronavirus Ubl domain as a novel modulator of viral protease stability and reveal manipulating the Ubl domain as a new approach for attenuating coronavirus replication and pathogenesis. PMID- 25694595 TI - A basic cluster in the N terminus of yellow fever virus NS2A contributes to infectious particle production. AB - The flavivirus NS2A protein is involved in the assembly of infectious particles. To further understand its role in this process, a charged-to-alanine scanning analysis was performed on NS2A encoded by an infectious cDNA clone of yellow fever virus (YFV). Fifteen mutants containing single, double, or triple charged to-alanine changes were tested. Five of them did not produce infectious particles, whereas efficient RNA replication was detectable for two of the five NS2A mutants (R22A-K23A-R24A and R99A-E100A-R101A mutants). Prolonged cultivation of transfected cells resulted in the recovery of pseudorevertants. Besides suppressor mutants in NS2A, a compensating second-site mutation in NS3 (D343G) arose for the NS2A R22A-K23A-R24A mutant. We found this NS3 mutation previously to be suppressive for the NS2Aalpha cleavage site Q189S mutant, also deficient in virion assembly. In this study, the subsequently suggested interaction between NS2A and NS3 was proven by coimmunoprecipitation analyses. Using selectively permeabilized cells, we could demonstrate that the regions encompassing R22A-K23A R24A and Q189S in NS2A are localized to the cytoplasm, where NS3 is also known to reside. However, the defect in particle production observed for the NS2A R22A K23A-R24A and Q189S mutants was not due to a defect in physical interaction between NS2A and NS3, as the NS2A mutations did not interrupt NS3 interaction. In fact, a region just upstream of R22-K23-R24 was mapped to be critical for NS2A NS3 interaction. Taken together, these data support a complex interplay between YFV NS2A and NS3 in virion assembly and identify a basic cluster in the NS2A N terminus to be critical in this process. IMPORTANCE: Despite an available vaccine, yellow fever remains endemic in tropical areas of South America and Africa. To control the disease, antiviral drugs are required, and an understanding of the determinants of virion assembly is central to their development. In this study, we identified a basic cluster of amino acids in the N terminus of YFV NS2A which inhibited virion assembly upon mutation. The defect was rescued by a spontaneously occurring mutation in NS3. Our study proves an interaction between NS2A and NS3, which, remarkably, was maintained for the NS2A mutant in the presence and absence of the NS3 mutation. This suggests a role for other viral and/or cellular proteins in virion assembly. Residues important for YFV virion production reported here only partially coincided with those reported for other flaviviruses, suggesting that the determinants for particle production are virus specific. Reconstruction of a YFV encoding tagged NS2A paves the way to identify further NS2A interaction partners. PMID- 25694596 TI - Functional analysis of the short isoform of orf virus protein OV20.0. AB - Orf virus (ORFV) OV20.0L is an ortholog of vaccinia virus (VACV) gene E3L. The function of VACV E3 protein as a virulence factor is well studied, but OV20.0 has received less attention. Here we show that like VACV E3L, OV20.0L encodes two proteins, a full-length protein and a shorter form (sh20). The shorter sh20 is an N-terminally truncated OV20.0 isoform generated when a downstream AUG codon is used for initiating translation. These isoforms differed in cellular localization, with full-length OV20.0 and sh20 found throughout the cell and predominantly in the cytoplasm, respectively. Nonetheless, both OV20.0 isoforms were able to bind double-stranded RNA (dsRNA)-activated protein kinase (PKR) and dsRNA. Moreover, both isoforms strongly inhibited PKR activation as shown by decreased phosphorylation of the translation initiation factor eIF2alpha subunit and protection of Sindbis virus infection against the activity of interferon (IFN). In spite of this apparent conservation of function in vitro, a recombinant ORFV that was able to express only the sh20 isoform was attenuated in a mouse model. IMPORTANCE: The OV20.0 protein of orf virus (ORFV) has two isoforms and contributes to virulence, but the roles of the two forms are not known. This study shows that the shorter isoform (sh20) arises due to use of a downstream initiation codon and is amino-terminally truncated. The sh20 form also differs in expression kinetics and cellular localization from full-length OV20.0. Similar to the full-length isoform, sh20 is able to bind dsRNA and PKR, inactivate PKR, and thus act as an antagonist of the interferon response in vitro. In vivo, however, wild-type OV20.0 could not be replaced with sh20 alone without a loss of virulence, suggesting that the functions of the isoforms are not simply redundant. PMID- 25694597 TI - Oncogenic human T-cell lymphotropic virus type 1 tax suppression of primary innate immune signaling pathways. AB - Human T-cell lymphotropic virus type I (HTLV-1) is an oncogenic retrovirus considered to be the etiological agent of adult T-cell leukemia (ATL). The viral transactivator Tax is regarded as the oncoprotein responsible for contributing toward the transformation process. Here, we demonstrate that Tax potently inhibits the activity of DEx(D/H) box helicases RIG-I and MDA5 as well as Toll dependent TIR-domain-containing adapter-inducing interferon-beta (TRIF), which function as cellular sensors or mediators of viral RNA and facilitate innate immune responses, including the production of type I IFN. Tax manifested this function by binding to the RIP homotypic interaction motif (RHIM) domains of TRIF and RIP1 to disrupt interferon regulatory factor 7 (IRF7) activity, a critical type I IFN transcription factor. These data provide further mechanistic insight into HTLV-1-mediated subversion of cellular host defense responses, which may help explain HTLV-1-related pathogenesis and oncogenesis. IMPORTANCE: It is predicted that up to 15% of all human cancers may involve virus infection. For example, human T-cell lymphotropic virus type 1 (HTLV-1) has been reported to infect up to 25 million people worldwide and is the causative agent of adult T cell leukemia (ATL). We show here that HTLV-1 may be able to successfully infect the T cells and remain latent due to the virally encoded product Tax inhibiting a key host defense pathway. Understanding the mechanisms by which Tax subverts the immune system may lead to the development of a therapeutic treatment for HTLV-1 mediated disease. PMID- 25694598 TI - CCCTC-binding factor recruitment to the early region of the human papillomavirus 18 genome regulates viral oncogene expression. AB - Host cell differentiation-dependent regulation of human papillomavirus (HPV) gene expression is required for productive infection. The host cell CCCTC-binding factor (CTCF) functions in genome-wide chromatin organization and gene regulation. We have identified a conserved CTCF binding site in the E2 open reading frame of high-risk HPV types. Using organotypic raft cultures of primary human keratinocytes containing high-risk HPV18 genomes, we show that CTCF recruitment to this conserved site regulates viral gene expression in differentiating epithelia. Mutation of the CTCF binding site increases the expression of the viral oncoproteins E6 and E7 and promotes host cell proliferation. Loss of CTCF binding results in a reduction of a specific alternatively spliced transcript expressed from the early gene region concomitant with an increase in the abundance of unspliced early transcripts. We conclude that high-risk HPV types have evolved to recruit CTCF to the early gene region to control the balance and complexity of splicing events that regulate viral oncoprotein expression. IMPORTANCE: The establishment and maintenance of HPV infection in undifferentiated basal cells of the squamous epithelia requires the activation of a subset of viral genes, termed early genes. The differentiation of infected cells initiates the expression of the late viral transcripts, allowing completion of the virus life cycle. This tightly controlled balance of differentiation-dependent viral gene expression allows the virus to stimulate cellular proliferation to support viral genome replication with minimal activation of the host immune response, promoting virus productivity. Alternative splicing of viral mRNAs further increases the complexity of viral gene expression. In this study, we show that the essential host cell protein CTCF, which functions in genome-wide chromatin organization and gene regulation, is recruited to the HPV genome and plays an essential role in the regulation of early viral gene expression and transcript processing. These data highlight a novel virus-host interaction important for HPV pathogenicity. PMID- 25694599 TI - Evidence supporting a role for TopBP1 and Brd4 in the initiation but not continuation of human papillomavirus 16 E1/E2-mediated DNA replication. AB - To replicate the double-stranded human papillomavirus 16 (HPV16) DNA genome, viral proteins E1 and E2 associate with the viral origin of replication, and E2 can also regulate transcription from adjacent promoters. E2 interacts with host proteins in order to regulate both transcription and replication; TopBP1 and Brd4 are cellular proteins that interact with HPV16 E2. Previous work with E2 mutants demonstrated the Brd4 requirement for the transactivation properties of E2, while TopBP1 is required for DNA replication induced by E2 from the viral origin of replication in association with E1. More-recent studies have also implicated Brd4 in the regulation of DNA replication by E2 and E1. Here, we demonstrate that both TopBP1 and Brd4 are present at the viral origin of replication and that interaction with E2 is required for optimal initiation of DNA replication. Both cellular proteins are present in E1-E2-containing nuclear foci, and the viral origin of replication is required for the efficient formation of these foci. Short hairpin RNA (shRNA) against either TopBP1 or Brd4 destroys the E1-E2 nuclear bodies but has no effect on E1-E2-mediated levels of DNA replication. An E2 mutation in the context of the complete HPV16 genome that compromises Brd4 interaction fails to efficiently establish episomes in primary human keratinocytes. Overall, the results suggest that interactions between TopBP1 and E2 and between Brd4 and E2 are required to correctly initiate DNA replication but are not required for continuing DNA replication, which may be mediated by alternative processes such as rolling circle amplification and/or homologous recombination. IMPORTANCE: Human papillomavirus 16 (HPV16) is causative in many human cancers, including cervical and head and neck cancers, and is responsible for the annual deaths of hundreds of thousands of people worldwide. The current vaccine will save lives in future generations, but antivirals targeting HPV16 are required for the alleviation of disease burden on the current, and future, generations. Targeting viral DNA replication that is mediated by two viral proteins, E1 and E2, in association with cellular proteins such as TopBP1 and Brd4 would have therapeutic benefits. This report suggests a role for these cellular proteins in the initiation of viral DNA replication by HPV16 E1-E2 but not for continuing replication. This is important if viral replication is to be effectively targeted; we need to understand the viral and cellular proteins required at each phase of viral DNA replication so that it can be effectively disrupted. PMID- 25694600 TI - A survey of the interactome of Kaposi's sarcoma-associated herpesvirus ORF45 revealed its binding to viral ORF33 and cellular USP7, resulting in stabilization of ORF33 that is required for production of progeny viruses. AB - The ORF45 protein of Kaposi's sarcoma-associated herpesvirus (KSHV) is a gammaherpesvirus-specific immediate-early tegument protein. Our previous studies have revealed its crucial roles in both early and late stages of KSHV infection. In this study, we surveyed the interactome of ORF45 using a panel of monoclonal antibodies. In addition to the previously identified extracellular regulated kinase (ERK) and p90 ribosomal S6 kinase (RSK) proteins, we found several other copurified proteins, including prominent ones of ~38 kDa and ~130 kDa. Mass spectrometry revealed that the 38-kDa protein is viral ORF33 and the 130-kDa protein is cellular USP7 (ubiquitin-specific protease 7). We mapped the ORF33 binding domain to the highly conserved carboxyl-terminal 19 amino acids (aa) of ORF45 and the USP7-binding domain to the reported consensus motif in the central region of ORF45. Using immunofluorescence staining, we observed colocalization of ORF45 with ORF33 or USP7 both under transfected conditions and in KSHV-infected cells. Moreover, we noticed ORF45-dependent relocalization of a portion of ORF33/USP7 from the nucleus to the cytoplasm. We found that ORF45 caused an increase in ORF33 protein accumulation that was abolished if either the ORF33- or USP7-binding domain in ORF45 was deleted. Furthermore, deletion of the conserved carboxyl terminus of ORF45 in the KSHV genome drastically reduced the level of ORF33 protein in KSHV-infected cells and abolished production of progeny virions. Collectively, our results not only reveal new components of the ORF45 interactome, but also demonstrate that the interactions among these proteins are crucial for KSHV lytic replication. IMPORTANCE: Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of several human cancers. KSHV ORF45 is a multifunctional protein that is required for KSHV lytic replication, but the exact mechanisms by which ORF45 performs its critical functions are unclear. Our previous studies revealed that all ORF45 protein in cells exists in high molecular-weight complexes. We therefore sought to characterize the interactome of ORF45 to provide insights into its roles during lytic replication. Using a panel of monoclonal antibodies, we surveyed the ORF45 interactome in KSHV infected cells. We identified two new binding partners of ORF45: the viral protein ORF33 and cellular ubiquitin-specific protease 7 (USP7). We further demonstrate that the interaction between ORF45 and ORF33 is crucial for the efficient production of KSHV viral particles, suggesting that the targeted interference with this interaction may represent a novel strategy to inhibit KSHV lytic replication. PMID- 25694602 TI - The retinoblastoma tumor suppressor promotes efficient human cytomegalovirus lytic replication. AB - The retinoblastoma (Rb) tumor suppressor controls cell cycle, DNA damage, apoptotic, and metabolic pathways. DNA tumor virus oncoproteins reduce Rb function by either inducing Rb degradation or physically disrupting complexes between Rb and its myriad binding proteins. Human cytomegalovirus (HCMV), a betaherpesvirus being investigated for potential roles in human cancers, encodes multiple lytic-phase proteins that inactivate Rb in distinct ways, leading to the hypothesis that reduced Rb levels and/or activity would benefit HCMV lytic infection. Paradoxically, we found that Rb knockdown prior to infection, whether transient or constitutive, impaired HCMV lytic infection at multiple stages, notably viral DNA replication, late protein expression, and infectious virion production. The existence of differentially modified forms of Rb, the temporally and functionally distinct means by which HCMV proteins interact with Rb, and the necessity of Rb for efficient HCMV lytic replication combine to highlight the complex relationship between the virus and this critical tumor suppressor. IMPORTANCE: Initial work examining viral protein modulation of cell cycle progression and oncogenic transformation revealed that these proteins inactivated the function of cellular tumor suppressor proteins. However, subsequent work, including experiments described here using human cytomegalovirus, demonstrate a more nuanced interaction that includes the necessity of cellular tumor suppressors for efficient viral replication. Understanding the positive impacts that cellular tumor suppressors have on viral infections may reveal new activities of these well-studied yet incompletely understood proteins. The basis for oncolytic viral therapy is the selective replication of viruses in transformed cells in which tumor suppressor function may be compromised. Understanding how tumor suppressors support viral infections may allow for the generation of modified oncolytic viruses with greater selective tumor cell replication and killing. PMID- 25694601 TI - Adenovirus replaces mitotic checkpoint controls. AB - Infection with adenovirus triggers the cellular DNA damage response, elements of which include cell death and cell cycle arrest. Early adenoviral proteins, including the E1B-55K and E4orf3 proteins, inhibit signaling in response to DNA damage. A fraction of cells infected with an adenovirus mutant unable to express the E1B-55K and E4orf3 genes appeared to arrest in a mitotic-like state. Cells infected early in G1 of the cell cycle were predisposed to arrest in this state at late times of infection. This arrested state, which displays hallmarks of mitotic catastrophe, was prevented by expression of either the E1B-55K or the E4orf3 genes. However, E1B-55K mutant virus-infected cells became trapped in a mitotic-like state in the presence of the microtubule poison colcemid, suggesting that the two viral proteins restrict entry into mitosis or facilitate exit from mitosis in order to prevent infected cells from arresting in mitosis. The E1B-55K protein appeared to prevent inappropriate entry into mitosis through its interaction with the cellular tumor suppressor protein p53. The E4orf3 protein facilitated exit from mitosis by possibly mislocalizing and functionally inactivating cyclin B1. When expressed in noninfected cells, E4orf3 overcame the mitotic arrest caused by the degradation-resistant R42A cyclin B1 variant. IMPORTANCE: Cells that are infected with adenovirus type 5 early in G1 of the cell cycle are predisposed to arrest in a mitotic-like state in a p53-dependent manner. The adenoviral E1B-55K protein prevents entry into mitosis. This newly described activity for the E1B-55K protein appears to depend on the interaction between the E1B-55K protein and the tumor suppressor p53. The adenoviral E4orf3 protein facilitates exit from mitosis, possibly by altering the intracellular distribution of cyclin B1. By preventing entry into mitosis and by promoting exit from mitosis, these adenoviral proteins act to prevent the infected cell from arresting in a mitotic-like state. PMID- 25694603 TI - Viral DNA replication-dependent DNA damage response activation during BK polyomavirus infection. AB - BK polyomavirus (BKPyV) reactivation is associated with severe human disease in kidney and bone marrow transplant patients. The interplay between viral and host factors that regulates the productive infection process remains poorly understood. We have previously reported that the cellular DNA damage response (DDR) is activated upon lytic BKPyV infection and that its activation is required for optimal viral replication in primary kidney epithelial cells. In this report, we set out to determine what viral components are responsible for activating the two major phosphatidylinositol 3-kinase-like kinases (PI3KKs) involved in the DDR: ataxia telangiectasia mutated (ATM) kinase and ATM and Rad3-related (ATR) kinase. Using a combination of UV treatment, lentivirus transduction, and mutant virus infection experiments, our results demonstrate that neither the input virus nor the expression of large T antigen (TAg) alone is sufficient to trigger the activation of ATM or ATR in our primary culture model. Instead, our data suggest that the activation of both the ATM- and ATR-mediated DDR pathways is linked to viral DNA replication. Intriguingly, a TAg mutant virus that is unable to activate the DDR causes substantial host DNA damage. Our study provides insight into how DDRs are activated by polyomaviruses in primary cells with intact cell cycle checkpoints and how the activation might be linked to the maintenance of host genome stability. IMPORTANCE: Polyomaviruses are opportunistic pathogens that are associated with several human diseases under immunosuppressed conditions. BK polyomavirus (BKPyV) affects mostly kidney and bone marrow transplant patients. The detailed replication mechanism of these viruses remains to be determined. We have previously reported that BKPyV activates the host DNA damage response (DDR), a response normally used by the host cell to combat genotoxic stress, to aid its own replication. In this study, we identified that the trigger for DDR activation is viral replication. Furthermore, we show that the virus is able to cause host DNA damage in the absence of viral replication and DDR activation. These results suggest an intricate relationship between viral replication, DDR activation, and host genome instability. PMID- 25694604 TI - Transfection of Sclerotinia sclerotiorum with in vitro transcripts of a naturally occurring interspecific recombinant of Sclerotinia sclerotiorum hypovirus 2 significantly reduces virulence of the fungus. AB - A recombinant strain of Sclerotinia sclerotiorum hypovirus 2 (SsHV2) was identified from a North American Sclerotinia sclerotiorum isolate (328) from lettuce (Lactuca sativa L.) by high-throughput sequencing of total RNA. The 5'- and 3'-terminal regions of the genome were determined by rapid amplification of cDNA ends. The assembled nucleotide sequence was up to 92% identical to two recently reported SsHV2 strains but contained a deletion near its 5' terminus of more than 1.2 kb relative to the other SsHV2 strains and an insertion of 524 nucleotides (nt) that was distantly related to Valsa ceratosperma hypovirus 1. This suggests that the new isolate is a heterologous recombinant of SsHV2 with a yet-uncharacterized hypovirus. We named the new strain Sclerotinia sclerotiorum hypovirus 2 Lactuca (SsHV2L) and deposited the sequence in GenBank with accession number KF898354. Sclerotinia sclerotiorum isolate 328 was coinfected with a strain of Sclerotinia sclerotiorum endornavirus 1 and was debilitated compared to cultures of the same isolate that had been cured of virus infection by cycloheximide treatment and hyphal tipping. To determine whether SsHV2L alone could induce hypovirulence in S. sclerotiorum, a full-length cDNA of the 14,538 nt viral genome was cloned. Transcripts corresponding to the viral RNA were synthesized in vitro and transfected into a virus-free isolate of S. sclerotiorum, DK3. Isolate DK3 transfected with SsHV2L was hypovirulent on soybean and lettuce and exhibited delayed maturation of sclerotia relative to virus-free DK3, completing Koch's postulates for the association of hypovirulence with SsHV2L. IMPORTANCE: A cosmopolitan fungus, Sclerotinia sclerotiorum infects more than 400 plant species and causes a plant disease known as white mold that produces significant yield losses in major crops annually. Mycoviruses have been used successfully to reduce losses caused by fungal plant pathogens, but definitive relationships between hypovirus infections and hypovirulence in S. sclerotiorum were lacking. By establishing a cause-and-effect relationship between Sclerotinia sclerotiorum hypovirus Lactuca (SsHV2L) infection and the reduction in host virulence, we showed direct evidence that hypoviruses have the potential to reduce the severity of white mold disease. In addition to intraspecific recombination, this study showed that recent interspecific recombination is an important factor shaping viral genomes. The construction of an infectious clone of SsHV2L allows future exploration of the interactions between SsHV2L and S. sclerotiorum, a widespread fungal pathogen of plants. PMID- 25694605 TI - Herpes simplex virus 1 upregulates p35, alters CDK-5 localization, and stimulates CDK-5 kinase activity during acute infection in neurons. AB - The cyclin-dependent kinase 5 (CDK-5) activating protein, p35, is important for acute herpes simplex virus 1 (HSV-1) replication in mice. This report shows that HSV-1 increases p35 levels, changes the primary localization of CDK-5 from the nucleus to the cytoplasm, and enhances CDK-5 activity during lytic or acute infection. Infected neurons also stained positive for the DNA damage response (DDR) marker gammaH2AX. We propose that CDK-5 is activated by the DDR to protect infected neurons from apoptosis. PMID- 25694606 TI - ORF57 overcomes the detrimental sequence bias of Kaposi's sarcoma-associated herpesvirus lytic genes. AB - Kaposi's sarcoma-associated herpesvirus (KSHV) encodes ORF57, which enhances the expression of intronless KSHV genes on multiple posttranscriptional levels. However, it remains elusive how ORF57 recognizes viral RNAs. Here, we demonstrate that ORF57 also increases the expression of the multiple intron-containing K15 gene. The nucleotide bias of the K15 cDNA revealed an unusual high AT content. Thus, we optimized the K15 cDNA by raising the frequency of GC nucleotides, yielding an ORF57-independent version. To further prove the importance of the sequence bias of ORF57-dependent RNAs, we grouped KSHV mRNAs according to their AT content and found a correlation between AT-richness and ORF57 dependency. More importantly, latent genes, which have to be expressed in the absence of ORF57, have a low AT content and are indeed ORF57 independent. The nucleotide composition of K15 resembles that of HIV gag, which cannot be expressed unless RNA export is facilitated by the HIV Rev protein. Interestingly, ORF57 can partially rescue HIV Gag expression. Thus, the KSHV target RNAs of ORF57 and HIV gag RNA may share certain motifs based on the nucleotide bias. A bioinformatic comparison between wild-type and sequence-optimized K15 revealed a higher density for hnRNP-binding motifs in the former. We speculate that binding of particular hnRNPs to KSHV lytic transcripts is the prerequisite for ORF57 to enhance their expression. IMPORTANCE: The mostly intronless genes of KSHV are only expressed in the presence of the viral regulator protein ORF57, but how ORF57 recognizes viral RNAs remains elusive. We focused on the multiple intron-containing KSHV gene K15 and revealed that its expression is also increased by ORF57. Moreover, sequences in the K15 cDNA mediate this enhancement. The quest for a target sequence or a response element for ORF57 in the lytic genes was not successful. Instead, we found the nucleotide bias to be the critical determinant of ORF57 dependency. Based on the fact that ORF57 has only a weak affinity for nucleic acids, we speculate that a cellular RNA-binding protein provides the sequence preference for ORF57. This study provides evidence that herpesviral RNA regulator proteins use the sequence bias of lytic genes and the resulting composition of the viral mRNP to distinguish between viral and cellular mRNAs. PMID- 25694607 TI - Host proteome correlates of vaccine-mediated enhanced disease in a mouse model of respiratory syncytial virus infection. AB - Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections in infants. Despite over 50 years of research, to date no safe and efficacious RSV vaccine has been licensed. Many experimental vaccination strategies failed to induce balanced T-helper (Th) responses and were associated with adverse effects such as hypersensitivity and immunopathology upon challenge. In this study, we explored the well-established recombinant vaccinia virus (rVV) RSV-F/RSV-G vaccination-challenge mouse model to study phenotypically distinct vaccine-mediated host immune responses at the proteome level. In this model, rVV G priming and not rVV-F priming results in the induction of Th2 skewed host responses upon RSV challenge. Mass spectrometry-based spectral count comparisons enabled us to identify seven host proteins for which expression in lung tissue is associated with an aberrant Th2 skewed response characterized by the influx of eosinophils and neutrophils. These proteins are involved in processes related to the direct influx of eosinophils (eosinophil peroxidase [Epx]) and to chemotaxis and extravasation processes (Chil3 [chitinase-like-protein 3]) as well as to eosinophil and neutrophil homing signals to the lung (Itgam). In addition, the increased levels of Arg1 and Chil3 proteins point to a functional and regulatory role for alternatively activated macrophages and type 2 innate lymphoid cells in Th2 cytokine-driven RSV vaccine-mediated enhanced disease. IMPORTANCE: RSV alone is responsible for 80% of acute bronchiolitis cases in infants worldwide and causes substantial mortality in developing countries. Clinical trials performed with formalin-inactivated RSV vaccine preparations in the 1960s failed to induce protection upon natural RSV infection and even predisposed patients for enhanced disease. Despite the clinical need, to date no safe and efficacious RSV vaccine has been licensed. Since RSV vaccines have a tendency to prime for unbalanced responses associated with an exuberant influx of inflammatory cells and enhanced disease, detailed characterization of primed host responses has become a crucial element in RSV vaccine research. We investigated the lung proteome of mice challenged with RSV upon priming with vaccine preparations known to induce phenotypically distinct host responses. Seven host proteins whose expression levels are associated with vaccine-mediated enhanced disease have been identified. The identified protein biomarkers support the development as well as detailed evaluation of next-generation RSV vaccines. PMID- 25694608 TI - Placental growth factor-1 and -2 induce hyperplasia and invasiveness of primary rheumatoid synoviocytes. AB - Inflammation-mediated oncogenesis has been implicated in a variety of cancer types. Rheumatoid synovial tissues can be viewed as a tumor-like mass, consisting of hyperplastic fibroblast-like synoviocytes (FLSs). FLSs of rheumatoid arthritis (RA) patients have promigratory and invasive characteristics, which may be caused by chronic exposure to genotoxic stimuli, including hypoxia and growth factors. We tested whether a transformed phenotype of RA-FLSs is associated with placental growth factor (PlGF), a representative angiogenic growth factor induced by hypoxia. In this study, we identified PlGF-1 and PlGF-2 as the major PlGF isoforms in RA-FLSs. Global gene expression profiling revealed that cell proliferation, apoptosis, angiogenesis, and cell migration were mainly represented by differentially expressed genes in RA-FLSs transfected with small interfering RNA for PlGF. Indeed, PlGF-deficient RA-FLSs showed a decrease in cell proliferation, migration, and invasion, but an increase in apoptotic death in vitro. PlGF gene overexpression resulted in the opposite effects. Moreover, exogeneous PlGF-1 and PlGF-2 increased survival, migration, and invasiveness of RA-FLSs by binding their receptors, Flt-1 and neuropilin-1, and upregulating the expression of antiapoptotic molecules, pErk and Bcl2. Knockdown of PlGF transcripts reduced RA-FLS proliferation in a xenotransplantation model. Collectively, in addition to their role for neovascularization, PlGF-1 and -2 promote proliferation, survival, migration, and invasion of RA-FLSs in an autocrine and paracrine manner. These results demonstrated how primary cells of mesenchymal origin acquired an aggressive and transformed phenotype. PlGF and its receptors thus offer new targets for anti-FLS therapy. PMID- 25694609 TI - FOXO1 mediates RANKL-induced osteoclast formation and activity. AB - We have previously shown that the transcription factor FOXO1 is elevated in conditions with high levels of bone resorption. To investigate the role of FOXO1 in the formation of osteoclasts, we examined mice with lineage-specific deletion of FOXO1 in osteoclast precursors and by knockdown of FOXO1 with small interfering RNA. The receptor activator for NF-kappaB ligand (RANKL), a principal bone-resorbing factor, induced FOXO1 expression and nuclear localization 2 d after stimulation in bone marrow macrophages and RAW264.7 osteoclast precursors. RANKL-induced osteoclast formation and osteoclast activity was reduced in half in vivo and in vitro with lineage-specific FOXO1 deletion (LyzM.Cre(+)FOXO1(L/L)) compared with matched controls (LyzM.Cre(-)FOXO1(L/L)). Similar results were obtained by knockdown of FOXO1 in RAW264.7 cells. Moreover, FOXO1-mediated osteoclast formation was linked to regulation of NFATc1 nuclear localization and expression as well as a number of downstream factors, including dendritic cell specific transmembrane protein, ATP6vod2, cathepsin K, and integrin alphav. Lastly, FOXO1 deletion reduced M-CSF-induced RANK expression and migration of osteoclast precursors. In the present study, we provide evidence that FOXO1 plays a direct role in osteoclast formation by mediating the effect of RANKL on NFATc1 and several downstream effectors. This is likely to be significant because FOXO1 and RANKL are elevated in osteolytic conditions. PMID- 25694610 TI - IkappaBNS regulates murine Th17 differentiation during gut inflammation and infection. AB - IL-17-producing Th17 cells mediate immune responses against a variety of fungal and bacterial infections. Signaling via NF-kappaB has been linked to the development and maintenance of Th17 cells. We analyzed the role of the unusual inhibitor of NF-kappaB, IkappaBNS, in the proliferation and effector cytokine production of murine Th17 cells. Our study demonstrates that nuclear IkappaBNS is crucial for murine Th17 cell generation. IkappaBNS is highly expressed in Th17 cells; in the absence of IkappaBNS, the frequencies of IL-17A-producing cells are drastically reduced. This was measured in vitro under Th17-polarizing conditions and confirmed in two colitis models. Mechanistically, murine IkappaBNS (-/-) Th17 cells were less proliferative and expressed markedly reduced levels of IL-2, IL 10, MIP-1alpha, and GM-CSF. Citrobacter rodentium was used as a Th17-inducing infection model, in which IkappaBNS (-/-) mice displayed an increased bacterial burden and diminished tissue damage. These results demonstrate the important function of Th17 cells in pathogen clearance, as well as in inflammation associated pathology. We identified IkappaBNS to be crucial for the generation and function of murine Th17 cells upon inflammation and infection. Our findings may have implications for the therapy of autoimmune conditions, such as inflammatory bowel disease, and for the treatment of gut-tropic infections. PMID- 25694611 TI - Immunoprevention of chemical carcinogenesis through early recognition of oncogene mutations. AB - Prevention of tumors induced by environmental carcinogens has not been achieved. Skin tumors produced by polyaromatic hydrocarbons, such as 7,12 dimethylbenz(a)anthracene (DMBA), often harbor an H-ras point mutation, suggesting that it is a poor target for early immunosurveillance. The application of pyrosequencing and allele-specific PCR techniques established that mutations in the genome and expression of the Mut H-ras gene could be detected as early as 1 d after DMBA application. Further, DMBA sensitization raised Mut H-ras epitope specific CTLs capable of eliminating Mut H-ras(+) preneoplastic skin cells, demonstrating that immunosurveillance is normally induced but may be ineffective owing to insufficient effector pool size and/or immunosuppression. To test whether selective pre-expansion of CD8 T cells with specificity for the single Mut H-ras epitope was sufficient for tumor prevention, MHC class I epitope focused lentivector-infected dendritic cell- and DNA-based vaccines were designed to bias toward CTL rather than regulatory T cell induction. Mut H-ras, but not wild-type H-ras, epitope-focused vaccination generated specific CTLs and inhibited DMBA-induced tumor initiation, growth, and progression in preventative and therapeutic settings. Transferred Mut H-ras-specific effectors induced rapid tumor regression, overcoming established tumor suppression in tumor-bearing mice. These studies support further evaluation of oncogenic mutations for their potential to act as early tumor-specific, immunogenic epitopes in expanding relevant immunosurveillance effectors to block tumor formation, rather than treating established tumors. PMID- 25694612 TI - Core fucosylation of IgG B cell receptor is required for antigen recognition and antibody production. AB - Ag recognition and Ab production in B cells are major components of the humoral immune response. In the current study, we found that the core fucosylation catalyzed by alpha1,6-fucosyltransferase (Fut8) was required for the Ag recognition of BCR and the subsequent signal transduction. Moreover, compared with the 3-83 B cells, the coalescing of lipid rafts and Ag-BCR endocytosis were substantially reduced in Fut8-knockdown (3-83-KD) cells with p31 stimulation and then completely restored by reintroduction of the Fut8 gene to the 3-83-KD cells. Indeed, Fut8-null (Fut8(-/-)) mice evoked a low immune response following OVA immunization. Also, the frequency of IgG-producing cells was significantly reduced in the Fut8(-/-) spleen following OVA immunization. Our results clearly suggest an unexpected mode of BCR function, in which the core fucosylation of IgG BCR mediates Ag recognition and, concomitantly, cell signal transduction via BCR and Ab production. PMID- 25694613 TI - UK preparedness for children with Ebola infection. PMID- 25694614 TI - Variable selection in the presence of missing data: resampling and imputation. AB - In the presence of missing data, variable selection methods need to be tailored to missing data mechanisms and statistical approaches used for handling missing data. We focus on the mechanism of missing at random and variable selection methods that can be combined with imputation. We investigate a general resampling approach (BI-SS) that combines bootstrap imputation and stability selection, the latter of which was developed for fully observed data. The proposed approach is general and can be applied to a wide range of settings. Our extensive simulation studies demonstrate that the performance of BI-SS is the best or close to the best and is relatively insensitive to tuning parameter values in terms of variable selection, compared with several existing methods for both low dimensional and high-dimensional problems. The proposed approach is further illustrated using two applications, one for a low-dimensional problem and the other for a high-dimensional problem. PMID- 25694615 TI - A systematic review of the effects of upper body warm-up on performance and injury. AB - PURPOSE: This systematic review was conducted to identify the impact of upper body warm-up on performance and injury prevention outcomes. METHODS: Web of Science, MEDLINE, SPORTDiscus, PsycINFO and Cochrane databases were searched using terms related to upper extremity warm-up. Inclusion criteria were English language randomised controlled trials from peer-reviewed journals in which investigation of upper body warm-up on performance and injury prevention outcomes was a primary aim. Included studies were assessed for methodological quality using the PEDro scale. A wide variety of warm-up modes and outcomes precluded meta-analysis except for one group of studies. The majority of warm-ups were assessed as having 'positive', 'neutral', 'negative' or 'specific' effects on outcomes. RESULTS: Thirty-one studies met the inclusion criteria with 21 rated as having 'good' methodological quality. The studies investigated a total of 25 warm up modes and 43 outcome factors that could be grouped into eight mode and performance outcome categories. No studies of upper body warm-up effects on injury prevention were discovered. CONCLUSIONS: Strong research-based evidence was found for the following: high-load dynamic warm-ups enhance power and strength performance; warm-up swings with a standard weight baseball bat are most effective for enhancing bat speed; short-duration static stretching warm-up has no effect on power outcomes; and passive heating/cooling is a largely ineffective warm-up mode. A clear knowledge gap in upper body warm-up literature is the lack of investigation of injury prevention outcomes. PMID- 25694616 TI - Independent evolution of the sexes promotes amphibian diversification. AB - Classic ecological theory predicts that the evolution of sexual dimorphism constrains diversification by limiting morphospace available for speciation. Alternatively, sexual selection may lead to the evolution of reproductive isolation and increased diversification. We test contrasting predictions of these hypotheses by examining the relationship between sexual dimorphism and diversification in amphibians. Our analysis shows that the evolution of sexual size dimorphism (SSD) is associated with increased diversification and speciation, contrary to the ecological theory. Further, this result is unlikely to be explained by traditional sexual selection models because variation in amphibian SSD is unlikely to be driven entirely by sexual selection. We suggest that relaxing a central assumption of classic ecological models-that the sexes share a common adaptive landscape-leads to the alternative hypothesis that independent evolution of the sexes may promote diversification. Once the constraints of sexual conflict are relaxed, the sexes can explore morphospace that would otherwise be inaccessible. Consistent with this novel hypothesis, the evolution of SSD in amphibians is associated with reduced current extinction threat status, and an historical reduction in extinction rate. Our work reconciles conflicting predictions from ecological and evolutionary theory and illustrates that the ability of the sexes to evolve independently is associated with a spectacular vertebrate radiation. PMID- 25694617 TI - Adaptive responses to cool climate promotes persistence of a non-native lizard. AB - Successful establishment and range expansion of non-native species often require rapid accommodation of novel environments. Here, we use common-garden experiments to demonstrate parallel adaptive evolutionary response to a cool climate in populations of wall lizards (Podarcis muralis) introduced from southern Europe into England. Low soil temperatures in the introduced range delay hatching, which generates directional selection for a shorter incubation period. Non-native lizards from two separate lineages have responded to this selection by retaining their embryos for longer before oviposition--hence reducing the time needed to complete embryogenesis in the nest--and by an increased developmental rate at low temperatures. This divergence mirrors local adaptation across latitudes and altitudes within widely distributed species and suggests that evolutionary responses to climate can be very rapid. When extrapolated to soil temperatures encountered in nests within the introduced range, embryo retention and faster developmental rate result in one to several weeks earlier emergence compared with the ancestral state. We show that this difference translates into substantial survival benefits for offspring. This should promote short- and long-term persistence of non-native populations, and ultimately enable expansion into areas that would be unattainable with incubation duration representative of the native range. PMID- 25694618 TI - Sexual conflict over parental care promotes the evolution of sex differences in care and the ability to care. AB - Strong asymmetries in parental care, with one sex providing more care than the other, are widespread across the animal kingdom. At present, two factors are thought to ultimately cause sex differences in care: certainty of parentage and sexual selection. By contrast, we here show that the coevolution of care and the ability to care can result in strong asymmetries in both the ability to care and the level of care, even in the absence of these factors. While the coevolution of care and the ability to care does not predict which sex evolves to care more than the other, once other factors give rise to even the slightest differences in the cost and benefits of care between the sexes (e.g. differences in certainty in parentage), a clear directionality emerges; the sex with the lower cost or higher benefit of care evolves both to be more able to care and to provide much higher levels of care than the other sex. Our findings suggest that the coevolution of levels of care and the ability to care may be a key factor underlying the evolution of sex differences in care. PMID- 25694619 TI - Ocean acidification induces biochemical and morphological changes in the calcification process of large benthic foraminifera. AB - Large benthic foraminifera are significant contributors to sediment formation on coral reefs, yet they are vulnerable to ocean acidification. Here, we assessed the biochemical and morphological impacts of acidification on the calcification of Amphistegina lessonii and Marginopora vertebralis exposed to different pH conditions. We measured growth rates (surface area and buoyant weight) and Ca ATPase and Mg-ATPase activities and calculated shell density using micro-computer tomography images. In A. lessonii, we detected a significant decrease in buoyant weight, a reduction in the density of inner skeletal chambers, and an increase of Ca-ATPase and Mg-ATPase activities at pH 7.6 when compared with ambient conditions of pH 8.1. By contrast, M. vertebralis showed an inhibition in Mg ATPase activity under lowered pH, with growth rate and skeletal density remaining constant. While M. vertebralis is considered to be more sensitive than A. lessonii owing to its high-Mg-calcite skeleton, it appears to be less affected by changes in pH, based on the parameters assessed in this study. We suggest difference in biochemical pathways of calcification as the main factor influencing response to changes in pH levels, and that A. lessonii and M. vertebralis have the ability to regulate biochemical functions to cope with short term increases in acidity. PMID- 25694620 TI - Kinship, parental manipulation and evolutionary origins of eusociality. AB - One of the hallmarks of eusociality is that workers forego their own reproduction to assist their mother in raising siblings. This seemingly altruistic behaviour may benefit workers if gains in indirect fitness from rearing siblings outweigh the loss of direct fitness. If worker presence is advantageous to mothers, however, eusociality may evolve without net benefits to workers. Indirect fitness benefits are often cited as evidence for the importance of inclusive fitness in eusociality, but have rarely been measured in natural populations. We compared inclusive fitness of alternative social strategies in the tropical sweat bee, Megalopta genalis, for which eusociality is optional. Our results show that workers have significantly lower inclusive fitness than females that found their own nests. In mathematical simulations based on M. genalis field data, eusociality cannot evolve with reduced intra-nest relatedness. The simulated distribution of alternative social strategies matched observed distributions of M. genalis social strategies when helping behaviour was simulated as the result of maternal manipulation, but not as worker altruism. Thus, eusociality in M. genalis is best explained through kin selection, but the underlying mechanism is likely maternal manipulation. PMID- 25694622 TI - Side-by-side secretion of Late Palaeozoic diverged courtship pheromones in an aquatic salamander. AB - Males of the advanced salamanders (Salamandroidea) attain internal fertilization without a copulatory organ by depositing a spermatophore on the substrate in the environment, which females subsequently take up with their cloaca. The aquatically reproducing modern Eurasian newts (Salamandridae) have taken this to extremes, because most species do not display close physical contact during courtship, but instead largely rely on females following the male track at spermatophore deposition. Although pheromones have been widely assumed to represent an important aspect of male courtship, molecules able to induce the female following behaviour that is the prelude for successful insemination have not yet been identified. Here, we show that uncleaved sodefrin precursor-like factor (SPF) protein pheromones are sufficient to elicit such behaviour in female palmate newts (Lissotriton helveticus). Combined transcriptomic and proteomic evidence shows that males simultaneously tail-fan multiple ca 20 kDa glycosylated SPF proteins during courtship. Notably, molecular dating estimates show that the diversification of these proteins already started in the late Palaeozoic, about 300 million years ago. Our study thus not only extends the use of uncleaved SPF proteins outside terrestrially reproducing plethodontid salamanders, but also reveals one of the oldest vertebrate pheromone systems. PMID- 25694621 TI - Elevated germline mutation rate in teenage fathers. AB - Men age and die, while cells in their germline are programmed to be immortal. To elucidate how germ cells maintain viable DNA despite increasing parental age, we analysed DNA from 24 097 parents and their children, from Europe, the Middle East and Africa. We chose repetitive microsatellite DNA that mutates (unlike point mutations) only as a result of cellular replication, providing us with a natural 'cell-cycle counter'. We observe, as expected, that the overall mutation rate for fathers is seven times higher than for mothers. Also as expected, mothers have a low and lifelong constant DNA mutation rate. Surprisingly, however, we discover that (i) teenage fathers already set out from a much higher mutation rate than teenage mothers (potentially equivalent to 77-196 male germline cell divisions by puberty); and (ii) ageing men maintain sperm DNA quality similar to that of teenagers, presumably by using fresh batches of stem cells known as 'A-dark spermatogonia'. PMID- 25694623 TI - Dynamics of pre- and post-choice behaviour: rats approximate optimal strategy in a discrete-trial decision task. AB - We simulate two types of environments to investigate how closely rats approximate optimal foraging. Rats initiated a trial where they chose between two spouts for sucrose, which was delivered at distinct probabilities. The discrete trial procedure used allowed us to observe the relationship between choice proportions, response latencies and obtained rewards. Our results show that rats approximate the optimal strategy across a range of environments that differ in the average probability of reward as well as the dynamics of the depletion-renewal cycle. We found that the constituent components of a single choice differentially reflect environmental contingencies. Post-choice behaviour, measured as the duration of time rats spent licking at the spouts on unrewarded trials, was the most sensitive index of environmental variables, adjusting most rapidly to changes in the environment. These findings have implications for the role of confidence in choice outcomes for guiding future choices. PMID- 25694624 TI - The phylogenetic utility and functional constraint of microRNA flanking sequences. AB - MicroRNAs (miRNAs) have recently risen to prominence as novel factors responsible for post-transcriptional regulation of gene expression. miRNA genes have been posited as highly conserved in the clades in which they exist. Consequently, miRNAs have been used as rare genome change characters to estimate phylogeny by tracking their gain and loss. However, their short length (21-23 bp) has limited their perceived utility in sequenced-based phylogenetic inference. Here, using reference taxa with established phylogenetic relationships, we demonstrate that miRNA sequences are of high utility in quantitative, rather than in qualitative, phylogenetic analysis. The clear orthology among miRNA genes from different species makes it straightforward to identify and align these sequences from even fragmentary datasets. We also identify significant sequence conservation in the regions directly flanking miRNA genes, and show that this too is of utility in phylogenetic analysis, as well as highlighting conserved regions that will be of interest to other fields. Employing miRNA sequences from 12 sequenced drosophilid genomes, together with a Tribolium castaneum outgroup, we demonstrate that this approach is robust using Bayesian and maximum-likelihood methods. The utility of these characters is further demonstrated in the rhabditid nematodes and primates. As next-generation sequencing makes it more cost-effective to sequence genomes and small RNA libraries, this methodology provides an alternative data source for phylogenetic analysis. The approach allows rapid resolution of relationships between both closely related and rapidly evolving species, and provides an additional tool for investigation of relationships within the tree of life. PMID- 25694625 TI - Leaf energy balance modelling as a tool to infer habitat preference in the early angiosperms. AB - Despite more than a century of research, some key aspects of habitat preference and ecology of the earliest angiosperms remain poorly constrained. Proposed growth ecology has varied from opportunistic weedy species growing in full sun to slow-growing species limited to the shaded understorey of gymnosperm forests. Evidence suggests that the earliest angiosperms possessed low transpiration rates: gas exchange rates for extant basal angiosperms are low, as are the reconstructed gas exchange rates for the oldest known angiosperm leaf fossils. Leaves with low transpirational capacity are vulnerable to overheating in full sun, favouring the hypothesis that early angiosperms were limited to the shaded understorey. Here, modelled leaf temperatures are used to examine the thermal tolerance of some of the earliest angiosperms. Our results indicate that small leaf size could have mitigated the low transpirational cooling capacity of many early angiosperms, enabling many species to survive in full sun. We propose that during the earliest phases of the angiosperm leaf record, angiosperms may not have been limited to the understorey, and that some species were able to compete with ferns and gymnosperms in both shaded and sunny habitats, especially in the absence of competition from more rapidly growing and transpiring advanced lineages of angiosperms. PMID- 25694626 TI - Climate and fishing steer ecosystem regeneration to uncertain economic futures. AB - Overfishing of large predatory fish populations has resulted in lasting restructurings of entire marine food webs worldwide, with serious socio-economic consequences. Fortunately, some degraded ecosystems show signs of recovery. A key challenge for ecosystem management is to anticipate the degree to which recovery is possible. By applying a statistical food-web model, using the Baltic Sea as a case study, we show that under current temperature and salinity conditions, complete recovery of this heavily altered ecosystem will be impossible. Instead, the ecosystem regenerates towards a new ecological baseline. This new baseline is characterized by lower and more variable biomass of cod, the commercially most important fish stock in the Baltic Sea, even under very low exploitation pressure. Furthermore, a socio-economic assessment shows that this signal is amplified at the level of societal costs, owing to increased uncertainty in biomass and reduced consumer surplus. Specifically, the combined economic losses amount to approximately 120 million ? per year, which equals half of today's maximum economic yield for the Baltic cod fishery. Our analyses suggest that shifts in ecological and economic baselines can lead to higher economic uncertainty and costs for exploited ecosystems, in particular, under climate change. PMID- 25694627 TI - Secondary metabolites in floral nectar reduce parasite infections in bumblebees. AB - The synthesis of secondary metabolites is a hallmark of plant defence against herbivores. These compounds may be detrimental to consumers, but can also protect herbivores against parasites. Floral nectar commonly contains secondary metabolites, but little is known about the impacts of nectar chemistry on pollinators, including bees. We hypothesized that nectar secondary metabolites could reduce bee parasite infection. We inoculated individual bumblebees with Crithidia bombi, an intestinal parasite, and tested effects of eight naturally occurring nectar chemicals on parasite population growth. Secondary metabolites strongly reduced parasite load, with significant effects of alkaloids, terpenoids and iridoid glycosides ranging from 61 to 81%. Using microcolonies, we also investigated costs and benefits of consuming anabasine, the compound with the strongest effect on parasites, in infected and uninfected bees. Anabasine increased time to egg laying, and Crithidia reduced bee survival. However, anabasine consumption did not mitigate the negative effects of Crithidia, and Crithidia infection did not alter anabasine consumption. Our novel results highlight that although secondary metabolites may not rescue survival in infected bees, they may play a vital role in mediating Crithidia transmission within and between colonies by reducing Crithidia infection intensities. PMID- 25694628 TI - The association of cholinergic and cold-induced urticaria: diagnosis and management. AB - Physical urticaria is often challenging to diagnose and manage. We present a case of both cholinergic and cold-induced urticaria and discuss the diagnosis and management strategies of these two important conditions. PMID- 25694629 TI - Non-traumatic depressed skull fracture in a neonate or 'ping pong' fracture. AB - This is a case study describing the finding of a depressed skull fracture in a neonate who was delivered without instrumentation and with no history of trauma. Depressed skull fractures are described as being associated with forceps delivery both vaginally and with caesarean section but are much rarer without instrumentation. This obvious abnormality was very concerning for the parents as it was not picked up on antenatal scans and there was no clear cause. There were both cosmetic and neurological concerns and we found no clear consensus on appropriate treatment and prognosis in the literature we had available. PMID- 25694630 TI - Peritoneal lymphomatosis: a rare presentation of follicular lymphoma mimicking peritoneal carcinomatosis. AB - Patients presenting with ascites associated with peritoneal disease have a wide differential diagnosis including both malignant and non-malignant related causes. We present the unusual case of a patient, clinically deteriorating, whose malignant peritoneal disease was due to an underlying follicular lymphoma. An urgent staging CT scan followed by a peritoneal biopsy allowed the patient to start chemotherapy within days of acute presentation to the hospital. This case emphasises the importance of obtaining tissue diagnosis urgently in these patients to ensure that the correct treatment can be started in a timely manner. PMID- 25694631 TI - Cardiac arrest following acute puerperal uterine inversion. AB - Although uterine inversion is a potentially life-threatening complication of childbirth, there are only six case reports of cardiac arrest due to acute inversion to date. We report a successful outcome in a patient with sickle cell disease who had a witnessed cardiac arrest due to acute puerperal uterine inversion. Revival from cardiac arrest and resuscitation was followed by manual repositioning of the uterus. She gradually recovered from the acute kidney injury that developed as sequelae of the cardiac arrest and subsequent circulatory shock. Awareness of this rare complication and timely intervention is the key to a successful outcome in these patients. PMID- 25694632 TI - Pneumatosis intestinalis an increasingly common radiological finding, benign or life-threatening? A case series. AB - This case series reviews two cases where elderly patients were found to have pneumatosis intestinalis on imaging. The two clinical presentations differed from one another, however, both were managed conservatively to good effect. In case one the patient presented with abdominal pain, a change in bowel habit and weight loss. In case two the patient presented with problematic diarrhoea, reduced oral intake, lethargy and weight loss. Both patients were haemodynamically stable and neither had an abnormal abdominal examination. Case 2 was started on oral metronidazole and by day 11 of treatment there was resolution of the pneumatosis on her abdominal X-ray and her diarrhoea had settled. These two cases illustrate the benefit of conservative management and avoidance of unnecessary surgical intervention in primary pneumatosis intestinalis. However, it is important to distinguish between these benign causes of pneumatosis intestinalis and those which are life-threatening in which surgery may be necessary. PMID- 25694633 TI - A pain in the joints. AB - Arthralgia is a rare but recognised complication of meningococcal septicaemia. We report a case of a 29-year-old man presenting with a 24 h history of fever, joint swelling and subsequent development of a non-blanching, petechial rash. He was treated for probable meningococcal septicaemia and the causative pathogen was later identified as Neisseria meningitidis. He was treated with ceftriaxone and after 10 days the pain and swelling in his joints improved. PMID- 25694634 TI - Atypical isolated nuclear oculomotor nerve syndrome: a diagnostic challenge. PMID- 25694635 TI - Eruptive furunculosis following the soak and smear regimen. AB - The 'soak and smear' regimen is a highly effective method for localised topical therapy employed by dermatologists for widespread inflammatory skin conditions. The regimen involves application of topical medication under occlusion after soaking in water. Complications from this treatment method are rare. We present a case of multiple, generalised methicillin-resistant Staphylococcus aureus (MRSA) positive furuncles arising in a patient as an unexpected consequence of therapy. The case highlights an unanticipated risk of a commonly employed treatment amid an epidemic of MRSA in the community. PMID- 25694636 TI - The successful use of lipectomy in the management of airway obstruction in a woman with HIV-associated lipodystrophy. AB - Lipodystrophy is a common complication of highly active antiretroviral therapy and is associated with significant comorbidities. Altered fat distribution, particularly lipohypertrophy of the dorsal cervical fat pad is associated with reduced quality of life as well as medical complications. We report the rare case of a patient with airway obstruction secondary to HIV-associated lipodystrophy. Ultrasound-assisted liposuction was successfully performed to relieve her airway obstruction and to facilitate a tracheostomy. To the best of our knowledge, this is the first documented case of its kind. We also provide a brief review of the literature on the current management options for HIV-associated lipodystrophy. PMID- 25694637 TI - Transcaval ureter: a rare embryological anomaly causing obstructive uropathy. AB - A 21-year-old woman presented with a longstanding history of episodic right flank pain related to fluid consumption and recurrent urinary tract infections. On examination, there was right costovertebral angle tenderness. Renal tract ultrasound demonstrated hydronephrosis and CT urography confirmed transcaval ureter. The patient's clinical presentation was likely due to obstruction associated with the right ureter passing through the opening created by the duplicated segment of the inferior vena cava. While asymptomatic transcaval ureter can be managed conservatively, severe symptoms or complications of ureteric obstruction may require surgical treatment. In this case, treatment comprised a laparoscopic ureteroureterostomy with an end-to-end anastomosis between the proximal and distal sections of the right ureter. The patient's postoperative recovery was uneventful and she reported resolution of the flank pain during the one year of follow-up. PMID- 25694638 TI - Correction of neglected vertical talus deformity in an adult. AB - Congenital vertical talus is an uncommon foot deformity that is characterised by a fixed dorsal dislocation of the navicular on the talar head and neck. Left untreated, a congenital vertical talus causes significant long-term disability. We present a case of neglected vertical talus in a middle-aged woman who was successfully treated with resection of the talar head and tendon transfers. PMID- 25694639 TI - Acute scrotal pain and priapism: an early sign of progression in metastatic renal cell carcinoma? AB - A 43 -year-old man was treated with pazopanib for metastatic renal cell carcinoma (RCC) with imaging studies suggesting a partial response to treatment. However, the patient presented numerous times with severe testicular pain and gradually increasing priapism. He underwent an inguinal orchidectomy for symptom control. Histopathology confirmed invasion of the cord and tunica vaginalis with metastatic RCC. Further CT of the abdomen and pelvis suggested non-progression of the disease. The patient continued to develop priapism for several weeks before imaging studies confirmed disease progression; a month later the patient died. Genital involvement in metastatic RCC is unusual but should alert clinicians to the possibility of disease progression. PMID- 25694640 TI - Sinonasal melanoma arising from conjunctival primary acquired melanosis. AB - A 66-year-old woman was treated with excision and cryotherapy for recurrent primary acquired melanosis (PAM) with atypia of the right conjunctiva. Four years later, she developed a melanoma of the ipsilateral inferior turbinate and nasolacrimal duct. She was treated with right medial maxillectomy and postoperative radiation therapy. This is the first reported case of conjunctival PAM resulting in delayed progression to melanoma in the nasolacrimal duct and sinonasal cavity. PMID- 25694641 TI - Allergic reaction to polysulphone membrane dialyser masquerading as infection. AB - Hypersensitivity reactions during haemodialysis are well documented in the literature. Most dialysis membrane reactions occur with ethylene oxide or non biocompatible membranes and less frequently with biocompatible membranes. The symptoms are non-specific except for the temporal relationship typically occurring during the haemodialysis. Patients who present with the non-classic type of reaction pose a diagnostic challenge and clinicians must have a high index of suspicion. We present a non-classic presentation of a hypersensitivity reaction to a polysulfone membrane dialyser with recurrent fevers during and after haemodialysis, initially thought to be due to infection. After a series of negative work ups for infection, dialysis membrane reaction was considered and the patient improved after change of the membrane. PMID- 25694642 TI - CT pleurogram for diagnosing an occult diaphragmatic tear. AB - A 27-year-old man road traffic accident victim, in his initial CT, showed fractures in left lower ribs, pleural effusion and splenic and pancreatic lacerations. The left pleural effusion, drained with an intercostal tube, did not show any significant reduction in size and pleural fluid amylase was abnormally high. A diaphragmatic tear was suspected. Contrast was injected through the intercostal tube and a CT was performed, which revealed a small diaphragmatic tear and communication of the pleural space with peritoneum and the pancreatic laceration site. PMID- 25694643 TI - Sternoclavicular septic arthritis due to methicillin-resistant Staphylococcus aureus in a patient with a suprapubic catheter. AB - We report a case of a 74-year-old man who presented to the emergency department with a 1-week history of fever. He had a meatal stenosis and had a suprapubic catheter for 10 months, and had a recent hospitalisation for urosepsis with bacteraemia due to methicillin-resistant Staphylococcus aureus after manipulation of the catheter. Clinical examinations were performed in the emergency department and the patient was hospitalised with the diagnosis of recurrent urinary tract infection. The following day, we noticed the development of a mass in the left sternoclavicular joint with inflammatory signs and excruciating pain. Ultrasonographic findings led to the diagnosis of left sternoclavicular synovitis, and methicillin-resistant S. aureus grew in blood cultures leading to the diagnosis of sternoclavicular septic arthritis. Treatment with vancomycin and gentamicin was started and maintained for 4 weeks with complete resolution of symptoms and no complications or sequelae. PMID- 25694644 TI - 3D reconstruction is important when evaluating MAPCAs for unifocalisation. PMID- 25694645 TI - Reactivation of Clostridium tertium bone infection 30 years after the Iran-Iraq war. PMID- 25694646 TI - Transient cardiogenic shock during a crisis of pheochromocytoma triggered by high dose exogenous corticosteroids. AB - We report a case of a 39-year-old woman who presented to the emergency department (ED) with symptoms of pharyngitis and fever. Diagnosed with streptococcal pharyngitis, she received antibiotics and dexamethasone, and was discharged. Within 24 h she returned to the ED with signs and symptoms of an acute coronary syndrome; she was thus given beta-blockers. Her coronary angiogram was normal. She developed cardiogenic shock with an ejection fraction (EF) of 10% and apical ballooning on echocardiography. Her condition improved with optimal medical therapy. Subsequent testing weeks later confirmed the presence of a pheochromocytoma. Following prazosin and an adrenalectomy, all her antihypertensive medications were weaned and her EF normalised. We believe the high-dose exogenous corticosteroids triggered a pheochromocytoma crisis. The concomitant use of beta-blockers without preceding alpha blockade resulted in cardiovascular collapse. Pheochromocytoma crisis must be included in the differential diagnosis of any dramatic haemodynamic collapse after administration of exogenous corticosteroid or beta-blockers. PMID- 25694647 TI - Immunoproteomic Identification of In Vivo-Produced Propionibacterium acnes Proteins in a Rabbit Biofilm Infection Model. AB - Propionibacterium acnes is well-known as a human skin commensal but can also act as an invasive pathogen causing implant-associated infections. In order to resolve these types of P. acnes infections, the implants must be removed, due to the presence of an established biofilm that is recalcitrant to antibiotic therapy. In order to identify those P. acnes proteins produced in vivo during a biofilm infection, we established a rabbit model of implant-associated infection with this pathogen. P. acnes biofilms were anaerobically grown on dextran beads that were then inoculated into the left tibias of rabbits. At 4 weeks postinoculation, P. acnes infection was confirmed by radiograph, histology, culture, and PCR. In vivo-produced and immunogenic P. acnes proteins were detected on Western blot using serum samples from rabbits infected with P. acnes after these bacterial proteins were separated by two-dimensional gel electrophoresis. Those proteins that bound host antibodies were then isolated and identified by tandem mass spectrometry. Radiographs and histology demonstrated a disruption in the normal bone architecture and adherent biofilm communities in those animals with confirmed infections. A total of 24 immunogenic proteins were identified; 13 of these proteins were upregulated in both planktonic and biofilm modes, including an ABC transporter protein. We successfully adapted a rabbit model of implant-associated infection for P. acnes to identify P. acnes proteins produced during a chronic biofilm-mediated infection. Further studies are needed to evaluate the potential of these proteins for either a diagnostic test or a vaccine to prevent biofilm infections caused by P. acnes. PMID- 25694649 TI - Incident Hepatitis C Virus Infections Among Users of HIV Preexposure Prophylaxis in a Clinical Practice Setting. PMID- 25694650 TI - Risk of Misinterpretation of Ebola Virus PCR Results After rVSV ZEBOV-GP Vaccination. PMID- 25694651 TI - Submicroscopic Plasmodium falciparum Infections Are Associated With Maternal Anemia, Premature Births, and Low Birth Weight. AB - BACKGROUND: Molecular, as opposed to microscopic, detection measures the real prevalence of Plasmodium falciparum infections. Such occult infections are common during pregnancy but their impact on pregnancy outcomes is unclear. We performed a longitudinal study to describe that impact. METHODS: In a cohort of 1037 Beninese pregnant women, we used ultrasound to accurately estimate gestational ages. Infection with P. falciparum, hemoglobin concentration, use of intermittent preventive treatment during pregnancy (IPTp) for malaria, and other parameters were recorded during pregnancy. Using multivariate analyses, we evaluated the impact of submicroscopic infections on maternal anemia, premature birth, and low birth weight. RESULTS: At inclusion, polymerase chain reaction (PCR) and microscopy detected infection in 40% and 16% of women, respectively. The proportion infected declined markedly after 2 doses of IPTp but rebounded to 34% (by PCR) at delivery. Submicroscopic infections during pregnancy were associated with lower mean hemoglobin irrespective of gravidity, and with increased anemia risk in primigravidae (odds ratio [OR], 2.23; 95% confidence interval [CI], .98 5.07). Prospectively, submicroscopic infections at inclusion were associated with significantly increased risks of low birth weight in primigravidae (OR, 6.09; 95% CI, 1.16-31.95) and premature births in multigravidae (OR, 2.25; 95% CI, 1.13 4.46). CONCLUSIONS: In this detailed longitudinal study, we document the deleterious impact of submicroscopic P. falciparum parasitemia during pregnancy on multiple pregnancy outcomes. Parasitemia occurs frequently during pregnancy, but routine microscopic and rapid diagnostic tests fail to detect the vast majority of episodes. Our findings imply caution in any revision of the current strategies for prevention of pregnancy-associated malaria. PMID- 25694652 TI - Nosocomial transmission of severe fever with thrombocytopenia syndrome in Korea. AB - Of the 27 healthcare workers (HCWs) who had contact with a fatally ill patient with severe thrombocytopenia syndrome in Korea (SFTS), 4 who were involved in cardiopulmonary resuscitation complained of fever and were diagnosed with SFTS via seroconversion. Exposure to respiratory secretions, blood, or gowns soiled by body fluids was significantly associated with infection of HCWs. PMID- 25694653 TI - Lopinavir/Ritonavir Monotherapy as Second-line Antiretroviral Treatment in Resource-Limited Settings: Week 104 Analysis of AIDS Clinical Trials Group (ACTG) A5230. AB - BACKGROUND: The AIDS Clinical Trials Group (ACTG) A5230 study evaluated lopinavir/ritonavir (LPV/r) monotherapy following virologic failure (VF) on first line human immunodeficiency virus (HIV) regimens in Africa and Asia. METHODS: Eligible subjects had received first-line regimens for at least 6 months and had plasma HIV-1 RNA levels 1000-200 000 copies/mL. All subjects received LPV/r 400/100 mg twice daily. VF was defined as failure to suppress to <400 copies/mL by week 24, or confirmed rebound to >400 copies/mL at or after week 16 following confirmed suppression. Subjects with VF added emtricitabine 200 mg/tenofovir 300 mg (FTC/TDF) once daily. The probability of continued HIV-1 RNA <400 copies/mL on LPV/r monotherapy through week 104 was estimated with a 95% confidence interval (CI); predictors of treatment success were evaluated with Cox proportional hazards models. RESULTS: One hundred twenty-three subjects were enrolled. Four subjects died and 2 discontinued prematurely; 117 of 123 (95%) completed 104 weeks. Through week 104, 49 subjects met the primary endpoint; 47 had VF, and 2 intensified treatment without VF. Of the 47 subjects with VF, 41 (33%) intensified treatment, and 39 of 41 subsequently achieved levels <400 copies/mL. The probability of continued suppression <400 copies/mL over 104 weeks on LPV/r monotherapy was 60% (95% CI, 50%-68%); 80%-85% maintained levels <400 copies/mL with FTC/TDF intensification as needed. Ultrasensitive assays on specimens with HIV-1 RNA level <400 copies/mL at weeks 24, 48, and 104 revealed that 61%, 62%, and 65% were suppressed to <40 copies/mL, respectively. CONCLUSIONS: LPV/r monotherapy after first-line VF with FTC/TDF intensification when needed provides durable suppression of HIV-1 RNA over 104 weeks. CLINICAL TRIALS REGISTRATION: NCT00357552. PMID- 25694654 TI - Predictive value of prior colonization and antibiotic use for third-generation cephalosporin-resistant enterobacteriaceae bacteremia in patients with sepsis. AB - BACKGROUND: To prevent inappropriate empiric antibiotic treatment in patients with bacteremia caused by third-generation cephalosporin (3GC)-resistant Enterobacteriaceae (3GC-R EB), Dutch guidelines recommend beta-lactam and aminoglycoside combination therapy or carbapenem monotherapy in patients with prior 3GC-R EB colonization and/or recent cephalosporin or fluoroquinolone usage. Positive predictive values (PPVs) of these determinants are unknown. METHODS: We retrospectively studied patients with a clinical infection in whom blood cultures were obtained and empiric therapy with broad-spectrum beta-lactams and/or aminoglycosides and/or fluoroquinolones was started. We determined the PPVs of prior colonization and antibiotic use for 3GC-R EB bacteremia, and the consequences of guideline adherence on appropriateness of empiric treatment. RESULTS: Of 9422 episodes, 773 (8.2%) were EB bacteremias and 64 (0.7%) were caused by 3GC-R EB. For bacteremia caused by 3GC-R EB, PPVs of prior colonization with 3GC-R EB (90-day window) and prior usage of cephalosporins or fluoroquinolones (30-day window) were 7.4% and 1.3%, respectively, and PPV was 1.8% for the presence of any of these predictors. Adherence to Dutch sepsis guideline recommendations was 27%. Of bacteremia episodes caused by 3GC-R and 3GC sensitive EB, 56% and 94%, respectively, were initially treated with appropriate antibiotics. Full adherence to guideline recommendations would hardly augment proportions of appropriate therapy, but could considerably increase carbapenem use. CONCLUSIONS: In patients receiving empiric treatment for sepsis, prior colonization with 3GC-R EB and prior antibiotic use have low PPV for infections caused by 3GC-R EB. Strict guideline adherence would unnecessarily stimulate broad-spectrum antibiotic use. PMID- 25694655 TI - Corrigendum to 'Biomolecular and clinical practice in malignant pleural mesothelioma and lung cancer: what thoracic surgeons should know'. PMID- 25694656 TI - Mitral valve surgery after percutaneous mitral commissurotomy: is repair still feasible? AB - OBJECTIVES: Due to progression of rheumatic disease, percutaneous mitral commissurotomy (PMC) is a palliative procedure. We aimed at evaluating the outcomes of patients requiring surgery for failure of PMC, focusing on the fate of the mitral valve (MV) (repair versus replacement). METHODS: From January 1993 through December 2012, 61 patients with previous PMC were submitted to MV surgery. Detailed operative findings were collected from all patients and an intraoperative anatomical score was introduced to predict reparability. Time to surgery, overall survival and freedom from reoperation were analysed. RESULTS: The mean time to surgery after PMC was 6.9+/-5.9 years and indications were restenosis in 25 patients (41%) and mitral regurgitation or mixed lesion in 36 (59%). Nine patients (14.8%) had more than one previous intervention. Intraoperative inspection of the valve revealed leaflet laceration outside the commissural area in 27 patients (44.3%). Valve repair was accomplished in 38 patients (62.3%). Pulmonary hypertension, calcification and intraoperative anatomical score were independently associated with the probability of valve replacement (OR 1.12, OR 7.03 and OR 4.49, respectively, P<0.05). There was no hospital mortality. MV area increased on average 1.6 cm2 after surgery to 2.7 cm2; 5-, 10- and 20-year survival rates were 98.1+/-1.9, 91+/-5.2 and 82.7+/ 9.2%, respectively. The rate of freedom from mitral reoperation (for repaired cases) at 5, 10 and 15 years was 100, 95.8+/-4.1 and 87.8+/-8.5%, respectively. There was no difference in survival between repaired or replaced MVs, but the former had less valve-related events during follow-up. CONCLUSION: The MV can be repaired after failed PMC, with very low complication rates and excellent long term results. Hence, whenever possible, these patients should be sent to reference centres where repair can be successfully achieved. PMID- 25694657 TI - Experience with mitral valve surgery after percutaneous mitral commissurotomy. PMID- 25694658 TI - "Mental health and veterinary suicides" - a comment. PMID- 25694659 TI - Antibiotic stewardship's golden moment: resistance or change? PMID- 25694660 TI - Ethical question of the month - February 2015. PMID- 25694661 TI - Mycoplasma hominis ssp. associated endocarditis with myocardial necrosis in an alpaca (Vicugna pacos) in Manitoba in 2011. AB - Severe endocarditis with myonecrosis, moderate to severe pleural and pericardial effusions, and mild ascites were found on necropsy in 3 alpacas. Mycoplasma hominis ssp. was detected on polymerase chain reaction (PCR) of fresh affected endocardial tissue in 1 alpaca. PMID- 25694662 TI - Surgical treatment of canine stifle disruption using a novel extracapsular articulated stifle stabilizing implant. AB - A 5-year-old Labrador retriever mixed breed dog was presented for an acute non weight-bearing left hind limb lameness. A stifle disruption was diagnosed. The patient was treated using a novel extracapsular articulated stifle stabilizing implant (SimitriTM). Twelve weeks after surgery the patient had full range of motion of the affected stifle and had begun to return to pre-injury activity. This is the first reported case of this condition being surgically managed successfully in this manner. PMID- 25694663 TI - The first case of porcine epidemic diarrhea in Canada. AB - In January, 2014, increased mortality was reported in piglets with acute diarrhea on an Ontario farm. Villus atrophy in affected piglets was confined to the small intestine. Samples of colon content were PCR-positive for porcine epidemic diarrhea virus (PEDV). Other laboratory tests did not detect significant pathogens, confirming this was the first case of PED in Canada. PMID- 25694664 TI - Laparoscopic-assisted cryptorchidectomy in 2 Vietnamese pot-bellied pigs (Sus scrofa). AB - This report describes laparoscopic-assisted cryptorchidectomy in 2 Vietnamese pot bellied pigs. Abdominal access was obtained by a modified-Hasson technique allowing for placement of a 6 mm laparoscopic trocar-cannula assembly. Following carbon dioxide insufflation, 2 para-preputial 6 mm instrument portals were established. The cryptorchid testicle was extracted from the abdomen following enlargement of the para-preputial instrument portal and cryptorchidectomy was performed extra-corporeally. PMID- 25694665 TI - Comminuted fracture of the accessory carpal bone removed via an arthroscopic assisted arthrotomy. AB - A 16-year-old American paint horse gelding was presented for evaluation of a left forelimb lameness grade III/V. Radiographs and computed tomography revealed a comminuted fracture of the accessory carpal bone involving the entire articulation with the distal radius and the proximal aspect of the articulation with the ulnar carpal bone. Multiple fragments were present in the palmar pouch of the antebrachiocarpal joint. An arthroscopic-assisted open approach was necessary to remove all fractured fragments. Subsequently the horse was re admitted for lameness and was treated successfully with antibiotics and long-term supportive bandaging. PMID- 25694666 TI - Demographics of the Canadian cow-calf industry for the period 1991 to 2011. AB - The Canadian cow-calf sector is about to undergo major transformative change because of shifts in Canada's population demographics. To understand the impact of this change on the Canadian beef cow-calf sector, Statistics Canada census data from 1991 to 2011 were analyzed for trends. From 2006 to 2011, the number of Canadian cow-calf producers and operations decreased by 24.6% and 26.0%, respectively. Furthermore, as of 2011, 61.9% of producers were > 50 y of age. The number of cow-calf producers is positioned to decrease by another 40% by 2021. If Canada's cow-calf industry is to maintain its current levels of production then the average herd size will need to increase markedly. The shift towards fewer but larger operations will impact the type of veterinary services demanded by cow calf producers, and the number of veterinarians required to service this industry. Veterinary colleges will need to examine whether they are producing graduates who will meet the changing demands of livestock producers. PMID- 25694667 TI - A systematic review of risk factors associated with the introduction of Mycobacterium avium spp. paratuberculosis (MAP) into dairy herds. AB - The objective of this study was to systematically collect and appraise the scientific evidence related to risk factors associated with the introduction of Mycobacterium avium spp. paratuberculosis (MAP) into a herd of cattle. An electronic search was conducted to collect relevant references addressing 2 specific questions: are i) purchasing/introduction of cattle into a herd, and ii) presence of wildlife or domestic animals, risk factors for the introduction of MAP into a herd? The screening was based on titles and abstracts and selected studies were fully analyzed. Seventeen manuscripts published between 1996 and 2011 were ultimately analyzed. Unit of interest was mainly the herd (n = 17). The specific description of the risk factors studied varied between studies. The principal study design was cross-sectional (n = 15). The review indicated that purchase/introduction of animals was an important risk factor and that the importance of wildlife or other domestic species as a mechanism for transmission into a cattle herd was not measurable. PMID- 25694668 TI - Plasma serotonin in horses undergoing surgery for small intestinal colic. AB - This study compared serotonin concentrations in platelet poor plasma (PPP) from healthy horses and horses with surgical small intestinal (SI) colic, and evaluated their association with postoperative ileus, strangulation and non survival. Plasma samples (with EDTA) from 33 horses with surgical SI colic were collected at several pre- and post-operative time points. Serotonin concentrations were determined using liquid-chromatography tandem mass spectrometry. Results were compared with those for 24 healthy control animals. The serotonin concentrations in PPP were significantly lower (P < 0.01) in pre- and post-operative samples from surgical SI colic horses compared to controls. However, no association with postoperative ileus or non-survival could be demonstrated at any time point. In this clinical study, plasma serotonin was not a suitable prognostic factor in horses with SI surgical colic. PMID- 25694669 TI - Computed tomography or rhinoscopy as the first-line procedure for suspected nasal tumor: a pilot study. AB - There are no evidence-based guidelines as to whether computed tomography (CT) or endoscopy should be selected as the first-line procedure when a nasal tumor is suspected in a dog or a cat and only one examination can be performed. Computed tomography and rhinoscopic features of 17 dogs and 5 cats with a histopathologically or cytologically confirmed nasal tumor were retrospectively reviewed. The level of suspicion for nasal neoplasia after CT and/or rhinoscopy was compared to the definitive diagnosis. Twelve animals underwent CT, 14 underwent rhinoscopy, and 4 both examinations. Of the 12 CT examinations performed, 11 (92%) resulted in the conclusion that a nasal tumor was the most likely diagnosis compared with 9/14 (64%) for rhinoscopies. Computed tomography appeared to be more reliable than rhinoscopy for detecting nasal tumors and should therefore be considered as the first-line procedure. PMID- 25694670 TI - Outcome of medial patellar ligament desmoplasty for treatment of intermittent upward fixation of the patella in 24 horses (2005-2012). AB - This retrospective study provides long-term results of medial patellar ligament (MPL) desmoplasty in horses with intermittent upward fixation of the patella (UFP) that were treated at a single referral hospital over a 7-year period. Follow-up interviews were conducted with owners, trainers, or referring veterinarians using a standardized questionnaire. Overall, 71% of horses returned to their intended use with only 18% at a higher level. Recurrence of UFP was noted in 33% of cases. Satisfaction with the procedure was generally low, with only 50% of owners being completely satisfied. Further investigation is warranted to determine appropriate medical and/or surgical therapy. PMID- 25694671 TI - What can't be taught. PMID- 25694672 TI - The double gold standards. PMID- 25694673 TI - Novel trends in development of dietary fiber rich meat products-a critical review. AB - Meat and meat products are generally recognized as good sources of high biological value proteins, fat-soluble vitamins, minerals, trace elements and bioactive compounds. Changes in socioeconomic factors in recent years have increased the consumer's preference for ready to eat foods including meat products. The processing of meat and meat products leads to generation of many functional compounds beneficial to human health but most of those foods are rich in fat, added salts but deficient in complex carbohydrates like dietary fiber and pose a health hazard that somehow is proved to be a predisposing factor for cardiovascular diseases, colon cancer, obesity including diabetes mellitus. With increasing consciousness among consumers about their nutrition and well being, there is a growing concern over nutritional diseases of affluence. Therefore an increase in dietary fiber inclusion in daily diet has been recommended. For adults, the recommended acceptable intakes of dietary fiber are 28-36 g/day, 70 80 % of which must be insoluble fiber. The insoluble fraction of dietary fiber has been related to intestinal regulation whereas soluble fiber is associated with decrease in cholesterol level and absorption of intestinal glucose. So incorporation of dietary fibers from different sources in meat products would help to enhance their desirability. Dietary fiber sources are generally agricultural byproducts that are comparatively cheap and incorporation in meat products reduces its overall cost. Whole grains and cereal brans are the rich source of insoluble fiber and pectins, gums, starch and other storage polysaccharides have high content of the soluble fraction. With this background, the effect of various dietary fibers on the quality attributes of meat and meat products with its physiological role has been reviewed here. PMID- 25694674 TI - Development of fish protein powder as an ingredient for food applications: a review. AB - The increasing awareness that dried fish protein can be applied for food fortification and production of value added/functional foods has encouraged the food industry to examine different methods for developing fish protein ingredient from different raw materials. Fish protein powder (FPP) is a dried and stable fish product, intended for human consumption, in which the protein is more concentrated than in the original fish flesh. Quality and acceptability of FPP depend on several factors. The fat content of the FPP is a critical issue because when it is oxidized a strong and often rancid flavour is produced. Protein content of FPP depends on the raw materials, amount of additives and moisture content, but it contains at least 65 % proteins. FPP is used in the food industry for developing re-structured and ready-to-eat food products. The FPP maintains its properties for 6 months at 5 degrees C but loses them rapidly at 30 degrees C. Deterioration of the FPP during storage is prevented by lowering the moisture content of the product and eliminating of oxygen from the package. The FPP can be applied as a functional ingredient for developing formulated ready-to-eat products. This article reviews methods for extracting fish proteins, drying methods, characteristics and applications of FPP and factors affecting FPP quality. PMID- 25694675 TI - Nutritional advantages of oats and opportunities for its processing as value added foods - a review. AB - Oats (Avena sativa L.) have received considerable attention for their high content of dietary fibres, phytochemicals and nutritional value. It is believed that consumption of oats possesses various health benefits such as hypocholesterolaemic and anticancerous properties. Oats have also recently been considered suitable in the diet of celiac patients. Owing to their high nutritional value, oat-based food products like breads, biscuits, cookies, probiotic drinks, breakfast cereals, flakes and infant food are gaining increasing consideration. Research and development on oat and its products may be helpful in combating various diseases known to mankind. This paper provides an overview of the nutritional and health benefits provided by oats as whole grains and its value added products. It is designed to provide an insight on the processing of oats and its effect on their functional properties. The manuscript also reviews various uses of oats and its fractions for clinical and industrial purposes and in development of value added food products. PMID- 25694676 TI - Reduction of phytic acid and enhancement of bioavailable micronutrients in food grains. AB - More than half of the world populations are affected by micronutrient malnutrition and one third of world's population suffers from anemia and zinc deficiency, particularly in developing countries. Iron and zinc deficiencies are the major health problems worldwide. Phytic acid is the major storage form of phosphorous in cereals, legumes, oil seeds and nuts. Phytic acid is known as a food inhibitor which chelates micronutrient and prevents it to be bioavailabe for monogastric animals, including humans, because they lack enzyme phytase in their digestive tract. Several methods have been developed to reduce the phytic acid content in food and improve the nutritional value of cereal which becomes poor due to such antinutrient. These include genetic improvement as well as several pre-treatment methods such as fermentation, soaking, germination and enzymatic treatment of grains with phytase enzyme. Biofortification of staple crops using modern biotechnological techniques can potentially help in alleviating malnutrition in developing countries. PMID- 25694677 TI - Palm-based medium-and-long-chain triacylglycerol (P-MLCT): production via enzymatic interesterification and optimization using response surface methodology (RSM). AB - Structured lipid such as medium-and long-chain triacylglycerol (MLCT) is claimed to be able to suppress body fat accumulation and be used to manage obesity. Response surface methodology (RSM) with four factors and three levels (+1,0,-1) faced centered composite design (FCCD) was employed for optimization of the enzymatic interesterification conditions of palm-based MLCT (P-MLCT) production. The effect of the four variables namely: substrate ratio palm kernel oil: palm oil, PKO:PO (40:60-100:0 w/w), temperature (50-70 degrees C), reaction time (0.5 7.5 h) and enzyme load (5-15 % w/w) on the P-MLCT yield (%) and by products (%) produced were investigated. The responses were determined via acylglycerol composition obtained from high performance liquid chromatography. Well-fitted models were successfully established for both responses: P-MLCT yield (R (2) = 0.9979) and by-products (R (2) = 0.9892). The P-MLCT yield was significantly (P < 0.05) affected by substrate ratio, reaction time and reaction temperature but not enzyme load (P > 0.05). Substrate ratio PKO: PO (100:0 w/w) gave the highest yield of P-MLCT (61 %). Nonetheless, substrate ratio of PKO: PO (90:10w/w) was chosen to improve the fatty acid composition of the P-MLCT. The optimized conditions for substrate ratio PKO: PO (90:10 w/w) was 7.26 h, 50 degrees C and 5 % (w/w) Lipozyme TLIM lipase, which managed to give 60 % yields of P-MLCT. Up scaled results in stirred tank batch reactor gave similar yields as lab scale. A 20 % increase in P-MLCT yield was obtained via RSM. The effect of enzymatic interesterification on the physicochemical properties of PKO:PO (90:10 w/w) were also studied. Thermoprofile showed that the P-MLCT oil melted below body temperature of 37 degrees C. PMID- 25694678 TI - The spatial distribution of beta-carotene impregnated in apple slices determined using image and fractal analysis. AB - Changes in the concentration profiles of beta-carotene caused by diffusion through parenchymatic dried apple tissue were characterized by image and fractal analysis. Apple slices were dried by convection, and then impregnated with an aqueous beta-carotene solution. Scanning electron microscopy images of dried apple slices were captured and the fractal dimension (FD) values of the textures of the images were obtained (FDSEM). It was observed that the microstructure of the foodstuff being impregnated have an important effect on the impregnation phenomenon, generating irregular concentration profiles of beta-carotene, which are numerically described by the fractal dimension FDPROFILES and are related to the diffusion process during impregnation in dried edible tissue. PMID- 25694679 TI - Optimization of processing parameters and ingredients for development of low-fat fibre-supplemented paneer. AB - Increasing demand of low calorie and high fibre containing products give impetus to dairy industry for development of a well palatable low calorie dairy products like paneer. The objective of the present study was to develop low-fat fibre supplemented paneer. The ingredients were chosen for low-fat fibre- supplemented paneer to reduce the cost and calorie content besides providing the functional benefits. Optimization of ingredients was carried out in terms of independent variables viz wheat bran (0.4-0.8 %), maltodextrin (1-5 %), coagulation temperature (60-80 degrees C) and amount of citric acid solution (150-210 ml). Response Surface Methodology (RSM) was used to design the experiments and to select the optimum levels of ingredients. Paneer was made by using different levels of ingredients by coagulating hot milk using citric acid solution followed by pressing and dipping in chilled water for texturization. These parameters were evaluated in terms of physico-chemical parameters viz water activity, pH and acidity. Instrumental texture profile analysis (TPA) of paneer during optimization trials was done using TAXT 2i Texture Analyzer. The textural responses namely hardness, adhesiveness, springiness, cohesiveness, gumminess and chewiness were measured via Texture Analyzer. The sensory properties namely flavor, appearance, body and texture, mouth feel and overall acceptability of paneer samples were evaluated by a semi-trained panel of judges using 9-point hedonic scale. Full second order polynomial was developed to predict each response. All the textural and sensory responses were statistically analysed. PMID- 25694680 TI - Polyphenols from fresh frozen tea leaves (Camellia assamica L.,) by supercritical carbon dioxide extraction with ethanol entrainer - application of response surface methodology. AB - Fresh frozen tea leaves (Camellia assamica L.) were extracted with SC-CO2 to obtain polyphenols rich in EGCG and compared with conventional solvent extraction. Extraction parameters such as temperature, pressure and solvent to material ratio were critical factors in extraction and optimized by response surface methodology (RSM). The maximum yield of extractable solids using SC-CO2 with ethanol entrainer was carried out at pressures 150 to 350 bar, temperatures from 40 degrees C to 60 degrees C and solvent to material ratio 100 to 200. The theoretical yield was 3.91 % (w/w), while experimental yield was 4.20 +/- 0.27 % (w/w) at temperature of 50 degrees C, pressure 250 bar and solvent to material ratio of 200. The chemical compositions of extracted solids were investigated by HPLC which showed 722.68-848.09 +/- 1.12 mg of EGCG/g of extractable solids were separated in SC-CO2. Also, 54.62 +/- 1.19 mg of EGCG/g of extractable solids was separated using conventional extraction which is quantitatively lesser than SC CO2 extraction yield. Thus, SC-CO2 extraction was proved to be effective technique in obtaining extracts rich in EGCG (>95 %). PMID- 25694681 TI - Utilization of chitosan as an antimicrobial agent for pasteurized palm sap (Borassus flabellifer Linn.) during storage. AB - The objective of this research was to assess the potential of chitosan for improvement the quality of pasteurized palm sap during storage. First, the effect of chitosan content on sensory attributes was investigated to select suitable concentration of chitosan for further study. Fresh palm sap was enriched with chitosan at various concentrations (0-2 g/L) and pasteurized at 80 degrees C for 10 min, consequently evaluated by consumers. It was found that samples added chitosan in the range of 0-1.00 g/L were considered acceptable. Thus, the addition chitosan in the concentration of 0-1.00 g/L was chosen for further study. The sample without chitosan addition was used as a control sample. Each selected sample was determined for their qualities during storage at 1 week interval. It was found that lightness and transmittance values of all samples tended to increase during storage. Lower PPO and invertase activity were observed in all chitosan-treated samples compared to control sample. Chitosan could minimize the loss of sucrose and the increase in glucose and fructose content during storage. In addition, an increase in chitosan concentration resulted in the increase in DPPH radical scavenging activity. Furthermore, the addition of chitosan could retard the development of microorganism during storage as demonstrated by lower microbial loads compared to control sample. It can be concluded that a combination of pasteurization with chitosan addition (0.50 g/L) and low temperature storage could preserve palm sap for approximately 6 weeks. Thus, the incorporation of chitosan in palm sap could be used as an alternative way to extend shelf life of pasteurized palm sap. PMID- 25694682 TI - Antioxidant and functional properties of tea protein as affected by the different tea processing methods. AB - The Box-Behnken design combined with response surface methodology was used to optimize alkali extraction of protein from tea. Three independent extraction variables (extraction time: X1; extraction temperature: X2; alkali concentration: X3) were evaluated. The antioxidant and functional properties of tea protein as affected by different tea processing were compared. The optimum conditions were: extraction time of 85 min, extraction temperature of 80 degrees C, and alkali concentration of 0.15 M. Under such conditions, the predicted maximum protein extracted yield was 20.73 %, which coincided with the experimental values. Three kinds of tea protein showed good antioxidant and functional properties. Tea processing method had a significant impact on the properties of tea protein. Protein from oolong tea showed the best properties and it might be used as a good source of potential antioxidant and additives in food industry. PMID- 25694683 TI - Effect of different pretreatments on functional properties of African catfish (Clarias gariepinus) skin gelatin. AB - Pretreatments with different types of alkali and acid were compared to determine their effects on gelatin extraction from African catfish (Clarias gariepinus) skin. The study was divided into three parts. In the first part, the skins were only treated with alkaline (Ca(OH)2 or NaOH) solution or pretreated with acetic acid solution. For second part, combination of alkali and acid pretreatment was carried out. For the third part, the skins were first treated with NaOH solution, followed by the treatment with acetic acid, citric acid or sulfuric acid solution. Functional properties including the yield of protein recovery, gel strength, viscosity, pH and viscoelastic properties were determined on gelatins obtained with different pretreatment conditions. Pretreatment with alkali removed noncollagenous proteins effectively, whilst acid pretreatment induced some loss of collagenous proteins. Combination of alkali and acid pretreatment not only removed the noncollagenous proteins and caused a significant amount of swelling, but also provided the proper pH condition for extraction, during which some cross linkages could be further destroyed but with less breakage of intramolecular peptide chains. Pretreatment of catfish skins with 0.2 N NaOH followed by 0.05 M acetic acid improved yield of protein recovery, gel strength, viscosity, melting temperature and gelling temperature of gelatin extract. PMID- 25694684 TI - Optimization of parameters for obtaining surimi-like material from mechanically separated chicken meat using response surface methodology. AB - Surimi is a semi-processed washed fish mince protein concentrate mixed with cryoprotectants for frozen storage, which is the primary constituent of processed foods. Mechanically separated chicken meat (MSCM) is a common ingredient of comminuted sausages mainly due to its low price. The present work aimed to define the adequate parameters to obtain surimi-like material from MSCM using response surface methodology, and to characterize the chemical and textural properties of this product. The MSCM was utilized in the elaboration of surimi-like material using the bleaching method with sodium bicarbonate and sodium chloride solutions. For this purpose, the effect of process parameters viz: temperature (T = 2, 7, and 12 degrees C), time (t = 5, 10, and 15 min/cycles) and washing solution:MSCM ratio (R = 2:1, 4:1, and 6:1 w/w) were evaluated using response surface methodology. The highest composite design averages obtained were 10.7 % for protein content, 1,003.4 g for breaking force, 645.8 g.cm for gel strength, 9.0 N for cutting strength, and 24.1 N.s for work of shearing at the optimum combination of processing conditions of 7 degrees C, 10 min and 4:1 washing solution:MSCM ratio, corresponding to the central points of the proposed experimental design. The obtained models had high determination coefficients, explaining 95.85, 98.23, 98.41, and 96.08 % of total variability in protein content, cutting strength, breaking force, and work of shearing variabilities, respectively. According to the folding test the surimi-like material presented the same characteristics of a high quality surimi (FT = 5). PMID- 25694685 TI - Polyphenolic rich traditional plants and teas improve lipid stability in food test systems. AB - The deleterious effects of lipid autoxidation are of major concern to the food industry and can be prevented by food antioxidants. In this vein, the phenolic contents and antioxidant potential of traditional plants of Mauritius such as P. betle L. (Piperaceae), M. koenigii L. Sprengel. (Rutaceae), O. gratissimum L. (Lamiaceae), O. tenuiflorum L. (Lamiaceae), and commercially available Mauritian green and black teas were evaluated. Their ferric reducing antioxidant power (FRAP) were compared to that of butylated hydroxytoluene (BHT) with the following order of potency: BHT > "Natural" commercial green tea > "Black Label" commercial black tea > O. gratissimum > P. betle > O. tenuiflorum > M. koenigii. The trolox equivalent antioxidant capacity (TEAC) assay reflected a similar antioxidative order for BHT and "Natural" commercial green tea, with however P. betle, O. tenuiflorum and O. gratissimum exhibiting higher activities than "Black Label" commercial black tea and M. koenigii. Based on their potent antioxidant capacity, P. betle (0.2 % m/m) and O. tenuiflorum (0.2 % m/m) extracts, and green tea (0.1 % m/m) infusate were compared with BHT (0.02 % m/m) on their ability to retard lipid oxidation in unstripped sunflower oil and mayonnaise during storage at 40 degrees C. P. betle and green tea were more effective than BHT in both food systems. Moreover, odour evaluation by a sensory panel showed that the plant extracts and green tea infusate effectively delayed the development of rancid odours in unstripped sunflower oil and mayonnaise (p < 0.05). PMID- 25694686 TI - Optimization of extraction and microencapsulation of bioactive compounds from red grape (Vitis vinifera L.) pomace. AB - Grape (Vitis vinifera L.) pomace constitutes a promising source of phenolic compounds, gallic acid, flavan-3-ols, flavonoids, stilbene and anthocyanins that are beneficial for human health. The objectives of this study were to optimize the extraction and microencapsulation of red grape pomace. Central composite designs with two factors were conducted for optimization using response surface methodology. The temperature (45-85 degrees C), and the time (2-8 h) were designed for the extraction. The results indicated that the extraction temperature and time introduced the increasing the extraction yield, total phenolic content, anthocyanin and resveratrol, but the long extraction time reduced the tannin content. The results showed that the optimize condition was the extraction at 80 +/- 1 degrees C for 2 h 53 min. This provided the highest content of polyphenolic compounds. The next experiment was microencapsulation of the extract which studied the amounts of maltodextrin (7-28 % w/v) and carboxymethylcellulose (CMC) (0-1.4 % w/v). The results showed that the optimized microencapsulation used 10.21 % w/v maltodextrin and 0.21 % w/v CMC to maximize all polyphenolic compounds, and also to minimize bitterness and astringency. This study illustrated that the optimal conditions for extraction and microencapsulation of the red grape extract have a high potential to produce functional ingredients. PMID- 25694687 TI - Recovery of functional materials with thermally stable antioxidative properties in squid muscle hydrolyzates by subcritical water. AB - Subcritical water hydrolysis was carried out to produce functional materials from squid muscle using a batch reactor. The reaction temperatures and pressures for hydrolysis of thermal dried squid muscle were maintained from 160 to 280 degrees C and 6 to 66 bar for 3 min. The ratio of material to water for hydrolysis was 1:25 (w/v) and it was stirred at 140 rpm. Hydrolysis yield was increased after increasing the temperature and pressure while the protein in hydrolyzate decreased with the rise of temperature. The reducing sugar yield was high at temperature 220 degrees C in subcritical water hydrolysis of squid muscle. Low molecular weight peptides were found in all hydrolyzates by SDS-PAGE. The highest yield of free and structural amino acid in hydrolyzate was 421.53 +/- 1.24 and 380.58 +/- 2.25 mg/100 g, respectively at 250 degrees C. All essential amino acids were identified in muscle hydrolyzates and it was high at 220 degrees C. Among the essential amino acids, leucine was the most abundant. Antioxidative properties were found in all hydrolyzates and it was high at 220 degrees C. More than 98 +/- 0.26 % ABTS antioxidant activity was retained in hydrolyzates after long time heat treatment. PMID- 25694688 TI - Quality assessment of baby food made of different pre-processed organic raw materials under industrial processing conditions. AB - The market for processed food is rapidly growing. The industry needs methods for "processing with care" leading to high quality products in order to meet consumers' expectations. Processing influences the quality of the finished product through various factors. In carrot baby food, these are the raw material, the pre-processing and storage treatments as well as the processing conditions. In this study, a quality assessment was performed on baby food made from different pre-processed raw materials. The experiments were carried out under industrial conditions using fresh, frozen and stored organic carrots as raw material. Statistically significant differences were found for sensory attributes among the three autoclaved puree samples (e.g. overall odour F = 90.72, p < 0.001). Samples processed from frozen carrots show increased moisture content and decrease of several chemical constituents. Biocrystallization identified changes between replications of the cooking. Pre-treatment of raw material has a significant influence on the final quality of the baby food. PMID- 25694689 TI - Effects of sulfur water extraction on anthocyanins properties of tepals in flower of saffron (Crocus sativus L). AB - A sulfur solution with different metabisulfite concentrations (100, 400, 700, 1,000 and 2,000 ppm) was used to extract anthocyanins from saffron tepals. The extraction process was compared with acidified ethanol solution at similar extraction times of 20, 40, 60, 120, and 180 min at 40 degrees C. The recovery of anthocyanins with sulfur solution was higher than ethanol extraction and reached to 700 mg anthocyanins/100 g, when the sulfur concentration and extraction time were 700 ppm and 60 min, respectively. HPLC analysis showed that anthocyanins extracted with sulfur solution followed by partial desulfurization and reducing sulfur content (to less than 250 ppm) had around 100 % more cyanidin 3 glucosides and 100 % less pelargonidin 3,5 glucosides in comparison with ethanol extraction. Additionally, the color of low-sulfured anthocyanins had more saturation (chroma), less lightness, and more stability than the one extracted with ethanol solution. While monomeric and polymeric anthocyanins extracted with sulfur solution had less than 1 % changes after 3 h extraction time, they had more than 12 % changes when they extracted with alcoholic solution at similar conditions. Overall, the sulfur method had a potential to extract stable anthocyanins from waste and discarded saffron tepals in aqueous solvent, and with higher quantity and quality (more attractive color) than conventional ethanol extraction method. PMID- 25694690 TI - Formulation and characterization of functional foods based on fruit and vegetable residue flour. AB - Fruits and vegetables are extensively processed and the residues are often discarded. However, due to their rich composition, they could be used to minimize food waste. This study aimed to develop food products based on the solid residue generated from the manufacture of an isotonic beverage. This beverage was produced based on integral exploitation of several fruits and vegetables: orange, passion fruit, watermelon, lettuce, courgette, carrot, spinach, mint, taro, cucumber and rocket. The remaining residue was processed into flour and its functional properties were evaluated. The fruit and vegetable residue (FVR) flour was incorporated with different levels (20 to 35 %) into biscuits and cereal bars. The proximate composition, microbiological stability until 90 days and consumer acceptance were analyzed. The FVR flour presented a higher water holding capacity than oil holding capacity, respectively 7.43 and 1.91 g g(-1) of flour, probably associated with its high levels of carbohydrates (53 %) and fibres (21.5 %). Biscuits enriched with 35 % of FVR flour presented significantly higher fibre, ranging from 57 % to 118 % and mineral contents, from 25 % to 37 % than when only 20 % was added. Cereal bars presented about 75 % of fibres and variable mineral contents between 14 % and 37 %. The incorporation of FVR did not change the fat content. The microbiological examinations are within acceptable limits according to international regulation. The incorporation of FVR flour did not impair consumer acceptance, the sensory attributes averaged around 6. The chemical, microbiological and sensorial results of the designed products attested for an alternative towards applying and reducing agro-industrial wastes. PMID- 25694691 TI - Optimization of seabuckthorn fruit yogurt formulation using response surface methodology. AB - The response surface methodology was used to optimize the formulation of seabuckthorn fruit yogurt. The independent variables were proportions of seabuckthorn fruit syrup and skimmed milk powder. The responses were counts of Streptococcus thermophilus and Lactobacillus bulgaricus, taste and viscosity of the product. Statistical analysis revealed that fruit syrup and skimmed milk powder significantly affected all the responses. Contour plots for each response were used to generate an optimum area by superimposition. Optimum formulation conditions of fruit syrup (15 %) and skimmed milk powder (12.5 %) are recommended for the blend formulation yielding an acceptable and good quality seabuckthorn fruit yogurt. Model validation was conducted using separate experiments at optimum conditions. The experimental values were found to be in close agreement to the predicted values and were within the acceptable limits indicating the suitability of the model in predicting quality attributes of seabuckthorn fruit yogurt. The resultant product also exhibited more amounts of fat, protein, carbohydrate and antioxidants viz., vitamin C, E, carotenoids, phenols and anthocyanins when compared to a commercial one. PMID- 25694692 TI - Effect of normal/dehydrated greens on the rheological, microstructural, nutritional and quality characteristics of paratha-an Indian flat bread. AB - The leaves of dill (Anethum graveolens) and fenugreek (Trigonella foenum-graecum L. Leguminosae) were dehydrated using low temperature low humidity dryer, packed in polypropylene bags and stored at refrigerated conditions. Dehydration process marginally reduced the chlorophyll, carotenoid and ascorbic acid contents. Replacement of whole wheat flour with dehydrated leaves (dill-DDL, fenugreek leaves DFL) at 0, 5, 7.5 and 10 % increased the water absorption (68.5 to 70.2 %), dough development time (3.5 to 5.9 min) and mixing tolerance index values (78 to 98 BU). Pasting temperature increased (69 to 74.1 degrees C), whereas the hot paste viscosity (255 to 210 BU) and cold paste viscosity values (355 to 295 BU) decreased with increase in the DDL/DFL content in the blend. Sensory evaluation of parathas prepared with either normal dill/fenugreek leaves (NDL/NFL) at 0, 12.5, 25 and 37.5 % or dehydrated leaves at 0, 5, and 7.5 % showed that parathas with 25 % of normal leaves and 7.5 % of dehydrated leaves were acceptable. Microstructure of the fenugreek leaves had more porous structure on dehydration. Parathas enriched with either of leaves were rich in dietary fiber, chlorophyll and carotenoid content. PMID- 25694693 TI - Retention of natural antioxidants of blends of groundnut and sunflower oils with minor oils during storage and frying. AB - Unrefined groundnut oil (GNO) and refined sunflower oil (SFO) were blended with four minor oils including laboratory refined red palmolein (RRPO), physically refined rice bran oil (RBO), unrefined sesame oil (SESO), and unrefined coconut oil (CNO) containing natural antioxidants viz., beta-carotene, tocopherols, oryzanol and lignans. The five blends prepared were GNO + RRPO (80:20), GNO + RBO (80:20), GNO + SESO (80:20), SFO + RRPO (50:50) and SFO + CNO (60:40). Prepared blends contained saturated fatty acids (SFA) (16.7-53.3 %); monounsaturated fatty acids (MUFA) (16.0-45.5 %) and polyunsaturated fatty acids (PUFA) (29.2-37.8 %). GNO blends viz., GNO + RRPO, GNO + RBO and GNO + SESO contained beta-carotene (10.7 mg/100 g), oryzanol (0.12 g/100 g) and lignans (0.35 g/100 g) respectively as natural antioxidants. SFO was enriched with beta-carotene (28.7 mg/100 g) and medium chain fatty acids (34.2 %) by blending with RRPO and CNO respectively. The oil blends (200 ml) were packed and stored at 38 degrees C/90 % relative humidity (RH) and 27 degrees C/65 % RH and samples were withdrawn at fixed intervals for analysis. Freshly prepared blends were also investigated for their frying performance. During storage, GNO + RBO blend showed highest oxidative stability probably due to the presence of oryzanol in the order GNO + RBO > GNO + SESO > GNO + RRPO. During frying, the peroxide value of GNO blends with RBO (rich in oryzanol) and SESO (rich in lignans) was less while the free fatty acid value was less in SFO blends with RRPO and CNO. Hence, blending of natural antioxidants rich minor oils (RRPO, RBO and SESO) with the major vegetable oils (GNO and SFO) may preserve them by lowering their rate of oxidation during storage and frying. PMID- 25694694 TI - Comparation sensory characteristic, non-volatile compounds, volatile compounds and antioxidant activity of MRPs by novel gradient temperature-elevating and traditional isothermal methods. AB - A novel gradient temperature-elevating Maillard reaction was developed to effectively produce light-colored MRPs. The main purpose of the present study was to compare the color, taste characteristic, non-volatile compounds, volatile compounds and antioxidant activity of MRPs prepared by the novel gradient temperature-elevating and traditional isothermal methods. The product prepared from soybean peptide, D-xylose and L-cysteine by gradient temperature-elevating method was termed MRP-60. Isothermal method was used to produce light and dark colored MRP, called PXC and PX, respectively. MRP-60 has not only the lowest brown intensity (A420, 0.088), also the highest overall acceptability taste from sensory evaluation. MRP-60 showed the lowest bitterness which could be attributed to the lowest content of bitter amino acids (1.48 mg/ml); MRP-60 also showed indistinctive mouthfulness compared with PXC which elucidated by the percentage of compounds with a molecular weight of 1,000-5,000 Da (15.03 %) and high antioxidant activity. Then, the MRPs prepared by gradient temperature-elevating method successfully attain desirable taste and high antioxidant activity. PMID- 25694695 TI - Effect of marination in gravy on the radio frequency and microwave processing properties of beef. AB - Dielectric properties (the dielectric constant (epsilon') and the dielectric loss factor (epsilon")) and the penetration depth of raw eye of round beef Semitendinosus muscle, raw beef marinated in gravy, raw beef cooked in gravy, and gravy alone were determined as a function of the temperature (20-130 degrees C) and frequency (27-1,800 MHz). Both epsilon' and epsilon" values increased as the temperature increased at low frequencies (27 and 40 MHz). At high frequencies (915 and 1,800 MHz), epsilon' showed a 50 % decrease while epsilon" increased nearly three fold with increasing temperature in the range from 20 to 130 degrees C. epsilon' increased gradually while epsilon" increased five fold when the temperature increased from 20 to 130 degrees C. Both epsilon' and epsilon" of all samples decreased with increase in frequency. Marinating the beef in gravy dramatically increased the epsilon" values, particularly at the lower frequencies. Power penetration depth of all samples decreased with increase temperature and frequency. These results are expected to provide useful data for modeling dielectric heating processes of marinated muscle food. PMID- 25694696 TI - Effect of ascorbyl palmitate on oxidative stability of chemically interesterified cottonseed and olive oils. AB - The effects of 400 ppm ascorbyl palmitate (AP) on fatty acids composition, tocopherol, peroxide value (PV) and malonaldehyde (MAD) contents of refined cottonseed oil (CO) and virgin olive oil (OO) during chemical interesterification (CI), and storage at 60 degrees C for 28 days were investigated. CI significantly decreased (p < 0.05) the tocopherol contents of CO and OO. PVs and MAD contents of oil samples considerably increased up to 20 min of CI, followed by a reduction at 30 min. The unsaturated fatty acids/saturated fatty acids (UFA/SFA) ratios of the samples showed slight but significant (p < 0.05) reduction during accelerated oxidation process. Oils with added 400 ppm AP had higher tocopherol, and lower PVs and MAD contents than their counterparts without AP during CI, and storage at 60 degrees C. AP increased the oxidative stability of interesterified and non-interesterified CO and OO. PMID- 25694697 TI - Studies on formulation of whey protein enriched concentrated tomato juice beverage. AB - Whey protein components derived from cheese whey and heat and acid coagulated Indian products (paneer, chhana, chakka) possess valuable functional and nutritional properties. Tomato products rich in lycopene are reported to be anticarcinogenic and antioxidative. The main objective of this study was to formulate a whey protein enriched tomato juice concentrate for use as beverage by employing Response Surface Methodology (RSM) engaging the Central Composite Rotatable Design (CCRD). The ingredients range used for this formulation comprised of Whey Protein Concentrate (WPC) 4-8 g, Cane sugar 10-20 g and Guar gum (stabilizer) 0.75-1.25 g in 100 g of concentrated tomato juice. The most preferred reconstituted beverage was obtained from the formulation developed with WPC 4.98 g, sugar 15.71 g and Guar gum 0.93 g added to 100 g tomato juice concentrate. PMID- 25694698 TI - Antioxidant properties, physico-chemical characteristics and proximate composition of five wild fruits of Manipur, India. AB - Antioxidant properties, physico-chemical characteristics and proximate composition of five wild fruits viz., Garcinia pedunculata, Garcinia xanthochymus, Docynia indica, Rhus semialata and Averrhoa carambola grown in Manipur, India were presented in the current study. The order of the antioxidant activity and reducing power of the fruit samples was found as R. semialata > D. indica > G. xanthochymus > A. carambola > G. pedunculata. Good correlation coefficient (R(2) > 0.99) was found among the three methods applied to determine antioxidant activity. Total phenolic content was positively correlated (R(2) = 0.960) with the antioxidant activity however, total flavonoid content was not positively correlated with the antioxidant activity. Physico-chemical and proximate composition of these fruits is documented for the first time. PMID- 25694699 TI - Seasonal variations of fatty acid profile in different tissues of farmed bighead carp (Aristichthys nobilis). AB - Bighead carp (Aristichthys nobilis) is one of the major farmed species of freshwater fish in China. Byproduct volume of bighead carp is significant at up to 60 % of whole fish weight. A better understanding of the nutritional composition is needed to optimize the use of these raw materials. The objective of this research was to characterize seasonal variations of fatty acid profile in different tissues (heads, bones, skin, scales, viscera, muscle and fins) of farmed bighead carp. The fatty acid composition of farmed bighead carp varied significantly with seasons and tissues. The highest lipid content was determined in viscera while the highest EPA and DHA composition were observed in muscle compared to the other tissues. Significantly higher SigmaEPA+DHA (%) was recorded in all tissues in summer (June) when compared with those of the other three seasons (p < 0.05). The n-3/n-6 fatty acid ratios in summer ranged from 3.38 to 3.69, nearly three times the ratios of the other three seasons. The results indicated that farmed bighead carp caught in summer could better balance the n-3 PUFA needs of consumers. The byproducts of bighead carp can be utilized for the production of fish oil. PMID- 25694700 TI - Studies on application of annatto (Bixa orellena L.) dye formulations in dairy products. AB - Annatto is often used to add color to dairy products such as butter, cheese, or puddings. In India usage of annatto is restricted to butter and cheese, however there are no tailor made formulations available to obtain standardized colour shades for the products. Hence a study was initiated to develop the appropriate annatto dye formulations and level of application in few dairy products (butter, cheese, paneer, biscuit cream, icing cream). Dye extracted from annatto seeds was used for the preparation of water soluble potassium carbonate formulation (nor bixin, 11.24 %), oil soluble formulation (1.35 % bixin) and an oil/water soluble propylene glycol formulation (PG formulation, 1.31 % bixin). Lovibond tintometer colour units of the commercial butter, cheese and biscuit cream samples were measured for standardizing the colour concentration in the experimental products. The present study evaluates the application and stability of these formulations in butter, cheese, paneer, biscuit cream, icing cream. The products were evaluated for stability of colour and bixin during storage period. The oil/water soluble propylene glycol formulation was found to be tailor-made for all the dairy products studied though the standardized levels varied between 3.75 and 5.0 mg/kg for butter, 3.75 mg/kg for cheese, 5.0-400 mg/kg for biscuit cream, 12.25 and 25 mg/kg for paneer, 5.0-500 mg/kg for icing cream. Increasing concentration in the range of 30-500 mg/kg yielded products with light cream to orange shades, useful for decorating cakes. The average recovery of bixin from the products immediately after processing was 90-98 %. Significant changes (P <= 0.05) were noticed in the colour units and recovery of bixin in all the products during storage of 6 months. PMID- 25694701 TI - Optimization of instant dalia dessert pre-mix production by using response surface methodology. AB - Dalia, a wheat-based, particulate containing dairy dessert is popularly consumed as a breakfast food and is also considered as a health food. Though popular throughout Northern parts of the country, its limited shelf-life even under refrigeration imposes severe restrictions on its organized manufacture and marketing. In order to promote dalia dessert as a marketable product, in the present study, a process was developed for manufacture of instant dalia pre-mix, as a dry product with long shelf-life, which could be attractively packaged and easily reconstituted for consumption. During the investigation, the effect of different levels of milk solids and wheat solids was studied on dalia pre-mix quality by employing a central composite rotatable design (CCRD). The suggested formulation had 17.82 % milk solids and 2.87 % wheat solids. This formulation was found to be most appropriate for manufacture of instant dalia pre-mix with predicted sensory scores (Max. 100) of 85.35, 41.98 and 67.27 for mouthfeel, consistency and flavor, respectively; the viscosity of the product was 941.0 cp. PMID- 25694702 TI - In vitro antioxidant and pancreatic alpha-amylase inhibitory activity of isolated fractions from water extract of Qingzhuan tea. AB - In the present work, Qingzhuan tea, a unique dark tea produced by post fermentation technology, was selected to investigate its antioxidant and pancreatic alpha-amylase inhibiting activities. Water extract of Qingzhuan tea was successively isolated by solvent partitioning procedures to obtain chloroform, ethyl acetate, n-butanol, sediment and residual aqua fractions. Of different fractions, the ethyl acetate fraction (QEF) had the highest total polyphenols and catechins contents, demonstrated the strongest DPPH radical scavenging activity and exhibited the greatest inhibitory effect on porcine pancreatic alpha-amylase activity in vitro. Further separation of QEF by a Sephadex LH-20 column generated eight subfractions (QEF1-QEF8), with QEF8 being the most active subfraction based on the assays above mentioned. The major active components in QEF8 were identified as catechins EGCG and ECG by LC-MS analysis, with contents of 22.29 % and 11.11 % respectively. Inhibitory effects of catechin standards EGCG and ECG on porcine pancreatic alpha-amylase activity were also observed. In conclusion, Qingzhuan tea or its water extract could be potentially used as complementary therapy ingredients for diabetes treatment through lowering postprandial blood glucose, and catechins EGCG and ECG may be the most efficient components in the water extract. PMID- 25694703 TI - Effect of microGARD on keeping quality of direct acidified Cottage cheese. AB - Direct acidified Cottage cheese could be kept well for only 10 to 12 days under refrigeration on account of its high moisture (~74 %) content and relatively high pH (~5.0). The study was, therefore, undertaken to improve the keeping quality of direct acidified Cottage cheese using MicroGARD. The effects of three different levels of MicroGARD 400 viz. 0.20, 0.35 and 0.50 % on the physico-chemical, microbiological and organoleptic properties were studied at four-day interval during storage under refrigeration (4-5 degrees C). Promising results were found using 0.50 % MicroGARD 400 for inhibiting psychrotrophs, yeasts and molds as well as retard the acidity development and proteolysis in Cottage cheese, thus extending its keeping quality. It was observed that addition of MicroGARD 400 at the level of 0.50 % considerably improved the flavour as well as the aesthetic quality of the product during storage and extended the shelf life of Cottage cheese from 12 to 26 days. PMID- 25694704 TI - Shelf life and storage stability of spray-dried bovine colostrum powders under different storage conditions. AB - Spray dried bovine colostrum (SDBC) powders were packaged in aluminium-laminated polyethylene (ALPE) and polyethylene terephthalate (PET) pouches and then stored under different conditions (25 degrees C and 50 % relative humidity (RH), 4 degrees C and 40-70 % RH, 50 degrees C and 20-50 % RH). The shelf life of SDBC powder was evaluated as 425.5 and 86.5 days in ALPE and PET pouches under 25 degrees C and 50 % RH, respectively. The storage stability of SDBC powder in terms of quality parameters including thiobarbituric acid (TBA), hydroxymethyl furfural (HMF), colour change, moisture content and IgG concentration was studied in both packaging materials under different storage conditions. Results showed that ALPE pouches were more suitable for packaging SDBC powder than PET pouches and storage condition of 4 degrees C and 40-70 % RH was relative suitable for keeping quality of SDBC powder. The glass transition concept was helpful for evaluating the chemical stability of SDBC powder during storage. PMID- 25694705 TI - Optimization of UF-Feta cheese preparation, enriched by peppermint extract. AB - Strong antioxidant activity, antimicrobial, antiviral, antitumor, and some antiallergenic potential actions have been reported in peppermint. For daily acceptance of the benefits of this plant, UF-Feta cheese, enriched by whole peppermint extract, was prepared with different levels of Peppermint Extract (PE) (220-660 MUg/g cheese), starter (1.3-2.7 g/100 Kg retentate), rennet (1.3-2.5 g/100 Kg retentate), and Ripening Time (RT) (10-50 days). Simultaneous effects of the considered variables were also investigated on Water-soluble Phenolic Content (WSPC), Antioxidant Activity (AOA), and Sensory Score (SS) by means of Response surface methodology. The results showed that although rennet concentration had a little positive effect on WSPC, its effect on AOA was significantly negative. It was determined that PE had a crucial role in acceptance of cheese samples and showed a negative effect on SS. More maturation of produced cheese samples effectively increased AOA. It was found that for producing cheese with maximum SS and AOA, the optimum values of variables should be applied as follows: PE, 227 MUg/g cheese; starter, 2.7 g/100 Kg retentate; rennet, 1.3 g/100 Kg retentate; RT, 41.7 days. PMID- 25694706 TI - Process optimization for a nutritious low-calorie high-fiber whey-based ready-to serve watermelon beverage. AB - Whey is a nutritious by product of some traditional Indian processed milk products and it needs to be utilized in an effective way in order to reduce environmental hazards associated with its untreated disposal. Low calorie watermelon beverage appears to be a simple, attractive and economic method of whey disposal. The experiment was designed by Central Composite Rotatable Design of Responce Surface Methodology. Three independent variables whey, Innova (r) fiber and sucralose were chosen at five levels within the respective ranges of 40 60 %, 2.0-5.0 % and 0.01-0.03 %. The effect of the variables on flavour, mouthfeel, after-taste, viscosity, total soluble solids (all to be maximized) and sedimentation (to be minimized) was observed. These three were the independent variables whose effect on flavour, mouthfeel, after-taste, viscosity, total soluble solids (all to be maximized) and sedimentation (to be minimized) were evaluated. Quadratic model fitted well to all dependent variables. The R(2) values for flavour, mouthfeel, aftertaste, viscosity, sedimentation and TSS were 95.57, 98.71, 95.50, 97.87, 99.26 and 98.17 %, respectively. Response surface methodology was used to optimize the level of processing parameters. Maximum scores for flavour (7.46), mouthfeel (7.49), after-taste (7.72), viscosity (13.55 cp) and total soluble solid (15.34 degrees Brix) and minimum score for sedimentation (1.55 ml/10 ml) were obtained when the formulation contained 51.46 % whey, 3.84 % Innova(r) fiber and 0.021 % sucralose. PMID- 25694707 TI - Formulation and physico-chemical analysis of whey-soymilk dahi. AB - The present investigation was undertaken to use whey for the production of nutritious whey-soya milk dahi. Neutralized whey (pH 7.0 +/- 0.2) was used to extract soya milk from cleaned, dried, dehulled and steamed soybean in soya milk extraction plant. Whey-soya milk was extracted having whey to soybean ratio of 5:1. It was further diluted with whey to get different whey to soybean ratios i.e. 9:1, 8:1, 7:1 and 6:1. To set dahi, skim milk powder was added to whey-soya milk so as to make the final total solid concentration of 16, 18 and 20 %. Dahi was prepared by inoculating different whey-soya milk ratios with vita brand of dahi. Results revealed that whey-soya milk having whey to soybean ratio of 5:1 and 20 % total solids was found to be most appropriate for preparation of dahi on the basis of time taken for firmly setting of dahi (5 h) and sensory evaluation scores (7.7 on 9 point hedonic scale). Whey-soya milk dahi was found to be at par with milk dahi (control) based on the sensory scores. Whey-soya milk dahi and milk dahi samples were stored at refrigeration temperature and evaluated for changes in physico-chemical (fat, protein, total sugar, total solids, pH, viscosity and syneresis) and sensory (color and appearance, flavor, consistency and overall acceptability) properties at an interval of 2 days up to 10 days. The results of the study revealed that whey-soya milk dahi could be stored up to 10 days with good sensory quality. PMID- 25694708 TI - Optimisation of gelatin extraction from Unicorn leatherjacket (Aluterus monoceros) skin waste: response surface approach. AB - Physical properties of gelatin extracted from Unicorn leatherjacket (Aluterus monoceros) skin, which is generated as a waste from fish processing industries, were optimised using Response Surface Methodology (RSM). A Box-Behnken design was used to study the combined effects of three independent variables, namely phosphoric acid (H3PO4) concentration (0.15-0.25 M), extraction temperature (40 50 degrees C) and extraction time (4-12 h) on different responses like yield, gel strength and melting point of gelatin. The optimum conditions derived by RSM for the yield (10.58%) were 0.2 M H3PO4 for 9.01 h of extraction time and hot water extraction of 45.83 degrees C. The maximum achieved gel strength and melting point was 138.54 g and 22.61 degrees C respectively. Extraction time was found to be most influencing variable and had a positive coefficient on yield and negative coefficient on gel strength and melting point. The results indicated that Unicorn leatherjacket skins can be a source of gelatin having mild gel strength and melting point. PMID- 25694709 TI - A study on monitoring of frying performance and oxidative stability of virgin coconut oil (VCO) during continuous/prolonged deep fat frying process using chemical and FTIR spectroscopy. AB - The performance or quality of the Virgin coconut oil (VCO) during continuous/prolonged deep fat frying of soaked bengal gram dhal was evaluated at 180 degrees C +/- 5 degrees C for 8 h with the help of physico-chemical and rheological parameters. Chemical changes indicated that the free fatty acid (FFA) content and TBA increased significantly (p <= 0.05) from 0.11 to 0.98 % lauric acid and 0.06 to 0.61 malonaldehyde/kg of oil respectively. Initially, the peroxide value (PV) of VCO sample was 3.25 meqO2/kg which increased to 9.12 meqO2/kg after 6 h of frying but at the end of frying the value of PV was again found to decrease (8.01 meqO2/kg). The regression coefficients (R(2)) between CD232, CT270 and frying time were 0.964 and 0.983 respectively. The L*, a* and b* colour values measured on the CIELAB colour scale showed a decrease in L* and increase in a*, b* values after 8 h of continuous frying. The p-AV and total polar compounds were increased significantly (p <= 0.05) from 2.41 to 17.93 and 2.77 to 8.14 % respectively. Initially, the viscosity of VCO was 49.87cp which increased to 69.87cp after 8 h of continuous frying. The FTIR spectra justify that VCO samples after 8 h of frying found to be stable and acceptable as there was no change occurred at 1,739 cm(-1) frequency which mainly corresponded to carbonylic compounds resulted from the hydroperoxide decompositions after 8 h of continuous frying. PMID- 25694710 TI - A comparative study on the effect of rosemary extract and sodium ascorbate on lipid and pigment oxidative stability of liver pate. AB - A comparative study on the antioxidant effect of rosemary extract (RE) and sodium ascorbate (SA) on lipid and colour oxidation of liver pate made of lard and pork liver was done. During the 48 hour experimental time all the pates were wrapped in a foil and stored in cold room of 3.5 degrees C under light of 1000 lux. Colour stability was monitored by instrumental colour measurement (CIE L*a*b* colour space) whereas lipid stability was measured by the determination of the 2 thiobarbituric acid reactive substances (TBARS). In the present study RE doses range (0,125, 250, 375 and 500 ppm) showed no significant (p>0.05) and linear effect on colour stability. However thez RE revealed a significant effect (p<0.05) against lipid oxidation and linearly reduces the TBARS number. The added SA doses (0, 250, 500, 750 and 1000 ppm) revealed significant (p<0.05) and linear effect in reducing discoloration. However the studied SA dose ranges showed no significant (p>0.05) effect on TBARS number. In this study RE was showed better performance against lipid oxidation and SA was potent against discoloration. The effect of the added spices used in manufacturing of the studied product showed no significant (p>0.05) effect against lipid and color oxidation. However the added spices revealed possible antagonistic and synergetic relationship with the studied the antioxidant systems (RE & SA). PMID- 25694711 TI - The impact of UV-C irradiation on spoilage microorganisms and colour of orange juice. AB - The effect of UV-C irradiation on inactivation of spoilage microorganisms and colour of freshly squeezed orange juice were investigated. Orange juice samples were intentionally fermented in order to increase the natural microflora which were mostly composed of yeasts and then exposed to UV-C irradiation at an intensity level of 1.32 mW/cm(2) and sample depth of 0.153 cm for several exposure times by using a collimated beam apparatus. Applied UV dose was in the range of 0 and 108.42 mJ/cm(2). Resistance of yeast to UV light and existence of suspended particles limited the effectiveness of the process. Survival data obtained for yeasts was either described by the Weibull or traditional first order model and goodness-of-fit of these models was investigated. Weibull model produced a better fit to the data with higher adjusted determination coefficient (R(2) adj) and lower mean square error (MSE) values which were 0.99 and 0.003, respectively. Time and UV dose of first decimal reduction were obtained as 5.7 min and 31 mJ/cm(2), respectively. The data suggests that biodosimetric studies performed by using inoculated microorganisms for assesment of the efficiency of UV irradiation treatment in the shelf life extension of juices must be carefully evaluated. UV-C irradiation had no influence on the colour of orange juice. PMID- 25694712 TI - Evaluation of the potential of squash pumpkin by-products (seeds and shell) as sources of antioxidant and bioactive compounds. AB - The transformation of byproducts and wastes generated by agro-food companies is of high importance since only a small portion of plant material is utilized directly for human consumption. Squash pumpkin is greatly used in Portugal and as by-products of its processing are generated tons of shell and seeds. In this study we aim to evaluate the potential of these wastes as sources of beneficial and bioactive compounds (antioxidants and antimicrobials), studying the effect of different extraction solvents and drying methods. The samples (fresh and cooked) were freeze-dried and oven-dried followed by extraction with different solvents that revealed the following decreasing order of efficiency: 70 % ethanol, 70 % methanol, 70 % acetone, ultra-pure water and 100 % dichloromethane. The oven dried samples showed higher values of antioxidant activity and phenolic content, with exception of the values of phenolics for the seeds material. The shell samples presented higher values (1.47 - 70.96 % inhibition) of antioxidant activity and total phenolic content (2.00 - 10.69 mg GAE/g DW). A positive correlation was found between these two parameters on the shell samples, however the squash seeds revealed a negative correlation between the phenolic content and the antioxidant activity. The results show that these industrial agro-food residues are potentially good sources of bioactive compounds with health benefits. PMID- 25694713 TI - Effects of synthetic and natural extraction chemicals on yield, composition and protein quality of soy protein isolates extracted from full-fat and defatted flours. AB - With increasing preference for all-natural foods to those involving synthetic chemicals, native isoelectrically precipitated soy protein isolate (SPI) was prepared using amaranth (Amaranthus tricolor L.) lye (pH > 12.5) and lemon extract, (pH < 2.5) as natural, food-plant-based chemicals. Protein content (91.21 %), yield (43.62 %) and digestibility correlation amino acid score (0.77) were obtained and were comparable to those of SPI prepared using synthetic chemicals (NaOH and HCl). Methionine and cystein-s were significantly higher in the natural SPI while glutamine and serine were higher in synthetic SPI (p < 0.01). Most of the determined minerals were higher in the natural SPI with potassium being the highest. Sodium was very high in the synthetic SPI. The rest of the minerals including phosphorus, iron and nickel, showed no significant difference. Anti-nutritional factors (trypsin inhibitors and phytic acid) were considerably lower in the natural SPI. Thus, a quality all-natural SPI can be produced using amaranth lye and lemon extract to address concerns regarding use of synthetic chemicals. PMID- 25694714 TI - Turkish Tombul hazelnut (Corylus avellana L.) protein concentrates: functional and rheological properties. AB - Turkish Tombul hazelnut consumed as natural or processed forms were evaluated to obtain protein concentrate. Defatted hazelnut flour protein (DHFP) and defatted hazelnut cake protein (DHCP) were produced from defatted hazelnut flour (DHF) and defatted hazelnut cake (DHC), respectively. The functional properties (protein solubility, emulsifying properties, foaming capacity, and colour), and dynamic rheological characteristics of protein concentrates were measured. The protein contents of samples varied in the range of 35-48 % (w/w, db) and 91-92 % (w/w, db) for DHF/DHC and DHFP/DHCP samples, respectively. The significant difference for water/fat absorption capacity, emulsion stability between DHF and DHC were determined. On the other hand, the solubility and emulsion activity of DHF and DHC were not significantly different (p > 0.05). Emulsion stability of DHFP (%46) was higher than that of DHCP (%35) but other functional properties were found similar. According to these results, the DHCP could be used as DHFP in food product formulations. The DHFP and DHCP samples showed different apparent viscosity at the same temperature and concentration, the elastic modulus (G' value) of DHPC was also found higher than that of DHFP samples. PMID- 25694715 TI - Antioxidant effect of apple phenolic on lipid peroxidation in Chinese-style sausage. AB - Chinese-style sausage is a very popular meat product obtained from a mixture of chopped pork meat, lard, salt, spices, additives (nitrate, nitrite, and antioxidants) and/or starter cultures. The antioxidative effect of apple phenolic on lipid oxidation in Chinese-style sausage compared with that of butylated hydroxy toluene (BHT) and ursolic acid were studied. Lipid oxidation was assessed through determination of thiobarbituric acid-reactive substances (TBARs) and volatile aldehydes. The content and composition of fatty acids in phospholipid were evaluated. At the optimum addition level, apple phenolic (0.5 g.kg(-1) in total fat) was more effective at inhibiting lipid oxidation than BHT (0.15 g.kg( 1) in total fat) and ursolic acid (0.5 g.kg(-1) in total fat) in Chinese-style sausages during 120 days storage. Moreover, apple phenolic exhibited stronger phospholipid protective capacity than ursolic acid and BHT at the end of storage. This study reveals a potential application of apple phenolic to enhance the oxidation stability of meat products during long storage. PMID- 25694716 TI - Cholesterol extraction from ghee using glass beads functionalized with beta cyclodextrin. AB - Beta-cyclodextrin (beta-CD) was covalently immobilized on glass surface. Functionalized glass surface was characterized by X-ray photoelectron spectroscopy (XPS) and elemental analysis. Glass surface functionalized with beta CD was used to remove cholesterol from ghee (clarified butter fat). 78.8 % cholesterol was reduced in 2 h at 25 degrees C and 170 rpm. Same surface was used repeatedly for 10 cycles and no reduction in cholesterol removal efficiency was observed. Modified glass surface showed almost no degradation in repeated use in cholesterol reduction experiments. PMID- 25694717 TI - Physico chemical characterization and the effect of processing on the quality characteristics of Sindura, Mallika and Totapuri mango cultivars. AB - Mango (Magnifera indica L) is grown in the tropical and sub tropical regions of India. The fruit has a high commercial value depending on the color, flavor and pulp characteristics of the cultivar. Sindura, Mallika and Totapuri cultivars grown in southern Karnataka were investigated for the physical chemical characteristics and the effect of processing on the quality characteristics. Sindura, Mallika and Totapuri mango cultivars had significantly different physico chemical and compositional characteristics. Sindura cultivar had a characteristic red color in the peel with high carotenoid content and slightly lower pulp content. Mallika contained higher pulp content with a pale yellow color in the peel and higher total soluble solids. Totapuri contained slightly lower pulp content than Mallika, lower total soluble solids and lower carotenoids among the cultivars. Sindura and Mallika pulps had significantly higher viscosity than Totapuri. Processing of the pulps resulted in significant decrease of carotenoids irrespective of the cultivar. Sensory quality of canned mango slices showed higher acceptability for Mallika followed by Sindura and Totapuri. Mango nectar prepared from Sindura was highly acceptable followed by Totapuri and Mallika. Processing of these underutilized mango cultivars into puree, nectar, juice beverages and slices, can result in value addition and popularization. PMID- 25694718 TI - Effect of processing techniques on nutritional composition and antioxidant activity of fenugreek (Trigonella foenum-graecum) seed flour. AB - Fenugreek (Pusa Early Bunching) seeds were processed by using different processing methods viz. soaking, germination and roasting. Raw and processed fenugreek seed flours were analyzed for nutritional composition, anti- nutritional, and antioxidant activity. Raw fenugreek seed flour contained higher amount of dietary fiber (45.4 %) followed by 41.7 % in soaked seed flour, 40.9 % in roasted fenugreek seed flour and 31.3 % in germinated fenugreek seed flour. Processing of fenugreek seeds improved in vitro starch digestibility and in vitro protein digestibility. Soaking, germination and roasting enhanced total phenolic content and the antioxidant activity of fenugreek seed flour as compared to raw fenugreek seed flour. The phenolic content of soaked, germinated and roasted fenugreek seed flours was 54.4, 80.8 and 48.5 mg of gallic acid equivalents/g of sample in contrast to raw fenugreek seed flour (45.4 mg of gallic acid equivalents/g of sample). The antioxidant activity of the extracts of soaked, germinated and roasted fenugreek seed flours was 60.7 %, 73.9 % and 32.0 % whereas as the raw fenugreek seed flour exhibited 18.1 % antioxidant activity. Processing of fenugreek seeds also decreased phytic acid content significantly (P < 0.05) as compared to raw seeds. PMID- 25694719 TI - Modification of fatty acid profile of cow milk by calcium salts of fatty acids and its use in ice cream. AB - This study was conducted to determine the effect of calcium salts of fatty acids (CSFA) on fatty acid profile of milk of "Sahiwal" cows and suitability of milk with modified fatty acids in the formulation of ice cream. Fatty acid profile of cow milk was modified by feeding CSFA to eighteen randomly stratified "Sahiwal" cows of first and early lactation divided into three groups. CSFA were offered at two different levels i.e. T1 (150 g per cow per day) T2 (300 g per cow per day) both treatments were compared with a control (T0) without any addition of calcium salts of fatty acids. Iso caloric and iso nitrogenous feeds were given to both experimental groups and control. Concentrations of short chain fatty acids in T0, T1 and T2 were 9.85 +/- 0.48a, 8.8 +/- 0.24b and 7.1 +/- 0.37c %, respectively and the concentrations of C18:1 and C18:2 increased (P < 0.05) from 27.6 +/- 1.32b % to 31.7 +/- 1.68a % and 2.15 +/- 0.09b % to 2.79 +/- 0.05a %, respectively, at T2 level. Incorporation of milk fat of T1 and T2 (modified fatty acids profile) in ice cream did not have any adverse effect on pH, acidity and compositional attributes of ice cream. Viscosity of T1 was 67.94 +/- 3.77a as compared to (T0) control 68.75 +/- 2.46a (CP). Firmness of experimental samples and control were almost similar (P > 0.05) overall acceptability score of T2 was 7.1 +/- 0.28b out of 9 (total score) which was more than 78 +/- 2.92 %. It was concluded that CSFA may be successfully incorporated up to T2 level (300 g per cow per day) into the feed of "Sahiwal" cows to produce milk with higher content of unsaturated fatty acids and it may be used in the formulation of ice cream with acceptable sensory characteristics and increased health benefits. PMID- 25694720 TI - Effect of modified atmosphere packaging on the shelf life of lal peda. AB - Lal peda is a traditional dairy-based sweet, popular in the Indian subcontinent, but it has a poor shelf life. The lal peda samples were packed in polyethylene bags filled with 3 different gaseous compositions (Air, 70 % N2: 30 % CO2 and 98 % N2) and stored at 10 degrees C. The shelf life was evaluated on the basis of changes in the microbial status of the product such as total plate count, yeast and molds and coliform counts and also the physico-chemical changes such as hydroxy methyl furfural (HMF), thiobarbituric acid (TBA) and free fatty acid (FFA). The microbial spoilage and the indices of chemical changes increased in all the samples with the progression of storage period. The samples packed with air showed significantly higher chemical deterioration and microbial spoilage as compared to the other two combinations. The results showed that samples packed with 70 % N2: 30 % CO2 combination had better shelf stability as compared to the samples packed under air and 98 % N2. PMID- 25694721 TI - An intelligent procedure for watermelon ripeness detection based on vibration signals. AB - In this paper, an efficient procedure for ripeness detection of watermelon was presented. A nondestructive method was used based on vibration response to determine the internal quality of watermelon. The responses of samples to vibration excitation were optically recorded by a Laser Doppler (LD) vibrometer. Vibration data was collected from watermelons of two qualities, namely, ripe and unripe. Vibration signals were transformed from time-domain to frequency-domain by fast Fourier transform (FFT). Twenty nine features were extracted from the FFT amplitude and phase angle of the vibration signals. K-nearest neighbor (KNN) analysis was applied as a classifier in decision-making stage. The experimental results showed that the usage of the FFT amplitude of the vibration signals gave the maximum classification accuracy. This method allowed identification at a 95.0 % level of efficiency. Hence, the proposed method can reliably detect watermelon ripeness. PMID- 25694722 TI - Omega-3 fatty acids enriched chocolate spreads using soybean and coconut oils. AB - Chocolate spreads were developed by incorporating two different soybean oil margarines, fat phases prepared using 85 % soybean oil (M1) and 1:1 blend of soybean oil and coconut oil (M2) with commercial palm stearin. Eight formulations were tried by varying skim milk powder (SMP)/fluid skimmed milk (FSM), type of fats (M1, M2, a commercial margarine and a table spread), sugar and cocoa powder and their quality characteristics were compared with a commercial hazelnut cocoa spread. The moisture and fat content were 5-6.1 % and 31.4-32.8 % for formulations with SMP and 21.5-24.7 % and 15.6-21.4 % respectively for those with FSM. Rheological studies of FSM spreads showed higher G" value (loss modulus) than G' (storage modulus) indicating better spreadability. Descriptive sensory analysis revealed that the products had acceptability score of 8.3 to 10.5 (maximum score: 15). Fat extracted from spreads prepared using M1 and M2 was found to contain 43.9 and 22.3 % linoleic acid and 2.1 and 4.4 % linolenic acid respectively, were free from trans fat while the commercial hazelnut spread had 9.8 % linoleic acid but did not contain linolenic acid. Hence, the developed chocolate spreads have the potential to overcome omega-3 deficiency, omega 6/omega-3 imbalance and to enhance the health standard of people. PMID- 25694723 TI - Stability and quality of herb (Pueraria Tuberosa)-milk model system. AB - The medicinal benefits of herbs could be conveyed via certain foods as carriers. Milk is one of the important carrier which has been effectively used to deliver phytochemicals presents in herbs (mainly polyphenols) for targeted health benefits in the traditional Indian system of medical science. The present study was conducted to evaluate the effect of herb components (Pueraria tuberosa) on properties of Pueraria tuberosa-milk model system. The herb was added into cow milk on the basis of sensory evaluation (0.4 %) by using 9-point hedonic scale. The physical and chemical changes were evaluated after various processing treatments viz. pasteurization (72 degrees C, 15 s), sterilization (121 degrees C, 15 min), separation etc. These changes were determined using viscosity, hydroxy methyl furfural (HMF) value, ethanol stability, colour characteristics and trolox equivalent antioxidant capacity (TEAC). It was observed that addition of Pueraria tuberosa to milk resulted in decreased HMF content, ethanol stability and lightness whereas antioxidant activity, redness and yellowness increased as compared to control. It can be concluded that addition of Pueraria tuberosa to milk at 0.4 % concentration altered the functional properties of milk and Pueraira tuberosa could be suitable for preparation of low heat treated functional dairy food products. PMID- 25694724 TI - Comparative efficacy of two standard methods for determination of iron and zinc in fruits, pulses and cereals. AB - Micronutrients are essential elements needed in small amounts for adequate human nutrition and include the elements iron and zinc. Both of these minerals are essential to human well-being and an adequate supply of iron and zinc help to prevent iron deficiency anaemia and zinc deficiency, two prevalent health concerns of the developing world. The levels of zinc and, iron were measured in the Banana, Papaya, Rice, Finger millet, Soybean and Urdbean. Standard Atomic absorption spectroscopy (AAS) method was also applied to all the samples for zinc and iron analysis and compared with inductively coupled plasma mass spectroscopy (ICP-MS). It was observed that there was no matrix interference affecting the determination of both elements interested in all the samples analyzed. Average concentration relative standard deviation and standard deviation were used for the statistical evaluation of the results for both elements. Correlation coefficient was used as statistical model to compare both the techniques. PMID- 25694725 TI - Separation/preconcentration and determination of quercetin in food samples by dispersive liquid-liquid microextraction based on solidification of floating organic drop -flow injection spectrophotometry. AB - A new dispersive liquid-liquid microextraction based on solidification of floating organic drop (DLLME-SFOD)-flow injection spectrophotometry (FI) method for the separation and preconcentration of trace amounts of quercetin was developed. 1-Undecanol and methanol was used as the extraction and disperser solvent, respectively. The factors influencing the extraction by DLLME-SFOD such as the volume of the extraction and disperser solvents, pH and concentration of salt were optimized. The optimal conditions were found to be; volume of the extraction solvent, 80 MUL; the volume of the disperser solvent, 100 MUL; and the pH of the sample, 3. The linear dynamic range and detection limit were 5.0 * 10( 8)-5.0 * 10(-7) mol L(-1) and 1 * 10(-8) mol L(-1), respectively. The relative standard deviation (R.S.D.) at 6.1 * 10(-8) mol L(-1) level of quercetin (n = 10) was found to be 2.8 %. The method was successfully applied to the determination of quercetin in the apple, grape, onion and tomato samples. Figure? PMID- 25694726 TI - Antioxidation and antiglycation of Fagopyrum tataricum ethanol extract. AB - Fagopyrum tataricum is used for the treatment of type 2 diabetes mellitus in Taiwan. The aim of this study was to evaluate the inhibitory effects of 75 % ethanol extract of buckwheat (EEB) and rutin on carbohydrate-metabolized enzymes, including alpha-amylase and alpha-glucosidase, which are related to hyperglycemia. The rutin dosage (40 MUg/mL) was equivalent to that of EEB (200 MUg/mL). In addition, the antioxidant and antiglycation activities of EEB and rutin were investigated. Results showed that both EEB and rutin exerted free radical (DPPH and ABTS) scavenging activity. They also attenuated protein glycation to lower the generation of advanced glycation end-products (AGEs) through the suppression of fructosamine and alpha-dicarbonyl compounds. Moreover, EEB and rutin also inhibited alpha-amylase and alpha-glucosidase activity. Taken together, these findings suggest that EEB and rutin may reduce oxidative stress, AGEs formation, and carbohydrate-metabolized enzymes hence EEB may use as protection agent in diabetic patients. PMID- 25694727 TI - Evaluation of antioxidant and antiradical properties of Pomegranate (Punica granatum L.) seed and defatted seed extracts. AB - Pomegranate seeds are byproducts of the Pomegranate juice industries that contains functional compounds such as phenols. This study was aimed to evaluate the effect of solvents on extraction from Pomegranate seed and Pomegranate defatted seed and to measure the yield extract and phenolic content and antioxidant properties. For this purpose, the seeds and defatted seeds were directly isolated from fruits and seeds by cold pressing respectively, then were crushed and extracted with different solvents, including water, Methanol, Acetone, Ethyl acetate and Hexane and finally the extracts of them were evaluted. Phenolic compounds, ferric reducing-antioxidant power and radicals scavenging property of extracts were measured. The results showed the highest extraction efficiencies were for Hexane and Acetone solvents in extraction of seed and defatted seed respectively. The highest phenolic content was obtained from Methanol seed extract. Reducing activity test proved that the Methanol extracts of Pomegranate seed and Pomegranate defatted seed had the highest reducing strength. Results of radical scavenging activity were similar to reducing activity results. The order of antioxidant capacity of Pomegranate seed and Pomegranate defatted seed were found to be Methanol > Water > Acetone > Butanol > Ethyl acetate > Hexane. It can be concluded Pomegranate seed, which possesses high levels of polyphenols, can be one of the sources of the natural antioxidants. The Methanol extract had a higher antioxidant efficiency than seed and defatted seed extracts. PMID- 25694728 TI - Postharvest operations of pistachio nuts. AB - The most important postharvest operations of pistachio nuts including handling, transportation, green hull removal, dehydration, bulk storage and packaging of pistachios were studied. Results showed that air temperature had pronounced effect on drying time and air velocity didn't any significant effect on drying time. The entire drying process occurred in falling rate period and constant rate period was not observed. The optimum conditions for bulk storage of pistachio nuts were between 0 and 10 degrees C and relative humidity (RH) of 65-70 % or kept at higher than 10 degrees C (e.g. 15 degrees C) and less than 32 % RH, and monolayer moisture content had the longest shelf life due to the minimum changes in its lipid quality factors. The higher temperatures and longer storage times will accelerated deteriorative reactions in pistachio nuts especially on fat component and nylon under vacuum is the best packages for pistachio nuts among other packaging materials were studied in this research. PMID- 25694729 TI - A less energy intensive process for dehydrating onion. AB - Onion powder has an extensive demand and wide application worldwide as flavour additive in convenience foods and medicinal products. Conventionally onion powder is prepared by hot air drying of onion slices followed by grinding. Convective air drying when used alone demands longer drying time and thus has a high expense of energy. As bulk of onion is water (82-87 %), removal of moisture prior to drying can reduce moisture loading on dryer and hence the energy consumption. Keeping this in view, onions were partially dewatered using centrifugal force before convective drying. The effect of partial mechanical dewatering and drying air temperature was studied on drying time, specific energy consumption and onion powder quality (colour and flavour). The combination process was also optimized to achieve increased drying rate and product quality comparable to products obtained using convective drying alone. Onions subjected to 60 % partial mechanical dewatering and hot air drying at 70 degrees C exhibited significantly (p <= 0.5) shortened drying time, decreased energy consumption and maintained colour and flavour of the dried product. PMID- 25694730 TI - The influence of cooking process on the microwave-assisted extraction of cottonseed oil. AB - Cooking process is one of the most energy and time consuming steps in the edible oil extraction factories. The main goal of this study was cottonseed oil extraction by microwave radiation and elimination of any heat treatment of cottonseeds before extraction. The effect of cooking process on the physicochemical properties of extracted oil from two varieties of cottonseed (Pak and Sahel) was evaluated by free fatty acid content, melting point, smoke point and refractive index. Our results didn't show any significant differences between cooked and uncooked samples (P > 0.05) regarding physicochemical characteristics. From GC analysis of extracted oils, it was found there is no significant difference in fatty acid composition of cooked, uncooked and control (conventional extraction) samples. The thermal stability (Rancimat) analysis of oil samples showed the cooking process could cause a slight increase in the stability of oils for both varieties (about 40 min). The cooking process also increased total extracted phenolic compounds and considerably decreased total gossypol content of the cottonseed oil; but the extraction efficiency didn't change considerably after elimination of the cooking process. It can be concluded that microwave rays can destroy the structure of oil cells during process and facilitate the oil extraction without any heat treatment before extraction. PMID- 25694731 TI - Studies on the nutraceuticals composition of wheat derived oils wheat bran oil and wheat germ oil. AB - Fat-soluble nutraceuticals of cereals are known for number of disease preventive activities. Hence wheat bran oil (WBO) and wheat germ oil (WGO) were extracted from wheat bran and germ which yielded 3.35 % and 7.35 % of oil, containing polyunsaturated fatty acids (PUFA) (64 %, 61.2 %) respectively. Both oils contained tocopherols and carotenoids, which were higher in wheat germ oil (273 mg/100 g, 12.23 mg/100 g) than wheat bran oil (190 mg/100 g, 2.21 mg/100 g). Steryl ferulates were also present in both the oils, but their content was eight fold higher in WBO than in WGO. Three major steryl ferulates identified by HPLC were campesteryl ferulate and sitostenyl ferulate, campestanyl ferulate and beta sitosteryl ferulate as in gamma-oryzanol and another ferulate, viz., sitostanyl ferulate. A strong IC50 value of 7.5 mg/mL and 21.6 mg/mL DPPH free radicals scavenging for wheat germ oil for wheat bran oil was observed. NMR ((13)C and (1)H) profile explored the evidence of distribution of antioxidant molecules in the unsaponifiable matter of wheat derived oil. Since oils rich in PUFA and minor components are required for the normal physiological activities, blending such oils with other edible oils of the diet in wheat growing countries like India may be useful to provide health benefits. PMID- 25694732 TI - Standardization of rate of sugar addition for the manufacture of Thabdi. AB - Traditional Indian Dairy Products are manufactured in India using an age old practice which varies from place to place. For manufacture of these products industrially, a standard formulation is required. Thabdi, a region specific, very popular heat desiccated milk product is one of such products which has not been studied scientifically. Sugar plays an important role in physico-chemical, sensory, textural characteristics and also the shelf life of any milk sweet. Hence for process standardization of Thabdi manufacture, different levels of sugar i.e. 4, 6, 8 and 10 (percent of milk) were studied so that an optimum level yielding best organoleptic characteristics in final product can be selected. The product was made from milk standardized to 0.66 Fat:SNF level and added with ghee @ 1.2 % of milk at the time of colour and texture development stage as selected from the earlier phase of study. Based on the results obtained, a level of 8 % sugar addition on the milk basis at the time of manufacture has been selected to have full taste and sensory attributes. PMID- 25694733 TI - Physico-chemical and textural properties of Santra burfi as influenced by orange pulp content. AB - The burfi prepared with addition of orange pulp in sweetened khoa is popularly known as Santra burfi in Maharashtra and it has great commercial potential owing to its typical taste. The present investigation was carried out with a view to generate technological data, which is requisite in product standardization and mechanization. The santra burfi was prepared by varying the rates of orange pulp addition and was tested for various textural properties such as hardness, cohesiveness, gumminess, chewiness, adhesiveness and springiness with TA-XT2i Texture Analyzer using two-bite compression. The data of product composition and quantified properties were analyzed using correlation and regression techniques. The hardness was found to have positive correlation with proteins, fat and ash content while the moisture and level of orange pulp had negative correlation. Similar trends were observed for springiness, gumminess, chewiness and cohesiveness with the exception of ash. On the contrary, the mean adhesiveness showed negative correlation with protein, fat and ash content and shown positive correlation with moisture content and level of orange pulp. The regression equations were also fitted for explaining the interrelationships between the textural properties as functions of product composition. PMID- 25694734 TI - Kavalactone content and chemotype of kava beverages prepared from roots and rhizomes of Isa and Mahakea varieties and extraction efficiency of kavalactones using different solvents. AB - The South Pacific islanders have consumed kava beverage for thousands of years. The quality of kava and kava beverage is evaluated through determination of the content of six major kavalactones including methysticin, dihydromethysticin, kavain, dihydrokavain, yangonin and desmethoxyyangonin. In this study, we determined contents of kavalactones in and chemotype of kava beverages prepared from roots and rhizomes of Isa and Mahakea varieties and extraction efficiency of five different solvents including hexane, acetone, methanol, ethanol and ethyl acetate. The six major kavalactones were detected in all kava beverages with these five solvents. Different solvents had different extraction efficiencies for kavalactones from the lyophilized kava preparations. The contents of kavalactones in the extracts with acetone, ethanol, and methanol did not differ significantly. Ethanol had the highest extraction efficiency for the six major kavalactones whereas hexane gave the lowest extraction efficiency. PMID- 25694735 TI - Application of foam-mat drying with egg white for carrageenan: drying rate and product quality aspects. AB - Drying is a significant step in the production of carrageenan. However, current drying process still deals with too long drying time and carrageenan quality degradation. The foam mat drying is an option to speed up drying process as well as retaining carrageenan quality. In this case, the carrageenan was mixed with egg white (albumin) as foaming agent and methyl cellulose for foam stabilizer. The foam will break the carrageenan gels and creates the porous structure resulting higher surface area for water transfer. This research studied the effect of egg white and methyl cellulose on carrageenan drying at various air temperature, and thickness. As a response, the water content versus time was observed and the drying rate was estimated. Meanwhile, the carrageenan texture was verified by X-RD (X-Ray Diffraction) and TEM (Transmission Electron Microscopy). Results showed that the presence of egg white stablized by methyl cellulose can speed up drying rate as well as retaining the crystalline structure of carrageenan. The higher albumin content, the faster drying rate. However, the addition of albumin and methyl cellulose restricted not more than 30 % in the mixture for keeping carrageenan quality and purity. By adding egg white 20 % and methyl cellulose 10 %, the water diffusion and drying rate can be two fold compared with carrageenan drying without foam. The improvement can be higher at the higher temperature and thinner carrageenan sheets. PMID- 25694736 TI - Effect of Asparagus racemosus (shatavari) extract on physicochemical and functional properties of milk and its interaction with milk proteins. AB - The effects of interaction of Asparagus racemosus (shatavari) with milk constituents and physico-chemical and functional characteristics of milk was studied. Addition of freeze dried aqueous shatavari extract at a concentration of 1 g /100 ml of milk showed a decrease in pH, rennet coagulation time and an increase in acidity, viscosity and heat stability at maximum. The extract also imparted brown colour to milk and showed an increase in a* (redness) and b* (yellowness) values but a decrease in L* (lightness) value. Proteins in milk were modified by reaction with shatavari extract. The derivatives formed were characterized in terms of SDS-PAGE. Electrophoretic pattern of sodium caseinate and whey containing 1% shatavari herb extract did not show any difference in band pattern i.e. there was no difference in mobility based on size of the proteins, but the intensity (width) of bands differed. PMID- 25694737 TI - Effect of processing on physicochemical composition, bioactive compounds and enzymatic activity of yellow mombin (Spondias mombin L.) tropical juice. AB - Yellow mombin (Spondias mombin, L.) is a tropical fruit that presents exotic taste and aroma, being source of carotenoids and phenolics compounds. It presents a good potential for processing, despite some restriction related with the presence of high amounts of peroxidase (POD) and pectinmethylesterase (PME) which can cause sensory changes in the product. This work addresses the evaluation of changes in POD and PME enzyme activity during the traditional industrial processing used to produce tropical juices in Brazil. The enzyme activity was determined after the main steps of the processing: fruit pulping, homogenization and pasteurization. Although both enzymes presented significant activity loss during processing, the final product showed residual activity for PME (25 %) and POD (2.5 %). PME showed to be more thermal resistant than POD in yellow mombin juice. Considering the compounds with antioxidant activity, yellow mombin presented high amounts of carotenoids and phenolics when compared to other tropical fruits such as passion fruit and pineapple. Although the processing of the fruit resulted in significative phenolic loss, the carotenoids content was not affected significantly by the processing. PMID- 25694738 TI - Detection of calcium based neutralizers in milk and milk products by AAS. AB - Current study was carried out with the intent to standardize detection and estimation method for calcium (Ca) based neutralizers in milk and milk based indigenous products (khoa and paneer) using atomic absorption spectroscopy (AAS). Neutralized milk, khoa and paneer samples were prepared using milk with developed acidity to which calculated quantity of neutralizer (Ca based) was added. Rosalic acid test results get masked at times due to developed acidity which neutralizes the alkalinity imparted by neutralizer and hence gives false result with time in neutralizer added samples. Atomic absorption spectroscopy proved to be an accurate estimate which could detect the abnormal rise in mineral concentration even with slight addition of neutralizers in comparison with control milk and milk products. Formalin, which is a commonly used preservative in milk samples for chemical analysis, did not have any significant impact on estimation of calcium in the neutralized milk during storage. PMID- 25694739 TI - Extraction and characterization of pectin methylesterase from Alyanak apricot (Prunus armeniaca L). AB - This study was carried out to determine some of the biochemical properties of pectin methylesterase (PME) from Alyanak apricot which is an important variety grown in Malatya region of Turkey. The enzyme had high activity in a pH range of 7.0-8.0 with the maximal activity occurring at pH 7.5. However, the enzyme activity at high and low pH values was very low. The optimum temperature for maximal PME activity was found to be 60 degrees C. The activity of PME has been enhanced by NaCl, particularly at 0.15 M. Km and Vmax values for Alyanak apricot PME using apple pectin as substrate were found to be 1.69 mg/mL (r(2) = 0.992) and 3.41 units/mL, respectively. The enzyme was stable at 30-45 degrees C/10 min whereas it lost nearly all of its activity at 80 degrees C/10 min. Ea and Z values were found to be 206.1 kJ/mol (r(2) = 0.993) and 10.62 degrees C (r(2) = 0.992), respectively. PMID- 25694740 TI - Shellac and Aloe vera gel based surface coating for shelf life extension of tomatoes. AB - Shellac (S) and Aloe vera gel (AG) were used to develop edible surface coatings for shelf-life extension of tomato fruits. The coating was prepared by dissolving de-waxed and bleached shellac in an alkaline aqueous medium as such as well as in combination with AG. Incorporation of AG in shellac coating improved permeability characteristics of the coating film towards oxygen and carbon dioxide and water vapours. The coatings when applied to tomatoes delayed senescence which was characterized by restricted changes in respiration and ethylene synthesis rates during storage. Texture of the fruits when measured in terms of firmness showed restricted changes as compared to untreated control. Similar observations were also recorded in the case of instrumental colour (L*, a* and b* values). The developed coatings extended shelf-life of tomatoes by 10, 8 and 12 days in case of shellac (S), AG and composite coating (S + AG) coated fruits, respectively; when kept at ambient storage conditions (28 +/- 2 degrees C). PMID- 25694741 TI - Effect of varying level of dried milk proportion on formulation and reconstitution of Phirni mix powder. AB - An investigation was undertaken to study the varying proportion of WMP to SMP (25:75, 50:50 and 75:25) for formulation of Phirni mix powder (PMP). The sensory quality of experimental Phirni increased consistently with the increase in the levels of WMP upto 50:50, thereafter, decreased significantly (p < 0.01). The maximum sensory scores were obtained with a proportion of 50:50 for all sensory attributes. The textural characteristics were found significant (p < 0.01) with the increase in the proportion of WMP. Further, the formulation was reconstitute by dispersing the PMP with varying levels of water (50 : 30, 50 : 40 and 50 : 50) and followed by cooked at 85 +/- 5 degrees C for different cooking time (5,10 and 15 min). The results obtained among the reconstituted water on the sensory and textural attributes were found significant (p < 0.01). The maximum sensory scores were observed at 10 min cooking time with 50: 40 proportion of PMP to water. PMID- 25694742 TI - GC-MS analysis of bioactive compounds from the whole plant ethanolic extract of Evolvulus alsinoides (L.) L. AB - Medicinal plants are at great interest to the researcher in the field of biotechnology, as most of the drug industries depend in medicinal plants for the production of pharmaceutical compounds. Plants are the traditional sources for many chemicals used as pharmaceutical biochemicals, fragrances, food colours and flavours in different countries especially in India. Most herbal medicines and their derivative products were often prepared from crude plant extracts, which comprise a complex mixture of different phytochemical constituents (plant secondary metabolites). The chemical features of these constituents differ considerably among different species. GC-MS method used for the analysis of the obtained extracts can be an interesting tool for testing the amount of some active principles in herbs used in cosmetic, drugs, pharmaceutical or food industry. The aim of this study was to carry out for identification of bioactive compounds from the whole plant ethanolic extract of Evolvulus alsinoides by Gas chromatography and Mass spectroscopy (GC-MS). GCMS analysis of ethanolic extract was done by standard protocol using the equipment Thermo GC-Trace Ultra Version: 5.0, Thermo MS DSQ II. The GC-MS analysis revealed the presence of various compounds like piperine, octodeconoic acids, hexadecanoic acid and squalene in the ethanolic extract of Evolvulus alsinoides. Hence, the Evolvulus alsinoides may have chemopreventive, anticancer, anti-microbial activity, antioxidant and antidiabetic activity due to the presence of secondary metabolites in the ethanolic extract. Due to the presence of esters which can be used as a flavoring agent in food industries. These findings support the traditional use of Evolvulus alsinoides in various disorders. Further studies are needed to isolate active principle of the extract as well as to elucidate their exact mechanism of action in various disorders. PMID- 25694743 TI - Effect of date (Phoenix dactylifera L.) seed extract on stability of olive oil. AB - In this study, the antioxidant effect of date (Phoenix dactylifera L., Arecaceae) seed extracts at different concentrations (0.5 %, 1.0 % and 1.5 %) on the oxidative stability of olive oil at 60 degrees C was determined. Butylated hydroxyanisole (BHA) was used as positive control in the experiment. All extracts exhibited antioxidant activity compared to BHA up to 21 days. When antioxidant effect of extract concentrations were compared with BHA, the effect of 0.5 % extract concentration was more remarkable for olive oil up to 21 days. After 14 days of assay, all of seed extracts was effective at 60 degrees C in comparison with control. On the other hand, an important increase was observed in both the peroxide and free fatty acidity values during the experiment period. It concluded that date seed extract could be used as a oxidative inhibitor agent in oil and oil products. PMID- 25694744 TI - Effect of incorporation of fermented bamboo shoot on physicochemical and microbial quality of pork pickle. AB - Replacement of commercial chemical preservative (Vinegar) by incorporating fermented bamboo shoot (FBS) products partially or completely and their effect on physicochemical, microbial and shelf life qualities on pork pickle products was studied. Different FBS products such as FBS extract, paste and powder were incorporated in the pork pickle products at the level of 50 to 100 % with or without vinegar and stored at room temperature for 90 days. Highest pH values and lowest titrable acidity was recorded in products with 50 and 100 % FBS powder. No significant differences were observed with respect to proximate composition i.e. percent moisture, protein, fat and ash contents among the products except the product with 100 % FBS powder which had significantly (p < 0.01) lower moisture content. Microbial load (Log total plate counts) and thiobarbituric acid (TBA) values were found to be increasing as the storage periods were advancing. Except the product with 100 % FBS powder which could be stored for 30 days only, other products could be stored upto 90 days without any physicochemical and microbial problems. It can be concluded from this study that natural and organic FBS extract and paste can be used successfully replacing the conventional chemical preservative (Vinegar) for preparation of pork pickle products and preserved more than 90 days at room temperature. However, FBS powder can be used for preservation of the pickle products for a short period (30 days). PMID- 25694745 TI - Effect of low-pressure cold plasma on surface microflora of meat and quality attributes. AB - The aim of this study was to investigate the effect of cold plasma treatment on the inactivation of microorganisms on meat surface and its influence on colour of meat and pH value. Nitrogen, argon and helium plasma were generated by high voltage discharge in a vacuum chamber (final 0.8 MPa) with exposure times of 5 and 10 min. Total number of microorganisms, psychrotrophs and number of yeast and mould were determined using plate method. Instrumental evaluation of colour parameters L* a* b* was performed by colorimeter Minolta Cr 400. Psychrotroph bacteria counts and total number of microorganisms exposed to helium and argon plasma for 10 min were reduced about 3 log cfu/cm(2) and 2 log cfu/cm(2), respectively. Increasing reductions of yeasts and moulds were also obtained and were about 3 cfu/cm(2) (helium) and 2,6 cfu/cm(2) (argon). The usage of nitrogen plasma has not resulted in any significant reduction of counts of psychrotrophs and total. number of microorganisms. Yeasts and moulds were little affected by nitrogen plasma and their numbers decrease about 1 log cfu/cm(2.) after 10 min of treatment. No significant differences in colour parameters and pH value after cold plasma treatment were observed. These results demonstrated that cold plasma has antimicrobial activity and could be a promising method of biodecontamination, but further investigations focusing on meat quality have to be determinate. PMID- 25694746 TI - Flow behaviour of gellan sol with selected cations. AB - An understanding of the flow behaviour of the sols before gel formation is important for developing nutrient enriched gels. The influence of cations like CaCl2 (0.05 and 0.1 %, w/w) and FeSO4 (0.05 and 0.1 %, w/w) on the rheological properties of 1 % gellan sol (w/w) prior to gelling was investigated. The apparent viscosity, reported at a shear-rate of 100 s(-1), indicated that the gellan dispersion without any cation possessed lower values compared to other samples containing different cations. The Cross model provided the best fit (0.97 <= r <= 0.99, p <= 0.01) compared to moderate fitting to power law model (0.94 <= r <= 0.98). Among the different Cross model parameters, the zero-shear viscosity (etao) increased with the addition of CaCl2 and FeSO4, and with an increase in their concentrations. Zero-shear viscosity values were 0.46 Pas for gellan sol, 0.79 Pas for gellan with 0.05 % (w/w) CaCl2, 1.41 Pas for gellan with 0.1 % CaCl2, 3.85 Pas for gellan with 0.05 % FeSO4 and 4.33 Pas for gellan with 0.1 % FeSO4. An increase in cation concentration from 0.05 to 0.10 % (w/w) marginally increased the relaxation time (lambda) values indicating the development of more solid characteristics in the sol. PMID- 25694747 TI - The prognostic value of intermedin in patients with breast cancer. AB - This study aimed to evaluate the prognostic value of preoperative plasma intermedin levels in breast cancer patients. Plasma intermedin levels of 252 breast cancer women and 100 healthy women were determined using radioimmunoassay kit. Adverse event was defined as first local recurrence, distant metastasis, second primary cancer of another organ, or death from any cause during 5-year follow-up. Disease-free survival was defined as the time between surgery and the date of any adverse event whichever appeared first. Overall survival was defined from surgery to death for any cause. The relationships between plasma intermedin levels and clinical outcomes of breast cancer patients were evaluated using multivariate analysis. The results showed that preoperative plasma intermedin levels were substantially higher in patients than in healthy subjects using t test. Intermedin was identified as an independent predictor for 5-year mortality, adverse event, disease-free survival, and overall survival using multivariate analysis. Based on receiver operating characteristic curve analysis, preoperative plasma intermedin levels had high predictive value for 5-year mortality and adverse event. In conclusion, preoperative plasma intermedin levels are highly associated with poor patient outcomes and intermedin may be a potential prognostic biomarker for patients with breast cancer. PMID- 25694748 TI - Local inflammation in fracture hematoma: results from a combined trauma model in pigs. AB - Background. Previous studies showed significant interaction between the local and systemic inflammatory response after severe trauma in small animal models. The purpose of this study was to establish a new combined trauma model in pigs to investigate fracture-associated local inflammation and gain information about the early inflammatory stages after polytrauma. Material and Methods. Combined trauma consisted of tibial fracture, lung contusion, liver laceration, and controlled hemorrhage. Animals were mechanically ventilated and under ICU-monitoring for 48 h. Blood and fracture hematoma samples were collected during the time course of the study. Local and systemic levels of serum cytokines and diverse alarmins were measured by ELISA kit. Results. A statistical significant difference in the systemic serum values of IL-6 and HMGB1 was observed when compared to the sham. Moreover, there was a statistical significant difference in the serum values of the fracture hematoma of IL-6, IL-8, IL-10, and HMGB1 when compared to the systemic inflammatory response. However a decrease of local proinflammatory concentrations was observed while anti-inflammatory mediators increased. Conclusion. Our data showed a time-dependent activation of the local and systemic inflammatory response. Indeed it is the first study focusing on the local and systemic inflammatory response to multiple-trauma in a large animal model. PMID- 25694749 TI - Evaluation of serum amyloid a as a marker of persistent inflammation in patients with rheumatoid arthritis. PMID- 25694750 TI - Involuntary euthanasia of severely ill newborns: is the Groningen Protocol really dangerous? AB - Advances in medicine can reduce active euthanasia of newborns with severe anomalies or unusual prematurity, but they cannot eliminate it. In the Netherlands, voluntary active euthanasia among adults and adolescents has been allowed since 2002, when the so-called Groningen Protocol (GP) was formulated as an extension of the law on extremely premature and severely ill newborns. It is maintained that, at bioethical level, it serves the principle of beneficence. Other European countries do not accept the GP, including Belgium. Admissibility of active euthanasia is a necessary, though inadequate, condition for acceptance of the GP. Greece generally prohibits euthanasia, although the legal doctrine considers some of the forms of euthanasia permissible, but not active or involuntary euthanasia. The wide acceptance of passive newborns euthanasia, especially when the gestational age of the newborns is 22-25 weeks ("grey zone"), admissibility of practices within the limits between active and passive euthanasia (e.g., withholding/withdrawing), of "indirect active euthanasia" and abortion of the late fetus, the tendency to accept after-birth-abortion (infanticide) in the bioethical theory, the lower threshold for application of withdrawing in neonatal intensive care units compared with pediatric intensive care units, all the above advocate wider acceptance of the GP. However, the GP paves the way for a wide application of involuntary (or pseudo-voluntary) euthanasia (slippery slope) and contains some ambiguous concepts and requirements (e.g., "unbearable suffering"). It is suggested that the approach to the sensitive and controversial ethical dilemmas concerning the severely ill newborns is done not through the GP, but rather, through a combination of virtue bioethics (especially in the countries of the so-called "Mediterranean bioethical zone") and of the principles of principlism which is enriched, however, with the "principle of mutuality" (enhancement of all values and principles, especially with the principles of "beneficence" and "justice"), in order to achieve the "maximal" bioethical approach, along with the establishment of circumstances and alternatives that minimize or eliminate the relevant bioethical dilemmas and conflicts between the fundamental principles. Thus, the most appropriate/fairest choices are made (by trained parents and physicians), considering all interests involved as much as possible. Hippokratia 2014; 18 (3): 196-203. PMID- 25694751 TI - Management and investigation of viral gastroenteritis nosocomial outbreaks: lessons learned from a recent outbreak, Greece, 2012. AB - BACKGROUND: A nosocomial outbreak in a 740-bed hospital in Athens, Greece, was investigated in January-February 2012. METHODS: Recommendations on infection control measures were given and two case-control studies were conducted among patients (study A) and health care workers (HCWs) (study B). Compliance to control measures was evaluated. RESULTS: The absence of a routine recording system of nosocomial-acquired gastroenteritis cases led to a 10 days delay in outbreak identification. In total, 63 gastroenteritis cases were identified; 30 HCWs and 33 patients. In the multivariable analysis of study A the disease incidence among patients was statistical significantly associated with a prior incident of vomitus in their room (OR=7.96, 95% CI=1.29-49.2). In study B, the incidence was associated with the history of direct contact with a symptomatic patient (OR=3.03, 95%CI 1.01-9.12). Twenty one (75%) of the symptomatic HCWs reported absence from work for a median of 2 days (range: 1-4). Seven (25.0%) continued to work despite being symptomatic. Only, 11.1% of patients were isolated or cohorted after developing symptoms. In-hospital virological testing was not feasible and one specimen sent to a university laboratory was positive for norovirus. CONCLUSIONS: An appropriately designed protocol regarding the detection, the management and the laboratory investigation of nosocomial gastroenteritis outbreaks should be followed in order effective containment to be reassured. Hippokratia 2014; 18 (3): 204-208. PMID- 25694752 TI - Vascular access in hemodialyis patients - registry data. AB - BACKGROUND: The use of arteriovenous fistula over a central venous catheter in hemodialysis patients is recommended whenever possible. It has become the gold standard among all the available permanent vascular accesses for hemodialysis as it is associated with less complications. The aim of our study was to analyze the type of vascular access in hemodialysis patients in our country, FYR of Macedonia and to see its association with other variables recorded by the National Renal Registry in 2009. MATERIAL AND METHODS: Data were collected by 18 hemodialysis centers in the country. A total of 1,457 patients were analyzed. One hundred and ninety one patients were incident, and 164 out of 1,457 died during the year. Except for 9 patients, all the others had data on type of vascular access, as well as data on any vascular access intervention performed during the year. RESULTS: The overall mean age was 58.8 +/- 13.1 years. Eighty-nine percent of the non-incident patients (prevalent plus those who died during the year) had arteriovenous fistula, 10.6% central venous catheter and 0.2% vascular graft. When incident to non-incident patients were compared, incident patients were significantly older, had significantly higher mortality and significantly lower percentage of arteriovenous fistula. Patients with arteriovenous fistula had significantly longer dialysis vintage and significantly less deaths compared to those with central venous catheters. CONCLUSIONS: The study showed that the number of non-incident hemodialysis patients with arteriovenous fistula in the country was high. The incident hemodialysis patients have high number of central venous catheters as vascular access for hemodialysis and significantly higher mortality compared to non-incident patients. Hippokratia 2014; 18 (3): 209-211. PMID- 25694753 TI - Nutrition assessment of children with advanced stages of chronic kidney disease-A single center study. AB - BACKGROUND: Malnutrition is a major problem among children with Chronic Kidney Disease (CKD) and it is essential to be recognized as early as possible. Aim of our study was to assess the nutrition status of children with CKD. METHODS: Nutrition status of 30 children (1-16 years) with CKD stages IIIV and on peritoneal dialysis was evaluated. Malnutrition risk was assessed by Pediatric Digital Scaled MAlnutrition Risk screening Tool (PeDiSMART) score software.Anthropometry was expressed as Z-scores for age and sex. Phase angle (PhA) and body cell mass were assessed by bioelectrical impedance analysis (BIA). Three-day food intake was recorded and analyzed. Biochemical indexes were assessed. RESULTS: Depending on the marker used for assessment 20-40% of our patients were malnourished. Intake/requirements ratio (median) was 86.5% for actual energy intake and 127% for actual protein intake. Multiple regression analysis has shown that the most determinant factor for Mid Upper Arm Circumference (MUAMC) was actual protein intake, Glomerular Filtration Rate (GFR) and age at diagnosis. PhA was mainly affected by GFR and energy intake. Statistically significant inverse correlation was found between PeDiSMART score and PhA (p=0.001), MUAMC (p=0.008) as well as protein intake (p=0.016). CONCLUSIONS: A considerable proportion of children with advanced CKD are undernourished. Regular dietitian evaluation based on novel tools as PeDiSMART score and PhA may identify earlier patients at risk for malnutrition. Hippokratia 2014; 18 (3): 212-216. PMID- 25694754 TI - Evaluation of use of antibiotics without prescription among young adults in Albania case study: Tirana and Fier District. AB - BACKGROUND: Self-medication is defined as the utilization of drugs to treat self diagnosed disorders or symptoms, or the irregular or continuous use of a prescribed drug for chronic or repeated diseases or symptoms. The main problem with self-medication with antimicrobials is the emergence of pathogenic resistance. Antimicrobial resistance is an existing problem world-wide, mainly in developing countries. The aims and objectives of the study presented in this article are to evaluate the prevalence of purchase of antibiotics without prescription and appropriateness of use among adults and to determine the impact of the education level on the sensibility level over the use of antibiotics. METHODS: This was a questionnaire based study of 3 month duration. The study includes data from 350 young adults (182 men/172 women, mean age +/- SD: 34.72 +/ 13.7 years), who visited ten different pharmacies located in the city of Tirana and the "Olympus" Private Medical Clinic in Fier between December 2012 and March 2013. Also a part of questionnaires was distributed by e-mail. RESULTS: The results of this study showed that out of 350 young adults, 273 (78.14%) of them used antibiotics as self medication. The most common reasons for self administration of antibiotics were fever 171 (29.23%), sore throat 170 (29.06%) and cough 83 (14.19%). In this study we observed that the most common source of information regarding self-medication is the pharmacy (community pharmacists) 166 (36.40%) and most common antibiotic used as self-medication is amoxicillin 70 (19.39%). Authors also determined the impact of education level over the use of antibiotics. The results showed that adults with low and medium education level (7.986% and 43.056% respectively) were most likely to use antibiotics as self medication. CONCLUSIONS: The findings from this study highlight the striking prevalence of self-medication among young adults in Albania and the lack of awareness about the risks associating their use. We recommend that a holistic approach must be taken to prevent this problem from escalating which would involve awareness and education regarding the implications of self medication, strategies to prevent the supply of medicines without prescription by pharmacies and strict rules regarding pharmaceutical advertising.Hippokratia 2014; 18 (3): 217-220. PMID- 25694755 TI - Low Density Lipoprotein transport in the normal human aortic arch. AB - BACKGROUND: To understand the genesis and progression of atherosclerosis is essential to elucidate the blood flow and the transport of molecules in the cardiovascular system. The purpose of this computational study is to elucidate the relationship between low wall shear stress (WSS) - high site concentration of low density lipoproteins (LDL) and atherosclerotic sites in the normal human aortic arch under physiological flow and mass transport conditions. METHODS: The numerical simulation couples the flow equations with the transport equation applying realistic boundary conditions at the wall in terms of blood-side concentration. The blood is considered to be non-Newtonian fluid obeying to the power law. Suitable mass transport conditions are specified at the wall. RESULTS: Aortic arch walls are exposed to cholesterolemic environment although the applied mass and flow conditions refer to normal human geometry and normal mass-flow conditions. The luminal surface LDL concentration varies inversely with the WSS. Regions of high LDL luminal surface concentration do not necessarily co-locate to the sites of lowest WSS. Concave sides of the aortic arch exhibit, relatively to the convex sides, elevated concentration of the LDL. The area averaged normalized LDL concentration over the entire normal aortic arch is 1.267. The daughter aortic arch vessels exhibit, relatively to the main aorta, elevated LDL concentrations. CONCLUSIONS: The near wall paths of the velocities might be the most important factor for the elevated LDL concentration at areas located either at the vicinity of bifurcations regions or at high curvature regions. Hippokratia 2014; 18 (3): 221-225. PMID- 25694756 TI - Therapeutic hypothermia in asphyxiated neonates with hypoxic-ischemic encephalopathy: A single-center experience from its first application in Greece. AB - BACKGROUND/AIM: Therapeutic hypothermia has become an established therapy in asphyxiated neonates with evidence of moderate/severe hypoxic-ischemic encephalopathy. Herein, we describe our recent experience with total body cooling in asphyxiated neonates, which is the first relevant report in Greece. PATIENTS AND METHODS: The medical records of all asphyxiated newborns treated with therapeutic hypothermia in our center between September 2010 and October 2013 were retrospectively reviewed. We recorded data related to neonatal-perinatal characteristics, whole body cooling and outcome. RESULTS: Twelve asphyxiated neonates [median gestational age 38 weeks (36-40)] received whole body cooling (rectal temperature 33.5 +/- 0.5 (o)C for 72 hours) during the study period for moderate (n=3) and severe (n=9) hypoxic-ischemic encephalopathy. Cooling was passive in 4 and active in 8 (66.7%) cases. Therapeutic hypothermia was initiated at the median age of 5 hours (0.5-11) after birth. Seven neonates survived (58.3%) to hospital discharge. On follow-up (7-35 months), neurodevelopment outcome was normal in 1 case, while 3, 1 and 2 subjects had mild, moderate and severe impairment, respectively. CONCLUSIONS: Our initial experience with whole body cooling supports its beneficial effect in asphyxiated neonates. This treatment should be offered in all centers involved in the care of such neonates using either simple means (passive cooling) or automated cooling devices. Hippokratia 2014; 18 (3): 226-230. PMID- 25694757 TI - Acute inflammatory arthritis in the elderly; Old flames, new sparks. AB - BACKGROUND: The overall world prevalence of rheumatoid arthritis (RA) ranges from 0.5-1.0%. The annual incidence of RA in most European countries ranges from roughly 0.4 to >2.5 per 1,000 adults, increasing with age. A significant proportion of newly diagnosed cases will evolve into true erosive RA. METHODS: The aim of this cohort study was to study the characteristics of new developing, acute (<1 year), rheumatoid arthritis in an elderly (>65 years) population; its presenting features, accompanying manifestations and laboratory findings. One hundred twenty eight patients (103?, 25?) who presented to the rheumatology outpatients clinic with new-onset RA were included in the study. 42.2% of the patients had pre-existing osteoarthritis. RESULTS: At presentation, 14.3% of the patients had systemic manifestations (fever, weight loss), 25.78% reported concomitant sicca symptomatology, and 50.9% were found to have abnormal haematological parameters (anemia and/or thrombocytosis). Clinical and laboratory parameters of the disease were analyzed and related to disease manifestations.. Haematological abnormalities were found to be associated both with increased inflammatory markers, as well as with increased titres of rheumatoid factor (RF), but not anti - cyclic citrullinated peptide (CCP) antibodies, in contrary to systemic manifestations which were not found to be related to the above mentioned parameters. CONCLUSIONS: As the global population is becoming older, physicians will be challenged with the recognition and treatment of these conditions and their particular features in an increasing number of geriatric patients; within the context of the specific characteristics and comorbidities of this age group. Hippokratia 2014; 18 (3): 231-233. PMID- 25694758 TI - The effect of Antithrombin-III on routine hematological and biochemical parameters in an experimental animal model of skeletal muscle ischemia reperfusion injury. AB - BACKGROUND: Antithrombin III (AT-III) has been shown to attenuate the local and systemic harmful effects of skeletal muscle ischemia-reperfusion (I-R) injury. The aim of the present study was to monitor the fluctuation of routine hematological and biochemical parameters in an experimental animal model of tourniquet-induced skeletal muscle I-R injury and to investigate how these are influenced by the protective administration of AT-III. METHODS: Sixty male Wistar rats were submitted to a 6-hour, tourniquet-induced, complete ischemia of the right hind-limb. Animals were divided into those receiving AT-III (dose, 250 IU/kg) 30 minutes before the reperfusion (group A, n=30) and those receiving placebo (group B, n =30). Another 10 animals were sham-operated (group C). White blood cell (WBC) and platelet (PLT) count, aspartate and alanine aminotransferases (AST and ALT), alkaline phosphatase (ALP), and gamma-glutamyl transferase (gamma-GT) were estimated in blood samples taken from the inferior vena cava at 3 different time points post-reperfusion (at baseline, at 30 minutes and at 4 hours) and groups A and B were compared using the Mann-Whitney U test. RESULTS: There were no statistically significant differences between the AT-III and the placebo groups at 0, 30 minutes and 4 hours with regard to the WBC, ALT and gamma-GT levels, however, there was a significant decrease of AST levels 4 hours post-reperfusion in the AT-III group compared to the placebo group (p=0.002). An increased PLT count and ALP levels 30 minutes post-reperfusion were also noted in the AT-III group compared to placebo (p<0.001; and p=0.001, respectively). CONCLUSIONS: Of the routine hematological and biochemical parameters tested, AST was found to be significantly suppressed at 4 hours in the AT-III-treated animals, suggesting a possible beneficial effect of AT-III in mouse skeletal muscle I-R injury. The effect of AT-III on PLTs and ALP levels merits further investigation. Hippokratia 2014; 18 (3): 234-239. PMID- 25694759 TI - Endogenous subclinical hyperthyroidism may not lead to bone loss in premenopausal women. AB - BACKGROUND: Osteoporosis is defined as the decrease in bone mineral density. It is a serious health problem showing the predisposed person with increased bone fracture risk. Hyperthyroidism is one of the major causes of secondary osteoporosis. The aim of this study was to assess bone mineral density in premenopausal women with endogenous subclinical hyperthyroidism. METHODS: A total of 168 subjects were included in this case-control study, of whom 86 and 82 participants were premenopausal women with subclinical hyperthyroidism and healthy premenopausal subjects, respectively. The patients with subclinical hyperthyroidism who were not receiving L-thyroxine treatment were included. The women in postmenopausal state or having chronic disease were excluded. The bone mineral densities of all subjects with dual energy X-ray absorptiometry were examined. RESULTS: The Z scores (femur and L1-4) of the study group were -0.15 +/ 1.15 and -0.23 +/- 1.03, respectively. The Z scores of the control group were 0.39 +/- 1.08 and -0.55 +/- 0.98, respectively. The differences between the groups were not statistically significant (p=0.14, 0.34, respectively). CONCLUSION: Our data suggest that contrary to exogenous subclinical hyperthyroidism, endogenous subclinical hyperthyroidism may not decrease bone mineral density in premenopausal women and it may not a risk factor for osteopenia or osteoporosis. Hippokratia 2014; 18 (3): 240-244. PMID- 25694760 TI - Observation of short-term catheter induced thrombosis in children treated with blood purification. AB - BACKGROUND: No studies have assessed the safety of short-term catheter-induced thrombosis in children treated with blood purification. The aim of this study was to determine the incidence and evolution of thrombosis in the children. METHODS: One hundred nineteen (119) children treated with blood purification were enrolled. The data of baseline characteristics, coagulation status and type of catheters were recorded. Thrombosis- related symptoms and signs, ultrasound examinations of the right femoral veins were followed for 2 months. The relationship between associated risk factors (age, sex and type of catheters) and thrombosis was analyzed. RESULTS: Of the 119 patients, 95 (79.8%) developed deep venous thrombosis (DVT) in the right external iliac veins. In only one patient it was clinically obvious. The incidence of thrombosis had no significant difference between the following subgroups: 1. Children under 6 years (14/15, 93.3%), 6-12 years (63/78, 80.7%) and above 12 years (18/26, 69.2%) (p=0.436); 2. Male (57/66, 86.3%) and female patients (38/53, 71.6%) (p=0.448); 3. Children catheterized with 8F (52/63, 82.5%) and 11F catheters (43/56, 76.7%) (p=0.435). Thrombolysis was achieved in 77 cases (77/80, 96.3%) with treatment of oral dipyridamole at one month and 80 cases (100%) at two months. CONCLUSION: Children treated with blood purification through short-term femoral venous catheters have an increased risk of developing DVT, which is usually asymptomatic and good in prognosis. Hippokratia 2014; 18 (3): 245-250. PMID- 25694761 TI - Computer-assisted evaluation of Mandibular Cortical Width (MCW) index as an indicator of osteoporosis. AB - BACKGROUND: To assess the diagnostic accuracy of mandibular cortical width (MCW) as an indicator of the presence of osteoporosis. MATERIALS AND METHODS: The study included 343 women between 45-75 years of age. After informed consent, all subjects underwent dual energy X-ray absorptiometry (DXA) of the hip and the lumbar spine (L1 to L4) in order to establish a gold standard diagnosis of osteoporosis and an orthopantomogram (OPG). From the initial subjects, 28 (8.2%) did not meet the inclusion criteria. In the final sample 315 patients were included, of whom 293 were postmenopausal (93.3%) and 22 perimenopausal (6.7%). Based on the DXA examination the sample was divided into three groups: a)normal controls (n=106), b)osteopenics (n=103) and c)osteoporotics (n=106). The MCW index was calculated by three different observers using the Emago image processing software. Inter - rater agreement was considered important since MCW was being tested as a possible screening tool for osteoporosis. RESULTS: Comparisons of MCW values between normal controls, osteopenic and osteoporotic women in our sample showed that these values clearly differentiate between the three groups, especially between normal and osteoporotic subjects. Furthermore, the receiver operator characteristic curve (ROC) analysis showed this to hold true in real diagnostic terms, giving a threshold value of 3.24 for differentiating between normal and osteoporotic women. CONCLUSIONS: With ROC values ranging between 0.80 and 0.87 we can reasonably assume that the MCW index is a reliable indication of the presence of osteoporosis in a patient. Hippokratia 2014; 18 (3): 251-257. PMID- 25694762 TI - Uterine artery embolization for treatment of symptomatic fibroids; a single institution experience. AB - BACKGROUND: Uterine fibroids are the most common reproductive tract tumours in females. Uterine artery embolization (UAE) is a fertility-sparing procedure for treatment of symptomatic fibroids. We evaluated the efficacy and safety of UAE in the treatment of 118 patients with symptomatic uterine fibroids in a single Academic Centre in the West of Ireland to determine whether fibroid and uterine size affect clinical outcomes and complications. METHODS: This was a retrospective cohort of 118 patients who underwent UAE for treatment of symptomatic fibroids between November 2006 and August 2011. Diagnosis of fibroids in symptomatic patients was established by magnetic resonance imaging (MRI) and/or transabdominal ultrasonography (US). Three different embolic agents were used. All patients had at least one follow-up using MRI, at three and/or 12 months. A non-validated questionnaire was used to report patient satisfaction with regards to symptoms improvement on a yes-or-no basis. RESULTS: Mean fibroid volume, uterine size and dominant fibroid size were significantly reduced at three months and one year follow-up (p = 0.00) and that was tallied with symptoms improvement (p < 0.05). Overall patient satisfaction at three months was 84% falling to 75.9% by 12 months (all p < 0.05). Few complications were reported (2.5%). No significant difference was observed in safety or efficacy for different embolic agents. CONCLUSION: The study confirms the safety and efficacy of UAE in the treatment of symptomatic fibroids. Hippokratia 2014; 18 (3): 258 261. PMID- 25694763 TI - Alpha1-microglobulin as an early biomarker of sepsis-associated acute kidney injury: a prospective cohort study. AB - BACKGROUND: Sepsis emerges as the leading risk factor for acute kidney injury (AKI) development in critically ill patients. Much effort has been invested so far on early diagnosis of AKI using promising biomarkers. This study aimed to determine whether urine alpha1-microglobulin (alpha1m), a lipocaline member previously used as an indicator of proximal tubular dysfunction, can early predict the development of sepsis-associated AKI (SAAKI) in critically ill patients. METHODS: A prospective, observational study was conducted in a single center Intensive Care Unit (ICU). Patients with normal renal function admitted to the ICU followed for sepsis and AKI development. Urine alpha1m levels were analyzed in pooled samples from 24-hour urine collections on sepsis onset and at various time points thereafter. The diagnostic performance of urine alpha1m was assessed using thenonparametriccalculation of the area under the curve (AUC) of the receiver operating characteristic (ROC) curve. RESULTS: Among 286 critically ill patients admitted to our ICU in a year, 45 patients with sepsis met the inclusion criteria. SAAKI developed in 16 septic patients (35.6%). Urine alpha1m levels were significantly elevated in all septic patients (average value of all samples on the day of sepsis: 46.02 +/- 7.17 mg/l) and showed a trend to increase in patients who finally developed SAAKI. The AUC for SAAKI prediction according to alpha1m urine levels 24-hours before SAAKI onset was 0.739 (sensitivity 87.5%, specificity 62.07%, cutoff level 47.9 mg/l). Urine alpha1m 24-hours before SAAKI, serum creatinine on sepsis onset and Acute Physiology and Chronic Health Evaluation II (APACHE II) score on sepsis onset emerged as the most powerful independent predictors of SAAKI. The combination of these three parameters improved the AUC for SAAKI prediction to 0.944. CONCLUSION: Urine alpha1m levels might help in the early prediction of SAAKI development and may prove useful biomarker. The pathogenetic implications of alpha1m in sepsis and SAAKI need further investigation. Hippokratia 2014; 18 (3): 262-268. PMID- 25694764 TI - Evaluation of potential salivary acetaldehyde production from ethanol in oral cancer patients and healthy subjects. AB - BACKGROUND: Acetaldehyde has been implicated as a major factor in oral carcinogenesis associated with alcohol consumption. In this study, saliva samples from oral cancer patients and healthy individuals were incubated in vitro with ethanol in order to investigate factors which can influence salivary acetaldehyde production. MATERIALS AND METHODS: A total of 66 individuals (40 males and 26 females, mean age 52 years) participated in the study. Participants were classified into three groups: Group 1 (oral cancer patients [n = 20]); Group 2 (poor dental health status [n = 25]) and Group 3 (good dental health status [n=21]). Every patient chewed a 1g piece of paraffin chewing gum for 1 minute then saliva samples were collected from all individuals. After in vitro incubation of the samples with ethanol, the levels of salivary acetaldehyde production was measured by head space gas chromatography. Kruskal-Wallis and Mann Whitney tests and Spearman's Correlations analysis were performed for statistical analyses. RESULTS: The salivary acetaldehyde production was significantly higher (p <0.0001) in both group 1 and group 2 when compared to group 3. However, there was no significant difference between group 1 and group 2. Poor dental health status, infrequent oral hygiene habits and dental visits, smoking and presence of a dental prosthesis were significant parameters for increased levels of salivary acetaldehyde production from alcohol. The evaluation of salivary acetaldehyde production after in vitro incubation with ethanol may be useful for early detection of oral cancer. CONCLUSION: According to the results of this study, the significantly higher levels of salivary acetaldehyde production in oral cancer patients and individuals with poor dental health status may suggest a possible link between increased salivary acetaldehyde production and oral cancer. Improved oral hygiene can effectively decrease the level of salivary acetaldehyde production in oral cavity. Hippokratia 2014; 18 (3): 269-274. PMID- 25694765 TI - Eosinophilic ascites, as a rare presentation of eosinophilic gastroenteritis. AB - BACKGROUND: Eosinophilic ascites is the most unusual presentation of eosinophilic gastroenteritis (EGE), caused by edema and eosinophilic inflammation of the small bowel wall's serosal layer. CASE REPORT: We report the case of a 37-year-old woman, who presented with diffuse abdominal pain, nausea, abdominal distension, moderate ascites and diarrhea of two weeks duration. The rest of physical and clinical examination was unremarkable, and her past medical history was uneventful. Magnetic Resonance Imaging showed the presence of ascites and diffuse thickening of small bowel wall, but did not detect a primary malignancy in the abdominal cavity; and no signs of portal hypertension or liver damage. Laboratory test results revealed essential peripheral blood eosinophilia, elevated serum IgE and marked increase of eosinophils in the abdominal fluid. Treatment with corticosteroids normalized laboratory tests results, and the ascites resolved immediately. CONCLUSIONS: EGE is a rare entity and it should be kept in mind in patients of unexplained ascites. The absence of primary malignancy on imaging, coupled with marked increase of fluid esinophilia and immediate response to treatment with steroids, confirm indirectly the diagnosis of EGE. Hippokratia 2014; 18 (3): 275-277. PMID- 25694766 TI - Primary retroperitoneal mucinous cystadenoma. A rare case with two cysts and review of the literature. AB - BACKGROUND: Primary retroperitoneal mucinous cystadenoma is a rare neoplasm, with benign biological behavior. Delay in diagnosis and treatment of this tumor may be fatal for the patient, because of complications, such as rupture, infection and malignant transformation. CASE PRESENTATION: We present a 23-year-old woman, who was admitted to the hospital because of a palpable abdominal mass and discomfort since 4 months. Computed Tomography and Magnetic Resonance Imaging scans were performed and showed two retroperitoneal cystic masses, which were excised by laparoscopy. Histological and immunohistochemical examination revealed that the inner surfaces of the cysts were lined by epithelium with features of mesothelial cells, in addition to ovarian mucinous cystadenoma. This is the 29(th) case and the second reported case with two contemporary cysts. CONCLUSION: The origin of retroperitoneal mucinous cystadenomas is still unclear. Pathological and immunohistochemical findings proved that these tumors resemble ovarian mucinous cystadenomas but are unattached to the ovary and can arise at any location in the retroperitoneum. Surgical excision of the aforementioned tumors is the treatment of choice. Hippokratia 2014; 18 (3): 278-281. PMID- 25694767 TI - A unique case of ruptured ectopic pregnancy in a patient with negative preg-nancy test - a case report and brief review of the literature. AB - INTRODUCTION: Despite the major advances made in the diagnosis and management of ectopic pregnancies in the last two decades, an accurate diagnosis can sometimes still be quite challenging, since it relies on the combination of ultrasound findings and serial serum beta-human chorionic gonadotrophin (beta-hCG) measurements. CASE PRESENTATION: This paper describes the case of a 36-year-old woman of Caucasian origin who was admitted to the emergency department of our clinic with clinical symptoms of hemorrhagic shock in combination with two negative pregnancy tests done by her at home and a negative urine test which was performed on her admission to the hospital. Quantitative measurement of beta-hCG in the serum of the patient was 13 mIU/mL. On admission, right tubal pregnancy was diagnosed on ultrasound and she underwent an emergency laparotomy due to signs of hemodynamic shock. CONCLUSION: It is sometimes a considerable challenge to identify a patient with an ectopic pregnancy at risk of rupture. This case of ectopic pregnancy which was followed by a negative pregnancy test illustrates the magnitude of the difficulties involved in the diagnosis of ectopic pregnancy. It also demonstrates the need to maintain a high clinical index of suspicion and to undertake careful clinical examination of the patient on the basis of the clinician's diagnostic research. Hippokratia 2014; 18 (3): 282-284. PMID- 25694768 TI - Cervical mass as the presenting manifestation of hepatocellular carcinoma. AB - BACKGROUND: Hepatocellular carcinoma is one of the most common cancers in the world due to its association with chronic hepatitis infections. Amongst the most usual metastasis of hepatocellular carcinoma are the lymph nodes, the lungs and the bones. Soft tissue metastases are extremely rare. CASE PRESENTATION: Herein, we report the case of a 73-years-old male patient who presented with cervical and upper extremities muscle pain along with paresthesias and a palpable mass on the cervical region. CONCLUSION: This unusual clinical manifestation along with the above-described rare presentations of hepatocellular carcinoma must be taken into account, especially among patients with chronic hepatitis infections. Hippokratia 2014; 18 (3): 285-287. PMID- 25694769 TI - Is the treatment of hearing loss in rheumatoid arthritis effective? PMID- 25694770 TI - Proteomic characterization of adrenal gland embryonic development reveals early initiation of steroid metabolism and reduction of the retinoic acid pathway. AB - BACKGROUND: Adrenal glands are essential endocrine organs composed of two embryological distinct tissues. Morphological changes during their development are well described, but less understood with regard to their molecular mechanisms. To identify proteins and pathways, which drive the initial steps of the specification of the endocrine function of the adrenal gland, rat's adrenal glands were isolated at different embryonic days (E): E14, E16, E18, E19 and postnatal day 1 (P1). RESULTS: The alteration of the proteome during the stages E16, E19 and P1 was investigated by combining two dimensional gel electrophoresis and mass spectrometric analysis. Out of 594 excised protein spots, 464 spots were identified, resulting in 203 non-redundant proteins. The ontogenic classification of the identified proteins according to their molecular function resulted in 10 different categories, whereas the classification of their biological processes resulted in 19 different groups. This gives an insight into the complex mechanisms underlying adrenal gland development. Interestingly, the expression of retinoic acid pathway proteins was decreased during the development of the adrenal gland, suggesting that this pathway is only important at early stages. On the other hand, key proteins of the cholesterol synthesis increased their expression significantly at E19 revealing the initiation of the endocrine specialization of the adrenal glands. CONCLUSIONS: This study presents the first comprehensive wide proteome analysis of three different stages of embryonic adrenal gland development. The identified proteins, which were expressed in early stages of development, will shed light on the molecular mechanisms underlying embryonic development of the adrenal gland. PMID- 25694771 TI - Revisiting the cost-effectiveness of universal HPV-vaccination in Denmark accounting for all potentially vaccine preventable HPV-related diseases in males and females. AB - OBJECTIVE: The purpose of this study was to assess the consequences of a national immunization program with HPV vaccine for both boys and girls in Denmark, including the prophylactic effects on all potentially vaccine preventable HPV associated diseases in male and female. METHODS: The study focussed on the quadrivalent vaccine which protects against HPV type 6, 11, 16 and 18, and the vaccine's protection against genital warts, cervical intraepithelial neoplasia, cervical cancer, anogenital cancer (anal, penile, vaginal and vulvar cancer) and head and neck cancer (oral cavity, oropharyngeal, hypopharyngeal and laryngeal cancer) were included in the analyses. In general, the analysis was performed in two phases. First, an agent-based transmission model that described the HPV transmission without and with HPV vaccination was applied. Second, an analysis of the incremental costs and effects was performed. The model did not include naturally-acquired immunity to HPV in the simulations. RESULTS: In the base case result (i.e. vaccination of girls only, 85% vaccination rate, private market price at ? 123 per dose ex. VAT) an ICER of 3583 ?/QALY (3-dose regime) is estimated when all HPV-related diseases are taken into account. Vaccination of girls & boys vs. vaccination of girls only an ICER of 28,031 ?/QALY (2-dose regime) and 41,636 ?/QALY (3-dose regime) is estimated. CONCLUSIONS: Extension of the current HPV programme in Denmark to include boys and girls is a cost effective preventive intervention that would lead to a faster prevention of cancers, cancer precursors and genital warts in men and women. PMID- 25694772 TI - International MS Falls Prevention Research Network: Report from the Front Lines. PMID- 25694773 TI - From the editor. PMID- 25694774 TI - Drawing on related knowledge to advance multiple sclerosis falls-prevention research. AB - There is much to be learned from falls-related research outside the field of multiple sclerosis (MS), as well as from work within the MS field but not specific to falls or falls prevention. This article describes three examples of such bodies of work that have potential to broaden approaches to falls-prevention research: 1) sensory components of postural control among older adults, 2) lessons learned from physical activity promotion among people with spinal cord injury (SCI), and 3) aging among people with MS. Age-related deterioration in visual, vestibular, and somatosensory systems or in sensory integration can adversely affect postural control and can contribute to falls in older people. Sensory-specific interventions designed for improving balance in older people could be adapted for preventing falls in individuals with MS. Spinal Cord Injury (SCI) Action Canada's strategy for disseminating physical activity promotion interventions for adults with SCI has been successful and widely accepted by community partners. Many of the peer-based interventions developed by SCI Action Canada are potentially relevant and could be adapted to the MS population for both physical activity promotion and falls prevention. Considering that older people with MS constitute a growing proportion of the MS population and over 70% of older people with MS report moderate to extreme balance problems, falls prevention should be one of the key components, particularly for MS management in older or more disabled groups. Overall, given people's different ages, symptoms, strengths, and barriers, a tailored MS falls-prevention intervention that includes peer/caregiver support is critical. PMID- 25694775 TI - Participation as an Outcome in Multiple Sclerosis Falls-Prevention Research: Consensus Recommendation from the International MS Falls Prevention Research Network. AB - Selecting the outcomes for an intervention trial is a key decision that influences many other aspects of the study design. One of the major tasks during the 3-day inaugural meeting of the International MS Falls Prevention Research Network was to identify the key outcomes for the falls-prevention intervention that was being designed by the Network members for testing across their multiple sites. Through a nominal group process, meeting participants described how engagement in important, meaningful everyday activities, beyond traditional basic and instrumental activities of daily living, should be a long-term outcome of a successful falls-prevention intervention for people with MS. Post-meeting work, which involved literature reviews and comparisons of definitions of major constructs identified during the meeting discussions, led to the consensus recommendation of including participation as a long-term outcome in MS falls prevention interventions. Participation reflects involvement in a life situation. This article explains the rationale for this recommendation and presents four measures that have the potential for use in tracking long-term participation outcomes in MS falls-prevention research. PMID- 25694776 TI - Fall Incidence as the Primary Outcome in Multiple Sclerosis Falls-Prevention Trials: Recommendation from the International MS Falls Prevention Research Network. AB - The aim of this article is to provide recommendations on behalf of the International MS Falls Prevention Research Network (IMSFPRN) for the primary outcome measure for multiple sclerosis (MS) falls-prevention interventions. The article will consider the definition of a fall, methods of measuring falls, and the elements of falls that should be recorded, as well as how these elements should be presented and analyzed. While this information can be used to inform the content of falls-prevention programs, the primary aim of the article is to make recommendations on how the outcome of these programs should be captured. PMID- 25694777 TI - Home or away? Choosing a setting for a falls-prevention program for people with multiple sclerosis. AB - Evidence suggests that choice of setting may be important in influencing the outcomes of rehabilitation programs, as well as optimizing participant satisfaction and adherence. This article aims to examine the factors that may inform the choice of setting for a falls-prevention program tailored to the needs of people with multiple sclerosis, including the influence of setting on program effectiveness, participant engagement, cost, and sustainability. Any new program should ensure that the choice of setting is informed by the intended program outcomes as well as an awareness of the opportunities and challenges presented by each type of setting. Evaluations of falls programs for older people suggest that immediate outcomes are similar regardless of setting; however, long-term outcomes may differ by setting, possibly owing to differential effects on adherence. Programs based away from home may offer benefits in terms of maintaining motivation, providing peer-support opportunities, and allowing regular access to facilitator input, while home-based programs offer unique opportunities for context-based practice and the integration of falls-prevention activities into real life. Additionally, home-based programs may address some of the long-term feasibility issues associated with programs away from home. A "mixed" program incorporating elements of home- and community-based activity may be the most sustainable and effective choice to achieve both long- and short-term goals within a falls-prevention program. However, currently there are significant gaps in knowledge relating to comparative program outcomes, cost, and long-term sustainability. PMID- 25694778 TI - Applying the RE-AIM Framework to Inform the Development of a Multiple Sclerosis Falls-Prevention Intervention. AB - Successfully addressing the problem of falls among people with multiple sclerosis (MS) will require the translation of research findings into practice change. This process is not easy but can be facilitated by using frameworks such as RE-AIM during the process of planning, implementing, and evaluating MS falls-prevention interventions. RE-AIM stands for Reach, Effectiveness, Adoption, Implementation, and Maintenance. Since its initial publication in 1999, the RE-AIM framework has become widely recognized across a range of disciplines as a valuable tool to guide thinking about the development and evaluation of interventions intended for widespread dissemination. For this reason, it was selected by the International MS Falls Prevention Research Network to structure initial discussions with clinicians, people with MS, and representatives of professional and MS societies about the factors we need to consider in the development of an MS falls prevention intervention for multisite testing that we hope will someday be disseminated widely. Through a combination of small-group work and large-group discussion, participants discussed four of the five RE-AIM elements. A total of 17 recommendations were made to maximize the reach (n = 3), adoption (n = 5), implementation (n = 4), and maintenance (n = 5) of the intervention the Network is developing. These recommendations are likely to be useful for any MS rehabilitation researcher who is developing and testing interventions that he or she hopes will be widely disseminated. PMID- 25694779 TI - Targeting Dynamic Balance in Falls-Prevention Interventions in Multiple Sclerosis: Recommendations from the International MS Falls Prevention Research Network. AB - Balance deficits are common in people with multiple sclerosis (MS) and are associated with past and future falls. People with MS tend to fall during activities of daily living and recreation that involve transitions between body positions and during walking and turning. The evident deficits in dynamic balance may be partly due to impairment in the collection or integration of sensory inputs or the execution of appropriate movements in moments of distraction. There is growing evidence that dynamic balance is modifiable and that improvements in dynamic balance are associated with reduction in falls. Consequently, it is imperative that balance measures be appropriate to capture changes in components of dynamic balance. There are numerous ways to measure dynamic balance. When selecting the appropriate dynamic balance measure for an MS falls-prevention trial, the inclusion criteria and content of intervention will inform the choice of measure. The International MS Falls Prevention Research Network (IMSFPRN) suggests that measures of dynamic balance be included as an outcome measure for use in falls-prevention trials. PMID- 25694780 TI - Whom to Target for Falls-Prevention Trials: Recommendations from the International MS Falls Prevention Research Network. AB - Effective falls-prevention approaches for people with multiple sclerosis (MS) are needed. A significant challenge in studying falls-prevention programs for people with MS is deciding whom to include in trials. This article presents and discusses potential criteria for selecting participants for trials of falls prevention interventions in MS. This narrative review reports on the inaugural meeting of the International MS Falls Prevention Research Network (IMSFPRN), which was held in March 2014 in Kingston, Ontario, Canada. Criteria considered were age, assistive device use, cognition, and fall history. The IMSFPRN reached consensus agreement to recommend that participants of all ages with varying levels of cognitive ability who are able to ambulate with or without assistance and who have a history of falling should be included in their future falls prevention trials. PMID- 25694781 TI - Poster Abstracts from the Fourth International Symposium on Gait and Balance in Multiple Sclerosis: The Role of CognitionCleveland Clinic * Cleveland, Ohio, USA * October 10 & 11, 2014. PMID- 25694782 TI - Duodenal Aspirates for Small Intestine Bacterial Overgrowth: Yield, PPIs, and Outcomes after Treatment at a Tertiary Academic Medical Center. AB - Duodenal aspirates are not commonly collected, but they can be easily used in detection of small intestinal bacterial overgrowth (SIBO). Proton pump inhibitor (PPI) use has been proposed to contribute to the development of SIBO. We aimed to determine the yield of SIBO-positive cultures detected in duodenal aspirates, the relationship between SIBO and PPI use, and the clinical outcomes of patients identified by this method. In a retrospective study, we analyzed electronic medical records from 1263 consecutive patients undergoing upper endoscopy at a tertiary medical center. Aspirates were collected thought out the third and fourth portions of the duodenum, and cultures were considered to be positive for SIBO if they produced more than 100,000 cfu/mL. Culture analysis of duodenal aspirates identified SIBO in one-third of patients. A significantly higher percentage of patients with SIBO use PPIs than patients without SIBO, indicating a possible association. Similar proportions of patients with SIBO improved whether or not they received antibiotic treatment, calling into question the use of this expensive therapy for this disorder. PMID- 25694783 TI - High Sensitive Sensor Fabricated by Reduced Graphene Oxide/Polyvinyl Butyral Nanofibers for Detecting Cu (II) in Water. AB - Graphene oxide (GO)/polyvinyl butyral (PVB) nanofibers were prepared by a simple electrospinning technique with PVB as matrix and GO as a functional nanomaterial. GO/PVB nanofibers on glassy carbon electrode (GCE) were reduced through electrochemical method to form reduced graphene oxide (RGO)/PVB nanofibers. The morphology and structure of GO/PVB nanofiber were studied by scanning election microscopy (SEM), transmission electron microscopy (TEM), and Fourier transform infrared (FTIR). RGO/PVB modified GCE was used for fabricating an electrochemical sensor for detecting Cu (II) in water. The analysis results showed that RGO/PVB modified GCE had good analytical results with the linear range of 0.06-2.2 MUM, detection limit of 4.10 nM (S/N = 3), and the sensitivity of 103.51 MUA.MUM( 1).cm(-2). PMID- 25694784 TI - Cutaneous and gastrointestinal symptoms in two patients with systemic mastocytosis successfully treated with omalizumab. AB - The pathogenesis of mastocytosis is not well defined and thus treatment remains challenging and remains on a palliative basis. We present two cases (a 48-year old woman and a 57-year-old man) with indolent systemic mastocytosis in whom omalizumab (anti-IgE) reduced gastrointestinal and cutaneous symptoms significantly. This observation provides additional insight into the effects of omalizumab on systemic mastocytosis. PMID- 25694785 TI - Health-seeking behaviors and self-care practices of people with filarial lymphoedema in Nepal: a qualitative study. AB - Background. Lymphatic filariasis is endemic in Nepal. This study aimed to investigate health-seeking behaviors and self-care practices of people with filarial Lymphoedema in Nepal. Methods. A cross-sectional study was conducted using qualitative methods in three endemic districts. Twenty-three patients with current Lymphoedema were recruited in the study. Results. Hydrocele was found to be a well-known condition and a major health problem in the studied communities. People with Lymphoedema primarily sought health care from traditional healers, whereas sometimes home-based care was their first treatment. Later Ayurvedic and allopathic hospital-based care were sought. Respondents reported various psychological problems such as difficulty in engaging in sexual intercourse, anxiety, worry and stress, depression, low self-esteem, feeling weak, fear of being abandoned, and fear of transmitting disease to the children. Standard foot care practices except washing were largely absent. Conclusions. Lymphoedema in the limbs and hydrocele were found to be major health problems. The traditional health care providers were the first contact of care for the majority of respondents. Only a few patients had been practicing standard foot care practices. PMID- 25694786 TI - Patterns of exposure to multiple metals and associations with neurodevelopment of preschool children from Montevideo, Uruguay. AB - While it is known that toxic metals contribute individually to child cognitive and behavioral deficits, we still know little about the effects of exposure to multiple metals, particularly when exposures are low. We studied the association between children's blood lead and hair arsenic, cadmium, and manganese and their performance on the Bayley Scales of Infant Development III. Ninety-two preschool children (age 13-42 months) from Montevideo, Uruguay, provided a hair sample and 78 had a blood lead level (BLL) measurement. Using latent class analysis (LCA), we identified four groups of exposure based on metal concentrations: (1) low metals, (2) low-to-moderate metals, (3) high lead and cadmium, and (4) high metals. Using the four-group exposure variable as the main predictor, and fitting raw scores on the cognitive, receptive vocabulary, and expressive vocabulary scales as dependent variables, both complete-case and multiple imputation (MI) analyses were conducted. We found no association between multiple-metal exposures and neurodevelopment in covariate-adjusted models. This study demonstrates the use of LCA together with MI to determine patterns of exposure to multiple toxic metals and relate these to child neurodevelopment. However, because the overall study population was small, other studies with larger sample sizes are needed to investigate these associations. PMID- 25694787 TI - Hepatoprotective, Antioxidant, and Anticancer Effects of the Tragopogon porrifolius Methanolic Extract. AB - Tragopogon porrifolius (Asteraceae), commonly referred to as white salsify, is an edible herb used in Lebanese folk medicine to treat cancer and liver dysfunction. In this study, we investigated the antioxidant activity of Tragopogon porrifolius methanolic extract, both in vitro and in vivo, in addition to its hepatoprotective and anticancer activities. Total phenolic and flavonoid contents were measured and found to be 37.0 +/- 1.40 mg GAE/g and 16.6 +/- 0.42 mg QE/g dry weight, respectively. In vitro antioxidant assays revealed an FRAP value of 659 +/- 13.8 umol Fe(2+)/g of extract and DPPH IC50 value 15.2 ug/mL. In rats subjected to CCl4-induced hepatotoxicity, significant increase in CAT, SOD, and GST levels was detected. The highest dose of the extract (250 mg/kg) recorded a fold increase of 1.68 for SOD, 2.49 for GST, and 3.2 for CAT. The extract also showed substantial decrease in AST (57%), ALT (56%), and LDH (65%) levels. Additionally, the extract caused a dose-dependent decrease in cell viability and proliferation. In conclusion, the methanolic extract of T. porrifolius displayed a relatively high antioxidant activity both in vitro and in vivo as well as hepatoprotective potential against liver toxicity in rats and anticancer effect on MDA-MB-231 and Caco-2 cells. PMID- 25694788 TI - Protective effects of total saponins of panax notoginseng on steroid-induced avascular necrosis of the femoral head in vivo and in vitro. AB - This research was designed to investigate the protective effects of TSPN on steroid-induced avascular necrosis of the femoral head (ANFH) and the likely mechanisms of those effects. As an in vivo study, TSPN was shown to be protective against steroid-induced ANFH due to the upregulation of VEGF-A. Furthermore, TSPN attenuated the apoptosis of osteocytes and reduced the expression of Caspase-3 relative to the model group. As an in vitro study, TSPN exerted a concentration dependent protective effect against apoptosis in MC3T3-E1 cells. Moreover, TSPN (at a dose of 100 MUg/mL) significantly reversed the dexamethasone-induced augmentation of Caspase-3 expression and activity. Therefore, our study demonstrated that TSPN had a protective effect against steroid-induced ANFH that was related to the upregulation of VEGF-A and the inhibition of apoptosis and Caspase-3 activation. PMID- 25694789 TI - Influence of spirituality on cool down reactions, work engagement, and life satisfaction in anthroposophic health care professionals. AB - This study aimed to analyse whether spirituality is a resource for health care professionals to deal with increasing stress and work burden, specifically to analyse associations between "cool down reactions" (which describe an emotional distancing towards patients and/or reduced engagement as a strategy to protect their own functionality), work burden, and life satisfaction. We specifically focussed on anthroposophic health care professionals because of their unique approach to distinct aspects of spirituality. In a cross-sectional survey using standardized questionnaires, 489 persons were enrolled (66% women, mean age 53 +/ 10 years, 41% physicians, 12% nurses, and 47% other health care professionals). They scored very high on all measures of spirituality and moderate to low with respect to "cool down reactions." Significant predictors of "cool down reactions" were low work vigor, perceived work burden, alcohol consumption, low life satisfaction, and religious orientation (R (2) = 0.20). In contrast, their life satisfaction was explained best (R (2) = 0.35) by vigor, with further positive influences of being a physician, conscious interactions, and living with a partner on one hand and negative influences of "cool down reactions," work burden, and transcendence convictions on the other hand. Thus, specific aspects of spirituality have only a small influence on anthroposophic health care professionals' "cool down reactions," but might buffer against a loss of vigor and dedication in their work. PMID- 25694790 TI - Dromokaition Psychiatric Hospital of Athens: from its establishment in 1887 to the era of deinstitutionalization. AB - Dromokaition Psychiatric Hospital opened its doors in 1887, following the donation made by Zorzis Dromokaitis from the island of Chios. Private donations and all forms of charities had contributed to a large extent in the establishment of hospitals across Greece, during the late 19th and the early 20th century. Dromokaition was one of them but it was also unique, as it was the first psychiatric hospital in Athens, admitting patients from every part of the country. This paper aimed at highlighting the long service of the institution through the different historical periods the country went through. We present the chronicle of its foundation, the development of its inner structure, and the medical and organizational influences which it received, along the way. The therapeutic methods used during the first decades of its operation reflected the corresponding European standards of the time. As a model institution from its foundation, it followed closely the prevailing European guidelines, throughout its historical path, either as an independent institution or as an integrated one within the National Health Service. PMID- 25694791 TI - Multiscale imaging of plants: current approaches and challenges. AB - We review a set of recent multiscale imaging techniques, producing high resolution images of interest for plant sciences. These techniques are promising because they match the multiscale structure of plants. However, the use of such high-resolution images is challenging in the perspective of their application to high-throughput phenotyping on large populations of plants, because of the memory cost for their data storage and the computational cost for their processing to extract information. We discuss how this renews the interest for multiscale image processing tools such as wavelets, fractals and recent variants to analyse such high-resolution images. PMID- 25694792 TI - Mental health care in Nepal: current situation and challenges for development of a district mental health care plan. AB - BACKGROUND: Globally mental health problems are a serious public health concern. Currently four out of five people with severe mental illness in Low and Middle Income Countries (LMIC) receive no effective treatment. There is an urgent need to address this enormous treatment gap. Changing the focus of specialist mental health workers (psychiatrists and psychologists) from only service delivery to also designing and managing mental health services; building clinical capacity of the primary health care (PHC) workers, and providing supervision and quality assurance of mental health services may help in scaling up mental health services in LMICs. Little is known however, about the mental health policy and services context for these strategies in fragile-state settings, such as Nepal. METHOD: A standard situation analysis tool was developed by the PRogramme for Improving Mental health carE (PRIME) consortium to systematically analyze and describe the current gaps in mental health care in Nepal, in order to inform the development of a district level mental health care plan (MHCP). It comprised six sections; general information (e.g. population, socio-economic conditions); mental health policies and plans; mental health treatment coverage; district health services; and community services. Data was obtained from secondary sources, including scientific publications, reports, project documents and hospital records. RESULTS: Mental health policy exists in Nepal, having been adopted in 1997, but implementation of the policy framework has yet to begin. In common with other LMICs, the budget allocated for mental health is minimal. Mental health services are concentrated in the big cities, with 0.22 psychiatrists and 0.06 psychologists per 100,000 population. The key challenges experienced in developing a district level MHCP included, overburdened health workers, lack of psychotropic medicines in the PHC, lack of mental health supervision in the existing system, and lack of a coordinating body in the Ministry of Health and Population (MoHP). Strategies to overcome these challenges included involvement of MoHP in the process, especially by providing psychotropic medicines and appointing a senior level officer to facilitate project activities, and collaboration with National Health Training Centers (NHTC) in training programs. CONCLUSIONS: This study describes many challenges facing mental health care in Nepal. Most of these challenges are not new, yet this study contributes to our understanding of these difficulties by outlining the national and district level factors that have a direct influence on the development of a district level mental health care plan. PMID- 25694793 TI - A survey of offloading practices for diabetes-related plantar neuropathic foot ulcers. AB - BACKGROUND: Offloading is key to preventing or healing plantar neuropathic foot ulcers in diabetes. Total contact casts or walkers rendered irremovable are recommended in guidelines as first-line options for offloading, however the use of such devices has been found to be low. This study aimed to investigate offloading practices for diabetes-related plantar neuropathic ulcers. METHODS: An online survey of closed and open-ended questions was administered via SurveyMonkey(r). Forty-one podiatrists experienced in high-risk foot practice, from 21 high-risk foot services around Australia, were approached to participate. RESULTS: The response rate was 88%. Participants reported using 21 modalities or combinations of modalities, for offloading this ulcer type. The most frequently used modalities under the forefoot and hallux were felt padding, followed by removable casts or walkers, then non-removable casts or walkers. Participants indicated that many factors were considered when selecting offloading modality, including: compliance, risk of adverse effects, psycho-social factors, restrictions on activities of daily living, work needs and features of the wound. The majority of participants (83%) considered non-removable casts or walkers to be the gold-standard for offloading this ulcer type, however they reported numerous, particularly patient-related, barriers to their use. CONCLUSIONS: Selecting offloading for the management of foot ulceration is complex. Felt padding, not the gold-standard non-removable cast or walker, was reported as the most commonly selected modality for offloading plantar neuropathic ulceration. However, further evaluation of felt padding in high quality clinical trials is required to ascertain its effectiveness for ulcer healing. PMID- 25694794 TI - End-of-Life Choices Are Necessary in Any Healthcare Reform. PMID- 25694795 TI - FEM and Von Mises analyses of different dental implant shapes for masticatory loading distribution. AB - The rehabilitation of edentulous patients is today a challenge for the clinicians. The healthy of the hard and soft issue may be considered a fundamental element for having long-term results. The dental implant progresses about the predictable and safe results made this technique chosen from a large group of practitioners. However some problems related intra-operative and postoperative conditions may create discomfort on the patients and consequently to the clinician. The unfavourable results are often related to the bone tissue quality but sometime the dental implant shape and the prosthesis framework may undergo to technical difficulties. The purpose of this work is, through the use of appropriate FEM models, to analyse the effect of all these parameters in the construction of a prosthesis type "Toronto", evaluating all the surgical and prosthetic components in order to direct the choices made by the surgeon and to optimize the distribution of loads reducing the patient's discomfort and having a long term clinical success. PMID- 25694796 TI - Radiological evaluation of the Cresco system in combination with Osseospeed implants: a preliminary 3-year report. AB - AIM: In this preliminary study, the 3-year radiological outcomes of Osseospeed implant-supported fixed complete or partial prostheses made with two different laboratory protocols were compared. METHODS: A convenience sample of 34 patients, who were either partially or completely edentulous in either jaw, were randomly assigned to two groups, of 17 patients each, using either a traditional laboratory protocol (control group) or the Cresco one (test group). The study's objective was an assessment of marginal bone loss around implants, measured on intraoral radiographs at 3-year follow-up. RESULTS: None of the implants inserted was lost during the study and radiological measurements of marginal bone level changes revealed that the mean marginal bone loss was respectively 0,73+/-0,33mm for test group and 0,88+/-1,13mm for control group. The differences between test and control groups were not statistically significant. CONCLUSION: This preliminary study did not demonstrate statistically significant differences in marginal bone loss around implant-prostheses prepared with the two different laboratory protocols, over the 3-year observational period. PMID- 25694797 TI - Digital work-flow. AB - OBJECTIVE: The project presents a clinical case in which the digital work-flow procedure was applied for a prosthetic rehabilitation in natural teeth and implants. MATERIALS: Digital work-flow uses patient's photo for the aesthetic's planning, digital smile technology for the simulation of the final restoration and real time scanning to register the two arches. Than the scanning are sent to the laboratory that proceed with CAD-CAM production. RESULTS: Digital work-flow offers the opportunities to easily speak with laboratory and patients, gives better clinical results and demonstrated to be a less invasiveness method for the patient. CONCLUSION: Intra-oral scanner, digital smile design, preview using digital wax-up, CAD-CAM production, are new predictable opportunities for prosthetic team. This work-flow, compared with traditional methods, is faster, more precise and predictable. PMID- 25694798 TI - Bilateral and multifocal Warthin's tumor of parotid gland: two case reports and review of literature. AB - Warthin's tumor is the second most common benign neoplasm of the parotid. Most of cases are represented by a single localization, while only a small percentage of patients presents bilateral lesions or unilateral multifocal pattern. Warthin's tumor has an excellent prognosis due to the low rate of recurrence after surgical treatment. Malignant transformation occurs in less than 1% of cases. The aim of this article is to present two unusual cases of Warthin's tumor and an updated review of the latest scientific literature. PMID- 25694799 TI - Implant stability in different techniques of surgical sites preparation: an in vitro study. AB - OBJECTIVE: In the last few decades the implantology has achieved excellent results in the prosthetic rehabilitation of the partially or totally edentulous patients. The clinicians, given the pressing demand by patients, must deal with the situations in which the lack of the availability and sometimes the low quality of the bone can lead to the treatment failure. Although the manufacturers recommend to follow codified surgical protocols, alternative techniques of preparation, apt to ensure a better primary implant stability, have been developed. The aim of this study was to determine in vitro, by using the resonance frequency (Osstell mentor), which technique of implant site preparation (piezo surgery, conventional, under-preparation, bone compaction, osteodistraction) is able to improve implant stability of type IV cancellous bone. METHODS: 10 pig ribs were prepared, and a surgical pre-drilled and calibrated guide for proper implant placement was used. On each rib, 5 implant sites were prepared, one for each technique. RESULTS: One-way ANOVA did not show statistically significant differences among the "implant stability quotient" (ISQ) values of the 5 techniques utilized. CONCLUSIONS: Thus, in light of these results, in the clinical practice of the type IV bone one technique is replaceable with the others, as none of them improves implant stability. The choice should instead be directed to the technique that accelerates the healing process and the osseointegration. PMID- 25694800 TI - Esthetic and function rehabilitation of severely worn dentition with prosthetic restorative approach and VDO increase. Case report. AB - OBJECTIVE: The aim of this study is to report a case of restorative treatment of severely worn dentition. In this case report, the erosive/abrasive worn dentition have been reconstructed with metal ceramic crown on the posterior teeth and with ceramic veneers on the anterior teeth 1.3 - 2.3 and 3.4 - 4.3. METHODS: A prosthetic treatment was proposed to a male patient of 58 years old having a clinically significant tooth wear. After clinical exam, impressions of maxillary and mandible arches were taken with alginate to obtain preliminary casts for diagnostic waxing to all maxillary and mandibular teeth and fabrication of all provisional crowns in acrylic resin for posterior teeth, and from the diagnostic wax-up were fabricated a silicone guide masks for anterior teeth. An increase in VDO should be determined on the basis of a need to accomplish satisfactory and aesthetically pleasing restorations; it was proposed to increase the incisal lenght of the maxillary anterior incisors, together with alteration of the VDO 3 mm anteriorly. The posterior teeth 1.6 - 1.5 - 1.4 - 2.4 - 2.6 - 3.5 - 3.6 - 3.7 4.4 - 4.7, where the amount of tissue lost was greater, were recontructed with metal ceramic crowns. Two implants (Nobel replace 4.3x10) was placed. The implant were located in the area 4.5 - 4.6. The anterior teeth were restored with veneers. DISCUSSION AND RESULTS: The prosthetic challenge with restoring severely worn dentitions is to preserve as much of the already diminished tooth structure as possible for retention while also providing enough interocclusal space for the restorative material. PMID- 25694801 TI - Maxillo-facial prosthesis (P.M.F): in a case of oral-nasal communication post surgery and post-radiotherapy. AB - In patients with oral-nasal communication the absence of alveolar and/or palatal hard and soft tissue, or contraction resulting from previous surgical repair, needed prosthetic rehabilitation. This clinical report describes a treatment of an oral-nasal communication through a mixed prosthetic rehabilitation, fixed and removable, with attachments performed by EDM technique. PMID- 25694802 TI - Implant surgery and oral anticoagulant therapy: case report. AB - OBJECTIVES: This work aims to assess the risks both thromboembolic that bleeding of a management protocol "non-conservative" in patients on oral anticoagulant therapy (OAT) to be undergoing implant surgery. MATERIALS AND METHODS: We decided to take a surgical "non-conservative" protocol, to insert four implants in the aesthetic zone, without using flapless surgery and the surgical template. In accordance with the hematologist, the value of INR is lowered and warfarin was replaced with heparin low molecular weight, to have a better coagulation's control. RESULTS: The modern guidelines impose a protocol of conservative management in patients with OAT, with minimally invasive surgery, flapless, and use of surgical template to reduce the risk of uncontrolled bleeding. This, thanks to the team-work between dentist and hematologist, thanks to careful adjustment of INR and the use of local haemostatic agents, were not encountered any problems with bleeding or intra or postoperative. CONCLUSION: Surgical treatment of patients with OAT is a real problem for the oral surgeon, to treat every time in association with the hematologist. Applying this type of surgical procedure, different from today's guidelines, in our experience there were no post-operative complications (bleeding or bleeding); osseointegration has not been compromised and the prosthetic rehabilitation was completed successfully. PMID- 25694803 TI - Gene expression analysis of human induced pluripotent stem cell-derived neurons carrying copy number variants of chromosome 15q11-q13.1. AB - BACKGROUND: Duplications of the chromosome 15q11-q13.1 region are associated with an estimated 1 to 3% of all autism cases, making this copy number variation (CNV) one of the most frequent chromosome abnormalities associated with autism spectrum disorder (ASD). Several genes located within the 15q11-q13.1 duplication region including ubiquitin protein ligase E3A (UBE3A), the gene disrupted in Angelman syndrome (AS), are involved in neural function and may play important roles in the neurobehavioral phenotypes associated with chromosome 15q11-q13.1 duplication (Dup15q) syndrome. METHODS: We have generated induced pluripotent stem cell (iPSC) lines from five different individuals containing CNVs of 15q11-q13.1. The iPSC lines were differentiated into mature, functional neurons. Gene expression across the 15q11-q13.1 locus was compared among the five iPSC lines and corresponding iPSC-derived neurons using quantitative reverse transcription PCR (qRT-PCR). Genome-wide gene expression was compared between neurons derived from three iPSC lines using mRNA-Seq. RESULTS: Analysis of 15q11-q13.1 gene expression in neurons derived from Dup15q iPSCs reveals that gene copy number does not consistently predict expression levels in cells with interstitial duplications of 15q11-q13.1. mRNA-Seq experiments show that there is substantial overlap in the genes differentially expressed between 15q11-q13.1 deletion and duplication neurons, Finally, we demonstrate that UBE3A transcripts can be pharmacologically rescued to normal levels in iPSC-derived neurons with a 15q11-q13.1 duplication. CONCLUSIONS: Chromatin structure may influence gene expression across the 15q11 q13.1 region in neurons. Genome-wide analyses suggest that common neuronal pathways may be disrupted in both the Angelman and Dup15q syndromes. These data demonstrate that our disease-specific stem cell models provide a new tool to decipher the underlying cellular and genetic disease mechanisms of ASD and may also offer a pathway to novel therapeutic intervention in Dup15q syndrome. PMID- 25694804 TI - Statistical analysis of twenty years (1993 to 2012) of data from mainland China's first intervention center for children with autism spectrum disorder. AB - BACKGROUND: Autism spectrum disorder (ASD) is characterized by persistent deficits in social communication and interaction, and restrictive and repetitive patterns of behavior, interests or activities. This study aimed to analyze trends in ASD diagnosis and intervention in 20 years of data from the Beijing Stars and Rain Education Institute for Autism (SR), the first autism intervention center in mainland China, and from a recent survey of members of the Heart Alliance, an industry association of autism intervention centers in China. METHODS: We analyzed the registration data at the SR from 1993 to 2012 for a total of 2,222 children who had a parent-reported diagnosis of ASD and 612 of 'autistic tendencies'. Most of the children who were the primary focus of our analyses were age six and under. We also analyzed results of a survey we conducted in 2013 of 100 member centers of the Heart Alliance. Generalized Estimating Equations, multiple linear regression and the Mann-Whitney test were used for data analysis. Statistically significant findings are reported here. RESULTS: The number of hospitals where SR children received their diagnosis increased from several in the early 1990s to 276 at present. The proportion of 'autistic tendencies' diagnosis increased 2.04-fold from 1998 to 2012 and was higher for children diagnosed at a younger age. The mean age at first diagnosis of ASD or 'autistic tendencies' decreased by 0.27 years every decade. A higher level of parental education was statistically significantly associated with an earlier diagnosis of the child. The mean parental age at childbirth increased by about 1.48 years per decade, and the mean maternal age was 1.40 and 2.10 years higher than that in the national population censuses of 2000 and 2010, respectively. At the time of the survey 3,957 children with ASD were being trained at the 100 autism intervention centers. Ninety-seven of these centers opened after the year 2000. Economically underdeveloped regions are still underserved. CONCLUSIONS: This study revealed encouraging trends and remaining challenges in ASD diagnosis and intervention among children at the SR over the past 20 years and the 100 autism intervention centers in China at present. PMID- 25694806 TI - Botulinum toxin-induced facial muscle paralysis affects amygdala responses to the perception of emotional expressions: preliminary findings from an A-B-A design. AB - BACKGROUND: It has long been suggested that feedback signals from facial muscles influence emotional experience. The recent surge in use of botulinum toxin (BTX) to induce temporary muscle paralysis offers a unique opportunity to directly test this "facial feedback hypothesis." Previous research shows that the lack of facial muscle feedback due to BTX-induced paralysis influences subjective reports of emotional experience, as well as brain activity associated with the imitation of emotional facial expressions. However, it remains to be seen whether facial muscle paralysis affects brain activity, especially the amygdala, which is known to be responsive to the perception of emotion in others. Further, it is unknown whether these neural changes are permanent or whether they revert to their original state after the effects of BTX have subsided. The present study sought to address these questions by using functional magnetic resonance imaging to measure neural responses to angry and happy facial expressions in the presence or absence of facial paralysis. RESULTS: Consistent with previous research, amygdala activity was greater in response to angry compared to happy faces before BTX treatment. As predicted, amygdala activity in response to angry faces was attenuated when the corrugator/procerus muscles were paralyzed via BTX injection but then returned to its original state after the effects of BTX subsided. This preliminary study comprises a small sample size and no placebo condition; however, the A-B-A design affords the present sample to serve as its own control. CONCLUSIONS: The current demonstration that amygdala responses to facial expressions were influenced by facial muscle paralysis offers direct neural support for the facial feedback hypothesis. Specifically, the present findings offer preliminary causal evidence that amygdala activity is sensitive to facial feedback during the perception of the facial expressions of others. More broadly, these data confirm the utility of using BTX to address the effect of facial feedback on neural responses associated with the perception, in addition to the experience or expression of emotion. PMID- 25671081 TI - Dipeptidyl peptidase-IV inhibitors used in type-2 diabetes inhibit a phospholipase C: a case of promiscuous scaffolds in proteins. AB - The long term side effects of any newly introduced drug is a subject of intense research, and often raging controversies. One such example is the dipeptidyl peptidase-IV (DPP4) inhibitor used for treating type 2 diabetes, which is inconclusively implicated in increased susceptibility to acute pancreatitis. Previously, based on a computational analysis of the spatial and electrostatic properties of active site residues, we have demonstrated that phosphoinositide specific phospholipase C (PI-PLC) from Bacillus cereus is a prolyl peptidase using in vivo experiments. In the current work, we first report the inhibition of the native activity of PI-PLC by two DPP4 inhibitors - vildagliptin (LAF-237) and K-579. While vildagliptin inhibited PI-PLC at micromolar concentrations, K-579 was a potent inhibitor even at nanomolar concentrations. Subsequently, we queried a comprehensive, non-redundant set of 5000 human proteins (50% similarity cutoff) with known structures using serine protease (SPASE) motifs derived from trypsin and DPP4. A pancreatic lipase and a gastric lipase are among the proteins that are identified as proteins having promiscuous SPASE scaffolds that could interact with DPP4 inhibitors. The presence of such scaffolds in human lipases is expected since they share the same catalytic mechanism with PI-PLC. However our methodology also detects other proteins, often with a completely different enzymatic mechanism, that have significantly congruent domains with the SPASE motifs. The reported elevated levels of serum lipase, although contested, could be rationalized by inhibition of lipases reported here. In an effort to further our understanding of the spatial and electrostatic basis of DPP4 inhibitors, we have also done a comprehensive analysis of all 76 known DPP4 structures liganded to inhibitors till date. Also, the methodology presented here can be easily adopted for other drugs, and provide the first line of filtering in the identification of pathways that might be inadvertently affected due to promiscuous scaffolds in proteins. PMID- 25694810 TI - The effects of physicochemical variables and tadpole assemblages on microalgal communities in freshwater temporary ponds through an experimental approach. AB - BACKGROUND: In freshwater systems, microalgae are the major biomass of microorganisms. They occur in ecosystems that are largely structured by the climatic regime, the physical and chemical environments with which they interact, and the biological interactions that occur within them. Amphibian larvae are most present in standing water habitats where they are important primary and secondary consumers and even predators. Studies conducted in America and Europe have shown that tadpoles play an important role in the regulation of the algal community structure and water quality in ecosystems. This article aimed to study the effects of the physicochemical variables and tadpole assemblages of four species on microalgae in artificial freshwater ponds using an experimental approach in the Pendjari area, a flora and fauna reserve located in the extreme north-west of Benin. RESULTS: The species of phytoplankton and periphyton recorded in ponds were among the taxonomical groups of chlorophytes, cyanophytes, euglenophytes, diatoms and dinoflagellates. Chlorophytes were the dominant group in the algal communities. Physicochemical variables affected the biomass of the different communities of algae in temporary freshwater ponds. Transparency and pond size were the most determinative variables of the structure of microalgae communities in ponds. Tadpoles of Kassina fusca, Ptychadena. bibroni, and Phrynomantis microps were important for the regulation of the water quality and algal community structure by grazing and filter-feeding. CONCLUSIONS: A decrease in the tadpole population in the artificial temporary ponds due to predation by carnivorous tadpoles of Hoplobatrachus occipitalis caused a disturbance of the algal community structure. This means that the decline of the amphibian population will critically lead to the impoverishment of ecosystems, thereby negatively influencing aquatic and terrestrial ecosystems. PMID- 25671081 TI - The dipeptidyl peptidase IV inhibitors vildagliptin and K-579 inhibit a phospholipase C: a case of promiscuous scaffolds in proteins. AB - The long term side effects of any newly introduced drug is a subject of intense research, and often raging controversies. One such example is the dipeptidyl peptidase-IV (DPP4) inhibitor used for treating type 2 diabetes, which is inconclusively implicated in increased susceptibility to acute pancreatitis. Previously, based on a computational analysis of the spatial and electrostatic properties of active site residues, we have demonstrated that phosphoinositide specific phospholipase C (PI-PLC) from Bacillus cereus is a prolyl peptidase using in vivo experiments. In the current work, we first report the inhibition of the native activity of PI-PLC by two DPP4 inhibitors - vildagliptin (LAF-237) and K-579. While vildagliptin inhibited PI-PLC at micromolar concentrations, K-579 was a potent inhibitor even at nanomolar concentrations. Subsequently, we queried a comprehensive, non-redundant set of 5000 human proteins (50% similarity cutoff) with known structures using serine protease (SPASE) motifs derived from trypsin and DPP4. A pancreatic lipase and a gastric lipase are among the proteins that are identified as proteins having promiscuous SPASE scaffolds that could interact with DPP4 inhibitors. The presence of such scaffolds in human lipases is expected since they share the same catalytic mechanism with PI-PLC. However our methodology also detects other proteins, often with a completely different enzymatic mechanism, that have significantly congruent domains with the SPASE motifs. The reported elevated levels of serum lipase, although contested, could be rationalized by inhibition of lipases reported here. In an effort to further our understanding of the spatial and electrostatic basis of DPP4 inhibitors, we have also done a comprehensive analysis of all 76 known DPP4 structures liganded to inhibitors till date. Also, the methodology presented here can be easily adopted for other drugs, and provide the first line of filtering in the identification of pathways that might be inadvertently affected due to promiscuous scaffolds in proteins. PMID- 25694811 TI - A pilot study of autologous tumor lysate-loaded dendritic cell vaccination combined with sunitinib for metastatic renal cell carcinoma. AB - BACKGROUND: Sunitinib, a tyrosine kinase inhibitor currently in use for the treatment of metastatic renal cell carcinoma (mRCC), has been reported to modulate immunosuppressive cells such as myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) in addition to exerting anti-angiogenic effects. We conducted a clinical trial of dendritic cell (DC)-based immunotherapy together with sunitinib in mRCC patients in an effort to enhance immunotherapeutic efficacy by inhibiting immunosuppressive cells. METHODS: Patients aged >=20 years with advanced or recurrent mRCC who underwent nephrectomy were eligible for this study. Autologous tumor samples were obtained by surgery under aseptic conditions and used for preparing autologous tumor lysate. About 4 weeks after surgery, leukapheresis was performed to isolate peripheral blood mononuclear cells (PBMCs). DCs were generated from adherent PBMCs in the presence of recombinant human granulocyte macrophage colony-stimulating factor (GM-CSF) (500 IU/ml) and recombinant human IL-4 (500 IU/ml). Autologous tumor lysate was loaded into mature DC by electroporation. Eight patients were enrolled in the study and received sunitinib at a dose of 50 mg p.o. daily for 28 days followed by 14 days of rest. Tumor lysate-loaded DCs were administered subcutaneously every two weeks, with concomitant sunitinib. RESULTS: No severe adverse events related to vaccination were observed. Sunitinib decreased the frequencies of MDSCs in peripheral blood of 5 patients and of Tregs in 3. Tumor lysate-reactive CD4 or CD8 T cell responses were observed in 5 patients, 4 of whom showed decreased frequencies of Tregs and/or MDSCs. The remaining 3 patients who failed to develop tumor-reactive T cell responses had high levels of IL-8 in their sera and did not show consistent reductions in MDSCs and Tregs. CONCLUSIONS: DC-based immunotherapy combined with sunitinib is safe and feasible for patients with mRCC. TRIAL REGISTRATION: UMIN000002136. PMID- 25694812 TI - Haze, health and disease. PMID- 25694813 TI - Chinese haze versus Western smog: lessons learned. AB - Air pollution in many Chinese cities has been so severe in recent years that a special terminology, the "Chinese haze", was created to describe China's air quality problem. Historically, the problem of Chinese haze has developed several decades after Western high-income countries have significantly improved their air quality from the smog-laden days in the early- and mid-20(th) century. Hence it is important to provide a global and historical perspective to help China combat the current air pollution problems. In this regard, this article addresses the followings specific questions: (I) What is the Chinese haze in comparison with the sulfurous (London-type) smog and the photochemical (Los Angeles-type) smog? (II) How does Chinese haze fit into the current trend of global air pollution transition? (III) What are the major mitigation measures that have improved air quality in Western countries? and (IV) What specific recommendations for China can be derived from lessons and experiences from Western countries? PMID- 25694814 TI - Link between environmental air pollution and allergic asthma: East meets West. AB - With the levels of outdoor air pollution from industrial and motor vehicle emissions rising rapidly in the fastly-industrializing countries of South East Asia, the prevalence of asthma and allergic diseases has also been increasing to match those in the West. Epidemiological and experimental exposure studies indicate a harmful impact of outdoor air pollution from vehicles and factories both on the development of allergic diseases and asthma and the increase in asthma symptoms and exacerbations. The level of outdoor pollution in Asia is much higher and more diverse than those encountered in Western countries. This may increase the impact of outdoor pollution on health, particularly lung health in Asia. This review discusses the constituents of air pollution in Asia with a special focus on studies in mainland China and Taiwan where the levels of pollution have reached high levels and where such high levels particularly in winter can cause a thick haze that reduces visibility. The onus remains on regulatory and public health authorities to curb the sources of pollution so that the health effects on the population particularly those with lung and cardiovascular diseases and with increased susceptibility can be mitigated. PMID- 25694815 TI - Mechanistic impact of outdoor air pollution on asthma and allergic diseases. AB - Over the past decades, asthma and allergic diseases, such as allergic rhinitis and eczema, have become increasingly common, but the reason for this increased prevalence is still unclear. It has become apparent that genetic variation alone is not sufficient to account for the observed changes; rather, the changing environment, together with alterations in lifestyle and eating habits, are likely to have driven the increase in prevalence, and in some cases, severity of disease. This is particularly highlighted by recent awareness of, and concern about, the exposure to ubiquitous environmental pollutants, including chemicals with oxidant-generating capacities, and their impact on the human respiratory and immune systems. Indeed, several epidemiological studies have identified a variety of risk factors, including ambient pollutant gases and airborne particles, for the prevalence and the exacerbation of allergic diseases. However, the responsible pollutants remain unclear and the causal relationship has not been established. Recent studies of cellular and animal models have suggested several plausible mechanisms, with the most consistent observation being the direct effects of particle components on the generation of reactive oxygen species (ROS) and the resultant oxidative stress and inflammatory responses. This review attempts to highlight the experimental findings, with particular emphasis on several major mechanistic events initiated by exposure to particulate matters (PMs) in the exposure-disease relationship. PMID- 25694816 TI - Adverse effects of outdoor pollution in the elderly. AB - With fewer newborns and people living longer, older people are making up an increasing fraction of the total population. Epidemiological evidence shows that older-age-related health problems affect a wide and expanding proportion of the world population. One of the major epidemiological trends of this century is the rise of chronic diseases that affect more elderly than younger people. A total of 3.7 million premature deaths worldwide in 2012 are attributable to outdoor air pollution; the susceptibility to adverse effects of air pollution is expected to differ widely between people and within the same person, and also over time. Frailty history, a measure of multi-system decline, modifies cumulative associations between air pollution and lung function. Moreover, pre-existing diseases may determine susceptibility. In the elderly, due to comorbidity, exposure to air pollutants may even be fatal. Rapid and not-well-planned urbanization is associated with high level of ambient air pollution, mainly caused by vehicular exhausts. In general, there is sufficient evidence of the adverse effects related to short-term exposure, while fewer studies have addressed the longer-term health effects. Increased pollution exposures have been associated with increased mortality, hospital admissions/emergency-room visits, mainly due to exacerbations of chronic diseases or to respiratory tract infections (e.g., pneumonia). These effects may also be modulated by ambient temperature and many studies show that the elderly are mostly vulnerable to heat waves. The association between heat and mortality in the elderly is well documented, while less is known regarding the associations with hospital admissions. Chronic exposure to elevated levels of air pollution has been related to the incidence of chronic obstructive pulmonary disease (COPD), chronic bronchitis (CB), asthma, and emphysema. There is also growing evidence suggesting adverse effects on lung function related to long-term exposure to ambient air pollution. Few studies have assessed long-term mortality in the elderly. It is still unclear what are the pollutants most damaging to the health of the elderly. It seems that elderly subjects are more vulnerable to particulate matter (PM) than to other pollutants, with particular effect on daily cardio-respiratory mortality and acute hospital admissions. Not many studies have targeted elderly people specifically, as well as specific respiratory morbidity. Most data have shown higher risks in the elderly compared to the rest of the population. Future epidemiological cohort studies need to keep investigating the health effects of air pollutants (mainly cardiopulmonary diseases) on the elderly. PMID- 25694817 TI - Chronic effects of air pollution on respiratory health in Southern California children: findings from the Southern California Children's Health Study. AB - Outdoor air pollution is one of the leading contributors to adverse respiratory health outcomes in urban areas around the world. Children are highly sensitive to the adverse effects of air pollution due to their rapidly growing lungs, incomplete immune and metabolic functions, patterns of ventilation and high levels of outdoor activity. The Children's Health Study (CHS) is a continuing series of longitudinal studies that first began in 1993 and has focused on demonstrating the chronic impacts of air pollution on respiratory illnesses from early childhood through adolescence. A large body of evidence from the CHS has documented that exposures to both regional ambient air and traffic-related pollutants are associated with increased asthma prevalence, new-onset asthma, risk of bronchitis and wheezing, deficits of lung function growth, and airway inflammation. These associations may be modulated by key genes involved in oxidative-nitrosative stress pathways via gene-environment interactions. Despite successful efforts to reduce pollution over the past 40 years, air pollution at the current levels still brings many challenges to public health. To further ameliorate adverse health effects attributable to air pollution, many more toxic pollutants may require regulation and control of motor vehicle emissions and other combustion sources may need to be strengthened. Individual interventions based on personal susceptibility may be needed to protect children's health while control measures are being implemented. PMID- 25694818 TI - Air pollution and COPD in China. AB - Recently, many researchers paid more attentions to the association between air pollution and chronic obstructive pulmonary disease (COPD). Haze, a severe form of outdoor air pollution, affected most parts of northern and eastern China in the past winter. In China, studies have been performed to evaluate the impact of outdoor air pollution and biomass smoke exposure on COPD; and most studies have focused on the role of air pollution in acutely triggering symptoms and exacerbations. Few studies have examined the role of air pollution in inducing pathophysiological changes that characterise COPD. Evidence showed that outdoor air pollution affects lung function in both children and adults and triggers exacerbations of COPD symptoms. Hence outdoor air pollution may be considered a risk factor for COPD mortality. However, evidence to date has been suggestive (not conclusive) that chronic exposure to outdoor air pollution increases the prevalence and incidence of COPD. Cross-sectional studies showed biomass smoke exposure is a risk factor for COPD. A long-term retrospective study and a long term prospective cohort study showed that biomass smoke exposure reductions were associated with a reduced decline in forced expiratory volume in 1 second (FEV1) and with a decreased risk of COPD. To fully understand the effect of air pollution on COPD, we recommend future studies with longer follow-up periods, more standardized definitions of COPD and more refined and source-specific exposure assessments. PMID- 25694819 TI - Carcinogenicity of ambient air pollution: use of biomarkers, lessons learnt and future directions. AB - The association between ambient air pollution (AAP) exposure and lung cancer risk has been investigated in prospective studies and the results are generally consistent, indicating that long-term exposure to air pollution can cause lung cancer. Biomarkers can enhance research on the health effects of air pollution by improving exposure assessment, increasing the understanding of mechanisms, and enabling the investigation of individual susceptibility. In this review, we assess DNA adducts as biomarkers of exposure to AAP and early biological effect, and DNA methylation as biomarker of early biological change and discuss critical issues arising from their incorporation in AAP health impact evaluations, such as confounding, individual susceptibilities, timing, intensity and duration of exposure, and investigated tissue. DNA adducts and DNA methylation are treated as paradigms. However, the lessons, learned from their use in the examination of AAP carcinogenicity, can be applied to investigations of other biomarkers involved in AAP carcinogenicity. PMID- 25694820 TI - What can individuals do to reduce personal health risks from air pollution? AB - In many areas of the world, concentrations of ambient air pollutants exceed levels associated with increased risk of acute and chronic health problems. While effective policies to reduce emissions at their sources are clearly preferable, some evidence supports the effectiveness of individual actions to reduce exposure and health risks. Personal exposure to ambient air pollution can be reduced on high air pollution days by staying indoors, reducing outdoor air infiltration to indoors, cleaning indoor air with air filters, and limiting physical exertion, especially outdoors and near air pollution sources. Limited evidence suggests that the use of respirators may be effective in some circumstances. Awareness of air pollution levels is facilitated by a growing number of public air quality alert systems. Avoiding exposure to air pollutants is especially important for susceptible individuals with chronic cardiovascular or pulmonary disease, children, and the elderly. Research on mechanisms underlying the adverse health effects of air pollution have suggested potential pharmaceutical or chemopreventive interventions, such as antioxidant or antithrombotic agents, but in the absence of data on health outcomes, no sound recommendations can be made for primary prevention. Health care providers and their patients should carefully consider individual circumstances related to outdoor and indoor air pollutant exposure levels and susceptibility to those air pollutants when deciding on a course of action to reduce personal exposure and health risks from ambient air pollutants. Careful consideration is especially warranted when interventions may have unintended negative consequences, such as when efforts to avoid exposure to air pollutants lead to reduced physical activity or when there is evidence that dietary supplements, such as antioxidants, have potential adverse health effects. These potential complications of partially effective personal interventions to reduce exposure or risk highlight the primary importance of reducing emissions of air pollutants at their sources. PMID- 25694822 TI - Establishing a national culture of health and its values. PMID- 25694821 TI - The fight against chronic respiratory diseases in the elderly: the European Innovation Partnership on Active and Healthy Aging and beyond. PMID- 25694823 TI - Efficacy and Safety of Corneal Transplantation Using Corneas from Foreign Donors versus Domestic Donors: A Prospective, Randomized, Controlled Trial. AB - Purpose. To assess the efficacy and safety of corneal transplantation using corneas from foreign donors. Methods. One hundred and eight patients needing therapeutic penetrating keratoplasty were randomly divided into 2 groups (54 cases/group): foreign group using foreign donor corneas and domestic group using domestic donor corneas. Clinical outcome and incidence of postoperative complications were compared between groups. Results. No significant difference with respect to the therapeutic outcome and postoperative Best Corrected Visual Acuity (BCVA) and neovascularization by final follow-up was observed between the two groups. The graft thickness in the foreign group was statistically higher than the domestic group at 1 month postoperatively, but not at 3, 6, and 12 months postoperatively. Corneal endothelial cell density in the domestic group was statistically higher than in the foreign group at 3, 6, and 12 months postoperatively. Corneal epithelial abnormalities in the foreign group were significantly higher than that in domestic group. The primary graft failure, incidence of graft survival, and postoperative complications such as immunologic rejection, graft infection, and secondary glaucoma were not significantly different between the two groups. Conclusions. Corneal transplantations using foreign donor corneas are as effective and safe as those using domestic donor corneas. PMID- 25694824 TI - Comparison of the changes in corneal endothelial cells after pars plana and anterior chamber ahmed valve implant. AB - Purpose. To compare the changes in corneal endothelial cells after pars plana Ahmed glaucoma valve (AGV) implantation with those after the anterior chamber AGV implantation for refractory glaucoma. Methods. The medical records of 18 eyes with pars plana implantation of AGV (ppAGV) were reviewed retrospectively and were compared with 18 eyes with the anterior chamber AGV (acAGV) implant. The preoperative and postoperative endothelial cells, intraocular pressure (IOP), and postoperative complications during the follow-up in both groups were compared. Results. The average follow-up was 18 months. The postoperative endothelial cells in the ppAGV and acAGV groups were 2044 +/- 303 and 1904 +/- 324, respectively (P = 0.25). The average percentage decrease in the endothelial cells in the ppAGV and acAGV groups at 18 months was 12.5% and 18.4%, respectively, and showed significant difference between the 2 groups (P = 0.01). No difference in IOP control and the number of postoperative glaucoma medications was observed between the 2 groups. Conclusions. Endothelial cell damage in the ppAGV group for refractory glaucoma appeared to be lower than that in the acAGV group. Therefore, pars plana implantation of AGV may be preferred as it may have lower level of endothelial cell damage while maintaining similar level of IOP control. PMID- 25694825 TI - Changes in Central Macular Thickness following Single Session Multispot Panretinal Photocoagulation. AB - Purpose. To determine changes in central subfield (CSF) macular thickness and best corrected visual acuity (BCVA) following single session, multispot panretinal photocoagulation (PRP). Methods. Forty eyes of 33 patients with newly diagnosed proliferative diabetic retinopathy were treated with single session, 20 millisecond, multispot PRP. Changes in central macular thickness and BCVA at 4- and 12-week follow-up were compared to baseline measurements. Results. Each eye received a mean (SD) of 2,750 (686.7) laser spots. At 4-week follow-up, there was a statistically significant 24.0 MUm increase in mean CSF thickness (P = 0.001), with a 17.4 MUm increase from baseline at 12-week follow-up (P = 0.002). Mean logMAR BCVA increased by 0.05 logMAR units (P = 0.03) at 4-week follow-up. At 12 week follow-up, BCVA had almost returned to normal with only an increase of 0.02 logMAR units compared to baseline (P = 0.39). Macular edema occurred in 2 eyes (5%) at 12-week follow-up. Conclusions. Macular thickening occurs following single session, 20-millisecond, multispot PRP, with a corresponding, mild change in BCVA. However, the incidence of macular edema appears to be low in these patients. Single session, 20-millisecond, multispot PRP appears to be a safe treatment for patients with proliferative diabetic retinopathy. PMID- 25694826 TI - Gastric band port site fixation: which method is best? AB - Laparoscopic adjustable gastric banding is a popular and successful bariatric surgical technique. Although short-term complications are few in number, long term complications are more common. One such complication is flippage of the gastric band port. This study compares three popular methods of port fixation and demonstrates that fixation with nonabsorbable mesh helps to prevent port flippage when compared to other techniques, reducing the need for repositioning operations. PMID- 25694827 TI - Combined liposuction and excision of lipomas: long-term evaluation of a large sample of patients. AB - Background. Lipomas are benign tumors of mature fat cells. They can be removed by liposuction, yet this technique is seldom employed because of concerns that removal may be incomplete and recurrence may be more frequent than after conventional excision. Objectives. We assessed the short- and long-term clinical outcomes and recurrence of combined liposuction and limited surgical excision of subcutaneous lipomas. Methods. From 2003 to 2012, 25 patients with 48 lipomas were treated with liposuction followed by direct excision through the same incision to remove residual lipomatous tissue. Initial postoperative follow-up ranged from 1 week to 3 months, and long-term outcomes, complications, and recurrence were surveyed 1 to 10 years postoperatively. Results. Lipomas on the head, neck, trunk, and extremities ranged from 1 to 15 cm in diameter. Early postoperative hematoma and seromas were managed by aspiration. Among 23 survey respondents (92%), patients were uniformly pleased with the cosmetic results; none reported recurrent lipoma. Conclusions. The combination of liposuction and excision is a safe alternative for lipoma removal; malignancy and recurrence are uncommon. Liposuction performed through a small incision provides satisfactory aesthetic results in most cases. Once reduced in size, residual lipomatous and capsular tissue can be removed without expanding the incision. These favorable outcomes support wider application of this technique in appropriate cases. PMID- 25694828 TI - Evolution of M. bovis BCG Vaccine: Is Niacin Production Still a Valid Biomarker? AB - BCG vaccine is usually considered to be safe though rarely serious complications have also been reported, often incriminating contamination of the seed strain with pathogenic Mycobacterium tuberculosis. In such circumstances, it becomes prudent to rule out the contamination of the vaccine seed. M. bovis BCG can be confirmed by the absence of nitrate reductase, negative niacin test, and resistance to pyrazinamide and cycloserine. Recently in India, some stocks were found to be niacin positive which led to a national controversy and closer of a vaccine production plant. This prompted us to write this review and the comparative biochemical and genotypic studies were carried out on the these contentious vaccine stocks at the Indian vaccine plant and other seeds and it was found that some BCG vaccine strains and even some strains of M. bovis with eugenic-growth characteristics mainly old laboratory strains may give a positive niacin reaction. Most probably, the repeated subcultures lead to undefined changes at the genetic level in these seed strains. These changing biological characteristics envisage reevaluation of biochemical characters of existing BCG vaccine seeds and framing of newer guidelines for manufacturing, production, safety, and effectiveness of BCG vaccine. PMID- 25694829 TI - Mycosis fungoides in Iranian population: an epidemiological and clinicopathological study. AB - Background. Mycosis fungoides (MF) is the most common subtype of cutaneous T-cell lymphoma. Extensive studies on Iranian MF patients are absent. The present study aimed to produce updated clinical information on Iranian MF patients. Methods. This was a retrospective, descriptive, single-center study, including all cases of MF seen in the Department of Dermatology, University Hospital of Isfahan, Iran, between 2003 and 2013. Data systematically recorded for each patient included clinical, biological, histological, and molecular findings. Results. Eighty-six patients with clinical and histologic diagnosis of MF were included in the study. Thirty-nine patients (45.3%) were male. Female predominance was observed in patients (male : female ratio is 1 : 1.2). Patients were between 7 and 84 years of age (median: 41). The interval from disease onset to diagnosis ranged from 0 to 55 years (median: 1 year). Eighteen cases (20.9%) had unusual variants of MF. The most common types included hypopigmented and poikilodermatous MF. Childhood cases of MF constituted 5.8% (5/86) of all patients. The early stages were seen in 82 cases (95.34%). Conclusion. The major differences in epidemiologic characteristics of MF in Iran are the lack of male predominance and the lower age of patients at the time of diagnosis. PMID- 25694830 TI - Triptorelin in the Relief of Lower Urinary Tract Symptoms in Advanced Prostate Cancer Patients: The RESULT Study. AB - This prospective, noninterventional, open-label, multicentre, Belgian study assessed the prevalence of moderate to severe lower urinary tract symptoms (LUTS) in patients with locally advanced or metastatic prostate cancer scheduled to receive triptorelin therapy and its effects on LUTS were evaluated focusing on symptom relief and changes in quality of life (QOL) related to urinary symptoms (November 2006 to May 2010). Inclusion criteria were age >18 years, histologically confirmed advanced or metastatic prostate cancer, and life expectancy >=12 months. Exclusion criteria were treatment with any LHRH analogue within the last 6 months or any other investigational agent within the last 3 months before study entry. Patients who received one or more triptorelin doses and had one or more efficacy assessments were evaluated. In total, 325 patients were included with a median age of 74 years (50 to 95 years). Mean age at first diagnosis was 73 +/- 8 years. Moderate (IPSS 8-19) to severe (IPSS >= 20) LUTS were observed in 62% of patients. Triptorelin reduced LUTS severity. This improvement was perceived within the first 24 weeks of treatment and was maintained after 48 weeks. A decrease in PSA level was also observed. PMID- 25694831 TI - Epidermoid cyst in the floor of the mouth of a 3-year-old. AB - Epidermoid cysts are a rare entity in the oral cavity and are even less frequent in the floor of the mouth, representing less than 0.01% of all the cases. We present the case of a 3-year-old girl with a growth in the floor of the mouth with 2 months of evolution and without changes since it was discovered by her parents. The lesion was asymptomatic; it did not cause dysphagia, dyspnea, or any other alteration. A CT scan with contrast was done which revealed the location and exact size of the lesion, allowing an intraoral approach for its excision. The histological examination confirmed the clinical speculation of an epidermoid cyst. PMID- 25694832 TI - Anticytotoxic T-lymphocyte antigen-4 induced autoimmune hypophysitis: a case report and literature review. AB - Objective. We describe a case of autoimmune hypophysitis induced by the anticytotoxic T-lymphocyte antigen-4 (CTLA-4) agent, ipilimumab. Methods. Case presentation and review of the literature. Results. Autoimmune hypophysitis, a previously described rare disorder, is being recognized more frequently as a side effect of novel immunomodulatory agents used in the treatment of malignancies such as melanoma. CTLA-4 agents are associated with immune-related adverse effects (irAE) which occur as a result of activation (or lack of inactivation) of the immune response. This impacts not only malignant cells but also different host organ-systems. Autoimmune hypophysitis is one of several endocrinopathies associated with these agents. Conclusion. It is important that endocrinologists become familiar with the endocrinopathies, such as autoimmune hypophysitis, associated with new immunomodulator agents which are being used with increasing frequency to treat a variety of malignancies. PMID- 25694833 TI - Rapid progression of primary sclerosing cholangitis complicated with ulcerative colitis. AB - Primary sclerosing cholangitis is a cholestatic condition with unknown etiology and long-standing, progressive course, leading to cirrhosis and requiring orthotropic liver transplant. In approximately 80%, primary sclerosing cholangitis is accompanied by inflammatory bowel disease, and in most cases the recognition of bowel disease precedes the diagnosis of primary sclerosing cholangitis. We describe a case of 22-year-old male diagnosed simultaneously with primary sclerosing cholangitis and ulcerative colitis, with a medical history suggesting uncommon prior development of the liver disease. Five months after the initial diagnosis, we observed advanced lesions of bile tree due to progression of primary sclerosing cholangitis, which led to the unusually fast necessity for the orthotopic liver transplant. PMID- 25694834 TI - Relapse of multiple myeloma presenting as extramedullary plasmacytomas in multiple organs. AB - Multiple myeloma is a neoplastic plasma cell disorder. It is characterized by collections of abnormal plasma cells accumulating in the bone marrow, where they interfere with the production of normal blood cells. It usually presents as a multisystemic involvement, whose symptoms and signs vary greatly. Some patients have slowly progressive disease while others have aggressive clinical behavior by extramedullary involvement. In addition to renal failure, anemia, hypercalcemia, lytic bone lesions, and immunodeficiency, it also affects multiple organ system, such as pancreas, adrenal glands, kidney, skin, lung, liver, spleen, lymph nodes, and bone. To raise awareness of the variable presentations of this disease, we report a 53-year-old male patient, with multiple myeloma in his first remission who relapsed with extramedullary plasmacytomas (EMPs) involving multiple organs, such as pancreas, adrenal glands, kidney, skin, lung, liver, spleen, and lymph nodes. PMID- 25694835 TI - Long complete remission achieved with the combination therapy of Cisplatin and gemcitabine in a patient with aggressive natural killer cell leukemia. AB - Aggressive natural killer cell leukemia (ANKL) is a rare and often lethal lymphoproliferative disorder. Patients may present with constitutional symptoms, jaundice, skin infiltration, lymphadenopathy, and hepatosplenomegaly. ANKL can progress quickly to multiorgan failure and survival is usually measured in weeks. Although a rapid and accurate diagnosis is critical, unfortunately there is no hallmark diagnostic marker of ANKL. We report a case of a 48-year-old male who was able to obtain a complete remission following cisplatin-based chemotherapy. We describe the details of the chemotherapy regimens used and a literature review of the treatment of ANKL. PMID- 25694836 TI - Cerebral Metastasis from Breast Cancer in a Male Patient with HIV. AB - Context. Breast cancer (BC) in men is a rare condition, corresponding to 1% of all neoplasms in this gender. Some studies show that up to 93% of BC cases in men are advanced disease. If its occurrence constitutes an uncommon fact, the appearance of a metastasis to the central nervous system (CNS) is extremely rare. The objective of the present study is to present the case of a male patient, bearer of HIV infection, who presented with BC and later metastasis to the CNS. We also include a brief review of the literature. Case Report. We describe a case of a male patient, 59 years old, with HIV infection and a history of BC treated 4 years earlier, which progressed into headache and vertigo. Neuroimaging exams showed lesions suggestive of cerebral metastasis and a stereotaxic biopsy confirmed BC metastasis. Conclusion. Breast cancer in men with metastasis to the CNS is a rare condition and similar reports were not found in the available databases. It should be pointed out that even though rare, it should be considered among the differential diagnoses for SNC metastases in men, although HIV infection favors the appearance of some types of cancer. PMID- 25694837 TI - Funicular myelosis in a butcher: it was the cream cans. AB - Background. Funicular myelosis is a known consequence of exposure to nitrous oxide. Nevertheless, there are only a few clinical trials assessing its long-term effects and there is no literature about the role of nutritional vitamin B12 supplementation in the context of nitrous oxide abuse. Case Descriptions. We diagnosed funicular myelosis in a young butcher, who consumed high amounts of meat regularly. Since the diagnostic process did not reveal any metabolic causes, reinterrogation of the patient uncovered recreational abuse of nitrous oxide out of whipped cream can gas cartridges. After stopping abuse and supplementation of vitamin B12, the patient recovered almost completely. Conclusions. In our case, even high nutritional vitamin B12 uptake could not compensate the noxious effects of nitrous oxide. Since there are emerging reports of increasing misuse, this should be considered in the diagnostic and therapeutic care of patients with nitrous oxide abuse. Furthermore, our case emphasizes that patients with vitamin B12 deficiency should be assessed for nitrous oxide abuse. PMID- 25694838 TI - Diffusion-Weighted MRI and FDG-PET in Diagnosis of Endometrial Stromal Nodule. AB - Preoperative differentiation of benign endometrial stromal nodule (ESN) from malignant low-grade endometrial sarcoma (LGESS) is challenging, because it requires histological evaluation of the tumor-myometrium interface, which is difficult to obtain in conventional endometrial curettage. A 72-year-old postmenopausal woman presented with 5-year history of persistent vaginal bleeding. Histological examination of the endometrial curettage specimen revealed hyperplasia of apparently normal endometrial stromal cells. T2-weighted magnetic resonance imaging (T2W-MRI) showed polypoid tumor occupying the entire uterine cavity. The tumor exhibited high signal intensity in diffusion-weighted MRI (DW MRI) and intense accumulation of (18)F-fluorodeoxyglucose (FDG) in positron emission tomography (PET). Intense FDG accumulation was also observed in the left internal iliac region. Total abdominal hysterectomy, bilateral salpingo oophorectomy, and pelvic lymphadenectomy were performed under the diagnosis of LGESS with lymph node metastasis. However, postoperative histological examination proved that the tumor was ESN without lymph node metastasis. Since mitotic figure is no longer included in the diagnostic criteria of ESN or LGESS, ESN could exhibit high cellularity and high proliferative activity as observed in this case. Therefore, DW-MRI or FDG-PET is not useful in the differentiation of ESN from LGESS. PMID- 25694839 TI - Rhabdomyosarcomatous Transformation of a Gastrointestinal Stromal Tumor following Treatment with Imatinib. AB - Rhabdomyosarcomatous dedifferentiation of GIST following tyrosine kinase inhibitor (TKI) therapy is rare, with only a handful of cases previously reported in the literature. Herein we present a case of metastatic GIST initially treated with imatinib that developed radiographic evidence of progression after 8 months of standard dose therapy with continued progression despite attempts at using dose-escalated imatinib 400 mg bid. Due to the patient's worsening clinical symptoms and radiographic concerns for colonic thickening, abscess, and extraluminal air, the patient underwent a palliative resection of a large heterogeneous mass arising from the posterior stomach and several metastatic foci. Pathology revealed a dedifferentiated GIST with rhabdomyosarcomatous features. This report will highlight the unique features of this case and review the existing literature. PMID- 25694840 TI - Valsalva-Like Retinopathy Secondary to Pancytopenia following Induction of Etoposide and Ifosfamide. AB - Etoposide and ifosfamide are chemotherapeutic agents used frequently in the treatment of sarcomas and hematologic malignancies. Ocular side effects are rarely reported. We describe a case of a patient on etoposide and ifosfamide who presented with unilateral vision loss, anemia, and thrombocytopenia. The patient was found to have a large subinternal limiting membrane hemorrhage in the right eye that is thought to be related to his anemia and thrombocytopenia. The hemorrhage resolved spontaneously after 10 days. This case illustrates how bone marrow suppression by chemotherapeutic agents may indirectly contribute to retinal hemorrhages resulting in at least transient vision loss. PMID- 25694841 TI - Separation of the proximal humeral epiphysis in the newborn: rapid diagnosis with ultrasonography. AB - Separation of the proximal humeral epiphysis (SPHE) is a well-known occurrence and may occur secondary to trauma, infection, and nonaccidental trauma. Since most newborns do not have the proximal humeral epiphysis ossified at birth, the diagnosis may be difficult to make on routine radiographs. Ultrasonography of the shoulder in the newborn is rapid, noninvasive, and nonionizing imaging techniques which can diagnose SPHE. In this report, we describe and emphasize the diagnostic utility of state-of-the-art ultrasonography for the diagnosis of SPHE. PMID- 25694842 TI - Targeting histone deacetylases: a novel approach in Parkinson's disease. AB - The worldwide prevalence of movement disorders is increasing day by day. Parkinson's disease (PD) is the most common movement disorder. In general, the clinical manifestations of PD result from dysfunction of the basal ganglia. Although the exact underlying mechanisms leading to neural cell death in this disease remains unknown, the genetic causes are often established. Indeed, it is becoming increasingly evident that chromatin acetylation status can be impaired during the neurological disease conditions. The acetylation and deacetylation of histone proteins are carried out by opposing actions of histone acetyltransferases (HATs) and histone deacetylases (HDACs), respectively. In the recent past, studies with HDAC inhibitors result in beneficial effects in both in vivo and in vitro models of PD. Various clinical trials have also been initiated to investigate the possible therapeutic potential of HDAC inhibitors in patients suffering from PD. The possible mechanisms assigned for these neuroprotective actions of HDAC inhibitors involve transcriptional activation of neuronal survival genes and maintenance of histone acetylation homeostasis, both of which have been shown to be dysregulated in PD. In this review, the authors have discussed the putative role of HDAC inhibitors in PD and associated abnormalities and suggest new directions for future research in PD. PMID- 25694843 TI - A Subsequent Human Neural Progenitor Transplant into the Degenerate Retina Does Not Compromise Initial Graft Survival or Therapeutic Efficacy. AB - PURPOSE: Stem and progenitor cell transplantation provides a promising clinical application for treating degenerative retinal diseases, including age-related macular degeneration (AMD) and retinitis pigmentosa (RP). Our previous studies have shown that a single subretinal injection of human cortical-derived neural progenitor cells (hNPCctx) into cyclosporine-treated Royal College of Surgeons (RCS) rats preserved both photoreceptors and visual function. However, it is still unknown whether nonautologous progenitor cell readministration for sustained vision is efficacious and safe in terms of the initial graft initiating an immune response to a subsequent graft. METHODS: A cell suspension containing 3*104 hNPCctx into one eye of cyclosporine-treated RCS rats at postnatal day 21 (P21), followed by a second transplantation at P95 into the previously untreated fellow eye. RESULTS: hNPCctx delayed photoreceptor degeneration and preserved visual function, as measured by electroretinography (ERG), optokinetic response (OKR), and luminance threshold recordings (LTRs). Visual function and photoreceptors of the initially treated eye were still preserved 6 weeks after hNPCctx were injected into the second eye. Antibodies against T-cell markers showed that CD3, CD4, and CD8 T cells were not detected at P90 and P140 in most cases. No detectable level of anti-nestin antibody was found in serum by enzyme linked immunosorbent assay (ELISA). CONCLUSIONS: This xenograft study with cyclosporine-treated animals demonstrates that readministration of hNPCctx into the fellow eye did not induce anti-graft immune responses or lower therapeutic efficacy of hNPCctx in preserving vision. Thus, readministration of progenitor cells to sustain long-term efficacy may be an option for long-term therapies of retinal degeneration. TRANSLATIONAL RELEVANCE: Redosing neural progenitors do not affect the efficacy of the initial grafts in protecting vision or induce unwanted immune responses. PMID- 25694844 TI - Nonlinear Trend Analysis of Longitudinal Pointwise Visual Field Sensitivity in Suspected and Early Glaucoma. AB - PURPOSE: We have shown previously that a nonlinear exponential model fits longitudinal series of mean deviation (MD) better than a linear model. This study extends that work to investigate the mode (linear versus nonlinear) of change for pointwise sensitivities. METHODS: Data from 475 eyes of 244 clinically managed participants were analyzed. Sensitivity estimates at each test location were fitted using two-level linear and nonlinear mixed effects models. Sensitivity on the last test date was forecast using a model fit from the earlier test dates in the series. The means of the absolute prediction errors were compared to assess accuracy, and the root means square (RMS) of the prediction errors were compared to assess precision. RESULTS: Overall, the exponential model provided a significantly better fit (P < 0.05) to the data at the majority of test locations (69%). The exponential model fitted the data significantly better at 85% of locations in the upper hemifield and 58% of locations in the lower hemifield. The rate of visual field (VF) deterioration in the upper hemifield was more rapid (mean, -0.21 dB/y; range, -0.28 to -0.13) than in the lower hemifield (mean, 0.14 dB/y; range, -0.2 to -0.09). CONCLUSIONS: An exponential model may more accurately track pointwise VF change, at locations damaged by glaucoma. This was more noticeable in the upper hemifield where the VF changed more rapidly. However, linear and exponential models were similar in their ability to forecast future VF status. TRANSLATIONAL RELEVANCE: The VF progression appears to accelerate in early glaucoma patients. PMID- 25694845 TI - From silos of care to circles of collaboration. PMID- 25694846 TI - The need for preventing chronic pain: the "big elephant in the room" of healthcare. PMID- 25694847 TI - "Never Only Opioids" and the Joint Commission: toward a Conservative, Whole system treatment standard for pain. PMID- 25694848 TI - Complementary and Integrative Healthcare in a Long-term Care Facility: A Pilot Project. AB - INTRODUCTION: The world's population is aging quickly, leading to increased challenges of how to care for individuals who can no longer independently care for themselves. With global social and economic pressures leading to declines in family support, increased reliance is being placed on community- and government based facilities to provide long-term care (LTC) for many of society's older citizens. Complementary and integrative healthcare (CIH) is commonly used by older adults and may offer an opportunity to enhance LTC residents' wellbeing. Little work has been done, however, rigorously examining the safety and effectiveness of CIH for LTC residents. OBJECTIVE: The goal of this work is to describe a pilot project to develop and evaluate one model of CIH in an LTC facility in the Midwestern United States. METHODS: A prospective, mixed-methods pilot project was conducted in two main phases: (1) preparation and (2) implementation and evaluation. The preparation phase entailed assessment, CIH model design and development, and training. A CIH model including acupuncture, chiropractic, and massage therapy, guided by principles of collaborative integration, evidence informed practice, and sustainability, was applied in the implementation and evaluation phase. CIH services were provided for 16 months in the LTC facility. Quantitative data collection included pain, quality of life, and adverse events. Qualitative interviews of LTC residents, their family members, and LTC staff members queried perceptions of CIH services. RESULTS: A total of 46 LTC residents received CIH care, most commonly for musculoskeletal pain (61%). Participants were predominantly female (85%) and over the age of 80 years (67%). The median number of CIH treatments was 13, with a range of 1 to 92. Residents who were able to provide self-report data demonstrated, on average, a 15% decline in pain and a 4% improvement in quality of life. No serious adverse events related to treatment were documented; the most common mild and expected side effect was increased pain (63 reports over 859 treatments). Qualitative interviews revealed most residents, family members and LTC staff members felt CIH services were worthwhile due to perceived benefits including pain relief and enhanced psychological and social wellbeing. CONCLUSION: This project demonstrated that with extensive attention to preparation, one patient-centered model of CIH in LTC was feasible on several levels. Quantitative and qualitative data suggest that CIH can be safely implemented and might provide relief and enhanced wellbeing for residents. However, some aspects of model delivery and data collection were challenging, resulting in limitations, and should be addressed in future efforts. PMID- 25694849 TI - Implementation of an integrative coping and resiliency program for nurses. AB - PURPOSE: To improve resiliency and reduce burnout in nurses through implementation of the Healing Pathways program (University of Maryland School of Medicine, Baltimore). Aims of this study include assessment of feasibility and acceptability and to explore changes in stress, coping, burnout, and mindfulness. DESIGN: A single-group, pre-, posttest design of an 8-week program in which participants attended weekly sessions that included Reiki, yoga, and meditation. Sample included 8 nurses with 1 advanced practice nurse, all female, ages ranging from 22 to 49 years, experience levels ranging from <1 year to 26 years. METHODS: Participants completed the Perceived Stress Scale, Coping Self-Efficacy Scale, Maslach Burnout Inventory, and Mindful Attention Awareness Scale before intervention, at last session, and 1 month after last session. Data were analyzed using one-way analysis of variance and qualitative narrative inquiry. FINDINGS: Improvements were noted in perceived stress, coping, burnout exhaustion subscale, and mindfulness. CONCLUSION: Healing Pathways was effective at reducing stress and improving coping and mindfulness in nurses. IMPLICATIONS: Nurses who invest time in self-care techniques including Reiki, yoga, and meditation improve their overall wellbeing and may provide higher-quality patient care. Implementation of an 8-week program in integrative self-care is feasible and important for the health of nurses. PMID- 25694850 TI - Preference and Expectation for Treatment Assignment in a Randomized Controlled Trial of Once- vs Twice-weekly Yoga for Chronic Low Back Pain. AB - BACKGROUND: In studies involving nonpharmacological complementary and alternative medicine interventions, participant blinding is very difficult. Participant expectations may affect perceived benefit of therapy. In studies of yoga as treatment for chronic low back pain, little is known about the relationship between patient expectations and preferences on outcomes. This study was designed to identify baseline predictors of preference and to determine if expectations and preferences for different doses of yoga affect back-related function and low back pain intensity. METHODS: This was a secondary data analysis of a 12-week randomized controlled trial comparing once-weekly vs twice-weekly yoga for treatment of chronic low back pain in 93 adults from a predominantly low-income minority population. At baseline, participants were asked about back function, back pain, treatment expectations, and treatment preferences. We created a variable "concordance" to describe the matching of participant preference to randomized treatment. Our outcome variables were change in back function and pain intensity after 12 weeks of yoga instruction. We performed logistic regression to identify predictors of preference for once- or twice-weekly yoga instruction. We created linear regression models to identify independent associations between expectations, preference, concordance, and outcomes. RESULTS: Worse back function at baseline was associated with 20% higher odds of preferring twice-weekly yoga (OR 1.2, CI 1.1, 1.3). Individuals with higher expectation scores for twice weekly yoga had 90% higher odds of preferring twice-weekly vs once-weekly yoga (OR 1.9, CI 1.3, 2.7). Individuals with higher expectation scores for once-weekly yoga had 40% less odds of preferring twice-weekly yoga (OR 0.6, CI 0.5, 0.9). After controlling for baseline characteristics, we found no statistically significant relationship between treatment outcomes, preference, expectation scores, or concordance. CONCLUSION: In a population of predominantly low-income minority participants with chronic low back pain, worse back function was associated with preference for more frequent yoga classes. Those who preferred more yoga classes had higher expectations for those classes. Twelve-week change in back pain intensity and back function were not affected by dosing preference, expectation score, or concordance. More research is needed to better measure and quantify preference, expectations, and their relationship to outcomes in yoga research. PMID- 25694851 TI - Buurtzorg nederland: a global model of social innovation, change, and whole systems healing. PMID- 25694853 TI - Food-specific IgG Antibody-guided Elimination Diets Followed by Resolution of Asthma Symptoms and Reduction in Pharmacological Interventions in Two Patients: A Case Report. AB - Asthma is one of the most common causes of office visits in the primary care and emergency care settings. Individuals are often able to maintain symptomatic control with long-term pharmacological therapy. Exacerbations of asthma commonly occur due to exposure to triggers such as viruses, pollutants, and allergens. While it is widely accepted that exposure to immunoglobulin E food allergens can exacerbate asthma symptoms, there is little evidence examining delayed immunoglobulin G-mediated reactions to food. Here we present two clinical cases of individuals who experienced a reduction in asthma symptoms, decreased dependence on pharmacological therapies, and increased quality of life by eliminating foods that demonstrated reactivity to immunoglobulin G levels identified through serum testing. PMID- 25694852 TI - Heart Rate Variability: New Perspectives on Physiological Mechanisms, Assessment of Self-regulatory Capacity, and Health risk. AB - Heart rate variability, the change in the time intervals between adjacent heartbeats, is an emergent property of interdependent regulatory systems that operates on different time scales to adapt to environmental and psychological challenges. This article briefly reviews neural regulation of the heart and offers some new perspectives on mechanisms underlying the very low frequency rhythm of heart rate variability. Interpretation of heart rate variability rhythms in the context of health risk and physiological and psychological self regulatory capacity assessment is discussed. The cardiovascular regulatory centers in the spinal cord and medulla integrate inputs from higher brain centers with afferent cardiovascular system inputs to adjust heart rate and blood pressure via sympathetic and parasympathetic efferent pathways. We also discuss the intrinsic cardiac nervous system and the heart-brain connection pathways, through which afferent information can influence activity in the subcortical, frontocortical, and motor cortex areas. In addition, the use of real-time HRV feedback to increase self-regulatory capacity is reviewed. We conclude that the heart's rhythms are characterized by both complexity and stability over longer time scales that reflect both physiological and psychological functional status of these internal self-regulatory systems. PMID- 25694854 TI - Health coaching: an update on the national consortium for credentialing of health & wellness coaches. AB - In September 2014, Global Advances in Health and Medicine editor Michele Mittelman, RN, MPH, interviewed four of the leaders in health and wellness coaching about trends in coaching and the progress of the National Consortium for Credentialing of Health & Wellness Coaches. Following are the transcripts of those interviews. Additionally, videos of the interviews are available at www.gahmj.com. PMID- 25694855 TI - Scanning the global literature. PMID- 25694856 TI - A hierarchical approach for speech-instrumental-song classification. AB - Audio classification acts as the fundamental step for lots of applications like content based audio retrieval and audio indexing. In this work, we have presented a novel scheme for classifying audio signal into three categories namely, speech, music without voice (instrumental) and music with voice (song). A hierarchical approach has been adopted to classify the signals. At the first stage, signals are categorized as speech and music using audio texture derived from simple features like ZCR and STE. Proposed audio texture captures contextual information and summarizes the frame level features. At the second stage, music is further classified as instrumental/song based on Mel frequency cepstral co-efficient (MFCC). A classifier based on Random Sample and Consensus (RANSAC), capable of handling wide variety of data has been utilized. Experimental result indicates the effectiveness of the proposed scheme. PMID- 25694857 TI - Robotic 3D scanner as an alternative to standard modalities of medical imaging. AB - There are special medical cases, where standard medical imaging modalities are able to offer sufficient results, but not in the optimal way. It means, that desired results are produced with unnecessarily high expenses, with redundant informations or with needless demands on patient. This paper deals with one special case, where information useful for examination is the body surface only, inner sight into the body is needless. New specialized medical imaging device is developed for this situation. In the Introduction section, analysis of presently used medical imaging modalities is presented, which declares, that no available imaging device is best fitting for mentioned purposes. In the next section, development of the new specialized medical imaging device is presented, and its principles and functions are described. Then, the parameters of new device are compared with present ones. It brings significant advantages comparing to present imaging systems. PMID- 25694858 TI - Successful management of rectovaginal fistula treated by endorectal advancement flap: report of two cases and literature review. AB - INTRODUCTION: Rectovaginal fistula (RVF) sometimes has a difficulty in treatment. This report describes two patients who suffered from RVF. CASE DESCRIPTIONS: One patient was a 76-year-old woman who had a RVF over 30 years after the 3rd childbirth. She underwent endorectal advancement flap (ERAF). She had a nighttime soiling after ERAF once a month, which disappeared one year after surgery. Second patient was a 23-year-old woman who had a RVF one month after the first childbirth. She underwent ERAF, and did not have any complications. DISCUSSION AND EVALUATION: Both patients did not develop recurrence for four years. Quality of life after ERAF was satisfactory in both patients. ERAF is a safe procedure in terms of both short and long outcomes. We also present a review of the literature concerning ERAF for RVF. CONCLUSIONS: ERAF can be a potential option as a treatment for RVF. PMID- 25694859 TI - Drug free remission after steroid-dependent disappearance of lymphoproliferative disorder in rheumatoid arthritis patient treated with TNF-alpha blockade: case study. AB - INTRODUCTION: TNF-alpha inhibitors plus MTX appear to have benefit in the longer term reduction of RA. Boolean long-term remission under drug-free conditions is rare. The therapeutic mechanism and the factor of predicting response have not been clarified yet. CASE DESCRIPTION: A 24-year-old female rheumatoid arthritis (RA) patient, who once attained complete remission (CR) with the combination therapy with tumor necrosis factor alpha (TNF-alpha) inhibitor adalimumab (ADA) and methotrexate (MTX), showed the occurrence of Epstain- Barr virus (EBV) associated lymphoproliferative disorder (LPD). Pulse treatment with methylprednisolone after the termination of anti TNF-alpha therapy resulted in the remission of EBV-associated LPD. The administration of prednisolone (PSL) was tapered off after the improvement of clinical symptoms and laboratory data. The patients achieved drug-free 12 months after urgent hospitalization and delivered healthy baby 2 years after hospital discharge. She has been complete drug-free Boolean remission for 5 years. DISCUSSION AND EVALUATION: The purpose of this brief case is report that we experienced the remission of LPD after CR with combined therapy with ADA and MTX. We believe this case report will be one of the paths for unveiling the pathogenesis and improving the treatment for RA. CONCLUSIONS: We believe this case report will be one of the paths for unveiling the pathogenesis and improving the treatment for RA. PMID- 25694860 TI - Education for values and bioethics. AB - "Education for Values and Bioethics" is a project which aims to help the student to build his/her personal ethics. It was addressed to ninth grade students (mean age 14) who frequented public education in all schools of the City of Porto, Portugal-EU in 2010-2013 (N-1164). This research and action project intended to promote the acquisition of knowledge in the following areas: interpersonal relationships, human rights, responsible sexuality, health, environment and sustainable development, preservation of public property, culture, financial education, social innovation and ethical education for work. The students were asked to answer to a knowledge questionnaire on bioethics. To assess the values it was used Leonard Gordon's Survey of Personal Values and Survey of Interpersonal Values. The results of this study show that the project contributes to an increase of knowledge in the area of bioethics. Also the students enrolled in the program showed a development with regards the acquisition of the basic values of pluralistic societies. It is also suggested that this general knowledge on bioethics could be especially helpful to students that want a career in health sciences. PMID- 25694861 TI - High fever and multi-nodular lung consolidations after whole lung lavage in a patient with pulmonary alveolar proteinosis. AB - INTRODUCTION: Whole lung lavage is the most effective method to treat pulmonary alveolar proteinosis (PAP), and most potential complications occur often during the lavage process, but few happen after lavage. Theoretically, pulmonary edema would be more common after whole lung lavage. However, no such case was reported in the literature. CASE DESCRIPTION: A 47-year-old Chinese male patient with PAP was referred to our hospital for whole lung lavage treatment. Although the clinical manifestations of PAP were improved, high fever was happened and multi nodular consolidations in chest CT scan were occurred after whole lung lavage. Secondary lung infection was suspected, but the patient was not treated with antibiotics immediately. After therapies like liquid limitation, glucocorticoid administration and diuretic treatment, the patient was improved gradually. Namely, newly nodular consolidations were almost completely absorbed in three days, along with the complete recovery of body temperature and associated inflammatory biomarkers. The diagnosis of secondary infection was excluded, and the final diagnosis of lavage fluid-induced pulmonary edema was confirmed. DISCUSSION AND EVALUATION: No such case has been reported that lavage fluid induced pulmonary edema is manifested by high fever and multi-consolidations in chest CT scan, which is similar to the secondary infection. CONCLUSIONS: For the first time, we described a rare complication of lavage fluid-induced pulmonary edema after whole lung lavage. As the obvious differences in treatments, it is very important for physicians to differentiate it from secondary infection. PMID- 25694862 TI - Whole lesion quantitative CT evaluation of renal cell carcinoma: differentiation of clear cell from papillary renal cell carcinoma. AB - PURPOSE: Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell cancer (RCC), followed by papillary RCC (pRCC). It is important to distinguish these two subtypes because of prognostic differences and possible changes in management, especially in cases undergoing active surveillance. The purpose of our study is to evaluate the use of voxel-based whole-lesion (WL) enhancement parameters on contrast enhanced computed tomography (CECT) to distinguish ccRCC from pRCC. MATERIALS AND METHODS: In this institutional review board-approved study, we retrospectively queried the surgical database for post nephrectomy patients who had pathology proven ccRCC or pRCC and who had preoperative multiphase CECT of the abdomen between June 2009 and June 2011. A total of 61 patients (46 with ccRCC and 15 with pRCC) who underwent robotic assisted partial nephrectomy for clinically localized disease were included in the study. Multiphase CT acquisitions were transferred to a dedicated three dimensional workstation, and WL regions of interest were manually segmented. Voxel-based contrast enhancement values were collected from the lesion segmentation and displayed as a histogram. Mean and median enhancement and histogram distribution parameters skewness, kurtosis, standard deviation, and interquartile range were calculated for each lesion. Comparison between ccRCC and pRCC was made using each imaging parameter. For mean and median enhancement, which had a normal distribution, independent t-test was used. For histogram distribution parameters, which were not normally distributed, Wilcoxon rank sum test was used. RESULTS: ccRCC had significantly higher mean and median whole WL enhancement (p < 0.01) compared to pRCC on arterial, nephrographic, and excretory phases. ccRCC had significantly higher interquartile range and standard deviation (p < 0.01) and significantly lower skewness (p < 0.01) compared to pRCC on arterial and nephrographic phases. ccRCC had significantly lower kurtosis compared to pRCC on only the arterial phase. CONCLUSION: Our study suggests that voxel-based WL enhancement parameters can be used as a quantitative tool to differentiate ccRCC from pRCC. Differentiating between the two main types of RCC would provide the patient and the treating physicians more information to formulate the initial approach to managing the patient's renal cancer. PMID- 25694863 TI - Verification of pure moment testing in a multi-degree of freedom spine testing apparatus. AB - BACKGROUND: Pure moment testing is a common method used in cadaveric spine testing. The fundamental basis for the widespread acceptance of applying a pure moment is uniform loading along the column of the spine. To our knowledge, this protocol has not been experimentally verified on a multi-degree of freedom testing apparatus. Given its ubiquitous use in spine biomechanics laboratories, confirmation of this comparative cadaveric test protocol is paramount. METHODS: Group A specimens (n =13) were used to test the pure moment protocol, by use of 3 constructs that changed the number of involved vertebrae, orientation, and rigidity of the spine construct. Group B specimens (n = 6) were used to determine whether potting orientation, testing order, or degradation affected the range of motion (ROM) by use of 8 constructs. Each group was subjected to 3 cycles of flexion-extension, lateral bending, and axial torsion. The data from the third cycle were used to calculate the ROM for each method. RESULTS: Group A testing resulted in significant differences in ROM across the 3 constructs for lateral bending and axial torsion (P < .02) and trended toward a difference for flexion extension (P = .055). Group B testing showed an increase in ROM across 8 constructs (P < .04) but no significant difference due to the orientation change. CONCLUSION: The increased ROM across constructs observed in both groups indicates that the cause is likely the testing order or degradation of the specimens, with orientation having no observed effect. The data do not invalidate pure moment testing, and its use should persist. PMID- 25694864 TI - Pullout of a lumbar plate with varying screw lengths. AB - BACKGROUND: Screw length pertains to stability in various orthopedic fixation devices. There is little or no information on the relationship between plate pullout strength and screw length in anterior lumbar interbody fusion (ALIF) plate constructs in the literature. Such a description may prove useful, especially in the treatment of osteoporotic patients where maximizing construct stability is of utmost importance. Our purpose is to describe the influence of screw length on ALIF plate stability in severely and mildly osteoporotic bone foam models. METHODS: Testing was performed on polyurethane foam blocks with densities of 0.08 g/cm(3) and 0.16 g/cm(3). Four-screw, single-level ALIF plate constructs were secured to the polyurethane foam blocks by use of sets of self tapping cancellous bone screws that were 20, 24, 28, 32, and 36 mm in length and 6.0 mm in diameter. Plates were pulled out at 1 mm/min to failure, as defined by consistently decreasing load despite increasing displacement. RESULTS: Pullout loads in 0.08-g/cm(3) foam for 20-, 24-, 28-, 32-, and 36-mm screws averaged 303, 388, 479, 586, and 708 N, respectively, increasing at a mean of 25.2 N/mm. In 0.16-g/cm(3) foam, pullout loads for 20-, 24-, 28-, 32-, and 36-mm screws averaged 1004, 1335, 1569, 1907, and 2162 N, respectively, increasing at a mean of 72.2 N/mm. CONCLUSIONS: The use of longer screws in ALIF plate installation is expected to increase construct stability. Stabilization from screw length in osteoporotic patients, however, is limited. PMID- 25694865 TI - Do presence and location of annular tear influence clinical outcome after lumbar total disc arthroplasty? A prospective 1-year follow-up study. AB - BACKGROUND: Lumbar total disc arthroplasty is often performed in patients with axial back pain. There are multiple etiologies for axial back pain, including disc degeneration and annular tears. The location of these annular tears can vary, producing differing preoperative symptomatology. Intraoperatively, disruptions in the annulus are identifiable, and it has been suggested that patients with discrete annular tears may have better clinical outcomes after surgery. The purpose of this study was to investigate whether the presence and location of annular tears have an effect on clinical outcomes after lumbar total disc arthroplasty. METHODS: Patients undergoing a single-level anterior disc replacement from L3-S1 at a single site by a single surgeon were evaluated preoperatively for the presence or absence of annular tears with magnetic resonance imaging. All patients were part of either the ProDisc (n = 41) (Synthes, Paoli, Pennsylvania) or Activ-L (n = 19) (Aesculap [B. Braun Melsungen AG], Tuttlingen, Germany) lumbar prospective clinical trials. In those patients with annular tears, the location of the tear (central, paracentral, or lateral) was documented. Patients were assessed at 6 and 12 months after lumbar total disc arthroplasty with the Oswestry Disability Index (ODI), visual analog scale (VAS) score for back pain, VAS score for leg pain, and radiographic imaging. All radiographic evaluations were conducted by an attending neuroradiologist and an attending spinal surgeon, and reliability testing was performed. An analysis of variance was performed among the 3 anatomic locations of annular tears. RESULTS: A total of 60 patients were included and had complete 12-month follow-up. The prevalence of annular tears among all patients was 42% (n = 25). Outcome data in patients without annular tears were as follows: ODI, 66% preoperatively and 26% postoperatively; VAS score for back pain, 8.0 preoperatively and 2.6 postoperatively; and VAS score for leg pain, 2.9 preoperatively and 1.2 postoperatively. Among those patients with tears, the prevalence of central tears was 80%, the prevalence of paracentral tears was 12%, and the prevalence of lateral tears was 8%. Outcome data in patients with central tears were as follows: ODI, 66% preoperatively and 26% postoperatively; VAS score for back pain, 7.8 preoperatively and 2.6 postoperatively; and VAS score for leg pain, 5.2 preoperatively and 0.5 postoperatively. Outcome data in patients with paracentral tears were as follows: ODI, 86% preoperatively and 59% postoperatively; VAS score for back pain, 8.8 preoperatively and 3.3 postoperatively; and VAS score for leg pain, 5.0 preoperatively and 5.4 postoperatively. Outcome data in patients with lateral tears were as follows: ODI, 6.5 preoperatively and 2.6 postoperatively; VAS score for back pain, 9.2 preoperatively and 0.2 postoperatively; and VAS score for leg pain, 1.4 preoperatively and 0.7 postoperatively. In those patients with paracentral tears, there was a significantly higher incidence of postoperative radicular symptoms both from an intensity standpoint and from a duration standpoint. Other complications did not vary among those patients with or without annular tears. CONCLUSIONS: Although patients with annular tears and patients without annular tears improve after lumbar artificial disc replacement, those with central annular tears or without tears have significantly lower disability scores than those with paracentral tears or lateral tears, whose outcome scores showed significantly less improvement (P <= .03). In particular, patients with central tears have less postoperative leg pain than those with paracentral annular tears. In this study the presence or absence of an annular tear on magnetic resonance imaging was not a significant predictive factor for clinical outcome. Further investigation regarding the effects of paracentral annular tears and surgical techniques should be explored. PMID- 25694866 TI - The importance of the anterior longitudinal ligament in lumbar disc arthroplasty: 36-Month follow-up experience in extreme lateral total disc replacement. AB - BACKGROUND: Current total disc replacement (TDR) for lumbar spine requires an anterior approach for implantation but presents inherent limitations, including risks to the abdominal structures, as well as resection of the anterior longitudinal ligament. By approaching the spine laterally, it is possible to preserve the stabilizing ligaments, which are a natural restraint to excessive rotations and translations, and thereby help to minimize facet stresses. This less invasive approach also offers a biomechanical advantage of placement of the device over the ring apophysis bilaterally; importantly, it also offers a greater opportunity for safer revision surgery, if necessary, by avoiding scarring of the anterior vasculature. We present the clinical and radiologic results of a lateral TDR device from a prospective single-center study. METHODS: A new metal-on-metal TDR device designed for implantation through a true lateral, retroperitoneal, transpsoatic approach (extreme lateral interbody fusion) was implanted in 36 patients with discography-confirmed 1- or 2-level degenerative disc disease. Clinical (pain and function) and radiographic (range of motion) outcome assessments were prospectively collected preoperatively, postoperatively, and serially up to a minimum of 36 months' follow-up. RESULTS: Between December 2005 and December 2006, 36 surgeries were performed in 16 men and 20 women (mean age, 42.6 years). These included 15 single-level TDR procedures at L3-4 or L4-5, 3 2 level TDR procedures spanning L3-4 and L4-5, and 18 hybrid procedures (anterior lumbar interbody fusion) at L5-S1 and TDR at L4-5 (17) or L3-4 (1). Operative time averaged 130 minutes, with mean blood loss of 60 mL and no intraoperative complications. Postoperative X-rays showed good device placement, with restoration of disc height, foraminal volume, and sagittal balance. All patients were up and walking within 12 hours of surgery, and all but 9 were discharged the next day (7 of those 9 were hybrid TDR-anterior lumbar interbody fusion cases). Postoperatively, 5 of 36 patients (13.8%) had psoas weakness and 3 of 36 (8.3%) had anterior thigh numbness, with both symptoms resolving within 2 weeks. Of the 36 patients, 4 (11%) had postoperative facet joint pain, all in hybrid cases. Visual analog scale pain scores and Oswestry Disability Index scores improved by 74.5% and 69.2%, respectively, from preoperatively to 3-year follow-up. Range of motion at 3 years postoperatively averaged 8.1 degrees . Signals of heterotopic ossification were present in 5 patients (13.9%), and 2 patients (5.5%) were considered to have fusion after 36 months. CONCLUSIONS: The clinical and radiographic results of a laterally placed TDR have shown maintenance of pain relief and functional improvement over a long-term follow-up period. The benefits of the lateral access-minimal morbidity, avoidance of mobilization of the great vessels, preservation of the anterior longitudinal ligament, biomechanically stable orientation, and broader revision options-promote a new option for motion preservation procedures. PMID- 25694867 TI - Clinical and radiographic outcomes of extreme lateral approach to interbody fusion with beta-tricalcium phosphate and hydroxyapatite composite for lumbar degenerative conditions. AB - BACKGROUND: Historically, iliac crest bone graft has been used as the graft of choice for lumbar spine fusion procedures. Because fusion techniques have become less invasive, the demand for minimally disruptive grafting options has increased. This prospective study was performed to assess clinical and radiographic outcomes of patients treated with an iliac crest bone graft alternative and lateral lumbar interbody fusion. METHODS: Fifty degenerative lumbar patients were treated with the extreme lateral approach to interbody fusion and a beta-tricalcium phosphate-hydroxyapatite graft with bone marrow aspirate (BMA) at 1 or 2 adjacent levels. BMA was collected from the iliac crest with a bone aspiration needle and applied to the FormaGraft (NuVasive, Inc., San Diego, California) in a 1:1 ratio. Radiolucent cages were filled with FormaGraft strips, granules, or blocks and implanted in a standard fashion. Clinical data were collected at baseline, 6 weeks, and 3, 6, and 12 months and included visual analog scale, Oswestry Disability Index, and Short Form 36 patient-reported assessments. Fusion assessments were made from neutral anteroposterior/lateral radiographs, lateral flexion/extension radiographs, and computed tomography images taken at least 12 months after surgery. RESULTS: Forty-four patients treated at 49 levels completed follow-up. The mean patient age was 54.7 +/- 10.8 years, and mean body mass index was 30.8 +/- 7.7 kg/m(2). Radiographic fusion was observed in 41 of 44 assessed levels (93.2%). Blood loss was less than 100 mL in 95.5% of patients. Of the patients, 93.2% spent 1 night or less in the hospital. By the 6-week follow-up, all clinical outcomes were significantly improved (P < .05). Improvements were maintained or increased throughout the course of follow up. CONCLUSIONS: This report shows that the technique of extreme lateral approach to interbody fusion in combination with FormaGraft and BMA in the interbody space is a safe and effective treatment option for interbody fusion of the lumbar spine when compared with other approaches and biologic options. PMID- 25694868 TI - Conus medullaris syndrome after epidural steroid injection: Case report. AB - BACKGROUND: Given the risk of paralysis associated with cervical transforaminal injection, is it time to reconsider transforaminal injections of the lumbar spine? Arguments for discontinuing lumbar injections have been discussed in the anesthesia literature, raising concern about the risks of epidural steroid injections (ESIs). METHODS: In a 47-year-old man, paraplegia of the lower extremities developed, specifically conus medullaris syndrome, after he underwent an ESI for recurrent pain. Correct needle placement was verified with epidurography. Immediately after the injection, the patient felt his legs "going dead"; paraplegia of the lower extremities was noted. RESULTS: An initial magnetic resonance imaging study performed after the patient was transferred to the emergency department was unremarkable. However, a later neurosurgical evaluation showed conus medullaris syndrome, and a second magnetic resonance imaging study showed the conus infarct. We conducted a search of the PubMed database of articles from 2002 to 2011 containing the following keywords: complications, lumbar epidural steroid injection(s), cauda equina syndrome, conus medullaris infarction, spinal cord infarction, spinal cord injury, paralysis, paresis, plegia, paresthesia, and anesthesia. CONCLUSIONS: Summarizing this case and 5 similar cases, we weigh the potential benefits and risks of ESI. Although one can safely assume that this severe, devastating complication is rare, we speculate that its true incidence remains unknown, possibly because of medicolegal implications. We believe that the rarity of this complication should not preclude the continued use of transforaminal ESI; rather, it should be emphasized for discussion with patients during the consent process. PMID- 25694869 TI - Biomechanics of a fixed-center of rotation cervical intervertebral disc prosthesis. AB - BACKGROUND: Past in vitro experiments studying artificial discs have focused on range of motion. It is also important to understand how artificial discs affect other biomechanical parameters, especially alterations to kinematics. The purpose of this in vitro investigation was to quantify how disc replacement with a ball and-socket disc arthroplasty device (ProDisc-C; Synthes, West Chester, Pennsylvania) alters biomechanics of the spine relative to the normal condition (positive control) and simulated fusion (negative control). METHODS: Specimens were tested in multiple planes by use of pure moments under load control and again in displacement control during flexion-extension with a constant 70-N compressive follower load. Optical markers measured 3-dimensional vertebral motion, and a strain gauge array measured C4-5 facet loads. RESULTS: Range of motion and lax zone after disc replacement were not significantly different from normal values except during lateral bending, whereas plating significantly reduced motion in all loading modes (P < .002). Plating but not disc replacement shifted the location of the axis of rotation anteriorly relative to the intact condition (P < 0.01). Coupled axial rotation per degree of lateral bending was 25% +/- 48% greater than normal after artificial disc replacement (P = .05) but 37% +/- 38% less than normal after plating (P = .002). Coupled lateral bending per degree of axial rotation was 37% +/- 21% less than normal after disc replacement (P < .001) and 41% +/- 36% less than normal after plating (P = .001). Facet loads did not change significantly relative to normal after anterior plating or arthroplasty, except that facet loads were decreased during flexion in both conditions (P < .03). CONCLUSIONS: In all parameters studied, deviations from normal biomechanics were less substantial after artificial disc placement than after anterior plating. PMID- 25694870 TI - Physical capability outcomes after total disc replacement with ProDisc-L. AB - BACKGROUND: Lumbar disc arthroplasty (total disc replacement [TDR]) outcomes have been evaluated using subjective, patient-reported measures of pain, health, and functional impairment. As a condition of TDR coverage, our institution's health plan required that objective physical performance data be collected. Thus our study was designed to explore (1) the feasibility of using preoperative and 1 year postoperative performance on functional capacity tasks as an outcome metric for TDR with ProDisc-L (PD-L) (Synthes Spine, West Chester, Pennsylvania), (2) the magnitude and significance of changes in preoperative and postoperative performance, and (3) whether changes noted in performance are reflected in the subjective measures. METHODS: Seven adapted WorkWell tasks (physical capability assessment tool [PCAT]) (WorkWell Systems, Duluth, Minnesota) were performed preoperatively and 1 year postoperatively by 18 patients who received either single-level or 2-level PD-L implants. Demographic and medical data were reviewed. RESULTS: The PCAT was implemented easily, and the tasks took approximately 30 minutes to complete. Percent improvement and preoperative and postoperative physical capability outcomes for each PCAT task are as follows: squat, 79% (10.7 +/- 7.1 repetitions vs 19.2 +/- 2.0 repetitions, P < .001); forward bend, 121% (110.2 +/- 68.8 seconds vs 243.6 +/- 77.2 seconds, P < .001); kneel, 92% (283.2 +/- 173.2 seconds vs 544.7 +/- 109.3 seconds, P < .001); floor to-waist lift, 128% (16.1 +/- 9.9 lb vs 36.7 +/- 20.3 lb, P < .001); horizontal carry, 119% (19.7 +/- 8.6 lb vs 43.2 +/- 18.3 lb, P < .001); push, 32% (67.7 +/- 19.2 lb vs 89.4 +/- 24.4 lb, P < .001); and pull, 40% (57.6 +/- 17.1 lb vs 80.9 +/- 26.4 lb, P < .001). Visual analog scale scores for pain (5.1 +/- 1.7 vs 1.4 +/- 1.6, P < .001), Oswestry Disability Index scores (49.0% +/- 13.2% vs 15.2% +/ 14.3%, P < .001), and amount of narcotic use (26.1 +/- 43.8 mg of morphine equivalent vs 1.9 +/- 7.3 mg of morphine equivalent, P = .031) also improved. In single-level cases, comparison of L4-5 versus L5-S1 showed significant differences only with the forward bend task (P = .002). CONCLUSIONS/CLINICAL RELEVANCE: The physical capability outcome may be a feasible outcome metric. PD-L implantation may result in substantial improvements in physical performance. Similar benefits shown in a larger series over a longer timeframe could have important implications for the long-term health, productivity, and cost of health care for this patient population. PMID- 25694871 TI - Intraoperative 3-dimensional imaging (O-arm) for assessment of pedicle screw position: Does it prevent unacceptable screw placement? AB - BACKGROUND: Pedicle screws are biomechanically superior over other spinal fixation devices. When improperly positioned, they lose this advantage and put adjacent structures at risk. Accurate placement is therefore critical. Postoperative computed tomography (CT) scans are the imaging gold standard and have shown malposition rates ranging from 2% to 41%. The O-arm (Medtronic Navigation, Louisville, Colorado) is an intraoperative CT scanner that may allow intervention for malpositioned screws while patients are still in the operating room. However, this has not yet been shown in clinical studies. The primary objective of this study was to assess the usefulness of the O-arm for evaluating pedicle screw position by answering the following question: What is the rate of intraoperative pedicle screw revision brought about by O-arm imaging information? A secondary question was also addressed: What is the rate of unacceptable thoracic and lumbar pedicle screw placement as assessed by intraoperative O-arm imaging? METHODS: This is a case series of consecutive patients who have undergone spine surgery for which an intraoperative 3-dimensional (3D) CT scan was used to assess pedicle screw position. The study comprised 602 pedicle screws (235 thoracic and 367 lumbar/sacral) placed in 76 patients, and intraoperative 3D (O-arm) imaging was obtained to assess screw position. Action taken at the time of surgery based on imaging information was noted. An independent review of all scans was also conducted, and all screws were graded as either optimal (no breach), acceptable (breach <=2 mm), or unacceptable (breach >2 mm). The rate of pedicle screw revision, as detected by intraoperative 3D CT scan, was determined. RESULTS: On the basis of 3D imaging information, 17 of 602 screws (2.8%) in 14 of 76 cases (18.4%) were revised at the time of surgery. On independent review of multiplanar images, 11 screws (1.8%) were found to be unacceptable, 32 (5.3%) were acceptable, and 559 (92.9%) were optimal. All unacceptable screws were revised to an optimal or acceptable position, and an additional 6 acceptable screws were revised to an optimal position. Thus, by the end of the cases, none of the 602 pedicle screws in the 76 surgical procedures was in an unacceptable position. CONCLUSION: The new-generation intraoperative 3D imaging system (O-arm) is a useful tool that allows more accurate assessment of pedicle screw position than plain radiographs or fluoroscopy alone. It prompted intraoperative repositioning of 2.8% of pedicle screws in our series. Most importantly, it allowed identification and revision of all unacceptably placed pedicle screws without the need for reoperation. PMID- 25694872 TI - The effect of minimally invasive posterior cervical approaches versus open anterior approaches on neck pain and disability. AB - BACKGROUND: The choice of surgical approach to the cervical spine may have an influence on patient outcome, particularly with respect to future neck pain and disability. Some surgeons suggest that patients with myelopathy or radiculopathy and significant axial pain should be treated with an anterior interbody fusion because a posterior decompression alone may exacerbate the patients' neck pain. To date, the effect of a minimally invasive posterior cervical decompression approach (miPCD) on neck pain has not been compared with that of an anterior cervical diskectomy or corpectomy with interbody fusion (ACF). METHODS: A retrospective review was undertaken of 63 patients undergoing either an miPCD (n = 35) or ACF (n = 28) for treatment of myelopathy or radiculopathy who had achieved a minimum of 6 months' follow-up. Clinical outcomes were assessed by a patient-derived neck visual analog scale (VAS) score and the neck disability index (NDI). Outcomes were analyzed by use of (1) a threshold in which outcomes were classified as success (NDI < 40, VAS score < 4.0) or failure (NDI > 40, VAS score > 4.0) and (2) perioperative change in which outcomes were classified as success (DeltaNDI >= - 15, DeltaVAS score >= - 2.0) or failure (DeltaNDI < - 15, DeltaVAS score < -2.0). Groups were compared by use of chi (2) tests with significance taken at P < .05. RESULTS: At last follow-up, the percentages of patients classified as successful using the perioperative change criteria were as follows: 42% for miPCD group versus 63% for ACF group based on neck VAS score (P = not significant [NS]) and 33% for miPCD group versus 50% for ACF group based on NDI (P < .05). At last follow-up, the percentages of patients classified as successful using the threshold criteria were as follows: 71% for miPCD group versus 82% for ACF group based on neck VAS score (P = NS) and 69% for miPCD group versus 68% for ACF group based on NDI (P = NS). CONCLUSIONS: In this small retrospective analysis, miPCD was associated with similar neck pain and disability to ACF. Given the avoidance of cervical instrumentation and interbody fusion in the miPCD group, these results suggest that further comparative effectiveness study is warranted. PMID- 25694873 TI - A novel radiographic targeting guide for percutaneous placement of transfacet screws in the cervical spine with limited fluoroscopy: A cadaveric feasibility study. AB - BACKGROUND: We describe a technique for percutaneous transfacet screw placement in the cervical spine without the need for lateral-view fluoroscopy. METHODS: Previously established articular pillar morphometry was used to define the ideal trajectory for transfacet screw placement in the subaxial cervical spine. A unique targeting guide was developed to allow placement of Kirschner wires across the facet joint at 90 degrees without the guidance of lateral-view fluoroscopy. Kirschner wires and cannulated screws were placed percutaneously in 7 cadaveric specimens. Placement of instrumentation was performed entirely under modified anteroposterior-view fluoroscopy. All specimens were assessed for acceptable screw placement by 2 fellowship-trained orthopaedic spine surgeons using computed tomography. Open dissection was used to confirm radiographic interpretation. Acceptable placement was defined as a screw crossing the facet joint, achieving purchase in the inferior and superior articular processes, and not violating critical structures. Malposition was defined as a violation of the transverse foramen, spinal canal, or nerve root or inadequate fixation. RESULTS: A total of 48 screws were placed. Placement of 45 screws was acceptable. The 3 instances of screw malposition included a facet fracture, a facet distraction, and a C6-7 screw contacting the C7 nerve root in a specimen with a small C7 superior articular process. CONCLUSIONS: Our data show that with the appropriate radiographic technique and a targeting guide, percutaneous transfacet screws can be safely placed at C3-7 without the need for lateral-view fluoroscopy during the targeting phase. Because of the variable morphometry of the C7 lateral mass, however, care must be taken when placing a transfacet screw at C6-7. CLINICAL RELEVANCE: This study describes a technique that has the potential to provide a less invasive strategy for posterior instrumentation of the cervical spine. Further investigation is needed before this technique can be applied clinically. PMID- 25694874 TI - Cervical total disc replacement using a novel compressible prosthesis: Results from a prospective Food and Drug Administration-regulated feasibility study with 24-month follow-up. AB - BACKGROUND: Anterior cervical fusion, an established procedure to treat cervical radiculopathy, sacrifices the natural function of the disc, while placing increased stresses on adjacent spinal levels. In contrast, the cervical total disc replacement (cTDR) maintains motion and decreases adjacent-level stresses. The purpose of this study was to investigate the safety and effectiveness of a next-generation cTDR device in patients with symptomatic cervical radiculopathy. METHODS: This is a multicenter Food and Drug Administration-regulated feasibility study to evaluate safety and effectiveness of the M6-C Artificial Cervical Disc for the treatment of patients with symptomatic cervical radiculopathy at 1 or 2 levels from C3 to C7. Neck Disability Index (NDI), visual analog scales (VAS) assessing neck and arm pain, Short Form 36 Health Survey (SF-36), safety, and radiographic outcomes were assessed preoperatively, at 6 weeks and 3, 6, 12, and 24 months postoperatively. RESULTS: Thirty patients were enrolled at 3 clinical sites. Patients were implanted at either 1 or 2 levels. Mean NDI improved from 67.8 to 20.8 (P < .0001) at 24 months. Significant improvement was also observed through 24-month follow-up in neck and arm pain VAS (P < .0001) and in physical (P < .005) and mental component scores of the SF-36 at 3, 6, and 12 months (P < .008). There were no serious adverse events related to the device or procedure as adjudicated by an independent clinical events committee. Radiographically, disc space height increased more than 50% with a correlative increase in the postoperative disc angle. Range of motion decreased slightly from baseline during early follow-up but increased slightly and were maintained throughout the follow up period. CONCLUSIONS: The M6-C cervical artificial disc represents a new generation of cTDR design. Results of this study found the M6-C device to produce positive clinical and radiographic outcomes similar to other cTDRs, warranting further investigation. PMID- 25694875 TI - A compliant-mechanism approach to achieving specific quality of motion in a lumbar total disc replacement. AB - BACKGROUND: The current generation of total disc replacements achieves excellent short- and medium-term results by focusing on restoring the quantity of motion. Recent studies indicate that additional concerns (helical axes of motion, segmental torque-rotation behavior) may have important implications in the health of adjacent segments as well as the health of the surrounding tissue of the operative level. The objective of this article is to outline the development, validation, and biomechanical performance of a novel, compliant-mechanism total disc replacement that addresses these concerns by including them as essential design criteria. METHODS: Compliant-mechanism design techniques were used to design a total disc replacement capable of replicating the moment-rotation response and the location and path of the helical axis of motion. A prototype was evaluated with the use of bench-top testing and single-level cadaveric experiments in flexion-extension, lateral bending, and axial torsion. RESULTS: Bench-top testing confirmed that the moment-rotation response of the disc replacement matched the intended design behavior. Cadaveric testing confirmed that the moment-rotation and displacement response of the implanted segment mimicked those of the healthy spinal segment. CONCLUSIONS: Incorporation of segmental quality of motion into the foundational stages of the design process resulted in a total disc replacement design that provides torque-rotation and helical axis-of-motion characteristics to the adjacent segments and the operative level facets that are similar to those observed in healthy spinal segments. PMID- 25694876 TI - An in vivo kinematic comparison of dynamic lumbar stabilization to lumbar discectomy and posterior lumbar fusion using radiostereometric analysis. AB - BACKGROUND: Biomechanical studies have shown that dynamic stabilization restores the neutral zone and stabilizes the motion segment. Unfortunately, there are limitations to clinical measurement of lumbar motion segments when using routine radiographs. Radiostereometric analysis is a 3-dimensional technique and can measure the spinal motion segment more accurately than techniques using plain film radiographs. The purpose of this study was measure and compare the range of motion after dynamic stabilization, posterior lumbar fusion (PLF), and lumbar discectomy. METHODS: Four patients who underwent lumbar decompression and dynamic stabilization (Dynesys; Zimmer Spine, Inc., Warsaw, Indiana) for treatment of lumbar spondylosis were compared with 4 patients with a similar diagnosis who were treated by PLF and pedicle screw fixation (PLF group) and 8 patients who had undergone lumbar microdiscectomy (discectomy group) for treatment of radiculopathy. During the surgical procedure, 3 to 5 tantalum beads were placed into each of the operative segments. The patients were followed up postoperatively at 1 month, 1 year, and 2 years. At each follow-up time point, segmental motions (flexion, extension, and total sagittal range of motion [SROM]) were measured by radiostereometric analysis. RESULTS: Flexion, extension, and SROM measured 1.0 degrees +/- 0.9 degrees , 1.5 degrees +/- 1.3 degrees , and 2.3 degrees +/- 1.2 degrees , respectively, in the Dynesys group; 1.0 degrees +/- 0.6 degrees , 1.1 degrees +/- 0.9 degrees , and 1.5 degrees +/- 0.6 degrees , respectively, in the PLF group; and 2.9 degrees +/- 2.4 degrees , 2.3 degrees +/- 1.5 degrees , and 4.7 degrees +/- 2.2 degrees , respectively, in the discectomy group. No significant difference in motion was seen between the Dynesys and PLF groups or between the Dynesys and discectomy groups in extension. Significant differences in motions were seen between the PLF and discectomy groups and between the Dynesys and discectomy groups in flexion (P = .007) and SROM (P = .002). There was no significant change in the measured motions over time. CONCLUSIONS: In this study a significantly lower amount of motion was seen after dynamic stabilization and PLF when compared with discectomy. A future study with a larger cohort is necessary to examine what effect, if any, these motions have on clinical outcomes. PMID- 25694877 TI - Prevention of vertebral body-splitting fractures after multilevel ProDisc-L implantation. AB - BACKGROUND: Prior studies of multilevel ProDisc-L (PD-L) implants (Synthes Spine, Inc., West Chester, Pennsylvania) using the standard US technique have used conventional radiography postoperatively. We found vertebral body-splitting fractures (VB-SFs) in interposed vertebral bodies after 5 sequential multilevel PD-L device implantations using the standard US technique. These were identified with postoperative computed tomography (CT) but were not visible on plain radiographs. In an additional patient, we found that a stress-relieving, pilot holes-only technique did not prevent VB-SFs. The 5 patients operated on with the standard technique composed the background series against which we compared the incidence of VB-SFs in patients operated on with a modification of the standard US technique-a combination of stress-relieving pilot holes, removal of cortex in the chisel path, and a fenestrated chisel (PH/CR/FC)-intended to reduce the incidence of VB-SFs in multilevel PD-L constructs. METHODS: Patients receiving multilevel PD-L implants at 2 sites-1 in the United States and the other in Germany-were operated on with the PH/CR/FC technique and their postoperative CT scans evaluated for the presence of VB-SFs. The frequency of VB-SFs in these patients was compared with that of the 5 patients from the background series who were operated on by the standard US technique. The groups' mean sex, age, body mass index, and vertebral body height, as well as average spinal T score, were also compared. RESULTS: No fractures were found in 13 interposed vertebral bodies in 11 patients operated on with the PH/CR/FC technique, as compared with 4 VB-SFs and 1 anterior keel cut-to-anterior keel cut fracture in 5 interposed vertebral bodies in 5 patients operated on with the US technique (P <= .001). Although the sample sizes were small, this difference in fracture rate was not associated with sex, age, body mass index, or average spinal T score. At up to 13 months of follow-up of patients in the background series, we found that VB-SFs tend not to bridge with bone, instead forming sclerotic margins. CONCLUSIONS: The PH/CR/FC technique studied reduced the incidence of VB-SF in multilevel PD-L implants. Because previously published multilevel studies did not use postoperative CT scans and because VB-SFs are not visible on conventional radiography, the incidence of VB-SFs in multilevel PD-L applications may be higher than previously reported. Our findings may contribute to prevention of complications in total disc replacement. PMID- 25694878 TI - Arthroscopic discectomy and interbody fusion of the thoracic spine: A report of ipsilateral 2-portal approach. AB - BACKGROUND: The standard approach to the thoracic disc is through thoracotomy. The video-assisted thoracoscopic approach has been used as an alternative to the open approach for nearly 20 years, and more recently, extracavitary, posterolateral approaches have been introduced. Both the transthoracic procedures involve deflating the lung for access to the spine, and postoperative thoracic drainage is necessary; postoperative morbidity can be significant. The retropleural procedures are in their infancy, but the published results are promising. The purpose of this study is to introduce the posterolateral arthroscopic thoracic decompression and fusion procedure, which is extrapleural, less disruptive to normal anatomy, and cost-effective. METHODS: Fifteen consecutive patients who underwent arthroscopic decompression and interbody fusion of the thoracic spine were prospectively studied according to the hospital's institutional review board protocol. The Short Form 36 and visual analog scale questionnaires were completed preoperatively and postoperatively. Paired t tests were used for statistical analysis. The patient was placed in the prone position on a radiolucent table, and instrumentation was performed under fluoroscopic control. Two portals were developed ipsilaterally (one for the arthroscope and the other for instruments) on the side of disc herniation, and a single portal was used on the contralateral side. Various instruments were used for disc excision and exploration of the spinal canal. Fusion was accomplished with bilateral corticocancellous dowels obtained from the iliac crests. Infiltration of the access channel and facet injections of the contiguous joints were performed with bupivacaine, for immediate postoperative pain control. RESULTS: Fifteen patients with a mean age of 54 years were followed up for 28 months postoperatively. The overall back pain score decreased from 7.2 (SD, 1.5) to 3 (SD, 2) after the procedure (P < .005). Eleven patients were satisfied with their current lifestyle postoperatively as opposed to one preoperatively. Two patients had reoccurrences. Hospital stay averaged 18.5 hours. The operating room cost and the cost of hospital stay was 51.9% of the cost of anterior open discectomy. CONCLUSIONS: The extrapleural, biportal, ipsilateral arthroscopic approach for the decompression and interbody fusion of the thoracic spine is feasible, cost-effective, less traumatic, and associated with minimal complications. The best results were obtained in patients with single-level thoracic disc herniation. The technique is applicable for most thoracic disc herniations. PMID- 25694879 TI - Minimally invasive trans-sacral approach to L5-S1 interbody fusion: Preliminary results from 1 center and review of the literature. AB - BACKGROUND: Lumbar interbody fusion has long been used for the treatment of painful degenerative spinal conditions. The anterior approach is not feasible in some patients, and the posterior approach is associated with a risk of neural complications and possibly muscle injury. A trans-sacral technique was developed that allows access to the L5-S1 disc space. The purposes of this study were to investigate the clinical outcome of trans-sacral interbody fusion in a consecutive series of patients from 1 center and to perform a comprehensive review of the literature on this procedure. METHODS: A literature search using PubMed was performed to identify articles published on trans-sacral axial lumbar interbody fusion (AxiaLIF). Articles reviewed included biomechanical testing, feasibility of the technique, and clinical results. The data from our center were collected retrospectively from charts for the consecutive series, beginning with the first case, of all patients undergoing fusion using the AxiaLIF technique. In most cases, posterior instrumentation was also used. A total of 41 patients with at least 6 months' follow-up were included (mean follow-up, 22.2 months). The primary clinical outcome measures were visual analog scales separately assessing back and leg pain and the Oswestry Disability Index. Radiographic assessment of fusion was also performed. RESULTS: In the group of 28 patients undergoing single level AxiaLIF combined with posterior fusion, the visual analog scale scores assessing back and leg pain and mean Oswestry Disability Index scores improved significantly (P < .01). In the remaining 13 patients, back pain improved significantly with a trend for improvement in leg pain. Reoperation occurred in 19.5% of patients; in half of these, reoperation was not related to the anterior procedure. CONCLUSIONS: A review of the literature found that the AxiaLIF technique was similar to other fusion techniques with respect to biomechanical properties and produced acceptable clinical outcomes, although results varied among studies. CLINICAL RELEVANCE: The AxiaLIF approach allows access to the L5 S1 interspace without violating the annulus or longitudinal ligaments and with minimal risk to dorsal neural elements. It may be a viable alternative to other approaches to interbody fusion at the L5-S1 level. It is important that the patients be selected carefully and surgeons are familiar with the presacral anatomy and the surgical approach. PMID- 25694880 TI - Cement interdigitation and bone-cement interface after augmenting fractured vertebrae: A cadaveric study. AB - BACKGROUND: The treatment of painful osteoporotic vertebral compression fractures with transpedicular cement augmentation has grown significantly over the last 20 years. There is still uncertainty about long-term and midterm effects of polymethyl methacrylate in trabecular bone. Preservation of the trabecular structures, as well as interdigitation of the cement with the surrounding bone, therefore has been gaining increasing attention. Interdigitation of cement is likely relevant for biological healing and the biomechanical augmentation process. In this study a cutting and grinding technique was used to evaluate the interdigitation for 4 augmentation techniques. METHODS: By use of a standardized protocol, wedge fractures were created in vertebrae taken from a fresh-frozen spine. Thereafter the vertebrae were assigned to 1 of 4 similar groups with regard to the vertebral size and force required to produce the fracture. The 4 groups were randomized to the following augmentation techniques: balloon kyphoplasty, radiofrequency (RF) kyphoplasty, shield kyphoplasty, and vertebral stenting. Histologic analysis was designed to examine the bone structure and interdigitation after the augmentation. RESULTS: For the void-creating procedures, the distance between bone and cement was 341.4 +/- 173.7 um and 413.6 +/- 167.6 um for vertebral stenting and balloon kyphoplasty, respectively. Specifically, the trabecular bone was condensed around the cement, forming a shield of condensed bone. The procedures without a balloon resulted in shorter distances of 151.2 +/- 111.4 um and 228.1 +/- 183.6 um for RF and shield kyphoplasty, respectively. The difference among the groups was highly significant (P < .0001). The percentage of interdigitation was higher for the procedures that did not use a balloon: 16.7% +/- 9.7% for balloon kyphoplasty, 20.5% +/- 12.9% for vertebral stenting, 66.45% +/- 12.35% for RF kyphoplasty, and 48.61% +/- 20.56% for shield kyphoplasty. The difference among the groups was highly significant (P < .00001). CONCLUSIONS: Cavity-creating procedures reduce the cement interdigitation significantly and may accordingly reduce the effectiveness of the augmentation procedures. PMID- 25694881 TI - Lumbar artificial disc replacement in Ehlers-Danlos syndrome: A case report and discussion of clinical management. AB - BACKGROUND: Ehlers-Danlos syndrome (EDS) is a heterogeneous collection of connective tissue disorders characterized by varying degrees of skin hyperextensibility, joint hypermobility, and tissue fragility. Surgical treatment of EDS patients is complicated by the extreme fragility of their vessels and tissues. The purpose of this case report is to present the management of an EDS patient with debilitating low-back pain. METHODS: A 52-year-old woman with a clinical diagnosis of EDS presented with degenerative disc disease at L4-5 that had not been alleviated by previous microdiscectomies. The clinical course, decision-making process, and treatment are discussed in this case report. RESULTS: The patient was referred for genetic evaluation, which classified her with type III EDS, or hypermobility type. We presented the patient with the risks and benefits of fusion versus artificial disc replacement (ADR), particularly with regard to her EDS diagnosis of the hypermobility subtype. Given the patient's lack of extreme spinal hypermobility on examination and the absence of clear contraindications regarding ADR in type III EDS, the decision was made to proceed with ADR. There were no surgical complications, and the patient's low back pain and radicular symptoms resolved with no evidence of implant migration or hypermobility at 1 year postoperatively. CONCLUSIONS: In this case report, the referral to a geneticist and consultation with a vascular surgeon were integral steps in the decision to proceed with surgery. Although the clarified diagnosis of type III EDS did not eliminate the potential risk for vascular compromise during surgery, it placed the patient at lower risk than patients with other subtypes of EDS. Similarly, her lack of extreme hypermobility made us more comfortable with pursuing ADR. Although we emphasize extreme caution when considering surgical treatment, this case report suggests that some patients with less severe forms of EDS may be able to successfully undergo anterior spine surgery, including ADR. PMID- 25694882 TI - Preoperative education for lumbar radiculopathy: A survey of US spine surgeons. AB - BACKGROUND: We sought to determine current utilization, importance, content, and delivery methods of preoperative education by spine surgeons in the United States for patients with lumbar radiculopathy. METHODS: An online cross-sectional survey was used to study a random sample of spine surgeons in the United States. The Spinal Surgery Education Questionnaire (SSEQ) was developed based on previous related surveys and assessed for face and content validity by an expert panel. The SSEQ captured information on demographics, content, delivery methods, utilization, and importance of preoperative education as rated by surgeons. Descriptive statistics were used to describe the current utilization, importance, content, and delivery methods of preoperative education by spine surgeons in the United States for patients with lumbar radiculopathy. RESULTS: Of 200 surgeons, 89 (45% response rate) responded to the online survey. The majority (64.2%) provide preoperative education informally during the course of clinical consultation versus a formal preoperative education session. The mean time from the decision to undergo surgery to the date of surgery was 33.65 days. The highest rated educational topics are surgical procedure (96.3%), complications (96.3%), outcomes/expectations (93.8%), anatomy (92.6%), amount of postoperative pain expected (90.1%), and hospital stay (90.1%). Surgeons estimated spending approximately 20% of the preoperative education time specifically addressing pain. Seventy-five percent of the surgeons personally provide the education, and nearly all surgeons (96.3%) use verbal communication with the use of a spine model. CONCLUSIONS: Spine surgeons believe that preoperative education is important and use a predominantly biomedical approach in preparing patients for surgery. Larger studies are needed to validate these findings. PMID- 25694883 TI - Analysis of adjacent segment reoperation after lumbar total disc replacement. AB - BACKGROUND: Fusion has long been used for treating chronic back pain unresponsive to nonoperative care. However, potential development of adjacent segment degeneration resulting in reoperation is a concern. Total disc replacement (TDR) has been proposed as a method for addressing back pain and preventing or reducing adjacent segment degeneration. The purpose of the study was to determine the reoperation rate at the segment adjacent to a level implanted with a lumbar TDR and to analyze the pre-TDR condition of the adjacent segment. METHODS: This study was based on a retrospective review of charts and radiographs from a consecutive series of 1000 TDR patients to identify those who underwent reoperation because of adjacent segment degeneration. Some of the patients were part of randomized studies comparing TDR with fusion. Adjacent segment reoperation data were also collected from 67 patients who were randomized to fusion in those studies. The condition of the adjacent segment before the index surgery was compared with its condition before reoperation based on radiographs, magnetic resonance imaging (MRI), and computed tomography. RESULTS: Of the 1000 TDR patients, 20 (2.0%) underwent reoperation. The mean length of time from arthroplasty to reoperation was 28.3 months (range, 0.5-85 months). Of the adjacent segments evaluated on preoperative MRI, 38.8% were normal, 38.8% were moderately diseased, and 22.2% were classified as having severe degeneration. None of these levels had a different grading at the time of reoperation compared with the pre-TDR MRI study. Reoperation for adjacent segment degeneration was performed in 4.5% of the fusion patients. CONCLUSIONS: The 2.0% rate of adjacent segment degeneration resulting in reoperation in this study is similar to the 2.0% to 2.8% range in other studies and lower than the published rates of 7% to 18% after lumbar fusion. By carefully assessing the presence of pre-existing degenerative changes before performing arthroplasty, this rate may be reduced even more. PMID- 25694884 TI - Comparison of in vivo and simulator-retrieved metal-on-metal cervical disc replacements. AB - BACKGROUND: Cervical disc arthroplasty is regarded as a promising treatment for myelopathy and radiculopathy as an alternative to cervical spine fusion. On the basis of 2-year clinical data for the PRESTIGE((r)) Cervical Disc (Medtronic, Memphis, Tennessee), the Food and Drug Administration recommended conditional approval in September 2006 and final approval in July 2007; however, relatively little is known about its wear and damage modes in vivo. The main objective was to analyze the tribological findings of the PRESTIGE((r)) Cervical Disc. This study characterized the in vivo wear patterns of retrieved cervical discs and tested the hypothesis that the total disc replacements exhibited similar surface morphology and wear patterns in vitro as in vivo. METHODS: Ten explanted total disc replacements (PRESTIGE((r)), PRESTIGE((r)) I, and PRESTIGE((r)) II) from 10 patients retrieved after a mean of 1.8 years (range, 0.3-4.1 years) were analyzed. Wear testing included coupled lateral bending ( +/-4.7 degrees ) and axial rotation ( +/-3.8 degrees ) with a 49 N axial load for 5 million cycles followed by 10 million cycles of flexion-extension ( +/-9.7 degrees ) with 148 N. Implant surfaces were characterized by the use of white-light interferometry, scanning electron microscopy, and energy dispersive spectroscopy. RESULTS: The explants generally exhibited a slightly discolored, elliptic wear region of varying dimension centered in the bearing center, with the long axis oriented in the medial-lateral direction. Abrasive wear was the dominant in vivo wear mechanism, with microscopic scratches generally oriented in the medial-lateral direction. Wear testing resulted in severe abrasive wear in a curvilinear fashion oriented primarily in the medial-lateral direction. All retrievals showed evidence of an abrasive wear mechanism. CONCLUSIONS: This study documented important similarity between the wear mechanisms of components tested in vitro and explanted PRESTIGE((r)) Cervical Discs; however, the severity of wear was much greater during the in vitro test compared with the retrievals. PMID- 25694885 TI - Endoscopic transforaminal decompression, interbody fusion, and percutaneous pedicle screw implantation of the lumbar spine: A case series report. AB - BACKGROUND: On the basis of the experiences gained from conventional open spinal procedures, a long list of desirable objectives have emerged with the evolution of the lesser invasive spinal procedures. At the top of that list is the desire to minimize the trauma of surgery. The rest of the objectives, which include reductions of operating time, surgical blood loss, hospital stay, postoperative narcotic medication, convalescence, complication rates, and escalating health care costs, as well as the desire of elderly patients to continue rigorous physical activities, largely depend on the ability to minimize the trauma of surgery. The purpose of this study was to investigate the feasibility of the least invasive lumbar decompression, interbody fusion and percutaneous pedicle screw implantation, to minimize surgical trauma without compromising the quality of the treatment outcome, as well as to minimize risk of complications. METHODS: In this case series, 60 patients with diagnoses of degenerative disc disease, degenerative motion segments with stenosis, and spondylolisthesis, in whom nonoperative treatments failed, were treated with endoscopic transforaminal decompression and interbody fusion by 1 surgeon in 2 centers. The outcome measures were as follows: operating time, intraoperative blood loss, hospital stay, Visual Analogue Scale (VAS) scores for back and leg pain, scores on the Roland-Morris Disability Questionnaire, and postoperative imaging studies. A consecutive series of patients who met the treatment criteria completed VAS forms and Roland-Morris questionnaires preoperatively. Surgical procedures included arthroscopic decompression of the foramina and the discs; endplate preparation and implantation of allograft bone chips and bone morphogenetic protein 2 on absorbable collagen sponge into the disc space; and percutaneous implantation of pedicle screws. Postoperatively, the patients again completed the VAS forms and Roland-Morris questionnaires. Their charts were reviewed for office notes, operative notes, hospital stay, medications, and imaging studies. The latest X ray and computed tomography scan films were reviewed and analyzed. Patients were followed up for a minimum of 6 months. The literature was reviewed for comparison of outcomes. RESULTS: Sixty patients met the inclusion criteria. The mean age was 52.8 years. The duration of illness averaged 5 years. Follow-up ranged from 6 to 25 months, with a mean of 12 months. Preoperative diagnoses included degenerative disc disease, degenerative motion segments with stenosis, and spondylolisthesis. The mean time in the operating room was 2 hours 54 minutes. Estimated blood loss averaged 57.6 mL. The duration of the hospital stay averaged 2.6 days. Preoperative back pain and leg pain were significantly reduced (P < .005). Forty seven imaging studies obtained at the last visit, including X-ray and computed tomography scans, showed solid fusion in 28 patients (59.6%), stable fixation in 17 (36.2%), and osteolysis around the pedicle screws in 2 (4.2%). All patients had improvement of motor function, whereas 2 patients complained of residual numbness. In addition, 8 patients (13%) complained of residual discomfort on extension of the lumbar spine. Two patients had pedicle screw-related complications requiring surgery. A review of the literature showed that endoscopic transforaminal decompression and interbody fusion performed better than open transforaminal lumbar interbody fusion/posterior lumbar interbody fusion, minimally invasive transforaminal lumbar interbody fusion, and extreme lateral lumbar interbody fusion, with regard to most parameters studied. CONCLUSIONS: The endoscopic transforaminal lumbar decompression, interbody fusion, and percutaneous pedicle screw instrumentation consistently produced satisfactory results in all demographics. It performed better than the alternative procedures for most parameters studied. PMID- 25694886 TI - Variability of manual lumbar spine segmentation. AB - BACKGROUND: The application of kinematic data acquired during biomechanical testing to specimen-specific, three-dimensional models of the spine has emerged as a useful tool in spine biomechanics research. However, the development of these models is subject to segmentation error because of complex morphology and pathologic changes of the spine. This error has not been previously characterized. METHODS: Eight cadaveric lumbar spines were prepared and underwent computed tomography (CT) scanning. After disarticulation and soft-tissue removal, 5 individual vertebrae from these specimens were scanned a second time. The CT images of the full lumbar specimens were segmented twice each by 2 operators, and the images of the individual vertebrae with soft tissue removed were segmented as well. The solid models derived from these differing segmentation sessions were registered, and the distribution of distances between nearest neighboring points was calculated to evaluate the accuracy and precision of the segmentation technique. RESULTS: Manual segmentation yielded root-mean-square errors below 0.39 mm for accuracy, 0.33 mm for intrauser precision, and 0.35 mm for interuser precision. Furthermore, the 95th percentile of all distances was below 0.75 mm for all analyses of accuracy and precision. CONCLUSIONS: These findings indicate that such models are highly accurate and that a high level of intrauser and interuser precision can be achieved. The magnitude of the error presented here should inform the design and interpretation of future studies using manual segmentation techniques to derive models of the lumbar spine. PMID- 25694887 TI - L5 radiculopathy caused by L5 nerve root entrapment by an L5-S1 anterior osteophyte. AB - BACKGROUND: L5 radiculopathy is a common problem that has several causes. Entrapment of the L5 nerve root by anterior osteophytes at the L5-S1 junction is rarely reported. Posterior decompression of the L5 nerve root is commonly performed, but anterior decompression of the L5 nerve root is not a frequently performed procedure. The purpose of this case report is to describe an uncommon case of L5 radiculopathy caused by the entrapment of the L5 nerve root by an anterior osteophyte. METHODS: We report the case of a 79-year-old man with a right lower extremity L5 radiculopathy causing excruciating pain, worsening with transitioning between seated and standing positions. Radiologic evaluation showed a large osteophyte coming off of the right anterolateral border of L5-S1. The osteophyte was excised through a right-sided anterior retroperitoneal approach. An anterior interbody fusion was performed at L5-S1. RESULTS: Postoperatively, the patient's pain was completely resolved. Six months after surgery, he remained symptom free. CONCLUSIONS: Osteophytes at the L5-S1 junction can entrap the L5 nerve root. If nonoperative treatment fails, the osteophyte can be excised and the nerve can be safely decompressed through an anterior retroperitoneal approach. PMID- 25694888 TI - Description of a transosseous approach to the L5-S1 disc and 2 clinical case reports. AB - BACKGROUND: The lumbosacral disc with the adjacent iliac crest and its relationships to neurologic, visceral, and vascular structures is difficult to approach with cannula-based retractor systems. Previous, less invasive approaches have been described to access this space. Anterior, presacral, and transforaminal approaches each have approach-related complications that have prevented their widespread adoption. A laterally based approach to this disc between the exiting L5 nerve root and traversing S1 nerve root would theoretically eliminate visceral and vascular complications but would necessarily course through the adjacent iliac crest. Our objective was to determine the feasibility of placing an interbody device into the L5-S1 disc space through a lateral transosseous approach. METHODS: Six transosseous pathways were created from the iliac crest, laterally through the sacral ala, and entering the L5-S1 intervertebral disc space (3 cadavers). The positions of the portals in relation to the local anatomy were evaluated anatomically and with computed tomographic sagittal, coronal, and axial planes. We measured the lengths, heights, and widths of the pathways; distance between the L5 and S1 nerve roots; endplate diameters; and angles necessary to access the space. In addition, 2 clinical cases using the transosseous pathway are presented. RESULTS: Computed tomographic scans and anatomic evaluations showed that there was an average 22-mm distance between the L5 and S1 nerve roots available to enter the L5-S1 disc space. The mean length of the pathway was 69 mm, and the mean height was 27 mm. The mean angle of the approach was 45 degrees off the posterior-anterior axis, and there was a 25 degrees upward angle from true lateral in the frontal plane. CONCLUSIONS: A lateral, transosseous approach to the L5-S1 disc space for placing an interbody device is feasible. A closed cannula-based technique may offer reduced approach related complications. Further studies will be required to determine the reproducibility and utility of this pathway. PMID- 25694889 TI - ProDisc-L learning curve: 24-Month clinical and radiographic outcomes in 44 consecutive cases. AB - BACKGROUND: Total disc replacement (TDR) promises preservation of spine biomechanics in the treatment of degenerative disc disease but requires more careful device placement than tradition fusion and potentially has a more challenging learning curve. METHODS: A cohort of 44 consecutive patients had 1 level lumbar disc replacement surgery at a single institution by a single surgeon. Patients were followed up clinically and radiographically for 24 months. Patients were divided into 2 groups of 22 sequential cases each. Clinically, preoperative and postoperative Oswestry Disability Index, visual analog scale, Short Form 12 (SF-12) Mental and Physical Components, and postoperative satisfaction were measured. Radiographically, preoperative and postoperative range of motion (ROM) dimensions, prosthesis deviation from the midline, and disc height were measured. TDR-related complications were noted. Logarithmic curve-fit regression analysis was used to assess the learning curve. RESULTS: Operative time decreased as cases progressed, with an asymptote after 22 cases. The operative time for the later group was significantly lower (P < .0005), but hospital stay was significantly longer (P = .03). There was no significant difference in amount of blood loss (P = .10) or prosthesis midline deviation (P = .86). Clinically, there was no significant difference in postoperative scores between groups in Oswestry Disability Index (P = .63), visual analog scale (P = .45), SF-12 Mental Component (P = .66), SF-12 Physical Component (P = .75), or postoperative satisfaction (P = .92) at 24 months. Radiographically, there was no significant difference in improvement between groups in ROM (P = .67) or disc height (P = .87 for anterior and P = .13 for posterior) at 24 months. For both groups, there was significant improvement for all clinical outcomes and disc height over preoperative values. One patient in the later group had device failure with subluxation of the polyethylene, which required revision. CONCLUSIONS/LEVEL OF EVIDENCE: Early experience can quickly reduce operative time but does not affect clinical outcomes or ROM significantly (level IV case series). CLINICAL RELEVANCE: Lumbar TDR is a rapidly learnable technique in treatment of degenerative disc disease. PMID- 25694890 TI - Examination of cervical spine kinematics in complex, multiplanar motions after anterior cervical discectomy and fusion and total disc replacement. AB - BACKGROUND: The biomechanical behavior of total disc replacement (TDR) and anterior cervical discectomy and fusion (ACDF) incomplex multiplanar motion is incompletely understood. The purpose of this study was to determine whether ACDF or TDR significantly affects in vitro kinematics through a range of complex, multiplanar motions. METHODS: Seven human cervical spines from C4-7 were used for this study. Intact cervical motion segments with and without implanted TDR and ACDF were tested by use of unconstrained pure bending moment testing fixtures in 7 mechanical modes: axial rotation (AR); flexion/extension (FE); lateral bending (LB); combined FE and LB; combined FE and AR; combined LB and AR; and combined FE, LB, and AR. Statistical testing was performed to determine whether differences existed in range of motion (ROM) and stiffness among spinal segments and treatment groups for each mechanical test mode. RESULTS: ACDF specimens showed increased stiffness compared with the intact and TDR specimens (P < .001); stiffness was not found to be different between TDR and intact specimens. ACDF specimens showed decreased ROM in all directions compared with TDR and intact specimens at the treated level. For the coupled motion test, including AR, LB, and FE, the cranial adjacent level (C4/C5) for the intact specimens (2.7 degrees ) showed significantly less motion compared with both the TDR (6.1 degrees , P = .009) and ACDF (6.8 degrees , P = .002) treatment groups about the LB axis. Testing of the C4/C5 and C6/C7 levels in all other test modes yielded no significant differences in ROM comparisons, although a trend toward increasing ROM in adjacent levels in ACDF specimens compared with intact and TDR specimens was observed. CONCLUSIONS: This study compared multiplanar motion under load displacement testing of subaxial cervical motion segments with and without implanted TDR and ACDF. We found a trend toward increased motion in adjacent levels in ACDF specimens compared with TDR specimens. Biomechanical multiplanar motion testing will be useful in the ongoing development and evaluation of spinal motion-preserving implants. PMID- 25694891 TI - Radiation exposure during the lateral lumbar interbody fusion procedure and techniques to reduce radiation dosage. AB - BACKGROUND: Fluoroscopy is widely used in spine surgery to assist with graft and hardware placement. Previous studies have not measured radiation exposure to a surgeon during minimally invasive lateral lumbar spine surgery for single-level discectomy and interbody cage insertion. This study was performed to model and measure radiation exposure to a surgeon during spine surgery using the direct lateral lumbar procedure. METHODS: The study was performed using a mannequin substituting for the surgeon and a cadaver substituting for the patient. Radiation was measured with dosimeters attached to 6 locations on the mannequin using a OEC Medical Systems 9800 C-arm fluoroscope (OEC Medical Systems, Salt Lake City, Utah). Three different fluoroscopy setups were tested: a standard imaging setup, a standard setup using pulsed-mode fluoroscopy, and a reversed setup. The experiment was tested 5 times per setup, and the dosimeters' values were recorded. RESULTS: The highest amount of radiation exposure occurred when obtaining an anteroposterior view of the spine in the standard setup. Compared with the standard setup, the pulsed-mode setting decreased the radiation exposure to the mannequin by a factor of 6 times (P < .001). Compared with the standard setup, the reversed setup also decreased the radiation exposure to the mannequin by a factor of 6 times (P < .001) and it had the lowest amount of radiation exposure to the eye level (P < .001). CONCLUSIONS: Care should be taken when one is obtaining an anteroposterior view of the lumbar spine during lateral lumbar procedures to limit radiation exposure. Radiation exposure to the surgeon can be greatly minimized by using either a pulsed imaging mode or the reversed setup. The reversed setup has the lowest amount of radiation exposure to the eye level. PMID- 25694892 TI - Pedicle screw instrumentation of thoracolumbar burst fractures: Biomechanical evaluation of screw configuration with pedicle screws at the level of the fracture. AB - BACKGROUND: Posterior fixation alone may not be adequate to achieve and maintain burst fracture reduction. Adding screws in the fractured body may improve construct stiffness. This in vitro study evaluates the biomechanical effect of inserting pedicle screws in the fractured body compared with conventional short- and long-segment posterior fixation. METHODS: Stable and unstable L2 burst fractures were created in 8 calf spines (aged 18 weeks). Constructs were tested at 8 Nm in the intact state and then with instrumentation consisting of long- and short-segment posterior fixation with and without screws in the fractured L2 vertebral body after (1) stable burst fracture and (2) unstable burst fracture. Range of motion was recorded at L1-3 for flexion-extension, lateral bending, and axial rotation. Statistical analysis was performed with repeated-measures analysis of variance, with significance set at P < .05. The data were normalized to the intact state (100%). RESULTS: Both long- and short-segment constructs with screws in the fractured body significantly reduced motion compared with the stable and unstable burst fracture in flexion-extension and lateral bending. Fracture screws enhanced construct stability by 68% (on average) relative to conventional short-segment posterior fixation and were comparable to long-segment posterior fixation. CONCLUSIONS: Screws at the fracture level improve construct stiffness. Short-segment constructs may suffice for stable burst fractures. More severe injuries may benefit from fracture screws and can be considered as an alternative treatment to long-segment constructs. PMID- 25694893 TI - Direct transoral reduction of anteriorly displaced type II odontoid fracture during anterior odontoid screw fixation: Review of literature. AB - BACKGROUND: The anteriorly displaced type II odontoid fracture is treated either conservatively by halo-vest brace immobilization or surgically by posterior atlantoaxial fusion. Anterior odontoid screw fixation is not advised for this pattern of odontoid fracture because of the difficult trajectory for screw insertion despite its advantage of salvaging the upper cervical spine rotatory range of movement. This article presents a new transoral manipulation technique for reduction of anteriorly displaced type II odontoid fracture and review of the literature. METHODS: A 24-year-old man presented 2 weeks after a motor vehicle accident with anteriorly displaced type II odontoid fracture. Intraoperatively, after unsuccessful attempts to reduce the anteriorly displaced type II odontoid fracture, complete reduction of the odontoid process and proper screw placement were achieved by direct transoral manipulation with an army-navy hand retractor. Additional manual pressure on the spinous process of the cervical spine at the same time has resulted in better reduction. The patient was followed up neurologically and radiologically to assess the reduction and healing of the odontoid fracture. RESULTS: Postoperatively, the patient was neurologically intact, and his computed tomography cervical spine scan showed proper placement of the odontoid screw with adequate reduction of the odontoid process. At the 3 month follow-up, the patient was neurologically intact and had painless full range of cervical spine movement, and his computed tomography cervical spine scan showed a well-healed odontoid fracture. CONCLUSIONS: Direct transoral manipulation with an army-navy hand retractor can be used to assist in reducing the anteriorly displaced type II odontoid fracture during anterior odontoid screw fixation. PMID- 25694894 TI - Posterior occipito-axial fixation applied C2 laminar screws for pediatric atlantoaxial instability caused by Down syndrome: Report of 2 cases. AB - BACKGROUND: Upper cervical spine instability is one of the most critical orthopedic problems in patients with Down syndrome. However, arthrodesis of the upper cervical spine in these patients can be very difficult to achieve and has a high complication rate because of mental retardation and accompanying various medical conditions of the vital organs. Even now, surgeries in such patients, especially pediatric cases, are challenging and the optimal operative procedure remains unsettled. The purpose of this study was to report 2 cases of pediatric atlantoaxial instability due to Down syndrome in which posterior occipito-axial fixation with C2 laminar screws was performed. METHODS: Case 1 was a girl aged 6 years 10 months who had atlantoaxial rotatory fixation with os odontoideum. Atlantoaxial rotatory fixation was incompletely reduced by halo traction, and it was not maintained without halo-ring and -vest fixation. Posterior occipito-axial fixation with bilateral C2 laminar screws was then performed. Case 2 was a boy aged 10 years 7 months who had atlantoaxial subluxation with os odontoideum. He also had incomplete quadriplegia, so he could neither walk nor have a meal by himself. Posterior occipito-axial fixation with right C2 pedicle and left C2 laminar screws was then carried out. RESULTS: In case 1 bone union was obtained at 3 months after surgery and the patient's symptoms were resolved. In case 2 bone union was obtained at 3 months after surgery and the paralysis was improved. CONCLUSIONS/LEVEL OF EVIDENCE: In cases of atlantoaxial instability due to Down syndrome, symptomatic patients often present between ages 5 and 15 years and mental retardation interferes with postoperative cervical immobilization. C2 laminar screws can be safely applied for the pediatric axis and biomechanically accomplished rigid fixation. The C2 laminar screw is one of the most useful options to achieve stability of the pediatric atlantoaxial complex without the risk of vertebral artery injuries (level IV case series). PMID- 25694895 TI - Does 360 degrees lumbar spinal fusion improve long-term clinical outcomes after failure of conservative treatment in patients with functionally disabling single level degenerative lumbar disc disease? Results of 5-year follow-up in 75 postoperative patients. AB - BACKGROUND: Surgical treatment of patients with mechanical degenerative disc disease has been controversial, but improvements in clinical outcomes have been shown in properly selected patients with disease-specific diagnoses, with fusion arguably now becoming the "gold standard" for surgical management of these patients. No published study thus far has been designed for prospective enrollment of patients with specific inclusion/exclusion criteria in whom at least 6 months of conservative therapy has failed and who are then offered a standardized surgical procedure and are followed up for 5 years. METHODS: The study group was composed of the patients in the prospective, randomized Food and Drug Administration Investigational Device Exemption trial comparing ProDisc-L (Synthes Spine, West Chester, Pennsylvania) with 360 degrees fusion for the treatment of single-level symptomatic disc degeneration. Of 80 patients randomized to 360 degrees fusion after failure of non-operative care, 75 were treated on protocol with single-level fusions. Follow-up of this treatment cohort was 97% at 2 years and 75% at 5 years and serves as the basis for this report. Patients in the trial were required to have failure of at least 6 months of nonoperative care and in fact had failure of an average of 9 months of nonoperative treatment. The mean Oswestry Disability Index score indicated greater than 60% impairment. The mean entry-level pain score on a visual analog scale was greater than 8 of 10. RESULTS: After fusion, not only did patients have significant improvements in measurable clinical outcomes such as the Oswestry Disability Index score and pain score on a visual analog scale but there were also substantial improvements in their functional status and quality of life. Specifically, over 80% of patients in this study had improvements in recreational status that was maintained 5 years after index surgery, indicating substantial improvements in life quality that were not afforded by months of conservative care. The percentage of patients using narcotics at the 5-year follow-up visit was less than half the percentage of patients who had used narcotics as part of their prior conservative treatment. CONCLUSIONS: The 5-year results of this post hoc analysis of 75 patients involved in a multicenter, multi-surgeon trial support 360 degrees fusion surgery as a predictable and lasting treatment option to improve pain and function in properly selected patients with mechanical degenerative disc disease. These improvements occurred dramatically immediately after surgery and have been maintained through the scope of this follow-up period, with 98% follow-up at 2 years and 75% of patients available at 5 years. PMID- 25694896 TI - Effects on inadvertent endplate fracture following lateral cage placement on range of motion and indirect spine decompression in lumbar spine fusion constructs: A cadaveric study. AB - BACKGROUND: The lateral transpsoas approach to interbody fusion is gaining popularity. Existing literature suggests that perioperative vertebra-related complications include endplate breach owing to aggressive enedplate preparation and poor bone quality. The acute effects of cage subsidence on stabilization and indirect decompression at the affected level are unknown. The purpose of this study was to compare the kinematics and radiographic metrics of indirect decompression in lumbar spines instrumented with laterally placed cages in the presence of inadvertent endplate fracture, which was determined radiographically, to specimens instrumented with lateral cages with intact endplates. METHODS: Five levels in 5 specimens sustained endplate fracture during lateral cage implantation followed by supplementary fixation (pedicle screw/rod [PSR]: n = 1; anterolateral plate [ALP]: n = 4), as part of a larger laboratory-based study. Range of motion (ROM) in these specimens was compared with 13 instrumented specimens with intact endplates. All specimens were scanned using computed tomography (CT) in the intact, noninstrumented condition and after 2-level cage placement with internal fixation under a 400-N follower load. Changes in disc height, foraminal area, and canal area were measured and compared between specimens with intact endplates and fractured endplates. RESULTS: Subsidence in the single PSR specimen and 4 ALP specimens was 6.5 mm and 4.3 +/- 2.7 mm (range: 2.2-8.3 mm), respectively. ROM was increased in the PSR and ALP specimens with endplate fracture when compared with instrumented specimens with intact endplates. In 3 ALP specimens with endplate fracture, ROM in some motion planes increased relative to the intact, noninstrumented spine. These increases in ROM were paralleled by increase in cage translations during cyclic loading (up to 3.3 mm) and an unpredictable radiographic outcome with increases or decreases in posterior disc height, foraminal area, and canal area when compared with instrumented specimens with intact endplates. CONCLUSIONS: Endplate fracture and cage subsidence noted radiographically intraoperatively or in the early postoperative period may be indicative of biomechanical instability at the affected level concomitant with a lack of neurologic decompression, which may require revision surgery. PMID- 25694897 TI - Biomechanical assessment and fatigue characteristics of an articulating nucleus implant. AB - BACKGROUND: Extrusion is a known complication of lumbar nucleus replacement devices. Despite this fact, this complication has not been well studied in an in vitro cadaveric model under fatigue-loading conditions. METHODS: Lumbar constructs (with treated and control levels) were tested in intact, postdisectomy, and postnucleus implant conditions under compression, torsion, and bending for initial biomechanical assessment. Constructs were then tested for 100(k) cycles under fatigue loading to assess extrusion risk. Potential adverse effects to vertebral and endplate fractures were assessed using gross dissection and macroscopic and micro-computed tomography evaluation techniques. RESULTS: Based on the initial biomechanical assessment, implantation of the nucleus device significantly increased disc height compared with the discectomy condition, and there were no significant differences between the intact and implanted conditions for range of motion or stiffness. All constructs completed the 100(k) cycles with no extrusions. There was evidence of implant shift toward the right lateral annulus on postfatigue images. Postfatigue dissection and imaging showed no evidence of macroscopic endplate or trabecular fractures. CONCLUSION: Using a 2 level lumbar in vitro construct, the biomechanical function of the treated level with an articulating nucleus implant was similar to intact. In vitro fatigue testing showed no implant extrusion and macroscopic changes to the bony structure or cartilaginous endplates when comparing treated and intact levels. PMID- 25694898 TI - Kinematic analysis following implantation of the PRESTIGE LP. AB - BACKGROUND: The clinical success of cervical arthroplasty hinges on the ability to preserve or improve the biomechanics of the functional spinal unit. The purpose of this study was to conduct a radiologic assessment of kinematic parameters preimplantation and postimplantation of the PRESTIGE LP Cervical Disc System (Medtronic, Memphis, Tennessee). METHODS: A total of 120 radiographs of 20 patients following single-level implantation of the PRESTIGE LP were retrospectively reviewed. Static and dynamic radiologic assessments were performed before surgery and at 1 year postoperation. Kinematic parameters including range of motion (ROM), horizontal translation, center of rotation (COR X, Y), anterior disc height and posterior disc height, and disc angle and shell angle were assessed for each spinal level using quantitative motion analysis software. Clinical outcomes were assessed using the short form health survey physical component scores and mental component scores. RESULTS: The mean physical component scores and mental component scores of the short form health survey (SF 36) improved significantly following surgery. At 1 year postoperation, ROM, translation, and COR X were preserved. The COR Y shifted superiorly from 3.17 +/- 2.08 mm preoperation to 0.98 +/- 2.23 mm postoperation (P < .001). The anterior disc height and posterior disc height were significantly increased following surgery (3.97 +/- 1.01 to 4.78 +/- 1.11 mm and 3.04 +/- 0.69 to 3.66 +/- 0.61 mm, respectively; P < .01). The preoperative disc angle was 3.32 degrees +/- 2.92 degrees and the postoperative shell angle was 1.11 degrees +/- 4.29 degrees , with a mean change of -2.22 degrees +/- 4.63 degrees (P < .05). CONCLUSIONS: The PRESTIGE LP maintained preoperative ROM, translation, and COR X values. The postoperative COR Y value changed significantly by shifting superiorly, accompanied by an increase in DH. There was a loss of lordosis at the level of surgery, with the PRESTIGE LP endplates having an almost parallel endplate configuration. PMID- 25694899 TI - Instrumented reduction of a fixed C1-2 subluxation using occipital and C2/C3 fixation: A case report. AB - BACKGROUND: Different strategies exist for reduction of the cervical spine. Placement of C1 lateral mass screws is a powerful technique but may be impossible in a degenerative or revision setting. We report the open, posterior-only, and instrumented reduction of a fixed C1-2 subluxation using occipital and C2/C3 fixation. The patient had rheumatoid arthritis and had undergone previous surgery of the cervical spine. METHODS: We performed a retrospective chart review and focused appraisal of the literature. RESULTS: Satisfactory reduction was achieved with this infrequently reported technique. CONCLUSIONS/LEVEL OF EVIDENCE: Spine surgeons may consider the described procedure a viable treatment alternative in problematic subluxations of the cervical spine. Level V. PMID- 25694900 TI - The value of adding posterior interbody fusion in the surgical treatment of degenerative lumbar spine disorders: A systematic review. AB - BACKGROUND: Posterolateral fusion (PF) is a common method by which to achieve fusion in lumbar spine surgery. It has been reported that posterior interbody fusion (PIF) yields a higher fusion rate and a better functional and clinical outcome. Our objective was to determine whether PIF improves the clinical and radiologic outcomes in adults surgically treated for degenerative lumbar spine conditions compared with PF. METHODS: We performed a systematic search of electronic databases, bibliographies, and relevant journals and meta-analyses. RESULTS: Of 2798 citations identified, 5 studies met our inclusion criteria (none of which was a randomized controlled trial), with a total of 148 patients in the PIF group (intervention) and 159 in the PF group (control). Pooled meta-analyses showed that nonunion rates were lower in the intervention group (relative risk, 0.22; 95% confidence interval [CI], 0.08-0.62). The intervention group had a significantly higher disc height (weighted mean difference, 3.2 mm; 95% CI, 1.9 4.4 mm) and lower residual percent slippage (weighted mean difference, 6.3%; 95% CI, 3.9%-8.7%) at final follow-up. There were no significant differences in segmental or total lumbar lordosis. Because of heterogeneity of results, no conclusions could be made with regard to functional benefits. CONCLUSIONS: This review suggests that PIF achieves a higher fusion rate and better correction of certain radiographic aspects of deformity over PF. It also showed a slight but not significant trend toward a better functional outcome in the PIF group. The lack of randomized controlled trials and the methodologic limitations of the available studies call for the planning and conduct of a sufficiently sized, methodologically sound study with clinically relevant outcome measures. Until this has been done, the current evidence regarding the beneficial effects of PIF should be interpreted with caution. PMID- 25694901 TI - Backing up the stories: The psychological and social costs of chronic low-back pain. AB - BACKGROUND: Chronic low-back pain is a widespread condition whose significance is overlooked. Previous studies have analyzed and evaluated the medical costs and physical symptoms of chronic low-back pain; however, few have looked beyond these factors. The purpose of this study was to analyze and evaluate the personal and psychosocial costs of chronic low-back pain. METHODS: To measure the various costs of chronic low-back pain, a questionnaire was generated using a visual analog scale, the Depression Anxiety and Stress Scale, the Short Form 36 Health Survey, and the 1998-1999 Australian Bureau of Statistics Household Expenditure Survey (for demographic questions). The comprehensive survey assessing physical, mental, emotional, social, and financial health was administered to 30 subjects aged 18 years or older who had visited a tertiary spine service with complaints of chronic low-back pain. RESULTS: It was found that subjects scored significantly higher on scales for depression, anxiety, and stress after the onset of chronic low-back pain than before the onset of back pain. Subjects also reported a reduction in work hours and income, as well as a breakdown in interpersonal relationships, including marital and conjugal relations. CONCLUSION: Chronic low-back pain affects the ability of a patient to work, creating both financial and emotional problems within a home. Relief is delayed for patients because of the sparse allocation of resources for chronic spinal care and inadequate prevention education. Despite this, many patients are exhorted to return to work before they are physically, mentally, or emotionally free of pain, resulting in poor outcomes for recovery. Ultimately, this aggregates into an adverse macrosocial effect, reducing not only the quality of life for individuals with chronic low-back pain but also workforce productivity. PMID- 25694902 TI - Technical note: Resolution of spontaneous electromyographic discharge following disk-space distraction during lateral transpsoas interbody fusion. AB - PURPOSE: The lateral transpsoas interbody fusion (LTIF) is an increasingly popular minimally invasive technique for lumbar interbody fusion. Although a posterior approach to the lumbar spine has traditionally been favored for the treatment of canal stenosis and neural foraminal stenosis, a growing body of evidence suggests that indirect decompression of the spinal canal and neural foramen can be achieved using a lateral transpsoas approach to the lumbar spine. We present 2 cases that may suggest a role for spontaneous electromyography (s EMG) monitoring in assessing the adequacy of decompression during LTIF. METHODS: The 2 cases presented in this technical note illustrate resolution of s-EMG firing during LTIF, following distraction across the disk space. Removal of the distracting device produced the return of s-EMG firing. Both of these cases were operated at the L2-3 level. RESULTS: In the first case, s-EMG firing was noted in the bilateral tibialis anterior leads. Resolution of EMG firing may suggest indirect decompression of the canal via ligamentotaxis as the L5 root traverses the L2-3 disk space. In the second case, s-EMG firing was noted in the left abductor hallucis and resolved with distraction of the L2-3 disk space. Again, this may be explained by canal decompression via ligamentotaxis as the S1 root traverses the L2-3 disk space. CONCLUSION: In both cases, distraction across the disk space resulted in resolution of s-EMG discharges-this correlated with an improvement in symptoms. These findings may suggest a role for s-EMG as a marker for adequacy of decompression in a select subset of patients undergoing LTIF. Further study is needed to determine if resolution of s-EMG is a useful measure of indirect decompression during LTIF. PMID- 25694903 TI - Overtightening of halo pins resulting in intracranial penetration, pneumocephalus, and epileptic seizure. AB - A 60-year-old man sustained an undisplaced type III odontoid fracture following a fall down a full flight of stairs. His medical history was remarkable for a partial pancreatectomy and splenectomy in 2006 for chronic pancreatitis. This had rendered him diabetic, on insulin, and he required long-term administration of penicillin V. The fracture was treated with a halo vest, and, unknowing of its potentially serious consequences, the patient continued to tighten the halo pins himself. He presented 1 month later following a witnessed seizure. A computed tomography scan was performed, which demonstrated 2 cranial perforations, with the halo pins penetrating the cranium and resultant pneumocephalus. He was started on antiepileptic medication and was placed in a pinless halo system. He had no further seizures and has made an uneventful neurological recovery. This paper serves to highlight the potential complications which may arise from the use of a halo vest. Proper patient education is essential to avoid these serious yet avoidable events, and patients with low bone density and the immunosuppressed should be monitored closely. PMID- 25694904 TI - Kyphoplasty versus vertebroplasty for painful osteoporotic vertebral compression fractures-which one is better? A systematic review and meta-analysis. AB - BACKGROUND: Whether kyphoplasty or vertebroplasty is better for painful osteoporotic vertebral compression fracture is a widely debated issue. Studies on the comparison of the 2 approaches are relative limited and a wide variation exists in the patient population, study design, and results. These factors make it difficult for workers in this field to know the exact value of the 2 approaches. OBJECTIVE: To perform a systematic review and meta-analysis to compare the clinical outcomes and complications of kyphoplasty versus vertebroplasty for painful osteoporotic vertebral compression fractures (OVCF). STUDY DESIGN: A systematic review and meta-analysis. METHODS: MEDLINE, EMBASE, and other databases were searched for all the relevant original articles published from January 1987 to September 2012 comparing kyphoplasty with vertebroplasty for painful OVCF. The following outcomes were mainly evaluated: visual analog scale (VAS), vertebral height, kyphosis angle, new vertebral fractures, and cement leakage. RESULTS: A total of 15 articles fulfilled all the inclusion criteria. The baseline characteristics such as sex, age, and number of prevalent fractures were comparable for both groups (P > .05). VAS score for the kyphoplasty group was significantly more than that for the vertebroplasty group at 1-3 days, 3 months, 6 months, 1 year, and 2 years after surgery (P < .05). Vertebral height in the kyphoplasty group was significantly higher than the vertebroplasty group at 3 months, 6 months, and 2 years (P < 0.05). Kyphosis angle in the kyphoplasty group was significantly lower at 3 months, 6 months, and 2 years (P < 0.05). The occurrence of new vertebral fractures in the kyphoplasty group had no significant difference with the vertebroplasty group at 3 months, 6 months, and 2 years (P > 0.05). The occurrence of cement leakage was significantly lower in the vertebroplasty group (P < 0.05). LIMITATIONS: The main limitations of this review are that the demographics and comorbidities of study participants were not reported. These possible sources of heterogeneity could not be examined. CONCLUSIONS: Percutaneous kyphoplasty is better than vertebroplasty in the treatment of painful OVCF. Kyphoplasty had better improvement at VAS score, vertebral height, and kyphosis angle with lower occurrence of cement leakage. PMID- 25694905 TI - Cost-utility analysis modeling at 2-year follow-up for cervical disc arthroplasty versus anterior cervical discectomy and fusion: A single-center contribution to the randomized controlled trial. AB - BACKGROUND: Patients with cervical disc herniations resulting in radiculopathy or myelopathy from single level disease have traditionally been treated with Anterior Cervical Discectomy and Fusion (ACDF), yet Cervical Disc Arthroplasty (CDA) is a new alternative. Expert suggestion of reduced adjacent segment degeneration is a promising future result of CDA. A cost-utility analysis of these procedures with long-term follow-up has not been previously reported. METHODS: We reviewed single institution prospective data from a randomized trial comparing single-level ACDF and CDA in cervical disc disease. Both Medicare reimbursement schedules and actual hospital cost data for peri-operative care were separately reviewed and analyzed to estimate the cost of treatment of each patient. QALYs were calculated at 1 and 2 years based on NDI and SF-36 outcome scores, and incremental cost effectiveness ratio (ICER) analysis was performed to determine relative cost-effectiveness. RESULTS: Patients of both groups showed improvement in NDI and SF-36 outcome scores. Medicare reimbursement rates to the hospital were $11,747 and $10,015 for ACDF and CDA, respectively; these figures rose to $16,162 and $13,171 when including physician and anesthesiologist reimbursement. The estimated actual cost to the hospital of ACDF averaged $16,108, while CDA averaged $16,004 (p = 0.97); when including estimated physicians fees, total hospital costs came to $19,811 and $18,440, respectively. The cost/QALY analyses therefore varied widely with these discrepancies in cost values. The ICERs of ACDF vs CDA with Medicare reimbursements were $18,593 (NDI) and $19,940 (SF-36), while ICERs based on actual total hospital cost were $13,710 (NDI) and $9,140 (SF-36). CONCLUSIONS: We confirm the efficacy of ACDF and CDA in the treatment of cervical disc disease, as our results suggest similar clinical outcomes at one and two year follow-up. The ICER suggests that the non significant added benefit via ACDF comes at a reasonable cost, whether we use actual hospital costs or Medicare reimbursement values, though the actual ICER values vary widely depending upon the CUA modality used. Long term follow-up may illustrate a different profile for CDA due to reduced cost and greater long-term utility scores. It is crucial to note that financial modeling plays an important role in how economic treatment dominance is portrayed. PMID- 25694906 TI - Strategy for salvage pedicle screw placement: A technical note. AB - BACKGROUND: Salvage surgery for failed lumbar spine fusion with a loosened pedicle screw is challenging. In general, the strategy includes replacement with larger and longer pedicle screws, augmentation with polymethylmethacrylate cement or hydroxyapatite granules, and extension of fused segments. The purpose of this study is to introduce a new technique for pedicle screw replacement after failed lumbar spine fusion. METHODS: Five salvage operations were performed using a different trajectory (DT) pedicle screw replacement technique based on 3 dimensional radiological information. Position of the alternative pedicle screws was planned carefully on the computer screen of a computed tomography-based navigation system before the operation. To obtain sufficient initial stability, 1 of 2 techniques was chosen, depending on the patient. One technique created a completely new route, which did not interfere with the existing screw hole, and the other involved penetration of the existing screw hole. RESULTS: DT pedicle screws were replaced successfully according to the preoperative plan. In all patients, bony union were achieved at the final follow-up period without any instrument failure. Extension of the fused segments could be avoided by using the DT pedicle screw replacement technique combined with transforaminal lumbar interbody fusion. CONCLUSIONS: The DT pedicle screw replacement technique is a treatment option for salvage lumbar spine surgery. CLINICAL RELEVANCE: The current technique is a treatment option for salvage operations that can both avoid extension of a fused segment and achieve successful bony union. PMID- 25694907 TI - Retrospective cost analysis of cervical laminectomy and fusion versus cervical laminoplasty in the treatment of cervical spondylotic myelopathy. AB - BACKGROUND: Cervical laminoplasty (CLP) and posterior cervical laminectomy and fusion (CLF) are well-established surgical procedures used in the treatment of cervical spondylotic myelopathy (CSM). In situations of clinical equipoise, an influential factor in procedural decision making could be the economic effect of the chosen procedure. The object of this study is to compare and analyze the total hospital costs and charges pertaining to patients undergoing CLP or CLF for the treatment of CSM. METHODS: We performed a retrospective review of 81 consecutive patients from a single institution; 55 patients were treated with CLP and 26 with CLF. CLP was performed via the double-door allograft technique that does not require implants, whereas laminectomy fusion procedures included metallic instrumentation. We analyzed 10,682 individual costs (HC) and charges (HCh) for all patients, as obtained from hospital accounting data. The Current Procedural Terminology codes were used to estimate the physicians' fees as such fees are not accounted for via hospital billing records. Total cost (TC) therefore equaled the sum of the hospital cost and the estimated physicians' fees. RESULTS: The mean length of stay was 3.7 days for CLP and 5.9 days for CLF (P < .01). There were no significant differences between the groups with respect to age, gender, previous surgical history, and medical insurance. The TC mean was $17,734 for CLP and $37,413 for CLF (P < .01). Mean HCh for CLP was 42% of that for CLF, and therefore the mean charge for CLF was 238% of that for CLP (P < .01). Mean HC was $15,426 for CLP and $32,125 for CLF (P < .01); the main contributor was implant cost (mean $2582). CONCLUSIONS: Our study demonstrates that, in clinically similar populations, CLP results in reduced length of stay, TC, and hospital charges. In CSM cases requiring posterior decompression, we demonstrate CLP to be a less costly procedure. However, in the presence of neck pain, kyphotic deformity, or gross instability, this procedure may not be sufficient and posterior CLF may be required. PMID- 25694908 TI - Multilevel extreme lateral interbody fusion (XLIF) and osteotomies for 3 dimensional severe deformity: 25 consecutive cases. AB - BACKGROUND: This is a retrospective review of 25 patients with severe lumbar nerve root compression undergoing multilevel anterior retroperitoneal lumbar interbody fusion and posterior instrumentation for deformity. The objective is to analyze the outcomes and clinical results from anterior interbody fusions performed through a lateral approach and compare these with traditional surgical procedures. METHODS: A consecutive series of 25 patients (78 extreme lateral interbody fusion [XLIF] levels) was identified to illustrate the primary advantages of XLIF in correcting the most extreme of the 3-dimensional deformities that fulfilled the following criteria: (1) a minimum of 40 degrees of scoliosis; (2) 2 or more levels of translation, anterior spondylolisthesis, and lateral subluxation (subluxation in 2 planes), causing symptomatic neurogenic claudication and severe spinal stenosis; and (3) lumbar hypokyphosis or flat-back syndrome. In addition, the majority had trunks that were out of balance (central sacral vertical line >=2 cm from vertical plumb line) or had sagittal imbalance, defined by a distance between the sagittal vertical line and S1 of greater than 3 cm. There were 25 patients who had severe enough deformities fulfilling these criteria that required supplementation of the lateral XLIF with posterior osteotomies and pedicle screw instrumentation. RESULTS: In our database, with a mean follow-up of 24 months, 85% of patients showed evidence of solid arthrodesis and no subsidence on computed tomography and flexion/extension radiographs. The complication rate remained low, with a perioperative rate of 2.4% and postoperative rate of 12.2%. The lateral listhesis and anterior spondylolisthetic subluxation were anatomically reduced with minimally invasive XLIF. The main finding in these 25 cases was our isolation of the major indication for supplemental posterior surgery: truncal decompensation in patients who are out of balance by 2 cm or more, in whom posterior spinal osteotomies and segmental pedicle screw instrumentation were required at follow up. No patients were out of sagittal balance (sagittal vertical line <3 cm from S1) postoperatively. Segmental instrumentation with osteotomies was also more effective for restoration of physiologic lumbar lordosis compared with anterior stand-alone procedures. CONCLUSIONS: This retrospective study supports the finding that clinical outcomes (coronal/sagittal alignment) improve postoperatively after minimally invasive surgery with multilevel XLIF procedures and are improved compared with larger extensile thoracoabdominal anterior scoliosis procedures. PMID- 25694909 TI - Preoperative laryngoscopic examination in patients undergoing repeat anterior cervical discectomy and fusion. AB - STUDY BACKGROUND: Patients who experience a recurrent laryngeal nerve injury (RLI) after undergoing an Anterior Cervical Discectomy and Fusion (ACDF) procedure may eventually become asymptomatic. If patients with an asymptomatic vocal cord abnormality undergo a subsequent ACDF they may be at risk for developing bilateral vocal cord paralysis (VCP). Bilateral VCP is a potentially life threatening problem, requiring emergent tracheotomy in some cases. A program of referring patients for preoperative laryngoscopic examinations (PLE) who were being considered for a revision ACDF was instituted. This study reviews the results of these examinations and determines if the information gained impacted management. METHODS: Patients who were referred for PLE prior to revision ACDF were identified from a prospectively maintained database during the period 2004 - 2010. All patients underwent examinations by an Otorhinolaryngologist specialist (ENT) using a nasopharyngoscope in combination with video stroboscopic examination. RESULTS: 23 patients were identified as having a PLE and subsequent revision ACDF. 18 patients underwent a single level ACDF and 5 patients underwent a previous 2 level surgery. Significant findings were found in 4 patients. 2 patients presented with asymptomatic VCP and 2 patients with chronic hoarseness. One was found with VCP and the other with a vocal cord mass. The revision procedures were performed on the same side as the previous ACDF. CONCLUSIONS: 17.3% of patients undergoing PLE exhibited abnormalities, affecting decision making regarding side of approach for revision ACDF. PLE is a simple and effective way of screening patients for abnormalities prior to revision ACDF surgery. PMID- 25694910 TI - Safety and feasibility of outpatient ACDF in an ambulatory setting: A retrospective chart review. AB - BACKGROUND: Outpatient spinal surgery is becoming increasingly common and in some areas is now the preferred course for certain procedures. Many different procedures, including ACDF, have been examined in the outpatient setting in the past few years but to our knowledge none have included the ambulatory setting. METHODS: All ACDF procedures performed during the time frame of the study were included. Charts were pulled and evaluated using the outcome measures. One and two-level ACDF were divided into respective cervical levels and individually analyzed. RESULTS: Single level ACDF comprised 62% (n = 74) of the total surgeries. Single level ACDF patients averaged a total hospital stay time of 4.7 hours, with a maximum total stay time of 8.2 hours and a minimum stay time of 0.8 hours. Two-level ACDF made up 38% (n = 45) of the total surgeries. The average total stay time for two level ACDF was 5.4 hours, with a maximum time of 9.6 hours and a minimum of 3.4 hours. All patients were comparable in age and gender. There were no major operating complications and neither re-admissions nor deaths after discharge. There were two transfers from ambulatory surgical centers to inpatient status for observation only. CONCLUSIONS: Outpatient one and two-level ACDF with plate fixation can safely be done on an outpatient ambulatory basis. The data suggest that all subaxial cervical levels can be treated. Patient fusion and satisfaction data were not obtained and thus cannot be commented upon. CLINICAL RELEVANCE: Ambulatory ACDF should be considered as a feasible option for reducing hospital stay as well as the associated healthcare costs. PMID- 25694911 TI - Pedicle violation and Navigational errors in pedicle screw insertion using the intraoperative O-arm: A preliminary report. AB - BACKGROUND: Use of computer-assisted insertion of pedicle screws has some advantages owing to the reportedly decreased incidence of pedicle breach and clinical events. Registration-based methods based on preoperative computed tomography imaging, 2D fluoroscopy, and 3D fluoroscopy are the most popular, however each has its limitations. O-arm-based navigation, which uses intraoperative acquisition and registration of navigated images, may overcome many of these disadvantages. We set out to study the clinical accuracy and navigational accuracy for pedicle screw insertion using our recently acquired O arm and present our preliminary findings. METHODS: The first 26 patients operated consecutively for L4-5 fusion were included in the study. O-arm-based navigation was used to insert the pedicle screws. Postoperative computed tomography images were acquired and assessed for pedicle breach and anterior cortical perforation. Planned trajectories of each screw were compared with the actual trajectories in the postoperative images to assess navigational accuracy in both axial and sagittal planes. RESULTS: A total of 104 screws were inserted. One screw (1%) breached the pedicle laterally. Nonsignificant anterolateral cortical perforations were noted in 7 screws (6.7%), all of which occurred at L5 level. The mean axial and sagittal navigational error was 2.3 degrees (+/-1.7) and 3.1 degrees (+/-2.3), respectively. There were no significant differences in the errors between L4 or L5 level. The occurrence of anterior perforation correlated with the degree of axial (P = .02) but not sagittal (P = .12) navigational error. There were no clinical events related to the screw insertion. CONCLUSION: Use of O-arm-guided pedicle screw insertion was associated with low incidence of pedicle breach (1%) and a low range of navigational error in both sagittal and axial planes. Anterolateral vertebral body perforation was higher at L5 without any negative clinical events. Despite the high need for technical support, we found that O-arm was a very efficient tool for accurate pedicle screw insertion. PMID- 25694912 TI - Clinical outcomes of a polyaxial interspinous fusion system. AB - BACKGROUND: Early interspinous process fixation constructs utilize rigid fixation plates with immobile spikes which increase the difficulty of device implantation when anatomic variations are encountered. Second generation systems have been designed with polyaxial properties with the goal of accommodating natural osseous anatomic variations to achieve optimal implant placement and fixation integrity. The purpose of this study was to evaluate clinical outcomes in patients treated with this device to supplement the biomechanical data from previous studies. METHODS: A retrospective, non-randomized, single-center chart review at or beyond the one year postoperative time point was conducted to collect preoperative and perioperative data on patients treated with a polyaxial intraspinous fixation system. A postoperative numerical pain rating scale and modified MacNab classification score were obtained from each patient in the cohort via phone survey. RESULTS: A total of 53 patients were included in the study. Median hospital stay was 2 days (range 1-7 days). There were no reported perioperative blood transfusions or cases of radiographic fracture/migration of the device at the 6 week post-operative time point. There was a significant improvement in pain index score in the overall patient study group and a satisfactory (excellent or good) MacNab result was obtained in 48% of all patients. Patients with preoperative pain scores greater than 8/10 reported more pain improvement than patients with preoperative pain scores less than 5 (0 points, p = 0.96, n = 8). Patients with a BMI less than 30 had significantly better MacNab outcome classifications than patients with a BMI greater than 30. CONCLUSIONS: The polyaxial interspinous fusion system produces significant clinical improvement when employed to treat patients with stenosis, herniated disc, or low grade spondylolisthesis. This device can be implanted with a low complication rate and short postoperative hospital admission time. Patients with high pre-operative pain score and BMI under 30 can be predictors of better clinical outcome and should be considered prior to implantation. PMID- 25694913 TI - Spinal fusion with demineralized calf fetal growth plate as novel biomaterial in rat model: a preliminary study. AB - BACKGROUND: Spinal fusions are being performed for various pathologies of the spine such as degenerative diseases, deformities, tumors and fractures. Recently, other bone substitutes such as demineralized bone matrix (DBM) have been developed for spinal fusion. Therefore, this study was conducted to evaluate the intertransverse posterolateral fusion with the Bovine fetal growth plate (DCFGP) and compare it with commercial DBM in rat model. METHODS: A total of 16 mature male rats (aged 4 months and weighing 200-300 g) were randomly divided in two groups. After a skin incision on posterolateral site, two separate fascial incisions were made 3 mm from the midline. A muscle-splitting approach was used to expose the transverse processes of L4 and L5. Group I (n = 8) underwent with implanted Bovine fetal growth plate among decorticated transverse processes. In group II (n = 8) commercial DBM was placed in the same manner. Fusion was evaluated by manual palpation, radiographical, gross and histopathological analysis. RESULTS: The manual palpation, radiological, gross and histopathological findings indicate high potential of the DCFGP in spinal fusion. At the 42nd postoperative day, new bone formation as evidenced by a bridge between L4 and L5 was visualized in all rats implanted with DCFGP and commercial DBM. The newly formed bone tissue was observed in all implanted areas on the 42nd day after operation in the two groups. CONCLUSIONS: The spinal fusion of the animals of both groups demonstrated more advanced osteogenic potential and resulted in proper fusion of the transverse process of lumbar vertebra. PMID- 25694914 TI - Annulo-nucleoplasty using Disc-FX in the management of lumbar disc pathology: early results. AB - BACKGROUND: Back pain due to Lumbar Disc Disease is a major clinical problem. The treatment options range from physiotherapy to fusion surgery. A number of minimally invasive procedures have also been developed in the recent past for its management. Disc-FX is a new minimally invasive technique that combines percutaneous discectomy, nuclear ablation and annular modification. Literature on its role in the management of lumbar disc pathology is scarce. METHODS: We included 24 consecutive patients who underwent the Disc-FX for back pain due to lumbar disc pathology non-responsive to non-operative treatment for a period of at least 6 months. Based on Magnetic Resonance Imaging (MRI) these patients fell into 2 groups - those with degenerative disc disease (DDD) (n = 12) and those with a contained lumbar disc herniation (CLDH)(n = 12). They were evaluated using the Visual analogue scale (VAS), Oswestry Disability Index (ODI) and Short Form 36 (SF-36) scores preoperatively and postoperatively. RESULTS: The mean age was 37.9 years (21-53 years). There were 17 males and 7 females. One patient in each subgroup was excluded from the final evaluation. Significant improvement was seen in all outcome measures. The overall rate of reintervention for persistent symptoms was 18.18% (4/22); in the CLDH subgroup, it was 36.36% (4/11). CONCLUSIONS AND LEVEL OF EVIDENCE: Early results after the Disc-FX procedure suggest that it s a reasonable treatment option for patients with back pain due to lumbar disc disease, especially for those with DDD who fail conservative treatment. It could be an alternative to procedures like fusion or disc replacement. This study presents Level IV evidence. CLINICAL RELEVANCE: We feel that our study establishes Disc-FX as a modality of treating symptomatic lumbar disc disease due to DDD. However, longer term prospective studies are needed to prove this and to evaluate its role in the treatment of patients with CLDH. PMID- 25694915 TI - "Outside-in" technique, clinical results, and indications with transforaminal lumbar endoscopic surgery: a retrospective study on 220 patients on applied radiographic classification of foraminal spinal stenosis. AB - OBJECTIVE: To analyze and describe appropriate surgical indications for endoscopically performed transforaminal decompression with the outside-in technique with foraminoplasty in patients with lateral stenosis with and without herniated disc. BACKGROUND AND SIGNIFICANCE: Endoscopic microdiscectomy is growing in popularity for the removal of lumbar disc herniations. Recent advances in surgical techniques allow for percutaneous endoscopically assisted bony decompression as well. MATERIALS AND METHODS: A retrospective study of 220 consecutive patients undergoing percutaneous endoscopic transforaminal foraminoplasty and microdiscectomy at 228 levels was conducted with intent of identifying appropriate surgical indications in patients with monoradiculopathy. The mean follow up was 46 months ranging from 26 to 54 months. Preoperatively, foraminal and lateral recess stenosis was graded on preoperative MRI and CT scans by dividing the lumbar neuroforamen into three zones: a) entry zone, b) middle zone, and c) exit zone. In addition, the presence of disc herniation causing neural element compression in the lateral recess and neuroforamen was noted. Disc herniations, if present, were recorded as either extruded and contained disc herniations. Surgical outcomes were classified according to the Macnab criteria. In addition, reductions in VAS scores were assessed. RESULTS: According to the Macnab criteria, excellent and good results were obtained in 85% (186/220) of patients with monoradiculopathy. The mean VAS score decreased from 7.5 +/- 1.5 preoperatively to 2.8 +/- 1.9 at the final follow-up (P < 0.01). Concomitant extruded disc herniations and contained disc bulges were recorded in 24 and 82 patients, respectively. There were no approach-related complications. Clinical failures occurred in patients with bony stenosis in the lateral recess and entry zone of the neuroforamen. Less favorable outcomes were observed in patients with concomitant contained disc herniations when compared to extruded disc herniations (P < 0.03) as well in patients older than 50 years of age (P < 0.021). CONCLUSIONS: Percutaneous, endoscopic decompression using outside-in technique works well in patients with monoradiculopathy due to lateral stenosis in the mid and exit zone of the neuroforamen. Decompression in the entry zone maybe inadequate using the transforaminal outside-in approach. Future studies with greater statistical power should determine as to whether pain relief was achieved via microdiscectomy or foraminoplasty. PMID- 25694916 TI - Sciatica: detection and confirmation by new method. AB - We need to overcome limitations of present assessment and also integrate newer research in our work about sciatica. Inflammation induces changes in the DRG and nerve root. It sensitizes the axons. Nociceptor is a unique axon. It is pseudo unipolar: both its ends, central and peripheral, behave in similar fashion. The nerve in periphery which carries these axons may selectively become sensitive to mechanical pressure--"mechanosensitized," as we coin the phrase. Many pain questionnaires are used and are effective in identifying neuropathic pain solely on basis of descriptors but they do not directly physically correlate nerve root and pain. A thorough neurological evaluation is always needed. Physical examination is not direct pain assessment but testing mobility of nerve root and its effect on pain generation. There is a dogmatic dominance of dermatomes in assessment of leg pain. They are unreliable. Images may not correlate with symptoms and pathology in about 28% of cases. Electrophysiology may be normal in purely inflamed nerve root. Palpation may help in such inflammatory setting to refine our assessment further. Confirmation of sciatica is done by selective nerve root block (SNRB) today but it is fraught with several complications and needs elaborate inpatient and operating room set up. We have used the unique property of the pseudo unipolar axon that both its ends have similar functional properties and so inject along its peripheral end sodium channel blockers to block the basic cause of the mechanosensitization namely upregulated sodium channels in the root or DRG. Thus using palpation we may be able to detect symptomatic nerve in stage of inflammation and with distal end injection, along same inflamed nerve we may be able to abolish and so confirm sciatica. Discussions of sciatica pain diagnosis tend to immediately shift and centre on the affected disc rather than the nerve. Theoretically it may be possible to detect the affected nerve by palpating the nerve and relieve pain moment we desensitize the nerve. PMID- 25694917 TI - Percutaneous interspinous distraction device for the treatment of lumbar spinal canal stenosis: clinical and radiographic results at 2-year follow-up. AB - OBJECTIVE: To evaluate the effectiveness of the In- space (Synthes, Umkirch, Germany) and the correlation between radiographic parameters and clinical outcome in patients with lumbar spinal canal stenosis (LSS). METHODS: Between June 2009 and May 2013, 56 patients with LSS underwent In-space by one senior surgeon. All of the patients were evaluated both clinically and radiographic measurements before the procedure and each visit at the postoperative follow-up. Preoperative and postoperative X-ray imaging was performed before the procedure and at follow up to assess the correlation with the clinical outcome. Radiological measurements and clinical outcomes were recorded to establish a relationship between the radiographic parameters and clinical outcome of this procedure. All patients had at least 2 years of follow-up. RESULTS: The mean VAS score of back pain decreased significantly (p < 0.05). CONCLUSIONS: Our data suggest that percutaneous interspinous devices are a good alternative to treat LSS. The device offers significant decrease in back pain, leg pain and ODI score with 2-year lasting relief from symptoms. The increased intervertebral foramenal space explains the improvement of leg pain, but the mechanism of back pain relief remains unclear. A very weak correlation between the radiographic changes and improvement of pain was found. PMID- 25694918 TI - Multi-center, prospective, randomized, controlled investigational device exemption clinical trial comparing Mobi-C Cervical Artificial Disc to anterior discectomy and fusion in the treatment of symptomatic degenerative disc disease in the cervical spine. AB - BACKGROUND: Anterior cervical discectomy and fusion (ACDF) is the gold standard for treating symptomatic cervical disc degeneration. Cervical total disc replacements (TDRs) have emerged as an alternative for some patients. The purpose of this study was to evaluate the safety and effectiveness of a new TDR device compared with ACDF for treating single-level cervical disc degeneration. METHODS: This was a prospective, randomized, controlled, multicenter Food and Drug Administration (FDA) regulated Investigational Device Exemption (IDE) study. A total of 245 patients were treated (164 TDR: 81 ACDF). The primary outcome measure was overall success based on improvement in Neck Disability Index (NDI), no subsequent surgical interventions, and no adverse events (AEs) classified as major complications. Secondary outcome measures included SF-12, visual analog scale (VAS) assessing neck and arm pain, patient satisfaction, radiographic range of motion, and adjacent level degeneration. Patients were evaluated preoperatively and postoperatively at 6 weeks, 3, 6, 12, 18, and 24 months. The hypothesis was that the TDR success rate was non-inferior to ACDF at 24 months. RESULTS: Overall success rates were 73.6% for TDR and 65.3% for ACDF, confirming non-inferiority (p < 0.0025). TDR demonstrated earlier improvements with significant differences in NDI scores at 6 weeks and 3 months, and VAS neck pain and SF-12 PCS scores at 6 weeks (p<0.05). Operative level range of motion in the TDR group was maintained throughout follow-up. Radiographic evidence of inferior adjacent segment degeneration was significantly greater with ACDF at 12 and 24 months (p < 0.05). AE rates were similar. CONCLUSIONS: Mobi-C TDR is a safe and effective treatment for single-level disc degeneration, producing outcomes similar to ACDF with less adjacent segment degeneration. LEVEL OF EVIDENCE: Level I. CLINICAL RELEVANCE: This study adds to the literature supporting cervical TDR as a viable option to ACDF in appropriately selected patients with disc degeneration. PMID- 25694919 TI - The surgical learning curve and accuracy of minimally invasive lumbar pedicle screw placement using CT based computer-assisted navigation plus continuous electromyography monitoring - a retrospective review of 627 screws in 150 patients. AB - OBJECTIVE: This study retrospectively assessed the accuracy of placement of lumbar pedicle screws placed by a single surgeon using a minimally-invasive, intra-operative CT-based computer navigated technique in combination with continuous electromyography (EMG) monitoring. The rates of incorrectly positioned screws were reviewed in the context of the surgeon's experience and learning curve. METHODS: Data was retrospectively reviewed from all consecutive minimally invasive lumbar fusions performed by the primary author over a period of over 4 years from April 2008 until October 2012. All cases that had utilized computer assisted intra-operative CT-based image guidance and continuous EMG monitoring to guide percutaneous pedicle screw placement were analysed for the rates of malposition of the pedicle screws. Pedicle screw malposition was defined as having occurred if the screw trajectory was adjusted intraoperatively due to positive EMG responses, or due to breach of the pedicle cortex by more than 2mm on intraoperative CT imaging performed at the end of the instrumentation procedure. Further analysis of the data was undertaken to determine if the rates of malposition changed with the surgeon's experience with the technique. RESULTS: Six hundred and twenty-seven pedicle screws were placed in one hundred and fifty patients. The overall rate of intraoperative malposition and subsequent adjustment of pedicle screw placement was 3.8% (24 of 627 screws). Screw malposition was detected by intraoperative CT imaging. Warning of potential screw misplacement was provided by use of the EMG monitoring. With increased experience with the technique, rates of intraoperative pedicle screw malposition were found to decrease from 5.1% of screws in the first fifty patients, to 2.0% in the last 50 patients. Only one screw was suboptimally placed at the end of surgery, which did not result in a neurological deficit. CONCLUSION: The use of CT-based computer-assisted navigation in combination with continuous EMG monitoring during percutaneous transpedicular screw placement results in very low rates of malposition and neural injury that compare favourably with previously reported rates. Pedicle screw placement accuracy continues to improve as the surgeon becomes more experienced with the technique. PMID- 25694920 TI - Segmental and global lordosis changes with two-level axial lumbar interbody fusion and posterior instrumentation. AB - BACKGROUND: Loss of lumbar lordosis has been reported after lumbar interbody fusion surgery and may portend poor clinical and radiographic outcome. The objective of this research was to measure changes in segmental and global lumbar lordosis in patients treated with presacral axial L4-S1 interbody fusion and posterior instrumentation and to determine if these changes influenced patient outcomes. METHODS: We performed a retrospective, multi-center review of prospectively collected data in 58 consecutive patients with disabling lumbar pain and radiculopathy unresponsive to nonsurgical treatment who underwent L4-S1 interbody fusion with the AxiaLIF two-level system (Baxano Surgical, Raleigh NC). Main outcomes included back pain severity, Oswestry Disability Index (ODI), Odom's outcome criteria, and fusion status using flexion and extension radiographs and computed tomography scans. Segmental (L4-S1) and global (L1-S1) lumbar lordosis measurements were made using standing lateral radiographs. All patients were followed for at least 24 months (mean: 29 months, range 24-56 months). RESULTS: There was no bowel injury, vascular injury, deep infection, neurologic complication or implant failure. Mean back pain severity improved from 7.8+/-1.7 at baseline to 3.3+/-2.6 at 2 years (p < 0.001). Mean ODI scores improved from 60+/-15% at baseline to 34+/-27% at 2 years (p < 0.001). At final follow-up, 83% of patients were rated as good or excellent using Odom's criteria. Interbody fusion was observed in 111 (96%) of 116 treated interspaces. Maintenance of lordosis, defined as a change in Cobb angle <= 5 degrees , was identified in 84% of patients at L4-S1 and 81% of patients at L1-S1. Patients with loss or gain in segmental or global lordosis experienced similar 2-year outcomes versus those with less than a 5 degrees change. CONCLUSIONS/CLINICAL RELEVANCE: Two-level axial interbody fusion supplemented with posterior fixation does not alter segmental or global lordosis in most patients. Patients with postoperative change in lordosis greater than 5 degrees have similarly favorable long-term clinical outcomes and fusion rates compared to patients with less than 5 degrees lordosis change. PMID- 25694921 TI - Validation and analysis of a multi-site MIS Prospective Registry through sub analysis of an MIS TLIF Subgroup. AB - STUDY DESIGN: Retrospective analysis of multi-site, prospectively collected database. OBJECTIVE: To assess the validity and utility of a prospective spine registry by sub-analysis of patients treated with MIS TLIF. BACKGROUND: The MIS registry is a large-scale, multi-center series of prospectively collected clinical information on outcomes, complications, and adverse events for minimally invasive spine procedures for the treatment of degenerative lumbar conditions. METHODS: Analysis was performed on the MIS Prospective Registry database. A subgroup of patients treated by MIS TLIF technique was identified. Statistical analyses were performed on pre and post-operative data collected using validated health related quality of life outcome tools. Missing 1-year patient follow-up data was obtained through progressive correspondence modalities. RESULTS: Data analysis was performed on 98 MIS TLIF patients (56 female, 42 male) with a median age of 64.5 years (range 25-91 years) which were extracted from a total registry population of 478 patients. The one year follow-up rate was 87%. A total of 64 single-level, 23 two-level, 3 three-level, and 3 combined TLIFs staged with an MIS lateral procedure were included. The primary surgical indications were spondylolisthesis (27%), central stenosis (25%), foraminal stenosis (14%), post laminectomy syndrome (14%) and degenerative scoliosis (6%). The peri-operative blood transfusion rate was 3%. Complications included intraoperative dural tear (n = 3), deep wound infection (n = 2), superficial dehiscence/cellulitis (n = 2). There was a 4% re-operation rate at the 1 year post-operative time point. Half of patients were discharged within 2 days (range 1-11 days, mean 2.97 days, median 2 days). All patients that were discharged on the first post-operative day (n = 14) underwent a single-level MIS TLIF procedure and had significantly lower pre-op disability index score than those discharged on POD 3-5 (43.7 +/- 15.5 vs. 56.0 +/- 18.3, p = 0.04). Average ODI scores in the subgroup of patients that had reached the one year postoperative time point were 46.5 pre-op (n = 46), and 26.2 at 1 year post-op (n = 40, p = 0.0001). There was significant improvement in VAS scores: pre-operative (back = 6.7, leg = 5.4, n = 46), and 1 year post-operative (back = 3.2, leg = 1.7, n = 40, p = 0.0001). Patients with pre-operative ODI scores greater than 50 demonstrated significant improvement starting at the 6 week post-operative time point (24 point improvement, n = 46, p < 0.001). A pre operative ODI between 35-50 showed significant improvement starting at 3 months (15.5 point improvement, n = 29, p = 0.05). Patients with a pre-operative ODI score less than 35 had an initial period of increased disability with a trend towards significant improvement by 3 months post-op (n = 20). CONCLUSIONS: Initial findings of the MIS Prospective Registry show patients can be enrolled in a relatively short time period and patient based questionnaires can successfully be obtained through a combination of clinic follow-up appointments and remote correspondence. Outcomes of the MIS Registry MIS TLIF subgroup were consistent with previously published MIS TLIF studies. Sub-analysis of data collected through level-specific patient diagnosis and treatment modalities permits outcome analysis of a wide breadth of spinal conditions and interventions. PMID- 25694922 TI - Thoracic and lumbar vertebrae morphology in Lenke type 1 female adolescent idiopathic scoliosis patients. AB - BACKGROUND: Pedicle screws are widely used in adolescent idiopathic scoliosis (AIS) surgeries. Pedicle screw malposition may lead to serious vascular and neurologic complications. Knowledge of the morphometric anatomy of the thoracic and lumbar vertebrae is essential for the surgeon while implanting pedicle screws. It has been reported that there is a reduction of pedicle width at the concavity of the curve in AIS patients. However, it is unclear if gender plays a role in this pedicle width pattern. The goal of this study is to assess the vertebrae morphology in a more homogeneous group of AIS patients - female patients with Lenke type 1 curve. METHODS: The thoracic and lumbar vertebra and pedicle morphometry of 17 consecutive Lenke type 1 female AIS patients was analyzed based on 1mm fine cut CT scans. Morphometric anatomy of 539 pedicles from T1 to L5 was studied. Measurements included pedicle length, chord length, transverse pedicle width, transverse pedicle angle and vertebral rotation angle. RESULTS: The mean age of the patients was 14 years old (range 12-18). The mean Cobb angle was 56 degrees (range 43 degrees -88 degrees ) and the mean angle of vertebral rotation varied between 4-13.8 degrees . The apical vertebra was between T7 and T11. The transverse pedicle width was significantly smaller (p < 0.05) on the concave side in the apical region of the thoracic spine (T7 and T8), measuring between 2.1-2.2 mm on the concave side and 2.7-3.1 mm on the convex side. Meanwhile, in some upper thoracic vertebrae (T3, T4, T5), the width was significantly bigger (p < 0.05) on the concave side than on the convex side, measuring between 2.8-4 mm on the concave side and 1.8-2.4 mm on the convex side. In the lumbar spine, the width varied between 4.1-9.9 mm without significant differences between the concave and convex sides (p > 0.05). The pedicle length varied between 15.4-28.7 mm and was significantly smaller (p < 0.05) on the concave side at T4, T5 and L2. The chord length was shortest at T1, measuring 32.4 mm and increased gradually to 54.3 mm at L3 but no statistical difference was found between the concave and convex sides. The transverse pedicle angle varied between 11.8 degrees and 35 degrees and was significantly bigger on the concave side at T7 and on the convex side at L1 (p < 0.05). CONCLUSIONS: The vertebrae morphology in Lenke type 1 female AIS patients is substantially different from the vertebrae in normal spines especially at the apex and in the upper thoracic region. This is consistent with some previous reports which did not distinguish between male and female patients. Our findings suggest that gender does not play a major role in the vertebrae morphology pattern of AIS patients. Furthermore, recognizing this pattern is critical in order to optimize pedicle screw instrumentation and may allow for some leeway adjustments in the pedicle screw trajectory regardless of the methods of implantation. PMID- 25694923 TI - Endoscopic foraminal decompression preceding oblique lateral lumbar interbody fusion to decrease the incidence of post operative dysaesthesia. AB - BACKGROUND: Lumbar interbody fusion has become a well established method to diminish axial back pain as well as radiculopathy in patients with degenerative disc disease, stenosis, and instability. The concept of indirect decompression of the neural foramen and spinal canal while performing fusion became popular in the mid 1990's with description of ALIF techniques. Morphometric analysis confirmed the extent of decompression of posterior elements with interbody height restoration. In an attempt to diminish potential complications associated with anterior or posterior approaches to the spine for interbody fusion, and with the hope of accomplishing fusion in a less invasive manner, lateral lumbar interbody fusion has become quite popular. This transpsoas approach to the disc space has been associated with a high incidence of neurologic complications. Even though this is the first technique to routinely recommend EMG monitoring to increase safety in the approach, neurologic injuries still occur. A newer oblique lateral lumbar interbody (OLLIF) approach has recently been described to lessen the incidence of neurologic injury. This technique also advocates use of EMG testing to lessen neurologic trauma. In spite of this precaution, neurologic insult has not been eliminated. In fact, even in patients whose electrical stimulation thresholds suggested a safe entry space into the disc, transient dysaesthesia continues to occur in 20-25 percent of cases. PURPOSE: This pilot study reflects data and observations of a subset of patients treated with endoscopic foraminotomy preceding oblique lateral lumbar interbody fusion (OLLIF) to assess specifically potential improvements in dysaesthesia rates. METHODS: A select subset of patients undergoing OLLIF failed to meet electrodiagnostic criteria for safe disc access through Kambin's triangle. These patients underwent an endoscopic foraminotomy and exiting nerve decompression prior to discectomy, endplate preparation and cage insertion. RESULTS: Dysaesthesia did not occur in these patients whom otherwise would have likely been at risk for neurologic deficit. CONCLUSIONS: These findings suggest that patients at risk for neurologic insult during oblique lateral lumbar interbody fusion can be protected by foraminoplasty. PMID- 25694924 TI - Transforaminal endoscopic lumbar decompression & foraminoplasty: a 10 year prospective survivability outcome study of the treatment of foraminal stenosis and failed back surgery. AB - BACKGROUND: Conventional diagnosis between axial and foraminal stenosis is suboptimal and long-term outcomes limited to posterior decompression. Aware state Transforaminal Endoscopic Lumbar Decompression and Foraminoplasty (TELDF) offers a direct aware state means of localizing and treating neuro-claudicant back pain, referred pain and weakness associated with stenosis failing to respond to conventional rehabilitation, pain management or surgery. This prospective survivability study examines the outcomes 10 years after TELDF in patients with foraminal stenosis arising from degeneration or failed back surgery. METHODS: For 10 years prospective data were collected on 114 consecutive patients with multilevel spondylosis and neuro-claudicant back pain, referred pain and weakness with or without failed back surgery whose symptoms had failed to respond to conventional rehabilitation and pain management and who underwent TELDF. The level responsible for the predominant presenting symptoms of foraminal stenosis, determined on clinical grounds, MRI and or CT scans, was confirmed by transforaminal probing and discography. Patients underwent TELDF at the spinal segment at which the predominant presenting symptoms were reproduced. Those that required treatment at an additional segment were excluded. Outcomes were assessed by postal questionnaire with failures being examined by the independent authors using the Visual Analogue Pain Scale (VAPS), the Oswestry Disability Index (ODI) and the Prolo Activity Score. RESULTS: Cohort integrity was 69%. 79 patients were available for evaluation after removal of the deceased (12), untraceable (17) and decliners (6) from the cohort. VAP scores improved from a pre-operative mean of 7.3 to 2.4 at year 10. The ODI improved from a mean of 58.5 at baseline to 17.5 at year 10. 72% of reviewed patients fulfilled the definition of an "Excellent" or "Good Clinical Impact" at review using the Spinal Foundation Outcome Score. Based on the Prolo scale, 61 patients (77%) were able to return and continue in full or part-time work or retirement activity post-TELDF. Complications of TELDF were limited to transient nerve irritation, which affected 19% of the cohort for 2 - 4 weeks. TELDF was equally beneficial in those with failed back surgery. CONCLUSIONS: TELDF is a beneficial intervention for the long-term treatment of severely disabled patients with neuro-claudicant symptoms arising from spinal or foraminal stenosis with a dural diameter of more than 3mm, who have failed to respond to conventional rehabilitation or chronic pain management. It results in considerable improvements in symptoms and function sustained 10 years later despite co-morbidity, ageing or the presence of failed back surgery. CLINICAL RELEVANCE: The long term outcome of TELDF in severely disabled patients with neuro-claudicant symptoms arising from foraminal stenosis which had failed to respond to conventional rehabilitation, surgery or chronic pain management suggests that foraminal pathology is a major cause of lumbar axial and referred pain and that TELDF should be offered as primary treatment for these conditions even in the elderly and infirm. The application of TELDF at multiple levels may further widen the benefits of this technique. PMID- 25694925 TI - Inter- and intra-observer reliability of measurement of pedicle screw breach assessed by postoperative CT scans. AB - BACKGROUND: Pedicle screws are used increasingly in spine surgery. Concerns of complications associated with screw breach necessitates accurate pedicle screw placement. Postoperative CT imaging helps to detect screw malposition and assess its severity. However, accuracy is dependent on the reading of the CT scans. Inter- and intra-observer variability could affect the reliability of CT scans to assess multiple screw types and sites. The purpose of this study was to assess the reliability of multi-observer analysis of CT scans for determining pedicle screw breach for various screw types and sites in patients with spinal deformity or degenerative pathologies. METHODS: Axial CT scan images of 23 patients (286 screws) were read by four experienced spine surgeons. Pedicle screw placement was considered 'In' when the screw was fully contained and/or the pedicle wall breach was <=2 mm. 'Out' was defined as a breach in the medial or lateral pedicle wall >2 mm. Intra-class coefficients (ICC) were calculated to assess the inter- and intra-observer reliability. RESULTS: Marked inter- and intra-observer variability was noticed. The overall inter-observer ICC was 0.45 (95% confidence limits 0.25 to 0.65). The intra-observer ICC was 0.49 (95% confidence limits 0.29 to 0.69). Underlying spinal pathology, screw type, and patient age did not seem to impact the reliability of our CT assessments. CONCLUSION: Our results indicate the evaluation of pedicle screw breach on CT by a single surgeon is highly variable, and care should be taken when using individual CT evaluations of millimeters of breach as a basis for screw removal. This was a Level III study. PMID- 25694926 TI - Endoscopic trans-iliac approach to L5-S1 disc and foramen - a report on clinical experience. AB - BACKGROUND: The lumbosacral junction is a difficult area for spine surgery because of the complex anatomy. In the era of minimally invasive spine surgery, the presence of the iliac wing has, at the level of lumbosacral junction, created a major obstacle in the paths of two of the major approaches, namely, the direct lateral and percutaneous posterolateral endoscopic approaches. A trans-iliac cadaver study published by the senior author and co-workers in 1997, suggested the possibility of an alternative approach to the lumbosacral junction. PURPOSE: To determine the feasibility of percutaneous, endoscopic trans-iliac approach to the L5-S1 disc and foramen. STUDY DESIGN: Prospective case series study. MATERIALS AND METHODS: 15 consecutive patients undergoing the transiliac approach to L5-S1 disc and foramen were included in the study. Pre- and postoperative visual analogue scale (VAS); Oswestry Disability Index (ODI); and intra-operative blood loss and operative time, were obtained for the study. Preoperative MRI or CT scan was used to determine the need for trans-iliac access. The procedure was performed with the patient in prone position and under monitored sedation for decompression. Endotracheal anesthesia was used for fusion cases. The transiliac access was established with a cannulated drill or core drill through the iliac wing. Once the trans-iliac window had been created, the rest of the procedure proceeded as for percutaneous endoscopic transforaminal decompression and fusion. RESULTS: 15 patients (9 male and 6 female) participated in the study. The VAS for back and leg pain significantly improved in all patients. The ODI dropped by more than 50%. There was minimal blood loss, and transient post-operative dysesthesia in 2 cases which resolved after 3 weeks. CONCLUSION: Endoscopic trans-iliac approach to the L5-S1 disc and foramen is feasible and safe. Decompression can be performed safely via trans-iliac access with minimal blood loss, and in a short operative time. PMID- 25694927 TI - Effectiveness of postoperative wound drains in one- and two-level cervical spine fusions. AB - BACKGROUND: Cervical drains have historically been used to avoid postoperative wound and respiratory complications such as excessive edema, hematoma, infection, re-intubation, delayed extubation, or respiratory distress. Recently, some surgeons have ceased using drains because they may prolong hospital stay, operative time, or patient discomfort. The objective of this retrospective case control series is to investigate the effectiveness of postoperative drains following one- and two-level cervical fusions. METHODS: A chart review was conducted at a single institution from 2010-2013. Outcome measures included operative time, hospital stay, estimated blood loss and incidence of wound complications (infection, hematoma, edema, and complications with wound healing or evacuation), respiratory complications (delayed extubation, re-intubation, and respiratory treatment), and overall complications (wound complications, respiratory complications, dysphagia, and other complications). Statistical analyses including independent samples t-test, chi-square, analysis of covariance, and linear regression were used to compare patients who received a postoperative drain to those who did not. RESULTS: The study population included 39 patients who received a postoperative drain and 42 patients who did not. There were no differences in demographics between the two groups. Patients with drains showed increased operative time (100.1 vs 69.3 min, p < 0.001), hospital stay (38.9 vs. 31.7 hrs, p = 0.021), and blood loss (62.7 vs 29.1 mL, p < 0.001) compared to patients without drains. The frequency of wound complications, respiratory complications, and overall complications did not vary significantly between groups. CONCLUSIONS/LEVEL OF EVIDENCE: Cervical drains may not be necessary for patients undergoing one- and two-level cervical fusion. While there were no differences in incidence of complications between groups, patients treated with drains had significantly longer operative time and length of hospital stay. CLINICAL RELEVANCE: This could contribute to excessive costs for patients treated with drains, despite the lack of compelling evidence of the advantages of this treatment in the literature and in the current study. PMID- 25694928 TI - Foreword, Percutaneous and Endoscopic MIS Special Issue. PMID- 25694929 TI - Postero-lateral disc prosthesis combined with a unilateral facet replacement device maintains quantity and quality of motion at a single lumbar level. AB - BACKGROUND: Mechanically replacing one or more pain generating articulations in the functional spinal unit (FSU) may be a motion preservation alternative to arthrodesis at the affected level. Baseline biomechanical data elucidating the quantity and quality of motion in such arthroplasty constructs is non-existent. PURPOSE: The purpose of the study was to quantify the motion-preserving effect of a posterior total disc replacement (PDR) combined with a unilateral facet replacement (FR) system at a single lumbar level (L4-L5). We hypothesized that reinforcement of the FSU with unilateral FR to replace the resected, native facet joint following PDR implantation would restore quality and quantity of motion and additionally not change biomechanics at the adjacent levels. STUDY DESIGN: In vitro study using human cadaveric lumbar spines. METHODS: Six (n = 6) cadaveric lumbar spines (L1-S1) were evaluated using a pure-moment stability testing protocol (+/-7.5 Nm) in flexion-extension (F/E), lateral bending (LB) and axial rotation (AR). Each specimen was tested in: (1) intact; (2) unilateral FR; and (3) unilateral FR + PDR conditions. Index and adjacent level ROM (using hybrid protocol) were determined opto-electronically. Interpedicular travel (IPT) and instantaneous center of rotation (ICR) at the index level were radiographically determined for each condition. ROM, ICR, and IPT measurements were compared (repeated measures ANOVA) between the three conditions. RESULTS: Compared to the intact spine, no significant changes in F/E, LB or AR ROM were identified as a result of unilateral FR or unilateral FR + PDR. No significant changes in adjacent L3-L4 or L5-S1 ROM were identified in any loading mode. No significant differences in IPT were identified between the three test conditions in F/E, LB or AR at the L4-L5 level. The ICRs qualitatively were similar for the intact and unilateral FR conditions and appeared to follow placement (along the anterior posterior (AP) direction) of the PDR in the disc space. CONCLUSION: Biomechanically, quantity and quality of motion are maintained with combined unilateral FR + PDR at a single lumbar spinal level. PMID- 25694930 TI - Prospective randomized controlled trial of The Stabilis Stand Alone Cage (SAC) versus Bagby and Kuslich (BAK) implants for anterior lumbar interbody fusion. AB - BACKGROUND: Degenerative disc disease is common and debilitating for many patients. If conservative extensive care fails, anterior lumbar interbody fusion has proven to be an alternative form of surgical management. The Stabilis Stand Alone Cage(SAC) was introduced as a method to obtain stability and fusion. The purpose of this study was to determine whether the Stabilis Stand Alone Cage (SAC) is comparable in safety and efficacy to the Bagby and Kuslich (BAK) device. METHODS: As part of a prospective, randomized, controlled FDA trial, 73 patients underwent anterior interbody fusion using either the SAC(56%) or the BAK device (44%). RESULTS: Background characteristics were similar between the two groups. There was no significant difference between the SAC and BAK groups in mean operative time or mean blood loss during surgery. Adverse event rates did not differ between the groups. Assessment of plain radiographs could not confirm solid fusion in 63% of control and 71% of study patients. Functional scores from Owestry and SF-36 improved in both groups by the two-year follow-up. There were no significant differences between the SAC and BAK patients with respect to outcome. CONCLUSIONS: Both the Stabilis Stand Alone Cage and the BAK Cage provided satisfactory improvement in function and pain relief, despite less than expected radiographic fusion rates. The apparent incongruency between fusion rates and functional outcomes suggests that either radiographs underestimate the true incidence of fusion, or that patients are obtaining good pain relief and improved function despite a lower rate of fusion than previously reported. This was a Level III study. PMID- 25694931 TI - Biomechanical characteristics of an integrated lumbar interbody fusion device. AB - INTRODUCTION: We hypothesized that an Integrated Lumbar Interbody Fusion Device (PILLAR SA, Orthofix, Lewisville, TX) will function biomechanically similar to a traditional anterior interbody spacer (PILLAR AL, Orthofix, Lewisville, TX) plus posterior instrumentation (FIREBIRD, Orthofix, Lewisville, TX). Purpose of this study was to determine if an Integrated Interbody Fusion Device (PILLAR SA) can stabilize single motion segments as well as an anterior interbody spacer (PILLAR AL) + pedicle screw construct (FIREBIRD). METHODS: Eight cadaveric lumbar spines (age: 43.9+/-4.3 years) were used. Each specimen's range of motion was tested in flexion-extension (FE), lateral bending (LB), and axial rotation (AR) under intact condition, after L4-L5 PILLAR SA with intervertebral screws and after L4 L5 360 degrees fusion (PILLAR AL + Pedicle Screws and rods (FIREBIRD). Each specimen was tested in flexion (8Nm) and extension (6Nm) without preload (0 N) and under 400N of preload, in lateral bending (+/-6 Nm) and axial rotation (+/-5 Nm) without preload. RESULTS: Integrated fusion using the PILLAR SA device demonstrated statistically significant reductions in range of motion of the L4-L5 motion segment as compared to the intact condition for each test direction. PILLAR SA reduced ROM from 8.9+/-1.9 to 2.9+/-1.1 degrees in FE with 400N follower preload (67.4%), 8.0+/-1.7 to 2.5+/-1.1 degrees in LB, and 2.2+/-1.2 to 0.7+/-0.3 degrees in AR. A comparison between the PILLAR SA integrated fusion device versus 360 degrees fusion construct with spacer and bilateral pedicle screws was statistically significant in FE and LB. The 360 degrees fusion yielded motion of 1.0+/-0.5 degrees in FE, 1.0+/-0.8 degrees in LB (p0.05). CONCLUSIONS: The PILLAR SA resulted in motions of less than 3 degrees in all modes of motion and was not as motion restricting as the traditional 360 degrees using bilateral pedicle screws. The residual segmental motions compare very favorably with published biomechanical studies of other interbody integrated fusion devices. PMID- 25694932 TI - Treatment of contained lumbar disc herniations using radiofrequency assisted micro-tubular decompression and nucleotomy: four year prospective study results. AB - BACKGROUND: Patients with radiculopathy caused by contained disc herniations are less likely to have good outcomes following discectomy surgery than patients with disc herniations that are not contained. The author presents his 4-year results from a prospective trial regarding the efficacy and safety of a tubular transforaminal radiofrequency-assisted manual decompression and annulus modulation of contained disc herniations in 58 patients. METHODS: Fifty-eight patients with lumbar radiculopathy due to a contained disc herniation were enrolled in a prospective clinical study. Visual analog scores (VAS) for back pain and leg pain, quality of life assessment, Macnab criteria, and SF-12 were collected from patients before treatment, at 2-years and 4-years post-treatment. RESULTS: At 4 years, results were obtained from 47 (81%) of patients. Compared to mean pre- treatment assessments, mean 4-year VAS for back pain improved from 8.6 to 2.3 points, and mean VAS for leg pain improved from 7.8 to 2.3. Eighty-three percent of respondents reported that they were "satisfied" or "very satisifed" with their quality of life at 4-years as per SF-12. At 4 years, recurrence was noted in 3 (6.4%) of respondents and no complications were reported. CONCLUSIONS: The 2-year and 4-year study results are nearly identical, suggesting durable benefit out to 4 years. These results also suggest that in carefully selected patients with sustained contained disc herniations who have failed conservative treatments, manual decompression combined with radiofrequency-assisted decompression and annulus modulation are very likely to have good outcomes 4 years post-treatment. PMID- 25694933 TI - Free-hand placement of iliac screws for spinopelvic fixation based on anatomical landmarks: technical note. AB - BACKGROUND: The placement of iliac screws is a biomechanically sound method for the stabilization of long multi-segment lumbar constructs. Traditional techniques for the placement of iliac screws often involve either substantial iliac muscle dissection for visualization of screw trajectory based on bony landmarks, or alternatively the use of intra-operative imaging to visualize these landmarks and guide screw placement. We describe an alternative free-hand method of iliac screw placement, one that needs neither significant muscle dissection nor intra operative imaging. METHODS: We performed this technique in 10 consecutive patients. Patient demographics, spinal pathology, post-operative complications, and screw hardware characteristics are described. RESULTS: We have successfully used this technique for the placement 20 iliac screws based on anatomic landmarks in 10 consecutive patients. There were no cortical breeches of the ileum and no penetrations into the acetabulum on post-operative imaging. There were no instances of hardware failure. Two patients developed deep vein thromboses after surgery, 1 had a pulmonary embolism. CONCLUSIONS: Based on our limited experience to date, free-hand placement of iliac screws is both easy to perform and safe for the patient. Further study and validation using this technique is warranted. PMID- 25694934 TI - Idiopathic spinal cord herniation with duplicated dura mater and dorsal subarachnoid septum. Report of a case and review of the literature. AB - BACKGROUND: Idiopathic spinal cord herniation (ISCH) is a rare condition and its pathogenesis remains unclear. The purpose of this case report is to present an ISCH case with dorsal subarachnoid septum suggesting the pathogenesis of ISCH being adhesions from preexisting inflammation. METHODS: Single case report. RESULTS: A 60-year-old woman presented with Brown-Sequard syndrome below the level of T6. Magnetic resonance imaging revealed the thoracic spinal cord was displaced ventrally, and the dorsal subarachnoid space was enlarged and had a septum between the spinal cord and dura mater. Intraoperatively, the dorsal dura mater was seen to be adherent and the subarachnoid septum was identified after durotomy. The inner layer defect of the duplicated dura mater was found in the ventral dura mater, through which the spinal cord had herniated. After releasing the septum, the adhesions around the dura mater, and the hiatus, the spinal cord was reduced. CONCLUSIONS: The present case indicates that adhesions around the dura mater can be the pathogenesis of ISCH. PMID- 25694935 TI - Five and ten year follow-up on intradiscal ozone injection for disc herniation. AB - BACKGROUND: Disc herniation is the most common cause for spinal surgery and many clinicians employ epidural steroid injections with limited success. Intradiscal injection of ozone gas has been used as an alternative to epidural steroids and surgical discectomy. Early results are positive but long-term data are limited. METHODS: One hundred and eight patients with confirmed contiguous disc herniation were treated with intradiscal injection of ozone in 2002-2003. One-hundred seven patients were available for telephone follow-up at 5 years. Sixty patients were available for a similar telephone follow-up at ten years. Patients were asked to describe their clinical outcome since the injection. Surgical events were documented. MRI images were reviewed to assess the reduction in disc herniation at six months. RESULTS: MRI films demonstrated a consistent reduction in the size of the disc herniation. Seventy-nine percent of patients had a reduction in herniation volume and the average reduction was 56%. There were 19 patients that ultimately had surgery and 12 of them occurred in the first six months after injection. One of these 12 was due to surgery at another level. Two surgeries involved an interspinous spacer indicated by stenosis or DDD. All other surgeries were discectomies. Of the patients that avoided surgery 82% were improved at 5 years and 88% were improved at 10 years. Other than subsequent surgeries, no spine-related complications were experienced. CONCLUSIONS/LEVEL OF EVIDENCE: We conclude that ozone is safe and effective in approximately 75% of patients with disc herniation and the benefit is maintained through ten years. This is a retrospective review and randomized trials are needed. CLINICAL RELEVANCE: Intradiscal ozone injection may enable patients to address their pain without multiple epidural injections and surgery. The benefit of ozone is durable and does not preclude future surgical options. The risk reward profile for this treatment is favorable. PMID- 25694936 TI - Endoscopically guided foraminal and dorsal rhizotomy for chronic axial back pain based on cadaver and endoscopically visualized anatomic study. AB - BACKGROUND: Conventional fluoroscopically guided continuous radiofrequency (CRF) and pulsed Radiofrequency (PRF) lesioning of the medial branch, dorsal ramus, a standard technique to treat facet pain, is compared to an endoscopic visually guided technique. The endoscopic technique (Figure 1) is designed to ablate a larger area of the transverse process where the medial branch crosses to innervate the facet. Endoscopically guided visualization provides confirmation of nerve ablation or transection in the most common location of the branches of the dorsal ramus innervating the facet joint. Fig. 1 Surgical setup for ablation of the medial, intermediate and lateral branches of the dorsal ramus. MATERIALS AND METHOD: A retrospective non randomized study of 50 initial patients assessed the efficacy of endoscopic rhizotomy. Patients with lumbar spondylosis and facet arthrosis who had at least 50% pain relief by medial branch blocks met the inclusion criteria for the visualized, surgically directed endoscopic technique. A specially designed cannula and endoscope (Richard Wolf, GmBh) (Figure 2) was developed specifically for this purpose. After completion of the initial 50 patient pilot study in 2005, utilizing a low-temperature, ultra-high frequency (1.7-4.0 MHz) bipolar energy radiofrequency source (Elliquence Int, Hewlett, NY) that demonstrated efficacy, 400 subsequent patients were added to this retrospective study by May 2013. The surgical technique refinement was guided by cadaveric variations observed from additional cadaver dissections (Figure 3) and endoscopic visualization of foraminal nerves that revealed variable locations of the dorsal ramus, including the medial branch. The anatomic variations supported a need for visualized rhizotomy. The inclusion criteria also involved increasing the percentage of back pain relief from medial branch blocks to a base of 75% estimated improvement in order to overcome the variable subjectiveness of a 50% improvement threshold that served to disappoint a small percentage of patients who overestimated the reported 50% improvement in hopes that they would qualify for the endoscopic guided procedure. Fig. 2 Richard Wolf YESS Rhizotomy Set. The cannulas, endoscope, bitip and surgical bipolar RF probes by Elliquence are configured ergonomically to provide excellent focal length imaging to keep image in focus with the endoscope scope resting on cannula. The bitip probe cuts tissue, and the RF probe thermally ablates tissue efficiently.Fig. 3 Cadaver dissection of the dorsal ramus and its branches out- lining the areas where branches of the dorsal ramus may be visualized and ablated before it reaches the facet joint. RESULTS: At one year follow-up in the initial study design, VAS improved 6.2-2.5, and ODI 48-28. All patients had VAS improvement equal or greater than injection. The results remained constant with additional surgical cases that continued to improve when technique and visualized rhizotomy allowed for greater surgical exploration and ablation of the targeted zone where more than just the medial branch could be ablated. Approximately 10 percent of the patients returned at one and two year follow-up with mild recurrence of their axial back pain, but none to the original level of pain. Additional rhizotomy of the upper lumbar facets provided additional relief in selected patients. CONCLUSIONS / LEVEL OF EVIDENCE 3: The cadaver studies demonstrated considerable variability in the location of the medial and lateral branches of the dorsal ramus. Variability was most common cephalad to L3-4. The dorsal ramus and its nerve branches can also be visualized in the foramen ventral to the intertransverse ligament. Neuromas and entrapment of the dorsal ramus has been identified endoscopically, and confirmed by H and E slides (Figure 4). In the upper lumbar spine, we were not able to find the medial branch to the facets consistently at same location. The nerve to the facet joint did not always cross the transverse process. Some branches enter the facet joint before crossing the transverse process adjacent to the tip of the SAP (Figure 5). The nerve can be mistaken for a furcal nerve or foraminal ligament. Nerve Ablation at above L3-4 levels may require lesioning of the dorsal ramus or targeting the nerve innervation on the facet wall, pedicle or capsule. Fig. 4 This H and E slide of the biopsied specimen is consistent with a peripheral nerve fiber.Fig. 5 This foraminal view of a branch of the dorsal ramus is in the foramen at the level of the SAP. The nerve runs along the ventral lateral aspect of the superior facet to the tip, and can also run in the vicinity of the foraminal ligament. Endoscopic rasps, trephines, kerrisons, and burrs can be used for foraminoplasty. The nerve should be preserved, if possible, but transection of a branch of the dorsal ramus contributes to axial back pain relief. Branches of the dorsal ramus originates in the foramen before exiting to traverse the transverse process. These nerves are difficult to differentiate from furcal nerves arising from the spinal nerves. Palpating the nerve using local anesthesia can sometimes demonstrate a pain response, but not always, depending on the level of sedation and anesthetic use. CLINICAL RELEVANCE: Endoscopically guided facet rhizotomy provides more consistent ablation of the medial and lateral branches of the lumbar dorsal ramus compared to radiographically guided pulsed radiofrequency. The variations in the location of facet innervation can explain the variability of clinical results in fluoroscopically guided RF lesioning. This observation dictates a need for visually guided MIS procedure for best results. PMID- 25694937 TI - Changes in neuroforaminal height with 2 level axial presacral lumbar interbody fusion at L4-S1. AB - BACKGROUND: The objective was to examine the changes in neuroforaminal height at L4-L5 and L5-S1 after insertion and graduated foraminal distraction using the 2 level transsacral implant in a cadaveric model. METHODS: Discectomy and transsacral instrumentation was performed in six fresh human cadavers at L4-S1. The neuroforaminal height was measured at L4-L5 and L5-S1 before and after insertion of the implant and then at each stage of manual distraction. RESULTS: Mean L4-5 neuroforaminal height increased from 18.2 +/- 3.1mm to 20.3+/- 2.9mm (11%) on the left and from 18.8+/-2.8mm to 20.6+/- 2.3mm (12%) on the right (P<0.05). Mean L5-S1 neuroforaminal height increased from 15.7+/-3.0mm to 18.4 +/ 2.8mm (17%) on the left and from 15.6 +/-2.1mm to 18.3 +/-1.8mm (17%) on the right (P<0.05). When the neuroforaminal height was plotted against amount of rotation of the screw driver it was found that the neuroforaminal height at L5-S1 increased by 1mm on average for every complete revolution of the screw driver. At least 2 full rotations of the screw driver were achieved in all cadavers. CONCLUSIONS: The transsacral screw construct distracted the disc space and neuroforaminal height in a cadaveric spine model without soft tissue envelope. During the initial process, manual control of disc space distraction predictably correlated with the increase in the neuroforaminal height to a maximum. However, further research is needed to look at variables affecting disc space pliability, implant subsidence, in vivo application, and clinical benefit of this procedure. PMID- 25694938 TI - Safety and efficacy of bioabsorbable cervical spacers and low-dose rhBMP-2 in multi-level ACDF. AB - INTRODUCTION: Many options for interbody spacer and graft biologic exist for multilevel anterior cervical discectomy and fusion (ACDF). The objective of this study is to evaluate the safety and efficacy of a bioabsorbable cervical spacer (BCS) (Cornerstone HSR, Medtronic Sofamor Danek) filled with low-dose rhBMP-2 (INFUSE, Medtronic Sofamor Danek) in multilevel ACDF. METHODS: 72 consecutive patients treated with a multi-level ACDF using BCS and rhBMP-2 (dosage between 0.5 to 0.7 mg per level) at a single institution were followed in an IRB approved, prospective registry. A total of 187 levels were treated (mean = 2.6), with 37 (51%) patients undergoing a 2-level procedure and 35 (49%) undergoing a 3 or 4-level procedure. Statistical analysis included frequency and ANOVA tests. Significance was accepted for p < 0.001. RESULTS: Average follow-up was 13.8 months. Mean patient age was 55.3 years, 70.8% were female, and 16.7% had undergone a previous cervical procedure. 29 (40%) patients had cervical spondylitic myelopathy, 27 (38%) had radiculopathy, 15 (21%) had a combination of both, and 1 (1%) patient had a previous nonunion. A total of 187 levels were treated with an ACDF, with 37 (51%) 2-level, 27 (38%) 3-level, and 8 (11%) 4 level cases. Average OR time, EBL, and LOS were 144 minutes, 49 mL, and 1.1 days, respectively. Major complications occurred in 5 (7%) patients: 2 returns to OR (1 nonunion, 1 seroma), 1 recurrent laryngeal nerve injury, and 2 hospital readmissions for excessive pre-vertebral swelling/dysphagia treated with steroids and observation. Minor complications occurred in 3 (4%) patients: 2 exacerbations of pre-existing medical conditions (1 atrial fibrillation, 1 COPD), and 1 hospital readmission for nausea/ headache due to narcotics. At last follow-up, NDI improved 43% from 43.6% to 25.0%. VAS neck pain improved 60% from 5.5 to 2.2 and VAS arm pain improved 52% from 5.8 to 2.6. SF-36 PCS improved 24% from 37.5 to 46.3 and MCS improved 18% from 43.2 to 50.9. All clinical improvements were statistically significant (p < 0.001). Patient satisfaction was high, with 97% of patients reported being satisfied with their surgical outcome, and 90% would undergo the procedure again. CONCLUSION: Patients in this series experienced significant clinical improvements, low complication rates, and high patient satisfaction. Symptomatic pseudoarthrosis was rare. BCS filled with low-dose rhBMP-2 appears to be a safe and effective option in multilevel ACDF. Further investigation is warranted. PMID- 25694939 TI - Endoscopic foraminal decompression for failed back surgery syndrome under local anesthesia. AB - BACKGROUND: The most common causes of failed back surgery are residual or recurrent herniation, foraminal fibrosis and foraminal stenosis that is ignored, untreated, or undertreated. Residual back ache may also be from facetal causes or denervation and scarring of the paraspinal muscles.(1-6) The original surgeon may advise his patient that nothing more can be done on the basis of his opinion that the nerve was visually decompressed by the original surgery, supported by improved post-op imaging and follow-up studies such as EMG and conduction velocity studies. Post-op imaging or electrophysiological assessment may be inadequate to explain all the reasons for residual or recurrent symptoms. Treatment of Failed back surgery by repeat traditional open revision surgery usually incorporates more extensive decompression causing increased instability and back pain, therefore necessitating fusion. The authors, having limited their practice to endoscopic MIS surgery over the last 15-20 years, report on their experience gained during that period to relieve pain by endoscopically visualizing and treating unrecognized causative patho-anatomy in FBSS.(7.) METHODS: Thirty consecutive patients with FBSS presenting with back and leg pain that had supporting imaging diagnosis of lateral stenosis and /or residual / recurrent disc herniation, or whose pain complaint was supported by relief from diagnostic and therapeutic injections (Figure 1), were offered percutaneous transforaminal endoscopic discectomy and foraminoplasty over a repeat open procedure. Each patient sought consultation following a transient successful, partially successful or unsuccessful open translaminar surgical treatment for disc herniation or spinal stenosis. Endoscopic foraminoplasty was also performed to either decompress the bony foramen for foraminal stenosis, or foraminoplasty to allow for endoscopic visual examination of the affected traversing and exiting nerve roots in the axilla, also known as the "hidden zone" of Macnab (Figure 2).(8, 9) The average follow up time was, average 40 months, minimum 12 months. Outcome data at each visit included Macnab, VAS and ODI. Fig. 1A diagnostic and therapeutic epidural gram may help identify unrecognized lateral recess stenosis underestimated by MRI. An excellent result from a therapeutic block lends excellent prognosis for a more lasting and "permanent" result from transforaminal endoscopic lateral recess decompression.Fig. 2Kambin's Triangle provides access to the "hidden zone" of Macnab by foraminoplasty. The foramen and lateral recess is decompressed by removing the ventral aspect and tip of the superior articular process to gain access to the axilla between the traversing and exiting nerve. FBSS contains patho-anatomy in the axilla between the traversing and exiting nerve that hides the pain generators of FBSS. RESULTS: The average pre-operative VAS improved from 7.2 to 4.0, and ODI 48% to 31%. While temporary dysesthesia occurred in 4 patients in the early post-operative period, all were happy, as all received additional relief of their pre-op symptoms. They were also relieved to be able to avoid "open" decompression or fusion surgery. CONCLUSIONS / LEVEL OF EVIDENCE 3: The transforaminal endoscopic approach is effective for FBSS due to residual/recurrent HNP and lateral stenosis. Failed initial index surgery may involve failure to recognize patho-anatomy in the axilla of the foramen housing the traversing and the exiting nerve, including the DRG, which is located cephalad and near the tip of SAP.(10) The transforaminal endoscopic approach effectively decompresses the foramen and does not further destabilize the spine needing stabilization.(11) It also avoids going through the previous surgical site. CLINICAL RELEVANCE: Disc narrowing as a consequence of translaminar discectomy and progressive degenerative narrowing and spondylolisthesis (Figure 3) as a natural history of degenerative disc disease can lead to central and lateral stenosis. The MRI may underestimate the degree of stenosis from a bulging or a foraminal disc protrusion and residual lateral recess stenosis. Pain can be diagnosed and confirmed by evocative discography and by clinical response to transforaminal diagnostic and therapeutic steroid injections.(12) Foraminal endoscopic decompression of the lateral recess is a MIS technique that does not "burn bridges" for a more conventional approach and it adds to the surgical armamentarium of FBSS. Fig. 3Cadaver Illustration of Foraminal Stenosis (courtesy of Wolfgang Rauschning). As the disc narrows, the superior articular process impinges on the exiting nerve and DRG, creating lateral recess stenosis, lumbar spondylosis, and facet arthrosis. PMID- 25694940 TI - The "inside out" transforaminal technique to treat lumbar spinal pain in an awake and aware patient under local anesthesia: results and a review of the literature. AB - Surgical management of back and leg pain is evolving and changing due to a better understanding of the patho-anatomy well correlated with its pathophysiology. Pain is better understood with in vivo visualization and probing of the pain generators using an endoscopic access rather than just relying on symptoms diagram and image correlation. This has resulted in a shared decision making involving patient and surgeon, focused on a broader spectrum of surgical as well as non-surgical treatments, and not just masking the pain generator. It has moved away from decisions based on diagnostic images alone, that, while noting the image alterations, cannot explain the pain experienced by each individual as images do not always show variations in nerve supply and patho-anatomy. The ability to isolate and visualize "pain" generators in the foramen and treating persistent pain by visualizing inflammation and compression of nerves, serves as the basis for transforaminal endoscopic (TFE) surgery. This has also resulted in better pre surgical planning with more specific and defined goals in mind. The "Inside out" philosophy of TFE surgery is safe and precise. It provides basic access to the disc and foramen to cover a large spectrum of painful pathologies. PMID- 25694941 TI - The surgical treatment of single level multi-focal subarticular and paracentral and/or far-lateral lumbar disc herniations: the single incision full endoscopic approach. AB - BACKGROUND: Surgery for same level multi-focal extruded lumbar disc herniations is technically challenging and the optimal method controversial. The subarticular disc herniation may pose the most challenging subtype requiring partial or complete facetectomy with or without fusion. The far-lateral disc herniation, often treated using a Wiltse approach, can also be difficult to access especially in the obese patient. When both the subarticular and far-lateral subtypes are simultaneously present at the same level with or without a paracentral disc herniation, a total facetectomy and interbody fusion (TLIF) or a total disc replacement (TDR) may be necessary. Endoscopic surgical techniques may reduce the need for these more invasive methods. METHODS: Fifteen patients (6 male and 9 female) who had same level multi-focal (subarticular as well as far-lateral and/or paracentral) extruded disc herniations underwent single incision unilateral endoscopic disc excision by the same surgeon at a single institution. Patients were prospectively followed for an average of 15.3 months (range 14-18 months) and outcomes were evaluated radiographically and clinically (Visual Analogue Scale (VAS) and Oswestry Disability Index (ODI). RESULTS: The mean operative time was 52 minutes with minimal blood loss in all cases. Fourteen of the 15 patients were discharged to home on the day of their surgery. The mean ODI and leg VAS scores improved from 22.9 +/- 3.2 to 12.9 +/- 2.7 (p < 0.005), and from 8.6 +/- 1.6 to 2.1 + 0.4 (p < 0.005), respectively. CONCLUSIONS: After an average of 15.3 months of follow-up, the clinical and radiographic results of full endoscopic surgical treatment of single level multi-focal (subarticular as well as far-lateral and/or paracentral) disc herniations are excellent. This study is a case series with mid-term follow-up (Level IV). CLINICAL RELEVANCE: Foraminal and extra-foraminal full endoscopic decompression appears to offer a safe minimally invasive solution to a complex pathologic problem. PMID- 25694942 TI - ISASS policy statement - minimally invasive sacroiliac joint fusion. PMID- 25694943 TI - Preoperative embolization versus local hemostatic agents in surgery of hypervascular spinal tumors. AB - BACKGROUND: Currently, there is no consensus about how to reduce the intraoperative risk of hemorrhage in spinal decompression surgery of hypervascular spinal tumors, such as aggressive hemangioma, multiple myeloma, plasmacytoma, metastasis of renal cell carcinoma. METHODS: A retrospective study of 110 patients, operated in our institute was held in the period between 2003 and 2013. There were 69 male and 41 female patients with extradural hypervascular spinal tumor. The study included 61 patients with metastasis of renal cell carcinoma, 27 with multiple myeloma, 15 with plasmacytoma and 7 with aggressive hemangioma. The first group included 57 patients who underwent preoperative tumor embolization. The second group consisted of 53 patients, which were treated surgically using intraoperative local hemostatic agents. We performed 2 types of treatment options: palliative decompression and total spondylectomy. The first group was divided into two subgroups: 30 patients with palliative decompression (1PD) and 27 with total spondylectomy (1TS). In the second group there were: 28 patients with palliative decompression (2PD) and 25 with total spondylectomy (2TS). The parameters under evaluation were the blood loss volume, drainage loss, operation time, hemoglobin level, possible complications and time of hospital stay. RESULTS: The average intraoperative blood loss for all embolized patients was slightly less than in subgroups with local hemostatic agents. No significant difference in blood loss volume was found between groups 1PD and 2PD (p > 0.05). In groups 1TS and 2TS, we did get significant difference (p < 0.05). Statistically significant difference in the average drainage loss was found between two methods of hemostasis in both subgroups (p < 0.05). The operation time was not significantly different between groups. Postoperative hemoglobin level reduce is almost equal in both groups of patients. Postoperative complications were also nearly equal in the groups. The average hospital stay was significantly less (p < 0.05) in groups with 2PD and 2TS. CONCLUSIONS: The research proves that for patients with hypervascular spinal tumors, who underwent palliative decompression, there is no significant difference between two methods of reducing blood loss. Therefore, we do not see reasons to use expensive and risky procedure of embolization for such patients. While for patients with total spondylectomy preoperative embolization is efficient to reduce intraoperative bleeding. PMID- 25694944 TI - ISASS Policy Statement - Cervical Artificial Disc. AB - Morgan Lorio, MD, FACS, Chair, ISASS Task Force on Coding & Reimbursement The ISASS Task Force reached out to Domagoj Coric, MD to provide a timely summation on cervical disc arthroplasty given his special interest and recent IASP championship of this innovative technology to insure enhanced spine patient access. The ISASS Task Force is pleased with this step towards published ISASS societal policy and applauds Dr. Coric's effort; if ISASS is to continue to succeed we must continually harness the voluntary talents and energies of our members with gratitude. PMID- 25694945 TI - ISASS Policy Statement - cervical interbody. AB - Morgan Lorio, MD, FACS, Chair, ISASS Task Force on Coding & Reimbursement In 2011, CPT code 22551 was revised to combine or bundle CPT codes 63075 and 22554 when both procedures were performed at the same site/same surgical session. The add on code +22552 is used to report each additional interspace. 2014 heralded a downward pressure on this now prime target code (for non-coverage?) 22551 through an egregious insurer attempt to redefine cervical arthrodesis, effectively removing spine surgeon choice and altering best practice without clinical evidence. Currently, spine surgeons are equally split on the use of allograft versus cages for cervical arthrodesis. Structural allograft, CPT code 20931, is reported once per same surgical session, regardless of the number of allografts used. CPT code 22851 which is designated solely for cage use, has a higher reimbursement than structural allograft, and may be reported for each inner space. Hence, the rationale behind why some payers wrongly consider "spine cages NOT medically necessary for cervical fusion." A timely consensus paper summarizing spine surgeon purview on the logical progressive evolution of cervical interbody fusion for ISASS/IASP membership was strategically identified as an advocacy focus by the ISASS Task Force. ISASS appreciates the authors' charge with gratitude. This article has both teeth and transparent clinical real world merit. PMID- 25694946 TI - Indications for lumbar total disc replacement: selecting the right patient with the right indication for the right total disc. AB - SUMMARY OF BACKGROUND DATA: As with any surgery, care should be taken to determine patient selection criteria for lumbar TDR based on safety and optimizing outcome. These goals may initially be addressed by analyzing biomechanical implant function and early clinical experience, ongoing evaluation is needed to refine indications. OBJECTIVE: The purpose of this work was to synthesize information published on general indications for lumbar TDR. A secondary objective was to determine if indications vary for different TDR designs. METHODS: A comprehensive literature search was conducted to identify lumbar TDR articles. Articles were reviewed and patient selection criteria and indications were synthesized. RESULTS: With respect to safety, there was good agreement in the literature to exclude patients with osteopenia/osteoporosis or fracture. Risk of injury to vascular structures due to the anterior approach was often addressed by excluding patients with previous abdominal surgery in the area of disc pathology or increased age. The literature was very consistent on the primary indication for TDR being painful disc degeneration unresponsive to at least 6 months of nonoperative care. Literature investigating the impact of previous spine surgery was mixed; however, prior surgery was not necessarily a contra-indication, provided the patient otherwise met selection criteria. The literature was mixed on setting a minimum preoperative disc height as a selection criterion. There were no publications investigating whether some patients are better/worse candidates for specific TDR designs. Based on the literature a proposal for patient selection criteria is offered. CONCLUSIONS: Several TDR indications and contra-indications are widely accepted. No literature addresses particular TDR design being preferable for some patients. As with any spine surgery, ongoing evaluation of TDR outcomes will likely lead to more detailed general and device design specific indications. PMID- 25694947 TI - A polarization-sensitive light field imager for multi-channel angular spectroscopy of light scattering in biological tissues. AB - BACKGROUND: Angular spectroscopy of light scattering can be used for quantitative analysis of cellular and subcellular properties, and thus promises a noninvasive methodology for in vivo assessment cellular integrity to complement in vitro histological examination. Spatial information is essential for accurate identification of localized abnormalities. However, conventional angular spectroscopy systems only provide single-channel measurement, which suffers from poor spatial resolution or requires time-consuming scanning over extended area. The purpose of this study was to develop a multi-channel angular spectroscopy for light field imaging in biological tissues. MATERIALS AND METHODS: A microlens array (MLA) (8*8) based light field imager for 64-channel angular spectroscopy was developed. A pair of crossed polarizers was employed for polarization sensitive recording to enable quantitative measurement at high signal specificity and sensitivity. The polarization-sensitive light field imager enables rapid measurement of multiple sampling volumes simultaneously at 18 MUm spatial resolution and 3 degrees angular-resolution. Comparative light field imaging and electrophysiological examination of freshly isolated and physiologically deteriorated lobster leg nerves have been conducted. RESULTS: Two-dimensional (2D) polarization-sensitive scattering patterns of the fresh nerves were highly elliptical, while they gradually lost the ellipticity and became rotationally symmetric (i.e., circular) as the nerves physiologically deteriorated due to repeated electrical stimulations. Characterized parameters, i.e., the ellipticity and the scattering intensity, rendered spatially various characteristics such as different values and deteriorating rates. CONCLUSIONS: The polarization-sensitive light field imager is able to provide multi-channel angular spectroscopy of light scattering with both spatial and angular resolutions. The light scattering properties of nerves are highly dependent on the orientation of nerves and their physiological status. Further development of polarization-sensitive multi-channel angular spectroscopy may promise a methodology for rapid and reliable identification of localized abnormalities in biological tissues. PMID- 25694948 TI - Ultrasound modulated optical tomography contrast enhancement with non-linear oscillation of microbubbles. AB - BACKGROUND: Ultrasound modulated optical tomography (USMOT) is an imaging technique used to provide optical functional information inside highly scattering biological tissue. One of the challenges facing this technique is the low image contrast. METHODS: A contrast enhancement imaging technique based on the non linear oscillation of microbubbles is demonstrated to improve image contrast. The ultrasound modulated signal was detected using a laser pulse based speckle contrast detection system. Better understanding of the effects of microbubbles on the optical signals was achieved through simultaneous measurement of the ultrasound scattered by the microbubbles. RESULTS: The length of the laser pulse was found to affect the system response of the speckle contrast method with shorter pulses suppressing the fundamental ultrasound modulated optical signal. Using this property, image contrast can be enhanced by detection of the higher harmonic ultrasound modulated optical signals due to nonlinear oscillation and destruction of the microbubbles. Experimental investigations were carried out to demonstrate a doubling in contrast by imaging a scattering phantom containing an embedded silicone tube with microbubbles flowing through it. CONCLUSIONS: The contrast enhancement in USMOT resulting from the use of ultrasound microbubbles has been demonstrated. Destruction of the microbubbles was shown to be the dominant effect leading to contrast improvement as shown by simultaneously detecting the ultrasound and speckle contrast signals. Line scans of a microbubble filled silicone tube embedded in a scattering phantom demonstrated experimentally the significant image contrast improvement that can be achieved using microbubbles and demonstrates the potential as a future clinical imaging tool. PMID- 25694949 TI - Image segmentation for integrated multiphoton microscopy and reflectance confocal microscopy imaging of human skin in vivo. AB - BACKGROUND: Non-invasive cellular imaging of the skin in vivo can be achieved in reflectance confocal microscopy (RCM) and multiphoton microscopy (MPM) modalities to yield complementary images of the skin based on different optical properties. One of the challenges of in vivo microscopy is the delineation (i.e., segmentation) of cellular and subcellular architectural features. METHODS: In this work we present a method for combining watershed and level-set models for segmentation of multimodality images obtained by an integrated MPM and RCM imaging system from human skin in vivo. RESULTS: Firstly, a segmentation model based on watershed is introduced for obtaining the accurate structure of cell borders from the RCM image. Secondly,, a global region based energy level-set model is constructed for extracting the nucleus of each cell from the MPM image. Thirdly, a local region-based Lagrange Continuous level-set approach is used for segmenting cytoplasm from the MPM image. CONCLUSIONS: Experimental results demonstrated that cell borders from RCM image and boundaries of cytoplasm and nucleus from MPM image can be obtained by our segmentation method with better accuracy and effectiveness. We are planning to use this method to perform quantitative analysis of MPM and RCM images of in vivo human skin to study the variations of cellular parameters such as cell size, nucleus size and other mophormetric features with skin pathologies. PMID- 25694950 TI - Longitudinal label-free optical-resolution photoacoustic microscopy of tumor angiogenesis in vivo. AB - BACKGROUND: Optical-resolution photoacoustic microscopy (OR-PAM) is a high resolution imaging technology capable of label-free imaging of the morphology and functions of the microvasculature in vivo. Previous studies of angiogenesis by OR PAM were carried out primarily with transgenic mice and the mouse ear model. While important findings have been generated using this approach, the application of OR-PAM to the more widely used subcutaneous dorsal tumor models remains challenging, largely due to the respiratory and cardiac motion artifacts, as well as the protruding tumor contours. METHODS AND MATERIALS: A noninvasive dorsal skin-fold (N-DSF) model, along with adaptive z-scanning and a corresponding experimental protocol, is developed. Mammary carcinoma cells (4T1) were administered subcutaneously to the backs of female BALB/c mice for tumor inoculation. The mice were anesthetized using a mixture of isofluorane and oxygen. RESULTS: In vivo OR-PAM of angiogenesis with subcutaneous dorsal tumor models in mice has been demonstrated. To test the performance of this method, we have monitored the growth of 4T1 mouse mammary carcinoma in BALB/c mice over a period of 9 days. The major features of tumor angiogenesis, including the change of vascular tortuosity, the dilation of vessel diameters, and the increase of blood supply, have been clearly captured with OR-PAM. CONCLUSIONS: In combination with N-DSF model, OR-PAM has demonstrated outstanding capacity to provide label free monitoring of angiogenesis in tumor. Thus, OR-PAM is of great potential to find broad biomedical applications in the pathophysiological studies of tumor and the treatments for anti-angiogenesis. PMID- 25694951 TI - Nonlinear optical microscopy for immunoimaging: a custom optimized system of high speed, large-area, multicolor imaging. AB - BACKGROUND: The nonlinear optical microscopy has become the current state-of-the art for intravital imaging. Due to its advantages of high resolution, superior tissue penetration, lower photodamage and photobleaching, as well as intrinsic z sectioning ability, this technology has been widely applied in immunoimaging for a decade. However, in terms of monitoring immune events in native physiological environment, the conventional nonlinear optical microscope system has to be optimized for live animal imaging. Generally speaking, three crucial capabilities are desired, including high-speed, large-area and multicolor imaging. Among numerous high-speed scanning mechanisms used in nonlinear optical imaging, polygon scanning is not only linearly but also dispersion-freely with high stability and tunable rotation speed, which can overcome disadvantages of multifocal scanning, resonant scanner and acousto-optical deflector (AOD). However, low frame rate, lacking large-area or multicolor imaging ability make current polygonbased nonlinear optical microscopes unable to meet the requirements of immune event monitoring. METHODS: We built up a polygon-based nonlinear optical microscope system which was custom optimized for immunoimaging with high-speed, large-are and multicolor imaging abilities. RESULTS: Firstly, we validated the imaging performance of the system by standard methods. Then, to demonstrate the ability to monitor immune events, migration of immunocytes observed by the system based on typical immunological models such as lymph node, footpad and dorsal skinfold chamber are shown. Finally, we take an outlook for the possible advance of related technologies such as sample stabilization and optical clearing for more stable and deeper intravital immunoimaging. CONCLUSIONS: This study will be helpful for optimizing nonlinear optical microscope to obtain more comprehensive and accurate information of immune events. PMID- 25694952 TI - Imaging endocervical mucus anatomy and dynamics in macaque female reproductive track using optical coherence tomography. AB - BACKGROUND: Endocervical mucus acts as an important barrier to block human immunodeficiency virus (HIV) infection and other sexually transmitted diseases (STDs). Disruption of the mucus layer increases the risk of infection for females. An effective method to image the mucus properties can serve as a pre screening step to risk-stratify the susceptible population. METHODS: We proposed to use optical coherence tomography (OCT) to quantitatively measure the thickness of endocervical mucus. We used a home-built bench-top OCT system to monitor the dynamic change in mucus thickness of a cultivated sample. We also fabricated a prototype endoscopic OCT probe to demonstrate potential in situ applications. RESULTS: We observed a 200% increase in the endocervical mucus thickness after cultivating in 37 degrees C phosphate buffered saline solution for 30 minutes. During mucus hydrolysis, we found that mucus layer thickness decreased to about 60% of its original value after applying neuraminidase. Three dimensional volumetric image of intact macaque inner vaginal wall was also acquired. CONCLUSIONS: We demonstrated that OCT can quantitatively measure the endocervical mucus thickness and its dynamics in ex vivo experiments. Endoscopic OCT has the potential to resolve fine structures inside macaque female reproductive track (FRT) for in vivo applications. PMID- 25694953 TI - The application of backscattered ultrasound and photoacoustic signals for assessment of bone collagen and mineral contents. AB - BACKGROUND: This study examines the backscattered ultrasound (US) and back propagating photoacoustic (PA) signals from trabecular bones, and their variations with reduction in bone minerals and collagen content. While the collagen status is directly related to the strength of the bone, diagnosis of its condition using US remains a challenge. METHODS: For both PA and US methods, coded-excitation signals and matched filtering were utilized to provide high sensitivity of the detected signal. The optical source was a 805-nm CW laser and signals were detected employing a 2.2-MHz ultrasonic transducer. Bone decalcification and decollagenization were induced with mild ethylenediaminetetraacetic acid (EDTA) and sodium hypochlorite solutions, respectively. RESULTS: The PA and US signals were measured on cattle bones, and apparent integrated backscatter/back-propagating (AIB) parameters were compared before and after demineralization and decollagenization. CONCLUSIONS: The results show that both PA and US are sensitive to mineral changes. In addition, PA is also sensitive to changes in the collagen content of the bone, but US is not significantly sensitive to these changes. PMID- 25694954 TI - Tripling the detection view of high-frequency linear-array-based photoacoustic computed tomography by using two planar acoustic reflectors. AB - BACKGROUND: Linear-array-based photoacoustic computed tomography (PACT) suffers from a limited view. Circular scanning does increase the detection view angle but is time-consuming. Therefore, it is desirable to increase the detection view angle of linear-array-based PACT without sacrificing imaging speed. METHODS: Two planar acoustic reflectors placed at 120 degrees to each other were added to a linear-array-based PACT system. Each reflector redirects originally undetectable photoacoustic waves back to the transducer array elements, and together they triple the original detection view angle of the PACT system. RESULTS: Adding two reflectors increased the detection view angle from 80 to 240 degrees. As a comparison, a single-reflector PACT has a detection view angle of only 160 degrees. A leaf skeleton phantom with a rich vascular network was imaged with the double-reflector PACT, and most of its features were recovered. CONCLUSIONS: The two acoustic reflectors triple the detection view angle of a linear-array-based PACT without compromising the original imaging speed. This nearly full-view detection capability produces higher-quality images than single-reflector PACT or conventional PACT without reflectors. PMID- 25694955 TI - In vivo imaging rhodopsin distribution in the photoreceptors with nano-second pulsed scanning laser ophthalmoscopy. AB - BACKGROUND: Rhodopsin is a biomarker for the function of rod photoreceptors, the dysfunction of which is related to many blinding diseases like retinitis pigmentosa and age-related macular degeneration. Imaging rhodopsin quantitatively may provide a powerful clinical tool for diagnosis of these diseases. To map rhodopsin distribution accurately in the retina, absorption by rhodopsin intermediates need to be minimized. METHODS AND MATERIALS: We developed nano second pulsed scanning laser ophthalmoscopy (SLO) to image rhodopsin distribution in the retina. The system takes advantage of the light-induced shift of rhodopsin absorption spectra, which in turn affects the fundus spectral reflection before and after photo-bleaching. By imaging the retina twice, one in the dark-adapted state and the other one in the light-adapted state, the rhodopsin absorption change can be calculated from the differential image, which is a function of the rhodopsin concentration in the rod photoreceptors. RESULTS: The system was successfully applied to in vivo imaging of rat retina in different bleaching conditions to verify its feasibility. Our studies showed that the differential image between the dark- and light-adapted states represents rhodopsin distribution in the retina. We also conducted a dynamic bleaching experiment to prove the importance of reducing light absorption of rhodopsin intermediates. CONCLUSIONS: The preliminary results showed that our nano-second pulsed-light SLO is promising in imaging the functional biomarker of the rod photoreceptors. By using nanosecond pulsed laser, in which one laser pulse generates one pixel of the image, the absorption of rhodopsin intermediates can be reduced. PMID- 25694956 TI - Real-time automated thickness measurement of the in vivo human tympanic membrane using optical coherence tomography. AB - BACKGROUND: Otitis media (OM), an infection in the middle ear, is extremely common in the pediatric population. Current gold-standard methods for diagnosis include otoscopy for visualizing the surface features of the tympanic membrane (TM) and making qualitative assessments to determine middle ear content. OM typically presents as an acute infection, but can progress to chronic OM, and after numerous infections and antibiotic treatments over the course of many months, this disease is often treated by surgically inserting small tubes in the TM to relieve pressure, enable drainage, and provide aeration to the middle ear. Diagnosis and monitoring of OM is critical for successful management, but remains largely qualitative. METHODS: We have developed an optical coherence tomography (OCT) system for high-resolution, depth-resolved, cross-sectional imaging of the TM and middle ear content, and for the quantitative assessment of in vivo TM thickness including the presence or absence of a middle ear biofilm. A novel algorithm was developed and demonstrated for automatic, real-time, and accurate measurement of TM thickness to aid in the diagnosis and monitoring of OM and other middle ear conditions. The segmentation algorithm applies a Hough transform to the OCT image data to determine the boundaries of the TM to calculate thickness. RESULTS: The use of OCT and this segmentation algorithm is demonstrated first on layered phantoms and then during real-time acquisition of in vivo OCT from humans. For the layered phantoms, measured thicknesses varied by approximately 5 um over time in the presence of large axial and rotational motion. In vivo data also demonstrated differences in thicknesses both spatially on a single TM, and across normal, acute, and chronic OM cases. CONCLUSIONS: Real time segmentation and thickness measurements of image data from both healthy subjects and those with acute and chronic OM demonstrate the use of OCT and this algorithm as a robust, quantitative, and accurate method for use during real-time in vivo human imaging. PMID- 25694957 TI - Image reconstruction of the absorption coefficients with l 1-norm minimization from photoacoustic measurements. AB - BACKGROUND: The photoacoustic (PA) imaging by considering light propagation into image reconstruction process can provide quantitative information of photon absorbers, such as hemoglobin and exogenous dyes, and to improve their imaging contrasts. METHODS: A 2D image reconstruction of the distribution of the light absorption coefficient from the PA measurements with light source and ultrasound transducer placed at the identical position was tested. The PA pressures were formulated with the PA wave equation and the photon diffusion equation. The relation between the PA pressure and the absorption coefficient was linearized. The image reconstruction was carried out by minimizing the squared error between the measured and calculated PA signals. The l 1-norm of the reconstructed image was simultaneously minimized to improve the localization of the reconstructed target in the image. The image reconstruction with the l 1-norm minimization was compared to that with the Tikhonov regularization by numerical simulation and phantom experiment. In phantom experiment, an aqueous solution of the intralipid and the indocyanine green was used as the measured object. The PA probe had optical fiber for illumination and piezoelectric film for detection placed at the identical position. RESULTS: The l 1-norm minimization reconstructed more localized target than the Tikhonov regularization. CONCLUSIONS: The l 1-norm minimization is useful for the sparse PA image reconstruction. PMID- 25694958 TI - Assessment of oxygen saturation in retinal vessels of normal subjects and diabetic patients with and without retinopathy using Flow Oximetry System. AB - PURPOSE: To assess oxygen saturation (StO2) in retinal vessels of normal subjects and diabetic patients with and without retinopathy using the modified version of the Flow Oximetry System (FOS) and a novel assessment software. METHODS: The FOS and novel assessment software were used to determine StO2 levels in arteries and veins located between 1 and 2 mm from the margin of the optic disc and in the macular area. RESULTS: Eighteen normal subjects, 15 diabetics without diabetic retinopathy (DM no DR), and 11 with non-proliferative diabetic retinopathy (NPDR) were included in final analysis. The mean [+/- standard deviation (SD)] StO2 in retinal arteries was 96.9%+/-3.8% in normal subjects; 97.4%+/-3.7% in DM no DR; and 98.4%+/-2.0% in NPDR. The mean venous StO2 was 57.5%+/-6.8% in normal subjects; 57.4%+/-7.5% in DM no DR; and 51.8%+/-6.8% in NPDR. The mean arterial and venous StO2 across the three groups were not statistically different (P=0.498 and P=0.071, respectively). The arterio-venous differences between the three study groups, however, were found to be statistically significant (P=0.015). Pairwise comparisons have demonstrated significant differences when comparing the A-V difference in the NPDR group to either normal subjects (P=0.02) or diabetic patients without DR (P=0.04). CONCLUSIONS: The arterio-venous difference was greater, and statistically significant, in patients with NPDR when compared to normal subjects and to patients with diabetes and no retinopathy. The mean venous StO2 was lower, but not statistically significant, in NPDR compared with diabetics without retinopathy and with normal subjects. PMID- 25694959 TI - Cranial window implantation on mouse cortex to study microvascular change induced by cocaine. AB - Cocaine-induced stroke is among the most serious medical complications associated with cocaine's abuse. However, the extent to which chronic cocaine may induce silent microischemia predisposing the cerebral tissue to neurotoxicity has not been investigated; in part, because of limitations of current neuroimaging tools, that is, lack of high spatiotemporal resolution and sensitivity to simultaneously measure cerebral blood flow (CBF) in vessels of different calibers quantitatively and over a large field of view (FOV). Optical coherence tomography (OCT) technique allows us to image three dimensional (3D) cerebrovascular network (including artery, vein, and capillary), and provides high resolution angiography of the cerebral vasculature and quantitative CBF velocity (CBFv) within the individual vessels in the network. In order to monitor the neurovascular changes from an in vivo brain along with the chronic cocaine exposure, we have developed an approach of implanting a cranial window on mouse brain to achieve long-term cortical imaging. The cranial window was implanted on sensorimotor cortex area in two animal groups, i.e., control group [saline treatment, ~0.1 cc/10 g/day, intraperitoneal injection (i.p.)] and chronic cocaine group (cocaine treatment, 30 mg/kg/day i.p.). After implantation, the cortex of individual animal was periodically imaged by OCT and stereoscope to provide angiography and quantitative CBFv of the cerebral vascular network, as well as the surface imaging of the brain. We have observed vascular hemodynamic changes (i.e., CBFv changes) induced by the cranial preparation in both animal groups, including the inflammatory response of brain shortly after the surgery (i.e., <5 days) followed by wound-healing process (i.e., >5 days) in the brain. Importantly, by comparing with the control animals, the surgical-related vascular physiology changes in the cortex can be calibrated, so that the cocaine-induced hemodynamic changes in the neurovasculature can be determined in the cocaine animals. Our results demonstrate that this methodology can be used to explore the neurovascular functional changes induced by the brain diseases such as drug addiction. PMID- 25694960 TI - High-resolution harmonic motion imaging (HR-HMI) for tissue biomechanical property characterization. AB - BACKGROUND: Elastography, capable of mapping the biomechanical properties of biological tissues, serves as a useful technique for clinicians to perform disease diagnosis and determine stages of many diseases. Many acoustic radiation force (ARF) based elastography, including acoustic radiation force impulse (ARFI) imaging and harmonic motion imaging (HMI), have been developed to remotely assess the elastic properties of tissues. However, due to the lower operating frequencies of these approaches, their spatial resolutions are insufficient for revealing stiffness distribution on small scale applications, such as cancerous tumor margin detection, atherosclerotic plaque composition analysis and ophthalmologic tissue characterization. Though recently developed ARF-based optical coherence elastography (OCE) methods open a new window for the high resolution elastography, shallow imaging depths significantly limit their usefulness in clinics. METHODS: The aim of this study is to develop a high resolution HMI method to assess the tissue biomechanical properties with acceptable field of view (FOV) using a 4 MHz ring transducer for efficient excitation and a 40 MHz needle transducer for accurate detection. Under precise alignment of two confocal transducers, the high-resolution HMI system has a lateral resolution of 314 um and an axial resolution of ?147 um with an effective FOV of 2 mm in depth. RESULTS: The performance of this high resolution imaging system was validated on the agar-based tissue mimicking phantoms with different stiffness distributions. These data demonstrated the imaging system's improved resolution and sensitivity on differentiating materials with varying stiffness. In addition, ex vivo imaging of a human atherosclerosis coronary artery demonstrated the capability of high resolution HMI in identifying layer-specific structures and characterizing atherosclerotic plaques based on their stiffness differences. CONCLUSIONS: All together high resolution HMI appears to be a promising ultrasound-only technology for characterizing tissue biomechanical properties at the microstructural level to improve the image-based diseases diagnosis in multiple clinical applications. PMID- 25694961 TI - Real-time epidural anesthesia guidance using optical coherence tomography needle probe. AB - Epidural anesthesia is one of the most widely used anesthesia methods. Due to lack of visual feedback to guide needle navigation, failure rate of epidural anesthesia is up to 20%, and the complication rate of peripheral nerve block approaches 10%, with the potential of permanent nerve damage. To address these difficulties, needle insertion under ultrasound guidance and fluoroscopy has been introduced. However, they do not provide adequate resolution and contrast to distinguish the tissue layers that the needle travels through or to specifically identify the epidural space. To improve the accuracy of epidural space identification, we developed a small hand-held optical coherence tomography (OCT) forward-imaging needle device for real-time epidural anesthesia surgery guidance and demonstrated its feasibility through ex vivo and in vivo animal experiments. With tissue structures visualized and differentiated at the needle tip, OCT needle imaging device will enhance clinical outcomes with regards to complication rates, induced pain, and procedure failure when compared to standard practice. Furthermore, this technology could be used in combination with ultrasound/fluoroscopy to enhance outcomes. PMID- 25694962 TI - Algorithms for improved 3-D reconstruction of live mammalian embryo vasculature from optical coherence tomography data. AB - BACKGROUND: Robust reconstructions of the three-dimensional network of blood vessels in developing embryos imaged by optical coherence tomography (OCT) are needed for quantifying the longitudinal development of vascular networks in live mammalian embryos, in support of developmental cardiovascular research. Past computational methods [such as speckle variance (SV)] have demonstrated the feasibility of vascular reconstruction, but multiple challenges remain including: the presence of vessel structures at multiple spatial scales, thin blood vessels with weak flow, and artifacts resulting from bulk tissue motion (BTM). METHODS: In order to overcome these challenges, this paper introduces a robust and scalable reconstruction algorithm based on a combination of anomaly detection algorithms and a parametric dictionary based sparse representation of blood vessels from structural OCT data. RESULTS: Validation results using confocal data as the baseline demonstrate that the proposed method enables the detection of vessel segments that are either partially missed or weakly reconstructed using the SV method. Finally, quantitative measurements of vessel reconstruction quality indicate an overall higher quality of vessel reconstruction with the proposed method. CONCLUSIONS: Results suggest that sparsity-integrated speckle anomaly detection (SSAD) is potentially a valuable tool for performing accurate quantification of the progression of vascular development in the mammalian embryonic yolk sac as imaged using OCT. PMID- 25694963 TI - Quantitative evaluation of SOCS-induced optical clearing efficiency of skull. AB - BACKGROUND: In vivo cortex optical imaging methods for visualization of both structural and functional architecture with high spatial-temporal resolution have shown tremendous advantages in the studies on neurons, glia and microvasculature. To overcome the strong scattering of skull above the cortex, several chronic cranial windows were proposed through craniotomy, but there are some problems. Here, an innovative skull optical clearing solution (SOCS) has been invented to make the skull transparent within 25 min, but SOCS-induced optical clearing efficacy of skull is to be evaluated. METHODS: Based on the measurements of divergence of beam spot, collimated transmittance of skull, the efficiency of skull optical clearing has been further evaluated quantitatively by comparing with the Monte Carlo simulation. RESULTS: The results show that the light beam bandwidth is 5.2+/-0.3 mm through the initial skull, and reduces to 2.0+/-0.2 mm trough the treated skull with SOCS; and the calculated scattering coefficient almost decreases to one third after the treatment. CONCLUSIONS: The quantitative evaluation of SOCS-induced optical clearing efficacy of skull provides an important reference for performing transcranial cortical optical imaging or operation based on skull optical clearing technique. PMID- 25694964 TI - What can biophotonics tell us about the 3D microstructure of articular cartilage? AB - Connective tissues such as articular cartilage have been the subject of study using novel optical techniques almost since the invention of polarized light microscopy (PLM). Early studies of polarized light micrographs were the main evidential basis for the establishment of quantitative models of articular cartilage collagen structure by Benninghoff and others. Even now, state of the art optical techniques including quantitative polarized light microscopy (qPLM), optical coherence tomography (OCT), polarization-sensitive optical coherence tomography (PS-OCT), second harmonic generation (SHG) microscopy, Fourier transform infrared (FTIR) microscopy, Raman and optical hyperspectral reflectance and fluorescence imaging are providing new insights into articular cartilage structure from the nanoscale through to the mesoscale. New insights are promised by emerging modalities such as optical elastography. This short review highlights some key recent results from modern optical techniques. PMID- 25694965 TI - Optical cryoimaging of mitochondrial redox state in bronchopulmonary-dysplasia injury models in mice lungs. AB - BACKGROUND: Bronchopulmonary dysplasia (BPD) is a major cause of morbidity and mortality in premature infants exposed to high levels of oxygen. This is mainly attributed to increased oxidative stress and angiogenesis defects impacting lung alveolarization. METHODS: Here we use optical imaging to investigate the role of Bcl-2 in modulation of oxidative stress and angiogenesis and pathogenesis of BPD. Cryoimaging of the mitochondrial redox state of mouse lungs was applied to determine the metabolic state of the lungs from Bcl-2 +/+ (control), Bcl-2 deleted in the endothelium (Bcl-2 VE-cad) and Bcl-2-deficient (Bcl-2 -/-; global null) using mitochondrial metabolic coenzymes NADH (Nicotinamide Adenine Dinucleotide), and FADH2 (Flavin Adenine Dinucleotide) as the primary electron carriers in oxidative phosphorylation. RESULTS: We observed a 47% and 26% decrease in the NADH redox in Bcl-2 deficient lungs, Bcl-2 -/- and Bcl-2 VE-cad, respectively. CONCLUSIONS: Thus, Bcl-2 deficiency is associated with a significant increase in oxidative stress contributing to reduced angiogenesis and enhanced pathogenesis of BPD. PMID- 25694966 TI - Anterior segment optical coherence tomography evaluation of ocular graft-versus host disease: a case study. AB - To explore ocular graft-versus-host disease (GVHD), anterior segment optical coherence tomography (AS-OCT) imaging of eyelids, tear meniscus, cornea and conjunctiva is performed in subsequent sessions on a patient who has ocular GVHD after allogeneic related donor stem cell transplant. The OCT results are presented together with those from a normal subject. OCT imaging is promising in visualizing several ocular GVHD manifestations, such as abnormal meibomian gland orifice (MGO), conjunctival keratinization, conjunctival hyperemia and chemosis, corneal epithelium opacification, thinning and sloughing. This case study demonstrates the capability of AS-OCT in the imaging and monitoring of ocular GVHD, which may be useful in the development of current ocular GVHD staging system and the clinical management for GVHD treatment. PMID- 25694967 TI - Pulsatile motion of trabecular meshwork in a patient with iris cyst by phase sensitive optical coherence tomography: a case report. AB - A 45-year-old man was diagnosed with a 3 mm * 3 mm iris cyst located at 9 o'clock behind iris and protruding into temporal angle by slit lamp examination, gonioscopy, and ultrasound biomicroscopy (UBM). Phase-sensitive optical coherence tomography (PhS-OCT) was applied on this case for the quantitative measurements of trabecular meshwork (TM) motion. The frequency of TM motion was with the same rhythm of the patient's peripheral pulse. Its amplitude on the closed angle region showed significant smaller than the open angle region. PhS-OCT can be a useful tool for the diagnosis and follow-up in ocular diseases surrounding iridocorneal angle. PMID- 25694968 TI - English language usage pattern in China mainland doctors: AME survey-001 initial analysis results. AB - PURPOSE: English is the most widely used language in medical community worldwide. Till now there is no study yet on how English language is being used among mainland Chinese doctors. The present survey aimed to address this question. METHODS: An online cross-sectional survey was carried out during the period of 23 Oct 2014 to 13 November 2014, totaling 22 days. This survey was conducted on the platform provided by DXY (www.dxy.cn), which is the largest medical and paramedical related website in China with registered medical doctor users of slightly more than one million. E-mails were sent to all DXY registered users to invite them to participate the survey which lasts approximately five-minute. The questionnaire included three major aspects: (I) the demographic characteristics of participants; (II) English reading pattern; and (III) paper publishing experience in international journals. To accommodate the complexity of relationships among variables, structural equation modeling (SEM) was employed to build the model. RESULTS: In total 1,663 DXY users completed the survey, which counted for ~1% of the total registered medical doctor users. There were more participants from relatively economically developed eastern coast areas. The age of participants was 33.6+/-7.4 years. There were 910 respondents from teaching hospitals (54.72%), followed by tertiary care hospitals (class-III hospital, 22.37%). Mainland Chinese doctors were more likely to consult medical materials in Chinese (63.5%) when they encounter clinical difficulties. Participants who were able to list English journals of their own specialty up to four were 44.02% for 0, 13.77% for one journal, 13.89% for two journals, 9.26% for three journals, and 19.06% for four journals. Most participants (82.86%) have read at least one English paper or one professional book in English, while 17.14% responded they never read a single English paper or professorial book in English. About 30.42% participants published at least one paper in English journals, and approximately half of them require professional English editing service. CONCLUSIONS: This limited survey shows Mainland Chinese doctors are more likely to use Chinese medical materials. Overall their familiarity with international English journals is relatively low. Improving English education at the undergraduate and post graduate levels is recommended. PMID- 25694969 TI - On the training of young doctors in China. PMID- 25694970 TI - Minimally invasive aortic valve replacement. PMID- 25694971 TI - Ministernotomy or minithoracotomy for minimally invasive aortic valve replacement: a Bayesian network meta-analysis. AB - BACKGROUND: Establishing the relative merits of ministernotomy (MS) and minithoracotomy (MT) approaches to minimally invasive aortic valve replacement (MIAVR) is difficult given the limited available direct evidence. Network meta analysis is a Bayesian approach that can combine direct and indirect evidence to better define the benefits and risks of MS and MT. METHODS: Electronic searches were performed using six databases from their inception to June 2014. Relevant studies utilizing a minimally invasive approach for aortic valve replacement were identified. Data were extracted and analyzed according to predefined clinical endpoints. Both traditional and Bayesian meta-analysis approaches were conducted. RESULTS: Compared to full sternotomy, MT was associated with longer cardiopulmonary bypass (CPB) duration (WMD, 9.99; 95% CI, 3.91, 16.07; I(2)=55%; P=0.001) and cross-clamp duration (WMD, 7.64; 95% CI, 2.86, 12.42; P=0.002; I(2)=74%). When compared to MS using network meta-analysis, no significant difference in duration was detected. Postoperative outcomes including 30-day mortality, stroke, and reoperation for bleeding and wound infection were comparable between MS and MT using both traditional and Bayesian meta-analysis techniques. CONCLUSIONS: The current evidence demonstrates that MIAVR via MS or MT is a safe and efficacious alternative to conventional median sternotomy. MT may be associated with longer CPB and cross-clamp durations, but has similar post operative outcomes compared to MS. An individualized approach tailored to both the patient and surgical team is likely to provide optimal outcomes. PMID- 25694972 TI - Minimally invasive reoperative aortic valve replacement: a systematic review and meta-analysis. AB - BACKGROUND: With prolonged life expectancy and more frequent use of biological prostheses, an increasingly higher proportion of patients are undergoing aortic valve replacement (AVR) after previous sternotomy. We critically appraised the quantity and quality of evidence to demonstrate the efficacy and safety of the minimally invasive (MIrAVR) versus conventional (CrAVR) approaches for reoperative AVR. METHODS: Electronic searches were performed using six databases from their inception to April 2014. Relevant studies utilizing a MIrAVR were identified. Data were extracted and analyzed according to predefined clinical endpoints. RESULTS: Four single-arm and seven comparative observational studies including a total of 441 MIrAVR patients were included for quality assessment, data extraction and analysis. In-hospital mortality ranged from 0-9.5%, and was similar between the MIrAVR and CrAVR groups (RR, 0.77; 95% CI, 0.39-1.54; P=0.46). Stroke rates ranged from 2.6-8% and were also similar between the two cohorts. The rates of pacemaker implantation, renal failure and reoperation for bleeding were not significantly different between the two groups. There were no reports of myocardial infarctions in the included studies. No significant difference in hospital stay was observed for the MIrAVR versus CrAVR group. CONCLUSIONS: The current literature suggests that MIrAVR has similar efficacy and mortality outcomes compared to CrAVR without compromise to myocardial protection or hospitalization duration. It appears to be a valid alternative option for patients requiring reoperative AVR. PMID- 25694973 TI - Minimally invasive aortic valve surgery: state of the art and future directions. AB - Minimally invasive aortic valve replacement (MIAVR) is defined as an aortic valve replacement (AVR) procedure that involves a small chest wall incision as opposed to conventional full sternotomy (FS). The MIAVR approach is increasingly being used with the aim of reducing the "invasiveness" of the surgical procedure, while maintaining the same efficacy, quality and safety of a conventional approach. The most common MIAVR techniques are ministernotomy (MS) and right anterior minithoracotomy (RT) approaches. Compared with conventional surgery, MIAVR has been shown to reduce postoperative mortality and morbidity, providing faster recovery, shorter hospital stay and better cosmetics results, requires less rehabilitations resources and consequently cost reduction. Despite these advantages, MIAVR is limited by the longer cross-clamp and cardiopulmonary bypass (CPB) times, which have raised some concerns in fragile and high risk patients. However, with the introduction of sutureless and fast deployment valves, operative times have dramatically reduced by 35-40%, standardizing this procedure. According to these results, the MIAVR approach using sutureless valves may be the "real alternative" to the transcatheter aortic valve implantation (TAVI) procedures in high risk patients "operable" patients. Prospective randomized trials are required to confirm this hypothesis. PMID- 25694974 TI - Minimally invasive concomitant aortic and mitral valve surgery: the "Miami Method". AB - Valve surgery via a median sternotomy has historically been the standard of care, but in the past decade various minimally invasive approaches have gained increasing acceptance. Most data available on minimally invasive valve surgery has generally involved single valve surgery. Therefore, robust data addressing surgical techniques in patients undergoing double valve surgery is lacking. For patients undergoing combined aortic and mitral valve surgery, a minimally invasive approach, performed via a right lateral thoracotomy (the "Miami Method"), is the preferred method at our institution. This method is safe and effective and leads to an enhanced recovery in our patients given the reduction in surgical trauma. The following perspective details our surgical approach, concepts and results for combined aortic and mitral valve surgery. PMID- 25694975 TI - Minimally invasive aortic valve replacement versus aortic valve replacement through full sternotomy: the Brigham and Women's Hospital experience. AB - BACKGROUND: Minimally invasive aortic valve surgery (mini AVR) is a safe and effective treatment option at many hospital centers, but there has not been widespread adoption of the procedure. Critics of mini AVR have called for additional evidence with direct comparison to aortic valve replacement (AVR) via full sternotomy (FS). METHODS: Our mini AVR approach is through a hemi-sternotomy (HS). We performed a propensity-score matched analysis of all patients undergoing isolated AVR via FS or HS at our institution since 2002, resulting in 552 matched pairs. Baseline characteristics were similar. Operative characteristics, transfusion rates, in-hospital outcomes as well as short and long term survival were compared between groups. RESULTS: Median cardiopulmonary bypass and cross clamp times were shorter in the HS group: 106 minutes [inter-quartile ranges (IQR) 87-135] vs. 124 minutes (IQR 90-169), P<=0.001, and 76 minutes (IQR 63-97) vs. 80 minutes (IQR 62-114), P<=0.005, respectively. HS patients had shorter ventilation times (median 5.7 hours, IQR 3.5-10.3 vs. 6.3 hours, IQR 3.9-11.2, P<=0.022), shorter intensive care unit stay (median 42 hours, IQR 24-71 vs. 45 hours, IQR 24-87, P<=0.039), and shorter hospital length of stay (median 6 days, IQR 5-8 vs. 7 days, IQR 5-10, P<=0.001) compared with the FS group. Intraoperative transfusions were more common in FS group: 27.9% vs. 20.0%, P<=0.003. No differences were seen in short or long term survival, or time to aortic valve re-intervention. CONCLUSIONS: Our study confirms the clinical benefits of minimally invasive AVR via HS, which includes decreased transfusion requirements, ventilation times, intensive care unit and hospital length of stay without compromising short and long term survival compared to conventional AVR via FS. PMID- 25694976 TI - Minimally invasive aortic valve replacement: the Leipzig experience. AB - BACKGROUND: Minimally invasive techniques are progressively challenging traditional approaches in cardiothoracic surgery. Minimally invasive aortic valve replacement (AVR) has become a routine procedure at our institution. METHODS: We retrospectively analyzed all patients undergoing minimally invasive isolated AVR between January 2003 and March 2014, at our institution. Mean follow-up was 4.7+/ 4.3 years (range: 0-18 years) and was 99.8% complete. RESULTS: There were 1,714 patients who received an isolated minimally invasive AVR. The mean (+/- SD) patient age was 65+/-12.8 years, ejection fraction 60%+/-12% and log EuroSCORE 5.3%+/-5.1%. Mean cross-clamp time was 58+/-18 minutes and mean cardiopulmonary bypass (CPB) time was 82.9+/-26.7 minutes. Thirty-day survival was 97.8%+/-0.4%, and 69.4%+/-1.7% at 10-years. The multivariate analysis revealed age at surgery [P=0.016; odds ratio (OR), 1.1], length of surgery time (P=0.002; OR, 1.01), female gender (P=0.023; OR, 3.54), preoperative myocardial infarction (MI) (P=0.006; OR, 7.87), preoperative stroke (P=0.001; OR, 13.76) and preoperative liver failure (P=0.015; OR, 10.28) as independent risk factors for mortality. Cox regression analysis revealed the following predictors for long term mortality: age over 75 years (P<0.001; OR, 3.5), preoperative dialysis (P<0.01; OR, 2.14), ejection fraction less than 30% (P=0.003; OR, 3.28) and urgent or emergency operation (P<0.001; OR, 2.3). CONCLUSIONS: Minimally invasive AVR can be performed safely and effectively with very few perioperative complications. The early and long-term outcomes in these patients are acceptable. PMID- 25694977 TI - Right infra-axillary mini-thoracotomy for aortic valve replacement. PMID- 25694978 TI - Central versus femoral cannulation during minimally invasive aortic valve replacement. AB - Minimally invasive aortic valve replacement (AVR) is rapidly becoming the preferred approach for aortic valve procedures in most centers worldwide. While femoral artery cannulation is still the most frequently used form of arterial perfusion strategy during less invasive AVR, some recent studies have showed a possible connection between retrograde perfusion and cerebral complications. In this article, we discuss the possible advantages of central aortic cannulation during right minimally invasive AVR and provide some technical aspects for a safe and efficient cannulation of the ascending aorta through a right minithoracotomy. PMID- 25694979 TI - Imaging and minimally invasive aortic valve replacement. AB - Cardiovascular imaging has been the most important tool allowing for innovation in cardiac surgery. There are now a variety of approaches available for treating aortic valve disease, including standard sternotomy, minimally invasive surgery, and percutaneous valve replacement. Minimally invasive cardiac surgery relies on maximizing exposure within a limited field of view. The complexity of this approach is increased as the relationship between the great vessels and the bony thorax varies between individuals. Ultimately, the success of minimally invasive surgery depends on appropriate choices regarding the type and location of the incision, cannulation approach, and cardioprotection strategy. These decisions are facilitated by preoperative imaging, which forms the focus of this review. PMID- 25694980 TI - Minimally invasive reoperative aortic valve replacement. AB - The operative mortality associated with repeat heart valve surgery is supposedly higher than the mortality associated with the primary operation. However, controversy still surrounds the risk factors and optimal surgical approach for patients requiring repeat cardiac surgery, particularly for those requiring aortic valve replacements (AVR). While the standard approach generally utilizes full sternotomy and peripheral cannulation, alternative approaches such as minimally invasive sternotomy may play an increasingly important role in this field. This study compares the advantages and disadvantages of a minimally invasive approach in redo AVR with the standard approach, highlighting difficulties and potential solutions. PMID- 25694981 TI - Minimally invasive aortic valve replacement: the "Miami Method". AB - For patients undergoing aortic valve replacement (AVR), a minimally invasive approach performed via a right anterior thoracotomy is the preferred method at our institution. This method has evolved over a 10-year span, being applied to over 1,500 patients with the commitment of one surgeon seeking to offer a simplistic and reproducible minimally invasive alternative. We believe that this is truly the least invasive approach to the aortic valve since it avoids sternal invasion. By virtue of being less traumatic, the morbidity is diminished and therefore the recovery is enhanced. We believe that this approach is most beneficial in the high risk patient such as the elderly, the obese, those with chronic obstructive pulmonary, chronic kidney disease and those requiring re operative surgery. This method has proven to be safe and effective in all patients requiring isolated AVR surgery. The only relative exclusion criteria would be a porcelain aorta with the inability to cannulate the patient. PMID- 25694982 TI - Right infra-axillary mini-thoracotomy for aortic valve replacement. PMID- 25694983 TI - Interventions on the aortic valve and proximal thoracic aorta through a minimally invasive approach. PMID- 25694984 TI - Concomitant minithoracotomy aortic and mitral valve surgery: the minimally invasive "Miami Method". PMID- 25694985 TI - Reoperative aortic valve replacement through upper hemisternotomy. PMID- 25694986 TI - Right anterior minithoracotomy for aortic valve replacement. PMID- 25694987 TI - Complications and conversions in minimally invasive aortic valve surgery. PMID- 25694988 TI - Aortic stenosis. PMID- 25694989 TI - Clinical assessment of fear of falling after stroke: validity, reliability and responsiveness of the Persian version of the Fall Efficacy Scale-International. AB - BACKGROUND: Fear of falling may be related to falling during stroke onset. The Fall Efficacy ScaleInternational (FES-I) with excellent psychometric properties, is an instrument developed to assess patients' concerns about fallings. The aim of this study was to determine validation of this scale in Iranian patients with stroke. METHODS: The "forward-backward" procedure was applied to translate the FES-I from English to Persian. One hundred-twenty patients who had suffered stroke, aged 40 to 80 years (55% male) completed the Persian FES-I, Geriatric Depression Scale-15 (GDS-15), General Health Questionnaire-28 (GHQ-28), Berg Balance Scale (BBS) and Timed up and Go (TUG) questionnaires. The interval time for the test-retest of the Persian scale was 7-14 days. RESULTS: The test-retest and inter-rater reliabilities of the Persian FES-I were excellent (ICC2,1=0.98, p<0.001) and the internal consistency was high (Cronbach's alpha=0.78). Factor analysis of the 16 items in the Persian scale showed only one significant factor. The total Persian FES-I score had a significantly negative correlation (p<0.001) with the BBS, but it had significantly positive correlation with the TUG, GHQ-28, and GDS-15. The difference in responsiveness scores across fallers and non fallers yielded a large effect size (0.46), which indicated a good discriminating validity. CONCLUSION: The Persian FES-I proved to be an effective and valuable measurement tool to assess stroke patients' fear of falling in practice and research setting. PMID- 25694990 TI - Association of the CTLA-4 1722TC polymorphism and systemic lupus erythematosus: a systematic review and meta analysis. AB - BACKGROUND: Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) is an important negative regulator of Tcell responses. The -1722TC polymorphism of the CTLA-4 gene may be associated with systemic lupus erythematosus (SLE) risk, but related results from previous studies have been inconsistent. We carried out a metaanalysis to assess this association more precisely. METHODS: A systematic search through PubMed, Science Direct, and OVID, Iran doc, Iranmedex and SID (Scientific Information Database) databases was performed with the last search updated on December 30, 2011. The odds of ratio (OR) and its 95% confidence interval (95%CI) were used to assess the strength of the association. We evaluated both fixed and random effect models, depending on the presence of between-study heterogeneity. The analyses were conducted using STATA software, version 11.0. RESULTS: A total of 9 independent studies on the CTLA-4 gene 1722TC polymorphism and SLE, including 1422 cases and 1417 controls were used in this meta-analysis. In the present meta-analysis, we found a significant association between -1722TC polymorphism and SLE risk in the overall analysis (TT versus TC/CC: OR=1.18, 95%CI 0.84-1.66, p= 0.32; TT/TC versus CC: OR = 2.06, 95%CI 1.07-3.99, p= 0.03; TT versus CC: OR = 2.32, 95%CI 1.62-3.32, p< 0.001; TC versus CC: OR = 1.99, 95%CI 1.42-2.78, p<0.001; TT versus TC: OR = 1.2, 95%CI 0.86-1.66,p= 0.28; T versus C: OR = 1.22, 95%CI 0.91-1.64,p= 0.16). In the subgroup analysis by ethnicity, -1722TC polymorphism was significantly associated with SLE risk in Asian population. CONCLUSION: This meta-analysis suggests a significant association between -1722TC polymorphism and SLE susceptibility. Large-scale and well-designed case-control studies are necessary to validate the risk identified in the present meta-analysis. PMID- 25694991 TI - Electric shock in patients administered to hospital: a descriptive study. PMID- 25694992 TI - Reconstruction of the anterior cruciate ligament: a comparison between bone patellar tendon-bone grafts and fourstrand hamstring grafts. AB - BACKGROUND: Disruption of anterior cruciate ligament (ACL) is a common ligamentous injury of the knee. The choice of graft for (ACL) reconstruction remains controversial. This prospective, randomized clinical trial aimed to compare clinical results of bone-patellar tendon-bone (BPTB) grafts and four strand semitendinosus-gracilis (ST) grafts for ACL reconstruction over a 3-year follow-up interval. METHODS: Seventy-one patients with an average age of 29+/- 4.5yearswere treated for torn ACL between 2008 and 2009. Forty-sixpatients underwent reconstruction with BPTB autograft, and 41 were treated with ST autograft. At the time of final follow-up, 37 patients in patella group and 34 patients in hamstring group were evaluated in terms of return to pre-injury activity level, pain, knee stability, range of motion, IKDC (International Knee Documentation Committee) score and complications. RESULTS: At 36thmonth of follow up, 34 (92%) and 28 (82%) patients in BPTB and ST group, respectively had good-to excellent IKDC score (p > 0.05). The activity levels were higher in BPTB group (p> 0.05). At 3rd yearof follow up, the Lachman test was graded normal, for 23 (62%) and 11 (32%) patients in BPTB and ST group, respectively (p=0.019). Regarding the pivot-shift test, 29 (79%) and 15 (44%) patients in patella and hamstring group, respectively had normal test at the latest follow-up (p=0.021).There were no significant differences in terms of thigh circumference difference, effusion, knee range of motion, pain and complications. CONCLUSION: The results indicate a trend toward increased graft laxity and pivot-shift grades in patients undergoing reconstruction with hamstring autograft compared with patella tendon. However, the two groups had comparable results in terms of activity level and knee function. PMID- 25694993 TI - Nurses' perceptions of evidence-based practice: a quantitative study at a teaching hospital in Iran. AB - BACKGROUND: Evidence-based practice (EBP) provides nurses a method to use critically appraised and scientifically proven evidence for delivering quality health care and the best decision that leads to quality outcomes. The purpose of this study was to measure the practice, attitude and knowledge/skill of evidence based practice of nurses in a teaching hospital in Iran. METHODS: This cross sectional study was conducted in 2011.The study sample was composed of 195 nurses who were working at the Fatemeh Zahra Hospital affiliated to Bushehr University of Medical Sciences (BPUMS). The survey instrument was a questionnaire based on Upton and Upton study. This tool measures Nurses' perceptions in the three sub scales of practice, attitude and knowledge/skill of evidence-based practice. Descriptive statistical analysis was used to analyze the data. Pearson correlation coefficients were used to examine the relationship between subscales. RESULTS: The overall mean score of the evidence-based practice in this study was 4.48+/-1.26 from 7, and the three subscales of practice, attitude and knowledge/skill in evidence-based practice were, 4.58+/-1.24, 4.57+/-1.35 and 4.39+/-1.20, respectively. There was a strong relationship between knowledge and performance subscale (r=0.73,p<0.01). CONCLUSION: Findings of the study indicate that more training and education are required for evidence-based nursing. Successful implementation of evidence-based nursing depends on organizational plans and empowerment programs in hospitals. Hence, hospital managers should formulate a comprehensive strategy for improving EBP. PMID- 25694994 TI - Comparing live lecture, internet-based & computer-based instruction: A randomized controlled trial. AB - BACKGROUND: Comparing computer and internet based instruction with traditional giving lecture would provide enough evidence to identify best teaching practice. In this study, we compared lecture, interactive internet based and computer based learning regarding medical students' knowledge acquisition and satisfaction in teaching pathophysiology of hematology and oncology. METHODS: Eighty four medical students were randomized into three groups and an identical faculty member conducted the instructions through the above mentioned methods. Students' knowledge was assessed one week before and immediately after the interventions by pre and posttest. Students' satisfaction was assessed using a validated 5-point Likert scale. RESULTS: The results showed that students' satisfaction was significantly higher in interactive internet based group than other ones (p=0.05). There were a significant increase between pre and posttest scores in all groups (p=0.000). We used ANCOVA to compare score changes in the study groups, with posttest scores as the dependent factor and pretest scores as covariate and knowledge acquisition was significantly higher in interactive internet based group than other two groups (p=0.026). CONCLUSION: The study showed that although interactive internet based instruction is a difficult and time consuming method, it is recommended to integrate this method to medical curricula. PMID- 25694995 TI - Effects of epidemiology learning software on nursing and midwifery students. AB - BACKGROUND: Being informed of new methods of teaching and comparing their outcome help teachers use more effective and efficient methods in developing and implementing new training courses. The aim of this study was to examine the efficacy of epidemiology learning software on learning epidemiology courses. METHODS: This quasi-experimental study included 101 nursing and midwifery students taking epidemiology course in two separate classes. One of the classes was selected as intervention group (taught via software) and another one as the control group. At the end of the semester, scores of the courses were analyzed using covarianceanalysis. RESULTS: After adjusting the effect of grade point average, covariance analysis indicated a significant difference in epidemiology scores between the two groups (p<0.001). The students taught through the software obtained significantly higher scores compared to the students in traditional group. CONCLUSION: By means of this training software, teachers can use several strategies for presenting lessons and increasing training efficacy, leading to active learning in students. PMID- 25694996 TI - The comparison of cross-education effect in young and elderly females from unilateral training of the elbow flexors. AB - BACKGROUND: Many studies have reported the increase in strength of the untrained contralateral limb after unilateral training. The aim of this study was to compare the cross education effect in the young and elderly persons. METHODS: In this quasi-experimental and pre-post study, 12 young people aged 28.25 +/-3.11 years and 12 elderly persons (aged 73.08 +/- 5.3 years) participated. The subjects had no history of strength training and upper limb movement impairments. Maximal isometric flexion strength in the dominant limb and the contralateral side before and after training were measured by tensiometer. Subjects performed elbow flexion exercises in the dominant side, using 3 sets of 10 repetition of the 60-70% maximal force for two weeks. Independent and paired t test were used to analyze between and within groups differences. RESULTS: The results showed that short-term isometric resistive exercise led to a significant increase of strength in trained and untrained limbs in both groups (p<0.05). There was not a significant difference between the two groups in the rate of strength increase, both in the upper limb that was exercised and also in the opposite side (p> 0.05). CONCLUSION: The increased muscle strength observed during training indicates positive effect of training in old adult. The increased muscle strength in untrained limb suggests the capacity of neuromuscular adaptation among old adults, suitable to be used in cases of limb immobility or unilateral impairment. PMID- 25694997 TI - Effects of carbamazepine on male reproductive hormones. AB - BACKGROUND: Reproductive endocrine disorders and sexual dysfunction are common among men with epilepsy. We investigated sexual hormone serum levels among men with newly diagnosed epilepsy, before starting any antiepileptic drug (AED), and then after starting carbamazepine (CBZ), to determine the role and effects of epilepsy versus CBZ in creating reproductive endocrine disorders. METHODS: In this prospective study, male patients 20 to 40 years of age who due to new-onset seizure(s) were referred to the outpatient epilepsy clinic at Shiraz University of Medical Sciences from 2009 through 2012 were studied. A blood sample was obtained to evaluate the serum levels of follicle stimulating hormone, luteinizing hormone, prolactin, testosterone, free-testosterone, dehydroepiandrosterone sulfate and sex hormone binding globulin. CBZ was started after blood works. After at least three months of taking CBZ, another blood sample was obtained to determine the serum levels of those hormones again. RESULTS: Twenty patients were included. Their mean age (+/- standard deviation) was 28 years (+/- 5). The statistical analysis with paired sample tests did not show any significant changes in serum levels of sex hormones before and after CBZ therapy. CONCLUSION: Despite the fact that, sexual dysfunction and reproductive disorders are common among men with epilepsy, the exact pathophysiology of these problems is not clear yet. Further studies are required to determine the exact role of epilepsy itself, AEDs, and other possible determinants. PMID- 25694998 TI - Distribution of the mutated delta 32 allele of CCR5 co-receptor gene in Iranian population. AB - BACKGROUND: The CCR5 is a chemokine receptor that serves as a co-receptor for HIV 1 attachment and entry to T lymphocytes. A 32bp deletion (?32) in this gene is believed to be associated with resistance to infection and delay disease progression. The aim of this study was to determine the?32 allele frequency in healthy individuals and HIV-infected individuals with AIDS. METHODS: In this experiment, 530 normal individuals from healthy Iranian population and 40 HIV infected samples from Western Clinic of Tehran were examined for?32 in CCR5 gene using polymerase chain reaction (PCR) techniques followed by agarose gel electrophoresis. RESULTS: Allele frequencies of the CCR5?32 in normal individuals were calculated to be 1.1% for heterozygous genotype and 0.19% for homozygous genotype. None of the co-receptor gene in HIV cases was found to be mutated in this study. CONCLUSION: Based on the findings of this study and the literature in Iran, we could conclude that Iranian people similar to neighbor countries such as Arabs are susceptible to HIV virus infection. PMID- 25694999 TI - Comparison of regular aerobic and yoga on the quality of life in patients with multiple sclerosis. AB - BACKGROUND: The pathophysiology of multiple sclerosis (MS) is characterized by fatigue, motor weakness, and spasticity, to name a few. MS symptoms may lead to physical inactivity associated with the development of secondary diseases. This study was to investigate the effect of regular aerobic and yoga on the quality of life of patients with MS. METHODS: The present quasi-experimental study was conducted on 90 patients with chronic MS chosen randomly and divided into two test and one control groups. Data were analyzed using SPSS software (version 11.5) through paired t-test, ANOVA, and Tukey's post hoc. RESULTS: There were no significant differences among the scores of quality of life in the three groups prior to investigation. Although they were significant after intervention. The mean score of yoga group was higher than that of aerobic group, and aerobic group showed a higher mean score compared with the control. CONCLUSION: Yoga and aerobic exercises may improve quality of life in patients with MS. It is highly recommended that the governor along with MS societies and other organizations servicing and supporting patients start to develop sport-regulated programs to help improve quality of life for these patients. PMID- 25695000 TI - Determinants of risky driving behavior: a narrative review. AB - Road traffic crashes (RTCs) account for great mortality and morbidity rates worldwide, resulting in substantial global burden. Factors contributing to RTC generally fall into three categories: environmental, vehicle, and human, with the human factor being by far the leading determinant. Obtaining an in-depth exploration of driving behavior and factors underpinning risky driving could be of particular importance to facilitate the establishment of effective policies. The present article provides insight to different aspects of risky driving behavior, at micro and macro levels, from individual attitudes, and psychological factors like personality, temperament, mood and emotions, to socioeconomic context, social norms, cultural backgrounds, level of law enforcement, and internalization of legality in the society. Risky driving behavior is a multidimensional issue and any effort to design and establish modification policies should be based on a comprehensive understanding of its determinants in different aspects. PMID- 25695001 TI - Short stay in general intensive care units: is it always necessary? AB - BACKGROUND: There are challenges ahead of short-term hospitalization of low-risk patients hospitalized only for monitoring of severe disease who may die soon after admission. The purpose of this study was to suggest strategies forthe management of ICU stay lengths and to ensure optimal use of ICU resources. METHODS: The study was conducted retrospectively on 246 patients admitted to 9 general ICUs in Tehran, from September 2011 to March 2012. Patients staying for<=2 days in the ICU were compared to each other after being categorized into two medical and surgical groups. RESULTS: Of 129 patients with<=2 days ICU stay (52.4%), 88.4% survived. Of these, 25 (19.4%) were placed in the medical and 104 (80.6%) to surgical groups. Survival rates were significantly greater in surgical group; only 7.7% of them were in need of mechanical ventilation in the first 24 hours of admission (p<0.001). In contrast to medical group, the average Acute Physiology and Chronic Health Evaluation (APACHE) II score in the surgical group was significantly lower (9.8+/-3.6 and 17.3+/-5.8) (p<0.001). CONCLUSION: The majority of patients with<=2 days LOS in the surgical group hospitalized for monitoring after surgery had low mortality rate and APACHE-II score. Therefore, it would seem that transferring such patients to the intermediate care unit leads to more efficient and optimal use of ICU resources. PMID- 25695002 TI - Association between non-matured arterio-venus fistula and blood pressure in hemodialysis patients. AB - BACKGROUND: Chronic Kidney Disease (CKD) is a complicated kidney problem causing permanent renal failure in progressive stages. The final stage of CKD is called ESRD in which most accepted management is Hemodialysis (HD). Arterio-Venus Fistula (AVF) is the most practical way of making proper access to the blood circulatory system; however, maturation of the AVF is a challenge, since there are number of variables interfering with the whole process. The purpose of this study was to evaluate potentially modifiable factors associated with Maturation Time (MT) after creation of a Vascular Access (VA). METHODS: In this cross sectional study, a total of 87 patients referred to the Hasheminejad Kidney Center for AVF creation in 2010 were evaluated. Patients were evaluated before and after the AVF creation and risk factors such as history of blood pressure abnormalities, diabetes and congestive heart failure, as well as the successive development of AVF was studied and finally processed using 'data mining' technology. RESULTS: The "Decision Trees" indicated the significant impact of the systolic blood pressure (SBP) in the delay of the patient's AVF maturation. Also, prediction of AVF maturation was made with 70.59% of precision in regard to their BP condition. CONCLUSION: This study demonstrated that monitoring the SBP is one of the important steps in management of the cardiovascular variables producing any delay in the process of the patient's HD. Also the data mining method can discover the hidden relationship between the patient's medical conditions in order to predict the potential disorders. PMID- 25695003 TI - X-ray radiation and the risk of multiple sclerosis: Do the site and dose of exposure matter? AB - BACKGROUND: The sporadic cases of radiation-activated multiple sclerosis (MS) has been previously described, with a few studies focused on the relationship between radiation and the risk of MS. The aim of our study was to evaluate the association between history of X-ray radiation and MS. METHODS: This case-control study was conducted on 150 individuals including 65 MS patients and 85 age- and sex-matched healthy controls enrolled using non-probability convenient sampling. Any history of previous Xray radiation consisted of job-related X-ray exposure, radiotherapy, radiographic evaluations including chest Xray, lumbosacral X-ray, skull X-ray, paranasal sinuses (PNS) X-ray, gastrointestinal (GI) series, foot X ray and brain CT scanning were recorded and compared between two groups. Statistical analysis was performed using independent t test, Chi square and receiver operating characteristics (ROC) curve methods through SPSS software. RESULTS: History of both diagnostic [OR=3.06 (95% CI: 1.32-7.06)] and therapeutic [OR=7.54 (95% CI: 1.5935.76) X-ray radiations were significantly higher among MS group. Mean number of skull X-rays [0.4 (SD=0.6) vs. 0.1 (SD=0.3), p=0.004] and brain CT scanning [0.9 (SD=0.8) vs. 0.5 (SD=0.7), p=0.005] was higher in MS group as well as mean of the cumulative X-ray radiation dosage [1.84 (SD=1.70) mSv vs. 1.11 (SD=1.54) mSv; p=0.008]. CONCLUSION: Our study was one of the first to show higher history of X-ray radiation in patients with MS compared to healthy controls. A possible association was also found between the dose and the site exposed to X-ray radiation and risk of developing MS. PMID- 25695004 TI - A rare case of prosthetic aortic valve endocarditis complicated with multiple fistula to peri aortic structure. AB - Multiple aorto-cardiac cavity communications is very rare but important complication of prosthetic aortic valve endocarditis. The case below illustrates multiple aorto-cardiac cavity fistula formation following prostethic aortic valve endocarditis presented with slowly progressive symptoms of heart failure. A brief review of surgical reconstruction and the existing literature are presented, including emphasis on pre and intra operative echocardiographic diagnosis and treatment. PMID- 25695005 TI - Epidemiologic characteristics of HIV-positive patients referring to behavioral diseases consultation center in Shiraz, Iran. AB - BACKGROUND: Acquired immune deficiency syndrome (AIDS) was firstly reported from California and soon became a pandemic in the world. This disease poses serious threats to humans' health. In this study, we intended to examine the characteristics of HIV-positive patients who referred to the Behavioral Diseases Consultation Center (BDCC) in Shiraz, Iran. METHODS: This was a cross-sectional descriptive study. HIV-positive patients, referring toBDCC of Shiraz University of Medical Scienceswere the population under the study. The data, collected through a checklist, were encoded and entered in to the SPSS 19. Then descriptive statistics such as mean, median, standard deviation and range were used to describe the variables. Also, the relationships between the variables were tested using X2 test. RESULTS: The mean and median age of the HIV-positive patients were 39 + 8.7 and 38years, respectively.Nearly327 (65.4%) of the studied population were male and 173 (34.6%) were female. With respect to marital status, 225 (45%) participants were married, 133 (27%) were single, 91 (18.2%) were divorced and 49 (9.8%) were widowed. Also, 265(53%) of the participants were infected through injection drug use, 198 (39.6%) through sexual route, 7 (1.4%) through blood and blood products, 6 (1.2%) through tattoos and 21 (4.2%) by other routes. Most of the participants had a HIV-positive history in their family, and 145 (29%) mentioned that their wives were HIV-positive. Moreover, 320 (62.7%) of the participants had a positive history of drug use, 176 (35.2%) did not have a history of drug abuse, and the status of 10 (2%) participants was not recognized. CONCLUSION: Although the results of this study highlighted that injection addiction remains the major transmission route inIran, the role of sexual transmission should be acknowledged in the future. PMID- 25695006 TI - Primary health care physicians' approach toward domestic violence in Tehran, Iran. AB - BACKGROUND: Primary health care physicians (PHCPs) are the first in the clinic to detect and help victims of intimate partner violence (IPV). Therefore, their attitude and practice toward domestic violence (DV) are important to manage this problem. The aim of current study was to compare the behavior and attitude of PHCPs about DV versus other health risk factors in Tehran, Iran. METHODS: A convenience sample of 220 PHCPs was evaluated. The study was carried out in April 2012. Two self-administered questionnaires were used to identify physicians' beliefs and behaviors on screening and intervention of DV and other health risk factors. All analyses were performed using SPSS version 18.0 (SPSS, Inc. Chicago, IL). RESULTS: One hundred and ninety eight questionnaires were analyzed. PHCPs' mean age was 39.06 (+/-7.5) years. Participants were just reported 10% screening of regular patients for DV compared with 29% to 48% for other health risk factors. Mean age of PHCPs was not associated with their approach toward the DV. Compared to male physicians, females spared more time for DV victims. Major of physicians (96%) believed that DV is not a private problem and is something that needs to be addressed cautiously. CONCLUSION: The results of this study indicated that DV screening occurs less than that of other health risk factors. Attitude of majority of PHCPs was positive for addressing this problem. PMID- 25695007 TI - Sleep quality and associated factors among patients with chronic heart failure in Iran. AB - BACKGROUND: Sleep disorders are common among patients with chronic heart failure (HF), and it can have a significant effect on patients' daily activities as well as their health. The purpose of this study was to assess sleep quality and its predictors in Iranian patients with chronic HF. METHODS: This cross-sectional study was conducted on a sample of 200 patients with HF in two hospitals of Tehran University of Medical Sciences from June to November 2009. These patients completed a demographic questionnaire, and their sleep quality was measured using the Pittsburgh Sleep Quality Index (PSQI). One-way analysis of variance (ANOVA), Kruskal-Wallis test, t-test and Linear regression were used for data analysis. RESULTS: Seventy-nine percent of patients (n = 158) reported poor sleep quality (PSQI > 5). The range of global PSQI scores was 3-20. Also, a significant relationship was found between PSQI scores and patients' age (p<0.004), gender (p< 0.042), educational level (p< 0.001), occupational status (p< 0.038), number of hospitalizations (p< 0.005), type of referral (p< 0.001), non-cardiac diseases (p< 0.001), diuretic use (p< 0.021) and left ventricular ejection fraction (p< 0.015). Three predictors were identified using regression analyses with stepwise methods, and included age, type of referral and educational level. CONCLUSION: The high prevalence of poor sleep quality highlighted the importance of sleep disorders in HF patients. There are many factors associated with sleep quality and sleep disorders that health providers should recognize for improved and effective management. PMID- 25695008 TI - Accuracy of pepsinogens for early diagnosis of atrophic gastritis and gastric cancer in Iranian population. AB - BACKGROUND: Currently, non-invasive methods for screening atrophic gastritis and gastric cancer are lacking. The purpose of this study was to evaluate the value of serological parameters including serum pepsinogen I (PGI), pepsinogen II (PGII) and pepsinogen I: II ratio for the screening atrophic gastritis and gastric cancer. METHODS: The study population consisted of 132 dyspeptic patients who had undergone upper endoscopy with biopsy. Blood samples for ELISA assays of serum PGI, PGII and IgG antibodies against Helicobacter pylori were drawn. Comparison between the two groups was done by Student's t- test, and Mann Whitney test. Cut-off points were calculated using receiver operating curves (ROC). RESULTS: Mean (+/-SD) age of the study population was 51.4 (+/-15.5) years. Values of PGI and PG ratio decreased significantly in the atrophic gastritis as compared with the control group (p<0.05). Values of PG and PG ratio didn't show any significant difference between the gastric cancer and control group (p>0.05). For patients with atrophic gastritis, the area under the ROC for PGI was 0.639 (95% CI:0.538-0.741, p=0.008) in which the best cut-off value was 40MUg/L (sensitivity 90%, specificity 67%, accuracy 69%, negative predictive value 92%, YI : 0.429). The area under the ROC for PG ratio was 0.711 (95% CI: 0.617-0.806, p=0.0001) and the best cut-off value was 8 (sensitivity 71%, specificity 71%, accuracy 71%, negative predictive value 86%,YI : 0.431). CONCLUSION: It seems that PGI, PGI: PGII ratio is potential biomarkers for screening atrophic gastritis with high sensitivity, specificity, accuracy and negative predictive value. Serology could be used as a screening method for the detection of precancerous states due to its convenience, relative low cost and safety. PMID- 25695009 TI - Dual-energy X-ray absorptiometry diagnostic discordance between Z-scores and T scores in a young Iranian population. AB - BACKGROUND: Dual-energy X-ray Absorptiometry (DXA) is considered the gold standard for non-invasive measurement of bone mass. T-scores and Z-scores are used to present the results of bone mass. The present study was designed to evaluate the discordance between T-scores and Z-scores calculated at a same level and its relation with age, gender and body mass index (BMI) in a representative sample of normal population. METHODS: This cross-sectional study was conducted as a part of a comprehensive survey, Iranian Multicenter Osteoporosis Study (IMOS), designed to assess bone health among healthy adults. Each individual underwent both L1-L4 antero-posterior lumbar spine and hip DXA scan. The difference between the T- and Z-scores measured at each of the four skeletal sites was then calculated. RESULTS: A -1.21 to 1.21 point difference was noted in the Z- and T- scores measured at each site. While the difference between the T-and Z-scores was less than 0.5 SD in most of the cases, the difference was higher than 1 SD in about 5% of the subjects. CONCLUSION: Standardization of Z-score definition and calculation techniques as well as developing an ethnicity-matched reference population is needed to improve the reliability of DXA-generated Z-scores. PMID- 25695010 TI - Domestic violence in Iranian infertile women. AB - BACKGROUND: Millions of men and women suffer from infertility worldwide. In many cultures, infertile women are at risk of social and emotional problems. Infertility may affect the public health in many countries. Domestic violence is the intentional use of physical force, power or threat against oneself, another person or another group or community which leads to injury, death, mental harm, lack of development or deprivation. This study aimed to assess the prevalence of domestic violence against infertile women who referred to the infertility centres of Tehran, Iran in 2011. METHODS: This was cross- sectional descriptive study conducted on 400 infertile women who were selected through convenient sampling method. The questionnaire used in this study included two sections: a demographic section with questions about demographic characteristics of the infertile women and their husbands; and the domestic violence questionnaire with questions about physical, emotional and sexual violence. Data were analysed by SPSS16; descriptive statistics, Spearman's test, t- test, one-way analysis of variance (ANOVA) and logistic regression were used for data analysis. RESULTS: Four hundred women with the average age of 30.50 +/- 6.16 years participated in the study; of whom, 34.7% experienced domestic violence physical violence (5.3%), emotional violence (74.3%) and sexual violence (47.3%). Domestic violence was significantly associated with unwanted marriage, number of IVFs, drug abuse, emotional status of the women, smoking and addiction or drug abuse of the spouse, mental and physical diseases of the husband (p< 0.05). CONCLUSION: Many of the current problems in this society, particularly in families are due to the transition of the society from a traditional model to a modern one. The majority of the infertile women experience violence in Iran. Domestic violence against infertile women is a problem that should not be ignored. Clinicians should identify abused women. Providing counseling services to women in infertility treatment centers is suggested to prevent domestic violence against infertile women. PMID- 25695011 TI - Students' perceptions of learning environments in Gonabad University of Medical Sciences. PMID- 25695012 TI - Effect of eccentric exercise-induced muscle damage on electromyographyic activity of quadriceps in untrained healthy females. AB - BACKGROUND: The aim of this study was to investigate muscle damage indicators and electromyography activities of quadriceps muscles at 25 degrees of hip flexion in untrained healthy females after an eccentric exercise induced muscle fiber damage. METHODS: A total of 14 healthy females participated in this pre experimental study. The subjects performed maximal eccentric quadriceps contractions at 25 of hip flexion. Maximum voluntary extensor isometric and concentric moments, angle of maximum moment for concentric contractions, perceived pain intensity, and pain pressure threshold were examined before, immediately, 48 hours, 120 hours and 14 days after eccentric exercise. Additionally, electromyography of three parts of quadriceps muscle, knee flexion range of motion and thigh circumference were measured before and after eccentric exercise. RESULTS: Significant reductions in maximum isometric moment and maximum concentric moment were observed at angular velocity of 60 per sec immediately after eccentric exercise (p<0.05). Both maximum isometric moment and maximum concentric moment recovered to the baseline 48 hours after eccentric exercise. Increased pain intensity and decreased knee joint range of motion manifested 48 hours after eccentric exercise. Pain pressure threshold for the quadriceps was higher 14 days after exercise as compared to 48 and 120 hours (p<0.05). No significant changes observed in electromyography and thigh circumference (p>0.05). CONCLUSION: Eccentric exercise performed at 25 of hip flexion resulted in muscle fiber injuries within the quadriceps muscle. However, electromyography of quadriceps muscle was not significantly different than the baseline. The result indicates that hip joint position may modify the effect of eccentric exercise on muscle activation. PMID- 25695013 TI - Barriers to and factors facilitating empowerment in elderly with COPD. AB - BACKGROUND: Empowerment of elderly people with chronic obstructive pulmonary disease (COPD) can increase their quality of life and feeling of well-being. However, few researches focused on the obstacles and factors facilitating empowerment in elderly people with COPD; and an adequate determining of these factors need an in-depth understanding of the meaning of these factors which influences empowerment. The objective of this study was to explore the barriers to and factors facilitating empowerment in elderly people with COPD. METHODS: This study was conducted with a qualitative approach using content analysis. Twenty- four participants were selected based on purposeful sampling. Data were collected through conducting in-depth semistructured interviews and making filed notes. Data analysis was performed according to the proposed steps by Granhym & Lund man (2004). RESULTS: The potential to empower the elderly with COPD was influenced by mediating factors; the nature of aging, the difficult nature of COPD, fear and hopelessness, the cultural values and beliefs, poor formal support systems and poor economic status were found to be the barriers; and incentive, trust to health care providers, the educable status of the elderly and increased experience were found to be facilitating factors. CONCLUSION: It seems that empowerment of the elderly with COPD was affected by many factors which mainly rooted in social factors, health care systems and personal resources. PMID- 25695014 TI - Menstrual disturbances and hormonal changes in women workers exposed to a mixture of organic solvents in a pharmaceutical company. AB - BACKGROUND: Chemicals are among risk factors that can affect women's reproductive system. This study is aimed to investigate the association of occupational exposure to a mixture of organic solvents with menstruation disturbances and hormonal changes among female workers. METHODS: Female workers of a pharmaceutical company were divided into three groups of non-exposed, lowexposed and highly-exposed to a mixture of organic solvents (formaldehyde, phenol, N hexane, and chloroform) based on workplace measurements. Menstrual disturbances (in terms of short cycles, long cycles, irregular cycles, and bleeding or spotting between periods) and mean of hormone levels (including follicle stimulating hormone, luteinizing hormone, thyroid stimulating hormone, prolactin, estrogen and progesterone levels) were compared between these three groups. For investigating associations, logistic regression was performed. RESULTS: Our study showed that mean length of cycles, duration of bleeding, and amount of flow and also prevalence of long cycles, irregular cycles, and bleeding or spotting between periods were higher in exposed groups (p<=0.05). Odds ratio for prevalence of menstrual disturbances in the low exposure group and high exposure group were 9.69 (p=0.001) and 3.40 (p=0.002) respectively compared to the reference group. Estrogen and progesterone levels were not affected (p> 0.05), but other hormones levels were significantly disturbed in the exposed groups compared with the non-exposed group (p=0.001). CONCLUSION: Occupational exposure to the mixture of organic solvents may be associated with the increase of menstrual disorders and hormonal changes in female workers. Based on our findings, periodic evaluation of reproductive system of female workers in pharmaceutical companies is recommended. PMID- 25695015 TI - Health technology assessment in Iran: challenges and views. AB - BACKGROUND: Various decisions have been made on technology application at all levels of the health system in different countries around the world. Health technology assessment is considered as one of the best scientific tools at the service of policy- makers. This study attempts to investigate the current challenges of Iran's health technology assessment and provide appropriate strategies to establish and institutionalize this program. METHODS: This study was carried out in two independent phases. In the first, electronic databases such as Medline (via Pub Med) and Scientific Information Database (SID) were searched to provide a list of challenges of Iran's health technology assessment. The views and opinions of the experts and practitioners on HTA challenges were studied through a questionnaire in the second phase which was then analyzed by SPSS Software version 16. This has been an observational and analytical study with a thematic analysis. RESULTS: In the first phase, seven papers were retrieved; from which, twenty- two HTA challenges in Iran were extracted by the researchers; and they were used as the base for designing a structured questionnaire of the second phase. The views of the experts on the challenges of health technology assessment were categorized as follows: organizational culture, stewardship, stakeholders, health system management, infrastructures and external pressures which were mentioned in more than 60% of the cases and were also common in the views. CONCLUSION: The identification and prioritization of HTA challenges which were approved by those experts involved in the strategic planning of the Department of Health Technology Assessment will be a step forward in the promotion of an evidence- based policy- making and in the production of comprehensive scientific evidence. PMID- 25695016 TI - Factors associated with delay in post-exposure prophylaxis in bitten people. AB - BACKGROUND: Although the incidence of animal bite is increasing in Iran, there is no sufficient knowledge about delayed Post-Exposure Prophylaxis (PEP). Hence, the aim of this study was to evaluate delayed PEP and its associated factors in bitten people. METHODS: This cross-sectional study was conducted in Tuyserkan district of Hamadan Province (West of Iran) from February 2011 to February 2012 and included 425 cases of animal bites recorded in the Rabies Treatment Center (RTC) using the census method. The associations between delayed PEP and each of the potential risk factors were investigated using Chi-square test. RESULTS: Of 425 registered cases, 71.8% were male and 81.2% were from rural areas. The mean age of the subjects was 32.4 years (+/-21.3). Dogs were the most frequent source of exposure (69.4%), and the most common bitten part of the body was legs (49.4%). With respect to the wounds, 16.2% of the cases had deep injuries. Overall, 37.2% of the cases received timely PEP (less than 6 hours). Delayed PEP was associated with sex (p= 0.001), type of animal (p= 0.020), injury status (p<0.001), place of residence (p= 0.006) and distance from RTC (p<0.001). CONCLUSION: Although all victims of animal bite injuries suspected to be rabid, they received complete PEP. However, delayed time of PEP was still very high. The factors associated with delayed PEP may help health care workers to prevent adverse disease outcomes. Furthermore, considering the results of this study, it is highly recommended that proper attention and emphasis be given to public educational programs on dog behavior, dogchild interaction, the risk of dog bites and bite wound management for the general population, particularly children. PMID- 25695017 TI - Does kidney transplantation with deceased or living donor affect graft survival? AB - BACKGROUND: There are growing numbers of patients with end-stage renal disease globally at an unexpected rate. Today, the most serious challenge in transplantation is organ shortage; hence, using deceased donor is increasingly encouraged. OBJECTIVES: The aim of the study was to investigate the differences in survival rates between kidney transplant recipients with deceased donor and living donor. PATIENTS AND METHODS: In a retrospective cohort study, 218 patients who had undergone kidney transplantation in our institute from April 2008 to September 2010 were recruited. Demographics and post-transplantation follow-up data including immunosuppression regimens, rejection episodes, and survival rates were evaluated. The patients were assigned to two groups according to the donor kidney transplantation: group I, living donor kidney transplants; and group II, deceased donor kidney transplants. RESULTS: Although there were no significant differences in one-year survival rates of patient and graft between study groups, three-years survival rates of patient and graft were significantly longer in living donor kidney transplants in comparison with the deceased donor kidney recipients (P = 0.006 and P = 0.004, respectively). In Cox-regression model after adjusting for other confounding factors such as age, sex, diabetes mellitus, and first- or second-time transplantation, overall patient and graft survivals were also significantly shorter in deceased kidney transplantation than those who received kidney from a living donor (HR, 3.5; 95% CI, 1.2-10.4; and P = 0.02 for patient survival; and HR, 5.4; 95% CI, 1.5-19.5; and P = 0.009 for graft survival). CONCLUSIONS: We found acceptable short-term survival in both groups; however, living donor recipients continue to have better long-term patient and graft survival rates. PMID- 25695018 TI - The effect of the physical and mental exercises during hemodialysis on fatigue: a controlled clinical trial. AB - BACKGROUND: Despite regular treatment by hemodialysis, patients on hemodialysis are affected by uremic syndrome, which is marked by fatigue. Fatigue is supposed as the most common and the most severe symptom ever reported by patients with chronic kidney disease. OBJECTIVES: This controlled study aimed to evaluate the effect of intradialytic physical and mental exercises on fatigue in patients on hemodialysis. PATIENTS AND METHODS: A total of 66 patients on long-term hemodialysis were selected via purposive sampling and were assigned to two groups, namely, control and experimental groups. The experimental group participated in a intradialytic training program twice a week for two months. The program was designed by a senior expert in physical education. Their fatigue was measured via a fatigue severity scale questionnaire before as well as one and two months after the intervention in both groups. RESULTS: The mean of the fatigue score within the research units was 42.37. Overall, 42.2% and 56.1% of the participants experienced medium and severe fatigue, respectively. The scores of fatigue decreased significantly from the beginning through two months after intervention in the experiment group. CONCLUSIONS: With respect to the findings of the study, this method of treatment is recommended due to being cost efficient, easy, applicable, and flexible for alleviating the effect of fatigue on the personal, psychological, and social aspects of life quality in patients on hemodialysis. PMID- 25695019 TI - Splenic Marginal Zone Lymphoma and Concurrent Membranoproliferative Glomerulonephritis With IgMKappa Deposits in a HCV-Seropositive Patient. AB - We report a case of membranoproliferative glomerulonephritis (MPGN) with IgMkappa light chain deposits in a patient with chronic hepatitis C infection and simultaneous onset of monoclonal IgMkappa gammopathy with concurrent small B-cell lymphoproliferative disease. The patient presented with hepatosplenomegaly and a uremic state that necessitated dialysis without any clinical signs of systemic disease apart from the chronic infection with hepatitis C virus. The diagnostic approach led to a renal biopsy that revealed MPGN with dominant IgMkappa deposits and interstitium infiltration by the lymphoid cells. The bone marrow biopsy findings were consistent with splenic marginal zone lymphoma, a rare lymphoproliferative disorder with a rare association with MPGN. Our case indicates high diagnostic value of renal biopsy for rare lymphoplasmacytic neoplasms with renal dysfunction as their predominant clinical manifestation. PMID- 25695020 TI - Renal failure caused by malakoplakia lesions of the urinary bladder. AB - MUalakoplakia is a rare inflammatory condition of the urogenital tract. The most frequently affected organ is urinary bladder. This condition has features of a granulomatous inflammation, the pathogenesis of which is not well understood. In this study, we presented a case of urinary bladder malakoplakia associated with advanced obstructive uropathy and renal failure. PMID- 25695021 TI - Effects of interleukin 2 receptor blockers on patient and graft survival in renal transplanted children. AB - BACKGROUND: Monoclonal antibodies block interleukin-2 receptors on alloantigen reactive T-Lymphocytes and induce selective immunosuppression. It is postulated that induction therapy with these agents in pediatric transplantation may decrease acute rejection and improve graft survival with no significant side effect or increase in the incidence of viral infections. OBJECTIVES: The aim of this study was to examine the effects of interleukin 2 receptor blockers on patient and graft survival in renal-transplanted children. PATIENTS AND METHODS: One hundred and eighty six children aged 7-13 years who received renal transplantation in university-affiliated hospital between 2003 and 2012 were enrolled in the study. All patients received prednisolone, cyclosporine and mycophenolate mofetil or azathioprine as basic immunosuppressive therapy. Patients were divided into two groups according to receiving induction therapy with IL2-receptor blockers. We investigated for acute rejection episodes, Cytomegalovirus (CMV) and BK virus infection and one and three year's survival of the patients and the grafts. RESULTS: From 186 renal-transplanted children included in this study, 36 patients were in treated group (group 1) and 150 patients in control group (group 2). The mean age of the patients was 10.4 +/- 2 years and 55.6% were males. In first six months of transplantation, eight patients in group one had one episode of acute rejection and no one had two episodes. Early acute rejection rate was 8.36 (22%). In the control group, 37 patients had one episode and three patients had two episodes of acute rejection (rejection rate 28.6%). Therefore, early acute rejection rates were lower in group one. Late acute rejection rates did not show any difference in group 1 and group 2 (27.7% vs. 27.3% respectively). There was lower prevalence of steroid resistance rejection in group 1 patients (5.5%) compared with 6.6% in group 2, but it did not reach statistical significance. None of the patients in IL2-R blocker group died at one year follow-up (patient survival 100%). However, in control group, four (2.6%) patients died toward the end of first year (patient survival 97.4%). When patients in group 1 and group 2 were age and sex matched with equal number the difference was significant (P < 0.05). CONCLUSIONS: Induction therapy with IL2-R blockers reduced the rate of early acute rejection, but had no effect on late acute rejections. Patient and graft survival were better in treated group, but did not reach statistical significance. A longer period of follow-up may be required to discern a clear advantage for induction therapy with these agents. PMID- 25695022 TI - Giant Urinary Bladder Diverticula presenting as Epigastric Mass and Dyspepsia. AB - INTRODUCTION: Bladder diverticulum is a result of bladder mucosa and submucosa herniation through the muscularis propria of bladder wall. Bladder diverticula are mostly seen in the elderly men in association with benign prostatic hyperplasia (BPH). CASE PRESENTATION: A 74-year-old man presented with complaints of vague epigastric discomfort, dyspepsia, and mild lower urinary tract symptoms. An ultrasonography of the abdomen showed bilateral hydroureteronephrosis, large cystic lesion with the size of 26.3 * 20.5 cm and in continuation of urinary bladder and prostate of 70 mL volume. Voiding cystourethrogram revealed a large diverticulum with its neck communicating with bladder on posterior aspect. Abdominopelvic contrast-enhanced computed tomography revealed bilateral hydronephrosis with large bladder diverticulum of 27.3 * 21.5 cm in size with smooth diverticular wall. On cystoscopy, the neck of diverticulum was seen at the posterior wall of bladder. Open prostatectomy and diverticulectomy were done simultaneously (Figure 3). Postoperative course was uneventful. The histopathological assessment showed features of chronic inflammation without any evidence of malignancy. On the third postoperative day, the urethral catheter was removed and suprapubic catheter was clamped. Patient was voiding well and cystography done on day 12 revealed smooth bladder contour without any leakage; hence, suprapubic catheter was removed. Patient was discharged in satisfactory condition. CONCLUSIONS: The elderly men are at high risk of developing bladder diverticulum, which may be due to high prevalence BPH in this group. Although presentation of bladder diverticulum is nonspecific, its effect on renal system is significant. Therefore, awareness of patients and physicians is necessary to prevent its consequences. PMID- 25695023 TI - Association of diet with prostate specific antigen and prostate volume. AB - BACKGROUND: Prostate is an important male reproductive system gland and its disorders can affect men's quality of life and health. Prostatitis, benign prostatic hyperplasia (BPH), and prostate adenocarcinoma are major disorders that can be found in all men in different ages. OBJECTIVES: The aim of this study was to investigate the association of diet with serum prostate specific antigen (PSA) level as well as prostate volume. PATIENTS AND METHODS: In this cross-sectional study, 950 men older than 40 years of age who had attended our clinic for a screening program for prostate cancer were enrolled. Data was extracted from the program database. The eligible cases included all noncancerous subjects with available data concerning serum PSA level and prostate volume; the patients had completed a 50-item self-administered food frequency questionnaire about their diet during the preceding two year. RESULTS: No overall association was found between the consumption of foods and prostate volume as well as serum PSA level. There was a significant correlations between age and serum PSA level (r = 0.24) as well as with prostate volume (r = 0.22) (P < 0.001). In addition, there was a significant correlation between serum PSA level and prostate volume (r = 0.41 and P < 0.001). CONCLUSIONS: The results of this study confirmed the previous reports regarding the serum PSA level correlation with prostate volume. There was no evidence that dietary patterns might have any important effect on prostate volume and serum PSA in this Iranian population. PMID- 25695024 TI - The accuracy of transrectal ultrasound-guided biopsy for decision making in prostate cancer. AB - BACKGROUND: The most important surgical complications of renal transplantation are stenosis and obstruction of anastomosis of the ureter to the bladder. Hence, routine use of ureteral stents to prevent such complications seems logical; however, the optimal time to remove the ureteral stent is still controversial. OBJECTIVES: The purpose of this study was to compare the benefits and complications of the early or delayed ureteral stent removal post transplantation. PATIENTS AND METHODS: All patients who underwent kidney transplantation in Modarres Hospital from May 2011 through March 2012 were recruited. The patients were allocated to three groups. Ureteral stent removed 10, 20, and 30 days after transplantation in groups one, two, and three, respectively. RESULTS: A total of 91 patients had undergone renal transplantation in our center. Ureteral stent was removed at 10, 20, and 30 days after surgery. Urologic complications among the three groups included hydronephrosis, urinoma, and collection around the graft; there was no statistically significant difference among study groups with regard to frequency of complications. CONCLUSIONS: We can remove the ureteral stent at shorter interval after renal transplantation with no increased risk of urologic complications. PMID- 25695025 TI - Corrigendum to: Lethal Pneumocystis jiroveci pneumonia 24 Years After Kidney Transplantation [Published in Nephro Urol Mon. 2014 March; 6(2): e13605. DOI: 10.5812/numonthly.13605]. PMID- 25695026 TI - Anemia and microvascular complications in patients with type 2 diabetes mellitus. AB - BACKGROUND: Although chronic kidney disease-induced anemia is more prevalent in patients with diabetes mellitus (DM), anemia is a common finding prior to manifestation of kidney disease. In presence of some risk factors at the time of diagnosing DM, microvascular complications must be considered. The effect of anemia as a risk factor on progression of DM complications is still unclear. OBJECTIVES: The aim of the study was to determine the prevalence of anemia and its association with microvascular complications in patients with type 2 DM. PATIENTS AND METHODS: This cross-sectional study was performed in the outpatient endocrinology clinic at Baqiyatallah University of Medical Sciences Hospital, Tehran, Iran. Study was done from February 2011 to February 2012. Patients with type 2 DM without any obvious symptom or sign of anemia were included in study. RESULTS: A total of 93 patients (30.4%) had anemia including 46 (15.1%) with normochromic normocytic, 44 (14.4%) with hyperchromic microcytic, and 3 (1%) with hyperchromic macrocytic anemias. There was a positive correlation between duration of DM and anemia. Microvascular complications were more frequent with normocytic or microcytic anemias. Glomerular filtration rate (GFR) was higher in patients without anemia; moreover, nephropathy was less frequent among them. Among patients with anemia, 43% had GFR of more than 90 mL/min and 19.4% had normoalbuminuria. Neuropathy, nephropathy, and retinopathy had strong association with anemia (odds ratio of 1.99, 1.7, and 1.5, respectively). CONCLUSIONS: Anemia is a common complication of DM and is associated with duration of disease and microvascular complications. PMID- 25695027 TI - Evaluation of sarcopenia in renal transplant recipients. AB - BACKGROUND: Chronic kidney disease can lead to sarcopenia; however, no study has described sarcopenia in the patients undergoing renal transplantation. OBJECTIVES: The aim of the present study was to assess the prevalence of sarcopenia in renal transplant recipients (RTR) and to evaluate the demographic and metabolic risk factors associated with sarcopenia in these patients. PATIENTS AND METHODS: Sarcopenia was diagnosed by measuring handgrip strength in 166 RTR (68 females and 98 males; mean age, 37.9 +/- 11.9 years). Basal metabolic rate, fat mass, free-fat mass, total body water, body mass index, and calf circumference were determined, along with blood biochemistry, vitamin D levels, and glomerular filtration rate. RESULTS: Among 166 patients, sarcopenia was present in 34 (20.5%). Handgrip, basal metabolic rate, free fat mass, and total body water were significantly lower in patients with sarcopenia in comparison with those without sarcopenia. There were no differences between patients with and without sarcopenia in terms of mean time since transplantation, the presence of diabetes mellitus, hypertension, coronary artery disease, hyperlipidemia, glomerular filtration rate, and body mass index. Univariate analysis revealed significant differences between patients with and without sarcopenia with respect to age (mean of 43.70 +/- 13.97 and 36.37 +/- 10.82 years, respectively; P = 0.007) and 25-OH vitamin D levels (median (IQR) of 12 (2-39) and 17.70 (3-68) MUg/L, respectively; P = 0.024). There was a statistically significant positive correlation between vitamin D levels and handgrip strength (r = 0.334; P < 0.001). Multivariate regression analysis determined that age was an independent predictive variable of sarcopenia in RTR (beta = 1.060; 95% CI, 1.017-1.105; and P = 0.006). CONCLUSIONS: Chronic renal disease contributes to sarcopenia, which may develop at an earlier age in RTR. PMID- 25695028 TI - Elevated Blood Pressure and Serum gamma -Glutamyltransferase as Significant Characteristics of Smokers With Chronic Kidney Disease. AB - BACKGROUND: Smoking is a risk factor for chronic kidney disease (CKD). However, it is speculated that only a small subset of sensitive smokers develop CKD. OBJECTIVES: We aimed to reveal the characteristics of such smokers sensitive to the renal effects of smoking with respect to cardiovascular (CV) risk factors associated with smoking and/or CKD. PATIENTS AND METHODS: Renal functions and CVD risk factors were assessed in middle-aged male workers. The patients were comprised of 336 nonsmokers, 332 smokers currently smoking up to one pack per day, and 38 who smoked more than one pack per day. CKD was determined by estimated glomerular filtration rate (eGFR) from serum creatinine and urinary albumin to creatinine ratio (ACR). The independent and interactive effects of smoking and CKD on the CVD risk factors adjusted for age, body mass index, alcohol consumption, and physical activity were statistically analyzed. RESULTS: In comparison to nonsmokers, smokers had significantly higher waist circumference, white blood cells (WBC), serum triglycerides, gamma glutamyltransferase (GGT), and C-reactive protein (CRP) and lower serum high density lipoprotein cholesterol and uric acid. On the other hand, blood pressure (BP) and WBC tended to be higher in those showing CKD than others. Serum GGT and fasting plasma glucose were significantly higher, and insulin resistance index of homeostatic model assessment (HOMA-IR) tended to be higher in those with CKD. Serum CRP was especially high in those with moderate to severe CKD. A significant interactive effect of smoking and CKD on BP and serum GGT levels was detected, i.e. BP and GGT were not different in the subjects among nonsmokers with and without CKD, but were conspicuously high among smokers with CKD. No significant interactive effect was found on either HOMA-IR or serum CRP. CONCLUSIONS: Smokers with a higher BP and/or serum GGT may be at a higher risk of developing CKD. The associations of BP and serum GGT with CKD in smokers are not entirely mediated by increased insulin resistance or chronic inflammation caused by smoking. PMID- 25695029 TI - Intrarenal pseudoaneurysm after percutaneous nephrolithotomy at solitary kidney. AB - INTRODUCTION: Percutaneous nephrolithotomy (PCNL) is a standard, safe, and efficient method for removing large renal calculi. Despite development of endourologic equipment, complications of the PCNL are still prevalent. Even though therapeutic modalities such as mini-micro PCNL have been developed in recent years, the complications are a serious concern yet. The most important complication is hemorrhage. The hemorrhage may be either arterial or venous. Venous hemorrhage is usually treated conservatively whereas the arterial one might require transarterial embolization (TAE). Arterial hemorrhage may cause serious problems, especially in the patients with solitary kidney. CASE PRESENTATION: In the presented patient, serious retroperitoneal hemorrhage and hypotension in the preoperative and postoperative periods resulted in acute renal failure (ARF). CONCLUSIONS: It was first report of selective TAE in a patient with ARF due to post-PCNL pseudoaneurysm in solitary kidney. Super-selective segmental embolization was performed successfully in this case and was shown to be a reliable and efficient procedure. PMID- 25695030 TI - Prevalence of chronic kidney disease and associated factors in senegalese populations: a community-based study in saint-louis. AB - BACKGROUND: Chronic kidney disease (CKD) is an emerging worldwide epidemic but littledata concerning African populations are available. OBJECTIVES: We aimed to assess prevalence of CKD in adult populations of Saint-Louis, northern Senegal. PATIENTS AND METHODS: In a population-based survey between January and May 2012, we included 1037 adults >= 18 years of age who resided in Saint-Louis. Socio demographic, clinical, and biologic data were collected during household visits. Serum creatinine was measured by Jaffe method. We estimated glomerular filtration rate (eGFR) using the four-variable Modification of Diet in Renal Disease (MDRD) equation and CKD was defined by eGFR< 60 mL/min/1.73 m(2) and/or albuminuria > 1 g/L. A multivariate logistic regression was performed to identify factors associated with CKD. RESULTS: The mean of participants' age was 47.9 +/- 16.9 years (range, 18-87) and sex ratio (male to female) was 0.52. Majority of participants lived in urban areas (55.3%) and had school education (65.6%). Hypertension, diabetes, and obesity were present respectively in 39.1%, 12.7%, and 23.4% of participants. Overall CKD prevalence was 4.9% (95% CI, 3.5-6.2) with eGFR< 30 mL/min/1.73 m(2) in 0.9%. Albuminuria > 1 g/L was found in 3.5% of patients. CKD was significantly more frequent among hypertensive patients in comparison with normotensive ones. Risk factors associated with CKD were hypertension (12% of risk excess) and age (3% of risk excess). CONCLUSIONS: CKD is frequent in adult population living in Northern Senegal. Main associated factors are hypertension and age. Prevention strategies are urgently needed to raise public awareness and promote early CKD detection and treatment in both urban and rural areas. PMID- 25695031 TI - Extramedullary hematopoiesis presenting as a right adrenal mass in a patient with Beta thalassemia. AB - INTRODUCTION: Extramedullary hematopoiesis in the kidney and adrenal are rarely reported in medical literature and are usually found as incidentaloma. It usually occurs in patients with hematologic disorder such as thalassemia. CASE PRESENTATION: The patient was a 23-year-old Iranian man with beta thalassemia who was admitted with a suprarenal mass. Adrenal mass was detected by ultrasonography and computed tomography. Results of biochemical evaluations were insignificant. The patient underwent right adrenalectomy. Gross and microscopic histopathologic examination demonstrated extramedullary hematopoiesis without any adrenal tissue. CONCLUSIONS: To the best of our knowledge, we document the first reported case of adrenal extramedullary hematopoiesis in Iran, which seems to be rare and remarkable. PMID- 25695032 TI - Effects of pretreatment with single-dose or intermittent oxygen on Cisplatin induced nephrotoxicity in rats. AB - BACKGROUND: Renal injury is the main side effect of cisplatin (CP), an anticancer drug. It has been shown that pretreatment with single-dose oxygen (0.5 to six hours) could reduce CP-induced renal toxicity in rats. OBJECTIVES: The present study aimed to compare the effects of pretreatment with single-dose and intermittent O2 on CP-induced nephrotoxicity. MATERIALS AND METHODS: Adult male rats were allocated to seven groups (eight rats in each group). The rats were kept in normal air or hyperoxic environment (O2, 80%) for either a single six hour period or intermittent six hours per day for seven days and then were subjected to intraperitoneal injection of saline or CP (5 mg/kg) at 48 hours, 72 hours, or seven days after exposure to O2. Three days after CP (or Saline) injection, renal function tests, renal tissue injury scores, and cleaved Caspase 3 and Bax/Bcl-2 genes expression (as markers of renal cell apoptosis) were assessed. RESULTS: Treatment with the 6-hour single-dose O2 reduced renal injury significantly when CP was administrated 48 hours after O2 pretreatment. Pretreatment with intermittent seven days of six hours per day had no protective effects and even relatively worsened renal injury when CP was injected 48 hours or 72 hours after the last session of O2 pretreatment. The beneficial effects of pretreatment with O2 on renal structure and function were seen if CP was administrates seven days after pretreatment with intermittent O2. CONCLUSIONS: The pattern of pretreatment with O2 could change this potential and highly protective strategy against CP-induced nephropathy to an ineffective or even mildly deteriorating one. Therefore, O2 administration before CP injection to patients with cancer, for therapeutic purposes or as a preconditioning approach, should be performed and investigated with caution until exact effects of different protocols has been determined in human. PMID- 25695033 TI - Minimally invasive management of biliary tract injury following percutaneous nephrolithotomy. AB - INTRODUCTION: Percutaneous nephrolithotomy is generally considered a safe option for the management of large complex or infectious upper urinary tract calculi. Biliary tract injury is a rare and potentially serious complication of percutaneous nephrolithotomy that can even lead to mortality, especially in cases where biliary peritonitis develops. All reported cases of biliary tract injury have been managed by either open or laparoscopic cholecystectomy. CASE PRESENTATION: Herein for the first time, we report a 39-year old woman with biliary tract injury following percutaneous nephrolithotomy who was managed less invasively by insertion of a percutaneous cholecystostomy tube. The patient was discharged home shortly thereafter, and the tube was later removed at a follow up visit after a normal cholangiogram. CONCLUSIONS: Biliary tract injury is a rare and potentially serious complication of percutaneous nephrolithotomy that can even lead to mortality. If a biliary tract injury is suspected during percutaneous renal procedures, diverting the bile away from the leak may resolve the problem without the need for a cholecystectomy. Ideally this can be done with ERCP and a stent, but in cases where this is not technically feasible; a percutaneous cholecystostomy can be successful at accomplishing the same result. PMID- 25695034 TI - Lack of improvement: a national assessment of readmission rates after pediatric bladder reconstruction. AB - BACKGROUND: Bladder reconstruction in the pediatric population is challenging for many reasons, including perioperative complications and readmissions. OBJECTIVES: On a national scale, determine readmission rates at 30, 60 and 90 days after bladder reconstruction in a pediatric population over a 7-year period, evaluating the influence of hospital and patient-specific variables. PATIENTS AND METHODS: Using the Pediatric Health Information System database, we identified patients 0 17 years of age, from 2004-2010, undergoing bladder reconstruction using ICD-9 procedure codes. Descriptive statistics characterized demographics, prevalence of surgeries, and readmission rates. Surgery prevalence over time was examined using linear regression. Readmission rates were compared using the Chi2 test. Regression was used to evaluate the influence of variables on readmission risk. RESULTS: We identified 1,985 patients for inclusion, of which 52.7% were female. Median age was 9 years. There has been no change in the prevalence of bladder reconstruction surgeries (P = 0.327). There was no change in 30-day (P = 0.272), 60-day (P = 0.788) or 90-day readmission rates (P = 0.924). Despite surgical volume adjustment, 90-day readmission rates did not significantly vary among the majority of hospitals. Initial LOS > 7 days (P < 0.001) and complex chronic condition males (P < 0.001) were significantly associated with 90-day readmission. CONCLUSIONS: No improvement in readmission rates after pediatric bladder reconstruction was observed during the study period. Nearly all centers have a similar readmission rate despite volume adjustment. PMID- 25695035 TI - Chronic kidney disease progression in elderly Iranian patients: a cohort study. AB - BACKGROUND: In the past few decades, Chronic Kidney Disease (CKD) - a disease with progressive decline in renal function - has become an important problem of global public health, not only in developed countries, but also in developing countries with less economic power. OBJECTIVES: In this study, CKD progression to death or End Stage Renal Disease (ESRD) in elderly Iranian patients was compared with younger counterparts. PATIENTS AND METHODS: This retrospective cohort study was conducted on CKD patients with estimated Glomerular Filtration Rate (eGFR) < 60 mL/min, in a nephrology clinic in Tehran from December of 2006 until December of 2012. eGFR trend, death and need to renal replacement therapy (RRT) were evaluated as outcomes and compared between patients younger and older than 60 years. Data were analyzed using SPSS version 13. RESULTS: Five-hundred and two patients were enrolled and followed up for an average of 37.6 months. Two thirds of the patients were older than 60 years. The incidence density of ESRD in patients younger and older than 60 years were 6.3 and 3.6 for 100 persons per year, respectively. Younger ones showed more rapid decline in their eGFR, while older patients had more stable renal function. CONCLUSIONS: It seems necessary to conduct more researches in order to redefine CKD and identify its prognostic markers in elderly population. PMID- 25695036 TI - Association between plasma selenium and glutathione peroxidase levels and severity of diabetic nephropathy in patients with type two diabetes mellitus. AB - BACKGROUND: Oxidative stress is thought to be involved in the pathogenesis of diabetic nephropathy. Selenium (Se), and antioxidant enzymes such as glutathione peroxidase (GPx) play an important protective role in diabetes complications. OBJECTIVES: This study aimed to evaluate the association between plasma Se and GPx levels with severity of diabetic nephropathy. PATIENTS AND METHODS: In a case control study, we measured plasma Se and GPx concentrations in patients with type two diabetes without microalbuminuria (group 1), with microalbuminuria (group 2), with macroalbuminuria (group 3), and healthy control subjects (group 4). We also assessed plasma glucose, urea, creatinine, and glycated hemoglobin levels in all study patients. RESULTS: Plasma Se and GPx concentrations were significantly lower in diabetic patients with macroalbuminuria than other study groups (P < 0.001). Albuminuria (Alb/Cr in random urine sample) had a negative correlation with plasma Se (r = -0.40, P = 0.01), and GPx (r = -0.23, P = 0.03) concentrations. CONCLUSIONS: Plasma Se and GPx levels were lower in type two diabetic patients with macroalbuminuria and related to the stage of diabetic nephropathy. PMID- 25695037 TI - Effect of testosterone on Cisplatin-induced nephrotoxicity in surgically castrated rats. AB - BACKGROUND: Cisplatin (CP) is an important antitumor drug with serious side effects such as nephrotoxicity. Estrogens can affect CP-induced nephrotoxicity; however, the role of testosterone (TS), the main male sex hormone, is not clear. OBJECTIVES: This study aimed to investigate the effect of TS on CP-induced nephrotoxicity in castrated male rats. MATERIALS AND METHODS: A total of 54 male Wistar rats were castrated and allocated into eight groups. Groups 1 through 3 respectively received 10, 50, and 100 mg/kg/wk of TS and group 4 received sesame oil for four weeks; then all four groups received 2.5 mg/kg/d CP for one week. Groups 5 through 8 received the same treatment regimen as groups 1 through 4 during first four weeks but instead of CP, they received saline for one week. Then the animals were sacrificed for biochemical and histopathologic studies. RESULTS: CP increased the serum levels of blood urea nitrogen (BUN), creatinine (Cr), and malondialdehyde (SMDA) as well as kidney weight (KW), bodyweight (BW) loss, and kidney tissue damage score (KTDS). It significantly decreased the serum and kidney levels of nitrite and serum level of TS in comparison with the control group (P < 0.05). However, coadministration of CP and low dose of TS significantly decreased the serum levels of BUN as well as Cr and KTDS (P < 0.05). Administration of high-dose TS alone increased the SMDA level, KTDS, and KW while decreased the BW significantly (P < 0.05). CONCLUSIONS: It seems that testosterone in low dose, i.e. physiologic dose, protects kidneys against CP induced nephrotoxicity; however, special care is needed in CP therapy of patients with high levels of TS. PMID- 25695038 TI - Measuring the quality of provided services for patients with chronic kidney disease. AB - BACKGROUND: The healthcare organizations need to develop and implement quality improvement plans for their survival and success. Measuring quality in the healthcare competitive environment is an undeniable necessity for these organizations and will lead to improved patient satisfaction. OBJECTIVES: This study aimed to measure the quality of provided services for patients with chronic kidney disease in Kerman in 2014. PATIENTS AND METHODS: This cross-sectional, descriptive-analytic study was performed from 23 January 2014 to 14 February 2014 in four hemodialysis centers in Kerman. All of the patients on chronic hemodialysis (n = 195) who were referred to these four centers were selected and studied using census method. The required data were collected using the SERVQUAL questionnaire, consisting of two parts: questions related to the patients' demographic characteristics, and 28 items to measure the patients' expectations and perceptions of the five dimensions of service quality, including tangibility, reliability, responsiveness, assurance, and empathy. The collected data were analyzed using SPSS 21.0 through some statistical tests, including independent samples t test, one-way ANOVA, and paired-samples t test. RESULTS: The results showed that the means of patients' expectations were more than their perceptions of the quality of provided services in all dimensions, which indicated that there were gaps in all dimensions. The highest and lowest means of negative gaps were related to empathy (-0.52 +/- 0.48) and tangibility (-0.29 +/- 0.51). In addition, among the studied patients' demographic characteristics and the five dimensions of service quality, only the difference between the patients' income levels and the gap in assurance were statistically significant (P < 0.001). CONCLUSIONS: Overall, the results of the present study showed that the expectations of patients on hemodialysis were more than their perceptions of provided services. The healthcare providers and employees should pay more attention to the patients' opinions and comments and use their feedback to solve the workplace problems and improve the quality of provided services. In addition, training the health staff to meet the patients' emotional needs and expectations is suggested. PMID- 25695039 TI - Restless leg syndrome: a neglected diagnosis. AB - CONTEXT: Restless legs syndrome (RLS) is an irresistible urge to move legs that usually occur during inactivity and at night. This neurologic condition is associated with increased risk of nocturnal hypertension as well as cardiovascular events and affects patient's sleep, which leads to anxiety, depression, and decreases quality of life. Presence of RLS in patients on hemodialysis is associated with higher mortality rate. Most of the times, patients have indescribable symptoms. The aim of this review was to provide physicians with information to be aware and turn their attention to the patient's symptoms, which are the most important clue to diagnosis of RLS. EVIDENCE ACQUISITION: For data extraction, we reviewed PubMed, Scopus, Google scholar, the Cochrane collaboration, and Up to Date databases with the keywords of restless legs syndrome, sleep disorders, and end-stage renal disease (ESRD). The most recent review articles, clinical trials, and cross-sectional studies with large sample sizes that had used International RLS Study Group criteria (IRLSSG) and had focused on demographic characteristics and renal function were included. This situation has described in primary and secondary forms. The former usually occurs in younger patients and seems to have genetic tendencies and the latter is due to the iron deficiency state, pregnancy, and ESRD. RESULTS: Two major theories are developed regarding the pathophysiology of RLS. The first one concerns central nervous system dopamine imbalance and the second one concerns intracellular iron dysregulation. The most common used pharmacologic agents in treatment of RLS are dopamine agonists. Other used therapeutic agents include levodopa, Alpha-2-delta calcium channel ligands, opioids, anticonvulsants, benzodiazepines, clonidine, iron therapy in low levels of serum ferritin, and nonpharmacologic therapies. CONCLUSIONS: The most important factor in diagnosis is physician's attention and clinical experience with this condition and using IRLSSG. PMID- 25695040 TI - Questioning the HIV-AIDS Hypothesis: 30 Years of Dissent. PMID- 25695041 TI - Development of enhanced primer sets for detection of norovirus. AB - Norovirus (NV) is a major viral pathogen that causes nonbacterial acute gastroenteritis and outbreaks of food-borne disease. The genotype of NV most frequently responsible for NV outbreaks is GII.4, which accounts for 60-80% of cases. Moreover, original and new NV variant types have been continuously emerging, and their emergence is related to the recent global increase in NV infection. In this study, we developed advanced primer sets (NKI-F/R/F2, NKII F/R/R2) for the detection of NV, including the variant types. The new primer sets were compared with conventional primer sets (GI-F1/R1/F2, SRI-1/2/3, GII F1/R1/F2, and SRII-1/2/3) to evaluate their efficiency when using clinical and environmental samples. Using reverse transcription polymerase chain reaction (RT PCR) and seminested PCR, NV GI and GII were detected in 91.7% (NKI-F/R/F2), 89.3% (NKII-F/R/R2), 54.2% (GI-F1/R1/F2), 52.5% (GII-F1/R1/F2), 25.0% (SRI-1/2/3), and 32.2% (SRII-1/2/3) of clinical and environmental specimens. Therefore, our primer sets perform better than conventional primer sets in the detection of emerged types of NV and could be used in the future for epidemiological diagnosis of infection with the virus. PMID- 25695042 TI - Targeting of prosurvival pathways as therapeutic approaches against primary effusion lymphomas: past, present, and Future. AB - Constitutively activated prosurvival pathways render cancer cells addicted to their effects. Consequently they turn out to be the Achilles' heels whose inhibition can be exploited in anticancer therapy. Primary effusion lymphomas (PELs) are very aggressive non-Hodgkin's B cell lymphomas, whose pathogenesis is strictly linked to Kaposi's sarcoma herpesvirus (KSHV) infection. Here we summarized previous studies from our and other laboratories exploring the cytotoxic effect of drugs inhibiting the main prosurvival pathways activated in PEL cells. Moreover, the immunogenicity of cell death, in terms of dendritic cell (DC) activation and their potential side effect on DCs, is discussed. PMID- 25695043 TI - Nuclear medicine in diagnosis of prosthetic valve endocarditis: an update. AB - Over the past decades cardiovascular disease management has been substantially improved by the increasing introduction of medical devices as prosthetic valves. The yearly rate of infective endocarditis (IE) in patient with a prosthetic valve is approximately 3 cases per 1,000 patients. The fatality rate of prosthetic valve endocarditis (PVE) remains stable over the years, in part due to the aging of the population. The diagnostic value of echocardiography in diagnosis is operator-dependent and its sensitivity can decrease in presence of intracardiac devices and valvular prosthesis. The modified Duke criteria are considered the gold standard for diagnosing IE; their sensibility is 80%, but in clinical practice their diagnostic accuracy in PVE is lower, resulting inconclusively in nearly 30% of cases. In the last years, these new imaging modalities have gained an increasing attention because they make it possible to diagnose an IE earlier than the structural alterations occurring. Several studies have been conducted in order to assess the diagnostic accuracy of various nuclear medicine techniques in diagnosis of PVE. We performed a review of the literature to assess the available evidence on the role of nuclear medicine techniques in the diagnosis of PVE. PMID- 25695044 TI - New insights into malignant B-cell disorders. PMID- 25695045 TI - Health safety of soft drinks: contents, containers, and microorganisms. AB - Soft drinks consumption is still a controversial issue for public health and public policy. Over the years, numerous studies have been conducted into the possible links between soft drink intake and medical problems, the results of which, however, remain highly contested. Nevertheless, as a result, increasing emphasis is being placed on the health properties of soft drinks, by both the industry and the consumers, for example, in the expanding area of functional drinks. Extensive legislation has been put in place to ensure that soft drinks manufacturers conform to established national and international standards. Consumers trust that the soft drinks they buy are safe and their quality is guaranteed. They also expect to be provided with information that can help them to make informed decisions about the purchase of products and that the information on product labels is not false or misleading. This paper provides a broad overview of available scientific knowledge and cites numerous studies on various aspects of soft drinks and their implications for health safety. Particular attention is given to ingredients, including artificial flavorings, colorings, and preservatives and to the lesser known risks of microbiological and chemical contamination during processing and storage. PMID- 25695046 TI - Aortic arch calcification predicts the renal function progression in patients with stage 3 to 5 chronic kidney disease. AB - INTRODUCTION: The presence of aortic arch calcification (AoAC) and cardiomegaly on chest radiography has been demonstrated as important risk factors for cardiovascular mortality in patients with chronic kidney disease (CKD). However, the interrelationship among AoAC, cardiomegaly, and renal function progression remains unclear. The aim of this study is to assess whether AoAC and cardiomegaly are independently associated with the renal function progression in patients with stages 3-5 CKD. METHODS: We retrospectively determined AoAC and cardiomegaly by chest X-ray in 237 patients, followed up for at least three years without entering dialysis and classified into 4 groups according to the presence or absence of AoAC and cardiomegaly. The change in renal function was measured by the slope of estimated glomerular filtration rate (eGFR). RESULTS: Of the 237 patients, the rate of eGFR decline was significantly higher in the group with coexistence of AoAC and cardiomegaly than any other groups. Baseline AoAC and proteinuria were independently associated with eGFR decline. AoAC were independently determined by age, eGFR slope, and cardiomegaly. CONCLUSIONS: The coexistence of AoAC and cardiomegaly is associated with faster eGFR decline. AoAC is an independent determinant of renal outcomes in patients with CKD stages 3-5. PMID- 25695047 TI - A protective role of arecoline hydrobromide in experimentally induced male diabetic rats. AB - OBJECTIVES: Arecoline, the most potent and abundant alkaloid of betel nut, causes elevation of serum testosterone and androgen receptor expression in rat prostate, in addition to increase in serum insulin levels in rats, leading to insulin resistance and type 2 diabetes-like conditions. This study investigated the role of arecoline on the reproductive status of experimentally induced type 1 diabetic rats. METHODS: Changes in the cellular architecture were analyzed by transmission electron microscopy. Blood glucose, serum insulin, testosterone, FSH, and LH were assayed. Fructose content of the coagulating gland and sialic acid content of the seminal vesicles were also analyzed. RESULTS: Arecoline treatment for 10 days at a dose of 10 mg/kg of body weight markedly facilitated beta-cell regeneration and reversed testicular and sex accessory dysfunctions by increasing the levels of serum insulin and gonadotropins in type 1 diabetic rats. Critical genes related to beta-cell regeneration, such as pancreatic and duodenal homeobox 1 (pdx-1) and glucose transporter 2 (GLUT-2), were found to be activated by arecoline at the protein level. CONCLUSION: It can thus be suggested that arecoline is effective in ameliorating the detrimental effects caused by insulin deficiency on gonadal and male sex accessories in rats with type 1 diabetes. PMID- 25695048 TI - Effect of dietary lead on intestinal nutrient transporters mRNA expression in broiler chickens. AB - Lead- (Pb-) induced oxidative stress is known to suppress growth performance and feed efficiency in broiler chickens. In an attempt to describe the specific underlying mechanisms of such phenomenon we carried out the current study. Ninety six one-day-old broiler chicks were randomly assigned to 2 dietary treatment groups of 6 pen replicates, namely, (i) basal diet containing no lead supplement (control) and (ii) basal diet containing 200 mg lead acetate/kg of diet. Following 3 weeks of experimental period, jejunum samples were collected to examine the changes in gene expression of several nutrient transporters, antioxidant enzymes, and heat shock protein 70 (Hsp70) using quantitative real time PCR. The results showed that addition of lead significantly decreased feed intake, body weight gain, and feed efficiency. Moreover, with the exception of GLUT5, the expression of all sugar, peptide, and amino acid transporters was significantly downregulated in the birds under Pb induced oxidative stress. Exposure to Pb also upregulated the antioxidant enzymes gene expression together with the downregulation of glutathione S-transferase and Hsp70. In conclusion, it appears that Pb-induced oxidative stress adversely suppresses feed efficiency and growth performance in chicken and the possible underlying mechanism for such phenomenon is downregulation of major nutrient transporter genes in small intestine. PMID- 25695049 TI - Frequency of migraine as a chief complaint in otolaryngology outpatient practice. AB - OBJECTIVE: To identify the frequency of typical (headache and dizziness) and common atypical (ear fullness, pressure, pain, tinnitus, facial fullness, and nasal congestion) migraine symptoms as chief complaints among patients presenting to otolaryngology clinic. METHODS: This is a descriptive study of prospectively collected data from a general otolaryngology practice. Typical migraine presentations were diagnosed by applying international headache society (IHS) criteria for migraine headache and Neuhauser's criteria for migrainous vertigo. Atypical otologic and rhinologic migraine symptoms were diagnosed using individualized criteria. Charts were reviewed at 6-month interval from the first presentation. RESULTS: Out of 1002 consecutive patients, 10.8% presented with "migrainous chief complaint." All migrainous chief complaint patients had a history of headache but not all of them presented with headache. Corrected female to male ratio in the migraine group was 3 to 1; age distributions were significantly different between the migraine and nonmigraine groups by applying t test. Out of the atypical complaints, 86% of the patients had a history of concomitant typical presentation. CONCLUSION: Actual diagnostic criteria for migraine do not satisfy the diversity of its presentation. Investigating the history of migraine is enough to diagnose most atypical presentations. Sound knowledge about migraine seems essential for any ENT practitioner. PMID- 25695050 TI - A therapeutic strategy for spinal cord defect: human dental follicle cells combined with aligned PCL/PLGA electrospun material. AB - Stem cell implantation has been utilized for the repair of spinal cord injury; however, it shows unsatisfactory performance in repairing large scale lesion of an organ. We hypothesized that dental follicle cells (DFCs), which possess multipotential capability, could reconstruct spinal cord defect (SCD) in combination with biomaterials. In the present study, mesenchymal and neurogenic lineage characteristics of human DFCs (hDFCs) were identified. Aligned electrospun PCL/PLGA material (AEM) was fabricated and it would not lead to cytotoxic reaction; furthermore, hDFCs could stretch along the oriented fibers and proliferate efficiently on AEM. Subsequently, hDFCs seeded AEM was transplanted to restore the defect in rat spinal cord. Functional observation was performed but results showed no statistical significance. The following histologic analyses proved that AEM allowed nerve fibers to pass through, and implanted hDFCs could express oligodendrogenic lineage maker Olig2 in vivo which was able to contribute to remyelination. Therefore, we concluded that hDFCs can be a candidate resource in neural regeneration. Aligned electrospun fibers can support spinal cord structure and induce cell/tissue polarity. This strategy can be considered as alternative proposals for the SCD regeneration studies. PMID- 25695051 TI - Salvage pelvic lymph node dissection in recurrent prostate cancer: surgical and early oncological outcome. AB - METHODOLOGY: Seventeen patients with prostate-specific antigen (PSA) rise following local treatment for prostate cancer with curative intent underwent open or minimally invasive salvage pelvic lymph node dissection (SLND) for oligometastatic disease (<4 synchronous metastases) or as staging prior to salvage radiotherapy. Biochemical recurrence after complete biochemical response (cBR) was defined as 2 consecutive PSA increases >0,2 ng/mL; and after incomplete biochemical response as 2 consecutive PSA rises. Newly found metastasis on imaging defined clinical progression (CP). Palliative androgen deprivation therapy (ADT) was initiated if >3 metastases were detected or if patients became symptomatic. Kaplan-Meier statistics were applied. RESULTS: Clavien-Dindo grade 1, 2, 3a, and 3b complications were seen in 6, 1, 1, and 2 patients, respectively. Median follow-up time was 22 months. Among 13 patients treated for oligometastatic disease, 8 (67%) had a PSA decline, with 3 patients showing cBR. Median PSA progression-free survival (FS) was 4.1 months and median CP-FS 7 months. Three patients started ADT, resulting in a 2-year ADT-FS rate of 79.5%. CONCLUSION: SLND is feasible, but postoperative complication rate seems higher than that for primary LND. Biochemical and clinical response duration is limited, but as part of an oligometastatic treatment regime it can defer palliative ADT. PMID- 25695052 TI - A complex genome-microRNA interplay in human mitochondria. AB - Small noncoding regulatory RNA exist in wide spectrum of organisms ranging from prokaryote bacteria to humans. In human, a systematic search for noncoding RNA is mainly limited to the nuclear and cytosolic compartments. To investigate whether endogenous small regulatory RNA are present in cell organelles, human mitochondrial genome was also explored for prediction of precursor microRNA (pre miRNA) and mature miRNA (miRNA) sequences. Six novel miRNA were predicted from the organelle genome by bioinformatics analysis. The structures are conserved in other five mammals including chimp, orangutan, mouse, rat, and rhesus genome. Experimentally, six human miRNA are well accumulated or deposited in human mitochondria. Three of them are expressed less prominently in Northern analysis. To ascertain their presence in human skeletal muscles, total RNA was extracted from enriched mitochondria by an immunomagnetic method. The expression of six novel pre-miRNA and miRNA was confirmed by Northern blot analysis; however, low level of remaining miRNA was found by sensitive Northern analysis. Their presence is further confirmed by real time RT-PCR. The six miRNA find their multiple targets throughout the human genome in three different types of software. The luciferase assay was used to confirm that MT-RNR2 gene was the potential target of hsa-miR-mit3 and hsa-miR-mit4. PMID- 25695053 TI - Automated training for algorithms that learn from genomic data. AB - Supervised machine learning algorithms are used by life scientists for a variety of objectives. Expert-curated public gene and protein databases are major resources for gathering data to train these algorithms. While these data resources are continuously updated, generally, these updates are not incorporated into published machine learning algorithms which thereby can become outdated soon after their introduction. In this paper, we propose a new model of operation for supervised machine learning algorithms that learn from genomic data. By defining these algorithms in a pipeline in which the training data gathering procedure and the learning process are automated, one can create a system that generates a classifier or predictor using information available from public resources. The proposed model is explained using three case studies on SignalP, MemLoci, and ApicoAP in which existing machine learning models are utilized in pipelines. Given that the vast majority of the procedures described for gathering training data can easily be automated, it is possible to transform valuable machine learning algorithms into self-evolving learners that benefit from the ever changing data available for gene products and to develop new machine learning algorithms that are similarly capable. PMID- 25695054 TI - The role of fundus autofluorescence imaging in the study of the course of posterior uveitis disorders. AB - BACKGROUND: To evaluate the correlation of fundus autofluorescence (FAF) with indocyanine green angiography (ICGA) in patients with various posterior uveitis disorders. METHODS: Interventional case series including 23 eyes of 15 patients with diagnosis of a specific type of retinochoroiditis, such as acute posterior multifocal placoid pigment epitheliopathy (APMPPE), serpiginous-like choroiditis, multifocal choroiditis (MFC), Harada disease, and syphilitic retinochoroiditis. Also, some cases with undefined retinochoroiditis were included. FAF and ICGA were performed and correlated at baseline and during follow-up after treatment. RESULTS: In ICGA, early hypofluorescence was found to be the hallmark of acute choroidal inflammation, resolving in later stages and remaining in the late phase in areas with retinal pigment epithelium (RPE) damage. Poorly defined hyperautofluorescent areas correlated with acute choroidal lesions. Hypoautofluorescent delineation suggested the initiation of RPE healing processes, correlating well with the late phase of ICGA and delineating the RPE damage. Early hyperautofluorescence with late hypofluorescence in ICGA indicated the presence of primary RPE involvement. CONCLUSION: FAF contributes to the interpretation of RPE disease and may be a useful tool for the follow-up of progressive inflammatory disorders. Comparative evaluation of FAF and ICGA allows a characterization of the sequence of inflammatory events and the level of tissue affected. PMID- 25695055 TI - Acupuncture may exert its therapeutic effect through microRNA 339/Sirt2/NFkappaB/FOXO1 axis. AB - Recently, we have found that a number of microRNAs (miRNAs) and proteins are involved in the response to acupuncture therapy in hypertensive rats. Our bioinformatics study suggests an association between these miRNAs and proteins, which include miR-339 and sirtuin 2 (Sirt2). In this paper, we aimed to investigate whether Sirt2 was a direct target of miR-339 in neurons. In human SH SY5Y cells, the luciferase assay implied that Sirt2 was likely a target of miRNA 339. Overexpression of miR-339 downregulated Sirt2 expression, while knockdown of miR-339 upregulated Sirt2 expression in human SH-SY5Y cells and rat PC12 cells. In addition, overexpression of miR-399 increased the acetylation of nuclear factor-kappaB (NF-kappaB) and forkhead box protein O1 (FOXO1) in SH-SY5Y cells, which are known targets of Sirt2. Our findings demonstrate that miR-339 regulates Sirt2 in human and rat neurons. Since Sirt2 plays a critical role in multiple important cellular functions, our data imply that acupuncture may act through epigenetic changes and subsequent action on their targets, such as miRNA 339/Sirt2/NF-kappaB/FOXO1 axis. Some physiological level changes of neurons after altering the miR-339 levels are needed to validate the suggested therapeutic role of miR-339/Sirt2/NF-kappaB/FOXO1 axis in response to acupuncture therapy in the future work. PMID- 25695056 TI - Analysis of the isomerase and chaperone-like activities of an amebic PDI (EhPDI). AB - Protein disulfide isomerases (PDI) are eukaryotic oxidoreductases that catalyze the formation and rearrangement of disulfide bonds during folding of substrate proteins. Structurally, PDI enzymes share as a common feature the presence of at least one active thioredoxin-like domain. PDI enzymes are also involved in holding, refolding, and degradation of unfolded or misfolded proteins during stressful conditions. The EhPDI enzyme (a 38 kDa polypeptide with two active thioredoxin-like domains) has been used as a model to gain insights into protein folding and disulfide bond formation in E. histolytica. Here, we performed a functional complementation assay, using a DeltadsbC mutant of E. coli, to test whether EhPDI exhibits isomerase activity in vivo. Our preliminary results showed that EhPDI exhibits isomerase activity; however, further mutagenic analysis revealed significant differences in the functional role of each thioredoxin-like domain. Additional studies confirmed that EhPDI protects heat-labile enzymes against thermal inactivation, extending our knowledge about its chaperone-like activity. The characterization of EhPDI, as an oxidative folding catalyst with chaperone-like function, represents the initial step to dissect the molecular mechanisms involved in protein folding in E. histolytica. PMID- 25695057 TI - Evaluation of osseous integration of PVD-silver-coated hip prostheses in a canine model. AB - Infection associated with biomaterials used for orthopedic prostheses remains a serious complication in orthopedics, especially tumor surgery. Silver-coating of orthopedic (mega)prostheses proved its efficiency in reducing infections but has been limited to surface areas exposed to soft tissues due to concerns of silver inhibiting osseous integration of cementless stems. To close this gap in the bactericidal capacity of silver-coated orthopedic prostheses extension of the silver-coating on surface areas intended for osseous integration seems to be inevitable. Our study reports about a PVD- (physical-vapor-deposition-) silver coated cementless stem in a canine model for the first time and showed osseous integration of a silver-coated titanium surface in vivo. Radiological, histological, and biomechanical analysis revealed a stable osseous integration of four of nine stems implanted. Silver trace elemental concentrations in serum did not exceed 1.82 parts per billion (ppb) and can be considered as nontoxic. Changes in liver and kidney functions associated with the silver-coating could be excluded by blood chemistry analysis. This was in accordance with very limited metal displacement from coated surfaces observed by laser ablation inductively coupled plasma-mass spectrometry (LA-ICP-MS) 12 months after implantation. In conclusion our results represent a step towards complete bactericidal silver coating of orthopedic prostheses. PMID- 25695058 TI - Clearance rate and BP-ANN model in paraquat poisoned patients treated with hemoperfusion. AB - In order to investigate the effect of hemoperfusion (HP) on the clearance rate of paraquat (PQ) and develop a clearance model, 41 PQ-poisoned patients who acquired acute PQ intoxication received HP treatment. PQ concentrations were determined by high performance liquid chromatography (HPLC). According to initial PQ concentration, study subjects were divided into two groups: Low-PQ group (0.05 1.0 MUg/mL) and High-PQ group (1.0-10 MUg/mL). After initial HP treatment, PQ concentrations decreased in both groups. However, in the High-PQ group, PQ levels remained in excess of 0.05 MUg/mL and increased when the second HP treatment was initiated. Based on the PQ concentrations before and after HP treatment, the mean clearance rate of PQ calculated was 73 +/- 15%. We also established a backpropagation artificial neural network (BP-ANN) model, which set PQ concentrations before HP treatment as input data and after HP treatment as output data. When it is used to predict PQ concentration after HP treatment, high prediction accuracy (R = 0.9977) can be obtained in this model. In conclusion, HP is an effective way to clear PQ from the blood, and the PQ concentration after HP treatment can be predicted by BP-ANN model. PMID- 25695059 TI - Low mutational burden of eight genes involved in the MAPK/ERK, PI3K/AKT, and GNAQ/11 pathways in female genital tract primary melanomas. AB - Mucosal melanomas exhibit discrete genetic features compared to cutaneous melanoma. Limited studies on gynecological melanomas revealed significant heterogeneity and low mutational burden. To gain further insight into their genetics and DNA repair efficiency, we systematically investigated the status of eight genes whose products are critically involved in the MAPK/ERK, PI3K/AKT, and GNAQ/11 pathways, including BRAF, NRAS, HRAS, KRAS, c-KIT, PI3K, GNAQ, and GNA11, in a series of 16 primary gynecological melanomas, covering all anatomical locations, ranging from stages I to III. Analysis either by real-time PCR coupled with fluorescence melting curve analysis or by PCR followed by direct sequencing, along with studies for DNA mismatch repair status using immunohistochemistry, disclosed that 15 out of the 16 cases displayed wild-type genotypes, with a single case of vulvar primary melanoma, harboring the activating mutation BRAF(V600E). Investigations on whether this could reflect partly an efficient mismatch repair (MMR) mechanism were confirmed by normal expression of hMLH1 and hMSH2, suggesting that the lack of mutations could be explained by the operation of alternative pathogenetic mechanisms modulating downstream effectors of the signaling pathways. Our data suggest the presence of additional genetic components and provide the impetus for systematic approaches to reveal these yet unidentified genetic parameters. PMID- 25695060 TI - Electroencephalographic changes associated with antinociceptive actions of lidocaine, ketamine, meloxicam, and morphine administration in minimally anaesthetized dogs. AB - Effects of ketamine and lidocaine on electroencephalographic (EEG) changes were evaluated in minimally anaesthetized dogs, subjected to electric stimulus. Six dogs were subjected to six treatments in a crossover design with a washout period of one week. Dogs were subjected to intravenous boluses of lidocaine 2 mg/kg, ketamine 3 mg/kg, meloxicam 0.2 mg/kg, morphine 0.2 mg/kg and loading doses of lidocaine 2 mg/kg followed by continuous rate infusion (CRI) of 50 and 100 mcg/kg/min, and ketamine 3 mg/kg followed by CRI of 10 and 50 mcg/kg/min. Electroencephalogram was recorded during electrical stimulation prior to any drug treatment (before treatment) and during electrical stimulation following treatment with the drugs (after treatment) under anaesthesia. Anaesthesia was induced with propofol and maintained with halothane at a stable concentration between 0.85 and 0.95%. Pretreatment median frequency was evidently increased (P < 0.05) for all treatment groups. Lidocaine, ketamine, and morphine depressed the median frequency resulting from the posttreatment stimulation. The depression of median frequency suggested evident antinociceptive effects of these treatments in dogs. It is therefore concluded that lidocaine and ketamine can be used in the analgesic protocol for the postoperative pain management in dogs. PMID- 25695061 TI - Is infusion of subhypnotic propofol as effective as dexamethasone in prevention of postoperative nausea and vomiting related to laparoscopic cholecystectomy? A randomized controlled trial. AB - BACKGROUND: Postoperative nausea and vomiting (PONV) is one of common complications in patients undergoing laparoscopic cholecystectomy (LC). Aim of this study was to compare the efficacy of subhypnotic (1 mg/kg/h) infusion of propofol with dexamethasone on PONV in patients undergoing LC. METHODS: A total of 120 patients were included in this randomized, double-blind, placebo controlled study. Patients were randomly assigned to 3 groups; patients of group dexamethasone (group D) were administrated 8 mg dexamethasone before induction of anesthesia, patients of group propofol (group P) were infused to subhypnotic (1 mg/kg/h) propofol during operation and patients of group control (group C) were applied infusion of 10% intralipid. The incidence of PONV and needs for rescue analgesic and antiemetic were recorded in the first 24 h postoperatively. RESULTS: In the 0-24 h, the incidence of PONV was significantly lower in the group D and group P compared with the group C (37.5%, 40%, and 72.5%, resp.). There was no significant difference in the incidence of PONV and use of antiemetics and analgesic between group D and group P. CONCLUSION: We concluded that infusion of propofol 1 mg/kg/h is as effective as dexamethasone for the prevention of PONV during the first 24 hours after anesthesia in patients undergoing LC. PMID- 25695062 TI - Strategy for the management of diabetic macular edema: the European vitreo retinal society macular edema study. AB - OBJECTIVE: To compare the efficacy of different therapies in the treatment of diabetic macular edema (DME). DESIGN: Nonrandomized, multicenter clinical study. PARTICIPANTS: 86 retina specialists from 29 countries provided clinical information on 2,603 patients with macular edema including 870 patients with DME. METHODS: Reported data included the type and number of treatment(s) performed, the pre- and posttreatment visual acuities, and other clinical findings. The results were analyzed by the French INSEE (National Institute of Statistics and Economic Studies). MAIN OUTCOME MEASURES: Mean change of visual acuity and mean number of treatments performed. RESULTS: The change in visual acuity over time in response to each treatment was plotted in second order polynomial regression trend lines. Intravitreal triamcinolone monotherapy resulted in some improvement in vision. Treatment with threshold or subthreshold grid laser also resulted in minimal vision gain. Anti-VEGF therapy resulted in more significant visual improvement. Treatment with pars plana vitrectomy and internal limiting membrane (ILM) peeling alone resulted in an improvement in vision greater than that observed with anti-VEGF injection alone. In our DME study, treatment with vitrectomy and ILM peeling alone resulted in the better visual improvement compared to other therapies. PMID- 25695063 TI - Androgen receptor, EGFR, and BRCA1 as biomarkers in triple-negative breast cancer: a meta-analysis. AB - OBJECTIVE: More and more evidences demonstrate that androgen receptor (AR), epidermal growth factor receptor (EGFR), and breast cancer susceptibility gene 1 (BRCA1) have unique clinical implications for targeted therapy or prognosis in triple-negative breast cancer (TNBC). Therefore, we conducted a meta-analysis to summarize the possible associations. METHODS: We retrieved published articles about AR, EGFR, and BRCA1 in TNBC from PubMed and EMBASE. The analysis was performed with Rev-Man 5.2 software. RESULTS: A total of 38 articles were eligible for the meta-analysis. Our study showed that the expression level of EGFR (OR = 6.88, P < 0.00001) and the prevalence of BRCA1 mutation (RR = 5.26, P < 0.00001) were higher in TNBC than non-TNBC. In contrast, the expression level of AR was lower in TNBC than non-TNBC (OR = 0.07, P < 0.00001). In the subgroup related to EGFR expression, the level of EGFR expression was significantly increased in Asians (OR = 9.60) compared with Caucasians (OR = 5.53) for TNBC patients. Additionally, the prevalence of BRCA1 mutation in Asians (RR = 5.43, P < 0.00001) was higher than that in Caucasians (RR = 5.16, P < 0.00001). CONCLUSIONS: The distinct expression of AR and EGFR and the prevalence of BRCA1 mutation indicated that AR, EGFR, and BRCA1 might be unique biomarkers for targeted therapy and prognosis in TNBC. PMID- 25695064 TI - Methods for obtaining and determination of squalene from natural sources. AB - Squalene is a natural dehydrotriterpenic hydrocarbon (C30H50) with six double bonds, known as an intermediate in the biosynthesis of phytosterol or cholesterol in plants or animals. We have briefly reviewed the natural sources for squalene and focused on the main methods and techniques to obtain and to determine it. Some of its applications in different fields of human activity are also mentioned. PMID- 25695065 TI - Third-degree hindpaw burn injury induced apoptosis of lumbar spinal cord ventral horn motor neurons and sciatic nerve and muscle atrophy in rats. AB - BACKGROUND: Severe burns result in hypercatabolic state and concomitant muscle atrophy that persists for several months, thereby limiting patient recovery. However, the effects of burns on the corresponding spinal dermatome remain unknown. This study aimed to investigate whether burns induce apoptosis of spinal cord ventral horn motor neurons (VHMNs) and consequently cause skeletal muscle wasting. METHODS: Third-degree hindpaw burn injury with 1% total body surface area (TBSA) rats were euthanized 4 and 8 weeks after burn injury. The apoptosis profiles in the ventral horns of the lumbar spinal cords, sciatic nerves, and gastrocnemius muscles were examined. The Schwann cells in the sciatic nerve were marked with S100. The gastrocnemius muscles were harvested to measure the denervation atrophy. RESULT: The VHMNs apoptosis in the spinal cord was observed after inducing third-degree burns in the hindpaw. The S100 and TUNEL double positive cells in the sciatic nerve increased significantly after the burn injury. Gastrocnemius muscle apoptosis and denervation atrophy area increased significantly after the burn injury. CONCLUSION: Local hindpaw burn induces apoptosis in VHMNs and Schwann cells in sciatic nerve, which causes corresponding gastrocnemius muscle denervation atrophy. Our results provided an animal model to evaluate burn-induced muscle wasting, and elucidate the underlying mechanisms. PMID- 25695066 TI - Feasibility and efficacy of percutaneous lateral lumbar discectomy in the treatment of patients with lumbar disc herniation: a preliminary experience. AB - OBJECTIVE: This study was aimed at evaluating the effectiveness and safety of percutaneous lateral lumbar discectomy (PLLD) in treating patients with lumber disc herniation. METHODS: A total of 183 patients with lumbar disc herniation were recruited to receive PLLD surgery from April 2006 to October 2011. All the adverse effects were recorded during the follow-up at 1, 3, 6, and 12 months after PLLD. The clinical outcomes were determined by visual analog scale and Japanese Orthopaedic Association SCORE. RESULTS: The surgery was performed successfully in all patients (102 males and 81 females aged from 21 to 66 years) with a mean 16.6-month follow-up (range from 26 to 65 months). No postoperative complications, including intestinal and vascular complications, nerve injuries, and postoperative infections, were associated with PLLD. At one month after surgery, visual analog scale (3.12 +/- 1.44 versus 6.76 +/- 2.31, P<0.05) was significantly lower than the baseline and was sustained until 24 months after surgery (3.25 +/- 1.78 versus 6.76 +/- 2.31, P<0.05). Besides that, Japanese Orthopaedic Association score (25.25 +/- 3.21 versus 11.78 +/- 2.38, P<0.05) was increased when compared to the baseline. CONCLUSIONS: PLLD was a promising, mini invasive, and effective treatment for lumber disc herniation. PMID- 25695067 TI - Clinical epidemiology and paraclinical findings in tuberculosis patients in north of Iran. AB - BACKGROUND: Mycobacterium tuberculosis (M.TB) causes a wide spectrum of clinical diseases. The prevalence of TB is different in various parts of Iran and throughout the world. The present study aimed to determine the clinical epidemiology and paraclinical findings of TB. METHODS: A cross-sectional study was conducted from 2008 to 2013. Patient demographic, clinical, and radiologic characteristics, picked up from the TB patient's files, were collected using a standard questionnaire format. Data was entered and analyzed using the SPSS version 16 statistical software and P value < 0.05 was considered statistically significant. RESULTS: Out of 212 patients enrolled in this study 62% were male and the mean age was about 50 years old. 98.6% were Iranian, and 46.2% were rural. Prevalence of smear-positive TB was 66.4%. Prevalence of positive PPD was 50.7% with no significant difference between HIV-positive and -negative patients (P = 0.8). Prevalence of diabetes mellitus was 17%. 36% of the patients had history of smoking and about 29.3% were addicted to narcotics. Cough was the most common symptom (94.5%) and 84% had sputum. 15 cases (7%) had extrapulmonary TB. The mean time between the onset of symptoms and admission was 46.5 days. The delay for admission between urban and rural populations was not significantly different (P = 0.68); but for those who were in prison, the delay was significant (P = 0.02). About 46% of the patients had cavitary lesions in CXRs. CONCLUSION: Timely diagnosis of TB especially in prisoners by understanding its most important epidemiologic characteristics and clinical features can help to make an early treatment and prevent spread of mycobacteria and their complications. PMID- 25695068 TI - TOP2A amplification and overexpression in hepatocellular carcinoma tissues. AB - Hepatocellular carcinoma (HCC) is the leading cause of cancer death in men worldwide owing to limited insights into pathogenesis and unsatisfactory efficacy of current therapies. HER2 and TOP2A genes are coamplified in breast and some other cancers. In this study, we investigated gene aberrations of HER2 and TOP2A and protein expressions of HER2, TOP2A, Ki-67, and p53 in tumor and matched nontumor tissues, as well as their associations with clinicopathological features. Gene aberrations were evaluated by FISH and protein expressions by IHC. Neither HER2 overexpression nor HER2 gene amplification was observed in both tumor tissues and matched nontumor tissues. By contrast, TOP2A overexpression was detected in 72.5% of tumor tissues but not detected in matched nontumor tissues. However, TOP2A gene amplification was not observed in both tumor and matched nontumor tissues. TOP2A overexpression was significantly associated with HCC tumor tissues (P < 0.001), hepatitis B surface antigen (HBsAg) in the serum (P = 0.004), and Ki-67 (P = 0.038) but not with age, tumor size, alpha-fetoprotein, TP53, and copy number of TOP2A gene and chromosome 17 centromere. In conclusion, TOP2A overexpression in HCC was not secondary to gene amplification. In addition, neither HER2 amplification nor overexpression could be used as prognostic and predictive marker in HCC. PMID- 25695069 TI - Managing hypercapnia in patients with severe ARDS and low respiratory system compliance: the role of esophageal pressure monitoring--a case cohort study. AB - PURPOSE: Patients with severe acute respiratory distress syndrome (ARDS) and hypercapnia present a formidable treatment challenge. We examined the use of esophageal balloon for assessment of transpulmonary pressures to guide mechanical ventilation for successful management of severe hypercapnia. MATERIALS AND METHODS: Patients with severe ARDS and hypercapnia were studied. Esophageal balloon was inserted and mechanical ventilation was guided by assessment of transpulmonary pressures. Positive end expiratory pressure (PEEP) and inspiratory driving pressures were adjusted with the aim of achieving tidal volume of 6 to 8 mL/kg based on ideal body weight (IBW), while not exceeding end inspiratory transpulmonary (EITP) pressure of 25 cm H2O. RESULTS: Six patients with severe ARDS and hypercapnia were studied. Mean PaCO2 on enrollment was 108.33 +/- 25.65 mmHg. One hour after adjustment of PEEP and inspiratory driving pressure guided by transpulmonary pressure, PaCO2 decreased to 64.5 +/- 16.89 mmHg (P < 0.01). Tidal volume was 3.96 +/- 0.92 mL/kg IBW before and increased to 7.07 +/- 1.21 mL/kg IBW after intervention (P < 0.01). EITP pressure before intervention was low with a mean of 13.68 +/- 8.69 cm H2O and remained low at 16.76 +/- 4.76 cm H2O (P = 0.18) after intervention. Adjustment of PEEP and inspiratory driving pressures did not worsen oxygenation and did not affect cardiac output significantly. CONCLUSION: The use of esophageal balloon as a guide to mechanical ventilation was able to treat severe hypercapnia in ARDS patients. PMID- 25695070 TI - In vitro metacyclogenesis of Leishmania (Viannia) braziliensis and Leishmania (Leishmania) amazonensis clinical field isolates, as evaluated by morphology, complement resistance, and infectivity to human macrophages. AB - This study was designed to assess in vitro metacyclogenesis of Leishmania (Viannia) braziliensis and Leishmania (Leishmania) amazonensis clinical field isolates obtained from patient lesions (L. braziliensis IMG3 and PPS6m; L. amazonensis MAB6). Metacyclogenesis was evaluated by different criteria, namely, promastigote size (morphometric analysis and flow cytometry), surface modifications (loss of lectin or monoclonal antibody (mAb) binding, complement resistance), and infectivity to human macrophages. Growth curves were similar for all parasites evaluated. The various features analyzed were expressed in a high percentage of promastigotes at 6th and 10th days of culture and a low percentage at the 2nd day. However, in most isolates, these features, considered as markers of metacyclogenesis, seemed to develop with different time courses, since the percentages of metacyclic forms detected with each technique were usually different. Parasites from 6th or 10th day and those negatively selected with lectin or mAb similarly infected human macrophages. From all isolates analyzed, L. amazonensis PH8 and MAB6 showed the highest and the lowest levels of susceptibility, respectively, to leishmanicidal activity of IFN-gamma/LPS activated macrophages. Our results showed that by using different techniques to evaluate different aspects of metacyclogenesis (morphological and biochemical modifications) different percentages of metacyclic promastigotes can be detected in each isolate culture. PMID- 25695071 TI - CT perfusion: technical developments and current and future applications. PMID- 25695072 TI - Hematopoietic stem and progenitor cells can be enriched by implanting biomaterial into spatium intermusculare. AB - Hematopoietic stem and progenitor cells (HSPCs) have been used successfully to treat patients with cancer and disorders of the blood and immune systems. In this study, we tried to enrich HSPCs by implanting biomaterials into the spatium intermusculare of mice hind limbs. Gelatine sponges were implanted into the spatium intermusculare of mice and then retrieved after 12 days. The presence of HSPCs in the migrating cells (MCs) was detected by phenotypically probing with CD34(+)Sca-1(+) and functionally confirming the presence of using colony-forming cell assay and assessing the long-term reconstitution ability. The frequency of CD34(+), Sca-1(+), and CD34(+)Sca-1(+) cells and colony formation unit in the MCs was much higher than that in the bone marrow (BM). Moreover, transplanted MCs were able to home to BM, muscle, and spleen, which induced an efficient long-term hematopoietic reconstitution in vivo. In addition, HSPCs within the MCs originated from the BM. Furthermore, the administration of G-CSF greatly reduced the time of implantation, and increased the number of MCs and frequency of HSPCs in the MCs. These data provide compelling evidence that HSPCs can be enriched by implanting biomaterial into spatium intermusculare. Implantation of biomaterial may be seen as the first step to a proof of their applicability to clinical practice in enriching HSPCs. PMID- 25695073 TI - Discrimination between newly formed and aged thrombi using empirical mode decomposition of ultrasound B-scan image. AB - Ultrasound imaging is a first-line diagnostic method for screening the thrombus. During thrombus aging, the proportion of red blood cells (RBCs) in the thrombus decreases and therefore the signal intensity of B-scan can be used to detect the thrombus age. To avoid the effect of system gain on the measurements, this study proposed using the empirical mode decomposition (EMD) of ultrasound image as a strategy to classify newly formed and aged thrombi. Porcine blood samples were used for the in vitro induction of fresh and aged thrombi (at hematocrits of 40%). Each thrombus was imaged using an ultrasound scanner at different gains (15, 20, and 30 dB). Then, EMD of ultrasound signals was performed to obtain the first and second intrinsic mode functions (IMFs), which were further used to calculate the IMF-based echogenicity ratio (IER). The results showed that the performance of using signal amplitude of B-scan to reflect the thrombus age depends on gain. However, the IER is less affected by the gain in discriminating between fresh and aged thrombi. In the future, ultrasound B-scan combined with the EMD may be used to identify the thrombus age for the establishment of thrombolytic treatment planning. PMID- 25695074 TI - Different short-term mild exercise modalities lead to differential effects on body composition in healthy prepubertal male rats. AB - Physical activity has a vital role in regulating and improving bone strength. Responsiveness of bone mass to exercise is age dependent with the prepubertal period suggested to be the most effective stage for interventions. There is a paucity of data on the effects of exercise on bone architecture and body composition when studied within the prepubertal period. We examined the effect of two forms of low-impact exercise on prepubertal changes in body composition and bone architecture. Weanling male rats were assigned to control (CON), bipedal stance (BPS), or wheel exercise (WEX) groups for 15 days until the onset of puberty. Distance travelled via WEX was recorded, food intake measured, and body composition quantified. Trabecular and cortical microarchitecture of the femur were determined by microcomputed tomography. WEX led to a higher lean mass and reduced fat mass compared to CON. WEX animals had greater femoral cortical cross sectional thickness and closed porosity compared to CON. The different exercise modalities had no effect on body weight or food intake, but WEX significantly altered body composition and femoral microarchitecture. These data suggest that short-term mild voluntary exercise in normal prepubertal rats can alter body composition dependent upon the exercise modality. PMID- 25695075 TI - R990G polymorphism of calcium sensing receptor gene is associated with high parathyroid hormone levels in subjects with vitamin D deficiency: a cross sectional study. AB - Single nucleotide polymorphisms (SNPs), R990G and A986S of the calcium sensing receptor (CaSR) gene, are shown to influence response of parathyroid hormone (PTH) in subjects with optimal vitamin D levels. This cross-sectional study was conducted in subjects with vitamin D deficiency (VDD) to observe associations between CaSR polymorphisms, plasma iPTH, and serum calcium levels. Adult females (n = 140) with known VDD, intact parathyroid hormone (iPTH), and calcium levels were recruited for genotype analysis. The frequencies of the 986 alleles GG, GT, and TT were 68%, 25%, and 7%, respectively, whereas the frequencies of the 990 alleles AA, AG, and GG were 80%, 8.9%, and 11.1%, respectively. The subjects with GG genotype of R990G polymorphism had higher iPTH levels (148.65 versus 91.47 and 86.1 pg/mL for GG versus AA, AG, resp., P = 0.008) and lower calcium levels (8.4 versus 9.04 and 9.07 mg/dL for GG versus AA, AG, resp., P = 0.002). No such association of A986S polymorphism with plasma iPTH or serum calcium levels was observed in the present study. Patients with VDD bearing the GG genotype of R990G SNPs are prone to have higher iPTH levels and lower calcium. PMID- 25695076 TI - Influence of malnutrition on adverse outcome in children with confirmed or probable viral encephalitis: a prospective observational study. AB - A prospective observational study was conducted in a tertiary care teaching hospital from August 2008 to August 2009 to explore the independent predictors of adverse outcome in the patients with confirmed/probable viral encephalitis. The primary outcome variable was the incidence of adverse outcomes defined as death or severe neurological deficit such as loss of speech, motor deficits, behavioural problems, blindness, and cognitive impairment. Patients with confirmed or probable viral encephalitis were classified into two groups based on their Z-score of weight-for-age as per WHO growth charts. Group I. Patients with confirmed or probable viral encephalitis with weight-for-age (W/A) Z-scores below -2SD were classified as undernourished. Group II. Patients with confirmed or probable viral encephalitis were classified as having normal nutritional status (weight-for-age Z-score >-2SD). A total of 114 patients were classified as confirmed or probable viral encephalitis based on detailed investigations. On multivariate logistic regression, undernutrition (adjusted OR: 5.05; 95% CI: 1.92 to 13.44) and requirement of ventilation (adjusted OR: 6.75; 95% CI: 3.63 to 77.34) were independent predictors of adverse outcomes in these patients. Thus, the results from our study highlight that the association between undernutrition and adverse outcome could be extended to the patients with confirmed/probable viral encephalitis. PMID- 25695077 TI - The oncofetal protein IMP3: a novel grading tool and predictor of poor clinical outcome in human gliomas. AB - Morphologic criteria illustrated in WHO guidelines are the most significant prognostic factor in human gliomas, but novel biomarkers are needed to identify patients with a poorer outcome. The present study examined the expression of the oncofetal protein IMP3 in a series of 135 patients affected by high-grade (grade III and IV) gliomas, correlating the results with proliferative activity, molecular parameters, and clinical and follow-up data. Overall, IMP3 expression was higher in glioblastomas (68%) than in grade III tumors (20%, P < 0.0001), and IMP3-positive high-grade gliomas showed a shorter overall and disease-free survival than negative ones (P = 0.0002 and P = 0.006, resp.). IMP3 expression was significantly associated with the absence of mutations of IDH1 gene (P = 0.0001) and with the unmethylated phenotype of MGMT in high-grade gliomas (P = 0.004). High Ki67 levels were correlated with better prognosis in glioblastomas but IMP3 expression was not correlated with the proliferation index. These findings confirm the role of IMP3 as a marker of poor outcome, also in consideration of its association with IDH1 wild-type phenotype and MGMT unmethylated status. The data suggest that IMP3 staining could identify a subgroup of patients with poor prognosis and at risk of recurrence in high-grade gliomas. PMID- 25695078 TI - Effects of adult male circumcision on premature ejaculation: results from a prospective study in China. AB - The purpose of this study is to investigate the effects of adult male circumcision on premature ejaculation (PE). Therefore, between December 2009 and March 2014, a total of 575 circumcised men and 623 uncircumcised men (control group) were evaluated. Detailed evaluations (including circumcision and control groups) on PE were conducted before circumcision and at the 3-, 6-, 9-, and 12 month follow-up visits after circumcision. Self-estimated intravaginal ejaculatory latency time (IELT), Patient-Reported Outcome measures, and 5-item version of the International Index of Erectile Function were used to measure the ejaculatory and erectile function for all subjects. The results showed that, during the one-year follow-up, men after circumcision experienced higher IELT and better scores of control over ejaculation, satisfaction with sexual intercourse, and severity of PE than men before circumcision (P < 0.001 for all). Similarly, when compared with the control group, the circumcised men reported significantly improved IELT, control over ejaculation, and satisfaction with sexual intercourse (P < 0.001 for all). These findings suggested that circumcision might have positive effects on IELT, ejaculatory control, sexual satisfaction, and PE severity. In addition, circumcision was significantly associated with the development of PE. PMID- 25695079 TI - Correlation between serum levels of high mobility group box-1 protein and pancreatitis: a meta-analysis. AB - BACKGROUND: Aberrant expression of high mobility group box-1 protein (HMGB1) contributes to the progression of various inflammatory diseases. This meta analysis focused on the clinical significance of serum HMGB1 levels in pancreatitis patients, with the goal of building a novel diagnostic score model. METHOD: We conducted a meta-analysis by searching in the PubMed, Embase, Web of Science, Cochrane Library, CISCOM, CINAHL, Google Scholar, China BioMedicine (CBM), and China National Knowledge Infrastructure (CNKI) databases without any language restrictions. Studies were pooled and standard mean difference (SMD) and its corresponding 95% confidence intervals (95% CIs) were calculated. Version 12.0 STATA software was used for statistical analysis. RESULTS: We performed a final analysis of 841 subjects from 12 clinical case-control studies. The meta analysis results showed a positive association between serum HMGB1 levels and the progression of pancreatitis. In the subgroup analysis by country, high serum level of HMGB1 may be related to pancreatitis progression in China, Korea, Hungary, and Japan populations (all P < 0.05). CONCLUSION: The present meta analysis indicated that serum HMGB1 level was statistically elevated in patients with pancreatitis, and thus serum levels of HMGB1 could be determined to be a useful biomarker for pancreatitis patients. PMID- 25695080 TI - Relationship between sum of the four limbs' pulse pressure and brachial-ankle pulse wave velocity and atherosclerosis risk factors in Chinese adults. AB - The aim of the present study was to analyze the relationship between the sum of the four limbs' pulse pressure (Sum-PP) and brachial-ankle pulse wave velocity (baPWV) and atherosclerosis risk factors and evaluate the feasibility of Sum-PP in diagnosing atherosclerosis systemically. For the purpose, a cross-sectional study was conducted on the basis of medical information of 20748 adults who had a health examination in our hospital. Both Sum-PP and baPWV exhibited significant variations among different human populations grouped by gender, smoking, drinking, and age. Interestingly, Sum-PP had similar varying tendency with baPWV in different populations. And further study in different populations showed that Sum-PP was significantly positively related to baPWV. We also investigated the relationship between Sum-PP, baPWV, and cardiovascular risk factors, respectively. We found that both Sum-PP and baPWV had significant positive correlation with atherosclerosis risk factors while both of them were negatively related to HDL-c. In addition, there was a significant close correlation between Sum-PP and baPWV in the whole population (r = 0.4616, P < 0.0001). Thus, Sum-PP is closely related to baPWV and is of important value for clinical diagnosis of atherosclerosis. PMID- 25695081 TI - OSAS surgery and postoperative discomfort: phase I surgery versus phase II surgery. AB - INTRODUCTION: This study aims to investigate the reasons that discourage the patients affected by OSAS to undergo orthognathic surgery and compares the postoperative discomfort of phase I (soft tissue surgery) and phase II (orthognathic surgery) procedures for treatment of OSAS. MATERIAL AND METHODS: A pool of 46 patients affected by OSAS was divided into two groups: "surgery patients" who accepted surgical treatments of their condition and "no surgery patients" who refused surgical procedures. The "surgery patients" group was further subdivided into two arms: patients who accepted phase I procedures (IP) and those who accepted phase II (IIP). To better understand the motivations behind the refusal of II phase procedures, we asked the patients belonging to both the IP group and "no surgery" group to indicate the main reason that influenced their decision to avoid II phase procedures. We also monitored and compared five parameters of postoperative discomfort: pain, painkiller assumption, length of hospitalization, foreign body sensation, and diet assumption following IP and IIP procedures. RESULTS: The main reason to avoid IIP procedures was the concern of a more severe postoperative discomfort. Comparison of the postoperative discomfort following IP versus IIP procedures showed that the former scored worse in 4 out of 5 parameters analyzed. CONCLUSION: IIP procedures produce less postoperative discomfort. IIP procedures, namely, orthognathic surgery, should be the first choice intervention in patients affected by OSAS and dentoskeletal malformation. PMID- 25695082 TI - Modifications in bone matrix of estrogen-deficient rats treated with intermittent PTH. AB - Bone matrix dictates strength, elasticity, and stiffness to the bone. Intermittent parathyroid hormone (iPTH), a bone-forming treatment, is widely used as a therapy for osteoporosis. We investigate whether low doses of intermittent PTH (1-34) change the profile of organic components in the bone matrix after 30 days of treatment. Forty 6-month-old female Wistar rats underwent ovariectomy and after 3 months received low doses of iPTH administered for 30 days: daily at 0.3 ug/kg/day (PTH03) or 5 ug/kg/day (PTH5); or 3 times per week at 0.25 ug/kg/day (PTH025). After euthanasia, distal femora were processed for bone histomorphometry, histochemistry for collagen and glycosaminoglycans, biochemical quantification of sulfated glycosaminoglycans, and hyaluronan by ELISA and TUNEL staining. Whole tibiae were used to estimate the bone mineral density (BMD). Histomorphometric analysis showed that PTH5 increased cancellous bone volume by 6% over vehicle-treated rats. In addition, PTH5 and PTH03 increased cortical thickness by 21% and 20%, respectively. Tibial BMD increased in PTH5-treated rats and this group exhibited lower levels of chondroitin sulfate; on the other hand, hyaluronan expression was increased. Hormonal administration in the PTH5 group led to decreased collagen maturity. Further, TUNEL-positive osteocytes were decreased in the cortical compartment of PTH5 whereas administration of PTH025 increased the osteocyte death. Our findings suggest that daily injections of PTH at low doses alter the pattern of organic components from the bone matrix, favoring the increase of bone mass. PMID- 25695083 TI - Prediction of local ultimate strain and toughness of trabecular bone tissue by Raman material composition analysis. AB - Clinical studies indicate that bone mineral density correlates with fracture risk at the population level but does not correlate with individual fracture risk well. Current research aims to better understand the failure mechanism of bone and to identify key determinants of bone quality, thus improving fracture risk prediction. To get a better understanding of bone strength, it is important to analyze tissue-level properties not influenced by macro- or microarchitectural factors. The aim of this pilot study was to identify whether and to what extent material properties are correlated with mechanical properties at the tissue level. The influence of macro- or microarchitectural factors was excluded by testing individual trabeculae. Previously reported data of mechanical parameters measured in single trabeculae under tension and bending and its compositional properties measured by Raman spectroscopy was evaluated. Linear and multivariate regressions show that bone matrix quality but not quantity was significantly and independently correlated with the tissue-level ultimate strain and postyield work (r = 0.65-0.94). Principal component analysis extracted three independent components explaining 86% of the total variance, representing elastic, yield, and ultimate components according to the included mechanical parameters. Some matrix parameters were both included in the ultimate component, indicating that the variation in ultimate strain and postyield work could be largely explained by Raman-derived compositional parameters. PMID- 25695084 TI - Oxygen transport in a three-dimensional microvascular network incorporated with early tumour growth and preexisting vessel cooption: numerical simulation study. AB - We propose a dynamic mathematical model of tissue oxygen transport by a preexisting three-dimensional microvascular network which provides nutrients for an in situ cancer at the very early stage of primary microtumour growth. The expanding tumour consumes oxygen during its invasion to the surrounding tissues and cooption of host vessels. The preexisting vessel cooption, remodelling and collapse are modelled by the changes of haemodynamic conditions due to the growing tumour. A detailed computational model of oxygen transport in tumour tissue is developed by considering (a) the time-varying oxygen advection diffusion equation within the microvessel segments, (b) the oxygen flux across the vessel walls, and (c) the oxygen diffusion and consumption within the tumour and surrounding healthy tissue. The results show the oxygen concentration distribution at different time points of early tumour growth. In addition, the influence of preexisting vessel density on the oxygen transport has been discussed. The proposed model not only provides a quantitative approach for investigating the interactions between tumour growth and oxygen delivery, but also is extendable to model other molecules or chemotherapeutic drug transport in the future study. PMID- 25695085 TI - Key proteins of activating cell death can be predicted through a kainic acid induced excitotoxic stress. AB - Epilepsy is a major neurological disorder characterized by spontaneous seizures accompanied by neurophysiological changes. Repeated seizures can damage the brain as neuronal death occurs. A better understanding of the mechanisms of brain cell death could facilitate the discovery of novel treatments for neurological disorders such as epilepsy. In this study, a model of kainic acid- (KA-) induced neuronal death was established to investigate the early protein markers associated with apoptotic cell death due to excitotoxic damage in the rat cortex. The results indicated that KA induces both apoptotic and necrotic cell death in the cortex. Incubation with high concentrations (5 and 500 MUM, >75%) and low concentrations (0.5 pM: 95% and 50 nM: 8%) of KA for 180 min led to necrotic and apoptotic cell death, respectively. Moreover, proteomic analysis using two dimensional gel electrophoresis and mass spectrometry demonstrated that antiapoptotic proteins, including heat shock protein 70, 3-mercaptopyruvate sulfurtransferase, tubulin-B-5, and pyruvate dehydrogenase E1 component subunit beta, were significantly higher in apoptosis than in necrosis induced by KA. Our findings provide direct evidence that several proteins are associated with apoptotic and necrotic cell death in excitotoxicity model. The results indicate that these proteins can be apoptotic biomarkers from the early stages of cell death. PMID- 25695086 TI - Small molecule inhibitor of type three secretion suppresses acute and chronic Chlamydia trachomatis infection in a novel urogenital Chlamydia model. AB - Previously, we reported that a compound from a group of thiohydrazides of oxamic acids, CL-55, possessed antichlamydial activity in vitro that was accompanied by a decreased translocation of the type three secretion effector, IncA, into the host cell. In this study, the antichlamydial activity of CL-55 was tested in vivo in DBA/2 mice infected with C. trachomatis serovar D. We found that intravaginal inoculation of DBA/2 mice with the clinically relevant strain, C. trachomatis serovar D, results in a course of infection and pathology similar to that observed in humans. The early stage of infection in this model was characterized by a shedding of Chlamydia in vaginal secretions followed by an ascending infection and inflammation in the upper genital tract. We found that CL-55 possessed antibacterial activity in vivo and was able to control C. trachomatis vaginal shedding, ascending infection, and inflammation in the upper genital organs in DBA/2 mice. Our data provide a proof of concept for the protective effect of the thiadiazinon, CL-55, against chlamydial infection in vivo and support the feasibility of further studies of its potential therapeutic applications. PMID- 25695087 TI - Sustained macrophage infiltration upon multiple intra-articular injections: an improved rat model of rheumatoid arthritis for PET guided therapy evaluation. AB - To widen the therapeutic window for PET guided evaluation of novel anti-RA agents, modifications were made in a rat model of rheumatoid arthritis (RA). Arthritis was induced in the right knee of Wistar rats with repeated boosting to prolong articular inflammation. The contralateral knee served as control. After immunization with methylated bovine serum albumin (mBSA) in complete Freund's adjuvant and custom Bordetella pertussis antigen, one or more intra-articular (i.a.) mBSA injections were given over time in the right knee. Serum anti-mBSA antibodies, DTH response, knee thickness, motion, and synovial macrophages were analyzed and [18F]FDG(-general inflammation) and (R)-[11C]PK11195 (macrophages )PET was performed followed by ex vivo tissue distribution. Significant anti-mBSA levels, DTH, swelling of arthritic knee, and sustained and prolonged macrophage infiltration in synovial tissue were found, especially using multiple i.a. injections. Increased [18F]FDG and (R)-[11C]PK11195 accumulation was demonstrated in arthritic knees as compared to contralateral knees, which was confirmed in ex vivo tissue distribution studies. Boosting proved advantageous for achieving a chronic model without remission. The model will offer excellent opportunities for repeated PET studies to monitor progression of disease and efficacy of novel therapeutic agents for RA in the same animal. PMID- 25695088 TI - Insight into bone-derived biological apatite: ultrastructure and effect of thermal treatment. AB - OBJECTIVES: This study aims at examining the ultrastructure of bone-derived biological apatite (BAp) from a series of small vertebrates and the effect of thermal treatment on its physiochemical properties. MATERIALS AND METHODS: Femurs/fin rays and vertebral bodies of 5 kinds of small vertebrates were firstly analyzed with X-ray microtomography. Subsequently, BAp was obtained with thermal treatment and low power plasma ashing, respectively. The properties of BAp, including morphology, functional groups, and crystal characteristics were then analyzed. RESULTS: The bones of grouper and hairtail were mainly composed of condensed bone. Spongy bone showed different distribution in the bones from frog, rat, and pigeon. No significant difference was found in bone mineral density of condensed bone and trabecular thickness of spongy bone. Only platelet-like crystals were observed for BAp obtained by plasma ashing, while rod-like and irregular crystals were both harvested from the bones treated by sintering. A much higher degree of crystallinity and larger crystal size but a lower content of carbonate were detected in the latter. CONCLUSION: Platelet-like BAp is the common inorganic component of vertebrate bones. BAp distributing in condensed and spongy bone may exhibit differing thermal reactivity. Thermal treatment may alter BAp's in vivo structure and composition. PMID- 25695089 TI - Recent novel high-tech researches in molecular biology. PMID- 25695090 TI - Helicase and its interacting factors: regulation mechanism, characterization, structure, and application for drug design. PMID- 25695091 TI - Imaging atherosclerosis with hybrid positron emission tomography/magnetic resonance imaging. AB - Noninvasive imaging of atherosclerosis could potentially move patient management towards individualized triage, treatment, and followup. The newly introduced combined positron emission tomography (PET) and magnetic resonance imaging (MRI) system could emerge as a key player in this context. Both PET and MRI have previously been used for imaging plaque morphology and function: however, the combination of the two methods may offer new synergistic opportunities. Here, we will give a short summary of current relevant clinical applications of PET and MRI in the setting of atherosclerosis. Additionally, our initial experiences with simultaneous PET/MRI for atherosclerosis imaging are presented. Finally, future potential vascular applications exploiting the unique combination of PET and MRI will be discussed. PMID- 25695092 TI - Large-vessel vasculitis: interobserver agreement and diagnostic accuracy of 18F FDG-PET/CT. AB - INTRODUCTION: (18)F-FDG-PET visualises inflammation. Both atherosclerosis and giant cell arteritis cause vascular inflammation, but distinguishing the two may be difficult. The goal of this study was to assess interobserver agreement and diagnostic accuracy of (18)F-FDG-PET for the detection of large artery involvement in giant cell arteritis (GCA). METHODS: 31 (18)F-FDG-PET/CT scans were selected from 2 databases. Four observers assessed vascular wall (18)F-FDG uptake, initially without and subsequently with predefined observer criteria (i.e., vascular wall (18)F-FDG uptake compared to liver or femoral artery (18)F FDG uptake). External validation was performed by two additional observers. Sensitivity and specificity of (18)F-FDG-PET were determined by comparing scan results to a consensus diagnosis. RESULTS: The highest interobserver agreement (kappa: 0.96 in initial study and 0.79 in external validation) was observed when vascular wall (18)F-FDG uptake higher than liver uptake was used as a diagnostic criterion, although agreement was also good without predefined criteria (kappa: 0.68 and 0.85). Sensitivity and specificity were comparable for these methods. The criterion of vascular wall (18)F-FDG uptake equal to liver (18)F-FDG uptake had low specificity. CONCLUSION: Standardization of image assessment for vascular wall (18)F-FDG uptake promotes observer agreement, enables comparative studies, and does not appear to result in loss of diagnostic accuracy compared to nonstandardized assessment. PMID- 25695093 TI - Modeling the responses to resistance training in an animal experiment study. AB - The aim of the present study was to test whether systems models of training effects on performance in athletes can be used to explore the responses to resistance training in rats. 11 Wistar Han rats (277 +/- 15 g) underwent 4 weeks of resistance training consisting in climbing a ladder with progressive loads. Training amount and performance were computed from total work and mean power during each training session. Three systems models relating performance to cumulated training bouts have been tested: (i) with a single component for adaptation to training, (ii) with two components to distinguish the adaptation and fatigue produced by exercise bouts, and (iii) with an additional component to account for training-related changes in exercise-induced fatigue. Model parameters were fitted using a mixed-effects modeling approach. The model with two components was found to be the most suitable to analyze the training responses (R(2) = 0.53; P < 0.001). In conclusion, the accuracy in quantifying training loads and performance in a rodent experiment makes it possible to model the responses to resistance training. This modeling in rodents could be used in future studies in combination with biological tools for enhancing our understanding of the adaptive processes that occur during physical training. PMID- 25695094 TI - The PI3K/Akt signaling pathway mediates the high glucose-induced expression of extracellular matrix molecules in human retinal pigment epithelial cells. AB - Prolonged hyperglycemia is an important risk factor of the pathogenesis of diabetic retinopathy (DR). Extracellular matrix molecules, such as fibronectin, collagen IV, and laminin, are associated with fibrotic membranes. In this study, we investigated the expression of fibronectin, collagen IV, and laminin in RPE cells under high glucose conditions. Furthermore, we also detected the phosphorylation of protein kinase B (Akt) under high glucose conditions in RPE cells. Our results showed that high glucose upregulated fibronectin, collagen IV, and laminin expression, and activated Akt in RPE cells. We also found that pretreatment with LY294002 (an inhibitor of phosphatidylinositol 3-kinase) abolished high glucose-induced expression of fibronectin, collagen IV, and laminin in RPE cells. Thus, high glucose induced the expression of fibronectin, collagen IV, and laminin through PI3K/Akt signaling pathway in RPE cells, and the PI3K/Akt signaling pathway may contribute to the formation of fibrotic membrane during the development of DR. PMID- 25695096 TI - A study on the rheological properties of recycled rubber-modified asphalt mixtures. AB - Using waste rubber in asphalt mixes has become a common practice in road construction. This paper presents the results of a study on the rheological characteristics of rubber-modified asphalt (RMA) concrete under static and dynamic loading conditions. A number of static and dynamic creep tests were conducted on RMA mix specimens with different rubber sizes and contents, and a series of resonant column tests were conducted to evaluate the shear modulus and damping values. To simulate the stress-strain response of traffic-induced loading, the measurements were taken for different confining pressures and strain levels. The results of the study indicated that rubber modification increases stiffness and damping ratio, making it a very attractive material for use in road construction. However the grain size of the rubber is very important. Although RMA may cost up to 100% more than regular asphalt, the advantages it brings, such as an increased service life of the road and proper waste utilization contributing to a more sustainable infrastructure, may justify the added cost. PMID- 25695095 TI - Epidemiological study of Japanese encephalitis virus in Vientiane, Lao PDR, in 1990s. AB - Phylogenetic analysis of Japanese encephalitis virus (JEV) was conducted using core-premembrane and envelope gene sequence data of two strains from Vientiane, Lao People's Democratic Republic, in 1993 and five from Okinawa, Japan, in 2002 and 2003, and previously published strains. The two Vientiane strains designated as LaVS56 and LaVS145 belonged to genotype 1 (G1) and the same subcluster of G1 as Australian strain in 2000, Thai strains in 1982-1985 and 2004-2005, and Vietnamese strain in 2005, but were distinct from the subcluster of recently distributing G1 strains widely in Asia including Okinawan strains and recent Lao strain in 2009. These clusters with own distinct distributions indicated involvements of different mechanisms and routes of spreading viruses and clarified that Australian G1 strain is from Southeast Asia, not from East Asia. Both Vientiane strains were antigenically close to P19-Br (G1, isolate, Thailand), but distinct from Nakayama (G3, prototype strain, Japan), Beijing-1 (G3, laboratory strain, China), and JaGAr#01 (G3, laboratory strain, Japan), demonstrated by cross-neutralization tests using polyclonal antisera. These results together with seroepidemiologic study conducted in Vientiane strongly suggest that diversified JEV cocirculated there in early 1990s. PMID- 25695097 TI - Examining behavioural coping strategies as mediators between work-family conflict and psychological distress. AB - We examined the mediating role of behavioral coping strategies in the association between work-family conflict and psychological distress. In particular, we examined the two directions of work-family conflict, namely, work interference into family and family interference into work. Furthermore, two coping styles in this study were adaptive and maladaptive coping strategies. This cross-sectional study was conducted among 429 Malaysian working women using self-reported data. The results of mediational analysis in the present study showed that adaptive coping strategy does not significantly mediate the effect of work-family conflict on psychological distress. However, maladaptive coping strategies significantly mediate the effect of work-family conflict on psychological distress. These results show that adaptive coping strategies, which aimed to improve the stressful situation, are not effective in managing stressor such as work-family conflict. We found that experiencing interrole conflict steers employees toward frequent use of maladaptive coping strategies which in turn lead to psychological distress. Interventions targeted at improvement of coping skills which are according to individual's needs and expectation may help working women to balance work and family demands. The important issue is to keep in mind that effective coping strategies are to control the situations not to eliminate work-family conflict. PMID- 25695098 TI - Family centered approach in primary health care: experience from an urban area of Mangalore, India. AB - INTRODUCTION: "Health for All" still eludes public health experts despite many approaches to prevent disease and promote health among urban poor. Several key illness factors lie beyond the conventional healthcare boundaries. OBJECTIVE: To examine the effectiveness of family centered approach (FCA) in addressing health and related issues in an urban area of Mangalore, India. METHOD: A longitudinal study was conducted in Bengre, an outreach centre of Mangalore from June 2011 to November 2013. Family folders were created with pertinent details. Demand generation and health education activities were conducted through two female community health link workers. An FCA package was implemented by medical and nursing interns, under supervision, to address the priority issues. Effect was assessed by comparing their practices and service utilization before and after the study. RESULTS: About 809 families participated in this study. Social, cultural, and religious factors were responsible for viciousness of malaria and maternal and child health issues. FCA improved their perceptions and practices towards health and related issues. Significant (P < 0.05) and sustained hike in service utilization was evident. CONCLUSION: FCA exposes key illness factors beyond the conventional care, eases need based healthcare implementation, and provides feasible and enduring solutions. Community involvement makes it more practicable. PMID- 25695099 TI - In vitro evaluation of proximal carious lesions using digital radiographic systems. AB - The study aimed to compare the sensitivity and specificity of digital radiographic systems for the diagnosis of proximal carious lesions. Extracted human teeth (3 canines, 3 premolars, and 3 molars) were submitted to one of three types of proximal lesions (demineralized area, cavity affecting the enamel alone, and cavity affecting enamel and dentin). Bitewing radiographs were obtained from each system (Sirona, Kodak, and Schick) and evaluated by 12 raters (4 dental students, 4 radiology specialists, and 4 dentists). The chi-squared test was used to determine the frequency of correct diagnoses among the different systems, raters, teeth, and types of lesion. Sensitivity and specificity regarding demineralized areas were calculated for each system. The frequencies of correct diagnoses were found: Schick (70.8%), Kodak (63.9%), Sirona (59.0%), specialists (69.4%), students (62.5%), dentists (61.8%), premolars (70.1%), canines (65.3%), and molars (58.3%). No significant differences were found among the different systems, raters, or teeth (P > 0.05). Sensitivity and specificity were 0.64 and 0.47 (Schick), 0.56 and 0.50 (Sirona), and 0.48 and 0.58 (Kodak). The most correct diagnoses were achieved using the Schick digital system on premolars and evaluated by specialists in radiology. The systems demonstrated low sensitivity and specificity for the diagnosis of demineralized areas. PMID- 25695101 TI - Emerging trends in soft set theory and related topics. PMID- 25695100 TI - Exosomes: novel biomarkers for clinical diagnosis. AB - Exosomes are 30-120 nm endocytic membrane-derived vesicles that participate in cell-to-cell communication and protein and RNA delivery. Exosomes harbor a variety of proteins, nucleic acids, and lipids and are present in many and perhaps all bodily fluids. A significant body of literature has demonstrated that molecular constituents of exosomes, especially exosomal proteins and microRNAs (miRNAs), hold great promise as novel biomarkers for clinical diagnosis. In this minireview, we summarize recent advances in the research of exosomal biomarkers and their potential application in clinical diagnostics. We also provide a brief overview of the formation, function, and isolation of exosomes. PMID- 25695102 TI - Some new sets of sequences of fuzzy numbers with respect to the partial metric. AB - In this paper, we essentially deal with Kothe-Toeplitz duals of fuzzy level sets defined using a partial metric. Since the utilization of Zadeh's extension principle is quite difficult in practice, we prefer the idea of level sets in order to construct some classical notions. In this paper, we present the sets of bounded, convergent, and null series and the set of sequences of bounded variation of fuzzy level sets, based on the partial metric. We examine the relationships between these sets and their classical forms and give some properties including definitions, propositions, and various kinds of partial metric spaces of fuzzy level sets. Furthermore, we study some of their properties like completeness and duality. Finally, we obtain the Kothe-Toeplitz duals of fuzzy level sets with respect to the partial metric based on a partial ordering. PMID- 25695103 TI - Change of mandibular position during two-phase orthodontic treatment of skeletal class II in the Chinese population. AB - The aim of this study was to evaluate the change in mandibular position during a two-phase orthodontic treatment of skeletal Class II malocclusion. Thirty consecutively treated Chinese male adolescents who had undergone two-phase treatment with Herbst appliance and fixed appliance and fulfilled the specific selection criteria were sampled. Cephalograms taken at T0 (before treatment), T1 (at the end of functional appliance treatment), and T2 (at the end of fixed appliance treatment) were analyzed. The change in sagittal positioning of the mandible was 6.8 +/- 3.44 mm in phase I (T0-T1), 0.4 +/- 2.79 mm in phase II (T1 T2), and 7.2 +/- 4.61 mm in total. The mandible came forward in 100% of the patients at T1. In phase II, it came forward in one-third (positive group) remained unchanged in one-third (stable group) and went backward in one-third (negative group) of the patients. At T2, it came forward twice as much in the positive group compared to the negative group. Mandibular length was significantly increased in 100% of the patients in both phases. In conclusion, during the treatment with functional appliance, the mandibular prognathism increases in all patients, whereas during the treatment with fixed appliance there is no significant change in mandibular prognathism. PMID- 25695104 TI - Constructing RBAC based security model in u-healthcare service platform. AB - In today's era of aging society, people want to handle personal health care by themselves in everyday life. In particular, the evolution of medical and IT convergence technology and mobile smart devices has made it possible for people to gather information on their health status anytime and anywhere easily using biometric information acquisition devices. Healthcare information systems can contribute to the improvement of the nation's healthcare quality and the reduction of related cost. However, there are no perfect security models or mechanisms for healthcare service applications, and privacy information can therefore be leaked. In this paper, we examine security requirements related to privacy protection in u-healthcare service and propose an extended RBAC based security model. We propose and design u-healthcare service integration platform (u-HCSIP) applying RBAC security model. The proposed u-HCSIP performs four main functions: storing and exchanging personal health records (PHR), recommending meals and exercise, buying/selling private health information or experience, and managing personal health data using smart devices. PMID- 25695105 TI - Improvement of the survival of human autologous fat transplantation by adipose derived stem-cells-assisted lipotransfer combined with bFGF. AB - Adipose-derived stem cells (ASCs) transplanted along with autologous adipose tissue may improve fat graft survival; however, the efficacy of ASCs has been diluted by low vascularization. This study was designed to test the hypothesis that basic fibroblast growth factor (bFGF) may improve the effects of ASCs because it owns the property to boost angiogenesis. In the present study, human fat tissues were mixed with ASCs, ASCs plus 100 U bFGF, or medium as the control and then injected subcutaneously into immunologically compromised nude mice for 12 weeks. Our findings demonstrated that mixture with the ASCs significantly increased the weight and volume of the fat grafts compared to control grafts, and histological analysis revealed that both ASCs and ASCs plus bFGF grafts consisted predominantly of adipose tissue and had significantly less fibrosis but greater microvascular density compared with control and also grafts mixed with ASCs had a high expression of angiogenic factors. More importantly, the bFGF treated fat grafts shown elevate in survival, vascularization, and angiogenic factors expression when compared with the grafts that received ASCs alone. These results indicated that bFGF together with ASCs can enhance the efficacy of autologous fat transplantation and increase blood vessel generation involved in the benefits from bFGF. PMID- 25695107 TI - From social networks to health: Durkheim after the turn of the millennium. Introduction. PMID- 25695106 TI - Comorbidities of COPD have a major impact on clinical outcomes, particularly in African Americans. AB - BACKGROUND: COPD patients have a great burden of comorbidity. However, it is not well established whether this is due to shared risk factors such as smoking, if they impact patients exercise capacity and quality of life, or whether there are racial disparities in their impact on COPD. METHODS: We analyzed data from 10,192 current and ex-smokers with (cases) and without COPD (controls) from the COPDGene(r) cohort to establish risk for COPD comorbidities adjusted for pertinent covariates. In adjusted models, we examined comorbidities prevalence and impact in African-Americans (AA) and Non-Hispanic Whites (NHW). RESULTS: Comorbidities are more common in COPD compared to those with normal spirometry (controls), and the risk persists after adjustments for covariates including pack years smoked. After adjustment for confounders, eight conditions were independently associated with worse exercise capacity, quality of life and dyspnea. There were racial disparities in the impact of comorbidities on exercise capacity, dyspnea and quality of life, presence of osteoarthritis and gastroesophageal reflux disease having a greater negative impact on all three outcomes in AAs than NHWs (p<0.05 for all interaction terms). CONCLUSIONS: Individuals with COPD have a higher risk for comorbidities than controls, an important finding shown for the first time comprehensively after accounting for confounders. Individual comorbidities are associated with worse exercise capacity, quality of life, and dyspnea, in African-Americans compared to non Hispanic Whites. PMID- 25695108 TI - Publisher's Note to "The association between kinematic risky driving among parents and their teenage children: Moderation by Shared Personality Characteristics". AB - The Publisher would like to inform readers that the article entitled "The association between kinematic risky driving among parents and their teenage children: Moderation by Shared Personality Characteristics" by Johnathon P. Ehsani, Bruce Simons-Morton, Yunlong Xie,Sheila G. Klauer, and Paul S. Albert has been removed from this issue, as it had been incorrectly included here rather than in the special issue for which it was intended. The article will be published in the correct issue in the near future. This is to ensure the continuity of the special issue is not lost. The Publisher would like to apologize for any inconvenience caused. PMID- 25695109 TI - 7th International Immunoglobulin Conference: Foreword. PMID- 25695111 TI - Association between sleep architecture and glucose tolerance in children and adolescents. AB - BACKGROUND: Short sleep duration is a contributing factor for decreased insulin sensitivity and hyperglycemia. Sleep architecture represents a cyclical pattern of sleep that shifts between sleep Stages N1, N2, N3 (slow wave sleep) and Stage R (rapid eye movement sleep). The aim of the present study was to examine the association between sleep architecture and glucose and insulin metabolism in both normal weight and overweight/obese children and adolescents. METHODS: A total of 118 subjects participated in the study. Subjects under-went overnight polysomnography (PSG) when the percentage of total sleep time (% TST) spent at each sleep stage was recorded and an oral glucose tolerance test together was performed the next morning. We assessed glucose tolerance, insulin sensitivity and pancreatic beta-cell function using 2-h glucose levels, the Matsuda index (IS(OGTT)), and insulin secretion-sensitivity index-2 (ISSI-2), respectively. RESULTS: After adjustment for age, gender, body mass index z-score, pubertal status, and obstructive apnea hypopnea index, Stage N3 (% TST) was positively associated with IS(OGTT), whereas Stage N1 (%TST) exerted an opposite effect on IS(OGTT). Higher sleep efficiency and longer TST were independently associated with lower 2-h glucose levels, higher ISSI-2 and/or higher IS(OGTT). CONCLUSIONS: Stage N3, sleep efficiency and TST were protective factors in maintaining glucose and insulin homeostasis; however, Stage N1 functioned in the opposite direction. PMID- 25695112 TI - Author response. PMID- 25695113 TI - Allelic variant in CTLA4 is associated with thyroid failure and faster beta cell exhaustion in latent autoimmune diabetes in adults. AB - BACKGROUND: The aim of the study was to investigate the role of the cytotoxic T lymphocyte-associated protein 4 (CTLA4) G6230A variant on the susceptibility of latent autoimmune diabetes in adults (LADA) as a whole and in the subset of patients who share autoimmune thyroid disease (AITD). METHODS: The study included 202 LADA, 1373 patients with early onset type 1 diabetes (T1D), 130 patients with late-onset T1D, 188 patients with non-autoimmune diabetes and 1904 healthy controls. Thyrotropin (thyrotropin-stimulating hormone; TSH) and antibodies against thyroid peroxidase were analyzed in all patients. The CTLA4 G6230A variant was assessed in LADA, early and late-onset T1D patients as well as in the controls. RESULTS: The frequency of CTLA4 G alleles and genotypes in LADA patients did not differ significantly from that in the other groups, regardless of its association with AITD. We found an increased frequency of G allele containing genotypes within LADA patients who had higher TSH compared with those with normal TSH (P = 0.002). Moreover, LADA patients carrying G allele-containing genotypes were more likely to require insulin therapy within 4 years of diagnosis (P = 0.002). CONCLUSIONS: The G6230A CTLA4 variant does not confer susceptibility to LADA in Sardinian patients even when associated with AITD. However, it helps identify a particular subset of LADA patients with more clinically severe disease, both for thyroid dysfunction and diabetes. PMID- 25695114 TI - Environmental risk assessors as honest brokers or stealth advocates. AB - Risk assessment ought to provide a solid, evidence base to risk management in the development of environmental policy and decisions, where the risk assessors act without advocacy as honest brokers of science advice. But there are concerns that the values of the risk assessors might undermine the objectivity of the process. For similar reasons, there is suspicion that more interaction between risk assessors and risk managers might contaminate the science. On the contrary, here the argument is that making risk assessment more management- and value-relevant, through more effective dialogue, provides a better foundation for objective science advice. PMID- 25695115 TI - Focal atrial tachycardias and atrial flutter: are they hot enough to make a thematic issue? PMID- 25695116 TI - Sitting is the new smoking! PMID- 25695117 TI - Preparing and ensuring competency of new nurse planners. AB - The addition of a nurse planner to a provider unit requires orientation to ensure understanding and adherence to accreditation criteria. After assessing new nurse planners' needs and experience, orientation can involve the use of different resources, mentorship, and competency verification. Communication is essential to address issues and maintain accreditation standards. PMID- 25695118 TI - How can radio frequency identification technology impact nursing practice? AB - Radio frequency identification (RFID) technology can save nurses time, improve quality of care, en hance patient and staff safety, and decrease costs. However, without a better understanding of these systems and their benefits to patients and hospitals, nurses may be slower to recommend, implement, or adopt RFID technology into practice. PMID- 25695119 TI - Another level of leadership: nurses on boards. AB - The movement to place nurses on boards of directors is growing, enriching boards with individuals possessing knowledge of clinical quality tied to care delivery models, human resource competencies and management, finance, and organizational change. Professional development educators are poised to advance a board's capacity to address complex health care problems. PMID- 25695120 TI - Using active engagement to teach leadership. AB - The current health care climate requires nurses to demonstrate leadership competencies. Incorporating leadership strategies into nursing continuing education is accomplished through methods such as role-play and clinical simulation activities. Simulation helps nurses to care for multiple patients, effectively delegate, consider quality and safety issues, and communicate effectively with health care team members. PMID- 25695121 TI - Developing an interprofessional continuing education symposium for health care educators in Qatar. AB - An international interprofessional continuing education symposium was developed and implemented by a global faculty team in Qatar in March 2014. This symposium was undertaken as part of the country's goal of improving the quality of health care. After an extensive planning process, health care educators engaged in multiple types of learning experiences to enrich their knowledge and skills. Evaluation data support the value of this experience. PMID- 25695125 TI - Highly efficient low-bandgap polymer solar cells with solution-processed and annealing-free phosphomolybdic acid as hole-transport layers. AB - We demonstrate a novel solution-processed method to fabricate a stable anode buffer layer without any annealing process. As we know, buffer layers in polymer solar cells (PSCs) are always prepared by the traditional high-vacuum thermal evaporation or annealing-treated spin-coating methods, but the fabricating processes are complicated and time-consuming. Here, a solution method without any annealing to fabricate phosphomolybdic acid (PMA) as anode buffers is presented, which brings an obvious improvement of power conversion efficiency (PCE) from 1.75% to 6.57% by optimizing the PMA concentrations and interface pretreatment with device structure shown as ITO/TiO2/PCDTBT:PC70BM/PMA/Ag. The improvement is ascribed to the fine energy-level matching and perfect surface modification. This annealing-free method greatly simplifies the device fabrication process and supplies a wide way to achieve a large area fabrication for PSCs. PMID- 25695126 TI - Quantum chemical investigation of meta-xylylene based one-dimensional polymer chain. AB - We have investigated unsubstituted and methyl substituted polyradical chains of meta-xylylene by using density functional theory-broken symmetry methodology (DFT BS). Optimization of geometry in the high-spin and low-spin states have been done at B3LYP/6-31G(d,p) and M06-2X/6-31G(d,p) levels in unrestricted methodology. Single-point calculations on the high-spin optimized geometries have been done by using the 6-311G(d,p) basis set. Each polyradical has been found to be nonplanar with a high-spin ground state. Each has a coupling constant larger than thermal energy. For each group of polyradicals, the coupling constant has been found to exponentially decrease with increase in the number of phenylene groups. The B3LYP infinite chain limit has been estimated for both the unsubstituted and substituted polyradicals. The individual inter-radical-site coupling constants have been estimated for the triradicals and tetraradicals using HDVV Hamiltonian in ORCA 3.0.1 code. These are also generally large and positive, revealing a strong intersite ferromagnetic interaction. The intersite coupling constant too decreases with increasing distance between the radical centers. Finally, we have used CRYSTAL09 package for calculations on the infinitely long one-dimensional and periodic polyradical chains. The coupling constants estimated from the periodic calculations are quite large at about 500 cm(-1) and somewhat greater than the limiting values calculated for the polyradicals with an increasing number of phenylene groups. This happens as the individual polyradicals of increasing size progressively deviate from periodicity, and thereby lessens the strength of through-bond spin-spin coupling. The calculated band gap of ~4.5 eV indicates that the infinitely long one-dimensional chains must be ferromagnetic and electron insulators. PMID- 25695127 TI - Inactivation of foodborne microorganisms using engineered water nanostructures (EWNS). AB - Foodborne diseases caused by the consumption of food contaminated with pathogenic microorganisms or their toxins have very serious economic and public health consequences. Here, we explored the effectiveness of a recently developed intervention method for inactivation of microorganisms on fresh produce, and food production surfaces. This method utilizes Engineered Water Nanostructures (EWNS) produced by electrospraying of water vapor. EWNS possess unique properties; they are 25 nm in diameter, remain airborne in indoor conditions for hours, contain Reactive Oxygen Species (ROS) and have very strong surface charge (on average 10 e/structure). Here, their efficacy in inactivating representative foodborne bacteria such as Escherichia coli, Salmonella enterica, and Listeria innocua, on stainless steel surfaces and on organic tomatoes, was assessed. The inactivation was facilitated using two different exposure approaches in order to optimize the delivery of EWNS to bacteria: (1) EWNS were delivered on the surfaces by diffusion and (2) a "draw through" Electrostatic Precipitator Exposure System (EPES) was developed and characterized for EWNS delivery to surfaces. Using the diffusion approach and an EWNS concentration of 24,000 #/cm3, the bacterial concentrations on the surfaces were reduced, depending on the bacterium and the surface type, by values ranging between 0.7 to 1.8 logs. Using the EPES approach and for an aerosol concentration of 50,000 #/cm3 at 90 min of exposure, results show a 1.4 log reduction for E. coli on organic tomato surfaces, as compared to the control (same conditions in regards to temperature and Relative Humidity). Furthermore, for L. innocua, the dose-response relationship was demonstrated and found to be a 0.7 and 1.2 logs removal at 12,000 and 23,000 #/cm3, respectively. The results presented here indicate that this novel, chemical-free, and environmentally friendly intervention method holds potential for development and application in the food industry, as a "green" alternative to existing disinfection methods. PMID- 25695128 TI - Risk factors for early onset of catheter-related bloodstream infection in an intensive care unit in China: a retrospective study. AB - BACKGROUND: Catheter-related bloodstream infection (CRBSI) is a life-threatening condition encountered in patients with long-term central venous catheter (CVC) indwelling. The objective was to investigate the clinical characteristics, treatment, and prognosis of CRBSI in the intensive care unit (ICU) in a Chinese center, as well as the risk factors for early CRBSI. MATERIAL AND METHODS: A total of 73 CRBSI patients were retrospectively studied in relation to patients' clinical and epidemiological data, microbiological culture, and treatment. Patients were treated at the Taizhou Hospital of Integrated Traditional Chinese and Western Medicine in Zhejiang (Zhejiang Wenlin, China) between January 2010 and December 2012. RESULTS: In this Chinese center, the most common pathogens were Gram-positive cocci, followed by Gram-negative bacilli and fungi. A high prevalence of antibiotic-resistant pathogens was detected, and a higher percentage of non-Candida albicans spp. was observed. Multivariate analysis showed that an acute physiology and chronic health evaluation II (APACHE II) score >20 and >3 types of underlying diseases were independent factors associated with CRBSI occurring within 14 days of CVC indwelling. Untimely CVC removal and/or inappropriate use of antibiotics led to significantly longer time to defervescence and time to negative conversion of blood culture (all P<0.05). CONCLUSIONS: In this Chinese center, Gram-positive bacteria are predominantly detected in CRBSI. APACHE II score >20 and the presence of >3 types of diseases were associated with earlier CRBSI onset. Timely removal of CVC and appropriate use of antibiotics resulted in improved outcomes. PMID- 25695130 TI - A new method to image heme-Fe, total Fe, and aggregated protein levels after intracerebral hemorrhage. AB - An intracerebral hemorrhage (ICH) is a devastating stroke that results in high mortality and significant disability in survivors. Unfortunately, the underlying mechanisms of this injury are not yet fully understood. After the primary (mechanical) trauma, secondary degenerative events contribute to ongoing cell death in the peri-hematoma region. Oxidative stress is thought to be a key reason for this delayed injury, which is likely due to free-Fe-catalyzed free radical reactions. Unfortunately, this is difficult to prove with conventional biochemical assays that fail to differentiate between alterations that occur within the hematoma and peri-hematoma zone. This is a critical limitation, as the hematoma contains tissue severely damaged by the initial hemorrhage and is unsalvageable, whereas the peri-hematoma region is less damaged but at risk from secondary degenerative events. Such events include oxidative stress mediated by free Fe presumed to originate from hemoglobin breakdown. Therefore, minimizing the damage caused by oxidative stress following hemoglobin breakdown and Fe release is a major therapeutic target. However, the extent to which free Fe contributes to the pathogenesis of ICH remains unknown. This investigation used a novel imaging approach that employed resonance Raman spectroscopic mapping of hemoglobin, X-ray fluorescence microscopic mapping of total Fe, and Fourier transform infrared spectroscopic imaging of aggregated protein following ICH in rats. This multimodal spectroscopic approach was used to accurately define the hematoma/peri-hematoma boundary and quantify the Fe concentration and the relative aggregated protein content, as a marker of oxidative stress, within each region. The results revealed total Fe is substantially increased in the hematoma (0.90 MUg cm(-2)), and a subtle but significant increase in Fe that is not in the chemical form of hemoglobin is present within the peri-hematoma zone (0.32 MUg cm(-2)) within 1 day of ICH, relative to sham animals (0.22 MUg cm(-2)). Levels of aggregated protein were significantly increased within both the hematoma (integrated band area 0.10 AU) and peri-hematoma zone (integrated band area 0.10 AU) relative to sham animals (integrated band area 0.056 AU), but no significant difference in aggregated protein content was observed between the hematoma and peri-hematoma zone. This result suggests that the chemical form of Fe and its ability to generate free radicals is likely to be a more critical predictor of tissue damage than the total Fe content of the tissue. Furthermore, this article describes a novel approach to colocalize nonheme Fe and aggregated protein in the peri-hematoma zone following ICH, a significant methodological advancement for the field. PMID- 25695131 TI - Mycoplasma CG- and GATC-specific DNA methyltransferases selectively and efficiently methylate the host genome and alter the epigenetic landscape in human cells. AB - Aberrant DNA methylation is frequently observed in disease, including many cancer types, yet the underlying mechanisms remain unclear. Because germline and somatic mutations in the genes that are responsible for DNA methylation are infrequent in malignancies, additional mechanisms must be considered. Mycoplasmas spp., including Mycoplasma hyorhinis, efficiently colonize human cells and may serve as a vehicle for delivery of enzymatically active microbial proteins into the intracellular milieu. Here, we performed, for the first time, genome-wide and individual gene mapping of methylation marks generated by the M. hyorhinis CG- and GATC-specific DNA cytosine methyltransferases (MTases) in human cells. Our results demonstrated that, upon expression in human cells, MTases readily translocated to the cell nucleus. In the nucleus, MTases selectively and efficiently methylated the host genome at the DNA sequence sites free from pre existing endogenous methylation, including those in a variety of cancer associated genes. We also established that mycoplasma is widespread in colorectal cancers, suggesting that either the infection contributed to malignancy onset or, alternatively, that tumors provide a favorable environment for mycoplasma growth. In the human genome, ~ 11% of GATC sites overlap with CGs (e.g., CGAT(m)CG); therefore, the methylated status of these sites can be perpetuated by human DNMT1. Based on these results, we now suggest that the GATC-specific methylation represents a novel type of infection-specific epigenetic mark that originates in human cells with a previous exposure to infection. Overall, our findings unveil an entirely new panorama of interactions between the human microbiome and epigenome with a potential impact in disease etiology. PMID- 25695132 TI - Severe fever with thrombocytopenia syndrome in Japan and public health communication. AB - A fatal case of severe fever with thrombocytopenia syndrome was reported in Japan in 2013. The ensuing process of public communication offers lessons on how to balance public health needs with patient privacy and highlights the importance of multilateral collaborations between scientific and political communities. PMID- 25695133 TI - Seizure clusters: characteristics and treatment. AB - PURPOSE OF REVIEW: Many patients with epilepsy experience 'clusters' or flurries of seizures, also termed acute repetitive seizures (ARS). Seizure clustering has a significant impact on health and quality of life. This review summarizes recent advances in the definition and neurophysiologic understanding of clustering, the epidemiology and risk factors for clustering and both inpatient and outpatient clinical implications. New treatments for seizure clustering/ARS are perhaps the area of greatest recent progress. RECENT FINDINGS: Efforts have focused on creating a uniform definition of a seizure cluster. In neurophysiologic studies of refractory epilepsy, seizures within a cluster appear to be self-triggering. Clinical progress has been achieved towards a more precise prevalence of clustering, and consensus guidelines for epilepsy monitoring unit safety. The greatest recent advances are in the study of nonintravenous route of benzodiazepines as rescue medications for seizure clusters/ARS. Rectal benzodiazepines have been very effective but barriers to use exist. New data on buccal, intramuscular and intranasal preparations are anticipated to lead to a greater number of approved treatments. Progesterone may be effective for women who experience catamenial clusters. SUMMARY: Seizure clustering is common, particularly in the setting of medically refractory epilepsy. Clustering worsens health and quality of life, and the field requires greater focus on clarifying of definition and clinical implications. Progress towards the development of nonintravenous routes of benzodiazepines has the potential to improve care in this area. PMID- 25695134 TI - Autism and the synapse: emerging mechanisms and mechanism-based therapies. AB - PURPOSE OF REVIEW: Recent studies have implicated hundreds of genetic variants in the cause of autism spectrum disorder (ASD). Genes involved in 'monogenic' forms of syndromic ASD converge on common pathways that are involved in synaptic development, plasticity and signaling. In this review, we discuss how these 'developmental synaptopathies' inform our understanding of the molecular disease in ASD and highlight promising approaches that have bridged the gap between the bench and the clinic. RECENT FINDINGS: Accumulating evidence suggests that synaptic deficits in syndromic and nonsyndromic ASD can be mapped to gene mutations in pathways that control synaptic protein synthesis and degradation, postsynaptic scaffold architecture and neurotransmitter receptors. This is recapitulated in models of Fragile X syndrome (FXS), Tuberous Sclerosis Complex (TSC), Angelman syndrome and Phelan-McDermid syndrome (PMS), all of which cause syndromic ASD. Important recent advances include the development of mouse models and patient-derived induced pluripotent stem cell (iPSC) lines that enable a detailed investigation of synaptic deficits and the identification of potential targets for therapy. Examples of the latter include mGluR5 antagonists in FXS, mTOR inhibitors in TSC and insulin-like growth factor 1 (IGF-1) in PMS. SUMMARY: Identifying converging pathways in syndromic forms of ASD will uncover novel therapeutic targets for non-syndromic ASD. Insights into developmental synaptopathies will lead to rational development of mechanism-based therapies and clinical trials that may provide a blueprint for other common pathways implicated in the molecular neuropathology of ASD. PMID- 25695135 TI - Epilepsy and malformations of cortical development: new developments. AB - PURPOSE OF REVIEW: Malformations of cortical development (MCD) are increasingly recognized as causes of epilepsy and neurodevelopmental disorders. This review summarizes recent developments in the classification, specifically focusing on how genetic and cellular pathway advances are changing our understanding of MCD and how this applies to clinical care. RECENT FINDINGS: Recent studies have shown that mutations can have variable impact on not only the pattern of MCD but also the location of cortical involvement. Regulatory G protein GPR56 mutations can selectively cause polymicrogyria in the Sylvian fissure bilaterally. In addition, recent data suggest that somatic mutations can be detected in about 30% of patients with diffuse and focal MCD but the majority are not detectable with common sequencing. Similarly, MRI at higher field is able to detect abnormalities not seen on clinical scanners. The classification scheme and pathogenesis of MCD converge by common genes affecting similar pathways, which, in turn, modify the classification of these disorders. These advances are impacting treatment and genetic management. SUMMARY: The classification of MCD in epilepsy has progressed from simple correlations with syndromes and imaging data to molecular pathways underscoring the significance of common mechanism in brain maldevelopment and epilepsy. PMID- 25695136 TI - Update on behavioral interventions for autism and developmental disabilities. AB - PURPOSE OF REVIEW: Given the explosion in published behavioral interventions over the past several years, this review highlights the latest trends over the past year (2014) for children with complex learning and developmental needs. RECENT FINDINGS: There were virtually no rigorous intervention studies published on developmental disorders in which the cause of the disorder is well known. Nearly all studies focus on autism spectrum disorder. Trends over the past year emphasize modular interventions with design improvements including comparisons of two active treatments and larger and more diverse samples. Far more community implemented treatments on understudied populations were conducted, including minimally verbal children, girls, very young infants, and low-resourced families. Finally, new pilot data on prevention and neural mechanisms were published. SUMMARY: An uptick in the number of rigorous tests of different interventions conducted in real-world settings with outcomes focused on core deficits bodes well for wide dissemination and implementation by nonspecialists in the community. Pilot and uncontrolled data on prevention and mechanism await further rigorous testing before conclusions can be drawn. PMID- 25695137 TI - Autism spectrum disorder in infancy: developmental considerations in treatment targets. AB - PURPOSE OF REVIEW: This review explores recent literature to prioritize aspects of development to be targeted by intervention for infants and toddlers with autism spectrum disorder (ASD). RECENT FINDINGS: Recent investigation of early development in ASD, including prospective studies of infants at increased risk (i.e., those with an affected older sibling) identifies impairments in four key developmental domains that are predictive of ASD. These domains are early attentional control, emotion regulation, social orienting/approach, and communication development. Reciprocal relationships exist among these domains, both in ASD and in typical development. Thus, these domains represent key intervention targets, informing treatment models under investigation in recent clinical trials. SUMMARY: By targeting the earliest and foundational manifestations of atypical development, we can capitalize on neural plasticity and build skills that are most likely to have scaffolding effects on development. The optimal timing and procedures of intervention remain empirical questions, but as the field moves toward earlier identification of risk, we are now poised to evaluate the impact of tailored approaches before the developmental cascade that leads to ASD is fully manifested. Consideration regarding community translation of ASD-specific interventions for infants and toddlers is also needed, with a focus on feasibility, cost-effectiveness, and sustainability. PMID- 25695138 TI - Developmental disorders. PMID- 25695139 TI - Dalhousie Pictorial Scales Measuring Dyspnea and Perceived Exertion during Exercise for Children and Adolescents. AB - RATIONALE: Alternative scales to measure dyspnea and perceived exertion have been sought due to concerns regarding understanding and validity of any Borg scale in pediatric populations. OBJECTIVES: To demonstrate content validity of Dalhousie Dyspnea and Perceived Exertion Scales developed for children and adolescents. METHODS: We obtained ratings for dyspnea and perceived exertion using both Borg CR-10 and Dalhousie Scales during incremental cycle exercise in 100 children and adolescents, healthy or with respiratory disease. Content validity was determined by correlating perceived leg exertion rating versus heart rate or %peak work capacity and dyspnea rating versus ventilation expressed as %peak ventilation. The stimulus-perceptual response was modeled as a quadratic function with a delay term. Reproducibility, cross-modality usage, and language effects were assessed in a small group of Italian children during treadmill exercise. MEASUREMENTS AND MAIN RESULTS: Pictorial ratings of dyspnea and perceived exertion measured by both scale ratings rose as expected with increasing exercise intensity in children and adolescents, demonstrating excellent correlation between perceived leg exertion versus exercise intensity and dyspnea rating versus ventilation (median Spearman rho >= 0.9) with either scale. There were no systematic differences in dyspnea or perceived exertion ratings between children with or without respiratory disease. Understandability and reproducibility of the Dalhousie scales was affirmed in Italian-speaking subjects performing treadmill exercise. CONCLUSIONS: Dalhousie Dyspnea and Perceived Exertion Scales offer an alternative to the Borg scale for use during exercise in pediatric subjects. Children and adolescents exhibit large variation in patterns of ratings of dyspnea and perceived exertion in incremental exercise. PMID- 25695140 TI - Recombinant mouse prion protein alone or in combination with lipopolysaccharide alters expression of innate immunity genes in the colon of mice. AB - The objectives of this study were to test whether recombinant mouse (mo)PrP alone or in combination with LPS or under simulated endotoxemia would affect expression of genes related to host inflammatory and antimicrobial responses. To test our hypotheses colon tissues were collected from 16 male mice (FVB/N strain) and mounted in an Ussing chamber. Application of moPrP to the mucosal side of the colon affected genes related to TLR- and NLR- signaling and antimicrobial responses. When LPS was added on the mucosal side of the colon, genes related to TLR, Nlrp3 inflammasome, and iron transport proteins were over-expressed. Addition of LPS to the serosal side of the colon up-regulated genes related to TLR- and NLR-signaling, Nlrp3 inflammasome, and a chemokine. Treatment with both moPrP and LPS to the mucosal side of the colon upregulated genes associated with TLR, downstream signal transduction (DST), inflammatory response, attraction of dendritic cells to the site of inflammation, and the JNK-apoptosis pathway. Administration of moPrP to the mucosal side and LPS to the serosal side of the colon affected genes related to TLR- and NLR-signaling, DST, apoptosis, inflammatory response, cytokines, chemokines, and antimicrobial peptides. Overall this study suggests a potential role for moPrP as an endogenous 'danger signal' associated with activation of colon genes related to innate immunity and antibacterial responses. PMID- 25695141 TI - Chromosomal Variability Between Populations of Electrophorus electricus Gill, 1864 (Pisces: Gymnotiformes: Gymnotidae). AB - The electric eel, Electrophorus electricus, the only species of its genus, has a wide distribution in the Amazon and Orinoco drainages. There is little previous information regarding the population variation in E. electricus, with only basic karyotype data from two populations (Amazon and Araguaia Rivers). Karyotypic description and analysis of CO1 barcode sequences were performed for E. electricus from three localities (Caripetuba, Irituia, and Maicuru Rivers). All samples share the 2n=52 (42 m-sm [meta-submetacentric] +10 st-a [subtelo acrocentric]) with previously studied material. However, the Maicuru River samples differ from the other populations, as they have B chromosomes. The distribution of noncentromeric constitutive heterochromatin between samples is relatively divergent. All samples analyzed present the Nucleolar Organizer Region (NOR) located in a single chromosome pair. In the samples from Caripetuba, NORs were colocalized with a heterochromatin block, whereas the NOR was flanked by heterochromatin in Maicuru River samples and pericentromeric heterochromatin adjacent NOR was found in Irituia River samples. Alignment of CO1 barcode sequences indicated no significant differentiation between the samples analyzed. Results suggest that karyotypic differences between samples from the Caripetuba, Irituia, and Amazon Rivers represent chromosome polymorphisms. However, differences between the samples from the Maicuru and Araguaia Rivers and the remaining populations could represent interpopulation differentiation, which has not had time to accrue divergence at the CO1 gene level. PMID- 25695142 TI - {110}-Layered B-cation ordering in the anion-deficient perovskite Pb2.4Ba2.6Fe2Sc2TiO13 with the crystallographic shear structure. AB - A novel anion-deficient perovskite-based compound, Pb(2.4)Ba(2.6)Fe(2)Sc(2)TiO(13), was synthesized via the citrate-based route. This compound is an n = 5 member of the AnBnO(3n-2) homologous series with unit cell parameters related to the perovskite subcell a(p)~ 4.0 A as a(p)?2 *a(p)* 5a(p)?2. The crystal structure of Pb(2.4)Ba(2.6)Fe(2)Sc(2)TiO(13) consists of quasi-2D perovskite blocks with a thickness of three octahedral layers separated by the 1/2[110](1[combining macron]01)(p) crystallographic shear (CS) planes, which are parallel to the {110} plane of the perovskite subcell. The CS planes transform the corner-sharing octahedra into chains of edge-sharing distorted tetragonal pyramids. Using a combination of neutron powder diffraction, (57)Fe Mossbauer spectroscopy and atomic resolution electron energy-loss spectroscopy we demonstrate that the B-cations in Pb(2.4)Ba(2.6)Fe(2)Sc(2)TiO(13) are ordered along the {110} perovskite layers with Fe(3+) in distorted tetragonal pyramids along the CS planes, Ti(4+) preferentially in the central octahedra of the perovskite blocks and Sc(3+) in the outer octahedra of the perovskite blocks. Magnetic susceptibility and Mossbauer spectroscopy indicate a broadened magnetic transition around T(N)~ 45 K and the onset of local magnetic fields at low temperatures. The magnetic order is probably reminiscent of that in other AnBnO(3n-2) homologues, where G-type AFM order within the perovskite blocks has been observed. PMID- 25695143 TI - Cooling it after drug induced hyperthermia. PMID- 25695144 TI - Ice water submersion for rapid cooling in severe drug-induced hyperthermia. AB - CONTEXT: The optimal method of cooling hyperthermic patients is controversial. Although controlled data support ice water submersion, many authorities recommend a mist and fan technique. We report two patients with drug-induced hyperthermia, to demonstrate the rapid cooling rates of ice water submersion. CASE DETAILS: Case 1. A 27-year-old man presented with a sympathomimetic toxic syndrome and a core temperature of 41.4 degrees C after ingesting 4-fluoroamphetamine. He was submerged in ice water and his core temperature fell to 38 degrees C within 18 minutes (a mean cooling rate of 0.18 degrees C/min). His vital signs stabilized, his mental status improved and he left on hospital day 2. Case 2. A 32-year-old man with a sympathomimetic toxic syndrome after cocaine use was transported in a body bag and arrived with a core temperature of 44.4 degrees C. He was intubated, sedated with IV benzodiazepines, and submerged in ice water. After 20 mins his temperature fell to 38.8 degrees C (a cooling rate of 0.28 degrees C/min). He was extubated the following day, and discharged on day 10. DISCUSSION: In these two cases, cooling rates exceeded those reported for mist and fan technique. Since the priority in hyperthermia is rapid cooling, clinical data need to be collected to reaffirm the optimal approach. PMID- 25695145 TI - High dead-space syringe use among people who inject drugs in Tijuana, Mexico. AB - BACKGROUND: High dead-space syringes (HDSS) are believed to confer an elevated risk of acquiring HIV and other blood-borne infections. OBJECTIVES: We identified prevalence and correlates of HDSS use among injection drug users (IDU) in Tijuana, Mexico, where syringe purchase and possession is legal without a prescription. METHODS: Beginning in 2011, IDU who reported being 18 years or older and injected drugs within the last month were recruited into a prospective study. At baseline and semi-annually, 557 IDU underwent HIV-testing and interviewer-administered surveys. Logistic regression was used to identify correlates of using HDSS. RESULTS: Of 557 IDU, 40% had ever used HDSS, mostly because no other syringe type was available (72%), or because they were easier to get (20%). Controlling for sex and age at first injection, use of HDSS was associated with cocaine as the first drug injected (Adjusted Odds Ratio [AOR]: 2.68; Confidence Interval 95% [CI]: 1.15-6.22), having been stopped or arrested by police (AOR: 1.84; 95% CI: 1.11-3.07), being deported from the US (AOR: 1.64; 95% CI:1.06-2.53), and believing it is illegal to carry syringes (AOR:1.78; 95% CI: 1.01-3.15). CONCLUSION: Use of HDSS is surprisingly common among IDU in Tijuana. Efforts are needed to expand coverage of low-dead space syringes through existing syringe exchange programs. Education is required to increase awareness of the harms associated with HDSS, and to inform IDU that syringe possession is legal across Mexico. PMID- 25695146 TI - Synthesis, crystal structure, and spectroscopy of the mixed-valent boroseleniteselenate B2Se3O10. AB - The first mixed-valent boroseleniteselenate B2Se3O10 was obtained as a colorless, hygroscopic compound from the reaction of boric acid (H3BO3) in concentrated selenic acid (H2SeO4) at 265 degrees C. H2SeO4 can be replaced by appropriate amounts of SeO2 and H2O2. The crystal structure was determined from single crystal data (P21/c, Z = 4, a = 4.3466(2) A, b = 7.0237(4) A, c = 22.1460(9) A, beta = 94.922(2) degrees , R1 = 0.036, wR2 = 0.096). It represents a new structure type that is characterized by a 3D net of BO4 tetrahedra, Se(VI)O4 tetrahedra, and trigonal-pyramidal Se(IV)O3 in a ratio of 2:1:2. (77)Se magic angle-spinning NMR investigations confirm the mixed-valent character because the chemical shifts are found in the typical regions, i.e., 1278 and 1202 ppm for Se(IV) and 972 ppm for Se(VI). The vibrational spectra show the typical modes according to the present polyhedra. In addition, NMR and vibrational spectra of the closely related B2Se2O7 are presented. PMID- 25695147 TI - Biomarker-guided personalised emergency medicine for all - hope for another hype? AB - Polymorbid patients, diverse diagnostic and therapeutic options, more complex hospital structures, financial incentives, benchmarking, as well as perceptional and societal changes put pressure on medical doctors, specifically if medical errors surface. This is particularly true for the emergency department setting, where patients face delayed or erroneous initial diagnostic or therapeutic measures and costly hospital stays due to sub-optimal triage. A "biomarker" is any laboratory tool with the potential better to detect and characterise diseases, to simplify complex clinical algorithms and to improve clinical problem solving in routine care. They must be embedded in clinical algorithms to complement and not replace basic medical skills. Unselected ordering of laboratory tests and shortcomings in test performance and interpretation contribute to diagnostic errors. Test results may be ambiguous with false positive or false negative results and generate unnecessary harm and costs. Laboratory tests should only be ordered, if results have clinical consequences. In studies, we must move beyond the observational reporting and meta-analysing of diagnostic accuracies for biomarkers. Instead, specific cut-off ranges should be proposed and intervention studies conducted to prove outcome relevant impacts on patient care. The focus of this review is to exemplify the appropriate use of selected laboratory tests in the emergency setting for which randomised controlled intervention studies have proven clinical benefit. Herein, we focus on initial patient triage and allocation of treatment opportunities in patients with cardiorespiratory diseases in the emergency department. The following five biomarkers will be discussed: proadrenomedullin for prognostic triage assessment and site-of-care decisions, cardiac troponin for acute myocardial infarction, natriuretic peptides for acute heart failure, D-dimers for venous thromboembolism, C-reactive protein as a marker of inflammation, and procalcitonin for antibiotic stewardship in infections of the respiratory tract and sepsis. For these markers we provide an overview on physiopathology, historical evolution of evidence, strengths and limitations for a rational implementation into clinical algorithms. We critically discuss results from key intervention trials that led to their use in clinical routine and potential future indications. The rational for the use of all these biomarkers, first, tackle diagnostic ambiguity and consecutive defensive medicine, second, delayed and sub-optimal therapeutic decisions, and third, prognostic uncertainty with misguided triage and site-of-care decisions all contributing to the waste of our limited health care resources. A multifaceted approach for a more targeted management of medical patients from emergency admission to discharge including biomarkers, will translate into better resource use, shorter length of hospital stay, reduced overall costs, improved patients satisfaction and outcomes in terms of mortality and re-hospitalisation. Hopefully, the concepts outlined in this review will help the reader to improve their diagnostic skills and become more parsimonious laboratory test requesters. PMID- 25695148 TI - Generation of a ciliary margin-like stem cell niche from self-organizing human retinal tissue. AB - In the developing neural retina (NR), multipotent stem cells within the ciliary margin (CM) contribute to de novo retinal tissue growth. We recently reported the ability of human embryonic stem cells (hESCs) to self-organize stratified NR using a three-dimensional culture technique. Here we report the emergence of CM like stem cell niches within human retinal tissue. First, we developed a culture method for selective NR differentiation by timed BMP4 treatment. We then found that inhibiting GSK3 and FGFR induced the transition from NR tissue to retinal pigment epithelium (RPE), and that removing this inhibition facilitated the reversion of this RPE-like tissue back to the NR fate. This step-wise induction reversal method generated tissue aggregates with RPE at the margin of central peripherally polarized NR. We demonstrate that the NR-RPE boundary tissue further self-organizes a niche for CM stem cells that functions to expand the NR peripherally by de novo progenitor generation. PMID- 25695149 TI - Wood ducks (Aix sponsa) as potential reservoirs for avian influenza and avian paramyxoviruses. AB - Influenza A viruses (IAVs) and avian paramyxoviruses (APMVs) are important pathogens of poultry worldwide, and both commonly occur in wild waterfowl, especially ducks in the family Anatidae. Although wood ducks (Aix sponsa) are members of the Anatidae, their behaviour differs from most other species in this family, which could affect the transmission of IAVs and APMVs. We collected cloacal and oropharyngeal swab and blood samples from more than 700 wood ducks across nine states in the eastern United States of America. No IAVs were isolated, and based on blocking enzyme-linked immunoassay ELISA results, antibodies to IAVs were only detected in 0.2% of samples. In contrast, 23 (3%) APMVs were isolated (22 Newcastle disease virus and 1 APMV-6), and antibodies to multiple serotypes of APMVs were detected in more than 60% of the samples. After hatch-year birds were more likely to be antibody positive for APMV-4 and APMV-6 compared to hatch-year birds. Female birds were more likely to be antibody positive for APMV-4 than were male birds. Our results indicate that wood ducks are probably not an important host for IAV but are frequently infected with APMVs. PMID- 25695150 TI - Role of p53beta in the inhibition of proliferation of gastric cancer cells expressing wild-type or mutated p53. AB - p53 is a tumor suppressor gene whose mutation is highly associated with tumorigenesis. The present study investigated the role of p53beta in the inhibition of proliferation of gastric cancer cell lines expressing wild-type or mutated p53. Wild-type p53 is expressed in MKN45 cells, but deleted in KATOIII cells, whereas mutated p53 is expressed in SGC7901 cells. The mRNA expression levels of p53beta and Delta133p53 were detected in MKN45, SGC-7901 and KATOIII gastric cancer cell lines using nested polymerase chain reaction (PCR). The mRNA expression levels of p53, p53beta and B-cell lymphoma 2-associated X protein (Bax) were detected in the MKN45 and SGC-7901 cells following treatment with cisplatin by reverse transcription-PCR. The inhibition of cellular proliferation following treatment with cisplatin was measured by MTT assay. The results of the present study demonstrated that both p53beta and Delta133p53 mRNA were expressed in the MKN45 cells, whereas only p53beta mRNA was expressed in the SGC7901 cells. No expression of p53beta or Delta133p53 mRNA was detected in the KATOIII cells. Following treatment with cisplatin, the number of both MKN45 and SGC-7901 cells was significantly reduced (P<0.001). In the MKN45 cells, p53beta, p53 and Bax mRNA expression levels gradually increased with the dose of cisplatin, and the expression of p53beta was positively correlated with the expression of p53 (tr=6.358, P<0.05) and Bax (tr=8.023, P<0.05). In the SGC-7901 cells, the expression levels of p53beta, p53 and Bax mRNA did not alter with the dose of cisplatin, and the expression of p53beta was positively correlated to the expression of p53 (tr=26.41, P<0.01) but not that of Bax. The present study identified the different roles of the p53beta isoform in gastric cancer cells with different p53 backgrounds. Enhanced knowledge regarding the p53 status is required for the development of specific biological therapies against gastric cancer. PMID- 25695151 TI - FoxO6 inhibits cell proliferation in lung carcinoma through up-regulation of USP7. AB - Emerging evidence has suggested that misregulation of oncogenes and/or tumor suppressors has a crucial role in the development of lung carcinoma. The present study demonstrated that the expression levels of forkhead box O6 (FOXO6) were downregulated in lung cancer tissue samples, as compared with those in adjacent normal tissue. Overexpression of FOXO6 inhibited the proliferation of A549 human lung cancer cells, whereas knockdown of endogenous FOXO6 expression enhanced cell proliferation. Furthermore, ectopic FOXO6 expression induced the expression of ubiquitin-specific-processing protease 7 (USP7). As a result of this regulation, FOXO6 overexpression led to an elevation of p53 protein expression levels in A549 cells. In conclusion, the results of the present study indicated that the FOXO6/USP7 molecular network has an important role in the regulation of lung cancer development. PMID- 25695152 TI - Bi(OTf)3-mediated cycloisomerization of gamma-alkynyl arylketones: application to the synthesis of substituted furans. AB - A novel Bi(OTf)3-mediated cycloisomerization of gamma-alkynyl arylketones 4, 7, or 10 with molecular sieve (MS) in MeNO2 affords 3-substituted furans 3, 8, or 11 at rt for 3 h in moderate to good yields. The method provides mild, less-toxic, atom-economic and efficient conditions. The mechanism has been studied and proposed. Moreover, this route can be enlarged to gram scale. PMID- 25695153 TI - Lack of effect of lamivudine on Ebola virus replication. PMID- 25695155 TI - Rickettsia rickettsii in Amblyomma patinoi ticks, Colombia. PMID- 25695154 TI - Widespread correlation patterns of fMRI signal across visual cortex reflect eccentricity organization. AB - The human visual system can be divided into over two-dozen distinct areas, each of which contains a topographic map of the visual field. A fundamental question in vision neuroscience is how the visual system integrates information from the environment across different areas. Using neuroimaging, we investigated the spatial pattern of correlated BOLD signal across eight visual areas on data collected during rest conditions and during naturalistic movie viewing. The correlation pattern between areas reflected the underlying receptive field organization with higher correlations between cortical sites containing overlapping representations of visual space. In addition, the correlation pattern reflected the underlying widespread eccentricity organization of visual cortex, in which the highest correlations were observed for cortical sites with iso eccentricity representations including regions with non-overlapping representations of visual space. This eccentricity-based correlation pattern appears to be part of an intrinsic functional architecture that supports the integration of information across functionally specialized visual areas. PMID- 25695156 TI - Is WHO ineffectual because its members are ministries not states? PMID- 25695157 TI - An annual pre-announced step-increase in tobacco excise in New Zealand. AB - New Zealand is implementing a policy of pre-announced 10 per cent annual increases in tobacco excise for 7 years (from 2010 to 2016). Internationally, little is known about smokers' receptiveness to persistent step-increases in tobacco excise. This article reports on data collected in 2013 (600 interviews in total). The New Zealand Smoking Monitor is a fortnightly survey of smokers and recent quitters; respondents are maintained on a panel and interviewed up to six times. We found that, one-quarter of respondents supported continuing with a 10 per cent annual increase. Eight in ten were aware that a pack of cigarettes will cost US$16.50 in 3 years, and six in ten believed knowing the future cost of cigarettes gave them a strong reason to stop smoking now. While most respondents did not want the annual excise increase to continue, how they perceived the impact of persistent excise increases suggests this policy has the potential to increase quit attempts. PMID- 25695158 TI - Public health at all levels in the recent Nigerian Ebola viral infection epidemic: lessons for community, public and international health action and policy. PMID- 25695160 TI - Laser scoop desobliteration: a method for minimally invasive remote recanalization of chronically occluded superficial femoral arteries. AB - Stenosis and occlusion of the superficial femoral artery (SFA) are most common in arterial occlusive disease. There are numerous interventional, surgical, and combined approaches to reconstitute maximum blood supply to the lower limb; however, despite intense clinical research, the long-term success rates are still poor. We present the first results with a catheter prototype for laser-based minimal invasive endarterectomy, called laser scoop desobliteration (LSD). The tip of a glass fiber containing a catheter was modified with a spatula head design and connected to an ultraviolet laser. It was tested in cadavers fixed with the Thiel embalming technique preserving tissue consistency, flexibility, and plasticity. After longitudinal arteriotomy of the SFA, a circular dissection between media and adventitia was performed. Then the LSD catheter was inserted and propagated with a progress of 1 mm/s. Afterward, the atheroma core, which showed a plain surface without substantial attaching tissue debris, was removed. Histological examination of the vessel wall showed that the dissection was performed at the media/adventitia interface. In summary, the constructed LSD catheter allowed a rapid and easy way to perform an endarterectomy, thereby offering an innovative approach in the treatment of chronic occluded SFA. PMID- 25695161 TI - Femtosecond laser ablation of dentin and enamel: relationship between laser fluence and ablation efficiency. AB - The objective was to study the relationship between laser fluence and ablation efficiency of a femtosecond laser with a Gaussian-shaped pulse used to ablate dentin and enamel for prosthodontic tooth preparation. A diode-pumped thin-disk femtosecond laser with wavelength of 1025 nm and pulse width of 400 fs was used for the ablation of dentin and enamel. The laser spot was guided in a line on the dentin and enamel surfaces to form a groove-shaped ablation zone under a series of laser pulse energies. The width and volume of the ablated line were measured under a three-dimensional confocal microscope to calculate the ablation efficiency. Ablation efficiency for dentin reached a maximum value of 0.020 mm3/J when the laser fluence was set at 6.51 J/cm2. For enamel, the maximum ablation efficiency was 0.009 mm3/J at a fluence of 7.59 J/cm2.Ablation efficiency of the femtosecond laser on dentin and enamel is closely related to the laser fluence and may reach a maximum when the laser fluence is set to an appropriate value. PMID- 25695162 TI - Small molecule binding sites on the Ras:SOS complex can be exploited for inhibition of Ras activation. AB - Constitutively active mutant KRas displays a reduced rate of GTP hydrolysis via both intrinsic and GTPase-activating protein-catalyzed mechanisms, resulting in the perpetual activation of Ras pathways. We describe a fragment screening campaign using X-ray crystallography that led to the discovery of three fragment binding sites on the Ras:SOS complex. The identification of tool compounds binding at each of these sites allowed exploration of two new approaches to Ras pathway inhibition by stabilizing or covalently modifying the Ras:SOS complex to prevent the reloading of Ras with GTP. Initially, we identified ligands that bound reversibly to the Ras:SOS complex in two distinct sites, but these compounds were not sufficiently potent inhibitors to validate our stabilization hypothesis. We conclude by demonstrating that covalent modification of Cys118 on Ras leads to a novel mechanism of inhibition of the SOS-mediated interaction between Ras and Raf and is effective at inhibiting the exchange of labeled GDP in both mutant (G12C and G12V) and wild type Ras. PMID- 25695163 TI - Clinical predictors for laboratory-confirmed influenza infections: exploring case definitions for influenza-like illness. AB - OBJECTIVE: To identify clinical signs and symptoms (ie, "terms") that accurately predict laboratory-confirmed influenza cases and thereafter generate and evaluate various influenza-like illness (ILI) case definitions for detecting influenza. A secondary objective explored whether surveillance of data beyond the chief complaint improves the accuracy of predicting influenza. DESIGN: Retrospective, cross-sectional study. SETTING: Large urban academic medical center hospital. PARTICIPANTS: A total of 1,581 emergency department (ED) patients who received a nasopharyngeal swab followed by rRT-PCR testing between August 30, 2009, and January 2, 2010, and between November 28, 2010, and March 26, 2011. METHODS: An electronic surveillance system (GUARDIAN) scanned the entire electronic medical record (EMR) and identified cases containing 29 clinical terms relevant to influenza. Analyses were conducted using logistic regressions, diagnostic odds ratio (DOR), sensitivity, and specificity. RESULTS: The best predictive model for identifying influenza for all ages consisted of cough (DOR=5.87), fever (DOR=4.49), rhinorrhea (DOR=1.98), and myalgias (DOR=1.44). The 3 best case definitions that included combinations of some or all of these 4 symptoms had comparable performance (ie, sensitivity=89%-92% and specificity=38%-44%). For children <5 years of age, the addition of rhinorrhea to the fever and cough case definition achieved a better balance between sensitivity (85%) and specificity (47%). For the fever and cough ILI case definition, using the entire EMR, GUARDIAN identified 37.1% more influenza cases than it did using only the chief complaint data. CONCLUSIONS: A simplified case definition of fever and cough may be suitable for implementation for all ages, while inclusion of rhinorrhea may further improve influenza detection for the 0-4-year-old age group. Finally, ILI surveillance based on the entire EMR is recommended. PMID- 25695164 TI - Comparison of immune response to the influenza vaccine in obese and nonobese healthcare workers. AB - OBJECTIVE: To determine whether there is a difference in antibody titers and functionality after receipt of the influenza vaccine for obese versus nonobese healthcare workers (HCW). DESIGN: Prospective observational study. SETTING: Tertiary medical center. PARTICIPANTS: Healthcare workers. METHODS Baseline influenza antibody titers for obese and nonobese HCW were recorded during the hospital's 2011 annual influenza vaccination day and follow-up antibody titers were measured 4 weeks later. Antibodies were measured using the hemagglutination inhibition assay and functionality was measured using the micro-neutralization method. RESULTS: Of 200 initial HCWs, 190 completed the study (97 obese and 93 nonobese). Seroprotection after immunization was not significantly different for nonobese compared with obese HCW for each strain (influenza A [H1N1], 99% and 99%; influenza A [H3N2], 100% and 99%; and influenza B, 67% and 71%, respectively) All geometric mean titers measured by micro-neutralization showed statistically significant increases in activity. In comparison, there was no difference in the 4-fold increase in H1N1 or B titers. There was a significant difference in the 4-fold increase of H3N2 titers between the nonobese and obese HCWs (82/93 [88%] vs 64/97 [66%], P=.003) In an ad hoc analysis we found that obese HCWs had a statistically greater number of 4-fold decreases in titers with H1N1 and H3N2. CONCLUSIONS: There was no significant difference in protection from influenza between obese and nonobese HCWs after immunization. PMID- 25695165 TI - Combining high-resolution contact data with virological data to investigate influenza transmission in a tertiary care hospital. AB - OBJECTIVE: Contact patterns and microbiological data contribute to a detailed understanding of infectious disease transmission. We explored the automated collection of high-resolution contact data by wearable sensors combined with virological data to investigate influenza transmission among patients and healthcare workers in a geriatric unit. DESIGN: Proof-of-concept observational study. Detailed information on contact patterns were collected by wearable sensors over 12 days. Systematic nasopharyngeal swabs were taken, analyzed for influenza A and B viruses by real-time polymerase chain reaction, and cultured for phylogenetic analysis. SETTING: An acute-care geriatric unit in a tertiary care hospital. PARTICIPANTS: Patients, nurses, and medical doctors. RESULTS: A total of 18,765 contacts were recorded among 37 patients, 32 nurses, and 15 medical doctors. Most contacts occurred between nurses or between a nurse and a patient. Fifteen individuals had influenza A (H3N2). Among these, 11 study participants were positive at the beginning of the study or at admission, and 3 patients and 1 nurse acquired laboratory-confirmed influenza during the study. Infectious medical doctors and nurses were identified as potential sources of hospital-acquired influenza (HA-Flu) for patients, and infectious patients were identified as likely sources for nurses. Only 1 potential transmission between nurses was observed. CONCLUSIONS: Combining high-resolution contact data and virological data allowed us to identify a potential transmission route in each possible case of HA-Flu. This promising method should be applied for longer periods in larger populations, with more complete use of phylogenetic analyses, for a better understanding of influenza transmission dynamics in a hospital setting. PMID- 25695166 TI - Implementation of antimicrobial stewardship policies in U.S. hospitals: findings from a national survey. AB - OBJECTIVE: To describe the use of antimicrobial stewardship policies and to investigate factors associated with implementation in a national sample of acute care hospitals. DESIGN: Cross-sectional survey. PARTICIPANTS: Infection Control Directors from acute care hospitals participating in the National Healthcare Safety Network (NHSN). METHODS: An online survey was conducted in the Fall of 2011. A subset of hospitals also provided access to their 2011 NHSN annual survey data. RESULTS: Responses were received from 1,015 hospitals (30% response rate). The majority of hospitals (64%) reported the presence of a policy; use of antibiograms and antimicrobial restriction policies were most frequently utilized (83% and 65%, respectively). Respondents from larger, urban, teaching hospitals and those that are part of a system that shares resources were more likely to report a policy in place (P<.01). Hospitals located in California were more likely to have policy in place than in hospitals located in other states (P=.014). CONCLUSION: This study provides a snapshot of the implementation of antimicrobial stewardship policies in place in U.S. hospitals and suggests that statewide efforts in California are achieving their intended effect. Further research is needed to identify factors that foster the adoption of these policies. PMID- 25695167 TI - Is procalcitonin-guided antimicrobial use cost-effective in adult patients with suspected bacterial infection and sepsis? AB - OBJECTIVE: Procalcitonin has emerged as a promising biomarker of bacterial infection. Published literature demonstrates that use of procalcitonin testing and an associated treatment pathway reduces duration of antibiotic therapy without impacting mortality. The objective of this study was to determine the financial impact of utilizing a procalcitonin-guided treatment algorithm in hospitalized patients with sepsis. DESIGN: Cost-minimization and cost-utility analysis. PATIENTS: Hypothetical cohort of adult ICU patients with suspected bacterial infection and sepsis. METHODS: Utilizing published clinical and economic data, a decision analytic model was developed from the U.S. hospital perspective. Effectiveness and utility measures were defined using cost-per clinical episode and cost per quality-adjusted life years (QALYs). Upper and lower sensitivity ranges were determined for all inputs. Univariate and probabilistic sensitivity analyses assessed the robustness of our model and variables. Incremental cost-effectiveness ratios (ICERs) were calculated and compared to predetermined willingness-to-pay thresholds. RESULTS: Base-case results predicted the use of a procalcitonin-guided treatment algorithm dominated standard care with improved quality (0.0002 QALYs) and decreased overall treatment costs ($65). The model was sensitive to a number of key variables that had the potential to impact results, including algorithm adherence (<42.3%), number and cost of procalcitonin tests ordered (>=9 and >$46), days of antimicrobial reduction (<1.6 d), incidence of nephrotoxicity and rate of nephrotoxicity reduction. CONCLUSION: The combination of procalcitonin testing with an evidence-based treatment algorithm may improve patients' quality of life while decreasing costs in ICU patients with suspected bacterial infection and sepsis; however, results were highly dependent on a number of variables and assumptions. PMID- 25695168 TI - Clostridium difficile recurrence is a strong predictor of 30-day rehospitalization among patients in intensive care. AB - OBJECTIVE: While incidence, mortality, morbidity, and recurrence rates of C. difficile infection (CDI) among the critically ill have been investigated, the impact of its recurrence on 30-day rehospitalization (ReAd), an important policy focus, has not been examined. DESIGN: Secondary analysis of a multicenter retrospective cohort study Patients Adult critically ill patients who survived their index hospitalization complicated by CDI METHODS: CDI was defined by diarrhea or pseudomembranous colitis and a positive assay for C. difficile toxins A and/or B. CDI recurrence (rCDI) was defined as diarrhea, positive C. difficile toxin and need for retreatment after cessation of therapy. Descriptive statistics and a logistic regression examined ReAd rates and characteristics, and factors that impact it. RESULTS: Among 287 hospital survivors, 76 (26.5%) required ReAd (ReAd+). At baseline, the ReAd+ group did not differ significantly from the ReAd- group based on demographics, comorbidities, APACHE II scores, or ICU type. ReAd+ patients were more likely to have hypotension at CDI onset (48.7% vs 34.1%, P=.025) and to require vasopressors (40.0% vs 27.1%, P=.038); they were less likely to require mechanical ventilation (56.0% vs 77.3%, P<.001). A far greater proportion of ReAd+ than ReAd- had developed a recurrence either during the index hospitalization or within 30 days after discharge (32.89% vs 2.84%, P<.001). In a logistic regression, rCDI was a strong predictor of ReAd+ (adjusted odd ratio, 15.33, 95% confidence interval, 5.68-41.40). CONCLUSIONS: Greater than 25% of all survivors of critical illness complicated by CDI require readmission within 30 days of discharge. CDI recurrence is a strong predictor of such rehospitalizations. PMID- 25695169 TI - Clostridium difficile infection (CDI) severity and outcome among patients infected with the NAP1/BI/027 strain in a non-epidemic setting. AB - OBJECTIVE: Determine whether the NAP1 strain identified by polymerase chain reaction (PCR)-based stool assay is correlated with CDI severity and clinical outcomes. METHODS: Medical records of adult patients with positive stool Xpert(r) Clostridium difficile PCR assay for an initial episode of CDI between January 2012 and January 2013 at a tertiary care hospital in Chicago were reviewed. Two patients diagnosed with CDI caused by a non-NAP1 strain (positive Xpert(r) C. difficile assay but negative Xpert(r) C. difficile Epi assay) were included for each patient diagnosed with CDI caused by a NAP1 strain (positive Epi assay). Patient charts were reviewed for markers of severity, risk factors, treatment regimens, and outcomes. RESULTS: Of 494 stool specimens, 90 (18%) that were positive for C. difficile by PCR were positive for NAP1 strain. In total, 37 patients with CDI due to NAP1 were matched with 74 patients with CDI due to non NAP1 strains. Multivariable model revealed individuals >=65 years old were 3 times more likely to have NAP1 strain than individuals <65 (P=.02). Residents of a nursing home prior to hospitalization were 10 times more likely to have NAP1 strain than patients residing in their homes (P=.001). More NAP1 cases had a change in treatment from metronidazole to oral vancomycin plus intravenous metronidazole (P=.01). The severity of CDI, incidence of mortality and recurrent CDI were similar between groups. CONCLUSIONS: In a nonepidemic setting, NAP1 strains were more common in older patients and individuals admitted from nursing homes. Identification of NAP1 by PCR of stool specimens was associated in a change of therapy but did not predict worse outcomes. Reporting strain results may not be clinically useful in routine settings. PMID- 25695170 TI - One-week versus 2-day ventilator circuit change in neonates with prolonged ventilation: cost-effectiveness and impact on ventilator-associated pneumonia. AB - OBJECTIVE: To investigate the impact of 1-week ventilator circuit change on ventilator-associated pneumonia and its cost-effectiveness compared with a 2-day change. DESIGN: An observational cohort study. SETTING: A tertiary level neonatal intensive care unit in a university-affiliated teaching hospital in Taiwan. Patients All neonates in the neonatal intensive care unit receiving invasive intubation for more than 1 week from July 1, 2011, through December 31, 2013. INTERVENTION: We investigated the impact of 2 ventilator circuit change regimens, either every 2 days or 7 days, on ventilator-associated pneumonia of our cohort. MEASUREMENTS AND MAIN RESULTS: A total of 361 patients were maintained on mechanical ventilators for 13,981 days. The 2 groups did not differ significantly in any demographic characteristics. The rate of ventilator-associated pneumonia was comparable between the 2-day group and the 7-day group (8.2 vs 9.5 per 1,000 ventilator-days, P=.439). The durations of mechanical ventilation and hospital stay, and rates of bloodstream infection and mortality, were also comparable between the 2 groups. Switching from a 2-day to a 7-day change policy would save our neonatal intensive care unit a yearly sum of US $29,350 and 525 working hours. CONCLUSION: Decreasing the frequency of ventilator circuit changes from every 2 days to once per week is safe and cost-effective in neonates requiring prolonged intubation for more than 1 week. PMID- 25695171 TI - Comparison of a silver-coated needleless connector and a standard needleless connector for the prevention of central line-associated bloodstream infections. AB - OBJECTIVE: To assess the impact of a novel, silver-coated needleless connectors (NCs) on central-line-associated bloodstream infection (CLABSI) rates compared with a mechanically identical NCs without a silver coating. DESIGN: Prospective longitudinal observation study SETTING Two 500-bed university hospitals PATIENTS: All hospitalized adults from November 2009 to June 2011 with non-hemodialysis central lines INTERVENTIONS: Hospital A started with silver-coated NCs and switched to standard NCs in September 2010; hospital B started with standard NCs and switched to silver-coated NCs. The primary outcome was the difference revealed by Poisson multivariate regression in CLABSI rate using standard Centers for Disease Control and Prevention surveillance definitions. The secondary outcome was a comparison of organism-specific CLABSI rates by NC type. RESULTS: Among 15,845 hospital admissions, 140,186 central-line days and 221 CLABSIs were recorded during the study period. In a multivariate model, the CLABSI rate per 1,000 central-line days was lower with silver-coated NCs than with standard NCs (1.21 vs 1.79; incidence rate ratio=0.68 [95% CI: 0.52-0.89], P=.005). A lower CLABSI rate per 1,000 central-line days for the silver-coated NCs versus the standard NCs was observed with S. aureus (0.11 vs 0.30, P=.02), enterococci (0.10 vs 0.27, P=.03), and Gram-negative organisms (0.28 vs 0.63, P=.003) but not with coagulase-negative staphylococci (0.31 vs 0.36) or Candida spp. (0.42 vs 0.40). CONCLUSIONS: The use of silver-coated NCs decreased the CLABSI rate by 32%. CLABSI reduction efforts should include efforts to minimize contamination of NCs. PMID- 25695172 TI - Factors influencing field testing of alcohol-based hand rubs. AB - BACKGROUND: According to the World Health Organization guidelines, field tests, in the context of a bid for the supply of alcohol-based hand rubs, should take into account climatic region, test period, products already in use, and type of use (hygienic or surgical) when assessing tolerance. This laborious method is often contested. OBJECTIVE: To conduct a post hoc analysis of the data of a large bid, including 5 factors, to validate the relevance of their inclusion. METHODS: For the purposes of the bid, products were compared in terms of the 4 World Health Organization tolerance criteria (appearance, intactness, moisture content, sensation) during product testing and were separated into groups on the basis of the studied factors. The post hoc analysis method included (1) comparison of the mean before-and-after difference based on the self-evaluation of the skin with the 4 World Health Organization tolerance criteria, between climatic regions, periods, products in use, test product, and the type of use; (2) generalized linear models, taking into account all studied factors. RESULTS: The analysis included data for 1,925 pairs of professionals. The means of the differences observed were independently and significantly associated with the test period (P<.001), the hygienic or surgical use (P=.010 to .041, not significant for appearance), the product already in use (significant for appearance P=.021), and the test product (P<.001). The association with climatic region was found to be significant only in the nonadjusted analysis. CONCLUSION: The type of use, the test period, and the product in use should be taken into account when designing field tests of alcohol-based hand rubs. PMID- 25695173 TI - Impact of electronic faucets and water quality on the occurrence of Pseudomonas aeruginosa in water: a multi-hospital study. AB - OBJECTIVE: To compare Pseudomonas aeruginosa prevalence in electronic and manual faucets and assess the influence of connecting pipes and water quality. SETTING: Faucets in 4 healthcare centers in Quebec, Canada. METHODS: Water samples from 105 electronic, 90 manual, and 14 foot-operated faucets were analyzed for P. aeruginosa by culture and enzymatic detection, and swab samples from drains and aerators were analyzed by culture. Copper and residual chlorine concentrations, temperature, and flow rate were measured. P. aeruginosa concentrations were analyzed in 4 consecutive volumes of cold water and a laboratory study was conducted on copper pipes and flexible hoses. RESULTS: P. aeruginosa contamination was found in drains more frequently (51%) than in aerators (1%) or water (culture: 4%, enzyme detection: 16%). Prevalence in water samples was comparable between manual (14%) and 2 types of electronic faucets (16%) while higher for foot-operated faucets (29%). However, type 2 electronic faucets were more often contaminated (31%) than type 1 (14%), suggesting that faucet architecture and mitigated volume (30 mL vs 10 mL) influence P. aeruginosa growth. Concentrations were 100 times higher in the first 250 mL than after flushing. Flexible hoses were more favorable to P. aeruginosa growth than copper and a temperature of 40 degrees C led to higher counts. CONCLUSIONS: The types of faucets and connecting pipes, flow rate, and water quality are important parameters influencing the prevalence and the concentrations of P. aeruginosa in faucets. High concentrations of P. aeruginosa in the first 250 mL suggest increased risk of exposure when using the first flush. PMID- 25695174 TI - In-hospital transfer is a risk factor for invasive filamentous fungal infection among hospitalized patients with hematological malignancies: a matched case control study. AB - OBJECTIVE: Immunocompromised patients now benefit from a longer life expectancy due to advanced medical techniques, but they are also weakened by aggressive treatment approaches and are at high risk for invasive fungal disease. We determined risk factors associated with an outbreak of invasive filamentous fungal infection (IFFI) among hospitalized hemato-oncological patients. METHODS: A retrospective, matched, case-control study was conducted between January 1, 2009, and April 31, 2011, including 29 cases (6 proven, 8 probable, and 15 possible) of IFFI and 102 matched control patients hospitalized during the same time period. Control patients were identified from the hospital electronic database. Conditional logistic regression was performed to identify independent risk factors for IFFI. RESULTS: Overall mortality associated with IFFI was 20.7% (8.0%-39.7%). Myelodysplastic syndrome was associated with a higher risk for IFFI compared to chronic hematological malignancies. After adjustment for major risk factors and confounders, >5 patient transfers outside the protected environment of the hematology ward increased the IFFI risk by 6.1-fold. The risk increased by 6.7-fold when transfers were performed during neutropenia. CONCLUSION: This IFFI outbreak was characterized by a strong association with exposure to the unprotected environment outside the hematology ward during patient transfer. The independent associations of a high number of transfers with the presence of neutropenia suggest that affected patients were probably not sufficiently protected during transport in the corridors. Our study highlights that a heightened awareness of the need for preventive measures during the entire care process of at-risk patients should be promoted among healthcare workers. PMID- 25695175 TI - Stratification of surgical site infection by operative factors and comparison of infection rates after hernia repair. AB - OBJECTIVE: To investigate whether operative factors are associated with risk of surgical site infection (SSI) after hernia repair. DESIGN: Retrospective cohort study. Patients Commercially insured enrollees aged 6 months-64 years with International Classification of Diseases, Ninth Revision, Clinical Modification procedure or Current Procedural Terminology, fourth edition, codes for inguinal/femoral, umbilical, and incisional/ventral hernia repair procedures from January 1, 2004, through December 31, 2010. METHODS: SSIs within 90 days after hernia repair were identified by diagnosis codes. The chi2 and Fisher exact tests were used to compare SSI incidence by operative factors. RESULTS: A total of 119,973 hernia repair procedures were analyzed. The incidence of SSI differed significantly by anatomic site, with rates of 0.45% (352/77,666) for inguinal/femoral, 1.16% (288/24,917) for umbilical, and 4.11% (715/17,390) for incisional/ventral hernia repair. Within anatomic sites, the incidence of SSI was significantly higher for open versus laparoscopic inguinal/femoral (0.48% [295/61,142] vs 0.34% [57/16,524], P=.020) and incisional/ventral (4.20% [701/16,699] vs 2.03% [14/691], P=.005) hernia repairs. The rate of SSI was higher following procedures with bowel obstruction/necrosis than procedures without obstruction/necrosis for open inguinal/femoral (0.89% [48/5,422] vs 0.44% [247/55,720], P<.001) and umbilical (1.57% [131/8,355] vs 0.95% [157/16,562], P<.001), but not incisional/ventral hernia repair (4.01% [224/5,585] vs 4.16% [491/11,805], P=.645). CONCLUSIONS: The incidence of SSI was highest after open procedures, incisional/ventral repairs, and hernia repairs with bowel obstruction/necrosis. Stratification of hernia repair SSI rates by some operative factors may facilitate accurate comparison of SSI rates between facilities. PMID- 25695176 TI - Protecting the frontline: designing an infection prevention platform for preventing emerging respiratory viral illnesses in healthcare personnel. AB - Healthcare personnel often find themselves on the frontlines of any epidemic, and may be at particularly high risk of acquiring respiratory viral illnesses when compared to the general population. Many aspects dictate how respiratory viruses spread both inside the hospital and out: Elements to consider include the specific type of virus being targeted for prevention, as well as environmental conditions and host factors, such as age and immune status. Due to the diverse nature of these agents, multiple modes of transmission, including contact, droplet, aerosol, and transocular, must be considered when designing an effective infection prevention program. In this review, we examine the data behind current theories of respiratory virus transmission and key elements of any respiratory illness prevention program. We also highlight other influences that may come into play, such as the cost-effectiveness of choosing one respiratory protection strategy over another. PMID- 25695177 TI - Impact of changes in the NHSN catheter-associated urinary tract infection (CAUTI) surveillance criteria on the frequency and epidemiology of CAUTI in intensive care units (ICUs). AB - The impact of the 2013 NHSN CAUTI definition on CAUTI rates was analyzed. A total of 107 CAUTI episodes were identified; 60 according to NHSN 2013 definitions only and 47 according to the 2012 and 2013 definitions. Physician-diagnosed "other infections" were more common among patients who had CAUTI only according to NHSN 2013 definitions (P<.001). PMID- 25695178 TI - State law mandates for reporting of healthcare-associated Clostridium difficile infections in hospitals. AB - US state and territorial laws were reviewed to identify Clostridium difficile infection reporting mandates. Twenty states require reporting either under state law or by incorporating federal Centers for Medicare & Medicaid Services' reporting requirements. Although state law mandates are more common, the incorporation of federal reporting requirements has been increasing. PMID- 25695179 TI - An evaluation of surgical site infection surveillance methods for colon surgery and hysterectomy in Colorado hospitals. AB - Surgical site infection (SSI) surveillance techniques for colon surgery and hysterectomy among Colorado infection preventionists were characterized through an online survey. Considerable variation was found in SSI surveillance practices, specifically varying use of triggers for SSI review, including laboratory values, healthcare personnel communication, and postoperative visits. PMID- 25695180 TI - Antibiotic susceptibility of urinary isolates in nursing home residents consuming cranberry capsules versus placebo. PMID- 25695181 TI - Reduction in acute gastroenteritis among military trainees: secondary effects of a hygiene-based cluster-randomized trial for skin and soft tissue infection prevention. PMID- 25695182 TI - Promoting the safety of healthcare workers in Africa: from HIV pandemic to ebola epidemic. PMID- 25695183 TI - Veterans Affairs Medical Center employee comments suggest additional educational targets to improve influenza vaccination campaigns. PMID- 25695184 TI - Achieving "zero" CLABSI and VAP after sequential implementation of central line bundle and ventilator bundle. PMID- 25695185 TI - Psychodidae (drain fly) infestation in an operating room. PMID- 25695186 TI - Versatile access to Martin's spirosilanes and their hypervalent derivatives. AB - A new route to Martin's spirosilanes has been devised. The original synthesis does not allow diversely substituted spirosilane derivatives to be synthesized, and thus their corresponding silicates. In this report, Martin's spirosilanes bearing alkyl, aryl, halogen, alkoxy, and trifluoromethyl substituents on the aryl ring have been prepared through a versatile four-step route. Addition of fluoride onto these Lewis acids as a prototypical reaction with a nucleophile yielded a library of stable fluorosilicates. Both sets of compounds have been characterized by X-ray crystallography. PMID- 25695187 TI - Manipulating directional cell motility using intracellular superparamagnetic nanoparticles. AB - This study investigated the ability for magnetic nanoparticles to influence cellular migration in the presence of an external magnetic field. We found that the direction of migrating keratinocytes can be controlled and the migration speed of fibroblasts can be increased with the internalisation of these nanoparticles in the presence of a magnetic field. The possibility of shepherding cells towards a region of interest through the use of internalized nanoparticles is an attractive prospect for cell tracking, cell therapies, and tissue engineering applications. PMID- 25695188 TI - Spatiotemporal analysis of Guaroa virus diversity, evolution, and spread in South America. AB - We conducted phylogeographic modeling to determine the introduction and spread of Guaroa virus in South America. The results suggest a recent introduction of this virus into regions of Peru and Bolivia over the past 60-70 years and emphasize the need for increased surveillance in surrounding areas. PMID- 25695189 TI - A pharmacodynamic evaluation of dexmedetomidine as an additive drug to ropivacaine for peripheral nerve blockade: A randomised, triple-blind, controlled study in volunteers. AB - BACKGROUND: Previous data have indicated the efficacy of dexmedetomidine as an additive to peripheral regional anaesthesia. There are no pharmacodynamic data regarding the addition of dexmedetomidine to local anaesthetics for perineural administration. OBJECTIVE: The objective of this study is to assess the dose dependency of dexmedetomidine when injected with ropivacaine for peripheral nerve blockade. DESIGN: A randomised, triple-blind, controlled study in volunteers. SETTING: Department of Clinical Pharmacology, Medical University of Vienna. PARTICIPANTS: Twenty-four volunteers. INTERVENTIONS: All volunteers received an ulnar nerve block with 22.5 mg ropivacaine alone (R), or mixed with 50 (RD50), 100 (RD100) or 150 MUg (RD150) dexmedetomidine. MAIN OUTCOME MEASURES: The primary outcome was the duration of complete sensory block to pinprick and time to complete recovery of pinprick. Secondary outcomes included block success and onset time, motor block, haemodynamic parameters and sedation level. RESULTS: There was a significant dose-dependent (P < 0.0001) increase in the mean duration (SD) of sensory block with dexmedetomidine: R: 8.7 (1.5) h, RD50: 16.4 (4.0) h, RD100: 20.4 (2.8) h and group RD150: 21.2 (1.7) h. Sedation was also enhanced in a dose-dependent (P < 0.001) manner. Two volunteers each receiving 150 MUg dexmedetomidine had postblock paraesthesia for 72 h. CONCLUSION: Dexmedetomidine mixed with ropivacaine produces a dose-dependent prolongation of sensory block and clinically relevant dose-dependent sedation. Dexmedetomidine 100 MUg may represent a balance between efficacy and sedation. PMID- 25695190 TI - Motor performance of children with Down syndrome and typical development at 2 to 4 and 26 months. AB - PURPOSE: To compare gross motor performance of children with Down syndrome (DS) and typical development (TD) at 2 to 4 months (Phase I) and at 2 years of age (Phase II) and to investigate the relation between early motor performance and later outcome. METHODS: Seventeen infants (10 with TD and 7 with DS) were assessed in Phase I using the Test of Infant Motor Performance (TIMP); 25 children were assessed in Phase II using the gross motor scale of the Bayley Scales of Infant and Toddler Development (Bayley-III); 10 participants were enrolled in both phases. RESULTS: TIMP and Bayley-III scores were lower in the DS group. In both groups, TIMP z scores were predictive of Bayley-III scores. CONCLUSIONS: Children with DS show difficulties in early postural control and activities requiring speed, postural control, and balance. The finding that early performance relates to later outcome reinforces the relevance of early and task specific intervention. PMID- 25695191 TI - Commentary on "Motor performance of children with Down syndrome and typical development at 2 to 4 and 26 months". PMID- 25695192 TI - Promoting self-exploration and function through an individualized power mobility training program. AB - PURPOSE: This case report describes the development and implementation of an intervention program that used a Power Wheelchair Trainer (Trainer) to enable an individual with severe impairments to participate in power mobility training. CASE DESCRIPTION: The participant was an 18 year-old female with spastic quadriplegic cerebral palsy, Gross Motor Function Classification Level V. The examination included the Power Mobility Screen and the Caregiver Priorities & Child Health Index of Life with Disabilities (CPCHILD). Switches on the participant's headrest provided control of the Trainer. Intervention consisted of power mobility training in an engaging environment that was set-up to focus on specific power mobility skills. RESULTS: Scores on the Power Mobility Screen and the CPCHILD were higher after intervention. DISCUSSION: The outcomes of this case report appear to support the use of the Trainer, which allowed the participant to practice power mobility skills and participate in self-exploration of her environment. PMID- 25695193 TI - Commentary on "Ultrasonographic measurements of paraspinal muscle thickness in adolescent idiopathic scoliosis: a comparison and reliability study". PMID- 25695194 TI - Ultrasonographic measurements of paraspinal muscle thickness in adolescent idiopathic scoliosis: a comparison and reliability study. AB - PURPOSE: To examine paraspinal muscle asymmetries in patients with mild adolescent idiopathic scoliosis (AIS) compared with controls using ultrasound (US) imaging and to determine reliability of the US imaging. METHODS: Twenty adolescents (10 with and 10 without AIS) whose muscle thickness of the deep paraspinals at T8 and the multifidus at L1 and L4 vertebral levels was determined using US imaging. RESULTS: Ultrasound imaging had good intrarater reliability (ICC3,3 = 0.83-0.99) and interrater reliability (ICC2,3 = 0.93-0.99). Significantly greater muscle thicknesses were found on the concave side at T8 and L1 compared with the corresponding convex side. Significantly greater normalized muscle thickness values were found on the concave side at T8, L1, and L4 in patients with mild AIS compared with controls. CONCLUSIONS: Ultrasound imaging is reliable for measuring the deep thoracic paraspinals and lumbar multifidus in adolescents with and without idiopathic scoliosis. Significant paraspinal muscle asymmetries were found in mild AIS. VIDEO ABSTRACT: For more insights from the authors, access Supplemental Digital Content 1, at http://links.lww.com/PPT/A76. PMID- 25695195 TI - Commentary on, "Relationships among age, gender, anthropometric characteristics, and dynamic balance in children 5 to 12 years old". PMID- 25695196 TI - Relationships among age, gender, anthropometric characteristics, and dynamic balance in children 5 to 12 years old. AB - PURPOSE: To examine relationships among age, gender, anthropometrics, and dynamic balance. METHODS: Height, weight, and arm and foot length were measured in 160 children with typical development aged 5 to 12 years. Dynamic balance was assessed using the Timed Up and Go (TUG) test, Pediatric Reach Test (PRT), and Pediatric Balance Scale (PBS). RESULTS: Moderate to good positive relationships (r = 0.61 and r = 0.56) were found between increasing age and PRT and PBS scores. A fair negative relationship (r = -0.49) was observed between age and TUG test. No significant gender-by-age group difference was observed. Age had the strongest influence on TUG and PBS scores; arm length had the strongest influence on PRT scores. CONCLUSIONS: Dynamic balance ability is directly related to chronological age. Age and arm length have the strongest relationships with balance scores. These findings may assist pediatric therapists in selecting dynamic balance tests according to age rather than specific diagnosis. PMID- 25695197 TI - DNA damage-induced nuclear translocation of Apaf-1 is mediated by nucleoporin Nup107. AB - Beside its central role in the mitochondria-dependent cell death pathway, the apoptotic protease activating factor 1 (Apaf-1) is involved in the DNA damage response through cell-cycle arrest induced by genotoxic stress. This non apoptotic function requires a nuclear translocation of Apaf-1 during the G1-to-S transition. However, the mechanisms that trigger the nuclear accumulation of Apaf 1 upon DNA damage remain to be investigated. Here we show that the main 4 isoforms of Apaf-1 can undergo nuclear translocation and restore Apaf-1 deficient MEFs cell cycle arrest in the S phase following genotoxic stress through activation of Chk-1. Interestingly, DNA damage-dependent nuclear accumulation of Apaf-1 occurs independently of p53 and the retinoblastoma (pRb) pathway. We demonstrated that Apaf-1 associates with the nucleoporin Nup107 and this association is necessary for Apaf-1 nuclear import. The CED-4 domain of Apaf-1 directly binds to the central domain of Nup107 in an ATR-regulated, phosphorylation-dependent manner. Interestingly, expression of the Apaf-1 interacting domain of Nup107 interfered with Apaf-1 nuclear translocation upon genotoxic stress, resulting in a marked reduction of Chk-1 activation and cell cycle arrest. Thus, our results confirm the crucial role of Apaf-1 nuclear relocalization in mediating cell-cycle arrest induced by genotoxic stress and implicate Nup107 as a critical regulator of the DNA damage-induced intra-S phase checkpoint response. PMID- 25695198 TI - Solvent/detergent-treated plasma: a tale of 30 years of experience. AB - Solvent/detergent-treated plasma was licensed >30 years ago. It has several specific characteristics, the most important being the standardized content of clotting factors, the lack of antibodies implicated in transfusion-related acute lung injury pathogenesis and the very high level of safety against transfusion related viral infections. Since 1992, many clinical studies have confirmed its safety and efficacy in a wide range of congenital and acquired bleeding disorders. After a brief analysis of the pharmaceutical characteristics of solvent/detergent plasma, this review will focus on the clinical experience with this virus-inactivated plasma. PMID- 25695199 TI - Daily subcutaneous parecoxib injection for cancer pain: an open label pilot study. AB - BACKGROUND: Nonsteroidal anti-inflammatory analgesics (NSAIDs) are useful in cancer pain but the specific use of subcutaneous parecoxib has not been previously reported. OBJECTIVE: This pilot study aimed to establish the efficacy and side effect profile of short-term sequential single daily dose subcutaneous parecoxib sodium in patients with severe cancer bone pain. METHODS: Nineteen hospitalized patients with advanced cancer and uncontrolled malignant bone pain (9 males, 10 females) received 24 courses of one, two, or three days sequential therapy with 'off-label' daily subcutaneous parecoxib. All patients were receiving opioid therapy; the median baseline daily oral equivalent dose (OED) of morphine was 180 mg. Pain was assessed at baseline, 24 hours, 48 hours, and 72 hours. Pain scores as assessed on an 11-point numeric pain rating scale (NPRS), any side effects including subcutaneous site reactions, as well as patient satisfaction rating with analgesia were recorded. A clinically significant decrease in pain scores was defined as a reduction of two or more points on the NPRS. RESULTS: Median pain score of all patient treatments decreased from 7 to 4.5 at 24 hours (p<0.001) and 4.0 at 48 hours. A response was seen in 17 (71%) of the 24 treatments at 24 hours. There was no difference between median negative change in pain scores in 19 (79%) treatments where pain was either strongly movement related, or in 22 (94%) treatments where local bone tenderness was more pronounced. No major side effects were observed during treatment. One patient died from pulmonary embolism after cessation of concurrent prophylactic low molecular weight heparin prior to staging liver biopsy. Subcutaneous site reactions occurred in 2 (8%) treatments and were mild and self limiting. CONCLUSIONS: Short-term daily subcutaneous parecoxib injection was effective for malignant bone pain when added to existing analgesic therapy and was well tolerated. Further research is warranted into the short-term use of parecoxib in hospitalized patients with intractable malignant bone pain. PMID- 25695200 TI - Autochthonous dengue fever, Tokyo, Japan, 2014. AB - After 70 years with no confirmed autochthonous cases of dengue fever in Japan, 19 cases were reported during August-September 2014. Dengue virus serotype 1 was detected in 18 patients. Phylogenetic analysis of the envelope protein genome sequence from 3 patients revealed 100% identity with the strain from the first patient (2014) in Japan. PMID- 25695201 TI - The understanding and experience of mixed emotions in 3-5-year-old children. AB - The term mixed emotions refers to the presence of two opposite-valence emotions toward a single target. Identifying when children begin to report experiencing and understanding mixed emotions is critical in identifying how skills such as adaptive functioning, coping strategies, environmental understanding, and socioemotional competence emerge. Prior research has shown that children as young as 5 years old can understand and experience mixed emotion, but perhaps appropriately sensitive methodologies can reveal these abilities in younger children. The present study evaluated 57 children between 3 and 5 years old for mixed emotion experience and understanding using an animated video clip in which a character experiences a mixed emotional episode. Ordinal logistic regression was utilized to examine the relation of gender, attention, and understanding of content to experience and understanding of mixed emotion. While only 12% of children reported experiencing mixed emotion while watching the clip, 49% of children-some as young as 3 years old-were able to recognize the mixed emotional experience of the character. Thus, mixed emotion understanding emerges earlier than previously identified and the expression of understanding may develop independently of the ability to report mixed emotion experience. These findings are discussed in relation to cognitive and developmental considerations. PMID- 25695202 TI - Erratum: Video-assisted thoracic surgery right sleeve lobectomy: Erratum. AB - [This corrects the article on p. 1831 in vol. 6, PMID: 25589983.]. PMID- 25695203 TI - Probing the influence of citrate-capped gold nanoparticles on an amyloidogenic protein. AB - Nanoparticles (NPs) are known to exhibit distinct physical and chemical properties compared with the same materials in bulk form. NPs have been repeatedly reported to interact with proteins, and this interaction can be exploited to affect processes undergone by proteins, such as fibrillogenesis. Fibrillation is common to many proteins, and in living organisms, it causes tissue-specific or systemic amyloid diseases. The nature of NPs and their surface chemistry is crucial in assessing their affinity for proteins and their effects on them. Here we present the first detailed structural characterization and molecular mechanics model of the interaction between a fibrillogenic protein, beta2-microglobulin, and a NP, 5 nm hydrophilic citrate-capped gold nanoparticles. NMR measurements and simulations at multiple levels (enhanced sampling molecular dynamics, Brownian dynamics, and Poisson-Boltzmann electrostatics) explain the origin of the observed protein perturbations mostly localized at the amino-terminal region. Experiments show that the protein-NP interaction is weak in the physiological-like, conditions and do not induce protein fibrillation. Simulations reproduce these findings and reveal instead the role of the citrate in destabilizing the lower pH protonated form of beta2 microglobulin. The results offer possible strategies for controlling the desired effect of NPs on the conformational changes of the proteins, which have significant roles in the fibrillation process. PMID- 25695204 TI - Regulation of the expression of claudin 23 by the enhancer of zeste 2 polycomb group protein in colorectal cancer. AB - Altered epigenetic mechanisms, similar to gene mutations, contribute to the pathogenesis and molecular heterogeneity of neoplasms, including colorectal cancer (CRC). Enhancer of zeste 2 (EZH2) is a histone methyltransferase, which is involved in epigenetic gene silencing and is aberrantly expressed in CRC. Therefore, the identification of the genes regulated by EZH2 in CRC is important to improve current understanding of its role in cancer epigenetics. The present study used chromatin immunoprecipitation (ChIP) followed by deep sequencing to assess genome-wide EZH2-DNA interactions in healthy or CRC mucosa samples. In total, 86.9/61.6 and 92.5/62.6 million tags were sequenced/mapped in healthy and CRC mucosa samples, respectively. The EZH2-binding densities were correlated with transcriptomic datasets and this demonstrated that the claudin-23 (CLDN23) gene, which encodes a component of cell-cell adhesion structures, was occupied by EZH2 and significantly silenced in CRC tissue. The measurement of DNA methylation at the CLDN23 promoter using pyrosequencing excluded the possibility that silencing of this gene in CRC patient samples was a result of DNA hypermethylation. Following treatment of the Colo205 and HT-29 CRC cell lines, with the EZH2 inhibitor, GSK126, the level of histone H3 lysine 27 trimethylation (H3K27me3) was reduced and the mRNA and protein expression levels of CLDN23 were increased. ChIP analysis confirmed that the level of H3K27m3 along the CLDN23 gene was decreased in the GSK126-treated cell lines. Furthermore, ChIP analysis of these samples detected histone H3 lysine 4 trimethylation (H3K4me3) at the CLDN23 promoter, demonstrating that the balance between H3K27me3 and H3K4me3 may underlie the regulation of the expression of CLDN23. The present study demonstrated an epigenetic link between the activity of the EZH2 methyltransferase at the CLDN23 locus and the expression of CLDN23 in CRC tissue. PMID- 25695205 TI - Integration of SrTiO3 on crystallographically oriented epitaxial germanium for low-power device applications. AB - SrTiO3 integration on crystallographic oriented (100), (110), and (111) epitaxial germanium (Ge) exhibits a potential for a new class of nanoscale transistors. Germanium is attractive due to its superior transport properties while SrTiO3 (STO) is promising due to its high relative permittivity, both being critical parameters for next-generation low-voltage and low-leakage metal-oxide semiconductor field-effect transistors. The sharp heterointerface between STO and each crystallographically oriented Ge layer, studied by cross-sectional transmission electron microscopy, as well as band offset parameters at each heterojunction offers a significant advancement for designing a new generation of ferroelectric-germanium based multifunctional devices. Moreover, STO, when used as an interlayer between metal and n-type (4 * 10(18) cm(-3)) epitaxial Ge in metal-insulator-semiconductor (MIS) structures, showed a 1000 times increase in current density as well as a decrease in specific contact resistance. Furthermore, the inclusion of STO on n-Ge demonstrated the first experimental findings of the MIS behavior of STO on n-Ge. PMID- 25695206 TI - What authors need to know about predatory publishing. PMID- 25695207 TI - Childhood adversity, mental health, and violent crime. AB - BACKGROUND: Little is understood about childhood traumatic brain injury (TBI) and lifetime violent crime perpetration. OBJECTIVES: The purpose was to evaluate TBI before the age of 15 years and other childhood environmental factors, mental health, and lifetime history of committing a violent crime. METHODS: A cross sectional study of 636 male and female offenders from a southeastern state prison population was conducted using Chi-squared tests, t tests, and logistic regression to determine factors associated with ever committing a violent crime. RESULTS: Committing a violent crime was associated with male gender, younger age, greater childhood sexual abuse (CSA), greater childhood emotional abuse, no TBI by the age of 15 years, and greater neighborhood adversity during childhood. DISCUSSION: Although TBI has been related to violent and nonviolent crime, this study showed that absence of TBI by the age of 15 years was associated with lifetime violent crime when adjusting for CSA, childhood emotional abuse, and neighborhood adversity during childhood. This builds upon neurobehavioral development literature suggesting that CSA and the stress of violence exposure without direct physical victimization may play a more critical role in lifetime violent criminal behavior than childhood TBI. Violence risk reduction must occur during childhood focusing on decreasing adversity, especially violence exposure as a witness as well as a direct victim. PMID- 25695208 TI - Characteristics of child sexual assault within a child advocacy center client population. AB - This descriptive study summarized data from a child advocacy center to illustrate how such information might be used to profile the scope and character of child sexual abuse (CSA) at the community level. This detailed information is not available from national or state data but is needed to understand the circumstances of the children receiving services and the type of care they may need. Variables included victim demographics, type of sexual abuse and relationship to the perpetrator, and the person to whom the victim was most likely to disclose their sexual assault. A total sample of 841 case reports was reviewed. Chi-square tests were used to determine if there were statistically significant associations between the age groupings, type of abuse, and the perpetrator according to age grouping. Those children most often seen at this child advocacy center were girls (73%); White (67%); and living with their mothers, with both parents, or with parent and stepparent (80%). The incidence of CSA increased for girls across age groups. However, boys aged 6-10 years comprised the greatest percentage of the male sample (56%) who experienced CSA. For all three age groups, over half of the perpetrators were identified as relatives. Most children (85%) experienced high-impact sexual abuse behaviors of fondling, penetration, or some combination thereof. Children most often disclosed CSA to their mothers. Understanding patterns of CSA at the local level provides guidance beyond national and state data to forensic nurses regarding child and family needs within their communities. PMID- 25695209 TI - The role of forensic death investigators interacting with the survivors of death by homicide and suicide. AB - When sudden unexpected death occurs, an investigation ensues in an attempt to discover the cause and manner of death. Autopsies are performed when reasons for death are not obvious. They are used to provide information, confirm the cause of death, and/or reveal conditions not recognized before death (Hendricks, 2011). One important reason for performing an autopsy is to help families to understand what happened to their loved one so that they can begin the process of grieving. The way that the initial notification and investigation is handled can have a bearing on how a family's grief progresses. Forensic nurses are in a unique position to bring a holistic approach to death investigation with a focus of care that includes not only the decedent but the surviving loved ones as well (Koehler, 2008). Forensic nurse death investigators can assist families through initial stages of grief in the investigation of death. PMID- 25695210 TI - Patient and staff views of quality in forensic psychiatric inpatient care. AB - The study describes and compares perceived quality of care among patients and staff using the Quality in Psychiatric Care-Forensic In-Patient and the Quality in Psychiatric Care-Forensic In-Patient Staff questionnaires. The questionnaires are both based on the perception of the quality of the forensic psychiatric care given to the patients, but the wording is adjusted to fit patients or staff. The study sample consisted of 66 patients and 202 staff members from 12 forensic units in Sweden. Using multiple regression analyses to adjust for demographic variables, it was found that patients perceived the quality of support and secluded environment lower than did staff, whereas staff had lower perceptions than patients of the quality of secure environment. The combination of these questionnaires provides new possibilities for assessing the quality of forensic psychiatric care and evaluating interventions, important factors in the management and planning of forensic care. PMID- 25695211 TI - The "It's No Secret" bra drive: an example of collaborative practice. AB - Evidence collection by sexual assault nurse examiners (SANEs) is a crucial part of the forensic medical examination. SANEs attempt to collect all possible evidence including swabs, slides, urine, blood, and clothing. Because biological evidence can be found on underwear, bras, and other clothing, the SANE often asks patients to relinquish these clothing items during the forensic medical examination. Some patients are reluctant to relinquish their bras, for varying reasons. The Riverside County Sexual Assault Multi-Disciplinary Team conducted a bra collection drive, in conjunction with Sexual Assault Awareness Month. The purpose of the bra drive was to enable the SANE to provide a replacement bra in exchange for the patient's bra, which may contain biological evidence. The community response was overwhelming and has already enabled the collection of bras from patients who were otherwise unwilling to give them up. PMID- 25695213 TI - Antiplatelet agents for preventing thrombosis after peripheral arterial bypass surgery. AB - BACKGROUND: Peripheral arterial disease (PAD) may cause occlusions (blockages) in the main arteries of lower limbs. One treatment option is bypass surgery using autologous (the patient's own tissue) vein graft or prosthetic (artificial) graft. A number of factors influence occlusion rates in these patients, including the material used. To prevent graft occlusion patients are usually treated with antiplatelet, antithrombotic drugs, or a combination of both. OBJECTIVES: To determine the effects of antiplatelet agents for the prevention of thrombosis in people with lower limb atherosclerosis who were undergoing femoropopliteal or femorodistal bypass grafting. Outcomes included the overall success of therapy (graft patency and limb salvage rates) and complications of treatment. SEARCH METHODS: For this update the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched June 2014) and the Cochrane Central Register of Controlled Trials (CENTRAL) (2014, Issue 5). We sought additional trials through screening the reference lists of relevant papers. SELECTION CRITERIA: Two review authors, RB and AL, independently reviewed studies found in the search and evaluated them based on the inclusion and exclusion criteria, resolving disagreements through discussion. DATA COLLECTION AND ANALYSIS: RB and AL independently extracted details of the selected studies for the update. We compared the treatment and control groups for important prognostic factors and differences described. If any data were unavailable, we sought further information from study authors. We synthesised data by comparing group results. We addressed unit of analysis issues by subgroup analysis. MAIN RESULTS: We include 16 studies with 5683 randomised participants. Nine different treatment groups were evaluated: aspirin (ASA) or aspirin and dipyridamole (ASA/DIP) versus placebo or nothing (six studies); ASA or ASA/DIP versus pentoxifylline (two studies); ASA/DIP versus indobufen (one study); ASA or ASA/DIP versus vitamin K antagonists (two studies); ASA/DIP versus low molecular weight heparin (one study); ticlopidine versus placebo (one study); ASA versus prostaglandin E1 (one study); ASA versus naftidrofuryl (one study); and clopidogrel and ASA versus ASA alone (one study). The treatment comparisons were evaluated separately, and, where possible, we performed subgroup analysis for venous grafts and prosthetic grafts and at different follow-up time points. The quality of evidence was low to moderate as many of the treatment comparisons had very few studies to contribute data, several of the included studies had unit of analysis issues, the treatment dosages varied between studies, and data for many outcomes important to this review were not given in any of the studies, or differed greatly between studies. Overall study quality was moderate, with the largest problem being that the majority of studies did not describe their methods of randomisation, allocation concealment or blinding of outcome assessors, leading to risk ratings of 'unclear'. The other main issue with study quality was studies not blinding participants or personnel.The treatment comparison with the most number of included studies, which allowed for robust conclusions, was that of aspirin (ASA) or ASA and dipyridamole (ASA/DIP) versus placebo or nothing, covered by six studies. For this treatment group, there was improved graft patency in the ASA or ASA/DIP treatment group, odds ratio (OR) 0.42 (95% confidence interval (CI) 0.22 to 0.83; P = 0.01; 952 participants). This effect was not seen for venous grafts alone at any of the time points, but was observed for all time points in prosthetic grafts, including the final time point of 12 months (OR 0.19, 95% CI 0.10 to 0.36; P < 0.00001; 222 participants). Only a single study evaluated secondary patency, for which there was no difference between treatment groups. For the comparison ASA or ASA/DIP versus placebo or nothing there was no difference for any of the side effects, including general, gastrointestinal, bleeding and wound/graft infection. Amputations, cardiovascular events and mortality were also similar between the treatment groups. The comparison of ASA or ASA/DIP versus vitamin K antagonists included two studies, one of which was very large, with over 2000 participants. There were no differences between treatment for primary graft patency at three, six, 12 or 24 months, and there was also no evidence of a difference for limb amputation, cardiovascular events or mortality. One large study (851 participants) evaluated clopidogrel and ASA versus ASA alone, and for all grafts there was no evidence of a difference of primary patency at 24 months. There was evidence of increased total bleeding in the clopidogrel and ASA group (OR 2.65, 95% CI 1.69 to 4.15) from an increase in mild (OR 2.34, 95% CI 1.37 to 4.00), and moderate bleeding (OR 4.13, 95% CI 1.37 to 12.45), but no difference in severe or fatal bleeding. There was no difference between the treatment groups for limb amputation or mortality. For the remaining treatment comparisons there is not currently enough evidence to draw any robust conclusions about the efficacy or safety of the treatment on graft patency after peripheral bypass. AUTHORS' CONCLUSIONS: Antiplatelet therapy with aspirin or with aspirin plus dipyridamole had a beneficial effect on primary patency of peripheral bypass grafts compared to placebo or no treatment. This effect was not evident when evaluating venous grafts alone, but antiplatelet therapy did have a beneficial effect on patency in those who had prosthetic grafts. There was no evidence of differences in side effects (including general, gastrointestinal, bleeding or infection), amputation, cardiovascular events or mortality between the treatment groups. However, the number of participants included in this analysis might be too small to detect a statistically significant effect for side effects, amputation, cardiovascular morbidity or mortality. We found no difference in primary graft patency when aspirin or aspirin with dipyridamole was compared to a vitamin K antagonist or when clopidogrel with aspirin was compared to aspirin alone. However, there was evidence of increase bleeding in the clopidogrel with aspirin group for the latter comparison. The remaining six treatment comparisons did not include enough data to draw any robust conclusions about their efficacy or safety at this time. PMID- 25695214 TI - Morita therapy for anxiety disorders in adults. AB - BACKGROUND: Morita therapy, first proposed in 1919, is a systematic psychological therapy for anxiety disorders that is based on eastern philosophy. It is mainly used as an alternative therapy for anxiety disorders in Asian countries such as Japan and China. Varying foci of treatment outcomes have been reported. To date, there has been no systematic review to investigate the strength of evidence for Morita therapy in anxiety disorders. OBJECTIVES: To assess the effects of Morita therapy compared with pharmacological therapy, other psychological therapy, no intervention or wait list for anxiety disorders in adults. SEARCH METHODS: We searched The Cochrane Collaboration Depression, Anxiety and Neurosis Group's Specialised Register (CCDANCTR, which includes relevant randomised controlled trials from MEDLINE (1950 to date), EMBASE (1974 to date) and PsycINFO (1967 to date)), Dissertation Abstracts International (DAI) and four main Chinese medical databases (Chongqing VIP Database, Wanfang Database, China Hospital Knowledge Database, China Biology Medicine disc) as described in the protocol of this review to December 2014. Furthermore, we extended our search in the Cochrane Central Register of Controlled Trials (CENTRAL) and the World Health Organization International Clinical Trials Registry Platform (ICTRP) and the Sagace, a web based search engine for biomedical databases in Japan. We applied no date or language restrictions. We contacted experts in the field for supplemental data. SELECTION CRITERIA: We included all relevant randomised controlled trials comparing Morita therapy with any other treatment in the treatment of anxiety disorders. DATA COLLECTION AND ANALYSIS: Two authors independently selected studies and extracted data. For homogenous dichotomous data, we calculated fixed effect risk ratios (RR), 95% confidence intervals (CI) and, where appropriate, numbers needed to treat for an additional beneficial outcome (NNTB) on an intention-to-treat basis. For continuous data, we calculated fixed-effect standardised mean differences (SMD) and 95% CI. MAIN RESULTS: We found seven small Chinese studies (449 participants), six of which provided useable data for meta-analysis. No study compared Morita therapy with an inactive control. Unclear randomisation methods, lack of blinding and low quality reporting of outcomes were common in the included studies. We graded the overall risk of bias as high and the quality of the evidence as very low.Two social phobia studies (75 outpatients) directly compared Morita therapy with pharmacological therapy. In this comparison, the pooled RR of global state was 1.85 (95% CI 1.27 to 2.69) and the NNTB was 3 (95% CI 2 to 5), indicating a significant difference between groups favouring Morita therapy in the short term (up to 12 weeks' post treatment). Data regarding drop-outs was insufficient and no description of adverse effects was provided. We graded the quality of the evidence for this comparison as very low, mainly due to high risk of bias in the studies and insufficient information in the results.Four studies (288 inpatients) investigated the effect of Morita therapy plus pharmacological therapy versus pharmacological therapy alone, three studies for the treatment of obsessive compulsive disorder (OCD) (228 participants) and one study for generalised anxiety disorder (60 participants). One of the OCD studies reported incomplete data of global state while the outcome of global state was missing in the other three studies. There was no significant difference between groups for drop-outs for any reason in two OCD studies in the short term (RR 1.76, 95% CI 0.47 to 6.67; I(2) = 44%). Information pertaining to drop-outs for adverse effects was unclear. We rated the risk of bias of this comparison as high. We graded the quality of the evidence as very low. AUTHORS' CONCLUSIONS: The evidence base on Morita therapy for anxiety disorders was limited. All studies included in this review were conducted in China, and the results may not be applicable to Western countries. These included studies were small, provided insufficient information about drop-outs and adverse effects, and contained considerable risk of bias. Therefore, we graded the evidence as very low quality and were unable to draw conclusions on the effectiveness of Morita therapy in the treatment of anxiety disorders. Well-designed future studies that employ adequate allocation concealment, recruit large sample sizes, report drop-outs and adverse effects, and report outcomes clearly and consistently are needed to establish the effectiveness of Morita therapy for anxiety disorders. PMID- 25695215 TI - Deltex1 antagonizes HIF-1alpha and sustains the stability of regulatory T cells in vivo. AB - Application of regulatory T cells (Tregs) in transplantation, autoimmunity and allergy has been extensively explored, but how Foxp3 and Treg stability is regulated in vivo is incompletely understood. Here, we identify a requirement for Deltex1 (DTX1), a contributor to T-cell anergy and Foxp3 protein level maintenance in vivo. Dtx1(-/-) Tregs are as effective as WT Tregs in the inhibition of CD4(+)CD25(-) T-cell activation in vitro. However, the suppressive ability of Dtx1(-/-) Tregs is greatly impaired in vivo. We find that Foxp3 expression is diminished when Dtx1(-/-) Tregs are co-transferred with effector T cells in vivo. DTX1 promotes the degradation of HIF-1alpha. Knockout of HIF 1alpha restores the Foxp3 stability and rescues the defective suppressive activity in Dtx1(-/-) Treg cells in vivo. Our results suggest that DTX1 exerts another level of control on Treg stability in vivo by sustaining the expression of Foxp3 protein in Tregs. PMID- 25695216 TI - In memoriam. Dr. Nigel Gray. PMID- 25695217 TI - Good cancers--bad cancers: good patients--bad patients? PMID- 25695218 TI - Recent insights emerging from malignant mesothelioma genome sequencing. PMID- 25695219 TI - Follow-up of patients after stereotactic radiation for lung cancer: a primer for the nonradiation oncologist. AB - BACKGROUND: The use of stereotactic ablative radiotherapy (SABR) as primary treatment for early stage non-small-cell lung cancer, or for ablation of metastases, has increased rapidly in the past decade. With local recurrence rates reported at approximately 10%, and a patient population that is becoming increasingly fit and amenable to salvage treatment, appropriate multidisciplinary follow-up care is critical. Appropriate follow-up will allow for detection and management of radiation-related toxicity, early detection of recurrent disease and differentiation of recurrence from radiation-induced lung injury. METHODS: This narrative review summarizes issues surrounding follow-up of patients treated with SABR in the context of a multidisciplinary perspective. We summarize treatment-related toxicities including radiation pneumonitis, chest wall pain, rib fracture, and fatal toxicity, and highlight the challenges of early and accurate detection of local recurrence, while avoiding unnecessary biopsy or treatment of benign radiation-induced fibrotic lung damage. RESULTS: Follow-up recommendations based on the current evidence and available guidelines are summarized. Imaging follow-up recommendations include serial computed tomography (CT) imaging at 3-6 months posttreatment for the initial year, then every 6-12 months for an additional 3 years, and annually thereafter. With suspicion of progressive disease, recommendations include a multidisciplinary team discussion, the use of high-risk CT features for accurate detection of local recurrence, and positron emission tomography/CT SUV max cutoffs to prompt further investigation. Biopsy and/or surgical or nonsurgical salvage therapy can be considered if safe and when investigations are nonreassuring. CONCLUSIONS: The appropriate follow-up of patients after SABR requires collaborative input from nearly all members of the thoracic multidisciplinary team, and evidence is available to guide treatment decisions. Further research is required to develop better predictors of toxicity and recurrence. PMID- 25695220 TI - MiR-205 and MiR-375 microRNA assays to distinguish squamous cell carcinoma from adenocarcinoma in lung cancer biopsies. AB - INTRODUCTION: Identification of adenocarcinoma (AC) and squamous cell carcinoma (SCC) histology of non-small-cell lung cancer (NSCLC) in biopsies is clinically important but can be inaccurate by routine histopathologic examination. We quantify this inaccuracy at a cancer center, and evaluate the utility of a microRNA-based method to histotype AC/SCC in biopsies. METHODS: RNA was extracted from tissue sections with greater than 90% tumor content that were macro- or micro-dissected from formalin-fixed, paraffin-embedded biopsy specimens. MicroRNAs in RNA from the biopsies and from resected tumors were quantified by TaqMan reverse transcription-polymerase chain reaction assays and normalized against the RNU6B housekeeping RNA. Publicly available microRNA expression datasets were examined. RESULTS: NSCLC subtyping of small biopsy specimens by routine histopathologic examination either failed or mistyped the histology of 21% of 190 cases. Using 77 resectates, an reverse transcription-polymerase chain reaction-based assay of microRNAs miR-21, miR-205, and miR-375 was developed to identify AC and SCC subtypes of NSCLC. This method identified the AC/SCC histotypes of 25 biopsies with an accuracy of 96%, and correctly histotyped all 12 cases for which the histology had been mistyped by routine histopathologic examination of the biopsy. Examination of publicly available datasets identified miR-205 and miR-375 as microRNAs with the best ability to histotype AC and SCC, and that levels of the two microRNAs in AC or SCC are unaffected by the pathologic stage of the tumor or the age or race of the patient. CONCLUSIONS: Histotypic microRNA assays can aid the subtyping of NSCLC biopsies as AC or SCC by standard histopathologic methods. PMID- 25695221 TI - Phase II trial of gefitinib in combination with bevacizumab as first-line therapy for advanced non-small cell lung cancer with activating EGFR gene mutations: the Okayama Lung Cancer Study Group Trial 1001. AB - PURPOSE: Whether bevacizumab enhances the effect of the epidermal growth factor receptor (EGFR) inhibitor gefitinib on EGFR mutant non-small cell lung cancers (NSCLCs) remains unknown. We conducted a phase II trial to investigate the efficacy and safety of gefitinib when combined with bevacizumab as first-line therapy in patients with advanced NSCLC harboring EGFR gene mutations. METHODS: In this trial, 42 patients with a performance status of 0 to 2 received gefitinib (250 mg/d) and bevacizumab (15 mg/kg, every 3 weeks). The primary end point of this study was the 1-year progression-free survival (PFS) rate. We assumed that a 1-year PFS rate of 55% would indicate potential usefulness and that a 1-year PFS rate of 40% would constitute the lower limit of interest. RESULTS: Forty-two patients were enrolled in the study with a median age of 73 (range 42-86) years. Activating EGFR gene mutations included exon 19 deletion (57%) and L858R point mutations in exon 21 (38%). The objective response rate was 73.8% and included two complete responses. The 1-year PFS rate and median PFS time were 56.7% (95% confidence interval [CI] 39.9-70.5) and 14.4 months (95% CI 10.1-19.2), respectively. The median PFS differed significantly between EGFR exon 19 deletion and the L858R point mutation (18.0 versus 9.4 months, respectively; p = 0.006). The median overall survival had not yet been reached. Severe adverse events included grade 3 skin rash (15%), hypertension (17%), aspartate transaminase/alanine aminotransferase elevation (17%), proteinuria (7%), intracranial hemorrhage (2%), and grade 4 perforation of the digestive tract (2%). There were no treatment-related deaths. CONCLUSION: Gefitinib in combination with bevacizumab as first-line therapy seems to be a favorable and well-tolerated treatment for patients with advanced NSCLC with activating EGFR gene mutations, especially those with EGFR exon 19 deletion mutations, although the primary end point was not met because the lower limit of the CI was less than 40%. PMID- 25695222 TI - Comparison of locoregional versus extended locoregional radiation volumes for patients with nonmetastatic gastro-esophageal junction carcinomas. AB - INTRODUCTION: To delineate an optimal clinical target volume (CTV) for gastroesophageal junction (GEJ) cancers by comparing locoregional versus extended locoregional radiation (RT) volumes. MATERIALS: This retrospective analysis examined 222 patients (111 matched pairs treated with locoregional versus extended locoregional RT) with nonmetastatic GEJ carcinomas treated with concurrent chemoradiation +/- surgery. The CTV for locoregional volumes was defined as gross tumor volume + elective coverage of first-echelon nodes and sometimes the celiac axis. The CTV for extended locoregional volumes was defined as gross tumor volume + elective coverage of celiac and splenic (+/- porta) nodes. Variables used for matching included sex, stage, performance status, histology, receipt of induction chemotherapy, type of concurrent chemotherapy, RT modality, receipt of surgery, type of surgery, and Siewert classification. Regression models stratified by matched pairs were fit to estimate effect of RT volume on clinical endpoints. RESULTS: Adjusting p values for multiple testing, patients treated with extended locoregional versus locoregional RT had increased odds of grade 2+ acute chemoradiation-associated gastrointestinal toxicity (odds ratio: 2.92, adj. p = 0.0447). However, differing RT volumes were not significantly associated with postoperative complication rates, pathologic T stage, frequency of positive perigastric/regional nodes on surgical specimen, distant-metastases progression-free survival, locoregional progression-free survival, or overall survival (adj. p > 0.05). Of the patients who did (n = 124) and did not (n = 72) receive elective celiac RT, two (1.6%) and two patients (2.8%), respectively, relapsed in the celiac nodes. No patients failed in the splenic or porta nodes. CONCLUSIONS: Most GEJ cancers can be safely treated without elective inclusion of splenic/porta nodes. PMID- 25695223 TI - Analysis of ERBB ligand-induced resistance mechanism to crizotinib by primary culture of lung adenocarcinoma with EML4-ALK fusion gene. AB - INTRODUCTION: Using cell line-based assays, the secretion of erythroblastic leukemia viral oncogene homologue (ERBB) ligands has been reported to contribute to resistance against crizotinib in lung cancer with the echinoderm microtubule associated protein-like 4 and anaplastic lymphoma kinase fusion gene. However, it is difficult to predict the role of the ligands in each patient. Here, we report an analysis of the mechanism of resistance behind crizotinib resistance using a primary culture of cancer cells from pleural effusion of an anaplastic lymphoma kinase-positive lung cancer patient who was clinically resistant to crizotinib. METHODS: Primary cancer cells were prepared as cancer tissue-originated spheroids (CTOSs) according to previously described methods. CTOSs were maintained in StemPro medium, and a sensitivity assay was performed under growth factor-free conditions, or under stimulation with epidermal growth factor (EGF) or neuregulin 1/heregulin. The effect of treatment with crizotinib alone or a combination of crizotinib and erlotinib was examined. RESULTS: Cancer cells (LB53) were established to be CTOSs from a patient who was clinically resistant to crizotinib. The CTOSs were sensitive to crizotinib under growth factor-free conditions in vitro, whereas resistant under stimulation with EGF or neuregulin 1. These ligands rescued the inhibition of intracellular signaling by crizotinib. Pleural effusion from the patient also activated EGF receptor signaling to the similar extent of EGF stimulation. The resistance to crizotinib by EGF was reversed by blocking EGF receptor signaling by erlotinib in vitro. CONCLUSION: Stimulation by ERBB ligands is suggested to be responsible for resistance to crizotinib in this patient. The CTOS method may enable analysis of resistance mechanism for targeted therapy in individual patients. PMID- 25695224 TI - Somatic STK11 and concomitant STK11/KRAS mutational frequency in stage IV lung adenocarcinoma adrenal metastases. AB - Somatic serine/threonine kinase 11 (STK11) also known as liver kinase B1 (LKB1) is a tumor suppressor gene and ranks as the third most frequently mutated gene in lung adenocarcinoma. However, current molecular testing guidelines recommend evaluating for epidermal growth factor receptor mutations and ALK fusions to guide therapy in all patients with advanced stage adenocarcinoma, regardless of gender, race, or smoking history. Identifying alternative "driver" mutations and using actionable targeted pharmacotherapy is a key approach to providing effective individualized medical care. The analytical sensitivity and parallel multigene approach of targeted next-generation sequencing is an attractive methodology for use for cytology specimens. The presented lung adenocarcinoma study revealed that STK11 mutations alone and concomitant KRAS/STK11 mutations were identified in 18.2% and 4.5% of solitary adrenal metastases, respectively. Molecular profiling of epidermal growth factor receptor tyrosine kinase inhibitor resistant tumors may help to identify patients who would most benefit from alternative single or dual pathway inhibition potentially leading to a revision in current molecular testing guidelines. PMID- 25695225 TI - Lipodermatosclerosis secondary to pemetrexed use. PMID- 25695226 TI - pN categories based on metastatic lymph node counts are still the cornerstone in operable esophageal cancer. PMID- 25695227 TI - Pulmonary metastasectomy: where is the evidence? PMID- 25695228 TI - Reply to "Pulmonary metastasectomy: where is the evidence?": absence of evidence is not evidence of absence! PMID- 25695229 TI - Identification of dopaminergic neurons of the substantia nigra pars compacta as a target of manganese accumulation. AB - Manganese serves as a cofactor to a variety of proteins necessary for proper bodily development and function. However, an overabundance of Mn in the brain can result in manganism, a neurological condition resembling Parkinson's disease (PD). Bulk sample measurement techniques have identified the globus pallidus and thalamus as targets of Mn accumulation in the brain, however smaller structures/cells cannot be measured. Here, X-ray fluorescence microscopy determined the metal content and distribution in the substantia nigra (SN) of the rodent brain. In vivo retrograde labeling of dopaminergic cells (via FluoroGoldTM) of the SN pars compacta (SNc) subsequently allowed for XRF imaging of dopaminergic cells in situ at subcellular resolution. Chronic Mn exposure resulted in a significant Mn increase in both the SN pars reticulata (>163%) and the SNc (>170%) as compared to control; no other metal concentrations were significantly changed. Subcellular imaging of dopaminergic cells demonstrated that Mn is located adjacent to the nucleus. Measured intracellular manganese concentrations range between 40-200 MUM; concentrations as low as 100 MUM have been observed to cause cell death in cell cultures. Direct observation of Mn accumulation in the SNc could establish a biological basis for movement disorders associated with manganism, specifically Mn caused insult to the SNc. Accumulation of Mn in dopaminergic cells of the SNc may help clarify the relationship between Mn and the loss of motor skills associated with manganism. PMID- 25695230 TI - Executive functions in men and postmenopausal women. AB - INTRODUCTION: This study was designed to assess sex differences in older adults (55-65 years old) in executive functions and to examine the influence of hormone therapy (HT) in postmenopausal women. METHOD: We have assessed task performance in memory, visuospatial, and executive functions in 29 women using HT, 29 women who never used HT, and 30 men. RESULTS: Men outperformed never users in task switching and updating. HT users outperformed never users in updating. HT users outperformed never users and men in visual divided attention. DISCUSSION: The present study support previous findings that sex and HT impact cognition and bring new insights on sex and HT-related differences in executive functions. PMID- 25695231 TI - Microarray expression profile of lncRNAs and the upregulated ASLNC04080 lncRNA in human endometrial carcinoma. AB - Long non-coding RNAs (lncRNAs) have been recognized as a regulator of gene expression, and the deregulation of lncRNAs have been reported to be correlated with carcinogenesis and cancer progression. To explore the function of lncRNA in endometrial carcinoma, we analyzed the expression profiles of lncRNAs and coding genes in 3 paired endometrial carcinoma and adjacent non-tumor tissues, using a microarray. The results of microarray analysis indicated a significant difference in lncRNA and coding gene expression between endometrial carcinoma and their paired adjacent non-tumor tissues. A total of 53 lncRNAs (fold change >2.0, p value <0.05) were found to be differently expressed in endometrial carcinoma compared to the normal controls. Among these ASLNC04080 was the most significantly upregulated lncRNA in microarray data, highly expressed in 22 out of 24 endometrial carcinoma tissues and HEC-1-B cell line. ASLNC04080 is 1867nt in length, consist of 6 exons, and locates at 1 p35.3(chr1: -28905061 - 28909492). In addition, 46 coding gene transcripts were differentially expressed (fold change >2.0, p-value <0.05) between endometrial carcinoma and adjacent non tumor tissues. Pathway and gene ontology analysis demonstrated that these deregulated transcripts were involved in multiple signal pathways, biological processes, cellular components and molecular functions. Moreover, the ASLNC04080 lncRNA expression was correlated with 19 coding genes, and may contribute to endometrial carcinoma genesis and progression by co-regulating with coding gene. Expression inhibition of lncRNA ASLNC04080 in HEC-1-B cells caused repression of cell proliferation, increased cell apoptosis, and G1 phase arrest. These results suggested a potential function of ASLNC04080 in endometrial carcinoma genesis and progression. PMID- 25695232 TI - Extensive Characterization of Platelet Gel Releasate From Cord Blood in Regenerative Medicine. AB - Platelet gel derived from peripheral blood is widely applied in many clinical fields of surgery as biomaterial containing growth factors with high proliferative properties. In 2010, we studied and patented a platelet gel derived from cord blood. In this study, due to the crucial role of the factors released by the platelet gel, we first extended the characterization of its releasate. Using a wide proteomic array and splitting the two components of the releasate, that is, platelets and plasma, we have been able to study their growth factor content. Interestingly, we discovered high levels of hormones and molecules able to support tissue growth in the cord blood platelet gel releasate and, in addition, higher concentrations of several angiogenic factors if compared with the peripheral blood counterpart. On the contrary, the latter was much richer in inflammatory factors. The second aim of our work was to study the effects on cell culture, immunophenotype, and function of mesenchymal stem cells exposed to these two platelet gel releasates as substitute for the animal serum. Since our findings nicely show that the use of the peripheral versus the cord blood platelet gel releasate can differently influence the mesenchymal stem cell commitment, we can suggest that in addition to its peculiar angiogenic properties cord blood platelet gel releasate shows excellent proliferative properties as cell culture supplement. PMID- 25695233 TI - Surgical applications of 3-dimensional printing and precision medicine. PMID- 25695235 TI - [Living medicine: The death of grandfather]. PMID- 25695234 TI - Nuclear Ep-ICD expression is a predictor of poor prognosis in "low risk" prostate adenocarcinomas. AB - INTRODUCTION: Molecular markers for predicting prostate cancer (PCa) that would have poor prognosis are urgently needed for a more personalized treatment for patients. Regulated intramembrane proteolysis of Epithelial cell adhesion molecule results in shedding of the extracellular domain (EpEx) and release of its intracellular domain (Ep-ICD) which triggers oncogenic signaling and might correlate to tumor aggressiveness. This study aimed to explore the potential of Ep-ICD and EpEx to identify PCa that have poor prognosis. METHODS: Immunohistochemical analysis of Ep-ICD and EpEx was carried out in normal prostate tissues (n = 100), benign prostate hyperplasia (BPH, n = 83), and prostate cancer (n = 249) using domain specific antibodies. The expression of Ep ICD and EpEx was correlated with clinico- pathological parameters and disease free survival (DFS). RESULTS: Reduced expression of nuclear Ep-ICD and membrane EpEx was observed in PCa in comparison with BPH and normal prostate tissues (p = 0.006, p < 0.001 respectively). For patients who had PCa with Gleason Score less than 7, preserved nuclear Ep-ICD emerged as the most significant marker in multivariate analysis for prolonged DFS, where these patients did not have recurrence during follow up of up to 12 years (p = 0.001). CONCLUSION: Reduced expression of nuclear Ep-ICD was associated with shorter disease free survival in patients with a Gleason Score less than 7 and may be useful in identifying patients likely to have aggressive tumors with poor prognosis. Furthermore, nuclear Ep-ICD can differentiate between normal and prostate cancer tissues for ambiguous cases. PMID- 25695236 TI - [Breast cancer in Mexico: a 10-year trend analysis on incidence and age at diagnosis]. AB - INTRODUCTION: Breast cancer is an important public health problem. Some countries have achieved a downward trend while in others, continues ascending. In Mexico, information on incidence and age at diagnosis is isolated in time, and knowledge on trend analysis is lacking. OBJECTIVE: To examine the 2003-2012 trend of the incidence rate and age at diagnosis of breast cancer in the northeast of Mexico. We also analyze the trend of positivity to nodes, hormone receptors and HER2; and its association with age at diagnosis. MATERIAL AND METHODS: This is an epidemiological study of breast cancer patients in a tertiary care hospital in Monterrey, Mexico (n = 3,488). Only new cases with a histology report were included; if this was not available, the cytology result was considered. Trend analysis was performed using the JoinPoint regression program Version 3.5. RESULTS: The breast cancer incidence rate increased from 26.7 to 49.8 per 100,000 between 2003 and 2011 (p < 0.05). The adjusted rate showed an annual percentage rate of change of +6.2% (95%CI 4.2, 8.2). The mean age was 55.7 +/- 13.7 years and remained stable over time. Nodes, hormone receptors and HER2 positivity rate also remained stable over time. Age < 50 years increased twice the risk for positivity to nodes (OR 2.0, 95%CI 1.4, 2.7), ER-PR- (OR 1.8, 95% CI 1.4, 2.4) and ER-PR-HER2- (OR 1.9, 95%CI 1.5, 2.5). CONCLUSIONS: The 10-year analysis showed a significant upward trend. This study represents a first effort in our country, for determining patterns on incidence and age at diagnosis of breast cancer, as well as that of biomarkers. PMID- 25695237 TI - Pre-transplant angiotensin II type 1receptor antibodies: a risk factor for decreased kidney graft function in the early post-transplant period? AB - Angiotensin II type 1 receptor antibodies (AT1Rab) are associated to a significantly lower graft survival and a higher risk of acute rejection after kidney transplantation. This study aimed to evaluate graft function and BPAR during the 1st year post-transplant (PT) in adult kidney transplant recipients (KTR), between 03/2009 and 08/2012. Pre-KT sera were screened for AT1Rab (ELISA) and HLA-DSA (Luminex). Three groups were analyzed: AT1Rab only (n = 13); HLA-DSA only (n = 8); and no AT1Rab or HLA-DSA (n = 90). No differences were observed in clinical characteristics across groups. A higher percentage of BPAR was observed in the AT1Rab positive group, but this difference was not significant. KTR with AT1Rab had a lower mean eGFR (20 mL/min/1.73m2) when compared to KTR with no Abs at 12 months. The significant difference in eGFR was observed since the 1st month PT. Multivariate analysis showed 4 factors independently and significantly associated with eGFR at 12mos PT: BPAR (-18.7 95%, CI -28.2 to -9.26, p<0.001), AT1Rab (-10.51, CI -20.9 to -0.095, p = 0.048), donor age (-0.42, CI -0.75 to 0.103 p = 0.010), and recipient age (-0.36, CI -0.67 to -0.048, p = 0.024). In this study AT1Rab in pre-transplant sera from KTR, was an independent and significant risk factor contributing to a lower eGFR 12 months. PT. This finding deserves to be confirmed in a larger KTR population. PMID- 25695238 TI - Impact of osteoporosis-associated vertebral fractures on health-related quality of life in the Mexican population. AB - OBJECTIVE: To measure the impact on the health-related quality of life (HRQoL) of a sample of Mexicans with vertebral fractures. MATERIAL AND METHODS: One hundred fifteen subjects with vertebral fractures were interviewed and compared with 135 subjects similar in age without the fracture. Subjects were men and women > 50 years of age with osteoporosis confirmed by bone mineral densitometry and with at least 1 vertebral fracture verified by vertebral morphometry and Xrays. The sample was recruited from two sources: The Clinica de Osteoporosis at the Instituto Nacional de Rehabilitacion and a random sample from the Latin American Osteoporosis Study. The Quality of Life Questionnaire of the European Foundation for Osteoporosis (QUALEFFO) validated in Spanish for the Mexican population was applied. Descriptive statistics were used for demographic and clinical aspects of the sample, as well as chi2 for categorical variables and Student t test for independent samples for continuous variables. A multiple linear regression (LR) was conducted to characterize predictive variables related to quality of life. RESULTS: Two hundred fifty subjects were interviewed; 64% of them were women. The average age of those interviewed was 73.4 +/- 11.4 years; 46% of the sample had vertebral fractures; of them 43% of were lumbar and 57% thoracic; the most frequent site was L1-T12. Significant changes were found in the group with fractures in pain, physical function, social function, and mental function (p < 0.05); in women, pain and social function were different between groups (p < 0.05); and those over 70 years also presented differences in physical, social, and mental function (p < 0.05); differences were found associated with the place of recruitment being worse in their quality of life those coming from the Clinica de Osteoporosis. Two or more fractures, age, being female and widowed were significant predictors for greater deterioration of HRQoL with the LR. CONCLUSION: This is the first study looking at the HRQoL in osteoporosis related fractures in Mexicans were quality of life deterioration on physical, social, and emotional functioning was demonstrated in subjects with two vertebral fractures. Age is a determining factor for greater deterioration in all studied domains. Differences between the samples obtained at the Clinica de Osteoporosis at the Instituto Nacional de Rehabilitacion and the random population exemplifying that asymptomatic fractures are common and not diagnosed. It is important to scrutinize vertebral fractures at the first level because their timely detection allows for their evaluation and treatment and diminishes the probability of a second fracture. Our results can be generalized to men and women over 50 who live in the central megalopolis and in other states of the Valley of Mexico. PMID- 25695239 TI - Tubular dysfunction and non-albuminuric renal disease in subjects with type 2 diabetes mellitus. AB - INTRODUCTION: Micro-albuminuria is considered an early marker of glomerular injury in patients with diabetes but it has yet to be determined whether testing for markers of tubular injury can also identify people who are at risk of progressive renal disease. OBJECTIVE: To evaluate markers of tubular injury and renal characteristics in a sample of community treated type 2 diabetic subjects. MATERIAL AND METHODS: We carry-out an assessment of a group of community diabetic patients, anthropometric measures, creatinine clearance, HbA1c, lipid profile, the mean fast serum glucose levels, albuminuria and alpha1-microglobulin (alpha1M) urine excretion were evaluated. RESULTS: From 95 included patients, 45.2% had alpha1M urinary excretion >= 10 MUg/gCr, 23.1% micro-albuminuria, 9.6% macroalbuminuria and 27.2% had a GFR < 60 mL/min. The most important risk factor associated with a1M excretion was fasting glucose level (OR 4.3, 95IC 1.7-11.1 p = 0.001); HbA1c >= 8% and age were the most important risk factors associated with GFR <= 60 mL/min. Most of patients had uncontrolled glucose levels and 45.1% patients with albuminuria were not receiving any drug with anti-proteinuric effects. CONCLUSIONS: Fasting glucose levels was the most important risk factor associated with tubular dysfunction; non-albuminuric presentation of CKD defined as GFR < 60 mL/min was frequent in our population, so is necessary to implement different strategies for surveillance in patients with type 2 diabetes aiming to delay progression to CKD. PMID- 25695240 TI - [Hearing gain with binaural-bimodal adaptation in patients with a cochlear implants]. AB - Binaural hearing allows the optimal performance of the auditory system with a better perception of the sounds that make up language and better discrimination in noisy environments. The use of binaural-bimodal stimulation includes a combination of 2 different pacing modes: a cochlear implant in one ear , and acoustic stimulation through a conventional hearing aid in the other. The aim of this study is to determine the hearing gain in patients with cochlear implant alone and hearing aid. Twenty prelingually hearing impaired patients, 11 female and 9 male subjects were recruited with mean age at implantation and 3.91 +/- 1.56 years and 6.07 +/- 2.18 years at the time of audiological assessment at six months post-implantation. Implanted patients were assessed per month after the surgery for the first telemetry subsequently were reassessed every month to make changes to schedules stimulation map according to the auditory responses and progress shown in speech therapy. When calculating the mean and standard deviation of the auditory response in implanted subjects, you can appreciate that in the group of patients with cochlear implant plus hearing aid using the values obtained were lower at all frequencies, indicating a higher gain using auditory hearing aid over a cochlear implant, in comparison to patients who only used the cochlear implant. Comparing auditory responses in patients implanted with and without hearing aid, statistically significant differences were observed at all frequencies except at 2 kHz, showing that there is a better discrimination in noisy environments. The patients use more AA gain greater hearing gain compared with patients who only used the IC. PMID- 25695241 TI - [Modification of thresholds T in cochlear implant patients as an alternative programming time in relation to the time]. AB - INTRODUCTION: Programming the cochlear implant (CI) has always been a challenge for all medical specialists in audiology, especially in pediatric patients without language secondary profound hearing loss. For this reason are searched alternatives to achieve normal hearing with the implant during programming in the shortest time possible. OBJECTIVE: To analyze whether through modification threshold T we get faster audiological threshold, describe the differences in time found in patients with sensorineural hearing loss IC users with thresholds T at 10% modified, and T thresholds modified according to clinical responses after obtaining audiological threshold within normal parameters and report the speech coding strategies commonly used at the start of the program and to reach above the hearing threshold to language area. MATERIAL AND METHODS: We performed an observational, cross-sectional, descriptive, comparative study in which we evaluated a total of 31 patients with sensorineural hearing loss, under six years, and both sexes, of cochlear implant users of Advanced Bionics, which were divided in two groups: Group I: 15 patients with modification of thresholds T to 10%, following the manufacturer's recommendations (unmodified) and Group II: 16 patients with T threshold modification according to clinical response cochlear (modified). Were reported strategies most used speech coding in both groups at the start of the program and to reach the threshold audiological within normal parameters. RESULTS: In patients in group I (not modified) were 256 days on average to reach threshold audiological and group II (modified) was 335.6 days. Without statistic significant p = 0.197, with an average of 295.8 days for both groups and the speech coding strategy more used was the Hi-Res P with Fidelity 120, modifying both groups only one patient from power up obtaining threshold. CONCKUSIONS: It was established that thresholds T patient's subjective threshold as compared to T of 10% automatically obtained by SoundWave is not necessary since there are no statistically significant differences in relation to time to take patients implanted normal hearing threshold. The speech coding strategies more widely used and accepted by the patient was the Hi-Res P with Fidelity 120. PMID- 25695242 TI - [Reference values for blood coagulation factor activity in the Mexican population]. AB - INTRODUCTION: During the fluid phase of hemostasis, fibrinogen is converted into fibrin, but other hemostatic factors are required. Reference values of hemostatic factors are established by manufacturers producing reagents using individuals with a specific genetic background. OBJECTIVE: To establish reference values for hemostatic factors in the Mexican indigenous and Mestizo populations. MATERIAL AND METHODS: We carried out a cross-sectional, descriptive study of healthy adult Mexicans. Clotting activity was evaluated using coagulometric assays. Blood donors were informed about the nature of the study and informed consent was obtained prior to blood being drawn. The protocol was approved by the Ethics Committee of our institution. RESULTS: One hundred and twenty samples were assayed (60 females and 60 males). Fibrinogen was higher in mestizos and in females. Reference values for factor XII ranged from 40-170% in indigenous subjects and from 36-159% in mestizos. Factor VIII ranged from 57-160% in indigenous subjects and from 51-209% in mestizo subjects. Reference values for the other hemostatic factors were also clearly different from the commercial reference values. Reference values for hemostatic factors in the Mexican population are different from traditionally used commercial reference values. There were significant differences between indigenous and mestizo Mexicans in the concentration of hemostatic factors with a tendency among mestizos to have higher factor concentrations. Low levels of plasma factor XII are frequent and perhaps may represent a risk factor for thrombotic events. Using these reference values may individualize the reposition of factors in Mexican hemophiliac patients. PMID- 25695243 TI - [Evaluation of the diagnostic utility scale of NOSEP-1 and NOSEP-1 modified in suspected nosocomial sepsis in preterm infants]. AB - INTRODUCTION: Nosocomial sepsis in premature neonates entertains a high rate of mortality. Diagnosis and timely treatment increase the therapeutic response. The nosocomial sepsis neonate prediction (NOSEP-1) scale has been utilized to evaluate neonatal sepsis; this scale required modifications to improve its sensitivity and specificity (NOSEP-1 modified). OBJECTIVE: To determine the diagnostic usefulness of the NOSEP-1 and NOSEP-1 modified scales when nosocomial sepsis is suspected in premature neonates. MATERIAL AND METHODS: Evaluation of the diagnostic test in premature neonates with data suggestive of sepsis. The gold standard was the hemoculture and the following diagnostic tests: nosocomial sepsis neonate prediction (NOSEP-1), with the following five items, including C reactive protein (CRP); neutrophils; platelets; evaluation of the 24-h parenteral nutrition test, and fever, while NOSEP-1 modified substitutes fever with thermal stability and days on parenteral nutrition are reduced from 14 to 3 days. Precision, sensitivity, specificity, and positive and negative predictive values were calculated. The Fagan nomogram determined diagnostic usefulness. We employed the SSPS ver. 20 statistical software Packaged and statistical significance of p < 0.05. RESULTS: We studied 77 premature neonates, with application of the gold standard and the diagnostic test. There were 36 (47%) positive hemocultures. NOSEP-1, > 9 in sepsis 24 (67%), without sepsis 15 (36%) (p = 0.012). NOSEP-1 modified, > 9 in sepsis 35 (97%), without sepsis 35 (88%) (p = 0.113). NOSEP-1: sensitivity, 66%; specificity, 63%; positive pressure volume (PPV), 61%; negative pressure volume (NPV), 68%; positive pressure rate (RPP), 1.82, and negative pressure rate (RPN), 1.14. NOSEP-1 modified scale: sensitivity 97%; specificity 14%; positive pressure value (PPV), 50%; negative pressure value (NPV), 85%; positive probability ratio (PPR), 0.53, and negative probability ratio (NPR), 0.19. Diagnostic usefulness: NOSEP-1, 64%, and NOSEP-1 Modified, 53%. CONCLUSIONS: The NOSEP-1 and the modified NOSEP-1 scales have limited usefulness for diagnosing nosocomial sepsis in premature neonates. PMID- 25695244 TI - ALECT2 amyloidosis: a new type of systemic amyloid highly prevalent in the Hispanic population. AB - Amyloidosis results from extracellular deposition of fibril-forming proteins and currently ~30 different proteins have been found to be amyloidogenic. Recently, a novel type of amyloidosis with a high incidence on Hispanic population has been described to be derived from leukocyte chemotactic factor 2 (ALECT2). The objective of the present article is to raise awareness on the presence of this entity for the medical community in Mexico. ALECT2 is a clinical entity characterized by deposition of the LECT2 protein mainly on liver and kidney. Renal ALECT2 affects elderly Hispanics who present with chronic renal insufficiency and bland urine sediment, not always associated to proteinuria. No treatment guidelines are reported for this disease but support measures including organ transplantation when required are recommended. Further genetic and clinical characterization of this entity is needed to help understanding the mechanisms by which this protein becomes amyloidogenic and how to prevent organ damage related to its deposition. PMID- 25695245 TI - [Clinical Forum: Prognosis of critically ill patients with haematological malignancies]. PMID- 25695246 TI - [Euthanasia and physician assisted suicide: what is the problem?]. AB - Some persons with refractory and unbearable suffering caused by an illness or medical condition wish to die by euthanasia or physician assisted suicide in order to have a certain and painless death. Physicians who agree to help a patient to die have previously confirmed that his/her illness cannot be cured, his/her suffering cannot be relieved and he/ she is of sound mind. Being well informed of his/her condition, the patient arrives to the conclusion that in his/her situation being death is better that being alive. How to explain that there are very few places in which physicians are allowed to help their patients to die? The main arguments against legalizing physician-assisted death are analyzed in this article. PMID- 25695247 TI - BRAF mutations among patients from the Northeast of Mexico with malignant melanoma. PMID- 25695248 TI - Correction: Photosynthetic diffusional constraints affect yield in drought stressed rice cultivars during flowering. PMID- 25695249 TI - Interferon-gamma promotes infection of astrocytes by Trypanosoma cruzi. AB - The inflammatory cytokine interferon-gamma (IFNgamma) is crucial for immunity against intracellular pathogens such as the protozoan parasite Trypanosoma cruzi, the causative agent of Chagas disease (CD). IFNgamma is a pleiotropic cytokine which regulates activation of immune and non-immune cells; however, the effect of IFNgamma in the central nervous system (CNS) and astrocytes during CD is unknown. Here we show that parasite persists in the CNS of C3H/He mice chronically infected with the Colombian T. cruzi strain despite the increased expression of IFNgamma mRNA. Furthermore, most of the T. cruzi-bearing cells were astrocytes located near IFNgamma+ cells. Surprisingly, in vitro experiments revealed that pretreatment with IFNgamma promoted the infection of astrocytes by T. cruzi increasing uptake and proliferation of intracellular forms, despite inducing increased production of nitric oxide (NO). Importantly, the effect of IFNgamma on T. cruzi uptake and growth is completely blocked by the anti-tumor necrosis factor (TNF) antibody Infliximab and partially blocked by the inhibitor of nitric oxide synthesis L-NAME. These data support that IFNgamma fuels astrocyte infection by T. cruzi and critically implicate IFNgamma-stimulated T. cruzi infected astrocytes as sources of TNF and NO, which may contribute to parasite persistence and CNS pathology in CD. PMID- 25695250 TI - Whole cell formaldehyde cross-linking simplifies purification of mitochondrial nucleoids and associated proteins involved in mitochondrial gene expression. AB - Mitochondrial DNA/protein complexes (nucleoids) appear as discrete entities inside the mitochondrial network when observed by live-cell imaging and immunofluorescence. This somewhat trivial observation in recent years has spurred research towards isolation of these complexes and the identification of nucleoid associated proteins. Here we show that whole cell formaldehyde crosslinking combined with affinity purification and tandem mass-spectrometry provides a simple and reproducible method to identify potential nucleoid associated proteins. The method avoids spurious mitochondrial isolation and subsequent multifarious nucleoid enrichment protocols and can be implemented to allow for label-free quantification (LFQ) by mass-spectrometry. Using expression of a Flag tagged Twinkle helicase and appropriate controls we show that this method identifies many previously identified nucleoid associated proteins. Using LFQ to compare HEK293 cells with and without mtDNA, but both expressing Twinkle-FLAG, identifies many proteins that are reduced or absent in the absence of mtDNA. This set not only includes established mtDNA maintenance proteins but also many proteins involved in mitochondrial RNA metabolism and translation and therefore represents what can be considered an mtDNA gene expression proteome. Our data provides a very valuable resource for both basic mitochondrial researchers as well as clinical geneticists working to identify novel disease genes on the basis of exome sequence data. PMID- 25695251 TI - Eye selector logic for a coordinated cell cycle exit. AB - Organ-selector transcription factors control simultaneously cell differentiation and proliferation, ensuring the development of functional organs and their homeostasis. How this is achieved at the molecular level is still unclear. Here we have investigated how the transcriptional pulse of string/cdc25 (stg), the universal mitotic trigger, is regulated during Drosophila retina development as an example of coordinated deployment of differentiation and proliferation programs. We identify the eye specific stg enhancer, stg-FMW, and show that Pax6 selector genes, in cooperation with Eya and So, two members of the retinal determination network, activate stg-FMW, establishing a positive feed-forward loop. This loop is negatively modulated by the Meis1 protein, Hth. This regulatory logic is reminiscent of that controlling the expression of differentiation transcription factors. Our work shows that subjecting transcription factors and key cell cycle regulators to the same regulatory logic ensures the coupling between differentiation and proliferation programs during organ development. PMID- 25695252 TI - On a model of pattern regeneration based on cell memory. AB - We present here a new model of the cellular dynamics that enable regeneration of complex biological morphologies. Biological cell structures are considered as an ensemble of mathematical points on the plane. Each cell produces a signal which propagates in space and is received by other cells. The total signal received by each cell forms a signal distribution defined on the cell structure. This distribution characterizes the geometry of the cell structure. If a part of this structure is removed, the remaining cells have two signals. They keep the value of the signal which they had before the amputation (memory), and they receive a new signal produced after the amputation. Regeneration of the cell structure is stimulated by the difference between the old and the new signals. It is stopped when the two signals coincide. The algorithm of regeneration contains certain rules which are essential for its functioning, being the first quantitative model of cellular memory that implements regeneration of complex patterns to a specific target morphology. Correct regeneration depends on the form and the size of the cell structure, as well as on some parameters of regeneration. PMID- 25695254 TI - Phasic and tonic pain differentially impact the interruptive function of pain. AB - The interruptive effect of painful experimental stimulation on cognitive processes is a well-known phenomenon. This study investigated the influence of pain duration on the negative effects of pain on cognition. Thirty-four healthy volunteers performed a rapid serial visual presentation task (RSVP) in which subjects had to detect (visual detection task) and count the occurrence of a target letter (working memory task) in two separate sessions while being stimulated on the left volar forearm with either short (2 sec) or long (18 sec) painful heat stimuli of equal subjective intensity. The results show that subjects performed significantly worse in the long pain session as indexed by decreased detection and counting performance. Interestingly, this effect on performance was also observed during control trials of the long pain session in which participants did not receive any painful stimulation. Moreover, subjects expected long painful stimulation to have a greater impact on their performance and individual expectation correlated with working memory performance. These findings suggest that not only the length of painful stimulation but also its expected ability to impair cognitive functioning might influence the interruptive function of pain. The exact relevance of expectation for the detrimental effects of pain on cognitive processes needs to be explored in more detail in future studies. PMID- 25695253 TI - Exclusion of the unfolded protein response in light-induced retinal degeneration in the canine T4R RHO model of autosomal dominant retinitis pigmentosa. AB - PURPOSE: To examine the occurrence of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) following acute light damage in the naturally occurring canine model of RHO-adRP (T4R RHO dog). METHODS: The left eyes of T4R RHO dogs were briefly light-exposed and retinas collected 3, 6 and 24 hours later. The contra-lateral eyes were shielded and used as controls. To evaluate the time course of cell death, histology and TUNEL assays were performed. Electron microscopy was used to examine ultrastructural alterations in photoreceptors at 15 min, 1 hour, and 6 hours after light exposure. Gene expression of markers of ER stress and UPR were assessed by RT-PCR, qRT-PCR and western blot at the 6 hour time-point. Calpain and caspase-3 activation were assessed at 1, 3 and 6 hours after exposure. RESULTS: A brief exposure to clinically-relevant levels of white light causes within minutes acute disruption of the rod outer segment disc membranes, followed by prominent ultrastructural alterations in the inner segments and the initiation of cell death by 6 hours. Activation of the PERK and IRE1 pathways, and downstream targets (BIP, CHOP) of the UPR was not observed. However increased transcription of caspase-12 and hsp70 occurred, as well as calpain activation, but not that of caspase-3. CONCLUSION: The UPR is not activated in the early phase of light-induced photoreceptor cell death in the T4R RHO model. Instead, disruption in rods of disc and plasma membranes within minutes after light exposure followed by increase in calpain activity and caspase-12 expression suggests a different mechanism of degeneration. PMID- 25695255 TI - Using high-resolution future climate scenarios to forecast Bromus tectorum invasion in Rocky Mountain National Park. AB - National Parks are hallmarks of ecosystem preservation in the United States. The introduction of alien invasive plant species threatens protection of these areas. Bromus tectorum L. (commonly called downy brome or cheatgrass), which is found in Rocky Mountain National Park (hereafter, the Park), Colorado, USA, has been implicated in early spring competition with native grasses, decreased soil nitrogen, altered nutrient and hydrologic regimes, and increased fire intensity. We estimated the potential distribution of B. tectorum in the Park based on occurrence records (n = 211), current and future climate, and distance to roads and trails. An ensemble of six future climate scenarios indicated the habitable area of B. tectorum may increase from approximately 5.5% currently to 20.4% of the Park by the year 2050. Using ordination methods we evaluated the climatic space occupied by B. tectorum in the Park and how this space may shift given future climate change. Modeling climate change at a small extent (1,076 km2) and at a fine spatial resolution (90 m) is a novel approach in species distribution modeling, and may provide inference for microclimates not captured in coarse scale models. Maps from our models serve as high-resolution hypotheses that can be improved over time by land managers to set priorities for surveys and removal of invasive species such as B. tectorum. PMID- 25695256 TI - Infected total ankle arthroplasty: risk factors and treatment options. AB - BACKGROUND: Infections in total ankle arthroplasty are a serious complication, about which there is little information in the current literature. METHODS: This is a retrospective review of infected total ankle arthroplasty at one institution from 1995 to 2012. Risk factors were compared between patients with infected total ankle arthroplasty and age- and sex-matched patients who did not have infection (control patients) within the same time period. RESULTS: 966 patients with total ankle arthroplasty were reviewed, and 29 cases of infected total ankle arthroplasty (3.2%) were identified. The incidence of infection in primary ankle arthroplasty was 2.4% and in revision arthroplasty was 4%. Risk factors for infection in our cohort included diabetes, prior ankle surgery, and wound healing problems more than 14 days postoperatively. No significant difference was found between groups with respect to risk factors including smoking, body mass index, and operative time. At latest follow-up, none of the patients had signs of persistent infection. Operative intervention of infected total ankle arthroplasty resulted in limb salvage in 79% of cases (a 21% amputation rate). At final follow up, 65.5% of cases were infection-free with retained arthroplasty. This was achieved by irrigation and debridement alone, 1-stage fusion, and most often 2 stage revision. The final outcome was fusion in 3 of 29 cases (10.3%). CONCLUSIONS: Given the morbidity of infected ankle arthroplasty, careful consideration should be made about performing arthroplasty in patients with multiple prior surgeries and comorbidities that predispose to wound-healing difficulties. LEVEL OF EVIDENCE: Level III, retrospective comparative study. PMID- 25695257 TI - Novel mutations in K13 propeller gene of artemisinin-resistant Plasmodium falciparum. AB - We looked for mutations in the Plasmodium falciparum K13 propeller gene of an artemisinin-resistant parasite on islands in Lake Victoria, Kenya, where transmission in 2012-2013 was high. The 4 new types of nonsynonymous, and 5 of synonymous, mutations we detected among 539 samples analyzed provide clues to understanding artemisinin-resistant parasites. PMID- 25695258 TI - Evaluating the underestimated risk factors associated with carotid artery stenosis. PMID- 25695259 TI - Trends in major risk factors for cardiovascular disease among adults in the Mississippi Delta region, Mississippi Behavioral Risk Factor Surveillance System, 2001-2010. AB - INTRODUCTION: The prevalences of major modifiable risk factors for cardiovascular disease (CVD) are disproportionately high in the 18-county Mississippi Delta region, and many of these risk factors disproportionately affect blacks. Temporal trends in the prevalence of CVD risk factors in the Mississippi Delta have not been determined. We examined trends in CVD risk factors from 2001 to 2010 in the region. METHODS: Longitudinal trends in prevalence of high blood pressure, high cholesterol, diabetes, obesity, physical inactivity, and current smoking were investigated using self-reported data from the Behavioral Risk Factor Surveillance System. Joinpoint regression models were used to examine annual percentage change (APC) in the prevalence of these risk factors. RESULTS: Overall, from 2001 to 2010, we observed significant increases in the prevalence of high cholesterol (APC, 4.22%), obesity (APC, 3.65%), and diabetes (APC, 3.54%). Among blacks, we found significant increases in the prevalence of high cholesterol (APC, 3.41%), obesity (APC, 3.48%), and diabetes (APC, 4.96%). Among whites, we found significant increases in high blood pressure (APC, 2.18%), high cholesterol (APC, 4.78%), obesity (APC, 4.18%), and physical inactivity (APC, 3.06%). We also observed a significant decrease in smoking among whites (APC, 1.99%). CONCLUSION: From 2001 to 2010, we found a significant increase in the prevalence of high cholesterol, diabetes, and obesity in the Mississippi Delta. We also observed racial differences in those prevalences. PMID- 25695260 TI - Recruitment strategies and the retention of obese urban racial/ethnic minority adolescents in clinical trials: the FIT families project, Michigan, 2010-2014. AB - INTRODUCTION: The successful recruitment and retention of participants is integral to the translation of research findings. We examined the recruitment and retention rates of racial/ethnic minority adolescents at a center involved in the National Institutes of Health Obesity Research for Behavioral Intervention Trials (ORBIT) initiative by the 3 recruitment strategies used: clinic, informatics, and community. METHODS: During the 9-month study, 186 family dyads, each composed of an obese African American adolescent and a caregiver, enrolled in a 6-month weight-loss intervention, a sequential multiple assignment randomized trial. We compared recruitment and retention rates by recruitment strategy and examined whether recruitment strategy was related to dyad baseline characteristics. RESULTS: Of the 186 enrolled families, 110 (59.1%) were recruited through clinics, 53 (28.5%) through informatics, and 23 (12.4%) through community. Of those recruited through community, 40.4% enrolled in the study, compared with 32.7% through clinics and 8.2% through informatics. Active refusal rate was 3%. Of the 1,036 families identified for the study, 402 passively refused to participate: 290 (45.1%) identified through informatics, 17 (29.8%) through community, and 95 (28.3%) through clinics. Recruitment strategy was not related to the age of the adolescent, adolescent comorbidities, body mass index of the adolescent or caregiver, income or education of the caregiver, or retention rates at 3 months, 7 months, or 9 months. Study retention rate was 87.8%. CONCLUSION: Using multiple recruitment strategies is beneficial when working with racial/ethnic minority adolescents, and each strategy can yield good retention. Research affiliated with health care systems would benefit from the continued specification, refinement, and dissemination of these strategies. PMID- 25695261 TI - An evaluation of health impact assessments in the United States, 2011-2014. AB - INTRODUCTION: The Center for Community Health and Evaluation conducted a 3-year evaluation to assess results of health impact assessments (HIAs) in the United States and to identify elements critical for their success. METHODS: The study used a retrospective, mixed-methods comparative case study design, including a literature review; site visits; interviews with investigators, stakeholders, and decision makers for 23 HIAs in 16 states that were completed from 2005 through 2013; and a Web-based survey of 144 HIA practitioners. RESULTS: Analysis of interviews with decision makers suggests HIAs can directly influence decisions in nonhealth-related sectors. HIAs may also influence changes beyond the decision target, build consensus and relationships among decision makers and their constituents, and give community members a stronger voice in decisions that affect them. Factors that may increase HIA success include care in choosing a project or policy to be examined' selecting an appropriate team to conduct the HIA; engaging stakeholders and decision makers throughout the process; crafting clear, actionable recommendations; delivering timely, compelling messages to appropriate audiences; and using multiple dissemination methods. Challenges to successful HIAs include underestimating the level of effort required, political changes during the conduct of the HIA, accessing relevant local data, engaging vulnerable populations, and following up on recommendations. CONCLUSION: Results of this study suggest HIAs are a useful tool to promote public health because they can influence decisions in nonhealth-related sectors, strengthen cross sector collaborations, and raise awareness of health issues among decision makers. PMID- 25695262 TI - Expression of the platelet-activating factor receptor enhances benzyl isothiocyanate-induced apoptosis in murine and human melanoma cells. AB - Melanoma cells often express platelet-activating factor receptor (PAF-R), which has been demonstrated to increase metastatic behavior. However, the effect of PAF R on the responsiveness of melanoma to naturally occurring cytotoxic agents remains to be elucidated. The present study aimed to determine the relative cytotoxicity and mechanism of benzyl isothiocyanate (BITC), a component of cruciferous vegetables, in melanoma cells expressing PAF-R. To evaluate the importance of PAF-R signaling in melanoma cell growth, PAF-R-negative murine B16F10 cells were transduced with a retrovirus containing the cDNA for PAF-R to generate cells stably expressing PAF-R (B16-PAF-R) or an empty vector (MSCV) to generate PAF-R-deficient B16-MSCV control cells. Activation of PAF-R, using the PAF-R agonist, 1-hexadecyl-2-N-methylcarbamoyl-3-glycerophosphocholine, induced an increase in the proliferation of B16-PAF-R cells compared with the B16-MSCV cells. Reverse transcription quantitative polymerase chain reaction revealed the presence of functional PAF-R in human melanoma SK23MEL cells, but not in SK5MEL cells. The present study investigated the effect of BITC treatments on the survival of murine and human melanoma cells, in the presence or absence of functional PAF-R. The results revealed that treatment with BITC decreased the survival rate of the PAF-R-positive and negative murine and human melanoma cells. However, the expression of PAF-R substantially augmented BITC-mediated cytotoxicity in the PAF-R-positive cells at lower concentrations compared with the PAF-R-negative cells. In order to determine the underlying mechanism, flow cytometric analysis was used, which demonstrated a significant increase in the generation of reactive oxygen species (ROS) in the B16-PAF-R cells compared with the B16-MSCV cells, which enhanced apoptosis by BITC, as measured by increased caspase-3/7 luminescence. Notably, the BITC-mediated decreased cell survival rate, increased ROS and increased apoptosis in the B16-PAF-R cells were significantly attenuated by the antioxidant, vitamin C, indicating ROS involvement. Additionally, the WEB2086 PAF-R antagonist, inhibited the BITC mediated enhancement of apoptosis in the B16-PAF-R cells, indicating a role for PAF-R-signaling in the BITC-mediated effects. These findings indicated that the selectivity of BITC towards PAF-R in melanoma offers a promising chemopreventive agent for PAF-R-positive melanoma treatment. PMID- 25695263 TI - Screening for characteristic microRNAs between pre-invasive and invasive stages of cervical cancer. AB - The aim of the present study was to investigate the characteristic microRNAs (miRNAs) expressed during the pre-invasive and invasive stages of cervical cancer. A gene expression profile (GSE7803) containing 21 invasive squamous cell cervical carcinoma samples, 10 normal squamous cervical epithelium samples and seven high-grade squamous intraepithelial cervical lesion samples, was obtained from the Gene Expression Omnibus. Differentially expressed genes (DEGs) were identified using significance analysis of microarray software, and a Gene Ontology (GO) enrichment analysis was conducted using the Database for Annotation, Visualization and Integrated Discovery. The miRNAs that interacted with the identified DEGs were selected, based on the TarBase v5.0 database. Regulatory networks were constructed from these selected miRNAs along with their corresponding target genes among the DEGs. The regulatory networks were visualized using Cytoscape. A total of 1,160 and 756 DEGs were identified in the pre-invasive and invasive stages of cervical cancer, respectively. The results of the GO enrichment demonstrated that the DEGs were predominantly involved in the immune response and the cell cycle, in the pre-invasive and invasive stages, respectively. Furthermore, a total of 18 and 26 characteristic miRNAs were screened in the pre-invasive and invasive stages, respectively. These miRNAs may be potential biomarkers and targets for the diagnosis and treatment of the different stages of cervical cancer. PMID- 25695264 TI - Experience matters: enrichment remodels synaptic inputs to adult-born neurons. AB - New neurons are continuously integrated into adult hippocampal circuitry and play important roles in cognitive and affective functions. In this issue of Neuron, Bergami et al. (2015) report an experience-dependent remodeling of the afferent connectivity of adult-born dentate granule neurons. PMID- 25695265 TI - Loosening pain's grip by tightening TRPV1-TRPA1 interactions. AB - TRPA1 and TRPV1 are ion channels crucial for pain sensation. In this issue of Neuron, Weng et al. (2015) demonstrate that the activity of TRPA1-TRPV1 heteromers is governed by Tmem100 and that disabling Tmem100 may be a novel pharmacologic strategy to combat pain. PMID- 25695266 TI - Neurons that Remember How We Got There. AB - In this issue of Neuron, Daie et al. (2015) show that the eye velocity-to position neural integrator not only encodes the position, but also how it was reached. Representing content and context in the same neuronal population may form a general coding principle. PMID- 25695268 TI - The outer subventricular zone and primate-specific cortical complexification. AB - Evolutionary expansion and complexification of the primate cerebral cortex are largely linked to the emergence of the outer subventricular zone (OSVZ), a uniquely structured germinal zone that generates the expanded primate supragranular layers. The primate OSVZ departs from rodent germinal zones in that it includes a higher diversity of precursor types, inter-related in bidirectional non-hierarchical lineages. In addition, primate-specific regulatory mechanisms are operating in primate cortical precursors via the occurrence of novel miRNAs. Here, we propose that the origin and evolutionary importance of the OSVZ is related to genetic changes in multiple regulatory loops and that cell-cycle regulation is a favored target for evolutionary adaptation of the cortex. PMID- 25695267 TI - Lysophosphatidic Acid signaling in the nervous system. AB - The brain is composed of many lipids with varied forms that serve not only as structural components but also as essential signaling molecules. Lysophosphatidic acid (LPA) is an important bioactive lipid species that is part of the lysophospholipid (LP) family. LPA is primarily derived from membrane phospholipids and signals through six cognate G protein-coupled receptors (GPCRs), LPA1-6. These receptors are expressed on most cell types within central and peripheral nervous tissues and have been functionally linked to many neural processes and pathways. This Review covers a current understanding of LPA signaling in the nervous system, with particular focus on the relevance of LPA to both physiological and diseased states. PMID- 25695269 TI - Spatiotemporal 16p11.2 protein network implicates cortical late mid-fetal brain development and KCTD13-Cul3-RhoA pathway in psychiatric diseases. AB - The psychiatric disorders autism and schizophrenia have a strong genetic component, and copy number variants (CNVs) are firmly implicated. Recurrent deletions and duplications of chromosome 16p11.2 confer a high risk for both diseases, but the pathways disrupted by this CNV are poorly defined. Here we investigate the dynamics of the 16p11.2 network by integrating physical interactions of 16p11.2 proteins with spatiotemporal gene expression from the developing human brain. We observe profound changes in protein interaction networks throughout different stages of brain development and/or in different brain regions. We identify the late mid-fetal period of cortical development as most critical for establishing the connectivity of 16p11.2 proteins with their co expressed partners. Furthermore, our results suggest that the regulation of the KCTD13-Cul3-RhoA pathway in layer 4 of the inner cortical plate is crucial for controlling brain size and connectivity and that its dysregulation by de novo mutations may be a potential determinant of 16p11.2 CNV deletion and duplication phenotypes. PMID- 25695270 TI - The adhesion GPCR GPR126 has distinct, domain-dependent functions in Schwann cell development mediated by interaction with laminin-211. AB - Myelin ensheathes axons to allow rapid propagation of action potentials and proper nervous system function. In the peripheral nervous system, Schwann cells (SCs) radially sort axons into a 1:1 relationship before wrapping an axonal segment to form myelin. SC myelination requires the adhesion G protein-coupled receptor GPR126, which undergoes autoproteolytic cleavage into an N-terminal fragment (NTF) and a seven-transmembrane-containing C-terminal fragment (CTF). Here we show that GPR126 has domain-specific functions in SC development whereby the NTF is necessary and sufficient for axon sorting, whereas the CTF promotes wrapping through cAMP elevation. These biphasic roles of GPR126 are governed by interactions with Laminin-211, which we define as a novel ligand for GPR126 that modulates receptor signaling via a tethered agonist. Our work suggests a model in which Laminin-211 mediates GPR126-induced cAMP levels to control early and late stages of SC development. PMID- 25695271 TI - Early- and late-born parvalbumin basket cell subpopulations exhibiting distinct regulation and roles in learning. AB - Brain networks can support learning by promoting acquisition of task-relevant information or by adhering to validated rules, but the mechanisms involved are poorly understood. Upon learning, local inhibitory parvalbumin (PV)-expressing Basket cell networks can switch to opposite configurations that either favor or interfere with further learning, but how this opposite plasticity is induced and relates to distinct learning requirements has remained unclear. Here, we show that PV Basket cells consist of hitherto unrecognized subpopulations, with distinct schedules of neurogenesis, input connectivities, output target neurons, and roles in learning. Plasticity of hippocampal early-born PV neurons was recruited in rule consolidation, whereas plasticity of late-born PV neurons was recruited in new information acquisition. This involved regulation of early-born neuron plasticity specifically through excitation, and of late-born neuron plasticity specifically through inhibition. Therefore, opposite learning requirements are implemented by distinct local networks involving PV Basket cell subpopulations specifically regulated through inhibition or excitation. PMID- 25695272 TI - Mycobacterium bovis BCG-associated osteomyelitis/osteitis, Taiwan. PMID- 25695273 TI - Red deer as maintenance host for bovine tuberculosis, Alpine region. AB - To estimate the prevalence of bovine tuberculosis in the Alpine region, we studied the epidemiology of Mycobacterium caprae in wildlife during the 2009-2012 hunting seasons. Free-ranging red deer (Cervus elaphus) were a maintenance host in a hot-spot area, mainly located in Austria. PMID- 25695274 TI - Treatment of Ebola virus infection with antibodies from reconvalescent donors. AB - Clinical evidence suggests that antibodies from reconvalescent donors (persons who have recovered from infection) may be effective in the treatment of Ebola virus infection. Administration of this treatment to Ebola virus-infected patients while preventing the transmission of other pathogenic viruses may be best accomplished by use of virus-inactivated reconvalescent plasma. PMID- 25695275 TI - Correction. AB - [This corrects the article DOI: 10.7224/1537-2073.2012-053.]. PMID- 25695276 TI - Predators and moustaches. PMID- 25695277 TI - Outcomes with gold wire and hydroxyapatite partial ossicular replacement prostheses in type 2 tympanoplasty: a preliminary study. AB - OBJECTIVES: To compare the hearing results and graft take rates of the recently developed gold wire prosthesis with those of the hydroxyapatite partial ossicular replacement prosthesis in patients with chronic otitis media. METHOD: This retrospective study examined patients who underwent type 2 tympanoplasty with a minimum follow up of one year. The study population consisted of 32 patients in the partial ossicular replacement prosthesis group and 26 patients in the gold wire group. The main outcome measures were the graft success rate and level of hearing improvement. Complications and extrusion rates were also noted. RESULTS: The graft take rate was 90.6 per cent for the partial ossicular replacement prosthesis group and 92.3 per cent for the gold wire group (p = 0.848). Pre operatively, there were no significant differences in the air or bone-conduction thresholds between groups. Post-operatively, the mean hearing gain was 18.5 +/- 14.0 dB in the partial ossicular replacement prosthesis group and 16.5 +/- 10.6 dB in the gold wire group (p = 0.555). The mean air-conduction thresholds were 26.6 +/- 12.4 and 32.6 +/- 10.5 dB, respectively (p = 0.027), and the mean bone conduction thresholds were 9.7 +/- 7.0 and 10.4 +/- 6.4 dB, respectively (p = 0.687). CONCLUSION: The success and complication rates provided by the gold wire prosthesis seem comparable to those of the hydroxyapatite partial ossicular replacement prosthesis. PMID- 25695278 TI - Biomechanical strength of glass ionomer cement in incudostapedial rebridging. AB - OBJECTIVE: To study the biomechanical properties of glass ionomer cement used for incudostapedial rebridging. METHODS: Two groups were established based on the size of the gap between the incus and stapes (1.0 mm in group 1 and 2.0 mm in group 2). Glass ionomer cement was applied to the gaps, and compression tests were performed. Maximum force was measured at the fracture point, and was divided by the cross-sectional area to obtain the maximum compressive strength. RESULTS: No significant difference was found in the maximum force for the two groups (p = 0.312). The glass ionomer cement diameter was significantly higher in group 2 than in group 1 (p = 0.006). The maximum compressive strength was significantly higher in group 1 than in group 2 (p = 0.042). CONCLUSION: The fragility of bone cement used in this study was 25.5 per cent higher for a 2 mm gap than for a 1 mm gap. We speculate that the use of bone cement may be safer for the repair of smaller incudostapedial defects. PMID- 25695279 TI - Expression and mutational analysis of Cip/Kip family in early glottic cancer. AB - BACKGROUND: Genetic alteration of cyclin-dependent kinase inhibitors has been associated with carcinogenesis mechanisms in various organs. OBJECTIVE: This study aimed to evaluate the expression and mutational analysis of Cip/Kip family cyclin-dependent kinase inhibitors (p21CIP1/WAF1, p27KIP1 and p57KIP2) in early glottic cancer. METHODS: Expressions of Cip/Kip family and p53 were determined by quantitative reverse transcription polymerase chain reaction and densitometry. For the analysis of p21 inactivation, sequence alteration was assessed using single-strand conformational polymorphism polymerase chain reaction. Additionally, the inactivation mechanism of p27 and p57 were investigated using DNA methylation analysis. RESULTS: Reduced expression of p27 and p57 were detected in all samples, whereas the expression of p21 was incompletely down regulated in 6 of 11 samples. Additionally, single-strand conformational polymorphism polymerase chain reaction analysis showed the p53 mutation at exon 6. Methylation of p27 and p57 was detected by DNA methylation assay. CONCLUSION: Our results suggest that the Cip/Kip family may have a role as a molecular mechanism of carcinogenesis in early glottic cancer. PMID- 25695280 TI - Primary otological manifestations of granulomatosis with polyangiitis: a case series. AB - OBJECTIVES: A primary otological presentation of granulomatosis with polyangiitis is rare. We present four cases of granulomatosis with polyangiitis with different otological manifestations. CASE REPORT: A literature review of granulomatosis with polyangiitis cases presenting to otolaryngologists was undertaken. A case series review of four patients presenting within a 12-month period was also performed. One patient had serous otitis media which worsened after myringotomy. Two patients presented with acute ear infection and facial palsy and one with acute mastoiditis. All were positive for antineutrophilic cytoplasmic antibody, and three had positive findings upon histological analysis. CONCLUSION: When acute supposed ear infections fail to respond to treatment (antibiotics or surgery), rarer causes of the symptoms should be considered. By reporting this case series, we aim to improve the early diagnosis of granulomatosis with polyangiitis to enable timely treatment and prevent systemic involvement. PMID- 25695281 TI - Not just another paediatric neck lump: metastatic cribriform adenocarcinoma of the palate in an adolescent. AB - OBJECTIVE: This paper reports the case of a 13-year-old girl with a 2-year history of left cervical lymph node swelling that was diagnosed as metastatic cribriform adenocarcinoma of the tongue and minor salivary gland. CASE REPORT: A 13-year-old girl with a left, level II cervical lymph node underwent excisional biopsy after an ultrasound suggested suspicious features. The histology indicated polymorphous low-grade adenocarcinoma, and a primary lesion in the left palate was identified. The patient underwent left maxillectomy, neck dissection and reconstruction. Histological analysis of resection specimens led to a revised diagnosis of cribriform adenocarcinoma of the tongue and minor salivary gland. CONCLUSION: Cribriform adenocarcinoma of the tongue and minor salivary gland has recently been described as a separate entity to polymorphous low-grade adenocarcinoma in light of histological and behavioural differences, including higher rates of metastasis at presentation. This is the first report in the world literature of an adolescent with this entity. It is possible that some previous reports of polymorphous low-grade adenocarcinoma in childhood would have been more accurately described as cribriform adenocarcinoma of the tongue and minor salivary gland. PMID- 25695282 TI - Visual loss in patients with sphenoethmoidal cells. AB - BACKGROUND: A sphenoethmoidal cell is a posterior ethmoid cell that pneumatises superiorly and/or laterally to the sphenoid sinus. Disease within such a cell may cause visual symptoms because of the close relationship of the optic nerve. CASE REPORTS: This paper reports four cases of chronic rhinosinusitis involving a sphenoethmoidal cell, two with visual loss. The management of such cases is discussed and the current literature is reviewed. CONCLUSION: Pathology within a sphenoethmoidal cell must be considered in cases of optic neuropathy. The presence of these cells may be relevant even in cases of seemingly uncomplicated rhinosinusitis as they are associated with a higher rate of optic nerve protrusion and dehiscence. PMID- 25695283 TI - Adenovirus-mediated LRIG1 expression enhances the chemosensitivity of bladder cancer cells to cisplatin. AB - Cisplatin (cis-diaminodichloroplatinum, CDDP) is one of the most effective chemotherapeutic agents that has been widely used in the treatment of many malignancies, including muscle invasive bladder cancer. However, development of CDDP resistance in cancer cells is a major obstacle to the effective treatment of bladder cancer. Therefore, the development of chemosensitizers to overcome the acquired resistance to chemotherapeutic agents is crucial. Previous studies have confirmed that the epidermal growth factor receptor (EGFR) and its signaling pathways are important in the chemoresistance of cancer cells against CDDP induced cell apoptosis. In a preliminary study we showed that leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) is the natural ligand of EGFR, and that the extracellular leucine-rich repeat (LRR) domain and immunoglobulin like domains of LRIG1 were able to bind to the extracellular domain of EGFR, resulting in the downregulation of EGFR expression. Based on these findings, we hypothesized that LRIG1 may enhance the chemosensitivity of bladder cancer cells to CDDP. In the present study, LRIG1 was overexpressed by the adenovirus vector to determine the effect of LRIG1 on chemosensitivity in the T24 bladder cancer cell line and explored the possible mechanisms. The results showed that CDDP inhibited the growth of the T24 cell line and induced activation of EGFR. Overexpression of LRIG1 increased the inhibitory effect of CDDP on the T24 cell line, which may be associated with inactivation of the EGFR signaling pathway, followed by the decrease of Bcl-2 expression and a concomitantly induced expression of Bax. Based on these results, we concluded that the upregulation of LRIG1 expression inhibited the EGFR signaling pathway, activated the mitochondrial pathway of apoptosis and eventually increased the sensitivity of bladder cancer cells to CDDP. PMID- 25695284 TI - Continuous exposure of non-small cell lung cancer cells with wild-type EGFR to an inhibitor of EGFR tyrosine kinase induces chemoresistance by activating STAT3. AB - Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have shown promising effects against the growth of non-small cell lung cancer (NSCLC) cells harboring EGFR mutations (EGFR-mts). However, many patients with NSCLC that are accepted for EGFR-TKI treatment followed by chemotherapy possess an unknown EGFR status including wild-type EGFR (EGFR-wt). Little is known about the potential effects of EGFR-TKI treatment prior to chemotherapy. We investigated the effects and underlying molecular events of 4 weeks of continuous exposure to EGFR-TKIs in the EGFR-wt NSCLC line H1299. This treatment dramatically increased the IC50 of several relevant chemotherapeutic agents: cisplatin (DDP) (29.25+/ 6.1 uM for gefitinib, 43.25+/-14.87 uM for erlotinib, and 6.92+/-1.15 uM for parental), paclitaxel (11.16+/-3.36 uM for gefitinib, 9.16+/-1.41 uM for erlotinib, and 2.09+/-0.44 uM for parental), gemcitabine (47.18+/-6.2 uM for gefitinib, 40.36+/-11.1 uM for erlotinib, and 16.00+/-3.38 uM for parental) and pemetrexed (11.78+/-4.07 uM for gefitinib, 15.97+/-7.23 uM for erlotinib, and 4.72+/-1.9 uM for parental). This chemoresistance was critically dependent on the activation of the mediator signal transducer and activator of transcription 3 (STAT3). In cells exposed to EGFR-TKIs for 4 weeks, activation of STAT3 was found to be unrelated to EGFR and to be independent of IL-6 and -22. Treatment with the STAT3 inhibitor NSC 74859 was able to reverse the TKI exposure-induced chemoresistance in EGFR-wt NSCLC cells. Similar phenomena were observed in H1975 cells harboring EGFR L858R and T790M mutations. Based on the observed molecular events following long exposure of an EGFR-wt NSCLC cell line to an EGFR-TKI, this study indicates that such drugs should be not recommended for EGFR-wt patients who can undergo chemotherapy. This study also suggests that STAT3 inhibitors may aid in the treatment NSCLC patients who exhibit EGFR-TKI resistance due to an acquired T790M mutation. PMID- 25695285 TI - Therapeutic Effects of Bone Marrow-Derived Mesenchymal Stem Cells in Models of Pulmonary and Extrapulmonary Acute Lung Injury. AB - Bone marrow-derived mesenchymal stem cells (MSCs) offer a promising therapy for acute lung injury (ALI). However, whether the same MSC treatments possess similar potential for different ALI models is not fully clear. The present study evaluated the distribution and therapeutic effects of intravenous MSC administration for the treatment of intratracheal lipopolysaccharide (LPS) induced intrapulmonary ALI and intravenous LPS/zymosan-induced extrapulmonary ALI, matched with lung injury severity, at 30 min and 1, 3, and 7 days. We found that MSC transplantation attenuated lung injury and inhibited lung inflammation in both ALI models. The benefits of MSCs were more significant in the intrapulmonary ALI mice. In vivo and ex vivo fluorescence imaging showed that MSCs primarily homed into the lung. However, more MSCs were recruited into the lungs of the intrapulmonary ALI mice than those of the extrapulmonary ALI mice over the time course. A few MSCs were also detected in the liver and spleen at days 3 and 7. In addition, the two ALI models showed different extrapulmonary organ dysfunction. A lower percentage of cell apoptosis and SDF-1alpha levels was found in the liver and spleen of the intrapulmonary ALI mice than in those of the extrapulmonary ALI mice. These results suggested that the two ALI models were accompanied with different degrees of extrapulmonary organ damage, which resulted in differences in the trafficking and accumulation of MSCs to the injured lung and consequently accounted for different therapeutic effects of MSCs for lung repair in the two ALI models. These data suggest that intravenous administration of MSCs has a greater potential for the treatment of intrapulmonary ALI than extrapulmonary ALI matched with lung injury severity; these differences were due to more recruitment of MSCs in the lungs of intrapulmonary ALI mice than those of extrapulmonary ALI mice. This finding may contribute to the clinical use of MSCs for the treatment of ALI. PMID- 25695286 TI - Chelating agent-free, vapor-assisted crystallization method to synthesize hierarchical microporous/mesoporous MIL-125 (Ti). AB - Titanium-based microporous heterogeneous catalysts are widely studied but are often limited by the accessibility of reactants to active sites. Metal-organic frameworks (MOFs), such as MIL-125 (Ti), exhibit enhanced surface areas due to their high intrinsic microporosity, but the pore diameters of most microporous MOFs are often too small to allow for the diffusion of larger reactants (>7 A) relevant to petroleum and biomass upgrading. In this work, hierarchical microporous MIL-125 exhibiting significantly enhanced interparticle mesoporosity was synthesized using a chelating-free, vapor-assisted crystallization method. The resulting hierarchical MOF was examined as an active catalyst for the oxidation of dibenzothiophene (DBT) with tert-butyl hydroperoxide and outperformed the solely microporous analogue. This was attributed to greater access of the substrate to surface active sites, as the pores in the microporous analogues were of inadequate size to accommodate DBT. Moreover, thiophene adsorption studies suggested the mesoporous MOF contained larger amounts of unsaturated metal sites that could enhance the observed catalytic activity. PMID- 25695287 TI - Effects of age and unaccustomed resistance exercise on mitochondrial transcript and protein abundance in skeletal muscle of men. AB - Mitochondrial dysfunction may contribute to age-associated muscle atrophy. Previous data has shown that resistance exercise (RE) increases mitochondrial gene expression and enzyme activity in older adults; however, the acute response to RE has not been well characterized. To characterize the acute mitochondrial response to unaccustomed RE, healthy young (21 +/- 3 yr) and older (70 +/- 4 yr) men performed a unilateral RE bout for the knee extensors. Muscle biopsies were taken at rest and 3, 24, and 48 h following leg press and knee extension exercise. The expression of the mitochondrial transcriptional regulator proliferator-activated receptor gamma coactivator 1-alpha (PGC-1alpha) mRNA was increased at 3 h postexercise; however, all other mitochondrial variables decreased over the postexercise period, irrespective of age. ND1, ND4, and citrate synthase (CS) mRNA were all lower at 48 h postexercise, along with specific protein subunits of complex II, III, IV, and ATP synthase. Mitochondrial DNA (mtDNA) copy number decreased by 48 h postexercise, and mtDNA deletions were higher in the older adults and remained unaffected by acute exercise. Elevated mitophagy could not explain the reduction in mitochondrial proteins and DNA, because there was no increase in ubiquitinated voltage-dependent anion channel (VDAC) or its association with PTEN-induced putative kinase 1 (Pink1) or Parkin, and elevated p62 content indicated an impairment or reduction in autophagocytic flux. In conclusion, age did not influence the response of specific mitochondrial transcripts, proteins, and DNA to a bout of RE. PMID- 25695288 TI - High-altitude ancestry and hypoxia acclimation have distinct effects on exercise capacity and muscle phenotype in deer mice. AB - The hypoxic and cold environment at high altitudes requires that small mammals sustain high rates of O2 transport for exercise and thermogenesis while facing a diminished O2 availability. We used laboratory-born and -raised deer mice (Peromyscus maniculatus) from highland and lowland populations to determine the interactive effects of ancestry and hypoxia acclimation on exercise performance. Maximal O2consumption (Vo(2max)) during exercise in hypoxia increased after hypoxia acclimation (equivalent to the hypoxia at ~4,300 m elevation for 6-8 wk) and was consistently greater in highlanders than in lowlanders. Vo(2max) during exercise in normoxia was not affected by ancestry or acclimation. Highlanders also had consistently greater capillarity, oxidative fiber density, and maximal activities of oxidative enzymes (cytochrome c oxidase and citrate synthase) in the gastrocnemius muscle, lower lactate dehydrogenase activity in the gastrocnemius, and greater cytochrome c oxidase activity in the diaphragm. Hypoxia acclimation did not affect any of these muscle traits. The unique gastrocnemius phenotype of highlanders was associated with higher mRNA and protein abundances of peroxisome proliferator-activated receptor gamma (PPARgamma). Vascular endothelial growth factor (VEGFA) transcript abundance was lower in highlanders, and hypoxia acclimation reduced the expression of numerous genes that regulate angiogenesis and energy metabolism, in contrast to the observed population differences in muscle phenotype. Lowlanders exhibited greater increases in blood hemoglobin content, hematocrit, and wet lung mass (but not dry lung mass) than highlanders after hypoxia acclimation. Genotypic adaptation to high altitude, therefore, improves exercise performance in hypoxia by mechanisms that are at least partially distinct from those underlying hypoxia acclimation. PMID- 25695290 TI - Opposite effects of hyperoxia on mitochondrial and contractile efficiency in human quadriceps muscles. AB - Exercise efficiency is an important determinant of exercise capacity. However, little is known about the physiological factors that can modulate muscle efficiency during exercise. We examined whether improved O2 availability would 1) impair mitochondrial efficiency and shift the energy production toward aerobic ATP synthesis and 2) reduce the ATP cost of dynamic contraction owing to an improved neuromuscular efficiency, such that 3) whole body O2 cost would remain unchanged. We used (31)P-magnetic resonance spectroscopy, surface electromyography, and pulmonary O2 consumption (Vo2p) measurements in eight active subjects during 6 min of dynamic knee-extension exercise under different fractions of inspired O2 (FiO2 , 0.21 in normoxia and 1.0 in hyperoxia). Vo2p (755 +/- 111 ml/min in normoxia and 799 +/- 188 ml/min in hyperoxia, P > 0.05) and O2 cost (P > 0.05) were not significantly different between normoxia and hyperoxia. In contrast, the total ATP synthesis rate and the ATP cost of dynamic contraction were significantly lower in hyperoxia than normoxia (P < 0.05). As a result, the ratio of the rate of oxidative ATP synthesis from the quadriceps to Vo2p was lower in hyperoxia than normoxia but did not reach statistical significance (16 +/- 3 mM/ml in normoxia and 12 +/- 5 mM/ml in hyperoxia, P = 0.07). Together, these findings reveal dynamic and independent regulations of mitochondrial and contractile efficiency as a consequence of O2 availability in young active individuals. Furthermore, muscle efficiency appears to be already optimized in normoxia and is unlikely to contribute to the well-established improvement in exercise capacity induced by hyperoxia. PMID- 25695289 TI - Roles for the sympathetic nervous system, renal nerves, and CNS melanocortin-4 receptor in the elevated blood pressure in hyperandrogenemic female rats. AB - Women with polycystic ovary syndrome (PCOS) have hyperandrogenemia and increased prevalence of risk factors for cardiovascular disease, including elevated blood pressure. We recently characterized a hyperandrogenemic female rat (HAF) model of PCOS [chronic dihydrotestosterone (DHT) beginning at 4 wk of age] that exhibits similar characteristics as women with PCOS. In the present studies we tested the hypotheses that the elevated blood pressure in HAF rats is mediated in part by sympathetic activation, renal nerves, and melanocortin-4 receptor (MC4R) activation. Adrenergic blockade with terazosin and propranolol or renal denervation reduced mean arterial pressure (MAP by telemetry) in HAF rats but not controls. Hypothalamic MC4R expression was higher in HAF rats than controls, and central nervous system MC4R antagonism with SHU-9119 (1 nmol/h icv) reduced MAP in HAF rats. Taking a genetic approach, MC4R null and wild-type (WT) female rats were treated with DHT or placebo from 5 to 16 wk of age. MC4R null rats were obese and had higher MAP than WT control rats, and while DHT increased MAP in WT controls, DHT failed to further increase MAP in MC4R null rats. These data suggest that increases in MAP with chronic hyperandrogenemia in female rats are due, in part, to activation of the sympathetic nervous system, renal nerves, and MC4R and may provide novel insights into the mechanisms responsible for hypertension in women with hyperandrogenemia such as PCOS. PMID- 25695291 TI - Glycemic state regulates melanocortin, but not nesfatin-1, responsiveness of glucose-sensing neurons in the nucleus of the solitary tract. AB - The nucleus of the solitary tract (NTS) is a medullary integrative center with critical roles in the coordinated control of energy homeostasis. Here, we used whole cell current-clamp recordings on rat NTS neurons in slice preparation to identify the presence of physiologically relevant glucose-sensing neurons. The majority of NTS neurons (n = 81) were found to be glucose-responsive, with 35% exhibiting a glucose-excited (GE) phenotype (mean absolute change in membrane potential: 9.5 +/- 1.1 mV), and 21% exhibiting a glucose-inhibited (GI) response (mean: 6.3 +/- 0.7 mV). Furthermore, we found glucose-responsive cells are preferentially influenced by the anorexigenic peptide alpha-melanocyte stimulating hormone (alpha-MSH), but not nesfatin-1. Accordingly, alterations in glycemic state have profound effects on the responsiveness of NTS neurons to alpha-MSH, but not to nesfatin-1. Indeed, NTS neurons showed increasing responsiveness to alpha-MSH as extracellular glucose concentrations were decreased, and in hypoglycemic conditions, all NTS neurons were depolarized by alpha-MSH (mean 10.6 +/- 3.2 mV; n = 8). Finally, decreasing levels of extracellular glucose correlated with a significant hyperpolarization of the baseline membrane potential of NTS neurons, highlighting the modulatory effect of glucose on the baseline excitability of cells in this region. Our findings reveal individual NTS cells are capable of integrating multiple sources of metabolically relevant inputs, highlight the rapid capacity for plasticity in medullary melanocortin circuits, and emphasize the critical importance of physiological recording conditions for electrophysiological studies pertaining to the central control of energy homeostasis. PMID- 25695292 TI - [The use of genetic testing by Internet]. PMID- 25695293 TI - [Vicissitudes of hepatitis C in Mexico]. PMID- 25695294 TI - [Prevalence of restless legs syndrome in 69,830 Mexican women]. AB - OBJECTIVE: To determine the prevalence of restless legs syndrome (RLS) in a group of Mexican women. MATERIAL AND METHODS: In 2011 a sample 69,830 Mexican women participating in a longitudinal study answered a questionnaire addressing the minimal diagnostic criteria for RLS. RESULTS: RLS prevalence was 15.6% and mean age 44.4 years (+/- 7.4). The prevalence among women < 30 years was 7.7% and among those >= 60 years 17.9%. Despite 54.5% of cases reporting high frequency of symptoms only 18.1% received treatment. CONCLUSIONS: RLS may affect a large, previously unrecognized proportion of the Mexican population. PMID- 25695295 TI - [Impact of eradication of Pseudomonas aeruginosa on survival in Mexican patients with cystic fibrosis]. AB - INTRODUCTION: Patients with cystic fibrosis (CF) present lower airway infection with Pseudomonas aeruginosa. Treatment of initial infection is fundamental to reduce subsequent damage. MATERIAL AND METHODS: We evaluated the efficacy of eradication treatment of P. aeruginosa in patients with CF from northeast Mexico using two protocols: inhaled colistin/oral ciprofloxacin and nebulized tobramycin 300 mg/oral ciprofloxacin. The intervention group included 17 patients with CF and recent infection with P. aeruginosa. The control group consisted of 23 chronically colonized patients of comparable age. RESULTS: Patients received 27 courses of eradication treatment. P. aeruginosa was eradicated in 21/27 (77.77%). The infection free period was 16.9, 11.7 months (colistin) and 17 +/- 9.7 months (tobramycin) with no statistically significant difference (P = 0.97). CONCLUSIONS: Treated patients maintained normal lung function, better nutritional status, and a better chest X-ray score. In the control group 17/23 (73.9%) patients died with no deaths in the study group. PMID- 25695296 TI - Poor performance of the total kappa/lambda light chain quantification in the diagnosis and follow-up of patients with multiple myeloma. AB - BACKGROUND: The gold standard for paraproteinemia screening in plasma cell disorders has been serum protein electro- phoresis (SPE) with immunofixation electrophoresis (IFx); serum total and free light chain quantifications have also been used. OBJECTIVE: To define the role of SPE, IFx and serum total light chain (sLC) determinations in patients with multiple myeloma (MM), both at diagnosis and at maximum response during treatment follow-up. MATERIAL AND METHODS: These serological studies were performed in a group of 62 patients with MM at diagnosis, and in a subset of 29 patients at the point of maximum response to treatment. RESULTS: At diagnosis, we found an abnormal SPE in 58%, an abnormal IFx in 92% and an abnormal sLC in 45% of the 62 patients; 64% had simultaneously abnormal results in all three serological studies. IFx alone proved to be the most sensitive of all three assays, followed by SPE, which was redundant in most instances with sLC and IFx. At maximum response, the abnormal SPE normalized in 7 cases, the abnormal IFx in 7 cases and the abnormal sLC in 7 cases. There were 12 instances in which an abnormal IFx was found despite normal sLC, and one case in which a normal IFx was found in the presence of abnormal sLC. The association between IFx and sLC was highly significant (r = 0.9274611, p < 0.000001), despite instances where a positive result for IFx was associated to a normal sLC. CONCLUSION: All three serological methods should ideally be simultaneously performed in patients with MM both at diagnosis and throughout therapy. In this series, the total sLC assay was not more sensitive than IFx neither at diagnosis nor during follow-up. PMID- 25695297 TI - [Pilot study: Wrist digital sphygmomanometers as an alternative for noninvasive blood pressure measurement in pediatric population]. AB - In current clinical practice, the mercury sphygmomanometer (MS) is being replaced by alternatives as aneroid sphygmomanometer and semiautomatic and automatic-type digital sphygmomanometers (DS). However, a validated DS in adults may not be appropriate for use in the pediatric population, particularly for wrist-type devices. A pilot study was conducted to determine if wrist DS can replace the MS for clinical use in children population. Measuring blood pressure for pediatric patients with wrist diameter greater 13.5 cm was made. The correlation between wrist DS and mercurial device was evaluated and compared by Bland-Altman. The flexible-bracelet wrist DS (CH-656C) showed discrepancies in the mean +/- standard deviation differences from 2.6 +/- 5.5 to 5.8 +/- 6.2 mmHg compared to the mercury device, while the rigid-wrist DS (CH-607) showed variations from 3.9 +/- 5.2 to 11.4 +/- 7.6 mmHg compared to the MS. For some cases, the agreement was not presented because the results are above the criteria of the American Association for Advancement Medical Instrumentation. This study revealed that the discrepancy of the results is so high for both digital devices, which makes it impossible suggest that any of them can replace the MS. Therefore, it is recommended that hospitals should ensure validation in the pediatric population before the wrist DS is used, particularly when it is utilized for diagnosis in children under 11 years. PMID- 25695298 TI - [Optical coherence tomography and visual evoked potentials in patients with type 2 diabetes with and without retinopathy: preliminary report]. AB - INTRODUCTION: Diabetic retinopathy remains the leading visual complication of diabetes mellitus type 2 (DM2) in productive patients. It evolves from a non proliferative stage, occasionally asymptomatic, until a proliferative phase with neovascularization, retinal detachment and blindness. There are many reports that compare visual, biochemical or electrophysiological parameters among diabetic patients and healthy controls. However, much less information has been published comparing parameters between diabetics with and without non-proliferative retinopathy. Thus, it is essential to know what changes take place in the retina and the visual post retinal pathway as the disease progresses, but before the establishment of a proliferative process involving blindness. Therefore, the purpose of this study was to compare and correlate electrophysiological and visual parameters of diabetics with and without non-proliferative retinopathy, using modern, non invasive techniques. These data will allow us to a better understanding of the process and to determine the use of these parameters in the monitoring of diabetes and its complications. MATERIAL AND METHODS: This is an observational, prospective, transversal and analytical study. Twenty-two patients with DM2 were divided into two groups (50% on each group): group with non proliferative retinopathy and group without retinopathy. We measured the central fovea thickness (CFT) by optical coherence tomography, the P100 wave of the Visual Evoked Potentials (VEP) and other visual and biochemical parameters. RESULTS: Retinopathy patients had lower visual acuity (p < 0.047), lower P100 amplitude (p < 0.043) and lower rate of rise (p < 0.026, 1-tailed). They also showed a more biochemical disturbance with higher glycemia (p < 0.015) and HbA1c (p < 0.033), and longer disease duration (p < 0.011), compared with those without retinopathy. Visual acuity showed a negative correlation with disease duration (r = -0.65; p < 0.017) and severity of ocular damage (r = -0.76; p < 0.007) in patients with retinopathy. CONCLUSIONS: Patients with retinopathy have lower visual acuity, decreased central visual fibers and a tendency to increase the ECF. Although the data favor the use of these non-invasive techniques to monitor the disease and prevent progression of visual complications, additional studies are needed with larger sample size to confirm the results obtained here. PMID- 25695299 TI - [Evaluation of dental treatment impact in a northwestern Mexican school children population]. AB - OBJECTIVE: To evaluate through functional teeth index, the impact in schoolchildren in communities with and without dental community support. MATERIAL AND METHODS: A cross-sectional study was carried out in communities with dental care provided by dental clinics of Sinaloa State University. The study sample was 2,083 schoolchildren. We used the criteria proposed by WHO for the index of decayed, missing-teeth (DMFT) for permanent dentition, index for prima- ry teeth (dmft) and the rate of functional teeth (RFT). For bivariate analysis, the nonparametric tests Pearson f and Mann-Whitney U were used. RESULTS: The comparisons of DMFT (0.20) and RFT (13.95) of children with and DMFT (0.43) and RFT (14.82) of children without community dental support showed statistical significant difference (p < 0.05). There was a statistically significant difference in DMFT and RFT between samples with and without community dental support (p < 0.05). The age showed a statistically significant difference between the DMFT and dmft (p < 0.05). Primary dentition required more dental care than permanent dentition. There was access for dental treatment, but it is not used for the population. CONCLUSIONS: The RFT provided precise information than DMFT, mainly due to register the changes of actions focused to recover the teeth function in the oral cavity. PMID- 25695300 TI - [Carbamazepine produces changes in the auditory pathway of Wistar rats]. AB - BACKGROUND: Different results have been reported by various authors in studies regarding the impact of the (carbamazepine) CBZ on the auditory evoked responses. OBJECTIVE: To evaluate the changes in auditory pathway at different sound intensities with CBZ at doses 30 mg/kg, in latencies and interpeak-interval brainstem auditory evoked potentials (BAEPs) in Wistar rats. MATERIAL AND METHODS: Twenty adult male Wistar rats (body weight mean, 280-300 g) were used as subjects in this study. BAEPs elicited by stimulus of (30, 50 and 70 dB nHL) intensity and BAEP were obtained with and without CBZ treatment. RESULTS: Peak latencies of BAEPs, between groups were different, in the group with CBZ peak latencies were delaying, but we compared interpeak-intervals between groups and we found significative differences in III-V and I-V at 70 dB nHL intensity. CONCLUSIONS: Our results suggest that CBZ modifies BAEPs interpeak-intervals at 70 dB, and latencies since they were delayed. Alterations in the generators of the later waves of BAEPs underlie, AED produced changes in hearing sensitivity with a single no toxic doses. Probably CBZ causes changes in endolymphatic ion composition in the rat inner ear, provoking that latency of BAEPs were delaying, but this requires further studies. PMID- 25695301 TI - [Pioglitazone hydrochloride a instrumental analytical perspective by Raman spectroscopy and HPLC]. AB - INTRODUCTION: The thiazolidinediones (pioglitazone) increases the action of insulin and produces the glycemic control in the patients with type 2 diabetes mellitus. Also, the pharmacological effect may be affected by the purity and pioglitazone plasma concentration. Therefore, the instrumental techniques offer a tool for characterization, identification and/or quantification of the pioglitazone; Raman spectroscopy offers several advantages due to its easy application methodology and structural analysis and the HPLC technique is the gold standard vs. other qualitative and quantitative techniques. OBJECTIVE: The aim of this work is to develop and validate analytical techniques for the characterization of pioglitazone hydrochloride by Raman spectroscopy and quantitative analysis in human plasma by HPLC. MATERIAL AND METHODS: The pioglitazone hydrochloride was analyzed by Raman spectroscopy with a 678 mW power and 3 integration time seconds. The analytical method for quantification by HPLC was validated with the guidelines of the NOM-177SSAl-1998. RESULTS: The Raman technique allowed us to elucidate the functional groups of the pioglitazone hydrochloride and the HPLC technique was linear, accurate, precise, specific and sensitive in the range of 30 to 2000 ng/mL under the chromatographic conditions specified. CONCLUSIONS: The structure analysis by Raman spectroscopy allowed us a complete characterization of the functional groups of pioglitazone hydrochloride effectively and non-destructively. Likewise, the analytical technique for the pioglitazone hydrochloride quantification by HPLC was linear, accurate, precise and sensitive in the range of 30 to 2000 ng/mL under the guidelines. PMID- 25695302 TI - [Cellular restriction factors that inhibit human immunodeficiency virus replication: new strategies in antiretroviral therapy]. AB - Human immunodeficiency virus requires receptors and cellular factors in target cells in order to complete a successful replication. Conversely, host cells express different proteins like TRIM5a, Tetherin BST-2, as well as cytidine deaminase proteins (APOBEC3) to suppress viral replication. These proteins, known as cellular restriction factors, provide an initial defense against infection as components of the innate immune response. The best characterized restriction factor is the cytidine deaminase APOBEC3G that has been shown to have an important role in HIV pathogenesis. Here, we review the current knowledge of host restriction factors, focusing on APOBEC3G, and possible therapeutic strategies against HIV infection. PMID- 25695303 TI - [Causes of insufficient effectiveness of diabetes treatment at primary care units, of the Instituto Mexicano del Seguro Social (IMSS)]. PMID- 25695304 TI - Detection and Identification of the Keto-Hydroperoxide (HOOCH2OCHO) and Other Intermediates during Low-Temperature Oxidation of Dimethyl Ether. AB - In this paper we report the detection and identification of the keto hydroperoxide (hydroperoxymethyl formate, HPMF, HOOCH2OCHO) and other partially oxidized intermediate species arising from the low-temperature (540 K) oxidation of dimethyl ether (DME). These observations were made possible by coupling a jet stirred reactor with molecular-beam sampling capabilities, operated near atmospheric pressure, to a reflectron time-of-flight mass spectrometer that employs single-photon ionization via tunable synchrotron-generated vacuum ultraviolet radiation. On the basis of experimentally observed ionization thresholds and fragmentation appearance energies, interpreted with the aid of ab initio calculations, we have identified HPMF and its conceivable decomposition products HC(O)O(O)CH (formic acid anhydride), HC(O)OOH (performic acid), and HOC(O)OH (carbonic acid). Other intermediates that were detected and identified include HC(O)OCH3 (methyl formate), cycl-CH2-O-CH2-O- (1,3-dioxetane), CH3OOH (methyl hydroperoxide), HC(O)OH (formic acid), and H2O2 (hydrogen peroxide). We show that the theoretical characterization of multiple conformeric structures of some intermediates is required when interpreting the experimentally observed ionization thresholds, and a simple method is presented for estimating the importance of multiple conformers at the estimated temperature (~100 K) of the present molecular beam. We also discuss possible formation pathways of the detected species: for example, supported by potential energy surface calculations, we show that performic acid may be a minor channel of the O2 + CH2OCH2OOH reaction, resulting from the decomposition of the HOOCH2OCHOOH intermediate, which predominantly leads to the HPMF. PMID- 25695305 TI - Dihydroquinoline Carbamate Derivatives as "Bio-oxidizable" Prodrugs for Brain Delivery of Acetylcholinesterase Inhibitors: [11C] Radiosynthesis and Biological Evaluation. AB - With the aim of improving the efficiency of marketed acetylcholinesterase (AChE) inhibitors in the symptomatic treatment of Alzheimer's disease, plagued by adverse effects arising from peripheral cholinergic activation, this work reports a biological evaluation of new central AChE inhibitors based on an original "bio oxidizable" prodrug strategy. After peripheral injection of the prodrug 1a [IC50 > 1 mM (hAChE)] in mice, monitoring markers of central and peripheral cholinergic activation provided in vivo proof-of-concept for brain delivery of the drug 2a [IC50 = 20 nM (hAChE)] through central redox activation of 1a. Interestingly, peripheral cholinergic activation has been shown to be limited in time, likely due to the presence of a permanent positive charge in 2a promoting rapid elimination of the AChE inhibitor from the circulation of mice. To support these assumptions, the radiosynthesis with carbon-11 of prodrug 1a was developed for additional ex vivo studies in rats. Whole-body biodistribution of radioactivity revealed high accumulation in excretory organs along with moderate but rapid brain uptake. Radio-HPLC analyses of brain samples confirm rapid CNS penetration of [(11)C]1a, while identification of [(11)C]2a and [(11)C]3a both accounts for central redox activation of 1a and pseudoirreversible inhibition of AChE, respectively. Finally, Caco-2 permeability assays predicted metabolite 3a as a substrate for efflux transporters (P-gp inter alia), suggesting that metabolite 3a might possibly be actively transported out of the brain. Overall, a large body of evidence from in vivo and ex vivo studies on small animals has been collected to validate this "bio-oxidizable" prodrug approach, emerging as a very promising strategy in the rational design of selective central AChE inhibitors. PMID- 25695306 TI - Erratum: A reference bacterial genome dataset generated on the MinION(TM) portable single-molecule nanopore sequencer. AB - [This corrects the article DOI: 10.1186/2047-217X-3-22.]. PMID- 25695307 TI - Effects of CO2 and seawater acidification on the early stages of Saccharina japonica development. AB - In this paper, we demonstrated that ocean acidification (OA) had significant negative effects on the microscopic development of Saccharina japonica in a short term exposure experiment under a range of light conditions. Under elevated CO2, the alga showed a significant reduction in meiospore germination, fecundity, and reproductive success. Larger female and male gametophytes were noted to occur under high CO2 conditions and high light magnified these positive effects. Under conditions of low light combined with high PCO2, the differentiation of gametophytes was delayed until the end of the experiment. In contrast, gametophytes were able to survive after having been subjected to a long-term acclimation period, of 105 days. Although the elevated PCO2 resulted in a significant increase in sporophyte length, the biomass abundance (expressed as individual density attached to the seed fiber) was reduced significantly. Further stress resistance experiments showed that, although the acidified samples had lower resistance to high light and high temperature conditions, they displayed higher acclimation to CO2-saturated seawater conditions compared with the control groups. These combined results indicate that OA has a severe negative effect on S. japonica, which may result in future shifts in species dominance and community structure. PMID- 25695308 TI - Efficacy of continuous catheter analgesia of the sciatic nerve after total knee arthroplasty. AB - PURPOSE: This study investigated and compared the outcomes after continuous femoral nerve block alone, continuous femoral nerve analgesia combined with single-shot sciatic nerve analgesia, and continuous femoral and sciatic nerve analgesia in patients with total knee replacement. METHODS: The retrospective study evaluated three groups: continuous femoral nerve analgesia alone, continuous femoral nerve analgesia combined with single-shot sciatic nerve analgesia and continuous femoral nerve analgesia combined with continuous sciatic nerve analgesia. All patients had a hemi- or total knee arthroplasty (TKA), which were performed by a single surgeon. The postoperative analgesia was managed by the same team. A total of 362 patient charts were evaluated from the years 2005 2012. Pain scored with a visual analogue scale (VAS) was recorded 8 hours and 24 hours postoperatively on a standardised form. The amount of opioids required with and without additional sciatic nerve analgesia was documented by monitoring the VAS. RESULTS: Overall, 364 patient files could be assessed. The VAS scores after 8 and 24 hours of patients with an additional continuous sciatic nerve catheter were lower (mean values 1.8 and 4.0, respectively) than those of patients with a continuous femoral catheter alone (mean values 2.7 and 4.9). After 8 and 24 hours, patients with a continuous sciatic nerve catheter had lower VAS scores than those with additional single-shot sciatic nerve anaesthesia (mean values 1.9 and 4.5). Pethidine consumption in the continuous sciatic nerve catheter group was lower (32% of patients) as compared with the two other groups (65%). The side effects of opioids per group consequently were also lower: 24% patients with side effects in the continuous sciatic nerve block group, 52% in the additional single shot sciatic nerve group, 44% in the femoral nerve block group. CONCLUSION: On the basis of these results, which correspond well to other studies of a topic that is under discussion in the literature, we adapted our postoperative pain regimen to continuous sciatic and femoral nerve analgesia for at least 24 hours after hemi- and total knee replacement. PMID- 25695309 TI - Copper-catalyzed [3 + 2] cycloaddition/oxidation reactions between nitro-olefins and organic azides: highly regioselective synthesis of NO2-substituted 1,2,3 triazoles. AB - A new copper-catalyzed [3 + 2] cycloaddition/oxidation reaction of nitro-olefins with organic azides has been developed to afford 1,4(-NO2),5-trisubstituted 1,2,3 triazoles. This reaction sequence has a broad substrate scope and affords NO2 substituted 1,2,3-triazoles with high regioselectivities and in good to excellent yields. The involved oxidative process overcomes the elimination of HNO2 for general cycloaddition of nitro-olefins with organic azides, which shows a high atom economy and potential applications. PMID- 25695310 TI - Templated repair of long bone defects in rats with bioactive spiral-wrapped electrospun amphiphilic polymer/hydroxyapatite scaffolds. AB - Effective repair of critical-size long bone defects presents a significant clinical challenge. Electrospun scaffolds can be exploited to deliver protein therapeutics and progenitor cells, but their standalone application for long bone repair has not been explored. We have previously shown that electrospun composites of amphiphilic poly(d,l-lactic acid)-co-poly(ethylene glycol)-co poly(d,l-lactic acid) (PELA) and hydroxyapatite (HA) guide the osteogenic differentiation of bone marrow stromal cells (MSCs), making these scaffolds uniquely suited for evaluating cell-based bone regeneration approaches. Here we examine whether the in vitro bioactivity of these electrospun scaffolds can be exploited for long bone defect repair, either through the participation of exogenous MSCs or through the activation of endogenous cells by a low dose of recombinant human bone morphogenetic protein-2 (rhBMP-2). In critical-size rat femoral segmental defects, spiral-wrapped electrospun HA-PELA with preseeded MSCs resulted in laminated endochondral ossification templated by the scaffold across the longitudinal span of the defect. Using GFP labeling, we confirmed that the exogenous MSCs adhered to HA-PELA survived at least 7 days postimplantation, suggesting direct participation of these exogenous cells in templated bone formation. When loaded with 500 ng of rhBMP-2, HA-PELA spirals led to more robust but less clearly templated bone formation than MSC-bearing scaffolds. Both treatment groups resulted in new bone bridging over the majority of the defect by 12 weeks. This study is the first demonstration of a standalone bioactive electrospun scaffold for templated bone formation in critical-size long bone defects. PMID- 25695311 TI - Comparison of porcine epidemic diarrhea viruses from Germany and the United States, 2014. AB - Since 2013, highly virulent porcine epidemic diarrhea virus has caused considerable economic losses in the United States. To determine the relation of US strains to those recently causing disease in Germany, we compared genomes and found that the strain from Germany is closely related to variants in the United States. PMID- 25695312 TI - Concerted proton-electron transfer in electrocatalytic O2 reduction by iron porphyrin complexes: axial ligands tuning H/D isotope effect. AB - The electrochemical O2 reduction by thiolate- and imidazole-bound iron porphyrin complexes and H/D isotope effects on 4e(-) (determined by rotating disc electrochemistry) and 2e(-) (determined by rotating ring disc electrochemistry) O2 reduction rates are investigated. The results indicate that a thiolate axial ligand shows an H/D isotope effect greater than 18 and 47 for the 4e(-) and 2e(-) O2 reductions, respectively. Alternatively, an imidazole axial ligand results in H/D isotope effects of 1.04 and 4.7 for the 4e(-) and 2e(-) O2 reduction, respectively. The catalytic O2 reduction mechanism is investigated in situ with resonance Raman coupled with rotating disc electrochemistry. The data indicate that the rate-determining step changes from O-O bond heterolysis of Fe(III)-OOH species for a thiolate axial ligand to an O-O bond heterolysis of an Fe(II)-OOH for an imidazole axial ligand. PMID- 25695313 TI - History of oocyte and embryo metabolism. AB - The basic pattern of metabolism in mammalian oocytes and early embryos was established in the 1960s and 1970s, largely in terms of the consumption of oxygen and the utilisation of nutrients present in culture media at the time, mainly glucose, pyruvate and lactate. The potential importance of endogenous fuels was also recognised but was largely ignored, only to be rediscovered quite recently. The 1980s and 1990s saw the arrival of a 'new generation' of culture media, characterised metabolically by the addition of amino acids, an initiative driven strongly by the need to improve embryo culture and selection methods in assisted reproductive technologies. This trend has continued alongside some basic metabolic studies and the general recognition of the importance of metabolism in all aspects of biology. A framework for future studies on oocyte and early embryo metabolism has been provided by: (1) the developmental origins of health and disease concept and recognition of the relationship between development, epigenetics and metabolism; (2) the need to understand cell signalling within, and between the cells of, the early embryo; and (3) the importance of identifying the mechanisms underlying dialogue between the oocyte and early embryo and the female reproductive tract. PMID- 25695314 TI - Development of a reversibly switchable fluorescent protein for super-resolution optical fluctuation imaging (SOFI). AB - Reversibly switchable fluorescent proteins (RSFPs) can be effectively used for super-resolution optical fluctuation imaging (SOFI) based on the switching and fluctuation of single molecules. Several properties of RSFPs strongly influence the quality of SOFI images. These properties include (i) the averaged fluorescence intensity in the fluctuation state, (ii) the on/off contrast ratio, (iii) the photostability, and (iv) the oligomerization tendency. The first three properties determine the fluctuation range of the imaged pixels and the SOFI signal, which are of essential importance to the spatial resolution, and the last may lead to artificial aggregation of target proteins. The RSFPs that are currently used for SOFI are low in averaged fluorescence intensity in the fluctuation state, photostability, and on/off contrast ratio, thereby limiting the range of application of SOFI in biological super-resolution imaging. In this study, we developed a novel monomeric green RSFP termed Skylan-S, which features very high photostability, contrast ratio, and averaged fluorescence intensity in the fluctuation state. Taking advantage of the excellent optical properties of Skylan-S, a 4-fold improvement in the fluctuation range of the imaged pixels and higher SOFI resolution can be obtained compared with Dronpa. Furthermore, super resolution imaging of the actin or tubulin structures and clathrin-coated pits (CCPs) in living U2OS cells labeled with Skylan-S was demonstrated using the SOFI technique. Overall, Skylan-S developed with outstanding photochemical properties is promising for long-time SOFI imaging with high spatial-temporal resolution. PMID- 25695315 TI - Development of a novel class of tubulin inhibitor from desmosdumotin B with a hydroxylated bicyclic B-ring. AB - A series of newly synthesized hydroxylated analogues of triethyldesmosdumotin B (TEDB) with a bicyclic B-ring exhibited a significantly different mode of action for affecting microtubule dynamics and spindle formation but had the same antiproliferative activity spectrum, including activity against multidrug resistant tumors. These analogues efficiently induced cell cycle arrest at prometaphase and caused formation of immature multipolar spindles. 6'-Hydroxyl TEDB-TB (8) disrupted bipolar spindle formation but had a negligible effect on interphase microtubules. On the basis of the predicted binding modes of the new compounds with tubulin dimer, compound 4 forms three hydrogen bonds (H-bonds) only with alpha-tubulin at the colchicine site; in contrast, 8 forms H-bonds with both alpha- and beta-tubulin. We predict that, when a compound/ligand, such as 8, forms H-bonds to both alpha- and beta-tubulins, spindle formation is disrupted more than the dynamics of interphase microtubules. This result may reflect the well-known greater dynamicity of spindle microtubules as compared with interphase microtubules. PMID- 25695316 TI - Synthesis of substituted resorcinol monomethyl ethers from 2-bromo-3 methoxycyclohex-2-en-1-ones. AB - 2-Bromo-3-methoxycyclohex-2-en-1-ones are readily alkylated at C-6 with reactive halides, and then treatment with DBU (2 equiv) in PhMe at room temperature results in smooth loss of bromide and aromatization to resorcinol monomethyl ethers of defined substitution pattern. PMID- 25695317 TI - Update on progress in selected public health programs after the 2010 earthquake and cholera epidemic--Haiti, 2014. AB - On January 12, 2010, an earthquake devastated Haiti's infrastructure, killing an estimated 230,000 persons and displacing more than 1.5 million. Ten months later, Haiti experienced the beginning of the largest cholera epidemic ever reported in a single country. Immediately after the earthquake and at the start of the cholera epidemic, health priorities in Haiti included improvement of surveillance and laboratory capacity for addressing public health threats in the general population and targeted surveillance and provision of improved water and sanitation in camps for internally displaced persons. As part of a multi-sector, post-earthquake response in collaboration with the Government of Haiti and others, CDC focused on supporting the recovery, expansion, or establishment of several key health programs. This update reports progress in selected health programs, services, and systems in Haiti as of the end of 2014. PMID- 25695318 TI - Hypothermia-related deaths--Wisconsin, 2014, and United States, 2003-2013. AB - Hypothermia is defined as a core body temperature of <95 degrees F (<35 degrees C) and is caused by environmental exposure, drug intoxication, or metabolic or nervous system dysfunction. Exposure to cold is a leading cause of weather related mortality and is responsible for approximately twice the number of deaths annually as exposure to heat in the United States. To understand the risk factors for hypothermia-related death and improve prevention efforts, during January 1 April 30, 2014, a period of record low temperatures, the Wisconsin Division of Public Health began active surveillance for hypothermia. Suspected hypothermia related deaths were reported by coroners or medical examiners and identified in death records. Hypothermia was confirmed as the cause of death by review of death investigation narratives. This report describes three selected cases of hypothermia-related deaths in Wisconsin and summarizes characteristics of all cases that occurred in the state during the period of active surveillance. A summary of hypothermia-related deaths for the United States during 2003-2013 also is presented for comparison and to assess national mortality trends. Hypothermia continues to be an important cause of weather-related death. Key risk factors include drug intoxication, mental illness, and social isolation. State and local health agencies might need to focus outreach on vulnerable populations and target interventions for groups at highest risk for death. PMID- 25695319 TI - Outbreak of Salmonella Newport infections linked to cucumbers--United States, 2014. AB - In August 2014, PulseNet, the national molecular subtyping network for foodborne disease surveillance, detected a multistate cluster of Salmonella enterica serotype Newport infections with an indistinguishable pulse-field gel electrophoresis (PFGE) pattern (XbaI PFGE pattern JJPX01.0061). Outbreaks of illnesses associated with this PFGE pattern have previously been linked to consumption of tomatoes harvested from Virginia's Eastern Shore in the Delmarva region and have not been linked to cucumbers or other produce items. To identify the contaminated food and find the source of the contamination, CDC, state and local health and agriculture departments and laboratories, and the Food and Drug Administration (FDA) conducted epidemiologic, traceback, and laboratory investigations. A total of 275 patients in 29 states and the District of Columbia were identified, with illness onsets occurring during May 20-September 30, 2014. Whole genome sequencing (WGS), a highly discriminating subtyping method, was used to further characterize PFGE pattern JJPX01.0061 isolates. Epidemiologic, microbiologic, and product traceback evidence suggests that cucumbers were a source of Salmonella Newport infections in this outbreak. The epidemiologic link to a novel outbreak vehicle suggests an environmental reservoir for Salmonella in the Delmarva region that should be identified and mitigated to prevent future outbreaks. PMID- 25695320 TI - Hepatitis A outbreak among adults with developmental disabilities in group homes- Michigan, 2013. AB - Hepatitis A virus (HAV) infections among persons with developmental disabilities living in institutions were common in the past, but with improvements in care and fewer persons institutionalized, the number of HAV infections has declined in these institutions. However, residents in institutions are still vulnerable if they have not been vaccinated. On April 24, 2013, a resident of a group home (GH) for adults with disabilities in southeast Michigan (GH-A) was diagnosed with hepatitis A and died 2 days later of fulminant liver failure. Four weeks later, a second GH-A resident was diagnosed with hepatitis A. None of the GH-A residents or staff had been vaccinated against hepatitis A. Over the next 3 months, six more cases of hepatitis A were diagnosed in residents in four other Michigan GHs. Three local health departments were involved in case investigation and management, including administration of postexposure prophylaxis (PEP). Serum specimens from seven cases were found to have an identical strain of HAV genotype 1A. This report describes the outbreak investigation, the challenges of timely delivery of PEP for hepatitis A, and the need for preexposure vaccination against hepatitis A for adults living or working in GHs for the disabled. PMID- 25695321 TI - Measles outbreak--California, December 2014-February 2015. AB - On January 5, 2015, the California Department of Public Health (CDPH) was notified about a suspected measles case. The patient was a hospitalized, unvaccinated child, aged 11 years with rash onset on December 28. The only notable travel history during the exposure period was a visit to one of two adjacent Disney theme parks located in Orange County, California. On the same day, CDPH received reports of four additional suspected measles cases in California residents and two in Utah residents, all of whom reported visiting one or both Disney theme parks during December 17-20. By January 7,seven California measles cases had been confirmed, and CDPH issued a press release and an Epidemic Information Exchange (Epi-X) notification to other states regarding this outbreak. Measles transmission is ongoing. PMID- 25695322 TI - Notes from the field: Fatal gastrointestinal mucormycosis in a premature infant associated with a contaminated dietary supplement--Connecticut, 2014. AB - In October 2014, a hospital in Connecticut notified CDC and the Connecticut Department of Public Health of a fatal case of gastrointestinal mucormycosis in a preterm infant. The infant, born at 29 weeks' gestation and weighing 1,400 grams (about 3 pounds), had developed signs and symptoms initially consistent with necrotizing enterocolitis approximately 1 week after birth. Exploratory laparotomy revealed complete ischemia of the gastrointestinal tract from the esophagus to the rectum; a portion of necrotic cecum was sent for microscopic examination. Following surgery, the infant developed multiple areas of vascular occlusion, including a large clot in the aorta, findings not usually associated with necrotizing enterocolitis. The infant died soon after. Histopathology results from the resected cecum revealed an angioinvasive fungal infection consistent with mucormycosis. Gastrointestinal mucormycosis is an extremely rare fungal infection caused by mold in the order Mucorales. It occurs predominantly in low birth weight infants, patients with diarrhea and malnutrition, and those receiving peritoneal dialysis; mortality is 85%. Local investigation revealed that the infant had received a dietary supplement, ABC Dophilus Powder, for 7 days, beginning on day 1 of life. PMID- 25695323 TI - Notes from the field: Use of unvalidated urine mycotoxin tests for the clinical diagnosis of illness--United States, 2014. AB - In February 2014, CDC's National Institute for Occupational Safety and Health received a request for a health hazard evaluation from a union representative in an office building. A female employee reported the onset of symptoms involving multiple organ systems upon returning to work after a prolonged absence. The employee searched the Internet for descriptions of symptoms matching hers, found a laboratory offering "toxic mold testing" direct to consumers, and submitted a urine sample, despite the absence of musty odors and signs of fungal growth in her office. The laboratory reported "positive" concentrations of two mycotoxins: ochratoxin at 2.8 parts per billion (ppb) and tricothecenes at 0.4 ppb. The laboratory cutoff for "positive" was >=2.0 ppb for ochratoxin and >=0.2 ppb for tricothecenes. The interpretation accompanying the laboratory report said the results "revealed that you have an unusual level of that mycotoxin(s) present in your body." PMID- 25695324 TI - Inhibition of livin expression suppresses cell proliferation and enhances chemosensitivity to cisplatin in human lung adenocarcinoma cells. AB - Livin is a novel member of the inhibitor of apoptosis protein family that has been reported to be overexpressed in various types of human malignancy. Although several studies have demonstrated that livin may be used as an effective target for tumor therapy, few studies have investigated its role in human lung adenocarcinoma. In the present study, two different methods were used in order to investigate the tumor-suppressing effect of livin in human lung adenocarcinoma cells. Firstly, small interfering (si)RNA technology was used to down regulate livin expression; siRNA-mediated knockdown of livin was confirmed using reverse transcription quantitative polymerase chain reaction and western blot analysis, and cell proliferations was assessed using an MTT assay in vitro. Secondly, inhibition of livin expression was induced through the synergistic inhibitory effect between flavopiridol and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Experimental results revealed that, following transfection of the livin gene-silencing vector, the gene expression of livin was markedly decreased, SPC-A1 cell proliferation was significantly reduced and the therapeutic effect of the chemotherapy drug cisplatin was markedly improved. This growth inhibitory effect was also observed in the flavopiridol and TRAIL combination treatment group. In the flavopiridol and TRAIL combination treatment group, the protein expression of livin was significantly reduced and the survival rate of SPC-A1 cells was significantly lower than the flavopiridol and TRAIL single operation group. In conclusion, the RNA silencing and the synergistic inhibitory effect between flavopiridol with TRAIL was able to effectively inhibit the expression of livin, significantly decrease SPC-A1 tumor cell proliferation and significantly enhance sensitivity to the chemotherapy drug cisplatin. These findings suggest that livin may be used as a novel target for tumor gene therapy. PMID- 25695325 TI - Mechanism of scrapie prion precipitation with phosphotungstate anions. AB - The phosphotungstate anion (PTA) is widely used to facilitate the precipitation of disease-causing prion protein (PrP(Sc)) from infected tissue for applications in structural studies and diagnostic approaches. However, the mechanism of this precipitation is not understood. In order to elucidate the nature of the PTA interaction with PrP(Sc) under physiological conditions, solutions of PTA were characterized by NMR spectroscopy at varying pH. At neutral pH, the parent [PW12O40](3-) ion decomposes to give a lacunary [PW11O39](7-) (PW11) complex and a single orthotungstate anion [WO4](2-) (WO4). To measure the efficacy of each component of PTA, increasing concentrations of PW11, WO4, and mixtures thereof were used to precipitate PrP(Sc) from brain homogenates of scrapie prion-infected mice. The amount of PrP(Sc) isolated, quantified by ELISA and immunoblotting, revealed that both PW11 and WO4 contribute to PrP(Sc) precipitation. Incubation with sarkosyl, PTA, or individual components of PTA resulted in separation of higher-density PrP aggregates from the neuronal lipid monosialotetrahexosylganglioside (GM1), as observed by sucrose gradient centrifugation. These experiments revealed that yield and purity of PrP(Sc) were greater with polyoxometalates (POMs), which substantially supported the separation of lipids from PrP(Sc) in the samples. Interaction of POMs and sarkosyl with brain homogenates promoted the formation of fibrillar PrP(Sc) aggregates prior to centrifugation, likely through the separation of lipids like GM1 from PrP(Sc). We propose that this separation of lipids from PrP is a major factor governing the facile precipitation of PrP(Sc) by PTA from tissue and might be optimized further for the detection of prions. PMID- 25695326 TI - Prenatal nicotine exposure induces gender-associated left ventricular-arterial uncoupling in adult offspring. AB - Alterations in vascular or myocardial structure and function have been demonstrated in offspring subjected to prenatal nicotine exposure (PNE), however, limited data are available on how these changes interact. The present study assessed the hypothesis that prenatal nicotine exposure induced gender-specific alterations of left ventricular-arterial coupling indices in adult offspring. Female Sprague-Dawley rats were exposed to either nicotine (8 mg/kg/day) or saline via subcutaneous osmotic mini-pumps throughout gestation. Male and female offspring, aged 12 months, underwent non-invasive echocardiography and invasive left ventricular cannulation. Left ventricular-arterial coupling was analysed as the ratio of effective arterial elastance (Ea) to ventricular end-systolic elastance (Ees). The left ventricular myocardium and aorta were stained with hematoxylin and eosin and the myocardial cell cross-sectional area was calculated. Simultaneously, the ratio of medium thickness to internal diameter in the aorta and mesenteric artery was determined. The fibrosis component of left ventricle myocardium was analyzed by Sirius-red staining and further confirmed by hydroxyproline determination. The elastic properties of the aortic wall were analyzed by van Gieson staining. PNE caused significant increases in pulse pressure (56.36 +/- 7.41 vs. 50.16 +/- 4.94 mmHg; P<0.05) and left ventricular meridional wall stress (78.25 +/- 9.12 vs. 69.64 +/- 7.58 kdyne/cm(2); P<0.05) in male offspring compared with the control. Conversely, no similar effect was observed in female offspring. An elevated augmentation index was noted in male and female pups. Additionally, Ea/Ees was reduced in PNE males compared with control males, due to a disproportionate increase in Ees vs. Ea whereas in females, Ea/Ees did not differ significantly due to tandem increase in Ea and Ees. In addition, collagen cross-linking was markedly higher in male offspring, whereas it was unaltered in females compared with their respective controls. Fragmentation of the elastic network in the aorta and the increased ratio of medial thickness to internal diameter in the mesenteric artery were more evident in male offspring when compared with female offspring. PNE caused combined ventricular-arterial stiffening in male and female offspring, with lower Ea/Ees in males, while Ea/Ees was preserved in females. Enhanced collagen cross-linking in the myocardium, underdeveloped elastic fibers in the aorta and remodeled resistance vessels were associated with pathological ventricular arterial mismatching. The results of the present study indicated that male offspring were more susceptible to the development of ventricular and arterial dysfunction in response to PNE compared with female offspring. PMID- 25695327 TI - High prevalence of hepatitis delta virus among persons who inject drugs, Vietnam. PMID- 25695328 TI - Tuberculosis microepidemics among dispersed migrants, Birmingham, UK, 2004-2013. AB - To determine if local transmission was responsible for rising tuberculosis incidence in a recently dispersed migrant community in Birmingham, UK, during 2004-2013, we conducted enhanced epidemiologic investigation of molecular clusters. This technique identified exact locations of social mixing and chains of apparent recent transmission, which can be helpful for directing resources. PMID- 25695329 TI - Noninvasive test for tuberculosis detection among primates. AB - Traditional testing methods have limited epidemiologic studies of tuberculosis among free-living primates. PCR amplification of insertion element IS6110 of Mycobacterium tuberculosis from fecal samples was evaluated as a noninvasive screening test for tuberculosis in primates. Active tuberculosis was detected among inoculated macaques and naturally exposed chimpanzees, demonstrating the utility of this test. PMID- 25695330 TI - Anti-leukemic effect of sodium metaarsenite (KML001) in acute myeloid leukemia with breaking-down the resistance of cytosine arabinoside. AB - Sodium metaarsenite (NaAs2O3: code name KML001) is an orally bioavailable arsenic compound with potential anti-cancer activity. However, the effect of KML001 has not been studied in acute myeloid leukemia (AML). We investigated the anti leukemic effect of KML001 in AML, and determined the mode of action of KML001. KML001 inhibited the cellular proliferation in all AML cell lines and primary AML blasts as well as HL-60R (cytosine arabinoside-resistant HL-60) cells, while As2O3 was not effective in primary AML blasts and AML cell lines including HL-60R cells. KML001 induced G1 arrest and apoptosis in HL-60 and HL-60R cells. KML001 inhibited the activation of STAT (signal transducer and activator of transcription) 1, 3, 5, NF-kappaB, AKT and PI3K, while phosphorylated PTEN was upregulated. In addition, activation of ERK, p38 and JNK was observed in KML001 induced growth inhibition of HL-60 and HL-60R cells. Furthermore, KML001 induced telomeric terminal restriction fragment (TRF) length shortening in a time dependent manner in HL-60 and HL-60R cells. Real-time PCR with RNA extracted from KML001-treated HL-60 and HL-60R cells showed a significant reduction of catalytic subunit of telomerase, hTERT, in a time-dependent manner. Additionally, gamma H2AX, a sensitive molecular marker of DNA damage, in HL-60 and HL-60R cells was induced by KML001. These results suggest that KML001 inhibits the proliferation of AML cells including cytosine arabinoside-resistant AML cells via various mechanisms such as cell cycle arrest, induction of apoptosis, inhibition of JAK/STAT and PI3K pathways, activation of MAPK pathway and telomere targeting. PMID- 25695331 TI - The use of spatial manipulation to examine goalkeepers' anticipation. AB - This study investigated whether anticipation and search strategies of goalkeepers are influenced by temporally and spatially manipulated video of a penalty. Participants were clustered into three groups depending on skill: goalkeepers (n = 17), field players (n = 20) and control group (n = 20). An eye tracker was worn whilst watching 40 videos of a striker kicking to four corners of a goal in random order. All 40 videos were temporally occluded at foot-to-ball contact, and the non-kicking leg of 20 videos was spatially manipulated. Results showed that goalkeepers had significantly better predictions than the two groups with no differences between the two testing conditions. According to effect size, the percentage of fixation location and viewing time of the kicking leg and ball were greater for the goalkeepers and field players group than the control group irrespective of testing conditions. The fixations on the kicking leg and ball in conjunction with comparable predictions between spatially manipulated and control conditions suggest that goalkeepers may not rely on the non-kicking leg. Furthermore, goalkeepers appear to use a global perceptual approach by anchoring on a distal fixation point/s of the penalty taker whilst using peripheral vision to obtain additional information. PMID- 25695332 TI - Human immunodeficiency virus-negative plasmablastic lymphoma: a comprehensive analysis of 114 cases. AB - Human immunodeficiency virus-negative plasma-blastic lymphoma (PBL) is an extremely rare entity. Its clinicopathological features, optimal treatment strategy and prognostic factors remain obsure. An extensive search was performed in the English language literature within the Pubmed database using the key words: 'plasmablastic lymphoma and human immunodeficiency virus-negative or immunocompetent'. Data from 114 patients from 52 articles were analyzed. The mean patient age at diagnosis was 58.90 years (range, 2-86). HIV-negative PBL showed a predilection for elderly individuals (patients older than 60 years, 56.14%) and affected more males than females (M:F, 2.29:1). Ann Arbor stage IV patients accounted for 39.22% while bone marrow involvement was less frequent (12.79%). The Ki-67 index was high with a mean expression of 83%. Epstein-Barr virus (EBV) infection was common being positive in 58.70% of the patients while herpesvirus-8 (HHV-8) infection was rare being positive in only 7.55% of the patients. Immunosuppression was noted in 28.16% of patients. The median overall survival (OS) was 19 months. The 1- and 2-year survival rates were 52.3 and 45.3%, respectively. Age, gender and primary site showed no strong relationship with OS while Immunosuppression, Ann Arbor stage IV and EBV negativity were able to predict a poorer OS. Either complete remission (CR) or partial remission (PR) was superior to the refractory group in OS (P<0.0001 and P=0.0066, respectively). For stage I patients, the application of radiotherapy did not improve the OS. In conclusion, HIV-negative PBL is a distinct entity likely occurring in elderly and immunosuppressed individuals. Immunosuppression status, Ann Arbor stage IV, EBV negativity and refractory to treatment are poor prognostic factors of OS in HIV negative PBL. PMID- 25695333 TI - Small-molecule inhibitors of ERK-mediated immediate early gene expression and proliferation of melanoma cells expressing mutated BRaf. AB - Constitutive activation of the extracellular-signal-regulated kinases 1 and 2 (ERK1/2) are central to regulating the proliferation and survival of many cancer cells. The current inhibitors of ERK1/2 target ATP binding or the catalytic site and are therefore limited in their utility for elucidating the complex biological roles of ERK1/2 through its phosphorylation and regulation of over 100 substrate proteins. To overcome this limitation, a combination of computational and experimental methods was used to identify low-molecular-mass inhibitors that are intended to target ERK1/2 substrate-docking domains and selectively interfere with ERK1/2 regulation of substrate proteins. In the present study, we report the identification and characterization of compounds with a thienyl benzenesulfonate scaffold that were designed to inhibit ERK1/2 substrates containing an F-site or DEF (docking site for ERK, FXF) motif. Experimental evidence shows the compounds inhibit the expression of F-site containing immediate early genes (IEGs) of the Fos family, including c-Fos and Fra1, and transcriptional regulation of the activator protein-1 (AP-1) complex. Moreover, this class of compounds selectively induces apoptosis in melanoma cells containing mutated BRaf and constitutively active ERK1/2 signalling, including melanoma cells that are inherently resistant to clinically relevant kinase inhibitors. These findings represent the identification and initial characterization of a novel class of compounds that inhibit ERK1/2 signalling functions and their potential utility for elucidating ERK1/2 and other signalling events that control the growth and survival of cancer cells containing elevated ERK1/2 activity. PMID- 25695334 TI - Characterization of the human gut microbiome during travelers' diarrhea. AB - Alterations in the gut microbiota are correlated with ailments such as obesity, inflammatory bowel disease, and diarrhea. Up to 60% of individuals traveling from industrialized to developing countries acquire a form of secretory diarrhea known as travelers' diarrhea (TD), and enterotoxigenic Escherichia coli (ETEC) and norovirus (NoV) are the leading causative pathogens. Presumably, TD alters the gut microbiome, however the effect of TD on gut communities has not been studied. We report the first analysis of bacterial gut populations associated with TD. We examined and compared the gut microbiomes of individuals who developed TD associated with ETEC, NoV, or mixed pathogens, and TD with no pathogen identified, to healthy travelers. We observed a signature dysbiotic gut microbiome profile of high Firmicutes:Bacteroidetes ratios in the travelers who developed diarrhea, regardless of etiologic agent or presence of a pathogen. There was no significant difference in alpha-diversity among travelers. The bacterial composition of the microbiota of the healthy travelers was similar to the diarrheal groups, however the beta-diversity of the healthy travelers was significantly different than any pathogen-associated TD group. Further comparison of the healthy traveler microbiota to those from healthy subjects who were part of the Human Microbiome Project also revealed a significantly higher Firmicutes:Bacteriodetes ratio in the healthy travelers and significantly different beta-diversity. Thus, the composition of the gut microbiome in healthy, diarrhea-free travelers has characteristics of a dysbiotic gut, suggesting that these alterations could be associated with factors such as travel. PMID- 25695335 TI - Alteration of Arabidopsis SLAC1 promoter and its association with natural variation in drought tolerance. AB - Natural variation for drought tolerance is a major issue in adaptation and geographic distribution of terrestrial plants. Despite the importance, little is known about the genes and molecular mechanisms that determine its naturally occurring diversity. We analyzed the intraspecific drought tolerance variation between 2 accessions of Arabidopsis thaliana, Columbia (Col)-0 and Wassilewskija (Ws)-2. Measurement of weight loss in detached seedlings demonstrated a clear difference between drought-tolerant Col-0 and drought-sensitive Ws-2. They also differed in their stomatal response under drought condition. Using a quantitative genetic approach, we found a significant quantitative locus on chromosome 1. Surveying in the locus, we extrapolated that the SLAC1 gene, which is associated with stomatal closure, was likely responsible for the difference of drought tolerance. Comparison of their nucleotide and amino acid sequences revealed that there were few differences in regions encoding SLAC1 protein but was a large deletion in SLAC1 promoter of Ws-2. Histochemical GUS staining showed that the SLAC1 expressed dominantly in guard cells of Col-0, but did less in guard cells of Ws-2. Quantitative PCR analysis also showed that transcript level of SLAC1 in guard cells was higher in Col-0 than in Ws-2. The SLAC1 transcription analyses indicate low accumulation of SLAC1 in guard cells of Ws-2. When taken together, our results suggest that the low drought tolerance of Ws-2 was associated with the deletion of the promoter region of Ws-2 SLAC1. PMID- 25695336 TI - Ocular tissue engineering: current and future directions. AB - Tissue engineering (TE) is a concept that was first emerged in the early 1990s to provide solutions to severe injured tissues and/or organs [1]. The dream was to be able to restore and replace the damaged tissue with an engineered version which would ultimately help overcome problems such as donor shortages, graft rejections, and inflammatory responses following transplantation. While an incredible amount of progress has been made, suggesting that TE concept is viable, we are still not able to overcome major obstacles. In TE, there are two main strategies that researchers have adopted: (1) cell-based, where cells are been manipulated to create their own environment before transplanted to the host, and (2) scaffold-based, where an extracellular matrix is created to mimic in vivo structures. TE approaches for ocular tissues are available and have indeed come a long way, over the last decades; however more clinically relevant ocular tissue substitutes are needed. Figure 1 highlights the importance of TE in ocular applications and indicates the avenues available based on each tissue.[...]. PMID- 25695337 TI - Modulation of the tumor microenvironment for cancer treatment: a biomaterials approach. AB - Tumors are complex tissues that consist of stromal cells, such as fibroblasts, immune cells and mesenchymal stem cells, as well as non-cellular components, in addition to neoplastic cells. Increasingly, there is evidence to suggest that these non-neoplastic cell components support cancer initiation, progression and metastasis and that their ablation or reprogramming can inhibit tumor growth. Our understanding of the activities of different parts of the tumor stroma in advancing cancer has been improved by the use of scaffold and matrix-based 3D systems originally developed for regenerative medicine. Additionally, drug delivery systems made from synthetic and natural biomaterials deliver drugs to kill stromal cells or reprogram the microenvironment for tumor inhibition. In this article, we review the impact of 3D tumor models in increasing our understanding of tumorigenesis. We also discuss how different drug delivery systems aid in the reprogramming of tumor stroma for cancer treatment. PMID- 25695338 TI - Diabetes among US- and foreign-born blacks in the USA. AB - OBJECTIVE: Little is known about diabetes status among US blacks by nativity. This study aims to measure differences in diabetes among US blacks by region of birth and examines potential explanations for subgroup differences. DESIGN: Data from 47,751 blacks aged 25-74 pooled from the 2000-2013 waves of the National Health Interview Survey were analyzed. Logistic regression models predicted self reported diabetes. The roles of education, income, body mass index (BMI), smoking, and duration of US residence were explored. RESULTS: Compared to the US born, foreign-born blacks had significantly lower reported diabetes prevalence (8.94% vs. 11.84%) and diabetes odds ratio [OR: 0.75; 95% confidence interval (CI): 0.62, 0.89], adjusting for socio-demographic characteristics. Further inclusion of education, income, household size, and smoking did not appreciably change the OR (0.77; 95% CI: 0.61, 0.86). Including an adjustment for BMI entirely eliminated the foreign-born advantage (OR 0.93; 95% CI: 0.78, 1.11). The foreign-born from the Caribbean/Americas had similar diabetes odds compared to the African-born. Among the foreign-born, an increased duration of US residence was associated with a higher diabetes odds, but these associations did not reach statistical significance (p > 0.05). CONCLUSION: The healthy immigrant advantage extended to diabetes among US blacks, a finding that is explained by lower levels of overweight/obesity among the foreign-born compared to the US-born. Nonetheless, more than 71.4% of the foreign-born were overweight or obese. Understanding the mechanisms through which exposure to the US environment leads to higher obesity and diabetes risk may aid prevention efforts for the rapidly growing foreign-born black subpopulation. PMID- 25695339 TI - The inflammatory marker suPAR after cardiac arrest. AB - BACKGROUND: Soluble urokinase plasminogen activator receptor (suPAR) is released in response to inflammatory stimuli, and plasma levels are associated with long term outcomes. The ischemia/reperfusion injury caused by cardiac arrest (CA) and resuscitation triggers an inflammatory response. This pilot study aimed at investigating suPAR levels in relation to outcome after CA and mild induced hypothermia. METHODS: suPAR levels were measured at 6, 36, and 72 hours in patients treated with hypothermia after CA. suPAR levels were analyzed in relation to survival after 6 months. Receiver operating characteristic curve (ROC)-analyses were performed, and area under the curve (AUC) was calculated. Time to return of spontaneous circulation (ROSC) was correlated to suPAR levels. RESULTS: Fifty-five patients (40 male, median 65 years) were included, and 33 (60%) were alive after 6 months. The suPAR levels were significantly higher in nonsurviving patients compared with survivors at 6 and 36 hours (p=0.006 and 0.034 respectively), but not at 72 hours. The suPAR levels increased from 6 to 72 hours (p<0.0001). Time to ROSC correlated positively with suPAR levels at 6 hours (p=0.003) but not at 36 and 72 hours. ROC analysis shoved an AUC of 0.76 at 6 hours. In the subgroup of CA of cardiac cause, the AUC was 0.84. CONCLUSION: suPAR levels at 6 and 36 hours after CA were significantly higher in nonsurviving patients compared with survivors; however, the overlap in suPAR levels between the outcome groups was substantial, reducing the prognostic value. There was a significant increase in suPAR levels during the first 72 hours after CA. PMID- 25695340 TI - High levels of agreement between clinic-based ethyl glucuronide (EtG) immunoassays and laboratory-based mass spectrometry. AB - BACKGROUND: Immunoassay urine drug screening cups that detect use for two or more days are commonly used in addiction treatment settings. Until recently, there has been no comparable immunoassay test for alcohol use in these settings. OBJECTIVES: The aim of this study was to assess the agreement of a commercially available ethyl glucuronide immunoassay (EtG-I) test conducted at an outpatient addiction clinic and lab-based EtG mass spectrometry (EtG-MS) conducted at a drug testing laboratory at three cut-off levels. High agreement between these two measures would support the usefulness of EtG-I as a clinical tool for monitoring alcohol use. METHODS: Forty adults with co-occurring alcohol dependence and serious mental illnesses submitted 1068 urine samples over a 16-week alcohol treatment study. All samples were tested using EtG-I on a benchtop analyzer and 149 were randomly selected for EtG-MS analysis at a local laboratory. Agreement was defined as the number of samples where EtG-I and EtG-MS were both above or below a specific cut-off level. Agreement was calculated at low cut-off levels (100 and 250 ng/ml), as well as at a higher cut-off level (500 ng/ml) recommended by most by commercial drug testing laboratories. RESULTS: Agreement between EtG-I and EtG-MS was high across all cut-off levels (90.6% at 100 ng/ml, and 96.6% at 250 and 500 ng/ml). CONCLUSIONS: EtG immunoassays conducted at low cut-off levels in point-of-care testing settings have high agreement with lab-based EtG-MS. EtG I can be considered a useful clinical monitoring tool for alcohol use in community-based addiction treatment settings. PMID- 25695341 TI - Youth and parent measures of self-efficacy for continuous glucose monitoring: survey psychometric properties. AB - BACKGROUND: This study aimed to describe the development and psychometric evaluation of novel youth and parent measures of self-efficacy related to continuous glucose monitoring (CGM) in pediatric patients with type 1 diabetes. This evaluation also assessed the predictive validity of the CGM Self-Efficacy (CGM-SE) surveys on CGM use and hemoglobin A1c (HbA1c) levels. SUBJECTS AND METHODS: Study participants included 120 youth with type 1 diabetes for >=1 year enrolled in a 2-year randomized clinical trial comparing CGM use with and without the addition of a family-focused CGM behavioral intervention. Youth and parents completed the CGM-SE surveys at randomization after a 1-week run-in to assess CGM tolerability. Analyses of predictive validity excluded the intervention group and included 61 youth in the control group in order to assess CGM use and HbA1c outcomes 3 and 6 months after randomization. RESULTS: At study entry, youth were 12.7+/-2.7 years old with a diabetes duration of 6.1+/-3.6 years and an HbA1c level of 8.0+/-0.8% (64+/-9 mmol/mol); blood glucose monitoring frequency was 6.8+/-2.4 times/day, and 84% received pump therapy. CGM-SE surveys had acceptable internal consistency (Cronbach's alpha=0.80 for youth and 0.82 for parents). Youth reporting higher baseline CGM self-efficacy (CGM-SE score of >80) had significantly greater CGM use and lower HbA1c level after 3 and 6 months compared with youth reporting lower baseline CGM self-efficacy (CGM-SE score of <=80). CONCLUSIONS: The CGM-SE surveys appear to have strong psychometric properties. CGM self-efficacy may offer an opportunity to assess the likelihood of CGM adherence and glycemic improvement in youth with type 1 diabetes in clinical and research settings. PMID- 25695342 TI - Marked Variability in Reported Minimal Residual Disease Lower Level of Detection of 4 Hematolymphoid Neoplasms: A Survey of Participants in the College of American Pathologists Flow Cytometry Proficiency Testing Program. AB - CONTEXT: Flow cytometry is often applied to minimal residual disease (MRD) testing in hematolymphoid neoplasia. Because flow-based MRD tests are developed in the laboratory, testing methodologies and lower levels of detection (LODs) are laboratory dependent. OBJECTIVES: To broadly survey flow cytometry laboratories about MRD testing in laboratories, if performed, including indications and reported LODs. DESIGN: Voluntary supplemental questions were sent to the 549 laboratories participating in the College of American Pathologists (CAP) FL3-A Survey (Flow Cytometry-Immunophenotypic Characterization of Leukemia/Lymphoma) in the spring of 2014. RESULTS: A total of 500 laboratories (91%) responded to the supplemental questions as part of the FL3-A Survey by April 2014; of those 500 laboratories, 167 (33%) currently perform MRD for lymphoblastic leukemia, 118 (24%) for myeloid leukemia, 99 (20%) for chronic lymphocytic leukemia, and 91 (18%) for plasma cell myeloma. Other indications include non-Hodgkin lymphoma, hairy cell leukemia, neuroblastoma, and myelodysplastic syndrome. Most responding laboratories that perform MRD for lymphoblastic leukemia reported an LOD of 0.01%. For myeloid leukemia, chronic lymphocytic leukemia, and plasma cell myeloma, most laboratories indicated an LOD of 0.1%. Less than 3% (15 of 500) of laboratories reported LODs of 0.001% for one or more MRD assays performed. CONCLUSIONS: There is major heterogeneity in the reported LODs of MRD testing performed by laboratories subscribing to the CAP FL3-A Survey. To address that heterogeneity, changes to the Flow Cytometry Checklist for the CAP Laboratory Accreditation Program are suggested that will include new requirements that each laboratory (1) document how an MRD assay's LOD is measured, and (2) include the LOD or lower limit of enumeration for flow-based MRD assays in the final diagnostic report. PMID- 25695343 TI - Characterization of an exo-inulinase from Arthrobacter: a novel NaCl-tolerant exo inulinase with high molecular mass. AB - A glycoside hydrolase family 32 exo-inulinase gene was cloned from Arthrobacter sp. HJ7 isolated from saline soil located in Heijing town. The gene encodes an 892-residue polypeptide with a calculated mass of 95.1 kDa and a high total frequency of amino acid residues G, A, and V (30.0%). Escherichia coli BL21 (DE3) cells were used as hosts to express the exo-inulinase gene. The recombinant exo inulinase (rInuAHJ7) showed an apparently maximal activity at pH 5.0-5.5 and 40 45 degrees C. The addition of 1.0 and 10.0 mM Zn(2+) and Pb(2+) had little or no effect on the enzyme activity. rInuAHJ7 exhibited good salt tolerance, retaining more than 98% inulinase activity at a concentration of 3.0%-20.0% (w/v) NaCl. Fructose was the main product of inulin, levan, and Jerusalem artichoke tubers hydrolyzed by the enzyme. The present study is the first to report the identification and characterization of an Arthrobacter sp exo-inulinase showing a high molecular mass of 95.1 kDa and NaCl tolerance. These results suggest that the exo-inulinase might be an alternative material for potential applications in processing seafood and other foods with high saline contents, such as marine algae, pickles, and sauces. PMID- 25695344 TI - Die-hard survivors: heterogeneity in apoptotic thresholds may underlie chemoresistance. AB - The unmatched efficacy of microtubule-targeting agents (MTAs) as chemotherapeutics was once assumed to originate from their impact on mitotic processes; however, this misconception is being eroded by amassing data that MTAs instead target interphase functions in patients' tumors. What remains murky is how MTAs target malignant cells over non-malignant ones if proliferation rates do not distinguish them. In many instances, malignant cells are actually more 'primed' for apoptosis than non-malignant ones. Nevertheless, even if most cells within the tumor are more apoptosis-susceptible than those in healthy tissues, there likely exist small subpopulations of apoptosis-resistant clones that engender incomplete responses to MTAs and relapse. Therefore, intratumor heterogeneity in terms of proximity to the apoptotic threshold must be better understood to facilitate the design of chemotherapeutic regimens, which may benefit from including drugs like BH3 mimetics that help in lowering the apoptotic threshold of tumor cells within these chemoresistant subpopulations. PMID- 25695345 TI - Fast-tracking novel drugs in pediatric oncology. PMID- 25695346 TI - Working memory in children predicts performance on a gambling task. AB - The authors investigated whether working memory (WM) plays a significant role in the development of decision making in children, operationalized by the Children's Gambling Task (CGT). A total of 105 children aged 6-7, 8-9, and 10-11 years old carried out the CGT. Children aged 6-7 years old were found to have a lower performance than older children, which shows that the CGT is sensitive to participant's age. The hypothesis that WM plays a significant role in decision making was then tested following two approaches: (a) an experimental approach, comparing between groups the performance on the CGT in a control condition (the CGT only was administered) to that in a double task condition (participants had to carry out a recall task in addition to the CGT); (b) an interindividual approach, probing the relationship between CGT performance and performance on tasks measuring WM efficiency. The between-groups approach evidenced a better performance in the control group. Moreover, the interindividual approach showed that the higher the participants' WM efficiency was, the higher their performance in the CGT was. Taken together, these two approaches yield converging results that support the hypothesis that WM plays a significant role in decision making in children. PMID- 25695347 TI - Simple, benign, aqueous-based amination of polycarbonate surfaces. AB - Polycarbonate is a desirable material for many applications due to its favorable mechanical and optical properties. Here, we report a simple, safe, environmentally friendly aqueous method that uses diamines to functionalize a polycarbonate surface with amino groups. The use of water as the solvent for the functionalization ensures that solvent induced swelling does not affect the optical or mechanical properties of the polycarbonate. We characterize the efficacy of the surface amination using X-ray photo spectroscopy, Fourier transform infrared spectroscopy (FT-IR), atomic force microscopy (AFM), and contact angle measurements. Furthermore, we demonstrate the ability of this facile method to serve as a foundation upon which other functionalities may be attached, including antifouling coatings and oriented membrane proteins. PMID- 25695350 TI - The total synthesis of (-)-cryptocaryol A. AB - A stereoselective total synthesis of (-)-cryptocaryol A (1) is described. Key features of the 17-step route include the use of three boron-mediated aldol reaction-reduction sequences to control all stereocenters and an Ando modification of the Horner-Wadsworth-Emmons olefination that permitted the installation of the Z double bond of the alpha-pyrone ring. PMID- 25695351 TI - Thermodynamic stability, kinetic inertness and relaxometric properties of monoamide derivatives of lanthanide(III) DOTA complexes. AB - A complete thermodynamic and kinetic solution study on lanthanide(III) complexes with monoacetamide (DOTAMA, L1) and monopropionamide (DOTAMAP, L2) derivatives of DOTA (DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) was undertaken with the aim to elucidate their stability and inertness in aqueous media. The stability constants of GdL1 and GdL2 are comparable, whereas a more marked difference is found in the kinetic inertness of the two complexes. The formation of the Eu(III) and Ce(III) complexes takes place via the formation of the protonated intermediates which can deprotonate and transform into the final complex through a OH(-) assisted pathway. GdL2 shows faster rates of acid catalysed decomplexation with respect to GdL1, which has a kinetic inertness comparable to GdDOTA. Nevertheless, GdL2 is one order of magnitude more inert than GdDO3A. A novel DOTAMAP-based bifunctional chelating ligand and its deoxycholic acid derivative (L5) were also synthesized. Since the coordinated water molecule in GdL2 is characterized by an exchange rate ca. two orders of magnitude greater than in GdL1, the relaxivity of the macromolecular derivatives of L5 should not be limited by the slow water exchange process. The relaxometric properties of the supramolecular adduct of GdL5 with human serum albumin (HSA) were investigated in aqueous solution by measuring the magnetic field dependence of the (1)H relaxivity which, at 20 MHz and 298 K, shows a 430% increase over that of the unbound GdL5 chelate. Thus, Gd(III) complexes with DOTAMAP macrocyclic ligands can represent good candidates for the development of stable and highly effective bioconjugate systems for molecular imaging applications. PMID- 25695352 TI - Left truncation bias as a potential explanation for the protective effect of smoking on preeclampsia. AB - BACKGROUND: We carried out a study to examine whether left truncation bias could explain the negative association between smoking and preeclampsia. METHODS: Monte Carlo and other simulation models were used to determine the effect of differential rates of early pregnancy loss among smokers on the relation between smoking and preeclampsia at >=20 weeks' gestation. Assumptions included no association between smoking and the abnormal placentation that characterizes preeclampsia, and higher rates of early pregnancy loss among smokers, pregnancies with abnormal placentation, and smokers with abnormal placentation. RESULTS: Monte Carlo simulation yielded a rate ratio for preeclampsia, given smoking of 0.85 (95% confidence interval = 0.73, 0.98). The protective effect of smoking was also evident in simulations that did not require assumptions about early pregnancy loss rates. CONCLUSION: Left truncation bias due to differential rates of early pregnancy loss among smokers is a plausible explanation for the inverse association between maternal smoking and preeclampsia. PMID- 25695353 TI - Mortality after the death of a spouse in Norway. AB - BACKGROUND: Previous studies on mortality of widowed individuals have produced varying estimates of mortality after the death of a spouse. This variation is because of the various data types used and methodologies applied, as well as to the failure to account for sources of bias. METHODS: We followed all married individuals in Norway (1,801,456 individuals) for 32 years, and information on marital status and death was collected for use in a new application of survival analysis in this field of research. RESULTS: We compared mortality of widowed individuals with that of married individuals. Widowed men and women had hazard ratios of 1.34 (95% confidence interval 1.31, 1.36) and 1.29 (1.26, 1.31), respectively, for the first year after spousal death. For the same period, values were highest in ages 60-64 years with 1.78 (1.57, 1.98) in men and 1.50 (1.35, 1.65) in women. Values dropped gradually with age and more rapidly in men than women to a low for ages 85-89 years of 1.24 (1.19, 1.29) in men and 1.25 (1.20, 1.31) in women. The risk was much higher 1 to 7 days after spousal death (1.69 [1.49, 1.88] in men and 1.76 [1.56, 1.96] in women), then it dropped during the first year and from then on remained stable to year 10, which was the last year considered. CONCLUSION: A considerable excess mortality risk was observed in widowed men and women from immediately after the loss of a spouse and for the next 10 years. PMID- 25695354 TI - Risk of breast cancer in relation to combined effects of hormone therapy, body mass index, and alcohol use, by hormone-receptor status. AB - BACKGROUND: Alcohol consumption, increased body mass index (BMI), and hormone therapy are risk factors for postmenopausal breast cancer, but their combined effects are not well understood. Because hormone therapy is effective for the relief of menopausal symptoms, the identification of "high-risk" users is important for therapeutic reasons. We investigated interactions between hormone therapy use and alcohol-use/high BMI status in relation to invasive breast cancer risk, both overall and according to estrogen receptor (ER) status. METHODS: Two Danish prospective cohorts were pooled, including 30,789 women ages 50+ years (study period 1981 to 2009). Information on risk factors was obtained in baseline questionnaires. We performed analyses using the Aalen additive hazards model. Serum estradiol and testosterone measurements were obtained in a subsample of approximately 1000 women. RESULTS: During 392,938 person-years of follow-up, 1579 women developed invasive breast cancer. Among nonusers of hormone therapy, the risk of breast cancer was slightly increased with overweight/obesity and increasing alcohol consumption. Compared with normal-weight nonusers, the risk of breast cancer was higher in hormone therapy users across all BMI strata (P for interaction = 0.003). A markedly higher risk of breast cancer was also observed for alcohol combined with hormone therapy use compared with abstinent nonusers (P for interaction = 0.02). These effects were primarily restricted to ER-positive cases. Combined effects of hormone therapy/high BMI and hormone therapy/alcohol on serum estradiol and testosterone supported the hypothesis of a hormonal pathway linking these exposures to breast cancer. CONCLUSION: These analyses suggest an increased risk of breast cancer associated with hormone therapy use-a risk that may be particularly strong among women consuming alcohol. PMID- 25695356 TI - Function-sparing intracapsular enucleation of cervical schwannomas. AB - PURPOSE OF REVIEW: We review our series of cervical schwannomas to evaluate the safety and efficacy of intracapsular enucleation for function-sparing tumor resection. RECENT FINDINGS: There were 43 tumors in total, including vagal (n = 20), sympathetic (n = 13), brachial plexus (n = 6), cervical plexus (n = 2), and two with no major neural involvement. Of the 16 vagal tumors that underwent enucleation, 15 had near-normal or normal voices at 1 year. Eight had normal vocal cord function, three had a partially mobile vocal cord with normal voice, and four had an immobile vocal cord with near-normal or normal voices. One patient had an immobile vocal cord requiring medialization laryngoplasty and arytenoid adduction. Of the 13 sympathetic schwannomas, three underwent enucleation. All three of these patients displayed Horner's triad in the early postoperative period; however, each of them significantly improved within the first 6 months. Of the patients with brachial plexus schwannomas, four underwent enucleation with no postoperative deficits in motor function to the arm. SUMMARY: Intracapsular enucleation of cervical schwannomas appears to be an effective long term oncologic treatment while providing significant improvement in functional outcomes. PMID- 25695357 TI - Electric field effects on the intermolecular interactions in water whiskers: insight from structures, energetics, and properties. AB - Modulation of intermolecular interactions in response to external electric fields could be fundamental to the formation of unusual forms of water, such as water whiskers. However, a detailed understanding of the nature of intermolecular interactions in such systems is lacking. In this paper, we present novel theoretical results based on electron correlation calculations regarding the nature of H-bonds in water whiskers, which is revealed by studying their evolution under external electric fields with various field strengths. We find that the water whiskers consisting of 2-7 water molecules all have a chain-length dependent critical electric field. Under the critical electric field, the most compact chain structures are obtained, featuring very strong H-bonds, herein referred to as covalent H-bonds. In the case of a water dimer whisker, the bond length of the novel covalent H-bond shortens by 25%, the covalent bond order increases by 9 times, and accordingly the H-bond energy is strengthened by 5 times compared to the normal H-bond in a (H2O)2 cluster. Below the critical electric field, it is observed that, with increasing field strength, H-bonding orbitals display gradual evolutions in the orbital energy, orbital ordering, and orbital nature (i.e., from typical pi-style orbital to unusual sigma-style double H-bonding orbital). We also show that, beyond the critical electric field, a single water whisker may disintegrate to form a loosely bound zwitterionic chain due to a relay-style proton transfer, whereas two water whiskers may undergo intermolecular cross-linking to form a quasi-two-dimensional water network. Overall, these results help shed new insight on the effects of electric fields on water whisker formation. PMID- 25695358 TI - Comparison of transflection and transmission FTIR imaging measurements performed on differentially fixed tissue sections. AB - The widespread and cost-effective use of transflection substrates in Fourier transform infrared (FTIR) imaging of clinical samples is affected by the presence of artefacts including the electric field standing wave (EFSW) and contributions from light dispersion. For IR-based diagnostics, the manifestation of undesirable artifacts can distort the spectra and lead to erroneous diagnosis. Nevertheless, there is no clear consensus in the literature about the degree of influence of these effects. The aim of this work is to contribute to this discussion by comparing transflection and transmission images of the same tissue. For this purpose two adjacent sections of the same tissue (lymphoma sample) were fixed onto a CaF2 window and a transflective slide for FTIR imaging. The samples in this case had a central area where based on morphology it was presumed the fixative did not penetrate to the same extent hence providing a comparable region for the two different substrates with a distinct physical/chemical difference. Transmission and transflection spectra from adjacent hyperspectral tissue images were combined in an extended dataset. Surprisingly, unsupervised hierarchical cluster analysis clustered together transflection and transmission spectra, being classified according to differences in tissue fixation instead of the geometry employed for the image acquisition. A more detailed examination of spectra from the peripheral zone of the tissue indicated that the main differences between the transflection and transmission spectra were: (1) a small shift of the amide I, (2) a larger "noise" component in the transflection spectra requiring more averaging to obtain representative spectra of tissue types, and (3) the phosphate bands were generally higher in absorbance in the transflection measurements compared to the transmission ones. The amide I shift and the larger spectral variance was consistent with results obtained in previous studies where the EFWS was present. The findings indicate that artifacts resulting from transflection measurements were small but consistent across the tissue, and therefore the use of transflection measurements could be employed for disease diagnosis. Accordingly, we recommend a straightforward multivariate comparison of images from transmission and transflection measurements in a combined data matrix obtained from adjacent sections of the tissue as a useful preliminary study for establishing the impact of the EFWS on the samples, before considering the routine use of transflection substrates for any new tissue studied. PMID- 25695359 TI - Solid-phase synthesis of diverse peptide tertiary amides by reductive amination. AB - The synthesis of libraries of conformationally constrained peptide-like oligomers is an important goal in combinatorial chemistry. In this regard an attractive building block is the N-alkylated peptide, also known as a peptide tertiary amide (PTA). PTAs are conformationally constrained because of allylic 1,3 strain interactions. We report here an improved synthesis of these species on solid supports through the use of reductive amination chemistry using amino acid terminated, bead-displayed oligomers and diverse aldehydes. The utility of this chemistry is demonstrated by the synthesis of a library of 10,000 mixed peptoid PTA oligomers. PMID- 25695355 TI - Time course and predictors of amblyopia improvement with 2 hours of daily patching. PMID- 25695362 TI - A critical appraisal of ventilation tube insertion in children with cleft palate. PMID- 25695363 TI - A critical appraisal of ventilation tube insertion in children with cleft palate- reply. PMID- 25695365 TI - Local and regional components of aerosol in a heavily trafficked street canyon in central London derived from PMF and cluster analysis of single-particle ATOFMS spectra. AB - Positive matrix factorization (PMF) has been applied to single particle ATOFMS spectra collected on a six lane heavily trafficked road in central London (Marylebone Road), which well represents an urban street canyon. PMF analysis successfully extracted 11 factors from mass spectra of about 700,000 particles as a complement to information on particle types (from K-means cluster analysis). The factors were associated with specific sources and represent the contribution of different traffic related components (i.e., lubricating oils, fresh elemental carbon, organonitrogen and aromatic compounds), secondary aerosol locally produced (i.e., nitrate, oxidized organic aerosol and oxidized organonitrogen compounds), urban background together with regional transport (aged elemental carbon and ammonium) and fresh sea spray. An important result from this study is the evidence that rapid chemical processes occur in the street canyon with production of secondary particles from road traffic emissions. These locally generated particles, together with aging processes, dramatically affected aerosol composition producing internally mixed particles. These processes may become important with stagnant air conditions and in countries where gasoline vehicles are predominant and need to be considered when quantifying the impact of traffic emissions. PMID- 25695366 TI - Amide and amine nucleophiles in polar radical crossover cycloadditions: synthesis of gamma-lactams and pyrrolidines. AB - In this work we present a direct catalytic synthesis of gamma-lactams and pyrrolidines from alkenes and activated unsaturated amides or protected unsaturated amines, respectively. Using a mesityl acridinium single electron photooxidant and a thiophenol cocatalyst under irradiation, we are able to directly forge these important classes of heterocycles with complete regiocontrol. PMID- 25695367 TI - Buruli ulcer in traveler from Suriname, South America, to the Netherlands. AB - We report Buruli ulcer in a man in the Netherlands. Phenotyping of samples indicate the Buruli pathogen was acquired in Suriname and activated by trauma on return to the Netherlands. Awareness of this disease by clinicians in non-Buruli ulcer-endemic areas is critical for identification. PMID- 25695368 TI - Restoration of Chemosensitivity in P-Glycoprotein-Dependent Multidrug-Resistant Cells by Dihydro-beta-agarofuran Sesquiterpenes from Celastrus vulcanicola. AB - Multidrug resistance (MDR) caused by the overexpression of ABC drug transporters is a major obstacle in clinical cancer chemotherapy and underlines the urgent need for the development of new, potent, and safe reversal agents. Toward this goal, reported herein are the structure elucidation and biological activity of nine new (1-9) and four known (10-13) dihydro-beta-agarofuran sesquiterpenes, isolated from the leaves of Celastrus vulcanicola, as reversers of MDR mediated by human P-glycoprotein expression. The structures of these compounds were elucidated by extensive NMR spectroscopic and mass spectrometric analysis, and their absolute configurations were determined by circular dichroism studies, chemical correlations (1a, 8a, and 8b), and biogenetic means. Four compounds from this series were discovered as potent chemosensitizers for MDR1-G185 NIH-3T3 murine cells (3, 4, 6, and 7), showing higher efficacies than the classical P glycoprotein inhibitor verapamil, a first-generation chemosensitizer, when reversing resistance to daunomycin and vinblastine at the lowest concentration tested of 1 MUM. PMID- 25695369 TI - Tetraanionic biphenyl lanthanide complexes as single-molecule magnets. AB - Inverse sandwich biphenyl complexes [(NN(TBS))Ln]2(MU-biphenyl)[K(solvent)]2 [NN(TBS) = 1,1'-fc(NSi(t)BuMe2)2; Ln = Gd, Dy, Er; solvent = Et2O, toluene; 18 crown-6], containing a quadruply reduced biphenyl ligand, were synthesized and their magnetic properties measured. One of the dysprosium biphenyl complexes was found to exhibit antiferromagnetic coupling and single-molecule-magnet behavior with Ueff of 34 K under zero applied field. The solvent coordinated to potassium affected drastically the nature of the magnetic interaction, with the other dysprosium complex showing ferromagnetic coupling. Ab initio calculations were performed to understand the nature of magnetic coupling between the two lanthanide ions bridged by the anionic arene ligand and the origin of single molecule-magnet behavior. PMID- 25695371 TI - Combining magnetic hyperthermia and photodynamic therapy for tumor ablation with photoresponsive magnetic liposomes. AB - The ongoing nanotech revolution has the potential to transform diagnostic and therapeutic methods. Stimuli-triggered nanotherapies based on remotely activated agents have become attractive alternatives to conventional chemotherapy. Herein, we designed an optimized smart nanoplatform based on dually loaded hybrid liposomes to achieve enhanced tumor therapy. The aqueous core was highly loaded with iron oxide nanoparticles, while the lipid bilayer was supplied with a photosensitizer payload. The double cargo translated into double functionality: generation of singlet oxygen under laser excitation and heat production under alternating magnetic field stimulation, coupling photodynamic therapy (PDT) to magnetic hyperthermia (MHT). These liposomes address both therapeutic agents within tumor cells, and the combined PDT/MHT therapy resulted in complete cancer cell death in vitro while total solid-tumor ablation was achieved in an in vivo rodent model. PMID- 25695370 TI - Maternal control of early embryogenesis in mammals. AB - Oocyte quality is a critical factor limiting the efficiency of assisted reproductive technologies (ART) and pregnancy success in farm animals and humans. ART success is diminished with increased maternal age, suggesting a close link between poor oocyte quality and ovarian aging. However, the regulation of oocyte quality remains poorly understood. Oocyte quality is functionally linked to ART success because the maternal-to-embryonic transition (MET) is dependent on stored maternal factors, which are accumulated in oocytes during oocyte development and growth. The MET consists of critical developmental processes, including maternal RNA depletion and embryonic genome activation. In recent years, key maternal proteins encoded by maternal-effect genes have been determined, primarily using genetically modified mouse models. These proteins are implicated in various aspects of early embryonic development, including maternal mRNA degradation, epigenetic reprogramming, signal transduction, protein translation and initiation of embryonic genome activation. Species differences exist in the number of cell divisions encompassing the MET and maternal-effect genes controlling this developmental window. Perturbations of maternal control, some of which are associated with ovarian aging, result in decreased oocyte quality. PMID- 25695372 TI - Clinical guidance for smallpox vaccine use in a postevent vaccination program. AB - This report outlines recommendations for the clinical use of the three smallpox vaccines stored in the U.S. Strategic National Stockpile for persons who are exposed to smallpox virus or at high risk for smallpox infection during a postevent vaccination program following an intentional or accidental release of the virus. No absolute contraindications exist for smallpox vaccination in a postevent setting. However, several relative contraindications exist among persons with certain medical conditions. CDC recommendations for smallpox vaccine use were developed in consideration of the risk for smallpox infection, risk for an adverse event following vaccination, and benefit from vaccination. Smallpox vaccines are made from live vaccinia viruses that protect against smallpox disease. They do not contain variola virus, the causative agent of smallpox. The three smallpox vaccines stockpiled are ACAM2000, Aventis Pasteur Smallpox Vaccine (APSV), and Imvamune. Surveillance and containment activities including vaccination with replication-competent smallpox vaccine (i.e., vaccine viruses capable of replicating in mammalian cells such as ACAM2000 and APSV) will be the primary response strategy for achieving epidemic control. Persons exposed to smallpox virus are at high risk for developing and transmitting smallpox and should be vaccinated with a replication-competent smallpox vaccine unless severely immunodeficient. Because of a high likelihood of a poor immune response and an increased risk for adverse events, smallpox vaccination should be avoided in persons with severe immunodeficiency who are not expected to benefit from vaccine, including bone marrow transplant recipients within 4 months of transplantation, persons infected with HIV with CD4 cell counts <50 cells/mm3, and persons with severe combined immunodeficiency, complete DiGeorge syndrome, and other severely immunocompromised states requiring isolation. If antivirals are not immediately available, it is reasonable to consider the use of Imvamune in the setting of a smallpox virus exposure in persons with severe immunodeficiency. Persons without a known smallpox virus exposure might still be at high risk for developing smallpox infection depending on the magnitude of the outbreak and the effectiveness of the public health response. Such persons will be defined by public health authorities and should be screened for relative contraindications to smallpox vaccination. Relative contraindications include atopic dermatitis (eczema), HIV infection (CD4 cell counts of 50-199 cells/mm3), other immunocompromised states, and vaccine or vaccine-component allergies. Persons with relative contraindications should be vaccinated with Imvamune when available and authorized for use by the Food and Drug Administration. These recommendations will be updated as new data on smallpox vaccines become available and further clinical guidance for other medical countermeasures including antivirals is developed. PMID- 25695373 TI - Expression of integrin-binding protein Nischarin in metastatic breast cancer. AB - The present study aimed to investigate the expression of Nischarin protein in primary breast cancer (PBC), and to evaluate its role in tumor metastasis. Paired specimens of breast cancer tissues and adjacent normal tissues were surgically obtained from 60 patients with PBC at the Zhejiang Cancer Hospital (Hangzhou, China). Nischarin protein concentrations were determined by an ELISA assay. Breast cancer tissues exhibited a significantly lower concentration of Nischarin (5.86 +/- 3.19 ng/ml) compared with that of the adjacent noncancerous tissues (9.25 +/- 3.65 ng/ml; P<0.001). Furthermore, cancer tissue from patients with lymph node metastasis had significantly lower levels of Nischarin protein (4.69 +/- 2.40 ng/ml) than those of patients without lymph node metastasis (7.04 +/- 3.47 ng/ml; P=0.004). There was no significant difference in Nischarin protein expression levels between patients with grade I, II or III PBC (grade I, 5.44 +/- 3.57 ng/ml; grade II, 6.42 +/- 3.85 ng/ml and grade III, 5.10 +/- 1.18 ng/ml; P=0.765). The significant differences in the expression of Nischarin between: i) Cancer tissue and noncancerous tissue and ii) patients with and without lymph node metastasis, suggested that Nischarin may have a significant role in tumor occurrence and metastasis of breast cancer. Nischarin expression may therefore be used as a marker to predict the invasiveness and metastasis of PBC. PMID- 25695374 TI - Exploring atomic defects in molybdenum disulphide monolayers. AB - Defects usually play an important role in tailoring various properties of two dimensional materials. Defects in two-dimensional monolayer molybdenum disulphide may be responsible for large variation of electric and optical properties. Here we present a comprehensive joint experiment-theory investigation of point defects in monolayer molybdenum disulphide prepared by mechanical exfoliation, physical and chemical vapour deposition. Defect species are systematically identified and their concentrations determined by aberration-corrected scanning transmission electron microscopy, and also studied by ab-initio calculation. Defect density up to 3.5 * 10(13) cm(-2) is found and the dominant category of defects changes from sulphur vacancy in mechanical exfoliation and chemical vapour deposition samples to molybdenum antisite in physical vapour deposition samples. Influence of defects on electronic structure and charge-carrier mobility are predicted by calculation and observed by electric transport measurement. In light of these results, the growth of ultra-high-quality monolayer molybdenum disulphide appears a primary task for the community pursuing high-performance electronic devices. PMID- 25695375 TI - Discovery, understanding, and bioapplication of organic fluorophore: a case study with an indolizine-based novel fluorophore, Seoul-Fluor. AB - Owing to its high sensitivity and great applicability, the fluorescence phenomenon has been considered as an inevitable research tool in the modern scientific fields of chemistry, biology, materials science, biomedical science, and their interfaces. Many strategies have been pursued to understand and manipulate the photophysical properties of fluorescent materials, but the scientific community has been focused on the repeated application of existing organic fluorophores or the identification of unique fluorescence properties in a trial-and-error basis without systematic studies. Moreover, recent studies are emphasizing the necessity of deeper understanding about the structure photophysical property relationship of organic fluorophores for the development of better fluorescent probes. Herein, we provide an overview of a novel fluorescent molecular framework, Seoul-Fluor, which can be rationally engineered to furnish a wide variety of fluorophores in terms of the photophysical properties. Seoul-Fluor is built on an indolizine-based fluorescent platform with three different positions to introduce various substituents: R(1) and R(2) substituents for electronic perturbation; R(3) substituent as a functional handle for bioconjugation. Over the past decade, we have demonstrated that the Seoul Fluor system has (i) tunable and predictable emission wavelength covering a full visible-color range; (ii) controllable quantum yield via photoinduced electron transfer phenomenon; and (iii) environment-sensitive fluorogenic properties that can be modified through intramolecular charge transfer processes. We convincingly demonstrated the prediction of photophysical properties, that is, emission wavelength and quantum yield, through the construction of a systematic set of analogues and the subsequent analysis of their photophysical properties without the highly sophisticated theoretical support. Guided by quantifiable parameters such as the Hammett substituent constants or energy levels of the molecular orbitals, this unique organic fluorophore can serve as a versatile molecular platform for the development of novel fluorescent switchable biosensors and fluorogenic bioprobes. In this Account, we will discuss the discovery and recent progress made on Seoul-Fluor, the rational design of Seoul-Fluor-based bioprobes, and their practical applications to specific biological processes that are facilitated by systematic studies of the structure-photophysical property relationships. PMID- 25695376 TI - Lentivirus-mediated knockdown of rhomboid domain containing 1 inhibits colorectal cancer cell growth. AB - Rhomboid domain containing 1 (RHBDD1), is a member of the rhomboid protease family, which has a pivotal role in the progression of numerous severe malignancies. However, its role in colorectal carcinoma (CRC) remains to be elucidated. In the present study, RHBDD1 was shown to be widely expressed in CRC cell lines. Lentivirus-mediated RNA interference was employed to knockdown RHBDD1 expression in RKO CRC cells. Functional analyses indicated that depletion of RHBDD1 expression resulted in significantly reduced CRC cell proliferation and colony formation, and induced a G0/G1 phase cell cycle arrest. The findings of the present study suggest that RHBDD1 may contribute to CRC tumorigenesis and serve as a potential therapeutic target in human CRC. PMID- 25695377 TI - Origin and consequences of silicate glass passivation by surface layers. AB - Silicate glasses are durable materials, but are they sufficiently durable to confine highly radioactive wastes for hundreds of thousands years? Addressing this question requires a thorough understanding of the mechanisms underpinning aqueous corrosion of these materials. Here we show that in silica-saturated solution, a model glass of nuclear interest corrodes but at a rate that dramatically drops as a passivating layer forms. Water ingress into the glass, leading to the congruent release of mobile elements (B, Na and Ca), is followed by in situ repolymerization of the silicate network. This material is at equilibrium with pore and bulk solutions, and acts as a molecular sieve with a cutoff below 1 nm. The low corrosion rate resulting from the formation of this stable passivating layer enables the objective of durability to be met, while progress in the fundamental understanding of corrosion unlocks the potential for optimizing the design of nuclear glass-geological disposal. PMID- 25695378 TI - Echinococcus vogeli in immigrant from Suriname to the Netherlands. PMID- 25695379 TI - [Innovation and leadership: a legacy to the process of clinical, basic and technological research in the Instituto Nacional de Rehabilitacion]. PMID- 25695380 TI - Clinical and biochemical findings in Mexican patients with distal renal tubular acidosis. AB - INTRODUCTION: Renal tubular acidosis (RTA) is a rare disease characterized by a normal serum anion gap, sustained metabolic acidosis, low concentration of plasma bicarbonate, variable hyperchloremia and hypokalemia and conserved glomerular filtration rate. RTA is developed during the first year of life and produces failure to thrive and anorexia. Primary distal RTA (type 1) is a renal syndrome with a reduced ability to excrete the acid load through the collecting ducts and impairment to concentrate the urine causing polyuria and dehydration. OBJECTIVE: Evaluate the current health status and describe the clinical findings and progress of Mexican patients with distal RTA. Demonstrate the distal urinary acidification defect by measuring the urinary pCO2 tension in alkaline urines. MATERIAL AND METHODS: We looked for infants in tertiary care hospitals with a clinical history of normal serum anion gap, metabolic acidosis, hypokalemia, hyperchloremia, nephrocalcinosis, sensorineural hearing loss and inability for urine acidification under systemic metabolic acidosis. Biochemical analysis were performed periodically. Alkali medication was not suspended in one patient to assess urinary acidification with oral administration of sodium bicarbonate (2 mEq/Kg) and acetazolamide (500 mg/1.73 m2 body surface). Urinary pCO2 levels were determined at 60 and 90 min. RESULTS: Three children, one adolescent and one adult with distal RTA were found. They had an infant history of dehydration, failure to thrive, anorexia, vomiting, muscle paralysis, hypercalciuria, urinary infections, polyuria, polydipsia and polyhidramnios during pregnancy. Severe nephrocalcinosis was detected in all patients whereas sensorineural hearing loss was developed in four cases. Under the alkali medication all cases but one were normocalciuric. A patient developed kidney failure. The urinary acidification test confirmed the innability to eliminate the acid load. CONCLUSION: Early diagnosis in infancy and continuos alkali medication were of great benefit for most of the patients. Urinary pCO2 levels in alkaline urine provided an index for collecting duct hydrogen-ion secretion. To our knowledge this is the first report of mexican patients with distal RTA. PMID- 25695381 TI - Idiopathic granulomatous mastitis. Experience at a cancer center. AB - BACKGROUND: Idiopathic granulomatous mastitis (IGM) is a benign breast disease that has been described as a rare granulomatous inflammation (GI). It can mimic inflammatory breast cancer. MATERIAL AND METHODS: We included women with a diagnosis of IGM referred to an oncologic hospital between January 01, 2007 and to March 31, 2011, with diagnosis of breast cancer, in whom biopsy reported GI, without other cause related. The aim of this study was to review the clinical, radiologic and pathologic characteristics of a cohort of women with IGM. RESULTS: We analyzed 58 patients; mean age was 38 +/- 12 years. Mammography showed diffuse asymmetry (n = 19) and focal asymmetry (n = 13); breast ultrasound showed heterogeneous and hypoechoic areas (n = 28) and lumps (n = 21) as the most frequent lesions. All biopsies showed lobulocentric GI. Treatment included antibiotics (n = 20), steroids (n = 8), both treatments (n = 20), surgical excision (n = 3) and observation (n = 7). Forty-three patients (74%) had complete remission; mean time to remission was 9.5 +/- 5.8 months. Fifteen (26%) had partial remission. Any patient had progression or relapse. CONCLUSIONS: IGM is a benign breast condition that may mimic breast inflammatory cancer. Ultrasonography and mammography findings reveal characteristic data that can be useful for establishing the diagnosis; however, biopsy is the gold standard for its diagnosis and should be taken in any patient even with a mild suspicion of cancer. PMID- 25695382 TI - Impact of a federal program on response rate & survival, in a cohort of patients with diffuse large B-cell lymphoma. Analysis in a single national reference institution in Mexico. AB - The actual standard of care of diffuse large B-cell lymphoma (DLBCL) includes rituximab in combination with chemotherapy, with response rates up to 76%. However, this treatment may not be accessible to many patients, particularly in developing countries, where most of the treatment must be paid from the pocket of patients or their families. In Mexico, since 2011 a federal program has fully covered this treatment of patients with DLBCL. At the Instituto Nacional de Cancerologia (INCan) in Mexico City, 214 new cases with this disease were treated without cost with the standard of care in 20 months. The mean age at diagnosis was 56.7 +/- 15.9 (22-91). This series of cases was compared with a retrospective analysis of cases with DLBCL attended at the INCan between 2006-2009. A total of 264 cases were retrospectively analyzed. No differences were found in demographic and clinical characteristics at time of diagnosis. However a clear positive impact was found in the group that received full treatment thanks to this new social coverage by this new social security program. The follow-up and completion of treatment was 99 %. In contrast; from 264 in the retrospective group (79%) were treated, but only 29 (10.9%) were able to receive an optimal treatment, including rituximab. These differences in treatments had a clearly impact on the response rate: 66.8 vs. 50.7% global response (full treatment vs. retrospective group, respectively). These results demonstrate the importance of social programs that may accessible standard treatment options in countries with limited resources. PMID- 25695383 TI - Association of fatty liver with cardiovascular risk factors and subclinical atherosclerosis in a Mexican population. AB - INTRODUCTION: Individuals with fatty liver (FL) have an increased risk of coronary artery disease (CAD) probably due to its association with cardiometabolic risk factors (CMRF). OBJECTIVE: To know the prevalence of FL and analyze its association with CMRF and subclinical atherosclerosis, in a sample of Mexican Mestizo population. MATERIAL AND METHODS: This study included 846 subjects from the Genetic of Atherosclerosis Disease (GEA) study (53 +/- 9 years, 50.7% women) without diabetes and no personal or family history of premature CAD. Blood samples were taken for measurements of lipids profile, uric acid, and insulin. The presence of FL was identified by computed tomography. Carotid intima media thickness (CIMT) was measured by B mode ultrasound, using the > 75 percentile as cutoff value to define subclinical atherosclerosis. RESULTS: The general prevalence of FL was 32.4%. In men, FL was associated with hyperuricemia, whereas in women, hyperuricemia, low level of high density lipoprotein cholesterol, and metabolic syndrome were the factors associated with this hepatic alteration. In women, FL was associated with a 66% higher probability of having high CIMT, independently of age, hypertension, dyslipidemia, and waist circumference, but not of HOMA-IR. CONCLUSIONS: In women, FL was associated with the presence of subclinical atherosclerosis independently of traditional CMRF. Our study suggests that, in women, insulin resistance could be a mediator of metabolic abnormalities and of subclinical atherosclerosis. PMID- 25695384 TI - Audiometric evaluation short and medium term in cochlear implants. AB - OBJECTIVE: Our purpose is report the results of cochlear implant program in this Institute, since our first surgery from November 2007, until December 2012. MATERIAL AND METHODS: A cross-sectional study, observational, descriptive, analyzing the information about thresholds before and after implantation, using patients files (diagnosis, onset of hearing loss, brainstem auditory evoked potential (BAEP), computed tomography (CT), magnetic resonance imaging (MRI), implanted ear, brand and model of cochlear implants (CI) and audiometric studies before and after the CI. RESULTS: We report the evolution of 68 patients, age ranged 1 year 8 months to 39 years 3 months old. 94% patients (n = 64) had pre lingual hearing loss being hereditary non-syndromic hearing loss the most common etiology (29.4%). 100% patients had auditory brainstem responses showing bilateral profound hearing loss, in the 77.9% type A tympanograms were obtained (Jerger's classification), and 100% had absence of stapedial reflexes and otoacoustic emissions with low reproducibility. CT reported as normal in 85.2% of patients, the findings: 5.8% had chronic mastoiditis changes, other findings reported in 1.4% of patients were: digastric right facial nerve, facial nerve canal dehiscence, enlarged vestibular aqueduct, occupation and poor pneumatization of mastoid air cells, lateral semicircular canals agenesis, incomplete partition of the cochlea with wide vestibular and vestibular aqueduct dilatation. Most frequent MR findings of skull with cerebellopontine angle approach were vascular loops of internal auditory canals unilaterally. In 10.2%, 55.8% of patients (n = 38) were implanted in the right ear, 56 (82.3%) with a CI from Advanced Bionics, HiRes 90K model, the remaining with Cochlear, Freedom and Nucleus 5 models. Developments in CI results by audiometric tests: prior to placement was 106.2 dB averages at frequencies assessed, one month later 62.4 dB, at 6 months 44 dB, and with satisfactory threshold 32.9 dB. 55.8% of patients (n = 38) with P + HiRes Fidelity 120 strategy, the remaining with Hires S + Fidelity 120, Hires S and ACE RE. DISCUSSION: Audiology service proposed to place the CI in the worst ear by threshold in audiometric tests, the otolaryngology service proposed the best ear from anatomical point view. Implanted in the INR more Advanced Bionics CI faq frequently due to the donation by the insurance for a new generation. Hearing thresholds using CI have improved since activation. PMID- 25695385 TI - Desynchronization/synchronization of parasagittal EEG rhythms during habituation to photostimulation in adults. AB - INTRODUCTION: Learning by habituation implies a gradual diminution of the organism's responses to non-relevant stimuli. These responses, resulting from electrical oscillations of the brain, can be analyzed through quantitative electroencephalography (qEEG). OBJECTIVE: To characterize the absolute power (AP) in the range of delta (delta), theta (theta), alpha (alpha), beta (beta) in cortical parasagittal regions during habituation to photostimulation (RPh). MATERIAL AND METHODS: We studied 81 undergraduate students. The EEG was recorded in a Nicolet; awake subjects with closed eyes were photostimulated (5 Hz for 2 s, 20 times, RPh). The UAMI/Yanez program identifies the RPh signal, chooses and collects 2-sec samples before (Pre) and during RPh, and instruments the Welch periodogram, which integrates the absolute power (AP) of delta, theta, alpha, and beta. We calculated the average AP (AAP) in Pre and RPh per frequency and lead. AAP differences were assessed with non-parametric tests. Linear regression was used to plot the AAPs of each Pre and each RPh sample, representing the resulting slope with its statistical significance. RESULTS: RPh increased the AAP of delta in frontal and frontocentral leads of both hemispheres, and its slopes were ascendant. AAP of theta increased in fronto-frontal and diminished in the other three leads, its slopes were ascendant in right central parietal and parieto occipital leads. AAP of alpha increased in fronto-frontal leads, did not change in fronto-central, and diminished in the other leads; its slopes were descendent in Pre and ascendant in RPh in both hemispheres. AAP of beta increased in the four leads; in Pre, beta slopes were descendent in parieto-occipital leads of both hemispheres. During RPh, delta slopes were ascendant in right parieto central and in both parieto-occipital leads. CONCLUSION: The progressive diminution of alpha's desynchronization, which ends in synchronization, is probably due to hyperpolarization of neuronal membranes and represents habituation. This is complemented with synchronization of the delta rhythm in anterior cortical areas and of theta and beta in areas of the right hemisphere. PMID- 25695386 TI - Intimate partner violence and depressive symptoms in pregnant Mexican women: national survey results. AB - OBJECTIVES: To analyze the link between intimate partner violence (IPV) reported in the past year and depressive symptoms in pregnant Mexican women. MATERIAL AND METHODS: The data were obtained from the National Addictions Survey (ENA) 2008. For the purposes of this paper, we analyzed a sample of women over 18 who reported being pregnant at the time of the interview (n = 250). When this number is weighted at the population level, it represents 881,575 women across the country. The chi2 test was used to analyze demographic characteristics, prevalence of depressive symptoms and intimate partner violence. A multiple logistic regression was performed to estimate predictors of depressive symptoms during pregnancy. RESULTS: The prevalence of any type of intimate partner violence (IPV) was 5.4% and of depressive symptoms was 16.2% (CES-D >= 16). A total of 53.4% of pregnant women who reported IPV during the past year had depressive symptoms whereas this occurred in 14.1% of those who had not been victimized. The variables that predicted depressive symptoms during pregnancy were having been a victim of IPV (OR = 6.23) and having nine years or less of schooling (OR = 5.26). Working outside the home and family income level did not increase the risk of depressive symptoms in this population. CONCLUSIONS: This population study, representative at the national level, provides an initial overview of the link between intimate partner violence and depressive symptoms in pregnant women in Mexico. The results highlight the need to expand research on the topics covered, as well as to detect both phenomena in a timely manner during pregnancy in order to propose the necessary care. PMID- 25695387 TI - The challenges of long-term sepsis survivors: when surviving is just the beginning. PMID- 25695388 TI - Gut microbiota as a key player in triggering obesity, systemic inflammation and insulin resistance. AB - Obesity-related systemic inflammation contributes to develop insulin resistance. The main factors involved in the relationship of obesity with systemic inflammation and insulin resistance have not been completely elucidated. Microbiota includes around 1013 to 1014 microbes harboring the human gut, which are clustered in approximately a thousand different bacterial species. Several studies suggest that imbalance in the intestinal bacterial population could result in obesity, systemic inflammation and metabolic dysfunction. Here, we review the main bacterial groups observed in obesity as well as their possible role in increasing the intestinal permeability and lipopolysaccharide-related endotoxemia. Furthermore, we point out the role of intestinal dysbiosis in the inflammatory activation of macrophages with the ability to infiltrate in the visceral adipose tissue and induce insulin resistance. Finally, we discuss the apparent beneficial use of prebiotics and probiotics in ameliorating both systemic inflammation and metabolic dysfunction. Present information may be useful in the future design of novel therapies focused on treating obesity and insulin resistance by restoring the gut microbiota balance. PMID- 25695389 TI - The microRNA biogenesis machinery: regulation by steroid hormones and alterations in cancer. AB - MicroRNAs are a class of non-coding RNAs that regulate gene expression at the post-transcriptional level. The major proteins of the canonical microRNA biogenesis pathway in human are: Drosha, DGCR8, DDX5, DDX17, Exportin 5, Dicer and Argonaute 2. Recent studies suggest that gene expression of some canonical microRNA biogenesis components could be regulated by steroid hormones. Furthermore, various alterations in microRNA biogenesis have been associated with diseases like cancer. Due to the importance of microRNAs in cell physiology, the study of the factors that regulate or affect their biogenesis is critical. PMID- 25695390 TI - [Challenges in controlling the spread of ebola and the need for a preparedness plan in Mexico]. PMID- 25695391 TI - Comparison of free kappa and lambda light chain immunoassays and total (bound and free) kappa and lambda light chain immunoassays. PMID- 25695392 TI - Unfolding a molecular trefoil derived from a zwitterionic metallopeptide to form self-assembled nanostructures. AB - While used extensively by nature to control the geometry of protein structures, and dynamics of proteins, such as self-organization, hydration forces and ionic interactions received less attention for controlling the behaviour of small molecules. Here we describe the synthesis and characterization of a novel zwitterionic metallopeptide consisting of a cationic core and three distal anionic groups linked by self-assembling peptide motifs. 2D NMR spectra, total correlated spectroscopy and nuclear Overhauser effect spectroscopy, show that the molecule exhibits a three-fold rotational symmetry and adopts a folded conformation in dimethyl sulfoxide due to Coulombic forces. When hydrated in water, the molecule unfolds to act as a self-assembling building block of supramolecular nanostructures. By combining ionic interactions with the unique geometry from metal complex and hydrophobic interactions from simple peptides, we demonstrate a new and effective way to design molecules for smart materials through mimicking a sophisticated biofunctional system using a conformational switch. PMID- 25695393 TI - Cholera in Yangon, Myanmar, 2012-2013. PMID- 25695394 TI - Vertical transmission of bacterial eye infections, Angola, 2011-2012. AB - To determine transmission rates for neonatal conjunctivitis causative microorganisms in Angola, we analyzed 312 endocervical and 255 conjunctival samples from mothers and newborns, respectively, during 2011-2012. Transmission rates were 50% for Chlamydia trachomatis and Neisseria gonorrhoeae and 10.5% for Mycoplasma genitalium. Possible pathogenic effects of M. genitalium in children's eyes are unknown. PMID- 25695395 TI - PGC-1alpha is responsible for survival of multiple myeloma cells under hyperglycemia and chemotherapy. AB - The association between hyperglycemia and outcomes during chemotherapy has been reported in several tumors, including multiple myeloma (MM). However, the underlying mechanism of how hyperglycemia affects the survival of MM cells during chemotherapy remain to be elucidated. MM cells were cultured in 10 mM glucose with or without chemotherapeutic agents. Following treatment of MM cells with dexamethasone or bortezomib, an MTT assay was used to evaluate the toxicity of dexamethasone or bortezomib on cell proliferation, and changes of reactive oxygen species (ROS) level were detected by flow cytometry (FCM) analysis. Small interference RNA (siRNA) was applied to inhibit the expression of peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha). Expressions of PGC-1alpha and antioxidant factors such as superoxide dismutase 2 (SOD-2), glutathione peroxidase 1 (GPX-1), and catalase (CAT) were measured by RT PCR prior to and following treatment. The results showed that the level of PGC 1alpha in MM cells cultured in high-glucose medium was upregulated prior to and following treatment of chemotherapeutic agents, and these cells showed less fold change of ROS after insult of drugs, when compared to the control. Genes encoding antioxidant factors such as SOD-2 and CAT were also upregulated. Inhibition of PGC-1alpha enhanced the toxicity of antitumor agents, associated with reduced expression of antioxidant factors, and elevated level of ROS. The present findings suggested that hyperglycemia may influence the anticancer effect of chemotherapeutic agents in MM by upregulating the expression of PGC-1alpha and associated antioxidant factors. Inhibition of PGC-1alpha or control of hyperglycemia may be beneficial in improving the efficacy of chemotherapy in MM patients with diabetes. PMID- 25695396 TI - miRNA-1207-5p is associated with cancer progression by targeting stomatin-like protein 2 in esophageal carcinoma. AB - Newly discovered intrinsic regulators, the miRNAs regulate gene expression by binding to the 3'-untranslated regions of the genome. Accumulating studies have indicated that miRNAs are aberrantly expressed in various human cancers. We found that miRNA-1207-5p (miR-1207-5p) was markedly downregulated in esophageal carcinoma (EC) tissues, and was correlated with EC differentiation, pathological stage and lymph node metastasis. Rates of apoptosis were increased and cell invasion ability was decreased in EC9706 and EC-1 cells transfected with a miR 1207-5p mimic. Stomatin-like protein 2 (STOML-2) was predicted to be a potential target of miR-1207-5p by bioinformatics analysis and this was confirmed by luciferase assay and western blotting. Our study showed that STOML-2 was negatively regulated by miR-1207-5p. Furthermore, overexpression of STOML-2 abolished the miR-1207-5p anti-invasion function. Based on these results, we proposed that miR-1207-5p might act as a potential therapeutic target in the treatment of EC. PMID- 25695397 TI - A comparative study of two different assay kits for the detection of secreted alkaline phosphatase in HPV antibody neutralization assays. AB - To assess immunogenicity and development of antibodies in the context of vaccination, it is critical to quantify titers of neutralizing antibodies. We have been employing the 293TT cell-based neutralization assay system to quantify anti-HPV neutralizing antibodies. In this system, human papillomavirus (HPV) pseudovirion (PsV) particles encapsidating secreted alkaline phosphatase (SEAP) gene are used to measure infection of 293TT cells in 72-hr cell-culture supernatants. SEAP has traditionally been measured by Great EscAPeTM SEAP Chemiluminescence Kit 2.0 (GE). To reduce the cost, and to potentially increase efficiency, we sought a cheaper kit with better detection capability. Performance characteristics of the newer chemiluminescence kit, ZiVa(r) Ultra SEAP Plus Assay (Ziva) and GE were compared using the 293TT system. Dose titration of HPV PsV 16 or 18 showed that signal-to-noise ratios at 48 and 72 hr post-infection were higher for ZiVa at nearly all doses. ZiVa was superior to GE as it was able to detect SEAP at 48 hr, as well as when lower numbers of 293TT cells were used. The ability of ZiVa to quantitate HPV-16 and -18 neutralizing antibody titers was tested using sera from Cervarix(r) immunized individuals. Spearman rank correlational analyses showed excellent correlations between the titers obtained with ZiVa and GE for anti-HPV16 (r = 0.9822, p < 0.0001) and anti-HPV18 (r = 0.9832, p < 0.0001) antibodies. We concluded that ZiVa is superior to GE in detecting SEAP, and the antibody titers in sera of vaccinated individuals were similar to those obtained with GE. Thus, Ziva is a suitable alternative to GE. PMID- 25695398 TI - PT-1 selectively activates AMPK-gamma1 complexes in mouse skeletal muscle, but activates all three gamma subunit complexes in cultured human cells by inhibiting the respiratory chain. AB - AMP-activated protein kinase (AMPK) occurs as heterotrimeric complexes in which a catalytic subunit (alpha1/alpha2) is bound to one of two beta subunits (beta1/beta2) and one of three gamma subunits (gamma1/gamma2/gamma3). The ability to selectively activate specific isoforms would be a useful research tool and a promising strategy to combat diseases such as cancer and Type 2 diabetes. We report that the AMPK activator PT-1 selectively increased the activity of gamma1- but not gamma3-containing complexes in incubated mouse muscle. PT-1 increased the AMPK-dependent phosphorylation of the autophagy-regulating kinase ULK1 (unc-51 like autophagy-activating kinase 1) on Ser555, but not proposed AMPK-gamma3 substrates such as Ser231 on TBC1 (tre-2/USP6, BUB2, cdc16) domain family, member 1 (TBC1D1) or Ser212 on acetyl-CoA carboxylase subunit 2 (ACC2), nor did it stimulate glucose transport. Surprisingly, however, in human embryonic kidney (HEK) 293 cells expressing human gamma1, gamma2 or gamma3, PT-1 activated all three complexes equally. We were unable to reproduce previous findings suggesting that PT-1 activates AMPK by direct binding between the kinase and auto-inhibitory domains (AIDs) of the alpha subunit. We show instead that PT-1 activates AMPK indirectly by inhibiting the respiratory chain and increasing cellular AMP:ATP and/or ADP:ATP ratios. Consistent with this mechanism, PT-1 failed to activate AMPK in HEK293 cells expressing an AMP-insensitive R299G mutant of AMPK-gamma1. We propose that the failure of PT-1 to activate gamma3-containing complexes in muscle is not an intrinsic feature of such complexes, but is because PT-1 does not increase cellular AMP:ATP ratios in the specific subcellular compartment(s) in which gamma3 complexes are located. PMID- 25695399 TI - Common genetic risk for melanoma encourages preventive behavior change. AB - There is currently great interest in using genetic risk estimates for common disease in personalized healthcare. Here we assess melanoma risk-related preventive behavioral change in the context of the Coriell Personalized Medicine Collaborative (CPMC). As part of on-going reporting activities within the project, participants received a personalized risk assessment including information related to their own self-reported family history of melanoma and a genetic risk variant showing a moderate effect size (1.7, 3.0 respectively for heterozygous and homozygous individuals). Participants who opted to view their report were sent an optional outcome survey assessing risk perception and behavioral change in the months that followed. Participants that report family history risk, genetic risk, or both risk factors for melanoma were significantly more likely to increase skin cancer preventive behaviors when compared to participants with neither risk factor (ORs = 2.04, 2.79, 4.06 and p-values = 0.02, 2.86 * 10-5, 4.67 * 10-5, respectively), and we found the relationship between risk information and behavior to be partially mediated by anxiety. Genomic risk assessments appear to encourage positive behavioral change in a manner that is complementary to family history risk information and therefore may represent a useful addition to standard of care for melanoma prevention. PMID- 25695400 TI - A role for actin polymerization in persistent pulmonary hypertension of the newborn. AB - Persistent pulmonary hypertension of the newborn (PPHN) is defined as the failure of normal pulmonary vascular relaxation at birth. Hypoxia is known to impede postnatal disassembly of the actin cytoskeleton in pulmonary arterial myocytes, resulting in elevation of smooth muscle alpha-actin and gamma-actin content in elastic and resistance pulmonary arteries in PPHN compared with age-matched controls. This review examines the original histological characterization of PPHN with attention to cytoskeletal structural remodeling and actin isoform abundance, reviews the existing evidence for understanding the biophysical and biochemical forces at play during neonatal circulatory transition, and specifically addresses the role of the cortical actin architecture, primarily identified as gamma-actin, in the transduction of mechanical force in the hypoxic PPHN pulmonary circuit. PMID- 25695401 TI - Prevalence of Streptococcus dysgalactiae subsp. equisimilis and S. equi subsp. zooepidemicus in a sample of healthy dogs, cats and horses. AB - AIMS: To estimate the prevalence of beta-haemolytic Lancefield group C streptococci in healthy dogs, cats and horses; to determine if frequent contact with horses was associated with isolation of these species from dogs and cats; and to characterise recovered S. equi subsp. zooepidemicus isolates by multilocus sequence typing. METHODS: Oropharyngeal swabs were collected from 197 dogs and 72 cats, and nasopharyngeal swabs from 93 horses. Sampling was carried out at the Massey University Veterinary Teaching Hospital, on sheep and beef farms or on premises where horses were present. All animals were healthy and were categorised as Urban dogs and cats (minimal contact with horses or farm livestock), Farm dogs (minimal contact with horses) and Stable dogs and cats (frequent contact with horses). Swabs were cultured for beta-haemolytic Streptococcus spp. and Lancefield group C streptococcal subspecies were confirmed by phenotypic and molecular techniques. RESULTS: Of the 197 dogs sampled, 21 (10.7 (95% CI= 4.0 25.4)%) tested positive for S. dysgalactiae subsp. equisimilis and 4 (2.0 (95% CI=0.7-5.5)%) tested positive for S. equi subsp. zooepidemicus. All these isolates, except for one S. dysgalactiae subsp. equisimilis isolate in an Urban dog, were from Stable dogs. S. dysgalactiae subsp. equisimilis was isolated from one Stable cat. Of the 93 horses, 22 (23.7 (95% CI=12.3-40.6)%) and 6 (6.5 (95% CI=2.8-14.1)%) had confirmed S. dysgalactiae subsp. equisimilis and S. equi subsp. zooepidemicus isolation respectively. Isolation of S. dysgalactiae subsp. equisimilis from dogs was associated with frequent contact with horses (OR=9.8 (95% CI=2.6-72.8)). Three different multilocus sequence type profiles of S. equi subsp. zooepidemicus that have not been previously reported in dogs were recovered. CONCLUSIONS AND CLINICAL RELEVANCE: Subclinical infection or colonisation by S. equi subsp. zooepidemicus and S. dysgalactiae subsp. equisimilis occurs in dogs and further research on inter-species transmission and the pathogenic potential of these Lancefield group C streptococci is needed. Complete speciation of beta-haemolytic streptococci should be recommended in clinical cases and the possible exposure to horses and their environment should be considered in epidemiological investigations. PMID- 25695402 TI - Role of tenascins in the ECM of gliomas. AB - Tenascins are a family of extracellular matrix molecules that are mainly expressed in embryonic development and down-regulated in adulthood. A re expression in the adult occurs under pathological conditions such as inflammation, regeneration or neoplasia. As the most prominent member of the tenascin family, TN-C, is highly expressed in glioma tissue and rising evidence suggests that TN-C plays a crucial role in cell migration or invasion - the most fatal characteristics of glioma - also the other members of this protein family have been investigated with regard to their impact on glioma biology. For all tenascins correlations between the expression levels of the different family members and the degree of malignancy and invasiveness of glial tumors could be detected. Overall, the former and recent results in the research on glioma and tenascins point at distinct roles of each of the molecules in glioma biology and the devastating properties of these tumors. PMID- 25695403 TI - CXCR2 Antagonist MK-7123. A Phase 2 Proof-of-Concept Trial for Chronic Obstructive Pulmonary Disease. AB - RATIONALE: An antagonist (MK-7123) of the cytokine receptor CXCR2 reduces neutrophil chemotaxis and thus may alleviate airway inflammation in chronic obstructive pulmonary disease (COPD). OBJECTIVES: To assess the efficacy, safety, and tolerability of three dose levels of MK-7123, compared with placebo, in patients with moderate to severe COPD. METHODS: This 6-month, double-blind study randomized patients with moderate to severe COPD (already on standard therapy) to daily MK-7123 at 10, 30, or 50 mg or placebo. The primary endpoint was change from baseline in post-bronchodilator FEV1. MEASUREMENTS AND MAIN RESULTS: A total of 616 patients (71% male; mean age, 63 yr; 45% current smokers; baseline FEV1 [SD], 1.43 L [0.45]; mean FEV1 percent predicted, 43.9%) were randomized. Only MK 7123 50 mg led to significant improvement in FEV1 over placebo (mean difference [SE], 67 ml [32]). Reduced sputum neutrophil count was observed among the 122 patients examined; P = 0.003 (3 mo) and P = 0.092 (6 mo) (MK-7123 50 mg vs. placebo). The stratum of current smokers, but not that of nonsmokers, showed significant improvement versus placebo in FEV1 (168 ml) and time-to-first exacerbation, and showed numerical improvement in St. George's Respiratory Questionnaire for COPD score. MK-7123 caused a dose-dependent decrease in absolute neutrophil count (ANC) and reduced inflammatory biomarkers matrix metallopeptidase-9 and myeloperoxidase in plasma and sputum; ANC lower than 1.5 * 10(9)/L led to discontinuations with higher doses of MK-7123 (18% in the MK-7123 50-mg group vs. 1% in placebo). Plasma C-reactive protein and fibrinogen increased with MK-7123 treatment. Rates of infections at 6 months were similar in all groups. CONCLUSIONS: Treatment with MK-7123 50 mg versus placebo led to significant improvement in FEV1 in patients with COPD, suggesting clinically important antiinflammatory effects with CXCR2 antagonism, although dose-related discontinuations were observed because of ANC decreases with MK-7123. Greater response was observed in smokers versus ex-smokers. Clinical trial registered with www.clinicaltrials.gov (NCT 01006616). PMID- 25695405 TI - TRIM proteins legitimately enter the MAGEic RING. PMID- 25695406 TI - Optimizing antiviral therapy for influenza: understanding the evidence. AB - Influenza is an important cause of annual epidemics of respiratory viral infection associated with significant morbidity and mortality. Three classes of drugs, the M2 ion channel, neuraminidase and RNA-dependent RNA polymerase inhibitors, are approved for the prevention and treatment of influenza. Due to widespread resistance to the class, the M2 ion channel inhibitors are not recommended currently for therapy. The only polymerase inhibitor, favipiravir, is approved only in Japan and its use is highly restricted. Despite significant data to support the early use of the neuraminidase inhibitors, their use in all patient populations is suboptimal. The data to support the early use of neuraminidase inhibitors will be reviewed, as will current data on the utilization rates in ambulatory and hospitalized populations. PMID- 25695407 TI - Molecular Mechanisms of Interaction Between Human Immune Cells and Far Eastern Tick-Borne Encephalitis Virus Strains. AB - Although studies have established that immune mechanisms are important in controlling tick-borne encephalitis virus (TBEV) infection, the interactions of different TBEV strains with cells of innate and adaptive immunity are not well understood. In this study, the ability of two Far Eastern subtype TBEV strains (Dal'negorsk and Primorye-183) with various degrees of pathogenicity for humans to modulate the expression of membrane molecules differently on human immune cells were investigated using a whole-blood flow cytometry-based assay. The whole blood samples (from 10 healthy donors) were infected with TBEV strains and analyzed for the virus binding to the blood cells, as well as expression of adhesion (CD11b and ICAM-1) and activation (CD69, CD25, CD95) molecules on the surfaces of monocytes, granulocytes, natural killer (NK) cells, and T-lymphocytes (CD4+, CD8+) at selected times (3, 6, and 24 h post-infection). It was found that the highly pathogenic Dal'negorsk strain penetrated rapidly and was actively replicated in the blood cells, inducing downregulation of CD11b, ICAM-1, and CD69 on monocytes and a significant decrease of NK cells expressing CD69, CD25, CD95, and CD8 T-lymphocytes expressing CD69 compared with the mock-infected cells. The nonpathogenic Primorye-183 strain penetrated slowly and was replicated in the blood cells, but caused a significant increase in the adhesion and activation of molecule expression to trigger innate defense mechanisms and enable the rapid elimination of the virus from the organism. Thus, TBEV-induced activation or suppression of adhesion and activation receptors expression form an essential part of fundamental virus properties, that is, virulence and pathogenicity. PMID- 25695408 TI - Post-assembly atomic layer deposition of ultrathin metal-oxide coatings enhances the performance of an organic dye-sensitized solar cell by suppressing dye aggregation. AB - Dye aggregation and concomitant reduction of dye excited-state lifetimes and electron-injection yields constitute a significant mechanism for diminution of light-to-electrical energy conversion efficiencies in many dye-sensitized solar cells (DSCs). For TiO2-based DSCs prepared with an archetypal donor-acceptor organic dye, (E)-2-cyano-3-(5'-(5''-(p-(diphenylamino)phenyl)-thiophen-2'' yl)thiophen-2'-yl)acrylic acid (OrgD), we find, in part via ultrafast spectroscopy measurements, that postdye-adsorption atomic layer deposition (ALD) of ultrathin layers of either TiO2 or Al2O3 effectively reverses residual aggregation. Notably, the ALD treatment is significantly more effective than the widely used aggregation-inhibiting coadsorbent, chenodeoxycholic acid. Primarily because of reversal of OrgD aggregation, and resulting improved injection yields, ALD post-treatment engenders a 30+% increase in overall energy conversion efficiency. A secondary contributor to increased currents and efficiencies is an ALD-induced attenuation of the rate of interception of injected electrons, resulting in slightly more efficient charge collection. PMID- 25695404 TI - Molecular basis of Klotho: from gene to function in aging. AB - The discovery of the Klotho (KL) gene, which was originally identified as a putative aging-suppressor gene, has generated tremendous interest and has advanced understanding of the aging process. In mice, the overexpression of the KL gene extends the life span, whereas mutations to the KL gene shorten the life span. The human KL gene encodes the alpha-Klotho protein, which is a multifunctional protein that regulates the metabolism of phosphate, calcium, and vitamin D. alpha-Klotho also may function as a hormone, although the alpha-Klotho receptor(s) has not been found. Point mutations of the KL gene in humans are associated with hypertension and kidney disease, which suggests that alpha-Klotho may be essential to the maintenance of normal renal function. Three alpha-Klotho protein types with potentially different functions have been identified: a full length transmembrane alpha-Klotho, a truncated soluble alpha-Klotho, and a secreted alpha-Klotho. Recent evidence suggests that alpha-Klotho suppresses the insulin and Wnt signaling pathways, inhibits oxidative stress, and regulates phosphatase and calcium absorption. In this review, we provide an update on recent advances in the understanding of the molecular, genetic, biochemical, and physiological properties of the KL gene. Specifically, this review focuses on the structure of the KL gene and the factors that regulate KL gene transcription, the key sites in the regulation of alpha-Klotho enzyme activity, the alpha-Klotho signaling pathways, and the molecular mechanisms that underlie alpha-Klotho function. This current understanding of the molecular biology of the alpha-Klotho protein may offer new insights into its function and role in aging. PMID- 25695409 TI - Enantioselective synthesis of alpha-phenyl- and alpha (dimethylphenylsilyl)alkylboronic esters by ligand mediated stereoinductive reagent-controlled homologation using configurationally labile carbenoids. AB - Chain extension of boronic esters by the action of configurationally labile racemic lithium carbenoids in the presence of scalemic bisoxazoline ligands was explored for the enantioselective synthesis of the two title product classes. Enantioenriched 2 degrees carbinols generated by oxidative work-up (NaOOH) of initial alpha-phenylalkylboronate products were obtained in 35-83% yield and 70 96% ee by reaction of B-alkyl and B-aryl neopentyl glycol boronates with a combination of O-(alpha-lithiobenzyl)-N,N-diisopropylcarbamate and ligand 3,3 bis[(4S)-4,5-dihydro-4-isopropyloxazol-2-yl] pentane in toluene solvent (-78 degrees C to rt) with MgBr2.OEt2 additive. Enantioenriched alpha (dimethylsilylphenylsilyl)alkylboronates were obtained in 35-69% yield and 9-57% ee by reaction of B-alkyl pinacol boronates with a combination of lithio(dimethylphenylsilyl)methyl 2,4,6-triisopropylbenzoate and ligand 2,2 bis[(4S)-4,5-dihydro-4-isopropyloxazol-2-yl]propane in cumene solvent (-45 degrees C to -95 degrees C to rt). The stereochemical outcome of the second type of reaction depended on the temperature history of the organolithium.ligand complex indicating that the stereoinduction mechanism in this case involves some aspect of dynamic thermodynamic resolution. PMID- 25695410 TI - Bioactivity, stability and phenolic characterization of Filipendula ulmaria (L.) Maxim. AB - The purpose of the present study was to evaluate the antioxidant and antimicrobial potential of Filipendula ulmaria (L.) Maxim. methanolic extracts, their stabilities under different pH and thermal conditions and in vitro digestibility. The results showed a considerable content of phenolic compounds in the extracts, especially total phenolic acids (47.47 mg CAE g(-1)) and flavonoids (45.47 mg RUE g(-1)) in aerial parts. HPLC analysis indicated the presence of spiraeoside in the aerial part extract. The extracts revealed an interesting antimicrobial effect against the tested microorganisms, especially bacteria E. coli and E. faecalis (MIC 0.156-0.625 mg mL(-1)), and fungi P. cyclopium and F. oxysporum (MIC 2.5-5 mg mL(-1)). The extracts exerted high antioxidant activities, particularly the root extract, paralleled by their considerable activities against the lipid oxidation process. The results of this study suggest that both extracts potentially could be functional food ingredients considering their good antioxidant and antimicrobial activities, and stability under different conditions. PMID- 25695412 TI - From evidence to practice. PMID- 25695411 TI - CMS sets new goals for reducing use of antipsychotic medications. PMID- 25695413 TI - Cholesterol management in geriatric patients: new guidelines. AB - Pharmacists play an important role in the management of primary care disease states such as hypercholesterolemia. The 2013 American College of Cardiology/American Heart Association (ACC/AHA) guidelines provide the pharmacist with pertinent treatment recommendations relevant to day-to-day clinical practice and geriatric care. This article reviews these new evidencebased guidelines for cholesterol management in general and for the elderly specifically. The new guidelines have implications for older adults remaining on or starting statin therapy. With this review, and based on the new guidelines, pharmacists will be informed on how to provide hyperlipidemia recommendations for the older adult. Monitoring of therapy, as well as adverse effects, will be reviewed, including differences among various practice settings. PMID- 25695414 TI - Updates in antiarrhythmic therapy for atrial fibrillation in geriatric patients. AB - OBJECTIVE: To provide a review of the current evidence for the use of antiarrhythmic therapy in the geriatric population. DATA SOURCES: A PubMed search of articles in the English language published from 1990 through August 2014 was performed using a combination of the following words: amiodarone, antiarrhythmic, atrial fibrillation, dofetilide, dronedarone, elderly, flecainide, geriatric, propafenone, sotalol. STUDY SELECTION/DATA EXTRACTION: Relevant original studies, review articles, and guidelines were assessed for use of antiarrhythmic therapy to manage atrial fibrillation (A fib) in the elderly. References from the above literature were also evaluated and included based on their relevance. DATA SYNTHESIS: The incidence of A fib increases as the population ages, which creates an increased need for clinicians to understand the place of antiarrhythmic therapy in management of A fib. This article provides a review of the current literature regarding this high-risk class of medications in the elderly population, with a focus on monitoring parameters and clinical considerations in the geriatric population. CONCLUSION: Elderly patients are more susceptible to the adverse effects of antiarrhythmic medications as a result of multiple factors, including decreased clearance and metabolism of medications as well as interactions caused by comorbid conditions and medications. Pharmacists can play a key role in a multidisciplinary team to monitor and educate patients on their antiarrhythmic therapy. PMID- 25695415 TI - Inhaler misuse in an older adult population. AB - OBJECTIVE: To determine the prevalence of inhaler misuse in an older adult population. DESIGN: Prospective observational study. SETTING: Two primary care outpatient clinics in a Veterans Affairs Medical Center in North Carolina. PARTICIPANTS: Male veterans 65 years of age and older (N = 24) prescribed a pressurized metered dose inhaler (pMDI) or a dry powder inhaler (DPI). MEASUREMENTS: Inhaler technique was evaluated using placebo inhaler devices and a standardized technique assessment form that included critical steps. Potential risk factors for misuse were obtained from the medical record, and the time for technique evaluation was collected. MAIN RESULTS: Study participants yielded 44 unique device observations. Patients were male with an average age of 82 years. All patients made at least one error, with a mean error rate of 2.5 errors/patient/inhaler, while 20 of 24 (83%) patients made at least one critical error with a mean error rate of 1.2 critical errors/patient/inhaler. Assessment of inhaler technique required 2.3 minutes/inhaler. Critical errors were made during 15 of 19 (79%) pMDI observations and 22 of 25 (88%) DPI observations. Patients with multiple inhalers or a history of stroke committed errors more often, although no risk factors demonstrated meaningful differences in error rates. CONCLUSIONS: Inhaler misuse in older adults is common, including committing critical errors that have been shown to reduce drug delivery. The time necessary for technique evaluation is relatively small. The high rate of misuse observed should serve as motivation for increased vigilance, individualized technique education, and routine re-assessment in the highly heterogeneous older adult population. PMID- 25695416 TI - An overview and study of beneficiaries' knowledge, attitudes, and perceptions of the medicare part d benefit. AB - PURPOSE: Medicare beneficiaries' knowledge, attitudes, and perceptions (KAP) of the Medicare Part D prescription drug benefit have been under evaluation since the 2006 inception of the Part D benefit. OBJECTIVE: This study sought to examine beneficiaries' satisfaction with their Medicare Part D prescription drug plan, knowledge of the coverage gap, attitudes about the relative importance of certain insurance parameters, and overall perceptions of the Part D benefit. DESIGN: Cross-sectional, descriptive study design. SETTING: Thirteen outreach events targeting Medicare beneficiaries in northern California during the 2012 open enrollment period. PARTICIPANTS: A total of 576 Medicare beneficiaries. INTERVENTIONS: Beneficiaries were asked questions related to their KAP of the Part D benefit as part of a plan to evaluate their need for assistance. Sociodemographic data were collected via a standardized survey. MAIN OUTCOME MEASURES: Identify variances in KAP related to beneficiary sociodemographic and clinical characteristics. RESULTS: Forty-seven percent of beneficiaries claimed to be "very" or "extremely" satisfied with Part D, yet only 40.3% of those with a prescription drug plan (PDP) rated their plan as "very good" or "excellent." Those automatically enrolled into their plan by Medicare were significantly less satisfied with their plan (P = 0.048). Almost three in four recipients not receiving Medicare subsidies have heard of the gap in prescription drug coverage, i.e., the "donut hole." Additionally, there were significant racial disparities in knowledge of the gap. Only 62.7% of beneficiaries indicated that "total out-of pocket cost during the year" was the most important plan characteristic for them. CONCLUSIONS: An understanding of beneficiaries' attitudes may help explain suboptimal Part D plan selection. Moreover, evaluating beneficiaries' knowledge of the Part D benefit can assist advocacy groups in creating educational materials to better assist this vulnerable population in choosing an appropriate plan. PMID- 25695417 TI - Alzheimer's disease and type 2 diabetes: what is the connection? AB - Alzheimer's disease (AD) is a progressive neurodegenerative condition primarily affecting individuals 65 years of age and older. There are few therapies available, and the disease is eventually fatal. Although the molecular mechanisms responsible for the development of AD remain unknown, a strong correlation between insulin dysfunction in type 2 diabetes mellitus and AD has recently been established. This has led to innovative research in the prevention and treatment of AD. Currently the most promising antidiabetic treatment options for AD are intranasal insulin and liraglutide, both of which are being investigated in ongoing clinical trials. Intranasal insulin showed promise in a pilot human trial, and while initial results appear positive, the clinical significance is unknown. Whereas current treatments only slow disease progression for a relatively short time, these new therapies may be able to reverse damage that has already occurred and potentially restore neurological function. PMID- 25695418 TI - Review of safety considerations in the elderly using sulfonylureas. AB - Sulfonylureas (SUs) are a class of medications used to treat type 2 diabetes mellitus that work by increasing insulin secretion in the pancreas. Second generation SUs are most often used today because of adverse effects with those in the first generation. However, there is still a risk of hypoglycemia even with the newer medications in the class. The American Diabetes Association encourages a patient-centered approach when initiating pharmacologic therapy. Understanding the pharmacokinetic differences among these medications can allow the consultant pharmacist to make a decision on which medication may be best suited for the patient. PMID- 25695419 TI - Atropine vs Patching. PMID- 25695420 TI - A new simple corneal limbal protection technique during corneal collagen cross linking. PMID- 25695421 TI - Protein corona composition of gold nanoparticles/nanorods affects amyloid beta fibrillation process. AB - Protein fibrillation process (e.g., from amyloid beta (Abeta) and alpha synuclein) is the main cause of several catastrophic neurodegenerative diseases such as Alzheimer's and Parkinson diseases. During the past few decades, nanoparticles (NPs) were recognized as one of the most promising tools for inhibiting the progress of the disease by controlling the fibrillation kinetic process; for instance, gold NPs have a strong capability to inhibit Abeta fibrillations. It is now well understood that a layer of biomolecules would cover the surface of NPs (so called "protein corona") upon the interaction of NPs with protein sources. Due to the fact that the biological species (e.g., cells and amyloidal proteins) "see" the protein corona coated NPs rather than the pristine coated particles, one should monitor the fibrillation process of amyloidal proteins in the presence of corona coated NPs (and not pristine coated ones). Therefore, the previously obtained data on NPs effects on the fibrillation process should be modified to achieve a more reliable and predictable in vivo results. Herein, we probed the effects of various gold NPs (with different sizes and shapes) on the fibrillation process of Abeta in the presence and absence of protein sources (i.e., serum and plasma). We found that the protein corona formed a shell at the surface of gold NPs, regardless of their size and shape, reducing the access of Abeta to the gold inhibitory surface and, therefore, affecting the rate of Abeta fibril formation. More specifically, the anti-fibrillation potencies of various corona coated gold NPs were strongly dependent on the protein source and their concentrations (10% serum/plasma (simulation of an in vitro milieu) and 100% serum/plasma (simulation of an in vivo milieu)). PMID- 25695422 TI - Effectiveness of a Multifaceted Community-Based Promotion Strategy on Use of GetHealthyHarlem.org, a Local Community Health Education Website. AB - The use of health communication extends beyond simply promoting or disseminating a particular product or proposed behavior change; it involves the systematic and strategic integration and execution of evidence-based, theory-driven, and community engagement strategies. Much like in public health intervention design based on health behavior theory, health communication seeks to encourage the target audience to make a positive behavior change through core concepts such as understanding and specifying the target audience, tailoring messages based on audience segmentation, and continually conducting evaluation of specific and overarching goals. While our first article "Development of a Culturally Relevant Consumer Health Information Website for Harlem, New York" focused on the design, development, and initial implementation of GetHealthyHarlem.org between 2004 and 2009, this article delves into the process of promoting the website to increase its use and then evaluating use among website visitors. Just as for the development of the website, we used community-based participatory research methods, health behavior theory, and health communication strategies to systemically develop and execute a health communication plan with the goals of increasing awareness of GetHealthyHarlem.org in Harlem, driving online traffic, and having the community recognize it as a respected community resource dedicated to improving health in Harlem. PMID- 25695423 TI - Room-temperature voltage tunable phonon thermal conductivity via reconfigurable interfaces in ferroelectric thin films. AB - Dynamic control of thermal transport in solid-state systems is a transformative capability with the promise to propel technologies including phononic logic, thermal management, and energy harvesting. A solid-state solution to rapidly manipulate phonons has escaped the scientific community. We demonstrate active and reversible tuning of thermal conductivity by manipulating the nanoscale ferroelastic domain structure of a Pb(Zr0.3Ti0.7)O3 film with applied electric fields. With subsecond response times, the room-temperature thermal conductivity was modulated by 11%. PMID- 25695424 TI - Mitogen-activated protein kinase phosphatase-1: a critical phosphatase manipulating mitogen-activated protein kinase signaling in cardiovascular disease (review). AB - Mitogen-activated protein kinase (MAPK) cascades are important players in the overall representation of cellular signal transduction pathways, and the deregulation of MAPKs is involved in a variety of diseases. The activation of MAPK signals occurs through phosphorylation by MAPK kinases at conserved threonine and tyrosine (Thr-Xaa-Tyr) residues. The mitogen-activated protein kinase phosphatases (MKPs) are a major part of the dual-specificity family of phosphatases and specifically inactivate MAPKs by dephosphorylating both phosphotyrosine and phosphoserine/phosphothreonine residues within the one substrate. MAPKs binding to MKPs can enhance MKP stability and activity, providing an important negative-feedback control mechanism that limits the MAPK cascades. In recent years, accumulating and compelling evidence from studies mainly employing cultured cells and mouse models has suggested that the archetypal MKP family member, MKP-1, plays a pivotal role in cardiovascular disease as a major negative modulator of MAPK signaling pathways. In the present review, we summarize the current knowledge on the pathological properties and the regulation of MKP-1 in cardiovascular disease, which may provide valuable therapeutic options. PMID- 25695425 TI - Semisynthetic Studies on and Biological Evaluation of N-Methyllaurotetanine Analogues as Ligands for 5-HT Receptors. AB - N-Methyllaurotetanine (1) has been reported to display good affinity for the 5 HT1A receptor, but no structure-affinity studies have been performed to date. The commercially available alkaloid boldine (2) was used as the starting material for synthesis of various C-9 alkoxy analogues of N-methyllaurotetanine in order to gauge the effect of C-9 alkylation on affinity and selectivity at 5-HT1A, 5-HT2A, and 5-HT7 receptors. Mitsunobu reactions were implemented in the alkylation steps leading to the analogues. Modest improvement in 5-HT1A affinity was observed upon alkylation for most analogues. Thus, the C-9 hydroxy group of 1 is not critical for affinity to the 5-HT1A receptor. Some analogues displayed high affinity for the 5-HT7 receptor, comparable to N-methyllaurotetanine, with moderate selectivity vs 5-HT1A and 5-HT2A receptors. PMID- 25695426 TI - Inhibition of personally-relevant angry faces moderates the effect of empathy on interpersonal functioning. AB - While empathy is typically assumed to promote effective social interactions, it can sometimes be detrimental when it is unrestrained and overgeneralized. The present study explored whether cognitive inhibition would moderate the effect of empathy on social functioning. Eighty healthy young adults underwent two assessments six months apart. Participants' ability to suppress interference from distracting emotional stimuli was assessed using a Negative Affective Priming Task that included both generic and personally-relevant (i.e., participants' intimate partners) facial expressions of emotion. The UCLA Life Stress Interview and Empathy Quotient were administered to measure interpersonal functioning and empathy respectively. Multilevel modeling demonstrated that higher empathy was associated with worse concurrent interpersonal outcomes for individuals who showed weak inhibition of the personally-relevant depictions of anger. The effect of empathy on social functioning might be dependent on individuals' ability to suppress interference from meaningful emotional distractors in their environment. PMID- 25695427 TI - Matrix metalloproteinase 2 is required for ovulation and corpus luteum formation in Drosophila. AB - Ovulation is critical for successful reproduction and correlates with ovarian cancer risk, yet genetic studies of ovulation have been limited. It has long been thought that the mechanism controlling ovulation is highly divergent due to speciation and fast evolution. Using genetic tools available in Drosophila, we now report that ovulation in Drosophila strongly resembles mammalian ovulation at both the cellular and molecular levels. Just one of up to 32 mature follicles per ovary pair loses posterior follicle cells ("trimming") and protrudes into the oviduct, showing that a selection process prefigures ovulation. Follicle cells that remain after egg release form a "corpus luteum (CL)" at the end of the ovariole, develop yellowish pigmentation, and express genes encoding steroid hormone biosynthetic enzymes that are required for full fertility. Finally, matrix metalloproteinase 2 (Mmp2), a type of protease thought to facilitate mammalian ovulation, is expressed in mature follicle and CL cells. Mmp2 activity is genetically required for trimming, ovulation and CL formation. Our studies provide new insights into the regulation of Drosophila ovulation and establish Drosophila as a model for genetically investigating ovulation in diverse organisms, including mammals. PMID- 25695428 TI - Consistency across repeated eyewitness interviews: contrasting police detectives' beliefs with actual eyewitness performance. AB - In the legal system, inconsistencies in eyewitness accounts are often used to discredit witnesses' credibility. This is at odds with research findings showing that witnesses frequently report reminiscent details (details previously unrecalled) at an accuracy rate that is nearly as high as for consistently recalled information. The present study sought to put the validity of beliefs about recall consistency to a test by directly comparing them with actual memory performance in two recall attempts. All participants watched a film of a staged theft. Subsequently, the memory group (N = 84) provided one statement immediately after the film (either with the Self-Administered Interview or free recall) and one after a one-week delay. The estimation group (N = 81) consisting of experienced police detectives estimated the recall performance of the memory group. The results showed that actual recall performance was consistently underestimated. Also, a sharp decline of memory performance between recall attempts was assumed by the estimation group whereas actual accuracy remained stable. While reminiscent details were almost as accurate as consistent details, they were estimated to be much less accurate than consistent information and as inaccurate as direct contradictions. The police detectives expressed a great concern that reminiscence was the result of suggestive external influences. In conclusion, it seems that experienced police detectives hold many implicit beliefs about recall consistency that do not correspond with actual recall performance. Recommendations for police trainings are provided. These aim at fostering a differentiated view on eyewitness performance and the inclusion of more comprehensive classes on human memory structure. PMID- 25695429 TI - FHL1 reduces dystrophy in transgenic mice overexpressing FSHD muscular dystrophy region gene 1 (FRG1). AB - Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal-dominant disease with no effective treatment. The genetic cause of FSHD is complex and the primary pathogenic insult underlying the muscle disease is unknown. Several disease candidate genes have been proposed including DUX4 and FRG1. Expression analysis studies of FSHD report the deregulation of genes which mediate myoblast differentiation and fusion. Transgenic mice overexpressing FRG1 recapitulate the FSHD muscular dystrophy phenotype. Our current study selectively examines how increased expression of FRG1 may contribute to myoblast differentiation defects. We generated stable C2C12 cell lines overexpressing FRG1, which exhibited a myoblast fusion defect upon differentiation. To determine if myoblast fusion defects contribute to the FRG1 mouse dystrophic phenotype, this strain was crossed with skeletal muscle specific FHL1-transgenic mice. We previously reported that FHL1 promotes myoblast fusion in vitro and FHL1-transgenic mice develop skeletal muscle hypertrophy. In the current study, FRG1 mice overexpressing FHL1 showed an improvement in the dystrophic phenotype, including a reduced spinal kyphosis, increased muscle mass and myofiber size, and decreased muscle fibrosis. FHL1 expression in FRG1 mice, did not alter satellite cell number or activation, but enhanced myoblast fusion. Primary myoblasts isolated from FRG1 mice showed a myoblast fusion defect that was rescued by FHL1 expression. Therefore, increased FRG1 expression may contribute to a muscular dystrophy phenotype resembling FSHD by impairing myoblast fusion, a defect that can be rescued by enhanced myoblast fusion via expression of FHL1. PMID- 25695430 TI - Malassezia intra-specific diversity and potentially new species in the skin microbiota from Brazilian healthy subjects and seborrheic dermatitis patients. AB - Malassezia yeasts are part of the resident cutaneous microbiota, and are also associated with skin diseases such as seborrheic dermatitis (SD). The role these fungi play in skin diseases and why they are pathogenic for only some individuals remain unclear. This study aimed to characterize Malassezia microbiota from different body sites in healthy and SD subjects from Brazil. Scalp and forehead samples from healthy, mild SD and severe SD subjects were collected. Non-scalp lesions from severe SD patients were also sampled. 5.8S rDNA/ITS2 amplicons from Malassezia sp. were analyzed by RFLP and sequencing. Results indicate that Malassezia microbiota did not group according to health condition or body area. Phylogenetic analysis revealed that three groups of sequences did not cluster together with any formally described species, suggesting that they might belong to potential new species. One of them was found in high proportions in scalp samples. A large variety of Malassezia subtypes were detected, indicating intra specific diversity. Higher M. globosa proportions were found in non-scalp lesions from severe SD subjects compared with other areas, suggesting closer association of this species with SD lesions from areas other than scalp. Our results show the first panorama of Malassezia microbiota in Brazilian subjects using molecular techniques and provide new perspectives for further studies to elucidate the association between Malassezia microbiota and skin diseases. PMID- 25695431 TI - Genetic diversity of Mycobacterium tuberculosis from Guadalajara, Mexico and identification of a rare multidrug resistant Beijing genotype. AB - Determining the genetic diversity of M. tuberculosis strains allows identification of the distinct Mycobacterium tuberculosis genotypes responsible for tuberculosis in different regions. Several studies have reported the genetic diversity of M. tuberculosis strains in Mexico, but little information is available from the state of Jalisco. Therefore, the aim of this study was to determine the genetic diversity of Mycobacterium tuberculosis clinical isolates from Western Mexico. Sixty-eight M. tuberculosis isolates were tested for susceptibility to first-line drugs using manual Mycobacteria Growth Indicator Tube method and genotyped using spoligotyping and IS6110-restriction fragment length polymorphism (RFLP) pattern analyses. Forty-seven (69.1%) isolates were grouped into 10 clusters and 21 isolates displayed single patterns by spoligotyping. Three of the 21 single patterns corresponded to orphan patterns in the SITVITWEB database, and 1 new type that contained 2 isolates was created. The most prevalent lineages were T (38.2%), Haarlem (17.7%), LAM (17.7%), X (7.4%), S (5.9%), EAI (1.5%) and Beijing (1.5%). Six (12.8%) of the clustered isolates were MDR, and type 406 of the Beijing family was among the MDR isolates. Seventeen (26.2%) isolates were grouped into 8 clusters and 48 isolates displayed single patterns by IS6110-RFLP. Combination of IS6110-RFLP and spoligotyping reduced the clustering rate to 20.0%. The results show that T, Haarlem, and LAM are predominant lineages among clinical isolates of M. tuberculosis in Guadalajara, Mexico. Clustering rates indicated low transmission of MDR strains. We detected a rare Beijing genotype, SIT406, which was a highly resistant strain. This is the first report of this Beijing genotype in Latin America. PMID- 25695432 TI - A maternal high fat diet programmes endothelial function and cardiovascular status in adult male offspring independent of body weight, which is reversed by maternal conjugated linoleic acid (CLA) supplementation. AB - Maternal high fat intake during pregnancy and lactation can result in obesity and adverse cardio-metabolic status in offspring independent of postnatal diet. While it is clear that maternal high fat intake can cause hypertension in adult offspring, there is little evidence regarding the role of dietary interventions in terms of reversing these adverse effects. Conjugated linoleic acid (CLA) is an omega 6 fatty acid with beneficial effects in obesity and metabolic status. However, the impact of CLA supplementation in the context of pregnancy disorders and high fat diet-induced developmental programming of offspring cardio-metabolic dysfunction has not been investigated. We have utilised a model of maternal overnutrition to examine the effects of CLA supplementation on programmed endothelial dysfunction during adulthood. Female Sprague-Dawley rats were fed either a purified control diet (CON) or purified control diet supplemented with 1% CLA (of total fat), a purified high fat (HF) diet (45%kcal from fat) and a purified HF diet supplemented with 1% CLA (of total fat) (HFCLA). All dams were fed ad libitum throughout pregnancy and lactation. Offspring were fed a standard chow diet from weaning (day 21) until the end of the study (day 150). Systolic blood pressure (SBP) was measured at day 85 and 130 by tail cuff plethysmography. At day 150, offspring mesenteric vessels were mounted on a pressure myograph and vascular responses to agonist-induced constriction and endothelium-dependent vasodilators were investigated. SBP was increased at day 85 and 130 in HF and HFCLA adult male offspring compared to CON and CLA groups with no effect of CLA supplementation. An overall effect of a maternal HF diet was observed in adult male vessels with a reduced vasoconstrictor response to phenylephrine and blunted vasodilatory response to acetylcholine (ACh). Furthermore, HF and HFCLA offspring displayed a reduction in nitric oxide pathway function and an increased compensatory EDHF function when compared to CON and CLA groups. These data suggest that a maternal HF diet causes a developmental programming of endothelial dysfunction and hypertension in male offspring which can be partially improved by maternal CLA supplementation, independent of offspring body weight. PMID- 25695433 TI - Benfotiamine attenuates inflammatory response in LPS stimulated BV-2 microglia. AB - Microglial cells are resident immune cells of the central nervous system (CNS), recognized as key elements in the regulation of neural homeostasis and the response to injury and repair. As excessive activation of microglia may lead to neurodegeneration, therapeutic strategies targeting its inhibition were shown to improve treatment of most neurodegenerative diseases. Benfotiamine is a synthetic vitamin B1 (thiamine) derivate exerting potentially anti-inflammatory effects. Despite the encouraging results regarding benfotiamine potential to alleviate diabetic microangiopathy, neuropathy and other oxidative stress-induced pathological conditions, its activities and cellular mechanisms during microglial activation have yet to be elucidated. In the present study, the anti-inflammatory effects of benfotiamine were investigated in lipopolysaccharide (LPS)-stimulated murine BV-2 microglia. We determined that benfotiamine remodels activated microglia to acquire the shape that is characteristic of non-stimulated BV-2 cells. In addition, benfotiamine significantly decreased production of pro inflammatory mediators such as inducible form of nitric oxide synthase (iNOS) and NO; cyclooxygenase-2 (COX-2), heat-shock protein 70 (Hsp70), tumor necrosis factor alpha alpha (TNF-alpha), interleukin-6 (IL-6), whereas it increased anti inflammatory interleukin-10 (IL-10) production in LPS stimulated BV-2 microglia. Moreover, benfotiamine suppressed the phosphorylation of extracellular signal regulated kinases 1/2 (ERK1/2), c-Jun N-terminal kinases (JNK) and protein kinase B Akt/PKB. Treatment with specific inhibitors revealed that benfotiamine-mediated suppression of NO production was via JNK1/2 and Akt pathway, while the cytokine suppression includes ERK1/2, JNK1/2 and Akt pathways. Finally, the potentially protective effect is mediated by the suppression of translocation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) in the nucleus. Therefore, benfotiamine may have therapeutic potential for neurodegenerative diseases by inhibiting inflammatory mediators and enhancing anti-inflammatory factor production in activated microglia. PMID- 25695434 TI - A parallel implementation of the Wuchty algorithm with additional experimental filters to more thoroughly explore RNA conformational space. AB - We present new modifications to the Wuchty algorithm in order to better define and explore possible conformations for an RNA sequence. The new features, including parallelization, energy-independent lonely pair constraints, context dependent chemical probing constraints, helix filters, and optional multibranch loops, provide useful tools for exploring the landscape of RNA folding. Chemical probing alone may not necessarily define a single unique structure. The helix filters and optional multibranch loops are global constraints on RNA structure that are an especially useful tool for generating models of encapsidated viral RNA for which cryoelectron microscopy or crystallography data may be available. The computations generate a combinatorially complete set of structures near a free energy minimum and thus provide data on the density and diversity of structures near the bottom of a folding funnel for an RNA sequence. The conformational landscapes for some RNA sequences may resemble a low, wide basin rather than a steep funnel that converges to a single structure. PMID- 25695435 TI - Cold acid elution (ELU Kit II). AB - Elution is a procedure for recovery of antibody attached to intact,immunoglobulin coated red blood cells (RBCs) by disrupting the antigen-antibody bonds. The recovered antibody is collected in an inert diluent and is referred to as an eluate. Testing of an eluate may be desired to identify antibody(ies) coating the RBCs of patients with a positive direct antiglobulin test. Many types of elution procedures have been developed and described; however,.an acid elution is suitable for antibody recovery in most cases, such as recovery of alloantibodies and warm-reactive autoantibodies.Studies have compared methods such as xylene, chloroform, digitnin acid, dichloromethane, citric acid, and Immucor Elu-KitII (cold acid elution). The ELU-Kit II has been shown to be quick and effective at eluting a wide range of alloantibodies as well as autoantibodies without the use of hazardous chemicals or costly reagent preparation time that some methods use. It is for these reasons that the ELU-Kit II is a very popular method for the elution of immunoglobulin G (IgG) antibodies. PMID- 25695436 TI - A case of masquerading alloantibodies: the value of a multitechnique approach. AB - In an immunohematology reference laboratory, samples received for antibody identification react in many different ways requiring a variety of approaches. Sometimes, the clues from initial testing can lead to faulty assumptions and misdirection. Fortunately, a well-supplied reference laboratory will have access to a variety of techniques and reagents that, when used together, can reveal the true identity of the antibodies involved. We present a case of a patient sample with an apparent group AB, D+ blood type showing strong reactivity with all cells tested in the forward and reverse ABO, in the D testing as well as in a three cell antibody screen. The initial assumption was that the plasma contained a cold autoantibody. Subsequent testing, including the use of gel column technology, ficin-treated cells, and antisera for phenotyping, showed the apparent cold autoantibody to bea red herring. Additional tube testing at immediate spin, 37 degrees C,and indirect antiglobulin test (IAT) revealed the presence of four alloantibodies: anti-M and anti-E reacting at immediate spin, 37 degrees C, and IAT plus anti-Fy(a) and anti-Jk(b) reacting at lAT. PMID- 25695437 TI - RHCE variant allele: RHCE*ce254G,733G. AB - A novel RHCE allele was identified in a 53-year-old African American female blood donor with an Rh phenotype of D+ CE-c+ e+ and a negative antibody screen. The donor's cells typed e+ with all antisera tested. By gel-based genotyping and Edna analysis, the two RHCE alleles in this donor were characterized.One allele was found to be the known allele RHCE*Ol.20.01(RHCE*ce733G) and the second was novel: RHCE*Ol.06.02(RHCE*ce254G,733G). PMID- 25695438 TI - Detection and identification of platelet-associated alloantibodies by a solid phase modified antigen capture enzyme-linked immunosorbent assay method and its correlation to platelet refractoriness in multiplatelet concentrate-transfused patients. AB - Platelets express a variety of polymorphic glycoproteins (GPs), such as GPIIb/IIIa, GPib/IX, GPla/Ila, GPIV, and class I human leukocyte antigen. In the platelet transfusion setting, alloimmunization involves the production of antibodies against these glycoproteins. Patients transfused with multiple units of platelet concentrates for longer periods are the main individuals with platelet alloimmunization. This study was performed to detect the development of platelet antibodies in patients who are transfused with multiple units of leukodepleted platelet concentrates, such as those with hemato-oncologic diseases and bone marrow failure syndromes. The method used was solid phase modified antigen capture enzyme-linked immunosorbent assay. Platelet refractoriness was assessed by measuring the corrected count increment at 1 and 24 hours after transfusion. PMID- 25695439 TI - Effects of pH changes of stock normal saline solution on 5 percent red cell suspension. AB - The red cell suspension (RCS) is a universally used indicator system to demonstrate antigen and antibody reactions in vitro.Saline solutions that are used in its preparation are preferred to be fresh to avoid changes in pH that may affect the results. Thus,buffered saline such as phosphate-buffered saline (PBS) is the ideal diluent because its pH is maintained for a certain period. However,normal saline solution (NSS) is more commonly used because it is inexpensive and easy to make. pH changes in the saline solutions and the RCSs were monitored for 1 week. Macroscopic examination of changes in degree of redness of RCS was also observed. Red blood cell (RBC) indices of the ethylenediaminetetraacetic acid(EDT A)-anticoagulated blood used in the preparation of the RCS were measured in the performance of an automated complete blood count. Qualitative examination of the crenation of RBCs was done on the prepared blood smears and graded by three registered medical technologists. Percentage crenation was then determined using an improved Neubauer counting chamber. Three trials were performed, and results were averaged. Statistical analysis showed hat there were significant differences in the average pH of PBS and NSS and the average pH of RCS-PBS and RCS-NSS over 1 week. RBC indices measured in EDTA-anticoagulated donor blood showed no significant difference. Macroscopic examination of changes in degree of redness of the RCS showed that color darkened over 1 week but only by a small degree. Qualitative and quantitative examination of crenation of RBCs in RCS-PBS and RCS-NSS both showed no significant differences over 1 week. The experimental group (RCS-NSS) continuously showed a higher grade of crenation than the control group (RCS-PBS). Crenation of RBCs still manifests microscopically despite the lack of a significant relationship between the pH of the saline solutions and the degree and percentage of crenation. Crenation, therefore,cannot be attributed to pH alone but occurs as a result of other factors. PMID- 25695440 TI - Reducing postoperative infections and red breast syndrome in patients with acellular dermal matrix-based breast reconstruction: the relative roles of product sterility and lower body mass index. AB - PURPOSE: The use of human acellular dermal matrices (ADM) has become routinely used in implant-based breast surgery. Notwithstanding the many benefits for tissue support, the morbidity associated with its use includes seroma and infection, among other potential complications. Some patients experience a specific complication called red breast syndrome (RBS), which has been linked to ADM use, but its exact etiology remains elusive. In our institution, AlloDerm aseptic regenerative tissue matrix was recently replaced with a ready-to-use sterile version that undergoes terminal sterilization, eliminating the need for rehydration. We want to determine if this change in processing affected complications, including RBS. METHODS: We conducted a retrospective chart review analyzing patients from January 1, 2011, to June 1, 2013, who underwent breast surgery with human ADM. Patients with aseptic AlloDerm were compared to patients with sterile AlloDerm. Data were analyzed using the Fisher exact test. RESULTS: A total of 167 reconstructed breasts from 105 patients met inclusion criteria: 56% (n=93) with aseptic ADM, 44% (n=74) with sterile ADM. When comparing the two, patients had a decrease in overall necrosis, infection, seroma, and RBS with sterile ADM. However, the rates did not reach statistical significance. For example, the incidence of RBS decreased from 7.5% to 2.7% (P=0.301) and seroma decreased from 8.6% to 2.7% (P=0.188). The infection rate proved to be equivocal at 11.8% with aseptic ADM to 10.8% with sterile ADM (P=1.000). The only statistically significant change was a decrease in the total complication rate from 41.9% to 27.0% (P=0.046). The absolute risk reduction for total complications was 14.9% with a number-needed-to-treat of 7. CONCLUSION: According to our study, sterile AlloDerm has a clinically decreased incidence of complications compared to aseptic AlloDerm. Whereas RBS decreased, it was interesting to see that it was not eliminated altogether. This suggests that the etiology may be unrelated to ADM processing and warrants further investigation. Overall, the most notable difference was the statistically significant decrease in the total complication rate. Therefore, the change to sterile AlloDerm seems to be beneficial. Further benefit arises from ease of preparation in the operating room. PMID- 25695441 TI - Effectiveness and safety of autologous fat grafting to the soft palate alone. AB - BACKGROUND: Posterior pharyngeal augmentation is an accepted method of treating velopharyngeal insufficiency (VPI). Techniques using autologous fat harvest, preparation, and grafting are well described. Based on the complications from retropharyngeal injection, we performed augmentation of the nasal surface of the palate to reduce hypernasality with decreased risks. METHODS: After Institutional Review Board approval, a chart review from 2010 to 2013 identified 46 patients with cleft palate, subjective and nasoendoscopic evidence of VPI treated with autologous fat grafting to the soft palate. Speech evaluation of velopharyngeal function was compared before and after autologous fat grafting. RESULTS: A total of 61 autologous fat grafting procedures were performed in 46 patients. The average age of the study population is 5.59 +/- 2.05 years. The majority underwent a single procedure (32/46 or 69.6%), 13 of 46 patients (28.2%) had 2 fat grafting procedures and only 1 patient (2.2%) had 3 fat grafting procedures. The fat was injected primarily in the soft palate. The recorded volume of fat grafted averaged 2.4 +/- 1.1 mL. Average operative time was 39 +/- 12.55 minutes. There were no local or donor site complications. Four patients were lost to follow-up. Of 34 patients with adequate speech follow-up, including Pittsburgh Weighted Speech Scale (PWSS) assessment, the average preoperative score of 8.17 +/- 3.59 was reduced to 5.17 +/- 3.14 postoperatively. Although 26 of 34 patients (76.5%) had an improvement in their PWSS score, only 13 of 34 patients (38.23%) saw an improvement in their PWSS category. CONCLUSIONS: Autologous fat grafting to the soft palate is a safe operation with minimal risks. Speech outcomes are subjectively enhanced in the majority of patients, with a full PWSS category improvement seen in 40% of the cases. Patient selection criteria to optimize results are provided. PMID- 25695442 TI - Online Patient Resources for Liposuction: A Comparative Analysis of Readability. AB - BACKGROUND: As patients strive to become informed about health care, inadequate functional health literacy is a significant barrier. Nearly half of American adults have poor or marginal health literacy skills and the National Institutes of Health and American Medical Association have recommended that patient information should be written at a sixth grade level. The aim of this study is to identify the most commonly used online patient information about liposuction and to evaluate its readability relative to average American literacy. METHODS: An internet search of "liposuction" was performed and the 10 most popular websites identified. User and location data were disabled and sponsored results excluded. All relevant, patient-directed articles were downloaded and formatted into plain text. Articles were then analyzed using 10 established readability tests. A comparison group was constructed to identify the most popular online consumer information about tattooing. Mean readability scores and specific article characteristics were compared. RESULTS: A total of 80 articles were collected from websites about liposuction. Readability analysis revealed an overall 13.6 grade reading level (range, 10-16 grade); all articles exceeded the target sixth grade level. Consumer websites about tattooing were significantly easier to read, with a mean 7.8 grade level. These sites contained significantly fewer characters per word and words per sentence, as well as a smaller proportion of complex, long, and unfamiliar words. CONCLUSIONS: Online patient resources about liposuction are potentially too difficult for a large number of Americans to understand. Liposuction websites are significantly harder to read than consumer websites about tattooing. Aesthetic surgeons are advised to discuss with patients resources they use and guide patients to appropriate information for their skill level. PMID- 25695443 TI - Histochemical and functional improvement of adipose-derived stem cell-based tissue-engineered cartilage by hyperbaric oxygen/air treatment in a rabbit articular defect model. AB - Cartilage is exposed to compression forces during joint loading. Therefore, exogenous stimuli are frequently used in cartilage tissue engineering strategies to enhance chondrocyte differentiation and extracellular matrix (ECM) secretion. In this study, human adipose-derived stem cells were seeded on a gelatin/polycaprolactone scaffold to evaluate the histochemical and functional improvement of tissue-engineered cartilage after hyperbaric oxygen/air treatment in a rabbit articular defect model. Behavior tests showed beneficial effects on weight-bearing and rear leg-supporting capacities after treatment of tissue engineered cartilage with 2.5 ATA oxygen or air. Moreover, positron emission tomography images and immunohistochemistry staining demonstrated hydroxyapatite formation and increased ECM synthesis, respectively, at the tissue-engineered cartilage graft site after high pressure oxygen/air treatment. Based on these results, we concluded that hyperbaric oxygen and air treatment can improve the quality of tissue-engineered cartilage in vivo by increasing the synthesis of ECM. PMID- 25695444 TI - Treatment of epidermal cysts with erbium: YAG laser fenestration: an alternative to surgical intervention. AB - BACKGROUND: Epidermal cysts, also called epidermal inclusion cysts or epidermoid cysts, are firm, slowly growing benign tumors commonly seen in young or middle aged adults. Surgical excision is the usual treatment for such lesions, with the inevitable sequelae of scarring, especially in the face, back, or sternal region. MATERIALS AND METHODS: To evaluate the safety and feasibility of erbium:yttrium aluminum garnet laser fenestration of epidermal cysts for patients concerned about scarring, from January 2010 to July 2013, 25 patients with cosmetic concerns underwent serial laser treatment using the fenestration technique to decompress the cyst contents. Patient' satisfaction, scarring, and complications were assessed and analyzed. RESULTS: Twenty-three of the 25 patients obtained satisfactory cosmetic outcomes with rapid healing and minimal invasiveness. There was no evidence of scar formation, and no complications were observed at follow up. Two patients received elective excision after reduction of the size of the cysts, and their scars were hidden well. CONCLUSION: Erbium:yttrium aluminum garnet laser fenestration might be a promising alternative to the surgical treatment of epidermal cysts, especially when the lesions are large or located in an aesthetically important area. PMID- 25695445 TI - Superficial or cutaneous malignant peripheral nerve sheath tumor--clinical experience at Taipei Veterans General Hospital. AB - BACKGROUND: Primary malignant peripheral nerve sheath tumors (MPNSTs) with a cutaneous or subcutaneous origin represent a small subset of MPNSTs thought to be derived from cutaneous neurofibromas or small peripheral nerves. Few cases of superficial MPNSTs originating from the skin have been reported in the literature. MATERIALS AND METHODS: From October 1999 to February 2014, 13 patients were diagnosed with superficial or cutaneous MPNSTs and received treatment at Taipei Veterans General Hospital. Clinical data were collected via retrospective chart review. A retrospective study was performed to compare superficial and deep-seated lesions in terms of local recurrence, distal metastasis, and survival analysis. The relevant literature is also briefly reviewed. RESULTS: The most frequent initial symptoms were local swelling and pain. Ten tumors were found in the extremities, and 3 tumors were located on the trunk. All patients underwent surgery with curative intent. Four patients developed local recurrence, and 3 developed distant metastasis. Three of 13 patients died after a follow-up period of 11 to 180 months (mean, 53.4). Compared to deep-seated MPNSTs, superficial MPNSTs had a lower histopathological grading and better survival rate. CONCLUSIONS: Superficial MPNSTs are a rare variant of MPNST. The relatively frequent lack of associated neurofibromatosis and superficial location within the dermis and subcutis may result in this entity being overlooked. According to our clinical experience, superficial MPNSTs might have better prognosis, but similar recurrence and metastasis rates compared with deep-seated lesions. Hence, awareness of this entity should prompt its consideration in the differential diagnosis of cutaneous sarcomas. PMID- 25695446 TI - The correlation between surface electromyography and bite force of mastication muscles in Asian young adults. AB - BACKGROUND: Mastication function is related to mandible movement, muscle strength, and bite force. No standard device for measuring bite force has been developed. A linear relationship between electromyographic activity and bite force has been reported by several investigators, but data on the reliability of this relationship remain limited in Asian young adults. AIM AND OBJECTIVES: The purpose of this study was to develop a clinically applicable, reliable, quantitative, and noninvasive system to measure the kinetic mastication function and observe the correlation between surface electromyography (sEMG) and bite force. MATERIALS AND METHODS: The study group consisted of 41 young healthy adults (24 men and 17 women). Surface electromyography was used to evaluate bilateral temporalis and masseter muscle activities, and an occlusal bite force system was used concurrently to measure the bite force during maximal voluntary biting. Bilateral symmetry was compared, and the correlation between EMG and bite force was calculated. RESULTS: The sEMG signals were 107.7+/-55.0 MUV and 106.0+/ 56.0 MUV (P=0.699) on right and left temporalis muscles and 183.7+/-86.2 MUV and 194.8+/-94.3 MUV (P=0.121) on right and left masseter muscles, respectively. The bite force was 5.0+/-3.2 kg on the right side and 5.7+/-4.0 kg on the left side (P=0.974). A positive correlation between sEMG and bite force was observed. The correlation coefficient between the temporalis muscle and bite force was 0.512, and that between the masseter muscle and bite force was 0.360. CONCLUSION: No significant difference between the bilateral electromyographic activities of the temporalis and masseter muscles and bilateral bite force was observed in young healthy adults in Taiwan. A positive correlation between sEMG signals and bite force was noted. By combining sEMG and bite force, we developed a clinically applicable, quantitative, reliable, and noninvasive system for evaluating mastication function by using characteristics of biofeedback. PMID- 25695447 TI - Single buccal sulcus approach with fluoroscan assistance for the management of simple zygomatic fractures. AB - BACKGROUND: Zygomatic fractures are associated with functional and aesthetic problems. The purpose of this study was to evaluate the adequacy of management and the surgical satisfaction of patients with simple zygomatic fractures treated through a single buccal sulcus approach and fluoroscan assistance. METHODS: Between 2008 and 2012, 42 patients with simple zygomatic fractures were included in the study. The surgical procedure was performed through a single buccal sulcus incision. The fracture sites were aligned under direct vision and fluoroscan assistance and stabilized with rigid internal fixation. The adequacy of reduction was evaluated based on postoperative plain radiographic films and computed tomographic scans using mirror image analyses. The satisfaction of functional and aesthetic results was also evaluated subjectively using a visual analog scale during follow-up. RESULTS: Twenty-nine male and thirteen female patients with a mean age of 33.2 years were evaluated. Motorcycle crashes (78.6%) were the most common mechanism of trauma. Based on follow-up imaging studies, 2 patients had inadequate reduction of zygomatic body, and there was a slight depression of the zygomatic arch in one patient. Ninety-three percent (39/42) of patients had satisfactory results, although one patient complained of malar asymmetry and another felt a depression in the arch area. Two patients complained of persistent hypesthesia during follow-up at 6 months. CONCLUSIONS: Our results suggest that a single buccal sulcus approach without lower eyelid or lateral eyebrow incision in the repair of simple fractures of the zygoma can be achieved with high patient satisfaction if the reduction and fixation are adequate and stable. PMID- 25695448 TI - Relationship Between Lymphedema and Arteriosclerosis: Higher Cardio-Ankle Vascular Index (CAVI) in Lymphedematous Limbs. AB - BACKGROUND: Arteriosclerosis is one of the most important public health issues because it is very common in developed countries and its sequelae are lethal. Lymphatic vessel insufficiency has been reported to be associated with atherogenesis. Lymphedema seems to affect progression of arteriosclerosis, but no clinical study has been reported. METHODS: Forty-eight limbs of 24 female patients with pelvic cancer-related lower extremity lymphedema (LEL) were evaluated. Cardio-ankle vascular index (CAVI), an indirect estimate of the arterial stiffness, was measured in each limb. Cardio-ankle vascular index was compared according to known arteriosclerosis risk factors including age (younger than 65 years vs 65 years), body mass index (BMI; <25 vs 25 kg/m), hypertension (HT), diabetes mellitus, hyperlipidemia (HL), and smoking, as well as according to LEL-related factors including duration of LEL (<5 years vs 5 years), pelvic irradiation, leg cellulitis, LEL index (<250 vs 250), and leg dermal backflow (LDB) stage (LDB stage 0/I vs LDB stage II/III/IV/V) using univariable analyses and multivariable analysis. RESULTS: Univariable analyses revealed statistically significant differences in CAVI between lower BMI and higher BMI [7.19 (0.75) vs 8.36 (1.24), P < 0.01], HT (-) and HT (+) [7.25 (0.81) vs 8.17 (1.29), P < 0.01], HL (-) and HL (+) [7.19 (0.74) vs 8.06 (1.27), P < 0.01], and lower LDB stage and higher LDB stage [6.87 (0.65) vs 7.76 (1.05), P < 0.01]. Multivariable analysis revealed statistically significant differences in CAVI between lower BMI and higher BMI (P < 0.01), shorter duration of LEL and longer duration of LEL [7.21 (1.04) vs 7.71 (0.97), P = 0.04], and lower LDB stage and higher LDB stage (P = 0.04) CONCLUSIONS: Higher BMI, longer duration of LEL, and higher LDB stage were independent factors associated with higher CAVI in pelvic cancer-related LEL. PMID- 25695449 TI - The impact of neoadjuvant hedgehog inhibitor therapy on the surgical treatment of extensive basal cell carcinoma. AB - BACKGROUND: Although hedgehog inhibitor therapy (HHIT) is offered as isolated medical treatment for extensive basal cell carcinoma (BCC), there is little evidence on the use of HHIT before definitive surgical intervention. In order to better define the utilization of HHIT for extensive BCC, we evaluated the impact of neoadjuvant HHIT on the subsequent surgical resection and reconstruction. METHODS: An IRB-approved, retrospective chart review was performed of patients who received HHIT as initial treatment for extensive BCC. Patients who discontinued HHIT and underwent surgical resection were included. Evaluation included BCC tumor response to HHIT, operative data, pathological data, radiation requirements, and evidence of tumor recurrence. RESULTS: Six patients were identified with tumors of the face/scalp (n = 4), trunk (n = 1) and upper extremity (n = 1). Hedgehog inhibitor therapy continued until tumors became unresponsive (n = 3, mean = 71 weeks) or side effects became intolerable (n = 3, mean = 31 weeks). In each case, a less extensive surgery was performed than estimated before HHIT. In 3 cases, significant bone resection was avoided. All resected specimens contained BCC. Four specimens exhibited clear margins. Postoperative radiation was performed in cases with positive margins (n = 2), and 1 patient experienced local recurrence. Length of follow-up was 5.7 to 11.8 months (mean = 8.23 months). CONCLUSIONS: Although HHIT was not curative for extensive BCC, HHIT can decrease the morbidity of surgical treatment and increase the likelihood of curative resection. For patients with extensive BCC, a combined neoadjuvant use of HHIT and surgical treatment should be considered. PMID- 25695450 TI - Suppression of alpha Smooth Muscle Actin Accumulation by Bovine Fetal Dermal Collagen Matrix in Full Thickness Skin Wounds. AB - The suppression of elements associated with wound contracture and unfavorable scarring is a potentially important strategy in clinical wound management. In this study, the presence of alpha smooth muscle actin (alphaSMA), a protein involved in wound contraction, was analyzed in a series of wounds in which bovine fetal collagen (BFC) acellular dermal matrix (PriMatrix) was used in staged split thickness skin graft procedures. The results obtained through histological and quantitative image analyses of incidental biopsies from these wounds demonstrated a suppression of alphaSMA in the wound regions occupied by assimilated BFC relative to increased levels of alphaSMA found in other areas of the wound. The alphaSMA levels found in assimilated BFC were similar to alphaSMA levels in uninjured human dermis. These findings suggest a mechanism by which application of BFC could decrease contraction of full thickness skin wounds. PMID- 25695451 TI - Craniofacial fracture patterns in all terrain vehicle injuries. AB - BACKGROUND: A multicenter, retrospective study was conducted to determine the frequency and distribution of craniofacial fractures sustained from all terrain vehicle (ATV) accidents. METHODS: Medical records of all patients presenting to 2 trauma centers with ATV-related craniofacial trauma from 2001 to 2013 were reviewed. Patient notes and radiographic images were analyzed for detailed craniofacial injury data. The identified fractures were classified as: frontal/skullbase, naso-orbital, maxilla/zygoma, and mandible. In addition, patient demographic information, length of stay, airway status, intensive care unit stay, Glasgow coma scale, use of safety equipment, associated traumatic brain injury, and surgical intervention were compiled. RESULTS: One hundred fifty six patients with craniofacial fractures secondary to ATV accidents presented from 2001 to 2013. The incidence of craniofacial fractures found in patients with ATV injuries was 12.2%. Sixty-one patients (39.1%) suffered frontal/skullbase fractures, 98 (62.8%) naso-orbital fractures, 62 (39.7%) maxillary/zygoma fractures, and 35 (22.4%) mandibular fractures. Forty-one patients (26.3%) required surgical intervention to correct their craniofacial injuries. CONCLUSIONS: The most common craniofacial fractures experienced in ATV injuries are naso-orbital fractures. The correlation of nonuse of safety equipment and associated traumatic brain injuries displays the importance of using helmets when operating ATVs. Future studies can be conducted examining ATV-related upper extremity injuries, among others. PMID- 25695452 TI - Functional and Therapeutic Indications of Liposuction: Personal Experience and Review of the Literature. AB - Liposuction is the most common cosmetic surgical procedure worldwide. It has evolved from being designed primarily for body contouring to becoming essential adjunct to various other aesthetic procedures, greatly enhancing their outcome. Despite its hard clear differentiation between an aesthetic and therapeutic indication for some pathologic conditions, liposuction has been increasingly applied to a gamut of disorders as a therapeutic tool or to improve function. In fact, liposuction has ceased to define a specific procedure and became synonymous to a surgical technique or tool same as the surgical knife, laser, electrocautery, suture material, or even wound-dressing products. At present, there seems to be an enormous potential for the application of the basic liposuction technique in ablative and reconstructive surgery outside the realm of purely aesthetic procedures. The present review contemplates the various nonaesthetic applications of liposuction, displaying the enormous potentials of what should be considered a basic surgical technique rather than a specific aesthetic procedure. Implications of this new definition of liposuction should induce third-party public payers and insurance companies to reconsider their remuneration and reimbursement policies. PMID- 25695453 TI - One-stage reconstruction of complex lower extremity deformity combining Ilizarov external fixation and sural neurocutaneous flap. AB - BACKGROUND: Complex lower extremity deformities include multidirectional foot and ankle deformities, which are complicated therapeutic and surgical challenges. Correction often requires several stages, which is time consuming and costly. The need to restore the physical, mechanical, and cosmetic aspects of the lower extremity results in a difficult balancing act between these concerns and the deformity correction and soft tissue reconstruction. METHODS: Between January 2009 and September 2011, we treated 5 patients with multidirectional foot and ankle deformities. Significant mobility limitation was caused by abnormal scarring, which led to abnormal gait and weight-bearing regions. We used a sural neurocutaneous flap to repair the soft tissue defects after scar-tissue removal in all patients and placed a circular hinged Ilizarov external fixator for gradual correction. RESULTS: All the flaps survived and resulted in good texture match and contour. The follow-up period was 19 to 26 months. The correction lasted 3 to 5 months, and all of the patients were able to walk with satisfactory gaits and without assistance. We encountered no complications, such as pin-track infection or drop foot in our series. CONCLUSION: Our approach, combining a sural neurocutaneous flap and Ilizarov external fixation, was a reliable and effective tool for one-stage reconstruction of complex lower extremity deformities. PMID- 25695455 TI - The radiographic and functional outcome of bilateral mandibular condylar head fractures: a comparison between open and closed treatment. AB - Bilateral mandibular condylar fractures accounts for 24% to 33% of condylar fractures but the indications of open reduction of bilateral condylar fracture are still controversial. It is generally accepted that displaced subcondylar fractures are indicated for open reduction, but the proper treatment of condylar head fractures are still variable. This retrospective study compares the radiographical and functional outcomes of bilateral condylar head fractures between open and closed reduction groups. MATERIALS AND METHODS: From February 1994 to June 2012, a total of 85 patients with bilateral condylar head fractures were retrospectively reviewed. Among this group, 41 cases underwent open reductions while the other 44 cases had closed reductions. Only adult patients with adequate follow-up and complete radiographic study were included in this study: consisting of 20 patients in the open group and 18 patients in the closed group.The subjective symptoms including temporomandibular joints (TMJ) symptoms, complications or adverse sequelae, and functional results, such as maximal mouth opening, were recorded. The outcome of patient's satisfaction was individually assessed by an independent reviewer. The computed tomographic results after treatment were evaluated between both groups. RESULTS: The mean follow-up period was 25.5+/-13.3 months. The open reduction group had better postoperative chewing functions, less malocclusion rates, less degree of TMJ pain (p=0.046), better radiographic outcome (p=0.036), and an overall satisfaction rate (p=0.039).There were 4 cases of failure in the closed reduction group. Subsequent open reduction (n=2) and redo closed reduction with intermaxillary fixation (n=2) were performed. Eleven patients in the close reduction group presented persistent malocclusion through objective evaluation. The subsequent treatment included further orthognathic surgery (n=1) and orthodontic treatment (n=7). Three of the patients refused further treatment. CONCLUSIONS: Open reduction for bilateral condylar head fractures presented an overall better functional and radiographic outcome, with higher patient satisfaction if condylar fracture segments were still feasible for rigid fixation. PMID- 25695456 TI - Alleviation of neuropathic scar pain using autologous fat grafting. AB - Traumatic wounds inflict small- and large-fiber sensory nerve damage, causing neuropathic pain in scar tissue, thus impairing patients' quality of life and leading to the development of psychological disorders. Autologous fat grafting has been clinically shown to improve scar quality, but few studies have explored the effects of this technique on pain. The purpose of this study was to assess the effect of fat grafting on treating neuropathic scar pain. From February 2008 to January 2013, 13 patients who were identified using the Douleur Neuropathique 4 Questions (scores>4/10) were enrolled in this study. The Visual Analog Scale (VAS) and Neuropathic Pain Symptom Inventory (NPSI) were used to evaluate pain preoperatively and 1 week, 4 weeks, and 24 weeks postoperatively. The mechanism of trauma, scar location and size, duration of allodynia, fat graft volume, pharmacologic therapy duration, and total follow-up time were recorded. Thirteen patients experiencing neuropathic pain were enrolled in this study. The mean+/-SD age was 33.08+/-16.35 years. The mean duration of pain was 4.29+/-2.85 months. The mean VAS score before treatment was 7.54+/-1.05. The mean VAS scores decreased by 4.38+/-1.66 after 1 week of treatment (P=0.009), 5.38+/-2.06 after 4 weeks of treatment, and 5.62+/-2.18 after 24 weeks of treatment. The mean NPSI scores were 49.38+/-13.25 before treatment, 25+/-14.4 after 1 week of treatment (P=0.004), 21+/-17.78 after 4 weeks of treatment, and 14.62+/-16.88 after 24 weeks of treatment. The 13 patients followed a mean of 24 weeks; 10 (77%) of the patients had improvement of 5 or greater on the VAS score. The mean follow-up period was 19.3+/-12.26 months (range, 6-38 months). No surgical complications were noted in this series. In our study, both VAS and NPSI scores decreased significantly, revealing that the autologous fat grafting can alleviate neuropathic scar pain 1 week after operation and in the long term. PMID- 25695457 TI - Robot-assisted free flap reconstruction of oropharyngeal cancer--a preliminary report. AB - BACKGROUND: The robotic surgical system provides a clear, magnified, 3 dimensional (3D) view as well as a precise and stable instrumental movement, which minimizes many technical difficulties that may be encountered in the surgical treatment of oropharyngeal tumors. A preliminary result of transoral robot-assisted free flap reconstruction of oropharyngeal cancer is presented herein. MATERIALS AND METHODS: Between May and December 2013, the Da Vinci Surgical System (Da Vinci Si, Intuitive Surgical, Sunnyvale, CA) was used in 5 (4 men and 1 woman) cases of oropharyngeal reconstruction. Robot-assisted reconstruction was performed for inset of the flap and for performing a venous anastomosis of the free radial forearm fasciocutaneous flap. RESULTS: All of the reconstructive surgeries were successful without flap failure or take-backs. There were no wound infections or fistulas. CONCLUSION: The application of a robotic surgical system seems to be a safe option in the free flap reconstruction of oropharyngeal defects without lip or mandible splitting. PMID- 25695458 TI - Presurgical Botulinum Toxin A Treatment Increases Angiogenesis by Hypoxia Inducible Factor-1alpha/Vascular Endothelial Growth Factor and Subsequent Superiorly Based Transverse Rectus Abdominis Myocutaneous Flap Survival in a Rat Model. AB - To date, there have been several experimental studies to assess tissue viability of transverse rectus abdominis myocutaneous (TRAM) flaps. Botulinum toxin A (BoTA) has gained popularity in many clinical fields, for a variety of therapeutic and aesthetic purposes. In addition, there have been reports regarding the positive effect of BoTA on flap survival by various mechanisms. In this study, we hypothesized that pretreatment with BoTA could augment the survival of TRAM flaps via increased hypoxia-inducible factor (HIF)1alpha/vascular endothelial growth factor (VEGF)-dependent angiogenesis.Twenty-four Sprague-Dawley rats were randomly divided into 2 groups: a control group and a BoTA group. Five days before superiorly based TRAM flap elevation, the BoTA group was pretreated with BoTA, whereas the control group was pretreated with normal saline. Gross flap survival rates were assessed, and quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) and Western blotting were performed for the evaluation of angiogenesis-related factors (CD34, HIF-1alpha, and VEGF).In the BoTA group, the gross flap survival rate was significantly higher than that in the control group on both ipsilateral (92.78.3 +/- 5.05% vs 86.8 +/- 3.88%, P = 0.009) and contralateral (91.57 +/- 5.79% vs 74.28 +/- 11.83%, P < 0.001) sides.The relative mRNA expression of CD34 and VEGF was significantly higher in the BoTA group than that in the control group in every zone, whereas the relative mRNA expression of HIF-1alpha was significantly higher in the BoTA group than that in the control group on contralateral sides. The relative protein expression of CD34, VEGF, and HIF 1alpha was significantly higher in the BoTA group than that in the control group in every zone.In conclusion, we demonstrate that presurgical BoTA treatment might increase angiogenesis by HIF-1alpha/VEGF, subsequently increase superiorly based TRAM flap survival in a rat model. PMID- 25695459 TI - The Average Size and Position of the Umbilicus in Young Men and Women. AB - INTRODUCTION: Abdominoplasty was the third most common cosmetic surgical procedure in 2012. The umbilicus is transposed within the abdominal skin flap during this procedure. Few studies address the size and location of the umbilicus with precise measurements as well as those that do report on a heterogeneous population. The goal of our study was to determine the average size and position of the ideal umbilicus by limiting the study to young men and women of normal body habitus. METHODS: Subjects were recruited in a University of Virginia Institutional Review Board-approved study. Demographics of the subjects were recorded. Each subject's umbilicus was assessed for height, width, and position relative to existing landmarks. RESULTS: Eighty subjects met the inclusion criteria: 43 women and 37 men. Most of the subjects were white (72.5%). The mean +/- SD BMI was 22.4 +/- 2.5 kg/m. The mean +/- SD height and width of the umbilicus was 2.1 +/- 0.6 cm and 2.3 +/- 0.7 cm, respectively. The umbilicus was located at a mean +/- SD of -0.7 +/- 1.3 cm in relation to the iliac crest (crest at zero). There were differences seen in the position between men and women. There were no statistical differences in measurements between the races. CONCLUSION: Our study serves as a guide for umbilical positioning with mean measurements for men and women, and categorized by sex and race. PMID- 25695460 TI - Patient perception of postoperative pain after administration of liposomal bupivacaine in plastic surgery. AB - BACKGROUND: Since obtaining FDA approval for postsurgical pain management in 2011, a number of well-designed studies have reported favorably on the safety and efficacy of liposomal bupivacaine (LB). However, the literature lacks adequate reports of patient perception of postoperative pain and subjective satisfaction. METHODS: A telephone survey of patients who received LB injection at time of operation at a single institution was contacted. Included were patients who underwent cosmetic, reconstructive, and/or breast procedures. Patients were asked to report their perception of pain on post-operative day (POD) 1 and 3 using the verbal scale (1-10). Additionally, patients reported on: understanding of medications received, overall satisfaction, perception of economic value, and perception of preference to elastomeric pump. RESULTS: A total of 75 patients met inclusion criteria and could be reached by telephone; 23(31%) cosmetic and 52(69%) reconstructive and/or breast procedures. Mean pain score reported 2.6 (0 9) POD 1 and 3.6 (0-8) POD 3.Thirty-six (48%) patients were aware they had received the medication. Seventy-three (98%) reported they would want LB again if they needed surgery in the future and would pay U.S. $230 [$100-$1000] for the medication. All (100%) patients favored LB over a perceived elastomeric pump device. CONCLUSIONS: Patient perception of efficacy after the injection of LB correlates with previous clinical findings. Our experience with LB injections for cosmetic and reconstructive breast procedures indicates that patients experienced low postoperative pain scores with high overall patient satisfaction. Additional studies comparing the use of LB to standard narcotic regimens and its use in multimodality pain management are warranted. PMID- 25695461 TI - Evaluating outcomes after correction of the breast conservation therapy deformity. AB - BACKGROUND: In an effort to preserve the native breast shape, most women with breast cancer are treated with breast conservation therapy (BCT). However, a breast deformity can develop after BCT and can be challenging to repair. The goal of this review was to evaluate outcomes based on the extent of the deformity and reconstructive technique. METHODS: Sixty-three patients treated for a BCT deformity between 2003 and 2012 were included. Data queried included demographics, extent of the deformity, type of reconstruction, and outcomes. A panel judged aesthetic outcomes, and patient satisfaction was determined using the validated Breast Q reconstruction questionnaire. Comparisons were made across reconstructive techniques. RESULTS: There were 22 grade I/II deformities, and 29 grade III/IV deformities. Local scar revision procedures and fat grafting were more common for grade I, and myocutaneous flaps were more common for grade IV. Bilateral reduction techniques (n = 20) and contralateral reduction only (n = 6) were most common for grade II/III defects. Augmentation was used in 9 grade III patients. Combined reconstructive techniques were required in 23% of the patients. Eighty-nine percent had a contralateral symmetry procedure. Complications occurred in 34.9%, with no significant variation across the different modes of reconstruction. There was a trend toward higher complication rates with increasing defect severity (0% for grade 1, 32% for grade 2, 39% for grade 3, and 50% for grade 4). Patients required an average of 1.3 procedures (range, 1-3), at an average follow-up of 2.5 years. Eighty percent of patients had only 1 reconstructive operation, 14% required a second operation, and 6% a third. Patient satisfaction was generally high and the mean aesthetic rating was 5 out of 7, and trended down with the extent of the deformity. Patients who underwent contralateral reduction only had the highest aesthetic scores (5.8/7). CONCLUSIONS: Reconstructive options for the correction of BCT deformities are numerous and need to be appropriately tailored for each patient in part based on the extent of the deformity. Although revisions are not uncommon, good patient satisfaction and esthetic outcomes can be achieved. PMID- 25695462 TI - Deuterated carbohydrate probes as 'label-free' substrates for probing nutrient uptake in mycobacteria by nuclear reaction analysis. AB - Understanding and probing small molecule uptake in cells is challenging, requiring sterically large chemical labels, or radioactive isotopes. Here, the uptake of deuterated sugars by Mycobacterium smegmatis, a non-pathogenic model of Mycobacterium tuberculosis, has been investigated using ion-beam (nuclear reaction) analysis demonstrating a new technique for label-free nutrient acquisition measurement. PMID- 25695463 TI - Management of noninvasive bladder cancers. AB - PURPOSE OF REVIEW: To summarize clinical management of nonmuscle-invasive bladder cancer (NMIBC) and discuss recent advances in the field. RECENT FINDINGS: NMIBC remains a common and expensive clinical entity. Prevention, early detection, and risk-adapted treatment are the mainstays of clinical management, all of which may improve as a result of recent research. Photodynamic diagnosis has demonstrated improved detection of nascent disease, and specific clinical scenarios have been identified in which photodynamic diagnosis may improve clinical outcomes. New intravesical chemotherapeutic and immunotherapeutic agents challenge our current paradigm for intermediate/high-risk NMIBC and may delay need for cystectomy after bacillus Calmette-Guerin failure. Progress in risk stratification increasingly permits individualized management regimens for NMIBC. SUMMARY: NMIBC includes many heterogeneous disease states with a variety of clinical behaviors that may evolve over time. Improved detection and risk stratification promise assignment of the optimal treatment option for an individual patient at a given time. PMID- 25695464 TI - Bipolar electrochemical method for dynamic in situ control of single metal nanowire growth. AB - Fabrication plays a key role in determining the unique electrical, optical, and catalytic properties of metal nanowires. Here we present a bipolar electrochemical method for dynamically monitoring and controlling the rate of single metal nanowire growth in situ without a direct electrical connection. Solutions of a metal precursor and a reducing agent are placed on either side of a silica nanochannel, and a pair of electrodes is used to apply a tunable electric potential across the channel. Metal nanowire growth is initiated by chemical reduction when the two solutions meet and continues until the nanochannel is blocked by the formation of a short metal wire segment. Further growth is driven by a bipolar electrochemical mechanism which enables the reduction of metal precursor ions at one end of the nanowire and the oxidation of the reducing agent at the other. The growth rate is monitored in real time by simultaneously recording both the faradaic current and optical microscope video and can be adjusted accordingly by changing the applied electric potential. The resulting nanowire is solid, electrically insulated, and can be used as a bipolar nanoelectrode. This technique can be extended to other electrochemical systems, as well, and provides a confined reaction space for studying the dynamics of any process that can be optically or electrically monitored. PMID- 25695465 TI - Recent advances in graphene and its metal-oxide hybrid nanostructures for lithium ion batteries. AB - Today, one of the major challenges is to provide green and powerful energy sources for a cleaner environment. Rechargeable lithium-ion batteries (LIBs) are promising candidates for energy storage devices, and have attracted considerable attention due to their high energy density, rapid response, and relatively low self-discharge rate. The performance of LIBs greatly depends on the electrode materials; therefore, attention has been focused on designing a variety of electrode materials. Graphene is a two-dimensional carbon nanostructure, which has a high specific surface area and high electrical conductivity. Thus, various studies have been performed to design graphene-based electrode materials by exploiting these properties. Metal-oxide nanoparticles anchored on graphene surfaces in a hybrid form have been used to increase the efficiency of electrode materials. This review highlights the recent progress in graphene and graphene based metal-oxide hybrids for use as electrode materials in LIBs. In particular, emphasis has been placed on the synthesis methods, structural properties, and synergetic effects of metal-oxide/graphene hybrids towards producing enhanced electrochemical response. The use of hybrid materials has shown significant improvement in the performance of electrodes. PMID- 25695466 TI - Reliability, Validity, and Minimal Detectable Change of Balance Evaluation Systems Test and Its Short Versions in Older Cancer Survivors: A Pilot Study. AB - BACKGROUND: Cancer is primarily a disease of older adults. About 77% of all cancers are diagnosed in persons aged 55 years and older. Cancer and its treatment can cause diverse sequelae impacting body systems underlying balance control. No study has examined the psychometric properties of balance assessment tools in older cancer survivors, presenting a significant challenge in the selection of outcome measures for clinicians treating this fast-growing population. PURPOSE: This study aimed to determine the reliability, validity, and minimal detectable change (MDC) of the Balance Evaluation System Test (BESTest), Mini-Balance Evaluation Systems Test (Mini-BESTest), and Brief-Balance Evaluation Systems Test (Brief-BESTest) in community-dwelling older cancer survivors. METHODS: This study was a cross-sectional design. Twenty breast and 8 prostate cancer survivors participated [age (SD) = 68.4 (8.13) years]. The BESTest and Activity-specific Balance Confidence (ABC) Scale were administered during the first session. Scores of Mini-BESTest and Brief-BESTest were extracted on the basis of the scores of BESTest. The BESTest was repeated within 1 to 2 weeks by the same rater to determine the test-retest reliability. For the analysis of the inter-rater reliability, 21 participants were randomly selected to be evaluated by 2 raters. A primary rater administered the test. The 2 raters independently and concurrently scored the performance of the participants. Each rater recorded the ratings separately on the scoring sheet. No discussion among the raters was allowed throughout the testing. Intraclass correlation coefficients (ICCs), standard error of measurement, minimal detectable change (MDC), and Bland-Altman plots were calculated. Concurrent validity of these balance tests with the ABC Scale was examined using the Spearman correlation. RESULTS: The BESTest, Mini BESTest, and Brief-BESTest had high test-retest (ICC = 0.90-0.94) and interrater reliability (ICC = 0.86-0.96), small standard error of measurement (0.86-2.47 points), and MDC (2.39-6.86 points). The Bland-Altman plot revealed no systematic errors. The scores of BESTest, Mini-BEST, and Brief-BEST were correlated significantly with those of ABC Scale (P < .01), supporting their concurrent validity. DISCUSSION: The BESTest, Mini-BESTest, and Brief-BESTest showed high interrater and test-retest reliability, and excellent concurrent validity with the ABC Scale for community-dwelling cancer survivors aged 55 years and older who had completed cancer treatments for at least 3 months. Future studies are necessary to determine the predictive values for determining fall risks using balance assessment tools in older cancer survivors. CONCLUSIONS: Clinicians can utilize the BESTest and its short versions to evaluate balance problems in community-dwelling older cancer survivors and apply the established MDC to assess the intervention outcomes. PMID- 25695467 TI - Identifying Balance Measures Most Likely to Identify Recent Falls. AB - BACKGROUND AND PURPOSE: Falls sustained by older adults are an increasing health care issue. Early identification of those at risk for falling can lead to successful prevention of falls. Balance complaints are common among individuals who fall or are at risk for falling. The purpose of this study was to evaluate the clinical utility of a multifaceted balance protocol used for fall risk screening, with the hypothesis that this protocol would successfully identify individuals who had a recent fall (within the previous 12 months). METHODS: This is a retrospective review of 30 individuals who self-referred for a free fall risk screening. Measures included case history, Activities-Specific Balance Confidence Scale, modified Clinical Test of Sensory Interaction on Balance, Timed Up and Go test, and Dynamic Visual Acuity. Statistical analyses were focused on the ability of the test protocol to identify a fall within the past 12 months and included descriptive statistics, clinical utility indices, logistic regression, receiver operating characteristic curve, area under the curve analysis, effect size (Cohen d), and Spearman correlation coefficients. RESULTS AND DISCUSSION: All individuals who self-referred for this free screening had current imbalance complaints, and were typically women (70%), had a mean age of 77.2 years, and had a fear of falling (70%). Almost half (46.7%) reported at least 1 lifetime fall and 40.0% within the past 12 months. Regression analysis suggested that the Timed Up and Go test was the most important indicator of a recent fall. A cutoff score of 12 or more seconds was optimal (sensitivity: 83.3%; specificity: 61.1%). CONCLUSIONS: Older adults with current complaints of imbalance have a higher rate of falls, fall-related injury, and fear of falling than the general community dwelling public. The Timed Up and Go test is useful for determining recent fall history in individuals with imbalance. PMID- 25695468 TI - Helping Older Adults Sustain Their Physical Therapy Gains: A Theory-Based Intervention to Promote Adherence to Home Exercise Following Rehabilitation. AB - BACKGROUND AND PURPOSE: The benefits of exercise gained by older adults during physical therapy are often not maintained once the program is over. This lack of sustained benefits is thought to be partially the result of poor adherence to the prescribed home exercise program to be continued once therapy is completed. Most of what is known about older adults' adherence to physical therapy and home exercise comes from research seeking to identify and understand predictors of adherence, rather than trying to enhance adherence explicitly. The purpose of this study was to test a theoretically grounded approach to promoting adherence to home exercise programs in older adults. METHOD: Sixty older adults (M age = 69.3 (6.87) years) in a program of physical therapy received 1 of 2 print messages and magnets promoting adherence to home exercise. The content of the messages was informed by the goal-specific tenets of socioemotional selectivity theory-one message described the emotional and meaningful benefits of home exercise, such as time with loved ones and independence, and one message described facts and information about physiological benefits, such as balance and strength. Adherence to home exercise was measured 2 weeks after participants were discharged from physical therapy by calculating the percentage of the prescribed exercises participants reported completing at home. RESULTS: An analysis of covariance indicated that there was no statistically significant difference in adherence rates between participants receiving either message. However, a 2*2 analysis of covariance did reveal a significant interaction between the type of message participants received and the time at which they received that message. Post hoc analyses separately examined the rates of adherence in participants who received the intervention message with time remaining in their therapy program and participants who received the intervention message on the day of discharge. In the subset of participants who received their intervention message with time remaining in their therapy program, those who received the emotion and meaning message were somewhat more adherent to their home exercise program than those who received the facts and information message (63.6% vs 50.8%; P = .07). Those who received the emotion and meaning message also performed on average more exercises outside of their home exercise program (2.4 vs 1.3; P = .06). DISCUSSION: Despite lacking a statistically significant difference between message groups, the results of this study suggest that highlighting the emotional and meaningful benefits of home exercise versus providing facts and information about the physiological benefits may encourage older adults to be adherent to their home exercise programs. This may especially be the case if they receive the information while still in therapy. As this was the first study to empirically test an intervention targeting adherence to post-physical therapy home exercise in older adults, future research is needed to better understand what motivates older adults to be adherent. PMID- 25695469 TI - Relationship Between Mobility and Arousal Level After Waking Up. AB - BACKGROUND AND PURPOSE: Falling is an unexpected event for older adults, but few studies have investigated falls related to arousal levels and mobility immediately after waking up in the morning. Therefore, the purpose of this study was to clarify the possible relationship of arousal level and mobility with falls in the early morning hours. METHODS: We investigated both arousal levels and mobility of 14 community-dwelling older adults after waking up, from 4:00 AM until 2:00 PM. Mobility and arousal levels were evaluated through the following tests: Timed Up and Go, Functional Reach, postural sway, and critical frequency of fusion. Baseline of mobility and arousal levels were measured before sleep and after 5 hours of sleep. Immediately after waking up, each participant's mobility and arousal levels were remeasured and then also remeasured 2 hours later, 6 hours later, and 10 hours later, respectively. Stanford Sleepiness Scale was also chosen to measure the internal state of subjective sleepiness and it was measured 7 times at 2-hour intervals after the participants woke up from sleep. RESULTS: Significant differences were found between before sleep and after awakening in the score of Timed Up and Go test and Stanford Sleepiness Scale. The speed of Timed Up and Go test after awaking was slower than that before sleep. The Stanford Sleepiness Scale showed high states of sleepiness. CONCLUSION: We found that the decrease in arousal level in the early morning may affect mobility. The awareness of the degree of arousal levels may increase fall prevention in older adults in the early morning hours. PMID- 25695470 TI - The Association Between Knee Extensor Force Steadiness, Force Accuracy, and Mobility in Older Adults Who Have Fallen. AB - BACKGROUND: Older adults often experience limited mobility, lower extremity muscle weakness, and increased fall risk. Furthermore, when older adults perform tasks that require control of submaximal force, impairments in their ability to maintain steady and accurate force output have been reported. Such problems may be related to deteriorating levels of mobility, particularly in older adults who have fallen. PURPOSE: The purpose of this study was to determine whether an association exists between muscle force steadiness (MFS) or muscle force accuracy (MFA) of the knee extensors and mobility in older adults who have fallen. METHODS: Twenty older adults ((Equation is included in full-text article.)= 77.5 +/- 7 years, 5 males and 15 females) with 2 or more comorbid conditions and who experienced a fall in the past year underwent assessment of maximal voluntary isometric contraction of the knee extensors. A submaximal target force of 50% of their maximal voluntary isometric contraction was used to determine concentric and eccentric (ECC) steadiness (the fluctuations in force production) and accuracy (the average distance of the mean force from the target force) measures. Mobility was indicated by the 6-minute walk test, the Timed Up and Go, stair ascent, and stair descent tests. Correlation analysis was used to assess the relationship between measures of muscle force control and mobility. RESULTS: The correlations between muscle force steadiness and mobility were not significant (P > .05) for either contraction type. However, MFA during ECC contractions only was correlated significantly with all measures of mobility-6 minute walk test (r = 0.48; P = .03), Timed Up and Go (r = 0.68; P = .01), stair ascent (r = 0.60; P = .01), and stair descent (r = 0.75; P < .01). CONCLUSION: The identification of the relationship between ECC MFA and mobility in older adults who have fallen is novel. Although the correlations are not causal, these relationships suggest that inaccurate force output during ECC contractions of the knee extensors is linked to impaired mobility. PMID- 25695471 TI - Effect of Home Exercise Program in Patients With Knee Osteoarthritis: A Systematic Review and Meta-analysis. AB - BACKGROUND: The Osteoarthritis Research Society International recommended that nonpharmacological methods include patient education programs, weight reduction, coping strategies, and exercise programs for the management of knee osteoarthritis (OA). However, neither a systematic review nor a meta-analysis has been published regarding the effectiveness of home exercise programs for the management of knee OA. PURPOSE: The purpose of this systematic review was to examine the evidence regarding the effect of home exercise programs with and without supervised clinic-based exercises in the management of knee OA. METHODS: We searched PubMed, CINAHL, Embase, Scopus, and PEDro for research articles published prior to September 2014 using key words such as pain, exercise, home exercise program, rehabilitation, supervised exercise program, and physiotherapy in combination with Medical Subject Headings "Osteoarthritis knee." We selected randomized and case-controlled trials published in English language. To verify the quality of the selected studies, we applied the PEDro Scale. Two evaluators individually selected the studies based on titles, excluding those articles that were not related to the objectives of this review. One evaluator extracted data from the included studies. A second evaluator independently verified extracted data for accuracy. RESULTS: A total of 31 studies were found in the search. Of these, 19 studies met the inclusion criteria and were further analyzed. Seventeen of these 19 studies reached high methodological quality on the PEDro scale. Although the methods and home exercise program interventions varied widely in these studies, most found significant improvements in pain and function in individuals with knee OA. DISCUSSIONS: The analysis indicated that both home exercise programs with and without supervised clinic-based exercises were beneficial in the management of knee OA. CONCLUSIONS: The large evidence of high quality trials supports the effectiveness of home exercise programs with and without supervised clinic-based exercises in the rehabilitation of knee OA. In addition, small but growing evidence supports the effectiveness of other types of exercise such as tai chi, balance, and proprioceptive training for individuals with knee OA. PMID- 25695472 TI - Physical Performance Measures Associated With Locomotive Syndrome in Middle-Aged and Older Japanese Women. AB - BACKGROUND: The Japanese Orthopaedic Association proposed a concept called locomotive syndrome (LS) to identify middle-aged and older adults at high risk of requiring health care services because of problems with locomotion. It is important to identify factors associated with the development of LS. Physical performance measures such as walking speed and standing balance are highly predictive of subsequent disability and mortality in older adults. However, there is little evidence about the relationship between physical performance measures and LS. PURPOSE: To determine the physical performance measures associated with LS, the threshold values for discriminating individuals with and without LS, and the odds ratio of LS according to performance greater than or less than these thresholds in middle-aged and older Japanese women. METHODS: Participants were 126 Japanese women (mean age = 61.8 years). Locomotive syndrome was defined as a score of 16 or more on the 25-question Geriatric Locomotive Function Scale. Physical performance was evaluated using grip strength, unipedal stance time with eyes open, seated toe-touch, and normal and fast 6-m walk time (6 MWT). Variables were compared between LS and non-LS groups. RESULTS: Fourteen participants (11.1%) were classed as having LS. Unipedal stance time, normal 6 MWT, and fast 6 MWT were significantly different between the 2 groups. The LS group had a shorter unipedal stance time and a longer normal and fast 6 MWT than the non-LS group. For these 3 variables, the area under the receiver operating characteristic curve was greater than 0.7, and the threshold for discriminating the non-LS and LS groups was 15 s for unipedal stance time, 4.8 s for normal 6 MWT and 3.6 s for fast 6 MWT. These variables were entered into a multiple logistic regression analysis, which indicated that unipedal stance time less than 15 s was significantly related to LS (odds ratio = 8.46; P < .01). CONCLUSION: Unipedal stance time was the physical performance measure that was most strongly associated with LS. This measure may be useful for early detection of LS. PMID- 25695473 TI - A Pilot Study of Determinants of Ongoing Participation in EnhanceFitness: A Community-Based Group Exercise Program for Older Adults. AB - BACKGROUND AND PURPOSE: Physical activity has many benefits for older adults, but adherence is often low. The purposes of this study were to (1) identify motivators and barriers for participation in EnhanceFitness (EF), a group-based exercise program; and (2) quantitatively examine the association between motivators, barriers and individual characteristics, and ongoing participation in the program. METHODS: This was a prospective, cross-sectional study. We mailed a pilot, investigator-developed survey to assess motivators and barriers to exercising to 340 adults who started a new EF class, regardless of their attendance rate. We precoded surveys on the basis of class attendance, with former participants defined as having no attendance a month or more before a 4 month fitness check. RESULTS: Of the 241 respondents (71% response rate), 61 (25%) were precoded as former participants and 180 (75%) as current participants. The mean age of respondents was 71 years and they were predominately female (89%). More than half of respondents were whites (58%), and almost half were married (46%). Former participants reported lower total motivation scores than current participants (P < .01) and had a significantly higher mean total barrier score (P < .001). The effects of 5 barriers ("Class was too hard," "Class was too easy," "I don't like to exercise," "Personal illness," and "Exercise caused pain") and 2 motivators ("I want to exercise" and "I plan exercise as part of my day") were significantly different between current and former participants. Discrete event history models show that dropout was related positively to ethnicity (whites were more likely to drop out) and health-related barriers. DISCUSSION: In newly formed EF classes, participants who drop out report more program, psychosocial, and health barriers, and fewer program and psychosocial motivators. Total barrier score and health barriers significantly predict a participant's dropping out, and white ethnicity is associated with a higher likelihood of dropping out. CONCLUSIONS: Employing strategies that address health barriers to participation could improve attendance rates for group-based exercise programs. PMID- 25695474 TI - Gold-catalyzed allene cycloisomerization for pyrrole synthesis: towards highly fluorinated BODIPY dyes. AB - A novel synthetic strategy toward highly fluorinated BODIPY dyes with exceptional photostabilities relying on sustainable gold catalysis has been developed. A key to the tailored pyrrole precursors is the gold catalysis performed in ionic liquids as the reaction medium, allowing a facile recycling of the catalysts. The dyes prepared are well-matching with the spectral windows of popular rhodamine dyes and possess high brightness while showing a distinctly higher photostability than the rhodamines especially in aprotic solvents. PMID- 25695475 TI - Cluster of two cases of botulism due to Clostridium baratii type F in France, November 2014. AB - The first two cases in France of botulism due to Clostridium baratii type F were identified in November 2014, in the same family. Both cases required prolonged respiratory assistance. One of the cases had extremely high toxin serum levels and remained paralysed for two weeks. Investigations strongly supported the hypothesis of a common exposure during a family meal with high level contamination of the source. However, all analyses of leftover food remained negative. PMID- 25695476 TI - Surveillance of infant pertussis in Sweden 1998-2012; severity of disease in relation to the national vaccination programme. AB - In Sweden, pertussis was excluded from the national vaccination programme in 1979 until acellular vaccination was introduced in a highly endemic setting in 1996. The general incidence dropped 10-fold within a decade, less in infants. Infant pertussis reached 40-45 cases per 100,000 in 2008 to 2012; few of these cases were older than five months. We present an observational 15-year study on the severity of infant pertussis based on 1,443 laboratory-confirmed cases prospectively identified from 1998 to 2012 in the national mandatory reporting system and followed up by telephone contact. Analyses were made in relation to age at onset of symptoms and vaccination history. Pertussis decreased in non vaccinated infants (2003 to 2012, p<0.001), indicating herd immunity, both in those too young to be vaccinated and those older than three months. The hospitalisation rates also decreased (last five-year period vs the previous five year periods, p <0.001), but 70% of all cases in under three month-old infants and 99% of cases with apnoea due to pertussis were admitted to hospital in 1998 to 2012. Median duration of hospitalisation was seven days for unvaccinated vs four days for vaccinated infants aged 3-5 months. Nine unvaccinated infants died during the study period. PMID- 25695477 TI - Timeliness of epidemiological outbreak investigations in peer-reviewed European publications, January 2003 to August 2013. AB - Timely outbreak investigations are central in containing communicable disease outbreaks; despite this, no guidance currently exists on expectations of timeliness for investigations. A literature review was conducted to assess the length of epidemiological outbreak investigations in Europe in peer-reviewed publications. We determined time intervals between outbreak declaration to hypothesis generation, and hypothesis generation to availability of results from an analytical study. Outbreaks were classified into two groups: those with a public health impact across regions within a country and requiring national coordination (level 3) and those with a severe or catastrophic impact requiring direction at national level (levels 4 and 5). Investigations in Europe published between 2003 and 2013 were reviewed. We identified 86 papers for review: 63 level 3 and 23 level 4 and 5 investigations. Time intervals were ascertained from 55 papers. The median period for completion of an analytical study was 15 days (range: 4-32) for levels 4 and 5 and 31 days (range: 9-213) for level 3 investigations. Key factors influencing the speed of completing analytical studies were outbreak level, severity of infection and study design. Our findings suggest that guidance for completing analytical studies could usefully be provided, with different time intervals according to outbreak severity. PMID- 25695478 TI - The One Health approach for the management of an imported case of rabies in mainland Spain in 2013. AB - After more than 30 years without any reported cases of rabies in terrestrial carnivores in mainland Spain, an imported case was detected in June 2013 in Toledo. Although the infected dog was moved across different locations and had contact with humans and dogs, the incident was controlled within a few days. An epidemiological investigation was performed and rabies-free status in terrestrial carnivores in mainland Spain was restored six months after the incident. Key to the successful management of this case were the previous vaccination of susceptible animals in the affected area before the case was detected, the collaboration of different authorities in decision making, and the application of control measures according to national and international regulations and to the One Health concept. PMID- 25695479 TI - ECDC calls for field epidemiologists to join activities in Guinea. PMID- 25695481 TI - Heterogeneous catalytic oxidation of As(III) on nonferrous metal oxides in the presence of H2O2. AB - The oxidation of As(III) (arsenite) to As(V) (arsenate), a critical pretreatment process for total arsenic removal, is easily achieved using chemical oxidation methods. Hydrogen peroxide (H2O2) is widely used as an environmentally benign oxidant but its practical use for the arsenite oxidation is limited by the strong pH dependence and slow oxidation kinetics. This study demonstrated that H2O2 induced oxidation of As(III) can be markedly enhanced in the presence of nonferrous metal oxides (e.g., WO3, TiO2, ZrO2) as a heterogeneous catalyst working over a wide pH range in ambient reaction conditions. In particular, TiO2 is an ideal catalyst because it is not only active and stable but also easily available and inexpensive. Although the photocatalytic oxidation of As(III) on TiO2 was intensively studied, the thermal catalytic activities of TiO2 and other nonferrous metal oxides for the arsenic oxidation have been little investigated. The heterogeneous oxidation rate increased with increasing the TiO2 surface area and [H2O2] and weakly depended on pH whereas the homogeneous oxidation by H2O2 alone was favored only at alkaline condition. The oxidation rate in the TiO2/H2O2 system was not reduced at all in the absence of dioxygen. It was not retarded at all by OH radical scavengers but markedly inhibited by hydroperoxyl radical scavengers. It is proposed that the surface complexation of H2O2 on TiO2 induces the generation of the surface hydroperoxyl radical through an inner-sphere electron transfer, which subsequently reacts with As(III). The catalytic activity of TiO2 was maintained without showing any sign of deactivation. The heterogeneous catalytic oxidation is proposed as a viable method for the preoxidation treatment of As(III)-contaminated water under ambient conditions. PMID- 25695482 TI - Moxifloxacin Prophylaxis against MDR TB, New York, New York, USA. AB - Contacts of persons infected with multidrug-resistant tuberculosis (MDR TB) have few prophylaxis options. Of 50 contacts of HIV- and MDR TB-positive persons who were treated with moxifloxacin, 30 completed treatment and 3 discontinued treatment because of gastrointestinal symptoms. Moxifloxacin was generally well tolerated; further research of its efficacy against MDR TB is needed. PMID- 25695483 TI - A urine-based methylation signature for risk stratification within low-risk prostate cancer. AB - BACKGROUND: Prostate cancer overdiagnosis and overtreatment represents a major problem. Many men with low-grade disease on biopsy are undergraded and they harbour high-grade disease at prostatectomy with no reliable way to identify these men. We used a novel urine-based 2-gene methylation test to identify prostate cancers with aggressive features. METHODS: Following a proof of concept study in 100 post-radical prostatectomy tissue samples, urine samples were tested from 665 men at multiple U.S. centers undergoing prostate needle biopsy for elevated prostate-specific antigen (2-10 ng ml(-1)). A prediction model was then developed from a combination of clinical factors and the urine-based markers. It was then prospectively tested for accurate prediction of adverse disease (surgical Gleason score ?7 and/or a pathological stage ?T3a) using urine from a separate cohort of 96 men before radical prostatectomy. RESULTS: Among pre prostatectomy men with a biopsy Gleason score <7, 41% had adverse disease of which 100% were correctly identified by the test with a negative predictive value of 100% (95% confidence interval, 86-100%). CONCLUSIONS: This urine-based test accurately identifies men with clinical low-risk disease who do not have adverse pathology in their prostates and would be excellent candidates for active surveillance. PMID- 25695484 TI - Hepatitis B virus infection is associated with gastric cancer in China: an endemic area of both diseases. AB - BACKGROUND: Hepatitis B virus (HBV) infection was demonstrated to be a risk factor of several cancers of the digestive system. In addition, liver cirrhosis, which could possibly result from chronic HBV infection, was associated with a higher risk of gastric cancer. However, the association of HBV infection and gastric cancer has not been investigated. METHODS: A retrospective case-control study with 580 cases and 580 controls matched for age, sex and year of diagnosis was conducted. The associations between gastric cancer and HBV infection were explored with univariate and multivariate unconditional logistic regression analysis. RESULTS: Hepatitis B surface antigen (HBsAg) was positively associated with gastric cancer (AOR (95% CI): 1.49 (1.06-2.10)). This association remained significant in patients without family history of gastric cancer (AOR (95% CI): (1.06-2.11)). For HBsAg-negative population, being anti-HBc positive/anti-HBs negative, which possibly indicated occult HBV infection, was also found to have some associations with gastric cancer. In addition, some synergistic effects between HBV infection and blood type A in gastric cancer were identified. CONCLUSIONS: The HBV infection was positively related with gastric cancer, especially for patients without family history of gastric cancer. Further prospective studies are warranted to confirm this relationship. PMID- 25695485 TI - IL8 polymorphisms and overall survival in pazopanib- or sunitinib-treated patients with renal cell carcinoma. AB - BACKGROUND: We evaluated germline single nucleotide polymorphisms (SNPs) for association with overall survival (OS) in pazopanib- or sunitinib-treated patients with advanced renal cell carcinoma (aRCC). METHODS: The discovery analysis tested 27 SNPs within 13 genes from a phase III pazopanib trial (N=241, study 1). Suggestive associations were then pursued in two independent datasets: a phase III trial (COMPARZ) comparing pazopanib vs sunitinib (N=729, study 2) and an observational study of sunitinib-treated patients (N=89, study 3). RESULTS: In study 1, four SNPs showed nominally significant association (P<=0.05) with OS; two of these SNPs (rs1126647, rs4073) in IL8 were associated (P<=0.05) with OS in study 2. Because rs1126647 and rs4073 were highly correlated, only rs1126647 was evaluated in study 3, which also showed association (P<=0.05). In the combined data, rs1126647 was associated with OS after conservative multiple-test adjustment (P=8.8 * 10(-5); variant vs reference allele hazard ratio 1.32, 95% confidence interval: 1.15-1.52), without evidence for heterogeneity of effects between studies or between pazopanib- and sunitinib-treated patients. CONCLUSIONS: Variant alleles of IL8 polymorphisms are associated with poorer survival outcomes in pazopanib- or sunitinib-treated patients with aRCC. These findings provide insight in aRCC prognosis and may advance our thinking in development of new therapies. PMID- 25695486 TI - Estrogen receptorbeta2 regulates interlukin-12 receptorbeta2 expression via p38 mitogen-activated protein kinase signaling and inhibits non-small-cell lung cancer proliferation and invasion. AB - Lung cancer is one of the most common types of cancer and is the leading cause of cancer-related mortality worldwide. Estrogens are known to be involved in the development and progression of non-small-cell lung cancer (NSCLC). These effects are initially mediated through binding of estrogen to estrogen receptors (ERs), in particular ERbeta2. Our preliminary studies demonstrated that ERbeta2 and interleukin-12 receptorbeta2 (IL-12Rbeta2) expression are correlated in NSCLC. The present study investigated the expression of these proteins in NSCLC cells and how changes in their expression affected cell proliferation and invasion. In addition, it aimed to explore whether p38 mitogen-activated protein kinase (p38MAPK) is involved in the regulation of IL-12Rbeta2 expression by ERbeta2. An immunocytochemical array was used to observe the distribution of ERbeta2 and IL 12Rbeta2. Co-immuoprecipitation was employed to observe the interaction between p38MAPK and IL-12Rbeta2, by varying the expression of ERbeta2 and p38MAPK. Western-blot analysis and reverse transcription-polymerase chain reaction assays were used to investigate the mechanism underlying ERbeta2 regulation of IL 12Rbeta2 expression. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, scratch wound healing and Transwell assays were used to investigate the impact of ERbeta2 on proliferative, invasive and migratory abilities of NSCLC cells. ERbeta2 was predominantly found in the cytoplasm and nucleus, whilst IL 12Rbeta2 was largely confined to the cytoplasm, although a degree of expression was observed in the nucleus. Compared with normal bronchial epithelial cells, IL 12Rbeta2 and ERbeta2 were overexpressed in the NSCLC cell groups. Coimmuoprecipitation demonstrated an interaction between p38MAPK and IL-12Rbeta2. ERbeta2 appeared to upregulate IL-12Rbeta2 expression and inhibition of p38MAPK attenuated this effect. ERbeta2 and IL-12Rbeta2 expression inhibited the proliferation, metastasis and invasion of NSCLC cell lines, but knockout of IL 12Rbeta2, even in the presence of ERbeta2, led to an increase in NSCLC cell proliferation and invasiveness. In conclusion, to the best of our knowledge this study is the first to demonstrate that IL-12Rbeta2 may be important in the mechanisms underlying ERbeta2 inhibition of NSCLC development, and that this interaction may be mediated via p38MAPK. PMID- 25695487 TI - Vasoactive intestinal peptide induces CD14+HLA-DR-/low myeloid-derived suppressor cells in gastric cancer. AB - Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of cells, which have been revealed to inhibit T-cell responses in tumor-bearing mice. In addition, a number of immune suppressive mechanisms have linked MDSCs and the development of human cancer. However, the role of MDSCs in human gastric cancer tissue remains to be elucidated as specific markers are lacking. Therefore, the aim of the present study was to investigate the frequency and immune suppressive function of MDSCs denoted in the present study as cluster of differentiation 14 (CD14)+human leukocyte antigen (HLA)-DR-/low in gastric cancer patients. In the present study, MDSCs were directly isolated and characterized from the tumor and adjacent normal tissue of gastric cancer patients. Functional analysis of the CD14+HLA-DR-/low MDSCs co-cultured with allogeneic CD4+ T cells were performed and compared with controls. In addition, the interferon-gamma (IFN-gamma) and interleukin (IL)-2 production was compared in order to investigate the capacity of vasoactive intestinal peptide (VIP) to induce CD14+HLA-DR(-/low) MDSC-mediated CD4+ T-cell dysfunction and whether IL-10 secretion is involved in this mechanism. As a result, the quantity of CD14+HLA-DR(-/low) cells in tumor tissue from gastric cancer patients was significantly higher than that in the adjacent normal tissue. In addition, CD14+HLA-DR-/low MDSCs isolated from tumor tissue were observed to inhibit the CD4+ T-cells' immune responses in comparison with those from the adjacent normal tissue. Furthermore, VIP was able to induce the differentiation of CD14+ mononuclear cells isolated from healthy donor peripheral blood mononuclear cells into activated MDSC cells. Of note, the immunosuppressive effect of VIP-induced CD14+HLA-DR(-/low) MDSCs on CD4+ T cells was mediated by IL 10 secretion, which was demonstrated in the subsequent decrease of IFN-gamma and IL-2 production. In conclusion, CD14+HLA-DR(-/low) cells were significantly increased in gastric cancer tissue and were shown to have a critical role in CD4+T-cell immunosuppression. In addition, VIP as a novel cytokine may induce the differentiation of CD14+ mononuclear cells towards CD14+HLA-DR(-/low) MDSCs. An improved understanding of phenotypic heterogeneity and the mechanism of generation of MDSCs in gastric cancer patients is important in the design of effective immunotherapeutic strategies. PMID- 25695488 TI - Increased risk for multidrug-resistant tuberculosis in migratory workers, Armenia. AB - To understand use of tuberculosis (TB) services for migrant workers, we conducted a cross-sectional census of 95 migrant workers with TB from Armenia by using medical record reviews and face-to-face interviews. Prolonged time between diagnosis and treatment, treatment interruption, and treatment defaults caused by migrant work might increase the risk for multidrug-resistant TB. PMID- 25695489 TI - Supervised automatic interpretation of technical documents: when interruption is a time saver. AB - The present study examined human-computer interactions in which the operator has to detect errors made by software designed to automatically recognize technical documents. The goal was to assess the effect of user-initiated interruptions of the recognition process to correct these errors. Participants were asked to check the interpretations, either with or without the possibility of interrupting the process. Results showed that interruptions can improve efficiency by decreasing task duration, especially in the post-recognition verification phase. Interruptions provide an opportunity to correct errors during rather than after the recognition process, which is easier because it requires fewer cognitive resources. PMID- 25695490 TI - Single oral dose pharmacokinetics of decursin and decursinol angelate in healthy adult men and women. AB - The ethanol extract of Angelica gigas Nakai (AGN) root has promising anti-cancer and other bioactivities in rodent models. It is currently believed that the pyranocoumarin isomers decursin (D) and decursinol angelate (DA) contribute to these activities. We and others have documented that D and DA were rapidly converted to decursinol (DOH) in rodents. However, our in vitro metabolism studies suggested that D and DA might be metabolized differently in humans. To test this hypothesis and address a key question for human translatability of animal model studies of D and DA or AGN extract, we conducted a single oral dose human pharmacokinetic study of D and DA delivered through an AGN-based dietary supplement Cogni.Q (purchased from Quality of Life Labs, Purchase, NY) in twenty healthy subjects, i.e., 10 men and 10 women, each consuming 119 mg D and 77 mg DA from 4 vegicaps. Analyses of plasma samples using UHPLC-MS/MS showed mean time to peak concentration (Tmax) of 2.1, 2.4 and 3.3 h and mean peak concentration (Cmax) of 5.3, 48.1 and 2,480 nmol/L for D, DA and DOH, respectively. The terminal elimination half-life (t1/2) for D and DA was similar (17.4 and 19.3 h) and each was much longer than that of DOH (7.4 h). The mean area under the curve (AUC0-48h) for D, DA and DOH was estimated as 37, 335 and 27,579 h?nmol/L, respectively. Gender-wise, men absorbed the parent compounds faster and took shorter time to reach DOH peak concentration. The human data supported an extensive conversion of D and DA to DOH, even though they metabolized DA slightly slower than rodents. Therefore, the data generated in rodent models concerning anti-cancer efficacy, safety, tissue distribution and pharmacodynamic biomarkers will likely be relevant for human translation. TRIAL REGISTRATION: ClinicalTrials.gov NCT02114957. PMID- 25695491 TI - Interaction between the tRNA-binding and C-terminal domains of Yeast Gcn2 regulates kinase activity in vivo. AB - The stress-activated protein kinase Gcn2 regulates protein synthesis by phosphorylation of translation initiation factor eIF2alpha. Gcn2 is activated in amino acid-deprived cells by binding of uncharged tRNA to the regulatory domain related to histidyl-tRNA synthetase, but the molecular mechanism of activation is unclear. We used a genetic approach to identify a key regulatory surface in Gcn2 that is proximal to the predicted active site of the HisRS domain and likely remodeled by tRNA binding. Mutations leading to amino acid substitutions on this surface were identified that activate Gcn2 at low levels of tRNA binding (Gcd- phenotype), while other substitutions block kinase activation (Gcn- phenotype), in some cases without altering tRNA binding by Gcn2 in vitro. Remarkably, the Gcn substitutions increase affinity of the HisRS domain for the C-terminal domain (CTD), previously implicated as a kinase autoinhibitory segment, in a manner dampened by HisRS domain Gcd- substitutions and by amino acid starvation in vivo. Moreover, tRNA specifically antagonizes HisRS/CTD association in vitro. These findings support a model wherein HisRS-CTD interaction facilitates the autoinhibitory function of the CTD in nonstarvation conditions, with tRNA binding eliciting kinase activation by weakening HisRS-CTD association with attendant disruption of the autoinhibitory KD-CTD interaction. PMID- 25695492 TI - Are total, intensity- and domain-specific physical activity levels associated with life satisfaction among university students? AB - BACKGROUND: Thorough information about the relationship between physical activity (PA) and life satisfaction is still lacking. Therefore, this study examined the cross-sectional relationships between life satisfaction and meeting the World Health Organization (WHO) moderate to vigorous-intensity PA recommendations, total volume and duration of PA, intensity-specific PA (walking, moderate- and vigorous-intensity), domain-specific PA (work, transport-related, domestic, and leisure-time), and 11 domain and intensity-specific PA types among university students. Additionally, we examined the associations between life satisfaction and gender, age, disposable income, community size, smoking, alcohol intake, body mass index (BMI), and self-rated health. METHODS: The study included a random sample of 1750 university students in Zagreb, Croatia (response rate = 71.7%; 62.4% females; mean age 21.5 +/- 1.8 years), using the International Physical Activity Questionnaire-long form and the Satisfaction with Life Scale. RESULTS: Higher life satisfaction was associated with female gender (beta = 0.13; p = <0.001), younger age (beta = -0.07; p = 0.024), higher disposable income (beta = 0.10; p = 0.001), and better self-rated health (beta = 0.30; p = <0.001). No significant association was found between life satisfaction and size of community (p = 0.567), smoking status (p = 0.056), alcohol consumption (p = 0.058), or BMI (p = 0.508). Among all PA variables, only leisure-time vigorous-intensity PA was significantly associated with life satisfaction after adjustments for socio demographic characteristics, lifestyle and self-rated general health (beta = 0.06; p = 0.045). CONCLUSIONS: This study indicated a weak positive relationship between leisure-time vigorous-intensity PA and life satisfaction, whilst no such association was found for other PA variables. These findings underscore the importance of analyzing domain and intensity-specific PA levels in future studies among university students, as drawing conclusions about the relationship between PA and life satisfaction based on total PA levels only may be misleading. PMID- 25695493 TI - Extrauterine epithelioid trophoblastic tumor arising in the ovary with multiple metastases: a case report. AB - Epithelioid trophoblastic tumor is a neoplasm of the chorionic-type intermediate trophoblasts. It is considered a rare gestational trophoblastic disease and is frequently misdiagnosed as carcinoma. Extrauterine epithelioid trophoblastic tumor has been reported in multiple anatomical sites. We report a case of a 50 year-old woman who presented with abdominal pain and distension. Her initial beta human chorionic gonatotropin level was 806.7 IU/L. Imaging showed a large complex ovarian mass with peritoneal and subcapsular hepatic deposits as well as pulmonary nodules. Morphological features of the tumor and its immunohistochemical reactivity to CK8/18, CK7, p63, and CD10 were consistent with the diagnosis of an extrauterine epithelioid trophoblastic tumor arising from the ovary. The differential diagnoses, including other ovarian tumors, were ruled out on the basis of morphology and negative immunostaining to a relatively extended panel of antibodies. A prolonged follow up of these cases and the recognition of such rare tumors in unusual sites are crucial to the diagnosing pathologist and treating physician. PMID- 25695494 TI - Factors associated with virological failure and suppression after enhanced adherence counselling, in children, adolescents and adults on antiretroviral therapy for HIV in Swaziland. AB - INTRODUCTION: This study explores factors associated with virological detectability, and viral re-suppression after enhanced adherence counselling, in adults and children on antiretroviral therapy (ART) in Swaziland. METHODS: This descriptive study used laboratory data from 7/5/2012 to 30/9/2013, which were linked with the national ART database to provide information on time on ART and CD4 count; information on enhanced adherence counselling was obtained from file review in health facilities. Multivariable logistic regression was used to explore the relationship between viral load, gender, age, time on ART, CD4 count and receiving (or not receiving) enhanced adherence counselling. RESULTS: From 12,063 patients undergoing routine viral load monitoring, 1941 (16%) had detectable viral loads. Children were more likely to have detectable viral loads (AOR 2.6, 95%CI 1.5-4.5), as were adolescents (AOR 3.2, 95%CI 2.2-4.8), patients with last CD4<350 cells/ul (AOR 2.2, 95%CI 1.7-2.9) or WHO Stage 3/4 disease (AOR 1.3, 95%CI 1.1-1.6), and patients on ART for longer (AOR 1.1, 95%CI 1.1-1.2). At retesting, 450 (54% of those tested) showed viral re-suppression. Children were less likely to re-suppress (AOR 0.2, 95%CI 0.1-0.7), as were adolescents (AOR 0.3, 95%CI 0.2-0.8), those with initial viral load> 1000 copies/ml (AOR 0.3, 95%CI 0.1-0.7), and those with last CD4<350 cells/ul (AOR 0.4, 95%CI 0.2-0.7). Receiving (or not receiving) enhanced adherence counselling was not associated with likelihood of re-suppression. CONCLUSIONS: Children, adolescents and those with advanced disease were most likely to have high viral loads and least likely to achieve viral suppression at retesting; receiving adherence counselling was not associated with higher likelihood of viral suppression. Although the level of viral resistance was not quantified, this study suggests the need for ART treatment support that addresses the adherence problems of younger people; and to define the elements of optimal enhanced adherence support for patients of all ages with detectable viral loads. PMID- 25695495 TI - Photophysical studies of metal to ligand charge transfer involving quadruply bonded complexes of molybdenum and tungsten. AB - Photoinduced metal-to-ligand charge transfer transitions afford numerous applications in terms of photon energy harvesting. The majority of metal complexes studied to date involve diamagnetic systems of d(6), d(8), and d(10) transition metals. These typically have very short-lived, ~100 fs, singlet metal to ligand charge transfer ((1)MLCT) states that undergo intersystem crossing to triplet metal to ligand charge transfer ((3)MLCT) states that are longer lived and are responsible for much of the photophysical studies. In contrast, the metal metal quadruply bonded complexes of molybdenum and tungsten supported by carboxylate, O2CR, and related amidinate ligands (RN)2C(R') have relatively long lived (1)MLCT states arising from M2delta to Lpi* transitions. These have lifetimes in the range 1-20 ps prior to intersystem crossing to T1 states that may be (3)MLCT or (3)MMdeltadelta* with lifetimes of 1-100 ns and 1-100 MUs, respectively. The M2 quadruply bonded complexes take the form M2L4 or M2L4-nL'n where n = 1-3. Thus, in their photoexcited MLCT states, these compounds pose the question of how the charge resides on the ligands. This Account reviews the current knowledge of how charge is positioned with time in S1 and T1 states with the aid of active IR reported groups located on the ligands, for example, C=X multiple bonds (X = C, N, or O). Several examples of localized and delocalized charge distributions are noted along with kinetic barriers to the interconversion of MLCT and deltadelta* states. On the 50th anniversary of the recognition of the MM quadruple bond, these complexes are revealing some remarkable features in the study of the photophysical properties of metal-ligand charge transfer states. PMID- 25695496 TI - Alterations in peripheral and central components of the auditory brainstem response: a neural assay of tinnitus. AB - Chronic tinnitus, or "ringing of the ears", affects upwards of 15% of the adult population. Identifying a cost-effective and objective measure of tinnitus is needed due to legal concerns and disability issues, as well as for facilitating the effort to assess neural biomarkers. We developed a modified gap-in-noise (GIN) paradigm to assess tinnitus in mice using the auditory brainstem response (ABR). We then compared the commonly used acoustic startle reflex gap-prepulse inhibition (gap-PPI) and the ABR GIN paradigm in young adult CBA/CaJ mice before and after administrating sodium salicylate (SS), which is known to reliably induce a 16 kHz tinnitus percept in rodents. Post-SS, gap-PPI was significantly reduced at 12 and 16 kHz, consistent with previous studies demonstrating a tinnitus-induced gap-PPI reduction in this frequency range. ABR audiograms indicated thresholds were significantly elevated post-SS, also consistent with previous studies. There was a significant increase in the peak 2 (P2) to peak 1 (P1) and peak 4 (P4) to P1 amplitude ratios in the mid-frequency range, along with decreased latency of P4 at higher intensities. For the ABR GIN, peak amplitudes of the response to the second noise burst were calculated as a percentage of the first noise burst response amplitudes to quantify neural gap processing. A significant decrease in this ratio (i.e. recovery) was seen only at 16 kHz for P1, indicating the presence of tinnitus near this frequency. Thus, this study demonstrates that GIN ABRs can be used as an efficient, non-invasive, and objective method of identifying the approximate pitch and presence of tinnitus in a mouse model. This technique has the potential for application in human subjects and also indicates significant, albeit different, deficits in temporal processing in peripheral and brainstem circuits following drug induced tinnitus. PMID- 25695498 TI - Role of race/ethnicity in pulmonary nontuberculous mycobacterial disease. PMID- 25695499 TI - Post-Chikungunya rheumatoid arthritis, Saint Martin. PMID- 25695497 TI - Low-carbohydrate diet and type 2 diabetes risk in Japanese men and women: the Japan Public Health Center-Based Prospective Study. AB - OBJECTIVE: Evidence is sparse and contradictory regarding the association between low-carbohydrate diet score and type 2 diabetes risk, and no prospective study examined the association among Asians, who consume greater amount of carbohydrate. We prospectively investigated the association of low-carbohydrate diet score with type 2 diabetes risk. METHODS: Participants were 27,799 men and 36,875 women aged 45-75 years who participated in the second survey of the Japan Public Health Center-Based Prospective Study and who had no history of diabetes. Dietary intake was ascertained by using a validated food-frequency questionnaire, and low-carbohydrate diet score was calculated from total carbohydrate, fat, and protein intake. The scores for high animal protein and fat or for high plant protein and fat were also calculated. Odds ratios of self-reported, physician diagnosed type 2 diabetes over 5-year were estimated by using logistic regression. RESULTS: During the 5-year period, 1191 new cases of type 2 diabetes were self-reported. Low-carbohydrate diet score for high total protein and fat was significantly associated with a decreased risk of type 2 diabetes in women (P for trend <0.001); the multivariable-adjusted odds ratio of type 2 diabetes for the highest quintile of the score were 0.63 (95% confidence interval 0.46-0.84), compared with those for the lowest quintile. Additional adjustment for dietary glycemic load attenuated the association (odds ratio 0.75, 95% confidence interval 0.45-1.25). When the score separated for animal and for plant protein and fat, the score for high animal protein and fat was inversely associated with type 2 diabetes in women, whereas the score for high plant protein and fat was not associated in both men and women. DISCUSSION: Low-carbohydrate diet was associated with decreased risk of type 2 diabetes in Japanese women and this association may be partly attributable to high intake of white rice. The association for animal-based and plant-based low-carbohydrate diet warrants further investigation. PMID- 25695500 TI - On sufficient statistics of least-squares superposition of vector sets. AB - The problem of superposition of two corresponding vector sets by minimizing their sum-of-squares error under orthogonal transformation is a fundamental task in many areas of science, notably structural molecular biology. This problem can be solved exactly using an algorithm whose time complexity grows linearly with the number of correspondences. This efficient solution has facilitated the widespread use of the superposition task, particularly in studies involving macromolecular structures. This article formally derives a set of sufficient statistics for the least-squares superposition problem. These statistics are additive. This permits a highly efficient (constant time) computation of superpositions (and sufficient statistics) of vector sets that are composed from its constituent vector sets under addition or deletion operation, where the sufficient statistics of the constituent sets are already known (that is, the constituent vector sets have been previously superposed). This results in a drastic improvement in the run time of the methods that commonly superpose vector sets under addition or deletion operations, where previously these operations were carried out ab initio (ignoring the sufficient statistics). We experimentally demonstrate the improvement our work offers in the context of protein structural alignment programs that assemble a reliable structural alignment from well-fitting (substructural) fragment pairs. A C++ library for this task is available online under an open-source license. PMID- 25695501 TI - Use of a problem-based learning exercise to teach the lean 8-step problem-solving method. AB - Doctor of nursing practice (DNP) graduates must be prepared to lead quality improvement (QI) initiatives in health care settings; however, effective and feasible teaching strategies pose a challenge for many DNP program faculties. This article describes a successful and practical problem-based learning exercise for students to work through the QI process using the Lean 8-step problem-solving method. Suggestions for faculty and recommendations for future activities are discussed. PMID- 25695502 TI - Temperature-dependent in-plane structure formation of an X-shaped bolapolyphile within lipid bilayers. AB - Polyphilic compound B12 is an X-shaped molecule with a stiff aromatic core, flexible aliphatic side chains, and hydrophilic end groups. Forming a thermotropic triangular honeycomb phase in the bulk between 177 and 182 degrees C but no lyotropic phases, it is designed to fit into DPPC or DMPC lipid bilayers, in which it phase separates at room temperature, as observed in giant unilamellar vesicles (GUVs) by fluorescence microscopy. TEM investigations of bilayer aggregates support the incorporation of B12 into intact membranes. The temperature-dependent behavior of the mixed samples was followed by differential scanning calorimetry (DSC), FT-IR spectroscopy, fluorescence spectroscopy, and X ray scattering. DSC results support in-membrane phase separation, where a reduced main transition and new B12-related transitions indicate the incorporation of lipids into the B12-rich phase. The phase separation was confirmed by X-ray scattering, where two different lamellar repeat distances are visible over a wide temperature range. Polarized ATR-FTIR and fluorescence anisotropy experiments support the transmembrane orientation of B12, and FT-IR spectra further prove a stepwise "melting" of the lipid chains. The data suggest that in the B12-rich domains the DPPC chains are still rigid and the B12 molecules interact with each other via pi-pi interactions. All results obtained at temperatures above 75 degrees C confirm the formation of a single, homogeneously mixed phase with freely mobile B12 molecules. PMID- 25695503 TI - Effects of long-term 50Hz power-line frequency electromagnetic field on cell behavior in Balb/c 3T3 cells. AB - Power-line frequency electromagnetic field (PF-EMF) was reported as a human carcinogen by some epidemiological research, but the conclusion is lack of robust experiment evidence. To identify the effects of long-term PF-EMF exposure on cell behavior, Balb/c 3T3 cells in exponential growth phase were exposed or sham exposed to 50 Hertz (Hz) PF-EMF at 2.3 mT for 2 hours (h) one day, 5 days every week. After 11 weeks exposure, cells were collected instantly. Cell morphology was observed under invert microscope and Giemsa staining, cell viability was detected by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay, cell cycle and apoptosis was examined by flow cytometry, the protein level of Proliferating Cell Nuclear Antigen (PCNA) and CyclinD1 was detected by western blot, cell transformation was examined by soft agar clone assay and plate clone forming test, and cell migration ability was observed by scratch adhesion test. It was found that after PF-EMF exposure, cell morphology, apoptosis, cell migration ability and cell transformation didn't change. However, compared with sham group, cell viability obviously decreased and cell cycle distribution also changed after 11 weeks PF-EMF exposure. Meanwhile, the protein level of PCNA and CyclinD1 significantly decreased after PF-EMF exposure. These data suggested that although long-term 50Hz PF-EMF exposure under this experimental condition had no effects on apoptosis, cell migration ability and cell transformation, it could affect cell proliferation and cell cycle by down-regulation the expression of PCNA and CyclinD1 protein. PMID- 25695504 TI - Efflux pump gene expression in multidrug-resistant Mycobacterium tuberculosis clinical isolates. AB - Isoniazid (INH) and rifampicin (RIF) are the two most effective drugs in tuberculosis therapy. Understanding the molecular mechanisms of resistance to these two drugs is essential to quickly diagnose multidrug-resistant (MDR) tuberculosis and extensive drug-resistant tuberculosis. Nine clinical Mycobacterium tuberculosis isolates resistant to only INH and RIF and 10 clinical pan-sensitive isolates were included to evaluate the expression of 20 putative drug efflux pump genes and sequence mutations in rpoB (RIF), katG (INH), the inhA promoter (INH), and oxyR-ahpC (INH). Nine and three MDR isolates were induced to overexpress efflux pump genes by INH and RIF, respectively. Eight and two efflux pump genes were induced to overexpress by INH and RIF in MDR isolates, respectively. drrA, drrB, efpA, jefA (Rv2459), mmr, Rv0849, Rv1634, and Rv1250 were overexpressed under INH or RIF stress. Most efflux pump genes were overexpressed under INH stress in a MDR isolates that carried the wild-type katG, inhA, and oxyR-ahpC associated with INH resistance than in those that carried mutations. The expression levels of 11 genes (efpA, Rv0849, Rv1250, P55 (Rv1410c), Rv1634, Rv2994, stp, Rv2459, pstB, drrA, and drrB) without drug inducement were significantly higher (P < 0.05) in nine MDR isolates than in 10 pan-sensitive isolates. In conclusion, efflux pumps may play an important role in INH acquired resistance in MDR M. tuberculosis, especially in those strains having no mutations in genes associated with INH resistance; basal expression levels of some efflux pump genes are higher in MDR isolates than in pan-sensitive isolates and the basal expressional differences may be helpful to diagnose and treat resistant tuberculosis. PMID- 25695505 TI - NF-kappaB regulates caspase-4 expression and sensitizes neuroblastoma cells to Fas-induced apoptosis. AB - Found in neurons and neuroblastoma cells, Fas-induced apoptosis and accompanied activation of NF-kappaB signaling were thought to be associated with neurodegenerative diseases. However, the detailed functions of NF-kappaB activation in Fas killing and the effect of NF-kappaB activation on its downstream events remain unclear. Here, we demonstrated that agonistic Fas antibody induces cell death in a dose-dependent way and NF-kappaB signaling is activated as well, in neuroblastoma cells SH-EP1. Unexpectedly, NF-kappaB activation was shown to be pro-apoptotic, as suggested by the reduction of Fas induced cell death with either a dominant negative form of IkappaBalpha (DN IkappaBalpha) or an IkappaB kinase-specific inhibitor. To our interest, when analyzing downstream events of NF-kappaB signaling, we found that DN-IkappaBalpha only suppressed the expression of caspase-4, but not other caspases. Vice versa, enhancement of NF-kappaB activity by p65 (RelA) overexpression increased the expression of caspase-4 at both mRNA and protein levels. More directly, results from dual luciferase reporter assay demonstrated the regulation of caspase-4 promoter activity by NF-kappaB. When caspase-4 activity was blocked by its dominant negative (DN) form, Fas-induced cell death was substantially reduced. Consistently, the cleavage of PARP and caspase-3 induced by Fas was also reduced. In contrast, the cleavage of caspase-8 remained unaffected in caspase-4 DN cells, although caspase-8 inhibitor could rescue Fas-induced cell death. Collectively, these data suggest that caspase-4 activity is required for Fas-induced cell apoptosis and caspase-4 may act upstream of PARP and caspase-3 and downstream of caspase-8. Overall, we demonstrate that NF-kappaB can mediate Fas-induced apoptosis through caspase-4 protease, indicating that caspase-4 is a new mediator of NF-kappaB pro-apoptotic pathway in neuroblastoma cells. PMID- 25695506 TI - ZnGa(2-x)In(x)S4 (0 <= x <= 0.4) and Zn(1-2y)(CuGa)(y)Ga(1.7)In(0.3)S4 (0.1 <= y <= 0.2): optimize visible light photocatalytic H2 evolution by fine modulation of band structures. AB - Band structure engineering is an efficient technique to develop desired semiconductor photocatalysts, which was usually carried out through isovalent or aliovalent ionic substitutions. Starting from a UV-activated catalyst ZnGa2S4, we successfully exploited good visible light photocatalysts for H2 evolution by In(3+)-to-Ga(3+) and (Cu(+)/Ga(3+))-to-Zn(2+) substitutions. First, the bandgap of ZnGa2-xInxS4 (0 <= x <= 0.4) decreased from 3.36 to 3.04 eV by lowering the conduction band position. Second, Zn1-2y(CuGa)yGa1.7In0.3S4 (y = 0.1, 0.15, 0.2) provided a further and significant red-shift of the photon absorption to ~500 nm by raising the valence band maximum and barely losing the overpotential to water reduction. Zn0.7Cu0.15Ga1.85In0.3S4 possessed the highest H2 evolution rate under pure visible light irradiation using S(2-) and SO3(2-) as sacrificial reagents (386 MUmol/h/g for the noble-metal-free sample and 629 MUmol/h/g for the one loaded with 0.5 wt % Ru), while the binary hosts ZnGa2S4 and ZnIn2S4 (synthesized using the same procedure) show 0 and 27.9 MUmol/h/g, respectively. The optimal apparent quantum yield reached to 7.9% at 500 nm by tuning the composition to Zn0.6Cu0.2Ga1.9In0.3S4 (loaded with 0.5 wt % Ru). PMID- 25695507 TI - Essential Role for endogenous siRNAs during meiosis in mouse oocytes. AB - The RNase III enzyme DICER generates both microRNAs (miRNAs) and endogenous short interfering RNAs (endo-siRNAs). Both small RNA species silence gene expression post-transcriptionally in association with the ARGONAUTE (AGO) family of proteins. In mammals, there are four AGO proteins (AGO1-4), of which only AGO2 possesses endonucleolytic activity. siRNAs trigger endonucleolytic cleavage of target mRNAs, mediated by AGO2, whereas miRNAs cause translational repression and mRNA decay through association with any of the four AGO proteins. Dicer deletion in mouse oocytes leads to female infertility due to defects during meiosis I. Because mouse oocytes express both miRNAs and endo-siRNAs, this phenotype could be due to the absence of either class of small RNA, or both. However, we and others demonstrated that miRNA function is suppressed in mouse oocytes, which suggested that endo-siRNAs, not miRNAs, are essential for female meiosis. To determine if this was the case we generated mice that express a catalytically inactive knock-in allele of Ago2 (Ago2ADH) exclusively in oocytes and thereby disrupted the function of siRNAs. Oogenesis and hormonal response are normal in Ago2ADH oocytes, but meiotic maturation is impaired, with severe defects in spindle formation and chromosome alignment that lead to meiotic catastrophe. The transcriptome of these oocytes is widely perturbed and shows a highly significant correlation with the transcriptome of Dicer null and Ago2 null oocytes. Expression of the mouse transcript (MT), the most abundant transposable element in mouse oocytes, is increased. This study reveals that endo-siRNAs are essential during meiosis I in mouse females, demonstrating a role for endo-siRNAs in mammals. PMID- 25695508 TI - Capture Hi-C identifies the chromatin interactome of colorectal cancer risk loci. AB - Multiple regulatory elements distant from their targets on the linear genome can influence the expression of a single gene through chromatin looping. Chromosome conformation capture implemented in Hi-C allows for genome-wide agnostic characterization of chromatin contacts. However, detection of functional enhancer promoter interactions is precluded by its effective resolution that is determined by both restriction fragmentation and sensitivity of the experiment. Here we develop a capture Hi-C (cHi-C) approach to allow an agnostic characterization of these physical interactions on a genome-wide scale. Single-nucleotide polymorphisms associated with complex diseases often reside within regulatory elements and exert effects through long-range regulation of gene expression. Applying this cHi-C approach to 14 colorectal cancer risk loci allows us to identify key long-range chromatin interactions in cis and trans involving these loci. PMID- 25695509 TI - Identification of the 1B vaccine strain of Chlamydia abortus in aborted placentas during the investigation of toxaemic and systemic disease in sheep. AB - CASE HISTORY: One hundred and forty Cheviot and 100 Suffolk cross Mule primiparous 1-2-year-old ewes, from a flock of about 700 ewes, were vaccinated with an attenuated live 1B strain Chlamydia abortus vaccine about 4 weeks before ram introduction (September 2011). Between 08 March and 01 April 2012, 50 2-year old ewes aborted and 29 of these died, despite antimicrobial and anti inflammatory treatment and supportive care. PATHOLOGICAL FINDINGS: Seven fetuses and three placentae from five 2-year-old ewes were submitted for pathological investigation. The aborted fetuses showed stages of autolysis ranging from being moderately fresh to putrefaction. Unusual, large multifocal regions of thickened membranes, with a dull red granular surface and moderate amounts of grey-white surface exudate were seen on each of the placentae. Intracellular, magenta staining, acid fast inclusions were identified in Ziehl Neelsen-stained placental smears. Immunohistochemistry for Chlamydia-specific lipopolysaccharide showed extensive positive labelling of the placental epithelia. LABORATORY FINDINGS: Molecular analyses of the aborted placentae demonstrated the presence of the 1B vaccine-type strain of C. abortus and absence of any wild-type field strain. The vaccine strain bacterial load of the placental tissue samples was consistent with there being an association between vaccination and abortion. DIAGNOSIS: Initial laboratory investigations resulted in a diagnosis of chlamydial abortion. Further investigations led to the identification of the 1B vaccine strain of C. abortus in material from all three of the submitted aborted placentae. CLINICAL RELEVANCE: Timely knowledge and understanding of any potential problems caused by vaccination against C. abortus are prerequisites for sustainable control of chlamydial abortion. This report describes the investigation of an atypical abortion storm in sheep, and describes the identification of the 1B vaccine strain of C. abortus in products of abortion. The significance of this novel putative association between the vaccine strain of C. abortus and severe clinical disease is unknown. Aspects of the approach that is described are relevant to the investigation of all outbreaks of ovine abortion, irrespective of the diagnosis. Awareness of the changing role of C. abortus as a major global cause of abortion ought to reinforce the importance of monitoring of adequate biosecurity in those countries which are currently free from chlamydial abortion. PMID- 25695510 TI - Transcriptional attenuation controls macrolide inducible efflux and resistance in Streptococcus pneumoniae and in other Gram-positive bacteria containing mef/mel(msr(D)) elements. AB - Macrolide resistance, emerging in Streptococcus pneumoniae and other Gram positive bacteria, is increasingly due to efflux pumps encoded by mef/mel(msr) operons found on discrete mobile genetic elements. The regulation of mef/mel(msr) in these elements is not well understood. We identified the mef(E)/mel transcriptional start, localized the mef(E)/mel promoter, and demonstrated attenuation of transcription as a mechanism of regulation of macrolide-inducible mef-mediated macrolide resistance in S. pneumoniae. The mef(E)/mel transcriptional start site was a guanine 327 bp upstream of mef(E). Consensus pneumococcal promoter -10 (5'-TATACT-3') and -35 (5'-TTGAAC-3') boxes separated by 17 bp were identified 7 bp upstream of the start site. Analysis of the predicted secondary structure of the 327 5' region identified four pairs of inverted repeats R1-R8 predicted to fold into stem-loops, a small leader peptide [MTASMRLR, (Mef(E)L)] required for macrolide induction and a Rho-independent transcription terminator. RNA-seq analyses provided confirmation of transcriptional attenuation. In addition, expression of mef(E)L was also influenced by mef(E)L-dependent mRNA stability. The regulatory region 5' of mef(E) was highly conserved in other mef/mel(msr)-containing elements including Tn1207.1 and the 5612IQ complex in pneumococci and Tn1207.3 in Group A streptococci, indicating a regulatory mechanism common to a wide variety of Gram positive bacteria containing mef/mel(msr) elements. PMID- 25695512 TI - Substrate stress relaxation regulates cell spreading. AB - Studies of cellular mechanotransduction have converged upon the idea that cells sense extracellular matrix (ECM) elasticity by gauging resistance to the traction forces they exert on the ECM. However, these studies typically utilize purely elastic materials as substrates, whereas physiological ECMs are viscoelastic, and exhibit stress relaxation, so that cellular traction forces exerted by cells remodel the ECM. Here we investigate the influence of ECM stress relaxation on cell behaviour through computational modelling and cellular experiments. Surprisingly, both our computational model and experiments find that spreading for cells cultured on soft substrates that exhibit stress relaxation is greater than cells spreading on elastic substrates of the same modulus, but similar to that of cells spreading on stiffer elastic substrates. These findings challenge the current view of how cells sense and respond to the ECM. PMID- 25695513 TI - Correction: Tap density equations of granular powders based on the rate process theory and the free volume concept. PMID- 25695514 TI - Correction: Prevalence and trend of major transfusion-transmissible infections among blood donors in Western China, 2005 through 2010. AB - [This corrects the article DOI: 10.1371/journal.pone.0094528.]. PMID- 25695515 TI - Paracentral acute middle maculopathy in sickle cell disease. PMID- 25695517 TI - Sororin is tethered to Cohesin SA2. PMID- 25695516 TI - Self-assembled hydrogels utilizing polymer-nanoparticle interactions. AB - Mouldable hydrogels that flow on applied stress and rapidly self-heal are increasingly utilized as they afford minimally invasive delivery and conformal application. Here we report a new paradigm for the fabrication of self-assembled hydrogels with shear-thinning and self-healing properties employing rationally engineered polymer-nanoparticle (NP) interactions. Biopolymer derivatives are linked together by selective adsorption to NPs. The transient and reversible interactions between biopolymers and NPs enable flow under applied shear stress, followed by rapid self-healing when the stress is relaxed. We develop a physical description of polymer-NP gel formation that is utilized to design biocompatible gels for drug delivery. Owing to the hierarchical structure of the gel, both hydrophilic and hydrophobic drugs can be entrapped and delivered with differential release profiles, both in vitro and in vivo. The work introduces a facile and generalizable class of mouldable hydrogels amenable to a range of biomedical and industrial applications. PMID- 25695518 TI - Structural mechanisms underlying sequence-dependent variations in GAG affinities of decorin binding protein A, a Borrelia burgdorferi adhesin. AB - Decorin-binding protein A (DBPA) is an important surface adhesin of the bacterium Borrelia burgdorferi, the causative agent of Lyme disease. DBPA facilitates the bacteria's colonization of human tissue by adhering to glycosaminoglycan (GAG), a sulfated polysaccharide. Interestingly, DBPA sequence variation among different strains of Borrelia spirochetes is high, resulting in significant differences in their GAG affinities. However, the structural mechanisms contributing to these differences are unknown. We determined the solution structures of DBPAs from strain N40 of B. burgdorferi and strain PBr of Borrelia garinii, two DBPA variants whose GAG affinities deviate significantly from strain B31, the best characterized version of DBPA. Our structures revealed that significant differences exist between PBr DBPA and B31/N40 DBPAs. In particular, the C terminus of PBr DBPA, unlike C-termini from B31 and N40 DBPAs, is positioned away from the GAG-binding pocket and the linker between helices one and two of PBr DBPA is highly structured and retracted from the GAG-binding pocket. The repositioning of the C-terminus allowed the formation of an extra GAG-binding epitope in PBr DBPA and the retracted linker gave GAG ligands more access to the GAG-binding epitopes than other DBPAs. Characterization of GAG ligands' interactions with wild-type (WT) PBr and mutants confirmed the importance of the second major GAG-binding epitope and established the fact that the two epitopes are independent of one another and the new epitope is as important to GAG binding as the traditional epitope. PMID- 25695519 TI - In vivo screening for anti-osteoporotic fraction from extract of herbal formula Xianlinggubao in ovariectomized mice. AB - BACKGROUND AND OBJECTIVES: Traditional Chinese Medicine (TCM) Fufang or formula Xianlinggubao (XLGB) is a prescribed TCM drug in China registered for prevention and treatment of osteoporosis. Fufang in TCM is comprised of a group of herbal compounds contributing in group to the treatment efficacy. The present study aims to identify the bioactive fraction(s) in XLGB extract that account(s) dominantly for its osteogenic effects. METHODS: The extract of XLGB formula was separated into three fractions using chromatography, i.e., XLGB-A, XLGB-B and XLGB-C. They were administrated to 4-month old ovariectomized (OVX) mice for 6 weeks to determine which bioactive fraction(s) were more effective for preventing OVX induced bone loss evaluated by microCT, biomechanical testing and biochemical markers. The main peaks of the key fraction were identified using reference compounds isolated from the fraction. In addition, the effects of the composite compounds in XLGB-B on osteoblasts' proliferation and mineralization were evaluated in UMR 106 cells. RESULTS: XLGB-B with a yield of 13.0% from herbal Fufang XLGB was identified as the most potential one among the three fractions for prevention of OVX-induced bone loss confirmed with bone mass, bone microarchitecture, bone strength and bone turnover markers. Nine compounds in HPLC fingerprint were identified in the XLGB-B fraction, including phenylpropanoids from Herba Epimedii, terpenes from Radix Dipsaci and coumarins from Fructus Psoraleae. In addition, the identified compounds effectively promoted proliferation and/or mineralization of osteoblast-like UMR 106 cells in vitro. CONCLUSION: XLGB-B with defined phytochemical structures was screened as the key fraction that demonstrated preventive effects on OVX-induced bone loss in mice. The present study laid down a foundation towards a new generation of herbal Fufang characterized with "less herbal materials for achieving equal treatment efficacy" in development strategy of TCM for prevention of OVX-induced osteoporosis. PMID- 25695520 TI - Effectiveness of traveller screening for emerging pathogens is shaped by epidemiology and natural history of infection. AB - During outbreaks of high-consequence pathogens, airport screening programs have been deployed to curtail geographic spread of infection. The effectiveness of screening depends on several factors, including pathogen natural history and epidemiology, human behavior, and characteristics of the source epidemic. We developed a mathematical model to understand how these factors combine to influence screening outcomes. We analyzed screening programs for six emerging pathogens in the early and late stages of an epidemic. We show that the effectiveness of different screening tools depends strongly on pathogen natural history and epidemiological features, as well as human factors in implementation and compliance. For pathogens with longer incubation periods, exposure risk detection dominates in growing epidemics, while fever becomes a better target in stable or declining epidemics. For pathogens with short incubation, fever screening drives detection in any epidemic stage. However, even in the most optimistic scenario arrival screening will miss the majority of cases. PMID- 25695521 TI - Macrophage inhibitory cytokine-1 (MIC-1/GDF15) gene deletion promotes cancer growth in TRAMP prostate cancer prone mice. AB - The divergent TGF-beta superfamily member, macrophage inhibitory cytokine-1 (MIC 1/GDF15), is overexpressed by most cancers, including prostate cancer (PCa). Whilst its circulating levels are linked to cancer outcome, the role MIC-1/GDF15 plays in cancer development and progression is incompletely understood. To investigate its effect on PCa development and spread, we have used TRAMP prostate cancer prone mice bearing a germline deletion of MIC-1/GDF15 (TRAMPMIC-/-). On average TRAMPMIC-/- mice died about 5 weeks earlier and had larger prostatic tumors compared with TRAMP mice that were wild type for MIC-1/GDF15 (TRAMPMIC+/+). Additionally, at the time of death or ethical end point, even when adjusted for lifespan, there were no significant differences in the number of mice with metastases between the TRAMPMIC+/+ and TRAMPMIC-/- groups. However, consistent with our previous data, more than twice as many TRAMP mice overexpressing MIC-1/GDF15 (TRAMPfmsmic-1) had metastases than TRAMPMIC+/+ mice (p<0.0001). We conclude that germ line gene deletion of MIC-1/GDF15 leads to increased local tumor growth resulting in decreased survival consistent with an overall protective role for MIC-1/GDF15 in early primary tumor development. However, in advancing disease, as we have previously noted, MIC-1/GDF15 overexpression may promote local invasion and metastatic spread. PMID- 25695522 TI - Polymorphisms in oxytocin and alpha1a adrenergic receptor genes and their effects on production traits in dairy buffaloes. AB - The use of molecular markers may auxiliary the buffalo breeding. The oxytocin (OXT) and the adrenergic receptor alpha1A (ADRA1A) may be involved in milk ejection in ruminants. The aim of this study was to verify the existence of polymorphisms in the OXT and ADRA1A genes and their associations with milk production traits. A total of 220 buffaloes were genotyped using PCR-RFLP for both genes. The SNP identified in the ADRA1A gene was associated with protein percentage in dairy buffaloes. This is the first report of such association in the literature, which has not been studied in other species. PMID- 25695523 TI - Dengue vaccine: come let's fight the menace. AB - Although dengue has a global distribution, the World Health Organization (WHO) South-East Asia region together with Western Pacific region bears nearly 75% of the current global disease burden. Globally, the societal burden has been estimated to be approximately 528 to 1300 disability-adjusted life years (DALY) per million to populations in endemic regions Dengue is believed to infect 50 to 100 million people worldwide a year with half a million life-threatening infections requiring hospitalization, resulting in approximately 12,500 to 25,000 deaths. Despite being known for decades and nearly half the world's population is at risk for infection with as many as 100 million cases occurring annually, the pitiable state is that we still have no antiviral drugs to treat it and no vaccines to prevent it. In recent years, however, the development of dengue vaccines has accelerated dramatically in tandem with the burgeoning dengue problem with a rejuvenated vigour. However, recent progress in molecular-based vaccine strategies, as well as a renewed commitment by the World Health Organization (WHO) to co-ordinate global efforts on vaccine development, finally provides hope that control of this serious disease may be at hand. Today, several vaccines are in various stages of advanced development, with clinical trials currently underway on 5 candidate vaccines. Trials in the most advanced stages are showing encouraging preliminary data, and the leading candidate could be licensed as early as 2015. PMID- 25695524 TI - Cross-platform meta-analysis of multiple gene expression profiles identifies novel expression signatures in acquired anthracycline-resistant breast cancer. AB - Anthracyclines are among the most effective and commonly used chemotherapeutic agents. However, the development of acquired anthracycline resistance is a major limitation to their clinical application. The aim of the present study was to identify differentially expressed genes (DEGs) and biological processes associated with the acquisition of anthracycline resistance in human breast cancer cells. We performed a meta-analysis of publically available microarray datasets containing data on stepwise-selected, anthracycline-resistant breast cancer cell lines using the RankProd package in R. Additionally, the gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases were used to analyze GO term enrichment and pathways, respectively. A protein-protein interaction (PPI) network was also generated using Cytoscape software. The meta analysis yielded 413 DEGs related to anthracycline resistance in human breast cancer cells, and 374 of these were not involved in individual DEGs. GO analyses showed the 413 genes were enriched with terms such as 'response to steroid metabolic process', 'chemical stimulus', 'external stimulus', 'hormone stimulus', 'multicellular organismal process', and 'system development'. Pathway analysis revealed significant pathways including steroid hormone biosynthesis, cytokine cytokine receptor interaction, drug metabolism-cytochrome P450, metabolism of xenobiotics by cytochrome P450, and arachidonic acid metabolism. The PPI network indicated that proteins encoded by TRIM29, VTN, CCNA1, and karyopherin alpha 5 (KPNA5) participated in a significant number of interactions. In conclusion, our meta-analysis provides a comprehensive view of gene expression patterns associated with acquired resistance to anthracycline in breast cancer cells, and constitutes the basis for additional functional studies. PMID- 25695525 TI - I Like You More if I Think You Like Me: The Effect of Metastereotypes on Attitudes Toward People With Deafness. AB - In the present article we aimed at investigating the role of metastereotypes and gender on hearing people's attitudes towards people with deafness. Ninety-six Italian hearing adults participated in a 2 * 2 experimental study. Participants were presented with the results of a fictitious but apparently real survey concerning the opinions people with deafness have of hearing people. Metastereotypes (positive vs. negative) were manipulated through this presentation. Results showed that metastereotypes interacted with participants' gender in determining their attitudes towards people with deafness: when positive metastereotypes were activated, women's attitudes appeared more favorable toward people with deafness if compared to the negative metastereotypes condition. No effect of metastereotypes was observed among male participants. In conclusion, the activation of metastereotypes can be a useful means in intervening to improve attitudes toward people with deafness. PMID- 25695526 TI - Validating the use of qualitative behavioral assessment as a measure of the welfare of sheep during transport. AB - We tested the application of qualitative behavioral assessment (QBA) as a welfare assessment tool. Sheep were exposed to road transport treatments, and behavioral expressions were compared between experimental treatments and validated by correlation with physiological measures. We compared journeys differing in ventilation (closed vs. open-sided trailer), flooring (grip vs. nongrip flooring), and driving styles (stop-start vs. continuous driving). Blood samples were collected immediately before loading and after unloading; heart rate and core body temperatures were recorded continuously. Continuous video footage was edited to show individual sheep to observers for QBA using free-choice profiling (observers used their own descriptive terms). There was significant consensus in observers' scores for the sheep in each experiment (p < .001). Observers distinguished between sheep exposed to flooring (p = .014) or driving-style (p = .005) treatments, but not between ventilation treatments. QBA scores were compared (p < .05) with plasma leptin, glucose, and insulin-like growth factor-1 concentrations; white blood cell profiles; red blood cell counts; hematocrit; body temperatures; and heart rate variability. Observer assessments reflected treatment differences, and correlations between behavioral expression and physiological responses were found. PMID- 25695527 TI - Clinical role or service specialisation and quality of care. PMID- 25695528 TI - Disease prevention guidelines put interprofessional collaboration to support healthy eating on the agenda. PMID- 25695529 TI - Considerations for using the 'brown bag' strategy to reconcile medications during routine outpatient office visits. AB - BACKGROUND: Among medication reconciliation studies, varying methods are used to determine which medications patients are actually taking. One recommended approach is to ask patients to "brown bag" their medications for routine office visits. AIMS: To determine if 'brown bag' practices performed during routine office visits improve the accuracy of provider-documented medication lists. METHODS: This cross-sectional pilot study was conducted in a university affiliated community geriatric clinic. Forty-six cognitively intact elders who managed their own medications enrolled. Participants self-selected into two groups: 'brown-baggers' (BBs) and 'non-brown-baggers' (NBBs). Three medication lists were compared for each patient: provider-documented in patient's chart (chart list); researcher-generated by post-appointment semistructured interview (point-of-care [POC] list); post-appointment semi-structured telephone interview (telephone list, reference standard). Accuracy of chart and POC lists were compared with reference lists among BBs and NBBs. RESULTS: Thirty-three (72%) patients brought some of their medications to scheduled appointments (BBs); of these, 39% bagged all of their medications. Excluding route as a variable, 35% of provider-documented chart lists were complete; only 6.5% were accurate. Some 76% of chart-documented medication lists contained inclusion, omission and/or dosing instruction discrepancies, with no differences between BBs and NBBs. However, POC lists obtained using a semi-structured interview included fewer inclusion and omission discrepancies among BBs than NBBs (42% v 77%, P = 0.05). In subset analyses by medication type, over-the-counter (OTC) medication documentation was more accurate among BBs than NBBs. Overall, chart lists contained two to three times more discrepancies than lists generated at POC. CONCLUSION: Most BBs do not bag all their medications for office visits. Chart list accuracy is no better among BBs than NBBs, although patients who 'brown bag' their medications for office visits may prompt providers to conduct a more thorough medication history. Lists generated by semistructured interviewing, regardless of BB status, are more accurate than chart lists. Findings challenge benefits of the 'brown bag' unless coupled with in-depth questioning and processes for transferring information to chart lists. PMID- 25695530 TI - The impact of patient participation direct enhanced service on patient reference groups in primary care: a qualitative study. AB - BACKGROUND: NHS policy documents continue to make a wide-ranging commitment to patient involvement. The Patient Participation Direct Enhanced Service (PP-DES), launched in 2011, aimed to ensure patients are involved in decisions about the range and quality of services provided and commissioned by their practice through patient reference groups (PRGs). The aim of this exploratory study is to review the impact of the PP-DES (2011-13) on a sample of PRGs and assess how far it has facilitated their involvement in decisions about the services of their general practices. METHODS: A qualitative methods design, using semi- structured interviews and focus groups, was employed to explore the experiences and views of GP practice staff (n = 24), PRG members (n = 80) at 12 GP practices, and other stakeholders (n = 4). RESULTS: Wide variation in the role and remit of the participating PRGs was found, which broadly ranged from activities to improve practice resources to supporting health promotion activities. The majority of PRG members were unfamiliar with the PP-DES scheme and its aims and purpose. Stakeholders and practice staff felt strongly that the main success of the PP-DES was that it had led to an increase in the number of PRGs being established in the locality. CONCLUSION: The PP-DES scheme has been a catalyst to establish PRGs. However, the picture was mixed in terms of the PRGs involvement in decisions about the services provided at their general practice as there was wide variation in the PRGs role and remit. The financial incentive alone, provided via the DES scheme, did not secure greater depth of PRG activity and power, however, as social factors were identified as playing an important role in PRGs' level of participation in decision making. Many PRGs have to become more firmly established before they are involved as partners in commissioning decisions at their practice. PMID- 25695531 TI - A qualitative exploration of the motives behind the decision to order a liver function test in primary care. AB - BACKGROUND: The number of tests ordered in primary care continues to increase influenced by a number of factors not all of which are concerned with diagnosis and management of disease. Liver function tests (LFTs) are a good example of inexpensive tests that are frequently ordered in patients with non-specific symptoms. They remain among the most frequently ordered tests despite their lack of specificity yet the full range of motives behind the decision to order an LFT remains unexplored. AIMS: To gain an understanding of the family practitioner's (FP) medical and non-medical motives for ordering an LFT and the influence of various social and technical factors on this decision. METHODS: We interviewed FPs across six practices who were participating in a prospective study of the efficacy of an abnormal LFT to indicate the development of a serious liver disease. Following content analysis of the data from the semi-structured interviews we used the 'attitude-social influence-efficacy' model to categorise the determinants of test ordering behaviour. RESULTS: Factors influencing an FP's decision to order a test were grouped into two broad categories; the first is 'internal' including expectation of efficacy and general attitude towards LFTs. The second group is 'external' and consists of themes of social influence, tests characteristics and defensive medicine. CONCLUSIONS: Whilst our sample acknowledged the clinical use of LFTs such as the routine monitoring of medication and liver-specific diagnostic purposes we also found that social and behavioural reasons are strong motivators to order an LFT and may take precedence over clinical factors. PMID- 25695532 TI - Guidelines adherence to lower urinary tract infection treatment in out-of-hours primary care in European countries. AB - BACKGROUND: The substantial prevalence of bacterial lower urinary tract infections (LUTIs) in out-of-hours (OOH) primary care is a reason for frequent prescription of antibiotics. Insight in guideline adherence in OOH primary care concerning treatment of LUTIs is lacking. AIMS: To check feasibility of the use of OOH routine data to assess guideline adherence for the treatment of LUTI in OOH primary care, in different regions of Europe. METHODS: We compared guidelines for diagnosis and treatment of uncomplicated LUTIs in nine European countries, followed by an observational study on available data of guideline adherence. In each region a convenience sample of registration data of at least 100 contacts per OOH primary care setting was collected. Data on adherence (% of contacts) was identified for type of antibiotic and for full treatment adherence (i.e. recommended type and dose and duration). RESULTS: Six countries were able to provide data on treatment of LUTIs. Four of them succeeded to collect data on type, dosage and duration of treatment. Mostly, trimethoprim was the treatment of first choice, sometimes combined with sulfamethoxazol or sulfamethizol. Adherence with the type of antibiotics varied from 25% to 100%. Denmark achieved a full treatment adherence of 40.0%, the Netherlands 72.7%, Norway 38.3%, and Slovenia 22.2%. CONCLUSION: Guidelines content is similar to a large extent in the participating countries. The use of OOH routine data for analysis of guideline adherence in OOH primary care seems feasible, although some challenges remain. Adherence regarding treatment varies and suggests room for improvement in most countries. PMID- 25695533 TI - Neuropeptide Y Y1 receptors mediate [corrected] targeted delivery of anticancer drug with encapsulated nanoparticles to breast cancer cells with high selectivity and its potential for breast cancer therapy. AB - By enabling nanoparticle-based drug delivery system to actively target cancer cells with high selectivity, active targeted molecules have attracted great attention in the application of nanoparticles for anticancer drug delivery. However, the clinical application of most active targeted molecules in breast cancer therapy is limited, due to the low expression of their receptors in breast tumors or coexpression in the normal and tumor breast tissues. Here, a neuropeptide Y Y1 receptors ligand PNBL-NPY, as a novel targeted molecule, is conjugated with anticancer drug doxorubicin encapsulating albumin nanoparticles to investigate the effect of Y1 receptors on the delivery of drug-loaded nanoparticles to breast cancer cells and its potential for breast cancer therapy. The PNBL-NPY can actively recognize and bind to the Y1 receptors that are significantly overexpressed on the surface of the breast cancer cells, and the drug-loaded nanoparticles are delivered directly into the cancer cells through internalization. This system is highly selective and able to distinguish the breast cancer cells from the normal cells, due to normal breast cells that express Y2 receptors only. It is anticipated that this study may provide a guidance in the development of Y1 receptor-based nanoparticulate drug delivery system for a safer and more efficient breast cancer therapy. PMID- 25695534 TI - Brucine diol-copper-catalyzed asymmetric synthesis of endo-pyrrolidines: the mechanistic dichotomy of imino esters. AB - Enantio- and diastereodivergent approaches to pyrrolidines are described by using catalyst- and substrate-controlled reaction pathways. A concerted endo-selective [3 + 2]-cycloaddition pathway is developed for the reaction of methyl imino ester, whereas endo-pyrrolidines with an opposite absolute stereochemical outcome are prepared by using the stepwise reaction pathway of tert-butyl imino ester. The development of catalyst- and substrate-controlled stereodivergent approaches highlights the inherent substrate-catalyst interactions in the [3 + 2] cycloaddition reactions of metalated azomethine ylides. PMID- 25695535 TI - Rapid detection of ESBL-producing Enterobacteriaceae in blood cultures. AB - We rapidly identified extended-spectrum beta-lactamase (ESBL) producers prospectively among 245 gram-negative bacilli-positive cultured blood specimens using the Rapid ESBL Nordmann/Dortet/Poirel test and direct bacterial identification using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. This combination identified ESBL-producing Enterobacteriaceae within 30 min and had high predictive values. PMID- 25695536 TI - Endemic and imported measles virus-associated outbreaks among adults, Beijing, China, 2013. AB - In 2013, a resurgence of measles occurred in Beijing, China. The outbreaks occurred among adults and were associated with endemic genotype H1 and imported genotype D8 viruses. Migrant workers were disproportionately represented in the outbreaks; thus, vaccinating such workers against measles may be an effective strategy toward the elimination of this disease. PMID- 25695537 TI - A case of heterogeneous sensitivity to panitumumab in cetuximab-refractory colorectal adenocarcinoma metastases. AB - We present the case of a 43-year-old-man with wild-type KRAS and BRAF colorectal adenocarcinoma that was metastatic to the liver and lung. The patient initially received neoadjuvant chemotherapy with FOLFOX and bevacizumab, followed by surgical resection of the primary tumor and hepatic metastases. His disease recurred shortly after surgery and he was treated with FOLFIRI plus the anti-EGFR antibody cetuximab. After this regimen failed to arrest his disease progression, treatment with FOLFIRI in combination with another anti-EGFR antibody, panitumumab was started. While on this therapy, the patient's lung nodules remained largely stable but metastatic lesions within the liver continued to progress. Our case highlights the differences between panitumumab and cetuximab, and contemplates the possible explanations for this patient's apparently heterogeneous disease progression within the liver despite stabilization of multiple pulmonary nodules. PMID- 25695538 TI - Deep-brain electrical microstimulation is an effective tool to explore functional characteristics of somatosensory neurons in the rat brain. AB - In neurophysiology researches, peripheral stimulation is used along with recordings of neural activities to study the processing of somatosensory signals in the brain. However, limited precision of peripheral stimulation makes it difficult to activate the neuron with millisecond resolution and study its functional properties in this scale. Also, tissue/receptor damage that could occur in some experiments often limits the amount of responses that can be recorded and hence reduces data reproducibility. To overcome these limitations, electrical microstimulation (ES) of the brain could be used to directly and more precisely evoke neural responses. For this purpose, a deep-brain ES protocol for rat somatosensory relay neurons was developed in this study. Three male Wistar rats were used in the experiment. The ES was applied to the thalamic region responsive to hindpaw tactile stimulation (TS) via a theta glass microelectrode. The resulting ES-evoked cortical responses showed action potentials and thalamocortical relay latencies very similar to those evoked by TS. This result shows that the developed deep-brain ES protocol is an effective tool to bypass peripheral tissue for in vivo functional analysis of specific types of somatosensory neurons. This protocol could be readily applied in researches of nociception and other somatosensory systems to allow more extensive exploration of the neural functional networks. PMID- 25695540 TI - Serum amyloid-A increases with disease stage in squamous cell cervical cancer patients. PMID- 25695541 TI - Astrocyte elevated gene-1 promotes progression of cervical squamous cell carcinoma by inducing epithelial-mesenchymal transition via Wnt signaling. AB - OBJECTIVE: The aim of this study was to investigate the association of astrocyte elevated gene-1 (AEG-1) with epithelial-mesenchymal transition of cervical squamous cell carcinoma (CSCC) and the underlying mechanisms. METHODS: The expression of proteins was determined by immunohistochemistry in tissues. Overexpression and knockdown of AEG-1 in SiHa cells were achieved by stable AEG-1 gene transfection (SiHa-AEG-1+) and AEG-1-siRNA (SiHa-AEG-1-), respectively. The cellular levels of messenger RNA and proteins were assessed with reverse transcription polymerase chain reaction and Western blotting, respectively. The cell invasion capacity was assessed by the chamber invasion assay. RESULTS: AEG-1 was overexpressed in clinical CSCC and associated with lymph node metastasis, parametrial involvement, stromal invasion, and vascular invasion. A high level of vimentin and a low level of E-cadherin were also detected in the cancer tissues. AEG-1 expression was positively correlated with vimentin expression and negatively with E-cadherin expression in CSCC tissues. In addition, high level of AEG-1 was related to unfavorable prognosis of CSCC. On a cellular level, overexpression of AEG-1 was found to lead to an up-regulation of vimentin and a down-regulation of E-cadherin on messenger RNA and protein level in SiHa cells, whereas AEG-1 knockdown led to a contrary result. Meanwhile, the nuclear levels of NF-kappaB p65 and beta-catenin were also increased in SiHa-AEG-1+, whereas their nuclear levels were decreased in SiHa-AEG-1-. Inhibition of Wnt signaling significantly reduced vimentin level and enhanced E-cadherin level in SiHa-AEG+, but inhibition of NF-kappaB signaling did not. SiHa-AEG-1+ and SiHa-AEG- showed an enhanced and a decreased invasive capacity, respectively. The enhanced invasiveness of SiHa-AEG-1+ was weakened by inhibition of Wnt signaling. CONCLUSIONS: AEG-1 was associated with the progression of CSCC by promoting epithelial-mesenchymal transition via Wnt signaling pathway. PMID- 25695542 TI - The expression of tumor-derived and stromal-derived matrix metalloproteinase 2 predicted prognosis of ovarian cancer. AB - OBJECTIVE: To evaluate the association of tumor-derived matrix metalloproteinase 2 (MMP-2) and stromal-derived MMP-2 expression with the prognosis of patients with ovarian cancer, a meta-analysis study was performed, which was aimed to comprehensively review the evidence of MMP-2 as prognostic biomarkers in ovarian cancers. METHODS: All relevant studies were searched in PubMed and Web of Science until May 30, 2014. Hazard ratios (HRs) with their 95% confidence intervals (CIs) were used to assess the association between MMP-2 expression (tumor-derived or stromal-derived) and prognosis of patients with ovarian cancer. Pooled odds ratios (ORs) and their 95% CIs were used to assess the correlation of MMP-2 expression with the clinicopathological features of patients with ovarian cancer. RESULTS: A total of 965 patients in 8 studies were included in this analysis. Among them, tumor-derived and stromal-derived MMP-2 expression was detected in 7 and 5 articles, respectively. The results revealed that ovarian cancer patients with positive tumor-derived MMP-2 expression showed a worse prognosis than did the ones with negative tumor-derived MMP-2 expression (HR, 1.52; 95% CI, 1.06 2.20). However, ovarian cancer patients with positive stromal-derived MMP-2 expression had not. In addition, we also found that tumor-derived MMP-2 expression was associated with distant metastasis (absent vs present; pooled OR, 4.52; 95% CI, 1.56-13.09; P = 0.001). CONCLUSIONS: These results suggested that positive tumor-derived MMP-2 expression could predict a lower overall survival rate and could be an independent dangerous prognostic factor in patients with ovarian cancer. PMID- 25695543 TI - Microsatellite instable and microsatellite stable primary endometrial carcinoma cells and their subcutaneous and orthotopic xenografts recapitulate the characteristics of the corresponding primary tumor. AB - OBJECTIVE: Well-characterized, low-passage, primary cell cultures established directly from patient tumors are an important tool for drug screening because these cultures faithfully recapitulate the genomic features of primary tumors. Here, we aimed to establish these cell cultures from primary endometrial carcinomas (ECs) and to develop subcutaneous and orthotopic xenograft models as a model to validate promising treatment options for EC in the in vivo setting. METHODS: Primary cell cultures of EC tumors were established and validated by analysing histologic and genetic characteristics, telomerase activity, and in vitro and in vivo growth characteristics. Using these primary cell cultures, subcutaneous and orthotopic mouse models were subsequently established. RESULTS: We established and characterized 7 primary EC cell cultures and corresponding xenograft models of different types of endometrioid tumors. Interestingly, we observed that the chance to successfully establish a primary cell culture seems higher for microsatellite instable than microsatellite stable tumors. For the first time, we also established an orthotopic murine model for EC derived from a primary cell culture. In contrast to EC cell lines, grafted tumor cultures preserved the original tumor structure and mimicked all histologic features. They also established abdominal and distant metastases, reflecting the tumorigenic behavior in the clinical setting. Remarkably, the established cell cultures and xenograft tumors also preserved the genetic characteristics of the primary tumor. CONCLUSIONS: The established EC cultures reflect the epithelial genetic characteristics of the primary tumor. Therefore, they provide an appropriate model to investigate EC biology and apply high-throughput drug screening experiments. In addition, the established murine xenograft models, in particular the orthotopic model, will be useful to validate promising therapeutic strategies in vivo, as the grafted tumors closely resemble the primary tumors from which they were derived. Microsatellite instable status seems to determine the success rate of establishing primary cell cultures. PMID- 25695544 TI - A nontoxic concentration of cisplatin induces autophagy in cervical cancer: selective cancer cell death with autophagy inhibition as an adjuvant treatment. AB - BACKGROUND: Increasing resistance to cisplatin as well as the severity of the adverse effects limit the use of this drug, particularly at high doses. Evidence has implicated the importance of autophagy in cancer resistance as well as the fact that various chemotherapy agents induce autophagy in cancer cells. We therefore aimed to first assess the role of autophagy in cisplatin treatment and second to assess whether a nontoxic concentration of cisplatin, together with autophagy inhibition, is able to maintain its cancer-specific cytotoxic action. METHODS: Three human cervical cell lines were used: a noncancerous ectocervical epithelial cell line (Ect1/E6E7) and 2 cancerous cervical cell lines (HeLa and CaSki). Autophagy was monitored through the presence of the classical protein markers LC-3 II and p62 under basal and treatment conditions, and inhibited using bafilomycin and autophagy protein 5 (ATG5) siRNA under treatment conditions. Cell death was analyzed through examination of the apoptotic markers PARP and caspase 3 through Western blotting, as well as the Caspase-Glo assay to confirm caspase 3/7 activity. Cervical biopsies were analyzed for the presence of LC-3 using Western blotting and immunofluorescence to determine if a correlation between autophagic levels and the progression of the disease exists. RESULTS: Cervical cancer cells exhibit increased basal autophagic levels in comparison to the noncancerous counterparts. Cisplatin treatment enhanced autophagic activity in all 3 cell lines. Inhibition of this autophagic response together with cisplatin treatment leads to significant increases in cancer cell death. Expression profiles of LC-3 in normal, premalignant (low-grade and high-grade squamous intraepithelial lesion), and cancerous cervical tissue revealed that autophagy is significantly up-regulated in HSILs and carcinoma cervical tissue, which emphasized the role of autophagy in the progression of the disease. CONCLUSIONS: The inhibition of autophagy improves the cytotoxicity of a nontoxic concentration of cisplatin and provides a promising new avenue for the future treatment of cervical cancer. PMID- 25695545 TI - Predicting surgical outcome in patients with International Federation of Gynecology and Obstetrics stage III or IV ovarian cancer using computed tomography: a systematic review of prediction models. AB - OBJECTIVE: Maximal cytoreduction to no residual disease is an important predictor of prognosis in patients with advanced-stage epithelial ovarian cancer. Preoperative prediction of outcome of surgery should guide treatment decisions, for example, primary debulking or neoadjuvant chemotherapy followed by interval debulking surgery. The objective of this study was to systematically review studies evaluating computed tomography imaging based models predicting the amount of residual tumor after cytoreductive surgery for advanced-stage epithelial ovarian cancer. METHODS: We systematically searched the literature for studies investigating multivariable models that predicted the amount of residual disease after cytoreductive surgery in advanced-stage epithelial ovarian cancer using computed tomography imaging. Detected studies were scored for quality and classified as model derivation or validation studies. We summarized their performance in terms of discrimination when possible. RESULTS: We identified 11 studies that described 13 models. The 4 models that were externally validated all had a poor discriminative capacity (sensitivity, 15%-79%; specificity, 32%-64%). The only internal validated model had an area under the receiver operating characteristic curve of 0.67. Peritoneal thickening, mesenterial and diaphragm disease, and ascites were most often used as predictors in the final models. We did not find studies that assessed the impact of prediction model on outcomes. CONCLUSIONS: Currently, there are no external validated studies with a good predictive performance for residual disease. Studies of better quality are needed, especially studies that focus on predicting any residual disease after surgery. PMID- 25695546 TI - Laparoscopic sentinel lymph node detection after hysteroscopic injection of technetium-99 in patients with endometrial cancer. AB - BACKGROUND AND OBJECTIVES: Endometrial cancer (EC) has an increasing incidence worldwide. Despite the unequivocal prognostic importance of nodal status, systematic lymphadenectomy is associated to elevated morbidity. Sentinel lymph node (SLN) biopsy is designed to avoid extensive nodal dissection and provide crucial oncologic information. The goal of this prospective study was to determine the feasibility, safety, and accuracy of laparoscopic SLN biopsy in EC obtained through hysteroscopic injection of technetium-99 (Tc-99). METHODS: From January 2008 to December 2012, a total of 42 women with EC were included in the study. We injected 20 mBq of Tc-99 hysteroscopically underneath the tumor minutes before definitive surgery. Thereafter, laparoscopic SLN identification /biopsy followed by pelvic and para-aortic lymphadenectomy, hysterectomy, and bilateral salpingo-oophorectomy were executed. RESULTS: The total number of removed nodes was 970. The detection rate of the method was 73% (31/42). Among the 70 isolated SLNs, 35% (24) were exclusively identified in the para-aortic area. Fourteen patients (45%) had SLN only in the pelvic region, whereas 11 (35%) had SLN in both pelvic and para-aortic areas and 6 women (20%) had isolated para-aortic SNL. Nodal metastases were histologically confirmed in 9 patients (22%), and SLN was identified in 7 of 9 patients (78%). Although the obtained specificity was 100% and the negative predictive value was 89%, the sensitivity was only 58% (false negative rate of 42%). CONCLUSIONS: We could demonstrate that endoscopic SLN biopsy obtained through hysteroscopic injection of Tc-99 is a feasible and safe method. Despite the restricted number of included patients in this series, the obtained sensitivity and false-negative rates raise some questions about the real accuracy of the procedure in EC. Larger validation trials requiring quality pelvic and para-aortic lymphadenectomy are essential to correctly evaluate the method. PMID- 25695547 TI - Clinicopathologic analysis with immunohistochemistry for DNA mismatch repair protein expression in synchronous primary endometrial and ovarian cancers. AB - OBJECTIVE: Synchronous primary endometrial and ovarian cancers have been an important topic in clinical medicine because it is sometimes difficult to distinguish whether there are 2 primary tumors or a single primary tumor and an associated metastasis. In addition, although these tumors are recommended for either immunohistochemistry for DNA mismatch repair (MMR) proteins or a microsatellite instability test in the Bethesda guidelines as Lynch syndrome associated cancers, few studies have completed these analyses. In this study, we characterized the clinicopathologic features and the expression pattern of MMR proteins in synchronous primary endometrial and ovarian cancers. METHODS: Clinicopathologic features and the expression pattern of MMR proteins (MLH1, MSH2, and MSH6) were characterized and analyzed in 32 synchronous primary endometrial and ovarian cancers. RESULTS: Most synchronous cancers are endometrioid type (endometrioid/endometrioid) (n = 24, 75%), grade 1 (n = 19, 59.4%), and diagnosed as stage I (n = 15, 46.9%) in both endometrium and ovary. It is worth mentioning that 75% of the patients (n = 24) had endometriosis, which was more common (n = 21, 87.5%) in endometrioid/endometrioid cancers, whereas only 3 cases (37.5%) were of different histology (P = 0.018). Loss of expression of at least 1 MMR protein was observed in 17 (53.1%) of the endometrial tumors and in 10 (31.3%) of ovarian tumors. Only 4 cases (12.5%) that had specific MMR protein loss showed the same type of loss for both endometrial and ovarian tumors, in which 3 of the cases were losses in MLH1. One case showed concordant MSH6 protein loss, although the cases did not meet the Amsterdam criteria II. CONCLUSIONS: These results suggest that most synchronous primary endometrial ovarian cancers are not hereditary cancers caused by germ line mutations but rather sporadic cancers. PMID- 25695548 TI - Increased association between endometriosis and endometrial cancer: a nationwide population-based retrospective cohort study. AB - OBJECTIVE: Association between endometriosis and ovarian cancer has been well established. Nonetheless, endometriosis may also be associated with endometrial cancer because of shared etiological mechanisms of both estrogen stimulation and chronic inflammation; however, the association between these 2 disorders has rarely been investigated. METHODS: The National Health Insurance Research Databases in Taiwan were retrieved and analyzed. The case cohort consisted of patients with a diagnosis of endometriosis between January 1997 and December 2000 (N = 15,488). For the construction of control cohort, 8 age- and sex-matched control patients for every patient in the case cohort were selected using a random sampling method (n = 123,904). All subjects were tracked for 10 years from the date of entry to identify whether they had developed endometrial cancer. The Cox proportional hazards regression model was used to evaluate 10-year event occurrence of endometrial cancer. RESULTS: During the 10-year follow-up period, 392 participants developed endometrial cancer, with 104 (0.7%) distributed in the case cohort and 288 (0.2%) in the control cohort. Multivariable Cox regression modeling demonstrates a higher risk for developing endometrial cancer in the case cohort than in the control cohort (adjusted hazard ratio [aHR], 2.83; 95% confidence interval [CI], 1.495.35; P < 0.01). Age at diagnosis of endometriosis shows a moderator effect: when 40 years or younger, the risk for developing endometrial cancer was comparable between the case cohort and the control cohort (aHR, 1.42; 95% CI, 0.55-3.70; P = 0.226), whereas when older than 40 years, the risk for developing endometrial cancer was higher in the former group than in the latter group (aHR, 7.08; 95% CI, 2.33-21.55; P = 0.007). CONCLUSIONS: Patients diagnosed with endometriosis may harbor an increased risk for developing endometrial cancer in their later life. Closer monitoring is advised for this patient population. PMID- 25695549 TI - Outcome of recurrent uterine papillary serous carcinoma treated with platinum based chemotherapy. AB - OBJECTIVE: The aim of this study was to estimate the outcome and response to platinum-based chemotherapy (CT) in patients with recurrent uterine papillary serous carcinoma (UPSC). METHODS: Patients with recurrent UPSC from 2000 to 2012 were included retrospectively. All patients received platinum-based CT for recurrent disease. Platinum-free interval was divided into less than 6 months (platinum resistant) and 6 months or longer (platinum sensitive). RESULTS: Twenty two patients with recurrent UPSC were included. The median age was 66.5 years. The majority of the patients initially presented with advanced-stage disease (68%). A total of 84% (18/22) received adjuvant CT; all regimens were platinum based.The overall response rate (RR) and stable disease were 50% and 36.4%. The mean duration of response and stable disease were 9.4 and 5.6 months. Among the platinum-sensitive group, the overall RR was 64.7% compared with 0% in the platinum-resistant group. Among the patients who received prior adjuvant platinum based CT, the RR was 38.8% compared with 100% among those who did not receive adjuvant CT. When stratified by platinum-based regimen, those who received the platinum-taxane regimen had a higher RR compared with those who received the platinum-gemcitabine regimen (62.5% vs 20%) among those who received prior adjuvant platinum therapy. The median progression-free survival and overall survival for the entire cohort were 8.4 and 24.9 months, respectively. The median progression-free survival was significantly longer for platinum-sensitive disease compared with platinum-resistant disease (10.2 vs 3.3 months, respectively; P = 0.002). Similarly, the median overall survival was longer for platinum-sensitive disease compared with platinum-resistant disease (27.1 vs 13.7 months, respectively). However, this difference was not statistically significant (P = 0.15). CONCLUSIONS: Platinum-based CT is an active regimen in recurrent UPSC even if patients received prior adjuvant platinum CT. Platinum-free interval predicts response and outcome of platinum-based CT in recurrent setting such as in ovarian cancer. Plantinum-taxane is more active than platinum-gemcitabine in recurrent UPSC. PMID- 25695550 TI - Cervical carcinoma in the European Union: an update on disease burden, screening program state of activation, and coverage as of March 2014. AB - OBJECTIVE: Cervical cancer (CC) is defined as a disease of disparity. This is due to marked differences in CC incidence and mortality between developed and developing countries. As a continent, Europe is no exception. This study examines the state of activation of CC screening in the European Union as of March 2014, reviews CC incidence and mortality data, and highlights the initiatives adopted to extend program coverage to nonresponders. METHODS: The present study is based on the most recent data available from PubMed-indexed journals, the Web sites of the health ministries of each member state, and the Web sites of national cancer observatories; failing these sources, information was sought in scientific journals published in the local language. RESULTS: In 2003, the European Council recommended that priority be given to organized screening program activation. Nonetheless, a number of European Union member states still lack population-based organized screening programs, and few have implemented programs directed at disadvantaged populations. CONCLUSIONS: Several investigations have demonstrated that the women at higher CC risk are unscreened and underscreened ones. Since then, several member states have made significant efforts to set up effective prevention programs by adopting international quality standards and centralizing screening organization and result evaluation. Several developed countries and some new central-eastern European member states have poorly organized prevention programs that result in poor women's health. Diagnosis of CC is emotionally traumatic, but it is highly preventable. When CC is found early, it is highly treatable and associated with long survival and good quality of life. PMID- 25695551 TI - Early cervical cancer impact of peritoneal vaginoplasty combined with laparoscopic radical hysterectomy improved sexual function. AB - OBJECTIVE: We investigated the impact of laparoscopic radical hysterectomy (LRH) in combination with peritoneal vaginoplasty (PV) in improving sexual function after radical hysterectomy (RH) in patients with early cervical cancer. METHODS: A total of 79 patients with early-stage cervical cancer younger than 45 years were assigned to receive LRH in combination with PV (the LRH-PV group; n = 31) or LRH alone (the LRH group; n = 48). Other 40 healthy females were selected as controls (the control group). The sexual function was assessed with Female Sexual Functioning Index (FSFI). The FSFI scores and sexual function in the postoperative 1 year were compared between the LRH-PV and LRH groups, LRH-PV and control groups, and LRH and control groups, respectively. RESULTS: Patients with LRH-PV showed significantly higher scores in sexual satisfaction, lubrication, pain, and total score than those with LRH alone (P < 0.05) but were not statistically different in scores regarding sexual desire, arousal, and orgasm (P > 0.05). Healthy controls showed the highest in total scores and 6 domains among all subjects. In addition, the FSFI total scores in the LRH-PV group, LRH group, and LRH-PV + LRH group were significantly decreased compared with the control (P < 0.05). CONCLUSIONS: Peritoneal vaginoplasty to lengthen the vagina improves sexual function of patients with early cervical cancer receiving LRH in sexual satisfaction, lubrication, and pain. PMID- 25695552 TI - Emotion and coping in the aftermath of medical error: a cross-country exploration. AB - OBJECTIVES: Making a medical error can have serious implications for clinician well-being, affecting the quality and safety of patient care. Despite an advancing literature base, cross-country exploration of this experience is limited, and a paucity of studies has examined the coping strategies used by clinicians. A greater understanding of clinicians' responses to making an error, the factors that may influence these, and the various coping strategies used are all essential for providing effective clinician support and ensuring optimal outcomes.The objectives were therefore to investigate the following: a) the professional or personal disruption experienced after making an error, b) the emotional response and coping strategies used, c) the relationship between emotions and coping strategy selection, d) influential factors in clinicians' responses, and e) perceptions of organizational support. METHODS: A cross sectional, cross-country survey of 265 physicians and nurses was undertaken in 2 large teaching hospitals in the United Kingdom and the United States. RESULTS: Professional and personal disruption was reported as a result of making an error. Negative emotions were common, but positive feelings of determination, attentiveness, and alertness were also identified. Emotional response and coping strategy selection did not differ because of location or perceived harm, but responses did appear to differ by professional group; nurses in both locations reported stronger negative feelings after an error. Respondents favored problem focused coping strategies, and associations were identified between coping strategy selection and the presence of particular emotions. Organizational support services, particularly including peers, were recognized as helpful, but fears over confidentiality may prohibit some staff from accessing these. CONCLUSIONS: Clinicians in the United Kingdom and the United States experience professional and personal disruption after an error. A number of factors may influence clinician recovery; these factors should be considered in the provision of comprehensive support programs so as to improve clinician recovery and ensure higher quality, safer patient care. PMID- 25695553 TI - When failure is not an option: creating excellence in sport through insights from Special Forces. PMID- 25695555 TI - Abdominal cryptococcosis in two dogs: diagnosis and medical management. AB - Canine cryptococcosis cases are typically reported as neurologic, disseminated, or both. There have been few reports of other parenchymal organ involvement. Dogs infected with Cryptococcus spp. are likely to develop central nervous system involvement, and those that are severely affected are treated aggressively with surgery and/or amphotericin B. This report describes two cases of canine abdominal cryptococcosis: one boxer with primary alimentary cryptococcosis alone and one miniature schnauzer with pancreatic and disseminated cryptococcosis. The boxer is unique in that the dog suffered from primary alimentary cryptococcosis without dissemination, secondary anemia due to gastrointestinal losses, and is the second case to have Cryptococcus spp. identified on fecal examination as part of the diagnostic workup. Unlike previous reports, surgery was not performed in either case, and both dogs were treated with fluconazole alone. Currently, both dogs are free from clinical signs, and Cryptococcus spp. antigen titers are negative at 17 and 15 mo after initial presentation. These cases suggest fluconazole may be effective therapy alone for canine abdominal cryptococcosis, negating the need for high-risk therapy options such as surgery and/or amphotericin B in some cases. PMID- 25695556 TI - Iatrogenic traumatic brain injury during tooth extraction. AB - An 8 yr old spayed female Yorkshire terrier was referred for evaluation of progressive neurological signs after a routine dental prophylaxis with tooth extractions. The patient was circling to the left and blind in the right eye with right hemiparesis. Neurolocalization was to the left forebrain. MRI revealed a linear tract extending from the caudal oropharynx, through the left retrobulbar space and frontal lobe, into the left parietal lobe. A small skull fracture was identified in the frontal bone through which the linear tract passed. Those findings were consistent with iatrogenic trauma from slippage of a dental elevator during extraction of tooth 210. The dog was treated empirically with clindamycin. The patient regained most of its normal neurological function within the first 4 mo after the initial injury. Although still not normal, the dog has a good quality of life. Traumatic brain injury is a rarely reported complication of extraction. Care must be taken while performing dental cleaning and tooth extraction, especially of the maxillary premolar and molar teeth to avoid iatrogenic damage to surrounding structures. PMID- 25695557 TI - Transobturator vaginal tape for treatment of urinary incontinence in spayed bitches. AB - This study investigated the long-term effectiveness and safety of a variant of the transobturator vaginal tape inside-out technique for acquired urinary incontinence. Twelve spayed female dogs were operated over a 2 yr period. No intraoperative complications were encountered. Transient dysuria was the most common postoperative complication (7 out of 12 dogs). On the 12th day postoperatively, incontinence was completely cured in 11 out of 12 dogs (92%). At the time of the second evaluation (median follow-up time was 21 mo), patients classified as "cured," "greatly improved," or "improved" were 25, 50, and 25% of the total, respectively. At the time of either the fourth evaluation or at the time of death (median follow-up time was 52 mo), 50% of the bitches (6 out of 12) had the same results as previously but the other 50% had leakage that reappeared sporadically. A fistula appeared on the path of the tape in two bitches at 28 and 32 mo postsurgically. The technique presented is effective and more cost effective than the standard technique and could constitute an attractive alternative; however, it could be associated with an immediate postoperative dysuria, delayed fistula formation, and a partial recurrence of clinical signs. PMID- 25695558 TI - Porcupine quill migration in the thoracic cavity of a German shorthaired pointer. AB - A 7 yr old German shorthaired pointer presented with progressive respiratory distress and lethargy. Two weeks prior to presentation, the dog had porcupine quills removed from the left forepaw, muzzle, and sternal area. At the time of presentation, the dog had bounding pulses and friction rubs in the right dorsal lung field. Harsh lung sounds and decreased lung sounds were ausculted in multiple lung fields. Radiographs revealed a pneumothorax and rounding of the cardiac silhouette suggestive of pericardial effusion. Computed tomographic imaging was performed and revealed multiple porcupine quills in the thoracic cavity. Surgery was performed and quills were found in multiple lung lobes and the heart. Following surgery the dog remained hypotensive. A post-operative echocardiogram revealed multiple curvilinear soft-tissue opacities in the heart. Given the grave prognosis the dog was subsequently euthanized and a postmortem examination was performed. A single porcupine quill was discovered in the left atrium above the mitral valve annulus. The quill extended across the aortic root, impinging on the coronary artery below the level of the aortic valve. To the authors' knowledge, this is the first known report of porcupine quill migration through the heart. PMID- 25695559 TI - Septicemia and Infection due to ESBL-producing K. pneumoniae Following Feline Renal Allograft Transplantation. AB - A 12 yr old castrated male domestic longhair underwent renal transplantation for treatment of chronic interstitial nephritis. Full-thickness intestinal biopsies obtained prior to transplantation revealed mild enteritis. Twelve months following transplantation, the patient underwent surgery for resection of a mesenteric mass causing septic peritonitis. The mesenteric mass was resected and an intestinal resection and anastomosis was performed. Extended-spectrum-beta lactamase producing Klebsiella pneumoniae was cultured from the resected tissue and urinary tract. Bacterial rods were noted to be circulating in the bloodstream, causing septicemia. Despite aggressive treatment of the septic peritonitis and septicemia using surgical debridement, drain placement, aggressive antibiotic therapy with IV meropenem, and vasopressor support, the patient succumbed to persistent hypotension and suffered cardiopulmonary arrest. Extended-spectrum-beta-lactamase-producing bacteria are of growing concern in human and veterinary medicine, maintaining susceptibility often only to carbapenem and aminoglycoside antibiotics. Resistance to even those antibiotics is emerging. Veterinary patients with a history of antibiotic therapy, central venous or urinary catheterization, immunosuppression, enteric surgery, and an extended stay in the intensive care unit may be predisposed. PMID- 25695560 TI - Angioleiomyosarcoma in the Nasal Vestibule of a Dog: Surgical Excision via a Modified Lateral Approach. AB - This case report describes an 11 yr old spayed female German shepherd dog weighing 42 kg that presented with intermittent epistaxis from the left nostril. A nonulcerated pale irregular polypoid mass was visualized within the left nares. Computed tomography revealed a pedunculated mass arising from the ventrolateral nasal mucosal of the left nasal cavity with no evidence of involvement or invasion of adjacent soft tissues or bony structures. Histological and immunohistochemical examination of rhinoscopic biopsies returned a diagnosis of an angioleiomyosarcoma. The mass was excised using a modified lateral approach to the nasal cavity. Fulguration of the wound bed was performed. Clean surgical margins were identified on histopathology. The dog remained clinically free of recurrence 28 mo postsurgically. Angioleiomyosarcomas are rare tumors originating from the smooth muscle cells of blood vessel walls and are included in the spectrum of perivascular wall tumor, a subgroup of soft-tissue sarcomas. PMID- 25695561 TI - Canine alopecia secondary to human topical hormone replacement therapy in six dogs. AB - Alopecia is a common presenting complaint in veterinary medicine and is known to occur secondary to numerous primary conditions. In this report, six unrelated dogs from three households were subsequently determined to have developed alopecia as a result of accidental transdermal exposure to their owners' topical hormone replacement therapy (THRT). All cases presented with alopecia ranging in duration from 2 mo to 2.5 yr. All dogs demonstrated alopecia affecting the ventral neck, thoracic and abdominal surfaces, proximal lateral extremities, and lateral trunk. At the time of initial presentation, five of six dogs were also noted to have physical exam findings suggestive of feminization. In all cases, serum total thyroxine was within normal reference range. Affected skin was biopsied in five dogs, and all samples demonstrated four similar histological characteristics: basal melanosis, epidermal and infundibular follicular hyperkeratosis, kenogen hair follicles, and small sebaceous glands. All dogs had elevated baseline estradiol levels, and four dogs had concurrent elevations of baseline progesterone. Average time to onset of clinical signs in those dogs was 5.5 mo after the owners started THRT. Following discontinuation of THRT by the owners, all dogs had complete resolution of their clinical signs by 5.5 mo. PMID- 25695562 TI - Anesthesiologists make a difference. PMID- 25695563 TI - Does it matter who the anesthesiologist is for my heart surgery? PMID- 25695564 TI - Facing the uncomfortable truth: your choice of anesthesiologist does matter. PMID- 25695565 TI - Cardiac surgery: all for one and one for all. PMID- 25695566 TI - Making a difference: the Anesthesia Quality Institute. PMID- 25695567 TI - Helping surgical patients quit smoking: time to bring it home. PMID- 25695568 TI - Proximal isovelocity surface area: the three-dimensional "correction". PMID- 25695569 TI - From Durban to Boston, a "modest proposal" to improve perioperative cardiovascular risk stratification. PMID- 25695570 TI - But is it safe? Hydroxyethyl starch in perioperative care. PMID- 25695571 TI - The impact of anesthesiologists on coronary artery bypass graft surgery outcomes. AB - BACKGROUND: One of every 150 hospitalized patients experiences a lethal adverse event; nearly half of these events involves surgical patients. Although variations in surgeon performance and quality have been reported in the literature, less is known about the influence of anesthesiologists on outcomes after major surgery. Our goal of this study was to determine whether there is significant variation in outcomes between anesthesiologists after controlling for patient case mix and hospital quality. METHODS: Using clinical data from the New York State Cardiac Surgery Reporting System, we conducted a retrospective observational study of 7920 patients undergoing isolated coronary artery bypass graft surgery. Multivariable logistic regression modeling was used to examine the variation in death or major complications (Q-wave myocardial infarction, renal failure, stroke) across anesthesiologists, controlling for patient demographics, severity of disease, comorbidities, and hospital quality. RESULTS: Anesthesiologist performance was quantified using fixed-effects modeling. The variability across anesthesiologists was highly significant (P < 0.001). Patients managed by low-performance anesthesiologists (corresponding to the 25th percentile of the distribution of anesthesiologist risk-adjusted outcomes) experienced nearly twice the rate of death or serious complications (adjusted rate 3.33%; 95% confidence interval [CI], 3.09%-3.58%) as patients managed by high-performance anesthesiologists (corresponding to the 75th percentile) (adjusted rate 1.82%; 95% CI, 1.58%-2.10%). This performance gap was observed across all patient risk groups. CONCLUSIONS: The rate of death or major complications among patients undergoing coronary artery bypass graft surgery varies markedly across anesthesiologists. These findings suggest that there may be opportunities to improve perioperative management to improve outcomes among high-risk surgical patients. PMID- 25695572 TI - Proposed research plan for the derivation of a new Cardiac Risk Index. AB - The Revised Cardiac Risk Index (RCRI) was incorporated into the American College of Cardiology/American Heart Association (ACC/AHA) recommendations for the preoperative evaluation of the cardiac patient for noncardiac surgery. The purpose of this review was to analyze studies on cardiovascular clinical risk prediction that had used the previous "standard best" model, the RCRI, as a comparator. This review aims to determine whether modification of the current risk factors or adoption of other risk factors or other risk indices would improve upon the discrimination of cardiac risk prediction when compared with the RCRI. This is necessary because recent risk prediction models have shown better discrimination for major adverse cardiac events, and the pre-eminence of the RCRI is now in question. There is now a need for a new "best standard" cardiovascular risk prediction model to supersede the RCRI. This is desirable because it would: (1) allow for a global standard of cardiovascular risk assessment; (2) provide a standard comparator in all risk prediction research; (3) result in comparable data collection; and (4) allow for individual patient data meta-analyses. This should lead to continued progress in cardiovascular clinical risk prediction. A review of the current evidence suggests that to improve the preoperative clinical risk stratification for adverse cardiac events, a new risk stratification model be built that maintains the clinical risk factors identified in the RCRI, with the following modifications: (1) additional glomerular filtration rate cut points (as opposed to a single creatinine cut point); (2) age; (3) a history of peripheral vascular disease; (4) functional capacity; and (5) a specific surgical procedural category. One would expect a substantial improvement in the discrimination of the RCRI with this approach. Although most noncardiac surgeries will benefit from a standard "generic" cardiovascular risk prediction model, there are data to suggest that patients with human immunodeficiency virus disease who are undergoing vascular surgery may benefit from specific cardiovascular risk prediction models. PMID- 25695573 TI - Hypertrophic cardiomyopathy: a review. AB - Hypertrophic cardiomyopathy (HCM) is a relatively common disorder that anesthesiologists encounter among patients in the perioperative period. Fifty years ago, HCM was thought to be an obscure disease. Today, however, our understanding and ability to diagnose patients with HCM have improved dramatically. Patients with HCM have genotypic and phenotypic variability. Indeed, a subgroup of these patients exhibits the HCM genotype but not the phenotype (left ventricular hypertrophy). There are a number of treatment modalities for these patients, including pharmacotherapy to control symptoms, implantable cardiac defibrillators to manage malignant arrhythmias, and surgical myectomy and septal ablation to decrease the left ventricular outflow obstruction. Accurate diagnosis is vital for the perioperative management of these patients. Diagnosis is most often made using echocardiographic assessment of left ventricular hypertrophy, left ventricular outflow tract gradients, systolic and diastolic function, and mitral valve anatomy and function. Cardiac magnetic resonance imaging also has a diagnostic role by determining the extent and location of left ventricular hypertrophy and the anatomic abnormalities of the mitral valve and papillary muscles. In this review on hypertrophic cardiomyopathy for the noncardiac anesthesiologist, we discuss the clinical presentation and genetic mutations associated with HCM, the critical role of echocardiography in the diagnosis and the assessment of surgical interventions, and the perioperative management of patients with HCM undergoing noncardiac surgery and management of the parturient with HCM. PMID- 25695574 TI - Perioperative aspirin management after POISE-2: some answers, but questions remain. AB - Aspirin constitutes important uninterrupted lifelong therapy for many patients with cardiovascular (CV) disease or significant (CV) risk factors. However, whether aspirin should be continued or withheld in patients undergoing noncardiac surgery is a common clinical conundrum that balances the potential of aspirin for decreasing thrombotic risk with its possibility for increasing perioperative blood loss. In this focused review, we describe the role of aspirin in treating and preventing cardiovascular disease, summarize the most important literature on the perioperative use of aspirin (including the recently published PeriOperative ISchemic Evaluation [POISE]-2 trial), and offer current recommendations for managing aspirin during the perioperative period. POISE-2 suggests that aspirin administration during the perioperative period does not change the risk of a cardiovascular event and may result in increased bleeding. However, these findings are tempered by a number of methodological issues related to the study. On the basis of currently available literature, including POISE-2, aspirin should not be administered to patients undergoing surgery unless there is a definitive guideline-based primary or secondary prevention indication. Aside from closed space procedures, intramedullary spine surgery, or possibly prostate surgery, moderate-risk patients taking lifelong aspirin for a guideline-based primary or secondary indication may warrant continuation of their aspirin throughout the perioperative period. PMID- 25695575 TI - Notch of the anterior leaflet of the tricuspid valve with severe tricuspid regurgitation. PMID- 25695576 TI - Long-term quit rates after a perioperative smoking cessation randomized controlled trial. AB - BACKGROUND: While surgery and perioperative smoking cessation interventions may motivate patients to quit smoking in the short term, it is unknown how often this translates into permanent cessation. In this study, we sought to determine the rates of long-term smoking cessation after a perioperative smoking cessation intervention and predictors of successful cessation at 1 year. METHODS: We previously reported short-term results from a perioperative randomized controlled trial comparing usual care with an intervention involving (1) brief counseling by the preadmission nurse, (2) smoking cessation brochures, (3) referral to a telephone quitline, and (4) a free 6-week supply of transdermal nicotine replacement. We now report our 1-year follow-up outcomes. RESULTS: Between October 2010 and April 2012, 168 patients were randomized. At 1 year, 127 patients (76%) were available for follow-up telephone interview. Smoking cessation occurred in 8% of control patients compared with 25% of patients in the intervention group (relative risk, 3.0; 95% confidence interval [CI], 1.2-7.8; P = 0.018). The number needed-to-treat to achieve smoking cessation for 1 patient at 1 year postoperatively was 5.9 (95% CI, 3.4-25.9). Multivariable logistic regression modeling found that the intervention (P = 0.020) and lower nicotine dependency at baseline (P < 0.001) were predictive of success at smoking cessation at 1 year. Poisson regression showed that adjusted for nicotine dependency, those randomized to the intervention group were 2.7 times (95% CI, 1.1-6.7; P = 0.028) more likely to achieve long-term cessation than those in the control group. Adjusted for randomization group, a low level of nicotine dependency resulted in a relative risk of quitting of 5.1 (95% CI, 2.0-12.8; P = 0.001). CONCLUSIONS: This study demonstrates that an intervention designed for a busy preadmission clinic results in decreased smoking rates not only around the time of surgery but also continued benefit in smoking cessation at 1 year. Perioperative care providers have a unique opportunity to assist patients in smoking cessation and achieve long-lasting results. PMID- 25695577 TI - Lidocaine preferentially inhibits the function of purinergic P2X7 receptors expressed in Xenopus oocytes. AB - BACKGROUND: Lidocaine has been widely used to relieve acute pain and chronic refractory pain effectively by both systemic and local administration. Numerous studies reported that lidocaine affects several pain signaling pathways as well as voltage-gated sodium channels, suggesting the existence of multiple mechanisms underlying pain relief by lidocaine. Some extracellular adenosine triphosphate (ATP) receptor subunits are thought to play a role in chronic pain mechanisms, but there have been few studies on the effects of lidocaine on ATP receptors. We studied the effects of lidocaine on purinergic P2X3, P2X4, and P2X7 receptors to explore the mechanisms underlying pain-relieving effects of lidocaine. METHODS: We investigated the effects of lidocaine on ATP-induced currents in ATP receptor subunits, P2X3, P2X4, and P2X7 expressed in Xenopus oocytes, by using whole-cell, two-electrode, voltage-clamp techniques. RESULTS: Lidocaine inhibited ATP-induced currents in P2X7, but not in P2X3 or P2X4 subunits, in a concentration-dependent manner. The half maximal inhibitory concentration for lidocaine inhibition was 282 +/- 45 MUmol/L. By contrast, mepivacaine, ropivacaine, and bupivacaine exerted only limited effects on the P2X7 receptor. Lidocaine inhibited the ATP concentration-response curve for the P2X7 receptor via noncompetitive inhibition. Intracellular and extracellular N-(2,6-dimethylphenylcarbamoylmethyl) triethylammonium bromide (QX-314) and benzocaine suppressed ATP-induced currents in the P2X7 receptor in a concentration-dependent manner. In addition, repetitive ATP treatments at 5-minute intervals in the continuous presence of lidocaine revealed that lidocaine inhibition was use-dependent. Finally, the selective P2X7 receptor antagonists Brilliant Blue G and AZ11645373 did not affect the inhibitory actions of lidocaine on the P2X7 receptor. CONCLUSIONS: Lidocaine selectively inhibited the function of the P2X7 receptor expressed in Xenopus oocytes. This effect may be caused by acting on sites in the ion channel pore both extracellularly and intracellularly. These results help to understand the mechanisms underlying the analgesic effects of lidocaine when it is administered locally at least. PMID- 25695578 TI - Heart failure in pregnant women: is it peripartum cardiomyopathy? AB - Peripartum cardiomyopathy is a rare but important cause of maternal morbidity and mortality. Women with peripartum cardiomyopathy often present with symptoms and signs of heart failure. The diagnosis of peripartum cardiomyopathy is made after all other causes of heart failure are excluded. Emphasis is on the immediate recognition of an unwell pregnant or recently pregnant woman, early diagnosis with the use of echocardiography, and the correct treatment of heart failure. PMID- 25695579 TI - Cranial nerve VI palsy after dural-arachnoid puncture. AB - In this article, we provide a literature review of cranial nerve (CN) VI injury after dural-arachnoid puncture. CN VI injury is rare and ranges in severity from diplopia to complete lateral rectus palsy with deviated gaze. The proposed mechanism of injury is cerebrospinal fluid leakage causing intracranial hypotension and downward displacement of the brainstem. This results in traction on CN VI leading to stretch and neural demyelination. Symptoms may present 1 day to 3 weeks after dural-arachnoid puncture and typically are associated with a postdural puncture (spinal) headache. Resolution of symptoms may take weeks to months. Use of small-gauge, noncutting spinal needles may decrease the risk of intracranial hypotension and subsequent CN VI injury. When ocular symptoms are present, early administration of an epidural blood patch may decrease morbidity or prevent progression of ocular symptoms. PMID- 25695580 TI - Perioperative neurotoxicity in the elderly: summary of the 4th International Workshop. AB - To learn the latest developments in the various forms of postoperative cognitive dysfunction, a group of scientists and physicians met in Stockholm for a full day of presentations and interactive discussions. This article summarizes the discussion; highlighting progress, challenges, and new directions in the area of perioperative neurotoxicity in our aging population. PMID- 25695581 TI - Surgeon-nurse anesthetist collaboration advanced surgery between 1889 and 1950. AB - To meet the need for qualified anesthetists, American surgeons recruited nurses to practice anesthesia during the Civil War and in the latter half of the 19th century. The success of this decision led them to collaborate with nurses more formally at the Mayo Clinic in Minnesota. During the 1890s, Alice Magaw refined the safe administration of ether. Florence Henderson continued her work improving the safety of ether administration during the first decade of the 20th century. Safe anesthesia enabled the Mayo surgeons to turn the St. Mary's Hospital into a surgical powerhouse. The prominent surgeon George Crile collaborated with Agatha Hodgins at the Lakeside Hospital in Cleveland to introduce nitrous oxide/oxygen anesthesia. Nitrous oxide/oxygen caused less cardiovascular depression than ether and thus saved the lives of countless trauma victims during World War I. Crile devised "anoci-association," an outgrowth of nitrous oxide/oxygen anesthesia. Hodgins' use of anoci-association made Crile's thyroid operations safer. Pioneering East Coast surgeons followed the lead of the surgeons at Mayo. William Halsted worked closely with Margaret Boise, and Harvey Cushing worked closely with Gertrude Gerard. As medicine became more complex, collaboration between surgeons and nurse anesthetists became routine and necessary. Teams of surgeons and nurse anesthetists advanced thoracic, cardiovascular, and pediatric surgery. The team of Evarts Graham and Helen Lamb performed the world's first pneumonectomy. Surgeon-nurse anesthetist collaboration seems to have been a uniquely American phenomenon. This collaboration facilitated both the "Golden Age of Surgery" and the profession we know today as nurse anesthesia. PMID- 25695582 TI - Game changers: the 20 most important anesthesia articles ever published. PMID- 25695584 TI - Factors determining the need for sedation during successful regional anesthesia: when is it necessary? PMID- 25695583 TI - Intrathecal RGS4 inhibitor, CCG50014, reduces nociceptive responses and enhances opioid-mediated analgesic effects in the mouse formalin test. AB - BACKGROUND: The regulator of G-protein signaling protein type 4 (RGS4) accelerates the guanosine triphosphatase activity of G(alphai) and G(alphao), resulting in the inactivation of G-protein-coupled receptor signaling. An opioid receptor (OR), a G(alphai)-coupled receptor, plays an important role in pain modulation in the central nervous system. In this study, we examined whether (1) spinal RGS4 affected nociceptive responses in the formalin pain test, (2) this RGS4-mediated effect was involved in OR activation, and (3) the u-OR agonist induced antinociceptive effect was modified by RGS4 modulation. METHODS: Formalin (1%, 20 uL) was injected subcutaneously into the right hindpaws of male 129S4/SvJae*C57BL/6J (RGS4(+/+) or RGS4(-/-)) mice, and the licking responses were counted for 40 minutes. The time periods (seconds) spent licking the injected paw during 0 to 10 minutes (early phase) and 10 to 40 minutes (late phase) were measured as indicators of acute nociception and inflammatory pain response, respectively. An RGS4 inhibitor, CCG50014, and/or a u-OR agonist, [D Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO), were intrathecally injected 5 minutes before the formalin injection. A nonselective OR antagonist, naloxone, was intraperitoneally injected 30 minutes before the CCG50014 injection. RESULTS: Mice that received the formalin injection exhibited typical biphasic nociceptive behaviors. The nociceptive responses in RGS4-knockout mice were significantly decreased during the late phase but not during the early phase. Similarly, intrathecally administered CCG50014 (10, 30, or 100 nmol) attenuated the nociceptive responses during the late phase in a dose-dependent manner. The antinociceptive effect of the RGS4 inhibitor was totally blocked by naloxone (5 mg/kg). In contrast, intrathecal injection of DAMGO achieved a dose-dependent reduction of the nociceptive responses at the early and late phases. This analgesic effect of DAMGO was significantly enhanced by the genetic depletion of RGS4 or by coadministration of CCG50014 (10 nmol). CONCLUSIONS: These findings demonstrated that spinal RGS4 inhibited the endogenous or exogenous OR-mediated antinociceptive effect in the formalin pain test. Thus, the inhibition of RGS4 activity can enhance OR agonist-induced analgesia. The enhancement of OR agonist induced analgesia by coadministration of the RGS4 inhibitor suggests a new therapeutic strategy for the management of inflammatory pain. PMID- 25695585 TI - The transfer of care. PMID- 25695586 TI - A new pharmacokinetic model of propofol: effect of age on clearance and impact of the terminal distribution phase. PMID- 25695587 TI - In response. PMID- 25695588 TI - Meeting regulatory standards while preparing for emergency surgeries. PMID- 25695589 TI - Triple play. PMID- 25695590 TI - Development of a liquid chromatography-tandem mass spectrometry method for the determination of sulfite in food. AB - Sulfites are widely used food preservatives that can cause severe reactions in sensitive individuals. As a result, the U.S. FDA requires that sulfites be listed on the label of any food product containing >10 mg/kg (ppm) sulfite (measured as sulfur dioxide). Currently, the optimized Monier-Williams (MW) method (AOAC Official Method 990.28) is the most common approach for determining sulfite concentrations in food samples. However, this method is time-consuming and lacks specificity in certain matrices. An improved rapid, sensitive, and selective method has been developed using electrospray ionization (ESI) high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) for the determination of sulfite in various food matrices. A total of 12 different types of foods were evaluated. These included dried fruits and vegetables, frozen seafood, sweeteners, and juices. The matrix is extracted with a buffered formaldehyde solution, converting free and reversibly bound sulfite to the stable formaldehyde adduct, hydroxymethylsulfonate (HMS). Extracts are prepared for injection using a C18 SPE cartridge to remove any lipophilic compounds. HMS is then separated from other matrix components using hydrophilic interaction chromatography (HILIC) and detected using multiple reaction monitoring (MRM). The method was validated at 5 concentrations in 12 food matrices. Accuracy data showed spiked recoveries ranging from 84 to 115% in representative foods. Six commercially available sulfited products were analyzed using the LC-MS/MS method, as well as the MW method, to determine if differences exist. PMID- 25695591 TI - Kidney regeneration using developing xenoembryo. AB - PURPOSE OF REVIEW: We provide an overview of the recent progress in kidney regeneration with a particular focus on our previous study, which used developing xenoembryos for differentiating human mesenchymal stem cells (hMSCs). The principle of the methodology, recent advances, and limitations and challenges associated with kidney regeneration are outlined. RECENT FINDINGS: Our primary study objective is to generate neokidney from dialysis patient-derived hMSCs. We previously showed that glial cell-derived neurotrophic factor-expressing hMSCs can differentiate into functional chimeric nephrons in developing mammalian embryos. Recently, we succeeded in eliminating xenotissues in transgenic oestrogen receptor-E2F transcription factor 1 (ER-E2F1) mice by introducing a suicide gene. We also showed MSCs derived from dialysis patients can be used for kidney regeneration. Blastocyst complementation strategy was used to generate chimeric nephrons by injecting mouse pluripotent stem cells into spalt-like transcription factor 1 (Sall1) knockout mouse blastocysts. SUMMARY: Kidney tissue can be generated from human mouse pluripotent stem cells or MSCs by several methods. The size and function of regenerated kidney tissue do not meet the transplantation requirements for clinical applications. Although many outstanding problems remain for kidney regeneration, including ethical issues and the formation of chimeric structures, the neokidney generation exclusively from dialysis patient-derived cells is expected to be a reality in the future. PMID- 25695592 TI - Technical aspects for live-donor organ procurement for liver, kidney, pancreas, and intestine. AB - PURPOSE OF REVIEW: This article reviews current strategies for living-donor organ procurement in liver, kidney, pancreas, and intestinal transplant. RECENT FINDINGS: Here we summarize current open and laparoscopic approaches to living donation of abdominal organs. SUMMARY: Living donation strategies expand the organ pool in the setting of a significant organ shortage. PMID- 25695593 TI - Regenerating the nephron with human pluripotent stem cells. AB - PURPOSE OF REVIEW: Nephrogenesis in humans is limited to the period of embryonic kidney development in utero, with no new nephrons formed after birth. Although the kidneys possess the capacity to self-repair segments of the nephron, nephron loss from acute or chronic kidney injury is irreversible and results in impaired function. Human pluripotent stem cells (PSCs), including embryonic stem cells and induced pluripotent stem cells, are an attractive source of cells to regenerate nephron progenitor cells (NPCs) and ultimately functional kidney tissue. NPCs are found exclusively during the period of embryonic development, but their nephron forming capacity makes them an ideal cell population to regenerate with PSCs. RECENT FINDINGS: Significant progress has been made in the effort to direct the differentiation of human PSCs into NPCs. Differentiation protocols designed to recapitulate the complex process of kidney organogenesis in vitro can generate cells that express characteristic NPC markers and these cells can assemble into three-dimensional nephron-like structures. Additional studies are required to evaluate the functionality of these putative kidney cells and to test their ability to integrate into three-dimensional organized kidney tissue structures, either spontaneously or facilitated by bioengineered structures or scaffolds with appropriate matrix materials. SUMMARY: The successful recreation of human nephrons from PSCs would offer a novel therapeutic approach to treating patients with kidney disease. PMID- 25695594 TI - Influence of the number and substitution position of phenyl groups on the aggregation-enhanced emission of benzene-cored luminogens. AB - The influence of the number and substitution position of phenyl groups on the aggregation-enhanced emission of benzene-cored luminogens is unambiguously revealed. PMID- 25695595 TI - Ku70 is essential for histone deacetylase inhibitor trichostatin A-induced apoptosis. AB - It was previously reported that the histone deacetylase inhibitor (HDACI) trichostatin A (TSA) induced B cell lymphoma 2 (Bcl-2)-associated X protein (Bax) dependent apoptosis in colorectal cancer (CRC) cells. In addition, Ku70 has been identified as a regulator of apoptosis, the mechanism of which proceeds via interacting with Bax. The aim of the present study was to investigate the role of Ku70 in TSA-induced apoptosis in the CRC cell lines HCT116 and HT29. The results showed that TSA induced the acetylation of Ku70, which was found to be associated with increased apoptosis. In addition, TSA treatment promoted the release of Bax from its complex with Ku70. Bax was then detected to have translocated from the cytoplasm into the mitochondria, while cytochrome c was detected to have translocated from the mitochondria into the cytoplasm. Furthermore, knockdown of Ku70 using small interfering RNA decreased TSA-induced apoptosis as well as downregulated the expression of Bax. These effects were rescued through pre treatment of cells with the proteasome inhibitor MG132. In conclusion, the results of the present study suggested that Ku70 acetylation mediated TSA-induced apoptosis in CRC cells. In addition, Ku70 was found to be indispensable in TSA induced apoptosis due to its role in protecting Bax from proteosomal degradation. PMID- 25695596 TI - Construction of anti-parallel G-quadruplexes through sequential templated click. AB - Biologically relevant DNA sequences were assembled onto addressable cyclopeptide scaffolds through sequential oxime and CuAAc reactions. The resulting conjugates are able to fold into well-defined anti-parallel DNA G-quadruplex structures, which exhibit high stability and reduced polymorphism. PMID- 25695597 TI - Node Handprinting: A Scalable and Accurate Algorithm for Aligning Multiple Biological Networks. AB - Due to recent advancements in high-throughput sequencing technologies, progressively more protein-protein interactions have been identified for a growing number of species. Subsequently, the protein-protein interaction networks for these species have been further refined. The increase in the quality and availability of these networks has in turn brought a demand for efficient methods to analyze such networks. The pairwise alignment of these networks has been moderately investigated, with numerous algorithms available, but there is very little progress in the field of multiple network alignment. Multiple alignment of networks from different organisms is ideal at finding abnormally conserved or disparate subnetworks. We present a fast and accurate algorithmic approach, Node Handprinting (NH), based on our previous work with Node Fingerprinting, which enables quick and accurate alignment of multiple networks. We also propose two new metrics for the analysis of multiple alignments, as the current metrics are not as sophisticated as their pairwise alignment counterparts. To assess the performance of NH, we use previously aligned datasets as well as protein interaction networks generated from the public database BioGRID. Our results indicate that NH compares favorably with current methodologies and is the only algorithm capable of performing the more complex alignments. PMID- 25695598 TI - Vibrio vulnificus VvhA induces NF-kappaB-dependent mitochondrial cell death via lipid raft-mediated ROS production in intestinal epithelial cells. AB - The Gram-negative bacterium Vibrio vulnificus produces hemolysin (VvhA), which induces cytotoxicity in mammalian cells. However, our understanding of the cytotoxic mechanism and the modes of action of VvhA are still fragmentary and incomplete. The recombinant protein (r) VvhA (50 pg/ml) significantly induces necrotic cell death and apoptosis in human intestinal epithelial (INT-407) cells. The apoptotic cell death induced by rVvhA is highly susceptible to the sequestration of cholesterol by methyl-beta-cyclodextrin, whereas for necrotic cell death, this shows a marginal effect. We found that rVvhA induces the aggregation of lipid raft components coupled with NADPH oxidase enzymes, in which rVvhA increased the interaction of NADPH oxidase 2 (NOX2, gp91(phox)) with a cytosolic protein NCF1 (p47(phox)) to facilitate the production of reactive oxygen species (ROS). rVvhA uniquely stimulated a conventional PKC isoform PKCalpha and induced the phosphorylation of both ERK and JNK, which are responsible for the activation of transcription factor NF-kappaB. rVvhA induced an NF-kappaB-dependent imbalance of the Bcl-2/Bax ratio, the release of mitochondrial cytochrome c, and caspase-3/-9 activation during its promotion of apoptotic cell death. In addition, rVvhA has the ability to inhibit the expression of cell cycle-related proteins, such as CDK2, CDK4, cyclin D1, and cyclin E. These results demonstrate that rVvhA induces NF-kappaB-dependent mitochondrial cell death via lipid raft-mediated ROS production by the distinct activation of PKCalpha and ERK/JNK in intestinal epithelial cells. PMID- 25695599 TI - Mer receptor tyrosine kinase mediates both tethering and phagocytosis of apoptotic cells. AB - Billions of inflammatory leukocytes die and are phagocytically cleared each day. This regular renewal facilitates the normal termination of inflammatory responses, suppressing pro-inflammatory mediators and inducing their anti inflammatory counterparts. Here we investigate the role of the receptor tyrosine kinase (RTK) Mer and its ligands Protein S and Gas6 in the initial recognition and capture of apoptotic cells (ACs) by macrophages. We demonstrate extremely rapid binding kinetics of both ligands to phosphatidylserine (PtdSer)-displaying ACs, and show that ACs can be co-opsonized with multiple PtdSer opsonins. We further show that macrophage phagocytosis of ACs opsonized with Mer ligands can occur independently of a requirement for alphaV integrins. Finally, we demonstrate a novel role for Mer in the tethering of ACs to the macrophage surface, and show that Mer-mediated tethering and subsequent AC engulfment can be distinguished by their requirement for Mer kinase activity. Our results identify Mer as a receptor uniquely capable of both tethering ACs to the macrophage surface and driving their subsequent internalization. PMID- 25695600 TI - Structural and biochemical changes underlying a keratoderma-like phenotype in mice lacking suprabasal AP1 transcription factor function. AB - Epidermal keratinocyte differentiation on the body surface is a carefully choreographed process that leads to assembly of a barrier that is essential for life. Perturbation of keratinocyte differentiation leads to disease. Activator protein 1 (AP1) transcription factors are key controllers of this process. We have shown that inhibiting AP1 transcription factor activity in the suprabasal murine epidermis, by expression of dominant-negative c-jun (TAM67), produces a phenotype type that resembles human keratoderma. However, little is understood regarding the structural and molecular changes that drive this phenotype. In the present study we show that TAM67-positive epidermis displays altered cornified envelope, filaggrin-type keratohyalin granule, keratin filament, desmosome formation and lamellar body secretion leading to reduced barrier integrity. To understand the molecular changes underlying this process, we performed proteomic and RNA array analysis. Proteomic study of the corneocyte cross-linked proteome reveals a reduction in incorporation of cutaneous keratins, filaggrin, filaggrin2, late cornified envelope precursor proteins, hair keratins and hair keratin-associated proteins. This is coupled with increased incorporation of desmosome linker, small proline-rich, S100, transglutaminase and inflammation associated proteins. Incorporation of most cutaneous keratins (Krt1, Krt5 and Krt10) is reduced, but incorporation of hyperproliferation-associated epidermal keratins (Krt6a, Krt6b and Krt16) is increased. RNA array analysis reveals reduced expression of mRNA encoding differentiation-associated cutaneous keratins, hair keratins and associated proteins, late cornified envelope precursors and filaggrin-related proteins; and increased expression of mRNA encoding small proline-rich proteins, protease inhibitors (serpins), S100 proteins, defensins and hyperproliferation-associated keratins. These findings suggest that AP1 factor inactivation in the suprabasal epidermal layers reduces expression of AP1 factor-responsive genes expressed in late differentiation and is associated with a compensatory increase in expression of early differentiation genes. PMID- 25695601 TI - Role of ion channels in regulating Ca2+ homeostasis during the interplay between immune and cancer cells. AB - Ion channels are abundantly expressed in both excitable and non-excitable cells, thereby regulating the Ca(2+) influx and downstream signaling pathways of physiological processes. The immune system is specialized in the process of cancer cell recognition and elimination, and is regulated by different ion channels. In comparison with the immune cells, ion channels behave differently in cancer cells by making the tumor cells more hyperpolarized and influence cancer cell proliferation and metastasis. Therefore, ion channels comprise an important therapeutic target in anti-cancer treatment. In this review, we discuss the implication of ion channels in regulation of Ca(2+) homeostasis during the crosstalk between immune and cancer cell as well as their role in cancer progression. PMID- 25695602 TI - JNK pathway activation is able to synchronize neuronal death and glial phagocytosis in Drosophila. AB - Glial phagocytosis of superfluous neurons and damaged or aberrant neuronal material is crucial for normal development and maintenance of the CNS. However, the molecular mechanisms underlying the relationship between neuronal death and glial phagocytosis are poorly understood. We describe a novel mechanism that is able to synchronize neuronal cell death and glial phagocytosis of dying neurons in the Drosophila embryonic CNS. This mechanism involves c-Jun N-terminal kinase (JNK) signaling, which is required for developmental apoptosis of specific neurons during embryogenesis. We demonstrate that the dJNK pathway gain-of function in neurons leads to dJNK signaling in glia, which results in upregulation of glial phagocytosis. Importantly, this promotion of phagocytosis is not mediated by upregulation of the glial phagocytic receptors SIMU and DRPR, but by increasing glial capacity to degrade apoptotic particles inside phagosomes. The proposed mechanism may be important for removal of damaged neurons in the developing and mature CNS. PMID- 25695603 TI - Ets-1 as an early response gene against hypoxia-induced apoptosis in pancreatic beta-cells. AB - Hypoxia complicates islet isolation for transplantation and may contribute to pancreatic beta-cell failure in type 2 diabetes. Pancreatic beta-cells are susceptible to hypoxia-induced apoptosis. Severe hypoxic conditions during the immediate post-transplantation period are a main non-immune factor leading to beta-cell death and islet graft failure. In this study, we identified the transcription factor Ets-1 (v-ets erythroblastosis virus E26 oncogene homolog 1) as an early response gene against hypoxia-induced apoptosis in pancreatic beta cells. Hypoxia regulates Ets-1 at multiple levels according to the degree of beta cell oxygen deprivation. Moderate hypoxia promotes Ets-1 gene transcription, whereas severe hypoxia promotes its transactivation activity, as well as its ubiquitin-proteasome mediated degradation. This degradation causes a relative insufficiency of Ets-1 activity, and limits the transactivation effect of Ets-1 on downstream hypoxic-inducible genes and its anti-apoptotic function. Overexpression of ectopic Ets-1 in MIN6 and INS-1 cells protects them from severe hypoxia-induced apoptosis in a mitochondria-dependent manner, confirming that a sufficient amount of Ets-1 activity is critical for protection of pancreatic beta cells against hypoxic injury. Targeting Ets-1 expression may be a useful strategy for islet graft protection during the immediate post-transplantation period. PMID- 25695605 TI - Cellular oxidative stress response mediates radiosensitivity in Fus1-deficient mice. AB - Mechanism of radiosensitivity of normal tissues, a key factor in determining the toxic side effects of cancer radiotherapy, is not fully understood. We recently demonstrated that deficiency of mitochondrial tumor suppressor, Fus1, increases radiosensitivity at the organismal, tissue and cellular levels. Since Fus1 deficient mice and cells exhibit high levels of oxidative stress, we hypothesized that dysregulation of cellular antioxidant defenses may contribute to the increased radiosensitivity. To address this potential mechanism, we treated the Fus1 KO mice with an inhibitor of pathogenic oxidative reactions, pyridoxamine (PM). Treatment with PM ameliorated IR-induced damage to GI epithelium of Fus1 KO mice and significantly increased the survival of irradiated mice. In cultured Fus1 KO epithelial cells, IR-induced oxidative stress was enhanced because of inadequate cellular antioxidant defenses, such as low levels and/or activities of cytochrome C, Sod 2 and STAT3. This resulted in dysregulation of IR-induced DNA damage response and DNA synthesis. Treatment of Fus1 KO cells with PM or Sod 2 mimetic Tempol normalized the oxidative stress response, thus compensating to a significant degree for inadequate antioxidant response. Our findings using Fus1 KO radiosensitive mice suggest that radiosensitivity is mediated via dysregulation of antioxidant response and defective redox homeostasis. PMID- 25695604 TI - APP intracellular domain acts as a transcriptional regulator of miR-663 suppressing neuronal differentiation. AB - Amyloid precursor protein (APP) is best known for its involvement in the pathogenesis of Alzheimer's disease. We have previously demonstrated that APP intracellular domain (AICD) regulates neurogenesis; however, the mechanisms underlying AICD-mediated regulation of neuronal differentiation are not yet fully characterized. Using genome-wide chromatin immunoprecipitation approaches, we found that AICD is specifically recruited to the regulatory regions of several microRNA genes, and acts as a transcriptional regulator for miR-663, miR-3648 and miR-3687 in human neural stem cells. Functional assays show that AICD negatively modulates neuronal differentiation through miR-663, a primate-specific microRNA. Microarray data further demonstrate that miR-663 suppresses the expression of multiple genes implicated in neurogenesis, including FBXL18 and CDK6. Our results indicate that AICD has a novel role in suppression of neuronal differentiation via transcriptional regulation of miR-663 in human neural stem cells. PMID- 25695606 TI - Sonic hedgehog through Gli2 and Gli3 is required for the proper development of placental labyrinth. AB - Sonic hedgehog (Shh) functions as a conserved morphogen in the development of various organs in metazoans ranging from Drosophila to humans. Here, we have investigated the potential roles and underlying mechanisms of Shh signaling in murine placentation. Immunostaining revealed the abundant expression of the main components of Shh pathway in both the trophectoderm of blastocysts and developing placentas. Disruption of Shh led to impaired vascularogenesis of yolk sac, less branching and malformation of placental labyrinth, thereby leading to a robust decrease in capacity of transplacental passages. Moreover, placenta-specific gene incorporation by lentiviral transduction of mouse blastocysts and blastocyst transplantation robustly knocked down the expression of Gli3 and Gli2 in placenta but not in embryos. Finally, Gli3 knockdown in Shh(-/-) placentas partially rescued the defects of both yolk sac and placental labyrinth, and robustly restored the capacity of transplacental passages. Gli2 knockdown in Shh(+/)(-) placentas affected neither the capacity of tranplacental passages nor the vascularogenesis of yolk sac, however, it partially phenocopied the labyrinthine defects of Shh(-/-) placentas. Taken together, these results uncover that both Shh/Gli2 and Shh/Gli3 signals are required for proper development of murine placentas and are possibly essential for pregnant maintenance. PMID- 25695607 TI - Annexin-1 regulated by HAUSP is essential for UV-induced damage response. AB - DNA damage can occur through diverse stimulations such as toxins, drugs, and environmental factors. To respond to DNA damage, mammalian cells induce DNA damage response (DDR). DDR signal activates a rapid signal transduction pathway, regulating the cell fate based on the damaged cell condition. Moreover, serious damaged cells have to be eliminated by the macrophage to maintain homeostasis. Because the DDR induces genomic instability followed by tumor formation, targeting the DDR signaling can be applied for the cancer therapy. Herpes virus associated ubiquitin-specific protease (HAUSP/USP7) is one of the well-known deubiquitinating enzymes (DUBs) owing to its relevance with Mdm2-p53 complex. The involvement of HAUSP in DDR through p53 led us to investigate novel substrates for HAUSP, which is related to DDR or apoptosis. As a result, we identified annexin-1 (ANXA1) as one of the putative substrates for HAUSP. ANXA1 has numerous roles in cellular systems including anti-inflammation, damage response, and apoptosis. Several studies have demonstrated that ANXA1 can be modified in a post translational manner by processes such as phosphorylation, SUMOylation, and ubiquitination. In addition, DNA damage gives various functions to ANXA1 such as stress response or cleavage-mediated apoptotic cell clearance. In the current study, our proteomic analysis using two-dimensional electrophoresis, matrix assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF MS) and nano LC-MS/MS, and immunoprecipitation revealed that ANXA1 binds to HAUSP through its HAUSP-binding motif (P/AXXS), and the cleavage and damage-responsive functions of ANXA1 upon UV-induced DNA damage may be followed by HAUSP-mediated deubiquitination of ANXA1. Intriguingly, the UV-induced damage responses via HAUSP-ANXA1 interaction in HeLa cells were different from the responses shown in the Jurkat cells, suggesting that their change of roles may depend on the cell types. PMID- 25695608 TI - In a three-dimensional reconstructed human epidermis filaggrin-2 is essential for proper cornification. AB - Atopic dermatitis is a chronic inflammatory skin disease with defects in the epidermal barrier. In a cohort of African-American children, a FLG2 nonsense mutation has been associated with the disease. In the epidermis of European patients, the expression of filaggrin-2, the filaggrin-related protein encoded by FLG2, is decreased. To describe the function of filaggrin-2 and evaluate the impact of its deficiency, its expression was downregulated using lentivirus mediated shRNA interference in a three-dimensional reconstructed human epidermis (RHE) model. This resulted in parakeratosis and a compact stratum corneum, presence of abnormal vesicles inside the corneocytes, increased pH and reduced amounts of free amino acids at the RHE surface, leading to increased sensitivity to UVB radiations. The expression of differentiation markers was slightly modified. However, we observed reduced proteolytic processing of corneodesmosin, hornerin and filaggrin in parallel with reduced amounts of caspase-14 and bleomycin hydrolase. Our data demonstrated that filaggrin-2 is important for a proper cornification and a functional stratum corneum. Its downregulation in atopic patients may be involved in the disease-associated epidermis impairment. PMID- 25695609 TI - Selective inhibition of HDAC8 decreases neuroblastoma growth in vitro and in vivo and enhances retinoic acid-mediated differentiation. AB - For differentiation-defective malignancies, compounds that modulate transcription, such as retinoic acid and histone deacetylase (HDAC) inhibitors, are of particular interest. HDAC inhibitors are currently under investigation for the treatment of a broad spectrum of cancer diseases. However, one clinical drawback is class-specific toxicity of unselective inhibitors, limiting their full anticancer potential. Selective targeting of individual HDAC isozymes in defined tumor entities may therefore be an attractive alternative treatment approach. We have previously identified HDAC family member 8 (HDAC8) as a novel target in childhood neuroblastoma. Using small-molecule inhibitors, we now demonstrate that selective inhibition of HDAC8 exhibits antineuroblastoma activity without toxicity in two xenograft mouse models of MYCN oncogene amplified neuroblastoma. In contrast, the unselective HDAC inhibitor vorinostat was more toxic in the same models. HDAC8-selective inhibition induced cell cycle arrest and differentiation in vitro and in vivo. Upon combination with retinoic acid, differentiation was significantly enhanced, as demonstrated by elongated neurofilament-positive neurites and upregulation of NTRK1. Additionally, MYCN oncogene expression was downregulated in vitro and tumor cell growth was markedly reduced in vivo. Mechanistic studies suggest that cAMP-response element-binding protein (CREB) links HDAC8- and retinoic acid-mediated gene transcription. In conclusion, HDAC-selective targeting can be effective in tumors exhibiting HDAC isozyme-dependent tumor growth in vivo and can be combined with differentiation inducing agents. PMID- 25695610 TI - Quantitative assessment of cardiac mechanical dyssynchrony and prediction of response to cardiac resynchronization therapy in patients with nonischaemic dilated cardiomyopathy using gated myocardial perfusion SPECT. AB - OBJECTIVE: The aim of the study was to evaluate gated myocardial perfusion SPECT (GMPS) in the prediction of response to cardiac resynchronization therapy (CRT) in nonischaemic dilated cardiomyopathy patients. PATIENTS AND METHODS: Thirty-two patients (23 men, mean age 57.5+/-12.1 years) with severe heart failure, who were selected for CRT implantation, were prospectively included in this study. Patients with coronary heart disease and structural heart diseases were excluded. 99mTc-MIBI GMPS and clinical evaluation were performed at baseline and 3 months after CRT implantation. In GMPS, first-harmonic fast Fourier transform was used to extract a phase array using commercially available software. Phase standard deviation (PSD) and phase histogram bandwidth (PHB) were used to quantify cardiac mechanical dyssynchrony (CMD). Left ventricular ejection fraction was evaluated. RESULTS: At baseline evaluation the mean NYHA class was 3.3+/-0.5, left ventricular ejection fraction was 23.2+/-5.3% and mean QRS duration was 150.3+/ 18.2 ms. PSD was 55.8+/-19.2 degrees and PHB was 182.1+/-75.8 degrees . At 3 month follow-up, 22 patients responded to CRT with improvement in NYHA class by more than 1 grade and in ejection fraction by more than 5%. Responders had significantly larger PSD (63.6+/-16.6 vs. 38.7+/-12.7 degrees ) and PHB (214.8+/ 63.9 vs. 110.2+/-43.5 degrees ) compared with nonresponders. Receiver-operating characteristic curve analysis demonstrated 86% sensitivity and 80% specificity at a cutoff value of 43 degrees for PSD and 86% sensitivity and 80% specificity at a cutoff value of 128 degrees for PHB in the prediction of response to CRT. CONCLUSION: Baseline PSD and PHB derived from GMPS are useful for prediction of response to CRT in nonischaemic dilated cardiomyopathy patients. PMID- 25695611 TI - Development of a simple kit-based method for preparation of pharmaceutical-grade 68Ga-DOTATOC. AB - INTRODUCTION: The use of germanium-68 (68Ge)/gallium-68 (68Ga) generators is still limited when compared with the 99Mo/99mTc counterpart, mainly because of the absence of commercial kits and a kit-based method for preparing Ga-labelled radiopharmaceuticals in a reliable way. The present study aimed to develop and optimize a reliable direct labelling of DOTATOC with 68Ga through a kit-based approach. MATERIALS AND METHODS: A fraction of the eluate of two different 68Ge/68Ga generators was directly injected into a vial prefilled with precursor, buffer and scavenger (the prototype of a potential lyophilized kit). The vial was directly warmed to 100 degrees C and then buffered with a 1.5 mol/l sodium ascorbate solution. The parameters influencing the reaction were studied and optimized. The efficacy of the method in terms of incorporation yield and quality of the final radiotracer was compared with preparations performed with two commercial automatic synthesizers by applying the tests prescribed in the European Pharmacopeia monograph for 68Ga-DOTATOC. RESULTS: Under optimal conditions, the overall radiochemical yields of the kit-based process were 73+/-4 and 69+/-3% not decay-corrected for the IGG100 and itG generator, respectively. The radiochemical purity was 95+/-3% and the preparations were compliant with all specifications given in the pharmacopoeia monograph. CONCLUSION: The feasibility of a kit-based approach for the preparation of 68Ga-DOTATOC was proved and a first home-made version of a putative lyophilized kit was proposed. PMID- 25695612 TI - Comparison of the EANM and SNM guidelines on diuretic renography in children. AB - OBJECTIVE: When taking into account the Society of Nuclear Medicine (SNM) and European Association of Nuclear Medicine (EANM) guidelines on diuretic renography in children, we see important divergences in the preparation, acquisition, processing, and interpretation of the results. In this study, we estimated the quality of renal drainage according to these two guidelines. PATIENTS AND METHODS: Ninety kidneys with hydronephrosis or severe vesicorenal reflux were processed and analyzed according to the SNM (estimation of the T1/2 of the washout curve and conclusions about the possible existence of obstruction) and EANM guidelines (estimation of normalized residual activity or NORA, and output efficiency or OE on the late postmicturition images, without any conclusion about the possible existence of obstruction). Among the 90 kidneys, 39, 20, and 31 were considered to have normal, equivocal, or poor drainage (obstruction), respectively, when the SNM guidelines were used. RESULTS: All 39 kidneys with good drainage according to SNM were also considered as normal using the EANM guidelines. Among the 20 equivocal cases based on T1/2, concordance between the two guidelines was obtained in only 35 and 0% when using NORA and OE (OE was considered normal in all 20 cases), respectively. Among the 31 cases defined as obstructed by SNM, only five were classified as 'poor drainage' using NORA and no single case was classified thus using OE. CONCLUSION: This limited study demonstrates that the use of different guidelines can lead to different interpretations of the results. This is unacceptable, and an agreement between both pediatric task groups of the SNM and EANM is urgently required. PMID- 25695613 TI - Elimination of scattered gamma rays from injection sites using upper offset energy windows in sentinel lymph node scintigraphy. AB - OBJECTIVE: The identification of sentinel lymph nodes (SLNs) near injection sites is difficult because of scattered gamma rays. The purpose of this study was to investigate the optimal energy windows for elimination of scattered gamma rays in order to improve the detection of SLNs. METHODS: The clinical study group consisted of 56 female patients with breast cancer. While the energy was centred at 140 keV with a 20% window for Tc-99m, this energy window was divided into five subwindows with every 4% in planar imaging. Regions of interest were placed on SLNs and the background, and contrast was calculated using a standard equation. The confidence levels of interpretations were evaluated using a five-grade scale. RESULTS: The contrast provided by 145.6 keV+/-2% was the best, followed by 140 keV+/-2%, 151.2 keV+/-2%, 134.4 keV+/-2% and 128.8 keV+/-2% in that order. When 128.8 keV+/-2% and 134.4 keV+/-2% were eliminated from 140 keV+/-10% (145.6 keV+/ 6%), the contrast of SLNs improved significantly. The confidence levels of interpretation and detection rate provided by the planar images with 140 keV+/ 10% were 4.74+/-0.58 and 94.8%, respectively, and those provided by 145.6 keV+/ 6% were 4.94+/-0.20 and 100%. CONCLUSION: Because lower energy windows contain many scattered gamma rays, upper offset energy windows, which exclude lower energy windows, improve the image contrast of SLNs near injection sites. PMID- 25695614 TI - Molecular detection of Ehrlichia chaffeensis in humans, Costa Rica. PMID- 25695615 TI - Rickettsial infections in monkeys, Malaysia. PMID- 25695616 TI - Human trachealis and main bronchi smooth muscle are normoresponsive in asthma. AB - RATIONALE: Airway smooth muscle (ASM) plays a key role in airway hyperresponsiveness (AHR) but it is unclear whether its contractility is intrinsically changed in asthma. OBJECTIVES: To investigate whether key parameters of ASM contractility are altered in subjects with asthma. METHODS: Human trachea and main bronchi were dissected free of epithelium and connective tissues and suspended in a force-length measurement set-up. After equilibration each tissue underwent a series of protocols to assess its methacholine dose response relationship, shortening velocity, and response to length oscillations equivalent to tidal breathing and deep inspirations. MEASUREMENTS AND MAIN RESULTS: Main bronchi and tracheal ASM were significantly hyposensitive in subjects with asthma compared with control subjects. Trachea and main bronchi did not show significant differences in reactivity to methacholine and unloaded tissue shortening velocity (Vmax) compared with control subjects. There were no significant differences in responses to deep inspiration, with or without superimposed tidal breathing oscillations. No significant correlations were found between age, body mass index, or sex and sensitivity, reactivity, or Vmax. CONCLUSIONS: Our data show that, in contrast to some animal models of AHR, human tracheal and main bronchial smooth muscle contractility is not increased in asthma. Specifically, our results indicate that it is highly unlikely that ASM half-maximum effective concentration (EC50) or Vmax contribute to AHR in asthma, but, because of high variability, we cannot conclude whether or not asthmatic ASM is hyperreactive. PMID- 25695617 TI - Effects of miRNA-455 on cardiac hypertrophy induced by pressure overload. AB - microRNAs (miRNAs or miRs) are essential in cardiac hypertrophy and in the development of heart failure. In the present study, we aimed to determine whether the restoration of miRNA-455 (miR-455) gene expression in vivo aggravates hypertrophy, but protects against adverse cardiac remodeling induced by pressure overload. Cardiac hypertrophy was induced by left ventricular pressure overload in male mice subjected to transverse aortic constriction (TAC). The mice were randomly selected to receive a tail vein injection of either miR-455 or green fluorescent protein per animal at 1, 8, 15 and 21 days following surgery. Cardiac hypertrophy, function and remodeling were evaluated by echocardiography, catheterization, histological analysis and the examination of the expression of specific genes and cardiac apoptosis. TAC (2 weeks following surgery) resulted in significant cardiac hypertrophy, which was significantly aggravated by treatment with miR-455. However, miR-455 replacement therapy markedly reduced myocardial fibrosis and inhibited apoptosis, suggesting that this therapy can prevent maladaptive ventricular remodeling. miR-455 was also identified and validated to target calreticulin, a protein that is critical for cardiac development. The restoration of miR-455 gene expression may thus be a potential therapeutic strategy to reverse pressure-induced cardiac hypertrophy and prevent maladaptive cardiac remodeling through the regulation of miR-455 at different time points following hypertrophy. PMID- 25695618 TI - TET2 and CSMD1 genes affect SBP response to hydrochlorothiazide in never-treated essential hypertensives. AB - BACKGROUND: Thiazide diuretics have been recommended as a first-line antihypertensive treatment, although the choice of 'the right drug in the individual essential hypertensive patient' remains still empirical. Essential hypertension is a complex, polygenic disease derived from the interaction of patient's genetic background with the environment. Pharmacogenomics could be a useful tool to pinpoint gene variants involved in antihypertensive drug response, thus optimizing therapeutic advantages and minimizing side effects. METHODS AND RESULTS: We looked for variants associated with blood pressure response to hydrochlorothiazide over an 8-week follow-up by means of a genome-wide association analysis in two Italian cohorts of never-treated essential hypertensive patients: 343 samples from Sardinia and 142 from Milan. TET2 and CSMD1 as plausible candidate genes to affect SBP response to hydrochlorothiazide were identified. The specificity of our findings for hydrochlorothiazide was confirmed in an independent cohort of essential hypertensive patients treated with losartan. Our best findings were also tested for replication in four independent hypertensive samples of European Ancestry, such as GENetics of drug RESponsiveness in essential hypertension, Genetic Epidemiology of Responses to Antihypertensives, NORdic DILtiazem intervention, Pharmacogenomics Evaluation of Antihypertensive Responses, and Campania Salute Network-StayOnDiur. We validated a polymorphism in CSMD1 and UGGT2. CONCLUSION: This exploratory study reports two plausible loci associated with SBP response to hydrochlorothiazide: TET2, an aldosterone-responsive mediator of alphaENaC gene transcription; and CSMD1, previously described as associated with hypertension in a case-control study. PMID- 25695619 TI - Monocyte chemotactic protein-1 promotes the proliferation and invasion of osteosarcoma cells and upregulates the expression of AKT. AB - Monocyte chemotactic protein-1 (MCP-1/CCL2) is an important immune factor, which may be important in cancer progression by promoting proliferation, invasion, metastasis and the tumor microenvironment. Previous studies have demonstrated that CCL2 affects the proliferation of osteosarcoma cells via the RANKL signaling pathway. However, the underlying mechanisms remain to be elucidated. To investigate the role of CCL2 in osteosarcoma cells, MTT, spheroid forming, wound healing and transwell assays were performed to examine the proliferation and invasion abilities of the osteosarcoma cells. It was revealed that the high-grade osteosarcoma cells exhibited increased expression levels of CCL2 compared with the low-grade osteosarcoma cells (P<0.001). Furthermore, knockdown of CCL2 decreased the proliferation and invasion abilities of the osteosarcoma cells (P<0.01). These results suggested that the expression of CCL2 is high in high grade osteosarcoma cells and promotes the proliferation and invasion of osteosarcoma cells. PMID- 25695620 TI - Human Umbilical Cord Mesenchymal Stem Cells Promote Breast Cancer Metastasis by Interleukin-8- and Interleukin-6-Dependent Induction of CD44(+)/CD24(-) Cells. AB - Although emerging evidence links mesenchymal stem cells (MSCs) with cancer metastasis, the underlying mechanisms are poorly understood. In the present study, we found that human umbilical cord-derived MSCs (UC-MSCs) promoted MCF-7 cell migration in vitro and metastasis in vivo. To explore the mechanisms, the characteristics of MCF-7 cells cocultured with UC-MSCs were assessed. The expression and secretion of interleukin-8 (IL-8) and IL-6 were induced in MCF-7 cells cocultured with UC-MSCs. However, neutralization of IL-8 or IL-6 secreted by UC-MSCs could attenuate the enhanced expression of IL-8 and IL-6 in MCF-7 cells cocultured with UC-MSCs, which subsequently alleviated the enhanced migration. Similar to UC-MSCs, exogenous human recombinant IL-8 or IL-6 also promoted IL-8 and IL-6 expression and MCF-7 cell migration. In addition to enhanced IL-8 and IL-6 expression, MCF-7 cells cocultured with UC-MSCs displayed enhanced mammosphere-forming ability and increased percentage of CD44(+)/CD24(-) cells. However, epithelial-to-mesenchymal transition (EMT) was not observed in MCF-7 cells cocultured with UC-MSCs. Taken together, these results suggested that IL-8 and IL-6 secreted by UC-MSCs activated the autocrine IL-8 and IL-6 signaling in MCF-7 cells and induced CD44(+)/CD24(-) cells, which subsequently promoted MCF 7 cell migration in vitro and metastasis in vivo. PMID- 25695621 TI - Concept for enhancement of the stability of calcium-bound pyrazolyl-substituted methanides. AB - Metalation of bis(3-thiophen-2-ylpyrazol-1-yl)phenylmethane [2, which is accessible from the reaction of bis(3-thien-2-ylpyrazol-1-yl)methanone (1) with triphosgene] with [(thf)2Ca{N(SiMe3)2}2] in tetrahydrofuran and subsequent crystallization from a mixture of toluene and 1,2-dimethoxyethane yield [(dme)Ca{C(Pz(th))2Ph}{N(SiMe3)2}] (3). The alpha,alpha-bis(3-thiophen-2 ylpyrazol-1-yl)benzyl ligand exhibits a kappa(2)N,kappaC-coordination mode with a Ca-C sigma-bond length of 262.8(2) pm. The crystalline compound is stable if air and moisture is strictly excluded; however, in solution; this calcium complex slowly degrades. PMID- 25695622 TI - Nonproteinogenic D-amino acids at millimolar concentrations are a toxin for anaerobic microorganisms relevant to early Earth and other anoxic planets. AB - The delivery of extraterrestrial organics to early Earth provided a potentially important source of carbon and energy for microbial life. Optically active organic compounds of extraterrestrial origin exist in racemic form, yet life on Earth has almost exclusively selected for L- over D-enantiomers of amino acids. Although D-enantiomers of proteinogenic amino acids are known to inhibit aerobic microorganisms, the role of concentrated nonproteinogenic meteoritic D-amino acids on anaerobic metabolisms relevant to early Earth and other anoxic planets such as Mars is unknown. Here, we test the inhibitory effect of D-enantiomers of two nonproteinogenic amino acids common to carbonaceous chondrites, norvaline and alpha-aminobutyric acid, on microbial iron reduction. Three pure strains (Geobacter bemidjiensis, Geobacter metallireducens, Geopsychrobacter electrodiphilus) and an iron-reducing enrichment culture were grown in the presence of 10 mM D-enantiomers of both amino acids. Further tests were conducted to assess the inhibitory effect of these D-amino acids at 1 and 0.1 mM. The presence of 10 mM D-norvaline and D-alpha-aminobutyric acid inhibited microbial iron reduction by all pure strains and the enrichment. G. bemidjiensis was not inhibited by either amino acid at 0.1 mM, but D-alpha-aminobutyric acid still inhibited at 1 mM. Calculations using published meteorite accumulation rates to the martian surface indicate D-alpha-aminobutyric acid may have reached inhibitory concentrations in little over 1000 years during peak infall. These data show that, on a young anoxic planet, the use of one enantiomer over another may render the nonbiological enantiomer an environmental toxin. Processes that generate racemic amino acids in the environment, such as meteoritic infall or impact synthesis, would have been toxic processes and could have been a selection pressure for the evolution of early racemases. PMID- 25695623 TI - How useful are corpus-based methods for extrapolating psycholinguistic variables? AB - Subjective ratings for age of acquisition, concreteness, affective valence, and many other variables are an important element of psycholinguistic research. However, even for well-studied languages, ratings usually cover just a small part of the vocabulary. A possible solution involves using corpora to build a semantic similarity space and to apply machine learning techniques to extrapolate existing ratings to previously unrated words. We conduct a systematic comparison of two extrapolation techniques: k-nearest neighbours, and random forest, in combination with semantic spaces built using latent semantic analysis, topic model, a hyperspace analogue to language (HAL)-like model, and a skip-gram model. A variant of the k-nearest neighbours method used with skip-gram word vectors gives the most accurate predictions but the random forest method has an advantage of being able to easily incorporate additional predictors. We evaluate the usefulness of the methods by exploring how much of the human performance in a lexical decision task can be explained by extrapolated ratings for age of acquisition and how precisely we can assign words to discrete categories based on extrapolated ratings. We find that at least some of the extrapolation methods may introduce artefacts to the data and produce results that could lead to different conclusions that would be reached based on the human ratings. From a practical point of view, the usefulness of ratings extrapolated with the described methods may be limited. PMID- 25695624 TI - The role of microRNAs in equine medicine: a review. AB - The search for new markers of diseases in human as well as veterinary medicine is ongoing. Recently, microRNAs (miRNAs or miRs) have emerged as potential new biomarkers. MiRNAs are short sequences of RNA (~22 nucleotides) that regulate gene expression via their target messenger RNA (mRNA). Circulating miRNAs in blood can be used as novel diagnostic markers for diseases due to their evolutionary conservation and stability. As a consequence of their systemic and manifold effects on the gene expression in various target organs, the concept that miRNAs could function as hormones has been suggested. This review summarizes the biogenesis, maturation, and stability of miRNAs and discusses their use as potential biomarkers in equine medicine. To date, over 700 equine miRNAs are identified with distinct subsets of miRNAs differentially expressed in a tissue specific manner. A physiological involvement of various miRNAs in the regulation of cell survival, steroidogenesis, and differentiation during follicle selection and ovulation in the monovular equine ovary has been demonstrated. Furthermore, miRNAs might be used as novel diagnostic markers for myopathies such as polysaccharide storage myopathy and recurrent exertional rhabdomyolysis as well as osteochondrosis. Preliminary data indicate that miRNAs in blood might play important roles in equine glucose metabolism pathway. Of note, breed differences have been reported regarding the normal equine miRNA signature. For disease prevention, it is of utmost importance to identify disease-associated biomarkers which help detect diseases before symptoms appear. As such, circulating miRNAs represent promising novel diagnostic markers in equine medicine. PMID- 25695625 TI - Klotho gene delivery ameliorates renal hypertrophy and fibrosis in streptozotocin induced diabetic rats by suppressing the Rho-associated coiled-coil kinase signaling pathway. AB - The present study aimed to investigate whether klotho gene delivery attenuated renal hypertrophy and fibrosis in streptozotocin-induced diabetic rats. A recombinant adeno-associated virus (rAAV) carrying mouse klotho full-length cDNA (rAAV.mKL), was constructed for in vivo investigation of klotho expression. Diabetes was induced in rats by a single tail vein injection of 60 mg/kg streptozotocin. Subsequently, the diabetic rats received an intravenous injection of rAAV.mKL, rAAV.green fluorescent protein (GFP) or phosphate-buffered saline (PBS). The Sprague-Dawley rat group received PBS and served as the control group. After 12 weeks, all the rats were sacrificed and ELISA, immunohistochemical and histological analyses, fluorescence microscopy, semi-quantitative reverse transcription-polymerase chain reaction and western blottin were performed. A single dose of rAAV.mKL was found to prevent the progression of renal hypertrophy and fibrosis for at least 12 weeks (duration of study). Klotho expression was suppressed in the diabetic rats, but was increased by rAAV.mKL delivery. rAAV.mKL significantly suppressed diabetes-induced renal hypertrophy and histopathological changes, reduced renal collagen fiber generation and decreased kidney hypertrophy index. In addition, rAAV.mKL decreased the protein expression levels of fibronectin and vimentin, while it downregulated the mRNA expression and activity of Rho-associated coiled-coil kinase (ROCK)I in the kidneys of the diabetic rats. These results indicated that klotho gene delivery ameliorated renal hypertrophy and fibrosis in diabetic rats, possibly by suppressing the ROCK signaling pathway. This may offer a novel approach for the long-term control and renoprotection of diabetes. PMID- 25695626 TI - New ruthenium nitrosyl pincer complexes bearing an O2 ligand. Mono-oxygen transfer. AB - We report on Ru((II))(MU(2)-O2) nitrosyl pincer complexes that can return to their original Ru(0) state by reaction with mono-oxygen scavengers. Potential intermediates were calculated by density functional theory (DFT) and a mechanism is proposed, revealing a new type of metal-ligand cooperation consisting of activation of the O2 moiety by both the metal center and the NO ligand. Reaction of the Ru(0) nitrosyl complex 1 with O2 quantitatively yielded the crystallographically characterized Ru((II)) (MU(2)-O2) nitrosyl complex 2. Reaction of 2 with the mono-oxygen scavengers phosphines or CO gave the Ru(0) complex 1 and phosphine oxides, or the carbonyl complex 3 (1 trapped by CO) and CO2, respectively. Reaction of 2 with 1 equiv of phosphine at room temperature or -40 degrees C resulted in immediate formation of half an equivalent of 1 and 1 equiv of phosphine oxide, while half an equivalent of 2 remained unchanged. Overnight reaction at room temperature of 2 with excess CO (>=3 equiv) resulted in 3 and CO2 gas as the only products. Reaction of 1 with 1 equiv of mono-oxygen source (dioxirane) at -78 degrees C yielded the Ru((II))(MU(2)-O2) complex 2. Similarly, reaction of the Ru(0) dearomatized complex 4 with O2 led to the crystallographicaly characterized Ru((II))(MU(2)-O2) complex 5. Further reaction of 5 with mono-oxygen scavengers (phosphines or CO) led to the Ru(0) complex 4 and phosphine oxides or complex 6 (4 trapped by CO) and CO2. When instead only 1 equiv of 5 was reacted with 1 equiv of phosphine at room temperature, immediate formation of half an equivalent of 4 and 1 equiv of phosphine oxide took place, while half an equivalent of 5 remained unchanged. When 5 reacted with an excess of CO (>=3 equiv), complex 6 and CO2 gas were the only products obtained. DFT studies indicate a new mode of metal-ligand cooperation involving the nitrosyl ligand in the oxygen transfer process. PMID- 25695627 TI - Mesophase in a thiolate-containing diacyl phospholipid self-assembled monolayer. AB - Maintaining the intrinsic features of mesophases is critically important when employing phospholipid self-assemblies to mimic biomembranes. Inorganic solid surfaces provide platforms to support, guide, and analyze organic self-assemblies but impose upon them a tendency to form well-ordered phases not often found in biomembranes. To address this, we measured mesophase formation in a thiolate self assembled monolayer (SAM) of diacyl phospholipid, 1,2-dipalmitoyl-sn-glycero-3 phosphothioethanol (DPPTE) on Au(111), and provide thermodynamic analysis on the mixing behavior of inequivalent DPPTE acyl chains. Our work has uncovered three fundamental issues that enable mesophase formation: (1) Elimination of templating effects of the solid surface, (2) Weakening intermolecular and molecule-substrate interactions in adsorbates, and (3) Equilibrium through entropy-driven self assembly. Thus, our work provides a more holistic understanding of phase behavior, from liquid phases to mesophases to highly crystalline phases, in organic self-assemblies on solid surfaces, which may extend their applications in nanodevices and to the wider fields of biology and medicine. PMID- 25695628 TI - Letter to the Editor regarding 'Celebrating Bidleman's 1988 "Atmospheric Processes"'. PMID- 25695629 TI - Integration of Hippo signalling and the unfolded protein response to restrain liver overgrowth and tumorigenesis. AB - The role of the unfolded protein response (UPR) in tissue homeostasis remains largely unknown. Here we find that loss of Mst1/2, the mammalian Hippo orthologues, or their regulator WW45, leads to a remarkably enlarged endoplasmic reticulum (ER) size-associated UPR. Intriguingly, attenuation of the UPR by tauroursodeoxycholic acid (TUDCA) diminishes Mst1/2 mutant-driven liver overgrowth and tumorigenesis by promoting nuclear exit and degradation of Hippo downstream effector Yap. Yap is required for UPR activity and ER expansion to alleviate ER stress. During the adaptive stage of the UPR, PERK kinase-eIF2alpha axis activates Yap, while prolonged ER stress-induced Hippo signalling triggers assembly of the GADD34/PP1 complex in a negative feedback loop to inhibit Yap and promote apoptosis. Significantly, the deregulation of UPR signals associated with Yap activation is found in a substantial fraction of human hepatocellular carcinoma (HCC). Thus, we conclude Yap integrates Hippo and UPR signalling to control liver size and tumorigenesis. PMID- 25695630 TI - When should acute exacerbations of COPD be treated with systemic corticosteroids and antibiotics in primary care: a systematic review of current COPD guidelines. AB - Not all patients with acute exacerbations of chronic obstructive pulmonary disease (COPD) benefit from treatment with systemic corticosteroids and antibiotics. The aim of the study was to identify criteria recommended in current COPD guidelines for treating acute exacerbations with systemic corticosteroids and antibiotics and to assess the underlying evidence. Current COPD guidelines were identified by a systematic literature search. The most recent guidelines as per country/organisation containing recommendations about treating acute exacerbations of COPD were included. Guideline development and criteria for treating acute exacerbations with systemic corticosteroids and antibiotics were appraised. Randomised controlled trials directly referred to in context with the recommendations were evaluated in terms of study design, setting, and study population. A total of 19 COPD guidelines were included. Systemic corticosteroids were often universally recommended to all patients with acute exacerbations. Criteria for treatment with antibiotics were mainly an increase in respiratory symptoms. Objective diagnostic tests or clinical examination were only rarely recommended. Only few criteria were directly linked to underlying evidence, and the trial patients represented a highly specific group of COPD patients. Current COPD guidelines are of little help in primary care to identify patients with acute exacerbations probably benefitting from treatment with systemic corticosteroids and antibiotics in primary care, and might contribute to overuse or inappropriate use of either treatment. PMID- 25695631 TI - Characterization of the mycobacterial acyl-CoA carboxylase holo complexes reveals their functional expansion into amino acid catabolism. AB - Biotin-mediated carboxylation of short-chain fatty acid coenzyme A esters is a key step in lipid biosynthesis that is carried out by multienzyme complexes to extend fatty acids by one methylene group. Pathogenic mycobacteria have an unusually high redundancy of carboxyltransferase genes and biotin carboxylase genes, creating multiple combinations of protein/protein complexes of unknown overall composition and functional readout. By combining pull-down assays with mass spectrometry, we identified nine binary protein/protein interactions and four validated holo acyl-coenzyme A carboxylase complexes. We investigated one of these--the AccD1-AccA1 complex from Mycobacterium tuberculosis with hitherto unknown physiological function. Using genetics, metabolomics and biochemistry we found that this complex is involved in branched amino-acid catabolism with methylcrotonyl coenzyme A as the substrate. We then determined its overall architecture by electron microscopy and found it to be a four-layered dodecameric arrangement that matches the overall dimensions of a distantly related methylcrotonyl coenzyme A holo complex. Our data argue in favor of distinct structural requirements for biotin-mediated gamma-carboxylation of alpha-beta unsaturated acid esters and will advance the categorization of acyl-coenzyme A carboxylase complexes. Knowledge about the underlying structural/functional relationships will be crucial to make the target category amenable for future biomedical applications. PMID- 25695632 TI - Accumulation of a bioactive benzoisochromanequinone compound kalafungin by a wild type antitumor-medermycin-producing streptomycete strain. AB - Medermycin and kalafungin, two antibacterial and antitumor antibiotics isolated from different streptomycetes, share an identical polyketide skeleton core. The present study reported the discovery of kalafungin in a medermycin-producing streptomycete strain for the first time. A mutant strain obtained through UV mutagenesis showed a 3-fold increase in the production of this antibiotic, compared to the wild type strain. Heterologous expression experiments suggested that its production was severely controlled by the gene cluster for medermycin biosynthesis. In all, these findings suggested that kalafungin and medermycin could be accumulated by the same streptomycete and share their biosynthetic pathway to some extent in this strain. PMID- 25695633 TI - Role of hydrogen sulfide in early blood-brain barrier disruption following transient focal cerebral ischemia. AB - We determined the role of endogenous hydrogen sulfide (H2S) in cerebral vasodilation/hyperemia and early BBB disruption following ischemic stroke. A cranial window was prepared over the left frontal, parietal and temporal cortex in mice. Transient focal cerebral Ischemia was induced by directly ligating the middle cerebral artery (MCA) for two hours. Regional vascular response and cerebral blood flow (CBF) during ischemia and reperfusion were measured in real time. Early BBB disruption was assessed by Evans Blue (EB) and sodium fluorescein (Na-F) extravasation at 3 hours of reperfusion. Topical treatment with DL propargylglycine (PAG, an inhibitor for cystathionine gamma-lyase (CSE)) and aspartate (ASP, inhibitor for cysteine aminotransferase/3-mercaptopyruvate sulfurtransferase (CAT/3-MST)), but not O-(Carboxymethyl)hydroxylamine hemihydrochloride (CHH, an inhibitor for cystathionine beta-synthase (CBS)), abolished postischemic cerebral vasodilation/hyperemia and prevented EB and Na-F extravasation. CSE knockout (CSE-/-) reduced postischemic cerebral vasodilation/hyperemia but only inhibited Na-F extravasation. An upregulated CBS was found in cerebral cortex of CSE-/- mice. Topical treatment with CHH didn't further alter postischemic cerebral vasodilation/hyperemia, but prevented EB extravasation in CSE-/- mice. In addition, L-cysteine-induced hydrogen sulfide (H2S) production similarly increased in ischemic side cerebral cortex of control and CSE-/- mice. Our findings suggest that endogenous production of H2S by CSE and CAT/3-MST during reperfusion may be involved in postischemic cerebral vasodilation/hyperemia and play an important role in early BBB disruption following transient focal cerebral ischemia. PMID- 25695635 TI - The myomucosal vertical Z-plasty in secondary cleft lip surgery: a novel technique for correction of the whistle deformity. AB - IMPORTANCE: To describe a novel technique for repair of the whistle deformity in secondary cleft lip surgery. OBSERVATIONS: Three patients who presented with a whistle deformity as a sequela of cleft lip surgery and underwent a novel myomucosal vertical Z-plasty tissue transposition at a tertiary academic medical center with a certified craniofacial center were retrospectively reviewed. Photodocumentation provides a measure of the aesthetic results. In the 3 patients, the technique was performed and the whistle deformity corrected such that the free margins of the lips were in full contact with the lips in a neutral resting position. No perioperative or postoperative complications were encountered. CONCLUSIONS AND RELEVANCE: A novel myomucosal vertical Z-plasty transposition should be added to the tools available to the cleft surgeon for addressing this common defect. PMID- 25695634 TI - Genetic diversity and population structure of Trypanosoma brucei in Uganda: implications for the epidemiology of sleeping sickness and Nagana. AB - BACKGROUND: While Human African Trypanosomiasis (HAT) is in decline on the continent of Africa, the disease still remains a major health problem in Uganda. There are recurrent sporadic outbreaks in the traditionally endemic areas in south-east Uganda, and continued spread to new unaffected areas in central Uganda. We evaluated the evolutionary dynamics underpinning the origin of new foci and the impact of host species on parasite genetic diversity in Uganda. We genotyped 269 Trypanosoma brucei isolates collected from different regions in Uganda and southwestern Kenya at 17 microsatellite loci, and checked for the presence of the SRA gene that confers human infectivity to T. b. rhodesiense. RESULTS: Both Bayesian clustering methods and Discriminant Analysis of Principal Components partition Trypanosoma brucei isolates obtained from Uganda and southwestern Kenya into three distinct genetic clusters. Clusters 1 and 3 include isolates from central and southern Uganda, while cluster 2 contains mostly isolates from southwestern Kenya. These three clusters are not sorted by subspecies designation (T. b. brucei vs T. b. rhodesiense), host or date of collection. The analyses also show evidence of genetic admixture among the three genetic clusters and long-range dispersal, suggesting recent and possibly on going gene flow between them. CONCLUSIONS: Our results show that the expansion of the disease to the new foci in central Uganda occurred from the northward spread of T. b. rhodesiense (Tbr). They also confirm the emergence of the human infective strains (Tbr) from non-infective T. b. brucei (Tbb) strains of different genetic backgrounds, and the importance of cattle as Tbr reservoir, as confounders that shape the epidemiology of sleeping sickness in the region. PMID- 25695636 TI - Pathogenic chytrid fungus Batrachochytrium dendrobatidis, but not B. salamandrivorans, detected on eastern hellbenders. AB - Recent worldwide declines and extinctions of amphibian populations have been attributed to chytridiomycosis, a disease caused by the pathogenic fungus Batrachochytrium dendrobatidis (Bd). Until recently, Bd was thought to be the only Batrachochytrium species that infects amphibians; however a newly described species, Batrachochytrium salamandrivorans (Bs), is linked to die-offs in European fire salamanders (Salamandra salamandra). Little is known about the distribution, host range, or origin of Bs. In this study, we surveyed populations of an aquatic salamander that is declining in the United States, the eastern hellbender (Cryptobranchus alleganiensis alleganiensis), for the presence of Bs and Bd. Skin swabs were collected from a total of 91 individuals in New York, Pennsylvania, Ohio, and Virginia, and tested for both pathogens using duplex qPCR. Bs was not detected in any samples, suggesting it was not present in these hellbender populations (0% prevalence, 95% confidence intervals of 0.0-0.04). Bd was found on 22 hellbenders (24% prevalence, 95% confidence intervals of 0.16 <= 0.24 <= 0.34), representing all four states. All positive samples had low loads of Bd zoospores (12.7 +/- 4.9 S.E.M. genome equivalents) compared to other Bd susceptible species. More research is needed to determine the impact of Batrachochytrium infection on hellbender fitness and population viability. In particular, understanding how hellbenders limit Bd infection intensity in an aquatic environment may yield important insights for amphibian conservation. This study is among the first to evaluate the distribution of Bs in the United States, and is consistent with another, which failed to detect Bs in the U.S. Knowledge about the distribution, host-range, and origin of Bs may help control the spread of this pathogen, especially to regions of high salamander diversity, such as the eastern United States. PMID- 25695638 TI - Origin of band gaps in graphene on hexagonal boron nitride. AB - Recent progress in preparing well-controlled two-dimensional van der Waals heterojunctions has opened up a new frontier in materials physics. Here we address the intriguing energy gaps that are sometimes observed when a graphene sheet is placed on a hexagonal boron nitride substrate, demonstrating that they are produced by an interesting interplay between structural and electronic properties, including electronic many-body exchange interactions. Our theory is able to explain the observed gap behaviour by accounting first for the structural relaxation of graphene's carbon atoms when placed on a boron nitride substrate, and then for the influence of the substrate on low-energy pi-electrons located at relaxed carbon atom sites. The methods we employ can be applied to many other van der Waals heterojunctions. PMID- 25695637 TI - Ribosomes slide on lysine-encoding homopolymeric A stretches. AB - Protein output from synonymous codons is thought to be equivalent if appropriate tRNAs are sufficiently abundant. Here we show that mRNAs encoding iterated lysine codons, AAA or AAG, differentially impact protein synthesis: insertion of iterated AAA codons into an ORF diminishes protein expression more than insertion of synonymous AAG codons. Kinetic studies in E. coli reveal that differential protein production results from pausing on consecutive AAA-lysines followed by ribosome sliding on homopolymeric A sequence. Translation in a cell-free expression system demonstrates that diminished output from AAA-codon-containing reporters results from premature translation termination on out of frame stop codons following ribosome sliding. In eukaryotes, these premature termination events target the mRNAs for Nonsense-Mediated-Decay (NMD). The finding that ribosomes slide on homopolymeric A sequences explains bioinformatic analyses indicating that consecutive AAA codons are under-represented in gene-coding sequences. Ribosome 'sliding' represents an unexpected type of ribosome movement possible during translation. PMID- 25695639 TI - Atropine vs Patching-Reply. PMID- 25695640 TI - Mitochondrial DNA sequence analyses and phylogenetic relationships among two Nigerian goat breeds and the South African Kalahari Red. AB - The first hypervariable (HV1) region of mitochondrial DNA (mtDNA) of two popular Nigerian goat breeds: West African Dwarf (WAD) (n=35) and Red Sokoto (RS) (n=37) and one exotic breed: Kalahari Red (KR) (n=38) imported from South Africa were sequenced to investigate sequence diversity, genetic structure, origin, and demographic history of the populations. A total of 68 polymorphic sites were found in 110 sequences that grouped into 68 haplotypes. Average haplotype and nucleotide diversities for all breeds were 0.982+/-0.005 and 0.02350+/-0.00213, respectively. Phylogenetic analysis revealed two mtDNA lineages (A and B). Lineage A was predominant and included all haplotypes from WAD and RS and 5 out of 11 haplotypes of KR goats. The remaining haplotypes (6) of KR belong to lineage B. The analysis of molecular variance revealed a high-within breed genetic variance of 82.4% and a low-between breed genetic variance of 17.6%. The three breeds clustered with Capra aegagrus as their wild ancestor. Mismatch distribution analysis showed that WAD, RS and haplogroup A have experienced population expansion events. The study has revealed very high diversity within the three breeds which are not strongly separated from each other based on mtDNA analysis. The information obtained on the genetic structure of the breeds will be useful in planning improvement and conservation programs for the local populations. PMID- 25695641 TI - Regulation of IGFBP-2 expression during fasting. AB - Insulin-like growth factor (IGF)-binding protein-2 (IGFBP-2), one of the most abundant circulating IGFBPs, is known to attenuate the biological action of IGF 1. Although the effect of IGFBP-2 in preventing metabolic disorders is well known, its regulatory mechanism remains unclear. In the present study, we demonstrated the transcriptional regulation of the Igfbp-2 gene by peroxisome proliferator-activated receptor (PPAR) alpha in the liver. During fasting, both Igfbp-2 and PPARalpha expression levels were increased. Wy14643, a selective PPARalpha agonist, significantly induced Igfbp-2 gene expression in primary cultured hepatocytes. However, Igfbp-2 gene expression in Pparalpha null mice was not affected by fasting or Wy14643. In addition, through transient transfection and chromatin immunoprecipitation assay in fasted livers, we determined that PPARalpha bound to the putative PPAR-responsive element between -511 bp and -499 bp on the Igfbp-2 gene promoter, indicating that the Igfbp-2 gene transcription is activated directly by PPARalpha. To explore the role of PPARalpha in IGF-1 signalling, we treated primary cultured hepatocytes with Wy14643 and observed a decrease in the number of IGF-1 receptors (IGF-1Rs) and in Akt phosphorylation. No inhibition was observed in the hepatocytes isolated from Pparalpha null mice. These results suggest that PPARalpha controls IGF-1 signalling through the up regulation of hepatic Igfbp-2 transcription during fasting and Wy14643 treatment. PMID- 25695642 TI - Stable maintenance of de novo assembled human artificial chromosomes in embryonic stem cells and their differentiated progeny in mice. AB - De novo assembled alphoid(tetO)-type human artificial chromosomes (HACs) represent a novel promising generation of high capacity episomal vectors. Their function and persistence, and any adverse effects, in various cell types in live animals, have not, however, been explored. In this study we transferred the alphoid(tetO)-HAC into mouse ES cells and assessed whether the presence of this extra chromosome affects their pluripotent properties. Alphoid(tetO)-HAC-bearing ES cells were indistinguishable from their wild-type counterparts: they retained self-renewal potential and full capacity for multilineage differentiation during mouse development, whereas the HAC itself was mitotically and transcriptionally stable during this process. Our data provide the first example of fully synthetic DNA behaving like a normal chromosome in cells of living animals. It also opens a new perspective into functional genetic studies in laboratory animals as well as stem cell-based regenerative medicine. PMID- 25695643 TI - Occlusal caries extension in relation to visual and radiographic diagnostic criteria: results from a microcomputed tomography study. AB - OBJECTIVE: This in vitro study aimed to evaluate occlusal caries extension in relation to visual and radiographic diagnostic criteria and their clinical value to indicate operative or preventive dental care. METHODS: A total of 196 third molars with clinically sound occlusal fissures or noncavitated lesions were collected. Before microcomputed tomography (MUCT) investigation, each tooth was examined visually and radiographically. Kuhnisch's MUCT-based caries-extension index (CE index) was used to determine the caries depth on a numeric scale (0 = sound; 0.01-0.99 = enamel caries; 1.0-1.99 = dentin caries). Sensitivities (SEs), specificities (SPs), and area under the receiver operating characteristic curve (Az value) were also calculated. RESULTS: Based on MUCT data, the following mean CE index values and standard deviations (SDs) were documented according to the visual criteria: sound = 0.6 (0.4); first visible signs = 0.9 (0.4); established lesions = 1.3 (0.3); microcavities = 1.4 (0.2); dentin exposure = 1.5 (0.2); and large cavities = 1.5 (0.3). The radiographic categories according to Marthaler (enamel caries [D0-2], caries in the outer half of dentin [D3], and caries in the inner half of dentin [D4]) were related to CE index values of 0.9 (0.4), 1.4 (0.2) and 1.6 (0.4), respectively. Caries detected visually or radiographically showed an SE of 84% and an SP of 85% (Az = 0.85). When both methods were used to predict dentin involvement simultaneously, SE = 27%, SP = 100%, and Az = 0.63; this combined visual and radiographic approach was associated with a perfect specificity and no false-negative decisions. The proportion of false-positive diagnoses was moderately high, and lesion extension in these cases was mainly limited to the outer 20% of the dentin. CONCLUSIONS: Our results might be useful for differentiating between preventive and operative dental care for pits and fissures. PMID- 25695644 TI - Neural basis of decision making guided by emotional outcomes. AB - Emotional events resulting from a choice influence an individual's subsequent decision making. Although the relationship between emotion and decision making has been widely discussed, previous studies have mainly investigated decision outcomes that can easily be mapped to reward and punishment, including monetary gain/loss, gustatory stimuli, and pain. These studies regard emotion as a modulator of decision making that can be made rationally in the absence of emotions. In our daily lives, however, we often encounter various emotional events that affect decisions by themselves, and mapping the events to a reward or punishment is often not straightforward. In this study, we investigated the neural substrates of how such emotional decision outcomes affect subsequent decision making. By using functional magnetic resonance imaging (fMRI), we measured brain activities of humans during a stochastic decision-making task in which various emotional pictures were presented as decision outcomes. We found that pleasant pictures differentially activated the midbrain, fusiform gyrus, and parahippocampal gyrus, whereas unpleasant pictures differentially activated the ventral striatum, compared with neutral pictures. We assumed that the emotional decision outcomes affect the subsequent decision by updating the value of the options, a process modeled by reinforcement learning models, and that the brain regions representing the prediction error that drives the reinforcement learning are involved in guiding subsequent decisions. We found that some regions of the striatum and the insula were separately correlated with the prediction error for either pleasant pictures or unpleasant pictures, whereas the precuneus was correlated with prediction errors for both pleasant and unpleasant pictures. PMID- 25695645 TI - Infraslow EEG activity modulates cortical excitability in postanoxic encephalopathy. AB - Infraslow activity represents an important component of physiological and pathological brain function. We study infraslow activity (<0.1 Hz) in 41 patients with postanoxic coma after cardiac arrest, including the relationship between infraslow activity and EEG power in the 3-30 Hz range, using continuous full-band scalp EEG. In all patients, infraslow activity (0.015-0.06 Hz) was present, irrespective of neurological outcome or EEG activity in the conventional frequency bands. In two patients, low-amplitude (10-30 MUV) infraslow activity was present while the EEG showed no rhythmic activity above 0.5 Hz. In 13/15 patients with a good outcome and 20/26 patients with a poor one, EEG power in the 3-30 Hz frequency range was correlated with the phase of infraslow activity, quantified by the modulation index. In 9/14 patients with burst-suppression with identical bursts, bursts appeared in clusters, phase-locked to the infraslow oscillations. This is substantiated by a simulation of burst-suppression in a minimal computational model. Infraslow activity is preserved in postanoxic encephalopathy and modulates cortical excitability. The strongest modulation is observed in patients with severe postanoxic encephalopathy and burst-suppression with identical bursts. PMID- 25695646 TI - Radiofrequency signal affects alpha band in resting electroencephalogram. AB - The aim of the present work was to investigate the effects of the radiofrequency (RF) electromagnetic fields (EMFs) on human resting EEG with a control of some parameters that are known to affect alpha band, such as electrode impedance, salivary cortisol, and caffeine. Eyes-open and eyes-closed resting EEG data were recorded in 26 healthy young subjects under two conditions: sham exposure and real exposure in double-blind, counterbalanced, crossover design. Spectral power of EEG rhythms was calculated for the alpha band (8-12 Hz). Saliva samples were collected before and after the study. Salivary cortisol and caffeine were assessed by ELISA and HPLC, respectively. The electrode impedance was recorded at the beginning of each run. Compared with the sham session, the exposure session showed a statistically significant (P < 0.0001) decrease of the alpha band spectral power during closed-eyes condition. This effect persisted in the postexposure session (P < 0.0001). No significant changes were detected in electrode impedance, salivary cortisol, and caffeine in the sham session compared with the exposure one. These results suggest that GSM-EMFs of a mobile phone affect the alpha band within spectral power of resting human EEG. PMID- 25695647 TI - Decoding thalamic afferent input using microcircuit spiking activity. AB - A behavioral response appropriate to a sensory stimulus depends on the collective activity of thousands of interconnected neurons. The majority of cortical connections arise from neighboring neurons, and thus understanding the cortical code requires characterizing information representation at the scale of the cortical microcircuit. Using two-photon calcium imaging, we densely sampled the thalamically evoked response of hundreds of neurons spanning multiple layers and columns in thalamocortical slices of mouse somatosensory cortex. We then used a biologically plausible decoder to characterize the representation of two distinct thalamic inputs, at the level of the microcircuit, to reveal those aspects of the activity pattern that are likely relevant to downstream neurons. Our data suggest a sparse code, distributed across lamina, in which a small population of cells carries stimulus-relevant information. Furthermore, we find that, within this subset of neurons, decoder performance improves when noise correlations are taken into account. PMID- 25695648 TI - Electrophysiological biomarkers of neuromodulatory strategies to recover motor function after spinal cord injury. AB - The spinal cord contains the circuitry to control posture and locomotion after complete paralysis, and this circuitry can be enabled with epidural stimulation [electrical enabling motor control (eEmc)] and/or administration of pharmacological agents [pharmacological enabling motor control (fEmc)] when combined with motor training. We hypothesized that the characteristics of the spinally evoked potentials after chronic administration of both strychnine and quipazine under the influence of eEmc during standing and stepping can be used as biomarkers to predict successful motor performance. To test this hypothesis we trained rats to step bipedally for 7 wk after paralysis and characterized the motor potentials evoked in the soleus and tibialis anterior (TA) muscles with the rats in a non-weight-bearing position, standing and stepping. The middle responses (MRs) to spinally evoked stimuli were suppressed with either or both drugs when the rat was suspended, whereas the addition of either or both drugs resulted in an overall activation of the extensor muscles during stepping and/or standing and reduced the drag duration and cocontraction between the TA and soleus muscles during stepping. The administration of quipazine and strychnine in concert with eEmc and step training after injury resulted in larger-amplitude evoked potentials [MRs and late responses (LRs)] in flexors and extensors, with the LRs consisting of a more normal bursting pattern, i.e., randomly generated action potentials within the bursts. This pattern was linked to more successful standing and stepping. Thus it appears that selected features of the patterns of potentials evoked in specific muscles with stimulation can serve as effective biomarkers and predictors of motor performance. PMID- 25695649 TI - Delineation of a frequency-organized region isolated from the mouse primary auditory cortex. AB - The primary auditory cortex (AI) is the representative recipient of information from the ears in the mammalian cortex. However, the delineation of the AI is still controversial in a mouse. Recently, it was reported, using optical imaging, that two distinct areas of the AI, located ventrally and dorsally, are activated by high-frequency tones, whereas only one area is activated by low-frequency tones. Here, we show that the dorsal high-frequency area is an independent region that is separated from the rest of the AI. We could visualize the two distinct high-frequency areas using flavoprotein fluorescence imaging, as reported previously. SMI-32 immunolabeling revealed that the dorsal region had a different cytoarchitectural pattern from the rest of the AI. Specifically, the ratio of SMI 32-positive pyramidal neurons to nonpyramidal neurons was larger in the dorsal high-frequency area than the rest of the AI. We named this new region the dorsomedial field (DM). Retrograde tracing showed that neurons projecting to the DM were localized in the rostral part of the ventral division of the medial geniculate body with a distinct frequency organization, where few neurons projected to the AI. Furthermore, the responses of the DM to ultrasonic courtship songs presented by males were significantly greater in females than in males; in contrast, there was no sex difference in response to artificial pure tones. Our findings offer a basic outline on the processing of ultrasonic vocal information on the basis of the precisely subdivided, multiple frequency-organized auditory cortex map in mice. PMID- 25695650 TI - Hyperactivity in the medial olivocochlear efferent system is a common feature of tinnitus and hyperacusis in humans. AB - Tinnitus and hyperacusis are common, burdensome sources of morbidity with a high rate of co-occurrence. Knudson et al. (J Neurophysiol 112: 3197-3208, 2014) demonstrated that efferent suppression of cochlear activity by the medial olivocochlear system is enhanced in individuals with tinnitus and/or hyperacusis. Their findings stress that atypical activity in the efferent auditory pathway may represent a shared substrate, as well as a potential therapeutic target, in tinnitus and hyperacusis. PMID- 25695651 TI - Adaptations of motoneuron properties to chronic compensatory muscle overload. AB - The aim of the study was to determine whether chronic muscle overload has measurable effect on electrophysiological properties of motoneurons (MNs), and whether duration of this overload influences intensity of adaptations. The compensatory overload was induced in the rat medial gastrocnemius (MG) by bilateral tenotomy of its synergists (lateral gastrocnemius, soleus, and plantaris); as a result, only the MG was able to evoke the foot plantar flexion. To assure regular activation of the MG muscle, rats were placed in wheel-equipped cages and subjected to a low-level treadmill exercise. The intracellular recordings from MG motoneurons were made after 5 or 12 wk of the overload, and in a control group of intact rats. Some of the passive and threshold membrane properties as well as rhythmic firing properties were considerably modified in fast-type MNs, while remaining unaltered in slow-type MNs. The significant changes included a shortening of the spike duration and the spike rise time, an increase of the afterhyperpolarization amplitude, an increase of the input resistance, a decrease of the rheobase, and a decrease of the minimum current necessary to evoke steady-state firing. The data suggest higher excitability of fast-type MNs innervating the overloaded muscle, and a shift towards electrophysiological properties of slow-type MNs. All of the adaptations could be observed after 5 wk of the compensatory overload with no further changes occurring after 12 wk. This indicates that the response to an increased level of chronic activation of MNs is relatively quick and stable. PMID- 25695652 TI - Repetitive mild traumatic brain injury induces ventriculomegaly and cortical thinning in juvenile rats. AB - Traumatic brain injury (TBI) most frequently occurs in pediatric patients and remains a leading cause of childhood death and disability. Mild TBI (mTBI) accounts for nearly 75% of all TBI cases, yet its neuropathophysiology is still poorly understood. While even a single mTBI injury can lead to persistent deficits, repeat injuries increase the severity and duration of both acute symptoms and long-term deficits. In this study, to model pediatric repetitive mTBI (rmTBI) we subjected unrestrained juvenile animals (postnatal day 20) to repeat weight-drop impacts. Animals were anesthetized and subjected to sham injury or rmTBI once per day for 5 days. Magnetic resonance imaging (MRI) performed 14 days after injury revealed marked cortical atrophy and ventriculomegaly in rmTBI animals. Specifically, beneath the impact zone the thickness of the cortex was reduced by up to 46% and the area of the ventricles increased by up to 970%. Immunostaining with the neuron-specific marker NeuN revealed an overall loss of neurons within the motor cortex but no change in neuronal density. Examination of intrinsic and synaptic properties of layer II/III pyramidal neurons revealed no significant difference between sham-injured and rmTBI animals at rest or under convulsant challenge with the potassium channel blocker 4-aminopyridine. Overall, our findings indicate that the neuropathological changes reported after pediatric rmTBI can be effectively modeled by repeat weight drop in juvenile animals. Developing a better understanding of how rmTBI alters the pediatric brain may help improve patient care and direct "return to game" decision making in adolescents. PMID- 25695653 TI - A comprehensive assessment of genioglossus electromyographic activity in healthy adults. AB - The genioglossus (GG) is an extrinsic muscle of the human tongue that plays a critical role in preserving airway patency. In the last quarter century, >50 studies have reported on respiratory-related GG electromyographic (EMG) activity in human subjects. Remarkably, of the studies performed, none have duplicated subject body position, electrode recording locations, and/or breathing task(s), making interpretation and integration of the results across studies extremely challenging. In addition, more recent research assessing lingual anatomy and muscle contractile properties has identified regional differences in muscle fiber type and myosin heavy chain expression, giving rise to the possibility that the anterior and posterior regions of the muscle fulfill distinct functions. Here, we assessed EMG activity in anterior and posterior regions of the GG, across upright and supine, in rest breathing and in volitionally modulated breathing tasks. We tested the hypotheses that GG EMG is greater in the posterior region and in supine, except when breathing is subject to volitional modulation. Our results show differences in the magnitude of EMG (%regional maximum) between anterior and posterior muscle regions (7.95 +/- 0.57 vs. 11.10 +/- 0.99, respectively; P < 0.001), and between upright and supine (8.63 +/- 0.73 vs. 10.42 +/- 0.90, respectively; P = 0.008). Although the nature of a task affects the magnitude of EMG (P < 0.001), the effect is similar for anterior and posterior muscle regions and across upright and supine (P > 0.2). PMID- 25695654 TI - Modulation of intracranial meningeal nociceptor activity by cortical spreading depression: a reassessment. AB - Cortical spreading depression (CSD), a putative migraine trigger, has been shown recently to promote multiple activation patterns of meningeal nociceptors. In the current study we used a modified experimental approach in a rat model to: 1) reassess the responses of meningeal nociceptors following a single CSD episode, 2) examine factors that may influence the propensity of meningeal nociceptors to develop a prolonged activation following a CSD, and 3) test the responses of meningeal nociceptors following multiple CSDs. A single CSD episode promoted persistent activation in about 50% of the nociceptors tested, similar to our previous report. Only two patterns of prolonged nociceptor activation were observed: biphasic activation and one with a delayed onset. Adelta units had shorter mean onset latency for the prolonged activation than C units. The prolonged activation onset latency was inversely correlated with the number of the nociceptors' receptive fields. The propensity to develop the prolonged activation following CSD was related to the presence of basal ongoing activity, but neither to the emergence of brief activation during the CSD phase nor to the nociceptors' responsiveness to inflammatory mediators or ATP. Finally, multiple CSDs did not promote a heightened nociceptive response compared with a single CSD. The present study confirms the ability of a single CSD to elicit persistent activation of meningeal nociceptors. CSD-evoked prolonged nociceptive responses may not be related to the inflammatory and ATP chemosensitivity of the neurons but rather to other neuronal properties, such as basal ongoing activity and number of receptive fields. PMID- 25695655 TI - Diverse cortical codes for scene segmentation in primate auditory cortex. AB - The temporal coherence of amplitude fluctuations is a critical cue for segmentation of complex auditory scenes. The auditory system must accurately demarcate the onsets and offsets of acoustic signals. We explored how and how well the timing of onsets and offsets of gated tones are encoded by auditory cortical neurons in awake rhesus macaques. Temporal features of this representation were isolated by presenting otherwise identical pure tones of differing durations. Cortical response patterns were diverse, including selective encoding of onset and offset transients, tonic firing, and sustained suppression. Spike train classification methods revealed that many neurons robustly encoded tone duration despite substantial diversity in the encoding process. Excellent discrimination performance was achieved by neurons whose responses were primarily phasic at tone offset and by those that responded robustly while the tone persisted. Although diverse cortical response patterns converged on effective duration discrimination, this diversity significantly constrained the utility of decoding models referenced to a spiking pattern averaged across all responses or averaged within the same response category. Using maximum likelihood-based decoding models, we demonstrated that the spike train recorded in a single trial could support direct estimation of stimulus onset and offset. Comparisons between different decoding models established the substantial contribution of bursts of activity at sound onset and offset to demarcating the temporal boundaries of gated tones. Our results indicate that relatively few neurons suffice to provide temporally precise estimates of such auditory "edges," particularly for models that assume and exploit the heterogeneity of neural responses in awake cortex. PMID- 25695656 TI - Isoflurane abolishes spontaneous firing of serotonin neurons and masks their pH/CO2 chemosensitivity. AB - Serotonin (5-hydroxytryptamine, 5-HT) neurons from the mouse and rat rostral medulla are stimulated by increased CO2 when studied in culture or brain slices. However, the response of 5-HT neurons has been variable when animals are exposed to hypercapnia in vivo. Here we examined whether halogenated inhalational anesthetics, which activate TWIK-related acid-sensitive K(+) (TASK) channels, could mask an effect of CO2 on 5-HT neurons. During in vivo plethysmography in mice, isoflurane (1%) markedly reduced the hypercapnic ventilatory response (HCVR) by 78-96% depending upon mouse strain and ambient temperature. In a perfused rat brain stem preparation, isoflurane (1%) reduced or silenced spontaneous firing of medullary 5-HT neurons in situ and abolished their responses to elevated perfusate Pco2. In dissociated cell cultures, isoflurane (1%) hyperpolarized 5-HT neurons by 6.52 +/- 3.94 mV and inhibited spontaneous firing. A subsequent decrease in pH from 7.4 to 7.2 depolarized neurons by 4.07 +/- 2.10 mV, but that was insufficient to reach threshold for firing. Depolarizing current restored baseline firing and the firing frequency response to acidosis, indicating that isoflurane did not block the underlying mechanisms mediating chemosensitivity. These results demonstrate that isoflurane masks 5-HT neuron chemosensitivity in vitro and in situ and markedly decreases the HCVR in vivo. The use of this class of anesthetic has a particularly potent inhibitory effect on chemosensitivity of 5-HT neurons. PMID- 25695657 TI - Evaluation of humoral, mucosal, and cellular immune responses following co immunization of HIV-1 Gag and Env proteins expressed by Newcastle disease virus. AB - The combination of multiple HIV antigens in a vaccine can broaden antiviral immune responses. In this study, we used NDV vaccine strain LaSota to generate rNDV (rLaSota/optGag) expressing human codon optimized p55 Gag protein of HIV-1. We examined the effect of co-immunization of rLaSota/optGag with rNDVs expressing different forms of Env protein gp160, gp120, gp140L [a version of gp140 that lacked cytoplasmic tail and contained complete membrane-proximal external region (MPER)] and gp140S (a version of gp140 that lacked cytoplasmic tail and distal half of MPER) on magnitude and breadth of humoral, mucosal and cellular immune responses in guinea pigs and mice. Our results showed that inclusion of rLaSota/optGag with rNDVs expressing different forms of Env HIV Gag did not affect the Env-specific humoral and mucosal immune responses in guinea pigs and that the potent immune responses generated against Env persisted for at least 13 weeks post immunization. The highest Env-specific humoral and mucosal immune responses were observed with gp140S+optGag group. The neutralizing antibody responses against HIV strains BaL.26 and MN.3 induced by gp140S+optGag and gp160+optGag were higher than those elicited by other groups. Inclusion of Gag with gp160, gp140S and gp140L enhanced the level of Env-specific IFN-gamma producing CD8(+) T cells in mice. Inclusion of Gag with gp160 and gp140L also resulted in increased Env-specific CD4(+) T cells. The level of Gag-specific CD8(+) and CD4(+) T cells was also enhanced in mice immunized with Gag along with gp140S and gp120. These results indicate lack of antigen interference in a vaccine containing rNDVs expressing Env and Gag proteins. PMID- 25695658 TI - FZD2 inhibits the cell growth and migration of salivary adenoid cystic carcinomas. AB - Several studies have reported that FZD2 regulates tumor biology in a complex manner. The aim of the present study was to identify the role of FZD2 in the cell growth and metastasis of salivary adenoid cystic carcinomas (SACCs). The expression of FZD2 in ACC-83 and ACC-LM cells were measured with real-time PCR. Immunohistochemical staining was used to detect the expression of FZD2 in clinical SACC samples with or without metastasis. Cell proliferation and Transwell assays were performed to explore the effects of FZD2 on cell growth and migration following the silencing of FZD2 with small interference RNAs and the overexpression of FZD2 with plasmid. Our data showed that FZD2 was downregulated in ACC-LM cells, which are an adenoid cystic carcinoma cell line with high metastatic potential, compared to ACC-83 cells, which have low metastatic potential. Additionally, the expression of FZD2 was lower in SACC tissues with metastasis compared to SACC tissues without metastasis (P<0.05). Cell proliferation and migration of ACC-83 cells were increased after the knockdown of FZD2 and decreased following overexpression of FZD2. Knockdown of FZD2 downregulated the expression of PAI-1. Our results suggest that FZD2 may be a tumor suppressor gene in SACCs that inhibits cell growth and migration. PMID- 25695659 TI - Gender Differences in the Social Cost of Affective Deviance. AB - The current study tested whether men and women receive different degrees of social punishment for violating norms of emotional expression. Participants watched videos of male and female targets (whose reactions were pre-tested to be equivalent in expressivity and valence) viewing either a positive or negative slideshow, with their emotional reaction to the slideshow manipulated to be affectively congruent, affectively incongruent, or flat. Participants then rated the target on a number of social evaluation measures. Displaying an incongruent emotional expression, relative to a congruent one, harmed judgments of women more than men. Women are expected to be more emotionally expressive than men, making an incongruent expression more deviant for women. These results highlight the importance of social norms in construing another person's emotion displays, which can subsequently determine acceptance or rejection of that person. PMID- 25695660 TI - Correction: Thymosin beta 4 protects mice from monocrotaline-induced pulmonary hypertension and right ventricular hypertrophy. AB - [This corrects the article DOI: 10.1371/journal.pone.0110598.]. PMID- 25695661 TI - Conjugation of iron oxide nanoparticles with RGD-modified dendrimers for targeted tumor MR imaging. AB - This article reports a new approach for the synthesis of ultrasmall iron oxide nanoparticles (NPs) conjugated with Arg-Gly-Asp (RGD)-modified dendrimers (G5.NHAc-RGD-Fe3O4 NPs) as a platform for targeted magnetic resonance (MR) imaging of C6 glioma cells. Ultrasmall Fe3O4 NPs synthesized via a solvothermal route were conjugated with RGD peptide-modified generation-5 poly(amidoamine) dendrimers (G5.NH2-RGD). The final G5.NHAc-RGD-Fe3O4 NPs were formed following the acetylation of the remaining dendrimer terminal amines. The as-prepared multifunctional Fe3O4 NPs were characterized using various techniques. The results of a cell viability assay, cell morphological observation, and hemolysis assay indicated that the G5.NHAc-RGD-Fe3O4 NPs exhibit excellent cytocompatibility and hemocompatibility over the studied concentration range. In addition, RGD conjugated onto the Fe3O4 NPs allows for the efficient targeting of the particles to C6 cells that overexpress alphavbeta3 receptors, which was confirmed via in vitro cell MR imaging and cellular uptake. Finally, the G5.NHAc RGD-Fe3O4 NPs were used in the targeted MR imaging of C6 glioma cells in mice. The results obtained from the current study indicate that the developed G5.NHAc RGD-Fe3O4 NPs offer significant potential for use as contrast agents in the targeted MR imaging of different types of tumors. PMID- 25695662 TI - Assessment of zoonotic transmission of Giardia and Cryptosporidium between cattle and humans in rural villages in Bangladesh. AB - Giardia and Cryptosporidium are important causes of diarrhoea in Bangladesh. The high prevalence of both parasites in humans and cattle in rural Bangladesh and the common use of water ponds by village inhabitants and their animals suggest a potential for zoonotic transmission. Direct transmission of Giardia and Cryptosporidium between cattle and their handlers and indirect transmission through water ponds was investigated. Faecal/stool samples were collected from 623 calves and 125 calf handlers in a cross-sectional survey. In two villages, water samples were collected monthly from water ponds and faecal/stool samples were collected monthly from inhabitants and their cattle. Giardia cysts and Cryptosporidium oocysts were detected in water samples and in faecal/stool samples and positive samples were genotyped, to determine their human or animal origin. The prevalence of Giardia and Cryptosporidium in calves was 22% and 5% respectively. In calf handlers, the prevalence of Giardia and Cryptosporidium was 11.2% and 3.2% respectively. Both in the cross-sectional survey and in the longitudinal study in the villages, G. duodenalis assemblage E was most prevalent in calves, while in humans assemblage AII, BIII and BIV were found. In cattle, Cryptosporidium parvum, C. bovis and C. andersoni were identified, but no Cryptosporidium sequences were obtained from humans. Giardia and Cryptosporidium were detected in 14/24 and 12/24 water samples respectively. G. duodenalis assemblage E and BIV (-like), as well as C. andersoni and C. hominis were identified. Although the presence of Giardia and Cryptosporidium in both water ponds suggests that water-borne transmission of Giardia and Cryptosporidium is possible, the genotyping results indicate that there is no significant direct or indirect (water-borne) transmission of Giardia between cattle and people in this area of rural Bangladesh. No conclusions could be drawn for Cryptosporidium, because of the low number of sequences that were obtained from human and water samples. PMID- 25695663 TI - Transstadial transmission of Borrelia turcica in Hyalomma aegyptium ticks. AB - Borrelia turcica comprises the third major group of arthropod-transmitted borreliae and is phylogenetically divergent from other Borrelia groups. The novel group of Borrelia was initially isolated from Hyalomma aegyptium ticks in Turkey and it was recently found in blood and multiple organs of tortoises exported from Jordan to Japan. However, the ecology of these spirochetes and their development in ticks or the vertebrate hosts were not investigated in detail; our aims were to isolate the pathogen and to evaluate the possibility of transstadial transmission of Borrelia turcica by H. aegyptium ticks. Ticks were collected from Testudo graeca tortoises during the summer of 2013 from southeastern Romania. Engorged nymphs were successfully molted to the adult stage. Alive B. turcica was isolated from molted ticks by using Barbour-Stoenner-Kelly (BSK) II medium. Four pure cultures of spirochetes were obtained and analyzed by PCR and sequencing. Sequence analysis of glpQ, gyrB and flaB revealed 98%-100% similarities with B. turcica. H. aegyptium ticks collected from T. graeca tortoises were able to pass the infection with B. turcica via transstadial route, suggesting its vectorial capacity. PMID- 25695664 TI - New duclauxamide from Penicillium manginii YIM PH30375 and structure revision of the duclauxin family. AB - Duclauxamide A1 (1), a new polyketide-derived heptacyclic oligophenalenone dimer with a N-2-hydroxyethyl moiety, was isolated from Penicillium manginii YIM PH30375. Spectroscopic analysis, X-ray single crystal diffraction, and (13)C NMR DFT calculations confirmed that compound 1 and other duclauxin analogues possess the unified S configuration at C-9', which corrects a long-standing misrepresentation of duclauxins as C-9'R epimers. A plausible biosynthetic pathway for duclauxins is proposed on the basis of previous acetate labeling results for duclauxin and sclerodin. PMID- 25695665 TI - Characteristics of tuberculosis cases that started outbreaks in the United States, 2002-2011. AB - A review of 26 tuberculosis outbreaks in the United States (2002-2011) showed that initial source case-patients had long infectious periods (median 10 months) and were characterized by substance abuse, incarceration, and homelessness. Improved timeliness of diagnosis and thorough contact investigations for such cases may reduce the risk for outbreaks. PMID- 25695666 TI - Mycobacterium bovis infection in humans and cats in same household, Texas, USA, 2012. AB - Mycobacterium bovis infection of cats is exceedingly rare in regions where bovine tuberculosis is not endemic. We describe the diagnosis and clinical management of pulmonary M. bovis infection in 2 indoor-housed cats and their association with at least 1 M. bovis-infected human in Texas, USA, in September 2012. PMID- 25695667 TI - Heterozygous deletion of ATG5 in Apc(Min/+) mice promotes intestinal adenoma growth and enhances the antitumor efficacy of interferon-gamma. AB - Autophagy related gene 5 (ATG5) was lost in 23% of the patients with colorectal cancer (CRC) and the role of loss of ATG5 in the pathogenesis of CRC remains unclear. Knockdown of ATG5 in cancer cells enhances the antitumor efficacy of lots of chemotherapeutic agents. However, there is still no animal model to validate these in vitro observations in vivo. In this study, we found that heterozygous deletion of ATG5 in Apc(Min/+) mice increased the number and size of adenomas as compared with those in Apc(Min/+)ATG5(+/+) mice. To investigate whether ATG5 deficiency could sensitize tumors to chemotherapies, we compared the antitumor effects of Interferon-gamma (IFN-gamma) between Apc(Min/+)ATG5(+/+) and Apc(Min/+)ATG5(+/-) mice, as IFN-gamma is a potential tumor suppressor for CRC and has been used clinically as an efficient adjuvant to chemotherapy of cancer. We revealed that heterozygous deletion of ATG5 significantly enhanced the antitumor efficacy of IFN-gamma. Early treatment of Apc(Min/+)ATG5(+/-) mice with IFN-gamma decreased tumor incidence rate to 16.7% and reduced the number of adenomas by 95.5% and late treatment led to regression of tumor. Moreover, IFN gamma treatment did not cause any evident toxic reaction. Mechanistic analysis revealed that heterozygous deletion of ATG5 activated EGFR/ERK1/2 and Wnt/beta catenin pathways in adenomas of Apc(Min/+) mice and enhanced the effects of IFN gamma-dependent inhibition of these 2 pathways. Our results demonstrate that ATG5 plays important roles in intestinal tumor growth and combination of IFN-gamma and ATG5 deficiency or ATG5-targeted inhibition is a promising strategy for prevention and treatment of CRC. PMID- 25695668 TI - Correlation of six-minute walking performance with quality of life is domain- and gender-specific in healthy older adults. AB - We analyzed the relationship between performance on the 6-min walk test (6MWT) and health-related quality of life (HRQoL) in older subjects. Our secondary aim was to determine the distance to be completed on the 6MWT for the subject to achieve a score of 50 on the Short Form (36) Health Survey (SF-36). Associations were tested using linear correlation and multivariate linear regression. Participants were 130 healthy older individuals. The predictive performance of the 6MWT based on an SF-36 score of 50 was assessed using a receiver operating characteristic curve and its area under curve (AUC). Associations were observed between physical functioning, role-emotional, social functioning, vitality, general health score, and 6MWT performance in women, after adjusting for confounding variables (coefficients: 0.57, 0.38, 0.40, and 0.46, respectively; p < 0.05). No association was found for men. The distance for the 6MWT to predict an SF-36 score of 50 was 481 m for men in the physical functioning (AUC: 0.79) and role-physical (AUC: 0.84) domains, and 420 m for women in role-emotional (AUC: 0.75), role-physical (AUC: 0.80), and general health (AUC: 0.80) domains. Our results indicate that superior 6MWT performance may be associated with better HRQoL in several domains in only healthy older women. No association between 6MWT performance and role-emotional, mental health, or vitality domains was found. We suggest that a score of 50 is represented by a 6MWT distance of 481 m for men and 420 m for women, at least in the role-physical domain. PMID- 25695670 TI - Discovery of a series of efficient, centrally efficacious BACE1 inhibitors through structure-based drug design. AB - The identification of centrally efficacious beta-secretase (BACE1) inhibitors for the treatment of Alzheimer's disease (AD) has historically been thwarted by an inability to maintain alignment of potency, brain availability, and desired absorption, distribution, metabolism, and excretion (ADME) properties. In this paper, we describe a series of truncated, fused thioamidines that are efficiently selective in garnering BACE1 activity without simultaneously inhibiting the closely related cathepsin D or negatively impacting brain penetration and ADME alignment, as exemplified by 36. Upon oral administration, these inhibitors exhibit robust brain availability and are efficacious in lowering central Amyloid beta (Abeta) levels in mouse and dog. In addition, chronic treatment in aged PS1/APP mice effects a decrease in the number and size of Abeta-derived plaques. Most importantly, evaluation of 36 in a 2-week exploratory toxicology study revealed no accumulation of autofluorescent material in retinal pigment epithelium or histology findings in the eye, issues observed with earlier BACE1 inhibitors. PMID- 25695671 TI - Magnetic resonance-based visualization of thermal ablative margins around hepatic tumors by means of systemic ferucarbotran administration before radiofrequency ablation: animal study to reveal the connection between excess iron deposition and T2*-weighted hypointensity in ablative margins. AB - OBJECTIVE: The objective of this study was to demonstrate experimentally that radiofrequency ablation (RFA) of ferucarbotran-accumulated healthy liver tissues causes excess iron deposition in the ablated liver tissues on postablation days and produces sustained T2*-weighted low signals indicative of ablative margins surrounding hepatic tumors. MATERIALS AND METHODS: We conducted 3 experiments using 30 rats. In experiment 1, we administered either ferucarbotran (n = 6) or saline (n = 4), acquired T2*-weighted images (T2*-WIs) of the liver by using a 3 T magnetic resonance scanner, and subsequently performed RFA of healthy liver lobes. We acquired follow-up T2*-WIs up to day 7 and histologically analyzed the liver specimens. In another 4 rats, we performed sham operation, instead of RFA, in ferucarbotran-accumulated liver lobes, followed by the same image acquisition and histological analysis. In experiment 2, we administered 59Fe-labeled ferucarbotran, subsequently performed either RFA (n = 4) or sham operation (n = 4) in the liver, and acquired autoradiograms of the liver specimens on day 7. In experiment 3, we conducted RFA treatment for 8 rats bearing orthotopic hepatic tumors after ferucarbotran administration and monitored tumor growth by using serial T2*-WIs. RESULTS: On days 4 and 7 of the experiment 1, T2*-WIs of 6 rats with systemic ferucarbotran administration and subsequent hepatic RFA showed low signal regions indicative of ablated liver tissues, whereas high-signal areas were seen in 4 saline-administered rats. Neither high nor low signal areas were detected in 4 sham-operated rats. Histologically, larger amounts of iron were observed in the RFA-induced necrotic liver tissues in the ferucarbotran administered rats than in the saline-administered-rats. The 59Fe autoradiography of the rats in experiment 2 revealed accumulation of ferucarbotran-derived iron in necrotic liver tissues. Among 6 hepatic tumors grown in 6 rats of the experiment 3, a total of 4 tumors were stable in size, but the other 2 increased markedly on day 7. Retrospectively, T2*-WIs showed the former tumor sites surrounded completely by low-signal areas on day 4. CONCLUSIONS: The RFA of ferucarbotran-accumulated healthy liver tissues in the rats caused excess iron deposition in the ablated liver tissues and produced sustained T2*-weighted hypointense regions. Similar hypointense regions surrounding hepatic tumors were indicative of ablative margins. PMID- 25695672 TI - Propofol Inhibits Lipopolysaccharide-Induced Inflammatory Responses in Spinal Astrocytes via the Toll-Like Receptor 4/MyD88-Dependent Nuclear Factor-kappaB, Extracellular Signal-Regulated Protein Kinases1/2, and p38 Mitogen-Activated Protein Kinase Pathways. AB - BACKGROUND: In this study, we investigated the effect of propofol, a commonly used IV anesthetic, on lipopolysaccharide (LPS)-induced inflammatory responses in astrocytes and explored the molecular mechanisms by which it occurs. METHODS: Astrocytes were stimulated with LPS (1.0 MUg/mL) in the absence and presence of different concentrations of propofol. The expression of astrocyte marker glial fibrillary acidic protein (GFAP) in astrocytes was detected using immunofluorescence staining and Western blot analysis. The levels of interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha were measured using an enzyme linked immunosorbent assay. The mRNA level of Toll-like receptor 4 (TLR4) was determined by semiquantitative reverse transcriptase-polymerase chain reaction. The protein expressions of TLR4, myeloid differentiation factor 88 (MyD88), p- extracellular signal-regulated protein kinases (ERK)1/2, p-c-Jun N-terminal kinase, p-p38 mitogen-activated protein kinase (MAPK), p-I-kappaBalpha, I kappaBalpha, and p-nuclear factor-kappaB (NF-kappaB)p65 were detected by Western blot. RESULTS: Our results show that after stimulation with LPS, the levels of IL 1beta, IL-6, and tumor necrosis factor-alpha and the expression of GFAP in astrocytes were up-regulated significantly. In addition, the expression of TLR4, MyD88, p-ERK1/2, p-c-Jun N-terminal kinase, p-p38 MAPK, and p-NF-kappaBp65 increased, whereas the expression of total I-kappaBalpha decreased upon stimulation with LPS. Propofol (10 MUM) reduced the secretion of proinflammatory cytokines, inhibited the expressions of GFAP, TLR4, MyD88, p-ERK1/2, p-p38 MAPK, and p-NF-kappaBp65 in astrocytes challenged with LPS. CONCLUSIONS: In the present study, propofol 10 MUM but not lower clinically relevant or higher supra-clinical concentrations attenuated LPS-induced astrocyte activation and subsequent inflammatory responses by inhibiting the TLR4/MyD88-dependent NF-kappaB, ERK1/2, and p38 MAPK pathways. PMID- 25695673 TI - Short-term glycemic control is effective in reducing surgical site infection in diabetic rats. AB - BACKGROUND: Patients and animals with diabetes exhibit enhanced vulnerability to bacterial surgical infections. Despite multiple retrospective studies demonstrating the benefits associated with glycemic control in reducing bacterial infection after cardiac surgery, there are fewer guidelines on the use of glycemic control for noncardiac surgeries. In the current study, we investigated whether long-term (begun 2 weeks before surgery) or immediate (just before surgery) glycemic controls, continued postoperatively, can reduce surgical site infection in type 1 diabetic-induced rats. METHODS: Rats were injected with streptozotocin to induce type 1 diabetes. Four groups of animals underwent surgery and thigh muscle Staphylococcus aureus bacteria challenge (1 * 10 colony forming units) at the time of surgery. Group 1 diabetic rats received insulin treatment just before surgery and continued until the end of study (short-term glycemic control group). Group 2 diabetic rats received insulin treatment 2 weeks before surgery and continued until the end of study (long-term glycemic control). Group 3 diabetic rats received no insulin treatment (no glycemic control group). Group 4 nondiabetic rats served as a healthy control group. Rats were euthanized at 3 or 6 days after surgery. Blood glucose and muscle bacterial burden were measured at 3 or 6 days after surgery. RESULTS: Glycemic control was achieved in both long- and short-term insulin-treated diabetic rats. Compared with untreated diabetic rats, the bacterial burden in muscle was significantly lower in both groups of glycemic controlled diabetic rats at 3 (all P < 0.003) and 6 (all P < 0.0001) days after surgery. CONCLUSIONS: A short-term glycemic control regimen, initiated just before surgery and bacterial exposure, was as effective in reducing surgical site infection as a long-term glycemic control in type 1 diabetic rats. These data suggest that immediately implementing glycemic control in type 1 diabetic surgical patients before undergoing noncardiac surgery may decrease the risk of infection. PMID- 25695674 TI - Needleless connectors substantially reduce flow of crystalloid and red blood cells during rapid infusion. AB - Although needleless connectors (NC) are frequently used in the perioperative setting, the potential of modern NCs to slow delivery of IV fluids has not been thoroughly studied. We examined flow characteristics of 5 NC models during pressurized delivery of crystalloid and banked red blood cells from a Level 1 warmer through various IV catheters. Crystalloid flow rates were reduced by 29% to 85% from control in catheters >18 gauge, while red blood cell flow reductions ranged from 22% to 76% in these catheters (all P < 0.0050). We suggest that practitioners consider eliminating NCs when large IV catheters are inserted for rapid fluid administration. PMID- 25695675 TI - EN3427: a novel cationic aminoindane with long-acting local anesthetic properties. AB - BACKGROUND: Currently approved local anesthetic drugs provide relatively brief local anesthesia that is appropriate and even desirable in some settings, but an extended duration of action beyond their capabilities would be a distinct benefit in other clinical situations. We implemented a drug discovery program that sought to identify novel local anesthetic molecules that specifically demonstrated a long-acting, preferential action on nociceptor sensory afferents that expressed transient receptor potential (TRP) channels. The hypothesis we tested was whether relatively membrane-impermeant local anesthetic molecules could confer long lasting anesthesia if neuronal access was facilitated by TRP channel activation. The current work describes in vivo studies on a lead molecule that emerged from the discovery program, EN3427, in several rodent pain models. METHODS: Studies were performed on male Sprague-Dawley rats using 2 models of acute mechanical paw pinch-evoked and pinprick-evoked nociceptive pain. Behavioral responses to noxious stimuli were assessed at baseline, that is, before any pharmacologic intervention, and at various timepoints after a single perisciatic or subcutaneous administration of either EN3427 alone or in combination with lidocaine. Paw withdrawal thresholds or cutaneous trunci reflexes were quantified, and pre-post drug values were compared statistically with analysis of variance followed by post hoc Dunnett multiple range test. RESULTS: A single perisciatic injection of lidocaine (2%) produced relief of paw-pinch-evoked pain that was significantly different from baseline through to the 1-hour timepoint (Dunnett multiplicity-adjusted P = 0.0081), as assessed using paw withdrawal or vocalization end points. EN3427 (0.2%), in the same model, produced a long lasting block, with pain thresholds being significantly above baseline through to the 18-hour timepoint (Dunnett multiplicity-adjusted P = 0.0002); the combination of EN3427 (0.2%) plus lidocaine (2%) produced even longer lasting analgesia, with pain thresholds being significantly above baseline through to the 24-hour timepoint (Dunnett multiplicity-adjusted P = 0.0073). Similar results were obtained with use of the pinprick approach. A single subcutaneous injection of lidocaine (2%) produced complete loss of sensation to cutaneous pinprick through 0.5 hours, but sensitivity thresholds were no different to baseline by the 1-hour timepoint, a similar injection of EN3427 alone (0.2%) produced a loss of sensation that was significantly different from baseline through the 8-hour timepoint (Dunnett multiplicity-adjusted P = 0.0045), and the combination of lidocaine (2%) plus EN3427 (0.2%) appeared to further enhance duration of analgesia, although this was significantly different from baseline only through the 10-hour timepoint (Dunnett multiplicity-adjusted P = 0.0048). Analgesic efficacy was dose related; using the combined injection approach, we found that increases in the dose of EN3427 with a fixed 2% lidocaine led to substantially extended analgesia and increasing doses of lidocaine combined with a fixed dose of EN3427 (0.2%) led to only modestly increased duration of action. CONCLUSIONS: The present studies demonstrate that a new molecular entity, EN3427, produces effective and long-lasting analgesia in 2 rodent pain models. The analgesic effects of EN3427 are significantly longer-lasting than lidocaine and are further extended when EN3427 is combined with lidocaine. The results are discussed with respect to a possible lidocaine-mediated TRP channel activation and facilitated neuronal access of EN3427, with subsequent entrapment conferring extended duration efficacy. PMID- 25695677 TI - Tridentate benzylthiols on Au(111): control of self-assembly geometry. AB - A set of hexasubstituted benzene derivatives with three thiol groups in the 1, 3, 5 positions and varied aliphatic substituents in the 2, 4, 6 positions (Me3-BTMT, Et3-BTMT, ODe3-BTMT) has been synthesized and self-assembled on Au(111). The resulting self-assembled monolayers (SAMs) are characterized by scanning tunneling microscopy (STM), X-ray photoelectron spectroscopy (XPS), and electrochemistry. The molecular orientation and long-range order are affected by the "gear effect" of the hexasubstituted benzene ring and van der Waals interactions between the physisorbed alkyl chains drive. Me3-BTMT adopts a standing up orientation which results in the highest molecular surface density but also the lowest degree of chemisorption (1 to 2 Au-S bonds per molecule). In contrast, Et3-BTMT favors a lying down orientation with a greater number of surface-bonded thiol groups (2 to 3) per molecule, associated with the peculiar geometry of this molecule. Finally, ODe3-BTMT adsorbs mainly in a lying down orientation, forming the SAM with the highest degree of chemisorption (all thiol groups are gold-bonded) and the lowest molecular areal density. PMID- 25695678 TI - Engineering of carbon based nanomaterials by ring-opening reactions of a reactive azlactone graphene platform. AB - A reactive azlactone-based graphene nanoplatform was successfully synthesized by the ligation of azido-azlactone with alkyne-terminated graphene via Cu(I) catalyzed cycloaddition. The reactive azlactone rings, grafted on graphene sheets, were subjected to highly efficient ring-opening reactions with functionalized primary amine derivatives incorporating an aminosilane coupling agent or a biological fragment. PMID- 25695679 TI - Thymosin beta4 promotes hepatoblastoma metastasis via the induction of epithelial mesenchymal transition. AB - Hepatoblastoma (HB) is the most common malignant hepatic tumor in children and complete surgical resection offers the highest possibility for cure in this disease. Tumor metastasis is the principle obstacle to the development of efficient treatments for patients with HB. The present study aimed to measure the expression levels of thymosin beta4 (Tbeta4) in liver samples from patients with HB and to investigate the involvement of Tbeta4 in HB metastasis. The expression of Tbeta4 was significantly higher in liver samples from patients with metastatic HB and in the HepG2 metastatic HB cell line, compared with that in adjacent healthy liver samples and in the L02 healthy hepatic cell line. By contrast, the expression levels of epithelial-cadherin (E-cadherin) and cytosolic accumulation of beta-catenin, the two most prominent markers involved in epithelial mesenchymal transition (EMT), were reduced in liver specimens from patients with metastatic HB compared with that of healthy adjacent control tissue. HepG2 cells were transfected with small interfering-RNA in order to downregulate Tbeta4 gene expression. This resulted in a reduced cell migratory capacity compared with control cells. Tbeta4 gene expression knockdown significantly inhibited transforming growth factor beta1-mediated-EMT in vitro by upregulating the expression of E-cadherin. The results of the present study suggested that Tbeta4 may promote HB metastasis via the induction of EMT, and that Tbeta4 may therefore be a target for the development of novel treatments for patients with HB. PMID- 25695680 TI - Copper catalysed amidation of aryl halides through chelation assistance. AB - A copper mediated C-N bond formation for the amidation of aryl halides using 8 aminoquinoline has been developed. This strategy provides efficient access to amides bearing two contiguous heterocyclic moieties and does not require the presence of additional ligands. PMID- 25695681 TI - A Variation of Cover-Free Families and Its Applications. AB - A cover-free family is a family of subsets of a finite set in which no one is covered by the union of r others. We study a variation of cover-free family: A binary matrix is (r, w]-consecutive-disjunct if for any w cyclically consecutive columns [Formula: see text] and another r cyclically consecutive columns [Formula: see text], there exists one row intersecting [Formula: see text] but none of [Formula: see text]. In group testing, the goal is to determine a small subset of positive items D in a large population [Formula: see text] by group tests. By applying consecutive-disjunct matrices, we solve threshold group testing of consecutive positives in [Formula: see text] group tests nonadaptively, and the decoding complexity is [Formula: see text] where u is a threshold parameter in threshold group testing and it is assumed that |D|<=d and [Formula: see text]. Meanwhile, we obtain that for group testing of consecutive positives, all positives can be identified in [Formula: see text] group tests nonadaptively and the decoding complexity is [Formula: see text]. PMID- 25695682 TI - Assessment of the genetic basis of rosacea by genome-wide association study. AB - Rosacea is a common, chronic skin disease that is currently incurable. Although environmental factors influence rosacea, the genetic basis of rosacea is not established. In this genome-wide association study, a discovery group of 22,952 individuals (2,618 rosacea cases and 20,334 controls) was analyzed, leading to identification of two significant single-nucleotide polymorphisms (SNPs) associated with rosacea, one of which replicated in a new group of 29,481 individuals (3,205 rosacea cases and 26,262 controls). The confirmed SNP, rs763035 (P=8.0 * 10(-11) discovery group; P=0.00031 replication group), is intergenic between HLA-DRA and BTNL2. Exploratory immunohistochemical analysis of HLA-DRA and BTNL2 expression in papulopustular rosacea lesions from six individuals, including one with the rs763035 variant, revealed staining in the perifollicular inflammatory infiltrate of rosacea for both proteins. In addition, three HLA alleles, all MHC class II proteins, were significantly associated with rosacea in the discovery group and confirmed in the replication group: HLA DRB1*03:01 (P=1.0 * 10(-8) discovery group; P=4.4 * 10(-6) replication group), HLA-DQB1*02:01 (P=1.3 * 10(-8) discovery group; P=7.2 * 10(-6) replication group), and HLA-DQA1*05:01 (P=1.4 * 10(-8) discovery group; P=7.6 * 10(-6) replication group). Collectively, the gene variants identified in this study support the concept of a genetic component for rosacea, and provide candidate targets for future studies to better understand and treat rosacea. PMID- 25695683 TI - Mucosal pemphigus vulgaris anti-Dsg3 IgG is pathogenic to the oral mucosa of humanized Dsg3 mice. AB - There are two major clinical subsets of pemphigus vulgaris (PV)-mucosal PV (mPV) and mucocutaneous PV (mcPV). The mPV subset exhibits anti-human desmoglein (Dsg) 3 autoantibodies that fail to recognize murine Dsg3 (mDsg3); thus, passive transfer experiments of mPV IgG into wild-type (WT) mice have been unsuccessful at inducing disease. We therefore generated a fully humanized Dsg3 (hDSG3) murine model utilizing a hDsg3 transgenic animal crossed to the mDsg3 knockout line. Expression of hDsg3 in the mucosa rescues the mDsg3 knockout phenotype. Well characterized mPV sera bind mucosal epithelia from the hDsg3 mice, but not mucosal tissues from WT mice, as detected by indirect immunofluorescence (IF). The majority of mPV sera preferentially recognize hDsg3 compared with mDsg3 by immunoprecipitation as well. Passive transfer of mPV IgG into adult hDsg3 mice, but not WT mice, induces suprabasilar acantholysis in mucosal tissues, thus confirming the pathogenicity of mPV anti-hDsg3 IgG in vivo. Human anti-hDsg3 antibodies are detected in perilesional mucosa as well as in sera of recipient mice by IF. These findings suggest that the Dsg3 epitopes targeted by pathogenic mPV IgG are human specific. This hDsg3 mouse model will be invaluable in studying the clinical transition from mPV to mcPV. PMID- 25695684 TI - Somatic Activating RAS Mutations Cause Vascular Tumors Including Pyogenic Granuloma. PMID- 25695685 TI - Disseminated Mycobacterium tuberculosis in imported Sooty Mangabey, Thailand. PMID- 25695686 TI - Bone-anchored Hearing Implant Surgery: Randomized Trial of Dermatome Versus Linear Incision Without Soft Tissue Reduction--Clinical Measures. AB - OBJECTIVE: Assessment of differences in soft tissue healing and long-term issues between two techniques for bone-anchored hearing implant (BAHI) surgery. STUDY DESIGN: Single-center, randomized, nonblinded study using balanced randomization (1:1). SETTING: Tertiary referral center in the Central Denmark Region. PATIENTS: Forty-seven adults with normal skin quality. INTERVENTION: Operation with a BAHI system with randomization to 1) dermatome technique with soft tissue removal and 2) linear incision with no soft tissue reduction. OUTCOME MEASURES: Holgers' score, pain, and sensibility loss assessed at 0, 3, 7, 10, 14, and 21 days and 1, 3, 6, and 12 months postoperatively. Implant loss. RESULTS: Forty-nine patients were randomized (linear incision, n = 25; dermatome, n = 24). Forty-seven patients were analyzed (linear incision, n = 25; dermatome, n = 22). Differences in proportions for grouped data (outcome 0 and outcome >0) for the total of all visits were Holgers' Index: 0.13 (p = 0.0004; 95% confidence interval [95% CI], 0.058-0.21); sensibility loss: 0.50 (p = 2.2 . 10; 95% CI, 0.42-0.58); pain: 0.096 (p = 0.006; 95% CI, 0.026-0.17). Soft tissue reactions and pain were most prominent in the early postoperative period, whereas issues with sensibility loss subsided throughout the 1-year follow-up period. No implants were lost. CONCLUSION: In a randomized trial for BAHI surgery, the linear incision with no subcutaneous reduction had a faster healing time and inflicted less pain and sensibility loss than the dermatome technique. The long-term soft tissue problems were similar in the two groups, thus favoring the linear incision, which is less invasive. PMID- 25695687 TI - Effect of ciliates in transfer of plasmid-mediated quinolone-resistance genes in bacteria. PMID- 25695688 TI - Association of hospital-level volume of extracorporeal membrane oxygenation cases and mortality. Analysis of the extracorporeal life support organization registry. AB - RATIONALE: Recent pediatric studies suggest a survival benefit exists for higher volume extracorporeal membrane oxygenation (ECMO) centers. OBJECTIVES: To determine if higher annual ECMO patient volume is associated with lower case-mix adjusted hospital mortality rate. METHODS: We retrospectively analyzed an international registry of ECMO support from 1989 to 2013. Patients were separated into three age groups: neonatal (0-28 d), pediatric (29 d to <18 yr), and adult (>=18 yr). The measure of hospital ECMO volume was age group-specific and adjusted for patient-level case-mix and hospital-level variance using multivariable hierarchical logistic regression modeling. The primary outcome was death before hospital discharge. A subgroup analysis was conducted for 2008-2013. MEASUREMENTS AND MAIN RESULTS: From 1989 to 2013, a total of 290 centers provided ECMO support to 56,222 patients (30,909 neonates, 14,725 children, and 10,588 adults). Annual ECMO mortality rates varied widely across ECMO centers: the interquartile range was 18-50% for neonates, 25-66% for pediatrics, and 33-92% for adults. For 1989-2013, higher age group-specific ECMO volume was associated with lower odds of ECMO mortality for neonates and adults but not for pediatric cases. In 2008-2013, the volume-outcome association remained statistically significant only among adults. Patients receiving ECMO at hospitals with more than 30 adult annual ECMO cases had significantly lower odds of mortality (adjusted odds ratio, 0.61; 95% confidence interval, 0.46-0.80) compared with adults receiving ECMO at hospitals with less than six annual cases. CONCLUSIONS: In this international, case-mix-adjusted analysis, higher annual hospital ECMO volume was associated with lower mortality in 1989-2013 for neonates and adults; the association among adults persisted in 2008-2013. PMID- 25695689 TI - Tumor-infiltrating lymphocytes genetically engineered with an inducible gene encoding interleukin-12 for the immunotherapy of metastatic melanoma. AB - PURPOSE: Infusion of interleukin-12 (IL12) can mediate antitumor immunity in animal models, yet its systemic administration to patients with cancer results in minimal efficacy and severe toxicity. Here, we evaluated the antitumor activity of adoptively transferred human tumor-infiltrating lymphocytes (TILs) genetically engineered to secrete single-chain IL12 selectively at the tumor site. EXPERIMENTAL DESIGN: Thirty-three patients with metastatic melanoma were treated in a cell dose-escalation trial of autologous TILs transduced with a gene encoding a single-chain IL12 driven by a nuclear factor of the activated T cells promoter (NFAT.IL12). No IL2 was administered. RESULTS: The administration of 0.001 to 0.1 * 10(9) NFAT.IL12-transduced TILs to 17 patients resulted in a single, objective response (5.9%). However, at doses between 0.3 and 3 * 10(9) cells, 10 of 16 patients (63%) exhibited objective clinical responses. The responses tended to be short, and the administered IL12-producing cells rarely persisted at 1 month. Increasing cell doses were associated with high serum levels of IL12 and IFNgamma as well as clinical toxicities, including liver dysfunction, high fevers, and sporadic life-threatening hemodynamic instability. CONCLUSIONS: In this first-in-man trial, administration of TILs transduced with an inducible IL12 gene mediated tumor responses in the absence of IL2 administration using cell doses 10- to 100-fold lower than conventional TILs. However, due to toxicities, likely attributable to the secreted IL12, further refinement will be necessary before this approach can be safely used in the treatment of cancer patients. PMID- 25695690 TI - Phase II Study of Nilotinib in Melanoma Harboring KIT Alterations Following Progression to Prior KIT Inhibition. AB - PURPOSE: Although durable responses can be achieved with tyrosine kinase inhibitors such as imatinib in melanomas harboring KIT mutations, the efficacy of alternative inhibitors after progression to imatinib and the activity of these agents on brain metastases are unknown. EXPERIMENTAL DESIGN: We conducted a phase II study of nilotinib 400 mg twice a day in two cohorts of patients with melanomas harboring KIT mutations or amplification: (A) those refractory or intolerant to a prior KIT inhibitor; and (B) those with brain metastases. The primary endpoint was 4-month disease control rate. Secondary endpoints included response rate, time-to-progression (TTP), and overall survival (OS). A Simon two stage and a single-stage design was planned to assess for the primary endpoint in cohorts A and B, respectively. RESULTS: Twenty patients were enrolled and 19 treated (11 in cohort A; 8 in cohort B). Three patients on cohort A [27%; 95% confidence interval (CI), 8%-56%] and 1 on cohort B (12.5%; 90% CI, 0.6%-47%) achieved the primary endpoint. Two partial responses were observed in cohort A (18.2%; 90% CI, 3%-47%); none were observed in cohort B. The median TTP and OS was 3.3 (90% CI, 2.1-3.9 months) and 9.1 months (90% CI, 4.3-14.2 months), respectively, in all treated patients. CONCLUSIONS: Nilotinib may achieve disease control in patients with melanoma harboring KIT alterations and whose disease progressed after imatinib therapy. The efficacy of this agent in KIT-altered melanoma with brain metastasis is limited. PMID- 25695691 TI - Phase I Study of Vorinostat as a Radiation Sensitizer with 131I Metaiodobenzylguanidine (131I-MIBG) for Patients with Relapsed or Refractory Neuroblastoma. AB - PURPOSE: (131)I-metaiodobenzylguanidine (MIBG) is a radiopharmaceutical with activity in neuroblastoma. Vorinostat is a histone deacetylase inhibitor that has radiosensitizing properties. The goal of this phase I study was to determine the MTDs of vorinostat and MIBG in combination. EXPERIMENTAL DESIGN: Patients <= 30 years with relapsed/refractory MIBG-avid neuroblastoma were eligible. Patients received oral vorinostat (dose levels 180 and 230 mg/m(2)) daily days 1 to 14. MIBG (dose levels 8, 12, 15, and 18 mCi/kg) was given on day 3 and peripheral blood stem cells on day 17. Alternating dose escalation of vorinostat and MIBG was performed using a 3+3 design. RESULTS: Twenty-seven patients enrolled to six dose levels, with 23 evaluable for dose escalation. No dose-limiting toxicities (DLT) were seen in the first three dose levels. At dose level 4 (15 mCi/kg MIBG/230 mg/m(2) vorinostat), 1 of 6 patients had DLT with grade 4 hypokalemia. At dose level 5 (18 mCi/kg MIBG/230 mg/m(2) vorinostat), 2 patients had dose limiting bleeding (one grade 3 and one grade 5). At dose level 5a (18 mCi/kg MIBG/180 mg/m(2) vorinostat), 0 of 6 patients had DLT. The most common toxicities were neutropenia and thrombocytopenia. The response rate was 12% across all dose levels and 17% at dose level 5a. Histone acetylation increased from baseline in peripheral blood mononuclear cells collected on days 3 and 12 to 14. CONCLUSIONS: Vorinostat at 180 mg/m(2)/dose is tolerable with 18 mCi/kg MIBG. A phase II trial comparing this regimen to single-agent MIBG is ongoing. PMID- 25695692 TI - Desmoplasia in Primary Tumors and Metastatic Lesions of Pancreatic Cancer. AB - PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is characterized by high levels of fibrosis, termed desmoplasia, which is thought to hamper the efficacy of therapeutics treating PDAC. Our primary focus was to evaluate differences in the extent of desmoplasia in primary tumors and metastatic lesions. As metastatic burden is a primary cause for mortality in PDAC, the extent of desmoplasia in metastases may help to determine whether desmoplasia targeting therapeutics will benefit patients with late-stage, metastatic disease. EXPERIMENTAL DESIGN: We sought to assess desmoplasia in metastatic lesions of PDAC and compare it with that of primary tumors. Fifty-three patients' primaries and 57 patients' metastases were stained using IHC staining techniques. RESULTS: We observed a significant negative correlation between patient survival and extracellular matrix deposition in primary tumors. Kaplan-Meier curves for collagen I showed median survival of 14.6 months in low collagen patients, and 6.4 months in high level patients (log rank, P < 0.05). Low-level hyaluronan patients displayed median survival times of 24.3 months as compared with 9.3 months in high-level patients (log rank, P < 0.05). Our analysis also indicated that extracellular matrix components, such as collagen and hyaluronan, are found in high levels in both primary tumors and metastatic lesions. The difference in the level of desmoplasia between primary tumors and metastatic lesions was not statistically significant. CONCLUSIONS: Our results suggest that both primary tumors and metastases of PDAC have highly fibrotic stroma. Thus, stromal targeting agents have the potential to benefit PDAC patients, even those with metastatic disease. PMID- 25695693 TI - Hotspot mutation panel testing reveals clonal evolution in a study of 265 paired primary and metastatic tumors. AB - PURPOSE: We used a clinical next-generation sequencing (NGS) hotspot mutation panel to investigate clonal evolution in paired primary and metastatic tumors. EXPERIMENTAL DESIGN: A total of 265 primary and metastatic tumor pairs were sequenced using a 46-gene cancer mutation panel capable of detecting one or more single-nucleotide variants as well as small insertions/deletions. Mutations were tabulated together with tumor type and percentage, mutational variant frequency, time interval between onset of primary tumor and metastasis, and neoadjuvant therapy status. RESULTS: Of note, 227 of 265 (85.7%) tumor metastasis pairs showed identical mutation calls. Of the tumor pairs with identical mutation calls, 160 (60.4%) possessed defining somatic mutation signatures and 67 (25.3%) did not exhibit any somatic mutations. There were 38 (14.3%) cases that showed at least one novel mutation call between the primary and metastasis. Metastases were almost two times more likely to show novel mutations (n = 20, 7.5%) than primary tumors (n = 12, 4.5%). TP53 was the most common additionally mutated gene in metastatic lesions, followed by PIK3CA and SMAD4. PIK3CA mutations were more often associated with metastasis in colon carcinoma samples. CONCLUSIONS: Clinical NGS hotspot panels can be useful in analyzing clonal evolution within tumors as well as in determining subclonal mutations that can expand in future metastases. PIK3CA, SMAD4, and TP53 are most often involved in clonal divergence, providing potential targets that may help guide the clinical management of tumor progression or metastases. PMID- 25695694 TI - The role of Toll-like receptor 3 and 4 in regulating the function of mesenchymal stem cells isolated from umbilical cord. AB - Mesenchymal stem cells (MSCs) have been applied to cell-based therapy due to their multiple differentiation ability, the low expression of co-stimulatory molecules and immunosuppressive properties. Despite their immunomodulatory role, the issue of the survival and permanence of MSCs at the site of injury has not yet been fully resolved. Therefore, in order to improve the therapeutic potential of MSCs, it is important to study the mechanisms mediating the relative instability of MSCs in clinical trials. The Toll-like receptors (TLRs) are an important component of innate and adaptive immune responses. In this study, we demonstrate that the activation of two TLRs, namely TLR3 and TLR4, in human umbilical cord-derived MSCs (UCMSCs) induces the expression of inflammatory markers. In addition, as shown by our results, TLR3 upregulated the expression of stem cell markers, while TLR4 downregulated their expression. The upregulation in the expression of the inflammatory markers did not alter the immune status of the UCMSCs or mediate the immune attack of the MSCs by allogeneic immune cells. We found that the activation of TLR3 inhibited the differentiation of UCMSCs into osteocytes, while that of TLR4 increased this differentiation to a certain extent. Taken together, the results of this study provide a new role for TLR3 and TLR4 as regulators of the biological functions of UCMSCs. PMID- 25695696 TI - NIH Initiates "centers without walls" to study SUDEP. PMID- 25695698 TI - Francois M. Abboud, MD AFCR president, 1971-1972. PMID- 25695713 TI - Francis Miller, MD AFMR president, 2010-2011. PMID- 25695714 TI - Amir A. Zeki, MD AFMR president, 2015-2016. PMID- 25695715 TI - Association of human fetuin-A rs4917 polymorphism with obesity in 2 cohorts. AB - BACKGROUND: Previous studies have shown association of the multifunctional hepatic protein alpha2HS-glycoprotein/human fetuin A with insulin resistance, type 2 diabetes mellitus, metabolic syndrome, obesity, and atherosclerosis. Reports of contribution of alpha2HS-glycoprotein/human fetuin A rs4917 single nucleotide polymorphism to the development of these pathologic processes are inconsistent. We aimed to investigate the association between variants of rs4917 and parameters of obesity, lipid status, the proinflammatory cytokine tumor necrosis factor alpha (TNF-alpha), adipokines (adiponectin, resistin), and insulin resistance in 2 cohorts. METHODS: Eighty-one healthy persons (cohort 1) and 157 patients with previous myocardial infarction (cohort 2) were included in this cross-sectional study. rs4917 Polymorphism was determined by the allele specific KASP by design genotyping assays. RESULTS: In cohort 1, T-nucleotide carriers had lower low-density lipoprotein cholesterol levels compared with non-T carriers. The serum concentration of TNF-alpha was found to be higher carrying the non-T allele in cohort 1; however, this difference was not observed in cohort 2. In cohort 2, T carriers had lower body mass index and abdominal and waist circumferences than did non-T carriers. The T nucleotide was more frequent in nonobese than in obese patients (chi = 5.217, P = 0.022). Nonobese, nondiabetic T carriers still had lower body mass index and waist circumference than did non-T carriers. CONCLUSIONS: Our data suggest that the T nucleotide in rs4917 is associated with more favorable lipid status among healthy persons (i.e., lower low-density lipoprotein cholesterol) and anthropologic parameters of obesity in cohort 2. The protective role of the T allele may also be associated with lower TNF-alpha levels found in healthy individuals. PMID- 25695717 TI - MicroRNA-183/182/96 cooperatively regulates the proliferation of colon cancer cells. AB - The microRNA (miR/miRNA)-182/183/96 cluster comprises miR-96, -182 and -183. The present study examined five previous microarray-based human colon cancer miR expression profiling studies and the expression of these three miRs was found to be upregulated in colon cancer tissues. Subsequently, in vitro assays were performed to determine the role of the miR-183/182/96 cluster in colon cancer cells. The results demonstrated that inhibiting miR-183, miR-182 or miR-96 with antisense oligonucleotide (ASO)-mimics inhibited the proliferation of colon cancer cells. Notably, further investigation revealed that inhibiting their expression simultaneously led to a more efficient reduction in cancer cell proliferation. These results suggested that miR-182/183/96, which resides in clusters in the genome, functioned synergistically in colon cancer and implied that co-expression of the miR cluster ASOs was efficient in reducing tumorigenesis, offering novel insight into the use of miRNAs in tumor therapy. PMID- 25695718 TI - Solvation-induced helicity inversion of pseudotetrahedral chiral copper(II) complexes. AB - The helicity of four-coordinated nonplanar complexes is strongly correlated to the chirality of the ligand. However, the stereochemical induction of either the Delta- or the Lambda-configuration at the metal ion is also modulated by environmental factors that change the conformational distribution of ligand rotamers. Calculation of the potential energy surface of bis{(R)-N-(1-(4-X phenyl)ethyl)salicylaldiminato-kappa(2)N,O}copper(II) with X = Cl at the density functional theory level showed a clear dependence of the helicity-determining angle theta between the two coordination planes on the relative population of different ligand conformers. The influence of different substituents (X = H, Cl, Br, and OCH3) on complex helicity was studied by determination of the absolute configuration at the metal ion in complexes with either (R)- or (S)-configured ligands. X-ray single-crystal analysis showed that (R)-configured ligands with H, Cl, Br induce Delta, while OCH3-substituted (R)-configured ligands induce Lambda in the solid state. According to vibrational circular dichroism and electronic circular dichroism studies in solution, however, all tested complexes with (R) ligands exhibited a propensity for Delta, with high diastereomeric ratio for X = Cl and X = Br and moderate diastereomeric ratio for X = H and X = OCH3 substituted ligands. Therefore, solvation of copper complexes with X = OCH3 goes along with helicity inversion. This solid-state versus solution study demonstrates that it is not sufficient to determine the chiral-at-metal configuration of a compound by X-ray crystallography alone, because the solution structure can be different. This is particularly important for the use of chiral at-metal complexes as catalysts in stereoselective synthesis. PMID- 25695719 TI - Identifying the biological basis of GWAS hits for endometriosis. AB - Endometriosis is a common estrogen-dependent gynecological disease influenced by multiple genetic and environmental factors. Genome-wide association studies (GWAS) have identified eight genomic regions with strong evidence for association with endometriosis risk and excellent replication in multiple studies. The results represent a significant breakthrough toward understanding endometriosis. However, the significance can be realized only when the associated DNA sequence variation is linked to the altered regulation and/or function of specific genes and pathways modifying endometriosis risk. This review sets out the multiple steps required to interpret the genetic association results, identify the specific genes likely to be responsible for the altered risk within each region, and obtain the necessary genomic evidence connecting the genetic results to the target genes. Strategies include fine mapping, functional annotation, genomics, and target gene identification through gene expression, epigenetics, and cell based studies to define direct interactions between causal single nucleotide polymorphisms (SNPs) and target genes. To help decode GWAS "hits" affecting endometriosis from multiple regions, there is an urgent need for well-powered genome-wide studies of the regulation of gene expression and epigenetic mechanisms in the endometrium and other reproductive tissues. The system genetics and genomic studies needed to follow-up GWAS signals will also provide insights into gene regulation influencing other reproductive functions. These studies require multidisciplinary research combining genetics, genomics, functional biology, and clinical research to determine the biological pathways responsible and translate the new knowledge into better outcomes for patients. PMID- 25695720 TI - Developmental programming by androgen affects the circadian timing system in female mice. AB - Circadian clocks play essential roles in the timing of events in the mammalian hypothalamo-pituitary-ovarian (HPO) axis. The molecular oscillator driving these rhythms has been localized to tissues of the HPO axis. It has been suggested that synchrony among these oscillators is a feature of normal reproductive function. The impact of fertility disorders on clock function and the role of the clock in the etiology of endocrine pathology remain unknown. Polycystic ovarian syndrome (PCOS) is a particularly devastating fertility disorder, affecting 5%-10% of women at childbearing age with features including a polycystic ovary, anovulation, and elevated serum androgen. Approximately 40% of these women have metabolic syndrome, marked by hyperinsulinemia, dyslipidemia, and insulin resistance. It has been suggested that developmental exposure to excess androgen contributes to the etiology of fertility disorders, including PCOS. To better define the role of the timing system in these disorders, we determined the effects of androgen-dependent developmental programming on clock gene expression in tissues of the metabolic and HPO axes. Female PERIOD2::luciferase (PER2::LUC) mice were exposed to androgen (dihydrotestosterone [DHT]) in utero (Days 16-18 of gestation) or for 9-10 wk (DHT pellet) beginning at weaning (pubertal androgen excess [PAE]). As expected, both groups of androgen-treated mice had disrupted estrous cycles. Analysis of PER2::LUC expression in tissue explants revealed that excess androgen produced circadian misalignment via tissue-dependent effects on phase distribution. In vitro treatment with DHT differentially affected the period of PER2::LUC expression in tissue explants and granulosa cells, indicating that androgen has direct and tissue-specific effects on clock gene expression that may account for the effects of developmental programming on the timing system. PMID- 25695721 TI - Uterine Telocytes: A Review of Current Knowledge. AB - Telocytes (TCs), a novel cell type, are briefly defined as interstitial cells with telopodes (Tps). However, a specific immunocytochemical marker has not yet been found; therefore, electron microscopy is currently the only accurate method for identifying TCs. TCs are considered to have a mesenchymal origin. Recently proteomic analysis, microarray-based gene expression analysis, and the micro-RNA signature clearly showed that TCs are different from fibroblasts, mesenchymal stem cells, and endothelial cells. The dynamics of Tps were also revealed, and some electrophysiological properties of TCs were described (such as membrane capacitance, input resistance, membrane resting potential, and absence of action potentials correlated with different ionic currents characteristics), which can be used to distinguish uterine TCs from smooth muscle cells (SMCs). Here, we briefly present the most recent findings on the characteristics of TCs and their functions in human pregnant and nonpregnant uteri. PMID- 25695722 TI - Equine sperm-neutrophil binding. AB - When mares are inseminated repeatedly, protein molecules from the seminal plasma (SP) prevent sperm-neutrophil binding and reduced fertility. The molecule(s) responsible for sperm-neutrophil binding is not known and the identification of beneficial SP proteins is complicated by their large numbers and abundant variation. We examined several important aspects of sperm-neutrophil binding to ultimately facilitate the identification and isolation of the molecule(s) responsible. First, we raised anti-equine P-selectin antibodies to determine the involvement of this adhesion molecule in sperm-neutrophil binding. While these antibodies identified equine P-selectin, they did not inhibit sperm-neutrophil binding. However, acrosome-reacted equine sperm expressed a molecule similar to the ligand recognition unit of P-selectin. Second, we attempted to characterize SP protein binding to equine sperm and gauge their affinity. Biotinylated SP proteins were incubated with fresh sperm, washed over a viscous medium, electrophoresed, and probed with avidin. Several SP proteins bound to sperm with a strong affinity to withstand these treatments. This finding may prove valuable for future attempts to identify and characterize specific SP molecules. Lastly, we compared the secretions from male sex organs/glands on sperm motility, sperm neutrophil binding, and their protein profile. We expected fewer proteins from individual organs/glands, which would facilitate isolation and identification of target molecules. While each secretion had a varying effect on motility and sperm neutrophil binding, the protein profile was as complex as that seen in whole SP, indicating that collection of proteins from individual sources will not facilitate this work. Together, these experiments answer several important questions related to sperm-neutrophil binding, sperm-SP proteins interaction, and the complexity of the SP proteome. PMID- 25695723 TI - Proteomics of the human endometrial glandular epithelium and stroma from the proliferative and secretory phases of the menstrual cycle. AB - Despite its importance in reproductive biology and women's health, a detailed molecular-level understanding of the human endometrium is lacking. Indeed, no comprehensive studies have been undertaken to elucidate the important protein expression differences between the endometrial glandular epithelium and surrounding stroma during the proliferative and midsecretory phases of the menstrual cycle. We utilized laser microdissection to harvest epithelial cells and stromal compartments from proliferative and secretory premenopausal endometrial tissue and performed a global, quantitative mass spectrometry-based proteomics analysis. This analysis identified 1224 total proteins from epithelial cells, among which 318 were differentially abundant between the proliferative and secretory phases (q < 0.05), and 1005 proteins from the stromal compartments, 19 of which were differentially abundant between the phases (q < 0.05). Several proteins were chosen for validation by immunohistochemistry in an independent set of uterine tissues, including carboxypeptidase M, tenascin C, neprilysin, and ectonucleotide pyrophosphatase/phosphodiesterase family member 3 (ENPP3). ENPP3, which was elevated in epithelial glandular cells in the secretory phase, was confirmed to be elevated in midsecretory-phase baboon uterine lavage samples and also observed to have an N-linked glycosylated form that was not observed in the proliferative phase. This study provides a detailed view into the global proteomic alterations of the epithelial cells and stromal compartments of the cycling premenopausal endometrium. These proteomic alterations during endometrial remodeling provide a basis for numerous follow-up investigations on the function of these differentially regulated proteins and their role in reproductive biology and endometrial pathologies. PMID- 25695724 TI - Materialist value orientations as correlates of the new ecological paradigm among university students in China. AB - The new ecological paradigm is an ecocentric view of the relationship between humanity and nature. This study analyzed the correlates of the new ecological paradigm in China using the responses of 1,148 university students to a questionnaire. The participating students were from Lanzhou University and Liaocheng University in China and ranged in age from 16 to 26 years. This study showed that two materialist value orientations, economic precedence over the environment and trust in technology, were negatively correlated with the new ecological paradigm. The correlates of basic values with the new ecological paradigm were mediated by economic precedence over the environment. Female students were more concerned about the environment than were male students. PMID- 25695725 TI - Morningness-eveningness, current depression, and past suicidality. AB - Previous research has reported that people who feel at their peak in the evening are more prone to depression and affective disorders. In a sample of 194 undergraduate students (54 men, 140 women; M age=21.6 yr., SD=1.4), using a simple correlational design, describing oneself as an evening person and scores on Horne and Ostberg's Morningness-Eveningess Scale were correlated with higher scores on measures of depression, hopelessness, defeat, and entrapment, but not with a report of past suicidal ideation or attempts, thereby supporting previous research findings. PMID- 25695726 TI - Improved functionality of graphene and carbon nanotube hybrid foam architecture by UV-ozone treatment. AB - Optimization of the electrode/electrolyte double-layer interface is a key factor for improving electrode performance of aqueous electrolyte based supercapacitors (SCs). Here, we report the improved functionality of carbon materials via a non invasive, high-throughput, and inexpensive UV generated ozone (UV-ozone) treatment. This process allows precise tuning of the graphene and carbon nanotube hybrid foam (GM) transitionally from ultrahydrophobic to hydrophilic within 60 s. The continuous tuning of surface energy can be controlled by simply varying the UV-ozone exposure time, while the ozone-oxidized carbon nanostructure maintains its integrity. Symmetric SCs based on the UV-ozone treated GM foam demonstrated enhanced rate performance. This technique can be readily applied to other CVD grown carbonaceous materials by taking advantage of its ease of processing, low cost, scalability, and controllability. PMID- 25695727 TI - Sulfate minerals: a problem for the detection of organic compounds on Mars? AB - The search for in situ organic matter on Mars involves encounters with minerals and requires an understanding of their influence on lander and rover experiments. Inorganic host materials can be helpful by aiding the preservation of organic compounds or unhelpful by causing the destruction of organic matter during thermal extraction steps. Perchlorates are recognized as confounding minerals for thermal degradation studies. On heating, perchlorates can decompose to produce oxygen, which then oxidizes organic matter. Other common minerals on Mars, such as sulfates, may also produce oxygen upon thermal decay, presenting an additional complication. Different sulfate species decompose within a large range of temperatures. We performed a series of experiments on a sample containing the ferric sulfate jarosite. The sulfate ions within jarosite break down from 500 degrees C. Carbon dioxide detected during heating of the sample was attributed to oxidation of organic matter. A laboratory standard of ferric sulfate hydrate released sulfur dioxide from 550 degrees C, and an oxygen peak was detected in the products. Calcium sulfate did not decompose below 1000 degrees C. Oxygen released from sulfate minerals may have already affected organic compound detection during in situ thermal experiments on Mars missions. A combination of preliminary mineralogical analyses and suitably selected pyrolysis temperatures may increase future success in the search for past or present life on Mars. PMID- 25695728 TI - An update to the toxicological profile for water-soluble and sparingly soluble tungsten substances. AB - Tungsten is a relatively rare metal with numerous applications, most notably in machine tools, catalysts, and superalloys. In 2003, tungsten was nominated for study under the National Toxicology Program, and in 2011, it was nominated for human health assessment under the US Environmental Protection Agency's (EPA) Integrated Risk Information System. In 2005, the Agency for Toxic Substances and Disease Registry (ATSDR) issued a toxicological profile for tungsten, identifying several data gaps in the hazard assessment of tungsten. By filling the data gaps identified by the ATSDR, this review serves as an update to the toxicological profile for tungsten and tungsten substances. A PubMed literature search was conducted to identify reports published during the period 2004-2014, in order to gather relevant information related to tungsten toxicity. Additional information was also obtained directly from unpublished studies from within the tungsten industry. A systematic approach to evaluate the quality of data was conducted according to published criteria. This comprehensive review has gathered new toxicokinetic information and summarizes the details of acute and repeated exposure studies that include reproductive, developmental, neurotoxicological, and immunotoxicological endpoints. Such new evidence involves several relevant studies that must be considered when regulators estimate and propose a tungsten reference or concentration dose. PMID- 25695729 TI - SOCS3 blocks HIF-1alpha expression to inhibit proliferation and angiogenesis of human small cell lung cancer by downregulating activation of Akt, but not STAT3. AB - Suppressor of cytokine signaling 3 (SOCS3) is a major negative regulator of signal transducer and activator of transcription 3 (STAT3) during tumorigenesis. Previous studies have indicated that SOCS3 also regulates other signaling pathways, such as PI3K/Akt. However, little is known about the specific molecular mechanisms by which SOCS3 regulates the proliferation and angiogenesis of small cell lung cancer (SCLC) cells. The present study investigated the effect of SOCS3 upregulation on the expression of hypoxia-inducible factor-1alpha (HIF-1alpha) and how this affects the proliferation and angiogenesis of SCLC cells. It was investigated whether this interaction is associated with STAT3 or the Akt signaling pathway. The results of the present study revealed that SOCS3 negatively regulates proliferation and angiogenesis of NCI-H446 cells and that HIF-1alpha is required in this process. The results also suggested a suppressive role of SOCS3 in Akt signaling, but not STAT3 signaling to block HIF-1alpha expression and a previously unidentified regulatory mechanism for Akt function. In conclusion, the present study suggested that SOCS3 targets the Akt signaling pathway to inhibit HIF-1alpha expression and affect the growth and angiogenesis of SCLC cells, and may therefore be considered as a potential novel therapeutic for the treatment of SCLC. PMID- 25695730 TI - Dual-functionalized metal-organic frameworks constructed from hexatopic ligand for selective CO2 adsorption. AB - A ligand design approach, which requires rational design of ligand based on the knowledge of specific target, was applied for the synthesis of two interesting and robust MOFs 1 and 2 containing unusual several types of copper(II) secondary building units (SBUs). Thanks to unsaturated metal centers (UMCs) and azo group, microporous material 1 exhibited not only high CO2 uptake but also an impressive selective adsorption of CO2 over CH4 and N2. Moreover, a high H2 uptake of 1 was also observed. PMID- 25695732 TI - Bone Marrow-Derived Mesenchymal Stem Cells and Their Conditioned Medium Attenuate Fibrosis in an Irreversible Model of Unilateral Ureteral Obstruction. AB - The therapeutic potential of mesenchymal stem cells (MSCs) and their conditioned medium (MSC-CM) has been extensively studied. MSCs can repair tissue, reduce local inflammation, and modulate the immune response. Persistent renal tubular interstitial inflammation results in fibrosis and leads to chronic kidney disease (CKD). Unilateral ureteral obstruction (UUO) is a very well-accepted renal fibrosis model. In this study, we evaluated factors influenced by the administration of MSCs or MSC-CM in the UUO model. MSCs extracted from rat bone marrow were cultivated in vitro and characterized by flow cytometry and cellular differentiation. Eight groups of female rats were used in experiments (n = 7, each), including Sham, UUO, UUO + MSC (obstruction + MSC), and UUO + CM (obstruction + MSC-CM) for 7 days of obstruction and Sham, UUO, UUO + MSC, and UUO + CM for 14 days of obstruction. The MSCs or MSC-CM was administered via the abdominal vena cava after total ligation of the left ureter. After 7 or 14 days, rats were euthanized, and serum and obstructed kidney samples were collected. MSCs or MSC-CM decreased the expression of molecules, such as Col1a1, alpha-SMA, and TNF-alpha. We also observed reductions in the levels of caspase 3, alpha-SMA, and PCNA in treated animals by immunohistochemistry. Our results suggest that the intravenous administration of MSCs or MSC-CM improves fibrosis progression and factors involved in apoptosis, inflammation, cell proliferation, and epithelial mesenchymal transition in Wistar rats subjected to UUO, indicating a potential tool for preventing CKD. PMID- 25695733 TI - Temperature-dependent infrared and calorimetric studies on arsenicals adsorption from solution to hematite nanoparticles. AB - To address the lack of systematic and surface sensitive studies on the adsorption energetics of arsenic compounds on metal (oxyhydr)oxides, we conducted temperature-dependent ATR-FTIR studies for the adsorption of arsenate, monomethylarsonic acid, and dimethylarsinic acid on hematite nanoparticles at pH 7. Spectra were collected as a function of concentration and temperature in the range 5-50 degrees C (278-323 K). Adsorption isotherms were constructed from spectral features assigned to surface arsenic. Values of K(eq), adsorption enthalpy, and entropy were extracted from fitting the Langmuir model to the data and from custom-built triple-layer surface complexation models derived from our understanding of the adsorption mechanism of each arsenical. These spectroscopic and modeling results were complemented with flow-through calorimetric measurements of molar heats of adsorption. Endothermic adsorption processes were predicted from the application of mathematical models with a net positive change in adsorption entropy. However, experimentally measured heats of adsorption were exothermic for all three arsenicals studied herein, with arsenate releasing 1.6 1.9 times more heat than methylated arsenicals. These results highlight the role of hydration thermodynamics on the adsorption of arsenicals, and are consistent with the spectral interpretation of type of surface complexes each arsenical form in that arsenate is mostly dominated by bidentate, MMA by a mixture of mono- and bidentate, and DMA by mostly outer sphere. PMID- 25695734 TI - Correction to "Ab initio reaction kinetics of hydrogen abstraction from methyl formate by hydrogen, methyl, oxygen, hydroxyl, and hydroperoxy radicals". PMID- 25695735 TI - A balance between membrane elasticity and polymerization energy sets the shape of spherical clathrin coats. AB - In endocytosis, scaffolding is one of the mechanisms to create membrane curvature by moulding the membrane into the spherical shape of the clathrin cage. However, the impact of membrane elastic parameters on the assembly and shape of clathrin lattices has never been experimentally evaluated. Here, we show that membrane tension opposes clathrin polymerization. We reconstitute clathrin budding in vitro with giant unilamellar vesicles (GUVs), purified adaptors and clathrin. By changing the osmotic conditions, we find that clathrin coats cause extensive budding of GUVs under low membrane tension while polymerizing into shallow pits under moderate tension. High tension fully inhibits polymerization. Theoretically, we predict the tension values for which transitions between different clathrin coat shapes occur. We measure the changes in membrane tension during clathrin polymerization, and use our theoretical framework to estimate the polymerization energy from these data. Our results show that membrane tension controls clathrin-mediated budding by varying the membrane budding energy. PMID- 25695736 TI - Potential benefits of cattle vaccination as a supplementary control for bovine tuberculosis. AB - Vaccination for the control of bovine tuberculosis (bTB) in cattle is not currently used within any international control program, and is illegal within the EU. Candidate vaccines, based upon Mycobacterium bovis bacillus Calmette Guerin (BCG) all interfere with the action of the tuberculin skin test, which is used to determine if animals, herds and countries are officially bTB-free. New diagnostic tests that Differentiate Infected from Vaccinated Animals (DIVA) offer the potential to introduce vaccination within existing eradication programs. We use within-herd transmission models estimated from historical data from Great Britain (GB) to explore the feasibility of such supplemental use of vaccination. The economic impact of bovine Tuberculosis for farmers is dominated by the costs associated with testing, and associated restrictions on animal movements. Farmers' willingness to adopt vaccination will require vaccination to not only reduce the burden of infection, but also the risk of restrictions being imposed. We find that, under the intensive sequence of testing in GB, it is the specificity of the DIVA test, rather than the sensitivity, that is the greatest barrier to see a herd level benefit of vaccination. The potential negative effects of vaccination could be mitigated through relaxation of testing. However, this could potentially increase the hidden burden of infection within Officially TB Free herds. Using our models, we explore the range of the DIVA test characteristics necessary to see a protective herd level benefit of vaccination. We estimate that a DIVA specificity of at least 99.85% and sensitivity of >40% is required to see a protective benefit of vaccination with no increase in the risk of missed infection. Data from experimentally infected animals suggest that this target specificity could be achieved in vaccinates using a cocktail of three DIVA antigens while maintaining a sensitivity of 73.3% (95%CI: 61.9, 82.9%) relative to post-mortem detection. PMID- 25695737 TI - Rural/urban and socioeconomic differentials in quality of antenatal care in Ghana. AB - BACKGROUND: Approximately 800 women die of pregnancy-related complications every day. Over half of these deaths occur in sub-Saharan Africa (SSA). Most maternal deaths can be prevented with high quality maternal health services. It is well established that use of maternal health services vary by place of residence and socioeconomic status (SES), but few studies have examined the determinants of quality of maternal health services in SSA. The purpose of this study is to examine the determinants of antenatal care (ANC) quality in Ghana-focusing on the role of place of residence and SES (education and wealth). The analysis also examines the interactions of these variables and the mediating role of ANC timing, frequency, facility type, and provider type. METHODS: The data are from the Ghana Maternal Health Survey (N = 4,868). Analytic techniques include multilevel linear regression with mediation and moderation analysis. RESULTS: Urban residence and higher SES are positively associated with higher ANC quality, but the urban effect is completely explained by sociodemographic factors. Specifically, about half of the urban effect is explained by education and wealth alone, with other variables accounting for the remainder. The effects of education are conditional on wealth and are strongest for poor women. Starting ANC visits early and attending the recommended four visits as well as receiving ANC from a higher level facility and from a skilled provider are associated with higher quality ANC. These factors partially explain the SES differentials. IMPLICATIONS: Ghanaian women experience significant disparities in quality of ANC, with poor illiterate women receiving the worst care. Targeted efforts to increase quality of ANC may significantly reduce maternal health disparities in Ghana and SSA. A particularly crucial step is to improve ANC quality in the lower level health facilities, where the most vulnerable women are more likely to seek ANC. PMID- 25695738 TI - Prions--not your immunologist's pathogen. PMID- 25695739 TI - Is there a relationship between research sponsorship and publication impact? An analysis of funding acknowledgments in nanotechnology papers. AB - This study analyzes funding acknowledgments in scientific papers to investigate relationships between research sponsorship and publication impacts. We identify acknowledgments to research sponsors for nanotechnology papers published in the Web of Science during a one-year sample period. We examine the citations accrued by these papers and the journal impact factors of their publication titles. The results show that publications from grant sponsored research exhibit higher impacts in terms of both journal ranking and citation counts than research that is not grant sponsored. We discuss the method and models used, and the insights provided by this approach as well as it limitations. PMID- 25695740 TI - It's time to dispel the myth of "asymptomatic" schistosomiasis. PMID- 25695741 TI - Sound symbolism facilitates word learning in 14-month-olds. AB - Sound symbolism, or the nonarbitrary link between linguistic sound and meaning, has often been discussed in connection with language evolution, where the oral imitation of external events links phonetic forms with their referents (e.g., Ramachandran & Hubbard, 2001). In this research, we explore whether sound symbolism may also facilitate synchronic language learning in human infants. Sound symbolism may be a useful cue particularly at the earliest developmental stages of word learning, because it potentially provides a way of bootstrapping word meaning from perceptual information. Using an associative word learning paradigm, we demonstrated that 14-month-old infants could detect Kohler-type (1947) shape-sound symbolism, and could use this sensitivity in their effort to establish a word-referent association. PMID- 25695742 TI - Ethmoid sinus mass. Sinonasal teratocarcinosarcoma. PMID- 25695743 TI - The Leishmania donovani histidine acid ecto-phosphatase LdMAcP: insight into its structure and function. AB - Acid ecto-phosphatase activity has been implicated in Leishmania donovani promastigote virulence. In the present study, we report data contributing to the molecular/structural and functional characterization of the L. donovani LdMAcP (L. donovani membrane acid phosphatase), member of the histidine acid phosphatase (HAcP) family. LdMAcP is membrane-anchored and shares high sequence identity with the major secreted L. donovani acid phosphatases (LdSAcPs). Sequence comparison of the LdMAcP orthologues in Leishmania sp. revealed strain polymorphism and species specificity for the L. donovani complex, responsible for visceral leishmaniasis (Khala azar), proposing thus a potential value of LdMAcP as an epidemiological or diagnostic tool. The extracellular orientation of the LdMAcP catalytic domain was confirmed in L. donovani promastigotes, wild-type (wt) and transgenic overexpressing a recombinant LdMAcP-mRFP1 (monomeric RFP1) chimera, as well as in transiently transfected mammalian cells expressing rLdMAcP-His. For the first time it is demonstrated in the present study that LdMAcP confers tartrate resistant acid ecto-phosphatase activity in live L. donovani promastigotes. The latter confirmed the long sought molecular identity of at least one enzyme contributing to this activity. Interestingly, the L. donovani rLdMAcP-mRFP1 promastigotes generated in this study, showed significantly higher infectivity and virulence indexes than control parasites in the infection of J774 mouse macrophages highlighting thereby a role for LdMAcP in the parasite's virulence. PMID- 25695744 TI - LIF-JAK1-STAT3 signaling delays contact inhibition of human corneal endothelial cells. AB - Human corneal endothelial cells (HCECs) responsible for corneal transparency have limited proliferative capacity in vivo because of "contact-inhibition." This feature has hampered the ability to engineer HCECs for transplantation. Previously we have reported an in vitro model of HCECs in which contact inhibition was re-established at Day 21, even though cell junction and cell matrix interaction were not perturbed during isolation. Herein, we observe that such HCEC monolayers continue to expand and retain a normal phenotype for 2 more weeks if cultured in a leukemia inhibitory factor (LIF)-containing serum-free medium. Such expansion is accompanied initially by upregulation of Cyclin E2 colocalized with nuclear translocation of phosphorylated retinoblastoma tumor suppressor (p-Rb) at Day 21 followed by a delay in contact inhibition through activation of LIF-Janus kinase1 (JAK1)-signal transducer and activator of transcription 3 (STAT3) signaling at Day 35. The LIF-JAK1-STAT3 signaling is coupled with upregulation of E2F2 colocalized with nuclear p-Rb and with concomitant downregulation of p16(INK4a), of which upregulation is linked to senescence. Hence, activation of LIF-JAK1-STAT3 signaling to delay contact inhibition can be used as another strategy to facilitate engineering of HCEC grafts to solve the unmet global shortage of corneal grafts. PMID- 25695745 TI - Collagenase treatment of Dupuytren's contracture using a modified injection method: a prospective cohort study of skin tears in 164 hands, including short term outcome. AB - BACKGROUND AND PURPOSE: Treatment of Dupuytren's contracture (DC) with collagenase Clostridium histolyticum (CCH) consists of injection followed by finger manipulation. We used a modified method, injecting a higher dose than recommended on the label into several parts of the cord, which allows treatment of multiple joint contractures in 1 session and may increase efficacy. We studied the occurrence of skin tears and short-term outcome with this procedure. PATIENTS AND METHODS: We studied 164 consecutive hands with DC, palpable cord, and extension deficit of >= 20o in the metacarpophalangeal (MCP) and/or proximal interphalangeal (PIP) joint (mean patient age 70 years, 82% men). A hand surgeon injected all the content of 1 CCH vial (approximately 0.80 mg) into multiple spots in the cord and performed finger extension under local anesthesia after 1 or 2 days. A nurse recorded skin tears on a diagram and conducted a standard telephone follow-up within 4 weeks. A hand therapist measured joint contracture before injection and at a median of 23 (IQR: 7-34) days after finger extension. RESULTS: A skin tear occurred in 66 hands (40%). The largest diameter of the tear was <= 5 mm in 30 hands and > 10 mm in 14 hands. Hands with skin tear had greater mean pretreatment MCP extension deficit than those without tear: 59o (SD 26) as opposed to 32o (SD 23). Skin tear occurred in 21 of 24 hands with MCP contracture of >= 75o. All tears healed with open-wound treatment. No infections occurred. Mean improvement in total (MCP + PIP) extension deficit was 55o (SD 28). INTERPRETATION: Skin tears occurred in 40% of hands treated with collagenase injections, but only a fifth of them were larger than 1 cm. Tears were more likely in hands with severe MCP joint contracture. All tears healed without complications. Short-term contracture reduction was good. PMID- 25695746 TI - Myostatin gene mutated mice induced with tale nucleases. AB - Myostain gene (MSTN) is expressed primarily in skeletal muscle, and negatively regulates skeletal muscle mass; it has been suggested that mice with MSTN inhibition have reduced adiposity and improved insulin sensitivity. Therefore, it is important to establish a fast and effective gene editing method. In this report, we established the myostatin mutated-mouse model by microinjection of Transcription Activator-Like Effector Nucleases (TALENs) mRNA within the mouse fertilized oocytes and achieved high rates of mutagenesis of the mouse MSTN in C57BL/6J. Six of 45 born mice carried target mutations and we appointed one as the parental mating with wild mouse to produce the F1 and backcross to produce the F2 generation. All the mutations of the mice were examined quickly and efficiently by high-resolution melting curve analysis (HRMA) and then verified by direct sequencing. We obtained the homozygous of the F2 generation which transmitted the mutant alleles to the progeny with 100% efficiency. Mutant mice exhibited increases in muscle mass comparable to those observed in wild-type mice. Therefore, combining TALEN-mediated gene targeting with HRMA technology is a superior method of constructing genetically modified mice through microinjection in the mouse fertilized oocytes with high efficiency and short time of selection. PMID- 25695747 TI - Analysis of the Campylobacter jejuni genome by SMRT DNA sequencing identifies restriction-modification motifs. AB - Campylobacter jejuni is a leading bacterial cause of human gastroenteritis. The goal of this study was to analyze the C. jejuni F38011 strain, recovered from an individual with severe enteritis, at a genomic and proteomic level to gain insight into microbial processes. The C. jejuni F38011 genome is comprised of 1,691,939 bp, with a mol.% (G+C) content of 30.5%. PacBio sequencing coupled with REBASE analysis was used to predict C. jejuni F38011 genomic sites and enzymes that may be involved in DNA restriction-modification. A total of five putative methylation motifs were identified as well as the C. jejuni enzymes that could be responsible for the modifications. Peptides corresponding to the deduced amino acid sequence of the C. jejuni enzymes were identified using proteomics. This work sets the stage for studies to dissect the precise functions of the C. jejuni putative restriction-modification enzymes. Taken together, the data generated in this study contributes to our knowledge of the genomic content, methylation profile, and encoding capacity of C. jejuni. PMID- 25695748 TI - Balancing charge in the complementarity-determining regions of humanized mAbs without affecting pI reduces non-specific binding and improves the pharmacokinetics. AB - Lowering the isoelectric point (pI) through engineering the variable region or framework of an IgG can improve its exposure and half-life via a reduction in clearance mediated through non-specific interactions. As such, net charge is a potentially important property to consider in developing therapeutic IgG molecules having favorable pharmaceutical characteristics. Frequently, it may not be possible to shift the pI of monoclonal antibodies (mAbs) dramatically without the introduction of other liabilities such as increased off-target interactions or reduced on-target binding properties. In this report, we explored the influence of more subtle modifications of molecular charge on the in vivo properties of an IgG1 and IgG4 monoclonal antibody. Molecular surface modeling was used to direct residue substitutions in the complementarity-determining regions (CDRs) to disrupt positive charge patch regions, resulting in a reduction in net positive charge without affecting the overall pI of the mAbs. The effect of balancing the net positive charge on non-specific binding was more significant for the IgG4 versus the IgG1 molecule that we examined. This differential effect was connected to the degree of influence on cellular degradation in vitro and in vivo clearance, distribution and metabolism in mice. In the more extreme case of the IgG4, balancing the charge yielded an ~7-fold improvement in peripheral exposure, as well as significantly reduced tissue catabolism and subsequent excretion of proteolyzed products in urine. Balancing charge on the IgG1 molecule had a more subtle influence on non-specific binding and yielded only a modest alteration in clearance, distribution and elimination. These results suggest that balancing CDR charge without affecting the pI can lead to improved mAb pharmacokinetics, the magnitude of which is likely dependent on the relative influence of charge imbalance and other factors affecting the molecule's disposition. PMID- 25695749 TI - Letter to the editor concerning: "Immunisation coverage of adults: a vaccination counselling campaign in the pharmacies in Switzerland". PMID- 25695750 TI - AAA+ chaperones and acyldepsipeptides activate the ClpP protease via conformational control. AB - The Clp protease complex degrades a multitude of substrates, which are engaged by a AAA+ chaperone such as ClpX and subsequently digested by the dynamic, barrel shaped ClpP protease. Acyldepsipeptides (ADEPs) are natural product-derived antibiotics that activate ClpP for chaperone-independent protein digestion. Here we show that both protein and small-molecule activators of ClpP allosterically control the ClpP barrel conformation. We dissect the catalytic mechanism with chemical probes and show that ADEP in addition to opening the axial pore directly stimulates ClpP activity through cooperative binding. ClpP activation thus reaches beyond active site accessibility and also involves conformational control of the catalytic residues. Moreover, we demonstrate that substoichiometric amounts of ADEP potently prevent binding of ClpX to ClpP and, at the same time, partially inhibit ClpP through conformational perturbance. Collectively, our results establish the hydrophobic binding pocket as a major conformational regulatory site with implications for both ClpXP proteolysis and ADEP-based anti bacterial activity. PMID- 25695751 TI - Sustainable Decisions Signal Sustainable Relationships: How Purchasing Decisions Affect Perceptions and Romantic Attraction. AB - In the pursuit of love, individuals strategically use luxury products to signal status and other attractive attributes. Might eco-friendly products also signal mate-relevant information? The current research examined inferences from eco friendly purchases and how they predict perceived suitability for short- and long term romantic relationships. Participants read descriptions of a stranger's eco friendly or luxury purchase decisions, reported their perceptions of the purchaser, and indicated their potential romantic interest in the purchaser. The influence of the relative price of the chosen product was also investigated. Compared to luxury purchasers, eco-friendly purchasers were ascribed greater warmth, competence, and good partner traits, but less physical appeal, and they were preferred for long-term but not short-term relationships. The social costs and benefits of "going green" are discussed in light of their implications for environmental sustainability efforts. PMID- 25695752 TI - Association of Smoking and CFH and ARMS2 Risk Variants With Younger Age at Onset of Neovascular Age-Related Macular Degeneration. AB - IMPORTANCE: The age at which the first signs of age-related macular degeneration (AMD) manifest is variable. Better insight into factors that influence disease onset has direct implications for preventive measures and patient counseling. OBJECTIVE: To identify risk factors for an earlier age at onset of neovascular AMD. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study, including patient data from the European Genetic Database collected between April 2006 and July 2010. All patients had at least 1 documented visit to the outpatient AMD clinic of the Radboud University Medical Center, Nijmegen, the Netherlands, a tertiary referral center for retinal disorders. In total, 275 patients with a known age at onset of neovascular AMD and a genetic risk analysis were included. MAIN OUTCOMES AND MEASURES: Effects of several genetic, sociodemographic, behavioral, and ocular factors on the age at onset of neovascular AMD. The mean differences in the age at onset were determined using general linear models with the age at onset as the dependent variable. RESULTS: Past smokers and current smokers developed neovascular AMD on average 4.9 (95% CI, 3.0-6.8) and 7.7 (95% CI, 5.3-10.0) years earlier, respectively, than never smokers (P < .001 for both). Compared with the reference group, the age at onset was 5.2 (95% CI, 2.8 7.7) years earlier for homozygous carriers of the A69S risk allele in the age related maculopathy susceptibility 2 (ARMS2) gene (P < .001). Homozygous carriers of the Y402H risk variant in the complement factor H (CFH) gene developed neovascular AMD 2.8 (95% CI, 0.5-5.0) years earlier (P = .02). Patients carrying 4 risk alleles in CFH and ARMS2 developed neovascular AMD 12.2 (95% CI, 6.2-18.3) years earlier than patients with zero risk alleles (P < .001). CONCLUSIONS AND RELEVANCE: Genetic and environmental risk factors influence the age at onset of neovascular AMD. Individuals at risk could be identified at an early age if and when preventive or therapeutic options become available. Insight into individual risk profiles might influence patients' consideration of interventions to increase their chance of avoiding vision loss from AMD. PMID- 25695753 TI - Specificity matters: criterion-related validity of contextualized and facet measures of conscientiousness in predicting college student performance. AB - To enhance the predictive validity of self-report personality measures, 2 distinct ways of increasing specificity of personality measures have been proposed in the literature-contextual specificity (i.e., providing a contextual referent) and content specificity (i.e., focusing on more specific constructs such as the Big Five facets). This study extends this line of research by examining whether there is an optimal way to configure, align, or integrate contextual and content specificity using measures of conscientiousness to predict college student success. A sample of 478 undergraduate students completed 4 measures of conscientiousness that varied in the level of content and contextual specificity. These forms of specificity were crossed to yield 4 distinct measures of conscientiousness. We then evaluated and compared the relative importance and the incremental importance of these different measures in the prediction of academic success. Superior predictive validity was found for both contextualized and facet measures of conscientiousness compared to a measure of global conscientiousness in predicting grade-point average and a broader behavioral criterion of student performance. When contextual and content specificity approaches were compared and combined, we observed the strongest predictive validity when the level of specificity is appropriately matched between predictor and criterion. PMID- 25695755 TI - Reaction of arynes with sulfoxides. AB - A S-O bond insertion reaction of sulfoxides with arynes is reported. This reaction represents a rare instance of semipolar single bond insertion in aryne chemistry. The study of mechanism indicates that a sulfur ylide triggered by aryne is the key intermediate, which further transfers its methylene group to carbonyl compounds to give epoxides and thioethers through a sequential process. PMID- 25695754 TI - Reassortant highly pathogenic influenza A(H5N6) virus in Laos. AB - In March 2014, avian influenza in poultry in Laos was caused by an emergent influenza A(H5N6) virus. Genetic analysis indicated that the virus had originated from reassortment of influenza A(H5N1) clade 2.3.2.1b, variant clade 2.3.4, and influenza A(H6N6) viruses that circulate broadly in duck populations in southern and eastern China. PMID- 25695756 TI - Component-controlled synthesis and assembly of Cu-Pd nanocrystals on graphene for oxygen reduction reaction. AB - Exploring low-cost, high-activity, and long-durability hybrid electrocatalysts for cathodic oxygen reduction reaction (ORR) is vital to advance fuel cells technologies. In this paper, a series of graphene (G)-CuxPdy (Cu4Pd, Cu3Pd, CuPd, CuPd3, CuPd4) nanocomposites (G-CuxPdy NCPs) is obtained by assembly of CuxPdy alloy nanocrystals (NCs) with controlled component ratios on G nanosheets using the "dispersing-mixing-vaporizing solvent" strategy and used as electrocatalysts for ORR. Compared with pure CuxPdy NCs, greatly enhanced interfacial electron transfer dynamics are observed in G-CuxPdy NCPs, which show a strong correlation with the alloy compositions of the NCPs. The electrocatalytic experiments in alkaline solution reveal that the ORR activities of those G-CuxPdy NCPs are also strongly dependent on alloy components and exhibit a double-volcano feature with variations of alloy components. Among them, G-Cu3Pd NCPs possess the highest electrocatalytic activity, which is much better than some reported electrocatalysts and commercial Pd/C catalyst and close to Pt/C catalyst. By correlating the Pd 3d binding energies and the sizes of CuxPdy NCs with the mass specific activities of G-CuxPdy NCPs and considering the interfacial electron transfer dynamics, the best catalytic activity of G-Cu3Pd NCPs may result from the unique electronic structure and the smallest size of Cu3Pd NCs as well as the strong synergistic effect between G and Cu3Pd NCs. Moreover, the durability of G Cu3Pd NCPs is superior to that of Pt/C catalyst, indicating that they are promising cathodic electrocatalysts for using in alkaline fuel cells. PMID- 25695757 TI - Ubiquitin-H2AX fusions render 53BP1 recruitment to DNA damage sites independent of RNF8 or RNF168. AB - The mammalian E3 ubiquitin ligases RNF8 and RNF168 facilitate recruitment of the DNA damage response protein 53BP1 to sites of DNA double-strand breaks (DSBs). The mechanism involves recruitment of RNF8, followed by recruitment of RNF168, which ubiquitinates histones H2A/H2AX on K15. 53BP1 then binds to nucleosomes at sites of DNA DSBs by recognizing, in addition to methyl marks, histone H2A/H2AX ubiquitinated on K15. We report here that expressing H2AX fusion proteins with N terminal bulky moieties can rescue 53BP1 recruitment to sites of DNA DSBs in cells lacking RNF8 or RNF168 or in cells treated with proteasome inhibitors, in which histone ubiquitination at sites of DNA DSBs is compromised. The rescue required S139 at the C-terminus of the H2AX fusion protein and was occasionally accompanied by partial rescue of ubiquitination at sites of DNA DSBs. We conclude that recruitment of 53BP1 to sites of DNA DSBs is possible in the absence of RNF8 or RNF168, but still dependent on chromatin ubiquitination. PMID- 25695758 TI - Reemergence of murine typhus in Galveston, Texas, USA, 2013. AB - Twelve patients with murine typhus were identified in Galveston, Texas, USA, in 2013. An isolate from 1 patient was confirmed to be Rickettsia typhi. Reemergence of murine typhus in Galveston emphasizes the importance of vector control and awareness of this disease by physicians and public health officials. PMID- 25695759 TI - Delineating the effect of semantic congruency on episodic memory: the role of integration and relatedness. AB - A fundamental challenge in the study of learning and memory is to understand the role of existing knowledge in the encoding and retrieval of new episodic information. The importance of prior knowledge in memory is demonstrated in the congruency effect-the robust finding wherein participants display better memory for items that are compatible, rather than incompatible, with their pre-existing semantic knowledge. Despite its robustness, the mechanism underlying this effect is not well understood. In four studies, we provide evidence that demonstrates the privileged explanatory power of the elaboration-integration account over alternative hypotheses. Furthermore, we question the implicit assumption that the congruency effect pertains to the truthfulness/sensibility of a subject-predicate proposition, and show that congruency is a function of semantic relatedness between item and context words. PMID- 25695760 TI - Phylogeography of the walnut twig beetle, Pityophthorus juglandis, the vector of thousand cankers disease in North American walnut trees. AB - Thousand cankers disease (TCD) of walnut trees (Juglans spp.) results from aggressive feeding in the phloem by the walnut twig beetle (WTB), Pityophthorus juglandis, accompanied by inoculation of its galleries with a pathogenic fungus, Geosmithia morbida. In 1960, WTB was only known from four U.S. counties (in Arizona, California, and New Mexico), but the species has now (2014) invaded over 115 counties, representing much of the western USA, and at least six states in the eastern USA. The eastern expansion places TCD in direct proximity to highly valuable (> $500 billion) native timber stands of eastern black walnut, Juglans nigra. Using mitochondrial DNA sequences, from nearly 1100 individuals, we examined variation among 77 samples of WTB populations across its extended range in the USA, revealing high levels of polymorphism and evidence of two divergent lineages. The highest level of genetic diversity for the different lineages was found in the neighboring Madrean Sky Island and Western New Mexico regions, respectively. Despite their proximity, there was little evidence of mixing between these regions, with only a single migrant detected among 179 beetles tested. Indeed, geographic overlap of the two lineages was only common in parts of Colorado and Utah. Just two haplotypes, from the same lineage, predominated over the vast majority of the recently expanded range. Tests for Wolbachia proved negative suggesting it plays no role in "driving" the spread of particular haplotypes, or in maintaining deep levels of intraspecific divergence in WTB. Genotyping of ribosomal RNA corroborated the mitochondrial lineages, but also revealed evidence of hybridization between them. Hybridization was particularly prevalent in the sympatric areas, also apparent in all invaded areas, but absent from the most haplotype-rich area of each mitochondrial lineage. Hypotheses about the specific status of WTB, its recent expansion, and potential evolutionary origins of TCD are discussed. PMID- 25695761 TI - Prevalence of pulmonary tuberculosis among adults in a north Indian district. AB - BACKGROUND: Recent population prevalence estimates of pulmonary tuberculosis (PTB) are not available for several areas in India. We conducted a field-based population survey at a north Indian district to estimate point prevalence of bacteriologically positive PTB. METHODS: A stratified cluster sampling design was used to conduct the survey in both urban and rural areas within the district. All adults aged more than 15 years, in 18 rural and 12 urban clusters of 3000 subjects each, were interviewed using a symptom card. Two sputum samples were collected from all persons having symptoms suggestive of PTB, or history of antitubercular treatment, for smear microscopy for acid-fast bacilli and mycobacterial culture. Those having at least one sputum specimen positive on microscopy and/or culture were categorized as having PTB. Prevalence was estimated after adjusting for cluster sampling and incomplete data (through individual level analysis with robust standard error). RESULTS: Of 91,030 eligible adult participants (47,714 men and 43,316 women), 85,770 (94.2%) completed the symptom cards. Of them, 2,898 persons were considered eligible for sputum examination and 2,839 (98.0%) provided at least one sample. Overall, 21 persons had bacteriologically positive PTB, and cluster level prevalence was estimated at 24.5 per 100,000 population (95% CI 12.8-36.2). Individual level analysis with robust standard error yielded a prevalence estimate of 24.1 per 100,000 populations (95% CI 12.8-35.4). CONCLUSION: The observed prevalence of bacteriologically positive PTB in this district is lower than empiric national estimates, probably as a result of successful implementation of tuberculosis control measures in the area. PMID- 25695762 TI - Relationship between glycosylated hemoglobin A1c and coronary flow reserve in patients with Type 2 diabetes mellitus. AB - Type 2 diabetes mellitus patients are at increased risk for macrovascular and microvascular complications. Both in vivo and in vitro studies of small arteries and arterioles of diabetic subjects demonstrate impaired endothelial function without anatomic lesions. Coronary flow reserve (CFR) is a surrogate marker of coronary microcirculatory endothelial function in diabetic patients without significant stenosis of the associated epicardial coronary artery. Glycosylated hemoglobin A1c is related to likelihood of occurrence of microvascular events. The objective of this article is to report on recent developments in multiple noninvasive techniques to assess CFR and their use in aiding the understanding of the relationship of CFR, glycemic control and cardiovascular outcomes. PMID- 25695763 TI - Rationally designed gibbous stimuli-responsive colloidal nanoparticles. AB - Multiphase colloidal copolymer nanoparticles, if properly designed, offer a number of unique properties and well-documented technological opportunities for drug delivery, nanolithography, high surface area colloidal crystals, or hollow nanoparticles, to name just a few. Using a simple free radical polymerization process, we synthesized copolymer nanoparticles with controlled stimuli responsive phase-separated gibbosities. The topography of the gibbous phase can be controlled by the copolymer composition and polymerization conditions. When pH sensitive monomers were copolymerized onto surface bulges, pH changes resulted in localized gibbous phase dimensional changes. Facilitated by monomer diffusion into interfacial particle seed solution regions, localized polymerization near the surface is responsible for the formation of phase-separated gibbous topographies. This general approach may offer a number of possibilities for controllable design of ordered heterogeneous copolymer morphologies for a variety of applications. PMID- 25695764 TI - Data-driven prediction and design of bZIP coiled-coil interactions. AB - Selective dimerization of the basic-region leucine-zipper (bZIP) transcription factors presents a vivid example of how a high degree of interaction specificity can be achieved within a family of structurally similar proteins. The coiled-coil motif that mediates homo- or hetero-dimerization of the bZIP proteins has been intensively studied, and a variety of methods have been proposed to predict these interactions from sequence data. In this work, we used a large quantitative set of 4,549 bZIP coiled-coil interactions to develop a predictive model that exploits knowledge of structurally conserved residue-residue interactions in the coiled-coil motif. Our model, which expresses interaction energies as a sum of interpretable residue-pair and triplet terms, achieves a correlation with experimental binding free energies of R = 0.68 and significantly out-performs other scoring functions. To use our model in protein design applications, we devised a strategy in which synthetic peptides are built by assembling 7-residue native-protein heptad modules into new combinations. An integer linear program was used to find the optimal combination of heptads to bind selectively to a target human bZIP coiled coil, but not to target paralogs. Using this approach, we designed peptides to interact with the bZIP domains from human JUN, XBP1, ATF4 and ATF5. Testing more than 132 candidate protein complexes using a fluorescence resonance energy transfer assay confirmed the formation of tight and selective heterodimers between the designed peptides and their targets. This approach can be used to make inhibitors of native proteins, or to develop novel peptides for applications in synthetic biology or nanotechnology. PMID- 25695765 TI - The effects of seed ingestion by livestock, dung fertilization, trampling, grass competition and fire on seedling establishment of two woody plant species. AB - The increasing rate of woody plant encroachment in grasslands or savannas remains a challenge to livestock farmers. The causes and control measures of woody plant encroachment are of common interest, especially where it negatively affects the objectives of an agricultural enterprise. The objectives of this study were to determine the effects of gut passage (goats, cattle), dung (nutrients), fire, grass competition and trampling on establishment of A. nilotica and D. cinerea seedlings. Germination trials were subjected to the following treatments: 1) seed passage through the gut of cattle and goats and unpassed/ untreated seeds (i.e. not ingested), 2) dung and control (no dung), 3) grass and control (mowed grass), 4) fire and control (no fire), 5) trampling and control (no trampling). The interaction of animal species, grass and fire had an effect on seedling recruitment (P < 0.0052). Seeds retrieved from goats and planted with no grass and with fire (6.81% +/- 0.33) had a significant effect on seedling recruitment than seeds retrieved from goats and planted with grass and no fire (2.98% +/- 0.33). Significantly more D. cinerea and A. nilotica seeds germinated following seed ingestion by goats (3.59% +/- 0.16) than cattle (1.93% +/- 0.09) and control or untreated seeds (1.69% +/- 0.11). Less dense grass cover, which resulted in reduced grass competition with tree seedlings for light, space and water, and improved seed scarification due to gut passage were vital for emergence and recruitment of Acacia seedlings. These results will contribute considerably to the understanding of the recruitment phase of woody plant encroachment. PMID- 25695766 TI - The discovery of macrocyclic XIAP antagonists from a DNA-programmed chemistry library, and their optimization to give lead compounds with in vivo antitumor activity. AB - Affinity selection screening of macrocycle libraries derived from DNA-programmed chemistry identified XIAP BIR2 and BIR3 domain inhibitors that displace bound pro apoptotic caspases. X-ray cocrystal structures of key compounds with XIAP BIR2 suggested potency-enhancing structural modifications. Optimization of dimeric macrocycles with similar affinity for both domains were potent pro-apoptotic agents in cancer cell lines and efficacious in shrinking tumors in a mouse xenograft model. PMID- 25695767 TI - Molecular mechanism of HIV-1 Tat interacting with human dopamine transporter. AB - Nearly 70% of HIV-1-infected individuals suffer from HIV-associated neurocognitive disorders (HAND). HIV-1 transactivator of transcription (Tat) protein is known to synergize with abused drugs and exacerbate the progression of central nervous system (CNS) pathology. Cumulative evidence suggest that the HIV 1 Tat protein exerts the neurotoxicity through interaction with human dopamine transporter (hDAT) in the CNS. Through computational modeling and molecular dynamics (MD) simulations, we develop a three-dimensional (3D) structural model for HIV-1 Tat binding with hDAT. The model provides novel mechanistic insights concerning how HIV-1 Tat interacts with hDAT and inhibits dopamine uptake by hDAT. In particular, according to the computational modeling, Tat binds most favorably with the outward-open state of hDAT. Residues Y88, K92, and Y470 of hDAT are predicted to be key residues involved in the interaction between hDAT and Tat. The roles of these hDAT residues in the interaction with Tat are validated by experimental tests through site-directed mutagensis and dopamine uptake assays. The agreement between the computational and experimental data suggests that the computationally predicted hDAT-Tat binding mode and mechanistic insights are reasonable and provide a new starting point to design further pharmacological studies on the molecular mechanism of HIV-1-associated neurocognitive disorders. PMID- 25695769 TI - Hydrolysis of coordinated diazoalkanes to yield side-on 1,2-diazene derivatives. AB - Diazoalkane complexes [Ru(eta(5)-C5Me5)(N2CAr1Ar2)(PPh3){P(OR)3}]BPh4 [R = Me (1), Et (2); Ar1 = Ar2 = Ph (a); Ar1 = Ph, Ar2 = p-tolyl (b); Ar1Ar2 = C12H8 (c)] were prepared by allowing chloro complexes RuCl(eta(5)-C5Me5)(PPh3)[P(OR)3] to react with diazoalkane Ar1Ar2CN2 in ethanol. The treatment of compounds 1 and 2 with H2O afforded 1,2-diazene derivatives [Ru(eta(5)-C5Me5)(eta(2) NH?NH)(PPh3){P(OR)3}]BPh4 (3 and 4) and ketone Ar1Ar2CO. A reaction path involving nucleophilic attack by H2O on the coordinated diazoalkane is proposed. The complexes were characterized spectroscopically (IR and NMR) and by X-ray crystal structure determination of [Ru(eta(5)-C5Me5)(eta(2) NH?NH)(PPh3){P(OMe)3}]BPh4 (3). PMID- 25695768 TI - SveDem, the Swedish Dementia Registry - a tool for improving the quality of diagnostics, treatment and care of dementia patients in clinical practice. AB - BACKGROUND: The Swedish Dementia Registry (SveDem) was developed with the aim to improve the quality of diagnostic work-up, treatment and care of patients with dementia disorders in Sweden. METHODS: SveDem is an internet based quality registry where several indicators can be followed over time. It includes information about the diagnostic work-up, medical treatment and community support (www.svedem.se). The patients are diagnosed and followed-up yearly in specialist units, primary care centres or in nursing homes. RESULTS: The database was initiated in May 2007 and covers almost all of Sweden. There were 28 722 patients registered with a mean age of 79.3 years during 2007-2012. Each participating unit obtains continuous online statistics from its own registrations and they can be compared with regional and national data. A report from SveDem is published yearly to inform medical and care professionals as well as political and administrative decision-makers about the current quality of diagnostics, treatment and care of patients with dementia disorders in Sweden. CONCLUSION: SveDem provides knowledge about current dementia care in Sweden and serves as a framework for ensuring the quality of diagnostics, treatment and care across the country. It also reflects changes in quality dementia care over time. Data from SveDem can be used to further develop the national guidelines for dementia and to generate new research hypotheses. PMID- 25695770 TI - Effects of heavy-resistance strength and balance training on unilateral and bilateral leg strength performance in old adults. AB - The term "bilateral deficit" (BLD) has been used to describe a reduction in performance during bilateral contractions when compared to the sum of identical unilateral contractions. In old age, maximal isometric force production (MIF) decreases and BLD increases indicating the need for training interventions to mitigate this impact in seniors. In a cross-sectional approach, we examined age related differences in MIF and BLD in young (age: 20-30 years) and old adults (age: >65 years). In addition, a randomized-controlled trial was conducted to investigate training-specific effects of resistance vs. balance training on MIF and BLD of the leg extensors in old adults. Subjects were randomly assigned to resistance training (n = 19), balance training (n = 14), or a control group (n = 20). Bilateral heavy-resistance training for the lower extremities was performed for 13 weeks (3 * / week) at 80% of the one repetition maximum. Balance training was conducted using predominately unilateral exercises on wobble boards, soft mats, and uneven surfaces for the same duration. Pre- and post-tests included uni and bilateral measurements of maximal isometric leg extension force. At baseline, young subjects outperformed older adults in uni- and bilateral MIF (all p < .001; d = 2.61-3.37) and in measures of BLD (p < .001; d = 2.04). We also found significant increases in uni- and bilateral MIF after resistance training (all p < .001, d = 1.8-5.7) and balance training (all p < .05, d = 1.3-3.2). In addition, BLD decreased following resistance (p < .001, d = 3.4) and balance training (p < .001, d = 2.6). It can be concluded that both training regimens resulted in increased MIF and decreased BLD of the leg extensors (HRT-group more than BAL-group), almost reaching the levels of young adults. PMID- 25695771 TI - Cardiovascular disease risk factor profiles of 263,356 older Australians according to region of birth and acculturation, with a focus on migrants born in Asia. AB - Risk factors for cardiovascular disease (CVD), such as obesity, diabetes, hypertension and physical inactivity, are common in Australia, but the prevalence varies according to cultural background. We examined the relationship between region of birth, measures of acculturation, and CVD risk profiles in immigrant, compared to Australian-born, older Australians. Cross-sectional data from 263,356 participants aged 45 and over joining the population-based 45 and Up Study cohort from 2006-2008 were used. Prevalence ratios for CVD risk factors in Australian- versus overseas-born participants were calculated using modified Poisson regression, adjusting for age, sex and socioeconomic factors and focusing on Asian migrants. The association between time resident in Australia and age at migration and CVD risk factors in Asian migrants was also examined. Migrants from Northeast (n = 3,213) and Southeast Asia (n = 3,942) had lower levels of overweight/obesity, physical activity and female smoking than Australian-born participants (n = 199,356), although differences in prevalence of overweight/obesity were sensitive to body-mass-index cut-offs used. Compared to Australian-born participants, migrants from Northeast Asia were 20-30% less likely, and from Southeast Asia 10-20% more likely, to report being treated for hypertension and/or hypercholesterolaemia; Southeast Asian migrants were 40-60% more likely to report diabetes. Northeast Asian-born individuals were less likely than Australian-born to have 3 or more CVD risk factors. Diabetes, treated hypertension and hypercholesterolaemia occurred at relatively low average body mass-index in Southeast Asian migrants. The CVD risk factor profiles of migrants tended to approximate those of Australian-born with increasing acculturation, in both favourable (e.g., increased physical activity) and unfavourable directions (e.g., increased female smoking). Minimizing CVD risk in migrant populations may be achieved through efforts to retain the healthy facets of the traditional lifestyle, such as a normal body mass index and low prevalence of smoking in women, in addition to adopting healthy aspects of the host country lifestyle, such as increased physical activity. PMID- 25695772 TI - Comparison of effects of p53 null and gain-of-function mutations on salivary tumors in MMTV-Hras transgenic mice. AB - p53 is an important tumor suppressor gene which is mutated in ~50% of all human cancers. Some of these mutants appear to have acquired novel functions beyond merely losing wild-type functions. To investigate these gain-of-function effects in vivo, we generated mice of three different genotypes: MMTV-Hras/p53(+/+), MMTV Hras/p53(-/-), and MMTV-Hras/p53R172H/R172H. Salivary tumors from these mice were characterized with regard to age of tumor onset, tumor growth rates, cell cycle distribution, apoptotic levels, tumor histopathology, as well as response to doxorubicin treatment. Microarray analysis was also performed to profile gene expression. The MMTV-Hras/p53(-/-) and MMTV-Hras/p53R172H/R172H mice displayed similar properties with regard to age of tumor onset, tumor growth rates, tumor histopathology, and response to doxorubicin, while both groups were clearly distinct from the MMTV-Hras/p53(+/+) mice by these measurements. In addition, the gene expression profiles of the MMTV-Hras/p53(-/-) and MMTV-Hras/p53(R172H/R172H) tumors were tightly clustered, and clearly distinct from the profiles of the MMTV Hras/p53(+/+) tumors. Only a small group of genes showing differential expression between the MMTV-Hras/p53(-/-) and MMTV-Hras/p53(R172H/R172H) tumors, that did not appear to be regulated by wild-type p53, were identified. Taken together, these results indicate that in this MMTV-Hras-driven salivary tumor model, the major effect of the p53 R172H mutant is due to the loss of wild-type p53 function, with little or no gain-of-function effect on tumorigenesis, which may be explained by the tissue- and tumor type-specific properties of this gain-of function mutant of p53. PMID- 25695773 TI - Happiness and social exclusion of indigenous peoples in Taiwan--a social sustainability perspective. AB - INTRODUCTION: Happiness and social inclusion are important indicators of social sustainability, as recommended in the Sustainable Development Goals; however, little is known about the social sustainable development of ethnic minorities. To fill this knowledge gap, special attention is paid to understanding the issues of social exclusion and happiness in relation to the indigenous peoples in Taiwan. METHODS: Data used were drawn from a nationwide representativeness survey of the Taiwanese Indigenous People in 2007; it included 2,200 respondents. This study employed binary logistic regression to examine the effects of different domains of social exclusion on the likelihood of perceiving happiness; other exogenous factors, were controlled. RESULTS: The results show that among the respondents, mountain indigenous peoples, females, the elderly and those who are healthier, wealthier, highly educated, possessing western beliefs, and are more likely to be happy, compared to their counterparts. As expected, the results reveal that the likelihood of being happy is higher for those who have received medical benefits, as well as those persons without housing problems or financial difficulties, compared to their excluded counterparts. However, no significant association is found between happiness and some social exclusion domains, such as child and youth benefits, and unemployment benefits. CONCLUSIONS: The disengagement of the indigenous peoples in mainstream society, with respect to the accessibility of welfare provisions, is a crucial element in regard to social exclusion and happiness. Several policy implications for the social sustainability of indigenous peoples can be inferred from these findings. For example, providing a mobile clinical tour, on-site health counseling, or homecare service can contribute to the removal of institutional and geographic barriers to medical welfare provisions for the mountain indigenes. Moreover, the government may devote more welfare resources to assist indigenous families and tribal communities to develop their own social safety net, instead of the individual oriented welfare provisions. PMID- 25695774 TI - Defective differentiation of adipose precursor cells from lipodystrophic mice lacking perilipin 1. AB - Perilipin 1 (Plin1) localizes at the surface of lipid droplets to regulate triglyceride storage and hydrolysis in adipocytes. Plin1 defect leads to low adiposity in mice and partial lipodystrophy in human. This study investigated the roles of Plin1 in adipocyte differentiation. Plin1 null (-/-) mice showed plenty of multilocular adipocytes and small unilocular adipocytes in adipose tissue, along with lack of a subpopulation of adipose progenitor cells capable of in vivo adipogenesis and along with downregulation of adipogenic pathway. Before initiation of differentiation, adipose stromal-vascular cells (SVCs) from Plin1-/ mice already accumulated numerous tiny lipid droplets, which increased in number and size during the first 12-h induction but thereafter became disappeared at day 1 of differentiation. The adipogenic signaling was dysregulated despite protein level of PPARgamma was near normal in Plin1-/- SVCs like in Plin1-/- adipose tissue. Heterozygous Plin1+/- SVCs were able to develop lipid droplets, with both the number and size more than in Plin1-/- SVCs but less than in Plin1+/+ SVCs, indicating that Plin1 haploinsufficiency accounts for attenuated adipogenesis. Aberrant lipid droplet growth and differentiation of Plin1-/- SVCs were rescued by adenoviral Plin1 expression and were ameliorated by enhanced or prolonged adipogenic stimulation. Our finding suggests that Plin1 plays an important role in adipocyte differentiation and provides an insight into the pathology of partial lipodystrophy in patients with Plin1 mutation. PMID- 25695775 TI - Role of pentraxin 3 in shaping arthritogenic alphaviral disease: from enhanced viral replication to immunomodulation. AB - The rising prevalence of arthritogenic alphavirus infections, including chikungunya virus (CHIKV) and Ross River virus (RRV), and the lack of antiviral treatments highlight the potential threat of a global alphavirus pandemic. The immune responses underlying alphavirus virulence remain enigmatic. We found that pentraxin 3 (PTX3) was highly expressed in CHIKV and RRV patients during acute disease. Overt expression of PTX3 in CHIKV patients was associated with increased viral load and disease severity. PTX3-deficient (PTX3(-/-)) mice acutely infected with RRV exhibited delayed disease progression and rapid recovery through diminished inflammatory responses and viral replication. Furthermore, binding of the N-terminal domain of PTX3 to RRV facilitated viral entry and replication. Thus, our study demonstrates the pivotal role of PTX3 in shaping alphavirus triggered immunity and disease and provides new insights into alphavirus pathogenesis. PMID- 25695776 TI - Analysis of nematode motion using an improved light-scatter based system. AB - BACKGROUND: The detailed assessment of nematode activity and viability still remains a relatively undeveloped area of biological and medical research. Computer-based approaches to assessing the motility of larger nematode stages have been developed, yet these lack the capability to detect and analyze the more subtle and important characteristics of the motion of nematodes. There is currently a need to improved methods of assessing the viability and health of parasitic worms. METHODS: We describe here a system that converts the motion of nematodes through a light-scattering system into an electrical waveform, and allows for reproducible, and wholly non-subjective, assessment of alterations in motion, as well as estimation of the number of nematode worms of different forms and sizes. Here we have used Brugia sp. microfilariae (L1), infective larvae (L3) and adults, together with the free-living nematode Caenorhabditis elegans. RESULTS: The motion of worms in a small (200 ul) volume can be detected, with the presence of immotile worms not interfering with the readings at practical levels (up to at least 500 L1 /200 ul). Alterations in the frequency of parasite movement following the application of the anti-parasitic drugs, (chloroquine and imatinib); the anti-filarial effect of the latter agent is the first demonstrated here for the first time. This system can also be used to estimate the number of parasites, and shortens the time required to estimate parasites numbers, and eliminates the need for microscopes and trained technicians to provide an estimate of microfilarial sample sizes up to 1000 parasites/ml. Alterations in the form of motion of the worms can also be depicted. CONCLUSIONS: This new instrument, named a "WiggleTron", offers exciting opportunities to further study nematode biology and to aid drug discovery, as well as contributing to a rapid estimate of parasite numbers in various biological samples. PMID- 25695777 TI - Modulation of network excitability by persistent activity: how working memory affects the response to incoming stimuli. AB - Persistent activity and match effects are widely regarded as neuronal correlates of short-term storage and manipulation of information, with the first serving active maintenance and the latter supporting the comparison between memory contents and incoming sensory information. The mechanistic and functional relationship between these two basic neurophysiological signatures of working memory remains elusive. We propose that match signals are generated as a result of transient changes in local network excitability brought about by persistent activity. Neurons more active will be more excitable, and thus more responsive to external inputs. Accordingly, network responses are jointly determined by the incoming stimulus and the ongoing pattern of persistent activity. Using a spiking model network, we show that this mechanism is able to reproduce most of the experimental phenomenology of match effects as exposed by single-cell recordings during delayed-response tasks. The model provides a unified, parsimonious mechanistic account of the main neuronal correlates of working memory, makes several experimentally testable predictions, and demonstrates a new functional role for persistent activity. PMID- 25695779 TI - Successful cardiac transplantation in an 11-year-old boy with ectodermal dysplasia and dilated cardiomyopathy. PMID- 25695778 TI - Guanine-modified inhibitory oligonucleotides efficiently impair TLR7- and TLR9 mediated immune responses of human immune cells. AB - Activation of TLR7 and TLR9 by endogenous RNA- or DNA-containing ligands, respectively, is thought to contribute to the complicated pathophysiology of systemic lupus erythematosus (SLE). These ligands induce the release of type-I interferons by plasmacytoid dendritic cells and autoreactive antibodies by B cells, both responses being key events in perpetuating SLE. We recently described the development of inhibitory oligonucleotides (INH-ODN), which are characterized by a phosphorothioate backbone, a CC(T)XXX3-5GGG motif and a chemical modification of the G-quartet to avoid the formation of higher order structures via intermolecular G-tetrads. These INH-ODNs were equally or significantly more efficient to impair TLR7- and TLR9-stimulated murine B-cells, macrophages, conventional and plasmacytoid dendritic cells than the parent INH-ODN 2088, which lacks G-modification. Here, we evaluate the inhibitory/therapeutic potential of our set of G-modified INH-ODN on human immune cells. We report the novel finding that G-modified INH-ODNs efficiently inhibited the release of IFN-alpha by PBMC stimulated either with the TLR7-ligand oligoribonucleotide (ORN) 22075 or the TLR9-ligand CpG-ODN 2216. G-modification of INH-ODNs significantly improved inhibition of IL-6 release by PBMCs and purified human B-cells stimulated with the TLR7-ligand imiquimod or the TLR9-ligand CpG-ODN 2006. Furthermore, inhibition of B-cell activation analyzed by expression of activation markers and intracellular ATP content was significantly improved by G-modification. As observed with murine B-cells, high concentrations of INH-ODN 2088 but not of G modified INH-ODNs stimulated IL-6 secretion by PBMCs in the absence of TLR ligands thus limiting its blocking efficacy. In summary, G-modification of INH ODNs improved their ability to impair TLR7- and TLR9-mediated signaling in those human immune cells which are considered as crucial in the pathophysiology of SLE. PMID- 25695780 TI - Organ donation and transplantation in Central America. PMID- 25695782 TI - Tissue engineered grafts--160 years after R. Virchow's Omnis Cellula e Cellula. PMID- 25695783 TI - Minimum information standards. PMID- 25695784 TI - Leslie Brent, PhD: Professor Emeritus and Emeritus Editor of Transplantation. PMID- 25695785 TI - New humanized mouse model of bronchiolitis obliterans syndrome. AB - Humanized animals are transplanted with human tissues and cells to study their behavior as they do in the human body. This commentary briefly summarizes the recent developments and discusses the limitations of these humanized animal models. PMID- 25695786 TI - Common errors in the implementation and interpretation of microarray studies. AB - Microarray analysis is used to tackle transplant-related problems as diverse as diagnosing rejection, predicting graft loss, and determining who can safely be removed from immunosuppression. Highly accurate predictions seem to be the norm. Unfortunately, many of these studies are flawed, either through questionable experimental design or improper validation methods. In addition, results are often presented in a misleading manner which exaggerates their true worth. In this paper, we describe the most common and serious errors and misrepresentations. PMID- 25695787 TI - Allogeneic CD4+CD25high T cells regulate obliterative bronchiolitis of heterotopic bronchus allografts in both porcinized and humanized mouse models. AB - BACKGROUND: Bronchiolitis obliterans syndrome is caused by a fibroproliferative process in lung allografts resulting in irreversible damage. In this study, we induced obliterative bronchiolitis and studied the contribution of regulatory T cells to its development in immune-deficient mice receiving heterotopic porcine bronchus transplants, and major histocompatibility complex-mismatched porcine peripheral blood mononuclear cell. Furthermore, we aimed to corroborate our findings in a humanized mouse model. METHODS: Heterotopic bronchus transplantation was performed in 33 NOD.rag(-/-)gammac(-/-) mice, using miniature pigs as tissue donors.The recipient mice then either received saline (negative control), unsorted MHC-mismatched PBMC (positive control), PBMC enriched with CD4(+)CD25(high) cells or PBMC depleted of CD4(+)CD25(high) cells for reconstitution. The results were validated in 28 NOD.rag(-/-)gammac(-/-) mice undergoing heterotopic human bronchus transplantation and reconstitution with allogeneic human PBMC. RESULTS: Histological lesions similar to those typical for obliterative bronchiolitis developed in vivo after reconstitution with allogeneic PBMC and were more severe in animals engrafted with PBMC depleted of CD4(+)CD25(high) cells. In contrast, the group reconstituted with PBMC enriched with CD4(+)CD25(high) cells showed well-preserved histology. The results of the humanized model confirmed those obtained in the porcinized model. CONCLUSIONS: In conclusion, both porcinized and humanized mouse models of heterotopic subcutaneous bronchus transplantation imitate the in vivo development of bronchiolitis obliterans syndrome-like lesions and reveal its sensitivity to T cell regulation. PMID- 25695788 TI - Transplantation of bone marrow mesenchymal stem cells promotes learning and memory functional recovery and reduces hippocampal damage in rats with alcohol associated dementia. AB - BACKGROUND: Chronic ethanol exposure leads to permanent damage to the central nervous system and produces cognitive deficits such as learning and memory impairment. The present study was designed to explore the therapeutic effect of bone marrow mesenchymal stem cells (BMMSCs) on a rat model of alcohol-associated dementia (AAD). METHODS: Bone marrow mesenchymal stem cells were prelabeled with 4',6-diamidino-2-phenylindole and directly transplanted into the hippocampus of AAD rats, an important site of alcohol effects that lead to cognitive deficits. The therapeutic effect of BMMSCs was evaluated by observing Morris water maze behavior, hippocampus morphology, and neuronal apoptosis. Still, the activities of antioxidant enzymes including total superoxide dismutase and glutathione peroxidase in rat hippocampus were measured, and the expression of brain-derived neurotrophic factor in rat hippocampus was also detected by the method of immunohistochemistry. RESULTS: Transplantation of BMMSCs directly into the hippocampus significantly improved the learning and memory function of AAD rats and prevented alcohol-induced hippocampal damages. Moreover, BMMSC transplantation inhibited neuron cell apoptosis and increased the activity of total superoxide dismutase in the hippocampus. Moreover, transplantation of BMMSCs improved the protein level of brain-derived neurotrophic factor in the hippocampus in parallel with behavioral and histologic recovery for AAD rats. CONCLUSIONS: The findings indicate that the functional benefit observed in the BMMSC-grafted AAD rats is caused by the reduction of oxidative damage and the production of trophic factors by BMMSCs. Bone marrow mesenchymal stem-cell transplantation may be a useful and feasible method for clinical treatment of alcohol-induced brain injuries. PMID- 25695789 TI - Living donors ages 60 or older in right lobe living donor liver transplantation. PMID- 25695790 TI - Nonsteroidal anti-inflammatory drug-induced intestinal graft loss 12 years after transplantation. PMID- 25695791 TI - Renal response following perioperative ketorolac analgesia in living kidney donation. PMID- 25695792 TI - Ultrasound modalities and quantification: developments of multiparametric ultrasonography, a new modality to detect, localize and target prostatic tumors. AB - PURPOSE OF REVIEW: An imaging tool providing reliable prostate cancer (PCa) detection and localization is necessary to improve the diagnostic pathway with imaging targeted biopsies. This review presents the latest developments in existing and novel ultrasound modalities for the detection and localization of PCa. RECENT FINDINGS: The ultrasound modalities that were very promising on introduction (HistoScanning and Doppler) have shown a wane in performance when tested in larger patient populations. In the meantime, novel ultrasound modalities have emerged in the field of PCa detection. Modalities, such as shear wave elastography (SWE) and contrast-enhanced ultrasound (CEUS) show very promising results. SWE produces an absolute elasticity measure and removes the need for manual compression of the tissue. The former allows comparison between scans and patients, the latter reduces the interoperator variability. Quantification of CEUS enables easily interpretable and accurate imaging of the microvascular changes associated with clinically significant prostate tumors. SUMMARY: The novel ultrasound modalities of SWE and CEUS imaging open the door for taking targeted biopsies based on the detection and localization of PCa by these novel modalities. This potentially improves PCa detection wherein significantly reducing the number of biopsy cores. PMID- 25695793 TI - In-bore MRI interventions: current status and future applications. AB - PURPOSE OF REVIEW: This review discusses the feasibility, recent advances and current status of in-bore MRI-guided interventional techniques for diagnosis and treatment of focal prostate cancer (PCa) and also explores the future applications, highlighting the emerging strategies for the treatment of PCa. RECENT FINDINGS: Multiparametric MRI has opened up opportunities for diagnosis and targeted therapeutics to the site of disease within the organ wherein minimizing the incidence of treatment-related toxicity of whole gland therapy. MRI-guided targeted biopsy has a higher detection rate for significant cancer and lower rate of detection of insignificant cancer. In comparison to ultrasound guided focal therapy, in-bore treatment provides the advantage of real time thermal monitoring during treatment and assessment of treatment coverage by an enhanced scan immediately post-treatment. Preliminary results of ongoing phase I and II in-bore focal PCa treatment trials via transperineal, transrectal and transurethral routes, using different energy modalities for the ablation, have shown promising results. SUMMARY: Advances in multiparametric-MRI has opened up opportunities for in-bore targeted focal treatment of PCa in the correctly selected patient. PMID- 25695794 TI - The epigenetic agents suberoylanilide hydroxamic acid and 5-AZA-2' deoxycytidine decrease cell proliferation, induce cell death and delay the growth of MiaPaCa2 pancreatic cancer cells in vivo. AB - Despite incremental advances in the diagnosis and treatment for pancreatic cancer (PC), the 5-year survival rate remains <5%. Novel therapies to increase survival and quality of life for PC patients are desperately needed. Epigenetic thera peutic agents such as histone deacetylase inhibitors (HDACi) and DNA methyltransferase inhibitors (DNMTi) have demonstrated therapeutic benefits in human cancer. We assessed the efficacy of these epigenetic therapeutic agents as potential therapies for PC using in vitro and in vivo models. Treatment with HDACi [suberoylanilide hydroxamic acid (SAHA)] and DNMTi [5-AZA-2' deoxycytidine (5-AZA-dc)] decreased cell proliferation in MiaPaCa2 cells, and SAHA treatment, with or without 5-AZA-dc, resulted in higher cell death and lower DNA synthesis compared to 5-AZA-dc alone and controls (DMSO). Further, combination treatment with SAHA and 5-AZA-dc significantly increased expression of p21WAF1, leading to G1 arrest. Treatment with epigenetic agents delayed tumour growth in vivo, but did not decrease growth of established pancreatic tumours. In conclusion, these data demonstrate a potential role for epigenetic modifier drugs for the management of PC, specifically in the chemoprevention of PC, in combination with other chemotherapeutic agents. PMID- 25695795 TI - Tumor cell targeting by iron oxide nanoparticles is dominated by different factors in vitro versus in vivo. AB - Realizing the full potential of iron oxide nanoparticles (IONP) for cancer diagnosis and therapy requires selective tumor cell accumulation. Here, we report a systematic analysis of two key determinants for IONP homing to human breast cancers: (i) particle size and (ii) active vs passive targeting. In vitro, molecular targeting to the HER2 receptor was the dominant factor driving cancer cell association. In contrast, size was found to be the key determinant of tumor accumulation in vivo, where molecular targeting increased tumor tissue concentrations for 30 nm but not 100 nm IONP. Similar to the in vitro results, PEGylation did not influence in vivo IONP biodistribution. Thus, the results reported here indicate that the in vitro advantages of molecular targeting may not consistently extend to pre-clinical in vivo settings. These observations may have important implications for the design and clinical translation of advanced, multifunctional, IONP platforms. PMID- 25695796 TI - Weight-bearing and mobilization in the postoperative care of ankle fractures: a systematic review and meta-analysis of randomized controlled trials and cohort studies. AB - PURPOSE: To determine the effectiveness and safety of interventions used for rehabilitation after open reduction and internal fixation of ankle fractures. METHODS: A systematic review and meta-analysis was performed using both randomized trials and cohort studies. The effect of mobilization, weight-bearing, and unprotected weight-bearing as tolerated on postoperative recovery was compared using the Olerud Molander score, return to work/daily activities, and the rate of complications. RESULTS: A total of 25 articles were included. Ankle exercises resulted in earlier return to work and/or daily activities compared to immobilization (mean difference (MD) -20.76 days; 95% confidence interval (CI) 40.02 to -1.50). There was no difference in the rate of complications between exercises and immobilization (risk ratio (RR) 1.22; 95% CI 0.60 to 2.45) or between early and late weight-bearing (RR 1.26; 95%CI 0.56 to 2.85). INTERPRETATION: Results of this meta-analysis show that following ankle surgery, 1) active exercises accelerate return to work and daily activities compared to immobilization, 2) early weight-bearing tends to accelerate return to work and daily activities compared to late weight-bearing. Active exercises in combination with immediate weight-bearing may be a safe option. PMID- 25695797 TI - Gene co-expression network analysis provides novel insights into myostatin regulation at three different mouse developmental timepoints. AB - Myostatin (Mstn) knockout mice exhibit large increases in skeletal muscle mass. However, relatively few of the genes that mediate or modify MSTN effects are known. In this study, we performed co-expression network analysis using whole transcriptome microarray data from MSTN-null and wild-type mice to identify genes involved in important biological processes and pathways related to skeletal muscle and adipose development. Genes differentially expressed between wild-type and MSTN-null mice were further analyzed for shared DNA motifs using DREME. Differentially expressed genes were identified at 13.5 d.p.c. during primary myogenesis and at d35 during postnatal muscle development, but not at 17.5 d.p.c. during secondary myogenesis. In total, 283 and 2034 genes were differentially expressed at 13.5 d.p.c. and d35, respectively. Over-represented transcription factor binding sites in differentially expressed genes included SMAD3, SP1, ZFP187, and PLAGL1. The use of regulatory (RIF) and phenotypic (PIF) impact factor and differential hubbing co-expression analyses identified both known and potentially novel regulators of skeletal muscle growth, including Apobec2, Atp2a2, and Mmp13 at d35 and Sox2, Tmsb4x, and Vdac1 at 13.5 d.p.c. Among the genes with the highest PIF scores were many fiber type specifying genes. The use of RIF, PIF, and differential hubbing analyses identified both known and potentially novel regulators of muscle development. These results provide new details of how MSTN may mediate transcriptional regulation as well as insight into novel regulators of MSTN signal transduction that merit further study regarding their physiological roles in muscle and adipose development. PMID- 25695798 TI - Correction: Aneugenic effects of epirubicin in somatic and germinal cells of male mice. AB - [This corrects the article DOI: 10.1371/journal.pone.0109942.]. PMID- 25695799 TI - Treatment of Mycobacterium abscessus subsp. massiliense tricuspid valve endocarditis. PMID- 25695800 TI - Correction: The secreted peptide PIP1 amplifies immunity through receptor-like kinase 7. AB - [This corrects the article DOI: 10.1371/journal.ppat.1004331.]. PMID- 25695801 TI - Recurrent evolution of melanism in South American felids. AB - Morphological variation in natural populations is a genomic test bed for studying the interface between molecular evolution and population genetics, but some of the most interesting questions involve non-model organisms that lack well annotated reference genomes. Many felid species exhibit polymorphism for melanism but the relative roles played by genetic drift, natural selection, and interspecies hybridization remain uncertain. We identify mutations of Agouti signaling protein (ASIP) or the Melanocortin 1 receptor (MC1R) as independent causes of melanism in three closely related South American species: the pampas cat (Leopardus colocolo), the kodkod (Leopardus guigna), and Geoffroy's cat (Leopardus geoffroyi). To assess population level variation in the regions surrounding the causative mutations we apply genomic resources from the domestic cat to carry out clone-based capture and targeted resequencing of 299 kb and 251 kb segments that contain ASIP and MC1R, respectively, from 54 individuals (13-21 per species), achieving enrichment of ~500-2500-fold and ~150x coverage. Our analysis points to unique evolutionary histories for each of the three species, with a strong selective sweep in the pampas cat, a distinctive but short melanism specific haplotype in the Geoffroy's cat, and reduced nucleotide diversity for both ancestral and melanism-bearing chromosomes in the kodkod. These results reveal an important role for natural selection in a trait of longstanding interest to ecologists, geneticists, and the lay community, and provide a platform for comparative studies of morphological variation in other natural populations. PMID- 25695802 TI - Toxoplasmosis and epilepsy--systematic review and meta analysis. AB - BACKGROUND: Toxoplasmosis is an important, widespread, parasitic infection caused by Toxoplasma gondii. The chronic infection in immunocompetent patients, usually considered as asymptomatic, is now suspected to be a risk factor for various neurological disorders, including epilepsy. We aimed to conduct a systematic review and meta-analysis of the available literature to estimate the risk of epilepsy due to toxoplasmosis. METHODS: A systematic literature search was conducted of several databases and journals to identify studies published in English or French, without date restriction, which looked at toxoplasmosis (as exposure) and epilepsy (as disease) and met certain other inclusion criteria. The search was based on keywords and suitable combinations in English and French. Fixed and random effects models were used to determine odds ratios, and statistical significance was set at 5.0%. PRINCIPAL FINDINGS: Six studies were identified, with an estimated total of 2888 subjects, of whom 1280 had epilepsy (477 positive for toxoplasmosis) and 1608 did not (503 positive for toxoplasmosis). The common odds ratio (calculated) by random effects model was 2.25 (95% CI 1.27-3.9), p = 0.005. CONCLUSIONS: Despite the limited number of studies, and a lack of high-quality data, toxoplasmosis should continue to be regarded as an epilepsy risk factor. More and better studies are needed to determine the real impact of this parasite on the occurrence of epilepsy. PMID- 25695803 TI - Stress and burnout in anaesthesia: a real world problem? AB - PURPOSE OF REVIEW: Stress and burnout have arisen as relevant problems to the healthcare workers and the health systems themselves. As anaesthesiologists work in stressful areas of the hospitals, we are exposed to these problems. In this review, we summarize recent studies regarding stress and burnout, exploring possible solutions. RECENT FINDINGS: Almost 50% of anaesthesiologists scored positive for some of the burnout domains in different surveys, with one-third reporting high levels. The management of this problem not only needs an institutional but also an individual approach. Some recent randomized clinical trials and longitudinal studies suggest that there is some benefit of using several techniques to control stress, although benefits are still modest and most of the studies are based on transversal surveys and self-reported questionnaires. SUMMARY: There is a lack of definitive evidence to guide the management of stress and burnout in medical professions in general and in anaesthesiology in particular. Longitudinal and interventional studies are needed to better determine ways of action. In the meantime, creating a positive work climate and institutional support as well as promoting control over one's job and the autonomy of employees are the most recommended strategies. Workers should also learn how to cope with stressors and practice personal strategies of wellness and resilience to fight against burnout. PMID- 25695804 TI - N-Annulated perylene-based metal-free organic sensitizers for dye-sensitized solar cells. AB - A series of novel metal-free organic sensitizers based on N-annulated perylene derivatives have been designed and synthesized, and exhibit broad absorption spectra in the visible region. The dye-sensitized solar cells exhibit overall conversion efficiencies ranging from 4.90% to 8.28% under AM 1.5 solar conditions. PMID- 25695805 TI - UK Renal Registry 17th Annual Report: Chapter 1 UK Renal Replacement Therapy Incidence in 2013: National and Centre-specific Analyses. AB - INTRODUCTION: This chapter describes the characteristics of adult patients starting renal replacement therapy (RRT) in the UK in 2013 and the incidence rates for RRT by Clinical Commissioning Groups and Health Boards (CCG/HBs) in the UK. METHODS: Basic demographic and clinical characteristics,including presentation time (time between first being seen by a nephrologist and start of RRT), and age/gender standardised incidence ratios in CCG/HBs, are reported on patients starting RRT at all UK renal centres. RESULTS: In 2013, RRT was started in 7,006 patients across the UK,with an incidence rate similar to 2012 at 109 per million population (pmp). There were wide variations between CCG/HBs in standardised incidence ratios. The median age for White patients was 66.0 and for non-White patients 57.0 years. Diabetic renal disease remained the single most common cause of renal failure (25%). By 90 days,66.1% of patients were on haemodialysis (HD), 19.0% on peritoneal dialysis (PD), 9.5% had a functioning transplant and 5.3% had died or stopped treatment. There continued to be variability between centres in the use of PD as an initial treatment. The mean eGFR at the start of RRT was 8.5 ml/min/1.73 m2 similar to previous years. Late presentation(,90 days) fell from 23.9% in 2006 to 18.4% in 2013. Fifty-one percent of patients who started on HD had died within five years of starting. This compared to 33% and 5% for those starting on PD or transplant respectively. CONCLUSIONS: The incidence of new patients starting RRT in the UK has remained largely unchanged for almost 10 years in contrast to the rising numbers of prevalent patients (+48% since 2003). The year on year increase in pre-emptive transplantation is encouraging but the variability between centres in the percentages starting on PD should be explored further. PMID- 25695806 TI - UK Renal Registry 17th Annual Report: Chapter 2 UK Renal Replacement Therapy Prevalence in 2013: National and Centre-specific Analyses. AB - INTRODUCTION: This chapter describes the characteristics of adult patients on renal replacement therapy (RRT) in the UK in 2013. METHODS: Data were electronically collected from all 71 renal centres within the UK. A series of cross sectional and longitudinal analyses were performed to describe the demographics of prevalent RRT patients in 2013 at centre and national level. RESULTS: There were 56,940 adult patients receiving RRT in the UK on 31st December 2013. The UK adult prevalence of RRT was 888 pmp which represented an annual increase of 4%,with transplantation the most common treatment modality(52%). There was variation between centres, Clinical Commissioning Groups and Health Boards. The number of patients increased by 1.2% for haemodialysis (HD) and 7.1% for functioning transplant but decreased 3.3% for peritoneal dialysis (PD). The number of patients receiving home HD has increased by 3% since 2012. Median RRT vintage for patients on HD was 3.4 years, PD 1.7 years and for transplant, 10.1 years. The median age of prevalent patients was 58 years (HD 67 years, PD 64 years, transplant 53 years)compared to 55 years in 2000. For all ages the prevalence rate in men exceeded that in women. The most common recorded renal diagnosis was glomerulonephritis (biopsy proven/not biopsy proven) (19%). CONCLUSIONS: The HD and transplant population continued to expand; but the prevalent PD population continues to decline. There were national, regional and centre level variations in prevalence rates. This has continued implications for service planning and ensuring equity of care for RRT patients. PMID- 25695807 TI - UK Renal Registry 17th Annual Report: Chapter 3 Demographic and Biochemistry Profile of Kidney Transplant Recipients in the UK in 2013: National and Centre specific Analyses. AB - INTRODUCTION: National transplant registries routinely focus on centre-specific patient and graft survival rates following renal transplantation. However other outcomes such as graft function (as measured by eGFR), haemoglobin and blood pressure are also important quality of care indicators. METHODS: Renal transplant activity, incident graft survival data and donor information were obtained from NHS Blood and Transplant. Laboratory and clinical variables and prevalent survival data were obtained from the UK Renal Registry. Data were analysed separately for prevalent and one year post-transplant patients. Results: The main increase in transplant activity in 2013 was the use of donors after brainstem death. The death-censored graft failure rate was similar to previous years at 2.4% and the transplant patient death rates remained stable at 2.4 per 100 patient years. There was centre variation in outcomes including eGFR and haemoglobin in prevalent and 1 year post transplant patients. Analysis of prevalent transplants by chronic kidney disease stage showed 13.4% with an eGFR,30 ml/min/1.73 m2 and 1.7% with an eGFR ,15 ml/min/1.73 m2. Of those with CKD stage 5T, 32.4% had haemoglobin concentrations ,100 g/L 28.4% phosphate concentrations 51.7 mmol/L and 16.8% adjusted calcium concentrations 52.5 mmol/L. Infection (26%) and malignancy (24%)remained amongst the commonest causes of death inpatients with a functioning renal transplant. CONCLUSION: Significant variations in clinical outcomes (unadjusted for patient specific variables) amongst kidney transplant recipients continued to exist in the UK and may reflect differences in healthcare delivery between renal centres. PMID- 25695808 TI - UK Renal Registry 17th Annual Report: Chapter 4 Demography of the UK Paediatric Renal Replacement Therapy Population in 2013. AB - AIMS: To describe the demographics of the paediatric renal replacement therapy (RRT) population under the age of 18 years in the UK and to analyse changes in demography over time. METHODS: Data were collected electronically from all 13 paediatric renal centres within the UK. A series of cross-sectional and longitudinal analyses were performed to describe the demographics of paediatric RRT patients. RESULTS: A total of 891 children and young people under 18 with established renal failure (ERF) were receiving treatment at paediatric nephrology centres in 2013. At the census date, 80.2% had a functioning transplant, 11.7%were receiving haemodialysis (HD) and 8.1% were receiving peritoneal dialysis (PD). In patients aged ,16 years the prevalence of ERF was 58.2 per million age related population(pmarp) and the incidence 9.3 pmarp. A third of the prevalent patients had one or more reported comorbidities.At transfer to adult services, 85.2% of patients had a functioning renal transplant. Pre-emptive transplantation was seen to occur in a third of children starting RRT under16 years, with lower rates seen in girls and ethnic minorities.Living donation as starting modality has continued to improve with an increase from 8.8% in 1999 2003 to 18.4% in 2009-2013. Survival in childhood amongst children starting RRT was the lowest in those aged less than two years. CONCLUSIONS: We report continued improvement in data quality and electronic submission of data returns. The data provided in this report show relatively stable trends of incidence and prevalence in children with established renal failure. PMID- 25695809 TI - UK Renal Registry 17th Annual Report: Chapter 5 Survival and Cause of Death in UK Adult Patients on Renal Replacement Therapy in 2013: National and Centre-specific Analyses. AB - INTRODUCTION: The analyses presented in this chapter examine (a) survival from the start of RRT of adult RRT patients; (b) projected life years remaining for adult patients starting RRT; (c) survival amongst prevalent adult dialysis patients alive on 31st December 2012; (d) the death rate in the UK compared to the general population; (e) cause of death for incident and prevalent adult RRT patients. METHODS: Survival of incident patients was calculated both from the start of RRT and from 90 days after start. One year survival for prevalent dialysis patients were calculated by following patients up for one year in 2013. The relative risk of death was compared with the general UK population. RESULTS: The age adjusted one year after 90 day survival for patients starting RRT in 2012 was 91.0% (90.9% in 2011). Age adjusted one year survival for prevalent dialysis patients remained relatively unchanged at 89.3% from the previous year. The age standardised mortality ratio for prevalent RRT patients compared with the general population was 16.2 for age group 35-39 and 2.6 at age 85+ years. In the prevalent RRT dialysis population, cardiovascular disease accounted for 27% of deaths, infection and other causes for 21% each and treatment withdrawal for 16% of deaths.The median life years remaining for a 25-29 year old starting RRT was 18.5 years and approximately 2.4 years for a 75+year old. CONCLUSIONS: Survival of patients starting RRT has improved substantially in last decade, overall, by age and for diabetic patients. PMID- 25695810 TI - UK Renal Registry 17th Annual Report: Chapter 6 Adequacy of Haemodialysis in UK Adult Patients in 2013: National and Centre-specific Analyses. AB - BACKGROUND: Outcomes in patients treated with haemodialysis(HD) are potentially influenced by the delivered dose of dialysis. The UK Renal Association publishes clinical practice guidelines recommendations for dialysis dose. The urea reduction ratio (URR) is a widely used measure of dialysis dose and has been historically the measure of adequacy reported by the UKRR. AIM: To determine the extent to which patients achieved the recommended UK target. METHODS: Two groups of patients were included in the analyses: the prevalent HD patients on 30th September 2013 and the incident HD patients for 2012. Centres returning data on ,50% of their patient population or centres with,20 patients with data were excluded from centre-specific comparisons. RESULTS: Data regarding URR were available for analysis from 64 renal centres in the UK. The proportion of patients in the UK who met the UK clinical practice guideline for URR (.65%) increased from 69% in 2000 to 89% in 2013. There was persistent variation observed between centres, with 22 centres attaining the RA clinical practice guideline in .90% of patients and 37 centres attaining the guideline in 70-90% of patients. The overall proportion of prevalent HD patients with a URR .65% has continued to improve over time. CONCLUSIONS: The delivered dose of HD,as measured by URR for patients with established renal failure,has increased over the last decade. Whilst the majority of UK patients achieved the target URR, there was wide variation between centres in the percentage of patients achieving the current guideline target. PMID- 25695811 TI - UK Renal Registry 17th Annual Report: Chapter 7 Haemoglobin, Ferritin and Erythropoietin amongst UK Adult Dialysis Patients in 2013: National and Centre specific Analyses. AB - BACKGROUND: The diagnosis and management of anaemia in chronic kidney disease and the standards to be achieved have been detailed in the UK Renal Association Anaemia of CKD guidelines. AIMS: To determine the attainment of standards for anaemia management in the UK. METHODS: Quarterly data were obtained for haemoglobin (Hb) and factors that influence Hb from renal centres in England,Wales, Northern Ireland (EW&NI) and the Scottish Renal Registry for the incident and prevalent renal replacement therapy (RRT) cohorts for 2013. RESULTS: In the UK, in 2013,50% of patients commenced dialysis therapy with Hb 5100 g/L (median Hb 100 g/L). Of patients presenting early, 53% started dialysis with Hb 5100 g/L compared to 36% of patients presenting late. The UK median Hb of haemodialysis (HD) & peritoneal dialysis (PD) patients was 112 g/L (inter quartile range (IQR) 103-120 g/L) and 113 g/L(IQR 103-122 g/L) respectively with 83% of patients having Hb .100 g/L for both treatment modalities. The median ferritin in HD and PD patients was 424 mg/L (IQR 280-616 mg/L) and 285 mg/L (IQR 167-473 mg/L) respectively with the majority of patients achieving ferritin 5100 mg/L.In EW&NI the median ESA dose was higher for HD than PD patients (7,333 vs. 4,000 IU/week). The percentage of patients treated with an ESA and having Hb .120 g/L ranged between centres from 3-29% for HD and from 0-26% for PD. CONCLUSIONS: There continues to be significant variation between centres in the use of iron and ESAi n order to achieve the target Hb (100-120 g/L). PMID- 25695812 TI - UK Renal Registry 17th Annual Report: Chapter 8 Biochemical Variables amongst UK Adult Dialysis Patients in 2013: National and Centre-specific Analyses. AB - INTRODUCTION: The UK Renal Association clinical practice guidelines include clinical performance measures for biochemical variables in dialysis patients. The UK Renal Registry(UKRR) annually audits dialysis centre performance against these measures as part of its role in promoting continuous quality improvement. METHODS: Cross sectional performance analyses were undertaken to compare dialysis centre achievement of clinical audit measures for prevalent haemodialysis (HD) and peritoneal dialysis (PD) cohorts in 2013. The biochemical variables studied were phosphate, adjusted calcium, parathyroid hormone and bicarbonate.In addition, longitudinal analyses were performed (2002-2013) to show changes in achievement of clinical performance measures over time. RESULTS: Fifty-seven percent of HD and 62% of PD patients achieved a phosphate within the range recommended by the RA clinical practice guidelines. Seventy-eight percent of HD and of PD patients had adjusted calcium between 2.2-2.5 mmol/L. Fifty-seven percent of HD and 63% of PD patients had parathyroid hormone between 16-72 pmol/L. Fifty-nine percent of HD and 79% of PD patients achieved the audit measure for bicarbonate. There was significant inter-centre variation for all variables studied. CONCLUSIONS: The UKRR consistently demonstrates significant inter-centre variation in achievement of biochemical clinical audit measures. Understanding the causes of this variation is an important part of improving the care of dialysis patients in the UK. PMID- 25695813 TI - UK Renal Registry 17th Annual Report: Chapter 9 Clinical, Haematological and Biochemical Parameters in Patients Receiving Renal Replacement Therapy in Paediatric Centres in the UK in 2013: National and Centre-specific Analyses. AB - BACKGROUND: The Paediatric Registry analyses renal replacement therapy (RRT) data in children. All 13 UK paediatric nephrology centres submit electronic data. AIMS: To provide centre specific data and to determine adherence to relevant audit standards. METHODS: Data analysis to calculate summary statistics and achievement of an audit standard. RESULTS: The median height z-score for children on dialysis was -2.0 and for children with a functioning transplant -1.3. Children transplanted before age 11 years improved their height z score subsequently, whereas those >11 maintained their height z-score, with all transplanted patients having a similar height z-score after 3 years of starting RRT.The median weight z-score for children on dialysis was -1.2, and for children with a functioning transplant -0.2.Of those with data, 75% of the prevalent paediatric RRT population had .1 risk factors for cardiovascular disease, with 1 in 10 having all three risk factors evaluated. For transplant patients, 76% achieved the systolic blood pressure (SBP)standard and 91% achieved the haemoglobin standard. For haemodialysis patients, 53% achieved the SBP standard,66% the haemoglobin standard, 84% the calcium standard,43% the phosphate standard and 43% achieved the parathyroid hormone (PTH) standard. For peritoneal dialysis patients, 61% achieved the SBP standard, 83% the haemoglobin standard, 71% the calcium standard, 56% the phosphate standard and 36% achieved the PTH standard. CONCLUSIONS: Quarterly data collection will improve quality and reporting. Continued focus on improving height and avoiding obesity is needed. Awareness and management of cardiovascular risk is an important long term strategy. PMID- 25695814 TI - UK Renal Registry 17th Annual Report: Chapter 10 2013 Multisite Dialysis Access Audit in England, Northern Ireland and Wales and 2012 PD One Year Follow-up: National and Centre-specific Analyses. AB - BACKGROUND: Dialysis access should be timely, minimize complications and maintain functionality. The aim of the second combined vascular and peritoneal dialysis access audit was to examine practice patterns with respect to dialysis access and highlight variations in practice between renal centres. METHODS: The UK Renal Registry collected centre-specific information on incident vascular and peritoneal dialysis access outcome measures in patients from England, Wales and Northern Ireland (EW&NI), including patient demographics, dialysis access type (at start of dialysis and three months after start of dialysis), surgical assessment and access functionality. Centres who had reported data on incident PD patients for the previous 2012 audit were additionally asked to provide one year follow up data for this group. The findings were compared to the audit measures stated in Renal Association clinical practice guidelines for dialysis access. RESULTS: Fifty-seven centres in EW&NI (representing 92% of all centres) returned data on first access from 3,663 incident HD patients and 1,022 incident PD patients. A strong relationship was seen between surgical assessment and the likelihood of starting HD with an arteriovenous fistula (AVF). Twenty-four centres were at least two standard deviations below the 65% target for incident patients starting haemodialysis on AVF and only eight centres (14%) were within two standard deviations of the 85% target for prevalent haemodialysis patients on AVF. CONCLUSIONS: There was wide practice variation across the UK in provision of both HD and PD access which requires further exploration. PMID- 25695815 TI - UK Renal Registry 17th Annual Report: Chapter 11 Centre Variation in Access to Renal Transplantation in the UK (2008-2010). AB - BACKGROUND: Renal transplantation is recognised as being the optimal treatment modality for many patients with established renal failure. This analysis aimed to explore inter-centre variation in access to renal transplantation in the UK. METHODS: Transplant activity and waiting list data were obtained from NHS Blood and Transplant, demographic and laboratory data were obtained from the UK Renal Registry. All incident RRT patients starting treatment between 1st January 2008 and 31st December 2010 from 71 renal centres were considered for inclusion. The cohort was followed until 31st December 2012 (or until transplantation or death, whichever was earliest). RESULTS: Age, ethnicity and primary renal diagnosis were associated with both accessing the kidney transplant waiting list and receiving a kidney transplant. A patient starting dialysis ina non-transplanting renal centre was less likely to be registered for transplantation (OR 0.74, 95% CI 0.68-0.81) or receive a transplant from a donor after cardiac death or a living kidney donor (OR 0.75, 95% CI 0.67-0.84) compared with patients cared for in transplanting renal centres. Once registered for kidney transplantation, patients in both transplanting and non-transplanting renal centres had an equal chance of receiving a transplant from a donor after brainstem death (OR 0.93, 95% CI 0.78 to 1.10). CONCLUSION: There was wide variation in access to kidney transplantation between UK renal centres which cannot be explained by differences in case mix. PMID- 25695816 TI - UK Renal Registry 17th Annual Report: Chapter 12 Epidemiology of Reported Infections amongst Patients Receiving Dialysis for Established Renal Failure in England in 2012 to 2013: a Joint Report from Public Health England and the UK Renal Registry. AB - INTRODUCTION: Infection remains one of the leading causes of mortality in established renal failure patients receiving renal replacement therapy (RRT). METHODS: Data were submitted to Public Health England (PHE) by NHS acute Trusts via Health Care Associated Infection Data Capture System (HCAI-DCS) including whether the patients were receiving dialysis. Individual renal units then confirmed the record either directly via the database or after being contacted. Data were collected for the period 1st May 2012 to the 30th April 2013. RESULTS: There were 31 episodes of MRSA bacteraemia, an overall rate of 0.13 per 100 dialysis patient years, representing a further year-on-year fall in MRSA rate. There were a higher number of MSSA episodes, 372 in total,with an overall rate of 1.59 per 100 dialysis patient years. The number of episodes of E. coli and C. difficile were 308 (1.32 per 100 dialysis patient years) and 123 (0.55 per 100 dialysis patient years) respectively. The presence of a central venous catheter was associated with an elevated risk of MRSA and MSSA bacteraemia. CONCLUSIONS: We present data relating to infections in renal dialysis patients reported to PHE in one year. The rate of MRSA bacteraemia episodes in England continues to fall. There is a higher rate of MSSA infections.We also report the results of the second year of E. coli and C. difficile data collection. Future cycles will give further ideas of the trend in incidences of these infections. Further work to refine the definitions and data collection is necessary to ensure consistency of reporting across centres. PMID- 25695817 TI - UK Renal Registry 17th Annual Report: Appendices. PMID- 25695828 TI - Porcine epidemic diarrhea virus replication in duck intestinal cell line. PMID- 25695829 TI - Reply to letter to the Editor from S. C. Arya and N. Agarwal. PMID- 25695830 TI - Endogenous abscisic acid promotes hypocotyl growth and affects endoreduplication during dark-induced growth in tomato (Solanum lycopersicum L.). AB - Dark-induced growth (skotomorphogenesis) is primarily characterized by rapid elongation of the hypocotyl. We have studied the role of abscisic acid (ABA) during the development of young tomato (Solanum lycopersicum L.) seedlings. We observed that ABA deficiency caused a reduction in hypocotyl growth at the level of cell elongation and that the growth in ABA-deficient plants could be improved by treatment with exogenous ABA, through which the plants show a concentration dependent response. In addition, ABA accumulated in dark-grown tomato seedlings that grew rapidly, whereas seedlings grown under blue light exhibited low growth rates and accumulated less ABA. We demonstrated that ABA promotes DNA endoreduplication by enhancing the expression of the genes encoding inhibitors of cyclin-dependent kinases SlKRP1 and SlKRP3 and by reducing cytokinin levels. These data were supported by the expression analysis of the genes which encode enzymes involved in ABA and CK metabolism. Our results show that ABA is essential for the process of hypocotyl elongation and that appropriate control of the endogenous level of ABA is required in order to drive the growth of etiolated seedlings. PMID- 25695831 TI - Autotoxic ginsenosides in the rhizosphere contribute to the replant failure of Panax notoginseng. AB - BACKGROUND AND AIMS: Sanqi ginseng (Panax notoginseng) growth is often hampered by replant failure. In this study, we aimed to examine the role of autotoxicity in Sanqi replant failures and assess the role of ginsenosides in autotoxicity. METHODS: The autotoxicities were measured using seedling emergence bioassays and root cell vigor staining. The ginsenosides in the roots, soils, and root exudates were identified with HPLC-MS. RESULTS: The seedling emergence and survival rate decreased significantly with the continuous number of planting years from one to three years. The root exudates, root extracts, and extracts from consecutively cultivated soils also showed significant autotoxicity against seedling emergence and growth. Ginsenosides, including R1, Rg1, Re, Rb1, Rb3, Rg2, and Rd, were identified in the roots and consecutively cultivated soil. The ginsenosides, Rg1, Re, Rg2, and Rd, were identified in the root exudates. Furthermore, the ginsenosides, R1, Rg1, Re, Rg2, and Rd, caused autotoxicity against seedling emergence and growth and root cell vigor at a concentration of 1.0 ug/mL. CONCLUSION: Our results demonstrated that autotoxicity results in replant failure of Sanqi ginseng. While Sanqi ginseng consecutively cultivated, some ginsenosides can accumulate in rhizosphere soils through root exudates or root decomposition, which impedes seedling emergence and growth. PMID- 25695832 TI - Analysis of the effect of locally applied inhomogeneous static magnetic field exposure on mouse ear edema--a double blind study. AB - The effect static magnetic field (SMF)-exposure may exert on edema development has been investigated. A 6 h long whole-body (WBSMF) or local (LSMF), continuous, inhomogeneous SMF-exposure was applied on anesthetized mice in an in vivo model of mustard oil (MO)-induced ear edema. LSMF was applied below the treated ear, below the lumbar spine, or below the mandible. Ear thickness (v) was checked 8 times during the exposure period (at 0, 0.25, 1, 2, 3, 4, 5, and 6 h). The effect size of the applied treatment (eta) on ear thickness was calculated by the formula eta = 100% * (1-v(j)/v(i)), where group i is the control group and j is the treated group. Results showed that MO treatment in itself induced a significant ear edema with an effect of 9% (p<0.001). WBSMF or LSMF on the spine in combination with MO treatment increased ear thickness even further resulting in an effect of eta>11% in both cases compared to SMF-exposure alone (p<0.001). In these cases SMF-exposure alone without MO treatment reduced ear thickness significantly (p<0.05), but within estimated experimental error. In cases of LSMF exposure on the head, a significant SMF-exposure induced ear thickness reduction was found (eta = 5%, p<0.05). LSMF-exposure on the spine affected ear thickness with and without MO treatment almost identically, which provides evidence that the place of local SMF action may be in the lower spinal region. PMID- 25695834 TI - Substrate-dependent activation of the Vibrio cholerae vexAB RND efflux system requires vexR. AB - Vibrio cholerae encodes six resistance-nodulation-division (RND) efflux systems which function in antimicrobial resistance, virulence factor production, and intestinal colonization. Among the six RND efflux systems, VexAB exhibited broad substrate specificity and played a predominant role in intrinsic antimicrobial resistance. The VexAB system was encoded in an apparent three gene operon that included vexR; which encodes an uncharacterized TetR family regulator. In this work we examined the role of vexR in vexRAB expression. We found that VexR bound to the vexRAB promoter and vexR deletion resulted in decreased vexRAB expression and increased susceptibility to VexAB antimicrobial substrates. Substrate dependent induction of vexRAB was dependent on vexR and episomal vexR expression provided a growth advantage in the presence of the VexAB substrate deoxycholate. The expression of vexRAB increased, in a vexR-dependent manner, in response to the loss of RND efflux activity. This suggested that VexAB may function to export intracellular metabolites. Support for this hypothesis was provided by data showing that vexRAB was upregulated in several metabolic mutants including tryptophan biosynthetic mutants that were predicted to accumulate indole. In addition, vexRAB was found to be upregulated in response to exogenous indole and to contribute to indole resistance. The collective results indicate that vexR is required for vexRAB expression in response to VexAB substrates and that the VexAB RND efflux system modulates the intracellular levels of metabolites that could otherwise accumulate to toxic levels. PMID- 25695835 TI - Icariin recovers the osteogenic differentiation and bone formation of bone marrow stromal cells from a rat model of estrogen deficiency-induced osteoporosis. AB - A number of recent studies have suggested that icariin (ICA), a class of phytochemical with numerous biological activities, may exert protective effects against postmenopausal bone loss. However, it remains unclear whether ICA regulates or improves the osteoblastic function of bone marrow stromal cells (BMSCs) in the treatment and prevention of osteoporosis. In the present study, the osteogenic differentiation of BMSCs from ovariectomy (OVX) rats was found to be significantly decreased in vitro compared with that in rats that had undergone a sham operation. Treatment with ICA at a dose of 10-5 M was shown to restore the osteogenic differentiation of BMSCs in OVX rats. The results indicated that ICA restored the differentiation and mineralization capacity of OVX-BMSCs, which had been induced by estrogen deficiency. The effects of this compound on alkaline phosphatase (ALP) activity and calcium deposition were also measured at various time points. The number of colonies and areas that stained positive for ALP expression, and mineralized bone nodules were analyzed histochemically at 14 and 21 days after the osteogenic induction. The expression of the runt-related transcription factor 2 and osterix bone metabolism biomarker proteins and genes were detected by western blotting and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The expression of factors involved in the estrogen signaling pathway, estrogen receptor alpha (ERalpha), progesterone receptor (PR) and trefoil factor 1 (PS-2), was also detected by western blotting and RT-qPCR. ICA enhanced the expression of ERalpha, PR, PS-2 in OVX-BMSCs, but this effect was abrogated when ICI 182780, an ER antagonist was added. Transplantation of BMSCs into nude mice demonstrated that ICA restored the osteogenic capability of OVX-BMSCs in vivo. Therefore, it may be that ICA acts through the estrogen pathway in order to improve and restore the osteogenic differentiation and mineralization of OVX-BMSCs, which are inhibited by estrogen deficiency and increasing age. PMID- 25695836 TI - Automated High-Performance Analysis of Lung Morphometry. AB - Automation of lung morphometric analysis is an asset in the study of lung pathophysiology because it is an assurance of robustness, reproducibility, and rapidity. The novel automated morphometric approach presented here meets these criteria. This new method collects multiple parameters, allowing quantitative elucidation of the pathophysiology of the developing and mature lungs. The automated morphometric analysis is reliable and allows the analysis of a greater proportion of each lung together with a higher number of samples and superior reproducibility than manual analysis. The use of this method revealed that treatment with 80% oxygen and lung development presented an opposite effect on most of the analyzed parameters. In conclusion, this novel approach allowed the collection of new fundamental morphometric data on lung development and a deeper comprehension of the effect of hyperoxia. PMID- 25695837 TI - Mechanistic implications in the phosphatase activity of Mannich-based dinuclear zinc complexes with theoretical modeling. AB - An "end-off" compartmental ligand has been synthesized by an abnormal Mannich reaction, namely, 2-[bis(2-methoxyethyl)aminomethyl]-4-isopropylphenol yielding three centrosymmetric binuclear MU-phenoxozinc(II) complexes having the molecular formula [Zn2(L)2X2] (Zn-1, Zn-2, and Zn-3), where X = Cl(-), Br (-), and I (-), respectively. X-ray crystallographic analysis shows that the ZnO3NX chromophores in each molecule form a slightly distorted trigonal-bipyramidal geometry (tau = 0.55-0.68) with an intermetallic distance of 3.068, 3.101, and 3.083 A (1-3, respectively). The spectrophotometrical investigation on their phosphatase activity established that all three of them possess significant hydrolytic efficiency. Michaelis-Menten-derived kinetic parameters indicate that the competitiveness of the rate of P-O bond fission employing the phosphomonoester (4 nitrophenyl)phosphate in 97.5% N,N-dimethylformamide is 3 > 1 > 2 and the kcat value lies in the range 9.47-11.62 s(-1) at 298 K. Theoretical calculations involving three major active catalyst forms, such as the dimer-cis form (D-Cis), the dimer-trans form (D-Trans), and the monoform (M-1 and M-2), systematically interpret the reaction mechanism wherein the dimer-cis form with the binuclear bridged hydroxide ion acting as the nucleophile and one water molecule playing a role in stabilizing the leaving group competes as the most favored pathway. PMID- 25695838 TI - TGF-beta3-expressing CD4+CD25(-)LAG3+ regulatory T cells control humoral immune responses. AB - Autoantibodies induce various autoimmune diseases, including systemic lupus erythematosus (SLE). We previously described that CD4(+)CD25(-)LAG3(+) regulatory T cells (LAG3(+) Treg) are regulated by Egr2, a zinc-finger transcription factor required for the induction of T-cell anergy. We herein demonstrate that LAG3(+) Treg produce high amounts of TGF-beta3 in an Egr2- and Fas-dependent manner. LAG3(+) Treg require TGF-beta3 to suppress B-cell responses in a murine model of lupus. Moreover, TGF-beta3- and LAG3(+) Treg-mediated suppression requires PD-1 expression on B cells. We also show that TGF-beta3-expressing human LAG3(+) Treg suppress antibody production and that SLE patients exhibit decreased frequencies of LAG3(+) Treg. These results clarify the mechanism of B-cell regulation and suggest therapeutic strategies. PMID- 25695839 TI - Ribonucleotide reductase M2 subunit expression and prognostic value in nasopharyngeal carcinoma. AB - The ribonucleotide reductase M2 subunit (RRM2) modulates the enzymatic activity of ribonucleotide reductase, and is involved in tumor progression. Recently, high levels of RRM2 expression were reported to correlate with poor survival outcomes in patients with colorectal and bladder cancer. However, changes in RRM2 expression in nasopharyngeal carcinoma (NPC), and its effect on the prognosis of this disease remain unknown. The aim of the present study was to analyze the expression of RRM2 in NPC cell lines, and to identify whether RRM2 may serve as a biomarker with which to assess the prognosis of NPC. The present study found that RRM2 expression was higher in NPC cell lines and tissue samples than in noncancerous nasopharyngeal epithelial cell lines and noncancerous tissues, as shown by reverse transcription-quantitative polymerase chain reaction analysis, western blotting and immunohistochemistry staining. Kaplan-Meier survival analysis demonstrated that patients with higher RRM2 expression levels had poorer disease-free survival outcomes than those with lower expression levels of RRM2. Univariate analysis showed that a lower survival rate was significantly associated with high RRM2 expression levels [hazard ratio (HR), 6.424; 95% confidence interval (CI), 2.381-17.333; P<0.001]. Multivariate analysis indicated that RRM2 expression is an independent prognostic factor for patients with NPC (HR, 3.461; 95 % CI, 1.204-9.949; P=0.021). Overexpression of RRM2 led to increased cell proliferation, colony formation, migration and invasion in vivo. These results suggest that high levels of RRM2 expression may be a useful predictor for survival in patients with NPC and may serve as a novel prognostic indicator for these individuals. PMID- 25695840 TI - A Novel Algorithm for Enhanced Structural Motif Matching in Proteins. AB - As widely discussed in literature, spatial patterns of amino acids, so-called structural motifs, play an important role in protein function. The functionally responsible part of proteins often lies in an evolutionarily highly conserved spatial arrangement of only a few amino acids, which are held in place tightly by the rest of the structure. Those recurring amino acid arrangements can be seen as patterns in the three-dimensional space and are known as structural motifs. In general, these motifs can mediate various functional interactions, such as DNA/RNA targeting and binding, ligand interactions, substrate catalysis, and stabilization of the protein structure. Hence, characterizing and identifying such conserved structural motifs can contribute to the understanding of structure function relationships. Therefore, and because of the rapidly increasing number of solved protein structures, it is highly desirable to identify, understand, and moreover to search for structurally scattered amino acid motifs. This work aims at the development and the implementation of a novel and robust matching algorithm to detect structural motifs in large sets of target structures. The proposed methods were combined and implemented to a feature-rich and easy-to-use command line software tool written in Java. PMID- 25695841 TI - Inhibition of autophagy by 3-methyladenine potentiates sulforaphane-induced cell death of BE(2)-C human neuroblastoma cells. AB - Sulforaphane (SFN) is an isothiocyanate present in cruciferous vegetables, which has been shown to exert an anti-cancer effect when tested in vitro and in vivo. The anti-cancer effects of SFN encompass induction of cytoprotective autophagy; therefore, the present study aimed to determine whether the chemopreventive activity of SFN may be potentiated by inhibition of autophagy. The present study provided detailed insight into the susceptibility of human neuroblastoma cells to treatment with synthetic SFN, in combination with an inhibitor of autophagy, 3 methyladenine (3-MA). The present study confirmed the suppression of the viability of the human neuroblastoma cell line BE(2)-C by SFN and reported the inhibition of DNA synthesis, as determined by a decrease in tritiated thymidine incorporation. Furthermore, the results verified the effectiveness of SFN in inducing apoptosis in the BE(2)-C cell line as demonstrated by caspase activation, increased protein expression levels of B-cell lymphoma 2-associated X protein and loss of mitochondrial membrane potential. Combined treatment of the cells with SFN with 3-MA proved to be effective in decreasing cell viability, through a mechanism that may proceed via the early induction of autophagy by SFN, followed by induction of apoptosis, as well as inhibition of autophagy by 3-MA. PMID- 25695842 TI - A novel device for measurement of subglottic stenosis in 3 dimensions during suspension laryngoscopy. AB - IMPORTANCE: A challenge in treating subglottic stenosis is assessment of airway caliber before and after management. At present, surgeons lack a simple, efficient, and precise method of measuring subglottic stenosis intraoperatively. We present a novel, easily reproducible tool for measurement of the diameter, location, and length of subglottic stenosis during suspension laryngoscopy. METHODS AND OBSERVATIONS: A set of 5 Kirschner wires (30-cm length and 1.6-mm diameter) were bent 90 degrees at both ends to produce a series of 10 short ends designed to measure airway diameter (0.3- to 2.1-cm length with 2-mm intervals). Short, bent ends of the measuring sticks were designed to measure airway diameter. Hash marks at 2-mm intervals were created along the long axis of the measuring sticks to measure subglottic stenosis length and location relative to the vocal cords. The measuring stick was tested in 10 adult patients undergoing suspension microlaryngoscopy for endoscopic treatment of subglottic stenosis between September 2012 and July 2013. The accuracy of the measuring stick was evaluated using an airway phantom. The measuring stick enabled easy and precise quantification of subglottic stenosis diameter (82.5% agreement with reference; interobserver agreement, r = 0.995; P < .001), length (72.5%; r = 0.995; P < .001) and location during suspension laryngoscopy. CONCLUSIONS AND RELEVANCE: The measuring stick is inexpensive and simple to construct. It allows for safe, accurate, and practical measurement of subglottic stenosis diameter, length, and location during suspension laryngoscopy. PMID- 25695843 TI - A safety and feasibility study of the use of 670 nm red light in premature neonates. AB - OBJECTIVE: Retinopathy of prematurity (ROP) is a vasoproliferative disorder of the retina affecting extremely preterm or low birth weight infants The aim of this study was to assess the feasibility and safety of 670 nm red light use in a neonatal intensive care unit. STUDY DESIGN: Neonates <30 weeks gestation and <1150 g were enrolled within 48 h of birth. Data collected included cause of preterm delivery, Apgar scores and birthweight. 670 nm red light was administered for 15 min per day from a distance of 25 cm, delivering 9 J cm(-)(2), from the time of inclusion in the study until 34 weeks postmenstrual age. Infants were assessed daily for the presence of any skin burns or other adverse signs. RESULT: Twenty-eight neonates were enrolled, seven 24 to 26 weeks and twenty-one 27 to 29 weeks gestation. The most common cause for preterm delivery was preterm labor (14/28) with five of these having evidence of chorioamnionitis. There were no skin burns or other documented adverse events. Entry into the study was readily achieved and treatment was well accepted by parents and nursing staff. CONCLUSION: 670 nm red light appears to be a safe and feasible treatment for further research in respect to ROP. PMID- 25695844 TI - Blunt Intraoral Trauma Resulting in Internal Carotid Artery Dissection and Infarction in a Child. AB - A 16-month-old child fell forward onto her toothbrush sustaining minor oropharyngeal injury. The following day, she became acutely lethargic with localizing neurologic signs of a cerebrovascular infarct. CTA and MR imaging demonstrated occlusion of the right internal carotid artery with a large right middle cerebral artery territory infarction. She was treated with decompressive craniectomy and anticoagulation but remained weak on the left side. Pediatric oropharyngeal injuries can rarely be complicated by internal carotid artery injury with dissection, thrombosis, or embolization to the cerebral circulation. For the best outcome, carotid dissection treatment requires prompt diagnosis at the initial onset of neurologic symptoms. However, further research is needed to determine the best management and advanced imaging work-up for neurologically intact children. PMID- 25695845 TI - Primary Care Follow-up After Emergency Department Visits for Routine Complaints: What Primary Care Physicians Prefer and What Emergency Department Physicians Currently Recommend. AB - OBJECTIVES: Given that the vast majority of pediatric patients that present to the emergency department (ED) are discharged home after their visit, one issue for study is the appropriate recommendations for follow-up after the ED visit. Numerous PubMed searches using various keywords revealed a gap in the literature regarding the desires of primary care physicians (PCPs) concerning follow-up after ED visits. This study was conducted to determine how pediatric emergency medicine (PEM) physicians' recommendations for follow-up align with the desires of (PCPs) for follow-up after ED visits. METHODS: An electronic survey was distributed to pediatric emergency physicians at one community-based academic institution regarding current recommendations for follow-up with PCPs for 12 common diagnoses seen in the ED. A similar survey was sent to pediatricians in the same community inquiring about their desires for follow-up after their patients are seen in the ED for the same diagnoses. RESULTS: Completion rates for the survey were 40/40 (100%) for PEM physicians and 78/145 (54%) for pediatricians. In 11/12 of the diagnoses included, PEM physicians recommended a statistically significant (P < 0.05) closer follow-up than desired by the PCPs. CONCLUSIONS: Recommendations for follow-up made by PEM physicians and desired by PCPs vary significantly. Overall, PEM physicians recommend closer follow-up than desired by PCPs for low acuity complaints. Closing of this gap may allow for a better allocation of resources and consistency of care. PMID- 25695846 TI - Spillover of Mycobacterium bovis from wildlife to livestock, South ?Africa. AB - During August 2012-February 2013, bovine tuberculosis was detected in communal livestock bordering the Greater Kruger National Park Complex (GKNPC) in South Africa. Using spacer oligonucleotide and variable number tandem repeat typing, we identified the Mycobacterium bovis strain endemic in GKNPC wildlife. Our findings indicate bovine tuberculosis spillover from GKNPC wildlife to neighboring livestock. PMID- 25695848 TI - Cell divisions are not essential for the direct conversion of fibroblasts into neuronal cells. AB - Direct lineage conversion is a promising approach for disease modeling and regenerative medicine. Cell divisions play a key role in reprogramming of somatic cells to pluripotency, however their role in direct lineage conversion is not clear. Here we used transdifferentiation of fibroblasts into neuronal cells by forced expression of defined transcription factors as a model system to study the role of cellular division in the direct conversion process. We have shown that conversion occurs in the presence of the cell cycle inhibitors aphidicolin or mimosine. Moreover, overexpression of the cell cycle activator cMyc negatively influences the process of direct conversion. Overall, our results suggest that cell divisions are not essential for the direct conversion of fibroblasts into neuronal cells. PMID- 25695849 TI - A pilot feasibility and acceptability study of yoga/meditation on the quality of life and markers of stress in persons living with HIV who also use crack cocaine. AB - BACKGROUND: Persons living with HIV (PLWH) who also use crack cocaine may have stressful, chaotic lives and typically do not engage in standard medical care that addresses a multitude of extenuating life circumstances. Yoga/meditation (YM) improves quality of life (QOL) and biomarkers of stress, but the effect of this intervention is almost unknown in PLWH, particularly those who use crack cocaine. OBJECTIVES: This pilot study sought to compare the feasibility and acceptability of 60-minute, twice-per-week sessions of YM for 2 months with those of no-contact control and to evaluate the effects of the intervention on QOL (according to the Short Form-36, Perceived Stress Scale [PSS], and Impact of Events Scale [IES]) and salivary cortisol and dehydroepiandrosterone sulfate (DHEA-S) among PLWH who use crack cocaine. DESIGN: Participants were randomly assigned to YM or no-contact control and were assessed at baseline, 2 months after the intervention, and 4 months' follow-up. RESULTS: The YM program was acceptable and feasible, with high overall attendance (89%) and individual participation in yoga sessions (83%). YM participants showed modest improvements on QOL. The PSS total score and the IES intrusion score improved significantly 2 months after the intervention, but cortisol and DHEA-S did not change. CONCLUSIONS: This pilot study showed a high level of feasibility and acceptability and modest effects on measures of QOL among PLWH who use crack cocaine. The results suggest utility of YM as a simple, safe, and inexpensive format to improve QOL in a population that has many medical difficulties and extenuating stressors. PMID- 25695850 TI - RNA testing now automated. PMID- 25695851 TI - Impact of sex on the prognostic value of high-sensitivity cardiac troponin I in the general population: the HUNT study. AB - BACKGROUND: A new, high-sensitivity assay for cardiac troponin I (hs-cTnI) permits evaluation of the prognostic value of cardiac troponins within the reference interval. Men have higher hs-cTnI concentrations than women, but the underlying pathophysiological mechanisms and prognostic implications are unclear. The aim of this study was to assess the potential impact of sex on the association between hs-cTnI and cardiovascular death. METHODS: By use of the Architect STAT High-Sensitive Troponin assay, we measured hs-cTnI in 4431 men and 5281 women aged >=20 years participating in the prospective observational Nord Trondelag Health Study (HUNT). RESULTS: hs-cTnI was detectable in 98.5% of men and 94.7% of women. During a mean follow-up period of 13.9 years, 708 cardiovascular deaths were registered. hs-cTnI was associated with the incidence of cardiovascular death [adjusted hazard ratio (HR) per 1 SD in log hs-cTnI 1.23 (95% CI 1.15-1.31)], with higher relative risk in women than men [HR 1.44 (1.31 1.58) vs 1.10 (1.00-1.20); Pinteraction < 0.001]. This finding was mediated by both lower risk associated with low hs-cTnI concentrations in women than in men and higher risk associated with high concentrations of hs-cTnI in women than in men. Male sex was associated with a higher risk of cardiovascular death [HR 1.28 (1.11-1.49)], but after adjustment for hs-cTnI, this association disappeared [HR 0.87 (0.75-1.02)]. CONCLUSIONS: The prognostic value of hs-cTnI concentrations in the general population is stronger in women than in men. Subtle impairment of cardiovascular status may contribute to higher hs-cTnI concentrations in men, reflecting sex-dependent differences in cardiovascular risk. PMID- 25695852 TI - Noncompetitive immunoassay detection system for haptens on the basis of antimetatype antibodies. AB - BACKGROUND: Small molecules classified as haptens are generally measured by competitive immunoassay, which is theoretically inferior to noncompetitive sandwich immunoassay in terms of sensitivity and specificity. We created a method for developing sandwich immunoassays to measure haptens on the basis of antimetatype antibodies. METHODS: We generated antimetatype monoclonal antibodies against a hapten-antibody immunocomplex using an ex vivo antibody development system, the Autonomously Diversifying Library (ADLib) system. We selected 2 haptens, estradiol (E2) and 25-hydroxyvitamin D [25(OH)D], as analytes. Sandwich immunoassays for these 2 haptens were developed by use of a 96-well microtiter plate and a fully automated chemiluminescence analyzer, and the performances of these immunoassays were investigated. RESULTS: The developed assays exhibited sensitivity high enough to detect target haptens in serum samples. The limit of detection of the ELISA for E2 was 3.13 pg/mL, and that of the fully automated chemiluminescent enzyme immunoassay (CLEIA) system was 2.1 ng/mL for 25(OH)D. The cross-reactivity with immunoreactive derivatives was effectively improved compared with the competitive assay. The CVs for the sandwich ELISA for E2 were 4.2%-12.6% (intraassay) and 6.2%-21.8% (total imprecision). The CVs for the sandwich CLEIA for 25(OH)D were 1.0%-2.3% (intraassay) and 1.9%-3.5% (total imprecision). In particular, the sandwich CLEIA for 25(OH)D showed correlations of r = 0.99 with both LC-MS/MS and a commercially available (125)I RIA. CONCLUSIONS: Our method represents a potentially simple and practical approach for routine assays of haptens, including vitamins, hormones, drugs, and toxins. PMID- 25695853 TI - Effects of fast-velocity eccentric resistance training on early and late rate of force development. AB - This study examined whether short-term maximal resistance training employing fast velocity eccentric knee extensor actions would induce improvements in maximal isometric torque and rate of force development (RFD) at early (<100 ms) and late phases (>100 ms) of rising torque. Twenty healthy men were assigned to two experimental groups: eccentric resistance training (TG) or control (CG). Participants on the TG trained three days a week for a total of eight weeks. Training consisted of maximal unilateral eccentric knee extensors actions performed at 180 degrees s-1. Maximal isometric knee extensor torque (MVC) and incremental RFD in successive 50 ms time-windows from the onset contraction were analysed in absolute terms (RFDINC) or when normalised relative to MVC (RFDREL). After eight weeks, TG demonstrated increases in MVC (28%), RFDINC (0-50 ms: 30%; 50-100 ms: 31%) and RFDREL (0-50 ms: 29%; 50-100 ms: 32%). Moreover, no changes in the late phase of incremental RFD were observed in TG. No changes were found in the CG. In summary, we have demonstrated, in active individuals, that a short period of resistance training performed with eccentric fast-velocity isokinetic muscle contractions is able to enhance RFDINC and RFDREL obtained at the early phase of rising joint torque. PMID- 25695854 TI - Lower Extremity Biomechanics and Self-Reported Foot-Strike Patterns Among Runners in Traditional and Minimalist Shoes. AB - Context : The injury incidence rate among runners is approximately 50%. Some individuals have advocated using an anterior-foot-strike pattern to reduce ground reaction forces and injury rates that they attribute to a rear-foot-strike pattern. The proportion of minimalist shoe wearers who adopt an anterior-foot strike pattern remains unclear. Objective : To evaluate the accuracy of self reported foot-strike patterns, compare negative ankle- and knee-joint angular work among runners using different foot-strike patterns and wearing traditional or minimalist shoes, and describe average vertical-loading rates. Design : Descriptive laboratory study. Setting : Research laboratory. Patients or Other Participants : A total of 60 healthy volunteers (37 men, 23 women; age = 34.9 +/ 8.9 years, height = 1.74 +/- 0.08 m, mass = 70.9 +/- 13.4 kg) with more than 6 months of experience wearing traditional or minimalist shoes were instructed to classify their foot-strike patterns. Intervention(s) : Participants ran in their preferred shoes on an instrumented treadmill with 3-dimensional motion capture. Main Outcome Measure(s) : Self-reported foot-strike patterns were compared with 2-dimensional video assessments. Runners were classified into 3 groups based on video assessment: traditional-shoe rear-foot strikers (TSR; n = 22), minimalist shoe anterior-foot strikers (MSA; n = 21), and minimalist-shoe rear-foot strikers (MSR; n = 17). Ankle and knee negative angular work and average vertical-loading rates during stance phase were compared among groups. Results : Only 41 (68.3%) runners reported foot-strike patterns that agreed with the video assessment (kappa = 0.42, P < .001). The TSR runners demonstrated greater ankle-dorsiflexion and knee-extension negative work than MSA and MSR runners (P < .05). The MSA (P < .001) and MSR (P = .01) runners demonstrated greater ankle plantar-flexion negative work than TSR runners. The MSR runners demonstrated a greater average vertical-loading rate than MSA and TSR runners (P < .001). Conclusions : Runners often cannot report their foot-strike patterns accurately and may not automatically adopt an anterior-foot-strike pattern after transitioning to minimalist running shoes. PMID- 25695855 TI - Plantar-plate disruptions: "the severe turf-toe injury." three cases in contact athletes. AB - OBJECTIVE: To present 3 cases of plantar-plate rupture and turf-toe injury in contact athletes at 1 university and to discuss appropriate diagnosis and treatment algorithms for each case. BACKGROUND: Turf toe is a common injury in athletes participating in outdoor cutting sports. However, it has been used as an umbrella term to describe many different injuries of the great toe. In some cases, the injury can be so severe that the plantar plate and sesamoid apparatus may be ruptured. These patients may be better managed with surgery than with traditional nonoperative interventions. DIFFERENTIAL DIAGNOSIS: Turf toe, plantar plate disruption, sesamoid fracture. TREATMENT: For stable injuries in which the plantar plate is not completely disrupted, nonoperative treatment with casting or a stiff-soled shoe, gradual weight bearing, and rehabilitation is the best practice. Unstable injuries require surgical intervention and plantar-plate repair. UNIQUENESS: Turf toe and injury to the first metatarsophalangeal joint are relatively common injuries in athletes, but few researchers have detailed the operative and nonoperative treatments of plantar-plate disruption in these patients. We examine 3 cases that occurred over 4 seasons on a collegiate football team. CONCLUSIONS: Turf toe represents a wide array of pathologic conditions involving the first metatarsophalangeal joint. Stress and instability testing are key components to assess in determining whether surgical intervention is warranted to restore optimal function. Stiffer-soled shoes or shoes with steel plate insertions may help to prevent these injuries and are useful tools for protection during the rehabilitation period. PMID- 25695856 TI - Cs2CO3-promoted carboxylation of N-tosylhydrazones with carbon dioxide toward alpha-arylacrylic acids. AB - A Cs2CO3-promoted carboxylation of N-tosylhydrazones and CO2 has been developed. The reaction proceeded efficiently at 80 degrees C under atmospheric CO2, gave the corresponding alpha-arylacrylic acids in moderate to good yields. This method was featured with (1) the employment of Cs2CO3 rather than (n)BuLi as the base; (2) a reaction temperature of 80 degrees C rather than -78 degrees C. PMID- 25695857 TI - Graphene oxide thin films: influence of chemical structure and deposition methodology. AB - We synthesized graphene oxide sheets of different functionalization by oxidation of two different starting materials, graphite and GANF nanofibers, followed by purification based on alkaline washing. The chemical structure of graphene oxide materials was determined by X-ray photoelectron spectroscopy (XPS), and the nanoplatelets were characterized by zeta potential and dynamic light scattering (DLS) measurements. The XPS results indicated that the chemical structure depends on the starting material. Two different deposition methodologies, Langmuir Blodgett (LB) and Langmuir-Schaefer (LS), were employed to build the graphene oxide thin films. The film morphology was analyzed by scanning electron microscopy (SEM). The SEM images allow us to conclude that the LB methodology provides the highest coverage. This coverage is almost independent of the chemical composition of sheets. Conversely, the coverage obtained by the LS methodology increases with the percentage of C-O groups attached to sheets. Surface-pressure isotherms of these materials were interpreted according to the Volmer model. PMID- 25695858 TI - Colloidal polymers with controlled sequence and branching constructed from magnetic field assembled nanoparticles. AB - The assembly of nanoparticles into polymer-like architectures is challenging and usually requires highly defined colloidal building blocks. Here, we show that the broad size-distribution of a simple dispersion of magnetic nanocolloids can be exploited to obtain various polymer-like architectures. The particles are assembled under an external magnetic field and permanently linked by thermal sintering. The remarkable variety of polymer-analogue architectures that arises from this simple process ranges from statistical and block copolymer-like sequencing to branched chains and networks. This library of architectures can be realized by controlling the sequencing of the particles and the junction points via a size-dependent self-assembly of the single building blocks. PMID- 25695859 TI - Extended Follow-up of Treated and Untreated Retinopathy in Incontinentia Pigmenti: Analysis of Peripheral Vascular Changes and Incidence of Retinal Detachment. AB - IMPORTANCE: Extended follow-up of treated and untreated retinopathy in incontinentia pigmenti (IP) has not previously been documented, to our knowledge. OBJECTIVE: To determine which eyes with IP are at risk for retinal detachment. DESIGN, SETTING, AND PARTICIPANTS: Observational cohort study of patients with IP who were retrospectively identified at a tertiary care academic center between 1976 and 2013. Fifty eyes of 25 female participants meeting clinical criteria for IP were followed up for at least 6 months. The last year of follow-up was between 1987 and 2014. MAIN OUTCOMES AND MEASURES: Progression of retinopathy or the development of retinal detachment was assessed with fluorescein angiography, clinical examination, or both. RESULTS: The median duration of follow-up was 9.3 years (range, 0.5-22.8 years). Over this period, 11 eyes (22%; 95% CI, 11%-33%) developed retinal detachment. The odds of retinal detachment were increased if there was retinal neovascularization (odds ratio, 11.61; 95% CI, 1.34-100.56; P = .03) or ischemic optic neuropathy (odds ratio, 5.27; 95% CI, 1.61-17.23; P = .006) on initial examination. A bimodal distribution of retinal detachments was observed, with most tractional detachments (7 eyes) occurring by age 2.5 years (median, 1.5 years; range, 14 days-7.0 years) and most rhegmatogenous detachments (4 eyes) occurring in adults (median age, 31.5 years; range, 14.0-47.0 years). Three eyes of young patients (<=2.5 years) developed tractional detachment, despite prophylactic ablation in 4 eyes; only one eye of older patients (>=14.0 years) developed retinal detachment following prophylactic ablation in 6 eyes. Persistent fetal vasculature appears to occur more commonly in IP (14%; 95% CI, 4%-25%) than in the general population. CONCLUSIONS AND RELEVANCE: All eyes with retinopathy due to IP should be monitored throughout adulthood for the development of retinal complications. During infancy and early childhood, ophthalmoscopic examination should be performed frequently so that prompt treatment can be initiated if there is progressive disease. Because of the nonrandomized nature of this study, the indications for prophylactic ablation and its success rate remain uncertain. Patients with less than 6 months of follow-up were excluded from the analysis, which could have biased this study cohort toward patients with more severe or less severe disease. PMID- 25695860 TI - In vitro and in vivo inhibition of human Fanconi anemia head and neck squamous carcinoma by a phytonutrient combination. AB - Head and neck squamous cell carcinoma (HNSCC) and acute myeloid leukemia are the major causes of mortality and morbidity in Fanconi anemia (FA) patients. The objective of this study was to investigate the antineoplastic activity of PB, an antineoplastic nutrient mixture (containing quercetin, curcumin, green tea, cruciferex and resveratrol) on human FA HNSCC in vitro and in vivo. Human FA HNSCC cell line OHSU-974 (Fanconi Anemia Research Fund) was cultured in RPMI medium supplemented with 20% FBS and anti-biotics. At near confluence, cells were treated in triplicate with different concentrations of PB: 0, 10, 25, 50, 75 and 100 ug/ml. Cells were also treated with PMA to induce MMP-9 activity. Cell proliferation was detected by MTT assay, secretion of MMPs by gelatinase zymography, invasion through Matrigel, migration by scratch test and morphology by hematoxylin and eosin (H&E) staining. In vivo, athymic male nude mice (n=12) were inoculated with 3x106 OHSU-974 cells subcutaneously and randomly divided into two groups: group A was fed a regular diet and group B a regular diet supplemented with 1% PB. Four weeks later, the mice were sacrificed and their tumors were excised, weighed and processed for histology. NM inhibited the growth of OHSU-974 tumor by 67.6% (p<0.0001) and tumor burden by 63.6% (p<0.0001). PB demonstrated dose-dependent inhibition of cell proliferation, with 27% (p=0.0003) and 48% (p=0.0004) toxicity at 75 and 100 ug/ml, respectively. Zymography revealed MMP-2 and PMA-induced MMP-9 secretion. PB suppressed secretion of both MMPs in a dose-dependent manner, with total block of both at 50 ug/ml. PB inhibited cell migration (by scratch test) and OHSU-974 invasion through Matrigel in a dose-dependent fashion with total block at 50 ug/ml. H&E staining showed no morphological changes below 50 ug/ml. The results suggest that PB has potential therapeutic use in the treatment of human FA HNSCC. PMID- 25695862 TI - Efficient and balanced charge transport revealed in planar perovskite solar cells. AB - Hybrid organic-inorganic perovskites have emerged as novel photovoltaic materials and hold great promise for realization of high-efficiency thin film solar modules. In this study, we unveil the ambipolar characteristics of perovskites by employing the transport measurement techniques of charge extraction by linearly increasing voltage (CELIV) and time-of-flight (TOF). These two complementary methods are combined to quantitatively determine the mobilities of hole and electron of CH3NH3PbI3 perovskite while revealing the recombination process and trap states. It is revealed that efficient and balanced transport is achieved in both CH3NH3PbI3 neat film and CH3NH3PbI3/PC61BM bilayer solar cells. Moreover, with the insertion of PC61BM, both hole and electron mobilities of CH3NH3PbI3 are doubled. This study offers a dynamic understanding of the operation of perovskite solar cells. PMID- 25695863 TI - Escape from crossover interference increases with maternal age. AB - Recombination plays a fundamental role in meiosis, ensuring the proper segregation of chromosomes and contributing to genetic diversity by generating novel combinations of alleles. Here, we use data derived from direct-to-consumer genetic testing to investigate patterns of recombination in over 4,200 families. Our analysis reveals a number of sex differences in the distribution of recombination. We find the fraction of male events occurring within hotspots to be 4.6% higher than for females. We confirm that the recombination rate increases with maternal age, while hotspot usage decreases, with no such effects observed in males. Finally, we show that the placement of female recombination events appears to become increasingly deregulated with maternal age, with an increasing fraction of events observed within closer proximity to each other than would be expected under simple models of crossover interference. PMID- 25695864 TI - Identification of novel aldose reductase inhibitors based on carboxymethylated mercaptotriazinoindole scaffold. AB - Fifteen compounds, sharing an indole-1-acetic acid moiety as a common fragment, were selected from commercial databases for testing aldose reductase inhibition. 3-Mercapto-5H-1,2,4-triazino[5,6-b]indole-5-acetic acid (13) was the most promising inhibitor, with an IC50 in the submicromolar range and high selectivity, relative to aldehyde reductase. The crystal structure of aldose reductase complexed with 13 revealed an interaction pattern explaining its high affinity. Physicochemical parameters underline the excellent "leadlikeness" of 13 as a promising candidate for further structure optimizations. PMID- 25695865 TI - Controlled van der Waals epitaxy of monolayer MoS2 triangular domains on graphene. AB - Multilayered heterostructures of two-dimensional materials have recently attracted increased interest because of their unique electronic and optical properties. Here, we present chemical vapor deposition (CVD) growth of triangular crystals of monolayer MoS2 on single-crystalline hexagonal graphene domains which are also grown by CVD. We found that MoS2 grows selectively on the graphene domains rather than on the bare supporting SiO2 surface. Reflecting the heteroepitaxy of the growth process, the MoS2 domains grown on graphene present two preferred equivalent orientations. The interaction between the MoS2 and the graphene induced an upshift of the Raman G and 2D bands of the graphene, while significant photoluminescence quenching was observed for the monolayer MoS2. Furthermore, photoinduced current modulation along with an optical memory effect was demonstrated for the MoS2-graphene heterostructure. Our work highlights that heterostructures synthesized by CVD offer an effective interlayer van der Waals interaction which can be developed for large-area multilayer electronic and photonic devices. PMID- 25695866 TI - Leptomeningeal enhancement on magnetic resonance imaging as a predictor of hemodynamic insufficiency. AB - OBJECTIVE: The objective of this study was to evaluate the value of leptomeningeal enhancement on magnetic resonance imaging in relation to relative cerebral blood flow (rCBF) and cerebrovascular reserve. METHODS: A retrospective analysis was performed for 31 patients with internal carotid artery or proximal middle cerebral artery occlusion without primary collateral flow, who underwent enhanced T1-weighted magnetic resonance imaging and acetazolamide-challenged perfusion computed tomography. They were graded into 3 groups in leptomeningeal enhancement on T1-weighted imaging. The rCBF and the percentage change of cerebral blood flow were obtained in the ipsilateral middle cerebral artery territory. RESULTS: The mean percentage changes of CBF were -13.7%, 6.9%, and 23.8% in prominent (n = 11), mild (n = 11), and equivalent (n = 9) increased enhancements, respectively. The degree of leptomeningeal enhancement was significantly reverse-correlated with percentage change of CBF (P < 0.001), whereas the rCBFs were not significantly different. CONCLUSIONS: The reverse correlation between leptomeningeal enhancement and cerebrovascular reserve suggests that increased enhancement may indicate impaired primary collaterals and hemodynamic insufficiency. Therefore, leptomeningeal enhancement degree can be used as an indicator of hemodynamic state in stroke. PMID- 25695867 TI - Subcutaneous packing in royal Egyptian mummies dated from 18th to 20th dynasties. AB - OBJECTIVE: It has been widely disseminated in the literature that subcutaneous packing, as part of mummification, was not usually done until the 21st dynasty. We aimed to study by computed tomography (CT) if subcutaneous packing was part of mummification of royal Egyptians dated to 18th to 20th dynasties. MATERIALS AND METHODS: We analyzed the 2- and 3-dimensional CT images of 13 royal mummies dated to circa 1550 to 1153 BC for presence of subcutaneous embalming materials. Among the studied mummies were Amenhotep III, Tutankhamun, Seti I, and Ramesses II. We reported the CT characters of any detected subcutaneous embalming materials and noted their impact on the morphology of the involved body part. We correlated the CT findings with the archeological literature. RESULTS: Computed tomographic images showed subcutaneous packing in 12 (92.3%) mummies; whereas the mummy that was previously known as "Thutmose I" showed no such evidence. Subcutaneous packing involved the faces (n = 11), necks (n = 4), torsos (n = 5), and/or extremities (n = 4) of the mummies. Subcutaneous filling materials showed variation in homogeneity and CT densities and they were likely composed of resin, bits of linen with resin, or other substances. Subcutaneous packing procedure succeeded in providing uniform full contour of the involved body regions without causing significant tissue damages. CONCLUSIONS: Subcutaneous packing procedure was used as part of mummification of royal Ancient Egyptians dated to 18th to 20th dynasties earlier than what was believed in archaeology. The Ancient Egyptian embalmers must have been skilled in dissection and possessed surgical tools that enabled them to perform this fine procedure. PMID- 25695868 TI - 3-T breast diffusion-weighted MRI by echo-planar imaging with spectral spatial excitation or with additional spectral inversion recovery: an in vivo comparison of image quality. AB - OBJECTIVE: To compare conventional diffusion-weighted imaging (DWI) with spectral spatial excitation (cDWI) and an enhanced DWI with additional adiabatic spectral inversion recovery (eDWI) for 3-T breast magnetic resonance imaging (MRI). METHODS: Twenty-four patients were enrolled in the study with both cDWI and eDWI. Three breast radiologists scored cDWI and eDWI images of each patient for fat suppression quality, geometric distortion, visibility of normal structure and biopsy-proven lesions, and overall image quality. Signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), and apparent diffusion coefficient (ADC) for evaluable tissues were measured. Statistical tests were performed for qualitative and quantitative comparisons. RESULTS: Diffusion-weighted imaging with spectral spatial excitation yielded significantly higher CNR and SNR on a lesion basis, and higher glandular CNR and SNR and muscle SNR on a patient basis. Enhanced DWI also yielded significantly higher qualitative scores in all categories. No significant difference was found in ADC values. CONCLUSIONS: Enhanced DWI provided superior image quality and higher CNR and SNR on a lesion basis. Enhanced DWI can replace cDWI for 3-T breast DWI. PMID- 25695869 TI - Diagnosis and management of patients with allergy to metal implants. AB - Cutaneous allergic reactions to implanted metal devices, for example, orthopedic, are well reported in the literature. Also, extracutaneous complications resulting from peri-implant inflammation have been observed in association with metal allergy. Nickel, cobalt, and chromium are the three most common triggers of both cutaneous and extracutaneous allergy-related complications. However, the diagnosis of metal implant allergy remains a challenge, that is, the synopsis of excluding differential diagnoses and the combination of different allergy diagnostic tools is needed. Thus, the management of metal implant allergy is also hampered by clinical uncertainty and unresolved scientific questions. PMID- 25695871 TI - Dance movement therapy for depression. AB - BACKGROUND: Depression is a debilitating condition affecting more than 350 million people worldwide (WHO 2012) with a limited number of evidence-based treatments. Drug treatments may be inappropriate due to side effects and cost, and not everyone can use talking therapies.There is a need for evidence-based treatments that can be applied across cultures and with people who find it difficult to verbally articulate thoughts and feelings. Dance movement therapy (DMT) is used with people from a range of cultural and intellectual backgrounds, but effectiveness remains unclear. OBJECTIVES: To examine the effects of DMT for depression with or without standard care, compared to no treatment or standard care alone, psychological therapies, drug treatment, or other physical interventions. Also, to compare the effectiveness of different DMT approaches. SEARCH METHODS: The Cochrane Depression, Anxiety and Neurosis Review Group's Specialised Register (CCDANCTR-Studies and CCDANCTR-References) and CINAHL were searched (to 2 Oct 2014) together with the World Health Organization's International Clinical Trials Registry Platform (WHO ICTRP) and ClinicalTrials.gov. The review authors also searched the Allied and Complementary Medicine Database (AMED), the Education Resources Information Center (ERIC) and Dissertation Abstracts (to August 2013), handsearched bibliographies, contacted professional associations, educational programmes and dance therapy experts worldwide. SELECTION CRITERIA: Inclusion criteria were: randomised controlled trials (RCTs) studying outcomes for people of any age with depression as defined by the trialist, with at least one group being DMT. DMT was defined as: participatory dance movement with clear psychotherapeutic intent, facilitated by an individual with a level of training that could be reasonably expected within the country in which the trial was conducted. For example, in the USA this would either be a trainee, or qualified and credentialed by the American Dance Therapy Association (ADTA). In the UK, the therapist would either be in training with, or accredited by, the Association for Dance Movement Psychotherapy (ADMP, UK). Similar professional bodies exist in Europe, but in some countries (e.g. China) where the profession is in development, a lower level of qualification would mirror the situation some decades previously in the USA or UK. Hence, the review authors accepted a relevant professional qualification (e.g. nursing or psychodynamic therapies) plus a clear description of the treatment that would indicate its adherence to published guidelines including Levy 1992, ADMP UK 2015, Meekums 2002, and Karkou 2006. DATA COLLECTION AND ANALYSIS: Study methodological quality was evaluated and data were extracted independently by the first two review authors using a data extraction form, the third author acting as an arbitrator. MAIN RESULTS: Three studies totalling 147 participants (107 adults and 40 adolescents) met the inclusion criteria. Seventy-four participants took part in DMT treatment, while 73 comprised the control groups. Two studies included male and female adults with depression. One of these studies included outpatient participants; the other study was conducted with inpatients at an urban hospital. The third study reported findings with female adolescents in a middle-school setting. All included studies collected continuous data using two different depression measures: the clinician-completed Hamilton Depression Rating Scale (HAM-D); and the Symptom Checklist-90-R (SCL-90-R) (self-rating scale).Statistical heterogeneity was identified between the three studies. There was no reliable effect of DMT on depression (SMD -0.67 95% CI -1.40 to 0.05; very low quality evidence). A planned subgroup analysis indicated a positive effect in adults, across two studies, 107 participants, but this failed to meet clinical significance (SMD -7.33 95% CI -9.92 to -4.73).One adult study reported drop-out rates, found to be non-significant with an odds ratio of 1.82 [95% CI 0.35 to 9.45]; low quality evidence. One study measured social functioning, demonstrating a large positive effect (MD -6.80 95 % CI -11.44 to -2.16; very low quality evidence), but this result was imprecise. One study showed no effect in either direction for quality of life (0.30 95% CI -0.60 to 1.20; low quality evidence) or self esteem (1.70 95% CI -2.36 to 5.76; low quality evidence). AUTHORS' CONCLUSIONS: The low-quality evidence from three small trials with 147 participants does not allow any firm conclusions to be drawn regarding the effectiveness of DMT for depression. Larger trials of high methodological quality are needed to assess DMT for depression, with economic analyses and acceptability measures and for all age groups. PMID- 25695870 TI - Evidence for a CDK4-dependent checkpoint in a conditional model of cellular senescence. AB - Cellular senescence, the stable cell cycle arrest elicited by various forms of stress, is an important facet of tumor suppression. Although much is known about the key players in the implementation of senescence, including the pRb and p53 axes and the cyclin dependent kinase inhibitors p16(INK4a) and p21(CIP1), many details remain unresolved. In studying conditional senescence in human fibroblasts that express a temperature sensitive SV40 large T-antigen (T-Ag), we uncovered an unexpected role for CDK4. At the permissive temperature, where pRb and p53 are functionally compromised by T-Ag, cyclin D-CDK4 complexes are disrupted by the high p16(INK4a) levels and reduced expression of p21(CIP1). In cells arrested at the non-permissive temperature, p21(CIP1) promotes reassembly of cyclin D-CDK4 yet pRb is in a hypo-phosphorylated state, consistent with cell cycle arrest. In exploring whether the reassembled cyclin D-CDK4-p21 complexes are functional, we found that shRNA-mediated knockdown or chemical inhibition of CDK4 prevented the increase in cell size associated with the senescent phenotype by allowing the cells to arrest in G1 rather than G2/M. The data point to a role for CDK4 kinase activity in a G2 checkpoint that contributes to senescence. PMID- 25695872 TI - Plasma sphingolipids: potential biomarkers for severe hepatic fibrosis in chronic hepatitis C. AB - The plasma profile of sphingolipids in hepatic fibrosis patients with chronic hepatitis C (CHC) is rarely considered at present. The association between plasma sphingolipids and severe fibrosis in CHC remains an obscure area of research. The aim of the present study was to assess the plasma profile of sphingolipids and to examine the association between plasma sphingolipids and severe fibrosis in CHC, in order to identify potential novel markers of severe fibrosis in CHC. A cohort of 120 treatment-naive patients with CHC were included in the present study. Liver biopsies were performed and routine serological indicators were measured. Plasma sphingolipids were detected using high performance liquid chromatography tandem mass spectrometry. A total of 44 plasma sphingolipids were detected. Plasma hexosylceramide (HexCer; d18:1/12:0), HexCer (d18:1/16:0) and HexCer (d18:1/22:0) were shown to be significantly different in patients with CHC between those with and without severe fibrosis (Metavir F >= 3; P < 0.05). HexCer (d18:1/12:0) was observed to be closely associated with severe fibrosis in CHC [odds ratio (OR)=1.03] following adjustment for confounding variables in a multivariate analysis. HexCer (d18:1/12:0) had diagnostic value for severe fibrosis in CHC [area under the curve (AUC)=0.69]. In patients with CHC who had developed significant fibrosis (Metavir F >= 2), HexCer (d18:1/12:0) remained closely associated with severe fibrosis (OR=1.08) in this subgroup. In addition, HexCer (d18:1/12:0) had sufficient diagnostic ability (AUC=0.73) to distinguish severe fibrosis in patients with CHC with significant fibrosis. In conclusion, the present study indicated that plasma HexCer (d18:1/12:0) exhibits a close correlation with severe hepatic fibrosis in CHC, particularly in patients who have significant fibrosis. Additionally, HexCer (d18:1/12:0) may be a potential marker of severe hepatic fibrosis in CHC. PMID- 25695873 TI - Plasma levels of cytokines and chemokines and the risk of mortality in HIV infected individuals: a case-control analysis nested in a large clinical trial. AB - BACKGROUND: All-cause mortality and serious non-AIDS events (SNAEs) in individuals with HIV-1 infection receiving antiretroviral therapy are associated with increased production of interleukin-6 which appears to be driven by monocyte/macrophage activation. Plasma levels of other cytokines or chemokines associated with immune activation might also be biomarkers of an increased risk of mortality and/or SNAEs. METHODS: Baseline plasma samples from 142 participants enrolled into the Strategies for Management of Antiretroviral Therapy study, who subsequently died, and 284 matched controls, were assayed for levels of 15 cytokines and chemokines. Cytokine and chemokine levels were analysed individually and when grouped according to function (innate/proinflammatory response, cell trafficking and cell activation/proliferation) for their association with the risk of subsequent death. RESULTS: Higher plasma levels of proinflammatory cytokines (interleukin-6 and tumour necrosis factor-alpha) were associated with an increased risk of all-cause mortality but in analyses adjusted for potential confounders, only the association with interleukin-6 persisted. Increased plasma levels of the chemokine CXCL8 were also associated with all cause mortality independently of hepatitis C virus status but not when analyses were adjusted for all confounders. In contrast, higher plasma levels of cytokines mediating cell activation/proliferation were not associated with a higher mortality risk and exhibited a weak protective effect when analysed as a group. CONCLUSION: Whereas plasma levels of interleukin-6 are the most informative biomarker of cytokine dysregulation associated with all-cause mortality in individuals with HIV-1 infection, assessment of plasma levels of CXCL8 might provide information about causes of mortality and possibly SNAEs. PMID- 25695874 TI - Willingness of Directed Living Donors and Their Recipients to Participate in Kidney Paired Donation Programs. AB - BACKGROUND: Participation of compatible living donors and recipients in kidney paired donation (KPD) could double the number of KPD transplants. We determined the willingness of previous directed donors and their recipients to participate in KPD and identified the association of various factors, including financial incentives, with willingness to participate. METHODS: Survey of previous directed living kidney donors and their recipients in a single Canadian center between 2001 and 2009. RESULTS: Among 207 of 222 eligible living donors contacted, 86 (42%) completed the anonymous survey: 93% (78/86) of donors indicated willingness to participate in KPD if this option had been provided at the time of donation. An increased willingness to participate was reported among the majority of respondents if reimbursements for lost wages and travel expenses were provided; however, cash payments between $5 000 and $50 000 had little impact on willingness. Willingness was also increased with an advantage to the recipient (younger donor or better human leukocyte antigen match), whereas delays beyond 3 months and donor travel were associated with reduced willingness to participate. Among 38 recipients approached during routine clinical follow-up visits over a 3 month period, 100% completed the survey, and 36 of 38 (92%) reported they would have been willing to participate in KPD. CONCLUSIONS: Over 90% of directed donors and recipients were willing to participate in KPD. Reimbursement for the costs of participation and improved efficiency of KPD (i.e., eliminating travel and reducing transplant times), but not cash payments, may increase participation of compatible donors and recipients in KPD. PMID- 25695875 TI - How do we assess whether the QT interval is abnormal: myths, formulae and fixed opinion. PMID- 25695876 TI - Cu(II)-catalyzed coupling of aromatic C-H bonds with malonates. AB - A new Cu(II)-catalyzed oxidative coupling of arenes with malonates has been developed using an amide-oxazoline directing group. The reaction proceeds via C(sp(2))-H activation and malonate coupling, followed by intramolecular oxidative N-C bond formation. A variety of arenes bearing different substituents are shown to be compatible with this reaction. PMID- 25695877 TI - Erratum to 'Variability of manual lumbar spine segmentation' [International Journal of Spine Surgery 6 (2012) 167-173]. AB - [This corrects the article DOI: 10.1016/j.ijsp.2012.04.002.]. PMID- 25695878 TI - Synthesis and structures of plutonyl nitrate complexes: is plutonium heptavalent in PuO3(NO3)2(-) ? AB - Gas-phase plutonium nitrate anion complexes were produced by electrospray ionization (ESI) of a plutonium nitrate solution. The ESI mass spectrum included species with all four of the common oxidation states of plutonium: Pu(III), Pu(IV), Pu(V), and Pu(VI). Plutonium nitrate complexes were isolated in a quadrupole ion trap and subjected to collision-induced dissociation (CID). CID of complexes of the general formula PuOx(NO3)y(-) resulted in the elimination of NO2 to produce PuOx+1(NO3)y-1(-), which in most cases corresponds to an increase in the oxidation state of plutonium. Plutonyl species, Pu(V)O2(NO3)2(-) and Pu(VI)O2(NO3)3(-), were produced from Pu(III)(NO3)4(-) and Pu(IV)(NO3)5(-), respectively, by the elimination of two NO2 molecules. CID of Pu(VI)O2(NO3)3(-) resulted in NO2 elimination to yield PuO3(NO3)2(-), in which the oxidation state of plutonium could be VII, a known oxidation state in condensed phase but not yet in the gas phase. Density functional theory confirmed the nature of Pu(V)O2(NO3)2(-) and Pu(VI)O2(NO3)3(-) as plutonyl(V/VI) cores coordinated by bidentate equatorial nitrate ligands. The computed structure of PuO3(NO3)2(-) is essentially a plutonyl(VI) core, Pu(VI)O2(2+), coordinated in the equatorial plane by two nitrate ligands and one radical oxygen atom. The computations indicate that in the ground spin-orbit free state of PuO3(NO3)2(-), the unpaired electron of the oxygen atom is antiferromagnetically coupled to the spin-triplet state of the plutonyl core. The results indicate that Pu(VII) is not a readily accessible oxidation state in the gas phase, despite that it is stable in solution and solids, but rather that a Pu(VI)-O. bonding configuration is favored, in which an oxygen radical is involved. PMID- 25695879 TI - TMC-1 attenuates C. elegans development and sexual behaviour in a chemically defined food environment. AB - Although diet affects growth and behaviour, the adaptive mechanisms that coordinate these processes in non-optimal food sources are unclear. Here we show that the C. elegans tmc-1 channel, which is homologous to the mammalian tmc deafness genes, attenuates development and inhibits sexual behaviour in non optimal food, the synthetic CeMM medium. In CeMM medium, signalling from the pharyngeal MC neurons and body wall muscles slows larval development. However, in the non-standard diet, mutation in tmc-1 accelerates development, by impairing the excitability of these cells. The tmc-1 larva can immediately generate ATP when fed CeMM, and their fast development requires insulin signalling. Our findings suggest that the tmc-1 channel indirectly affects metabolism in wild type animals. In addition to regulating the development, we show that mutating tmc-1 can relax diet-induced inhibition of male sexual behaviour, thus indicating that a single regulator can be genetically modified to promote growth rate and reproductive success in new environments. PMID- 25695880 TI - Lead(II) complex formation with L-cysteine in aqueous solution. AB - The lead(II) complexes formed with the multidentate chelator L-cysteine (H2Cys) in an alkaline aqueous solution were studied using (207)Pb, (13)C, and (1)H NMR, Pb LIII-edge X-ray absorption, and UV-vis spectroscopic techniques, complemented by electrospray ion mass spectrometry (ESI-MS). The H2Cys/Pb(II) mole ratios were varied from 2.1 to 10.0 for two sets of solutions with CPb(II) = 0.01 and 0.1 M, respectively, prepared at pH values (9.1-10.4) for which precipitates of lead(II) cysteine dissolved. At low H2Cys/Pb(II) mole ratios (2.1-3.0), a mixture of the dithiolate [Pb(S,N-Cys)2](2-) and [Pb(S,N,O-Cys)(S-HCys)](-) complexes with average Pb-(N/O) and Pb-S distances of 2.42 +/- 0.04 and 2.64 +/- 0.04 A, respectively, was found to dominate. At high concentration of free cysteinate (>0.7 M), a significant amount converts to the trithiolate [Pb(S,N-Cys)(S HCys)2](2-), including a minor amount of a PbS3-coordinated [Pb(S-HCys)3](-) complex. The coordination mode was evaluated by fitting linear combinations of EXAFS oscillations to the experimental spectra and by examining the (207)Pb NMR signals in the chemical shift range deltaPb = 2006-2507 ppm, which became increasingly deshielded with increasing free cysteinate concentration. One-pulse magic-angle-spinning (MAS) (207)Pb NMR spectra of crystalline Pb(aet)2 (Haet = 2 aminoethanethiol or cysteamine) with PbS2N2 coordination were measured for comparison (deltaiso = 2105 ppm). The UV-vis spectra displayed absorption maxima at 298-300 nm (S(-) -> Pb(II) charge transfer) for the dithiolate PbS2N(N/O) species; with increasing ligand excess, a shoulder appeared at ~330 nm for the trithiolate PbS3N and PbS3 (minor) complexes. The results provide spectroscopic fingerprints for structural models for lead(II) coordination modes to proteins and enzymes. PMID- 25695881 TI - Bisphosphonates and glucose homeostasis: a population-based, retrospective cohort study. AB - CONTEXT: Evidence suggests that the human skeleton might be involved in the regulation of glucose homeostasis. OBJECTIVE: The objective of the study was to investigate the effect of exposure to bisphosphonates on the risk of incident type 2 diabetes mellitus (T2DM). DESIGN: This was a population-based, retrospective, open cohort study over the period 1995-2010. SETTING: The study was conducted from The Health Improvement Network database from the United Kingdom in a primary care setting. PATIENTS: A total of 35 998 individuals aged older than 60 years, without diabetes at baseline and with more than 1 year's exposure to bisphosphonates, and 126 459 age-, gender-, body mass index- and general practice-matched unexposed individuals participated in the study. INTERVENTIONS: There were no interventions. MAIN OUTCOME MEASURE: A new diagnosis of T2DM during the 16-year-long observation period, determined by Read codes and adjusted incidence rate ratio in bisphosphonate-exposed compared with unexposed groups, was the main outcome measure. RESULTS: The risk of incident T2DM was significantly lower in patients exposed to bisphosphonates compared with matched controls [adjusted incidence rate ratio 0.52, 95% confidence interval (CI) 0.48 0.56, P < .0001]. In subgroup analyses, the findings remained consistent in males [0.77 (95% CI 0.66-0.89)], females [0.49 (95% CI 0.45-0.53)], obese [0.54 (95% CI 0.50-0.59)], individuals exposed to steroid treatment [0.47 (95% CI 0.34-0.64)], and over different types of bisphosphonate medication. Analysis of duration of treatment suggested a brief increase in the risk of T2DM (1 to 2.5 y of exposure), followed by a progressive, sustained decrease as the years of exposure accumulated. CONCLUSIONS: This observational evidence suggests exposure to bisphosphonates was associated with a significant 50% reduction in the risk of incident T2DM. PMID- 25695882 TI - Diagnostic value of ACTH stimulation test in determining the subtypes of primary aldosteronism. AB - BACKGROUND: Adrenal venous sampling is recommended as the golden standard for subtyping primary aldosteronism (PA). However, it is invasive and inconvenient, and seeking a better way to make differential diagnosis of PA is necessary. OBJECTIVE: The objective of the study was to evaluate the diagnostic value of ACTH stimulation test under 1 mg dexamethasone suppression test (DST) in determining the subtypes of PA. METHODS: Ninety-five patients with PA confirmed by saline infusion test were included in this study. According to adrenal venous sampling and histopathology, 39 patients were diagnosed as bilateral adrenal hyperplasia (BAH), 37 as aldosterone-producing adenoma (APA), and 19 as unilateral adrenal hyperplasia (UAH). An ACTH stimulation test under 1 mg DST was performed in all patients. Plasma aldosterone and cortisol levels were measured every 30 minutes until 120 minutes after the iv injection of 50 IU ACTH. RESULTS: During the ACTH stimulation test, aldosterone levels in APA and UAH were similar (P > .05) but higher than those in BAH (P < .001). Furthermore, stimulated aldosterone levels of unilateral PA (APA and UAH) were significantly higher than bilateral PA (BAH) (P < .001). Receiver-operated characteristics curve analyses showed the aldosterone after ACTH stimulation was effective for distinguishing between unilateral PA and bilateral PA. The diagnostic accuracy was highest at 120 minutes after ACTH stimulation, and the optimal cutoff value of the aldosterone was 77.90 ng/dL, with a sensitivity of 76.8%, a specificity of 87.2%, a positive predictive value of 89.6%, and a negative predictive value of 72.3%. CONCLUSIONS: The ACTH stimulation test under 1 mg DST is useful to determine the subtypes of PA, especially in unilateral and bilateral PA, and may guide further treatment in PA patients. PMID- 25695883 TI - Follicular fluid concentrations of lipids and their metabolites are associated with intraovarian gonadotropin-stimulated androgen production in women undergoing in vitro fertilization. AB - CONTEXT: Although growing evidence points toward a role of lipotoxicity in the development of hyperandrogenesis, the main feature of polycystic ovary syndrome, few studies directly assessed this association in vivo in humans, and none targeted the ovarian milieu. OBJECTIVE: The main objective of this study was to correlate follicular fluid (FF) T levels with lipids, lipid metabolites, and inflammation markers. DESIGN: This was a cross-sectional study. SETTING: Recruitment was performed in two fertility clinics at one private and one academic center. PARTICIPANTS: Eighty women requiring in vitro fertilization were recruited during one of their scheduled visit at the fertility clinic. All women aged between 18 and 40 years with a body mass index between 18 and 40 kg/m(2) were invited to participate. INTERVENTION(S): There were no interventions. MAIN OUTCOME MEASURE(S): At the time of oocyte aspiration, FF was collected and analyzed for total T, lipids [nonesterified fatty acids (NEFAs) plus triglycerides], NEFA metabolites (acylcarnitines; markers of ineffective NEFAs beta-oxidation), and inflammatory marker composition. The hypothesis being tested was formulated before the data collection. RESULTS: FF T levels were significantly correlated with FF levels of lipids (r = 0.381, P = .001; independently of IL-6), acylcarnitines (r >= 0.255, all P = .008; not independently of lipids), and IL-6 (r = 0.300, P = .009, independently of lipids). Additionally, FF lipid levels were significantly and strongly correlated with acylcarnitines (r >= 0.594; all P < .001). CONCLUSIONS: These results suggest that ovarian androgen production is related to intraovarian exposure to lipids, independently of inflammation and mainly through ineffective NEFA beta oxidation (as shown by higher acylcarnitine levels). Inflammation is also associated with intraovarian androgenesis, independently of lipids. PMID- 25695884 TI - MicroRNA-93 promotes ovarian granulosa cells proliferation through targeting CDKN1A in polycystic ovarian syndrome. AB - CONTEXT: MicroRNAs (miRNAs) are small, noncoding RNAs that negatively regulate gene expression post-transcriptionally. Whether differently expressed miRNAs contribute to promoting granulosa cell proliferation in polycystic ovarian syndrome disease (PCOS) remains unknown. OBJECTIVE: We explored whether certain miRNAs are involved in the ovarian dysfunction of PCOS and the mechanism of increased granulosa cells proliferation. Patients and Cells: miRNA expression was analyzed in excised ovarian cortexes from 16 women with PCOS and 8 non-PCOS. An immortalized human granulosa (KGN) cell was used for the mechanism study. MAIN OUTCOME MEASURES: Expressions of miRNAs in ovarian cortexes were measured using qRT-PCR and KGN granulosa cells were cultured for proliferation assays after overexpression or inhibition of miR-93 or after insulin treatment. Bioinformatics were used to identify the potential miRNA targets. Protein expression analysis, luciferase assays, and rescue assays were used to confirm the substrate of miR 93. RESULTS: MiR-93 expression was higher in PCOS ovarian cortex and its identified target, CDKN1A, was downregulated. MiR-93 overexpression promoted cell proliferation and G1 to S transition. Knocking down CDKN1A promoted cell growth and cell cycle progression in granulosa cells, and CDKN1A re-introduction reversed the promotional role of miR-93. High concentrations of insulin induced upregulation of miR-93, stimulated KGN cells proliferation and reduced CDKN1A expression. CONCLUSIONS: miR-93 was increased in PCOS granulosa cells and targeted CDKN1A to promote proliferation and cell cycle progression. Insulin could upregulate the expression of miR-93 and stimulate cell proliferation. This might provide a new insight into the dysfunction of granulosa cells in PCOS. PMID- 25695885 TI - Clinical and biochemical factors associated with area and metabolic activity in the visceral and subcutaneous adipose tissues by FDG-PET/CT. AB - CONTEXT: Body fat distribution and inflammation may play a role in metabolic derangements and cardiovascular disease in obesity. OBJECTIVE: The aim of this study is to investigate clinical and biochemical factors associated with area and metabolic activity in the visceral and subcutaneous adipose tissues (VAT and SAT). PARTICIPANTS: (18)F-fluorodeoxyglucose-positron emission tomography and computed tomography imaging was performed in 251 consecutive subjects (62.6 +/- 9.3 y) for risk screening. MAIN OUTCOME MEASURES: We examined which clinical, anthropometric, metabolic, and inflammatory variables including advanced glycation end products (AGEs) and pigment epithelium-derived factor (PEDF) were independently associated with area and metabolic activity in VAT and SAT. Adipose tissue area was determined with computed tomography, whereas metabolic activity was assessed by (18)F-fluorodeoxyglucose uptake expressed as a target to background ratio (TBR) of blood-normalized standardized uptake. RESULTS: Serum levels of AGEs and PEDF were 9.81 +/- 3.21 U/mL and 14.0 (range 10.8-17.7) MUg/mL, respectively. Although the area in VAT and SAT was associated with waist circumference and sex, each adipose tissue area and TBR had different metabolic risk profiles. The TBR value in VAT was higher than that in SAT. In a multiple stepwise regression analysis, AGEs and medication for hypertension were independently associated with VAT TBR (R(2) = 0.102), whereas medication for diabetes, mean intima-media thickness, AGEs, and PEDF were the independent correlates of SAT TBR (R(2) = 0.132). CONCLUSIONS: The present study demonstrated that area and metabolic activity in VAT and SAT could be differently regulated, suggesting the involvement of AGEs and PEDF in adipose tissue inflammation. PMID- 25695886 TI - Elevated serum advanced glycation endproducts in obese indicate risk for the metabolic syndrome: a link between healthy and unhealthy obesity? AB - CONTEXT: Although obesity can predispose to the metabolic syndrome (MS), diabetes, and cardiovascular disease, not all obese subjects develop MS, hence the need for new indicators of risk for this syndrome. Advanced glycation end products (AGEs) correlate with factors involved in the MS, including inflammation and insulin resistance (IR). Because AGEs can be derived from food and are modifiable, it is important to determine whether they are a risk factor for MS. OBJECTIVE: The objective of this study was to assess the association of endogenous and exogenous AGEs with MS criteria. DESIGN: The following data were collected in a cross-sectional study of subjects with and without the MS: serum AGEs (sAGEs) and mononuclear cell AGEs, metabolites, pro- and antiinflammatory markers, body fat mass measures, including abdominal magnetic resonance imaging, and caloric and dietary AGE (dAGE) consumption. SETTING: The study was conducted in the general community. PARTICIPANTS: Participants included 130 MS and 139 non MS subjects of both sexes, older than 50 years. RESULTS: sAGEs ((epsilon)N carboxymethyllysine, methylglyoxal) were markedly elevated in obese persons with more than one other MS criteria but not in obese without MS criteria. sAGEs directly correlated with markers of IR (HOMA) and inflammation (leptin, TNFalpha, RAGE) and inversely with innate defenses (SIRT1, AGE receptor 1 [AGER1], glyoxalase-I, adiponectin). sAGEs correlated with dAGEs but not with calories, nutrient consumption, or fat mass measures. Consumption of dAGE, but not of calories, was markedly higher in MS than in non-MS. CONCLUSION: High sAGEs, a modifiable risk factor for IR, may indicate risk for the MS, type 2 diabetes, and cardiovascular disease. High dietary AGE consumption and serum AGE levels may link healthy obesity to at-risk obesity. PMID- 25695887 TI - Comparative efficacy of radiofrequency and laser ablation for the treatment of benign thyroid nodules: systematic review including traditional pooling and bayesian network meta-analysis. AB - PURPOSE: To compare the efficacy of radiofrequency ablation (RFA) and laser ablation (LA) for treatment of benign solid thyroid nodules, using a systematic review including traditional pooling and Bayesian network meta-analysis. MATERIALS AND METHODS: A comprehensive literature search in PubMed-MEDLINE, EMBASE, and the Cochrane Library databases identified prospective studies evaluating the percentage mean change [absolute mean change (mL)] in nodule volume after RFA or LA. Studies from January 1, 2000, to November 1, 2013, were included. Review of 128 potential papers, including a full-text review of 33, identified 10 eligible papers covering a total of 184 patients for meta-analysis. The percentage mean change [absolute mean change] in nodule volume over a 6-month follow-up was compared between RFA and LA. RESULTS: Based on the traditional frequentist approach, the pooled percentage mean changes (95% confidence interval) of RFA and LA were 76.1% (70.1-82.1) and 49.9% (41.4-58.5), respectively, and the pooled absolute mean changes (95% confidence interval) of RFA and LA were 8.9 mL (6.6-11.2) and 5.2 mL (4.3-6.1), respectively. Based on the Bayesian network meta-analysis, RFA achieved a larger pooled percentage mean change (95% credible interval) and absolute mean change (95% credible interval) compared to LA [77.8% (67.7-88.0) vs 49.5% (26.7-72.4), and 9.2 mL (5.8-11.9) vs 5.3 mL (2.1-8.5), respectively]. The RFA group has the highest probability of having the most efficacious treatment (98.7%). There were no major complications after either RFA or LA. CONCLUSIONS: RFA appears to be superior to LA in reducing benign solid thyroid nodule volume, despite the smaller number of treatment sessions without major side effects. PMID- 25695888 TI - Impact of corticosteroid-binding globulin deficiency on pregnancy and neonatal sex. AB - CONTEXT: Plasma corticosteroid-binding globulin (CBG) transports cortisol but high progesterone levels at the maternal-fetal interface can displace cortisol from its steroid-binding site. A secretion-deficient CBG mutant (A51V) in ~1 of 36 Chinese causes low circulating CBG levels. OBJECTIVE: Assess the implications of a CBG deficiency on pregnancy outcomes. PARTICIPANTS AND DESIGN: From 1978 Chinese women screened at 12-16 weeks' gestation, 50 A51V carriers were identified and 46 were followed with 60 controls throughout pregnancy. Blood samples from another 2051 pregnant women were obtained at term to determine the secondary sex ratio (SSR) of newborns in an extended cohort (n = 101) of A51V mothers. OUTCOME MEASURES AND RESULTS: Among women recruited at 12-16 weeks' gestation, serum CBG increased progressively during pregnancy but was lower (P < .0001) in heterozygous A51V carriers than controls. Two women homozygous for A51V had very low serum CBG but their pregnancies progressed normally. The A51V mothers did not differ from controls in body mass index, gestational age at delivery, duration of parturition, blood pressure, gravidity, infant birth weight and size, or placental weights, and reported no unusual clinical symptoms. Peripheral CBG and progesterone levels correlated (r = 0.459) during first and second trimesters. Progesterone levels were much higher in intervillous blood and correlated (r = 0.637) with CBG levels. A female-skewed SSR in newborns of A51V mothers (0.77) differed (P < .05) from the SSR (1.17) in a reference cohort. CONCLUSIONS: CBG influences progesterone levels in peripheral blood and at the maternal-fetal interface. The female-skewed SSR suggests that male fetal survival is compromised in CBG-deficient mothers. PMID- 25695889 TI - Pituitary adenoma with paraganglioma/pheochromocytoma (3PAs) and succinate dehydrogenase defects in humans and mice. AB - CONTEXT: Germline mutations in genes coding succinate dehydrogenase (SDH) subunits A, B, C, and D have been identified in familial paragangliomas (PGLs)/pheochromocytomas (PHEOs) and other tumors. We described a GH-secreting pituitary adenoma (PA) caused by SDHD mutation in a patient with familial PGLs. Additional patients with PAs and SDHx defects have since been reported. DESIGN: We studied 168 patients with unselected sporadic PA and with the association of PAs, PGLs, and/or pheochromocytomas, a condition we named the 3P association (3PAs) for SDHx germline mutations. We also studied the pituitary gland and hormonal profile of Sdhb(+/-) mice and their wild-type littermates at different ages. RESULTS: No SDHx mutations were detected among sporadic PA, whereas three of four familial cases were positive for a mutation (75%). Most of the SDHx deficient PAs were either prolactinomas or somatotropinomas. Pituitaries of Sdhb(+/-) mice older than 12 months had an increased number mainly of prolactin secreting cells and several ultrastructural abnormalities such as intranuclear inclusions, altered chromatin nuclear pattern, and abnormal mitochondria. Igf-1 levels of mutant mice tended to be higher across age groups, whereas Prl and Gh levels varied according to age and sex. CONCLUSION: The present study confirms the existence of a new association that we termed 3PAs. It is due mostly to germline SDHx defects, although sporadic cases of 3PAs without SDHx defects also exist. Using Sdhb(+/-) mice, we provide evidence that pituitary hyperplasia in SDHx-deficient cells may be the initial abnormality in the cascade of events leading to PA formation. PMID- 25695890 TI - Glucagon cell hyperplasia and neoplasia with and without glucagon receptor mutations. AB - CONTEXT: Glucagon cell adenomatosis (GCA) was recently recognized as a multifocal hyperplastic and neoplastic disease of the glucagon cells unrelated to multiple endocrine neoplasia type 1 and von-Hippel-Lindau disease. OBJECTIVE: The study focused on the molecular analysis of the glucagon receptor (GCGR) gene in GCA and a description of the clinicopathological features of GCA with and without GCGR mutations. DESIGN: Pancreatic tissues from patients showing multiple glucagon cell tumors were morphologically characterized and macro- or microdissected. All exons of the GCGR gene were analyzed for mutations by Sanger and next-generation sequencing. Genotyping for all detected GCGR variants was performed in 2560 healthy individuals. PATIENTS: Six patients with GCA, and the parents of one patient were included in the study. MAIN OUTCOME MEASURES: The main outcome measures were the correlations between the patients' GCGR mutation status and the respective clinicopathological data. RESULTS: GCGR germline mutations were found in three of six patients. Patient 1 harbored a homozygous stop mutation. This patient's parents showed an identical but heterozygous GCGR mutation. Patient 2 had two different heterozygous point mutations leading each to premature stop codons. Patient 3 exhibited two homozygous missense mutations. No GCGR mutations were identified in the three other patients and in a large cohort of healthy subjects. The patients harboring GCGR mutations exhibited a greater number of tumors and larger tumors than patients with wild-type GCGR. One of the patients with wild-type GCGR showed lymph node micrometastases. CONCLUSIONS: GCA with GCGR germline mutations seems to follow an autosomal-recessive trait. By interrupting the GCGR signaling pathways GCGR mutations probably cause GCA via glucagon cell hyperplasia. GCA also occurs in patients without GCGR mutations, but seems to be associated with fewer and smaller tumors. PMID- 25695891 TI - Association of ferritin elevation and metabolic syndrome in males. Results from the Aragon Workers' Health Study (AWHS). AB - CONTEXT: Ferritin concentration is associated with metabolic syndrome, but the possibility of a nonlinear association has never been explored. OBJECTIVE: This study aimed to examine the relationship between serum ferritin levels and the metabolic syndrome in Spanish adult males. DESIGN: This was a cross-sectional analysis of baseline data from the Aragon Workers' Health Study. SETTING: Healthy workers from a factory were studied during their annual checkup. PARTICIPANTS: Spanish male adults (n = 3386) between the ages of 19 and 65 years participated. We excluded participants with ferritin > 500 MUg/L, ferritin < 12 MUg/L, or C reactive protein > 10 mg/L. MAIN OUTCOME MEASURE: Metabolic syndrome was defined according to the 2009 consensus definition from the Joint Interim Statement of several international societies. RESULTS: Metabolic syndrome prevalence was 27.1%. We found a positive association between elevated iron stores, measured as serum ferritin concentration, and metabolic syndrome and its criteria. Participants within the highest serum ferritin quintile had a higher risk than those in the lowest quintile for central obesity (odds ratio [OR], 1.88; 95% confidence interval [CI], 1.46-2.42), hypertriglyceridemia (OR, 2.15; 95% CI, 1.69-2.74), and metabolic syndrome (OR, 1.92; 95% CI, 1.48-2.49). The association was nonlinear and occurred at serum ferritin concentrations > 100 MUg/L (~ 33th percentile). Ferritin was also associated with insulin resistance, measured by homeostatic model assessment-insulin resistance (HOMA-IR) (P trend < .001). CONCLUSIONS: Our findings suggest that serum ferritin is significantly associated with metabolic syndrome and its criteria (especially central obesity and hypertriglyceridemia), suggesting that ferritin could be an early marker of metabolic damage in the development of metabolic syndrome. PMID- 25695892 TI - Circulating MKRN3 levels decline prior to pubertal onset and through puberty: a longitudinal study of healthy girls. AB - CONTEXT: Puberty is initiated by a complex interaction of suppressing and stimulating factors. Genetic studies of familial central precocious puberty have suggested makorin ring finger protein 3 (MKRN3) as a major inhibitor of GnRH secretion during childhood. Furthermore, genetic variation near MKRN3 (rs12148769) affects age at menarche in healthy girls. OBJECTIVE: The purpose of this study was to evaluate whether serum levels of MKRN3 declined before pubertal onset in healthy girls. DESIGN: This was a population-based longitudinal study of healthy Danish girls and a cohort study of early maturing girls. SETTING: The study was performed in the general community and in a tertiary referral center for pediatric endocrinology. PATIENTS OR OTHER PARTICIPANTS: Healthy girls (n = 38) aged 9.3 years (range, 5.9-11.3 years) at baseline and followed for 6.0 years (2.7-7.6 years) (2006-2014) with blood sampling every 6 months and early maturing girls (n = 13) with breast development ay <8.3 years of age were included. MAIN OUTCOME MEASURES: Serum levels of MKRN3 were measured in 354 samples (median, 9 per girl; range, 2-14 per girl), and genotyping of variants near MKRN3 (rs12148769 and rs12439354) was performed. RESULTS: MKRN3 concentrations declined preceding pubertal onset; the geometric mean (95% confidence interval) 3 years before pubertal onset vs the last visit before pubertal onset was 304 pg/mL (264 350 pg/mL) vs 257 pg/mL (243-273 pg/mL), corresponding to a reduction of 15% (1 27%) (P = .033). In prepubertal girls, circulating MKRN3 correlated negatively with gonadotropin levels: for FSH, r = -0.262 (P = .015) and for LH, r = -0.226 (P = .037). After adjustment, MKRN3 levels were lower in early maturing girls than in age-matched prepubertal girls: 171 pg/mL (<25-333 pg/mL) vs 262 pg/mL (94 624 pg/mL) (P = .051). Genetic variants near MKRN3 did not correlate with serum levels of MKRN3. CONCLUSIONS: Declining levels of circulating MKRN3 preceded pubertal onset. The negative correlation between MKRN3 and gonadotropins further supports MKRN3 as a major regulator of hypothalamic GnRH secretion during childhood. Undetectable or low MKRN3 levels were observed in a subgroup of patients with early onset of puberty. PMID- 25695893 TI - Double vision is a major manifestation in moderate to severe graves' orbitopathy, but it correlates negatively with inflammatory signs and proptosis. AB - CONTEXT: Double vision (diplopia) is a major determinant of work disability in patients with Graves' orbitopathy (GO), but is not part of the classification NOSPECS classification of GO. OBJECTIVE: The objectives of the study were to quantitate diplopia in patients with moderate to severe GO and to study associations with other disease and patient variables. DESIGN: This was a single center prospective study of consecutive patients at the time of referral. SETTING: The study was conducted at the University Hospital Thyroid-Eye Clinic. PATIENTS: Patients included 216 patients diagnosed with moderate to severe and active GO. MAIN OUTCOME MEASURES: Binocular diplopia in field of gaze and monocular fields of motility were prospectively recorded on diagrams and measured by planimetry. Fields of diplopia were correlated to other disease and patient variables. RESULTS: Six patients had only one functional eye and were excluded. Among the remaining 210 patients, diplopia was present in 75.2%. In patients with diplopia, this ranged from 5% to 100% (observed in 11.4% of patients) of binocular field of gaze. The field of diplopia correlated positively with eye motility restriction and with asymmetrical affection of orbits but negatively with signs of inflammation and proptosis that often are the main outcome measures in clinical studies of GO therapy. CONCLUSION: Diplopia is very common in moderate to severe GO and a major cause for active therapy. In moderate to severe GO, the field of diplopia correlates negatively with some other indicators of disease activity, which may be explained by the physiological properties of binocular fusion. PMID- 25695894 TI - Impairment of anaerobic capacity in adults with growth hormone deficiency. AB - CONTEXT: The anaerobic energy system underpins the initiation of all physical activities, including those of daily living. GH supplementation improves sprinting in recreational athletes, a performance measure dependent on the anaerobic energy system. The physiological and functional link between GH and the anaerobic energy system is unknown. OBJECTIVE: The objective was to investigate whether anaerobic capacity is impaired in adults with GH deficiency (GHD) and to assess its functional significance. DESIGN: This was a cross-sectional study. PARTICIPANTS: The participants were 13 adults with GHD and 13 age-, gender- and body mass index-matched normal subjects. MAIN OUTCOME MEASURES: Anaerobic power (watts) was assessed by the 30-second Wingate test, and aerobic capacity was assessed by the VO2max (L/min) test. The functional assessment comprised the stair-climb test, chair-stand test, and 7-day pedometry. Quality of life (QoL) was assessed by the QoL-AGHDA questionnaire. Lean body mass (LBM) was quantified by dual-energy x-ray absorptiometry. RESULTS: Mean anaerobic power (5.8 +/- 0.4 vs 7.1 +/- 0.3 W . kg LBM(-1); P < .05) and VO2max were significantly lower in adults with GHD. The duration of the stair-climb test was longer (19.4 +/- 0.7 vs 16.5 +/- 0.7 s; P < .01) in adults with GHD and correlated negatively (R(2) = 0.7; P < .0001) with mean anaerobic power. The mean number of chair-stand repetitions and daily step counts were lower, and the QoL-AGHDA score was higher in adults with GHD (P < .05). In a multiple regression analysis, age, gender, LBM, and GH status were significant predictors of mean anaerobic power. Mean anaerobic power significantly predicted stair-climb performance (P < .01) and QoL (P < .05). CONCLUSIONS: Anaerobic capacity is subnormal, and it independently predicts stair-climbing capacity and QoL in adults with GHD. We conclude that GH regulates anaerobic capacity, which determines QoL and selective aspects of physical function. PMID- 25695895 TI - The Alteration of Neonatal Raphe Neurons by Prenatal-Perinatal Nicotine. Meaning for Sudden Infant Death Syndrome. AB - Nicotine may link maternal cigarette smoking with respiratory dysfunctions in sudden infant death syndrome (SIDS). Prenatal-perinatal nicotine exposure blunts ventilatory responses to hypercapnia and reduces central respiratory chemoreception in mouse neonates at Postnatal Days 0 (P0) to P3. This suggests that raphe neurons, which are altered in SIDS and contribute to central respiratory chemoreception, may be affected by nicotine. We therefore investigated whether prenatal-perinatal nicotine exposure affects the activity, electrical properties, and chemosensitivity of raphe obscurus (ROb) neurons in mouse neonates. Osmotic minipumps, implanted subcutaneously in 5- to 7-day pregnant CF1 mice, delivered nicotine bitartrate (60 mg kg(-1) d(-1)) or saline (control) for up to 28 days. In neonates, ventilation was recorded by head-out plethysmography, c-Fos (neuronal activity marker), or serotonin autoreceptors (5HT1AR) were immunodetected using light microscopy, and patch-clamp recordings were made from raphe neurons in brainstem slices under normocarbia and hypercarbia. Prenatal-perinatal nicotine exposure decreased the hypercarbia induced ventilatory responses at P1-P5, reduced both the number of c-Fos-positive ROb neurons during eucapnic normoxia at P1-P3 and their hypercapnia-induced recruitment at P3, increased 5HT1AR immunolabeling of ROb neurons at P3-P5, and reduced the spontaneous firing frequency of ROb neurons at P3 without affecting their CO2 sensitivity or their passive and active electrical properties. These findings reveal that prenatal-perinatal nicotine reduces the activity of neonatal ROb neurons, likely as a consequence of increased expression of 5HT1ARs. This hypoactivity may change the functional state of the respiratory neural network leading to breathing vulnerability and chemosensory failure as seen in SIDS. PMID- 25695896 TI - Immunoregulatory Effects of Mesenchymal Stem Cell-Derived Extracellular Vesicles on T Lymphocytes. AB - The immunomodulatory activity of mesenchymal stem cells (MSCs) is largely mediated by paracrine factors. We have recently shown that the immunosuppressive effects of MSCs on B lymphocytes in peripheral blood mononuclear cell (PBMC) culture can be reproduced by extracellular vesicles (EVs) isolated from MSC culture supernatants. Here we investigated the effect of bone marrow-derived MSC EVs on T cells on PBMC cultures stimulated with anti-CD3/CD28 beads. Stimulation increased the number of proliferating CD3(+) cells as well as of regulatory T cells (Tregs). Coculture with MSCs inhibited the proliferation of CD3(+) cells, with no significant changes in apoptosis. Addition of MSC-EVs to PBMCs did not affect proliferation of CD3(+) cells, but induced the apoptosis of CD3(+) cells and of the CD4(+) subpopulation and increased the proliferation and the apoptosis of Tregs. Moreover, MSC-EV treatment increased the Treg/Teff ratio and the immunosuppressive cytokine IL-10 concentration in culture medium. The activity of indoleamine 2,3-dioxygenase (IDO), an established mediator of MSC immunosuppressive effects, was increased in supernatants of PBMCs cocultured with MSCs, but was not affected by the presence of MSC-EVs. MSC-EVs demonstrate immunomodulatory effects on T cells in vitro. However, these effects and the underlying mechanisms appear to be different from those exhibited by their cells of origin. PMID- 25695897 TI - Stem cell therapy for cardiovascular diseases: a progressive journey. AB - PURPOSE OF REVIEW: This review presents the findings from a select group of clinical trials of stem cell therapy for both acute and chronic heart disease. These studies are used to highlight the insight gained through such investigations and the remaining challenges. RECENT FINDINGS: Clinical trials assessing the use of adult stem cells for treating patients with heart disease have produced encouraging results that suggest these therapies are well tolerated and could potentially improve clinical outcomes, including left ventricular function, infarct size and the occurrence of future adverse clinical events. However, most have shown only modest benefits, and the results often appear to be inconsistent across trials. Nevertheless, analyses from these trials have provided useful information regarding factors that affect the potency of these therapies, the mechanisms underlying their effects and the patient populations most likely to derive benefits. SUMMARY: Stem cell therapy has the potential to overcome the limited regenerative capacity of the heart and induce cardiac repair and regeneration. The challenge lies in finding the most effective approach, which can only be determined through larger rigorously conducted clinical trials. PMID- 25695898 TI - Women, the menopause, hormone replacement therapy and coronary heart disease. AB - PURPOSE OF REVIEW: Cardiovascular disease considerations are associated with the menopause. Despite a misconception that women have a minimal risk for coronary heart disease (CHD), it is the major cause of female deaths. This review highlights issues of hormone replacement therapy (HRT) and CHD in women. RECENT FINDINGS: A woman under age 60, who suffers a myocardial infarction (MI), has a 2 year post-MI mortality of 28.9%; it is 19.6% in men. CHD and MI in women are subtle. In addition, female mortality from CHD increases after the menopause. The increased inflammatory risk factor status of women plays a role in development of atherosclerosis, before and after the menopause. Until after the menopause, women overall have a lower CHD mortality rate. Menopause is associated with unique symptoms, especially vasomotor ones; preexisting cardiovascular disease further exacerbates problems associated with the menopause. Use of HRT after the menopause is a major issue. Early menopause at age 39 years or younger and late menopause at age 56 years or older increase cardiovascular risk. HRT should not be prescribed for cardiovascular risk prevention, but when less than 10 years from menopause at a normal age, women can be reassured that cardiovascular risk from HRT is very low. SUMMARY: Prescription of HRT should never be made only for cardiovascular risk reduction. However, when symptom-related and other indications are present, HRT is appropriate and well tolerated in the early years after menopause with onset at a normal age. PMID- 25695899 TI - Unusual product formation in a 1,1-carboboration reaction. AB - The reaction of the cross-conjugated enediyne Me2C[double bond, length as m dash]C(C[triple bond, length as m-dash]CSiMe3)2 () with B(C6F5)3 gives the unusual borabicyclo[4.3.0]nonadiene product . The reaction sequence is initiated by 1,1-carboboration and is suggested to take a short subsequent sequence involving borane induced H migration reactions from the geminal pair of methyl groups. PMID- 25695900 TI - Free online otolaryngology educational modules: a pilot study. AB - IMPORTANCE: Otolaryngology residents need concise, easily accessible modules to expand educational opportunities between surgical cases. These modules should be inexpensive to create and improve learning outcomes. OBJECTIVE: The purpose of this pilot study was to assess whether otolaryngology residents at multiple institutions used online video modules to supplement their studying for the Otolaryngology Training Exam, whether the modules had any effect on their Otolaryngology Training Examination Scores, and to obtain survey feedback about the modules. DESIGN, SETTING, AND PARTICIPANTS: This randomized trial was conducted in 3 academic departments of otolaryngology in the United States among 37 residents enrolled in 3 otolaryngology residency programs. INTERVENTIONS: Residents were randomized into 2 groups, one with access to the educational modules and the other with no access. MAIN OUTCOMES AND MEASURES: Otolaryngology training examination scores were obtained from the year prior to the intervention (2012) and the year following module access (2013). Residents with access to the modules were also surveyed to assess use and obtain feedback about the modules. RESULTS: Otolaryngology training examination scores improved significantly from 2012 to 2013 among both residents who had access to the modules and those who did not in the sections of head and neck, laryngology, and sleep medicine. However, scores in the sections of pediatric otolaryngology (8% increase, P = .03), otology (7% increase, P = .02), and facial plastic surgery (10% increase, P = .02) improved from 2012 to 2013 only among residents with access to the modules. All respondents rated the videos as very helpful, with a rating of 4 of 5 on a Likert scale. CONCLUSIONS AND RELEVANCE: Online otolaryngology educational modules are an inexpensive way to expand resident learning opportunities. Despite the lack of quantifiable improvement in otolaryngology training examination scores in this study, use of online modules sends a message to otolaryngology residents that their education is a priority; self-study outside the hospital and clinics is necessary and expected; and that instructors are willing to try more nontraditional or progressive forms of education to increase resident knowledge. PMID- 25695902 TI - Errata. PMID- 25695903 TI - Decreased symptoms of depression after mindfulness-based stress reduction: potential moderating effects of religiosity, spirituality, trait mindfulness, sex, and age. AB - OBJECTIVE: Mindfulness-based stress reduction (MBSR) is a secular meditation training program that reduces depressive symptoms. Little is known, however, about the degree to which a participant's spiritual and religious background, or other demographic characteristics associated with risk for depression, may affect the effectiveness of MBSR. Therefore, this study tested whether individual differences in religiosity, spirituality, motivation for spiritual growth, trait mindfulness, sex, and age affect MBSR effectiveness. METHODS: As part of an open trial, multiple regression was used to analyze variation in depressive symptom outcomes among 322 adults who enrolled in an 8-week, community-based MBSR program. RESULTS: As hypothesized, depressive symptom severity decreased significantly in the full study sample (d=0.57; p<0.01). After adjustment for baseline symptom severity, moderation analyses revealed no significant differences in the change in depressive symptoms following MBSR as a function of spirituality, religiosity, trait mindfulness, or demographic variables. Paired t tests found consistent, statistically significant (p<0.01) reductions in depressive symptoms across all subgroups by religious affiliation, intention for spiritual growth, sex, and baseline symptom severity. After adjustment for baseline symptom scores, age, sex, and religious affiliation, a significant proportion of variance in post-MBSR depressive symptoms was uniquely explained by changes in both spirituality (beta=-0.15; p=0.006) and mindfulness (beta=-0.17; p<0.001). CONCLUSIONS: These findings suggest that MBSR, a secular meditation training program, is associated with improved depressive symptoms regardless of affiliation with a religion, sense of spirituality, trait level of mindfulness before MBSR training, sex, or age. Increases in both mindfulness and daily spiritual experiences uniquely explained improvement in depressive symptoms. PMID- 25695904 TI - Excited state evolution of DNA stacked adenines resolved at the CASPT2//CASSCF/Amber level: from the bright to the excimer state and back. AB - Deactivation routes of bright pipi* (La) and excimer charge transfer (CT) states have been mapped for two stacked quantum mechanical (CASPT2//CASSCF) adenines inside a solvated DNA double strand decamer (poly(dA).poly(dT)) described at the molecular mechanics level. Calculations show that one carbon (C2) puckering is a common relaxation coordinate for both the La and CT paths. By mapping the lowest crossing regions between La and CT states, together with the paths connecting the two states, we conclude that at least one CT state can be easily accessible. The lowest-lying conical intersections between ground state (GS) and CT states have been fully characterized in a realistic DNA environment for the first time. We show that the path to reach this crossing region from the CT minima involves high barriers that are not consistent with experimental data lifetimes. Instead, the multiexponential decay recorded in DNA, including the longest (ca. 100 picoseconds) lifetime component detected in oligomeric single- and double stranded systems, is compatible with both intra-monomer relaxation processes along the La deactivation path (involving small barriers) and the population of the excimer (CT) state that behaves as a trap. In the latter case, deactivation is feasible only going back to the La state by following its preferred decay coordinate. PMID- 25695905 TI - Science in sailing: interdisciplinary perspectives in optimizing sailing performance. PMID- 25695906 TI - Kawasaki disease shock syndrome: case report. AB - Kawasaki disease (KD) is a systemic vasculitis which presents with stable vital signs. Shock rarely occurs in such cases, but it may occur in the acute phase of KD. This report describes a 7-year-old boy with KD shock syndrome (KDSS) who presented with persistent fever, injected conjunctiva, a polymorphic skin rash, echocardiography indicating coronary artery dilatation, and shock. The patient's haemodynamic status markedly improved with immunoglobulin therapy. Early recognition of KDSS can be challenging; however, delay in diagnosis can increase the risk of coronary artery abnormalities and death. PMID- 25695907 TI - Children's Perceptions of Hypothetical Peers With Undesirable Characteristics: Role of the Peers' Desire to Change, Source of Effort to Change, and Outcome. AB - The present study, involving sixth- to eighth-grade students, is an extension of a prior investigation (Barnett, Livengood, Sonnentag, Barlett, & Witham, 2010) that examined children's perceptions of hypothetical peers with various undesirable characteristics. Results indicate that children's perceptions of hypothetical peers with an undesirable characteristic are influenced by the peers' desire to change, the source of effort to change, and the peers' success or failure in changing the characteristic. The children anticipated responding more favorably to peers who were successful in overcoming an undesirable characteristic than peers who were unsuccessful. Regardless of the peers' outcome, the children anticipated responding more favorably to peers who tried to change than peers who relied on the effort of adult authorities to motivate change. The children perceived successful peers as experiencing more positive affect than their unsuccessful counterparts, especially if the success was presented as a fulfillment of the peers' desire to change their undesirable characteristic. Finally, the children's ratings reflected the belief that, among peers who failed to change their undesirable characteristic, lacking the desire to change increases the relative likelihood that the characteristic will be permanent. PMID- 25695908 TI - Cortical thickness and prosocial behavior in school-age children: A population based MRI study. AB - Prosocial behavior plays an important role in establishing and maintaining relationships with others and thus may have important developmental implications. This study examines the association between cortical thickness and prosocial behavior in a population-based sample of 6- to 9-year-old children. The present study was embedded within the Generation R Study. Magnetic resonance scans were acquired from 464 children whose parents had completed the prosocial scale of the Strengths and Difficulties Questionnaire. To study the association between cortical thickness and prosocial behavior, we performed whole-brain surface-based analyses. Prosocial behavior was related to a thicker cortex in a cluster that covers part of the left superior frontal and rostral middle frontal cortex (p < .001). Gender moderated the association between prosocial behavior and cortical thickness in a cluster including the right rostral middle frontal and superior frontal cortex (p < .001) as well as in a cluster covering the right superior parietal cortex, cuneus, and precuneus (p < .001). Our results suggest that prosocial behavior is associated with cortical thickness in regions related to theory of mind (superior frontal cortex, rostral middle frontal cortex cuneus, and precuneus) and inhibitory control (superior frontal and rostral middle frontal cortex). PMID- 25695909 TI - Transport of polymeric nanoparticulate drug delivery systems in the proximity of silica and sand. AB - The contamination of the environment with traditional therapeutics due to metabolic excretion, improper disposal, and industrial waste has been well recognized. However, knowledge of the environmental distribution and fate of emerging classes of nanomedicine is scarce. This work investigates the effect of surface chemistry of polymeric nanoparticulate drug delivery systems (PNDDS) on their adsorption dynamics and transport in the vicinity of environmentally relevant surfaces for a concentration comparable with hospital and pharmaceutical manufacturing effluents. To this end, five different types of paclitaxel-based nanomedicine having different polymer stabilizers were employed. Their transport behavior was characterized via quartz crystal microbalance, sand column, spectrofluorometry, and dynamic light scattering techniques. PNDDS having positive zeta-potential displayed strong adsorption onto silica surfaces and no mobility in porous media of quartz sand, even in the presence of humic acid. The mobility of negatively charged PNDDS strongly depended on the amount and type of salt present in the aqueous media: Without any salt, such PNDDS demonstrated no adsorption on silica surfaces and high levels of mobility in sand columns. The presence of CaCl2 and CaSO4, even at low ionic strengths (i.e. 10 mM), induced PNDDS adsorption on silica surfaces and strongly limited the mobility of such PNDSS in sand columns. PMID- 25695910 TI - Activation of Melatonin Signaling Promotes beta-Cell Survival and Function. AB - Type 2 diabetes mellitus (T2DM) is characterized by pancreatic islet failure due to loss of beta-cell secretory function and mass. Studies have identified a link between a variance in the gene encoding melatonin (MT) receptor 2, T2DM, and impaired insulin secretion. This genetic linkage raises the question whether MT signaling plays a role in regulation of beta-cell function and survival in T2DM. To address this postulate, we used INS 832/13 cells to test whether activation of MT signaling attenuates proteotoxicity-induced beta-cell apoptosis and through which molecular mechanism. We also used nondiabetic and T2DM human islets to test the potential of MT signaling to attenuate deleterious effects of glucotoxicity and T2DM on beta-cell function. MT signaling in beta-cells (with duration designed to mimic typical nightly exposure) significantly enhanced activation of the cAMP-dependent signal transduction pathway and attenuated proteotoxicity induced beta-cell apoptosis evidenced by reduced caspase-3 cleavage (~40%), decreased activation of stress-activated protein kinase/Jun-amino-terminal kinase (~50%) and diminished oxidative stress response. Activation of MT signaling in human islets was shown to restore glucose-stimulated insulin secretion in islets exposed to chronic hyperglycemia as well as in T2DM islets. Our data suggest that beta-cell MT signaling is important for the regulation of beta-cell survival and function and implies a preventative and therapeutic potential for preservation of beta-cell mass and function in T2DM. PMID- 25695911 TI - Vitamin D research and clinical practice: at a crossroads. PMID- 25695912 TI - UV photofragmentation and IR spectroscopy of cold, G-type beta-O-4 and beta-beta dilignol-alkali metal complexes: structure and linkage-dependent photofragmentation. AB - Ultraviolet photofragmentation spectroscopy and infrared spectroscopy were performed on two prototypical guaiacyl (G)-type dilignols containing beta-O-4 and beta-beta linkages, complexed with either lithium or sodium cations. The complexes were generated by nanoelectrospray ionization, introduced into a multistage mass spectrometer, and subsequently cooled in a 22-pole cold ion trap to T ~ 10 K. A combination of UV photofragment spectroscopy and IR-UV double resonance spectroscopy was used to characterize the preferred mode of binding of the alkali metal cations and the structural changes so induced. Based on a combination of spectral evidence provided by the UV and IR spectra, the Li(+) and Na(+) cations are deduced to preferably bind to both dilignols via their linkages, which constitute unique, oxygen-rich binding pockets for the cations. The UV spectra reflect this binding motif in their extensive Franck-Condon activity involving low-frequency puckering motions of the linkages in response to electronic excitation. In the pinoresinol*Li(+)/Na(+) complexes involving the beta-beta linkage, the spectra also showed an inherent spectral broadening. The photofragment mass spectra are unique for each dilignol*Li(+)/Na(+) complex, many of which are also complementary to those produced by collision-induced dissociation (CID), indicating the presence of unique excited state processes that direct the fragmentation. These results suggest the potential for site selective fragmentation and for uncovering fragmentation pathways only accessed by resonant UV excitation of cold lignin ions. PMID- 25695913 TI - miR-181c promotes proliferation via suppressing PTEN expression in inflammatory breast cancer. AB - Primary inflammatory breast cancer (IBC) accounts for ~6% of new breast cancer cases. Even with multimodality treatment, the 5-year disease-free survival is <45%, thus making IBC the most deadly form of locally advanced breast cancer. Better understanding of the pathogenesis of IBC is essential to the design of effective therapy. We found that miR-181c was upregulated in IBC, implying that it could be a useful prognostic marker for IBC and a novel therapeutic target for the intervention of disease. Elucidating why the gene is overexpressed and how to downregulate it will help us to further understand the pathogenesis and progression of the disease and offer new targets for therapies. In this study, we showed that miR-181c as an oncogene promoted proliferation and it inhibited PTEN protein expression by targeting 3'-UTR of PTEN mRNA in IBC SUM149 cells. Moreover, PTEN was not only downregulated in IBC, but also inhibited proliferation in SUM149 cells and introduction of PTEN cDNA lacking the predicted sites of 3'-UTR abrogated miR-181c cellular function, suggesting that miR-181c inhibited proliferation by downregulating PTEN expression in IBC. Thus, targeting miR-181c and restoration of PTEN can be used in conjunction with other therapies to prevent progression of IBC. PMID- 25695914 TI - Antagonistic interplay between hypocretin and leptin in the lateral hypothalamus regulates stress responses. AB - The hypothalamic-pituitary-adrenal (HPA) axis functions to coordinate behavioural and physiological responses to stress in a manner that depends on the behavioural state of the organism. However, the mechanisms through which arousal and metabolic states influence the HPA axis are poorly understood. Here using optogenetic approaches in mice, we show that neurons that produce hypocretin (Hcrt)/orexin in the lateral hypothalamic area (LHA) regulate corticosterone release and a variety of behaviours and physiological hallmarks of the stress response. Interestingly, we found that Hcrt neuronal activity and Hcrt-mediated stress responses were inhibited by the satiety hormone leptin, which acts, in part, through a network of leptin-sensitive neurons in the LHA. These data demonstrate how peripheral metabolic signals interact with hypothalamic neurons to coordinate stress and arousal and suggest one mechanism through which hyperarousal or altered metabolic states may be linked with abnormal stress responses. PMID- 25695915 TI - Metals in obex and retropharyngeal lymph nodes of Illinois white-tailed deer and their variations associated with CWD status. AB - Prion proteins (PrP(C)) are cell membrane glycoproteins that can be found in many cell types, but specially in neurons. Many studies have suggested PrP(C)'s participation in metal transport and cellular protection against stress in the central nervous system (CNS). On the other hand PrP(Sc), the misfolded isoform of PrP(C) and the pathogenic agent in transmissible spongiform encephalopathies (TSE), has been associated with brain metal dyshomeostasis in prion diseases. Thus, changes in metal concentration associated with protein misfolding and aggregation have been reported for human and animal prion diseases, as well as for other neurodegenerative disorders, such as Parkinson's and Alzheimer's disease. The use of metal concentrations in tissues as surrogate markers for early detection of TSEs has been suggested. Studies on the accumulation of metals in free-ranging white-tailed deer have not been conducted. This study established concentrations of copper, iron, manganese, and magnesium in 2 diagnostic tissues used for CWD testing (obex and retropharyngeal lymph nodes (RLN)). We compared these concentrations between tissues and in relation to CWD status. We established reference intervals (RIs) for these metals and explored their ability to discriminate between CWD-positive and CWD-negative animals. Our results indicate that independent of CWD status, white-tailed deer accumulate higher concentrations of Fe, Mn and Mg in RLN than in obex. White-tailed deer infected with CWD accumulated significantly lower concentrations of Mn and Fe than CWD negative deer. These patterns differed from other species infected with prion diseases. Overlapping values between CWD positive and negative groups indicate that evaluation of these metals in obex and RLN may not be appropriate as a diagnostic tool for CWD infection in white-tailed deer. Because the CWD-negative deer were included in constructing the RIs, high specificities were expected and should be interpreted with caution. Due to the low sensitivity derived from the RIs, we do not recommend using metal concentrations for disease discrimination. PMID- 25695916 TI - Compression of lateral antebrachial cutaneous nerve in waitresses. AB - OBJECTIVE: In a retrospective survey of our electrophysiology laboratory, we encountered 3 cases of lateral antebrachial cutaneous nerve (LACN) compression in waitresses and propose direct compression of LACN by carrying heavy trays on the lateral bicipital tendon. LACN, a branch of musculocutaneous nerve, provides sensory innervations to lateral forearm. Causes of LACN involvement include venipuncture, elbow surgery, and trauma. METHODS: We encountered 6 cases of LACN neuropathy, 3 cases that were in slim waitresses carrying heavy trays. History and physical examination and forearm electrophysiologic studies (EPS) were performed in 3 waitresses at initial and follow-up visits. Antidromic stimulation of LACN was undertaken by Spindler and Felsenthals technique. Latency, amplitude, and conduction velocity were measured and compared with contralateral limb. RESULTS: All 3 patients were female waitresses aged 35-42 years, presented with few months of painful paresthesias of distal forearm, worse during working hours. Tinel sign at lateral cubital fossa was positive in all. EPS confirmed delayed latency, low amplitude, and slow conduction velocity of LACN on symptomatic side compared with normal. All 3 patients revealed electrophysiologic abnormalities consistent with LACN compression due to heavy trays in slim waitresses and considered occupational hazard. Treatment included nortriptyline or gabapentin and avoidance of heavy trays. Clinical and EPS findings improved over 8 months. CONCLUSIONS: We described 3 cases of LACN compression in waitresses from edges of heavy trays with typical symptoms and abnormal electrophysiological studies and improvement by avoiding compression and with analgesics. We propose inadequate fatty tissue in antecubital fossa contributed to compression of LACN. PMID- 25695917 TI - Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) presenting with polyneuropathy--a case series. AB - OBJECTIVES: We aim to characterize a group of patients with eosinophilic granulomatosis with polyangiitis (EGPA) with an initial presentation of peripheral neuropathy. METHODS: A retrospective analysis of 11 patients with EGPA. RESULTS: The most common chief complaint was neuropathic limb pain and numbness (100%), followed by extremity weakness (82%). Nine (82%) patients had acute to subacute onset. All patients had a history of asthma and serum eosinophilia of more than 11%. Combining clinical and electrophysiological data, 10 (91%) patients demonstrated notable asymmetric involvement, whereas 1 patient presented with a length-dependent symmetrical axonal polyneuropathy. All patients improved significantly after immunotherapy, with average time to improvement of 9 weeks. Ten (91%) patients improved steadily and experienced no relapse, whereas 1 relapsed within the first year. CONCLUSIONS: EGPA should be suspected in patients with asymmetric axonal peripheral neuropathy associated with asthma and eosinophilia. Early diagnosis and aggressive treatment help to achieve favorable outcome. PMID- 25695918 TI - Necrotizing myopathies: an update. AB - Necrotizing myopathy is defined by the predominant pathological feature of necrosis of muscle fibers in the absence of substantial lymphocytic inflammatory infiltrates. Most commonly necrotizing myopathies are divided into immune mediated (IMNM) and nonimmune mediated (NIMNM). IMNM has been associated with anti-signal recognition particle antibodies, connective tissue diseases, cancer, post-statin exposure with 3-hydroxy-3-methylglutaryl-coenzyme A antibodies, and viral infections including HIV and hepatitis C. NIMNM is linked to medications and toxic exposures. Both IMNM and NIMNM are typically characterized by proximal weakness, although the severity can vary substantially. Myalgias are reported by some, but not all, patients. Pathological findings on muscle biopsy include predominant fiber necrosis with little or no inflammatory infiltrate. In IMNM, there is variable evidence for the deposition of membrane attack complex on capillaries and muscle fibers, although membrane attack complex deposition on capillaries is typically less than is seen in dermatomyositis; class I major histocompatibility complex expression on muscle fibers is variable but typically less than is seen in polymyositis. Immunohistochemical abnormalities are not typically seen in NIMNM. Treatment of IMNM involves immunosuppressive therapy, although there are no controlled trials to guide particular treatment choices. Treatment of NIMNM involves removal of the toxic exposure. PMID- 25695919 TI - Practical rules for electrodiagnosis in suspected multifocal motor neuropathy. AB - Multifocal motor neuropathy (MMN) with conduction block (CB) is a rare chronic immune-mediated neuropathy, but important to diagnose as it is treatable. The key features in prototypic MMN are electrodiagnostic demonstration of focal CB away from common sites of entrapment and normal sensory conduction across these sites. However, there are challenges in distinguishing CB from the effects of abnormal temporal dispersion. Consensus electrodiagnostic criteria, reinforced by modeling studies, are available to support definite or probable CB. In addition, consideration of technical issues can guard against false-positive and false negative conclusions. These include limb temperature, stimulus site, inadvertent stimulating electrode movement, and supramaximal and submaximal responses, as well as the possibility of Martin-Gruber anastamosis. Robust evidence supports the treatment of MMN with intravenous immunoglobulin, and guidelines have been developed. Application of practical and simple rules including a 4-step diagnostic algorithm can help practitioners correctly diagnose this treatable condition and improve patient outcomes. PMID- 25695920 TI - A novel mutation in motor domain of KIF5A associated with an HSP/axonal neuropathy phenotype. AB - SPG10 is an autosomal dominant hereditary spastic paraplegia (HSP) caused by mutations in the gene KIF5A encoding the heavy chain of kinesin, a motor protein implied in motility functions within cells. Most of the KIF5A mutations are clustered in 2 areas of motor domain of the protein, the switch regions I and II, that are necessary for microtubules interaction. The set of mutations in KIF5A described so far account for a spectrum of clinical heterogeneity ranging from pure HSP to isolated peripheral nerve involvement (Charcot-Marie-Tooth phenotype) or complicated HSP phenotypes. We here describe a patient presenting with progressive walking difficulties and burning dysesthesias, numbness, and pain at distal segments of the 4 limbs. Neurological examination revealed severe spastic gait and vibratory and proprioception sensory reduction in the lower limbs. Motor and sensory nerve conduction studies disclosed axonal damage of peripheral nerves at lower limbs. We identified the novel variant c.967C>T in the KIF5A gene resulting in the R323W change, which is located at the C-terminus of the motor domain of the KIF5A protein, just upstream the linker region but out of the switch regions. Our findings confirm that the "mixed" central-peripheral involvement is the most frequent clinical picture related to KIF5A motor domain mutations and that motor domain "in toto," even outside of the switch regions, is a hot spot for pathogenic mutations. We stress the concept that detection of a peripheral axonal neuropathy in an autosomal dominant HSP patient should be regarded as an important diagnostic tool and should guide clinicians to seek, first of all, KIF5A mutations. PMID- 25695921 TI - A case of good syndrome presumed secondary to metastatic pancreatic thymoma in a patient presenting with a myasthenic crisis postthymectomy. AB - INTRODUCTION: Myasthenia gravis (MG) is an autoimmune disorder characterized by autoantibodies against the postsynaptic nicotinic acetylcholine receptors, muscle specific tyrosine kinase, low-density lipoprotein receptor-related protein 4, and agrin. The incidence of thymoma in MG is reported as ~10%-15%. The incidence of extrathoracic metastatic thymoma is exceedingly rare and may present years after resection. Associations between thymoma and immunodeficiency have also been described, including Good syndrome. METHODS AND RESULTS: We describe the clinical course, investigations, and treatments performed in a patient presenting with a myasthenic crisis in the setting of acetylcholine receptor antibody-positive generalized MG 10 years postthymectomy. Computed tomography imaging revealed 2 pancreatic lesions, but no residual thoracic thymoma. Biopsy confirmed metastatic pancreatic thymoma, which was successfully resected. His course was further complicated by cytomegalovirus retinitis with a depressed CD4 count and perniosis. DISCUSSION: This presentation was felt to be consistent with Good immunodeficiency syndrome. PMID- 25695922 TI - Two families with MYH7 distal myopathy associated with cardiomyopathy and core formations. AB - INTRODUCTION: Laing distal myopathy is caused by MYH7 gene mutations. Multiple families have been reported with varying patterns of skeletal and cardiac involvement as well as histopathological findings. CASE SERIES: We report 2 families with p.Glu1508del mutation with detailed electrophysiological and muscle pathology findings. RESULTS: All patients displayed the classic phenotype with weakness starting in the anterior compartment of the legs with a "hanging great toe." It was followed by finger extensors involvement, relatively sparing the extensor indicis proprius, giving the appearance of a "pointing index" finger. All the affected individuals had a dilated cardiomyopathy and core formations on muscle biopsy. Unexpectedly, neurogenic changes were also observed in some individuals. Both families were initially misdiagnosed with either central core disease or hereditary neuropathy. CONCLUSIONS: Recognizing the classic phenotype, screening for cardiac involvement that may be clinically silent, and determining the mode of inheritance help with selecting the appropriate genetic test. PMID- 25695924 TI - Objective and Subjective Improvement of Hearing in Noise After Surgical Correction of Unilateral Congenital Aural Atresia in Pediatric Patients: A Prospective Study Using the Hearing in Noise Test, the Sound-Spatial-Quality Questionnaire, and the Glasgow Benefit Inventory. AB - OBJECTIVES: The aim of this study was to assess the objective and subjective long term binaural benefits of surgical correction in children with unilateral congenital aural atresia, using an open-set sentence test in noise and subjective questionnaires. DESIGN: A prospective study was performed between August 2010 and February 2013. This study included pediatric patients who had unilateral conductive hearing loss (normal bone conduction hearing) on the atretic side but normal air conduction hearing on the normal side and were scheduled to undergo a primary canaloplasty. Pure-tone audiometry, the hearing in noise test (HINT), and questionnaires (Sound-Spatial-Qualities of Hearing Scale; Glasgow Benefit Inventory [GBI]) were administered preoperatively and at 6 and 12 months postoperatively. RESULTS: Among 34 consecutive patients who initially met enrollment criteria, 26 subjects (23 boys and 3 girls) aged 10 to 16 years (mean 12.3 years) completed this study. Canaloplasty and hearing restoration procedures were performed uneventfully in all patients. The mean air conduction thresholds were significantly improved from 63.9 to 35.0 dB (6 months) and 39.4 dB (12 months) after surgery (p < 0.001). In HINT, speech understanding in noise that was presented toward the newly opened atretic ear significantly improved at 1 year postoperatively (p = 0.014). In noise toward the normal ear, speech understanding significantly improved after surgery, from -0.1 dB preoperatively to -2.0 dB at 6 months (p = 0.002) and -1.8 dB at 12 months (p = 0.005) (p for quadratic trend = 0.036). The composite score improved from -2.6 dB preoperatively to -3.4 dB at 6 months and -3.6 dB at 12 months (p = 0.045; p for linear trend = 0.005). The Sound-Spatial-Qualities of Hearing Scale scores in all domains significantly improved 1 year after surgery (p < 0.034). The mean GBI scores in each domain ranged from 14.2 to 49.4. Total GBI score was correlated with better signal to noise ratio in noise toward the atretic ear as measured by HINT at postoperative 1 year (Spearman rho = 0.482, p = 0.013). CONCLUSIONS: Teenaged patients with unilateral congenital aural atresia showed satisfactory hearing improvement after canaloplasty with hearing restoration surgery. In a serial long-term follow-up, speech understanding in noise measured by HINT improved over time. One year after surgery, teenaged children acquired binaural hearing (binaural squelch), as measured by the HINT with noise presented to the newly opened atretic ear. Subjective questionnaires also showed improvements in binaural hearing function and quality of life. PMID- 25695925 TI - A Retrospective Multicenter Study Comparing Speech Perception Outcomes for Bilateral Implantation and Bimodal Rehabilitation. AB - OBJECTIVES: To compare speech perception outcomes between bilateral implantation (cochlear implants [CIs]) and bimodal rehabilitation (one CI on one side plus one hearing aid [HA] on the other side) and to explore the clinical factors that may cause asymmetric performances in speech intelligibility between the two ears in case of bilateral implantation. DESIGN: Retrospective data from 2247 patients implanted since 2003 in 15 international centers were collected. Intelligibility scores, measured in quiet and in noise, were converted into percentile ranks to remove differences between centers. The influence of the listening mode among three independent groups, one CI alone (n = 1572), bimodal listening (CI/HA, n = 589), and bilateral CIs (CI/CI, n = 86), was compared in an analysis taking into account the influence of other factors such as duration of profound hearing loss, age, etiology, and duration of CI experience. No within-subject comparison (i.e., monitoring outcome modifications in CI/HA subjects becoming CI/CI) was possible from this dataset. Further analyses were conducted on the CI/CI subgroup to investigate a number of factors, such as implantation side, duration of hearing loss, amount of residual hearing, and use of HAs that may explain asymmetric performances of this subgroup. RESULTS: Intelligibility ranked scores in quiet and in noise were significantly greater with both CI/CI and CI/HA than with a CI alone group, and improvement with CI/CI (+11% and +16% in quiet and in noise, respectively) was significantly better than with CI/HA (+6% and +9% in quiet and in noise, respectively). From the CI/HA group, only subjects with ranked preoperative aided speech scores >60% performed as well as CI/CI participants. Furthermore, CI/CI subjects displayed significantly lower preoperative aided speech scores on average compared with that displayed by CI/HA subjects. Routine clinical data available from the present database did not explain the asymmetrical results of bilateral implantation. CONCLUSIONS: This retrospective study, based on basic speech audiometry (no lateralization cues), indicates that, on average, a second CI is likely to provide slightly better postoperative speech outcome than an additional HA for people with very low preoperative performance. These results may be taken into consideration to refine surgical indications for CIs. PMID- 25695926 TI - Societal value of generic medicines beyond cost-saving through reduced prices. AB - OBJECTIVE: This paper aims to provide an overview of the added societal value of generic medicines beyond their cost-saving potential through reduced prices. In addition, an observational case study will document the impact of generic entry on access to pharmacotherapy in The Netherlands and an illustrative exercise was carried out to highlight the budget impact of generic entry. METHODS: A narrative literature review was carried out to explore the impact of generic medicines on access to pharmacotherapy, innovation and medication adherence. Data from the Medicines and Medical Devices Information Project database in The Netherlands were used for the case study in which the impact of generic medicine entrance on the budget and the number of users was calculated as an illustrative exercise. RESULTS: Generic medicines have an additional societal value beyond their cost saving potential through reduced prices. Generic medicines increase access to pharmacotherapy, provide a stimulus for innovation by both originator companies and generic companies and, under the right circumstances, have a positive impact on medication adherence. CONCLUSION: Generic medicines offer more to society than just their cost-saving potential through reduced prices. As such, governments must not focus only on the prices of generic medicines as this will threaten their long-term sustainability. Governments must therefore act appropriately and implement a coherent set of policies to increase the use of generic medicines. PMID- 25695927 TI - Cyclin-dependent kinase pathway aberrations in diverse malignancies: clinical and molecular characteristics. AB - Aberrations in the cyclin-dependent kinase (CDK) pathways that regulate the cell cycle restriction point contribute to genomic instability and tumor proliferation, and can be targeted by recently developed CDK inhibitors. We therefore investigated the clinical correlates of CDK4/6 and CDKN2A/B abnormalities in diverse malignancies. Patients with various cancers who underwent molecular profiling by targeted next generation sequencing (Foundation Medicine; 182 or 236 cancer-related genes) were reviewed. Of 347 patients analyzed, 79 (22.8%) had aberrant CDK 4/6 or CDKN2A/B. Only TP53 mutations occurred more frequently than those in CDK elements. Aberrations were most frequent in glioblastomas (21/26 patients; 81%) and least frequent in colorectal cancers (0/26 patients). Aberrant CDK elements were independently associated with EGFR and ARID1A gene abnormalities (P < 0.0001 and p = 0.01; multivariate analysis). CDK aberrations were associated with poor overall survival (univariate analysis; HR[95% CI] = 2.09 [1.35-4.70]; p = 0.004). In multivariate analysis, PTEN and TP53 aberrations were independently associated with poorer survival (HR = 4.83 and 1.92; P < 0.0001 and p = 0.01); CDK aberrations showed a trend toward worse survival (HR = 1.67; p = 0.09). There was also a trend toward worse progression-free survival (PFS) with platinum-containing regimens in patients with abnormal CDK elements (3.5 versus 5.0 months, p = 0.13). In conclusion, aberrations in the CDK pathway were some of the most common in cancer and independently associated with EGFR and ARID1A alterations. Patients with abnormal CDK pathway genes showed a trend toward poorer survival, as well as worse PFS on platinum-containing regimens. Further investigation of the prognostic and predictive impact of CDK alterations across cancers is warranted. PMID- 25695928 TI - WOCN Society and AUA Position Statement on Preoperative Stoma Site Marking for Patients Undergoing Urostomy Surgery. AB - Marking the optimal location for a stoma preoperatively enhances the likelihood of a patient's independence in stoma care, predictable pouching system wear times, and resumption of normal activities. Urologists and certified ostomy nurses are the optimal clinicians to select and mark stoma sites, as this skill is a part of their education, practice, and training. However, these providers are not always available, particularly in emergency situations. The purpose of this position statement, developed by the Wound, Ostomy and Continence Nurses Society in collaboration with the American Urological Association and the American Society of Colon and Rectal Surgeons, is to provide a guideline to assist clinicians (especially those who are not surgeons or WOC nurses) in selecting an effective stoma site. PMID- 25695929 TI - WOCN Society and ASCRS Position Statement on Preoperative Stoma Site Marking for Patients Undergoing Colostomy or Ileostomy Surgery. AB - Marking the optimal location for a stoma preoperatively enhances the likelihood of a patient's independence in stoma care, predictable pouching system wear times, and resumption of normal activities. Colon and rectal surgeons and certified ostomy nurses are the optimal clinicians to select and mark stoma sites, as this skill is a part of their education, practice, and training. However, these providers are not always available, particularly in emergency situations. The purpose of this position statement, developed by the Wound, Ostomy and Continence Nurses Society in collaboration with the American Society of Colon and Rectal Surgeons and the American Urological Association, is to provide a guideline to assist clinicians (especially those who are not surgeons or WOC nurses) in selecting an effective stoma site. PMID- 25695930 TI - Process evaluation of an intervention program to reduce occupational quartz exposure among Dutch construction workers. AB - OBJECTIVES: Evaluate the process of an intervention in the construction industry to reduce quartz exposure. METHODS: In a cluster randomized controlled trial, data on seven process aspects (ie, recruitment, reach, dose delivered, dose received, fidelity, satisfaction, and context) were quantitatively collected on manager and worker levels. RESULTS: Dose delivered was 95% for the plenary sessions and 20% for the worksite visit. Although the protocol was mostly implemented as intended, dose received was lower than expected. Both managers and workers appreciated the intervention and recommended the intervention for future implementation. Workers attending all intervention sessions were most satisfied about the intervention. CONCLUSIONS: High rates for dose delivered and fidelity for the plenary sessions and relatively high satisfaction rates were achieved. Furthermore, continuous monitoring of contextual factors beforehand and alongside the implementation of interventions is recommended. PMID- 25695931 TI - In vivo odourant response properties of migrating adult-born neurons in the mouse olfactory bulb. AB - Juxtaglomerular neurons (JGNs) of the mammalian olfactory bulb are generated throughout life. Their integration into the preexisting neural network, their differentiation and survival therein depend on sensory activity, but when and how these adult-born cells acquire responsiveness to sensory stimuli remains unknown. In vivo two-photon imaging of retrovirally labelled adult-born JGNs reveals that ~90% of the cells arrive at the glomerular layer after day post injection (DPI) 7. After arrival, adult-born JGNs are still migrating, but at DPI 9, 52% of them have odour-evoked Ca(2+) signals. Their odourant sensitivity closely resembles that of the parent glomerulus and surrounding JGNs, and their spontaneous and odour-evoked spiking is similar to that of their resident neighbours. Our data reveal a remarkably rapid functional integration of adult-born cells into the preexisting neural network. The mature pattern of odour-evoked responses of these cells strongly contrasts with their molecular phenotype, which is typical of immature, migrating neuroblasts. PMID- 25695932 TI - Guarana (Paullinia cupana) Improves Anorexia in Patients with Advanced Cancer. AB - PURPOSE: Anorexia is prevalent in cancer patients with advanced disease. In this pilot phase II, open label, nonrandomized trial, we evaluated the efficacy and safety of guarana (Paullinia cupana) in patients with cancer and weight loss. METHODS: We included advanced cancer patients with decreased appetite and weight loss of more than 5% from their baseline. All of the patients received 50 mg of the crude dry extract of guarana twice a day for 4 weeks. The trial was designed in two phases (Simon model). We considered a positive response in the first phase to be at least 5% weight gain or a three-point improvement in the appetite scale in at least three of the first 18 evaluable patients. RESULTS: Of the 34 eligible patients, 30 were included and 18 completed the protocol. Only one patient abandoned the protocol due to toxicity (grade II arthralgia). No grade 3 or 4 toxicities and no significant differences in nausea, weight loss, or quality of life (FACT-G) occurred. Only two of the 18 patients who completed the study had weight gain above 5% from their baseline, whereas six patients had at least a 3 point improvement in the visual appetite scale. The M.D. Anderson Symptom Inventory (MDASI) was used to evaluate several symptoms, and we observed a significant decrease in the lack of appetite (p = 0.02) and in somnolence (p = 0.0142). CONCLUSION: We concluded that the weight stabilization and increased appetite that we observed in this study justify further studies of guarana in this patient population. PMID- 25695933 TI - Impact of relative contraindications to home management in emergency department patients with low-risk pulmonary embolism. AB - RATIONALE: Studies of adults presenting to the emergency department (ED) with acute pulmonary embolism (PE) suggest that those who are low risk on the PE Severity Index (classes I and II) can be managed safely without hospitalization. However, the impact of relative contraindications to home management on outcomes has not been described. OBJECTIVES: To compare 5-day and 30-day adverse event rates among low-risk ED patients with acute PE without and with outpatient ineligibility criteria. METHODS: We conducted a retrospective multicenter cohort study of adults presenting to the ED with acute low-risk PE between 2010 and 2012. We evaluated the association between outpatient treatment eligibility criteria based on a comprehensive list of relative contraindications and 5-day adverse events and 30-day outcomes, including major hemorrhage, recurrent venous thromboembolism, and all-cause mortality. MEASUREMENTS AND MAIN RESULTS: Of 423 adults with acute low-risk PE, 271 (64.1%) had no relative contraindications to outpatient treatment (outpatient eligible), whereas 152 (35.9%) had at least one contraindication (outpatient ineligible). Relative contraindications were categorized as PE-related factors (n = 112; 26.5%), comorbid illness (n = 42; 9.9%), and psychosocial barriers (n = 19; 4.5%). There were no 5-day events in the outpatient-eligible group (95% upper confidence limit, 1.7%) and two events (1.3%; 95% confidence interval [CI], 0.1-5.0%) in the outpatient-ineligible group (P = 0.13). At 30 days, there were five events (two recurrent venous thromboemboli and three major bleeding events) in the outpatient-eligible group (1.8%; 95% CI, 0.7-4.4%) compared with nine in the ineligible group (5.9%; 95% CI, 2.7-10.9%; P < 0.05). This difference remained significant when controlling for PE severity class. CONCLUSIONS: Nearly two-thirds of adults presenting to the ED with low-risk PE were potentially eligible for outpatient therapy. Relative contraindications to outpatient management were associated with an increased frequency of adverse events at 30 days among adults with low-risk PE. PMID- 25695934 TI - Biomarkers for disease progression of primary sclerosing cholangitis. AB - PURPOSE OF REVIEW: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown origin. There is no medical treatment of proven benefit on survival; once patients have progressed to end-stage liver disease, the only treatment option is liver transplantation. RECENT FINDINGS: Over the last years, some progress has been made in identifying biomarkers of PSC disease progression. Categories that can be distinguished include clinical and biochemical biomarkers, histology, imaging, prognostic modelling and genetics. With this review, we summarize biomarkers for progression of PSC from these six categories, which have been studied to date. SUMMARY: Biomarkers for the progression of PSC disease course can be used for several purposes. First of all, they can be implemented as surrogate endpoints for clinical trials. Second, biomarkers of disease progression form the basis of prognostic modelling, which is needed for proper patient counselling and management. Lastly, these biomarkers may yield a better understanding of PSC pathogenesis. PMID- 25695935 TI - Heterobimetallic rhenium nitrido complexes containing the Klaui tripodal ligand [Co(eta(5)-C5H5){P(O)(OEt)2}3](-). AB - Rhenium nitrido complexes containing the Klaui tripodal ligand [Co(eta(5) C5H5){P(O)(OEt)2}3](-) (LOEt(-)) have been synthesised and their reactions with [Ir(I)(cod)Cl]2 (cod = 1,5-cyclooctadiene) and [Rh(II)2(OAc)4] (OAc(-) = acetate) have been studied. The treatment of [Bu(n)4N][Re(VI)(N)Cl4] with NaLOEt in methanol afforded the Re(VI) nitride [Re(VI)(LOEt)(N)Cl(OMe)] (1). Reactions of 1 with [Ir(I)(cod)Cl]2 and [Rh(II)2(OAc)4] gave the MU-nitrido complexes [(LOEt)(OMe)ClRe(VI)(MU-N)Ir(I)(cod)Cl] (2) and [Rh(II)2(OAc)4{(MU N)Re(VI)(LOEt)(OMe)Cl}2] (4), respectively. [(LOEt)Cl(PPh3)Re(V)(MU N)Ir(I)(cod)Cl] (3) and [(LOEt)Cl(PPh3)Re(VI)(MU-N)Ir(I)(cod)Cl][PF6] (3.PF6) have been synthesised from the reactions of [Ir(I)(cod)Cl]2 with [Re(V)LOEt(N)Cl(PPh3)] and [Re(VI)LOEt(N)Cl(PPh3)](PF6), respectively. Similarly, the redox pair [Rh(II)2(OAc)4{(MU-N)Re(V)(LOEt)(PPh3)Cl}2] (5) and [Rh(II)2(OAc)4{(MU-N)Re(VI)(LOEt)(PPh3)Cl}2](PF6)2 (.(PF6)2) have been synthesised from the reactions of [Rh2(OAc)4] with [Re(V)LOEt(N)Cl(PPh3)] and [Re(VI)LOEt(N)Cl(PPh3)](PF6), respectively. While [(LOEt)Cl2Ru(VI)(MU N)Ir(I)(cod)] (6) was obtained from [Ru(VI)(LOEt)(N)Cl2] and [Ir(I)(cod)Cl]2, the interaction between [Ru(VI)(LOEt)(N)Cl2] and [Rh(II)2(OAc)4] in CH2Cl2 is reversible. The crystal structures of complexes 2, 3, 3.PF6, 5, 5.(PF6)2 and 6 have been determined. X-ray crystallography indicates that the nitrido bridges in 2, 3, 3.PF6 and 6 can be described as MN-Ir (M = Re, Ru) showing Ir-N multiple bond character, whereas the interaction between Re=N and Rh in 5 and 5.(PF6)2 is mostly of the donor-acceptor type. The electrochemistry of the Re nitrido complexes has been investigated by cyclic voltammetry. PMID- 25695936 TI - Human Bone Marrow Stromal Cells Differentiate Into Corneal Tissue and Prevent Ocular Graft-Versus-Host Disease in Mice. AB - Clinical trials have assessed the use of human bone marrow stromal cells (hBMSCs) for the treatment of immune-related disorders such as graft-versus-host disease (GVHD). In the current study, we show that GFP(+)-transduced hBMSCs generated from bone marrow migrate and differentiate into corneal tissue after subconjunctival injection in mice. Interestingly, these hBMSCs display morphological features of epithelial, stromal, and endothelial cells and appear at different layers and with different morphologies depending on their position within the epithelium. Furthermore, these cells display ultrastructural properties, such as bundles of intermediate filaments, interdigitations, and desmosomes with GFP(-) cells, which confirms their differentiation into corneal tissues. GFP(+)-transduced hBMSCs were injected at different time points into the right eye of lethally irradiated mice undergoing bone marrow transplantation, which developed ocular GVHD (oGVHD). Remarkably, hBMSCs massively migrate to corneal tissues after subconjunctival injection. Both macroscopic and histopathological examination showed minimal or no evidence of GVHD in the right eye, while the left eye, where no hBMSCs were injected, displayed features of GVHD. Thus, in the current study, we confirm that hBMSCs may induce their therapeutic effect at least in part by differentiation and regeneration of damaged tissues in the host. Our results provide experimental evidence that hBMSCs represent a potential cellular therapy to attenuate oGVHD. PMID- 25695937 TI - Polycystic echinococcosis in Pacas, Amazon region, Peru. AB - In the Peruvian Amazon, paca meat is consumed by humans. To determine human risk for polycystic echinococcosis, we examined wild pacas from 2 villages; 15 (11.7%) of 128 were infected with Echinococcus vogeli tapeworms. High E. vogeli prevalence among pacas indicates potential risk for humans living in E. vogeli contaminated areas. PMID- 25695939 TI - Current developments in fluorescent PET (photoinduced electron transfer) sensors and switches. AB - Following a brief introduction to the principle of fluorescent PET (photoinduced electron transfer) sensors and switches, the outputs of laboratories in various countries from the past year or two are categorized and critically discussed. Emphasis is placed on the molecular design and the experimental outcomes in terms of target-induced fluorescence enhancements and input/output wavelengths. The handling of single targets takes up a major fraction of the review, but the extension to multiple targets is also illustrated. Conceptually new channels of investigation are opened up by the latter approach, e.g.'lab-on-a-molecule' systems and molecular keypad locks. The growing trends of theoretically-fortified design and intracellular application are pointed out. PMID- 25695940 TI - Special issue on pediatric acute-onset neuropsychiatric syndrome. PMID- 25695941 TI - Clinical presentation of pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections in research and community settings. AB - BACKGROUND: The first cases of pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) were described >15 years ago. Since that time, the literature has been divided between studies that successfully demonstrate an etiologic relationship between Group A streptococcal (GAS) infections and childhood-onset obsessive-compulsive disorder (OCD), and those that fail to find an association. One possible explanation for the conflicting reports is that the diagnostic criteria proposed for PANDAS are not specific enough to describe a unique and homogeneous cohort of patients. To evaluate the validity of the PANDAS criteria, we compared clinical characteristics of PANDAS patients identified in two community practices with a sample of children meeting full research criteria for PANDAS. METHODS: A systematic review of clinical records was used to identify the presence or absence of selected symptoms in children evaluated for PANDAS by physicians in Hinsdale, Illinois (n=52) and Bethesda, Maryland (n=40). RESULTS were compared against data from participants in National Institute of Mental Health (NIMH) research investigations of PANDAS (n=48). RESULTS: As described in the original PANDAS cohort, males outnumbered females (95:45) by ~ 2:1, and symptoms began in early childhood (7.3+/-2.7 years). Clinical presentations were remarkably similar across sites, with all children reporting acute onset of OCD symptoms and multiple comorbidities, including separation anxiety (86-92%), school issues (75 81%), sleep disruptions (71%), tics (60-65%), urinary symptoms (42-81%), and others. Twenty of the community cases (22%) failed to meet PANDAS criteria because of an absence of documentation of GAS infections. CONCLUSIONS: The diagnostic criteria for PANDAS can be used by clinicians to accurately identify patients with common clinical features and shared etiology of symptoms. Although difficulties in documenting an association between GAS infection and symptom onset/exacerbations may preclude a diagnosis of PANDAS in some children with acute-onset OCD, they do appear to meet criteria for pediatric acute-onset neuropsychiatric syndrome (PANS). PMID- 25695942 TI - Five youth with pediatric acute-onset neuropsychiatric syndrome of differing etiologies. AB - BACKGROUND: Pediatric acute-onset neuropsychiatric syndrome (PANS) is diagnosed by the abrupt onset of new obsessive compulsive disorder (OCD) or food restricting symptoms, and at least two of a variety of other neuropsychiatric symptoms. Detailed clinical presentation of youth with this condition has not yet been provided in the literature. METHODS: We review the clinical charts of five youth meeting criteria for PANS in our PANS Clinic. These five patients were selected for differing underlying causes thought to be driving an inflammatory response that appeared to impact psychiatric symptoms. RESULTS: Five youth with varying potential etiologies impacting neuropsychiatric symptoms were identified. These youth were from 8 to 18 years old at the onset of their PANS illness, and had bacterial, autoimmune, and unknown etiologies. Treatment directed at presumed etiologies ranged from antibiotics to intravenous gamma globulin (IVIG) to other immunomodulatory regimens, and appeared to improve the psychiatric illness. CONCLUSIONS: Youth with PANS may present in differing ways, with psychiatric and physical symptoms overlapping with inflammatory or infectious diseases, pain syndromes, and other psychiatric diagnoses. Patients' psychiatric symptoms may respond to treatments targeting the underlying cause of physical illness. Faced with a pediatric patient demonstrating the abrupt onset or exacerbation of psychiatric and physical symptoms, clinicians should consider PANS in their differential diagnosis. PMID- 25695943 TI - Multidisciplinary clinic dedicated to treating youth with pediatric acute-onset neuropsychiatric syndrome: presenting characteristics of the first 47 consecutive patients. AB - BACKGROUND: Abrupt, dramatic onset obsessive-compulsive disorder (OCD) and/or eating restriction with at least two coinciding symptoms (anxiety, mood dysregulation, irritability/aggression/oppositionality, behavioral regression, cognitive deterioration, sensory or motor abnormalities, or somatic symptoms) defines pediatric acute-onset neuropsychiatric syndrome (PANS). Descriptions of clinical data in such youth are limited. METHODS: We reviewed charts of 53 consecutive patients evaluated in our PANS Clinic; 47 met PANS symptom criteria but not all met the requirement for "acute onset." Patients meeting full criteria for PANS were compared with patients who had a subacute/insidious onset of symptoms. RESULTS: Nineteen of 47 (40%) patients in the study had acute onset of symptoms. In these patients, autoimmune/inflammatory diseases and psychiatric disorders were common in first-degree family members (71% and 78%, respectively). Most acute-onset patients had a relapsing/remitting course (84%), prominent sleep disturbances (84%), urinary issues (58%), sensory amplification (66%), gastrointestinal symptoms (42%), and generalized pain (68%). Inflammatory back pain (21%) and other arthritis conditions (28%) were also common. Suicidal and homicidal thoughts and gestures were common (44% and 17%, respectively) as were violent outbursts (61%). Group A streptococcus (GAS) was the most commonly identified infection at onset (21%) and during flares (74%). Rates of the above mentioned characteristics did not differ between the acute-onset group and the subacute/insidious-onset groups. Low levels of immunoglobulins were more common in the subacute/insidious-onset group (75%) compared with the acute-onset group (22%), but this was not statistically significant (p=0.06). CONCLUSIONS: In our PANS clinic, 40% of patients had acute onset of symptoms. However, those with and without acute onset of symptoms had similar symptom presentation, rates of inflammatory conditions, somatic symptoms, and violent thoughts and behaviors. GAS infections were the most commonly identified infection at onset and at symptom flares. Because of the wide variety of medical and psychiatric symptoms, youth with PANS may require a multidisciplinary team for adequate care management. PMID- 25695944 TI - Biophysical mechanisms that maintain biodiversity through trade-offs. AB - Trade-offs are thought to arise from inevitable, biophysical limitations that prevent organisms from optimizing multiple traits simultaneously. A leading explanation for biodiversity maintenance is a theory that if the shape, or geometry, of a trade-off is right, then multiple species can coexist. Testing this theory, however, is difficult as trait data is usually too noisy to discern shape, or trade-offs necessary for the theory are not observed in vivo. To address this, we infer geometry directly from the biophysical mechanisms that cause trade-offs, deriving the geometry of two by studying nutrient uptake and metabolic properties common to all living cells. To test for their presence in vivo we isolated Escherichia coli mutants that vary in a nutrient transporter, LamB, and found evidence for both trade-offs. Consistent with data, population genetics models incorporating the trade-offs successfully predict the co maintenance of three distinct genetic lineages, demonstrating that trade-off geometry can be deduced from fundamental principles of living cells and used to predict stable genetic polymorphisms. PMID- 25695945 TI - Short-Chain Fatty Acids Protect Against High-Fat Diet-Induced Obesity via a PPARgamma-Dependent Switch From Lipogenesis to Fat Oxidation. AB - Short-chain fatty acids (SCFAs) are the main products of dietary fiber fermentation and are believed to drive the fiber-related prevention of the metabolic syndrome. Here we show that dietary SCFAs induce a peroxisome proliferator-activated receptor-gamma (PPARgamma)-dependent switch from lipid synthesis to utilization. Dietary SCFA supplementation prevented and reversed high-fat diet-induced metabolic abnormalities in mice by decreasing PPARgamma expression and activity. This increased the expression of mitochondrial uncoupling protein 2 and raised the AMP-to-ATP ratio, thereby stimulating oxidative metabolism in liver and adipose tissue via AMPK. The SCFA-induced reduction in body weight and stimulation of insulin sensitivity were absent in mice with adipose-specific disruption of PPARgamma. Similarly, SCFA-induced reduction of hepatic steatosis was absent in mice lacking hepatic PPARgamma. These results demonstrate that adipose and hepatic PPARgamma are critical mediators of the beneficial effects of SCFAs on the metabolic syndrome, with clearly distinct and complementary roles. Our findings indicate that SCFAs may be used therapeutically as cheap and selective PPARgamma modulators. PMID- 25695946 TI - Effects of Acute and Antecedent Hypoglycemia on Endothelial Function and Markers of Atherothrombotic Balance in Healthy Humans. AB - The aim of this study was to determine the effects of single and repeated episodes of clamped hypoglycemia on fibrinolytic balance, proinflammatory biomarkers, proatherothrombotic mechanisms, and endothelial function. Twenty healthy individuals (12 male and 8 female) were studied during separate 2-day randomized protocols. Day 1 consisted of either two 2-h hyperinsulinemic (812 +/- 50 pmol/L)-euglycemic (5 +/- 0.1 mmol/L) or hyperinsulinemic (812 +/- 50 pmol/L) hypoglycemic (2.9 +/- 0.1 mmol/L) clamps. Day 2 consisted of a single 2-h hyperinsulinemic-hypoglycemic clamp. Two-dimensional Doppler ultrasound was used to determine brachial arterial endothelial function. Plasminogen activator inhibitor 1, vascular cell adhesion molecule-1, intracellular adhesion molecule 1, E-selectin, P-selectin, TAT (thrombin/antithrombin complex), tumor necrosis factor-alpha, and interleukin-6 responses were increased (P < 0.05) during single or repeated hypoglycemia compared with euglycemia. Endogenous and exogenous nitric oxide (NO)-mediated vasodilation were both impaired by repeated hypoglycemia. Neuroendocrine and autonomic nervous system (ANS) responses were also blunted by repeated hypoglycemia (P < 0.05). In summary, acute moderate hypoglycemia impairs fibrinolytic balance; increases proinflammatory responses, platelet activation, and coagulation biomarkers; and reduces NO-mediated endothelial function in healthy individuals. Repeated episodes of hypoglycemia further impair vascular function by additionally reducing exogenously NO-mediated endothelial function and increasing coagulation biomarkers. We conclude that despite reduced neuroendocrine and ANS responses, antecedent hypoglycemia results in greater endothelial dysfunction and an increased proatherothrombotic state compared with a single acute episode of hypoglycemia. PMID- 25695947 TI - Human Adipocytes Induce Inflammation and Atrophy in Muscle Cells During Obesity. AB - Inflammation and lipid accumulation are hallmarks of muscular pathologies resulting from metabolic diseases such as obesity and type 2 diabetes. During obesity, the hypertrophy of visceral adipose tissue (VAT) contributes to muscle dysfunction, particularly through the dysregulated production of adipokines. We have investigated the cross talk between human adipocytes and skeletal muscle cells to identify mechanisms linking adiposity and muscular dysfunctions. First, we demonstrated that the secretome of obese adipocytes decreased the expression of contractile proteins in myotubes, consequently inducing atrophy. Using a three dimensional coculture of human myotubes and VAT adipocytes, we showed the decreased expression of genes corresponding to skeletal muscle contractility complex and myogenesis. We demonstrated an increased secretion by cocultured cells of cytokines and chemokines with interleukin (IL)-6 and IL-1beta as key contributors. Moreover, we gathered evidence showing that obese subcutaneous adipocytes were less potent than VAT adipocytes in inducing these myotube dysfunctions. Interestingly, the atrophy induced by visceral adipocytes was corrected by IGF-II/insulin growth factor binding protein-5. Finally, we observed that the skeletal muscle of obese mice displayed decreased expression of muscular markers in correlation with VAT hypertrophy and abnormal distribution of the muscle fiber size. In summary, we show the negative impact of obese adipocytes on muscle phenotype, which could contribute to muscle wasting associated with metabolic disorders. PMID- 25695948 TI - Therapeutic Potential of Anti-Angiogenic Multitarget N,O-Sulfated E. Coli K5 Polysaccharide in Diabetic Retinopathy. AB - Vascular endothelial growth factor (VEGF) blockers have been developed for the treatment of proliferative diabetic retinopathy (PDR), the leading cause of visual impairments in the working-age population in the Western world. However, limitations to anti-VEGF therapies may exist because of the local production of other proangiogenic factors that may cause resistance to anti-VEGF interventions. Thus, novel therapeutic approaches targeting additional pathways are required. Here, we identified a sulfated derivative of the Escherichia coli polysaccharide K5 [K5-N,OS(H)] as a multitarget molecule highly effective in inhibiting VEGF driven angiogenic responses in different in vitro, ex vivo, and in vivo assays, including a murine model of oxygen-induced retinopathy. Furthermore, K5-N,OS(H) binds a variety of heparin-binding angiogenic factors upregulated in PDR vitreous humor besides VEGF, thus inhibiting their biological activity. Finally, K5 N,OS(H) hampers the angiogenic activity exerted in vitro and in vivo by human vitreous fluid samples collected from patients with PDR. Together, the data provide compelling experimental evidence that K5-N,OS(H) represents an antiangiogenic multitarget molecule with potential implications for the therapy of pathologic neovessel formation in the retina of patients with PDR. PMID- 25695950 TI - Correction to well-defined star-shaped conjugated macroelectrolytes as efficient electron-collecting interlayer for inverted polymer solar cells. PMID- 25695951 TI - Dramatic enhancement of genome editing by CRISPR/Cas9 through improved guide RNA design. AB - Success with genome editing by the RNA-programmed nuclease Cas9 has been limited by the inability to predict effective guide RNAs and DNA target sites. Not all guide RNAs have been successful, and even those that were, varied widely in their efficacy. Here we describe and validate a strategy for Caenorhabditis elegans that reliably achieved a high frequency of genome editing for all targets tested in vivo. The key innovation was to design guide RNAs with a GG motif at the 3' end of their target-specific sequences. All guides designed using this simple principle induced a high frequency of targeted mutagenesis via nonhomologous end joining (NHEJ) and a high frequency of precise DNA integration from exogenous DNA templates via homology-directed repair (HDR). Related guide RNAs having the GG motif shifted by only three nucleotides showed severely reduced or no genome editing. We also combined the 3' GG guide improvement with a co-CRISPR/co conversion approach. For this co-conversion scheme, animals were only screened for genome editing at designated targets if they exhibited a dominant phenotype caused by Cas9-dependent editing of an unrelated target. Combining the two strategies further enhanced the ease of mutant recovery, thereby providing a powerful means to obtain desired genetic changes in an otherwise unaltered genome. PMID- 25695952 TI - Characterizing and controlling intrinsic biases of lambda exonuclease in nascent strand sequencing reveals phasing between nucleosomes and G-quadruplex motifs around a subset of human replication origins. AB - Nascent strand sequencing (NS-seq) is used to discover DNA replication origins genome-wide, allowing identification of features for their specification. NS-seq depends on the ability of lambda exonuclease (lambda-exo) to efficiently digest parental DNA while leaving RNA-primer protected nascent strands intact. We used genomics and biochemical approaches to determine if lambda-exo digests all parental DNA sequences equally. We report that lambda-exo does not efficiently digest G-quadruplex (G4) structures in a plasmid. Moreover, lambda-exo digestion of nonreplicating genomic DNA (LexoG0) enriches GC-rich DNA and G4 motifs genome wide. We used LexoG0 data to control for nascent strand-independent lambda-exo biases in NS-seq and validated this approach at the rDNA locus. The lambda-exo controlled NS-seq peaks are not GC-rich, and only 35.5% overlap with 6.8% of all G4s, suggesting that G4s are not general determinants for origin specification but may play a role for a subset. Interestingly, we observed a periodic spacing of G4 motifs and nucleosomes around the peak summits, suggesting that G4s may position nucleosomes at this subset of origins. Finally, we demonstrate that use of Na(+) instead of K(+) in the lambda-exo digestion buffer reduced the effect of G4s on lambda-exo digestion and discuss ways to increase both the sensitivity and specificity of NS-seq. PMID- 25695953 TI - A novel neutralizing antibody targeting pregnancy-associated plasma protein-a inhibits ovarian cancer growth and ascites accumulation in patient mouse tumorgrafts. AB - The majority of ovarian cancer patients acquire resistance to standard platinum chemotherapy and novel therapies to reduce tumor burden and ascites accumulation are needed. Pregnancy-associated plasma protein-A (PAPP-A) plays a key role in promoting insulin-like growth factor (IGF) pathway activity, which directly correlates to ovarian cancer cell transformation, growth, and invasiveness. Herein, we evaluate PAPP-A expression in tumors and ascites of women with ovarian cancer, and determine the antitumor efficacy of a neutralizing monoclonal PAPP-A antibody (mAb-PA) in ovarian cancer using primary patient ovarian tumorgrafts ("Ovatars"). PAPP-A mRNA expression in patient ovarian tumors correlated with poor outcome and was validated as a prognostic surrogate in Ovatar tumors. Following confirmation of mAb-PA bioavailability and target efficacy in vivo, the antitumor efficacy of mAb-PA in multiple Ovatar tumor models was examined and the response was found to depend on PAPP-A expression. Strikingly, the addition of mAb-PA to standard platinum chemotherapy effectively sensitized platinum resistant Ovatar tumors. PAPP-A protein in ascites was also assessed in a large cohort of patients and very high levels were evident across the entire sample set. Therefore, we evaluated targeted PAPP-A inhibition as a novel approach to managing ovarian ascites, and found that mAb-PA inhibited the development, attenuated the progression, and induced the regression of Ovatar ascites. Together, these data indicate PAPP-A as a potential palliative and adjunct therapeutic target for women with ovarian cancer. PMID- 25695954 TI - Radiosensitization of Primary Human Glioblastoma Stem-like Cells with Low-Dose AKT Inhibition. AB - Glioblastoma (GBM) is the most frequent and lethal brain cancer. The lack of early detection methods, the presence of rapidly growing tumor cells, and the high levels of recurrence due to chemo- and radioresistance make this cancer an extremely difficult disease to treat. Emerging studies have focused on inhibiting AKT activation; here, we demonstrate that in primary GBM tumor samples, full-dose inhibition of AKT activity leads to differential responses among samples in the context of cell death and self-renewal, reinforcing the notion that GBM is a heterogeneous disease. In contrast, low-dose AKT inhibition when combined with fractionation of radiation doses leads to a significant apoptosis-mediated cell death of primary patient-derived GBM cells. Therefore, low-dose-targeted therapies might be better for radiosensitization of primary GBM cells and further allow for reducing the clinical toxicities often associated with targeting the AKT/PI3K/mTOR pathway. This work emphasizes the discrepancies between cell lines and primary tumors in drug testing, and indicates that there are salient differences between patients, highlighting the need for personalized medicine in treating high-grade glioma. PMID- 25695955 TI - PD-L1 Expression as a Predictive Biomarker in Cancer Immunotherapy. AB - The resurgence of cancer immunotherapy stems from an improved understanding of the tumor microenvironment. The PD-1/PD-L1 axis is of particular interest, in light of promising data demonstrating a restoration of host immunity against tumors, with the prospect of durable remissions. Indeed, remarkable clinical responses have been seen in several different malignancies including, but not limited to, melanoma, lung, kidney, and bladder cancers. Even so, determining which patients derive benefit from PD-1/PD-L1-directed immunotherapy remains an important clinical question, particularly in light of the autoimmune toxicity of these agents. The use of PD-L1 (B7-H1) immunohistochemistry (IHC) as a predictive biomarker is confounded by multiple unresolved issues: variable detection antibodies, differing IHC cutoffs, tissue preparation, processing variability, primary versus metastatic biopsies, oncogenic versus induced PD-L1 expression, and staining of tumor versus immune cells. Emerging data suggest that patients whose tumors overexpress PD-L1 by IHC have improved clinical outcomes with anti PD-1-directed therapy, but the presence of robust responses in some patients with low levels of expression of these markers complicates the issue of PD-L1 as an exclusionary predictive biomarker. An improved understanding of the host immune system and tumor microenvironment will better elucidate which patients derive benefit from these promising agents. PMID- 25695956 TI - Biomarker signatures correlate with clinical outcome in refractory metastatic colorectal cancer patients receiving bevacizumab and everolimus. AB - A novel combination of bevacizumab and everolimus was evaluated in refractory colorectal cancer patients in a phase II trial. In this retrospective analysis, plasma samples from 49 patients were tested for over 40 biomarkers at baseline and after one or two cycles of drug administration. Analyte levels at baseline and change on-treatment were correlated with progression-free survival (PFS) and overall survival (OS) using univariate Cox proportional hazard modeling. Multivariable analyses were conducted using Cox modeling. Significant changes in multiple markers were observed following bevacizumab and everolimus treatment. Baseline levels of six markers significantly correlated with PFS and OS, including CRP, Gro-alpha, IGFBP-1, TF, ICAM-1, and TSP-2 (P < 0.05). At C2D1, changes of IGFBP-3, TGFbeta-R3, and IGFBP-2 correlated with PFS and OS. Prognostic models were developed for OS and PFS (P = 0.0002 and 0.004, respectively). The baseline model for OS consisted of CRP, Gro-alpha, and TF, while the on-treatment model at C2D1 included IGFBP-2, IGFBP-3, and TGFbeta-R3. These data demonstrated that multiple biomarkers were significantly modulated in response to bevacizumab and everolimus. Several markers correlated with both PFS and OS. Interestingly, these markers are known to be associated with inflammation and IGF signaling, key modulators of mTOR biology. PMID- 25695957 TI - RNA Interference Using c-Myc-Conjugated Nanoparticles Suppresses Breast and Colorectal Cancer Models. AB - In this article, we report the development and preclinical validation of combinatorial therapy for treatment of cancers using RNA interference (RNAi). RNAi technology is an attractive approach to silence genes responsible for disease onset and progression. Currently, the critical challenge facing the clinical success of RNAi technology is in the difficulty of delivery of RNAi inducers, due to low transfection efficiency, difficulties of integration into host DNA and unstable expression. Using the macromolecule polyglycidal methacrylate (PGMA) as a platform to graft multiple polyethyleneimine (PEI) chains, we demonstrate effective delivery of small oligos (anti-miRs and mimics) and larger DNAs (encoding shRNAs) in a wide variety of cancer cell lines by successful silencing/activation of their respective target genes. Furthermore, the effectiveness of this therapy was validated for in vivo tumor suppression using two transgenic mouse models; first, tumor growth arrest and increased animal survival was seen in mice bearing Brca2/p53-mutant mammary tumors following daily intratumoral treatment with nanoparticles conjugated to c-Myc shRNA. Second, oral delivery of the conjugate to an Apc-deficient crypt progenitor colon cancer model increased animal survival and returned intestinal tissue to a non-wnt-deregulated state. This study demonstrates, through careful design of nonviral nanoparticles and appropriate selection of therapeutic gene targets, that RNAi technology can be made an affordable and amenable therapy for cancer. PMID- 25695958 TI - Preclinical pharmacological evaluation of letrozole as a novel treatment for gliomas. AB - We present data that letrozole, an extensively used aromatase inhibitor in the treatment of estrogen receptor-positive breast tumors in postmenopausal women, may be potentially used in the treatment of glioblastomas. First, we measured the in vitro cytotoxicity of letrozole and aromatase (CYP19A1) expression and activity in human LN229, T98G, U373MG, U251MG, and U87MG, and rat C6 glioma cell lines. Estrogen receptor (ER)-positive MCF-7 and ER-negative MDA-MB-231 cells served as controls. Cytotoxicity was determined employing the MTT assay, and aromatase activity using an immunoassay that measures the conversion of testosterone to estrogen. Second, in vivo activity of letrozole was assessed in Sprague-Dawley rats orthotopically implanted with C6 gliomas. The changes in tumor volume with letrozole treatment (4 mg/kg/day) were assessed employing MUPET/CT imaging, employing [(18)F]-fluorodeoxyglucose (F18-FDG) as the radiotracer. Brain tissues were collected for histologic evaluations. All glioma cell lines included here expressed CYP19A1 and letrozole exerted considerable cytotoxicity and decrease in aromatase activity against these cells (IC50, 0.1 3.5 MUmol/L). Imaging analysis employing F18-FDG MUPET/CT demonstrated a marked reduction of active tumor volume (>75%) after 8 days of letrozole treatment. Immunohistochemical analysis revealed marked reduction in aromatase expression in tumoral regions of the brain after letrozole treatment. Thus, employing multifaceted tools, we demonstrate that aromatase may be a novel target for the treatment of gliomas and that letrozole, an FDA-approved drug with an outstanding record of safety may be repurposed for the treatment of such primary brain tumors, which currently have few therapeutic options. PMID- 25695960 TI - Structure-guided statistical textural distinctiveness for salient region detection in natural images. AB - We propose a simple yet effective structure-guided statistical textural distinctiveness approach to salient region detection. Our method uses a multilayer approach to analyze the structural and textural characteristics of natural images as important features for salient region detection from a scale point of view. To represent the structural characteristics, we abstract the image using structured image elements and extract rotational-invariant neighborhood based textural representations to characterize each element by an individual texture pattern. We then learn a set of representative texture atoms for sparse texture modeling and construct a statistical textural distinctiveness matrix to determine the distinctiveness between all representative texture atom pairs in each layer. Finally, we determine saliency maps for each layer based on the occurrence probability of the texture atoms and their respective statistical textural distinctiveness and fuse them to compute a final saliency map. Experimental results using four public data sets and a variety of performance evaluation metrics show that our approach provides promising results when compared with existing salient region detection approaches. PMID- 25695959 TI - Contribution of hepatic organic anion-transporting polypeptides to docetaxel uptake and clearance. AB - The antimicrotubular agent docetaxel is a widely used chemotherapeutic drug for the treatment of multiple solid tumors and is predominantly dependent on hepatic disposition. In this study, we evaluated drug uptake transporters capable of transporting radiolabeled docetaxel. By screening an array of drug uptake transporters in HeLa cells using a recombinant vaccinia-based method, five organic anion-transporting polypeptides (OATP) capable of docetaxel uptake were identified: OATP1A2, OATP1B1, OATP1B3, OATP1C1, and Oatp1b2. Kinetic analysis of docetaxel transport revealed similar kinetic parameters among hepatic OATP1B/1b transporters. An assessment of polymorphisms (SNPs) in SLCO1B1 and SLCO1B3 revealed that a number of OATP1B1 and OATP1B3 variants were associated with impaired docetaxel transport. A Transwell-based vectorial transport assay using MDCKII stable cells showed that docetaxel was transported significantly into the apical compartment of double-transfected (MDCKII-OATP1B1/MDR1 and MDCKII OATP1B3/MDR1) cells compared with single-transfected (MDCKII-OATP1B1 and MDCKII OATP1B3) cells (P < 0.05) or control (MDCKII-Co) cells (P < 0.001). In vivo docetaxel transport studies in Slco1b2(-/-) mice showed approximately >5.5-fold higher plasma concentrations (P < 0.01) and approximately 3-fold decreased liver to-plasma ratio (P < 0.05) of docetaxel compared with wild-type (WT) mice. The plasma clearance of docetaxel in Slco1b2(-/-) mice was 83% lower than WT mice (P < 0.05). In conclusion, this study demonstrates the important roles of OATP1B transporters to the hepatic disposition and clearance of docetaxel, and supporting roles of these transporters for docetaxel pharmacokinetics. PMID- 25695961 TI - Reproductive toxicity of a mixture of regulated drinking-water disinfection by products in a multigenerational rat bioassay. AB - BACKGROUND: Trihalomethanes (THMs) and haloacetic acids (HAAs) are regulated disinfection by-products (DBPs); their joint reproductive toxicity in drinking water is unknown. OBJECTIVE: We aimed to evaluate a drinking water mixture of the four regulated THMs and five regulated HAAs in a multigenerational reproductive toxicity bioassay. METHODS: Sprague-Dawley rats were exposed (parental, F1, and F2 generations) from gestation day 0 of the parental generation to postnatal day (PND) 6 of the F2 generation to a realistically proportioned mixture of THMs and HAAs at 0, 500*, 1,000*, or 2,000* of the U.S. Environmental Protection Agency's maximum contaminant levels (MCLs). RESULTS: Maternal water consumption was reduced at >= 1,000*; body weights were reduced at 2,000*. Prenatal and postnatal survival were unaffected. F1 pup weights were unaffected at birth but reduced at 2,000* on PND6 and at >= 1,000* on PND21. Postweaning F1 body weights were reduced at 2,000*, and water consumption was reduced at >= 500*. Males at 2,000* had a small but significantly increased incidence of retained nipples and compromised sperm motility. Onset of puberty was delayed at 1,000* and 2,000*. F1 estrous cycles and fertility were unaffected, and F2 litters showed no effects on pup weight or survival. Histologically, P0 (parental) dams had nephropathy and adrenal cortical pathology at 2,000*. CONCLUSIONS: A mixture of regulated DBPs at up to 2,000* the MCLs had no adverse effects on fertility, pregnancy maintenance, prenatal survival, postnatal survival, or birth weights. Delayed puberty at >= 1,000* may have been secondary to reduced water consumption. Male nipple retention and compromised sperm motility at 2,000* may have been secondary to reduced body weights. PMID- 25695962 TI - Two cases of congenital myasthenic syndrome with vocal cord paralysis. PMID- 25695964 TI - Leukoaraiosis and stroke recurrence risk in patients with and without atrial fibrillation. AB - OBJECTIVE: We aimed to investigate the association between leukoaraiosis and long term risk of stroke recurrence adjusting for clinical scores developed and validated for the prediction of stroke risk, such as CHADS2 (congestive heart failure, hypertension, age >=75 years, diabetes mellitus, and stroke or TIA) and CHA2DS2-VASc (congestive heart failure, hypertension, age >=75 years, diabetes mellitus, stroke or TIA, vascular disease, age 65-74 years, sex category). METHODS: Study population was derived from the Athens Stroke Registry and was categorized in 2 subgroups according to the presence of atrial fibrillation (AF). Cox proportional hazards analysis was performed to assess the independent predictors of stroke recurrence. To investigate whether leukoaraiosis adds to the prognostic accuracy of CHADS2 and CHA2DS2-VASc scores, we used the likelihood ratio test. Overall model assessment was performed with Nagelkerke R(2) and Harrell C statistic. Kaplan-Meier analyses were also performed. RESULTS: Among 1,892 patients, there were 320 (16.9%) with leukoaraiosis and 670 (35.4%) with AF. In the Kaplan-Meier analysis, there was significant difference in cumulative probability of stroke recurrence between patients with and without leukoaraiosis in the non-AF group (p < 0.01), but not in the AF group (p = 0.46). On Cox multivariate analysis, leukoaraiosis was found to be a significant independent predictor of stroke recurrence only in the non-AF group, in the models adjusting for CHADS2 (hazard ratio: 1.86, 95% confidence interval: 1.35-2.56) and CHA2DS2 VASc (hazard ratio: 1.82, 95% confidence interval: 1.32-2.51) scores. Leukoaraiosis was not a predictor of stroke recurrence in the AF group. Leukoaraiosis did not improve the predictive accuracy of the 2 scores, whether in the non-AF group (Harrell C statistic: 0.56 vs 0.59 [p = 0.31] for the model including CHADS2; 0.56 vs 0.59 [p = 0.44] for the model including CHA2DS2-VASc) or the AF group (Harrell C statistic: 0.63 vs 0.62 for the model including CHADS2; 0.64 vs 0.64 for the model including CHA2DS2-VASc). CONCLUSIONS: Leukoaraiosis is an independent predictor of stroke recurrence in non-AF stroke patients. However, leukoaraiosis did not increase the accuracy of the CHADS2 and CHA2DS2-VASc scores to predict stroke recurrence in AF or non-AF stroke patients. PMID- 25695963 TI - MRI characteristics of neuromyelitis optica spectrum disorder: an international update. AB - Since its initial reports in the 19th century, neuromyelitis optica (NMO) had been thought to involve only the optic nerves and spinal cord. However, the discovery of highly specific anti-aquaporin-4 antibody diagnostic biomarker for NMO enabled recognition of more diverse clinical spectrum of manifestations. Brain MRI abnormalities in patients seropositive for anti-aquaporin-4 antibody are common and some may be relatively unique by virtue of localization and configuration. Some seropositive patients present with brain involvement during their first attack and/or continue to relapse in the same location without optic nerve and spinal cord involvement. Thus, characteristics of brain abnormalities in such patients have become of increased interest. In this regard, MRI has an increasingly important role in the differential diagnosis of NMO and its spectrum disorder (NMOSD), particularly from multiple sclerosis. Differentiating these conditions is of prime importance because early initiation of effective immunosuppressive therapy is the key to preventing attack-related disability in NMOSD, whereas some disease-modifying drugs for multiple sclerosis may exacerbate the disease. Therefore, identifying the MRI features suggestive of NMOSD has diagnostic and prognostic implications. We herein review the brain, optic nerve, and spinal cord MRI findings of NMOSD. PMID- 25695965 TI - Prevalence and distribution of VZV in temporal arteries of patients with giant cell arteritis. AB - OBJECTIVE: Varicella-zoster virus (VZV) infection may trigger the inflammatory cascade that characterizes giant cell arteritis (GCA). METHODS: Formalin-fixed, paraffin-embedded GCA-positive temporal artery (TA) biopsies (50 sections/TA) including adjacent skeletal muscle and normal TAs obtained postmortem from subjects >50 years of age were examined by immunohistochemistry for presence and distribution of VZV antigen and by ultrastructural examination for virions. Adjacent regions were examined by hematoxylin & eosin staining. VZV antigen positive slides were analyzed by PCR for VZV DNA. RESULTS: VZV antigen was found in 61/82 (74%) GCA-positive TAs compared with 1/13 (8%) normal TAs (p < 0.0001, relative risk 9.67, 95% confidence interval 1.46, 63.69). Most GCA-positive TAs contained viral antigen in skip areas. VZV antigen was present mostly in adventitia, followed by media and intima. VZV antigen was found in 12/32 (38%) skeletal muscles adjacent to VZV antigen-positive TAs. Despite formalin fixation, VZV DNA was detected in 18/45 (40%) GCA-positive VZV antigen-positive TAs, in 6/10 (60%) VZV antigen-positive skeletal muscles, and in one VZV antigen-positive normal TA. Varicella-zoster virions were found in a GCA-positive TA. In sections adjacent to those containing VZV, GCA pathology was seen in 89% of GCA-positive TAs but in none of 18 adjacent sections from normal TAs. CONCLUSIONS: Most GCA positive TAs contained VZV in skip areas that correlated with adjacent GCA pathology, supporting the hypothesis that VZV triggers GCA immunopathology. Antiviral treatment may confer additional benefit to patients with GCA treated with corticosteroids, although the optimal antiviral regimen remains to be determined. PMID- 25695966 TI - Mechanistic links between cellular trade-offs, gene expression, and growth. AB - Intracellular processes rarely work in isolation but continually interact with the rest of the cell. In microbes, for example, we now know that gene expression across the whole genome typically changes with growth rate. The mechanisms driving such global regulation, however, are not well understood. Here we consider three trade-offs that, because of limitations in levels of cellular energy, free ribosomes, and proteins, are faced by all living cells and we construct a mechanistic model that comprises these trade-offs. Our model couples gene expression with growth rate and growth rate with a growing population of cells. We show that the model recovers Monod's law for the growth of microbes and two other empirical relationships connecting growth rate to the mass fraction of ribosomes. Further, we can explain growth-related effects in dosage compensation by paralogs and predict host-circuit interactions in synthetic biology. Simulating competitions between strains, we find that the regulation of metabolic pathways may have evolved not to match expression of enzymes to levels of extracellular substrates in changing environments but rather to balance a trade off between exploiting one type of nutrient over another. Although coarse grained, the trade-offs that the model embodies are fundamental, and, as such, our modeling framework has potentially wide application, including in both biotechnology and medicine. PMID- 25695967 TI - Structure of a left-handed DNA G-quadruplex. AB - Aside from the well-known double helix, DNA can also adopt an alternative four stranded structure known as G-quadruplex. Implications of such a structure in cellular processes, as well as its therapeutic and diagnostic applications, have been reported. The G-quadruplex structure is highly polymorphic, but so far, only right-handed helical forms have been observed. Here we present the NMR solution and X-ray crystal structures of a left-handed DNA G-quadruplex. The structure displays unprecedented features that can be exploited as unique recognition elements. PMID- 25695968 TI - Galphai/o-coupled receptor signaling restricts pancreatic beta-cell expansion. AB - Gi-GPCRs, G protein-coupled receptors that signal via Galpha proteins of the i/o class (Galphai/o), acutely regulate cellular behaviors widely in mammalian tissues, but their impact on the development and growth of these tissues is less clear. For example, Gi-GPCRs acutely regulate insulin release from pancreatic beta cells, and variants in genes encoding several Gi-GPCRs--including the alpha 2a adrenergic receptor, ADRA2A--increase the risk of type 2 diabetes mellitus. However, type 2 diabetes also is associated with reduced total beta-cell mass, and the role of Gi-GPCRs in establishing beta-cell mass is unknown. Therefore, we asked whether Gi-GPCR signaling regulates beta-cell mass. Here we show that Gi GPCRs limit the proliferation of the insulin-producing pancreatic beta cells and especially their expansion during the critical perinatal period. Increased Gi GPCR activity in perinatal beta cells decreased beta-cell proliferation, reduced adult beta-cell mass, and impaired glucose homeostasis. In contrast, Gi-GPCR inhibition enhanced perinatal beta-cell proliferation, increased adult beta-cell mass, and improved glucose homeostasis. Transcriptome analysis detected the expression of multiple Gi-GPCRs in developing and adult beta cells, and gene deletion experiments identified ADRA2A as a key Gi-GPCR regulator of beta-cell replication. These studies link Gi-GPCR signaling to beta-cell mass and diabetes risk and identify it as a potential target for therapies to protect and increase beta-cell mass in patients with diabetes. PMID- 25695969 TI - Reply to Tskhovrebova et al.: Titin's IA junction does not control thick filament length. PMID- 25695970 TI - Titin ruler hypothesis not refuted. PMID- 25695971 TI - Reply to Kuhne et al.: Still good evidence that people search for meaning when they approach a new decade in chronological age. PMID- 25695972 TI - Big changes before big birthdays? Panel data provide no evidence of end-of-decade crises. PMID- 25695973 TI - Reply to Warneken: Social experience can illuminate early-emerging behaviors. PMID- 25695974 TI - Are social norms and reciprocity necessary for early helping? PMID- 25695975 TI - The impact of trauma-center care on mortality and function following pelvic ring and acetabular injuries. AB - BACKGROUND: Lower mortality and improved physical function following major polytrauma have been associated with treatment at level-I trauma centers compared with that at hospitals without a trauma center (nontrauma centers). This study investigated the impact of trauma-center care on outcomes after pelvic and acetabular injuries. METHODS: Mortality and quality-of-life-related scores were compared among patients treated in eighteen level-I trauma centers and fifty-one nontrauma centers in fourteen U.S. states. Complete data were obtained on 829 adult trauma patients (eighteen to eighty-four years old) who had at least one pelvic ring or acetabular injury (Orthopaedic Trauma Association [OTA] classification of 61 or 62). We used inverse probability of treatment weighting to adjust for observable confounding. RESULTS: After adjusting for case mix, we found that, for patients with more severe acetabular injuries (OTA 62-B or 62-C), in-hospital mortality was significantly lower at trauma centers compared with nontrauma centers (relative risk [RR], 0.10; 95% confidence interval [CI], 0.02 to 0.47), as was death within ninety days (RR, 0.10; 95% CI, 0.02 to 0.47) and within one year (RR, 0.21; 95% CI, 0.06 to 0.76). Patients with combined pelvic ring and acetabular injuries treated at a trauma center had lower mortality at ninety days (RR, 0.34; 95% CI, 0.14 to 0.82) and at one year (RR, 0.30; 95% CI, 0.14 to 0.68). Care at trauma centers was also associated with mortality risk reduction for those with unstable pelvic ring injuries (OTA 61-B or 61-C) at one year (RR, 0.71; 95% CI, 0.24 to 0.91). Seventy-eight percent of included subjects discharged alive were available for interview at twelve months. For those with more severe acetabular injuries, average absolute differences in the Short Form 36 (SF-36) physical function component and the Musculoskeletal Function Assessment at one year were 11.4 (95% CI, 5.3 to 17.4) and 13.2 (1.7 to 24.7), respectively, indicating statistically and clinically significant improved outcomes following treatment at a trauma center for those patients. CONCLUSIONS: Mortality was reduced for patients with unstable pelvic and severe acetabular injuries when care was provided in a trauma center compared with a nontrauma center. Moreover, those with severe acetabular fractures experienced improved physical function at one year. Patients with these injuries represent a well defined subset of trauma patients for whom our findings suggest preferential triage or transfer to a level-I trauma center. PMID- 25695976 TI - Effect of tear location on propagation of isolated supraspinatus tendon tears during increasing levels of cyclic loading. AB - BACKGROUND: The morphology of the supraspinatus tendon may affect tear propagation. It was hypothesized that tears located in the anterior third of the supraspinatus tendon would propagate more readily and would require lower loads to reach critical amounts of tear propagation than those located in the middle third of the supraspinatus tendon. METHODS: Twenty-three fresh-frozen human cadaveric shoulders were tested under increasing levels of cyclic loading. Tears were created in the anterior third (Group A, n=10) or the middle third (Group M, n=13) of the supraspinatus tendon. The maximum load at which a critical tear retraction was reached and the tear area for the final loading set were compared between groups. A correlation analysis was also performed for age compared with maximum load. RESULTS: No significant differences were found between the anterior third tear group (Group A) and the middle-third tear group (Group M) in maximum load (p=0.09) or tear area (p=0.6). However, Group A first reached a 100% increase in tear size at a significantly lower load than Group M (p=0.03). Strong negative correlations were detected between age and maximum load in Group A (tau= 0.82) and Group M (r=-0.63). CONCLUSIONS: Other factors being equal, tears in the anterior supraspinatus tendon may propagate more readily than tears in the tendon's middle part. Age may be a factor for tear propagation. CLINICAL RELEVANCE: Older patients and patients with tears in the anterior supraspinatus should be followed especially carefully. PMID- 25695977 TI - Extensor mechanism allograft reconstruction for extensor mechanism failure following total knee arthroplasty. AB - BACKGROUND: Extensor mechanism disruption following total knee arthroplasty is a rare but devastating complication. The purpose of this study was to report our experience with extensor mechanism allograft reconstruction for chronic extensor mechanism failure. METHODS: Fifty consecutive extensor mechanism allograft reconstructions were performed in forty-seven patients with a mean age of 67.6 years who were followed for a mean time of 57.6 months (range, twenty-four to 125 months). The operative technique included the use of a fresh-frozen, correctly sized full extensor mechanism allograft that was tensioned tightly in full extension. Patients were evaluated clinically with use of the Knee Society score, and reconstructions were considered failures if the patient had a score of <60 points or a recurrent extensor lag of >30 degrees or if they required revision or removal of the allograft. RESULTS: Nineteen reconstructions (38%) were considered failures, including four revised to a second extensor mechanism allograft due to failure of the allograft, five for deep infection, and ten considered clinical failures secondary to a Knee Society score of <60 points or an extensor lag of >30 degrees . The mean Knee Society score improved from 33.9 to 75.9 points (p<0.0001). The estimated Kaplan-Meier survivorship with failure for any reason as the end point was 56.2% (95% confidence interval, 39.4% to 70.1%) at ten years. CONCLUSIONS: Extensor mechanism disruption following total knee arthroplasty is a difficult complication to treat, with modest outcomes. Extensor mechanism allograft reconstruction is a reasonable option; however, patients must be informed regarding the substantial risk of complications, and although initial extensor mechanism function may be restored, expectations regarding longer-term outcomes are more guarded. PMID- 25695978 TI - Uncemented jumbo cups for revision total hip arthroplasty: a concise follow-up, at a mean of twenty years, of a previous report. AB - Uncemented jumbo cups are commonly used for acetabular revision because they are technically straightforward to implant and provide good intermediate-term results. Understanding long-term survival is particularly important because this method is common and because jumbo cups do not provide notable bone stock restoration. The purpose of the present study was to determine the twenty-year results of jumbo cup use during revision total hip arthroplasty. In the original publication, we reported on eighty-nine patients who underwent revision with an uncemented jumbo cup with a single design (Harris-Galante) prior to 1993. The Harris Hip Score (HHS), radiographic results, and Kaplan-Meier survivorship curves were evaluated. Mean follow-up was twenty years. The mean postoperative HHS was 71 compared with 56 preoperatively (p=0.001). A total of five jumbo cups were revised for aseptic loosening; one, for infection; and one, for recurrent dislocation. Eight liners were revised with retention of the metal acetabular component: six during femoral component revision, one for wear, and one for recurrent dislocations. Twenty-year survivorship was 88% free from aseptic loosening of the metal acetabular component, 85% free from aseptic loosening or radiographic evidence of definite loosening of the metal acetabular component, and 83% free from revision of the metal acetabular component for any reason. The twenty-year results of revision with uncemented jumbo acetabular components demonstrated acceptable clinical outcomes and radiographic stability. These results justify the use of jumbo cups as a common method of acetabular revision. PMID- 25695979 TI - Total hip arthroplasty after operatively treated acetabular fracture: a concise follow-up, at a mean of twenty years, of a previous report. AB - Acetabular fractures increase the risk of posttraumatic arthritis and thus the risk of total hip arthroplasty (THA). We previously presented the ten-year results of THA performed for posttraumatic arthritis after an acetabular fracture; we now present the twenty-year outcomes. The original publication included sixty-six patients who underwent THA between 1970 and 1993 for posttraumatic arthritis after open reduction and internal fixation (ORIF) of an acetabular fracture. Clinical outcomes, implant survivorship, radiographic results, and complications were evaluated. A total of thirty-six patients had died. The mean Harris hip score was 80 at the latest follow-up. Nineteen acetabular and/or femoral components had been revised: eleven for aseptic loosening, seven for osteolysis, and one for instability. Twenty-year survivorship of the acetabular component was 71% free from revision for aseptic loosening and 57% free from revision for any reason. THA after ORIF of an acetabular fracture was associated with fair implant survivorship at twenty years after surgery. It is possible that newer implants with improved fixation surfaces and bearing materials may enhance long-term results, as the most common reasons for failure at twenty years were aseptic loosening and osteolysis. PMID- 25695980 TI - Ilfeld abduction orthosis is an effective second-line treatment after failure of Pavlik harness for infants with developmental dysplasia of the hip. AB - BACKGROUND: Closed reduction and spica casting is the most commonly recommended choice for infants with developmental dysplasia of the hip (DDH) for whom Pavlik harness treatment has failed, but it requires general anesthesia in addition to the challenges of spica cast care. The purposes of this study were to evaluate the effectiveness of Ilfeld bracing for infants for whom Pavlik harness treatment is unsuccessful and to compare these results with those for a similar cohort of patients directly undergoing closed reduction and spica casting. METHODS: We reviewed the cases of a consecutive series of children with DDH who had failure of Pavlik harness treatment and were subsequently managed with Ilfeld bracing (the BR cohort) and compared this cohort with a similar historical group of infants who had failure of Pavlik harness treatment but had standard closed reduction and spica casting (the CR cohort). The cohorts were compared with respect to clinical and ultrasonographic data at the time of Pavlik discontinuation. At one year, the hip stability and acetabular index were assessed; the presence of osteonecrosis was graded according to the criteria described by Salter et al. RESULTS: Twenty-eight hips (nineteen infants) made up the BR cohort and twenty-two hips (sixteen infants) made up the CR cohort. Ultrasonographic indices (including the alpha angle and the percentage of femoral head coverage) were comparable between the two cohorts (p=0.66 and 0.19, respectively). Following treatment, a stable reduction was achieved in twenty three (82%) of twenty-eight hips in the BR cohort compared with twenty (91%) of twenty-two hips in the CR cohort. At one year, acetabular indices were similar between both cohorts (mean and standard deviation, 27 degrees +/-6 degrees for the BR cohort versus 27 degrees +/-5 degrees for the CR cohort; p=0.62); however, osteonecrosis developed in three hips in the CR cohort compared with none in the BR cohort. CONCLUSIONS: In our series of infants with DDH for whom Pavlik harness treatment had failed, Ilfeld bracing had success rates comparable with those for closed reduction and spica cast treatment. With the added advantages of avoiding general anesthesia and spica casting as well as a potentially lower rate of osteonecrosis, rigid abduction bracing should be considered as the next step for infants who have had failed Pavlik harness treatment prior to proceeding with closed reduction and spica casting. PMID- 25695981 TI - Unsatisfactory outcome of arthrodesis performed after septic failure of revision total knee arthroplasty. AB - BACKGROUND: Periprosthetic infection is one of the most dreaded orthopaedic complications. Current treatment procedures include one-stage or two-stage revision total knee arthroplasty. If the periprosthetic infection is no longer controllable after several revision total knee arthroplasties, many surgeons regard knee arthrodesis as a promising option. The aim of our study was to ascertain whether intramedullary nailing results in the suppression or eradication of an infection and to identify risk factors for persistent infection. METHODS: All patients who had undergone intramedullary nailing following septic failure of revision total knee arthroplasty between 1997 and 2013 were included in the study. Pathogens, risk factors predisposing to persistent infection, and the rate of persistent infections were recorded. In addition, a visual analog scale (VAS) and Knee injury Osteoarthritis Outcome Score (KOOS), Knee Society Score (KSS), Lysholm, Short Form-36 (SF-36), and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) questionnaires were completed to assess clinical outcomes and quality of life. RESULTS: Twenty-six patients were included in the study. Thirteen (50%) had a persistent infection requiring additional revision surgery. Nineteen patients (73%) reported persistent pain (VAS score of >3). All scores showed marked impairment of quality of life. CONCLUSIONS: Intramedullary nailing following septic failure of revision total knee arthroplasty must be regarded with skepticism, and we cannot recommend it. Repeat revision total knee arthroplasty or amputation should be considered as an alternative in such difficult cases. PMID- 25695982 TI - Local delivery of the cationic steroid antibiotic CSA-90 enables osseous union in a rat open fracture model of Staphylococcus aureus infection. AB - BACKGROUND: Treatment of infected open fractures remains a major clinical challenge. In this study, we investigated the novel broad-spectrum antibiotic CSA 90 (cationic steroid antibiotic-90) as an antimicrobial agent. METHODS: CSA-90 was screened in an osteoblast cell culture model for effects on differentiation and mineralization. Local delivery of CSA-90 was then tested alone and in combination with recombinant human bone morphogenetic protein-2 (rhBMP-2) in a mouse ectopic bone formation model (n=40 mice) and in a rat open fracture model inoculated with pathogenic Staphylococcus aureus (n=84 rats). RESULTS: CSA-90 enhanced matrix mineralization in cultured osteoblasts and increased rhBMP-2 induced bone formation in vivo. All animals in which an open fracture had been inoculated with Staphylococcus aureus and not treated with local CSA-90, including those treated with rhBMP-2, had to be culled prior to the experimental end point (six weeks) because of localized osteolysis and deterioration of overall health, whereas CSA-90 prevented establishment of infection in all open fractures in which it was used (p<=0.012). Increased union rates were seen for the fractures treated with rhBMP-2 or with the combination of rhBMP-2 and CSA-90 compared with that observed for the fractures treated with CSA-90 alone (p=0.04). CONCLUSIONS: CSA-90 can promote osteogenesis and be used for prevention of Staphylococcus aureus infection in preclinical models. CLINICAL RELEVANCE: Local delivery of CSA-90 represents a novel strategy for prevention of infection and may have specific benefits in the context of orthopaedic injuries. PMID- 25695983 TI - Prevalence of radiographic parameters predisposing to femoroacetabular impingement in young asymptomatic Chinese and white subjects. AB - BACKGROUND: Osteoarthritis of the hip is five to ten times more common in white people than in Chinese people. Little is known about the true prevalence of femoroacetabular impingement or its role in the development of osteoarthritis in the Chinese population. A cross-sectional study of both white and Chinese asymptomatic individuals was conducted to compare the prevalences of radiographic features posing a risk for femoroacetabular impingement in the two groups. It was hypothesized that that there would be proportional differences in hip anatomy between the white and Asian populations. METHODS: Pelvic computed tomography scans of 201 subjects (ninety-nine white Belgians and 102 Chinese; 105 men and ninety-six women) without hip pain who were eighteen to forty years of age were assessed. The original axial images were reformatted to three-dimensional pelvic models simulating standardized radiographic views. Ten radiographic parameters predisposing to femoroacetabular impingement were measured: alpha angle, anterior offset ratio, and caput-collum-diaphyseal angle on the femoral side and crossover sign, ischial spine projection, acetabular anteversion angle, center-edge angle, acetabular angle of Sharp, Tonnis angle, and anterior acetabular head index on the acetabular side. RESULTS: The white subjects had a less spherical femoral head than the Chinese subjects (average alpha angle, 56 degrees compared with 50 degrees ; p<0.001). The Chinese subjects had less lateral acetabular coverage than the white subjects, with average center-edge angles of 35 degrees and 39 degrees (p<0.001) and acetabular angles of Sharp of 38 degrees and 36 degrees (p<0.001), respectively. A shallower acetabular configuration was predominantly present in Chinese women. CONCLUSIONS: Significant differences in hip anatomy were demonstrated between young asymptomatic Chinese and white subjects. However, the absolute size of the observed differences appears to contrast with the reported low prevalence of femoroacetabular impingement in Chinese individuals compared with the high prevalence in white populations. PMID- 25695984 TI - Sandwich allografts for long-bone nonunions in patients with osteogenesis imperfecta: a retrospective study. AB - BACKGROUND: Patients with osteogenesis imperfecta often develop nonunions, as internal fixation has limited applicability in this condition. We report the outcomes of a modified "sandwich technique" in the treatment of long-bone nonunions in patients with osteogenesis imperfecta; this technique brings circumferential stabilization and normal collagen to the nonunion site. METHODS: From May 2003 through February 2012, twelve patients (eight females, four males; median age, 39.0 years; range, eleven to seventy-eight years) who had osteogenesis imperfecta (Sillence type I [three], type III [eight], and type IV [one]) and a combined total of thirteen nonunions (two humeral, two radial, three femoral, four tibial, and two ulnar; median duration, 15.0 months; range, six to 204 months) were treated at our institution with compressed sandwich allograft cortical struts. The struts were fashioned to be wide enough to allow for increased osteoconductive surface area and to approximate a hemicylindrical shape. Treatment history and demographics data were acquired through retrospective chart review. Follow-up radiographs were analyzed by two attending orthopaedic surgeons to determine radiographic findings. The median follow-up time was 4.6 years (range, 2.1 to 10.3 years). RESULTS: All thirteen nonunions, including one requiring a second graft procedure, healed with abundant, smooth allograft incorporation, resulting in an initial healing rate of 92% because of a refracture in one patient. This patient's nonunion ultimately healed with additional allograft struts and a new intramedullary rod. One patient required removal of prominent screws. The final follow-up examinations revealed no pain or refracture at the original nonunion site. All patients regained their prefracture level of function. CONCLUSIONS: Sandwich allograft struts constitute a durable, safe method for the stabilization and healing of persistent long-bone nonunions in patients with osteogenesis imperfecta. All patients showed incorporation of the allograft to the native diaphysis. PMID- 25695985 TI - Morbid obesity: a significant risk factor for failure of two-stage revision total hip arthroplasty for infection. AB - BACKGROUND: Morbid obesity (BMI [body mass index], >=40 kg/m2) is associated with a higher risk of complications, including infection and implant failure, following primary total hip arthroplasty. The purpose of this study was to compare the results of two-stage revision total hip arthroplasty for infection in a morbidly obese patient cohort (BMI, >=40 kg/m2) and nonobese patients (BMI, <30 kg/m2). METHODS: Using an institutional total joint registry, we reviewed the medical records of 653 patients treated with two-stage revision total hip arthroplasty for periprosthetic joint infection over a twenty-year period (1987 to 2007). Patients were stratified according to preoperative BMI. Thirty-three patients (fourteen male and nineteen female) with a BMI of >=40 kg/m2 were identified. These patients were matched 1:2 with a cohort of sixty-six patients (twenty-eight male and thirty-eight female) of the same sex and similar age (91% within two years) who were not obese (BMI, <30 kg/m2). All patients had a minimum of five years of clinical follow-up (mean, 8.1 years in the morbidly obese group and 10.3 years in the nonobese group). RESULTS: Compared with nonobese patients, morbidly obese patients had significantly greater rates of reinfection (18% compared with 2%, p<0.005), revision (42% compared with 11%, p<0.001) and reoperation for any reason (61% compared with 12%, p<0.001). Prior to surgery, the mean Harris Hip Score had been 50.6 in the morbidly obese group and 48.8 in the nonobese group, and these scores improved significantly in both groups postoperatively (p<0.01). CONCLUSIONS: Morbidly obese patients have markedly elevated risks of reinfection, reoperation, and component resection as well as poorer intermediate-term clinical outcome scores compared with nonobese patients following revision total hip arthroplasty for periprosthetic joint infection. PMID- 25695986 TI - Weight-bearing-line analysis in supramalleolar osteotomy for varus-type osteoarthritis of the ankle. AB - BACKGROUND: We determined the preoperative and postoperative passing points of the mechanical axis of the lower limb at the level of the tibial plafond using a new method involving a full-length standing posteroanterior radiograph that includes the calcaneus (a hip-to-calcaneus radiograph) and correlated them to the clinical results after supramalleolar osteotomy for ankle osteoarthritis. METHODS: We reviewed the hip-to-calcaneus radiographs of fifty lower limbs of forty-one patients treated for lower limb malalignment at our institution. The mechanical axis point of the ankle was the point at which the mechanical axis divides the coronal length of the plafond, expressed as a percentage. Four independent observers performed all measurements twice. Supramalleolar tibial osteotomy was performed in twenty-seven ankles (twenty-four patients) to treat moderate varus-type osteoarthritis of the ankle. The mean follow-up period was 2.8 years (range, two to 5.3 years). Clinical assessment was based on the American Orthopaedic Foot & Ankle Society (AOFAS) scale. RESULTS: Interobserver and intraobserver reliability in identifying the mechanical ankle joint axis point were very high. The mean postoperative mechanical axis point was 50% (range, 13% to 70%) in ankles for which the preoperative point was <=0%, whereas the mean postoperative point was 81% (range, 48% to 113%) in ankles for which the preoperative point was >0%. The mean change in AOFAS score was significantly less for patients with a preoperative point of <=0% than for those with a preoperative point of >0% (p=0.004). Improvement was significantly greater in ankles with a postoperative mechanical ankle joint axis point of >=80% than in ankles with a postoperative mechanical ankle joint axis point of <60% (p=0.030). CONCLUSIONS: Traditional tibial correction resulted in great variation in the locations of the postoperative mechanical ankle joint axis point. In ankles with the preoperative point more medial than the tibial plafond, the point was insufficiently moved to the lateral side, and the clinical outcomes were less satisfactory. PMID- 25695987 TI - Operative care did not benefit closed, displaced, intra-articular calcaneal fractures. PMID- 25695988 TI - Epidural injections with glucocorticoid and lidocaine for spinal stenosis did not confer additional benefit compared with lidocaine alone. PMID- 25695989 TI - Topical tranexamic acid was noninferior to intravenous tranexamic acid in controlling blood loss during total knee arthroplasty. PMID- 25695990 TI - What's new in pediatric orthopaedics. AB - This past year has seen an increase in the quality of studies in pediatric orthopaedics, and the completion of BrAIST demonstrated that high-level studies of important questions can be addressed in pediatric orthopaedics. The current commitment of improving quality of care for children promises a healthy future for pediatric orthopaedics. PMID- 25695992 TI - Erratum. PMID- 25695991 TI - A new approach to managing patients with problematic metal hip implants: the use of an Internet-enhanced multidisciplinary team meeting: AAOS exhibit selection. AB - BACKGROUND: Over one million patients worldwide are estimated to have a metal-on metal hip arthroplasty. To improve the management of these patients and reduce surgeon uncertainty regarding decision-making, we designed an Internet-enhanced multidisciplinary team (iMDT) working approach. METHODS: From August 2012 to April 2014, the iMDT discussed 215 patients with 266 metal-on-metal hip arthroplasties. Of these, 236 primary arthroplasties (132 hip resurfacing and 104 total hip) were analyzed. The remaining thirty cases involved problematic revised hips and were therefore excluded. The possible recommendations of the iMDT were monitoring, further investigation, or surgery. The concordance between the recommendation and the actual management was used to assess the usefulness of this approach in reducing uncertainty in surgeon-level decision-making. RESULTS: The median Oxford Hip Score was 35 (range, 4 to 48), and median cobalt and chromium levels in whole blood were 3.54 ppb (range, 0.18 to 161.46 ppb) and 3.17 ppb (range, 0.20 to 100.67 ppb), respectively. Magnetic resonance imaging revealed abductor muscle atrophy in ninety-two (39%) of the hips and a pseudotumor in eighty (34%). The iMDT recommended monitoring of 146 (61.9%) of the hips, further investigation of thirty (12.7%), and surgery in sixty (25.4%). The actual outcome was concordant with the recommendation in 211 (91.7%) of the hips. CONCLUSIONS: Our iMDT approach to the metal-on-metal hip burden combines the tacit knowledge of an expert panel, regulatory guidance, and up-to-date evidence to improve decision-making among surgeons. The high level of concordance between the recommendation and the actual outcome, combined with the feasibility of the methods used, suggest that this method effectively reduces uncertainty among surgeons and may lead to improved patient outcomes. PMID- 25695993 TI - The AOA-JOA 2014 exchange traveling fellowship: Banzai and beyond. AB - The American Orthopaedic Association-Japanese Orthopaedic Association (AOA-JOA) traveling fellowship was established in 1992 as a method for creating collaboration between the American and Japanese orthopaedic communities and providing a friendly exchange of current practices and scientific endeavors. The fellowship is designed to allow early-career orthopaedic surgeons the opportunity to participate in international travel and scholarship. This year's traveling fellows (Hassan Mir, Wakenda Tyler, Leo Kroonen, and Dan Zlotolow) all hail from different parts of the United States and have a variety of practice subspecialties. During the fellowship, the fellows were able to visit five academic centers that spanned the entire country of Japan as well as the JOA meeting in Kobe. The experience is one that contributed to the growth and development of each fellow's practices and depth of understanding of orthopaedic surgery. PMID- 25695994 TI - Caring for the critically injured. Commentary on an article by Saam Morshed, MD, PhD, MPH, et al.: "The impact of trauma-center care on mortality and function following pelvic ring and acetabular injuries". PMID- 25695995 TI - Are anterior supraspinatus tendon tears more prone to propagation? Commentary on an article by Daisuke Araki, MD, PhD, et al., "Effect of tear location on propagation of isolated supraspinatus tendon tears during increasing levels of cyclic loading". PMID- 25695996 TI - Extensor allograft: the consummate treatment for extensor disruption after total knee arthroplasty. Commentary on an article by Nicholas M. Brown, MD, et al.: "Extensor mechanism allograft reconstruction for extensor mechanism failure following total knee arthroplasty". PMID- 25695997 TI - Joining forces to drive biomedical translation. PMID- 25695998 TI - (Re)solving atherosclerosis. AB - Delivery of nanoparticles with arterial tropism containing the annexin A1 fragment Ac2-26 reduces signs of lesion instability in a mouse model of advanced atherosclerosis (Fredman et al., this issue). PMID- 25695999 TI - Targeted nanoparticles containing the proresolving peptide Ac2-26 protect against advanced atherosclerosis in hypercholesterolemic mice. AB - Chronic, nonresolving inflammation is a critical factor in the clinical progression of advanced atherosclerotic lesions. In the normal inflammatory response, resolution is mediated by several agonists, among which is the glucocorticoid-regulated protein called annexin A1. The proresolving actions of annexin A1, which are mediated through its receptor N-formyl peptide receptor 2 (FPR2/ALX), can be mimicked by an amino-terminal peptide encompassing amino acids 2-26 (Ac2-26). Collagen IV (Col IV)-targeted nanoparticles (NPs) containing Ac2 26 were evaluated for their therapeutic effect on chronic, advanced atherosclerosis in fat-fed Ldlr(-/-) mice. When administered to mice with preexisting lesions, Col IV-Ac2-26 NPs were targeted to lesions and led to a marked improvement in key advanced plaque properties, including an increase in the protective collagen layer overlying lesions (which was associated with a decrease in lesional collagenase activity), suppression of oxidative stress, and a decrease in plaque necrosis. In mice lacking FPR2/ALX in myeloid cells, these improvements were not seen. Thus, administration of a resolution-mediating peptide in a targeted NP activates its receptor on myeloid cells to stabilize advanced atherosclerotic lesions. These findings support the concept that defective inflammation resolution plays a role in advanced atherosclerosis, and suggest a new form of therapy. PMID- 25696000 TI - Regulation of immune responses to protein therapeutics by transplacental induction of T cell tolerance. AB - Central tolerance plays a key role in modulating immune responses to self and exogenous antigens. The absence of self-antigen expression, as in patients with genetic deficiencies, prevents the development of antigen-specific immune tolerance. Hence, a substantial number of patients develop neutralizing antibodies to the corresponding protein therapeutics after replacement treatment. In this context, the administration of missing antigens during fetal development, a key period for self-tolerance establishment, should confer early and long lasting antigen-specific tolerance. To this end, we exploited the physiological pathway of the neonatal Fc receptor (FcRn) through which maternal immunoglobulins are transplacentally transferred to fetuses. We demonstrate that Fc-fused antigens administered to pregnant mice reach fetal lymphoid organs in an FcRn dependent manner, accumulate in antigen-presenting cells of myeloid origin, and promote the generation of both thymic and peripheral antigen-specific regulatory T cells. This strategy was successfully pursued in a mouse model of hemophilia A, where maternofetal transfer of the Fc-fused immunodominant domains of coagulation factor VIII conferred antigen-specific tolerance. Transplacental tolerance induction with Fc-fused proteins may thus prove valuable to prevent alloimmunization after replacement protein therapy for congenital deficiencies. PMID- 25696001 TI - Rational development and characterization of humanized anti-EGFR variant III chimeric antigen receptor T cells for glioblastoma. AB - Chimeric antigen receptors (CARs) are synthetic molecules designed to redirect T cells to specific antigens. CAR-modified T cells can mediate long-term durable remissions in B cell malignancies, but expanding this platform to solid tumors requires the discovery of surface targets with limited expression in normal tissues. The variant III mutation of the epidermal growth factor receptor (EGFRvIII) results from an in-frame deletion of a portion of the extracellular domain, creating a neoepitope. We chose a vector backbone encoding a second generation CAR based on efficacy of a murine scFv-based CAR in a xenograft model of glioblastoma. Next, we generated a panel of humanized scFvs and tested their specificity and function as soluble proteins and in the form of CAR-transduced T cells; a low-affinity scFv was selected on the basis of its specificity for EGFRvIII over wild-type EGFR. The lead candidate scFv was tested in vitro for its ability to direct CAR-transduced T cells to specifically lyse, proliferate, and secrete cytokines in response to antigen-bearing targets. We further evaluated the specificity of the lead CAR candidate in vitro against EGFR-expressing keratinocytes and in vivo in a model of mice grafted with normal human skin. EGFRvIII-directed CAR T cells were also able to control tumor growth in xenogeneic subcutaneous and orthotopic models of human EGFRvIII(+) glioblastoma. On the basis of these results, we have designed a phase 1 clinical study of CAR T cells transduced with humanized scFv directed to EGFRvIII in patients with either residual or recurrent glioblastoma (NCT02209376). PMID- 25696002 TI - NPC1L1 is a key regulator of intestinal vitamin K absorption and a modulator of warfarin therapy. AB - Vitamin K (VK) is a micronutrient that facilitates blood coagulation. VK antagonists, such as warfarin, are used in the clinic to prevent thromboembolism. Because VK is not synthesized in the body, its intestinal absorption is crucial for maintaining whole-body VK levels. However, the molecular mechanism of this absorption is unclear. We demonstrate that Niemann-Pick C1-like 1 (NPC1L1) protein, a cholesterol transporter, plays a central role in intestinal VK uptake and modulates the anticoagulant effect of warfarin. In vitro studies using NPC1L1 overexpressing intestinal cells and in vivo studies with Npc1l1-knockout mice revealed that intestinal VK absorption is NPC1L1-dependent and inhibited by ezetimibe, an NPC1L1-selective inhibitor clinically used for dyslipidemia. In addition, in vivo pharmacological studies demonstrated that the coadministration of ezetimibe and warfarin caused a reduction in hepatic VK levels and enhanced the pharmacological effect of warfarin. Adverse events caused by the coadministration of ezetimibe and warfarin were rescued by oral VK supplementation, suggesting that the drug-drug interaction effects observed were the consequence of ezetimibe-mediated VK malabsorption. This mechanism was supported by a retrospective evaluation of clinical data showing that, in more than 85% of warfarin-treated patients, the anticoagulant activity was enhanced by cotreatment with ezetimibe. Our findings provide insight into the molecular mechanism of VK absorption. This new drug-drug interaction mechanism between ezetimibe (a cholesterol transport inhibitor) and warfarin (a VK antagonist and anticoagulant) could inform clinical care of patients on these medications, such as by altering the kinetics of essential, fat-soluble vitamins. PMID- 25696003 TI - Differential SIRT1 expression in hepatocellular carcinomas and cholangiocarcinoma of the liver. AB - Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) are two major liver malignancies. Although some phenotypic overlap is known, HCC and CCA are usually different with regard to etiology, histology, and prognosis. Gene expression and deacetylase activity of the class III histone deacetylase SIRT1 are up-regulated in cancer cells due to oncogene overexpression or loss of function of tumor suppressor genes. SIRT1 may play a critical role in tumor initiation, progression, and drug resistance by blocking senescence and apoptosis, and promoting cell growth and angiogenesis, but pleiotropic effects (synchronous or metachronous anti-proliferation and anti-apoptotic mechanisms) have been suggested in some cancers. Our aim was to investigate the expression of SIRT1 in liver epithelial malignancies. Thirty carcinomas of the liver, including 16 HCC and 14 CCA cases, were investigated by immunohistochemistry using monoclonal antibodies against SIRT1 and p53. Western blot analysis (WBA) was carried out for expression of SIRT1 in three CCA cell lines, one HCC cell line, and one cell line of Papova-immortalized normal hepatocytes. An expression of SIRT1 was found in 11 of 16 (68.75%) HCC and in 5 of 14 (35.71%) CCA. Moreover, we found an expression of p53 in 8 out of 16 (50%) HCC and 13 out of 14 (92.86%) CCA. WBA showed expression of SIRT1 in all cell lines studied, although a stronger signal was seen in the HCC cell line. Immunohistochemical data did not correlate to clinical stage or other clinical or histopathological parameters. Sirtuin 1 is a phylogenetically-conserved family of deacetylases and our data seem to indicate that (1) pleiotropic effects may be present in hepatic epithelial malignancies, and (2) there is no specificity of SIRT1 for either HCC or CCA. PMID- 25696004 TI - Beta-catenin expression patterns in matched pre- and post-neoadjuvant chemotherapy-resistant breast cancer. AB - BACKGROUND: beta-catenin is a critical component of the cadherin cell-to-cell adhesion pathway and a key participant in the Wnt signaling pathway. Activation of beta-catenin signaling in the Wnt pathway is a known contributor to tumor cancer progression and metastasis and may result in resistance to chemotherapeutic agents. The aim of this study is to evaluate the patterns of expression of beta-catenin in breast carcinoma cells before and after neoadjuvant chemotherapy. Discovery of the molecular mechanisms responsible for resistance to chemotherapy treatment could result in more effective therapy, and improve outcome and survival. DESIGN: Twenty-nine matched pre-treatment and post neoadjuvant chemotherapy breast carcinomas were subjected to immunohistochemical study using anti-beta-catenin antibody. Normal staining was defined as crisp membrane staining in >90% tumor cells; aberrant expression was nuclear staining in >5% tumor cells. RESULTS: Of the 29 included cases, five cases of invasive lobular carcinoma lacked beta-catenin immunoreactivity pre- and post-treatment. Mildly reduced membranous staining was seen in two post-treatment samples. One case of triple-negative ductal carcinoma had reduced pre- and post-treatment staining. All other cases showed normal pre- and post-treatment beta-catenin expression. No aberrant staining was identified. CONCLUSION: In our study, there was no difference in the expression of beta-catenin in pre- and post-neoadjuvant chemotherapy specimens. These results do not suggest that beta-catenin plays a role in conferring neoadjuvant chemotherapy resistance. PMID- 25696005 TI - Fibroblast growth factor 23 predicts coronary calcification and poor prognosis in patients with chronic kidney disease stages 3-5D. AB - OBJECTIVE: To investigate the relationship of fibroblast growth factor-23 (FGF23) to coronary calcification and prognosis in patients with chronic kidney disease (CKD) stages 3-5D. METHOD: We determined serum levels of intact FGF23 in 150 patients with CKD stages 3-5D, using an enzyme-linked immunosorbent assay (ELISA). The coronary calcification was detected with multi-slice CT, and its relationship to FGF23 was analyzed. These patients were followed up over a period of 35+/-3 months. RESULT: Serum FGF23 levels of patients with CKD stages 3-5D were significantly higher than those of the healthy control group (p<0.01). There was a significant positive correlation between serum FGF23 levels and coronary calcification score (CaS) (r=0.177, p<0.05). Age, dialysis vintage, and FGF23 levels were independent risk factors for coronary calcification in patients with CKD stages 3-5D. Receiver-operating characteristic (ROC) curves showed that the sensitivity and specificity of FGF23 were 62.5% and 75.9%, respectively, for diagnosing coronary calcification, with an area of 0.705 under the curve (p<0.01). Kaplan-Meier analysis revealed that survival rates were significantly better in patients with lower FGF23 levels (p<0.05). In Cox regression analysis, FGF23 levels and severe coronary calcification (CaS>400) were independent risk factors for all-cause mortality. CONCLUSION: Serum FGF23 level in patients with CKD stages 3-5D was significantly higher than in the healthy controls. These increased FGF23 levels are likely associated with coronary calcification and poor prognosis. PMID- 25696006 TI - Prevalence of Howell-Jolly body-like inclusions in HIV patients and their correlation with CD4 counts and HIV RNA viral load. AB - Previous reports have described the rare occurrence of detached nuclear fragments resembling Howell-Jolly bodies within neutrophils from HIV patients, organ transplant recipients, and patients on immunosuppressive drugs. To date, their potential clinical significance is unknown, and pathologists tend to disregard their presence. Our study sought to find a correlation between these inclusions and the overall disease state, specifically within the HIV patient population. Eighty-three peripheral smears, all from different patients, were examined for the presence of inclusions and compared with recent CD4 counts and HIV RNA viral loads. Six cases contained inclusions, yielding a prevalence of 7.2%. These six patients had a mean CD4 count of 546+/-305 cells/MUL compared to 247+/-242 cells/MUL in those lacking inclusions (p<0.006) and viral loads of 1,686+/-3,446 copies/mL compared to 241,882+/-1,137,229 copies/mL in those lacking inclusions (p=0.6). These findings indicate that the presence of Howell-Jolly body-like inclusions may be viewed as a potential biomarker indicative of a low risk for disease progression and/or good response to therapy based upon higher CD4 counts and relatively favorable viral loads. PMID- 25696007 TI - Everolimus method comparison between Waters MassTrakTM Immunosuppressants XE (IUO) kit and an in-house laboratory developed LC-MS/MS method in renal transplant patients. AB - Everolimus is an immunosuppressant drug that was approved for prophylactic use in the United States to prevent organ rejection in adult kidney and liver transplant recipients. Therapeutic drug management (TDM) is required to optimize the dose for efficacy and to minimize toxicity. Prior to the development of immunoassay reagents for everolimus, laboratory developed chromatographic methods were routinely used to support TDM for everolimus testing. However, the use of high performance liquid chromatography coupled to tandem mass spectrometry (HPLC MS/MS)for everolimus TDM is not widely utilized in hospitals or transplant centers due to either a lack of mass spectrometry instrumentation or resources for assay development. An everolimus reagent kit and method was developed by Waters Corporation for use on the Waters ACQUITY TQD mass spectrometer system. PURPOSE: The purpose for this study was to evaluate the investigational use only (IUO) Waters MassTrak Immunosuppressants XE (IUO) kit on a Waters ACQUITY((r)) ultra performance liquid chromatography (UPLC) coupled to an ACQUITY((r)) TQD mass spectrometer and to compare this test system to a laboratory developed mass spectrometry assay for everolimus. METHOD: We evaluated precision and performed a patient comparison study on 56 renal transplant patients that received everolimus against a validated in house HPLC-MS/MS method. RESULTS: 5-day precision was performed on two patient pooled samples and analyzed in triplicate. Total imprecision for the low patient pool (3.77 ng/mL) and high patient pool (10.87 ng/mL) was <15 %CV. Deming regression analysis was performed for the patient comparison and the linear regression equation was y=0.973x+0.03, Sy/x 0.55, and the correlation coefficient was 0.9815. CONCLUSION: The Waters MassTrak Immunosuppressants XE (IUO) kit and method had good correlation between the concentration range of 3-15 ng/mL to the established in-house HPLC-MS/MS method. PMID- 25696008 TI - Identification of Mycobacterium tuberculosis and rifampin resistance in clinical specimens using the Xpert MTB/RIF assay. AB - PURPOSE: The Xpert MTB/RIF assay is a novel real-time polymerase chain reaction technique for the detection of the Mycobacterium tuberculosis (MTB) complex and rifampin (RIF) resistance. We evaluated the performance of this assay in identifying MTB and resistance to RIF in clinical specimens. MATERIALS AND METHODS: We analyzed clinical specimens from 383 patients with suspected TB who were hospitalized at a secondary hospital in Korea. Specimens were processed using the Xpert MTB/RIF assay, acid-fast bacilli smear and culture, and drug susceptibility test (DST). RESULTS: Among the 444 clinical samples analyzed, the Xpert MTB/RIF assay identified MTB in 56 (13.8%) of 405 respiratory specimens, but did not detect MTB in the remaining 39 non-respiratory specimens. Of the 65 pulmonary TB patients, 52 (80.0%) were confirmed by using mycobacterial culture as a reference standard. The sensitivity, specificity, PPV, and NPV of the Xpert MTB/RIF assay were 73.85%, 99.03%, 94.12%, and 94.72%, respectively. Among five patients with RIF resistance determined by the Xpert MTB/RIF assay, four (80%) were confirmed as suffering from multidrug-resistant (MDR) TB by DST. CONCLUSIONS: The Xpert MTB/RIF assay appears to be an accurate, simple, and useful technique for detecting MTB, especially in respiratory specimens. However, RIF resistance, if detected, should be verified with DST. PMID- 25696009 TI - Immune responses to a recombinant Rv0057-Rv1352 fusion protein of Mycobacterium tuberculosis. AB - The identification and characterization of antigens of Mycobacterium tuberculosis help in understanding the mechanisms of protective immunity and in improving diagnostic methods for TB. Rv0057 and Rv1352 proteins are new T-cell antigens, found to play roles in TB infection. In this study, a recombinant fusion protein Rv0057-Rv1352 was made and analyzed for its immunological characteristics and potential utility. It showed good immunoreactivity with serum from TB patients by western blotting. The antibody levels against Rv0057-Rv1352 were significantly higher in sera from 69 TB patients than in sera from 60 patients with non-TB respiratory diseases (P<0.001). The sensitivities of a diagnostic ELISA test based on detecting Rv0057-Rv1352 antibody (60.3%) or 38 kDa-16 kDa antibody (58.8%) were comparable to commercial rapid test B (75.4%), and significantly higher (p<0.001) than bacteriological methods (15.9%), rapid test A (20.3%), or rapid test C (29.0%). The specificities of Rv0057-Rv1352 (93.3%) or 38 kDa-16 kDa antibody tests (93.3%) were equivalent to the rapid tests A (93.3%) and C (86.7%), and significantly higher than rapid test B (63.3%, p<0.001). When 38 kDa 16 kDa was used together with Rv0057-Rv1352, the test sensitivity reached 85.5%, and its specificity remained high (86.7%). The test was as sensitive with bacterium-positive TB patients as with bacterium-negative. In an ELISPOT assay for cellular immunity, Rv0057-Rv1352 stimulated T lymphocytes to produce fewer spots secreting IFN-gamma than CFP10-ESAT6 fusion protein did (p>0.05). These results suggest that Rv0057-Rv1352 has potential for the serodiagnosis of active pulmonary TB. PMID- 25696010 TI - Association between serum free thyroxine (FT4) and uric acid levels in populations without overt thyroid dysfunction. AB - In this study, we investigated the relationship between thyroid function and serum uric acid (UA) levels in subjects without overt thyroid dysfunction. A total of 6,085 patients were included in this cross-sectional study. Free thyroxine (FT4) levels were positively and linearly associated with serum UA levels (p<0.001), even after adjusting for age, thyroid-stimulating hormone, renal function, and other metabolic components (B 37.13; 95%CI 25.99-48.28; p<0.001). Furthermore, quartile analysis indicated that the prevalence of hyperuricemia was significantly elevated with increasing FT4 levels (quartile II: OR 1.232, 95%CI 1.022-1.486, p=0.029; quartile III: OR 1.234, 95%CI 1.025-1.486, p=0.026; quartile IV: OR 1.409, 95%CI 1.168-1.701, p<0.001). In summary, FT4 is linearly associated with serum UA levels in subjects lacking clinical thyroid dysfunction, and the prevalence of hyperuricemia is elevated with increasing FT4 levels. PMID- 25696011 TI - Serum myosin light chain kinase in type 2 diabetes mellitus: a cross-sectional study. AB - The present study was designed to identify changes in human serum caused by myosin light chain kinase (MLCK) in the context of Type 2 diabetes mellitus (T2DM), and to determine whether it had correlations with other biomarkers of T2DM. A total of 336 patients with T2DM and 90 sex- and age-matched, apparently healthy subjects were selected. The serum MLCK of all participants was detected by quantitative ELISA. Our results showed that the concentration of MLCK in the T2DM group was significantly higher than in control samples, and there were no correlations with age, FBG, TC, HDL-C, LDL-C or HbA1c. These findings suggest that serum MLCK is associated with T2DM, which gives some clues for identifying new biomarkers for the diagnosis of T2DM and its complications. PMID- 25696012 TI - Effect of small interference RNA on the acetylcholine-sensitive potassium channel in H9c2 cells. AB - BACKGROUND: The acetylcholine-sensitive potassium channel (IK(ACh)) expresses only in the atrium, not in the ventricle. The main component of the rat IK(ACh) channel is the Kir3.4 protein, and its encoding gene is the KCNJ5 gene. IK(ACh) inhibitors provide a promising treatment for atrial fibrillation without side effects on the ventricle. At present, however, there is no specific IK(ACh) inhibitor. Small interference RNA (siRNA) has the advantages of high specificity and high efficiency. Our aim is to use siRNA to inhibit the IK(ACh) channel on H9c2 cells derived from rat cardiomyocytes. METHODS: Three pairs of siRNAs targeting the rat IK(ACh) channel were synthesized. H9c2 cells were divided into six groups: control, negative siRNA control, siRNA sequence 1, siRNA sequence 2, siRNA sequence 3, and amiodarone. The KCNJ5 gene and Kir3.4 protein were measured, and IK(ACh) currents were recorded by patch-clamp. RESULTS: The negative siRNA control and siRNA sequence 1 had no inhibitory effects on the IK(ACh) channel. siRNA sequences 2 and 3 could cause a significant decrease in KCNJ5 gene expression, Kir3.4 protein, and IK(ACh) currents (p<0.05). Amiodarone could inhibit the IK(ACh) currents but had no effect on KCNJ5 gene expression and Kir3.4 protein. CONCLUSION: siRNA could effectively inhibit the IK(ACh) channel and is a potential therapy for atrial fibrillation. PMID- 25696013 TI - Selection of superior reference genes' combination for quantitative real-time PCR in B-cell lymphomas. AB - Normalization of real-time quantitative PCR data to appropriate reference genes is crucial to accurately interpret results. Many genes commonly used as reference standards do not perform as expected, depending on cell type and experimental design. In our previous work, we addressed the issue of suitable reference genes for lymphoid tissue and successfully applied the normalization factor-based approach to discriminate lymphoid malignancies according to their cyclin D1 mRNA level. Here, we addressed the problem of reference gene selection and sufficient number on an enlarged sample set with seven candidate genes. The experimental set included 165 samples of spleens, lymph nodes, and peripheral blood mononuclear cells from patients with different types of non-Hodgkin lymphomas along with non neoplastic lymphoid specimens. For the first time, we compared all major stability ranking algorithms of Visual Basic for Applications (VBA) applets geNorm, BestKeeper, and NormFinder and tested candidate reference genes on a large and heterogeneous set of fresh clinical lymphoid samples. We concluded that a normalization-based approach using three reference genes (YWHAZ, UBC and ACTB) allows for robust reduction of the variance in real-time PCR results and that the further addition of reference genes does not improve data normalization. This creates a clinically applicable tool for PCR-based lymphoma diagnostics. PMID- 25696014 TI - T-cell/histiocyte-rich large B-cell lymphoma in pediatric patients: an under recognized entity? AB - T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) is a distinct subtype of diffuse large B-cell lymphoma (DLBCL) under-recognized in the pediatric population. A meticulous workup is necessary to avoid a misdiagnosis of nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) or classical Hodgkin lymphoma (HL). A strong degree of suspicion and an emphasis on immunohistochemical staining are required to reach the diagnosis. Few children with advanced stage disease have been described to date. We report two pediatric patients with high stage THRLBCL and highlight their clinical and pathological features. PMID- 25696015 TI - The utility of B-cell receptor gene rearrangement studies in diagnosing diffuse large B-cell lymphoma with plasmacytic differentiation. AB - We present the case of a 50-year-old man with nodal diffuse large B-cell lymphoma characterized by CD10, BCL-6, and BCL-2 expression and a complex karyotype, including t(14;18)(q32;q21) and del6q, suggesting transformation from an antecedent follicular lymphoma. Following rituximab-based chemotherapy, residual nodal disease was characterized by a proliferation of plasmacytoid cells positive for CD138, MUM-1, and cytoplasmic kappa light chain. Immunoglobulin heavy chain and kappa light chain gene rearrangement studies detected the same clone in the diagnostic and post-therapy lymph node specimens. This case illustrates the diagnostic utility of B-cell receptor gene rearrangement studies in detecting a clonal relationship in lymphoma cases with extensive morphologic and immunophenotypic variation following chemotherapy. PMID- 25696016 TI - Congenital peribronchial myofibroblastic tumor: case report of an asymptomatic infant with a rapidly enlarging pulmonary mass and review of the literature. AB - BACKGROUND: Congenital peribronchial myofibroblastic tumor (CPMT) is a rare, benign lung tumor of infants, with only 19 reported cases worldwide. It is often diagnosed by prenatal imaging or in the immediate postnatal period due to co morbidities like polyhydramnios, fetal hydrops, respiratory distress, and heart failure. OBSERVATION: We report the oldest known infant (8 weeks old) diagnosed with CPMT, and present his clinical course including the relevant radiographic and histopathologic findings. CONCLUSIONS: CPMT is a rare tumor that should be considered among other primary lung tumors of infancy (developmental, benign, and malignant) even if not detected prenatally or in the immediate postnatal period. PMID- 25696017 TI - A novel splice site mutation in the PAX6 gene in a Korean family with isolated aniridia. AB - Aniridia is a rare congenital ocular disorder of complete or partial iris hypoplasia. Frequently associated ocular changes include corneal abnormalities, cataract, glaucoma, and foveal hypoplasia. In most cases, aniridia is caused by decreased dosage of the paired box 6 (PAX6) gene, which is located in chromosome 11p13. We report the case of a Korean family with isolated aniridia inherited in an autosomal dominant manner. The proband was a one-month-old boy. He presented with bilateral complete aniridia and congenital glaucoma. His four-year-old sister had bilateral complete aniridia, glaucoma, and a corneal ulcer. His father had bilateral microcornea and cataract without aniridia. Using PAX6 sequencing analysis, we identified a deletion at the splice donor site of intron 8 in the proband (c.357+1delG). To our knowledge, this variant has not been previously described. PMID- 25696018 TI - Mutation screening in candidate genes in four Chinese brachydactyly families. AB - Autosomal dominant brachydactyly (BD) is a skeletal disorder with several subtypes, including brachydactyly type A1 (BDA1) and brachydactyly type B1 (BDB1). Mutations in Indian hedgehog (IHH) are usually associated with BDA1, whereas heterozygous mutations in receptor tyrosine kinase-like orphan receptor 2 (ROR2) are mainly responsible for BDB1. On the basis of the clinical phenotype identification, we screened IHH and ROR2 by the candidate gene approach using PCR direct sequencing. We found three known mutations of IHH (c.283_285delGAG, p.E95del; c.298 G>A, p.D100N; c.300C>G, p.D100E) in three Chinese families with BDA1, and a novel heterozygous nonsense mutation of ROR2 (c.2273C>A, p.S758X) in a BDB1 family. It was noted that c.300C>G mutation was a new nucleotide substitution compared to the reported c.300C>A, which led to the same amino acid change (p.D100E). The novel nonsense mutation p.S758X was verified by absence in the unaffected family members and the 100 randomly-selected controls. In this paper, we report three recurrent mutations with a new nucleotide substitution of IHH in three Chinese families with BDA1 and a novel nonsense mutation in BDB1 pedigree. We therefore recommend the approach of candidate gene screening as the first choice for genetic testing for BD. PMID- 25696019 TI - Osteogenesis imperfecta Type I caused by a novel mutation in the start codon of the COL1A1 gene in a Korean family. AB - Osteogenesis imperfecta (OI) comprises a heterogeneous group of disorders characterized by susceptibility to bone fractures ranging in severity from perinatal death to a subtle increase in fracture frequency. We report the case of a patient who appeared healthy at birth and did not experience any fractures until 12 months of age. We observed blue sclera, frequent fractures without commensurate trauma, nearly normal stature, the absence of dentinogenesis imperfecta, no bony deformity, and no limitation of mobility in the patient--all characteristics suggestive of OI Type I. The patient's mother also had blue sclera and a history of frequent fracture episodes until the age of 15 years. A novel COL1A1 missense mutation (c.2T>G) disrupting the start codon of the gene (ATG to AGG (Met1Arg)) was found in the patient and his mother. PMID- 25696020 TI - A case report of a fetus with mosaic autosomal variegated aneuploidies and literature review. AB - Mosaic variegated aneuploidy (MVA) is a recessive condition characterized by mosaic aneuploidies, predominantly trisomies and monosomies, involving multiple chromosomes and tissues. The phenotype of MVA syndrome includes severe microcephaly and growth deficiency, central nervous system anomalies, mental retardation, mild physical anomalies, and predisposition to cancer. We report a case of true fetal mosaicism for variegated aneuploidies detected in amniotic fluid cells. A 33-year-old primigravida woman at 5 weeks 1 day of gestation was referred to our tertiary hospital because of a high-risk pregnancy associated with IgA nephropathy. In a quadruple screening test performed at the 15(th) week of gestation, alpha fetoprotein was 73.4 IU/mL (2.792 MoM), suggesting that she was at high risk of neural tube defect. Following amniocentesis performed at the 17 weeks' gestation, chromosome examination of amniocyte culture showed premature chromatic separation in 63% of the metaphases (58/92) and a high frequency of gain and loss of chromosomes. Repeat amniocentesis at 21 weeks' gestation consistently showed the presence of multiple mosaic autosomal variegated aneuploidies. Ultrasonography at 21 weeks' gestation revealed relatively small head circumference for gestational age (<3%) and vermis defect, suggesting that the fetus would have microcephaly and Dandy-Walker malformation. Cytogenetic analysis with peripheral blood of the parents showed normal karyotype. In summary, we hereby report the cytogenetic analysis and prenatal findings of MVA. PMID- 25696021 TI - A novel NOTCH2 mutation identified in a Korean family with Hajdu-Cheney syndrome showing phenotypic diversity. AB - Hajdu-Cheney syndrome (HCS) and serpentine fibula-polycystic kidney syndrome (SFPKS) share many similarities, including craniofacial abnormalities, bony deformities, and renal involvement. Because mutations in exon 34 of NOTCH2 have been identified recently in both HCS and SFPKS patients, it has been suggested that these two syndromes be classed as the same disorder. A 3-year-old boy presented with polycystic kidneys and club feet detected during the fetal period; however, acroosteolysis and curved fibulae were not observed. His mother showed osteoporosis and had a history of compression fractures in the spine without renal anomalies. Although the same novel mutation in NOTCH2 was found in both the mother and her son, these patients displayed different clinical manifestations. In this report, we present a familial case of HCS in a boy and his mother that was suspected on physical examination and radiological findings. We speculate that HCS and SFPKS are a single disease entity with a wide spectrum of clinical manifestations associated with truncating mutations in exon 34 of NOTCH2. PMID- 25696023 TI - Erratum. PMID- 25696022 TI - Letter to the editor: A working model for real time quality assurance in anatomic pathology. PMID- 25696024 TI - Faster pacing for fast atrial arrhythmias, an infeasible fact. PMID- 25696025 TI - DDD versus DDDR pacing: effects on the occurrence of atrial arrhythmias and the quality of life in patients with the sick sinus syndrome. AB - OBJECTIVE: To evaluate the efficiency of adaptive rate dual-chamber pacing to control the recurrence of atrial arrhythmias in patients with the brady-tachy variant of the sick sinus syndrome (SSS) with or without associated AV block. METHOD: A total of 23 patients were included in this double-blind, randomised, crossover study. In each patient a CPI 1230 dual pacemaker was implanted. The pacemaker was programmed blind to the investigator in a randomised order to four different pacing modalities for a period of four weeks each: DDD, lower rate 60 PPM; DDD, lower rate 80 PPM; DDD-R, lower rate 60 PPM; and DDD-R, lower rate 80 PPM. The incidence of atrial tachyarrhythmia events was determined by interrogating the event counter of the pacemaker, 24-hour Holter monitoring in each mode and documentation of the need for reprogramming, electro-cardioversion and antiarrhythmic medication. The quality of life in each pacing mode was assessed by quality-of-life questionnaires and patient diaries. RESULTS: None of the pacing modes were significantly better for the whole patient group with respect to the suppression of atrial arrhythmias. However, there were significant individual differences in the occurrence of atrial tachyarrhythmias and tolerance for each mode. CONCLUSION: In dual-chamber pacing for patients with the brady tachy variant of the SSS, the ideal programming cannot be predicted. Individual mode setting with usage of the pacemaker event counter should be performed to find the best antitachycardia mode. PMID- 25696026 TI - Hybrid pharmacological and ablative therapy for the management of symptomatic atrial fibrillation. AB - BACKGROUND: Hybrid therapy for atrial fibrillation class 1C and class III antiarrhythmic drugs (AAD) can convert atrial fibrillation (AF) into an isthmus dependent atrial flutter (AFL) in more than 10% of patients. Hybrid pharmacological and ablative therapy offers a safe and effective approach to achieving and maintaining sinus rhythm. We evaluated the efficacy of this hybrid approach in the management of paroxysmal or persistent AF. METHODS: Eighteen patients with symptomatic AF treated with AAD and typical anticlockwise/clockwise AFL underwent radiofrequency (RF) ablation of AFL with an anatomical approach. RESULTS: RF ablation was successful in all patients. All but one patient continued with AAD. Four patients (22%) had recurrences of AFL. Two of them also had a recurrence of AF. Another three patients had recurrences of AF only, and finally, one patient developed an atrial tachycardia more than one year after the procedure. In conclusion, 11 patients (61%) did not experience recurrences of AF/AFL after tricuspid valve annulus (TV)-inferior caval vein (IVC) isthmus ablation with continuing antiarrhythmic drugs. CONCLUSION: Hybrid pharmacological and ablative therapy is a safe and effective treatment for the management of patients with symptomatic AF. PMID- 25696027 TI - Assessment of quality of life in patients with angina pectoris: Progress made by the Dutch Mononitrate Quality-Of-Life (DUMQOL) Study Group. AB - BACKGROUND: Two major issues in quality of life (QOL) research are the patient's opinion as a contributing factor in QOL assessments, and the lack of sensitivity of QOL assessments. OBJECTIVES: To review results from recent research by the Dutch Mononitrate Quality Of Life (DUMQOL) Study Group relevant to these two issues. METHODS: Using a test battery including Stewart's Short Form (SF)-36 Questionnaire and the DUMQOL-50 questionnaire, the DUMQOL Study Group tested the hypothesis that the patient's opinion might be an independent determinant of QOL. To do this, a stepwise multiple regression analysis of data from 82 patients attending an outpatient clinic with stable angina pectoris was performed. Secondly, using an odds ratio approach to QOL scores in 1350 outpatients with stable angina pectoris who were attending a clinic, the DUMQOL Study Group assessed the question whether relative scores might provide increased precision in estimating the effects of patient characteristics on QOL data. RESULTS: Psychological distress was the most important contributor to QOL (beta 0.43, p<0.0001). Also, the patient's opinion on his/her QOL significantly contributed to QOL (beta 0.22, p=0.032). Physical health status according to the patient's judgement only made a borderline contribution (beta 0.19, p=0.71), while the physician's judgement was not associated with QOL at all (beta 0.11, p=0.87). Regarding the second issue, increased QOL difficulties were observed in New York Heart Association (NYHA) angina class III-IV patients, in patients with comorbidity, as well as in female and elderly patients. Odds ratios can be used in these categories to predict the benefit from treatments. CONCLUSIONS: Recent QOL research of the DUMQOL Study Group allows conclusions to be drawn that are relevant to clinical practice. QOL should be defined in a subjective rather than an objective method. The patient's opinion is an important independent contributor to QOL. The comparison of absolute QOL scores lacks the sensitivity to truly estimate QOL. The odds ratio approach of QOL scores provides increased precision in estimating QOL. PMID- 25696028 TI - Isolated systolic hypertension as a treatable risk factor. AB - Isolated systolic hypertension (ISH) is characterised by elevated systolic (SBP) and somewhat lowered diastolic blood pressure (DBP). ISH occurs predominantly in elderly hypertensives as a result of aortic stiffness, which increases with age. Elevated SBP and even more so widened pulse pressure (PP=SBP-DBP) are recognised as important risk factors for stroke and ischaemic heart disease. ISH therefore requires consistent drug therapy, combined with lifestyle advice. It is important to lower SBP without reducing DBP too much, in order to avoid a further widening of the PP. Large-scale intervention studies (SHEP, SYST-EUR, SYST-China, and INSIGHT) have demonstrated that thiazide diuretics and calcium antagonists are the drugs of choice to protect against stroke and MI. ACE inhibitors, AT1 blockers and omapatrilate may be considered because of their haemodynamic effects and their additional benefit in patients with heart failure or diabetes. Nitrates and NO-donors reduce SBP more than DBP because of their effects on the large conduit arteries. Spironolactone is of potential interest since it may reduce aortic stiffness. PMID- 25696029 TI - Lambl's excrescences of the mitral valve. AB - A young male patient, just recovered from a recent transient ischaemic attack, was operated on for mitral valve insufficiency due to suspected endocarditis. Multiple wear-and-tear lesions were found at the line of closure of the mitral valve, which appeared to be Lambl's excrescences. The valve was replaced. PMID- 25696031 TI - ? PMID- 25696030 TI - Anomalous origin of all coronary arteries from the right coronary cusp. PMID- 25696032 TI - ? PMID- 25696033 TI - Heart plan for Europe: a healthy European initiative with a major role for national societies. PMID- 25696034 TI - Left main coronary artery dissection during percutaneous coronary intervention treated by stenting. AB - AIM: Outcome after stenting for iatrogenic left main coronary artery (LMCA) dissection during percutaneous coronary intervention (PCI). METHODS: From our database all patients with a PCI complicated by an LMCA dissection, between 1996 and 2001, were selected and medical records were reviewed. RESULTS: Eighteen patients out of 7199 (0.25%) were found with an LMCA dissection during a PCI for unstable (n=14) and stable angina (n=4). Antegrade dissections were caused by guiding catheters (n=6). Retrograde dissections were caused by stent implantation (n=7) and balloon angioplasty (n=5). All patients were treated by stent implantation in the LMCA. Three patients died (17%) within ten days of the procedure. Emergency surgery was performed in four patients (22%) because of persistent ischaemia due to low coronary flow. One patient was operated one day later because of unstable angina and a failed attempt to recanalise the left descending coronary artery. The other ten patients (56%) with a stent in the LMCA were free of cardiac complaints after a follow-up period of 3.0 years (range 1.9 5.0). Cardiac catheterisation in six patients between three and eight months did not show stenosis of the LMCA stent. CONCLUSION: LMCA dissection during a PCI can be treated by stent implantation, especially when the dissection is limited to the LMCA. When flow cannot be restored adequately, resulting in ischaemia and haemodynamic instability, LMCA stenting may serve as a bridge to emergency CABG. PMID- 25696035 TI - Clinical experience with pericardiocentesis and extended drainage in a population with a high prevalence of HIV. AB - BACKGROUND: The data presented were generated in a prospective study on the immunopathogenesis and management of tuberculous (TB) pericarditis at Tygerberg Hospital in Cape Town. We report our experience with 2D echocardiographically guided pericardiocentesis in 170 consecutive patients who presented to us with large pericardial effusions since 1995. METHODS: All patients referred to our department with echocardiographically confirmed large pericardial effusions underwent a clinical assessment followed by pericardiocentesis and drainage by an indwelling pigtail catheter. The appearance and amount of drained effusion were noted and fluid was sent for diagnostic assessment. The pigtail catheter was kept in place and fluid was aspirated once daily until the aspirate was less than 100 ml, at which stage the catheter was removed. RESULTS: A chest wall puncture site was chosen in 165 of the 170 patients (97%), while the subcostal approach was only used in five patients. Echocardiographic signs of tamponade were seen in 88% of cases. In the majority of patients (68.2%) a diagnosis of TB could be established and of these 46.6% were HIV positive. TB could not be proven in only three HIV-positive patients (1.8% of all patients). Neither hospital stay nor complications were increased in the HIV-positive group when compared with the HIV negative group and no patient developed intrapericardial sepsis. No death could be attributed with certainty to the procedure. One patient developed non-fatal tamponade within 24 hours after the tap and in another patient a left ventricular thrombus was noted on echo after 16 days. Twenty-four patients underwent a pericardial window procedure according to protocol for diagnostic purposes. In another four patients a window was performed for therapeutic reasons. The most common minor complication was local pain at the site of catheter insertion. Repeat drainage was necessary in only six (3.5%) cases. CONCLUSIONS: 2D echocardiographically directed pericardiocentesis with extended catheter drainage has an excellent profile in terms of simplicity, safety and efficacy, even in a population with a very high prevalence of HIV. PMID- 25696036 TI - Implantable loop records in paediatric pratice. AB - BACKGROUND: Symptoms of syncope and palpitations are not uncommon in children with and without heart disease. They present a diagnostic dilemma when conventional cardiovascular testing is inconclusive. The implantable loop recorder (ILR) has been shown to play an important role in diagnosing recurrent syncope in adult patients. In paediatric practice its role still has to be defined. AIM: The aim of this article is to assess the diagnostic yield of the ILR in children and young adults. METHODS: Seven patients, four male and three female, were included in the study. The mean age at implantation was 12.8 years, with a range from 0.8 to 25.9 years. RESULTS: The symptoms leading to ILR implantation were recurrent syncope or near-syncope (n=3), syncope in combination with palpitations (n=2), and syncope with an acute life-threatening event (ALTE) (n=2). Previous testing included 12-lead ECG (n=7), echo (n=7), 24-hour Holter (n=7), four-week ambulatory Holter (n=3), exercise test (n=4) and invasive electrophysiological study (n=3). Over a mean follow-up period of 7.5 months (range 3 to 16 months), four (57%) patients continued to have symptoms. CONCLUSIONS: The ILR enabled the correct diagnosis to be established in all four patients with persistent symptoms allowing appropriate therapy to be given. PMID- 25696037 TI - Methods in molecular cardiology: the polymerase chain reaction. AB - Several polymerase chain reaction (PCR) techniques are described in this review to give insight into the potential applications for cardiovascular research. Although PCR can be performed in several ways, all applications are based on the same general principle, the amplification of DNA or RNA by the enzyme polymerase. This amplification provides the opportunity to detect, identify and multiply a single copy of DNA or RNA, in or outside the cell. This powerful technique can be used in several directions of DNA and RNA research resulting in the ability to specifically detect the presence and activity of genes. The use of these techniques in cardiovascular research is discussed here. PMID- 25696038 TI - Severe haemorrhage following intrapleural streptokinase therapy for haemothorax after myocardial revascularisation with the left internal mammary artery. AB - Administration of intrapleural streptokinase is a well-accepted therapy for the treatment of haemothorax following myocardial revascularisation with the inner mammary artery (IMA). The present report describes a patient who developed severe hypotension with an accompanying drop in haemoglobin concentration induced by the sixth consecutive instillation of intrapleural streptokinase. This case suggests that the standard streptokinase therapy of six to eight instillations might be too much for these patients. PMID- 25696039 TI - Left ventricular outflow tract obstruction as a consequence of Sanfilippo's disease. PMID- 25696040 TI - ? PMID- 25696042 TI - Time from symptom onset to treatment of patients with acute ST-elevation myocardial infarction. PMID- 25696041 TI - ? PMID- 25696043 TI - Clinical relevance of the gap between pre-marketing trials and medical practice: the case of the cardiovascular drugs. AB - OBJECTIVES/BACKGROUND: The external validity of trial results of new cardiovascular drugs is limited, because the short-term studies are performed with relatively small, highly selected populations. Using qualitative methods, we examined the clinical relevance of under-representation of subgroups of patients, and the underlying arguments. METHODS: Interviews with 47 physicians and pharmacists involved in the pre- or post-marketing evaluation of cardiovascular drugs, addressing the issue in general and for two new drugs, losartan and atorvastatin, in particular. RESULTS: The respondents were generally familiar with the under-representation of elderly patients, female patients, and patients with comorbidity in pre-marketing trials, but less familiar with details of representation in the cases of losartan and atorvastatin. In particular under representation of patients with comorbidity was considered relevant. Arguments to confirm or refute the relevance referred to trial methodology, applicability of trial results or aspects of patient treatment. Conditional arguments referred to the aim of the trial, population size, therapeutic drug class or the timing of trials prior to or after drug registration. CONCLUSIONS: To optimise the connection between pre-marketing clinical research and practice, trials should focus more on patient groups relevant to medical practice. If such research is not feasible prior to registration, it should be conducted afterwards. Drug information should allow practitioners to determine variations in the relative effects between subpopulations. PMID- 25696044 TI - Time from symptom onset to treatment and outcome in prehospital thrombolysis for acute ST-elevation myocardial infarction. AB - BACKGROUND: Prehospital thrombolysis for acute ST-elevation myocardial infarction shortened treatment by 60 minutes, and created a large patient group who were treated within two hours. OBJECTIVES: We analysed our database of patients undergoing prehospital treatment for acute ST-elevation myocardial infarction in search of characteristics for a better outcome in the early treatment group. METHODS: From 1994 to 2000 a total of 475 patients were treated using prehospital administration of anistreplase (in 407 patients) or reteplase (in 68 patients) after diagnosis was confirmed with transtelephonic transmission of the ECG. There was no age limit. The patient data were divided into two groups: one treated within two hours after onset of pain (291 patients, 62%), and one treated later (171 patients, 37%). Thirty-day mortality, symptoms and clinical signs of heart failure were used as parameters of outcome. Both univariate and stepwise logistic regression analyses were used to test 30-day mortality against age, actual time to treatment, prior myocardial infarction, hypertension, diabetes, anterior myocardial infarction, Killip class, systolic blood pressure and heart rate at presentation. RESULTS: Overall 30-day mortality was 9.1%. Overall heart failure was in 16.6% of patients. Both mortality (5.5% vs. 15.5%, p<0.02) and heart failure (12.7% vs. 23.2%, p<0.02) were significantly lower in the early treatment group compared with the group treated late. Independent parameters showing a relation with 30-day mortality were age, time to treatment, hypertension and prior myocardial infarction. Age, time to treatment, hypertension and hyperlipidaemia were identified as predicting heart failure within the first 30 days. CONCLUSION: With prehospital thrombolysis, both 30-day mortality and heart failure were lower in an early treatment group with acute ST-elevation myocardial infarction. Independent variables for 30-day mortality were age, hypertension, prior myocardial infarction and time to treatment, and age, hypertension, hyperlipidaemia and time to treatment were independent predictors for heart failure. PMID- 25696045 TI - Combination and triple therapy in patients with stable angina pectoris not adequately controlled by optimal beta-blocker therapy. AB - In 60 to 80% of patients with stable angina pectoris at low risk for future coronary events, monotherapy with a beta-blocker is an effective treatment. When patients with stable angina pectoris and low risk for events do not respond adequately to optimal beta-blocker monotherapy, combination therapy or even triple therapy is may be recommended, but little is known of the actual benefit of such a strategy. We reviewed the evidence from the literature on the effectiveness of combination and triple therapy. Combination therapy with a calcium antagonist or nitrate was found to be more effective than beta-blocker monotherapy in the majority of studies, but only an estimated 30% of patients objectively benefit from these combination therapies. Direct comparison shows that combination therapy of a beta-blocker with a calcium antagonist is more effective than the combination of a beta-blocker with a nitrate. An inadequate response to beta-blocker monotherapy is more effectively improved by addition of a calcium antagonist than by alternative use of a calcium antagonist. The use of triple therapy is controversial and not recommended in patients with mild angina pectoris, while for patients with severe angina pectoris not responding to combination therapy of a beta-blocker with a nitrate, triple therapy may be of advantage, although the number of patients studied has been small. PMID- 25696046 TI - Implantable diagnostic and therapeutic devices in children. AB - Many advances have been made in the use of implantable diagnostic and therapeutic devices in adults. In children the indications for and diagnostic and therapeutic value of these devices still have to be determined. Our aim is to provide an overview of the clinical use of diagnostic and therapeutic devices in children. The role of implantable loop recorders (ILR), the feasibility and safety of transvenous pacing in neonates, the value of permanent pacing in children with recurrent syncope or reflex anoxic seizures and the role of implantable cardioverter defibrillator devices are highlighted with relevant case histories. PMID- 25696048 TI - Erratum: Left main coronary artery dissection during percutaneous coronary intervention treated by stenting. AB - [This corrects the article on p. 395 in vol. 10.]. PMID- 25696047 TI - Persistent left superior vena cava diagnosed during pacemaker implantation. PMID- 25696049 TI - ? PMID- 25696050 TI - ? PMID- 25696051 TI - Project report: adult congenital heart disease. PMID- 25696052 TI - Prevention of sudden cardiac death in high-risk patients: implications of the results of primary prevention studies. PMID- 25696053 TI - Value of myocardial SPECT in early detection of ischaemia in children with sickle cell anaemia. AB - BACKGROUND: Cardiovascular complications of sickle cell anaemia (SCA) are relatively infrequent compared with other cerebral and skeletal insults. However, myocardial infarction and cardiac dysfunction have been reported in autopsied patients with SCA. When left ventricular functional parameters of gated SPECT and echocardiography were compared incidentally in children with SCA, some 26% of patients were found to have evident myocardial ischaemia. This stimulated the current work with the aim to further analyse these incidental findings and evaluate the possible role of SPECT in early detection of coronary insufficiency in children with SCA. PATIENTS AND METHODS: Twenty-seven patients (19 girls, 8 boys), mean age 9.2+/-4.2 years, with SCA were examined by baseline ECG, echocardiography and gated SPECT. They were all free from any cardiac symptoms. Intravenous injection of 5 to 10 mCi 99MTc-MIBI or 99MTc-Myoview was administered, according to the predetermined weight-dependent paediatric dose. Stress SPECT was obtained 45 to 60 minutes after tracer injection, which took place at peak physical exercise (6 patients) or 3 to 4 minutes after IV infusion of dipyridamole pharmacological stress (21 patients). Rest SPECT study was acquired 4 to 5 hours later after a second injection of 99MTc-MIBI/Myoview. A semiquantitative nine-segment stress/rest bull's eye model was used to assess to the presence/extent of myocardial ischaemia. RESULTS: Myocardial perfusion was normal in 20 patients (74%). Seven patients (26%) had significant perfusion defects in the stress images. Four of them showed perfusion defect in one or two segments. Complete reversibility in the rest study was seen in all patients. Two patients showed a mixture of reversible and fixed perfusion defects in four segments. One patient had evident left ventricular dilatation with multiple fixed and reversible defects (cardiomyopathy). In this case, a diffusely reduced myocardial wall contractility was seen and a low LVEF of 42% as assessed by echocardiography. This was the only case showing agreement between the echo and SPECT findings. In the whole cohort the EF% and FS% by echocardiography were 61.7+/-5.9% and 33.2+/-3.4% respectively (mean+/-SD). There were no significant relations between myocardial perfusion abnormalities when compared with EF% and FS%; (p>0.05). CONCLUSION: Cardiac involvement in the form of myocardial ischaemia should be regarded as a high-risk complication in patients with SCA. Myocardial perfusion scintigraphy succeeded in the early detection of myocardial perfusion abnormalities in patients with SCA. PMID- 25696054 TI - Differential effect of female gender on coronary artery disease and peripheral artery disease. AB - BACKGROUND: Women are relatively protected against coronary artery disease (CAD). Whether female gender has a similar protective influence on the development of peripheral artery disease (PAD) has not been extensively investigated and was the main subject of our study. METHODS: We analysed 2707 consecutive patients (2008 men and 699 women) who underwent a first diagnostic coronary angiography for suspicion of CAD and 2367 consecutive patients (1426 men and 941 women) who underwent a first ankle arm index measurement because of suspicion of PAD. RESULTS: We found that a positive diagnosis for CAD and PAD was more common in men compared with women (80.7% vs 57.9%, p<0.0001 and 68.0% vs 60.7%, p<0.0001). Once CAD or PAD was established, severity of disease was similar for men and women, which pleads against a referral bias. Women had a reduced risk of CAD after adjustment for risk factors (odds ratio [OR] 0.32, 95% confidence interval [CI] 0.22-0.46, p<0.0001), but not of PAD (OR 0.82, 95% CI 0.66-1.03, p=NS). In patients with CAD and in those with PAD, women were older, more often had diabetes and hypertension, while men were more likely to be current smokers. Hypertension, smoking and diabetes were associated with CAD in both men and women. Current smoking was associated with PAD in men and women. Hypertension and diabetes were associated with PAD in women but not in men. CONCLUSION: After adjustment for risk factors, the female protection for CAD seems to less present for PAD. PMID- 25696055 TI - Limited role of Ca2+-activated Cl- current in early afterdepolarisations. AB - OBJECTIVES: The proarrhythmic, early afterdepolarisations during phase two of the action potential (phase-2 EADs) are associated with secondary Ca2+ release from the sarcoplasmic reticulum. This makes it probable that the Ca2+-activated Cl- current (ICl(Ca)) may contribute to phase-2 EADs. Activation of ICl(Ca) during phase two of the action potential will result in a repolarising current and may thus be expected to prevent excessive depolarisation of phase-2 EADs. The present study was designed to test this hypothesis. METHODS: The contribution of ICl(Ca) during phase-2 EADs was studied in enzymatically isolated sheep ventricular myocytes using the patch-clamp methodology. EADs were induced at a stimulus frequency of 0.5 Hz by exposure of the myocytes to 1 MUM noradrenaline. RESULTS: The ICl(Ca) blocker 4,4'-diisothiocyanostilbene-2,2'-disulphonic acid (DIDS, 0.5 mM) abolished phase-1 repolarisation of the action potential in all myocytes tested. This indicates that ICl(Ca) is present in all myocytes. However, DIDS had no effect on phase-2 EAD characteristics. CONCLUSION: In sheep ventricular myocytes, ICl(Ca) contributes to phase-1 repolarisation of the action potential, but plays a limited role in phase-2 EADs. PMID- 25696056 TI - The clinical significance of whole blood viscosity in (cardio)vascular medicine. AB - Whole blood is a non-Newtonian fluid, which means that its viscosity depends on shear rate. At low shear, blood cells aggregate, which induces a sharp increase in viscosity, whereas at higher shear blood cells disaggregate, deform and align in the direction of flow. Other important determinants of blood viscosity are the haematocrit, the presence of macro-molecules in the medium, temperature and, especially at high shear, the deformability of red blood cells. At the sites of severe atherosclerotic obstructions or at vasospastic locations, when change of vessel diameter is limited, blood viscosity contributes to stenotic resistance thereby jeopardising tissue perfusion. However, blood viscosity plays its most important role in the microcirculation where it contributes significantly to peripheral resistance and may cause sludging in the postcapillary venules. Apart from the direct haemodynamic significance, an increase in blood viscosity at low shear by red blood cell aggregation is also associated with increased thrombotic risk, as has been demonstrated in atrial fibrillation. Furthermore, as increased red blood cell aggregation is a reflection of inflammation, hyperviscosity has been shown to be a marker of inflammatory activity. Thus, because of its potential role in haemodynamics, thrombosis and inflammation, determination of whole blood viscosity could provide useful information for diagnostics and therapy of (cardio)vascular disease. PMID- 25696058 TI - Bullet immigration to the heart. PMID- 25696057 TI - Isolation of residual sinus node during catheter ablation for the treatment of inappropriate sinus tachycardia. AB - Inappropriate sinus tachycardia is an unusual arrhythmia that is difficult to treat. To date, catheter ablation has concentrated on modifying the sinus node to attain rate control. We describe a patient where sinoatrial block was created by radiofrequency ablation for the treatment of inappropriate sinus tachycardia. PMID- 25696059 TI - ? PMID- 25696060 TI - ? PMID- 25696061 TI - Cardiovascular drug therapy 1971-2002 and beyond: Farewell lecture presented by P.A. van Zwieten at his retirement ceremony as professor and chairman of the Department of Pharmacotherapy at the University of Amsterdam, Wednesday 29 May 2002. PMID- 25696063 TI - Chronic His bundle pacing: a precise and precarious therapy. PMID- 25696064 TI - Rhythmic sensory stimulation improves fitness by conditioning the autonomic nervous system. AB - BACKGROUND: Endurance training is known to alter the functioning of the autonomic nervous system, a major goal when pursuing fitness. Here, we test the hypothesis that the training-associated rhythmic sensations alone, hence without the usual accompanying physical exercise, accomplish this effect. METHOD: We studied sixteen resting healthy male volunteers, age (mean+/-SD) 25.9+/-3.7 years. During one hour we applied, at marching pace (2 bursts per second), bipolar transcutaneous electrical sensory nerve stimulation to both feet. The stimulation intensity was controlled in such a way that discharges of sensory fibres in the tibial and fibular nerves were induced, while motor fibres were not excited. Heart rate, blood pressure, and baroreflex sensitivity were measured before and after stimulation. RESULTS: Baseline baroreflex sensitivity and systolic blood pressure were 8.7+/-4.5 ms.mmHg-1 and 117.5+/-6.4 mmHg, respectively. Directly after rhythmic sensory stimulation baroreflex sensitivity had increased to 10.0+/ 4.1 ms.mmHg-1 (p<0.05). One day later, systolic blood pressure had lowered to 111.7+/-5.5 mmHg (p<0.01). CONCLUSIONS: Rhythmic sensory stimulation entails autonomic adaptations that are comparable with those of exercise. This demonstration of sensory-induced autonomic adaptations without any muscular involvement may help to design alternative, low-effort fitness programmes for specific categories of sedentary, diseased or disabled persons. PMID- 25696065 TI - A multifactorial smoking cessation programme for patients with coronary artery disease: experiences and preliminary results. AB - BACKGROUND: Smoking is a known risk factor for coronary artery disease (CAD) and recurrent cardiac events in patients with established CAD. Although cessation can lead to a risk reduction of up to 50% following an initial myocardial infarction, at least 20% of cardiac patients continue to smoke. AIMS: To describe and evaluate the effects of a comprehensive, multifactorial smoking cessation programme in outpatients with CAD, and to delineate variables that impede smoking cessation. STUDY DESIGN: Patients with a confirmed diagnosis of CAD recruited from the outpatient cardiology clinic, Dijkzigt University Hospital, Rotterdam, participated in the cessation programme and were followed for three months. Endpoint was smoking cessation. METHODS: Purpose-designed and validated questionnaires were used to assess smoking history, sociodemographic and psychological parameters. Information on cardiac history was sampled from medical records. Height and blood pressure were measured at baseline, and weight and expiratory CO at every group session of the cessation programme. RESULTS: One third of the patients recruited for the programme achieved cessation at three months. Quitters generally smoked less, were less addicted, scored lower on anxiety and depression, and had more recently been diagnosed with CAD. Type D personality was an impediment to cessation (OR:3.50; 95% CI: 0.40-35.48). CONCLUSION: Thirty-two percent of the patients achieved cessation at three months. Cessation efforts should be started in-hospital or as early as possible following diagnosis. An interdisciplinary and multifactorial approach seems warranted, in particular given the negative influence of anxiety, depression, and Type D personality on cessation. PMID- 25696062 TI - Association of objectively measured physical activity with cardiovascular risk in mobility-limited older adults. AB - BACKGROUND: Data are sparse regarding the impacts of habitual physical activity (PA) and sedentary behavior on cardiovascular (CV) risk in older adults with mobility limitations. METHODS AND RESULTS: This study examined the baseline, cross-sectional association between CV risk and objectively measured PA among participants in the Lifestyle Interventions and Independence for Elders (LIFE) study. The relationship between accelerometry measures and predicted 10-year Hard Coronary Heart Disease (HCHD) risk was modeled by using linear regression, stratified according to CVD history. Participants (n=1170, 79+/-5 years) spent 642+/-111 min/day in sedentary behavior (ie, <100 accelerometry counts/min). They also spent 138+/-43 min/day engaging in PA registering 100 to 499 accelerometry counts/min and 54+/-37 min/day engaging in PA >=500 counts/min. Each minute per day spent being sedentary was associated with increased HCHD risk among both those with (0.04%, 95% CI 0.02% to 0.05%) and those without (0.03%, 95% CI 0.02% to 0.03%) CVD. The time spent engaging in activities 100 to 499 as well as >=500 counts/min was associated with decreased risk among both those with and without CVD (P<0.05). The mean number of counts per minute of daily PA was not significantly associated with HCHD risk in any model (P>0.05). However, a significant interaction was observed between sex and count frequency (P=0.036) for those without CVD, as counts per minute was related to HCHD risk in women (beta=-0.94, -1.48 to -0.41; P<0.001) but not in men (beta=-0.14, -0.59 to 0.88; P=0.704). CONCLUSIONS: Daily time spent being sedentary is positively associated with predicted 10-year HCHD risk among mobility-limited older adults. Duration, but not intensity (ie, mean counts/min), of daily PA is inversely associated with HCHD risk score in this population-although the association for intensity may be sex specific among persons without CVD. CLINICAL TRIAL REGISTRATION URL: www.clinicaltrials.gov Unique identifier: NCT01072500. PMID- 25696066 TI - The NVVC working group guidelines for the management of patients with non-ST elevation acute coronary syndromes. PMID- 25696068 TI - Permanent direct His bundle pacing: initial report showing technical feasibility of an alternative pacing therapy. AB - To prevent deterioration of left ventricular function during right ventricular apical pacing, permanent direct His bundle stimulation can be considered in selected patients with low left ventricular ejection fraction and a normal His ventricle conduction time. We describe our first short-term experiences with permanent direct His bundle pacing in three patients. In two patients His bundle stimulation was still effective at six weeks' follow-up. In one patient loss of capture was registered, after which conventional RV apical pacing was performed. PMID- 25696067 TI - Coronary artery fistulas. AB - The aetiology of congenital coronary artery fistulas remains a challenging issue. Coronary arteries with an anatomically normal origin may, for obscure reasons, terminate abnormally and communicate with different single or multiple cardiac chambers or great vessels. When this occurs, the angiographic morphological appearance may vary greatly from discrete channels to plexiform network of vessels. Coronary arteriovenous fistulas (CAVFs) have neither specific signs nor pathognomonic symptoms; the spectrum of clinical features varies considerably. The clinical presentation of symptomatic cases can include angina pectoris, myocardial infarction, fatigue, dyspnoea, CHF, SBE, ventricular and supraventricular tachyarrhythmias or even sudden cardiac death. CAVFs may, however, be a coincidental finding during diagnostic coronary angiography (CAG). CAG is considered the gold standard for diagnosing and delineating the morphological anatomy and pathway of CAVFs. There are various tailored therapeutic modalities for the wide spectrum of clinical manifestations of CAVFs, including conservative pharmacological strategy, percutaneous transluminal embolisation and surgical ligation. PMID- 25696069 TI - One vessel with triple-vessel disease. PMID- 25696070 TI - ? PMID- 25696071 TI - ? PMID- 25696073 TI - ? PMID- 25696072 TI - Einthoven meeting 2002: 9-11 June, Leiden. PMID- 25696074 TI - More evidence in favour of early blockade of the renin-angiotensin system. PMID- 25696075 TI - Vitamins C. E and beta-carotene fired and statins for president? PMID- 25696076 TI - Angiographic determination of myocardial reperfusion by primary coronary angioplasty for acute myocardial infarction. AB - BACKGROUND: The primary objective of reperfusion therapies for acute myocardial infarction is not only restoration of blood flow in the epicardial coronary artery but also complete and sustained reperfusion of the infarcted part of the myocardium. METHODS: We studied 777 patients who underwent primary coronary angioplasty during a six-year period and investigated the value of angiographic evidence of myocardial reperfusion (myocardial blush grade) in relation to the extent of ST-segment elevation resolution, enzymatic infarct size, left ventricular function, and long-term mortality. The myocardial blush immediately after the angioplasty procedure was graded by two experienced investigators, who were otherwise blinded to all clinical data: 0: no myocardial blush, 1: minimal myocardial blush, 2: moderate myocardial blush, and 3: normal myocardial blush. RESULTS: The myocardial blush was related to the extent of the early ST-segment elevation resolution on the 12-lead electrocardiogram. Patients with blush grades 3, 2 and 0/1 had enzymatic infarct sizes of 757, 1143 and 1623 (p<0.0001), respectively, and ejection fractions of 0.50, 0.46 and 0.39, respectively (p<0.0001). After a mean+/-SD follow-up of 1.9+/-1.7 years, mortality rates of patients with myocardial blush grades 3, 2 and 0/1 were 3%, 6% and 23% (p<0.0001), respectively. Multivariate analysis showed that the myocardial blush grade was a predictor of long-term mortality, independent of Killip class, Thrombolysis In Myocardial Infarction (TIMI) grade flow, left ventricular ejection fraction, and other clinical variables. CONCLUSION: In patients after reperfusion therapy, the myocardial blush grade as seen on the coronary angiogram can be used to describe the effectiveness of myocardial reperfusion, and is an independent predictor of long-term mortality. PMID- 25696077 TI - Rate control versus electrical cardioversion for atrial fibrillation: A randomised comparison of two treatment strategies concerning morbidity, mortality, quality of life and cost-benefit - the RACE study design. AB - BACKGROUND: Persistent atrial fibrillation (AF) does not terminate spontaneously and may cause left ventricular dysfunction and thromboembolic complications. For restoration of sinus rhythm electrical cardioversion (ECV) is most effective. However, AF frequently relapses, necessitating re-ECV and institution of potentially harmful antiarrhythmic drugs. If AF is accepted, rate control and prevention of thromboembolic complications using negative chronotropic drugs and warfarin is pursued. It is our hypothesis that rate control therapy is not inferior to ECV therapy in preventing morbidity and mortality. METHODS: RACE (RAte Control versus Electrical cardioversion for atrial fibrillation) is a randomised comparison of serial ECV therapy (repeat ECV as soon as possible after a relapse and institution of an antiarrhythmic drug: sotalol, class IC drug and amiodarone) and rate control therapy (resting heart rate <100 bpm using digitalis, calcium channel blockers and/or beta-blockers) in patients with persistent AF. Morbidity (heart failure, side effects of drugs, thromboembolic complications, bleeding and pacemaker implantation), mortality, quality of life and cost-effectiveness are primary and secondary endpoints. Included are patients with a recurrence of persistent AF, present episode <1 year and a maximum of two previous successful ECVs during the last two years. This study is a multicentre study in 31 centres throughout the Netherlands. All 520 patients have now been included. Follow-up is two years. The results are expected this year. PMID- 25696078 TI - The NVVC guidelines for the management of patients with ST-elevation acute coronary syndromes (STE-ACS). PMID- 25696079 TI - Methods in molecular cardiology: DNA sequencing. AB - Sequencing is one the major breakthroughs in molecular cardiology. The development of this technique has made it possible to determine the exact order of the nucleotides in DNA. The exact order is relevant for the formation of proteins, through the genetic code. Sequencing is even more important for the identification of genetic variation and disease-causing mutations. The elucidation of the human genome is based on the continuous improvement of this technique, reducing the cost and increasing efficiency. Initially, complex chemical reactions were performed using isotopes to unravel the base sequence in genes. Nowadays, fluorescent capillary-based techniques are available to determine the genetic information. Here, the historical development of the technique is described. In addition, examples are provided on how sequencing is used in clinical medicine. PMID- 25696080 TI - Stress echocardiography: methods, indications and results. AB - Stress echocardiography has become an important clinical tool to detect cardiac ischaemia and viability in addition to single photon emission tomography. Stress echocardiography has a high positive and negative predictive value, is less expensive than the nuclear methods and has no radiation exposure. It can easily be used in an emergency room and coronary care unit. Because of its feasibility, low cost and high diagnostic accuracy, it will become a very important technique in every hospital and will soon be a real alternative to the more time-consuming and expensive nuclear techniques. The current article gives a review of the methods of stress echocardiography. PMID- 25696081 TI - Glossopharyngeal neuralgia with syncope: a case report. AB - We present the case of a 60-year-old woman with known glossopharyngeal neuralgia who was admitted to hospital because of recurrent syncopes associated with episodes of painful sensations in the caudal region of her tongue. Rhythm observation showed prolonged asystole, which was accompanied by a loss of consciousness. The asystole was preceded by an episode of pain. We concluded that the bradyarrhythmia and syncopes where associated with the glossopharyngeal neuralgia. Because of the life-threatening condition, we inserted a permanent dual-chamber pacing device. After implantation of the pacemaker, the patient had no further syncopes, although she still complained of episodic tongue pain. PMID- 25696082 TI - Osborn waves in hypothermia. PMID- 25696084 TI - ? PMID- 25696083 TI - ? PMID- 25696085 TI - ? PMID- 25696086 TI - The continuous postprandial state of man and its influence on atherosclerosis. PMID- 25696087 TI - Prevalence of coronary atherosclerosis in patients with aortic valve replacement. AB - BACKGROUND: Because of a high prevalence of coronary artery disease in patients with aortic valve disease, coronary angiography is recommended before aortic valve replacement. However, during the last three decades, a decline in mortality due to coronary heart disease has been observed in the general population in both Western Europe and the United States. It is unknown whether preoperative angiography is still mandatory in all patients. AIM: To assess the prevalence of angiographically defined coronary artery disease in patients with aortic valve replacement and trends during a ten-year period. METHODS: We performed a retrospective cross-sectional study of patients undergoing aortic valve replacement between 1988 and 1998 in our institution. Patients with a history of coronary artery disease and patients younger than 25 years were excluded. Coronary atherosclerosis was defined as one or more coronary artery luminal stenosis of 50% or more on preoperative coronary angiography. RESULTS: During the study period 1339 patients had aortic valve replacement in our institution, data on 1322 (98%) were available for analysis. Previous coronary artery disease was documented in 124 patients (10%). After exclusion of 17 patients (no angiography), data on a total of 1181 patients were analysed. Coronary atherosclerosis was present in 472 patients (40%) on preoperative coronary angiography. Several well-known risk factors of ischaemic heart disease were associated with coronary atherosclerosis. The prevalence of angiographically defined coronary atherosclerosis varied between 30% and 50% per year. There was, however, no significant trend during the study period. Multivariate analyses, to adjust for potential differences in risk factors during the observation period, did not change this conclusion. CONCLUSIONS: The prevalence of angiographically defined coronary artery disease in patients scheduled for aortic valve replacement is still high. From 1988 to 1998, no significant change was observed in angiographic measures of coronary atherosclerosis in patients with aortic valve replacement. Therefore, it is advised to perform coronary angiography before aortic valve surgery. PMID- 25696088 TI - Methods in molecular cardiology: protein analysis. AB - Several protein analysis techniques are described in this review to give insight into the potential applications for research. Protein analysis can be performed in several ways. All techniques are derived from the same general principle, the migration of charged particles in an electrical field. Electrophoresis of biomolecules, like proteins, provides the possibility to identify and characterise the molecules based upon different chemical properties. Immobilisation of the proteins after electrophoresis on paper is necessary to allow easy handling of the materials (blotting). These techniques also provide information on the state of a protein, whether it is activated or inactivated. To show the use of the described techniques in cardiology, two applications are provided in this review. PMID- 25696089 TI - C-reactive protein as a pro-inflammatory mediator in cardiovascular disease by its ability to activate complement: additional proof and hypothetical mechanisms. AB - This study was financially supported by the Netherlands Heart Foundation, grant numbers 93-119 and 97-088. Dr. Niessen is a recipient of the Dr. E. Dekker programme of the Netherlands Heart Foundation (D99025). PMID- 25696090 TI - The impact factor of leading cardiovascular journals: where is your paper best cited? PMID- 25696092 TI - Paradoxical thromboembolism. PMID- 25696091 TI - Imaging of a non-coronary sinus of Valsalva aneurysm with transthoracic echocardiography and multi-slice computed tomography. AB - A 46-year-old female with a giant aneurysm of the non-coronary sinus of Valsalva, associated with moderate aortic valve regurgitation, is described. The aneurysm was detected by echocardiography in a patient who was complaining of paroxysmal palpitations. The patient was accepted for aneurysmectomy. In this case report the possible aetiologies and clinical aspects of the aneurysm are reviewed. Treatment and the role of multi-sliced computed tomography (MSCT) in heart disease are discussed. PMID- 25696093 TI - ? PMID- 25696095 TI - Einthoven dissertatie cardiologie prijzen 2001. PMID- 25696094 TI - ? PMID- 25696096 TI - ? PMID- 25696097 TI - Familial primary arrhythmia syndromes: Nice to know or need to know. PMID- 25696098 TI - Smoking behaviour of patients undergoing cardiac surgery. AB - OBJECTIVES: Investigate smoking behaviour and opinions on tobacco use in patients undergoing cardiac surgery. METHODS: In this descriptive study, 200 patients were preoperatively asked to complete a questionnaire on their 'smoking habits'. Smoking behaviour, smoking cessation, tobacco and health, smoking in hospital and smoking after the operation were the main subjects. Eighty percent of the questionnaires (161 patients) could be used in the study. The total group was divided into three groups: group A: patients smoking at the moment of hospitalisation, group B: patients who had stopped smoking and group C: patients who had never smoked. RESULTS: There is a difference in the answers between the three groups. For most patients the relation between tobacco use and cardiovascular disease is not clear; there is obviously an information gap. More than 50% of the patients do not agree with smoking in hospital, not even in 'smokers rooms'. Most patients have the intention of stopping smoking after their heart operation. This is an individual decision and support seems minimal. CONCLUSION: This study confirms that the relation between smoking and cardiovascular diseases is not clear for many cardiac patients. Hospitalisation can be a good moment for smoking cessation, but support is necessary. PMID- 25696099 TI - Early and late effects of coumarin therapy started before percutaneous coronary intervention: Clinical, angiographic and cost-effective outcome of the Balloon Angioplasty and Anticoagulation Study (BAAS). AB - BACKGROUND: Coronary angioplasty frequently creates a thrombogenic surface with subsequent mural thrombosis that may lead to acute complications and possibly stimulates the development of restenosis. Whether coumarins can prevent these complications is unclear. METHODS: In the Balloon Angioplasty and Anticoagulation Study (BAAS), the effect of coumarins started before the procedure on early and late outcome was studied. Patients were randomised to aspirin only or to aspirin plus coumarins. Half of the patients were randomised to undergo six-month angiographic follow-up. Study medication was started one week before coronary angioplasty and the target international normalised ratio (INR) was 2.1-4.8 during angioplasty and six-month follow-up. 'Optimal' anticoagulation was defined as an INR in the target range for at least 70% of the follow-up time. In addition, cost-effectiveness of coumarin treatment was measured. RESULTS: At one year death, myocardial infarction, target-lesion revascularisation and stroke were observed in 14.3% of the 530 patients randomised to aspirin plus coumarin versus in 20.3% of the 528 patients randomised to aspirin alone (relative risk 0.71; 95% CI 0.54-0.93). The incidence of major bleedings and false aneurysms during hospitalisation was 3.2% and 1.0%, respectively, (relative risk 3.39; 95% CI 1.26-9.11). Optimal anticoagulation was an independent predictor of late thrombotic events (relative risk, 0.33; 95% CI, 0.19-0.57). Quantitative coronary analysis was performed of 301 lesions in the ASA group and of 297 lesions in the coumarin group. At six months, the minimal luminal diameter was similar in the ASA and coumarin group. However, optimal anticoagulation was an independent predictor of angiographic outcome at six months. Optimal anticoagulation led to a 0.21 mm (95% CI: 0.05-0.37) larger MLD as compared with suboptimal anticoagulation whereas aspirin use led to a 0.12 mm (95% CI -0.28-0.04) smaller MLD. When including all costs, the savings associated with coumarin treatment were estimated at ? 235 per patient after one year. CONCLUSIONS: Coumarin pretreatment reduces early and late events in patients undergoing percutaneous coronary intervention at the expense of a small increase in nonfatal bleeding complications. Furthermore, an optimal level of anticoagulation is associated with a significantly better outcome as compared with a suboptimal level of anticoagulation. In addition, coumarin treatment reduces costs. PMID- 25696100 TI - Technique of pulmonary vein isolation by catheter ablation. AB - In selected patients with atrial fibrillation, the fibrillation episodes may be initiated by single or short bursts of ectopy often originating from one or more pulmonary veins (PVs). Therefore, electrical isolation of these veins by catheter ablation is currently being explored as a treatment modality for patients with paroxysmal and even more permanent types of atrial fibrillation. At present, two different techniques are used: 1) selective ablation of electrical connections between left atrium and myocardial sleeves inside the PVs; and 2) contiguous encircling lesions around and outside the PV ostia. With both techniques, moderate to high success rates have been reported with a limited follow-up duration. Both types of procedure are very complex and require a highly skilful team. With the variable anatomy of the PVs, non-invasively acquired angiographic images may serve as a roadmap for catheter manipulation. Modern three-dimensional catheter navigation techniques can be applied to facilitate accurate catheter positioning with limited fluoroscopic exposure. Experimental and clinical research is needed to define patient selection criteria. PMID- 25696101 TI - Surgical revascularization for 'atherosclerotic' coronary artery aneurysms associated with multiple obstructive coronary artery disease. AB - Coronary artery aneurysms (CAA) were originally described in a series of post mortem studies but are now more commonly observed during the widely used coronary angiography. This article reports on four adult patients with CAA associated with obstructive coronary atherosclerosis. Arterial and venous conduits were successfully performed in all four. The aetiology and treatment are discussed. PMID- 25696103 TI - ? PMID- 25696102 TI - Alternating bundle branch block. PMID- 25696104 TI - ? PMID- 25696105 TI - ? PMID- 25696106 TI - Unexpected news from the scientific sessions of the American College of Cardiology. PMID- 25696107 TI - Left ventricular assist device as bridge to transplantation in patients with end stage heart failure: Eight-year experience with the implantable HeartMate LVAS. AB - OBJECTIVE: To evaluate the use of left ventricular assist devices (LVAD) as bridge to heart transplantation (HTx) in patients with end-stage heart failure. METHOD: Between March 1993 and December 2001, 38 patients with refractory end stage heart failure underwent HeartMate LVAD (Thoratec, Pleasanton Calif.) implantation. RESULTS: A total of 33 of the 38 patients (87%) survived the implantation and perioperative period. There were five perioperative deaths (13%), two due to right ventricular failure, two as a result of bleeding and one probably due to septic shock at the time of LVAD implantation. Three patients (9%) died late in the postoperative period due to septic shock, mechanical failure of the device and a cerebral embolus resulting from LVAD endocarditis, initiated by an acute cholecystitis. Twelve patients (32%) had one or more infectious episodes during long-term assist, of which one patient died. Four patients are still on the device, waiting for a heart transplantation. Twenty-six patients (76%) underwent HTx after 206+/-129 days of support. CONCLUSION: These results show the efficacy of LVAD support as a bridge to heart transplantation in patients with end-stage heart failure. Major long-term complications are infections and mechanical failure of the device. PMID- 25696108 TI - DDDR pacing for symptomatic patients with hypertrophic obstructive cardiomyopathy: The first experience in the Netherlands with pacing in HOCM. AB - BACKGROUND: Hypertrophic obstructive cardiomyopathy (HOCM) is a primary cardiac disorder with a heterogeneous expression. When medical therapy fails in patients with symptomatic HOCM, three additional therapeutic strategies exist: ventricular septal myectomy, alcohol-induced percutaneous transluminal septal myocardial ablation (PTSMA) of the first septal branch of the anterior descending artery and pacemaker implantation. In this paper we present the results of seven patients in whom a dual-chamber pacemaker was implanted to reduce the gradient in the left ventricular outflow tract (LVOT) and to relieve their symptoms. METHODS: In patients with drug refractory symptomatic HOCM, not eligible for surgery, pacemaker therapy was recommended. Symptomatic HOCM was defined as symptoms of angina and dyspnoea, functional class NYHA 3-4 and a resting LVOT gradient during Doppler echocardiography of more than 2.75 m/s (30 mmHg). In these patients, a dual-chamber pacemaker was implanted with a right ventricular lead positioned in the right ventricular apex and an atrial lead positioned in the right atrial appendage. In all patients the AV setting was programmed between 50 and 100 ms, using Doppler echocardiography to determine the optimal filling and to ensure ventricular capture. RESULTS: A statistically significant reduction of the LVOT gradient was observed in all patients. The pre-implantation gradient in the LVOT measured by Doppler echocardiography varied from 3-5.8 m/s with a mean of 4.7+/ 1.1 m/s. The post-implantation gradient varied from 1.4-2.6 m/s with a mean of 1.9+/-0.4 m/s (p<0.001). Symptomatic improvement was present in all patients. NYHA functional class went from 3-4 (mean 3.1+/-0.5) pre-implantation to 1-2 mean (1.3+/-0.4) after implantation (p<0.001). During a mean follow-up of 2.3+/-1.1 years, the improvement in functional class was maintained. CONCLUSION: Our preliminary results demonstrate that dual-chamber pacing is an effective and safe treatment for symptomatic patients with HOCM. PMID- 25696109 TI - Cardiac rehabilitation and the changing cardiac rehabilitation directions in Hoensbroeck rehabilitation centre. AB - Hoensbroeck Rehabilitation Centre has been providing inpatient and outpatient cardiac rehabilitation services since 1980. In these twenty years the patient population has changed considerably. Rehabilitation is currently focussing on the complex and often old patient. The programme that has been developed during this period consists of standard activities that are mainly group oriented. However, certain activities are provided on an individual basis. Based upon this variety of activities, a tailor-made programme can be composed for every individual patient. If the Hoensbroeck programme is compared with the directions given by the Dutch Society of Cardiology and the Netherlands Heart Foundation, the main difference is the use of an integrated approach instead of separate modules. In our view, this is a must for complex cardiac rehabilitation. PMID- 25696110 TI - Successful aortic valve replacement in a patient with AIDS. AB - In trying to assess the benefit of cardiac surgery in AIDS patients, the question arises whether a patient with a deficient immune system can tolerate open heart surgery well enough to make the operation worthwhile. Surgical procedures and cardiopulmonary bypass have been noted to alter immune function (Diettrich et al., Ide et al.). Therefore, the presence of clinical AIDS is often still regarded as a contraindication to cardiac surgery. In this report we describe an AIDS patient who developed endocarditis of the native aortic valve. The endocarditis was successfully treated with antibiotic drugs, but the patient was left with damaged valves. Over the months he developed a massive aortic insufficiency and underwent aortic valve replacement. The patient did well after surgery, and is alive and well 18 months after the operation, suggesting that cardiac surgery might be a good and valuable treatment option in AIDS patients. PMID- 25696112 TI - ? PMID- 25696111 TI - Two chamber pacemaker implantation and a persistent left superior caval vein. PMID- 25696114 TI - New perspectives on clopidogrel in the acute and long-term management of atherothrombosis: ACC, 51st Annual Scientific Session, Atlanta, 17-20 March 2002. PMID- 25696113 TI - ? PMID- 25696115 TI - Promoter methylation of fas apoptotic inhibitory molecule 2 gene is associated with obesity and dyslipidaemia in Chinese children. AB - Fas apoptotic inhibitory molecule 2 (FAIM2) is an obesity-related gene, but the mechanisms by which FAIM2 is involved in obesity are not understood. Epigenetic alterations are important factors in the development of obesity. The purpose of this study was to investigate the potential associations of FAIM2 promoter methylation with obesity and components of dyslipidaemia in Chinese children. We studied FAIM2 promoter methylation in 59 obese and 39 lean children using the Sequenom MassARRAY platform. The methylation levels at 8 CpG sites in the FAIM2 promoter were significantly different between the obese and lean subjects, especially the methylation level at CpG site 500 (p = 0.01). The methylation levels at several of the examined CpG sites were significantly associated with dyslipidaemia and its components after adjusting for age, gender and body mass index (BMI). The methylation levels at two CpG sites (sites -362 and -360 and site -164) were highly significantly associated with high level of triglycerides (p = 0.00002 and 0.0009, respectively). This study provides the first evidence that the methylation levels of the FAIM2 promoter are significantly associated with obesity and are independently associated with dyslipidaemia and its components in Chinese children. PMID- 25696116 TI - Oral nitrite therapy improves vascular function in diabetic mice. AB - AIM: We tested the hypothesis that short-term oral sodium nitrite supplementation would improve vascular dysfunction in obese, diabetic mice. METHODS AND RESULTS: Vascular function was determined in control mice and in db/db mice receiving drinking water with or without sodium nitrite (50 mg/L) for 5 weeks. Nitrite supplementation increased plasma nitrite concentrations in db/db mice (0.19+/ 0.02 uM vs 0.80+/-0.26 uM; p < 0.05). Db/db mice had lower endothelium-dependent dilation (EDD) in response to increasing doses of acetylcholine versus heterozygous control mice (71.2% +/- 14.3% vs 93% +/- 7.0%; p < 0.05), and sodium nitrite supplementation restored endothelium-dependent dilation to control levels (92.9% +/- 2.3% vs 93% +/- 7.0%; p < 0.05). The improvement in endothelial function was accompanied by a reduction in intrinsic stiffness, but not by alterations in plasma or vascular markers of inflammation. CONCLUSION: These data suggest that sodium nitrite may be a novel therapy for treating diabetes-related vascular dysfunction; however, the mechanisms of improvement are unknown. PMID- 25696117 TI - C-peptide as a risk factor of coronary artery disease in the general population. AB - OBJECTIVE: To analyse the association between serum C-peptide and coronary artery disease in the general population. METHODS: Follow-up study of 6630 adults from the general population. They were stratified into group 1 (no insulin resistance: C-peptide < third tercile and glycaemia < 100 mg/dL), group 2 (initial insulin resistance: C-peptide ? third tercile and glycaemia < 100 mg/dL) and group 3 (advanced insulin resistance: glycaemia ? 100 mg/dL). RESULTS: After 3.5 years of follow-up, group 2 had a higher incidence of myocardial infarction (relative risk (RR) = 4.2, 95% confidence interval (CI) = 1.7-10.6) and coronary artery disease (RR = 3.5, 95% CI = 1.9-6.6) than group 1. Group 3 also had increased incidences of both diseases. In multivariable analysis of the entire population, groups 2 and 3 showed significant risks of myocardial infarction and coronary artery disease (RR > 3 and RR > 2, respectively). However, when people with diabetes were excluded, the increased risks were corroborated only in group 2 for myocardial infarction (RR = 2.8, 95% CI = 1.1-6.9; p = 0.025) and coronary artery disease (RR = 2.4, 95% CI = 1.3-4.6; p = 0.007). CONCLUSION: Elevated C-peptide is associated with the incidence of myocardial infarction and coronary artery disease in the general population. It can be an earlier predictor of coronary events than impaired fasting glucose. PMID- 25696118 TI - 100 years of electrocardiography; who was Willem Einthoven? (1860-1927). PMID- 25696119 TI - A large family characterised by nocturnal sudden death. AB - BACKGROUND: We recently identified a novel mutation in large family characterised by premature nocturnal sudden death. In the present paper we provide an overview of the findings in this family. METHODS: From 1958 onwards, when the first patient presented, we collected clinical data on as many family members as possible. After identification in 1998 of the underlying genetic disorder (SCN5A, 1795insD), genotyping was performed diagnostically. RESULTS: Since 1905 unexplained sudden death occurred in 26 family members, 17 of whom died during the night. Besides sudden death, symptomatology was rather limited; only six patients reported syncopal attacks. In one of them, a 13-year-old boy, asystolic episodes up to nine seconds were documented. Until now, the mutation has been found in 114 family members (57 males, 57 females). Carriers of the mutant gene exhibited bradycardia-dependent QT-prolongation, intrinsic sinus node dysfunction, generalised conduction abnormalities, a paucity of ventricular ectopy, and the Brugada sign. Cardiomyopathy or other structural abnormalities were not found in any of the carriers. Electrophysiological studies showed that mutant channels were characterised by markedly reduced INa amplitude, a positive shift of voltage-dependence of activation and a substantial negative shift of voltage-dependence of inactivation of INa. From 1978 onwards, a pacemaker for anti-brady pacing was implanted for prevention of sudden death. In patients in whom a prophylactic pacemaker was implanted no unexplained sudden death occurred, whereas 5 sudden deaths occurred in the group of patients who did not receive a pacemaker. CONCLUSION: We have described a large family with a SCN5A-linked disorder (1795insD) with features of LQT3, Brugada syndrome and familial conduction system disease. Anti-brady pacing was successful in preventing sudden death. The mode of death is possibly bradycardic. PMID- 25696120 TI - Molecular imaging of cell death in intracardiac tumours: A new approach to differential diagnosis in cardiac tumours. AB - BACKGROUND: Primary endocardial tumours are rare, but may impose a difficult clinical problem. The definite diagnosis regarding the nature of the tumour is often made after surgery. This is due to the fact that current non-invasive imaging techniques are unable to inform us about the nature of the tumour. In addition, invasive techniques can not be used to obtain biological information of the tumour in these cases, because they carry a high risk of embolic complications. OBJECTIVE: To assess the possibility of a novel modality of imaging, molecular imaging, in the diagnosis of primary intracardiac tumours. METHODS: We evaluated two patients with a primary cardiac tumour. Prior to therapy, we infused human recombinant annexin-V Tc99-m and thallium 201. We used a dual isotope single photon emission computed tomography technique. This allowed us to obtain information about the relation between the anatomical position of the left ventricle and the uptake of the labelled annexin-V within the thoracic cavity. RESULTS: The patient with a malignant primary cardiac tumour showed uptake of labelled annexin-V within the area of the tumour. After surgery, the malignant nature was confirmed by histological analysis. The patient with a benignant intracardiac tumour showed no uptake of annexin-V within the area of the tumour. CONCLUSION: This novel imaging technique, molecular imaging, may be of help to differentiate non-invasively between a malignant and benignant primary intracardiac tumour. PMID- 25696121 TI - Cardiac sarcoidosis: Case-studies and a brief review of the literature. AB - Sarcoidosis is a multi-system granulomatous disorder of unknown aetiology. Symptomatic cardiac involvement occurs in approximately 5% of patients. The prevalence of sarcoidosis in the Netherlands is unknown, but estimated to be approximately 20 per 100,000 population (3200 patients). We report on five patients who presented with different manifestations of cardiac sarcoidosis, and give a brief review on the current management of this condition. Magnetic Resonance Imaging (MRI) can be of great help in diagnosing this condition as well as in the follow-up of the response to therapy. PMID- 25696122 TI - A usual presentation of an unusual diagnosis. AB - Chest pain is one of the most common acute medical emergencies and a significant proportion of cases will manifest in one of the acute coronary syndromes. We report a case in which an intermittent non-specific chest pain led to the detection of primary mediastinal large B-cell lymphoma. PMID- 25696123 TI - Contrast medium echocardiography-assisted pericardiocentesis of loculated pericardial fluid. PMID- 25696124 TI - ? PMID- 25696125 TI - ? PMID- 25696126 TI - Adults with congenital heart disease: a growing population. PMID- 25696127 TI - The role of predicted intracranial bleeding risk in the choice of reperfusion strategy in patients with acute myocardial infarction. AB - OBJECTIVES: Intracranial haemorrhage after thrombolytic therapy for acute myocardial infarction occurs in 0.5-3% of patients. Prediction models have been developed to predetermine the intracranial bleeding risk, but have rarely been used for assigning the optimal reperfusion strategy. This might result in the use of thrombolytic therapy when primary PTCA would be preferable. METHODS: Prospective data were gathered in 1365 candidates for reperfusion therapy. Risk of intracranial haemorrhage was determined with a risk score derived from large scale clinical trials. Patients were divided into three groups based on their risk of intracranial haemorrhage: <1%, 1-3% and >3% and stratified by age. RESULTS: An intracranial bleeding risk exceeding 3% was found in 120 patients (9%). These high-risk patients were often treated with thrombolysis (87%). Intracranial bleeding actually occurred in four out of 120 patients (3.3%) in this highest risk group, while no bleeding occurred in the other risk groups. CONCLUSION: The actual incidence of intracranial bleeding is similar to the predicted bleeding risk in high-risk patients. These high-risk patients are predominantly older than 70 years. Nearly all patients exceeding a 3% risk of intracranial haemorrhage were treated with thrombolytic therapy. Primary angioplasty should be preferred in patients aged over 70 years since success rates of direct PTCA are no worse in elderly compared with younger patients. PMID- 25696128 TI - Angiographic determinants of infarct size after successful percutaneous intervention for acute ST-elevation myocardial infarction: the impact of distal embolisation. AB - BACKGROUND: We investigated the impact of distal embolisation and other angiographic determinants in patients after successful primary angioplasty for acute myocardial infarction. METHODS: Angiographic data were assessed on the coronary angiogram carried out immediately after successful (TIMI 2 or 3) coronary angioplasty in 631 consecutive patients with acute myocardial infarction. Embolisation was defined as a distal filling defect with an abrupt 'cutoff' in >=1 of the peripheral coronary artery branches of the infarct-related artery, distal to the site of angioplasty. Endpoints were left ventricular ejection fraction (LVEF) and enzymatic infarct size. RESULTS: Left anterior descending artery related myocardial infarction, impaired myocardial blush and distal embolisation were independent determinants of infarct size. Distal embolisation was present in 102 patients (16%) and was associated with a larger enzymatic infarct size (LDH Q48 2250 vs. 1532, p=0.001) and a lower LVEF (41% vs. 44%, p=0.04). There was no difference in the frequency of distal embolisation between patients treated with or without stents. CONCLUSIONS: In successful primary angioplasty, infarct-related artery, impaired myocardial blush and distal embolisation are independent determinants of infarct size. Distal embolisation can be visualised in 16% of the patients and is associated with a larger enzymatic infarct size and lower LVEF. Intracoronary stenting is not associated with an increased risk of distal embolisation during primary angioplasty. PMID- 25696129 TI - Ischaemia-induced cellular electrical uncoupling and ventricular fibrillation. AB - Sudden death resulting from ventricular fibrillation (VF) during acute myocardial ischaemia forms an important contribution to mortality associated with infarction. Its temporal distribution is not known, but 30% of mortality occurs within the first 60 minutes. Two distinct phases of arrhythmias have been demonstrated in laboratory animals subjected to coronary occlusion. The mechanism of the second, 1B phase (which is associated with more lethal events than the first, 1A phase) is largely unknown but appears to be related to cellular uncoupling, i.e. the closure of gap junctions. Gap junctions are intercellular communication channels that are permeable for ions and metabolites and are necessary for normal propagation of electrical activation. It has been suggested that closure of gap junctions results in a largely inhomogeneous substrate in which microreentry forms the electrophysiological mechanism for VF. However, there is growing support for the hypothesis that arrhythmias relate to the persistence of residual coupling rather than to the occurrence of uncoupling. With this, the ischaemic midmyocardium can depress the intrinsically viable tissue of the ischaemic subepicardium and subendocardium and cause conduction slowing and block leading to arrhythmias. Progression of uncoupling terminates this interaction and allows the subepicardium and subendocardium to recover. Indeed, electrophysiological properties recover subepicardially whereas the midmyocardial tissue becomes inexcitable. In addition, activation patterns during VF become restricted to the two-dimensional plane of the subepicardium. These observations support the hypothesis of residual coupling as an arrhythmogenic mechanism during the delayed phase of acute ischaemia. Whether this mechanism is equally important in patients with remodelled and failing hearts can at this time only be speculated upon. However, modifying intercellular coupling might turn out a new antiarrhythmic therapy. PMID- 25696131 TI - A continuous abdominal murmur at preoperative cardiovascular examination. PMID- 25696130 TI - Fast and slow narrow complex tachycardia in one patient: two of a kind? AB - A 35-year-old female was referred to our hospital. For more than ten years, she had had complaints of two types of paroxysmal palpitations, both with a sudden onset. The first type was rapid and often accompanied by light-headedness; the second she described as much less rapid, better tolerated, and often terminated by the Valsalva manoeuvre. The incidence and duration of both types of paroxysms were increasing. In the emergency room of the referring hospital, the tachycardia was terminated with intravenous verapamil. The electrophysiological study revealed normal conduction parameters. Premature atrial beats (due to catheter manipulation) or delivered atrial extra stimuli over a wide range easily induced two types of tachycardia. AV node modification by radiofrequency ablation using the posterior approach was performed. With this approach, RF ablation of the caudal extension of the AV node is performed, which modifies the slow pathway, so that the reentrant circuit is interrupted. After this intervention, no tachycardia whatsoever could be induced and during followup (8 months), no recurrent arrhythmia of any kind occurred. PMID- 25696132 TI - ? PMID- 25696134 TI - The days of molecular medicine: San Diego 13-17 March 2002. PMID- 25696133 TI - ? PMID- 25696136 TI - Abstracts of the scientific meeting of the Netherlands Society of Cardiology (NVVC): 24-26 October 2002, De Heerlickheijd, Ermelo. PMID- 25696135 TI - ? PMID- 25696137 TI - MRI in the detection of stenosis in coronary artery bypass grafts: are invasive techniques still needed? PMID- 25696138 TI - Decision-making in aortic valve replacement: bileaflet mechanical valves versus stented bioprostheses. AB - BACKGROUND: Valve prosthesis selection for patients who require aortic valve replacement is dependent on several interrelated factors. Often, more than one valve type seems suitable for the individual patient and selection of a valve type may be difficult. METHODS: The application of an evidence-based microsimulation model as an objective tool to support the choice between a bileaflet mechanical prosthesis and a stented bioprosthesis in the individual patient is described. In addition, a pilot study investigating the effect of knowledge gained by this microsimulation model on prosthetic valve choice by cardiothoracic surgeons and cardiologists is presented for two hypothetical patients. RESULTS: After implantation of a mechanical valve, bleeding and thromboembolism are common, especially in the elderly. After implantation of a bioprosthesis, reoperation for structural failure is the most important valve related complication, especially in younger patients. Life expectancy after aortic valve replacement is markedly reduced compared with the general Dutch age matched population, regardless of the type of valve implanted. In the pilot study knowledge gained by the microsimulation model caused a shift in the preference towards a mechanical prosthesis in clinical experts. CONCLUSION: Microsimulation incorporating current epidemiological data provides an objective tool to estimate prognosis for individual patients after aortic valve replacement with different valve prostheses. It may develop towards a useful clinical decision support system for valve prosthesis selection. PMID- 25696139 TI - The importance of patency of the infarct-related artery in treatment of patients with acute myocardial infarction. AB - OBJECTIVE: To study the impact of patency of the infarct-related artery on the coronary angiogram, both before and after primary angioplasty for acute myocardial infarction, on 30-day mortality. METHOD: Data of 1702 consecutive patients treated with primary angioplasty for acute myocardial infarction were collected prospectively from 1994 to 2000. RESULTS: Patients with a (partially) patent infarct artery before primary angioplasty had less damage to the myocardium and a lower 30-day mortality (1.6% versus 3.4%, p=0.04) compared with patients with an occluded artery. Patients with pre-hospital treatment with aspirin and heparin more often presented with a patent artery before angioplasty (31% versus 20%, p<0.001). After primary angioplasty, 95% of patients had a patent artery with a 30-day mortality of 2.2%. The 5% of patients with failed angioplasty had extensive myocardial damage and a 30-day mortality rate of 17%. CONCLUSION: Patency of the infarct-related artery on the coronary angiogram, both before and after primary angioplasty, has a major impact on 30-day mortality. PMID- 25696141 TI - Arrhythmogenic right ventricular dysplasia and sudden cardiac death in endurance athletes. AB - Arrhythmogenic right ventricular dysplasia (ARVD) is a cardiomyopathy with several time-dependent clinical presentations. The clinical characteristics depend on the penetration grade of the disease. There are two different histological patterns consisting of a lipomatous and a fibrolipomatous form. The presence of arrhythmias in the ARVD syndrome constitutes an important risk factor for sudden cardiac death in athletes. In this article, we describe two professional endurance athletes who died suddenly. One of these athletes had asymptomatic ARVD, the other had symptomatic polymorphic ventricular tachycardias. Both athletes showed fatty penetration of the disease in both the right and left ventricle; one of them also showed fatty involvement at the atrial level and in the other there were signs of myocarditis consistent with ARVD. In the last few years magnetic resonance imaging has become an important diagnostic tool in patients with ARVD. PMID- 25696140 TI - Arrhythmogenic right ventricular dysplasia/cardiomyopathy: new avenues for diagnosis and treatment. AB - Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is a heart muscle disorder of unknown course that is characterised pathologically by fatty or fibrofatty replacement of the right ventricular myocardium and electrical instability. Clinical manifestations include structural and functional malformations of the right ventricle, electrocardiographic abnormalities, and presentation of ventricular tachycardias with left bundle branch pattern or sudden death. The disease is often familial with an autosomal inheritance. In addition to right ventricular dilatation, right ventricular aneurysms are typical deformities of ARVD/C and they are distributed in the so-called 'triangle of dysplasia', i.e. the right ventricular outflow tract, apex and infundibulum. Ventricular aneurysms at these sites can be considered highly suggestive for ARVD/C. Another typical hallmark of ARVD/C is fatty or fibrofatty infiltration of the right ventricular free wall with potential extension to the left ventricle. These functional and morphological characteristics are relevant to clinical imaging investigations such as contrast angiography, echocardiography, radionuclide angiography, ultrafast-computed tomography and magnetic resonance (MR) imaging. Among these techniques, MR imaging allows the most comprehensive assessment of the heart, in particular because it provides functional and flow dynamic information in addition to anatomic images. Furthermore, MR imaging offers the specific advantage of visualising adipose infiltration as a bright signal of the right ventricular myocardium. Non-pharmacological treatment by radio-frequency ablation and implantable defibrillators will play an increasing role in the treatment of patients with ARVD/C, especially in case of drug ineffectivity. Despite new diagnostic and therapeutic approaches in ARVD/C, there remain many unanswered issues since the current guidelines present criteria that are highly specific but lack sensitivity. Therefore, optimal assessment of diagnostic criteria would require a prospective evaluation from a large population obtained by an international registry. PMID- 25696142 TI - Role of echocardiography in diagnosis of left atrial myxoma. PMID- 25696143 TI - ? PMID- 25696144 TI - ? PMID- 25696145 TI - Evaluation of antiatherosclerotic drugs by Raman spectroscopy. PMID- 25696146 TI - Recent breakthroughs in the genetics of atrial fibrillation. PMID- 25696147 TI - Long-term clinical outcome of ST-segment elevation myocardial infarction patients with and without diabetes mellitus in the Zwolle trial. AB - OBJECTIVES: We sought to compare long-term survival after ST-segment elevation myocardial infarction (STEMI) in patients with and without diabetes mellitus (DM) treated with primary percutaneous coronary intervention (PCI) or thrombolytic therapy. BACKGROUND: DM is an adverse prognostic factor after STEMI. However, there is only limited information about long-term clinical outcome in STEMI patients with DM treated with PCI or thrombolysis. METHODS: Patients with STEMI (n=395) were randomised to treatment either with intravenous streptokinase or PCI. Mean follow-up was 8+/-2 years. We studied long-term mortality of patients with DM (n=32) and without DM (n=363) and the interaction with the treatment regimen. RESULTS: After eight years, a total of 17 patients with DM (53%) died compared with 88 (24%) patients without DM (OR 3.5, p<0.001). Reduced left ventricular ejection fraction (LVEF) after STEMI was more often present in patients with DM compared with patients without DM (31% vs. 15%, p=0.01). Multivariate analysis revealed that DM (OR 2.6, 95% CI 1.4-4.7, p=0.002), reduced LVEF (OR 2.4, 95% CI 1.5-3.8, p<0.001) and age >=60 years (OR 2.4, 95% CI 1.5 3.8, p<0.001) were independent risk factors for long-term mortality. Patients with DM treated with PCI had less LVEF (13% vs. 53%, p=0.01) and lower long-term mortality rates (38% vs. 69%, p=0.08) compared with treatment with thrombolysis. CONCLUSIONS: STEMI patients with DM are a high-risk group with higher long-term mortality rates compared with patients without DM. PCI is the treatment of choice, particularly in DM patients. PMID- 25696148 TI - Identification of patients at risk for early out-of-hospital mortality after redocoronary artery surgery. AB - OBJECTIVE: Analyse risk factors and construct a predictive model for identification of patients at risk of early out-of-hospital mortality after coronary reoperations (RECABG). METHODS: 505 patients, discharged from hospital after a RECABG (1987-1998), were studied by univariate and multivariate analysis. A stepwise selective procedure (p<0.05) was used to identify a subset of variables with prognostic value for early out-of-hospital mortality. This subset was used to calculate a prognostic score 'S' and a predicted probability 'p' for early out-of-hospital mortality, p=1/1+ e-s. Sensitivity analysis was used for evaluation. RESULTS: The best predictive variables for early out-of-hospital mortality were diabetes (p=0.002), lung disease (p=0.05), emergency operation (p=0.0001) and a perioperative myocardial infarction (p=0.0001). Emergency operation (p=0.001) and antegrade/retrograde cardioplegia (p<0.0000) were independent predictors of a perioperative myocardial infarction. The prognostic accuracy (ROC area) was 86%. Patients were classified into low risk (5%), intermediate risk (15%), high risk (30%) and very high risk (>=40%). A predicted probability of >=0.40 was used as cut-off point. The specificity of this test was 99%, sensitivity 33%, predictive value of a positive test 79%, and 95% for a negative test. CONCLUSION: The results show that patients discharged from hospital after RECABG can be stratified according to their early out-of-hospital risk. A perioperative myocardial infarction is the major independent risk factor and can be affected by use of retrograde cardioplegia. PMID- 25696149 TI - Methods in molecular cardiology: quantitative real-time polymerase chain reaction. AB - Changes in mRNA expression levels occur during physiological and pathological processes in the cardiovascular system. An increase in DNA transcription results in increased mRNA levels and will subsequently cause an increase in levels of proteins that regulate processes inside and outside the cell. To determine alterations in mRNA levels, traditional methods such as Northern blotting and ribonuclease protection assay can be used; however, large amounts of RNA are necessary and the methods are very labour intensive. In this review, we focus on one of the newest advancements in polymerase chain reaction (PCR) technology, real-time or quantitative PCR, using small amounts of RNA to determine expression levels. We discuss the technique in general and describe two different approaches. PMID- 25696150 TI - Wake up call for Dutch cardiologists. AB - Drug-eluting stents have been available in the Netherlands since April 2002. Despite the revolutionary randomised data demonstrating their low rate of restenosis compared with conventional bare stents, their market penetration rate is estimated at only between 15 and 25%. The reasons are twofold - a perception that only high-risk groups benefit and that these new stents are more expensive. This article seeks to show that both high- and low-risk subgroups of patients requiring intervention benefit, and that these stents are cost-effective, both on an individual and on a societal level. It also puts forward a strong case for the immediate recognition of this new device by the insurance companies to allow Dutch patients to benefit from this remarkable technology. PMID- 25696151 TI - Between the devil and the deep blue sea: an unusual kind of late cardiac tamponade with a therapeutic dilemma. AB - A 67-year-old patient underwent a left pneumectomy because of a moderately differentiated squamous cell carcinoma. Two weeks later, while still in hospital, he suddenly experienced an acute increase in dyspnoea. Pulmonary embolism was considered. However, echocardiography showed compression of the right ventricle and right atrium by an intrapericardial mass, confirmed by computed tomography. Following signs of a large thrombus in the inferior vena cava, pericardiocentesis was considered undesirable due to possible dislocation resulting from the sudden changes in intrapericardial pressure. Re-thoracotomy was equally undesirable because of the recent operation and status of the patient. After stabilisation and extensive consulting the patient was referred for pericardiocentesis by sternotomy. Huge blood clots were removed from the pericardial space. No thrombus mass was found in the inferior vena cava. The patient recovered uneventfully. PMID- 25696153 TI - A patient with chest pain. PMID- 25696152 TI - Noncompaction cardiomyopathy. PMID- 25696154 TI - ? PMID- 25696155 TI - ? PMID- 25696156 TI - DANAMI-2: the end of the thrombolytic era. PMID- 25696157 TI - Cardiological risk factors for depressive symptoms after a first myocardial infarction. AB - OBJECTIVE: To detect possible cardiological risk factors in the acute phase of MI for developing depressive symptoms after first MI. DESIGN: Retrospective analysis of cardiac and psychiatric data of 111 consecutive patients admitted with a first MI. METHODS: During one year, all consecutive patients with a first MI, less than 12 hours chest pain and a maximal aspartate aminotransferase (ASAT) value of at least 80 U/l, admitted to the University Hospital of Maastricht, were screened for the presence of depressive symptoms using the 90-item 'Symptom checklist' (SCL-90) questionnaire at one month post-MI. Inclusion criteria were fulfilled by 111 patients; 28 patients refused to participate in the study. RESULTS: No correlation was found between LVEF, peak ASAT, peak CK value and characteristics, location or mode of treatment of the MI and depressive symptoms post-MI. A statistically significant negative correlation was found between SCL-90 depression score and cardiac tissue loss as defined by cumulative ASAT release at 24, 48 and 72 hours after the acute event (p values 0.029, 0.028 and <0.009, respectively) at the one month post-MI screening. CONCLUSIONS: No cardiological parameters were correlated to depressive symptoms post-MI. If there was a connection at all, this appeared to be a negative correlation between infarct size as measured by ASAT release and the occurrence of depressive symptoms at one month post-MI. PMID- 25696158 TI - Transcatheter pulmonary valve perforation and balloon dilatation in neonates with pulmonary atresia and intact ventricular septum. AB - BACKGROUND: Pulmonary atresia and intact ventricular septum is characterised by a great morphological variety. Treatment is not uniform. OBJECTIVE: To evaluate our experience with transcatheter valvotomy and balloon dilatation in neonates with pulmonary atresia and intact ventricular septum. DESIGN: Retrospective. METHODS: Between January 1997 and September 2000 five neonates with pulmonary atresia and intact ventricular septum underwent transcatheter valvotomy and balloon dilatation. RESULTS: The catheter intervention was performed at a mean age of 27 days (range 3-95 days). The atretic pulmonary valve was successfully perforated in all neonates. Subsequent balloon dilatation was successful in four neonates. Balloon dilatation was unsuccessful in one patient, who underwent an elective surgical valvotomy of the pulmonary valve after five days. Three patients needed a modified Blalock-Taussig shunt after a mean of 23 days. Four patients required repeated balloon dilatation after a mean of 227 days. Mean follow-up was 2.7 years (range 1-5 years). CONCLUSIONS: Transcatheter perforation of the pulmonary valve membrane and balloon dilatation is a good, safe initial therapy in selected neonates with pulmonary atresia and intact ventricular septum. This procedure can prevent open-heart surgery in these patients in the first months of life. PMID- 25696159 TI - Electrical isolation of pulmonary veins using cryothermal energy: study design and initial results. AB - : In the September 2003 issue of the Netherlands Heart Journal, the wrong figures where inserted in this article. The article is reprinted here with the correct figures. BACKGROUND: Atrial fibrillation (AF) is the most frequently encountered arrhythmia. Radiofrequency pulmonary vein (PV) ablation is promising for symptomatic paroxysmal AF, but is associated with a significant risk of PV stenosis. OBJECTIVES: To assess the efficacy of cryothermal PV ablation and the incidence of PV stenosis. METHODS: Highly symptomatic patients with paroxysmal or persistent AF were eligible for cryothermal ablation. Multislice spiral CT scans were performed before, and three months after ablation. AF burden was assessed using transtelephonic ECG recording and by telephone enquiry. RESULTS: An attempt was made to isolate 27 PVs in 15 patients. In total, 20 PVs could be isolated (74% acute success). No significant difference in PV diameter was seen before and after ablation. Five out of 12 patients with paroxysmal AF were completely without AF after one ablation procedure. An additional two patients reported a significant reduction in symptoms. In the three patients with persistent AF no improvement was reported. CONCLUSION: Cryothermal PV ablation was effective in isolation of the targeted PVs. It appears to be safe, as no PV stenosis was seen in this study three months after the ablation. Taking into account a learning curve, we consider the clinical results to be very promising. PMID- 25696160 TI - Hormone replacement therapy and heart disease: the remains of the oestrogen hypothesis. AB - BACKGROUND: While observational data for postmenopausal women using hormone replacement therapy (HRT) have shown a protective effect against cardiovascular disease, prospective, randomised trials have demonstrated a harmful effect on the vascular system. DESIGN AND RESULTS: The effects of HRT on lipids, haemostatic parameters, inflammation, and the vascular wall are described. Reasons for the different results of observational and experimental studies of HRT are postulated. The timing of hormonal supplementation seems crucial. Used chronically, HRT has no harmful effects; however, first-time use of HRT after a recent cardiovascular event results in an early increase in adverse cardiovascular events. In most observational studies, women started HRT for postmenopausal symptoms, whereas in experimental studies women started HRT 10 to 20 years or longer after the menopause. CONCLUSION: HRT has more effect in maintaining vascular health than in alleviating endothelial dysfunction. HRT is not beneficial but harmful in women at risk of a cardiovascular event. The interval between the menopause and starting HRT plays a crucial role in the effectiveness of HRT on the vascular system. PMID- 25696161 TI - New information about resynchronisation. AB - Chronic atrio-biventricular pacing appears to become a very attractive and promising additive therapy for congestive heart failure with systolic left ventricular impairment. The best results can only be achieved by an optimal interaction between the cardiologists involved. Until now no sort of cardiac intervention has ever required such close and ongoing cooperation to serve the cardiac patient. These efforts are welcomed because congestive heart failure strongly reduces the quality of mental health and physical functioning. By means of questions and answers on new information about cardiac resynchronisation, this special article aims to provide more insight into the role of this complex pacing therapy. PMID- 25696162 TI - Mechanically induced complete atrioventricular block during retrograde catheter ablation of a left-sided incessant tachycardia. AB - Concern for potentially lethal complications related to transseptal catheterisation, such as perforation of the aorta, has made this approach less attractive over the last decades. Nevertheless, this method is now increasingly being used for ablation of left-sided arrhythmias. We report a transient complication of a retrograde procedure in a patient with a left-sided 'Coumel type' incessant tachycardia. We had to proceed to transseptal catheterisation, as the complication recurred during the second attempt even when using a less rigid transaortic radiofrequency catheter. The transseptal approach using a less stiff cryoenergy catheter was performed without complications. PMID- 25696163 TI - Anomalous isolated single left origin coronary system. PMID- 25696164 TI - The AV-node revisited. PMID- 25696165 TI - ? PMID- 25696166 TI - ? PMID- 25696167 TI - Erratum: Rectification. AB - [This corrects the article on p. 383 in vol. 11.]. PMID- 25696168 TI - Abstracts Nederlandse Vereniging voor Thoraxchirurgie: 26 september 2003. PMID- 25696169 TI - Expression of euthyroid sick syndrome in postischaemic heart disease is related to increased cardiovascular mortality: new options for intervention?: Heart and hormones. PMID- 25696170 TI - Evaluation of long-term quality of life after reoperative coronary artery surgery: preliminary results. AB - OBJECTIVE: The risks of reoperative coronary artery bypass surgery (RECABG) still exceed those of a primary revascularisation and late results are not very favourable either. The subject of the present study is an evaluation of the long term quality of life after RECABG. METHODS: We studied the outcome of 541 patients who underwent a RECABG from January 1987 to December 1998. The endpoint of the study was December 2002, or the patient's death. Quality of life, using the EuroQol registration, was evaluated. RESULTS: Hospital mortality was 6.7%. Follow-up was 95.6% complete, mean 7.7 years. There were 177 late deaths. The cumulative survival rates were 83.8, 76.9, and 60.6%, and cardiac survival rates were 84.8, 78.5, and 66.5%, at the one-year, five-year and ten-year follow-up, respectively. For 255 patients (89%), NYHA and EuroQol information was complete. In total 23% of the patients were in NYHA class I, 51% in class II, 21% in class III and 5% were in class IV. In the EuroQol registration, 54% of the patients declared they had no mobility problems, 85% no problems with self-care, and 65% no problems with usual activities. However, 60% suffered from moderate pain or discomfort, and 33% from anxiety or depression. On the visual analogue scale (mean 63.5), 13% of the patients scored >90, 68% between 50 and 90, and 19% of the patients <50. CONCLUSION: The long-term results of cumulative survival and cardiac survival, and NYHA class in our patient population who underwent RECABG are comparable with other studies. Quality of life is acceptable regarding the high risk of a RECABG. PMID- 25696171 TI - First Dutch experience with percutaneous left atrial appendage transcatheter occlusion. AB - BACKGROUND: Patients with atrial fibrillation (AF) have an increased risk of thromboembolic stroke, dependent on clinical variables. Oral anticoagulation significantly decreases the risk of stroke or embolism, but sometimes this is difficult to manage and may be contraindicated. Approximately 90% of atrial thrombi in nonrheumatic AF are found in the left atrial appendage (LAA). A new device has been developed which allows percutaneous LAA occlusion (PLAATO) and might be an alternative to oral anticoagulation. Feasibility in dogs and humans was described previously. METHODS AND RESULTS: As part of an international multicentre trial, three patients received a percutaneous transcatheter LAA occlusion device. Implantations were performed without general anaesthesia, guided by intracardiac and transoesophageal echocardiography and without major complications. The implantations were well tolerated by the patients, who entered a long-term follow-up to be compared with a historical control group. CONCLUSION: Transseptal percutaneous LAA occlusion is feasible. Its role as an alternative to oral anticoagulation, however, needs to be further defined. PMID- 25696172 TI - Recently completed trials on the drug treatment of hypertension: comments on ALLHAT and ANBP-2. AB - Recently the results of two important large-scale studies on hypertension management were published and intensely debated: ALLHAT and ANBP-2. In particular the ALLHAT study was discussed and subjected to criticism. The positive and negative aspects of this study are the subject of the present survey. ALLHAT has reemphasised the important role of thiazide diuretics in the treatment of hypertension. However, there should also be an important position for the various other well-known drugs such as beta-blockers, ACE inhibitors, calcium antagonists and AT1-blockers (sartans). The choice of the drug(s) to be prescribed is largely determined by the comorbidity, which occurs frequently in elderly hypertensives. Furthermore, combination therapy is applied more and more frequently. PMID- 25696173 TI - Aortic coarctation: the need for lifelong surveillance. AB - Survival of patients with aortic coarctation improved dramatically after surgical repair became available and the number of patients who undergo surgery and reach adulthood is steadily increasing. However, life expectancy is still not as normal as in unaffected peers. Cardiovascular complications are frequent and require indefinite follow-up. Concern falls chiefly into five categories: recoarctation, endocarditis, stenotic and/or incompetent coexisting bicuspid aortic valve, aortic aneurysm formation and systemic hypertension. In this review, these complications, with particular reference to late hypertension, are discussed and strategies for the clinical management of postcoarctectomy patients are described. PMID- 25696174 TI - Ventricular fibrillation and rhabdomyolysis after administration of succinylcholine. AB - Succinylcholine is a depolarising muscle relaxant. Because of its quick onset of action, it is particularly used in situations which require urgent intubation. However, there have been several reports of cardiac arrest after administration of succinylcholine. We describe the case of a young woman who developed ventricular fibrillation and rhabdomyolysis following succinylcholine administration. Possible mechanisms and treatment are discussed. PMID- 25696175 TI - Constrictive pericarditis. PMID- 25696176 TI - ? PMID- 25696177 TI - ? PMID- 25696178 TI - ? PMID- 25696179 TI - ? PMID- 25696180 TI - Pharmacological stress: a useful exercise? PMID- 25696181 TI - Effect of physical activity after a cardiac event on smoking habits and/or Quetelet index. AB - OBJECTIVES: To further elucidate earlier findings, the present study investigated whether physical activity could serve as a positive stimulus to modify other changeable cardiac risk factors. METHODS: Participants were 140 patients who had completed a cardiac rehabilitation programme focused on physical activity. Their present level of physical activity, smoking habits and Quetelet index were investigated as well as that before the cardiac event, in retrospect. Current feelings of anxiety and depression were also assessed. Participants were divided into two categories according to their present level of physical activity after finishing the rehabilitation programme, compared with that before the cardiac event. RESULTS: It appeared that the more physically active category contained more smokers. Although many of them had quitted smoking, significantly more persisted in their smoking habits compared with the patients who did not increase their physical activity. Significantly less depression was found in the more active patients. CONCLUSIONS: Although it could not be confirmed that physical activity stimulated a positive change in smoking and Quetelet index, the more active patients appeared to be less depressed. PMID- 25696182 TI - Monophasic action potentials and Ca2+ transients in ischaemically preconditioned rabbit ventricular muscle. AB - BACKGROUND: ATP-sensitive K+ (KATP) channels play an important role in the protective mechanism underlying ischaemic preconditioning. Ample evidence indicates, however, that action potential shortening is not a prerequisite for the cardioprotective effect of preconditioning. METHODS: Monophasic action potential duration (MAPD), tissue resistance, intracellular Ca2+ (Indo-1) and mechanical activity were simultaneously assessed in arterially perfused rabbit papillary muscles. We studied four experimental protocols preceding sustained ischaemia: 1. control perfusion (n=6), 2. ischaemic preconditioning (PC; n=4), 3. pretreatment with a KATP channel blocker, glibenclamide (15 MUmol/1), prior to ischaemic preconditioning (PC+glib; n=3), 4. glibenclamide pretreatment only (Glib; n=2). RESULTS: In the PC group an increase in the diastolic Ca2+ level and a prolongation of the Ca2+ transient just prior to the induction of sustained ischaemia correlate to the postponement of the onset of irreversible ischaemic damage, as established by a rise in [Ca2+]i, electrical uncoupling and contracture. Glibenclamide antagonised these changes in the Ca2+ transient and the cardioprotection induced by preconditioning. MAPD was equal in all experimental groups. CONCLUSIONS: Prolongation of the Ca2+ transient and increase of diastolic [Ca2+]i just prior to the induction of sustained ischaemia and not action potential shortening are involved in the cardioprotective effect of ischaemic preconditioning. Therefore, a glibenclamide-sensitive mechanism, other than the sarcolemmal KATP channels, is involved in the protective effect of ischaemic preconditioning. Changes in Ca2+ metabolism may play a crucial role in ischaemic preconditioning. PMID- 25696183 TI - Should class III drugs be initiated in hospital to prevent drug-induced torsade de pointes arrhythmias? AB - OBJECTIVES: In the US, the FDA requires in-hospital institution of class III drugs. This study retrospectively assessed whether these criteria, which differ markedly from the Dutch exclusion criteria, could predict sotalol-induced torsade de pointes arrhythmias (TdP). METHOD: Oral sotalol effect in a control group (50 patients, 62+/-12 years, 23 men, 27 women) was compared with five patients developing TdP (75+/-5years, all women), using known and new (JTU area measured in lead V2) risk parameters. Paroxysmal atrial fibrillation was the most common indication for sotalol treatment. RESULTS: At baseline the strict US regulations would have identified four of five TdP patients on the basis of individual K+ levels, creatinine clearance and QTc. However, 7 of 49 controls would also have been excluded, although they did not develop documented TdP in the >2 years follow-up. Sotalol slightly increased QTc (361+/-34 to 387+/-33ms) in controls, due to heart rate reduction. In the TdP group, sotalol dramatically increased QTc (467+/-33 to 626+/-52 ms, +35%, p<0.05) accompanied by deep negative TU waves and an increased JTU area and all could be identified as risk patients. CONCLUSION: Patients developing TdP on oral sotalol can be identified using the FDA risk criteria and hospitalisation may therefore be appropriate. A European prospective study is required to investigate the costs, sensitivity and specificity of this strategy. PMID- 25696184 TI - Methods in molecular cardiology: proteome analysis. AB - Proteins are involved in virtually every cellular function, they control regulatory mechanisms and are modified in diseases (either cause or effect). To understand the function and adaptation of a cell, the researcher has to be able to identify proteins and visualise the concentrations and form in which the proteins are expressed. The technique is called 'proteomics' or 'proteome analysis'. In this article proteomics will be explained from starting material to detection and analysis of the individual proteins. It will give an indication of the work involved and how it can be implemented in cardiovascular research. PMID- 25696185 TI - Dobutamine stress magnetic resonance imaging suffices for the demonstration of myocardial ischaemia and viability. AB - We report three patients in whom dobutamine stress magnetic imaging (DS-MRI) was essential in assessing myocardial ischaemia. Two patients were referred to the cardiologist because of chest pain. Patient A had typical exertional angina and a normal resting electrocardiogram (ECG). Patient B had typical exercise-induced angina and had recently experienced an attack of severe chest pain at rest for 15 minutes. The ECG showed a complete left bundle branch block (LBBB). Patient C was referred for heart failure of unknown origin. There were no symptoms of chest pain during rest or exercise. Echocardiography in this patient demonstrated global left ventricular (LV) dilatation, systolic dysfunction and a small dyskinetic segment in the inferior wall. In all these patients exercise stress testing had failed to demonstrate myocardial ischaemia. Patients A and C produced normal findings whereas in patient B the abnormal repolarisation due to pre existent LBBB precluded a diagnosis of ischaemia. Breath-hold DS-MRI was performed to study LV wall motion and wall thickening at rest through increasing doses of dobutamine. A test was considered positive for myocardial ischaemia if wall motion abnormalities developed at high-dose levels of the drug (20 MUg/kg/min or more with a maximum of 40 MUg/kg/min) in previously normal vascular territories or worsened in a segment that was normal at baseline. Recovery of wall thickening in a previously hypokinetic or akinetic segment at a low dose of dobutamine (5-10 MUg/kg/min) was taken as proof of viability. Patients A and B developed hypokinesia progressing into akinesia at high-dose dobutamine in the anteroseptal area of the LV indicative of ischaemia. These findings were corroborated by coronary angiography demonstrating severe coronary artery disease which led to coronary artery bypass grafting (CABG) in patient A and balloon angioplasty in patient B. In patient C global recovery of LV contractions during low-dose dobutamine was followed by hypokinesia in the inferoseptal area during high-dose dobutamine. This biphasic response indicates myocardial viability as well as ischaemia. CABG was carried out because of multiple stenoses in the left coronary artery. Post-operatively LV function normalised. DS-MRI is a valuable method for detecting myocardial ischaemia and viability in patients with suspected coronary artery, and can be applied in every hospital with MRI equipment at its disposal. PMID- 25696187 TI - ? PMID- 25696186 TI - Thrombus in transit. PMID- 25696188 TI - ? PMID- 25696189 TI - Results of the CREDO study: AHA Chicago, 18 November 2002. PMID- 25696190 TI - Quality of life in adults with congenital heart disease. PMID- 25696191 TI - Corrected TIMI frame count and frame count velocity. AB - BACKGROUND: Little is known about the differences between the corrected thrombolysis in myocardial infarction (TIMI) frame count (CTFC) and the 'frame count velocity' (FCV), an estimate of blood flow velocity derived from the TFC and the length of the related vessel, in each of the three epicardial coronary arteries. METHODS: After angioplasty of 119 coronary vessels, 50 left anterior descending (LAD), 27 left circumflex (LCX) and 42 right coronary arteries (RCA), the CTFC was compared with the FCV assessed by measuring the length of the coronary arteries with an intracoronary guidewire. RESULTS: The three vessels show a significant difference in mean length (the LAD was 14.5+/-1.6 cm, LCX 12.8+/-1.9 cm and RCA 11.3+/-1.4 cm, p<0.001 for all comparisons), making it possible to convert the TFC to the FCV with reasonable accuracy without having to use a guidewire. The mean length of the LCX and the RCA was found to be considerably longer than in previous reports on which the CTFC is based. In addition, with this method the estimation of the coronary blood flow velocity in the RCA is significantly higher compared with the LAD and LCX (23.0+/-7.9 cm/sec versus 17.6+/-7.4 cm/sec and 16.4+/-6.3 cm/sec, respectively, p<0.001). CONCLUSION: With the TFC and the average length of the related coronary artery presented in this study, the FCV can be calculated for each of the three vessels resulting in a simple and, compared with the CTFC, more accurate angiographic estimation of the coronary blood flow velocity. PMID- 25696192 TI - Clinical significance of reverse redistribution on technetium-99m tetrofosmin single-photon emission computed tomography: an 18-month follow-up study. AB - BACKGROUND: The clinical and prognostic significance of reverse redistribution on technetium-99m (99mTc) single-photon emission computed tomography (SPECT) is unclear. OBJECTIVES: To determine outcomes of chest pain patients showing reverse redistribution after 99mTc tetrofosmin SPECT versus SPECT showing no reverse redistribution. METHODS: Patient outcomes (death, nonfatal myocardial infarction, coronary artery bypass grafting and percutaneous transluminal coronary angioplasty) within 18 months after 99mTc tetrofosmin SPECT were determined in two populations of ambulatory patients, most of whom had been evaluated because of chest pain: a population of 57 patients whose SPECT images showed reverse redistribution without reversible or fixed defects, versus a control population of 98 patients whose SPECT images were normal (no reverse redistribution, no reversible defects, no fixed defects). RESULTS: Stepwise logistic regression analysis showed that the population of patients with reverse redistribution did not have a worse 18-month outcome in comparison with the control population of patients without reverse redistribution (3.5% versus 9.2%, respectively; p=0.15 corrected for age and gender). CONCLUSION: Reverse redistribution on 99mTc tetrofosmin SPECT does not appear to be an unfavourable prognostic factor in ambulatory chest pain patients. PMID- 25696193 TI - Precordial electrode placement in women. AB - BACKGROUND: Precordial ECG electrode positioning was standardised in the early 1940s. However, it has been customary for the V3 to V6 electrodes to be placed under the left breast in women rather than in the correct anatomical positions relating to the 4th and 5th interspaces. For this reason, a comparison between the two approaches to chest electrode positioning in women was undertaken. METHODS: In total 84 women were recruited and ECGs recorded with electrodes in the correct anatomical position and also in the more commonly used positions under the breast. As a separate study, 299 healthy women were recruited to study normal limits of leads V3 to V6 recorded with electrodes in the correct anatomical positions and compare them with published normal limits with electrodes in the more commonly used locations. RESULTS: It was shown that there was less variability with electrodes in the correct anatomical positions and that there were significant differences between the new limits of normality compared with the old established limits. CONCLUSION: Expansion of the database and further analysis of the data is required to make a definitive recommendation with respect to precordial electrode placement in women. PMID- 25696194 TI - Statins in type 2 diabetes mellitus: target on lipids and vascular wall function. AB - The typical dyslipidaemia in type 2 diabetes mellitus shows high levels of triglycerides, low levels of highdensity lipoprotein cholesterol (HDL-c) and small dense low-density lipoprotein (LDL) particles. In these patients low-dose atorvastatin (10 mg) results in a significant and relevant reduction in triglycerides and LDL-c. High-dose atorvastatin (80 mg) results in a better LDL-c reduction. The endothelial dysfunction is likely to be caused by factors related to insulin resistance and not by dyslipidaemia alone. The results from the DALI study (Diabetes Atorvastatin Lipid Intervention) on lipids and endothelial function are discussed, together with two invasive endothelial function studies in diabetics and hypertriglyceridaemic patients. The subgroup of diabetics in the large secondary prevention trials using statins are analysed with respect to total cholesterol lowering and death due to coronary heart disease and nonfatal myocardial infarction. PMID- 25696195 TI - Balloon aortic valvuloplasty as a bridge to aortic valve replacement in a patient with severe calcific aortic stenosis. AB - This case report describes a patient with severe calcific aortic stenosis who was initially considered inoperable because of a very poor left ventricular function and severe pulmonary hypertension. After balloon aortic valvuloplasty, the clinical and haemodynamic status of the patient improved to such an extent that subsequent aortic valve replacement was considered possible and eventually proved to be successful. Balloon aortic valvuloplasty has value as a potential bridge to aortic valve replacement when the risks for surgery are considered to be too high. PMID- 25696197 TI - ? PMID- 25696196 TI - Shortness of breath six years after bypass surgery. PMID- 25696198 TI - ? PMID- 25696199 TI - Rate or rhythm control for persistent atrial fibrillation. PMID- 25696200 TI - Hormones and the heart: Does the cardiovascular system need growth hormone in adult life? PMID- 25696201 TI - The impact of an implantable cardioverter defibrillator: the Leiden follow-up study of ICD patients and their partners. AB - OBJECTIVES: The goal of this study was to evaluate 1) the presence of psychosocial problems in both ICD patients and their partners, and 2) the relation between psychosocial problems and various clinical variables. METHODS: Questionnaires were sent to 219 ICD patients and their partners. RESULTS: Sixty eight percent of the ICD patients, 122 (81%) male, aged 59+/-12 years, and 62% of their partners, 28 (21%) male, aged 58+/-11 years, returned the questionnaires. Anxiety, depression or nervousness was reported by 49%, 30% and 52% respectively of the patients and by 36%, 24% and 66% of the partners. In patients, mental health problems were associated with a lower left ventricular ejection fraction (p=0.006), younger age (p=0.029), employment (p=0.011), unpleasant experiences from ICD discharges (p=0.032), prior myocardial infarction (p=0.019) and a higher NYHA functional class (p=0.05). Nervousness was more often reported by partners of ICD patients with prior myocardial infarction (p=0.049). Sixty percent of the partners had a need for counselling or support groups. CONCLUSION: Psychosocial problems are present in ICD patients and their partners and are associated with a number of clinical variables. A specific ICD rehabilitation programme should therefore not only be offered to ICD patients but to their partners as well. PMID- 25696202 TI - Results of a heart failure outpatient clinic in a non-university hospital with a two-year follow-up. AB - The growing number of heart failure patients has stimulated the development of intensified guidance and follow-up of these patients using specific outpatient clinics and specialised nurses. This is also the case in the Netherlands, where the first positive results of this system have been obtained in academic settings. In this article we present data from an intensified programme for CHF patients as obtained at a non-university cardiology department. It demonstrates that also in this setting the use of a cardiologist, a heart failure outpatient clinic and a specialised nurse dedicated to these patients results in a significant decrease in readmission rate. Furthermore patient characteristics are described. Finally the important role of the nurse is stressed by indicating the number and content of telephone calls he is receiving, resulting in medication changes in 58% of calls. PMID- 25696203 TI - Novel ways to noninvasively detect inflammation of the myocardium: contrast enhanced MRI and myocardial contrast echocardiography. AB - Both contrast-enhanced magnetic resonance imaging (CE-MRI) and myocardial contrast echocardiography (MCE) are promising tools to detect cardiac inflammation. CE-MRI can be used to characterise the location and extent of myocardial inflammation, since areas of abnormal signal enhancement associated with regional wall motion abnormalities reliably indicate areas of active myocarditis. In MCE, chemically composed microbubbles can be visualised by ultrasound and used to determine the status of the cardiac microvasculature. If there is any inflammation the microbubbles will be phagocytosed by neutrophils and monocytes, thus enabling the degree of inflammation to be assessed. These noninvasive techniques may allow early diagnosis and accurate evaluation of myocardial inflammation. PMID- 25696204 TI - Pacemaker lead endocarditis: A rare diagnosis with a varied presentation. AB - We present a patient with a pacemaker lead endocarditis who showed no signs of pocket infection but with high fever and signs of infection in the routine laboratory tests. A diagnosis of pacemaker lead endocarditis must be considered in all patients with fever and infection parameters who have a pacemaker inserted, not only in the first weeks after implantation but also late after implantation, as long as no other cause of infection has been found. Transthoracal echocardiography alone is not sensitive enough to establish the correct diagnosis. Transoesophageal echocardiography (TEE) is mandatory to demonstrate the presence or absence of a vegetation on a pacemaker lead. PMID- 25696206 TI - Carotid sinus clues. PMID- 25696205 TI - Electrocardiogram of patient with syncope and history of cardiac transplantation. PMID- 25696207 TI - ? PMID- 25696208 TI - ? PMID- 25696209 TI - Einthoven Dissertation Prizes 2002. PMID- 25696210 TI - Ebstein's anomaly in the adult patient. PMID- 25696211 TI - Prehospital use of adenosine by ambulance services in the Netherlands: Daily practice, literature overview and practical recommendations. AB - BACKGROUND: The prehospital use of adenosine in the treatment of supraventricular arrhythmias has recently been implemented in standard ambulance care. However, establishing the origin and nature of the arrhythmia with certainty is an absolute requirement for using adenosine. METHODS: The ability of the ambulance nurse to predict supraventricular arrhythmias and the necessity of prehospital treatment of arrhythmias in general was evaluated. To do this, cardiologists at the Academic Medical Centre of Amsterdam were consulted and a literature search by means of an electronic search in Pubmed was performed. The search was complemented by a second survey concerning antagonists of adenosine using the keywords: adenosine and theophylline. Moreover, the Ambulance Nurse textbook, the National Protocol for Ambulance Care as well as the explanatory memorandum to the protocol were consulted. RESULTS: No strong indication for the prehospital use of adenosine was found, while detrimental effects of the drug can occur. There is no literature showing the ability of ambulance staff to correctly interpret complex cardiac arrhythmias in the Netherlands; the current ambulance protocol does not prevent an incorrect choice of therapy and medication. CONCLUSION: It is strongly advised against using antiarrhythmic medication for the treatment of tachycardias in a prehospital setting if this treatment can be postponed to the hospital environment. PMID- 25696212 TI - Simultaneous measurement of right and left ventricular volume by the conductance catheter technique in the newborn lamb. AB - BACKGROUND: Measurement of absolute ventricular volume with the conductance catheter technique has been documented extensively for the left ventricle (LV). More recently, the same technique has been applied in studies of right ventricular (RV) performance. In the present study we performed simultaneous measurements of LV and RV volumes. Conversion of measured conductances to absolute volumes requires the assessment of slope factor alpha (alpha) and parallel conductance correction volume (Vc) for both the RV and LV. We investigated the magnitude and variability of these calibration factors during a typical study period of four hours. METHODS: In five anaesthetised, ventilated newborn lambs, conductance catheters were introduced into the LV and RV and a thermodilution catheter was positioned in the pulmonary artery. Alphas and Vc's were determined by thermodilution and hypertonic saline dilution, respectively, at one hourly intervals. At the same time points, biventricular haemodynamic parameters were obtained. Results were analysed by multiple linear regression analysis. RESULTS: During the course of the experiments all haemodynamic parameters were stable. There were no significant changes in Vc or alpha for either ventricle. RV-Vc was systematically higher than LV-Vc: both as absolute values and as percentage of the uncalibrated conductance signal (79% for RV, and 49% for LV, respectively). This probably reflects the geometrical differences of the two ventricles. Right ventricular ejection fraction (RV-EF) was higher than left ventricular ejection fraction (LV-EF), and neither changed significantly during four hours. CONCLUSION: These results show that calibration factors alpha and Vc for the RV, as well as EF, show values that are consistent with the observed haemodynamic stability and in line with the LV factors. These results indicate that the conductance catheter method can be used satisfactorily for biventricular function assessment. PMID- 25696213 TI - The double-switch procedure for atrioventricular and ventriculoarterial discordance. AB - BACKGROUND: Late ventricular failure remains a major concern in patients with congenitally corrected transposition of the great arteries (ccTGA). A new treatment for this condition is the double-switch procedure. METHODS: Three consecutive children with atrioventricular and ventriculoarterial discordance (congenitally corrected transposition of the great arteries) and associated ventricular septal defect underwent pulmonary artery banding in infancy, followed by a double-switch procedure and closure of the ventricular septal defect at a median age of 5.8 years (range 4.5 to 6 years). RESULTS: There were no major procedure-related complications and the median duration of hospital stay was 13 days. One patient required stent implantation in the superior vena cava five months after surgery to relieve a persistent caval stenosis associated with recurrent pleural and pericardial effusions. Apart from this, no other complications have occurred over a median follow-up of five months. CONCLUSION: The double-switch procedure offers the potential advantage of restoring the morphological left ventricle to systemic ventricle. Longer-term follow-up of this procedure is warranted. PMID- 25696214 TI - Methods in molecular cardiology: microarray technology. AB - It has become more and more evident that changes in expression levels of genes can play an important role in cardiovascular diseases. Specific gene expression profiles may explain, for example, the pathophysiology of myocardial hypertrophy and pump failure and may provide clues for therapeutic interventions. Knowledge of gene expression patterns can also be applied for diagnostic and prognostic purposes, in which differences in gene activity can be used for classification. DNA microarray technology has become the method of choice to simultaneously study the expression of many different genes in a single assay. Each microarray contains many thousands of different DNA sequences attached to a glass slide. The amount of messenger RNA, which is a measure of gene activity, is compared for each gene on the microarray by labelling the mRNA with different fluorescently labelled nucleotides (Cy3 or Cy5) for the test and reference samples. After hybridisation to the microarray the relative amounts of a particular gene transcript in the two samples can be determined by measuring the signal intensities for the fluorescent groups (Cy3 and Cy5) and calculating signal ratios. This paper describes the development of in-house microarray technology, using commercially available cDNA collections. Several technical approaches will be compared and an overview of the pitfalls and possibilities will be presented. The technology will be explained in the context of our project to determine gene expression differences between normal, hypertrophic and failing heart. PMID- 25696215 TI - Papillary fibroelastoma of the mitral valve. AB - We present a case of a 69-year-old woman with a history of stroke five years previously and an abnormal ECG prior to eye surgery. There were no signs of cardiac disease. Echocardiography disclosed a tumour of the papillary muscle. Surgical excision was performed and histological examination confirmed the diagnosis of a papillary fibroelastoma. PMID- 25696216 TI - Acute haemodynamic consequences and simultaneous echocardiographic images of severe systolic anterior motion of the anterior mitral valve leaflet following aortic valve replacement. PMID- 25696217 TI - ? PMID- 25696218 TI - ? PMID- 25696219 TI - Abstracts Voorjaarsvergadering Nederlandse Vereniging voor Thoraxchirurgie: Utrecht, 12 april 2003. PMID- 25696220 TI - Abstracts Voorjaarscongres Nederlandse Werkgroep Hartstimulatie: Amersfoort, 5 april 2003. PMID- 25696221 TI - Abstracts Najaarscongres Nederlandse Werkgroep Hartstimulatie: Alkmaar, 22 november 2002. PMID- 25696222 TI - Genetic secrets from the heart revealed through the zebrafish. PMID- 25696223 TI - Immediate and intermediate results of stent therapy for aortic coarctation. AB - OBJECTIVES: The aim of the study was to assess the immediate and intermediate outcomes of stent therapy for coarctation or recoarctation of the aorta. SETTING: Tertiary referral centres. METHODS: A case review of all patients who have undergone stent implantation for coarctation of aorta in the Netherlands and Belgium. RESULTS: Stents were implanted in 33 patients (mean age 21+/-16 years) and successful outcome occurred acutely in 32 of these 33 patients. Peak systolic blood pressure decreased from 149+/-37 to 124+/-24 mmHg. The pressure gradient decreased from 37+/-16 to 7+/-7 mmHg. The diameter of the coarctation segment increased from 7.3+/-3.8 to 13.3+/-3.9 mm. Three patients had major complications and three had minor complications. During a mean follow-up of 21+/-17 months recoarctation was found in ten patients, seven of whom have undergone further procedures. There were no deaths at follow-up. CONCLUSIONS: Stent implantation is a good alternative to balloon dilation in selected patients with coarctation of the aorta. However, follow-up evaluation reveals a varying incidence of recoarctation and the long-term outcomes need to be determined. PMID- 25696224 TI - Heart rate variability and sympathovagal balance: pharmacological validation. AB - RATIONALE: We validated heart rate (HR) and six time and six frequency domain measures of heart rate variability (HRV) as estimators of autonomic outflow in 44 young healthy male subjects. Gold standards for autonomic outflow were the Rosenblueth-Simeone factors m (sympathetic tone) and n (vagal tone), and the sympathovagal balance m.n, determined by two-stage complete autonomic blockade. METHODS: Rank correlations were computed between HR and the HRV measures obtained before autonomic blockade, and m, n and m.n. Also, the maximal mean performances (averaged sensitivity and specificity) for HR and HRV as discriminators between low and high values of m, n or m.n were computed. RESULTS: The spectral HRV measures showed less good correlations and performances than the time domain HRV measures. Correlations with sympathetic tone were all below 0.31. Respiratory sinus arrhythmia during 15 cycles/min metronome breathing was superior in estimating vagal tone and sympathovagal balance (correlations -0.71/-0.73; both performances 0.82), heart rate scored similarly for assessing the sympathovagal balance (correlation 0.71; performance 0.82). CONCLUSIONS: It does not appear justified to evaluate HR or HRV in terms of sympathetic tone, vagal tone, or sympathovagal balance. HR and HRV are specifically weak in assessing sympathetic tone. Respiratory sinus arrhythmia during 15 cycles/min metronome breathing is superior in assessing vagal tone. Current HRV analysis techniques offer no advantages compared with HR in assessing the sympathovagal balance. PMID- 25696225 TI - Methods in molecular cardiology: suppression subtraction hybridisation. AB - Identification of differentially expressed genes in pathological tissues may provide more insight into the molecular mechanism involved in the development or progression of disease. Suppression subtraction hybridisation (SSH) allows the identification of novel, differentially expressed genes without prior knowledge about gene expression patterns or functional and biochemical protein characteristics. This review provides a general overview of the SSH method and gives two examples of SSH in the cardiovascular field. PMID- 25696226 TI - C-reactive protein as a prognostic tool in cardiovascular practices: should CRP testing be ordered along with lipid profiles? AB - CRP has a graded, dose-response relationship to the occurrence of clinical cardiovascular events that remains after adjustment for other risk factors, with moderately strong associations between the lower and upper tertiles (RR~2). It may have clinical utility in improving the estimation of absolute risks of patients with a calculated ten-year risk between 10 and 20%. Individuals at low risk (<10% per 10 years) will be unlikely to have a high risk identified through CRP testing. Additional prospective studies or new statistical analysis of previous studies are needed to establish the added predictive value of CRP above that of currently established risk factors. Thus, currently available evidence suggests that CRP testing should not be ordered along with lipid profiles. PMID- 25696227 TI - Giant negative T waves after treatment of severe hyperkalaemia. AB - We present the case of a 79-year-old female with severe hyperkalaemia and severe prerenal insufficiency due to dehydration and nephrotoxic medications, including spironolactone. The ECG showed AV nodal rhythm and tented T waves. After treatment with fluids, insulin, polystyrene sulphonate and sodium bicarbonate, the serum potassium level and kidney function normalised. Several days later, she developed QT prolongation with giant negative T waves without signs of ischaemia. In this report, we review the effect of hyperkalaemia on cardiac ion channel function and the associated changes on the ECG. In addition, the causes and mechanisms of giant negative T waves are discussed. PMID- 25696228 TI - From normal to Mahaim to Ebstein electrocardiogram. PMID- 25696230 TI - ? PMID- 25696229 TI - A long RP supraventricular tachycardia. PMID- 25696231 TI - ? PMID- 25696232 TI - Out-of-hospital arrest: from innocent bystander to involved citizen responder. PMID- 25696233 TI - Development of the Rotterdam Quality of Life Questionnaire for Heart Transplant Recipients. AB - BACKGROUND: Heart transplantation is a unique and life-threatening event followed by role and lifestyle adjustments, feelings of dependency, and fears about infections and rejection of the donor heart. Generic quality of life measures are unlikely to cover aspects pertinent to transplant recipients. The disease specific measures available are lengthy and not feasible for use in clinical practice. AIM: The purpose of the current study was to develop a brief and reliable disease-specific instrument to measure quality of life in heart transplant patients. STUDY DESIGN: Survey. METHODS: The Rotterdam Quality of Life Questionnaire for Heart Transplant Recipients was developed according to a series of steps that included in-depth interviews with heart transplant patients, transcription of interviews to form a comprehensive item pool, reduction of the item pool through submission to a panel of healthcare professionals and transplant patients, and further reduction of the item pool through construct formation and statistical analyses. From July to September 2000, all surviving patients (n=237) following heart transplantation at the Erasmus Medical Centre, Rotterdam were asked to fill in the 55-item questionnaire, 205 (86%) of whom replied. RESULTS: Twelve of the 55 original items were identified as contributing to overall quality of life in heart transplant patients based on four a priori selected constructs. Submission of the 12 items to a factor analysis confirmed that the four-factor structure accounted for 62% of the variance. The reliability of the four subscales was adequate. Mean scores on subscales reflected light to moderate impairment in quality of life. CONCLUSION: The Rotterdam Quality of Life Questionnaire for Heart Transplant Recipients is a brief disease-specific instrument that measures quality of life in heart transplant patients. Although further studies are required to elaborate on the psychometric properties of the scale, the preliminary reliability of the scale looks promising. PMID- 25696234 TI - Long-term mortality of chest pain patients managed according to a decision scheme that aims to avoid inappropriate hospitalisations. AB - OBJECTIVE: A triage decision scheme was developed to avoid unnecessary hospitalisations for suspected acute coronary syndromes. The current investigation aimed at evaluating the long-term survival of patients who were managed according to this scheme. SUBJECTS: Patients (n=964) with symptoms suggestive of acute cardiac pathology, who were seen by a general practitioner, and for whom a pre-hospital ECG was recorded by the ambulance service in 1993 1994. METHODS: During the year 2000 a follow-up of the entire cohort was performed, and the vital status of patients was determined via the civil registry office. Cox's multivariable regression analyses were performed to evaluate the relation between final (hospital discharge) diagnosis and long-term outcome. RESULTS: The median follow-up was 6.0 years (4.6-6.6). Six-year mortality of the entire cohort was 30%. Long-term mortality was significantly lower in patients identified to be at low risk, who are not hospitalised, than in hospitalised patients (six-year mortality 7.5% versus 33.1%; p<0.0001). Longterm outcome was strongly associated with the final hospital discharge diagnosis. CONCLUSION: Our data support the usefulness and appropriateness of the applied diagnostic scheme that aims to avoid unjustified hospital and CCU admissions in patients with acute chest pain. PMID- 25696235 TI - Do arrhythmias still deserve our intellectual efforts?: The 2002 Wenckebach Lecture of the Netherlands Society of Cardiology. AB - At the 74th meeting of the American Medical Association in San Francisco (1923) Professor Karel Frederik Wenckebach (figure 1) reported how favourably quinine converted atrial fibrillation. He honestly told the audience that his observations relied on the experience of a Dutch merchant who used to terminate his palpitations with quinine, a drug that he took daily for malaria while staying in the Dutch colonies. During his presentation he also emphasised that quinine worked better for atrial fibrillation of recent onset, an observation that is well known today. This story teaches us that simply listening to the patient and thinking about the significance of the patient's words can lead to diagnostic or therapeutic progress. Such a professional attitude is perfectly illustrated by Sir James Mackenzie's statement in 1918: 'The progress of medicine will be hampered, till the general practitioner becomes an investigator.' PMID- 25696236 TI - Aortic-left ventricular discontinuity of noninfectious origin. AB - The existence of a cavity of noninfectious origin between the annulus of the ascending aorta and the left ventricle is described. Aortic-left ventricular discontinuity occurred as a late complication of aortic valve replacement in an octogenarian. A patient with severe symptomatic aortic valve stenosis underwent aortic valve replacement and aortic root enlargement into the noncoronary sinus with pericardial tissue. Four months after her valve surgery the patient presented with shortness of breath. Angiocardiography and transoesophageal echocardiography revealed a complex, irregular pouch at the right coronary cusp side of the valve with paravalvular leakage back into the left ventricular outflow tract. Reoperation was performed, the disconnection between the aortic annulus and the left ventricle was repaired and the valve was replaced. The aortic-left ventricular discontinuity did not involve the area where aortic root enlargement was performed. No evidence of infection was found and the most likely cause of the reported complication is mechanical in nature. PMID- 25696237 TI - Cardiac tumour. PMID- 25696238 TI - I don't know what it is, but it doesn't feel right. PMID- 25696239 TI - ? PMID- 25696240 TI - ? PMID- 25696241 TI - COMPANION - a friend indeed. PMID- 25696242 TI - Quality of life with heart failure: psychosocial determinants to be considered by cardiologists. AB - BACKGROUND: Independent determinants of QOL (quality of life) with heart disease have been recognised and include factors such as severity of medical condition, comorbidity, and concomitant medication. Psychosocial factors, as 'ability to cope with the unpleasantness of the medical condition', 'want of information', and 'social identification' have an important influence on self-perceived wellbeing, but their influence on health-related QOL domains and self-perceived QOL in patients with heart failure has not been systematically studied. OBJECTIVE: To assess correlation between such psychosocial factors and QOL in patients with heart failure. METHODS: Patients from the outpatient heart failure clinic of the Martini Hospital, a 1000-bed community hospital in the city of Groningen, the Netherlands, were included if their ejection fractions were <40% and their medical diagnosis according to their cardiologists was stable chronic congestive heart failure. The following QOL estimators were applied: Pearlin's Mastery Scale, Stewart's Short Form 36 Quality of Life Questionnaire, Dupuy's Index of Wellbeing, Cantrill's Self-perceived Quality of Life Scale, Mester's Want of Information Scale. Internal consistency of the multi-item scales was estimated by Cronbach's alphas. Linear and multiple linear regression analyses were performed of the data. RESULTS: Sixty patients were enrolled, 41 males and 19 females, average age 68 years (range 51 to 84 years). 'Ability to cope with the unpleasantness of the medical condition' was not only an independent determinant of self-perceived and health-related QOL (both p<0.001), but also of each domain of health-related QOL separately (p<0.001 for each domain). Lack of 'adequate medical information' and 'negative social identification' (identification with fellow-sufferers who are doing worse) were negative predictors of 'ability to cope' (p<0.01 and <0.001 respectively). 'Negative social identification' was also an independent determinant of self-perceived QOL, both unadjusted and after adjustment for 'ability to cope' and 'adequate medical information'. CONCLUSION: Relevant recommendations from this paper to be considered by cardiologists during everyday office hours could include: 1. Patients who express having difficulties in coping with the unpleasant aspects of their underlying heart condition have low health-related QOL as well as low self perceived QOL. 2. Providing adequate medical information is a significant contributor to both better 'ability to cope' and better self-perceived QOL. 3. Avoiding identifying with fellow-sufferers who are doing worse and, instead, starting to identify with those who are doing better, are significant contributors to both better 'ability to cope' and better self-perceived QOL. PMID- 25696243 TI - Electrical isolation of pulmonary veins using cryothermal energy: study design and initial results. AB - BACKGROUND: Atrial fibrillation (AF) is the most frequently encountered arrhythmia. Radiofrequency pulmonary vein (PV) ablation is promising for symptomatic paroxysmal AF, but is associated with a significant risk of PV stenosis. OBJECTIVES: To assess the efficacy of cryothermal PV ablation and the incidence of PV stenosis. METHODS: Highly symptomatic patients with paroxysmal or persistent AF were eligible for cryothermal ablation. Multislice spiral CT scans were performed before, and three months after ablation. AF burden was assessed using transtelephonic ECG recording and by telephonic enquiry. RESULTS: An attempt was made to isolate 27 PVs in 15 patients. In total, 20 PVs could be isolated (74% acute success). No significant difference in PV diameter was seen before and after ablation. Five out of 12 patients with paroxysmal AF were completely without AF after one ablation procedure. An additional two patients reported a significant reduction in symptoms. In the three patients with persistent AF no improvement was reported. CONCLUSION: Cryothermal PV ablation was effective in isolation of the targeted PVs. It appears to be safe, as no PV stenosis was seen in this study three months after the ablation. Taking into account a learning curve, we consider the clinical results to be very promising. PMID- 25696245 TI - Transvenous implantation of a ventricular pacing lead in a patient with an artificial tricuspid valve prosthesis. AB - The preference for treatment of symptomatic bradycardia is transvenous right ventricular pacing combined with atrial synchronisation if applicable. In the case of congenital anomalies where no conduit is present between the peripheral veins and the right ventricle, it is not possible to place the ventricular pacing lead in the right ventricle. Also the presence of an artificial valve in the tricuspid position excludes placement of an endocardial right ventricular pacing lead. Since the introduction of biventricular pacing, new guiding catheters and leads used as a transvenous route for left ventricular pacing are available. We report implantation of a ventricular pacing lead in the great cardiac vein for permanent ventricular pacing in a patient with a tricuspid valve prosthesis. PMID- 25696246 TI - Myocardial ischaemia and left bundle branch block. PMID- 25696244 TI - Imaging of coronary atherosclerosis and identification of the vulnerable plaque. AB - Identification of the vulnerable plaque responsible for the occurrence of acute coronary syndromes and acute coronary death is a prerequisite for the stabilisation of this vulnerable plaque. Comprehensive coronary atherosclerosis imaging in clinical practice should involve visualisation of the entire coronary artery tree and characterisation of the plaque, including the three-dimensional morphology of the plaque, encroachment of the plaque on the vessel lumen, the major tissue components of the plaque, remodelling of the vessel and presence of inflammation. Obviously, no single diagnostic modality is available that provides such comprehensive imaging and unfortunately no diagnostic tool is available that unequivocally identifies the vulnerable plaque. The objective of this article is to discuss experience with currently available diagnostic modalities for coronary atherosclerosis imaging. In addition, a number of evolving techniques will be briefly discussed. PMID- 25696248 TI - ? PMID- 25696247 TI - A case of wide QRS complex tachycardia. PMID- 25696250 TI - Abstracts of the Scientific Meeting of the Netherlands Society of Cardiology (NVVC): 25 April 2003, Okura Hotel, Amsterdam. PMID- 25696249 TI - ? PMID- 25696251 TI - Risk management in patients with atherosclerosis: the toothbrush or the drill. PMID- 25696252 TI - Quality of secondary cardiovascular prevention in specialised care in the Netherlands: the SOLID study. AB - OBJECTIVE: To determine the extent to which Dutch patients with a history of cardiovascular disease and high cholesterol levels, treated in specialised care, are achieving low-cholesterol targets as defined by national guidelines. DESIGN: Hospital-based cohort study. SETTING: Practices of 41 hospital-based cardiologists and internists in the Netherlands. SUBJECTS: 7377 patients. RESULTS: Forty-one percent of the patients with an indication for secondary cardiovascular prevention by lipid-lowering drug treatment were receiving medication and were achieving cholesterol targets, 42% were receiving lipid lowering medication but had cholesterol levels above target, 11% were not receiving treatment, and 5% had no recent lipid measurements. CONCLUSION: Compared with previous studies, the SOLID study shows that a relatively large percentage of the Dutch patients under specialised care with a history of cardiovascular disease and an indication for cholesterol-reducing therapy are currently being treated. A considerable proportion of the patients, however, are still not receiving optimal treatment and more than 10% are not being treated at all. PMID- 25696253 TI - Predictors of early ventricular fibrillation before reperfusion therapy for acute ST-elevation myocardial infarction. AB - BACKGROUND: Early VF accounts for the majority of deaths during the acute phase of acute MI. In patients treated with fibrinolytics, in-hospital VF occurs most frequently with inferior MI. Contrariwise, out-of-hospital VF seems to be associated with anterior wall MI and preinfarction angina (preconditioning) may protect against VF. AIM: To study clinical characteristics of patients with or without VF before or during reperfusion therapy. STUDY DESIGN AND METHODS: From January 1995 until December 2001, we treated 2826 patients for acute MI and reviewed the clinical records of all patients. Patients who developed early VF were classified according to the first episode of VF: either before or during the angioplasty procedure. RESULTS: VF developed in 219 (8%) patients. Early VF before reperfusion therapy (n=145, 5%) was independently related to anterior MI (RR 2.3 (95% CI 1.53-3.50), p<0.001), absence of preinfarction angina (RR 2.1 (95% CI 1.38-3.24), p=0.001) and Killip class >1 (RR 3.8 (95% CI 2.34-6.10), p<0.001). The majority of patients with VF during angioplasty (n=74, 3%) had inferior MI (61%). CONCLUSION: Early VF before reperfusion therapy is independently associated with anterior MI, absence of preinfarction angina and Killip class >1, whereas the majority of patients with VF during angioplasty have inferior MI. PMID- 25696254 TI - Genetic programme of cardiogenesis: implications for therapeutic application. AB - It has become accepted that new cardiomyocytes can be derived from stem cells. Although the potential for therapeutic application is evident, the reported efficiency of differentiation varies greatly from 0.02 to 54%. To obtain clinically relevant numbers of newly differentiated cardiac cells, stem cell differentiation should be as efficient as possible. A plausible way to increase the efficiency of differentiation of stem cells into cardiomyocytes is through the introduction of cardiac specific regulatory genes in the stem cells. This review summarises the role of several key transcription factors in cardiogenesis. PMID- 25696255 TI - Recommendations for pacemaker implantation for the treatment of atrial tachyarrhythmias and resynchronisation therapy for heart failure: A report from the task force on pacemaker indications of the Dutch Working Group on Cardiac Pacing. AB - Today, new pacing algorithms and stimulation methods for the prevention and interruption of atrial tachyarrhythmias can be applied on patients who need bradycardia pacing for conventional reasons. In addition, biventricular pacing as additive treatment for patients with severe congestive heart failure due to ventricular systolic dysfunction and prolonged intraventricular conduction has shown to improve symptoms and reduce hospital admissions. These new pacing technologies and the optimising of the pacing programmes are complex, expensive and time-consuming. Based on many clinical studies the indications for these devices are beginning to emerge. To support the cardiologist's decision-making and to prevent waste of effort and resources, the 'ad hoc committee' has provided preliminary recommendations for implantable devices to treat atrial tachyarrhythmias and to extend the treatment of congestive heart failure respectively. PMID- 25696256 TI - Giant rhabdomyoma of the right ventricle. AB - A giant intrathoracic mass causing foetal dysrhythmias, polyhydramnios and foetal hydrops necessitated a caesarean section in a male infant of 35 weeks gestation. Despite the benign histology of cardiac rhabdomyomas and the observation of spontaneous regression, there may be significant associated morbidity and mortality, especially in neonates. There is a high incidence of associated tuberous sclerosis. PMID- 25696258 TI - Not so usual. PMID- 25696257 TI - Myocardial bridging. PMID- 25696259 TI - ? PMID- 25696261 TI - Recent clinical developments in the treatment of atrial fibrillation: 25th 'Wolfheze' Congress, 22 November 2003. PMID- 25696260 TI - ? PMID- 25696262 TI - Heart failure and cardiovascular endocrinology: Heart and hormones. PMID- 25696263 TI - Multidisciplinary structured lifestyle intervention reduces the estimated risk of cardiovascular morbidity and mortality. AB - BACKGROUND: Current guidelines for prevention and treatment of cardiovascular disease (CVD) emphasise the importance of a healthy lifestyle. However, successful lifestyle intervention is proving to be a challenge for healthcare professionals. OBJECTIVES: Evaluation of the effect of lifestyle intervention on cardiovascular risk factors, on reaching treatment targets and on the estimated risk of cardiovascular morbidity and mortality. METHODS: The effect of a six month multidisciplinary structured lifestyle intervention programme was assessed in 186 patients with and without a history of CVD. RESULTS: Multidisciplinary structured lifestyle intervention reduced the estimated ten-year risk of cardiovascular morbidity and mortality. The relative risk reduction was similar in patients with and without a history of CVD, the absolute risk reduction was higher in patients with a history of CVD. In both groups blood pressure and body weight decreased, and the maximal work rate and maximal oxygen uptake increased significantly. Blood levels of total cholesterol and cholesterol/HDL ratio decreased significantly in patients with a history of CVD. In addition, target levels for blood pressure and physical fitness were more frequently reached in both patient groups. CONCLUSION: Multidisciplinary structured lifestyle intervention had beneficial effects on cardiovascular risk factors. Relative risk reduction was similar in patients with and without evidence of cardiovascular disease. Follow-up is needed to see how well these effects can be maintained. PMID- 25696264 TI - Pacemaker safety and long-distance running. AB - OBJECTIVE: To prove that long-distance running is safe for athletes with pacemaker devices, pacemaker function was evaluated in nine long-distance runners. METHOD: Nine runners participated in a nine-month training programme that involved running for 1000 or 2000 km in preparation for either a full or a half marathon. A professional coach, three cardiologists and a technician - all with running experience - conducted the training and medical checkups. Commercial heart rate monitors were used during training to assess heart rates at rest, and during exercise and long-distance running. Sensing and pacing functions of the pacemaker system were tested during training sessions as well as during the race. In addition, the ChampionChip (a time registration device used in competition) and the Polar heart rate monitor (a widely used self-monitoring device) were tested for possible interference with the pacemaker. RESULTS: All nine athletes completed the Amsterdam 2001 half or full marathon without any pacemaker dysfunction. A short survey after two years showed no pacemaker dysfunction. CONCLUSION: Long-distance running is safe for athletes with pacemaker implants. Overall fitness and sufficient endurance training remain the prerequisites for maintaining the condition necessary for successful completion of a marathon regardless of medical status. In our study, it became clear that for patients who had received a pacemaker because of complete heart block, the upper rate of the pacemaker programme needed to be adjusted to 170 to 180 ppm to insure 1:1 atrio ventricular synchrony during high atrial rates. It is concluded that there is no a priori reason for cardiologists to advise against long-distance running in athletes with pacemakers. Patients with known or suspected structural heart disease should be screened according the recommendations. PMID- 25696265 TI - Stress echocardiography for risk assessment of diabetic patients. AB - Coronary artery disease in patients suffering from diabetes mellitus will become an increasing problem in the future. Because diabetic patients benefit from treatment of symptomatic but also asymptomatic coronary artery disease, early diagnosis is warranted. The diagnostic techniques used to detect ischaemia, with a focus on stress echocardiography, are described. PMID- 25696266 TI - How to target uncertainty in Dutch invasive cardiovascular care. AB - Current meetings of the Netherlands Society of Cardiology and the Working Group on Intervention Cardiology have shown that new strategic developments in the Dutch healthcare system have created much turbulence and uncertainty amongst members of the organisations. Both on-site and off-site new cardiac centres with and without surgical backup, respectively, are arising or being planned throughout the Netherlands. These strategic adaptations are related to service delivery failure, despite appropriate quality measures. To understand the reasoning behind this uncertainty and how to deal with it, we need to explore its origin and thinking. Its rationale is based on the assumption that each organisation relies on its ability to survive through innovation and transformation. Cardiologists and cardiac surgeons are key players in a large group of stakeholders participating in the chain of cardiovascular care. In addition, the Dutch healthcare system is deeply embedded in a historical sociopolitical environment. This may explain why ongoing uncertainty may beget more uncertainty. What are the consequences for the content of the route forward? PMID- 25696268 TI - A 77-year-old female with cardiac infiltration of chronic myelomonocytic leukaemia. PMID- 25696267 TI - 'White elephants' and a distinguished monkey - or the need for a proactive follow up in amiodarone therapy. AB - Two patients presented with a rather unusual form and documentation of amiodarone toxicity. General aspects on this topic are addressed with emphasis on neurotoxicity and pulmonary disease. The need for rational prescribing and a scrupulous follow-up is stressed in view of apparent unawareness of general physicians and organ-related specialists alike regarding these very phenomena. PMID- 25696269 TI - Tachycardia terminated by adenosine. PMID- 25696270 TI - NETHERLANDS SOCIETY OF CARDIOLOGY. PMID- 25696271 TI - ? PMID- 25696272 TI - ? PMID- 25696273 TI - ESC Congress 2004: national scientific contributions. PMID- 25696274 TI - Enhancing reverse cholesterol transport/raising HDL cholesterol: new options for prevention and treatment of cardiovascular disease. AB - High-density lipoprotein cholesterol (HDL-c) plays a crucial role in the concept of reverse cholesterol transport and has many other beneficial properties which may interfere with atherogenesis and plaque rupture. Low HDL-c levels are currently considered to be an important risk factor for the development of cardiovascular disease. However until recently no effective and safe treatment for powerfully increasing HDL-c selectively was available. This short overview describes possible new therapeutic approaches that may be able to raise HDL-c levels or improve HDL-c metabolism/reverse cholesterol transport. Today, the most important targets to be evaluated are inhibition of cholesteryl ester transfer protein (CETP) and increasing the HDL-c level by infusion of engineered HDL particles. Trials to prove clinical benefit of new HDL-c raising approaches are underway and may well be a new starting point for an optimised prevention and treatment of atherosclerotic cardiovascular disease. PMID- 25696275 TI - The Phantom in our opera - or the hidden ways of the autonomic nervous system in cardiac patients. AB - The role of the autonomic nervous system in the understanding of pathophysiological mechanisms in a variety of cardiovascular clinico-pathological conditions is highlighted from a clinician's point of view with the focus on coronary mimicry, enhanced sympathetic tone and syndrome X. A unique case is presented where sinus node dysfunction in pandysautonomia seemed to be an early sign of hypothalamic glioblastoma. In addition, relevant literature on this topic is addressed to put distinct clinical patterns into a broader perspective. PMID- 25696277 TI - Acute anteroseptal myocardial infarction. PMID- 25696276 TI - Neurological symptoms and cerebrovascular accidents: manifestations of left-sided cardiac tumours in adults. AB - We present two adult patients with a left-sided cardiac tumour in whom the diagnosis was established by transthoracic and transoesophageal echocardiography. They both presented with a cerebrovascular accident. Cardiac surgery for tumour excision was offered but refused by one and successfully performed in the other. In one of the patients, right femoro-crural bypass was undertaken because of arterial insufficiency. The patient who refused surgical intervention died secondary to severe septic shock. In the other patient serial transthoracic and transoesophageal echocardiography showed no tumour recurrence at four years of follow-up post tumour extirpation. PMID- 25696278 TI - Nightly phenomena, day time work? PMID- 25696279 TI - Heart failure: chapter 6. Pharmacological treatment of chronic heart failure. PMID- 25696280 TI - NETHERLANDS SOCIETY OF CARDIOLOGY. PMID- 25696281 TI - ? PMID- 25696282 TI - ? PMID- 25696283 TI - Somatic stem cells and cardiac repair: where is the science? PMID- 25696284 TI - Difficulties in diagnosing chronic constrictive pericarditis. AB - This presentation calls attention to the many problems involved in the positive, aetiological and differential diagnosis of chronic constrictive pericarditis. We mention the difficulties in aetiological diagnosis in the absence of an episode of acute pericarditis in the past medical history and the clinical findings similar to vascular decompensated cirrhosis or idiopathic restrictive cardiomyopathy. ECG and two-dimensional echocardiography do not have an important role in diagnosis, and in the absence of computed tomography and magnetic resonance imaging, chest radiography, especially a lateral view, could establish the diagnosis. A delay in diagnosis creates difficulties in the surgical treatment, but this treatment improves the patient's condition in the long term more than the short term. PMID- 25696285 TI - Piercing the left lung with a pacemaker lead, an uncommon complication. AB - Although percutaneous insertion of pacemaker leads is a simple and safe method, it remains a procedure with a relatively high complication rate. We describe an uncommon and avoidable complication of this technique: piercing the lung with a pacemaker lead in an obese patient after direct puncture of the subclavian vein. PMID- 25696286 TI - Under the volcano, or pheochromocytoma revisited. AB - Pheochromocytoma is a well-defined clinical entity often remembered in clinical practice, but seldom encountered. Rather often, however, these patients are initially referred to a cardiologist and then a correct diagnosis is important because this disease is curable and may otherwise be lethal. Somehow clinical signs and symptoms are embedded in a sort of subconscious memory but specific knowledge is rather limited as far as, for example, the pathophysiological background is concerned. Perhaps this has something to do with the fact that already in 1922 a syndrome of paroxysmal hypertension associated with an adrenal medullary tumour was reported and that its nature and clinicopathological manifestations were described as early as the 1950s. Nevertheless it is not amiss to shed some new light upon old and established views not only for the better of our patients but as a catalyst for the motivation in search of coherence as well. The patient presented here pairs a very unusual case with unusual features. The pathophysiology is revealed with the closely monitored sequence of events. At a time where the medical professional leans heavily on test results and sophisticated technology it is refreshing to see how basic diagnostic tools pay off in clarifying and understanding as well. PMID- 25696287 TI - Inhibition of a dual chamber pacemaker by oversensing of far-field atrial depolarisation in a patient after His-bundle ablation. AB - After His-bundle ablation, a 54-year-old pacemaker-dependent patient suffered from severe presyncopal attacks one year after pacemaker replacement. The attacks were caused by ventricular inhibition due to atrial far-field sensing during paroxysmal atrial flutter. PMID- 25696288 TI - Pulmonary atresia with ventricular septal defect and an atypical duct. PMID- 25696290 TI - NETHERLANDS SOCIETY OF CARDIOLOGY. PMID- 25696289 TI - Heart failure: chapter 8. Treatment of end-stage heart failure. PMID- 25696291 TI - ? PMID- 25696292 TI - ? PMID- 25696293 TI - Pulmonary vein isolation to cure atrial fibrillation: is the circle complete? PMID- 25696295 TI - Effectiveness of a physiotherapeutic exercise programme for chronic heart failure patients. AB - BACKGROUND: This pilot study was conducted to evaluate the design and effects of a physiotherapeutic exercise programme on exercise capacity, muscle strength and quality of life in patients with chronic heart failure. METHODS: Eighteen patients with chronic heart failure were randomly assigned to either a training group (n=9) participating in a physiotherapeutic exercise programme or a regular care control group (n=9). At baseline and after three months patients underwent a maximal bicycle test, a six-minute walk test, a respiratory test, three muscle strength tests and a number of questionnaires pertaining to quality of life. RESULTS: Compared with the control group, a positive trend in the results of the training group was found. All measures showed a greater increase in the intervention group than in the control group. In five measures the difference was significant: 1. distance covered during the six-minute walk test (p=.036), 2. Borg rating of perceived exertion after this walk test (p=.006), 3. 'care and housekeeping' of the activities daily life questionnaire (p=.004), 4. 'symptoms' (p=.048) and 5. 'quality of life' (p=.040) of the Kansas City Cardiomyopathy Questionnaire. CONCLUSION: The study in chronic heart failure patients suggests both that the design of our training programme is workable and that our physiotherapeutic exercises produce positive effects. Further research with more patients is necessary to generalise these results to the population of patients with stable chronic heart failure. To assess the long-term effects of the programme, follow-up research is necessary. PMID- 25696294 TI - Inhibition of the tissue factor pathway of coagulation by recombinant nematode anticoagulant protein c2 during elective coronary stent implantation. AB - BACKGROUND: Exposure of tissue factor (TF) to the circulation during coronary stent implantation initiates coagulation activation and may contribute to the risk of thrombotic complications. In this study, we investigated whether inhibition of TF-factor VIIa by recombinant Nematode Anti-coagulant Protein c2 (rNAPc2) is able to suppress haemostatic and inflammatory activity in patients undergoing elective intracoronary stenting. METHODS: In a randomised, double blind design, 102 patients received either placebo or rNAPc2 (biological half life >50 hours) at doses of 3.5, 5.0, 7.5 and 10.0 MUg/kg as a single subcutaneous administration two to six hours before angioplasty. All patients also received aspirin, clopidogrel and unfractionated heparin (activated clotting time >250 seconds during angioplasty). Serial blood samples were collected before and after the intervention. RESULTS: At 30 hours after stenting, all rNAPc2 treatment groups but not the placebo group demonstrated a reduction from baseline of prothrombin fragment F1+2 and D-dimer plasma levels (to 23 and 12% below baseline values at the highest dose, respectively), which were significantly lower in three rNAPc2 groups compared with placebo (p<=0.03). TF plasma levels were initially reduced in all rNAPc2 groups and returned to baseline values 18 hours after stent implantation. These three markers all increased to above baseline values in the placebo group. Levels of P-selectin, antithrombin III and interleukin-8 were not or only slightly affected by the intervention or by rNAPc2, whereas a significant 2.8 to 4.1 fold increase of C-reactive protein plasma levels was found in all patient groups after the procedure. CONCLUSION: In contrast to the inflammatory response, coagulation activation after elective coronary stent implantation, which is observed in spite of the use of multiple antithrombotic drugs, can be attenuated by inhibition of the TF-factor VIIa complex using rNAPc2. Inhibition of the TF-mediated pathway of coagulation may be an important target to prevent thrombotic complications after coronary stenting. PMID- 25696296 TI - The value of (NT-pro) BNP in the diagnosis, prognosis and treatment of congestive heart failure. AB - Congestive heart failure constitutes one of the major causes of morbidity and mortality in Western countries. However, it is often misdiagnosed and the validity of the diagnosis is often difficult to establish. The clinical signs are not very sensitive and symptoms are nonspecific. Secretion of natriuretic peptides is increased in situations of cardiac overload. Testing the levels of these peptides, especially BNP and NT-proBNP, appears to offer a significant advance in the diagnosis and treatment of heart failure. In this article we would like to discuss the value of natriuretic peptides in congestive heart failure and give a short review of the literature. PMID- 25696297 TI - Role of echocardiography in the diagnosis and management of infective endocarditis. AB - Infective endocarditis is one of the most common causes of serious infection and carries a high risk of morbidity and mortality. It represents the fourth leading cause of life-threatening infections after urosepsis, pneumonia, and intra abdominal sepsis. There is still a continuous rise in the incidence of infective endocarditis, with a rate of about 20,000 new cases in the United States alone. This rise in incidence of infective endocarditis is mainly caused by increasing numbers of intravenous drug abusers, patients with artificial valves and elderly patients. In this paper, we will briefly review the crucial role of echocardiography in the diagnosis and management of infective endocarditis. PMID- 25696299 TI - Metastatic right ventricular obstruction. PMID- 25696298 TI - An unusual presentation with persistent left superior vena cava. AB - Persistent left superior vena cava (LSVC) is the most common congenital systemic venous anomaly, which may give rise to several problems. We present a case in which a persistent LSVC was an unsuspected finding. A 70-year-old male presented with intracerebral empyema which may have been caused by venous septic emboli from the left arm and facilitated by a persistent LSVC draining directly into the left atrium. Visualisation of the anomaly was performed with echocardiography and magnetic resonance angiography. In addition we present a brief review of the literature concerning this disorder. PMID- 25696300 TI - A fainting lady with some extrasystoles. PMID- 25696301 TI - ? PMID- 25696302 TI - ? PMID- 25696303 TI - Therapeutic challenges in the treatment of cardiovascular diseases: issues and answers: American Heart Association meeting, Orlando, Florida, November 2003. PMID- 25696304 TI - Implementing guidelines in cardiology: of hospitals and launderettes. PMID- 25696305 TI - Reflections of six years of lead extraction: influence on indications and technique. AB - BACKGROUND: Endovascular techniques have become the standard approach for extraction of pacemaker and ICD leads. However, with experience, the indications and technical approach have evolved. INDICATIONS: In a population referred for lead extraction, we could not found a relation between the number of leads implanted and the incidence of occlusion of the access vein. Moreover, there is evidence that the lead extraction itself is accompanied with an increased risk of post-procedural venous occlusion. Electrical interference can be avoided in most cases, even in ICD patients. As complications of extraction have to be taken into account as well, it is therefore not in the patient's interest to extract chronically implanted non-functional superfluous leads. In contrast, lead extraction is a most effective way to cure pacemaker or ICD related infections, even if previous conservative therapy has failed. However, in patients at high risk, extraction might be deferred to attempt device saving therapy first. TECHNIQUE: Although leads can be removed with traction for almost all implant times, after six months additional tools are increasingly necessary to safely and completely extract them. No single technique suffices for all procedures: powered sheaths - as the laser sheath - and a femoral workstation with retrievers should be available when extraction is attempted. COMPLICATIONS: Venous or myocardial perforation is a life-threatening complication of lead extraction. In these circumstances, time lacks to safely transfer a patient for emergency surgery and therefore the only safe environment to perform lead extraction is the operating theatre with cardiosurgical standby. PMID- 25696306 TI - Pneumothorax resulting from subclavian puncture: a complication of permanent pacemaker lead implantation. AB - Pneumothorax is a mild complication during pacemaker lead implantation using the subclavian puncture technique. We report on five-year experience in 433 pacemaker lead implantation procedures in 379 patients. The cephalic vein route was solely used in twelve patients. Three procedures were performed over time in four patients and one patient needed four repetitive punctures for pacemaker lead implantation and replacement. Thus 421 punctures were carried out in 367 patients. Eleven case of pneumothorax were observed: in eight patients (1.9%) a partial pneumothorax occurred and in three patients (0.7%) the pneumothorax was nearly complete. In the latter patients a chest tube was inserted and hospital admission was prolonged for 3, 6 and 6 days, respectively. Old age with a corresponding abnormality in the form of chest deformation were predominantly found in the patients with this type of complication. PMID- 25696307 TI - Role of plaque inflammation in acute and recurrent coronary syndromes. AB - Inflammation plays an important role in the initiation, development, progression and complications of atherosclerotic vascular disease. Our present knowledge of the elementary role of inflammation for the onset of plaque rupture in atherosclerotic coronary lesions primarily stems from autopsy studies. However, the introduction of directional coronary atherectomy catheters has provided a unique opportunity to directly investigate the role of inflammation in coronary syndromes. In this report we describe the role of coronary plaque inflammation, as determined by immunohistochemistry, on the presentation of coronary syndromes and on the clinical outcome following percutaneous interventions. PMID- 25696308 TI - Continuously improving the practice of cardiology. AB - Guidelines for the management of patients with cardiovascular disease are designed to assist cardiologists and other physicians in their practice. Surveys are conducted to assess whether guidelines are followed in practice. The results of surveys on acute coronary syndromes, coronary revascularisation, secondary prevention, valvular heart disease and heart failure are presented. Comparing surveys conducted between 1995 and 2002, a gradual improvement in use of secondary preventive therapy is observed. Nevertheless, important deviations from established guidelines are noted, with a significant variation among different hospitals in the Netherlands and in other European countries. Measures for further improvement of clinical practice include more rapid treatment of patients with evolving myocardial infarction, more frequent use of clopidogrel and glycoprotein IIb/IIIa receptor blockers in patients with acute coronary syndromes, more frequent use of beta-blockers in patients with heart failure and more intense measures to encourage patients to stop smoking. Targets for the proportion of patients who might receive specific therapies are presented. PMID- 25696309 TI - Percutaneous transvenous retrieval of intracardiac port-a-cath catheter fragment: a case report. AB - A female patient, 36 years of age, with a metastasised left breast cancer received several courses of chemotherapy for aggressive local tumour growth and multiple metastatic activity. In the current patient, surgical ablation of the left breast was carried out. Also loco-regional radio-therapy was conducted. To facilitate the administration of chemotherapy courses and prevent thrombophlebitis a vascular access port (port-a-cath) was surgically inserted via the right subclavian vein. After a few successful administrations of chemotherapeutic drugs the vascular port stopped functioning. It was demonstrated that a detached catheter fragment had dislodged into the right ventricle. Successful percutaneous, transvenous removal of the entrapped catheter fragment by the Gooseneck retrieval loop snare from the right ventricle was performed via the right femoral vein access. The procedure was uncomplicated and the patient tolerated the procedure well. PMID- 25696311 TI - One to one, one to two, two to one? What is the rhythm? PMID- 25696310 TI - An unusual case of syncope. PMID- 25696312 TI - ? PMID- 25696313 TI - ? PMID- 25696314 TI - 28 April 2004: 70 years Netherlands Society of Cardiology: What has it brought and taught us? PMID- 25696315 TI - Long-term follow-up of coronary angioplasty in patients with diabetes compared with nondiabetics. AB - BACKGROUND: Some reports have indicated that in patients with diabetes mellitus and multivessel disease, coronary artery bypass surgery is preferred over percutaneous coronary intervention (PCI). We retrospectively compared outcome PCI in diabetic and nondiabetic patients. METHODS: Ninety-seven diabetics and 971 nondiabetics were included and randomised before PCI to aspirin alone or aspirin plus coumadin. Fifty diabetics and 481 nondiabetics underwent follow-up angiography. The primary endpoint comprised all-cause mortality, myocardial infarction or targetvessel revascularisation. RESULTS: Baseline characteristics were similar between the groups except for significantly more males and smokers among the nondiabetics. The diabetics had significantly more previous strokes, more left anterior descending coronary artery disease as well as more restenotic lesions and multivessel disease. At 30 days, the primary endpoint had occurred in five diabetics (5.2%) and 47 nondiabetics (4.9%), (p=0.8) and at one year in 17 (17.5%) and in 165 (17.1%), respectively (p=0.9). Event-free survival remained comparable during long-term follow-up (four years). Multivariate analysis showed no differences for the occurrence of any event (p=0.9, 95% CI 0.6-1.7). At six months, the minimal luminal diameter was significantly smaller in the diabetics (1.55+/-0.76 mm vs. 1.78+/-0.66 mm, p=0.01). Diabetics also had more restenosis (41% vs. 23%, p=0.003). CONCLUSION: Despite angiographical differences at six months between the diabetics and nondiabetics, both short-term and long-term clinical follow-up appeared to be similar. PMID- 25696316 TI - Prehospital triage for angiography-guided therapy for acute myocardial infarction. AB - BACKGROUND: Time between symptom onset and effective reperfusion is of paramount importance in patients with acute myocardial infarction (MI) treated with reperfusion therapy. In the PHIAT (Pre-Hospital Infarction Angioplasty Triage) project, safety and feasibility of in-ambulance electrocardiography facilities for prehospital triage for direct transfer to an interventional centre to undergo immediate coronary angiography and angiography-guided therapy were evaluated. METHODS AND RESULTS: The ambulances were equipped with a defibrillator and electrocardiography unit with computerised electrocardiographic analysis. Patients with acute MI symptoms and fulfilling certain criteria compatible with a large MI were included and pretreated with heparin and aspirin during transportation. During the study period, 284 patients were included. Eleven percent did not have an acute MI. PCI, performed in 94% (n=239) of the patients, was successful in 94%. Prehospital triage reduced time to treatment. In 32% of the patients triage resulted in direct transportation to the interventional centre instead of to the nearest community hospital. All-cause mortality was 9% after a mean follow-up of nine months. No serious bleeding complications were seen. CONCLUSION: Prehospital triage in the ambulance is safe and feasible. A striking percentage (11%) of the identified patients does not have an acute MI and this is more than has been reported from prehospital thrombolysis trials. PMID- 25696317 TI - Recommendations and cardiological evaluation of athletes with arrhythmias: Part 1. AB - Besides the consensus meeting in Amersfoort in 1988 and the Bethesda conference in 1994 recommendations are not available in the Netherlands for screening and evaluation of athletes with cardiac arrhythmias. Guidelines for competitive athletes with cardiac arrhythmias in the United States and Italy were published in 2000. In 1998 Estes et al. published the most important opinions on sudden cardiac death, screening and evaluation of athletes and arrhythmias. This study addresses the physiological and morphological consequences of athletic training, cardiac pathology and risk stratification for sudden cardiac death. Recommendations for competitive athletes with cardiovascular abnormalities, arrhythmias and proposals for specific protocols are given. PMID- 25696318 TI - Congenital and drug-induced long-QT syndrome: an update. AB - The congenital long-QT syndrome is a potentially life-threatening condition characterised clinically by prolonged QT intervals, syncope and sudden cardiac death. The abnormally prolonged repolarisation is the result of mutations in genes encoding cardiac ion channels. The diagnosis of long-QT syndrome is based on clinical, electrocardiographic, and genetic criteria. Beta-blocking therapy is important in the treatment of long-QT syndrome, although pacemakers and implantable cardioverter defibrillators (ICD) are useful in certain categories of patients. In the near future, mutation-specific treatment will probably become a novel approach to this potentially lethal syndrome. Drug-induced long-QT syndrome has been associated with silent mutations and common polymorphisms in potassium and sodium channel genes associated with congenital long-QT syndrome. Genetic screening for such mutations and polymorphisms may become an important instrument in preventing drug-induced 'torsades de pointes' arrhythmias in otherwise asymptomatic patients. PMID- 25696320 TI - The lost coil. PMID- 25696319 TI - Transhepatic approach for catheter ablation of accessory pathway in a child with complex congenital heart disease. AB - We report on a 22-month-old boy with drug-resistant atrioventricular reentrant tachycardia and complex structural heart disease consisting of right atrial isomerism, mirror image orientation of the intrathoracic veins, hemi-azygos continuation to the left superior vena cava, separate drainage of the hepatic veins into the left-sided atrium, congenitally corrected transposition, pulmonary atresia, and atrial and ventricular septal defects. Access to the heart for radiofrequency (RF) ablation was obtained by percutaneous puncture of a hepatic vein, the left internal jugular vein, and femoral artery. The accessory pathway was localised to the free wall of the left-sided AV groove and successfully ablated. There were no procedure-related complications. RF ablation of an accessory pathway is feasible in young children with complex structural heart disease and abnormal systemic venous return. In such patients access to the heart must be planned with knowledge of the anatomy and judicious use of the hepatic venous approach. PMID- 25696321 TI - Syncopated rhythm. PMID- 25696322 TI - Heart failure: chapter 1. Pathophysiology and molecular aspects of heart failure. PMID- 25696323 TI - ? PMID- 25696324 TI - ? PMID- 25696325 TI - University News: Einthoven Dissertation Prizes 2003. PMID- 25696326 TI - MS-CT coronary angiography - an emerging technique. PMID- 25696327 TI - Taekling the challenges of interpretation of conventional coronary angiography using multidetector CT coronary angiography. AB - BACKGROUND: Although conventional catheter angiography is still regarded as the gold standard for anatomical visualisation of the coronary artery tree, it faces a number of challenges and pitfalls concerning the interpretation of the acquired images. AIM: The aim of this review is to demonstrate that multidetector computed tomography (MDCT) can provide information that is not or only partially acquired by coronary angiography (CAG). METHODS: For different interpretation issues and pitfalls, we establish whether MDCT can provide better, i.e. more standardised and reproducible, information on the basis of both the properties of the technique and clinical examples. RESULTS: Advantages of MDCT are full three- and four-dimensional coverage of the heart and contrast enhancement of all vascular compartments together with a superior low contrast resolution. MDCT shortcomings are the low temporal resolution and related to this the lack of flow information compared with catheter coronary angiography. MDCT is shown to meet most of the blind spots and pitfalls described for catheter coronary angiography. CONCLUSION: Cardiac and coronary MDCT provides diagnostic information, which equals CAG diagnosis in most cases, and in some cases even provides a better diagnosis. This could influence the value of the sensitivity and specificity numbers published comparing noninvasive techniques with catheter coronary angiography (gold standard). Due to the added advantages of CT and its continuous improvement of temporal and spatial resolution, it might eventually replace diagnostic catheter coronary angiography. PMID- 25696328 TI - Validation of Fick cardiac output calculated with assumed oxygen consumption: a study of cardiac output during epoprostenol. AB - OBJECTIVE: To test the validity of using assumed oxygen consumption for Fick cardiac output during administration of epoprostenol. METHODS: In 24 consecutive patients Fick cardiac output calculated with assumed oxygen consumption according to LaFarge and Miettinen (COLM) and according to Bergstra et al. (COBE) were compared with thermodilution cardiac output (COTH). Pulmonary vascular resistance (PVR) was calculated with each cardiac output (CO) value. If PVR exceeded 200 dyne.s.cm-5, administration of epoprostenol (Ep) was started, and at maximal dose the above-mentioned measurements were repeated. RESULTS: In all 24 patients COBE agreed significantly with COTH, mean difference -0.145 1.min-1, 95% confidence interval (CI) -0.402 to 0.111, limits of agreement (LA) -1.336 to 1.045. COLM was significantly lower than COTH, -1.165 1.min-1, p<0.05, 95% CI -1.510 to -0.819, LA -2.768 to 0.438. In 16 patients (67%) administration of epoprostenol was indicated. During Ep infusion the CO values calculated with oxygen consumption according to LaFarge and Miettinen (EpCOLM) were also significantly lower than thermodilution CO (EpCOTH), mean difference -1.281 1.min-1, p<0.05, 95% CI -1.663 to -0.900, LA -2.685 to 0.122. The agreement of CO values calculated with oxygen consumption according to Bergstra et al. (EpCOBE) and EpCOTH remained, mean difference -0.115 1.min-1, 95% CI -0.408 to 0.178, LA -1.191 to 0.962. CONCLUSION: Before as well as during administration of epoprostenol, it is justified to use CO values calculated with oxygen consumption according to Bergstra et al. instead of thermodilution CO; CO values calculated with oxygen consumption according to LaFarge and Miettinen show significant underestimation. PMID- 25696330 TI - Ten greatest discoveries of the 20th century in cardiovascular medicine. AB - The Netherlands Society of Cardiology (NVVC) was founded 70 years ago on 28 April 1934. When looking back at the history of our Society on its 70th anniversary, it might be a nice opportunity to mention ten great discoveries in cardiology in the 20th century. PMID- 25696329 TI - Recommendations and cardiological evaluation of athletes with arrhythmias: Part 2. AB - Confronted with a competitive or recreational athlete, the physician has to discriminate between benign, paraphysiological and pathological arrhythmias. Benign arrhythmias do not represent a risk for SCD, nor do they induce haemodynamic consequences during athletic activities. These arrhythmias are not markers for heart disease. Paraphysiological arrhythmias are related to athletic performance. Long periods of endurance training induce changes in rhythm, conduction and repolarisation. These changes are fully reversible and disappear when the sport is terminated. Pathological arrhythmias have haemodynamic consequences and express disease, such as sick sinus syndrome, cardiomyopathy or inverse consequences of physical training. Arrhythmias can be classified as bradyarrhythmias and tachyarrhythmias. Conduction disorders can be seen in fast as well as in slow arrhythmias. PMID- 25696331 TI - Coexistence of a bradycardia- and tachycardia-dependent bundle branch block. AB - Aberrant ventricular conduction is a rare phenomenon as compared with the more frequently occurring antrioventricular conduction disturbances. It leads to widening of the QRS complex, which is either due to a complete or functional block in one of the bundle branches or a block within the intramyocardial conduction system itself. Mechanisms that are potentially involved in the genesis of aberrant ventricular conduction are sudden shortening of cycle length (tachycardia-dependent phase III), antegrade block with retrograde concealed conduction, or bradycardia-dependent block (enhanced phase IV). In this paper, we present a patient with aberrant ventricular conduction with the occurrence of a tachycardia-dependent, as well as a bradycardia-dependent bundle branch block, which is an even rarer phenomenon. PMID- 25696332 TI - The FOLLOWPACE study: a prospective study on the (cost-)effectiveness of routine follow-up visits in patients with a pacemaker. AB - In the Netherlands, following implantation of a pacemaker (PM) commonly two or three out-patient follow-up visits are scheduled in the first year to check the patient's health and the PM programme, in order to guarantee optimal patient outcome. Anually, about 200,000 follow-up visits of 20 minutes are performed, in total about 80,000 working hours. The question arises whether and to what extent these regular follow-up checks are truly necessary for the prognosis of the patient and whether they are cost-effective. Yet no information is available on how frequently and extensively a routine PM follow-up visit should be performed. This is probably because it is largely unknown which factors - either documented at PM implantation or at the follow-up visits - predict the occurrence of complications. The FOLLOWPACE study is designed to address these issues. Below we briefly discuss the rationale, objectives and expected results of FOLLOWPACE. PMID- 25696334 TI - Out of the frying pan and into the fire. PMID- 25696333 TI - Intracardiac mass in right atrium with nonfatal embolisation to right pulmonary artery. PMID- 25696335 TI - Heart failure: chapter 2. Epidemiology: prevalence, incidence, prognosis. PMID- 25696336 TI - ? PMID- 25696337 TI - ? PMID- 25696338 TI - The ONTARGET trial programme: new HOPE for the future: New Orleans, 9 March 2004. PMID- 25696339 TI - The endocannabinoid system, a new target to multi-risk management: New Orleans, 10 March 2004. PMID- 25696340 TI - University News: Einthoven Dissertation Prizes 2004. PMID- 25696341 TI - Recommendations for pacemaker implantation for the treatment of atrial tachyarrhythmias and resynchronisation therapy for heart failure. PMID- 25696342 TI - Exercise: integral part in the multidisciplinary approach to heart failure management? PMID- 25696343 TI - Primary prevention: prime time?: ICD trials (and tribulations). PMID- 25696344 TI - Impaired platelet inhibitory effect of a single dose of acetylsalicylic acid in patients with unstable coronary artery syndrome in comparison with healthy volunteers. AB - BACKGROUND AND AIM: Controversial reports have been published about the efficiency of potent platelet inhibitors in patients with coronary artery syndrome (CAS). We therefore questioned whether a functional change in platelets affects the patient's response to ASA. STUDY DESIGN AND METHODS: Nineteen consecutive patients presenting with unstable coronary syndrome and 15 healthy volunteers were included. No platelet inhibitory drugs or coumarin were used in either group before the study. Platelet aggregation tests were performed on baseline samples and after a single dose of ASA. Afterwards, all patients underwent coronary angiography to exclude non-CAS. RESULTS: In the patient group (n=15 after exclusion) no significant increase in bleeding constant was found after ASA, using a PFA analyser, in contrast to the control group. The maximal velocity and the maximal percentage optical platelet aggregation using ADP was significantly more reduced in the control group. ASA did not significantly reduce the thromboxane B2 production in the patient group. CONCLUSION: ASA has less platelet inhibitory effects in patients with unstable CAS in comparison with healthy volunteers. Platelets, in the hyperactive state of unstable CAS, prove to be less subject to inhibition. This might add to the explanation of the lack of efficiency of platelet inhibitory drugs to prevent thrombotic complications after PTCA and platelet aggregation onto stent surfaces in patients with acute CAS. PMID- 25696345 TI - Statin therapy and mortalitiy in patients with ST-segment elevation myocardial infarction treated with primary angioplasty. AB - BACKGROUND: Statin therapy can reduce long-term mortality in several subgroups of patients with coronary artery disease, but the benefits after primary angioplasty for ST-segment elevation myocardial infarction (STEMI) have yet to be established. Thus the aim of the current study was to determine whether statin therapy is associated with a reduction in mortality in patients with STEMI treated with primary angioplasty. METHODS: Our population is represented by a total of 1513 consecutive in-hospital survivors treated with primary angioplasty for STEMI between April 1997 and October 2001. Patients were divided into two groups according to statin therapy (statin group, n=893; control group, n=620) at discharge. Clinical follow-up was performed at one year. Multivariate analysis was performed including a propensity score for statin use. RESULTS: At one-year follow-up statin therapy was associated with a significantly lower mortality (1.2 vs. 71.%, RR [95% CI] 0.16 [0.09-0.32], p<0.0001). Also at multivariate analysis, including the propensity score, statin therapy was associated with a significant mortality reduction (adjusted RR [95% CI] 0.24 [0.12-0.47], p<0.0001). CONCLUSION: Statin therapy at discharge was associated with a significant reduction in one-year mortality after primary angioplasty for STEMI. Therefore, the use of statins after STEMI is highly recommended. PMID- 25696346 TI - Physical training in patients with chronic heart failure: An elaboration of the statements from the Committee on Cardiac Rehabilitation of the Netherlands Society of Cardiology and the Netherlands Heart Foundation and review of studies on physical training in chronic heart failure. AB - Chronic heart failure (CHF) can be defined as a complex of symptoms and signs caused by cardiac dysfunction. Dyspnoea on exertion, fatigue, reduced exercise tolerance and fluid retention are hallmarks of the syndrome. Reduced peripheral blood flow, endothelial dysfunction, alterations in skeletal muscle structure and function, an increased activity of the muscle ergoreflex, as well as autonomic and neurohormonal activation reduce exercise performance, ultimately leading to physical deconditioning in CHF patients. The beneficial effects of physical training for CHF patients are increasingly acknowledged. Based on European and American guidelines on physical training in CHF, results from controlled randomised trials (summarised in this paper) and expert opinions, the Dutch Committee on Cardiac Rehabilitation has formulated statements on physical training in CHF. In addition, recommendations implementing physical training programmes in CHF patients are given. The selection criteria, contraindications and methods, and duration of a physical training programme in heart failure are discussed. Concomitant with the training programme, a multidisciplinary intervention programme is needed to stimulate patients to adopt and maintain an active and healthy lifestyle. PMID- 25696347 TI - A review of pulmonary arterial hypertension: Part 1. Novel insights and classification. AB - Pulmonary arterial hypertension (PAH) is a disease characterised by an increased pulmonary artery pressure. The precapillary pulmonary arteries show distinct pathobiological changes, i.e. medial hypertrophy, intimal fibrosis, microthrombi and plexiform lesions. Although the pathogenesis is not completely understood, pulmonary vascular proliferation and remodelling, due to a variety of mediators, is believed to play the pathogenetic key role. Genetic research reveals molecular deformities and gene mutations associated with phenotypic PAH. This article covers novel insights into pathobiology, pathogenesis and genes of PAH, which led to a novel classification system and a diagnostic work-up, emanated from the World Health Organisation Symposium on Pulmonary Hypertension in Venice in June 2003. PMID- 25696349 TI - Cor triatriatum. PMID- 25696348 TI - Arteriovenous fistula after intervertebral disk surgery at L4-L5. AB - We describe a 34-year-old woman who had symptoms of heart failure due to an arteriovenous fistula between the right iliac artery and the inferior vena cava caused by surgery for a herniated intervertebral disk. The literature is reviewed. An intra-arterial placed covered stent was successfully used to close the fistula. PMID- 25696350 TI - Midventricular obstruction causing abnormal flow patterns in hypertrophic cardiomyopathy. PMID- 25696351 TI - I think a niece of mine was referred to a neurologist. PMID- 25696353 TI - ? PMID- 25696352 TI - Heart failure: chapter 3. Underlying pathology in heart failure 'Failure of the circulation versus failure of the heart' PMID- 25696354 TI - ? PMID- 25696355 TI - Differences in guidelines for the diagnostic evaluation and treatment of atrial fibrillation. PMID- 25696356 TI - Safety, efficacy and costs associated with direct coronary stenting compared with stenting after predilatation: A randomised controlled trial. AB - OBJECTIVES: Comparison of the in-hospital success rates, procedural costs and short-term clinical outcomes of direct stenting versus stenting after balloon predilatation. METHODS: Altogether, 400 patients with angina pectoris and/or myocardial ischaemia due to coronary stenoses in a single native vessel were randomised to either direct stenting or stenting after predilatation. Baseline characteristics were evenly distributed between the two groups. RESULTS: Procedural success rates were similar (96.0% direct stenting group vs. 94.5% predilatation) as well as final successful stent implantation (98.3 vs. 97.8%), while the primary success rate of direct stenting alone was 88.3%, p=0.01. In multivariate analysis, angiographic lesion calcification was an independent predictor of unsuccessful direct stenting (odds ratio 7.1, 95% confidence interval 2.8-18.2, p<0.0001). Rates of troponin I rises >0.15 MUg/l, used as a measure of distal embolisation, were similar in both groups (17.8 vs. 17.1%). Rates of major adverse cardiac events at 30 days were 4.5% in the direct stenting group versus 5.5% in the predilated group (ns). Direct stenting was associated with savings in fluoroscopy time, and angiographic contrast agent use, and a reduction in utilisation of angioplasty balloons (0.4 vs. 1.17 balloons per patient, p<0.001). Mean per patient procedural costs associated with direct stenting versus predilatation were ?2545+/-914 versus ?2763+/-842 (p=0.01), despite the implantation of more stents in the directly stented group. CONCLUSION: Compared with a strategy of stenting preceded by balloon predilatation, direct stenting was equally safe and effective, with similar in hospital and 30-day clinical outcomes, and modest procedural cost-savings. A calcified lesion predicted unsuccessful direct stenting. PMID- 25696357 TI - Secondary prevention after PCI: the cost-effectiveness of statin therapy in the Netherlands. AB - BACKGROUND: Little is known about the cost-effectiveness of secondary prevention after percutaneous coronary intervention (PCI). The aim of this study was to estimate the cost-effectiveness of statin therapy. METHODS: A cost-effectiveness analysis was performed using data from the Lescol Intervention Prevention Study (LIPS). In the LIPS trial, patients with normal-to-moderate hypercholesterolaemia who had undergone a first PCI were randomised to receive either fluvastatin 40 mg twice-daily plus dietary counselling or dietary counselling alone. A Markov model was used to estimate the incremental costs per quality-adjusted life year (QALY) and life year gained (LYG). Costs were based on prices and reimbursed charges, utility data were drawn from literature. Monte Carlo simulations and multivariate analysis were used to assess uncertainty. RESULTS: Routine statin treatment costs an additional ?734 (SD ?686) per patient over ten years compared with controls. It resulted in an additional 0.078 (0.047) QALYs or 0.082 (0.041) LYG. The incremental costs per QALY and LYG were ?9312 (?14,648) and ?8954 (?16,617) respectively. Anticipating a willingness to pay of ?20,000 per QALY, there is a 75.1% chance that fluvastatin treatment is cost-effective. CONCLUSION: Statin therapy with fluvastatin is economically efficient with regard to reducing heart disease in the Netherlands when given routinely to all patients following PCI. PMID- 25696358 TI - A review of pulmonary arterial hypertension: Part 2: Current and expected treatments. AB - Medical therapy for pulmonary arterial hypertension (PAH) focuses on pulmonary vascular remodelling and smooth muscle cell proliferation. This article covers the drugs which are approved or are in sight and the evidence-based treatment strategies that target the different pathobiological pathways, emanated from the World Health Organisation Symposium on Pulmonary Hypertension in Venice, June 2003. In addition we briefly look at the 'Venice consensus' on surgical treatment. In the past five and a half years more than 360 patients were seen for pulmonary hypertension in the Free University Medical Centre (VUmc). Present-day treatment, research studies and novel treatment strategies in the VUmc will be reviewed. Future treatments will be on the basis of insights into pathobiology, pathogenesis and genes in PAH and should focus on drug combinations, which theoretically target different or similar pathobiological pathways. PMID- 25696359 TI - Fibrinolysis and primary PCI for ST-elevation myocardial infarction: call for a more refined perspective. AB - The latest meta-analysis comparing fibrinolysis with primary percutaneous intervention (PCI) has fuelled the discussion regarding the best reperfusion therapy for acute ST-elevation myocardial infarction. As far as patients presenting to centres with intervention facilities are concerned, the superiority of primary PCI has been unequivocally demonstrated. However, only a small proportion of patients with St-elevation myocardial infarction primarily present to an intervention centre, the majority go to a hospital without these facilities. The optimal reperfusion strategy for patients presenting to a nonintervention centre or for patients presenting in the prehospital setting has been studied less extensively and the question remains as to whether all these patients should be transferred to an intervention centre to undergo primary PCI. The available data to date on interhospital transport for primary PCI do show a mortality benefit for primary PCI. Yet, as far as inferences to clinical practice are concerned, it remains to be seen whether these studies are truly representative: almost half of patients in the transportation trials received streptokinase, they were treated relatively late, and the subsequent revascularisation strategy was rather conservative. The impact of primary PCI as compared with prehospital fibrinolysis in patients presenting in the prehospital setting has so far only been addressed in the randomised CAPTIM trial, without significant differences in outcome. Additional studies are warranted, with early treatment as primary focus. For patients presenting to non-intervention centres or prehospitally, the impact of triage, and of combined pharmaco-invasive reperfusion strategies are promising fields of further exploration. PMID- 25696360 TI - Arrhythmogenic right ventricular dysplasia as a possible cause of sudden cardiac death: a case report and clinical review. AB - Sudden cardiac death can be described as an unexplained natural death due to a cardiac cause. It occurs within a short period, one hour or less, after onset of symptoms in a person without any prior medical history. Among the many causes of unexplained sudden cardiac death, we would like to specifically discuss arrhythmogenic right ventricular dysplasia as a rare cause in otherwise healthy and usually young individuals. PMID- 25696361 TI - A 60-year-old male with dyspnoea. PMID- 25696362 TI - Just one collapse during soccer. PMID- 25696363 TI - ? PMID- 25696364 TI - Scientific meeting on the 40th Anniversary of the NHF and the 70th Anniversary of the NSC: 15 April 2004, Pieterskerk Leiden. PMID- 25696366 TI - Abstracts Nederlandse Vereniging voor Thoraxchirurgie: 14 May 2004. PMID- 25696365 TI - Results of the MATCH trial on stroke prevention: Mannheim, 13-14 May 2004. PMID- 25696367 TI - A wake-up call for male/female disparities in coronary heart disease. PMID- 25696368 TI - Mitral valve regurgitation: accurate blood flow quantification with MRI. AB - BACKGROUND: The quantification of transvalvular blood flow through the mitral valve (MV) and regurgitant flow in particular is difficult with echocardiography, which is the method of choice to diagnose patients selected for valve repair or replacement. With magnetic resonance imaging, information on the intraventricular blood flow can be obtained. Several scanning techniques have attempted to assess the regurgitant flow. These techniques either do not directly assess the complete flow through the MV, or they do not measure the flow at the location of the valve. AIM: To investigate the accuracy of a novel method using three-directional velocity-encoded MRI to acquire the transvalvular blood flow directly from the intraventricular blood flow field, also representing the regurgitant flow during systole. METHODS: Ten volunteers without cardiac valvular disease were recruited. The transvalvular MV flow volume was measured with three-directional velocity encoded MRI (3-dir MV flow). RESULTS: The transvalvular flow measurements correlate very well with the flow measured in the aorta (rp=0.92, p<0.01). The small differences (mean -5+/-7 ml) are insignificant (p=0.06) and demonstrate the high accuracy of the new method. Intra- and inter-observer studies showed non significant mean differences of 0.9+/-5.1 ml and 1.3+/-5.6 ml, respectively, thereby proving the high reproducibility. CONCLUSION: Three-directional velocity encoded MRI is a patient-friendly and easy-to-use method suitable for quantifying the regurgitant MV flow in clinical practice. PMID- 25696369 TI - BEta versus Gamma Utrecht Trial-Cypher (BEGUT-CYPHER): Is intracoronary brachytherapy still superior to drug-eluting stents? AB - DESIGN: Prospective, randomised single-centre pilot study comparing a beta with a gamma source and a sirolimus-eluting stent in patients with an estimated high risk of restenosis (40 to 50%). PURPOSE: Although the majority of patients referred for revascularisation are now being treated with percutaneous coronary intervention (PCI) combined with stenting, a small number still suffer from recurrent restenosis which can be invalidating for the patient and frustrating for the cardiologist due to repeated PCIs. In this prospective single-centre pilot study we will test the hypothesis of three different treatment strategies to use in this special patient subset, to determine if we can find a positive 'trend' in one arm, in order to either make a selection for one of the treatment strategies, or to provide a base to expand the study into a larger multicentre randomised study. TIME COURSE AND ENROLLMENT: A total of 120 patients will be included, 40 in each treatment arm. All patients with either in-stent and/or native restenosis and/or diabetics and/or type C lesions (ACC/AHA) are eligible. The usual exclusion criteria for intracoronary brachytherapy and prolonged antiplatelet therapy are applied. All lesions <44 mm in length and with a vessel diameter 2.4>4.0 mm are suitable. Angiographic, intravascular ultrasound imaging and clinical follow-up at one year will become available in the first quarter of 2005. PMID- 25696370 TI - Local drug and gene delivery through microbubbles and ultrasound. AB - Although gene therapy has great potential as a treatment for diseases, clinical trials are slowed down by the development of a safe and efficient gene delivery system. In this review, we will give an overview of the viral and nonviral vehicles used for drug and gene delivery, and the different nonviral delivery techniques, thereby focusing on delivery through ultrasound contrast agents. The development of ultrasound contrast agents containing encapsulated microbubbles has increased the possibilities not only for diagnostic imaging, but for therapy as well. Microbubbles have been shown to be able to carry drugs and genes, and destruction of the bubbles by ultrasound will result in local release of their contents. Furthermore, ligands can be attached so that they can be targeted to a specific target tissue. The recent advances of microbubbles as vehicles for delivery of drugs and genes will be highlighted. PMID- 25696371 TI - Methods in molecular cardiology: in silico cloning. AB - Advancements in sequencing technology have made it possible to obtain more information about the DNA sequence, structure and the transcript products of the genome from different species. This information is collected in DNA databases. These databases contain many genes of which the functions have not yet been discovered. By using online biotechnology tools novel genes and their transcripts can be identified. The identification of novel genes using DNA database analysis is referred to as in silico cloning. In silico cloning may not only provide new information on genes and their biological function, it may also lead to identification of molecular targets for drug discovery activities. In this review we describe the process of in silico cloning and its application in biomedical research. PMID- 25696372 TI - 'Brugada ECG' elicited by imipramine overdose. AB - The ECG hallmark of the Brugada syndrome is ST-segment elevation in the right precordial leads. However, a 'Brugada ECG' may also occasionally be caused by other conditions. We report a case of a Brugada ECG due to an overdose of imipramine, a tricyclic antidepressant. The patient, a 66-year-old woman, was admitted to the emergency unit in a comatose state, due to autointoxication with imipramine. In addition to other signs of massive sodium-channel blockade, the ECG showed typical ST-segment elevation in the right precordial and the inferior leads. The abnormalities resolved quickly after administration of sodium bicarbonate. PMID- 25696373 TI - 'Lost and found': a coronary guidewire remnant. PMID- 25696374 TI - A hormonal FBI. PMID- 25696375 TI - A patient with syncope: a shocking experience. PMID- 25696376 TI - Heart failure: chapter 4. Evaluation of patients with suspected heart failure. PMID- 25696377 TI - A ROADMAP for renal and cardiovascular protection in diabetes patients. PMID- 25696378 TI - Acute intervention for myocardial infarction. PMID- 25696379 TI - NETHERLANDS SOCIETY OF CARDIOLOGY. PMID- 25696380 TI - ? PMID- 25696381 TI - ? PMID- 25696382 TI - 26th Congress of the European Society of Cardiology. PMID- 25696383 TI - Hot line I: Prevention and medical treatment: Munich, 29 August 2004. PMID- 25696384 TI - Hot line II: Acute coronary syndromes/medical treatment II: Munich, 29 August 2004. PMID- 25696385 TI - Hot line III: Inflammation in coronary disease: Munich, 30 August 2004. PMID- 25696387 TI - Genetic tools in cardiovascular disease - what should the clinician know?: Munich, 29 August 2004. PMID- 25696386 TI - Evidence-based clinical application of noninvasive imaging: Munich, 29 August 2004. PMID- 25696388 TI - How to manage the symptomatic patient with atrial fibrillation: Munich, 30 August 2004. PMID- 25696389 TI - INTERHEART - a global study of risk factors for acute myocardial infarction in 52 countries: Munich, 29 August 2004. PMID- 25696390 TI - Management of the asymptomatic patient with valve disease: from guidelines to practice: Munich, 30 August 2004. PMID- 25696392 TI - Diabetes and the heart - the Euro Heart Survey on the diabetic state of patients with coronary artery disease: Munich, 29 August 2004. PMID- 25696391 TI - Cell therapy - the genie is out of the tissue culture bottle: Munich, 30 August 2004. PMID- 25696393 TI - Caring for patients with type 2 diabetes - a responsibility to be shared between cardiologists and diabetologists: Munich, 30 August 2004. PMID- 25696394 TI - Bivalirudin, a new thrombin-specific anticoagulant in acute coronary syndromes and percutaneous coronary intervention: Munich, 28 August 2004. PMID- 25696395 TI - The endocannabinoid system: a new therapeutic target for multi-risk factor management: Munich, 30 August 2004. PMID- 25696396 TI - Revitalising medical options in the treatment of atrial fibrillation: Munich, 30 August 2004. PMID- 25696397 TI - From INSIGHT to ACTION - signposting the future of calcium antagonists in cardiovascular medicine: Munich, 30 August 2004. PMID- 25696398 TI - Reducing cardiovascular risk: dual inhibition for lipid management: Munich, 30 August 2004. PMID- 25696399 TI - Heart failure and the electrical prescription: Munich, 31 August 2004. PMID- 25696400 TI - The metabolic connection in cardiovascular risk: Munich, 31 August 2004. PMID- 25696401 TI - Endothelin receptor antagonism - improving outcomes in pulmonary arterial hypertension: Munich, 31 August 2004. PMID- 25696402 TI - Statin therapy: setting new standards in the management of dyslipidaemia: Munich, 28 August 2004. PMID- 25696403 TI - If channels: a new target for the treatment of stable angina: Munich, 31 August 2004. PMID- 25696404 TI - Optimalisation of preclinical, clinical and chronic care for patients with acute MI: MISSION! possible. PMID- 25696405 TI - Indication and timing of percutaneous mitral balloon valvotomy and the role of atrial fibrillation. AB - Percutaneous transvenous mitral balloon valvotomy (PTMV) has been proven to be an effective and safe method for treatment of patients with severe mitral valve stenosis. This technique has become an accepted alternative for surgical commissurotomy, not only in young patients with pliable valves, but also in selected older patients with extensive valvular pathology. This review highlights the significance of coexisting atrial fibrillation, patient selection and timing of PTMV in patients with mitral valve stenosis. PMID- 25696406 TI - Methods in molecular cardiology: DHPLC mutation detection analysis. AB - An increasing number of mutations have been identified in genes involved in cardiac disorders which has led to novel insights in the pathophysiology of inherited cardiac diseases. As a result of these findings, techniques specialised in automated high-throughput analysis are implemented to handle the increasing number of diagnostic genetic requests. Denaturing high-performance liquid chromatography (DHPLC) is one such novel technique that fulfils the criteria of speed, sensitivity and accuracy. This issue focuses on the basic principle of the technique and illustrates how genetic alterations can be identified. PMID- 25696407 TI - Successful management of postinfarction ventricular septal rupture. AB - Ventricular septal rupture is a rare but devastating complication of acute myocardial infarction. Especially in patients with cardiogenic shock, right ventricular dysfunction or an inferior infarct mortality is very high. We present a case in which an 83-year-old patient survived rupture of the ventricular septum complicating an inferior myocardial infarction. Unlike most patients his haemodynamic status did not deteriorate and delayed elective surgical repair was carried out successfully. PMID- 25696408 TI - Coronary artery spasm: a rare cause of syncope. PMID- 25696409 TI - Appearances can be deceiving. PMID- 25696410 TI - The emerging role of the platelet in the progression and management of atherothrombotic disease: American Heart Association Meeting, New Orleans, Louisiana, November 2004. PMID- 25696411 TI - NATIONAL MULTICENTRE STUDIES. PMID- 25696412 TI - ? PMID- 25696413 TI - Getting to grips with vascular care. PMID- 25696414 TI - ? PMID- 25696415 TI - Preparticipation cardiovascular screening in young athletes in the Netherlands. PMID- 25696416 TI - Measuring quality of life in heart failure: one versus multiple items. AB - BACKGROUND: Symptoms of heart failure and consequences of treatment can have a great impact on patients' lives. Improving quality of life is generally recognised as one of the major goals of treatment. The purpose of this study was to determine the relationship between a one-item quality-of-life measure (Ladder of Life) and the Minnesota Living with Heart Failure Questionnaire and possible equality. METHOD: 231 patients who were admitted with symptoms of chronic heart failure to a cardiology ward in a general hospital (53% male, age 75+/-11, LVEF 40+/-16) completed the Minnesota Living with Heart Failure Questionnaire (MLwHFQ) and were asked to rate their sense of well-being on the Ladder of Life (10= best possible life, 0= worst possible life). Demographic and clinical data were obtained by chart review. RESULTS: The overall well-being score on the Ladder of Life correlated significantly with the total MLwHFQ (r=-0.36, p<0.001). However, there is a large variation in MLwHFQ scores (12-83) in patients who score a relatively high overall well-being (>6, relatively good Q0L). A large variation in MLwHFQ scores (10-105) also exists in patients with a relatively low score on the Ladder of Life (<1, low QOL). CONCLUSION: Assessment of quality of life with a simple and practical tool using the one-item Ladder of Life can give clinicians and researchers important information on the quality of life of patients. Whether such a single-item question is responsive enough to detect changes in treatment and predict readmission needs to be studied in more detail. PMID- 25696417 TI - Practical implications of having a dedicated heart failure programme. AB - BACKGROUND: The prevalence of heart failure (HF) is gaining epidemic proportions. Recent data stress the importance of multidisciplinary strategies for the management of HF patients, but the practical consequences of such programmes remain unclear. OBJECTIVE: To describe our experience with a dedicated heart failure programme involving two HF nurses and a cardiologist. METHOD: All patients admitted to the cardiology department with NYHA class III-IV heart failure were included. After admission, patients received optimal medical therapy according to current guidelines, and extensive instructions from a dedicated HF nurse. On discharge they were given comprehensive lists of medications and symptoms, and a weighing list. They were advised to call a nurse in case of questions or problems. RESULTS: 861 patients were included: 63% >75 years, 47% with LVEF >45%. From 2000 onwards, the number of patients admitted once a year increased but seemed to level off in 2004. Most phone calls involved weight changes as well as general physical complaints. In 1266 (46%) of calls, the medication change was a consequence of a problem raised by the patient. The nurse received and answered almost all phone calls. CONCLUSION: The patient group will grow substantially during the first years of the programme, but the number of patients seen in the outpatient clinic appears to stabilise after five years. Many issues regarding the care of these patients can be handled by the HF nurse. PMID- 25696418 TI - Angioplasty of the left main coronary artery: Mid-term follow-up at University Medical Centre Groningen. AB - BACKGROUND: Coronary angioplasty is being increasingly performed in complex lesions of the unprotected and protected left main (LM) coronary artery. OBJECTIVES: To assess the impact of patient and operator related clinical variables of success and to evaluate the subsequent mid-term effects of percutaneous treatment of LM coronary stenosis. METHODS: In a tertiary referral, high-volume angioplasty centre a total of 118 consecutive surgical and nonsurgical patients with protected and unprotected LM lesions were treated and evaluated in a retrospective observational study. RESULTS: There were 57 protected and 61 unprotected patients, including 13 patients with an acute myocardial infarction (AMI). Mean age was 67 years (range 33-90). The length of the stenotic segment was 4.8+/-2.3 mm, mean lumen diameter 1.1+/-0.6 mm and percentage diameter stenosis 63.6+/-14.6%. There were seven (5.9%) in-hospital cardiac deaths which presented with AMI and cardiogenic shock. All seven patients had unprotected LM lesions. Average follow-up was eight months (range 1 to 36 months). Major adverse cardiac events (MACE) during follow-up comprised eight (6.8%) cardiac deaths, three (2.5%) myocardial infarctions, eight (6.8%) subjects with coronary bypass surgery and 16 (13.6%) repeated angioplasties. The total event rate (MACE, n=43) at the end of the follow-up period was 36.4%. There were more MACE in the unprotected group than in the protected group (41 vs. 31.6%, p<0.05). CONCLUSION: This study supports prior data on LM angioplasty. LM stenting in AMI, however, showed less favourable in-hospital and late outcome. PMID- 25696419 TI - Are cardiac interventions without onsite surgery worth the risk? AB - There is a considerable decline in the use of CABG for failed PCI and the pressure to perform cardiac interventions in centres without onsite surgery is high. But is it necessary to increase the number of PCI centres in a densely populated country as the Netherlands? Advocates for expansion suggest a better patient outcome, but the evidence is not very solid. Arguments such as transport time are probably quite valid in large countries, but do not pertain to the Netherlands. Increasing the number of PCI centres will inevitably lead to fewer procedures per centre, per cardiologist and more complications and higher mortality. Waiting lists are no longer a relevant issue. Other less altruistic reasons might be the driving force. Percutaneous coronary intervention (PCI) is considered a commercially attractive intervention by cardiologists and institutions and seems to be the main motive for extension of the number of PCI centres. PMID- 25696420 TI - Acute coronary syndrome during pregnancy. AB - Two cases of myocardial infarction during the second trimester of pregnancy are presented. Both patients were treated with thrombolytic therapy. In the first case the treatment was successful, in the other patient thrombolysis only temporarily relieved the symptoms. Therefore, angiography was performed and a significant stenosis in the left anterior descending coronary artery was successfully treated with balloon angioplasty. Both women delivered a healthy child, the first child was born at term, the second at a gestational age of 33 weeks. Percutaneous intervention versus thrombolytic therapy in pregnancy is discussed. PMID- 25696422 TI - Intracardiac catheter mimicking right atrial mass. PMID- 25696421 TI - A giant pseudoaneurysm becoming apparent after cardiac resynchronisation therapy. AB - A 57-year-old male patient with coronary artery disease developed a pseudoaneurysm after an inferior infarct in 1997. He underwent coronary bypass surgery and resection of the pseudoaneurysm located at the inferior wall. Unfortunately, the pseudoaneurysm recurred due to dehiscence of the patch, necessitating a second surgical intervention. After six years he developed progressive heart failure due to severe left ventricular dysfunction. He was referred to our institution for cardiac resynchronisation therapy (CRT) because of drug refractory heart failure which was associated with a left bundle branch block, ejection fraction of 12%, and a NYHA class IV status. After successful implantation of a biventricular pacemaker, a remarkable clinical recovery was observed. Left ventricular function improved and echocardiography now demonstrated that the pseudoaneurysm at the inferior wall had recurred for the third time. This diagnosis could not be established by preoperative echocardiography. PMID- 25696423 TI - Heart in heart: Double orifice mitral valve. PMID- 25696425 TI - NATIONAL MULTICENTRE STUDIES. PMID- 25696424 TI - The ECG of a (cardio)myopathy? PMID- 25696426 TI - The AED: realistic policy. PMID- 25696428 TI - Interventional cardiology in the Netherlands. PMID- 25696427 TI - Classical pitfall. PMID- 25696429 TI - MRI for diagnosing aortic valve stenosis: a comparison study of MRI and ultrasound. AB - BACKGROUND: In cases when Doppler ultrasound examinations are not reliable for determining the severity of aortic valve stenosis, patients undergo a catheterisation. Cardiac magnetic resonance imaging (MRI) is a promising tool for the determination of this disease. AIM: We investigated the value of MRI as a substitute for catheterisation in such circumstances, by comparing MRI measurements with Doppler ultrasound measurements. METHODS: Five volunteers and ten patients entered this study, which was approved by the Institutional Ethics Committee. A 1.0T MRI scanner was used for cardiac MRI. On the same day, a Doppler ultrasound examination was performed. The maximum velocity and the orifice area of the aortic valve (called orifice) were compared. RESULTS: A good correlation was observed between the maximum velocity measured with MRI and that measured with ultrasound (r2=0.95) and between the orifice determined by MRI and by ultrasound (r2=0.94); however, the orifice determined by MRI is consistently larger than the orifice determined by ultrasound. CONCLUSION: MRI measurements of velocity and orifice of the aortic valve correlate well with Doppler ultrasound measurement. MRI is a useful diagnostic tool and can be a good substitute for catheterisation, in particular because it allows simultaneous acquisition of anatomical and functional information. PMID- 25696430 TI - Cost-effectiveness of eplerenone plus standard treatment compared with standard treatment in patients with myocardial infarction complicated by left ventricular systolic dysfunction and heart failure in the Netherlands. AB - AIMS: Following the results of the EPHESUS study in patients with heart failure after myocardial infarction, a cost-effectiveness analysis was undertaken from a Dutch societal perspective to evaluate the lifetime benefits and costs of eplerenone as add-on to standard treatment. METHODS: Life-years gained in the eplerenone arm during the trial period were extrapolated to lifetime life-years gained using three sources of life expectancy data (Framingham Heart Study, Saskatchewan Health Database and Worcester Heart Attack Registry). Resource use measured included direct medical costs of hospitalisation, medications including eplerenone, outpatient diagnostic tests and procedures, and emergency room visits. Incremental cost-effectiveness ratios were calculated for life-years gained and quality-adjusted life-years gained. RESULTS: Eplerenone prolonged lifetime survival by five weeks at an additional cost of ?803. The incremental cost-effectiveness ratio was about ?8000 per life-year gained, well below the only published Dutch benchmark for cost-effectiveness of ?18,000. Probabilistic sensitivity analyses showed the results to be robust when varying the discount rate applied to benefits and costs, the hospitalisation costs, and the source of life expectancy data used. CONCLUSION: Treatment with adjunctive eplerenone is effective in preventing deaths and prolonging life. PMID- 25696431 TI - Regional implementation of the NWC guideline on ST-elevation myocardial infarction: Report from the Task Force Prehospital Triage Zuidoost Brabant (PHT ZoB). AB - BACKGROUND: The NVVC guideline on ST-elevation myocardial infarction forms the basis for the regional prehospital triage (PHT) project in Zuidoost Brabant. In this project diagnosis and treatment strategies are determined in the ambulance. AIM: To summarise quality assessment and clinical results after one year. METHODS: We evaluated the protocol and patient record form, the patient's call, assignment of tasks, diagnosis, treatment, time intervals, information to hospitals, cooperation and data transmission. Time delays were compared with time delays in a regional dry run before the start of the project and with time delays reported in the literature. RESULTS: Patients still wait over one hour before seeking medical attention. The GP received the majority (65%) of patient calls. In half of all cases (51%), GPs call the ambulance centre only after they have seen the patient. When the patient calls the ambulance centre (35%), information to the GP is either prompt or absent. In 77% of calls to 112 it remains unclear whether the GP was informed at all. The treatment strategy was correct in 97% of cases. Time between symptoms and call decreased in comparison with our local preliminary investigation. Quality assessment after one year shows protocol deviations that are either logical procedural improvements or correctable flaws with no substantial negative influence. CONCLUSION: Short-term clinical results are good, but structured follow-up is needed to reduce mortality in the long term, especially after thrombolysis. A guideline is a snapshot of a dynamic process. The PHT project allows rapid adaptations to be made to new paradigms. PMID- 25696432 TI - Nuclear cardiac imaging for the assessment of myocardial viability. AB - An important aspect of the diagnostic and prognostic work-up of patients with ischaemic cardiomyopathy is the assessment of myocardial viability. Patients with left ventricular dysfunction who have viable myocardium are the patients at highest risk because of the potential for ischaemia but at the same time benefit most from revascularisation. It is important to identify viable myocardium in these patients, and radionuclide myocardial scintigraphy is an excellent tool for this. Single-photon emission computed tomography perfusion scintigraphy (SPECT), whether using 201thallium, 99mTc-sestamibi, or 99mTc- tetrofosmin, in stress and/or rest protocols, has consistently been shown to be an effective modality for identifying myocardial viability and guiding appropriate management. Metabolic and perfusion imaging with positron emission tomography radiotracers frequently adds additional information and is a powerful tool for predicting which patients will have an improved outcome from revascularisation. New techniques in the nuclear cardiology field, such as attenuation corrected SPECT, dual isotope simultaneous acquisition (DISA) SPECT and gated FDG PET are promising and will further improve the detection of myocardial viability. Also the combination of multislice computed tomography scanners with PET opens possibilities of adding coronary calcium scoring and noninvasive coronary angiography to myocardial perfusion imaging and quantification. PMID- 25696433 TI - Dutch guidelines for interventional cardiology: institutional and operator competence and requirements for training. AB - Interventional cardiology is an expanding field within cardiovascular medicine and today it is generally accepted that cardiologists require specific training, knowledge and skills. Hospitals where coronary interventions are performed must be properly equipped and able to provide specialised care. Percutaneous coronary interventions are frequently used for coronary revascularisation. The public should have confidence in the uniformity of high quality care. Therefore, such quality of care should be maintained by certification of the individual operators, general guidelines for institutional requirements and formal audits. The Netherlands Society of Cardiology (NVVC) will be implementing a new registration system for cardiologists with a subspecialisation that will include registration for interventional cardiology. The NVVC asked the Working Group of Interventional Cardiology (WIC) to update the 1994 Dutch guidelines on operator and institutional competence, and requirements for training in interventional cardiology in order to incorporate them into the official directives. The present guidelines represent the expert opinion of the Dutch interventional cardiology community and are in accordance with international regulations. After two rounds of discussion, the NVVC approved the guidelines in November 2004 during the autumn meeting. PMID- 25696434 TI - Anomalous origin of the left coronary artery connected to the pulmonary artery in a 31-year-old woman. AB - Anomalous origin of the left coronary artery connected to the pulmonary artery (ALCAPA) is a rare congenital defect with a high mortality rate in infancy if left untreated. It may cause myocardial ischaemia and can lead to myocardial infarction, mitral dysfunction, cardiac arrhythmias, heart failure and sudden death. Without operation, survival into adulthood is rare. We report clinical findings, diagnostic characteristics and therapy in a 31-year-old woman with ALCAPA and preserved left ventricular function. PMID- 25696436 TI - The ions have it. PMID- 25696435 TI - Aortic valve perforation as a complication of acute infective endocarditis. PMID- 25696437 TI - NATIONAL MULTICENTRE STUDIES. PMID- 25696438 TI - Incidence and prognosis of myocardial infarction in the Netherlands based on a national record linkage study combining different registers. PMID- 25696439 TI - Hubble, bubble, toil and trouble..: Which way in PV ablation? PMID- 25696440 TI - Pulmonary vein antrum isolation guided by phased-array intracardiac echocardiography: A third way to do PV ablation. AB - BACKGROUND: Pulmonary vein isolation (PVI) has emerged as an important strategy in the treatment of patients with atrial fibrillation (AF). The two most frequently used techniques are segmental PVI and left atrial circumferential ablation. AIM: To describe and discuss pulmonary vein antrum isolation guided by phased-array intracardiac echocardiography (ICE) as an alternative approach, and to present initial results. METHODS: Patients with symptomatic AF were included. The antra (the larger circumferential area around the PVs) were isolated guided by ICE. ICE was also used to titrate the ablation energy. RESULTS: 38 patients (3 with persistent AF) were included. Of the 35 patients with paroxysmal AF, 24 are without recurrences, and in six the incidence of paroxysms was significantly reduced after one procedure and a mean follow-up of 201 days. No major complications occurred. CONCLUSION: Pulmonary vein antrum isolation guided by ICE is a promising technique in AF ablation and has the potential to avoid severe complications. PMID- 25696441 TI - Evaluation of cardiac emboli source. AB - BACKGROUND: Evaluating the source of cardiac embolism is one of the most frequent reasons for cardiac consultation. METHODS: In 2003, 99 patients were referred for the evaluation of the source of cardiac emboli. Evaluation included history, physical examination, ECG, transoesophageal echocardiography (TOE) with contrast and 24-hour Holter electrocardiography. RESULTS: Altogether, 58 men and 41 women were studied. In 32 patients a possible source of the cardiac emboli was found. Two patients were in atrial fibrillation. Of the patients, 16 had a patent foramen ovale (PFO) and six patients a PFO and atrial septum aneurysm (ASA). Two patients had a thrombus in the left atrial appendage and 14 had severe atherosclerosis in the aortic arch. In eight patients we found two possible cardiac sources of embolism. 24-hour Holter recording did not detect any emboligenic arrhythmias. CONCLUSION: A possible cardiac source of embolism was found in 32% of the patients referred. TOE is the ideal tool to visualise the interatrial septum, left atrial appendage and aortic arch. We advise performing a TOE with contrast in young stroke patients and in older patients with a stroke likely to be caused by an embolism of cardiac origin. 24-hour Holter recording did not detect any emboligenic arrhythmias and should only be done in selected cases. PMID- 25696442 TI - Radiofrequency catheter septal ablation for hypertrophic obstructive cardiomyopathy in children. AB - BACKGROUND: The definitive therapeutic options for symptomatic obstructive cardiomyopathy in childhood are restricted. At present, extensive surgical myectomy is the only procedure that is of proven benefit. PATIENTS AND METHODS: Three patients, aged 5, 11 and 17 years, respectively, with progressive hypertrophic obstructive cardiomyopathy and increasing symptoms were considered for radiofrequency catheter septal ablation. The peak Doppler gradient recorded on several occasions ranged between 50 to 90mmHg. Via a femoral arterial approach, the His bundle was initially plotted and marked using the LocaLisa navigation system. Subsequently, using a cooled tip catheter a series of lesions were placed in the hypertrophied septum, taking care to stay away from the His bundle. A total of 17, 50 and 45 lesions were applied in the three patients. In one case, the procedure was complicated by two episodes of ventricular fibrillation requiring DC cardioversion but without any neurological sequelae. RESULTS: The preablation peak-to-peak gradient between left ventricle and aorta was 50 mmHg, 60 mmHg and 60 mmHg, respectively, and remained unchanged immediately after the procedure. All patients were discharged from hospital 48 hours later. Serial measurement of serum troponin T and CK-MB isoenzyme confirmed significant myocardial necrosis. Follow-up echocardiography both at seven days and at six weeks postablation confirmed a beneficial haemodynamic result, with reduction of left ventricular outflow obstruction and relief of symptoms. CONCLUSION: In young children, in whom alcohol-induced septal ablation is not an option, radiofrequency catheter ablation offers an alternative to surgery, with the benefits of repeatability and a lower risk of procedure-related permanent AV block. PMID- 25696443 TI - Hypertrophic cardiomyopathy in daily practice: an introduction on diagnosis, prognosis and treatment. AB - Hypertrophic cardiomyopathy (HCM) is a complex, inherited cardiac disease that has been subject to intense investigation since it was first described in 1957. Over the past 40 years, understanding has evolved regarding the diagnosis, prognosis and treatment of HCM. Analyses of HCM populations from nonreferral centres have refined the insights into the natural history and the occurrence of sudden cardiac death, which is the most devastating component of its natural history. Therapeutic strategies are diverse and may vary during the course of the disease. Optimal therapy depends on symptoms, haemodynamic findings and the presence of risk factors for sudden cardiac death. At present, invasive therapy for patients with obstructive HCM and drug-refractory symptoms includes surgery or percutaneous transluminal septal myocardial ablation. This report summarises the diagnostic criteria, clinical course and therapeutic management of HCM. Attention is also paid to certain issues of special interest in this disease. PMID- 25696444 TI - Hypothermia resulting in characteristic ECG changes mimicking an acute myocardial infarction: Osborn waves and atrial fibrillation. AB - Hypothermia can cause several ECG changes which can be mistaken for other cardiac diseases, most importantly acute transmural ischaemia. These ECG changes correlate strongly with the degree of hypothermia and the prognosis of the patient. This brief report presents a 32-year-old male who was seen after a drowning accident. After resuscitation a 12-lead electrocardiogram showed changes typical for hypothermia: atrial fibrillation and Osborn waves. The ECG of the patient normalised after rewarming. PMID- 25696446 TI - Right you are. PMID- 25696445 TI - Accelerated idioventricular rhythm: a sign of reperfusion. PMID- 25696447 TI - NATIONAL MULTICENTRE STUDIES. PMID- 25696448 TI - 5th Annual Scientific Meeting NHF: 11 October 2005, Amsterdam. PMID- 25696449 TI - Multidisciplinary heart failure programmes: where do we stand in the Netherlands? PMID- 25696450 TI - Risk factors for drug-induced long-QT syndrome. AB - Congenital long-QT syndrome (cLQTS) is a ventricular arrhythmia that is characterised by a prolonged QT interval on the surface electro-cardiogram (ECG). Clinical symptoms include sudden loss of consciousness (syncopes), seizures, cardiac arrest and sudden death. The prevalence of this inherited disease is approximately one in 10,000 in Caucasians. Over the last decade, more than 200 different diseases causing mutations have been identified in five genes that encode ion channels involved in the delicate balance of inward and outward K/Ca currents during the cardiac action potential. A prolonged QT interval accompanied by very similar clinical symptoms as in cLQTS can also occur in otherwise healthy individuals after the intake of specific drug(s). This phenomenon is known as 'acquired' or 'drug-induced' long-QT syndrome. Because the clinical symptoms of the two forms are very similar, the question arises whether a common underlying genetic basis also exists. Several studies indicate that only a minority (approximately 10%) of the drug-induced LQTS cases can be explained by a mutation or polymorphism in one of the known LQTS genes. Even though the disease can often at least partially be explained by environmental factors, mutations or polymorphisms in other genes are also expected to be involved, including genes encoding drug-metabolising enzymes, adrenergic receptors, hormone-related genes and mitochondrial genes. This article reviews the current knowledge on risk factors for drug-induced LQTS, with a special emphasis on the role of genetic determinants. PMID- 25696451 TI - ACS, myocardial bridging, Tako-tsubo syndrome and mitral regurgitation. AB - Isolated systolic compression of the mid portion of the left anterior descending artery (LAD) by a bridge of overlying cardiac muscle is an infrequent but well recognised angiographic anomaly that is often considered harmless. The long-term prognosis appears to be excellent, but occasional reports of patients with angina pectoris, myocardial infarction and sudden death indicate that this is not always true. The prevalence of the anomaly in the normal population is unknown, but the incidence is low and ischaemic events are rare. Tako-tsubo-like left ventricular dysfunction syndrome (TTS) is characterised by ischaemia, anterior ST-segment elevation, no significant coronary artery disease and reversible ampulla-like left ventricular ballooning in postmenopausal females after emotional or physical stress. Dynamic left ventricular outflow tract (LVOT) obstruction is a rare but potentially fatal complication of acute anterior wall infarction. We present a patient with an acute coronary syndrome (ACS) with ST-segment elevation in the anterior leads, transient TTS and transient LVOT obstruction with systolic anterior motion (SAM) of the mitral valve and severe mitral regurgitation. This is the first report of myocardial bridging associated with TTS, and the first report of TTS associated with dynamic LVOT obstruction with SAM and mitral regurgitation. PMID- 25696452 TI - An unusual case of cardiomyopathy in a 75-year-old woman. AB - In this report we describe a 75-year-old woman who presented with an acute coronary syndrome and transient catecholamine-induced cardiomyopathy with severe pulmonary oedema necessitating mechanical ventilation. During mechanical ventilation several episodes of hypertension occurred despite severe left ventricular systolic dysfunction. A pheochromocytoma was diagnosed and after successful surgical resection the patient's condition improved. Three months after surgery myocardial scintigraphic examination demonstrated a normal ejection fraction and no signs of adenosine-induced ischaemia. PMID- 25696453 TI - A young woman with atypical chest pain. PMID- 25696455 TI - NATIONAL MULTICENTRE STUDIES. PMID- 25696454 TI - Where do the extras come from? PMID- 25696456 TI - ? PMID- 25696457 TI - Reconnaissance conducted by the Netherlands Heart Foundation. PMID- 25696458 TI - ? PMID- 25696459 TI - Strategies and expectations of the use of automated external defibrillators. PMID- 25696460 TI - Inheritance of congenital heart disease. AB - Congenital heart defects (CHD) are the most common developmental anomalies and are the leading noninfectious cause of mortality in newborn babies. It has been estimated that between four and ten live-born infants per 1000 have a cardiac malformation (0.4 to 1.0%), 40% of which are diagnosed in the first year of life. The European Registration of Congenital Anomalies (EUROCAT) reported a prevalence of 58.9/10,000 live births in the northern part of the Netherlands (0.6%). Hoffman estimated that the true prevalence of CHD may be as high as 53 per 1000 pregnancies (5.3%), including a 20% occurrence of heart defects in spontaneous abortion, a 10% occurrence in stillbirth, and a 1% occurrence in live birth. PMID- 25696461 TI - Possible complications of subclavian crush syndrome. AB - A 70-year-old woman with symptomatic Mobitz type II atrioventricular block underwent implantation of a dual-chamber pacemaker 11 years ago. The leads were inserted through a percutaneous puncture of the right subclavian vein, using standard techniques. Both leads were passive fixation leads. Due to battery failure and end of life criteria, the pulse generator (PG) had been routinely replaced six years previously. Predischarge pacemaker control revealed normal pacing, sensing thresholds and impedance for both leads. Because of a syncopal attack subsequent to lead fractures, most likely secondary to right subclavian crush syndrome (SCS) of both leads, she underwent a double lead re-implantation one year after PG replacement by access via left subclavian vein puncture. After a symptom-free period of few years she was re-analysed because of palpitations, dizziness, angina pectoris and tiredness. Pulmonary embolisation and myocardial perfusion defects were detected utilising scintigraphic techniques. Chest X-ray revealed the crushed atrial lead dislocated from the right subclavian region and lodged into the right ventricle towards the inferior septum. Because she was symptomatic, a retrieval technique was applied and the crushed atrial lead was pulled back from the right ventricle and securely fixed to its former position. On maintenance medical treatment, she remains well. PMID- 25696462 TI - Drug-induced long-QT syndrome: a case report. AB - An elderly psychiatric female patient with a long-lasting severe resistant depression was referred for medical examination because of gastrointestinal complaints. The ECG revealed a strongly extended QT interval. No other cardiological abnormalities were observed. The patient's symptoms as well as the QT interval and biochemical abnormalities could be reduced by changing psychiatric drug treatment and reduction of concomitant medication. PMID- 25696463 TI - Magnetic resonance imaging of recurrent left ventricular pseudoaneurysm following surgical repair. PMID- 25696464 TI - An uncommon finding after administration of adenosine. PMID- 25696466 TI - NATIONAL MULTICENTRE STUDIES. PMID- 25696465 TI - Heart failure: chapter 8. Education and counselling of heart failure patients: the role of a heart failure clinic. PMID- 25696467 TI - ? PMID- 25696468 TI - Netherlands Heart Foundation's public campaign on stroke: Recognise a stroke be FAST. PMID- 25696469 TI - ? PMID- 25696470 TI - Arrhythmogenic right ventricular dysplasia/cardiomyopathy: unresolved issues and need for registries. PMID- 25696471 TI - Genetic polymorphisms and endothelial dysfunction in patients with essential hypertension: a cross-sectional case-control study. AB - BACKGROUND: Both in animal models and humans an association between endothelial constitutive nitric oxide synthase (ecNOS) gene polymorphism and the development of hypertension has been found. However, the relation between ecNOS polymorphism and endothelial function in patients with hypertension has not been systematically studied. Genes of the renin-angiotensin system include the angiotensin-converting enzyme (ACE) gene, and the angiotensin II type 1 receptor (ATIR) gene, and have been associated with essential hypertension. However, no consistent data are available about the relation between polymorphisms of these genes and the presence of endothelial dysfunction in such patients. OBJECTIVES: To assess the presence of genetic polymorphisms and of endothelial dysfunction in patients with essential hypertension. To determine the effects of gene polymorphisms on endothelial dysfunction in these subjects. METHODS: In 129 patients with essential hypertension and the same number of age-matched controls polymorphisms of the ecNOS gene, ACE gene, and AT1R gene were analysed by polymerase chain reactions. Endothelial function was assessed by maximal endothelial dependent vasodilation in response to reactive hyperaemia using high resolution ultrasound examinations of the brachial arteries. To assess correlation between genetic markers, endothelial function, and the presence of hypertension both univariate and multivariate analyses were used including Pearson's and Spearman's correlation coefficients, and multiple logistic regressions. RESULTS: The size of endothelium-dependent vasodilation between patients and controls differed by 16% (p<0.02). However, the presence of genetic polymorphisms of the ecNOS, ACE, and AT1R genes did not significantly differ between patients and controls. Neither were there any statistically significant differences in endothelial function between various genotypes of the three genes. This was so for both the patients and the controls, although in all of these comparisons the controls overall displayed a slightly better endothelial function than the patients did. Multiple regression analysis with endothelial dysfunction as dependent and the presence of gene polymorphisms as independent variables did not reveal any significant correlation either. CONCLUSION: A significant relation between endothelial dysfunction and essential hypertension was demonstrated. However, no relations between genetic markers and the presence of essential hypertension or between endothelial dysfunction and genetic markers were established. The failure of our study to demonstrate the latter may be due to confounders. Also, other genes may be more important in the pathogenesis of endothelial dysfunction and essential hypertension. The current study underscores that endothelial dysfunction and hypertension are not simple genetic disorders, and that they are, essentially, multicausal. PMID- 25696472 TI - Changing profile of elderly patients undergoing coronary bypass surgery. AB - OBJECTIVE: Are elderly patients now undergoing CABG at higher risk than several years ago? METHODS: 1536 patients, aged between 70 and 77 years, who underwent CABG between January 1987 and December 2001, were analysed. Group A 1987-1989 (n=177); group B 1990-1992 (n=243); group C 1993-1995 (n=362); group D 1996-1998 (n=418); and group E 1999-2001 (n=336). The Euroscore evaluated operative risk. RESULTS: There was an increase in the percentage of the study population from 12.5 to 24.1% (p=0.000). Mean age increased from 72.1+/-1.8 to 73.2+/-1.9 years (p=0.047). The percentage of patients with neurological (p=0.002), renal (p=0.013) and lung disease (p=0.04), a previous PTCA (p=0.000), left main stenosis (p=0.003), impaired ventricular function (p=0.000) and reoperations (p=0.01) increased. Emergency/urgent operations (p=0.001) decreased. Hospital mortality decreased from 7.3 to 5.7% (p=0.34). Only neurological problems increased significantly (p=0.03). The calculated operative risk by Euroscore remained stable (p=0.28). To eliminate the influence of the urgent/emergency situation, the Euroscore was recalculated, supposing that all patients were elective. At that moment a significant increase in the operative risk was seen (p=0.02). CONCLUSION: Over the last few years there has not only been an increase in the number of older patients undergoing CABG, but even in this older population there is an increasing number of high-risk patients. PMID- 25696473 TI - Reduction of endothelial dysfunction following VEGF gene therapy. AB - BACKGROUND/OBJECTIVES: Vascular endothelial growth factor (VEGF) is a potent angiogenic factor. VEGF gene therapy improves perfusion of ischaemic myocardium in experimental models and possibly in patients with end-stage coronary artery disease. In addition to its proliferative and migratory effect on endothelial cells, it also activates and upregulates eNOS. Therefore, we investigated coronary endothelium-dependent vasodilatation in patients before and after VEGF gene therapy. METHODS: The effect of intracoronary acetylcholine infusion on coronary diameter was assessed at baseline and after three months of follow-up in patients with end-stage coronary artery disease treated with VEGF gene and in controls scheduled for elective PTCA (acetylcholine test at diagnostic angiography and before a subsequently scheduled PTCA). RESULTS: Eight out of ten VEGF patients experienced a reduction in anginal symptoms. Angiographic evidence for improved collateral filling was evident in two out of six patients. The vasoconstrictive response to acetylcholine was partly converted into dilatation. In contrast, the acetylcholine response in control patients remained vasoconstrictive. CONCLUSION: VEGF gene therapy has an important beneficial effect on the functional characteristics of the myocardial vascular network. Therefore, this therapy can potentially play an important role in all stages of the atherosclerotic process. PMID- 25696474 TI - Cerebroprotective effects of angiotensin II (AT 1) receptor antagonists? AB - The results of the Acute Candesartan Cilexetil Therapy in Stroke Survivors (ACCESS) study show that treatment with an angiotensin receptor blocker (ARB) in the acute phase of a stroke improves mortality and cardiovascular morbidity. In addition, direct comparative antihypertensive trials have demonstrated beneficial effects of ARBs in preventing stroke. These possible cerebro-protective effects of ARBs are supported by animal studies, demonstrating that stimulation of the AT2 receptor was related to a reduction in both cerebral infarct size and mortality. In the present report, we review both pathophysiological and clinical evidence for possible cerebroprotective effects of ARBs, independent of their effect on blood pressure. PMID- 25696475 TI - Evaluation of haemodynamics by cardiac catheterisation: historical perspective and present practice. AB - In 1956, three men were awarded the Nobel Prize in Physiology or Medicine, in particular 'for their discoveries concerning heart catheterisation and pathological changes in the circulatory system'. Their names in alphabetical order: Andre F. Cournand, Werner Forssmann and Dickinson W. Richards. Forssmann's experiment dated from 1929, while Cournand and Richards started their work in 1941. The order in which they presented their Nobel lectures on 11 December 1956 was Forssmann, Richards, Cournand. PMID- 25696476 TI - Normalisation of the ECG in a patient with right bundle branch block by cardiac pacing. AB - Right ventricular apical pacing (RVA) appears to have potential deleterious effects on myocardial systolic and diastolic left ventricular function, especially in patients with intact AV conduction. Therefore, new pacing sites in the right ventricle are being explored to overcome these detrimental effects. Alternative pacing sites in the right ventricle are the right ventricular outflow tract (RVOT) and the right ventricular septum (RVS). In this case report, we demonstrate an exceptional form of ventricular fusion, namely normalisation of the QRS complex in a patient with pre-existing right bundle branch block by RVS pacing. To our knowledge, this is the first report in the literature where right ventricular pacing could restore a complete RBBB to a normal QRS complex by stimulating distally from the anatomical position of the RBBB, due to fusion between artificial right ventricular stimulation and intrinsic conduction over the left bundle of the specific His-Purkinje system. PMID- 25696477 TI - Large pseudo aneurysm due to ruptured ostial coronary button after Bentall procedure in a patient with Marfan syndrome. PMID- 25696478 TI - The turtle and the hare. PMID- 25696479 TI - NATIONAL MULTICENTRE STUDIES. PMID- 25696480 TI - The psychological impact of a cardiovascular disease. PMID- 25696481 TI - Beta-blocking agents in congestive heart failure: for each heart failure patient? PMID- 25696482 TI - Depression as an independent determinant of decreased heart rate variability in patients post myocardial infarction. AB - OBJECTIVE: Depression is associated with an increased risk of cardiac morbidity and mortality in patients following myocardial infarction (MI). Our objective was to investigate the potential role of the autonomic nervous system in mediating this detrimental effect. METHODS: The study group consisted of 95 consecutive post-MI patients without depression and 53 post-MI patients with depression. Depressive symptoms were assessed by the Beck Depression Inventory (BDI). Activity of the autonomic nervous system was assessed by analysing heart rate variability (HRV) using 24-hour ambulatory electrocardiographic recordings as obtained three months post MI. RESULTS: Higher age, female gender and left ventricular ejection fraction <0.40 were associated with lower HRV (SDANN, and very-low-frequency and low-frequency power, but not RMSSD and high-frequency power), as was depression. In the multivariate analysis, age and left ventricular ejection fraction but not gender emerged to be independently associated with HRV. After adjustment for these two covariates, depression remained significantly associated with low HRV. CONCLUSIONS: Patients with depression in the present post-MI study are characterised by decreased longer-range HRV compared with the patients without depression, independent of other clinical variables. This observation supports the concept that one of the mechanisms underlying the detrimental effect of depression on post-MI prognosis may be that depression adds to the autonomic derangement post MI. PMID- 25696483 TI - The EuroSCORE as predictor for prolonged hospital and intensive care stay after cardiac surgery? AB - OBJECTIVE: Validation of the EuroSCORE as predictor for a prolonged hospital and intensive care stay after CABG vs. institution-specific scoring systems. METHODS: For the evaluation of a prolonged hospital stay, 3359 patients were included in the analysis of EuroSCORE vs. the CORRAD morbidity score. For a prolonged intensive care stay, 1638 patients were included in the analysis of the EuroSCORE vs. the PICUS score. RESULTS: There was no significant difference in hospital stay between the three different EuroSCORE risk groups. The difference in hospital stay between the high-risk and low-risk groups, identified by the CORRAD morbidity score, was significant (6.9 vs.11.2 days). For a prolonged intensive care stay, the patients identified as high risk by the EuroSCORE and by the PICUS score also had a significantly longer intensive care stay; however, the discriminatory power was low. CONCLUSION: The EuroSCORE is not of value as a predictive system for a prolonged hospital stay. There is a relation between the high-risk patients identified by the EuroSCORE and a prolonged intensive care stay. PMID- 25696484 TI - Mitral valve repair is not always needed in patients with functional mitral regurgitation undergoing coronary artery bypass grafting and/or aortic valve replacement. AB - BACKGROUND AND AIM: Functional mitral regurgitation (FMR) is defined as mitral regurgitation in the absence of intrinsic valvular abnormalities. We prospectively evaluated the effect of coronary artery bypass grafting (CABG) and/or aortic valve replacement (AVR), without additional mitral valve repair, on the degree of moderate or severe FMR. STUDY DESIGN AND METHODS: From a cohort of 2829 patients undergoing CABG and/or AVR in the St. Antonius Hospital, 67 patients were identified with moderate or severe FMR by transthoracic and transoesophageal Doppler echocardiography. RESULTS: Two out of the 67 patients (3%) died perioperatively. During follow-up (3-18 months) mitral regurgitation decreased by one grade in 29 patients, by two grades in 28, by three grades in five patients and remained unchanged in one patient (p=0.0001). Of all patients, 85% had grade I mitral regurgitation or less. Grade II mitral regurgitation remained in nine patients with a previous large myocardial infarction and/or annular calcifications. NYHA class improved from 3.1+0.5 to 1.4+0.4 (p=0.0001). Ejection fraction increased from 46 to 55% (p=0.0001). Overall, left atrial and left ventricular end-diastolic dimensions decreased significantly. In contrast, no decrease in dimensions was seen in patients with postoperative grade II mitral regurgitation. CONCLUSION: FMR may improve significantly following CABG and/or AVR, although a previous large myocardial infarction and/or annular calcifications may affect outcome. PMID- 25696485 TI - The rationale of surgical pulmonary vein isolation for treatment of atrial fibrillation. AB - With the development of less invasive surgical approaches and new ablation techniques, surgical treatment of atrial fibrillation has gained increasing interest over the past decade. Contrary to the complex Maze procedure, new less laborious approaches with pulmonary vein isolation as the main focus are within the reach of most cardiothoracic surgeons. However, although important new pathophysiological mechanisms have emerged in recent years due to extensive basic and clinical research, several uncertainties and hurdles concerning this treatment modality remain. This article reviews the rationale of surgical pulmonary vein isolation, based on these increased insights. Furthermore, important technical aspects including the possible advantages of an epicardial approach, the optimal left-sided lesion set and the need for transmurality are discussed in depth. PMID- 25696486 TI - Hypertension in perspective. AB - Decisions about the management of hypertensive patients should not be based on the level of blood pressure alone, but also on the presence of other risk factors, target organ damage and cardiovascular and renal disease. The results of echocardiography and carotid ultrasonography aids in the stratification of absolute cardiovascular risk as recently advocated by the guidelines of the European Society of Hypertension 2003. Therefore, the detection of target organ damage by ultrasound techniques allows an accurate identification of high-risk patients. Cardiovascular risk stratification only based on a simple routine work up can often underestimate overall risk, thus leading to a potentially inadequate therapeutic management especially of low-medium risk patients. PMID- 25696487 TI - Coronary artery dissection following blunt chest trauma: a case report. AB - Coronary artery dissection following blunt chest trauma is rare. We report the case of a 43-year-old woman who was admitted with a subacute inferior myocardial infarction due to dissection of the right coronary artery. Ten days earlier, she had sustained a minimal chest trauma. The literature is reviewed and management is discussed. PMID- 25696488 TI - Shortness of breath due to an atrial mass. PMID- 25696490 TI - NATIONAL MULTICENTRE STUDIES. PMID- 25696489 TI - Now you see it, now you don't. PMID- 25696492 TI - Einthoven Dissertation Prizes 2004. PMID- 25696491 TI - CAVARIS: the heart of cardiovascular research. PMID- 25696493 TI - Sudden cardiac death and heart failure: can we make a difference? PMID- 25696494 TI - Acute pulmonary congestion in patients with systolic heart failure versus diastolic heart failure: experience of a heart emergency unit. AB - BACKGROUND: Acute pulmonary congestion can be caused by systolic and diastolic heart failure. Whether this distinction is reflected in clinical outcome is unknown. AIM: To compare outcome after an episode of acute pulmonary congestion in patients with systolic heart failure and diastolic heart failure. METHODS: A retrospective, descriptive study was conducted on consecutive patients who presented with acute pulmonary congestion. Clinical outcome was evaluated based on mortality, number of hospital re-admissions, visits to the cardiology outpatient clinic and cardiovascular events. RESULTS: Altogether 86 patients were enrolled in this study: 59 patients (68%) had systolic dysfunction and 27 (32%) had diastolic dysfunction. Mean age was 75.6+/-11.0 in the systolic heart failure group and 80.1+/-9.4 years in the diastolic heart failure group. Mean follow-up was 427 days. Men and women were equally distributed between both patient groups. Re-admission and mortality rates were comparable between both groups. When combining cardiovascular events and mortality, patients with diastolic heart failure had more favourable outcome after acute pulmonary congestion than patients with systolic heart failure (37 vs. 70%, p=0.03). CONCLUSION: The proportions of patients presenting with acute pulmonary congestion due to diastolic heart failure were comparable with those found in literature. Patients were mainly elderly and as often male as female. Readmission and mortality rates were comparable between both patient groups. However, patients with diastolic heart failure had a more favourable prognosis when combining cardiovascular events and mortality. PMID- 25696495 TI - Cost-effectiveness of intracoronary flow velocity measurements and myocardial perfusion scintigraphy for management of intermediate coronary lesions. AB - BACKGROUND: Coronary flow velocity reserve (CFVR) is an alternative for myocardial perfusion scintigraphy (SPECT) in assessing functional severity of coronary lesions. For the acceptance of CFVR in daily clinical decision-making, cost-effectiveness must be proven. AIM: Economic evaluation of different diagnostic management strategies using CFVR compared with SPECT for making decisions regarding use of PTCA of an intermediate coronary lesion in patients with multivessel disease. METHODS: The incremental cost-effectiveness analysis was based on data from a prospective multicentre study in 201 patients with multivessel coronary artery disease. Four management strategies, assuming performance of angioplasty after positive test result(s), were compared: SPECT alone, CFVR alone (cut-off value of 2.0), and combined strategies of SPECT and CFVR with one ('extensive') or two ('restrictive') positive test(s). Probabilistic sensitivity analyses were performed using Monte Carlo simulation. Primary outcome was the probability of a cardiac event-free first year with respect to the intermediate lesion. RESULTS: A 10% event rate was observed, which was predominantly associated with ischaemia-driven revascularisations. A strategy based on CFVR was most effective. The restrictive strategy had the lowest costs and was most cost-effective; with increasing willingness-to-pay values (above ?20,000) a CFVR-alone strategy became equally cost-effective. CONCLUSION: It is mandatory to measure CFVR to decide upon angioplasty of the intermediate lesion in patients with multivessel coronary artery disease. This decision can be based on the restrictive strategy (i.e. performance of PTCA in case of abnormal test results of both SPECT and CFVR) or solely on CFVR, depending on society's willingness-to-pay to prevent cardiac events. PMID- 25696496 TI - Nonmuscle myosin heavy chain-B expression in balloon-dilated and stented arteries: a study in the atherosclerotic Yucatan micropig. AB - BACKGROUND: Restenosis after balloon angioplasty is in part due to remodelling, whereas restenosis after stenting is entirely due to neointima formation. Nonmuscle myosin heavy chain-B (NMMHC-B) is expressed by vascular smooth muscle cells and because of its overexpression in restenotic lesions after balloon angioplasty, NMMHC-B is proposed as a potential therapeutic target. Because the mechanisms underlying restenosis after balloon angioplasty or after stenting are different we hypothesised that the expression of NMMHC-B would differ in balloon dilated versus stented arteries. METHODS: To study the localisation and time course of expression of NMMHC-B, we performed stenting or balloon dilation in peripheral arteries of 16 atherosclerotic Yucatan micropigs and used serial intravascular ultrasound (IVUS) and angiography to measure geometric dimensions following balloon angioplasty or stenting. In situ hybridisation techniques were used to detect NMMHC-B mRNA. 5'-bromo-2'-deoxyuridine (BrdU) was administered to detect proliferating cells. By counting the number of silver grains in the different layers of the artery, we could compare the amount of expression at the different time points between the groups. RESULTS: In intima and media, NMMHC-B expression increased after balloon dilation and stenting and peaked at 7 days. In stented arteries, the expression of NMMHC-B remained high for up to 42 days after injury, whereas in balloon-dilated arteries it had normalised. In the adventitia of balloon-dilated arteries, but not of stented arteries, NMMHC-B expression peaked at 7 days. NMMHC-B expression was not limited to proliferating cells. CONCLUSION: NMMHC-B is expressed near sites of active repair after arterial injury, but not limited to proliferating cells. The different pattern of NMMHC-B expression after balloon dilation compared with stenting may be related to arterial remodelling, because stented arteries that do not remodel lack this conspicuous adventitial expression at 7 days. PMID- 25696498 TI - Adolescent with occluded left main coronary artery. AB - Here we report unexpected findings in a 17-year-old female patient referred for coronary angiography and percutaneous intervention. During the angiography we observed a complete occlusion of the left main coronary artery (LMCA). The occurrence of coronary abnormalities at this age is extremely rare and mostly caused by congenital abnormalities. The diagnosis of premature atherosclerosis at this age is unlikely unless the patient suffers from severe lipoprotein disease. Here we describe a rare case of LMCA occlusion, the most likely cause of the disease and the potential implications for therapy. PMID- 25696497 TI - Potential beneficial mechanisms of insulin (glucose-potassium) in acute myocardial infarction. AB - In the time-span of almost a century, a large amount of experimental evidence has been accumulated that underlines the importance of glucose metabolism during ischaemia/reperfusion of the heart. As early as 1912, Goulston suggested that treatment with glucose could be beneficial in several heart diseases. The first experimental results on the mechanical effects of insulin and glucose in the isolated heart were reported by Visscher and Muller in 1926. In 1935, Evans and colleagues showed that the uptake of glucose is increased in the ischaemic myocardium. Almost 30 years later, Sodi-Pallares and colleagues suggested that metabolic interference during myocardial ischaemia with GIK infusion decreased electrocardiographic signs of ischaemia. They also showed that glucose-insulin potassium (GIK) infusion resulted in a lower occurrence of arrhythmias. They attributed this effect mainly to the influx of potassium in ischaemic cardiomyocytes. In order to further stimulate potassium transport into the cell, insulin was administered. Consequently, the rise of intercellular calcium is curtailed by the influx of potassium and so the incidence of arrhythmias is reduced. However, systemic infusion of insulin stimulates the uptake of glucose in many celltypes, which may result in hypoglycaemic episodes. Consequently, it is not possible to administer potassium and insulin in high concentrations without adding glucose. Interventions in the glucose metabolism in the clinical arena, whether or not used to correct acute hyperglycaemia, encompass three potentially effective elements: glucose, insulin and potassium. PMID- 25696499 TI - 'Spontaneous' cholesterol embolisation syndrome after successful prehospital thrombolysis for acute myocardial infarction. PMID- 25696501 TI - NATIONAL MULTICENTRE STUDIES. PMID- 25696500 TI - It's not what you think it is. PMID- 25696502 TI - Polypill and polymeal: the NHF's view on possible wonder drugs. PMID- 25696503 TI - Piercing the left lung with a pacemaker lead, an uncommon complication. PMID- 25696504 TI - GIK in acute myocardial infarction: lessons from CREATE-ECLA, GIPS II and DIGAMI 2. PMID- 25696505 TI - Anaemia predicts cardiovascular events in patients with stable coronary artery disease. AB - BACKGROUND: Anaemia is an independent risk factor for cardiovascular (CV) events in patients with heart failure and patients with chronic kidney disease. The effect of anaemia on CV outcomes in patients with coronary artery disease (CAD) remains unclear. Therefore, we investigated the prognostic value of anaemia in this group of patients. METHODS: Patients with stable angina pectoris, referred for a first diagnostic coronary angiography, were eligible for this study. Only subjects with significant coronary artery disease (>50% luminal narrowing) were used for analysis (n=143). Cardiovascular events were defined as cardiovascular death, acute myocardial infarction and hospitalisation for unstable angina pectoris. Anaemia was defined according to WHO criteria as haemoglobin level <=8 mmol/l in men and <=7.5 mmol/l in women. RESULTS: The mean age of the population was 61.5+/-9.4 years. During follow-up (44+/-19 months), 19 CV events occurred. The diagnosis of anaemia predicted CV events, even when adjusted for other risk factors (hazard ratio 5.73, 95% confidence interval 1.49-22.13, p=0.01). In univariate analysis, serum erythropoietin levels predicted CV outcomes (p<0.05); however, this association was lost when adjusted for haemoglobin concentration. CONCLUSION: Anaemia is associated with worse outcome in patients with established CAD and could be used as a prognostic indicator in this group of patients. PMID- 25696506 TI - Off-pump coronary artery bypass surgery compared with stent implantation and on pump bypass surgery: clinical outcome and cost-effectiveness at one year. AB - BACKGROUND: Coronary revascularisation by means of surgery or percutaneous intervention plays an important role in the management of patients with ischaemic heart disease. Coronary bypass surgery without cardiopulmonary bypass (off-pump surgery) has been reintroduced into clinical practice to avoid complications related to the use of cardiopulmonary bypass. It is unknown whether off-pump surgery can match the outcomes of bypass surgery with cardiopulmonary bypass (on pump surgery) or intracoronary stent implantation. METHODS: The Octopus study comprised two multicentre randomised trials. In the Octopump trial, on-pump surgery was compared with off-pump surgery (139 vs. 142 patients). In the Octostent trial stent implantation was compared with off-pump surgery (138 vs. 142 patients). The primary cardiac endpoint was survival free from the following cardiovascular events: stroke, myocardial infarction and repeated coronary revascularisation. Secondary endpoints included quality of life and cost effectiveness. The uncertainty surrounding the cost-effectiveness analysis was addressed by bootstrapping. RESULTS: Octopump trial: at one year, event-free survival in the on-pump group was 90.6% and in the off-pump group 88.0% (difference 2.6%, 95% CI-4.6 to 9.8). Quality-adjusted years of life were 0.83 and 0.82 (p=0.81), respectively. On-pump surgery was associated with ?2089 (14.1%) additional direct medical costs per patient (p<0.01). Off-pump was more cost-effective than on-pump surgery in 95% of bootstrap estimates. Octostent trial: at one year, event-free survival in the stent group was 85.5% and in the off-pump surgery group 91.5% (difference -6.0%, 95% CI -13.5 to 1.4). Quality adjusted years of life were 0.82 and 0.79 (p=0.09), respectively. Stent implantation reduced direct medical costs by ?2813 (26.0%) per patient (p=0.01). Stent implantation was more cost-effective in 95% of bootstrap estimates. CONCLUSION: In selected patients eligible for bypass surgery, there was no difference in cardiac outcome between on-pump and off-pump surgery. Off-pump surgery, however, was more cost-effective than on-pump surgery and may be preferred from an economic perspective. In selected patients eligible for percutaneous coronary intervention, stent implantation was more cost-effective than off-pump surgery while maintaining comparable cardiac outcome. Therefore, stent implantation rather than off-pump surgery can be recommended as a first choice revascularisation strategy. PMID- 25696507 TI - Molecular genetic analysis of six Dutch families with atrial fibrillation. AB - BACKGROUND: Atrial fibrillation (AF), the most common cardiac arrhythmia, is characterised by rapid and irregular contraction of the atrium. The risk of AF increases with age and AF increases the risk of various heart disorders, stroke and mortality. AF can occur in a sporadic or familial form. The underlying mechanism leading to AF is not well known but genetic analysis can increase our insight into the molecular pathways in AF. Detailed information on the molecular mechanisms of a disorder increase options for diagnosis and treatment. Recently, a gain-of-function mutation in exon of the KCNQ1 gene located on chromosome 11 was identified in a large Chinese AF family. KCNQ1 associates with KCNE1 or KCNE2 (both located on chromosome 21) to form cardiac potassium channels. Subsequent analysis of Chinese families showed a KCNE2 mutation in two families. Other genetic studies show linkage to chromosome 6 and 10, indicating genetic heterogeneity. A number of studies have shown that altered expression of the atrial connexin40 protein is a risk factor for AF. Connexin genes encode gap junction proteins that are important in cardiac conduction and for normal wave propagation. OBJECTIVES/METHODS: In this study we analysed the role of KCNQ1, KCNE1 coding region and Cx40 promoter region in six Dutch AF families by sequence analysis. CONCLUSION: No mutations were found in these genes. The absence of mutations indicates genetic heterogeneity in familial AF; however, further research is needed. Candidate genes are being sequenced, linkage analysis in a large family will be performed and additional AF families will be collected. PMID- 25696508 TI - The practicing physician's current perspective on therapeutic options in coronary artery disease. AB - Over the past decades the management of patients with stable as well as unstable manifestations of coronary artery disease has evolved in every aspect of routine clinical practice. Modern diagnostic modalities allow reliable and objective assessment of both the anatomical and functional consequences of the early as well as advanced stages of this disease, which remains one of the most important causes of morbidity and mortality worldwide. Pharmacological therapy now includes several classes of drugs with mortality benefits documented by randomised controlled trials. Surgical and percutaneous revascularisation techniques have shown rapid technical improvements and are now applicable in a wide range of clinical conditions. In this paper we will attempt to place the current status of the three therapeutic options for patients with coronary artery disease into perspective. It is important to realise that it is impossible to write a complete overview, a Pubmed search: 'PCI or drug therapy or surgery for coronary artery disease' results in 1,152,117 hits. Therefore, we have chosen the viewpoint of the practicing physician to synthesise this abundance of information in the context of modern clinical practice in a high volume cardiothoracic and cardiological practice. PMID- 25696509 TI - Be smart, don't kick the heart. AB - Blunt chest trauma is a rare cause of cardiac pathology. Nevertheless, a variety of life-threatening cardiac diseases can be caused by blunt chest traumas. In this case report we describe a myocardial infarction associated with kickboxing. We also review the literature describing myocardial infarction associated with blunt chest trauma. PMID- 25696511 TI - One is enough, two is too many. PMID- 25696510 TI - Electrocardiographic findings of life-threatening hypokalaemia. PMID- 25696512 TI - NATIONAL MULTICENTRE STUDIES. PMID- 25696513 TI - Vascular risk management: 1 + 1 makes more than 2. PMID- 25696514 TI - Do we need the cardiologist in the prehospital triage for STEMI? PMID- 25696515 TI - An extended family suddenly confronted with a life-threatening hereditary arrhythmia. AB - OBJECTIVE: This exploratory study serves to illustrate the psychological impact on an extended family in the process of genetic counselling and testing for a potentially life-threatening arrhythmia, the long-QT syndrome (LQTS). METHOD: All members of the third generation and their partners (n=11) were interviewed, the mutation carriers with partners twice. In addition they completed measures for anxiety and depression three times in 18 months. RESULTS: During the interviews these family members emphasised the damaged solidarity when the family is divided into carriers and noncarriers of a mutation in a LQTS predisposing gene. This demonstrates one way in which a family can react to the reality of being at risk of a potentially severe disease. Rewriting family history and mourning early death seem other ways to deal with this. The distress scores, especially of the women, were moderate to clinically high, not because of their own chance of having an arrhythmia but more due to their children's risk. CONCLUSION: Mothers need educational even more than emotional support, because the lifestyle of their carrier children is in need of radical change. The setting of a combined outpatient cardiogenetic clinic with a medical and psychosocial staff meets such needs efficiently. PMID- 25696516 TI - Safety and feasibility of prehospital thrombolysis in combination with active rescue PCI strategy for acute ST-elevation myocardial infarction. AB - BACKGROUND/OBJECTIVES: The purpose of this observational study was to provide an impression of the outcomes of prehospital thrombolysis in combination with an active coronary angioplasty intervention (PCI) strategy for acute ST-elevation myocardial infarction. METHODS: In a group of 151 consecutive patients the following parameters were measured: time delay, percentage of reperfusion, reocclusion, stroke, death, need for PCI and the number of protocol violations. RESULTS: The diagnosis by the ambulance paramedics was made in 8+/-6 minutes, followed by thrombolysis in 13+/-7 minutes (median+/-SD). In 2% (3) of the patients the thrombolytic agent was erroneously administered without complications. The elapsed time from onset of symptoms to treatment was a median of 112+/-77 minutes. Five percent (7) of the patients died in the first 30 days and 2% (3) suffered an intracerebral haemorrhage. Reperfusion was documented in 76% (112) of the patients, from which 18% (20) reoccluded in the following 24 hours. In patients where reperfusion was not established or reocclusion occurred, patients underwent rescue/facilitated PCI: in total 37% (55 patients). After three months 9% (13) of the patients had severly impaired (EF <40%) left ventricular function. CONCLUSION: In our region, we successfully implemented the prehospital thrombolysis system achieving a competitive call-to-needle time and reperfusion rate. The percentage of patients who violated the protocol, suffered an intracerebral haemorrhage, died and/or had severely impaired left ventricular function was acceptable. PMID- 25696517 TI - Myocardial viability assessment: poor correlation between electromechanical cardiac mapping and positron emission tomography in severe coronary artery disease. AB - BACKGROUND: An intracardial electromechanical mapping system has recently been introduced which offers the ability to perform on-line myocardial viability assessment in the catheterisation laboratory. Only a small number of studies have been performed to validate this potentially very useful technique. AIM: We sought to assess the correlation between viability assessment performed with both positron emission tomography (PET) and electromechanical cardiac mapping (EMM) in patients suffering from severe coronary artery disease, since PET is considered the golden standard in myocardial viability assessment. METHODS: Patients undergoing both EMM and PET analysis were systematically scanned for viability assessment. EMM analysis was performed for both linear local shortening and unipolar voltage. PET analysis consisted of dipyridamole stress and fluoro-deoxy d-glucose (FDG) measurements. All data were converted to nine-segment bull's-eye maps to allow comparison. One single operator analysed all the data, blinded for clinical status. RESULTS: 34 patients suffering from severe coronary artery disease underwent both PET and EMM analysis. In total 253 EMM segments had more than four contact points and could be used for analysis. Unipolar voltage showed a trend towards lower values in infarcted segments; however, linear local shortening did not show any correlation. CONCLUSION: In this study viability assessment by EMM did not correspond with PET analysis. Although the advantage of having some form of online myocardial assessment is evident, operators should bare in mind that the quantitative EMM measurements are not an absolute substitute for nuclear imaging. PMID- 25696518 TI - Progress in noninvasive coronary artery imaging using multislice CT. AB - Conventional coronary angiography (CAG) has been the reference standard for the assessment of coronary artery disease since its introduction in 1958. However, several studies have shown that diagnostic CAG has an average morbidity of 2% and a mortality of approximately 0.1%. In the last decade, progress in medical imaging has opened the way to noninvasive assessment of the coronary arteries at lower cost and risk. Of the different modalities, multislice CT (MSCT) has made the biggest step forward. At the 2005 European Congress of Radiology (ECR), experiences with the latest developments in noninvasive coronary artery imaging were reported. This report summarises the advances in the use of MSCT in coronary stenosis detection, emergency decision-making, plaque imaging, and the analysis of cardiac function and late enhancement. Also, attention is paid to new strategies to reduce MSCT-related radiation exposure. PMID- 25696519 TI - Residual angina pectoris after percutaneous coronary intervention for acute coronary syndrome. AB - Fractional flow reserve (FFR) is an important diagnostic tool to guide decision making in the cardiac catheterisation laboratory and for evaluation of percutaneous coronary interventions (PCI). Especially the pressure pullback curve at maximal hyperaemia is convincing in demonstrating the exact location and severity of a coronary stenosis. This pressure pullback curve can also demonstrate the presence of diffuse disease. We present a case in which FFR with pressure pullback curve seven days after a PCI, which did not result in complete symptom relief, indicates the presence of diffuse disease. Based on this result the patient was treated medically. PMID- 25696520 TI - Inferoposterior myocardial infarction originating from an unexpected coronary vessel. PMID- 25696522 TI - NATIONAL MULTICENTRE STUDIES. PMID- 25696521 TI - Management of narrow QRS tachycardia. PMID- 25696523 TI - From Cardiovascular Genomics Initiative to NHF Genomics Task Force. PMID- 25696524 TI - Food for thought and thanks. PMID- 25696526 TI - Abstracts of the Scientific Meeting of the Netherlands Society of Cardiology (NVVC): 21-22 April 2005, Hotel Okura, Amsterdam, Part I. PMID- 25696525 TI - Abstracts of the Scientific Meeting of the Netherlands Society of Cardiology (NVVC): 21-22 April 2005, Hotel Okura, Amsterdam. PMID- 25696527 TI - Abstracts of the Scientific Meeting of the Netherlands Society of Cardiology (NVVC): 21-22 April 2005, Hotel Okura, Amsterdam, Part II. PMID- 25696528 TI - Abstracts of the Netherlands Society of Thoracic Surgery (NvT): 21-22 April 2005, Hotel Okura, Amsterdam. PMID- 25696529 TI - Abstracts of the Netherlands Society of Thoracic Surgery (NvT): 21-22 April 2005, Hotel Okura, Amsterdam. PMID- 25696531 TI - Hot line I: Heart failure/cardiac function: Stockholm, 4 September 2005. PMID- 25696530 TI - 27th Congress of the European Society of Cardiology. PMID- 25696532 TI - Hot line II: Stockholm, 5 September 2005. PMID- 25696533 TI - Hot line III: Stenting/revascularisation/thrombosis: Stockholm, 6 September 2005. PMID- 25696534 TI - Acute myocardial infarction: update 2005: Stockholm, 4 September 2005. PMID- 25696535 TI - Acute coronary syndrome without ST elevation: what is new?: Stockholm, 4 September 2005. PMID- 25696536 TI - Women at heart: Stockholm, 4-7 September 2005. PMID- 25696537 TI - Insights into the management of atrial fibrillation in clinical practice in Europe: results of the Euro Heart Survey on atrial fibrillation: Stockholm, 5 September 2005. PMID- 25696538 TI - Obesity as a global risk factor for cardiovascular disease: Stockholm, 5 September 2005. PMID- 25696539 TI - Highlights on heart failure guidelines: Stockholm, 6 September 2005. PMID- 25696540 TI - The essential role of cholesterol absorption in lipid management: Stockholm, 3 September 2005. PMID- 25696541 TI - Guidelines and beyond: focus on the next move in lipid management: Stockholm, 3 September 2005. PMID- 25696542 TI - Secondary prevention of coronary artery disease: the established role of perindopril: Stockholm, 5 September 2005. PMID- 25696543 TI - Ageing and heart failure: what's new?: Stockholm, 5 September 2005. PMID- 25696544 TI - If inhibition: from pure heart rate reduction to treatment of stable angina: Stockholm, 6 September 2005. PMID- 25696546 TI - Abstracts of the Netherlands Society of Thoracic Surgery (NvT): 7 October 2005, Nieuwegein. PMID- 25696545 TI - Abstracts of the Scientific Meeting of the Netherlands Society of Cardiology (NVVC): 27-29 October 2005, De Heerlickheijd, Ermelo. PMID- 25696547 TI - Congenital coronary artery fistulas in adults; need for a registry? PMID- 25696548 TI - Dutch survey of congenital coronary artery fistulas in adults. AB - AIMS: This Dutch survey focused on the clinical presentation, noninvasive and invasive diagnostic methods, and treatment modalities of adult patients with congenital coronary artery fistulas (CAFs). METHODS: Between 1996 and 2003, the initiative was taken to start a registry on congenital CAFs in adults. In total 71 patients from a diagnostic coronary angiographic population of 30,829 at 28 hospitals were collected from previously developed case report forms. Patient demographic data, clinical presentation, noninvasive and invasive techniques and treatment options were retrospectively collected and analysed. RESULTS: Out of 71 patients with angiographically proven CAFs, 51 (72%) had 63 congenital solitary fistulas and 20 (28%) had 31 congenital coronary-ventricular multiple microfistulas. Patients with pseudofistulas were excluded from the registry. Coronary angiograms were independently re-analysed for morphology and specific fistula details. The majority (72%) of the fistulas were unilateral, 24% were bilateral and only 4% were multilateral. The morphological characteristics of these 94 fistulas were as follows: the origin was multiple in 47% and single in 53%; the termination was multiple in 52% and single in 48%; and the pathway of the fistulous vessels was tortuous/multiple in 66%, tortuous/single in 28%, straight/multiple in 3% and straight/single in 3%. Percutaneous transluminal embolisation (PTE) was performed in two (3%) patients; surgical ligation was undertaken in 13 (18%) patients. The overwhelming majority of the patients (56; 79%) were treated with conservative medical management. The total mortality was 6% (4/71) at a mean follow-up period of approximately five years. Cardiac mortality accounted for 4% (3/71); in all three patients, death could possibly be attributed to the presence of the fistula. CONCLUSION: Registry of congenital coronary artery fistulas in adults in the Netherlands is feasible. In spite of restrictions imposed by the Dutch Privacy Law, it was possible to include 71 adult patients with congenital coronary artery fistulas who were eligible for thorough evaluation. PMID- 25696549 TI - Selection of patients for cardiac resynchronisation therapy (CRT) in an unselected heart failure population. AB - BACKGROUND: In patients with chronic heart failure (CHF), the presence of conduction delay across the myocardium is a well-known feature. During recent years an increasing number of CHF patients have been treated with cardiac resynchronisation therapy (CRT). So far in many protocols patients have been selected using the criteria of left ventricular ejection fraction (LVEF) <=35% concomitant with signs of widening of the QRS on the surface electrocardiogram, either with or without left bundle branch block (LBBB) morphology. METHODS: In this article we discuss which of the patients admitted with CHF to a regular cardiology practice could be candidates for this therapy. Data were obtained from January 2000 to December 2004 on a total of 861 CHF patients, of whom 309 had an LVEF <=35%. Of these patients, 123 patients showed a QRS width >120 msec, while 81 patient had a QRS width >140 msec. In total, 89 patients had an LBBB morphology on the electrocardiogram, while 21 patients had univentricular pacing devices in situ. In those patients with an LVEF >35%, QRS width was 108+/-27msec. CONCLUSION: A substantial number of patients presenting with CHF in a regular cardiology practice are suitable candidates for CRT therapy according to currently used criteria of QRS width and LVEF. This number could be increased even more if recent information concerning intraventricular conduction delay in CHF patients with less widening of the QRS complex were to be applied, as judged by echocardiographic techniques. PMID- 25696550 TI - A quantitative analysis of the effect of glucose-insulin-potassium in acute myocardial infarction. AB - OBJECTIVE: To review the currently available data to investigate the clinical benefit of high- and low-dose glucose-insulin-potassium (GIK) in patients with ST segment elevation acute myocardial infarction (STEMI). DESIGN: Quantitative analysis of all randomised trials on GIK in patients with STEMI. Electronic and manual searches for randomised controlled trials of GIK in STEMI were performed with regard to inclusion criteria, dose of GIK and additional use of reperfusion therapy, and a meta-analysis with the primary endpoint 30-day mortality was performed. PATIENTS: Data from 16 randomised trials, involving 26,273 patients, were included. RESULTS: Studies were conducted between 1962 and 2005. Overall, hospital mortality was 9.6% after GIK compared with 10.2% in controls (p=0.088). GIK infusion was not associated with an increase in major adverse events. CONCLUSION: This quantitative analysis of GIK in patients with STEMI did not show a beneficial or detrimental effect of GIK infusion on 30-day mortality. GIK infusion should not be part of the standard therapy for patients with STEMI. PMID- 25696551 TI - Electron beam computed tomography with suspected CAD: the preferred initial diagnostic test in clinically stable patients. PMID- 25696552 TI - Electron beam computed tomography with suspected CAD: not the preferred initial diagnostic test in clinically stable patients. PMID- 25696553 TI - A patient with dizziness, tachycardia and a DDDR pacemaker. AB - An 84-year-old female patient presented to the coronary care unit with dizziness. A DDD-R minute ventilation sensor pacemaker had been implanted eight years previously. The ECG showed an atrial and ventricular paced rhythm of 140 beats/min. After disconnecting the patient from the cardiac monitor the pacemaker rate dropped gradually to 90 beats/min. The cardiac rhythm monitoring system applies low-amplitude electrical pulses in order to measure respiration rate by transthoracic impedance (TTI) measurement. The minute ventilation pacemaker sensor is driven by the same TTI measurement for rate response. Inappropriate interference between these two systems caused a sensor-driven high pacemaker rate. The dizziness was not related to the sensor-driven high rate. PMID- 25696554 TI - An unusual cause of electrical artefact on the ECG. PMID- 25696556 TI - NATIONAL MULTICENTRE STUDIES. PMID- 25696555 TI - Should I be worried? PMID- 25696557 TI - Genetic factors in arrhythmogenic right ventricular cardiomyopathy: need for a DNA bank! PMID- 25696558 TI - Echocardiographic and electron beam tomographic assessment of stenosis in patients with aortic valve disease: gradient versus valve area. AB - BACKGROUND: Transthoracic echocardiography (TTE) is routinely used to evaluate aortic valve stenosis. However, it does not give reliable results in every patient. There is growing interest in electron-beam tomography (EBT) as a noninvasive cardiac imaging technique. The usefulness of EBT to evaluate aortic stenosis has yet to be evaluated. AIM: To compare EBT with TTE in assessing severity of aortic stenosis. METHODS: In total 47 patients (18 females, 29 males) underwent a contrast-enhanced EBT scan and TTE within 6+/-20 days. The calcium score of the aortic valve was determined and the aortic valve area (AVA) was measured by planimetry. A complete TTE study, during which the peak pressure gradient across the aortic valve was measured, was performed in all patients by an experienced sonographer. RESULTS: There was a significant correlation between AVA assessed by EBT and peak pressure gradient (r=-0.38, p=0.009). The calcium score of the aortic valve assessed by EBT correlated with peak pressure gradient (r=0.48, p=0.001). CONCLUSION: EBT is a useful noninvasive method to evaluate the severity of aortic stenosis. It holds the possibility of assessing the AVA as well as quantification of the degree of calcification. PMID- 25696559 TI - Interference detection in implantable defibrillators induced by therapeutic radiation therapy. AB - BACKGROUND: Electromagnetic fields and ionising radiation during radiotherapy can influence the functioning of ICDs. Guidelines for radiotherapy treatment were published in 1994, but only based on experience with pacemakers. Data on the influence of radiotherapy on ICDs is limited. OBJECTIVES: We determined the risk to ICDs of interference detection induced by radiotherapy. METHODS: In our study we irradiated 11 ICDs. The irradiation was performed with a 6 megavolt photon beam. In each individual device test, a total of 20 Gray was delivered in a fractionated fashion. During each irradiation the output stimulation rate was monitored and electrogram storage was activated. In case of interference the test was repeated with the ICD outside and the lead(s) inside and outside the irradiation field. RESULTS: With the ICD inside the irradiation field, interference detection was observed in all ICDs. This caused pacing inhibition or rapid ventricular pacing. Ventricular tachycardia (VT) or ventricular fibrillation (VF) detection occurred, which would have caused tachycardia terminating therapy. If the ICD was placed outside the irradiation field, no interference was observed. CONCLUSION: Interference by ionising radiation on the ICDs is demonstrated both on bradycardia and tachycardia therapy. This can have consequences for patients. Recommendations for radiotherapy are presented in this article. PMID- 25696560 TI - Psychological consequences of myocardial infarction: a self-regulation perspective on health-related quality of life and cardiac rehabilitation. AB - The aim of this review was to gain insight into prevalence of and interventions targeted specifically at psychological distress and health-related quality of life (HRQL) after a myocardial infarction (MI). For this purpose, self-regulation theory was introduced as frame of reference. Psychological distress and a reduction in HRQL after an MI are prevalent and can, for some patients, be persistent. This can negatively influence secondary prevention efforts, adherence, return to work and progression of the underlying coronary heart disease. At the same time, the effectiveness of cardiac rehabilitation programmes in improving HRQL is inconclusive. By starting off from a theoretical framework, effective strategies can be either identified or developed. Self-regulation theory is concerned with the process of goal setting and goal attainment and offers a model for explaining well-being and quality of life. The usefulness of this theory is supported by empirical evidence. Psychological factors derived from this theoretical framework (e.g. higher order goal disturbance) are associated with psychological distress and HRQL in the short and medium term after an MI and should thus be the target of cardiac rehabilitation programmes. PMID- 25696561 TI - Congenital cardiology: recent advances emphasise the need for collaboration. AB - The population of adult patients with congenital heart disease is steadily growing, due to the developments in cardiac surgery and thereby decreased mortality. However, morbidity in these patients is substantial. Patients with repaired lesions often need reoperations later in life. Most congenital heart defects, operated or not, have the potential to lead to clinical heart failure. Arrhythmias affect up to 50% of patients with congenital heart disease. The prevalence of pulmonary hypertension due to a left-to-right shunt among patients with a congenital heart defect is estimated at 4 to 10%. Advances in diagnostics, interventional and surgical therapy will result in new populations of adult survivors with even more complex disease. Collaboration of cardiologists with expertise in different areas of modern cardiology, such as electrophysiology, imaging and percutaneous interventions, is necessary for optimal care and management of these patients. PMID- 25696562 TI - Intracoronary abciximab. AB - Here we report the potential benefits of the use of intracoronary abciximab during percutaneous coronary intervention for an acute myocardial infarction. PMID- 25696563 TI - A phantom lung tumour in congestive heart failure. PMID- 25696565 TI - NATIONAL MULTICENTRE STUDIES. PMID- 25696564 TI - Not so fast.. PMID- 25696566 TI - Neointimal hyperplasia and endothelial function after percutaneous coronary intervention. AB - Percutaneous coronary revascularisation has become much safer and efficacious since its introduction more than 25 years ago. Currently, the need for surgical backup is small and the rate of late complications is lower than 10%. Further improvements are being studied, especially directed towards more biocompatible stents, using pharmacological principles with wider therapeutic windows and enhancing the vascular healing response/reendothelialisation. This article reviews several activities within the ICIN theme group 'Vessel Wall'. PMID- 25696567 TI - When lamin A/C fails, the heart suffers. PMID- 25696568 TI - Open access echocardiography: should we proceed? PMID- 25696569 TI - Remembrance of things past: time regained. PMID- 25696570 TI - Open access echocardiography is feasible in the Netherlands. AB - OBJECTIVES: In an urban region in the Netherlands, general practitioners (GPs) were offered an open access echocardiographic service. We report the outcomes of the first two years of this project. METHODS: GPs were given a course on the indications and restrictions for diagnostic referral as well as the interpretation of echocardiographic results. Indications were restricted to 'dyspnoea', 'cardiac murmur' and 'peripheral oedema'. A uniform request form was developed, using ticking boxes for quick completion. The echocardiogram was performed within one week after the request. Results were interpreted by the cardiologist according to the criteria of the Dutch, European and American Societies of Echocardiography. RESULTS: Sixty GPs from 43 general practices participated, covering a practice population of 130,000 persons. During a period of 24 months, 198 patients were referred. Only 1.5% of the workload of the echocardiography department was due to requests from GPs. The GPs kept well to the agreements on indications for echocardiography (91% approved reasons). An abnormal echocardiographic outcome was found in 53% of all patients. For 'cardiac murmur' this was 52%, for 'dyspnoea' 63%, and for 'peripheral oedema' 58%. Left ventricular dysfunction was present in 49 patients (25%); diastolic dysfunction was present in most of them (39 patients, 19%). Systolic dysfunction (LVEF < 40%) was found in 19 patients (10%). Twenty patients (10%) appeared to have relevant aortic or mitral valve disease. CONCLUSION: GPs did not overuse the open access echocardiographic service; they possibly used it conservatively. To prevent underdiagnosis of left ventricular dysfunction, diagnostic strategies in which electrocardiogram, NT-pro-BNP and echocardiography are combined, should be developed. PMID- 25696571 TI - Rationale of the SEAS study: Serial Echocardiography After Subarachnoid haemorrhage, a prospective national, multicentre, multidisciplinary, cohort study to evaluate cardiac abnormalities following intracranial haemorrhage. AB - The SEAS study is a prospective national, multicentre, multidisciplinary, cohort study in which the cardiac abnormalities following aneurysmal subarachnoid haemorrhage are studied. Incidence, clinical implications and predictive variables of cardiac abnormalities following aneurysmal subarachnoid haemorrhage will be studied. Cardiac abnormalities are defined as ECG changes, echocardiographic function abnormalities, and biochemical changes. A total of 350 patients will be included over a period of three years including follow-up. PMID- 25696572 TI - The left bundle branch block revised with novel imaging modalities. AB - Left bundle branch block (LBBB) is related to abnormal cardiac conduction and mechanical asynchrony and is associated with hypertension and coronary artery disease. Improved evaluation of left ventricular (LV) mechanical asynchrony is needed, because of the increasing number of patients with LBBB and heart failure. In this paper, we describe tissue Doppler imaging (TDI), strain (rate) imaging and tissue tracking in LBBB patients. A variety of patterns of mechanical activation can be observed in LBBB patients. A recent development, referred to as tissue synchronisation imaging, colour codes TDI time-to-peak systolic velocities of segments and displays mechanical asynchrony. Furthermore, real-time 3D echocardiography provides new regional information about mechanical asynchrony. Contained in an LV model and projected on a bull's eye plot, this modality helps to display the spatial distribution of mechanical asynchrony. Finally, segmental time-to-peak circumferential strain curves, produced by cardiac magnetic resonance imaging, provide additional quantification of LV mechanical asynchrony. Effects of LBBB on regional and global cardiac function are impressive, myocardial involvement seems to play a role and with the help of these novel imaging modalities, new insights continue to develop. PMID- 25696573 TI - Angiotensin II receptor antagonists (AT1-blockers, ARBs, sartans): similarities and differences. AB - A survey is presented of the registered non-peptidergic angiotensin II receptor antagonists (AT1 blockers, ARBs, sartans) and their general properties and similarities. Accordingly, their receptor profile, pharmacokinetic and therapeutic applications are discussed. In addition, attention is paid to the individual characteristics of the AT1 blockers now available. A few components of this category offer additional potentially beneficial properties, owing to their pharmacological or metabolic characteristics. Such additional properties are critically discussed for eprosartan, losartan, telmisartan and valsartan. PMID- 25696574 TI - Embolization of a huge tricuspid valve vegetation in a patient with intravenous drug abuse and HIV infection with an remarkable recovery. AB - We describe a patient with bacterial tricuspid valve endocarditis as a result of using intravenous drugs, and HIV infection. The course was complicated by embolisation of this huge vegetation; the follow-up was remarkable. Although this condition is life threatening, it was accompanied by a relatively slight derangement in the haemodynamic and respiratory condition of the patient. We describe the implications of intravenous drug use and HIV infection for the management of this condition. PMID- 25696576 TI - Palpitations again, have a close look. PMID- 25696575 TI - Coronary-cameral fistula associated with acquired mitral stenosis and left atrial thrombus in an adult female patient. PMID- 25696577 TI - NATIONAL MULTICENTRE STUDIES. PMID- 25696579 TI - Netherlands Heart Journal: accepted into PubMed Central! PMID- 25696578 TI - Hyperthermia in ancient Rome - or nonpharmaceutical management of heart failure in antiquity. AB - Sand bathing, a tool applied in ancient medicine, is depicted here with special interest for its use in heart failure. A modern-day equivalent of hyperthermia and its effect on cardiovascular function is discussed, thus putting a real idea in antiquity to the test. PMID- 25696580 TI - Long-term outcome after heart transplantation performed in the University Medical Centre Groningen. AB - BACKGROUND: Ten years ago, there was a difference of opinion about the suitability of ventilated patients with end-stage cardiac failure for heart transplantation (HTX). Although guidelines at that time qualified mechanical ventilation as a contraindication, we thought those patients could be candidates for HTX. In the same period a number of other patients received a donor heart in our centre. In this article we describe the clinical course and survival after these procedures. METHODS: We performed a retrospective study using our post HTX database. All patients undergoing transplants in our hospital were selected. Patients underwent echocardiography, scintigraphy (MUGA), ergo-spirometry (VO2 peak), blood tests and completed a quality of life questionnaire (SF-36). All tests were completed in the 1st quarter of 2006. RESULTS: Eight patients were identified; three were mechanically ventilated at the time of HTX. All eight patients were treated according to the standard protocol. Repeated surveillance cardiac biopsies were taken. One patient died 3.5 years after HTX due to an acute myocardial infarction. Seven patients, including the three patients on a ventilator at the time of the HTX, are alive, resulting in a survival rate of 88%. The current median survival time is 126 months (range 55 to 184 months). All patients are in good cardiac condition. The SF-36 domains of social functioning and mental health show high scores, the average score of general health and vitality is moderate. CONCLUSION: Survival of our eight transplanted patients after a median period of ten years was 88%, which is at least comparable with data from larger series. This finding suggests that HTX can be performed effectively and safely in a low volume centre. The finding that all three patients on a ventilator prior to HTX are alive is remarkable. It appears that mechanical ventilation is not always an absolute contraindication for HTX. PMID- 25696581 TI - Cardiac complications in type 2 diabetic patients with mild anginal symptoms and documented reversible myocardial perfusion defects: Results of the MERIDIAN trial. AB - BACKGROUND/OBJECTIVE: To compare early invasive treatment with continued pharmacological treatment in patients with diabetes mellitus type 2, mild anginal symptoms and documented myocardial ischaemia. METHODS: Patients with type 2 diabetes mellitus and mild anginal symptoms underwent myocardial perfusion scintigraphy (MPS). Patients with myocardial ischaemia were randomly assigned to early invasive or continued pharmacological treatment. All patients were followed for the occurrence of MACE (death, nonfatal myocardial infarction or hospitalisation for unstable angina pectoris). RESULTS: A total of 156 patients were randomised when the sponsor (ZonMW) prematurely terminated the study because of a slow recruitment rate. With a mean follow-up of 2.1+/-0.6 years, 9 of 79 patients assigned to early invasive treatment developed MACE compared with 10 of 77 patients randomised to continued pharmacological treatment, annual event rate 5.4 vs. 6.3%, hazard ratio 0.89, 95% CI 0.36 to 2.20, p=0.34. Due to the limited number of included patients and the low event rate, the study did not have sufficient power for the study objective. CONCLUSION: Patients with diabetes mellitus type 2, mild anginal symptoms and documented myocardial ischaemia, under appropriate medical treatment, have a lower than anticipated annual event rate of MACE of +/-5 to 6% which questions the beneficial effect of early revascularisation. PMID- 25696582 TI - Sudden cardiac death: time to make a difference: Pro ICD. PMID- 25696583 TI - Selection of patients for ICD therapy still under debate: Contra ICD. PMID- 25696584 TI - Implantable device recalls: are we throwing away the baby with the bath water? AB - Over the past year, there has been a sharp increase in the number of recalls, or 'field safety corrective actions' concerning implantable defibrillators. This may be due to an actual rise in device or component-related problems (for which there is some evidence), overzealous reporting of potential problems (which is apparent), or most probably a combination of the two. In this day and age of increasing numbers of ICD implantations, it is essential that all concerned realise that ICDs are no more infallible than other man-made devices and that the incidence of complications is therefore likely to increase commensurately. It is also important to weigh the procedural risk of replacing the device against the risk not only of device failure, but more importantly related harm to the patient. Odds actually favour replacement in very few cases. Above all this demands critical attention to communication between stakeholders, medical, industry, patients and press. This article attempts to place a number of these issues in some perspective, and offer future directions for management of ICD recalls and safety actions. PMID- 25696585 TI - Heart transplantation in the Netherlands: quo vadis? AB - Heart transplantation is limited by the lack of donor organs. Twenty years after the start of the Dutch transplant programmes in Rotterdam and Utrecht the situation has even worsened, despite efforts to increase the donor pool. The Dutch situation seems to be worse than in other surrounding countries, and several factors that may influence donor organ availability and organ utilisation are discussed. The indications and contraindications for heart transplantation are presented, which are rather restrictive in order to select optimal recipients for the scarce donor hearts. Detailed data on donor hearts, rejected for transplantation, are shown to give some insight into the difficult process of dealing with marginal donor organs. It is concluded that with the current low numbers of acceptable quality donor hearts, there is no lack of capacity in the two transplanting centres nor is the waiting list limiting the number of transplants. The influence of our current legal system on organ donation, which requires (prior) permission from donor and relatives, is probably limited. The most important determinants of donor organ availability are: 1. The potential donor pool, consisting of brain dead victims of (traffic) accidents and CVAs and 2. Lack of consent to a request for donation. The potential donor pool is remarkably small in the Netherlands, due to relatively low numbers of (traffic) accidents, with an almost equal number of CVA-related brain dead patients compared with neighbouring countries. Lack of consent can only be pushed back by improved public awareness of the importance of donation and improved skills of professionals in asking permission in case there is no previous consent. PMID- 25696586 TI - A patient with four artificial heart valves after ergotamine therapy. AB - A 67-year-old female was evaluated in the out-patient clinic because of shortness of breath on exertion and regular spells of fever. She had been taking ergotamine tartrate to treat migraine for more than 30 years. The patient had undergone aortic-valve replacement for aortic insufficiency three years before. On echocardiographic evaluation, severe retraction and insufficiency of the remaining native heart valves was demonstrated. Endocarditis and carcinoid syndrome were excluded. The mitral, tricuspid and pulmonary valves were all replaced by a mechanical valvular prosthesis. Pathological-anatomical evaluation of the three replaced valves and the aortic valve replaced three years earlier disclosed identical findings, compatible with long-term ergotamine use. Nine months after surgery, a sick sinus syndrome developed necessitating implantation of a DDDR pacemaker with a right atrial and a coronary sinus lead. Functional class according to the New York Heart Association improved from class III to I. After stopping the ergotamine, the fever disappeared. However, the migraine spells reoccurred which are now being treated with paracetamol. PMID- 25696587 TI - Intrarenal mycotic aneurysms in infectious endocarditis. PMID- 25696588 TI - Wide complexes intervening regular sinus rhythm. PMID- 25696589 TI - NATIONAL MULTICENTRE STUDIES. PMID- 25696590 TI - CT imaging of the heart. PMID- 25696591 TI - ECG screening of newborns to avoid sudden infant death syndrome? PMID- 25696592 TI - Refractory hyperglycaemia induced by glucose-insulin-potassium infusion in acute myocardial infarction. AB - BACKGROUND: Recent randomised clinical trials have not confirmed the beneficial effects of glucose-insulin-potassium (GIK) infusion observed in experimental models of myocardial ischaemia and infarction. METHODS: We investigated glucose levels and insulin dose in 107 patients treated with reperfusion therapy and GIK for acute myocardial infarction. RESULTS: Despite high insulin infusion rates, persistent hyperglycaemia occurred in 37% of the patients. These patients had significantly larger infarctions, as measured by enzyme release (p=0.006). In a multivariate model predicting high troponin levels, refractory hyperglycaemia remained a significant parameter (p=0.02). CONCLUSION: These findings suggest that refractory hyperglycaemia caused by high-dose glucose infusion may, at least in part, explain the discrepancy between the experimental and clinical data. PMID- 25696593 TI - Myocardial revascularisation in women: evaluation of hospital mortality and morbidity. AB - BACKGROUND: Although women are reported to be at higher risk for mortality and morbidity after coronary artery bypass graft (CABG), there is no consensus in literature. METHOD: Pre-, peri- and postoperative hospital data of 8578 patients undergoing an isolated myocardial revascularisation from January 1987 to December 2004 were analysed. Of these patients, 2083 (24.3%) were female. RESULTS: Female patients were significantly older (p=0.001), and risk factors as diabetes (p=0.001), hypertension (p=0.001), hyperlipidaemia (p=0.001) were significantly more prevalent than in men. The incidence of preoperative myocardial infarction (p=0.001) and triple-vessel disease (p=0.001) was lower, but the incidence of unstable angina (NYHA IV) (p=0.001) was significantly higher than in men. Significantly fewer women (p=0.04) received an arterial graft. Postoperatively, there was no significant difference in the registered morbidity, with the exception of a lower incidence of female patients with non-sinus rhythm (p=0.001) and a higher incidence of pulmonary problems (p=0.006). Hospital mortality was not significantly different between the genders: 3.5 vs. 3.4% (p=0.9). A preoperative myocardial infarction was identified as the only independent predictor for hospital mortality. CONCLUSION: The preoperative profiles of women and men undergoing CABG are dissimilar. However, the incidences of hospital mortality, and morbidity were not statistically different. Female gender was not identified as predictor for death or adverse outcome. PMID- 25696594 TI - Primary angioplasty: preprocedural pharmacological therapy. AB - Primary coronary angioplasty has been shown to be an effective reperfusion therapy for patients with acute myocardial infarction, not only for those who present to PTCA centres but also for patients who present to hospitals without angioplasty facilities. With the increasing use of primary angioplasty more patients will be transferred to a (tertiary) PTCA centre. An increase in treatment delay is associated with a worse clinical outcome. The importance of an open infarct-related vessel at acute angiography is becoming clear. Pharmacological pretreatment of patients during transportation to a PTCA centre with the aim to open the infarct-related vessel in advance might be beneficial. Glycoprotein IIb/IIIa receptor blockers seem to be the agents of choice for facilitated PTCA. The safety and (cost) effectiveness of this pretreatment of patients transported to undergo primary angioplasty remain to be evaluated. PMID- 25696596 TI - Bad teeth and strange behaviour. PMID- 25696595 TI - Acute myeloid leukaemia as a cause of acute ischaemic heart disease. AB - Ischaemic heart disease is almost invariably the result of atherosclerotic degeneration of the coronary arteries. However, other causes of ischaemic heart disease should always be considered. Here we describe two patients with a classic presentation of ischaemic heart disease resulting from acute leukaemia. The pathophysiological mechanisms of acute leukaemia leading to ischaemic heart disease are discussed. PMID- 25696597 TI - FBI: fast broad and irregular tachycardia. PMID- 25696598 TI - NATIONAL MULTICENTRE STUDIES. PMID- 25696599 TI - The statins: similarities and differences. PMID- 25696600 TI - Health-related quality of life relative to clinical outcomes in patients with atrial fibrillation treated with ventricular rate stabilisation pacing. AB - AIMS: It is uncertain whether patient perception of atrial fibrillation (AF) is based on the fast ventricular rate as such or the irregularity of the ventricular responses. This trial was designed to confirm the effectiveness of a ventricular rate stabilisation (VRS) algorithm in reducing ventricular irregularity during permanent pacing in patients with AF and to assess the patient preference and effect on quality of life (QoL). METHODS: In this multicentre single-blind randomised crossover trial, 184 patients with drug-refractory permanent (n=91) or paroxysmal (n=93) AF received a VVI(R) or DDD(R) pacemaker respectively and were paced in a randomised sequence with VRS on or off for two months. Clinical assessments (QoL, New York Heart Association (NYHA) classification, echocardiography, six-minute walk test and Holter recording) were carried out at baseline, at randomisation and after each crossover period. QoL assessment was performed using Aquarel, a new disease-specific QoL questionnaire for pacemaker patients, the Short Form 36 survey (SF-36), the Duke Activity Status Index (DASI) and the Symptom Checklist frequency and severity scores. At the end of the study patients preferences for VRS-on or VRS-off were recorded. RESULTS: VRS pacing reduced ventricular irregularity without increasing the mean ventricular rate. VRS-on was preferred by 65.8% of patients with paroxysmal AF; patients with permanent AF had no preference. QoL did not show improvement during VRS pacing on any of the instruments. CONCLUSION: VRS pacing is effective in reducing ventricular rhythm irregularity. QoL does not improve during VRS pacing but preference for VRS pacing appears particularly outspoken for patients with paroxysmal AF. PMID- 25696601 TI - Glucose and potassium derangements by glucose-insulin-potassium infusion in acute myocardial infarction. AB - BACKGROUND: High-dose glucose-insulin-potassium infusion (GIK) has been suggested to be beneficial in acute myocardial infarction (MI). Recently new large trials have shown no effect of GIK on mortality. To investigate whether metabolic derangement could have negated the potential beneficial effect, we studied the relation between systemic glucose and potassium levels and outcome. METHODS: Patients with signs and symptoms of ST-segment-elevation MI and treated with primary percutaneous coronary intervention (PCI) were randomised to no infusion or high-dose GIK, i.e. 80 mmol potassium chloride in 500 ml 20% glucose at a rate of 3 ml/kg/hour and 50 units short-acting insulin in 50 ml 0.9% sodium chloride for 12 hours. RESULTS: A total of 6991 glucose values and 7198 potassium values were obtained in 476 GIK patients and 464 controls. Mean serum glucose was significantly higher in the GIK group (9.3+/-4.5 mmol/l vs. 8.4+/-2.9 mmol/l, p<0.001). Mean potassium level was significantly higher in the GIK group (4.2+/ 0.5 mmol/l vs. 3.9+/-0.4 mmol/l, p<0.001). Incidence of hyperglycaemia (glucose >11.0 mmol/l) occurred in 70.8% of GIK patients and 33.8% of controls (p<0.001). Hypokalaemia was less common in the GIK group (23.5 vs. 41.2%, p<0.001). Incidence of hyperkalaemia and hypoglycaemia did not differ significantly between the two groups. In multivariate analysis age, previous cardiovascular disease, Killip class >1, unsuccessful PCI and mean glucose after admission were associated with increased one-year mortality. CONCLUSION: In ST-segment-elevation MI patients treated with primary PCI, high-dose GIK induced hyperglycaemia and prevented hypokalaemia. Derangement of the glucose metabolism was related to one year mortality. PMID- 25696602 TI - Rationale of the REPARATOR study: A randomised trial with serial cardiac MRI follow-up testing the ability of atorvastatin to reduce reperfusion damage after primary PCI for acute MI. AB - The REPARATOR study is a multicentre clinical trial in which the effect of 80 mg atorvastatin on microvascular (re)perfusion and late ventricular remodelling, and infarct size in patients presenting with an acute ST-elevation myocardial infarction is studied. Primary endpoint is end-systolic volume index at three months measured by quantitative cine magnetic resonance imaging (MRI). Secondary endpoints are cardiac MI (CMR) measurements of global and regional left ventricular function, MRI measurements of infarct size on admission, one week and three months as well as changes between MRI investigations, biochemical markers of infarct size, blush grade, and TIMI frame count. A total of 50 patients will be enrolled. Including three months follow-up, the study will last for six months. PMID- 25696603 TI - Unexplained left ventricular hypertrophy: consider a diagnosis of Fabry's disease. AB - Lysosomal storage disorders are a group of disorders characterised by the deficiency of a specific lysosomal hydrolase. These diseases are rare, with only a few hundred patients in the Netherlands. Fabry's disease, an X-linked lysosomal storage disorder, is caused by a deficiency of the lysosomal enzyme alpha galactosidase A which results in, among other things, left ventricular hypertrophy, renal failure and cerebrovascular events. Patients with Fabry's disease, especially males, have a decreased life expectancy. Recent studies have shown that Fabry's disease may be much more common among patients with left ventricular hypertrophy (LVH) than previously thought. Up to 7% of male patients with left ventricular hypertrophy and up to 12% of female patients with unexplained LVH were found to suffer from Fabry's disease. Thus, Fabry's disease should be considered in patients with unexplained LVH. This case report summarises the main features of the disease. In addition recent developments concerning prevalence, diagnosis and the current available treatments are discussed and an algorithm on who and how to screen for Fabry's disease is presented. PMID- 25696604 TI - Definitive PCI for severe coronary disease masquerading as troponin-negative ACS. PMID- 25696606 TI - NATIONAL MULTICENTRE STUDIES. PMID- 25696605 TI - A pre-excited wide QRS complex: is that all there is? PMID- 25696608 TI - Dr E. Dekker programme of the Netherlands Heart Foundation: the 2005 winners. PMID- 25696607 TI - Conduction reserve and arrhythmias. PMID- 25696609 TI - Drug-eluting stents in primary percutaneous coronary intervention for acute myocardial infarction. PMID- 25696610 TI - Coronary risk factors and metabolic disorders in first-degree relatives of normocholesterolaemic patients with premature atherosclerosis. AB - AIMS: Despite agreement on the need for screening for the presence of cardiovascular risk factors in first-degree family members of patients with premature coronary artery disease (CAD), this is not routinely carried out in relatives of normocholesterolaemic patients. We evaluated cardiovascular risk factors in family members of normocholesterolaemic patients with premature CAD. METHODS: Eligible index subjects were patients with premature CAD (<55 years in men and <65 years in women), who had undergone percutaneous transluminal coronary angioplasty. Patients with fasting total cholesterol levels >6.5 mmol/l were excluded. Sixteen index subjects were included with a mean age of 49+/-8 years and total cholesterol levels of 5.5+/-0.8 mmol/l. Sixty-four first-degree relatives from these 16 pedigrees were screened, namely 18 children, 42 siblings and four parents. National Cholesterol Education Program III guidelines were used to identify candidates for lipid-lowering treatment. Furthermore, the presence of four additional metabolic disorders was investigated: the metabolic syndrome, increased levels of lipoprotein(a) (Lp(a)), hyperhomocysteinaemia and postprandial hyperlipidaemia. RESULTS: Of 64 relatives free of CAD, 34 subjects (53%) fulfilled the criteria to receive therapeutic advice, 20 of whom (31% of the relatives) were candidates for drug therapy. Sixty-one relatives were available for a full assessment of metabolic disorders and in 37 relatives (61%) at least one metabolic abnormality was present. Twelve subjects had hyper-Lp(a), seven subjects had postprandial hyperlipidaemia and two had the metabolic syndrome. Furthermore, 16 subjects had a combination of at least two out of four metabolic disorders. CONCLUSION: Careful evaluation of coronary risk factors and metabolic variables in first-degree relatives of normocholesterolaemic CAD patients identifies a significant number of subjects at increased coronary risk in whom primary prevention measures should be initiated. PMID- 25696611 TI - Cardiac surgery and operative mortality in 1992 and 2002: the St Antonius experience. AB - OBJECTIVE: Comparing the changes in open-heart surgical procedures and hospital mortality in 1992 with 2002. DESIGN AND SETTING: Retrospective investigation at St Antonius Hospital in Nieuwegein. METHOD: A comparison of the open-heart surgical procedures, hospital mortality and age distribution of the operated patients was made, using the database of the Department of Cardiothoracic Surgery. RESULTS: The total number of open-heart surgical procedures increased. There were more combined procedures, aortic valve replacements and reconstructions of the thoracic aorta. The total number of reoperations decreased. In 2002 the use of an arterial conduit for coronary bypass procedures reached 94%, and the radial artery was used for the first time. The mean patient age and the hospital mortality were higher in 2002. CONCLUSION: Comparing cardiovascular surgery in 1992 to 2002 showed an increase in complicated procedures and older age groups of patients. This may be the reason for higher overall mortality. The mean patient age increased considerably from 1992 to 2002, together with the number of combined procedures and aortic valve replacements with biological valve prostheses. These trends give cardiovascular surgery a challenging future, to treat the patient adequately and keeping the mortality and complication rates low. PMID- 25696612 TI - Erectile dysfunction in patients with cardiovascular disease. AB - Erectile dysfunction is a highly prevalent disease, especially in cardiovascular compromised men. Many of the well-established risk factors for cardiovascular disease are also risk factors for erectile dysfunction. A correlation between erectile dysfunction and endothelial dysfunction is well established. It is postulated that erectile dysfunction with an arteriovascular aetiology can predate and be an indicator of potential coronary artery disease. In this paper we will attempt to increase awareness among cardiologists for the predictive value of erectile dysfunction for future cardiovascular disease in order to optimise cardiovascular risk management. The treatment of erectile dysfunction and cardiovascular interactions is also discussed in detail. PMID- 25696613 TI - Aortic dissection presenting as acute myocardial infarction: potential harm of antithrombin and antiplatelet therapy. AB - In the treatment of acute myocardial infarction, antithrombin and antiplatelet therapy are indicated according to the current guidelines. When a patient presents with symptoms and signs of acute myocardial infarction, an extensive list of diagnoses should be considered. Because of the nonspecific symptoms of aortic dissection, the disease may be easily misdiagnosed. A high clinical suspicion of aortic dissection is therefore required. Once aortic dissection has been diagnosed, surgical intervention provides the only definitive treatment for these patients, regardless of antithrombin and antiplatelet therapy. PMID- 25696614 TI - Aorta-right ventricular fistula detected a few days after thoracotomy for penetrating chest trauma. PMID- 25696615 TI - T-wave alternans in a patient with long-QT syndrome type 3. PMID- 25696616 TI - An old lady with chest pain. PMID- 25696617 TI - NATIONAL MULTICENTRE STUDIES. PMID- 25696618 TI - Launch of large-scale research programme on cell therapy. PMID- 25696619 TI - Future perspective: getting GRIP on intensive insulin therapy in acute myocardial infarction. PMID- 25696620 TI - Applicability of bosentan in Dutch patients with Eisenmenger syndrome: preliminary results on safety and exercise capacity. AB - BACKGROUND: The purpose of this study was to investigate the applicability of bosentan treatment in a broad selection of patients with Eisenmenger syndrome. METHODS: Dutch patients with Eisenmenger syndrome in New York Heart Association functional class III, 9 (41%) male and 13 (59%) female, including 11 patients with Down syndrome (50%), aged 20 to 61 years (median 37 years), were screened for an open-label, standardised treatment protocol. Patients underwent clinical examinations, six-minute walk test (6-MWT), resting oxygen saturation measurements, cardiac MRI, Doppler echocardiography, lung function tests and exercise capacity testing by peak oxygen consumption at baseline. At 12 weeks of treatment 6-MWT and at 26 weeks 6-MWT and Doppler echocardiography were repeated. RESULTS: Median follow-up of the patients who started bosentan treatment was five months (range 0.5 to 9.6 months). Oxygen saturation at baseline was 83% (range 76 to 91%) and did not decrease during treatment. Compared with baseline, 6-MWT increased after 12 weeks from 333+/-93 m to 384+/-89 m. None of the patients discontinued medication and no liver function abnormalities were observed. Of all Doppler echocardiographic and MRI parameters measured for right ventricular function, tricuspid annular peak systolic velocities using tissue Doppler imaging (TDI-S) was the only independent predictor for six-minute walk test (beta=0.8, p=0.001). CONCLUSION: Bosentan may be safely applied in patients with Eisenmenger syndrome combined with complex congenital heart disease or with Down syndrome. Our preliminary results suggest that exercise tolerance improves during the first months of bosentan treatment. PMID- 25696621 TI - Drug-eluting stents for all patients. PMID- 25696622 TI - Drug-eluting stents not for all patients. PMID- 25696623 TI - Recommended transoesophageal echocardiographic evaluation of mitral valve regurgitation. AB - Valve replacement in patients with mitral valve regurgitation is indicated when symptoms occur or left ventricular function becomes impaired. Using different surgical techniques, mitral valve reconstruction has lead to earlier interventions with good clinical results. In order to determine the possibility of a mitral valve reconstruction, echocardiographic parameters are necessary. With transoesophageal echocardiography a segmental analysis of the entire mitral valve can be performed; mitral valve motion abnormalities and severity and direction of the regurgitation jet can be judged. From this analysis clues for underlying pathology can be derived as well as the eligibility of a successful mitral valve reconstruction. This article focuses on transoesophageal examination with segmental analysis in patients with mitral valve regurgitation. PMID- 25696624 TI - Pitfalls in cardiology: myocardial ischaemia in carbon monoxide poisoning. AB - Carbon monoxide poisoning is a major cause of morbidity and mortality worldwide. Immediate and proper treatment is crucial for prognosis and is merely dependent on accurate diagnosis. However, correct diagnosis can be difficult due to the aspecific symptomatology in CO poisoning. In this report a case is discussed in which a patient with accidental CO poisoning presented primarily with syncope, extensive ECG changes and elevated troponin levels. In addition, a limited review of the current literature is provided. PMID- 25696626 TI - Palpitations and dizziness in a 65-year-old man. PMID- 25696625 TI - Anomalous isolated single origin coronary artery. PMID- 25696627 TI - NATIONAL MULTICENTRE STUDIES. PMID- 25696628 TI - Challenges for the 'new' Netherlands Heart Foundation. PMID- 25696629 TI - Molecular mechanisms of cardiac disease and regeneration: A focus on stem and progenitor cells. PMID- 25696630 TI - Einthoven Dissertation Prizes 2006. PMID- 25696631 TI - Percutaneous coronary intervention in the Netherlands: preservation of cardiovascular care and expertise in the patient with coronary artery disease through regional engagement. PMID- 25696633 TI - Erratum: ECG screening of newborns to avoid sudden infant death syndrome? AB - [This corrects the article on p. 43 in vol. 14.]. PMID- 25696632 TI - Percutaneous coronary intervention in the Netherlands: preservation of cardiovascular care and expertise in the patient with coronary artery disease through regional engagement: Comment. PMID- 25696634 TI - Pulmonary arterial hypertension associated with congenital heart disease: the efficacy of drug treatment in symptomatic patients. PMID- 25696635 TI - The effect of electrical neurostimulation on collateral perfusion. AB - BACKGROUND/OBJECTIVES: Clinical data have shown that electrical neurostimulation may improve myocardial ischaemia. Our aim was to investigate the possible effect of electrical neurostimulation on collateral perfusion. METHODS: Thirty patients with stable angina and significant single-vessel coronary artery disease scheduled for elective percutaneous coronary intervention (PCI) were randomised into three groups. In all patients two balloon inflations were performed, one for predilatation of the lesion, the second for stent delivery. Group one received active neurostimulation during the first ischaemic episode (predilatation), group two during the second ischaemic episode (stent delivery), and group three received placebo neurostimulation continuously. During both ischaemic episodes the collateral flow index was determined. RESULTS: No significant differences were found between active, inactive or placebo neurostimulation. In a post-hoc analysis the patients were stratified for presence or absence of significant collaterals. In patients with pre-existing significant collaterals, the collateral flow index was significantly higher during active neurostimulation compared with inactive neurostimulation (p=0.012) and compared with the merged inactive and placebo groups (p=0.011). CONCLUSION: The present data show no effect of electrical neurostimulation on collateral perfusion in patients with single-vessel disease. In a post-hoc analysis in patients with evidence of collaterals, defined as a collateral flow index of >0.24, an increase in collateral perfusion was found during electrical neurostimulation. PMID- 25696636 TI - Intracardiac rhabdomyomas producing symptoms in infancy: the role of radiofrequency catheter ablation. AB - BACKGROUND: Cardiac rhabdomyomas, although benign, may produce symptoms related to arrhythmia or mechanical obstruction. Surgical excision is the therapy of choice for symptomatic rhabdomyomas in infancy. PATIENTS AND METHODS: Two infants with intracardiac rhabdomyomas producing symptoms underwent radiofrequency catheter ablation of the tumour. In patient 1 the diagnosis of multiple rhabdomyomas associated with recurrent supraventricular tachyarrhythmias and foetal hydrops was made in utero. After birth, several antiarrhythmic agents were administered, without successful suppression of the tachyarrhythmia. At seven months of age, the infant had one large residual tumour on the left atrial aspect of the anterior mitral valve leaflet with associated pre-excitation and re entrant supraventricular tachyarrhythmia suggestive of a left-sided pathway. Catheter ablation of the accessory pathway was performed via a retrograde femoral arterial approach, targeting the earliest site of ventricular activation. Patient 2 presented as a neonate with multiple rhabdomyomas, one of which, measuring 15 mm * 15 mm, was producing severe mitral valve inflow obstruction resulting in symptoms of heart failure due to a large left-to-right shunt at atrial level and persistent pulmonary hypertension. Via the femoral vein, a 5F ablation catheter was advanced across the atrial septum, and the tumour directly ablated. RESULTS: Echocardiography performed 24 hours later demonstrated alteration in tumour morphology, with the development of a large central echolucent area, followed by progressive tumour shrinkage in both infants. Patient 1 was discharged at 24 hours, and patient 2 at seven days post-ablation, without symptoms. Follow-up at four weeks confirmed further tumour shrinkage. CONCLUSION: Transcatheter tumour ablation may be beneficial in selected infants and children. PMID- 25696637 TI - Chronic thromboembolic pulmonary hypertension. AB - Chronic thromboembolic pulmonary hypertension (CTEPH) is a rapidly progressive and deadly disease, resulting from incomplete resolution of acute pulmonary embolism. Historically, the incidence of CTEPH was significantly underestimated but it may be as high as 3.8% following acute pulmonary embolism. Although the medical management of CTEPH may be supportive, the only curative treatment is pulmonary endarterectomy (PEA). However, a careful screening programme is mandatory to select CTEPH patients who are likely to benefit from PEA. In this review we discuss the pathophysiology, clinical and diagnostic pitfalls, surgical treatment, outcome after surgery, and the potential benefit of medical treatment in inoperable CTEPH patients. PMID- 25696638 TI - Right lower lobe oedema as a rare sign of left heart failure. AB - Two cases of right lower lobe oedema are presented as a supposedly very rare sign of left heart failure after myocardial infarction in the presence of acute mitral regurgitation. Causes of unilateral oedema and its clinical relevance in the diagnostic and therapeutic perspectives are discussed, and a review of the literature on this topic is presented. PMID- 25696640 TI - Carcinoid heart disease: a rare cause of right ventricular dysfunction. PMID- 25696639 TI - Diagnosis of pericardial effusion: correlation between echocardiography and computed tomography. PMID- 25696641 TI - Multimodality coronary artery imaging in a high-risk patient. PMID- 25696642 TI - From the waste paper basket: total AV block? PMID- 25696643 TI - NATIONAL MULTICENTRE STUDIES. PMID- 25696644 TI - Dr E. Dekker programme of the Netherlands Heart Foundation: Personal grants for cardiovascular talents. PMID- 25696645 TI - Five of a kind. PMID- 25696646 TI - Absence of the right superior vena cava: first look at history. PMID- 25696647 TI - Tachycardiomyopathy with familial predisposition masquerading as peripartum cardiomyopathy. AB - A 28-year-old pregnant lady presented with cardiomyopathy and atrial tachycardia. The patient had severe heart failure and syncope. Her past medical history was uneventful. Her mother, however, had received an implantable cardioverter defibrillator (ICD) after an out-of-hospital cardiac arrest due to idiopathic ventricular fibrillation. The patient was scheduled for programmed stimulation, during which a monomorphic ventricular tachycardia was induced. An ICD was then implanted. Following radiofrequency ablation of the atrial tachycardia, left ventricular function recovered completely. Given the family history, a genetic predisposition to both arrhythmias and tachycardiomyopathy needs to be considered. PMID- 25696648 TI - Unmasking accessory pathway conduction due to AV block following tricuspid valve replacement. AB - Atrioventricular block during radiofrequency (RF) ablation of an accessory pathway may be due to inadvertent RF damage or catheter pressure to the conduction system, or a pre-existent conduction defect. Conversely, block in the normal conduction system may unmask pre-excitation. We describe a case where total infra-Hisian block complicated tricuspid valve surgery, unmasking a hitherto undiagnosed left lateral accessory pathway. PMID- 25696649 TI - Cardioverter defibrillator implantation in a patient with absent right superior vena cava. AB - Left-sided superior vena cava (LSVC) is the most common venous thoracic anomaly. Absence of the right superior vena cava (RSVC) on the other hand is very rare. We describe a patient with this abnormal venous system, who was admitted to our centre for an implantation of a cardioverter defibrillator (ICD). PMID- 25696650 TI - Pacing for conduction disturbances in Steinert's disease: a new indication for biventricular ICD? AB - Cardiac involvement in classical Steinert muscular dystrophy (dystrophia myotonica, MD1) is characterised by atrial arrhythmias, AV conduction disturbance, ventricular arrhythmias and heart failure. In MD1 patients complaints of fatigue and reduced exercise tolerance are well explained by the muscular weakness, but the same symptoms can be attributed to arrhythmia, atrioventricular block and heart failure. As cardiac pathology is often encountered in MD1 patients, an ECG, echocardiogram and Holter registrations should be performed on a routine basis. We report on two patients with MD1 who developed Mobitz II block as initial presentation of cardiac disease. PMID- 25696651 TI - A successful afternoon's struggle inserting a pacemaker. PMID- 25696652 TI - Left atrial myxoma as a cause of stroke. PMID- 25696654 TI - Real-time three-dimensional echocardiographic evaluation of left ventricular thrombus - a live case. PMID- 25696653 TI - Biventricular thrombi in a patient with doxorubicin-induced cardiomyopathy. PMID- 25696656 TI - NATIONAL MULTICENTRE STUDIES. PMID- 25696655 TI - A narrow QRS complex tachycardia sensitive to Isoptin. PMID- 25696657 TI - GENCOR: a national registry for patients and families suffering from a familial heart disease in the Netherlands. AB - INTRODUCTION: Developments in DNA-diagnostic techniques allow us to identify a significant proportion of patients with gene mutations causing familial heart diseass (arrhythmia syndromes, cardiomyopathies etc.) and to identify family members in early stages of the disease and/or even before symptoms occur. Early treatment can prevent sudden cardiac death and disease progression. However, data on long-term outcome in unselected genotyped patients are scarce due to a lack of large registries. In 2005, a national internet-based registry for familial heart diseases in the Netherlands, named GENCOR, was developed in collaboration with the Interuniversity Cardiology Institute of the Netherlands (ICIN). OBJECTIVES: GENCOR aims to assess the prevalence of familial heart diseases in patients and families in the Netherlands and to facilitate research to improve the quality of diagnostics and therapy in familial heart diseases. METHODS: Patients who visit the (cardio)genetic outpatient clinic are informed about GENCOR and asked to consent to the storage of information about cardiac examinations, family history and DNA diagnostics from all their visits. Patient data are entered into the internet-based GENCOR database by the cardiologist or clinical geneticist in attendance. Additional information can be stored for scientific research. RESULTS: Four university hospitals are actively obtaining informed consent from the patients, which resulted in the inclusion of more than 300 patients. In 2006, more university hospitals will start using GENCOR and the aim is that all university hospitals will participate. Three research projects have already started using GENCOR. CONCLUSION: GENCOR is already a success, regarding the number of included patients and the related research projects set up within a limited period of time. GENCOR provides easy internet-based access for authorised cardiologists, clinical geneticists and scientists throughout the country. PMID- 25696658 TI - Determinants of increased levels of von Willebrand factor and coagulation factor VIII in patients with venous thrombosis. PMID- 25696659 TI - Do patients benefit from drug-eluting stents in acute myocardial infarction? PMID- 25696660 TI - Attending to links in the safety chain for drug-eluting stents. PMID- 25696661 TI - Progression of calcifications in breast arteries in women at high risk for coronary heart disease events. AB - OBJECTIVE: To study changes in breast artery calcifications (BAC) over time and its relation with coronary heart disease (CHD) risk factors. METHODS: Breast arterial calcifications were studied at baseline and after five years follow-up in 453 women participating in the Raloxifene Use for The Heart (RUTH) study. All mammograms were scored by two observers. With logistic regression analysis the independent effect of risk factors on the progression of BAC was evaluated. RESULTS: BAC was present in 94 of 453 (21%) women at baseline and in 116 of 453 (26%) women after 5.0+/-1.04 years. Progression of BAC was seen in 44 of 453 (10%) women. In 22 participants (5%) BAC was not present at baseline, while in 22 participants (5%) the severity of BAC merely changed from grade 1 to grade 2 calcification. Age was significantly associated with progression of BAC (OR 1.09, 95% CI 1.03 to 1.14). Multivariate regression analysis with adjustment for age and the duration of follow-up showed no association between CHD risk factors and the progression of BAC. Lipid-lowering drugs protected for progression (adjusted OR 0.5, 95% CI 0.22 to 0.98). The strongest determinant in the progression of BAC was BAC at baseline (adjusted OR 4.2, 95% CI 2.10 to 8.27). CONCLUSION: Progression of BAC is not associated with CHD risk factors, but with increasing age and BAC at baseline. Lipid-lowering drugs protect against progression of BAC. PMID- 25696662 TI - Quality of life of patients on the waiting list for coronary angiography. AB - BACKGROUND: Providing adequate medical information and ensuring that patients do not identify with fellow-sufferers who are doing worse are significant contributors to a better quality of life (QOL) in cardiac patients. In addition, in these patients gender and the level of psychic tension are significant predictors of QOL. We do not know (1) whether we can improve QOL by increasing patients' ability to cope with the unpleasant aspects of the underlying condition, (2) whether gender and level of psychic tension interact or act independently. OBJECTIVE: To assess both questions. METHODS: Thirty-eight patients on the waiting list for coronary angiography were assessed with validated test batteries. To increase the patients' ability to cope, they were randomly assigned to read either (1) the comments of a patient who had previously been treated successfully or (2) general information. The former information, unlike the latter, was assumed to improve coping ability and, thus, provide better QOL. Homogeneity of the patient group was estimated by Cronbach's alphas. For analysis, linear regression and general factorial analyses of variance were applied. RESULTS: The group was psychologically homogeneous as indicated by Cronbach's alphas which were generally over 75%. There was a significant or close to significant association between the use of coping information and a better mobility and social performance QOL (p<0.05 and p<0.06). High levels of psychic tension were associated with low self-perceived QOL and low psychological scores (both p<0.02). Female gender was associated with lower mobility, lower psychological scores and lower overall QOL (p<0.05, p<0.02 and p<0.05). A significant or close to significant interaction was observed between gender and psychic tension as combined determinants of self-perceived QOL, mobility index, and overall QOL index (p<0.03, p<0.09, and p<0.05). Separate assessments of these determinants showed that female gender was the strongest determinant of a low QOL. CONCLUSION: In patients on the waiting list for coronary angiography, an increased ability to cope with the unpleasant aspects of a possible underlying heart condition improves QOL. Female gender and a high level of psychic tension place patients at risk for a low QOL. It is to be hoped that this paper will raise physicians' awareness of these psychological mechanisms and that they will be given adequate attention in the future, particularly in female patients. PMID- 25696663 TI - Antiplatelet therapy in patients undergoing coronary stenting: The risk of late stent thrombosis. AB - BACKGROUND: Anticoagulation after coronary stenting is essential to prevent stent thrombosis. Drug-eluting stents, which are the preferred therapy, may be associated with a higher tendency for stent thrombosis. METHODS: Patients who underwent coronary stent placement and presented with late stent thrombosis are described. RESULTS: Eight patients with stent thrombosis are presented. Early discontinuation of the antithrombotic medication is associated with the occurrence of these complications. CONCLUSION: Long-term antithrombotic therapy seems essential to prevent stent thrombosis, especially for patients treated with drug-eluting stents. PMID- 25696664 TI - The metabolic syndrome - background and treatment. AB - The metabolic syndrome (MBS) is characterised by a clustering of cardiovascular and metabolic risk factors. This syndrome is now widely recognised as a distinct pathological entity, and it is receiving a great deal of attention in the medical literature but also in the lay press. Globally speaking, persons with MBS have a clustering of the following risk factors: [List: see text] MBS is associated with important cardio/cerebrovascular and metabolic risks. Prevention and treatment are therefore of great importance. Preventive measures involving lifestyle are mandatory. In addition, MBS patients require pharmacological treatment, usually for the rest of their lives. Complex patterns of drug treatment will be required, since all the different, heterogenous pathophysiological problems will require appropriate treatment. After an introduction to MBS, this article provides an extensive and critical review of the drug treatment of this complex pathological entity. PMID- 25696665 TI - Purulent pericarditis, an uncommon entity in modern practice: a case report. AB - We report an 82-year-old female with pneumococcal pneumonia. Antimicrobial therapy was started in an early stage of the disease. On the 10th day of admission she developed peripheral pitting oedema with elevated jugular venous pressure and a drop in blood pressure. Her electrocardiogram showed sinus tachycardia and concave upward ST-segment elevation in almost all leads. A transthoracic two-dimensional echocardiogram revealed a large circumferential pericardial effusion, with diastolic collapse of the right atrium and a mitral inflow pattern that suggested cardiac tamponade. Emergency pericardiocentesis was performed, releasing 600 cc of thick green purulent material, followed by good haemodynamic recovery. The haemodynamic state, pneumonic infiltrate and inflammatory parameters responded gradually to antimicrobial therapy and the patient recovered and was discharged after six weeks. We conclude that even susceptible strains of Streptococcus pneumonia in a patient with no predisposing factors may still cause purulent pericarditis, even in the era of adequate antibiotic therapy. PMID- 25696666 TI - A clearly visible V wave in the pulmonary artery pressure curve caused by severe mitral valve regurgitation. PMID- 25696667 TI - Self-terminating torsades de pointes in a patient with bradycardia-induced long QT syndrome. PMID- 25696668 TI - And what about the ECG? PMID- 25696669 TI - NATIONAL MULTICENTRE STUDIES. PMID- 25696670 TI - Abstracts of the Scientific Meeting of the Netherlands Society of Cardiology (NVVC): 20-21 April 2006, Hotel Okura, Amsterdam. PMID- 25696671 TI - Abstracts of the Scientific Meeting of the Netherlands Society of Cardiology (NVVC). PMID- 25696672 TI - 28th Congress of the European Society of Cardiology / World Congress of Cardiology. PMID- 25696673 TI - Hot line I: Barcelona, 3 September 2006. PMID- 25696674 TI - Hot line II: Barcelona, 5 September 2006. PMID- 25696675 TI - Clinical trial update II: Barcelona, 3 September 2006. PMID- 25696676 TI - Clinical trial update III: Barcelona, 4 September 2006. PMID- 25696677 TI - Thromboembolic risk factors after cardioversion for atrial fibrillation: Barcelona, 3 September 2006. PMID- 25696678 TI - Sudden cardiac death in heart failure: Barcelona, 4 September 2006. PMID- 25696679 TI - Cardiac regeneration in 2006: Barcelona, 4 September 2006. PMID- 25696680 TI - Setting a new standard in cholesterol management (absorption and synthesis): Barcelona, 2 September 2006. PMID- 25696681 TI - CB1 blockade with rimonabant: a new therapeutic approach for the management of patients at high cardiometabolic risk: Barcelona, 2 September 2006. PMID- 25696682 TI - Diet and lifestyle approaches in the prevention of cardiovascular disease: Barcelona, 4 September 2006. PMID- 25696683 TI - Abstracts of the Scientific Meeting of the Netherlands Society of Cardiology (NVVC): 26-28 October 2006, De Heerlickheid, Ermelo. PMID- 25696684 TI - Abstracts of the Netherlands Society of Thoracic Surgery (NVT): 19 May 2006, Mercure Hotel Nieuwegein. PMID- 25696685 TI - Abstracts of the Autumn Meeting of the NVT-NVA-NVIC: 17 November 2006, NBC de Blokhoeve te Nieuwegein. PMID- 25696686 TI - Netherlands Heart Journal: just a change of name or more? PMID- 25696687 TI - Completeness of revascularisation by percutaneous coronary intervention. AB - OBJECTIVE: To evaluate the relationship between the completeness of revascularisation by percutaneous coronary intervention and the one-year occurrence of adverse cardiac events in patients with multivessel disease. PATIENTS: Patients with stable or unstable angina pectoris, or with exercise induced ischaemia, were enrolled in the Coronary Angioplasty versus Bypass Revascularisation Investigation (CABRI). METHODS: In CABRI, patients were randomised to coronary bypass grafting (CABG; n=513) or angioplasty (PTCA; n=541). Revascularisation in patients randomised to PTCA was defined as complete if no lesions with a diameter stenosis <50% remained post-procedure. Patients with complete revascularisation were distinguished from those with one, two, and three or more remaining lesions, respectively. Differences in baseline characteristics and in the one-year occurrence of death, myocardial infarction, (re)CABG, and (re)PTCA between these subgroups were evaluated. Comparisons were made with patients randomised to CABG. RESULTS: Complete revascularisation was obtained in 148 patients randomised to PTCA (27%). In 147 (27%) cases one lesion remained, while there were 122 (23%) and 119 (22%) patients with two and three or more remaining lesions, respectively. Five (1%) patients could not be classified. The one-year rates of either death or MI were 9.5%, 5.4%, 8.2%, and 12.6% in the respective PTCA subgroups (p=0.225), and 6.2% in patients randomised to CABG (comparison with three or more remaining lesions after PTCA: p=0.017). The percentages of repeat interventions during one-year follow-up were 29.7%, 29.3%, 39.3%, and 51.3% (p<0.001), much higher than after CABG (3.5%; p<0.001). CONCLUSION: Complete revascularisation by PTCA in multivessel coronary disease did not result in a lower death or MI rate compared with incomplete revascularisation. Overall the patient's prognosis after PTCA is similar to CABG, but patients with three or more remaining lesions after PTCA had a worse prognosis than CABG patients. PMID- 25696688 TI - Prediction of success and major complications during elective coronary angioplasty. AB - BACKGROUND: Complications from coronary angioplasty remain a concern despite improvements in technology and operator's skills. Identification of high-risk patients is important with regard to surgical standby and other precautions that have to be taken for such patients. METHODS: Prior to elective coronary angioplasty, the probability of success and the risk of complications were estimated on the basis of angiographic and clinical characteristics. A total of 2365 consecutive elective procedures were evaluated. Estimates for success and complications were classified into three categories: high, intermediate or low probability. RESULTS: Angioplasty success was achieved in 1025 of 1056 (97%) procedures with high success probability; in 833 of 914 (91%) with intermediate success probability and 304 of 395 (77%) with low success probability. Complications occurred in five of 271 (2%) procedures with an anticipated low risk of complications, in 72 of 1973 (4%) procedures with a intermediate risk and in 13 of 121 (11%) procedures with a high risk of complications. Out of a total of 28, 22 (80%) surgical bypass procedures were performed in the intermediate anticipated risk category. CONCLUSIONS: For groups of patients, reliable prediction of success and complications is possible. However, most emergency bypass surgery after failed angioplasty is performed in patients with a predicted intermediate risk of complications. Interventional cardiologists are not able to identify in advance the majority of patients who will need surgery for failed angioplasty. PMID- 25696689 TI - Factors influencing immediate and long-term outcome of electrical cardioversion of persistent atrial fibrillation and flutter. AB - BACKGROUND: To investigate which factors influence the immediate and long-term outcome of elective electrical cardioversion for persistent (>48h) atrial fibrillation or flutter. METHODS: In 255 patients, 435 electrical cardioversions were performed. Relevant clinical, electrocardiographic and echocardiographic factors were registered at each cardioversion. Each factor was tested separately in relation to immediate success and the outcome at six months and one year after cardioversion. RESULTS: In 70% of the patients, sinus rhythm was restored immediately after electrical cardioversion. After six months only 20% of the patients were still in sinus rhythm, and one year after cardioversion this figure had dropped to 14%. Sotalol used during electrical cardioversion resulted in the highest immediate success. Furthermore, atrial flutter, two or fewer electrical shocks and shocks <=200 Joules resulted in the highest immediate success rate, whilst hypertensive heart disease resulted in the lowest immediate success rate. However, only shocks <=200 Joules and a first cardioversion promoted the persistence of sinus rhythm after six months. A normal electrocardiogram, two or more cardioversions in the past and the use of a beta-blocking drug other than sotalol during cardioversion increased the chance of recurrence within six months. The duration of the arrhythmia >one month to 200 Joules and more than two cardioversions in the past were associated with a high number of recurrences one year later. With multivariate analysis we found that atrial flutter, low energy levels, low number of shocks and a long QTc-interval influence the immediate success positively. However, no factor influenced the persistence of sinus rhythm at six months and one year. CONCLUSION: In patients with persistent atrial fibrillation or flutter, only about 15% are in sinus rhythm one year after attempted cardioversion. Atrial fibrillation rather than flutter, high energy shocks and previous cardioversions negatively influenced the immediate success of cardioversion. However, none of the clinical, electrocardiographic or echocardiographic baseline factors studied could be identified as playing a role in the prediction of long-term sinus rhythm. PMID- 25696690 TI - Endovascular extraction techniques for pacemaker and ICD lead extraction: Part 1. AB - In the last few years, comprehensive endovascular techniques have been developed to extract chronically implanted pacemaker and defibrillator leads. It is important that referring physician have knowledge of the advantages and limitations of the different techniques. In this paper we discuss the techniques and results of the currently used endovascular extraction techniques. PMID- 25696693 TI - ? PMID- 25696692 TI - Apical hypertrophic cardiomyopathy. PMID- 25696695 TI - University news: Einthoven Dissertatie Cardiologie Prijzen 2000. PMID- 25696694 TI - ? PMID- 25696691 TI - Mechanisms of cell death in acute myocardial infarction: pathophysiological implications for treatment. AB - The purpose of this review is to draw attention to the growing list of pathophysiological phenomena occurring in blood, the vessel wall and cardiac tissue during myocardial infarction. A further aim is to point to the complexity of factors, contributing to cardiac dysfunction and the implications for therapy, aimed at limiting myocardial cell death. Not all pathophysiological mechanisms have been elucidated yet, indicating the necessity for further research in this area. In addition we describe interventions which have shown promise in animal studies, those which may show promise in humans, and those which are accepted as therapies of choice. PMID- 25696696 TI - Mechanoreceptors: elusive and important activators of cardiac growth. PMID- 25696697 TI - Polynomial analysis of ambulatory blood pressure measurements. AB - BACKGROUND: In normotensive subjects blood pressures follow a circadian rhythm. A circadian rhythm in hypertensive patients is less well established, and may be clinically important, particularly with rigorous treatments of daytime blood pressures. METHODS: Polynomial analysis of ambulatory blood pressure monitoring (ABPM) data were used to identify and study circadian rhythms in ten mildly hypertensive patients both untreated and after single-dose treatment with different categories of antihypertensive agents. ABPM monitoring was performed using validated Space Lab Medical Inc portable equipment, polynomial regression analyses of the systolic blood pressures using Harvard Graphics 3 as well as SPSS Statistical Software. Polynomial curves were compared with the observed data as measured. RESULTS: Fourth order polynomial curves provided the best fit not only for individual data but also for group means. A clear circadian rhythm could be identified, with a day-by-day reproducibility as measured by intra-class correlation, as high as 0.64 versus 0.46 for the observed data, and a goodness of fit as measured by level of correlation between observed and modelled data as high as 0.912. The 4th order polynomial curves provided trough-peak ratios with a median value of 0.85 versus 0.65 for the observed data. Also, the approach enabled comparison of the patterns of reaction to single-dose treatment with different categories of antihypertensive drugs. Reproducibility of polynomial analysis of ABPM data is fundamentally better than that of observed data, and this is so not only with means of populations but also with individual data. CONCLUSIONS: We assume that the difference in reproducibility is due to the potential of polynomial analysis to remove exogenic components from the data and thus visualise the true endogenic circadian rhythm of blood pressures. The method enables us to study circadian rhythms both in treated and untreated patients with mild hypertension, and could be used to predict night-time blood pressure from observed daytime values. PMID- 25696698 TI - Percutaneous transluminal septal myocardial ablation in hypertrophic cardiomyopathy. AB - BACKGROUND: Percutaneous transluminal septal myocardial ablation (PTSMA) is a new interventional technique to treat patients with hypertrophic cardiomyopathy. METHODS: Small doses of ethanol 96% were injected into a targeted septal artery causing a chemical myocardial infarction. Three patients were evaluated, including a follow-up of three months. RESULTS: There were no complications during the procedure LVOT gradient was reduced from 120+/-140 mmHg. At follow-up, all three patients showed improvement in validity. CONCLUSION: The method requires an echocardiographic contrast determination of the myocardium at risk for ethanol treatment, in addition to haemodynamic monitoring. PMID- 25696700 TI - Ruptured aneurysm of a ductus arteriosus diverticulum in an adult. AB - An adult female was admitted for emergency surgery of a massively bleeding suspected aneurysm of the descending aorta. It proved to be a rupture of an aneurysm of a nonpatent ductus arteriosus or ductal diverticulum, a very rare lesion that is usually diagnosed on post-mortem. Adhesion of a previous ipsilateral lobectomy contributed to her survival. The aneurysm was resected. PMID- 25696699 TI - Endovascular extraction techniques: Part 2: Complications and indications. AB - The use of lead extraction is expanding with the introduction of new endovascular extraction techniques. Indications for extraction of chronically implanted pacemaker leads have been classified as mandatory, necessary or discretionary, but their rationale is often based on clinical judgement without corresponding support from the literature. We reviewed the literature of pacemaker lead-related complications as a starting point for discussing the indications for lead extraction. PMID- 25696701 TI - Left to right shunt as a result of acute infective endocarditis. PMID- 25696702 TI - ? PMID- 25696703 TI - ? PMID- 25696705 TI - ? PMID- 25696704 TI - Pluripotent stem cells: biology and applications: Durango Colorado, 6-11 February 2001. PMID- 25696706 TI - ? PMID- 25696708 TI - The new aspirin is born. PMID- 25696707 TI - University news: Myocardial functional imaging; an evaluation with quantitative gated SPECT. PMID- 25696709 TI - Endovascular extraction techniques: Part 3: Results and indications in patients with an ICD. AB - INTRODUCTION: We report our experience with lead extraction in patients with an implantable cardioverter defibrillator (ICD) and discuss the indications for extraction in these patients. PATIENTS: Eighteen patients with an ICD (mean age 58+/-12 years) were referred for lead extraction: two patients with infection and 16 with lead dysfunction. METHODS: Lead extraction was performed with a laser sheath (Excimer) if traction with a locking device was insufficient. New leads were implanted during the same procedure, if applicable. RESULTS: Shock leads were successfully extracted in 16 patients and additional pace-sense leads in seven patients. In two patients, the shock conductor was considered unaffected and only a pace-sense lead was exchanged or an additional pace-sense lead inserted. After extraction, new shock leads were implanted in 14 patients. Major complications occurred in one patient: a pericardial tamponade after perforation of the superior caval vein necessitating acute surgery. CONCLUSION: Lead extraction with a laser sheath is effective in ICD patients, but major complications can occur. Our current policy with malfunctioning leads is to extract all leads in which insulation defects cannot be ruled out to avoid interference, but to abandon leads that are without insulation defects and properly insulated. In case of infection, extraction remains the primary treatment of choice. PMID- 25696710 TI - Friction and fluid: correlating pericardial effusion and pericardial friction rub. AB - BACKGROUND: In this study the relationship between pericardial friction rub (PFR) and the degree of pericardial effusion was investigated. METHODS: A retrospective study was performed involving all patients for whom the diagnosis pericarditis was made on clinical grounds (type of chest pain, fever, laboratory findings and/or electrocardiographic signs) in the period 1990-1999. In this patient group (n=138) the presence of PFR was correlated against the amount of pericardial effusion measured echocardiographically. RESULTS: No statistically significant correlation between the presence of PFR and the amount of pericardial effusion was observed. It is, therefore, a misconception that the presence of a PFR signifies absence or only a small volume of pericardial effusion. Our results are in line with the literature. CONCLUSION: Based on this study and results presented in the literature, we postulate that the friction rub associated with pericarditis is not caused by friction of the 'roughened' pericardial layers, as is commonly propagated. Instead fibrin strands caused by the inflammation, connecting the two pericardial layers, may function as snares and generate, through the movements of the heart, the typical triphasic pericardial friction rub. PMID- 25696711 TI - Recreational myocardial infarction legacy of the 1990s. AB - Cocaine is a common drug of abuse with a potential lethal cardiac toxicity. Although cocaine abuse has reached epidemic proportions, the number of cardiovascular complications observed clinically remains low. Over 30% of men and 20% of women between the ages of 26 and 34 have used cocaine at least once. Moreover, more than 30 million Americans have used cocaine at some time, and more than five million are regular abusers. Chest pain is one of the most common reasons for cocaine users to seek medical attention. Over 64,000 patients are evaluated annually for cocaine-related chest pain, of whom more than 57% are admitted to hospital for possible myocardial ischaemia, at an annual cost of more than $83 million. PMID- 25696712 TI - Unexpected overdose with diltiazem: value of toxicological screening. AB - We describe a 59-year-old woman who was admitted in deep coma with bradycardia, hypotension and fixed pupils. The cause of her severe condition was unclear. Cerebral and myocardial infarction was excluded. Temporary transcutaneous pacing was not successful, nor was atropine or norepinephrine (noradrenaline), but the patient responded well to isoprenaline infusion. Since she was known to have a psychiatric history, toxicological screening was performed which showed a severe diltiazem overdose. Later we discovered that she took diltiazem for angina pectoris. The patient survived and was discharged without neurological or cardiological deficits after two days of treatment. This case report emphasises the importance of toxicological screening in unconscious patients with no apparent cause. We review the clinical features and treatment options of diltiazem overdose and discuss the value of toxicological screening. PMID- 25696714 TI - ? PMID- 25696713 TI - Pneumopericardium. PMID- 25696715 TI - ? PMID- 25696716 TI - Results of the CURE study: Orlando, 18-21 March 2001. PMID- 25696717 TI - Abstracts Nederlandse Werkgroep Hartstimulatie: Lustrum nvt, oktober 2000, Amsterdam. PMID- 25696718 TI - Guidelines on line? PMID- 25696719 TI - Prognostic importance of left ventricular function after angioplasty or thrombolysis for acute myocardial infarction. AB - OBJECTIVES: To compare long-term clinical outcome after acute myocardial infarction treated with primary coronary angioplasty or thrombolytic therapy, and to study the determinants of survival. BACKGROUND: Primary coronary angioplasty results in a higher patency rate and a better short-term survival when compared with thrombolytic therapy, but so far limited information has been available regarding long-term clinical outcome. METHODS: Patients with acute myocardial infarction (n=395) were randomised to treatment with either intravenous streptokinase or primary angioplasty, and were followed for up to eight years. RESULTS: A total of 105 patients died, 42 patients in the primary coronary angioplasty group compared with 63 patients in the streptokinase group (p=0.03). Death and nonfatal reinfarction occurred in 53 patients in the angioplasty group, compared with 94 patients in the streptokinase group (p<0.001). The major cause of long-term mortality is sudden death. Multivariate analysis showed that left ventricular function was the most important predictor for both total mortality and sudden death. CONCLUSION: The benefits of primary coronary angioplasty compared with streptokinase are well sustained during long-term follow-up. PMID- 25696720 TI - Prognostic significance of nonfatal myocardial reinfarction in survivors of a first infarction. AB - BACKGROUND: Patients who develop a reinfarction are at increased risk for subsequent reinfarctions and death. However, follow-up studies in these patients are rare. OBJECTIVE: The purpose of this study was to examine the risk of mortality after a first myocardial reinfarction and to determine the independent contribution of nonfatal reinfarction to the risk of subsequent mortality. METHODS: The prognostic value of nonfatal reinfarction was assessed in a large series (n=3097) of patients with a first myocardial infarction who participated in the ASPECT trial, comparing coumarin or matching placebo. RESULTS: A second myocardial infarction was documented in 299 patients (82% Q-wave infarctions), 45 (15%) of which were fatal. Of the 254 nonfatal reinfarctions, 31 patients (12%) died during subsequent follow-up. After adjustment for baseline characteristics, the relative risks of nonfatal reinfarction for subsequent cardiac mortality at one month were: 2.90 (1.49-5.64), at one year: 2.50 (1.47-4.23) and at three years: 2.71 (1.77-4.17). Rates of death or a second reinfarction in patients who did not undergo a revascularisation procedure after a first reinfarction were almost three times higher than in patients who did have PTCA or bypass surgery after a reinfarction (38% versus 14%; p<0.0001). CONCLUSION: This study population with three-year follow-up confirms that nonfatal reinfarction carries a strong and independent risk for recurrent reinfarction and subsequent mortality. Thus, prevention of reinfarction by intensive treatment might contribute in reduction of mortality. PMID- 25696721 TI - Cl- current blockade reduces triggered activity based on delayed afterdepolarisations. AB - OBJECTIVES: Increasing evidence suggests that a Ca2+-activated Cl- current (ICl(Ca)) contributes to the transient inward current (Iti), the current responsible for proarrhythmic delayed after-depolarisations (DADs). Because the equilibrium potential for Cl- ions (ECl) in myocytes is around - 50 mV, activation of the ICl(Ca) results in an inward depolarising current at resting membrane potential and ICl(Ca) may thus be responsible for a part of the depolarisation during a DAD. In this study, we investigated the ionic nature of Iti and the effects of Cl- current blockade on DADs. METHODS AND RESULTS: The ionic mechanisms of Iti and underlying DADs were studied in sheep ventricular myocytes using the patch-clamp methodology. The DADs were induced in the myocytes by exposure to 1 MUM noradrenaline and the Iti were elicited by repetitive depolarisations from -93 mV to +37 mV in the presence of the drug. The current voltage relation of Iti reversed in sign around -20 mV. The outward Iti was completely blocked by the anion current blocker 4,4'-diisothiocyanatostilbene 2,2'-disulphonic acid (DIDS), whereas the inward Iti was only slightly affected. The DIDS-sensitive component of Iti was outwardly rectifying with a reversal potential close to ECl. The DIDS-insensitive component of Iti was abolished by blockade of the Na+-Ca2+ exchanger by substitution of extracellular Na+ by equimolar Li+. Interestingly, DIDS reduced the DAD amplitude and triggered activity based on DADs. CONCLUSION: In sheep ventricular myocytes, Iti consists of two ionic mechanisms: a Cl- current and a Na+-Ca2+ exchange current. Blockade of the Cl- current may be potentially antiarrhythmic by lowering DAD amplitude and triggered activity based on DADs. PMID- 25696722 TI - Oestrogen, atherosclerosis and cardiovascular disease in women: Epidemiological studies on menopause and hormone replacement therapy. AB - What part menopause and hormone replacement therapy (HRT) play in the risk of cardiovascular disease in women after middle-age is still debated. The associations between menopause, HRT and cardiovascular disease as well as atherosclerosis were examined in a large cohort study. Our results suggest menopause has an unfavorable association with several cardiovascular risk factors, structural characteristics of the large arteries, on atherosclerosis and on coronary heart disease. HRT was shown to protect women from development of atherosclerosis in the lower extremities and in the common carotid artery. This suggests that the mechanisms underlying this protection include inhibition of the atherosclerotic process. Our analyses of a randomised, placebo-controlled study could not confirm the effect on HRT on atherosclerosis of the common carotid artery. As findings from large randomised trials do not confirm the benefit of estrogen therapy for prevention of cardiovascular disease no definite conclusions can be drawn, and HRT should not be recommended for this purpose in clinical practice. PMID- 25696723 TI - 71-year-old male with progressive dyspnoea and peripheral oedema: a case of cardiac amyloidosis. AB - We present the case of a 71-year-old male with progressive dyspnoea. On physical examination there was evidence of congestive heart failure. The complete blood count was normal and twelve-lead ECG showed low voltage in the standard leads. Chest x-ray showed cardiomegaly, pulmonary congestion and left pleural effusion. Two-dimensional echocardiography and Doppler ultrasound studies revealed biatrial enlargement and a restrictive diastolic filling pattern. Serum protein electrophoresis was abnormal showing a monoclonal elevation of IgG. Amyloid heart disease was suspected. Fat pad biopsy showed findings consistent with amyloid heart disease. Melphalan and prednisone were initiated to help slow the progression of disease. PMID- 25696725 TI - ? PMID- 25696724 TI - Intermittent jamming of a mitral valve prosthesis. PMID- 25696726 TI - ? PMID- 25696728 TI - ? PMID- 25696727 TI - ACC Orlando 17-21 March 2001. PMID- 25696729 TI - Abstracts voorjaarsvergadering Nederlandse Vereniging voor Thoraxchirurgie: 18 mei 2001. PMID- 25696730 TI - Primary ventricular fibrillation in acute myocardial infarction: an inherited disease? PMID- 25696731 TI - Clinical benefit, survival and adverse events in patients with implantable cardioverter defibrillators: the initial Rotterdam experience. AB - BACKGROUND: The implantable cardioverter defibrillator (ICD) has become a widely accepted therapy for patients with severe life-threatening ventricular tachyarrhythmias. The aim of this study was to illustrate the possible advantages of ICDs with respect to survival and clinical events. METHODS AND RESULTS: Between 1998 and 2000, 92 patients (aged 58+/-15 years; ejection fraction 36+/ 15%; coronary artery disease 71%) were treated with an ICD in combination with an endocardial lead system. Benefit of the ICD was estimated as the difference between total cardiac death and the projected death rate of fast ventricular tachyarrhythmias (>200 bpm), assuming that most fast ventricular tachyarrhythmias would have been fatal without termination by the ICD. Adverse events were classified according to European standards. The cardiac mortality rate was 5.5% and 9.8%, at one and two years respectively. The recurrence rate of fast VT (>200 bpm) was 22.4% and 30.2%, at one and two years respectively. The observed difference between cardiac death and projected death was very significant (p=0.002) and suggests a clear benefit from ICD implantation. Low ejection fraction (<35%) and NYHA class >=II correlated with a higher projected death. The most common adverse event was inappropriate therapy (18%). CONCLUSION: The results from our small series support the existing data that especially patients with poor ejection fraction (<35%) benefit from ICD implantation. The adverse event rate was low. However, inappropriate therapy remains a matter of concern. Given the high workload of correct screening and follow-up, we expect that the actual number of centres in the Netherlands permitted to implant ICDs will be unable to cope with the widening spectrum of ICD indications. PMID- 25696732 TI - What's up in heart failure care in the Netherlands? AB - OBJECTIVES: To provide an overview of heart failure management programmes in the Netherlands. METHODS: A descriptive study was performed consisting of two phases, a screening phase in which all hospitals (n=109) and 105 home care organisations were approached by telephone to assess availability of heart failure management programmes. In phase 2, content and organisation of the programmes were described by a questionnaire. RESULTS: At the moment, the majority of hospitals (75%) have a heart failure management programme or are developing such a programme. In 19 home care organisations (18%) a programme was available and three organisations had concrete plans to start one in the short term. Components of heart failure programmes differ considerably, with a follow-up after discharge from hospital as the most often reported component. Other components of programmes include patient education, increased access to healthcare professionals and adjusting medication. Exercise programmes are not often available. Organisational aspects with regard to setting, financing and staffing also differ between various programmes. CONCLUSION: There is a considerable increase in the number of heart failure management programmes in the Netherlands, both hospital based and home based. Many questions regarding the most optimal content and organisation of heart failure management programmes remain unanswered. PMID- 25696733 TI - Initial experience with single lead intracardial cardioversion for refractory atrial fibrillation. AB - BACKGROUND: Chronic atrial fibrillation (AF) is a common arrhythmia, associated with a substantial morbidity (thromboemboli, worsening left ventricular function). Established therapy for pharmacological refractory AF is high-energy trans-thoracic electric cardioversion (TTCV), but this strategy is ineffective for 10-30% of the patients. The purpose of the present study is to establish the safety and efficacy of low-energy intracardiac cardioversion (ICCV) with a relatively new balloon-guided single-catheter system with dual chamber pacing possibility for this group of patients. METHODS: Patients in whom an attempt to restore sinus rhythm (SR) by TTCV under antiarrhythmic therapy failed were eligible for the study. For the ICCV-attempt, a single flow-guided atrial cardioversion catheter was used. Low-energy biphasic shocks of increasing energy (6-15 J) were delivered, if necessary in combination with intravenous amiodarone, until SR was restored. In case of early recurrence of AF, another attempt was made with immediate post-shock overdrive pacing (AOO) in order to suppress premature atrial activity. RESULTS: Initially, 14 of the 16 treated patients (90%) were converted to SR successfully. In eight patients additional amiodarone i.v. was administered and in six patients atrial overpacing was used after ICCV. In seven and five patients, respectively, these strategies were successful. Long term follow-up (1-3 months) showed that in nine patients (56%) SR was preserved; eight of them on oral amiodarone. No adverse events were seen during the procedure and follow-up, especially no bleedings, despite puncturing under adequate anticoagulation therapy. CONCLUSION: ICCV using a single atrial cardioversion catheter is a safe and effective method to restore SR in patients in whom TTCV failed previously. Long-term follow-up of this procedure is comparable to that of other studies. Results are influenced by antiarrhythmic drug therapy, compliance and patient selection. PMID- 25696734 TI - Molecular adaptations in human atrial fibrillation: mechanisms of protein remodelling. AB - The chance that the treatment of atrial fibrillation (AF) is successful depends on the duration of the arrhythmia. The low efficacy of cardioversion therapy after long-term AF can be explained by the occurrence of cellular adaptation mechanisms. In this article we describe ion-channel protein remodelling and structural changes in the atria of patients with persistent and paroxysmal AF and its relation with electrical remodelling. PMID- 25696735 TI - A case of early postmyocardial infarction syndrome. AB - A 65-year old woman was admitted with an inferior infarction. Six hours later she developed a pericarditis with specific ECG alterations in the anterior wall accompanied with pericardial and pleural effusion. This early form of true pericarditis after acute myocardial infarction can be explained as an exacerbation of a latent inflammation, whether or not triggered by the acute infarction. PMID- 25696737 TI - ? PMID- 25696736 TI - Left ventricular diverticulum. PMID- 25696738 TI - ? PMID- 25696739 TI - Scientific conference on therapeutic angiogenesis and myocardial laser revascularisation: Santa Fe, United States, 24-27 January 2001. PMID- 25696740 TI - Abstracts Nederlandse Werkgroep Hartstimulatie: Opgericht 1973 onder auspicien van de Nederlandse Vereniging voor Cardiologie en de Nederlandse Hartstichting. PMID- 25696741 TI - University news: Heart failure, myocardial ischaemia and neurohormonal activation. PMID- 25696742 TI - Pulmonary valve insertion late after repair of Fallot's tetralogy. PMID- 25696743 TI - Right ventricular dysfunction and the role of pulmonary valve replacement after correction of tetralogy of Fallot. AB - BACKGROUND: Correction of tetralogy of Fallot (ToF) often leads to pulmonary regurgitation, sometimes warranting pulmonary valve replacement (PVR), for which the indications and timing to achieve optimal results are not yet clear. This retrospective study describes follow-up and reinterventions in our ToF population. METHODS: Review of all consecutive patients operated for ToF between 1977 and 2000. Included are date and type of repair, Doppler echocardiography (2D echo), ECGs, re-operations and physical condition. RESULTS: Total repair was performed in 270 patients, mean age 1.9+/-2.5 years, 82 were excluded because of follow-up abroad. Right ventriculotomy was used in 92%, transatrial VSD closure in 8%, while 69% received a transannular outflow patch. Pulmonary atresia required a pulmonary graft in 13 (8%) patients. Overall 20-year survival was 88%. Last follow-up: ECG showed RBBB in 67% (QRS complex 129+/-29.3 msec). RVOT aneurysms were detected in 16%. 2D-echo demonstrated mild pulmonary insufficiency (PI) in 40%, severe in 31%, dilated RV in 76%, both increasing with post-repair age. In 39%, RV dimensions were equal or even exceeded LV dimensions, 45% showed tricuspid insufficiency and the RA was enlarged in 14%. Reintervention was necessary in 39/185 patients, this included angioplasty for residual stenosis and PVR (22/19 homografts, six patients in PA group) at a mean age of 11.2 years after correction. In seven patients, the RV returned to normal dimensions and symptoms disappeared, but in three severe dysfunction developed. Eleven others still have RV dilatation and/or PI. In total, 75% were free of reintervention in the first ten years. The right atrial approach diminishes severe RV dilatation and prolonged QRS duration (p=0.001 and 0.007). Early correction reduces the risk of re-operation (p=0.011). CONCLUSIONS: Severe RV dilatation (39%) and PI (31%) secondary to outflow tract repair in ToF are frequently occurring sequels developing slowly over time. Timing of PVR remains controversial, still best guided by the clinical condition. PMID- 25696744 TI - Beta blockade in neurocardiogenic dysfunction: results of a clinical study. AB - BACKGROUND: Few placebo-controlled studies with beta-blockers have been performed in patients suffering from neurocardiogenic syncope. METHODS: We investigated the efficacy of metoprolol in 26 patients with recurrent syncope, suspected to be of neurocardiogenic origin, and positive tilt table test (TTT) outcome in a single centre, double-blind, placebo-controlled, crossover study, with treatment periods of two weeks. Therapeutic efficacy was defined as a negative TTT after metoprolol and a positive TTT after placebo. Therapeutic failure was defined as a positive TTT after metoprolol and a positive or negative TTT after placebo. Patients with a negative TTT test after both metoprolol and placebo comprised the third group. RESULTS: The 24 patients who completed the study consisted of 14 females and 10 males, mean age 53 years, range 18-75 years. Therapeutic efficacy was observed in nine patients, therapeutic failure in eight patients and seven patients had a negative TTT after both placebo and metoprolol. According to the exact binomial test for paired proportions, the 95% confidence interval is 12 to 38% and p<0.01 in favour of treatment with metoprolol. CONCLUSION: These findings indicate a favourable effect of metoprolol. PMID- 25696745 TI - Cardiovascular screening at a public event: results from 'For your heart's sake' AB - BACKGROUND: At the public event 'For your heart's sake' ('Het leven is hart...Zorg er goed voor'), the opportunity to measure the well-known major cardiovascular risk factors was offered to visitors. METHODS: The screening took place at seven risk assessment stations. Blood pressure was taken with an Omron manometer in a sitting position, and the total plasma cholesterol was measured. Risk for future cardiovascular events was calculated with the Framingham risk formula. RESULTS: A cardiovascular risk profile was obtained in 784 persons. Their mean age was 48 years. Smoking prevalence was 21%. The mean cholesterol concentration was 5.2 mmol/L. Only 3% of the subjects had cholesterol levels above 8 mmol/L. The prevalence of hypertension (systolic blood pressure of at least 140 mmHg) was 16%. Risk for a cardiac event in the next ten years >10% was found to be present in 4%, while 1% (7 men) had a calculated risk >20%. CONCLUSIONS: Although the cardiovascular screening programme attracted a relatively healthy sample of the Dutch population, prevalence of high blood pressure and elevated cholesterol levels was high, and the risk for future atherosclerotic disease elevated in many older men and women. These results are another plea for continued efforts to reduce the burden of atherosclerotic cardiovascular disease through primary prevention. PMID- 25696746 TI - A guideline for uniform and optimal atherosclerotic risk factor assessment across clinical specialities in a large hospital. AB - Solid evidence is available concerning the beneficial effect of atherosclerotic risk factor management both in primary and secondary prevention. However, recent registries have indicated considerable potential for improvement of clinical practice concerning secondary prevention of atherosclerosis. The guideline 'Secondary Prevention of Atherosclerosis' is aimed at the improvement and standardisation of atherosclerotic risk factor assessment in cardiovascular patients hospitalised at the Academic Medical Centre in Amsterdam. The guideline was developed by a task force, consisting of physicians from the Departments of Cardiology, Cardiothoracic Surgery, Internal Medicine, Interventional Radiology, Neurology, Pharmacology and Vascular Surgery. The guideline offers a standardised method for the identification of atherosclerotic risk factors and provides thresholds for treatment, treatment goals and the treatment of choice. A form listing all relevant data is completed before discharge and is mailed with the discharge letter to the referring physician and to the general practitioner. PMID- 25696747 TI - Continuing medical education in Europe: NVVC, CVOI, ESC, UEMS and EBAC. AB - The European Board for Accreditation in Cardiology (EBAC) is a joint initiative of the European Society of Cardiology (ESC) and the Cardiology Section of the Union of European Medical Specialists or Union Europeenne des Medecins Specialistes (UEMS). EBAC operates independently from these parent organisations. The ESC is the highest cardiovascular scientific authority in Europe and the most important provider of Continuing Medical Education (CME) in cardiology. The UEMS officially represents the European medical specialists at the European Union (EU). The UEMS consists of different mono-specialist sections, among which the Cardiology Section. The recognition of the importance of CME and the need for quality standards and quality control led the UEMS to establish the European Accreditation Council for CME (EACCME) in January 2000. CME activities that seek European accreditation have to comply with the regulations of this council. As a consequence of the establishment of EACCME, the mono-specialist sections of the UEMS together with the different European scientific societies started to create accreditation boards with the aim to assess international CME activities in accordance with the regulations of UEMS and EACCME. EBAC was founded in 2000. EBAC accreditation is complimentary to national CME accreditation. The Netherlands Society of Cardiology (Nederlandse Vereniging voor Cardiologie, NVVC) and its Institute for CME, the Netherlands Institute for Continuing Cardiovascular Education (Cardio-Vasculair Onderwijs Instituut, CVOI) formally recognise EBAC accreditation and Attendance Certificates. PMID- 25696748 TI - Temporal arrest. AB - Two patients are presented in which documented periods of asystole were caused by temporal epilepsy. Pacemaker implantation prevented total collapse but episodes of near collapse continued. After institution of anti-epileptic drug treatment both patients are free of symptoms. PMID- 25696749 TI - Congenital fistula between the LAD and the right ventricle. PMID- 25696750 TI - ? PMID- 25696751 TI - ? PMID- 25696752 TI - Percutaneous septal ablation: a new treatment for hypertrophic obstructive cardiomyopathy. PMID- 25696753 TI - Percutaneous transluminal septal myocardial ablation (PTSMA) for symptomatic patients with hypertrophic obstructive cardiomyopathy: first experience. AB - BACKGROUND: Recently, percutaneous transluminal septal myocardial ablation (PTSMA) has been introduced as treatment for symptomatic patients with hypertrophic obstructive cardiomyopathy (HOCM). METHODS: We describe our first experience in 24 patients who were treated in our institution during the year 2000. RESULTS: The procedure was initially successful in all but one patient. In that patient the septal branch that was perfusing the proximal septum could not be found. The procedure was complicated in three patients. One patient died suddenly on the second day after the procedure. Two additional patients needed a permanent pacemaker for persisting total heart block. In the other 22 patients the procedure was successful with an acute decrease of the mean outflow tract gradient from 89+/-43 mmHg to 21+/-19 mmHg. In those 19 patients who had a follow up of at least three months (mean follow-up 172+/-87 days), the mean NYHA class decreased from 2.7+/-0.7 before PTSMA to 0.6+/-0.9 at the last follow-up. The echocardiographic gradient decreased from 92+/-39 mmHg before the procedure to 26+/-23 mmHg at the last follow-up. CONCLUSIONS: Our preliminary results demonstrate that PTSMA is an effective treatment for symptomatic patients with HOCM. PMID- 25696754 TI - A nineteen-millimetre aortic valve prosthesis: is this really a risk? AB - BACKGROUND: Aortic valve replacement in patients with a small aortic root is a subject of ongoing controversy. We summarised our clinical experience with aortic valve replacement with 19 mm valves and combined this with a review of literature. METHODS: Between January 1994 and December 1999, 603 patients underwent aortic valve replacement; 51 of these patients (8.3%) received a 19 mm heart valve prosthesis. The mean age was 72+/-9.7 years. Twenty-eight patients had concomitant coronary artery disease, six patients a combined mitral or tricupid valve disease. In four patients, the intervention was a reoperation. The mean EuroSCORE of the total group was 6.4+/-2.8, and 34 patients had a high operative risk. RESULTS: Hospital mortality was 7.8% (4/51 patients). Follow-up of 47 hospital survivors was complete. At 12 months the survival was 90%, at 24 months 85% and at 48 months 60%. NYHA class improved at least one class in 35 patients (85%), and 34 patients declared that their quality of life had improved since the operation. CONCLUSION: Aortic valve replacement with a small (19 mm) prosthesis can be performed with an acceptable operative mortality and results in excellent symptomatic improvement and quality of life. PMID- 25696755 TI - Clinical characteristics and outcome of patients with acute myocardial infarction and preinfarction angina. AB - OBJECTIVES/BACKGROUND: Preinfarction angina is associated with reduced myocardial infarct size in patients treated with thrombolysis. Our objective was to assess the relation between preinfarction angina and infarct size, left ventricular function and clinical outcome in patients treated with primary angioplasty (PTCA) and compare this with patients treated with thrombolysis. METHODS: In the Zwolle Infarction Study, 953 patients were treated for acute myocardial infarction between 1990 and 1996; 761 patients underwent primary PTCA and 192 patients received thrombolysis as reperfusion therapy. RESULTS: Preinfarction angina was present in about 50% of the patients, who were categorised into angina <=24 hours and angina >24 hours before infarction. Patients in both treatment groups have a longer ischaemic time when preinfarction angina is present. In patients treated with thrombolysis, preinfarction angina <=24 hours results in a smaller enzymatic infarct. Thrombolysis seems to be more effective when preinfarction angina occurs within the 24 hours prior to myocardial infarction. Collateral filling of the infarct-related artery is more often seen in patients with preinfarction angina. In the primary PTCA group, a longer ischaemic time in patients with preinfarction angina does not result in increased infarct size, and this effect remains after excluding patients with collateral filling. CONCLUSIONS: The protective effect of preinfarction angina is likely to be due to better collateral filling of the infarct-related artery and to ischaemic preconditioning of the myocardium. PMID- 25696756 TI - Beta blockers in heart failure haemodynamics, clinical effects and modes of action. AB - Treatment for heart failure may be directed at relieving symptoms and/or improving prognosis. One of the primary aims of research in heart failure is to alter the progressive decline in pump function and thereby improve prognosis. For many years, diuretics have been known as therapeutics in heart failure and they are very effective in symptom relief. Vasodilators and inotropes also have beneficial effects on symptom relief especially in the acute phase through changes in cardiac output, filling pressures and renal perfusion. However, although these treatments produce short-term relief, none have been shown to influence the disease process and thereby improve mortality. Indeed, many of these drugs may even lead to untoward long-term clinical outcomes as has been shown for example for milrinone and ibopamine. There is overwhelming evidence that drugs interfering with the neurohormonal activation in heart failure not only produce symptomatic relief but are also capable of attenuating disease progression with concomitant reductions in both morbidity and mortality. About a decade ago, convincing and large-scale evidence showed that ACE inhibitors produced favourable effects by antagonising the activated renin-angiotensin system. More recently, beta-blockers, which antagonise the activated sympathetic system, were shown to be beneficial in the long term in moderate severe heart failure in terms of significant improvements in both morbidity and mortality. The RALES study further amplified the concept that drugs that interact in the neurohormonal system have beneficial effects. In this study, spironolactone, a weak, potassium-sparing diuretic counteracting aldosterone showed a reduction in mortality in more severe forms of heart failure. PMID- 25696757 TI - Safety of statins in the new millennium. AB - Looking at the world today and six months ago in retrospect, it becomes clear that things have changed dramatically. Not only are global economic forecasts in turmoil, other certainties have also been proven to be not as steadfast as we had hoped and expected. Safety in the world has gained a different perspective since the assault on the twin towers of the World Trade Centre in New York and the Pentagon. The safety of medicine and especially statins has also become an issue since the withdrawal of cerivastatin because of its possible association with an increased rate of rhabdomyolysis under certain circumstances. PMID- 25696758 TI - Ruptured aneurysm of the left sinus of Valsalva into the pericardium. AB - Recently, a 67-year-old female patient came to our attention after a collapse, due to cardiac tamponade caused by a ruptured sinus of Valsalva aneurysm (SVA) and intrapericardial bleeding. Despite surgical intervention the patient died before correction. PMID- 25696759 TI - Acute myocardial infarction due to left main occlusion. PMID- 25696760 TI - ? PMID- 25696761 TI - ? PMID- 25696763 TI - Erratum: Scientific conference on therapeutic angiogenesis and myocardial laser revascularisation. AB - [This corrects the article on p. 256 in vol. 9.]. PMID- 25696762 TI - ? PMID- 25696764 TI - University news: The autologous pulmonary valve in the systemic circulation: Clinical and experimental results of the Ross operation. PMID- 25696765 TI - Revascularisation of the unprotected left main: surgery or angioplasty? PMID- 25696766 TI - Adverse psychological outcome in women with coronary artery disease. AB - OBJECTIVES: To investigate gender differences on psychological outcome following cardiac disease, and to identify predictors of psychological distress. METHODS: In total, 536 consecutive cardiac patients <=70 years were identified from medical records to participate in the study: 36 of them proved to have died since the index event. The mean time since the index event was one year and seven months. Of the 500 patients, 357 (71%) agreed to attend an interview on biomedical risk factors and fill in a psychological questionnaire. Complete psychological data were available for 287 (80%) patients. RESULTS: Women scored significantly higher on anxiety, depression, vital exhaustion and social inhibition, and lower on wellbeing compared with men. Gender, age, percutaneous transluminal coronary angioplasty, smoking and admission for a recurrent event since the index event were independent predictors of psychological outcome. CONCLUSION: These results add to current knowledge on gender differences and show that women have an adverse outcome on a range of psychological variables. This has implications for secondary prevention and rehabilitation. Longitudinal studies are needed to assess the implications of adverse psychological outcome in women on prognosis. PMID- 25696767 TI - Signal transduction of mechanical stress in myocytes and fibroblasts derived from neonatal rat ventricles. AB - BACKGROUND: In cardiomyocytes and cardiac fibroblasts, stretch induces a growth response. METHODS: To investigate which signal transduction pathways are involved in the stretch-induced growth response of cardiomyocytes and cardiac fibroblasts, we used a model of mechanical stress in which cells are submitted to biaxial cyclic stretch. RESULTS: In stretched cardiomyocytes major bands of tyrosine phosphorylated (P-Tyr) proteins of 58, 49, and 27 kDa were detected and minor bands of 65 and 40 kDa. Furthermore, major bands of serine/threonine phosphorylated (P-Ser/Thr) proteins of 46, 42, and 21 kDa were detected. Phosphorylation of the 40 kDa P-Tyr protein increased significantly upon stretch. In cardiac fibroblasts major bands of P-Tyr proteins of 63, 53, and 23 kDa were detected and minor bands of 72 and 39 kDa. In addition, major bands of P-Ser/Thr proteins of 51, 47, and 23 kDa were detected and minor bands of 54 and 33 kDa. Phosphorylation of the 54 and 33 kDa P-Ser/Thr proteins increased significantly upon stretch. Phosphorylated JNK 1 and JNK 2 activities were not detected in fibroblasts. In cardiomyocytes levels of phosphorylated JNK 1 and 2 were very low, but tend to increase upon stretch. Phosphorylated p38 MAPK could not be identified in both cell types. The intensity of phosphorylation of paxillin increased upon stretch in both cell types, although the increases were only significantly different in stretched fibroblasts. Finally, stretch increased PLC activity in cardiomyocytes as well as in fibroblasts. CONCLUSION: Our findings are in favour of mechanotransduction of the stretch signal via integrins and focal adhesion components such as FAK, Src kinase, PLC and paxillin. The activation of the last two focal adhesion components by stretch of cardiomyocytes and fibroblasts is demonstrated in this article. PMID- 25696768 TI - Clinical efficacy of the use of information technology in cardiology: initial results of angiographic teleconsultation in the Netherlands. AB - BACKGROUND: With the increasing use of cineless diagnostic angiography laboratories, modern telecommunication networks provide an excellent opportunity to transfer dynamic cardiac catheterisation images from a referring centre to a cardiac intervention centre. This electronic data transfer may lead to improved patient care and reduced waiting times. METHODS: Two departments of cardiology started a pilot project using a digital ISDN-30 point-to-point data-line connection between Alkmaar and Amsterdam over which MPEG compressed angiograms are sent. The network consists of a PC based client/server structure and two ISDN modular routers. RESULTS: From June 1998 to January 2001, 127 patients were referred for urgent PTCA or CABG using this network. All patients were admitted to the CCU for unstable angina and had a suitable anatomy for coronary angioplasty or coronary artery bypass surgery. In all cases the MPEG compressed images were successfully stored on the server and could be accessed in Amsterdam. During the pilot phase all X-ray runs (11 + 3) were sent. Following transmission, all patients were accepted for intervention. Review of the DICOM images from the CD-Medical immediately before the PTCA or CABG did not change the planned strategy. The patients were successfully treated 1 to 2 days after data transmission. During this phase, the average variable costs of this network was ? 5.90 per patient as opposed to ? 69.00 when using a courier service. CONCLUSION: This study shows that personal computer-based telecommunication network systems are feasible for clinical use in daily practise. Access to a remotely located cardiac intervention centre can be achieved promptly at low costs and improves patient care by reducing waiting times. PMID- 25696770 TI - Prognostic value of viability assessment in chronic ischaemic LV dysfunction. PMID- 25696769 TI - Essential thrombocythaemia as cause of myocardial infarction. AB - Abnormalities in the number and function of platelets may contribute to thromboembolic complications in patients with essential thrombocythaemia (ET). Rarely this can lead to an acute myocardial ischaemic syndrome. We describe a young patient with a myocardial infarction, in whom ET was found as the probable cause. We discuss the clinical presentation of ET and the therapeutic possibilities. PMID- 25696771 TI - ? PMID- 25696772 TI - ? PMID- 25696773 TI - University News: Genetic variation of clotting factors and the risk of myocardial infarction: study of myocardial infarction. PMID- 25696774 TI - Diagnostic Tower of Babel: need for diagnostic systems synchronization and comprehensible language. PMID- 25696775 TI - Internet addiction is associated with social anxiety in young adults. AB - BACKGROUND: Problematic Internet use or excessive Internet use is characterized by excessive or poorly controlled preoccupations, urges, or behaviors regarding computer use, and Internet access that leads to impairment or distress. Cross sectional studies on samples of patients reported high comorbidity of Internet addiction with psychiatric disorders, especially affective disorders (including depression), anxiety disorders (generalized anxiety disorder, social anxiety disorder), and attention-deficit/hyperactivity disorder. METHODS: We have investigated the association between Internet addiction and social anxiety in 2 samples of 120 university students (60 males and 60 females in each sample). RESULTS: We found a correlation between Internet addiction and social anxiety in the 2 samples (r=0.411, P<.001; r=0.342, P<.01) respectively. Secondly, we found no difference between males and females on the level of Internet addiction. Thirdly, we did not find a preference for social networks among participants with high levels of social anxiety. CONCLUSIONS: The results of the study support previous evidence for co-occurrence of Internet addiction and social anxiety, but further studies need to clarify this association. PMID- 25696776 TI - Getting the word out: cognitive-behavioral therapy for trichotillomania (hair pulling disorder) and excoriation (skin-picking) disorder. AB - BACKGROUND: To date, there has been no investigation of dissemination outcomes for cognitive-behavioral training programs for body-focused repetitive behaviors (BFRBs). METHODS: Sixty-three past participants of the Trichotillomania Learning Center (TLC) intensive professional training institutes completed an online survey assessing referral sources, skills utilization, and treatment outcomes before and after training. The intensive training focused on the treatment of trichotillomania (hair-pulling) disorder and excoriation (skin-picking) disorder using in-person or videotaped didactics, role playing, and case presentations with supervision upon request. RESULTS: Participants endorsed a greater number of referral sources and BFRB patients after attending training. Paired t tests indicated significant pre- to post-training increases in self-reported utilization of all individual cognitive-behavioral therapy (CBT) skills as well as overall mean skills usage (both P<.001). Changes after training in the reported percent of abstinent patients and mean reduction in symptom severity were also noted. CONCLUSIONS: The TLC intensive professional training institutes may be useful for disseminating CBT skills for the treatment of BFRBs, but additional research is warranted. PMID- 25696777 TI - Traumatic event exposure and gambling: associations with clinical, neurocognitive, and personality variables. AB - BACKGROUND: Epidemiological research has shown high comorbidity rates between at risk/problem (ARP) gambling and trauma. However, few studies have assessed the neurocognitive implications of this comorbidity, and even fewer have been conducted with young adults. The present study sought to determine the neurocognitive, clinical, personality types associated with trauma in ARP gamblers. METHODS: The present study analyzed young adult gamblers age 18 to 29 drawn from a study investigating impulsivity. Of the 230 gamblers, 52 (22.6%) reported experiencing a traumatic event during their life to which they responded with intense fear, helplessness, or horror. The remaining participants indicated no experience with trauma. RESULTS: ARP gamblers who had experienced trauma showed significant neurocognitive deficits on tasks related to decision-making, risk adjustment, sustained attention, and spatial working memory. We did not detect significant differences in gambling severity. Trauma was associated with lower perceived quality of life and self-esteem, and higher rates of current comorbid diagnoses, suicidality, substance use disorders, and nicotine use. CONCLUSIONS: This study suggests that trauma may not exacerbate the severity of gambling in ARP gamblers. However, significant differences in supplemental clinical and neurocognitive measures may indicate that trauma is an important consideration when assessing problems beyond those related directly to gambling severity. PMID- 25696778 TI - Maintenance treatment for obsessive-compulsive disorder: findings from a naturalistic setting. AB - BACKGROUND: Although the utility of medication in the acute treatment of adult obsessive-compulsive disorder (OCD) is well-established, the role of maintenance therapy is not as well-studied. This study examines the efficacy of long-term treatment for, and predictors of, stability in medicated patients with adult OCD. METHODS: Using the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), we retrospectively evaluated 84 OCD patients who responded to a 10- to 12-week, open label, acute treatment in a naturalistic clinic setting. Patients were followed based on their medication response for 1 to 92 months (mean 34.3), or until they terminated therapy. We evaluated Y-BOCS scores every 6 months or sooner, if clinically indicated. RESULTS: Of the 84 patients, 39 (46.4%) responded, having relapsed within a 5-year period. Predictors of longer duration of stability were adjunctive cognitive-behavioral therapy (CBT), lack of comorbid disorders, lower Y-BOCS score after treatment, and larger decrease in Y-BOCS score during treatment phase. CONCLUSIONS: Our results show the importance of maintenance treatment of OCD, noting the benefits of long-term response to adjunctive CBT and of achieving maximal acute response. It is becoming crucial to develop larger maintenance studies with more uniform design to better assess the natural course of treated OCD and improve treatment strategies. PMID- 25696779 TI - Psychogenic parkinsonism: clinical spectrum and diagnosis. AB - BACKGROUND: Patients with psychogenic parkinsonism (PP), like those with Parkinson's disease (PD), may have tremor, bradykinesia, rigidity, and gait disturbances. Unusual features predominate in PP, but clear psychogenic signs may not be obvious. Because PP may be difficult to diagnose, identifying a wider spectrum of disease manifestations that point toward psychogenic rather than organic parkinsonism could be useful for clinicians. METHODS: We retrospectively reviewed the charts and clinical data for all patients referred for parkinsonism to a single physician at our movement disorders clinic from 1980 to 2012. RESULTS: Patients with PP represented 1.5% of all patients referred for parkinsonism. Among 36 patients with PP, the most common complaints were tremor (31), gait disturbance (18), fatigue (12), and diminished balance (10). Neurologic examination revealed 12 patients with unusual (functional) postures, 5 with a normal exam, and none with micrographia, hypophonia, or hypomimia. Seven of 36 patients improved, 6 of these with antidepressant therapy. CONCLUSIONS: PP is not rare in a movement disorders practice. Leg tremor is more likely in PP than in PD, whereas falls are rare. Unusual (nonphysiologic) postures may be present. The outcome generally is not favorable, although antidepressants are beneficial in some patients with disease duration of <2 years. The presence of micrographia, hypophonia, or hypomimia strongly suggests an organic cause of parkinsonism rather than PP. PMID- 25696780 TI - Using the INTERMED complexity instrument for a retrospective analysis of patients presenting with medical illness, substance use disorder, and other psychiatric illnesses. AB - BACKGROUND: The financial and treatment challenges of complex patients must be addressed with adequate assessment and evaluation. The INTERMED complexity instrument (INTERMED) has been developed for this purpose, but to date has not been used retrospectively. The current study represents a retrospective validity investigation of INTERMED with patients with substance use disorder comorbid with other psychiatric and medical conditions (triple diagnoses). Such patients were expected to generate high complexity scores on the INTERMED instrument. METHODS: Information on 66 patients with triple diagnoses was submitted to the INTERMED complexity grid. These data were subjected to cluster analysis and other analytic procedures. RESULTS: Total INTERMED scores reflected elevated complexity for patients with triple diagnoses. As a group, they represented a single cluster of complex patients. CONCLUSIONS: The validity of the INTERMED complexity assessment was corroborated in relation to retrospective data. In addition to elevations in the biological domain that hospital personnel typically confront, findings related to coping deficiencies and problems in living conditions were noteworthy in requiring comprehensive interventions. PMID- 25696781 TI - Egosyntonic and egodystonic: accounting for continuities and discontinuities between personality traits and personality disorders. AB - BACKGROUND: Egosyntonic and egodystonic features describe differences between trait-based and state-based mental disorders. Many diagnoses, most particularly personality disorder (PD), show both features. These complex forms of psychopathology are an amalgam of traits and symptoms in which both egosyntonicity and egodystonicity can be present but vary in prominence. This distinction might help resolve the long-standing controversy as to whether PDs are best classified using dimensions or categories. METHOD: Narrative review. RESULTS: PDs in which egosyntonic features tend to predominate can be understood as amplified trait profiles. PDs associated with highly egodystonic clinical symptoms that more closely resemble major mental disorders may be usefully classified using both categories and dimensions. CONCLUSIONS: PDs with stronger egosyntonic features are more suitable for dimensional diagnosis. When egodystonic symptoms are more prominent, categorical diagnoses can be useful. PMID- 25696782 TI - Is lithium a neuroprotective agent? AB - BACKGROUND: Lithium was the first clinically effective mood stabilizer marketed worldwide. However, the medical literature suggests that lithium may have an indication as a neuroprotective agent. METHODS: This review discusses the pharmacologic activity and potential effectiveness of lithium in the context of Alzheimer disease (AD) and Parkinson's disease (PD), the 2 most prominent neurodegenerative disorders in the United States. The toxicities of lithium, including lithium-induced extrapyramidal symptoms (LI-EPS) and cognitive impairments at therapeutic blood levels, are discussed. Cases that are thought to illustrate LI-EPS and cognitive impairments are critiqued. RESULTS: Animal studies have shown positive results regarding the neuroprotective and antioxidant properties of lithium. Human studies indicate a potential benefit of lithium for improving cognition. Ongoing replicative studies are attempting to confirm the effectiveness and efficacy of lithium for treating patients diagnosed with AD or PD. CONCLUSIONS: The available medical literature supports the conclusion that lithium should be considered as a research candidate medication for the treatment of neurologic diseases of dementias and PD. PMID- 25696783 TI - Stigma, social anxiety, and illness severity in bipolar disorder: Implications for treatment. AB - BACKGROUND: Studies indicate that comorbid anxiety disorders predict a more severe course of illness in bipolar disorder (BD). The relatively high prevalence of social anxiety in BD points to the potential role that socio-cultural factors, such as stigma, play in exacerbating the progression of this disorder. Stigma creates social anxiety in affected individuals because it essentially forces them into a vulnerable social status that is marked by public disgrace. Although the etiology of debilitating social anxiety in BD may involve multiple factors, stigma deserves particular clinical attention because research in this area indicates that it is common and its internalization is associated with poor outcome. METHODS: We conducted a literature review using search terms related to stigma, social anxiety, bipolar disorder, illness severity, and outcomes. The electronic databases searched included PsychINFO, PubMed, JSTOR, and EBSCOhost Academic Search Complete with limits set to include articles published in English. RESULTS: The literature indicates that internalized stigma often triggers the core psychological experiences of social anxiety and is highly correlated with clinical and functional outcome in BD. On a psychological level, internalized stigma and social anxiety can create distress that triggers symptoms of BD. From a biological perspective, stigma constitutes a chronic psychosocial stressor that may interact with the pathophysiology of BD in inflammatory ways. CONCLUSIONS: The connection between stigma and social anxiety, and their combined effects on people with BD, carries important implications for psychiatric care. To obtain an accurate clinical formulation, initial evaluations may seek to examine stigma-related experiences and determine their relationship to anxiety symptoms and psychosocial functioning. In addition, direct interventions for reducing the ill effects of stigma in BD deserve clinical attention, because they may carry the potential to enhance outcomes. PMID- 25696784 TI - Culture, impaired access to mental health care, and bipolar disorder: case analysis. PMID- 25696785 TI - Clozapine revisited: Impact of clozapine vs olanzapine on health care use by schizophrenia patients on Medicaid. AB - BACKGROUND: Our purpose was to evaluate health care use and cost patterns for clozapine compared with olanzapine in the treatment of schizophrenia. METHODS: Health care outcomes were measured over a 1-year posttreatment period for episodes of antipsychotic therapy initiated between 1997 and 2002. Four episode categories were defined: restart after lapse in therapy, switch after break, switch without break, and augmentation. We estimated the impact of clozapine or olanzapine using mixed model regression for costs by type of service and days of uninterrupted drug therapy. Time to admission in an acute hospital, psychiatric hospital, or longterm care facility, and time to suicide attempt were compared using Cox proportional hazards models. RESULTS: Clozapine increased duration of therapy and decreased risk of psychiatric hospitalization or suicide attempts compared to olanzapine. However, increased drug costs and use of community mental health centers (CMHC) for complete blood count (CBC) monitoring overwhelmed any offsetting savings. CONCLUSIONS: Clozapine is more expensive than olanzapine over the first year of treatment, primarily due to frequent CMHC visits required for CBC monitoring. However, fewer psychiatric hospitalizations, reduced suicide attempts, and longer duration of treatment should generate more benefits over time, which could eventually outweigh clozapine's higher first-year costs. PMID- 25696786 TI - Cross-cultural comparison of compulsive stealing (kleptomania). PMID- 25696787 TI - Waste not, want not. PMID- 25696788 TI - Screening for Lynch syndrome: a no-brainer: BRAF V600E mutation-specific immunohistochemistry: caveat emptor. PMID- 25696789 TI - Quality pathology and laboratory diagnostic services are key to improving global health outcomes: improving global health outcomes is not possible without accurate disease diagnosis. PMID- 25696790 TI - Effectiveness of multiple initiatives to reduce blood component wastage. AB - OBJECTIVES: Blood component waste is an important issue at all hospitals. As an initiative of the patient blood management program at a regional health care system, the causes and extent of blood product wastage were identified, and targeted interventions to effect a reduction were implemented. METHODS: Multiple low-cost interventions, including educational outreach, print and digital messaging, and improved transportation and component identification modalities, were implemented beginning in January 2013. The impact on reducing RBC, platelet (PLT), and plasma wastage in the 16 months after intervention implementation was compared with the wastage rates in the 16 months before these interventions had been implemented. RESULTS: Overall, the RBC wastage rate as a percentage of the number of units issued decreased from 0.67% to 0.56% (P = .001) after the interventions were implemented, while the PLT wastage rate decreased from 3.71% to 2.81% (P < .001). The plasma wastage rate increased from 1.14% to 1.40% (P < .001). The initial cost of these interventions was approximately $310. The net cost savings of the reduced waste was estimated at $131,520, excluding intervention costs. CONCLUSIONS: Relatively inexpensive interventions can have a prompt and dramatic impact on reducing blood wastage with regard to both cost and resource savings. PMID- 25696791 TI - A modified Lynch syndrome screening algorithm in colon cancer: BRAF immunohistochemistry is efficacious and cost beneficial. AB - OBJECTIVES: Somatic BRAF mutation in colon cancer essentially excludes Lynch syndrome. We compared BRAF V600E immunohistochemistry (IHC) with BRAF mutation in core, biopsy, and whole-section slides to determine whether IHC is similar and to assess the cost-benefit of IHC. METHODS: Resection cases (2009-2013) with absent MLH1 and PMS2 and prior BRAF mutation polymerase chain reaction results were chosen (n = 57). To mimic biopsy specimens, tissue microarrays (TMAs) were constructed. In addition, available biopsies performed prior to the resection were available in 15 cases. BRAF V600E IHC was performed and graded on TMAs, available biopsy specimens, and whole-section slides. Mutation status was compared with IHC, and cost-benefit analysis was performed. RESULTS: BRAF V600E IHC was similar in TMAs, biopsy specimens, and whole-section slides, with only four (7%) showing discordance between IHC and mutation status. Using BRAF V600E IHC in our Lynch syndrome screening algorithm, we found a 10% cost savings compared with mutational analysis. CONCLUSIONS: BRAF V600E IHC was concordant between TMAs, biopsy specimens, and whole-section slides, suggesting biopsy specimens are as useful as whole sections. IHC remained cost beneficial compared with mutational analysis, even though more patients needed additional molecular testing to exclude Lynch syndrome. PMID- 25696792 TI - Use of hTERT and HPV E6/E7 mRNA RT-qPCR TaqMan assays in combination for diagnosing high-grade cervical lesions and malignant tumors. AB - OBJECTIVES: Human papillomavirus (HPV) is a major cause of cervical cancer, which is the second most common cancer in women. HPV E6 initiates degradation of cellular tumor suppressor protein p53, induces human telomerase reverse transcriptase (hTERT) activity, and then leads to progressive cervical carcinogenesis. METHODS: In this study, the CervicGen HPV RT-qDX assay (Optipharm, Osong, Republic of Korea), which detects 16 HPV high-risk subtypes (HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 68, and 69), and the CervicGen hTERT RT-qDX assay (Optipharm) were evaluated using 545 ThinPrep (Hologic, Bedford, MA) Papanicolaou samples. RESULTS: The positivity for the HPV E6/E7 messenger RNA (mRNA) assay was 94.4%, 95.2%, 82.4%, 46.5%, 25.0%, and 1.1% in squamous cell carcinomas, high-grade squamous intraepithelial lesions (HSILs), atypical squamous cells--cannot exclude HSIL, low-grade squamous intraepithelial lesions, atypical squamous cells of undetermined significance, and normal cytology samples, respectively. Five cervical intraepithelial neoplasia grade 2+ samples were not detected by the HPV E6/E7 mRNA assay, but they exhibited positive signals in the hTERT mRNA assay. Notably, the hTERT mRNA expression level was increased in high-grade cervical lesions but was very low in all 288 normal samples. CONCLUSIONS: These data suggest that the combination of HPV E6/E7 and hTERT mRNA expression levels could be used in a complementary manner in diagnosing high-grade cervical lesions and malignant tumors and might be useful as a predictive marker in monitoring low-grade cervical lesions. PMID- 25696793 TI - Effects of levonorgestrel-releasing intrauterine system on lymphangiogenesis of adenomyosis. AB - OBJECTIVES: Lymphangiogenesis may be involved in the pathogenesis of adenomyosis. We investigated the lymphatic vessels of patients with adenomyosis, including those treated with levonorgestrel-releasing intrauterine system (LNG-IUS). METHODS: Full-thickness uterine samples were obtained from patients who received hysterectomies. Twenty-one patients with adenomyosis and 17 patients with adenomyosis who were treated with LNG-IUS were included. Eighteen patients with cervical intraepithelial neoplasia served as controls. Immunohistochemical staining was performed with antibodies against podoplanin and lymphatic vessel endothelial hyaluronan receptor 1. The lymphovascular density (LVD) was analyzed in each sample by the "hot spot" method. RESULTS: The LVDs were significantly higher in the endometrial and myometrial tissues of patients with adenomyosis compared with those of patients treated with the LNG-IUS or controls. No significant differences were noted between the LNG-IUS-treated group and controls. Evaluation of the LVDs according to the menstrual cycle showed that the differences in the endometrial tissues of the adenomyosis group and those of the LNG-IUS-treated group or the controls were more prominent during the secretory phase. CONCLUSIONS: Treatment with the LNG-IUS resulted in reduced lymphangiogenesis and LVD in the endometrial and myometrial tissues of patients with adenomyosis. Reduced lymphangiogenesis may be one mechanism by which the LNG IUS reduces adenomyosis-related symptoms. PMID- 25696794 TI - Diagnostic and prognostic value of BCL2 rearrangement in 53 patients with follicular lymphoma presenting as primary skin lesions. AB - OBJECTIVES: To study the diagnostic value of BCL2 rearrangement in follicle center lymphoma (FCL) presenting as primary skin lesions, evaluate its prevalence and the prognostic value in primary cutaneous FCL (PCFCL), and assess prognostic factors in PCFCL. METHODS: Fifty-three patients with a cutaneous presentation of FCL without a history of nodal lymphoma were selected retrospectively. Clinical and histologic data were collected together with staging and follow-up data. A fluorescence in situ hybridization (FISH) test for BCL2 split probes was performed on skin biopsy specimens. RESULTS: Initial staging procedures identified 47 PCFCLs and six cases of secondary skin involvement of FCL (SSIFCL). FISH detected seven cases carrying a BCL2 rearrangement: four (8.5%) of 47 PCFCLs and three (50%) of six SSIFCLs. These seven cases coexpressed BCL2 and CD10. In PCFCL, cutaneous relapse rate was 42.6%. A small/medium centrocytic cell population was associated with a higher probability of skin relapse in univariate (P = .008) and multivariate (P = .028) analysis, and BCL2 rearrangement detection was associated with secondary extracutaneous spreading (P = .05). CONCLUSIONS: We observed that BCL2 rearrangement in PCFCL is rare, associated with initial positivity of staging (diagnostic value) or with secondary extracutaneous spreading (prognostic value). In selected cases with BCL2-CD10 coexpression, FISH testing could detect patients with poor outcome and require closer monitoring. PMID- 25696795 TI - Left-sided early-onset vs late-onset colorectal carcinoma: histologic, clinical, and molecular differences. AB - OBJECTIVES: Carcinomas of the left colon represent a neoplasm of older patients (late onset), but epidemiologic evidence has been showing an increasing incidence in patients 50 years or younger (early onset). In this study, we investigate pathologic and molecular features of early- and late-onset carcinoma of the left colon. METHODS: We selected 22 patients 50 years or younger and 21 patients 70 years or older with left-sided colorectal carcinoma (CRC). All samples were evaluated for pathologic features, microsatellite instability, and KRAS and BRAF mutations. Moreover, both groups were analyzed to identify CpG island methylator phenotype features and assessed with restriction landmark genome scanning (RLGS) to unveil differential DNA methylation patterns. RESULTS: Early-onset patients had advanced pathologic stages compared with late-onset patients (P = .0482). All cases showed a microsatellite stable profile and BRAF wild-type sequence. Early onset patients (43%) more frequently had mutations at KRAS codon 12 compared with late-onset patients (14%) (P =.0413). RLGS showed that patients younger than 50 years who had CRC had a significantly lower percentage of methylated loci than did patients 70 years or older (P = .04124), and differential methylation of several genomic loci was observed in the two groups. CONCLUSIONS: Our results suggest that left-sided CRCs may present differential patterns of aberrant DNA methylation when they are separated by age. PMID- 25696796 TI - Interobserver variability of mitotic index and utility of PHH3 for risk stratification in gastrointestinal stromal tumors. AB - OBJECTIVES: Accurate grading of gastrointestinal stromal tumors (GISTs), based on mitotic index, can be problematic. METHODS: In this study, we compared interobserver variability in detecting mitosis on H&E with PHH3 immunohistochemistry (IHC). In addition, we examined the correlation between H&E mitosis and Ki-67 and the association of PHH3 and Ki-67 with overall survival. Four pathologists independently reviewed 50 GIST cases. RESULTS: Intraclass correlation coefficients showed good interobserver variability for mitotic counts on both H&E (0.918; 95% confidence interval [CI], 0.874-0.950) and PHH3 IHC (0.923; 95% CI, 0.882-0.953). Nineteen (38%) cases were graded higher and five (10%) cases were downgraded by at least one observer using PHH3 compared with H&E. Using receiver operating characteristic curve analysis, a PHH3 cutoff of seven or more mitoses was associated with worse overall survival (P = .028). Ki 67 showed poor correlation with H&E mitotic counts and overall survival (P = .077). CONCLUSIONS: PHH3 may thus be a valuable adjunct for risk stratification in GISTs. PMID- 25696797 TI - Impact of an educational intervention on the frequency of daily blood test orders for hospitalized patients. AB - OBJECTIVES: During hospitalizations, blood is drawn for diagnostic laboratory tests to help guide patient care. Often, blood tests continue to be ordered even in the face of clinical and laboratory stability. Blood draws are painful and costly, and they may be associated with anemia. We hypothesized that provider education could reduce the frequency of daily blood tests ordered for hospitalized patients. METHODS: During a 2-month intervention period, internal medicine providers were educated through flyers displayed in providers' offices and periodic email communications reminding them to order daily blood tests only if the results would change patient care. Two-month preintervention data from 982 patients and 2-month postintervention data from 988 patients were analyzed. The primary outcome measured was the number of daily blood tests ordered per patient per day. RESULTS: Mean orders of CBC decreased from 1.46 to 1.37 tests per patient per day (P < .05) after the intervention. Basic metabolic panel orders were reduced from 0.91 to 0.83 tests per patient per day (P < .05). Cost analyses showed a reduction of $6.33 per patient day based on the decrease in the number of daily laboratory tests ordered. CONCLUSIONS: Provider education and reminders can reduce the frequency of daily blood tests ordered by providers for hospitalized patients. This can decrease health care costs and may reduce the risk of complications such as anemia. PMID- 25696798 TI - Liver metastases of small intestine neuroendocrine tumors: Ki-67 heterogeneity and World Health Organization grade discordance with primary tumors. AB - OBJECTIVES: We examined Ki-67 heterogeneity within single and between synchronous liver metastases of small intestine neuroendocrine tumors. METHODS: There were 27 patients (10 men and 17 women) with two or more liver metastases. The Ki-67 index was used to classify the tumors into World Health Organization grade 1, 2, or 3. The association between Ki-67 heterogeneity and tumor size of liver metastases was analyzed. Correlation of tumor grade with patient survival was also evaluated. RESULTS: Primary tumors from 20 patients were graded, including 17 grade 1 and three grade 2. A total of 188 liver metastases were resected, including 122 (65%) grade 1, 47 (25%) grade 2, and 19 (10%) grade 3. The highest tumor grade was grade 1 in 10 (37%), grade 2 in nine (33%), and grade 3 in eight (30%) patients. Patients with one or more grade 3 liver lesions had a shorter progression-free survival compared with those with grade 1/2 tumors (P < .001). A positive association was found between tumor size and Ki-67 index (P = .04), as well as between tumor size and intratumoral Ki-67 heterogeneity (P < .001). CONCLUSIONS: Intratumoral and intertumoral Ki-67 heterogeneity is common and positively correlated with tumor size. The presence of one or more grade 3 liver lesions predicts a worse prognosis. PMID- 25696799 TI - Building capacity in laboratory medicine in Africa by increasing physician involvement: a laboratory medicine course for clinicians. AB - OBJECTIVES: To describe a 4-day laboratory medicine course for clinicians given at Addis Ababa University, Ethiopia, designed to improve the use of laboratory based diagnoses. METHODS: Each day was dedicated to one of the following topics: hematology, blood bank/transfusion medicine and coagulation, chemistry, and microbiology. The course included lectures, case-based learning, laboratory tours, and interactive computer case-based homework. The same 12-question knowledge quiz was given before and after the course. RESULTS: Twenty-eight participants took the quiz before and 21 after completing the course. The average score was 5.28 (range, 2-10) for the initial quiz and 8.09 (range, 4-11) for the second quiz (P = .0001). Two of 12 and 8 of 12 questions were answered correctly by more than 60% of trainees on the initial and second quiz, respectively. CONCLUSIONS: Knowledge and awareness of the role of the laboratory increased after participation in the course. Understanding of laboratory medicine principles by clinicians will likely improve use of laboratory services and build capacity in Africa. PMID- 25696800 TI - Visual memory effects on intraoperator study design: determining a minimum time gap between case reviews to reduce recall bias. AB - OBJECTIVES: The objective of this research was to determine test intervals between intraoperator case reviews to minimize the impact of recall. METHODS: Three pathologists were presented with a group of 120 slides and subsequently challenged with a study set of 120 slides after 2-week and 4-week intervals. The challenge set consisted of 60 slides seen during the initial review and 60 slides previously unseen within the study. Pathologists rendered a diagnosis for each slide and indicated whether they recalled seeing the slide previously (yes/no). RESULTS: Two weeks after having been shown 60 cases from a challenge set of 120 cases, the pathologists correctly remembered 26, 22, and 24 cases or 40% overall. After 4 weeks, the pathologists correctly recalled 31% of cases previously seen. CONCLUSIONS: Pathologists were capable of recalling from memory cases seen previously at 2 and 4 weeks. Recall rates may be sufficiently high to affect intraobserver study design. PMID- 25696801 TI - BGX-Ki-67 index as a supplementary marker to MIB-1 index, enabling more precise distinction between luminal A and B subtypes of breast carcinoma and eliminating the problem of membranous/cytoplasmic MIB-1 staining. AB - OBJECTIVES: We compared clinical utility of MIB-1 and BGX-Ki-67 clones of anti-Ki 67 antibody in a group of 156 patients with invasive ductal breast cancer. METHODS: MIB-1 labeling index (MIB-1LI) and BGX labeling index (BGXLI) were evaluated immunohistochemically both in primary tumors (T) and synchronous lymph node metastasis (LNM). RESULTS: In addition to nuclear MIB-1 staining, in 23 of 145 and 19 of 144 T and LNM, respectively, membranous/cytoplasmic labeling was found. In these cases, BGX-Ki-67 showed exclusively nuclear labeling and presented significantly higher labeling index. High BGXLI(T) was a significant independent negative prognostic factor for disease-free survival. Moreover, based on BGXLI(T)/BGXLI(LNM), patients with high MIB-1LI(T) were stratified into low- and high-risk carriers. CONCLUSIONS: In carcinomas with membranous/cytoplasmic MIB-1 staining, additional assessment of BGXLI is recommended. It may help in defining breast cancer subtype and in selection of individuals at risk who, despite appropriate therapy, would benefit from more frequent controls aimed at earlier implementation of second-line treatment. PMID- 25696802 TI - Immunohistochemical distinction of primary sweat gland carcinoma and metastatic breast carcinoma: can it always be accomplished reliably? AB - OBJECTIVES: Even with adequate history, the distinction of cutaneous metastatic breast carcinoma from primary sweat gland carcinoma can be difficult. Although previous studies have attempted to separate these tumors with various immunohistochemical panels, those series have been limited by small numbers of patients as well as the inclusion of benign sweat gland tumors. METHODS: In this analysis, stains for p63, CK5/6, and D2-40 were included, as well as GATA3 and mammaglobin, in an evaluation of 21 primary sweat gland carcinomas and 33 examples of cutaneous metastatic breast carcinoma. RESULTS: Immunoreactivity for p63, CK5/6, D2-40, GATA3, and mammaglobin was respectively observed in 81%, 71%, 52%, 71%, and 5% of sweat gland carcinomas compared with 6%, 6%, 6%, 91%, and 45% of metastatic breast carcinomas. These differences were statistically significant for p63, CK5/6, and D2-40. For the diagnosis of metastatic breast carcinoma, GATA3 was the most sensitive marker (91%), but its sensitivity was substantially lower. Mammaglobin was 95% specific for breast carcinoma but again suffered from limited sensitivity (45%) in this context. CONCLUSIONS: These data suggest that p63 and CK5/6 are specific determinants for sweat gland carcinoma in the stated setting. In the absence of those analytes, metastatic breast carcinoma cannot always be identified to the exclusion of a primary tumor. This diagnostic scenario continues to require the procurement of a detailed clinical history regarding the number and duration of skin lesions in any given case. PMID- 25696803 TI - VE1 antibody is not highly specific for the BRAF V600E mutation in thyroid cytology categories with the exception of malignant cases. AB - OBJECTIVES: We evaluated the utility of the VE1 antibody that can detect a mutant protein resulting from the BRAF V600E mutation as a diagnostic tool for thyroid fine-needle aspiration cytology (FNAC). METHODS: We performed VE1 immunocytochemistry on 202 FNAC specimens from surgically confirmed thyroid nodules. The results were compared with the molecular analyses of the BRAF mutation in these specimens matched with their corresponding histology. RESULTS: Diagnoses of FNAC specimens included benign (9.4%), atypia of undetermined significance/follicular lesion of undetermined significance (11.4%), follicular neoplasm/suspicious for follicular neoplasm (2.0%), suspicious for malignancy (9.4%), and malignancy (65.8%). VE1 immunostaining was positive in 71.3% of FNAC specimens. The overall sensitivity of the VE1 antibody was 88.8%, specificity was 71.2%, positive predictive value was 88.2%, negative predictive value was 72.4%, and diagnostic accuracy was 83.7%. CONCLUSIONS: VE1 immunocytochemistry in thyroid FNAC as a screening test for BRAF mutations is highly specific for malignant category cases but can be suboptimal due to its high false-positive rate for the nonmalignant cases. PMID- 25696804 TI - Normal villous architecture with increased intraepithelial lymphocytes: a duodenal manifestation of Crohn disease. AB - OBJECTIVES: To assess a possible association between inflammatory bowel disease (IBD) and the histologic finding in duodenal biopsy specimens of increased intraepithelial lymphocytes (IELs) with normal villous architecture. METHODS: We identified all patients with duodenal biopsy specimens obtained between 2000 and 2010 showing increased IELs and normal architecture. Among the 74 such patients who also had IBD, we characterized the clinical features of IBD and reviewed all available upper gastrointestinal biopsy specimens. RESULTS: Fifty-eight patients had Crohn disease, 13 had ulcerative colitis, and three had IBD, type unclassified. No duodenal sample with increased IELs had other histologic features of IBD. Among gastric biopsy specimens from 34 patients with Crohn disease, nearly half (16) had focal gastritis. CONCLUSIONS: We propose that Crohn disease be included in the differential diagnosis for increased IELs with normal villous architecture in duodenal biopsy specimens, particularly when gastric biopsy specimens show focal gastritis. PMID- 25696809 TI - Erratum. PMID- 25696805 TI - Dual HER2 gene protein assay: focused study of breast cancers with 2+ immunohistochemical expression. AB - OBJECTIVES: The combined gene protein assay (GPA) can simultaneously assess HER2 gene copy number and protein on a single slide using bright-field microscopy. METHODS: GPA was compared with a fluorescence in situ hybridization (FISH) assay on 50 invasive breast carcinomas with a 2+ score on immunohistochemistry (IHC). RESULTS: The cases were categorized into positive, equivocal, or negative for HER2 gene amplification using the 2013 American Society of Clinical Oncology/College of American Pathologists criteria. This resulted in 82% agreement (41 of 50) between FISH and GPA. In addition, 25 known IHC 3+ breast carcinomas analyzed by GPA showed protein overexpression and clusters of HER2 gene consistent with unequivocal amplification, and 22 known IHC-negative cases were negative for HER2 gene amplification by GPA. CONCLUSIONS: Although GPA is an alternative to both IHC and FISH, it may be an unnecessary test for IHC 0/1+/3+ cases. The clinical utility of GPA appears to be similar to other in situ hybridization assays (ie, adjudicator of HER2 status for IHC 2+ cases). PMID- 25696810 TI - Setting the pace for GI motility: ryanodine receptors and IP3 receptors within interstitial cells of Cajal. Focus on "Intracellular Ca2+ release from endoplasmic reticulum regulates slow wave currents and pacemaker activity of interstitial cells of Cajal". PMID- 25696811 TI - Vinpocetine modulates metabolic activity and function during retinal ischemia. AB - Vinpocetine protects against a range of degenerative conditions and insults of the central nervous system via multiple modes of action. Little is known, however, of its effects on metabolism. This may be highly relevant, as vinpocetine is highly protective against ischemia, a process that inhibits normal metabolic function. This study uses the ischemic retina as a model to characterize vinpocetine's effects on metabolism. Vinpocetine reduced the metabolic demand of the retina following ex vivo hypoxia and ischemia to normal levels based on lactate dehydrogenase activity. Vinpocetine delivered similar effects in an in vivo model of retinal ischemia-reperfusion, possibly through increasing glucose availability. Vinpocetine's effects on glucose also appeared to improve glutamate homeostasis in ischemic Muller cells. Other actions of vinpocetine following ischemia-reperfusion, such as reduced cell death and improved retinal function, were possibly a combination of the drug's actions on metabolism and other retinal pathways. Vinpocetine's metabolic effects appeared independent of its other known actions in ischemia, as it recovered retinal function in a separate metabolic model where the glutamate-to-glutamine metabolic pathway was inhibited in Muller cells. The results of this study indicate that vinpocetine mediates ischemic damage partly through altered metabolism and has potential beneficial effects as a treatment for ischemia of neuronal tissues. PMID- 25696812 TI - miR-9 enhances the transactivation of nuclear factor of activated T cells by targeting KPNB1 and DYRK1B. AB - The fast response to stimuli and subsequent activation of the nuclear factor of activated T cells (NFAT) signaling pathway play an essential role in human T cell functions. MicroRNAs (miRNAs) are increasingly implicated in regulation of numerous biological and pathological processes. In this study we demonstrate a novel function of miRNA-9 (miR-9) in regulation of the NFAT signaling pathway. Upon PMA-ionomycin stimulation, miR-9 was markedly increased, consistent with NFAT activation. Overexpression of miR-9 significantly enhanced NFAT activity and accelerated NFAT dephosphorylation and its nuclear translocation in response to PMA-ionomycin. Karyopherin-beta1 (KPNB1, a nucleocytoplasmic transporter) and dual-specificity tyrosine phosphorylation-regulated kinase 1B (DYRK1B) were identified as direct targets of miR-9. Functionally, miR-9 promoted IL-2 production in stimulated human lymphocyte Jurkat T cells. Collectively, our data reveal a novel role for miR-9 in regulation of the NFAT pathway by targeting KPNB1 and DYRK1B. PMID- 25696813 TI - On the origins of that most transformative of biological systems - the nervous system. PMID- 25696814 TI - The origin and evolution of synaptic proteins - choanoflagellates lead the way. AB - The origin of neurons was a key event in evolution, allowing metazoans to evolve rapid behavioral responses to environmental cues. Reconstructing the origin of synaptic proteins promises to reveal their ancestral functions and might shed light on the evolution of the first neuron-like cells in metazoans. By analyzing the genomes of diverse metazoans and their closest relatives, the evolutionary history of diverse presynaptic and postsynaptic proteins has been reconstructed. These analyses revealed that choanoflagellates, the closest relatives of metazoans, possess diverse synaptic protein homologs. Recent studies have now begun to investigate their ancestral functions. A primordial neurosecretory apparatus in choanoflagellates was identified and it was found that the mechanism, by which presynaptic proteins required for secretion of neurotransmitters interact, is conserved in choanoflagellates and metazoans. Moreover, studies on the postsynaptic protein homolog Homer revealed unexpected localization patterns in choanoflagellates and new binding partners, both which are conserved in metazoans. These findings demonstrate that the study of choanoflagellates can uncover ancient and previously undescribed functions of synaptic proteins. PMID- 25696815 TI - Evolution of voltage-gated ion channels at the emergence of Metazoa. AB - Voltage-gated ion channels are large transmembrane proteins that enable the passage of ions through their pore across the cell membrane. These channels belong to one superfamily and carry pivotal roles such as the propagation of neuronal and muscular action potentials and the promotion of neurotransmitter secretion in synapses. In this review, we describe in detail the current state of knowledge regarding the evolution of these channels with a special emphasis on the metazoan lineage. We highlight the contribution of the genomic revolution to the understanding of ion channel evolution and for revealing that these channels appeared long before the appearance of the first animal. We also explain how the elucidation of channel selectivity properties and function in non-bilaterian animals such as cnidarians (sea anemones, corals, jellyfish and hydroids) can contribute to the study of channel evolution. Finally, we point to open questions and future directions in this field of research. PMID- 25696816 TI - Ether-a-go-go family voltage-gated K+ channels evolved in an ancestral metazoan and functionally diversified in a cnidarian-bilaterian ancestor. AB - We examined the evolutionary origins of the ether-a-go-go (EAG) family of voltage gated K(+) channels, which have a strong influence on the excitability of neurons. The bilaterian EAG family comprises three gene subfamilies (Eag, Erg and Elk) distinguished by sequence conservation and functional properties. Searches of genome sequence indicate that EAG channels are metazoan specific, appearing first in ctenophores. However, phylogenetic analysis including two EAG family channels from the ctenophore Mnemiopsis leidyi indicates that the diversification of the Eag, Erg and Elk gene subfamilies occurred in a cnidarian/bilaterian ancestor after divergence from ctenophores. Erg channel function is highly conserved between cnidarians and mammals. Here we show that Eag and Elk channels from the sea anemone Nematostella vectensis (NvEag and NvElk) also share high functional conservation with mammalian channels. NvEag, like bilaterian Eag channels, has rapid kinetics, whereas NvElk activates at extremely hyperpolarized voltages, which is characteristic of Elk channels. Potent inhibition of voltage activation by extracellular protons is conserved between mammalian and Nematostella EAG channels. However, characteristic inhibition of voltage activation by Mg(2+) in Eag channels and Ca(2+) in Erg channels is reduced in Nematostella because of mutation of a highly conserved aspartate residue in the voltage sensor. This mutation may preserve sub-threshold activation of Nematostella Eag and Erg channels in a high divalent cation environment. mRNA in situ hybridization of EAG channels in Nematostella suggests that they are differentially expressed in distinct cell types. Most notable is the expression of NvEag in cnidocytes, a cnidarian-specific stinging cell thought to be a neuronal subtype. PMID- 25696817 TI - Electrogenesis in the lower Metazoa and implications for neuronal integration. AB - Electrogenic communication appears to have evolved independently in a variety of animal and plant lineages. Considered here are metazoan cells as disparate as the loose three-dimensional parenchyma of glass sponges, the two-dimensional epithelial sheets of hydrozoan jellyfish and the egg cell membranes of the ctenophore Beroe ovata, all of which are capable of generating electrical impulses. Neuronal electrogenesis may have evolved independently in ctenophores and cnidarians but the dearth of electrophysiological data relating to ctenophore nerves means that our attention is focused on the Cnidaria, whose nervous systems have been the subject of extensive study. The aim here is to show how their active and passive neuronal properties interact to give integrated behaviour. Neuronal electrogenesis, goes beyond simply relaying 'states of excitement' and utilizes the equivalent of a set of basic electrical 'apps' to integrate incoming sensory information with internally generated pacemaker activity. A small number of membrane-based processes make up these analogue applications. Passive components include the decremental spread of current determined by cellular anatomy; active components include ion channels specified by their selectivity and voltage dependence. A recurring theme is the role of inactivating potassium channels in regulating performance. Although different aspects of cnidarian behaviour are controlled by separate neuronal systems, integrated responses and coordinated movements depend on interactions between them. Integrative interactions discussed here include those between feeding and swimming, between tentacle contraction and swimming and between slow and fast swimming in the hydrozoan jellyfish Aglantha digitale. PMID- 25696818 TI - Peptide-gated ion channels and the simple nervous system of Hydra. AB - Neurons either use electrical or chemical synapses to communicate with each other. Transmitters at chemical synapses are either small molecules or neuropeptides. After binding to their receptors, transmitters elicit postsynaptic potentials, which can either be fast and transient or slow and longer lasting, depending on the type of receptor. Fast transient potentials are mediated by ionotropic receptors and slow long-lasting potentials by metabotropic receptors. Transmitters and receptors are well studied for animals with a complex nervous system such as vertebrates and insects, but much less is known for animals with a simple nervous system like Cnidaria. As cnidarians arose early in animal evolution, nervous systems might have first evolved within this group and the study of neurotransmission in cnidarians might reveal an ancient mechanism of neuronal communication. The simple nervous system of the cnidarian Hydra extensively uses neuropeptides and, recently, we cloned and functionally characterized an ion channel that is directly activated by neuropeptides of the Hydra nervous system. These results demonstrate the existence of peptide-gated ion channels in Hydra, suggesting they mediate fast transmission in its nervous system. As related channels are also present in the genomes of the cnidarian Nematostella, of placozoans and of ctenophores, it should be considered that the early nervous systems of cnidarians and ctenophores have co-opted neuropeptides for fast transmission at chemical synapses. PMID- 25696819 TI - The role of G protein-coupled receptors in the early evolution of neurotransmission and the nervous system. AB - The origin and evolution of the nervous system is one of the most intriguing and enigmatic events in biology. The recent sequencing of complete genomes from early metazoan organisms provides a new platform to study the origins of neuronal gene families. This review explores the early metazoan expansion of the largest integral transmembrane protein family, the G protein-coupled receptors (GPCRs), which serve as molecular targets for a large subset of neurotransmitters and neuropeptides in higher animals. GPCR repertories from four pre-bilaterian metazoan genomes were compared. This includes the cnidarian Nematostella vectensis and the ctenophore Mnemiopsis leidyi, which have primitive nervous systems (nerve nets), the demosponge Amphimedon queenslandica and the placozoan Trichoplax adhaerens, which lack nerve and muscle cells. Comparative genomics demonstrate that the rhodopsin and glutamate receptor families, known to be involved in neurotransmission in higher animals are also widely found in pre bilaterian metazoans and possess substantial expansions of rhodopsin-family-like GPCRs. Furthermore, the emerging knowledge on the functions of adhesion GPCRs in the vertebrate nervous system provides a platform to examine possible analogous roles of their closest homologues in pre-bilaterians. Intriguingly, the presence of molecular components required for GPCR-mediated neurotransmission in pre bilaterians reveals that they exist in both primitive nervous systems and nerve cell-free environments, providing essential comparative models to better understand the origins of the nervous system and neurotransmission. PMID- 25696821 TI - Elements of a 'nervous system' in sponges. AB - Genomic and transcriptomic analyses show that sponges possess a large repertoire of genes associated with neuronal processes in other animals, but what is the evidence these are used in a coordination or sensory context in sponges? The very different phylogenetic hypotheses under discussion today suggest very different scenarios for the evolution of tissues and coordination systems in early animals. The sponge genomic 'toolkit' either reflects a simple, pre-neural system used to protect the sponge filter or represents the remnants of a more complex signalling system and sponges have lost cell types, tissues and regionalization to suit their current suspension-feeding habit. Comparative transcriptome data can be informative but need to be assessed in the context of knowledge of sponge tissue structure and physiology. Here, I examine the elements of the sponge neural toolkit including sensory cells, conduction pathways, signalling molecules and the ionic basis of signalling. The elements described do not fit the scheme of a loss of sophistication, but seem rather to reflect an early specialization for suspension feeding, which fits with the presumed ecological framework in which the first animals evolved. PMID- 25696820 TI - Neuronal polarity: an evolutionary perspective. AB - Polarized distribution of signaling molecules to axons and dendrites facilitates directional information flow in complex vertebrate nervous systems. The topic we address here is when the key aspects of neuronal polarity evolved. All neurons have a central cell body with thin processes that extend from it to cover long distances, and they also all rely on voltage-gated ion channels to propagate signals along their length. The most familiar neurons, those in vertebrates, have additional cellular features that allow them to send directional signals efficiently. In these neurons, dendrites typically receive signals and axons send signals. It has been suggested that many of the distinct features of axons and dendrites, including the axon initial segment, are found only in vertebrates. However, it is now becoming clear that two key cytoskeletal features that underlie polarized sorting, a specialized region at the base of the axon and polarized microtubules, are found in invertebrate neurons as well. It thus seems likely that all bilaterians generate axons and dendrites in the same way. As a next step, it will be extremely interesting to determine whether the nerve nets of cnidarians and ctenophores also contain polarized neurons with true axons and dendrites, or whether polarity evolved in concert with the more centralized nervous systems found in bilaterians. PMID- 25696822 TI - The ctenophore lineage is older than sponges? That cannot be right! Or can it? AB - Recent phylogenetic analyses resulting from collection of whole genome data suggest that ctenophores, or comb jellies, are sister to all other animals. Even before publication, this result prompted discussion among researchers. Here, I counter common criticisms raised about this result and show that assumptions placing sponges as the basal-most extant animal lineage are based on limited evidence and questionable premises. For example, the idea that sponges are simple and the reported similarity of sponge choanocytes to Choanflagellata do not provide useful characters for determining the positions of sponges within the animal tree. Intertwined with discussion of basal metazoan phylogeny is consideration of the evolution of neuronal systems. Recent data show that neural systems of ctenophores are vastly different from those of other animals and use different sets of cellular and genetic mechanisms. Thus, neural systems appear to have at least two independent origins regardless of whether ctenophores or sponges are the earliest branching extant animal lineage. PMID- 25696824 TI - The search for ancestral nervous systems: an integrative and comparative approach. AB - Even the most basal multicellular nervous systems are capable of producing complex behavioral acts that involve the integration and combination of simple responses, and decision-making when presented with conflicting stimuli. This requires an understanding beyond that available from genomic investigations, and calls for a integrative and comparative approach, where the power of genomic/transcriptomic techniques is coupled with morphological, physiological and developmental experimentation to identify common and species-specific nervous system properties for the development and elaboration of phylogenomic reconstructions. With careful selection of genes and gene products, we can continue to make significant progress in our search for ancestral nervous system organizations. PMID- 25696823 TI - Convergent evolution of neural systems in ctenophores. AB - Neurons are defined as polarized secretory cells specializing in directional propagation of electrical signals leading to the release of extracellular messengers - features that enable them to transmit information, primarily chemical in nature, beyond their immediate neighbors without affecting all intervening cells en route. Multiple origins of neurons and synapses from different classes of ancestral secretory cells might have occurred more than once during ~600 million years of animal evolution with independent events of nervous system centralization from a common bilaterian/cnidarian ancestor without the bona fide central nervous system. Ctenophores, or comb jellies, represent an example of extensive parallel evolution in neural systems. First, recent genome analyses place ctenophores as a sister group to other animals. Second, ctenophores have a smaller complement of pan-animal genes controlling canonical neurogenic, synaptic, muscle and immune systems, and developmental pathways than most other metazoans. However, comb jellies are carnivorous marine animals with a complex neuromuscular organization and sophisticated patterns of behavior. To sustain these functions, they have evolved a number of unique molecular innovations supporting the hypothesis of massive homoplasies in the organization of integrative and locomotory systems. Third, many bilaterian/cnidarian neuron specific genes and 'classical' neurotransmitter pathways are either absent or, if present, not expressed in ctenophore neurons (e.g. the bilaterian/cnidarian neurotransmitter, gamma-amino butyric acid or GABA, is localized in muscles and presumed bilaterian neuron-specific RNA-binding protein Elav is found in non neuronal cells). Finally, metabolomic and pharmacological data failed to detect either the presence or any physiological action of serotonin, dopamine, noradrenaline, adrenaline, octopamine, acetylcholine or histamine - consistent with the hypothesis that ctenophore neural systems evolved independently from those in other animals. Glutamate and a diverse range of secretory peptides are first candidates for ctenophore neurotransmitters. Nevertheless, it is expected that other classes of signal and neurogenic molecules would be discovered in ctenophores as the next step to decipher one of the most distinct types of neural organization in the animal kingdom. PMID- 25696825 TI - The nervous system of Xenacoelomorpha: a genomic perspective. AB - Xenacoelomorpha is, most probably, a monophyletic group that includes three clades: Acoela, Nemertodermatida and Xenoturbellida. The group still has contentious phylogenetic affinities; though most authors place it as the sister group of the remaining bilaterians, some would include it as a fourth phylum within the Deuterostomia. Over the past few years, our group, along with others, has undertaken a systematic study of the microscopic anatomy of these worms; our main aim is to understand the structure and development of the nervous system. This research plan has been aided by the use of molecular/developmental tools, the most important of which has been the sequencing of the complete genomes and transcriptomes of different members of the three clades. The data obtained has been used to analyse the evolutionary history of gene families and to study their expression patterns during development, in both space and time. A major focus of our research is the origin of 'cephalized' (centralized) nervous systems. How complex brains are assembled from simpler neuronal arrays has been a matter of intense debate for at least 100 years. We are now tackling this issue using Xenacoelomorpha models. These represent an ideal system for this work because the members of the three clades have nervous systems with different degrees of cephalization; from the relatively simple sub-epithelial net of Xenoturbella to the compact brain of acoels. How this process of 'progressive' cephalization is reflected in the genomes or transcriptomes of these three groups of animals is the subject of this paper. PMID- 25696826 TI - Larval nervous systems: true larval and precocious adult. AB - The apical organ of ciliated larvae of cnidarians and bilaterians is a true larval organ that disappears before or at metamorphosis. It appears to be sensory, probably involved in metamorphosis, but knowledge is scant. The ciliated protostome larvae show ganglia/nerve cords that are retained as the adult central nervous system (CNS). Two structures can be recognized, viz. a pair of cerebral ganglia, which form the major part of the adult brain, and a blastoporal (circumblastoporal) nerve cord, which becomes differentiated into a perioral loop, paired or secondarily fused ventral nerve cords and a small perianal loop. The anterior loop becomes part of the brain. This has been well documented through cell-lineage studies in a number of spiralians, and homologies with similar structures in the ecdysozoans are strongly indicated. The deuterostomes are generally difficult to interpret, and the nervous systems of echinoderms and enteropneusts appear completely enigmatic. The ontogeny of the chordate CNS can perhaps be interpreted as a variation of the ontogeny of the blastoporal nerve cord of the protostomes, and this is strongly supported by patterns of gene expression. The presence of 'deuterostomian' blastopore fates both in an annelid and in a mollusk, which are both placed in families with the 'normal' spiralian gastrulation type, and in the chaetognaths demonstrates that the chordate type of gastrulation could easily have evolved from the spiralian type. This indicates that the latest common ancestor of the deuterostomes was very similar to the latest common pelago-benthic ancestor of the protostomes as described by the trochaea theory, and that the neural tube of the chordates is morphologically ventral. PMID- 25696827 TI - Evolution of basal deuterostome nervous systems. AB - Understanding the evolution of deuterostome nervous systems has been complicated by the by the ambiguous phylogenetic position of the Xenocoelomorpha (Xenoturbellids, acoel flat worms, nemertodermatids), which has been placed either as basal bilaterians, basal deuterostomes or as a sister group to the hemichordate/echinoderm clade (Ambulacraria), which is a sister group of the Chordata. None of these groups has a single longitudinal nerve cord and a brain. A further complication is that echinoderm nerve cords are not likely to be evolutionarily related to the chordate central nervous system. For hemichordates, opinion is divided as to whether either one or none of the two nerve cords is homologous to the chordate nerve cord. In chordates, opposition by two secreted signaling proteins, bone morphogenetic protein (BMP) and Nodal, regulates partitioning of the ectoderm into central and peripheral nervous systems. Similarly, in echinoderm larvae, opposition between BMP and Nodal positions the ciliary band and regulates its extent. The apparent loss of this opposition in hemichordates is, therefore, compatible with the scenario, suggested by Dawydoff over 65 years ago, that a true centralized nervous system was lost in hemichordates. PMID- 25696828 TI - Multiple myeloma: a model for scientific and clinical progress. AB - Multiple myeloma (MM) is a unique cancer paradigm for investigating the mechanisms involved in the transition from a premalignant condition (monoclonal gammopathy of undetermined significance) into a malignant disease (MM). In the pathogenesis of myeloma, the dialogue between plasma cells and their microenvironment is as important as the genotypic characteristics of the tumor clone. MM is genetically highly complex, with almost all patients displaying cytogenetic abnormalities and frequent intraclonal heterogeneity that play a critical role in the outcome of the disease. In fact, it is likely that myeloma will soon no longer be considered as a single entity. This, along with the availability of an unexpected number of new treatment possibilities, has reinforced the need for better tools for prognosis and for monitoring treatment efficacy through minimal residual disease techniques. The outcome of MM patients has significantly improved in the last 2 decades, first through the introduction of high-dose therapy followed by autologous stem cell transplantation and, more recently, due to the use of proteasome inhibitors (bortezomib and carfilzomib) and immunomodulatory agents (thalidomide, lenalidomide, and pomalidomide). Moreover, the need to reexamine the diagnostic criteria of early MM and the possibility of early intervention opens up new therapeutic avenues. New drugs are also emerging, including second- and third-generation proteasome inhibitors and immunomodulators, monoclonal antibodies, histone deacetylase inhibitors, and kinesin spindle protein inhibitors, among others. Our goal is to find a balance among efficacy, toxicity, and cost, with the ultimate aim of achieving a cure for this disease. PMID- 25696829 TI - Geriatric perspective: how to assess fitness for chemotherapy in acute myeloid leukemia. AB - Characterizing "fitness" in the context of therapeutic decisions for older adults with acute myeloid leukemia (AML) is challenging. Available evidence is strongest in identifying those older adults who are frail at the time of diagnosis by characterizing performance status and comorbidity burden. However, many older adults with adequate performance status and absence of major comorbidity are "vulnerable" and may experience clinical and functional decline when stressed with intensive therapies. More refined assessments are needed to differentiate between fit and vulnerable older adults regardless of chronologic age. Geriatric assessment has been shown to add information to routine oncology assessment and improve risk stratification for older adults with AML. This review highlights available evidence for assessment of "fitness" among older adults diagnosed with AML and discusses future treatment and research implications. PMID- 25696830 TI - Treating acute myeloid leukemia in older adults. AB - Acute myeloid leukemia (AML) is a disease of older adults, with a median age of 67 years at presentation. In the past, only a third of older patients (defined as individuals older than 60-65 years of age) with AML received definitive therapy for their disease due to concerns about their overall fitness and potential treatment-related mortality. However, compelling epidemiological data have shown unequivocally that older AML patients up to 80 years old both tolerate and survive longer after therapy than their untreated counterparts. Current therapeutic options for elderly individuals with AML include intensive chemotherapy with a cytarabine and anthracycline backbone, hypomethylating agents (decitabine and azacitidine), low-dose cytarabine, investigational agents, and supportive care with hydroxyurea and transfusions. Over the last few years, there has been increasing debate regarding the appropriate therapeutic approach to take in older adults given the diversity of the geriatric patient population and heterogeneous AML disease biology. This article discusses how performance status, comorbidities, disease characteristics, quality of life concerns, and long-term treatment goals affect the selection of appropriate therapy for older adults with AML. Risks and benefits of each treatment approach based on the most recent medical literature are discussed. Finally, a treatment algorithm summarizing these data and incorporating geriatric assessment and molecular and cytogenetic markers predictive of therapeutic response is proposed to aid in the clinical decision-making process. PMID- 25696831 TI - Allogeneic hematopoietic cell transplantation for acute myeloid leukemia in older adults. AB - Acute myeloid leukemia (AML) is primarily a disease of the elderly and the numbers of these patients are increasing. Patients >=60 years of age continue to have poor prognosis. Preliminary results suggest benefit from reduced-intensity allogeneic hematopoietic cell transplantation (HCT) in selected patients 60-80 years of age. However, although patients in this age range comprise >50% of those with AML, they currently constitute only 17% of those offered HCT. In the absence of prospective randomized studies comparing HCT and chemotherapy, the decision to recommend HCT rests on retrospective analyses of the risks of relapse and nonrelapse mortality after each approach. There is strong evidence that pre-HCT comorbidities can predict HCT-related morbidity and mortality. Age alone does not appear predictive and, particularly if the risk of relapse with chemotherapy is high, should not be the sole basis for deciding against HCT. Use of geriatric assessment tools, inflammatory biomarkers, and genetic polymorphism data may further aid in predicting nonrelapse mortality after HCT. Disease status and pretreatment cytogenetics with FLT3-TID, NPM-1, and CEBP-alpha status are the main factors predicting relapse and these are likely to be supplemented by incorporation of other molecular markers and the level of minimal residual disease after chemotherapy. HLA-matched related and unrelated donor grafts seem preferable to those from other donor sources. Donor age is of no clear significance. Models combining comorbidities with AML risk factors are useful in risk assessment before HCT. In this chapter, we integrated information on AML specific, HCT-specific, and patient-specific risk factors into a risk-adapted approach to guide decisions about HCT versus no HCT. PMID- 25696832 TI - Intermediate-risk acute myeloid leukemia therapy: current and future. AB - In recent years, research in molecular genetics has been instrumental in deciphering the molecular heterogeneity of acute myeloid leukemia (AML), in particular the subset of patients with "intermediate-risk" cytogenetics. However, at present, only the markers NPM1, CEBPA, and FLT3 have entered clinical practice. Treatment of intermediate-risk AML patients eligible for intensive therapy has not changed substantially. The "3 + 7" induction therapy still represents the standard of care. The addition of the immunoconjugate gemtuzumab ozogamicin to therapy has been shown to improve outcome; however, the drug is not approved for this use. A common standard for postremission therapy is the administration of repeated cycles of intermediate- to high-dose cytarabine. Allogeneic stem cell transplantation may offer a survival benefit for many patients with intermediate-risk AML. Patients are best selected based on the genetic profile of the leukemia cells and the risk associated with the transplantation itself. A myriad of novel agents targeting mutant leukemia drivers or deregulated pathways are in clinical development. In the past, many novel compounds have not met expectations; nonetheless, with the rapid developments in comprehensive molecular profiling and new drug design, there is the prospect of personalizing therapy and improving patient outcome. PMID- 25696833 TI - Epigenetic targeting and personalized approaches for AML. AB - Acute myeloid leukemia (AML) is a genetically heterogeneous clonal hematopoietic stem cell disorder and the majority of patients with AML die from their disease. The treatment paradigms for AML were developed decades ago and, although there have been improvements in the outcomes of selected younger patients and those with specific cytogenetic and molecular genetic characteristics, the overall survival for older patients remains dismal. Over the last few years, next generation sequencing technologies have identified recurrent mutations in genes encoding proteins involved in the epigenetic regulation of transcription in most patients with AML. This discovery has led to new insights into the role of the epigenome in AML and opens the possibility of epigenetically targeted therapies. This chapter describes how epigenetic dysregulation plays a role in AML and highlights current and future treatment strategies that attempt to exploit epigenetic targets. PMID- 25696834 TI - Future prospects for contact factors as therapeutic targets. AB - Anticoagulants currently used in clinical practice to treat or prevent thromboembolic disease are effective, but place patients at increased risk for serious bleeding because they interfere with plasma enzymes (thrombin and factor Xa) that are essential for hemostasis. In the past 10 years, work with genetically altered mice and studies in baboons and rabbits have demonstrated that the plasma contact proteases factor XI, factor XII, and prekallikrein contribute to the formation of occlusive thrombi despite having limited roles in hemostasis. In the case of factor XI, epidemiologic data from human populations indicate that elevated levels of this protein increase risk for stroke and venous thromboembolism and may also influence risk for myocardial infarction. These findings suggest that inhibiting contact activation may produce an antithrombotic effect without significantly compromising hemostasis. This chapter reviews strategies that are being developed for therapeutic targeting of factor XI and factor XII and their performances in preclinical and early human trials. PMID- 25696835 TI - Recent insights into the role of the contact pathway in thrombo-inflammatory disorders. AB - The contact pathway of coagulation consists of the proteins factor XI, factor XII, prekallikrein, and high-molecular-weight kininogen. Activation of the contact system leads to procoagulant and proinflammatory reactions. The contact system is essential for surface-initiated coagulation, as exemplified by aPTT, but there is probably no role for the contact system in initiating physiologic in vivo coagulation. However, over the last few years, there has been renewed interest, especially because of experimental evidence suggesting that the contact system contributes to thrombosis. Knockout mice deficient in one of the contact proteins were protected against artificially induced thrombosis. Furthermore, inhibiting agents such as monoclonal antibodies, antisense oligonucleotides, and small molecules were found to prevent thrombosis in rodents and primates in both venous and arterial vascular beds. Although it remains to be established whether targeting the contact system will be effective in humans and which of the contact factors is the best target for anticoagulation, it would constitute a promising approach for future effective and safe antithrombotic therapy. PMID- 25696836 TI - Epidemiologic and clinical data linking factors XI and XII to thrombosis. AB - Currently available evidence supports the contention that elevated levels of factor XI (fXI) are associated with a greater risk of venous thromboembolism and ischemic stroke, but, less convincingly, with myocardial infarction. Conversely, reduced plasma levels of fXI seem to offer some protection from venous thromboembolism and stroke, but not myocardial infarction. Factor XI-deficient patients are at risk for certain types of bleeding, particularly posttraumatic hemorrhage on mucosal surfaces where there is a high endogenous fibrinolytic activity. In contrast, the situation with fXII in human thrombosis remains enigmatic. Deficiency of fXII is clearly not associated with any bleeding risk, but neither does it seem to be protective against thrombosis. The longstanding debate as to whether partial fXII deficiency represents a risk factor for thrombosis remains unresolved, with seemingly conflicting results depending on study design, type of assay used, and analyte evaluated. The possibility that elevated fXII levels represent a risk factor for thrombosis is not borne out in the literature. PMID- 25696838 TI - Timing of allogeneic stem cell transplantation for myelodysplastic syndromes and aplastic anemia. AB - Allogeneic hematopoietic stem cell transplantation (HSCT) for myelodysplastic syndrome (MDS) is a potentially curative procedure, but is associated with a significant risk of morbidity and mortality. With the recent approval of disease modifying agents, the appropriate timing of allogeneic HSCT needs to be addressed. Similarly, the optimal use of these disease-modifying agents before HSCT needs to be determined. In severe aplastic anemia, HSCT is a proven cure, but HLA-matched sibling donors are found in fewer than 25% of newly diagnosed patients. The use of early unrelated donor HSCT is an evolving concept that will become more accepted as improvements in HSCT outcomes continue. PMID- 25696837 TI - Biology of BM failure syndromes: role of microenvironment and niches. AB - The BM microenvironment and its components regulate hematopoietic stem and progenitor cell (HSC) fate. An abnormality in the BM microenvironment and specific dysfunction of the HSC niche could play a critical role in initiation, disease progression, and response to therapy of BM failure syndromes. Therefore, the identification of changes in the HSC niche in BM failure syndromes should lead to further knowledge of the signals that disrupt the normal microenvironment. In turn, niche disruption may contribute to disease morbidity, resulting in pancytopenia and clonal evolution, and its understanding could suggest new therapeutic targets for these conditions. In this chapter, we briefly review the evidence for the importance of the BM microenvironment as a regulator of normal hematopoiesis, summarize current knowledge regarding the role of dysfunctions in the BM microenvironment in BM failure syndromes, and propose a strategy through which niche stimulation can complement current treatment for myelodysplastic syndrome. PMID- 25696839 TI - Established and novel agents for myelodysplastic syndromes. AB - The myelodysplastic syndromes (MDS) are the most commonly diagnosed myeloid malignancy, with >15 000 new cases identified in the United States yearly. Prognostic scoring systems supplant a formal staging approach and, in general, divide patients into those with lower-risk and those with higher-risk MDS. Although treatment goals for patients with lower-risk disease focus on minimizing transfusions and optimizing quality of life, in higher-risk MDS, the goal is to delay transformation to acute leukemia and to prolong survival. In lower-risk patients, isolated cytopenias are treated with erythropoiesis-stimulating agents or growth factors such as thrombopoietin mimetics. For patients with the del(5q) cytogenetic abnormality or those who fail these initial approaches, lenalidomide may be tried, as can experimental agents. Lower-risk patients with multiple cytopenias may be treated with immunosuppressive drugs or low-dose hypomethylating agents. For patients with higher-risk disease, hypomethylating agents are the preferred initial treatment approach, with evaluation for hematopoietic cell transplantation at diagnosis. Several novel agents are being developed for MDS patients who have failed hypomethylating drugs. PMID- 25696840 TI - Diagnosis of 'double hit' diffuse large B-cell lymphoma and B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma: when and how, FISH versus IHC. AB - Identification of large B-cell lymphomas that are "extra-aggressive" and may require therapy other than that used for diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS), is of great interest. Large B-cell lymphomas with MYC plus BCL2 and/or BCL6 rearrangements, so-called 'double hit' (DHL) or 'triple hit' (THL) lymphomas, are one such group of cases often recognized using cytogenetic FISH studies. Whether features such as morphologic classification, BCL2 expression, or type of MYC translocation partner may mitigate the very adverse prognosis of DHL/THL is controversial. Classification of the DHL/THL is also controversial, with most either dividing them up between the DLBCL, NOS and B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma (BCLU) categories or classifying at least the majority as BCLU. The BCLU category itself has many features that overlap those of DHL/THL. Currently, there is growing interest in the use of MYC and other immunohistochemistry either to help screen for DHL/THL or to identify "double expressor" (DE) large B-cell lymphomas, defined in most studies as having >=40% MYC+ and >=50%-70% BCL2+ cells. DE large B-cell lymphomas are generally aggressive, although not as aggressive as DHL/THL, are more common than DHL/THL, and are more likely to have a nongerminal center phenotype. Whether single MYC rearrangements or MYC expression alone is of clinical importance is controversial. The field of the DHL/THL and DE large B-cell lymphomas is becoming more complex, with many issues left to resolve; however, great interest remains in identifying these cases while more is learned about them. PMID- 25696841 TI - Impact of MYC on malignant behavior. AB - MYC, a member of the helix-loop-helix leucine zipper family of nuclear transcription factors, is a potent proto-oncogene primarily identified as the target of the t(8;14)(q24;q32) chromosome translocation in Burkitt lymphoma. Activation of the MYC gene in normal cells both results in enhanced cellular proliferation and up-regulation of pro-apoptotic pathways, reflecting the tight regulation of the molecule in the normal cellular system. In the process of transformation, these secondary inhibitory functions of the MYC molecule have to be overcome through secondary mutations of the MYC gene itself and/or by abrogating the inhibitory effects of physiological regulators and/or repressors of proliferation such as BCL2, BCL6, BLIMP1, or others. Most aggressive lymphomas, therefore, harbor additional oncogenic alterations that cooperate with MYC deregulation, with different alterations identified in human solid or hematological tumors. These alterations are likely to counteract the pro apoptotic function of MYC. MYC gene alterations in diffuse large B-cell lymphomas and in B-cell lymphomas, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma are frequently associated with BCL2 or/and BCL6 translocations conferring a very aggressive behavior. This review summarizes inherent factors of the biology and function of MYC important in the process of transformation, especially taking account the interdependence of MYC on various cellular networks that have to be co-deregulated to achieve the full malignant phenotype. PMID- 25696842 TI - Double-hit lymphomas: current paradigms and novel treatment approaches. AB - Double-hit lymphomas (DHLs) are a heterogeneous group of mature B-cell lymphomas that harbor concurrent rearrangements of MYC and BCL2 or, occasionally, BCL6. Several studies have now shown that they are associated with a very aggressive clinical course and poor outcome after standard R-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) therapy, with few patients surviving beyond 2 years. Due to their rarity, there is a paucity of data evaluating patient outcomes with alternative strategies to R-CHOP and no consensus on how they should be optimally managed. Recent studies have demonstrated that a significant proportion of diffuse large B-cell lymphoma (DLBCL) cases have high protein expression of MYC and BCL2 as detected by IHC. These so-called "double expressor" DLBCLs are also associated with a poor outcome after R-CHOP, even when MYC and BCL2 rearrangements are absent. There is much interest in developing new strategies for DHL and better characterizing the underlying biology that drives their poor prognosis. Alternative chemotherapy platforms to R-CHOP, such as DA EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab), are under investigation for MYC-rearranged DLBCL, including DHL, and several novel small-molecule inhibitors of MYC and BCL2 are in development. PMID- 25696843 TI - Role of MYD88 in lymphoplasmacytic lymphoma diagnosis and pathogenesis. AB - Lymphoplasmacytic lymphoma (LPL) is a distinct B-cell lymphoproliferative disorder primarily characterized by bone marrow infiltration of lymphoplasmacytic cells. When LPL produces a serum monoclonal immunoglobulin of the IgM class, it is termed Waldenstrom macroglobulinemia (WM). The differential diagnosis between LPL and other types of morphologically similar B-cell tumors that may also have plasmacytic differentiation and/or secretion of IgM paraproteins is not always clear-cut based solely on the pathologic and phenotypic features of the tumor. Although the current treatments for LPL/WM are initially effective in inducing responses in most patients, they are not curative and show decreasing efficacy with repeated administrations, ultimately resulting in the selection of a chemoresistant clone. Next-generation sequencing studies have identified somatic mutations of MYD88, a key component of the Toll-like receptor signaling machinery, in ~90% of LPL/WM. Deregulated MYD88 signaling promoted by mutations sustains tumor cell survival in LPL/WM, demonstrating that they are gain-of function driver events in this lymphoma. This review discusses the molecular and biological mechanisms underlying MYD88 mutations in LPL/WM, the role of MYD88 mutations as molecular biomarker for the refinement of diagnosis and the improvement classification of LPL/WM, and novel targeted therapeutic strategies for LPL/WM based on the pharmacological manipulation of MYD88 signaling to which this lymphoma is addicted. PMID- 25696844 TI - Mutations in chronic lymphocytic leukemia and how they affect therapy choice: focus on NOTCH1, SF3B1, and TP53. AB - Chronic lymphocytic leukemia (CLL) is characterized by a relatively small number of recurrent genetic defects. These can be evaluated by clinically available methods such as fluorescent in situ hybridization and targeted sequencing approaches to provide data that can be very helpful in prognostication and planning of treatment. Acquired defects in the p53 pathway, activating mutations of NOTCH1, and dysfunctional mutations of SF3B1 and BIRC3 identify patients with higher risk of progressive disease, poorer responses to conventional chemoimmunotherapy, and shorter survival. Risk stratification using these data can identify patients with aggressive CLL who require careful monitoring and are unlikely to have durable responses to chemoimmunotherapy at disease progression. Patients with defective DNA damage repair mechanisms because of p53 dysfunction should be considered for non-chemotherapy-based regimens including tyrosine kinase inhibitors, BCL2 inhibitors, monoclonal antibodies, and immunological therapies including allogeneic transplantation and chimeric antigen receptor targeted T cells. Conversely, patients with no high-risk mutations can usually be monitored for a prolonged time and are likely to have durable responses to chemoimmunotherapy at disease progression. New technologies for genetic analysis such as targeted next-generation sequencing have the potential to make these analyses cheaper, faster, and more widely available. Comprehensive genetic analysis of patients both at diagnosis and before treatment for progressive disease could become an integral component of care for CLL. PMID- 25696845 TI - BCR pathway inhibition as therapy for chronic lymphocytic leukemia and lymphoplasmacytic lymphoma. AB - Chronic lymphocytic leukemia (CLL) and lymphoplasmacytic lymphoma (LPL) are malignancies of mature B cells. In LPL, mutations of the adaptor protein MYD88 (L265P) in the Toll-like receptor pathway have been recognized recently as being a hallmark of the disease and indicate a dependence of the tumor on this pathway. In CLL, functional studies have implicated BCR activation in the tissue microenvironment as a pivotal pathway in the pathogenesis. Bruton's tyrosine kinase (BTK) and the PI3Kdelta isoform are essential for BCR signaling and also seem to be required for signal transduction in LPL cells, even if the role of BCR signaling in this disease remains less well defined. Ibrutinib, a covalent inhibitor of BTK approved by the Food and Drug Administration as a second-line treatment for CLL, and idelalisib, a selective inhibitor of PI3Kdelta, achieve excellent clinical responses in both diseases irrespective of classic markers indicating high-risk disease. Several additional inhibitors targeting BTK and PI3Kdelta, as well as the spleen tyrosine kinase, have entered clinical trials. This review discusses the biologic basis for kinase inhibitors as targeted therapy for CLL and LPL and summarizes the clinical experience with these agents. PMID- 25696846 TI - The role of FDG-PET in defining prognosis of Hodgkin lymphoma for early-stage disease. AB - Given the excellent survival rates for early-stage Hodgkin lymphoma (HL), the young age of many patients, and concerns regarding acute and late treatment related toxicities, there is a desire to have a predictive tool that enables therapy to be tailored toward the individual patient. Early (or interim) (18)F fluorodeoxyglucose positron emission tomography with computerized tomography (FDG PET/CT), as a test of tumor sensitivity to ongoing/planned therapy, has been shown to be prognostic for survival in HL. Based on results of interim FDG PET/CT, therapy may be subsequently modified through minimization or via intensification for low- and high-risk patient populations, respectively (ie, response-adapted therapy). Important data have been generated to standardize the interpretability and reproducibility of interim FDG-PET/CT (eg, the Deauville 5 point system), and observational and noncontrolled prospective studies have produced evidence supporting the hypothesis that response-adapted therapy may potentially serve as a predictive tool. Furthermore, results from noninferiority phase 3 clinical trials randomizing early-stage HL patients with negative interim FDG-PET/CT to combined modality therapy versus chemotherapy alone have been reported. The current collective findings from these randomized early-stage HL studies have shown that acute relapse rates are lower with combined modality therapy, even in patients with negative interim FDG-PET/CT. Additional randomized response-adapted studies are ongoing and novel FDG-PET/CT applications involving quantitative techniques and innovative imaging modalities are being investigated to identify more robust imaging biomarkers. Treatment of early-stage HL remains a clinical management choice for physicians and patients to make with consideration of acute and long-term outcomes. PMID- 25696847 TI - The classical Hodgkin lymphoma tumor microenvironment: macrophages and gene expression-based modeling. AB - Despite the high cure rate in classical Hodgkin lymphoma (CHL), more accurate tailoring of upfront treatment is required to maximize cure while avoiding unnecessary short- and long-term treatment side effects. To this end, the unique tumor microenvironment of CHL has been searched extensively for prognostic biomarkers. Beyond targeted immunohistochemistry (IHC) studies, gene expression profiling (GEP) of diagnostic whole tissue biopsies has allowed a de novo approach to biomarker discovery. Among numerous candidate biomarkers, an association between the number of tumor-associated macrophages in the microenvironment and outcomes after ABVD (doxorubicin + bleomycin + vinblastine + dacarbazine) chemotherapy emerged, and multiple subsequent studies have validated this biological relationship using IHC. These studies have also defined key aspects for macrophage interrogation, including the characteristics of the CD68 and CD163 antibodies, appropriate scoring methodologies, and the identification of specific patient populations in which macrophage IHC may not be prognostic. The GEP studies also led to the development of gene expression-based prognostic models for advanced-stage CHL, with new technologies allowing reliable gene expression quantitation using RNA from routinely produced formalin-fixed paraffin embedded biopsies. The bridge to predictive biomarkers that can be used reliably to inform upfront treatment selection requires further studies to demonstrate that these biomarkers can identify robustly, at diagnosis, patients at high risk of treatment failure with ABVD and that this risk may be overcome using alternative treatments. PMID- 25696848 TI - Treatment of relapsed classical Hodgkin lymphoma in the brentuximab vedotin era. AB - Classical Hodgkin lymphoma (HL) relapses after or is refractory to upfront multiagent chemotherapy in 20%-30% of patients. Effective salvage therapy for relapsed or refractory HL is limited, and advancements are needed. Brentuximab vedotin (BV), an anti-CD30 antibody-drug conjugate, has demonstrated significant activity and manageable toxicities in advanced HL. Currently approved as a monotherapy for patients with HL that is relapsed or refractory to multiple lines of chemotherapy or autologous stem cell transplantation, BV is now being evaluated earlier in the course of disease and in combination with other therapies. This review discusses the successful translation of BV from its conception to the clinical setting and highlights ongoing trials that may ultimately expand its role in relapsed or refractory HL and improve outcomes for patients. PMID- 25696849 TI - Indolent lymphoma: follicular lymphoma and the microenvironment-insights from the microscope. AB - Follicular lymphomas (FLs) are neoplasms of germinal center (GC) B cells, which retain many of the morphologic, immunophenotypic, genetic, and functional features of normal GC B cells. Both normal GCs and neoplastic follicles of FL also contain non-neoplastic cells (microenvironment) that influence and are influenced by the GC and FL B cells and are likely important for tumor cell survival. Many insights into the nature of the GC/FL microenvironment have come from morphologic and immunophenotypic analysis, both before and after the discoveries from gene expression profiling. This chapter reviews what we have learned from the microscope and highlights the pitfalls involved in trying to enumerate cells in the microenvironment for clinical prognostication. PMID- 25696850 TI - Indolent lymphoma: follicular lymphoma and the microenvironment-insights from gene expression profiling. AB - As shown with gene expression profiling (GEP), the development and progression of follicular lymphoma (FL) involves complex interactions between neoplastic B cells and the surrounding microenvironment. GEP further reveals that the tumor microenvironment may predict survival in patients with FL and influence the response to therapy and the risk of transformation. Here, we briefly review GEP technology and summarize the role of the tumor microenvironment in FL diagnosis, prognosis, and transformation. Genes expressed by infiltrating T cells and macrophages appear to be the most important predictors of survival, clinical behavior, and outcome. These findings provide a basis for future studies into the pathogenesis and pathophysiology of FL and may ultimately provide guidance in the choice of therapy and the identification of potential therapeutic targets. PMID- 25696851 TI - Therapeutic targeting of microenvironment in follicular lymphoma. AB - Immune and nonimmune microenvironmental factors play a critical role in the progression, transformation, and resistance to therapy in follicular lymphoma (FL). A recent increase in our understanding of the role of microenvironment in FL biology has led to the development of novel therapeutic strategies targeting the nonimmune and immune microenvironment. These include immunomodulatory drugs, immune checkpoint inhibitors, immnunoconjugates, and small-molecule inhibitors with an impact on the microenvironment in addition to direct antitumor activity. These agents are now at different stages of clinical development, ranging from early clinical trials in relapsed disease to phase 3 studies in the upfront setting, including combinations with other agents such as monoclonal antibodies and chemotherapy. It is important to recognize that, although the current upfront therapy of FL is associated with favorable outcomes in the majority of patients, a significant proportion experience early disease progression and develop treatment resistance and transformation to aggressive lymphoma. Although the development of "chemo-free" combinations using drugs targeting the microenvironment offers a promising approach to minimize toxicity, the identification of patients at risk of relapse and the use of biomarkers allowing the personalization of therapy will likely play a major role in the development of maintenance strategies. Against this landscape of currently available therapy options, this chapter discusses the clinical status of therapies targeting the microenvironment in FL. PMID- 25696852 TI - The genomic landscape of acute lymphoblastic leukemia in children and young adults. AB - Our understanding of the genetic basis of childhood acute lymphoblastic leukemia (ALL) has been greatly advanced by genomic profiling and sequencing studies. These efforts have characterized the genetic basis of recently described and poorly understood subtypes of ALL, including early T-cell precursor ALL, Philadelphia chromosome-like (Ph-like) ALL, and ALL with intrachromosomal amplification of chromosome 21, and have identified several rational therapeutic targets in high-risk ALL, notably ABL1-class and JAK-STAT inhibitors in Ph-like ALL. Deep sequencing studies are also refining our understanding of the genetic basis of clonal heterogeneity and relapse. These studies have elucidated the nature of clonal evolution during disease progression and identified genetic changes that confer resistance to specific therapeutic agents, including CREBBP and NT5C2. Genomic profiling has also identified common and rare inherited genetic variants that influence the risk of developing leukemia. These efforts are now being extended to ALL in adolescents and adults with the goal of fully defining the genetic landscape of ALL to further improve treatment outcomes in high-risk populations. PMID- 25696853 TI - Clinically defining and managing high-risk pediatric patients with acute lymphoblastic leukemia. AB - For children with acute lymphoblastic leukemia, the identification of those at higher risk of disease recurrence and modifying therapy based on this risk is a critical component to the provision of optimal care. The specific definitions of high-risk ALL vary across cooperative groups, but the themes are consistent, being largely based on leukemia biology and disease response. Intensification of conventional chemotherapy for those with high-risk disease has led to improved outcomes. It is anticipated that the development of rational targeted therapy for specific biologically unique subsets of children with leukemia will contribute to ongoing progress in improving the outcomes for children with acute lymphoblastic anemia. PMID- 25696854 TI - Balancing cure and long-term risks in acute lymphoblastic leukemia. AB - Cure rates for children and adolescents with acute lymphoblastic leukemia (ALL) have improved dramatically over the last few decades. With this success has come increasing recognition of the adverse late effects of treatment. The significant long-term sequelae in the earliest cohort of long-term survivors treated in the 1970s and 1980s are well documented. To reduce the incidence of these late effects, the majority of pediatric patients treated on more contemporary regimens receive less intensive treatment than did those treated 30-40 years ago. However, current therapies are not risk free; children treated with contemporary regimens remain at risk for developing long-term toxicities, including cardiac dysfunction, osteonecrosis, neurocognitive impairment, and second malignant neoplasms. One of the great challenges facing clinical investigators today is to identify interventions that will reduce the frequency and severity of long-term toxicities without adversely affecting cure rates. The use of dexrazoxane as a cardioprotectant (to prevent anthracycline-associated cardiotoxicity) and alternate-week dosing of dexamethasone (to reduce the risk of osteonecrosis) are examples of 2 such successful strategies. This article provides an overview of the long-term toxicities associated with current therapies and reviews results of clinical trials designed to minimize the burden of cure in long-term survivors. PMID- 25696855 TI - CNS prophylaxis in pediatric acute lymphoblastic leukemia. PMID- 25696856 TI - Iron clad: iron homeostasis and the diagnosis of hereditary iron overload. AB - Iron is an ubiquitous metal of vital importance to the normal physiologic processes of many organisms. Over the last 2 decades, the discovery of mutations in genes leading to hereditary disorders of iron overload, iron deficiency, and iron maldistribution have accelerated our understanding of human iron homeostasis. This chapter provides an updated overview of the human iron cycle, regulation of iron homeostasis, and how perturbations in these homeostatic mechanisms lead to iron overload disease and provides strategies for the diagnosis of hereditary iron overload. PMID- 25696857 TI - Guidelines for quantifying iron overload. AB - Both primary and secondary iron overload are increasingly prevalent in the United States because of immigration from the Far East, increasing transfusion therapy in sickle cell disease, and improved survivorship of hematologic malignancies. This chapter describes the use of historical data, serological measures, and MRI to estimate somatic iron burden. Before chelation therapy, transfusional volume is an accurate method for estimating liver iron burden, whereas transferrin saturation reflects the risk of extrahepatic iron deposition. In chronically transfused patients, trends in serum ferritin are helpful, inexpensive guides to relative changes in somatic iron stores. However, intersubject variability is quite high and ferritin values may change disparately from trends in total body iron load over periods of several years. Liver biopsy was once used to anchor trends in serum ferritin, but it is invasive and plagued by sampling variability. As a result, we recommend annual liver iron concentration measurements by MRI for all patients on chronic transfusion therapy. Furthermore, it is important to measure cardiac T2* by MRI every 6-24 months depending on the clinical risk of cardiac iron deposition. Recent validation data for pancreas and pituitary iron assessments are also presented, but further confirmatory data are suggested before these techniques can be recommended for routine clinical use. PMID- 25696858 TI - Iron age: novel targets for iron overload. AB - Excess iron deposition in vital organs is the main cause of morbidity and mortality in patients affected by beta-thalassemia and hereditary hemochromatosis. In both disorders, inappropriately low levels of the liver hormone hepcidin are responsible for the increased iron absorption, leading to toxic iron accumulation in many organs. Several studies have shown that targeting iron absorption could be beneficial in reducing or preventing iron overload in these 2 disorders, with promising preclinical data. New approaches target Tmprss6, the main suppressor of hepcidin expression, or use minihepcidins, small peptide hepcidin agonists. Additional strategies in beta-thalassemia are showing beneficial effects in ameliorating ineffective erythropoiesis and anemia. Due to the suppressive nature of the erythropoiesis on hepcidin expression, these approaches are also showing beneficial effects on iron metabolism. The goal of this review is to discuss the major factors controlling iron metabolism and erythropoiesis and to discuss potential novel therapeutic approaches to reduce or prevent iron overload in these 2 disorders and ameliorate anemia in beta thalassemia. PMID- 25696859 TI - Defining minimal residual disease in acute myeloid leukemia: which platforms are ready for "prime time"? AB - The past 40 years have witnessed major advances in defining the cytogenetic aberrations, mutational landscape, epigenetic profiles, and expression changes underlying hematological malignancies. Although it has become apparent that acute myeloid leukemia (AML) is highly heterogeneous at the molecular level, the standard framework for risk stratification guiding transplant practice in this disease remains largely based on pretreatment assessment of cytogenetics and a limited panel of molecular genetic markers, coupled with morphological assessment of bone marrow (BM) blast percentage after induction. However, application of more objective methodology such as multiparameter flow cytometry (MFC) has highlighted the limitations of morphology for reliable determination of remission status. Moreover, there is a growing body of evidence that detection of subclinical levels of leukemia (ie, minimal residual disease, MRD) using MFC or molecular-based approaches provides powerful independent prognostic information. Consequently, there is increasing interest in the use of MRD detection to provide early end points in clinical trials and to inform patient management. However, implementation of MRD assessment into clinical practice remains a major challenge, hampered by differences in the assays and preferred analytical methods employed between routine laboratories. Although this should be addressed through adoption of standardized assays with external quality control, it is clear that the molecular heterogeneity of AML coupled with increasing understanding of its clonal architecture dictates that a "one size fits all" approach to MRD detection in this disease is not feasible. However, with the range of platforms now available, there is considerable scope to realistically track treatment response in every patient. PMID- 25696860 TI - Goals for chronic myeloid leukemia TK inhibitor treatment: how little disease is too much? AB - Tyrosine kinase inhibitors, now numbering 5 for the treatment of Philadelphia chromosome-positive leukemia, have proven ability to reduce clonal disease burden rapidly, dramatically, and durably, especially in chronic myeloid leukemia in the chronic phase. Deep molecular remissions are likely in most chronic phase patients and expectations on timing of response have been developed, validated as best as possible, and evolved over time. Increasing attention has been given to the initial decline of Bcr-Abl1 transcripts and the ultimate depth of molecular remission, overshadowing but not displacing the traditional role of cytogenetic response. This chapter reviews the evolution of response milestones for chronic phase chronic myeloid leukemia and tries to answer the question of how little disease is too much. PMID- 25696861 TI - Prognostic significance of early molecular response in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors. AB - A 55-year-old man presented with splenomegaly (10 cm below left costal margin) and leucocytosis (145 * 10(9)/L). Differential showed neutrophilia with increased basophils (2%), eosinophils (1.5%), and left shift including myeloblasts (3%). A diagnosis of chronic myeloid leukemia in chronic phase was established after marrow cytogenetics demonstrated the Philadelphia chromosome. Molecular studies showed a BCR-ABL1 qPCR result of 65% on the International Scale. Imatinib therapy at 400 mg daily was initiated due to patient preference, with achievement of complete hematological response after 4 weeks of therapy. BCR-ABL1 at 1 and 3 months after starting therapy was 37% and 13%, respectively (all reported on International Scale). Is this considered an adequate molecular response? PMID- 25696862 TI - Detection and management of minimal residual disease in acute lymphoblastic leukemia. AB - The detection of minimal residual disease (MRD) has become part of the state-of the-art diagnostics to guide treatment both in pediatric and adult acute lymphoblastic leukemia (ALL). This applies to the treatment of de novo and recurrent ALL. In high-risk ALL, MRD detection is considered an important tool to adjust therapy before and after hematopoietic stem cell transplantation. Precise quantification and quality control is instrumental to avoid false treatment assignment. A new methodological approach to analyzing MRD has become available and is based on next-generation sequencing. In principle, this technique will be able to detect a large number of leukemic subclones at a much higher speed than before. Carefully designed prospective studies need to demonstrate concordance or even superiority compared with those techniques in use right now: detection of aberrant expression of leukemia-specific antigens by flow cytometry of blood or bone marrow, or detection of specific rearrangements of the T-cell receptor or immunoglobulin genes by real-time quantitative polymerase chain reaction using DNA of leukemic cells. In some cases with known fusion genes, such as BCR/ABL, reverse transcriptase-polymerase chain reaction has been used as additional method to identify leukemic cells by analyzing RNA in patient samples. MRD detection may be used to modulate treatment intensity once it has been demonstrated at well-defined informative checkpoints that certain levels of MRD can reliably predict the risk of relapse. In addition, MRD is used as end point to determine the activity of a given agent or treatment protocol. If activity translates into antileukemic efficacy, MRD may be considered a surrogate clinical end point. PMID- 25696863 TI - All transplantation-eligible patients with myeloma should receive ASCT in first response. AB - In this last decade, one of the major advances in the management of multiple myeloma has been the introduction of the novel agents thalidomide, bortezomib, and lenalidomide as part of frontline treatment in young patients eligible for high-dose therapy (HDT) and autologous stem cell transplantation (ASCT). These drugs have markedly improved the rate of complete remission both before and after ASCT without substantially increasing toxicity. The implementation of an "optimal strategy" consisting of novel-agent-based induction, HDT, and the use of novel agents in consolidation and maintenance may result in a 5-year survival rate of 80% and cure might be considered in a subset of patients who present with good prognostic features at the time of diagnosis. Nevertheless, the high efficacy of the novel agents has led some groups to test these agents upfront without ASCT. At the end of 2014, preliminary randomized data favor early ASCT plus novel agents over novel agents alone. Therefore, the optimal approach to the treatment of multiple myeloma is still to propose the most effective treatment that should involve the use of frontline ASCT in young patients eligible for HDT. PMID- 25696864 TI - Early or delayed transplantation for multiple myeloma in the era of novel therapy: does one size fit all? AB - For the last 20 years, high-dose therapy with autologous stem cell transplantation (ASCT) for multiple myeloma has been considered a standard frontline treatment for younger patients with adequate organ function. With the introduction of novel agents, specifically thalidomide, bortezomib, and lenalidomide, the role of ASCT has changed in several ways. First, novel agents have been incorporated successfully as induction regimens, increasing the response rate before ASCT, and are now being used as part of both consolidation and maintenance with the goal of extending progression-free and overall survival. These approaches have shown considerable promise with significant improvements in outcome. Furthermore, the efficacy of novel therapeutics has also led to the investigation of these agents upfront without the immediate application of ASCT, and compelling preliminary results have been reported. Next-generation novel agents and the use of monoclonal antibodies have raised the possibility of not only successful salvage strategies to facilitate delayed transplantation for younger patients, but also the prospect of an nontransplantation approach achieving the same outcome. Moreover, this could be achieved without incurring acute toxicity or long-term complications that are inherent to high-dose alkylation, and melphalan exposure in particular. At present, the role of ASCT has therefore become an area of debate: should it be used upfront in all eligible patients, or should it be used as a salvage treatment at the time of progression for patients achieving a high quality of response with initial therapy? There is a clear need to derive a consensus that is useful for clinicians considering both protocol-directed and non-protocol-directed options for their patients. Participation in ongoing prospective randomized trials is considered vital. While preliminary randomized data from studies in Europe favor early ASCT with novel agents, differences in both agents and the combinations used, as well as limited information on overall survival and benefit for specific patient subsets, suggest that one size does not fit all. Specifically, the optimal approach to treatment of younger patients eligible for ASCT remains a key area for further research. A rigid approach to its use outside of a clinical study is difficult to justify and participation in prospective studies should be a priority. PMID- 25696865 TI - A practical approach to relapsed multiple myeloma. AB - There has been tremendous progress made in multiple myeloma in the last decade, resulting in improved overall survival for all patients, including those with high-risk disease and those ineligible for transplantation. However, despite the addition of several novel agents, unprecedented response rates, and our ability to achieve complete remission in the majority of patients, the disease remains incurable in nearly all and will require repeated therapies. With many options available to the clinician, there is no simple or ideal sequence of treatments that has been established, so the choice of relapsed therapy is based on a series of factors that include response and tolerability of prior therapies, risk status, available novel agents, aggressiveness of relapse, renal function, performance status, cost, etc. This chapter provides practical guidance in selecting relapsed therapies structured through a series of 5 questions that can inform the decision. Specific emphasis is placed on the 2 most recent novel agents, carfilzomib and pomalidomide, but agents in development are also included. PMID- 25696866 TI - How does JAK2V617F contribute to the pathogenesis of myeloproliferative neoplasms? AB - A decade on from the discovery of the JAK2V617F mutation in the majority of patients with myeloproliferative neoplasms (MPNs), JAK2V617F is now firmly installed in the hematology curriculum of medical students and the diagnostic testing algorithm of clinicians. Furthermore, the oral JAK1/JAK2 inhibitor ruxolitinib, rationally designed to target activated JAK2 signaling in MPN, has been approved by the Food and Drug Administration (FDA) of the United States for the past 3 years for the treatment of intermediate- and advanced-phase myelofibrosis. Notwithstanding this, JAK2V617F continues to stimulate the MPN research community and novel insights into understanding the mechanisms by which JAK2V617F contributes to the pathogenesis of MPN are continually emerging. In this chapter, we focus on recent advances in 4 main areas: (1) the molecular processes coopted by JAK2V617F to induce MPN, (2) the role that JAK2V617F plays in phenotypic diversity in MPN, (3) the functional impact of JAK2V617F on hematopoietic stem cells, and (4) therapeutic strategies to target JAK2V617F. Although great strides have been made, significant deficits still exist in our understanding of the precise mechanisms by which JAK2V617F-mutant hematopoietic stem cells emerge and persist to engender clonal hematopoiesis in MPN and in developing strategies to preferentially target the JAK2V617F-mutant clone therapeutically. Critically, although myelofibrosis remains arguably the greatest clinical challenge in JAK2V617F-mediated MPN, the current understanding of myelofibrosis-specific disease biology remains quite rudimentary. Therefore, many important biological questions pertaining to JAK2V617F will continue to engage and challenge the MPN research community in the coming decade. PMID- 25696867 TI - Therapy for myeloproliferative neoplasms: when, which agent, and how? AB - Myeloproliferative neoplasms, including polycythemia vera (PV), essential thrombocythemia, and myelofibrosis (MF) (both primary and secondary), are recognized for their burdensome symptom profiles, life-threatening complications, and risk of progression to acute leukemia. Recent advancements in our ability to diagnose and prognosticate these clonal malignancies have paralleled the development of MPN-targeted therapies that have had a significant impact on disease burden and quality of life. Ruxolitinib has shown success in alleviating the symptomatic burden, reducing splenomegaly and improving quality of life in patients with MF. The role and clinical expectations of JAK2 inhibition continues to expand to a variety of investigational arenas. Clinical trials for patients with MF focus on new JAK inhibitors with potentially less myelosuppression (pacritinib) or even activity for anemia (momelotinib). Further efforts focus on combination trials (including a JAK inhibitor base) or targeting new pathways (ie, telomerase). Similarly, therapy for PV continues to evolve with phase 3 trials investigating optimal frontline therapy (hydroxyurea or IFN) and second line therapy for hydroxyurea-refractory or intolerant PV with JAK inhibitors. In this chapter, we review the evolving data and role of JAK inhibition (alone or in combination) in the management of patients with MPNs. PMID- 25696868 TI - The evolving genomic landscape of myeloproliferative neoplasms. AB - Our understanding of the genetic basis of the Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) has moved forward at a staggering pace over the last decade. With the discoveries of underlying mutations in JAK2, MPL, and, most recently, calreticulin (CALR), that together account for ~90% of patients with MPNs, these conditions are now among the best characterized of hematological malignancies. While JAK-STAT pathway activation has been shown to be central to the pathogenesis of the MPN phenotype, the mechanism by which mutant CALR alters cellular function to result in myeloid proliferation remains unclear. Other mutations in several epigenetic modifiers, such as ASXL1, DNMT3a, TET2, EZH2, IDH1, and IDH2, as well as in genes involved in mRNA splicing, such as SF3B1 and U2AF2, have also been described in recent years in patients with MPNs, and evidence is emerging as to how these may be contributing to disease biology. From a therapeutic perspective, the discovery of aberrations in JAK2 has rapidly translated into the successful clinical use of JAK inhibitors in MPNs. Mutant calreticulin has the potential to be a tumor-specific therapeutic target because the mutations generate a novel protein C-terminus. In this chapter, we detail the genomic alterations that underlie MPNs, with a focus on the recent discovery of mutations in CALR, and explore the clinical and biological relevance of the altered genomic landscape in MPNs. PMID- 25696869 TI - New insights into treatment of venous thromboembolism. AB - Several advances have occurred over the last 2 years in the clinical management of venous thromboembolism (VTE), as evidenced by several high-profile publications in top-tier medical journals. The translation of the knowledge gained into routine clinical practice is an important challenge so that VTE is managed optimally and established and new anticoagulants are used effectively and safely. This chapter reviews issues of VTE treatment from acute management to treatment of long-term complications, addressing new data gained in the last 2 years and putting them into a clinical context, with the goal of improved everyday VTE management. PMID- 25696870 TI - Central venous catheter-related thrombosis. AB - Thrombotic complications associated with the use of central venous catheters (CVCs) are common and lead to distressing patient symptoms, catheter dysfunction, increased risk of infections, long-term central venous stenosis, and considerable costs of care. Risk factors for catheter-related thrombosis include use of larger, multilumen, and peripherally inserted catheters in patients with cancer receiving chemotherapy. Symptomatic catheter-related thrombosis is treated with anticoagulation, generally without removing the catheter. The intensity and duration of anticoagulation depend on the extent of thrombosis, risk of bleeding, and need for continued use of a CVC. To date, the clinical benefit of prophylactic doses of anticoagulant has been disappointing and these agents are not used routinely for this purpose. This chapter focuses on recent evidence, remaining controversies, and practical approaches to reducing the burden of thrombosis associated with CVCs. PMID- 25696872 TI - Management of incidental splanchnic vein thrombosis in cancer patients. AB - A 75-year-old male with metastatic pancreatic cancer is undergoing chemotherapy with gemcitabine. A portal vein thrombosis was incidentally found on surveillance CT scan. He does not report any new abdominal pain or ascites. Should anticoagulation be used to treat asymptomatic portal vein thrombosis? PMID- 25696871 TI - Prevention and treatment of venous thromboembolism in patients with cancer. AB - Robust evidence remains scarce in guiding best practice in the prevention and treatment of venous thromboembolism in patients living with cancer. Recommendations from major consensus guidelines are largely based on extrapolated data from trials performed mostly in noncancer patients, observational studies and registries, studies using surrogate outcomes, and underpowered randomized controlled trials. Nonetheless, a personalized approach based on individual risk assessment is uniformly recommended for inpatient and outpatient thromboprophylaxis and there is consensus that anticoagulant prophylaxis is warranted in selected patients with a high risk of thrombosis. Prediction tools for estimating the risk of thrombosis in the hospital setting have not been validated, but the use of prophylaxis in the ambulatory setting in those with a high Khorana score is under active investigation. Symptomatic and incidental thrombosis should be treated with anticoagulant therapy, but little is known about the optimal duration. Pharmacologic options for prophylaxis and treatment are still restricted to unfractionated heparin, low molecular weight heparin, and vitamin K antagonists because there is currently insufficient evidence to support the use of target-specific, non-vitamin K-antagonist oral anticoagulants. Although these agents offer practical advantages over traditional anticoagulants, potential drug interaction with chemotherapeutic agents, gastrointestinal problems, hepatic and renal impairment, and the lack of rapid reversal agents are important limitations that may reduce the efficacy and safety of these drugs in patients with active cancer. Clinicians and patients are encouraged to participate in clinical trials to advance the care of patients with cancer associated thrombosis. PMID- 25696873 TI - Laboratory methods to detect antiphospholipid antibodies. AB - This chapter reviews several important themes pertaining to the antiphospholipid syndrome (APS), including a description of the clinical features, a discussion of the main autoantigen, beta 2-glycoprotein I (beta2GPI), and insights into the characteristics of the pathogenic anti-beta2GPI autoantibodies. Evidence-based considerations for when to test for APS are explored, along with the clinical significance of patients testing positive on multiple APS assays, so-called triple positivity. A detailed review of recently published laboratory guidelines for the detection of lupus anticoagulant and the solid-phase anticardiolipin and anti-beta2GPI ELISAs is undertaken. Finally, a brief review of nonclassification criteria laboratory assays with potential future diagnostic utility is presented. PMID- 25696874 TI - Monitoring target-specific oral anticoagulants. AB - Target-specific oral anticoagulants are approved for use for the prevention of stroke in atrial fibrillation and for the prevention and treatment of venous thrombosis without the need for laboratory monitoring. However, there are clinical settings in which laboratory measurement of anticoagulant effect is needed. These may include patients with life-threatening bleeding or those requiring emergency surgery, in the setting of renal or hepatic failure, or patients with thrombosis on therapy. This chapter reviews the use of laboratory testing to assess the anticoagulant effect of these drugs. In addition, because these drugs can interfere with other laboratory testing, available data on these interactions are presented. PMID- 25696875 TI - What is the effect of rivaroxaban on routine coagulation tests? AB - A 78-year-old female presents to the emergency department with a traumatic hip fracture. Her past medical history is significant for atrial fibrillation for which she receives rivaroxaban 20 mg daily. Her dose was last taken 12 hours ago. Routine bloodwork conducted in the emergency department shows prothrombin time, international normalized ratio, and activated partial thromboplastin time within the normal range, and estimated glomerular filtration rate of 50 mL/min/1.73 m(2) (normal is >90 mL/min/1.73 m(2)) You are asked by the surgical team to confirm that it is safe to proceed with surgery at this time using neuraxial anesthesia. PMID- 25696876 TI - Genetic basis of congenital platelet disorders. AB - Over the past 4 decades, a better understanding of the genetic origins of inherited platelet disorders has illuminated avenues of investigation in megakaryopoiesis and has identified targets of pharmacologic intervention. Many of these discoveries have been translated into clinical medicine. The success of inherited platelet disorder research is underpinned by broader advances in methodology through the biochemical and molecular revolution of the 20(th) and 21(st) centuries, respectively. Recently, modern genomics techniques have affected platelet and platelet disorders research, allowing for the discovery of several genes involved in platelet production and function and for a deeper understanding of the RNA and miRNA networks that govern platelet function. In this short review, we focus on recent developments in the genetic elucidation of several disorders of platelet number and in the molecular architecture that determines the "genetic makeup" of a platelet in health and disease. PMID- 25696877 TI - Pharmacogenomics of antiplatelet drugs. AB - Clopidogrel, a platelet P2Y12 inhibitor, is one of the most widely prescribed drugs in cardiovascular medicine because it reduces ischemic and thrombotic complications. It is a prodrug requiring biotransformation into the active metabolite by the hepatic cytochrome 450 system, especially the CYP2C19 enzyme. Candidate gene studies and genome-wide association studies have identified loss of-function CYP2C19 variants to be associated with a diminished pharmacologic response. Specifically, compared with noncarriers, carriers of at least one copy of a loss-of-function CYP2C19 allele have ~30% lower levels of active clopidogrel metabolite and ~25% relatively less platelet inhibition with clopidogrel. Moreover, in patients treated with clopidogrel predominantly for percutaneous coronary intervention, carriers of 1 or 2 CYP2C19 loss-of-function alleles are at increased risk for major adverse cardiovascular outcomes, with an ~1.5-fold increase in the risk of cardiovascular death, myocardial infarction, or stroke as well as an ~3-fold increase in risk for stent thrombosis. Tripling the dose of clopidogrel in carriers of a CYP2C19 loss-of-function allele can achieve on treatment platelet reactivity comparable to that seen with the standard 75 mg dose in wild-type individuals, but the impact on clinical outcomes remains unknown. Alternatively, 2 third-generation P2Y12 inhibitors are available: prasugrel and ticagrelor. These drugs are superior to clopidogrel in reducing ischemic outcomes and are unaffected by CYP2C19 loss-of-function alleles. PMID- 25696878 TI - Management of MPN beyond JAK2. AB - Thrombocytosis has a large number of potential underlying causes, but the dominant group of hematological conditions for consideration in this setting are the myeloproliferative neoplasms (MPNs). In this chapter, we consider several key linked questions relating to the management of thrombocytosis in MPNs and discuss several issues. First, we discuss the differential diagnosis of thrombocytosis, which myeloid disorders to consider, and practical approaches to the discrimination of each individual MPN from other causes. Second, there have been several major advances in our understanding of the molecular biology of these conditions and we discuss how these findings are likely to be practically applied in the future. Third, we consider whether there is evidence that thrombocytosis contributes to the complications known to be associated with MPN: thrombosis, hemorrhage and transformation to leukemia and myelofibrosis. Last, we review current ideas for risk stratification and management of essential thrombocythemia and polycythemia vera as the 2 entities within the MPN family that are most frequently associated with thrombocytosis. PMID- 25696879 TI - Lasting power of new clotting proteins. AB - Hemophilia is a genetic disease caused by a deficiency of one of the coagulation proteins. The term usually refers to either hemophilia A, factor VIII (FVIII), with an incidence of ~1 in 5000 male births, or hemophilia B, factor IX (FIX), with an incidence of ~1 in 30 000 male births. When severe, the disease leads to spontaneous life-threatening bleeding episodes. Current therapy requires frequent intravenous infusions of therapeutic factor concentrates. Most patients administer the infusions at home every few days and must limit their physical activities to avoid bleeding when the factor activity levels are below normal. In March 2014, a new therapeutic FIX preparation was approved for clinical use in Canada and the United States and, in June 2014, a new FVIII preparation was approved for clinical use in the United States. Over the next couple of years, other new factor products for FIX, FVIIa, and FVIII, which are currently in late stages of clinical trials, will likely also be approved. These new factors have been engineered to extend their half-life in circulation, thus providing major therapeutic advances for patients with hemophilia primarily by allowing treatment with fewer infusions per month. In the clinical trials so far, >500 patients have successfully used these extended half-life products regularly for >1 year to prevent spontaneous bleeding, to treat successfully any bleeding episodes, and to provide effective coagulation for major surgery. Essentially all infusions were well tolerated and effective. These promising new therapies should allow patients to use fewer infusions to maintain appropriate clotting factor activity levels in all clinical settings. PMID- 25696880 TI - Toward optimal therapy for inhibitors in hemophilia. AB - Treatment of patients with hemophilia A and B has undergone significant advances during the past 2 decades. However, despite these advances, the development of antibodies that inhibit the function of infused clotting factor remains a major challenge and is considered the most significant complication of hemophilia treatment. This chapter reviews current tools available for the care of patients with inhibitors and highlights areas where progress is imminent or strongly needed. For management of bleeding, bypassing agents remain the mainstay of therapy. Recombinant factor VIIa and activated prothrombin complex concentrates are similarly effective in populations of patients with hemophilia and inhibitors; however, individuals may show a better response to one agent over another. Recent studies have shown that prophylaxis with bypassing agents can reduce bleeding episodes by ~50%-80%. The prophylactic use of bypassing agents is an important tool to reduce morbidity in patients before they undergo immune tolerance induction (ITI) and in those with persistent high titer inhibitors, but cost and lack of convenience remain barriers. Because of the significant burden that inhibitors add to the individual patient and the health care system, inhibitor eradication should be pursued in as many patients as possible. ITI is an effective tool, particularly in patients with severe hemophilia A and good risk profiles, and leads to a return to a normal factor VIII response in ~60% of patients. However, for the group of patients who fail to respond to ITI or have hemophilia B, new and improved tools are needed. PMID- 25696881 TI - Risky business of inhibitors: HLA haplotypes, gene polymorphisms, and immune responses. AB - The development of neutralizing antibodies against factor VIII (FVIII inhibitors) and factor IX (FIX inhibitors) is the major complication in hemophilia care today. The antibodies neutralize the biological activity of FVIII and FIX and render replacement therapies ineffective. Antibodies are generated as a result of a cascade of tightly regulated interactions between different cells of the innate and the adaptive immune system located in distinct compartments. Any event that modulates the repertoire of specific B or T cells, the activation state of the innate and adaptive immune system, or the migration pattern of immune cells will therefore potentially influence the risk for patients to develop inhibitors. This chapter reviews our current understanding of different pathways of antibody development that result in different qualities of antibodies. Potential differences in differentiation pathways leading to high-affinity neutralizing or low-affinity non-neutralizing antibodies and the potential influence of gene polymorphisms such as HLA haplotype, FVIII haplotype, and polymorphisms of immunoregulatory genes are discussed. PMID- 25696882 TI - Anticoagulation and in vitro fertilization and ovarian stimulation. AB - Assisted reproductive technology is widely used to treat couples affected by infertility. Complications associated with assisted reproduction include venous thromboembolism, ovarian hyperstimulation syndrome, and recurrent implantation failure. It has also been proposed that thrombophilia may be associated with an increased likelihood of these events. Although data are limited, antithrombotic therapy is frequently used to enhance the likelihood of successful assisted reproduction. This chapter reviews the risks of venous and arterial thromboembolism associated with assisted reproduction, as well as available data regarding the impact of thrombophilia on the risks of thromboembolism and failure of implantation. The role of antithrombotic therapy in reducing the likelihood of these events, along with recommendations from various guidelines, are also discussed. PMID- 25696883 TI - Pregnancy and venous thromboembolism: 'TIPPS' for risk stratification. AB - Pregnancy-associated venous thromboembolism (VTE) is a leading cause of maternal mortality, but is relatively uncommon. It is clear that the antepartum and postpartum periods have different magnitudes of risk and distinct risk factors for VTE and therefore must be considered separately. Absolute daily risks of VTE must be understood and explored when deciding to prescribe antepartum or postpartum thromboprophylaxis and must also be balanced against the downsides of prophylaxis. When the risks for VTE and bleeding are both low, other burdens of thromboprophylaxis must be weighed in and a decision made after an individualized patient values- and patient preferences-based discussion. Risk stratification is essential to ensure that the practicing clinician strikes the right balance. PMID- 25696884 TI - Anticoagulation in pregnancy complications. AB - Women with acquired and inherited thrombophilia are thought to be at increased risk for pregnancy complications, including recurrent pregnancy loss and, depending on the type of thrombophilia, severe preeclampsia. This review discusses the associations between the types of thrombophilia and types of complications, as well as the currently available clinical trial evidence regarding the use of aspirin and heparin to prevent these pregnancy complications. In women with antiphospholipid syndrome, guidelines recommend prescribing aspirin and heparin to women with recurrent miscarriage. The same regimen is suggested for late pregnancy complications by some, but not all, experts. Aspirin or low-molecular-weight heparin to improve pregnancy outcome in women with unexplained recurrent miscarriage has no benefit and should not be prescribed. Whether anticoagulant therapy prevents recurrent miscarriage in women with inherited thrombophilia or in women with severe pregnancy complications remains controversial because of inconsistent results from trials. Aspirin modestly decreases the risk of severe preeclampsia in women at high risk. PMID- 25696885 TI - Platelets: more than a sack of glue. AB - Platelets are primary effector cells in hemostasis. Emerging evidence over the last decade, however, demonstrates that platelets also have critical roles in immunity and inflammation. These nontraditional functions of platelets influence the development, progression, and evolution of numerous diseases, including arthritis, cancer, cardiovascular disease, and infectious syndromes. This chapters reviews recently discovered attributes of platelets that contribute to human disease, paying particular attention to the inflammatory activities of this anucleate cytoplast. PMID- 25696886 TI - RBCs as targets of infection. AB - RBCs can be targets of infection directly or indirectly. When the microorganism enters the RBC directly, RBC damage becomes a fundamental aspect of the disease process. Malaria is the best example of an organism that directly targets the RBC, but others are Babesia and Bartonella. RBCs can also be indirect targets of infectious agents. This can occur when molecules are bound to the surface of the RBC, leading to immunologic clearance; when microorganism-produced toxins damage the RBC membrane, leading to hemolysis; when previous crypt-antigens are exposed, leading to accelerated removal; when microorganism-produced toxins alter RBC antigens to a different phenotype, or when microorganism suppression of erythropoiesis occurs due to specific binding to RBC precursors. PMID- 25696887 TI - Flamethrowers: blood cells and cancer thrombosis risk. AB - Cancer patients are at an increased risk of venous thromboembolism. The clotting system is activated in most cancer patients, which is reflected by specific parameters such as an increased thrombin generation and elevated D-dimer levels. Blood cells, especially WBCs and platelets, play an important role in this activation process. Neutrophils and monocytes are subpopulations of WBCs that increase the thrombotic potential by different mechanisms. Neutrophils are activated by tumor cells and can release DNA, generating highly thrombogenic neutrophil extracellular traps. Monocytes are able to synthesize and express significant quantities of procoagulant tissue factor on their surfaces upon activation. An increased risk of VTE has been found in patients with solid tumors and elevated platelet count and in those with high-grade gliomas and low platelet count. Small circulating membrane vesicles, also called microparticles (MPs), which largely derive from platelets, contribute to the procoagulant potential. Specifically, procoagulant MPs could play a role in tumor-associated thrombosis in pancreatic cancer. Interventional studies are under way that are investigating the benefits of thromboprophylaxis in patients identified to be at high risk of VTE through risk-scoring models that include blood count parameters. The "flames" thrown by blood cells, such as neutrophil extracellular traps and MPs, although exciting, still have to be investigated for their usefulness in the clinical setting. PMID- 25696888 TI - Reproductive issues in sickle cell disease. AB - As medical advances improve survival, reduce disease-related morbidity, and improve quality of life, reproductive issues will take higher priority in the sickle cell disease (SCD) community. A wide variety of topics are addressed in this chapter, including fertility, gonadal failure, erectile dysfunction, and menstrual issues in SCD. Etiologies of impaired male fertility are multifactorial and include hypogonadism, erectile dysfunction, sperm abnormalities, and complications of medical therapies. Much less is known about the prevalence and etiology of infertility in women with SCD. Other reproductive issues in women included in this review are pain and the menstrual cycle, contraception, and preconception counseling. Finally, long-term therapies for SCD and their impact on fertility are presented. Transfusional iron overload and gonadal failure are addressed, followed by options for fertility preservation after stem cell transplantation. Focus is placed on hydroxyurea therapy given its benefits and increasing use in SCD. The impact of this agent on spermatogenesis, azoospermia, and the developing fetus is discussed. PMID- 25696889 TI - Pulmonary hypertension in sickle cell disease: diagnosis and management. AB - The increased survival of patients with sickle cell disease (SCD) into adulthood is associated with an increased incidence of multiorgan dysfunction and a progressive systemic and pulmonary vasculopathy. The high prevalence of an elevated tricuspid regurgitant jet velocity and its association with an increased risk of death in adult patients is well established. However, there has been controversy regarding the prevalence of pulmonary hypertension (PH) and its association with mortality in SCD. Multiple recently published reports demonstrate that PH as diagnosed by right heart catheterization is common in adult SCD patients, with a prevalence of 6%-11%. Furthermore, PH is associated with an increased risk of death in SCD patients. In this chapter, we provide evidence for the high prevalence of PH in SCD and its association with mortality and make recommendations for its evaluation and management. Finally, we provide the rationale for screening for this life-threatening complication in adult patients with SCD. PMID- 25696890 TI - Does hydroxyurea prevent pulmonary complications of sickle cell disease? AB - A 27-year-old man with sickle cell disease (HbSS) presents to the sickle cell clinic for follow-up after a screening echocardiogram revealed an increased tricuspid regurgitant velocity of 2.7 m/s. He has a history of 2 painful crises per year and has been hospitalized 3 times over the past 10 years for management of painful crises. He had one episode of acute chest syndrome at age 15 that was treated with an RBC exchange transfusion, supplemental oxygen, and intravenous antibiotics; he did not require mechanical ventilation. He has not had additional episodes of acute chest syndrome and does not have a history of stroke, retinopathy, or leg ulcers. The patient has never been treated with hydroxyurea. He wants to know whether hydroxyurea will prevent future pulmonary complications related to sickle cell disease. PMID- 25696891 TI - Breakthrough: new guidance for silent cerebral ischemia and infarction in sickle cell disease. AB - Silent cerebral infarction (SCI) is a highly prevalent and morbid condition in sickle cell disease (SCD). SCI can occur beginning in the first year of life and becomes more common with increasing age. Potentially modifiable risk factors for SCI include anemia and blood pressure. Headache does not appear to be associated with SCI, so neurologically normal children with headache do not necessarily warrant screening MRI for SCI. SCI does affect cognition, but biological determinants of cognition are not more important than socioeconomic factors. The recent identification of acute silent cerebral ischemic events indicates that the total burden of ischemic injury to the brain in SCD is far greater than previously realized. Acute anemic events appear to increase the risk of acute silent cerebral ischemic events and SCI dramatically. The medical management of SCI is not yet defined, but documentation of the presence of SCI may qualify affected individuals for special resources because comprehensive interventions are needed to optimize patients' academic and vocational outcomes. PMID- 25696892 TI - Thrombotic microangiopathy and indications for therapeutic plasma exchange. AB - Thrombotic microangiopathy (TMA) is a clinicopathological condition associated with a wide variety of medical conditions. TMA is classically characterized by microangiopathic hemolytic anemia, thrombocytopenia, and microvascular thrombi that cause end-organ damage. The most prominent diagnoses associated with TMA are thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS). Although TTP and HUS can have similar clinical and laboratory features and are often lumped together as a combined entity referred to as "TTP/HUS," the pathologic processes causing TMA and optimal therapies for these conditions are different. Empiric use of therapeutic plasma exchange (TPE) in the setting of TMA is common. The high risk of morbidity and mortality associated with some causes of TMA justify rapid institution of this relatively low-risk procedure. However, many causes of TMA do not respond to TPE and prolonged courses of exchange in the absence of an underlying diagnosis may cause a detrimental delay in appropriate medical therapy. The American Society of Apheresis has published guidelines for the use of TPE for several distinct conditions associated with TMA. This list is not comprehensive and the use of TPE for other causes of TMA may be considered if the mechanism of the underlying disease process provides a clear rationale for this intervention. PMID- 25696893 TI - Red cell exchange: special focus on sickle cell disease. AB - The primary function of red blood cells (RBCs) is to deliver oxygen from the lungs to tissues. Tissue hypoxia occurs when the oxygen-carrying capacity of RBCs is compromised due primarily to 3 causes: (1) a reduction in circulating RBC mass, (2) an increase in circulating RBC mass, or (3) abnormal hemoglobin (Hb) that either does not sufficiently release oxygen to tissues (high-oxygen-affinity hemoglobin) or occludes the microvasculature due to deformed RBCs (sickled RBCs). To improve oxygenation in patients with reduced or increased RBC mass, RBC administration (simple transfusion) or RBC removal (RBC depletion) is performed, respectively. However, for patients with abnormal Hb, RBCs containing abnormal Hb are removed and replaced by healthy volunteer donor RBCs by red cell exchange (RCE). RCE can be performed by manual exchange or by automated exchange using a blood cell separator (erythrocytapheresis). In this review, indications for RCE in sickle cell disease using the evidence-based American Society for Apheresis categories(1) are presented and the rationale for RCE in each disorder are discussed. Simple transfusion versus RCE and manual RCE versus automated RCE are compared. Finally, this review briefly presents some of the challenges of performing erythrocytapheresis in small children and discusses various choices for central venous access during RCE.(2.) PMID- 25696894 TI - Leukocytapheresis for the treatment of hyperleukocytosis secondary to acute leukemia. AB - Patients presenting with new or recurrent acute leukemia, particularly of the myeloid lineage, with WBC counts exceeding 100 * 10(9)/L are often considered for leukocytapheresis, especially if they are experiencing symptoms of leukostasis. These symptoms are thought to occur because of blast aggregates and WBC thrombi in the circulation, which reduce blood flow. Leukostasis may cause various complications, including hyperviscosity syndrome, vascular occlusion resulting in intracranial hemorrhages and respiratory failure, and perivascular leukemic infiltrates. Leukostasis occurs more commonly with a high WBC count and with leukemias of monocytoid lineage such as acute myelomonocytic leukemia, which is a reflection of the nature of the leukemic blasts. Leukocytapheresis is used in an effort to quickly decrease a patient's circulating blast count, which can both prevent the development of leukostasis and provide symptomatic relief of leukostasis. However, the impact of leukocytapheresis on early- and long-term mortality is controversial, with several studies producing conflicting results. In this chapter, the pathophysiology of leukostasis, performance of leukocytapheresis, and efficacy of this treatment are reviewed. PMID- 25696895 TI - Replacing bad (F)actors: hemophilia. AB - Hemophilia A and B are bleeding disorders that result from functional deficiencies in specific circulating blood clotting factors termed factor VIII (FVIII) and factor IX (FIX), respectively, and collectively display an incidence of 1 in 4000 male births. Stem cell transplantation therapies hold the promise of providing a cure for hemophilia, but currently available transplantable stem cell products do not confer endogenous FIX or FVIII biosynthesis. For this reason, stem cell-based approaches for hemophilia have focused primarily on genetic engineering of pluripotent or multipotent stem cells. While pluripotent stem cells have been branded with high expectation and promise, they remain poorly characterized in terms of clinical utility and safety. In contrast, adult-lineage restricted stem cells are established agents in the clinical armamentarium. Of the clinically established stem cell types, hematopoietic stem cells (HSCs) are the most utilized and represent the standard of care for several genetic and acquired diseases. Furthermore, HSCs are ideal cellular vehicles for gene therapy applications because they self-renew, repopulate the entire blood lineage while concurrently amplifying the transgene copy number >10(6) fold, and also have direct access to the bloodstream. Current research on HSC transplantation gene therapy approaches for hemophilia A and B is focused on the following: (1) identification of safe and efficient methods of nucleic acid transfer, (2) optimization of transgene product expression, (3) minimization of conditioning regimen-related toxicity while maintaining HSC engraftment, and (4) overcoming preexisting immunity. Based on the existing data and current rate of progress, clinical trials of HSC transplantation gene therapy for hemophilia are predicted to begin in the coming years. PMID- 25696896 TI - Smoothing the crescent curve: sickle cell disease. AB - Sickle cell disease (SCD) is an inherited disorder secondary to a point mutation at the sixth position of the beta chain of human hemoglobin that results in the replacement of valine for glutamic acid. This recessive genetic abnormality precipitates the polymerization of the deoxygenated form of hemoglobin S that induces a major distortion of red blood cells (sickle red blood cells), which decreases sickle red blood cell deformability, leading to chronic hemolysis and vasoocclusion. These processes can result in severe complications, including chronic pain, end organ dysfunction, stroke, and early mortality. The only proven curative therapy for patients with SCD is myeloablative conditioning and allogeneic stem cell transplantation from HLA-matched sibling donors. In this review, we discuss the most recent advances in allogeneic stem cell transplantation in SCD, including more novel approaches such as reduced toxicity conditioning and the use of alternative allogeneic donors (matched unrelated donors, umbilical cord blood transplantation, haploidentical donors) and autologous gene correction stem cell strategies. Prospects are bright for new stem cell approaches for patients with SCD that will enable curative stem and genetic correction therapies for a greater number of patients suffering from this chronic and debilitating condition. PMID- 25696897 TI - Eliminating SCID row: new approaches to SCID. AB - Treatments for patients with SCID by hematopoietic stem cell transplantation (HSCT) have changed this otherwise lethal primary immune deficiency disorder into one with an increasingly good prognosis. SCID has been the paradigm disorder supporting many key advances in the field of HSCT, with first-in-human successes with matched sibling, haploidentical, and matched unrelated donor allogeneic transplantations. Nevertheless, the optimal approaches for HSCT are still being defined, including determining the optimal stem cell sources, the use and types of pretransplantation conditioning, and applications for SCID subtypes associated with radiosensitivity, for patients with active viral infections and for neonates. Alternatively, autologous transplantation after ex vivo gene correction (gene therapy) has been applied successfully to the treatment of adenosine deaminase-deficient SCID and X-linked SCID by vector-mediated gene addition. Gene therapy holds the prospect of avoiding risks of GVHD and would allow each patient to be their own donor. New approaches to gene therapy by gene correction in autologous HSCs using site-specific endonuclease-mediated homology-driven gene repair are under development. With newborn screening becoming more widely adopted to detect SCID patients before they develop complications, the prognosis for SCID is expected to improve further. This chapter reviews recent advances and ongoing controversies in allogeneic and autologous HSCT for SCID. PMID- 25696898 TI - Optimal disease surveillance strategies in non-Hodgkin lymphoma. AB - Given the paucity of randomized controlled trial data, defining the ideal strategy for surveillance imaging in patients with non-Hodgkin lymphoma (NHL) has become increasingly challenging. The routine use of frequent surveillance scans has been a common component of patient care. Emerging data from prospective and retrospective observational studies and modeling approaches have highlighted the performance characteristics of imaging modalities and the challenges with this form of secondary screening. The majority of patients with relapsed lymphoma have clinical signs or symptoms that prompt further evaluation, and only a small proportion of patients experience relapse detected on a routine scan while being otherwise asymptomatic. Surveillance imaging is costly, may expose patients to minimal risks of mortality due to radiation-related secondary malignancies, and can lead to false-positive findings, leading to unnecessary biopsies. In addition, no prospective study has demonstrated a significant improvement in overall survival for those patients whose disease is discovered on a routine scan versus those who present with clinical symptoms. In this chapter, we examine the baseline risks of relapse for various NHL subtypes that provide the context for surveillance, review the data on imaging modalities, and establish a framework for discussing optimal surveillance strategies with individual patients. Patients should be counseled on the risks and benefits of routine surveillance imaging and decisions regarding surveillance should be made on an individual basis using patient-specific risk factors, response to induction therapy, and patient preferences with a bias toward using surveillance imaging in the 2 years after treatment only in those NHL patients with the greatest likelihood of benefit. PMID- 25696899 TI - Current survivorship recommendations for patients with Hodgkin lymphoma: focus on late effects. AB - Long-term survivors of Hodgkin lymphoma (HL) are at an increased risk for a range of late complications, with subsequent malignant neoplasm and cardiovascular disease representing the 2 leading causes of death in these patients. Raising awareness, close follow-up, and adoption of selected early-detection and risk reduction strategies may help to reduce the adverse impact of these late effects on patients. This chapter reviews known long-term complications of HL therapy, risk factors, and the timing of their occurrence. Where available, data on the efficacy of screening for selected late effects of HL are presented. Current evidence-based and consensus-based recommendations on follow-up of long-term HL survivors are also reviewed. As HL therapy evolves over time, late effects and implications on follow-up of patients treated in the contemporary era should be considered and opportunities for future research should be explored. PMID- 25696900 TI - Caring for the long-term survivor after allogeneic stem cell transplantation. AB - Survivors of allogeneic hematopoietic cell transplantation (HCT) are at risk of developing long-term complications such as subsequent malignancies and cardiopulmonary compromise. The prevalence of chronic health conditions approaches 75% among allogeneic HCT survivors and that for severe or life threatening conditions exceeds 20%. This chapter describes the burden of morbidity carried by HCT survivors to help healthcare providers and policy makers understand the scope of the problem and the need for life-long follow-up and proactive care for this vulnerable population. PMID- 25696901 TI - Bleeding complications of targeted oral anticoagulants: what is the risk? AB - The vitamin K antagonists (VKAs) are a widely used class of agent to prevent thromboembolism. In recent years, numerous alternatives to VKAs have been developed, the target-specific oral anticoagulants (TSOACs), which are available in clinical practice. Currently available agents target thrombin and factor Xa. The most significant side effect of these agents, as with VKAs, is the development of bleeding complications. In this review, the risks of major bleeding complications with the TSOACs will be discussed. Data from meta analyses, randomized controlled trials, and observational studies will be used to highlight bleeding complications associated with TSOACs and warfarin. We highlight the most common causes of major bleeding, GI and intracranial hemorrhage. PMID- 25696902 TI - The target-specific oral anticoagulants: practical considerations. AB - More than 4 years have passed since the first approval of a target-specific oral anticoagulant (TSOAC) in the United States, and the number of clinicians who have prescribed (or considered prescribing) one or more of these medications is increasing. Although these agents may, in properly selected patients, offer advantages over more traditional therapies, their lack of familiarity can be intimidating. Clinicians who are prescribing the TSOACs face a number of management questions not definitively answered by the registration trials. This chapter reviews some of these situations, including updated information on the periprocedural management of TSOACs and the latest evidence about how to best measure TSOAC effect. The lack of an antidote and other considerations that may be relevant when deciding between newer and more traditional anticoagulant medications are also discussed. PMID- 25696903 TI - What is the role of hemodialysis for dabigatran-associated major bleeding? AB - A 70-year-old male with a history of atrial fibrillation who is being anticoagulated with dabigatran etexilate presents to the emergency room with melena. He reports taking his most recent dose of dabigatran more than 2 hours ago. On examination, he is hypotensive and tachycardic, and he continues to have melanotic stools. Laboratory testing reveals a calculated creatinine clearance of 15 mL/min, a prothrombin time of 16.5 seconds (reference range: 11.8-15.2 seconds), an international normalized ratio of 1.2 (reference range: 0.9-1.2), and an activated partial thromboplastin time of 50 seconds (reference range: 22.2 33.0 seconds). You are asked by the emergency medicine physician whether hemodialysis should be considered to decrease the patient's plasma dabigatran level. PMID- 25696904 TI - Reversing targeted oral anticoagulants. AB - Dabigatran, rivaroxaban, and apixaban are orally active anticoagulants that are approved in many countries. Dabigatran inhibits thrombin, whereas rivaroxaban and apixaban are factor Xa inhibitors. In clinical trials, these novel oral anticoagulants were at least as effective as warfarin for preventing stroke in patients with atrial fibrillation, but with a lower rate of serious bleeding. However, the lack of true antidotes for these agents has caused concern when patients suffer life-threatening bleeding or trauma or require emergent invasive procedures. True antidotes are under development for all of these agents. In the meantime, activated and nonactivated prothrombin complex concentrates have been used as reversal agents. Factor VIIa may also be effective for reversal of the factor Xa inhibitors. Reversal of novel oral anticoagulants by these hemostatic agents has not been studied in bleeding human patients, so their true efficacy and appropriate dosing are not known. PMID- 25696905 TI - Clinical and laboratory diagnosis of VWD. AB - VWD is the most common inherited bleeding disorder and is due to a deficiency and/or abnormality of VWF. VWD is inherited in an autosomal-dominant or autosomal recessive pattern, but women are apparently more symptomatic. Three main criteria are required for correct diagnoses of VWD: (1) positive bleeding history since childhood, (2) reduced VWF activity in plasma, and (3) history of bleeding in the family. The bleeding score, together with baseline VWF levels and family history, have been proposed as more evidence-based criteria for VWD. Measurements of a reduced VWF activity in plasma are essential for the diagnosis of VWD; assays for the evaluation of the interactions between VWF and platelet glycoprotein Ib receptor with or without ristocetin, as well as VWF collagen binding, are currently in use. However, other tests such as VWF antigen, factor VIII, ristocetin-induced platelet agglutination, multimeric analysis, VWF propeptide, VWF/FVIII binding assay, and assessment of biological response to desmopressin are necessary to characterize VWD types. Levels of VWF activities <30 U/dL have been associated with a bleeding phenotype and the presence of mutations in the VWF gene. PMID- 25696906 TI - New insights into genotype and phenotype of VWD. AB - Recent advances in VWD research have improved our understanding of the genotype and phenotype of VWD. The VWF gene is highly polymorphic, with a large number of sequence variations reported in healthy individuals. This can lead to some difficulty when attempting to discern genotype-phenotype correlations because sequence variations may not represent disease. In type 1 VWD, mutations can be found throughout the VWF gene, but likely pathogenic sequence variations are found in only ~2/3 of type 1 VWD patients. Sequence variations in type 2 VWD are located in the region corresponding to the defect in the VWF protein found in each type 2 variant. In type 3 VWD, sequence variations are not confined to a specific region of the VWF gene and also include large deletions that may not be picked up using conventional sequencing techniques. Use of genetic testing may be most helpful in diagnosis of type 2 VWD, in which a larger number of known, well characterized mutations are present and demonstration of one of these may help to confirm the diagnosis. Bleeding symptoms in general are more severe with decreasing VWF levels and more severe in type 2 and type 3 VWD compared with type 1 VWD. Prediction of phenotype for an individual patient, however, is still difficult, and the addition of genetic data will be most helpful in ascertaining the correct diagnosis for VWD patients. PMID- 25696907 TI - Management of VWD. AB - VWD is the most common inherited bleeding disorder known. It is caused by a deficiency or dysfunction of the VWF molecule. Bleeding risk varies between modest increases in bleeding seen only with procedures to major risk of spontaneous hemorrhage depending upon the type of VWD. The treatment approach to VWD has changed little in the past 2 decades, but there are numerous subtleties in optimal management. Management includes the prevention or treatment of bleeding by raising endogenous VWF levels with medications such as desmopressin or providing exogenous VWF concentrates. Fibrinolytic inhibitors and topical hemostatic agents are also effective adjunctive measures. Bleeding specific to women presents a special challenge because of heavy menstrual bleeding and pregnancy. Successful management of pregnancy in patients with VWD involves coordination with obstetrics, anesthesia, and the coagulation laboratory monitoring VWF:RCo and FVIII:C levels. Prophylactic treatment with VWF concentrates is emerging as an effective preventive therapy in patients with severe disease. Antibodies to VWF present a special challenge in the management of rare patients with type 3 disease. New therapies on the horizon include recombinant VWF, anti-VWF aptamers, and medications such as IL-11 to raise VWF levels. The key to effective treatment of VWD is an accurate diagnosis of the specific type and selection of hemostatic products appropriate for the clinical situation. PMID- 25696908 TI - The science behind the hypoxic niche of hematopoietic stem and progenitors. AB - In blood, oxygen is transported principally by hemoglobin tetrameric molecules in erythocytes, which allow for the delivery to tissue cells. When anemia occurs, such as perisurgically or after trauma, blood transfusion is administered to replace the deficit in oxygen-carrying capacity. During embryogenesis and later in adult life, tissue oxygen levels control multiple key cellular functions. Low tissue oxygen levels in particular are physiologically relevant to stem cells by controlling their metabolism and cell fate. In adult life, hematopoietic stem cells reside in specified BM microenvironments/niches, where their quiescence and differentiation are presumably also influenced by cell-intrinsic and cell extrinsic (niche) factors. Novel imaging technologies have allowed determination of the spatial localization of hematopoietic stem/progenitor cells (HSPCs), as well as the topography of oxygen distribution in BM cavities. Together, these recent advances have contributed to the emergence of a novel model that challenges the previous concept of a hypoxic hematopoietic stem cell niche characterized by poorly perfused endosteal zones with the deepest hypoxia. HSPCs display a hypoxic phenotype despite residing in close association with arterial or sinusoidal vascular networks. The entire BM cavity is hypoxic and unexpectedly exhibits an opposite oxygen gradient to the one initially proposed because arteriole-rich endosteal zones are relatively less hypoxic than deeper regions of the BM perfused by dense sinusoidal networks. Therefore, further studies are warranted to elucidate to what extent differences in oxygen tensions in these diverse microenvironments influence HSPC homeostasis. PMID- 25696909 TI - Transfusion strategies in hematologic and nonhematologic disease. AB - Substantial progress has been made in our understanding of the risks and benefits of RBC transfusion through the performance of large clinical trials. More than 7000 patients have been enrolled in trials randomly allocating patients to higher transfusion thresholds (~9-10 g/dL), referred to as liberal transfusion, or lower transfusion thresholds (~7-8 g/dL), referred to as restrictive transfusion. The results of most of the trials suggest that a restrictive transfusion strategy is safe and, in some cases, superior to a liberal transfusion strategy. However, in patients with myocardial infarction, brain injury, stroke, or hematological disorders, more large trials are needed because preliminary evidence suggests that liberal transfusion might be beneficial or trials have not been performed at all. PMID- 25696910 TI - Bloodless medicine: what to do when you can't transfuse. AB - A better understanding of risks associated with allogeneic blood transfusions (ABTs), along with a growing population of patients who do not accept transfusions, have led to the emergence of new treatment paradigms with "bloodless medicine." In this chapter, we review prior studies describing management and outcomes in patients who refuse transfusion (referred to as "bloodless patients" herein) and summarize the approaches used at our institution. Bloodless management for surgical patients includes treatment of preoperative anemia, use of autologous blood salvage, and minimizing blood loss with procedures. Other adjuncts for both medical and surgical patients include minimizing blood loss from laboratory testing using pediatric phlebotomy tubes and conservative testing. Anemia can be treated with erythropoiesis-stimulating agents, as well as iron, folate, and B12 when indicated. Although there are limited retrospective studies and no prospective studies to guide management, prior reports suggest that outcomes for surgical patients managed without ABTs are comparable to historic controls. A recent risk-adjusted, propensity-matched, case-control study of outcomes of all hospitalized patients who refused ABT at a large academic health center showed that bloodless management was not an independent predictor of adverse outcomes. Surprisingly, there was a lower overall mortality in the bloodless group and discharge hemoglobin levels were similar for both bloodless and control groups. Further research is now needed to optimize therapy and identify novel interventions to manage bloodless patients. Lessons learned from bloodless patients are likely to benefit all patients given recent evidence suggesting that patients who avoid ABTs do as well, if not better, than those who accept transfusions. PMID- 25696911 TI - Chimeric antigen receptor T-cell therapy for ALL. AB - Relapsed and refractory leukemias pose substantial challenges in both children and adults, with very little progress being made in more than a decade. Targeted immunotherapy using chimeric antigen receptor (CAR)-modified T cells has emerged as a potent therapy with an innovative mechanism. Dramatic clinical responses with complete remission rates as high as 90% have been reported using CAR modified T cells directed against the B-cell-specific antigen CD19 in patients with relapsed/refractory acute lymphoblastic leukemia. Supraphysiologic T-cell proliferation, a hallmark of this therapy, contributes to both efficacy and the most notable toxicity, cytokine release syndrome, posing a unique challenge for toxicity management. Further studies are necessary to identify additional targets, standardize approaches to cytokine release syndrome management, and determine the durability of remissions. PMID- 25696912 TI - Cytotoxic T lymphocytes for leukemia and lymphoma. AB - This chapter focuses on the recent advances in adoptive T-cell immunotherapies, not only for patients after hematopoietic stem cell transplantation, but also in the autologous setting using T cells early in the disease process for the treatment of the highest-risk patients with leukemias and lymphomas. The particular emphasis is to highlight the role of T-cell therapies for hematologic malignancies using a non-gene-transfer approach to direct specificity, including the clinical use of T-cell therapies for EBV-associated lymphomas and strategies for targeting nonviral lymphoma- and leukemia-associated antigens. PMID- 25696913 TI - Maximizing GVL in allogeneic transplantation: role of donor lymphocyte infusions. AB - Donor lymphocyte infusions (DLIs) can induce complete and durable remissions in some patients with hematologic malignancies who have relapsed after allogeneic transplantation, providing definitive evidence of a GVL effect. Despite the great promise initially envisioned for DLI as a method to augment GVL after transplantation, it utility is limited by low response rates in diseases other than chronic myelogenous leukemia and by the development of GVHD, the principal complication of DLI. To maximize GVL potency while minimizing toxicity, cellular effectors active in GVL need to be elucidated. Insight into mechanisms of GVL, such as reversal of in situ T-cell exhaustion, may allow identification of patients who will respond to DLI based on the presence of tumor-infiltrating lymphocytes in the BM. Understanding the clinical factors that influence the effectiveness and abrogate the toxicity of DLI, such as cell dose and timing of DLI after transplantation, will allow further optimization of DLI. This chapter reviews novel strategies that maximize the GVL effect of DLI by enhancing activity while limiting toxicity. PMID- 25696914 TI - Screening for and management of hepatitis B virus reactivation in patients treated with anti-B-cell therapy. AB - Reactivation of hepatitis B virus (HBV) is a potentially fatal complication after anti-B-cell therapy. It can develop not only in patients seropositive for hepatitis B surface antigen (HBsAg), but also in those with resolved HBV infection who are seronegative for HBsAg but seropositive for antibodies against hepatitis B core antigen (anti-HBc) and/or antibodies against HBsAg (anti-HBs). The risk of HBV reactivation depends on the balance between replication of the virus and the immune response of the host. Anti-CD20 monoclonal antibody rituximab in combination with steroid-containing chemotherapy (R-CHOP: rituximab + cyclophosphamide + hydroxydaunorubicin + vincristine + prednisone/prednisolone) is an important risk factor for HBV reactivation in HBsAg-negative patients. More obviously, HBsAg-positive patients are considered to be at very high risk for HBV reactivation and, in the rituximab era, 59%-80% of these patients develop HBV reactivation after R-CHOP-like chemotherapy. Patients with resolved HBV infection should also be considered at high risk of HBV reactivation, the incidence of which is reported to be 9%-24% in such lymphoma patients. All patients should be screened to identify risk groups for HBV reactivation before initiating anti-B cell therapy by measuring serum HBV markers including HBsAg, anti-HBc and anti HBs. To prevent the development of hepatitis due to HBV reactivation after anti-B cell therapy, antiviral prophylaxis is recommended for HBsAg-positive patients and/or patients in whom HBV DNA is detectable at baseline, whereas regular monitoring of HBV DNA-guided preemptive antiviral therapy is a reasonable and useful approach for patients with resolved HBV infection. PMID- 25696915 TI - HIV-associated non-Hodgkin lymphoma: viral origins and therapeutic options. AB - HIV infection is associated with an increased risk of malignancy, especially B cell lymphoid malignancies. Many of these lymphomas are further driven by concomitant infection with viruses such as Epstein-Barr virus or Human Herpesvirus 8, the latter being implicated in uncommon types of lymphomas seen in the setting of HIV-1 infection. Treatment outcomes have improved due to infusional chemotherapy, high-dose chemotherapy, and effective antiretroviral therapy. Successful functional cure of HIV-1 infection has been demonstrated with the use of allogeneic hematopoietic stem cell transplantation. This result spurred a change in the field of HIV-1 management so that, ultimately, the goals of therapy would shift from not only curing the underlying lymphoma, but also curing the HIV-1 infection. Treatment options will be discussed with an emphasis on hematopoietic cell-based therapy for the underlying HIV infection. PMID- 25696916 TI - Hepatitis C virus-associated B-cell non-Hodgkin lymphomas. AB - Epidemiological studies have demonstrated an increased risk of developing B-cell lymphomas in patients with chronic hepatitis C virus (HCV) infection. However, the strength of the association shows great geographic discrepancies, with higher relative risk in countries with high HCV prevalence. It remains unclear whether additional environmental and genetic factors are involved or if the international variability is simply a consequence of the variable infection prevalence. Therefore, a causal relationship remains controversial. Other confounding factors may affect the comparability of the different studies, including the method of HCV assessment, the selection of normal controls, the lymphoma classification used, and the year of publication. The most convincing proof is the observation, mainly limited to some indolent subtypes, of B-cell lymphoma regressions after HCV eradication with IFN and ribavirin. However, the molecular mechanisms of the HCV-induced lymphomagenesis are mainly hypothetical. According to the model considered to be most plausible, lymphoma growth is a consequence of the continuous antigenic stimulation of the B-cell immunologic response induced by the chronic viral infection. This review summarizes the current epidemiological and biological evidence of a role of HCV in lymphomagenesis, describing the putative mechanisms for a causative relationship. The clinical characteristics and management difficulties of the HCV-associated lymphomas are also discussed. HCV treatment with IFN cannot be given safely in concomitance with cytotoxic lymphoma treatment because of hematological and liver toxicity. However, novel and better tolerated antiviral regimens are under development and will hopefully make the treatment of both lymphoma and hepatitis easier in the future. PMID- 25696917 TI - Five hematologic tests and treatments to question. AB - Choosing Wisely(r) is a medical stewardship initiative led by the American Board of Internal Medicine Foundation in collaboration with professional medical societies in the United States. The American Society of Hematology (ASH) released its first Choosing Wisely(r) list in 2013. Using the same evidence-based methodology as in 2013, ASH has identified 5 additional tests and treatments that should be questioned by clinicians and patients under specific, indicated circumstances. The ASH 2014 Choosing Wisely(r) recommendations include: (1) do not anticoagulate for more than 3 months in patients experiencing a first venous thromboembolic event in the setting of major, transient risk factors for venous thromboembolism; (2) do not routinely transfuse for chronic anemia or uncomplicated pain crises in patients with sickle cell disease; (3) do not perform baseline or surveillance computed tomography scans in patients with asymptomatic, early-stage chronic lymphocytic leukemia; (4) do not test or treat for heparin-induced thrombocytopenia if the clinical pretest probability of heparin-induced thrombocytopenia is low; and (5) do not treat patients with immune thrombocytopenia unless they are bleeding or have very low platelet counts. PMID- 25696918 TI - Hallek M. Signaling the end of chronic lymphocytic leukemia: new frontline treatment strategies. Hematology Am Soc Hematol Educ Program. 2013;2013:138-150. PMID- 25696919 TI - An open-label phase 2 trial of entospletinib (GS-9973), a selective spleen tyrosine kinase inhibitor, in chronic lymphocytic leukemia. AB - Small-molecule inhibitors of kinases involved in B-cell receptor signaling are an important advance in managing lymphoid malignancies. Entospletinib (GS-9973) is an oral, selective inhibitor of spleen tyrosine kinase. This multicenter, phase 2 study enrolled subjects with relapsed or refractory chronic lymphocytic leukemia (CLL; n = 41) or non-Hodgkin lymphoma (n = 145). Participants received 800 mg entospletinib twice daily. We report efficacy outcomes in the CLL cohort (n = 41) and safety outcomes in all cohorts (N = 186). The primary end point was a progression-free survival (PFS) rate at 24 weeks in subjects with CLL. The PFS rate at 24 weeks was 70.1% (95% confidence interval [CI], 51.3%-82.7%); median PFS was 13.8 months (95% CI, 7.7 months to not reached). The objective response rate was 61.0% (95% CI, 44.5%-75.8%), including 3 subjects (7.3%) who achieved nodal response with persistent lymphocytosis. Fifty-four subjects (29.0%) had serious adverse events (SAEs). The most common treatment-emergent SAEs included dyspnea, pneumonia, febrile neutropenia, dehydration, and pyrexia. Common grade 3/4 laboratory abnormalities included neutropenia (14.5%) and reversible alanine aminotransferase/aspartate aminotransferase elevations (13.4%). Entospletinib demonstrates clinical activity in subjects with relapsed or refractory CLL with acceptable toxicity. This trial was registered at www.clinicaltrials.gov as #NCT01799889. PMID- 25696920 TI - Functions of BET proteins in erythroid gene expression. AB - Inhibitors of bromodomain and extraterminal motif proteins (BETs) are being evaluated for the treatment of cancer and other diseases, yet much remains to be learned about how BET proteins function during normal physiology. We used genomic and genetic approaches to examine BET function in a hematopoietic maturation system driven by GATA1, an acetylated transcription factor previously shown to interact with BETs. We found that BRD2, BRD3, and BRD4 were variably recruited to GATA1-regulated genes, with BRD3 binding the greatest number of GATA1-occupied sites. Pharmacologic BET inhibition impaired GATA1-mediated transcriptional activation, but not repression, genome-wide. Mechanistically, BETs promoted chromatin occupancy of GATA1 and subsequently supported transcriptional activation. Using a combination of CRISPR-Cas9-mediated genomic engineering and shRNA approaches, we observed that depletion of either BRD2 or BRD4 alone blunted erythroid gene activation. Surprisingly, depletion of BRD3 only affected erythroid transcription in the context of BRD2 deficiency. Consistent with functional overlap among BET proteins, forced BRD3 expression substantially rescued defects caused by BRD2 deficiency. These results suggest that pharmacologic BET inhibition should be interpreted in the context of distinct steps in transcriptional activation and overlapping functions among BET family members. PMID- 25696922 TI - Authors' reply. PMID- 25696921 TI - G-protein-coupled receptor kinase 2-mediated desensitization of adiponectin receptor 1 in failing heart. AB - BACKGROUND: Phosphorylative desensitization of G-protein-coupled receptors contributes significantly to post-myocardial infarction (MI) remodeling and heart failure (HF). Here, we determined whether adiponectin receptors (AdipoRs) 1 and 2 (the 7-transmembrane domain-containing receptors mediating adiponectin functions) are phosphorylatively modified and functionally impaired after MI. METHODS AND RESULTS: Post-MI HF was induced by coronary artery occlusion. Receptor phosphorylation, kinase expression, and adiponectin function were determined via in vivo, ex vivo, and in vitro models. AdipoR1 and AdipoR2 are not phosphorylated in the normal heart. However, AdipoR1 was significantly phosphorylated after MI, peaking at 7 days and remaining significantly phosphorylated thereafter. The extent of post-MI AdipoR1 phosphorylation positively correlated with the expression level of GPCR kinase (GRK) 2, the predominant GRK isoform upregulated in the failing heart. Cardiac-specific GRK2 knockout virtually abolished post-MI AdipoR1 phosphorylation, whereas virus-mediated GRK2 overexpression significantly phosphorylated AdipoR1 and blocked adiponectin metabolic-regulatory/anti inflammatory signaling. Mass spectrometry identified serine-7, threonine-24, and threonine-53 (residues located in the n-terminal intracellular AdipoR1 region) as the GRK2 phosphorylation sites. Ex vivo experiments demonstrated that adenosine monophosphate-activated protein kinase activation and the anti-tumor necrosis factor-alpha effect of adiponectin were significantly inhibited in cardiomyocytes isolated from nonischemic area 7 days after MI. In vivo experiments demonstrated that acute adiponectin administration-induced cardiac GLUT4 translocation and endothelial nitric oxide synthase phosphorylation were blunted 7 days after MI. Continuous adiponectin administration beginning 7 days after MI failed to protect the heart from adverse remodeling and HF progression. Finally, cardiac-specific GRK2 knockdown restored the cardioprotective effect of adiponectin. CONCLUSION: AdipoR1 is phosphorylatively modified and desensitized by GRK2 in failing cardiomyocytes, contributing to post-MI remodeling and HF progression. PMID- 25696923 TI - Authors' reply. PMID- 25696924 TI - IAEA radiation protection initiatives. PMID- 25696925 TI - IAEA issues 2014 edition of climate change and nuclear power. PMID- 25696926 TI - Bioremediation, Bioenergy and Stress Biology, issue 2014. PMID- 25696927 TI - [Microbial metabolites that inhibit sterol biosynthesis, their chemical diversity and characteristics of mode of action]. AB - Inhibitors of sterol biosynthesis (ISB) are widespread in nature and characterized by appreciable diversity both in their chemical structure and mode of action. Many of these inhibitors express noticeable biological activity and approved themselves in development of various pharmaceuticals. In this review there is a detailed description of biologically active microbial metabolites with revealed chemical structure that have ability to inhibit sterol biosynthesis. Inhibitors of mevalonate pathway in fungous and mammalian cells, exhibiting hypolipidemic or antifungal activity, as well as inhibitors of alternative non mevalonate (pyruvate gliceraldehyde phosphate) isoprenoid pathway, which are promising in the development of affective antimicrobial or antiparasitic drugs, are under consideration in this review. Chemical formulas of the main natural inhibitors and their semi-synthetic derivatives are represented. Mechanism of their action at cellular and biochemical level is discussed. Special attention is given to inhibitors of 3-hydroxy-3-methylglutaryl Coenzyme A (HMG-CoA) reductase (group of lovastatin) and inhibitors of acyl-CoA-cholesterol-acyl transferase (ACAT) that possess hypolipidemic activity and could be affective in the treatment of atherosclerosis. In case of inhibitors of late stages of sterol biosynthesis (after squalene formation) special attention is paid to compounds possessing evident antifungal and antitumoral activity. Explanation of mechanism of anticancer and antiviral action of microbial ISB, as well as the description of their ability to induce apoptosis is given. PMID- 25696928 TI - [Novel conformational peptide antigen, which simulates an immunodominant epitope of the 2nd extracellular loop of beta1-adrenoceptor. Computer simulation, synthesis, spatial structure]. AB - By means of computer simulation has been built polypeptide antigen conformational structure that imitates the immunodominant epitope of the 2nd extracellular loop of beta1-adrenoreceptor. A linear 25-membered peptide corresponding to calculated sequence was synthesized by means of solid-phase methoyd using Fmoc-technology, then directed by the closure ofdisulfide bridges was obtained original bicyclic polypeptide corresponding to the proposed structure of the conformational antigen. With the help of high-resolution NMR spectroscopy 3D structure of synthetic conformational antigen was investigated. It was shown that the structure of the bicyclic polypeptide similar to that of building computer model. Bicyclic conformational antigen was suitable for the detection of autoantibodies in the blood serum of patients with rhythm and conductivity violation without evidence of organic disease of the cardiovascular system. PMID- 25696929 TI - [Molecular mechanism of AB5 toxin A-subunit translocation into the target cells]. AB - AB5 toxins are pore-forming protein complexes, which destroy eukaryotic target cells inactivating essential enzyme complexes through protein ADP-ribosylation or glycosylation by enzymatically active A1 subunits. The B-subunit pentamer interacts with the target cell receptor, induces membrane pore formation, and initiates receptor-mediated endocytosis. In the present article, we propose a model of A1-subunit translocation in the form of a globular structure, as opposed to the generally accepted hypothesis of A-subunit unfolding in the acidic milieu of the endosome followed by its transport in the form of unfolded polypeptide and refolding in the cytoplasm. This model is based on physical-chemical processes and explains why an endosome, but not an exosome, is formed. A-subunit translocation into the cytosol is driven by the proton potential difference generated by K/Na- and H(+)-ATPases. After reduction of the disulphide bond between A1 and A2 fragments by intracellular enzymes, B-subunit returns back into the endosome, where they are destroyed by endosomal proteases, and the pore is closed. Endosome integrates into the cellular membrane, and membrane-bound enzymatic complexes (ATPases and others) return back to their initial position. The proposed model of receptor-mediated endocytosis is a universal molecular mechanism of translocation of effector toxin molecule subunits or any other proteins into the target cell, as well as of cell membrane reparation after any cell membrane injury by pore-forming complexes. PMID- 25696930 TI - [Investigation of active center of deoxynucleoside monophosphate kinase of bacteriophage T5 by site-directed mutagenesis]. AB - Based on the computer model of active center of bacteriophage T5 deoxyribonucleoside monophosphate kinase amino acid residues essential for the enzyme activity were determined. As the result of site-directed mutagenesis, cloning and expression of the gene in E. coli series of proteins were obtained with single amino acid substitutions of conservative active center residues- S13A, D16N, T17N, T17S, R130K, K131E, Q134A, G137A, T138A, W150F, W150A, D170N, R172I, E176Q. Electrophoretically homogeneous preparations of mutant forms were purified using ion exchange and affinity chromatographic steps. Measuring of the specific enzyme activities of these enzymes for the natural acceptors of phosphoryl group (dAMP, dCMP, dGMP, dTMP) revealed that substitutions of charged residues of NMP-binding domain-namely, R130, R172, D170 and E176-lead to almost complete loss of enzyme activity. It was shown that presence of OH-group at position 17 is also important for catalytic activity. Based on the changes in specific activities we suppose that arginine residues at positions 130 and 172 participate in binding of gamma-phosphoryl of donor and alpha-phosphoryl of acceptor. Also, aspartic acid at 16 position of ATP-binding site (P-loop) probably assists in the binding of acceptor, first of all dTMP. Unequal decrease in enzyme activities for different substrates of partially active mutants--G137A, T138A, T17N, Q134A, S13A, D16N--indicate that in the binding of various substrates different amino acid residues take part. PMID- 25696931 TI - [Immunoassay of nine serological tumor markers on hydrogel-based microchip]. AB - A prototype of test-system for simultaneous quantitative assay of nine tumor markers in blood serum was developed. The main constituent of the test-system is OM-9 biochip containing immobilized antibodies against nine oncomarkers: alpha fetoprotein (AFP), carcinoembryonic antigen (CEA), human chorionic gonadotropin (HCG), cancer antigen 15-3 (CA 15-3), cancer antigen 125 (CA 125), cancer antigen 19-9 (CA 19-9), prostate-specific antigen, total (PSAtot) and free (PSAfree) forms, neuron-specific enolase (NSE). The biochip-based assay procedure for carrying out simultaneous quantitative determination of nine tumor markers in patient's blood serum: two-steps sandwich-immunoassay, was proposed. The main analytical characteristics of the method were obtained. The results permit to consider the prototype of the test-system as a promising instrument for clinical application. The test-system prototype was tested using blood serum samples of oncological patients (252 samples) and healthy donors (185 samples). Increased concentrations of one or more tumor markers above the normal level were found in 76.6% cases of oncological patients and only in 6% cases of healthy donors. For colorectal cancer patients group, application of modern statistical methods of data-processing in medical researchers, i.e. ROC-analysis and logistic regression, indicted that the simultaneous assay of nine tumor markers on biochips showed much more diagnostic significance (area under the ROC-curve (AUC) reached 0.84) than traditional assay of 2 tumor markers, CEA and CA 19-9 (AUC = 0.59). The developed biochip-based test-system can be recommended both for the estimation of people's health, e.g., for standard medical examination, and for tracking of tumoral process in postsurgical period or after specific tumor treatment. PMID- 25696932 TI - [Composites of peptide nucleic acids with titanium dioxide nanoparticles. II+. Dissociation of DNA/PNA duplexes within TiO2 x polylysine x DNA/PNA nanocomposites and in solution. Effect of polylysine]. AB - When creating effective drugs it is important not only to transport them into the cells, but also important to have the possibility of release them from the "transporter" after delivery into the cell. It was shown that peptide nucleic acids (PNA) in nanocomposite TiO2 x PL x DNA/PNA dissociate with typical shape of the thermal denaturation curve, and polylysine (PL) in the nanocomposite has practically no effect on the dissociation of the DNA/PNA duplexes. These data suggest that the PNA in the nanocomposite TiO2 x PL x DNA/PNA have been immobilized reversible and able to dissociate and be released from TiO2-carrier into solution. In contrast that, the dissociation of DNA/DNA and DNA/PNA duplexes in physiological solution at the presence of PL--was not observed. PL in solution abnormally strong influences on the nature of the optical density dependence on temperature and time for D-duplexes and in a less degree--for P-duplexes. It has been suggested, that PL with DNA/DNA duplexes in physiological solution forms triple polycomplexes (-DNA/DNA x PL)m, consisting of several (m) chains of PL connected with DNA/DNA duplexes. And such polycomplexes able to aggregate and precipitate. PL in solution can interact with DNA/PNA duplexes to form monocomplexes PL x (DNA/PNA)n consisting of one chain PL and one or more (n) DNA/PNA duplexes that do not precipitate, however the dissociation of DNA/PNA duplexes from such monocomplexes is difficult. PMID- 25696933 TI - [Synthesis and biological properties of alpha-thymidine 5'-aryl phosphonates]. AB - The interaction of CDI-activated diethyl phosphonoacetate with methyl 4 aminobenzoat or 3,5-difluoromethylphenylamine followed by treatment with Me3SiBr in DMF led to N-aryl aminocarbonylmethyl phosphonates and their ethyl esters. Their coupling with 3'-acetyl-alpha-thymidine followed by removal of the acetyl groups gave (alpha-D-thymidine-5'-il) N-[4-(methoxycarbonyl-, aminocarbonyl- and carboxy)phenyl]-aminocarbonylmethyl phosphonates, (alpha-D-thymidine-5'-il)-[3,5 bis(trifluoromethyl)phenylaminocarbonyl]methyl phosphonate and their ethyl esters. The phosphonates were stable in different conditions, low cytotoxic (in Vero and K562 cells) and were able to penetrate into K562 cells. The only ethyl ester of (alpha-D-thymidine-5'-il) N-[4-(methoxycarbonyl)phenyl] aminocarbonylmethyl phosphonate in high concentration (200 MUg/mL) inhibited in vitro the growth of laboratory sensitive strain of Mycobacterium tuberculosis H37Rv. PMID- 25696934 TI - [Calix[4]arenes C-136 and C-137 hyperpolarize myometrium mitochondria membranes]. AB - Calixarenes--supramolecular compounds interacting with bioactive molecules and ions that causes the changes in biochemical and biophysical processes. The aim of this work was to study the effects of calix[4]arenes C-136, C-137 and C-138 on the level of polarization of rat myometrium mitochondria membrane. Structure of synthesized calix[4]arene molecules was confirmed by the methods of 1H NMR and infra-red spectroscopy. Calix[4]arenes C-136 and C-137 possess two chalcone amide moieties at the lower rim, while the calix[4]arene C-138--only one. In case of calix[4]arenes C-136 and C-137 take place, accordingly, absence or presence of phenolic hydroxyl groups at the lower rim on the calix[4]arene skeleton. It was shown that calix[4]arenes C-136, C-137 and C-138 form micelles in a water medium and in the dimethylformamide (DMF). The irradiation of micelles with argon laser on flow cytometer results in appearance of autofluorescence. In the water medium calix[4]arene micelles interact with positively charged potential-sensitive fluorescent probe TMRM, that can testify to the presence of negative charge in these structures. However calix[4]arene micelles in DMF solution do not interact with TMRM. Mitochondrial membrane potential was measured using fluorescent dyes MTG and TMRM with confocal microscopy and fluorescent dye TMRM with flow cytometry. Experiments were conducted on myometrium cells in culture and on suspension of digitonin-permeabilized uterus myocytes. It was shown that a fluorescent signal was stable during time of experiment. Calix[4]arenes C-136 and C-137 (10 MUM) hyperpolarize mitochondria membranes. A maximal effect was 173%. At the same time calix[4]arene C-138 did not influence on mitochondria membrane potential. Connection comes into question between structural organization of investigated calix[4]arene molecules and their influence on polarization of mitochondria membrane. PMID- 25696935 TI - Novel urea and thiourea derivatives of thiazole-glutamic acid conjugate as potential inhibitors of microbes and fungi. AB - Since discovery and development of effective as well as safe drugs has brought a progressive era in human healthcare that is accompanied by the appearance of drug resistant bacterial strains, there is constant need of new antibacterial agent having novel mechanisms of action to act against the harmful pathogens. In the present study, several N-terminal substituted urea/thiourea derivatives were synthesized by the reaction of glutamic acid and 3-(1-piperazinyl)-1,2 benzisothiazole with various substituted phenyl isocyanates/isothiocyanates. Elemental analysis, IR, 1H NMR, 13C NMR and mass spectral data confirmed the structure of the newly synthesized compounds. The derivatives were investigated for their antibacterial and antifungal activities against various pathogens of human origin by agar well diffusion method and microdilution method. The preliminary antimicrobial bioassay reveals that the compounds containing fluoro and bromo as substituents showed promising antimicrobial activity. PMID- 25696936 TI - [Cytotoxicity of cytosine deaminase and herpes simplex virus thymidine kinase genes in melanoma cells is independent on promoter strength]. AB - In preparation of the therapeutic genetic constructs aimed to the gene-programmed enzymatic transformation of the non-toxic prodrug into toxin within cancer cells the right choice of regulatory elements (promoters and enhancers) is essential. This is widely accepted that the efficiency of the gene therapy constructions is dependent, in particular, on the strength of promoters driving the expression of the therapeutic genes. In this work we demonstrated, using the melanoma-specific promoters and enhancers of human melanoma inhibitory activity and mouse tyrosinase gene, that for the development of cytotoxic effect the promoter strength is not of primary importance. In the case of HSVtk, coding for the herpes simplex virus thymidine kinase, and FCU1, coding for cytosine deaminase/uracil phosphoribosyltransferase hybrid protein genes, their cytotoxic activity was determined by the quantity of the added prodrug. PMID- 25696937 TI - [Hepatoprotective activity of betulonic acid amides containing a piperidine or pyrrolidine nitroxide moiety]. AB - Betulonic acid amides containing a nitroxyl radical moiety possess antiholestatic effects in mice. Introduction ofpiperidine nitroxide moiety into lupan core increases its hepatoprotective activity. Oral administration of piperidine nitroxide derivative in dose 50 mg/kg doesn't stimulate transplanted tumor growth and raises a lifespan of mice. PMID- 25696938 TI - Extraction and characterization of Aegle marmelos derived polymer as a pharmaceutical excipient. AB - BACKGROUND: Natural polymers have been used as pharmaceutical excipients. They are easily available, cheap, less toxic andbiodegradable. Many of them have been identified and research is ongoing regarding their characterization. OBJECTIVE: The present study depicts the extraction and characterization of Aegle marmelos derived polymer which can be used as a pharmaceutical excipient. MATERIAL AND METHODS: A water based extraction method was used to extract Aegle marmelos derived polymer. Its yield was found to be 15.07%. Characterization was based on various parameters such as a test for carbohydrates, test for purity, organoleptic properties, ash value, solubility behavior, pH, swelling index, surface tension, viscosity, particle size, loss on drying, bulk density, bulkiness, powder flow behavior, etc. RESULT: The polymer was yellowish-brown and showed poor flow (angle of repose 19.28 degrees +/- 0.883) with neutral pH, i.e. 7, and bulkiness depicting the heaviness of polymer. The extracted polymer showed solubility in warm water and insolubility in organic solvents. CONCLUSIONS: The results easily predict the fact that the yield of the polymer was quite good, so it can be used as a commercial source of mucilage. The isolated polymer can be used as a pharmaceutical excipient in different dosage forms. 2 / PMID- 25696939 TI - Effects of modification and incorporation techniques on disintegrant properties of wheat (Triticum aestivum) starch in metronidazole tablet formulations. AB - BACKGROUND: Natural polymers serve as cheap, non-toxic, biocompatible excipients in drug delivery. OBJECTIVES: Starch from wheat (Triticum aestivum) was investigated as a disintegrant in metronidazole tablet formulations in comparison with sodium starch glycolate (SSG), a standard, synthetic but relatively more expensive disintegrant. MATERIAL AND METHODS: Native wheat starch (NAS) was modified by pregelatinization (PGS) and microwave irradiation (MCW). The starches were characterized using swelling capacity, angle of repose, density measurements, Carr's index and Hausner's ratio. Metronidazole tablet formulations were made with the starches incorporated by intragranular (IG), extra-granular (EG) or intra/extragranular (IG/EG) methods. Tablet properties of crushing strength, disintegration time and dissolution tests were determined. RESULTS: Native wheat starch had better hydration capacity than the modified starches, with PGS having a higher swelling capacity than the MCW. Modified starches formed better compacts than both NAS and SSG as indicated by the higher crushing strength of tablets containing modified starches. Intragranular incorporation gave a higher crushing strength than both EG and IG/EG methods. The ranking for disintegration time of tablets was IG/EG > IG > EG among the incorporation methods and SSG > PGS > MCW > NAS among the starches (EG > IG/EG). The difference between IG/EG and EG was significant (p < 0.05) but not significant between IG and other incorporation methods (MCW > SSG > PGS). Native and modified wheat starches exhibited better disintegrant properties than sodium starch glycolate in metronidazole tablet formulations. CONCLUSIONS: The mode of disintegrant incorporation and modification of wheat starch had different effects on tablet properties of metronidazole formulations. The modification technique and method of disintegrant incorporation should be determined based on desired tablet properties. PMID- 25696940 TI - Preparation and characterization of starch-metal silicate Co-precipitates- evaluation as tablet superdisintegrant. AB - BACKGROUND: Starch is a potential biomaterial used for various pharmaceutical applications because of its unique physicochemical and functional characteristics. A number of modification techniques, such as physical, chemical, enzymatic and genetic or a combination of any of these methods have been reported with the aim of enhancing the positive attributes and eliminating the shortcomings of the native starches. OBJECTIVES: The present studies deal with the development of co-precipitates of corn starch with different silicates (Mg, Ca, Al) with an aim of using it as a tablet superdisintegrant. Co-precipitates of starch with different silicates were prepared and FTIR-ATR, XRD and SEM techniques were used for the characterization of conjugates. MATERIAL AND METHODS: The conjugate were analyzed for various powder evaluation test like angle of repose, bulk density, tapped density, Hausner's ratio, Carr's index, swelling index and effective pore radius. RESULTS: The prepared co-precipitates were found to possess good powder flow properties. The swelling and effective pore radius of all co-precipitates (SMgC, SAlC and SCaC) was found in the range between 30-100% and 15.89-21.71 MUm respectively. Different ratios of the prepared co-precipitates were used to formulate fast disintegrating tablets. Fast disintegrated tablets formulated using starch silicate conjugates as superdisintegrant were evaluated for diameter, thickness, hardness, friability, tensile strength, in vitro tablet disintegration, water absorption ratio, wetting time and in vitro dissolution studies. The effective pore radius and swelling of the co-precipitates were correlated with the in vitro disintegration, water absorption ratio and wetting time of the tablets. CONCLUSIONS: It was concluded that silicated co-precipitates of starch could be used as superdisintegrants in pharmaceutical tablet formulations. PMID- 25696941 TI - [Evaluation of the Peusner's coefficients matrix for polymeric membrane and ternary non-electrolyte solutions]. AB - BACKGROUND: A system of network forms of Kedem-Katchalsky (K-K) equations for ternary non-electrolyte solutions is made of eight matrix equations containing Peusner's coefficients R(ij), L(ij), H(ij), W(ij), K(ij), N(ij), S(ij) or P(ij) (i, j ? {1, 2, 3}). The equations are the result of symmetric or hybrid transformation of the classic form of K-K equations by the use of methods of Peusner's network thermodynamics (PNT). OBJECTIVES: Calculating concentration dependences of the determinant of Peusner's coefficients matrixes R(ij), L(ij), H(ij), W(ij), S(ij), N(ij), K(ij) and P(ij) (i, j ? {1, 2, 3}). MATERIAL AND METHODS: The material used in the experiment was a hemodialysis Nephrophan membrane with specified transport properties (L(p), sigma, Omega) in aqueous glucose and ethanol solution. The method involved equations for determinants of the matrixes coefficients R(ij), L(ij), H(ij), W(ij), S(ij), N(ij), K(ij) or P(ij) (i, j ? {1, 2, 3}). RESULTS: The objective of calculations were dependences of determinants of Peusner's coeffcients matrixes R(ij), L(ij), H(ij), W(ij), S(ij), N(ij), K(ij) or P(ij) (i, j ? {1, 2, 3}) within the conditions of solution homogeneity upon an average concentration of one component of solution in the membrane (C1) with a determined value of the second component (C2). CONCLUSIONS: The method of calculating the determinants of Peusner's coeffcients matrixes R(ij), L(ij), H(ij), W(ij), S(ij), N(ij), K(ij) or P(ij) (i, j ? {1, 2, 3}) is a new tool that may be applicable in studies on membrane transport. Calculations showed that the coefficients are sensitive to concentration and composition of solutions separated by a polymeric membrane. PMID- 25696942 TI - [Concentration dependencies of W(ij) Peusner's coefficient for different composition and concentration of the non-electrolyte ternary solutions]. AB - BACKGROUND: The network forms of Kedem-Katchalsky (K-K) equations for ternary non electrolyte solutions may contain one of the eight Peusner's coefficients: R(ij), L(ij), H(ij), W(ij), N(ij), K(ij), S(ij) or P(ij) (i, J ? {1, 2, 3}). These coefficients form the third degree matrixes ofPeusner's coefficients [R], [L], [H], [W], [N], [K], [S] or [P]. OBJECTIVES: Calculation of dependencies of the Peusner's coefficients W(ij) (i, j ? {1, 2, 3}) and det [W], on the average concentration of one component in the membrane solution (C1) for several different values of the second component set (C2). MATERIAL AND METHODS: Glucose transport in aqueous ethanol solutions through Nephrophan membrane transport with known transport parameters (L(p), sigma, Omega), using the network K-K equations for the ternary non-electrolytes solutions containing Peusner's coefficient W(ij) (i, j ? {1, 2, 3}) were analyzed. RESULTS: Family dependencies of Peusner's coefficients W(ij) (i, j ? {1, 2, 3}) on the average concentration of one component in the membrane solution (C1) for several different values of a second set of component (C2) for the homogeneity of the solutions were calculated. Conclusions. Calculations showed that coefficients W12, W21, W22, W23, W32 and det [W] are sensitive to concentrations (C1) and (C2) of solutions separated by a polymeric membrane. PMID- 25696943 TI - [Problems concerning diseases of internal organs (medico-biological aspect)]. AB - This review considers the views of I.V. Davydovsky expounded in his book The Problems of Causality in Medicine. Etiology (1962). The author was the first to apply the philosophical method to address such fundamental medical concepts as etiology and pathogensis. The most important issues concerning diseases of internal organs are reviewed with special reference to their etiology; an attempt is undertaken to further develop and update them. PMID- 25696944 TI - [The role of cytokines in the development and clinical course of cardiac insufficiency]. AB - The review is focused on the main premises of the theory of progressive cardiac insufficiency based on the notion of immune activation and systemic inflammation as markers of adverse prognosis and high risk of cardiovascular complications. The relationship between blood cytokine level/composition and severity of cardiac insufficiency is illustrated. Classification of cytokines is considered along with possible causes of their increased concentration and involvement in the development and clinical course of this condition. Special attention is given to the studies of methods for the correction of enhanced cytokine levels. The importance of further studies on the influence of cytokines on the clinical course of cardiac insufficiency is emphasized. PMID- 25696945 TI - [Pathology diagnostics by human breath analyze]. AB - Modern medicine experiences deficit of inexpensive rapid screening technologies despite progress in the development of diagnostic methods for various diseases. A promising approach is the analysis of exhaled air known to contain thousands of volatile organic substances whose composition differs considerably in health and disease. We isolated certain compounds that may be used as biomarkers of cardiovascular pathology (nitric oxide, carbon monoxide, pentane, isoprene, acetone). There is a variety of methods for the detection of substances in the exhaled air; such as gas spectrography, mass spectrometry, etc. However, ion mobility spectrometry appears the most suitable technique for the purpose of screening studies due to its high speed and sensitivity, small size of the apparatus, and possibility to measure trace amounts of the substances of interest. Possibilities to diagnose lung cancer based on exhaled air composition are considered. PMID- 25696946 TI - [Anesthetic aspects of the problem of morbid obesity in pregnancy]. AB - The prevalence of morbid obesity has been grown at a very heart rate in developed countries during the last decades. Over-weight pregnant women make up a group of risk of such serious complications as gestational hypertension, preeclampsia, gestational diabetes, increased frequency of Cesarean sections, and uterine inertia. Morbid obesity creates problems in anesthetic support. Obesity is associated with many physiological changes that compromise the adaptive ability in pregnant and delivering women. This review describes clinical and functional peculiarities of pregnancy, labor, and perioperative period in women with morbid obesity. Main physiological changes in these patients are described. Clinical aspects of the problem of practical significance for obstetricians/anesthetists are discussed. PMID- 25696947 TI - [A comprehensive analysis of incidence of myocardial infarction in Vladikavkaz depending on solar and geomagnetic activity]. AB - The data on myocardial infarction morbidity in Vladikavkaz for 2007-2010 were analysed with reference to solar and geomagnetic activity. Time series of morbidity in men and women were constructed and their seasonal constituent was distinguished. It was found that the number of myocardial infarctions increases on day with enhanced geomagnetic activity especially among subjects aged 50-69 years. Regression analysis of the relationship between the number of sunspots and myocardial infarctions yielded the equation of piecewise linear regression showing that 42% of the cases were due to the changes in the number of sunspots. Medium strength negative correlation was found between the number of myocardial infarctions and the recurrence index of Bz-component of the interplanetary magnetic field. It suggests an important role of chaotic dynamics of external factors in the development of myocardial infarction. PMID- 25696948 TI - [Changes in the serum marker of cardiac fibrosis and inflammation associated with atrial fibrillation]. AB - This work was designed to study characteristics of cardiac fibrosis and inflammation associated with idiopathic atrial fibrillation (AF) and AF with concomitant arterial hypertension (AH). The same parameters were investigated in connection with different types of arrhythmia. It is shown that patients with AF have increased levels of serum markers of fibrosis and inflammation (C terminalpropeptide of type I procollagen (PICP) and IL-6); they are especially high in case of combination ofAF and AH. Characteristics of fibrosis are related to the form of AF. PICP levels increase in patients with chronic and recurrent AF. Activity of matrix metalloproteinase-9 (MMP-9) does not depend on the type of AF whereas concentration of tissue metalloproteinase inhibitor-1 (TMPI-1) tends to decrease in case of permanent AF. Patients with recurrent and especially permanent AF have higher IL-6 levels than practically healthy subjects. Permanent AF is associated with a slightly elevated level of tumour necrosis factor-alpha. PMID- 25696949 TI - [24-hr monitoring arterial pressure in outpatients with cardiovascular risk factors in the Far North]. AB - AIM: To study peculiar features of daily AP rhythm and profile in men with cardiovascular risk factors residing in the Far North. MATERIALS AND METHODS: The study included 115 servicemen divided into 3 groups (hypertensive disease (HD), hypertonic type neurocirculatory asthenia (NCA) and risk factor of cardiovascular diseases other than AH). HD was diagnosed based on multiple AP measurements and 24-hr monitoring. RESULTS: HD was associated with elevated mean AP, load indices and AP variability All patients had pathological type of morning dynamics. Normal daily rhythm of systolic AP (SAP) was documented in 66.1% of the patients with HD and in 68% with cardiovascular risk factors without AH. Normal daily rhythm ofdiastolic AP (DAP) was recorded in 63.5% of the patients with HD and in 72% with cardiovascular risk factors without AH. In group 2, normal daily rhythms of SAP and DAP were found in 44 and 56% of the cases respectively. CONCLUSION: Men residing in the Far North under conditions of anomalous photoperiod need medicamentous correction of AP regardless of AH type. Ambulatory BP monitoring should be preferred for the assessment of the efficacy of antihypertensive therapy. PMID- 25696950 TI - [Features hemodynamics and its relationship with some clinical manifestations in women with connective tissue dysplasia]. AB - AIM: To elucidate genetically determined character of cardiovascular pathology with realization of its clinical manifestations at systemic, organ and tissue levels in patients with connective tissue dysplasia (CTD) at obstetric gynecological setting. MATERIALS AND METHODS: This study involved 614 women with classified and non-classified forms of CTD including 268 primigravidas, mean age 24.8 +/- 3.46 yr (group 1) and 346 gynecological patients with genital prolapse, mean age 44.5 +/- 10 yr (group 2). Each group was divided into subgroups 1A and 2A with predominant clinical manifestations on the part of the stromal-muscular component and 1B and 2B with the predominance of the vascular component. The methods used included laboratory analysis, ECG, ultrasound, echocardiographic , X ray, combined urodynamic studies, MGT and laser flowmetry. RESULTS: Prolapse of mitral valve (PMV) was diagnosed in 100 and 88.3% of the patients in groups 1 and 2 respectively with regurgitation in 1-2 valves in 140 (52.1%) and 143 (47.7%) ones, primary varicosis in 41 (15.2%) and 136 (39.5%), mixomatous degeneration in 65 (24.3%) and 107 (30.9%), predisposition to tissue hemorrhage in 37 (13.8%) and 64 (18.5%), vegetovascular dystonia in 50 and 60%. Patients of subgroup 1A with joint hypermobility and PMV exhibited a higher degree of uterine maturity (4.6 +/ 1.75 scores). Rapid labor correlated with apical forms of genital prolapse (subgroups 1A, 2A); in the latter subgroup, they occurred in 83% ofthe patients, grade III rectocele occurred in 62.5%, protrusion and relaxation of pelvic floor in 50%. Pathology of the anorectal segment of pelvic diaphragm was diagnosed in more than 50% of the parous and nulliparous women (subgroups 1A and 2A). End diastolic volume was 102.7 +/- 31.08 and 65.7 +/- 59.48 ml in subgroups 2A and 2B respectively in association with a decrease of left ventricle mass to 135.6 +/- 36.6 and 168.5 +/- 86.97 g Hyperemic bloodflow prevailed in subgroup 1A while microcirculation index increased to 6.6 +/- 1.84, perfusion coefficient to 2.2 +/ 0.91, variation coefficient to 28.9 +/- 5.46, relative HF amplitude to 21.9 +/- 5.1 (control: 18.3 +/- 1.29). CONCLUSION: CTD is always realized at the level of cardiovascular system. Its form and the type of dysregulation of suprasegmental CNS regions are genetically determined and inter-related In combination with minor cardiac abnormalities, they determine the type of hemodynamics including microcirculation and the degree of dysmorphism in the form of disorders in pelvic organs and structures including changes in the stromal-vascular histion level. The type of hemodynamics (microcirculation) determines dysregulatory processes in cells and intercellular matrix with the development of pathomorphological changes in the form of rheologic disturbances, vasculitis, thickening and loosening of basal membrane, smooth cell dystrophy, swelling of collagen fibers, loss of their elasticity, and reduction of the collagenous network. PMID- 25696951 TI - Clinical variants of severe pneumonia. AB - Pneumonia is a most common human disease and a leading cause of death from infectious pathology. The mortality rate amounts to 5.20% despite the improvement of the existing methods of treatment. Over 37,000 patients die from pneumonia each year in Russia. Severe pneumonia is an especially serious challenge. The aim of this work was to study the incidence of severe clinical variants of pneumonia (SP), elucidation of its main phenotypes and predictors of adverse outcome. It included retrospective analysis of 101 cases of SP diagnosed based on generally accepted criteria. The clinical symptoms of SP, its incidence, relationship between SP and sepsis are considered along with predictors of adverse outcome. The main phenotypes of SP are distinguished according the leading resuscitation syndrome (SP with sepsis without multiple organ failure (6.9%) including SP with clinical manifestations of acute respiratory failure/acute respiratory distress syndrome (4.0%), SP with severe sepsis (93.1%) including SP with septic shock (26.7%). Bacteremia was documented in 10.1% of the patients. Estimation of the cases with favourable outcome of SP using APACHE II, MODS-2 and SOFGA integral scales gave values of 12.4, 4.7 and 5.4 respectively. They were increased by a factor of 1.7, (APACHE II) and 1.9 (MODS-2 and SOFA) in the patients who died from pneumonia. These values can be regarded as predictors of adverse outcome of SP. PMID- 25696952 TI - [Peculiarities of clinical manifestations of chronic abdominal ischemia syndrome]. AB - Peculiarities of clinical manifestations of chronic abdominal ischemia syndrome were studied. Clinical diagnostics of this condition encounters difficulties for the lack of pathognomonic symptoms, diversity of symptoms and similarity with other abdominal diseases. The study involving 110 patients with chronic abdominal pain syndrome included assessment of medical histories, duration of the disease, signs of concomitant gastroenetologic pathology (meteorism, colonic dysfunction, reduced body mass, etc.). The data obtained illustrate peculiarities of the clinical picture giving reason to suspect chronic abdominal ischemia syndrome at the early stage of its development. Such features as the absence of treatment effect, increased frequency, duration and severity of abdominal pain, its extension to all parts of the abdomen and association with food intake, colonic dysfunction (meteorism, constipation) and reduced body mass require exclusion of this syndrome in patients with persistent abdominal pain. The data obtained may be used in early diagnostics of chronic abdominal ischemia syndrome and differentiate it from other abdominal diseases. PMID- 25696953 TI - [Caroli's disease: diagnostic problems and possibilities of treatment]. AB - Caroli's disease is a rare congenital condition characterized by segmental non obstructive fibrocystic dilation of intrahepatic bile ducts. Dilated ducts may be infected and contain stones. This review of the modern literature describes few known cases of the disease, analyses its clinical features and results of treatment. The principal diagnostic methods include visualization by ultrasound study, CT, MRT, retrograde and transhepatic cholangiography. Surgical intervention is the method of choice for the treatment of the disease including resection of liver, placement of hepatico-jejunal anastomoses and transplantation. The choice depends on the extent of the lesion and anticipated complications. The authors' observation of the patient with Caroli's disease in a 35 year-old woman is presented. It was successfully treated by left-hand bisegmentectomy even though the disease was diagnosed 14 years after the first symptoms. It is recommended that the disease, even if a rare one, should be included in the algorithm of differential diagnostics ofrecurrent abdominal pain with manifestations of cholestasis or fever of an unknown origin. PMID- 25696954 TI - [Therapeutic strategy for patients with atrial fibrillation--ciliary arrhythmia]. AB - Atrial fibrillation (AF) is the commonest heart arrhythmia with the estimated incidence of 1-2%. It affects over 6 mln persons in Europe, its prevalence is expected to be twice the current level within the next 50 years. AF is known to increase the risk of ischemic stroke by five times and be the cause of each fifth stroke. Ischemic stroke in AF patients as a rule has a fatal outcome and leads to more severe disability than stroke of different nature; also, it recurs more frequently. Modern approaches to the treatment of this pathology by antiarrhythmic medicines, defibrillation, and new antithrombotic agents as recommended by international societies of cardiologies. PMID- 25696955 TI - [Gender-related differences in the efficacy of treatment of hypertensive and coronary heart diseases in aged and elderly patients by angiotensin II receptor blockers and angiotensin converting enzyme inhibitors]. AB - The aim of the work was to study hemodynamics and clinical symptoms before and after treatment of arterial hypertension (AH) and coronary heart disease (CHD) using angiotensin II receptor blockers and angiotensin converting enzyme inhibitors depending on the patients' sex. A total of 150 patients with AH and CHD were examined (80 women and 70 men, mean age 70 a 66 yr respectively). Eighty two of them (group 1) were given receptor blockers (losap, losartan, lorista, bloctran) and 63 (group 2) inhibitors (prestarium, noliprel). Effectiveness of treatment was evaluated from the results of 24-hr AP monitoring, daily self control of AP (as described by Korotkov) and responds to questionnaires. The effectiveness of receptor blockers showed marked gender-specific differences. Specifically, they reduced systolic and diastolic pressure and improved well being in women. In men, this treatment decreased the frequency of angina attacks, headache, and heart throbs. Enzyme inhibitors caused a greater reduction of diastolic AP in women but less pronounced gender-related changes in dynamics of main AP and ECG parameters than receptor blockers. PMID- 25696956 TI - [A case of favourable outcome of the treatment of extremely severe acute poisoning with methanol]. AB - A case of favourable outcome of the treatment of extremely severe acute poisoning after prolonged exposure to lethal doses of methanol is reported. The complex treatment included urgent and effective elimination of the poison (multiple gastric lavage, hemodialysis), antidote therapy (administration of ethanol), correction of decompensated metabolic acidosis (alkali therapy and infusion therapy with reamberin). These measures had beneficial effect on the clinical course of poisoning and ensured its favourable outcome. PMID- 25696957 TI - [Medical College (on the occasion of the 250th anniversary of its foundation)]. PMID- 25696958 TI - [Intensity of intravascular microcoagulation in chronic obstructive pulmonary disease with atherotrombosis and thrombophilia]. AB - The growing occurrence of thrombophilic conditions in recent years, the discovery of new forms of thrombophilia, the involvement of intravascular microcoagulation in the development of many diseases make their study of primary importance especially in patients with chronic obstructive pulmonary disease and atherothrombosis. Such investigations would facilitate a deeper understanding of the detailed mechanisms of thrombosis in these patients and thereby contribute to the optimization of their treatment and prevention. PMID- 25696959 TI - [Metabolic syndrome and melatonin]. AB - Metabolic syndrome (MS) is characterized by the following symptoms: obesity, AH, dyslipidemia, insulin resistance. Pathophysiologically, MS is underlain by disorders of many biochemical and physiological processes, such as elevated levels of low density lipoproteins, hyperstimulation of pancreatic b-cells, increased insulin secretion, substitution of lipid metabolism for carbohydrate one, overgrowth of adipose tissue, excess production of adiponectin, leptin and other signal molecules and a rise in their local intravascular concentration, weight gain. Endogenous and exogenous melatonin inhibits these pathophysiological mechanisms, normalizes metabolism, equilibrates insulin secretion, prevents pancreatic hyperfunction, phosphorylates insulin receptors, inactivates active oxygen and nitrogen species including those produced in LDLP metabolism. Melatonin has specific MT1 and MT2 receptors localized in all body cells. Due to this, it exerts combined preventive action in patients with MS. Recently, melatonin has been reported to have therapeutic effect in MS; it may be recommended to treat this condition. PMID- 25696960 TI - [The role of necrosis and inflammation markers in prognostication of acute coronary heart disease]. AB - With the incessant growth of cardiovascular mortality, mainly due to myocardial infarction makes prognostication of acute coronary syndrome a principal goal of clinical practice. Biochemical markers (creatine phosphokinase-MB and troponins) are extensively used for diagnostics and prediction of acute coronary heart syndrome (ACS). However, drawbacks of necrosis markers necessitate the search for new ones identifiable at early stages of atherosclerotic plaque instability. Lately atherosclerosis has been considered as an immuno-inflammatory reaction involving cytokines, chemokines, C-reactive protein, natriuretic peptide, and tumor necrosis factor-alpha. Their prognostic value has been demonstrated in many clinical studies, but these data are contradictory and need to be confirmed. PMID- 25696961 TI - [Assessment of the microcirculation system by laser Doppler flowmetry]. AB - Laser Doppler flowmetry (LDF) is extensively used to study microcirculatory disorders, a main problem facing modern medicine. A wealth of data have been obtained on microcirculation in diabetes mellitus, HD, venous insufficiency and other diseases. This review focuses on basic principles of the method for the assessment of microcirculatory disorders by LDF using the domestically produced equipment. The main elements of the microcirculation system, capillary hemodynamics, and mechanisms of its regulation are described. The main elements and terms of LDF are considered, such as microcirculation index, flux, and variation coefficient along with elements of analysis of the amplitude-frequency fluctuation spectrum and different types of tissue blood flow. Active factors of microcirculation control modulate the blood flow from the vascular wall; their action is mediated through its muscular component. Passive factors cause variations of blood flow outside the microcirculation system; they are the pulsed wave originating from arteries and the sucking action of the venous respiratory pump. Under normal conditions, the vasomotor rhythm driven by the pacemaker in the precapillary segment of the microcirculation bed predominates. The compensatory role of other regulatory mechanisms increases with decreasing contribution of vasomotion to the active modulation of microcirculation hemodynamics. A change in the low to high frequency rhythm ratio reflects the microcirculation index (MI). In case of well-balanced active vasomotor and passive compensatory modulations of tissue blood flow observed in normoemic type of microcirculation, MI amounts to 2.2 +/- 0.05. Enhancement of high-frequency and pulsed fluctuation spectra results in a decrease of MI to 1.73 +/- 0.04 (hyperemic type) and 1.86 +/- 0.053 (hypoemic type). PMID- 25696962 TI - [Ulcerative colitis and Crohn's disease. Part 1. Definition, terminology, prevalence, etiology and patogenesis, clinical features, complications, classification]. AB - Definitions of ulcerative colitis (UC) and Crohn's disease (CD) are given, related terminological problems are discussed, the prevalence of UC and CD in the population is considered along with their etiology pathogenesis, clinical symptoms, complications and extraintestinal (systemic) lesions. Classification and diagnostics of UC and CD are discussed with special reference to current international recommendations on their diagnostics and differential treatment. PMID- 25696963 TI - [Serum markers of inflammation and lipid-releasing ability of leukocytes in patients with arterial hypertension and angina of effort]. AB - Detection of cardiovascular risk factors remains a challenging problem. The inflammatory mechanisms behind atherosclerosis imply active involvement of neutrophils and realization of lipid-releasing ability of leukocytes (LRAL) mediated through the synthesis of proatherogenic proteins with the formation of protein-lipid complexes accumulated around atherosclerotic lesions. Studies of compromised protein-synthesizing function and mechanisms regulating LRAL are currently underway. The aim of the present work was to investigate serum markers of inflammation and LRAL in arterial hypertension (AH) without coronary heart disease (CHD) or AH + angina of effort. One group comprised 20 patients with AH without CHD the other included 20 patients with AH and CHD. Control group consisted of 18 healthy subjects. LRAL was measured in vitro in addition to serum IL-6, IL-8, CRP, and TNF-alpha. Effect of TNF-alpha on LRAL was evaluated in vitro in CHD patients. It was shown that mean LRAL in healthy subjects and patients with AH without CHD were not significantly different whereas IL-8 and CRP levels were markedly elevated in AH patients. Patients with AH and CHD had maximum LRAL and IL-6, IL-8, CRP, TNF-alpha levels. The study showed the possibility of increase in LRAL under effect of proinflammatory cytokines. LRFAL and inflammatory mechanisms contribute to the development of CHD and can be used for diagnostics of CHD in AH patients. PMID- 25696964 TI - [Simultaneous quantification of soluble fibrin and D-dimer in blood plasma for the assessment of the threat of thrombosis]. AB - Soluble fibrin and D-dimer are the most specific markers of blood coagulation cascade and the threat of thrombosis. Two immunoassay test systems were designed using the fibrin-specific and D-dimer-specific monoclonal antibodies. The clinical trials of the test systems were carried out in Ukraine. The high informative value of soluble fibrin quantification as a prognostic indicator of the threat of thrombosis associated with hip replacement and endoprosthetics of the abdominal aorta was shown. Independent D-dimer quantification is less informative. Simultaneous quantification of soluble fibrin and D-dimer before operation and at different time intervals after it is required for the prediction of postoperative thrombotic complications and monitoring the efficiency of antithrombotic therapy. Only in this case it is possible to get information about the state of the balance between blood coagulation and fibrinolytic systems, and determine the degree of the threat of thrombosis. PMID- 25696965 TI - [Effect of dyssynchrony on myocardial remodeling in patients with chronic heart failure associated with type 2 diabetes mellitus]. AB - The study included patients with chronic heart failure (CHF) associated with type 2 diabetes mellitus (DM). Dyssynchrony (DS) is a frequent cause of unfavourable prognosis in CHF patients. The relationship between DS and left ventricle (LV) geometry in patients with CHF and DM is virtually unexplored. AIM: To estimate effects of DS and left bundle branch block (LBBB) on LV geometry in patients with CHF and DM. MATERIALS AND METHODS: The study included 61 patients with CHF of ischemic etiology (NYHA II-IV FC) divided between 4 groups. Group 1: patients with CHF without type 2 DM, group 2: patients with CHF and type 2 DM, group 3: patients with CHF, type 2 DM, and DS, group 4: patients with CHF, type 2 DM, DS, and LBBB. Interventricular DS was determined by standard Doppler EchoCG in the pulsed-wave regime. RESULTS AND DISCUSSION: Remodeling in patients of group 1 and 2 was presented mainly by concentric heart hypertrophy (73.3% and 57.89% respectively, p < 0.05) compared with 20 and 14.3% in groups 3 and 4 (p < 0.05). Concentric remodeling occurred in 33.3 and 28.5% of the patients in groups 3 and 4 respectively. Eccentric hypertrophy was documented in all groups except group 1; it was more frequent in the presence of DS (46.6 and 57.14% in groups 3 and 4 respectively). Normal LV geometry and concentric hypertrophy was characteristic of patients with NYHA II FC CHF and eccentric hypertrophy in those with NYHA ILL IV FC CHF. CONCLUSION: Myocardial remodeling associated with DM2 and DS is characterized by formation of different types of myocardial geometry. Structural and functional changes in LV myocardium represented by eccentric hypertrophy are especially well pronounced in patients with CHF, type 2 DM, DS, and LBBB. PMID- 25696966 TI - [Clinical associations of genetic variants of interleukins with the formation of chronic lympholeukemia in elderly patients]. AB - We investigated association of polymorphisms of interleukin IA (IL-1A), interleukin 4 (IL-4), interleukin 5 (IL-5), interleukin-8 (1L-8) genes in elderly patients with predisposition to the development of chronic lym,nphocytic leukemia (CLL). Risk factor of chronic lymphocytic leukemia is a genetic variant -590T IL 4 (OR = 1,45) and protective factor -590S IL-4 (OR = 0,68). Genetic markers -590T IL-4 (OR = 2,46), -590TT IL-4 (OR = 6,65) and mix-590TT genotype of IL-4 allele 703S-IL-5 (OR = 6.70) were associated with stage 0-1 chronic lymphocytic leukemia whereas genetic markers -889T IL-1A (OR = 1,51), -703T IL-5 (OR = 1,52) and a combination of genotype -703ST IL-5 allele-251A IL-8 (OR = 2.85) were related to the development of stage II of the disease. Risk factor for the formation of II IV stages of chronic lymphocytic leukemia is a genetic variant -703T IL-5 (OR = 1,95). PMID- 25696967 TI - [Treatment of hepatic insufficiency in benign mechanical jaundice]. AB - The aim of this work was to estimate hepatic dysfunction and improve treatment of benign mechanical jaundice using an injection hepatoprotector. The study included 124 patients of whom 74 were given remaxol. 50 control subjects received basal therapy. The patients were randomized by the random sampling method. Severity of cholestasis was evaluated from the total and fractional bilirubin content and gamma-glutamyl transpeptidase (GGT) level; AST and ALT activities were used to detect cytolysis. Liver synthetic function was estimated from prothrombin index (PTI) and coagulation function from fibrinogen level, PTI and APTT. Endogenous intoxication during biliary tract decompression was assessed by calculating the leukocyte intoxication index from the Kalf-Kalif formula. It was shown that remaxol suppresses cytolysis, reduces total and fractional bilirubin levels, improves bilirubin excretion in bile and decreases activity of hepatocyte excretory enzymes. PMID- 25696968 TI - [Challenges and advances in diagnostics, prevention and treatment of hepatorenal syndrome]. AB - Hepatorenal syndrome (HRS) is an exclusion diagnosis in patients with decompensated liver cirrhosis. True hepatic functional insufficiency is sometimes unobvious. Differential diagnostics of HRS encounters difficulty despite new diagnostic criteria. HRS can be prevented by the correct treatment of portal hypertension and hepatic insufficiency under careful monitoring. Effective conservative therapy may significantly change the short-term prognosis and facilitate remission in selected patients. Terlipressin is the agent of choice for HRS therapy aimed at the promotion of intrahospital survival for the subsequent referral of the patient to liver transplantation. PMID- 25696969 TI - [Chronic autoimmune thyroiditis as a predictor and precursor of metaplasia]. AB - In recent years an increase in the incidence of chronic autoimmune thyroiditis (CAT) and its transformation into thyroid cancer (TC) and thyroid lymphoma (TL) have been recorded. The article discusses etiologic and pathogenetic relationship between CAT, TC, TL, PDS and MEN syndromes. Clinical, laboratory, intrascopic and morphological diagnostics of CAT and comorbidities is considered. The algorithm for the choice of the treatment is presented. PMID- 25696970 TI - [Hemorrhagic fever with abdominal syndrome disguised as acute appendicitis]. AB - A case of hemorrhagic fever with renal and abdominal syndromes in the form of appendicitis is reported. PMID- 25696971 TI - [On the scientific results of the XX century: contribution of Russian researchers to the solution of the problem of atherosclerosis]. PMID- 25696972 TI - [Non-canonical activities of the proteasomes]. AB - 26S proteasome is a highly specialized evolutionarily conserved ribonucleoprotein machine to instantly restore order in the intracellular proteome. It is composed of the 20S core particle and attached there to regulatory complexes. In addition to a comprehensively studied ubiquitin-proteasome pathway of protein degradation, proteasomes are involved (directly or indirectly) in most stages of the regulation of gene expression (at the levels of transcription, splicing, mRNA stability control, etc.). In the present review an attempt to systematize the recent literature on proteasomes' role in the regulation of transcription at all stages, including the modulation of the activity and stability of transcription factors, chromatin remodulation, elongation and termination of RNA synthesis is made. In addition, very interesting but controversial feature of the proteasome: their ability to bind and hydrolyze certain types of RNA, is observed. Obviously, universal role of proteasomes in gene regulation is determined by complicated composition of these protein complexes possessing a unique set of different enzymatic activities: ATPase/helicase, proteolytic and ribonuclease, which, depending on the case, can be used together or separately. PMID- 25696973 TI - [Analysis of irradiation-induced repair foci in mouse embryonic stem cells]. AB - Somatic cells in response to DNA damage activate two important protective mechanisms: G1 checkpoint control and a program for recognizing and repairing DNA defects (DDR signaling). Both mechanisms are triggered by the activation of common sensor kinases ATM and ATR, which in turn phosphorylate downstream targets. Mouse embryonic stem cells (mESCs) lack of G1 checkpoint and undergo only temporary G2 delay after DNA damage. We have analyzed the ability of mESCs to detect DNA damage and to form repair foci after irradiation. We showed irradiation-induced activation of ATM and ATR is followed by formation of gammaH2AX foci co-localized with DNA repair proteins Rad51, DNA-PK and adapter protein 53BP1. Furthermore, we checked contribution of ATM/Chk2 and ATR/Chk1 cascades to cell cycle control and viability of mESCs after DNA damage. Inhibition of ATR/Chk1 cascade leads to accumulation of G1 phase cells, whereas perturbation of ATM/Chk2 activity causes no such effect. Moreover, inhibition of ATR/Chk1 activity, but not ATM/Chk2, substantially augments the killing effect of ionizing radiation on mESCs. In summary, our results indicate that mESCs are capable of recognizing DNA damage and forming repair foci, but their DDR signaling it seems to be distinct from somatic cells and tightly connected with maintaining of pluripotency and self-renewal. PMID- 25696974 TI - [Activation of adenylyl cyclase in rats testes and ovaries using thienopyrimidine derivatives]. AB - Signaling systems regulated by luteinizing hormone (LH) and human chorionic gonadotropin (hCG) and having LH receptor as a sensor component play an important role in the functioning of the reproductive tissues. The use of LH and hCG in medicine for the treatment of diseases of the reproductive system and in auxiliary reproductive technologies is limited by their high cost, the need to use parenteral administration, and side effects. In recent years there has been the development of low molecular weight agonists of LH receptor that are devoid of these disadvantages and can be administered orally. The most effective among them are thienopyrimidine derivatives, in particular compound Org 43553. The purpose of this study was to investigate the influence of newly synthesized analogs of Org 43553, 5-amino-N-(tert-butyl)-4-(3-(isonicotinamide)phenyl)-2 (methylthio)thieno[2,3-d]pyrimidine-6-carboxamide (compound 1) and 5-amino-N (tert-butyl)-2-(methylthio)-4--(3-(thiophene-3-carboxamido)phenyl)thieno[2,3 d]pyrimidine-6-carboxamide (compound 2), on the basal and LH-stimulated adenylyl cyclase (AC) activity in plasma membranes fractions isolated from rat testes and ovaries. Compounds 1 and 2 have been shown to stimulated the basal AC activity in membranes isolated from the testes and ovaries in a dose dependent manner, and compound 2 was more effective in comparison with compound 1. EC50 values for the effects of the compounds 1 and 2 on the AC activity were 1.05-1.12 and 0.28-0.37 MUM, respectively. Stimulating effect of hCG on the AC activity retained in the presence of the thienopyrimidine derivatives, and at low, non-saturating, concentrations of the hormone the additivity of the effects ofhCG and compounds 1 and 2 on AC activity was observed. This indicates that the thienopyrimidine derivatives interact with allosteric site localized in the transmembrane channel of LH receptor, and do not overlap with the binding site of gonadotropins, located in the N-terminal ectodomain. Effect of compounds 1 and 2 was tissue specific, and was not found in tissues where no LH receptors. Our data indicate that compounds 1 and 2 may be a prototype for drugs that regulate the function of male and female reproductive systems. PMID- 25696975 TI - [The effect of cyclooxygenase and lipoxygenase inhibitors on Ca(2+)-responses induced by glutoxim and molixan in macrophages]. AB - Glutoxim and molixan belong to a new generation of disulfide-containing drugs with immunomodulatory, hepatoprotective and hemopoetic effect. Using Fura-2AM microfluorimetry, the possible involvement of the cyclooxygenase and lipoxygenase pathways of arachidonic acid oxidation in the effect of glutoxim and molixan on the intracellular Ca2+ concentration in rat peritoneal macrophages has been investigated. We have shown for the first time that preincubation of the cells with the cyclooxygenase inhibitors, indomethacin and aspirin, or lipoxygenase inhibitors, nordihydroguaiaretic acid, caffeic acid and baicalein, almost completely prevents the intracellular Ca2+ concentration increase induced by glutoxim or molixan. The obtained data indicate the involvement of products and/or enzymes of the arachidonic acid cyclooxygenase and lipoxygenase metabolism pathways in the effect of glutoxim and molixan on the processes of Ca2+ signaling in macrophages. PMID- 25696976 TI - [The perichromatin compartment of the cell nucleus]. AB - In this review, the data on the structure and composition of the perichromatin compartment, a special border area between the condensed chromatin and the interchromatin space of the cell nucleus, are discussed in the light of the concept of nuclear functions in complex nuclear architectonics. Morphological features, molecular composition and functions of main extrachromosomal structures of the perichromatin compartment, perichromatin fibrils (PFs) and perichromatin granules (PGs) including nuclear stress-bodies (nSBs) that are derivates of the PGs under heat shock, are presented. A special attention was paid to the features of the molecular compositions of PFs and PGs in different cell types and at different physiological conditions. PMID- 25696977 TI - [Effects of biogenic and abiogenic disulphides upon endothelial cells in culture: comparison of three methods of viability assessment]. AB - Effects of biogenic and abiogenic disulphides on viability of human umbilical vein endothelial cells in culture has been investigated using three methods: the neutral red uptake assay, quantification of intracellular ATP, and modifications of Mosmann method, the essence of which is the reduction of tetrazolium salts, MTT and MTS, by cells. 2,2'-dithio-bis(N,N-diethyl)ethanamine (DS) was used as an abiogenic disulphide. As for biogenic disulphides, we used GSSG and garlic oil (GO), the principal component of which is diallyl disulphide (DADS). It has been found that DS and GO have a similar cytotoxic effect upon the endothelial cells (EC50 - 0.6 mM). GSSG in concentrations up to 1 mM did not effect the viability of endothelial cells. It has been demonstrated for the first time that DS and GO can serve as mediators of plasma membrane oxidoreductase activity, tetrazolium salts being as the substrate; this may cause false-negative effect. Thus, the Mosmann method has serious limitations when testing the cytotoxicity of disulphides, though can be used in studying the mechanism of action of disulphides. PMID- 25696978 TI - [Changes in heat shock protein synthesis and thermotolerance of Arabidopsis thaliana seedlings as a result of inhibition of Hsp90 by geldanamycin]. AB - The influence of geldanamycin (GA), which is a specific inhibitor of heat shock protein Hsp90 activities, on synthesis of Hsp70 and Hsp90 and thermotolerance of Arabidopsis thaliana seedlings has been studied. Incubation of seedlings with GA was shown to induce synthesis of these stress proteins under normal conditions. Treatment of seeds with the Hsp90 inhibitor resulted in the elevated constitutive levels of Hsp70 and Hsp90 in seedlings as well as increased induction of their synthesis under heat shock, at that the effect of GA increased with its concentration. These up-regulation of Hsp promoted thermotolerance of seedlings. The obtained results are considered as evidence for autoregulation of heat shock protein synthesis and regulation of plant tolerance by Hsp90. PMID- 25696979 TI - [Extracellular proteasomes purification methods and the evaluation of proteasomal peptidase activities]. AB - In this paper, we present a comparative analysis of different methods of purification of proteasomes from the culture medium in which proerithroleukemia human K562 cells were grown. The results obtained allowed us to purify proteasomes from samples of conditioned cell culture medium and control the quality of the proteasome preparations at all stages of their separation. Extracellular proteasomes purified via different approaches possess all the three types of peptidase activity described for intracellular counterparts. PMID- 25696980 TI - [Antibodies to DNA stimulates death of mononuclear cells of healthy persons in vitro]. AB - We have shown that polyclonal antibody IgG to native DNA leads to increased levels of apoptosis of moonuclear cells of healthy persons in vitro. Possible biological role of antibodies to DNA is discussed. PMID- 25696981 TI - [Fatty acid profile of Pseudomonas aurantiaca DNA-bound lipids according to ESI LC-MS mass-spectrometry]. AB - Approach to the study of prokaryotic chromatin lipidome has been realized based on analysis of fatty acid profile of DNA-bound lipids using electrospray ionization mass spectrometry ESI-LC-MS. By this method, we found 16 : 0 and 18 : 1 fatty acids, which are contained in the first fraction (weakly bound to DNA), and 14 : 0, 16 : 1 and 18 : 2 fatty acids, which are contained in the second fraction (strongly bound to DNA). PMID- 25696982 TI - [3-Hydroxy-1,5-diaryl-4-pivaloyl-2,5-dihydro-2-pyrrolones induce the mitotic exit failure and cell death in tumor cells in vitro]. AB - Some compound refering to the 3-hydroxy-1,5-diaryl-4-pivaloyl-2,5-dihydro-2 pyrrolones have been found to cause an increase in the number of mitotic cells and their subsequent death in vitro. This increased in the number of mitotic cells was not associated with increased cellular proliferative activity and was likely due to mitotic exit failure. Of note, the effect was more pronounced in the tumor cells when compared to human fibroblasts. Further studies are needed to investigate the molecular mechanisms of action of the compounds belonging to the class of 3-hydroxy-1,5-diaryl-4-pivaloyl-2,5-dihydro-2-pyrrolones. PMID- 25696983 TI - [Characteristic of circulating immune complexes in the blood of children with asthma]. AB - Circulating immune complexes (CIC), which are heterogeneous in size and composition population of antibodies and antigens, are critical mediators of the immune system. Precipitation of the CIC on the vascular wall and basal cell membranes causes a variety of biological effects: activation of the complement system in accordance with the classical pathway, activation of macrophages initiating the development of a local inflammatory process involving mast cells and neutrophils. In the present study, we have examined the content and physical characteristics of the CIC in the serum of children with atopic asthma and healthy individuals. We have found that the concentration of CIC in patients is 2 fold higher than in control group. The presence of the most pathogenic medium sized complexes was determined in 9% of healthy children and 85.6% of children with asthma. PMID- 25696984 TI - [Metabolic profiling for characteristics of Trichoderma from buried soils]. AB - Previously, 135 strains of Trichoderma isolated from buried soils of Tatarstan have been identified as T. asperellum, T. viride, T. atroviride, T. harzianum, T. hamatum, T. citrinoviride and T. longibrachiatum. At this stage, the biochemical analysis of the strains was carried out using the Biolog system, which being a simple screening test enables rapid preparation of strains based on 95 substrates. We have revealed that each species has only a specific substrate utilisation profile. Biochemical analysis provides a large amount of information that can then be used for optimization of biotechnological processes, in particular, the selection of effective nutrient media. PMID- 25696985 TI - [Anticancer properties of Trichoderma asperellum 302 from buried soils]. AB - Melanoma is one of the most malignant tumors, which leaves no chance of survival in the case of the "bang". There are various ways to treat tumors, however, recently in the field of cancer research, there are studies in which fungal metabolites have been used as antitumor agents. In this study we examined the effect of the culture fluid of the fungus Trichoderma asperellum 302 on the growth and development of melanoma B 16. We have shown that these culture fluid has anticancer properties, causing destruction of tumor tissue. Obtained data open new possibilities and prospects for the use of active substances derived from fungi in the complex therapy of cancer. PMID- 25696986 TI - [Structure of amyloid-beta peptides in a complex with model membranes]. AB - Structures of amyloid-beta peptides Abeta1-40, Abeta10-35, Abeta13-23 and Abeta16 22 in a complex with model membranes in solution were obtained on the analysis of NMR experimental data. It has been established that the process of peptide micelle complex formation occurs through the amino acid residues L17, F19, F20 and G29-M35. PMID- 25696987 TI - [Human and animal cells adhesion on the modified glass]. AB - 2D matrix for cells cultivation has been created using ionic plasma processing of silicate glass. We have shown that the CD-1 mouse hepatocytes are adsorbed on the modified and the control glass after 24 h cultivation. Number of these cells on the modified glass was 2.8-0.2 more as compared with that in control on a smooth glass. Human fibroblasts adsorbed on a modofied glass matrix had normal configuration and their number was 1.5 +/- 0.5 times greater that the number of cells in the control of smooth glass matrix. PMID- 25696988 TI - [Dexamethasone affect on the expression of bcl-2 and mTOR genes in T-lymphocytes from healthy donors]. AB - Synthetic glucocorticoids are able to activate apoptosis in the cells by regulating the transcription of the respective genes. Effect of dexamethasone on apoptosis is an established fact. However, its influence on another program of cell death autophagy, is currently unproven. Therefore, in this paper we have analyzed the influence of dexamethasone on the expression of bcl-2 and mTOR genes in T-lymphocytes from healthy donors. The results showed that dexamethasone reduced the expression of bcl-2 and mTOR genes. However, the nature of the effect of dexamethasone on mTOR and bcl-2 expression was different: the expression of bcl-2 gene in the long-term cultivation was maintained at the same reduced level, while the expression of mTOR was first reduced and then increased. PMID- 25696989 TI - [Polymorphism of the CETP gene promoter region and its influence on protein activity in coronary heart disease]. AB - The paper shows the lack of association of two polymorphic loci localized in the promoter region of the gene CETP (rs1800775 and rs4783961) with the risk of coronary heart disease in the population of the Republic of Tatarstan. Also, there are no differences in the activity of the enzyme among the carriers of different genotypes. PMID- 25696990 TI - [NESPRINS--nuclear envelope proteins ensuring integrity]. AB - This review describes the nesprins (nuclear envelope spectrin-repeat proteins), which are recently discovered family of nuclear envelope proteins. These proteins play an important role in maintaining the cellular architecture and establish the link between the nucleus and other sub-cellular compartments. Many tissue specific diseases including lipodystrophies, hearing loss, cardiac and skeletal myopathies are associated with nesprins mutations. These proteins comprise of multiple tissue specific isoforms which contain spectrin repeats providing interaction of nesprins with other nuclear membrane proteins, cytoskeleton and intranuclear matrix. We summarize recent findings and suggestions about nesprins structural organization and function inside the cell. Human diseases caused by abnormal nesprins expression are also described. PMID- 25696991 TI - [Role of microparticles in intercellular communication]. AB - Adaptive reactions involving different body systems are essential for human living activity. These adaptive reactions are based both on contact cell interactions and distant cell-to-cell transfer of secreted molecules. Transfer of bioactive substances is realized both on system and local levels. Currently, there is lack of information about mechanisms of transport in the intercellular space. Secretion of biologically active molecules within microparticles is considered to be one of the possible modes of signal transduction. Microparticles are microvesicles generated on the cell membrane surface. They may contain molecules derived from membrane, cytoplasm and nucleus. Blood plasma microparticles are established to be involved in blood coagulation, inflammation and immune response. In this review we summarize current concepts of microparticles as signal carriers participating in intercellular communication. PMID- 25696992 TI - [Cytological analysis of the reaction of the nucleolar RNA and RNA-binding proteins to oxidative stress in HeLa cells]. AB - The organization and functional activity of the nucleoli of mammalian cells can be modified in response to various stress factors. However, data on the reaction of nucleoli to oxidative stress remain limited. In this paper, we have studied the localization of nucleolar RNAs and two RNA-binding proteins--fibrillarin, a pre-rRNA processing factor, and nucleophosmin/B23, a pre-ribosome assembly factor, in HeLa cells exposed to 1 mM H2O2 up to four hours. We have shown that under the conditions used H2O2 does not induce death, but inhibits rDNA transcription, reduces the total RNA content in the cells and the amount of 18S rRNA in the nucleoli, and causes relocalization of fibrillarin and nucleophosmin/B23 to the nucleoplasm. To date, similar changes in the localization of fibrillarin were described in mammalian cells only after HgCl2 treatment. Redistribution of nucleophosmin/B23 observed in H2O2-treated cells occurred in mammalian cells under inhibition of rDNA transcription and early rRNA processing. Overall, this study shows the high sensitivity of the nucleoli of HeLa cells to acute oxidative stress, which is clearly evident on the cytological level. PMID- 25696993 TI - [The influence of testosterone and beta-estradiol on T-lymphocytes activation associated with IL-2 production and expression of CD25 (IL-2Ralpha) molecules]. AB - We have shown that testosterone and beta-estradiol in vitro have effects on naive (CD45RA+) and priming (CD45RO+) T-lymphocytes, which associated with the production of IL-2 and CD25/IL-2Ralpha expression. Testosterone can inhibit naive and priming T-cell function activity in our study. Moreover it was shown that naive lymphocytes are more sensitive to testosterone than primed. We have found dose dependent suppressive beta-estradiol effect on IL-2 production by activated CD45RA+ and CD45RO+ lymphocytes which leads to uniform decreasing CD25-positive T cells number. PMID- 25696994 TI - [Aberrant expression of sox2 gene in malignant gliomas]. AB - Both genetic and epigenetic changes underlite the mechanisms of tumor initiation and progression. In the present study we analyze sox2 gene expression and its epigenetic regulation in primary cultures of malignant gliomas. The sox2 expression was detected in the vast majority (74%) of the investigated gliomas and absent in morphologically normal brain tissue. This indicates the process of glioma malignant transformation. We have also shown that the association of different areas of the sox2 gene with important epigenetic markers, posttranslational modifications of H3 histone H3K4ac and H3K9met3, does not correlate with the sox2 expression. However, this may indicate the stochastic nature of the regulation of sox2 gene expression in malignant gliomas. PMID- 25696995 TI - [Modification of silicon nanoparticles with silver or gold attenuates its biocompatibility in vitro]. AB - The effects of crystalline silicon nanoparticles covered with gold or silver on the viability and state of organelles of cultured human peripheral blood mononuclear cells have been investigated. Exposure to nanosized Si, Si/Ag, Si/Au provoked an increase in the leved of reactive oxygen species in the cells, but did not cause significant reduction in cell viability. Si/Au nanoparticles reduced activity of lysosomes and mitochondria, Si/Ag--only mitochondria. We have concluded that the surface modification by gold or silver may reduce the biocom atibility of the crystalline silicon nanoparticles. PMID- 25696996 TI - [Effect of plant hormones on the components of secretory pathway in human normal and tumor cells]. AB - Plant hormones play a key role in plant growth and differentiation. Many hormones are known as potential antitumor agents, yet others appear to affect the secretory activity and are produced by mammalian cells as pro-inflammatory cytokines. The goal of this research was to study the effect of abscisic and gibberellic acids on the secretory system of human cultured epidermoid carcinoma cells A431 and keratinocytes HaCat. Immunocytochemical and morphometric analysis demonstrated that subtoxic concentration of plant hormones induced the broadening of the ER network and increased the size of Golgi complex. Electron microscopy studies confirmed the hypertrophic changes of the Golgi apparatus, specifically, the swelling of cisternae in the trans-compartment of dictyosomes after exposure to abscisic acid, and swelling of cis- and trans-compartment of dictyosomes after exposure to abscisic acid, and swelling of cis- and trans-compartments of dictyosomes after exposure to gibberellic acid. Using of Click-iT technique allowed to detect the elevation of the total protein synthesis only in A431 cells exposed to abscisic acid. Cumulative data suggests that, under these conditions, the hypertrophy of Golgi apparatus may reflect the enhanced secretory activity of cells. In other experiments, the hypertrophy of Golgi is not related to increased protein synthesis and therefore may suggest the stress-related changes of ER and Golgi apparatus. Our results demonstrate that morphologically similar reaction of cellular organelles, such as hypertrophy of Golgi apparatus, is the result of different functional activities, and that molecular mechanisms underlying the changes induced in cells need further investigations. PMID- 25696997 TI - [Peptide 612-627 of thyrotropin receptor and its modified derivatives as the regulators of adenylyl cyclase in the rat thyroid gland]. AB - The regulation of the specific activity of the thyroid gland is carried by thyroid-stimulating hormone (TSH) through TSH receptor (TSHR). This receptor is coupled to different types of G-proteins, including the G(s)-proteins, through which TSH stimulates the enzyme adenylyl cyclase (AC). As the application of TSH in medicine is limited, the development of selective regulators of TSHR with agonistic and antagonistic activity is carried out. One of the approaches to their creation is to develop the peptides corresponding to functionally important regions of TSHR which are located in its intracellular loops (ICL) and are involved in the binding and activation of G-proteins. We have synthesized peptide corresponding to the C-terminal region 612-627 of the third ICL of TSHR and its derivatives modified by palmitic acid residue (at the N- or the C-terminus) or by polylysine dendrimer (at the N-terminus), and studied their effect on the basal and TSH-stimulated AC activity in the membrane fraction isolated from the rat thyroid. The most active was peptide 612-627-K(Pal)A modified by palmitate at the C-terminus, where in TSHR the hydrophobic transmembrane region is located. At the micromolar concentrations the peptide increased AC activity and reduced the AC stimulating effect of TSH. The action of the 612-627-K(Pal)A has been directed onto TSHR homologous to it, as indicated by the following facts: 1) the inhibition of G(s)-protein, the downstream component of AC system, by treating the membranes with cholera toxin led to the blocking of peptide AC effect, 2) this effect was not detected in the tissues where no TSHR, 3) the peptide did not significantly affect the AC stimulating effects of hormones acting via other receptors. The unmodified peptide and the peptide with N-terminal dendrimer are far behind the 612-627-K(Pal)A in their ability to activate AC in the thyroid, while the peptide modified by palmitate at the N-terminus was inactive. At the same time, the peptide modified by dendrimer was comparable to the 612-627 K(Pal)A in the ability to inhibit the AC effect of TSH, but, although to a lesser extent that it decreased the AC effects of other hormones, demonstrating the low receptor specificity. Thus, these data point to the high efficiency of peptide 612-627-K(Pal)A, as a regulator of TSHR, and the prospects of creating the drugs based on it to control the thyroid functions in pathology. PMID- 25696998 TI - [Stress proteins in the cells of Porphyra purpurea (Rhodophyta) thallus]. AB - Heat shock proteins have been revealed for the first time by the methods of Western blotting using alkaline phosphatase and ECL in the cells of Porphyra purpurea from Kattegat area of the Baltic Sea in normal and experimental stress conditions. It was demonstrated with application of monoclonal anti-Hsp70 antibodies that a slight band about 70 kDa is present constitutively at the film; additionally the polypeptide of about 40 kDa ("Hsp40") has been detected. After heat shock at 28 degrees C during 1 hr significant "expenditure" of Hsp70 was observed, as well as the pronounced induction of "Hsp40"; the induction was expressed especially strongly in 24 hr after the stress application. PMID- 25696999 TI - [The possibilities and perspectives of using scaffold technology for bone regeneration]. AB - The article deals with the one of the topical problem of tissue engineering--the design and implementation of biomaterials that could replace and repair bone defects. This review presents the recent studies of the potential of scaffold technology in bone tissue regeneration. This article contains information about the basic parameters and properties of modern scaffold systems. The results of experimental in vitro and in vivo studies on the use of matrices made of various materials are shown. Advantages and disadvantages of various materials used for the production of scaffolds are discussed. Attention is paid to the advantages combinations of different materials to achieve the desired structural and functional properties. Particular attention is paid to technologies and systems of targeted delivery and controlled release of factors that stimulate bone tissue regeneration. Different strategies for modulating tissue reactions and immune responses that take place during scaffold implantation are presented. PMID- 25697000 TI - [Endomembrane system of fungi: traditional and modern conceptions]. AB - The review is devoted to the endomembrane system in Fungi, which is mostly presented in cell by membrane organelles, taking part in exo- and endocytosis. Main tenets of the modern model of exo- and endocytosis are covered by the example of the apical cells of filamentous fungi. Particular attention is given to studies of endomembrane system, which were carried out by electron microscopy in the last century--the era in science preceding the prevalence of methods of fluorescence microscopy, immune and molecular genetic tagging. Endomembrane organelles, which are described in classical studies, but have not been identified or differentiated from other organelles modern specialists are under consideration. Among these organelles are lomasomes, plasmalemmasomes, membranosomes and myelin-like bodies. Possible reasons for the "loss" of given structures in today's science and its place in modern proposed model of endomembrane system are discussed. In addition, some specific questions are mentioned, namely: the presence of mushroom mycelium endobionts, morphologically similar to endomembrane organelles, and the increase of number of endomembrane structures in bracket fungi, limited in nitrogen nutrition. PMID- 25697001 TI - [Comparative characteristics of mesenchymal stem cell lines derived from bone marrow and muscle of limb of early human embryo]. AB - In this work, we have carried out a comparative analysis of the characteristics of mesenchymal stem cell lines isolated from different tissues of 5-6-weeks homan embryo: bone marrow (line FetMSC) and muscle of limb (line M-FetMSC). The basic characteristics of these lines were obtained at the 6th passage. Average population doubling time was 33.0 +/- 1.4 h (FetMSC) and 25.0 +/- 0.1 h (M FetMSC). Growth curves also indicated active proliferation of cells of both lines. Numerical and structural karyotypic analysis showed that both lines have a normal karyotype: 46, XY. In order to determine the status of the lines, cell surface markers were analyzed by flow cytometry. The analysis revealed the presence of surface antigens specific for human MSCs, CD44, CD73, CD90, CD105, HLA-ABC, vimentin, and the lack of CD34 and HLA-DR, in both lines. The ability to differentiate into osteogenic, chondrogenic and adipogenic directions has been also shown for both lines. Im- munofluorescence and flow cytometry analysis has detected no expression of the surface antigen TRA-1-60 in both lines, but has revealed high expression of the surface antigen SSEA-4 and low expression of transcription factor Oct-4 characteristic of human embryonic stem cells. In these lines, immunofluorescence analysis has shown the presence of the markers of early differentiation in the derivates of three germ layers characteristic of human embryonic stem cells, which provides significant opportunities for MSC to be useful, in corresponding microenvironments, for repair of tissue injures. Dispite confirming MSC status for FetMSC and M-FetMSC lines, a number of interlinear differences related to growth characteristics and differentiation potential were revealed. Adipogenic differentiatiation potential of M-FetMSC line was reduced compared with FetMSC line. Immunofluorescence analysis showed that, in the process of skeletal-muscle differentiation, Z-disks were revealed only in sarcomeres of M-FetMSC line. These findings suggest the possible influence of different microenvironments in which the cells are in the body before their transfer in vitro. PMID- 25697002 TI - [Change of expression of integrins on multipotent mesenchymal stromal cells isolated from human adipose tissue during long cultivation]. AB - An expression ofintegrins on multipotent mesenchymal stromal cells (MMSCs), isolated from human subcutaneous adipose tissue during long cultivation was studied. Results of the comparative analysis of MMSCs on the 2nd and 17th passages of cultivation revealed considerable distinctions in expression of alpha1, alpha4 and alpha6 integrins on these cells. Strong decrease for 87.2 and 11.2%, quantities of the cells which have been positively stained by AT against CD49a (alpha1 integrin) and CD49d (alpha4 integrin), respectively was observed. The share of the cells which have been positively stained by AT against CD49f (alpha6 integrin) and CD49b (alpha2 integrin) on the contrary was increased during long cultivation by 9.9 and 2.3%, respectively. The high expression of beta1 integrin (98%) on MMSCs, wasn't changed significantly in the course of long cultivation. As a result of induction of MMSCs to a differentiation in the osteogenic direction it was revealed that cells on the 17th passage of cultivation concede by efficiency of formation of cells of bone tissue and extracellular matrix in vitro to cells which induced on the 2nd passage. Thus, long cultivation of MMSCs which is required for building of cellular population after isolation, influences on a cytoskeleton and adhesive abilities of cells that it is necessary to consider when using them for cellular technologies, including for modeling of this or that tissue in three-dimensional scaffolds. PMID- 25697003 TI - [Role of MEK/ERK pathway in the regulation of HDACI-induced senescence of transformed rat embryo fibroblasts]. AB - A key regulator of cellular senescence, mTORC1 complex, is the target of many signaling cascades including Ras/Raf/MEK/ERK-signaling cascade. In this paper we investigated the role of MEK/ERK-branch of this cascade in the process of cellular senescence induced by histone deacetylase inhibitor (HDACI) sodium butyrate (NaBut), in transformed rat embryo fibroblasts. Suppression of MEK/ERK activity by inhibitor PD0325901 does not prevent activation of mTORC1 complex induced by NaBut treatment. After the suppression of MEK/ERK, activity of mTORC1 increased as well as complex mTORC2. Activation of mTOR-containing complexes accompanied by the reorganization of the actin cytoskeleton with the formation of actin stress fibers and the appearance of some markers of cellular senescence. In contrast to NaBut-induced senescence accumulation of proteins was not observed, which may be due to increased activity of the degradation processes. Furthermore, the induction of senescence in conditions suppressed MEK/ERK leads to a drastic decrease in cell viability. Thus, NaBut-induced senescence upon suppressed activity of MEK/ERK-branch of MAP kinase cascade has a more pronounced tumor suppressor effect associated with stronger activation of both mTOR-complexes, reorganization of the actin cytoskeleton and protein degradation. PMID- 25697004 TI - [Morphology of NCTC cells upon a contact with type I collagen added to culture medium]. AB - The morphometric characteristics of NCTC cells upon their contact with type I collagen added to culture medium were studied. The cells were plated on plastic in the colony form. In a day after seeding, the culture medium was changed for the same medium complemented with 0.1% type I collagen. And the cells were incubated in this medium for 30 min more. Then the cells were washed out of collagen. Using time-lapse microscopy, the cell state at a colony edge was registered during 7 h. The area, spreading, and polarization of the cells were evaluated. It is shown that the contact with collagen did not affect the cell area, decreased cell spreading and sharply reduced a portion of polarized cells. These results probably demonstrate sensitivity of NCTC cells to the presence of type I collagen in culture medium and suggest that the cell response involves inhibition of long filopodia formation. PMID- 25697005 TI - [Modulation of apoptosis in mononuclear cells with different variants of polymorphism C-262T in catalase gene]. AB - Catalase is a clue enzyme metabolizing hydrogen peroxide under conditions of oxidative stress. It is known that the C-262T polymorphism in catalase gene is implicated in higher risk of some diseases onset. In this article we have evaluated the viability of mononuclear leukocytes isolated from patients with different variants of C-262T polymorphism in catalase gene (CC, CT, TT) under conditions of hydrogen peroxide induced oxidative stress. It has been revealed that cells with TT variant of polymorphism have lower viability in the presence of hydrogen peroxide in a concentration of 1000 MUM/L in comparison with cells having CC and CT genotypes. Furthermore, unlike CC and CT variants, cells with TT polymorphism showed no activation of mitochondrial apoptotic pathway even with hydrogen peroxide at a concentration of 1 mM. The data obtained may explain the increased risk of diseases related with the activity of the antioxidant system in patients with 262 TT promoter polymorphism in catalase gene. PMID- 25697006 TI - [N-palmitoylated peptide 232-245 of rat type 4 melanocortin receptor possessing agonistic activity]. AB - Melanocortin receptors of the type 4 (M4R) play a key role in the regulation of feeding behavior, neuroendocrine functions, and energy metabolism. The alterations in their functional activity induce obesity, metabolic syndrome, depression, and mental disorders, which makes the search of selective regulators of M4R to be one of the actual problems of molecular endocrinology. Promising for the development of such regulators is to design peptides corresponding to functionally important regions of M4R. The purpose of this study was to study the influence of synthesized N-palmitoylated peptide Palm-Thr-Gly-Thr-Ile-Arg-Gln-Gly Ala-Asn-(Nle)-Lys-Gly-Ala-Ile232-245-amide (Palm-232-245) structurally corresponding to the C-terminal half of the third intracellular loop (ICL-3) of rat M4R on functional activity of adenylyl cyclase signaling system (ACSS) in the fractions of synaptosomal membranes isolated from the brains of male rats. It has been shown that, at a concentration of 10(-7) M and higher, Palm-232-245 stimulates the basal activity of adenylyl cyclase (AC) in the synaptosomal membranes and increases the basal level of GTP binding with the EC50 values of 71 and 267 nM, respectively. Under the combined action of low concentrations of the peptide (10(-7)-10(-6) M) and M4R agonists, alpha-melanocyte-stimulating hormone (alpha-MSH) and THIQ (10(-7) M), we observed an additivi stimulatory effect on AC, which disappeared when the peptide concentration was increased to 10(-4)-10( 3) M. In the synaptosomal membranes preincubated with 10(-5) M peptide, the maximum stimulatory effect of M4R agonists on AC activity was lower than that in controls, and EC50 values for this effect, on the contrary, increased. In the case of combined action of the peptide and hormones (gamma-MSH, serotonin, PACAP 38) that activate AC via the other receptors, the additivity of their stimulating effects on the ACSS persisted throughout the range of peptide concentrations. The effect of the peptide was not observed in myocardial and testicular membranes no in which there is M4R homologous to the peptide. Thus, N-palmitoylated peptide Palm-232-245 specifically activates the ACSS in the rat brain by acting as intracellular M4R agonist. This may be used to create drugs regulating brain melanocortin system and physiological processes that depend on it. PMID- 25697007 TI - [Subpopulation of calbindin-immunoreactive interneurons in the dorsal horn of the mice spinal cord]. AB - In the dorsal horn of the spinal cord in the plates I-IV on the thoracic and lumbar levels different subpopulations of interneurons immunoreactive for calbindin 28 kDa (CAB IR), which are specific to each plate. In the area of the medial edge of the dorsal horn, we have found a special subpopulation of CAB IR interneurons whose morphometric characteristics differ from CAB IR interneurons subpopulations of said plates. The number of CAB IR interneurons was maximal in the plate II at all levels of the spinal cord. Leveled differences are more CAB IR interneurons and larger area of the cross sections at the lumbar level. PMID- 25697008 TI - [Mosaic forms of ataxia-telangiectasia]. AB - Ataxia-telangiectasia (AT) is a severe hereditary autosomal recessive neurodegenerative disease associated with accelerated aging and caused by mutation in both alleles of atm gene. This gene encodes a key protein of cell response to DNA damage--an ATM protein kinase. Normally, upon formation of DNA double strand breaks ATM is autophosphorylated and its active form phospho-ATM (P ATM) appears. Here we describe a mosaic form of AT in which cells of the same patient with normal atm gene demonstrated the accumulation of P-ATM in response to DNA double-strand breaks-inducing factors whereas in cells bearing a mutant form of atm P-ATM was not detected. The epigenetic markers such as histone deacetylases SIRT1 and SIRT6, and trimethylated forms of histone H3 - H3K9me3 and H3K27me3--were studied in the nuclei of primary fibroblasts derived from patients with different forms of AT and the increase of SIRT6 level was revealed. PMID- 25697009 TI - [Opioids--triggers of adaptive phenomenon of ischemic preconditioning of heart]. AB - It was established that short-term ischemia/reperfusion evokes an increase in myocardial tissue of enkephalin levels. A blockade of delta-opioid receptors abolishes the cardioprotective effect of ischemic preconditioning both in vivo and in vitro. An inhibition of kappa-opioid receptors abolishes the cardioprotective effect of ischemic preconditioning only in vitro. Agonists of mu , delta1- delta- and kappa1-opioid receptors mimic the cardioprotective effect of preconditioning. Consequently, it can be argued that endogenous opioid peptides are triggers of ischemic preconditioning. PMID- 25697010 TI - [Glutamatergic excitation of cortical neurons depending on site of origin on the neuronal membrane and cholinergic regulation under hypothermic condition]. AB - In sensorimotor cortical slices of guinea pig in the course of cooling of incubating fluid from 34 to 21-22 delta C it was shown that hypothermia does not influence on the evoked spike reactions to iontophoretic application of glutamate to the soma, but glutamate action on the dendritic locus causes the shot latency somatic spike response during hypothermic increasing of the rate of spontaneous activity and long latency spike response--during hypothermic fall of activity. While the cooling rate of spontaneous activity in the slow firing neurons was mainly increasing and in the high firing neurons (above 4 spikes per second)- decreasing. The changes in spontaneous activity began at 30 degrees C along with the decreased spike reactions to iontophoretic applications of acetylcholine and efficacy of dendro-somatic propagation. At the same temperature the fall of spike amplitude was initiated and increased with further hypothermia. It is proposed that the basis for hypothermic changes of neuronal activity.is the decreased rate of M-cholinergic process at 27-29 degrees C. Neurons of different physiological properties display different sensitivity to hypothermic factor. PMID- 25697011 TI - [The administration of interleukin-1beta during early postnatal develop ment impairs FGF2, but not TIMP1, mRNA expression in brain structures of adult rats]. AB - According to the Neurodevelopmental hypothesis, the long-lasting cognitive deficit in schizophrenia and other types of neuropathology may occur by injurious factors, such as hypoxia, traumas, infections that take place during pre- and postnatal development, at least at early stages. These pathological conditions are often associated with the high production of pro-inflammatory cytokine interleukin-1B (IL-1B) by the cells of immune and nervous systems. We investigated the expression of genes involved in the neuroplastic regulation (Fgf2 and Timp2) in medial prefrontal cortex and dorsal and ventral regions of hippocampus of adult rats that were treated with IL-1beta between P15 and P21. The learning impairment in IL-1beta-treated rats is accompanied by lower FGF-2 mRNA levels in medial prefrontal cortex and ventral (not dorsal) hippocampus, but TIMP-1 was not affected. No differences in TIMP-1 and FGF-2 mRNA expressions were observed in untrained IL-1beta-treated when compared to control rats. PMID- 25697012 TI - [Characteristics of load dependent relaxation of normal and hypertrophied myocardium in male and female rats]. AB - Under monocrotaline treatment of rat right ventricle myocardium preparations significant changes in morphometric indices for male, but not for female preparations are adduced as compared to the control group. Peculiarities of adaptation of mechanocalcium uncoupling mechanism, one of important regulation mechanisms of rat myocardial contractility, were first revealed. Myocardial pressure overload results in the increase of time to peak force without alteration of characteristic time of isometric tension, relaxation for male rats under myocardial hypertrophy compared with control group rats. In addition, the decrease of the load dependent relaxation index in the male rats was obtained. Characteristics of myocardial contractility of female rats have not significant changes as compared to the control group. PMID- 25697013 TI - [Effect of different therapy options on bronchial contraction in rats with modeled obstructive pulmonary disease]. AB - In the model of chronic obstructive pulmonary disease, produced in rats by 60-day exposure to nitrogen dioxide, the effect of different options of combination therapy (corticosteroids, anticholinergics, adrenergic agonists) on the functional state of the bronchi was studied. The contractile activity of strips of the bronchi caused by nerve or smooth muscle stimulation was evaluated. Corticosteroid monotherapy resulted in deterioration of the functional state of the bronchial wall neuromuscular apparatus due to corticosteroid resistance, evolving under the influence of long-term exposure to nitrogen dioxide. Application of M-anticholinergic tiotropium had a beneficial effect on the functional state of the bronchi smooth muscles, leading to the full restoration of the bronchial wall contractile activity and removal the morphological manifestations of inflammatory lung tissue remodeling. Most effective in terms of impact on the functional state of the bronchial wall neuromuscular apparatus was corticosteroid therapy combined with M-cholinolytik or beta2-adrenoagonist. PMID- 25697014 TI - [Role intramural ganglion airway on action of histamine]. AB - Influence of low concentration histamine on reactivity isolated trachea and bronchus preparations of rat induced field stimulation were studied. Application of 0.01-10 mkg histamine decreased responses preparation of trachea to 83% and bronchus to 79% at smooth muscle stimulation dose-depended manner. At postganglionic nerves stimulation histamine potentiated contraction of trachea without ganglions to 123%, trachea with ganglions to 110% and decreased contraction of bronchus to 87%. At stimulation ofpreganglionic nerves histamine evoked insignificant changes of contraction. With novocaine treatment of preparations histamine decreased responses of trachea by 19-30% at preganglionic stimulation, while responses of bronchus reduced by 8.2% only. Capsaicin treatment potentiated responses of trachea and bronchus on the effect of histamine induced preganglionic stimulation by 12-14%. We conclude that the action of histamine depends on the presence of ganglions and kind of stimulation. Different structures airways have various availability histamine-receptors and it determines the reaction of smooth muscle for histamine. PMID- 25697015 TI - [Seasonal peculiarities of the ground squirrel (Spermophilus undulatus) and Wistar rats circadian activity]. AB - The seasonal peculiarities of the circadian activity of hibernator, Yakutian long tail ground squirrels (S. undulatus) (n = 35) and non hibernator, Wistar rats (n = 35), were studied. The locomotor activity was registered in each subject individually during 5-17 days by means of "Animex" in the different periods of annual cycle. It was shown that ground squirrels were animals with daily type of activity. On the contrary, the Wistar rats demonstrated nocturne type of locomotors activity. The active period in rats was longer than in ground squirrels. It included not only at night, but morning time in spring, and daytime -in summer. The circadian differences between hibernators and non-hibernators were kept during all annual cycle at night time, but in daytime--only in spring and summer time. PMID- 25697016 TI - [Motivation effect on EEG spectral power and heart rate parameters in students during examination stress]. AB - EEG spectral power was calculated in 24 students (18-21 years) with different levels of motivation and anxiety (tested by Spielberger) in two experimental conditions: during the common educational process and the examination stress. Before examination tests, in subjects with high motivation and anxiety level the relative delta activity power increased in right frontal (F4) brain areas. In students with medium motivation immediately before an examination the relative beta2-activity power increased in right frontal (F4) brain areas. It is suggested that delta oscillati- ons reflect activity of the defensive motivational system, whereas beta2 oscillations may be associated with the achievement motivation. PMID- 25697017 TI - [M. sternocleidomastoideus mechanical stimulation produces lateralized effect on body schema perception]. AB - Neck muscles play important role in body schema perception, pose and motor control. The mechanical neck muscles stimulation can influence these processes. On present investigation the kinesiology tape (KT) application was used as a local mechanical stimulation for M. sternocleidomastoideus. The results confirmed the influence of the KT application on the body schema perception. Moreover, the influence effect was lateralized in dependence on the side of the KT application. In most of the subjects the KT left application diminished the reaction time in the body schema mental rotation task. The right the KT application has not shown this effect. The possible causes of the KT application lateralized effect can be the proprioceptive asymmetry in neck muscles or the hemispheric functional asymmetry of the body schema perception process. The results may be useful for understanding the neurological nature of asymmetric body schema perception impairments as well as for the development of sport training methods. PMID- 25697018 TI - [The influence of orthostatic test on changes of the heart rate variability observed in aboriginals of Magadan region]. AB - 255 adolescents, aged 13-17, from the north native minorities underwent an active orthostatic test to study the changes in the heart rate variability accounting for the subjects original vegetative types of the nervous regulation. The analysis of interquartile ranges of the heart rate variability values enabled to find individual peculiarities of regulatory mechanisms of reciprocal relationships between parasympathetic and sympathetic components of the vegetative nervous system. The findings testified that, irrespectively of the age, up to 45% of the examinees had optimal levels of reactivity and balance of the components of the vegetative nervous system. The other reactions covered 4 18%. At the same time, low (paradoxical) or excessive vegetative reactivity could be found in each typified group, but, to a greater extent, it was observed in the sympathetic adolescents. Of note that, the individuals with expressed misbalance of regulatory components were revealed who demonstrated the difference in the heart rate variability indices before and during the active orthostatic test going beyond the ranges of the 10th and 90th percentiles. That can be considered as elevated risks for dysadaptation in those individuals under extra functional exercises. PMID- 25697019 TI - [Academician of RAS Ushakov Igor Borisovich (on his 60th birthday)]. PMID- 25697020 TI - [Physiology of labour: modern theoretical and scientific-practical aspects]. AB - Physiology of labour is the science that studies human being in the professional activity process. Theoretical and practical aspects include two fundamental and interrelated trends based on the theory of functional system. The first area concerns the development of criteria-based foundations of differential diagnostics of organism' various functional states, the return of functions and reserve opportunities. The second area is devoted physiological-ergonomic and hygienic standardization of labor process factors, different intensity and duration muscular and mental loads permissible levels substantiation, as well as in view of gender, age and other personal qualities of the employee. PMID- 25697021 TI - [Psychophysiological mechanisms of formation and development of functional states]. AB - The modern approaches to the problem of formation and development of human functional states was presented. Described grounded theoretical results of experimental studies of the concept of "pattern of functional state" as a description of the functional state in terms of the characteristics of the activity of functional systems to ensure its formation and development in accordance with the dominant. Presented the characteristics of patterns of functional states, determining the reliability of human activities in extreme conditions. PMID- 25697022 TI - [Participation of peripheral sensory structures of autonomic nervous system in the mechanisms of neuroimmune interactions]. AB - On the basis of the electrophysiological research carried out with immunohystochemical methods on rats, it is found, that introduction of products of mast cell degranulation into blood as well as endogenous release of mast cell mediators with either the compound 48/80 or introduction of egg albumin to presensitized rats, enhances activity of mesenteric afferent nerve fibers. The obtained data provide evidence that intestinal afferents contribute an early signal to the brain regarding potential pathogens. The question of whether or not the intrinsic enteric neurons are involved in these processes, however, has not been carefully studied. So we investigated this problem and found that the enteric neurons express receptor of innate immunity TLR4 and nociceptive vanilloid receptor TRPV1, by means ofimmunohistochemical method. The analysis of neurons distribution revealed that vanilloid receptors are expressed by neurons localized mainly in myenteric plexus whereas TLR4-immunoreactive neurons generally are present in submucous plexus. It is also established coexpression of both receptors in the single intrinsic enteric neuron. In conclusion, our findings indicate that sensory terminals of external afferent fibers as well as intrinsic neurons of intestine can modulate reactions of the organism to endotoxins and thus may be involved in reception of inflammatory and immune responses. PMID- 25697023 TI - [The problems of experimental investigation of spaceflight factors combined influence on animals organism functions]. AB - The brief analytic review of exceedingly important, tough, but the insufficient investigated problem of experimental investigation of spaceflight factors (SF) combined influence on animal organism functions is the content of this paper. The basic limited factor for interplanetary spaceflights is ionizing radiation. Therefore, in the paper studies the matters of the effects of combined influence and the different nonradiation SF. In this case the possible disturbances of central nervous system functions are the most important, because they present the basic danger for space mission performance and the cosmonauts life directly in spaceflight. Besides of that, in the paper studies the matters of character of interaction and mutual modifications of the combined effects of different SF: hypodynamia, G force, vibration, hypoxia, hyperthermia. The effects of this factor may have additive, potentiative, synergic or antagonistic character. In studies of SF combined influence effects the accentuation of the key factor and organism system that is targeted for this factor influence is necessary. PMID- 25697024 TI - [Modulation of GABA- and kainate-activated currents by metabotropic receptors in isolated rat cortical neurons]. AB - Whole-cell patch-clamp recordings from isolated neurons from rat prefrontal cortex have been made to study GABAb and mGluR receptor modulation of currents induced by applications of GABA and kainate. The GABAb-receptor antagonist CGP 55845 (5 microM) enhanced the peak by 26 +/- 13% (n = 6) but had no effect on the steady-state of GABA-activated current. Bath application of GABAb-receptor agonist baclofen (50 microM) enhanced the GABAa currents by 9 +/- 2% (n = 8). Kainate-activated currents were not affected by baclofen. Both GABA-activated currents and kainate-activated currents were not affected by trans-ACPD (MGluR agonist). These results suggest that in cortex postsynaptic response of GABAa receptors can be modulated by GABAb-receptors. PMID- 25697025 TI - [Assessment of adaptation risk in the individual prenosological control]. AB - Trends in the development of modern ideas about health as the ability to adapt require personalization and preventive orientation in evaluating and predicting individual health. It can be realized only on the basis ofprenosological approach, which is necessary in medicine and physiology of labor, in particular- in the aviation and space medicine. The article analyzes the concept of adaptation risks and its application for health, assessing on the basis of the results of space and Earth modeling studies of autonomic regulation according to the HRV (heart rate variability) analysis. It is demonstrated that the developed methods for individual prenosological control have high diagnostic efficiency. PMID- 25697026 TI - [The study of functional status in the perception of visual information depending on the method of technical color mixing on LCD and DLP projectors technology]. AB - The case of compare two ways of projection color visual images, characterized by different spatial-temporal characteristics of visual stimuli, presents the methodology and the set of techniques. Received comparative data, identifying risks of regulation disorder of the functional state and development general, mental and visual fatigue during prolonged strenuous visual activity, according to two types of test tasks, which are the most typical for the use of modern projectors to work with the audience, both inthe process of implementation of learning technologies and the collective take responsible decisions by expert groups that control of complex technological processes. PMID- 25697027 TI - [Age dynamics and seasonal variations of parameters of cerebral circulation in children and adolescents from European north]. AB - Age dynamics and seasonal variations in cerebral blood flow was studied by means of transcranial Doppler in 95 the natives of the Arkhangelsk region school students aged 7 to 18 years. The results of longitudinal (from 2005 to 2014) study of students are presented. The linear blood flow velocity (BFV) showed gradual declining from junior to senior school age, and BFV were in the middle cerebral artery below average, and in the basilar artery--above mid latitude standards. The influence of the seasonal factor is more pronounced in the younger (for boys) and intermediate (for girls) age group and leveled in the older group. The largest seasonal changes were obtained in BFV in carotid arteries, the relative constancy--in BFV in the basilar artery. Estimated by the resistivity index RI circulatory resistance in the younger and intermediate school students groups decreased in the carotid arteries in the spring and summer, and in the posterior cerebral artery territory--in the winter. BFV rate variability identifies groups of children with varying degrees of "sensitivity" to the influence of seasonal factors. PMID- 25697028 TI - [Neurophysiologic mechanisms of combat post-extreme state of health]. AB - The effects of ecological and occupational stress (EOS) on brain neurodynamics of Soviet and Afghanistan servicemen have been studied. The investigations have been made in Afghanistan. Neurophysiological characteristics of traumatic stress and consequences of combat trauma were studied in patients wounded in Afghanistan, in the acute phase as well as since 0.5-3 years after leaving the battlefield. The combined effect of combat situation, hot climate, highlands and desert forms EOS. It does not cause an adaptation process in servicemen. EOS is characterized by changes in bioelectrical indices of brain in interhemispheric relations both as a whole and in isolated rhythm components of EEG, by activating the stress limiting system. It exhibits pathopsychological and autonomic components which remain significant during 3 years after leaving the combat conditions. The formation of a general adaptation syndrome is prevented in explosion trauma under the influence of EOS. PMID- 25697029 TI - [The Fifth World Symposium on Pulmonary Hypertension]. PMID- 25697030 TI - [Relevant issues in the pathology and pathobiology of pulmonary hypertension]. AB - Knowledge of the pathobiology of pulmonary hypertension (PH) continues to accelerate. However, fundamental gaps remain in our understanding of the underlying pathological changes in pulmonary arteries and veins in the different forms of this syndrome. Although PH primarily affects the arteries, venous disease is increasingly recognized as an important entity. Moreover, prognosis in PH is determined largely by the status of the right ventricle, rather than the levels of pulmonary artery pressures. It is increasingly clear that although vasospasm plays a role, PH is an obstructive lung panvasculopathy. Disordered metabolism and mitochondrial structure, inflammation, and dysregulation of growth factors lead to a proliferative, apoptosis-resistant state. These abnormalities may be acquired, genetically mediated as a result of mutations in bone morphogenetic protein receptor-2 or activin-like kinase-1, or epigenetically inherited (as a result of epigenetic silencing of genes such as superoxide dismutase-2). There is a pressing need to better understand how the pathobiology leads to severe disease in some patients versus mild PH in others. Recent recognition of a potential role of acquired abnormalities of mitochondrial metabolism in the right ventricular myocytes and pulmonary vascular cells suggests new therapeutic approaches, diagnostic modalities, and biomarkers. Finally, dissection of the role of pulmonary inflammation in the initiation and promotion of PH has revealed a complex yet fascinating interplay with pulmonary vascular remodeling, promising to lead to novel therapeutics and diagnostics. Emerging concepts are also relevant to the pathobiology of PH, including a role for bone marrow and circulating progenitor cells and microribonucleic acids. Continued interest in the interface of the genetic basis of PH and cellular and molecular pathogenetic links should further expand our understanding of the disease. (J Am Coll Cardiol 2013;62:D4-12) a 2013 by the American College of Cardiology Foundation. PMID- 25697031 TI - [Genetics and genomics of pulmonary arterial hypertension]. AB - Major discoveries have been obtained within the last decade in the field of hereditary predisposition to pulmonary arterial hypertension (PAH). Among them, the identification of bone morphogenetic protein receptor type 2 (BMPR2) as the major predisposing gene and activin A receptor type II-like kinase-1 (ACVRL1, also known as ALK1) as the major gene when PAH is associated with hereditary hemorrhagic telangiectasia. The mutation detection rate for the known genes is approximately 75% in familial PAH, but the mutation shortfall remains unexplained even after careful molecular investigation of these genes. To identify additional genetic variants predisposing to PAH, investigators harnessed the power of next generation sequencing to successfully identify additional genes that will be described in this report. Furthermore; common genetic predisposing factors for PAH can be identified by genome-wide association studies and are detailed in this paper. The careful study of families and routine genetic diagnosis facilitated natural-history studies based on large registries of PAH patients to be set up in different countries. These longitudinal or cross-sectional studies permitted the clinical characterization of PAH in mutation carriers to be accurately described. The availability of molecular genetic diagnosis has opened up a new field for patient care, including genetic counseling for a severe disease, taking into account that the major predisposing gene has a highly variable penetrance between families. Molecular information can be drawn from the genomic study of affected tissues in PAH, in particular, pulmonary vascular tissues and cells, to gain insight into the mechanisms leading to the development of the disease. High throughput genomic techniques, on the basis of next-generation sequencing, now allow the accurate quantification and analysis of ribonucleic acid, species, including micro-ribonucleic acids, and allow for a genome-wide investigation of epigenetic or regulatory mechanisms, which include deoxyribonucleic acid methylation, histone methylation, and acetylation, or transcription factor binding. (J Am Coll Cardiol 2013;62:D13-21) a 2013 by the American College of Cardiology Foundation. PMID- 25697032 TI - [Right heart adaptation to pulmonary arterial hypertension: physiology and pathobiology]. AB - Survival in patients with pulmonary arterial hypertension (PAH) is closely related to right ventricular (RV) function. Although pulmonary load is an important determinant of RV systolic function in PAH, there remains a significant variability in RV adaptation to pulmonary hypertension. In this report, the authors discuss the emerging concepts of right heart pathobiology in PAH. More specifically, the discussion focuses on the following questions. 1) How is right heart failure syndrome best defined? 2) What are the uderlying molecular mechanisms of the failing right ventricle in PAH? 3) How are RV contractility and function and their prognostic implications best assessed? 4) What is the role of targeted RV therapy? Throughout the report, the authors highlight differences between right and left heart failure and outline key areas of future investigation. (J Am Coll Cardiol 2013;62:D22-33) a 2013 by the American College of Cardiology Foundation). PMID- 25697033 TI - [Updated clinical classification of pulmonary hypertension]. AB - In 1998, a clinical classification of pulmonary hypertension (PH) was established, categorizing PH into groups which share similar pathological and hemodynamic characteristics and therapeutic approaches. During the 5th World Symposium held in Nice, France, in 2013, the consensus was reached to maintain the general scheme of previous clinical classifications. However, modifications and updates especially for Group 1 patients (pulmonary arterial hypertension [PAH]) were proposed. The main change was to withdraw persistent pulmonary hypertension of the newborn (YPPH) from Group 1 because this entity carries more differences than similarities with other PAH subgroups. In the current classification, PPHN is now designated number 1". Pulmonary hypertension associated with chronic hemolytic anemia has been moved from Group 1 PAH to Group 5, unclear/multifactorial mechanism. In addition, it was decided to add specific items related to pediatric pulmonary hypertension in order to create a comprehensive, common classification for both adults and children. Therefore, congenital or acquired left-heart inflow/outflow obstructive lesions and congenital cardiomyopathies have been added to Group 2, and segmental pulmonary hypertension has been added to Group 5. Last, there were no changes for Groups 2, 3, and 4. (J Am Coll Cardiol 2013;62:D34-41) a 2013 by the American College of Cardiology Foundation. PMID- 25697034 TI - [Definitions and diagnosis of pulmonary hypertension]. AB - Pulmonary hypertension (PH) is defined by a mean pulmonary artery pressure 25 mm Hg at rest, measured during right heart catheterization. There is still insufficient .evidence to add an exercise criterion to this definition. The term pulmonary arterial hypertension (PAH) describes a subpopulation of patients with PH characterized hemodynamically by the presence of pre-capillary PH including an end-expiratory pulmonary artery wedge pressure (PAWP) 15 mm Hg and a pulmonary vascular resistance >3 Wood units. Right heart catheterization remains essential for a diagnosis of PH or PAH. This procedure requires further standardization, including uniformity of the pressure transducer zero level at the midthoracic line, which is at the level of the left atrium. One of the most common problems in the diagnostic workup of patients with PH is the distinction between PAH and PH due to left heart failure with preserved ejection fraction (HFpEF). A normal PAWP does not rule out the presence of HFpEF. Volume or exercise challenge during right heart catheterization may be useful to unmask the presence of left heart disease, but both tools require further evaluation before their use in general practice can be recommended. Early diagnosis of PAH remains difficult, and screening programs in asymptomatic patients are feasible only in high-risk populations, particularly in patients with systemic sclerosis, for whom recent data suggest that a combination of clinical assessment and pulmonary function testing including diffusion capacity for carbon monoxide, biomarkers, and echocardiography has a higher predictive value than echocardiography alone. (J Am Coll Cardiol 2013;62: D42-50) (c)2013 by the American College of Cardiology Foundation. PMID- 25697035 TI - [Pulmonary arterial hypertension: epidemiology and registries]. AB - Registries of patients with pulmonary arterial hypertension (PAH) have been instrumental in characterizing the presentation and natural history of the disease and provide a basis for prognostication. Since the initial accumulation of data conducted in the 1980s, subsequent registry databases have yielded information about the demographic factors, treatment, and survival of patients and have permitted comparisons between populations in different eras and environments. Inclusion of patients with all subtypes of PAH has also allowed comparisons of these subpopulations. We describe herein the basic methodology by which PAH registries have been conducted, review key insights provided by registries, summarize issues related to interpretation and comparison of the results, and discuss the utility of data to predict survival outcomes. Potential sources of bias, particularly related to the inclusion of incident and/or prevalent patients and missing data, are addressed. A fundamental observation of current registries is that survival in the modern treatment era has improved compared with that observed previously and that outcomes among PAH subpopulations vary substantially. Continuing systematic clinical surveillance of PAH will be important as treatment evolves and as understanding of mechanisms advance. Considerations for future directions of registry studies include enrollment of a broader population of patients with pulmonary hypertension of all clinical types and severity and continued globalization and collaboration of registry databases. (J Am Coil Cardiol 2013;62:D51-9) (c)2013 by the American College of Cardiology Foundation. PMID- 25697036 TI - [Updated treatment algorithm of pulmonary arterial hypertension]. AB - The demands on a pulmonary arterial hypertension (PAH) treatment algorithm are multiple and in some ways conflicting. The treatment algorithm usually includes different types of recommendations with varying degrees of scientific evidence. In addition, the algorithm is required to be comprehensive but not too complex, informative yet simple and straightforward. The type of information in the treatment algorithm are heterogeneous including clinical, hemodynamic, medical, interventional, pharmacological and regulatory recommendations. Stakeholders (or users) including physicians from various specialties and with variable expertise in PAH nurses, patients and patients' associations, healthcare providers, regulatory agencies and industry are often interested in the PAH treatment algorithm for different reasons. These are the considerable challenges faced when proposing appropriate updates to the current evidence-based treatment algorithm.The current treatment algorithm may be divided into 3 main areas: 1) general measures, supportive therapy referral strategy, acute vasoreactivity testing and chronic treatment with calcium channel blockers; 2) initial therapy with approved PAH drugs; and 3) clinical response to the initial therapy, combination therapy, balloon atrial septostomy and lung transplantation. All three sections will be revisited highlighting information newly available in the past 5 years and proposing updates where appropriate. The European Society of Cardiology grades of recommendation and levels of evidence will be adopted to rank the proposed treatments. (J Am Coll Cardiol 2013;62:D60-72) (c)2013 by the American College of Cardiology Foundation. PMID- 25697037 TI - [Treatment goals of pulmonary hypertension]. AB - With significant therapeutic advances in the field of pulmonary arterial hypertension, the need to identify clinically relevant treatment goals that correlate with long-term outcome has emerged as 1 of the most critical tasks. Current goals include achieving modified New York Heart Association functional class I or II, 6-min walk distance >380 m, normalization of right ventricular size and function on echocardiograph, a decreasing or normalization of B-type natriuretic peptide (BNP), and hemodynamics with right atrial pressure <8 mm Hg and cardiac index >2.5 L/dk/m2. However, to more effectively prognosticate in the current era of complex treatments, it is becoming clear that the "bar" needs to be set higher, with more robust and clearer delineations aimed at parameters that correlate with long-term outcome; namely, exercise capacity and right heart function. Specifically, tests that accurately and noninvasively determine right ventricular function, such as cardiac magnetic resonance imaging and BNP/N terminal pro-B-type natriuretic peptide, are emerging as promising indicators to serve as baseline predictors and treatment targets. Furthermore, studies focusing on outcomes have shown that no single test can reliably serve as a long-term prognostic marker and that composite treatment goals are more predictive of long term outcome. It has been proposed that treatment goals be revised to include the following: modified New York Heart Association functional class I or II, 6-min walk distance 380 to 440 m, cardiopulmonary exercise test-measured peak oxygen consumption >15 ml/min/kg and ventilatory equivalent for carbon dioxide <45 l/min/l/min, BNP level toward "normal," echocardiograph and/or cardiac magnetic resonance imaging demonstrating normal/near-normal right ventricular size and function, and hemodynamics showing normalization of right ventricular function with right atrial pressure <8 mm Hg and cardiac index >2.5 to 3.0 l/min/m2. (J Am Coll Cardiol 2013;62:D73-81) (c)2013 by the American College of Cardiology Foundation. PMID- 25697038 TI - [New trial designs and potential therapies for pulmonary artery hypertension]. AB - A greater understanding of the epidemiology, pathogenesis, and pathophysiology of pulmonary artery hypertension (PAH) has led to significant advances, but the disease remains fatal. Treatment options are neither universally available nor always effective, underscoring the need for development of novel therapies and therapeutic strategies. Clinical trials to date have provided evidence of efficacy, but were limited in evaluating the scope and duration of treatment effects. Numerous potential targets in varied stages of drug development exist, in addition to novel uses of familiar therapies. The pursuit of gene and cell based therapy continues, and device use to help acute deterioration and chronic management is emerging. This rapid surge of drug development has led to multicenter pivotal clinical trials and has resulted in novel ethical and global clinical trial I concerns. This paper will provide an overview of the opportunities and challenges that await the development of novel treatments for PAH. (J Am Coil Cardiol 2013;62:D82-91) (c)2013 by the American College of Cardiology Foundation. PMID- 25697039 TI - [Chronic thromboembolic pulmonary hypertension]. AB - Since the last World Symposium on Pulmonary Hypertension in 2008, we have witnessed numerous and exciting developments in chronic thromboembolic pulmonary hypertension (CTEPH). Emerging clinical data and advances in technology have led to reinforcing and updated guidance on diagnostic approaches to pulmonary hypertension, guidelines that we hope will lead to better recognition and more timely diagnosis of CTEPH. We have new data on treatment practices across international boundaries as well as long-term outcomes for CTEPH patients treated with or without pulmonary endarterectomy. Furthermore, we have expanded data on alternative treatment options for select CTEPH patients, including data from multiple clinical trials of medical therapy, including 1 recent pivotal trial, and compelling case series of percutaneous pulmonary angioplasty. Lastly, we have garnered more experience, and on a larger international scale, with pulmonary endarterectomy, which is the treatment of choice for operable CTEPH. This report overviews and highlights these important interval developments as deliberated among our task force of CTEPH experts and presented at the 2013 World Symposium on Pulmonary Hypertension in Nice, France. (J Am Coil Cardiol 2013;62:D92-9) (c)2013 by the American College of Cardiology Foundation. PMID- 25697040 TI - [Pulmonary hypertension due to left heart diseases]. AB - Pulmonary hypertension (PH), a common complication of left heart diseases (LHD), negatively impacts symptoms, exercise capacity, and outcome. Although the true prevalence of PH-LHD is unknown, a subset of patients might present significant PH that cannot be explained by a passive increase in left-sided filling pressures. The term "out-of-proportion" PH has been used to identify that population without a clear definition, which has been found less than ideal and created confusion. We propose a change in terminology and a new definition of PH due to LHD. We suggest to abandon "out-of-proportion" PH and to distinguish "isolated post-capillary PH" from "post-capillary PH with a pre-capillary component" on the basis of the pressure difference between diastolic pulmonary artery pressure and pulmonary artery wedge pressure. Although there is no validated treatment for PH-LHD, we provide insights into management and discuss completed and randomized trials in this condition. Finally, we provide recommendations for future clinical trials to establish safety and efficacy of novel compounds to target this area of unmet medical need. (J Am Coll Cardiol 2013;62:D100-8) (c)2013 by the American College of Cardiology Foundation. PMID- 25697041 TI - [Pulmonary hypertension in chronic lung diseases]. AB - Chronic obstructive lung disease (COPD) and diffuse parenchymal lung diseases (DPLD), including idiopathic pulmonary fibrosis (IPF) and sarcoidosis, are associated with a high incidence of pulmonary hypertension (PH), which is linked with exercise limitation and a worse prognosis. Patients with combined pulmonary fibrosis and emphysema (CPFE) are particularly prone to the development of PH. Echocardiography and right heart catheterization are the principal modalities for the diagnosis of COPD and DPLD. For discrimination between group 1 PH patients with concomitant respiratory abnormalities and group 3 PH patients (PH caused by lung disease), patients should be transferred to a center with expertise in both PH and lung diseases for comprehensive evaluation. The task force encompassing the .authors of this article provided criteria for this discrimination and suggested using the following definitions for group 3 patients, as exemplified for COPD, IPF, and CPFE: COPD/IPF/CPFE without PH (mean pulmonary artery pressure [mPAP]<25mmHg); COPD/IPF/CPFE with PH (mPAP25mmHg); PH-COPD, PH-IPF, and PH CPFE); COPD/IPF/CPFE with severe PH (mPAP 35 mmHg or mPAP 25 mmHg with low cardiac index [CI <2.0.l/min/m2]; severe PH-COPD, severe PH-IPF, and severe PH CPFE). The "severe PH group" includes only a minority of chronic lung disease patients who are suspected of having strong general vascular abnormalities (remodeling) accompanying the parenchymal disease and with evidence of an exhausted circulatory reserve rather than an exhausted ventilatory reserve underlying the limitation of exercise capacity. Exertional dyspnea disproportionate to pulmonary function tests, low carbon monoxide diffusion capacity, and rapid decline of arterial oxygenation upon exercise are typical clinical features of this subgroup with poor prognosis. Studies evaluating the effect of pulmonary arterial hypertension drugs currently not approved for group 3 PH patients should focus on this severe PH group, and for the time being, these patients should be transferred to expert centers for individualized patient care. (J Am Coll Cardiol 2013;62:D109-16) (c)2013 by the American College of Cardiology Foundation. PMID- 25697042 TI - [Pediatric pulmonary hypertension]. AB - Pulmonary hypertension (PH) is a rare disease in newborns, infants, and children that is associated with significant morbidity and mortality. In the majority of pediatric patients, PH is idiopathic or associated with congenital heart disease and rarely is associated with other conditions such as connective tissue or thromboembolic disease. Incidence data from the Netherlands has revealed an annual incidence and point prevalence of 0.7 and 4.4 for idiopathic pulmonary arterial hypertension and 2.2 and 15.6 for pulmonary arterial hypertension, respectively, associated with congenital heart disease (CHD) cases per million children. The updated Nice classification for PH has been enhanced to include a greater depth of CHD and emphasizes persistent PH of the newborn and developmental lung diseases, such as bronchopulmonary dysplasia and congenital diaphragmatic hernia. The management of pediatric PH remains challenging because treatment decisions continue to depend largely on results from evidence based adult studies and the clinical experience of pediatric experts. (J Am Coll Cardiol 2013;62:D117-26) (c)2013 by the American College of Cardiology Foundation. PMID- 25697044 TI - Melatonin and brain inflammaging. AB - Melatonin is known to possess several properties of value for healthy aging, as a direct and indirect antioxidant, protectant and modulator of mitochondrial function, antiexcitotoxic agent, enhancer of circadian amplitudes, immune modulator and neuroprotectant. It is levels tend to decrease in the course of senescence and are more strongly reduced in several neurodegenerative disorders, especially Alzheimer's disease, and in diseases related to insulin resistance such as diabetes type 2. Although the role of melatonin in aging and age-related diseases has been repeatedly discussed, the newly emerged concept of inflammaging, that is, the contribution of low-grade inflammation to senescence progression has not yet been the focus of melatonin research. This review addresses the multiple protective actions of melatonin and its kynuramine metabolites that are relevant to the attenuation of inflammatory responses and progression of inflammaging in the brain, i.e. avoidance of excitotoxicity, reduction of free radical formation by support of mitochondrial electron flux, prevention of NADPH oxidase activation and suppression of inducible nitric oxide synthase, as well as downregulation of proinflammatory cytokines. The experimental evidence is primarily discussed on the basis of aging and senescence accelerated animals, actions in the immune system, and the relationship between melatonin and sirtuins, having properties of aging suppressors. Sirtuins act either as accessory components or downstream factors of circadian oscillators, which are also under control by melatonin. Inflammaging is assumed to strongly contribute to neurodegeneration of the circadian master clock observed in advanced senescence and, even more, in Alzheimer's disease, a change that affects countless physiological functions. PMID- 25697045 TI - An effective electrochemical biosensing platform for the detection of reduced glutathione. AB - A biosensor was developed using glutathione peroxidase (GSH-Px) as the enzyme. Firstly, platinum (Pt) nanoparticles were deposited onto a glassy carbon paste electrode (GCPE), and then GSH-Px was immobilized by means of gelatin that was then crosslinked with glutaraldehyde. The measurement was based on the electrochemical oxidation of GSH to its disulfide form in the presence of hydrogen peroxide. The linear range was found to be between 10 and 250 MUM, with a correlation coefficient of R(2) = 0.9968. The R.S.D value for 25 MUM GSH (n = 6) was calculated as 2.92%. Finally, the proposed biosensor was used to analyze GSH in a synthetically prepared plasma sample, and a promising recovery value was obtained. PMID- 25697046 TI - Comparative analysis of cardiovascular effects of selenium nanoparticles and sodium selenite in zebrafish embryos. AB - Selenium acts as an important element in the prevention and treatment of cardiovascular diseases but their health-related effects have not been fully explored. As a novel attempt, zebrafish embryos were treated separately with SeNPs (5-25 MUg/ml) and sodium selenite (5-25 MUg/ml) starting at early blastula stage. Abnormalities were also observed in the morphology of the zebrafish embryos. The SeNPs-treated embryos exhibited concentration-dependent increased in mortality, pericardial edema, and cardiac arrhythmia. In contrast, sodium selenite showed no significant malformation effect in developing zebrafish embryos. The results of the present study conclude that the SeNPs were more toxic than sodium selenite. The results also suggest that lower concentrations of SeNPs and sodium selenite can be used as possible therapeutic agents for cardiovascular related problems. PMID- 25697043 TI - Striatal cholinergic dysfunction as a unifying theme in the pathophysiology of dystonia. AB - Dystonia is a movement disorder of both genetic and non-genetic causes, which typically results in twisted posturing due to abnormal muscle contraction. Evidence from dystonia patients and animal models of dystonia indicate a crucial role for the striatal cholinergic system in the pathophysiology of dystonia. In this review, we focus on striatal circuitry and the centrality of the acetylcholine system in the function of the basal ganglia in the control of voluntary movement and ultimately clinical manifestation of movement disorders. We consider the impact of cholinergic interneurons (ChIs) on dopamine acetylcholine interactions and examine new evidence for impairment of ChIs in dysfunction of the motor systems producing dystonic movements, particularly in animal models. We have observed paradoxical excitation of ChIs in the presence of dopamine D2 receptor agonists and impairment of striatal synaptic plasticity in a mouse model of DYT1 dystonia, which are improved by administration of recently developed M1 receptor antagonists. These findings have been confirmed across multiple animal models of DYT1 dystonia and may represent a common endophenotype by which to investigate dystonia induced by other types of genetic and non genetic causes and to investigate the potential effectiveness of pharmacotherapeutics and other strategies to improve dystonia. PMID- 25697047 TI - Hexagonal cobalt oxyhydroxide-carbon dots hybridized surface: high sensitive fluorescence turn-on probe for monitoring of ascorbic acid in rat brain following brain ischemia. AB - In this study, we report a novel and efficient fluorescence probe synthesized by Tris(hydroxymethyl)aminomethane-derived carbon dots (CDs)-modified hexagonal cobalt oxyhydroxide(CoOOH) nanoflakes (Tris-derived CDs-CoOOH) for monitoring of cerebral ascorbic acid (AA) in brain microdialysate. The as-prepared Tris-derived CDs with the fluorescence quantum yield of 7.3% are prepared by a one-step pyrolysis strategy of the sole precursor and used as the signal output. After being hybridized with CoOOH nanoflakes to form Tris-derived CDs-CoOOH, the luminescence of the Tris-derived CDs can be efficiently quenched by CoOOH via fluorescence resonance energy transfer (FRET). Due to the specific redox reaction between the enediol group of AA and hexagonal CoOOH nanoflakes, AA can reduce the hexagonal CoOOH nanoflakes in the Tris-derived CDs-CoOOH and lead to collapse of the hybrized structure, then the release of Tris-derived CDs, and thus finally the fluorescence recovery. Moreover, cobalt ions (II), generated by CoOOH nanoflakes oxidizing AA, almost have no obvious interference on the fluorescence probe, i.e., Tris-derived CDs, which could be ascribed to the surface of Tris derived CDs containing a few strong chelation groups such as amino/carboxyl/thiol groups, instead of plenty of -OH groups with weak chelation with Co(2+). On the basis of this feature, the Tris-derived CDs-CoOOH fluorescent probe demonstrates a linear range from 100 nM to 20 MUM with the detection limit of ~50 nM, i.e., with an improved sensitivity toward AA detection. Compared with other turn-on fluorescent methods using convenient fluorophore-nitroxide fluorescent probes for detection of AA, the method demonstrated here possesses a facial synthesis route, lower limit of detection, and wider linear range, which validates sensing of AA in the cerebral systems during the calm/ischemia process. This study provides a fluorescence assay for the simple yet facial detection of AA in the cerebral systems and assists in the understanding of the biological processes in the physiological and pathological study. PMID- 25697049 TI - The neural basis of perceiving person interactions. AB - This study examined whether the grouping of people into meaningful social scenes (e.g., two people having a chat) impacts the basic perceptual analysis of each partaking individual. To explore this issue, we measured neural activity using functional magnetic resonance imaging (fMRI) while participants sex-categorized congruent as well as incongruent person dyads (i.e., two people interacting in a plausible or implausible manner). Incongruent person dyads elicited enhanced neural processing in several high-level visual areas dedicated to face and body encoding and in the posterior middle temporal gyrus compared to congruent person dyads. Incongruent and congruent person scenes were also successfully differentiated by a linear multivariate pattern classifier in the right fusiform body area and the left extrastriate body area. Finally, increases in the person scenes' meaningfulness as judged by independent observers was accompanied by enhanced activity in the bilateral posterior insula. These findings demonstrate that the processing of person scenes goes beyond a mere stimulus-bound encoding of their partaking agents, suggesting that changes in relations between agents affect their representation in category-selective regions of the visual cortex and beyond. PMID- 25697048 TI - Target sites for transcallosal fibers in human visual cortex - A combined diffusion and polarized light imaging study. AB - Transcallosal fibers of the visual system have preferential target sites within the occipital cortex of monkeys. These target sites coincide with vertical meridian representations of the visual field at borders of retinotopically defined visual areas. The existence of preferential target sites of transcallosal fibers in the human brain at the borders of early visual areas was claimed, but controversially discussed. Hence, we studied the distribution of transcallosal fibers in human visual cortex, searching for an organizational principle across early and higher visual areas. In-vivo high angular resolution diffusion imaging data of 28 subjects were used for probabilistic fiber tracking using a constrained spherical deconvolution approach. The fiber architecture within the target sites was analyzed at microscopic resolution using 3D polarized light imaging in a post-mortem human hemisphere. Fibers through a seed in the splenium of the corpus callosum reached the occipital cortex via the forceps major and the tapetum. We found target sites of these transcallosal fibers at borders of cytoarchitectonically defined occipital areas not only between early visual areas V1 and V2, V3d and V3A, and V3v and V4, but also between higher extrastriate areas, namely V4 (ventral) and posterior fusiform area FG1 as well as posterior fusiform area FG2 and lateral occipital cortex. In early visual areas, the target sites coincided with the vertical meridian representations of retinotopic maps. The spatial arrangement of the fibers in the 'border tuft' region at the V1/V2 border was found to be more complex than previously observed in myeloarchitectonic studies. In higher visual areas, our results provided additional evidence for a hemi-field representation in human area V4. The fiber topography in posterior fusiform gyrus indicated that additional retinotopic areas might exist, located between the recently identified retinotopic representations phPITv/phPITd and PHC-1/PHC-2 in lateral occipital cortex and parahippocampal gyrus. PMID- 25697050 TI - Investigation of the influence of mallet and chisel techniques on the lingual fracture line and comparison with the use of splitter and separators during sagittal split osteotomy in cadaveric pig mandibles. AB - In bilateral sagittal split osteotomy the proximal and distal segments of the mandible are traditionally separated using chisels. Modern modifications include prying and spreading the segments with splitters. This study investigates the lingual fracture patterns and status of the nerve after sagittal split osteotomy (SSO) using the traditional chisel technique and compares these results with earlier studies using the splitter technique. Lingual fractures after SSO in cadaveric pig mandibles were analysed using a lingual split scale and split scoring system. Iatrogenic damage to the inferior alveolar nerve was assessed. Fractures started through the caudal cortex more frequently in the chisel group. This group showed more posterior lingual fractures, although this difference was not statistically significant. Nerve damage was present in three cases in the chisel group, but was not observed in the splitter group. A trend was apparent, that SSO using the chisel technique instead of the splitter technique resulted in more posterior lingual fracture lines, although this difference was not statistically significant. Both techniques resulted in reliable lingual fracture patterns. Splitting without chisels could prevent nerve damage, therefore we propose a spreading and prying technique with splitter and separators. However, caution should be exercised when extrapolating these results to the clinic. PMID- 25697051 TI - Analysis of implant-failure predictors in the posterior maxilla: a retrospective study of 1395 implants. AB - The aim of this study was to analyze predictors for dental implant failure in the posterior maxilla. A database was created to include patients being treated with dental implants posterior to the maxillary cuspids. Independent variables thought to be predictive of potential implant failure included (1) sinus elevation, (2) implant length, (3) implant diameter, (4) indication, (5) implant region, (6) timepoint of implant placement, (7) one-vs. two-stage augmentation, and (8) healing mode. Cox regression analysis was used to evaluate the influence of predictors 1-3 on implant failure as dependent variable. The predictors 4-9 were analyzed strictly descriptively. The final database included 592 patients with 1395 implants. The overall 1- and 5-year implant survival rates were 94.8% and 88.6%, respectively. The survival rates for sinus elevation vs. placement into native bone were 94.4% and 95.4%, respectively (p = 0.33). The survival rates for the short (<10 mm), the middle (10-13 mm) and the long implants (>13 mm) were 100%, 89% and 76.8%, respectively (middle-vs. long implants p = 0.62). The implant survival rates for the small- (<3.6 mm), the middle- (3.6-4.5 mm) and the wide diameter implants (>4.5 mm) were 92.5%, 87.9% and 89.6%, respectively (p = 0.0425). None of the parameters evaluated were identified as predictor of implant failure in the posterior maxilla. PMID- 25697052 TI - Total and near-total lower lip reconstruction: 20 years experience. AB - BACKGROUND: Reconstruction of total and near-total lower lip defects presents a formidable challenge for the reconstructive plastic surgeon. Many methods have been described, and each has its own advantages and disadvantages. The aim of this article is to discuss the selection of techniques and report our experience of total or near-total lower lip reconstruction. MATERIAL AND METHODS: Over a 20 year period from January 1993 to December 2013, a total of 87 patients underwent total or near-total lower lip reconstruction. Bilateral Yu's flaps were used in 61 patients, double mental neurovascular V-Y island advancement flaps in 16 patients, bilateral Mutaf's techniques in 4 patients, and reconstruction with free radial forearm flaps in 6 other patients. Drooling Rating Scale (DRS) and Patient and Observer Scar Assessment Scale (POSAS) were used to evaluate oral competency and esthetic outcomes. RESULTS: All patients underwent single-stage total or near-total lower lip reconstruction successfully. There were no flap failures. Only 1 patient who accepted the bilateral Yu's flaps developed microstomia, having difficulty in wearing her dentures postoperatively. Oral competencies were well preserved in other patients, and esthetic results were satisfactory. CONCLUSION: Based on our experience, we recommend using the bilateral local techniques or free flap introduced in this article, according to the extent of defects and the patient's general condition, to achieve a personalized ideal reconstruction of the lower lip. PMID- 25697053 TI - 7-Ketocholesterol and 5,6-secosterol induce human endothelial cell dysfunction by differential mechanisms. AB - 7-Ketocholesterol and 5,6-secosterol are cholesterol autoxidation products generated under oxidative stress by two distinct mechanisms. They are present in atherosclerotic plaques and are candidate players in the disease initiation and progression. While 7-ketocholesterol affects at cellular level, in particular apoptosis, are well known and reported on diverse cell lines, 5,6-secosterol is a recently discovered oxysterol with relatively few reports on the potential to affect endothelial cell functions. Endothelial cells have a central role in cardiovascular disease as they provide the barrier between blood and the vessel wall where atherosclerosis starts and progresses. Insults to endothelial cells provoke their dysfunction favoring pro-atherogenic and pro-thrombotic effects. In the present work, we tested 7-ketocholesterol and 5,6-secosterol on endothelial cells - focusing on apoptosis and the associated mitochondrial/lysosome alterations - and on endothelial function using the in vitro model of arterial relaxation of aortic rings. Our data provide evidence that 7-ketocholesterol and 5,6-secosterol are efficient instigators of apoptosis, which for 5,6-secosterol is associated to PKC and p53 up-regulation. In addition 5,6-secosterol is a potent inhibitor of endothelial-dependent arterial relaxation through PKC dependent mechanisms. This may contribute to pro-atherogenic and pro-thrombotic mechanisms of 5,6-secosterol and highlights the role of cholesterol autoxidation in cardiovascular disease. PMID- 25697054 TI - 24(S)-Hydroxycholesterol induces RIPK1-dependent but MLKL-independent cell death in the absence of caspase-8. AB - 24(S)-Hydroxycholesterol (24S-OHC), which is enzymatically produced in the brain, is known to play an important role in maintaining brain cholesterol homeostasis. We have previously reported that 24S-OHC induces a type of non-apoptotic programmed necrosis in neuronal cells expressing little caspase-8. Necroptosis has been characterized as a type of programmed necrosis in which activation of receptor-interacting protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like (MLKL) is involved in the signaling pathway. In the present study, we investigated the involvement of these three proteins in 24S-OHC-induced cell death. We found that RIPK1 but neither RIPK3 nor MLKL was expressed in human neuroblastoma SH-SY5Y cells, while all three proteins were expressed in human T lymphoma caspase-8-deficient Jurkat (Jurkat(Cas8-/-)) cells. In Jurkat(Cas8-/-) cells, tumor necrosis factor alpha (TNFalpha)-induced cell death was significantly suppressed by treatment with respective inhibitors of RIPK1, RIPK3, and MLKL. In contrast, only RIPK1 inhibitor showed significant suppression of 24S OHC-induced cell death, and even this was less prominent than was observed in TNFalpha-induced cell death. In Jurkat(Cas8-/-) cells, knockdown of either RIPK1 or RIPK3 caused moderate but significant suppression of 24S-OHC-induced cell death, but no such effect was observed as a result of knockdown of MLKL. Collectively, these results suggest that, for both SH-SY5Y cells and Jurkat(Cas8 /-) cells, 24S-OHC-induced cell death is dependent on RIPK1 but not on MLKL. We therefore conclude that, in the absence of caspase-8 activity, 24S-OHC induces a necroptosis-like cell death which is RIPK1-dependent but MLKL-independent. PMID- 25697055 TI - Total synthesis of steroids and heterosteroids from BISTRO. AB - Due to their high profile biological activity, the steroids are among the most important secondary metabolites. A review of literature on the total synthesis of steroids starting from BISTRO (1,8-bis(trimethylsilyl)-2,6-octadiene) is presented. PMID- 25697056 TI - Phytosterols as precursors for the synthesis of aromatase inhibitors: Hemisynthesis of testololactone and testolactone. AB - Using beta-sitosterol and stigmasterol as precursor materials, a concise and efficient hemisynthesis of aromatase inhibitors: testololactone and testolactone was accomplished in a well-established reaction scheme. It involves highly effective Oppaneur oxidation of both beta-sitosterol as well as stigmasterol to generate the required enone moiety in ring 'A' of the desired steroid system. The Oppaneur oxidation products of both beta-sitosterol and stigmasterol were then subjected to oxidative cleavage of the side chain to produce 4-androstene-3,17 dione. Baeyer-Villiger oxidation of 4-androstene-3,17-dione using m-CPBA yielded testololactone. Dehydrogenation of 4-androstene-3,17-dione using phenylselenyl chloride in ethyl acetate followed by selenoxide elimination with H2O2 in dichloromethane furnished androstenedienone. Baeyer-Villiger oxidation of the resulting androstenedienone yielded the desired testolactone (overall yield 33%). This expeditious reaction scheme may be exploited for the bulk production of aromatase inhibitors (especially testolactone marketed under the brand name Teslac) from the most abundant and naturally occurring phytosterols like beta sitosterol. PMID- 25697057 TI - Cholesterol and stigmasterol within a sunflower oil matrix: Thermal degradation and oxysterols formation. AB - The characteristics of the lipid matrix surrounding sterols exert a great influence in their thermal oxidation process. The objective of this work was to assess the oxidation susceptibility of equal amounts of cholesterol and stigmasterol within a sunflower oil lipid matrix (ratio 1:1:200) during heating (180 degrees C, 0-180min). Remaining percentage of sterols was determined and seven sterol oxidation products (SOPs) were analysed for each type of sterol along the heating treatment. Evolution of the fatty acid profile and vitamin E content of the oil was also studied. Overall oxidation status of the model system was assessed by means of Peroxides Value (PV) and TBARS. PV remained constant from 30min onwards and TBARS continued increasing along the whole heating treatment. Degradation of both cholesterol and stigmasterol fitted a first order curve (R(2)=0.937 and 0.883, respectively), with very similar degradation constants (0.004min(-1) and 0.005min(-1), respectively). However, higher concentrations of oxidation products were found from cholesterol (79MUg/mg) than from stigmasterol (53MUg/mg) at the end of the heating treatment. Profile of individual oxidation products was similar for both sterols, except for the fact that no 25-hydroxystigmasterol was detected. 7alpha-Hydroxy and 7-keto derivatives were the most abundant SOPs at the end of the treatment. PUFA and vitamin E suffered a significant degradation along the process, which was correlated to sterols oxidation. PMID- 25697058 TI - Accurate and sensitive liquid chromatography/tandem mass spectrometry simultaneous assay of seven steroids in monkey brain. AB - BACKGROUND: Following its secretion mainly by the adrenal glands, dehydroepiandrosterone (DHEA) acts primarily in the cells/tissues which express the enzymes catalyzing its intracellular conversion into sex steroids by the mechanisms of intracrinology. Although reliable assays of endogenous serum steroids are now available using mass spectrometry (MS)-based technology, sample preparation from tissue matrices remains a challenge. This is especially the case with high lipid-containing tissues such as the brain. With the combination of a UPLC system with a sensitive tandem MS, it is now possible to measure endogenous unconjugated steroids in monkey brain tissue. METHODS: A Shimadzu UPLC LC-30AD system coupled to a tandem MS AB Sciex Qtrap 6500 system was used. RESULTS: The lower limits of quantifications are achieved at 250 pg/mL for DHEA, 200 pg/mL for 5-androstenediol (5-diol), 12 pg/mL for androstenedione (4-dione), 50 pg/mL for testosterone (Testo), 10 pg/mL for dihydrotestosterone (DHT), 4 pg/mL for estrone (E1) and 1 pg/mL for estradiol (E2). The linearity and accuracy of quality controls (QCs) and endogenous quality controls (EndoQCs) are according to the guidelines of the regulatory agencies for all seven compounds. CONCLUSION: We describe a highly sensitive, specific and robust LC-MS/MS method for the simultaneous measurement of seven unconjugated steroids in monkey brain tissue. The single and small amount of sample required using a relatively simple preparation method should be useful for steroid assays in various peripheral tissues and thus help analysis of the role of locally-made sex steroids in the regulation of specific physiological functions. PMID- 25697059 TI - Perspectives on lantibiotic discovery - where have we failed and what improvements are required? AB - The increasing resistance of bacteria to conventional antimicrobial therapy within both the nosocomial and community environment has enforced the urgent requirement for the discovery of novel agents. This has stimulated increased research efforts within the field of lantibiotic discovery. Lantibiotics are ribosomally synthesised, post-translationally modified antimicrobial peptides that exhibit antimicrobial activity against a range of multi-drug-resistant (MDR) bacteria. The success of these agents as a novel treatment of MDR infections is exemplified by: the clinical development of MU1140 (mutacin 1140) and NAI-107 (microbisporicin), which are in late pre-clinical trials against gram-positive bacteria; NVB302 that has completed Phase I clinical trials for the treatment of Clostridium difficile infections and; duramycin that has completed Phase II clinical trials in the treatment of cystic fibrosis. Despite these potential successes, the traditional method of lantibiotic discovery involving the induction, production and identification is often an inefficient, time-consuming process creating a barrier to the efficient discovery of novel lantibiotics. The introduction of novel and innovative identification methods, including the application of probes and the ability to improve the stability and activity of agents via mutagenesis offer encouraging new areas to explore. The rapid expansion of available genome sequences of a wide variety of bacteria has revealed multiple interesting lantibiotic clusters that have the potential to be effective antimicrobials. However, due to the inefficient expression, screening and production methods currently employed, they are being assessed inefficiently and not rapidly enough to keep up with the ever-increasing demand for new agents. PMID- 25697060 TI - Frailty in NHANES: Comparing the frailty index and phenotype. AB - The two most commonly employed frailty measures are the frailty phenotype and the frailty index. We compared them to examine whether they demonstrated common characteristics of frailty scales, and to examine their association with adverse health measures including disability, self-reported health, and healthcare utilization. The study examined adults aged 50+ (n=4096) from a sequential, cross sectional sample (2003-2004; 2005-2006), National Health and Nutrition Examination Survey. The frailty phenotype was modified from a previously adapted version and a 46-item frailty index was created following a standard protocol. Both measures demonstrated a right-skewed distribution, higher levels of frailty in women, exponential increase with age and associations with high healthcare utilization and poor self-reported health. More people classified as frail by the modified phenotype had ADL disability (97.8%) compared with the frailty index (56.6%) and similarly for IADL disability (95% vs. 85.6%). The prevalence of frailty was 3.6% using the modified frailty phenotype and 34% using the frailty index. Frailty index scores in those who were classified as robust by the modified phenotype were still significantly associated with poor self-reported health and high healthcare utilization. The frailty index and the modified frailty phenotype each confirmed previously established characteristics of frailty scales. The agreement between frailty and disability was high with each measure, suggesting that frailty is not simply a pre-disability stage. Overall, the frailty index classified more people as frail, and suggested that it may have the ability to discriminate better at the lower to middle end of the frailty continuum. PMID- 25697061 TI - Nociceptin/orphanin FQ and stress regulate synaptophysin expression in the rat fundic and colonic mucosa. AB - Nociceptin/orphanin FQ (N/OFQ), the endogenous ligand of the N/OFQ peptide (NOP) receptor, is a neuropeptide regulating gastrointestinal functions. The present study investigated the influence of acute cold-restraint stress and of short- and long-lasting peripheral infusion of N/OFQ on the level of synaptophysin, an exocytotic protein involved in neural plasticity. Exposure to cold-restraint stress for 3h or subcutaneous infusion of N/OFQ, 1 MUg/kg/h for 4h, induced a significant increase of the area of synaptophysin-immunoreactive nerve fibers in the fundic mucosa, while prolonged subcutaneous infusion of N/OFQ, 1 MUg/kg/h for 52 h and for 14 days, did not modify the synaptophysin-immunostained fibers. In the colonic mucosa stress exposure and subcutaneous infusion of N/OFQ, at any time point considered, had no significant effect on the area of synaptophysin immunoreactive nerve fibers. Synaptophysin immunoreactive nerve fibers were decreased in knockout rats for the NOP receptor gene both in the fundic and colonic mucosa. Synaptophysin-immunoreactivity was demonstrated in cells located in the basal portion of the fundic mucosa. Our study is the first to show that the N/OFQ/NOP receptor system influences the expression of synaptophysin and hence the process of exocytosis both in nerve terminals and in cells. PMID- 25697062 TI - MiR-124 promotes bone marrow mesenchymal stem cells differentiation into neurogenic cells for accelerating recovery in the spinal cord injury. AB - In this research, mouse BMMSCs were isolated from bone marrow, induced to differentiate into neurogenic cells in vitro, and transplanted into the injured spinal cord after over-expression of miR-124. The results showed that the BMMSCs could induce the differentiation to neurogenic cells under the special condition medium, but when the miR-124 was over-expressed, the differentiation efficiency of neurogenic cells from BMMSCs could be promoted. This reason was demonstrated that polypyrimidine tract-binding protein 1 (PTBP1) showed a repressor for polypyrimidine tract-binding protein 2 (PTBP2) during neuronal differentiation, miR-124 reduces PTBP1 levels, leading to the accumulation of correctly spliced PTBP2 mRNA and a dramatic increase in PTBP2 protein. miR-124 promoted neurogenic cells from BMMSCs were successful colonized into injured spinal cord for participation in tissue-repair. In conclusion, our research shows that the miR 124 promoted the differentiation of neuronal cells from BMMSCs, and this mechanism was miR-124 reduced the expression of PTBP1, increased the expression of PTBP2. PMID- 25697063 TI - A clinicopathological study of perineural invasion and vascular invasion in oral tongue squamous cell carcinoma. AB - The risk factors for recurrence of head and neck cancer are classified as being of high or intermediate risk. Those of intermediate risk include multiple positive nodes without extracapsular nodal spread, perineural/vascular invasion, pT3/T4 primary tumours, and positive level IV/V nodes. However, little evidence is available to validate these intermediate risk factors. We analyzed perineural/vascular invasion in 89 patients who underwent radical surgery for oral tongue squamous cell carcinoma, whose records were reviewed retrospectively. Perineural invasion was found in 27.0% of cases and vascular invasion in 23.6%; both had a strong relationship with histopathological nodal status (P = 0.005). The 5-year disease-specific survival (DSS) and overall survival rates of patients with perineural invasion were significantly lower than those of patients without perineural invasion (P < 0.001 and P = 0.002, respectively). The 5-year DSS of UICC stage I and II cases with perineural/vascular invasion was significantly lower than those without (P < 0.001 and P = 0.008, respectively). Perineural invasion and vascular invasion are risk factors for regional metastasis and a poor prognosis. We recommend elective neck dissection when perineural/vascular invasion is found in clinical stage I and II cases. The accumulation of further evidence to consider intermediate risks is required. PMID- 25697064 TI - A videofluoroscopic study comparing severe swallowing disorders in patients treated surgically or with radiation for oropharyngeal cancer. AB - The aim of this study was to analyze the causal mechanisms of severe swallowing disorders after the treatment of oropharyngeal cancer. Twenty-six patients with severe swallowing disorders at >=12 months after treatment for oropharyngeal cancer were analyzed retrospectively using videofluoroscopy. Fourteen patients (54%) had been treated with surgery (+/-postoperative radiotherapy), while 12 patients (46%) had been treated with (chemo)radiotherapy. Videofluoroscopy analysis showed a localized alteration in the surgical excision area resulting in impaired tongue root retraction in the surgical group (P=0.012), while general impairment of the pharyngeal, laryngeal, and upper oesophagus sphincter was found in the non-surgical group. Aspirations in the surgical group most often occurred after swallowing, while in the non-surgical group, they occurred during and after swallowing (P=0.039). This analysis by videofluoroscopy provides important insights into the mechanisms giving rise to swallowing disorders after the treatment of oropharyngeal cancer. PMID- 25697065 TI - The timing of acid-induced increase in saliva secretion in transplanted submandibular glands. AB - The purpose of this study was to determine the timing of acid-induced increase in saliva secretion and to investigate the possibility of parasympathetic reinnervation of transplanted submandibular glands (SMGs). Citric acid stimulation-induced changes in secretion of transplanted SMGs were evaluated in 27 patients who underwent SMG transplantation for keratoconjunctivitis sicca (KCS); (99m)Tc scintigraphy and Schirmer tests were done at 1, 3, 6, and 9 months after transplantation. Acetylcholinesterase staining was conducted to confirm the presence of parasympathetic reinnervation in three SMGs at 6 and 9 months after transplantation. Schirmer tests showed significantly increased secretion of the transplanted SMGs after acid stimulation at 6 and 9 months, but not at 1 and 3 months. On (99m)Tc scintigraphy, no decline was detected on the dynamic time activity curve after acid stimulation at 1 and 3 months, but a decline was detected in nine glands at 6 months and in 19 glands at 9 months. No decline was observed in the remaining eight glands at 9 months after transplantation. The histology findings were consistent with scintigraphy results. In conclusion, acid induced increase in saliva secretion occurs at >=6 months after SMG transplantation, and parasympathetic reinnervation of the transplanted SMG might occur. PMID- 25697066 TI - Therapeutic polo-like kinase 1 inhibition results in mitotic arrest and subsequent cell death of blasts in the bone marrow of AML patients and has similar effects in non-neoplastic cell lines. AB - Polo-like kinase 1 (PLK1) is an important regulator of the cell cycle and is overexpressed in various solid and hematological malignancies. Small molecule inhibitors targeting PLK1, such as BI2536 or BI6727 (Volasertib) are a promising therapeutic approach in such malignancies. Here, we show a loss of specifically localized PLK1 in AML blasts in vivo, accompanied by mitotic arrest with transition into apoptosis, in bone marrow biopsies of AML patients after treatment with BI2536. We verify these results in live cell imaging experiments with the AML cell line HL-60, and demonstrate that non-neoplastic, immortalized lymphoblastoid cells are also sensitive to PLK1 inhibition. It is demonstrated that normal granulopoietic precursors have similar PLK1 expression levels as leukemic blasts. These results are in line with the adverse effects of PLK1 inhibition and underline the great potential of PLK1 inhibitors in the treatment of AML. PMID- 25697067 TI - Cognitive and executive functions, social cognition and sense of coherence in adults with fetal alcohol syndrome. AB - BACKGROUND: Primary disabilities in children with fetal alcohol syndrome (FAS) are the results of alcohol's teratogen effect on the fetal brain. Reduced cognitive and executive functions and social cognition are examples of such disabilities. Little is known about primary disabilities in adults with FAS as well as their sense of coherence (SoC). There is thus a need for knowledge about FAS in adulthood. AIMS: To investigate cognitive and executive functions, social cognition and SoC in adults with FAS. METHODS: Twenty adults with FAS (mean age: 30 years) were compared with 20 individuals matched on gender and age. Berg's Card-sorting Test-64, the Tower of Hanoi, Raven's Coloured Progressive Matrices, Digit Span, Faux Pas and the Swedish version of Antonovsky's Sense of Coherence Scale (SoC-29) were used. RESULTS: The FAS group had a weak SoC and displayed deficits in the neuropsychological tests sensitive to cognitive and executive functions and social cognition. The FAS group's median SoC score was 112, lower than the comparison group's median of 133 (P < 0.001). The FAS group had median scores of 29.0 on Raven's Matrices. The median for Digit Span was 5 forwards and 3 backwards, lower than in the comparison group (P < 0.001). CONCLUSIONS: Reduced cognitive and executive functions and impaired social cognition are assumed to have a major impact on life for adults with FAS. We suggest that the findings showing that adults with FAS had a weak SoC, with particularly low scores on the manageability scale, reflect their experiences of living with those primary disabilities. CLINICAL IMPLICATIONS: This study may enhance healthcare for individuals prenatally exposed to alcohol. In general, it contributes with knowledge about this group of individuals who need to be more visible in healthcare, and particularly, it demonstrates some of the neuropsychological disabilities they might have. PMID- 25697068 TI - Chronic lipopolysaccharide infusion fails to induce depressive-like behaviour in adult male rats. AB - BACKGROUND: Chronic inflammation is implicated in numerous diseases, including major depression and type 2 diabetes mellitus (T2DM). Since depression and T2DM often co-exist, inflammatory pathways are suggested as a possible link. Hence, the establishment of an immune-mediated animal model would shed light on mechanisms possibly linking depression and metabolic alterations. OBJECTIVE: In this study we investigated a behavioural and metabolic paradigm following chronic infusion with low doses of lipopolysaccharide (LPS) using osmotic minipumps in male rats. METHODS: Behavioural testing consisted of evaluating activity level in the open field and depressive-like behaviour in the forced swim test. Metabolic assessment included measurement of body weight, food and water intake, and glucose and insulin levels during an oral glucose tolerance test. RESULTS: LPS infused rats showed acute signs of sickness behaviour, but chronic LPS infusion did not induce behavioural or metabolic changes. CONCLUSION: These results suggest that although inflammation is immediately induced as indicated by acute sickness, 4 weeks of chronic LPS administration via osmotic minipumps did not result in behavioural changes. Therefore, this paradigm may not be a suitable model for studying the underlying mechanisms that link depression and T2DM. PMID- 25697069 TI - [Effect of cell therapy in patients with chronic ischaemic heart disease--a survey of a Cochrane review]. AB - The present Cochrane review included 23 studies randomized placebo-controlled clinical trials with a total of 1,255 patients. The effect of autologous cell therapy versus placebo was examined on left ventricular ejection fraction (LVEF), adverse effects and mortality in patients with chronic ischaemic heart disease. Patients treated with cell therapy had improved LVEF and functional status compared to patients who received placebo. There were no cell-related and only few procedure-related side effects. A positive effect of cell therapy on long term survival was also demonstrated. PMID- 25697070 TI - [Premature vaginal delivery with breech presentation]. AB - Only a few cases of extremely premature deliveries with breech presentation are described in the literature. We report on a vaginal breech presentation case of a living child without neurologic problems after six months. Therefore, breech presentation may be a possibility when performing a vaginal delivery of extremely premature children. PMID- 25697071 TI - [Severe bradycardia in general anaesthesia in a patient treated with cholinesterase inhibitors for dementia]. AB - Patients suffering from Alzheimer's disease, Parkinson's disease and dementia with Lewy bodies can be treated well with the cholinesterase inhibitors rivastigmine or donepezil, and because of the increasing number of these patients undergoing surgery in general anaesthesia we find it urgent to draw attention to possible complications such as severe bradycardia or third-degree heart block when propofol and remifentanil are being used. PMID- 25697072 TI - [Clinical considerations in the interpretation of elevated troponin levels]. AB - The essential role of cardiac troponin (cTn) in the diagnosis of acute myocardial infarction has led to the development of high-sensitivity assays, which are able to detect very small amounts of myocardial necrosis. However, although elevated blood levels of cTn indicate myocardial injury, they do not provide a causal explanation. The differential diagnosis of minor elevations of the cTn-level is broad and includes both acute and chronic cardiac and non-cardiac conditions. The purpose of this paper is to review common causes of elevated cTn-levels in daily clinical practice. PMID- 25697073 TI - [Ischaemic preconditioning for protection against reperfusion injury in non cardiac surgery]. AB - Remote ischaemic preconditioning is a non-invasive intervention that is done by transient occlusion of the blood flow to a limb with a blood pressure cuff. The intervention initiates a systemic endogenous protective response, which may confer multi-organ protection against acute ischaemia reperfusion injury. Originally discovered as a therapeutic strategy in cardiac surgery for protecting the myocardium against ischaemia reperfusion injury, it has been discovered that remote ischaemic preconditioning may confer protection against surgical stress and reperfusion injury in non-cardiac surgery. PMID- 25697074 TI - High risk human papillomavirus persistence among HIV-infected young women in South Africa. AB - OBJECTIVES: Persistence of infection with high-risk Human papillomaviruses (HR HPV) increases the risk of incident and progressive precancerous lesions of the cervix. Rates of HR-HPV persistence have been shown to be increased among HIV infected adult women, however there is a paucity of literature addressing HPV persistence in the young HIV-infected population. We compared rates of HR-HPV persistence between HIV-infected and HIV-uninfected young women. METHODS: We obtained self-collected vaginal swabs at six-month intervals from 50 HIV uninfected and 33 HIV-infected young women recruited through a community youth center (age 17-21 years) and compared rates of HR-HPV persistence. HR-HPV testing was conducted using the Roche's Linear Array(r) HPV Test. RESULTS: Eighty-three prevalent (upon baseline testing) and incident (upon subsequent testing) individual HR-HPV infections were identified among 43 members of the cohort (23 HIV-uninfected and 20 HIV-infected). At twelve months, 19% of baseline HR-HPV infections continued to be present with a statistically significant difference between HIV-uninfected and HIV-infected participants (4% versus 31%; p=0.01). CONCLUSIONS: HIV-infected young women in our cohort had a seven-fold increased rate of persistence of HR-HPV overall at 12 months, indicating an increased risk for incident and progressive precancerous lesions. Identification of persistent infection with HR-HPV may complement cytological findings in determining the need for colposcopy. PMID- 25697075 TI - Regiospecific synthesis of tetrasubstituted phthalocyanines and their liquid crystalline order. AB - Metal-free and metal(II) all-endo-tetraalkoxy-phthalocyanines of C4h symmetry are synthesised regiospecifically from 3-(2-butyloctyloxy)phthalonitrile with lithium octanolate and subsequent metal ion exchange. The voluminous, yet not overly large, and racemically disordered alkoxy substituent not only renders the cyclotetramerisation regiospecific, but also leads to liquid crystalline self assembly with attainable clearing temperatures and persisting columnar organisation at room temperature. A rare hexagonal mesophase with twelve columns per hexagonal unit cell is found in the metal-free homologue, whereas the metal complexes show rectangular mesophases. The clearing temperature increases with increasing axial component of the metal ion coordination sphere. At low temperature, significant antiferromagnetic exchange between magnetic centres is observed for the Co(II) homologue, whereas the magnetic centres are magnetically independent in the Cu(II) derivative, in line with the observed higher clearing temperature in the Co(II) case that testifies of stronger interdisk interactions. PMID- 25697077 TI - Predicting the reactivity of hydride donors in water: thermodynamic constants for hydrogen. AB - The chemical reactivity of hydride complexes can be predicted using bond strengths for homolytic and heterolytic cleavage of bonds to hydrogen. To determine these bond strengths, thermodynamic constants describing the stability of H(+), H, H(-), and H2 are essential and need to be used uniformly to enable the prediction of reactivity and equilibria. Due to discrepancies in the literature for the constants used in water, we propose the use of a set of self consistent constants with convenient standard states. PMID- 25697078 TI - Positional flexibility: syntheses and characterization of six uranium chalcogenides related to the 2H hexagonal perovskite family. AB - Six new uranium chalcogenides, Ba4USe6, Ba3FeUSe6, Ba3MnUSe6, Ba3MnUS6, Ba3.3Rb0.7US6, and Ba3.2K0.8US6, related to the 2H hexagonal perovskite family have been synthesized by solid-state methods at 1173 K. These isostructural compounds crystallize in the K4CdCl6 structure type in space group D3d6-R3c of the trigonal system with six formula units per cell. This structure type is remarkably flexible. The structures of Ba3FeUSe6, Ba3MnUSe6, and Ba3MnUS6 consist of infinite infinity1[MUQ66-] chains (M = Fe or Mn; Q = S or Se) oriented along the c axis that are separated by Ba atoms. These chains are composed of alternating M-centered octahedra and U-centered trigonal prisms sharing triangular faces; in contrast, in the structures of Ba4USe6, Ba3.3Rb0.7US6, and Ba3.2K0.8US6, there are U-centered octahedra alternating with Ba-, Rb-, or K centered trigonal prisms. Moreover, the Ba4USe6, Ba3FeUSe6, Ba3MnUSe6, and Ba3MnUS6 compounds contain U4+, whereas Ba3.3Rb0.7US6 and Ba3.2K0.8US6 are mixed U4+/5+ compounds. Resistivity and MU-Raman spectroscopic measurements and DFT calculations provide additional insight into these interesting subtle structural variations. PMID- 25697079 TI - Physicochemical characterisation and radical-scavenging activity of Cucurbitaceae seed oils. AB - Oils extracted from Cucurbitaceae seeds were characterised for their fatty acid and tocopherol compositions. In addition, some physicochemical characteristics, total phenolic contents and the radical-scavenging activities were determined. Oil content amounted to 23.9% and 27.1% in melon and watermelon seeds, respectively. Physicochemical characteristics were similar to those of other edible oils and the oils showed significant antioxidant activities. Fatty acid composition showed total unsaturated fatty acid content of 85.2-83.5%, with linoleic acid being the dominant fatty acid (62.4-72.5%), followed by oleic acid (10.8-22.7%) and palmitic acid (9.2-9.8%). The oils, especially watermelon seed oil, showed high total tocopherol and phenolic contents. The gamma-tocopherol was the predominant tocopherol in both oils representing 90.9 and 95.6% of the total tocopherols in melon and watermelon seed oils, respectively. The potential utilisation of melon and watermelon seed oils as a raw material for food, chemical and pharmaceutical industries appears to be favourable. PMID- 25697080 TI - Effectiveness of individualized fall prevention program in geriatric rehabilitation hospital setting: a cluster randomized trial. AB - BACKGROUND AND AIMS: There is no conclusive evidence that hospital fall prevention programs can reduce the number of falls. We aimed to investigate the effect of a targeted individualized falls prevention program in a geriatric rehabilitation hospital. METHODS: This was a two-stage cluster-controlled trial carried out in five geriatric rehabilitation wards. Participants were 752 patients with mean age 83.2 years. The intervention was a two-phase targeted intervention falls prevention program. The intervention included an assessment of patient's risk by a risk assessment tool and an individual management that includes medical, behavioral, cognitive and environmental modifications. Patients with moderate risk received additionally orientation guidance, and mobility restriction. Patients determined as high risk were additionally placed under permanent personal supervision. Outcome measures were falls during hospital stay. RESULTS: In both stages of the trial, intervention and control wards were almost similar at baseline for individual patient characteristics. Overall, 37 falls occurred during the study. No significant difference was found in fall rates during follow-up between intervention and control wards: 1.306 falls per 1000 bed days in the intervention groups and 1.763-1.826 falls per 1000 bed days in the control groups. The adjusted hazard ratio for falls in the intervention groups was 1.36 (95 % confidence interval 0.89-1.77) (P = 0.08) in the first stage and 1.27 (95 % confidence interval 0.92-1.67) (P = 0.12) in the second stage. CONCLUSION: These results suggest that in a geriatric rehabilitation hospital a targeted individualized intervention falls prevention program is not effective in reducing falls. PMID- 25697081 TI - Pregnant women in Timis County, Romania are exposed primarily to low-level (<10MUg/l) arsenic through residential drinking water consumption. AB - Excessive arsenic content in drinking water poses health risks to millions of people worldwide. Inorganic arsenic (iAs) in groundwater exceeding the 10MUg/l maximum contaminant level (MCL) set by the World Health Organization (WHO) is characteristic for intermediate-depth aquifers over large areas of the Pannonian Basin in Central Europe. In western Romania, near the border with Hungary, Arad, Bihor, and Timis counties use drinking water coming partially or entirely from iAs contaminated aquifers. In nearby Arad and Bihor counties, more than 45,000 people are exposed to iAs over 10MUg/l via public drinking water sources. However, comparable data are unavailable for Timis County. To begin to address this data gap, we determined iAs in 124 public and private Timis County drinking water sources, including wells and taps, used by pregnant women participating in a case-control study of spontaneous loss. Levels in water sources were low overall (median=3.0; range=<0.5-175MUg/l), although higher in wells (median=3.1, range=<0.5-1.75) than in community taps (median=2.7, range=<0.5-36.4). In a subsample of 20 control women we measured urine biomarkers of iAs exposure, including iAs (arsenite and arsenate), dimethylarsinic acid (DMA), and methylarsonic acid (MMA). Median values were higher among 10 women using iAs contaminated drinking water sources compared to 10 women using uncontaminated sources for urine total iAs (6.6 vs. 5.0MUg/l, P=0.24) and DMA (5.5 vs. 4.2MUg/l, P=0.31). The results suggested that the origin of urine total iAs (r=0.35, P=0.13) and DMA (r=0.31, P=0.18) must have been not only iAs in drinking-water but also some other source. Exposure of pregnant women to arsenic via drinking water in Timis County appears to be lower than for surrounding counties; however, it deserves a more definitive investigation as to its origin and the regional distribution of its risk potential. PMID- 25697082 TI - Behavior of cesium in municipal solid waste incineration. AB - As a result of the Fukushima Daiichi Nuclear Power Plant accident on March 11, 2011 in Japan radioactive nuclides, primarily (134)Cs and (137)Cs were released, contaminating municipal solid waste and sewage sludge in the area. Although stabilizing the waste and reducing its volume is an important issue differing from Chernobyl nuclear power plant accident, secondary emission of radioactive nuclides as a result of any intermediate remediation process is of concern. Unfortunately, there is little research on the behavior of radioactive nuclides during waste treatment. This study focuses on waste incineration in an effort to clarify the behavior of radioactive nuclides, specifically, refuse-derived fuel (RDF) with added (133)Cs (stable nuclide) or (134)Cs (radioactive nuclide) was incinerated in laboratory- and pilot-scale experiments. Next, thermogravimetric (TG) and differential thermal analysis (DTA) of stable Cs compounds, as well as an X-ray absorption fine structure (XAFS) analysis of Cs concentrated in the ashes were performed to validate the behavior and chemical forms of Cs during the combustion. Our results showed that at higher temperatures and at larger equivalence ratios, (133)Cs was distributed to the bottom ash at lower concentration, and the influence of the equivalence ratio was more significant at lower temperatures. (134)Cs behaved in a similar fashion as (133)Cs. We found through TG-DTA and XAFS analysis that a portion of Cs in RDF vaporizes and is transferred to fly ash where it exists as CsCl in the MSW incinerator. We conclude that Cs-contaminated municipal solid wastes could be incinerated at high temperatures resulting in a small amount of fly ash with a high concentration of radioactive Cs, and a bottom ash with low concentrations. PMID- 25697083 TI - Validation of FRAX without BMD: an age-related analysis of the Fifth Korean National Health and Nutrition Examination Survey (KNHANES V-1, 2010). AB - Although the Fracture Risk Assessment Tool (FRAX) is widely used to evaluate probabilities of fractures, there is no consensus regarding whether it is accurate when bone mineral density (BMD) is not included. This cross-sectional study aimed to compare the 10-year predicted fracture probabilities calculated using FRAX with and without BMD. Data were collected from the 2010 Fifth Korean National Health and Nutrition Examination Survey, and 2706 participants (1260 men and 1446 women) aged 50-90 years were analyzed. Ten-year predicted probabilities for major osteoporotic and hip fractures were calculated using the FRAX model. In men, the 10-year probabilities without BMD were 3.9+/-1.8% and 1.3+/-1.4% for major osteoporotic and hip fractures, respectively. In women, the 10-year probabilities without BMD were 7.7+/-4.4% and 2.6+/-2.9% for major osteoporotic and hip fractures, respectively. These probabilities were significantly correlated with the probabilities calculated using FRAX with BMD (all, p<0.001). When participants were divided into 10-year age groups and compared with the 10 year predicted fracture probability with BMD, the 10-year predicted fracture probability without BMD was lower in men 50-59 years old, similar to men 60-69 years old, and higher in men >=70 years old. The FRAX scores without BMD were generally lower for all women. The FRAX model without BMD appears to be a slightly lower fracture probability compared to that calculated with BMD, especially in younger participants. Although these results have important clinical implications for areas with limited ability to evaluate BMD, they must be confirmed by a large prospective study. PMID- 25697076 TI - Prevalence of Stable Angina in Spain. Results of the OFRECE Study. AB - INTRODUCTION AND OBJECTIVES: The objective of the OFRECE study was to estimate the prevalence of stable angina in Spain. This prevalence is currently unknown, due to a lack of recent studies and to changes in the epidemiology and treatment of ischemic heart disease. METHODS: This cross-sectional study involved a representative sample of the Spanish population aged 40 years or older, obtained via 2-stage random sampling: in the first stage, primary care physicians were randomly selected from each Spanish province, whereas in the second stage 20 people were selected from the population assigned to each physician. The prevalence was weighted by age, sex, and geographical area. Participants were classified as having angina if they met the "definite angina" criteria of the Rose questionnaire and as having confirmed angina if the angina was confirmed by a cardiologist or if they had a history of acute ischemic heart disease or revascularization. RESULTS: Of the 11 831 people invited to participate, 8378 (71%) were analyzed (mean age, 59.2 years). The weighted prevalence of definite angina (Rose) was 2.6% (95% confidence interval, 2.1%-3.1%) and was higher in women (2.9%) than in men (2.2%), whereas that of confirmed angina was 1.4% (95% confidence interval, 1.0%-1.8%), without differences between men (1.5%) and women (1.3%). The prevalence of definite angina (Rose) increased with age (0.7% in patients aged 40 to 49 years and 7.1% in those aged 70 years or older), history of cardiovascular disease, and cardiovascular risk factors, except smoking. CONCLUSIONS: The prevalence of definite angina (Rose) in the Spanish population aged 40 years or older was 2.6%, whereas that of confirmed angina was 1.4%. Both prevalences increased with age, cardiovascular risk factors, and cardiovascular history. PMID- 25697084 TI - Adolescence physical activity is associated with higher tibial pQCT bone values in adulthood after 28-years of follow-up--the Cardiovascular Risk in Young Finns Study. AB - High peak bone mass and strong bone phenotype are known to be partly explained by physical activity during growth but there are few prospective studies on this topic. In this 28-year follow-up of Cardiovascular Risk in Young Finns Study cohort, we assessed whether habitual childhood and adolescence physical activity or inactivity at the age of 3-18 years were associated with adult phenotype of weight-bearing tibia and the risk of low-energy fractures. Baseline physical activity and data on clinical, nutritional and lifestyle factors were assessed separately for females and males aged 3-6-years (N=395-421) and 9-18-years (N=923 965). At the age of 31-46-years, the prevalence of low-energy fractures was assessed with a questionnaire and several tibial traits were measured with pQCT (bone mineral content (BMC; mg), total and cortical cross-sectional areas (mm(2)), trabecular (for the distal site only) and cortical (for the shaft only) bone densities (mg/cm(3)), stress-strain index (SSI; mm(3), for the shaft only), bone strength index (BSI; mg(2)/cm(4), for the distal site only) and the cortical strength index (CSI, for the shaft only)). For the statistical analysis, each bone trait was categorized as below the cohort median or the median and above and the adjusted odds ratios (OR) were determined. In females, frequent physical activity at the age of 9-18-years was associated with higher adulthood values of BSI, total and cortical areas, BMC, CSI and SSI at the tibia independently of many health and lifestyle factors (ORs 0.33-0.53, P<=0.05; P-values for trend 0.002-0.05). Cortical density at the tibial shaft showed the opposite trend (P value for trend 0.03). Similarly in males, frequent physical activity was associated with higher values of adult total and cortical areas and CSI at the tibia (ORs 0.48-0.53, P<=0.05; P-values for trend 0.01-0.02). However, there was no evidence that childhood or adolescence physical activity was associated with lower risk of low energy fractures during the follow-up. In conclusion, frequent habitual physical activity in adolescence seems to confer benefits on tibial bone size and geometry in adulthood. PMID- 25697085 TI - Squamous cell carcinoma in a thyroglossal duct cyst: A case report with review of the literature. AB - Carcinoma arising within a thyroglossal duct cyst (TGDC) is exceedingly uncommon, occurring in about 1% of TGDC (Chrisoulidou et al., 2013 [1]). Since the first description of TGDC carcinoma in 1911 by Brentano, approximately 200 cases have been reported in the world literature, mostly as single case reports making its true incidence difficult to determine (Hanna, 1996 [2]). There are numerous reports in the literature of papillary and follicular TGDC carcinoma, but only limited reports of squamous cell carcinoma. In order for a lesion to qualify as squamous cell carcinoma of a TGDC, the lesion must arise from the epithelial lining. Recognition and understanding of this entity are important in staging and planning of treatment. Exclusion of primary squamous cell carcinoma arising from an adjacent structure or metastatic central compartment nodal disease is important in the evaluation for diagnosis to be confirmed. A thorough work up should be undertaken to exclude other primary malignancies that may have metastasized. We present a unique case of squamous cell carcinoma, along with supporting pathology and radiology imaging. We then review this rare entity and provide some insight into the diagnosis and management. PMID- 25697086 TI - Long term surgical and hearing outcomes in the management of tympanomastoid paragangliomas. AB - OBJECTIVE: To analyze the long term outcomes after surgery in tympanomastoid paragangliomas. STUDY DESIGN: Retrospective study. METHODS: The charts of 145 patients with tympanomastoid paragangliomas managed between 1988 and 2013 were reviewed. The clinical features, audiological data, pre- and postoperative notes were noted. The tumors were staged according to the modified Fish and Mattox classification. The surgical approaches for all patients were formulated according to the surgical algorithm developed at our center. RESULTS: 34 (23.5%), 46 (31.7%), 22 (15.2%), 18 (12.4%) and 25 (17.2%) patients were diagnosed to have TMP class A1, A2, B1, B2 and B3 tumors respectively. Gross tumor resection was achieved in 141 (97.2%) patients. The facial nerve was uncovered in four patients and infiltrated in three. The cochlea was found eroded in seven cases. The mean follow-up was 48.4 months. Recurrence was seen in one patient (0.7%). In the cases where the facial nerve was preserved (n=143), the nerve function was graded as HB grade 1 in 138 patients (97%). Postoperatively, the mean AC showed an improvement in all categories except in class B2 and B3, which corresponds to the classes that include patients who underwent subtotal petrosectomy. CONCLUSION: We report the long term surgical outcomes in tympanomastoid paragangliomas in the largest series published till date. It is possible to completely eradicate all types of tympanomastoid paragangliomas with minimum sequelae by choosing the correct surgical approach to achieve adequate exposure for individual tumor classes as described in our classification and algorithm. LEVEL OF EVIDENCE: IIb. PMID- 25697087 TI - The advantages and drawbacks of routine magnetic resonance imaging for long-term post-treatment locoregional surveillance of oral cavity squamous cell carcinoma. AB - PURPOSE: Assess the clinical utility and accuracy of routine surveillance head and neck magnetic resonance imaging (HN-MRI) for the detection of locoregional recurrence in patients with a history of oral cavity squamous cell carcinoma (OCSCC) without concurrent suspicious symptoms or signs 6 months or more after treatment. MATERIALS AND METHODS: For OCSCC patients who underwent routine (defined as: without concurrent suspicious symptoms or signs) surveillance HN-MRI at 6 months or more after treatment completion, we retrospectively determined the detection rate of locoregional disease and false positive rate. RESULTS: Out of an original cohort of 533 OCSCC patients, 46 patients, who were disease-free 6 months after treatment, had undergone 108 routine HN-MRIs from 6 to 48 months after surgery without the presence of concurrent suspicious symptoms or signs and had 6 months of subsequent follow up. 1 out of 46 (2.2%) had a true positive regional recurrence. 10 out of 46 (21.7%) patients experienced a false positive locoregional finding. CONCLUSIONS: Routine HN-MRI for locoregional surveillance of OCSCC, when used in patients without concurrent suspicious symptoms or exam findings over 6 months since treatment, may be unnecessary and costly given the very low rate of recurrence and high false positive rate. Our study supports the National Comprehensive Cancer Network guideline of limiting imaging after 6 months of primary treatment completion to patients with suspicious clinical findings. Nonetheless, managing physicians should continue to be empowered to use surveillance imaging based on risk profiles and unique circumstances for each patient. PMID- 25697088 TI - Neuro-otologic manifestations of tuberculosis. "The great imitator". AB - OBJECTIVE: To demonstrate the different neuro-otologic clinical presentations of tuberculosis. STUDY DESIGN: Retrospective clinical analysis. RESULT: 83.3% of the cases of ear or central nervous system TB were without concomitant lung disease. 2 cases had primary infection in the central nervous system. The neuro-otologic manifestation was as follows: 85.7% sensorineural hearing loss; 42% polyneuropathy. 71.4% had granulation tissue. 2 had normal otoscopy. In 6 patients the histopathology and Ziehl Neelsen were confirmatory. One case was confirmed by the positive response to treatment with antituberculosis drugs. CONCLUSIONS: Tuberculosis has a wide variety of neurotologic manifestations from chronic otitis media cadres to vestibular, audiological and neurological manifestations as well as a large variability in imaging studies. PMID- 25697089 TI - Evaluation of two community-controlled peer support services for assessment and treatment of hepatitis C virus infection in opioid substitution treatment clinics: The ETHOS study, Australia. AB - AIM: Peer support services have been shown to be beneficial in increasing uptake and adherence to treatment in other areas but few examples of these services exist in hepatitis C (HCV) care. This study examined the performance of two community-controlled peer support services operating within a larger study aimed at increasing access to HCV care and treatment for opiate substitution treatment (OST) clients, ETHOS. METHODS: Semi-structured interviews were conducted in two clinics with three groups of participants: clients (n=31), staff (n=8) and peer workers (n=3) and examined the operation of the service in relation to process, outputs and impacts. RESULTS: There was a very strong positive response to the peer worker services reported by staff and clients who had and had not interacted with a peer worker. A number of changes were reported that were not explicit goals of the service including providing access to additional services for clients and staff, peer workers acting as mediators between clients and staff and a less tangible notion of a changing "feel" of the clinic to a more positive and client-friendly social and physical space. Explicit goals of the service were also reported in peer workers supporting clients to consider and prepare for treatment (via blood tests and other assessments) as well as provide information and support about treatment. CONCLUSIONS: The peer support service was acceptable to clients and clinic staff. All groups of participants noted that the service met its goals of engaging clients, building trusting relationships and providing instrumental support for clients to access HCV treatment. Peer workers may also contribute to more effective deployment of health resources by preparing clients for clinical engagement with HCV health workers. PMID- 25697090 TI - Primary functions of the quadratus femoris and obturator externus muscles indicated from lengths and moment arms measured in mobilized cadavers. AB - BACKGROUND: The small muscles of the pelvis and hip are often implicated in painful conditions. Although the quadratus femoris and obturator externus are usually described as external rotators of the hip, little is known about how they change their lengths and moment arms during human movement. Therefore, more precise measurements defining the positions and directions for their maximal strength and stretch are needed to better describe their functions and guide the clinical approach to pain. METHODS: Repeated measurements of the muscle lengths and range of motion were obtained using wires simulating dissected muscles on human cadaver hips. The lengths were measured at every 15 degrees of flexion with and without maximal range of ab/adduction, rotation, and combinations of the two motions. Measurements were obtained from normal hips (n=3), and movement lengthening relations were later differentiated into movement-moment arm relations. FINDINGS: The quadratus femoris showed maximum lengthening by flexion, adduction or abduction, and internal rotation, with the largest moment arms observed for extension in the deduced force-length efficient range of 60-90 degrees flexion. The obturator externus showed maximum lengthening by extension, abduction, and internal rotation, with the largest moment arms observed for flexion and adduction in the deduced force-length efficient range around the hip's neutral position. INTERPRETATION: Our findings indicate that maximal strength of the quadratus femoris muscle will be delivered in a flexed position towards extension, while maximal strength of the obturator externus muscle will be delivered in an extended position towards flexion and adduction. PMID- 25697091 TI - Bayesian outcome-based strategy classification. AB - Hilbig and Moshagen (Psychonomic Bulletin & Review, 21, 1431-1443, 2014) recently developed a method for making inferences about the decision processes people use in multi-attribute forced choice tasks. Their paper makes a number of worthwhile theoretical and methodological contributions. Theoretically, they provide an insightful psychological motivation for a probabilistic extension of the widely used "weighted additive" (WADD) model, and show how this model, as well as other important models like "take-the-best" (TTB), can and should be expressed in terms of meaningful priors. Methodologically, they develop an inference approach based on the Minimum Description Length (MDL) principles that balances both the goodness-of-fit and complexity of the decision models they consider. This paper aims to preserve these useful contributions, but provide a complementary Bayesian approach with some theoretical and methodological advantages. We develop a simple graphical model, implemented in JAGS, that allows for fully Bayesian inferences about which models people use to make decisions. To demonstrate the Bayesian approach, we apply it to the models and data considered by Hilbig and Moshagen (Psychonomic Bulletin & Review, 21, 1431-1443, 2014), showing how a prior predictive analysis of the models, and posterior inferences about which models people use and the parameter settings at which they use them, can contribute to our understanding of human decision making. PMID- 25697092 TI - New, recurrent, and prevalent mutations: Clinical and molecular characterization of 26 Chinese patients with 17alpha-hydroxylase/17,20-lyase deficiency. AB - BACKGROUND: Combined 17alpha-hydroxylase/17,20-lyase deficiency (17OHD), caused by mutations in the CYP17A1 gene, is a rare autosomal recessive form of congenital adrenal hyperplasia and characterized by hyporeninemic hypokalemic hypertension, primary amenorrhea and absence of secondary sexual characteristics. SUBJECTS AND METHODS: Twenty six 17OHD subjects from 23 Chinese families were recruited. The CYP17A1 gene was sequenced and 17alpha-hydroxylase/17,20-lyase enzymatic activities were assessed in vitro. RESULTS: Eight CYP17A1 mutations were identified in 23 patients. Of eight mutations, c.985_987delinsAA/p.Y329Kfs and c.1460_1469del/p.D487_F489del mutations accounted for 60.8% (28/46) and 21.7% (10/46) of the mutant alleles, respectively. The enzymatic activities for both mutations were completely abolished. We also identified three novel mutations c.971_972insG/p.K325Afx, c.1464_1466delT/p.F489Sfx and c.1386G>T/p.R462S. The enzymatic activities for c.971_972insG/p.K325Afx and c.1464_1466delT/p.F489Sfx mutations were almost completely abolished, whereas the mutation c.1386G>T/p.R462S only resulted in partial reduction of 17alpha-hydroxylase (34.6%) and 17,20 lyase activities (27.0%), which is correlated with the partial 17OHD phenotype in this patient. CONCLUSION: The c.985_987delinsAA/p.Y329Kfs and c.1460_1469del/p.D487_F489del mutations are prevalent in Chinese 17OHD patients. The genetic defects are well correlated with the phenotypes in both complete and partial forms of 17OHD. PMID- 25697093 TI - Pancreatic beta-cell identity, glucose sensing and the control of insulin secretion. AB - Insulin release from pancreatic beta-cells is required to maintain normal glucose homoeostasis in man and many other animals. Defective insulin secretion underlies all forms of diabetes mellitus, a disease currently reaching epidemic proportions worldwide. Although the destruction of beta-cells is responsible for Type 1 diabetes (T1D), both lowered beta-cell mass and loss of secretory function are implicated in Type 2 diabetes (T2D). Emerging results suggest that a functional deficiency, involving de-differentiation of the mature beta-cell towards a more progenitor-like state, may be an important driver for impaired secretion in T2D. Conversely, at least in rodents, reprogramming of islet non-beta to beta-cells appears to occur spontaneously in models of T1D, and may occur in man. In the present paper, we summarize the biochemical properties which define the 'identity' of the mature beta-cell as a glucose sensor par excellence. In particular, we discuss the importance of suppressing a group of 11 'disallowed' housekeeping genes, including Ldha and the monocarboxylate transporter Mct1 (Slc16a1), for normal nutrient sensing. We then survey the changes in the expression and/or activity of beta-cell-enriched transcription factors, including FOXO1, PDX1, NKX6.1, MAFA and RFX6, as well as non-coding RNAs, which may contribute to beta-cell de-differentiation and functional impairment in T2D. The relevance of these observations for the development of new approaches to treat T1D and T2D is considered. PMID- 25697094 TI - Comparative structural analysis of the caspase family with other clan CD cysteine peptidases. AB - Clan CD forms a structural group of cysteine peptidases, containing seven individual families and two subfamilies of structurally related enzymes. Historically, it is most notable for containing the mammalian caspases, on which the structures of the clan were founded. Interestingly, the caspase family is split into two subfamilies: the caspases, and a second subfamily containing both the paracaspases and the metacaspases. Structural data are now available for both the paracaspases and the metacaspases, allowing a comprehensive structural analysis of the entire caspase family. In addition, a relative plethora of structural data has recently become available for many of the other families in the clan, allowing both the structures and the structure-function relationships of clan CD to be fully explored. The present review compares the enzymes in the caspase subfamilies with each other, together with a comprehensive comparison of all the structural families in clan CD. This reveals a diverse group of structures with highly conserved structural elements that provide the peptidases with a variety of substrate specificities and activation mechanisms. It also reveals conserved structural elements involved in substrate binding, and potential autoinhibitory functions, throughout the clan, and confirms that the metacaspases are structurally diverse from the caspases (and paracaspases), suggesting that they should form a distinct family of clan CD peptidases. PMID- 25697095 TI - Proline dehydrogenase 2 (PRODH2) is a hydroxyproline dehydrogenase (HYPDH) and molecular target for treating primary hyperoxaluria. AB - The primary hyperoxalurias (PH), types 1-3, are disorders of glyoxylate metabolism that result in increased oxalate production and calcium oxalate stone formation. The breakdown of trans-4-hydroxy-L-proline (Hyp) from endogenous and dietary sources of collagen makes a significant contribution to the cellular glyoxylate pool. Proline dehydrogenase 2 (PRODH2), historically known as hydroxyproline oxidase, is the first step in the hydroxyproline catabolic pathway and represents a drug target to reduce the glyoxylate and oxalate burden of PH patients. This study is the first report of the expression, purification, and biochemical characterization of human PRODH2. Evaluation of a panel of N-terminal and C-terminal truncation variants indicated that residues 157-515 contain the catalytic core with one FAD molecule. The 12-fold higher k(cat)/K(m) value of 0.93 M-1.s-1 for Hyp over Pro demonstrates the preference for Hyp as substrate. Moreover, an anaerobic titration determined a K(d) value of 125 MUM for Hyp, a value ~1600-fold lower than the K(m) value. A survey of ubiquinone analogues revealed that menadione, duroquinone, and CoQ1 reacted more efficiently than oxygen as the terminal electron acceptor during catalysis. Taken together, these data and the slow reactivity with sodium sulfite support that PRODH2 functions as a dehydrogenase and most likely utilizes CoQ10 as the terminal electron acceptor in vivo. Thus, we propose that the name of PRODH2 be changed to hydroxyproline dehydrogenase (HYPDH). Three Hyp analogues were also identified to inhibit the activity of HYPDH, representing the first steps toward the development of a novel approach to treat all forms of PH. PMID- 25697096 TI - Iron alters cell survival in a mitochondria-dependent pathway in ovarian cancer cells. AB - The role of iron in the development of cancer remains unclear. We previously reported that iron reduces cell survival in a Ras/mitogen-activated protein kinase (MAPK)-dependent manner in ovarian cells; however, the underlying downstream pathway leading to reduced survival was unclear. Although levels of intracellular iron, ferritin/CD71 protein and reactive oxygen species did not correlate with iron-induced cell survival changes, we identified mitochondrial damage (via TEM) and reduced expression of outer mitochondrial membrane proteins (translocase of outer membrane: TOM20 and TOM70) in cell lines sensitive to iron. Interestingly, Ru360 (an inhibitor of the mitochondrial calcium uniporter) reversed mitochondrial changes and restored cell survival in HEY ovarian carcinoma cells treated with iron. Further, cells treated with Ru360 and iron also had reduced autophagic punctae with increased lysosomal numbers, implying cross-talk between these compartments. Mitochondrial changes were dependent on activation of the Ras/MAPK pathway since treatment with a MAPK inhibitor restored expression of TOM20/TOM70 proteins. Although glutathione antioxidant levels were reduced in HEY treated with iron, extracellular glutamate levels were unaltered. Strikingly, oxalomalate (inhibitor of aconitase, involved in glutamate production) reversed iron-induced responses in a similar manner to Ru360. Collectively, our results implicate iron in modulating cell survival in a mitochondria-dependent manner in ovarian cancer cells. PMID- 25697097 TI - Measuring what matters: top-ranked quality indicators for hospice and palliative care from the American Academy of Hospice and Palliative Medicine and Hospice and Palliative Nurses Association. AB - CONTEXT: Measuring quality of hospice and palliative care is critical for evaluating and improving care, but no standard U.S. quality indicator set exists. OBJECTIVES: The Measuring What Matters (MWM) project aimed to recommend a concise portfolio of valid, clinically relevant, cross-cutting indicators for internal measurement of hospice and palliative care. METHODS: The MWM process was a sequential consensus project of the American Academy of Hospice and Palliative Medicine (AAHPM) and Hospice and Palliative Nurses Association (HPNA). We identified candidate indicators mapped to National Consensus Project (NCP) Palliative Care Guidelines domains. We narrowed the list through a modified Delphi rating process by a Technical Advisory Panel and Clinical User Panel and ratings from AAHPM and HPNA membership and key organizations. RESULTS: We narrowed the initial 75 indicators to a final list of 10. These include one in the NCP domain Structure and Process (Comprehensive Assessment), three in Physical Aspects (Screening for Physical Symptoms, Pain Treatment, and Dyspnea Screening and Management), one in Psychological and Psychiatric Aspects (Discussion of Emotional or Psychological Needs), one in Spiritual and Existential Aspects (Discussion of Spiritual/Religious Concerns), and three in Ethical and Legal Aspects (Documentation of Surrogate, Treatment Preferences, and Care Consistency with Documented Care Preferences). The list also recommends a global indicator of patient/family perceptions of care, but does not endorse a specific survey instrument. CONCLUSION: This consensus set of hospice and palliative care quality indicators is a foundation for standard, valid internal quality measurement for U.S. SETTINGS: Further development will assemble implementation tools for quality measurement and benchmarking. PMID- 25697098 TI - Toward understanding the stem-cell origin and molecular regulation of rice tillering. PMID- 25697099 TI - Association of the late cornified envelope-3 genes with psoriasis and psoriatic arthritis: a systematic review. AB - Psoriasis (Ps) and psoriatic arthritis (PsA) are genetically complex diseases with strong genetic evidence. Recently, susceptibility genes for Ps and PsA have been identified within the late cornified envelop (LCE) gene cluster, especially the cluster 3 (LCE3) genes. It is noteworthy that the deletion of LCE3B and LCE3C (LCE3C_LCE3B-del) is significantly associated with these two diseases. Gene-gene interactions between LCE3 genes and other genes are associated with Ps and PsA. LCE3 genes also have pleiotropic effect on some autoimmune diseases, such as rheumatoid arthritis, atopic dermatitis and systemic lupus erythematosus. Further studies need to focus on the potential function of LCE3 genes in the pathogenesis of Ps and PsA in the future. PMID- 25697100 TI - Regeneration across metazoan phylogeny: lessons from model organisms. AB - Comprehending the diversity of the regenerative potential across metazoan phylogeny represents a fundamental challenge in biology. Invertebrates like Hydra and planarians exhibit amazing feats of regeneration, in which an entire organism can be restored from minute body segments. Vertebrates like teleost fish and amphibians can also regrow large sections of the body. While this regenerative capacity is greatly attenuated in mammals, there are portions of major organs that remain regenerative. Regardless of the extent, there are common basic strategies to regeneration, including activation of adult stem cells and proliferation of differentiated cells. Here, we discuss the cellular features and molecular mechanisms that are involved in regeneration in different model organisms, including Hydra, planarians, zebrafish and newts as well as in several mammalian organs. PMID- 25697101 TI - MONOCULM 3, an ortholog of WUSCHEL in rice, is required for tiller bud formation. AB - WUSCHEL (WUS) plays an essential role for the maintenance of meristem activity in dicots, but its function is still elusive in monocots. We isolated a new monoculm mutant, monoculm 3 (moc3), in which a point mutation causes the premature termination of rice O. sativa WUS (OsWUS). Morphological observation revealed that the formation of tiller buds was disrupted in moc3. MOC3 was localized in the nuclear and could interact with TOPLESS-RELATED PROTEINS (TPRs). The expression of MOC3 was induced by cytokinins and defection of MOC3 affected the expression of several two-component cytokinin response regulators, OsRRs and ORRs. Our results suggest that MOC3 is required for the formation of axillary buds and has a complex relationship with cytokinins. PMID- 25697102 TI - Crowdfunding effort identifies the causative mutation in a patient with nystagmus, microcephaly, dystonia and hypomyelination. PMID- 25697103 TI - No intestinal stem cell regeneration after complete progenitor ablation in Drosophila adult midgut. PMID- 25697104 TI - AURKA Phe31Ile polymorphism interacted with use of alcohol, betel quid, and cigarettes at multiplicative risk of oral cancer occurrence. AB - OBJECTIVES: The expression levels of two DNA repair genes (CHAF1A and CHAF1B) and a chromosome segregation gene (AURKA) were susceptible to arecoline exposure, a major alkaloid of areca nut. We hypothesize that genetic variants of these genes might also be implicated in the risk of oral cancer and could be modified by substance use of betel quid or alcohol and cigarettes. MATERIAL AND METHODS: A case-control study, which included 507 patients with oral cancer and 717 matched controls, was performed in order to evaluate the cancer susceptibility by the tagging single-nucleotide polymorphisms (tagSNPs) in AURKA, CHAF1A, and CHAF1B using a genotyping assay and gene-environment interaction analysis. RESULTS: The Phe31Ile polymorphism (rs2273535, T91A) of AURKA was significantly associated with an increased risk of oral cancer (odds ratio (OR) = 2.1, 95% confidence interval (CI) 1.2-3.5). The gene dosage of the 91A allele also showed a significant trend in risk of oral cancer (P = 0.008). Furthermore, we found the AURKA 91AA homozygote was modifiable by substance use of alcohol, betel quid, and cigarettes (ABC), leading to increased risk of oral cancer in an additive or a multiplicative model (combined effect indexes = 1.2-4.0 and 1.5-2.2, respectively). However, no association was observed between the genetic variants of CHAF1A or CHAF1B and oral cancer risk in the study. CONCLUSION: These findings reveal the functional Phe31Ile polymorphism tagSNP of AURKA may be a strong susceptibility gene in ABC-related oral cancer occurrence. CLINICAL RELEVANCE: The results of this betel-related oral cancer study provide the evidence of environment-gene interaction for early prediction and molecular diagnosis. PMID- 25697105 TI - PBT2 inhibits glutamate-induced excitotoxicity in neurons through metal-mediated preconditioning. AB - Excitotoxicity is the pathological process by which neuronal death occurs as a result of excessive stimulation of receptors at the excitatory synapse such as the NMDA receptor (NMDAR). Excitotoxicity has been implicated in the acute neurological damage from ischemia and traumatic brain injury and in the chronic neurodegeneration in Alzheimer's disease (AD) and Huntington's disease (HD). As a result NMDAR antagonists have become an attractive therapeutic strategy for the potential treatment of multiple neurodegenerative diseases. However NMDAR signaling is dichotomous in nature, with excessive increases in neuronal intracellular calcium through excessive NMDAR activity being lethal but moderate increases to intracellular calcium levels during normal synaptic function providing neuroprotection. Subsequently indiscriminant inhibition of this receptor is best avoided as was concluded from previous clinical trials of NMDAR antagonists. We show that the metal chaperone, PBT2, currently in clinical trials for HD, is able to protect against glutamate-induced excitotoxicity mediated through NMDARs. This was achieved by PBT2 inducing Zn(2+)-dependent increases in intracellular Ca(2+) levels resulting in preconditioning of neurons and inhibition of Ca(2+)-induced neurotoxic signaling cascade involving calpain activated cleavage of calcineurin. Our study demonstrates that modulating intracellular Ca(2+) levels by a zinc ionophore is a valid therapeutic strategy to protect against the effects of excitotoxicity thought to underlie both acute and chronic neurodegenerative diseases. PMID- 25697106 TI - The effect of haemolysis on the metabolomic profile of umbilical cord blood. AB - OBJECTIVES: Metabolomics is defined as the comprehensive study of all low molecular weight biochemicals, (metabolites) present in an organism. Using a systems biology approach, metabolomics in umbilical cord blood (UCB) may offer insight into many perinatal disease processes by uniquely detecting rapid biochemical pathway alterations. In vitro haemolysis is a common technical problem affecting UCB sampling in the delivery room, and can hamper metabolomic analysis. The extent of metabolomic alteration which occurs in haemolysed samples is unknown. DESIGN AND METHODS: Visual haemolysis was designated by the laboratory technician using a standardised haemolysis index colour chart. The metabolomic profile of haemolysed and non-haemolysed UCB serum samples from 69 healthy term infants was compared using both (1)H-NMR and targeted DI and LC MS/MS approach. RESULTS: We identified 43 metabolites that are significantly altered in visually haemolysed UCB samples, acylcarnitines (n=2), glycerophospholipids (n=23), sphingolipids (n=7), sugars (n=3), amino acids (n=4) and Krebs cycle intermediates (n=4). CONCLUSION: This information will be useful for researchers in the field of neonatal metabolomics to avoid false findings in the presence of haemolysis, to ensure reproducible and credible results. PMID- 25697107 TI - Predictive role of circulating endothelial-derived microparticles in cardiovascular diseases. AB - Endothelial-derived microparticles (EMPs) are a novel biological marker of endothelium injury and vasomotion disorders that are involved in pathogenesis of cardiovascular, metabolic, and inflammatory diseases. Circulating levels of EMPs are thought to reflect a balance between cell stimulation, proliferation, apoptosis, and cell death. Increased EMPs may be defined in several cardiovascular diseases, such as stable and unstable coronary artery disease, acute and chronic heart failure, hypertension, arrhythmias, thromboembolism, asymptomatic atherosclerosis as well as renal failure, metabolic disorders (including type two diabetes mellitus, abdominal obesity, metabolic syndrome, insulin resistance) and dyslipidemia. This review highlights the controversial opinions regarding impact of circulating EMPs in major cardiovascular and metabolic diseases and summarizes the perspective implementation of the EMPs in risk stratification models. PMID- 25697108 TI - Viral and cellular mechanisms of the innate immune sensing of HIV. AB - HIV-1 replicates in immune cells that normally respond to incoming viruses and induce antiviral immune responses. Under this constant surveillance, how HIV-1 interacts with the host to escape immune control and causes immunopathology is still being untangled. Recently, a series of HIV-1 interactions with innate sensors of viruses expressed by immune target cells have been identified. Here, we review the HIV-1 factors that escape, engage and regulate these innate immune sensors. We discuss the general principles of these interactions as well as the remarkable cell-type specificity of the regulatory mechanisms and their resulting immune responses. Innate sensors directly intersect viral replication with immunity, and understanding their triggering, or lack thereof, improves our ability to design immune interventions. PMID- 25697109 TI - A model of engagement in reflective writing-based portfolios: Interactions between points of vulnerability and acts of adaptability. AB - BACKGROUND: Portfolios are widely used for meeting new accreditation standards in the age of competency-based medicine. However, the method of learning through portfolio has been suggested to be vulnerable. AIM: The aim of this study was to explore conditions affecting the experience of teaching and learning from the perspective of both students and mentors in a reflective writing-based portfolio initiative. METHOD: Using mixed-methods rooted in grounded theory, 139 students and 13 mentors completed questionnaires, 23 students participated in four focus groups and 9 mentors in individual interviews. RESULTS: The overarching theme in our data was student-mentor engagement. Our results confirm previous literature describing portfolio as a vulnerable method of learning, extend this concept by identifying and categorizing specific points of vulnerability, and contribute new knowledge regarding acts of adaptability, which serve to strengthen the student mentor relationship. CONCLUSION: Engagement is central to the success of portfolio and is shaped by a dynamic interaction between points of vulnerability and acts of adaptability. We propose a model of engagement in portfolio that can be used for faculty development to optimize student-mentor engagement. PMID- 25697110 TI - Comparability of outcome frameworks in medical education: Implications for framework development. AB - BACKGROUND: Given the increasing mobility of medical students and practitioners, there is a growing need for harmonization of medical education and qualifications. Although several initiatives have sought to compare national outcome frameworks, this task has proven a challenge. Drawing on an analysis of existing outcome frameworks, we identify factors that hinder comparability and suggest ways of facilitating comparability during framework development and revisions. METHODS: We searched MedLine, EmBase and the Internet for outcome frameworks in medical education published by national or governmental organizations. We analyzed these frameworks for differences and similarities that influence comparability. RESULTS: Of 1816 search results, 13 outcome frameworks met our inclusion criteria. These frameworks differ in five core features: history and origins, formal structure, medical education system, target audience and key terms. Many frameworks reference other frameworks without acknowledging these differences. Importantly, the level of detail of the outcomes specified differs both within and between frameworks. CONCLUSION: The differences identified explain some of the challenges involved in comparing outcome frameworks and medical qualifications. We propose a two-level model distinguishing between "core" competencies and culture-specific "secondary" competencies. This approach could strike a balance between local specifics and cross-national comparability of outcome frameworks and medical education. PMID- 25697111 TI - Self-authorship theory and medical education: AMEE Guide No. 98. AB - Responding to the healthcare needs of the twenty-first century is a challenge for medical education, requiring a holistic curriculum that stimulates intellectual growth and facilitates personal development of all learners. Self-authorship theory has a focus on the essential development of cognitive maturity, an integrated identity and mature relationships. The educational application of self authorship situates learning in the experiences of learners and challenges learners' current worldview enabling them to take responsibility for their own decisions and actions. Implications for curriculum development and implementation are discussed, including the need to provide a challenging, yet supportive, learning environment. The use of self-authorship theory to inform educational research is also discussed. PMID- 25697112 TI - The capability approach for medical education: AMEE Guide No. 97. AB - The capability approach, with its origins in economic and human development work, has a focus on the freedom of persons to make choices about how they wish to lead a valued life. There has been increasing recognition within general education that the capability approach offers a theoretical and practical framework to both implement and evaluate educational interventions that are designed to increase social justice, such as widening participation. There is great potential for the capability approach to also offer medical education a creative way for changing and evaluating curricula, with an emphasis on the teacher facilitating students to achieve their potential by recognising their aspirations and challenging the constraining factors to achieve their aspirations. PMID- 25697113 TI - Is there a common basis between hiatal hernia and hemorrhoidal disease? AB - In this letter-to-editor, we hypothesize that there is a link between hemorrhoidal disease and hiatal hernia. We underline common risk factors for both and present a cross-sectional patient data. Therefore, we emphasize the necessity of new studies to clarify this coincidence. Clinical benefit of establishment of this link is to delay or prevent development of hiatal hernia as a result of appropriate preventive measures. Accordingly, postoperative period of hiatal hernia operations may also be relieved or recurrence risk may also be decreased with this precautions. PMID- 25697114 TI - Serum levels of toxic AGEs (TAGE) may be a promising novel biomarker in development and progression of NASH. AB - Nonalcoholic fatty liver disease (NAFLD) ranges from simple steatosis to nonalcoholic steatohepatitis (NASH), leads to fibrosis and potentially cirrhosis, liver failure, and hepatocellular carcinoma, and is one of the most common causes of liver disease worldwide. NAFLD has also been implicated in other medical conditions such as insulin resistance, obesity, metabolic syndrome, hyperlipemia, hypertension, cardiovascular disease, and diabetes. Continuous hyperglycemia has been implicated in the pathogenesis of diabetic micro- and macro-vascular complications via various metabolic pathways, and numerous hyperglycemia-induced metabolic and hemodynamic conditions exist, including the increased generation of various types of advanced glycation end-products (AGEs). We recently demonstrated that glyceraldehyde-derived AGEs (Glycer-AGEs), the predominant components of toxic AGEs (TAGE), played an important role in the pathogenesis of angiopathy in diabetic patients. Moreover, a growing body of evidence suggests that the interaction between TAGE and the receptor for AGEs may alter intracellular signaling, gene expression, and the release of pro-inflammatory molecules and also elicits the generation of oxidative stress in numerous types of cells including hepatocytes and hepatic stellate cells. Serum levels of TAGE were significantly higher in NASH patients than in those with simple steatosis and healthy controls. Moreover, serum levels of TAGE inversely correlated with adiponectin (adiponectin is produced by adipose tissue and is an anti inflammatory adipokine that can increase insulin sensitivity). Furthermore, immunohistochemical staining of TAGE showed intense staining in the livers of patients with NASH. Serum levels of TAGE may be a useful biomarker for discriminating NASH from simple steatosis. The administration of atorvastatin (10 mg daily) for 12 months significantly improved NASH-related metabolic parameters and significantly decreased serum levels of TAGE. The steatosis grade and NAFLD activity score were also significantly improved. These results demonstrated that atorvastatin decreased the serum levels of TAGE in NASH patients with dyslipidemia and suggest the usefulness of TAGE as a biomarker for the attenuation of NASH. Serum levels of TAGE were significantly higher in non-B or non-C hepatocellular carcinoma (NBNC-HCC) patients than in NASH subjects without HCC or control subjects. TAGE may be involved in the pathogenesis of NBNC-HCC, and could, therefore, be a biomarker that could discriminate NBNC-HCC from NASH. We propose that serum levels of TAGE are promising novel targets for the diagnosis of and therapeutic interventions against NASH. PMID- 25697116 TI - Could astrocytes be the primary target of an offending agent causing the primary degenerative diseases of the human central nervous system? A hypothesis. AB - Most of the named primary degenerative diseases of the human central nervous system have been attributed to a direct, primary damage of some particular population of neurons. Within the spectrum of these illnesses there are disorders like amyotrophic lateral sclerosis, fronto-temporal dementia, Alzheimer's dementia, Parkinson's disease, Huntington's dementia and cerebellar ataxias affecting exclusively the human species. In the last years it has been shown that non-neural cells, mainly astrocytes, have a crucial role in the starting and development of these diseases. We suggest that the causative agent of these illnesses gets home first within the astrocytes, rather than the neurons, making them sick by modifying the structure of some proteins; from these cells the abnormal process would start a trip to other astrocytes having the same genetic, metabolic, structural and functional profiles that the originally affected astrocytes have, going through the gap junctions which connect that particular population devoted to a particular set of neurons. This appears to be a likely hypothesis because the astrocytes related to a defined population of neurons have their own, private properties and characteristics needed to support one particular set of neurons performing a defined function, making them a different and unique population, a fact which would limit the spreading of the disease to those astrocytes, sparing other astrocyte populations which do not share those characteristics. If this were the mechanism underlying these illnesses, the neurons, which their health depends on those astrocytes, would be deprived of their patronage and would start all the changes that characterizes a programmed cell death, and the clinical manifestations of a defined pathology would consequently appear. PMID- 25697115 TI - A possible role of aryl hydrocarbon receptor in spontaneous preterm birth. AB - Preterm birth (PTB) is defined as birth before 37 weeks of gestation and is a leading cause of neonatal mortality and morbidity. To date, the etiology of spontaneous PTB (sPTB) remains unclear; however, intrauterine bacterial infection induced inflammation is considered to be one of the major triggers. Aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor. Upon activation, AhR signaling mediates many biological processes. AhR is abundantly expressed in human placentas, primarily in trophoblasts, and several fetal organs and tissues. The activation of AhR signaling can modulate inflammatory responses via promoting production of pro-inflammatory cytokines by the placenta and fetal membranes. These cytokines could enhance expression and/or activity of cyclooxygenase-2 (COX2) in human trophoblasts and amniotic epithelia, which in turn stimulate synthesis and release of prostaglandins (PGs; e.g., PGE2 and PGF2alpha). Given the discovery of a number of natural and endogenous AhR ligands in human, we hypothesize that in a subset of patients with high AhR expression in placentas and fetal membranes, repeated exposure to these AhR ligands hyperactivates AhR, inducing hyperactivation of the cytokines/COX2/PGs pathway, resulting in myometrial contractions, ultimately leading to sPTB. We further hypothesize that hyperactivation of this AhR pathway can induce sPTB either directly or in synergy with the bacterial infection. Proof of this hypothesis may provide a novel mechanism underlying sPTB. PMID- 25697117 TI - Bisphosphonate osteo-necrosis of the jaws [BONJ], from defective function of oral epithelial intercellular junctions? AB - Bone osteonecrosis of the jaws (BONJ) is prevalent when diseases are treated with high bisphosphonate doses. The mouth is unique in that it has epithelial covered bony protuberances jutting into an infective environment. Should epithelium over these bony prominences be disrupted, abraded or ulcerated by trauma, extraction or therapy, not only will the mucosa not heal, but in vulnerable cases, where less-vital bone is present, there is development of BONJ. BONJ development is explained by BP's depleting available calcium ions from healthy functioning of epithelial gap junctions and disrupting the balance between osteogenesis and osteoclasis. PMID- 25697118 TI - Effect of the components' interface on the synthesis of methanol over Cu/ZnO from CO2/H2: a microkinetic analysis based on DFT + U calculations. AB - The elucidation of chemical reactions occurring on composite systems (e.g., copper (Cu)/zincite (ZnO)) from first principles is a challenging task because of their very large sizes and complicated equilibrium geometries. By combining the density functional theory plus U (DFT + U) method with microkinetic modeling, the present study has investigated the role of the phase boundary in CO2 hydrogenation to methanol over Cu/ZnO. The absence of hydrogenation locations created by the interface between the two catalyst components was revealed based on the calculated turnover frequency under realistic conditions, in which the importance of interfacial copper to provide spillover hydrogen for remote Cu(111) sites was stressed. Coupled with the fact that methanol production on the binary catalyst was recently believed to predominantly involve the bulk metallic surface, the spillover of interface hydrogen atoms onto Cu(111) facets facilitates the production process. The cooperative influence of the two different kinds of copper sites can be rationalized applying the Bronsted-Evans Polanyi (BEP) relationship and allows us to find that the catalytic activity of ZnO-supported Cu catalysts is of volcano type with decrease in the particle size. Our results here may have useful implications in the future design of new Cu/ZnO based materials for CO2 transformation to methanol. PMID- 25697119 TI - Crystalline silicon core fibres from aluminium core preforms. AB - Traditional fibre-optic drawing involves a thermally mediated geometric scaling where both the fibre materials and their relative positions are identical to those found in the fibre preform. To date, all thermally drawn fibres are limited to the preform composition and geometry. Here, we fabricate a metre-long crystalline silicon-core, silica-cladded fibre from a preform that does not contain any elemental silicon. An aluminium rod is inserted into a macroscopic silica tube and then thermally drawn. The aluminium atoms initially in the core reduce the silica, to produce silicon atoms and aluminium oxide molecules. The silicon atoms diffuse into the core, forming a large phase-separated molten silicon domain that is drawn into the crystalline silicon core fibre. The ability to produce crystalline silicon core fibre out of inexpensive aluminium and silica could pave the way for a simple and scalable method of incorporating silicon based electronics and photonics into fibres. PMID- 25697121 TI - Controlled coupling of a single nanoparticle in polymeric microstructure by low one-photon absorption-based direct laser writing technique. AB - We investigated the coupling of a single nanoparticle (NP) into a polymer-based photonic structure (PS). The low one-photon absorption microscopy with a two-step technique allowed us first to accurately determine the location of a NP and then to embed it as desired into an arbitrary PS. The coupling of a gold NP and a polymer-based PS was experimentally investigated showing a six-fold photon collection enhancement as compared to that of a NP in unpatterned film. The simulation results based on finite-difference time-domain calculation method confirmed this observation and showed a 2.86-fold enhancement in extraction efficiency thanks to the NP/PS coupling. PMID- 25697123 TI - Contribution of impaired myofibril and ryanodine receptor function to prolonged low-frequency force depression after in situ stimulation in rat skeletal muscle. AB - The aim of this study was to examine whether prolonged low-frequency force depression (PLFFD) that occurs in situ is the result of decreased myofibrillar Ca(2+) sensitivity and/or reduced sarcoplasmic reticulum (SR) Ca(2+) release. Intact rat gastrocnemius muscles were electrically stimulated via the sciatic nerve until force was reduced to ~50% of the initial and dissected 30 min following the cessation of stimulation. Skinned fibre and whole muscle analyses were performed in the superficial region composed exclusively of type IIB fibres. Fatiguing stimulation significantly reduced the ratio of force at low frequency to that at high frequency to 65% in skinned fibres (1 vs. 50 Hz) and 73% in whole muscles (20 vs. 100 Hz). In order to evaluate changes in myofibrillar Ca(2+) sensitivity and ryanodine receptor caffeine sensitivity, skinned fibres were activated in Ca(2+)- and caffeine-containing solutions, respectively. Skinned fibres from fatigued muscles displayed decreased caffeine sensitivity together with increased myofibrillar Ca(2+) sensitivity. Treatment with 2,2' dithiodipyridine and reduced glutathione induced a smaller increase in myofibrillar Ca(2+)sensitivity in fatigued than in rested fibres. In fatigued muscles, S-glutathionylation of troponin I was increased and submaximal SR Ca(2+) release, induced by 4-chloro-m-cresol, was decreased. These findings suggest that in the early stage of PLFFD that occurs in fast-twitch muscles of exercising animals and humans, S-glutathionylation of troponin I may attenuate PLFFD by increasing myofibrillar Ca(2+) sensitivity and that under such a circumstance, PLFFD may be ascribable to failure of SR Ca(2+) release. PMID- 25697124 TI - Effects of a brief mindfulness-based intervention program for stress management among medical students: the Mindful-Gym randomized controlled study. AB - Pursuing undergraduate medical training can be very stressful and academically challenging experience. A 5-week mindfulness-based stress management (MBSM/Mindful-Gym) program was developed to help medical students cope with stress. The aim of this study was to evaluate the effectiveness of the intervention in reducing stress among students in a medical school in Malaysia. Seventy-five medical students participated in the program. They were stratified according to years of studies and randomly allocated to intervention (N = 37) and control groups (N = 38). The following outcome variables were measured at pre- and post-intervention: mindfulness (with Mindful Awareness Attention Scale); perceived stress (with Perceived Stress Scale); mental distress (with General Health Questionnaire), and self-efficacy (with General Self-efficacy Scale). Hierarchical multiple regressions were used to analyse the effect of group (intervention vs. control) on changes in the outcome variables. There were significant improvements at one week post-intervention in all outcome variables: mindfulness (beta = 0.19, DeltaR2 = 0.04, p = .040, f (2) = 0.05), perceived stress (beta = -0.26, DeltaR2 = 0.07, p = .009, f (2) = 0.10); mental distress (beta = -0.28, DeltaR2 = 0.10, p = .003, f (2) = 0.15); and self-efficacy (beta = 0.30, DeltaR2 = 0.09, p < .001, f (2) = 0.21). Six months after the intervention, those who had joined the program reported higher self-efficacy compared to those in the control group (beta = 0.24, DeltaR2 = 0.06, p = .020, f (2) = 0.08); but there was no difference in other outcome measures. More than 90% of the participants found the program applicable in helping patients and all reported that they would recommend it to others. This study indicates that the program is potentially an effective stress management program for medical students in Malaysia. PMID- 25697125 TI - Bariatric surgery in morbidly obese adolescents: a systematic review and meta analysis. AB - Pubmed, Embase, and Cochrane were systematically reviewed for available evidence on bariatric surgery in adolescents. Thirty-seven included studies evaluated the effect of laparoscopic adjustable gastric banding (LAGB), Roux-en-Y gastric bypass (RYGB), or laparoscopic sleeve gastrectomy (LSG) in patients <=18 years old. Fifteen of 37 studies were prospective, including one RCT. Mean body mass index (BMI) loss after LAGB was 11.6 kg/m(2) (95% CI 9.8-13.4), versus 16.6 kg/m(2) (95% CI 13.4-19.8) after RYGB and 14.1 kg/m(2) (95% CI 10.8-17.5) after LSG. Two unrelated deaths were reported after 495 RYGB procedures. All three bariatric procedures result in substantial weight loss and improvement of comorbidity with an acceptable complication rate, indicating that surgical intervention is applicable in appropriately selected morbidly obese adolescents. PMID- 25697126 TI - Long-term Effect of Ileal Transposition on Adipokine Serum Level in Zucker (Orl) Lepr(fa) Fatty Rats. AB - BACKGROUND: Ileal transposition surgery is an increasingly used procedure in combination with sleeve gastrectomy to control obesity and type 2 diabetes mellitus (T2DM). A short-term effect on glycemia amelioration after the ileal transposition (IT) procedure is observed; however, it appears that the effect is time dependent, and it remains uncertain if this effect is also linked with an adipose tissue hormonal activity. METHODS: Twenty male Zucker rats underwent IT or sham surgery. Six months after surgery, serum levels of adiponectin, vaspin, resistin, chemerin RBP4 were analyzed using ELISA kits. Tissue concentrations of glycogen sythase kinase alfa (GSK-3alpha), glucose 6-phosphatase (G6PC), glycogen phosphorylase (PYGM), and phosphofructokinase (PFK) in muscle and GLUT4 in visceral fat, white adipose tissue, and muscle were assessed in duplicate by an enzyme-linked immunosorbent assay (ELISA) kit. Additionally, the transposed ileum and analogical ileal segment of sham-operated rats were processed for histomorphometry analysis. RESULTS: The animals which underwent IT showed significantly a higher adiponectin and vaspin serum level. Concentrations of resistin decreased after IT surgery but were not significantly different between the groups. The plasma level of chemerin decreased significantly after IT and correlated negatively with adiponectin serum level in the IT group. The effects of IT on RBP4 serum level appeared to be significantly lower than those in the sham group and correlated with GLUT4 concentration in IT white adipose tissue negatively, but positively with the sham group. CONCLUSIONS: The data suggest that ileum transposition leads to a stimulatory effect on important adipokines involved in glucose metabolism. The adipokine serum level could be a useful biomarker of postoperative physiological state. PMID- 25697127 TI - [11C]Choline PET/CT predicts survival in hormone-naive prostate cancer patients with biochemical failure after radical prostatectomy. AB - PURPOSE: Over the last decade, PET/CT with radiolabelled choline has been shown to be useful for restaging patients with prostate cancer (PCa) who develop biochemical failure. The limitations of most clinical studies have been poor validation of [(11)C]choline PET/CT-positive findings and lack of survival analysis. The aim of this study was to assess whether [(11)C]choline PET/CT can predict survival in hormone-naive PCa patients with biochemical failure. METHODS: This retrospective study included 302 hormone-naive PCa patients treated with radical prostatectomy who underwent [(11)C]choline PET/CT from 1 December 2004 to 31 July 2007 because of biochemical failure (prostate-specific antigen, PSA, >0.2 ng/mL). Median PSA was 1.02 ng/mL. PCa-specific survival was estimated using Kaplan-Meier curves. Cox regression analysis was used to evaluate the association between clinicopathological variables and PCa-specific survival. The coefficients of the covariates included in the Cox regression analysis were used to develop a novel nomogram. RESULTS: Median follow-up was 7.2 years (1.4 - 18.9 years). [(11)C]Choline PET/CT was positive in 101 of 302 patients (33%). Median PCa specific survival after prostatectomy was 14.9 years (95% CI 9.7 - 20.1 years) in patients with positive [(11)C]choline PET/CT. Median survival was not achieved in patients with negative [(11)C]choline PET/CT. The 15-year PCa-specific survival probability was 42.4% (95% CI 31.7 - 53.1%) in patients with positive [(11)C]choline PET/CT and 95.5% (95% CI 93.5 - 97.5 %) in patients with negative [(11)C]choline PET/CT. In multivariate analysis, [(11)C]choline PET/CT (hazard ratio 6.36, 95% CI 2.14 - 18.94, P < 0.001) and Gleason score >7 (hazard ratio 3.11, 95% CI 1.11 - 8.66, P = 0.030) predicted PCa-specific survival. An internally validated nomogram predicted 15-year PCa-specific survival probability with an accuracy of 80%. CONCLUSION: Positive [(11)C]choline PET/CT after biochemical failure predicts PCa-specific survival in hormone-naive PCa patients. Prospective studies are warranted to confirm our results before more extensive use of [(11)C]choline PET/CT for prognostic stratification of PCa patients. PMID- 25697129 TI - Temperament and character traits associated with the use of alcohol, cannabis, cocaine, benzodiazepines, and hallucinogens: evidence from a large Brazilian web survey. AB - OBJECTIVES: To evaluate how personality traits are associated with occasional use, abuse, and dependence of alcohol, cannabis, cocaine, benzodiazepines, and hallucinogens in a large availability sample of adults via online questionnaires. METHODS: The sample consisted of 8,646 individuals (24.7% men and 75.3% women) who completed an anonymous web survey. Involvement with drugs and temperament/character traits were assessed through the Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) and the Temperament and Character Inventory - Revised (TCI-R), respectively. Interactions among variables were analyzed using MANOVA with Bonferroni adjustment. RESULTS: Novelty seeking was the trait most associated with increased involvement with alcohol, cannabis, and cocaine. There was a significant association between harm avoidance and benzodiazepine use. Persistence was lower in cannabis-, benzodiazepine-, and cocaine-dependent subjects, as well as in hallucinogen abusers. Self-directedness was reduced in dependents of all drug classes. No strong relationships were found between other temperament or character dimensions and the severity of drug use. CONCLUSIONS: Novelty seeking was associated with increased involvement with all drugs studied in this sample, although to a lesser extent with benzodiazepines and hallucinogens. The temperament and character profile for benzodiazepine use was different from that of other drugs due to the relationship with higher harm avoidance and self-transcendence and lower self-directedness. PMID- 25697130 TI - One platform solid multicolour emission of terthiophene compounds controlled by mixed self-assembly. AB - Via the mixed self-assembling procedure, solid multicolour emission materials based on an amphiphilic terthiophene compound are obtained from a unimolecular platform. Upon controlling the concentration of the cationic surfactant dodecyltriethyl ammonium bromide (DEAB) in the precipitate-monomer equilibrium system of the terthiophene compound TTC4L, mixed self-assembly of TTC4L-DEAB results in diverse structures (including plates, spheres, and needles) with different emission colours. The multicolour emissions are triggered by the different distances between the terthiophene groups in these mixed self assemblies. Each distance corresponds to a specific molecular state of terthiophene groups, so that emissions corresponding to the monomers, excimers, and aggregates are obtained. Upon variation of the ratio of DEAB and TTC4L, the relative fraction of emissions corresponding to the monomers, excimers, and aggregates of TTC4L changes. This approach may act as a simple method to control the stacking mode of the oligothiophene group which is anticipated to realize unimolecular-platform multicolour emissions. PMID- 25697131 TI - Time-course of trigeminal versus olfactory stimulation: evidence from chemosensory evoked potentials. AB - Habituation of responses to chemosensory signals has been explored in many ways. Strong habituation and adaptation processes can be observed at the various levels of processing. For example, with repeated exposure, amplitudes of chemosensory event-related potentials (ERP) decrease over time. However, long-term habituation has not been investigated so far and investigations of differences in habituation between trigeminal and olfactory ERPs are very rare. The present study investigated habituation over a period of approximately 80 min for two olfactory and one trigeminal stimulus, respectively. Habituation was examined analyzing the N1 and P2 amplitudes and latencies of chemosensory ERPs and intensity ratings. It was shown that amplitudes of both components - and intensity ratings - decreased from the first to the last block. Concerning ERP latencies no effects of habituation were seen. Amplitudes of trigeminal ERPs diminished faster than amplitudes of olfactory ERPs, indicating that the habituation of trigeminal ERPs is stronger than habituation of olfactory ERPs. Amplitudes of trigeminal ERPs were generally higher than amplitudes of olfactory ERPs, as it has been shown in various studies before. The results reflect relatively selective central changes in response to chemosensory stimuli over time. PMID- 25697133 TI - Evaluation of TeleMOVE: a Telehealth Weight Reduction Intervention for Veterans with Obesity. AB - BACKGROUND: The rates of overweight and obesity are high among United States Veterans, necessitating the development of accessible weight reduction interventions. PURPOSE: This observational study evaluated the efficacy of a novel home-based telehealth weight loss intervention (TeleMOVE) for Veterans with obesity. METHODS: We obtained weight measures of 171 patients before and after one and two 90-day cycles of TeleMOVE. RESULTS: Enrollment in the first 90-day cycle of TeleMOVE was associated with significant weight loss (M = 8.62 lbs, SD = 9.85). Those who subsequently enrolled in the second, identical, cycle lost significantly more weight overall (M = 11.68 lbs, SD = 12.53) than those who only enrolled in the first cycle (M = 5.55 lbs, SD = 8.23). However, this difference was due to two-cycle participants losing significantly more weight during the first cycle alone (M = 10.52, SD = 10.32). CONCLUSIONS: TeleMOVE is a promising intervention, warranting a further investigation of its efficacy. PMID- 25697132 TI - Exercise as Treatment for Anxiety: Systematic Review and Analysis. AB - BACKGROUND: Exercise has been shown to reduce symptoms of anxiety, but few studies have studied exercise in individuals preselected because of their high anxiety. PURPOSE: The objective of this study is to review and critically evaluate studies of exercise training in adults with either high levels of anxiety or an anxiety disorder. METHODS: We conducted a systematic review of randomized clinical trials (RCTs) in which anxious adults were randomized to an exercise or nonexercise control condition. Data were extracted concerning anxiety outcomes and study design. Existing meta-analyses were also reviewed. RESULTS: Evidence from 12 RCTs suggested benefits of exercise, for select groups, similar to established treatments and greater than placebo. However, most studies had significant methodological limitations, including small sample sizes, concurrent therapies, and inadequate assessment of adherence and fitness levels. CONCLUSIONS: Exercise may be a useful treatment for anxiety, but lack of data from rigorous, methodologically sound RCTs precludes any definitive conclusions about its effectiveness. PMID- 25697134 TI - Do Young Adults Perceive That Cigarette Graphic Warnings Provide New Knowledge About the Harms of Smoking? AB - BACKGROUND: Although much research on graphic cigarette warnings has focused on motivational responses, little focus has been given to how much individuals learn from these labels. PURPOSE: This study aims to investigate whether graphic warnings provide greater perceived new knowledge of smoking consequences compared to text-only warnings, and to test a mediational model whereby perceived new knowledge promotes discouragement from smoking through its impact on worry. METHODS: In two studies, young adult smokers and nonsmokers (ages 18-25) evaluated graphic + text and corresponding text-only labels on perceived knowledge, worry about the harms addressed by the warning, and discouragement from smoking. RESULTS: Compared to text-only labels, graphic + text labels were rated as providing better understanding, more new knowledge, and being more worrisome and discouraging. Perceived new knowledge predicted greater discouragement from smoking directly and through worry. CONCLUSIONS: Graphic warnings may be more efficacious than text-based warnings in increasing knowledge and worry about harms, and discouragement from smoking. PMID- 25697135 TI - Which Images and Features in Graphic Cigarette Warnings Predict Their Perceived Effectiveness? Findings from an Online Survey of Residents in the UK. AB - BACKGROUND: Many countries are implementing graphic warnings for cigarettes. Which graphic features influence their effectiveness remains unclear. PURPOSE: To identify features of graphic warnings predicting their perceived effectiveness in discouraging smoking. METHOD: Guided by the Common-Sense Model of responses to health threats, we content-analyzed 42 graphic warnings for attributes of illness risk representations and media features (e.g., photographs, metaphors). Using data from 15,536 survey participants, we conducted stratified logistic regressions testing which attributes predict participant selections of warnings as effective. RESULTS: Images of diseased body parts predicted greater perceived effectiveness; OR = 6.53-12.45 across smoking status (smoker, ex-smoker, young non-smoker) groups. Features increasing perceived effectiveness included images of dead or sick persons, children, and medical technology; focus on cancer; and photographs. Attributes decreasing perceived effectiveness included infertility/impotence, addictiveness, cigarette chemicals, cosmetic appearance, quitting self-efficacy, and metaphors. CONCLUSIONS: These findings on representational and media attributes predicting perceived effectiveness can inform strategies for generating graphic warnings. PMID- 25697136 TI - Illness Perception Profiles and Their Association with 10-Year Survival Following Cardiac Valve Replacement. AB - OBJECTIVE: The aim of the present study was to examine whether profiles of illness perceptions are associated with 10-year survival following cardiac valve replacement surgery. METHODS: Illness perceptions were evaluated in 204 cardiac patients awaiting first-time valve replacement and again 1 year post-operatively using cluster analysis. All-cause mortality was recorded over a 10-year period. At 1 year, 136 patients were grouped into one of four profiles (stable positive, stable negative, changed from positive to negative, changed from negative to positive). RESULTS: The median follow-up was 3063 days (78 deaths). After controlling for clinical covariates, including markers of function, patients who changed illness perceptions from positive to negative beliefs 1 year post-surgery had an increased mortality risk (hazard ratio (HR) = 3.2, 95% confidence interval (CI) 1.2-8.3, p = .02) compared to patients who held positive stable perceptions. CONCLUSIONS: Following cardiac valve replacement, developing negative illness perceptions over the first post-operative year predicts long-term mortality. Early screening and intervention to alter this pattern of beliefs may be beneficial. PMID- 25697137 TI - Pro-inflammatory effects of interleukin-35 in rheumatoid arthritis. AB - OBJECTIVE: Interleukin-35 (IL-35) is a heterodimeric member of the IL-12 family consisting of p35/IL-12a and EBI3/IL-27b subunits. Expressed in murine Treg cells, IL-35 controls inflammatory diseases in mouse models. However, human IL-35 is expressed in Teff cells rather than in Treg cells and is shown to be upregulated under inflammatory conditions. Our aim was to examine the involvement of IL-35 in the pathogenesis of rheumatoid arthritis (RA). METHODS: Immunohistochemical and immunofluorescence analysis was used to determine the expression and localization of IL-35 and its subunits (p35/EBI3) and IL-35 receptor (IL12Rbeta2/gp130) in RA, osteoarthritis (OA) and psoriatic arthritis (PsA) synovial tissues. Expression of p35/EBI3 subunits and release of inflammatory cytokines upon stimulation with IL-35 were assessed in RA synovial fibroblasts (SFs) and peripheral blood mononuclear cells (PBMCs). RESULTS: Both IL-35 and its subunits were upregulated in RA in comparison with OA or PsA synovium. Using cell-specific markers, p35 and EBI3 were identified in macrophages, dendritic cells, SFs, and T as well as B cells in RA synovium. Both p35 and EBI3 were induced by TNFalpha in RASFs and PBMCs. IL-35 dose-dependently upregulated release of pro-inflammatory mediators IL-1beta, IL-6 and MCP-1 in PBMCs. While gp130 receptor subunit was upregulated in RA synovium and was expressed in RASFs and PBMCs, there was no difference in IL12Rbeta2 expression subunit among tissues and its presence in RASFs was lacking. CONCLUSION: Upregulation of IL-35 at sites of inflammation in RA and its pro-inflammatory potential suggests that IL-35 might play an important role in RA pathogenesis. PMID- 25697138 TI - LPS stimulates and Hsp70 down-regulates TLR4 to orchestrate differential cytokine response of culture-differentiated innate memory CD8(+) T cells. AB - Nonconventional innate memory CD8(+) T cells characteristically expressing CD44, CD122, eomesodermin (Eomes) and promyelocytic leukemia zinc finger (PLZF) were derived in culture from CD4(+)CD8(+) double positive (DP) thymocytes of normal BALB/c and C57BL/6 mice. These culture-differentiated cells constitutively express toll-like receptor (TLR)4 and release interferon (IFN)-gamma and interleukin (IL)-10. We show the TLR4-ligand lipopolysaccharide (LPS) stimulate the TLR and up-regulate IFN-gamma skewing the cells towards type 1 polarization. In presence of LPS these cells also express suppressor of cytokine signaling (SOCS)1 and thus suppress IL-10 expression. In contrast, heat shock protein (Hsp)70 down-regulated TLR4 augmenting the anti-inflammatory cytokine IL-10. In association with IL-10 release IFN-gamma was abrogated. The programmed cell death (PD)-1 mostly present in regulatory T cells was stimulated in these IL-10 producing cells by Hsp70 and not LPS indicating the cells can be driven to two contrast outcomes by the two TLR4 ligands. Our work provides a scope for in vitro monitoring of CD8(+) T cells to decipher important immune therapeutic option during infection or sepsis. PMID- 25697139 TI - Leishmania donovani skews the CD56(+) Natural Killer T cell response during human visceral leishmaniasis. AB - The objective of this study was to understand the categorical function of CD4(+)CD56(+) and CD8(+)CD56(+) NKT cells in human visceral leishmaniasis. These cell populations were significantly deregulated in human peripheral blood during VL. The in vitro experiments showed that CD4(+)NKT cells, but not CD8(+)NKT cells, migrated towards the Leishmania donovani infection site. Additionally, CD4(+)NKT cells from VL subjects primarily expressed CD25(+)Foxp3 and IL-10 compared with healthy subjects. However, CD8(+)NKT cells expressed primarily IFN gamma and killer cell immunoglobulin receptor compared with healthy subjects. Because the ratio of CD4(+) and CD8(+)NKT cells was 1:10, adoptive transfer of CD3(+)CD56(+) NKT cells effectively reduced the L. donovani burden in infected macrophages. This study concludes that although CD4(+)NKT cells are pathogenic and accumulate at the infection site, CD8(+)NKT cells may be protective in contact with target cells. PMID- 25697140 TI - Association of TNF-alpha-(308(GG)), IL-10(-819(TT)), IL-10(-1082(GG)) and IL 1R1(+1970(CC)) genotypes with the susceptibility and progression of leprosy in North Indian population. AB - Leprosy is an infectious disease caused by M. leprae. We analyzed 48 cytokine polymorphisms in 13 (pro as well as anti-inflammatory) cytokine genes using PCR SSP assay in 102 leprosy patients and 120 healthy controls with intent to find out a link between cytokine polymorphisms and disease susceptibility. TNF-alpha ( 308) GG, IL-10 (-819) TT, IL-10 (-1082) GG and IL1R (+1970) CC genotypes are found to be predominant (p=0.01, p=0.02, p=0.0001 and p=0.001, respectively) in both tuberculoid as well as lepromatous leprosy patients. This observation suggests these genotypes as play the central role(s) in the progression of disease. CBA assay demonstrates the varied serum concentration of these cytokines with respect to their genotypes. The above genotypes appeared as high producer genotypes in our study. Even in presence of high produce genotypes, TNF-alpha level are found to be affected/masked by the presence of IL-10 in leprosy patients. Expressional masking of TNF-alpha is associated with the expression of IL-10 in these patients. This is one the negative impact of SNP-SNP interaction in leprosy patients. Therefore, we can conclude that cytokine gene polymorphisms determine the predisposition to the leprosy progression. PMID- 25697141 TI - CE-Chirp(r) ABR in cerebellopontine angle surgery neuromonitoring: technical assessment in four cases. AB - Continuous monitoring of wave V of auditory brainstem response (ABR), also called brainstem auditory evoked potential (BAEP), is the most common method used in intraoperative neuromonitoring (IONM) functionality of cochlear nerve during surgery in cerebellopontine angle (CPA). CE-Chirp(r) ABR represents a recent development of classical ABR. CE-Chirp(r) is a new acoustic stimulus used in newborn hearing testing, designed to provide enhanced neural synchronicity and faster detection of larger amplitude wave V. In four cases, CE-Chirp(r) ABR was performed during cerebellopontine angle (CPA) surgery. CE-Chirp(r) ABR represented a safe and effective method in neuromonitoring functionality of vestibulocochlear nerve. A faster neuromonitoring feedback to surgical equipe was possible with CE-Chirp ABR(r). PMID- 25697142 TI - Clinical-radiological improvement following low-tech surgical treatment of an extensive cervical-medullary idiopathic syringomyelia in a low-resource African neurosurgical practice. AB - Surgical intervention is not so commonly deployed for idiopathic syringomyelia, even the symptomatic ones; is only undertaken, in the current era, after thorough clinical evaluation and extensive high-resolution neuroimaging; and is more assuredly performed, high-tech, in health facilities in the developed world with cutting edge logistic supports. In the practice environment of a low-resource African developing country, a 41-year-old young man recently presented in severe clinical-neurological deficit, Nurick grade 5, with an extensive cervical medullary idiopathic syringomyelia. In spite of severe preoperative and intraoperative resource limitations, he successfully underwent spinal surgical decompression, fenestration of syrinx, and expansile duraplasty. He improved clinically postoperatively and achieved mobility, Nurick grade 3, before hospital discharge. He sustained this improvement, Nurick grade 3 to 2, 20 months post-op. He is now independent, needing only a walking stick to aid ambulation, and an MRI at this time showed only minimal focal post-op changes but total disappearance of the syrinx. PMID- 25697143 TI - Clinical characteristics of patients with asymptomatic intracranial meningiomas and results of their surgical management. AB - Surgery performed during the asymptomatic phase of meningioma remains controversial. The effects of surgery and the factors associated with postsurgical complications and patient prognosis were studied to optimize surgical decisions for clinicians who treat asymptomatic patients. The medical records of 513 patients with meningiomas (112 patients were asymptomatic) treated at our hospital from May 2007 to April 2012 were retrospectively reviewed. The results were analyzed with univariate and multivariate analyses. Asymptomatic meningiomas were characterized by a more common cerebral hemispheric location, a smaller size, and a lack of peritumoral edema. A significantly higher Simpson I resection rate of 95.2 % was achieved in tumors located in the cerebral hemisphere; in contrast, a rate of 66.7 % was obtained in tumors located at the skull base (P = 0.003). The overall postsurgical complication rate was 13.6 %, which was lower than the rate of 21.7 % in the symptomatic patients. Hemiplegia was the most common complication, which occurred most often in the patients with tumors in parietal locations (P = 0.015). Ninety-two percent of the asymptomatic patients achieved a Glasgow Outcome Scale (GOS) score of 5 1 year after the operation, and significantly more patients younger than 60 years of age obtained a GOS score of 5 compared with patients older than 60 years of age (P = 0.006). To achieve maximal tumor resection and good patient recovery, tumor location and patient age should be carefully considered prior to choosing to perform surgery in asymptomatic patients. PMID- 25697144 TI - Socioeconomic Status, Waist-to-Hip Ratio, and Short-Term Heart Rate Variability in Cambodians with Type 2 Diabetes. AB - BACKGROUND: Diabetes, adiposity, and socioeconomic status (SES) are all associated with decreased heart rate variability (HRV), a marker of autonomic function predictive of mortality. Cambodians have high rates of diabetes and low SES. How these factors interact to explain HRV has not been examined. PURPOSE: The aims of this study were to investigate associations among waist-to-hip ratio, socioeconomic status, and HRV among Cambodians with diabetes. METHOD: Sixty patients with type 2 diabetes for >=1 year, not taking insulin, aged 35-80 years were recruited from the Cambodian Diabetes Association. The 2010 Ministry of Health survey regarding household conditions was used to measure SES. Waist-to hip ratio was measured two times and averaged. For HRV, beat-to-beat intervals were recorded on ambulatory ECG recorders, and short-term HRV was calculated in the time domain and in the frequency domain using spectral analysis. Cross sectional data were analyzed using a series of multiple linear regressions using SPSS v21. RESULTS: Participants were of mean age of 56 years old, 60 % female, with National Glycohemoglobin Standardization Program (NGSP) HbA1c mean = 8.4. Participants were poor (e.g., 18 % did not have flush toilets), had high waist-to hip ratios (mean = 0.91), and had HRV values below published norms. In linear regression, there was a significant interaction between waist-to-hip ratio and SES explaining HRV in the time domain (standard deviation of the R-R interval (SDNN), beta = .33, t = 2.61, p < .05) and the frequency domain (log transformed very low frequency (Ln VLF), LF, and total power; all p < .05). Among those with lower SES only, higher waist-to-hip ratio was associated with lower HRV. Findings remained significant after controlling for age, sex, and HbA1c. CONCLUSION: Central adiposity shows a stronger deleterious association with autonomic tone among individuals with more adverse social conditions. PMID- 25697145 TI - The mysteries of Blaise Pascal's sutures. PMID- 25697146 TI - Observations on epilepsy associated with low-grade tumors and focal cortical dysplasias. PMID- 25697147 TI - Bucillamine prevents cisplatin-induced ototoxicity through induction of glutathione and antioxidant genes. AB - Bucillamine is used for the treatment of rheumatoid arthritis. This study investigated the protective effects of bucillamine against cisplatin-induced damage in auditory cells, the organ of Corti from postnatal rats (P2) and adult Balb/C mice. Cisplatin increases the catalytic activity of caspase-3 and caspase 8 proteases and the production of free radicals, which were significantly suppressed by pretreatment with bucillamine. Bucillamine induces the intranuclear translocation of Nrf2 and thereby increases the expression of gamma glutamylcysteine synthetase (gamma-GCS) and glutathione synthetase (GSS), which further induces intracellular antioxidant glutathione (GSH), heme oxygenase 1 (HO 1) and superoxide dismutase 2 (SOD2). However, knockdown studies of HO-1 and SOD2 suggest that the protective effect of bucillamine against cisplatin is independent of the enzymatic activity of HO-1 and SOD. Furthermore, pretreatment with bucillamine protects sensory hair cells on organ of Corti explants from cisplatin-induced cytotoxicity concomitantly with inhibition of caspase-3 activation. The auditory-brainstem-evoked response of cisplatin-injected mice shows marked increases in hearing threshold shifts, which was markedly suppressed by pretreatment with bucillamine in vivo. Taken together, bucillamine protects sensory hair cells from cisplatin through a scavenging effect on itself, as well as the induction of intracellular GSH. PMID- 25697148 TI - Trapezius muscle activity increases during near work activity regardless of accommodation/vergence demand level. AB - AIM: To investigate if trapezius muscle activity increases over time during visually demanding near work. METHODS: The vision task consisted of sustained focusing on a contrast-varying black and white Gabor grating. Sixty-six participants with a median age of 38 (range 19-47) fixated the grating from a distance of 65 cm (1.5 D) during four counterbalanced 7-min periods: binocularly through -3.5 D lenses, and monocularly through -3.5 D, 0 D and +3.5 D. Accommodation, heart rate variability and trapezius muscle activity were recorded in parallel. RESULTS: General estimating equation analyses showed that trapezius muscle activity increased significantly over time in all four lens conditions. A concurrent effect of accommodation response on trapezius muscle activity was observed with the minus lenses irrespective of whether incongruence between accommodation and convergence was present or not. CONCLUSIONS: Trapezius muscle activity increased significantly over time during the near work task. The increase in muscle activity over time may be caused by an increased need of mental effort and visual attention to maintain performance during the visual tasks to counteract mental fatigue. PMID- 25697149 TI - Effects of resistance training on neuromuscular characteristics and pacing during 10-km running time trial. AB - PURPOSE: The purpose of this study was to analyze the impact of an 8-week strength training program on the neuromuscular characteristics and pacing adopted by runners during a self-paced endurance running. METHODS: Eighteen endurance runners were allocated into either strength training group (STG, n = 9) or control group (CG, n = 9) and performed the following tests before and after the training period: (a) incremental test, (b) running speed-constant test, (c) 10-km running time trial, (d) drop jump test, (e) 30-s Wingate anaerobic test, (f) maximum dynamic strength test (1RM). During 1RM, the electromyographic activity was measured. RESULTS: In the STG, the magnitude of improvement for 1RM (23.0 +/- 4.2 %, P = 0.001), drop jump (12.7 +/- 4.6 %, P = 0.039), and peak treadmill speed (2.9 +/- 0.8 %, P = 0.013) was significantly higher compared to CG. This increase in the 1RM for STG was accompanied by a tendency to a higher electromyographic activity (P = 0.080). The magnitude of improvement for 10-km running performance was higher (2.5 %) for STG than for CG (-0.7 %, P = 0.039). Performance was improved mainly due to higher speeds during the last seven laps (last 2800 m) of the 10-km running trial. There were no significant differences between before and after training period for maximal oxygen uptake, respiratory compensation point, running economy, and anaerobic performance for both groups (P > 0.05). CONCLUSIONS: These findings suggest that a strength training program offers a potent stimulus to counteract fatigue during the last parts of a 10-km running race, resulting in an improved overall running performance. PMID- 25697150 TI - Lower-volume muscle-damaging exercise protects against high-volume muscle damaging exercise and the detrimental effects on endurance performance. AB - PURPOSE: This study examined whether lower-volume exercise-induced muscle damage (EIMD) performed 2 weeks before high-volume muscle-damaging exercise protects against its detrimental effect on running performance. METHODS: Sixteen male participants were randomly assigned to a lower-volume (five sets of ten squats, n = 8) or high-volume (ten sets of ten squats, n = 8) EIMD group and completed baseline measurements for muscle soreness, knee extensor torque, creatine kinase (CK), a 5-min fixed-intensity running bout and a 3-km running time-trial. Measurements were repeated 24 and 48 h after EIMD, and the running time-trial after 48 h. Two weeks later, both groups repeated the baseline measurements, ten sets of ten squats and the same follow-up testing (Bout 2). RESULTS: Data analysis revealed increases in muscle soreness and CK and decreases in knee extensor torque 24-48 h after the initial bouts of EIMD. Increases in oxygen uptake [Formula: see text], minute ventilation [Formula: see text] and rating of perceived exertion were observed during fixed-intensity running 24-48 h after EIMD Bout 1. Likewise, time increased and speed and [Formula: see text] decreased during a 3-km running time-trial 48 h after EIMD. Symptoms of EIMD, responses during fixed-intensity and running time-trial were attenuated in the days after the repeated bout of high-volume EIMD performed 2 weeks after the initial bout. CONCLUSIONS: This study demonstrates that the protective effect of lower-volume EIMD on subsequent high-volume EIMD is transferable to endurance running. Furthermore, time-trial performance was found to be preserved after a repeated bout of EIMD. PMID- 25697151 TI - Neural circuits: a nucleus of fear. PMID- 25697156 TI - Sensory systems: noisy nociception. PMID- 25697157 TI - Development, evolution and pathology of neocortical subplate neurons. AB - Subplate neurons have an essential role in cortical circuit formation. They are among the earliest formed neurons of the cerebral cortex, are located at the junction of white and grey matter, and are necessary for correct thalamocortical axon ingrowth. Recent transcriptomic studies have provided opportunities for monitoring and modulating selected subpopulations of these cells. Analyses of mouse lines expressing reporter genes have demonstrated novel, extracortical subplate neurogenesis and have shown how subplate cells are integrated under the influence of sensory activity into cortical and extracortical circuits. Recent studies have revealed that the subplate is involved in neurosecretion and modification of the extracellular milieu. PMID- 25697158 TI - Exploring the origins of grey matter damage in multiple sclerosis. AB - Multiple sclerosis is characterized at the gross pathological level by the presence of widespread focal demyelinating lesions of the myelin-rich white matter. However, it is becoming clear that grey matter is not spared, even during the earliest phases of the disease. Furthermore, grey matter damage may have an important role both in physical and cognitive disability. Grey matter pathology involves both inflammatory and neurodegenerative mechanisms, but the relationship between the two is unclear. Histological, immunological and neuroimaging studies have provided new insight in this rapidly expanding field, and form the basis of the most recent hypotheses on the pathogenesis of grey matter damage. PMID- 25697159 TI - The connectomics of brain disorders. AB - Pathological perturbations of the brain are rarely confined to a single locus; instead, they often spread via axonal pathways to influence other regions. Patterns of such disease propagation are constrained by the extraordinarily complex, yet highly organized, topology of the underlying neural architecture; the so-called connectome. Thus, network organization fundamentally influences brain disease, and a connectomic approach grounded in network science is integral to understanding neuropathology. Here, we consider how brain-network topology shapes neural responses to damage, highlighting key maladaptive processes (such as diaschisis, transneuronal degeneration and dedifferentiation), and the resources (including degeneracy and reserve) and processes (such as compensation) that enable adaptation. We then show how knowledge of network topology allows us not only to describe pathological processes but also to generate predictive models of the spread and functional consequences of brain disease. PMID- 25697160 TI - Intrinsic plasticity: an emerging player in addiction. AB - Exposure to drugs of abuse, such as cocaine, leads to plastic changes in the activity of brain circuits, and a prevailing view is that these changes play a part in drug addiction. Notably, there has been intense focus on drug-induced changes in synaptic excitability and much less attention on intrinsic excitability factors (that is, excitability factors that are remote from the synapse). Accumulating evidence now suggests that intrinsic factors such as K+ channels are not only altered by cocaine but may also contribute to the shaping of the addiction phenotype. PMID- 25697161 TI - Secondary surgery after vaginal prolapse repair with mesh is more common for stress incontinence and voiding dysfunction than for mesh problems or prolapse recurrence. AB - OBJECTIVES: To explore the need for secondary surgical procedures after transvaginal prolapse repair with mesh. METHODS: Women that had prolapse repair (Prolift((r)) or Elevate((r))) were reviewed for reoperation and clinical/demographic data such as prior prolapse repair, prolapse grade, operative details, length of stay (LOS) and time to reoperation. Pearson's Chi square, Fisher's exact tests and Wilcoxon rank tests were used. RESULTS: 77/335 women (23%) had 100 additional procedures. Median (range) time to reoperation was 51 (5-1168) days: four (1%) had primary prolapse surgery at a different site, three (1%) repeat prolapse repair from the same site, 23 (7%) surgery for complications and 50 (15%) had stress urinary incontinence (SUI)/sling-related procedures. When no reoperation versus reoperation groups were compared, mean LOS (1.8 vs. 2.0 days; p = 0.044) and follow-up (228 vs. 354 days; p = 0.002) were longer in the reoperations group; postoperative hemoglobin was lower (10.8 vs. 10.4; p = 0.031). Patients with a prolapse reoperation were 10 years younger (67 vs. 57 years; p = 0.027) than patients that either had a reoperation for other reasons or had no reoperations. Patients with concomitant sling and persistent SUI requiring repeat SUI surgery were older (mean 72 vs. 66 years; p = 0.038), had prior prolapse repair (53 vs. 27%; p = 0.017) and had anterior compartment mesh (84 vs. 56%; p = 0.037); median operative times (78 vs. 104 min; p = 0.008) and mean LOS were shorter (median 1.6 vs. 1.9 days; p = 0.045). For patients without concomitant sling, no demographic or perioperative differences were found between those that did (n = 10) and did not (n = 86) develop de novo SUI that required reoperation. CONCLUSIONS: Most reoperations were for sling management and SUI; few were for mesh complications or prolapse recurrence. PMID- 25697162 TI - Erratum to: Glucose, blood pressure and cholesterol levels and their relationships to clinical outcomes in type 2 diabetes: a retrospective cohort study. PMID- 25697163 TI - Human islet distribution programme for basic research: activity over the last 5 years. PMID- 25697164 TI - Clinical technology specialists. PMID- 25697165 TI - Light at Night and Measures of Alertness and Performance: Implications for Shift Workers. AB - Rotating-shift workers, particularly those working at night, are likely to experience sleepiness, decreased productivity, and impaired safety while on the job. Light at night has been shown to have acute alerting effects, reduce sleepiness, and improve performance. However, light at night can also suppress melatonin and induce circadian disruption, both of which have been linked to increased health risks. Previous studies have shown that long-wavelength (red) light exposure increases objective and subjective measures of alertness at night, without suppressing nocturnal melatonin. This study investigated whether exposure to red light at night would not only increase measures of alertness but also improve performance. It was hypothesized that exposure to both red (630 nm) and white (2,568 K) lights would improve performance but that only white light would significantly affect melatonin levels. Seventeen individuals participated in a 3 week, within-subjects, nighttime laboratory study. Compared to remaining in dim light, participants had significantly faster reaction times in the GO/NOGO test after exposure to both red light and white light. Compared to dim light exposure, power in the alpha and alpha-theta regions was significantly decreased after exposure to red light. Melatonin levels were significantly suppressed by white light only. Results show that not only can red light improve measures of alertness, but it can also improve certain types of performance at night without affecting melatonin levels. These findings could have significant practical applications for nurses; red light could help nurses working rotating shifts maintain nighttime alertness, without suppressing melatonin or changing their circadian phase. PMID- 25697166 TI - [In Process Citation]. PMID- 25697167 TI - [In Process Citation]. PMID- 25697168 TI - [In Process Citation]. PMID- 25697169 TI - [In Process Citation]. PMID- 25697170 TI - [Diagnostics and treatment of phenylketonuria]. AB - Primary phenylalanine hydroxylase deficiency, also known as phenylketonuria, results in accumulation of phenylalanine in the blood. Early identification and treatment prevents the majority of clinical sequelae to the disease, but psychological and neurodevelopmental problems can occur in some patients. This article reviews the symptoms, diagnosis, classification and strategies of treatment and management of phenylketonuria. Finally we review new pharmacological and non-pharmaco-logical means of treatment. PMID- 25697171 TI - [Femoral neck fracture in a patient with osteopetrosis]. AB - Osteopetrosis is a rare hereditary bone disease characterized by increased bone density. Patients with adult osteopetrosis are often diagnosed incidentally by X ray or on the presence of recurrent fractures. Internal fixations of fractures in patients with osteopetrosis are challenging due to the increased bone density, and special surgical equipment is often necessary. Non-union and malunion occur frequently making close post-operative monitoring important. We present a case of adult osteopetrosis with a femoral neck fracture. PMID- 25697172 TI - [A varix of the vortex vein ampulla is a rare differential diagnosis of malignant melanoma of the choroid]. AB - Melanoma of the choroid is the most frequent primary intra-ocular malignancy whereas a varix of the vortex vein ampulla is a benign, rare and asymptomatic condition requiring no treatment. A varix of the vortex vein ampulla is usually found accidentally and can easily be mistaken for a choroidal melanoma, a naevus or a haemorrhage. We present a case of a varix of the vortex vein ampulla, which can be distinguished from other more serious conditions by using simple clinical methods. PMID- 25697173 TI - [Blunt diaphragmatic rupture following low-energy trauma]. AB - Traumatic rupture of the diaphragm following blunt trauma is rare. It is most commonly seen in high-velocity impact from motor vehicle accidents. However, we present a case report of a 17-year-old man who sustained an isolated left-sided diaphragmatic rupture with visceral herniation as a result of a low-velocity fall. Consequently blunt diaphragmatic rupture should be suspected in every case of blunt trauma. PMID- 25697174 TI - [Mesenteric cyst is a rare origin for abdominal pain in children]. AB - A ten-year-old boy with known episodes of moderate abdominal pain during 18 months suddenly developed severe abdominal pain, and a CT scan showed a 25 * 15 cm cystic process. The patient was operated and a mesenteric cyst was removed along with 15 cm of small bowel. Post-operative course was uneventful. Mesenteric cysts are rare, but should be considered as an origin for abdominal pain in children, particularly after exclusion of more common diagnoses. PMID- 25697175 TI - Serum levels of carcinoembryonic antigen (CEA) in patients with bipolar disorder. AB - OBJECTIVE: Carcinoembryonic antigen (CEA) is an oncofetal glycoprotein that is widely used as a tumour marker in adenocarcinomas. However, several non neoplastic conditions, including acute and chronic inflammation and other inflammation-related conditions, are characterised by increased CEA concentrations. Bipolar disorder (BD) ranks seventh among the worldwide burden of non-fatal diseases. Inflammatory biomarkers have been considered as one of the main key pillars of a multifactorial approach for prediction of BD in an at-risk population. BP is accompanied by activation of inflammatory, cell-mediated and negative immunoregulatory cytokines. METHODS: We measured the levels of CEA in serum samples from 44 individuals with euthymic BP out-patients and 45 healthy controls. Patients were diagnosed according to the DSM-IV criteria. CEA was measured by an electrochemiluminescence immunoassay. RESULTS: The mean serum CEA concentration was 2.36+/-1.52 and 1.77+/-0.98 ug/l in patients and controls, respectively. CEA levels were significantly increased in euthymic BP patients when compared with controls (p=0.031). CONCLUSIONS: This study suggests that CEA is increased in BD and supports a role for immune activation in the core pathological mechanisms of BP. CEA levels may be a secondary marker for diagnosing BP. PMID- 25697176 TI - Replisome function during replicative stress is modulated by histone h3 lysine 56 acetylation through Ctf4. AB - Histone H3 lysine 56 acetylation in Saccharomyces cerevisiae is required for the maintenance of genome stability under normal conditions and upon DNA replication stress. Here we show that in the absence of H3 lysine 56 acetylation replisome components become deleterious when replication forks collapse at natural replication block sites. This lethality is not a direct consequence of chromatin assembly defects during replication fork progression. Rather, our genetic analyses suggest that in the presence of replicative stress H3 lysine 56 acetylation uncouples the Cdc45-Mcm2-7-GINS DNA helicase complex and DNA polymerases through the replisome component Ctf4. In addition, we discovered that the N-terminal domain of Ctf4, necessary for the interaction of Ctf4 with Mms22, an adaptor protein of the Rtt101-Mms1 E3 ubiquitin ligase, is required for the function of the H3 lysine 56 acetylation pathway, suggesting that replicative stress promotes the interaction between Ctf4 and Mms22. Taken together, our results indicate that Ctf4 is an essential member of the H3 lysine 56 acetylation pathway and provide novel mechanistic insights into understanding the role of H3 lysine 56 acetylation in maintaining genome stability upon replication stress. PMID- 25697177 TI - An estimate of the average number of recessive lethal mutations carried by humans. AB - The effects of inbreeding on human health depend critically on the number and severity of recessive, deleterious mutations carried by individuals. In humans, existing estimates of these quantities are based on comparisons between consanguineous and nonconsanguineous couples, an approach that confounds socioeconomic and genetic effects of inbreeding. To overcome this limitation, we focused on a founder population that practices a communal lifestyle, for which there is almost complete Mendelian disease ascertainment and a known pedigree. Focusing on recessive lethal diseases and simulating allele transmissions, we estimated that each haploid set of human autosomes carries on average 0.29 (95% credible interval [0.10, 0.84]) recessive alleles that lead to complete sterility or death by reproductive age when homozygous. Comparison to existing estimates in humans suggests that a substantial fraction of the total burden imposed by recessive deleterious variants is due to single mutations that lead to sterility or death between birth and reproductive age. In turn, comparison to estimates from other eukaryotes points to a surprising constancy of the average number of recessive lethal mutations across organisms with markedly different genome sizes. PMID- 25697178 TI - Dietary trans-10, cis-12-conjugated linoleic acid alters fatty acid metabolism and microbiota composition in mice. AB - The main aim of the present study was to investigate the effects of dietary trans 10, cis-12-conjugated linoleic acid (t10c12-CLA) on intestinal microbiota composition and SCFA production. C57BL/6 mice (n 8 per group) were fed a standard diet either supplemented with t10c12-CLA (0.5 %, w/w) (intervention) or with no supplementation (control), daily for 8 weeks. Metabolic markers (serum glucose, leptin, insulin and TAG, and liver TAG) were assessed by ELISA commercial kits, tissue long-chain fatty acids and caecal SCFA by GC, and microbial composition by 16S rRNA pyrosequencing. Dietary t10c12-CLA significantly decreased visceral fat mass (P< 0.001), but did not affect body weight (intervention), when compared with no supplementation (control). Additionally, lipid mass and composition were affected by t10c12-CLA intake. Caecal acetate, propionate and isobutyrate concentrations were higher (P< 0.05) in the t10c12-CLA-supplemented group than in the control group. The analysis of the microbiota composition following 8 weeks of t10c12-CLA supplementation revealed lower proportions of Firmicutes (P= 0.003) and higher proportions of Bacteroidetes (P= 0.027) compared with no supplementation. Furthermore, t10c12-CLA supplementation for 8 weeks significantly altered the gut microbiota composition, harbouring higher proportions of Bacteroidetes, including Porphyromonadaceae bacteria previously linked with negative effects on lipid metabolism and induction of hepatic steatosis. These results indicate that the mechanism of dietary t10c12-CLA on lipid metabolism in mice may be, at least, partially mediated by alterations in gut microbiota composition and functionality. PMID- 25697179 TI - Facile one-step photochemical fabrication and characterization of an ultrathin gold-decorated single glass nanopipette. AB - The inner surface of a conical glass nanopipette was modified with ultrathin gold film by a facile one-step photochemical approach, using HAuCl4 and ethanol as common reagents with the aid of UV irradiation. The method is simple, straightforward, time-saving, and environmentally friendly. The morphology and component of the as-prepared ultrathin gold film was thoroughly characterized by transmission electron microscopy (TEM), energy-dispersive X-ray (EDX) analysis, and X-ray photoelectron spectroscopy (XPS). The mechanism of the gold film growth was briefly discussed. Other small photochemical reagents with a hydroxy group, e.g., ethylene glycol, methanol, and glucose, may also work but with a different rate of reaction. The facile ultrathin gold decoration of a single glass nanopipette renders the glass nanopipette-based nanopore platform very easy for surface chemical modifications and potential sensing applications. The success of the gold decoration on the inner surface of the glass nanopore was further confirmed electrochemically by surface modification of a small thiol molecule (cysteine), and the pH (surface charge)-dependent ionic current rectification behaviors through the nanopore were investigated. Due to its facile preparation, the method and the Au-decorated glass nanopore would find promising and extended applications in ultrasensitive detection and biosensing. PMID- 25697180 TI - Quantifying the adsorption of ionic silver and functionalized nanoparticles during ecotoxicity testing: Test container effects and recommendations. AB - Silver nanoparticles (Ag-NPs) are used in a wide variety of products, prompting concerns regarding their potential environmental impacts. To accurately determine the toxicity of Ag-NPs it is necessary to differentiate between the toxicity of the nanoparticles themselves and the toxicity of ionic silver (Ag) released from them. This is not a trivial task given the reactive nature of Ag in solution, and its propensity for both adsorption and photoreduction. In the experiments reported here, we quantified the loss of silver from test solutions during standard ecotoxicity testing conducted using a variety of different test container materials and geometries. This sensitive (110m)Ag isotope tracing method revealed a substantial underestimation of the toxicity of dissolved Ag to the green algae Pseudokirchneriella subcapitata when calculated only on the basis of the initial test concentrations. Furthermore, experiments with surface functionalized Ag-NPs under standard algal growth inhibition test conditions also demonstrated extensive losses of Ag-NPs from the solution due to adsorption to the container walls, and the extent of loss was dependent on Ag-NP surface functionality. These results hold important messages for researchers engaged in both environmental and human nanotoxicology testing, not only for Ag-NPs but also for other NPs with various tailored surface chemistries, where these phenomena are recognized but are also frequently disregarded in the experimental design and reporting. PMID- 25697181 TI - Repeated exposure to carbon nanotube-based aerosols does not affect the functional properties of a 3D human epithelial airway model. AB - Carbon nanotubes (CNTs) represent one of the most promising engineered nanomaterials, with possible applications in advanced engineering and biomedical technologies. During their production, human exposure to CNTs may occur via inhalation. Therefore, the aim of this study was to mimic inhalation of multi walled CNTs (MWCNTs) in vitro as realistically as possible, by producing MWCNTs aerosols via an Air-Liquid Interface Cell Exposure System (ALICE), combined with a 3D epithelial airway barrier model cultivated at the air-liquid interface (ALI). To address the consequences of an extended exposure period, repeated exposures of MWCNTs (total deposition 1.15 MUg/cm(2)) were applied to the co culture system, either over one day (one day repeated exposure) or three days (three day repeated exposure scenario). Although in both repeated exposure scenarios MWCNTs were found to interact with the different cell types, they did not induce any cytotoxicity or alterations in cell morphology, nor did they elucidate any significant increase in pro-inflammatory markers compared to control cultures. Similar results were also observed following single MWCNTs exposures at deposited concentrations of 0.14, 0.20 and 0.39 ug/cm(2). Cells exposed repeatedly to MWCNTs for three days, however did show a decrease in reduced glutathione levels, although not significant (p > 0.05). In conclusion, we have presented a realistic in vitro alternative to mimic occupational exposure of MWCNTs and by applying this approach it was shown that repeated MWCNT exposures to lung cell cultures at the ALI elicit a limited biological impact over a three day period. PMID- 25697182 TI - 5-Day repeated inhalation and 28-day post-exposure study of graphene. AB - Graphene has recently been attracting increasing attention due to its unique electronic and chemical properties and many potential applications in such fields as semiconductors, energy storage, flexible electronics, biosensors and medical imaging. However, the toxicity of graphene in the case of human exposure has not yet been clarified. Thus, a 5-day repeated inhalation toxicity study of graphene was conducted using a nose-only inhalation system for male Sprague-Dawley rats. A total of three groups (20 rats per group) were compared: (1) control (ambient air), (2) low concentration (0.68 +/- 0.14 mg/m(3) graphene) and (3) high concentration (3.86 +/- 0.94 mg/m(3) graphene). The rats were exposed to graphene for 6 h/day for 5 days, followed by recovery for 1, 3, 7 or 28 days. The bioaccumulation and macrophage ingestion of the graphene were evaluated in the rat lungs. The exposure to graphene did not change the body weights or organ weights of the rats after the 5-day exposure and during the recovery period. No statistically significant difference was observed in the levels of lactate dehydrogenase, protein and albumin between the exposed and control groups. However, graphene ingestion by alveolar macrophages was observed in the exposed groups. Therefore, these results suggest that the 5-day repeated exposure to graphene only had a minimal toxic effect at the concentrations and time points used in this study. PMID- 25697183 TI - Anti-epidermal growth factor receptor-targeted therapy in upper gastrointestinal tract cancers: a meta-analysis. AB - This meta-analysis evaluated the efficacy and safety of anti-epidermal growth factor receptor (EGFR) treatment of patients with upper gastrointestinal (GI) tract cancers. A systematic search of multiple databases identified seven randomized controlled trials. Anti-EGFR combination therapy improved disease control rate (DCR) in all patients and progression-free survival (PFS) in patients receiving the same dose of standard therapy as patients receiving standard therapy alone. Combinations of anti-EGFR with non-capecitabine chemotherapy further improved DCR, whereas combinations with capecitabine masked the benefits of DCR and worsened PFS. Overall survival was apparently lower in patients without metastasis, and PFS was apparently improved in patients with squamous cell carcinoma of the esophagus and esophagogastric junction. Anti-EGFR treatment was associated with higher rates of cardiac events, hand-foot syndrome, rash, hypomagnesemia, diarrhea and mucositis and lower rates of neutropenia. Combinations of anti-EGFR agents with non-capecitabine chemotherapy or better supportive care may benefit patients with upper GI tract cancers. PMID- 25697184 TI - Understanding social hierarchies: The neural and psychological foundations of status perception. AB - Social groups across species rapidly self-organize into hierarchies, where members vary in their level of power, influence, skill, or dominance. In this review, we explore the nature of social hierarchies and the traits associated with status in both humans and nonhuman primates, and how status varies across development in humans. Our review finds that we can rapidly identify social status based on a wide range of cues. Like monkeys, we tend to use certain cues, like physical strength, to make status judgments, although layered on top of these more primitive perceptual cues are sociocultural status cues like job titles and educational attainment. One's relative status has profound effects on attention, memory, and social interactions, as well as health and wellness. These effects can be particularly pernicious in children and adolescents. Developmental research on peer groups and social exclusion suggests teenagers may be particularly sensitive to social status information, but research focused specifically on status processing and associated brain areas is very limited. Recent evidence from neuroscience suggests that there may be an underlying neural network, including regions involved in executive, emotional, and reward processing, that is sensitive to status information. We conclude with questions for future research as well as stressing the need to expand social neuroscience research on status processing to adolescents. PMID- 25697185 TI - Safety of IPX066 , an extended release carbidopa-levodopa formulation, for the treatment of Parkinson's disease. AB - INTRODUCTION: Levodopa (LD) is the most effective treatment for Parkinson's disease (PD). However, chronic use of LD commonly results in the development of motor complications, including wearing off and dyskinesia. The presumption that the short serum half-life of LD is associated with the development of motor complications has raised the need to develop treatments with increased durations of stable LD concentrations. AREAS COVERED: We conducted a PubMed search for IPX066 articles and also reviewed abstracts from meetings that included this topic. IPX066 is a newly developed formulation of extended release carbidopa-LD (CD-LD) with a one to four ratio of CD to LD, that was approved by the FDA in January 2015 for the treatment of PD, post-encephalitic parkinsonism, and parkinsonism that may follow carbon monoxide or manganese intoxication. It will be marketed by the trade name Rytary(r). A Phase III clinical trial showed that IPX066 is efficacious in improving motor symptoms in early PD patients. In advanced PD patients with motor fluctuations, IPX066 reduced off time and increased on time without troublesome dyskinesia compared to CD-LD immediate release and CD-LD with entacapone. IPX066 had an acceptable safety profile. Adverse events of IPX066 from the different trials are presented. EXPERT OPINION: IPX066 will probably have a role in the treatment of advanced PD with motor fluctuations. IPX066 could also be used initially when LD therapy is prescribed, but the question of whether this usage could reduce or prevent the development of motor complications is yet to be answered. PMID- 25697186 TI - Fiber-enhanced Raman multi-gas spectroscopy: what is the potential of its application to breath analysis? PMID- 25697187 TI - Feasibility of immuno-PCR technology platforms as an ultrasensitive tool for the detection of anti-drug antibodies. AB - AIM: During the early clinical development of a receptor-IgG1 fusion protein (Drug X), a risk based strategy was utilized to evaluate immunogenicity from Phase I through Proof of Concept clinical studies. MATERIALS & METHODS: Three different technology platforms, enzyme-linked immunosorbant assay, electrochemiluminescent assay and newly emerging immuno-PCR were utilized for evaluation of immunogenic response. RESULTS: An ELISA with adequate sensitivity but significant drug interference was replaced by electrochemiluminescent method with improved drug tolerance; however, an inverse correlation was observed between the administered dose and the incidence of anti-drug antibodies. Further evaluation of an immuno-PCR showed reduced drug interference enabling the detection of anti-drug antibodies in the presence of excess amount of Drug X. CONCLUSION: Immuno PCR assay proved to be a feasible platform for anti-drug antibody characterization. PMID- 25697188 TI - Matrix effect explained by unexpected formation of peptide in acidified plasma. AB - AIM: Peak distortion and strong signal enhancement was observed when applying a bioanalytical method based on mixed-mode SPE, hydrophilic interaction chromatography and ESI-MS to acidified rabbit plasma samples. RESULTS: High resolution ESI-MS and N-terminal peptide sequencing revealed a peptide NFQNAL, which was confirmed by H/D exchange ESI-MS. CONCLUSION: The peptide causing the observed matrix effect was formed by enzymatic degradation of serum albumin at pH 3. Degradation required both acidification and presence of other plasma constituents in addition to albumin to take place. The degree of signal enhancement correlated to the level of NFQNAL in the ion source as measured by MS, with a maximal enhancement factor of 3 at intermediate levels of NFQNAL. The interference was eliminated by changing to another type of hydrophilic interaction chromatography column. PMID- 25697189 TI - ELISA microplate: a viable immunocapture platform over magnetic beads for immunoaffinity-LC-MS/MS quantitation of protein therapeutics? AB - AIM: Evaluate the performance of ELISA microplates versus commonly used magnetic beads for biological sample cleanup and/or enrichment in immunoaffinity-LC-MS/MS to reduce tedious beads washing procedures and a relatively high assay cost. MATERIALS & METHODS: ELISA microplates were used as immunicapture platform and compared with magnetic beads for sample cleanup for LC-MS/MS quantitation of protein therapeutics. RESULTS: One unmodified and two surface-activated microplates provided comparable linear ranges and sensitivities for a therapeutic protein (mass 78 kDa) using a human serum sample of 100 ul with 1:1 dilution compared with Tosylactivated magnetic beads using 200 ul of human serum without sample dilution. The assays' precision and accuracy were all within acceptable ranges. No nonspecific binding or other selectivity issues were observed. CONCLUSION: The results suggested an ELISA microplate could be a viable immunocapture platform for immunoaffinity-LC-MS/MS quantitation of protein therapeutics. PMID- 25697190 TI - A rapid LC-MS/MS quantification of peramivir using a simple and inexpensive sample precipitation: application to PK. AB - AIM: Peramivir is a newly approved selective neuraminidase inhibitor designed to inhibit influenza virus infection. METHODOLOGY/RESULTS: We report a robust and sensitive method utilizing simple precipitation extraction with LC-MS/MS for the high-throughput quantification. Addition of 0.06 M of ammonium formate and 0.1% formic acid in mobile phase could help reduce the matrix effect. This method uses 100 ul of plasma and covers a linear concentration range from 5 to 10,000 ng/ml. Other validation parameters are also evaluated and meet regulatory expectations by US FDA guidelines. CONCLUSION: The developed HPLC-MS/MS method has been successfully applied to support a clinical pharmacokinetic study. The strategy presented here can be applied elsewhere and may be useful for other amphiphilic drugs. PMID- 25697191 TI - Stabilization of clinical samples collected for quantitative bioanalysis--a reflection from the European Bioanalysis Forum. AB - In bioanalysis of small molecules, the analyte concentration in the measured samples should reflect the concentration during sample collection. Precautions may be needed to prevent over- or under-estimation of the obtained result. This might require the addition of stabilizers to prevent degradation or nonspecific binding. For unstable drugs, it is essential to know how analytes can be stabilized before the start of the clinical study. Although the stabilization methods are well documented, the impact of the stabilization on the clinical workflow is not properly addressed. Already during method development, the clinical implications in terms of personnel safety, ease of use, training possibilities and staff capacity should be taken into account, and validation of the bioanalytical method should reflect collection procedures. PMID- 25697192 TI - What is the right blood hematocrit preparation procedure for standards and quality control samples for dried blood spot analysis? AB - Remco Koster is a research analyst and PhD candidate at the University Medical Center Groningen and University of Groningen. He has been working in the field of bioanalysis for over 13 years, where he has developed numerous analytical methods using LC-MS/MS. His main research focus is the influence of various matrices on the development and performance of analytical methods using LC-MS/MS. The development of high-speed extraction and analysis methods for drugs and drugs of abuse in human matrices like blood, plasma, hair, saliva and dried blood spots often leads to improved procedures for preparation of standards and quality control samples, sample handling and validation. Two hematocrit preparation procedures for standards and quality control samples were evaluated in order to improve the quality of procedures for dried blood spot validation and analysis. PMID- 25697194 TI - Comparative immunogenicity assessment: a critical consideration for biosimilar development. AB - An appropriate assessment strategy with validated anti-drug antibody (ADA) assays is critical for comparative evaluation of immunogenicity between a proposed biosimilar and its reference product. The strategy should aim to identify potential differences in immune responses between these products. While an ADA assay employing the proposed biosimilar product as the detecting reagent has been generally recommended for such evaluation, a product-specific assay using the product of interest may be of use as it offers a capability of detecting antibodies against specific epitopes from the respective product. Regardless of assay strategy, the performance of the assay must be fully assessed and method needs to be validated to meet the comparative purpose of immunogenicity assessment. PMID- 25697193 TI - Protein dielectrophoresis and the link to dielectric properties. AB - There is a growing interest in protein dielectrophoresis (DEP) for biotechnological and pharmaceutical applications. However, the DEP behavior of proteins is still not well understood which is important for successful protein manipulation. In this paper, we elucidate the information gained in dielectric spectroscopy (DS) and electrochemical impedance spectroscopy (EIS) and how these techniques may be of importance for future protein DEP manipulation. EIS and DS can be used to determine the dielectric properties of proteins predicting their DEP behavior. Basic principles of EIS and DS are discussed and related to protein DEP through examples from previous studies. Challenges of performing DS measurements as well as potential designs to incorporate EIS and DS measurements in DEP experiments are also discussed. PMID- 25697195 TI - Quantitation of protein post-translational modifications using isobaric tandem mass tags. AB - Post-translational modifications (PTMs) of proteins are known to modulate many cellular processes and their qualitative and quantitative evaluation is fundamental for understanding the mechanisms of biological events. Over the past decade, improvements in sample preparation techniques and enrichment strategies, the development of quantitative labeling strategies, the launch of a new generation of mass spectrometers and the creation of bioinformatics tools for the interrogation of ever larger datasets has established MS-based quantitative proteomics as a powerful workflow for global proteomics, PTM analysis and the elucidation of key biological mechanisms. With the advantage of their multiplexing capacity and the flexibility of an ever-growing family of different peptide-reactive groups, isobaric tandem mass tags facilitate quantitative proteomics and PTM experiments and enable higher sample throughput. In this review, we focus on the technical concept and utility of the isobaric tandem mass tag labeling approach to PTM analysis, including phosphorylation, glycosylation and S-nitrosylation. PMID- 25697196 TI - Corrigendum. AB - In the White Paper by Benno Ingelse, Begona Barroso, Nicholas Gray, Verena Jakob Rodamer, Clare Kingsley, Corinna Sykora, Petra Vinck, Martina Wein & Stephen White, 'European Bioanalysis Forum: recommendation on dealing with hemolyzed and hyperlipidemic matrice.' Bioanalysis 6(23), 3113-3120 (2014), a reference was missed out. The newly added reference is [24], added on page 3116 at the end of the following sentence: 'Regarding the bioanalytical field, there is no consensus about the definition of hyperlipidemic plasma as there is no commercially available source of standardized hyperlipidemic matrix [24].' And the reference is as follows: Mayrand-Provencher L, Furtado M, Mess J-N, Dumont I, Garofolo F. Choosing the appropriate matrix to perform a scientifically meaningful lipemic plasma test in bioanalytical method validation. Bioanalysis 6(12), 1639-1646 (2014). The editors of Bioanalysis would like to sincerely apologize for any inconvenience or confusion this may have caused our readers. PMID- 25697197 TI - Treating Multiple Incident Post-Traumatic Stress Disorder (PTSD) in an Inner City London Prison: The Need for an Evidence Base. AB - BACKGROUND: Mental health problems have been found to be more prevalent in prison populations, and higher rates of post-traumatic stress disorder (PTSD) have been found in sentenced populations compared to the general population. Evidence-based treatment in the general population however has not been transferred and empirically supported into the prison system. AIMS: The aim of this manuscript is to illustrate how trauma focused work can be applied in a prison setting. METHOD: This report describes a two-phased approach to treating PTSD, starting with stabilization, followed by an integration of culturally appropriate ideas from narrative exposure therapy (NET), given that the traumas were during war and conflict, and trauma-focused cognitive behavioural therapy (TF-CBT). RESULTS: PTSD and scores on paranoia scales improved between start and end of treatment; these improvements were maintained at a 6-month follow-up. CONCLUSION: This case report 1 illustrates successful treatment of multiple incident PTSD in a prison setting using adaptations to TF-CBT during a window of opportunity when individuals are more likely to be free from substances and live in relative stability. Current service provision and evidence-based practice for PTSD is urgently required in UK prisons to allow individuals to engage in opportunities to reduce re-offending, free from mental health symptoms. PMID- 25697198 TI - Unusual presentation of polyarteritis nodosa with unilateral pseudoaneurysm of the posterior tibial artery. PMID- 25697199 TI - Fabrication of electron beam deposited tip for atomic-scale atomic force microscopy in liquid. AB - Recently, possibilities of improving operation speed and force sensitivity in atomic-scale atomic force microscopy (AFM) in liquid using a small cantilever with an electron beam deposited (EBD) tip have been intensively explored. However, the structure and properties of an EBD tip suitable for such an application have not been well-understood and hence its fabrication process has not been established. In this study, we perform atomic-scale AFM measurements with a small cantilever and clarify two major problems: contaminations from a cantilever and tip surface, and insufficient mechanical strength of an EBD tip having a high aspect ratio. To solve these problems, here we propose a fabrication process of an EBD tip, where we attach a 2 MUm silica bead at the cantilever end and fabricate a 500-700 nm EBD tip on the bead. The bead height ensures sufficient cantilever-sample distance and enables to suppress long-range interaction between them even with a short EBD tip having high mechanical strength. After the tip fabrication, we coat the whole cantilever and tip surface with Si (30 nm) to prevent the generation of contamination. We perform atomic scale AFM imaging and hydration force measurements at a mica-water interface using the fabricated tip and demonstrate its applicability to such an atomic scale application. With a repeated use of the proposed process, we can reuse a small cantilever for atomic-scale measurements for several times. Therefore, the proposed method solves the two major problems and enables the practical use of a small cantilever in atomic-scale studies on various solid-liquid interfacial phenomena. PMID- 25697200 TI - [First Latin American Congress of residency training in medical specialties]. PMID- 25697201 TI - [Interhospital pediatric transport: a growing necessity of the Chilean healthcare network]. PMID- 25697202 TI - [Advances in the management of children with intestinal failure]. AB - Intestinal failure is defined as the reduction of a functional gut mass below the minimal necessary for adequate digestion and absorption of nutrients and fluids. Intestinal failure is the final result of a number of different causes, being short bowel syndrome the most recognized. Its prevalence is low, but the impact in quality of life among patients and their families is critical. Furthermore, is associated with high economic costs, both for the patient and the health provider. Its main feature is the need for long-term parenteral nutritional support with high morbidity and mortality associated complications, such as line derived bloodstream infections and liver disease. The management of these patients should be performed by a multidisciplinary team, and be aimed at promoting adaptation and recovery of bowel function to achieve intestinal autonomy. PMID- 25697203 TI - [Use of procalcitonin as diagnostic marker in acute gastroenteritis]. AB - INTRODUCTION: There is no hematological marker that reliably differentiates between bacterial and nonbacterial acute gastroenteritis (AGE). The objective of this study is to evaluate procalcitonin (PCT) as a marker for bacterial AGE and analyze its relationship with hospital admission. PATIENTS AND METHOD: A prospective study of children diagnosed with AGE was conducted at the emergency room during a period of seven months, which required blood and stool samples. Epidemiological, clinical and analytical variables were analyzed. Patients with chronic digestive disease, prolonged diarrhea, immunodeficiency or prior antibiotic treatment were excluded. The study was approved by the Ethics Committee and an informed consent was requested. RESULTS: 45 patients were analyzed. Children with bacterial GEA were older (p=0.027) and presented higher median PCT and C-reactive protein concentrations (CRP) (p=0.001). The PCT and CRP values that best discriminated bacterial infection were PCT>=0.05 mg/L (sensibility 64.3%, specificity 83.9%, positive probability coefficient (PPC): 4), and CRP>=3 mg/dL (sensibility 78.6%, specificity 90.3%, PPC: 8). No association between the elevation of these markers and higher hospitalization probability was found. CONCLUSION: Procalcitonin, like CRP, is elevated in bacterial gastroenteritis (p=0.001), but these markers are not a predictor of hospitalization. PMID- 25697204 TI - [Factors associated with prolonged hospital stay in infants]. AB - OBJECTIVE: To evaluate factors present on newborn admission to a neonatal intensive care and associated with a prolonged hospital stay. PATIENTS AND METHOD: Non-matched case-control study, with 555 infants, 111 with more than 7 days of hospital stay and 444 who stayed hospitalized between 1 and 7 days, between 2005 and 2010. Pre hospitalization maternal factors (age, pregnancy, health insurance, education, prenatal care, marital status, history of preeclampsia, prolonged rupture of membranes, chorioamnionitis infection) and neonatal ones (age at admission, gestational age, birth weight, gender, delivery practice, route of admission, Apgar and type of resuscitation) that were associated with prolonged hospital stay were analyzed. Analyses were conducted using STATA 11.0 and logistic regression in the multivariate analysis. RESULTS: Maternal factors such as prenatal care with less than 5 doctor visits (AOR 2.7, 95% CI 1.3-5.5), lack of social health insurance (AOR 1.9, 95% CI 1.4-29), pregnant three or more times (AOR 1.7, 95% CI 1.1-2.7), neonatal birth weight under 2,000 g (AOR 4.2, 95% CI 1.9-9.5), need for cardiopulmonary resuscitation (AOR 4.2, 95% CI 2-9.1), gestational age less than 36 weeks (AOR 3.9, 95% CI 2 7.7) and admission to the neonatal unit through emergency room or referral from another hospital (AOR 2.8, 95% CI 1.7-4.6) were associated with hospital stays longer than 7 days. CONCLUSIONS: In-hospital complications that affect a prolonged stay at the health center were social health insurance, maternal education and prenatal care, and these should be considered in the evaluation of the hospital care quality indicators. PMID- 25697205 TI - [Pediatric outpatient consultation at the emergency department of a university hospital]. AB - INTRODUCTION: To determine the epidemiological profile of pediatric consultations treated at the emergency department (ED) is essential for planning processes of medical care and to guide education programs and research. OBJECTIVES: To describe the characteristics of the child population and the main reasons for consultation (RFC) seen in a pediatric emergency service. PATIENTS AND METHOD: A retrospective, descriptive clinical study was conducted regarding the visits to the Children's Emergency Service of an academic hospital in Santiago, for a period of twelve months. RFC were analyzed by age group, severity, seasonality, disposition and frequency of recurrent visits. RESULTS: 24,531 pediatric consultations were evaluated, 51.9% were male (n=12,720). The age of the patients ranged between one day old and 15 years, with a median age of 36.5 months. 1.5% of patients were newborns (NB), 17.6% were infants (n=4,326), 51.9% were preschoolers (n=12,725) and 29% were school children (n=7,118). Major RFC were fever (n=6,643, 28.2%), gastrointestinal symptoms (n=5,606, 23.8%) and respiratory symptoms (n=5,018, 21.3%), which did not differ significantly according to gender. Most patients (95.5%) were sent to their homes. The risk of hospitalization was more elevated in NB and in those with jaundice (OR=7.20, 95% CI 3.12 to 16.6), neurological symptoms (OR=6.90, 95% CI 4.60 -10.4) and poisoning (OR=6.45, 95% CI 2.82 to 14.7). About 4% were repeat visits, especially in the NB group. CONCLUSIONS: The epidemiological profile of pediatric consultations seen at the ED was similar to that described in previous studies. However, a lower rate of hospitalization was found even though the patients had similar risk profile. PMID- 25697206 TI - [Nutritional diagnosis of school children on an island of the VIII region]. AB - Mocha Island is part of the commune of Lebu, VIII region. By isolating location, conditions of life of its inhabitants are often deficient. OBJECTIVE: To characterize the nutritional status of children attending the G-501 school in Mocha Island using anthropometric assessment, in order to determine the magnitude of malnutrition due to excessive food intake in this population. PATIENTS AND METHOD: Weight and measurement of 80 children enrolled in school (out of 88) were calculated during the medical round of December 2012, classifying their nutritional status according to the recommended table for each age. RESULTS: Qf the children, 24 (30%) had normal or eutrophic nutritional diagnosis, 25 (31.25%) were overweight and 31 (38.75) were obese. There are more overweight and obese girls than boys. From a total of 120 children aged 0-14 living on the island, 56 had malnutrition due to excessive food intake (46.66%). CONCLUSIONS: The odds of obesity and overweight in rural, isolated and poor environments are alarming and require the creation of strategies that result in improved lifestyles for these children as well as their families. PMID- 25697207 TI - [Cardiorespiratory capacity in children living at moderate altitude]. AB - OBJECTIVE: To determine the cardiorespiratory capacity of school children living at moderate altitude. PATIENTS AND METHOD: 795 children (394 children and 401 girls) were selected from urban public schools in Arequipa, Peru at moderate altitude (2,320 m). Anthropometric variables (body mass, height, body fat percentage) and cardiorespiratory capacity were assessed using the Course Navette test, considering the following categories: deficient, poor, fair, good, very good and excellent. RESULTS: The results showed significant differences in all categories (p<0.05). It was described that the median values of the poor and deficient categories in both gender were lower than what is considered acceptable (p<0.05). It was concluded that 19% of boys and 21% of girls showed low level of cardiorespiratory capacity and a low negative correlation with overweight (r= 0.20 to -0.22) and a moderate negative correlation with obesity (r=-0.39 to 0.42) were described for both genders. CONCLUSIONS: Low levels of cardiorespiratory capacity in boys and girls living at moderate altitude are observed, which is negatively correlated with excess body weight. The results suggest that 1 in 5 children are likely to suffer some type of cardiovascular event. PMID- 25697208 TI - [Transcatheter embolization device as a promising option in the treatment of pulmonary sequestration. Case reports]. AB - INTRODUCTION: Pulmonary sequestration (PS) has been treated for many years with conventional surgical removal of the ectopic lung tissue and ligation of aberrant vessels that arise from the aorta. There is evidence, especially in English language literature that supports the use of transcatheter arterial embolization through a device for occlusion of the anomalous vessel, as a safe option and definitive treatment for intralobar PS. OBJECTIVE: To show our experience pioneering the technique of PS treatment through transcatheter embolization. CASE REPORT: The case reports of two teenagers aged 13 and 14 and a 26-day-old newborn that developed intralobar PS are described. The diagnosis was made through computerized axial tomography (CT scan) and successfully and without complication, during early and long term follow-up, treated by arterial embolization transcatheter. CONCLUSION: The use of transcatheter arterial embolization is a less invasive and definitive treatment for patients with PS. PMID- 25697209 TI - [Renal extramedullary hematopoiesis. Case report]. AB - Extramedullary hematopoiesis (EMH) is defined as the formation and development of erythrocytic, granulocytic and megakaryocytic cell lines outside the bone marrow; it is a rare occurrence, which is limited to case reports. OBJECTIVE: To describe a case of renal EMH secondary to chronic hypoxia. CASE REPORT: The patient is a 16 year old teenager who developed chronic hypoxia, central cyanosis, clubbing and lives more than 2,500 m above sea level. Chronic hypoxia is probably secondary to pulmonary hypertension, neither detected nor previously treated. The Consultation was due to a mass in the left upper quadrant for the last three months. An Echocardiogram showed pulmonary hypertension that could not be assessed by hemodynamic parameters. A computed tomography showed bilateral left renal pelvic masses. The hemogram showed polycythemia, so bone marrow aspiration was performed, which rule out malignant pathology. A biopsy of the renal mass reported EMH with three hematopoietic cell lines. CONCLUSION: This EMH case is a response to chronic hypoxia rather than to a bone marrow lesion as it has usually been described. PMID- 25697210 TI - [Heart failure as early manifestation of neonatal hyperthyroidism. Case report]. AB - Neonatal hyperthyroidism is usually a self-limited condition frequently associated with transplacental passage of thyroid stimulating antibodies secondary to maternal autoimmune disorders. To timely detect mothers with this medical antecedents decreases the risk for fetal adverse events. OBJECTIVE: To report a case of neonatal hyperthyroidism associated with intrauterine growth restriction and heart failure. CASE REPORT: A 36 week-old newborn with birth weight of 1,240 g. Symptoms were tachycardia, distal coldness, exophthalmos, hepatomegaly and tremors. Echocardiogram ruled out structural heart disorders. Due to maternal symptoms suggestive of hyperthyroidism, TSH tests were performed showing 0.01 ulU/ml, free T4 7.7 ng/dl, so the diagnosis of neonatal hyperthyroidism was confirmed. It was treated with methimazole and propanol, alleviating the symptoms and decreasing the levels of free T4. CONCLUSIONS: To know the maternal history helps identify and manage neonatal complications of hyperthyroidism. Heart failure and other cardiopulmonary disorders are determinants of mortality during early neonatal period. High-risk newborns should receive follow up assessments. PMID- 25697211 TI - [Clinical, genetic and molecular characterization of the X-linked chronic granulomatous disease. A case report of a new splicing mutation]. AB - Chronic granulomatous disease (CGD) is caused by mutations in the genes that encode five of the subunits of the human NADPH oxidase. The most common form is caused by mutations in CYBB, the human gene encoding gp 91 phox. OBJECTIVE: To identify the molecular defects causing CGD. CASE REPORT: A male patient with a history of acute diarrhea and recurrent perianal abscess since two months old. At 6 months, the patient presented a chronic inflammatory disease of the colon and bacterial colitis. After three years, he developed infections in the lower and perianal respiratory tract. The cDNA analysis identified abnormal mRNA expression, which was confirmed by sequencing. Specifically the exclusion of exon 2 was observed. Additionally, gDNA sequencing identified an alteration in the acceptor splice site of intron 1, including a deletion followed by insertion of three nucleotides (c.46-14_-11delTTCT insGAA). CONCLUSIONS: The first molecular study of a patient with CGD due to splicing pattern change, reported in Colombia, is presented. The definition of the mutation and its correlation with the phenotype is essential to provide appropriate genetic counseling to patients and their families. PMID- 25697212 TI - [Clinical-radiological case]. PMID- 25697213 TI - [Pros and cons of legalizing marijuana]. AB - There are already several countries that have accepted marijuana as a soft drug, separating it from more dangerous ones. Yarious therapeutic properties have even been attributed to its use. Others, however, think that its use should be prohibited due to the mental interference and behavioral changes produced either by its occasional use as well as the permanent mental damage linked to chronic marijuana use. In order to clarify this divergence of opinions, the scientific literature is reviewed. It is concluded that there is a serious risk, especially for teenagers, associated to chronic marijuana use due to the presence of more frequent psychotic and schizophrenic episodes, which can be permanent, while consumption during pregnancy results in brain damage to the fetus, similar to fetal alcohol syndrome. Scientific research also indicated that smoking marijuana produces an even more severe bronchial damage than tobacco, with risk of lung cancer. In conclusion, the notion that marijuana is a risk-free soft drug is a serious mistake, based on the available conclusive scientific research that shows the opposite. PMID- 25697214 TI - Radiator-induced erythema ab igne in 8-year-old girl. AB - The cutaneous lesion of erythema ab Igne are characterized by a reticulate erythema, hyperpigmentation, fine scaling, epidermal atrophy and telangiectasias, and reticulated erythema. We report a case of erythema ab igne on the hands of a 8-year-old girl, induced by classic homemade radiator. PMID- 25697215 TI - [Public and quality]. PMID- 25697216 TI - Recent developments in the implementation of novel designs for early-phase combination studies. PMID- 25697217 TI - Survival following early-stage colon cancer: an ACCENT-based comparison of patients versus a matched international general population?. AB - BACKGROUND: Post-treatment survival experience of early colon cancer (CC) patients is well described in the literature, which states that cure is probable for some patients. However, comparisons of treated patients' survival versus that expected from a matched general population (MGP) are limited. PATIENTS AND METHODS: A total of 32 745 patients from 25 randomized adjuvant trials conducted from 1977 to 2012 in 41 countries were pooled. Observed long-term survival of these patients was compared with expected survival matched on sex, age, country, and year, both overall and by stage (II and III), sex, treatment [surgery, 5 fluorouracil (5-FU), 5-FU + oxaliplatin], age (<70 and 70+), enrollment year (pre/post 2000), and recurrence (yes/no). Comparisons were made at randomization and repeated conditional on survival to 1, 2, 3, and 5 years. CC and MGP equivalence was tested, and observed Kaplan-Meier survival rates compared with expected MGP rates 3 years out from each landmark. Analyses were also repeated in patients without recurrence. RESULTS: Within most cohorts, long-term survival of CC patients remained statistically worse than the MGP, though conditional survival generally improved over time. Among those surviving 5 years, stage II, oxaliplatin-treated, elderly, and recurrence-free patients achieved subsequent 3 year survival rates within 5% of the MGP, with recurrence-free patients achieving equivalence. CONCLUSIONS: Conditional on survival to 5 years, long-term survival of most CC patients on clinical trials remains modestly poorer than an MGP, but achieves MGP levels in some subgroups. These findings emphasize the need for access to quality care and improved treatment and follow-up strategies. PMID- 25697218 TI - Imidazole derivative-functionalized carbon dots: using as a fluorescent probe for detecting water and imaging of live cells. AB - A highly sensitive carbon dot-imidazole (CD-imidazole) nanoprobe is prepared through covalently conjugating imidazole group onto the surface of carbon dots for water fluorescence. In organic solvents, quenching of fluorescence occurs via photoinduced electron transfer (PET) process from the imidazole nitrogen to the CD acceptor. Addition of a trace amount of water into CD nanocomposites in various organic solvents leads to a fluorescence turn-on response, which can be attributed to the suppression of PET due to the formation of the "free" ion pair by proton transfer from the carboxyl groups that are on the CDs surface to the imidazole nitrogen through a water-bridge. This phenomenon can be used for the highly selective detection of trace amounts of water in organic solvents. Laser confocal microscope experiment shows the potential utilization of CD-imidazole for the probed proton-transfer reactions in living cells. PMID- 25697219 TI - A novel synthetic route to transition metal phosphide nanoparticles. AB - A novel synthetic route was developed to prepare nano-sized and well-dispersed phosphides of transition metals (Mo, Ni, and Co) from their corresponding oxide precursors. The current approach produced metal phosphides in dimethyl ether (DME) using the rapid heating reduction (RHR) method. The synthesis of phosphides in DME was interesting, since the composition of gas-phase products was predominantly H2, CO and CH4 with a minor amount of CO2 but without H2O. Based on XRD and MS results, the formation mechanism of the phosphides was proposed. The overall synthesis process cannot simply be regarded as the reduction of an oxide precursor and the decomposition of DME. The product distribution should be ascribed to a combination of other catalytic reactions. In addition, it is noteworthy that compared with the traditional method, viz. temperature-programmed reduction in H2 (TPR-H2), the present method used a higher heating rate to shorten the reaction time and can yield more finely dispersed metal phosphide nanoparticles. The good dispersion of phosphide nanoparticles is probably achieved due to the fact that no H2O was released in the RHR-DME process, which can avoid strong hydrothermal sintering. PMID- 25697220 TI - Surfactant-induced rigidity of interfaces: a unified approach to free and dip coated films. AB - The behavior of thin liquid films is known to be strongly affected by the presence of surfactants at the interfaces. The detailed mechanism by which the latter enhance film stability is still a matter of debate, in particular concerning the influence of surface elastic effects on the hydrodynamic boundary condition at the liquid/air interfaces. In the present work, "twin" hydrodynamic models neglecting surfactant transport to the interfaces are proposed to describe the coating of films onto a solid plate (Landau-Levich-Derjaguin configuration) as well as soap film pulling (Frankel configuration). Experimental data on the entrained film thickness in both configurations can be fitted very well using a single value of the surface elasticity, which is in good agreement with independent measurements by mean of surface expansion experiments in a Langmuir through. The analysis thus shows that soap films or dip coating experiments may be used to measure the surface elasticity of surfactant solutions in the insoluble limit, namely as long as the film generation dynamics is fast compared to the surfactant adsorption timescale. PMID- 25697221 TI - Development of an on-animal separation-based sensor for monitoring drug metabolism in freely roaming sheep. AB - The development of an on-animal separation-based sensor that can be employed for monitoring drug metabolism in a freely roaming sheep is described. The system consists of microdialysis sampling coupled to microchip electrophoresis with electrochemical detection (MD-ME-EC). Separations were accomplished using an all glass chip with integrated platinum working and reference electrodes. Discrete samples from the microdialysis flow were introduced into the electrophoresis chip using a flow-gated injection approach. Electrochemical detection was accomplished in-channel using a two-electrode isolated potentiostat. Nitrite was separated by microchip electrophoresis using reverse polarity and a run buffer consisting of 50 mM phosphate at pH 7.4. The entire system was under telemetry control. The system was first tested with rats to monitor the production of nitrite following perfusion of nitroglycerin into the subdermal tissue using a linear probe. The data acquired using the on-line MD-ME-EC system were compared to those obtained by off-line analysis using liquid chromatography with electrochemical detection (LC-EC), using a second microdialysis probe implanted parallel to the first probe in the same animal. The MD-ME-EC device was then used on-animal to monitor the subdermal metabolism of nitroglycerin in sheep. The ultimate goal is to use this device to simultaneously monitor drug metabolism and behavior in a freely roaming animal. PMID- 25697222 TI - Direct single-molecule observations of local denaturation of a DNA double helix under a negative supercoil state. AB - Effects of a negative supercoil on the local denaturation of the DNA double helix were studied at the single-molecule level. The local denaturation in lambdaDNA and lambdaDNA containing the SV40 origin of DNA replication (SV40ori-lambdaDNA) was directly observed by staining single-stranded DNA regions with a fusion protein comprising the ssDNA binding domain of a 70-kDa subunit of replication protein A and an enhanced yellow fluorescent protein (RPA-YFP) followed by staining the double-stranded DNA regions with YOYO-1. The local denaturation of lambdaDNA and SV40ori-lambdaDNA under a negative supercoil state was observed as single bright spots at the single-stranded regions. When negative supercoil densities were gradually increased to 0, -0.045, and -0.095 for lambdaDNA and 0, 0.047, and -0.1 for SV40ori-lambdaDNA, single bright spots at the single-stranded regions were frequently induced under higher negative supercoil densities of 0.095 for lambdaDNA and -0.1 for SV40ori-lambdaDNA. However, single bright spots of the single-stranded regions were rarely observed below a negative supercoil density of -0.045 and -0.047 for lambdaDNA and SV40ori-lambdaDNA, respectively. The probability of occurrence of the local denaturation increased with negative superhelicity for both lambdaDNA and SV40ori-lambdaDNA. PMID- 25697223 TI - Utility of electronystagmography in the prediction of post-operative outcome following cochlear implantation. AB - OBJECTIVE: To examine the relationship between pre-operative electronystagmography and videonystagmography test results and post-operative outcomes in dizziness, auditory sensitivity and speech recognition. METHODS: A retrospective chart review was performed. Auditory sensitivity and speech perception ability were tested pre- and post-operatively in 37 adult cochlear implant recipients. Auditory sensitivity was evaluated using either pure tones (for testing with earphones) or frequency-modulated warble tones (for sound-field testing). Speech perception ability was evaluated using Northwestern University Auditory Test Number 6. RESULTS: No correlation was found between pre-operative electronystagmography test results and post-operative subjective dizziness. However, pre-operative electronystagmography testing and post-operative hearing sensitivity as measured by warble tone average (dB HL) correlated significantly at six months or later after cochlear implant activation (r >= -0.34, n = 34, p < 0.05). CONCLUSION: This study, which has a level of evidence 4, demonstrates that pre-operative electronystagmography testing has a potential use in predicting post-operative outcomes in hearing sensitivity following cochlear implantation. However, larger studies are needed to confirm this novel finding. PMID- 25697224 TI - Tunable upconversion luminescence in self-crystallized Er(3+):K(Y(1-x)Yb(x))3F10 nano-glass-ceramics. AB - K(Y1-xYbx)3F10 (x = 0-1) solid-solution nanocrystals embedded glass ceramics were fabricated via glass self-crystallization. Using Eu(3+) as a structural probe, the partition of lanthanide activators into the K(Y1-xYbx)3F10 lattice was evidenced. As a consequence, color-tunable upconversion luminescence from green to red was easily realized by modifying Yb(3+) content in the Er(3+)-doped nano glass-ceramics. PMID- 25697225 TI - Combined use of clozapine and ECT: a review. AB - OBJECTIVE: This paper aims to review the available evidence for the use of clozapine and electroconvulsive therapy (ECT) in combination. METHODOLOGY: Electronic searches were carried out to identify reports describing the combined use of clozapine and ECT. RESULTS: Forty reports including 208 patients were identified. The majority of reports were in the form of case reports and case series, with few retrospective and open-label studies. The majority of patients were aged between 18 and 65 years and diagnosed with schizophrenia or schizoaffective disorder. Most of the patients refractory to clozapine were started on ECT as an augmentation therapy; however, in some reports, both ECT and clozapine were started concurrently, and in few cases clozapine was started after ECT. In terms of effectiveness, 37.5-100% patients improved in short-term, and sustained long-term improvement (3 weeks to 24 months) was described in few studies. In terms of the side-effect profile, five patients each had delirium and tachycardia and only four patients were described to have prolonged seizures. Overall, the combination was considered effective and safe. CONCLUSION: There is evidence for the effectiveness and safety of the clozapine-ECT combination and it should be used in patients with treatment-resistant schizophrenia who do not respond to clozapine. PMID- 25697226 TI - A N3S(thioether)-ligated Cu(II)-superoxo with enhanced reactivity. AB - Previous efforts to synthesize a cupric superoxide complex possessing a thioether donor have resulted in the formation of an end-on trans-peroxo-dicopper(II) species, [{(Ligand)Cu(II)}2(MU-1,2-O2(2-))](2+). Redesign/modification of previous N3S tetradentate ligands has now allowed for the stabilization of the monomeric, superoxide product possessing a S(thioether) ligation, [((DMA)N3S)Cu(II)(O2(*-))](+) (2(S)), as characterized by UV-vis and resonance Raman spectroscopies. This complex mimics the putative Cu(II)(O2(*-)) active species of the copper monooxygenase PHM and exhibits enhanced reactivity toward both O-H and C-H substrates in comparison to close analogues [(L)Cu(II)(O2(* ))](+), where L contains only nitrogen donor atoms. Also, comparisons of [(L)Cu(II/I)](n+) compound reduction potentials (L = various N4 vs (DMA)N3S ligands) provide evidence that (DMA)N3S is a weaker donor to copper ion than is found for any N4 ligand-complex. PMID- 25697227 TI - Acetylsalicylic acid does not alter thermo-effector responses during mild whole body passive heat stress in young men. AB - Acetylsalicylic acid (ASA), aspirin, exerts potent systemic effects that may interfere with normal thermo-effector responses. We investigated the influence of commonly ingested ASA doses on measures of skin blood flow (SkBF) and local sweat rate (SR) during whole-body, passive heat stress. Seven male participants completed counter-balanced trials to compare ASA treatments (single dose 325 mg or 4 consecutive days 81 mg (4-d 81 mg)) to control (no ASA). Laser-Doppler flowmetry provided an index of SkBF. A ventilated capsule measured local sweat rate via capacitance hygrometry. Mean body temperature ([Formula: see text]) was increased by 1 degrees C above baseline using a water-perfused suit. [Formula: see text] was similar at the onset of cutaneous vasodilation among trials. Cutaneous vascular conductance, expressed as a percentage change from baseline, was not different among trials. Additionally, [Formula: see text] at the onset of local SR and SR sensitivity did not differ among trials. While ASA has previously been shown to influence SkBF during heat stress, it is possible our cohort's relatively young age may have contributed to our dissimilar results. PMID- 25697228 TI - Hemorrhagic complications associated with PR3-ANCA crescentic glomerulonephritis. AB - Hemorrhagic complications of anti-neutrophil cytoplasmic autoantibody (ANCA) associated vasculitis are life-threatening conditions. Of these, alveolar hemorrhage is the most common and well-described hemorrhagic complication and is a prominent component of the pulmonary-renal syndrome. The clinical presentation of alveolar hemorrhage is highly variable ranging from mild to serious disease that may require respiratory support. Less attention has been directed at hemorrhagic complications that have been reported in other organs and which may be as severe or more severe with regard to morbidity and mortality. For example, among the most serious non-pulmonary complications are those related to cerebral and gastrointestinal hemorrhage. Cerebral hemorrhage is the clearly the most critical issue with a persistent high mortality rate. The prognosis of gastrointestinal hemorrhage, once an ominous complication has improved with medical and surgical intervention. Not to be dismissed are the consequences of hemorrhagic issues related to skin, soft tissue or muscle involvement. Muscle hematomas, while rare, also accompanied by significant morbidity. PMID- 25697229 TI - Influence of de novo donor-specific antibody on early renal allograft function recovery. AB - BACKGROUND: The aim of the present study is to investigate the impact of de novo donor-specific antibodies (dnDSA) on early graft function, to provide objective reference for early clinical diagnosis and reasonable individualized treatment. METHODS: 305 cases of renal transplant patients for the first time were observed in this study. Follow-up time for all recipients was 6 months after operation. HLA antibody, DSA, renal function were monitored after transplant. RESULTS: In total of 305 cases, 66 cases (21.64%) were HLA antibody positive and 21 cases (6.89%) showed acute rejection (AR) in 6 months after transplant. The HLA antibody-positive patients included six cases of dnDSA-positive and 60 cases of dnDSA-negative. The incidence of AR was 2.09% (5/239) in HLA antibody-negative patients, 18.33% (11/60) in HLA antibody positive with DSA-negative patients, and 83.33% (5/6) in HLA antibody-positive patients with DSA-positive. There was a big difference between DSA-negative and DSA-positive patients (p < 0.01). The recovery time of AR patients with DSA-positive were longer than DSA-negative patients, and the recovery graft function of AR patient with DSA-positive were not as good as those with DSA-negative. CONCLUSIONS: The appearance of dnDSA in the early stage of kidney transplantation is a warning sign of AR occurrence. Dynamic monitoring of HLA antibody and DSA could predict the state of graft function, and play an important role in the prevention of AR, timely and effectively. PMID- 25697230 TI - Effect of cholecalciferol replacement on vascular calcification and left ventricular mass index in dialysis patients. AB - OBJECTIVE: The aim of this study was to determine the effect of oral cholecalciferol treatment on vascular calcification, left ventricular mass index (LVMI) and other cardiac functions in dialysis patients. DESIGN AND METHODS: A six-month course of oral cholecalciferol treatment was recommended to dialysis patients with vitamin D insufficiency. While 26 patients were given cholecalciferol treatment, 17 patients who could not tolerate to therapy received standard therapy. Initial biochemical parameters were measured, and they were measured again after 6 months of treatment. Echocardiographic measurements were also performed, and the vascular calcification score (VCS) was calculated at baseline and at the 6th month. RESULTS: The cholecalciferol replacement group showed no significant change in LVMI and VCS values (p > 0.05). However, while LVMI was similar between groups at initial evaluation, it was lower in the cholecalciferol group at the 6th month when compared to the standard treatment group (141.8 +/- 40.2 g/m(2) vs. 166.3 +/- 31.4 g/m(2); p = 0.04). Likewise, left ventricular diastolic diameters (48.8 +/- 5.1 mm vs. 47.5 +/- 4.6 mm; p = 0.023) and left atrial diameters (41.2 +/- 8.9 mm vs. 38.9 +/- 8.1 mm; p = 0.006) decreased in the cholecalciferol group. Additionally, significant increases were observed in serum 25-hydroxyvitamin D (25(OH)D) and albumin levels, with a significant decrease in serum C-reactive protein levels. CONCLUSION: A lesser increase in left ventricular mass and better diastolic functions was observed in dialysis patients after 6 months of cholecalciferol treatment. PMID- 25697231 TI - Impact of endogenous hydrogen sulfide on toll-like receptor pathway in renal ischemia/reperfusion injury in rats. AB - In this study, we investigated the impact of endogenous hydrogen sulfide (H2S) on toll-like receptors (TLRs)-mediated inflammatory response and apoptosis in renal ischemia-reperfusion injury (IRI). Twenty-four male Wistar rats were randomly divided into four groups: sham, IR, IR + propargylglycine (PAG) and IR + hydroxylamine (HA). After right nephrectomy, rats were given saline for the sham and IR group, PAG for the IR + PAG group and HA for the IR + HA group, through the left renal artery for 20 min. Five minutes after drug administration, all rats except sham underwent 45 min of left renal ischemia followed by 24 h of reperfusion. Kidneys were harvested for histological and biochemical evaluation. Levels of TLRs, downstream signaling molecules and pro-inflammatory cytokines were determined by Western blot or immunohistochemistry. Hematoxylin and eosin (H&E) stained renal sections were used for histological grading of renal injury. Apoptotic cells were detected by TUNEL assay. Compared to the sham group, rats in the IR group showed higher renal levels of TLR-2, TLR-4, nuclear NF-kappaB p65, phosphorylated ASK1, phosphorylated TRAF2, IL-1beta, IL-6, IL-18 and TNF-alpha (p < 0.05), and exhibited acute kidney injury (p < 0.05) and apoptosis (p < 0.05). Compared to the IR group, rats receiving PAG or HA showed significantly higher levels of TLR-2, TLR-4, nuclear NF-kappaB p65, phosphorylated ASK1, phosphorylated TRAF2, IL-1beta, IL-6, IL-18 and TNF-alpha (p < 0.01), more severe acute kidney injury (p < 0.05) and increased apoptosis (p < 0.01). Thus, inflammatory response and apoptosis mediated by TLRs are involved in renal IRI. Inhibition of endogenous H2S significantly activated inflammatory response and apoptosis, and thus promoted renal IRI. PMID- 25697232 TI - Identification and treatment of intra-abdominal fetal skeletal remains: A consequence of illicit and unsafe abortion. AB - OBJECTIVE: The safety of abortions has always been a matter of concern for women's health. Unsafe abortion is one of the most neglected health-care problems in developing countries due to lack of awareness of the legal issues and limited access to authorised services often leading the women to poor quality of abortion in unsafe settings through untrained health personnel. CASE REPORT: Two rare cases of second trimester unsafe abortions are reported here in which women presented after several weeks with well-preserved remains of fetal skeleton in their abdomen along with complicated multiple visceral injuries. Both these second trimester abortions were performed by untrained village abortionists for sex selection and unwanted pregnancy in an unmarried adolescent girl. The management in the unmarried girl was further complicated due to undisclosed history of abortion. CONCLUSION: These reports of unsafe abortion highlight the need for clinicians to have a high index of suspicion for an undisclosed abortion when treating any morbid woman of reproductive age with a bizarre abdominal clinical picture. PMID- 25697233 TI - Development and formative evaluation of an innovative mHealth intervention for improving coverage of community-based maternal, newborn and child health services in rural areas of India. AB - BACKGROUND: A new cadre of village-based frontline health workers, called Accredited Social Health Activists (ASHAs), was created in India. However, coverage of selected community-based maternal, newborn and child health (MNCH) services remains low. OBJECTIVE: This article describes the process of development and formative evaluation of a complex mHealth intervention (ImTeCHO) to increase the coverage of proven MNCH services in rural India by improving the performance of ASHAs. DESIGN: The Medical Research Council (MRC) framework for developing complex interventions was used. Gaps were identified in the usual care provided by ASHAs, based on a literature search, and SEWA Rural's1 three decades of grassroots experience. The components of the intervention (mHealth strategies) were designed to overcome the gaps in care. The intervention, in the form of the ImTeCHO mobile phone and web application, along with the delivery model, was developed to incorporate these mHealth strategies. The intervention was piloted through 45 ASHAs among 45 villages in Gujarat (population: 45,000) over 7 months in 2013 to assess the acceptability, feasibility, and usefulness of the intervention and to identify barriers to its delivery. RESULTS: Inadequate supervision and support to ASHAs were noted as a gap in usual care, resulting in low coverage of selected MNCH services and care received by complicated cases. Therefore, the ImTeCHO application was developed to integrate mHealth strategies in the form of job aid to ASHAs to assist with scheduling, behavior change communication, diagnosis, and patient management, along with supervision and support of ASHAs. During the pilot, the intervention and its delivery were found to be largely acceptable, feasible, and useful. A few changes were made to the intervention and its delivery, including 1) a new helpline for ASHAs, 2) further simplification of processes within the ImTeCHO incentive management system and 3) additional web-based features for enhancing value and supervision of Primary Health Center (PHC) staff. CONCLUSIONS: The effectiveness of the improved ImTeCHO intervention will be now tested through a cluster randomized trial. PMID- 25697234 TI - Enzyme-specific sensors via aggregation of charged p-phenylene ethynylenes. AB - Chemical and biological sensors are sought for their ability to detect enzymes as biomarkers for symptoms of various disorders, or the presence of chemical pollutants or poisons. p-Phenylene ethynylene oligomers with pendant charged groups have been recently shown to have ideal photophysical properties for sensing. In this study, one anionic and one cationic oligomer are combined with substrates that are susceptible to enzymatic degradation by phospholipases or acetylcholinesterases. The photophysical properties of the J-aggregated oligomers with the substrate are ideal for sensing, with fluorescence quantum yields of the sensors enhanced between 30 and 66 times compared to the oligomers without substrate. The phospholipase sensor was used to monitor the activity of phospholipase A1 and A2 and obtain kinetic information, though phospholipase C did not degrade the sensor. The acetylcholinesterase sensor was used to monitor enzyme activity and was also used to detect the inhibition of acetylcholinesterase by three different inhibitors. Phospholipase A2 is a biomarker for heart and circulatory disease, and acetylcholinesterase is a biomarker for Alzheimer's, and indicative of exposure to certain pesticides and nerve agents. This work shows that phenylene ethynylene oligomers can be tailored to enzyme-specific sensors by careful selection of substrates that induce formation of a molecular aggregate, and that the sensing of enzymes can be extended to enzyme kinetics and detection of inhibition. Furthermore, the aggregates were studied through all-atom molecular dynamics, providing a molecular-level view of the formation of the molecular aggregates and their structure. PMID- 25697235 TI - Interfacial binding of divalent cations to calixarene-based Langmuir monolayers. AB - The interactions of Langmuir monolayers produced through the self-assembly of an amphiphilic p-carboxycalix[4]arene (1) with a series of divalent, fourth-period transition metals, at the air-water interface, were investigated. Changes in the interfacial behavior of 1 in response to the presence of CuCl2, CoCl2, MnCl2, and NiCl2 were studied by means of Langmuir compression isotherms and Brewster angle microscopy (BAM). The measurements revealed that the self-assembly properties of 1 are significantly affected by Cu(2+) ions. The interactions of 1-based monolayers with Co(2+) and Cu(2+) ions were further investigated by means of synchrotron radiation-based X-ray reflectivity (XRR), X-ray near-total-reflection fluorescence (XNTRF), and grazing incidence X-ray diffraction (GIXD). XNTRF and XRR analyses revealed that the monolayer of 1 binds more strongly to Cu(2+) than Co(2+) ions. In the presence of relatively high concentrations of Cu(2+) ions in the subphase (1.4 * 10(-3) M), XNTRF exhibited anomalous depth profile behavior and GIXD measurements showed considerably strong diffuse scattering. Both measurements suggest the formation of Cu(2+) clusters contiguous to the monolayer of 1. PMID- 25697236 TI - Attitudes and Preferences towards Self-help Treatments for Depression in Comparison to Psychotherapy and Antidepressant Medication. AB - BACKGROUND: Self-help is an effective treatment for depression. Less is known, however, about how acceptable people find different self-help treatments for depression. AIMS: To investigate preferences and attitudes toward different self help treatments for depression in comparison to psychotherapy and antidepressants. METHOD: N = 536 people who were not actively seeking treatment for depression were randomly assigned to read about one of five treatment options (bibliotherapy, Internet-based self-help, guided self-help, antidepressants, or psychotherapy) before rating how acceptable they found the treatment. Participants also ranked the treatments in order of preference. RESULTS: Psychotherapy and guided self-help were found to be the most acceptable and preferred treatment options. Antidepressants and bibliotherapy were found to be the least acceptable treatments, with antidepressants rated as the most likely to have side effects. Preference data reflected the above findings - psychotherapy and guided self-help were the most preferred treatment options. CONCLUSIONS: The findings highlight differences in attitudes and preferences between guided and unguided self-help interventions; and between self-help interventions and psychotherapy. Future research should focus on understanding why unguided self help interventions are deemed to be less acceptable than guided self-help interventions for treating depression. PMID- 25697237 TI - High-quality, single-layered epitaxial graphene fabricated on 6H-SiC (0001) by flash annealing in Pb atmosphere and mechanism. AB - High-quality epitaxial graphene is produced on silicon carbide by flash annealing of 6H-SiC in a lead (Pb) atmosphere at ~1400 degrees C for 30 s. Nearly three top bilayers of SiC are decomposed due to fast heating and cooling, and sublimation of Si atoms from SiC is retarded by the Pb atmosphere. The synergetic effects promote the growth of continuous single-layered graphene sheets on the SiC terraces, and a model is established to elucidate the effects and growth mechanism. PMID- 25697238 TI - Microsurgical management of posterior cerebral artery aneurysms: A report of thirty cases in modern era. AB - OBJECTIVE: We reviewed a series of 30 cases of posterior cerebral artery (PCA) aneurysms to examine the outcomes of microsurgical techniques, which is an important alternative to endovascular interventions in localities where access to the latter renders practical difficulty. We also aimed to introduce the initial experience about the clinical application of intraoperative computed tomography (CT) in treatment of PCA aneurysm. METHODS: Thirty patients with PCA aneurysm treated using microsurgery in our department between January 1996 and July 2014 were reviewed retrospectively. RESULTS: The case series included 13 females and 17 males with a mean age of 44 years, ranging from 8 to 78 years. Eighteen aneurysms were ruptured, five aneurysms caused a direct mass effect, and the remaining seven aneurysms were found incidentally. Most aneurysms were located in the P1 segment or the P1-P2 junction of the PCA (63%). Eighteen aneurysms (60%) were large or giant in size (>= 10 mm). Seventeen aneurysms were directly clipped, six trapped, one wrapped, one electrocoagulated and resected, and five trapped or proximal clipped with a bypass. Intraoperative perfusion CT (PCT) and CT angiography (CTA) were applied to provide immediate information regarding cerebral hemodynamics and anatomy of vessels in six patients. Twenty-six patients (87%) showed good clinical outcomes according to the modified Rankin Scale score (<= 2) at the mean clinical follow-up period of 34 (range: 1-78) months, including the patients using intraoperative CT, and one (3%) patient was dead. CONCLUSION: Microsurgical therapy for patients with PCA aneurysms can have a positive outcome with correctly selected techniques. Personalized microsurgical treatment paradigms are determined by the anatomical location, shape and size of the PCA aneurysm, and the clinical features of the patient. Intraoperative PCT and CTA can improve the efficacy of the surgical treatment. PMID- 25697239 TI - Lanthanide hydroxide ribbons assembled in a 2D network: slow relaxation of the magnetization in the dysprosium(III) complex. AB - A novel infinite lanthanide hydroxide ribbon was successfully assembled in a 2D network, which exhibits slow relaxation of the magnetization at low temperature. PMID- 25697240 TI - A highly selective fluorescent probe for sulfide ions based on aggregation of Cu nanocluster induced emission enhancement. AB - In this study, S(2-) ions were found to enhance the fluorescence of cysteine capped Cu nanoclusters (Cu NCs). High resolution transmission electron microscopy (HRTEM), Fourier-transform infrared spectroscopy (FT-IR), scanning electron microscopy-energy dispersive X-ray (SEM-EDX) measurements, zeta potential and X ray photoelectron spectroscopy (XPS) measurements demonstrated that the S(2-) ion induced aggregation of the Cu NCs contributed to the fluorescence enhancement of the dispersed Cu NCs. Based on these findings, a highly selective fluorescent probe was developed for the determination of H2S using the S(2-) ion-enhanced fluorescence of the as-prepared Cu NCs. The relative fluorescence intensity was proportional to the concentration of S(2-) in the range from 0.2 to 50 MUM. The detection limit (S/N = 3) was 42 nM. The proposed method has been successfully applied to determine H2S produced from toys called "Fart Bomb" with recoveries of 97.6-101.8%. The results of the proposed method were in good agreement with those determined by a standard methylene blue method. This work is not only of importance for a better understanding of the aggregation induced emission (AIE) properties of the Cu NCs but also of great potential to find extensive biological applications for H2S. PMID- 25697241 TI - Binuclear platinum-iridium complexes: synthesis, reactivity and luminescence. AB - The chemistry of the heterobinuclear platinum-iridium complex [PtIr(CO)3(MU dppm)2][PF6], 1, dppm = Ph2PCH2PPh2, is described. The reaction of a hydride with 1 gave [HPtIr(CO)2(MU-dppm)2], by displacement of the carbonyl ligand from platinum, while reaction of 1 with dihydrogen, hydrogen chloride or Ph2MeSiH gave the fluxional complex [PtIrH4(CO)(MU-dppm)2][PF6], [PtIrH2Cl2(CO)(MU dppm)2][PF6], or [PtIrH(SiMePh2)(CO)2(MU-dppm)2][PF6], respectively, by oxidative addition at iridium. Complex 1 reacted, often regioselectively, with several alkynes to give the MU-eta(1),eta(1) bridging alkyne complexes [PtIr(MU RCCR')(CO)2(MU-dppm)2][PF6], R = H, R' = Ph, 4-C6H4Me, CO2Me; R = Ph, R' = CO2Me; R = R' = CO2Me. The complex [PtIr(MU-HCC-4-C6H4Me)(CO)2(MU-dppm)2][PF6] reacted reversibly with CO to give [PtIr(MU-HCC-4-C6H4Me)(CO)3(MU-dppm)2][PF6] and [PtIr(CO)3(MU-dppm)2][PF6], 1. With HCl, [PtIr(MU-HCC-4-C6H4Me)(CO)2(MU dppm)2][PF6] reacted to give [PtIrHCl(MU-HCC-4-C6H4Me)(CO)2(MU-dppm)2][PF6], by oxidative addition at iridium, and then the alkenylplatinum derivative [PtIrCl{HC=CH(4-C6H4Me)}(CO)2(MU-dppm)2][PF6]. [PtIr(MU-HCC-4-C6H4Me)(CO)2(MU dppm)2][PF6] reacted slowly with dihydrogen to give 4-MeC6H4CH=CH2 and [PtIrH4(CO)(MU-dppm)2][PF6]. The complex [PtIr(MU-HCCPh)(CO)2(MU-dppm)2][PF6] is intensely luminescent in solution at room temperature, with features characteristic of a d(8)-d(8) face-to-face complex. PMID- 25697242 TI - [Attachment and loss: rediscovering John Bowlby]. PMID- 25697243 TI - [Pathophysiology of sodium disorders in children]. AB - Dysnatremia is among the most common electrolyte disorders in clinical medicine and its improper management can have serious consequences associated with increased morbidity and mortality of patients. The aim of this study is to update the pathophysiology of dysnatremia and review some simple clinical and laboratory tools, easy to interpret, that allow us to make a quick and simple approach. Dysnatremia involves water balance disorders. Water balance is directly related to osmoregulation. There are mechanisms to maintain plasma osmolality control; which are triggered by 1-2% changes. Hypothalamic osmoreceptors detect changes in plasma osmolality, regulating the secretion of Antidiuretic Hormone (ADH), which travels to the kidneys resulting in more water being reabsorbed into the blood; therefore, the kidney is the main regulator of water balance. When a patient is suffering dysnatremia, it is important to assess how his ADH-renal axis is working. There are causes of this condition easy to identify, however, to differentiate a syndrome of inappropriate ADH secretion from cerebral salt wasting syndrome is often more difficult. In the case of hypernatremia, to suspect insipidus diabetes and to differentiate its either central or nephrogenic origin is essential for its management. In conclusion, dysnatremia management requires pathophysiologic knowledge of its development in order to make an accurate diagnosis and appropriate treatment, avoiding errors that may endanger the health of our patients. PMID- 25697244 TI - [Improving cystic fibrosis survival as a result of management in a specialized center with 10-year follow-up]. AB - INTRODUCTION: Cystic fibrosis (CF), the most common genetic disease among whites, is a multisystem disease that requires a coordinated multidisciplinary approach to get better results regarding survival and quality of life. This is why a Cystic Fibrosis Center (CFC) was held in Mendoza, Argentina, with the assumption that the organization and management of CF, according to international standards would improve survival. PATIENTS AND METHOD: 106 patients with CF have been evaluated since 1975 in this Center. Patients were grouped for follow-up monitoring as the 1999, 2002, 2005 and 2008 cohort studies. The chi-square test was used to compare survival rates and the nonparametric Mann-Whitney test was used to calculate the median age of the population. RESULTS: In 2008, survival at 17 years old was 80% compared with 45% for the same age in 1999 (p < 0,001). The median age of the total CF population increased from 4 (1985) to 12 years old (2008) (p < 0,003). CONCLUSIONS: A multidisciplinary standardized approach of this condition in a CF Center can significantly increase survival. PMID- 25697245 TI - [Thyroid function in obese children]. AB - INTRODUCTION: Study results regarding thyroid function in obese children are unknown. The objective of this study was to describe the levels of thyroid stimulating hormone (TSH), free plasma thyroxine (FT4), associated factors and frequency of hypothyroidism in these children. PATIENTS AND METHOD: A retrospective study of medical records of 260 obese children who consulted a physician for the first time between January 2007 and June 2012. Age, gender, puberty, weight, height and waist circumference (WC) were considered; body mass index (BMI z -score), weight/height (IPT) and height/age (NCHS 2000) were calculated, and TSH and FT4 were measured. RESULTS: 210 patients aged 2 to 18 years were included, 59% female, 51.4% prepubescent children, 23.9% were overweight and 76.1% obese. 70.8% of the children surveyed had central obesity. TSH and FT4 values were 2.31 MUUI/mL (0.69 to 8.07) and 1.289 +/- 0.17 ng/dL, respectively. Hypothyroidism was found in 21 patients (10%), 20 of these presented it as subclinical condition. An inverse correlation was present between age and log TSH and a direct correlation was described between log TSH and zBMI. Qnly zBMI was significant (p < 0.001, adjusted R2 8.2%, beta 0.19) after using multiple regression. No differences in age, gender, nutritional status and puberty between euthyroid and hypothyroid patients were found. CONCLUSION: 9.5% of patients presented subclinical hypothyroidism, which supports TSH screening in obese children. PMID- 25697246 TI - [Red blood cell transfusions in very low birth weight newborns]. AB - INTRODUCTION: It has been reported that 80% of very low birth weight infants (VLBWI) are receiving packed red blood cell transfusions (PRBCtr), and in 90% of cases, the indication is the replacement of the blood collected. The existence of guidelines for transfusion practices has had a great impact on the decline in the number of transfusions. The aim of this paper is to describe the characteristics of VLBW infants who are packed red blood cell transfusion receptors. PATIENTS AND METHODS: This is a descriptive cross-sectional study, which included the medical records of all VLBW newborns older than 72 hours, released from the Neonatology department of the Hospital Valdivia Base, between 2005 and 2006. Birth weight, gestational age, pulmonary surfactant, hyaline membrane, mechanical ventilation, bronchopulmonary dysplasia, sepsis and packed red blood cell transfusions were evaluated. Guidelines for packed red cell transfusions were used at the Hospital. RESULTS: 93 newborns were evaluated and 62 of them were transfused (66.7%); they received 2.1 +/- 0.9 PRBC transfusion and the exposure to different donors was 2.1 +/- 0.9. The VLBW infants susceptible to be PRBCtr receptor were those younger than 30 weeks' gestational age, weighing less than 1,250 g and with respiratory failure, mechanical ventilation and sepsis. CONCLUSION: The observed percentages of transfused infants with very low birth weight, median PRBCtr and exposure to different donors can be attributed to the existence of guidelines for neonatal transfusion practices and a team of highly experienced neonatologists. PMID- 25697247 TI - [Meconium evacuation to improve feeding tolerance in very low birth weight preterm infants (Emita Protocol)]. AB - INTRODUCTION: It has been reported that feeding tolerance in preterm infants is associated with an early passage of meconium. Prospective, randomized or historical control studies that stimulate meconium evacuation have reported varied results. This study was intented to evaluate the use of enemas to speed up meconium evacuation, facilitating feeding tolerance. PATIENTS AND METHOD: A controlled multicenter randomized trial that evaluated the use of physiological saline enemas with glycerol (0.8 ml glycerol + 3 ml saline or 1 ml glycerol + 5 ml saline depending on babies weighing less or more than 800 g at birth, respectively) versus simulation. This procedure was performed in the first 96 hours of life in infants with birth weight between 500 and 1,250 g. Maternal (preterm delivery, clinical chorioamnionitis, gestational hypertension, administration of magnesium sulfate and prenatal corticosteroids, fetal Doppler altered, type of delivery, gender, weight and gestational age, assessment of Apgar and need for assisted ventilation and oxygenotherapy) and nutritional history (age when feeding volumes of 100 ml/kg/day and full enteral feeding were reached, age to remove meconium, number of days on parenteral nutrition, weight at 28 days, weekly volumes of breast milk and preterm formula) were described. RESULTS: No significant differences were obtained regarding the age to reach full enteral intake or 100 ml/kg/day were found among the 101 patients in the study. Also, no differences in the following secondary variables are observed: number of episodes of late sepsis with or without positive blood culture, hyperbilirubinemia, necrotizing enterocolitis and intraventricular hemorrhage. CONCLUSIONS: The routine use of saline enemas and glycerin in this study does not alter the enteral feeding tolerance in very low birth weight preterm infants. PMID- 25697248 TI - [Epidemiological study of Pediculosis in elementary schools of Arica, northern Chile]. AB - Pediculosis is an ectoparasitosis infestation that has not received much attention in northern Chile despite it is a common reoccurring condition among school-age children. The objective of this study is to determine the prevalence of Pediculus humanus capitis infestation in elementary schools of Arica. PATIENTS AND METHOD: A group of 665 elementary school students from the Province of Arica were screened between August and November 2010; 467 children who met the inclusion criteria were selected. After parents and students signed an informed consent, the diagnosis was carried out through examination of the head with naked eye in each participating school, recording the presence of Pediculus humanus capitis, infestation level and parasite stage. RESULTS: 40.3% (188) of the children presented Pediculosis; the six schools studied were affected. Pediculosis infestation in girls reached 55.2% (138/250) and 23% (50/217) in boys. CONCLUSION: The school population of Arica is significantly affected by Pediculosis and its prevalence is similar to other regions. PMID- 25697249 TI - [Language difficulties in preschool children with a history of extreme prematurity]. AB - INTRODUCTION: Preterm infants are prone to present language development difficulties. There is evidence that verbal deficits are common and adversely affect social interaction as well as school learning. In Chile, these skills are not evaluated by the premature follow-up program; therefore, the extent of this problem is unknown. The objective of this study is to describe the language difficulties of a group of preschoolers with a history of extreme prematurity. PATIENTS AND METHODS: Thirty children aged 4 and 5 years old, with a history of extreme prematurity, but without severe neurological damage or hearing loss were evaluated through language tests at the Premature Follow-up Polyclinic of the Eastern Cordillera Health Reference Center. RESULTS: 73.3% of the children assessed had deficits in some area of the language. Of these, 77.3% had comprehensive and expressive difficulties. In this group, 86.4% showed significant difficulties in narrative skills. DISCUSSION: A high preterm infant proportion presents language difficulties in preschool, resulting in the need of including specific intervention programs that promote better language development for this population. PMID- 25697250 TI - [Hyper IgE syndrome: three case reports]. AB - INTRODUCTION: Autosomal dominant Hyper IgE syndrome (HIES-AD) is a primary immunodeficiency associated with connective tissue, skeletal, vascular and brain disorders. The pathogenesis of immune deficiency lies in an alteration of Th17 cells which explains the special susceptibility of these patients to S. aureus and Candida infections. OBJECTIVE: To describe three children diagnosed with hyper IgE syndrome and conduct a study on the subject, with special focus on the dominant form of the disease. CASE REPORTS: 3 children with HIES-AD (2 males and one female) with eczema since birth, skin, ear, lung, and lymph node infections, and serum IgE levels over 2,000 IU/ml and eosinophilia values, treated with antibiotics and topically, and 7 year follow-up. CONCLUSIONS: It is a rare condition that requires a high index of suspicion and early management of infections. One of its main diagnoses is atopic syndrome with recurrent infections but both conditions differ in context, response and resolution against infections and lack of other phenotypic characteristics. PMID- 25697251 TI - [Hematological and neurological compromise due to vitamin B12 deficit in infant of a vegetarian mother: case report]. AB - INTRODUCTION: Vitamin B12 deficiency is extremely common in strict vegetarians and their variants. Infants of vegetarian mothers have a higher risk of deficiency and are more prone to its effects. OBJECTIVE: To report a case in order to warn people about the importance of suspected vitamin B12 deficiency in children of vegetarian mothers. CASE REPORT: A 12-month old infant, daughter of a longtime vegetarian woman, who presented neurological and hematological compromise due to vitamin B12 deficiency, is discussed. After a short period of parenteral administration of cyanocobalamin and enteral nutrition, the patient evolved with clinical and laboratory improvement, although she still had residual development delay. CONCLUSIONS: Vitamin B12 deficiency is often not suspected by the pediatrician in healthy infants. Clinical manifestations can be nonspecific, such as apathy, food refusal and progressive impairment of psychomotor development. A nutritional anamnesis performed on the mother (with great emphasis on those strict vegetarians) to estimate her reserves in the period prior to, during and after delivery can be critical to detect the risk of this vitamin deficiency in young children. PMID- 25697252 TI - [Situs inversus totalis - 2 case reports]. AB - INTRODUCTION: Situs inversus totalis is a rare find and only a small percentage are associated with heart disease; its diagnosis is usually made incidentally. OBJECTIVE: To discuss the diagnostic features of situs inversus totalis and the importance of early diagnosis. CASE REPORTS: Two pediatric patients aged 9 and 14 years who were incidentally diagnosed are reported. The first case presented chest pain and during cardiac auscultation, increased heart sounds were heard on the right precordium and attenuated on the left. An electrocardiogram (ECG) showed P wave and QRS axis equal to +150 degrees , narrow QRS voltage attenuated in V3-V6 precordial leads, and negative T waves in leads V1-V4 and aVL. Chest radiography confirmed dextrocardia, and gastric bubble was on the right and hepatic shadow on the left. Echocardiography showed classic mirror dextrocardia without associated malformations. In the second case, dextrocardia was found incidentally after radiography was requested for the evaluation of scoliosis. ECG showed QRS of +120 degrees , P wave axis of +150 degrees and narrow QRS voltage axis attenuated on left precordial leads. Doppler echocardiography confirmed dextrocardia without associated anomalies. Abdominal ultrasound found the liver in left upper quadrant and the spleen in right upper quadrant. CONCLUSIONS: Early diagnosis of situs inversus totalis is important because the thoracic and abdominal surgical approach is different and certain diseases could be presented with unusual characteristics. Also, after the diagnosis of situs inversus, the presence of associated pathologies such as primary ciliary dyskinesia can be studied (Kartagener syndrome). PMID- 25697253 TI - [Papillary thyroid cancer: case reports of four family cases]. AB - INTRODUCTION: Papillary thyroid cancer (PTC) is the most common endocrine malignancy, representing 80% of all thyroid cancers; only 10% of cases are manifested before age 21 and have an estimated incidence of 0.54 cases per 100,000 people. In children it is diagnosed at a more advanced stage of the disease but with good therapeutic response and very low mortality. OBJECTIVE: To present four family cases with PTC, discuss the particular characteristics and the importance of early diagnosis. CASE REPORTS: 4 families with members affected by family papillary thyroid carcinoma are presented, all pediatric cases were manifested after a direct member adult case was diagnosed, therefore pediatric patients were early detected, but despite a timely treatment, the disease was advanced at the time of diagnosis. The pediatric cases are 3 females and 1 male with an average age of 12 1/2 years old at diagnosis. DISCUSSION: The family variety of papillary thyroid carcinoma (2 or more direct members affected), represents 5% of papillary cancers. It is transmitted through autosomal dominant inheritance with incomplete penetrance and variable expressivity. It occurs at a younger age than the sporadic type, and it is more aggressive with greater local invasion (32%), recurrence (20-50%) and lymphatic metastases (57 %), and it is associated with benign thyroid diseases and often, it is multifocal. CONCLUSION: The family papillary thyroid cancer is a disease with worse prognosis than the sporadic variety; therefore, a high index of suspicion is required in affected families for early diagnosis and treatment. PMID- 25697254 TI - [Pediatric asthma control and quality of life questionnaires]. AB - The assessment of symptoms and quality of life are important aspects in the control of childhood asthma. Questionnaires regarding symptoms control and quality of life give valuable information about the disease from the perspective of the child and his family. The aim of this study is to discuss the most important characteristics of this type of questionnaire such as age range, language of validation, number of questions, administration mode, the evaluated period and fields, and the minimum clinically relevant difference. The ACT questionnaires, for children older than 11 years of age, and CAN questionnaires, for children between 2 and 14 years of age in their Spanish versions, are suitable for measuring asthma control in our country. Regarding quality of life, PAQLQ for children between 7 and 17 years of age and PACQLQ for their care givers are the most popular oversees; Spanish versions have been adapted for Chile. PMID- 25697255 TI - [Dyslipidemia management in children and adolescents: recommendations of the Nutrition Branch of the Chilean Society of Pediatrics]. AB - The prevalence of dyslipidemia has dramatically increased in children and adolescents, and many of these cases are associated with increased obesity. As this condition represents cardiovascular risk in the future, the bases of its treatment should be widely known. In the vast majority of patients, there will be lifestyle changes, specific diet and increased physical activity, usually all of these resulting in a favorable response. Only a minority will require drug treatment, which must be prescribed by a specialist in the context of a comprehensive cardiovascular risk assessment, including the patient and his family. The prevention of cardiovascular risk factors should be performed by all members of the health team. This article presents the recommendations of the Nutrition specialists of the Chilean Society of Pediatrics for screening, diagnosis and treatment of dyslipidemia in childhood. PMID- 25697256 TI - [Consensus on evaluation and management of apparent life-threatening events in infancy (ALTE)]. AB - Apparent life threatening events are defined as an acute episode in which the observer fears an infant < 1 year may die. ALTE is characterized by some combination of apnea, color or muscle tone change, chocking and has to be followed by cardiorespiratory reanimation. The present consensus paper reviews international and national evidence concerning diagnosis, etiologies, hospitalization criteria and indications for home monitoring. PMID- 25697259 TI - Sensitivity enhancement by population transfer in Gd(III) spin labels. AB - In order to enhance echo signals observed with selective pulses, equilibrium populations of the energy levels of S = 7/2 Gd(III) spin labels are rearranged with frequency-swept passage pulses. To transfer population from as many energy levels as possible, the 2 MUs long passage pulses range over more than 1 GHz. Application of this technique at Q-band frequencies to three different Gd(III) complexes and spin dynamics simulations reveal large signal enhancements beyond 100% for Gd(III) complexes with zero-field splitting parameters below 1 GHz. For complexes with larger splittings, experimental enhancements are on the order of 90%. Moreover, population transfer is combined with distance measurements on a model system with a pair of Gd(III) ions. As a result, a signal enhancement of 85% is achieved without inducing changes in the obtained distance information. Besides this enhancement by population transfer, a dipolar modulation depth of 9% is demonstrated, which results in a total enhancement of 3.3 with respect to data obtained with monochromatic rectangular pulses. The limitations of the population transfer technique are discussed. In particular, the extraordinary broad pulse bandwidths caused heating effects and pulse distortions, which constrain the pulse length and thus the achievable signal enhancement. PMID- 25697260 TI - Bilateral glossopharyngeal nerve palsy following tonsillectomy: a very rare and difficult complication of a common procedure. AB - OBJECTIVES: Tonsillectomy is one of the most commonly performed otolaryngological procedures. Bilateral palsy of the glossopharyngeal nerve is an exceedingly rare complication that can result in significant morbidity. This case report aimed to raise awareness of this complication and outline management strategies. CASE REPORT: A 31-year-old woman who underwent routine tonsillectomy presented with progressive numbness of the palate, dysgeusia, xerostomia, paraesthesia of the tongue and the feeling of something in her throat within 2 weeks of surgery. She reported the post-operative onset of snoring. Examination revealed a symmetrically low, 'dropped' soft palate. Over time, her symptoms have lessened, but dysgeusia and snoring remain. CONCLUSION: The position of the glossopharyngeal nerve in the tonsillar bed makes it prone to injury during tonsillectomy, especially if 'hot' methods are used. Bilateral injury can result in significant morbidity that can be difficult to treat. Patients should be warned about this risk and care should be taken to minimise it. PMID- 25697261 TI - Acute gastrointestinal illness in two Inuit communities: burden of illness in Rigolet and Iqaluit, Canada. AB - Food- and waterborne disease is thought to be high in some Canadian Indigenous communities; however, the burden of acute gastrointestinal illness (AGI) is not well understood due to limited availability and quality of surveillance data. This study estimated the burden of community-level self-reported AGI in the Inuit communities of Rigolet, Nunatsiavut, and Iqaluit, Nunavut, Canada. Cross sectional retrospective surveys captured information on AGI and potential environmental risk factors. Multivariable logistic regression models identified potential AGI risk factors. The annual incidence of AGI ranged from 2.9-3.9 cases/person per year in Rigolet and Iqaluit. In Rigolet, increased spending on obtaining country foods, a homeless person in the house, not visiting a cabin recently, exposure to puppies, and alternative sources of drinking water were associated with increased odds of AGI. In Iqaluit, eating country fish often, exposure to cats, employment status of the person responsible for food preparation, not washing the countertop with soap after preparing meat, a homeless person in the house, and overcrowding were associated with increased odds of AGI. The results highlight the need for systematic data collection to better understand and support previously anecdotal indications of high AGI incidence, as well as insights into unique AGI environmental risk factors in Indigenous populations. PMID- 25697262 TI - The rs9982601 polymorphism of the region between the SLC5A3/MRPS6 and KCNE2 genes associated with a prevalence of myocardial infarction and subsequent long-term mortality. AB - INTRODUCTION: rs9982601 (C>T) is a polymorphism of the noncoding region between the SLC5A3/MRPS6 and KCNE2 genes. It has been shown to be associated with early onset myocardial infarction (MI) with T as a risk allele. OBJECTIVES: The aim of our study was to investigate the association of the rs9982601 polymorphism with long-term overall mortality from MI and prevalence of MI in a Polish population. PATIENTS AND METHODS: The study involved patients with MI treated invasively. Individuals who underwent paternity testing served as a population group. Genotyping was performed by the TaqMan method. The analyzed endpoint was the overall long-term mortality. RESULTS: The study group comprised 981 patients (mean age, 62.8 +/-12.1 years; 259 women [26.4%]). The percentages of TT, CT, and CC genotypes were 3.1%, 25.6%, and 71.3%, respectively, in the whole group, and 2.4%, 16.8%, and 80.8% (P = 0.01) in the population group (n = 167). During follow-up (median, 1826 days), 157 patients died (16%). No significant differences were observed between the genotypes either in clinical characteristics or in mortality. However, in a subgroup of high-risk patients (GRACE risk score of 155 points or higher, n = 428), low-risk CC homozygotes had a significantly better survival rate compared with the other genotypes (hazard ratio, 0.64; 95% confidence interval, 0.43-0.96; P = 0.03). CONCLUSIONS: We showed that the rs9982601 polymorphism of the region between SLC5A3/MRPS6 and KCNE2 genes is associated with long-term mortality in high-risk patients after MI. Additionally, our study supports the previous reports on the correlation of this polymorphism with the prevalence of MI. PMID- 25697263 TI - Factors Influencing Medical School Graduates Toward a Career in Psychiatry: Analysis from the 2011-2013 Association of American Medical Colleges Graduation Questionnaire. AB - OBJECTIVE: Various factors influence choice of medical specialty. Previous research grouped specialties into controllable lifestyle, primary care, and surgical. This study compared factors influencing individuals to choose psychiatry versus other specialties. METHODS: Data came from the 2011-2013 Association of American Medical Colleges Graduation Questionnaire. The authors grouped responses, ranging from no influence to minor, moderate, and strong influence, into psychiatry and controllable lifestyle, primary care, and surgical specialties and analyzed the data using one-way analysis of variance. RESULTS: The analyses included 29,227 students, of which 1329 (4.5%) elected psychiatry; 10,998 (37.6%), controllable lifestyle specialties; 12,320 (42.2%), primary care specialties; and 4580 (15.7%), surgical specialties. Students choosing psychiatry reported less influence of competitiveness, student debt, and salary expectations than those choosing controllable lifestyle and surgical specialties (p < 0.0001) and more influence of work/life balance than those choosing primary care and surgical specialties (p < 0.0001). They reported less influence of family expectations than those choosing controllable lifestyle specialties (p < 0.0001). They reported more influence of fit with personality than controllable lifestyle, primary care, and surgical specialties (p < 0.004). CONCLUSIONS: Students entering psychiatry do not fit the traditional categories of controllable lifestyle, primary care, and surgical profiles, but fall between controllable lifestyle and primary care specialties. Recruitment efforts may need to address this different pattern of influences. PMID- 25697264 TI - GSTM1, GSTT1, and NQO1 polymorphisms in cervical carcinogenesis. AB - The aim of the study is to investigate the clinical significance of glutathione-S transferase GSTM1, GSTT1, and NQO1 c.609C>T (rs1800566) genetic polymorphisms in cervical carcinogenesis. GSTM1, GSTT1, and NQO1 polymorphisms together with human papillomavirus (HPV) types were examined in a total of 192 cervical smear in exfoliated cervical cell samples using polymerase chain reaction (PCR) system and real-time polymerase chain reaction (PCR) system. The 19 patients with high-grade squamous intraepithelial lesion had statistically higher frequency of null GSTT1 genotype than 9 with low-grade squamous intraepithelial lesion (LSIL) among the 67 patients with high-risk HPV (P = 0.024). The 24 patients with HSIL had also statistically higher frequency of NQO1 (CT+TT) genotype than 14 with LSIL among the 67 patients with high-risk HPV (P = 0.024). GSTT1 null and NQO1 genotype in cervical cell samples may be associated with more severe precancerous lesions of the cervix in a Japanese population. PMID- 25697265 TI - Design, synthesis, and protein crystallography of biaryltriazoles as potent tautomerase inhibitors of macrophage migration inhibitory factor. AB - Optimization is reported for biaryltriazoles as inhibitors of the tautomerase activity of human macrophage migration inhibitory factor (MIF), a proinflammatory cytokine associated with numerous inflammatory diseases and cancer. A combined approach was taken featuring organic synthesis, enzymatic assaying, crystallography, and modeling including free-energy perturbation (FEP) calculations. X-ray crystal structures for 3a and 3b bound to MIF are reported and provided a basis for the modeling efforts. The accommodation of the inhibitors in the binding site is striking with multiple hydrogen bonds and aryl aryl interactions. Additional modeling encouraged pursuit of 5-phenoxyquinolinyl analogues, which led to the very potent compound 3s. Activity was further enhanced by addition of a fluorine atom adjacent to the phenolic hydroxyl group as in 3w, 3z, 3aa, and 3bb to strengthen a key hydrogen bond. It is also shown that physical properties of the compounds can be modulated by variation of solvent-exposed substituents. Several of the compounds are likely the most potent known MIF tautomerase inhibitors; the most active ones are more than 1000-fold more active than the well-studied (R)-ISO-1 and more than 200-fold more active than the chromen-4-one Orita-13. PMID- 25697267 TI - Learning client-centred practice short report: experience of OT students interacting with "expert patients". AB - BACKGROUND: Client-centered care, a core value of occupational therapy (OT) and the gold standard of health care, presents challenges in practice. Learning client-centered practice (CCP) in health professional education has been linked to use of "expert patients". How this learning occurs was acknowledged as a gap in research. OBJECTIVES: This article aims to describe OT students' experience interacting with "expert patients"; describe students' learning regarding CCP; identify conditions for learning CCP. METHODS: MScOT students participated in a qualitative study with the research question: "How does the students' experience interacting with the 'expert patient' relate to learning regarding client-centred practice?" In-depth interviews were conducted with six OT students subsequent to their "expert patient" sessions. Transcripts were analyzed using CAQDAS. FINDINGS: Students described admiration, discomfort, humility, and gratefulness; learning regarding collaboration; respect for autonomy; and recognition of client expertise. Three coexistent conditions fostered learning regarding CCP: the client is an expert; students experience power; and the environment includes guided reflection/discussion. CONCLUSION: This study adds to the literature particular conditions that facilitate learning client-centered practice. All stakeholders in health professional education can benefit. PMID- 25697266 TI - Executive functioning in autism spectrum disorders: influence of task and sample characteristics and relation to symptom severity. AB - Impaired executive functioning (EF) has been proposed to underlie symptoms of autism spectrum disorders (ASD). However, insight in the EF profile of ASD individuals is hampered due to task impurity and inconsistent findings. To elucidate these inconsistencies, we investigated the influence of task and sample characteristics on EF in ASD, with an extended test battery designed to reduce task impurity. Additionally, we studied the relation between EF and ASD symptoms. EF (inhibition, cognitive flexibility, generativity, working memory and planning) was measured in open-ended versus structured assessment situations, while controlling for possible confounding EF and non-EF variables. The performance of 50 individuals with ASD was compared with that of 50 age, gender and IQ matched typically developing (TD) individuals. The effects of group (ASD versus TD), age (children versus adolescents) and gender were examined, as well as the correlation between age, IQ, ASD symptoms and EF. Individuals with ASD showed impairments in all EF domains, but deficits were more pronounced in open-ended compared to structured settings. Group differences did not depend on gender and only occasionally on participants' age. This suggests that inconsistencies between studies largely result from differences in task characteristics and less from differences in the investigated sample features. However, age and IQ strongly correlated with EF, indicating that group differences in these factors should be controlled for when studying EF. Finally, EF correlated with both social and non-social ASD symptoms, but further research is needed to clarify the nature of this relationship. PMID- 25697268 TI - SUZY forcepsTM for the removal of an esophageal coin from a child. PMID- 25697269 TI - The clinical course of anesthetic induction in lung transplant recipients with pulmonary complications after hematopoietic stem cell transplantation. AB - PURPOSE: We examined the clinical course of anesthetic induction in lung transplant recipients with pulmonary complications after hematopoietic stem cell transplantation (post-HSCT), focusing on ventilatory management. We aimed to determine the incidence of oxygen desaturation during anesthetic induction and severe respiratory acidosis after anesthetic induction in post-HSCT lung transplant recipients, and to explore factors associated with their development. METHODS: Nineteen consecutive patients who underwent lung transplantation post HSCT at Kyoto University Hospital (Japan) were retrospectively studied. Data regarding patient characteristics, preoperative examination, and clinical course during anesthetic induction were analyzed. RESULTS: The incidence of oxygen desaturation (SpO2 < 90 %) during anesthetic induction and severe respiratory acidosis (pH < 7.2) after anesthetic induction were 21.1 and 26.3 %, respectively. Reduced dynamic compliance (Cdyn) during mechanical ventilation was significantly associated with oxygen desaturation during anesthetic induction (p = 0.01), as well as severe respiratory acidosis after anesthetic induction (p = 0.01). The preoperative partial pressure of carbon dioxide in arterial blood (PaCO2; r = -0.743, p = 0.002) and body mass index (BMI; r = 0.61, p = 0.021) significantly correlated with Cdyn, and multivariate analysis revealed that both PaCO2 and BMI were independently associated with Cdyn. CONCLUSIONS: Oxygen desaturation during anesthetic induction and severe respiratory acidosis after anesthetic induction frequently occur in post-HSCT lung transplant recipients. Low Cdyn may, at least partially, explain oxygen desaturation during anesthetic induction and severe respiratory acidosis after anesthetic induction. Moreover, preoperative hypercapnia and low BMI were predictive of low Cdyn. PMID- 25697270 TI - The human carbonic anhydrase isoenzymes I and II (hCA I and II) inhibition effects of trimethoxyindane derivatives. AB - Carbonic anhydrases (CAs, EC 4.2.1.1) had six genetically distinct families described to date in various organisms. There are 16 known CA isoforms in humans. Human CA isoenzymes I and II (hCA I and hCA II) are ubiquitous cytosolic isoforms. Acetylcholine esterase (AChE. EC 3.1.1.7) is a hydrolase that hydrolyzes the neurotransmitter acetylcholine relaying the signal from the nerve. In this study, some trimethoxyindane derivatives were investigated as inhibitors against the cytosolic hCA I and II isoenzymes, and AChE enzyme. Both hCA isozymes were inhibited by trimethoxyindane derivatives in the low nanomolar range. These compounds were good hCA I inhibitors (Kis in the range of 1.66-4.14 nM) and hCA II inhibitors (Kis of 1.37-3.12 nM) and perfect AChE inhibitors (Kis in the range of 1.87-7.53 nM) compared to acetazolamide as CA inhibitor (Ki: 6.76 nM for hCA I and Ki: 5.85 nM for hCA II) and Tacrine as AChE inhibitor (Ki: 7.64 nM). PMID- 25697271 TI - Synthesis of some acrylophenones with N-methylpiperazine and evaluation of their cytotoxicities. AB - In this study, the compounds having acrylophenone structure, 1-aryl-2-(N methylpiperazinomethyl)-2-propen-1-one dihydrochlorides, were synthesized and their chemical structures were identified with (1)H NMR, (13)C NMR and HRMS spectra. The cytotoxicities of the compounds were tested towards Ca9-22 (human gingival carcinoma), HSC-2 (human oral squamous carcinoma), HSC-3 (human oral squamous carcinoma) and HSC-4 (human oral squamous carcinoma) cell lines as tumor cell lines and HGF (gingival fibroblasts), HPLF (periodontal ligament fibroblasts) and HPC (pulp cells) cell lines as non-tumor cell lines. PSE of the compound TA2, which has a methyl substituent on phenyl ring, pointed out the compound TA2 as a leader compound to be considered. PMID- 25697272 TI - Effects of employment of distinct strategies to capture antibody on antibody delivery into cultured cells. AB - The characteristics of antibody delivery into cultured HeLa cells were examined using two delivery systems. Both systems used a cell-penetrating peptide as a tool for intrusion of an antibody into the cells, but either a "protein A derivative" or "hydrophobic motif" was employed to capture the antibody. When we examined the uptake of the Alexa Fluor-labeled antibody by the use of these two systems, both systems were found to effectively deliver the antibody into the cultured cells. However, when we compared the amount of antibody delivered by these systems with the amount of transferrin uptake, the former was 10 times smaller than the latter. The lower efficiency of antibody delivery than transferrin uptake seemed to be attributable to the involvement of the antibody delivery reagent, which failed to catch the antibody molecule. This interpretation was validated by an experiment using a larger amount of antibody, and the amount of antibody delivered by the "protein A derivative" system under this condition was determined to be 13 ng proteins/10(5) cells. The antibody delivery achieved by the "protein A derivative" or "hydrophobic motif" showed two differences, i.e., a difference in intracellular distribution of the delivered antibody molecules and a difference in the fluorescence spectrum observed with cellular lysates. Possible reasons for these differences between the two delivery systems are discussed. PMID- 25697273 TI - Clinical results of the re-fixation of a Chevron olecranon osteotomy using an intramedullary cancellous screw and suture tension band. AB - Exposure of the distal humerus in case of an articular fracture is often performed through a Chevron osteotomy of the olecranon. Several options have been described for re-fixation of the Chevron osteotomy. Pull-out of the hard-wear is often seen as complication. In this study, an evaluation of the re-fixation of the Chevron osteotomy through a cancellous screw and suture tension band was performed. The data of 19 patients in whom a Chevron osteotomy was re-fixated with a cancellous screw in combination with a suture tension band were used. Evaluation was performed by assessment of the post-operative X-rays and documentation of complications. In all 19 cases, evaluation of the post-operative X-rays showed complete consolidation without dislocation or other complications. Re-fixation of a Chevron osteotomy of the olecranon with a large cancellous screw with a suture tension band provides adequate stability to result in proper healing of the osteotomy in primary cases when early post-operative mobilisation is allowed. Complications as pull-out of the hard-wear were not reported. PMID- 25697274 TI - Cold exposure affects carbohydrates and lipid metabolism, and induces Hog1p phosphorylation in Dekkera bruxellensis strain CBS 2499. AB - Dekkera bruxellensis is a yeast known to affect the quality of wine and beer. This species, due to its high ethanol and acid tolerance, has been reported also to compete with Saccharomyces cerevisiae in distilleries producing fuel ethanol. In order to understand how this species responds when exposed to low temperatures, some mechanisms like synthesis and accumulation of intracellular metabolites, changes in lipid composition and activation of the HOG-MAPK pathway were investigated in the genome sequenced strain CBS 2499. We show that cold stress caused intracellular accumulation of glycogen, but did not induce accumulation of trehalose and glycerol. The cellular fatty acid composition changed after the temperature downshift, and a significant increase of palmitoleic acid was observed. RT-PCR analysis revealed that OLE1 encoding for Delta9-fatty acid desaturase was up-regulated, whereas TPS1 and INO1 didn't show changes in their expression. In D. bruxellensis Hog1p was activated by phosphorylation, as described in S. cerevisiae, highlighting a conserved role of the HOG-MAP kinase signaling pathway in cold stress response. PMID- 25697275 TI - Speech perception with F0mod, a cochlear implant pitch coding strategy. AB - OBJECTIVE: The fundamental frequency modulation (F0mod) sound processing strategy was developed to improve pitch perception with cochlear implants. In previous work it has been shown to improve performance in a number of pitch-related tasks such as pitch ranking, familiar melody identification, and Mandarin Chinese tone identification. The objective of the current study was to compare speech perception with F0mod and the standard clinical advanced combination encoder (ACE) strategy. STUDY SAMPLE: Seven cochlear-implant listeners were recruited from the clinical population of the University Hospital Leuven. DESIGN: F0mod was implemented on a real-time system. Speech recognition in quiet and noise was measured for seven cochlear-implant listeners, comparing F0mod with ACE, using three different Dutch-language speech materials. Additionally the F0 estimator used was evaluated physically, and pitch ranking performance was compared between F0mod and ACE. RESULTS: Immediately after switch-on of the F0mod strategy, speech recognition in quiet and noise were similar for ACE and F0mod, for four out of seven listeners. The remaining three listeners were subjected to a short training protocol with F0mod, after which their performance was reassessed, and a significant improvement was found. CONCLUSIONS: As F0mod improves pitch perception, for the seven subjects tested it did not interfere with speech recognition in quiet and noise, and has a low computational complexity, it seems promising for implementation in a clinical sound processor. PMID- 25697276 TI - Isolated prenatal ultrasound findings predict the postnatal course in gastroschisis. AB - PURPOSE: The aim of the study was to identify which prenatal ultrasonographic findings in fetuses with gastroschisis correlate with complicated postnatal outcome. METHODS: Ultrasound findings at the 30th week of pregnancy and medical reports were statistically analyzed to identify independent prenatal ultrasonographic predictors of postnatal outcome. RESULTS: Completed prenatal data were gathered from 64 pregnancies. Prenatal intra-abdominal bowel dilatation (cutoff 10 mm) correlated with the presence of atresia (p < 0.01), longer administration of parenteral nutrition, extended hospital stay (median 53 vs. 21 days; 68 vs. 36 days, both p < 0.05), and greater number of additional surgical procedures (p < 0.05). Infants with antenatal presence of thickened bowel wall (greater than or equal to 3 mm) required longer administration of parenteral nutrition (median 34 vs. 20 days; p < 0.01) and prolonged stay (median 44 vs. 37 days; p < 0.05). Presence of oligohydramnion (amniotic fluid index below 8 cm) was connected with longer administration of parenteral nutrition in newborns (median 30 vs. 16 days; p < 0.05). CONCLUSION: The isolated presence of oligohydramnion with amniotic fluid index below 8 cm, thickened bowel wall equal to or more than 3 mm and the prenatal intra-abdominal dilatation with 10 mm cutoff had significant predictive value for the adverse postnatal outcome of patients with gastroschisis. PMID- 25697277 TI - The influence of social media and easily accessible online information on the aesthetic plastic surgery practice: literature review and our own experience. AB - INTRODUCTION: Patients interested in aesthetic plastic surgery procedures increasingly seek advice on social media and rely on easily accessible online information. The investigatory goal was to determine the impact of this phenomenon on the everyday aesthetic plastic surgery practice. METHODS AND PATIENTS: Five hundred consecutive patients completed a questionnaire prior to their consultation with a plastic surgeon at our clinic. A questionnaire was also completed by 128 plastic surgeons practising in 19 different countries. A literature review was performed. RESULTS: Almost all patients (95%) used the internet to collect information prior to consultation, for 68% of them it being their first search method. Social media were used by 46% of patients and 40% of these were strongly influenced when choosing a specific doctor. The majority of plastic surgeons (85%) thought the information found on social media could lead to unrealistic expectations. However, 45% of plastic surgeons believed that their consultations became easier after the advent of social media, 29% found them more difficult. A literature review showed a high percentage of poor quality internet websites regarding plastic surgery and an increase in use of social media among plastic surgeons. CONCLUSION: The internet and social media play an important and growing role in plastic surgery. This results in more informed patients but may create unrealistic expectations. Even if the internet provides ample information, it cannot replace the face-to-face consultation, which always should remain a detailed process, covering both risks and limitations of alternative procedures. Available literature on how social media influences the medical practice is still scarce and further research is needed. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266. PMID- 25697278 TI - Diamond network: template-free fabrication and properties. AB - A porous diamond network with three-dimensionally interconnected pores is of technical importance but difficult to be produced. In this contribution, we demonstrate a simple, controllable, and "template-free" approach to fabricate diamond networks. It combines the deposition of diamond/beta-SiC nanocomposite film with a wet-chemical selective etching of the beta-SiC phase. The porosity of these networks was tuned from 15 to 68%, determined by the ratio of the beta-SiC phase in the composite films. The electrochemical working potential and the reactivity of redox probes on the diamond networks are similar to those of a flat nanocrystalline diamond film, while their surface areas are hundreds of times larger than that of a flat diamond film (e.g., 490-fold enhancement for a 3 MUm thick diamond network). The marriage of the unprecedented physical/chemical features of diamond with inherent advantages of the porous structure makes the diamond network a potential candidate for various applications such as water treatment, energy conversion (batteries or fuel cells), and storage (capacitors), as well as electrochemical and biochemical sensing. PMID- 25697279 TI - [Alternatives to heparin and protamine anticoagulation for cardiopulmonary bypass in cardiac surgery]. AB - PURPOSE: Heparin anticoagulation followed by protamine reversal is commonly used in cardiopulmonary bypass (CPB) cardiac procedures, but this strategy has some limitations. The primary objective of this study was to determine the reliable alternatives for anticoagulation during CPB for cardiac surgery. For each drug proposed, the secondary objectives were to outline the main advantages and disadvantages, to propose a therapeutic protocol, and to provide a cost-benefit analysis. SOURCE: A systematic review of the literature was performed between September 2012 and December 2013. It was based on the protocol established by the "Cochrane collaboration Handbook". Twenty articles were analyzed. The Theriaque database from the University Hospital of Grenoble made the economic analysis possible. PRINCIPAL FINDINGS: Seven alternative anticoagulation strategies were considered: danaparoid sodium, lepirudin, argatroban, bivalirudin, ancrod, idraparinux, and EP217609. Danaparoid sodium has issues with individual variability. Several studies (EVOLUTION-ON, CHOOSE-ON) proposed a reliable therapeutic protocol for bivalirudin. Ancrod resulted in an increase in the transfusion of blood products. Direct thrombin inhibitors offer a promising alternative. EP217609 is a synthetic anticoagulant currently undergoing Phase IIa clinical trials. It is an indirect inhibitor of factor Xa, a direct inhibitor of free and bound thrombin, and can be neutralized by avidin. CONCLUSIONS: The ideal anticoagulation strategy for cardiac surgery with CPB does not exist. Heparin and protamine remain the gold standard for anticoagulation therapy. To date, bivalirudin is the most promising molecule despite its high cost and lack of a readily available antagonist. PMID- 25697280 TI - A simple maneuver for confirmation of the guidewire during ultrasound-guided internal jugular vein cannulation. PMID- 25697281 TI - Magnitude differences in agronomic, chemical, nutritional, and structural features among different varieties of forage corn grown on dry land and irrigated land. AB - In this study, eight varieties of corn forage grown in semiarid western Canada (including Pioneer P2501, Pioneer P39m26, Pioneer P7443, Hyland HL3085, Hyland HLBaxxos, Hyland HLR219, Hyland HLSR22, and Pickseed Silex BT) were selected to explore the effect of irrigation implementation in comparison with nonirrigation on (1) agronomic characteristics, (2) basic chemical profiles explored by using a near-infrared reflectance (NIR) system, and (3) protein and carbohydrate internal structural parameters revealed by using an attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR) system. Also, principal component analysis (PCA) was performed on spectroscopic data for clarification of differences in molecular structural makeup among the varieties. The results showed that irrigation treatment significantly increased (P < 0.05) contents of dry matter (DM) and organic matter (OM) but decreased crude protein (CP) of corn forages. Significant interactions of irrigation treatment and corn variety were observed on most agronomic characteristics (DM yield, T/ha, days to tasseling, days to silking) and crude fiber (CF) and ether extract (EE) contents as well as some spectral data such as cellulosic compounds (CELC) peak intensity, peak ratios of CHO third peak to CELC, alpha-helix to beta-sheet, and CHO third peak to amide I. Additionally, the spectral ratios of chemical functional groups that related to structural and nonstructural carbohydrates and protein polymers in forages did not remain constant over corn varieties cultivated with and without water treatment. Moreover, different cultivars had different growth, structure, and nutrition performances in this study. Although significant differences could be found in peak intensities, PCA results indicated some structural similarities existed between two treated corn forages with the exception of HL3085 and HLBaxxos. In conclusion, irrigation and corn variety had interaction effects on agronomic, chemical, nutritional, and structural features. Further study on the optimum level of irrigation for corn forage cultivation might be helpful in semiarid regions such as western Canada. PMID- 25697282 TI - Treatment of recurrent vesicourethral anastomotic stricture after radical prostatectomy using plasma-button vaporization. AB - OBJECTIVE: The aim of this study was to evaluate the efficiency of plasma-button vaporization (PBV) in the treatment of recurrent vesicourethral anastomotic stricture (VUAS) following retropubic radical prostatectomy (RRP). MATERIALS AND METHODS: A total of 28 patients (28/138, 20.2%) who had been diagnosed with recurrent VUAS after undergoing RRP to treat localized prostate cancer between January 2008 and January 2014 were treated using PBV. The anastomosis site was vaporized from all quadrants using a PBV electrode. The preoperative and postoperative serum prostate-specific antigen, prostate size, body mass index, pathological tumour stage and previous transurethral resection of the prostate were recorded. RESULTS: All patients had localized prostate cancer (stage <= PT3a), and all RRP operations were performed by the same surgeon in a single centre. The mean age was 65.2 +/- 7.34 years (range 51-73 years). All patients had undergone previous attempts to open the bladder neck: 21 patients (75%) by dilatation and seven (25%) by internal urethrotomy. The procedure was performed once in 23 patients and twice in five patients. After a mean follow-up of 24 months (range 6-66 months), 25 patients (89.2%) had a well-healed and widely patent bladder neck. CONCLUSIONS: The PBV technique proved to be efficient and successful in the treatment of recurrent anastomotic stenosis developing after RRP in terms of both short- and long-term outcomes. The removal of fibrotic tissue with vaporization and avoiding cauterization due to minimal haemorrhage were considered advantageous with regard to recurrence. PMID- 25697283 TI - Changes in articular cartilage following arthroscopic partial medial meniscectomy. AB - PURPOSE: To examine degenerative changes in all cartilage surfaces of the knee following arthroscopic partial medial meniscectomy. METHODS: For this prospective cohort study, 14 patients (five female) with a mean age of 47.9 +/- 12.9 years who had undergone isolated arthroscopic partial medial meniscectomy were evaluated. Cartilage-sensitive magnetic resonance imaging (MRI) scans were acquired from the operated knees before the index operations, as well as at 6, 12, and 24 months after surgery. The MRI scans were assessed for the prevalence, severity, and size of cartilage degenerations. The clinical outcome was assessed using the SF-36 physical and mental component score and the International Knee Documentation Committee Knee Evaluation Form and was correlated with radiological findings. RESULTS: There was a significant increase in the severity of cartilage lesions in the medial tibial plateau (P = 0.019), as well as a trend towards an increase in the lateral tibial plateau. The size of the cartilage lesions increased significantly in the medial femoral condyle (P = 0.005) and lateral femoral condyle (P = 0.029), as well as in the patella (P = 0.019). Functional outcome scores improved significantly throughout the follow-up period. There was no correlation between cartilage wear and functional outcome. CONCLUSIONS: Arthroscopic partial medial meniscectomy is associated with adverse effects on articular cartilage and may lead to an increase in the severity and size of cartilage lesions. Post-operative cartilage wear predominantly affected the medial compartment and also affected the other compartments of the knee. Strategies to reduce subsequent osteoarthritic changes need to involve all compartments of the knee. LEVEL OF EVIDENCE: IV. PMID- 25697284 TI - Increasing incidence of acute Achilles tendon rupture and a noticeable decline in surgical treatment from 1994 to 2013. A nationwide registry study of 33,160 patients. AB - PURPOSE: The purpose of this study is to investigate the incidence of acute Achilles tendon rupture in Denmark from 1994 to 2013 with focus on sex, age, geographical areas, seasonal variation and choice of treatment. METHODS: The National Patient Registry was retrospectively searched to find the number of acute Achilles tendon rupture in Denmark during the time period of 1994-2013. Regional population data were retrieved from the services of Statistics Denmark. RESULTS: During the 20-year period, 33,160 ruptures occurred revealing a statistically significant increase in the incidence (p < 0.001, range = 26.95 31.17/100,000/year). Male-to-female ratio was 3:1 and average age 45 years for men and 44 years for women. There was a statistically significant increasing incidence for people over 50 years. A higher incidence in rural compared with urban geographical areas was found, but this was not statistically significant. There was a statistically significant decreasing incidence of patients treated with surgery from 16.9/105 in 1994 to 6.3/105 in 2013. CONCLUSIONS: The incidence of acute Achilles tendon rupture increased from 1994 to 2013 based on increasing incidence in the older population. There was no difference in incidence of acute Achilles tendon rupture in the rural compared with urban geographical areas. A steady decline in surgical treatment was found over the whole period, with a noticeable decline from 2009 to 2013, possibly reflecting a rapid change in clinical practice following a range of high-quality randomized clinical trials (RCT). LEVEL OF EVIDENCE: IV. PMID- 25697285 TI - My Therapist is a Student? The Impact of Therapist Experience and Client Severity on Cognitive Behavioural Therapy Outcomes for People with Anxiety Disorders. AB - BACKGROUND: Allocation of trainee therapist cases is often performed based on intuition and clinical circumstances, with lack of empirical evidence on the role of severity of presenting problem. This has the potential to be anxiety-provoking for supervisors, trainees and service users themselves. AIMS: To determine how therapist experience interacts with symptom severity in predicting client outcomes. METHOD: An intention-to-treat analysis of annual outcome data for primary and secondary care clients seen by a specialist anxiety disorders service. 196 clients were stratified into mild, moderate and baseline severe symptoms of anxiety (GAD-7) and depression (PHQ-9). We measured percentage change on these measures, as well as number of sessions and therapy dropout. We also examined rates of reliable and clinically significant change on disorder-specific measures. We hypothesized that qualified therapists would achieve better outcomes than trainees, particularly for severe presentations. RESULTS: Overall, outcomes were comparable between trainee and qualified therapists on all measures, and trainees additionally utilized fewer therapy sessions. There was however an interaction between anxiety severity (GAD-7) and therapist group, such that severely anxious clients achieved greater symptom improvement with qualified as compared to trainee therapists. Further, for trainee but not qualified therapists, baseline anxiety was negatively associated with rate of reliable and clinically significant change on disorder-specific measures. CONCLUSIONS: These findings indicate generally favourable outcomes for trainee therapists delivering manualized treatments for anxiety disorders. They additionally suggest that trainee therapists may benefit from additional support when working with clients that present with severe anxiety. PMID- 25697286 TI - Tandem expression in E. coli of type III PKS and P450 genes from marine Streptomyces olivaceus FXJ 7.023 gives production of phenol and indole. AB - The draft genome sequence of marine Streptomyces olivaceus strain FXJ 7.023 contains a cryptic Type III polyketide synthase (type III PKS) gene cluster, which is similar to the Streptomyces coelicolor THN biosynthesis gene cluster. A putative type III PKS (SoRppA) gene and its adjacent gene for cytochrome P450 158A2 (SoCYP158A2) of this gene cluster were cloned by PCR screening through a fosmid genomic library of S. olivaceus FXJ 7.023. Tandem expression of SoRppA and SoCYP158A2 in Escherichia coli strain BL21 (DE3) plysS resulted in obvious biosynthesis of phenol and indole, while heterologous expression of SoRppA or SoCYP158A2 alone did not. The engineered strain sorppAcyp158a2BL21 showed tolerance to phenol concentration up to 0.75 g/L. Continuous biosynthesis of phenol and indole by the immobilized engineered strain on macroporousresin was achieved, and the productivities of phenol and indole in extractant-free culture in 102 h were 0.08 and 1.525 g/L/h, respectively, with the highest production reached 0.67 and 14.48 g/L, respectively. These results suggest that the engineered strain and immobilized continuous fermentation process may provide potential for "green" production of phenol and indole. PMID- 25697287 TI - Latent and active aurone synthase from petals of C. grandiflora: a polyphenol oxidase with unique characteristics. AB - MAIN CONCLUSION: Aurone synthase belongs to the novel group 2 polyphenol oxidases and the presented kinetic characterization suggests a differing aurone biosynthesis in Asteraceae species compared to snapdragon. Aurone synthases (AUS) are polyphenol oxidases (PPO) physiologically involved in the formation of yellow aurone pigments in petals of various Asteraceae species. They catalyze the oxidative conversion of chalcones into aurones. Latent (58.9 kDa) and active (41.6 kDa) aurone synthase from petals of C. grandiflora was purified by a quantitative removal of pigments using aqueous two-phase separation and several subsequent chromatographic steps. The purified enzymes were identified as cgAUS1 (A0A075DN54) and sequence analysis revealed that cgAUS1 is a member of a new group of plant PPOs. Mass determination experiments of intact cgAUS1 gave evidence that the C-terminal domain, usually shielding the active site of latent polyphenol oxidases, is linked to the main core by a disulfide bond. This is a novel and unique structural feature of plant PPOs. Proteolytic activation in vivo leads to active aurone synthase possessing a residual peptide of the C-terminal domain. Kinetic characterization of purified cgAUS1 strongly suggests a specific involvement in 4-deoxyaurone biosynthesis in Coreopsis grandiflora (Asteraceae) that differs in various aspects compared to the 4-hydroxyaurone formation in Antirrhinum majus (Plantaginaceae): cgAUS1 is predicted to be localized in the thylakoid lumen, it possesses exclusively diphenolase activity and the results suggest that aurone formation occurs at the level of chalcone aglycones. The latent enzyme exhibits allosteric activation which changes at a specific product concentration to a constant reaction rate. The presented novel structural and functional properties of aurone synthase provide further insights in the diversity and role of plant PPOs. PMID- 25697289 TI - Vitamin D and risk of CVD: a review of the evidence. AB - This review summarises evidence for an association between vitamin D status and CVD and the mechanisms involved. Vitamin D3 is predominantly provided by the action of UVB from sunlight on skin. Average UK diets supply 2-3 MUg/d vitamin D but diets containing at least one portion of oily fish per week supply about 7 MUg/d. Pharmacological doses of vitamin D2 (bolus injection of 7500 MUg or intakes >50 MUg/d) result in a smaller increase in plasma 25(OH)D than those of D3 but physiological doses 5-25 MUg/d seem equivalent. Plasma 25(OH)D concentrations are also influenced by clothing, obesity and skin pigmentation. Up to 40 % of the population have plasma 25(OH)D concentrations <25 nmol/l in the winter compared with <10 % in the summer. The relative risk of CVD death is 1.41 (95 % CI 1.18, 1.68) greater in the lowest quintile of plasma 25(OH)D according to meta-analysis of prospective cohort studies. Acute deficiency may inhibit insulin secretion and promote inflammation thus increasing the risk of plaque rupture and arterial thrombosis. Chronic insufficiency may increase arterial stiffness. There is no evidence to support claims of reduced CVD from existing trials with bone-related health outcomes where vitamin D was usually co administered with calcium. Although several trials with cardiovascular endpoints are in progress, these are using pharmacological doses. In view of the potential toxicity of pharmacological doses, there remains a need for long-term trials of physiological doses of D2 and D3 with CVD incidence as the primary outcome. PMID- 25697288 TI - High-throughput sequencing reveals differential expression of miRNAs in tomato inoculated with Phytophthora infestans. AB - MAIN CONCLUSION: The characterization and compare expression profiling of the miRNA transcriptome lay a solid foundation for unraveling the complex miRNA mediated regulatory network in tomato resistance mechanisms against LB. MicroRNAs (miRNAs) are a class of small endogenous non-coding RNAs with 20-24 nt. They have been identified in many plants with their diverse regulatory roles in biotic stresses. The knowledge, that miRNAs regulate late blight (LB), caused by Phytophthora infestans, is rather limited. In this study, we used miRNA-Seq to investigate the miRNA expression difference between the tomatoes treated with and without P. infestans. A total of 42,714,516 raw reads were generated from two small RNA libraries by high-throughput sequencing. Finally, 207 known miRNAs and 67 new miRNAs were obtained. The differential expression profile of miRNAs in tomato was further analyzed with twofold change (P value <=0.01). A total of 70 miRNAs were manifested to change significantly in samples treated with P. infestans, including 50 down-regulated miRNAs and 20 up-regulated miRNAs. Moreover, a total of 73 target genes were acquired for 28 differentially expressed miRNAs by psRNATarget analysis. By enrichment pathway analysis of target genes, plant-pathogen interaction was the most highly relevant pathway which played an important role in disease defense. In addition, 30 miRNAs were selected for qRT-PCR to validate their expression patterns. The expression patterns for targets of miR6027, miR5300, miR476b, miR159a, miR164a and miRn13 were selectively examined, and the results showed that there was a negative correlation on the expression patterns between miRNAs and their targets. The targets have previously been reported to be related with plant immune and involved in plant-pathogen interaction pathway in this study, suggesting these miRNAs might act as regulators in process of tomato resistance against P. infestans. These discoveries will provide us useful information to explain tomato resistance mechanisms against LB. PMID- 25697290 TI - Annealing and transport studies of suspended molybdenum disulfide devices. AB - We fabricate suspended molybdenum disulfide (MoS2) field effect transistor devices and develop an effective gas annealing technique that significantly improves device quality and increases conductance by 3-4 orders of magnitude. Mobility of the suspended devices ranges from 0.01 to 46 cm(2) V(-1) s(-1) before annealing, and from 0.5 to 105 cm(2) V(-1) s(-1) after annealing. Temperature dependence measurements reveal two transport mechanisms: electron-phonon scattering at high temperatures and thermal activation over a gate-tunable barrier height at low temperatures. Our results suggest that transport in these devices is not limited by the substrates, but likely by defects, charge impurities and/or Schottky barriers at the metal-MoS2 interfaces. Finally, this suspended MoS2 device structure provides a versatile platform for other research areas, such as thermal, optical and mechanical studies. PMID- 25697291 TI - On the gold-ligand covalency in linear [AuX2](-) complexes. AB - Gold compounds, clusters, and nanoparticles are widely used as catalysts and therapeutic medicines; the interactions between gold and its ligands in these systems play important roles in their chemical properties and functionalities. In order to elucidate the nature of the chemical interactions between Au(I) and its ligands, herein we use several theoretical methods to study the chemical bonding in a variety of linear [AuX2](-) complexes, where X = halogen atoms (F, Cl, Br, I, At and Uus), H, OH, SH, OCH3, SCH3, CN and SCN. It is shown that the most important bonding orbitals in these systems have significant contributions from the Au sd hybridized atomic orbitals. The ubiquitous linear or quasi-linear structures of [AuX2](-) are attributed to the well-balanced optimal overlap in both sigma and pi bonding orbitals and minimal repulsion between the two negatively charged ligands. The stability of these complexes is related to the covalency of the Au-X bond and a periodic trend is found in the evolution of covalency along the halogen group ligands. The special stability of [Au(CN)2](-) is a result of strong covalent and ionic interactions. For the superheavy element Uus, the covalency of Au-Uus is enhanced through the spin-orbit interactions. PMID- 25697292 TI - Colonic transit in the empty colon after defunctioning ileostomy: do we really know what happens? AB - BACKGROUND: There is disagreement amongst surgeons about the use of oral mechanical bowel preparation (MBP) prior to low anterior resection with diverting ileostomy. Colonic transit in the early post-operative period is an important factor in determining the role of MBP, as propagation of any stool remaining in the defunctioned colon may exacerbate morbidity in the event of anastomotic leak. We studied colonic transit time in the first 7 days following low anterior resection with diverting ileostomy. METHODS: We conducted a prospective observational study of patients with rectal cancer undergoing elective low anterior resection with diverting ileostomy in a tertiary colorectal unit. Twenty radio-opaque markers were inserted into the caecum via the distal limb of the loop ileostomy at surgery. Plain abdominal radiographs were taken on post operative days 1, 3 and 5. The primary endpoint was passage of the markers to the neorectum. Data were collected on treatment, return of gastrointestinal function and complications. RESULTS: Twenty-two patients (mean age 68.5 years; 18 males) participated in the study. In 20 patients, all markers remained in the right colon on day 7. Three markers were present in the left colon in one patient, and eight markers were present in the neorectum in another patient, on the seventh day. CONCLUSIONS: Colonic transit may be abolished by the presence of diverting ileostomy. It should now be established whether clearance of the left colon alone, using enemas, is sufficient for patients undergoing low anterior resection, thus avoiding the morbidity associated with oral MBP. PMID- 25697293 TI - Laparoscopic-assisted extralevator abdominoperineal excision using a parastomal prophylactic mesh and a biological mesh for pelvic floor reconstruction. PMID- 25697294 TI - Adsorption at air-water and oil-water interfaces and self-assembly in aqueous solution of ethoxylated polysorbate nonionic surfactants. AB - The Tween nonionic surfactants are ethoxylated sorbitan esters, which have 20 ethylene oxide groups attached to the sorbitan headgroup and a single alkyl chain, lauryl, palmityl, stearyl, or oleyl. They are an important class of surfactants that are extensively used in emulsion and foam stabilization and in applications associated with foods, cosmetics and pharmaceuticals. A range of ethoxylated polysorbate surfactants, with differing degrees of ethoxylation from 3 to 50 ethylene oxide groups, have been synthesized and characterized by neutron reflection, small-angle neutron scattering, and surface tension. In conjunction with different alkyl chain groups, this provides the opportunity to modify their surface properties, their self-assembly in solution, and their interaction with macromolecules, such as proteins. Adsorption at the air-water and oil-water interfaces and solution self-assembly of the range of ethoxylated polysorbate surfactants synthesized are presented and discussed. PMID- 25697295 TI - Diagnostic triage for sarcoma: an effective model for reducing referrals to the sarcoma multidisciplinary team. AB - OBJECTIVE: Soft-tissue lesions are common and often benign. Owing to the rarity of soft-tissue sarcomas (STSs), evidence has shown that patients are increasingly referred urgently onto the 2-week wait pathway, which may have a detrimental impact on the management of patients with a proven STS. Imaging plays a vital role in lesion characterization and can be used to triage referrals to reduce the caseload of a sarcoma multidisciplinary team (MDT). In our institution, we established a sarcoma diagnostic triage meeting (SDTM). This study aimed to determine the effectiveness of the SDTM in reducing non-sarcomatous referrals to the main sarcoma MDT. METHODS: A retrospective review of the SDTM minutes from July 2011 to June 2012 was performed. Data collected for each case included details of referrer, referral modality and referral outcome. RESULTS: 165 cases were reviewed. 58% of referrals underwent a core biopsy or surgical excision with 85% benign pathology, the commonest being lipoma. 15% of referrals were sarcomatous lesions and were referred onwards to the main MDT. CONCLUSION: A total of 82% of the patients referred urgently with a suspicious soft-tissue mass was managed by the SDTM and hence not referred onwards to the East Midlands Sarcoma Service MDT. A diagnostic triage is effective in reducing the caseload burden of the main MDT and allowing it to be more effective. ADVANCES IN KNOWLEDGE: Referrals based on imaging can be prioritized by diagnostic triage. Diagnostic triage established in our institution reduced 82% of MDT referrals allowing a more focused MDT discussion on patients with a proven sarcoma. PMID- 25697296 TI - Improvement of sudden bilateral hearing loss after vertebral artery stenting. AB - Bilateral deafness is a rare but possible symptom of vertebrobasilar ischemia. We report a case of sudden bilateral sensorineural hearing loss caused by bilateral vertebral artery (VA) occlusion which dramatically improved after stenting. A 54 year-old man was admitted with sudden onset of bilateral deafness, vertigo, and drowsy mental status. Brain diffusion-weighted MRI showed acute infarction involving both the posterior inferior cerebellar artery and left posterior cerebral artery territory. Cerebral angiography showed bilateral distal VA occlusion, and emergency intracranial stenting was performed in the left VA. After reperfusion therapy his symptoms gradually improved, including hearing impairment. Endovascular stenting may be helpful in a patient with sudden deafness caused by bilateral VA occlusion. PMID- 25697297 TI - Bilateral putaminal necrosis and bronopol toxicity. AB - Among alcohols, methanol intoxication is the most frequently associated with cerebral toxicity, causing retinal damage and putaminal necrosis. This consequence is believed to be due to the transformation of methanol into formic acid. We describe the case of a patient who presented with acute impairment of consciousness and tetraparesis after she had been drinking several bottles of a topical antiseptic solution (Lysoform Medical) containing 2-bromo-2-nitro-1,3 propandiol (bronopol) among excipients, in order to lose weight during previous months. Moreover, she had been on a strict slimming diet. Soon after admission, a severe respiratory and metabolic impairment became rapidly evident, requiring an intensive care unit admission. Cerebral MRI showed the presence of bilateral putaminal necrosis. She recovered in 10 days, surprisingly, without any evident clinical neurological signs. Methanol, also bronopol, when diluted in aqueous solution, at warm temperature and/or higher pH, may release formaldehyde, which is converted into formic acid, a basal ganglia toxic compound. PMID- 25697298 TI - Let's review Chance fracture. PMID- 25697299 TI - Enterobacter cloacae pericardial effusion in a frail elderly patient. AB - We report a case of a frail 82-year-old man with seronegative rheumatoid arthritis and a recent pacemaker insertion, admitted with pulmonary oedema and a symptomatic pericardial effusion. He was treated with diuretics and an urgent pericardiocentesis, a sample from which cultured Enterobacter cloacae. A subsequent abdominal CT scan revealed faecal loading, an abnormal anorectal canal and sigmoid colon and a bowel perforation. Endoscopy, biopsies and histopathology confirmed a diagnosis of cytomegalovirus (CMV) colitis with coexistent fungal infection. The E. cloacae infection was successfully treated with 6 weeks of intravenous meropenem, while the CMV and fungal infections were treated with a combination of valganciclovir and fluconazole. We postulate that the bowel perforation resulted from a combination of CMV colitis, faecal loading and steroid therapy and led to bacterial translocation of E. cloacae and the development of the pericardial effusion. This case represents an unusual pathophysiology for the development of an E. cloacae pericardial effusion. PMID- 25697300 TI - Unique MRI findings for differentiation of an early stage of hepatic alveolar echinococcosis. AB - CT scan and ultrasonography images revealed two small uniformly low-density and hypoechoic lesions in the liver, respectively, 7 years after curative resection of rectal cancer, in a 74-year-old man. The area of the liver including the two lesions was segmentally resected. Two lesions were histopathologically confirmed as early but active stage alveolar echinococcosis (AE) caused by accidental ingestion of eggs of the fox tapeworm, Echinococcus multilocularis. This case is very unique and rare, since early stage hepatic AE cases have only accidentally been confirmed from cases in which malignant hepatic tumours were suspected, and because two independent AE lesions were detected. Abdominal MRI showed two isointense tumour lesions with small areas of high-signal intensity in their centres on T2-weighted images. MRI findings appear to reflect the macroscopic view and microscopic findings of early stage AE with active cyst in the centre of each hepatic lesion well. PMID- 25697301 TI - Hip arthritis presenting as knee pain. AB - A 68-year-old man with a history of left total knee replacement presented to his general practitioner with left knee pain. He reported pain onset after a fall in the garden. An X-ray of the knee was arranged but showed no abnormality to explain the pain. He was treated with simple analgesia. However, he reattended with the same knee pain. A further X-ray of the knee was requested, but again showed no abnormality. On his fourth presentation in 6 months, a further musculoskeletal examination was undertaken. This time the hip was also examined and showed that maximal pain was in fact on rotation of the hip joint. A subsequent X-ray of the hip showed severe osteoarthritis of the left hip with complete joint space loss and flattening of the femoral head. The patient was referred to an orthopaedic surgeon for a left hip replacement. PMID- 25697302 TI - Haemorrhagic rupture of hepatic simple cysts. AB - Haemorrhagic rupture is a life-threatening complication of a hepatic simple cyst. A 63-year-old man presented with severe acute abdominal pain and a massive haemoperitoneum resulting from haemorrhagic rupture of a large hepatic cyst. The haemorrhagic rupture was aggravated by an overdose of vitamin K-antagonist treatment. CT scans revealed a large hepatic simple cyst. The patient was successfully treated conservatively with resuscitation, transfusion therapy and administration of coagulation agents. To date, there is no clear evidence regarding optimal treatment of haemorrhagic hepatic cyst rupture. The risk of recurrent bleeding from the haemorrhagic hepatic simple cyst, and the need for final treatment to avoid rebleeding either by percutaneous sclerotherapy, endovascular embolisation, surgical cyst resection, or surgical deroofing, is discussed. PMID- 25697303 TI - A metal (Co)-organic framework-based chemiluminescence system for selective detection of L-cysteine. AB - A metal (Co)-Organic Framework (Co-MOF) was first found to catalyze the chemiluminescence (CL) of luminol. On the basis of X-ray photoelectron spectroscopy, powder X-ray diffraction, CL spectral, UV-visible absorption spectral, and electron spin resonance (ESR) spectral studies, as well as the research of the influence of various free radical scavengers, a possible CL mechanism was proposed. The enhanced CL might be attributed to the formation of a peroxide analogous complex between the oxygen-related radicals and the active metal site of the Co-MOF material. The established Co-MOF-luminol CL system was successfully applied to determine L-cysteine (CySH), based on the selective and sensitive enhancing effect of CySH on this CL system. Under the optimized conditions, CySH was selectively detected in the range 0.1-10 MUM with a detection limit of 18 nM. This novel CL system obviously gives impetus to the new research field of metal-organic frameworks (MOFs) in chemiluminescence. PMID- 25697304 TI - Using molecular tools to identify the geographical origin of a case of human brucellosis. AB - Although Malta is historically linked with the zoonosis brucellosis, there had not been a case of the disease in either the human or livestock population for several years. However, in July 2013 a case of human brucellosis was identified on the island. To determine whether this recent case originated in Malta, four isolates from this case were subjected to molecular analysis. Molecular profiles generated using multilocus sequence analysis and multilocus variable number tandem repeat for the recent human case isolates and 11 Brucella melitensis strains of known Maltese origin were compared with others held on in-house and global databases. While the 11 isolates of Maltese origin formed a distinct cluster, the recent human isolation was not associated with these strains but instead clustered with isolates originating from the Horn of Africa. These data was congruent with epidemiological trace-back showed that the individual had travelled to Malta from Eritrea. This work highlights the potential of using molecular typing data to aid in epidemiological trace-back of Brucella isolations and assist in monitoring of the effectiveness of brucellosis control schemes. PMID- 25697305 TI - Influence of a nearby substrate on the reorganization energy of hole exchange between dye molecules. AB - A numerical method is presented to estimate the influence of a nearby substrate on the polarization energy and outer sphere reorganization energy (lambdao) for intermolecular hole transfer for a series of dye molecules. The calculation considers the net charge distribution of the oxidised molecule (determined from quantum chemical calculation of the highest occupied molecular orbital of the neutral molecule within the frozen orbital approximation) encapsulated within a conformal cavity, by the molecules total electron density. An analytical point charge approximation was used at longer range. The molecular cavity was either surrounded by a single polarizable continuum, or, to simulate a nearby substrate, embedded at different positions relative to the interface between two semi infinite slabs with different dielectric constants. The calculated lambdao values in the single dielectric medium were linearly related to the outer-sphere reorganisation energy calculated from DFT with a polarizable continuum model, validating the approach. In the two phase system, variations in lambdao was sensitive to the position of the substrate relative to the molecule and differences in the Pekar factor (1/epsilono - 1/epsilonr) for the media. For dye molecules in ACN positioned touching a TiO2 substrate lambdao was typically about 20% lower than in pure ACN depending on the molecular configuration. Our approach can be adapted to systems of more than two media. PMID- 25697306 TI - Reflexive Principlism as an Effective Approach for Developing Ethical Reasoning in Engineering. AB - An important goal of teaching ethics to engineering students is to enhance their ability to make well-reasoned ethical decisions in their engineering practice: a goal in line with the stated ethical codes of professional engineering organizations. While engineering educators have explored a wide range of methodologies for teaching ethics, a satisfying model for developing ethical reasoning skills has not been adopted broadly. In this paper we argue that a principlist-based approach to ethical reasoning is uniquely suited to engineering ethics education. Reflexive Principlism is an approach to ethical decision-making that focuses on internalizing a reflective and iterative process of specification, balancing, and justification of four core ethical principles in the context of specific cases. In engineering, that approach provides structure to ethical reasoning while allowing the flexibility for adaptation to varying contexts through specification. Reflexive Principlism integrates well with the prevalent and familiar methodologies of reasoning within the engineering disciplines as well as with the goals of engineering ethics education. PMID- 25697307 TI - Evaluation of cadmium in greenhouse soils and agricultural products of Jiroft (Iran) using microwave digestion prior to atomic absorption spectrometry determination. AB - This study determines total levels of potentially toxic trace element, Cd (II) in Jiroft (Kerman, Iran) greenhouse soil and agricultural products that are grown in these greenhouses (tomatoes and cucumbers), and the comparison with soil outside of greenhouse using microwave digestion prior to flame atomic absorption spectrometry determination. The results show that the cadmium concentration in greenhouse soil is 0.9-1.9 mg kg(-1) and out of greenhouse is 0.4-1.0 mg kg(-1). Also, cadmium concentration range in tomatoes and cucumbers is about 0.07-0.40 mg kg(-1). The obtained results show that the concentration of this metal in greenhouse soil is higher than outside soil samples and is below the safe limit. PMID- 25697308 TI - Effects of sewage water irrigation of cabbage to soil geochemical properties and products safety in peri-urban Peshawar, Pakistan. AB - Irrigation of agricultural land with municipal wastewater has become a serious environmental issue due to soil contamination. The objective of the present study was to investigate the extent of contamination of vegetables grown on soil irrigated with untreated sewage water for the last four decades in suburban Peshawar. Samples of sewage water, soil, and vegetables were collected from three different sectors selected for the study. Heavy metals like Pb, Cr, Cd, Cu, Zn, and Ni in the three media were determined with atomic absorption spectrometer (AAS). Statistical analysis of data revealed that the distribution order of these metals is quite different in the analyzed samples. Some of the heavy metals, viz., Cr, Cd, Zn, and Ni, have high skewness with non-normal frequency distribution. The soil of polluted areas showed highest mean concentration of Zn (51.25 mg kg(-1)), followed by Pb (43.51 mg kg(-1)), Cu (43.3 mg kg(-1)), Ni (37.05 mg kg(-1)), Cr (28.18 mg kg(-1)), and Cd (8.51 mg kg(-1)), which were 43, 22, 33, 26, 20, and 6 times higher than the control area, respectively. The ammonium bicarbonate diethylenetriaminepenta acetic acid (AB-DTPA) extractable concentrations of Ni, Cr, and Cu in soil of polluted sectors were 12, 10, and 10 times greater than the those in control sector, respectively. Linear regression analysis revealed that enhanced levels of these toxic heavy metals in cabbage (Brassica oleracea) were strongly correlated with extractable and total heavy metal concentration in the soil. Significant difference (at P < 0.012) was observed in the Pb concentration in cabbage of polluted sectors. Zn showed the highest transfer factor (TF) followed by Ni and Cu. Heavy metal concentration in sewage water and soil has exceeded the maximum permissible limits of World Health Organization (WHO 1997). PMID- 25697309 TI - Assessment of species and antimicrobial resistance among Enterobacteriaceae isolated from mallard duck faeces. AB - Mallard ducks have demonstrated to be a likely reservoir for zoonotic E. coli strains; thus, it is possible that these ducks could also act as a reservoir for other Enterobacteriaceae members. The present study was initiated to evaluate the species distribution of Enterobacteriaceae other than E. coli in 175 fresh faecal samples collected from a population of mallard ducks. Sixty-four samples displayed detectable colonies of Enterobacteriaceae (excluding E. coli), which resulted in 75 pulsed-field gel electrophoresis (PFGE) types. Seventy-five single representatives of each PFGE type were subjected to identification with API 32NE and MALDI TOF MS systems due to the practical difficulties in species differentiation of Enterobacteriaceae. Those isolated were found to be from nine genera: Buttiauxella (15 %), Citrobacter (5 %), Enterobacter (32 %), Hafnia (1 %), Leclercia (1 %), Pantoea (7 %), Raoultella (21 %), Rahnella (7 %) and Serratia (11 %). Evaluation of antimicrobial resistance phenotypes using the disc method and detection of resistance genes using the microarray method revealed that these microbes possess resistance to beta-lactams, aminoglycosides, macrolides, quinolones, rifamycine, sulphonamides, streptogramins and diaminopyrimidines. In conclusion, mallard ducks harbour a variety of non pathogenic and pathogenic Enterobacteriaceae species like Enterobacter cloacae and Enterobacter amnigenus in their intestine and could act as a reservoir of resistant Enterobacteriaceae. PMID- 25697310 TI - Modeling the relationship between landscape characteristics and water quality in a typical highly intensive agricultural small watershed, Dongting lake basin, south central China. AB - Understanding the relationship between landscape characteristics and water quality is critically important for estimating pollution potential and reducing pollution risk. Therefore, this study examines the relationship between landscape characteristics and water quality at both spatial and temporal scales. The study took place in the Jinjing River watershed in 2010; seven landscape types and four water quality pollutions were chosen as analysis parameters. Three different buffer areas along the river were drawn to analyze the relationship as a function of spatial scale. The results of a Pearson's correlation coefficient analysis suggest that "source" landscape, namely, tea gardens, residential areas, and paddy lands, have positive effects on water quality parameters, while forests exhibit a negative influence on water quality parameters because they represent a "sink" landscape and the sub-watershed level is identified as a suitable scale. Using the principal component analysis, tea gardens, residential areas, paddy lands, and forests were identified as the main landscape index. A stepwise multiple regression analysis was employed to model the relationship between landscape characteristics and water quality for each season. The results demonstrate that both landscape composition and configuration affect water quality. In summer and winter, the landscape metrics explained approximately 80.7 % of the variance in the water quality variables, which was higher than that for spring and fall (60.3 %). This study can help environmental managers to understand the relationships between landscapes and water quality and provide landscape ecological approaches for water quality control and land use management. PMID- 25697311 TI - Performance of wetland forbs transplanted into marshes amended with oil sands processed water. AB - Companies mining oil sands in Alberta (Canada) face the challenge of reclaiming wetlands under water use restrictions. Wetland reclamation after mining will generate marshes characterized by elevated salinity and residual hydrocarbons. Oil sands wetlands are also impoverished in forbs, suggesting that their establishment may be constrained by water chemistry. We transplanted skullcap, mint, and smartweed plants into experimental trenches that simulated two possible reclamation scenarios: wetlands amended with on-site freshwater or with oil sands processed water (OSPW). The main scientific question was is OSPW a suitable water amendment as freshwater for reclaiming wetland forb habitat? As a surrogate of plant health, we studied plant ecophysiology (gas exchange, leaf fluorescence), leaf chemistry, and plant growth. Results showed that there were no differences in skullcap mineral contents under either treatment; however, mint and smartweed plants subjected to OSPW had a significantly higher Na content than those under freshwater. Smartweed dark-adapted leaf fluorescence showed a reduced photochemistry in OSPW relative to plants in freshwater. Mint leaves exhibited lower stomatal conductance in OSPW than in freshwater, a condition that negatively affected transpiration and carboxylation. Skullcap plants grown in OSPW had lower net CO2 assimilation rates than those in freshwater but did not show any other ecophysiological difference between treatments. Mint plants experienced growth reductions (i.e., shoot height) in OSPW. Our results show, for the first time in the literature, that plants photosynthetic capacity was negatively affected by OSPW. Conditions in OSPW proved to be suitable for establishment as transplanted forbs showed 100 % survival after the first growing season. However, impaired physiological functions in plants subjected to OSPW indicated that OSPW amendment created a less hospitable habitat for wetland forbs than freshwater. PMID- 25697312 TI - [Pediatric research in Chile and Revista Chilena de Pediatria indexed in the mainstream]. PMID- 25697313 TI - [The discussion about abortion in Chile]. PMID- 25697314 TI - [Update on acute management of inborn errors of metabolism]. AB - Inborn metabolic disorders are genetic diseases which are uncommon each one, but together they are not. They are characterized by an enzimatic defect that blocks a metabolic pathway, producing specific signs and symptoms. The current article pretends be an updated guideline for their acute management which is based on: 1) Inmediate life support, hydroelectrolyte balance and sample procurement, 2) Avoiding the production of toxic endogenous metabolites and anabolism promotion, 3) The supplementation of substrates and 4) The removal of toxic substances. Their prompt suspicious, identification and treatment starting will be crucial for neurological prognosis and prevention of death. PMID- 25697315 TI - [Adherence to vitamin D supplementation and determinant factors during the first year of life]. AB - INTRODUCTION: Breastfed infants under one year of age may not get enough vitamin D; therefore a vitamin supplement is needed. The adherence to this policy has not yet been evaluated in Chile. OBJECTIVE: To evaluate the adherence to vitamin D supplementation in children less than one year old and the determinant factors involved. PATIENTS AND METHOD: A cross-sectional study was carried out in three Catholic University Health Network centers. Breastfed infants under one year of age were included in the study. Their parents/guardians filled out a questionnaire about adherence to supplementation and its determinant factors. RESULTS: 170 infants were recruited. 164 of them received supplementation, with a good adherence of 68.9%. The main reason for non-adherence was due to maternal forgetfulness. The identified risk factor for poor adherence was the number of maternal children. CONCLUSIONS: Vitamin D supplementation in Chile reaches high levels, but its adherence is poor. More education to parents on ways to avoid forgetting the supplement is needed as well as on identifying risk factors during medical consultations. PMID- 25697316 TI - [Validation study of attachment questionnaire in adolescents]. AB - INTRODUCTION: There are not enough specially developed tools to study attachment during adolescence in our country. The objective of this research is to adapt and validate the AAQ (Adolescent Attachment Questionnaire) for the Chilean population. PATIENTS AND METHOD: A cross-sectional study was conducted in 199 adolescents between 11 and 19 years old. The AAQ is a self-report questionnaire consisting of 9 items, three scales of three statements each: a) Availability scale; b) Goal corrected Partnership scale and c) Angry distress scale. The items were answered with Likert-type responses. The AAAQ was originally validated in a sample of 824 adolescents, 691 of which corresponded to non-clinical population and 133 corresponded to clinical population, demonstrating satisfactory internal reliability. To create the spanish version of the questionnaire, a translation retranslation procedure was used evaluating semantic, content, construct and reliability validity. RESULTS: The results showed adequate internal consistency of the instrument with Cronbach alpha's values between 0.52 and 0.74. Also, the factorial structure of the AAQ English version was replicated. Finally, temporary rules for the interpretation of results that consider age differences for one of the 3 scales are presented. CONCLUSIONS: It is concluded that the instrument is suitable for use because it is a short self-administered questionnaire that shows similar psychometric characteristics to the original English version. PMID- 25697317 TI - [Thoracoscopic repair of esophageal atresia with and without tracheoesophageal fistula]. AB - INTRODUCTION: Esophageal atresia (EA) is the interruption of the continuity of the esophagus, with or without persistent communication with the trachea. Recent advances in surgical techniques have made possible correction with minimally invasive surgery (MIS). OBJECTIVE: To evaluate the management of thoracoscopic technique in the treatment of EA. PATIENTS AND METHOD: Retrospective analysis of medical records in two centers was carried out between 2007 and 2012. Variables such as gestational age, gender, weight, type of esophageal atresia, malformations, surgery and postoperative complications were recorded. RESULTS: Twenty patients, 15 of them with type III EA, 4 with type I and one unclassifiable, were part of the study. 13 patients underwent ligation, cut of tracheoesophageal fistula and end to end anastomosis. Two underwent laparoscopic gastrostomy and fistula ligation. One patient required conversion and underwent esophagostomy plus gastrostomy. 4 patients without fistula required laparoscopic gastrostomy and aspiration of the proximal esophagus to be able to perform esophageal anastomosis. In the postoperative period, pleural drainage and a transanastomotic feeding tube were installed. Seven patients required esophageal dilations and 4 patients developed stenosis due to reflux. Two had recurrent fistula, one with spontaneous resolution and another with endoscopic resolution. Three children died: two of them due to pathologies not related to surgery and one as a result of limitation of therapeutic effort after fistula patency. DISCUSSION: Esophageal atresia repair with MIS is a safe and effective option with excellent exposure and visualization of anatomic landmarks and little associated morbidity. PMID- 25697318 TI - [CFTR gene sequencing in a group of Chilean patients with cystic fibrosis]. AB - INTRODUCTION: Cystic fibrosis (CF) is an autosomal recessive genetic disorder caused by mutations of the CFTR gene, in which over 1,900 different mutations have been identified. In Chile, the diagnosis panel with the 36 most common mutations detects approximately 50% of all alleles, while for Caucasians, it is nearly 90%. The objective of this study is to expand the capacity of mutational screening in Chilean patients and look for recurrent mutations at the national level. METHOD: The detection of unknown pathogenic alleles was assessed by CFTR gene sequencing in a selected group of patients from the National Cystic Fibrosis Foundation (NCFF). 39 patients, who met the CF diagnostic criteria and had only one allele identified according to the mutational panel, were studied. Massive sequencing was performed throughout the investigation and the main CFTR databases were used for analysis. RESULTS: The second pathogenic allele was identified in 16 of 39 patients of this study (41%), finding eleven different mutations that had not been reported in our population. We believe that the reason is that one of the variants had not been previously described. CONCLUSIONS: Mutations that had been described mainly in Hispanic and/or Mediterranean populations were identified. We found a variation that had not been previously reported, but not enough recurrent mutations that could explain the low rate of detection were found. Knowledge about mutations can provide appropriate genetic counseling and will be critical to evaluate the potential use of new targeted therapies for treating them. PMID- 25697319 TI - [Association between overweight and early childhood caries]. AB - OBJECTIVE: To determine whether overweight is a risk factor for the development of early childhood caries (ECC) in preschoolers. PATIENTS AND METHOD: An observational retrospective cohort study was performed in 196 children under 2 years of age at Calbuco Hospital, Los Lagos Region, Chile, who were admitted between 2007 and 2009. Patients were grouped based on their nutritional status at admission in the two following categories: eutrophic and overweighed children as a result of excessive intake. Information regarding caries incidence and nutritional status were annually retrieved from records until the age of 5 years, according to medical and dental records. RESULTS: At the beginning of the study, 33.67% were overweight and 16.33% were obese, reaching 40% overweight and 20.56% obese at four years of age. The incidence of early childhood caries in overweighed children was 57.14% compared to 40.82% in normal weight children (p = 0.022), with 1.4 RR (95% CI, 1044-1.88). CONCLUSIONS: The increased risk of early childhood decay in overweighed patients makes necessary to create instances of timely mutual referral between the professional that diagnoses overweighed children and the pediatric dentist in order to develop preventive treatments for both diseases. PMID- 25697320 TI - [Adherence to recommendations to reduce the risk of Sudden infant Death Syndrome]. AB - INTRODUCTION: Recommendations for Sudden Infant Death Syndrome (SIDS) are available, although it is uncertain the degree of adherence to these measures. The aim of the study is to assess the adherence to recommendations to reduce the risk of SIDS, seeking factors associated to the noncompliance with these recommendations. PATIENTS AND METHOD: 468 infants were enrolled in two maternity hospitals, one public and one private. Postpartum and 4-month assessments were performed. A questionnaire was used adapting a model validated by the International Child Care Practices Study. RESULTS: Adherence to obstetric recommendations was higher (75.4%) than to pediatric recommendations (53.3%). Regarding pediatric recommendations, a compliance decrease was detected after 4 months. Follow-ups showed decrease in breastfeeding (p < 0.001 84.9% vs 48.6%) and supine position (61.2% vs 21.2%, p < 0.001). CONCLUSIONS: The decreased adherence to recommendations for SIDS prevention was mainly observed in younger and less educated women, who were not in a relationship and living in poor housing quality and crowded environments. PMID- 25697321 TI - [Phenotypic variability of cystic fibrosis: case report of twins with F508/F508 mutation]. AB - INTRODUCTION: Cystic fibrosis (CF) is an autosomal recessive disease caused by a mutation in the CFTR gene, resulting in an alteration of a protein involved in sodium and chloride transport in the apical plasma membrane of epithelial cells in respiratory and intestinal tracts. It primarily presents respiratory compromise, affecting other systems in different ways. Meconium ileus is a gastrointestinal manifestation that occurs in 10-20% of patients, which is not entirely attributable to a specific CFTR mutation. OBJECTIVE: To report a case of monozygotic twins diagnosed with CF (F508) in whom phenotypic variation is evident based on the expression of meconium ileus, showing that there are external modifiers in the development of this complication. CASE REPORT: monoamniotic monochorionic twin pregnancy which resulted in preterm births. One of the patient presented meconium ileus at birth leading to CF suspicion and establishing the diagnosis by (F508/F508) molecular analysis in both twins. CONCLUSION: Phenotypic variability in these twins supports the hypothesis proposed by different authors that there are other gene expression-modulation factors of the disease as well as environmental modifiers that must be taken into account when dealing with this disease. PMID- 25697322 TI - [Tension gastrothorax as a cause of death by obstructive shock - case report]. AB - INTRODUCTION: Tension gastrothorax is caused by the herniation of the stomach into the thorax due to a congenital defect of the diaphragm; the Bochdaleck diaphragmatic hernia (HDB) is the most frequent type. OBJECTIVE: Tension gastrothorax should be considered as a differential diagnosis in patients with obstructive shock and tension pneumothorax. CASE REPORT: A previously healthy 10 month-old male infant, who presented increased respiratory distress, increased volume of the left hemithorax, absence of breath sounds, ipsilateral hyper resonance, 76% saturation, cold skin and capillary filling > 5 seconds, followed by a cardio-respiratory arrest. Due to clinical suspicion of pneumothorax, needle decompression was performed reversing cardiac arrest, but with persistent hemodynamic and respiratory instability; chest radiograph suggested diaphragmatic hernia. He underwent surgery confirming the presence of a diaphragmatic hernia of 5 cm. CONCLUSIONS: The evolution of this case shows the difficulty differentiating a tension gastrothorax from tension pneumothorax in patients admitted to the emergency room who are in serious condition; therefore, a high index of suspicion is needed for its identification. PMID- 25697323 TI - [Pathophysiology, differential diagnosis and treatment of severe emotional apnea: based on report case]. AB - INTRODUCTION: Emotional apneas (EA) are non-epileptic paroxysmal events affecting 5% of healthy children. The diagnosis is based on a stereotyped sequence of clinical events that start with tears caused by emotional stimulus, resulting in an autonomic nervous system alteration with transient color change, pale or cyanotic. 15% of the cases are associated with loss of consciousness, changes in tone or tonic-clonic movements secondary to hypoxia. OBJECTIVE: To report a case of severe EA and to review the differential diagnosis and preventive treatments. CASE REPORT: A 15-month old infant with cyanotic emotional apnea since 8 months of age, triggered by pain, disgust or fear, increasing in frequency (3-4 per day) and intensity with altered consciousness and hypotonia. At 12 months, the patient also presented generalized tonic-clonic seizures of 3 minutes long, reason why the infant was admitted to the emergency service. Normal psychomotor development as well as normal physical, neurological and laboratory test results (without anemia) were found. Electroencephalography and brain MRI presented no abnormalities. Preventive therapy using Piracetam was performed in order to reduce crisis, which occurred in the first month of treatment. CONCLUSIONS: In most cases, a timely information delivery to parents is enough due to the benign nature and natural history of EA. However, when the frequency and severity of EA impact the child and family, to rule out heart disease or epilepsy and to seek preventive treatment options are required. PMID- 25697324 TI - [Perineal groove in pediatric gynecology: a report of 2 cases]. AB - INTRODUCTION: the perineal groove is a very uncommon anorectal anomaly. It is the result of an unknown embryology anomaly. The perineal groove is a wet sulcus extending from de fourchette to the anus. It is a benign pathology and tends to resolve spontaneously. OBJECTIVE: We report two cases of girls diagnosed with perineal groove and their follow up. CASES REPORTS: The first case is an 18 days old baby girl, that during her first clinical examination there was found a painless lineal lesion in the perineum from the fourchette to the anus, which created a big anxiety in her family. She was cared at the Pediatric Gynecology Unit, with local lubrication, doing well with the epithelization of it. The second case is an 8 year-old girl who consulted because, when being a child, she was diagnosed with a perineal lesion, but she didn't receive any special treatment and now she feels some aches in the perineum. CONCLUSIONS: The perineal groove is a benign entity pretty unknown by general practitioners or pediatricians. It is important to be up to date with this condition to avoid alarming misinterpretations. PMID- 25697325 TI - [Ventilator-induced diaphragmatic dysfunction]. AB - The ventilator-induced diaphragmatic dysfunction is a group of disorders caused by the inactivity of the diaphragm muscle during controlled mechanical ventilation. From a structural point of view, the diaphragm subjected to mechanical ventilation undergoes an atrophy process, in which decreased synthesis and increased muscle protein degradation are observed. Recent research has identified different molecular signaling pathways that link both processes in the diaphragm, describing compelling evidence that shows that oxidative stress contributes to this phenomenon. Also, functional changes characterized by a reduction in stress and fatigue resistance, associated with an increase in the maximum shortening velocity are observed. The purpose of the present review is to analyze the impact of mechanical ventilation on the structure and function of the diaphragm muscle. Clinical implications and potential preventive steps are discussed. Since the duration of mechanical ventilation is the primary responsible for the absence of mechanical stimulation on the diaphragm, the use of ventilatory strategies for successful early weaning and early use of partial modalities should be the main pillars in the prevention of this condition. PMID- 25697328 TI - Concurrent partnerships in Cape Town, South Africa: race and sex differences in prevalence and duration of overlap. AB - INTRODUCTION: Concurrent partnerships (CPs) have been suggested as a risk factor for transmitting HIV, but their impact on the epidemic depends upon how prevalent they are in populations, the average number of CPs an individual has and the length of time they overlap. However, estimates of prevalence of CPs in Southern Africa vary widely, and the duration of overlap in these relationships is poorly documented. We aim to characterize concurrency in a more accurate and complete manner, using data from three disadvantaged communities of Cape Town, South Africa. METHODS: We conducted a sexual behaviour survey (n = 878) from June 2011 to February 2012 in Cape Town, using Audio Computer-Assisted Self-Interviewing to collect sexual relationship histories on partners in the past year. Using the beginning and end dates for the partnerships, we calculated the point prevalence, the cumulative prevalence and the incidence rate of CPs, as well as the duration of overlap for relationships begun in the previous year. Linear and binomial regression models were used to quantify race (black vs. coloured) and sex differences in the duration of overlap and relative risk of having CPs in the past year. RESULTS: The overall point prevalence of CPs six months before the survey was 8.4%: 13.4% for black men, 1.9% for coloured men, 7.8% black women and 5.6% for coloured women. The median duration of overlap in CPs was 7.5 weeks. Women had less risk of CPs in the previous year than men (RR 0.43; 95% CI: 0.32 0.57) and black participants were more at risk than coloured participants (RR 1.86; 95% CI: 1.17-2.97). CONCLUSIONS: Our results indicate that in this population the prevalence of CPs is relatively high and is characterized by overlaps of long duration, implying there may be opportunities for HIV to be transmitted to concurrent partners. PMID- 25697329 TI - Endometriosis of the lumbosacral plexus: report of a case with foot drop and chronic pelvic pain. PMID- 25697330 TI - Amphiphilic perylene-calix[4]arene hybrids: synthesis and tunable self-assembly. AB - The first highly water-soluble perylene-calix[4]arene hybrid with the calixarene scaffold acting as a structure-determining central platform is presented. In this tetrahedrally shaped amphiphilic architecture the hydrophilic and hydrophobic subunits are oriented at the opposite side of the calixarene platform. The hydrophobic part contains the two perylene diimide moieties, which enable strong pi-pi interactions in self-assembly processes. Two hydrophilic Newkome-type dendrons provide sufficient water solubility at slightly basic conditions. The tetrahedrally shaped amphiphile displays an unprecedented aggregation behavior down to concentrations as low as 10(-7) mol L(-1). The intriguing self-assembly process of the compound in water as well as under changed polarity conditions, achieved by addition of THF, could be monitored by the complemented use of cryogenic transmission electron microscopy (cryo-TEM), UV-vis spectroscopy, and fluorescence spectroscopy. Molecular-dynamics and molecular modeling simulations helped in understanding the interplay of supramolecular and optical behavior. PMID- 25697331 TI - Exploring pain in the Andes--learning from the Quichua (Inca) people experience. AB - There is a mounting recognition that culture profoundly shapes human pain experience. The 28 million indigenous people of the Andes in South America, mainly the Quichua (Inca) people, share a distinctive culture. However, little is known about their pain experience and suffering. The aim of the present study was to explore how Quichua adults perceive, describe, and cope with the pain. An exploratory qualitative/descriptive study was conducted with a convenience sample of 40 Quichua adults, including 15 women and 25 men, in the Northern Highlands of Ecuador. Data were collected through structured interviews of approximately 3 h, using a Quichua questionnaire called "The Nature of Pain" [Nanay Jahua Tapuicuna]. The interviews covered the notions of causation of pain, vulnerability to pain, responses to pain, aggravating factors, frequent locations of pain, types of pain, duration, characteristics of pain, control of pain, pathways to care, and preventive measures of pain. Basic descriptive analyses were performed. The Quichuas' pain experience is complex and their strategies to cope with it are sophisticated. According to the Quichuas, emotions, life events, co-morbid conditions, and spirits, among others factors play an important role in the origin, diagnosis, and treatment of pain. They strongly embrace biomedicine and physicians as well as Quichua traditional medicine and traditional healers. Family members and neighbors are also valuable sources of health care and pain control. The pathway to pain care that the Quichua people prefer is inclusive and pluralistic. The knowledge of the Quichua ethnographic "emic" details of their belief system and coping strategies to control pain are clinically useful not only for the health professional working in the Andes, some Quichua cultural characteristics related to pain could be useful to the culturally competent health practitioner who is making efforts to provide high-quality medical care in rural and multicultural societies around the world. PMID- 25697332 TI - Mathematical modeling and physical reality in noncovalent interactions. AB - The Hellmann-Feynman theorem provides a straightforward interpretation of noncovalent bonding in terms of Coulombic interactions, which encompass polarization (and accordingly include dispersion). Exchange, Pauli repulsion, orbitals, etc., are part of the mathematics of obtaining the system's wave function and subsequently its electronic density. They do not correspond to physical forces. Charge transfer, in the context of noncovalent interactions, is equivalent to polarization. The key point is that mathematical models must not be confused with physical reality. PMID- 25697333 TI - Anterior transpedicular screws in conjunction with plate fixation and fusion for the treatment of subaxial cervical spine diseases. AB - OBJECTIVE: This study aimed at exploring the clinical application of anterior transpedicular screw (ATPS) and plate in the reconstruction of subaxial cervical spine. METHODS: 8 cases were reconstructed by ATPS and plate in the subaxial cervical spine from Jan 2009 to Dec 2011. X-rays and computed tomography images were collected to evaluate the position of ATPS. Magnetic resonance imaging was also included to evaluate the result of decompression, the existence of epidural hematoma and the morphology of the cervical spinal cord. Japanese Orthopaedic Association scores were observed before and after operation as a functional estimation. RESULTS: All of the eight cases were followed up from 3 to 36 months with the average of 15.5 months. A total of 16 ATPS were implanted in the subaxial cervical spine in the eight patients. All the screws were inserted smoothly. Bone fusion was found in all the subjects 4.5 months after operation on average. No loosening or breakage of the internal fixation was observed in our study. Hoarseness was observed in one case due to distraction injury of the recurrent laryngeal nerve, which disappeared after 3 weeks' conservative treatment. Dysphagia was complained by two patients after surgery, which was alleviated 3 months later. There were four screws deviating less than 1 mm (Grade 1), two medially and two laterally. All the anterior compressions were removed completely in this group. Only a small amount of epidural hematoma was found in four cases on MRI images before discharge. The average JOA scores were significantly improved from 5.6 +/- 1.4 before surgery to 14.5 +/- 0.8 at discharge (P < 0.01), which decreased to 13.2 +/- 1.2 at 3 months after operation, but improved again to 15.2 +/- 0.8 at 1 year after operation. CONCLUSION: Although there are some complications, ATPS with plate is an effective and safe technique for anterior reconstruction in the subaxial cervical spine. Only those spine centers with sufficient experience in complex cervical spine reconstruction surgery can conduct this technique according to strict indications. PMID- 25697334 TI - Scoliosis correction surgery for patients with McCune-Albright syndrome using pedicle screws: a report of two cases with different characteristics and a review of the literature. AB - PURPOSE: Scoliosis can occur secondary to McCune-Albright syndrome (MAS); it can be progressive and sometimes requires surgical treatment. It is still unclear if pedicle screw (PS) fixation in these patients with poor bone quality can be considered an effective treatment for scoliosis. The purpose of this study is to report two MAS patients with spinal fibrous dysplasia (FD) who underwent scoliosis surgeries with the PS system. METHODS: Case 1: a 12-year-old girl. Standing posteroanterior radiographs revealed a 58 degrees right curve from T7 to L2. Computed tomography (CT) showed small areas of FD throughout the spine. A posterior spinal arthrodesis from T4 to L3 using PS fixation was performed with a CT-based navigation system. Case 2: a 26-year-old woman. Radiographs in the standing position revealed a right 87 degrees curve from T8 to L2 and a 55 degrees kyphosis from T8 to T12. CT images showed multiple areas of severe spinal FD causing angular deformity and collapse of vertebral bodies. The patient underwent posterior spinal arthrodesis from T8 to her pelvis using a CT-based navigation system for PS fixation. RESULTS: Superior scoliosis corrections were obtained using PS instrumentation, attaining complete bony union in both cases without major complications. However, Case 2 had some technical difficulties in treating due to the multiple large FD lesions. CONCLUSIONS: PS fixation can be considered an effective treatment for correcting scoliosis and maintaining the correction at follow-up in MAS patients with poor bone quality. However, great care must be taken when performing correction and follow-up. PMID- 25697336 TI - Studies of hepatocyte growth factor in bronchoalveolar lavage fluid in chronic interstitial lung diseases. AB - INTRODUCTION: Previous studies have suggested that hepatocyte growth factor (HGF) inhibits lung fibrosis as an antagonist of transforming growth factor beta (TGF-beta). OBJECTIVES: We assessed HGF expression levels in the lower airways of patients with selected interstitial lung diseases. PATIENTS AND METHODS: HGF levels were examined by an enzyme-linked immunosorbent assay in bronchoalveolar lavage (BAL) fluid supernatants from patients with pulmonary sarcoidosis (PS, n = 52), idiopathic pulmonary fibrosis (IPF, n = 23), nonspecific interstitial pneumonia (NSIP, n = 14), extrinsic allergic alveolitis (EAA, n = 6), bronchiolitis obliterans organizing pneumonia (BOOP, n = 8), chronic eosinophilic pneumonia (EP, n = 6), and in control subjects (n = 13). Intracellular HGF expression in BAL cells was evaluated by flow cytometry. RESULTS: HGF concentrations were elevated in BAL fluid from nonsmokers with IPF (261 +/-204 pg/ml, P <0.02), smokers with IPF (220 +/-13 pg/ml, P <0.001), and smokers with PS (172 +/-33 pg/ml, P <0.02), as compared with controls (148 +/-17 pg/ml for nonsmokers; 137 +/-9 pg/ml for smokers). HGF levels were positively correlated with TGF-beta concentrations in BAL fluid (r = 0.3; P = 0.02) and negatively-with vital capacity (r = -0.2; P = 0.02). BAL neutrophils, and, for the first time, BAL lymphocytes, were identified as intracellular HGF-positive cells. CONCLUSIONS: Our results do not support evidence for strong antifibrotic HGF activity. The highest HGF concentrations were observed in BAL fluid from patients with IPF, and they were also positively correlated with TGF-beta levels. Thus, although the local protective mechanisms such as the HGF expression are upregulated in chronic interstitial lung diseases, they are not enough to prevent lung fibrosis. PMID- 25697335 TI - Development and preliminary testing of PROGRESS: a Web-based education program for prostate cancer survivors transitioning from active treatment. AB - PURPOSE: This formative research study describes the development and preliminary evaluation of a theory-guided, online multimedia psycho-educational program (PROGRESS) designed to facilitate adaptive coping among prostate cancer patients transitioning from treatment into long-term survivorship. METHODS: Guided by the Cognitive-Social Health Information Processing Model (C-SHIP) and using health communications best practices, we conducted a two-phase, qualitative formative research study with early stage prostate cancer patients (n = 29) to inform the Web program development. Phase 1 included individual (n = 5) and group (n = 12) interviews to help determine intervention content and interface. Phase 2 employed iterative user/usability testing (n = 12) to finalize the intervention. Interview data were independently coded and collectively analyzed to achieve consensus. RESULTS: Survivors expressed interest in action-oriented content on (1) managing treatment side effects, (2) handling body image and comorbidities related to overweight/obesity, (3) coping with emotional and communication issues, (4) tips to reduce disruptions of daily living activities, and (5) health skills training tools. Patients also desired the use of realistic and diverse survivor images. CONCLUSIONS: Incorporation of an established theoretical framework, application of multimedia intervention development best practices, and an evidence-based approach to content and format resulted in a psycho-educational tool that comprehensively addresses survivors' needs in a tailored fashion. IMPLICATIONS FOR CANCER SURVIVORS: The results suggest that an interactive Web-based multimedia program is useful for survivors if it covers the key topics of symptom control, emotional well-being, and coping skills training; this tool has the potential to be disseminated and implemented as an adjunct to routine clinical care. PMID- 25697337 TI - "Doctor, Why Didn't You Adopt My Baby?" Observant Participation, Care, and the Simultaneous Practice of Medicine and Anthropology. AB - Medical anthropology has long appreciated the clinical encounter as a rich source of data and a key site for critical inquiry. It is no surprise, then, that a number of physician-anthropologists have used their clinical insights to make important contributions to the field. How does this duality challenge and enhance the moral practice and ethics of care inherent both to ethnography and to medicine? How do bureaucratic and professional obligations of HIPAA and the IRB intersect with aspirations of anthropology to understand human experience and of medicine to heal with compassion? In this paper, I describe my simultaneous fieldwork and clinical practice at an urban women's jail in the United States. In this setting, being a physician facilitates privileged access to people and spaces within, garners easy trust, and enables an insider perspective more akin to observant participation than participant observation. Through experiences of delivering the infants of incarcerated pregnant women and of being with the mothers as they navigate drug addiction, child custody battles, and re incarceration, the roles of doctor and anthropologist become mutually constitutive and transformative. Moreover, the dual practice reveals congruities and cracks in each discipline's ethics of care. Being an anthropologist among informants who may have been patients reworks expectations of care and necessitates ethical practice informed by the dual roles. PMID- 25697338 TI - Autophagic flux and autophagosome morphogenesis require the participation of sphingolipids. AB - Apoptosis and autophagy are two evolutionary conserved processes that exert a critical role in the maintenance of tissue homeostasis. While apoptosis is a tightly regulated cell program implicated in the removal of damaged or unwanted cells, autophagy is a cellular catabolic pathway that is involved in the lysosomal degradation and recycling of proteins and organelles, and is thereby considered an important cytoprotection mechanism. Sphingolipids (SLs), which are ubiquitous membrane lipids in eukaryotes, participate in the generation of various membrane structures, including lipid rafts and caveolae, and contribute to a number of cellular functions such as cell proliferation, apoptosis and, as suggested more recently, autophagy. For instance, SLs are hypothesized to be involved in several intracellular processes, including organelle membrane scrambling, whilst at the plasma membrane lipid rafts, acting as catalytic domains, strongly contribute to the ignition of critical signaling pathways determining cell fate. In particular, by targeting several shared regulators, ceramide, sphingosine-1-phosphate, dihydroceramide, sphingomyelin and gangliosides seem able to differentially regulate the autophagic pathway and/or contribute to the autophagosome formation. This review illustrates recent studies on this matter, particularly lipid rafts, briefly underscoring the possible implication of SLs and their alterations in the autophagy disturbances and in the pathogenesis of some human diseases. PMID- 25697339 TI - Characteristics and outcomes of Klebsiella pneumoniae bacteraemia in Hong Kong. AB - BACKGROUND: We compared clinical outcomes between patients with healthcare associated and community-acquired Klebsiella pneumoniae bacteraemia and identified predictors associated with mortality and high treatment cost in Hong Kong. METHODS: This was a retrospective cohort study of patients with K. pneumoniae bacteraemia in a teaching hospital. Adult patients with K. pneumoniae in blood cultures were included. Demographics and clinical data were retrieved from medical records. RESULTS: The analysis included 208 patients. The mean age was 68.6 +/- 16.8 years. The Pitt bacteraemia score was 2.2 +/- 2.8. In all, 54.8% cases were healthcare-associated infections. The 30-day mortality rate was 32.7%. The mortality rate of patients with healthcare-associated bacteraemia was significantly higher than for community-acquired cases (p < 0.001). Extended spectrum beta-lactamase (ESBL)-producing K. pneumoniae accounted for 15.4% of cases. Intra- abdominal infection was the most common infection (32.7%). Prior use of immunosuppressive agents and antimicrobial therapy were two major predisposing factors for infection. The treatment cost was USD12 282 +/- 11 751 and the length of hospitalization was 9.0 +/- 6.7 days. Multivariate analysis showed that liver disease (odds ratio (OR) = 3.06; 95% confidence interval (CI) = 1.38-6.78), malignancy (OR = 6.86; 95% CI = 3.25-14.48), pneumonia (OR = 5.25; 95% CI = 2.05-13.41) and Pitt score > 1 (OR = 2.50; 95% CI = 1.25-5.00) were associated with mortality. Malignancy (OR = 2.94; 95% CI = 1.33-6.49), Pitt score > 1 (OR = 4.15; 95% CI = 1.87-9.24) and age < 72 years (OR = 2.86; 95% CI = 1.35 5.88) were associated with high treatment cost. CONCLUSIONS: The 30-day mortality and treatment cost of patients with K. pneumoniae bacteraemia were high in Hong Kong. Based upon the risk factors identified, infection control and treatment algorithms for K. pneumoniae bacteraemia in patients with malignancy or liver disease are highly warranted. PMID- 25697340 TI - Evolution of the Telomere-Associated Protein POT1a in Arabidopsis thaliana Is Characterized by Positive Selection to Reinforce Protein-Protein Interaction. AB - Gene duplication is a major driving force in genome evolution. Here, we explore the nature and origin of the POT1 gene duplication in Arabidopsis thaliana. Protection of Telomeres (POT1) is a conserved multifunctional protein that modulates telomerase activity and its engagement with telomeres. Arabidopsis thaliana encodes two divergent POT1 paralogs termed AtPOT1a and AtPOT1b. AtPOT1a positively regulates telomerase activity, whereas AtPOT1b is proposed to negatively regulate telomerase and promote chromosome end protection. Phylogenetic analysis uncovered two independent POT1 duplication events in the plant kingdom, including one at the base of Brassicaceae. Tests for positive selection implemented in PAML revealed that the Brassicaceae POT1a lineage experienced positive selection postduplication and identified three amino acid residues with signatures of positive selection. A sensitive and quantitative genetic complementation assay was developed to assess POT1a function in A. thaliana. The assay showed that AtPOT1a is functionally distinct from single-copy POT1 genes in other plants. Moreover, for two of the sites with a strong signature of positive selection, substitutions that swap the amino acids in AtPOT1a for residues found in AtPOT1b dramatically compromised AtPOT1a function in vivo. In vitro-binding studies demonstrated that all three sites under positive selection specifically enhance the AtPOT1a interaction with CTC1, a core component of the highly conserved CST (CTC1/STN1/TEN1) telomere protein complex. Our results reveal a molecular mechanism for the role of these positively selected sites in AtPOT1a. The data also provide an important empirical example to refine theories of duplicate gene retention, as the outcome of positive selection here appears to be reinforcement of an ancestral function, rather than neofunctionalization. We propose that this outcome may not be unusual when the duplicated protein is a component of a multisubunit complex whose function is in part specified by other members. PMID- 25697341 TI - Less is more: an adaptive branch-site random effects model for efficient detection of episodic diversifying selection. AB - Over the past two decades, comparative sequence analysis using codon-substitution models has been honed into a powerful and popular approach for detecting signatures of natural selection from molecular data. A substantial body of work has focused on developing a class of "branch-site" models which permit selective pressures on sequences, quantified by the omega ratio, to vary among both codon sites and individual branches in the phylogeny. We develop and present a method in this class, adaptive branch-site random effects likelihood (aBSREL), whose key innovation is variable parametric complexity chosen with an information theoretic criterion. By applying models of different complexity to different branches in the phylogeny, aBSREL delivers statistical performance matching or exceeding best in-class existing approaches, while running an order of magnitude faster. Based on simulated data analysis, we offer guidelines for what extent and strength of diversifying positive selection can be detected reliably and suggest that there is a natural limit on the optimal parametric complexity for "branch-site" models. An aBSREL analysis of 8,893 Euteleostomes gene alignments demonstrates that over 80% of branches in typical gene phylogenies can be adequately modeled with a single omega ratio model, that is, current models are unnecessarily complicated. However, there are a relatively small number of key branches, whose identities are derived from the data using a model selection procedure, for which it is essential to accurately model evolutionary complexity. PMID- 25697342 TI - No X-chromosome dosage compensation in human proteomes. AB - The X and Y chromosomes of placental and marsupial mammals originated from a pair of autosomes. Ohno proposed that the expression levels of X-linked genes must have been doubled in males to compensate for the degeneration of their Y homologs. Recent mRNA sequencing experiments, however, found at most weak or infrequent X-chromosome dosage compensation. Nonetheless, dosage compensation need not occur at the mRNA level, because ultimately it is the protein concentration that matters. Analyzing human proteomic data from 22 tissues, we here report that X upregulation is absent at the protein level, indicating that Ohno's hypothesis is also invalid at the protein level. PMID- 25697343 TI - Proliferative and signaling activities of insulin analogues in endometrial cancer cells. AB - Insulin analogues have been developed to achieve further improvement in the therapy of diabetes. However, modifications introduced into the insulin molecule may enhance their affinity for the insulin-like growth factor-1 receptor (IGF1R). Hyperinsulinemia has been identified as a risk factor for endometrial cancer. We hypothesized that insulin analogues may elicit atypical proliferative and signaling activities in endometrial cancer cells. Our results demonstrate that glargine, but not detemir, stimulated cell proliferation, displayed an anti apoptotic effect, and had a positive effect on cell cycle progression in endometrial cancer cell lines ECC-1 and USPC-1. In addition, we showed that glargine and detemir induced dual activation of the insulin receptor (INSR) and IGF1R in both cell types. Furthermore, we showed that glargine elicited signaling events that are markedly different from those induced by insulin. In conclusion, our data support the concept that, although insulin analogues were designed to display insulin-like metabolic effects, glargine and, possibly, additional analogues exhibit IGF1-like activities and, accordingly, may function as IGF1 analogues. PMID- 25697344 TI - Eicosapentaenoic acid upregulates VEGF-A through both GPR120 and PPARgamma mediated pathways in 3T3-L1 adipocytes. AB - Vascular endothelial growth factor-A (VEGF-A) released from adipocytes promotes angiogenesis; and thereby ameliorates the local hypoxia-induced adipose inflammation and insulin resistance. Here, we newly found that eicosapentaenoic acid (EPA) upregulated both mRNA expression and release of VEGF-A in mature 3T3 L1 adipocytes. Silencing mRNA of G-protein coupled receptor 120 (GPR120) and specific inhibition of peroxisome proliferator-activated receptor gamma (PPARgamma) by GW9662 respectively attenuated the EPA-induced augmentation of VEGF-A release by adipocytes. Furthermore, transfection of GPR120 gene alone and PPARgamma gene alone to HEK293 cells respectively increased the promoter activity of VEGF-A as assessed by luciferase reporter assay, which was further augmented when both genes were co-transfected. Promoter deletion analysis and chromatin immunoprecipitation assay revealed that co-transfection of GPR120 enhanced EPA induced PPARgamma binding to PPAR-response element in VEGF-A promoter region. Thus, by the synchronized activation of a membrane receptor GRP120 and a nuclear receptor PPARgamma, EPA enhances VEGF-A production in adipocytes. PMID- 25697346 TI - Nerve-stretching in the 19th century. AB - Operative nerve-stretching was first described in 1872 to relieve incurable pain from sciatica and tabes dorsalis. It became popular for 20 years and numerous articles were published on the subject. It had many complications but relief was only transient and, consequently, it fell into disuse. This paper analyses the literature, contemporary views on the benefits of nerve stretching and its influence on more recent neurological practice. PMID- 25697345 TI - Arginine vasopressin inhibits adipogenesis in human adipose-derived stem cells. AB - Intracellular Ca(2+) signaling is important for stem cell differentiation and there is evidence it may coordinate the process. Arginine vasopressin (AVP) is a neuropeptide hormone secreted mostly from the posterior pituitary gland and increases Ca(2+) signals mainly via V1 receptors. However, the role of AVP in adipogenesis of human adipose-derived stem cells (hASCs) is unknown. In this study, we identified the V1a receptor gene in hASCs and demonstrated that AVP stimulation increased intracellular Ca(2+) concentration during adipogenesis. This effect was mediated via V1a receptors, Gq-proteins and the PLC-IP3 pathway. These Ca(2+) signals were due to endoplasmic reticulum release and influx from the extracellular space. Furthermore, AVP supplementation to the adipogenic medium decreased the number of adipocytes and adipocyte marker genes during differentiation. The effect of AVP on adipocyte formation was reversed by the V1a receptor blocker V2255. These findings suggested that AVP may function to inhibit adipocyte differentiation. PMID- 25697347 TI - Illustrating microorganisms: Sir William Watson Cheyne (1852-1932) and bacteriology. AB - Sir William Watson Cheyne is largely known to medical history as Lord Lister's 'trusted assistant'.1 He spent a lifetime defending Joseph Lister's (1827-1912) antiseptic principle in the wake of scepticism and misunderstanding. However, his main contribution to Lister's work was in the embryonic field of bacteriology in the 1870s-1890s, which brought him into contact with continental researchers, particularly Robert Koch (1843-1910). In this field, Cheyne built an independent reputation as an assessor, chronicler and promoter of continental laboratory methodology. He pioneered bacteriological training in British teaching hospitals and incorporated laboratory testing into case notes as standard procedure. This paper reconsiders Cheyne's contribution to the development of bacteriology in British medicine at the end of the 19th century. It examines his motives in promoting new laboratory techniques and the methods he used to embed them in hospital procedure. It also considers how he continued to use bacteriological arguments to keep the Listerian antiseptic principle on the medical agenda well after Lister withdrew from active involvement in the field. PMID- 25697348 TI - Ludwig Edelstein (1902-1965): a German historian of medicine in North American exile and the emergence of the modern Hippocratic Oath. AB - Already emerging as an original thinker in the field of classical philology and history of medicine, German scholar Ludwig Edelstein became one of many scholars who lost his academic position when the National Socialists came to power in early 1933. This paper details his life before and after his difficult transition from Europe to North America, while reviewing the lasting significance of his translation and commentary on the Hippocratic Oath. PMID- 25697349 TI - Ludovico Maria Barbieri (1662-1728), the unknown 17th century physician. AB - During the 17th century, Ludovico Maria Barbieri from Imola, Italy, discussed the requirement of a gas, seemingly oxygen, for living beings to function. On 6 December 1680, he published his only known work 'Spiritus nitro-aerei operations in microcosmo' in which he reviewed the function of oxygen and the apparatus he used based on the use of experiments rather than just theory. The scarcity of information about his life and work has resulted usually in him being a neglected figure in Italy. In this manuscript we uncover the extant information about his life and reveal that he had been a restless spirit and a great example to the 17th century scientific method. PMID- 25697350 TI - Walter Mercer's (1891-1971) contribution to the surgical treatment of low back pain. AB - In 1936, Walter Mercer described a new method for the operative treatment of patients with spondylolisthesis. Using a transabdominal approach in two patients he inserted iliac crest bone graft into the intervertebral disc. His publication in the Edinburgh Medical Journal caused a furore as the levels operated on did not reflect the description and one of the two patients died post-operatively. However, Mercer continued to promote the operation in his textbooks. The anterior approach to the lumbar spine is now performed routinely. This paper explores Mercer's contribution to anterior spinal surgery. PMID- 25697351 TI - Dame Maud McCarthy (1859-1949): Matron-in-Chief, British Expeditionary Forces France and Flanders, First World War. AB - Emma Maud McCarthy was one of the most decorated nurses of the First World War. Born in Sydney in 1859, she trained as a nurse at The London Hospital in England. She was one of the first nurses to go to the South African War and in 1914 was one of the first members of Queen Alexandra's Imperial Nursing Service. Maud McCarthy went to France as Matron-in-Chief of British, Colonial and US nursing services until the end of hostilities in 1918. After the First World War she became Matron-in-Chief of the Territorial Army Nursing Service and retired five years later. She was appointed Dame Grand Cross in 1918 and earned awards from Britain, France, Belgium and America. Her influence on nursing was profound. One of the first senior nurses to recognise the impact of war on minds, she set up separate units for men who had self-harmed and she pioneered nurse anaesthetists in the British Armed Forces. Dame Maud McCarthy was an administrator par excellence whose determination to provide the best conditions possible for both her nurses and the men for whom they cared made possible the highest standards of nursing care in the First World War. PMID- 25697352 TI - Limitations of the trail making test part-B in assessing frontal executive dysfunction. AB - Part B of the Trail Making Test (TMT-B) is one of the most widely used neuropsychological tests of "executive" function. A commonly held assumption is that the TMT-B can be used to detect frontal executive dysfunction. However, so far, research evidence has been limited and somewhat inconclusive. In this retrospective study, performance on the TMT-B of 55 patients with known focal frontal lesions, 27 patients with focal non-frontal lesions and 70 healthy controls was compared. Completion time and the number of errors made were examined. Patients with frontal and non-frontal lesions performed significantly worse than healthy controls for both completion time and the number of errors. However, there was no significant difference for both completion time and the number of errors when patients with frontal and non-frontal lesions were compared. Performance was also not significantly different between patients with focal lesions within different regions of the frontal lobe (orbital, left lateral, right lateral, medial). Our findings suggest that the TMT-B is a robust test for detection of brain dysfunction. However, its capacity for detecting frontal executive dysfunction appears rather limited. Clinicians should be cautious when drawing conclusions from performance on the TMT-B alone. PMID- 25697353 TI - Surface-immobilised micelles via cucurbit[8]uril-rotaxanes for solvent-induced burst release. AB - The fabrication, characterisation and controlled burst release of naphthol functionalised micellar (NFM) nanostructures, which were grafted onto gold surfaces through cucurbit[8]uril (CB[8]) mediated host-guest interactions are described. NFMs undergo a facile change in morphology from micelles to diblock copolymers in direct response to exposure to organic solvents, including tetrahydrofuran (THF), toluene and chloroform. This induced transition in conformation lends itself to potential applications including nanocarriers for triggered burst-release of guest molecules. Nile Red was investigated as a NFM encapsulated model hydrophobic cargo inside the surface-attached micelles, which could be fully released upon exposure to THF as measured by both atomic force microscopy and UV/vis spectroscopy. PMID- 25697354 TI - Photodynamic therapy-mediated cancer vaccination enhances stem-like phenotype and immune escape, which can be blocked by thrombospondin-1 signaling through CD47 receptor protein. AB - Like most of the strategies for cancer immunotherapy, photodynamic therapy mediated vaccination has shown poor clinical outcomes in application. The aim of this study is to offer a glimpse at the mechanisms that are responsible for the failure based on cancer immuno-editing theory and to search for a positive solution. In this study we found that tumor cells were able to adapt themselves to the immune pressure exerted by vaccination. The survived tumor cells exhibited enhanced tumorigenic and stem-like phenotypes as well as undermined immunogenicity. Viewed as a whole, immune-selected tumor cells showed more malignant characteristics and the ability of immune escape, which might contribute to the eventual relapse. Thrombospondin-1 signaling via CD47 helped prevent tumor cells from becoming stem-like and rendered them vulnerable to immune attack. These findings prove that the TSP-1/CD47/SIRP-alpha signal axis is important to the evolution of tumor cells in the microenvironment of immunotherapy and identify thrombospondin-1 as a key signal with therapeutic benefits in overcoming long term relapse, providing new evidence for the clinical promise of cancer vaccination. PMID- 25697355 TI - Rewired metabolism in drug-resistant leukemia cells: a metabolic switch hallmarked by reduced dependence on exogenous glutamine. AB - Cancer cells that escape induction therapy are a major cause of relapse. Understanding metabolic alterations associated with drug resistance opens up unexplored opportunities for the development of new therapeutic strategies. Here, we applied a broad spectrum of technologies including RNA sequencing, global untargeted metabolomics, and stable isotope labeling mass spectrometry to identify metabolic changes in P-glycoprotein overexpressing T-cell acute lymphoblastic leukemia (ALL) cells, which escaped a therapeutically relevant daunorubicin treatment. We show that compared with sensitive ALL cells, resistant leukemia cells possess a fundamentally rewired central metabolism characterized by reduced dependence on glutamine despite a lack of expression of glutamate ammonia ligase (GLUL), a higher demand for glucose and an altered rate of fatty acid beta-oxidation, accompanied by a decreased pantothenic acid uptake capacity. We experimentally validate our findings by selectively targeting components of this metabolic switch, using approved drugs and starvation approaches followed by cell viability analyses in both the ALL cells and in an acute myeloid leukemia (AML) sensitive/resistant cell line pair. We demonstrate how comparative metabolomics and RNA expression profiling of drug-sensitive and -resistant cells expose targetable metabolic changes and potential resistance markers. Our results show that drug resistance is associated with significant metabolic costs in cancer cells, which could be exploited using new therapeutic strategies. PMID- 25697356 TI - Proapoptotic activities of protein disulfide isomerase (PDI) and PDIA3 protein, a role of the Bcl-2 protein Bak. AB - Protein disulfide isomerase (PDI) family proteins are classified as enzymatic chaperones for reconstructing misfolded proteins. Previous studies have shown that several PDI members possess potential proapoptotic functions. However, the detailed molecular mechanisms of PDI-mediated apoptosis are not completely known. In this study, we investigated how two members of PDI family, PDI and PDIA3, modulate apoptotic signaling. Inhibiting PDI and PDIA3 activities pharmacologically alleviates apoptosis induced by various apoptotic stimuli. Although a decrease of PDIA3 expression alleviates apoptotic responses, overexpression of PDIA3 exacerbates apoptotic signaling. Importantly, Bak, but not Bax, is essential for PDIA3-induced proapoptotic signaling. Furthermore, both purified PDI and PDIA3 proteins induce Bak-dependent, but not Bax-dependent, mitochondrial outer membrane permeabilization in vitro, probably through triggering Bak oligomerization on mitochondria. Our results suggest that both of PDI and PDIA3 possess Bak-dependent proapoptotic function through inducing mitochondrial outer membrane permeabilization, which provides a new mechanism linking ER chaperone proteins and apoptotic signaling. PMID- 25697357 TI - Myeloperoxidase-dependent lipid peroxidation promotes the oxidative modification of cytosolic proteins in phagocytic neutrophils. AB - Phagocytic neutrophils generate reactive oxygen species to kill microbes. Oxidant generation occurs within an intracellular phagosome, but diffusible species can react with the neutrophil and surrounding tissue. To investigate the extent of oxidative modification, we assessed the carbonylation of cytosolic proteins in phagocytic neutrophils. A 4-fold increase in protein carbonylation was measured within 15 min of initiating phagocytosis. Carbonylation was dependent on NADPH oxidase and myeloperoxidase activity and was inhibited by butylated hydroxytoluene and Trolox, indicating a role for myeloperoxidase-dependent lipid peroxidation. Proteomic analysis of target proteins revealed significant carbonylation of the S100A9 subunit of calprotectin, a truncated form of Hsp70, actin, and hemoglobin from contaminating erythrocytes. The addition of the reactive aldehyde 4-hydroxynonenal (HNE) caused carbonylation, and HNE glutathione adducts were detected in the cytosol of phagocytic neutrophils. The post-translational modification of neutrophil proteins will influence the functioning and fate of these immune cells in the period following phagocytic activation, and provides a marker of neutrophil activation during infection and inflammation. PMID- 25697358 TI - Structural and enzymatic analysis of TarM glycosyltransferase from Staphylococcus aureus reveals an oligomeric protein specific for the glycosylation of wall teichoic acid. AB - Anionic glycopolymers known as wall teichoic acids (WTAs) functionalize the peptidoglycan layers of many Gram-positive bacteria. WTAs play central roles in many fundamental aspects of bacterial physiology, and they are important determinants of pathogenesis and antibiotic resistance. A number of enzymes that glycosylate WTA in Staphylococcus aureus have recently been identified. Among these is the glycosyltransferase TarM, a component of the WTA de novo biosynthesis pathway. TarM performs the synthesis of alpha-O-N-acetylglycosylated poly-5'-phosphoribitol in the WTA structure. We have solved the crystal structure of TarM at 2.4 A resolution, and we have also determined a structure of the enzyme in complex with its substrate UDP-GlcNAc at 2.8 A resolution. The protein assembles into a propeller-like homotrimer in which each blade contains a GT-B type glycosyltransferase domain with a typical Rossmann fold. The enzymatic reaction retains the stereochemistry of the anomeric center of the transferred GlcNAc-moiety on the polyribitol backbone. TarM assembles into a trimer using a novel trimerization domain, here termed the HUB domain. Structure-guided mutagenesis experiments of TarM identify residues critical for enzyme activity, assign a putative role for the HUB in TarM function, and allow us to propose a likely reaction mechanism. PMID- 25697359 TI - p15RS/RPRD1A (p15INK4b-related sequence/regulation of nuclear pre-mRNA domain containing protein 1A) interacts with HDAC2 in inhibition of the Wnt/beta-catenin signaling pathway. AB - We previously reported that p15RS (p15INK4b-related sequence), a regulation of nuclear pre-mRNA domain containing protein, inhibited Wnt signaling by interrupting the formation of the beta-catenin.TCF4 complex. However, how p15RS functions as an intrinsic repressor to repress transcription remains unclear. In this study, we show that p15RS, through a specific interaction with HDAC2 (histone deacetylase 2), a deacetylase that regulates gene transcription, maintains histone H3 in a deacetylated state in the promoter region of Wnt targeted genes where beta-catenin.TCF4 is bound. We observed that histone deacetylase inhibitors impair the ability of p15RS in inhibiting Wnt/beta-catenin signaling. Depletion of HDAC2 markedly disabled p15RS inhibition of Wnt/beta catenin-mediated transcription. Interestingly, overexpression of p15RS decreases the level of acetylated histone H3 in the c-MYC promoter. Finally, we demonstrate that p15RS significantly enhances the association of HDAC2 and TCF4 and enhances the occupancy of HDAC2 to DNA, resulting in the deacetylation of histone H3 and the failure of beta-catenin interaction. We propose that p15RS acts as an intrinsic transcriptional repressor for Wnt/beta-catenin-mediated gene transcription at least partially through recruiting HDAC2 to occupy the promoter and maintaining deacetylated histone H3. PMID- 25697360 TI - Comparative laboratory evolution of ordered and disordered enzymes. AB - Intrinsically disordered proteins are ubiquitous in nature. To assess potential evolutionary advantages and disadvantages of structural disorder under controlled laboratory conditions, we directly compared the evolvability of weakly active ordered and disordered variants of dihydrofolate reductase by genetic selection. The circularly permuted Escherichia coli enzyme, which exists as a molten globule in the absence of ligands, and a well folded deletion mutant of the Bacillus stearothermophilus enzyme served as starting points. Both scaffolds evolved at similar rates and to similar extents, reaching near-native activity after three rounds of mutagenesis and selection. Surprisingly, however, the starting structural properties of the two scaffolds changed only marginally during optimization. Although the ordered and disordered proteins accumulated distinct sets of mutations, the changes introduced likely improved catalytic efficiency indirectly in both cases by bolstering the network of dynamic conformational fluctuations that productively couple into the reaction coordinate. PMID- 25697361 TI - BET bromodomains regulate transforming growth factor-beta-induced proliferation and cytokine release in asthmatic airway smooth muscle. AB - Airway smooth muscle (ASM) mass is increased in asthma, and ASM cells from patients with asthma are hyperproliferative and release more IL-6 and CXCL8. The BET (bromo- and extra-terminal) family of proteins (Brd2, Brd3, and Brd4) govern the assembly of histone acetylation-dependent chromatin complexes. We have examined whether they modulate proliferation and cytokine expression in asthmatic ASM cells by studying the effect of BET bromodomain mimics JQ1/SGCBD01 and I BET762. ASM cells from healthy individuals and nonsevere and severe asthmatics were pretreated with JQ1/SGCBD01 and I-BET762 prior to stimulation with FCS and TGF-beta. Proliferation was measured by BrdU incorporation. IL-6 and CXCL8 release was measured by ELISA, and mRNA expression was measured by quantitative RT-PCR. ChIP using a specific anti-Brd4 antibody and PCR primers directed against the transcriptional start site of IL-6 and CXCL8 gene promoters was performed. Neither JQ1/SGCBD01 nor I-BET762 had any effect on ASM cell viability. JQ1/SGCBD01 and I-BET762 inhibited FCS+TGF-beta-induced ASM cell proliferation and IL-6 and CXCL8 release in healthy individuals (>= 30 nM) and in nonsevere and severe asthma patients (>=100 nM), with the latter requiring higher concentrations of these mimics. JQ1/SGCBD01 reduced Brd4 binding to IL8 and IL6 promoters induced by FCS+TGF-beta. Mimics of BET bromodomains inhibit aberrant ASM cell proliferation and inflammation with lesser efficiency in those from asthmatic patients. They may be effective in reducing airway remodeling in asthma. PMID- 25697362 TI - NADPH oxidase-generated hydrogen peroxide induces DNA damage in mutant FLT3 expressing leukemia cells. AB - Internal tandem duplication of the FMS-like tyrosine kinase (FLT3-ITD) receptor is present in 20% of acute myeloid leukemia (AML) patients and it has been associated with an aggressive AML phenotype. FLT3-ITD expressing cell lines have been shown to generate increased levels of reactive oxygen species (ROS) and DNA double strand breaks (DSBs). However, the molecular basis of how FLT3-ITD-driven ROS leads to the aggressive form of AML is not clearly understood. Our group has previously reported that inhibition of FLT3-ITD signaling results in post translational down-regulation of p22(phox), a small membrane-bound subunit of the NADPH oxidase (NOX) complex. Here we demonstrated that 32D cells, a myeloblast like cell line transfected with FLT3-ITD, have a higher protein level of p22(phox) and p22(phox)-interacting NOX isoforms than 32D cells transfected with the wild type FLT3 receptor (FLT3-WT). The inhibition of NOX proteins, p22(phox), and NOX protein knockdowns caused a reduction in ROS, as measured with a hydrogen peroxide (H2O2)-specific dye, peroxy orange 1 (PO1), and nuclear H2O2, as measured with nuclear peroxy emerald 1 (NucPE1). These reductions in the level of H2O2 following the NOX knockdowns were accompanied by a decrease in the number of DNA DSBs. We showed that 32D cells that express FLT3-ITD have a higher level of both oxidized DNA and DNA DSBs than their wild type counterparts. We also observed that NOX4 and p22(phox) localize to the nuclear membrane in MV4-11 cells expressing FLT3-ITD. Taken together these data indicate that NOX and p22(phox) mediate the ROS production from FLT3-ITD that signal to the nucleus causing genomic instability. PMID- 25697363 TI - Conformational changes leading to T7 DNA delivery upon interaction with the bacterial receptor. AB - The majority of bacteriophages protect their genetic material by packaging the nucleic acid in concentric layers to an almost crystalline concentration inside protein shells (capsid). This highly condensed genome also has to be efficiently injected into the host bacterium in a process named ejection. Most phages use a specialized complex (often a tail) to deliver the genome without disrupting cell integrity. Bacteriophage T7 belongs to the Podoviridae family and has a short, non-contractile tail formed by a tubular structure surrounded by fibers. Here we characterize the kinetics and structure of bacteriophage T7 DNA delivery process. We show that T7 recognizes lipopolysaccharides (LPS) from Escherichia coli rough strains through the fibers. Rough LPS acts as the main phage receptor and drives DNA ejection in vitro. The structural characterization of the phage tail after ejection using cryo-electron microscopy (cryo-EM) and single particle reconstruction methods revealed the major conformational changes needed for DNA delivery at low resolution. Interaction with the receptor causes fiber tilting and opening of the internal tail channel by untwisting the nozzle domain, allowing release of DNA and probably of the internal head proteins. PMID- 25697364 TI - Differential proteome-metabolome profiling of YCA1-knock-out and wild type cells reveals novel metabolic pathways and cellular processes dependent on the yeast metacaspase. AB - The yeast Saccharomyces cerevisiae expresses one member of the metacaspase Cys protease family, encoded by the YCA1 gene. Combination of proteomics and metabolomics data showed that YCA1 deletion down-regulated glycolysis, the TCA cycle and alcoholic fermentation as compared with WT cells. Deltayca1 cells also showed a down-regulation of the pentose phosphate pathway and accumulation of pyruvate, correlated with higher levels of certain amino acids found in these cells. Accordingly, there is a decrease in protein biosynthesis, and up regulation of specific stress response proteins like Ahp1p, which possibly provides these cells with a better protection against stress. Moreover, in agreement with the down-regulation of protein biosynthesis machinery in Deltayca1 cells, we have found that regulation of transcription, co-translational protein folding and protein targeting to different subcellular locations were also down regulated. Metabolomics analysis of the nucleotide content showed a significant reduction in Deltayca1 cells in comparison with the WT, except for GTP content which remained unchanged. Thus, our combined proteome-metabolome approach added a new dimension to the non-apoptotic function of yeast metacaspase, which can specifically affect cell metabolism through as yet unknown mechanisms and possibly stress-response pathways, like HOG and cell wall integrity pathways. Certainly, YCA1 deletion may induce compensatory changes in stress response proteins offering a better protection against apoptosis to Deltayca1 cells rather than a loss in pro-apoptotic YCA1-associated activity. PMID- 25697365 TI - Meta-analysis of porcine circovirus type 2 (PCV2) vaccines. PMID- 25697366 TI - Oligoclonal bands and increased cytokine levels in idiopathic intracranial hypertension. AB - OBJECTIVES: The pathogenesis of idiopathic intracranial hypertension (IIH) is currently unknown and there are speculations about the contribution of some immunologic factors. The aim of this study is to investigate the presence of oligoclonal bands (OCBs) and cerebrospinal fluid (CSF) and/or serum cytokine levels in patients with IIH. METHODS: Patients fulfilling revised diagnostic criteria for IIH were included. Their demographic, clinical, ophthalmologic and laboratory features were examined. Serum and CSF samples were detected by isoelectric focusing and immunoblotting for OCBs. The samples of IIH patients and control groups were investigated by ELISA for cytokine levels. RESULTS: We detected OCBs in eight (30.77%) patients diagnosed with IIH. There were no other obvious clinical and laboratory differences of IIH profiles between the patients with and without OCBs, but frequency of vision loss was significantly higher in the group with OCBs in comparison to OCB negatives (p = 0.038). Patients with IIH had highly elevated TNF-alpha, IFN-gamma, IL-4, IL-10, IL-12, IL-17 in their sera compared to patients with multiple sclerosis (MS) and healthy controls. Furthermore, all cytokines except TNF-alpha in the CSF were found significantly higher in IIH patients compared to MS controls. CONCLUSION: The presence of OCBs and elevated cytokine levels in IIH patients may support an immunologic background in the pathophysiological pathway of this disorder. PMID- 25697367 TI - Lipid-based nanoformulations for active delivery. PMID- 25697368 TI - Emulsomes meet S-layer proteins: an emerging targeted drug delivery system. AB - Here, the use of emulsomes as a drug delivery system is reviewed and compared with other similar lipidic nanoformulations. In particular, we look at surface modification of emulsomes using S-layer proteins, which are self-assembling proteins that cover the surface of many prokaryotic organisms. It has been shown that covering emulsomes with a crystalline S-layer lattice can protect cells from oxidative stress and membrane damage. In the future, the capability to recrystallize S-layer fusion proteins on lipidic nanoformulations may allow the presentation of binding functions or homing protein domains to achieve highly specific targeted delivery of drug-loaded emulsomes. Besides the discussion on several designs and advantages of composite emulsomes, the success of emulsomes for the delivery of drugs to fight against viral and fungal infections, dermal therapy, cancer, and autoimmunity is summarized. Further research might lead to smart, biocompatible emulsomes, which are able to protect and reduce the side effects caused by the drug, but at the same time are equipped with specific targeting molecules to find the desired site of action. PMID- 25697369 TI - Polydiacetylene nanovesicles as carriers of natural phenylpropanoids for creating antimicrobial food-contact surfaces. AB - The ultimate goal of this study was developing antimicrobial food-contact materials based on natural phenolic compounds using nanotechnological approaches. Among the methyl-beta-cyclodextrin-encapsulated phenolics tested, curcumin showed by far the highest activity toward Escherichia coli with a minimum inhibitory concentration of 0.4 mM. Curcumin was enclosed in liposome-type polydiacetylene/phosholipid nanovesicles supplemented with N-hydroxysuccinimide and glucose. The fluorescence spectrum of the nanovesicles suggested that curcumin was located in their bilayer region. Free-suspended nanovesicles tended to bind to the bacterial surface and demonstrated bactericidal activity toward Gram-negative (E. coli) and vegetative cells of Gram-positive (Bacillus cereus) bacteria reducing their counts from 5 log CFU mL(-1) to an undetectable level within 8 h. The nanovesicles were covalently bound to silanized glass. Incubation of E. coli and B. cereus with nanovesicle-coated glass resulted in a 2.5 log reduction in their counts. After optimization this approach can be used for controlling microbial growth, cross-contamination, and biofilm formation on food contacting surfaces. PMID- 25697370 TI - Multilevel Dynamic Generalized Structured Component Analysis for Brain Connectivity Analysis in Functional Neuroimaging Data. AB - We extend dynamic generalized structured component analysis (GSCA) to enhance its data-analytic capability in structural equation modeling of multi-subject time series data. Time series data of multiple subjects are typically hierarchically structured, where time points are nested within subjects who are in turn nested within a group. The proposed approach, named multilevel dynamic GSCA, accommodates the nested structure in time series data. Explicitly taking the nested structure into account, the proposed method allows investigating subject wise variability of the loadings and path coefficients by looking at the variance estimates of the corresponding random effects, as well as fixed loadings between observed and latent variables and fixed path coefficients between latent variables. We demonstrate the effectiveness of the proposed approach by applying the method to the multi-subject functional neuroimaging data for brain connectivity analysis, where time series data-level measurements are nested within subjects. PMID- 25697371 TI - A Latent Transition Analysis Model for Latent-State-Dependent Nonignorable Missingness. AB - Psychologists often use latent transition analysis (LTA) to investigate state-to state change in discrete latent constructs involving delinquent or risky behaviors. In this setting, latent-state-dependent nonignorable missingness is a potential concern. For some longitudinal models (e.g., growth models), a large literature has addressed extensions to accommodate nonignorable missingness. In contrast, little research has addressed how to extend the LTA to accommodate nonignorable missingness. Here we present a shared parameter LTA that can reduce bias due to latent-state-dependent nonignorable missingness: a parallel-process missing-not-at-random (MNAR-PP) LTA. The MNAR-PP LTA allows outcome process parameters to be interpreted as in the conventional LTA, which facilitates sensitivity analyses assessing changes in estimates between LTA and MNAR-PP LTA. In a sensitivity analysis for our empirical example, previous and current membership in high-delinquency states predicted adolescents' membership in missingness states that had high nonresponse probabilities for some or all items. A conventional LTA overestimated the proportion of adolescents ending up in a low delinquency state, compared to an MNAR-PP LTA. PMID- 25697372 TI - Gender difference in treatment and mortality of patients with ST-segment elevation myocardial infarction admitted to Victorian public hospitals: a retrospective database study. AB - BACKGROUND: Death from acute coronary syndrome (ACS) is avoidable with early reperfusion therapy, however, evidence suggests inequity in women's ACS treatment within a number of international healthcare systems, when compared to men's. Research indicates mortality rates are higher in some age groups of women when compared to men for the sub-group of ACS known as ST-segment elevation myocardial infarction (STEMI). OBJECTIVE: To determine whether patient sex was associated with patterns of reperfusion treatment variation or increased inhospital mortality in patients with STEMI. METHODS: We undertook retrospective analyses on a government database for patients admitted to Victorian public hospitals with STEMI. Patients were categorised into two age groups: 18-64 and 65-84 years (inclusive), to determine whether patient sex and these age groups influenced treatment from 2005 to 2008 and mortality from 2005 to 2010. RESULTS: Both younger and older women received less frequent angioplasty with stent and more often received no reperfusion treatment than men in corresponding younger and older age groups (p=0.006 and p<0.001, respectively). Overall, women in both age groups were more likely to die inhospital than men from equivalent age groups with STEMI (p<0.001, both groups). CONCLUSIONS: Proportionately, both younger and older women received less interventional reperfusion therapy for STEMI than their male cohorts, and died more often during admission than men. Further research needs to be undertaken to verify the findings and causes, and guide future research to ensure application of evidence to treatment in patients with STEMI. PMID- 25697373 TI - Ultra-high adsorption capacity of zeolitic imidazole framework-67 (ZIF-67) for removal of malachite green from water. AB - Zeolitic imidazole frameworks (ZIFs), a new class of adsorbents, are proposed to adsorb Malachite Green (MG) in water. Particularly, ZIF-67 was selected owing to its stability in water and straightforward synthesis. The as-synthesized ZIF-67 was characterized and used to adsorb MG from water. Factors affecting the adsorption capacity were investigated including mixing time, temperature, the presence of salts and pH. The kinetics, adsorption isotherm and thermodynamics of the MG adsorption to ZIF-67 were also studied. The adsorption capacity of ZIF-67 for MG could be as high as 2430mgg(-1) at 20 degrees C, which could be improved at the higher temperatures. Such an ultra-high adsorption capacity of ZIF-67 was almost 10-times of those of conventional adsorbents, including activated carbons and biopolymers. A mechanism for the high adsorption capacity was proposed and possibly attributed to the pi-pi stacking interaction between MG and ZIF-67. ZIF 67 also could be conveniently regenerated by washing with ethanol and the regeneration efficiency could remain 95% up to 4 cycles of the regeneration. ZIF 67 was also able to remove MG from the aquaculture wastewater, in which MG can be typically found. These features enable ZIF-67 to be one of the most effective and promising adsorbent to remove MG from water. PMID- 25697374 TI - Macular pigment spatial distribution effects on glare disability. AB - PURPOSE: This project explored the relationship of the macular pigment optical density (MPOD) spatial profile with measures of glare disability (GD) across the macula. METHODS: A novel device was used to measure MPOD across the central 16 degrees of retina along four radii using customized heterochromatic flicker photometry (cHFP)at eccentricities of 0 degrees , 2 degrees , 4 degrees , 6 degrees and 8 degrees . MPOD was measured as discrete and integrated values at all measured retinal loci. GD was calculated as a difference in contrast sensitivity (CS) between no glare and glare conditions using identical stimuli presented at the same eccentricities. GD was defined as [(CSNo Glare CSGlare)/CSNo Glare] in order to isolate the glare attenuation effects of MPOD by controlling for CS variability among the subject sample. Correlations of the discrete and integrated MPOD with GD were compared. RESULTS: The cHFP identified reliable MPOD spatial distribution maps demonstrating a 1st-order exponential decay as a function of increasing eccentricity. There was a significant negative correlation between both measures of foveal MPOD and GD using 6 cycles per degree (cpd) and 9 cpd stimuli. Significant correlations were found between corresponding parafoveal MPOD measures and GD at 2 and 4 degrees of eccentricity using 9 cpd stimuli with greater MPOD associated with less glare disability. CONCLUSIONS: These results are consistent with the glare attenuation effects of MP at higher spatial frequencies and support the hypothesis that discrete and integrated measures of MPOD have similar correlations with glare attenuation effects across the macula. Additionally, peak foveal MPOD appears to influence GD across the macula. PMID- 25697375 TI - Permanent uncoupling of male-specific CYP2C11 transcription/translation by perinatal glutamate. AB - Perinatal exposure of rats and mice to the typically reported 4mg/g bd wt dose of monosodium glutamate (MSG) results in a complete block in GH secretion as well as obesity, growth retardation and a profound suppression of several cytochrome P450s, including CYP2C11, the predominant male-specific isoform--all irreversible effects. In contrast, we have found that a lower dose of the food additive, 2mg/g bd wt on alternate days for the first 9days of life results in a transient neonatal depletion of plasma GH, a subsequent permanent overexpression of CYP2C11 as well as subnormal (mini) GH pulse amplitudes in an otherwise normal adult masculine episodic GH profile. The overexpressed CYP2C11 was characterized by a 250% increase in mRNA, but only a 40 to 50% increase in CYP2C11 protein and its catalytic activity. Using freshly isolated hepatocytes as well as primary cultures exposed to the masculine-like episodic GH profile, we observed normal induction, activation, nuclear translocation and binding to the CYP2C11 promoter of the GH-dependent signal transducers required for CYP2C11 transcription. The disproportionately lower expression levels of CYP2C11 protein were associated with dramatically high expression levels of an aberrant, presumably nontranslated CYP2C11 mRNA, a 200% increase in CYP2C11 ubiquitination and a 70-80% decline in miRNAs associated, at normal levels, with a suppression of CYP2C expression. Whereas the GH-responsiveness of CYP2C7 and CYP2C6 as well as albumin was normal in the MSG-derived hepatocytes, the abnormal expression of CYP2C11 was permanent and irreversible. PMID- 25697376 TI - Metformin inhibits 7,12-dimethylbenz[a]anthracene-induced breast carcinogenesis and adduct formation in human breast cells by inhibiting the cytochrome P4501A1/aryl hydrocarbon receptor signaling pathway. AB - Recent studies have established that metformin (MET), an oral anti-diabetic drug, possesses antioxidant activity and is effective against different types of cancer in several carcinogen-induced animal models and cell lines. However, whether MET can protect against breast cancer has not been reported before. Therefore, the overall objectives of the present study are to elucidate the potential chemopreventive effect of MET in non-cancerous human breast MCF10A cells and explore the underlying mechanism involved, specifically the role of cytochrome P4501A1 (CYP1A1)/aryl hydrocarbon receptor (AhR) pathway. Transformation of the MCF10A cells into initiated breast cancer cells with DNA adduct formation was conducted using 7,12-dimethylbenz[a]anthracene (DMBA), an AhR ligand. The chemopreventive effect of MET against DMBA-induced breast carcinogenesis was evidenced by the capability of MET to restore the induction of the mRNA levels of basic excision repair genes, 8-oxoguanine DNA glycosylase (OGG1) and apurinic/apyrimidinic endonuclease1 (APE1), and the level of 8-hydroxy-2 deoxyguanosine (8-OHdG). Interestingly, the inhibition of DMBA-induced DNA adduct formation was associated with proportional decrease in CYP1A1 and in NAD(P)H: quinone oxidoreductase 1 (NQO1) gene expression. Mechanistically, the involvements of AhR and nuclear factor erythroid 2-related factor-2 (Nrf2) in the MET-mediated inhibition of DMBA-induced CYP1A1 and NQO1 gene expression were evidenced by the ability of MET to inhibit DMBA-induced xenobiotic responsive element and antioxidant responsive element luciferase reporter gene expression which suggests an AhR- and Nrf2-dependent transcriptional control. However, the inability of MET to bind to AhR suggests that MET is not an AhR ligand. In conclusion, the present work shows a strong evidence that MET inhibits the DMBA mediated carcinogenicity and adduct formation by inhibiting the expression of CYP1A1 through an AhR ligand-independent mechanism. PMID- 25697377 TI - Genome-wide DNA methylation identifies trophoblast invasion-related genes: Claudin-4 and Fucosyltransferase IV control mobility via altering matrix metalloproteinase activity. AB - Previously we showed that extravillous cytotrophoblast (EVT) outgrowth and migration on a collagen gel explant model were affected by exposure to decidual natural killer cells (dNK). This study investigates the molecular causes behind this phenomenon. Genome wide DNA methylation of exposed and unexposed EVT was assessed using the Illumina Infinium HumanMethylation450 BeadChip array (450 K array). We identified 444 differentially methylated CpG loci in dNK-treated EVT compared with medium control (P < 0.05). The genes associated with these loci had critical biological roles in cellular development, cellular growth and proliferation, cell signaling, cellular assembly and organization by Ingenuity Pathway Analysis (IPA). Furthermore, 23 mobility-related genes were identified by IPA from dNK-treated EVT. Among these genes, CLDN4 (encoding claudin-4) and FUT4 (encoding fucosyltransferase IV) were chosen for follow-up studies because of their biological relevance from research on tumor cells. The results showed that the mRNA and protein expressions of both CLDN4 and FUT4 in dNK-treated EVT were significantly reduced compared with control (P < 0.01 for both CLDN4 and FUT4 mRNA expression; P < 0.001 for CLDN4 and P < 0.01 for FUT4 protein expression), and were inversely correlated with DNA methylation. Knocking down CLDN4 and FUT4 by small interfering RNA reduced trophoblast invasion, possibly through the altered matrix metalloproteinase (MMP)-2 and/or MMP-9 expression and activity. Taken together, dNK alter EVT mobility at least partially in association with an alteration of DNA methylation profile. Hypermethylation of CLDN4 and FUT4 reduces protein expression. CLDN4 and FUT4 are representative genes that participate in modulating trophoblast mobility. PMID- 25697378 TI - PLLA nanofibrous paper-based plasmonic substrate with tailored hydrophilicity for focusing SERS detection. AB - We report a new paper-based surface enhanced Raman scattering (SERS) substrate platform contributed by a poly(l-lactic acid) (PLLA) nanofibrous paper adsorbed with plasmonic nanostructures, which can circumvent many challenges of the existing SERS substrates. This PLLA nanofibrous paper has three-dimensional porous structure, extremely clean surface with good hydrophobicity (contact angle is as high as 133.4 degrees ), and negligible background interference under Raman laser excitation. Due to the strong electrostatic interaction between PLLA nanofiber and cetyltrimethylammonium bromide (CTAB) molecules, the CTAB-coated gold nanorods (GNRs) are efficiently immobilized onto the fibers. Such a hydrophobic paper substrate with locally hydrophilic SERS-active area can confine analyte molecules and prevent the random spreading of molecules. The confinement leads to focusing effect and the GNRs-PLLA SERS substrate is found to be highly sensitive (0.1 nM Rhodamine 6G and malachite green) and exhibit excellent reproducibility (~8% relative standard deviation (RSD)) and long-term stability. Furthermore, it is also cost-efficient, with simple fabrication methodology, and demonstrates high sample collection efficiency. All of these benefits ensure that this GNRs-PLLA substrate is a really perfect choice for a variety of SERS applications. PMID- 25697379 TI - The effects of yoga on the quality of life and depression in elderly breast cancer patients. AB - OBJECTIVE: The aim of the study was to investigate the effects of yoga on the quality of life in patients with cancer. DESIGN: Twenty patients (10 were in yoga program, 10 were in exercise group) between 65 and 70 years of age under going treatment for cancer were included in the study. Physical characteristics of the patients were recorded and general physiotherapy assessments performed. Eight sessions of a classical yoga program including warming and breathing exercises, asanas, relaxation in supine position, and meditation and 8 sessions of classical exercise program were applied to participants. MAIN OUTCOME MEASURES: Before and after yoga and exercise program, quality of life assessments for the patients were conducted using the Nottingham Health Profile (NHP). Patients' depression levels were assessed using the Beck Depression Inventory. Their level of pain, fatigue and sleep quality was evaluated using the visual analog scale (VAS). RESULTS: It was found that all patients' quality of life scores after the yoga and exercise program were better than scores obtained before the yoga and exercise program (p < 0.05). When the post treatment data of the groups were compared in terms of NHP and subcategories, ER, SI, S, PA and the total scores of NHP were found significantly different in favor of Group I (p < 0.05). However EL and P scores of the NHP were not different between the groups (p > 0.05). When the groups were compared in terms of depression, pain, fatigue, and sleep quality, statistically significant differences were found in all parameters between pre and post treatment values for both groups (p < 0.05). When the post treatment values of the groups were compared, fatigue and sleep quality were found statistically different between the groups in favor of Group I (p < 0.05). CONCLUSIONS: It can be concluded that yoga is valuable in helping to diminish depression, pain, fatigue and helps cancer patients to perform daily and routine activities, and increases the quality of life in elderly patients with breast cancer. PMID- 25697380 TI - Complementary medicines in medicine: Conceptualising terminology among Australian medical students using a constructivist grounded theory approach. AB - Terminology around the use of complementary medicines (CM) within medical discourse is ambiguous. Clear collective discourse within the medical context is required. This study reports the findings of a Constructivist Grounded Theory Method study used to explore medical students' conceptualisation of terminology and associated value components around CMs as evidenced within their discourse community. The results show that terminology surrounding CMs within medicine is politically charged and fraught with value judgements. Terms used to describe CMs were considered, many of which were deemed problematic. Categorisation of specific medicines was also deemed inappropriate in certain contexts. Conceptualisation of CM terminology, categorisation and value implications, discriminated between levels of evidence for CMs and provided insights into the social change of medicine towards emergence of an evidence-based integrative approach. The results show that terminology surrounding CM is a social construct consistent with fluid conceptualisation and operationalisation in different social contexts. PMID- 25697381 TI - Split latissimus dorsi muscle flap repair of acquired, nonmalignant, intrathoracic tracheoesophageal and bronchoesophageal fistulas. AB - The development of a fistula between the tracheobronchial tree and oesophagus due to nonmalignant causes is uncommon. Division of the fistula with muscle flap interposition eliminates contact between the tracheobronchial segment and the oesophagus, theoretically decreasing the chance of recurrence as well as providing a robust blood supply to aid in healing. The split latissimus dorsi muscle flap is a well-suited flap for such repairs because of the ability to simultaneously cover two separate apertures (tracheobronchial and oesophageal). The authors describe the split latissimus dorsi muscle flap with step-by-step technique for repair of intrathoracic aerodigestive fistulas. PMID- 25697382 TI - Prognostic Significance of Peri-procedural Myocardial Infarction in the Era of High Sensitivity Troponin: A Validation of the Joint ACCF/AHA/ESC/WHF Universal Definition of Type 4a Myocardial Infarction with High Sensitivity Troponin T. AB - AIMS: This study aims to validate the joint ACCF/AHA/ESC/WHF Universal Definition of peri-procedural myocardial infarction (PMI) with high sensitivity troponin T (hsTnT). METHODS: A retrospective cohort study encompassing patients admitted to our institution between May 2012 and April 2013 was performed. RESULTS: 630 patients underwent percutaneous coronary interventions during the study period. Among them, 459 patients met the inclusion criteria and were eligible for analyses. 76.9% of these patients were male, while the mean age was 68.6. PMI was observed in 4.3% of the patients based on the Universal Definition. The predictors of PMI were chronic kidney disease (OR: 3.0, p=0.026), family history of cardiovascular disease (OR: 2.7, p=0.043) and use of IIb/IIIa inhibitors (OR 4.2, p=0.01). MACE was reported in 4.4% of the patients at 12 months, and was significantly and independently associated with PMI (OR 7.3, p=0.003) in a multivariate model which accounted for lesion complexity, patients' baseline clinical information, dual-antiplatelet status at follow-up and various procedural characteristics. The post-procedural hsTnT was much higher in those who suffered MACE than those who did not (156 v.s. 43 ng/L, p<0.001). CONCLUSION: PMI as defined by the current Universal Definition using hsTnT is an independent predictor of adverse clinical outcome at 12 months in patients undergoing PCI. Accordingly, PMI remains a clinically relevant factor in current practice and should be considered a key outcome measure in clinical trials and a potential target for therapy. PMID- 25697383 TI - Delivery of a Small-For-Gestational-Age Infant and Risk of Maternal Cardiovascular Disease--A Population-Based Record Linkage Study. AB - BACKGROUND: Delivery of small for gestational age (SGA) infants has been associated with increased risk of future maternal cardiovascular disease (CVD). However, whether the risk increases progressively with the greater severity of SGA and number of SGA infants has not been explored. METHODS: A population-based record linkage study was conducted among 812,732 women delivering live born, singleton infants at term between 1994 and 2011 in New South Wales, Australia. Birth records were linked to the mothers' subsequent hospitalisation or death records to identify CVD events (coronary heart disease, cerebrovascular events, and chronic heart failure) after a median of 7.4 years. Cox proportional hazard regression was used to estimate adjusted hazard ratios (AHR) [95% confidence interval (CI)] for the associations between the severity (moderate or extreme) of SGA and number of SGA infants and subsequent risk of maternal CVD, accounting for maternal age at last birth, socioeconomic status, parity, smoking, (pre gestational and gestational) diabetes, and (chronic and pregnancy) hypertension. RESULTS: Compared to mothers of non-SGA infants, AHRs [95%CI] of CVD among mothers of moderately and extremely SGA infants were 1.36 [1.23-1.49], and 1.66 [1.47-1.87], respectively, while AHRs among mothers with 1, 2, and >=3 SGA infants were 1.42 [1.30-1.54], 1.65 [1.34-2.03], and 2.42 [1.52-3.85], respectively, indicating a dose-response relationship. AHRs of specific CVD categories showed a similar pattern. CONCLUSIONS: Delivery of an SGA infant was associated with a dose-dependent increase in the risk of maternal CVD according to both the severity of SGA and number of previous SGA infants. PMID- 25697384 TI - Measure the Vascular Flow Volume rather than Vascular Stenosis and Pressure Gradient. AB - We aimed to investigate the extent to which measurements of flow volume (FV) with colour flow duplex ultrasonography (CDU) could predict tissue perfusion. A 68 year-old male patient was admitted to our clinic complaining of intermittent claudication in the right leg. Digital subtraction angiography showed total occlusion of the right femoral artery. The right popliteal artery (PA) was filling by collaterals. CDU showed that the FV in the right PA was higher than in the left. Arterial-venous FV measurement with CDU should be performed rather than the detection of arterial stenosis to assess whether intervention is necessary. PMID- 25697385 TI - Successful Heart Transplant after Ten Hours Out-of-body Time using the TransMedics Organ Care System. AB - OBJECTIVE: We report the successful transplantation of a heart following an out of-body time of 611 minutes into a recipient with dilated cardiomyopathy and left ventricular assist device implant. PATIENTS: Our patient was urgently waiting for a cardiac transplant whilst receiving LVAD support. Recurrent VF and repeated AICD shocks necessitated this action. RESULTS: Although requiring ECMO and inotropic support in the first 17 hours post-transplant, the patient was discharged from hospital on day 15 post-transplant with normal cardiac function. CONCLUSION: We report some of the salient points of the process and discuss the utility of this technology to an Australian transplant unit. PMID- 25697386 TI - Endobronchial biopsies on aspirin and prasugrel. AB - Patients are generally required to stop antiplatelet therapy prior to elective invasive procedures. Some patients receive dual antiplatelet therapy for recent vascular procedures such as drug-eluting coronary stenting, and early discontinuation of antiplatelet agents could lead to a significant risk of stent thrombosis. Most bronchoscopic procedures are performed on patients using Aspirin but not on those using Clopidogrel or Prasugrel. In this report, we describe a unique case of a patient with a recent placement of drug-eluting stents, who required endobronchial biopsies for evaluation of lung cancer recurrence. The procedure was performed successfully and safely with no complications. PMID- 25697387 TI - Terminal-stage prognostic analysis in candidemia. AB - BACKGROUND: Candidemia has an extremely high mortality rate but is not always the direct cause of death. Therefore, determining the effect of candidemia on death is extremely difficult. METHODS: We investigated prognostic factors in patients with culture-proven candidemia at 2 Japanese university teaching hospitals from April 2009 through May 2013. To examine the effects of comorbid conditions, the Charlson comorbidity index was determined, and patients were subjectively classified into 3 clinical prognostic stages (terminal [death expected within 1 month], semiterminal [death expected within 6 months], and nonterminal [expected to live more than 6 months]). The Cox proportional hazard model was used for univariate and multivariate analyses of factors possibly affecting survival. RESULTS: On univariate analysis, factors identified as associated with an increased mortality rate were: admission to an internal medicine department, Candida glabrata, immunosuppression, hypotension, hypoxemia, and a terminal prognostic stage. Factors associated with a decreased mortality rate were: serum albumin, endophthalmitis investigation, and nonterminal prognostic stage. The mortality rate was significantly related to the prognostic stage on multivariate analysis (P < 0.0001), was increased by age (P = 0.0014), and was decreased by a delayed start of antifungal therapy (P = 0.0374). CONCLUSION: In contrast to earlier studies, the present study has found that later antifungal usage is associated with a decreased mortality rate in cases of candidemia. More important than candidemia in causing the deaths of patients with candidemia were the patients' background and comorbidity status. Therefore, rigorous methods should be used when investigating causes of death in terminally ill patients with candidemia. PMID- 25697388 TI - Converting campus waste into renewable energy - a case study for the University of Cincinnati. AB - This paper evaluates the implementation of three waste-to-energy projects at the University of Cincinnati: waste cooking oil-to-biodiesel, waste paper-to-fuel pellets and food waste-to-biogas, respectively. The implementation of these waste to-energy (WTE) projects would lead to the improvement of campus sustainability by minimizing waste management efforts and reducing GHG emissions via the displacement of fossil fuel usage. Technical and economic aspects of their implementation were assessed and the corresponding GHG reduction was estimated. Results showed that on-site implementation of these projects would: (1) divert 3682L (974 gallons) of waste cooking oil to 3712L (982 gallons) of biodiesel; (2) produce 138tonnes of fuel pellets from 133tonnes of waste paper (with the addition of 20.75tonnes of plastics) to replace121tonnes of coal; and (3) produce biogas that would be enough to replace 12,767m(3) natural gas every year from 146tonnes of food waste. The economic analysis determined that the payback periods for the three projects would be 16months for the biodiesel, 155months for the fuel pellet, and 74months for the biogas projects. The reduction of GHG emission from the implementation of the three WTE projects was determined to be 9.37 (biodiesel), 260.49 (fuel pellets), and 11.36 (biogas) tonnes of CO2-eq per year, respectively. PMID- 25697389 TI - Recovery potential of German sewage sludge ash. AB - Incineration of sewage sludge is expected to increase in the future due to growing concerns about the direct use of sludge in agriculture. Sewage sludge is the pollutant sink of wastewater treatment and thus loaded with contaminants that might pose environmental hazards. Incineration degrades organic pollutants efficiently, but since the ash is currently mostly disposed of, all valuable component like phosphorus (P) and technologically relevant metals present in the sewage sludge ash (SSA) are removed from the economic cycle entirely. We conducted a complete survey of SSA from German mono-incineration facilities and determined the theoretical recovery potential of 57 elements. German SSA contains up to 19,000 t/a P which equals approximately 13% of phosphorus applied in the German agriculture in form of phosphate rock based mineral fertilizers. Thus, SSA is an important secondary resource of P. However, its P-solubility in ammonium citrate solution, an indicator for the bioavailability, is only about 26%. Treatment of SSA is recommended to enhance P bioavailability and remove heavy metals before it is applied as fertilizer. The recovery potential for technologically relevant metals is generally low, but some of these elements might be recovered efficiently in the course of P recovery exploiting synergies. PMID- 25697390 TI - A cytoplasmic helix is required for pentamer formation of the Escherichia coli MscL mechanosensitive channel. AB - Many membrane proteins such as ion channels are oligomers, but the determinants of the degree of oligomerization are not fully understood. Mechanosensitive channel with large conductance (MscL), which is ubiquitous in bacteria, is a homopentamer with two transmembrane helices and a cytoplasmic helix in each subunit. The carboxyl-terminal cytoplasmic helices assemble into a pentameric bundle that resembles cartilage oligomeric matrix protein. To address the role of cytoplasmic helices in the pentamer formation of Escherichia coli MscL, we generated MscL constructs with various deletions at the carboxyl terminus and translated them in a cell-free system. Deletions of Leu-129 and the downstream sequence resulted in formation of various oligomers without preference to pentamers, suggesting that nearly the whole cytoplasmic helix is required for MscL pentamer formation. PMID- 25697391 TI - We need a Public Health Act fit for 21st century. PMID- 25697392 TI - Collaborative tuberculosis strategy for England. PMID- 25697393 TI - The NR2B antagonist, ifenprodil, corrects the l-DOPA-induced deficit of bilateral movement and reduces c-Fos expression in the subthalamic nucleus of hemiparkinsonian rats. AB - The use of NR2B antagonists in Parkinsonism is still controversial. To examine their anti-parkinsonian effects, the NR2B antagonist, ifenprodil, and L-DOPA were administered together and separately in hemiparkinsonian rats (hemi-PD) that were subjected to a cylinder test. Recovery from hypoactivity was achieved by single administration of 3-7 mg/kg of L-DOPA; however, improvement in the deficit of bilateral forelimb use was not observed. When administered alone, ifenprodil had no anti-parkinsonian effects; however, combined administration of ifenprodil and 7 mg/kg of L-DOPA significantly reversed the deficit of bilateral forelimb use without adversely affecting the L-DOPA-induced improvement in motor activity. Next, in order to identify the brain area influenced by L-DOPA and ifenprodil, quantitative analysis of L-DOPA-induced c-Fos immunoreactivity was performed in various brain areas of hemi-PD following administration of L-dopa with and without ifenprodil. Among brain areas with robust c-Fos expression within the motor loop circuit in dopamine-depleted hemispheres, co-administered ifenprodil markedly attenuated L-DOPA-induced c-Fos expression in only the subthalamic nucleus (STN), suggesting that the STN is the primary target for the anti parkinsonian action of NR2B antagonists. PMID- 25697394 TI - Modulation of spinal glial reactivity by intrathecal PPF is not sufficient to inhibit mechanical allodynia induced by nerve crush. AB - Spinal glial reactivity has been strongly implicated in pain that follows peripheral nerve injury. Among the many therapeutic agents that have been tested for anti-allodynia through immune modulation is the atypical methylxanthine propentofylline. While propentofylline shows a potent anti-allodynia effect after nerve transection injury, we here demonstrate that, when propentofylline is used intrathecally at the effective immune-modulatory dose, allodynia after rat nerve crush injury is completely preserved. Microglial/macrophage Iba-1 and astrocytic GFAP expression, increased in the dorsal horn of nerve crushed animals, was, however, effectively attenuated by propentofylline. Effective modulation of spinal glial reactivity is, thus, no assurance for anti-allodynia. PMID- 25697395 TI - Neuroanatomical and behavioral deficits in mice haploinsufficient for Pericentriolar material 1 (Pcm1). AB - The pericentriolar material (PCM) is composed of proteins responsible for microtubule nucleation/anchoring at the centrosome, some of which have been associated with genetic susceptibility to schizophrenia. Here, we show that mice haploinsufficient for Pericentriolar material 1 (Pcm1(+/-)), which encodes a component of the PCM found to bear rare loss of function mutations in patients with psychiatric illness, manifest neuroanatomical phenotypes and behavioral abnormalities. Using ex vivo magnetic resonance imaging of the Pcm1(+/-) brain, we detect reduced whole brain volume. Pcm1 mutant mice show impairment in social interaction, specifically in the social novelty phase, but not in the sociability phase of the three-chamber social interaction test. In contrast, Pcm1(+/-) mice show normal preference for a novel object, suggesting specific impairment in response to novel social stimulus. In addition, Pcm1(+/-) mice display significantly reduced rearing activity in the open field. Pcm1(+/-) mice behave normally in the elevated plus maze, rotarod, prepulse inhibition, and progressive ratio tests. Together, our results suggest that haploinsufficiency at the Pcm1 locus can induce a range of neuroanatomical and behavioral phenotypes that support the candidacy of this locus in neuropsychiatric disorders. PMID- 25697397 TI - Lack of ceramide synthase 2 suppresses the development of experimental autoimmune encephalomyelitis by impairing the migratory capacity of neutrophils. AB - Ceramide synthases (CerS) synthesise ceramides of defined acyl chain lengths, which are thought to mediate cellular processes in a chain length-dependent manner. In experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), we observed a significant elevation of CerS2 and its products, C24-ceramides, in CD11b(+) cells (monocytes and neutrophils) isolated from blood. This result correlates with the clinical finding that CerS2 mRNA expression and C24-ceramide levels were significantly increased by 2.2- and 1.5 fold, respectively, in white blood cells of MS patients. The increased CerS2 mRNA/C24-ceramide expression in neutrophils/monocytes seems to mediate pro inflammatory effects, since a specific genetic deletion of CerS2 in blood cells or a total genetic deletion of CerS2 significantly delayed the onset of clinical symptoms, due to a reduced infiltration of immune cells, in particular neutrophils, into the central nervous system. CXCR2 chemokine receptors, expressed on neutrophils, promote the migration of neutrophils into the central nervous system, which is a prerequisite for the recruitment of further immune cells and the inflammatory process that leads to the development of MS. Interestingly, neutrophils isolated from CerS2 null EAE mice, as opposed to WT EAE mice, were characterised by significantly lower CXCR2 receptor mRNA expression resulting in their reduced migratory capacity towards CXCL2. Most importantly, G-CSF-induced CXCR2 expression was significantly reduced in CerS2 null neutrophils and their migratory capacity was significantly impaired. In conclusion, our data strongly indicate that G-CSF-induced CXCR2 expression is regulated in a CerS2-dependent manner and that CerS2 thereby promotes the migration of neutrophils, thus, contributing to inflammation and the development of EAE and MS. PMID- 25697396 TI - Toxic role of prostaglandin E2 receptor EP1 after intracerebral hemorrhage in mice. AB - Inflammatory mechanisms mediated by prostaglandins may contribute to the progression of intracerebral hemorrhage (ICH)-induced brain injury, but they are not fully understood. In this study, we examined the effect of prostaglandin E2 receptor EP1 (EP1R) activation and inhibition on brain injury in mouse models of ICH and investigated the underlying mechanism of action. ICH was induced by injecting collagenase, autologous blood, or thrombin into the striatum of middle aged male and female mice and aged male mice. Effects of selective EP1R agonist ONO-DI-004, antagonist SC51089, and nonspecific Src family kinase inhibitor PP2 were evaluated by a combination of histologic, magnetic resonance imaging (MRI), immunofluorescence, molecular, cellular, and behavioral assessments. EP1R was expressed primarily in neurons and axons but not in astrocytes or microglia after ICH induced by collagenase. In middle-aged male mice subjected to collagenase induced ICH, EP1R inhibition mitigated brain injury, brain edema, cell death, neuronal degeneration, neuroinflammation, and neurobehavioral deficits, whereas its activation exacerbated these outcomes. EP1R inhibition also was protective in middle-aged female mice and aged male mice after collagenase-induced ICH and in middle-aged male mice after blood- or thrombin-induced ICH. EP1R inhibition also reduced oxidative stress, white matter injury, and brain atrophy and improved functional outcomes. Histologic results were confirmed by MRI. Src kinase phosphorylation and matrix metalloproteinase-9 activity were increased by EP1R activation and decreased by EP1R inhibition. EP1R regulated matrix metalloproteinase-9 activity through Src kinase signaling, which mediated EP1R toxicity after collagenase-induced ICH. We conclude that prostaglandin E2 EP1R activation plays a toxic role after ICH through mechanisms that involve the Src kinases and the matrix metalloproteinase-9 signaling pathway. EP1R inhibition could be a novel therapeutic strategy to improve outcomes after ICH. PMID- 25697398 TI - Behavioral stress reduces RIP140 expression in astrocyte and increases brain lipid accumulation. AB - Receptor-interacting protein 140 (RIP140) is highly expressed in the brain, and acts in neurons and microglia to affect emotional responses. The present study reveals an additional function of RIP140 in the brain, which is to regulate brain lipid homeostasis via its action in astrocytes. We found forced swim stress (FSS) significantly reduces the expression level of RIP140 and elevates cholesterol content in the brain. Mechanistically, FSS elevates endoplasmic reticulum stress, which suppresses RIP140 expression by increasing microRNA 33 (miR33) that targets RIP140 mRNA's 3'-untranslated region. Consequentially, cholesterol biosynthesis and export are dramatically increased in astrocyte, the major source of brain cholesterol. These results demonstrate that RIP140 plays an important role in maintaining brain cholesterol homeostasis through, partially, regulating cholesterol metabolism in, and mobilization from, astrocyte. Altering RIP140 levels can disrupt brain cholesterol homeostasis, which may contribute to behavioral stress-induced neurological disorders. PMID- 25697399 TI - 2HiGWAS: a unifying high-dimensional platform to infer the global genetic architecture of trait development. AB - Whole-genome search of genes is an essential approach to dissecting complex traits, but a marginal one-single-nucleotide polymorphism (SNP)/one-phenotype regression analysis widely used in current genome-wide association studies fails to estimate the net and cumulative effects of SNPs and reveal the developmental pattern of interplay between genes and traits. Here we describe a computational framework, which we refer to as two-side high-dimensional genome-wide association studies (2HiGWAS), to associate an ultrahigh dimension of SNPs with a high dimension of developmental trajectories measured across time and space. The model is implemented with a dual dimension-reduction procedure for both predictors and responses to select a sparse but full set of significant loci from an extremely large pool of SNPs and estimate their net time-varying effects on trait development. The model can not only help geneticists to precisely identify an entire set of genes underlying complex traits but also allow them to elucidate a global picture of how genes control developmental and dynamic processes of trait formation. We investigated the statistical properties of the model via extensive simulation studies. With the increasing availability of GWAS in various organisms, 2HiGWAS will have important implications for genetic studies of developmental compelx traits. PMID- 25697400 TI - Great saphenous vein aneurysm: A differential diagnosis of femoral hernia and review. AB - INTRODUCTION: Venous aneurysms are unusual clinical entities that might be difficult to diagnose and usually appear as an asymptomatic incidental finding on physical examination or imaging study and discovered only during the surgical exploration. They are important differential diagnosis of groin and other subcutaneous mass. PRESENTATION OF CASE: We report a case of a 67-years-old woman who had a groin mass misdiagnosed as femoral hernia, which was subsequently diagnose as great saphena vein aneurysm in the intraoperative set and treated with ligature and resection. DISCUSSION: In conclusion, venous aneurysms of the superficial system are lesions that are important differential diagnosis of groin and other subcutaneous mass. CONCLUSION: Diagnosis is readily available by duplex ultrasonography; however, in most cases, the diagnosis is done only in the operative field. PMID- 25697401 TI - Unusual 30-year durability of Hancock II porcine bioprosthesis in tricuspid position. AB - INTRODUCTION: We describe an unusual durability of a Hancock II porcine bioprosthesis in tricuspid position. Sustainability of bioprostheses is known to be limited especially in young patients. PRESENTATION OF THE CASE: A 52-year old Caucasian woman with a history of multiple valve interventions. Her clinical presentation of dyspnoea and lower limb oedema led to the diagnosis of severe tricuspid valve stenosis and right heart failure, and was managed by the replacement of the tricuspid bioprosthesis by another bioprosthesis 30-years after the initial implantation. DISCUSSION: Calcification is the leading cause of bioprosthesis structural deterioration. This immune-induced phenomenon is more pronounced in young patients. Although several patient-related and valve-related factors influence the durability of a xenograft, unknown factors may be of some importance. CONCLUSION: To our knowledge, this is the first report of a 30-year durability of tricuspid bioprosthesis in a young recipient. In the absence of extensive calcifications, pannus formation covering the whole prosthesis, peculiar hemodynamics and other unknown factors might have contributed to an extended durability in this young patient. PMID- 25697402 TI - Aggressive malignant phyllodes tumor. AB - INTRODUCTION: Originally described in 1838 by Muller, phyllodes tumor is a rare fibroepithelial neoplasm which represents roughly 0.3-0.9% of all breast cancers. Phyllodes tumor are divided into benign, borderline and malignant histologic categories. Malignant phyllodes tumor represent anywhere from 10-30% of all phyllodes tumors. This group has both the potential to recur locally and metastasize, however not all malignant phyllodes behave this way. The challenge lays in predicting which tumor will recur locally or metastasize. Distinguishing this subset of malignant phyllodes tumor is paramount. PRESENTATION OF CASE: We present a case of malignant phyllodes which presented with metastatic disease. What is fascinating about this case is not only the initial presentation but also the aggressiveness of this variation of phyllodes tumor. The patient initially presented with a large mass which encompassed her whole right breast. On surgical pathology the mass measured roughly 31cm in diameter and weighed over 10kg. Within 5 weeks from surgery the patient had suffered brain metastases and also 6 local recurrent tumors. The patient passed roughly 11 weeks after her first visit to our office. CONCLUSION: Despite biopsy proven malignant phyllodes tumor, it was near impossible to predict such a rapid course of disease progression in our patient. Our case illustrates the unpredictable nature of this disease in general and it possibly sheds light on a variant of the disease which had undergone an aggressive transformation. PMID- 25697403 TI - Chitinase gene responses and tissue sensitivity in an intertidal mud crab (Macrophthalmus japonicus) following low or high salinity stress. AB - Changes in salinity affect the physiological status of the marine habitat including that of the intertidal mud crab Macrophthalmus japonicus. Chitinases play significant biological roles in crustaceans such as morphogenesis, nutrient digestion, and pathogen defense. In this study, the osmoregulatory function of three chitinase gene transcripts was determined compared to seawater (SW, 31 +/- 1 psu) in M. japonicus gills and hepatopancreas under different salinities (10, 25, and 40 psu) for 1, 4, and 7 days. In SW-exposed crab, quantitative real-time PCR analysis showed chitinase 1 (Mj-chi1) and chitinase 4 (Mj-chi4) transcripts constitutively expressed in all the tested tissues with strong expression in hepatopancreas, but chitinase 5 (Mj-chi5) showed highest expression in stomach. When exposed to different salinities, Mj-chi1 showed significant up-regulation at day 4 whereas Mj-chi4 showed late up-regulation (day 7) at all the salinities in hepatopancreas. In the gills, early up-regulation (day 1) in Mj-chi1 and time dependent late up-regulation (day 7) in Mj-chi4 at high salinity were observed. These results indicate the possibility of using Mj-chi4 as a marker against salinity changes. Moreover, our results further suggest that Mj-chi1 and Mj-chi4 transcriptions were significantly affected by changes in salinity; however, Mj chi5 in gills was less affected by salinity and showed no effect in hepatopancreas. Thus, chitinase transcription modulations in the gills are more sensitive than hepatopancreas to salinity stress. Further, present data indicate the possible existence of different physiological roles among chitinase gene families, which need to be clarified in more detail by future biochemical and physiological functional studies. PMID- 25697404 TI - Recent advances in the development of new auristatins: structural modifications and application in antibody drug conjugates. AB - Dolastatin 10 is a powerful antineoplastic agent and microtubule inhibitor that was discovered by Pettit et al. and published in 1987. Since then, many research groups have engaged in SAR studies of synthetic analogues, termed "auristatins". It was eventually discovered that auristatins are of great value as payloads in antibody drug conjugates (ADCs), which led to the FDA-approved ADC brentuximab vedotin (Seattle Genetics). Currently, over 30 ADCs in clinical trials employ auristatins as payloads, and there is a great interest in the research community, both on academic and industrial sides, to further study these analogues. This review will provide an overview of the recent advancements in auristatin development spanning a time frame of about the past ten years. The main focus will be to describe structural changes made to the auristatin peptide and their resulting biological activities in tumor cell proliferation assays. Selected ADC examples will also be described. PMID- 25697405 TI - Ecotoxicogenomic assessment of diclofenac toxicity in soil. AB - Diclofenac is widely used as nonsteroidal anti-inflammatory drug leaving residues in the environment. To investigate effects on terrestrial ecosystems, we measured dissipation rate in soil and investigated ecotoxicological and transcriptome-wide responses in Folsomia candida. Exposure for 4 weeks to diclofenac reduced both survival and reproduction of F. candida in a dose-dependent manner. At concentrations >= 200 mg/kg soil diclofenac remained stable in the soil during a 21-day incubation period. Microarrays examined transcriptional changes at low and high diclofenac exposure concentrations. The results indicated that development and growth were severely hampered and immunity-related genes, mainly directed against bacteria and fungi, were significantly up-regulated. Furthermore, neural metabolic processes were significantly affected only at the high concentration. We conclude that diclofenac is toxic to non-target soil invertebrates, although its mode of action is different from the mammalian toxicity. The genetic markers proposed in this study may be promising early markers for diclofenac ecotoxicity. PMID- 25697406 TI - Roquin binds microRNA-146a and Argonaute2 to regulate microRNA homeostasis. AB - Roquin is an RNA-binding protein that prevents autoimmunity and inflammation via repression of bound target mRNAs such as inducible costimulator (Icos). When Roquin is absent or mutated (Roquin(san)), Icos is overexpressed in T cells. Here we show that Roquin enhances Dicer-mediated processing of pre-miR-146a. Roquin also directly binds Argonaute2, a central component of the RNA-induced silencing complex, and miR-146a, a microRNA that targets Icos mRNA. In the absence of functional Roquin, miR-146a accumulates in T cells. Its accumulation is not due to increased transcription or processing, rather due to enhanced stability of mature miR-146a. This is associated with decreased 3' end uridylation of the miRNA. Crystallographic studies reveal that Roquin contains a unique HEPN domain and identify the structural basis of the 'san' mutation and Roquin's ability to bind multiple RNAs. Roquin emerges as a protein that can bind Ago2, miRNAs and target mRNAs, to control homeostasis of both RNA species. PMID- 25697407 TI - Outbreaks attributed to fresh leafy vegetables, United States, 1973-2012. AB - Leafy vegetables are an essential component of a healthy diet; however, they have been associated with high-profile outbreaks causing severe illnesses. We reviewed leafy vegetable-associated outbreaks reported to the Centers for Disease Control and Prevention between 1973 and 2012. During the study period, 606 leafy vegetable-associated outbreaks, with 20 003 associated illnesses, 1030 hospitalizations, and 19 deaths were reported. On average, leafy vegetable associated outbreaks were larger than those attributed to other food types. The pathogens that most often caused leafy vegetable-associated outbreaks were norovirus (55% of outbreaks with confirmed aetiology), Shiga toxin-producing Escherichia coli (STEC) (18%), and Salmonella (11%). Most outbreaks were attributed to food prepared in a restaurant or catering facility (85%). An ill food worker was implicated as the source of contamination in 31% of outbreaks. Efforts by local, state, and federal agencies to control leafy vegetable contamination and outbreaks should span from the point of harvest to the point of preparation. PMID- 25697408 TI - Doing more with less: performance improvement in humanitarian endocrine surgery. PMID- 25697409 TI - Erratum to: Age and Obesity are Independent Predictors of Bile Duct Injuries in Patients Undergoing Laparoscopic Cholecystectomy. PMID- 25697410 TI - Can a fixed-ratio combination of insulin degludec and liraglutide help Type 2 diabetes patients to optimize glycemic control across the day? AB - 'IDegLira' combines insulin degludec (IDeg) with the glucagon-like peptide-1 analog liraglutide (Lira) at a ratio of 1 unit IDeg to 0.036 mg Lira. The two components have complementary therapeutic actions for the treatment of Type 2 diabetes. Studies have shown that combinations of basal insulin with glucagon like peptide-1 receptor agonists can be clinically successful, lowering elevated blood glucose with a low risk of hypoglycemia and weight gain. IDegLira is being assessed in a series of studies (two already published), which provide insights into its clinical utility in previously insulin-naive patients and those failing to achieve good glycemic control on a basal-only insulin regimen. This article critically examines the available data to assess the product's likely clinical profile. PMID- 25697413 TI - Antibiotic synergy against viridans streptococci isolated in infective endocarditis. PMID- 25697411 TI - Pharmacological strategies for prevention of postoperative atrial fibrillation. AB - Atrial fibrillation (AF) complicating cardiac surgery continues to be a major problem that increases the postoperative risk of stroke, myocardial infarction, heart failure and costs and can affect long-term survival. The incidence of AF after surgery has not significantly changed over the last two decades, despite improvement in medical and surgical techniques. The mechanism and pathophysiology underlying postoperative AF (PoAF) is incompletely understood and results from a combination of acute and chronic factors, superimposed on an underlying abnormal atrial substrate with increased interstitial fibrosis. Several anti-arrhythmic and non-anti-arrhythmic medications have been used for the prevention of PoAF, but the effectiveness of these strategies has been limited due to a poor understanding of the basis for the increased susceptibility of the atria to AF in the postoperative setting. In this review, we summarize the pathophysiology underlying the development of PoAF and evidence behind pharmacological approaches used for its prevention in the postoperative setting. PMID- 25697412 TI - Effect of reducing the paediatric stavudine dose by half: a physiologically-based pharmacokinetic model. AB - Owing to significant dose-related toxicity, the adult stavudine dose was reduced in 2007. The paediatric dose, however, has not been reduced. Although the intended paediatric dose is 1 mg/kg twice daily (b.i.d.), the current weight-band dosing approach results in a mean actual dose of 1.23+/-0.47 mg/kg. Both efficacy and mitochondrial toxicity depend on the concentration of the intracellular metabolite stavudine triphosphate (d4T-TP). We simulated the effect of reducing the paediatric dose to 0.5 mg/kg. A physiologically-based pharmacokinetic model consisting of 13 tissue compartments plus a full ADAM model was used to describe the elimination of stavudine. The volume of distribution at steady-state and apparent oral clearance were simulated and the resulting AUC profile was compared with literature data in adult and paediatric populations. A biochemical reaction model was utilised to simulate intracellular d4T-TP levels for both the standard and proposed reduced paediatric doses. Simulated and observed exposure after oral dosing showed adequate agreement. Mean steady-state d4T-TP for 1.23 mg/kg b.i.d. was 27.9 (90% CI 27.0-28.9) fmol/10(6) cells, 25% higher than that achieved by the 40 mg adult dose. The 0.5 mg/kg dose resulted in d4T-TP of 13.2 (12.7-13.7) fmol/10(6) cells, slightly higher than the adult dose of 20 mg b.i.d. [11.5 (11.2 11.9) fmol/10(6) cells], which has excellent antiviral efficacy and substantially less toxicity. Current paediatric dosing may result in even higher d4T-TP than the original 40 mg adult dose. Halving the paediatric dose would significantly reduce the risk of mitochondrial toxicity without compromising antiviral efficacy. PMID- 25697414 TI - Effects of aging and gender on striatal and extrastriatal [123I]FP-CIT binding in Parkinson's disease. AB - To investigate the effects of aging and gender on brain dopamine and serotonin transporter bindings, we analyzed [(123)I]FP-CIT single-photon emission computed tomography scans of 231 Parkinson's disease (PD) patients and 230 controls. An automated region-of-interest-based method (BRASS automated analysis software) was used for striatal regions and a voxel-based method (Statistical Parametric Mapping software, SPM8) for the entire brain. In controls, aging was associated with a decline of 3.6%-4.6% per decade in striatal binding. Multiple extrastriatal regions also showed age-related declines. In PD patients, age related declines were only observed in the caudate nuclei, thalamus, olfactory, and cingulate cortices with a comparable rate of decline as that in controls. Female subjects had higher caudate nucleus binding compared with males with a similar near-significant difference in the right putamen. The results demonstrate that the aging effect is limited in PD, which is possibly because of disease related excess variation, and the results do not support the theory of accelerated aging of the dopaminergic system in PD. Women have higher caudate nucleus dopamine transporter binding compared with men in both normal and degenerated dopamine systems. PMID- 25697415 TI - Generation and In Vitro Expansion of Hepatic Progenitor Cells from Human iPS Cells. AB - Stem cells have the unique properties of self-renewal and multipotency (producing progeny belonging to two or more lineages). Induced pluripotent stem (iPS) cells can be generated from somatic cells by simultaneous expression of pluripotent factors (Oct3/4, Klf4, Sox2, and c-Myc). They share the same properties as embryonic stem (ES) cells and can differentiate into several tissue cells, i.e., neurons, hematopoietic cells, and liver cells. Therefore, iPS cells are suitable candidate cells for regenerative medicine and analyses of disease mechanisms.The liver is the major organ that regulates a multitude of metabolic functions. Hepatocytes are the major cell type populating the liver parenchyma and express several metabolic enzymes that are necessary for liver functions. Although hepatocytes are essential for maintaining homeostasis, it is difficult to alter artificial and transplanted cells because of their multifunctionality, donor shortage, and immunorejection risk. During liver development, hepatic progenitor cells in the fetal liver differentiate into both mature hepatocytes and cholangiocytes. As hepatic progenitor cells have bipotency and high proliferation ability, they could present a potential source for generating transplantable cells or as a liver study model. Here we describe the induction and purification of hepatic progenitor cells derived from human iPS cells. These cells can proliferate for a long term under suitable culture conditions. PMID- 25697416 TI - Generation of Human Induced Pluripotent Stem Cells Using RNA-Based Sendai Virus System and Pluripotency Validation of the Resulting Cell Population. AB - Human induced pluripotent stem cells (hiPSCs) provide a platform for studying human disease in vitro, increase our understanding of human embryonic development, and provide clinically relevant cell types for transplantation, drug testing, and toxicology studies. Since their discovery, numerous advances have been made in order to eliminate issues such as vector integration into the host genome, low reprogramming efficiency, incomplete reprogramming and acquisition of genomic instabilities. One of the ways to achieve integration-free reprogramming is by using RNA-based Sendai virus. Here we describe a method to generate hiPSCs with Sendai virus in both feeder-free and feeder-dependent culture systems. Additionally, we illustrate methods by which to validate pluripotency of the resulting stem cell population. PMID- 25697417 TI - Transcriptomic study of mouse embryonic neural stem cell differentiation under ethanol treatment. AB - Neural stem cells (NSCs) can be differentiated into one of three cell lineages: neurons, astrocytes or, oligodendrocytes. Some neurotoxins have the ability to deregulate this dynamic process. NSC cell fate can be altered by ethanol as reported previously. Our aim was to investigate the alteration of genes by ethanol during NSC differentiation and to explore the molecular mechanism underlying this phenomenon. Here, mouse fetal forebrain derived NSCs were differentiated for 2 days with or without of ethanol (50 mM). We performed a comparative microarray analysis at day two using GeneChip((r)) Mouse Genome 430A 2.0 arrays. Microarray analysis showed that the expressions of 496 genes were altered by ethanol (56 and 440 were up- and down-regulated, respectively). Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed the association of the following altered genes in the Wnt signaling pathway: Wnt5a, Csnk2a1, Tcf7l2, Ccnd2, Nlk, Tbl1x, Tbl1xr1, Rac2 and Nfatc3. Quantitative real time PCR analysis also demonstrated the relative expression levels of these genes. As Wnt signaling is a player of brain development, ethanol-induced alterations may contribute to improper development of the brain. Our data could be a useful resource for elucidating the mechanism behind the ethanol neurotoxicity in developing brain. PMID- 25697418 TI - The mRNA expression of immune-related genes in crossbred and Tharparkar cattle in response to in vitro infection with Theileria annulata. AB - Tropical theileriosis is a major protozoan disease of cattle and is associated with high rates of morbidity and mortality. Indigenous cattle (Bos indicus) are less affected by this disease than exotic and crossbred cattle. Genetic basis of resistance to tropical theileriosis in indigenous cattle is not well studied. Recent reports suggest that number of immune response genes expressed differentially in exotic and indigenous breeds play an important role in breed specific resistance to tropical theileriosis. Such studies comparing expression of these genes in crossbred cattle and indigenous cattle are lacking. The present study compares the mRNA expression of immune-related genes in response to Theileria annulata infection in indigenous and crossbred cattle. Peripheral blood mononuclear cells (PBMCs) were isolated from blood samples of indigenous (Tharparkar) and crossbred (HF/BS/Jersey * Hariana) cattle and challenged with prepared ground-up tick supernatant carrying Theileria annulata sporozoites in vitro. qPCR was employed to measure relative mRNA expression of toll-like receptor 10 (TLR10), signal-regulatory protein alpha (SIRPA), MHC class II DQalpha (BoLA-DQA), musculoaponeurotic fibrosarcoma (MAF) and prion protein (PRNP) genes in infected and control PBMCs from crossbred and indigenous cattle. On the basis of comparative fold change analysis, significant up-regulation in SIRPA, PRNP and MHC DQalpha genes and significant down-regulation in TLR10, cMAF and MAFB genes in crossbreds as compared to indigenous cattle was observed. Results of the present study suggest that breed specific differential expression of the genes under study may contribute to the breed specific resistance to Theileria annulata infection in indigenous cattle compared to crossbred cattle. PMID- 25697419 TI - Inherited Retinal Dystrophies: the role of gene expression regulators. AB - Inherited Retinal Dystrophies (IRDs) are a clinically and genetically heterogeneous group of rare disorders characterized by a significant impairment in retinal function and vision. More than 150 genes have been associated with retinal dystrophies and the genetic overlap among different IRDs renders diagnosis and prognosis challenging. In this In Focus article, we give a summary on the pathogenic role of gene expression regulators in IRDs. Emphasis is given on key transcription factors that participate to regulatory gene networks controlling photoreceptor specification and maintenance, and their possible relevance as therapeutic targets. The increasing knowledge on the composition and function of these transcriptional regulatory networks indicates that intervening on transcription factors may be instrumental for a more effective treatment of some forms of IRDs, although the development of appropriate molecular tools to target them remains a formidable challenge. PMID- 25697420 TI - Pharmacokinetics and pharmacodynamics of ticagrelor and prasugrel in healthy male Korean volunteers. AB - PURPOSE: A combination of clopidogrel and aspirin is the standard treatment for patients with acute coronary syndrome and those undergoing percutaneous coronary intervention. Two novel antiplatelet agents, ticagrelor and prasugrel, have been shown to rapidly and more effectively inhibit the P2Y12 receptor compared with clopidogrel. The aim of this study was to evaluate and compare the pharmacokinetics (PK) and pharmacodynamics (PD) of ticagrelor and prasugrel in healthy male Korean volunteers. METHODS: Two separate studies were conducted. One study was performed by using a single-sequence, open-label, crossover design in 12 volunteers who received a single oral dose of ticagrelor (180 mg) and then a single oral dose of prasugrel (60 mg for 4 volunteers and 30 mg for 8 volunteers) with a 7-day washout period. The other study was a randomized, open-label, parallel-group investigation in which 8 volunteers received a single oral dose of prasugrel (10 mg for 4 volunteers and 30 mg for 4 volunteers). In each study, blood samples for PK and platelet aggregation inhibition analysis were serially collected after the administration of each dose. Plasma concentrations of ticagrelor, AR-C124910XX (the active metabolite of ticagrelor), R-95913 (the inactive metabolite of prasugrel), and R-138727 (the active metabolite of prasugrel) were measured by using a validated LC-MS/MS method. PK was analyzed by using a noncompartmental method. Maximal platelet aggregations were assessed with light transmission aggregometry after induction with 20 MUmol/L of adenosine diphosphate. FINDINGS: Twenty healthy male Korean volunteers participated in the 2 studies. Plasma concentrations of ticagrelor and AR-C124910XX were obtained from 12 subjects, R-95913 from 20 subjects, and R-138727 from 8 subjects. Both ticagrelor and prasugrel were rapidly absorbed, with the shortest median Tmax of 2.0 and 2.25 hours for ticagrelor and AR-C124910XX, respectively, and a Tmax of 0.5 hour for both R-95913 and R-138727. Strong inhibition of platelet aggregation was shown after administration of both ticagrelor and prasugrel, with slightly stronger and more rapid inhibition with prasugrel in the tested doses. Inhibitory activities of prasugrel lasted longer than those of ticagrelor, reflecting the difference in binding kinetics between the 2 drugs. IMPLICATIONS: Prasugrel 30 and 60 mg exhibited slightly stronger, more rapid, and sustainable platelet inhibitory effects compared with ticagrelor 180 mg. These differing effects should be considered when determining the efficacy and adverse effects of ticagrelor and prasugrel. ClinicalTrials.gov identifier: NCT01876797 and NCT02075268. PMID- 25697421 TI - An Open-label Comparison of a New Generic Sevoflurane Formulation With Original Sevoflurane in Patients Scheduled for Elective Surgery Under General Anesthesia. AB - PURPOSE: To compare the stability, effectiveness, and safety profiles of a new generic sevoflurane with those of the original sevoflurane formulation in patients undergoing elective surgery. METHODS: An accelerated 3-month storage test was performed to evaluate the compositional changes in generic sevoflurane stored in glass bottles. In addition, 182 patients were randomly allocated to receive generic (n = 89 [54 men and 35 women]; mean [SD] age, 49.9 [11.6] years) or original (n = 93 [61 men and 32 women]; mean [SD] age, 49.6 [11.1] years) sevoflurane at a gas flow of 3 L/min for approximately 3 hours. The mean minimum alveolar concentration (MAC) during sevoflurane anesthesia was evaluated, and gas samples for measuring compound A were collected from the inspiratory limb of the circuit at preset intervals. Blood samples for measuring serum inorganic fluoride were obtained at preset intervals (pharmacokinetic group: generic/original sevoflurane = 45/46). Renal biomarkers, such as N-acetyl-beta-glucosaminidase, alpha- and pi-glutathione-S-transferase, albumin, urine protein and osmolality, serum creatinine and osmolality, creatinine clearance, and blood urea nitrogen, were measured at preset intervals (renal biomarker group: generic/original sevoflurane = 44/47). Adverse reactions were monitored for 72 hours after discontinuation of sevoflurane use. FINDINGS: Generic sevoflurane contained in glass bottles was stable for 3 months. The mean MAC was similar for generic and original sevoflurane (median [range], 0.93 [0.67-1.29] vs 0.94 [0.63-1.5] vol%). Adverse event rates were similar (90.3% vs 84.3%), as were the AUClast of inorganic fluoride (333.7 [112.7-1264.7] vs 311.9 [81.5-1266.5] hours.MUmol/L) and compound A (51.8 [6.3-204.5] vs 55.3 [10.8-270.6] hours.ppm). Biomarkers associated with renal injury were not significantly different between the 2 formulations. IMPLICATIONS: No significant difference was found in the mean MAC between generic and original sevoflurane. ClinicalTrials.gov identifier: NCT01096212. PMID- 25697422 TI - Protein expression profiling in head fragments during planarian regeneration after amputation. AB - Following amputation, a planarian tail fragment can regrow into a complete organism including a well-organized brain within about 2-3 weeks, thus restoring the structure and function to presurgical levels. Despite the enormous potential of these animals for regenerative medicine, our understanding of the exact mechanism of planarian regeneration is incomplete. To better understand the molecular nature of planarian head regeneration, we applied two-dimensional electrophoresis (2-DE)/matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF)/time-of-flight mass spectrometry (TOF MS) technique to analyze the dynamic proteomic expression profiles over the course of 6 to 168 h post decapitation. This approach identified a total of 141 differentially expressed proteins, 47 of which exhibited exceptionally high fold changes (>=3-fold change). Of these, Rx protein, an important regulator of head and brain development, was considered to be closely related to planarian head regeneration because of its exceptional high expression almost throughout the time course of regeneration process. Functional annotation analysis classified the 141 proteins into eight categories: (1) signaling, (2) Ca(2+) binding and translocation, (3) transcription and translation, (4) cytoskeleton, (5) metabolism, (6) cell protection, (7) tissue differentiation, and (8) cell cycle. Signaling pathway analysis indicated that Wnt1/Ca(2+) signaling pathway was activated during head regeneration. Integrating the analyses of proteome expression profiling, functional annotation, and signaling pathway, amputation-induced head reformation requires some mechanisms to promote cell proliferation and differentiation, including differential regulation of proapoptotic and antiapoptotic proteins, and the regulation of proliferation and differentiation-related proteins. Importantly, Wnt1/Ca(2+) signaling pathway upregulates Rx expression, finally facilitating the differentiation of neoblasts into various cell types. Taken together, our study demonstrated that proteomic analysis approach used by us is a powerful tool in understanding molecular process related to head regeneration of planarian. PMID- 25697423 TI - C-Terminal glycine-gated radical initiation by GTP 3',8-cyclase in the molybdenum cofactor biosynthesis. AB - The molybdenum cofactor (Moco) is an essential redox cofactor found in all kingdoms of life. Genetic mutations in the human Moco biosynthetic enzymes lead to a fatal metabolic disorder, Moco deficiency (MoCD). Greater than 50% of all human MoCD patients have mutations in MOCS1A, a radical S-adenosyl-l-methionine (SAM) enzyme involved in the conversion of guanosine 5'-triphosphate (GTP) into cyclic pyranopterin monophosphate. In MOCS1A, one of the frequently affected locations is the GG motif constituted of two consecutive Gly at the C-terminus. The GG motif is conserved among all MOCS1A homologues, but its role in catalysis or the mechanism by which its mutation causes MoCD was unknown. Here, we report the functional characterization of the GG motif using MoaA, a bacterial homologue of MOCS1A, as a model. Our study elucidated that the GG motif is essential for the activity of MoaA to produce 3',8-cH2GTP from GTP (GTP 3',8-cyclase), and that synthetic peptides corresponding to the C-terminal region of wt-MoaA rescue the GTP 3',8-cyclase activity of the GG-motif mutants. Further biochemical characterization suggested that the C-terminal tail containing the GG motif interacts with the SAM-binding pocket of MoaA, and is essential for the binding of SAM and subsequent radical initiation. In sum, these observations suggest that the C-terminal tail of MoaA provides an essential mechanism to trigger the free radical reaction, impairment of which results in the complete loss of catalytic function of the enzyme, and causes MoCD. PMID- 25697424 TI - Push or Pull? Proton Responsive Ligand Effects in Rhenium Tricarbonyl CO2 Reduction Catalysts. AB - Proton responsive ligands offer control of catalytic reactions through modulation of pH-dependent properties, second coordination sphere stabilization of transition states, or by providing a local proton source for multiproton, multielectron reactions. Two fac-[Re(I)(alpha-diimine)(CO)3Cl] complexes with alpha-diimine = 4,4'- (or 6,6'-) dihydroxy-2,2'-bipyridine (4DHBP and 6DHBP) have been prepared and analyzed as electrocatalysts for the reduction of carbon dioxide. Consecutive electrochemical reduction of these complexes yields species identical to those obtained by chemical deprotonation. An energetically feasible mechanism for reductive deprotonation is proposed in which the bpy anion is doubly protonated followed by loss of H2 and 2H(+). Cyclic voltammetry reveals a two-electron, three-wave system owing to competing EEC and ECE pathways. The chemical step of the ECE pathway might be attributed to the reductive deprotonation but cannot be distinguished from chloride dissociation. The rate obtained by digital simulation is approximately 8 s(-1). Under CO2, these competing reactions generate a two-slope catalytic waveform with onset potential of -1.65 V vs Ag/AgCl. Reduction of CO2 to CO by the [Re(I)(4DHBP-2H(+))(CO)3](-) suggests the interaction of CO2 with the deprotonated species or a third reduction followed by catalysis. Conversely, the reduced form of [Re(6DHBP)(CO)3Cl] converts CO2 to CO with a single turnover. PMID- 25697425 TI - Cystatin C is an Independent Risk Factor and Therapeutic Target for Acute Ischemic Stroke. AB - Cystatin C (CysC) has been used as a renal function indicator and a strong predictor of cardiovascular events. In this study, we determined the prognostic value of serum CysC in patients with acute ischemic stroke (AIS) and examined its protective role on ischemic brain injury. First-ever stroke patients (601 cases) and control subjects (325 cases) were recruited. Serum CysC level in patients with AIS were significantly higher than that in controls. Multivariate logistic regression analyses showed that elevated CysC is an independent risk factor of AIS; the odds ratio (95 % confidence interval) was 9.80 (3.12-30.83). The integrated population was divided into quintiles according to serum CysC. Compared with the first quintile, the odds ratios of risk for AIS in fourth quintile and fifth quintile were 1.92 (1.08-3.40) and 2.88 (1.49-5.54), respectively. Serum CysC was not associated with neurological deficits and the location of ischemic area; however, serum CysC in patients decreased after one week therapy. This was consistent with CysC expression after ischemia/reperfusion injury in a mouse focal ischemia/reperfusion injury model. Exogenous CysC exerted neuroprotective effects by reducing infarct volume in this animal stroke model. Therefore, serum CysC is highly associated with AIS and is an independent prediction marker for AIS. Since our findings demonstrated the protection of exogenous CysC on ischemic brain injury, CysC is a novel and promising therapeutic target for AIS. PMID- 25697426 TI - The effects of cigarette smoking on male fertility. AB - Cigarette smoking, one of the main causes of preventable morbidity and mortality, has a multitude of well-known side effects. The relationship between cigarette smoking and infertility has been studied for decades; however, large-scale, population-wide prospective studies are lacking. The majority of the current literature is in the form of retrospective studies focused on the effects of smoking on semen analyses. This article discusses the results of these studies and reviews the postulated mechanisms. The effects of smoking on assisted reproduction and in vitro fertilization outcomes are noted. The consequences of smoking while pregnant on future fertility as well as the outcomes of second-hand smoke are analyzed. The current evidence suggests that men should be advised to abstain from smoking in order to improve reproductive outcomes. PMID- 25697427 TI - [A milk bank in Chile]. PMID- 25697428 TI - [Evidence-based medicine: can we trust the results of well-designed randomized trials?]. AB - Evidence based medicine assists in clinical decision-making by integrating critically appraised information with patient's values and preferences within an existing clinical context. A fundamental concept in this paradigm is the hierarchy of information. The randomized clinical trial is recognized as one of the designs that is less prone to bias and therefore of higher methodological quality. Clinical guidelines are one of the principal tools that evidence based medicine uses to transfer scientific information to clinical practice and many of their recommendations are based on these type of studies. In this review we present some of the limitations that the results can have, in even well designed and executed randomized clinical trials. We also discuss why valid results in these types of studies could not necessarily be extrapolated to the general population. Although the randomized clinical trial continues to be one of the best methodological designs, we suggest that the reader be careful when interpreting its results. PMID- 25697429 TI - [A prolonged capillary refill is predictor of low central venous oxygen saturation]. AB - INTRODUCTION: Educational programs in pediatric life support endorse a capillary refill time>2 s as an indicator of shock. In the emergency room, a barrier to the implementation of an early goal directed therapy, aiming at central venous oxygen saturation (ScvO2)>=70% is the insertion of central venous catheter (CVC). OBJECTIVE: To establish the predictive value of capillary refill time>2 s to detect ScvO2<70% in children admitted to Intensive Care Units. PATIENTS AND METHOD: Prospective study. We included 48 children admitted in the first 24 hours in ICU with superior vena cava CVC. Simultaneously, we measured ScvO2 and capillary refill time in the heel of upper extremity or toe. RESULTS: There were 75 paired measurements ScvO2 (75,9+/-8,4%) and capillary refill capillary (1,9+/ 1,0 s). We found an inverse correlation between capillary refill time and ScvO2 (r-0,58). The ROC curve analysis revealed an excellent ability for the capillary fill time>2 s to predict ScvO2<70% (AUC 0,94) (95% CI 0,87-0,98). CONCLUSIONS: A prolonged capillary refill time>2 s, is a predictor of ScvO2<70% in children admitted to ICU, which supports the current recommendations. This finding may be relevant in emergency units where the use of CVC is limited and ScvO2 is not available. PMID- 25697430 TI - [Characteristics of drug interactions in a pediatric intensive care unit]. AB - INTRODUCTION: The aim of this study is to calculate the theoretical frequency of potential drug interactions (PDI) and their characteristics in the therapeutic plan of hospitalized patients in a Pediatric Intensive Care Unit (PICU). PATIENTS AND METHODS: An observational study was conducted which analyzed PICU prescriptions between September and November 2011. The inclusion criteria included to be hospitalized in a PICU, requirements of at least 3 drugs, except those topically applied, either gender, no age limit, no hospital stay required. The Micromedex(r) 2.0 program was used to detect and classify PDI. RESULTS: Of 223 patients, 100 met inclusion criteria, 610 prescriptions were analyzed and 815 drugs were prescribed. 1,240 PDI were detected in 44 patients; 12 patients received more than 10 drugs each, presenting 1,162 PDI (93.7% of total PDI). 8 patients were hospitalized for more than 10 days, presenting 1,035 PDI (83.5% of total PDI). According to PDI theoretical severity, 37.5% were high, 51.7% moderate, 6.7% low and 4.1% contraindicated. The therapeutic group most involved was antimicrobials (17.6%) and the most frequently involved individual drugs were chloral hydrate (15.9%), midazolam (14.1%) and vecuronium (13.4%). CONCLUSION: PDI were more frequent in patients associated with major polypharmacy and longer hospital stay. PMID- 25697431 TI - [Father involvement in childbirth]. AB - INTRODUCTION: Recent initiatives have promoted the participation of fathers in the early care of their children. OBJECTIVE: To assess the results of a program to encourage parental involvement in childbirth. Parents of healthy term newborns were randomly allocated to participate either in the birth experience or control. PATIENTS AND METHODS: The protocol included: to dry the skin, umbilical cord cutting off, weight, height, and finally give him/her to the mother for the skin to-skin contact. Heart rate (HR), respiratory (RR) and temperature were evaluated one hour later. In the first outpatient clinic assessment, mothers completed a questionnaire. 127 fathers participated either in the birth experience or control. RESULTS: 62 followed the protocol and 65 the control. Both newborn groups were comparable. Also were fathers in age, education and rurality; mothers in primiparity. Significant differences: night care (37/62, 10/65 59.6% vs 15.4%, p<0.01); post prandial assistance (50/62, 14/65 80.6% vs 21.5%, p<0.01); participation in bathing (38/62, 61.3% vs 15/65, 23.1%, p<0.01); newborn visit upon arrival at home (46/62, 74.2% vs 22/65, 33.8%, p<0.01); helping in crying episodes (42/62, 67.7% vs 17/65, 26.1%, p<0.01). There was stability in HR, RR and temperature one hour postpartum. Only one case of complication among parents (fainting). CONCLUSIONS: There were more cases of early care behaviors among participating fathers at birth, even belonging to a discouraging socio cultural environment. PMID- 25697432 TI - [Strengths and difficulties in emotional adjustment of Aymara children from the perspective of children, parents and teachers]. AB - OBJECTIVE: To describe capabilities and difficulties in emotional adjustment experienced by children living in the Chilean Aymara city of Arica. PATIENTS AND METHOD: 610 students between 5th and 8th grade, in addition to their parents and teachers were surveyed using the Strengths and Difficulties Questionnaire (SDQ), comparing Aymara children to those without indigenous heritage. 25 items divided into five scales were evaluated: Emotional, behavioral problems, hyperactivity, relationship problems with peers and prosocial behaviors, classifying the respondents into three levels, Normal, Border and Abnormal. RESULTS: There were no significant differences among the groups studied, where discrepancies in almost all cases show a slight effect (d>=|0.2|). Also, no relevant effects were observed regarding the type of assessor on the assessment of each dimension. Despite this, it was observed that Aymara children showed lower scores than their peers in "behavioral problems" according to their teachers, but this difference was also mild (partial eta2>0.01). CONCLUSIONS: Aymara Children showed similar strengths and difficulties than non-Aymara students in situations that require emotional adjustment. PMID- 25697433 TI - [Monitoring indicators of the program "Chile Grows with You" 2008-2011]. AB - OBJECTIVE: To monitor coverage and outcomes associated with the activities of the integrated protection system for early childhood Chile Grows with You (CHCC), which includes the comprehensive psychosocial development of children between 18 months and 3 years old, in each of the 29 Health Services of the country, as well as the changes observed after 4 years. MATERIAL AND METHOD: Database analysis of all local public networks in the country between 2008 and 2011 was performed. The application of the test regarding psychomotor development, prevalence of development delay and risk, participation of mothers in educational workshops, home visits and recovery rate of deficient children by age were studied. Median and observed changes of each indicator were analyzed developing a ranking based on the results observed. RESULTS: Approximately 75% of children were evaluated, with a prevalence of delay or risk of about 5% and a rate of recovery close to 50%. The participation of mothers in educational workshops increased from 7.6 to 11.0% (p<0.001) and home visits to developmentally delayed children increased 6 times between 2009 and 2011 (p<0.001). Most changes were positive, although the prevalence of developmentally delayed children under 2 years slightly increased (0.6%), and the recovery of 3 year olds decreased (-14.4%). A great variability was observed among the Health Services. CONCLUSIONS: There are some positive results in relation to psychomotor development, with significant regional differences. A lower than expected deficit rate regarding psychomotor development was observed, which implies the need to further analyze the instrument used or the conditions of application. PMID- 25697434 TI - [Ellis van Creveld. Case report]. AB - INTRODUCTION: Ellis-van Creveld (EVC) (OMIM # 225500) syndrome is a rare skeletal dysplasia disorder transmitted by autosomal recessive inheritance. The diagnosis is made based on phenotypic characteristics such as chondrodysplasia, heart defects and polydactyly. The prognosis depends mainly on the severity of the disease, diagnosis and comprehensive management of the condition. OBJECTIVE: To describe a patient diagnosed with EVC syndrome. CASE REPORT: Newborn diagnosed with EVC syndrome who presented dysmorphic facies, shortened long bones, rhizomelic shortening, small hands, brachydactyly, single transverse palmar crease, postaxial polydactyly in the upper limbs, bilateral preaxial polysyndactyly in lower limbs and hypoplastic nails, complex heart defects and narrow thorax. The evolution was unfavorable; the patient died 8 weeks after birth from complications due to heart defects. CONCLUSIONS: EVC syndrome is rare and unknown; therefore, it is important to spread its characteristics within the pediatric community, emphasizing that it affects multiple organ systems and requires a multidisciplinary approach to treat individually each patient, to provide genetic and reproductive counseling to couples and to give information regarding child development expectations. PMID- 25697435 TI - [Skene duct cyst in female newborns--case reports]. AB - INTRODUCTION: The Skene duct cyst, classified as a paraurethral cyst, is a rare congenital abnormality in female neonates and it may manifest throughout the course of life. The incidence varies from 1 in 2000 to 3000 female births. OBJECTIVE: To expose the characteristics and symptoms of a Skene duct cyst at different stages of child development in order to carry out a timely suspicion and diagnosis. CASE REPORT: The first case is a female newborn who presented a painless yellowish tumor adjacent to the urethral meatus, which drained spontaneously; the second case is a teenager who consulted due to leucorrhea for a year and a three-centimeter diameter paraurethral injury between the labia minora, which required surgical treatment and study of the paraurethral mass. CONCLUSIONS: Based on the literature review, we concluded that the frequency of Skene duct cyst is higher than the number of reported cases. Cyst removal, marsupialization, puncture and aspiration are all effective treatment methods. Spontaneous drainage is also appropriate in certain cases. We suggest the use of the least aggressive technique according to each case. PMID- 25697436 TI - [Complex febrile Seizures or Dravet syndrome?: Description of 3 case reports]. AB - INTRODUCTION: Dravet syndrome (DS) is one of the most intractable forms of epilepsy that begins in infancy. This syndrome is characterized by beginning with complex febrile seizures (FS) in a healthy infant and progresses to refractory epilepsy with psychomotor regression. The detection of a SCN1A mutation encoding the sodium channel can confirm the diagnosis. OBJECTIVE: To report 3 confirmed cases of genetically DS. CASE REPORTS: We describe 3 girls diagnosed with complex FS that started when they were between 2 and 7 months old. FS were frequent, hemi generalized and myoclonic associated with recurrent febrile status epilepticus (SE). Despite FS and SE recurrence, the psychomotor development, electrophysiological studies and magnetic resonance imaging (MRI) of the brain were normal. After a year, they developed afebrile seizures progressing to refractory epilepsy with developmental regression. A molecular study detected SCN1A mutation confirming DS. The specific antiepileptic treatment and prevention of febrile episodes allowed partial control of epilepsy with some recovery of psychomotor skills. CONCLUSIONS: The high frequency complex FS associated with recurrent SE in a previously healthy infant should alert about the possibility of DS. Molecular diagnostics helps us to establish a drugs and non-drug therapies treatment, as well as long-term prognosis and genetic counseling. PMID- 25697437 TI - [Common bile duct stricture caused by vascular ring: a case report]. AB - INTRODUCTION: The most common congenital malformations of the bile duct are biliary atresia and choledochal cyst. In addition, the most common liver anatomical variation is the right hepatic artery aberration. The goal of this study is to characterize a patient with this disease and propose the hepatoduodenal anastomosis as surgical treatment. CASE REPORT: One-month-old patient with suspected congenital biliary atresia due to progressive jaundice and acholia since birth. Liver tests consistent with a cholestatic pattern and brain MRI scan consistent with biliary atresia. Periods of decreased bilirubin and sporadic slight pigmentation of depositions were described. The surgical finding was a bile duct stricture due to a vascular ring caused by aberrant right hepatic artery. Resection of bile duct and hepatic-duodenal bypass were performed. The patient evolved satisfactorily from this condition. CONCLUSION: There are few reports of biliary obstruction due to vascular malformations. It is important to keep in mind that not all neonatal jaundice episodes are caused by biliary atresia or choledochal cyst. The clinical course, laboratory tests and imaging should be considered and in the case of suspicion, further exploration should take place. PMID- 25697438 TI - [Accreditation process of pediatric healthcare professionals in Chile]. AB - In Chile since 1984, the Autonomous Corporation for Certification of Medical Specialties (CONACEM) has certified 12,294 medical specialists. The Pediatrics discipline began its certification processes in 1984; it had certified 1,329 specialists by December, 2012. There are three possible ways to get certified: a) to have passed the Training Graduate Degree Program, taken by 57% of the applicants; b) to meet the requirements for Training in Practice for 5 years, achieved by 39% of applicants; c) to have been trained oversees according to validated programs. There are 11 accredited 3-year long university programs, which take place in Santiago and Provinces with a total annual capacity of 96 students. With the exception of doctors approved by accredited medical university programs, the rest of the applicants must pass a practical examination. A written examination has been added since 2002, whose approval is required to take the practical examination, which has proven to have good discrimination (22% average rejection in 11 years). The certifications granted today are good for 10 years and recertification is good for 7 years. The expiration of the certification process is related to recertification. This review discusses the reasons behind it and discusses the requirements and a table of credits to complete. Current legislation requires the action of at least one certification body, a condition that has been legally and uniquely granted by the Ministry of Health to CONACEM since 2/11/2014. PMID- 25697439 TI - [Could infant euthanasia be ever acceptable?]. AB - The recent enactment of a law that allows infant euthanasia in Belgium raises questions with varied answers. To contribute to a better understanding of the topic, euthanasia and legislation concepts are described. After a bioethical analysis, we propose as conclusion that children euthanasia could only be acceptable in very exceptional situations in which palliative measures have failed. The answer should be that it is not acceptable in our setting, not until we have public policies, protocols and palliative care services for terminally ill children. PMID- 25697440 TI - [Clinical-radiological case for diagnosis]. PMID- 25697441 TI - [The lactary of the Manuel Arriaran Hospital. Two years of operation]. PMID- 25697445 TI - What are the ethical issues in treating a patient with bilateral leg gangrene incapable of consenting to amputation secondary to psychiatric illness? AB - BACKGROUND: Bilateral and simultaneous lower extremity amputations unrelated to diabetes and peripheral vascular disease are uncommon, although they may be necessary in patients with severe blast injuries. Such amputations, however, usually are performed in patients who are able to understand and consent to the treatment. CASE DESCRIPTION: We present the case of a 29-year-old woman who experienced drug-induced psychosis and underwent substantial hypothermic injuries; most notably, irreversible frostbite injuries to both lower extremities, leading to dry and mummified gangrene. As a result of her psychiatric illness, fluctuating catatonic state, and lack of insight into her clinical condition, she was deemed incapable of making decisions regarding her medical care and her mother was made substitute decision maker. The orthopaedic service was consulted regarding possible surgical treatment of her gangrenous feet that were stable and aseptic after limb preservation efforts (including hyperbaric oxygen) had been tried without success. They recommended close clinical monitoring and continued psychiatric treatment. The family, including the substitute decision maker, citing the patient's best interest, rejected the recommendations of the surgical team and demanded immediate surgical transtibial amputation of both lower legs. LITERATURE REVIEW: To our knowledge, such a unique case has not been reported. CLINICAL RELEVANCE: We examined the decision-making process, the difficulties of caring for such a patient, and the ethical issues that arose. PMID- 25697446 TI - Reply to the letter to the editor: infrapatellar saphenous neuralgia after TKA can be improved with ultrasound-guided local treatments. PMID- 25697447 TI - Photoelectrochemistry of n-type antimony sulfoiodide nanowires. AB - In the presented work the photoelectrochemical properties of SbSI along with the electronic structure (i.e. conduction and valence band edge potentials as well as conductivity type) of sonochemically obtained nanowires are discussed for the first time. The spectroscopic investigations indicate interesting optical properties, including surface isotope effect and excitonic emission. The photoelectrochemical investigation of SbSI revealed the occurrence of the photoelectrochemical photocurrent switching effect. It may be defined as a change in photocurrent direction (generated at the illuminated semiconducting electrode immersed in electrolyte) due to an appropriate polarization of the electrode versus the reference electrode. It is often observed for semiconductors as a result of the reduction of molecular oxygen dissolved in the electrolyte. However, in the case of SbSI, the photocurrent switching was recorded regardless of the presence of molecular oxygen in the electrolyte, probably due to the reduction of triiodide species formed at anodic polarization of the SbSI electrode, in an iodide-containing electrolyte. The switching potential (i.e. the potential where anodic-to-cathodic photocurrent transition occurs) equals to ca. 0.4 V versus standard hydrogen electrode, which is close to the formal potential of the I(-)/I3(-) redox couple. Therefore, this semiconducting material is of potential interest for the construction of new photovoltaic systems, novel optoelectronic switches and logic devices. PMID- 25697448 TI - Shaken baby expert must disclose fitness to practise charges when asked to give evidence in new cases. PMID- 25697449 TI - Coexistence of electrical conductivity and ferromagnetism in a hybrid material formed from reduced graphene oxide and manganese oxide. AB - The coexistence of electrical conductivity and ferromagnetism has been achieved in a reduced graphene oxide/manganese oxide hybrid (rGO-Mn) synthesized by chemical reduction of a graphene oxide and Mn(2+) (as its GO-Mn(2+) complex) using hydrazine. The rGO-Mn and GO-Mn(2+) complexes were characterized by Fourier transform infrared spectroscopy (FT-IR), Raman spectroscopy, X-ray photoelectron spectroscopy (XPS) and transmission electron microscopy (TEM). In rGO-Mn the Mn was present as manganese oxide nanoparticles located on the rGO nanosheets. This rGO-Mn exhibits both electrical conductivity and ferromagnetism. The synthesis of hybrids incorporating rGO and metal oxides is proposed as a useful strategy for generation of new multifunctional nano-composite materials. PMID- 25697450 TI - Simultaneous Determination of Methoxylated Polybrominated Diphenyl Ethers and Polybrominated Diphenyl Ethers in Water, Soil and Sediment from China by GC-MS. AB - Polybrominated diphenyl ethers (PBDEs) are widely used brominated flame retardants, which are increasingly reported in the environment. Methoxylated polybrominated diphenyl ethers (MeO-PBDEs) are structural analogs to PBDEs and reported as natural products and novel pollutants present in the environment. First, a new isotopic dilution GC-MS method was developed in this study to simultaneously determine 13 PBDEs and 8 MeO-PBDEs in water, soil and sediment. Liquid/liquid extraction, pressurized liquid extraction and multi-layer silica gel column chromatography cleanup were used, and some important steps and crucial parameters were modified and intensified compared with the other literatures. Besides, the conditions of GC and MS were also optimized. The limits of quantitation values of 0.005-0.1 and 0.02-0.1 ug L(-1) in water were calculated for PBDEs and MeO-PBDEs, respectively; so did 0.25-5 and 1-5 ug kg(-1) dry weight in soil and sediment. In addition, good repeatability and accuracy of the whole method were achieved. Moreover, 60 water and 30 sediment samples for aquaculture crayfish and freshwater fish collected from aquatic products production base, 40 soil samples collected from agricultural products production base and also 20 Yangtze River water samples and 20 Hanjiang River water samples collected from different sampling situations near Wuhan, Hubei province along the Yangtze River and the Hanjiang River were analyzed to determine whether they are contaminated by PBDEs and MeO-PBDEs. Using the established methods, it was found that PBDEs or MeO-PBDEs emerged in 4 of 60 water samples for aquatic products, 3 of 40 soils, and 2 of 30 sediments and in low ug kg(-1) dry weight for soil and sediments and low ug L(-1) for water. PMID- 25697451 TI - Is resistant starch protective against colorectal cancer via modulation of the WNT signalling pathway? AB - Epidemiological and experimental evidence suggests that non-digestible carbohydrates (NDC) including resistant starch are protective against colorectal cancer. These anti-neoplastic effects are presumed to result from the production of the SCFA, butyrate, by colonic fermentation, which binds to the G-protein coupled receptor GPR43 to regulate inflammation and other cancer-related processes. The WNT pathway is central to the maintenance of homeostasis within the large bowel through regulation of processes such as cell proliferation and migration and is frequently aberrantly hyperactivated in colorectal cancers. Abnormal WNT signalling can lead to irregular crypt cell proliferation that favours a hyperproliferative state. Butyrate has been shown to modulate the WNT pathway positively, affecting functional outcomes such as apoptosis and proliferation. Butyrate's ability to regulate gene expression results from epigenetic mechanisms, including its role as a histone deacetylase inhibitor and through modulating DNA methylation and the expression of microRNA. We conclude that genetic and epigenetic modulation of the WNT signalling pathway may be an important mechanism through which butyrate from fermentation of resistant starch and other NDC exert their chemoprotective effects. PMID- 25697452 TI - The restless mind while driving: drivers' thoughts behind the wheel. AB - Recent research has clearly shown that inattention when driving has an indisputable impact on road safety. "Mind wandering" (MW), an inattentional state caused by a shift in attention from the ongoing task to inner thoughts, is not only frequent in everyday activities but also known to impact performance. There is a growing body of research investigating the concept of MW, suggesting potential causes that could foster such a phenomenon. Only one epidemiological study has focused on this issue in a critical driving context (Galera et al., 2012), and it revealed the harmful effects of MW in increasing the risk of a car crash. Experimental studies rather consider that driver would adduce in MW (Lemercier et al., 2014). When the driving context is too hard or the thought too difficult to proceed, driver reduced their MW. The aim of this paper is to examine this issue using the most recent trip of ordinary drivers whose MW state did not lead to a road accident. Using a questionnaire, information was collected about the participants' most recent trip as a driver, including: (1) personal characteristics, (2) context in which MW occurs, (3) awareness of MW episodes and finally (4) characteristics of the thoughts. RESULTS: revealed that MW affected 85.2% of the drivers, who spent on average 34.74% of their trip in a MW state. Moreover, we found that the contexts which favor MW are situations in which less of the driver's attention is needed to drive, such as familiar commutes, monotonous motorways or by-passes, or when drivers were alone in their cars. In these MW situations, the drivers quickly became aware of their MW episodes. Thoughts tend to involve neutral private concerns, related to present- or future oriented content. Our findings suggest that MW is a functional state aiming to solve current problems. Future investigations should focus on this critical concept of MW when driving, both to identify safety issues and to provide suitable solutions for drivers subject to a wandering mind. PMID- 25697453 TI - The effects of surface neuromuscular electrical stimulation on post-stroke dysphagia: a systemic review and meta-analysis. AB - OBJECTIVE: In this study, we intended to evaluate whether swallow treatment with neuromuscular electrical stimulation is superior to that without neuromuscular electrical stimulation, and whether neuromuscular electrical stimulation alone is superior to swallow therapy. METHODS: We searched the PubMed and Scopus databases from their earliest record to 31 December 2014 for randomized and quasi randomized controlled trials that used neuromuscular electrical stimulation to treat post-stroke dysphagia. The Jadad scale was used to assess the quality of the included studies. We extracted the mean differences and standard deviation (SD) between baseline and posttreatment or posttreatment mean and SD for selected outcomes measured in the experimental and control groups for subsequent meta analyses. RESULTS: Eight studies were identified. For the comparison "swallow treatment with neuromuscular electrical stimulation vs. swallow treatment without neuromuscular electrical stimulation," we found a significant standardized mean difference (SMD) of 1.27 (95% confidence interval (CI) = 0.51-2.02, P = 0.001) with significant heterogeneity (I(2) = 85%). The meta-analysis for the comparison of neuromuscular electrical stimulation alone and swallow therapy demonstrated a non-significant SMD of 0.25 (95% CI = -0.16-0.65, P = 0.23) without significant heterogeneity (I(2) = 16%). CONCLUSION: Swallow treatment with neuromuscular electrical stimulation seems to be more effective than that without neuromuscular electrical stimulation for post-stroke dysphagia in the short term considering the limited number of studies available. Evidence was insufficient to indicate that neuromuscular electrical stimulation alone was superior to swallow therapy. PMID- 25697454 TI - Does attentional focus during balance training in people with Parkinson's disease affect outcome? A randomised controlled clinical trial. AB - OBJECTIVE: To compare the effects of attentional focus to augment balance outcomes in individuals with Parkinson's disease. DESIGN: Randomised controlled clinical trial. SETTING: University gait and balance research laboratory. PARTICIPANTS: Forty-nine individuals with idiopathic Parkinson's disease. INTERVENTIONS: Participants were randomly assigned into one of four groups (three balance intervention groups and one control). The three intervention groups all received the same 4-week balance training program augmented with either external, internal, or no focus instructions. The control group did not receive any balance training. MAIN MEASURES: Outcomes were measured at baseline, post intervention, 2 weeks post intervention, and 8-weeks post intervention and included: Sensory Organization Test, Berg Balance Scale, Self-Selected Gait Velocity, Dynamic Gait Index, Activities-Specific Balance Confidence Scale, and obstacle course completion time. RESULTS: There were no differences among the groups in trajectory over the course of the trial for all outcomes (ps ? .135). All groups improved from baseline to post intervention and from baseline to 2-weeks post intervention for all outcomes (ps ? .003), except Self-Selected Gait Velocity, which did not change over the course of the trial (P = .121). CONCLUSIONS: Attentional focus instructions to augment a 4-week balance training program did not result in any change over and above a control group in measures of gait and balance in individuals with Parkinson's disease. Additionally, while all four groups improved, there was no difference among the groups, including the control, suggesting that the 4-week balance training program in this trial was not effective. PMID- 25697455 TI - Longitudinal analysis of age-related changes in intraocular pressure in South Korea. AB - PURPOSE: To assess the changes in intraocular pressure (IOP) with age in South Korea. METHODS: Subjects aged 20-79 who had been receiving health examinations at a university hospital were enrolled. They completed physical and ophthalmic examinations. Subjects with ocular disease that could possibly affect their IOP were excluded. The relationships between IOP and age, blood pressure, heart rate, body mass index, blood chemistry, and electrolyte were analyzed using a linear mixed model. RESULTS: Of the 33 712 subjects, 31 857 participants were enrolled. In a cross-sectional analysis, IOP also showed a negative correlation in all age groups (respectively, P<0.001). In particular, patients in their 60s~80s had a less steep decreasing slope of IOP with age than patients in their 20s~30s (correlation coefficient -0.260 and -0.168, respectively). In longitudinal analysis, negative trend was shown in the slope of tendency in total subjects. When analyzing the effect of gender on the relationship between age and IOP, females had a less steep decreasing slope of IOP with age than males by 0.05 mm Hg. With regard to systemic parameters, systolic blood pressure and heart rate were positively correlated with IOP (P<0.001). CONCLUSION: IOP was significantly decreased with age, although the amount of change was small. In women and older age groups, IOP was less decreased than that of men and young age groups. In addition, IOP was positively associated with systolic blood pressure and heart rate. PMID- 25697456 TI - Is the 1-day postoperative IOP check needed post uncomplicated phacoemulsification in patients with glaucoma and ocular hypertension? AB - PURPOSE: To determine whether the 1-day postoperative intraocular pressure (IOP) check following routine uncomplicated phacoemulsification is necessary in patients with pre-existing glaucoma and ocular hypertension (OHT), if acetazolamide prophylaxis is used. To investigate the practice of U.K. glaucoma specialists in IOP rise prophylaxis and follow-up regimes. PATIENTS AND METHODS: The IOP 1-day postoperatively was analysed against the last recorded IOP before phacoemulsification in a cohort of patients with glaucoma or OHT who underwent uncomplicated phacoemulsification cataract surgery between December 2009 and September 2012, where it was routine practice to give acetazolamide postoperatively. U.K. and Eire Glaucoma Society members were surveyed via an online questionnaire to analyse practice among U.K. glaucoma specialists. RESULTS: One hundred and seven eyes were studied: 99 with glaucoma and 8 with OHT. The mean IOP change was -0.8 mm Hg with only two eyes measuring >30 mm Hg postoperatively (2%). Both these eyes received 750 mg acetazolamide. Eighteen (17%) eyes had an IOP rise of at least 30%. In the survey of practice there were 65 respondents. Twenty-one (32%) respondents did not use IOP prophylaxis. Only 17 (26%) of respondents routinely reviewed their patients 1-day postoperatively. CONCLUSION: Our prophylactic acetazolamide regime does not completely eliminate the risk of an IOP >30 mm Hg on day 1 post routine phacoemulsification in glaucoma/OHT patients. Patients with pre-existing glaucoma, despite acetazolamide prophylaxis, will require IOP management decisions on the first postoperative day after uncomplicated phacoemulsification surgery. U.K. expert practice is non uniform with regard to IOP prophylaxis, and the 1-day review, and further discussion and formulation of consensus appears necessary. PMID- 25697457 TI - Randomised clinical trial evaluating best-corrected visual acuity and central macular thickness after 532-nm subthreshold laser grid photocoagulation treatment in diabetic macular oedema. AB - PURPOSE: To compare best-corrected visual acuity (BCVA) and central macular thickness (CMT) after 532-nm subthreshold laser grid photocoagulation and threshold laser grid photocoagulation for the treatment of diabetic macular oedema (DME). PATIENTS AND METHODS: Twenty-three patients (46 eyes) with binocular DME were enroled in this study. The two eyes of each patient were divided into a subthreshold photocoagulation group and a threshold photocoagulation group. The eyes of the subthreshold group underwent 532-nm patter scan laser system (PASCAL) 50% end point subthreshold laser grid photocoagulation therapy, whereas the threshold photocoagulation group underwent short-pulse grid photocoagulation with a 532-nm PASCAL system. BCVA and CMT were assessed in all patients before treatment, 7 days after treatment, and 1, 3, and 6 months after treatment. RESULTS: After grid photocoagulation, the mean BCVA improved in both the subthreshold group, and the threshold group, and the two groups did not differ statistically significantly from each other. Similarly, the macular oedema diminished in both groups after treatment, and the two groups did not differ statistically significantly from each other with regard to CMT. CONCLUSION: Both 532-nm subthreshold laser grid photocoagulation and threshold laser grid photocoagulation can improve the visual acuity and reduce CMT in DME patients. PMID- 25697458 TI - The accuracy of the Edinburgh Red Eye Diagnostic Algorithm. AB - PURPOSE: To assess the diagnostic accuracy of the Edinburgh Red Eye Algorithm. METHODS: This was a prospective study. A questionnaire was designed and made available to clinicians referring patients to the acute ophthalmology service within Edinburgh. The questionnaire involved them using the algorithm to reach a diagnosis in patients presenting with red eye(s). Patients were then referred to the emergency eye clinic and the questionnaire faxed to the clinic or sent with the patients. Patients were then examined by an experienced ophthalmologist (not blinded) to reach a 'gold standard' diagnosis. The concordance between the 'algorithm assisted' diagnosis and the 'gold standard' was then assessed. RESULTS: All patients presenting with red eye(s) were eligible for inclusion. Forty-one questionnaires were completed, two were excluded. The algorithm assisted diagnosis was correct 72% (28/39) of the time. It correctly diagnosed: acute angle closure glaucoma in 100% of cases (4/4); iritis in 82% (9/11); stromal keratitis in 63% (5/8); epithelial keratitis in 70% (7/10); and infective conjunctivitis in 50% (3/6). DISCUSSION: The diagnostic accuracy of The Edinburgh Red Eye Diagnostic Algorithm is 72, rising to 76% when only the most serious red eye(s) causes are included. The diagnostic accuracy of non-ophthalmologists when assessing patients presenting with red eye(s) is greater when the algorithm is used. We hope that the use of this algorithm will prevent delayed presentations of certain serious eye conditions and reduce the morbidity from delayed treatment. PMID- 25697459 TI - Macular hole in retinitis pigmentosa patients: microincision vitrectomy with polydimethylsiloxane as possible treatment. AB - PURPOSE: To investigate long-term retinal changes after microincision pars plana vitrectomy surgery (MIVS) for macular hole (MH) in retinitis pigmentosa (RP) patients-retrospective and observational study. METHODS: Three RP patients suffering from MH were evaluated by means of best corrected visual acuity, anterior and posterior binocular examination, spectralis high-resolution optical coherence tomography, MP-1 microperimetry (MP-1), and full-field electroretinogram (ERG), before MIVS and during the 36-month follow-up. Patients underwent simultaneous MIVS and microincision cataract surgery; IOL was positioned in capsular bag. Patients were hospitalised for 2 days after the surgery. Surgical procedure was performed according the following schedule: surgical removal of crystalline lens, MIVS with 23-gauge sutureless system trocars, core vitreous body removal, peeling of the inner limiting membrane, and balanced sterile saline solution-air-micro-structured polydimethylsiloxane (PDMS) exchange. PDMS tamponade, after 6 months starting from MIVS, was removed. RESULTS: In all patients visual acuity increased after vitrectomy as a consequence of complete MH closure and restoration of retinal architecture. None of the patients developed ocular hypertension, or re-opening of MH during the 3 year follow-up. MP-1 bivariate contour ellipse area was reduced in its dimensions and improved in all patients demonstrating a better fixation. CONCLUSIONS: MIVS could be an effective treatment in RP patients with MH if medical therapy is not applicable or not sufficient. Finally more studies will be needed to improve knowledge about this genetic disease. PMID- 25697460 TI - Nanostructure characterisation of flow-formed Cr-Mo-V steel using transmission Kikuchi diffraction technique. AB - Nowadays flow-forming has become a desired near net shape manufacturing method as it provides excellent mechanical properties with improved surface finish and significant manufacturing cost reduction. However, the material is subjected to excessive plastic deformation during flow-forming process, generating a very fine and complex microstructure. In addition, the intense dislocation density and residual stress that is generated in the component during processing makes the microstructure characterisation using conventional micro-analytical tools challenging. Thus, the microstructure/property relationship study in such a material is rather difficult. In the present study a flow-formed Cr-Mo-V steel nanostructure and crystallographic texture were characterised by means of Transmission Kikuchi Diffraction (TKD). Here, TKD is shown to be a powerful technique in revealing very fine martensite laths within an austenite matrix. Moreover, fine precipitates in the order of 20-70 nm on the martensite lath boundaries were clearly imaged and characterised. This greatly assisted in understanding the preferable site formation of the carbides in such a complex microstructure. The results showed that the actual TKD spatial resolution was in the range of 5-10 nm using 25 kV for flow-formed Cr-Mo-V steel. PMID- 25697461 TI - Estimation of dislocation density from precession electron diffraction data using the Nye tensor. AB - The Nye tensor offers a means to estimate the geometrically necessary dislocation density of a crystalline sample based on measurements of the orientation changes within individual crystal grains. In this paper, the Nye tensor theory is applied to precession electron diffraction automated crystallographic orientation mapping (PED-ACOM) data acquired using a transmission electron microscope (TEM). The resulting dislocation density values are mapped in order to visualize the dislocation structures present in a quantitative manner. These density maps are compared with other related methods of approximating local strain dependencies in dislocation-based microstructural transitions from orientation data. The effect of acquisition parameters on density measurements is examined. By decreasing the step size and spot size during data acquisition, an increasing fraction of the dislocation content becomes accessible. Finally, the method described herein is applied to the measurement of dislocation emission during in situ annealing of Cu in TEM in order to demonstrate the utility of the technique for characterizing microstructural dynamics. PMID- 25697462 TI - Towards an optimum design for electrostatic phase plates. AB - Charging of physical phase plates is a problem that has prevented their routine use in transmission electron microscopy of weak-phase objects. In theory, electrostatic phase plates are superior to thin-film phase plates since they do not attenuate the scattered electron beam and allow freely adjustable phase shifts. Electrostatic phase plates consist of multiple layers of conductive and insulating materials, and are thus more prone to charging than thin-film phase plates, which typically consist of only one single layer of amorphous material. We have addressed the origins of charging of Boersch phase plates and show how it can be reduced. In particular, we have performed simulations and experiments to analyze the influence of the insulating Si3N4 layers and surface charges on electrostatic charging. To optimize the performance of electrostatic phase plates, it would be desirable to fabricate electrostatic phase plates, which (i) impart a homogeneous phase shift to the unscattered electrons, (ii) have a low cut-on frequency, (iii) expose as little material to the intense unscattered beam as possible, and (iv) can be additionally polished by a focused ion-beam instrument to eliminate carbon contamination accumulated during exposure to the unscattered electron beam (Walter et al., 2012, Ultramicroscopy, 116, 62-72). We propose a new type of electrostatic phase plate that meets the above requirements and would be superior to a Boersch phase plate. It consists of three free standing coaxial rods converging in the center of an aperture (3-fold coaxial phase plate). Simulations and preliminary experiments with modified Boersch phase plates indicate that the fabrication of a 3-fold coaxial phase plate is feasible. PMID- 25697463 TI - Foot-to-foot bioelectrical impedance accurately tracks direction of adiposity change in overweight and obese 7- to 13-year-old children. AB - Body composition measurements are valuable when evaluating pediatric obesity interventions. We hypothesized that foot-to-foot bioelectrical impedance analysis (BIA) will accurately track the direction of adiposity change, but not magnitude, in part due to differences in fat patterning. The purposes of this study were to examine the accuracy of body composition measurements of overweight and obese children over time using dual-energy x-ray absorptiometry (DXA) and BIA and to determine if BIA accuracy was affected by fat patterning. Eighty-nine overweight or obese children (48 girls, 41 boys, age 7-13 years) participating in a randomized controlled trial providing a family-centered, lifestyle intervention, underwent DXA and BIA measurements every 3 months. Bland-Altman plots showed a poor level of agreement between devices for baseline percent body fat (%BF; mean, 0.398%; +2SD, 8.685%; -2SD, -7.889%). There was overall agreement between DXA and BIA in the direction of change over time for %BF (difference between visits 3 and 1: DXA -0.8 +/- 0.5%, BIA -0.7 +/- 0.5%; P = 1.000) and fat mass (FM; difference between visits 3 and 1: DXA 0.7 +/- 0.5 kg, BIA 0.6 +/- 0.5 kg; P = 1.000). Bioelectrical impedance analysis measurements of %BF and FM at baseline were significantly different in those with android and gynoid fat (%BF: 35.9% +/- 1.4%, 32.2% +/- 1.4%, P < .003; FM: 20.1 +/- 0.8 kg, 18.4 +/- 0.8, P < .013). Bioelectrical impedance analysis accurately reports the direction of change in FM and FFM in overweight and obese children; inaccuracy in the magnitude of BIA measurements may be a result of fat patterning differences. PMID- 25697464 TI - Exploring the Potential for Moral Hazard When Clinical Trial Research is Conducted in Rural Communities: Do Traditional Ethics Concepts Apply? AB - Over the past 20 years, clinical research has migrated from academic medical centers to community-based settings, including rural settings. This evolving research environment may present some moral hazards or challenges that could undermine traditionally accepted standards for the protection of human subjects. The study described in this article was designed to explore the influence of motives driving the decisions to conduct clinical trial research in rural community settings. The researchers conducted semi-structured interviews with 80 participants who conducted clinical trials with rural subjects. The interviews provided a way to examine the influence of budgetary factors when deciding to conduct a clinical study, how information about the budget and the purpose of the study is conveyed to research participants, and the potential willingness of clinicians and coordinators to enroll in the kinds of studies they offer. The findings suggest that clinical trial research in rural communities may challenge clinicians' abilities to balance the needs of the patient with the needs of the research enterprise. Few respondents seemed to recognize the traditionally recognized hazards of a dual relationship, specifically the moral risks of trying to attend to the interests of both patient and industry. It seems important to re examine how we protect human subjects and what such protection should look like as research becomes part of the way medical care is provided, even in very rural areas. PMID- 25697465 TI - Effects of posture and squatting on the dynamics of micturition. PMID- 25697466 TI - Effects of posture and squatting on the dynamics of micturition: response to Bush and Liedl. PMID- 25697467 TI - Acute porphyria in a patient with Arnold Chiari malformation. AB - BACKGROUND: Acute porphyria and Arnold Chiari malformation are both uncommon genetic disorders without known association. The insidious onset, non-specific clinical manifestations, and precipitating factors often cause diagnosis of acute porphyria to be missed, particularly in patients with comorbidities. CASE REPORT: A women with Arnold Chiari malformation type II who was treated with oxybutynin and antibiotics, including Bactrim for neurogenic bladder and recurrent urinary tract infection, presented with non-specific abdominal pain, constipation, and diarrhea. After receiving Flagyl for C. difficile colitis, the patient developed psychosis, ascending paralysis, and metabolic derangements. She underwent extensive neurological workup due to her congenital neurological abnormalities, most of which were unremarkable. As a differential diagnosis of Guillain Barre syndrome, acute porphyria was then considered and ultimately proved to be the diagnosis. After hematin administration and intense rehabilitation, the patient slowly recovered from the full-blown acute porphyria attack. CONCLUSIONS: This case report, for the first time, documents acute porphyria attack as a result of a sequential combination of 3 common medications. This is the first case report of the concomitant presence of both acute porphyria and Arnold Chiari malformation, 2 genetic disorders with unclear association. PMID- 25697468 TI - Development of an enhanced bovine viral diarrhea virus subunit vaccine based on E2 glycoprotein fused to a single chain antibody which targets to antigen presenting cells. AB - Bovine viral diarrhea virus (BVDV) is an important cause of economic losses worldwide. E2 is an immunodominant protein and a promising candidate to develop subunit vaccines. To improve its immunogenicity, a truncated E2 (tE2) was fused to a single chain antibody named APCH, which targets to antigen-presenting cells. APCH-tE2 and tE2 proteins were expressed in the baculovirus system and their immunogenicity was firstly compared in guinea pigs. APCH-tE2 vaccine was the best one to evoke a humoral response, and for this reason, it was selected for a cattle vaccination experiment. All the bovines immunized with 1.5 MUg of APCH-tE2 developed high levels of neutralizing antibodies against BVDV up to a year post immunization, demonstrating its significant potential as a subunit vaccine. This novel vaccine is undergoing scale-up and was transferred to the private sector. Nowadays, it is being evaluated for registration as the first Argentinean subunit vaccine for cattle. PMID- 25697469 TI - Surgical management for displaced pediatric proximal humeral fractures: a cost analysis. AB - PURPOSE: The purpose of this investigation was to determine which of the following methods of fixation, percutaneous pinning (PP) or intramedullary nailing (IMN), was more cost-effective in the treatment of displaced pediatric proximal humeral fractures (PPHF). METHODS: A retrospective cohort of surgically treated PPHF over a 12-year period at a single institution was performed. A decision analysis model was constructed to compare three surgical strategies: IMN versus percutaneous pinning leaving the pins exposed (PPE) versus leaving the pins buried (PPB). Finally, sensitivity analyses were performed, assessing the cost-effectiveness of each technique when infection rates and cost of deep infections were varied. RESULTS: A total of 84 patients with displaced PPHF underwent surgical stabilization. A total of 35 cases were treated with IMN, 32 with PPE, and 17 with PPB. The age, sex, and preoperative fracture angulation were similar across all groups. A greater percentage of open reduction was seen in the IMN and PPB groups (p = 0.03), while a higher proportion of physeal injury was seen in the PPE group (p = 0.02). Surgical time and estimated blood loss was higher in the IMN group (p < 0.001 and p = 0.01, respectively). The decision analysis revealed that the PPE technique resulted in an average cost saving of $4,502 per patient compared to IMN and $2,066 compared to PPB. This strategy remained cost-effective even when the complication rates with exposed implants approached 55 %. CONCLUSIONS: Leaving pins exposed after surgical fixation of PPHF is more cost-effective than either burying pins or using intramedullary fixation. PMID- 25697470 TI - Nomograms for predicting the prognosis of stage IV colorectal cancer after curative resection: a multicenter retrospective study. AB - PURPOSE: Although stage IV colorectal cancer (CRC) encompasses a wide variety of clinical conditions with diverse prognoses, no statistical model for predicting the postoperative prognosis of stage IV CRC has been established. Thus, we here aimed to construct a predictive model for disease-free survival (DFS) and overall survival (OS) after curative surgery for stage IV CRC using nomograms. METHODS: The study included 1133 stage IV CRC patients who underwent curative surgical resection in 19 institutions. Patients were divided into derivation (n = 586) and validation (n = 547) groups. Nomograms to predict the 1- and 3-year DFS rates and the 3- and 5-year OS rates were constructed using the derivation set. Calibration plots were constructed, and concordance indices (c-indices) were calculated. The predictive utility of the nomogram was validated in the validation set. RESULTS: The postoperative carcinoembryonic antigen (CEA) level, depth of tumor invasion (T factor), lymph node metastasis (N factor), and number of metastatic organs were adopted as variables for the DFS-predicting nomogram, whereas the postoperative CEA level, T factor, N factor, and peritoneal dissemination were adopted for the nomogram to predict OS. The nomograms showed moderate calibration, with c-indices of 0.629 and 0.640 in the derivation set and 0.604 and 0.637 in the validation set for DFS and OS, respectively. CONCLUSIONS: The nomograms developed were capable of estimating the probability of DFS and OS on the basis of only 4 variables, and may represent useful tools for postoperative surveillance of stage IV CRC patients in routine practice. PMID- 25697471 TI - Mechanical hyperalgesia in rats with diabetic polyneuropathy is selectively inhibited by local peripheral nociceptin/orphanin FQ receptor and u-opioid receptor agonism. AB - Peripheral receptors may contribute to the effects of systemically administered centrally available analgesics. In the present study, we analysed the effect of local peripheral injection of the nociceptin/orphanin FQ peptide (NOP) receptor agonist Ro65-6570 and compared it to the u-opioid peptide (MOP) receptor agonist morphine in streptozotocin-induced diabetic polyneuropathy in rats. Ro65-6570 and morphine were injected intraplantarly into the hind paw of diabetic rats, and mechanical withdrawal thresholds were determined in both paws (ipsi- and contralateral to the injection site). Ro65-6570 in the dose range of 7.1 71.4nmol/animal showed antihyperalgesic effects with maximal efficacy of 57.1+/ 15.4% maximal possible effect (MPE) at the dose of 23.8nmol/animal. Intraplantar administration of morphine showed dose-dependent antihyperalgesic effects in the dose range of 25.8-257.8nmol/animal in a similar efficacy range with a maximal efficacy of 76.0+/-12.1% MPE at the dose of 257.8nmol/animal. Both compounds did not induce overt confounding side effects across the tested dose range. The NOP receptor antagonist J-113397 and the MOP receptor antagonist naloxone, intraplantarly co-administered with the respective agonists, selectively and completely prevented the antihyperalgesic action of the respective NOP and MOP receptor agonist. These results indicate that the activation of peripheral NOP and MOP receptors by Ro65-6570 and morphine, respectively, mediated antihyperalgesic effects in rats with diabetic polyneuropathy. PMID- 25697472 TI - Effect of a single treatment with tadalafil on blood flow in lower urinary tract tissues in rat models of bladder overdistension/emptying and abdominal aorta clamping/release. AB - Impaired blood flow in lower urinary tract (LUT) tissues is a pathophysiological cause of LUT symptoms. We investigated the effects of the phosphodiesterase 5 (PDE5) inhibitor tadalafil on the sustained decrease in bladder blood flow (BBF) and time-dependent changes in BBF and prostate blood flow (PBF) resulting from ischemia/reperfusion in two rat models. In a rat model of bladder overdistension/emptying (O/E), the bladder was overdistended by saline infusion and emptied after 2h. Tadalafil was administered intraduodenally immediately after emptying. In a rat model of clamping/release (C/R), the abdominal aorta was clamped for 2h after a single oral dose of tadalafil and then the clamp was released. BBF in O/E and C/R rats and PBF in C/R rats were measured by laser Doppler flow imaging. BBF decreased on overdistension and partially recovered after emptying. A progressive decrease in BBF was observed after O/E, and this was prevented by tadalafil treatment. Both BBF and PBF decreased during clamping of the abdominal aorta and partially recovered after clamp removal. Oral pretreatment with tadalafil partially or completely prevented the decreases in BBF and PBF not only after clamp removal but also during clamping. PDE5 mRNA was highly expressed in the bladder and the supporting vasculature. Tadalafil inhibited the O/E-induced decrease in BBF and the C/R-induced time-dependent decreases in BBF and PBF. PDE5 inhibition by tadalafil may improve both BBF and PBF. PMID- 25697473 TI - Chlorpheniramine produces spinal motor, proprioceptive and nociceptive blockades in rats. AB - This study aimed to assess the local anesthetic effects of chlorpheniramine in spinal anesthesia and is compared with mepivacaine, a widely-used local anesthetic. Spinal anesthesia with chlorpheniramine and mepivacaine was constructed in a dosage-dependent fashion after the rats were injected intrathecally. The spinal block effect of chlorpheniramine in motor function, nociception, and proprioception was compared to that of mepivacaine. We revealed that intrathecal chlorpheniramine and mepivacaine exhibited a dose-dependent spinal block of motor function, nociception, and proprioception. On the 50% effective dose (ED50) basis, the ranks of potencies in motor function, nociception, and proprioception were chlorpheniramine>mepivacaine (P<0.01 for the differences). On the equianesthetic basis (ED25, ED50, ED75), the duration of spinal anesthesia with chlorpheniramine was greater than that of mepivacaine (P<0.01 for the differences). Instead of mepivacaine, chlorpheniramine produced a greater duration of sensory blockade than the motor blockade. These preclinical data showed that chlorpheniramine has a better sensory-selective action over motor block to produce more potent and long-lasting spinal anesthesia than mepivacaine. PMID- 25697474 TI - Biocides in the Yangtze River of China: spatiotemporal distribution, mass load and risk assessment. AB - Nineteen biocides were investigated in the Yangtze River to understand their spatiotemporal distribution, mass loads and ecological risks. Fourteen biocides were detected, with the highest concentrations up to 166 ng/L for DEET in surface water, and 54.3 ng/g dry weight (dw) for triclocarban in sediment. The dominant biocides were DEET and methylparaben, with their detection frequencies of 100% in both phases. An estimate of 152 t/y of 14 biocides was carried by the Yangtze River to the East China Sea. The distribution of biocides in the aquatic environments was significantly correlated to Gross Domestic Product (GDP), total phosphorus (TP) and total nitrogen (TN), suggesting dominant input sources from domestic wastewater of the cities along the river. Risk assessment showed high ecological risks posed by carbendazim in both phases and by triclosan in sediment. Therefore, proper measures should be taken to reduce the input of biocides into the river systems. PMID- 25697475 TI - Sources, occurrence and predicted aquatic impact of legacy and contemporary pesticides in streams. AB - We couple current findings of pesticides in surface and groundwater to the history of pesticide usage, focusing on the potential contribution of legacy pesticides to the predicted ecotoxicological impact on benthic macroinvertebrates in headwater streams. Results suggest that groundwater, in addition to precipitation and surface runoff, is an important source of pesticides (particularly legacy herbicides) entering surface water. In addition to current use active ingredients, legacy pesticides, metabolites and impurities are important for explaining the estimated total toxicity attributable to pesticides. Sediment-bound insecticides were identified as the primary source for predicted ecotoxicity. Our results support recent studies indicating that highly sorbing chemicals contribute and even drive impacts on aquatic ecosystems. They further indicate that groundwater contaminated by legacy and contemporary pesticides may impact adjoining streams. Stream observations of soluble and sediment-bound pesticides are valuable for understanding the long-term fate of pesticides in aquifers, and should be included in stream monitoring programs. PMID- 25697476 TI - Non-selective NSAIDs improve the amyloid-beta-mediated suppression of memory and synaptic plasticity. AB - Alzheimer's disease (AD) is characterized by the formation of amyloid beta (Abeta) plaques in the brain. Dysfunctional excitatory synaptic transmission and neuronal plasticity are generally accepted as primary events in the development of AD. There is evidence to suggest that both COX-1 expression and COX-2 expression are changed in the brain of AD patients. However, the impact of COX dependent mechanisms on synaptic dysfunction underlying the memory deficit is not fully elucidated. In the present study effects of non-selective NSAIDs (aspirin and sodium salicylate) on associated memory impairment as well as Abeta-mediated suppression of synaptic plasticity in the hippocampus were examined. Abeta1-42 (5MUg/MUl) and ibotenic acid (5MUg/MUl) were injected bilaterally into the dorsal hippocampus of rats and the spatial memory and long term potentiation (LTP) were assessed by water maze performance and in vivo field potential recording, respectively. Field excitatory post synaptic potentials (fEPSP) were recorded from stratum radiatum of area CA1 following Schaffer collateral stimulation. Behavioral study revealed that both sub-chronic high dose of sodium salicylate (SS) and chronic low dose of aspirin improved the spatial memory impairment of Abeta treated rats, however the effects of SS were lower than those of aspirin. Animals treated with SS and aspirin showed a significant decrease in escape latency (SS: F(1, 24)=15.85, p<0.01, aspirin: F(1, 22)=25.24, p<0.001, ANOVA). Furthermore, in probe test, animals treated with aspirin (p<0.05) but not SS (p>0.05) spent more time (one-way ANOVA) in target quadrant zone. Both applied drugs restored the suppression of fEPSP slope LTP that was induced by Abeta treatment (unpaired t-test, p<0.001). Aspirin showed a preventative effect also against Abeta-induced changes in LTP and memory task when applied before Abeta administration. Since aspirin and SS improved synaptic dysfunction, we can suggest that COX-dependent mechanisms may play a role in synaptic dysfunction in an experimental model of AD. PMID- 25697477 TI - A 5-HT3 receptor antagonist potentiates the behavioral, neurochemical and electrophysiological actions of an SSRI antidepressant. AB - More effective treatments for major depression are needed. We studied if the selective 5-HT3 receptor antagonist ondansetron can potentiate the antidepressant potential of the selective serotonin (5-HT) reuptake inhibitor (SSRI) paroxetine using behavioral, neurochemical and electrophysiological methods. Flinders Sensitive Line (FSL) rats, treated with ondansetron, and/or a sub-effective dose of paroxetine, were assessed in the forced swim test. The effects of an acute intravenous administration of each compound alone and in combination were evaluated with respect to 5-HT neuronal firing rate in the dorsal raphe nucleus (DRN). Effects of s.c. administration of the compounds alone and in combination on extracellular levels of 5-HT were assessed in the ventral hippocampus of freely moving rats by microdialysis. The results showed that ondansetron enhanced the antidepressant activity of paroxetine in the forced swim test. It partially prevented the suppressant effect of paroxetine on DRN 5-HT neuronal firing and enhanced the paroxetine-induced increase of hippocampal extracellular 5-HT release. These findings indicate that 5-HT3 receptor blockade potentiates the antidepressant effects of SSRIs. Since both paroxetine and ondansetron are used clinically, it might be possible to validate this augmentation strategy in depressed patients. PMID- 25697478 TI - Anticipating designer drug-resistant cancer cells. AB - Successful use of anticancer designer drugs is likely to depend on simultaneous combinations of these drugs to minimize the development of resistant cancer cells. Considering the knowledge base of cancer signaling pathways, mechanisms of designer drug resistance should be anticipated, and early clinical trials could be designed to include arms that combine new drugs specifically with currently US Food and Drug Administration (FDA)-approved drugs expected to blunt alternative signaling pathways. In this review, we indicate examples of alternative signal pathways for recent anticancer drugs, and the use of original, Python-based software to systematically identify signaling pathways that could facilitate resistance to drugs targeting a particular protein. Pathway alternatives can be assessed at http://www.alternativesignalingpathways.com, developed with this review article. PMID- 25697479 TI - Cruzain inhibitors: efforts made, current leads and a structural outlook of new hits. AB - Human African trypanosomiasis and Chagas disease are the main causes of heart failure in developing countries. The disadvantages of current therapy include: undesirable side-effects, resistance, lack of efficacy on late-stage disease and lack of pediatric formulations. Efforts to find new compound hits have spanned SAR studies to very high-throughput and virtual screens and drug repurposing. The integrated analysis of these strategies on the discovery of anti-Chagas agents is timely. This work accounts for the progress on the development of cruzain inhibitors following these avenues, with emphasis on structural aspects of the ligand-cruzain recognition process. PMID- 25697480 TI - Farnesol inhibits tumor growth and enhances the anticancer effects of bortezomib in multiple myeloma xenograft mouse model through the modulation of STAT3 signaling pathway. AB - Aberrant activation of signal transducer and activator of transcription 3 (STAT3) is frequently observed in multiple myeloma (MM) cancer and can upregulate the expression of several genes involved in proliferation, survival, metastasis, and angiogenesis. The effect of farnesol (FOH) on STAT3 activation, associated protein kinases, its regulated gene products, cellular proliferation, and apoptosis was examined. The in vivo effect of FOH on the growth of human MM xenograft tumors alone and in combination with bortezomib (Bor) in athymic nu/nu female mice was also investigated. We found that FOH suppressed both constitutive and inducible STAT3 activation at Tyr705 in MM cells. The suppression of STAT3 was mediated through the inhibition of activation of upstream JAK1, JAK2, and c Src kinases. Also, treatment with the protein tyrosine phosphatase (PTP) inhibitor, pervanadate treatment reversed the FOH-induced down-regulation of STAT3, possibly indicating the involvement of a PTP. Indeed, we found that FOH treatment induces the increased expression of SHP-2 protein and knockdown of the SHP-2 gene by small interfering RNA suppressed the ability of FOH to inhibit STAT3 activation. FOH inhibited proliferation and significantly potentiated the apoptotic effects of bortezomib (Bor) in U266 cells. When administered intraperitoneally, FOH enhanced Bor-induced growth suppression of human MM xenograft tumors in athymic nu/nu female mice. Our results suggest that FOH is a novel blocker of STAT3 signaling pathway and exerts both anti-proliferative and apoptotic activities in MM in vitro and in vivo. PMID- 25697481 TI - Restoration of miR-424 suppresses BCR-ABL activity and sensitizes CML cells to imatinib treatment. AB - MicroRNAs (miRNAs) are small noncoding RNAs that participate in many biological processes by posttranscriptionally regulating gene expression. Dysregulation of miRNA expression has been shown to be typical of many neoplasms. Chronic myeloid leukemia (CML) is a disorder of hematopoietic stem cells carrying the Philadelphia (Ph) chromosome and an oncogenic BCR-ABL tyrosine kinase fusion gene. While the development of tyrosine kinase inhibitors (TKIs) like imatinib has revolutionized treatment of CML, it has become increasingly clear in recent years that TKI treatment alone will not be curative in many cases. Thus, further dissection of the regulatory networks that drive BCR-ABL-induced malignant transformation may help to identify other novel therapeutic approaches that complement TKI treatment. In this study we demonstrate that the expression of miR 424 is markedly low in CML cell lines and patient samples at time of diagnosis. With the aid of bioinformatics analysis we revealed a conserved target site for miR-424 in the 3'-untranslated region (UTR) of the ABL gene. Via luciferase assays, we showed that miR-424 directly targets BCR-ABL. Overexpression of miR 424 was shown to suppress proliferation and induce apoptosis of K562 cells as well as sensitize these cells to imatinib treatment. These findings strongly suggest that miR-424 acts as a tumor suppressor by downregulating BCR-ABL expression. Up-regulation of miR-424 in CML cells may therefore have a therapeutic effect against this disease. PMID- 25697482 TI - Mutant p53 (p53-R248Q) functions as an oncogene in promoting endometrial cancer by up-regulating REGgamma. AB - P53 mutation plays a pivotal role in tumorigenesis of endometrial cancer (EC), here we report that the gain-of-function mutant p53-R248Q targets the proteasome activator REGgamma to promote EC progression. Increased p53 expression significantly correlated with high pathological grade and lymph node metastasis in EC specimens. Manipulation of p53-R248Q in EC cells caused coincident changes in REGgamma expression, and chromatin immunoprecipitation coupled with PCR further indicated that p53-R248Q bound to the REGgamma gene promoter at a p53 responsive element. Silencing of REGgamma in EC cells attenuated the cell proliferation, migration and invasion abilities, whereas overexpression of p53 R248Q rescued these activities. Overexpression of REGgamma also induced an epithelial-mesenchymal transition phenotype. Moreover, a mouse xenograft tumor model showed that REGgamma promoted tumor growth, further demonstrating a p53 R248Q-REGgamma oncogenic pathway. Finally, examination of EC and normal endometrium specimens confirmed the oncogenic role of REGgamma, in that REGgamma was more highly overexpressed in p53-positive specimens than in p53-negative specimens. Our data suggest that REGgamma is a promising therapeutic target for EC with the p53-R248Q mutation. PMID- 25697483 TI - Blockage of LMP1-modulated store-operated Ca(2+) entry reduces metastatic potential in nasopharyngeal carcinoma cell. AB - Epstein-Barr virus (EBV)-encoded latent membrane proteins (LMPs) expedite progression of EBV-relevant cancers. Of the full set of LMPs, latent membrane protein 1 (LMP1) was identified to uniquely augment store-operated Ca(2+) entry (SOCE). Previously, we reported that the suppression of SOCE exhibited inhibitory effects on cell migration and the extravasation from vasculature in EBV-negative nasopharyngeal carcinoma (NPC) cells. In this follow-up study, we aimed to expand our understanding of the modulation of SOCE by LMP1 and test the possibility that blockage of LMP1-modulated SOCE affects the LMP1-promoted metastatic potential. Here we showed that suppressions of the LMP1-boosted SOCE blunted the LMP1 promoted cell migration, VEGF-mediated angiogenesis and permeabilization in vitro. Blockage of SOCE inhibited vasculature-invasion of circulating cells and distant metastatic colonization in vivo. Notably, utilizing VEGFR2-EGFP-tag zebrafish we revealed that the LMP1-expressing cells arrested in a small-caliber vessel mobilized surrounding endothelial cells to facilitate vasculature invasion. Thus, the LMP1-boosted SOCE promotes metastatic potential of NPC cells by solidifying their collaborations with the nearby non-cancer cells through the manipulation of oncogenic Ca(2+) signaling. Our study highlights the advantage of using both conventional mammal and transgenic zebrafish for developing a novel therapeutic strategy targeting the multiple steps of invasion-metastasis cascade. PMID- 25697484 TI - Pleiotropic effects of spongean alkaloids on mechanisms of cell death, cell cycle progression and DNA damage response (DDR) of acute myeloid leukemia (AML) cells. AB - We investigated cytotoxic mechanisms evoked by the spongean alkaloids aaptamine (Aa) and aeroplysinin-1 (Ap), applied alone and in combination with daunorubicin, employing acute myeloid leukemia (AML) cells. Aa and Ap reduced the viability of AML cells in a dose dependent manner with IC50 of 10-20 uM. Ap triggered apoptotic cell death more efficiently than Aa. Both alkaloids increased the protein level of S139-phosphorylated H2AX (gammaH2AX), which however was independent of the induction of DNA damage. Expression of the senescence markers p21 and p16 was increased, while the phosphorylation level of p-Chk-2 was reduced following Aa treatment. As a function of dose, Aa and Ap protected or sensitized AML cells against daunorubicin. Protection by Aa was paralleled by reduced formation of ROS and lower level of DNA damage. Both Aa and Ap attenuated daunorubicin-stimulated activation of the DNA damage response (DDR) as reflected on the levels of gammaH2AX, p-Kap-1 and p-Chk-1. Specifically Ap restored the decrease in S10 phosphorylation of histone H3 resulting from daunorubicin treatment. The cytoprotective effects of Aa and Ap were independent of daunorubicin import/export. Both Aa and Ap abrogated daunorubicin-induced accumulation of cells in S-phase. Inhibition of DNA synthesis was specific for Ap. The data show that Aa and Ap have both congruent and agent-specific pleiotropic effects that are preferential for anticancer drugs. Since Ap showed a broader spectrum of anticancer activities, this compound is suggested as novel lead compound for forthcoming in vivo studies elucidating the usefulness of spongean alkaloids in AML therapy. PMID- 25697485 TI - TLR3 triggering regulates PD-L1 (CD274) expression in human neuroblastoma cells. AB - Neuroblastoma is the most common extracranial solid tumor in children, causing 12% of all pediatric cancer mortality. Neuroblastoma specific T-cells have been detected in patients, but usually fail to attack and eradicate the tumors. Tumor immune evasion may thus play an important role in neuroblastoma pathogenicity. Recent research in adult cancer patients shows that targeting T-cell check-point molecules PD-1/PD-L1 (or CD279/CD274) may bolster immune reactivity against solid tumors. Also, infections can be associated with spontaneous neuroblastoma regression. In our current study, we therefore investigated if antibody targeting of PD-L1 and triggering of selective pathogen-receptor Toll-like receptors (TLRs) potentiates immunogenicity of neuroblastoma cells. We find this to be the case. TLR3 triggering induced strong upregulation of both MHC class I and PD-L1 on neuroblastoma cells. At the same time TGF-beta levels decreased and IL-8 secretion was induced. The combined neuroblastoma cell treatment using PD-L1 blockade and TLR3 triggering using virus analog poly(I:C) moreover induced CD4(+) and CD8(+) T-cell activation. Thus, we propose combined treatment using PD-L1 blockade with synthetic TLR ligands as an avenue toward new immunotherapy against human neuroblastoma. PMID- 25697486 TI - Erratum to: Differential expression of perilipin 2 and 5 in human skeletal muscle during aging and their association with atrophy-related genes. PMID- 25697487 TI - External fixation using locking plate in distal tibial fracture: a finite element analysis. AB - BACKGROUND: External fixation of tibial fractures using a locking plate has been reported with favorable results in some selected patients. However, the stability of external plate fixation in this fracture pattern has not been previously demonstrated. We investigated the stability of external plate fixation with different plate-bone distances. METHODS: In this study, the computational processing model of external fixation of a distal tibial metaphyseal fracture utilizing the contralateral femoral less invasive stabilization system plate was analyzed. The plate was placed on the anteromedial aspect of tibia with different plate-bone distances: 1, 10, 20, and 30 mm. RESULTS: Under axial load, the stiffness of construct in all groups was higher than intact tibia. Under axial load with an internal rotational force, the stiffness of construct with 1 and 10 mm plate-bone distances was similar to that of an intact tibia and the stiffness of the construct with 20 and 30 mm distances was lower than that of an intact tibia. Under axial load with an external rotational force, the stiffness of the construct in all groups was lower than that of an intact tibia. The maximum plate stresses were concentrated at the two most distal screws and were highest in the construct with the 10 mm plate-bone distance, and least in the construct with a 1 mm plate-bone distance. CONCLUSIONS: To guarantee a stable external plate fixation in distal tibial fracture, the plate-bone distance should be less than 30 mm. PMID- 25697488 TI - Topography of cortical thinning associated with white matter hyperintensities in Parkinson's disease. AB - BACKGROUND: Although white matter hyperintensities (WMHs) are associated with cognitive impairments in Parkinson's disease (PD), the relationships between WMHs and cortical atrophy in regard to cognitive impairments are unknown. Here, we investigated the topography of cortical thinning related to deep (DWMHs) and periventricular WMHs (PWMHs) and their differential impacts on cognitive performance in PD. METHODS: We enrolled 87 patients with non-demented PD and evaluated WMH scores using a semi-quantitative visual rating system. The patients were divided into low-, moderate-, and high-grade groups based on WMH severity for total WMHs (TWMHs), DWMHs, and PWMHs, and cortical thickness was measured using a surface-based method according to the WMHs severity. Additionally, the correlations between WMH-associated cortical thinning and neuropsychological performance were analyzed. RESULTS: The detailed neuropsychological test demonstrated that PD patients with high-grade WMHs showed poorer performance on frontal lobe-based cognitive tasks compared with those with low-grade DWMHs. The areas of cortical thinning were more extensive in patients with DWMHs, involving the entire frontal areas and restricted temporoparietal areas, whereas in patients with PWMHs, cortical thinning was localized in the small frontal areas. A multiple regression analysis of the relationships between WMH-associated cortical thickness and cognition revealed that DWMH-associated frontal thickness had an independent effect on frontal lobe-based cognition, while frontal thickness related to PWMHs did not have a significant correlation with cognitive tasks. CONCLUSIONS: These data suggest that in patients with PD, DWMHs are closely coupled with decreased cortical thickness in the frontal areas and may lead to declines in executive function. PMID- 25697489 TI - Technical aspects of clinical videoconferencing: a large scale review of the literature. AB - Telemedicine has been increasingly researched during the past few decades and the technology used by health care providers and recipients has changed dramatically. However, little has been published on technical characteristics of video consultations and how these characteristics have changed over time due to rapid advancement of information and communication technology. We aimed to summarize various types of technologies used for interactive videoconferencing between health care providers and patients, and identify the trend of their change from 2002 to 2012. A comprehensive electronic search was performed using PubMed, Embase and CINAHL databases which yielded 2,411 unique records. After screening at title/abstract level, full texts of 505 articles were retrieved and explored for technical information of videoconferencing. The trend of number of publications fluctuated between 41 and 47 articles with no specific pattern, though a dip in 2004 (n = 35) and drastic increase in 2012 (n = 68) was evident. The equipment used for videoconferencing was not mentioned in 15% of the papers. Dedicated VC systems (CODECs), were the most commonly used hardware, followed by computer/laptop/notebook. The connection speed (bandwidth) was not reported in 46% of the papers. The proportion of articles reporting the connection speed declined over time. Details of image quality and frame rate were mentioned in 11% and 5% of the papers, respectively. The results of this study showed that a high proportion of telemedicine papers lack sufficient technical details that limits their repeatability and generalizability. PMID- 25697490 TI - User preferences for text message-delivered skin cancer prevention and early detection. AB - Evidence is needed for the acceptability and user preferences of receiving skin cancer-related text messages. We prepared 27 questions to evaluate attitudes, satisfaction with program characteristics such as timing and spacing, and overall satisfaction with the Healthy Text program in young adults. Within this randomised controlled trial (age 18-42 years), 546 participants were assigned to one of three Healthy Text message groups; sun protection, skin self-examination, or attention-control. Over a 12-month period, 21 behaviour-specific text messages were sent to each group. Participants' preferences were compared between the two interventions and control group at the 12-month follow-up telephone interview. In all three groups, participants reported the messages were easy to understand (98%), provided good suggestions or ideas (88%), and were encouraging (86%) and informative (85%) with little difference between the groups. The timing of the texts was received positively (92%); however, some suggestions for frequency or time of day the messages were received from 8% of participants. Participants in the two intervention groups found their messages more informative, and triggering behaviour change compared to control. Text messages about skin cancer prevention and early detection are novel and acceptable to induce behaviour change in young adults. PMID- 25697491 TI - Use of a voice and video internet technology as an alternative to in-person urgent care clinic visits. AB - This study aimed to determine the feasibility of patient-initiated online Internet urgent care visits, and to describe patient characteristics, scope of care, provider adherence to protocols, and diagnostic and therapeutic utilization. A total of 456 unique patients were seen via Internet-based technology during the study period, generating 478 consecutive total patient visits. Of the 82 patients referred for an in-person evaluation, 75 patients (91.5%) reported to the clinic as instructed. None of the 82 patients recommended for in-person evaluation required an emergency department referral, hospital admission or urgent consultative referral. We conclude that real-time online primary and urgent care visits are feasible, safe and potentially beneficial in increasing convenient access to urgent and primary care. PMID- 25697492 TI - Effect of short message service as a reminder on breast self-examination in breast cancer patients: a randomized controlled trial. AB - This study was a single-blind randomized controlled trial to assess the effectiveness of SMS as a reminder for breast self-examination (BSE). Participants who underwent surgery for breast cancer were recruited and randomized to the intervention group or the control group. Subjects in the intervention group received one text message on the first day of every month that reminded them to complete monthly BSE and the other text message on the fifteenth day of every month that contained information about breast cancer. Primary and secondary outcomes were self-reported BSE adherence and the frequency of BSE over 6 months. Between August 2010 and December 2011, 216 patients were randomly assigned to the SMS group (n = 110) or the control group (n = 106). A total of 202 patients were included in the final analysis. Self-reported BSE adherence and the frequency of BSE over the past six months were significantly higher in the intervention group than in the control group. Multivariate analysis showed that the SMS was the only significant factor for BSE adherence (p < 0.001). The short term results of our study suggest that SMS is an effective and low-cost method to enhance adherence to BSE with existing information technology infrastructure. PMID- 25697493 TI - Successful implantation of autologous valved conduits with self-expanding stent (stent-biovalve) within the pulmonary artery in beagle dogs. AB - OBJECTIVES: To evaluate the functionality of an autologous heart valve with stent (Stent-biovalve or SBV) after implantation in the pulmonic valve position in beagle dogs. ANIMALS: Five beagle dogs. METHODS: A mold with an aperture of a tri leaflet structure was constructed from a pair of concave and convex rods to which a nitinol (NiTi) stent was mounted. This mold was embedded in a dorsal subcutaneous pouch in beagle dogs for 4 weeks. At the time of the removal, the surfaces of the molds were completely covered with connective tissues, tri leaflet valves were formed and the NiTi stent was tightly connected to the structure. RESULTS: The mean burst strength of the SBV leaflet was 2710 mmHg (range 2280-3116 mmHg), which was approximately equal to that of the native pulmonic valve leaflet. After implantation in the pulmonary position, the SBV showed good functionality as a pulmonic valve. At 84 days after implantation, the SBV was replaced with autologous fibroblasts and collagenous tissues, and showed organization similar to that of native heart valves. CONCLUSION: Stent-Biovalves achieved good valvular function with laminar flow in the pulmonic valve position of beagle dogs. PMID- 25697494 TI - Improving diabetes prevention with benefit based tailored treatment: risk based reanalysis of Diabetes Prevention Program. AB - OBJECTIVE: To determine whether some participants in the Diabetes Prevention Program were more or less likely to benefit from metformin or a structured lifestyle modification program. DESIGN: Post hoc analysis of the Diabetes Prevention Program, a randomized controlled trial. SETTING: Ambulatory care patients. PARTICIPANTS: 3060 people without diabetes but with evidence of impaired glucose metabolism. INTERVENTION: Intervention groups received metformin or a lifestyle modification program with the goals of weight loss and physical activity. MAIN OUTCOME MEASURE: Development of diabetes, stratified by the risk of developing diabetes according to a diabetes risk prediction model. RESULTS: Of the 3081 participants with impaired glucose metabolism at baseline, 655 (21%) progressed to diabetes over a median 2.8 years' follow-up. The diabetes risk model had good discrimination (C statistic=0.73) and calibration. Although the lifestyle intervention provided a sixfold greater absolute risk reduction in the highest risk quarter than in the lowest risk quarter, patients in the lowest risk quarter still received substantial benefit (three year absolute risk reduction 4.9% v 28.3% in highest risk quarter; numbers needed to treat of 20.4 and 3.5, respectively). The benefit of metformin, however, was seen almost entirely in patients in the top quarter of risk of diabetes. No benefit was seen in the lowest risk quarter. Participants in the highest risk quarter averaged a 21.4% three year absolute risk reduction (number needed to treat 4.6). CONCLUSIONS: Patients at high risk of diabetes have substantial variation in their likelihood of receiving benefit from diabetes prevention treatments. Using this knowledge could decrease overtreatment and make prevention of diabetes far more efficient, effective, and patient centered, provided that decision making is based on an accurate risk prediction tool. PMID- 25697495 TI - What can screening measures tell us about risk for depression in patients with diabetes? PMID- 25697496 TI - Urine-derived Stem Cells, A New Source of Seed Cells for Tissue Engineering. AB - Tissue engineering, as a frontier of medicine, is aimed at regeneration of tissue and organ which can be used for the therapy of many diseases, such as trauma, cancer, and deformity. Some pluripotent stem cells are considered to be suitable for seed cells for tissue engineering, for example, bone marrow mesenchymal stem cells, adipose-derived stem cells and epidermal stem cells. Urine-derived stem cells (USCs) have been reported, and regarded as a candidate for seed cells in tissue engineering because of low-cost collection and isolation, efficient proliferation, and multidifferentiation potential, which have been documented in recent years. In this paper, we will introduce the biological characteristics of USCs and their potential applications in tissue engineering. PMID- 25697497 TI - Potential Clinical Use of Differentiated Cells From Embryonic or Mesencyhmal Stem Cells in Orthopaedic Problems. AB - Stem cells are classified by their tissue source. Embryonic stem cells that are derived from the inner cell mass of blastocyst stage embryos are highly proliferative in their undifferentiated state. A multipotent type of mesenchymal stem cells is isolated from various types of tissues such as bone marrow, fat tissue etc. The dynamics of embryonic and adult stem cell cycles are profoundly dissimilar from the culture of stem cells. After improving the culture conditions and differentiation potentials, differentiated stem cells are the first cells to be preferred in modern regenerative medicine and tissue engineering. This review article focuses on the cell-based therapy of orthopedic problems. We explore the challenges associated with bone repair and regeneration using embryonic or mesenchymal stem cells that are in undifferentiated or/and differentiated condition. This paper also discusses optimizing the best cell type, differentiation condition and using them on bone tissue engineering for future investigations. PMID- 25697498 TI - Aligned Biomimetic Scaffolds as a New Tendency in Tissue Engineering. AB - Ideal scaffolds for tissue engineering should have the same characteristics and morphology as the tissue. However, the microstructure of many native tissues has anisotropic characteristics, and the extracellular matrix has an orderly arrangement. Thus, aligned biomimetic scaffolds, a class of directional scaffolds, were proposed and researched to further mimic the permutations of tissue. This review covers the biomaterials, technology for the aligned biomimetic scaffolds and applications in tissue engineering. The aligned biomimetic scaffolds are extremely promising for tissue engineering because they can align the directions of cell growth, affect gene expression and significantly enhance cell reprogramming efficiency. PMID- 25697499 TI - MicroRNA Regulation of Embryonic Stem Cell Pluripotency and Differentiation. AB - Embryonic stem cells (ES cells) hold great potential for regenerative medicine. Grasp of the underlying elaborate machinery is required for clinical application. MicroRNAs serve as important post-transcriptional regulators of various normal and pathological processes. Substantial headway has been made in deciphering miRNAs' roles in establishment, maintenance and exit from pluripotency in ES cells. Here, we summarize current and ongoing research on microRNAs' roles of pluripotency maintenance and germ layer specification and possible mechanism to script the cell fate. PMID- 25697500 TI - Advances in reprogramming to pluripotency. AB - Pluripotent stem cells (PSCs) derived from somatic cells represent a powerful experimental tool for investigating the molecular mechanisms underlying the disease phenotype; with prospects to advance medical therapies. They also have significant potential as a renewable source of autologous cells for cellular therapy. Various approaches for PSC derivation from somatic cells have been reported in the literature. The method used for reprogramming is particularly relevant as it may affect the characteristics and quality of PSCs. This review will present an overview of the basic strategies and methods for reprogramming to pluripotency. These strategies will be briefly discussed in the context of how the mechanism of reprogramming could influence PSC characteristics with respect to safety and quality. Aspects of the reprogramming approach that can influence PSC properties, such as culture conditions and donor cell source, are also discussed. PMID- 25697501 TI - Making sense of dementia: Exploring the use of the Markers of Assimilation of Problematic Experiences in Dementia scale to understand how couples process a diagnosis of dementia. AB - This qualitative study aimed to see whether the Markers of Assimilation of Problematic Experiences in Dementia (MAPED) scale could be applied to couples. It aimed to explore the interactions between couples and how this affected the levels of assimilation. Semi-structured interviews were conducted with four heterosexual couples. The results suggested that MAPED can be usefully applied to couples. It highlighted the oscillating process which couples undergo as they process a dementia diagnosis. This supports the notion that making sense of a dementia diagnosis is not static, but a fluctuating and ever changing process. The strategies couples employed either facilitated or prevented the expression and integration of the Problematic Voice. The study highlights the importance of supporting couples together during a dementia diagnosis. PMID- 25697502 TI - Excitatory stimulation of the right inferior parietal cortex lessens implicit religiousness/spirituality. AB - Although religiousness and spirituality (RS) are considered two fundamental constituents of human life, neuroscientific investigation has long avoided the study of their neurocognitive basis. Nevertheless, recent investigations with brain imaging and brain damaged patients, and more recently with brain stimulation methods, have documented important associations between RS beliefs and experiences and frontoparietal neural activity. In this study, we further investigated how individuals' implicit RS self-representations can be modulated by changes in right inferior parietal lobe (IPL) excitability, a key region associated to RS. To this end, we combined continuous theta burst stimulation (cTBS), intermittent TBS (iTBS), and sham TBS with RS-related, Implicit Association Test (IAT) and with a control self-esteem (SE) IAT in a group of fourteen healthy adult individuals. A specific decrease of implicit RS, as measured with the IAT effect, was induced by increasing IPL excitability with iTBS; conversely cTBS, which is supposedly inhibitory, left participants' implicit RS unchanged. The performance in the control SE-IAT was left unchanged by any TBS stimulation. These data showed the causative role of right IPL functional state in mediating plastic changes of implicit RS. Implications of these results are also discussed in the light of the variability of behavioral effects associated with TBS. PMID- 25697503 TI - Alu RNA regulates the cellular pool of active ribosomes by targeted delivery of SRP9/14 to 40S subunits. AB - The human genome contains about 1.5 million Alu elements, which are transcribed into Alu RNAs by RNA polymerase III. Their expression is upregulated following stress and viral infection, and they associate with the SRP9/14 protein dimer in the cytoplasm forming Alu RNPs. Using cell-free translation, we have previously shown that Alu RNPs inhibit polysome formation. Here, we describe the mechanism of Alu RNP-mediated inhibition of translation initiation and demonstrate its effect on translation of cellular and viral RNAs. Both cap-dependent and IRES mediated initiation is inhibited. Inhibition involves direct binding of SRP9/14 to 40S ribosomal subunits and requires Alu RNA as an assembly factor but its continuous association with 40S subunits is not required for inhibition. Binding of SRP9/14 to 40S prevents 48S complex formation by interfering with the recruitment of mRNA to 40S subunits. In cells, overexpression of Alu RNA decreases translation of reporter mRNAs and this effect is alleviated with a mutation that reduces its affinity for SRP9/14. Alu RNPs also inhibit the translation of cellular mRNAs resuming translation after stress and of viral mRNAs suggesting a role of Alu RNPs in adapting the translational output in response to stress and viral infection. PMID- 25697504 TI - Restriction-modification system with methyl-inhibited base excision and abasic site cleavage activities. AB - The restriction-modification systems use epigenetic modification to distinguish between self and nonself DNA. A modification enzyme transfers a methyl group to a base in a specific DNA sequence while its cognate restriction enzyme introduces breaks in DNA lacking this methyl group. So far, all the restriction enzymes hydrolyze phosphodiester bonds linking the monomer units of DNA. We recently reported that a restriction enzyme (R.PabI) of the PabI superfamily with half pipe fold has DNA glycosylase activity that excises an adenine base in the recognition sequence (5'-GTAC). We now found a second activity in this enzyme: at the resulting apurinic/apyrimidinic (AP) (abasic) site (5'-GT#C, # = AP), its AP lyase activity generates an atypical strand break. Although the lyase activity is weak and lacks sequence specificity, its covalent DNA-R.PabI reaction intermediates can be trapped by NaBH4 reduction. The base excision is not coupled with the strand breakage and yet causes restriction because the restriction enzyme action can impair transformation ability of unmethylated DNA even in the absence of strand breaks in vitro. The base excision of R.PabI is inhibited by methylation of the target adenine base. These findings expand our understanding of genetic and epigenetic processes linking those in prokaryotes and eukaryotes. PMID- 25697505 TI - CarD stabilizes mycobacterial open complexes via a two-tiered kinetic mechanism. AB - CarD is an essential and global transcriptional regulator in mycobacteria. While its biological role is unclear, CarD functions by interacting directly with RNA polymerase (RNAP) holoenzyme promoter complexes. Here, using a fluorescent reporter of open complex, we quantitate RPo formation in real time and show that Mycobacterium tuberculosis CarD has a dramatic effect on the energetics of RNAP bound complexes on the M. tuberculosis rrnAP3 ribosomal RNA promoter. The data reveal that Mycobacterium bovis RNAP exhibits an unstable RPo that is stabilized by CarD and suggest that CarD uses a two-tiered, concentration-dependent mechanism by associating with open and closed complexes with different affinities. Specifically, the kinetics of open-complex formation can be explained by a model where, at saturating concentrations of CarD, the rate of bubble collapse is slowed and the rate of opening is accelerated. The kinetics and open complex stabilities of CarD mutants further clarify the roles played by the key residues W85, K90 and R25 previously shown to affect CarD-dependent gene regulation in vivo. In contrast to M. bovis RNAP, Escherichia coli RNAP efficiently forms RPo on rrnAP3, suggesting an important difference between the polymerases themselves and highlighting how transcriptional machinery can vary across bacterial genera. PMID- 25697506 TI - Oxalic acid complexes: promising draw solutes for forward osmosis (FO) in protein enrichment. AB - Highly soluble oxalic acid complexes (OACs) were synthesized through a one-pot reaction. The OACs exhibit excellent performance as draw solutes in FO processes with high water fluxes and negligible reverse solute fluxes. Efficient protein enrichment was achieved. The diluted OACs can be recycled via nanofiltration and are promising as draw solutes. PMID- 25697507 TI - Do older Chinese people's diets meet the Chinese Food Pagoda guidelines? Results from the China Health and Nutrition Survey 2009. AB - OBJECTIVE: To evaluate dietary intake based on the Chinese Food Pagoda (CFP) and to determine what factors may be associated with adherence to CFP guidelines for older Chinese. DESIGN: This cross-sectional population-based study used 24 h recall over three consecutive days to assess dietary intake and adherence to CFP among older Chinese participating in the China Health and Nutrition Survey 2009. SETTING: Nine provinces across four diverse regions (Northeast, East Coast, Central and West). SUBJECTS: A total of 2745 older Chinese, aged 60-69 years (n 1563) and >=70 years (n 1182), with dietary data. RESULTS: None of the participants reached all ten food group recommendations. More than half of the participants exceeded the recommended amount for grains (63%), oil (62.8%) and salt (55.7%). Ten per cent of the participants consumed dairy, while merely 0.5% met the recommended amount. Average Chinese Food Pagoda Score (CFPS) was 3.3 in men and 3.5 in women, far below the maximum possible score of 10. Women had 0.26 higher CFPS than men (P<0.001; 95% CI 0.16, 0.36). People living in medium and high urbanicity areas had significantly higher scores than those living in low urbanicity areas (P<0.001). Also, there were significant differences in CFPS according to gender, BMI, work status, education level and region. CONCLUSIONS: Few older Chinese are meeting the intake of the various food groups based on the recommendations in the CFP guidelines, thus increasing the risk of malnutrition and non-communicable diseases. Action is needed to increase dissemination and uptake of nutrition education, with interventions targeted at socio-economic regions. Moreover, specific dietary guidelines for older Chinese people should be developed. PMID- 25697508 TI - B(12)-mediated, long wavelength photopolymerization of hydrogels. AB - Medical hydrogel applications have expanded rapidly over the past decade. Implantation in patients by noninvasive injection is preferred, but this requires hydrogel solidification from a low viscosity solution to occur in vivo via an applied stimuli. Transdermal photo-cross-linking of acrylated biopolymers with photoinitiators and lights offers a mild, spatiotemporally controlled solidification trigger. However, the current short wavelength initiators limit curing depth and efficacy because they do not absorb within the optical window of tissue (600-900 nm). As a solution to the current wavelength limitations, we report the development of a red light responsive initiator capable of polymerizing a range of acrylated monomers. Photoactivation occurs within a range of skin type models containing high biochromophore concentrations. PMID- 25697509 TI - An objective assessment tool for basic surgical knot-tying skills. AB - OBJECTIVE: To determine if a knot-tying checklist can provide a valid score and if the checklist can be used by novice surgeons in a reliable manner. METHODS: This study was conducted at the Surgical Skills Center at the University of California, San Francisco. A knot-tying checklist was developed from a kinesthetic knot-tying curriculum. Novice (67 first-year medical students) and experienced surgeons (8 residents postgraduate year 3 and higher and 2 attending physicians) were videotaped performing 4 knot-tying tasks, and the videotapes were rated with a global score and a checklist by interns (n = 3) and experienced (n = 3) surgeons. RESULTS: Both interns and experienced surgeons can use the knot tying checklist with acceptable reliabilities (>0.8 with 3 raters). The checklist is able to differentiate between novice and experienced surgeons, when used by both interns and experienced raters. The expert knot-tying score correlated with the global score overall (r = 0.88) and for each task (r was 0.82 for task 1, 0.85 for task 2, 0.80 for task 3, and 0.81 for task 4). CONCLUSIONS: The knot tying checklist provides a valid score for basic surgical knot-tying and can be used by novice and experienced raters. Its use supports peer assessment of performance in a surgical skills laboratory setting. PMID- 25697510 TI - Building a global surgery initiative through evaluation, collaboration, and training: the Massachusetts General Hospital experience. AB - OBJECTIVE: The Massachusetts General Hospital (MGH) Department of Surgery established the Global Surgery Initiative (GSI) in 2013 to transform volunteer and mission-based global surgery efforts into an educational experience in surgical systems strengthening. The objective of this newly conceived mission is not only to perform advanced surgery but also to train surgeons beyond MGH through international partnerships across disciplines. At its inception, a clear pathway to achieve this was not established, and we sought to identify steps that were critical to realizing our mission statement. SETTING: Massachusetts General Hospital, Boston, MA, USA and Mbarara Regional Referral Hospital, Mbarara, Uganda PARTICIPANTS: Members of the MGH and MRRH Departments of Surgery including faculty, fellows, and residents RESULTS: The MGH GSI steering committee identified 4 steps for sustaining a robust global surgery program: (1) administer a survey to the MGH departmental faculty, fellows, and residents to gauge levels of experience and interest, (2) catalog all ongoing global surgical efforts and projects involving MGH surgical faculty, fellows, and residents to identify areas of overlap and opportunities for collaboration, (3) establish a longitudinal partnership with an academic surgical department in a limited-resource setting (Mbarara University of Science and Technology (MUST) at Mbarara Regional Referral Hospital (MRRH)), and (4) design a formal curriculum in global surgery to provide interested surgical residents with structured opportunities for research, education, and clinical work. CONCLUSIONS: By organizing the collective experiences of colleagues, synchronizing efforts of new and former efforts, and leveraging the funding resources available at the local institution, the MGH GSI hopes to provide academic benefit to our foreign partners as well as our trainees through longitudinal collaboration. Providing additional financial and organizational support might encourage more surgeons to become involved in global surgery efforts. Creating a partnership with a hospital in a limited-resource setting and establishing a formal global surgery curriculum for our residents allows for education and longitudinal collaboration. We believe this is a replicable model for building other academic global surgery endeavors that aim to strengthen health and surgical systems beyond their own institutions. PMID- 25697511 TI - Bridging the gap: theory-based design of a microsurgical skills course for ophthalmology residents. AB - OBJECTIVE: Although theory-based schemes for course design are widely used in educational settings, making use of cognitive theory in the design of surgical skills courses in ophthalmology is rare. The primary aim of this study is to describe the application of instructional design, an established theory-based approach in course design, to the development of a surgical skills course for ophthalmology residents. The secondary aim of this study is to assess the educational effect of this theory-based course. DESIGN: A 1-day skills course was designed according to Gagne's events of instruction model, which was employed as a template for the instructional sequence of learning steps. Skills acquisition following the implementation of the model was measured with precourse and postcourse assessments. SETTING: Moorfields Eye Hospital organized the 1-day annual intermediate surgical skills course, which was hosted at the Royal College of Ophthalmologists' microsurgical skills laboratory. PARTICIPANTS: A total of 20 ophthalmology residents of Moorfields Eye Hospital participated in the study. RESULTS: A 1-day surgical skills course was formulated according to the instructional design principles outlined. The 4 objectives of the course (corneal suturing, corneal gluing, intravitreal injections, and eyelid suturing) were addressed in a parallel fashion as to allow for multiple objectives to be processed simultaneously, in the context of the instructional design sequence. Assessments demonstrated significant improvement in skills acquisition for the 4 course objectives. CONCLUSIONS: Instructional design is a valuable tool for planning effective surgical training courses as it is portable, allowing its application to a wide variety of outcomes and settings, and its terminology is simple and understandable to those working in clinical education. PMID- 25697512 TI - Rhinosinusitis: evidence and experience: October 18 and 19, 2013 - Sao Paulo. PMID- 25697514 TI - Rhodopsin purification from dark-adapted bovine retina. AB - Structural and biophysical studies of rhodopsin have long depended upon the ready availability of bovine retina from the meat-packing industry and the relative ease of obtaining homogenous preparations of rhodopsin in the quantities and purities necessary for such study. Herein we present a modular purification methodology employing a combination of several strategies, beginning with sucrose gradient isolation of rod outer segments (ROS) from bovine retina, detergent solubilization of ROS, selective extraction of rhodopsin starting from this detergent-solubilized ROS, and further purification via size-exclusion chromatography, resulting in a preparation of high-purity rhodopsin at high concentration suitable for crystallization or other biophysical study. PMID- 25697513 TI - The G protein-coupled receptor rhodopsin: a historical perspective. AB - Rhodopsin is a key light-sensitive protein expressed exclusively in rod photoreceptor cells of the retina. Failure to express this transmembrane protein causes a lack of rod outer segment formation and progressive retinal degeneration, including the loss of cone photoreceptor cells. Molecular studies of rhodopsin have paved the way to understanding a large family of cell-surface membrane proteins called G protein-coupled receptors (GPCRs). Work started on rhodopsin over 100 years ago still continues today with substantial progress made every year. These activities underscore the importance of rhodopsin as a prototypical GPCR and receptor required for visual perception-the fundamental process of translating light energy into a biochemical cascade of events culminating in vision. PMID- 25697515 TI - Mammalian expression, purification, and crystallization of rhodopsin variants. AB - After 25 years of intensive research, the understanding of how photoreceptors in the eye perceive light and convert it into nerve signals has largely advanced. Central to this is the structural and mechanistic exploration of the G protein coupled receptor rhodopsin acting as a dim-light sensing pigment in the retina. Investigation of rhodopsin by X-ray crystallographic, electron microscopic, and biochemical means depends on the ability to produce and isolate pure rhodopsin protein. Robust and well-defined protocols permit the production and crystallization of rhodopsin variants to investigate the inactive ground, the fully activated metarhodopsin II state, or disease-causing rhodopsin mutations. This chapter details how we express and purify biologically active variants of rhodopsin from HEK293S GnTI(-) cells in a quality and quantity suitable for biochemical assays, crystallization, and structure determination. PMID- 25697516 TI - Imaging of rhodopsin crystals with two-photon microscopy. AB - Two-photon microscopy has been shown to be an invaluable tool for detecting and monitoring protein crystallization trials and characterizing membrane protein crystals. This imaging method has proven especially useful for rhodopsin, because of the dependence of rhodopsin's fluorescence spectra on the isomerization state of its intrinsic chromophore (retinylidene) and, as such, it can provide additional information about the identity and functional state of rhodopsin in crystals. Here, we describe the acquisition of images and two-photon excitation and emission spectra using a commercial two-photon microscope, along with detailed instructions for the handling of rhodopsin crystals and specific examples of rhodopsin data. PMID- 25697517 TI - Functional stability of rhodopsin in a bicelle system: evaluating G protein activation by rhodopsin in bicelles. AB - Rhodopsin is a prototypical member of the G protein-coupled receptors (GPCRs). This photoreceptor is responsible for initiating the visual signaling transduction cascade upon interaction with its heterotrimeric G protein, transducin (Gt), after light activation. Like all transmembrane proteins, rhodopsin is embedded within a phospholipid bilayer. Many studies have proposed that the membrane composition of this bilayer is an important factor for receptor function during the activation process. Here we describe the methods and assays used to evaluate the function of purified and reconstituted rhodopsin in bicelles. PMID- 25697518 TI - The rhodopsin-arrestin-1 interaction in bicelles. AB - G-protein-coupled receptors (GPCRs) are essential mediators of information transfer in eukaryotic cells. Interactions between GPCRs and their binding partners modulate the signaling process. For example, the interaction between GPCR and cognate G protein initiates the signal, while the interaction with cognate arrestin terminates G-protein-mediated signaling. In visual signal transduction, arrestin-1 selectively binds to the phosphorylated light-activated GPCR rhodopsin to terminate rhodopsin signaling. Under physiological conditions, the rhodopsin-arrestin-1 interaction occurs in highly specialized disk membrane in which rhodopsin resides. This membrane is replaced with mimetics when working with purified proteins. While detergents are commonly used as membrane mimetics, most detergents denature arrestin-1, preventing biochemical studies of this interaction. In contrast, bicelles provide a suitable alternative medium. An advantage of bicelles is that they contain lipids, which have been shown to be necessary for normal rhodopsin-arrestin-1 interaction. Here we describe how to reconstitute rhodopsin into bicelles, and how bicelle properties affect the rhodopsin-arrestin-1 interaction. PMID- 25697519 TI - Detection of structural waters and their role in structural dynamics of rhodopsin activation. AB - Conserved structural waters trapped within GPCRs may form water networks indispensable for GPCR's signaling functions. Radiolysis-based hydroxyl radical footprinting (HRF) strategies coupled to mass spectrometry have been used to explore the structural waters within rhodopsin in multiple signaling states. These approaches, combined with (18)O labeling, can be used to identify the locations of structural waters in the transmembrane region and measure rates of water exchange with bulk solvent. Reorganizations of structural waters upon activation of signaling can be explicitly observed with this approach, and this provides a unique look at the structural modules driving the signaling process. PMID- 25697520 TI - Probing conformational changes in rhodopsin using hydrogen-deuterium exchange coupled to mass spectrometry. AB - Hydrogen-deuterium exchange coupled to mass spectrometry is a powerful tool to evaluate changes in protein conformation between two or more states. Here, we describe a complete methodology that can be used to assess conformational changes in rhodopsin accompanying its transition from the inactive to activated state upon light exposure. This approach may be employed to investigate the structure and conformational changes of various membrane proteins. PMID- 25697521 TI - Analysis of conformational changes in rhodopsin by histidine hydrogen-deuterium exchange. AB - Hydrogen-deuterium exchange (HDX) is a technique that measures the exchange of protein hydrogens for deuteriums in a D2O-containing buffer, providing readout of the structural dynamics. Histidine hydrogen-deuterium exchange mass spectrometry (His-HDX-MS) is a variation of this technique that measures the slow HDX of imidazole C2 hydrogens of histidines. This measurement, when accompanied by pH titration, provides both pK as and half-lives (t 1/2) of the HDX reaction for individual histidine residues in proteins. The pK a and t 1/2 values indicate the electrostatic environment and the degree of side-chain solvent accessibility of the histidine residues, respectively. Herein we describe an experimental protocol to characterize rhodopsin by His-HDX-MS. This technique can be used to monitor different states of rhodopsin and might be useful for monitoring longtime scale events in other GPCRs. PMID- 25697522 TI - Investigation of rhodopsin dynamics in its signaling state by solid-state deuterium NMR spectroscopy. AB - Site-directed deuterium NMR spectroscopy is a valuable tool to study the structural dynamics of biomolecules in cases where solution NMR is inapplicable. Solid-state (2)H NMR spectral studies of aligned membrane samples of rhodopsin with selectively labeled retinal provide information on structural changes of the chromophore in different protein states. Moreover (2)H NMR relaxation time measurements allow one to study the dynamics of the ligand during the transition from the inactive to the active state. Here we describe the methodological aspects of solid-state (2)H NMR spectroscopy for functional studies of rhodopsin, with an emphasis on the dynamics of the retinal cofactor. We provide complete protocols for the preparation of NMR samples of rhodopsin with 11-cis-retinal selectively deuterated at the methyl groups in aligned membranes. In addition we review optimized conditions for trapping the rhodopsin photointermediates; and we address the challenging problem of trapping the signaling state of rhodopsin in aligned membrane films. PMID- 25697523 TI - Sequential structural changes in rhodopsin occurring upon photoactivation. AB - We describe the use of solid-state magic angle spinning NMR spectroscopy for characterizing the structure and dynamics of dark, inactive rhodopsin and the active metarhodopsin II intermediate. Solid-state NMR spectroscopy is well suited for structural measurements in both detergent micelles and membrane bilayer environments. We first outline the methods for large-scale production of stable, functional rhodopsin containing (13)C- and (15)N-labeled amino acids. The expression methods make use of eukaryotic HEK293S cell lines that produce correctly folded, fully functional receptors. We subsequently describe the basic methods used for solid-state magic angle spinning NMR measurements of chemical shifts and dipolar couplings, which provide information on rhodopsin structure and dynamics, and describe the use of low-temperature methods to trap the active metarhodopsin II intermediate. PMID- 25697524 TI - Dynamic single-molecule force spectroscopy of rhodopsin in native membranes. AB - Membrane proteins are an important class of proteins in biology and therapeutics. Understanding the dynamic nature of the molecular interactions that stabilize membrane protein structure is critical to dissect the mechanism of action and dysfunction of these proteins. Single-molecule force spectroscopy (SMFS) and dynamic SMFS (DFS) are emerging nanotechniques that allow the study of membrane proteins under the physiologically relevant conditions of a lipid bilayer and buffer conditions. These techniques directly probe the molecular interactions underlying protein structure and reveal unique insights about their properties. Outlined in this report will be procedures on how to conduct SMFS and DFS on rhodopsin in native retinal membranes. Rhodopsin is a membrane protein belonging to the G protein-coupled receptor family of proteins, one of the largest families of proteins in nature. PMID- 25697525 TI - High-resolution atomic force microscopy imaging of rhodopsin in rod outer segment disk membranes. AB - Atomic force microscopy (AFM) is a powerful imaging technique that allows recording topographical information of membrane proteins under near-physiological conditions. Remarkable results have been obtained on membrane proteins that were reconstituted into lipid bilayers. High-resolution AFM imaging of native disk membranes from vertebrate rod outer segments has unveiled the higher-order oligomeric state of the G protein-coupled receptor rhodopsin, which is highly expressed in disk membranes. Based on AFM imaging, it has been demonstrated that rhodopsin assembles in rows of dimers and paracrystals and that the rhodopsin dimer is the fundamental building block of higher-order structures. PMID- 25697526 TI - Detection of rhodopsin dimerization in situ by PIE-FCCS, a time-resolved fluorescence spectroscopy. AB - Rhodopsin self-associates in the plasma membrane. At low concentrations, the interactions are consistent with a monomer-dimer equilibrium (Comar et al., J Am Chem Soc 136(23):8342-8349, 2014). At high concentrations in native tissue, higher-order clusters have been observed (Fotiadis et al., Nature 421:127-128, 2003). The physiological role of rhodopsin dimerization is still being investigated, but it is clear that a quantitative assessment is essential to determining the function of rhodopsin clusters in vision. To quantify rhodopsin interactions, I will outline the theory and methodology of a specialized time resolved fluorescence spectroscopy for measuring membrane protein-protein interactions called pulsed-interleaved excitation fluorescence cross-correlation spectroscopy (PIE-FCCS). The strength of this technique is its ability to quantify rhodopsin interactions in situ (i.e., a live cell plasma membrane). There are two reasons for restricting the scope to live cell membranes. First, the compositional heterogeneity of the plasma membrane creates a complex milieu with thousands of lipid, protein, and carbohydrate species. This makes it difficult to infer quaternary interactions from detergent solubilized samples or construct a model phospholipid bilayer that recapitulates all of the interactions present in native membranes. Second, organizational structure and dynamics is a key feature of the plasma membrane, and fixation techniques like formaldehyde cross-linking and vitrification will modulate the interactions. PIE-FCCS is based on two-color fluorescence imaging with time-correlated single-photon counting (TCSPC) (Becker et al., Rev Sci Instrum 70:1835-1841, 1999). By time-tagging every detected photon, the data can be analyzed as a fluorescence intensity distribution, fluorescence lifetime histogram, or fluorescence (cross )correlation spectra (FCS/FCCS) (Becker, Advanced time-correlated single-photon counting techniques, Springer, Berlin, 2005). These analysis tools can then be used to quantify protein concentration, mobility, clustering, and Forster resonance energy transfer (FRET). In this paper I will focus on PIE-FCCS, which interleaves two wavelength excitation events in time so that the effects of spectral cross-talk and FRET can be isolated. In this way it is possible to characterize monomer-dimer-oligomer equilibria with high accuracy (Muller et al., Biophys J 89:3508-3522, 2005). Currently, PIE-FCCS requires a customized equipment configuration that will be described below. There is an excellent protocol that outlines traditional FCCS on a commercially available instrument (Bacia and Schwille, Nat Protoc 2:2842-2856, 2007). The PIE-FCCS approach is a relatively recent advance in FCCS that has been used in live cell assays to quantify lipid-anchored protein clustering (Triffo et al., J Am Chem Soc 134:10833-10842, 2012), epidermal growth factor receptor dimerization (Endres et al., Cell 152:543-556, 2013), and recently the dimerization of opsin (Comar et al., J Am Chem Soc 136(23):8342-8349, 2014). This paper will outline the theory and instrumentation requirements for PIE-FCCS, as well as the data collection and analysis process. PMID- 25697527 TI - Oligomeric state of rhodopsin within rhodopsin-transducin complex probed with succinylated concanavalin A. AB - Rhodopsin-a prototypical G protein-coupled receptor (GPCR)-is abundantly expressed in the eye and stabilized by its covalently bound chromophore 11-cis retinal. The signal of light is amplified and transmitted through the binding of heterotrimeric G protein transducin (G t ) to photoactivated rhodopsin following downstream pathways activation leading to light sensing in the brain. As demonstrated by atomic force microscopy (AFM), rhodopsin exists in the native membrane of the rod outer segment disks as dimers highly organized in tightly packed oligomers. However, functional importance of this organization is still debated. To clarify the role of the rhodopsin dimer in signaling activation and thus the binding of transducin, the complex between rhodopsin and transducin can be formed, purified, and probed with succinylated concanavalin A. This method can be potentially applied to other GPCRs to verify their oligomeric state. PMID- 25697528 TI - Quantification of arrestin-rhodopsin binding stoichiometry. AB - We have developed several methods to quantify arrestin-1 binding to rhodopsin in the native rod disk membrane. These methods can be applied to study arrestin interactions with all functional forms of rhodopsin, including dark-state rhodopsin, light-activated metarhodopsin II (Meta II), and the products of Meta II decay, opsin and all-trans-retinal. When used in parallel, these methods report both the actual amount of arrestin bound to the membrane surface and the functional aspects of arrestin binding, such as which arrestin loops are engaged and whether Meta II is stabilized. Most of these methods can also be applied to recombinant receptor reconstituted into liposomes, bicelles, and nanodisks. PMID- 25697529 TI - Rhodopsin transient complexes investigated by systems biology approaches. AB - The fast kinetics characterizing the phototransduction cascade in virtually any species require that rhodopsin (Rh) form transient molecular complexes with a multitude of other proteins. Isolating such transient interactions in vitro and in vivo is a challenging task, although understanding their dynamics is essential to fully understand Rh function. Here, an established bottom-up systems biology approach is summarized, which links individual biomolecular processes to the whole-cell response, namely, the light-dependent suppression of the photoreceptor dark current. The known biochemical interactions occurring in the phototransduction cascade are integrated into a comprehensive computational model that can be numerically simulated, making it possible to: (a) virtually follow the time course of transient complexes formed by Rh with other molecules, including the cognate G protein transducin (Gt), rhodopsin kinase (RK), and arrestin (Arr), and (b) focus on specific receptor states, including multiple phosphorylations and activity of the chromophore-free receptor (opsin, Ops). Successful predictions of retinal disease-associated states, such as those related to vitamin A deficiency and Leber congenital amaurosis, have been obtained with the methodology presented herein. PMID- 25697530 TI - Three-dimensional architecture of murine rod cilium revealed by cryo-EM. AB - The connecting cilium of the rod photoreceptor is a tubular structure that bridges two adjacent cellular compartments, the inner segment, the major site of biosynthesis and energy metabolism, and the outer segment, a highly specialized ciliary structure responsible for phototransduction. The connecting cilium allows for active processes of protein sorting and transport to occur between them. Mutations affecting the cargo, their transporters, and the structural components of the primary cilium and basal body lead to aberrant trafficking and photoreceptor cell death. Understanding the overall design of the cilium, its architectural organization, and the function of varied protein complexes within the structural hierarchy of the cilium requires techniques for visualizing their native three-dimensional structures at high magnification. Here we describe methods for isolating retinas from mice, purifying fragments of rod cells that include much of the inner segment and the rod photoreceptor cilia, vitrifying the cell fragments, and determining their structures by cryo-electron tomography. PMID- 25697531 TI - Monitoring of rhodopsin trafficking and mistrafficking in live photoreceptors. AB - Outer segment (OS) directed trafficking is required for accomplishing the extremely high concentration of rhodopsin and explicitly high photon sensitivity of rod photoreceptor cells. Aberrant targeting of rhodopsin often leads to blinding disorders, due to various mechanisms causing rhodopsin mislocalization. Until recently, it has been challenging to monitor the dynamics of rhodopsin biogenesis and trafficking. Here, we describe a new method to visualize rhodopsin trafficking in living and unfixed Xenopus laevis rod photoreceptors. By harnessing the photochemical property of a photoconvertible fluorescent protein Dendra2, it is now possible to encode temporal information into colors and resolve spatiotemporal distribution of rhodopsin-Dendra2 fusion proteins in individual rod photoreceptors. PMID- 25697532 TI - Measurements of rhodopsin diffusion within signaling membrane microcompartments in live photoreceptors. AB - High-resolution multiphoton imaging of live cells has become an invaluable method to study protein dynamics in highly compartmentalized subcellular environments. Here we describe procedures that we recently developed to quantify rhodopsin mobility within and between retinal rod photoreceptor light signaling microcompartments, the disc membrane lobules, using multiphoton fluorescence relaxation after photoconversion. PMID- 25697533 TI - Kinetics of rhodopsin's chromophore monitored in a single photoreceptor. AB - Absorption of light isomerizes the retinyl chromophore of the photoreceptor pigment rhodopsin from 11-cis to all-trans, generating the photoactivated rhodopsin form. The photoisomerization of the chromophore however destroys rhodopsin, and its regeneration requires the removal of the all-trans and the supply of fresh 11-cis chromophore. The all-trans chromophore is removed through a series of steps beginning with its release from photoactivated rhodopsin in the form of all-trans-retinal, leaving behind the apoprotein opsin. All-trans-retinal is then reduced to all-trans-retinol, which is transported out of the photoreceptor. Rhodopsin is regenerated from opsin and fresh 11-cis-retinal arriving to the photoreceptor from the retinal pigment epithelium. Both all-trans and 11-cis-retinal can form precursors of lipofuscin, a pigment that accumulates with age in the lysosomal compartment of the retinal pigment epithelium. All trans-retinal, all-trans-retinol, and lipofuscin precursors all emit significant and distinct fluorescence signals, allowing their monitoring in single photoreceptor cells with fluorescence imaging. Here we describe the procedures for measuring these fluorophores in single mouse rod photoreceptors. PMID- 25697534 TI - Supplementation with vitamin a derivatives to rescue vision in animal models of degenerative retinal diseases. AB - The perception of light begins when photons reach retinal tissue located at the back of the eye and photoisomerize the visual chromophore 11-cis-retinal to all trans-retinal within photoreceptor cells. Isomerization of 11-cis-retinal activates the protein rhodopsin located in photoreceptor outer segments, thereby inducing a phototransduction cascade leading to visual perception. To maintain vision, 11-cis-retinal is regenerated in the retinal pigmented epithelium (RPE) via the visual cycle and delivered back to the photoreceptor cells where it may again bind to rhodopsin. Distinct pathological mechanisms have been observed to contribute to inherited retinal degenerative diseases including severe delay in 11-cis-retinal regeneration and delayed clearance of all-trans-retinal, which leads to the accumulation of harmful retinoid by-products. In the last decade, our group has conducted several proof-of-concept (POC) studies with retinoid derivatives aimed at developing treatments for retinal degenerative diseases caused by an impaired visual cycle. Here, we will introduce experimental procedures, which have been developed for POC studies involving retinoid biology. PMID- 25697535 TI - Sustained delivery of retinoids to prevent photoreceptor death. AB - Delivery of hydrophobic compounds to photoreceptors within the retina presents unique challenges due to the anatomy and physiology of the eye. Derivatives of vitamin A (retinoids) are essential to the function and survival of photoreceptors and in the absence of an intrinsic mechanism to metabolize these compounds (visual cycle) leads to extensive loss of photoreceptors and visual function. In this chapter, we describe a method for the sustained delivery of retinoids to young mice that lack a functioning visual cycle to promote survival of photoreceptors. PMID- 25697536 TI - High-throughput screening assays to identify small molecules preventing photoreceptor degeneration caused by the rhodopsin P23H mutation. AB - High-throughput screening (HTS) is one of the major techniques for discovering promising molecules for drug development. Rhodopsin mutations cause the most common autosomal dominant form of retinitis pigmentosa, an inherited retinal degenerative disease that currently has no effective treatment. To find an optimal pharmacological treatment for rhodopsin-associated retinitis pigmentosa, we performed two cell-based HTSs with mammalian cells expressing the P23H rod opsin mutant and identified two sets of novel compounds for further validation and characterization. The first HTS screen identified pharmacological chaperones of P23H opsin that increased its translocation from the endoplasmic reticulum to the plasma membrane. The second HTS screen selected small molecules that enhanced the clearance of the mutant opsin while vision could be sustained by the healthy gene allele expressing wild-type rhodopsin. Here we describe the methodology of these two HTS assays in detail. PMID- 25697537 TI - Gene therapy to rescue retinal degeneration caused by mutations in rhodopsin. AB - Retinal gene therapy has proven safe and at least partially successful in clinical trials and in numerous animal models. Gene therapy requires characterization of the progression of the disease and understanding of its genetic cause. Testing gene therapies usually requires an animal model that recapitulates the key features of the human disease, though photoreceptors and cells of the retinal pigment epithelium produced from patient-derived stem cells may provide an alternative test system for retinal gene therapy. Gene therapy also requires a delivery system that introduces the therapeutic gene to the correct cell type and does not cause unintended damage to the tissue. Current systems being tested in the eye are nanoparticles, pseudotyped lentiviruses, and adeno-associated virus (AAV) of various serotypes. Here, we describe the techniques of AAV vector design as well as the in vivo and ex vivo tests necessary for assessing the efficacy of retinal gene therapy to treat retinal degeneration caused by mutations in the rhodopsin gene. PMID- 25697538 TI - Mitochondrial microsatellite instability in patients with metastatic colorectal cancer. AB - Mitochondrial microsatellite instability (mtMSI), a change in length in mtDNA microsatellite sequences between normal and tumor tissue, has been described as a frequent occurrence in colorectal cancer (CRC). We evaluated the prevalence and prognostic value of mtMSI and its relation to nuclear microsatellite instability (MSI) in patients with metastatic CRC (mCRC). At six loci (D310, D514, D16184, ND1, ND5, and COX1), the mitochondrial DNA sequence was analyzed in normal and tumor tissue, and the mtMSI status was determined. We evaluated the prevalence and outcome in terms of overall survival (OS) in 83 CRC patients with a MSI tumor (including 39 patients with Lynch syndrome) and in 99 mCRC patients with a microsatellite stable (MSS) tumor. A meta-analysis was performed to compare our findings with existing data. mtMSI at the D-loop region was found in 54.4 % (99 out of 182) of all patients. Prevalence of mtMSI was most pronounced at the D310 locus (50.5 %). Prevalence of mtMSI at the D-loop region was not different among patients with MSI compared to MSS tumors. There was no effect of mtMSI on prognosis in patients with MSI or MSS tumors. Prevalence of mtMSI was high in mCRC patients with both MSI and MSS tumors, but there was no correlation with prognosis. mtMSI was particularly present at the D310 locus. PMID- 25697539 TI - Long-term survival in a case of ETANTR with histological features of neuronal maturation after therapy. AB - Embryonal tumor with abundant neuropil and true rosettes (ETANTR) is a rare subtype of primitive neuroectodermal tumors and one of the most aggressive brain tumors in children. The neoplasm harbors a specific genetic alteration, amplification of the miRNA cluster C19MC at 19q13.42. We report a case of a 21 month-old boy with a mass in the left fronto-opercular region. The lesion was partially resected and pathology examination revealed an ETANTR with immunoreativity for LIN28A protein and amplification of the C19MC locus. The child received the PNET infant indications followed by high-dose thiotepa which resulted in a significant reduction of the mass. Subsequently, a second operation was carried out and the residual mass removed. Histology at this time showed a low-grade lesion composed of neuronal cells ranging from neurocytes to ganglion cells embedded in abundant neuropil with no immature embryonal component and multilayered rosettes. In addition to these features, a decrease in the number of nuclei with amplification of the C19MC locus was also observed. Thirty-one months after the second operation, the patient is alive and well. Such long-term survival could be explained by neuronal maturation induced by therapy associated with reduction of neoplastic cells with amplification of C19MC locus. This case suggests that the induction of differentiation may represent an optimal treatment strategy for very aggressive malignancies as ETANTR. PMID- 25697540 TI - Clinicopathological characteristics of urothelial bladder cancer in patients less than 40 years old. AB - Urothelial bladder cancer (UBC) is rare in young patients and as a result little information as to tumor type and clinical course are available. We present clinicopathological data of a large series of patients less than 40 years with bladder carcinoma. We included in this retrospective study covering the period from 1992 to 2013 patients less than 40 years with a first diagnosis of bladder cancer. Lesions were classified according to the WHO 2004 classification by uropathologists of ten centers. Stage, grade, multifocality, smoking habits, recurrence, and survival were studied. The cohort comprised of 152 patients, 113 males and 39 females with a mean age of 33.2 years. The large majority of the patients (142) was diagnosed with an urothelial carcinoma, the ten others with various histopathological diagnoses. In the age group less than 30 years old, 40.3 % of the cases concerned a papillary urothelial neoplasia of low malignant potential (PUNLMP). In the age group over 30 years, the proportion of PUNLMP decreased to 27.2 %. Only 5.6 % of the UBC was associated with carcinoma in situ. In 14.1 %, a high grade muscle invasive UC was found; 7.0 % had lymph node and 4.9 % distant metastasis at time of presentation. Four patients presented with a history of schistosomiasis; all had an infiltrating carcinoma. After initial resection, 36 patients relapsed, 17 % as PUNLMP, 53 % as pTa low grade, and 30 % as pTa-pT2 high grade UC. During follow-up, 6 % of the patients died. PUNLMP is the most frequent entity in this patient group. It is important that the PUNLMP entity is maintained in future classification systems. PMID- 25697542 TI - Initial presentation of a giant gastrointestinal stromal tumour of the stomach with recurrent spontaneous intra-peritoneal haemorrhage. AB - INTRODUCTION: Gastrointestinal stromal tumours are a rare group of tumours of the digestive tract. In the majority of cases, at the time of the diagnosis, tumours are usually small and patients are asymptomatic or have non-specific symptoms. The occurrence of digestive haemorrhage is relatively common; however, the manifestation with a spontaneous hemoperitoneum is extremely rare, specially if chronic and non-emergent. CASE REPORT: We report an unusual case of a 65-year-old man with a history of alcohol abuse, presenting with abdominal distension due to ascites and a constitutional syndrome. He was found to have a gastrointestinal stromal tumour (GIST) of the stomach associated with a chronic hemoperitoneum, due to recurrent spontaneous haemorrhage. In an elective setting, the lesion was resected completely without rupturing the tumour pseudo-capsule and the patient had an uneventful postoperative course. The tumour was classified as a moderate risk lesion for aggressive biological behaviour, and imatinib mesylate was initiated as an adjuvant to treatment. No evidence of disease recurrence after one year was noted. DISCUSSION AND CONCLUSION: GISTs are uncommon and rarely present with spontaneous intra-peritoneal haemorrhage, which may be life threatening. In our understanding, this is the first reported case of the reviewed literature presenting with a chronic hemoperitoneum, due to recurrent brisk episodes of tumour haemorrhage. Tumour rupture and large tumour size are two poor independent prognostic tumour factors for recurrence. Despite this, the patient remains free of disease after surgery and instituted adjuvant imatinib mesylate. PMID- 25697541 TI - Clinical, epidemiological and virological features of acute hepatitis B in Italy. AB - PURPOSE: To evaluate the association of hepatitis B virus (HBV) genotypes, basal core promoter (BCP)/precore (PC) and S gene mutations with the clinical epidemiological characteristics of acute hepatitis B (AHB) in Italy. METHODS: During July 2005-January 2007, 103 symptomatic AHB patients were enrolled and prospectively followed up at 15 national hospitals. HBV genotypes, BCP/PC and S gene variants were determined by nested-PCR and direct sequence analysis. RESULTS: Genotype D, A and F were detected in 49, 45 and 6% of patients, respectively. BCP, PC, and BCP plus PC variants were found in 3.1, 11.3 and 7.2% of patients, respectively. At enrollment, 68.3% of patients were hepatitis B e antigen (HBeAg)-positive and 31.7% HBeAg-negative. BCP/PC mutations were more common in HBeAg-negative than in HBeAg-positive patients (p < 0.0001). Compared to genotype D patients, those harboring non-D genotypes were more frequently males (p = 0.023), HBeAg-positive (p < 0.001), had higher bilirubin (p = 0.014) and viremia (p = 0.034) levels and less frequently carried BCP/PC mutations (p < 0.001). Non-D genotype patients more often were from Central Italy (p = 0.001) and reported risky sexual exposure (p = 0.021). Two patients had received vaccination before AHB: one harbored genotype F; the other showed a S gene mutation. Four patients developed fulminant AHB; mutations were found in 2 of 3 patients who underwent BCP/PC sequencing. After a 6-month follow-up, only 2 (2.8%) patients developed persistent infection. CONCLUSION: AHB by non-D genotypes is increasing in Italy and is associated with risky sexual exposure. The ability of some genotypes to cause persistent and/or severe infection in Italy warrants larger studies for clarification. PMID- 25697543 TI - Anaplastic carcinoma in submandibular region: A diagnostic dilemma. AB - INTRODUCTION: Thyroid carcinoma arising in an extrathyroid area is a rare entity. PRESENTATION OF CASE: We report a case of anaplastic carcinoma in the submandibular region occurring in a 70-year-old woman. DISCUSSION: The location of the mass along with no evidence of primary tumor at the orthotopic thyroid gland posed a diagnostic dilemma: was this an ectopic thyroid carcinoma or rather a case of occult differentiated thyroid carcinoma metastasis that transformed to anaplastic carcinoma? Based on the histopathological findings we concluded that the tumor arised in ectopic thyroid tissue. Although the mass was completely resected, the patient died 10 months after diagnosis due to pulmonary metastases. CONCLUSION: Conclusively, the possibility of ectopic thyroid tissue, with or without disease, should be considered in cases of a mass in the submandibular region. PMID- 25697544 TI - Solution-processed zinc oxide/polyethylenimine nanocomposites as tunable electron transport layers for highly efficient bulk heterojunction polymer solar cells. AB - In this study, we employed polyethylenimine-doped sol-gel-processed zinc oxide composites (ZnO:PEI) as efficient electron transport layers (ETL) for facilitating electron extraction in inverted polymer solar cells. Using ultraviolet photoelectron spectroscopy, synchrotron grazing-incidence small-angle X-ray scattering and transmission electron microscopy, we observed that ZnO:PEI composite films' energy bands could be tuned considerably by varying the content of PEI up to 7 wt %-the conduction band ranged from 4.32 to 4.0 eV-and the structural order of ZnO in the ZnO:PEI thin films would be enhanced to align perpendicular to the ITO electrode, particularly at 7 wt % PEI, facilitating electron transport vertically. We then prepared two types of bulk heterojunction systems-based on poly(3-hexylthiophene) (P3HT):phenyl-C61-butryric acid methyl ester (PC61BM) and benzo[1,2-b:4,5-b]dithiophene-thiophene-2,1,3-benzooxadiazole (PBDTTBO):phenyl-C71-butryric acid methyl ester (PC71BM)-that incorporated the ZnO:PEI composite layers. When using a composite of ZnO:PEI (93:7, w/w) as the ETL, the power conversion efficiency (PCE) of the P3HT:PC61BM (1:1, w/w) device improved to 4.6% from a value of 3.7% for the corresponding device that incorporated pristine ZnO as the ETL-a relative increase of 24%. For the PBDTTBO:PC71BM (1:2, w/w) device featuring the same amount of PEI blended in the ETL, the PCE improved to 8.7% from a value of 7.3% for the corresponding device that featured pure ZnO as its ETL-a relative increase of 20%. Accordingly, ZnO:PEI composites can be effective ETLs within organic photovoltaics. PMID- 25697545 TI - Dietary alterations and restrictions following surgery for upper gastrointestinal cancers: Key components of a health-related quality of life intervention. AB - PURPOSE: The surgical treatment of upper gastrointestinal (GI) cancers, specifically esophageal and gastric cancers, often result in extensive health related quality of life (HRQOL) concerns, particularly those associated with dietary adjustments. This paper provides a review of HRQOL changes following esophagectomy and gastrectomy, and describes key components of an intervention to improve dietary adjustments following surgery. METHODS: Intervention development was informed by 1) current published evidence on HRQOL changes for patients following upper GI surgery, 2) examination of usual post-operative care related to dietary restrictions to identify areas for continued education and support and 3) the inclusion of a conceptual framework (the Chronic Care Model) to guide intervention design and inform the selection of appropriate outcome measures. RESULTS: Three key components of an HRQOL intervention are identified, and should focus on HRQOL concerns associated with dietary alterations and restrictions following treatment, involve family caregivers, and be tailored and flexible to patient and family caregiver's needs and preferences. CONCLUSIONS: Evidence-based interventions to support long-term dietary alterations and restrictions following upper GI surgery are lacking, despite evidence confirming its impact on morbidity and mortality. Interventions are needed to support dietary adjustments, prevent malnutrition and excessive weight loss, and enhance HRQOL following surgery for upper GI cancers. PMID- 25697546 TI - Living with a high-grade glioma: A qualitative study of patients' experiences and care needs. AB - PURPOSE: Patients with high-grade glioma (HGG) face debilitating symptoms and a poor prognosis. The aims of this study were to better understand how patients with HGG experience life with a brain tumor, and to explore their professional care needs. METHODS: We conducted a qualitative research of HGG patients' experiences using semi-structured interviews and using a Grounded Theory approach. Participants were recruited during patients' hospital visits for treatment or follow-up at the University Hospitals Leuven, Belgium. Seventeen HGG patients were interviewed for the study. RESULTS: Interviews showed that HGG diagnosis left patients feeling like everything was surreal. From that point on, their life was marked by loss. HGG patients sometimes felt disregarded by family caregivers, professional caregivers, and the health care system. They felt as if they were on the "sidelines" of their own life. Despite the devastating experience of living with this type of brain tumor, HGG patients also expressed great inner strength, and they tried to maintain hope. Their pivotal professional care needs concerned information, communication, and accessibility. CONCLUSIONS: Diagnosis of HGG changes life drastically. Our results highlight the need for professional caregivers to be more considerate and supportive of patients with this life-changing diagnosis. Additionally, professional caregivers need to acknowledge these patients as persons and strive to empower them in order to bolster their personal strength. PMID- 25697547 TI - The psychosocial needs of gynaecological cancer survivors: A framework for the development of a complex intervention. AB - PURPOSE: To develop and pilot test an intervention targeting the women's psychosocial needs during the follow-up period after surgical treatment for gynaecological cancer. METHODS: The project consisted of four phases. Phase 1 involved development of an intervention on the basis of meetings with key healthcare professionals, a literature review and six semi-structured interviews with women who attended the existing follow-up program. The Guided Self Determination (GSD) method developed in diabetes care was identified as an appropriate framework for the intervention. GSD consists of reflection sheets for patients and advanced professional communication skills. The GSD method was adapted to women in a follow-up program after gynaecologic cancer treatment (GSD GYN-C). Phase 2 involved primary pilot testing of the intervention and the findings were used to modify the intervention in phase 3. This modification involved the development of additional reflection sheets and a fidelity assessment tool. A systematic training program was arranged for the GSD-GYN-C nurses. Phase 4 involved secondary pilot testing where nurses and women confirmed the applicability of GSD-GYN-C and final adjustments were made. Selected measurements were tested for sensitivity during pilot testing. Data from phase 2 and 4 were also used to select the primary outcome and calculate power for a future randomized clinical trial (RCT). RESULTS: Pilot testing supported our hypothesis that GSD-GYN-C may be transferable and useful to survivors of gynaecological cancer. CONCLUSION: GSD-GYN-C was developed and validated and is now ready for evaluation in an RCT. PMID- 25697548 TI - The DPP-4 inhibitor linagliptin and the GLP-1 receptor agonist exendin-4 improve endothelium-dependent relaxation of rat mesenteric arteries in the presence of high glucose. AB - The aim of the study was to investigate the effects of the DPP-4 inhibitors and GLP-1R agonist, exendin-4 on the mechanism(s) of endothelium-dependent relaxation in rat mesenteric arteries exposed to high glucose concentration (40 mM). Organ bath techniques were employed to investigate vascular endothelial function in rat mesenteric arteries in the presence of normal (11 mM) or high (40 mM) glucose concentrations. Pharmacological tools (1MUM TRAM-34, 1MUM apamin, 100 nM Ibtx, 100 MUM l-NNA, 10 MUM ODQ) were used to distinguish between NO and EDHF-mediated relaxation. Superoxide anion levels were assessed by L-012 and lucigenin enhanced chemiluminescence techniques. Incubation of mesenteric rings with high glucose for 2 h caused a significant increase in superoxide anion generation and a significant impairment of endothelium-dependent relaxation. Exendin-4 and DPP-4 inhibitor linagliptin, but not sitagliptin or vildagliptin, significantly reduced vascular superoxide and improved endothelium-dependent relaxation in the presence of high glucose. The beneficial actions of exendin-4, but not linagliptin, were attenuated by the GLP-1R antagonist exendin fragment (9-39). Further experiments demonstrated that the presence of high glucose impaired the contribution of both nitric oxide and endothelium-dependent hyperpolarisation to relaxation and that linagliptin improved both mechanisms involved in endothelium-dependent relaxation. These findings demonstrate that high glucose impaired endothelium dependent relaxation can be improved by exendin-4 and linagliptin, likely due to their antioxidant activity and independently of any glucose lowering effect. PMID- 25697549 TI - Long-term safety of early consumption of Lactobacillus fermentum CECT5716: A 3 year follow-up of a randomized controlled trial. AB - Lactobacillus fermentum CECT5716 is a probiotic strain originally isolated from human breast milk. Previous clinical studies in infants showed that the early administration of a milk formula containing this probiotic strain was safe and may be useful for the prevention of community-acquired infections. This is a 3 year follow-up study aimed at evaluating the long-term effects produced by the early consumption of an infant formula supplemented with L. fermentum CECT5716 (experimental group, EG) compared with a control formula without the probiotic (control group, CG). The infants included in this follow-up study had previously completed a 5-month randomized double-blind controlled trial (from 1 to 6 months of age), where the safety and tolerance of the probiotic formula was evaluated. The main outcome of the follow-up study was the growth of the children. The secondary outcomes included the incidence of infectious and non-infectious diseases, parameters related with intestinal function and faecal microbiota. At 3 years, the mean values of weight, length and head circumference were similar in children of the EG compared with those of the CG. No differences were observed in the incidence of infectious and non-infectious diseases or disorders related with intestinal function. The pattern of faecal microbiota was also similar between both groups. In conclusion, this 3-year study shows that the early administration of the probiotic of L. fermentum CECT5716 in an infant formula is safe and it does not produce measurable differences in children compared with a control formula. PMID- 25697550 TI - Endothelial dysfunction in young healthy men is associated with aspirin resistance. AB - The aim of this study was to investigate the relation between endothelial dysfunction and aspirin response in a young healthy population (102 men aged 18 40). Initial concentrations of the NO pathway metabolites (ADMA, l-arginine, SDMA), cardiovascular risk markers, oxidative stress markers (MDA, thiol index), sICAM1, sVCAM1, PAI-1, sE-selectin, sP-selectin, VEGF, thromboxane B2, 6-keto PGF1alpha and arachidonate-induced platelet aggregation (to separate aspirin resistant from sensitive group) were measured. Flow-mediated-vasodilation (FMD) was measured before and after intravenous infusion of 16.0 g of l-arginine. Measurements were repeated following aspirin administration (75 mg/24 h) for 4 days. Both groups were homogenous regarding demographic and biochemical characteristics reflecting cardiovascular risk. Aspirin resistant subjects were characterized by lower baseline FMD and higher FMD following aspirin and l arginine treatment, as compared to aspirin sensitive control. MDA and nitrotyrosine were greater, whereas thiol index was lower in aspirin resistant men. The sICAM1, sVCAM1, PAI-1, sE-selectin, sP-selectin and VEGF levels were similar in the analyzed groups. Thromboxane in aspirin resistant subjects was greater both at baseline and following aspirin therapy. However, a significant decrease following aspirin treatment was present in both groups. Aspirin resistance in young men is associated with endothelial dysfunction, which could be due to oxidative stress resulting from lipid peroxidation. PMID- 25697551 TI - Heavy metal levels in mud crabs (Scylla spp.) from East Bataan Coast. AB - Heavy metal levels (Pb and Cu) on adult mud crabs (Scylla spp.) from the East Bataan Coast were determined. Muscle tissue from each crab was processed through nitric acid digestion and analyzed using atomic absorption spectroscopy. The average concentrations in the samples were 3.37 * 10(-3) and 1.01 mg/L-both within WHO acceptable limits. These were contrasted with the levels found in sediments from catch and grow-out sites (17.9, 14.5, 37.8, and 31.3 mg/L) and were found to be significantly lower in concentration. It takes 3-8 months before adult mud crabs can be harvested from grow-out ponds, and the data suggests that the organisms, even when constantly exposed to high levels of Pb and Cu, do not bio-accumulate toxic levels of these heavy metals. Mud crabs constitute a major economic natural resource in the Philippines and in the province of Bataan. Commanding high prices due to the quality of its meat, it is also a preferred culture product due to its impressive size, rapid growth rate, and high flesh content. Mud crab culture in Bataan is primarily driven by grow-out of captured juveniles in pen or pond cultures sourced from nearby bodies of water-making them vulnerable to prolonged exposure to pollutants. The East Bataan Coast shares its waters with the polluted Manila Bay, giving rise to the concern of the quality of seafood acquired from the area. PMID- 25697552 TI - Pesticide and trace metal occurrence and aquatic benchmark exceedances in surface waters and sediments of urban wetlands and retention ponds in Melbourne, Australia. AB - Samples of water and sediments were collected from 24 urban wetlands in Melbourne, Australia, in April 2010, and tested for more than 90 pesticides using a range of gas chromatographic (GC) and liquid chromatographic (LC) techniques, sample 'hormonal' activity using yeast-based recombinant receptor-reporter gene bioassays, and trace metals using spectroscopic techniques. At the time of sampling, there was almost no estrogenic activity in the water column. Twenty three different pesticide residues were observed in one or more water samples from the 24 wetlands; chemicals observed at more than 40% of sites were simazine (100%), atrazine (79%), and metalaxyl and terbutryn (46%). Using the toxicity unit (TU) concept, less than 15% of the detected pesticides were considered to pose an individual, short-term risk to fish or zooplankton in the ponds and wetlands. However, one pesticide (fenvalerate) may have posed a possible short term risk to fish (log10TUf > -3), and three pesticides (azoxystrobin, fenamiphos and fenvalerate) may have posed a risk to zooplankton (logTUzp between -2 and 3); all the photosystem II (PSII) inhibiting herbicides may have posed a risk to primary producers in the ponds and wetlands (log10TUap and/or log10TUalg > -3). The wetland sediments were contaminated with 16 different pesticides; no chemicals were observed at more than one third of sites, but based on frequency of detection and concentrations, bifenthrin (33%, maximum 59 MUg/kg) is the priority insecticide of concern for the sediments studied. Five sites returned a TU greater than the possible effect threshold (i.e. log10TU > 1) as a result of bifenthrin contamination of their sediments. Most sediments did not exceed Australian sediment quality guideline levels for trace metals. However, more than half of the sites had threshold effect concentration quotients (TECQ) values >1 for Cu (58%), Pb (50%), Ni (67%) and Zn (63%), and 75% of sites had mean probable effect concentration quotients (PECQ) >0.2, suggesting that the collected sediments may have been having some impact on sediment-dwelling organisms. PMID- 25697553 TI - Cometabolism of methyl tert-butyl ether by a new microbial consortium ERS. AB - The release of methyl tert-butyl-ether (MTBE) into the environment has increased the worldwide concern about the pollution of MTBE. In this paper, a microbial consortium was isolated from the soil sample near an oil station, which can degrade MTBE directly with a low biomass yield and MTBE degrading efficiency. Further research has indicated that this consortium can degrade MTBE efficiently when grown on n-octane as the cometabolic substrate. The results of 16S rDNA based on phylogenetic analysis of the selected operating taxonomic units (OTUs) involved in the consortium revealed that one OTU was related to Pseudomonas putida GPo1, which could cometabolically degrade MTBE on the growth of n-octane. This may help explain why n-octane could be the optimal cometabolic substrate of the consortium for MTBE degradation. Furthermore, the degradation of MTBE was observed along with the consumption of n-octane. Different K s values for MTBE were observed for cells grown with or without n-octane, suggesting that different enzymes are responsible for the oxidation of MTBE in cells grown on n-octane or MTBE. The results are discussed in terms of their impacts on our understanding of MTBE biodegradation and cometabolism. PMID- 25697554 TI - Development of a set of bacterial biosensors for simultaneously detecting arsenic and mercury in groundwater. AB - There is a growing need for effective and inexpensive environmental monitoring strategies for assessing heavy metal contamination levels. We developed a set of bacterial biosensors to simultaneously detect multiple bioavailable heavy metals (As(III) and Hg(II)). The biosensors provide a choice of the two reporter systems, luxCDABE and gfp, combined with metal responsive regulatory elements (ars and mer for As(III) and Hg(II), respectively). The results showed that the induction of the luxCDABE-based constructs was more sensitive than that of the gfp-based constructs for the detection of As(III) and Hg(II). In addition, both the luminescent and fluorescent biosensors readily distinguished As and Hg concentrations in groundwater samples to meet the groundwater quality standards. Due to the potentially complicated chemicals present in environmental samples, using a set of bacterial biosensors with different reporter genes to simultaneously determine the bioavailable proportions of heavy metals is desirable. PMID- 25697555 TI - Assessment of soil organic contamination in a typical petrochemical industry park in China. AB - The concentrations of total petroleum hydrocarbons (TPH), n-alkanes (n-C8 through n-C40), and 16 polycyclic aromatic hydrocarbons (PAHs) in soils were determined to assess the level of organic contamination in soils from the Da-gang Petrochemical Industry Park with several big state-run enterprises, a recent rapid flourishing park in China. The results showed that the concentration of TPH in soil was high, up to 20 ng/g-12.8478%; in particular, the content in most sites ranged from 1 to 2%. Thus, it is clear that soil environment in the Da-gang Petrochemical Industry Park has been seriously polluted by TPH according to the Nemerow pollution index method. Furthermore, the average concentration of Sigma(n C>16 through n-C34) in 30 sampling sites was above the maximum limit set for F3 under all the conditions in the Canada-wide standards for petroleum hydrocarbons (PHC CWS) with 43.33-93.33% soil samples exceeding F3 standards, and n-alkanes possessing higher concentrations were proved much abundant alkanes in this study. Besides, the predominance of even n-alkanes and lower carbon preference index (CPI) demonstrated that n-alkanes in surface soils were mainly caused by anthropogenic inputs, while the concentration of Sigma16-PAHs was in the range of 1652.5-8217.3 ng/g and the BaA/(BaA + Chr) and Flu/(Flu + Pyr) ratios indicated that pyrogenic PAHs may be the dominant PAHs in most soils with the contribution of petrogenic hydrocarbons in some sites. PMID- 25697556 TI - NHS will not improve while new models of care delivery remain "minority interest," conference hears. PMID- 25697558 TI - Regulation of a nickel-cobalt efflux system and nickel homeostasis in a soil actinobacterium Streptomyces coelicolor. AB - In Streptomyces coelicolor, a soil actinobacterium capable of morphological differentiation and complex secondary metabolism, nickel deficiency is sensed by Nur, a Ni-specific Fur family regulator that controls nickel uptake systems (NikABCDE and NikMNOQ) and both Fe-containing and Ni-containing superoxide dismutases (SodF and SodN). On the other hand, the nickel efflux system and its regulator have not been elucidated. In this study, we demonstrate that an ArsR/SmtB family metalloregulator NmtR, a close homologue of NmtR from Mycobacterium tuberculosis, controls a putative efflux pump of P1-type ATPase (NmtA) in S. coelicolor. NmtR binds to the nmtA promoter region to repress its transcription, and is dissociated in the presence of Ni(ii) and Co(ii). Disruption of the nmtA gene makes cells more sensitive to nickel and cobalt, consistent with its predicted role in encoding a Ni-Co-efflux pump. Growth of S. coelicolor in complex YEME medium is only marginally inhibited by up to 0.5 mM Ni(ii), with significant growth retardation at 1 mM. Nur-regulated sodF and nikA genes are repressed at less than 0.1 MUM added NiSO4 whereas NmtR-regulated nmtA transcription is induced at 0.5 mM or more Ni(ii). This reveals the extreme sensitivity of S. coelicolor to nickel deficiency as well as tolerance to surplus nickel. How this organism and possibly other actinomycetes have evolved to develop such a highly Ni-tolerant physiology and how the highly sensitive regulator Nur and the obtuse regulator NmtR achieve their characteristic Ni sensitivity are interesting questions to solve in the future. PMID- 25697557 TI - Tocilizumab in giant cell arteritis: Multicenter open-label study of 22 patients. AB - OBJECTIVE: To assess the efficacy of tocilizumab (TCZ) in giant cell arteritis (GCA) patients with refractory disease and/or with unacceptable side effects due to corticosteroids. METHODS: A retrospective multicenter open-label study on 22 GCA patients treated with TCZ at standard dose of 8mg/kg/month. The main outcomes were achievement of disease remission and reduction of corticosteroid dose. RESULTS: The mean age +/- standard deviation of patients was 69 +/- 8 years. The main clinical features at TCZ onset were polymyalgia rheumatica (n = 16), asthenia (n = 7), headache (n =5), constitutional symptoms (n = 4), jaw claudication (n = 2), and visual loss (n = 2). Besides corticosteroids and before TCZ onset, 19 of 22 patients had also received several conventional immunosuppressive and/or biologic drugs. Of 22 patients, 19 achieved rapid and maintained clinical improvement following TCZ therapy. Also, after a median follow-up of 9 (interquartile range: 6-19) months, the C-reactive protein level had fallen from 1.9 (1.2-5.4) to 0.2 (0.1-0.9)mg/dL (p < 0.0001) and the erythrocyte sedimentation rate decreased from 44 (20-81) to 12 (2-20)mm/1st hour (p = 0.001). The median dose of prednisone was also tapered from 18.75 (10-45) to 5 (2.5-10)mg/day (p < 0.0001). However, TCZ had to be discontinued in 3 patients due to severe neutropenia, recurrent pneumonia, and cytomegalovirus infection. Moreover, 1 patient died after the second infusion of TCZ due to a stroke in the setting of an infectious endocarditis. CONCLUSION: TCZ therapy leads to rapid and maintained improvement in patients with refractory GCA and/or with unacceptable side effects related to corticosteroids. However, the risk of infection should be kept in mind when using this drug in patients with GCA. PMID- 25697559 TI - Effect of linker flexibility and length on the functionality of a cytotoxic engineered antibody fragment. AB - Engineered antibody fragments often contain natural or synthetic linkers joining the antigen-binding domain and multimerization regions, and the roles of these linkers have largely been overlooked. To investigate linker effects on structural properties and functionality, six bivalent cytotoxic antibody fragments with of linkers of varying flexibility and length were constructed: (1) 10-AA mouse IgG3 upper hinge region, (2) 20-AA mouse IgG3 upper hinge region repeat, (3) 10-AA glycine and serine linker, (4) 20-AA glycine and serine linker repeat, (5) 21-AA artificial linker, and (6) no-linker control. Interestingly, a higher cytotoxicity was observed for fragments bearing the rigid short linkers compared to the flexible longer linkers. More importantly, amino acid composition related to the rigidity/flexibility was found to be of greater importance upon cytotoxicity than linker length alone. To further study the structure-function relationship, molecular modelling and dynamics simulation were exploited. Resultantly, the rigid mouse IgG3 upper hinge region was predicted to enhance structural stability of the protein during the equilibrium state, indicating the improved cytotoxicity over other combinations of fragments. This prediction was validated by measuring the thermal stability of the mouse IgG3 upper hinge as compared to the artificial linker, and shown to have a higher melting temperature which coincides with a higher structural stability. Our findings clearly suggest that appropriate linker design is required for enhancing the structural stability and functionality of engineered antibody fragments. PMID- 25697560 TI - Antioxidant properties of melatonin and its potential action in diseases. AB - In recent years, relationship between free radicals and oxidative stress with aging, cancer, atherosclerosis, neurodegenerative disorders, diabetes, and inflammatory diseases became increasingly clear. Confirming the role of oxidants in numerous pathological conditions such as cancer, the antioxidants developed as therapeutics have been proven ineffective. It is well established that melatonin (MLT) and its metabolites are able to function as endogenous free-radical scavengers and broadspectrum antioxidants. Numerous studies also proved the role of MLT and its derivatives in many physiological processes and therapeutic functions, such as the regulation of circadian rhythm and immune functions. The aim of this review is to arouse attention to MLT as a potentially valuable agent in the prevention and/or treatment of some diseases. PMID- 25697561 TI - Anti-inflammatory and antioxidant properties of Piper species: a perspective from screening to molecular mechanisms. AB - Identifying novel therapeutic agents from natural sources and their possible intervention studies has been one of the major areas in biomedical research in recent years. Piper species are highly important - commercially, economically and medicinally. Our groups have been working for more than two decades on the identification and characterization of novel therapeutic lead molecules from Piper species. We have extensively studied the biological activities of various extracts of Piper longum and Piper galeatum, and identified and characterized novel molecules from these species. Using synthetic chemistry, various functional groups of the lead molecules were modified and structure activity relationship (SAR) studies identified synthetic molecules with better efficacy and lower IC50 values. Moreover, the mechanisms of actions of some of these molecules were studied at the molecular level. The objective of this review is to summarize experimental data published from our laboratories and others on antioxidant and anti-inflammatory potentials of Piper species and their chemical constituents. PMID- 25697562 TI - Kinase inhibitors with redox and anti-inflammatory activities. AB - The development of inflammatory immune response is related to an activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) signaling. The intracellular molecules from this pathway are sensitive to the alterations in the microenvironment. The changes in cellular redox state, proliferation, gene expression pattern and genomic stability during inflammation induce the activation of non-canonical and atypical NK-kappaB signaling increasing the crosstalk with molecules involved in neddylation, cell cycle checkpoints regulation and DNA repair. This review article describes the reactive oxygen species (ROS)-sensitive kinases from the NF-kappaB pathway and presents the effects of their suppression by small kinase inhibitors. It illustrates that selective targeting of the redox sensor molecules from the inflammatory NK- kappaB cascades can influence cell survival and metabolism as well. We think that this issue is important when evaluating the drug efficacy in clinical studies and their side effects. PMID- 25697563 TI - Regression of oxidative stress by targeting eNOS and Nrf2/ARE signaling: a guided drug target for cardiovascular diseases. AB - Cardiovascular diseases (CVDs) are the major health concern and the leading cause of death. Imbalance between free radicals and anti-oxidant defence is associated with cellular dysfunctions leading to the pathophysiology of various diseases including cardiac and vascular diseases. The stress responsive transcription factor NF-E2-related factor 2/antioxidant response element (Nrf2/ARE) regulates the expression of many detoxifying genes. Nitric oxide (NO) produced by endothelial nitric oxide synthase (eNOS) is an important regulator of vascular function. Involvement of NO in modulating Nrf2 signaling is well established. Thus, it is apparent that increasing NO bioavailability and antioxidant status in vascular and myocardial tissue can be considered as a potential strategy to prevent the onset of vascular dysfunction and CVDs and is therefore of therapeutical interest. Based on the marked protective effect of Nrf2/ARE signalling and intriguing links between antioxidant mechanism and endothelial derived NO, the aim of the present review is to compile conclusive evidence for the involvement of NO-Nrf2/ARE axis in the regulation of cardiovascular function. This review also discusses on improving eNOS and Nrf2 signalling by Nrf2 activators which holds promise for countering cardiac and vascular disorders. PMID- 25697564 TI - Interest of antioxidant agents in parasitic diseases. The case study of coumarins. AB - Tropical parasitic diseases, especially those produced by protozoan parasites, are a major public health problem in many countries, and their impact in the health burden is significant. Oxidative processes proved to be related to these diseases, being the antioxidant agents promising therapeutic solutions for them. Therefore, this review provides an overview of published manuscripts regarding both activities. In particular, the interest of the coumarin derivatives as antioxidant agents with application in parasitic diseases is discussed in this manuscript. The recent findings in this field are highlighted. PMID- 25697565 TI - Cardiovascular effects of coumarins besides their antioxidant activity. AB - Coumarins are a large group of substances, primarily of plant origin. Like their more intensively examined congeners flavonoids, many of them are antioxidants. Although such properties may be advantageous in cardiovascular diseases, it has been shown that coumarins exhibit direct effects on the cardiovascular system which are not based on antioxidant activity. The most common example is the well known drug warfarin, a synthetic compound derived from natural dicoumarol. Moreover, other coumarins have been shown to possess antiplatelet and vasodilatory potential. Interestingly, the former effect may be mediated by the inhibition of various pathways leading to platelet aggregation, their differing effects on those pathways being due to structural differences between the various coumarins. Conversely, their vasodilatory potential is linked in the majority of cases to the inhibition of increases in intracellular calcium concentration in vascular smooth muscle cells, and in several coumarins also to NO-mediated vasodilatation. Available data on both activities are summarized in this review. At the end of this review, relevant data are provided from a few studies testing the in vivo effects of coumarins on major cardiovascular diseases; the clinical use of warfarin and other coumarin anticoagulants, as well as the limited data on the clinical use of coumarins in chronic venous insufficiency and the possible toxicological effects of coumarins. PMID- 25697566 TI - Dipyridamole: a drug with unrecognized antioxidant activity. AB - Dipyridamole was introduced on the market as coronary vasodilator drug more than half a century ago and is still used as antithrombotic and vasodilator. Among cellular targets, it inhibits phosphodiesterases and raises extracellular levels of adenosine through inhibition of adenosine reuptake by red blood cells. As a consequence, endocellular levels of cyclic nucleotides are upregulated. The rise of cGMP in vascular smooth muscle cells and of cAMP in platelets provide the mechanism of vasodilation and antithrombosis, which are further potentiated by the release of PGI2 consequent on the increase in endothelial cell cAMP. These effects support the use of dipyridamole in cardiovascular diseases in which the drug is approved for the secondary prevention of cerebrovascular events. On the other hand, dipyridamole has been shown to possess a potent, little perceived, antioxidant activity of potential use in the several fields where pathophysiological pathways are dependent on oxidative stress, including those occurring in atherosclerosis, thrombosis, CNS-related diseases, and cancer. PMID- 25697567 TI - Solar cells and photocatalytic systems: general discussion. PMID- 25697568 TI - Inducible RNAi system and its application in novel therapeutics. AB - RNA interference (RNAi) was discovered as a cellular defense mechanism more than decade ago. It has been exploited as a powerful tool for genetic manipulation. Characterized with specifically silencing target gene expression, it has great potential application for disease treatment. Currently, there are human clinical trials in progress or planned. Despite the excitement regarding this prominent technology, there are many obstacles and concerns that prevent RNAi from being widely used in the therapeutic field. Among them, the non-spatial and non temporal control is the most difficult challenge, as well as off-target effects and triggering type I immune responses. Inducible RNAi technology can effectively regulate target genes by inducer-mediated small hairpin RNA expression. Combination with inducible regulation systems this makes RNAi technology more sophisticated and may provide a wider application field. This review discusses approaches of inducible RNAi systems, the potential problem areas and solutions and their therapeutic applications. Given the limitations discussed herein being resolved, we believe that inducible RNAi will be a major therapeutic modality within the next several years. PMID- 25697569 TI - Histopathological alterations in the prostates of Mongolian gerbils exposed to a high-fat diet and di-n-butyl phthalate individually or in combination. AB - Both high-fat diet and exposure to endocrine-disrupting chemicals have been implicated in susceptibility to pathological prostate lesions, but the consequences of combining the two have not yet been examined. We evaluated the effects of gestational and postnatal exposure to a high-fat diet (20% fat) and low doses of di-n-butyl phthalate (DBP; 5mg/kg/day), individually or in combination, on the tissue response and incidence of pathological lesions in the ventral prostate of adult gerbils. Continuous intake of a high-fat diet caused dyslipidemia, hypertrophy, and promoted the development of inflammatory, premalignant and malignant prostate lesions, even in the absence of obesity. Life time DBP exposure was obesogenic and dyslipidemic and increased the incidence of premalignant prostate lesions. Combined exposure to DBP and a high-fat diet also caused prostate hypertrophy, but the effects were less severe than those of individual treatments; combined exposure neither induced an inflammatory response nor altered serum lipid content. PMID- 25697570 TI - Absence of developmental toxicity in a canine model after infusion of a hemoglobin-based oxygen carrier: Implications for risk assessment. AB - Bovine-derived hemoglobin-based oxygen carriers (HBOCs) have been investigated for use in humans (HBOC-201) and approved for veterinary medicine (HBOC-301). We infused pregnant beagles with HBOC-201 to test whether HBOC-induced developmental toxicity previously observed in rats would occur in a species devoid of an inverted visceral yolk sac (invVYS). Phase 1 assessed developmental toxicity of 6g/kg HBOC-201 on gestational day (GD) 21. Phase 2 investigated single infusions of 6g/kg HBOC-201 on one of GDs 21, 25, 29 or 33. Phase 3 studied multiple sequential infusions on GDs 21, 23,25,27,29, 31, and 33 at 0.52g/kg/day (3.6g/kg total dose). Mild to moderate maternal toxicity occurred in all phases. There was an unequivocal absence of developmental toxicity in all phases. Overall, our hypothesis that HBOC, which interferes with the function of the invVYS, would not affect the offspring in dogs was supported. The implications relative to human risk are discussed. PMID- 25697571 TI - Very low-dose (femtomolar) 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) disrupts steroidogenic enzyme mRNAs and steroid secretion by human luteinizing granulosa cells. AB - 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is the most toxic congener of the polyhalogenated aromatic hydrocarbons (PAH), which causes anatomical abnormalities and developmental defects, impairs ovulation and reduces fertility. TCDD's endocrine-disrupting effects are, in part, caused by a direct action at the ovary. Herein we investigated the in-vitro effects of environmentally relevant doses of TCDD on estradiol-17beta (E2) production by human luteinizing granulosa cells (hLGC) obtained from women stimulated for in-vitro fertilization (IVF). TCDD at all concentrations tested (3.1fM, 3.1pM and 3.1nM) significantly decreased E2 secretion when assayed for by radioimmunoassay (RIA). Herein we confirm that TCDD alters E2 secretion by hLGC in a time-, not dose-dependent fashion and are the first to show decreases in E2 secretion with fM concentrations of TCDD. Using real-time quantitative PCR (RT-qPCR), the decreased E2 secretion correlates with a decrease in the mRNA expression levels two enzymes in the estrogen biosynthesis pathway: CYP11A1 and CYP19A1. PMID- 25697572 TI - Genome sequencing in myelodysplastic syndromes: can molecular mutations predict benefit from hypomethylating agent therapy? AB - Evaluation of: Bejar R, Lord A, Stevenson K, et al. TET2 mutations predict response to hypomethylating agents in myelodysplastic syndrome patients. Blood 2014 Oct 23;124(17):2705-12. Patients with myelodysplastic syndromes (MDS) have clinically variable courses even within the same prognostic subgroups. Although hypomethylating agents (HMAs) have been shown to improve outcomes in patients with high-risk MDS, many patients do not derive benefit. There is an urgent clinical need to identify patients with low probability of benefiting from HMAs but no reliable clinical predictors or biomarkers have been discovered to date. Although some recurrent molecular mutations in MDS carry independent prognostic value, their ability to predict benefit from HMAs is not clear. Here, we discuss an important article in which sequencing from samples of 213 patients identified recurrent mutations associated with response to HMAs. Although an important step in the right direction, the clinical implications of these findings are far from optimal and identification of biomarkers that can reliably predict benefit from HMAs and other therapies in patients with MDS remains a top clinical and a research priority. PMID- 25697573 TI - Dysbindin (DTNBP1) variants are associated with hallucinations in schizophrenia. AB - BACKGROUND: Dystrobrevin binding protein 1 (DTNBP1) is a schizophrenia susceptibility gene involved with neurotransmission regulation (especially dopamine and glutamate) and neurodevelopment. The gene is known to be associated with cognitive deficit phenotypes within schizophrenia. In our previous studies, DTNBP1 was found associated not only with schizophrenia but with other psychiatric disorders including psychotic depression, post-traumatic stress disorder, nicotine dependence and opiate dependence. These findings suggest that DNTBP1 may be involved in pathways that lead to multiple psychiatric phenotypes. In this study, we explored the association between DTNBP1 SNPs (single nucleotide polymorphisms) and multiple psychiatric phenotypes included in the Diagnostic Interview of Psychosis (DIP). METHODS: Five DTNBP1 SNPs, rs17470454, rs1997679, rs4236167, rs9370822 and rs9370823, were genotyped in 235 schizophrenia subjects screened for various phenotypes in the domains of depression, mania, hallucinations, delusions, subjective thought disorder, behaviour and affect, and speech disorder. SNP-phenotype association was determined with ANOVA under general, dominant/recessive and over-dominance models. RESULTS: Post hoc tests determined that SNP rs1997679 was associated with visual hallucination; SNP rs4236167 was associated with general auditory hallucination as well as specific features including non-verbal, abusive and third-person form auditory hallucinations; and SNP rs9370822 was associated with visual and olfactory hallucinations. SNPs that survived correction for multiple testing were rs4236167 for third-person and abusive form auditory hallucinations; and rs9370822 for olfactory hallucinations. CONCLUSION: These data suggest that DTNBP1 is likely to play a role in development of auditory related, visual and olfactory hallucinations which is consistent with evidence of DTNBP1 activity in the auditory processing regions, in visual processing and in the regulation of glutamate and dopamine activity. PMID- 25697574 TI - Effect of loop composition on the stability and folding kinetics of RNA hairpins with large loops. AB - RNA hairpins are ubiquitous structural elements in biological RNAs, where they have the potential to regulate RNA folding and interactions with other molecules. There are established methods for predicting the thermodynamic stability of an RNA hairpin, but there are still relatively few detailed examinations of the kinetics of folding. Nonetheless, several recent studies indicate that hairpin folding does not proceed via a simple two-state model. Here, we monitor fluorescence from hairpins constructed as molecular beacons in ensemble, fluorescence correlation spectroscopy, and stopped-flow experiments to describe the folding of RNA hairpins with long (15 nucleotide) loops. Our results show that folding of these hairpins occurs through more than two states and that the mechanism of folding includes a fast intermediate phase observed on the tens of microseconds time scale and a slow phase, attributed to formation of the native folded hairpin loop and stem, observed on the milliseconds time scale. The composition of the RNA loop determines the time scale of intermediate and native folded states. Hairpins with a polyuracil loop sequence exhibit slower relaxation of the intermediate state and faster relaxation of the native folded state when compared to that of hairpins with cytosine or adenine in the loop. We hypothesize this composition dependence could be attributed to nucleobase stacking in cytosine and adenine containing regions of the loop, which would be absent in hairpins containing polyuracil loops. Such base stacking could destabilize the intermediate folds, thereby speeding the relaxation of the intermediate relative to similar sized hairpins with no base stacking in the loop. Likewise, the lower intermediate stability could prolong the relaxation of the native folded state. PMID- 25697575 TI - Unilateral malformation: adaptation of the frequency modulation system. PMID- 25697576 TI - Comparative effects of high-dose atorvastatin versus moderate-dose rosuvastatin on lipid parameters, oxidized-LDL and inflammatory markers in ST elevation myocardial infarction. AB - BACKGROUND: The important role of oxidized low density lipoprotein (oxidized-LDL) in preclinic atherosclerosis and pathophysiology of acute coronary syndromes studies have reported. Oxidation of LDL activates many inflammatory and atherogenic pathways and plays a pivotal role in atherosclerosis. Our aim in this study is to compare the effects of 80 mg daily dose of atorvastatin and 20 mg daily dose of rosuvastatin on lipid profiles and the levels of oxidized-LDL and inflammatory markers in ST elevation myocardial infarction (STEMI). METHODS: One hundred and twenty patients with STEMI were enrolled in this study. The patients were randomly assigned to receive atorvastatin (80 mg/day) or rosuvastatin (20 mg/day) by using a ratio of 1:1 after revascularization. The levels of total cholesterol (TC), triglyceride (TG), high density lipoprotein cholesterol (HDL C), LDL-C, apolipoprotein B and apolipoprotein A were compared between groups after 4-week therapy. The values of oxidized-LDL, tumor necrosis factor receptor 1 and 2, Interleukin-6 and hs-CRP were also compared between groups. The Student's t test was used to detect absolute and percent changes between groups, and p < 0.05 was considered as statistically significant for all tests. RESULTS: After treatment in both treatment groups LDL-C, oxidized-LDL, hs-CRP, tumor necrosis factor receptor 1 and 2, Interleukin-6 values significantly decreased according to baseline. The only difference was in HDL-C levels. HDL-C slightly decreased in atorvastatin group while it increased in the rosuvastatin group compared baseline (-1.4 +/- 8.9 mg/dl vs 2.0 +/- 9.4 mg/dl, p = 0.04). CONCLUSION: We reported that both statin treatment regiments have comparable effects on LDL-C, oxidized-LDL and inflammatory markers. Moreover, it was observed that rosuvastatin was more effective in terms of ability to increase HDL C level. Based on these findings, 20 mg daily dose of rosuvastatin may be an alternative to 80 mg daily dose of atorvastatin in patients with acute coronary syndrome. PMID- 25697577 TI - HDL cholesterol as a predictor for the incidence of lower extremity amputation and wound-related death in patients with diabetic foot ulcers. AB - OBJECTIVE: We examined whether HDL cholesterol levels are a predictor for an incidence of lower-extremity amputation (LEA) and wound-related death in patients with diabetic foot ulcers (DFUs). RESEARCH DESIGN AND METHODS: This was a single center, observational, longitudinal historical cohort study of 163 Japanese ambulatory patients with DFUs, 45 woman and 118 men, with a mean (standard deviation) age of 62 (14) years. The primary composite endpoint was defined as the worst of the following outcomes for each individual; (1) minor amputation, defined as amputation below the ankle, (2) major amputation, defined as amputation above the ankle, and (3) wound-related death. RESULTS: During the median follow-up period of 5.1 months, 67 patients (41.1%) reached the endpoint (43 minor amputations, 16 major amputations, and 8 wound-related deaths). In the univariate Cox proportional hazard model analysis, lower HDL cholesterol levels (mmol/L) were significantly associated with the incidence of the primary composite endpoint (hazard ratio 0.16 [95% CI 0.08-0.32], p < 0.001). In the multivariate Cox proportional hazard model analysis using a stepwise variable selecting procedure, HDL cholesterol levels in addition to the presence of ankle brachial index <0.9 or >=1.4 and serum albumin levels were selected as independent risk factors for the incidence of the endpoint (hazard ratio 0.30 [95% CI 0.14-0.63], p = 0.002). Similar results were obtained when HDL cholesterol levels were treated as a categorical variable (>=1.03 mmol/L or less). CONCLUSIONS: HDL cholesterol levels might be a novel clinical predictor for the incidence of LEA and wound-related death in patients with DFUs. PMID- 25697578 TI - Electron Spin Relaxation of Hole and Electron Polarons in pi-Conjugated Porphyrin Arrays: Spintronic Implications. AB - Electron spin resonance (ESR) spectroscopic line shape analysis and continuous wave (CW) progressive microwave power saturation experiments are used to probe the relaxation behavior and the relaxation times of charged excitations (hole and electron polarons) in meso-to-meso ethyne-bridged (porphinato)zinc(II) oligomers (PZnn compounds), which can serve as models for the relevant states generated upon spin injection. The observed ESR line shapes for the PZnn hole polaron ([PZnn](+*)) and electron polaron ([PZnn](-*)) states evolve from Gaussian to more Lorentzian as the oligomer length increases from 1.9 to 7.5 nm, with solution-phase [PZnn](+*) and [PZnn](-*) spin-spin (T2) and spin-lattice (T1) relaxation times at 298 K ranging, respectively, from 40 to 230 ns and 0.2 to 2.3 MUs. Notably, these very long relaxation times are preserved in thick films of these species. Because the magnitudes of spin-spin and spin-lattice relaxation times are vital metrics for spin dephasing in quantum computing or for spin polarized transport in magnetoresistive structures, these results, coupled with the established wire-like transport behavior across metal-dithiol-PZnn-metal junctions, present meso-to-meso ethyne-bridged multiporphyrin systems as leading candidates for ambient-temperature organic spintronic applications. PMID- 25697579 TI - Food safety in Thailand 1: it is safe to eat watermelon and durian in Thailand. AB - OBJECTIVES: The wide use of pesticides raises serious concerns regarding food safety and environmental impacts. There is increasing public concern about the potential health risks linked with exposure to pesticides. Regulation of maximum residue limits (MRL) of pesticide residues in food commodities has been established in many developed countries. For developing countries, like Thailand, this regulation often exists in law, but is not completely enforced in practice. Thus, pesticide residue levels in vegetables and fruits have not been thoroughly monitored. The present study aimed to examine potential health risks associated with pesticide exposure by determining the pesticide residues in two commonly consumed fruits, watermelon and durian. METHODS: The fruit samples were purchased from markets in central provinces of Thailand and assayed for the content of 28 pesticides. Analysis of pesticides was performed by multiresidue extraction and followed by GC-MS/MS detection. RESULTS: Of 28 pesticides investigated, 5 were detected in 90.7% of the watermelon samples (n = 75) and 3 in 90% of durian samples (n = 30). Carbofuran, chlorpyrifos, diazinon, dimethoate and metalaxyl were found in watermelons, whereas dichlorvos, dimethoate and metalaxyl were detected in durians. However, their levels were much lower than the recommended MRL values. CONCLUSIONS: These pesticide levels detected in the fruits are unlikely to harm the consumers; therefore it is safe to eat watermelon and durian in Thailand. While our results found negligible risk associated with pesticide exposure from consuming these common tropical fruits, special precautions should be considered to decrease total exposure to these harmful pesticides from various foods. PMID- 25697580 TI - Exposure to the 'Dark Side of Tanning' skin cancer prevention mass media campaign and its association with tanning attitudes in New South Wales, Australia. AB - Melanoma is the most common cancer among 15- to 29-year-olds in Australia, with rates increasing with age. The 'Dark Side of Tanning' (DSOT) mass media campaign was developed in 2007 to influence attitudes related to tanning. This study aimed to assess recall and impact of the DSOT campaign. Data were collected using online surveys of 13- to 44-year-olds living in New South Wales in the summer months of 2007-2010 (n = 7490). Regression models were used to determine predictors of recall of DSOT and to investigate associations between exposure to the campaign and tanning attitudes. The campaign achieved consistently high recall (unprompted recall 42-53% during campaign periods; prompted recall 76 84%). Those who recalled DSOT advertisements had a higher likelihood of reporting negative tanning attitudes compared with those who reported no recall, after adjusting for other factors (odds ratio [OR] 1.13, 95% confidence interval [CI] 1.01-1.27 for unprompted recall; OR 1.19, 95% CI 1.03-1.36 for prompted recall). Being interviewed in later campaign years was also a significant predictor of negative tanning attitudes (e.g. fourth year of campaign versus first year: OR 1.24, 95% CI 1.01-1.53). These results suggest that mass media campaigns have potential to influence tanning-related attitudes and could play an important role in skin cancer prevention. PMID- 25697581 TI - We can do that! Collaborative assessment of school environments to promote healthy adolescent nutrition and physical activity behaviors. AB - Evidence for effectiveness of school-based studies for prevention of adolescent obesity is equivocal. Tailoring interventions to specific settings is considered necessary for effectiveness and sustainability. The PRECEDE framework provides a formative research approach for comprehensive understanding of school environments and identification of key issues/areas to focus resources and energies. No reported studies have tested applicability of the PRECEDE framework in schools in relation to obesity. Adolescents (n = 362), parents (n = 349) and teachers (n = 146) from six secondary schools participated in two quantitative studies and two qualitative studies. Data collected from these studies permitted confirmation of adolescent overweight/obesity a health issue for schools; the need for secondary schools to focus health promotion efforts on healthy nutrition, with inclusion of parents/homes and appreciation for gender differences in developing interventions. Community buy-in and commitment to school-based obesity prevention programs may be dependent on initially addressing what may be perceived as minor issues, and developing policies to guide practices within schools in relation to supply and access to healthy foods, use of sporting equipment and participation in physical activities. The PRECEDE framework allows systematic assessment of school environments and provided opportunity to identify realistic and relevant interventions for promoting healthy adolescent physical activity and nutrition behaviors. PMID- 25697582 TI - Physical activity in the mass media: an audience perspective. AB - Physical activity's role in promoting health is highlighted in public health campaigns, news and current affairs, reality television and other programs. An investigation of audience exposure, beliefs and reactions to media portrayals of physical activity offers insights into the salience and influence of this communication. An audience reception study was conducted involving in-depth interviews with 46 adults in New South Wales, Australia. The sample was stratified by gender, age group, area of residence and body mass index. Most respondents could only recall media coverage of physical activity with prompting. Television was the primary channel of exposure, with reality television the dominant source, followed by news programs and sports coverage. The messages most readily recalled were the health risks of inactivity, especially obesity, and the necessity of keeping active. Physical activity was regarded as a matter of personal volition, or for children, parental responsibility. Respondents believed that the media had given physical activity inadequate attention, focused too heavily on risks and not provided practical advice. In Australia, there is a need to counter the framing of physical activity by reality television, and engage the media to generate understanding of the socioecological determinants of inactivity. Physical activity campaigns should deliver positive and practical messages. PMID- 25697583 TI - Fasudil prevents calcium oxalate crystal deposit and renal fibrogenesis in glyoxylate-induced nephrolithic mice. AB - Nephrolithiasis is a common kidney disease and one of the major causes of chronic renal insufficiency. We develop and utilize a glyoxylate induced mouse model of kidney calcium oxalate crystal deposition for studying the pharmacological effects of fasudil, a Rho associated protein kinase (ROCK) specific inhibitor, on the kidney injury and fibrosis caused by calcium oxalate crystallization and deposition. Glyoxylate was administrated intraperitoneally to C57BL/6J mice for five consecutive days to establish a mouse model of kidney calcium oxalate crystal formation and deposition. The results showed that the protein expression levels of E-cad and Pan-ck were lower, and the protein expression levels of alpha SMA and Vim were higher, in the kidney tissue of the glyoxylate induced model mice compared with the control mice. The changes in protein expression were weakened when the animals were pretreated with fasudil before glyoxylate administration. Expression of ROCK, PAI-1, and p-Smad proteins in the kidney tissue increased in response to glyoxylate treatment, and the increase was eased when the animals were pretreated with fasudil. Expression of Smad2 and Smad3 in the kidney tissue remained unchanged after glyoxylate administration. Cell apoptosis and proliferation in the kidney cortex and medulla were enhanced in response to the glyoxylate induced calcium oxalate crystal formation and deposition, and fasudil pre-treatment was able to attenuate the enhancement. The results suggest that Fasudil reduces the glyoxylate induced kidney calcium crystal formation and deposition and slows down the kidney fibrogenesis caused by calcium crystal deposition. The possible mechanism may be related the regulatory effects on Rho/ROCK signal transduction and epithelial-mesenchymal transition (EMT). PMID- 25697584 TI - Genetics and immunotherapy: using the genetic landscape of gliomas to inform management strategies. AB - Recent work in genetics has identified essential driver mutations in gliomas and has profoundly changed our understanding of tumorigenesis. New insights into the molecular basis of glioma has informed the development of therapies demonstrating considerable potential, including immunotherapeutic approaches such as peptide and dendritic cell vaccines against EGFRvIII. However, the selective targeting of one component of a dysregulated pathway may be inadequate for a durable clinical response, given the intratumoral heterogeneity of glioblastoma (GBM) and hypermutated profiles displayed by tumor recurrences. Immune checkpoint blockade with anti-cytotoxic T lymphocyte antigen-4 (CTLA) and anti-programmed cell death 1 (PD-1) have demonstrated encouraging results in clinical trials with other solid tumors, and recent data suggest that this type of therapy may be particularly useful for tumors with high mutational burdens. Although the survival for patients with GBM has remains grim, the use of immunotherapy may finally change patient outcomes. PMID- 25697585 TI - Associations between depression and all-cause and cause-specific risk of death: a retrospective cohort study in the Veterans Health Administration. AB - OBJECTIVE: Depression may be associated with increased mortality risk, but there are substantial limitations to existing studies assessing this relationship. We sought to overcome limitations of existing studies by conducting a large, national, longitudinal study to assess the impact of depression on all-cause and cause-specific risk of death. METHODS: We used Cox regression models to estimate hazard ratios associated with baseline depression diagnosis (N=849,474) and three year mortality among 5,078,082 patients treated in Veterans Health Administration (VHA) settings in fiscal year (FY) 2006. Cause of death was obtained from the National Death Index (NDI). RESULTS: Baseline depression was associated with 17% greater hazard of all-cause three-year mortality (95% CI hazard ratio [HR]: 1.15, 1.18) after adjusting for baseline patient demographic and clinical characteristics and VHA facility characteristics. Depression was associated with a higher hazard of three-year mortality from heart disease, respiratory illness, cerebrovascular disease, accidents, diabetes, nephritis, influenza, Alzheimer's disease, septicemia, suicide, Parkinson's disease, and hypertension. Depression was associated with a lower hazard of death from malignant neoplasm and liver disease. Depression was not associated with mortality due to assault. CONCLUSIONS: In addition to being associated with suicide and injury-related causes of death, depression is associated with increased risk of death from nearly all major medical causes, independent of multiple major risk factors. Findings highlight the need to better understand and prevent mortality seen with multiple medical disorders associated with depression. PMID- 25697586 TI - The link between ambivalence over emotional expression and depressive symptoms among Chinese breast cancer survivors. AB - OBJECTIVE: Ambivalence over emotional expression (AEE) is the conflict between wanting to express emotion yet fearing the consequences of such expression. Recent literature reveals a close link between AEE and depressive symptoms among college students. Although cancer survivors experience intense emotions, few studies have examined the relationship between AEE and depressive symptoms and the underlying mechanisms among cancer survivors. Furthermore, relevant research is absent among Asians, whose culture discourages emotional expression. The present study investigated AEE's associations with depressive symptoms in Asian breast cancer survivors, and examined intrusive thoughts as a mediator. Intrusive thoughts are repetitive and unwanted thoughts about stressful events. We hypothesized that AEE would increase intrusive thoughts which in turn would increase depressive symptoms. METHODS: A total of 118 Chinese American breast cancer survivors completed a questionnaire packet containing the Ambivalence over Emotional Expression Questionnaire (AEQ), Brief Symptom Inventory (BSI), and the Impact of Event Scale (IES). RESULTS: AEE was positively associated with depressive symptoms (beta=.45, p<.001) and intrusive thoughts (beta=.41, p<.001). Additionally, intrusive thoughts partially explained the relationship between AEE and depressive symptoms (z=3.77, p<.001). CONCLUSIONS: These results suggest that Chinese breast cancer survivors who are highly ambivalent over emotional expression may have increased risk for depressive symptoms, and such relationships can be partially explained by a cognitive mechanism: intrusive thoughts. Future research may explore other mediators and design interventions specifically targeted at reducing AEE and intrusive thoughts with the ultimate goal of reducing depression. PMID- 25697587 TI - [Management of hyperhidrosis]. AB - Hyperhidrosis continues to be undertreated in our view, despite its propensity to considerably impair quality of life. We shall break down therapeutic approaches to hyperhidrosis into several steps: (a) determine the physiological causes of excess sweating; (b) establish the type of hyperhidrosis involved and screen for causes of secondary hyperhidrosis before diagnosing essential hyperhidrosis; (c) evaluate the severity of the hyperhidrosis by means of a validated scale (HDSS score), Minor's starch-iodine test or gravimetric analysis; (d) select one of the medical therapies currently available, i.e. topical therapy (antiperspirants, iontophoresis or botulinum toxin injection), systemic therapy (oxybutynin) or surgery (thoracic sympathectomy). PMID- 25697588 TI - Cross-hemispheric Alternating Current Stimulation During a Nap Disrupts Slow Wave Activity and Associated Memory Consolidation. AB - BACKGROUND: Slow Wave Activity (SWA), the low frequency (<4 Hz) oscillations that characterize Slow Wave Sleep (SWS) are thought to relate causally to declarative memory consolidation during nocturnal sleep. Evidence is conflicting relating SWA to memory consolidation during nap however. OBJECTIVE/HYPOTHESIS: We applied transcranial alternating current stimulation (tACS) - which, with a cross hemispheric electrode montage (F3 and F4 - International 10:20 EEG system), is able to disrupt brain oscillations-to determine if disruption of low frequency oscillation generation during afternoon nap is causally related to disruption in declarative memory consolidation. METHODS: Eight human subjects each participated in stimulation and sham nap sessions. A verbal paired associate learning (PAL) task measured memory changes. During each nap period, five 5-min stimulation (0.75 Hz cross-hemispheric frontal tACS) or sham intervals were applied with 1 min post-stimulation intervals (PSI's). Spectral EEG power for Slow (0.7-0.8 Hz), Delta (1.0-4.0 Hz), Theta (4.0-8.0 Hz), Alpha (8.0-12.0 Hz), and Spindle-range (12.0-14.0) frequencies was analyzed during the 1-min preceding the onset of stimulation and the 1-min PSI's. RESULTS: As hypothesized, power reduction due to stimulation positively correlated with reduction in word-pair recall post-nap specifically for Slow (P < 0.0022) and Delta (P < 0.037) frequency bands. CONCLUSIONS: These results provide preliminary evidence suggesting a causal and specific role of SWA in declarative memory consolidation during nap. PMID- 25697589 TI - Intrasession Reliability of Single and Paired Pulse TMS Evoked From the Biceps Brachii Representation of the Human Motor Cortex. PMID- 25697590 TI - Transcranial Direct Current Stimulation in Epilepsy. AB - BACKGROUND: Transcranial direct current stimulation (tDCS) is an emerging non invasive neuromodulation therapy in epilepsy with conflicting results in terms of efficacy and safety. OBJECTIVE: Review the literature about the efficacy and safety of tDCS in epilepsy in humans and animals. METHODS: We searched studies in PubMed, MedLine, Scopus, Web of Science and Google Scholar (January 1969 to October 2013) using the keywords 'transcranial direct current stimulation' or 'tDCS' or 'brain polarization' or 'galvanic stimulation' and 'epilepsy' in animals and humans. Original articles that reported tDCS safety and efficacy in epileptic animals or humans were included. Four review authors independently selected the studies, extracted data and assessed the methodological quality of the studies using the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions, PRISMA guidelines and Jadad Scale. A meta-analysis was not possible due to methodological, clinical and statistical heterogeneity of included studies. RESULTS: We analyzed 9 articles with different methodologies (3 animals/6 humans) with a total of 174 stimulated individuals; 109 animals and 65 humans. In vivo and in vitro animal studies showed that direct current stimulation can successfully induce suppression of epileptiform activity without neurological injury and 4/6 (67%) clinical studies showed an effective decrease in epileptic seizures and 5/6 (83%) reduction of inter-ictal epileptiform activity. All patients tolerated tDCS well. CONCLUSIONS: tDCS trials have demonstrated preliminary safety and efficacy in animals and patients with epilepsy. Further larger studies are needed to define the best stimulation protocols and long-term follow-up. PMID- 25697591 TI - Reversal of Practice-related Effects on Corticospinal Excitability has no Immediate Effect on Behavioral Outcome. AB - BACKGROUND: Motor training usually increases the excitability of corticospinal outputs to the trained muscles. However, it is uncertain to what extent the change in excitability is a critical component of behavioral learning or whether it is a non-specific side effect. OBJECTIVE/HYPOTHESIS: We used a depotentiation protocol to abolish the training-induced increase of corticospinal excitability and tested whether this had any immediate effect on the improved motor performance. METHODS: We used an index finger abduction task in which behavioral improvement is known to be associated with M1 excitability changes as monitored by the amplitude of motor-evoked potentials produced by single-pulse transcranial magnetic stimulation (TMS). These effects could be reversed by a depotentiation protocol using a short form of continuous theta-burst stimulation (cTBS150). Participants underwent three experimental interventions: 'motor training', 'motor training plus cTBS150' and 'cTBS150'. M1 excitability and TMS-evoked finger movements were assessed before the experimental interventions and 5 min, 15 min, and 30 min thereafter. Motor retention was tested 45 min after the experimental interventions. RESULTS: During training, acceleration of the practiced movement improved. At the end of training, M1 excitability and the acceleration of TMS evoked index finger movements in the direction of training had increased and the enhanced performance was retained when tested 45 min later. The depotentiation protocol, delivered immediately after the end of training, reversed the excitability changes in M1 but did not affect the acceleration of the TMS-evoked finger movement nor the retention of performance. The depotentiation protocol alone did not modify M1 excitability. CONCLUSIONS: The present study indicates that in the short term, increases in corticospinal excitability are not related to immediate changes in behavioral motor outcome. PMID- 25697592 TI - Therapeutic drug monitoring in the treatment of invasive aspergillosis with voriconazole in cancer patients--an evidence-based approach. AB - Invasive aspergillosis (IA) is a life-threatening complication in hematological cancer patients. Voriconazole (VCZ) is the established first-line treatment of IA. VCZ has a nonlinear pharmacokinetic profile and exhibits considerable variability of drug exposure. Therefore, therapeutic drug monitoring (TDM) of VCZ may help to improve treatment results in IA patients, but evidence-based data on the clinical use of TDM in patients treated with VCZ for IA are scarce. Evidence based guidance is needed to support decisions on the use of TDM in routine VCZ therapy of IA. Our present analysis assessed published studies for evidence-based criteria for TDM of VCZ to improve efficacy and safety of IA therapy in cancer patients. Literature searches of MEDLINE and Cochrane database were performed. We identified 27 clinical studies reporting on the use of plasma level monitoring and/or TDM for VCZ. For each study, strength of recommendation and quality of evidence were categorized according to predefined criteria. A number of studies were published on plasma level monitoring (PLM) and TDM in VCZ therapy of IA. Across studies, VCZ levels >5-5.5 mg/L were found to be associated with toxicity, while reaching minimum levels of >1-2 mg/L appeared to improve efficacy. Timing, frequency, and intervention thresholds and dosage increments of VCZ for adjustment of plasma levels remain to be established. Currently, there is still no conclusive evidence for recommendations in routine clinical practice. More data from prospective randomized studies with TDM are desirable to provide a solid evidence basis for these approaches. PMID- 25697593 TI - Antithrombin III is probably not a suitable biomarker for diagnosis of primary central nervous system lymphoma. AB - Antithrombin III (AT III) in cerebrospinal fluid (CSF) has been suggested to have high specificity and sensitivity in separating primary central nervous system (CNS) lymphoma from other neurological conditions. We measured with ELISA CSF and serum AT III and albumin levels in 12 lymphoma patients with CNS involvement, 30 lymphoma patients without CNS involvement, and 41 patients with non-neoplastic neurological diseases. AT III immunostaining was also carried out, in lymphoma patients. Both CSF AT III and albumin levels were higher in lymphoma patients with CNS involvement. AT III/albumin ratio in CSF was the most sensitive and specific measure for diagnosis. Lowest it was in patients with known CNS lymphoma. Serum AT III levels were lower both in CNS lymphoma and systemic lymphoma. CSF AT III levels were shown to be higher in lymphoma patients with CNS involvement, when AT III/albumin ratios were lower. This was probably a result of lowered serum AT III levels, indicating that high levels of AT III in CSF might reflect only leakage of the blood-brain barrier. Thus, AT III fails to be a specific marker for diagnosis of lymphoma CNS involvement. PMID- 25697594 TI - Microemboli alter the acute stress response and cause prolonged expression of MCP 1 in the hippocampus. AB - Microvascular ischemia is linked to cardiovascular disease pathology, as well as alterations in mood and cognition. Ischemia activates the hypothalamic-pituitary adrenal (HPA) axis and through chronic activation, alters HPA axis function. Dysregulation of the HPA axis can lead to the chronic release of glucocorticoids, a hyper-inflammatory cerebral response, cell damage, and changes in behavior. Although the interactions between injury and HPA axis activity have been established in global ischemia, HPA-related repercussions of diffuse ischemic damage and subsequent inflammation have not been assessed. The current study used a rat model of microsphere embolism (ME) ischemia to test the hypothesis that microvascular ischemia would lead to long term alterations in HPA axis function and inflammatory activity. Furthermore, given the pro-inflammatory nature of chronic stress, we assessed the implications of chronic stress for gene expression of inflammatory factors and key components of the glucocorticoid receptor response, following microvascular ischemia. Results indicated that ME altered the response to an acute stress fourteen days following ME injury and increased hippocampal expression of monocyte chemoattractant protein 1 (Mcp-1) as long as 4 weeks following ME injury, without concomitant effects on gene expression of the glucocorticoid receptor or its co-chaperones. Furthermore, no exacerbative effects of chronic stress exposure were observed following ME injury beyond the effects of ME injury alone. Together, these results indicate that ME injury is sufficient to alter both HPA axis activity and cerebral inflammation for a prolonged period of time following injury. PMID- 25697595 TI - Hypomagnesemia and atherogenic dyslipidemia in chronic kidney disease: surrogate markers for increased cardiovascular risk. AB - BACKGROUND: Recent reports suggest that 40-70 % chronic kidney disease (CKD) patients receiving dialysis have significant coronary artery disease. Magnesium depletion is being considered as the missing link between the cardiovascular risk factors and atherosclerosis in CKD. The present work aimed to study the association between magnesium status and lipid alterations in pre-dialysis CKD patients attending the Nephrology Clinic in a tertiary care hospital in South India. METHODS: 90 cases of CKD and 90 age and gender matched healthy controls were included in the study. Framingham risk scoring was done and presence of metabolic syndrome was assessed. Lipid profile, serum and urine magnesium, blood glucose, calcium, phosphorus, urea and creatinine levels were assayed in all study subjects. RESULTS: In this study we observed a significantly lower serum magnesium levels and dyslipidemic alterations, a significantly raised total cholesterol and low-density lipoprotein and non-HDL in patients with CKD. We also observed a significant correlation between the lowered serum magnesium concentrations and atherogenic dyslipidemia, suggesting a link to increased cardiovascular risk in CKD patients. CKD patients had higher risk of cardiovascular disease (according to their Framingham risk score), which also showed significant correlation with the hypomagnesaemia. CONCLUSIONS: Our results suggest a strong association of hypomagnesemia and atherogenic dyslipidemia in patients with CKD. This gains particular importance in the high cardiovascular risk-borne CKD patients, as supplementing magnesium would go a long way in reducing the risk of cardiovascular morbidity and mortality in CKD. PMID- 25697596 TI - Utility of (18)F FDG-PET/CT for predicting prognosis of luminal-type breast cancer. AB - Postoperative prognosis is better for hormonal receptor-positive breast cancer than for other phenotypes; however, there are no definitive predictive factors for relapse or survival. This study aimed to evaluate the maximum standardized uptake value (SUVmax) on (18)F-fluoro-2-deoxy-glucose positron emission tomography/computed tomography (FDG-PET/CT) and clinicopathological characteristics as possible predictors of postoperative relapse-free survival (RFS) and overall survival (OS) in hormonal receptor-positive breast cancer patients. We evaluated 262 patients with Stage I-III breast cancer diagnosed as luminal type (luminal A, 166; luminal B, 96 patients) who underwent preoperative FDG-PET/CT between January 2006 and December 2011 at two institutions. The relationships among SUVmax and clinicopathological factors (age, clinical T/N stage, nuclear grade, lymph node metastasis and vascular invasion) were evaluated. A phantom study was performed to correct differences in PET/CT analysis between two institutions. The patients were divided according to the SUVmax cutoff on receiver operating characteristic (ROC) analysis for OS (<=6.0 group vs. >6.0 group, AUC = 0.742). Clinical T-factor and nuclear grade were significantly correlated with SUVmax (p < 0.0001 and p = 0.0092, respectively). In the uni- and multivariate analyses using the Cox model for relapse, SUVmax was significant (p = 0.013 and p = 0.055, respectively) among characteristics. RFS curves showed that prognosis was significantly better for the SUVmax <= 6.0 group than for the SUVmax > 6.0 group (p = 0.004). Similarly, SUVmax was significant for OS (p = 0.007 and p = 0.008). OS was significantly different between the SUVmax <= 6.0 and >6.0 groups (p < 0.001). SUVmax was useful for predicting outcomes in patients with luminal-type breast cancer. PMID- 25697597 TI - The Fabry disease-associated lipid Lyso-Gb3 enhances voltage-gated calcium currents in sensory neurons and causes pain. AB - Fabry disease is an X-linked lysosomal storage disorder characterised by accumulation of glycosphingolipids, and accompanied by clinical manifestations, such as cardiac disorders, renal failure, pain and peripheral neuropathy. Globotriaosylsphingosine (lyso-Gb3), a deacylated form of globotriaosylceramide (Gb3), has emerged as a marker of Fabry disease. We investigated the link between Gb3, lyso-Gb3 and pain. Plantar administration of lyso-Gb3 or Gb3 caused mechanical allodynia in healthy mice. In vitro application of 100nM lyso-Gb3 caused uptake of extracellular calcium in 10% of sensory neurons expressing nociceptor markers, rising to 40% of neurons at 1MUM, a concentration that may occur in Fabry disease patients. Peak current densities of voltage-dependent Ca(2+) channels were substantially enhanced by application of 1MUM lyso-Gb3. These studies suggest a direct role for lyso-Gb3 in the sensitisation of peripheral nociceptive neurons that may provide an opportunity for therapeutic intervention in the treatment of Fabry disease-associated pain. PMID- 25697598 TI - Cognitive decline is associated with reduced surface GluR1 expression in the hippocampus of aged rats. AB - Individual differences in cognitive aging exist in humans and in rodent populations, yet the underlying mechanisms remain largely unclear. Activity dependent delivery of GluR1-containing AMPA receptor (AMPARs) plays an essential role in hippocampal synaptic plasticity, learning and memory. We hypothesize that alterations of surface GluR1 expression in the hippocampus might correlate with age-related cognitive decline. To test this hypothesis, the present study evaluated the cognitive function of young adult and aged rats using Morris water maze. After the behavioral test, the surface expression of GluR1 protein in hippocampal CA1 region of rats was determined using Western blotting. The results showed that the surface expression of GluR1 in the hippocampus of aged rats that are cognitively impaired was much lower than that of young adults and aged rats with preserved cognitive abilities. The phosphorylation levels of GluR1 at Ser845 and Ser831 sites, which promote the synaptic delivery of GluR1, were also selectively decreased in the hippocampus of aged-impaired rats. Correlation analysis reveals that greater decrease in surface GluR1 expression was associated with worse behavioral performance. These results suggest that reduced surface GluR1 expression may contribute to cognitive decline that occurs in normal aging, and different pattern of surface GluR1 expression might be responsible for the individual differences in cognitive aging. PMID- 25697599 TI - Cytokines as therapeutic targets in rheumatoid arthritis and other inflammatory diseases. AB - The human immune system involves highly complex and coordinated processes in which small proteins named cytokines play a key role. Cytokines have been implicated in the pathogenesis of a number of inflammatory and autoimmune diseases. Cytokines are therefore attractive therapeutic targets in these conditions. Anticytokine therapy for inflammatory diseases became a clinical reality with the introduction of tumor necrosis factor (TNF) inhibitors for the treatment of severe rheumatoid arthritis. Although these therapies have transformed the treatment of patients with severe inflammatory arthritis, there remain significant limiting factors: treatment failure is commonly seen in the clinic; safety concerns remain; there is uncertainty regarding the relevance of immunogenicity; the absence of biomarkers to direct therapy decisions and high drug costs limit availability in some healthcare systems. In this article, we provide an overview of the key efficacy and safety trials for currently approved treatments in rheumatoid arthritis and review the major lessons learned from a decade of use in clinical practice, focusing mainly on anti-TNF and anti interleukin (IL)-6 agents. We also describe the clinical application of anticytokine therapies for other inflammatory diseases, particularly within the spondyloarthritis spectrum, and highlight differential responses across diseases. Finally, we report on the current state of trials for newer therapeutic targets, focusing mainly on the IL-17 and IL-23 pathways. PMID- 25697600 TI - Glycaemic load versus carbohydrate counting for insulin bolus calculation in patients with type 1 diabetes on insulin pump. AB - AIMS: To evaluate feasibility and effectiveness on short-term blood glucose control of using glycaemic load counting (GLC) versus carbohydrate counting (CC) for prandial insulin dosing in patients with type 1 diabetes (T1D). METHODS: Nine T1D patients on insulin pump, aged 26-58 years, HbA1c 7.7 +/- 0.8 % (61 +/- 8.7 mmol/mol), participated in this real-life setting study. By a crossover design, patients were randomised to calculate their pre-meal insulin dose based on the insulin/glycaemic load ratio (GLC period) or the insulin/carbohydrate ratio (CC period) for 1 week, shifting to the alternate method for the next week, when participants duplicated their first week food plan. Over either week, a blind subcutaneous continuous glucose monitoring was performed, and a 7-day food record was filled in. RESULTS: Total daily insulin doses (45 +/- 10 vs. 44 +/- 9 I.U.; M +/- SD, p = 0.386) and basal infusion (26 +/- 7 vs. 26 +/- 8 I.U., p = 0.516) were not different during GLC and CC periods, respectively. However, the range of insulin doses (difference between highest and lowest insulin dose) was wider during GLC, with statistical significance at dinner (8.4 +/- 6.2 vs. 6.0 +/- 3.9 I.U., p = 0.041). Blood glucose iAUC after lunch was lower, albeit not significantly, during GLC than CC period (0.6 +/- 8.6 vs. 3.4 +/- 8.2 mmol/l?3 h, p = 0.059). Postprandial glucose variability, evaluated as the maximal amplitude after meal (highest minus lowest glucose value), was significantly lower during GLC than CC period at lunch (4.22 +/- 0.28 vs. 5.47 +/- 0.39 mmol/l, p = 0.002) and dinner (3.89 +/- 0.33 vs. 4.89 +/- 0.33, p = 0.026). CONCLUSIONS: Calculating prandial insulin bolus based on glycaemic load counting is feasible in a real life setting and may improve postprandial glucose control in people with T1D. PMID- 25697601 TI - Dysphagia and hematemesis: A rare presentation of a vascular complication. PMID- 25697602 TI - Students' performance in the different clinical skills assessed in OSCE: what does it reveal? AB - INTRODUCTION: The purpose of this study was to compare students' performance in the different clinical skills (CSs) assessed in the objective structured clinical examination. METHODS: Data for this study were obtained from final year medical students' exit examination (n=185). Retrospective analysis of data was conducted using SPSS. Means for the six CSs assessed across the 16 stations were computed and compared. RESULTS: Means for history taking, physical examination, communication skills, clinical reasoning skills (CRSs), procedural skills (PSs), and professionalism were 6.25+/-1.29, 6.39+/-1.36, 6.34+/-0.98, 5.86+/-0.99, 6.59+/-1.08, and 6.28+/-1.02, respectively. Repeated measures ANOVA showed there was a significant difference in the means of the six CSs assessed [F(2.980, 548.332)=20.253, p<0.001]. Pairwise multiple comparisons revealed significant differences between the means of the eight pairs of CSs assessed, at p<0.05. CONCLUSIONS: CRSs appeared to be the weakest while PSs were the strongest, among the six CSs assessed. Students' unsatisfactory performance in CRS needs to be addressed as CRS is one of the core competencies in medical education and a critical skill to be acquired by medical students before entering the workplace. Despite its challenges, students must learn the skills of clinical reasoning, while clinical teachers should facilitate the clinical reasoning process and guide students' clinical reasoning development. PMID- 25697603 TI - Depression in Gulf War veterans: a systematic review and meta-analysis. AB - BACKGROUND: Although post-traumatic stress disorder (PTSD) has been a focus of attention in 1990/1991 Gulf War veterans, the excess risk of depression has not been clearly identified. We investigated this through a systematic review and meta-analysis of studies comparing depression in Gulf War veterans to depression in a comparison group of non-deployed military personnel. METHOD: Multiple electronic databases and grey literature were searched from 1990 to 2012. Studies were assessed for eligibility and risk of bias according to established criteria. RESULTS: Of 14 098 titles and abstracts assessed, 14 studies met the inclusion criteria. Gulf War veterans had over twice the odds of experiencing depression [odds ratio (OR) 2.28, 95% confidence interval (CI) 1.88-2.76] and dysthymia or chronic dysphoria (OR 2.39, 95% CI 2.0-2.86) compared to non-deployed military personnel. This finding was robust in sensitivity analyses, and to differences in overall risk of bias and psychological measures used. CONCLUSIONS: Despite divergent methodologies between studies, depression and dysthymia were twice as common in Gulf War veterans and are important medical conditions for clinicians and policymakers to be aware of in managing Gulf War veterans' health. PMID- 25697604 TI - Effects of Tannic Acid on the Ischemic Brain Tissue of Rats. AB - Many studies of brain ischemia have shown the role played by massive ischemia induced production of reactive oxygen species, the main mechanism of neuronal death. However, currently, there is no treatment choice to prevent cell death triggered by reactive oxygen species. In our study, we researched the effects of tannic acid, an antioxidant, on the ischemic tissue of rats with induced middle cerebral artery occlusion. The animals were divided into three groups of eight animals. The sham group were only administered 10 % ethanol intraperitoneally, the second group had middle cerebral artery occlusion induced and were given 10 % ethanol intraperitoneally, while the third group had middle cerebral artery occlusion with 10 mg/kg dose tannic acid dissolved in 10 % ethanol administered within half an hour intraperitoneally. The rats were sacrificed 24 h later, and brain tissue was examined biochemically and histopathologically. Biochemical evaluation of brain tissue found that comparing the ischemic group with no treatment with the tannic acid-treated ischemia group; the superoxide dismutase (SOD) levels were higher, malondialdehyde (MDA) levels were lower, and nuclear respiratory factor-1 (NRF-1) was higher in the tannic acid-treated group. Histopathological examination showed that the histopathological results of the tannic acid group were better than the group not given tannic acid. Biochemical and histopathological results showed that tannic acid administration had an antioxidant effect on the negative effects of ischemia in brain tissue. PMID- 25697605 TI - Antimicrobial activity of natural products from the flora of Northern Ontario, Canada. AB - CONTEXT: The number of multidrug resistant (MDR) microorganisms is increasing and the antimicrobial resistance expressed by these pathogens is generating a rising global health crisis. In fact, there are only a few antimicrobial agents left that can be used against MDR bacteria and fungi. OBJECTIVE: In this study, the antimicrobial activities of selected natural products from the flora of Northern Ontario against selected microorganisms are reported. MATERIALS AND METHODS: Plants were collected from Sault Ste. Marie, Ontario, Canada, and ethanol extracts were prepared using EtOH:H2O (1:1, v/v). Fungal cultures used in this study were Candida albicans ATCC 10231 and Schizosaccharomyces octosporus. Bacterial cultures employed included Staphylococcus aureus ATCC 29213, Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853, Mycobacterium phlei ATCC 11758, and Streptococcus lactis ATCC 19435. The microplate resazurin assay was used to screen for antimicrobial activity. RESULTS: Extracts of four plant species Chimaphila umbellata L. (Pyrolaceae), Betula papyrifera Marshall (Betulaceae), Rhus typhina L. (Anacardiaceae), and Fraxinus pennsylvanica Marshall (Oleaceae), and six compounds (gallic acid, ethyl gallate, caffeic acid, sinapic acid, gentisic acid, and chlorogenic acid) demonstrated antibacterial or antifungal activities with MICs ranging from 62.5 to 1000 ug/mL, respectively, for a chemical fraction of an extract from Betula papyrifera against the bacterium S. aureus. DISCUSSION AND CONCLUSION: The present study has shown that certain plant extracts and select fractions and standard chemical compounds exhibit antimicrobial effects. Prince's Pine, Chimaphila umbellate, White Birch, Betula papyrifera, Staghorn Sumac, Rhus typhina, and Green Ash, Fraxinus pennsylvanica were the principal extracts exhibiting notable antibacterial and/or antifungal activities; while gallic acid, ethyl gallate, and caffeic acid demonstrated antibacterial activities and sinapic acid, gentisic acid, and chlorogenic acid demonstrated antifungal activities. PMID- 25697606 TI - An identified antioxidant peptide obtained from ostrich (Struthio camelus) egg white protein hydrolysate shows wound healing properties. AB - CONTEXT: Ostrich (Struthio camelus) egg possesses a high amount of food proteins and thus plays an important role in nutrition. OBJECTIVE: Ostrich egg white proteins were hydrolyzed with pepsin and pancreatin to examine its antioxidant properties and further characterized the most active peptide. MATERIALS AND METHODS: Ostrich egg white protein hydrolysate (OEWPH) was fractionized using reversed phase high-pressure liquid chromatography (HPLC). The antioxidant activity of OEWPH and its HPLC fraction were investigated based on their scavenging capacity1,1-diphenyl-2-picrylhydrazyl (DPPH) radical, 2,2'-azinobis (3 ethylbenzothiazoline-6-sulphonic acid) diammonium salt (ABTS), superoxide ([Formula: see text]), hydroxyl (OH(*-)) radicals, and Cu(+2) chelating. In a wound healing assay, paravertebral excision (1 cm diameter) was made on the skin and the percentage of wound closure was measured at defined intervals (0, 3, 7, and 14 d). RESULTS: A potent antioxidant peptide named DG-10 with the sequence DAESLSRLLG (MW: 1060.18 +/- 0.5 Da) was identified from OEWPH. The peptide DG-10 showed DPPH (IC50 = 0.0085 mg/ml), ABTS(*+) (IC50 = 0.56 mg/ml), superoxide (IC50 = 0.36 mg/ml), and hydroxyl (IC50 = 0.4 mg/ml) radical scavenger and copper chelating activity (IC50 = 0.28 mg/ml). In vitro cultured HFLF-pI 5, the cell model, also revealed that DG-10 could protect HFLF-pI 5 cells against H2O2 treated necrosis. Ointment composed of DG-10 peptide exhibited wound-healing properties on adult rats (Wistar strain). The percentage of wound closure in peptide-treated group was 98% by day 14. DISCUSSION AND CONCLUSION: Our results suggested that DG-10 is a natural agent obtained from ostrich egg possessing considerable antioxidant and wound-healing properties. PMID- 25697607 TI - Green biosynthesis of silver nanoparticles using Quercus brantii (oak) leaves hydroalcoholic extract. AB - CONTEXT: There is an ever-growing need to develop green, non-toxic, and eco friendly procedures for synthesis and assembly of nanoparticles (NPs) with the desired morphologies and sizes. The hydroalcoholic extract of Persian oak leaves [Quercus brantii Lindl. (Fagaceae)] contains high content of phenolic and flavonoid compounds with strong antioxidant activities, and it seems that this plant can be considered a good candidate for metal nanoparticle synthesis. OBJECTIVE: The potential of Q. brantii leaves in the production of silver NPs and the effect of the extract ethanol concentration on the produced NPs were studied. MATERIALS AND METHODS: Quercus brantii leaves were freshly collected, air-dried at room temperature, powdered, and sieved. Hydroalcoholic extracts (70% and 96%) were prepared by percolation of the plant powder. The reaction mixtures contained (final concentrations): AgNO3 (1 mM) as the substrate, plant extract as the biocatalyst, and phosphate buffer (pH = 7, 100 mM) as the reaction medium. Silver ions were determined using atomic absorption analysis. Particle size distribution of NPs was analyzed using Nano-Zeta Sizer (Malvern Instruments Ltd, Malvern, UK). Samples for TEM were prepared by drop-coating the silver nanoparticle suspensions onto carbon-coated copper grids. RESULTS: Hydroalcoholic extract (96%) of Q. brantii successfully produced quite small (as small as 0.83 nm and the mean size of 6 nm), spherical, and poly-dispersed NPs with low aggregates. The conversion was fast and completed in 5 h. DISCUSSION AND CONCLUSION: This plant and the extraction method seem to be quiet attractive for industrial scale production of NPs. PMID- 25697608 TI - The relationship between platelet indices and postmenopausal osteoporosis. PMID- 25697610 TI - [Legalization of marijuana, the freedom that threatens public health]. PMID- 25697609 TI - Dietary patterns in India and their association with obesity and central obesity. AB - OBJECTIVE: Obesity is a growing problem in India, the dietary determinants of which have been studied using an 'individual food/nutrient' approach. Examining dietary patterns may provide more coherent findings, but few studies in developing countries have adopted this approach. The present study aimed to identify dietary patterns in an Indian population and assess their relationship with anthropometric risk factors. DESIGN: FFQ data from the cross-sectional sib pair Indian Migration Study (IMS; n 7067) were used to identify dietary patterns using principal component analysis. Mixed-effects logistic regression was used to examine associations with obesity and central obesity. SETTING: The IMS was conducted at four factory locations across India: Lucknow, Nagpur, Hyderabad and Bangalore. SUBJECTS: The participants were rural-to-urban migrant and urban non migrant factory workers, their rural and urban resident siblings, and their co resident spouses. RESULTS: Three dietary patterns were identified: 'cereals savoury foods' (cooked grains, rice/rice-based dishes, snacks, condiments, soups, nuts), 'fruit-veg-sweets-snacks' (Western cereals, vegetables, fruit, fruit juices, cooked milk products, snacks, sugars, sweets) and 'animal-food' (red meat, poultry, fish/seafood, eggs). In adjusted analysis, positive graded associations were found between the 'animal-food' pattern and both anthropometric risk factors. Moderate intake of the 'cereals-savoury foods' pattern was associated with reduced odds of obesity and central obesity. CONCLUSIONS: Distinct dietary patterns were identified in a large Indian sample, which were different from those identified in previous literature. A clear 'plant food based/animal food-based pattern' dichotomy emerged, with the latter being associated with higher odds of anthropometric risk factors. Longitudinal studies are needed to further clarify this relationship in India. PMID- 25697611 TI - [Catching up on celiac disease]. AB - Knowledge about celiac disease continues to grow and amaze those who investigate, seek and treat this condition. Gone are the days when it was considered just a rare child's digestive disease. It is now recognized as a highly prevalent autoimmune condition that affects children and adults with digestive and extra digestive symptoms of diverse intensity, disorder that may be either mono, oligo or asymptomatic from a digestive point of view. Today, it is an underdiagnosed condition, not actively considered, and often mistakes are made regarding its diagnosis, treatment and gluten-free diet monitoring. This article reviews the current definition of the disease, clinical presentations, potential patients, how to search for the disease, how the diagnosis is made and characteristics of the treatment and monitoring of celiac patients, all based on internationally agreed standards, and emphasizing those aspects that have proven to be useful in other countries regarding the management of the disease. PMID- 25697612 TI - [Clinical features of Eosinophilic Colitis in infants with persistent rectal bleeding]. AB - The most common presentation of cow's milk protein allergy (CMP) in infants is known as eosinophilic colitis (EC). The aim of this study is to evaluate EC characteristics in infants evaluated with colonoscopy due to the presence of rectorrhagia. PATIENTS AND METHODS: A retrospective case-control study. Left sided colonoscopy records of infants with persistent rectal bleeding, conducted between January 2006 and March 2011, were reviewed. The cases corresponded to infants with rectal biopsy compatible with EC and controls with negative biopsy. Telephone questionnaires to parents were conducted, evaluating personal and family history. RESULTS: Complete records were obtained in 61 (79%) of the 77 procedures. 33 (54%) of them were males. Examination average age was 6.3 +/- 5.9 months. 25 (41%) patients had EC on their histology. Between cases and controls, no significant difference in gestational age, birth weight and gender, only regarding age at the time of rectal bleeding, were observed. There was also no difference in personal history regarding obstructive bronchitis, allergic rhinitis, family history of asthma, allergic rhinitis or other food allergies. Those who received artificial feeding did not presented greater risk of EC. The most common symptoms in the cases did not differ significantly from the controls. CONCLUSIONS: The prevalence of EC in the children studied was 40.9%. Our results show that there are groups of patients with persistent rectal bleeding in which there is no personal or family history that helps diagnosing EC. An endoscopic study could be considered in these patients to establish a correct diagnosis of this condition, avoid unnecessary diets and not to delay the detection of other diseases. PMID- 25697613 TI - [Incidence and prevalence of burn injuries in children under the age of 20 years]. AB - OBJECTIVE: To estimate the incidence of burn injuries in 2011 and prevalence in population < 20 years old in three districts of Chile's Metropolitan Region. PATIENTS AND METHOD: A Prevalence census study of 4,968 households in the mentioned areas. Probability, representative, and two-stage cluster sampling, with sampling error < 5%, was applied. Complex sample modules were used to analyze data using SPSS 17.0. The census was conducted in the site, asking in each selected household those 18 and older, about household composition by gender and age to identify those < 20 years with burns that occurred sometime in their life or in 2011. RESULTS: A burn incidence of 2.02% [95% CI: 1.63-2.61%] and a prevalence of 13.50% [95% CI: 11.8815.31%] were obtained. The highest incidence was reported in female patients (2.31%) [95% CI: 1.77- 2.99%]. In males < 5 years of age, the incidence was 2.76% [95% CI: 1.42-5.28%] and in females, it was 2.46% [95% CI: 1.37-4.36%]. The municipality of Lo Prado had the highest incidence (2.73%) [95% CI: 1.82-4.07%]; Pudahuel recorded the highest prevalence (14.01%) [95% CI: 11.87-16.46%]. CONCLUSION: In 20 years, the incidence of burns in patients < 15 years of age fell by 46.4%. On average in the communities studied, 1 in 7 children/adolescent has suffered burns between birth and the time of his 20th birthday. PMID- 25697614 TI - [Gastrointestinal foreign body in children]. AB - Gastrointestinal foreign bodies (FB) are frequent complaints in the emergency departments, with esophageal foreign bodies as the most frequent cases. Symptoms are varied and depend on the location of the FB, with several techniques available for removal. OBJECTIVE: To describe the FB removed by endoscopy in children as well as the consulting population characteristics. PATIENTS AND METHOD: Patient chart reviews of those who, during the last six years, underwent gastrointestinal endoscopy were performed. Descriptive statistics were used to analyze the data. RESULTS: 51 patients, 28 males and 23 females, with average age of four years old, underwent endoscopy due to FB intake. The most common symptoms were drooling (45%) and dysphagia (35%); the FBs were extracted mostly under general anesthesia. Coins were the most common foreign bodies found (57%) and they were mainly located in the esophagus (91%). All bodies were extracted by direct endoscopy or endoscopically assisted extraction; lesions that corresponded to erosions were found in 19 (37%) patients and ulcers in 4 (8%). There were no complications. CONCLUSIONS: Endoscopic removal of gastrointestinal FBs is a safe procedure. Given the risk of serious injury, especially in foreign bodies in the esophagus, performing endoscopy within a reasonable time must always be considered. Management protocols are necessary to unify the standards of those working in emergency rooms, having in mind that the most important strategy is prevention. PMID- 25697615 TI - [Epidemiology of burns in children and adolescents from Chile's Metropolitan Region]. AB - OBJECTIVE: To determine demographic, clinical and health care factors associated to prevalence of burns in children less than 20 years of age in the districts of Cerro Navia, Lo Prado and Pudahuel, and their comparison with incidence in 2011. PATIENTS AND METHOD: Population survey based on probability and two-stage stratified complex sample of households, registering 4,968 households. In 302 of them randomly selected, the mother/adult present at the time of the injury took a survey. A questionnaire of 50 questions (20 minutes), created by 6 experts and previously validated, was conducted by 10 interviewers and 3 supervisors. People were contacted by telephone before visiting them at their homes. The non-response rate was 6%, after up to 3 home visits. RESULTS: Regarding prevalence, the male to-female ratio was 1.16:1. Main reasons were hot objects (42.4%) and liquids (41.5%). 84.1% of burns occurred inside the home and in the afternoon (50.7%). 93.3% of the burns took place with an adult present. Hands were the most affected areas (46.7%). 30.2% were left with scars the first time of the accident. 34.4% of the burn victims did not require health care and 8.4% of them required hospitalizations. Over 60% of respondents reported that they poured cold water on the burn as a first step. CONCLUSION: Relevant information was obtained to be used in burn prevention in children and adolescents. Recall bias is the main limitation of the study. PMID- 25697616 TI - [Renal function in pediatric patients with allogeneic hematopoietic progenitor cell transplantation]. AB - Patients with hematopoietic stem cell transplantation can develop some degree of renal failure. The aim of this descriptive study is to evaluate markers of kidney injury in pediatric patients undergoing allogeneic hematopoietic stem cell transplantation between 1991 and 2011. PATIENTS AND METHOD: A descriptive study of pediatric patients with allogeneic transplant of hematopoietic precursors between 1991 and 2011. The patients were between 1 month and 18 years of age at the time of the study and had at least 6 months of follow up. Clinical and nutritional history, continuous blood pressure monitoring (ABPM), urine tests, proteinuria, creatinine and renal and bladder ultrasonography imaging were evaluated. RESULTS: During this period 65 patients were transplanted, of which 13 patients were included. 46% (n = 6) showed diverse degrees of renal compromise defined by altered renal parenchymal echogenicity, clinic or masked hypertension and/or microalbuminuria. CONCLUSION: In this clinical group, almost half of the patients patients had some degree of renal injury in their evolution. We consider essential to assess the renal function in the follow-up of these patients. PMID- 25697617 TI - [Inferior vena cava thrombosis and endocarditis in a premature patient: case report]. AB - Thrombosis of the inferior vena cava represents a significant percentage of all venous thrombosis that take place during the neonatal period, generally associated with risk factors such as the use of central venous catheter. The incidence of bacterial endocarditis in preterm infants is low. OBJECTIVES: To characterize the case of a preterm neonate with both conditions and to detail the disease changing spectrum in the neonatal population and its therapeutic possibilities. CASE REPORT: Premature newborn, 31 + 5 weeks of gestation who presented Enterococcus faecalis bacteremia, developed progressive thrombosis of the inferior vena cava and right atrium secondary to the use of umbilical venous catheter, with subsequent diagnosis of endocarditis. He was treated with anticoagulation with subcutaneous low molecular weight heparin. Given a favorable evolution, it was decided to continue the anticoagulation therapy for 4-6 weeks, and at the time of discharge, aspirin treatment was given. CONCLUSIONS: The preterm infant with infective endocarditis and intracardiac thrombus presents an interesting management dilemma. Treatment should be individualized according to the clinical evolution and safety profile of thrombolytic and/or anticoagulant agents. Availability and advantages of low molecular weight heparin have led to its use as an alternative treatment in neonates and infants with deep venous thrombosis. PMID- 25697618 TI - [Mixed facial lymphatic malformation: case report]. AB - Lymphangiomas are a common form of vascular malformation of the lymphatic vessels, mainly in the head and neck region. Most cases are progressive evolution and require a multidisciplinary approach. Currently, the first therapeutic option is sclerotherapy, leaving surgery for the treatment of remaining lesions. OBJECTIVE: To present a case of facial lymphatic malformation (LM) treated with sclerotherapy, surgery and orthodontics in a 15-year follow up. CASE REPORT: A one-year-old female patient who consulted health professionals due to a progressive volume increase of the soft parts of her right cheek. The imaging study confirmed the diagnosis of microcystic lymphatic malformation. It was managed with OK-432 sclerotherapy and Bleomycin. At 2 years of age, the patient response was considered adequate; an intralesional submandibular surgical excision was then performed, with partial resection of the lesion. The biopsy confirmed the diagnosis of microcystic LM. Six months after, a re-resection was planned using the same approach and removing the remaining lesion, with favorable development until the age of 9 years when the patient required surgery and orthodontic management due to intraoral recurrence. No major developments until the age of 13 when a new orthodontic surgery and handling are planned to perform right oral commissure suspension. CONCLUSION: LM management by sclerotherapy, surgery, and orthodontics has shown the advantages of a multidisciplinary long term treatment in this case. PMID- 25697619 TI - [Reaction to a black henna tattoo treated with mometasone furoate and silicone gel: case report]. AB - Black henna tattoos have paraphenylenediamine (PPD), which contains a product of herbal origin, which due to its molecular characteristics is capable of inducing, in susceptible individuals, a type IV hypersensitivity reaction. It clinically manifests as a contact dermatitis that usually when it disappears, scarring and hypopigmentation are left in the injured area. OBJECTIVE: To describe the case of a patient with hypersensitivity to henna tattoo and to present the most relevant phenomena associated with this condition. CASE REPORT: The case of a 6 year-old patient with a black henna tattoo on his right leg, who was diagnosed with contact dermatitis probably attributed to PPD, is presented. Mometasone furoate and topical silicone gel treatment was started with good response. CONCLUSION: Mometasone furoate and silicone gel are a good possible therapeutic option for treating contact dermatitis caused by PPD as the dermatosis was resolved without residual lesions. PMID- 25697620 TI - [Radiographic assessment of catheters in a neonatal intensive care unit (NICU)]. AB - Intravascular catheters are widely used in Neonatal Intensive Care Units. The major types of intravascular access in the newborn are peripheral catheters, venous or arterial umbilical catheters, central venous catheters and peripherally inserted central venous catheters (PICC). Anomalous positioning of catheters, especially umbilical catheters, is quite frequent as their installation is without imaging guidance. The radiographic assessment of the catheter performed by pediatricians and/or radiologists, who must be able to recognize those poorly positioned as they can cause serious complications, is essential. This article contains a sample of correct and misplaced catheter x-ray often used in a NICU. PMID- 25697621 TI - [Maternal eating disorders and their influence on eating behavior of the children: a review of the literature]. AB - BACKGROUND: There is conclusive evidence about the influence of mothers with eating disorders (ED) on their children. OBJECTIVE: To describe different aspects about mothers with ED and its implications in the feeding, growing and development in their children. METHOD: A review of specialized textbooks and the available literature in PubMed was made. RESULTS: Mothers with previous or present ED show restrictive eating patterns, a deficient affective bond with their own mothers, exhibit more psychiatric comorbidities, mainly depression and anxiety; in addition, feelings of guilt and shame, early cessation of breastfeeding, high control of food consumption of their children, and/or pressure them to eat, irregular mealtimes, unbalanced and monotonous meals, proneness to slimness, a critical attitude about the body shape of their daughters. Breastfeeding implies a critical period for the irruption or relapse of an ED due to the adjustment to the characteristic body shape changes during pregnancy. CONCLUSIONS: There is a particular relationship between a maternal ED and its occurrence in their children, and it can be considered a risk factor for its development. PMID- 25697622 TI - [Sensibilization to reduce language disabilities in children with a history of extreme prematurity]. PMID- 25697623 TI - Fabrication of RGD micro/nanopattern and corresponding study of stem cell differentiation. AB - Micropatterns of gold (Au) nanoarrays on inorganic and polymeric substrates were fabricated by combining block copolymer micelle nanolithography to obtain gold nanoarrays on glass, photolithography plus hydrofluoric acid (HF) etching to generate microislands, and transfer lithography to shift the gold micro/nanopatterns from glass to a bioinert poly(ethylene glycol) (PEG) hydrogel surface. Further the modification of the gold nanodots via cell-adhesive arginine glycine-aspartate (RGD) ligands was carried out to achieve peptide micro/nanopatterns. Whereas the micro/nanopatterns of noble metals could be useful in various applications, the peptide micro/nanopatterns especially enable persistent cell localization on adhesive micropatterns of RGD nanoarrays on the background of potently nonfouling PEG hydrogels, and thus offer a powerful tool to investigate cell-material interactions on both molecular and cellular levels. As a demonstration, we cultured human mesenchymal stem cells (hMSCs) on micro/nanopatterns with RGD nanoarrays of nanospacings 46 and 95 nm, and with micropans of side lengths 35 and 65 MUm (four groups in total). The osteogenic and adipogenic differentiation of hMSCs was conducted, and the potential effect of RGD nanospacing and the effect of cell spreading size on cell differentiation were decoupled for the first time. The results reveal that RGD nanospacing, independent of cell spreading size, acts as a strong regulator of cell tension and stem cell differentiation, which cannot be concluded unambiguously based on either merely micropatterns or nanopatterns. PMID- 25697624 TI - Society of American Gastrointestinal and Endoscopic Surgeons Response to "No Evidence for Efficacy of Radiofrequency Ablation for Treatment of Gastroesophageal Reflux Disease: A Systematic Review and Meta-analysis". PMID- 25697625 TI - Helicobacter pylori Associated With Obstructive Sleep Apnea Might Contribute to Sleep, Cognition, and Driving Performance Disturbances in Patients With Cirrhosis. PMID- 25697626 TI - Study of diabetic gastroparesis. PMID- 25697627 TI - Where Contrast Does Not Belong: A Rare Cause of Abdominal Pain. PMID- 25697628 TI - Endoscopic Management of Gastrointestinal Leaks and Fistulae. AB - Gastrointestinal leaks and fistulae can be serious acute complications or chronic morbid conditions resulting from inflammatory, malignant, or postsurgical states. Endoscopic closure of gastrointestinal leaks and fistulae represents major progress in the treatment of patients with these complex presentations. The main goal of endoscopic therapy is the interruption of the flow of luminal contents across a gastrointestinal defect. In consideration of the proper endoscopic approach to luminal closure, several basic principles must be considered. Undrained cavities and fluid collections must often first be drained percutaneously, and the percutaneous drain provides an important measure of safety for subsequent endoscopic luminal manipulations. The size and exact location of the leak/fistula, as well as the viability of the surrounding tissue, must be defined. Almost all complex leaks and fistulae must be approached in a multidisciplinary manner, collaborating with colleagues in nutrition, radiology, and surgery. Currently, gastrointestinal leaks and fistulae may be managed endoscopically by using 1 or more of the following modalities: stent placement, clip closure (including through-the-scope clips and over-the-scope devices), endoscopic suturing, and the injection of tissue sealants. In this article, we discuss these modalities and review the published outcomes data regarding each approach as well as practical considerations for successful closure of luminal defects. PMID- 25697629 TI - Synthesis, Characterization, Antioxidant Status, and Toxicity Study of Vanadium Rutin Complex in Balb/c Mice. AB - A new trend was developed for the formation of a complex between vanadium and flavonoid derivatives in order to increase the intestinal absorption and to reduce the toxicity of vanadium compounds. The vanadium-rutin complex was characterized by several spectroscopic techniques like ultraviolet (UV)-visible, Fourier transform infrared (FTIR), NMR, mass spectrometry, and microscopic evaluation by scanning electron microscopy. The mononuclear complex was formed by the interaction between vanadium and rutin with 1:2 metal to ligand stoichiometry. Antioxidant activity of the complex was evaluated by 1,1-diphenyl 2 picrylhydrazyl, ferric-reducing power, and 2,2'-azin-obis 3 ethylbenzothiazoline-6-sulphonic acid methods. It was shown that radical scavenging activity and ferric-reducing potential of free rutin was lower as compared with vanadium-rutin complex. The study was also investigated for oral acute toxicity and 28 days repeated oral subacute toxicity study of vanadium rutin complex in balb/c mice. The vanadium-rutin complex showed mortality at a dose of 120 mg/kg in the balb/c mice. In 28 days repeated oral toxicity study, vanadium-rutin complex was administered to both sex of balb/c mice at dose levels of 90, 45, and 20 ppm, respectively. In addition, subacute toxicity study of vanadium-rutin complex (at 90 ppm dose level) showed increase levels of white blood cell (WBC), total bilirubin, alanine aminotransferase (ALT), alkaline phosphatase (ALP), aspartate aminotransferase (AST), creatinine, and blood urea nitrogen and decrease level of total protein (TP) as compared with control group. Histopathological study of vanadium-rutin showed structural alteration in the liver, kidney, and stomach at 90 ppm dose level. No observed toxic level of vanadium-rutin complex at 20 ppm dose level could be good for further study. PMID- 25697630 TI - [An update on limitations of intravenous thrombolysis to treat acute ischemic stroke]. AB - The benefit of intravenous thrombolysis with rt-pa has been demonstrated in acute ischemic stroke up to 4 h 30 after the first symptoms. The number of patients with stroke treated by rt-pa remains low at less than 5%. In the license of rt-pa in acute ischemic stroke, there are numerous contra-indications explained by the fear of cerebral hemorrhagic complications. These contra-indications are based on the first therapeutic trials published more than 15 years ago, but are not all evidence-based. Large post-marketing registers and new randomized trials have shown a favorable ratio benefit/risk of rt-pa in acute ischemic strokes in some classical contra-indications. Reconsidering some of the official contra indications would increase the target population with treatable acute ischemic stroke using rt-pa to 20%. PMID- 25697631 TI - Differentiation of gluteus medius and minimus activity in weight bearing and non weight bearing exercises by M-mode ultrasound imaging. AB - BACKGROUND: Knowledge on task-specific activity of the deep hip abductor muscles is limited and is required for determining appropriate hip abductor exercises. OBJECTIVES: To assess the temporal differentiation of activity of gluteus minimus and the deep and the superficial regions of gluteus medius during weight bearing and non-weight bearing exercises. DESIGN: Repeated measures design on a single recording occasion. METHOD: M-mode ultrasound was used to capture activity related muscle motion of the gluteus minimus and medius muscles in 20 healthy volunteers during weight shift, hip hitch, side-lying abduction and active leg lengthening exercises. M-mode traces were computer-processed for detecting muscle motion onsets. Mean onset differences between muscle regions and their intra individual variability were assessed. RESULTS: In contrast to side-lying abduction, the weight shift and hip hitch exercises resulted in larger onset variability between the gluteus minimus and deep gluteus medius (P < 0.001) and also between the deep and superficial regions of the gluteus medius (P < 0.05). CONCLUSIONS: Weight bearing exercises promoted a greater functional differentiation between deep and superficial hip abductor muscles. PMID- 25697632 TI - Anopheles species diversity and distribution of the malaria vectors of Thailand. AB - In Thailand, seven Anopheles species within three species assemblages have been incriminated as important malaria vectors. Comprehensive maps showing the countrywide geographical distribution of primary and secondary malaria vector species have not yet been developed; the maps that do exist are typically restricted to specific areas or are out of date. In addition, with the advent of molecular-based species-identification tools, the geographical locations of various sibling species have been more clearly defined in the country. This review has compiled published data on the known distribution of important malaria vectors in Thailand based on genetic and molecular identification assays from 1994 to 2014, with maps of relevant species distribution provided herein. PMID- 25697633 TI - Poor glycemic control in type 2 diabetes in the South of the Sahara: the issue of limited access to an HbA1c test. AB - BACKGROUND: Management of type 2 diabetes remains a challenge in Africa. The objective of this study was to evaluate the prevalence and predictors of poor glycemic control in patients with type 2 diabetes living in sub-Saharan. PATIENTS AND METHODS: This was a cross-sectional study involving 1267 people (61% women) with type 2 diabetes (mean age 58 years) recruited across health facilities in Cameroon and Guinea. Predictors of poor glycemic control (HbA1c >=7.0% (53 mmol/mol)) were investigated via logistic regressions. RESULTS: The mean body mass index was 27.4 +/- 5.8 kg/m(2), and 74% of patients had poor glycemic control. Predictors of poor glycemic control in multivariable regression models were recruitment in Guinea [odd ratio: 2.91 (95% confidence interval 2.07 to 4.11)], age <65 years [1.40 (1.04 to 1.88)], diabetes duration >=3 years [2.36 (1.74 to 3.21)], treatment with: oral glucose control agents [3.46 (2.28 to 5.26)], insulin alone or with oral glucose control agents [7.74 (4.70 to 12.74)] and absence of a previous HbA1c measurement in Guinea [2.96 (1.30 to 6.75)]. CONCLUSION: Poor control of blood glucose is common in patients with type 2 diabetes in these two countries. Limited access to HbA1c appears to be a key factor associated with poor glycemic control in Guinea, and should be addressed by health policies targeting improvement in the outcomes of diabetes care. PMID- 25697634 TI - How family members manage risk around functional decline: the autonomy management process in households facing dementia. AB - Most dementia research investigates the social context of declining ability through studies of decision-making around medical treatment and end-of-life care. This study seeks to fill an important gap in research about how family members manage the risks of functional decline at home. Drawing on three waves of in depth interviewing in 2012-2014, it investigates how family members in US households manage decline in an affected individual's natural range of daily activities over time. The findings show that early on in the study period affected individuals were perceived to have awareness of their decline and routinely drew on family members for support. Support transformed when family members detected that the individual's deficit awareness had diminished, creating a corresponding increase in risk of self-harm around everyday activities. With a loss of confidence in the individual's ability to regulate his or her own activities to avoid these risks, family members employed unilateral practices to manage the individual's autonomy around his or her activity involvements. These practices typically involved various deceits and ruses to discourage elders from engaging in activities perceived as potentially dangerous. The study concludes by discussing the implications that the social context of interpretive work around awareness and risk plays an important role in how families perceive an elder's functional ability and manage his or her activity involvements. PMID- 25697635 TI - Mental health service use by cleanup workers in the aftermath of the Deepwater Horizon oil spill. AB - High rates of mental health (MH) problems have been documented among disaster relief workers. However, few workers utilize MH services, and predictors of service use among this group remain unexplored. The purpose of this study was to explore associations between predisposing, illness-related, and enabling factors from Andersen's behavioral model of treatment-seeking and patterns of service use among participants who completed at least one full day of cleanup work after the Deepwater Horizon oil spill and participated in home visits for the NIEHS GuLF STUDY (N = 8931). Workers reported on MH symptoms and whether they had used counseling or medication for MH problems since the oil spill. Hierarchical logistic regression models explored associations between predictors and counseling and medication use in the full sample, and type of use (counseling only, medication only, both) among participants who used either service. Analyses were replicated for subsamples of participants with and without symptom inventory scores suggestive of probable post-disaster mental illness. Having a pre-spill MH diagnosis, pre-spill service use, more severe post-spill MH symptoms, and healthcare coverage were positively associated with counseling and medication use in the full sample. Among participants who used either service, non-Hispanic Black race, pre-spill counseling, lower depression, and not identifying a personal doctor or healthcare provider were predictive of counseling only, whereas older age, female gender and pre-spill medication were predictive of medication only. The results were generally consistent among participants with and without probable post-disaster mental illness. The results suggest variability in which factors within Andersen's behavioral model are predictive of different patterns of service use among disaster relief workers. PMID- 25697636 TI - Geographical accessibility to healthcare and malnutrition in Rwanda. AB - The prevalence of stunting in children less than five years of age is elevated in Rwanda. It is one of the main health challenges upon which the government is struggling to achieve progress. Health centers and district hospitals in Rwanda are expected to provide a package of health services including nutrition related activities, nutritional rehabilitation, education, and growth monitoring. They can hence play a potent role in alleviating malnutrition and stunting in Rwanda. This study tested whether travel time from household clusters to the nearest health center was significantly and negatively associated with the distribution of height-for-age z-scores of younger than five year old children in the eastern province of Rwanda. Data for 974 children was extracted from the Rwanda Demographic and Health Survey (DHS) database. However, since DHS does not contain any information on travel time to health centers, the latter was simulated using AccessMod 4.0, an extension to ArcGIS 9.3.1 that simulates health facilities' catchment areas and travel times to health facilities. Travel time was found to be negatively associated with height-for-age z-scores at the 5% level in a stepwise regression analysis that controlled for wealth index, mother's primary and secondary education, sex of the child, preceding birth interval, and birth order of the child. Field measurements are needed to validate travel time. If validated, results point to the importance of improved access to healthcare facilities as a potential pathway in reducing stunting in Rwanda. PMID- 25697637 TI - Flexible positions, managed hopes: the promissory bioeconomy of a whole genome sequencing cancer study. AB - Genomic research has rapidly expanded its scope and ambition over the past decade, promoted by both public and private sectors as having the potential to revolutionize clinical medicine. This promissory bioeconomy of genomic research and technology is generated by, and in turn generates, the hopes and expectations shared by investors, researchers and clinicians, patients, and the general public alike. Examinations of such bioeconomies have often focused on the public discourse, media representations, and capital investments that fuel these "regimes of hope," but also crucial are the more intimate contexts of small-scale medical research, and the private hopes, dreams, and disappointments of those involved. Here we examine one local site of production in a university-based clinical research project that sought to identify novel cancer predisposition genes through whole genome sequencing in individuals at high risk for cancer. In depth interviews with 24 adults who donated samples to the study revealed an ability to shift flexibly between positioning themselves as research participants on the one hand, and as patients or as family members of patients, on the other. Similarly, interviews with members of the research team highlighted the dual nature of their positions as researchers and as clinicians. For both parties, this dual positioning shaped their investment in the project and valuing of its possible outcomes. In their narratives, all parties shifted between these different relational positions as they managed hopes and expectations for the research project. We suggest that this flexibility facilitated study implementation and participation in the face of potential and probable disappointment on one or more fronts, and acted as a key element in the resilience of this local promissory bioeconomy. We conclude that these multiple dimensions of relationality and positionality are inherent and essential in the creation of any complex economy, "bio" or otherwise. PMID- 25697638 TI - Atherosclerosis-Related Circulating MicroRNAs as a Predictor of Stroke Recurrence. AB - MicroRNAs (miRNAs) are short sequenced non-coding RNAs that posttranscriptionally regulate gene expression. We investigated circulating miRNA expression levels in acute stroke patients and its relationship with future vascular event. We included acute ischemic stroke patients who admitted to a university hospital between May 1, 2011, and July 31, 2012, and the patients with vascular risk factors but not incident stroke as controls. We collected 5 ml of venous blood, and circulating miRNA levels were evaluated by quantitative real-time polymerase chain reaction. Five miRNAs (miR-17, miR-21, miR-106a, miR-126, and miR-200b), which had been reported to be related to atherosclerosis, were measured. The levels of miRNAs were compared with the presence of acute stroke, vascular risk factors, stroke subtypes, and stroke recurrence after index stroke. A total of 120 patients were included in the study, with 83 acute stroke patients. The levels of miR-17 were significantly increased in acute stroke patients, and the levels of miR-126 had positive correlation with cerebral atherosclerosis (r = 0.254, p = 0.021). Among the 83 stroke patients, eight experienced stroke recurrence during follow-up and higher level of miR-17 was associated with shorter event-free survival (p = 0.047). This study shows that the miR-17 level was elevated in acute ischemic stroke and associated with future stroke recurrence. PMID- 25697639 TI - Effect of sucrose consumption on serum insulin, serum cortisol and insulin sensitivity in migraine: evidence of sex differences. AB - The aim of this study was to compare the effect of sucrose on biomarkers of energy metabolism and utilization in migrainous men and women. A total of 20 participants (7=Migraine (female), 5=Migraine (male), 8=Non-migraine control) submitted to an oral sucrose tolerance test (OSTT), which required them to fast for 15 h overnight and then ingest 75 g sucrose dissolved in 175 g water at 9 AM the next morning. Blood sampling for the assessment of serum insulin, serum cortisol and plasma glucose was conducted upon arrival at 0900 h and then at regular 15-min intervals across a 150-min period. Comparison of insulin sensitivity indexes that rely on fasting glucose and insulin data failed to find evidence of insulin resistance in migraineurs or controls. Prior to sucrose consumption the level of fasting serum cortisol at 0-min on average was significantly higher in migraineurs. However, no significant group differences in the level of fasting serum insulin and plasma glucose at 0-min were noted. Following sucrose consumption: the level of serum insulin was significantly higher in female migraineurs; the level of serum cortisol was significantly higher in male migraineurs; glucose/insulin (G/I) ratio was significantly higher in male migraineurs at 135-min and 150-min; insulin/cortisol (I/C) ratio was significantly different with the I/C ratio lower in male migraineurs and higher in female migraineurs; area under the curve (AUC) insulin was significantly different across groups with AUC insulin lower in male migraineurs and higher in female migraineurs; and AUC cortisol was significantly higher in male migraineurs. It was concluded that the effect of sucrose on biomarkers of energy metabolism and utilization in male and female migraineurs is not the same. Therefore, the factors underlying migraine pathogenesis in men and women may also be different. PMID- 25697643 TI - Preferential carriage of class 2 integrons in Acinetobacter baumannii CC113 and novel singletons. AB - Our understanding of the distribution of integrons associated with multidrug resistance in Acinetobacter baumannii isolates around the world remains incomplete. The association between the class 1 and 2 integron A. baumannii positive isolates (n = 60), recovered since 1982 from 11 Argentinean hospitals, and the circulating lineages, was investigated. While class 2 integrons were highly significantly associated with clonal lineage CC113B/CC79P (P = 0.009) and novel singletons (P = 0.001), class 1 integrons were found not to be associated with CC109B/CC1P or other lineages. The study reveals a differential distribution of class 2 integrons in lineages, and suggests that the prevalence of intI2 in Argentina is related to the emergence of novel singletons in recent years and to the abundance of CC113B/CC79P, which has been the local dominant lineage for several decades. PMID- 25697644 TI - Annexin A2 regulates angiogenesis and invasion phenotypes of malignant glioma. AB - We have established a pair of animal models (J3T-1 and J3T-2) with different invasive and angiogenic phenotypes, and demonstrated that annexin A2 is expressed at higher levels in J3T-1 than J3T-2 cells. The function of annexin A2 in relation to angiogenesis and invasion was investigated using these models. Stable silencing or overexpression of annexin A2 in J3T-1 and J3T-2 cells (J3T-1shA and J3T-2A cells) was established and used. Thirty human glioblastoma samples were evaluated for expression of annexin A2, vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF). Immunohistochemical and quantitative reverse-transcription polymerase chain reaction analyses revealed higher expression of annexin A2, VEGF and PDGF in J3T-1 and J3T-2A cells. Cultured J3T-1 and J3T-2A cells exhibited higher adhesive ability to endothelial cells. Histopathological analysis of animal brain tumors revealed that J3T-1 and J3T-2A tumors displayed marked angiogenesis and invasion along the neovasculature, whereas J3T-2 and J3T-1shA tumors exhibited diffuse, infiltrative invasion without angiogenesis. Positive expression of annexin A2 was observed in tumor cells surrounding dilated vessels in 25/30 human glioblastoma specimens. Our results reveal that the phenotype of glioma invasion is closely related to angiogenesis. We identify annexin A2 as a factor regulating angiogenesis and invasion of malignant gliomas. PMID- 25697645 TI - Almost quantum correlations. AB - Quantum theory is not only successfully tested in laboratories every day but also constitutes a robust theoretical framework: small variations usually lead to implausible consequences, such as faster-than-light communication. It has even been argued that quantum theory may be special among possible theories. Here we report that, at the level of correlations among different systems, quantum theory is not so special. We define a set of correlations, dubbed 'almost quantum', and prove that it strictly contains the set of quantum correlations but satisfies all but-one of the proposed principles to capture quantum correlations. We present numerical evidence that the remaining principle is satisfied too. PMID- 25697648 TI - Fast masking of repeated primer binding sites in eukaryotic genomes. AB - In this article we describe the working principle and a list of practical applications for GenomeMasker-a program that finds and masks all repeated DNA motifs in fully sequenced genomes. The GenomeMasker exhaustively finds and masks all repeated DNA motifs in studied genomes. The software is optimized for PCR primer design. The algorithm is designed for high-throughput work, allowing masking of large DNA regions, even entire eukaryotic genomes. Additionally, the software is able to predict all alternative PCR products from studied genomes for thousands of candidate PCR primer pairs. Practical applications of the GenomeMasker are shown for command-line version of the GenomeMasker, which can be downloaded from http://bioinfo.ut.ee/download/. Graphical Web interfaces with limited options are available at http://bioinfo.ut.ee/genometester/ and http://bioinfo.ut.ee/snpmasker/. PMID- 25697647 TI - Visceral adipose tissue is associated with insulin resistance in hemodialyzed patients. AB - BACKGROUND: It has not been definitively established which factors affect insulin resistance (IR) and whether dialysis decreases IR. The aim of this study was to investigate factors that may have an influence on homeostasis model assessment (HOMA-IR) in hemodialyzed patients (HDpts) and to compare IR between HDpts and healthy subjects. MATERIAL AND METHODS: We examined 33 HDpts and paired 33 subjects of the control group, matched for sex, age, and BMI. We analyzed concentrations of insulin, glucose, leptin, resistin, and total and high molecular-weight adiponectin (HMWad) in serum. Using computed tomography in HDpts, we evaluated visceral adipose tissue (VAT), concentrations of visfatin, CRP, and IL-6. RESULTS: HOMA-IR (median, 1.3 vs. 1.4, P=0.19), insulin (median 6.8 vs. 6.0 uIU/mL, P=0.7), glucose (79 mg/dL vs. 93 mg/dL, P=0.001). IR in HDpts is dependent on VAT (r=0.36, P=0.04) and this relationship is stronger than the relationship of BMI and IR (r=0.3, P=0.1). In HDpts we found higher concentrations of leptin (P=0.001) and resistin (P<0.001), with no relation to IR. HMWad and its percentage in relation to total adiponectin are higher in HDpts (P=0.03 and P<0.001, respectively). CONCLUSIONS: HOMA-IR in HDpts does not differ from the control group. In HDpts it depends on the quantity of VAT and this relationship is stronger than with BMI. In HDpts leptin and resistin do not influence IR. HMWad and its percentage in total adiponectin are significantly higher in HDpts. PMID- 25697649 TI - Primer design for PCR reactions in forensic biology. AB - The polymerase chain reaction (PCR) is a popular method to copy DNA in vitro. Its invention revolutionized fields ranging from clinical medicine to anthropology, molecular biology, and forensic biology. The method employs one of many available heat-stable DNA polymerases in a reaction that is repeated many times in situ. The DNA polymerase reads a template DNA strand and using the components of the reaction mix, catalyzes the addition of free 2'-deoxynucleotide triphosphate nitrogenous bases to short segment of DNA that forms a complement with the template via Watson-Crick base pairing. This short segment of DNA is referred to as a PCR primer and it is essential to the success of the reaction. The most widely used application of PCR in forensic labs is the amplification of short tandem repeat (STR) loci used in DNA typing. The STRs are routinely evaluated in concert with 16 or more reactions, a multiplex, run in one test tube simultaneously. In a multiplex, it is essential that the primers work specifically and accurately on the intended reactions without hindering the other reactions. The primers, which are very specific, also can be used to probe single nucleotide polymorphisms (SNPs) in a DNA sequence of interest by single base extension. Primers are often designed using one of many available automated software packages. Here the process of manually designing PCR primers for forensic biology using no-cost software is described. PMID- 25697646 TI - Pathologic and therapeutic implications for the cell biology of parkin. AB - Mutations in the E3 ligase parkin are the most common cause of autosomal recessive Parkinson's disease (PD), but it is believed that parkin dysfunction may also contribute to idiopathic PD. Since its discovery, parkin has been implicated in supporting multiple neuroprotective pathways, many revolving around the maintenance of mitochondrial health quality control and governance of cell survival. Recent advances across the structure, biochemistry, and cell biology of parkin have provided great insights into the etiology of parkin-linked and idiopathic PD and may ultimately generate novel therapeutic strategies to slow or halt disease progression. This review describes the various pathways in which parkin acts and the mechanisms by which parkin may be targeted for therapeutic intervention. This article is part of a Special Issue entitled 'Neuronal Protein'. PMID- 25697650 TI - Design of primers and probes for quantitative real-time PCR methods. AB - Design of primers and probes is one of the most crucial factors affecting the success and quality of quantitative real-time PCR (qPCR) analyses, since an accurate and reliable quantification depends on using efficient primers and probes. Design of primers and probes should meet several criteria to find potential primers and probes for specific qPCR assays. The formation of primer dimers and other non-specific products should be avoided or reduced. This factor is especially important when designing primers for SYBR((r)) Green protocols but also in designing probes to ensure specificity of the developed qPCR protocol. To design primers and probes for qPCR, multiple software programs and websites are available being numerous of them free. These tools often consider the default requirements for primers and probes, although new research advances in primer and probe design should be progressively added to different algorithm programs. After a proper design, a precise validation of the primers and probes is necessary. Specific consideration should be taken into account when designing primers and probes for multiplex qPCR and reverse transcription qPCR (RT-qPCR). This chapter provides guidelines for the design of suitable primers and probes and their subsequent validation through the development of singlex qPCR, multiplex qPCR, and RT-qPCR protocols. PMID- 25697651 TI - Large-scale nucleotide sequence alignment and sequence variability assessment to identify the evolutionarily highly conserved regions for universal screening PCR assay design: an example of influenza A virus. AB - The development of a diagnostic polymerase chain reaction (PCR) or quantitative PCR (qPCR) assay for universal detection of highly variable viral genomes is always a difficult task. The purpose of this chapter is to provide a guideline on how to align, process, and evaluate a huge set of homologous nucleotide sequences in order to reveal the evolutionarily most conserved positions suitable for universal qPCR primer and hybridization probe design. Attention is paid to the quantification and clear graphical visualization of the sequence variability at each position of the alignment. In addition, specific problems related to the processing of the extremely large sequence pool are highlighted. All of these steps are performed using an ordinary desktop computer without the need for extensive mathematical or computational skills. PMID- 25697652 TI - Low-concentration initiator primers improve the amplification of gene targets with high sequence variability. AB - The amplification and detection of diverse strains of an infectious virus or bacteria, or variants within a gene family is important for both clinical and basic research but can be difficult using conventional PCR. This report describes and illustrates a novel closed-tube method for amplifying and characterizing heterogeneous target sequences using members of the CTX-M beta-lactamase gene family. Different subgroups of CTX-M genes exhibit low sequence identity, but accurate and efficient detection of these variants is critical because they all confer resistance to penicillin, cefotaxime, and other antibiotics of the beta lactam class. The method combines a single pair of "thermodynamic consensus primers" (tcPrimers) with one or more "initiator primers" (iPrimers), added at low concentration (5-10 nM). Each iPrimer improves the initial amplification of one or more variants because it has fewer mismatches to its intended target than the more abundant tcPrimers. As a result of initial amplification, each heterogeneous sequence is shifted stepwise toward a better match with the tcPrimers. As soon as the tcPrimer hybridization takes place, amplification proceeds with high efficiency. The tcPrimer pairs can be designed for symmetric PCR or for Linear-After-The-Exponential (LATE)-PCR. LATE-PCR offers the advantage of generating single-stranded DNA that can be characterized for different gene variants in the same closed tube, using low-temperature mismatch-tolerant fluorescent probes. PMID- 25697653 TI - Multiplex PCR primer design for simultaneous detection of multiple pathogens. AB - Multiplex PCR provides a powerful tool for simultaneous detection and discrimination of multiple pathogens or different subtypes of a causative agent from humans, animals, and plants in a single reaction, and saves time and cost in the clinical diagnostic laboratory. Here, we describe the specific protocol of multiplex PCR primer design for simultaneous identification of more than one target from a same specimen. Different sizes of amplicons and similar T m values of primer sets are essential to successfully develop a feasible multiplex PCR assay. PMID- 25697654 TI - Degenerate primer design for highly variable genomes. AB - The application of degenerate PCR primers towards target amplification and sequencing is a useful technique when a population of organisms under investigation is evolving rapidly, or is highly diverse. Degenerate bases in these primers are specified with ambiguity codes that represent alternative nucleotide configurations. Degenerate PCR primers allow the simultaneous amplification of a heterogeneous population by providing a mixture of PCR primers each of which anneal to an alternative genotype found in the isolated sample. However, as the number of degenerate bases specified in a pair of primers rises, the likelihood of amplifying unwanted alternative products also increases. These alternative products may confound downstream data analyses if their levels begin to obfuscate the desired PCR products. This chapter describes a set of computational methodologies that may be used to minimize the degeneracy of designed primers, while still maximizing the proportion of genotypes assayed in the targeted population. PMID- 25697655 TI - Allele-specific real-time polymerase chain reaction as a tool for urate transporter 1 mutation detection. AB - Allele-specific polymerase chain reaction (ASPCR) method has long been applied for the detection of nucleotide variations and genotyping, which are detected by the presence or absence of DNA amplification PCR products. Recently, Real-Time PCR genotyping has fast developed and offered a rapid method of detecting mutations without the need of gel electrophoresis as with ASPCR. Here, we describe an easy and rapid touchdown real-time PCR method for the detection of nucleotide variations. Using our method we successfully detect two main mutations in human urate transporter 1 (SLC22A12), W258X and R90H, and validate the results. The method can potentially be applied to genotype of various other nucleotide variations. PMID- 25697656 TI - MultiPLX: automatic grouping and evaluation of PCR primers. AB - In this chapter we describe MultiPLX-a tool for automatic grouping of PCR primers for multiplexed PCR. Both generic working principle and step-by-step practical procedures with examples are presented. MultiPLX performs grouping by calculating many important interaction levels between the different primer pairs and then distributes primer pairs to groups so that the strength of unwanted interactions is kept below user-defined compatibility level. In addition it can be used to select optimal primer pairs for multiplexing from list of candidates. MultiPLX can be downloaded from http://bioinfo.ut.ee/?page_id=167. Graphical web-based interface to most functions of MultiPLX is available at http://bioinfo.ut.ee/multiplx/. PMID- 25697657 TI - In silico PCR primer designing and validation. AB - Polymerase chain reaction (PCR) is an enzymatic reaction whose efficiency and sensitivity largely depend on the efficiency of the primers that are used for the amplification of a concerned gene/DNA fragment. Selective amplification of nucleic acid molecules initially present in minute quantities provides a powerful tool for analyzing nucleic acids. In silico method helps in designing primers. There are various programs available for PCR primer design. Here we described designing of primers using web-based tools like "Primer3" and "Web Primer". For designing the primer, DNA template sequence is required that can be taken from any of the available sequence databases, e.g., RefSeq database. The in silico validation can be carried out using BLAST tool and Gene Runner software, which check their efficiency and specificity. Thereafter, the primers designed in silico can be validated in the wet lab. After that, these validated primers can be synthesized for use in the amplification of concerned gene/DNA fragment. PMID- 25697658 TI - Primer design using Primer Express(r) for SYBR Green-based quantitative PCR. AB - To quantitate the gene expression, real-time RT-PCR or quantitative PCR (qPCR) is one of the most sensitive, reliable, and commonly used methods in molecular biology. The reliability and success of a real-time PCR assay depend on the optimal experiment design. Primers are the most important constituents of real time PCR experiments such as in SYBR Green-based detection assays. Designing of an appropriate and specific primer pair is extremely crucial for correct estimation of transcript abundance of any gene in a given sample. Here, we are presenting a quick, easy, and reliable method for designing target-specific primers using Primer Express((r)) software for real-time PCR (qPCR) experiments. PMID- 25697659 TI - Designing primers for SNaPshot technique. AB - The SNaPshot technique, also known as minisequencing, is a primer extension-based method developed for the analysis of Single Nucleotide Polymorphisms (SNPs). Using this technique, it is possible to analyze more than 50 SNPs distributed throughout the genome in a single multiplex reaction, making it an advantage when compared with traditional sequencing reaction. In this chapter, you will find a step-by-step guide to design a multiplex primer assay for SNaPshot reaction. PMID- 25697660 TI - Rapid and simple method of qPCR primer design. AB - Quantitative real-time polymerase chain reaction (qPCR) is a powerful tool for analysis and quantification of gene expression. It is advantageous compared to traditional gel-based method of PCR, as gene expression can be visualized "real time" using a computer. In qPCR, a reporter dye system is used which intercalates with DNA's region of interest and detects DNA amplification. Some of the popular reporter systems used in qPCR are the following: Molecular Beacon((r)), SYBR Green((r)), and Taqman((r)). However, success of qPCR depends on the optimal primers used. Some of the considerations for primer design are the following: GC content, primer self-dimer, or secondary structure formation. Freely available software could be used for ideal qPCR primer design. Here we have shown how to use some freely available web-based software programs (such as Primerquest((r)), Unafold((r)), and Beacon designer((r))) to design qPCR primers. PMID- 25697661 TI - PRIMEGENSw3: a web-based tool for high-throughput primer and probe design. AB - Highly specific and efficient primer and probe design has been a major hurdle in many high-throughput techniques. Successful implementation of any PCR or probe hybridization technique depends on the quality of primers and probes used in terms of their specificity and cross-hybridization. Here we describe PRIMEGENSw3, a set of web-based utilities for high-throughput primer and probe design. These utilities allow users to select genomic regions and to design primer/probe for selected regions in an interactive, user-friendly, and automatic fashion. The system runs the PRIMEGENS algorithm in the back-end on the high-performance server with the stored genomic database or user-provided custom database for cross-hybridization check. Cross-hybridization is checked not only using BLAST but also by checking mismatch positions and energy calculation of potential hybridization hits. The results can be visualized online and also can be downloaded. The average success rate of primer design using PRIMEGENSw3 is ~90 %. The web server also supports primer design for methylated sequences, which is used in epigenetic studies. Stand-alone version of the software is also available for download at the website. PMID- 25697662 TI - Selecting specific PCR primers with MFEprimer. AB - Selecting specific primers is crucial for polymerase chain reaction (PCR). Nonspecific primers will bind to unintended genes and result in nonspecific amplicons. MFEprimer is a program for checking the specificity of PCR primers against the background DNA. In this chapter, we introduce: (1) the factors that affect the specificity of primers; (2) the principle of MFEprimer and its settings; (3) how to use the MFEprimer to examine the specificity of primers. PMID- 25697663 TI - Clinical applications of preimplantation genetic testing. AB - Genetic diagnostic technologies are rapidly changing the way medicine is practiced. Preimplantation genetic testing is a well established application of genetic testing within the context of in vitro fertilization cycles. It involves obtaining a cell(s) from a developing embryo in culture, which is then subjected to genetic diagnostic analysis; the resulting information is used to guide which embryos are transferred into the uterus. The potential applications and use of this technology have increased in recent years. Experts agree that preimplantation genetic diagnosis is clinically appropriate for many known genetic disorders. However, some applications of such testing, such as preimplantation genetic screening for aneuploidy, remain controversial. Clinical data suggest that preimplantation genetic screening may be useful, but further studies are needed to quantify the size of the effect and who would benefit most. PMID- 25697664 TI - Isolation of Vermamoeba vermiformis and associated bacteria in hospital water. AB - To detect new potential pathogens in hospital water, we isolated free-living amoebae in water samples taken from three different hospitals in Marseille (France). The samples were inoculated in media containing saline buffer and various bacteria as nutrient sources. The isolated amoebae were identified by gene sequencing. Among the 105 water samples, taken from 19 sites, we isolated 14 amoebae, of which 9 Vermamoeba vermiformis and 5 Acanthamoeba sp. None of the amoebae showed the presence of obligate bacterial endosymbionts. Because V. vermiformis was most commonly isolated, we used an axenic collection strain to isolate amoeba-resistant bacteria from the same sites. The isolated bacterial species included Stenotrophomonas maltophilia and Legionella sp. Legionella taurinensis was isolated for the first time in association with amoebae. A strict intracellular bacterium was isolated, that may represent a new genus among the Chlamydiales. We propose that it be named "Candidatus Rubidus massiliensis". Our study shows that the isolation and identification of new pathogens associated with amoebae, which were previously performed using Acanthamoeba sp., should instead use V. vermiformis because this organism is more commonly associated with humans and is an essential complement of Acanthamoeba sp. co-culture to study the ecology of hospital water supplies. PMID- 25697665 TI - Further characterization of a highly attenuated Yersinia pestis CO92 mutant deleted for the genes encoding Braun lipoprotein and plasminogen activator protease in murine alveolar and primary human macrophages. AB - We recently characterized the Deltalpp Deltapla double in-frame deletion mutant of Yersinia pestis CO92 molecularly, biologically, and immunologically. While Braun lipoprotein (Lpp) activates toll-like receptor-2 to initiate an inflammatory cascade, plasminogen activator (Pla) protease facilitates bacterial dissemination in the host. The Deltalpp Deltapla double mutant was highly attenuated in evoking bubonic and pneumonic plague, was rapidly cleared from mouse organs, and generated humoral and cell-mediated immune responses to provide subsequent protection to mice against a lethal challenge dose of wild-type (WT) CO92. Here, we further characterized the Deltalpp Deltapla double mutant in two murine macrophage cell lines as well as in primary human monocyte-derived macrophages to gauge its potential as a live-attenuated vaccine candidate. We first demonstrated that the Deltapla single and the Deltalpp Deltapla double mutant were unable to survive efficiently in murine and human macrophages, unlike WT CO92. We observed that the levels of Pla and its associated protease activity were not affected in the Deltalpp single mutant, and, likewise, deletion of the pla gene from WT CO92 did not alter Lpp levels. Further, our study revealed that both Lpp and Pla contributed to the intracellular survival of WT CO92 via different mechanisms. Importantly, the ability of the Deltalpp Deltapla double mutant to be phagocytized by macrophages, to stimulate production of tumor necrosis factor-alpha and interleukin-6, and to activate the nitric oxide killing pathways of the host cells remained unaltered when compared to the WT CO92 infected macrophages. Finally, macrophages infected with either the WT CO92 or the Deltalpp Deltapla double mutant were equally efficient in their uptake of zymosan particles as determined by flow cytometric analysis. Overall, our data indicated that although the Deltalpp Deltapla double mutant of Y. pestis CO92 was highly attenuated, it retained the ability to elicit innate and subsequent acquired immune responses in the host similar to that of WT CO92, which are highly desirable in a live-attenuated vaccine candidate. PMID- 25697666 TI - Topological organization of connectivity strength in the rat connectome. AB - The mammalian brain is a complex network of anatomically interconnected regions. Animal studies allow for an invasive measurement of the connections of these networks at the macroscale level by means of neuronal tracing of axonal projections, providing a unique opportunity for the formation of detailed 'connectome maps'. Here we analyzed the macroscale connectome of the rat brain, including detailed information on the macroscale interregional pathways between 67 cortical and subcortical regions as provided by the high-quality, open-access BAMS-II database on rat brain anatomical projections, focusing in particular on the non-uniform distribution of projection strength across pathways. First, network analysis confirmed a small-world, modular and rich club organization of the rat connectome; findings in clear support of previous studies on connectome organization in other mammalian species. More importantly, analyzing network properties of different connection weight classes, we extend previous observations by showing that pathways with different topological roles have significantly different levels of connectivity strength. Among other findings, intramodular connections are shown to display a higher connectivity strength than intermodular connections and hub-to-hub rich club connections are shown to include significantly stronger pathways than connections spanning between peripheral nodes. Furthermore, we show evidence indicating that edges of different weight classes display different topological structures, potentially suggesting varying roles and origins of pathways in the mammalian brain network. PMID- 25697668 TI - Efficient Conversion of CO2 to CO Using Tin and Other Inexpensive and Easily Prepared Post-Transition Metal Catalysts. AB - The development of affordable electrocatalysts that can drive the reduction of CO2 to CO with high selectivity, efficiency, and large current densities is a critical step on the path to production of liquid carbon-based fuels. In this work, we show that inexpensive triflate salts of Sn(2+), Pb(2+), Bi(3+), and Sb(3+) can be used as precursors for the electrodeposition of CO2 reduction cathode materials from MeCN solutions, providing a general and facile electrodeposition strategy, which streamlines catalyst synthesis. The ability of these four platforms to drive the formation of CO from CO2 in the presence of [BMIM]OTf was probed. The electrochemically prepared Sn and Bi catalysts proved to be highly active, selective, and robust platforms for CO evolution, with partial current densities of jCO = 5-8 mA/cm(2) at applied overpotentials of eta < 250 mV. By contrast, the electrodeposited Pb and Sb catalysts do not promote rapid CO generation with the same level of selectivity. The Pb material is only ~10% as active as the Sn and Bi systems at an applied potential of E = -1.95 V and is rapidly passivated during catalysis. The Sb-comprised cathode material shows no activity for conversion of CO2 to CO under analogous conditions. When taken together, this work demonstrates that 1,3-dialkylimidazoliums can promote CO production, but only when used in combination with an appropriately chosen electrocatalyst material. More broadly, these results suggest that the interactions between CO2, the imidazolium promoter, and the cathode surface are all critical to the observed catalysis. PMID- 25697669 TI - Does safety climate predict safety performance in Italy and the USA? Cross cultural validation of a theoretical model of safety climate. AB - Previous studies have acknowledged the relevance of assessing the measurement equivalence of safety related measures across different groups, and demonstrating whether the existence of disparities in safety perceptions might impair direct group comparisons. The Griffin and Neal (2000) model of safety climate, and the accompanying measure (Neal et al. [NGH], 2000), are both widely cited and utilized. Yet neither the model in its entirety nor the measure have been previously validated across different national contexts. The current study is the first to examine the NGH measurement equivalence by testing whether their model of safety climate predicting safety performance is tenable in both English speaking and non-English speaking countries. The study involved 616 employees from 21 organizations in the US, and 738 employees from 20 organizations in Italy. A multi-group confirmatory factor analytic approach was used to assess the equivalence of the measures across the two countries. Similarly, the structural model of relations among the NGH variables was examined in order to demonstrate its cross-country invariance. Results substantially support strict invariance across groups for the NGH safety scales. Moreover, the invariance across countries is also demonstrated for the effects of safety climate on safety knowledge and motivation, which in turn positively relate to both compliance and participation. Our findings have relevant theoretical implications by establishing measurement and relational equivalence of the NGH model. Practical implications are discussed for managers and practitioners dealing with multi national organizational contexts. Future research should continue to investigate potential differences in safety related perceptions across additional non-English speaking countries. PMID- 25697667 TI - Obesity-related immune responses and their impact on surgical outcomes. AB - The obesity epidemic represents a critical disease burden with broad clinical consequences. At the same time, obesity has been linked to inferior surgical outcomes and considered a contraindication for some elective surgical procedures. A growing body of mechanistic evidence has accumulated linking obesity to changes of metabolism and immune responses. This concept provides an integrated inflammatory network based on the perception of obesity as a state of chronic low grade inflammation. With a more detailed understanding of this dynamic network and mechanistic insights, novel treatment and management strategies may be developed with the goal to optimize surgical outcomes in obese patients. PMID- 25697670 TI - Validation of the Behaviour of Young Novice Drivers Scale (BYNDS) in a New Zealand young driver population. AB - The Behaviour of Young Novice Drivers Scale, the BYNDS (Scott-Parker et al., 2010), is a reliable and valid self-report 44-item instrument which explores the frequency of a breadth of risky driving behaviours which appear to place young and novice drivers at an increased risk of road crash injury. As part of a larger collaborative research project, the Australian-developed BYNDS was piloted in a sample of 20 young New Zealand drivers n=14 aged 16-18 years, 9 males; n=6 aged 19-24 years, 2 males. The wording of 21 BYNDS items was modified to reflect the cultural context of the participating New Zealand drivers. The refined BYNDS was applied in a sample of 325 young drivers n=116 aged 16-18 years, 65 males; n=209 aged 19-24 years, 98 males, and the factor structure examined, including exploratory factor analysis for each gender. The 5-factor structure of the BYNDS was supported, with young drivers reporting considerable engagement in risky driving exposure, moderate engagement in transient violations and mood-related driving, and less fixed violations and driving misjudgements. Risky driving exposure was predictive of self-reported crash involvement for both males and females, suggesting targeted intervention regarding when, and the circumstances under which, the young driver is on the road. PMID- 25697671 TI - On the existence and characterization of molecular electrides. AB - Electrides are ionic compounds thus far appearing in the solid state, where the anionic part is constituted by isolated electrons. We herein provide an unambiguous computational means to distinguish electrides from similar species, proving the existence of some electrides in the gas phase. We also put forward a recipe to design new electrides. PMID- 25697672 TI - Interstrain differences of ionotropic glutamate receptor subunits in the hippocampus and induction of hippocampal sclerosis with pilocarpine in mice. AB - Rodent strains used in epilepsy research have various neurological characteristics. These differences were suggested to be attributed to the diverse densities of the ionotropic glutamate receptor (iGluR) subunits. However, previous studies failed to find interstrain differences in the hippocampal receptor levels. We supposed that a detailed layer-to-layer analysis of the iGluR subunits in the hippocampus might reveal strain-dependent differences in their base lines and reactions induced by pilocarpine (PILO) between two mouse strains without documented ancestors. Levels of iGluR subunits in Balb/c and NMRI mice were compared using semiquantitative immunohistochemistry. The alterations in the neuronal circuitry were validated by neuropeptide Y (NPY) and neuronal nuclear antigen (NeuN) immunostainings. Immunohistochemistry showed interstrain laminar differences in some subunits of both the control and PILO-treated animals. The seizure-induced irreversible neuronal changes were accompanied by reduced GluA1 and GluA2 levels. Their changes were inversely correlated in the individual NMRI mice by Pearson's method. Increase in NPY immunoreactivity showed positive correlation with GluA1, and negative correlation with GluA2. The NMRI strain was susceptible to PILO-induced hippocampal sclerosis, while the Balb/c animals showed resistance. Basal levels of iGluRs differ in mouse strains, which may account for the interstrain differences in their reactions to the convulsant. PMID- 25697673 TI - Utilization of hydroxypropyl carboxymethyl cellulose in synthesis of silver nanoparticles. AB - Hydroxypropyl carboxymethyl cellulose samples having varying degrees of substitution and varying degrees of polymerization were used to reduce silver nitrate to silver nanoparticles. UV spectral analysis of silver nanoparticles colloidal solution reveal that increasing the pH of the reduction solution leads to improvement in the intensity of the absorption band for silver nanoparticles, to be maximum at pH 11. The absorption peak intensity also enhanced upon prolonging the reaction duration up to 60 min. The conversion of silver ions to metallic silver nanoparticles was found to be temperature-dependent and maximum transformation occurs at 60 degrees C. The reduction efficiency of hydroxypropyl carboxymethyl cellulose was found to be affected by its degree of polymerization. Colloidal solutions of silver nanoparticles having concentration up to 1000 ppm can be prepared upon fixing the ratio between silver nitrate and hydroxypropyl carboxymethyl cellulose at 0.017-0.3g per each 100ml of the reduction solution. PMID- 25697674 TI - Immunological properties of Andean starch films are independent of their nanometric roughness and stiffness. AB - Starch is a natural material extracted from roots, seeds, stems and tubers of different plants. It can be processed as a thermoplastic to produce a variety promising products for biomedical applications, including foams, sheets and films. In the present work, we investigated the immunological properties of microfilms prepared with starches extracted from six different types of Andean potatoes and their relationship with the different film-surface features. We confirmed the biocompatibility of all the films using THP-1 human monocytes, noticing only slight decrease in cell viability in two of the tested starches. We also analyzed pro-inflammatory cytokine release and immune cell surface receptor modulation on THP-1 plated onto the films. Our data show differences in the immunological profile of the same cells cultured onto the different starch films. Furthermore, we examined whether the dissimilar stiffness or the nanometric roughness of the films might influence the immune stimulation of the THP-1 monocytes. Our results demonstrate no correlation between cultured THP-1 immune activation and surface film characteristics. We conclude that different Andean native potato starch films have specific ability to interact with cell membranes of immune cells, conceivably due to the different spatial localization of amylose and amylopectin in the diverse starches. PMID- 25697675 TI - Polyhydroxyalkanoate from marine Bacillus megaterium using CSMCRI's Dry Sea Mix as a novel growth medium. AB - Oceans have significant potential to empower mankind and thus marine organisms are believed to be an enormous source for useful biomolecules. Polyhydroxyalkanoates (PHAs) are biological macromolecules that can be applied in nearly all fields. In the present study, Bacillus megaterium strain JK4h has been exploited for maximum PHB production using novel Dry Sea Mix (DSM) via Central Composite Design (CCD) of Response Surface Methodology (RSM) approach. The isolate was found to be producing 56.77% Cell Dry Weight (CDW) of PHAs within 24h, with optimized combinations of peptone, yeast extract and glucose. The PHB yield had been increased 2.61 fold compared to un-optimized experiments. The obtained PHA/PHB had been chemically characterized through Nuclear Magnetic Resonance (NMR), Fourier Transform Infrared Spectroscopy (FTIR), Thermo Gravimetric Analysis (TGA) and Differential Scanning Calorimetry (DSC). The results indicate the successful optimization for maximum production of biological macromolecule and it was found to be highly pure polyhydroxybutyrate (PHB). Thus, DSM can be served as a novel and cost effective medium for PHA production offering the use of marine resources as a "green" sustainable alternative. PMID- 25697676 TI - Serum metabolomics reveals that arsenic exposure disrupted lipid and amino acid metabolism in rats: a step forward in understanding chronic arsenic toxicity. AB - Chronic arsenic exposure through drinking water threatens public health worldwide. Although its multiorgan toxicity has been reported, the impact of chronic arsenic exposure on the metabolic network remains obscure. In this study, male Sprague Dawley rats were exposed to 0.5, 2 or 10 ppm sodium arsenite for three months. An ultra-high performance liquid chromatography/mass spectrometry based metabolomics approach was utilized to unveil the global metabolic response to chronic arsenic exposure in rats. Distinct serum metabolome profiles were found to be associated with the doses. Eighteen differential metabolites were identified, and most of them showed dose-dependent responses to arsenic exposure. Metabolic abnormalities mainly involved lipid metabolism and amino acid metabolism. The metabolic alterations were further confirmed by hepatic gene expression. Expressions of cpt2, lcat, cact, crot and mtr were significantly elevated in high dose groups. This study provides novel evidence to support the association between arsenic exposure and metabolic disruption, and it contributes to understanding the mechanism of chronic arsenic toxicity. PMID- 25697677 TI - Colistin, mechanisms and prevalence of resistance. AB - BACKGROUND: Infections caused by multi-drug-resistant Gram-negative bacteria, particularly Acinetobacter baumannii, Pseudomonas aeruginosa and Klebsiella pneumoniae, that cause nosocomial infections, represent a growing problem worldwide. The rapid increase in the prevalence of Gram-negative pathogens that are resistant to fluoroquinolones and aminoglycosides as well as all beta lactams, including carbapenems, monobactam, cephalosporins and broad-spectrum penicillins, has prompted the reconsideration of colistin as a valid therapeutic option. Colistin is an old class of cationic, which act by disrupting the bacterial membranes resulting in cellular death. Although there has been a significant recent increase in the data gathered on colistin, focusing on its chemistry, antibacterial activity, mechanism of action and resistance, pharmacokinetics, pharmacodynamics and new clinical application, the prevalence of colistin resistance has been very little reported in the literature. This review concentrates on recent literature aimed at optimizing the clinical use of this important antibiotic. METHODS: The available evidence from various studies (microbiological and clinical studies, retrieved from the PubMed, and Scopus databases) regarding the mechanisms and prevalence of resistance was evaluated. RESULTS: Increasing use of colistin for treatment of infections caused by these bacteria has led to the emergence of colistin resistance in several countries worldwide. Although resistance to polymyxins is generally less than 10%, it is higher in the Mediterranean and South-East Asia (Korea and Singapore), where colistin resistance rates are continually increasing. CONCLUSION: There is a critical need for effective infection prevention and control measures and strict use of antibiotics in the world to control the rise and spread of colistin resistance. PMID- 25697678 TI - Sublethal toxicity of chlorpyrifos to salmonid olfaction after hypersaline acclimation. AB - Salmonid habitats can be impacted by several environmental factors, such as salinization, which can also affect salmonid tolerance to anthropogenic stressors, such as pesticides. Previous studies have shown that hypersaline acclimation enhances the acute toxicity of certain organophosphate and carbamate pesticides to euryhaline fish; however, sublethal impacts have been far less studied. The current study aims to determine how hypersaline acclimation and exposure to the organophosphate chlorpyrifos (CPF) impact salmonid olfaction. Combined acclimation and exposure to CPF was shown to impact rainbow trout olfaction at the molecular, physiological, and behavioral levels. Concurrent exposure to hypersalinity and 0.5MUg/L CPF upregulated four genes (chloride intracellular channel 4, G protein zgc:101761, calcium calmodulin dependent protein kinase II delta, and adrenergic alpha 2C receptor) that inhibit olfactory signal transduction. At the physiological level, hypersalinity and chlorpyrifos caused a decrease in sensory response to the amino acid l-serine and the bile salt taurocholic acid. Combined acclimation and exposure also negatively impacted behavior and reduced the avoidance of a predator cue (l-serine). Thus, acclimation to hypersaline conditions and exposure to environmentally relevant concentrations of chlorpyrifos caused an inhibition of olfactory signal transduction leading to a decreased response to odorants and impairment of olfactory mediated behaviors. PMID- 25697679 TI - Evaluation of single and joint toxicity of perfluorooctane sulfonate, perfluorooctanoic acid, and copper to Carassius auratus using oxidative stress biomarkers. AB - Perfluorooctane sulfonate, perfluorooctanoic acid, and copper have been recently regarded as ubiquitous environmental contaminants in aquatic ecosystems worldwide. However, data on their possible combined toxic effects on aquatic organisms are still lacking. In this study, a systematic experimental approach was used to assess the impacts of these chemicals and their mixtures on hepatic antioxidant status of Carassius auratus after 4 days. Oxidative stress was apparently observed for joint exposure by determining biochemical parameters (superoxide dismutase, catalase, glutathione peroxidase, reduced glutathione, and malondialdehyde). The integrated biomarker response index was calculated to rank the toxicity order, from which the synergistic effect was tentatively proposed for joint-toxicity action. In addition, these treatments significantly altered trace element homeostasis in different fish tissues, and the concentration distribution of these test chemicals was also measured. Taken together, these results provided some valuable toxicological data on the joint effects of perfluorinated compounds and heavy metals on aquatic species, which can facilitate further understanding on the potential risks of other coexisting pollutants in the natural aquatic environment. PMID- 25697680 TI - Magnesium-based implants: a mini-review. AB - The goal of this review is to bring to the attention of the readership of Magnesium Research another facet of the importance of magnesium, i.e. magnesium based biomaterials. A concise history of biomaterials and magnesium are thus presented. In addition, historical and current, clinical magnesium-based applications are presented. PMID- 25697681 TI - Photoresponsive Host-Guest Functional Systems. PMID- 25697682 TI - Loss of dihydrolipoyl succinyltransferase (DLST) leads to reduced resting heart rate in the zebrafish. AB - The genetic underpinnings of heart rate regulation are only poorly understood. In search for genetic regulators of cardiac pacemaker activity, we isolated in a large-scale mutagenesis screen the embryonic lethal, recessive zebrafish mutant schneckentempo (ste). Homozygous ste mutants exhibit a severely reduced resting heart rate with normal atrio-ventricular conduction and contractile function. External electrical pacing reveals that defective excitation generation in cardiac pacemaker cells underlies bradycardia in ste (-/-) mutants. By positional cloning and gene knock-down analysis we find that loss of dihydrolipoyl succinyltransferase (DLST) function causes the ste phenotype. The mitochondrial enzyme DLST is an essential player in the citric acid cycle that warrants proper adenosine-tri-phosphate (ATP) production. Accordingly, ATP levels are significantly diminished in ste (-/-) mutant embryos, suggesting that limited energy supply accounts for reduced cardiac pacemaker activity in ste (-/-) mutants. We demonstrate here for the first time that the mitochondrial enzyme DLST plays an essential role in the modulation of the vertebrate heart rate by controlling ATP production in the heart. PMID- 25697683 TI - Supercharged green fluorescent proteins as bimodal reporter genes for CEST MRI and optical imaging. AB - Superpositively charged mutants of green fluorescent protein (GFP) demonstrated a dramatically improved chemical exchange saturation transfer (CEST) MRI contrast compared to their wild type counterparts. The mutants +36 GFP and +48 GFP were successfully expressed in mammalian cells and retained part of their fluorescence, making them a new potential bimodal reporter gene. PMID- 25697684 TI - Molecular mechanisms of peripartum cardiomyopathy: A vascular/hormonal hypothesis. AB - Peripartum cardiomyopathy (PPCM) is characterized by the development of systolic heart failure in the last month of pregnancy or within the first 5 months postpartum. The disease affects between 1:300 and 1:3000 births worldwide. Heart failure can resolve spontaneously but often does not. Mortality rates, like incidence, vary widely based on location, ranging from 0% to 25%. The consequences of PPCM are thus often devastating for an otherwise healthy young woman and her newborn. The cause of PPCM remains elusive. Numerous hypotheses have been proposed, with mixed supporting evidence. Recent work has suggested that PPCM is a vascular disease, triggered by the profound hormonal changes of late gestation. We focus here on these new mechanistic findings, and their potential implication for understanding and treating PPCM. PMID- 25697685 TI - Dengue virus envelope domain III protein based on a tetravalent antigen secreted from insect cells: Potential use for serological diagnosis. AB - In the present study, we developed a tetravalent protein by connecting the receptor-binding envelope domain III (EDIII) of the four dengue virus serotypes in the order of D1-D3-D4-D2. Using a baculovirus expression system, the protein was secreted into the supernatant of infected sf9 cells in a stable form with preserved native conformation. Using immobilized affinity chromatography, the recombinant EDIII (rEDIII) protein was purified with a yield of 300MUg per 10(6) cells. The purity and reactivity of the protein were determined via SDS-PAGE and Western blot respectively. A MAC-ELISA method based on the secreted rEDIII protein was subsequently established and evaluated using a panel of pre characterized dengue IgM-positive and -negative human sera. We obtained a specificity of 100% and sensitivity of 93% using this method. Our data collectively suggest that the secreted tetravalent rEDIII protein has potential utility in the diagnosis of dengue virus infections. PMID- 25697686 TI - Effect of synthesis solvent on the breathing behavior of MIL-53(Al). AB - This work reports the effect of using dimethylformamide (DMF) as the solvent for synthesizing MIL-53(Al). This well-known breathing MOF is typically prepared using hydrothermal methods. The two materials synthesized in DMF at 120 degrees C and 220 degrees C show significant deviations from the breathing behavior exhibited by the material synthesized hydrothermally. Powder X-ray diffraction confirmed that MIL-53(Al) synthesized in DMF at 120 degrees C remains in the large-pore form under all conditions, while the other material synthesized at 220 degrees C undergoes a more gradual breathing transition than is observed for MIL 53(Al) prepared by traditional methods. Solid-state NMR was employed to elucidate additional structural information and gain insight into the role synthesis solvent plays on breathing behavior. The CO2 and water adsorption of these large pore stabilized materials were studied, and the differences in adsorption behavior compared to MIL-53(Al) prepared by traditional methods was discussed. PMID- 25697687 TI - A one-step short-time synthesis of Ag@SiO2 core-shell nanoparticles. AB - A performance of shell-thickness precise control in silver-silica coating core shell nanoparticles is presented. 60nm sized citrate-stabilized silver nanoparticles are directly silica coated using a modified Stober process. Tetraethyl orthosilicate is used as a silica precursor and ammonium hydroxide as catalyst in an alcoholic solvent to promote the seeded silica growth. By simply varying the synthesis reaction time from 4 to 60min, the silica shell thickness is increased from 5.1nm to 76.4nm. This well-controlled synthesis is then transposed to 40, 80 and 100nm sized silver cores in order to show the independence of the silica shell growth on the nanoparticle core size. Optical properties, i.e. localized surface plasmon resonance, of the produced silver silica core-shell are also investigated. PMID- 25697688 TI - A nanoporous palladium-nickel alloy with high sensing performance towards hydrogen peroxide and glucose. AB - The nanoporous (NP) PdNi alloy is easily fabricated by one-step mild dealloying of PdNiAl precursor alloy in NaOH solution. Characterized by the nanoporous network architecture with the ligament size as small as 5nm, NP-PdNi alloy exhibits higher electrocatalytic activity towards the oxidation of H2O2 and glucose compared with NP-Pd and Pd/C catalysts. The electrochemical sensor constructed based on NP-PdNi alloy shows high sensing performance towards H2O2 and glucose with a wide linear range, long-term stability, and fast amperometric response. Moreover, NP-PdNi alloy exhibits high resistance towards Cl(-) poisoning as well as good anti-interference towards ascorbic acid, urci acid, and dopamine. This work provides a simple and green route to construct highly active and sensitive electrochemical sensor for detecting H2O2 and glucose. PMID- 25697689 TI - Characterizing Anharmonic Vibrational Modes of Quinones with Two-Dimensional Infrared Spectroscopy. AB - Two-dimensional infrared (2D IR) spectroscopy was used to study the vibrational modes of three quinones--benzoquinone, naphthoquinone, and anthraquinone. The vibrations of interest were in the spectral range of 1560-1710 cm(-1), corresponding to the in-plane carbonyl and ring stretching vibrations. Coupling between the vibrational modes is indicated by the cross peaks in the 2D IR spectra. The diagonal and off-diagonal anharmonicities range from 4.6 to 17.4 cm( 1) for the quinone series. In addition, there is significant vibrational coupling between the in-plane carbonyl and ring stretching vibrations. The diagonal anharmonicity, off-diagonal anharmonicity, and vibrational coupling constants are reported for benzoquinone, naphthoquinone, and anthraquinone. PMID- 25697690 TI - Chinese vaccine products go global: vaccine development and quality control. AB - Through the continuous efforts of several generations, China has become one of the few countries in the world that is capable of independently addressing all the requirements by the Expanded Program on Immunization. Regulatory science is applied to continuously improve the vaccine regulatory system. Passing the prequalification by WHO has allowed Chinese vaccine products to go global. Chinese vaccine products not only secure disease prevention and control domestically but also serve the needs for international public health. This article describes the history of Chinese vaccine development, the current situation of Chinese vaccine industry and its contribution to the prevention and control of infectious diseases. We also share our experience of national quality control and vaccine regulation during the past decades. China's experience in vaccine development and quality control can benefit other countries and regions worldwide, including the developing countries. PMID- 25697691 TI - Identification of the function of extracellular polymeric substances (EPS) in denitrifying phosphorus removal sludge in the presence of copper ion. AB - Industrial wastewater containing heavy metals that enters municipal wastewater treatment plants inevitably has a toxic impact on biological treatment processes. In this study, the impact of Cu(II) (0, 1.5, 2, 2.5, 3 mg/L) on the performance of denitrifying phosphorus removal (DPR) and microbial community structures was investigated. Particularly, the dynamic change in the amount and composition of extracellular polymeric substances (EPS), and the role of EPS in P removal, were assessed using three-dimensional excitation-emission matrix fluorescence spectroscopy combined with parallel factor (PARAFAC) analysis. The results showed that, after long-term adjustment, the P removal efficiency was maintained at 95 +/- 2.7% at Cu(II) addition up to 2.5 mg/L, but deteriorated when the Cu(II) addition was 3 mg/L. The EPS content, including proteins and humic substances, increased with increasing Cu(II) additions at concentrations <=2.5 mg/L. This property of EPS was beneficial for protecting phosphate-accumulating organisms (PAOs) against heavy metals, as both proteins and humic substances are strong ligands for Cu(II). Therefore, the PAOs abundance was still relatively high (67 +/- 3%) when Cu(II) accumulation in sludge was up to 10 mg/g SS. PARAFAC confirmed that aromatic proteins could be transformed into soluble microbial byproduct-like material when microorganisms were subjected to Cu(II) stress, owing to their strong metal ion complexing capacity. The increase in the percentage of humic-like substances enhanced the detoxification function of the sludge EPS. EPS accounted for approximately 26-47% of P removed by adsorption when Cu(II) additions were between 0 and 2.5 mg/L. The EPS function, including binding toxic heavy metals and P storage, enhanced the operating stability of DPR systems. This study provides us with a better understanding of (1) the tolerance of DPR sludge to copper toxicity and (2) the function of sludge EPS in the presence of heavy metals in biological P removal systems. PMID- 25697692 TI - UV-activated persulfate oxidation and regeneration of NOM-Saturated granular activated carbon. AB - A new method of ultraviolet light (UV) activated persulfate (PS) oxidation was investigated to regenerate granular activated carbon (GAC) in drinking water applications. The improvements in iodine and methylene blue numbers measured in the GAC after ultraviolet- (UV) activated persulfate suggested that the GAC preloaded with natural organic matter (NOM) was chemically regenerated. An experimental matrix for UV-activated persulfate regeneration included a range of persulfate doses and different UV wavelengths. Over 87% of the initial iodine number for GAC was restored under the optimum conditions, perfulfate dosage 60 g/L and UV exposure 1.75 * 10(4) mJ/cm(2). The persulfate dosages had little effect on the recovery of the methylene blue number, which was approximately 65%. Persulfate activation at 185 nm was superior to activation at 254 nm. UV activation of persulfate in the presence of GAC produced acid, lowering the solution pH. Higher persulfate concentrations and UV exposure resulted in greater GAC regeneration. Typical organic and inorganic byproducts (e.g., benzene compounds and sulfate ions) were measured as a component of treated water quality safety. This study provides a proof-of-concept that can be used to optimize pilot scale and full-scale UV-activated persulfate for regeneration of NOM-saturated GAC. PMID- 25697693 TI - Effect of polyhydroxyalkanoates on dark fermentative hydrogen production from waste activated sludge. AB - Polyhydroxyalkanoates (PHA), an intracellular energy and carbon storage polymer, can be accumulated in activated sludge in substantial quantities under wastewater dynamic treatment (i.e., substrate feast-famine) conditions. However, its influence on hydrogen production has never been investigated before. This study therefore evaluated the influences of PHA level and composition in waste activated sludge (WAS) on hydrogen production. The results showed that with the increase of sludge PHA content from 25 to 178 mg per gram volatile suspended solids (VSS) hydrogen production from WAS alkaline anaerobic fermentation increased from 26.5 to 58.7 mL/g VSS. The composition of PHA was also found to affect hydrogen production. When the dominant composition shifted from polyhydroxybutyrate (PHB) to polyhydroxyvalerate (PHV), the amount of generated hydrogen decreased from 51.2 to 41.1 mL/g VSS even under the same PHA level (around 130 mg/g VSS). The mechanism studies exhibited that the increased PHA content accelerated both the cell solubilization and the hydrolysis process of solubilized substrates. Compared with the PHB-dominant sludge, the increased PHV fraction not only slowed the hydrolysis process but also caused more propionic acid production, with less theoretical hydrogen generation in this fermentation type. It was also found that the increased PHA content enhanced the soluble protein conversion of non-PHA biomass. Further investigations with enzyme analyses showed that both the key hydrolytic enzyme activities and hydrogen forming enzyme activities were in the sequence of the PHB-dominant sludge > the PHV-dominant sludge > the low PHA sludge, which was in accord with the observed order of hydrogen yield. PMID- 25697694 TI - Modelling simultaneous anaerobic methane and ammonium removal in a granular sludge reactor. AB - Anaerobic nitrogen removal technologies offer advantages in terms of energy and cost savings over conventional nitrification-denitrification systems. A mathematical model was constructed to evaluate the influence of process operation on the coexistence of nitrite dependent anaerobic methane oxidizing bacteria (n damo) and anaerobic ammonium oxidizing bacteria (anammox) in a single granule. The nitrite and methane affinity constants of n-damo bacteria were measured experimentally. The biomass yield of n-damo bacteria was derived from experimental data and a thermodynamic state analysis. Through simulations, it was found that the possible survival of n-damo besides anammox bacteria was sensitive to the nitrite/ammonium influent ratio. If ammonium was supplied in excess, n damo bacteria were outcompeted. At low biomass concentration, n-damo bacteria lost the competition against anammox bacteria. When the biomass loading closely matched the biomass concentration needed for full nutrient removal, strong substrate competition occurred resulting in oscillating removal rates. The simulation results further reveal that smaller granules enabled higher simultaneous ammonium and methane removal efficiencies. The implementation of simultaneous anaerobic methane and ammonium removal will decrease greenhouse gas emissions, but an economic analysis showed that adding anaerobic methane removal to a partial nitritation/anammox process may increase the aeration costs with over 20%. Finally, some considerations were given regarding the practical implementation of the process. PMID- 25697695 TI - Alkyl polyglucose enhancing propionic acid enriched short-chain fatty acids production during anaerobic treatment of waste activated sludge and mechanisms. AB - Adding alkyl polyglucose (APG) into an anaerobic treatment system of waste activated sludge (WAS) was reported to remarkably improve the production of short chain fatty acids (SCFAs), especially propionic acid via simultaneously accelerating solubilization and hydrolysis, enhancing acidification, inhibiting methanogenesis and balancing carbon to nitrogen (C/N) ratio of substrate. Not only the production of SCFAs, especially propionic acid, was significantly improved by APG, but also the feasible operation time was shortened. The SCFAs yield at 0.3 g APG per gram of total suspended solids (TSS) within 4 d was 2988 +/- 60 mg chemical oxygen demand (COD) per liter, much higher than that those from sole WAS or sole WAS plus sole APG. The corresponding yield of propionic acid was 1312 +/- 25 mg COD/L, 7.9-fold of sole WAS. Mechanism investigation showed that during anaerobic treatment of WAS in the presence of APG both the solubilization and hydrolysis were accelerated and the acidification was enhanced, while the methanogenesis was inhibited. Moreover, the activities of key enzymes involved in WAS hydrolysis and acidification were improved through the adjustment of C/N ratio of substrates with APG. The abundance of microorganisms responsible for organic compounds hydrolysis and SCFAs production was also observed to be greatly enhanced with APG via 454 high-throughput pyrosequencing analysis. PMID- 25697696 TI - Effect of dissolved oxygen concentration on iron efficiency: Removal of three chloroacetic acids. AB - The monochloroacetic, dichloroacetic and trichloroacetic acid (MCAA, DCAA and TCAA) removed by metallic iron under controlled dissolved oxygen conditions (0, 0.75, 1.52, 2.59, 3.47 or 7.09 mg/L DO) was investigated in well-mixed batch systems. The removal of CAAs increased first and then decreased with increasing DO concentration. Compared with anoxic condition, the reduction of MCAA and DCAA was substantially enhanced in the presence of O2, while TCAA reduction was significantly inhibited above 2.59 mg/L. The 1.52 mg/L DO was optimum for the formation of final product, acetic acid. Chlorine mass balances were 69-102%, and carbon mass balances were 92-105%. With sufficient mass transfer from bulk to the particle surface, the degradation of CAAs was limited by their reduction or migration rate within iron particles, which were dependent on the change of reducing agents and corrosion coatings. Under anoxic conditions, the reduction of CAAs was mainly inhibited by the available reducing agents in the conductive layer. Under low oxic conditions, the increasing reducing agents and thin lepidocrocite layer were favorable for CAA dechlorination. Under high oxic conditions, the redundant oxygen competing for reducing agents and significant lepidocrocite growth became the major restricting factors. Various CAA removal mechanisms could be potentially applied to explaining the effect of DO concentration on iron efficiency for contaminant reduction in water and wastewater treatment. PMID- 25697697 TI - The effect of basic pH and carbonate ion on the mechanism of photocatalytic destruction of cylindrospermopsin. AB - This study investigated the mechanistic effects of basic pH and the presence of high carbonate concentration on the TiO2 photocatalytic degradation of the cyanobacterial toxin cylindrospermopsin (CYN). High-performance liquid chromatography combined with quadrupole time-of-flight electrospray ionization tandem mass spectrometry (LC/Q-TOF-ESI-MS) was employed for the identification of reaction byproducts. The reaction pathways were proposed based on the identified degradation byproducts and radical chemistry. In high pH system (pH = 10.5) similar reaction byproducts as those in neutral pH system were identified. However, high pH appeared to inhibit sulfate elimination with less sulfate elimination byproducts detected. In the presence of carbonate in the photocatalytic process, hydroxyl radical reaction would be largely inhibited since carbonate ion would react with hydroxyl radical to form carbonate radical. The second order rate constant of carbonate radical with CYN was estimated to be 1.4 * 10(8) M(-1)s(-1), which is much smaller than that of hydroxyl radical. However, the more significant abundance of carbonate radical in the reaction solution strongly contributed to the transformation of CYN. Carbonate radical has higher reaction selectivity than hydroxyl radical and hence, played a different role in the photocatalytic reaction. It would promote the formation of byproduct m/z 420.12 which has not been identified in the other two studied photocatalytic systems. Besides, the presence of carbonate ion may hinder the removal of toxicity originated from uracil moiety due to the low reaction activity of carbonate radical with uracil moiety in CYN molecule. This work would further support the application of photocatalytic technologies for CYN treatment and provide fundamental information for the complete assessment of CYN removal by using TiO2 photocatalysis process. PMID- 25697698 TI - An Eighteen-Month Helicobacter Infection Does Not Induce Amyloid Plaques or Neuroinflammation in Brains of Wild Type C57BL/6J Mice. AB - There is increasing evidence to support the role of infectious agents in the progression of Alzheimer's disease (AD), especially Helicobacter pylori (H. pylori). The impact of Helicobacter infection on the brain of non-AD predisposed mice was studied. For that, C57BL/6J mice were infected by oral gavage with H. pylori SS1 (n = 6) and Helicobacter felis (H. felis) (n=6) or not infected (n = 6) for evaluation of neuroinflammation (anti-GFAP and anti-iba1 immunohistochemistry) and amyloid-beta deposition (thioflavin-S stain and anti Abeta immunohistochemistry). After 18-month of infection, H. pylori SS1 and H. felis infection induced a strong gastric inflammation compared to non-infected mice, but did not induce brain neuroinflammation or amyloid-beta deposition. PMID- 25697699 TI - Mortality in mild cognitive impairment varies by subtype, sex, and lifestyle factors: the Mayo Clinic Study of Aging. AB - BACKGROUND: Etiologic differences in mild cognitive impairment (MCI) subtypes may impact mortality. OBJECTIVE: To assess the rate of death in MCI overall, and by subtype, in the population-based Mayo Clinic Study of Aging. METHODS: Participants aged 70-89 years at enrollment were clinically evaluated at baseline and 15-month intervals to assess diagnoses of MCI and dementia. Mortality in MCI cases versus cognitively normal (CN) individuals was estimated using Cox proportional hazards models. RESULTS: Over a median follow-up of 5.8 years, 331 of 862 (38.4%) MCI cases and 224 of 1,292 (17.3%) cognitively normal participants died. Compared to CN individuals, mortality was elevated in persons with MCI (hazard ratio [HR] = 1.79; 95% CI: 1.41 to 2.27), and was higher for non-amnestic MCI (naMCI; HR = 2.40; 95% CI: 1.72 to 3.36) than for amnestic MCI (aMCI; HR = 1.61; 95% CI: 1.25 to 2.09) after adjusting for confounders. Mortality varied significantly by sex, education, history of heart disease, and engaging in moderate physical exercise (p for interaction <0.05 for all). Mortality rate estimates were highest in MCI cases who were men, did not exercise, had heart disease, and had higher education versus CN without these factors, and for naMCI cases versus aMCI cases without these factors. CONCLUSIONS: These findings suggest stronger impact of etiologic factors on naMCI mortality. Prevention of heart disease, exercise vigilance, may reduce MCI mortality and delayed MCI diagnosis in persons with higher education impacts mortality. PMID- 25697701 TI - Gene Dosage Dependent Aggravation of the Neurological Phenotype in the 5XFAD Mouse Model of Alzheimer's Disease. AB - In the present report, we extend previous findings in the 5XFAD mouse model with regard to a characterization of behavioral deficits and neuropathological alterations. We demonstrate that these mice develop a robust age-dependent motor phenotype and spatial reference memory deficits when bred to homozygosity, leading to a strongly reduced age of onset of behavioral symptoms. At postnatal day sixteen, abundant AbetaPP was detected in subiculum and cortical pyramidal neurons. From six weeks on, intraneuronal Abeta could be detected which was much more abundant in homozygous mice. The same gene-dosage effect was seen on memory and motor deficits. While at 2 months of age neither heterozygous nor homozygous 5XFAD mice show any neurological phenotype except for alterations in anxiety behavior, at 5 months they were clearly evident. Interestingly, despite abundant motor deficiencies, homozygous 5XFAD mice were able to perform the acquisition training of the Morris water maze task with no difference in the swimming performance between the groups. Therefore the aggravated spatial memory and spatial reference memory deficits of the homozygous mice correlated with the elevated soluble and insoluble Abeta levels. Homozygous 5XFAD mice represent a model with several advantages in comparison to the heterozygous mice, developing amyloid pathology much more rapidly together with a neurological phenotype. These advantages allow reducing the number of animals for Alzheimer's disease research. PMID- 25697700 TI - Depressive Symptoms and Biomarkers of Alzheimer's Disease in Cognitively Normal Older Adults. AB - Even low levels of depressive symptoms are associated with an increased risk of cognitive decline in older adults without overt cognitive impairment (CN). Our objective was to examine whether very low, "subthreshold symptoms of depression" are associated with Alzheimer's disease (AD) biomarkers of neurodegeneration in CN adults and whether these associations are specific to particular depressive symptoms. We analyzed data from 248 community-dwelling CN older adults, including measurements of cortical amyloid burden, neurodegeneration markers of hippocampal volume (HV) and cerebral 18F-fluorodeoxyglucose (FDG) metabolism in a composite of AD-related regions and the 30-item Geriatric Depression Scale (GDS). Participants with GDS >10 were excluded. General linear regression models evaluated the cross-sectional relations of GDS to HV or FDG in separate backward elimination models. Predictors included GDS total score, age, gender, premorbid intelligence, a binary amyloid variable and its interaction with GDS. Principal component analyses of GDS item scores revealed three factors (the Dysphoria, Apathy-Anhedonia, and Anxiety-Concentration Factors). In secondary analyses, GDS total score was replaced with the three factor scores in repeated models. Higher GDS score (p = 0.03) was significantly associated with lower HV and was marginally related (p = 0.06) to FDG hypometabolism. In secondary models, higher Dysphoria (p = 0.02) and Apathy-Anhedonia (p = 0.05) were related to lower HV while higher Apathy-Anhedonia (p = 0.003) was the sole factor related to FDG hypometabolism. Amyloid was not a significant predictor in any model. In conclusion, very low-level dysphoria, apathy and anhedonia may point to neurodegeneration in AD-related regions but this association appears to be independent of amyloid burden. PMID- 25697702 TI - A Bird's-Eye View of Alzheimer's Disease Research: Reflecting Different Perspectives of Indexers, Authors, or Citers in Mapping the Field. AB - During the last 30 years, Alzheimer's disease (AD) research, aiming to understand the pathophysiology and to improve the diagnosis, management, and, ultimately, treatment of the disease, has grown rapidly. Recently, some studies have used simple bibliometric approaches to investigate research trends and advances in the field. In our study, we map the AD research field by applying entitymetrics, an extended concept of bibliometrics, to capture viewpoints of indexers, authors, or citers. Using the full-text documents with reference section retrieved from PubMed Central, we constructed four types of networks: MeSH-MeSH (MM), MeSH Citation-MeSH (MCM), Keyphrase-Keyphrase (KK), and Keyphrase-Citation-Keyphrase (KCK) networks. The working hypothesis was that MeSH, keyphrase, and citation relationships reflect the views of indexers, authors, and/or citers, respectively. In comparative network and centrality analysis, we found that those views are different: indexers emphasize amyloid-related entities, including methodological terms, while authors focus on specific biomedical terms, including clinical syndromes. The more dense and complex networks of citing relationships reported in our study, to a certain extent reflect the impact of basic science discoveries in AD. However, none of these could have had clinical relevance for patients without close collaboration between investigators in translational and clinical-related AD research (reflected in indexers and authors' networks). Our approach has relevance for researches in the field, since they can identify relations between different developments which are not otherwise evident. These developments combined with advanced visualization techniques, might aid the discovery of novel interactions between genes and pathways or used as a resource to advance clinical drug development. PMID- 25697703 TI - Hippocampal disconnection in early Alzheimer's disease: a 7 tesla MRI study. AB - BACKGROUND: In patients with Alzheimer's disease (AD), atrophy of the entorhinal cortex (ERC) and hippocampal formation may induce degeneration of connecting white matter tracts. OBJECTIVE: We examined the association of hippocampal subfield and ERC atrophy at 7 tesla MRI with fornix and parahippocampal cingulum (PHC) microstructure in patients with early AD. METHODS: Twenty-five patients with amnestic mild cognitive impairment (aMCI) (n = 15) or early AD (n = 10) and 17 controls underwent 3 tesla diffusion MRI to obtain fractional anisotropy (FA) of the fornix and PHC and 7 tesla MRI to obtain ERC and hippocampal subfield volumes. Linear regression analyses were performed, adjusted for age, gender, and intracranial volume. RESULTS: Fornix FA was significantly lower and subiculum, cornu ammonis (CA) 1, and dentate gyrus &CA4 volume were significantly smaller in patients with MCI or AD as compared to controls. In patients with MCI or AD, fornix FA was positively associated with subiculum volume (beta = 0.53, 95% CI 0.10; 0.96), but not with ERC/other subfield volumes. PHC FA was not associated with ERC/subfield volumes. CONCLUSION: These findings indicate that in early AD subiculum atrophy is associated with lower FA of the fornix, which primarily consists of axons originating in the subiculum. This suggests that degeneration of subicular cell bodies and their axons are related processes in early AD. PMID- 25697704 TI - Axonal Terminals Exposed to Amyloid-beta May Not Lead to Pre-Synaptic Axonal Damage. AB - BACKGROUND: Synaptic deficits and neuronal loss are the major pathological manifestations of Alzheimer's disease. However, the link between the early synaptic loss and subsequent neurodegeneration is not entirely clear. Cell culture studies have shown that amyloid-beta (Abeta) applied to axonal terminals can cause retrograde degeneration leading to the neuronal loss, but this process has not been demonstrated in live animals. OBJECTIVE: To test if Abeta applied to retinal ganglion cell axonal terminals can induce axonal damage in the optic nerve and optic tract in mice. METHODS: Abeta was injected into the terminal field of the optic tract, in the left lateral geniculate nucleus of wildtype C57BL/6 mice. Following the injection, monthly diffusion tensor imaging was performed. Three months after the injection, mice underwent visual evoked potential recordings, and then sacrificed for immunohistochemical examination. RESULTS: There were no significant changes seen with diffusion tensor imaging in the optic nerve and optic tract 3 months after the Abeta injection. The myelin and axons in these regions remained intact according to immunohistochemistry. The only significant changes observed in this study were delayed transduction and reduced amplitude of visual evoked potentials, although both Abeta and its reversed form caused similar changes. CONCLUSION: Despite the published in vitro studies, there was no significant axonal damage in the optic nerve and optic tract after injecting Abeta onto retinal ganglion cell axonal terminals of wildtype C57BL/6 mice. PMID- 25697705 TI - Impact of CRFR1 Ablation on Amyloid-beta Production and Accumulation in a Mouse Model of Alzheimer's Disease. AB - Stress exposure and the corticotropin-releasing factor (CRF) system have been implicated as mechanistically involved in both Alzheimer's disease (AD) and associated rodent models. In particular, the major stress receptor, CRF receptor type 1 (CRFR1), modulates cellular activity in many AD-relevant brain areas, and has been demonstrated to impact both tau phosphorylation and amyloid-beta (Abeta) pathways. The overarching goal of our laboratory is to develop and characterize agents that impact the CRF signaling system as disease-modifying treatments for AD. In the present study, we developed a novel transgenic mouse to determine whether partial or complete ablation of CRFR1 was feasible in an AD transgenic model and whether this type of treatment could impact Abeta pathology. Double transgenic AD mice (PSAPP) were crossed to mice null for CRFR1; resultant CRFR1 heterozygous (PSAPP-R1(+/-)) and homozygous (PSAPP-R1(-/-)) female offspring were used at 12 months of age to examine the impact of CRFR1 disruption on the severity of AD Abeta levels and pathology. We found that both PSAPP-R1(+/-) and PSAPP-R1(-/-) had significantly reduced Abeta burden in the hippocampus, insular, rhinal, and retrosplenial cortices. Accordingly, we observed dramatic reductions in Abeta peptides and AbetaPP-CTFs, providing support for a direct relationship between CRFR1 and Abeta production pathways. In summary, our results suggest that interference of CRFR1 in an AD model is tolerable and is efficacious in impacting Abeta neuropathology. PMID- 25697706 TI - Zinc in Alzheimer's Disease: A Meta-Analysis of Serum, Plasma, and Cerebrospinal Fluid Studies. AB - To evaluate whether zinc levels in serum, plasma, and cerebrospinal fluid are altered in Alzheimer's disease (AD), we performed meta-analyses of 27 studies on the topic published from 1983 to 2014. The subjects' sample obtained by merging studies was a pooled total of 777 AD subjects and 1,728 controls for serum zinc studies, 287 AD subjects and 166 controls for plasma zinc, and of 292 AD subjects and 179 controls for CSF zinc. The main result of this meta-analysis is the very high heterogeneity among the studies either in demographic terms or in methodological approaches. Although we considered these effects in our analyses, the heterogeneity persisted and it has to be taken into account in the interpretation of the results. Our meta-analysis indicated that serum zinc appears significantly decreased in AD patients compared with healthy controls, and this result is confirmed when serum and plasma studies were analyzed together. If we considered the age-matched studies, the meta-analysis carried out on only six studies showed no significant difference in zinc levels between AD and healthy controls (SMD =-0.55, 95% CI (-1.18; 0.09); p = 0.094; I2 = 91%). In the light of these findings, we speculated about the possibility that the decreases observed could indicate a possible dietary zinc deficiency and we suggested that the possible involvement of zinc alterations in AD may have an interplay with copper metabolism. PMID- 25697707 TI - Neuropsychological profiles and verbal abilities in lifelong bilinguals with mild cognitive impairment and Alzheimer's disease. AB - Bilingualism is associated with enhanced executive functioning and delayed onset of mild cognitive impairment (MCI) and Alzheimer's disease (AD). Here, we investigated neuropsychological differences between mono- and bilingual patients with MCI and AD as well as the respective effects of dementia on the dominant and non-dominant language of bilinguals. 69 patients with MCI (n = 22) or AD (n = 47) and 17 healthy controls were included. 41 subjects were classified as lifelong bilinguals (mean age: 73.6; SD = 11.5) and 45 as monolinguals (mean age: 78.1; SD = 10.9). Neuropsychological performance was assessed on the CERAD-NP, the clock drawing test, and the logical memory subscale of the Wechsler Memory Scale. Neuropsychological profiles showed only minor nonsignificant differences between mono- and bilingual subjects when compared between diagnostic groups. Bilingual MCI patients scored significantly lower on the verbal fluency and picture naming task in their dominant language than bilingual controls. Bilingual AD patients showed a reduced performance in their nondominant language when compared to bilingual MCI patients and bilingual controls (main effect language dominance: verbal fluency task p < 0.001; BNT p < 0.001). Bilingual MCI and AD patients show a similar pattern of neuropsychological deficits as monolingual patients do. The dominant language appears to be compromised first in bilingual MCI patients, while severe deficits of the nondominant language develop later in the course with manifestation of AD. These findings are important for the diagnostic work up of bilingual patients and the development of improved care concepts for bilingual patients such as migrant populations. PMID- 25697708 TI - Drosophila models of Alzheimer's disease: advances, limits, and perspectives. AB - Amyloid-beta protein precursor (AbetaPP) and the microtubule-associated protein tau (MAPT) are the two key players involved in Alzheimer's disease (AD) and are associated with amyloid plaques and neurofibrillary tangles respectively, two key hallmarks of the disease. Besides vertebrate models, Drosophila models have been widely used to understand the complex events leading to AD in relation to aging. Drosophila benefits from the low redundancy of the genome which greatly simplifies the analysis of single gene disruption, sophisticated molecular genetic tools, and reduced cost compared to mammals. The aim of this review is to describe the recent advances in modeling AD using fly and to emphasize some limits of these models. Genetic studies in Drosophila have revealed some key aspects of the normal function of Appl and Tau, the fly homologues of AbetaPP and MAPT that may be disrupted during AD. Drosophila models have also been useful to uncover or validate several pathological pathways or susceptibility genes, and have been readily implemented in drug screening pipelines. We discuss some limitations of the current models that may arise from differences in structure of Appl and Tau compared to their human counterparts or from missing AbetaPP or MAPT protein interactors in flies. The advent of new genome modification technologies should allow the development of more realistic fly models and to better understand the relationship between AD and aging, taking advantage of the fly's short lifespan. PMID- 25697709 TI - Detection of novel Chlamydiae and Legionellales from human nasal samples of healthy volunteers. AB - Chlamydiae are intracellular bacterial parasites of eukaryotes, ranging from amoebae to humans. They comprise many novel members and are investigated as emerging pathogens. Environmental studies highlighted similarities between the ecologies of chlamydiae and legionellae, both groups being important agents of respiratory infections. Herein, we analyzed nasal samples from healthy persons, searching for the presence of amoebae, chlamydiae and legionellae. From a total of 25 samples, we recovered by PCR eight samples positive to chlamydiae and six samples positive to legionellae. Among these samples, four were positive to both organisms. The sequencing of 16S rDNAs allowed to identify (i) among Chlamydiae: Parachlamydia acanthamoebae, Chlamydophila psittaci, Chlamydophila felis, and members of Rhabdochlamydiaceae, Simkaniaceae and E6 lineage and (ii) among Legionellaceae: Legionella longbeachae, Legionella bozemanii and Legionella impletisoli. Unexpectedly, we also recovered Diplorickettsia sp. Amoebae collected from nasal mucosae, Acanthamoeba and Vermamoeba, were endosymbiont free, and chlamydiae revealed refractory to amoeba coculture. This study shows common exposure to chlamydiae and legionellae and suggests open air activities like gardening as a probable additional source of infection. PMID- 25697710 TI - Multifocal retinopathy in Dachshunds with CLN2 neuronal ceroid lipofuscinosis. AB - The CLN2 form of neuronal ceroid lipofuscinosis is an autosomal recessively inherited lysosomal storage disease that is characterized by progressive vision loss culminating in blindness, cognitive and motor decline, neurodegeneration, and premature death. CLN2 disease results from mutations in the gene that encodes the soluble lysosomal enzyme tripeptidyl peptidase-1. A null mutation in the TPP1 gene encoding this enzyme causes a CLN2-like disease in Dachshunds. Dachshunds that are homozygous for this mutation serve as a model for human CLN2 disease, exhibiting clinical signs and neuropathology similar to those of children with this disorder. Affected dogs reach end-stage terminal disease status at 10-11 months of age. In addition to retinal changes typical of CLN2 disease, a retinopathy consisting of multifocal, bullous retinal detachment lesions was identified in 65% of (TPP1-/-) dogs in an established research colony. These lesions did not occur in littermates that were heterozygous or homozygous for the normal TPP1 allele. Retinal changes and the functional effects of this multifocal retinopathy were examined objectively over time using ophthalmic examinations, fundus photography, electroretinography (ERG), quantitative pupillary light response (PLR) recording, fluorescein angiography, optical coherence tomography (OCT) and histopathology. The retinopathy consisted of progressive multifocal serous retinal detachments. The severity of the disease-related retinal thinning was no more serious in most detached areas than in adjacent areas of the retina that remained in close apposition to the retinal pigment epithelium. The retinopathy observed in these dogs was somewhat similar to canine multifocal retinopathy (CMR), a disease caused by a mutation of the bestrophin gene BEST1. ERG a-wave amplitudes were relatively preserved in the Dachshunds with CLN2 disease, whether or not they developed the multifocal retinopathy. The retinopathy also had minimal effects on the PLR. Histological evaluation indicated that the CLN2 disease-related retinal degeneration was not exacerbated in areas where the retina was detached except where the detached areas were very large. DNA sequence analysis ruled out a mutation in the BEST1 exons or splice junctions as a cause for the retinopathy. Perfect concordance between the TPP1 mutation and the retinopathy in the large number of dogs examined indicates that the retinopathy most likely occurs as a direct result of the TPP1 mutation. Therefore, inhibition of the development and progression of these lesions can be used as an indicator of the efficacy of therapeutic interventions currently under investigation for the treatment of CLN2 disease in the Dachshund model. In addition, these findings suggest that TPP1 mutations may underlie multifocal retinopathies of unknown cause in animals and humans. PMID- 25697711 TI - Diagnosis and treatment of restless legs syndrome in progressive supranuclear palsy. AB - Restless legs syndrome (RLS) has only been recently investigated in a small cohort of progressive supranuclear palsy (PSP) patients and it has been reported to have variable prevalence (among 3.7-58%). However little is known about its management. Here, we report a case of severe RLS occurring during the course of PSP. Diagnostic issues and therapeutic approaches are discussed. PMID- 25697713 TI - Combat-related PTSD in military court: a diagnosis in search of a defense. AB - As more veterans return from Iraq and Afghanistan, Posttraumatic Stress Disorder (PTSD) often returns with them. As a result, PTSD has quickly become the most prevalent mental disorder diagnosis among active duty United States (U.S.) military. Although numerous studies have not only validated PTSD but have chronicled its negative behavioral impact, it remains a controversial diagnosis. It is widely diagnosed by all types of mental health professionals for even minimal trauma, and DSM-IV PTSD criteria have wide overlap with other mood and anxiety disorders. This, however, has not stopped PTSD from being used in civilian courts in the U.S. as a mental disorder to establish grounds for mental status defenses, such as insanity, diminished capacity, and self-defense, or as a basis for sentencing mitigation. Not surprisingly, PTSD has recently found its way into military courts, where some defense attorneys are eager to draw upon its understandable and linear etiology to craft some type of mental incapacity defense for their clients. As in the civilian sphere, this has met with mixed success due to relevance considerations. A recent court-martial, U.S. v. Lawrence Hutchins III, has effectively combined all the elemental nuances of PTSD in military court. PMID- 25697714 TI - Meta-analysis supports the diagnostic value of GP73 in primary liver cancer. PMID- 25697715 TI - Mycobacterium smegmatis MSMEG_3705 encodes a selective major facilitator superfamily efflux pump with multiple roles. AB - Mycobacterium smegmatis mc(2)155 MSMEG_3705 gene was annotated to encode a transporter protein that contains 12 alpha-helical transmembrane domains. We predicted MSMEG_3705 encoding a major facilitator superfamily (MFS) member. To confirm the prediction, the M. smegmatis mc(2)155 MSMEG_3705 gene was deleted. The MSMEG_3705 deletion mutant strain M. smegmatis mc(2)155 ?MSMEG_3705 was more sensitive to capreomycin. Moreover, M. smegmatis mc(2)155 ?MSMEG_3705 strain accumulated more ethidium bromide intracellular than wild-type M. smegmatis mc(2)155. Quite unexpectedly, M. smegmatis mc(2)155 ?MSMEG_3705 grew faster than the wild-type M. smegmatis mc(2)155. The upregulation of the expression of MSMEG_3706, a gene encoding isocitrate lyase downstream MSMEG_3705, in the deletion mutant, might underlie such faster growth in the mutant. The study showed that MSMEG_3705 encodes a genuine MFS member and plays significant role in bacterial growth and antibiotics resistance. PMID- 25697716 TI - Multivisceral resections for gastrointestinal stromal tumors: are the risks justifiable? AB - BACKGROUND: Surgical resection is the cornerstone of treatment for non-metastatic gastrointestinal stromal tumors (GISTs). Multivisceral resection (MVR) for locally advanced tumors is often required to achieve negative margins. The purpose of this study was to review the peri-operative and long-term oncologic outcomes for patients who required MVR versus single-organ resection (SOR) for GISTs. METHODS: All patients who underwent treatment for GISTs at a tertiary cancer center between 2001 and 2011 were identified. Patient characteristics and clinical outcomes were compared using the chi-squared/Fisher's exact test and Student's t-test. Disease-free (DFS) and overall survival (OS) were analyzed using the Kaplan-Meier product-limit method. RESULTS: 33 patients underwent MVR and 77 underwent SOR. Tumors in the MVR group were larger and had a higher mitotic index. MVR patients had longer operative times, greater operative blood loss and more peri-operative complications. There was no significant difference in the final margin status between the two groups (R0 resection: SOR 92.2%, MVR 81.8%, p = 0.1303). 5-year DFS was significantly lower in the MVR cohort (44.4% vs. 78.9%, p = 0.0090), but there was no difference in 5-year OS (80.2% vs. 90.5%, p = 0.2547). CONCLUSIONS: MVR patients had more aggressive tumors and more complications; however, there was no difference in 5-year OS between the MVR and SOR cohorts. These findings support the use of MVR in the appropriately selected patient. Further studies are necessary to fully define its clinical application. PMID- 25697717 TI - Subcutaneous Injection Depth Does Not Affect the Pharmacokinetics or Glucodynamics of Insulin Lispro in Normal Weight or Healthy Obese Subjects. AB - BACKGROUND: An 8-mm needle length is commonly used for insulin injections; however, recent recommendations suggest shorter needles may help patients avoid intramuscular injections and reduce pain, while maintaining adequate glucose control. The goal of these analyses was to compare the pharmacokinetics (PK) and glucodynamics (GD) of insulin lispro after a 5-mm or an 8-mm injection depth administration in 2 populations: normal weight (study 1) or obese (study 2). METHODS: In both open-label, randomized, 2-period crossover euglycemic clamp studies, subjects received single 0.25 U/kg insulin lispro doses on 2 occasions (at 5-mm and 8-mm injection depths); samples for PK and GD analyses were collected up to 6 hours postdose. Noncompartmental PK parameters AUC0-tlast, AUC0 infinity, Cmax and GD parameters Gtot, Rmax, tRmax were log-transformed prior to analysis using a mixed effects model. RESULTS: There were no apparent differences between PK profiles at the 5-mm or 8-mm injection depth in either study, demonstrated by the ratios of geometric means of AUC0-tlast, AUC0-infinity, and Cmax being close to 1, with 90% confidence intervals (CI) within (0.80, 1.25). There were no apparent differences between GD profiles at either injection depth with the ratios of Gtot and Rmax near unity and 90% CIs that included 1. In both studies, the tRmax values were similar between injection depths, with a small median of pairwise differences and a 90% CI that included zero. CONCLUSIONS: Injection depths in the 5-8 mm range did not affect the PK or GD of insulin lispro in normal weight or obese subjects. PMID- 25697718 TI - Escaping the Hemoglobin A1c-Centric World in Evaluating Diabetes Mellitus Interventions. AB - Any intervention in patients with diabetes must consider its effect on both the incidence of hypoglycemia and hemoglobin A1c. Yet, there is no single metric that expresses these key factors simultaneously. Such a composite metric would permit clinicians, regulators, manufacturers, payers, and researchers to more easily evaluate the merits of an intervention as well as enable the comparison of qualitatively different interventions. This article proposes a composite metric, the hypoglycemia-A1c score (HAS), as the basis for a more comprehensive approach for the stakeholders in diabetes treatment to better understand how an intervention affects diabetes management. The article also demonstrates how additional parameters such as effects on weight, quality of life, and costs could be included in such a scoring system. PMID- 25697719 TI - Reimbursement programs and health technology assessment for diabetes devices and supplies: a Canadian perspective. AB - The reimbursement model for medical devices and supplies used in the management of diabetes in Canada, along with the process for assessing new health technologies, can be complicated. Various provincial programs, including Ontario's Assistive Devices Program and the Ontario Monitoring for Health Program, reimburse the costs associated with certain devices and supplies for diabetes management. In addition, provincial advisory committees, such as the Ontario Health Technology Advisory Committee, review and make recommendations on the adoption of new health technologies in each province. This article provides an overview of the reimbursement programs available for diabetes devices and supplies and reviews the process for assessing new health technologies using the province of Ontario as an example. PMID- 25697720 TI - Nonenhanced peripheral MR-angiography (MRA) at 3 Tesla: evaluation of quiescent interval single-shot MRA in patients undergoing digital subtraction angiography. AB - Quiescent-interval single-shot MRA (QISS-MRA) is a promising nonenhanced imaging technique for assessment of peripheral arterial disease (PAD). Previous studies at 3 Tesla included only very limited numbers of patients for correlation of QISS MRA with digital subtraction angiography (DSA) as standard of reference (SOR). The aim of this prospective institutional review board-approved study was to compare QISS-MRA at 3 Tesla with DSA in a larger patient group. Our study included 32 consecutive patients who underwent QISS-MRA, contrast-enhanced MRA (CE-MRA), and DSA. Two readers independently performed a per-segment evaluation of QISS-MRA and CE-MRA for image quality and identification of non-significant stenosis (<50%) versus significant stenosis (50-100%). The final dataset included 1,027 vessel segments. Reader 1 and 2 rated image quality as diagnostic in 96.8 and 98.0% of the vessel segments on QISS-MRA and in 99.3 and 98.4% of the vessel segments on CE-MRA, respectively. DSA was available for 922 segments and detected significant stenosis in 133 segments (14.4%). Consensus reading yielded the following diagnostic parameters for QISS-MRA versus CE-MRA: sensitivity: 83.5% (111/133) versus 82.7% (110/133), p = 0.80; specificity: 93.9% (741/789) versus 95.7% (755/789), p = 0.25; and diagnostic accuracy: 92.4% (852/922) versus 93.8% (865/922), p = 0.35. In conclusion, using DSA as SOR, QISS-MRA and CE-MRA at 3 Tesla showed similar diagnostic accuracy in the assessment of PAD. A limitation of QISS-MRA was the lower rate of assessable vessel segments compared to CE-MRA. PMID- 25697721 TI - Effect of vitamin D deficiency and supplementation on myocardial deformation parameters and epicardial fat thickness in patients free of cardiovascular risk. AB - Vitamin D deficiency is associated with impaired myocardial deformation parameters and cardiovascular disease (CVD). Increased epicardial fat thickness (EFT) is also associated with increased risk of CVD. The aim of the study is to evaluate the effect of vitamin D deficiency and supplementation on myocardial deformation parameters and EFT. The study population consisted of 50 patients with vitamin D deficiency who were free of cardiovascular risk (mean age: 42.6 +/ 8.9 years, 37 female). Patients were treated with oral administration of vitamin D3. Myocardial deformation parameters and EFT were evaluated before and after treatment of those patients. Vitamin D levels significantly increased after treatment (30.5 +/- 10.5 vs. 9.9 +/- 5.3 nmol/l, p < 0.001). There was no significant difference between conventional echocardiographic parameters before and after treatment. Baseline EFT was significantly higher than post-treatment measurements (35.2 +/- 8.0 vs. 27.5 +/- 5.6 mm, p < 0.001). Post-treatment myocardial deformation parameters were also significantly higher than baseline measurements. Baseline vitamin D levels correlated with baseline EFT and left ventricular global longitudinal strain (LV-GLS). Post-treatment vitamin D levels also correlated with post-treatment EFT, body mass index, and LV-GLS. Baseline vitamin D level was an independent predictor of baseline LV-GLS (p = 0.002). Patients with impaired LV-GLS had significantly lower vitamin D levels than patients with normal LV-GLS (6.6 +/- 3.8 vs. 11.0 +/- 5.3 nmol/l, p = 0.005). Baseline vitamin D level was also an independent predictor of baseline impaired LV-GLS (p = 0.010). Vitamin D supplementation has beneficial effects on myocardial deformation parameters and EFT. Moreover, baseline vitamin D levels are a predictor of impaired LV-GLS. PMID- 25697722 TI - Carotid endarterectomy versus stenting: Does the flow really change? An Echo Color-Doppler analysis. AB - To assess potential hemodynamic differences after carotid endarterectomy (CEA) and carotid artery stenting (CAS) and their eventual impact on clinical management. Between July 2012 and October 2013 two groups of 30 patients each referred for CEA or CAS were prospectively enrolled in two tertiary hospital care centers. Pre-procedural imaging assessment of carotid artery disease was performed with Echo-Color-Doppler (ECD) and computed tomography angiography (CTA). ECD was repeated within 24 h and 1, 6 and 12 months after surgical/endovascular procedures. Peak systolic velocity (PSV) and end diastolic velocity (EDV) were assessed at two standard sites: common carotid artery (CCA) and distal internal carotid artery (ICA). Twenty-four hours ECD findings highly differ between the two populations. CCA PSV in the CEA and CAS groups was respectively 44.88 +/- 9.16 and 69.20 +/- 20.04 cm/s (p = 0.002); CCA EDV was 16.11 +/- 2.29 and 19.13 +/- 6.42 cm/s (p = 0.065); ICA PSV was 46.11 +/- 7.9 and 94.02 +/- 57.7 cm/s (p = 0.0012); ICA EDV was 20.22 +/- 4.33 and 30.47 +/- 18.33 cm/s (p = 0.025). One month, 6 months and 1 year findings confirmed the different trend in the two cohorts; in particular, at 1 year: CCA PSV was 50.94 +/- 12.44 and 60.59 +/- 26.84 cm/s (p = 0.181); CCA EDV was 17.11 +/- 3.46 and 19 +/- 16.35 cm/s (p = 0.634); ICA PSV was 51.66 +/- 10.1 and 70.86 +/- 20.64 cm/s (p = 0.014); ICA EDV was 25.05 +/- 8.65 and 32.66 +/- 13 cm/s (p = 0.0609). ECD follow up of patients undergone CEA or CAS may play a critical role in the clinical management. Strict surveillance of blood flow velocities allows reducing false positive re-stenosis diagnosis and choosing the best anti-aggregation therapies. Within the first month CEA patients benefit from a lower risk condition in comparison with CAS patients, due to a significantly faster PSV drop; moreover, long-term CCA PSV after CEA could be used as a surrogate marker of neointima formation. PMID- 25697723 TI - Cardiac mechanics in heart transplant recipients with and without transplant vasculopathy. AB - Evaluation of cardiac mechanics in heart transplant recipients (HTR) is of paramount importance. Assessment of strain through echocardiography is suited to describe cardiac function and might allow characterizing patients with and without transplant vasculopathy (TVP) a risk factor of impaired organ function and rejection. For this study 41 HTR immediately after and 1-3 years after transplantation were examined in a retrospective approach with 2-dimensional speckle tracking echocardiography to assess longitudinal, radial and circumferential strain and strain rate. The cohort consists of 33 men and 8 women with a median age of 54 years (1st, 3rd; 45.7, 65.3) with seven cases diagnosed with TVP during follow-up, as diagnosed by coronary angiography. The overall cohort showed an improvement of global longitudinal strain from baseline to 1 and 3 years with -14.2% (-16.9, -12.3%) to -16.1% (-17.5, -14.3%) and -16.7% (-18, 13.7%), p = 0.036. For patients developing TVP, global longitudinal strain was not different from baseline up to the maximum of 3 years -16.6% (-16.7-13.8%) to 16.4% (-17.3, -14.7%) and -17.6% (-18.7, -16.9%) with p = 0.21. Radial strain and torsion showed a trend to decrease after transplantation with time. Circumferential strain remained stable in HTR but decreased in subjects with TVP. Longitudinal Strain and strain rate showed no relevant changes in HTR with and without TVP. Radial strain and torsion declined in HTR as well as TVP patients with time. Speckle tracking imaging is useful to assess organ function in HTR, however coronary angiography is still needed to rule out TVP. PMID- 25697724 TI - Qualitatively and quantitatively evaluating harm-reduction goal setting among chronically homeless individuals with alcohol dependence. AB - INTRODUCTION: Most treatment programs for alcohol dependence have prioritized alcohol abstinence as the primary treatment goal. However, abstinence-based goals are not always considered desirable or attainable by more severely affected populations, such as chronically homeless people with alcohol dependence. Because these individuals comprise a multimorbid and high-utilizing population, they are in need of more focused research attention that elucidates their preferred treatment goals. The aim of this secondary study was therefore to qualitatively and quantitatively document participant-generated treatment goals METHODS: Participants were currently or formerly chronically homeless individuals (N=31) with alcohol dependence who participated in a pilot of extended-release naltrexone and harm-reduction counseling. Throughout the treatment period, study interventionists elicited participants' goals and recorded them on an open-ended grid. In subsequent weeks, progress towards and achievement of goals was obtained via self-report and recorded by study interventionists. Conventional content analysis was performed to classify participant-generated treatment goals RESULTS: Representation of the three top categories remained stable over the course of treatment. In the order of their frequency, they included drinking-related goals, quality-of-life goals and health-related goals. Within the category of drinking related goals, participants consistently endorsed reducing drinking and alcohol related consequences ahead of abstinence-based goals. Quantitative analyses indicated participants generated an increasing number of goals over the course of treatment. Proportions of goals achieved and progressed towards kept pace with this increase CONCLUSIONS: Findings confirmed hypotheses that chronically homeless people with alcohol dependence can independently generate and achieve treatment goals towards alcohol harm reduction and quality-of-life improvement. PMID- 25697725 TI - Web-based treatment for substance use disorders: differential effects by primary substance. AB - INTRODUCTION: This secondary analysis of data from a large, multi-site effectiveness trial (NCT01104805) sought to determine whether effects of a web based behavioral treatment (Therapeutic Education System [TES]) differed by participants' self-identified primary drug of abuse. METHODS: The all-comers sample of individuals entering outpatient psychosocial counseling treatment for substance abuse (N=497) cited cannabis (22.9%; n=114), stimulants (34.4%, n=171), opioids (21.7%, n=108), or alcohol (20.9%, n=104) as their primary substance of abuse. Participants were randomly assigned to receive treatment-as-usual (TAU) with or without TES substituted for approximately 2h of usual counseling. Multivariate analyses of abstinence outcomes examined interactions of treatment effects with primary substance. RESULTS: Adjusted odds ratios (AORs) demonstrated that primary stimulant users receiving TES were more likely to be abstinent in the final four weeks of treatment compared to stimulant users receiving TAU (AOR=3.59, 95% CI=1.25-10.27). Adjusted odds ratios for alcohol (AOR=3.15, 95% CI=0.85-11.65) and cannabis (AOR=2.64, 95% CI=0.73-9.52) also were of similar magnitude to stimulants but did not reach significance. Abstinence among primary opioid users was not improved by the TES intervention (AOR=0.35, 95% CI=0.09 1.47). CONCLUSIONS: This study supports the TES web-delivered treatment as a viable intervention for the majority of substance users entering outpatient counseling treatment, with demonstrated effectiveness among stimulant users and promising effects in alcohol and cannabis users but little or no effect in primary opioid users. Web-delivered treatments hold promise for expanding the availability of effective behavioral interventions for the majority of substance use disorders. PMID- 25697726 TI - Item Response Theory analysis of the Autonomy over Tobacco Scale (AUTOS). AB - INTRODUCTION: The Autonomy over Tobacco Scale (AUTOS) is composed of 12-symptoms of nicotine dependence. While it has demonstrated excellent reliability and validity, several psychometric properties have yet to be investigated. We aimed to determine (1) whether items functioned differently across demographic groups, (2) the likelihood that individual symptoms would be endorsed by smokers at different levels of diminished autonomy, and (3) the degree of information provided by each item and the reliability of the full AUTOS across the range of diminished autonomy. METHODS: Data for this study come from two convenience samples of American adult current smokers (n=777; 69% female; 88% white; Mage=34 years, range: 18-78), of whom 66% were daily smokers (Mcigarettes/smoking day=10.1, range: <1-70). Participants completed the AUTOS online as part of "a research study about the experiences people have when they smoke." RESULTS: After p value correction, items remained invariant across sex and minority status, while two items functioned differently according to age, with minimal impact on the total AUTOS score. Discriminative power of the items was high. The greatest amount of information is provided at just under one-half SD above the mean and the least at the extremes of diminished autonomy. The AUTOS maintains acceptable reliability (>0.70) across the range of diminished autonomy within which more than 95% of smokers' scores could be anticipated to fall. CONCLUSION: The AUTOS is a versatile and psychometrically sound instrument for measuring the loss of autonomy over tobacco use. PMID- 25697727 TI - Cigarette smoke exposure reveals a novel role for the MEK/ERK1/2 MAPK pathway in regulation of CFTR. AB - BACKGROUND: Cystic fibrosis transmembrane conductance regulator plays a key role in maintenance of lung fluid homeostasis. Cigarette smoke decreases CFTR expression in the lung but neither the mechanisms leading to CFTR loss, nor potential ways to prevent its loss have been identified to date. METHODS: The molecular mechanisms leading to down-regulation of CFTR by cigarette smoke were determined using pharmacologic inhibitors and silencing ribonucleic acids (RNAs). RESULTS: Using human bronchial epithelial cells, here we show that cigarette smoke induces degradation of CFTR that is attenuated by lysosomal inhibitors, but not proteasome inhibitors. Cigarette smoke can activate multiple signaling pathways in airway epithelial cells, including the MEK/Erk1/2 MAPK (MEK: mitogen activated protein kinase/ERK kinase Erk1/2: extracellular signal-regulated kinase 1/2 MAPK: Mitogen-activated protein kinase) pathway regulating cell survival. Interestingly, pharmacological inhibition of the MEK/Erk1/2 MAPK pathway prevented the loss of plasma membrane CFTR upon cigarette smoke exposure. Similarly, decreased expression of Erk1/2 using silencing RNAs prevented the suppression of CFTR protein by cigarette smoke. Conversely, specific inhibitors of the c-Jun N-terminal kinase (JNK) or p38 MAPK pathways had no effect on CFTR decrease after cigarette smoke exposure. In addition, inhibition of the MEK/Erk1/2 MAPK pathway prevented the reduction of the airway surface liquid observed upon cigarette smoke exposure of primary human airway epithelial cells. Finally, addition of the antioxidant N-acetylcysteine inhibited activation of Erk1/2 by cigarette smoke and precluded the cigarette smoke-induced decrease of CFTR. CONCLUSIONS: These results show that the MEK/Erk1/2 MAPK pathway regulates plasma membrane CFTR in human airway cells. GENERAL SIGNIFICANCE: The MEK/Erk1/2 MAPK pathway should be considered as a target for strategies to maintain/restore CFTR expression in the lung of smokers. PMID- 25697728 TI - Mismatch repair-dependent metabolism of O6-methylguanine-containing DNA in Xenopus laevis egg extracts. AB - The cytotoxicity of SN1-type alkylating agents such as N-methyl-N'-nitrosourea (MNU), N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), or the cancer chemotherapeutics temozolomide, dacarbazine and streptozotocin has been ascribed to the persistence of O(6)-methylguanine ((me)G) in genomic DNA. One hypothesis posits that (me)G toxicity is caused by futile attempts of the mismatch repair (MMR) system to process (me)G/C or (me)G/T mispairs arising during replication, while an alternative proposal suggests that the latter lesions activate DNA damage signaling, cell cycle arrest and apoptosis directly. Attempts to elucidate the molecular mechanism of (me)G-induced cell killing in vivo have been hampered by the fact that the above reagents induce several types of modifications in genomic DNA, which are processed by different repair pathways. In contrast, defined substrates studied in vitro did not undergo replication. We set out to re examine this phenomenon in replication-competent Xenopus laevis egg extracts, using either phagemid substrates containing a single (me)G residue, or methylated sperm chromatin. Our findings provide further support for the futile cycling hypothesis. PMID- 25697729 TI - 2-Hydrazinobenzothiazole-based etheno-adduct repair protocol (HERP): a method for quantitative determination of direct repair of etheno-bases. AB - Etheno-DNA adducts are mutagenic and lead to genomic instability. Enzymes belonging to Fe(II)/2-oxoglutarate-dependent dioxygenase family repair etheno-DNA adducts by directly removing alkyl chain as glyoxal. Presently there is no simple method to assess repair reaction of etheno-adducts. We have developed a rapid and sensitive assay for studying etheno-DNA adduct repair by Fe(II)/2-oxoglutarate dependent dioxygenases. Using AlkB as model Fe(II)/2-oxoglutarate-dependent dioxygenases, we performed in vitro repair of etheno-adducts containing DNA and detected glyoxal by reacting with 2-hydrazinobenzothiazole which forms complex yellow color compound with distinct absorption spectrum with a peak absorption at 365 nm. We refer this method as 2-hydrazinobenzothiazole-based etheno-adduct repair protocol or HERP. Our novel approach for determining repair of etheno adducts containing DNA overcomes several drawbacks of currently available radioisotope-based assay. PMID- 25697730 TI - Amino acid composition of human uterine fluid: association with age, lifestyle and gynaecological pathology. AB - STUDY QUESTION: Do the amino acid levels of human uterine fluid vary with age, BMI, phase of menstrual cycle, benign pathology or diet? SUMMARY ANSWER: The levels of 18 amino acids in human uterine fluid were shown to be affected only by maternal diet. WHAT IS KNOWN ALREADY: Murine, bovine and ovine uterine amino acid content has been reported, but no reliable data on the human exist. Murine studies have demonstrated that the intrauterine periconceptional nutritional environment is affected by maternal diet. STUDY DESIGN, SIZE, DURATION: Uterine secretions were aspirated from 56 women aged 18-45 years. The women were recruited preoperatively from gynaecological theatre operating schedules or hysterosalpingo-contrast-sonography (HyCoSy) lists. A proportion of these women had proven fertility; however, the majority were being investigated for subfertility. The BMI, gynaecological history and dietary pattern of these women were also assessed. PARTICIPANTS/MATERIALS, SETTING, METHODS: Reverse phase high performance liquid chromatography was used to analyse the concentrations of 18 amino acids within the uterine fluid and blood serum. The results were analysed against the women's stage of cycle, age, BMI and diet. MAIN RESULTS AND THE ROLE OF CHANCE: The profile of 18 amino acids in uterine fluid was described. In total, human uterine fluid was observed to contain an amino acid concentration of 3.54 mM (interquartile range: 2.27-6.24 mM). The relative concentrations of 18 amino acids were not significantly altered by age, BMI, cycle phase or the presence of specific benign gynaecological pathologies. However, a diet identified by a validated scoring system as being less healthy was associated with higher concentrations of asparagine (P = 0.018), histidine (P = 0.011), serine (P = 0.033), glutamine (P = 0.049), valine (P = 0.025), phenylalanine (P = 0.019), isoleucine (P = 0.025) and leucine (P = 0.043) in the uterine fluid compared with a healthier diet, defined as one with a higher intake of fresh vegetables, fruit, whole-grain products and fish and a low intake of red and processed meat and high fat dairy products. There were no significant correlations between serum amino acid concentrations and those in the uterine fluid. LIMITATIONS, REASONS FOR CAUTION: Our results enabled us to detect the effect of diet on the concentrations of amino acids in human uterine fluid; however, the study may not have had sufficient numbers to detect mild effects of BMI or age. WIDER IMPLICATIONS OF THE FINDINGS: These findings increase our understanding of the nutritional environment encountered by the preimplantation embryo, and indicate how periconceptional diet may alter this. Given the importance of early embryo environment for programming of development and future health, this information may aid in the development of nutritional interventions aimed at optimizing the preimplantation phase of human embryo development in vivo. STUDY FUNDING/COMPETING INTERESTS: This work was funded by the NIHR, the Medical Research Council (G0701153) and the University of Southampton and was supported by the NIHR BRC in Nutrition and Southampton University NHS Foundation Trust. The authors declare no conflicts of interest. PMID- 25697731 TI - [Evaluation of referral process of the hypertensive patient in Spain: DERIVA study]. AB - INTRODUCTION: An adequate communication between levels of medical attention is the key point for optimal treatment and outcomes of the hypertensive population. AIMS: The aim of this study was to evaluate the adequacy of the hypertensive patients' derivation from Primary Care to Specialized Care. As secondary objectives, the information registered on the derivation report was assessed and concordance between derivation reason and final diagnosis was analysed. DESIGN: This is an observational, descriptive, multicentre study. SITE: Study conducted at the national level. PARTICIPANTS: Specialty Care Physicians receiving hypertensive patients referred from primary care. PRINCIPAL MEASUREMENTS: On the baseline visit, the specialist physicians assessed the quality of the derivation records and attended the patient. After the study, final diagnosis and treatment is suggested on the final visit. RESULTS: 1769 subjects were included, mean aged 62,4 (13,6) years, 45% female. Time of diagnosis of hypertension was 8,0 (7,7) years. More than the half of the derivation records contained very good information (5,4%; CI4,3-6,5) or sufficient (50,7%; CI48,4-53,0). In 7,1% (IC5,9 8,3) derivation cause was not specified. 74,7% of the derivations were considered as appropriate, though 30% were late. Concordance between derivation reasons and final diagnosis was low (kappa index 0,208). CONCLUSIONS: A quarter of the hypertensive population is unnecessary derived to Secondary Care and 30% of the appropriately derived was late. We should improve the interrelation of attention in the hypertension and cardiovascular area between the both attention levels. PMID- 25697732 TI - Borderline personality disorder, but not euthymic bipolar disorder, is associated with a failure to sustain reciprocal cooperative behaviour: implications for spectrum models of mood disorders. AB - BACKGROUND: Borderline personality disorder (BPD) and bipolar disorder (BD) have overlapping clinical presentations and symptoms - sources of persistent clinical confusion. Game-theory can characterize how social function might be sub-optimal in the two disorders and move the field beyond the anecdotal description of clinical history. Here, we tested the hypothesis that BPD and BD can be distinguished on the basis of diminished reciprocal altruism in iterated Prisoner's Dilemma (PD) games. METHOD: Twenty females with BPD, 20 females with euthymic BD and 20 healthy (non-clinical) females, matched for age and cognitive ability, were assessed for Axis-I and personality disorders, and completed psychometric measures of state affect, impulsivity and hostility. Participants completed two iterated PD games and a test of gaze-cueing. RESULTS: In the PD games, BPD participants failed to show statistically stable preferences to cooperate with social partners (playing tit-for-tat) and made significantly fewer cooperative responses compared to BD or controls (ANOVA main effect p = 0.03, post-hoc Tukey p < 0.05 for both comparisons). BPD participants were also less likely to sustain cooperation following experiences involving mutual cooperation than the other groups. Neither BPD nor BD participants demonstrated impairments in shifting visual attention on the basis of other peoples' gaze. CONCLUSIONS: These data indicate that BPD is (selectively) associated with difficulties in establishing, and then maintaining, reciprocal cooperation, involving altruism. These difficulties are not seen in euthymic BD. Our data support the differentiation of BPD from BD and offer fresh insights into the social difficulties experienced by individuals with diagnoses of BPD. PMID- 25697733 TI - Are the less common compartment syndromes less of a problem? PMID- 25697734 TI - Major trauma centres and trauma networks - the potential impact on surgical training. PMID- 25697735 TI - The effect of introducing a Trauma Network on patient flow, hospital finances and trainee operating. AB - In April 2012 the National Health Service in England introduced the Trauma Network system with the aim of improving the quality of trauma care. In this study we wished to determine how the introduction of the Trauma network has affected patient flow, hospital finances and orthopaedic trauma training across our region. The overall pattern of trauma distribution was not greatly affected, reflecting the relative rarity of major trauma in the UK. A small decrease in the total number of operations performed by trainees was noted in our region. Trainees at units designated as Major Trauma Centres gained slightly more operative experience in trauma procedures overall, and specifically in those associated with high energy, such as long bone nail insertion and external fixation procedures. However, there have been no significant changes in this pattern since the introduction of the Trauma Networks. Falling operative numbers presents a challenge for delivering high quality training within a surgical training programme, and each case should be seen as a vital educational opportunity. Best practice tariff targets for trauma were delivered for 99% of cases at our MTCs. Future audit and review to analyse the evolving role of the MTCs is desirable. PMID- 25697736 TI - Motor abilities of adolescents with a disruptive behavior disorder: The role of comorbidity with ADHD. AB - The aim of this study was to explore the incidence, type and severity of motor impairment in male adolescents with a disruptive behavior disorder (DBD) and evaluate the role of comorbid ADHD. The Bruininks-Oseretsky test of motor proficiency, Second Edition was administered to examine a detailed motor profile and to compare the motor abilities of individuals with DBD (n = 99) to those of controls (n = 87). Additional subgroup analyses were conducted within the clinical population and encompassed (1) analyzing differences in motor profiles between individuals diagnosed with oppositional defiant disorder (ODD) or conduct disorder (CD) and (2) comparing the motor profiles of individuals with or without comorbid ADHD. The results indicated that individuals with a DBD showed a mixed motor impairment profile. Even after controlling for IQ, the DBD group obtained significantly lower scores in comparison to controls. The ODD and CD subgroups showed a similar motor profile. Presence of comorbid ADHD did not produce major differences in the motor profile. As approximately 79% of the adolescents with a DBD suffered from motor impairment, motor ability needs to be adequately addressed in research as well as in clinical practice. PMID- 25697737 TI - Sick Leave and Work Participation Among Parents of Children with Autism Spectrum Disorder in the Stockholm Youth Cohort: A Register Linkage Study in Stockholm, Sweden. AB - This population-based register study explored the association between having a child with/without autism spectrum disorder (ASD) and parental sick leave and work participation. Parents of children with ASD living in Stockholm, Sweden in 2006 were more likely to be on sick leave, not in the labor force, or earning low income when compared to parents who did not have a child with ASD and these results remained after adjusting for familial socioeconomic factors and parental psychiatric care. Sick leave among parents was associated with having a child with ASD without intellectual disability (ID) but not ASD with ID. Although Sweden has policies helping families with children with ASD this study suggests that there exist unmet needs among these parents. PMID- 25697738 TI - Great Expectations: The Role of Rules in Guiding Pro-social Behaviour in Groups with High Versus Low Autistic Traits. AB - Measuring autistic traits in the general population has proven sensitive for examining cognition. The present study extended this to pro-social behaviour, investigating the influence of expectations to help others. A novel task describing characters in need of help was administered to students scoring high versus low on the Autism-Spectrum Quotient. Scenarios had two variants, describing either a 'clear-cut' or 'ambiguous' social rule. Participants with high versus low autistic traits were less pro-social and sympathetic overall towards the characters. The groups' ratings of characters' expectations were comparable, but those with high autistic traits provided more rule-based rationales in the clear-cut condition. This pattern of relatively intact knowledge in the context of reduced pro-social behaviour has implications for social skill training programmes. PMID- 25697739 TI - Clinical effectiveness of split-virion versus subunit trivalent influenza vaccines in older adults. AB - BACKGROUND: Inactivated influenza vaccines are manufactured using either split virion or subunit methods. These 2 methods produce similar hemagglutinin antibody responses, but different cellular immune responses. METHODS: We compared the effectiveness of split-virion influenza vaccines to that of subunit influenza vaccines using prospectively collected data from adults aged >=50 years who sought care for acute respiratory illness during 3 influenza seasons: 2008-2009, 2010-2011, and 2011-2012 using a case-positive, control test-negative study design. RESULTS: Complete data were available for 539 participants, of whom 68 (12.6%) had influenza detected. Influenza-infected patients were younger (P<.001), were more likely to have received no vaccine or the subunit influenza vaccine than the split-virion vaccine (P<.001), and more likely to have sought care in either the emergency department or the acute care clinic than the hospital (P=.001). Split-virion vaccine effectiveness was 77.8% (95% confidence interval [CI], 58.5%-90.3%) compared with subunit vaccine effectiveness of 44.2% (95% CI, -11.8% to 70.9%), giving a difference in vaccine effectiveness of 33.5% (95% CI, 6.9%-86.7%). CONCLUSIONS: Studies need to be done to further explore if there are differences in clinical effectiveness in older adults for the 2 vaccine manufacturing methods. PMID- 25697740 TI - Is the quality of sushi ruined by freezing raw fish and squid? A randomized double-blind trial with sensory evaluation using discrimination testing. AB - BACKGROUND: Sushi is a traditional Japanese cuisine enjoyed worldwide. However, using raw fish to make sushi may pose risk of certain parasitic infections, such as anisakidosis, which is most reported in Japan. This risk of infection can be eliminated by freezing fish; however, Japanese people are hesitant to freeze fish because it is believed that freezing ruins sushi's taste. METHODS: A randomized double-blind trial with discrimination testing was conducted to examine the ability of Japanese individuals to distinguish between frozen and unfrozen sushi. A pair of mackerel and squid sushi, one once frozen and the other not, was provided to the participants, and they were asked to answer which one tasted better. RESULTS: Among 120 rounds of discrimination testing involving the consumption of 240 pieces of mackerel sushi, unfrozen sushi was believed to taste better in 42.5% (51 dishes) of cases, frozen sushi was thought to taste better in 49.2% (59 dishes), and the participants felt the taste was the same in 8.3% (10 dishes). The odds ratio for selecting unfrozen sushi as "tastes better" over frozen sushi was 0.86 (95% confidence interval [CI], .59-1.26; P = .45). For squid, unfrozen sushi was believed to be superior 48.3% of the time (58 dishes), and frozen sushi, 35.0% of the time (42 dishes). They were felt to be the same in 16.7% (20 dishes) (odds ratio, 1.38; 95% CI, .93-2.05; P = .11). CONCLUSIONS: Freezing raw fish did not ruin sushi's taste. These findings may encourage the practice of freezing fish before using it in sushi, helping to decrease the incidence of anisakidosis. PMID- 25697741 TI - Oral Bacitracin: A Consideration for Suppression of Intestinal Vancomycin Resistant Enterococci (VRE) and for VRE Bacteremia From an Apparent Gastrointestinal Tract Source. PMID- 25697742 TI - Risk factors for fatal outcome from rocky mountain spotted Fever in a highly endemic area-Arizona, 2002-2011. AB - BACKGROUND: Rocky Mountain spotted fever (RMSF) is a disease that now causes significant morbidity and mortality on several American Indian reservations in Arizona. Although the disease is treatable, reported RMSF case fatality rates from this region are high (7%) compared to the rest of the nation (<1%), suggesting a need to identify clinical points for intervention. METHODS: The first 205 cases from this region were reviewed and fatal RMSF cases were compared to nonfatal cases to determine clinical risk factors for fatal outcome. RESULTS: Doxycycline was initiated significantly later in fatal cases (median, day 7) than nonfatal cases (median, day 3), although both groups of case patients presented for care early (median, day 2). Multiple factors increased the risk of doxycycline delay and fatal outcome, such as early symptoms of nausea and diarrhea, history of alcoholism or chronic lung disease, and abnormal laboratory results such as elevated liver aminotransferases. Rash, history of tick bite, thrombocytopenia, and hyponatremia were often absent at initial presentation. CONCLUSIONS: Earlier treatment with doxycycline can decrease morbidity and mortality from RMSF in this region. Recognition of risk factors associated with doxycycline delay and fatal outcome, such as early gastrointestinal symptoms and a history of alcoholism or chronic lung disease, may be useful in guiding early treatment decisions. Healthcare providers should have a low threshold for initiating doxycycline whenever treating febrile or potentially septic patients from tribal lands in Arizona, even if an alternative diagnosis seems more likely and classic findings of RMSF are absent. PMID- 25697743 TI - Rocky mountain spotted fever characterization and comparison to similar illnesses in a highly endemic area-Arizona, 2002-2011. AB - BACKGROUND: Rocky Mountain spotted fever (RMSF) has emerged as a significant cause of morbidity and mortality since 2002 on tribal lands in Arizona. The explosive nature of this outbreak and the recognition of an unexpected tick vector, Rhipicephalus sanguineus, prompted an investigation to characterize RMSF in this unique setting and compare RMSF cases to similar illnesses. METHODS: We compared medical records of 205 patients with RMSF and 175 with non-RMSF illnesses that prompted RMSF testing during 2002-2011 from 2 Indian reservations in Arizona. RESULTS: RMSF cases in Arizona occurred year-round and peaked later (July-September) than RMSF cases reported from other US regions. Cases were younger (median age, 11 years) and reported fever and rash less frequently, compared to cases from other US regions. Fever was present in 81% of cases but not significantly different from that in patients with non-RMSF illnesses. Classic laboratory abnormalities such as low sodium and platelet counts had small and subtle differences between cases and patients with non-RMSF illnesses. Imaging studies reflected the variability and complexity of the illness but proved unhelpful in clarifying the early diagnosis. CONCLUSIONS: RMSF epidemiology in this region appears different than RMSF elsewhere in the United States. No specific pattern of signs, symptoms, or laboratory findings occurred with enough frequency to consistently differentiate RMSF from other illnesses. Due to the nonspecific and variable nature of RMSF presentations, clinicians in this region should aggressively treat febrile illnesses and sepsis with doxycycline for suspected RMSF. PMID- 25697744 TI - Effect of palmitic acid on the characteristics and release profiles of rotigotine loaded microspheres. AB - BACKGROUND: The initial burst release is a major obstacle to the development of microsphere-formulated drug products. PURPOSE: To investigate the influence of palmitic acid on the characteristics and release profiles of rotigotine-loaded poly(d,l-lactide-co-glycolide) microspheres. MATERIALS AND METHODS: Rotigotine loaded microspheres (RMS) were prepared using the oil-in-water emulsion solvent evaporation technique. The in vitro characteristics of the RMS were evaluated with scanning electron microscopy (SEM), differential scanning calorimetry (DSC) and a particle size analyzer. The in vitro drug release and in vivo pharmacokinetics of the RMS were investigated. RESULTS AND DISCUSSION: The SEM results showed that the addition of palmitic acid changed the surface morphology of the microspheres from smooth to dimpled and then to non-smooth as the palmitic acid content increased. DSC revealed the existence of molecularly dispersed forms of palmitic acid in the microspheres. The in vitro and in vivo release profiles indicated that the addition of 5% and 8% palmitic acid significantly decreased the burst release of rotigotine from the microspheres, and the late-stage release was delayed as the palmitic acid content increased across the investigated range (5-15%). CONCLUSION: The addition of palmitic acid to the microspheres significantly affects the release profile of rotigotine from RMS. PMID- 25697745 TI - Prevalence of overweight and underweight and its associated factors among male and female university students in Thailand. AB - Lifestyle habits of Thai society lead young people to conditions of potential cardiovascular risk. The purpose of this study was to assess the prevalence of overweight/obese and underweight along with associated factors in a sample of Thai university students. Using a cross-sectional survey, we assessed anthropometric measurements and a self-administered questionnaire among university students selected by stratified random sampling. The sample included 860 undergraduate university students from Mae Fah Luang University in Thailand (27.3% males), with age ranging from 18 to 25 years (M=20.1, SD=1.3 years). Results indicated that the median BMI was 20.2, which was higher in men than in women. Overall, 21.5% were underweight (<18 BMI) and 20.8% were overweight (7.8% overweight [>=23 BMI] and 13% obese [>=25 BMI]). More men than women were overweight and obese, whereas more women than men were underweight. Multinomial logistic regression analyses revealed that among men, older age, trying to eat fibre, and trying to lose weight were associated with overweight or obesity and among women trying to lose weight, depression symptoms and normal sleep duration were associated with overweight or obesity. The risk of underweight was greater among men living off campus, having a high income background, and short sleep duration and among women with low physical activity and who were not trying to lose weight. Considering the large percentage of overweight and underweight found in this study and the associated possible negative health consequences, it is suggested to include information on the assessment of adequate weight in health promotion programmes. PMID- 25697746 TI - Performance and mortality of farmed hares. AB - Performance and mortality of hares were evaluated for 2 consecutive years in a large farm in Veneto Region (Northern Italy). On average, fertile reproductive pairs (n=318) gave birth 4.8 times and produced 11.4 live leverets, weaned 8.4 leverets and produced 7.0 growing hares (60 days) every year. Mean mortality was 3.6%, 22.9%, 9.7% and 2.5% in newborn (0 to 2 days of age), suckling (3 to 25 days), growing (26 to 60 days) and sub-adult (61 days until sale) hares, respectively. The main causes of mortality were enteric diseases (75.5%, 75.9% and 12.1% in suckling, growing and sub-adult hares, respectively), followed by respiratory diseases (3.4%, 8.0% and 36.2% in suckling, growing and sub-adult hares, respectively), starvation (11.3% and 8.8% in suckling and growing hares, respectively) and trauma (7.1%, 2.3% and 30.2% in suckling, growing and sub-adult hares, respectively). In reproducing hares, mortality was 24.7% and 15.4% in 2010 and 2011, respectively. Respiratory diseases (34.8%) and ulcerative pododermatitis (18.9%) were the most common pathological changes detected in reproducing hares. Farmed hares seem to be affected by diseases resembling those of rabbits reared under intensive conditions. It seems necessary to improve the husbandry of hares to reach satisfactory technical standards and to preserve their health. PMID- 25697747 TI - Circulating levels of platelet alpha-granule cytokines in trauma patients. AB - OBJECTIVE AND DESIGN: To elucidate whether platelets differentiate cytokine release following trauma, we prospectively measured three major platelet-derived cytokines in 213 trauma patients on hospital arrival. METHODS: We measured plasma levels of the anti-inflammatory beta-thromboglobulins (betaTGs), transforming growth factor-beta1 (TGFbeta1) and the pro-inflammatory platelet factor 4 (PF4) cytokines. We also measured soluble glycoprotein VI (sGPVI), procoagulant platelet microparticles (PMPs) and white blood cell (WBC) counts, and evaluated in vitro platelet function in primary and secondary haemostasis by aggregometry and thromboelastometry, respectively. We evaluated associations of each cytokine by multivariate regression including injury severity score (ISS), WBC counts, sGPVI and platelet counts as explanatory variables. RESULTS: Severely injured patients (ISS > 15) had higher levels of betaTGs and TGFbeta1 (both p < 0.01) but lower levels of PF4 (p = 0.02). GPVI and PMPs levels correlated with TGFbeta1 and PF4 whereas we found no significant association between cytokine levels and measures of haemostasis. By multivariate regression, a high WBC count was associated with high levels of TGFbeta1 (p = 0.01) and betaTGs (p < 0.01) but with low levels of PF4 (p = 0.03). CONCLUSION: Severely injured patients had higher levels of betaTGs and TGFbeta1 but lower levels of the PF4; a high WBC count predicted this anti-inflammatory profile of platelet cytokines. PMID- 25697748 TI - Adaptation of a small-molecule hydrogen-bond donor catalyst to an enantioselective hetero-Diels-Alder reaction hypothesized for brevianamide biosynthesis. AB - Chiral diamine-derived hydrogen-bond donors were evaluated for their ability to effect stereocontrol in an intramolecular hetero-Diels-Alder (HDA) reaction hypothesized in the biosynthesis of brevianamides A and B. Collectively, these results provide proof of principle that small-molecule hydrogen-bond catalysis, if even based on a hypothetical biosynthesis construct, holds significant potential within enantioselective natural product synthesis. PMID- 25697749 TI - Intravenous Thrombolytic Therapy for Acute Ischemic Stroke with Subclavian Arterial Steal Syndrome: A Case Report. PMID- 25697750 TI - Chemopreventive Effects of Azadirachta indica on Cancer Marker Indices and Ultrastructural Changes During 1,2-Dimethylhydrazine-Induced Colon Carcinogenesis in Rats. AB - The present study elucidated the prospective of Azadirachta indica supplementation, if any, in affording chemoprevention by modulating the altered cancer markers and ultrastructural changes in DMH-induced colorectal carcinogenesis in rats. The rats were segregated into four groups viz., normal control, DMH treated, A. indica treated, and DMH+AI treated. Initiation and induction of colon carcinogenesis were achieved through weekly subcutaneous injections of DMH (30 mg/kg body weight) for both 10 and 20 weeks. A. indica extract was supplemented to rats at a dose rate of 100 mg/kg body weight of animals thrice a week on alternative days, ad libitum for two different time durations of 10 and 20 weeks. The study observed a significant increase in the number of aberrant crypt foci in colons of DMH-treated rats at both the time intervals which were decreased significantly upon AI supplementation. Also, a significant increase was seen in the enzyme activity of alkaline phosphatase, which, however, was moderated upon AI administration to DMH-treated rats. Changes in the ultrastructural architecture of colonic cells were apparent following both the treatment schedules of DMH; however, the changes were prominent following 20 weeks of DMH treatment. The most obvious changes were seen in the form of altered nuclear shape and disruption of cellular integrity, which were appreciably improved upon AI supplementation. In conclusion, the study shows the chemopreventive abilities of AI against DMH-induced colorectal carcinogenesis in rats. PMID- 25697751 TI - Determination of 18 Types of Amino Acids in the Serum of Ischemic Stroke Patients by High Performance Liquid Chromatography-diode Array Detector Derivatized with 6 Aminoquinolyl-N-hydroxysuccinimidyl Carbamate. AB - In this study, we develop a fast and convenient method for the detection of 18 types of free amino acids in the serum of ischemic stroke patients. We use high performance liquid chromatography-diode array detector and thermo C18 column to separate 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate-derivatized amino acids. We find that Gln, His, Gly, Arg, and Cys levels are significantly lower in the serum of ischemic stroke patients comparing with normal persons. Our data indicate that this simple method can be used to detect free amino acids in serum with accurate and reliable results. This study provides a basis for the clinical treatment of ischemic stroke patients and suggests that amino acids can be supplemented to the patients during clinical treatment, which may improve patient prognosis. PMID- 25697752 TI - Surgical cryoablation for ventricular tachyarrhythmia arising from the left ventricular outflow tract region. AB - BACKGROUND: Ventricular arrhythmias (VAs) from the left ventricular outflow tract (LVOT) region can be inaccessible for ablation because of epicardial fat or overlying coronary arteries. OBJECTIVE: We describe surgical cryoablation of this type of VA. METHODS: From March 2009 to 2014, 190 consecutive patients with VAs originating from the LVOT underwent ablation at our institution. Four patients (2%) underwent surgical cryoablation for highly symptomatic VAs after failing catheter ablation. RESULTS: In all patients, endocardial or percutaneous epicardial mapping was consistent with origin in the LVOT. In 2 patients, the points of earliest activation during VAs were marked with a bipolar pacing lead in the overlying cardiac vein for guidance during surgery. Surgical cryoablation was successful in 3 of the 4 patients. The fourth patient subsequently had successful endocardial catheter ablation. During a mean follow-up of 22 +/- 16 months (range 4-42 months), all patients showed abolition of or marked reduction in symptomatic VA. However, 1 patient subsequently required percutaneous intervention to the left anterior descending coronary artery; another developed progressive left ventricular systolic dysfunction caused by nonischemic cardiomyopathy; and a third patient underwent permanent pacemaker implantation because of complete atrioventricular block after concomitant aortic valve replacement. CONCLUSION: Surgical cryoablation is an option for highly symptomatic drug-resistant VAs emanating from the LVOT region. Despite extensive preoperative mapping, the procedure is not effective for all patients, and coronary injury is a risk. PMID- 25697753 TI - Phytohormones in microalgae: a new opportunity for microalgal biotechnology? AB - Phytohormones, including auxin, abscisic acid (ABA), cytokinin (CK), ethylene (ET), and gibberellins (GAs), have been found in a broad spectrum of microalgal lineages. Although the functional role of microalgal endogenous phytohormones remains elusive, molecular evidence from the oleaginous microalga Nannochloropsis oceanica suggests that endogenous ABA and CK are functional and that their physiological effects are similar to those in higher plants. In this Opinion article, proceeding from genome-based metabolic reconstruction, we suggest that modern higher plant phytohormone biosynthesis pathways originate from ancient microalgae even though some of the microalgal phytohormone signaling pathways remain unknown. Dissection and manipulation of microalgal phytohormone systems could offer a new view of phytohormone evolution in plants and present new opportunities in developing microalgal feedstock for biofuels. PMID- 25697754 TI - Over Half of U.S. Infants Sleep in Potentially Hazardous Bedding. PMID- 25697755 TI - Binge drinking and tuberculosis prevention. PMID- 25697757 TI - Discrete and polymeric cobalt organophosphates: isolation of a 3-D cobalt phosphate framework exhibiting selective CO2 capture. AB - Structurally diverse mononuclear, dinuclear, and tetranuclear cobalt organophosphates and a three-dimensional framework based on a D4R cobalt phosphate are reported. The role of auxiliary ligands in determining the nuclearity of the phosphate clusters has further been established. Reaction of cobalt acetate tetrahydrate with 2,6-di-iso-propylphenylphosphate (dippH2) in methanol or DMSO in the presence of ancillary N-donor ligands leads to the formation of mononuclear octahedral cobalt phosphate [Co(dippH)2(py)4] (1), dinuclear octahedral cobalt phosphates [Co(dipp)(NN)(MeOH)2]2.2MeOH (NN = bpy 2; phen 3), tetrahedral cobalt phosphates [Co(dipp)(L)2]2.2(MeOH) (L = imz 4; dmpz 5) and symmetric and asymmetric tetranuclear tetrahedral cobalt phosphates [Co(dipp)(2-apy)]4 (6) and [Co4(dipp)4(2-apy)3(DMSO)].(DMSO).(H2O) (7), in nearly quantitative yields. The use of a linear N-donor ditopic linker, 3,6-di(pyridin-4 yl)-1,2,4,5-tetrazine (dptz), as the ancillary ligand leads to the formation of a robust three dimensional, four-fold interpenetrated network based on the D4R platform, {[Co(dipp)(dptz)0.5]4}n (8), under ambient conditions. The new compounds have been characterized by analytical, thermo-analytical and spectroscopic techniques. Further, the molecular structures of compounds 1-8 have been established using single crystal X-ray diffraction studies. Compound 1 is a mononuclear complex in which the dippH ligands occupy trans-positions around the octahedral cobalt ion. The core structure of compounds 2-5, a Co2P2O4 ring, resembles the S4R (single-4-ring) SBU of zeolites, whereas the Co4P4O12 inorganic core found in compounds 6 and 7 resembles the D4R (double-4-ring) SBU. Cobalt organophosphate framework 8 shows significant CO2 adsorption at 273 K (7.73 wt% at 1 bar and 18.21 wt% at 15.5 bar) with high selectivity to CO2 uptake over N2 and H2 at 273 K. Magnetic studies of these symmetric complexes indicate the presence of weak antiferromagnetic interactions between the metal ions via the phosphate bridging moiety. PMID- 25697756 TI - Variability in Acetaminophen Labeling Practices: a Missed Opportunity to Enhance Patient Safety. AB - Confusion regarding a drug's active ingredient may lead to simultaneous use of multiple acetaminophen-containing prescriptions and increase the risk of unintentional overdose. The objective of this study was to examine prescription labeling practices for commonly prescribed acetaminophen-containing analgesics, specifically focusing on how active ingredient information and concomitant use warnings were conveyed. Patients with new acetaminophen-containing prescriptions were recruited upon discharge from an emergency department in Chicago or at an outpatient, hospital-based pharmacy in Atlanta. Label information was transcribed from prescription bottles and patients' knowledge of active ingredient was assessed by in-person interviews. Among the 245 acetaminophen-containing prescriptions, hydrocodone was the most common second active ingredient (n = 208, 84.8 %) followed by oxycodone (n = 28, 11.4 %). Acetaminophen was identified by its full name on 6.9 % (n = 17) of labels; various abbreviations were used in 93.1 % of cases. One hundred forty-seven bottles used auxiliary warning labels with the majority of labels (n = 130, 88.4 %) warning about maximum dose and 11.5 % (n = 17) about concomitant use. Most of the study participants (n = 177, 72.2 %) were not able to identify acetaminophen as an active ingredient in their prescription. There was no significant association between the use of unabbreviated labels including warning information and patients' awareness of acetaminophen as an active ingredient (36.4 vs. 27.3 %, p = 0.50). We noted high variability in labeling practices and warning information conveyed to patients receiving acetaminophen-containing prescriptions. Missed opportunities to adequately convey risk information may contribute to the burden of acetaminophen related liver injury. PMID- 25697758 TI - Dicopper(II) metallacyclophanes as multifunctional magnetic devices: a joint experimental and computational study. AB - Metallosupramolecular complexes constitute an important advance in the emerging fields of molecular spintronics and quantum computation and a useful platform in the development of active components of spintronic circuits and quantum computers for applications in information processing and storage. The external control of chemical reactivity (electro- and photochemical) and physical properties (electronic and magnetic) in metallosupramolecular complexes is a current challenge in supramolecular coordination chemistry, which lies at the interface of several other supramolecular disciplines, including electro-, photo-, and magnetochemistry. The specific control of current flow or spin delocalization through a molecular assembly in response to one or many input signals leads to the concept of developing a molecule-based spintronics that can be viewed as a potential alternative to the classical molecule-based electronics. A great variety of factors can influence over these electronically or magnetically coupled, metallosupramolecular complexes in a reversible manner, electronic or photonic external stimuli being the most promising ones. The response ability of the metal centers and/or the organic bridging ligands to the application of an electric field or light irradiation, together with the geometrical features that allow the precise positioning in space of substituent groups, make these metal organic systems particularly suitable to build highly integrated molecular spintronic circuits. In this Account, we describe the chemistry and physics of dinuclear copper(II) metallacyclophanes with oxamato-containing dinucleating ligands featuring redox- and photoactive aromatic spacers. Our recent works on dicopper(II) metallacyclophanes and earlier ones on related organic cyclophanes are now compared in a critical manner. Special focus is placed on the ligand design as well as in the combination of experimental and computational methods to demonstrate the multifunctionality nature of these metallosupramolecular complexes. This new class of oxamato-based dicopper(II) metallacyclophanes affords an excellent synthetic and theoretical set of models for both chemical and physical fundamental studies on redox- and photo-triggered, long-distance electron exchange phenomena, which are two major topics in molecular magnetism and molecular electronics. Apart from their use as ground tests for the fundamental research on the relative importance of the spin delocalization and spin polarization mechanisms of the electron exchange interaction through extended pi-conjugated aromatic ligands in polymetallic complexes, oxamato-based dicopper(II) metallacyclophanes possessing spin-containing electro- and chromophores at the metal and/or the ligand counterparts emerge as potentially active (magnetic and electronic) molecular components to build a metal-based spintronic circuit. They are thus unique examples of multifunctional magnetic complexes to get single-molecule spintronic devices by controlling and allowing the spin communication, when serving as molecular magnetic couplers and wires, or by exhibiting bistable spin behavior, when acting as molecular magnetic rectifiers and switches. Oxamato-based dicopper(II) metallacyclophanes also emerge as potential candidates for the study of coherent electron transport through single molecules, both experimentally and theoretically. The results presented herein, which are a first step in the metallosupramolecular approach to molecular spintronics, intend to attract the attention of physicists and materials scientists with a large expertice in the manipulation and measurement of single-molecule electron transport properties, as well as in the processing and addressing of molecules on different supports. PMID- 25697759 TI - First report of identification of livestock-associated MRSA ST9 in retail meat in England. AB - Sixty percent of all meat consumed in the UK is imported from European countries where there have been increasing reports of methicillin-resistant Staphylococcus aureus (MRSA) identified in food-producing animals, but rarely from such animals in the UK. Thirty samples each of raw chicken, pork and beef, sourced in England, were collected from retail outlets in Greater Manchester. MRSA was recovered from three chicken samples and one each of pork and beef, all from prepackaged supermarket meat. Four isolates were identified as representatives of the most common human healthcare-associated MRSA clone in the UK [EMRSA-15, spa type t032, belonging to multilocus sequence type clonal complex 22 (MLST-CC22)], suggesting contamination from human source(s) during meat processing. The fifth isolate (from chicken) was multiply-resistant (including oxacillin, ciprofloxacin, erythromycin, clindamycin and tetracycline), identified as ST9-SCCmecIV, spa type t1939 and lacked the immune evasion cluster, a characteristic of livestock associated strains. This lineage has been identified previously from animals and meat products in Asia and mainland Europe but not the UK. PMID- 25697760 TI - Methodological aspects of the molecular and histological study of prostate cancer: focus on PTEN. AB - Prostate cancer is among the most frequent cancers in men, and despite its high rate of cure, the high number of cases results in an elevated mortality worldwide. Importantly, prostate cancer incidence is dramatically increasing in western societies in the past decades, suggesting that this type of tumor is exquisitely sensitive to lifestyle changes. Prostate cancer frequently exhibits alterations in the PTEN gene (inactivating mutations or gene deletions) or at the protein level (reduced protein expression or altered sub-cellular compartmentalization). The relevance of PTEN in this type of cancer is further supported by the fact that the sole deletion of PTEN in the murine prostate epithelium recapitulates many of the features of the human disease. In order to study the molecular alterations in prostate cancer, we need to overcome the methodological challenges that this tissue imposes. In this review we present protocols and methods, using PTEN as proof of concept, to study different molecular characteristics of prostate cancer. PMID- 25697762 TI - Erratum to: The impact of hydrophobic hernia mesh coating by omega fatty acid on atraumatic fibrin sealant fixation. AB - Erratum to: Hernia DOI 10.1007/s10029-014-1304-y. The authors would like to notify readers that unfortunately, Fig. 1 and associated captions are incorrectly published in the original publication. The correct figure and legend are given here. PMID- 25697761 TI - Biophysical methods for the characterization of PTEN/lipid bilayer interactions. AB - PTEN, a tumor suppressor protein that dephosphorylates phosphoinositides at the 3 position of the inositol ring, is a cytosolic protein that needs to associate with the plasma membrane or other subcellular membranes to exert its lipid phosphatase function. Upon membrane association PTEN interacts with at least three different lipid entities: An anionic lipid that is present in sufficiently high concentration to create a negative potential that allows PTEN to interact electrostatically with the membrane, phosphatidylinositol-4,5-bisphosphate, which interacts with PTEN's N-terminal end and the substrate, usually phosphatidylinositol-3,4,5-trisphosphate. Many parameters influence PTEN's interaction with the lipid bilayer, for example, the lateral organization of the lipids or the presence of other chemical species like cholesterol or other lipids. To investigate systematically the different steps of PTEN's complex binding mechanism and to explore its dynamic behavior in the membrane bound state, in vitro methods need to be employed that allow for a systematic variation of the experimental conditions. In this review we survey a variety of methods that can be used to assess PTEN lipid binding affinity, the dynamics of its membrane association as well as its dynamic behavior in the membrane bound state. PMID- 25697763 TI - Extracorporeal shock wave therapy and ultrasound therapy improve pain and function in patients with carpal tunnel syndrome. A randomized controlled trial. AB - BACKGROUND: Ultrasound (US) therapy improves symptoms in carpal tunnel syndrome (CTS) patients. Extracorporeal shock wave therapy (ESWT) uses acoustic energy to determine its clinical effects, as US-therapy does. AIM: The aim of this study was to compare the short-term efficacy of US and ESWT on mild and moderate CTS. STUDY DESIGN: Randomized controlled trial. SETTING: University outpatient service. POPULATION: Twenty-five patients with mild to moderate CTS, for a total of 42 wrists. METHODS: patients were randomized to receive US, cryo-US or ESWT, and were evaluated for pain and function before treatment started, at the end of treatment, and four and 12 weeks after the end of the treatment. RESULTS: Significant improvement was noted in all groups for pain (P<0.05) and functionality (P<0.05). Patients in ESWT group show greater pain improvement at 12-weeks follow-up when compared with both US and cryo-US groups (P<0.05). CONCLUSION: Patients affected by CTS might benefit from the application of US, cryo-US or ESWT. Benefits persist 3 months after the end of treatment. CLINICAL REHABIL IMPACT: Clinicians might consider the possibility of a short-term non surgical management for mild-to-moderate CTS. PMID- 25697764 TI - An octave-spanning mid-infrared frequency comb generated in a silicon nanophotonic wire waveguide. AB - Laser frequency combs, sources with a spectrum consisting of hundred thousands evenly spaced narrow lines, have an exhilarating potential for new approaches to molecular spectroscopy and sensing in the mid-infrared region. The generation of such broadband coherent sources is presently under active exploration. Technical challenges have slowed down such developments. Identifying a versatile highly nonlinear medium for significantly broadening a mid-infrared comb spectrum remains challenging. Here we take a different approach to spectral broadening of mid-infrared frequency combs and investigate CMOS-compatible highly nonlinear dispersion-engineered silicon nanophotonic waveguides on a silicon-on-insulator chip. We record octave-spanning (1,500-3,300 nm) spectra with a coupled input pulse energy as low as 16 pJ. We demonstrate phase-coherent comb spectra broadened on a room-temperature-operating CMOS-compatible chip. PMID- 25697765 TI - Face washing promotion for preventing active trachoma. AB - BACKGROUND: Trachoma remains a major cause of avoidable blindness among underprivileged populations in many developing countries. It is estimated that about 146 million people have active trachoma and nearly six million people are blind due to complications associated with repeat infections. OBJECTIVES: The objective of this review was to assess the effects of face washing promotion for the prevention of active trachoma in endemic communities. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (2015, Issue 1), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to January 2015), EMBASE (January 1980 to January 2015), PubMed (January 1948 to January 2015), Latin American and Caribbean Health Sciences Literature Database (LILACS) (January 1982 to January 2015), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com) (accessed 10 January 2014), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 26 January 2015.To identify further relevant trials we checked the reference lists of the included trials. Also, we used the Science Citation Index to search for references to publications that cited the trials included in the review. We contacted investigators and experts in the field to identify additional trials. SELECTION CRITERIA: We included randomized controlled trials (RCTs) or quasi-RCTs that compared face washing with no treatment or face washing combined with antibiotics against antibiotics alone. Trial participants were residents of endemic trachoma communities. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed trial quality. We contacted trial authors for additional information when needed. Two trials met our inclusion criteria; but we did not conduct meta analysis due to methodological heterogeneity. MAIN RESULTS: We included two cluster-RCTs, which provided data from 2447 participants. Both trials were conducted in areas endemic to trachoma: Northern Australia and Tanzania. The follow-up period was three months in one trial and 12 months in the other; both trials had about 90% participant follow-up at final visit. Overall the quality of the evidence is uncertain due to the trials not reporting many design methods and the differences in outcomes reported between trials.Face washing combined with topical tetracycline was compared with topical tetracycline alone in three pairs of villages in one trial. The trial found that face washing combined with topical tetracycline reduced 'severe' active trachoma compared with topical tetracycline alone at 12 months (adjusted odds ratio (OR) 0.62, 95% confidence interval (CI) 0.40 to 0.97); however, the trial did not find any important difference between the intervention and control villages in reducing other types of active trachoma (adjusted OR 0.81, 95% CI 0.42 to 1.59). Intervention villages had a higher prevalence of clean faces than the control villages among children with severe trachoma (adjusted OR 0.35, 95% CI 0.21 to 0.59) and any trachoma (adjusted OR 0.58, 95% CI 0.47 to 0.72) at 12 months follow-up. The second trial compared eye washing to no treatment or to topical tetracycline alone or to a combination of eye washing and tetracycline drops in children with follicular trachoma. At three months, the trial found no evidence of benefit of eye washing alone or in combination with tetracycline eye drops in reducing follicular trachoma amongst children with follicular trachoma (risk ratio (RR) 1.03, 95% CI 0.96 to 1.11; one trial, 1143 participants). AUTHORS' CONCLUSIONS: There is evidence from one trial that face washing combined with topical tetracycline may be effective in reducing severe active trachoma and in increasing the prevalence of clean faces at one year follow-up. Current evidence is inconclusive as to the effectiveness of face washing alone or in combination with topical tetracycline in reducing active or severe trachoma. PMID- 25697766 TI - Open access publishing: scholarly or predatory? PMID- 25697767 TI - Childhood trauma exposure and toxic stress: what the PNP needs to know. AB - Trauma exposure in childhood is a major public health problem that can result in lifelong mental and physical health consequences. Pediatric nurse practitioners must improve their skills in the identification of trauma exposure in children and their interventions with these children. This continuing education article will describe childhood trauma exposure (adverse childhood experiences) and toxic stress and their effects on the developing brain and body. Adverse childhood experiences include a unique set of trauma exposures. The adverse childhood experiences or trauma discussed in this continuing education offering will include childhood exposure to emotional abuse, physical abuse, sexual abuse, emotional neglect, physical neglect, domestic violence, household substance abuse, household mental illness, parental separation or divorce, and a criminal household member. Thorough and efficient methods of screening for trauma exposure will be discussed. Appropriate intervention after identification of trauma exposure will be explored. PMID- 25697768 TI - Lupus in Latin-American patients: lessons from the GLADEL cohort. AB - The need for comprehensive published epidemiologic and clinical data from Latin American systemic lupus erythematosus (SLE) patients motivated the late Dr Alarcon-Segovia and other Latin American professionals taking care of these patients to spearhead the creation of the G: rupo L: atino A: mericano D: e E: studio del L: upus (GLADEL) cohort in 1997. This inception cohort recruited a total of 1480 multiethnic (Mestizo, African-Latin American (ALA), Caucasian and other) SLE patients diagnosed within two years from the time of enrollment from 34 Latin American centers with expertise in the diagnosis and management of this disease. In addition to the initial 2004 description of the cohort, GLADEL has contributed to improving our knowledge about the course and outcome of lupus in patients from this part of the Americas. The major findings from this cohort are highlighted in this review. They have had important clinical implications for the adequate care of SLE patients both in Latin America and worldwide where these patients may have emigrated. PMID- 25697769 TI - The association between antiphospholipid antibodies and pregnancy morbidity, stroke, myocardial infarction, and deep vein thrombosis: a critical review of the literature. AB - In a previous systematic literature search, we demonstrated that the frequencies of antiphospholipid antibodies (aPL) in general-population patients with pregnancy morbidity (PM), deep vein thrombosis (DVT), myocardial infarction (MI), and stroke (ST) are 6%, 10%, 11%, and 14%. To determine the association between aPL and clinical outcomes, we conducted a follow-up analysis of the 120 studies included in the original paper. Based on the analysis of 81 studies, a significant difference in the frequency of aPL criteria tests between patients and controls emerged considering all the outcomes together (10% versus 3%). In particular, a significant difference was reported for overall PM, pregnancy loss (PrL), late PrL, severe preeclampsia (PEC), ST, MI, and DVT. No difference emerged for early PrL, intrauterine growth restriction (IUGR), PEC, eclampsia (EC), and HELLP. A positive association was found in more than half of the studies for overall PrL, severe PEC, HELLP, ST, MI, and DVT and in less than half for early and late PrL, PEC, EC, and IUGR. The positive association between aPL and clinical outcomes included in the antiphospholipid syndrome classification criteria is not supported by every study, being particularly inconsistent for early PL, IUGR, PEC, EC, and HELLP. PMID- 25697770 TI - Evaluation of early cardiac dysfunction in patients with systemic lupus erythematosus with or without anticardiolipin antibodies. AB - The aim of this study was to use transthoracic Doppler echocardiographic (TTE) imaging methods to identify cardiac dysfunction, an indicator of subclinical atherosclerosis in asymptomatic systemic lupus erythematosus (SLE) patients in terms of cardiac effects. This study involved 80 patients: a study group (n = 50) and control group (n = 30). They were categorized into four subgroups: anticardiolipin antibodies (aCL) (+) (n = 14) and aCL (-) (n = 36); systemic lupus erythematosus disease activity index (SLEDAI) >= 6 (n = 15) and SLEDAI < 6 (n = 35); disease period >= 5 years (n = 21) and disease period < 5 years (n = 29); major organ involvement (+) (n = 19), major organ involvement (-) (n = 31). The ratio of mitral peak velocity of early filling to early diastolic mitral annular velocity (E/E') for the study group was found to be higher than the control (p < 0.01). Systolic septal motion velocity (Ssm) was lower in the study group compared with the control (p < 0.01). Left atrium (LA) dimension was greater in the study group than the control (p < 0.01). Ssm was found to be lower in the aCL (+) patients compared with the control and aCL (-) groups (p < 0.01, p < 0.05, respectively). LA dimension was greater in the aCL (+) and (-) groups compared with the control, (p < 0.01, p < 0.05, respectively) and aCL groups compared with each other (p < 0.05). The E/E' ratio for the aCL (+) and (-) groups was found to be greater than the control (p < 0.05). In the study, both the Ssm and the late diastolic septal velocity (sA') was found to be lower in the SLEDAI >= 6 group compared with SLEDAI<6 group, (p < 0.001, p < 0.05, respectively). LA dimension was statistically greater in the SLEDAI >= 6 group compared with the SLEDAI <6 group (p < 0.001). E' and early diastolic septal velocity (sE') were statistically lower in the disease period >5 years group compared with the disease period <5 years group (p < 0.01, p < 0.05, respectively). Carrying out regular scans with TTE image of SLE patients is important in order to identify early cardiac involvement during monitoring and treatment. Identifying early cardiac involvement in SLE may lead to a reduction in mortality and morbidity rates. PMID- 25697771 TI - The role of antiphospholipid autoantibodies in the cognitive deficits of patients with systemic lupus erythematosus. AB - OBJECTIVE: To analyze the role of the antiphospholipid autoantibodies (aPL) on the neuropsychological deficits in systemic lupus erythematosus (SLE) patients, comparing groups of patients with antiphospholipid syndrome (APS; n = 15), SLE with aPL (n = 12), and SLE without aPL (n = 27), and a healthy control group (n = 31). METHODS: Patients fulfilled the American College of Rheumatology SLE classification criteria or the Sydney criteria for APS. All participants were woman, and groups were matched on age and education. A standardized cognitive examination classified patients as cognitively declined or impaired according to the American College of Rheumatology. RESULTS: Differences between the groups were found in all of the studied variables, comprising attention and executive functions (sustained and selective attention, fluency, and inhibition), and memory (verbal and visual). Post-hoc analyses showed cognitive performance was equivalent between APS and SLE with aPL. Differences between SLE without aPL and control groups were found only in four of the 10 studied variables, while differences in all but two memory variables were found between SLE without aPL and control groups. Furthermore, cognitive deficit was three times more frequent in APS and SLE with aPL patients than for the control group (80%, 75%, and 16%, respectively), and two times more frequent compared to SLE patients without aPL (48%). CONCLUSIONS: Our results support the relationship between aPL and cognitive symptoms in SLE. Also, almost half of the patients with SLE and no aPL showed cognitive problems, pointing to the multifactorial causes of cognitive problems in SLE. Future research with larger sample size is guaranteed to replicate our results. PMID- 25697772 TI - Lifestyle habits and fatigue among people with systemic lupus erythematosus and matched population controls. AB - OBJECTIVE: The objective of this paper is to identify clusters of fatigue in patients with systemic lupus erythematosus (SLE) and matched controls, and to analyze these clusters with respect to lifestyle habits, health-related quality of life (HRQoL), anxiety and depression. METHODS: Patients with SLE (n = 305) and age- and gender-matched population controls (n = 311) were included. Three measurements of fatigue (Fatigue Severity Scale (FSS), Vitality (VT, from SF-36) and Multidimensional Assessment of Fatigue scale (MAF) and hierarchic cluster analysis were used to define clusters with different degrees of fatigue. Lifestyle habits were investigated through questionnaires. HRQoL was assessed with the SF-36 and anxiety/depression with the Hospital Anxiety and Depression Scale. RESULTS: Three clusters, denominated "High," "Intermediate" and "Low" fatigue clusters, were identified. The "High" contained 80% patients, and 20% controls (median; VT 25, FSS 5.8, MAF 37.4). These had the most symptoms of depression (51%) and anxiety (34%), lowest HRQoL (p < 0.001) and they exercised least frequently. The "Intermediate" (48% patients and 52% controls) (median; VT 55, FSS 4.1, MAF 23.5) had similarities with the "Low" regarding sleep/rest whereas social status and smoking were closer to the "High." The"Low" contained 22% patients and 78% controls (median; VT 80, FSS 2.3, MAF 10.9). They had the highest perceived HRQoL (p < 0.001), least symptoms of anxiety (10%), no depression, smoked least (13%) and reported the highest percentage (24%) of exercising >= 3 times/week. CONCLUSION: Fatigue is common, but not a general feature of SLE. It is associated with depression, anxiety, low HRQoL and less physical exercise. Patients with SLE and population controls with a healthy lifestyle reported lower levels of fatigue. Whether lifestyle changes can reduce fatigue, which is a major problem for a majority of SLE patients, needs to be further explored. PMID- 25697773 TI - Automated retinal image analysis for diabetic retinopathy in telemedicine. AB - There will be an estimated 552 million persons with diabetes globally by the year 2030. Over half of these individuals will develop diabetic retinopathy, representing a nearly insurmountable burden for providing diabetes eye care. Telemedicine programmes have the capability to distribute quality eye care to virtually any location and address the lack of access to ophthalmic services. In most programmes, there is currently a heavy reliance on specially trained retinal image graders, a resource in short supply worldwide. These factors necessitate an image grading automation process to increase the speed of retinal image evaluation while maintaining accuracy and cost effectiveness. Several automatic retinal image analysis systems designed for use in telemedicine have recently become commercially available. Such systems have the potential to substantially improve the manner by which diabetes eye care is delivered by providing automated real-time evaluation to expedite diagnosis and referral if required. Furthermore, integration with electronic medical records may allow a more accurate prognostication for individual patients and may provide predictive modelling of medical risk factors based on broad population data. PMID- 25697774 TI - Incidence and risk of hypertension with ramucirumab in cancer patients: a meta analysis of published studies. AB - BACKGROUND AND OBJECTIVE: Ramucirumab is a novel antiangiogenic agent approved as second-line therapy for patients with advanced stomach cancer and gastroesophageal junction adenocarcinoma. Although existing evidence from clinical trials has demonstrated hypertension is one of the major adverse events of this agent, overall risks have yet to be reported. METHODS: We carried out a meta-analysis of published studies to determine the overall incidence and relative risk (RR) of hypertension associated with ramucirumab. Statistical analyses were conducted to calculate the summary incidence, RRs, and 95 % confidence intervals (CIs) by using a random effects model. RESULTS: Eleven studies with a total of 3,851 patients with multiple cancers were included. The overall incidence of all-grade hypertension was 20.0 % (95 % CI 15.0-26.0) with 8.6 % (95 % CI 6.3-11.7) being high-grade hypertension. The risk of developing hypertension was greater in ramucirumab-treated patients (RR for all grades 2.77, 95 % CI 1.94-3.94, p < 0.001, RR for high-grade 3.58, 95 % CI 2.45-5.23, p < 0.001). CONCLUSIONS: Administration of ramucirumab to patients with cancer is associated with increased risk of hypertension. PMID- 25697775 TI - Triple helix conformation-specific blinking of Cy3 in DNA. AB - We report that Cy3 undergoes triple helix conformation-specific blinking in DNA. Blinking patterns were affected by the stabilization of the Hoogsteen base-pair, suggesting that not only the presence but also the fluctuating behaviour of the triple helix can be monitored by the changes in the Cy3 blinking patterns. PMID- 25697777 TI - Structures and functions of protein disulfide isomerase family members involved in proteostasis in the endoplasmic reticulum. AB - The endoplasmic reticulum (ER) is an essential cellular compartment in which an enormous number of secretory and cell surface membrane proteins are synthesized and subjected to cotranslational or posttranslational modifications, such as glycosylation and disulfide bond formation. Proper maintenance of ER protein homeostasis (sometimes termed proteostasis) is essential to avoid cellular stresses and diseases caused by abnormal proteins. Accumulating knowledge of cysteine-based redox reactions catalyzed by members of the protein disulfide isomerase (PDI) family has revealed that these enzymes play pivotal roles in productive protein folding accompanied by disulfide formation, as well as efficient ER-associated degradation accompanied by disulfide reduction. Each of PDI family members forms a protein-protein interaction with a preferential partner to fulfill a distinct function. Multiple redox pathways that utilize PDIs appear to function synergistically to attain the highest quality and productivity of the ER, even under various stress conditions. This review describes the structures, physiological functions, and cooperative actions of several essential PDIs, and provides important insights into the elaborate proteostatic mechanisms that have evolved in the extremely active and stress-sensitive ER. PMID- 25697776 TI - A PDI-catalyzed thiol-disulfide switch regulates the production of hydrogen peroxide by human Ero1. AB - Oxidative folding in the endoplasmic reticulum (ER) involves ER oxidoreductin 1 (Ero1)-mediated disulfide formation in protein disulfide isomerase (PDI). In this process, Ero1 consumes oxygen (O2) and releases hydrogen peroxide (H2O2), but none of the published Ero1 crystal structures reveal any potential pathway for entry and exit of these reactants. We report that additional mutation of the Cys(208)-Cys(241) disulfide in hyperactive Ero1alpha (Ero1alpha-C104A/C131A) potentiates H2O2 production, ER oxidation, and cell toxicity. This disulfide clamps two helices that seal the flavin cofactor where O2 is reduced to H2O2. Through its carboxyterminal active site, PDI unlocks this seal by forming a Cys(208)/Cys(241)-dependent mixed-disulfide complex with Ero1alpha. The H2O2 detoxifying glutathione peroxidase 8 also binds to the Cys(208)/Cys(241) loop region. Supported by O2 diffusion simulations, these data describe the first enzymatically controlled O2 access into a flavoprotein active site, provide molecular-level understanding of Ero1alpha regulation and H2O2 production/detoxification, and establish the deleterious consequences of constitutive Ero1 activity. PMID- 25697778 TI - Protein disulfide-isomerase, a folding catalyst and a redox-regulated chaperone. AB - Protein disulfide-isomerase (PDI) was the first protein-folding catalyst to be characterized, half a century ago. It plays critical roles in a variety of physiological events by displaying oxidoreductase and redox-regulated chaperone activities. This review provides a brief history of the identification of PDI as both an enzyme and a molecular chaperone and of the recent advances in studies on the structure and dynamics of PDI, the substrate binding and release, and the cooperation with its partners to catalyze oxidative protein folding and maintain ER redox homeostasis. In this review, we highlight the structural features of PDI, including the high interdomain flexibility, the multiple binding sites, the two synergic active sites, and the redox-dependent conformational changes. PMID- 25697779 TI - MKK3 mediates inflammatory response through modulation of mitochondrial function. AB - Mitochondria are increasingly recognized as drivers of inflammatory responses. MAP kinase kinase 3 (MKK3), a dual-specificity protein kinase, is activated in inflammation and in turn activates p38 MAP kinase signaling. Here we show that MKK3 influences mitochondrial function and acts as a critical mediator of inflammation. MKK3-deficient (MKK3(-/-)) mice and bone marrow-derived macrophages (BMDMs) secreted smaller amounts of cytokines than wild type (WT) after lipopolysaccharide (LPS) exposure. There was improved mitochondrial function, as measured by basal oxygen consumption rate, mitochondrial membrane potential, and ATP production, in MKK3(-/-) BMDMs. After LPS exposure, MKK3(-/-) BMDMs did not show a significant increase in cellular reactive oxygen species production or in mitochondrial superoxide compared to WT. Activation of two important inflammatory mediators, i.e., the nuclear translocation of NF-kappaB and caspase-1 activity (a key component of the inflammasome), was lower in MKK3(-/-) BMDMs. p38 and JNK activation was lower in MKK3(-/-) BMDMs compared to WT after exposure to LPS. Knockdown of MKK3 by siRNA in wild-type BMDMs improved mitochondrial membrane potential, reduced LPS-induced caspase-1 activation, and attenuated cytokine secretion. Our studies establish MKK3 as a regulator of mitochondrial function and inflammatory responses to LPS and suggest that MKK3 may be a therapeutic target in inflammatory disorders such as sepsis. PMID- 25697780 TI - Ligand-enabled beta-C-H arylation of alpha-amino acids using a simple and practical auxiliary. AB - Pd-catalyzed beta-C-H functionalizations of carboxylic acid derivatives using an auxiliary as a directing group have been extensively explored in the past decade. In comparison to the most widely used auxiliaries in asymmetric synthesis, the simplicity and practicality of the auxiliaries developed for C-H activation remains to be improved. We previously developed a simple N-methoxyamide auxiliary to direct beta-C-H activation, albeit this system was not compatible with carboxylic acids containing alpha-hydrogen atoms. Herein we report the development of a pyridine-type ligand that overcomes this limitation of the N methoxyamide auxiliary, leading to a significant improvement of beta-arylation of carboxylic acid derivatives, especially alpha-amino acids. The arylation using this practical auxiliary is applied to the gram-scale syntheses of unnatural amino acids, bioactive molecules, and chiral bis(oxazoline) ligands. PMID- 25697781 TI - Dopaminergic medication alters auditory distractor processing in Parkinson's disease. AB - Parkinson's disease (PD) patients show signs of cognitive impairment, such as executive dysfunction, working memory problems and attentional disturbances, even in the early stages of the disease. Though motor symptoms of the disease are often successfully addressed by dopaminergic medication, it still remains unclear, how dopaminergic therapy affects cognitive function. The main objective of this study was to assess the effect of dopaminergic medication on visual and auditory attentional processing. 14 PD patients and 13 matched healthy controls performed a three-stimulus auditory and visual oddball task while their EEG was recorded. The patients performed the task twice, once on- and once off medication. While the results showed no significant differences between PD patients and controls, they did reveal a significant increase in P3 amplitude on- vs. off-medication specific to processing of auditory distractors and no other stimuli. These results indicate significant effect of dopaminergic therapy on processing of distracting auditory stimuli. With a lack of between group differences the effect could reflect either 1) improved recruitment of attentional resources to auditory distractors; 2) reduced ability for cognitive inhibition of auditory distractors; 3) increased response to distractor stimuli resulting in impaired cognitive performance; or 4) hindered ability to discriminate between auditory distractors and targets. Further studies are needed to differentiate between these possibilities. PMID- 25697782 TI - Proactive and retroactive transfer of middle age adults in a sequential motor learning task. AB - We assessed the effects of aging in the transfer of motor learning in a sequential manual assembly task that is representative for real working conditions. On two different days, young (18-30 years) and middle-aged adults (50 65 years) practiced to build two products that consisted of the same six components but which had to be assembled in a partly different order. Assembly accuracy and movement time during tests, which were performed before and after the practice sessions, were compared to determine proactive and retroactive transfer. The results showed proactive facilitation (i.e., benefits from having learned the first product on learning the second one) in terms of an overall shortening of movement time in both age-groups. In addition, only the middle-aged adults were found to show sequence-specific proactive facilitation, in which the shortening of movement time was limited to components that had the same the order in the two products. Most likely, however, the sequence-specific transfer was an epiphenomenon of the comparatively low rate of learning among the middle-aged adults. The results, however, did reveal genuine differences between the groups for retroactive transfer (i.e., effects from learning the second product on performance of the first). Middle-aged adults tended to show more pronounced retroactive interference in terms of a general decrease in accuracy, while younger adults showed sequence-specific retroactive facilitation (i.e., shortening of movement times for components that had the same order in the two products), but only when they were fully accurate. Together this suggests that in the learning of sequential motor tasks the effects of age are more marked for retroactive transfer than for proactive transfer. PMID- 25697784 TI - Sigmoid colon diverticulum perforated by a chicken bone. PMID- 25697785 TI - Proinflammatory and anti-inflammatory cytokine profile in pediatric patients with irritable bowel syndrome. AB - BACKGROUND AND OBJECTIVES: There is evidence that patients with irritable bowel syndrome (IBS) have a low degree of inflammation in the intestinal mucosa. The aim of the study was to evaluate the profile of pro- and anti-inflammatory cytokines in plasma in Mexican pediatric patients with IBS. PATIENTS AND METHODS: Fifteen patients with IBS according to Rome III criteria for childhood and 15 healthy children, matched by age and sex, were included in the study. Plasma levels of tumoral necrosis factor alpha (TNF-alpha), interleukins 10 and 12 (IL 10, IL-12) and transforming growth factor beta (TGF-beta) were quantified and compared between groups. RESULTS: Plasma levels of IL-10 were lower in patients with IBS (86.07+21.3 pg/mL vs. 118.71+58.62 pg/mL: P=.045) and IL-12 levels were higher in patients with IBS compared to the control group of healthy children (1,204.2+/-585.9 pg/mL vs. 655.04+/-557.80 pg/mL; P=.011). The IL-10/IL-12 index was lower in patients with IBS (0.097+/-0.07 vs. 0.295+/-0.336; P=.025). Plasma concentration of TGF-beta was higher in patients with IBS (545.67+/-337.69 pg/mL vs. 208.48+/-142.21 pg/mL; P=.001). There was no difference in plasma levels of TNF-alpha between groups. CONCLUSIONS: This study suggests that children with IBS have a state of altered immune regulation. This is consistent with the theory of low-grade inflammatory state in these patients. Further studies are needed to elucidate the role played by these cytokines, specifically TGF-beta in the pathogenesis of IBS. PMID- 25697786 TI - Association between the presence of sperm in the vasal fluid during vasectomy reversal and postoperative patency: a systematic review and meta-analysis. AB - OBJECTIVE: To investigate the association between the presence of sperm in the vasal fluid during vasectomy reversal (VR) and postoperative patency. METHODS: We performed a systematic review and meta-analysis of the English-language literature reporting on the association between the presence of sperm in the intraoperative vasal fluid (ie, whole or parts vs none) and patency (ie, patent or not) after microsurgical vasovasostomy for men with obstructive azoospermia due to vasectomy. Odds ratios (OR) and 95% confidence intervals were calculated to quantify the strength of the association reported by each study. Meta-analysis was performed using a random-effects model. RESULTS: Four case series and 2 retrospective cohort studies of a total of 1293 eligible patients were identified. The mean age at VR was 37.8 years, and the mean obstructive interval was 7.1 years. The unadjusted OR of postoperative patency was 4.1 times higher (95% confidence interval, 2.3-7.3) given the presence of intravasal sperm or sperm parts as opposed to their absence at the time of VR (Q = 3.4; df = 5; P = .6; I(2) = 22%). The pooled OR should be interpreted with caution as only the 2 retrospective cohort studies reported meaningful data on this association. Because of inconsistent reporting, analysis of other vasal fluid characteristics (eg, consistency) and outcomes (eg, pregnancy) was not possible. CONCLUSION: The presence of whole sperm or sperm parts in the vasal fluid during VR is positively associated with postoperative patency. Our review highlights the poor methodological quality of existing evidence and underscores the need for more thorough follow up and higher standards of reporting in future studies. PMID- 25697787 TI - Renin-angiotensin system inhibitors linked to anemia: a systematic review and meta-analysis. AB - BACKGROUND: The objective of this meta-analysis was to evaluate the risk of anemia in patients who received renin-angiotensin system (RAS) inhibitors. METHODS: A literature search was performed using MEDLINE, EMBASE, and Cochrane Database of Systematic Reviews from inception through November, 2014. Studies that reported relative risks, odd ratios or hazard ratios comparing the anemia risk in patients who received angiotensin-converting-enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) vs. those who did not were included. We performed the prespecified sensitivity analysis including only only studies with confounder adjusted analysis. Pooled risk ratios (RRs) and 95% confidence interval (CI) were calculated using a random-effect, generic inverse variance method. RESULTS: Seven studies (2 cohort and 5 cross-sectional studies) with 29,061 patients were included in the analysis to assess the risk of anemia and the RAS inhibitors use. The pooled RR of anemia in patients receiving ACEIs was 1.56 (95% CI, 1.40-1.73, I(2) = 17%). When meta-analysis was limited only to studies with confounder adjusted analysis, the pooled RR of anemia in patients using ACEIs was 1.57 (95% CI, 1.43-1.73, I(2) = 0%) The pooled RR of anemia in patients receiving ARBs was 1.60 (95% CI, 1.27-2.00, I(2) = 39%). The meta analysis of studies with confounder adjusted analysis demonstrated the pooled RR of anemia in patients using ARBs of 1.59 (95% CI, 1.38-1.83, I(2) = 0%). CONCLUSIONS: Our meta-analysis demonstrates an association between anemia and the use of RAS inhibitors. Hematological parameters should be monitored in patients treated with RAS inhibitors. PMID- 25697788 TI - Diameter-dependent thermoelectric figure of merit in single-crystalline Bi nanowires. AB - The diameter-dependent thermoelectric properties of individual single-crystalline Bi nanowires grown by the on-film formation of nanowires method have been investigated. The electrical resistivity, Seebeck coefficient, and thermal conductivity were measured as functions of the nanowire diameter using an individual nanowire device. The thermoelectric figure of merit (ZT) calculated from the measured thermoelectric properties shows an increase from the bulk value to a maximum value of 0.28 at 109 nm-diameter, followed by a decrease upon further decreasing the diameter. This non-monotonic diameter dependence of ZT in Bi nanowires reveals simultaneous positive and negative contributions to the thermoelectric efficiency, driven by the change in intrinsic properties, which originates from the diameter-dependent classical and quantum size effects. PMID- 25697789 TI - Utilization of a high-throughput shoot imaging system to examine the dynamic phenotypic responses of a C4 cereal crop plant to nitrogen and water deficiency over time. AB - The use of high-throughput phenotyping systems and non-destructive imaging is widely regarded as a key technology allowing scientists and breeders to develop crops with the ability to perform well under diverse environmental conditions. However, many of these phenotyping studies have been optimized using the model plant Arabidopsis thaliana. In this study, The Plant Accelerator((r)) at The University of Adelaide, Australia, was used to investigate the growth and phenotypic response of the important cereal crop, Sorghum bicolor L. Moench and related hybrids to water-limited conditions and different levels of fertilizer. Imaging in different spectral ranges was used to monitor plant composition, chlorophyll, and moisture content. Phenotypic image analysis accurately measured plant biomass. The data set obtained enabled the responses of the different sorghum varieties to the experimental treatments to be differentiated and modelled. Plant architectural instead of architecture elements were determined using imaging and found to correlate with an improved tolerance to stress, for example diurnal leaf curling and leaf area index. Analysis of colour images revealed that leaf 'greenness' correlated with foliar nitrogen and chlorophyll, while near infrared reflectance (NIR) analysis was a good predictor of water content and leaf thickness, and correlated with plant moisture content. It is shown that imaging sorghum using a high-throughput system can accurately identify and differentiate between growth and specific phenotypic traits. R scripts for robust, parsimonious models are provided to allow other users of phenomic imaging systems to extract useful data readily, and thus relieve a bottleneck in phenotypic screening of multiple genotypes of key crop plants. PMID- 25697790 TI - A defence-related Olea europaea beta-glucosidase hydrolyses and activates oleuropein into a potent protein cross-linking agent. AB - Oleuropein, the major secoiridoid compound in olive, is involved in a sophisticated two-component defence system comprising a beta-glucosidase enzyme that activates oleuropein into a toxic glutaraldehyde-like structure. Although oleuropein deglycosylation studies have been monitored extensively, an oleuropein beta-glucosidase gene has not been characterized as yet. Here, we report the isolation of OeGLU cDNA from olive encoding a beta-glucosidase belonging to the defence-related group of terpenoid-specific glucosidases. In planta recombinant protein expression assays showed that OeGLU deglycosylated and activated oleuropein into a strong protein cross-linker. Homology and docking modelling predicted that OeGLU has a characteristic (beta/alpha)8 TIM barrel conformation and a typical construction of a pocket-shaped substrate recognition domain composed of conserved amino acids supporting the beta-glucosidase activity and non-conserved residues associated with aglycon specificity. Transcriptional analysis in various olive organs revealed that the gene was developmentally regulated, with its transcript levels coinciding well with the spatiotemporal patterns of oleuropein degradation and aglycon accumulation in drupes. OeGLU upregulation in young organs reflects its prominent role in oleuropein-mediated defence system. High gene expression during drupe maturation implies an additional role in olive secondary metabolism, through the degradation of oleuropein and reutilization of hydrolysis products. PMID- 25697791 TI - The identification of new cytosolic glutamine synthetase and asparagine synthetase genes in barley (Hordeum vulgare L.), and their expression during leaf senescence. AB - Glutamine synthetase and asparagine synthetase are two master enzymes involved in ammonium assimilation in plants. Their roles in nitrogen remobilization and nitrogen use efficiency have been proposed. In this report, the genes coding for the cytosolic glutamine synthetases (HvGS1) and asparagine synthetases (HvASN) in barley were identified. In addition to the three HvGS1 and two HvASN sequences previously reported, two prokaryotic-like HvGS1 and three HvASN cDNA sequences were identified. Gene structures were then characterized, obtaining full genomic sequences. The response of the five HvGS1 and five HvASN genes to leaf senescence was then studied. Developmental senescence was studied using primary and flag leaves. Dark-exposure or low-nitrate conditions were also used to trigger stress induced senescence. Well-known senescence markers such as the chlorophyll and Rubisco contents were monitored in order to characterize senescence levels in the different leaves. The three eukaryotic-like HvGS1_1, HvGS1_2, and HvGS1_3 sequences showed the typical senescence-induced reduction in gene expression described in many plant species. By contrast, the two prokaryotic-like HvGS1_4 and HvGS1_5 sequences were repressed by leaf senescence, similar to the HvGS2 gene, which encodes the chloroplast glutamine synthetase isoenzyme. There was a greater contrast in the responses of the five HvASN and this suggested that these genes are needed for N remobilization in senescing leaves only when plants are well fertilized with nitrate. Responses of the HvASN sequences to dark-induced senescence showed that there are two categories of asparagine synthetases, one induced in the dark and the other repressed by the same conditions. PMID- 25697792 TI - MicroRNA: a new target for improving plant tolerance to abiotic stress. AB - MicroRNAs (miRNAs) are an extensive class of endogenous, small RNA molecules that sit at the heart of regulating gene expression in multiple developmental and signalling pathways. Recent studies have shown that abiotic stresses induce aberrant expression of many miRNAs, thus suggesting that miRNAs may be a new target for genetically improving plant tolerance to certain stresses. These studies have also shown that miRNAs respond to environmental stresses in a miRNA , stress-, tissue-, and genotype-dependent manner. During abiotic stress, miRNAs function by regulating target genes within the miRNA-target gene network and by controlling signalling pathways and root development. Generally speaking, stress induced miRNAs lead to down-regulation of negative regulators of stress tolerance whereas stress-inhibited miRNAs allow the accumulation and function of positive regulators. Currently, the majority of miRNA-based studies have focused on the identification of miRNAs that are responsive to different stress conditions and analysing their expression profile changes during these treatments. This has predominately been accomplished using deep sequencing technologies and other expression analyses, such as quantitative real-time PCR. In the future, more function and expression studies will be necessary in order to elucidate the common miRNA-mediated regulatory mechanisms that underlie tolerance to different abiotic stresses. The use of artificial miRNAs, as well as overexpression and knockout/down of both miRNAs and their targets, will be the best techniques for determining the specific roles of individual miRNAs in response to environmental stresses. PMID- 25697793 TI - Common and specific responses to availability of mineral nutrients and water. AB - Changes in resource (mineral nutrients and water) availability, due to their heterogeneous distribution in space and time, affect plant development. Plants need to sense these changes to optimize growth and biomass allocation by integrating root and shoot growth. Since a limited supply of water or nutrients can elicit similar physiological responses (the relative activation of root growth at the expense of shoot growth), similar underlying mechanisms may affect perception and acquisition of either nutrients or water. This review compares root and shoot responses to availability of different macronutrients and water. Attention is given to the roles of root-to-shoot signalling and shoot-to-root signalling, with regard to coordinating changes in root and shoot growth and development. Involvement of plant hormones in regulating physiological responses such as stomatal and hydraulic conductance is revealed by measuring the effects of resource availability on phytohormone concentrations in roots and shoots, and their flow between roots and shoots in xylem and phloem saps. More specific evidence can be obtained by measuring the physiological responses of genotypes with altered hormone responses or concentrations. We discuss the similarity and diversity of changes in shoot growth, allocation to root growth, and root architecture under changes in water, nitrate, and phosphorus availability, and the possible involvement of abscisic acid, indole-acetic acid, and cytokinin in their regulation. A better understanding of these mechanisms may contribute to better crop management for efficient use of these resources and to selecting crops for improved performance under suboptimal soil conditions. PMID- 25697794 TI - At the border: the plasma membrane-cell wall continuum. AB - Plant cells rely on their cell walls for directed growth and environmental adaptation. Synthesis and remodelling of the cell walls are membrane-related processes. During cell growth and exposure to external stimuli, there is a constant exchange of lipids, proteins, and other cell wall components between the cytosol and the plasma membrane/apoplast. This exchange of material and the localization of cell wall proteins at certain spots in the plasma membrane seem to rely on a particular membrane composition. In addition, sensors at the plasma membrane detect changes in the cell wall architecture, and activate cytoplasmic signalling schemes and ultimately cell wall remodelling. The apoplastic polysaccharide matrix is, on the other hand, crucial for preventing proteins diffusing uncontrollably in the membrane. Therefore, the cell wall-plasma membrane link is essential for plant development and responses to external stimuli. This review focuses on the relationship between the cell wall and plasma membrane, and its importance for plant tissue organization. PMID- 25697795 TI - Exploring the pleiotropy of hos1. AB - Understanding of the roles that HIGH EXPRESSION OF OSMOTICALLY RESPONSIVE GENE 1 (HOS1) plays in the plant's ability to sense and respond to environmental signals has grown dramatically. Mechanisms through which HOS1 affects plant development have been uncovered, and the broader consequences of hos1 on the plant's ability to perceive and respond to its environment have been investigated. As such, it has been possible to place HOS1 as a key integrator of temperature information in response to both acute signals and cues that indicate time of year into developmental processes that are essential for plant survival. This review summarizes knowledge of HOS1's form and function, and contextualizes this information so that it is relevant for better understanding the processes of cold signalling, flowering time, and nuclear pore complex function more broadly. PMID- 25697796 TI - Differentiating phosphate-dependent and phosphate-independent systemic phosphate starvation response networks in Arabidopsis thaliana through the application of phosphite. AB - Phosphite is a less oxidized form of phosphorus than phosphate. Phosphite is considered to be taken up by the plant through phosphate transporters. It can mimic phosphate to some extent, but it is not metabolized into organophosphates. Phosphite could therefore interfere with phosphorus signalling networks. Typical physiological and transcriptional responses to low phosphate availability were investigated and the short-term kinetics of their reversion by phosphite, compared with phosphate, were determined in both roots and shoots of Arabidopsis thaliana. Phosphite treatment resulted in a strong growth arrest. It mimicked phosphate in causing a reduction in leaf anthocyanins and in the expression of a subset of the phosphate-starvation-responsive genes. However, the kinetics of the response were slower than for phosphate, which may be due to discrimination against phosphite by phosphate transporters PHT1;8 and PHT1;9 causing delayed shoot accumulation of phosphite. Transcripts encoding PHT1;7, lipid-remodelling enzymes such as SQD2, and phosphocholine-producing NMT3 were highly responsive to phosphite, suggesting their regulation by a direct phosphate-sensing network. Genes encoding components associated with the 'PHO regulon' in plants, such as At4, IPS1, and PHO1;H1, generally responded more slowly to phosphite than to phosphate, except for SPX1 in roots and MIR399d in shoots. Two uncharacterized phosphate-responsive E3 ligase genes, PUB35 and C3HC4, were also highly phosphite responsive. These results show that phosphite is a valuable tool to identify network components directly responsive to phosphate. PMID- 25697797 TI - PETAL LOSS, a trihelix transcription factor that represses growth in Arabidopsis thaliana, binds the energy-sensing SnRK1 kinase AKIN10. AB - Organogenesis in plants involves differential growth. Rapidly growing primordia are distinguished from the meristem and each other by slower growing boundaries. PETAL LOSS (PTL) is a trihelix transcription factor of Arabidopsis that represses growth in boundaries between newly arising sepals. To identify partners involved in this growth limitation, a young inflorescence cDNA library was screened by yeast two-hybrid technology with PTL as bait. The most frequent prey identified was AKIN10, the catalytic alpha-subunit of the Snf1-related kinase1 (SnRK1). Interaction was mapped to the C-terminal (non-kinase) half of AKIN10 and the N terminal portion of PTL. Binding of PTL was specific to AKIN10 as there was little binding to the related AKIN11. The interaction was confirmed by co immunoprecipitation in vitro. Fluorescently tagged products of 35S:YFP-AKIN10 and 35S:CFP-PTL also interacted when transiently expressed together in leaf cells of Nicotiana benthamiana. In this case, most of the cytoplasmic AKIN10 was preferentially moved to the nucleus where PTL accumulated, possibly because a nuclear export sequence in AKIN10 was now masked. During these experiments, we observed that AKIN10 could variably accumulate in the Golgi, shown by its co localization with a tagged Golgi marker and through its dispersal by brefeldin A. Tests of phosphorylation of PTL by AKIN10 gave negative results. The functional significance of the PTL-AKIN10 interaction remains open, although a testable hypothesis is that AKIN10 senses lower energy levels in inter-sepal zones and, in association with PTL, promotes reduced cell division. PMID- 25697798 TI - Inside a plant nucleus: discovering the proteins. AB - Nuclear proteins are a vital component of eukaryotic cell nuclei and have a profound effect on the way in which genetic information is stored, expressed, replicated, repaired, and transmitted to daughter cells and progeny. Because of the plethora of functions, nuclear proteins represent the most abundant components of cell nuclei in all eukaryotes. However, while the plant genome is well understood at the DNA level, information on plant nuclear proteins remains scarce, perhaps with the exception of histones and a few other proteins. This lack of knowledge hampers efforts to understand how the plant genome is organized in the nucleus and how it functions. This review focuses on the current state of the art of the analysis of the plant nuclear proteome. Previous proteome studies have generally been designed to search for proteins involved in plant response to various forms of stress or to identify rather a modest number of proteins. Thus, there is a need for more comprehensive and systematic studies of proteins in the nuclei obtained at individual phases of the cell cycle, or isolated from various tissue types and stages of cell and tissue differentiation. All this in combination with protein structure, predicted function, and physical localization in 3D nuclear space could provide much needed progress in our understanding of the plant nuclear proteome and its role in plant genome organization and function. PMID- 25697799 TI - Predicting hepatotoxicity using ToxCast in vitro bioactivity and chemical structure. AB - The U.S. Tox21 and EPA ToxCast program screen thousands of environmental chemicals for bioactivity using hundreds of high-throughput in vitro assays to build predictive models of toxicity. We represented chemicals based on bioactivity and chemical structure descriptors, then used supervised machine learning to predict in vivo hepatotoxic effects. A set of 677 chemicals was represented by 711 in vitro bioactivity descriptors (from ToxCast assays), 4,376 chemical structure descriptors (from QikProp, OpenBabel, PaDEL, and PubChem), and three hepatotoxicity categories (from animal studies). Hepatotoxicants were defined by rat liver histopathology observed after chronic chemical testing and grouped into hypertrophy (161), injury (101) and proliferative lesions (99). Classifiers were built using six machine learning algorithms: linear discriminant analysis (LDA), Naive Bayes (NB), support vector machines (SVM), classification and regression trees (CART), k-nearest neighbors (KNN), and an ensemble of these classifiers (ENSMB). Classifiers of hepatotoxicity were built using chemical structure descriptors, ToxCast bioactivity descriptors, and hybrid descriptors. Predictive performance was evaluated using 10-fold cross-validation testing and in-loop, filter-based, feature subset selection. Hybrid classifiers had the best balanced accuracy for predicting hypertrophy (0.84 +/- 0.08), injury (0.80 +/- 0.09), and proliferative lesions (0.80 +/- 0.10). Though chemical and bioactivity classifiers had a similar balanced accuracy, the former were more sensitive, and the latter were more specific. CART, ENSMB, and SVM classifiers performed the best, and nuclear receptor activation and mitochondrial functions were frequently found in highly predictive classifiers of hepatotoxicity. ToxCast and ToxRefDB provide the largest and richest publicly available data sets for mining linkages between the in vitro bioactivity of environmental chemicals and their adverse histopathological outcomes. Our findings demonstrate the utility of high throughput assays for characterizing rodent hepatotoxicants, the benefit of using hybrid representations that integrate bioactivity and chemical structure, and the need for objective evaluation of classification performance. PMID- 25697800 TI - N-methyl pyrrolidone/bone morphogenetic protein-2 double delivery with in situ forming implants. AB - Bone morphogenetic proteins (BMPs) are growth and differentiation factors involved during development in morphogenesis, organogenesis and later mainly in regeneration processes, in particular in bone where they are responsible for osteoinduction. For more than a decade, recombinant human (rh)BMP-2 has been used in the clinic for lumbar spinal fusion at non-physiological high dosages that appear to be causative for side effects, like male sterility. A possible strategy to reduce the effective amount of rhBMP-2 in the clinic is the co-delivery with an enhancer of BMPs' activity. In an earlier study, we showed that N methylpyrrolidone (NMP) enhances BMP activity in vitro and in vivo. Here we report on the development of a slow and sustained double delivery of rhBMP-2 and NMP via an in situ forming implant based on poly(lactide-co-glycolide). The results showed that the release of NMP can be adjusted by varying the lactide/glycolide ratio and the polymer's molecular weight. The same applied to rhBMP-2, with release rates that could be sustained from two to three weeks. In the in vivo model of a critical size defect in the calvarial bone of rabbits, the implant containing 50mol% lactide performed better than the one having 75mol% lactide in terms of defect bridging and extent of bony regenerated area. In situ forming implants for the double delivery of the BMP enhancer NMP and rhBMP-2 appear to be promising delivery systems in bone regeneration. PMID- 25697801 TI - A defensin from clam Venerupis philippinarum: Molecular characterization, localization, antibacterial activity, and mechanism of action. AB - Antimicrobial peptides (AMPs) are important mediators of the primary host defense system against microbial invasion. In the present study, we cloned and characterized a member of the invertebrate defensin from the clam Venerupis philippinarum, designated VpDef. Amino acid sequence analysis showed that VpDef was similar to defensins from marine mollusks and ticks. In non-stimulated clams, RT-PCR and immunohistochemical analysis revealed that both VpDef mRNA and the encoding peptide were constitutively expressed in hemocytes and mantles, as well as in other major tissues. VpDef transcripts were significantly induced in hemocytes at different time intervals post Vibrio anguillarum infection. The recombinant VpDef (rVpDef) showed the highest activity against Gram-positive bacteria Micrococcus luteus and less effective to Gram-negative bacteria. In addition, incubation of rVpDef with M. luteus at 1 * and 3 * MIC could induce an obvious decrease of the membrane potential and notable changes of membrane permeability in a dose-dependent manner. Membrane integrity and bacterial viability analysis also revealed that rVpDef increased the membrane permeability of M. luteus and then resulted in cell death at 2 * and 10 * MIC. Overall, these results suggest that VpDef has an important function in host defense against invasive pathogens, probably killing microbes by inducing membrane lesions. PMID- 25697802 TI - Scavenger receptor B protects shrimp from bacteria by enhancing phagocytosis and regulating expression of antimicrobial peptides. AB - Scavenger receptors (SRs) are involved in innate immunity through recognizing pathogen-associated molecular patterns (PAMPs) and in pathogenesis of diseases through interactions with damage-associated molecular patterns (DAMPs). The roles of SRs in invertebrate innate immunity still need to be elucidated. Here we identify a class B scavenger receptor from kuruma shrimp, Marsupenaeus japonicus, designated MjSR-B1. The recombinant MjSR-B1 agglutinated bacteria in a calcium dependent manner and bound lipopolysaccharide and lipoteichoic acid. After knockdown of MjSR-B1, both the bacterial clearance and phagocytotic ability of M. japonicus against V. anguillarum and S. aureus were impaired, and several phagocytosis related genes were downregulated. The expression levels of antimicrobial peptides were also downregulated. Overexpression of MjSR-B1 led to enhanced bacterial clearance, phagocytosis rate and upregulation of phagocytosis related and antimicrobial peptide genes. However, overexpression of mutant MjSR B1DeltaC, which lacks the carboxyl tail of MjSR-B1, had none of these effects. Our results indicate that MjSR-B1 can protect shrimp from bacteria by promoting phagocytosis and by enhancing the expression of antimicrobial peptides. PMID- 25697803 TI - Thin carbon layer coated Ti(3+)-TiO2 nanocrystallites for visible-light driven photocatalysis. AB - Black TiO2 containing Ti(3+) attracts enormous attention due to its excellent visible-light driven photocatalytic activity. Herein, an in situ thermal decomposition approach to synthesize uniform thin carbon coated Ti(3+)-TiO2 nanocrystals is presented. During the oleic acid-assisted solvothermal process, the crystal size and morphology of TiO2 were controlled through oleic acid with carboxylic acid groups. Then the residual small quantities of oleic acid anchored on TiO2 were used as a carbon source, which could be in situ pyrolyzed into a carbon layer on TiO2 at high temperature and under an inert atmosphere. Meanwhile, Ti(4+) species were partly reduced into Ti(3+) states/oxygen vacancies on the surface of TiO2 due to the carbothermal reduction reaction for the carbon encapsulated Ti(3+)-TiO2 structure. A series of characterizations indicated that the 20-25 nm TiO2 nanocrystals obtained were wrapped evenly by 1-2 nm carbon layers, which had an important effect on the energy band structure change of TiO2. The presence of the carbon layer also improves the Ti(3+) stability and the conduction behavior of the composites. The Ti(3+) states/oxygen vacancies created on the surface of TiO2 were responsible for the remarkable photogenerated charge separation and extended visible-light absorption range. Furthermore, Ti(3+) states/oxygen vacancies and the carbon layer together could enhance the adsorption ability of O2 so as to promote the photogenerated electrons captured by the adsorbed O2, leading to a great increase in the charge separation. As a result, the composites exhibit high photocatalytic performance for organic pollutants under visible light irradiation. This simple and new method may pave the way to practical applications for efficient photocatalytic degradation under visible light. PMID- 25697804 TI - At the crossroads. PMID- 25697805 TI - Electrocatalytic hydrodehalogenation of atrazine in aqueous solution by Cu@Pd/Ti catalyst. AB - Electrocatalytic hydrodehalogenation is a cost-effective approach to degrade halogenated organic pollutants in groundwater, and Pd-based catalysts have been found to be an efficient cathode material for this purpose. In this work, a novel Cu@Pd bimetallic catalyst loaded on Ti plate was prepared via combined electrodeposition and galvanic replacement for electrocatalytic hydrodehalogenation of atrazine, a typical halogenated pollutant. The obtained bimetallic catalyst with uniformly dispersed Pd nanoparticles possessed a large electrochemically active surface area of 572 cm2. The Cu@Pd/Ti cathode exhibited a higher electrocatalytic efficiency towards atrazine reduction than the individual Pd/Ti or Cu/Ti cathodes, and achieved up to 91.5% within 120 min under a current density of 1 mA cm(-2). Such an electrocatalytic reduction followed pseudo-first-order kinetics with a rate constant of 0.0214 min(-1). Atrazine was selectively transformed to dechlorinated atrazine, and its degradation pathway was identified. Current density was found to have a critical influence on the atrazine reduction due to the competitive hydrogen evolution reaction at a higher current density. The fabricated bimetallic catalyst also exhibited a good stability. This work provides an efficient and stable electrocatalyst for chlorinated contaminate removal and groundwater remediation. PMID- 25697806 TI - Kinetics of nitrous oxide production by denitrification in municipal solid waste. AB - As one of the Nitrous Oxide (N2O) production pathways, denitrification plays an important role in regulating the emission of N2O into the atmosphere. In this study, the influences of different substrate concentrations and transient conditions on the denitrification rate and N2O-reducing activities were investigated. Results revealed that N2O production rates (i.e. denitrification rates) were stimulated by increased total organic carbon (TOC) concentration, while it was restrained under high oxygen concentrations. Moreover, the impact of nitrate concentrations on N2O production rates depended on the TOC/NO3--N ratios. All the N2O production rate data fitted well to a multiplicative Monod equation, with terms describing the influence of TOC and nitrate concentrations, and an Arrhenius-type equation. Furthermore, results demonstrated that high temperatures minimized the N2O-reducing activities in aged municipal solid waste, resulting in an accumulation of N2O. On the other hand, a transient condition caused by changing O2 concentrations may strongly influence the N2O production rates and N2O-reducing activities in solid waste. Finally, based on the results, we believe that a landfill aeration strategy properly designed to prevent rising temperatures and to cycle air injection is the key to reducing emissions of N2O during remediation of old landfills by means of in situ aeration. PMID- 25697807 TI - Uncorrected pre-operative mitral valve regurgitation is not associated with adverse outcomes after continuous-flow left ventricular assist device implantation. AB - BACKGROUND: Mitral valve regurgitation (MR) is prevalent in patients with heart failure. Because very few data exist examining the influence of significant pre operative MR on outcomes after left ventricular assist device (LVAD) implantation, we evaluate our experience. METHODS: Between October 1996 and August 2013, 756 patients underwent primary LVAD implantation at our institutions. Of these, 508 patients received a continuous-flow LVAD and represent the contemporary cohort for this analysis. Devices implanted included the HeartMate II in 410 patients (81%) and HeartWare HVAD in 98 patients (19%). Based on availability of pre-operative echocardiography, 491 patients were divided into 2 study groups according to degree of pre-operative MR; 189 patients (39%) had moderate to severe or greater MR (MR group), and 302 (61%) had less than moderate to severe MR (less MR group). Median age at operation (60 years in MR group vs 58 years in less MR group, p = 0.19), male sex (78% in MR group vs 81% in less MR group, p = 0.42), and ischemic etiology (46% in MR group vs 51% in less MR group, p = 0.35) were similar between groups. RESULTS: There were 40 early deaths (7.9%), and follow-up was available in all 468 early survivors for 641 patient-years of support. Patients in the MR group had higher late survival (2 years, 75%; 4 years, 65%) compared with patients in the less MR group (2 years, 66%; 4 years, 48%; p < 0.04). Cox proportional hazards model confirmed the independent interaction between MR and late survival (hazard ratio 0.62, p = 0.04). CONCLUSIONS: There was improved survival in patients with severe pre operative MR after continuous-flow LVAD implantation in our cohort. These findings may lend insight into the possible lack of value of addressing significant MR at the time of LVAD implantation. PMID- 25697808 TI - Characterization of lipid films by an angle-interrogation surface plasmon resonance imaging device. AB - Surface topographies of lipid films have an important significance in the analysis of the preparation of giant unilamellar vesicles (GUVs). In order to achieve accurately high-throughput and rapidly analysis of surface topographies of lipid films, a homemade SPR imaging device is constructed based on the classical Kretschmann configuration and an angle interrogation manner. A mathematical model is developed to accurately describe the shift including the light path in different conditions and the change of the illumination point on the CCD camera, and thus a SPR curve for each sampling point can also be achieved, based on this calculation method. The experiment results show that the topographies of lipid films formed in distinct experimental conditions can be accurately characterized, and the measuring resolution of the thickness lipid film may reach 0.05 nm. Compared with existing SPRi devices, which realize detection by monitoring the change of the reflective-light intensity, this new SPRi system can achieve the change of the resonance angle on the entire sensing surface. Thus, it has higher detection accuracy as the traditional angle interrogation SPR sensor, with much wider detectable range of refractive index. PMID- 25697809 TI - Interaction of gold nanoparticles with Doxorubicin mediated by supramolecular chemistry. AB - A copolymer containing beta-cyclodextrin, catechol and polyethylene glycol groups in its side chain was designed for the in situ synthesis and coating of gold nanoparticles (Au@PEG-CD NPs). These platforms were designed as a smart carrier and traceable delivery probe of the chemotherapeutic Doxorubicin drug (Dox). The coated polymer forms stable complexes with Dox in water with a high binding constant (K=2.3*10(4) M(-1) at 25 degrees C), which is one hundred times greater than those reported for its complexation with native betaCD. Therefore, Au@PEG-CD NPs were able to load 0.01 mg of the drug per mg of NP and to release up to 60% of it in 48 h at 37 degrees C. In addition, Au@PEG-CD NPs had the capacity to act as a quencher of Dox fluorescence when it was complexed with betaCD in the NP organic shell. This feature allows the Dox release to be tracked by monitoring the recovery of its fluorescence in real time. Therefore, the Dox release kinetics and the influence of temperature on the thermal stability of Dox/CD complexes on Au@PEG-CD NP were investigated. The increase in temperature favors the dissociation of the complexes and subsequent Dox release from the NP. The first order rate constant for drug releasing was 1.1*10(-2) min(-1) with a half life time of 63 min at 37 degrees C. Finally, the great potential of the carrier/probe double nature of Au@PEG-CD NPs was demonstrated in real time inside HeLa cells. PMID- 25697811 TI - Presentation and complications associated with cirrhosis of the liver. AB - OBJECTIVE: To provide an understanding of the detrimental impact of cirrhosis and its complications, strengths and weaknesses of current treatment options for the management of these complications, and new developments in this rapidly changing field. RESEARCH DESIGN AND METHODS: Relevant publications were identified via PubMed and Cochrane databases, with additional references obtained by reviewing bibliographies from selected articles. RESULTS: Cirrhosis, a progressive liver disease, is characterized by fibrosis caused by chronic liver injury. Liver fibrosis impairs hepatic function and causes structural changes that result in portal hypertension. Most patients with cirrhosis remain asymptomatic until they develop decompensated cirrhosis. At this stage, patients experience complications associated with portal hypertension (i.e., the abnormal increase in portal vein pressure), including ascites, spontaneous bacterial peritonitis (SBP), hepatic encephalopathy (HE), hepatorenal syndrome, portopulmonary hypertension, or variceal bleeding. In addition, intestinal microbial translocation in patients with cirrhosis might also cause SBP and HE. Because the survival rate for patients with cirrhosis substantially decreases once complications develop, the key goals in treating patients with cirrhosis include both managing the underlying liver disease and preventing and treating related complications. In patients with compensated cirrhosis, the management strategy is to prevent variceal bleeding and other complications that can lead to decompensated cirrhosis. Patients with decompensated cirrhosis are typically referred for liver transplantation, and the main focus of pre-transplant management is to eliminate the cause of cirrhosis (e.g., excess alcohol consumption, hepatitis virus) and prevent the recurrence of each decompensating complication. CONCLUSIONS: Although substantial progress has been made to prevent the complications and mortality associated with cirrhosis, liver transplantation in combination with resolution of the etiology of cirrhosis remains the only curative option for most patients. Emerging therapies such as anti-fibrotic agents hold promise in potentially halting or reversing the progression of cirrhosis, even in patients with decompensated cirrhosis. PMID- 25697812 TI - Property development for biaxial drawing of ethylene-tetrafluoroehtylene copolymer films and resultant fractural behavior analyzed by in situ X-ray measurements. AB - The property development of the ethylene-tetrafluoroethylene copolymer (ETFE) membrane induced by simultaneous biaxial drawing was investigated. Commonly, tensile strength can be increased by drawing; conversely, tear resistance decreases. In this study, the balance between tensile strength and tear resistance for the resultant ETFE membrane was optimized achieved by a combination of lamination of low molecular weight (LMW) and high molecular weight (HMW) layers and subsequent biaxial drawing. The structural factor determining tear resistance of these biaxially drawn membranes was determined based on in situ small-angle X-ray scattering (SAXS) measurement during tensile deformation simulating tearing tests. Lozenge shaped scattering, which indicated inclined lamellae, was observed during such tensile deformation of the resultant membranes. Remarkably, this inclined lamellar structure was observed for the pure LMW membrane; however, it also appeared at the interface between LMW and HMW layers within biaxially drawn membranes. For the membrane exhibiting the highest tearing strength, the fraction of such inclined lamella increased up to the critical strain corresponding to the actual sample breaking. These results confirm that the inclined lamellar structure absorbed strain during membrane tearing. PMID- 25697814 TI - Farmedial versus anteromedial portal drilling of the femoral tunnel in ACL reconstruction: a computed tomography analysis. AB - INTRODUCTION: The success of ACL reconstruction is predicated on a variety of factors. Tunnel placement plays one of the most significant roles in achieving knee kinematics and function. The purposes of this study were to compare femoral tunnel position, angle, length and posterior wall blow-out after ACL reconstruction with hamstring tendons autograft through either a farmedial portal or an anteromedial portal technique. MATERIALS AND METHODS: We evaluated 36 patients who underwent ACL reconstruction between January 2014 and July 2014 in our institute, in a prospective, randomised cohort study. All the surgical procedures were performed by a sports fellowship-trained orthopaedic surgeon with experience in both portal reaming. The operated knees were evaluated with 0.5 mm fine CT scans of 3-D CT between days 3 and 5 postoperatively. RESULTS: According to the 3-D CT measurements, the mean femoral tunnel length was significantly longer (p < 0.05) in the FAM group compared with the AM group. The femoral bone tunnel length averaged 34.2 +/- 3.6 mm versus 36.6 +/- 3.0 mm (p = 0.042) in AM and the FAM groups, respectively. The femoral tunnel position, as evaluated with use of the quadrant method, was more anterior in the FAM transportal technique group, and the difference between the two groups was significant (p < 0.05). CONCLUSION: FAM tranportal drilling of the femoral tunnel creates longer and anterior femoral tunnels with regard to the AM portal drilling techniques. Additional studies with clinical outcomes are required for the clinical relevance of these techniques and to show which one is superior. LEVEL OF EVIDENCE: Level I, prospective randomised comparative cohort study. PMID- 25697813 TI - Survey on the management of acute first-time anterior shoulder dislocation amongst Dutch public hospitals. AB - INTRODUCTION: The primary aim of this study was to record how orthopaedic surgeons are currently managing acute first-time anterior shoulder dislocation (AFASD) 8 years after introduction of the Dutch national guideline: "acute primary shoulder dislocation, diagnostics and treatment" in 2005. The second aim was to evaluate how these surgeons treat recurrent instability after AFASD. MATERIALS AND METHODS: An online questionnaire regarding the management of AFASD and recurrent shoulder instability was held amongst orthopaedic surgeons of all 98 Dutch hospitals. RESULTS: The overall response rate was 60%. Of the respondents, 75% had a local protocol for managing AFASD, of which 28% had made changes in their treatment protocol after the introduction of the national guideline. The current survey showed wide variety in the overall treatment policies for AFASD. Twenty-seven percent of the orthopaedic surgeons were currently unaware of the national guideline. The variability in treatment for AFASD was present throughout the whole treatment from which policy at the emergency department; when to operate for recurrent instability; type of surgical technique for stabilization and type of fixation of the labrum. As for the treatment of recurrent instability, the same variability was seen: 36% of the surgeons perform only arthroscopic procedures, 7% only open and 57% perform both open and arthroscopic procedures. CONCLUSIONS: Despite the introduction of the national guideline for the initial management of AFASD in 2005, still great variety among orthopaedic surgeons in the Netherlands was present. As for the surgical stabilization technique, the vast majority of the respondents are performing an arthroscopic shoulder stabilization procedure at the expense of the more traditional open procedure as a first treatment option for post-traumatic shoulder instability. PMID- 25697815 TI - Triple hourglass-like fascicular constriction of the posterior interosseous nerve: a rare cause of PIN syndrome. AB - Supinator syndrome or posterior interosseous nerve (PIN) syndrome is a compression neuropathy of the deep branch of the radial nerve in the region of the Arcade of Frohse. An extremely rare cause of an acute onset supinator syndrome is the hourglass-like fascicular constriction of the posterior interosseous nerve due to torsion. To our knowledge, only a limited number of cases which describe the sonographic appearance of fascicular torsions are known in the literature. We present a rare case of a supinator syndrome associated with hourglass-like constrictions of the PIN diagnosed by means of sonography. PMID- 25697816 TI - Recommendations for the diagnosis and management of hypertrophic cardiomyopathy in 2014. PMID- 25697817 TI - Detection of water quality parameters in Hangzhou Bay using a portable laser fluorometer. AB - A field, light-weight laser fluorometer based on the method of laser induced fluorescence was developed for water quality monitoring. The basic instrument configuration uses a high pulse repetition frequency microchip laser, a confocal reflective fluorescent probe and a broadband hyperspectral micro spectrometer; it weights only about 1.7 kg. Simultaneous estimates of three important water quality parameters, namely, chlorophyll a (chl-a), colored dissolved organic matter (CDOM), and total suspended matter (TSM) measured by the laser fluorometer were observed to agree well with those measured by traditional methods (0.27-0.84 MUg L(-3) chl-a, R(2)=0.88; 0.104-0.295 m(-)(1) CDOM absorption, R(2)=0.90; and 59.8-994.9 mg L(-)(3) TSM, R(2)=0.86) in Hangzhou Bay water. Subsequently, distribution and characteristics of CDOM and chl-a laser fluorescence in Hangzhou Bay were analyzed, which will enhance our understanding of biogeochemical processes in this complex estuarine system at high-resolution, high-frequency and long-term scale. PMID- 25697818 TI - Comparative assessment of water quality parameters of mariculture for fish production in Hong Kong Waters. AB - The objective of the study is to evaluate the effect of fish cultivation on water quality in fish culture zone (FCZ) and analysed by Principle Component Analysis (PCA). 120 surface water samples were collected from Hong Kong Waters (60 samples in Victoria Harbour and another 60 in Ma Wan FCZ). Significant difference was found in dissolved oxygen (MW: 59.6%; VH: 81.3%), and Escherichia coli (MW: 465 CFU/100 ml; VH: 162.5 CFU/100 ml). Three principle components are responsible for water quality variations in the studying sites. The first component included E. coli (0.625) and dissolved oxygen (0.701). The second included E. coli (0.387) and ammonical-nitrogen (0.571). The third included E. coli (0.194) and ammonical nitrogen (0.287). This framework provides information to assess the relative contribution of eco-aquaculture to nutrient loads and the subsequent risk of eutrophication. To conclude, a rigorous monitoring of water quality is necessary to assess point and nonpoint source pollution. Besides, appropriate remediation techniques should be used to combat water pollution and achieve sustainability. PMID- 25697819 TI - The GPMDB REST interface. AB - The Global Proteome Machine and Database (GPMDB) representational state transfer (REST) service was designed to provide simplified access to the proteomics information in GPMDB using a stable set of methods and parameters. Version 1 of this interface gives access to 25 methods for retrieving experimental information about protein post-translational modifications, amino acid variants, alternate splicing variants and protein cleavage patterns. AVAILABILITY AND IMPLEMENTATION: GPMDB data and database tables are freely available for commercial and non commercial use. All software is also freely available, under the Artistic License. http://rest.thegpm.org/1 (GPMDB REST Service), http://wiki.thegpm.org/wiki/GPMDB_REST (Service description and help), and http://www.thegpm.org (GPM main project description and documentation). The code for the interface and an example REST client is available at ftp://ftp.thegpm.org/repos/gpmdb_rest PMID- 25697820 TI - Sambamba: fast processing of NGS alignment formats. AB - Sambamba is a high-performance robust tool and library for working with SAM, BAM and CRAM sequence alignment files; the most common file formats for aligned next generation sequencing data. Sambamba is a faster alternative to samtools that exploits multi-core processing and dramatically reduces processing time. Sambamba is being adopted at sequencing centers, not only because of its speed, but also because of additional functionality, including coverage analysis and powerful filtering capability. AVAILABILITY AND IMPLEMENTATION: Sambamba is free and open source software, available under a GPLv2 license. Sambamba can be downloaded and installed from http://www.open-bio.org/wiki/Sambamba.Sambamba v0.5.0 was released with doi:10.5281/zenodo.13200. PMID- 25697821 TI - Extending P450 site-of-metabolism models with region-resolution data. AB - MOTIVATION: Cytochrome P450s are a family of enzymes responsible for the metabolism of approximately 90% of FDA-approved drugs. Medicinal chemists often want to know which atoms of a molecule-its metabolized sites-are oxidized by Cytochrome P450s in order to modify their metabolism. Consequently, there are several methods that use literature-derived, atom-resolution data to train models that can predict a molecule's sites of metabolism. There is, however, much more data available at a lower resolution, where the exact site of metabolism is not known, but the region of the molecule that is oxidized is known. Until now, no site-of-metabolism models made use of region-resolution data. RESULTS: Here, we describe XenoSite-Region, the first reported method for training site-of metabolism models with region-resolution data. Our approach uses the Expectation Maximization algorithm to train a site-of-metabolism model. Region-resolution metabolism data was simulated from a large site-of-metabolism dataset, containing 2000 molecules with 3400 metabolized and 30 000 un-metabolized sites and covering nine Cytochrome P450 isozymes. When training on the same molecules (but with only region-level information), we find that this approach yields models almost as accurate as models trained with atom-resolution data. Moreover, we find that atom resolution trained models are more accurate when also trained with region resolution data from additional molecules. Our approach, therefore, opens up a way to extend the applicable domain of site-of-metabolism models into larger regions of chemical space. This meets a critical need in drug development by tapping into underutilized data commonly available in most large drug companies. AVAILABILITY AND IMPLEMENTATION: The algorithm, data and a web server are available at http://swami.wustl.edu/xregion. PMID- 25697822 TI - Comparative study of the effectiveness and limitations of current methods for detecting sequence coevolution. AB - MOTIVATION: With rapid accumulation of sequence data on several species, extracting rational and systematic information from multiple sequence alignments (MSAs) is becoming increasingly important. Currently, there is a plethora of computational methods for investigating coupled evolutionary changes in pairs of positions along the amino acid sequence, and making inferences on structure and function. Yet, the significance of coevolution signals remains to be established. Also, a large number of false positives (FPs) arise from insufficient MSA size, phylogenetic background and indirect couplings. RESULTS: Here, a set of 16 pairs of non-interacting proteins is thoroughly examined to assess the effectiveness and limitations of different methods. The analysis shows that recent computationally expensive methods designed to remove biases from indirect couplings outperform others in detecting tertiary structural contacts as well as eliminating intermolecular FPs; whereas traditional methods such as mutual information benefit from refinements such as shuffling, while being highly efficient. Computations repeated with 2,330 pairs of protein families from the Negatome database corroborated these results. Finally, using a training dataset of 162 families of proteins, we propose a combined method that outperforms existing individual methods. Overall, the study provides simple guidelines towards the choice of suitable methods and strategies based on available MSA size and computing resources. AVAILABILITY AND IMPLEMENTATION: Software is freely available through the Evol component of ProDy API. PMID- 25697823 TI - DNA-functionalized Pt nanoparticles as catalysts for chemically powered micromotors: toward signal-on motion-based DNA biosensor. AB - We present here the construction of a DNA biosensor based on a tubular micromotor that only produces motion-based signal in the presence of DNA target. This "turn on" characteristic of the sensor is achieved by the addition of Pt nanoparticle DNA conjugate as the motion-inducing catalyst for the micromotors through DNA hybridization. Our work potentially offers new design strategies for motion-based biosensors with higher specificity. PMID- 25697824 TI - Predictors of mortality among patients with compensated and decompensated liver cirrhosis: the role of bacterial infections and infection-related acute-on chronic liver failure. AB - OBJECTIVE: Population-based data on the impact of bacterial infections on the course of compensated and decompensated cirrhosis as well as the occurrence, predictors of infection-related acute-on-chronic liver failure (ACLF) and its fatal outcome are limited. MATERIAL AND METHODS: All patients with incident cirrhosis in the period 2001-2010, residing in an area of 600,000 inhabitants, were retrospectively identified. All serious bacterial infections (resulting in or occurring during an inpatient hospital episode) during this period were analyzed. Infection site and acquisition type, comorbid illness (Charlson comorbidity index) and infection severity features were analyzed. Patients were followed up until death, transplant, or the end of 2011. RESULTS: Overall, 398 serious bacterial infections occurred in 241/633 (38%) patients (106/332 diagnosed with compensated and 135/301 with decompensated disease; follow-up time was 2276 patient-years). ACLF occurred in 95/398 (24%) serious infections with an in-hospital mortality of 50%. In logistic regression analysis, the model for end stage liver disease score, active alcohol misuse and healthcare-associated infections were predictors of infection-related ACLF (p < 0.05 for all). In hospital mortality in infections with ACLF was related to albumin levels, Charlson comorbidity index >1 and occurrence of one or more organ failures (p > 0.05 for all). In Cox regression analysis, infection-related ACLF was an independent negative predictor of transplant-free survival in decompensated patients (p = 0.049). CONCLUSIONS: In a population-based cirrhotic cohort, infection-related ACLF was a negative predictor of survival in decompensated disease. Infection-related ACLF was frequent and related to cirrhosis severity and infection acquisition type, as well as to high inpatient mortality, in particular in patients with significant comorbidity. PMID- 25697825 TI - Correction to "adaptation in constitutional dynamic libraries and networks, switching between orthogonal metalloselection and photoselection processes". PMID- 25697826 TI - Motor neurons with differential vulnerability to degeneration show distinct protein signatures in health and ALS. AB - The lethal disease amyotrophic lateral sclerosis (ALS) is characterized by the loss of somatic motor neurons. However, not all motor neurons are equally vulnerable to disease; certain groups are spared, including those in the oculomotor nucleus controlling eye movement. The reasons for this differential vulnerability remain unknown. Here we have identified a protein signature for resistant oculomotor motor neurons and vulnerable hypoglossal and spinal motor neurons in mouse and man and in health and ALS with the aim of understanding motor neuron resistance. Several proteins with implications for motor neuron resistance, including GABAA receptor alpha1, guanylate cyclase soluble subunit alpha-3 and parvalbumin were persistently expressed in oculomotor neurons in man and mouse. Vulnerable motor neurons displayed higher protein levels of dynein, peripherin and GABAA receptor alpha2, which play roles in retrograde transport and excitability, respectively. These were dynamically regulated during disease and thus could place motor neurons at an increased risk. From our analysis is it evident that oculomotor motor neurons have a distinct protein signature compared to vulnerable motor neurons in brain stem and spinal cord, which could in part explain their resistance to degeneration in ALS. Our comparison of human and mouse shows the relative conservation of signals across species and infers that transgenic SOD1G93A mice could be used to predict mechanisms of neuronal vulnerability in man. PMID- 25697827 TI - Cultural adaptation and validation of a peninsular Spanish version of the MSTCQ(c) (Multiple Sclerosis Treatment Concerns Questionnaire). AB - INTRODUCTION: Although subcutaneous treatments for multiple sclerosis (MS) have been shown to be effective, adverse reactions and pain may adversely affect treatment satisfaction and adherence. This study presents an adapted and validated Spanish version of the Multiple Sclerosis Treatment Concerns Questionnaire(c) (MSTCQ), which evaluates satisfaction with the injection device (ID) across 4 domains: injection system (A), side effects (B) (flu-like symptoms, reactions, and satisfaction), experience with treatment (C) and benefits (D). METHODS: Two study phases: 1) Cultural adaptation process with input from experts (n=6) and patients (n=30). 2) Validation obtained by means of an observational, cross-sectional, multi-centre study evaluating 143 adult MS patients using an ID. Tools employed: MSTCQ(c), Patient-Reported Indices for Multiple Sclerosis (PRIMUS(c)), and Treatment Satisfaction Questionnaire for Medication (TSQM(c)). Psychometric properties: Feasibility (percentage of valid cases and floor/ceiling effects); Reliability (Cronbach alpha) and test-retest correlation (n=41, intraclass correlation coefficient, ICC); and construct validity (factor analysis of domains A and B) and convergent validity (Spearman rank-order correlation for MSTCQ(c) vs TSQM(c)). RESULTS: Mean age (SD) was 41.94 (10.47) years, 63% of the group were women, and 88.11% presented relapsing-remitting MS. Mean (SD) EDSS score was 2.68 (1.82) points. MSTCQ(c) completion was high (0%-2.80% missing data). Internal consistency was high at alpha=0.89 for the total score (A+B) and alpha=0.76, 0.89, and 0.92 for domains A, B, and C, respectively. The version demonstrated excellent test-retest reliability for the total (ICC=0.98) and for domains A, B, and C: ICC=0.82, 0.97, and 0.89, respectively. Factor analysis corroborated the internal structure of the original questionnaire. The association between total and domain scores on both the MSTCQ(c) and the TSQM(c) was moderately strong (Rho=0.42-0.74) and significant (P<.05 and P<.01). CONCLUSION: The Spanish version of MSTCQ(c) demonstrates appropriate psychometric properties. PMID- 25697828 TI - Binocular vertical diplopia following chemical labyrinthectomy with gentamicin: A case report and review of literature. PMID- 25697829 TI - Structural and Activity Profile Relationships Between Drug Scaffolds. AB - Core structures of current drugs have been assembled and their structural relationships and activity profiles have been explored. Drug scaffolds were frequently involved in different types of structural relationships. In addition, a variety of activity profile relationships between structurally related drug scaffolds were detected, ranging from closely overlapping to distinct profiles. Furthermore, when structural and activity profile relationships of scaffolds from drugs and bioactive compounds were compared, systematic differences were detected. Consensus activity profiles were introduced as a new approach for the qualitative and quantitative assessment of activity similarity of structurally related drugs represented by the same scaffold. On the basis of consensus activity profiles, scaffolds representing drugs active against distinct targets can be distinguished from drugs having similar target profiles and target hypotheses can be derived for individual drugs. Given the results of our analysis, drug scaffolds have been systematically organized according to structural and activity profile criteria. Our scaffold sets and the associated information are made freely available. PMID- 25697830 TI - Impact of transient hypotension on regional cerebral blood flow in humans. AB - We examined the impact of progressive hypotension with and without hypocapnia on regional extracranial cerebral blood flow (CBF) and intracranial velocities. Participants underwent progressive lower-body negative pressure (LBNP) until pre syncope to inflict hypotension. End-tidal carbon dioxide was clamped at baseline levels (isocapnic trial) or uncontrolled (poikilocapnic trial). Middle cerebral artery (MCA) and posterior cerebral artery (PCA) blood velocities (transcranial Doppler; TCD), heart rate, blood pressure and end-tidal carbon dioxide were obtained continuously. Measurements of internal carotid artery (ICA) and vertebral artery (VA) blood flow (ICABF and VABF respectively) were also obtained. Overall, blood pressure was reduced by ~20% from baseline in both trials (P<0.001). In the isocapnic trial, end-tidal carbon dioxide was successfully clamped at baseline with hypotension, whereas in the poikilocapnic trial it was reduced by 11.1 mmHg (P<0.001) with hypotension. The decline in the ICABF with hypotension was comparable between trials (-139 +/- 82 ml; ~30%; P<0.0001); however, the decline in the VABF was -28 +/- 22 ml/min (~21%) greater in the poikilocapnic trial compared with the isocapnic trial (P=0.002). Regardless of trial, the blood flow reductions in ICA (-26 +/- 14%) and VA (-27 +/- 14%) were greater than the decline in MCA (-21 +/- 15%) and PCA (-19 +/- 10%) velocities respectively (P <= 0.01). Significant reductions in the diameter of both the ICA (~5%) and the VA (~7%) contributed to the decline in cerebral perfusion with systemic hypotension, independent of hypocapnia. In summary, our findings indicate that blood flow in the VA, unlike the ICA, is sensitive to changes hypotension and hypocapnia. We show for the first time that the decline in global CBF with hypotension is influenced by arterial constriction in the ICA and VA. Additionally, our findings suggest TCD measures of blood flow velocity may modestly underestimate changes in CBF during hypotension with and without hypocapnia, particularly in the posterior circulation. PMID- 25697831 TI - MR imaging assessment of myocardial edema with T2 mapping. AB - Cardiac magnetic resonance (CMR) provides a high signal-to-noise ratio, high spatial and temporal resolutions, as well as a delayed-enhancement sequence and is therefore considered a reference technique in the field of cardiac imaging. However, currently available sequences are not adequate to assess some pathologic conditions, such as myocardial edema. T2 mapping sequences generate parametric images that are based on the transverse relaxation time (T2) for each voxel. In case of edema, the T2 relaxation time is longer. This review summarizes current knowledge on CMR T2 mapping for assessing myocardial edema. PMID- 25697832 TI - Social interactions, emotion and sleep: A systematic review and research agenda. AB - Sleep and emotion are closely linked, however the effects of sleep on socio emotional task performance have only recently been investigated. Sleep loss and insomnia have been found to affect emotional reactivity and social functioning, although results, taken together, are somewhat contradictory. Here we review this advancing literature, aiming to 1) systematically review the relevant literature on sleep and socio-emotional functioning, with reference to the extant literature on emotion and social interactions, 2) summarize results and outline ways in which emotion, social interactions, and sleep may interact, and 3) suggest key limitations and future directions for this field. From the reviewed literature, sleep deprivation is associated with diminished emotional expressivity and impaired emotion recognition, and this has particular relevance for social interactions. Sleep deprivation also increases emotional reactivity; results which are most apparent with neuro-imaging studies investigating amygdala activity and its prefrontal regulation. Evidence of emotional dysregulation in insomnia and poor sleep has also been reported. In general, limitations of this literature include how performance measures are linked to self-reports, and how results are linked to socio-emotional functioning. We conclude by suggesting some possible future directions for this field. PMID- 25697833 TI - Interleukin-6 as a predictor of symptom resolution in psychological distress: a cohort study. AB - BACKGROUND: Elevated levels of interleukin-6 (IL-6) have been associated with the development of common mental disorders, such as depression, but its role in symptom resolution is unclear. METHOD: We examined the association between IL-6 and symptom resolution in a non-clinical sample of participants with psychological distress. RESULTS: Relative to high IL-6 levels, low levels at baseline were associated with symptom resolution at follow-up [age- and sex adjusted risk ratio (RR) = 1.15, 95% confidence interval (CI) 1.06-1.25]. Further adjustment for covariates had little effect on the association. Symptomatic participants with repeated low IL-6 were more likely to be symptom-free at follow up compared with those with repeated high IL-6 (RR = 1.21, 95% CI 1.03-1.41). Among the symptomatic participants with elevated IL-6 at baseline, IL-6 decreased along with symptom resolution. CONCLUSIONS: IL-6 is potentially related to the mechanisms underlying recovery from symptoms of mental ill health. Further studies are needed to examine these mechanisms and to confirm the findings in relation to clinical depression. PMID- 25697834 TI - Predator-prey models with component Allee effect for predator reproduction. AB - We present four predator-prey models with component Allee effect for predator reproduction. Using numerical simulation results for our models, we describe how the customary definitions of component and demographic Allee effects, which work well for single species models, can be extended to predators in predator-prey models by assuming that the prey population is held fixed. We also find that when the prey population is not held fixed, then these customary definitions may lead to conceptual problems. After this discussion of definitions, we explore our four models, analytically and numerically. Each of our models has a fixed point that represents predator extinction, which is always locally stable. We prove that the predator will always die out either if the initial predator population is sufficiently small or if the initial prey population is sufficiently small. Through numerical simulations, we explore co-existence fixed points. In addition, we demonstrate, by simulation, the existence of a stable limit cycle in one of our models. Finally, we derive analytical conditions for a co-existence trapping region in three of our models, and show that the fourth model cannot possess a particular kind of co-existence trapping region. We punctuate our results with comments on their real-world implications; in particular, we mention the possibility of prey resurgence from mortality events, and the possibility of failure in a biological pest control program. PMID- 25697835 TI - Ecological constraints on the origin of neurones. AB - The basic functional characteristics of spiking neurones are remarkably similar throughout the animal kingdom. Their core design and function features were presumably established very early in their evolutionary history. Identifying the selection pressures that drove animals to evolve spiking neurones could help us interpret their design and function today. This paper provides a quantitative argument, based on ecology, that animals evolved neurones after they started eating each other, about 550 million years ago. We consider neurones as devices that aid an animal's foraging performance, but incur an energetic cost. We introduce an idealised stochastic model ecosystem of animals and their food, and obtain an analytic expression for the probability that an animal with a neurone will fix in a neurone-less population. Analysis of the fixation probability reveals two key results. First, a neurone will never fix if an animal forages low value food at high density, even if that neurone incurs no cost. Second, a neurone will fix with high probability if an animal is foraging high-value food at low density, even if that neurone is expensive. These observations indicate that the transition from neurone-less to neurone-armed animals can be facilitated by a transition from filter-feeding or substrate grazing to episodic feeding strategies such as animal-on-animal predation (macrophagy). PMID- 25697836 TI - Role of the AMPK signaling pathway in early brain injury after subarachnoid hemorrhage in rats. AB - BACKGROUND: AMP-activated protein kinase (AMPK) is a key metabolic and stress sensor/effector. Few investigations have been performed to study the role of AMPK in subarachnoid hemorrhage (SAH)-induced early brain injury (EBI). This study was undertaken to investigate the time course of AMPK activation in the early stage of SAH and to evaluate the influence of AICAR (which is known to mimic AMP and activates AMPK) and compound C (a commonly used AMPK inhibitor) on EBI in rats following SAH. METHODS: Adult male rats were divided into six groups: control, sham, SAH, SAH + vehicle, SAH + AICAR and SAH + compound C. SAHs were induced by a modified endovascular perforation method. Immunohistochemistry, real-time PCR and Western blot were used to detect the spatial and dynamic expression of AMPK after SAH. Cortical apoptosis and the expressions of apoptosis-related proteins such as FOXO3a (forkhead box, class O, 3a) and Bim (Bcl-2-interacting mediator of cell death) were detected after different drug interventions. RESULTS: We found SAH induced prolonged activation of AMPK. Treatment with AICAR markedly induced overactivation of AMPK and upregulation of FOXO3a and Bim. AICAR also significantly exacerbated cerebral apoptosis and neurological impairment following SAH. On the other hand, pre-administration of compound C attenuated EBI in this SAH model by modulating cerebral apoptosis by inhibiting FOXO3a and Bim. CONCLUSIONS: Our findings suggest that the AMPK pathway may play an important role in SAH-induced neuronal apoptosis, and the use of AMPK inhibitors can provide neuroprotection in EBI after SAH. PMID- 25697837 TI - A burr hole is not a burr hole--answer to the editor. PMID- 25697838 TI - Microbial conversion of synthetic and food waste-derived volatile fatty acids to lipids. AB - Lipid accumulation in the oleaginous yeast Cryptococcus albidus was evaluated using mixtures of volatile fatty acids (VFA) as substrates. In general, batch growth under nitrogen limitation led to higher lipid accumulation using synthetic VFA. During batch growth, an initial COD:N ratio of 25:1mg COD:mg N led to maximum intracellular lipid accumulation (28.3 +/- 0.7% g/g dry cell weight), which is the maximum reported for C. albidus using VFA as the carbon source, without compromising growth kinetics. At this feed COD:N ratio, chemostat cultures fed with synthetic VFA yielded statistically similar intracellular lipid content as batch cultures (29.9 +/- 1.9%, g/g). However, batch cultures fed with VFA produced from the fermentation of food waste, yielded a lower lipid content (14.9 +/- 0.1%, g/g). The lipid composition obtained with synthetic and food waste-derived VFA was similar to commercial biodiesel feedstock. We therefore demonstrate the feasibility of linking biochemical waste treatment and biofuel production using VFA as key intermediates. PMID- 25697840 TI - Consumers' perception of generic substitution in Iran. AB - BACKGROUND: The growth of pharmaceutical expenditure and patients' out of pocket has motivated policy makers to encourage patients to substitution of brands medicines with their generic alternatives called generic substitution. OBJECTIVES: As the patients are final decision makers to accept generic substitution, the aim of this study is to evaluate the patient perception about generic medicines and underlying factors which can promote the generic acceptance. SETTING: The study was done in community pharmacies in Tehran, the capital city of Iran. METHOD: A cross-sectional descriptive study inviting people purchasing their drug at community pharmacies were per-formed using a self administrated anonymous questionnaire (N=1309). MAIN OUTCOMES MEASURES: Besides the demographic section, 16 items of developed questionnaire were categorized to five main factors including: patients' perception about efficiency, safety and cost of generic medicines, patient trust on physicians and pharmacists' advice. RESULTS: Findings of completed questionnaires showed among the aforementioned factors the physician has the first priority to encourage patients to use of generics medicines which followed respectively by pharmacist's role, cost of medicines, efficacy, and safety concerns. CONCLUSION: In conclusion, the trust of Iranian's society on the physicians and pharmacists advice would create a credible opportunity to reduce pharmaceutical expenditures as well as patients' out of pocket by promotion of generic substitution. PMID- 25697839 TI - First trimester phthalate exposure and anogenital distance in newborns. AB - STUDY QUESTION: Is first trimester phthalate exposure associated with anogenital distance (AGD), a biomarker of prenatal androgen exposure, in newborns? SUMMARY ANSWER: Concentrations of diethylhexyl phthalate (DEHP) metabolites in first trimester maternal urine samples are inversely associated with AGD in male, but not female, newborns. WHAT IS KNOWN ALREADY: AGD is a sexually dimorphic measure reflecting prenatal androgen exposure. Prenatal phthalate exposure has been associated with shorter male AGD in multiple animal studies. Prior human studies, which have been limited by small sample size and imprecise timing of exposure and/or outcome, have reported conflicting results. STUDY DESIGN, SIZE, DURATION: The Infant Development and the Environment Study (TIDES) is a prospective cohort study of pregnant women recruited in prenatal clinics in San Francisco, CA, Minneapolis, MN, Rochester, NY and Seattle, WA in 2010-2012. Participants delivered 787 infants; 753 with complete data are included in this analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS: Any woman over 18 years old who was able to read and write English (or Spanish in CA), who was <13 weeks pregnant, whose pregnancy was not medically threatened and who planned to deliver in a study hospital was eligible to participate. Analyses include all infants whose mothers provided a first trimester urine sample and who were examined at or shortly after birth. Specific gravity (SpG) adjusted concentrations of phthalate metabolites in first trimester urine samples were examined in relation to genital measurements. In boys (N = 366), we obtained two measures of anogenital distance (AGD) (anoscrotal distance, or AGDAS and anopenile distance, AGDAP) as well as penile width (PW). In girls (N = 373), we measured anofourchette distance (AGDAF) and anoclitoral distance (AGDAC). We used multivariable regression models that adjusted for the infant's age at exam, gestational age, weight-for-length Z score, time of day of urine collection, maternal age and study center. MAIN RESULTS AND THE ROLE OF CHANCE: Three metabolites of DEHP were significantly and inversely associated with both measures of boys' AGD. Associations (beta, 95% confidence interval (CI)) between AGDAS and (log10) SpG-adjusted phthalate concentrations were: -1.12 (-2.16, -0.07) for mono-2-ethylhexyl phthalate (MEHP), -1.43, (-2.49, -0.38) for mono-2-ethyl-5-oxohexyl phthalate (MEOHP), and -1.28 ( 2.29, -0.27) for mono-2-ethyl-5-hydroxyhexyl (MEHHP). Associations were of similar magnitude for AGDAP. Associations were weaker and not statistically significant for PW. No other phthalate metabolites were associated with any genital measurement in boys. No phthalate metabolites were associated with either AGD measure in girls. LIMITATIONS, REASONS FOR CAUTION: Exposure assessment was based on a single first trimester urine sample, which may have introduced exposure misclassification. In addition, significant between-center differences suggest that this measurement is difficult to standardize. WIDER IMPLICATIONS OF THE FINDINGS: Our findings are consistent with multiple rodent studies and most human studies which were far smaller. The data we report here suggest that even at current low levels, environmental exposure to DEHP can adversely affect male genital development resulting in reproductive tract changes that may impact reproductive health later in life. These findings have important implications for public policy since most pregnant women are exposed to this ubiquitous chemical. STUDY FUNDING/COMPETING INTERESTS: Funding for TIDES was provided by the following grants from the National Institute of Environmental Health Sciences: R01ES016863-04 and R01 ES016863-02S4. The authors report no conflict of interest. PMID- 25697841 TI - Myelin basic protein associates with AbetaPP, Abeta1-42, and amyloid plaques in cortex of Alzheimer's disease brain. AB - The goal of this study was to show that myelin and axons in cortical gray matter are damaged in Alzheimer's disease (AD) brain. Superior temporal gyrus gray matter of AD patients (9 male, 14 female) was compared to cognitively normal controls (8 male, 7 female). Myelin basic protein (MBP) and a degraded myelin basic protein complex (dMBP) were quantified by Western blot. Brain sections were immunostained for MBP, dMBP, axonal neurofilament protein (NF), autophagy marker microtubule-associated proteins 1A/B light chain 3B precursor (LC3B), amyloid beta protein precursor (AbetaPP), and amyloid markers amyloid beta1-42 (Abeta1 42) and FSB. Co-immunoprecipitation and mass spectroscopy evaluated interaction of AbetaPP/Abeta1-42 with MBP/dMBP. Evidence of axonal injury in AD cortex included appearance of AbetaPP in NF stained axons, and NF at margins of amyloid plaques. Evidence of myelin injury in AD cortex included (1) increased dMBP in AD gray matter compared to control (p < 0.001); (2) dMBP in AD neurons; and (3) increased LC3B that co-localized with MBP. Evidence of interaction of AbetaPP/Abeta1-42 with myelin or axonal components included (1) greater binding of dMBP with AbetaPP in AD brain; (2) MBP at the margins of amyloid plaques; (3) dMBP co-localized with Abeta1-42 in the core of amyloid plaques in AD brains; and (4) interactions between Abeta1-42 and MBP/dMBP by co-immunoprecipitation and mass spectrometry. We conclude that damaged axons may be a source of AbetaPP. dMBP, MBP, and NF associate with amyloid plaques and dMBP associates with AbetaPP and Abeta1-42. These molecules could be involved in formation of amyloid plaques. PMID- 25697844 TI - Guidelines for standard preclinical experiments in the mouse model of myasthenia gravis induced by acetylcholine receptor immunization. AB - Myasthenia gravis (MG) is an autoimmune disorder characterized by generalized muscle weakness due to neuromuscular junction (NMJ) dysfunction brought by acetylcholine receptor (AChR) antibodies in most cases. Although steroids and other immunosuppressants are effectively used for treatment of MG, these medications often cause severe side effects and a complete remission cannot be obtained in many cases. For pre-clinical evaluation of more effective and less toxic treatment methods for MG, the experimental autoimmune myasthenia gravis (EAMG) induced by Torpedo AChR immunization has become one of the standard animal models. Although numerous compounds have been recently proposed for MG mostly by using the active immunization EAMG model, only a few have been proven to be effective in MG patients. The variability in the experimental design, immunization methods and outcome measurements of pre-clinical EAMG studies make it difficult to interpret the published reports and assess the potential for application to MG patients. In an effort to standardize the active immunization EAMG model, we propose standard procedures for animal care conditions, sampling and randomization of mice, experimental design and outcome measures. Utilization of these standard procedures might improve the power of pre-clinical EAMG experiments and increase the chances for identifying promising novel treatment methods that can be effectively translated into clinical trials for MG. PMID- 25697845 TI - White matter involvement after TBI: Clues to axon and myelin repair capacity. AB - Impact-acceleration forces to the head cause traumatic brain injury (TBI) with damage in white matter tracts comprised of long axons traversing the brain. White matter injury after TBI involves both traumatic axonal injury (TAI) and myelin pathology that evolves throughout the post-injury time course. The axon response to initial mechanical forces and secondary insults follows the process of Wallerian degeneration, which initiates as a potentially reversible phase of intra-axonal damage and proceeds to an irreversible phase of axon fragmentation. Distal to sites of axon disconnection, myelin sheaths remain for prolonged periods, which may activate neuroinflammation and inhibit axon regeneration. In addition to TAI, TBI can cause demyelination of intact axons. These evolving features of axon and myelin pathology also represent opportunities for repair. In experimental TBI, demyelinated axons exhibit remyelination, which can serve to both protect axons and facilitate recovery of function. Myelin remodeling may also contribute to neuroplasticity. Efficient clearance of myelin debris is a potential target to attenuate the progression of chronic pathology. During the early phase of Wallerian degeneration, interventions that prevent the transition from reversible damage to axon disconnection warrant the highest priority, based on the poor regenerative capacity of axons in the CNS. Clinical evaluation of TBI will need to address the challenge of accurately detecting the extent and stage of axon damage. Distinguishing the complex white matter changes associated with axons and myelin is necessary for interpreting advanced neuroimaging approaches and for identifying a broader range of therapeutic opportunities to improve outcome after TBI. PMID- 25697846 TI - Relationship between the Charlson Comorbidity Index and cost of treating hip fractures: implications for bundled payment. AB - BACKGROUND: The aim of this study is to investigate how the Charlson Comorbidity Index (CCI) scores contribute to increased length of stay (LOS) and healthcare costs in hip fracture patients. MATERIALS AND METHODS: Through retrospective analysis at an Urban level I trauma center, charts for all patients over the age of 60 years who presented with low-energy hip fracture were evaluated. 615 patients who underwent operative fixation of hip fracture or hemiarthroplasty secondary to hip fracture were identified using Current Procedural Terminology (CPT) codes search and included in the study. Data was collected on patient demographics, medical comorbidities, and hospitalization length; from this, the CCI score and the cost to the institution (with an average cost/day of inpatient stay of $4,530) were calculated. RESULTS: Multivariate linear regression analysis modeled the length of stay as a function of CCI score. Each unit increase in the CCI score corresponded to an increase in length of hospital stay and hospital costs incurred [effect size = 0.21; (0.0434-0.381); p = 0.014]. Patients with a CCI score of 2 (compared to a baseline CCI score of 0), on average, stayed 1.92 extra days in the hospital, and incurred $8,697.60 extra costs. CONCLUSIONS: The CCI score is associated with length of stay and hospital costs incurred following treatment for hip fracture. The CCI score may be a useful tool for risk assessment in bundled payment plans. LEVEL OF EVIDENCE: Level III. PMID- 25697847 TI - Complications of calcific tendinitis of the shoulder: a concise review. AB - Calcific tendinitis (CT) of the rotator cuff (RC) muscles in the shoulder is a disorder which remains asymptomatic in a majority of patients. Once manifested, it can present in different ways which can have negative effects both socially and professionally for the patient. The treatment modalities can be either conservative or surgical. There is poor literature evidence on the complications of this condition with little consensus on the treatment of choice. In this review, the literature was extensively searched in order to study and compile together the complications of CT of the shoulder and present it in a clear form to ease the understanding for all the professionals involved in the management of this disorder. Essentially there are five major complications of CT: pain, adhesive capsulitis, RC tears, greater tuberosity osteolysis and ossifying tendinitis. All the above complications have been explained right from their origin to the control measures required for the relief of the patient. LEVEL OF EVIDENCE: 5. PMID- 25697848 TI - Complement in therapy and disease: Regulating the complement system with antibody based therapeutics. AB - Complement is recognized as a key player in a wide range of normal as well as disease-related immune, developmental and homeostatic processes. Knowledge of complement components, structures, interactions, and cross-talk with other biological systems continues to grow and this leads to novel treatments for cancer, infectious, autoimmune- or age-related diseases as well as for preventing transplantation rejection. Antibodies are superbly suited to be developed into therapeutics with appropriate complement stimulatory or inhibitory activity. Here we review the design, development and future of antibody-based drugs that enhance or dampen the complement system. PMID- 25697849 TI - High dosage of monosodium glutamate causes deficits of the motor coordination and the number of cerebellar Purkinje cells of rats. AB - Monosodium glutamate (MSG) has been widely used throughout the world as a flavoring agent of food. However, MSG at certain dosages is also thought to cause damage to many organs, including cerebellum. This study aimed at investigating the effects of different doses of MSG on the motor coordination and the number of Purkinje cells of the cerebellum of Wistar rats. A total of 24 male rats aged 4 to 5 weeks were divided into four groups, namely, control (C), T2.5, T3, and T3.5 groups, which received intraperitoneal injection of 0.9% sodium chloride solution, 2.5 mg/g body weight (bw) of MSG, 3.0 mg/g bw of MSG, and 3.5 mg/g bw of MSG, respectively, for 10 consecutive days. The motor coordination of the rats was examined prior and subsequent to the treatment. The number of cerebellar Purkinje cells was estimated using physical fractionator method. It has been found that the administration of MSG at a dosage of 3.5 mg/g bw, but not at lower dosages, caused a significant decrease of motor coordination and the estimated total number of Purkinje cells of rats. There was also a significant correlation between motor coordination and the total number of Purkinje cells. PMID- 25697850 TI - Effects of airborne Aspergillus on serum aflatoxin B1 and liver enzymes in workers handling wheat flour. AB - OBJECTIVE: The present work aimed to investigate the relationship between occupational exposure to airborne molds, serum aflatoxin B1 (AFB1), and liver enzymes of workers handling wheat flour. METHODS: The study included 90 bakers, 100 flour milling workers, and 100 controls with no exposure to flour dust. Workplace aspects such as temperature and relative humidity were measured. Airborne fungi were collected and identified. In all subjects included, the serum levels of AFB1, serum albumin (Alb), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) were measured. RESULTS: Air temperature and relative humidity were found to be higher in bakeries than in flour mill sections. Airborne Aspergillus species were isolated in dust particles <8 um in size. The concentration of Aspergillus flavus and Aspergillus niger were higher in bakeries than in the flour mill sections. They were higher in the grinding section than in other mill sections. The serum AFB1-Alb adduct and ALP levels were significantly higher in bakers compared to milling workers (p < 0.0001, p = 0.05), respectively. The liver enzymes AST and ALT were significantly higher among milling workers and bakers than controls (p < 0.05, p < 0.0001), respectively. The duration of exposure was significantly correlated with serum AFB1 in bakers. Moreover, there was significant correlation between serum AFB1, each of ALT and AST levels in bakers. CONCLUSIONS: chronic occupational exposure to high concentrations of Aspergillus in workplaces may cause elevations in serum levels of AFB1 and liver enzymes in workers exposed to flour dust. Hence, worker protection measures should be consistently adopted and enforced at the workplace. PMID- 25697851 TI - Left Ventricular Reverse Remodeling With Biventricular Versus Right Ventricular Pacing in Patients With Atrioventricular Block and Heart Failure in the BLOCK HF Trial. AB - BACKGROUND: Biventricular pacing in heart failure (HF) improves survival, relieves symptoms, and attenuates left ventricular (LV) remodeling. However, little is known about biventricular pacing in HF patients with atrioventricular block because they are typically excluded from biventricular trials. METHODS AND RESULTS: The Biventricular versus Right Ventricular Pacing in Heart Failure Patients with Atrioventricular Block (BLOCK HF) trial randomized patients with atrioventricular block, New York Heart Association symptom classes I to III HF, and LV ejection fraction <=50% to biventricular or right ventricular pacing. Doppler echocardiograms were obtained at randomization (after 30 to 60 days of right ventricular pacing postimplant) and every 6 months through 24 months. Data analysis comparing changes in 10 prespecified echo parameters over time was conducted using a Bayesian design. LV end systolic volume index was also evaluated as a predictor of mortality/morbidity. Of 691 randomized subjects, 624 had paired Doppler echocardiogram data for >=1 analyses at 6, 12, 18, or 24 months. Biventricular pacing significantly reduced LV volume indices and intraventricular mechanical delay, and improved LV ejection fraction, consistent with LV reverse remodeling. These parameters showed little change with right ventricular pacing alone, indicating no systematic reverse remodeling with right ventricular pacing. LV end systolic volume index was predictive of mortality/morbidity; the estimated risk increased up to 1% for every 1 mL/m(2) increase in LV end systolic volume index. CONCLUSIONS: LV end systolic volume index is a significant predictor of mortality/morbidity in this population. Cardiac structure and function are improved with biventricular pacing for patients with atrioventricular block and LV systolic dysfunction. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00267098. PMID- 25697852 TI - Randomized pilot trial of gene expression profiling versus heart biopsy in the first year after heart transplant: early invasive monitoring attenuation through gene expression trial. AB - BACKGROUND: The endomyocardial biopsy (EMB) is considered the gold standard in rejection surveillance post cardiac transplant, but is invasive, with risk of complications. A previous trial suggested that the gene expression profiling (GEP) blood test was noninferior to EMB between 6 and 60 months post transplant. As most rejections occur in the first 6 months, we conducted a single-center randomized trial of GEP versus EMB starting at 55 days post transplant (when GEP is valid). METHODS AND RESULTS: Sixty heart transplant patients meeting inclusion criteria were randomized beginning at 55 days post transplant to either GEP or EMB arms. A positive GEP >=30 between 2 and 6 months, or >=34 after 6 months, prompted a follow-up biopsy. The primary end point included a composite of death/retransplant, rejection with hemodynamic compromise or graft dysfunction at 18 months post transplant. A coprimary end point included change in first-year maximal intimal thickness by intravascular ultrasound, a recognized surrogate for long-term outcome. Corticosteroid weaning was assessed in both the groups. The composite end point was similar between the GEP and EMB groups (10% versus 17%; log-rank P=0.44). The coprimary end point of first-year intravascular ultrasound change demonstrated no difference in mean maximal intimal thickness (0.35+/-0.36 versus 0.36+/-0.26 mm; P=0.944). Steroid weaning was successful in both the groups (91% versus 95%). CONCLUSIONS: In this pilot study, GEP starting at 55 days post transplant seems comparable with EMB for rejection surveillance in selected heart transplant patients and does not result in increased adverse outcomes. GEP also seems useful to guide corticosteroid weaning. Larger randomized trials are required to confirm these findings. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT014182482377. PMID- 25697853 TI - Immune-spaying as an alternative to surgical spaying in Iberian*Duroc females: effect on quality characteristics and fatty acid profile in dry-cured shoulders and loins. AB - The aim of this study was to assess the effect of immune-spaying on meat quality characteristics and fatty acid profile of dry-cured shoulders and loins by comparing Iberian*Duroc surgically spayed females, immune-spayed females and entire females. There were no significant differences on the physicochemical composition of dry-cured shoulders; however the intramuscular fat content of dry cured loins was higher in immune-spayed females than entire ones, but not significantly different from spayed females. Immune-spayed females showed the highest values, which could improve the sensory quality of Iberian dry-cured loins, since it is considered an index of high quality. On the other hand, the PUFA content of both dry-cured shoulders and loins proved to be lower in immune spayed than spayed females, which could prevent excessive fat oxidation responsible for rancidity. Therefore, immune-spaying could be a viable alternative to surgical spaying from the meat quality point of view. PMID- 25697854 TI - Perinatal outcomes in singleton and twin ICSI pregnancies following hysteroscopic correction of partial intrauterine septa. AB - PURPOSE: To investigate the perinatal outcomes of patients with clinical pregnancies from ICSI treatments who had previously undergone hysteroscopic surgery to correct partial intrauterine septa and compare them to outcomes of patients with no intrauterine anomalies. METHOD: A retrospective observational analysis of 2024 ultrasound confirmed pregnancies from ICSI treatments performed between January 2005 and June 2012. The patients were grouped according to their intrauterine status, and sub-grouped according to the number of fetal hearts observed; singleton control (n=1128), twin control (n=566), singleton septum (n=217) and twin septum (n=113). The primary outcomes analyzed were miscarriage, preterm, very preterm, stillbirth, vanishing twin and live delivery rates, as well as low birth weight and very low birth weight rates. RESULT(S): The live birth rate (89,9 %) in the singleton control subgroup was non-significantly higher than the live birth rate (85,3 %) in the septum subgroup, with a RR of 1,05 (p=0,0583, 95 % CI 0,9943-1,1182) for live birth. In contrast the live birth rate (91,3 %) in twin control subgroup was significantly higher than the live birth rate (84,1 %) in the septum subgroup, with a RR 1,09 (p=0,0282, 95 % CI 0,9988-1,1819). Non-significantly, higher miscarriage and stillbirth rates were the main contributors to the reduced live birth rates. The singleton and twin septum subgroups also had higher rates of premature and very premature delivery and LBWs and vLBW, especially in the singleton septum subgroup. CONCLUSION(S): The hysteroscopic correction of intrauterine septa may not eliminate all risks for premature delivery. PMID- 25697855 TI - Handedness and behavioural inhibition system/behavioural activation system (BIS/BAS) scores: A replication and extension of Wright, Hardie, and Wilson (2009). AB - The Annett Hand Preference Questionnaire (AHPQ) as modified by Briggs and Nebes was administered along with Carver and White's behavioural inhibition system (BIS) and behavioural activation system (BAS) scale and a shortened form of the Big Five personality questionnaire to 92 university students. After eliminating the data from five respondents who reported having changed handedness and one outlier, there was a significant sex difference in mean BIS scores, with females (n = 43) scoring higher than males (n = 43). Replicating the results of Wright, Hardie and Wilson, non-right-handers (n = 36) had significantly higher mean BIS score than right-handers (n = 50). Controlling for sex of participant, neuroticism and BAS sub-scale scores in hierarchical regression analyses left this BIS effect substantially unaffected. There was no handedness or sex difference on any of the three BAS sub-scales. Further analyses revealed no association between strength, as distinct from direction, of handedness and BIS (or BAS) scores. The findings are discussed with reference to recent developments in reinforcement sensitivity theory on which BIS/BAS variables are based. PMID- 25697856 TI - A comparison of actual and theoretical treatments of glenoid fractures. AB - BACKGROUND: There is no consensus on the operative treatment of glenoid fractures. The purpose of this study was to see whether there was a difference between how patients with a glenoid fracture would receive treatment according to theoretical operative indications based on the measurement of computed tomography (CT) scans and radiographs and the treatment they actually received in our institutions. METHODS: A total of 457 patients with a scapular fracture were treated in two level 1 trauma centres between January 2002 and August 2011. Ninety-eight patients with a glenoid fracture were retrospectively analyzed. Intra-articular gap, medial or lateral (M/L) displacement, angular deformity, and glenopolar angle (GPA) were measured on CT scans or radiographs to determine theoretical indications for operative treatment. RESULTS: Twenty-four patients (25%) actually had operative treatment, while 35 patients (36%) fulfilled at least one theoretical criterion to proceed with operative treatment with a medium correlation between theoretical indications for surgery and the actual operative treatment. All the patients with a theoretical indication for surgery had an intra-articular gap with a step-off of >4 mm. A bony Bankart lesion with shoulder dislocation and injury in sports was retained in the best multivariable model as indications for the actual surgery. CONCLUSION: Theoretical guidelines for surgery on glenoid fractures may not have much influence on the current treatment. LEVEL OF EVIDENCE: Therapeutic, level III. PMID- 25697857 TI - Internal anterior fixators for pelvic ring injuries: Do monaxial pedicle screws provide more stiffness than polyaxial pedicle screws? AB - OBJECTIVES: Little is known about the mechanical properties of internal anterior fixators (known as INFIX), which have been proposed as subcutaneous alternatives to traditional anterior external fixators for pelvic ring disruptions. We hypothesised that INFIX has superior biomechanical performance compared with traditional external fixators because the distance from the bar to the bone is reduced. METHODS: Using a commercially available synthetic bone model, 15 unstable pelvic ring injuries were simulated by excising the pubic bone through the bilateral superior and inferior rami anteriorly and the sacrum through the bilateral sacral foramen posteriorly. Three test groups were established: (1) traditional supra-acetabular external fixation, (2) INFIX with polyaxial screws, (3) INFIX with monaxial screws. Load was applied, simulating lateral compression force. Outcome measure was construct stiffness. RESULTS: The traditional external fixator constructs had an average stiffness of 6.21 N/mm +/- 0.40 standard deviation (SD). INFIX with monaxial screws was 23% stiffer than the traditional external fixator (mean stiffness, 7.66 N/mm +/- 0.86 SD; p = .01). INFIX with polyaxial screws was 26% less stiff than INFIX with monaxial screws (mean stiffness, 5.69 N/mm +/- 1.24 SD; p = .05). No significant difference was noted between polyaxial INFIX and external fixators (mean stiffness, 6.21 N/mm +/- 0.40 SD; p=.65). CONCLUSIONS: The performance of INFIX depends on the type of screw used, with monaxial screws providing significantly more stiffness than polyaxial screws. Despite the mechanical advantage of being closer to the bone, polyaxial INFIX was not stiffer than traditional external fixation. PMID- 25697858 TI - Factors predicting patient-reported functional outcome scores after humeral shaft fractures. AB - PURPOSE: The aim of this study was to determine patient variables that are independent predictors of validated functional outcome scores after humeral diaphyseal fractures. METHODS: Adult patients with humeral shaft fractures were retrospectively recruited from a level 1 trauma centre over an 8-year period. Basic demographic information was obtained along with Disabilities of the Arm, Shoulder and Hand (DASH), Simple Shoulder Test (SST) and Short Form 12 (SF-12) physical component summary (PCS) and mental component summary (MCS). Regression analysis was performed to identify patient factors associated with satisfactory outcomes, defined as DASH<21; SST>=10; PCS>=40; and MCS>=40. Of 95 eligible patients, 77 were recruited. Participants had an average age of 47+/-20 years. Forty-five patients were treated with surgery and 32 healed non-operatively. The average follow-up was 48+/-29 months. RESULTS: Satisfactory DASH scores decreased with increase in age (odds ratio (OR) 0.95; P=0.023). Satisfactory SST scores were more likely in patients without a history of psychiatric illness (OR 6.3; P=0.01). Satisfactory SF-12 PCS scores were more likely with no psychiatric history (OR 12; P=0.007) and in patients with private insurance (OR 11.4; P=0.03), but these scores decreased with rising Charlson comorbidity index (CCI; OR 0.50; P=0.023). Satisfactory SF-12 MCS scores increased in the absence of psychiatric history (OR 39; P=0.003), and decreased with rising CCI score (OR 0.54; P=0.035). Analysis of patients younger than 50 years of age (n=38) revealed that the absence of psychiatric history increased the odds of satisfactory DASH scores (OR 10.4; P=0.04). Patients aged >=50 (n=39) had worse DASH scores with increasing age (OR 0.89; P=0.037), better SST scores with middle-third fractures compared to proximal (OR 7.8; P=0.039), better SF-12 PCS with no psychiatric history (OR 16.1; P=0.018) and worse scores with rising CCI (OR 0.50; P=0.036), while rising CCI decreased the odds of satisfactory SF-12 MCS scores (OR 0.47; P=0.046). Treatment modality, associated fractures and classification as "high energy" mechanism were not associated with outcome. CONCLUSION: Patient age, history of psychiatric illness, insurance type, fracture location and Charlson comorbidity index scores had a statistically significant effect on patient reported functional outcomes following treatment of humeral shaft fractures, regardless of treatment modality, injury mechanism and associated fractures. The impact of these variables may be age dependent. PMID- 25697859 TI - Wrist and scaphoid fractures: a 17-year review of NHSLA litigation data. AB - Wrist and scaphoid fractures are common injuries seen and treated in everyday orthopaedic practice. The purpose of the study was to assess the trends and reasons for litigation related to wrist and scaphoid fractures within the NHS. Under a freedom of information (FOI) request, data from 1995 to 2012 were provided by the National Health Service Litigation Authority (NHSLA) on all litigation claims made as a result of wrist and scaphoid fractures. A total of 1354 claims relating to the hand and wrist were identified. Wrist and scaphoid fractures accounted for 492 (36.3%) of these claims, and 365 of these claims were settled, representing 74.2% of all wrist and scaphoid fracture claims. Overall, the most common reason for lost claims was due to incorrect, missed or delayed diagnosis (43.5%). Alleged mismanagement (29.5%), poor care (10.1%) and incompetent surgery (8.0%) were other common causes for litigation. This paper augments previous work published in this area and explores litigation trends specific to wrist and scaphoid fractures. We discuss the trends and reasons for litigation in this area, suggesting areas for improvement that may aid health care professionals who deal with these injuries and potentially help reduce future litigation. PMID- 25697860 TI - Effects of D-cycloserine on extinction of mesolimbic cue reactivity in alcoholism: a randomized placebo-controlled trial. AB - RATIONALE: Mesocorticolimbic reactivity to alcohol-associated cues has been shown to be associated with relapse to renewed drinking and to be decreased by cue exposure-based extinction training (CET). Evidence from preclinical studies suggests that the extinction of conditioned alcohol-seeking behavior might be facilitated by drugs increasing N-methyl-D-aspartate (NMDA) receptor-associated memory consolidation. OBJECTIVES: In this study, we assessed the efficacy of CET treatment supplemented with the partial NMDA-receptor agonist D-cycloserine (DCS) at reducing mesolimbic cue reactivity (CR), craving, and relapse risk in alcoholism. METHODS: In a randomized, placebo-controlled, double-blind study, we recruited 76 recently detoxified abstinent alcohol-dependent patients. Thirty-two (16 DCS, 16 placebo) patients showed cue-induced ventral-striatal activation measured with functional magnetic resonance imaging (fMRI) prior to treatment and were thus included in the efficacy analyses. After inpatient detoxification, patients underwent nine sessions of CET spaced over 3 weeks, receiving either 50 mg DCS or placebo 1 h prior to each CET session. FMRI was conducted before treatment and 3 weeks after treatment onset. RESULTS: Following treatment with CET plus DCS, cue-induced brain activation in the ventral and dorsal striatum was decreased compared to treatment with CET plus placebo. Elevated posttreatment ventral striatal CR and increased craving (assessed using the Obsessive Compulsive Drinking Scale) were associated with increased relapse risk. CONCLUSIONS: DCS was shown to augment the effect of CET for alcohol-dependent subjects. The interaction between craving and ventral-striatal CR on treatment outcome suggests that CET might be especially effective in patients exhibiting both high craving and elevated CR. PMID- 25697861 TI - Modafinil and its metabolites enhance the anticonvulsant action of classical antiepileptic drugs in the mouse maximal electroshock-induced seizure model. AB - RATIONALE: Seizures occur when the excitability of brain circuits is not sufficiently restrained by inhibitory mechanisms. Although modafinil is reported to reduce GABA-activated currents and extracellular GABA levels in the brain, the drug exerts anticonvulsant effects in animal studies. OBJECTIVES: The aim of this study was to determine the effects of modafinil and its metabolites (sulfone and carboxylic acid) on the anticonvulsant action of four classical antiepileptic drugs (AEDs)-carbamazepine (CBZ), phenobarbital (PB), phenytoin (PHT), and valproate (VPA). METHODS: Anticonvulsant activity was assessed with the maximal electroshock seizure threshold (MEST) test and MES test in mice. Brain concentrations of AEDs were measured to ascertain any pharmacokinetic contribution to the observed anticonvulsant effects. RESULTS: Intraperitoneal injection of 75 mg kg(-1) of modafinil or its metabolites significantly elevated the threshold for electroconvulsions in mice, whereas 50 mg kg(-1) of each compound enhanced the anticonvulsant activity of CBZ, PHT, and VPA, but not that of PB. A 25-mg kg(-1) dose of modafinil or its sulfone metabolite enhanced anticonvulsant activity of VPA. Modafinil and its metabolites (50 mg kg(-1)) did not alter total brain concentrations of PB and VPA but did elevate CBZ and PHT. CONCLUSIONS: Enhancement of anticonvulsant actions of VPA by modafinil in the mouse MES model is a pharmacodynamic effect. Collectively, our data suggest that modafinil may be a safe and beneficial adjunct to the therapeutic effects of AEDs in human patients. PMID- 25697862 TI - Obituary: J. David LEander, Ph.D. : (April 8, 1944-November 14, 2014). PMID- 25697863 TI - Species differential regulation of COX2 can be described by an NFkappaB-dependent logic AND gate. AB - Cyclooxygenase 2 (COX2), a key regulatory enzyme of the prostaglandin/eicosanoid pathway, is an important target for anti-inflammatory therapy. It is highly induced by pro-inflammatory cytokines in a Nuclear factor kappa B (NFkappaB) dependent manner. However, the mechanisms determining the amplitude and dynamics of this important pro-inflammatory event are poorly understood. Furthermore, there is significant difference between human and mouse COX2 expression in response to the inflammatory stimulus tumor necrosis factor alpha (TNFalpha). Here, we report the presence of a molecular logic AND gate composed of two NFkappaB response elements (NREs) which controls the expression of human COX2 in a switch-like manner. Combining quantitative kinetic modeling and thermostatistical analysis followed by experimental validation in iterative cycles, we show that the human COX2 expression machinery regulated by NFkappaB displays features of a logic AND gate. We propose that this provides a digital, noise-filtering mechanism for a tighter control of expression in response to TNFalpha, such that a threshold level of NFkappaB activation is required before the promoter becomes active and initiates transcription. This NFkappaB-regulated AND gate is absent in the mouse COX2 promoter, most likely contributing to its differential graded response in promoter activity and protein expression to TNFalpha. Our data suggest that the NFkappaB-regulated AND gate acts as a novel mechanism for controlling the expression of human COX2 to TNFalpha, and its absence in the mouse COX2 provides the foundation for further studies on understanding species-specific differential gene regulation. PMID- 25697864 TI - DNA barcoding for identification of sand fly species (Diptera: Psychodidae) from leishmaniasis-endemic areas of Peru. AB - Phlebotomine sand flies are the only proven vectors of leishmaniases, a group of human and animal diseases. Accurate knowledge of sand fly species identification is essential in understanding the epidemiology of leishmaniasis and vector control in endemic areas. Classical identification of sand fly species based on morphological characteristics often remains difficult and requires taxonomic expertise. Here, we generated DNA barcodes of the cytochrome c oxidase subunit 1 (COI) gene using 159 adult specimens morphologically identified to be 19 species of sand flies, belonging to 6 subgenera/species groups circulating in Peru, including the vector species. Neighbor-joining (NJ) analysis based on Kimura 2 Parameter genetic distances formed non-overlapping clusters for all species. The levels of intraspecific genetic divergence ranged from 0 to 5.96%, whereas interspecific genetic divergence among different species ranged from 8.39 to 19.08%. The generated COI barcodes could discriminate between all the sand fly taxa. Besides its success in separating known species, we found that DNA barcoding is useful in revealing population differentiation and cryptic diversity, and thus promises to be a valuable tool for epidemiological studies of leishmaniasis. PMID- 25697865 TI - Bioconjugated fluorescent silica nanoparticles for the rapid detection of Entamoeba histolytica. AB - Rapid detection of Entamoeba histolytica based on fluorescent silica nanoparticle (FSNP) indirect immunofluorescence microscopy was evaluated. Silica nanoparticles were synthesized using Stober's method, with their surface activated to covalently bind to, and immobilize, protein A. For biolabeling, FSNP was added to conjugated E. histolytica trophozoites with monoclonal anti-E. histolytica IgG1 for microscopic observation of fluorescence. Fluorescent silica nanoparticle sensitivity was determined with axenically cultured E. histolytica serially diluted to seven concentrations. Specificity was evaluated using other intestinal protozoa. Fluorescent silica nanoparticles detected E. histolytica at the lowest tested concentration with no cross-reaction with Entamoeba dispar, Entamoeba moshkovskii, Blastocystis sp., or Giardia lamblia. Visualization of E. histolytica trophozoites with anti-E. histolytica antibody labeled with fluorescein isothiocyanate (FITC) was compared with that using anti-E. histolytica antibody bioconjugated FSNP. Although FITC and FSNP produced similar results, the amount of specific antibody required for FITC to induce fluorescence of similar intensity was fivefold that for FSNP. Fluorescent silica nanoparticles delivered a rapid, simple, cost-effective, and highly sensitive and specific method of detecting E. histolytica. Further study is needed before introducing FSNP for laboratory diagnosis of amoebiasis. PMID- 25697866 TI - Combinations of ascaridole, carvacrol, and caryophyllene oxide against Leishmania. AB - To date there are no vaccines against Leishmania and chemotherapy remains the mainstay for the control of leishmaniasis. The drugs currently used for leishmaniasis therapy are significantly toxic, expensive, and result in a growing frequency of refractory infections. In this study, we evaluated the effect of combinations of the main components of essential oil from Chenopodium ambrosioides (ascaridole, carvacrol, and caryophyllene oxide) against Leishmaniaamazonensis. Anti-leishmanial effects of combinations of pure compounds were evaluated in vitro and the fractional inhibitory concentration (FIC) indices were calculated. BALB/c mice infected with L. amazonensis were treated with different concentrations of ascaridole-carvacrol combinations by intralesional doses every 4 days. Disease progression and parasite burden in infected tissues were determined. In vitro experiments showed a synergistic effect of the combination of ascaridole-carvacrol against promastigotes of Leishmania with a FIC index of 0.171, while indifferent activities were observed for ascaridole caryophyllene oxide (FIC index=3.613) and carvacrol-caryophyllene oxide (FIC index=2.356) combinations. The fixed ratio method showed that a 1:4 ascaridole carvacrol ratio produced a better anti-protozoal activity on promastigotes, lower cytotoxicity, and synergistic activity on intracellular amastigotes (FIC index=0.416). Significant differences (p<0.05) in lesion size and parasite burden were demonstrated in BALB/c mice experimentally infected and treated with the ascaridole-carvacrol combinations compared with control animals. Carvacrol showed significant higher anti-radical activity in the DPPH assay compared with caryophyllene oxide. Electron spin resonance spectroscopy in combination with spin trapping suggested the presence of carbon-centered radicals after activation of ascaridole by Fe(2+). The intensity of the signals is preferably decreased upon addition of carvacrol. The ascaridole-carvacrol combination could represent a future alternative to monotherapeutic anti-leishmanial agents. PMID- 25697867 TI - Analysis of acetohydroxyacid synthase variants from branched-chain amino acids producing strains and their effects on the synthesis of branched-chain amino acids in Corynebacterium glutamicum. AB - Acetohydroxy acid synthase (AHAS) controls carbon flux through the branch point and determines the relative rates of the synthesis of isoleucine, valine and leucine, respectively. However, it is strongly regulated by its end products. In this study, we characterized AHAS variants from five branched-chain amino acids producing strains. Amino acid substitution occurred in both catalytic subunit and regulatory subunit. Interestingly, AHAS variants reduced sensitivity to feedback inhibition by branched-chain amino acids (BCAAs). Although AHAS with amino acid substitution in regulatory subunit showed higher resistance, amino acid substitution in catalytic subunit could also endow AHAS with resistance to feedback inhibition. In addition, AHAS variants from V2 and L5 displayed about 1.4-fold higher specific activity compared to other AHAS variants. On the other hand, AHAS variant from V1 exhibited the highest resistance to BCAAs, 87% of original activity left even in the presence of 10mM BCAAs. Recombinant Corynebacteriumglutamicum strains were further constructed to investigate the effects of expressing AHAS variants on the synthesis of BCAAs and alanine (main by-product) in C. glutamicum. BCAAs production was increased with the increase of resistance to feedback inhibition, although valine showed a significant increase. For instance, C. g-1BN could accumulate 9.51g/l valine, 0.450g/l leucine and 0.180g/l isoleucine, and alanine was reduced to 0.477g/l. These AHAS variants are important for further improving performance of BCAAs-producing strain. PMID- 25697868 TI - Heart-specific overexpression of (pro)renin receptor induces atrial fibrillation in mice. AB - BACKGROUND: Atrial fibrillation (AF) is the most common cardiac arrhythmia, causing substantial cardiovascular morbidity and mortality. The renin-angiotensin system (RAS) has been shown to be involved in the pathophysiology of AF. The (pro)renin receptor [(p)RR] is the last identified member of RAS. However, the role of (p)RR in AF is still unknown. METHODS AND RESULTS: Circulating levels of (p)RR were determined using an immunosorbent assay in 22 patients with AF (paroxysmal or persistent) and 22 healthy individuals. The plasma levels of (p)RR increased 3.6-fold in AF patients (P<0.001), indicating a relationship between (p)RR and AF. To investigate the role of (p)RR in the regulation of cardiac arrhythmia, we generated a transgenic mouse with overexpression of human (p)RR gene specifically in the heart. Electrocardiograms from (p)RR transgenic mice showed typical atrial flutter since 2 months, then spontaneously converted to atrial fibrillation by 10 months. The atria of the transgenic mice demonstrated significant dilation and fibrosis, and exhibited a high incidence of sudden death. Additionally, the genes of SERCA and HCN4, which are involved in the electrophysiology of AF, were significantly down-regulated and up-regulated respectively in transgenic mice atria. The phosphorylation of Erk1/2 significantly increased in the atria of the transgenic mice, and the activated Erk1/2 was found predominantly in cardiac fibroblasts, suggesting that the transgenic (p)RR gene may induce atrial fibrillation by activation of Erk1/2 in the cardiac fibroblasts of the atria. CONCLUSIONS: (p)RR promotes atrial structural and electrical remodeling in vivo, which indicates that (p)RR plays an important role in the pathological development of AF. PMID- 25697869 TI - The efficacy and safety of mechanical hemodynamic support in patients undergoing high-risk percutaneous coronary intervention with or without cardiogenic shock: Bayesian approach network meta-analysis of 13 randomized controlled trials. AB - BACKGROUND: Studies have reported conflicting results regarding efficacy of mechanical hemodynamic support using intra-aortic balloon pump (IABP) or percutaneous ventricular assisted device (pVAD) in patients undergoing high-risk PCI. We performed a Bayesian network meta-analysis comparing the safety and efficacy of mechanical hemodynamic support devices and medical therapy (MT). METHODS AND RESULTS: RCTs comparing overall mortality of IABP versus MT or IABP versus pVAD in high-risk PCI populations were included. The primary endpoint was overall mortality, using the longest available follow-up in each study. This analysis included 2843 patients from 13 trials. In network meta-analysis, overall survival benefit was not significant with IABP (RR 0.84, 95% CrI 0.56-1.24) or pVAD (RR 0.95, 95% CrI 0.42-2.06), compared with MT. IABP or pVAD also did not show early survival benefit compared with MT. In terms of bleeding, pVAD was the worst (versus IABP: RR 29.4, 95% CrI 5.99-221.0; versus MT: RR 41.7, 95% CrI 8.19 330.0), which was mainly driven by the higher incidence of bleeding in the ECMO and TandemHeart, while IABP was worse than MT (RR 1.41, 95% CrI 1.01-2.08). The incidence of acute limb ischemia or vascular complication was not different between treatment groups. CONCLUSIONS: In this meta-analysis, routine elective use of IABP or pVAD did not reduce mortality, while it increased bleeding, compared with MT in high-risk PCI population or even in the patients with cardiogenic shock. Thoughtful selection of appropriate patients and balancing the risk and benefit should be the prerequisites to the use of mechanical hemodynamic support devices. PMID- 25697870 TI - Non-invasive assessment of coronary artery disease in patients with left bundle branch block. AB - There is a high prevalence of coronary artery disease (CAD) in patients with left bundle branch block (LBBB); however there are many other causes for this electrocardiographic abnormality. Non-invasive assessment of these patients remains difficult, and all commonly used modalities exhibit several drawbacks. This often leads to these patients undergoing invasive coronary angiography which may not have been necessary. In this review, we examine the uses and limitations of commonly performed non-invasive tests for diagnosis of CAD in patients with LBBB. PMID- 25697871 TI - Left atrial volume is more important than the type of atrial fibrillation in predicting the long-term success of catheter ablation. AB - BACKGROUND: The type of atrial fibrillation (AF) is the sole prognostic factor that affects the level of recommendation for catheter ablation in the current guidelines. Despite being recognized as a predictor of recurrence, relatively little emphasis is given to left atrium (LA) size. The aim of this study was to assess the relative importance of LA volume and type of AF as predictors of outcome after PVI. METHODS: We assessed 809 consecutive patients with symptomatic drug-refractory AF (584 male, mean age 57 +/- 11 years) undergoing 905 percutaneous PVI procedures in two centers. LA volume was assessed by cardiac CT and/or electroanatomical mapping prior to AF ablation. The study endpoint was symptomatic and/or documented AF recurrence. RESULTS: The majority of patients (73.2%, n=592) had paroxysmal AF. The mean indexed LA volume was 55 +/- 20 ml/m(2). During a follow-up of 2.4 +/- 1.7 years, there were 280 recurrences. The relapse rate of patients with paroxysmal AF in the highest tertile of LA volume was higher than the relapse rate of patients with non-paroxysmal AF in the lowest tertile (20.0% vs. 10.9% per person-year, respectively, p=0.041). LA volume (HR 1.16 for each 10 ml/m(2), 95% CI 1.09-1.23, p<0.001), female gender (HR 1.55, 95% CI 1.19-2.03, p=0.001), and non-paroxysmal AF (HR 1.31, 95% CI 1.01-1.69, p=0.039) were the only independent predictors of AF recurrence. Split-sample cross-validation resampling confirmed LA volume as the strongest predictor of relapse after PVI. CONCLUSION: Left atrial volume seems to be more important than the type of atrial fibrillation in predicting the long-term success of pulmonary vein isolation. PMID- 25697872 TI - Risk of fractures in subjects with antihypertensive medications: A nationwide claim study. AB - BACKGROUND: The effect of antihypertensives on fracture has important clinical implications, since antihypertensives are frequently prescribed with lifelong exposure. This study aimed to compare risk of fracture between antihypertensive medication classes and non-users among adults. METHODS: Nationwide claim data from January 1, 2007 to December 31, 2011 were analyzed. Among 8,315,709 subjects with antihypertensive prescriptions in nationwide medical claim database in South Korea, 528,522 subjects, who initiated single-drug antihypertensives or non users, were analyzed. Subjects were classified as non-user, alpha-blocker (AB), angiotensin-converting-enzyme-inhibitor (ACEI), angiotensin-receptor-blocker (ARB), beta-blocker (BB), calcium-channel-blocker (CCB), and diuretic users. Subjects with combination antihypertensive medications were excluded. RESULTS: A total of 16,805 fracture outcomes were observed during mean follow-up duration of 1.9 years. Fracture rate per 10,000 person-years varied significantly across type of antihypertensives, with ARB having the lowest rate (152.7, 95% confidence interval (CI) 145.4-160.4), and AB having the highest rate (323.7, 95% CI 237.4 441.4). Non-users had fracture rates (152.2, 95% CI 148.7-155.7) similar to ARB users. In models adjusting for age, gender, comorbidity score, diagnosis of diabetes, diagnosis of osteoporosis, osteoporosis treatment, and osteoporosis related diseases, AB users (adjusted hazard ratio (aHR)=2.26), ACEI users (aHR=1.68), diuretic users (aHR=1.45), CCB users (aHR=1.23), and BB users (aHR=1.15) showed significantly increased risk of fractures compared with non users (P<0.05). Only the fracture risk of ARB users (aHR=1.00, 95% CI 0.95-1.05) was not significantly different from the non-users. CONCLUSIONS: The use of antihypertensives except for ARB is associated with increased risk of fracture, with ACEI and AB having higher risk among hypertensive adults. PMID- 25697873 TI - Impact of physical training on normal age-related changes in left ventricular longitudinal function. PMID- 25697874 TI - Comparison of long-term safety and efficacy outcomes after drug-eluting and bare metal stent use across racial groups: Insights from NHLBI Dynamic Registry. AB - BACKGROUND: Long-term data on outcomes after percutaneous coronary intervention (PCI) with drug-eluting stent (DES) and bare-metal stent (BMS) across racial groups are limited, and minorities are under-represented in existing clinical trials. Whether DES has better long-term clinical outcomes compared to BMS across racial groups remains to be established. Accordingly, we assessed whether longer term clinical outcomes are better with DES compared to BMS across racial groups. METHODS: Using the multicenter National Heart, Lung, and Blood Institute (NHLBI) sponsored Dynamic Registry, 2-year safety (death, MI) and efficacy (repeat revascularization) outcomes of 3326 patients who underwent PCI with DES versus BMS were evaluated. RESULTS: With propensity-score adjusted analysis, the use of DES, compared to BMS, was associated with a lower risk for death or MI at 2 years for both blacks (adjusted Hazard Ratio (aHR)=0.41, 95% CI 0.25-0.69, p<0.001) and whites (aHR=0.67, 95% CI 0.51-0.90, p=0.007). DES use was associated with a significant 24% lower risk of repeat revascularization in whites (aHR=0.76, 95% CI 0.60-0.97, p=0.03) and with nominal 34% lower risk in blacks (aHR=0.66, 95% CI 0.39-1.13, p=0.13). CONCLUSION: The use of DES in PCI was associated with better long-term safety outcomes across racial groups. Compared to BMS, DES was more effective in reducing repeat revascularization in whites and blacks, but this benefit was attenuated after statistical adjustment in blacks. These findings indicate that DES is superior to BMS in all patients regardless of race. Further studies are needed to determine long-term outcomes across racial groups with newer generation stents. PMID- 25697875 TI - Hemodynamic shear stress modulates endothelial cell autophagy: Role of LOX-1. AB - OBJECTIVES: Shear stress, autophagy and LOX-1 are important players in atherogenesis. Direct impact of shear stress on autophagy development in endothelial cells and role of LOX-1 therein are undelineated. METHODS AND RESULTS: A parallel-plate flow chamber was used to vary shear stress (3 to 30 dyn/cm(2)), and determine autophagy in endothelial cells. We observed that low shear stress (3 dyn/cm(2)) enhanced autophagy (expression of LC3-II) 2-3 fold, and increasing shear stress (15 to 30 dyn/cm(2)) resulted in a gradual decline. Autophagy increased when cells were treated with an inflammatory stimulus lipopolysaccharide (LPS). LOX-1 expression paralleled autophagy development. The in vitro observations were confirmed in the in vivo setting by studying autophagy (LC3-II and Beclin-1) and LOX-1 expression in wild-type mice given LPS. Expression of both autophagy and LOX-1 was most pronounced in aorto-iliac bifurcation region where shear stress is lower compared with aortic arch, thoracic aorta and iliac artery. To define the role of LOX-1 in the development of autophagy, we studied LOX-1 knockout mice. These mice despite LPS administration exhibited less autophagy (vs. wild-type mice). Role of LOX-1 in the regulation of autophagy was further established with LOX-1 inhibition (siRNA transfection and use of antibody) or overexpression (cDNA transfection), which showed that LOX-1 knockdown reduced while LOX-1 overexpression enhanced LC3-II expression in endothelial cells. CONCLUSIONS: These observations suggest that low shear stress is a powerful regulator on autophagy, particularly in state of inflammation, and LOX-1 plays an important role in shear stress induced autophagy. PMID- 25697876 TI - Galectin-3 and myocardial fibrosis in nonischemic dilated cardiomyopathy. AB - BACKGROUND: Left ventricular (LV) fibrosis, assessed by late gadolinium enhancement (LGE) at cardiac magnetic resonance imaging (MRI), is a marker of LV remodeling, and holds prognostic value in nonischemic dilated cardiomyopathy (NICM). Galectin-3 has been shown to participate in tissue fibrogenesis and to be a prognosticator in heart failure. Our aim was to investigate the relationships between galectin-3 circulating level and myocardial fibrosis at MRI in patients with NICM. METHODS AND RESULTS: One-hundred-fifty patients were enrolled (males 73%; age 58, SD 14 years), with a NICM diagnosis according to the World Health Organization criteria. All patients underwent a comprehensive clinical assessment and biohumoral characterization, including galectin-3 assay, and cardiac MRI, with LGE assessment of fibrosis. Median galectin-3 value was 14.4 ng/mL (IQR 11.7 19.0 ng/mL), and LGE was detected in 106 (71%) patients. Patients with LGE had higher galectin-3 than those without (15.4, 11.8-21.0, vs 13.1, 11.7-16.4 ng/mL, p=0.006). Among univariate predictors of LGE presence (galectin-3, male sex, disease duration, arterial hypertension, left and right ventricular ejection fraction, left ventricular stroke volume), galectin-3 maintained its predictive value at multivariate analysis, together with sex, hypertension, disease duration and right ventricular ejection fraction. At receiver operating characteristic analysis the optimal galectin-3 cut-off for LGE prediction was 14.6 ng/mL (AUC 0.651, sensitivity 57%, specificity 73%). CONCLUSIONS: Galectin-3 is associated with LGE-assessed myocardial replacement fibrosis in patients with NICM. These results support the hypothesis that galectin-3 is involved in cardiac fibrosis and remodeling in NICM, and that its assay may help to select subgroups at higher risk. PMID- 25697877 TI - Presence of myocardial hypoenhancement on multidetector computed tomography after primary percutaneous coronary intervention in acute myocardial infarction predicts poor prognosis. AB - BACKGROUND: Recent research has suggested that patients with greater delayed contrast-enhanced size by multidetector computed tomography (MDCT) are more likely to experience adverse cardiac events and have poor prognoses over the long term. The myocardial hypoenhancement area in the delayed contrast-enhanced effect suggests microvascular obstruction. The outcomes of patients with a hypoenhancement area detected by MDCT have not been clear. We examined the clinical importance of myocardial hypoenhancement detected by delayed contrast enhanced MDCT after percutaneous coronary intervention (PCI) in patients with acute myocardial infarction. METHODS AND RESULTS: In 80 patients with acute myocardial infarction, MDCT was performed immediately after primary PCI. We investigated the outcomes of the patients with hypoenhancement detected by MDCT. Myocardial hypoenhancement was observed in 14 patients (17.5%). All 14 of these patients with hypoenhancement had a transmural infarction, and their infarct volume was significantly higher than those of the patients without hypoenhancement (n=66). During the median follow-up period of 309 days, the appearance of myocardial hypoenhancement was associated with the presence of slow flow/no-reflow, time from onset to reperfusion >=6 h, aging, smoking, chronic kidney disease, and hyper-low-density lipoprotein cholesterolemia. The incidence of major adverse cardiovascular events (MACE) was significantly higher in the patients with hypoenhancement compared to those without hypoenhancement, regardless of the myocardial infarct volume. CONCLUSIONS: These results indicate that the presence of myocardial hypoenhancement in delayed contrast-enhanced MDCT after PCI as well as the extent of infarct area is an important predictor of MACE. PMID- 25697878 TI - Anaphylaxis to anakinra in a pediatric patient with systemic juvenile idiopathic arthritis successfully treated with canakinumab: a case-based review. AB - We present the case of a 2-year-old boy with a history of necrotizing enterocolitis (NEC) with ileostomy diagnosed with systemic juvenile idiopathic arthritis (sJIA) at 10 months of age controlled on anti-interleukin-1 (anti-IL-1) therapy (anakinra). At 17 months of age, ileostomy reversal and bowel re anastomosis was scheduled with anakinra discontinued 3 days prior to the surgery and steroids initiated in its place. Ten days postoperatively, anakinra was re started for signs of sJIA flare. Three months later, he developed persistent peripheral eosinophilia and subsequent anaphylactic reaction 6 months postoperatively. The patient safely tolerated an alternative anti-IL-1 agent (canakinumab). Anaphylaxis to anakinra has not been previously reported in the pediatric literature. This case highlights an important issue in a pediatric patient with sJIA: safety of an alternate anti-IL-1 agent, following development of allergy to one initial agent. PMID- 25697879 TI - Effect of fibrolytic enzymes added to a Andropogon gayanus grass silage concentrate diet on rumen fermentation in batch cultures and the artificial rumen (Rusitec). AB - In vitro batch cultures were used to screen four fibrolytic enzyme mixtures at two dosages added to a 60 : 40 silage : concentrate diet containing the C(4) tropical grass Andropogon gayanus grass ensiled at two maturities - vegetative stage (VS) and flowering stage (FS). Based on these studies, one enzyme mixture was selected to treat the same diets and evaluate its impact on fermentation using an artificial rumen (Rusitec). In vitro batch cultures were conducted as a completely randomized design with two runs, four replicates per run and 12 treatments in a factorial arrangement (four enzyme mixtures*three doses). Enzyme additives (E1, E2, E3 and E4) were commercial products and contained a range of endoglucanase, exoglucanase and xylanase activities. Enzymes were added to the complete diet 2 h before incubation at 0, 2 and 4 MUl/g of dry matter (DM). Gas production (GP) was measured after 3, 6, 12, 24 and 48 h of incubation. Disappearance of DM (DMD), NDF (NDFD) and ADF (ADFD) were determined after 24 and 48 h. For all four enzyme mixtures, a dosage effect (P>0.05) DM, N, NDF or ADF disappearance after 48 h of incubation nor daily ammonia-N, volatile fatty acids or CH(4) production. However, enzyme application increased (P<0.05) microbial N production in feed particle-associated (loosely-associated) and silage feed particle-bound (firmly associated) fractions. With A. gayanus silage diets, degradation may not be limited by microbial colonization, but rather by the ability of fibrolytic enzymes to degrade plant cell walls within this recalcitrant forage. PMID- 25697880 TI - Identification of chemical constituents and larvicidal activity of essential oil from Murraya exotica L. (Rutaceae) against Aedes aegypti, Anopheles stephensi and Culex quinquefasciatus (Diptera: Culicidae). AB - This study was conducted to evaluate the phytochemical composition and larvicidal effect of leaf essential oil from Murraya exotica against early fourth-instar larvae of Aedes aegypti, Anopheles stephensi and Culex quinquefasciatus. Gas chromatography (GC) and gas chromatography mass spectrometry (GC-MS) analyses revealed that the essential oil contained 27 components. The major chemical components identified were beta-humulene (40.62%), benzyl benzoate (23.96%), beta caryophyllene (7.05%) and alpha-terpinene (5.66%). The larval mortality was observed after 12 and 24 h of exposure period. The results revealed that essential oil showed varied levels of larvicidal activity against A. aegypti, A. stephensi and C. quinquefasciatus. After 12 h of exposure period, the larvicidal activities were LC50 = 74.7 and LC90 = 152.7 ppm (A. aegypti), LC50 = 56.3 and LC90 = 107.8 ppm (A. stephensi ), and LC50 = 74.4 and LC90 = 136.9 ppm (C. quinquefasciatus) and the larvicidal activities after 24 h of exposure period were LC50 = 35.8 and LC90 = 85.4 ppm (A. aegypti), LC50 = 31.3 and LC90 = 75.1 ppm (A. stephensi), and LC50 = 43.2 and LC90 = 103.2 ppm (C. quinquefasciatus). These results suggest that leaf essential oil from M. exotica is a promising and eco-friendly source of natural larvicidal agent against A. aegypti, A. stephensi and C. quinquefasciatus. PMID- 25697881 TI - Epidemiology of augmented renal clearance in mixed ICU patients. AB - BACKGROUND: Augmented renal clearance (ARC) or renal hyperfiltration is increasingly reported in intensive care unit (ICU) patients. The goal of this analysis was to study the epidemiology of ARC in a cohort of mixed ICU patients METHODS: Single center retrospective cohort study of adult ICU patients (12/2008 2/2010). When data were available, urinary creatinine clearance (CLCR) was calculated for all patients throughout their ICU stay. ARC was defined as a body surface adjusted CLCR>=130 mL/min/1.73m2. We sought to study the incidence of ARC and identify patient characteristics associated with ARC. RESULTS: A total of 1081 patients were included in the analysis, generating 4472 ICU patient days. Median age was 62 y (IQR 50-72), and 63% were male. The initial CLCR was 86 (39 151) mL/min and the maximal CLCR was 145 (76-237) mL/min. ARC occurred in 55.8% of patients, and was about as frequent in men and women (37%% vs. 35%%, P=0.73). Patients with ARC were younger (57 vs. 67 years, P<0.001) and were less frequently treated with vasopressors (27% vs. 39%, P<0.01). ARC incidence was 36.6 ARC days per 100 ICU days. ARC throughout the ICU stay occurred in 32.8% of patients. CONCLUSION: ARC was a frequent finding in this cohort of ICU patients, with more than half of the patient expressing ARC at least once during their ICU stay, and an incidence of 36.6 ARC days/100 patient days. PMID- 25697882 TI - The evolution of nutritional support in long term ICU patients: from multisystem organ failure to persistent inflammation immunosuppression catabolism syndrome. AB - Multiple organ failure (MOF) is an evolving pathologic phenotype that plagues intensive care units globally. This manuscript aims to depict the evolution of single organ failure through multiple organ failure, ending in the newest phenotype called persistent inflammation, immunosuppression, catabolism syndrome (PICS). Among the other MOF phenotypes discussed are systemic inflammatory response syndrome (SIRS) and compensatory anti-inflammatory response syndrome. Along with a review of the four phenotypes of MOF there is a review of the current literature on nutritional supplementation. Discussed in these sections are possible etiologies for the various progression of MOF, total enteral nutrition (TPN) versus early enteral nutrition (EEN), early versus late parenteral nutrition, glycemic control, and new enteral formulas. Finally, as the newest phenotype, PICS, has evolved we try to make inferences from similar pathologic states to recommend nutritional support that has proven beneficial. PMID- 25697883 TI - Influence of N-heteroaromatic pi-pi stacking on supramolecular assembly and coordination geometry; effect of a single-atom change in the ligand. AB - In order to understand how the polarization of aromatic systems, through the introduction of a nitrogen heteroatom, affects the pi-pi interactions and crystal packing of mercury coordination compounds, in this study, N-(quinolin-2 yl)pyrazine-2-carboxamide and N-(quinolin-3-yl)pyrazine-2-carboxamide ligands were employed in the synthesis of five Hg(II) complexes, [HgBr2(L2=quin)2]n, 1, [HgI2(L2=quin)], 2, [HgCl2(L3=quin)]n, 3, [Hg3Br6(L3=quin)2]n, 4, and [Hg3I6(L3=quin)2]n, 5. X-ray single crystal diffraction analysis of these compounds revealed that all the complexes have polymeric structures except complex 2, which is a discrete compound. Complexes 1 and 3 have 1D and 2D polymeric structures, respectively, while complexes 4 and 5 are 3D coordination polymers. In comparison to homologous complexes containing the N-(naphthalene-2 yl)pyrazine-2-carboxamide ligand, L2=naph, interestingly, the structural analysis clearly shows that the replacement of the naphthyl CH group with a nitrogen atom changes the spatial extent of the pi-electron cloud and the polarity of the aromatic ring, from L2=naph adducts to L2=quin and L3=quin adducts, and the propensity to form pi-pi interactions increases. These pi-pi stacking interaction synthons affect the coordination geometry and structural assembly. This study reveals the undeniable contribution of pi-pi stacking interactions to the organization and stabilization of some of the crystal structures reported here. PMID- 25697884 TI - Doctors and divorce. PMID- 25697885 TI - Unfolding the promise of translational targeting in neurodegenerative disease. AB - With the rise of aging populations, new challenges for health care systems are emerging. Degenerative conditions of the central nervous system share a strikingly great deal of similarities, particularly the production and buildup of malfolded proteins. As a result, stress pathways within the endoplasmic reticulum become activated, triggering widespread neuronal apoptosis. New pharmacological compounds targeting this response are emerging as promising treatment strategies. This review examines the current evidence for protein aggregation in neurodegenerative disease states and discusses future mechanisms of therapeutically targeting the endoplasmic reticulum. PMID- 25697886 TI - Diverse small circular DNA viruses circulating amongst estuarine molluscs. AB - Our understanding of the diversity and abundance of circular replication associated protein (Rep) - encoding single stranded (CRESS) DNA viruses has increased considerably over the last few years due to a combination of modern sequencing technologies and new molecular tools. Studies have used these to identify and recover CRESS DNA viruses from a range of different marine organisms, including copepods, shrimp and molluscs. In our study we identified 79 novel CRESS DNA viruses from three mollusc species (Austrovenus stutchburyi, Paphies subtriangulata and Amphibola crenata) and benthic sediments from the Avon Heathcote estuary in Christchurch, New Zealand. The genomes recovered have varying genome architectures, with all encoding at least two major ORFs that have either unidirectional or bidirectional organisation. Analysis of the Reps of the viral genomes showed they are all highly diverse, with only one Rep sequence sharing 65% amino acid identity with the Rep of gastropod-associated circular DNA virus (GaCSV). Our study adds significantly to the wealth of CRESS DNA viruses recovered from freshwater and marine environments and extends our knowledge of the distribution of these viruses. PMID- 25697887 TI - Multilocus spacer analysis revealed highly homogeneous genetic background of Asian type of Borrelia miyamotoi. AB - Borrelia miyamotoi, a member of the relapsing fever group borreliae, was first isolated in Japan and subsequently found in Ixodes ticks in North America, Europe and Russia. Currently, there are three types of B. miyamotoi: Asian or Siberian (transmitted mainly by Ixodes persulcatus), European (Ixodesricinus) and American (Ixodesscapularis and Ixodespacificus). Despite the great genetic distances between B. miyamotoi types, isolates within a type are characterised by an extremely low genetic variability. In particular, strains of B. miyamotoi of Asian type, isolated in Russia from the Baltic sea to the Far East, have been shown to be identical based on the analysis of several conventional genetic markers, such as 16S rRNA, flagellin, outer membrane protein p66 and glpQ genes. Thus, protein or rRNA - coding genes were shown not to be informative enough in studying genetic diversity of B. miyamotoi within a type. In the present paper, we have attempted to design a new multilocus technique based on eight non-coding intergenic spacers (3686bp in total) and have applied it to the analysis of intra type genetic variability of V. miyamotoi detected in different regions of Russia and from two tick species, I. persulcatus and Ixodespavlovskyi. However, even though potentially the most variable loci were selected, no genetic variability between studied DNA samples was found, except for one nucleotide substitution in two of them. The sequences obtained were identical to those of the reference strain FR64b. Analysis of the data obtained with the GenBank sequences indicates a highly homogeneous genetic background of B. miyamotoi from the Baltic Sea to the Japanese Islands. In this paper, a hypothesis of clonal expansion of B. miyamotoi is discussed, as well as possible mechanisms for the rapid dissemination of one B. miyamotoi clone over large distances. PMID- 25697888 TI - Price difference as a predictor of the selection between brand name and generic statins in Japan. AB - OBJECTIVES: This study aimed to explore the predictors of the selection between brand name drug (BR) and generic drug (GE) and to clarify the quantitative relationship about selection. METHODS: We identified "incident users" who dispensed statins between April 2008 and June 2011 in commercially databases consisted of dispensing claims databases (DCD) of out-of-hospital pharmacies and hospital claims databases (HCD) of in-house pharmacies in Japan. Predictors of the selection between BR and GE, including price difference (PD), the price of BR, their interaction and percent change of the price of GE relative to BR were explored by logistic regression using DCD and HCD separately. RESULTS: We extracted records of 670 patients who have opportunity for selection both BR and GE. Logistic regression analysis demonstrated that PD, the price of BR, interaction between them, and prescriber affiliation were factors significantly associated with the selection in the DCD; logit (p)=9.735-0.251*PD-0.071*the price of BR+0.002*PD*the price of BR-1.816*affiliation+0.220*gender 0.008*age+0.038*monthly medical fee. PD was inversely proportional to BR choice in DCD and lead to the opposite result in HCD. Numerical simulation of selection revealed that the quantitative relationships heavily depend on situations. CONCLUSIONS: PD and the price of BR are predictors of the selection between BR and GE interactively in out-of-hospital pharmacies, but not in in-house pharmacies of medical facilities. Results may support policies which increase the power of out-of-hospital pharmacies for selection. PMID- 25697889 TI - Is Hemoglobin A1c or Perioperative Hyperglycemia Predictive of Periprosthetic Joint Infection or Death Following Primary Total Joint Arthroplasty? AB - We sought to determine if HbA1c and perioperative hyperglycemia were positively associated with the incidence of PJI. We retrospectively reviewed the VA VINCI database on patients who underwent primary joint arthroplasty between 2001 and 2011 and had HbA1c and perioperative blood glucose levels. Of 13,272 patients, 38% (n=5035) had an elevated perioperative HbA1c >=7%. While there was no increased risk of infection associated with elevated HbA1c (HR 0.86, P=0.23), mortality was increased (HR 1.3, P=0.01). Preoperative hyperglycemia was associated with an increased incidence of PJI (HR 1.44, P=0.008). While HbA1c did not perfectly correlate with the risk of PJI, perioperative hyperglycemia did, and may be a target for optimization to decrease the burden of PJI. PMID- 25697890 TI - Bundled payment programs: how to get started: assessing readiness and bringing the stakeholders to the table. AB - Bundled or episode based payments are new reimbursement models that shift the financial incentives for providing healthcare from simple transactional volume to accountable quality, cost and outcomes. This transformation to a value-based healthcare delivery paradigm will mandate increased collaboration between multiple and diverse stakeholders. Before implementing such a program, it is incumbent upon providers to critically assess their readiness and understand the complexity of what is tantamount to a major cultural conversion. PMID- 25697891 TI - Influence of Intraoperative Soft Tissue Balance on Postoperative Active Knee Extension in Posterior-Stabilized Total Knee Arthroplasty. AB - We evaluated the influence of intraoperative soft tissue balance on postoperative active knee extension using Offset Repo-Tensor(r) among 73 varus osteoarthritic knees underwent primary posterior-stabilized total knee arthroplasty. The joint center gap between osteotomized surfaces and the component gap after femoral trial component placement were measured using a joint distraction force of 40lb. The active knee extension angle was measured 4weeks after surgery. The postoperative extension angle was not correlated with the joint center gap at 0 degrees , but positively correlated with the component gap at 0 degrees , and the joint looseness at 0 degrees which was calculated by subtracting insert thickness from the component gap. Thus, intraoperative soft tissue measurement with femoral trial component placement would be useful to predict the postoperative knee extension angle. PMID- 25697892 TI - Evaluating online information regarding the direct anterior approach for total hip arthroplasty. AB - We evaluated the quality of information available on the Internet regarding the direct anterior approach (DAA). The top 50 Web sites from three major search engines (Google, Yahoo!, and Bing) were tabulated utilizing the search term direct anterior hip replacement. Of these, only 22% were authored by a hospital/university, while 60% were by a private physician/clinic. Most Web sites presented the DAA as "better" than other surgical approaches describing benefits, such as accelerated recovery though only 35% described risks of the approach. While only 39% of sites presented patient eligibility criteria, greater than 75% had the ability to make an appointment. Web sites regarding the DAA provide patients with a limited perspective and may be focused on attracting new patients, as opposed to accurately educating them. PMID- 25697893 TI - Oral omega-3 fatty acids treatment in computer vision syndrome related dry eye. AB - PURPOSE: To assess the efficacy of dietary consumption of omega-3 fatty acids (O3FAs) on dry eye symptoms, Schirmer test, tear film break up time (TBUT) and conjunctival impression cytology (CIC) in patients with computer vision syndrome. SETTING AND DESIGN: Interventional, randomized, double blind, multi-centric study. METHODS: Four hundred and seventy eight symptomatic patients using computers for more than 3h per day for minimum 1 year were randomized into two groups: 220 patients received two capsules of omega-3 fatty acids each containing 180mg eicosapentaenoic acid (EPA) and 120mg docosahexaenoic acid (DHA) daily (O3FA group) and 236 patients received two capsules of a placebo containing olive oil daily for 3 months (placebo group). The primary outcome measure was improvement in dry eye symptoms and secondary outcome measures were improvement in Nelson grade and an increase in Schirmer and TBUT scores at 3 months. RESULTS: In the placebo group, before dietary intervention, the mean symptom score, Schirmer, TBUT and CIC scores were 7.5+/-2, 19.9+/-4.7mm, 11.5+/-2s and 1+/-0.9 respectively, and 3 months later were 6.8+/-2.2, 20.5+/-4.7mm, 12+/-2.2s and 0.9+/-0.9 respectively. In the O3FA group, these values were 8.0+/-2.6, 20.1+/ 4.2mm, 11.7+/-1.6s and 1.2+/-0.8 before dietary intervention and 3.9+/-2.2, 21.4+/-4mm, 15+/-1.7s, 0.5+/-0.6 after 3 months of intervention, respectively. CONCLUSION: This study demonstrates the beneficial effect of orally administered O3FAs in alleviating dry eye symptoms, decreasing tear evaporation rate and improving Nelson grade in patients suffering from computer vision syndrome related dry eye. PMID- 25697894 TI - Prognostic nomogram for overall survival in previously untreated patients with extranodal NK/T-cell lymphoma, nasal-type: a multicenter study. AB - The aim of this study was to develop a widely accepted prognostic nomogram for extranodal NK/T-cell lymphoma, nasal-type (NKTCL). The clinical data from 1383 patients with NKTCL treated at 10 participating institutions between 2000 and 2011 were reviewed. A nomogram was developed that predicted overall survival (OS) based on the Cox proportional hazards model. To contrast the utility of the nomogram against the widely used Ann Arbor staging system, the International Prognostic Index (IPI) and the Korean Prognostic Index (KPI), we used the concordance index (C-index) and a calibration curve to determine its predictive and discriminatory capacity. The 5-year OS rate was 60.3% for the entire group. The nomogram included five important variables based on a multivariate analysis of the primary cohort: stage; age; Eastern Cooperative Oncology Group performance status; lactate dehydrogenase; and primary tumor invasion. The calibration curve showed that the nomogram was able to predict 5-year OS accurately. The C-index of the nomogram for OS prediction was 0.72 for both cohorts, which was superior to the predictive power (range, 0.56-0.64) of the Ann Arbor stage, IPI and KPI in the primary and validation cohorts. The proposed nomogram provides an individualized risk estimate of OS in patients with NKTCL. PMID- 25697895 TI - Developmental enhancers revealed by extensive DNA methylome maps of zebrafish early embryos. AB - DNA methylation undergoes dynamic changes during development and cell differentiation. Recent genome-wide studies discovered that tissue-specific differentially methylated regions (DMRs) often overlap tissue-specific distal cis regulatory elements. However, developmental DNA methylation dynamics of the majority of the genomic CpGs outside gene promoters and CpG islands has not been extensively characterized. Here, we generate and compare comprehensive DNA methylome maps of zebrafish developing embryos. From these maps, we identify thousands of developmental stage-specific DMRs (dsDMRs) across zebrafish developmental stages. The dsDMRs contain evolutionarily conserved sequences, are associated with developmental genes and are marked with active enhancer histone posttranslational modifications. Their methylation pattern correlates much stronger than promoter methylation with expression of putative target genes. When tested in vivo using a transgenic zebrafish assay, 20 out of 20 selected candidate dsDMRs exhibit functional enhancer activities. Our data suggest that developmental enhancers are a major target of DNA methylation changes during embryogenesis. PMID- 25697896 TI - Increased number of forkhead box P3+ tumor-infiltrating lymphocytes correlates with high preoperative albumin level and better survival in patients with stage II or III colorectal cancer. AB - Tumor-infiltrating lymphocytes (TILs) that test positive for forkhead box P3 (FOXP3) and elevated preoperative serum albumin levels have been positively associated with survival in colorectal cancer (CRC). This study aimed to investigate correlations among FOXP3+ TILs, preoperative serum albumin, overall survival, and other clinicopathological features of CRC patients. Surgical specimens from 340 stage II-III CRC patients were stained immunohistochemically for the presence of FOXP3+ TILs. Serum albumin levels were determined using an automatic biochemistry analyzer. Associations between various clinicopathological features and patient survival were analyzed via a Cox proportional hazards regression model. The correlation between FOXP3+ TILs and preoperative serum albumin was assessed using Pearson's correlation analysis. Survival curves were constructed by the Kaplan-Meier method. A high FOXP3+ TIL density (>15/five high power fields), elevated preoperative serum albumin (>=35 g/L), and proximal colon carcinoma were significantly associated with better survival, and high FOXP3+ TIL number and elevated preoperative serum albumin were independent predictors of better survival. The correlation between the number of FOXP3+ TILs and preoperative serum albumin level was significant but neither of these correlated with gender, age, tumor size, tumor differentiation, mucinous tumor, T4 stage, postoperative chemotherapy, or tumor location. Our findings suggest that increased FOXP3+ TILs and high preoperative serum albumin levels are independent prognostic markers for improved survival in CRC patients. Furthermore, the number of FOXP3+ TILs correlates with preoperative serum albumin levels in these patients. PMID- 25697897 TI - DNA methylation and expression of the folate transporter genes in colorectal cancer. AB - Folate has a central role in the cell metabolism. This study aims to explore the DNA methylation pattern of the folate transporter genes FOLR1, PCFT, and RFC1 as well as the corresponding protein expressions in colorectal cancer (CRC) tissue and adjacent non-cancerous mucosa (ANCM). Our results showed statistically significant differences in the DNA-methylated fraction of all three genes at several gene regions; we identified three differentially methylated CpG sites in the FOLR1 gene, five CpG sites in the PCFT gene, and six CpG sites in the RFC1 gene. There was a pronounced expression of the FRalpha and RFC proteins in both the CRC and ANCM tissues, though the expression was attenuated in cancer compared to the paired ANCM tissues. The PCFT protein was undetectable or expressed at a very low level in both tissue types. Higher methylated fractions of the CpG sites 3-5 in the RFC1 gene were associated with a lower protein expression, suggestive of epigenetic regulation by DNA methylation of the RFC1 gene in the colorectal cancer. Our results did not show any association between the RFC and FRalpha protein expression and tumor stage, TNM classification, or tumor location. In conclusion, this is the first study to simultaneously evaluate both DNA methylation and protein expression of all three folate transporter genes, FOLR1, PCFT, and RFC1, in colorectal cancer. The results encourage further investigation into the possible prognostic implications of folate transporter expression and DNA methylation. PMID- 25697898 TI - IL-6 originated from breast cancer tissue-derived mesenchymal stromal cells may contribute to carcinogenesis. AB - Tumor microenvironment is an important factor, which sustains and promotes the tumors by inflammatory signals. Interleukin-6 (IL-6) is known as a multifunctional cytokine, which is a major activator of the signaling pathway of Janus kinases (JAKs)/signal transducer and activator of transcription 3 (STAT3). In this study, we aimed to investigate the effect of IL-6 in the tumor microenvironment on carcinogenesis. For this purpose, healthy breast tissue derived stromal cells (HBT-SCs) and malign breast tissue-derived stromal cells (MBT-SCs) were co-cultured with MCF-7 (human breast adenocarcinoma cell line) cells using semipermeable membranes. The cell proliferation was monitored with water-soluble tetrazolium (WST) and carboxyfluorescein succinimidyl ester (CFSE) assays. Protein levels were measured by enzyme-linked immunosorbent assay (ELISA) and Western blot hybridization, while gene expressions were measured by real-time PCR. The results demonstrated that IL-6 protein levels increased significantly in the supernatants of MBT-SCs when they were co-cultured with MCF-7 cells. In accordance with this, the expression of IL-6 was significantly higher in MBT-SCs. Additionally, the expression of STAT3 in MCF-7 cells increased slightly when they were co-cultured with MBT-SCs. Considering together, there is an important interaction between tumor microenvironment and tumor cells mediated by IL-6 signaling. Thereby, the targeting on IL-6 signaling in the treatment of cancer might effectively prevent the tumor progression. PMID- 25697899 TI - Combination treatment with perifosine and MEK-162 demonstrates synergism against lung cancer cells in vitro and in vivo. AB - Lung cancer is a global health problem. The search for new therapeutic approaches for the treatment of lung cancer is important. Here, we reported that the AKT inhibitor perifosine and the MEK?ERK inhibitor MEK-162 synergistically induced lung cancer cell (A549 and H460 lines) growth inhibition and apoptosis. The combined efficiency was significantly higher than either agent alone. For the molecular study, perifosine and MEK-162 worked together to concurrently block AKT, mammalian target of rapamycin (mTOR) complex 1 (mTORC1), and MEK-ERK signalings in lung cancer cells, while either agent alone only affected one or two signalings with lower efficiency. In vivo, MEK-162 and perifosine co administration dramatically inhibited A549 lung cancer xenograft growth, without inducing apparent toxicities. The synergistic activity in vivo was again superior than either agent alone. Thus, perifosine and MEK-162 combination is biologically plausible by acting through effects on different proliferation and survival related signaling pathways. Our in vitro and in vivo results support the feasibility of investigating the synergism regimen in clinical tests. PMID- 25697900 TI - Understanding and managing compliance in the nature conservation context. AB - Nature conservation relies largely on peoples' rule adherence. However, noncompliance in the conservation context is common: it is one of the largest illegal activities in the world, degrading societies, economies and the environment. Understanding and managing compliance is key for ensuring effective conservation, nevertheless crucial concepts and tools are scattered in a wide array of literature. Here I review and integrate these concepts and tools in an effort to guide compliance management in the conservation context. First, I address the understanding of compliance by breaking it down into five key questions: who?, what?, when?, where? and why?. A special focus is given to 'why?' because the answer to this question explains the reasons for compliance and noncompliance, providing critical information for management interventions. Second, I review compliance management strategies, from voluntary compliance to coerced compliance. Finally, I suggest a system, initially proposed for tax compliance, to balance these multiple compliance management strategies. This paper differs from others by providing a broad yet practical scope on theory and tools for understanding and managing compliance in the nature conservation context. PMID- 25697901 TI - Vanadium removal from LD converter slag using bacteria and fungi. AB - Removal of vanadium from Linz-Donawits (LD) converter slag was investigated by means of three different species of microbial systems: Acidithiobacillus thiooxidans (autotrophic bacteria), Pseudomonas putida (heterotrophic bacteria) and Aspergillus niger (fungi). The bioleaching process was carried out in both one-step and two-step process and the leaching efficiencies in both cases were compared. Formation of inorganic and organic acids during the leaching process caused mobilization of vanadium. In order to reduce toxic effects of the metal species on the above mentioned microorganisms, a prolonged adaptation process was performed. Both bacteria, A. thiooxidans and P. putida were able to remove more than 90% of vanadium at slag concentrations of 1-5 g L(-1) after 15 days. Also, the maximum achievable vanadium removal in the fungal system was approximately 92% at a slag concentration of 1 g L(-1) after 22 days. PMID- 25697902 TI - Empowering marginalized communities in water resources management: addressing inequitable practices in Participatory Model Building. AB - Within the field of water resource management, Group Model Building (GMB) is a growing method used to engage stakeholders in the development of models that describe environmental and socioeconomic systems to create and test policy alternatives. While there is significant focus on improving stakeholder engagement, there is a lack of studies specifically looking at the experiences of marginalized communities and the barriers that prevent their fuller participation in the decision-making process. This paper explores the common issues and presents recommended improved practices, based on anti-oppression, related to the stages of problem framing, stakeholder identification and selection, workshop preparation, and workshop facilitation. For problem defining and stakeholder selection, the major recommendations are to engage diverse stakeholder communities from the earliest stages and give them control over framing the project scope. With regards to planning the model building workshops, it is recommended that the facilitation team work closely with marginalized stakeholders to highlight and address barriers that would prevent their inclusion. With the actual facilitation of the workshops, it is best to employ activities that allow stakeholders to provide knowledge and input in mediums that are most comfortable to them; additionally, the facilitation team needs to be able to challenge problematic interpersonal interactions as they manifest within conversations. This article focuses on building comfortability with political language so that the systemic oppression in which existing participatory processes occur can be understood, thus allowing GMB practitioners to engage in social justice efforts. PMID- 25697903 TI - Vibrational properties and specific heat of core-shell Ag-Au icosahedral nanoparticles. AB - The vibrational density of states (VDOS) of metal nanoparticles can be a fingerprint of their geometrical structure and determine their low-temperature thermal properties. Theoretical and experimental methods are available nowadays to calculate and measure it over a size range of 1-4 nm. In this work, we present theoretical results regarding the VDOS of Ag-Au icosahedral nanoparticles with a core-shell structure in that size range (147-923 atoms). The results are obtained by changing the size and type of atoms in the core-shell structure. For all sizes investigated, a smooth and monotonic variation of the VDOSs from Ag to Au is obtained by increasing the number of core Au atoms, and vice versa. Nevertheless, the Ag561Au362 nanoparticle, with a Ag core, shows an anomalous enhancement at low frequencies. An analysis of the calculated VDOSs indicates that as a general trend the low-frequency region is mainly due to the shell contribution, whereas at high frequencies the core effect would be dominant. A linear variation with size is obtained for the period of quasi-breathing mode (QBM), in agreement with the behaviour obtained for pure Ag and Au nanoparticles. A non-monotonic variation is obtained for the QBM frequency as a function of the Ag concentration for all nanoparticles investigated. The calculated specific heat at low temperatures of the Ag-Au nanoparticles is smaller (larger) than the corresponding one calculated for the pure Au (Ag) nanoparticles of same size. Nevertheless, the enhancement of VDOS at low frequencies of the Ag561Au362 nanoparticle with a Ag core induced larger values of specific heat than those of the pure Au923 nanoparticle in the temperature range of 5-15 K. PMID- 25697904 TI - Is the difference between right and left ATLs due to the distinction between general and social cognition or between verbal and non-verbal representations? AB - The present review aimed to check two proposals alternative to the original version of the 'semantic hub' hypothesis, based on semantic dementia (SD) data, which assumed that left and right anterior temporal lobes (ATLs) store in a unitary, amodal format all kinds of semantic representations. The first alternative proposal is that the right ATL might subsume non-verbal representations and the left ATL lexical-semantic representations and that only in the advanced stages of SD, when atrophy affects the ATLs bilaterally, the semantic impairment becomes 'multi-modal'. The second alternative suggestion is that right and left ATLs might underlie two different domains of knowledge, because general conceptual knowledge might be supported by the left ATL, and social cognition by the right ATL. Results of the review substantially support the first proposal, showing that the right ATL subsumes non-verbal representations and the left ATL lexical-semantic representations. They are less conclusive about the second suggestion, because the right ATL seems to play a more important role in behavioral and emotional functions than in higher level social cognition. PMID- 25697905 TI - Correction to A survey of tremtone, dehydrotremetone, and structurally related compounds in Isocoma spp. (Goldenbush) in the southwestern United States. PMID- 25697906 TI - Upregulated, 7q21-22 amplicon candidate gene SHFM1 confers oncogenic advantage by suppressing p53 function in gastric cancer. AB - Chromosomal aberrations are hallmarks of cancers and the locus of frequent genomic amplifications often harbors key cancer driver genes. Many genomic amplicons remain larger with hundreds of genes and the key drivers remain to be identified by an amplification-wide systematic analysis. The 7q21.12-q22.3 genomic amplification is frequent in gastric cancers which occur in ~10% of the patients and multiple cell lines. This 7q21.12-q22.3 amplicon has not yet been completely analyzed towards identifying the driver genes and their functional contribution in oncogenesis. The amplitude and prevalence indicate the important role conferred by this amplicon in gastric cancers. Among the 159 genes of this amplicon, 12 genes are found over-expressed in primary gastric tumors and cell lines. Many of the over-expressed genes show negative association with p53 transcriptional activity. RNAi based functional screening of the genes reveal, SHFM1 as key gastric cancer driver gene. SHFM1 confers cell cycle progression and resistance to p53 stabilizing drugs in gastric cancer cells. SHFM1 also activates Src, MAPK/ERK and PI3K/Akt signaling pathways. This is the first integrative genomic investigation of 7q21.12-q22.3 amplicon revealing the potential oncogenic candidacy of 12 genes. The oncogenic contribution of SHFM1, mediated by the p53 suppressive feature has been demonstrated in gastric cancer cells. PMID- 25697907 TI - Dumbbell-like Au-Fe3O4 nanoparticles: a new nanostructure for supercapacitors. AB - Monodispersed dumbbell-like Au-Fe3O4 nanoparticles (NPs) were synthesized and studied for use in supercapacitors. These dumbbell NPs show Au/Fe3O4-size dependent capacitive behaviors and the 7-14 nm Au-Fe3O4 NPs have the best specific capacitance of 464 F g(-1) at 1 A g(-1) and capacity retention of 86.4% after 1000 cycles, much larger than pure Fe3O4 NPs (160 F g(-1) and 72.8% retention). This capacitive enhancement is believed to arise from the Au-induced increase in electron transfer across the dumbbell-like NPs. Thise report demonstrates a new strategy to enhance oxide NP capacitance for applications in high performance supercapacitors. PMID- 25697908 TI - CapsidMaps: protein-protein interaction pattern discovery platform for the structural analysis of virus capsids using Google Maps. AB - Structural analysis and visualization of protein-protein interactions is a challenging task since it is difficult to appreciate easily the extent of all contacts made by the residues forming the interfaces. In the case of viruses, structural analysis becomes even more demanding because several interfaces coexist and, in most cases, these are formed by hundreds of contacting residues that belong to multiple interacting coat proteins. CapsidMaps is an interactive analysis and visualization tool that is designed to benefit the structural virology community. Developed as an improved extension of the phi-psi Explorer, here we describe the details of its design and implementation. We present results of analysis of a spherical virus to showcase the features and utility of the new tool. CapsidMaps also facilitates the comparison of quaternary interactions between two spherical virus particles by computing a similarity (S)-score. The tool can also be used to identify residues that are solvent exposed and in the process of locating antigenic epitope regions as well as residues forming the inside surface of the capsid that interact with the nucleic acid genome. CapsidMaps is part of the VIPERdb Science Gateway, and is freely available as a web-based and cross-browser compliant application at http://viperdb.scripps.edu. PMID- 25697909 TI - Communication in healthcare interactions in dementia: a systematic review of observational studies. AB - BACKGROUND: Communication is affected by dementia, even in the early stages. Studies directly observing how patients, companions and healthcare professionals communicate have not yet been reviewed. METHODS: Eight databases were searched, and hand searches of relevant journals and grey literature were performed up to August 2014. Two authors reviewed abstracts independently and collectively reviewed for agreement of inclusion. Findings were narratively synthesized. RESULTS: 23 studies were identified observing: diagnostic, follow up, day center, primary care and research consent interactions. Companions were present in 14 studies. Three themes emerged: emotional impact of diagnosis, level of patient involvement and participant strategies to save face and cope with cognitive impairment. Eight studies observed diagnostic disclosure describing emotional reactions, with professionals using mitigating language and rarely checking patient understanding. Studies reported varying patient involvement, showing marginalization in primary care but not in assessments or diagnostic feedback. Patients used humor and metaphor to compensate for difficulties retrieving information and responding appropriately, suggesting preserved awareness of the pragmatics of interaction. Companion roles fluctuated between patient advocate and professional informant. Professionals encountered challenges adapting to heterogeneous patient groups with varying capabilities and needs. CONCLUSIONS: Patient-companion-professional communication in dementia care raises various ethical questions: how to strike a balance between different communicative needs of patients and companions; clarity versus sensitivity in delivery of the diagnosis; and whether to minimize or expose interactional difficulties and misunderstanding to enrich patient understanding and involvement. Healthcare professionals need guidance in delivering a diagnosis and strategies to optimize patient and companion participation. PMID- 25697910 TI - In-situ preparation of N-TiO2/graphene nanocomposite and its enhanced photocatalytic hydrogen production by H2S splitting under solar light. AB - Highly monodispersed nitrogen doped TiO2 nanoparticles were successfully deposited on graphene (N-TiO2/Gr) by a facile in-situ wet chemical method for the first time. N-TiO2/Gr has been further used for photocatalytic hydrogen production using a naturally occurring abundant source of energy i.e. solar light. The N-TiO2/Gr nanocomposite composition was optimized by varying the concentrations of dopant nitrogen and graphene (using various concentrations of graphene) for utmost hydrogen production. The structural, optical and morphological aspects of nanocomposites were studied using XRD, UV-DRS, Raman, XPS, FESEM, and TEM. The structural study of the nanocomposite shows existence of anatase N-TiO2. Further, the details of the components present in the composition were confirmed with Raman and XPS. The morphological study shows that very tiny, 7-10 nm sized, N-TiO2 nanoparticles are deposited on the graphene sheet. The optical study reveals a drastic change in absorption edge and consequent total absorption due to nitrogen doping and presence of graphene. Considering the extended absorption edge to the visible region, these nanocomposites were further used as a photocatalyst to transform hazardous H2S waste into eco-friendly hydrogen using solar light. The N-TiO2/Gr nanocomposite with 2% graphene exhibits enhanced photocatalytic stable hydrogen production i.e. ~5941 MUmol h(-1) under solar light irradiation using just 0.2 gm nanocomposite, which is much higher as compared to P25, undoped TiO2 and TiO2/Gr nanocomposite. The enhancement in the photocatalytic activity is attributed to 'N' doping as well as high specific surface area and charge carrier ability of graphene. The recycling of the photocatalyst shows a good stability of the nanocomposites. This work may provide new insights to design other semiconductor deposited graphene novel nanocomposites as a visible light active photocatalyst. PMID- 25697911 TI - Lack of attentional retraining effects in cigarette smokers attempting cessation: a proof of concept double-blind randomised controlled trial. AB - BACKGROUND: Observational studies have shown that attentional bias for smoking related cues is associated with increased craving and relapse. Laboratory experiments have shown that manipulating attentional bias may change craving. Interventions to reduce attentional bias could reduce relapse in smokers seeking to quit. We report a clinical trial of attentional retraining in treatment seeking smokers. METHODS: This was a double-blind randomised controlled trial that took place in UK smoking cessation clinics. Smokers interested in quitting were randomised to five weekly sessions of attentional retraining (N=60) or placebo training (N = 58) using a modified visual probe task from one week prior to quit day. Both groups received 21 mg nicotine patches (from quit day onwards) and behavioural support. Primary outcomes included change in attentional bias reaction times four weeks after quit day on the visual probe task and craving measured weekly using the Mood and Physical Symptoms Scale. Secondary outcomes were changes in withdrawal symptoms, time to first lapse and prolonged abstinence. RESULTS: No attentional bias towards smoking cues was found in the sample at baseline (mean difference = 3 ms, 95% CI = -2, 9). Post-training bias was not significantly lower in the retraining group compared with the placebo group (mean difference = -9 ms, 95% CI = -20, 2). There was no difference between groups in change in craving (p = 0.89) and prolonged abstinence at four weeks (risk ratio = 1.00, 95% CI = 0.70, 1.43). CONCLUSIONS: Taken with one other trial, there appears to be no effect from clinic-based attentional retraining using the visual probe task. Attentional retraining conducted out of clinic may prove more effective. CLINICAL TRIAL REGISTRATION: UK Clinical Trials ISRCTN 54375405. PMID- 25697912 TI - Escalation of cocaine consumption in short and long access self-administration procedures. AB - BACKGROUND: Escalation of consumption is a hallmark of cocaine addiction. Many animal models reveal escalation by increasing the duration of drug access (e.g., 6-24 h/day) after longer histories of self-administration. We recently developed a method that reveals escalation early post-acquisition under shorter access conditions. However, whether or not rats will escalate cocaine consumption both early post-acquisition under short access (2 h/day) conditions, and later under long access (6 h/day) conditions, has not been demonstrated. METHODS: All rats acquired cocaine self-administration (0.8 mg/kg, i.v.) under 2 h conditions, and then continued 2h self-administration for an additional 13 sessions. Then, rats were assigned either to 2 or 6h conditions, and self-administered cocaine (0.8 mg/kg, i.v.) for an additional 19 sessions. In addition, four cocaine-induced locomotor activity measurements were taken for each rat: before cocaine exposure, after non-contingent cocaine administration, and after escalation in the short and long access experimental phases. RESULTS: Following acquisition, rats displayed a robust escalation of intake during 2 h sessions. Rats that self administered cocaine in continued 2h sessions exhibited stable intake, whereas rats that self-administered cocaine in 6h sessions further escalated intake. Despite the second escalation in 6h rats, cocaine-induced locomotor activity did not differ between 2 and 6h rats. CONCLUSIONS: Escalation of cocaine self administration can occur in the same rats both early post-acquisition, and later under long access conditions. Importantly, this early post-acquisition period provides a new opportunity to determine the mechanisms first involved in the escalation phenomenon. PMID- 25697913 TI - Independent effects of HIV infection and cocaine dependence on neurocognitive impairment in a community sample living in the southern United States. AB - BACKGROUND: Prior studies have established that methamphetamine and HIV can have additive deleterious effects on neurocognitive functioning, but there has been relatively little research on other stimulants like cocaine. This study investigated the effects of cocaine and HIV on neurocognitive impairment in a large, well-characterized sample. METHODS: The sample included 193 adults across four groups: HIV-positive cocaine users (n = 48), HIV-negative cocaine users (n = 53), HIV-positive non-drug users (n = 60), and HIV-negative non-drug users (n = 32). Cocaine users met criteria for lifetime dependence and had past-month cocaine use. A comprehensive battery assessed substance abuse and neurocognitive functioning. RESULTS: Participants were mostly male (66%) and African-American (85%), with a mean age of 46.09 years. The rate of global impairment was 33%, with no significant main effects across groups on likelihood of impairment. There were main effects for cocaine on processing speed and executive functioning, with cocaine users having greater impairment (F = 9.33 and F = 4.22, respectively), and for HIV on attention, with HIV-infected persons having greater impairment (F = 5.55). There was an interaction effect for executive functioning, with the three patient groups having greater impairment than controls (F = 5.05). Nonparametric analyses revealed significant additive impairment in the presence of both HIV and cocaine for processing speed. CONCLUSIONS: While cocaine does not appear to increase vulnerability to global HIV-associated neurocognitive impairment, it does have independent adverse effects on executive functioning and processing speed. Given prior evidence that domain-specific deficits predict real world impairments, our results may help explain the poorer behavioral and functional outcomes observed in HIV-infected cocaine users. PMID- 25697914 TI - Dealing with bone marrow biopsies in the staging of classical Hodgkin lymphoma: an old issue revisited in the (18)F-fluorodeoxyglucose-positron emission tomography era. AB - Bone marrow biopsy is recommended for staging of classical Hodgkin lymphoma. The aim of this study was to compare bone marrow evaluation by histology with that obtained by (18)F-fluorodeoxyglucose-positron emission tomography (FDG-PET). One hundred and three cases of Classical Hodgkin Lymphoma were reviewed. All patients were submitted to FDG-PET evaluation. Bone marrow biopsy results were compared with clinical data and FDG-PET results. Ninety-one cases had available bone marrow biopsies. Overall, there were 16 positive and one suspect case. In five cases, the FDG-PET scan was positive and biopsy was negative: 1/5 was found to correspond to a bone fracture, 3/5 showed marked reactive bone marrow changes and in 1/5 no explanation for the discrepancy was found. FDG-PET showed high sensitivity, supporting the idea that when it is negative, biopsy could be avoided. Care should be taken in patients with a positive FDG-PET, where confirmation by bone marrow biopsy should be recommended. PMID- 25697915 TI - Polymorphisms in GRIA1 gene are a risk factor for asparaginase hypersensitivity during the treatment of childhood acute lymphoblastic leukemia. AB - l-asparaginase is an effective antineoplastic agent used in chemotherapy of acute lymphoblastic leukemia. The drug effect may be compromised by an elicited immune response, resulting in the production of anti-asparaginase antibodies causing an anaphylactic reaction or silent inactivation of the enzyme. To elucidate possible genetic predisposition for inter-individual differences in asparaginase hypersensitivity, we studied single nucleotide polymorphisms (SNPs) in the GRIA1 gene in 146 pediatric patients treated with l-asparaginase. Allergic reaction to l-asparaginase occurred in 49.3% of patients. We observed a statistically significant association between SNPs in the GRIA1 gene and the occurrence of asparaginase allergy: rs4958351 with p = 0.003, rs4958676 with p = 0.005, rs6889909 with p = 0.005, rs6890057 with p = 0.005 and rs10070447 with p = 0.006. We found a statistically significant correlation between asparaginase allergy and event-free survival (p-value 0.005). PMID- 25697916 TI - Multimarker testing with ST2 in chronic heart failure. AB - Despite important progress in recent decades, mortality remains high for patients with chronic heart failure. Risk stratification may be refined by the use of biomarkers for different pathophysiological processes that established mortality risk factors do not directly reflect. Biomarkers that are currently available can provide information about at least 7 pathobiological processes operative in HF, help to identify the specific processes involved in individual patients, and aid in constructing management plans. However, the additional prognostic information gained by any biomarker over a clinical risk model plus other biomarkers needs to be determined with adequate statistical tools. A major problem in selecting a biomarker profile is the proportional increase in economic burden; thus, the addition of any biomarker to a profile should be justified by adequate discrimination, calibration, reclassification, and likelihood analyses. Three studies that implemented such rigorous analyses have assessed a multimarker panel in chronic heart failure that incorporated the biomarker ST2: the Penn HF Study, the Barcelona Study, and the ProBNP Outpatient Tailored Chronic Heart Failure (PROTECT) biomarker substudy. In all 3 studies, a multimarker panel appeared to provide significant information over conventional risk stratification. The latter 2 reports proposed that ST2 might be superior to natriuretic peptides. The Barcelona Bio-HF calculator (www.bcnbiohfcalculator.cat) is a novel risk calculator that considers clinical variables, treatment, and biomarkers (i.e., N terminal pro-brain natriuretic peptide [NT-proBNP], ST2, and high sensitivity troponin T [hsTnT]). The optimal panel of markers, the change in these markers over time, and how these changes might help guide therapeutic interventions remain to be defined. PMID- 25697917 TI - ST2 and multimarker testing in acute decompensated heart failure. AB - Most data on heart failure biomarkers have been derived from patient cohorts with chronic disease. However, risk prediction in patients admitted with acute decompensated heart failure (ADHF) remains a challenge. ADHF is not a single disease: it presents in various manners, and different causes may underlie ADHF, which may be reflected by different biomarkers. Soluble suppression of tumorigenicity 2 (ST2) has been shown to be a strong independent predictor of short-, mid-, and long-term outcome in ADHF. Furthermore, combining biomarkers may help further improve the prognostic power of ST2. The ProBNP Investigation of Dyspnea in the Emergency Department study showed that elevated plasma levels of ST2 together with elevated levels of 4 other biomarkers have clear incremental values to predict outcome in ADHF. The Multinational Observational Cohort on Acute Heart Failure study is an international collaborative network that recruited 5,306 patients hospitalized for ADHF that demonstrated that ST2 and midregional pro-adrenomedulin had independently strong value to predict 30-day and 1-year outcome in patients with ADHF. The Multinational Observational Cohort on Acute Heart Failure study also showed that C-reactive protein plus ST2 better classified risk in patients with ADHFs than ST2 alone. Combining biomarkers for risk prediction or risk stratification might have clinical and more importantly pathophysiological meaning. PMID- 25697918 TI - Extracting versus abandoning sterile pacemaker and defibrillator leads. AB - Nonfunctional or recalled cardiac implantable electronic device leads can be revised with either lead extraction (LE) or lead capping (LC). Factors that influence this decision and comparative outcomes of these strategies are unclear. We reviewed data from our institution to identify patients who received LE (n = 296) or LC (n = 192) from 2006 to 2012. Patients with infectious indications for lead removal were excluded. We compared unanticipated device-related procedures, defined as cardiac implantable electronic device procedures not for device upgrade or battery depletion, using a proportional hazards model adjusted for differences in baseline characteristics. Secondary outcomes were procedural complications, hospitalizations, and all-cause mortality. Patients who received LE were younger and more likely to have an operator with extraction experience (76% vs 26%, p <0.001). Leads removed by experienced extractors versus nonextractors had longer dwell times (4.2 +/- 3.6 vs 0.9 +/- 1.1 years, p <0.001). Over a median follow-up of 3.0 (interquartile range = 3.2) years, the adjusted risk of unanticipated device-related procedures was similar for LE versus LC (hazard ratio 1.04, 95% confidence interval 0.62 to 1.75). Complications, hospitalization rates, and mortality rates were also similar between the 2 groups. In conclusion, lead revision strategy is influenced by operator extraction experience and dwell time of leads. In our analysis, we found no difference in outcomes between the 2 strategies. PMID- 25697919 TI - Soluble ST2--analytical considerations. AB - Suppression of tumorigenicity 2 (ST2, also known as interleukin [IL]-1 receptor like-1) is an IL-1 receptor family member with transmembrane (ST2L) and soluble isoforms (sST2). ST2L is a membrane-bound receptor, and IL-33 is the functional ligand for ST2L. sST2, a soluble truncated form of ST2L, is secreted into the circulation and functions as a "decoy" receptor for IL-33, inhibiting IL-33/ST2L signaling. Blood concentrations of sST2 are increased in inflammatory diseases and heart disease and are considered a valuable prognostic marker in both conditions. In multiple clinical trials, sST2 has emerged as a clinically useful prognostic biomarker in patients with cardiac diseases. Interestingly, sST2 even provides prognostic information in low-risk community-based populations. In this review, we will discuss analytical considerations of measuring circulating sST2 including pre-analytical issues, such as in vitro stability of sST2, biological variation of sST2, and postanalytical issues, such as reference ranges and comparisons to diseased cohorts. PMID- 25697920 TI - The vital role of the right ventricle in the pathogenesis of acute pulmonary edema. AB - The development of acute pulmonary edema involves a complex interplay between the capillary hydrostatic, interstitial hydrostatic, and oncotic pressures and the capillary permeability. We review the pathophysiological processes involved and illustrate the concepts in a number of common clinical situations including heart failure with normal and reduced ejection fractions, mitral regurgitation, and arrhythmias. We also describe other rarer causes including exercise, swimming, and diving-induced acute pulmonary edema. We suggest a unifying framework in which the critical abnormality is a mismatch or imbalance between the right and left ventricular stroke volumes. In conclusion, we hypothesize that increased right ventricular contraction is an important contributor to the sudden increase in capillary hydrostatic pressure, and therefore, a central mechanism involved in the development of alveolar edema. PMID- 25697922 TI - Interferon regulatory factor 9 plays a dual function in health and disease. PMID- 25697921 TI - Real-life safety and efficacy of vildagliptin as add-on to metformin in patients with type 2 diabetes in Turkey--GALATA study. AB - OBJECTIVE: To evaluate tolerability/safety and the efficacy of the combination of vildagliptin plus metformin in a real-life population of patients with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS: This multicenter, single arm, 6 month, observational, prospective cohort study was conducted at 39 centers across Turkey. T2DM patients on vildagliptin and metformin for <=4 weeks were enrolled regardless of their previous antidiabetic therapy. MAIN OUTCOME MEASURES: Efficacy was evaluated by measuring hemoglobin A1c (HbA1c) levels. Tolerability/safety parameters evaluated included hypoglycemic events, gastrointestinal events, peripheral edema and weight gain. RESULTS: This study enrolled 665 patients with a mean +/- standard deviation (SD) age of 55.1 +/- 10.2 years and female predominance (n = 394, 59.2%). Safety was assessed in all enrolled patients. Hypoglycemia was reported in 10 (1.5%) patients (95% confidence interval = 0.8-2.7%). Efficacy was assessed in 289 (43.5%) patients treated for 6 +/- 1 months; these patients showed a mean decrease in HbA1c of 0.8% from baseline value of 7.8% (p < 0.001). The percentages of patients who achieved HbA1c targets of <=6.5% and <=7.0% were significantly increased, from 10.7% to 33.6% and from 22.1% to 52.6%, respectively (p < 0.001 each). The decrease in HbA1c was independent of baseline HbA1c (<=8% vs. 8-10% vs. >=10%), age (<=65 vs. >65 years) and body mass index (<30 vs. >=30 kg/m(2)) (p < 0.001 each). In total, 136 adverse events (AEs) were observed in 71 (10.7%) patients; 10 (1.5%) patients experienced hypoglycemia and gastrointestinal AEs were most commonly reported (n = 29, 4.4%). CONCLUSIONS: In a 'real-life' setting, the vildagliptin and metformin combination was associated with significant improvements in reaching target HbA1c levels, even in elderly and obese patients with T2DM. Moreover, vildagliptin and metformin demonstrated a good overall tolerability/safety profile. PMID- 25697923 TI - Konstantinos Logothetopoulos (1878-1961): the controversial life of an eminent gynaecologist. AB - INTRODUCTION: Professor Konstantinos Logothetopoulos is considered one of the founders of modern Gynaecology in Greece. MATERIAL AND METHODS: The establishment of new hospitals and medical institutes in Greece, the invention of the Logo-pack and organization of the first radiotherapy centre in Greece confirm his title as a distinguished medical doctor. However, he collaborated with the Nazi occupiers during the Second World War and for this reason he is considered a traitor as his decision to become Prime Minister overshadows the image of the distinguished professor and cancels all his contribution to Greek gynaecology. CONCLUSION: The aim of this article is to illustrate truths and facts of the life of a prominent doctor and to prove how his political decisions damaged irreversibly his career. PMID- 25697924 TI - Port-site metastases in patients with gynecological cancer after robot-assisted operations. AB - INTRODUCTION: Port-site metastasis is an extremely rare event in patients with cancer treated with robotic-assisted surgery. However, as robotic procedures are increasing, the incidence of port-site metastases might also increase. The purpose of our review is to evaluate the up-to-now existing literature data on robotic port-site metastasis in the field of gynecological oncology. MATERIALS AND METHODS: The authors retrieved the included results of the study after performing a systematic search in PubMed, Scopus, and Cochrane Library. RESULTS: In total, 20 patients were included in the study. The mean age of them was 56.3 (range 27-82) years. In the majority of the cases, endometrial cancer was responsible for port-site recurrences. The port-site metastasis occurred after 1 36 months postoperatively with the tumor measuring from 0.8 to 10.5 cm. As far as the management of this type of local recurrence, the most common therapeutic strategy adopted was the local excision followed by combined radiotherapy/chemotherapy. CONCLUSIONS: Robotic surgery is a rather new technique and port-site metastasis is a rare complication of it. Due to this fact, we could not reach safe conclusions. The purpose of this study was to raise doctor's clinical suspicion level to such a rare complication. Additional studies should be performed with the intention to clarify both port-site metastasis rates in gynecological oncology patients, as well as to elucidate the possible mechanisms of this type of local recurrence. PMID- 25697925 TI - The role of microRNAs in the pathogenesis of endometrial cancer: a systematic review. AB - INTRODUCTION: Epigenetics seem to play a primary role in the current research on the pathogenesis of different types of endometrial cancer. Data so far indicate that microRNAs regulate different pathways that could lead to carcinogenesis when not functioning properly. The aim of this review is to summarize current knowledge on microRNAs that have been associated with endometrial cancer development. MATERIAL AND METHODS: From July 2014 to August 2014, we conducted a comprehensive research utilizing major online search engines (Pubmed, Crossref, Google Scholar). The main keywords used in our search were endometrial cancer/carcinoma; microRNA; epigenetics; novel biomarkers; pathogenesis. RESULTS: Overall, we identified 155 studies, although only 77 were eligible for this review. Different miRNAs were identified to contribute either promoting the carcinogenesis in the endometrium or inhibiting different steps of endometrial cancer development. Tumour growth, cell proliferation, apoptosis and invasion metastasis have been identified as the main processes where miRNAs seem to be implicated. CONCLUSIONS: microRNAs are effective regulators of gene expression that has a significant role in the pathogenesis of endometrial cancer. Research concerning possible therapeutic implications has been promising, although there is still a significant distance to be covered between research observations and clinical results. Extensive preclinical and translational research is still required to improve the efficacy and minimize unwanted effects of miRNAs-based therapy. PMID- 25697926 TI - Colposcopic acetowhitening of vulvar lesion: a validity study. AB - OBJECTIVE: To evaluate the acetowhite changes of the vulva as a predictor for high grade vulvar intraepithelial neoplasia. METHODS: We performed retrospective analysis from 344 patients referred to our gynecology oncology clinic for genital dysplasia. All patients underwent vulvar colposcopy. Vulvar biopsies were performed for acetowhite changes and visible vulvar lesions such as ulceration, hyperpigmentation, and thickening of the vulvar tissue. High grade vulvar dysplasia was defined as vulvar intraepithelial neoplasia 2 or worse. Results of the vulvar pathology were collected and sensitivity, specificity, negative and positive predictive values. RESULTS: Of the 344 women who underwent vulvoscopy 241 patients had acetowhite lesions, of whom 89 had true high grade dysplasia. Using colposcopic acetowhite changes as a marker for high grade vulvar dysplasia, the test's sensitivity was 97 %, specificity was 40 %, negative predictive value was 98 %, and the positive predictive value was 37 %. CONCLUSION: Acetowhitening of the vulva has high sensitivity but low specificity as a predictor of high grade vulvar intraepithelial neoplasia. The absence of acetowhite lesion can reassure that high grade vulvar lesion is absent. PMID- 25697927 TI - Dentoalveolar trauma and minor trauma as precipitating factors for medication related osteonecrosis of the jaw (ONJ): a retrospective study of 149 consecutive patients from the Copenhagen ONJ Cohort. AB - OBJECTIVE: Medication-related osteonecrosis of the jaw (ONJ) is often preceded by dentoalveolar trauma. The aim of this study was to examine the frequency of dentoalveolar trauma precipitated ONJ and compare trauma-precipitated ONJ with spontaneously developing ONJ. STUDY DESIGN: This was a retrospective study. All patients were examined according to a standard ONJ chart. RESULTS: Among 149 consecutive ONJ patients from the Copenhagen Cohort, 95 (64%) had a dentoalveolar trauma before referral (trauma group): dental extractions (n = 80); denture related sore mouth (n = 12); and others (n = 3). The remaining 54 patients had spontaneous ONJ (spontaneous group). The mean time from oral trauma to referral for ONJ was 8 months. CONCLUSION: This study documented that dentoalveolar trauma precipitated ONJ in the majority of cases. However, even minor trauma, such as intubation and impression tray lesions, precipitated ONJ in a few cases (1%). Besides the occurrence of fistula to the skin and a difference in the male-to female ratio, we found no significant difference between the spontaneous and trauma groups. PMID- 25697928 TI - Data, data everywhere but not a byte to share...? PMID- 25697929 TI - MMP-7, MMP-8, and MMP-9 in oral and cutaneous squamous cell carcinomas. AB - OBJECTIVES: Oral squamous cell carcinoma (OSCC) and cutaneous squamous cell carcinoma (CSCC) are epithelial neoplasms, of which OSCC has a worse prognosis. Matrix metalloproteinases (MMPs) are involved in the initiation, invasion, metastasis, and defense of cancer. This study aimed to compare differences in MMP expression in these cancers. STUDY DESIGN: Sixty-one patients with early-stage (T1-T2 N0 M0) cancers, of which 36 were OSCC and 25 CSCC, were enrolled into this study. Immunohistochemical staining was performed with MMP-7, MMP-8, and MMP-9 antibodies. RESULTS: MMP-7 expression was stronger in OSCC than in CSCC, mainly in the invasive front. MMP-8 was absent and MMP-9 was mildly expressed in OSCC and CSCC cells. However, MMP-8 and MMP-9 were positive in peritumoral inflammatory cells in both cancers. In addition, MMP-7, MMP-8, and MMP-9 were not associated with the overall survival of patients with OSCC and CSCC patients. CONCLUSIONS: The increased expression of MMP-7 in the invasive front may partly explain the aggressiveness of OSCC. PMID- 25697930 TI - Medical conditions and medication use in a U.S. dental school clinic population. AB - OBJECTIVES: The aim of the study was to characterize coexisting medical conditions and medication use in patients treated at a US dental school in 2010 and to assess their implications on providing dental care. STUDY DESIGN: Data on the types and prevalence of self-reported medical conditions and the use of medications were extracted from the electronic health records of 1797 adult patients and compared against their socioeconomic status (SES). RESULTS: Within this sample, 8.7% were classified as American Society of Anesthesiologists (ASA) physical status (PS) 1. The remainder were designated PS 2 to PS 4 for smoking, having one or more medical conditions that ranged from myasthenia gravis (<1%) to hypertension (24%), or both. Medications for hypertension were the most frequently reported (23%), followed by more than 40 other classes of drugs. CONCLUSIONS: Dental practitioners must be prepared to treat larger numbers of older patients, whose life expectancies continue to increase as advances in pharmacotherapeutics and biomedical technologies improve the control of their chronic medical conditions. PMID- 25697931 TI - Direct and CBCT dentogingival tissue thickness measurements. PMID- 25697943 TI - Correction to Anthraquinone Derivatives as Potent Inhibitors of c-Met Kinase and the Extracellular Signaling Pathway. AB - [This corrects the article DOI: 10.1021/ml4000047.]. PMID- 25697944 TI - Acute exposure to 17alpha-ethinylestradiol disrupts audience effect on male female interactions in Betta splendens. AB - Endocrine disrupting chemicals can negatively impact the morphology and behavior of organisms inhabiting polluted waters. Male-typical behaviors are often reduced after exposure, suggesting that exposure may have population-level effects. One way in which exposure may exert population-level effects is by interfering with communication within a network of individuals. Acute exposure to the estrogen mimic 17alpha-ethinylestradiol (EE2) disrupts the ability of male Siamese fighting fish, Betta splendens, to modify their behavior during male-male interactions when an audience is present. However, it is unknown whether audience effects during male-female interactions may be similarly altered. To examine this, male-female pairs that were given an acute exposure to EE2 or remained unexposed interacted in the presence of a female, male, or no audience. Sex differences were found between unexposed males and females. More interactant directed gill flaring was displayed by control males when a male audience was present while control females performed this behavior more in the presence of an audience, regardless of sex. Both males and females in the control group performed more interactant-directed tail beats in the presence of a female audience. EE2 exposure made all audience effects disappear as treated males and females did not differ in their responses between audience types. These results demonstrate that acute exposure to EE2 may disrupt behavioral adjustments to audience type within a social network. This disruption may, in turn, influence population dynamics in this species as both males and females use information obtained from observing interactions in later encounters with the observed individuals. PMID- 25697945 TI - Abstracts from the Second Meeting of the Biennial Conference Series to Promote Global Health, April 22-24, 2015, Hangzhou, China. PMID- 25697946 TI - Learning clinical skills in the simulation suite: the lived experiences of student nurses involved in peer teaching and peer assessment. AB - BACKGROUND: The benefits of peer teaching and assessment are well documented within nurse education literature. However, research to date has predominantly focused on the advantages and disadvantages for the inexperienced learner, with a dearth of knowledge relating to the perceptions of senior nursing students involved in teaching their peers. AIM: This study sought to investigate the student experience of taking part in a peer teaching and assessment initiative to include the perceptions of both first year nursing students and second/third year participants. METHOD: Data were collected via open-ended questionnaires and analysed with qualitative 'Framework' analysis. FINDINGS: This initiative received a generally positive response both from students being taught and also from those acting as facilitators. Perceived benefits included the social learning experience, development of teaching skills, self-awareness and the opportunity to communicate both good and bad news. Suggestions for improvement included additional time working in small groups, specific supplementary learning materials and the introduction of peer teaching and assessment into other areas of the Adult Nursing Programme. CONCLUSIONS: Peer teaching and assessment principles represent valuable strategies which can be utilised in nurse education to develop clinical skills and prepare nurses for real-life scenarios. Further research needs to investigate how to enhance the student learning experience and to fully exploit the potential for simulated experience to prepare students for their future role as registered nurses in clinical practice. PMID- 25697947 TI - Cinema may help break the silence around child sexual abuse in India. PMID- 25697948 TI - Early recognition of possible pitfalls in histological diagnosis of celiac disease. AB - OBJECTIVE: A state-of-the-art assessment of duodenal biopsies by the pathologist in the diagnosis of celiac disease (CelD) is of highest importance. However, inaccurate characterization of specific features can lead to misdiagnosis. Our hypothesis is that a detailed histological report guarantees a good quality and helps in the primary diagnostic process by preventing false-positive diagnosis of CelD. MATERIAL AND METHODS: A total of 52 patients primarily diagnosed with CelD and suspicion of misdiagnosis were selected for this retrospective study. External histological reports of duodenal biopsies were obtained and later reassessed by an experienced in-house pathologist. For an objective evaluation a histology quality score (HQS) was created. Both pathological reports were compared and causes for a possible misdiagnosis were analyzed. Diagnostic systems by Catassi and Korponay-Szabo were compared with each other. RESULTS: The original diagnosis had been confirmed in 27% by our pathologist. The HQS was significantly lower (worse) in cases where the original diagnosis were dismissed than in confirmed CelD (p = 0.018). The new diagnostic approach by Catassi and Korponay-Szabo showed a sensitivity of 89% and 83%, respectively, a specificity of 97%, a positive predictive value of 94% and a negative predictive value of 94% and 92%, respectively. CONCLUSIONS: A low quality of the histological evaluation can lead to a high probability of misdiagnosing CelD. By applying the HQS the physician can estimate whether the report is fraught with uncertainty. Ideally the score minimizes false-positive results and prevents a delay of the correct diagnosis. PMID- 25697949 TI - The Anatolian Journal of Cardiology and social policy interaction. PMID- 25697950 TI - What we have learned from the ESC position paper on arrhythmias in acute coronary syndromes. PMID- 25697951 TI - Multiple biomarkers of the cytotoxicity induced by BDE-47 in human embryonic kidney cells. AB - Polybrominated diphenyl ethers (PBDEs) are widely used as brominated flame retardants in a variety of industrial products. Among these PBDEs, 2,2',4,4' tetra-bromodiphenyl ether (BDE-47) is one of the most predominant congeners inducing multiple toxicities, including hepatotoxicity, neurotoxicity, cytotoxicity, genotoxicity, carcinogenecity and immunotoxicity in human body. In this study, the cytotoxicity of BDE-47 in human embryonic kidney cells (HEK293) was investigated by a set of bioassays, including cell proliferation, apoptosis, oxidative stress and metabolic responses as well as gene expressions related to apoptosis. Results showed that BDE-47 induced an inverted U-shaped curve of cell proliferation in HEK293 cells from 10(-6) to 10(-4) M. Cell apoptosis and ROS overproduction were detected at 10(-5) M of BDE-47 (p<0.05). In addition, the expressions of Bcl-2 family-encoding genes (Bad, Hrk and Bcl-2) increased significantly in 10(-4)M group (p<0.05). Metabolic responses indicated that BDE 47 mainly caused disturbance in energy metabolism marked by differentially altered ethanol, glutathione, creatine, aspartate, UDP-glucose and NAD(+). The increased lactate/alanine ratios indicated the higher reductive state induced by BDE-47 in all exposures confirmed by the overproduction of ROS. PMID- 25697952 TI - Polychlorinated biphenyls (PCBs) and polybrominated biphenyl ethers (PBDEs) in environmental samples from Ny-Alesund and London Island, Svalbard, the Arctic. AB - Polychlorinated biphenyls (PCBs) and polybrominated biphenyl ethers (PBDEs) were determined in environmental samples collected from Ny-Alesund and London Island, Svalbard, the Arctic. Total PCB concentrations (?25PCBs) varied from 0.57 to 2.52 ng g(-1) dry weight (dw) in soil, 0.30 to 1.16 ng g(-1) dw in plants and 0.56 to 0.98 ng g(-1) dw in reindeer dung. The non-Aroclor congener of CB-11 was predominant in most samples compared to other congeners, accounting for 16.0+/ 9.8% to the ?25PCBs. The ?13PBDEs concentrations were 1.7-416, 36.7-495 and 28.1 104 pg g(-1) dw in soil, plants and reindeer dung, respectively. The signature of enantioselective biotransformation was observed in all samples for chiral CB-95, whereas in parts of samples for other chiral PCBs. Bioaccumulation factors (BAFs) in six plant species varied within individual contaminant congeners and plant species, with BAFs less than 1 for ?PCBs and higher than 1 for ?PBDEs. BAF values decreased with increasing soil concentrations, suggesting that high background levels in soil restricted the accumulation of these contaminants by plants. PMID- 25697953 TI - Real-space imaging of macroscopic diffusion and slow flow by singlet tagging MRI. AB - Magnetic resonance imaging can be used to study motional processes such as flow and diffusion, but the accessible timescales are limited by longitudinal relaxation. The spatially selective conversion from magnetization to long-lived singlet order in designer molecules makes it possible to tag a region of interest for an extended period of time, of the order of several minutes. Here we exploit this concept of "singlet tagging" to monitor diffusion over a macroscopic scale as well as very slow flow. PMID- 25697954 TI - TaRAR1 and TaSGT1 associate with TaHsp90 to function in bread wheat (Triticum aestivum L.) seedling growth and stripe rust resistance. AB - RAR1 and SGT1 are important co-chaperones of Hsp90. We previously showed that TaHsp90.1 is required for wheat seedling growth, and that TaHsp90.2 and TaHsp90.3 are essential for resistance (R) gene mediated resistance to stripe rust fungus. Here, we report the characterization of TaRAR1 and TaSGT1 genes in bread wheat. TaRAR1 and TaSGT1 each had three homoeologs, which were located on wheat groups 2 and 3 chromosomes, respectively. Strong inhibition of seedling growth was observed after silencing TaSGT1 but not TaRAR1. In contrast, decreasing the expression of TaRAR1 or TaSGT1 could all compromise R gene mediated resistance to stripe rust fungus infection. Protein-protein interactions were found among TaRAR1, TaSGT1 and TaHsp90. The N-terminus of TaHsp90, the CHORD-I and CHORD-II domains of TaRAR1 and the CS domain of TaSGT1 may be instrumental for the interactions among the three proteins. Based on this work and our previous study on TaHsp90, we speculate that the TaSGT1-TaHsp90.1 interaction is important for maintaining bread wheat seedling growth. The TaRAR1-TaSGT1-TaHsp90.2 and TaRAR1 TaSGT1-TaHsp90.3 interactions are involved in controlling the resistance to stripe rust disease. The new information obtained here should aid further functional investigations of TaRAR1-TaSGT1-TaHsp90 complexes in regulating bread wheat growth and disease resistance. PMID- 25697955 TI - Differential regulation of genes by retrotransposons in rice promoters. AB - Rice genome harbors genes and promoters with retrotransposon insertions. There is very little information about their function. The effect of retrotransposon insertions in four rice promoter regions on gene regulation, was investigated using promoter-reporter gene constructs with and without retrotransposons. Differences in expression levels of gus and egfp reporter genes in forward orientation and rfp in reverse orientation were evaluated in rice plants with transient expression employing quantitative RT-PCR analysis, histochemical GUS staining, and eGFP and RFP fluorescent microscopy. The presence of SINE in the promoter 1 (P1) resulted in higher expression levels of the reporter genes, whereas the presence of LINE in P2 or gypsy LTR retrotransposon in P3 reduced expression of the reporter genes. Furthermore, the SINE in P1 acts as an enhancer in contrast with the LINE in P2 and the gypsy LTR retrotransposon in P3 which act as silencers. CTAA and CGG motifs in these retrotransposons are the likely candidates for the downregulation compared to TCTT motif (SINE) which is a candidate for the upregulation of gene expression. The effect of retrotransposons on gene regulation correlated with the earlier investigation of conservation patterns of these four retrotransposon insertions in several rice accessions implying their evolutionary significance. PMID- 25697956 TI - The influence of personal BMI on body size estimations and sensitivity to body size change in anorexia spectrum disorders. AB - In this cross-sectional study, we investigated the influence of personal BMI on body size estimation in 42 women who have symptoms of anorexia (referred to henceforth as anorexia spectrum disorders, ANSD), and 100 healthy controls. Low BMI control participants over-estimate their size and high BMI controls under estimate, a pattern which is predicted by a perceptual phenomenon called contraction bias. In addition, control participants' sensitivity to size change declines as their BMI increases as predicted by Weber's law. The responses of women with ANSD are very different. Low BMI participants who have ANSD are extremely accurate at estimating body size and are very sensitive to changes in body size in this BMI range. However, as BMI rises in the ANSD participant group, there is a rapid increase in over-estimation concurrent with a rapid decline in sensitivity to size change. We discuss the results in the context of signal detection theory. PMID- 25697957 TI - Speech Prosody Across Stimulus Types for Individuals with Parkinson's Disease. AB - BACKGROUND: Up to 89% of the individuals with Parkinson's disease (PD) experience speech problem over the course of the disease. Speech prosody and intelligibility are two of the most affected areas in hypokinetic dysarthria. However, assessment of these areas could potentially be problematic as speech prosody and intelligibility could be affected by the type of speech materials employed. OBJECTIVE: To comparatively explore the effects of different types of speech stimulus on speech prosody and intelligibility in PD speakers. METHODS: Speech prosody and intelligibility of two groups of individuals with varying degree of dysarthria resulting from PD was compared to that of a group of control speakers using sentence reading, passage reading and monologue. Acoustic analysis including measures on fundamental frequency (F0), intensity and speech rate was used to form a prosodic profile for each individual. Speech intelligibility was measured for the speakers with dysarthria using direct magnitude estimation. RESULTS: Difference in F0 variability between the speakers with dysarthria and control speakers was only observed in sentence reading task. Difference in the average intensity level was observed for speakers with mild dysarthria to that of the control speakers. Additionally, there were stimulus effect on both intelligibility and prosodic profile. CONCLUSIONS: The prosodic profile of PD speakers was different from that of the control speakers in the more structured task, and lower intelligibility was found in less structured task. This highlighted the value of both structured and natural stimulus to evaluate speech production in PD speakers. PMID- 25697958 TI - Local Change in Urinary Bladder Contractility Following CNS Dopamine Denervation in the 6-OHDA Rat Model of Parkinson's Disease. AB - BACKGROUND: Urinary problems, including urinary frequency, urgency, and nocturia are some of the non-motor symptoms that correlate most with poor quality of life in Parkinson's disease. However, the mechanism behind these symptoms is poorly understood, in particular regarding peripheral bladder pathophysiology following dopamine degeneration. OBJECTIVE: In this study, we compared the contractile responsiveness of urinary bladder from the 6-OHDA unilateral rat model of Parkinson's disease with that of normal untreated animals. METHODS: The contractility of the urinary detrusor muscle was evaluated in bladder strip preparations using electrical field stimulation, and muscarinic and purinoceptor stimulations in an vitro organ bath setup. RESULTS: Our data show that the overall contractile response following electrical field stimulation was significantly higher (43% at maximum contraction by 20-40 Hz stimulation) in the 6-OHDA-lesioned rats as compared to control animals. This increase was associated with a significant increase in the cholinergic contractile response, where the muscarinic agonist methacholine produced a 44% (at 10 -4 M concentration) higher response in the 6-OHDA-treated rats as compared to controls with a significant left-shift of the dose response. This indicates an altered sensitivity of the muscarinic receptor system following the specific central 6-OHDA-induced dopamine depletion. In addition a 36% larger contraction of strips from the 6-OHDA animals was also observed with purinoceptor activation using the agonist ATP (5*10 -3 M) during atropine treatment. CONCLUSIONS: Our data shows that it is not only the central dopamine control of the micturition reflex that is altered in Parkinson's disease, but also the local contractile function of the urinary bladder. The current study draws attention to a mechanism of urinary dysfunction in Parkinson's disease that has previously not been described. PMID- 25697959 TI - Site-directed mutagenesis around the CuA site of a polyphenol oxidase from Coreopsis grandiflora (cgAUS1). AB - Aurone synthase from Coreopsis grandiflora (cgAUS1), catalyzing conversion of butein to sulfuretin in a type-3 copper center, is a rare example of a polyphenol oxidase involved in anabolism. Site-directed mutagenesis around the CuA site of AUS1 was performed, and recombinant enzymes were analyzed by mass spectrometry. Replacement of the coordinating CuA histidines with alanine resulted in the presence of a single copper and loss of diphenolase activity. The thioether bridge-building cysteine and a phenylalanine over the CuA site, exchanged to alanine, have no influence on copper content but appear to play an important role in substrate binding. PMID- 25697960 TI - Measuring the linear and nonlinear elastic properties of brain tissue with shear waves and inverse analysis. AB - We use supersonic shear wave imaging (SSI) technique to measure not only the linear but also the nonlinear elastic properties of brain matter. Here, we tested six porcine brains ex vivo and measured the velocities of the plane shear waves induced by acoustic radiation force at different states of pre-deformation when the ultrasonic probe is pushed into the soft tissue. We relied on an inverse method based on the theory governing the propagation of small-amplitude acoustic waves in deformed solids to interpret the experimental data. We found that, depending on the subjects, the resulting initial shear modulus [Formula: see text] varies from 1.8 to 3.2 kPa, the stiffening parameter [Formula: see text] of the hyperelastic Demiray-Fung model from 0.13 to 0.73, and the third- [Formula: see text] and fourth-order [Formula: see text] constants of weakly nonlinear elasticity from [Formula: see text]1.3 to [Formula: see text]20.6 kPa and from 3.1 to 8.7 kPa, respectively. Paired [Formula: see text] test performed on the experimental results of the left and right lobes of the brain shows no significant difference. These values are in line with those reported in the literature on brain tissue, indicating that the SSI method, combined to the inverse analysis, is an efficient and powerful tool for the mechanical characterization of brain tissue, which is of great importance for computer simulation of traumatic brain injury and virtual neurosurgery. PMID- 25697961 TI - Cellular organization of siderophore biosynthesis in Pseudomonas aeruginosa: Evidence for siderosomes. AB - Pyoverdine I (PVDI) and pyochelin (PCH) are the two major siderophores produced by Pseudomonas aeruginosa PAO1 to import iron. The biochemistry of the biosynthesis of these two siderophores has been described in detail in the literature over recent years. PVDI assembly requires the coordinated action of seven cytoplasmic enzymes and is followed by a periplasmic maturation before secretion of the siderophore into the extracellular medium by the efflux system PvdRT-OpmQ. PCH biosynthesis also involves seven cytoplasmic enzymes but no periplasmic maturation. Recent findings indicate that the cytoplasmic enzymes involved in each of these two siderophore biosynthesis pathways can form siderophore-specific multi-enzymatic complexes called siderosomes associated with the inner leaflet of the cytoplasmic membrane. This organization may optimize the transfer of the siderophore precursors between the various participating enzymes and avoid the diffusion of siderophore precursors, able to chelate metals, throughout the cytoplasm. Here, we describe these recently published findings and discuss the existence of these siderosomes in P. aeruginosa. PMID- 25697962 TI - The first zeolite with a tri-directional extra-large 14-ring pore system derived using a phosphonium-based organic molecule. AB - A new germanosilicate zeolite (denoted as ITQ-53) with extra-large pores has been synthesised using tri-tertbutylmethylphosphonium cation as the organic structure directing agent (OSDA). Rotation electron diffraction (RED) was used to identify ITQ-53 from an initially-synthesised sample containing impurities, and to solve its structure. The structure was refined against PXRD data of pure ITQ-53 samples obtained after synthesis optimisation. ITQ-53 is the first example of extra-large pore zeolites with tri-directional interconnected 14 * 14 * 14-ring channels. It is stable up to at least 650 degrees C. The structure of ITQ-53 changes from monoclinic to orthorhombic upon calcination. PMID- 25697963 TI - PINK1/Parkin-mediated mitophagy in mammalian cells. AB - Mitochondria-specific autophagy (mitophagy) is a fundamental process critical for maintaining mitochondrial fitness in a myriad of cell types. Particularly, mitophagy contributes to mitochondrial quality control by selectively eliminating dysfunctional mitochondria. In mammalian cells, the Ser/Thr kinase PINK1 and the E3 ubiquitin ligase Parkin act cooperatively in sensing mitochondrial functional state and marking damaged mitochondria for disposal via the autophagy pathway. Notably, ubiquitin and deubiquitinases play vital roles in modulating Parkin activity and mitophagy efficiency. In this review, we highlight recent breakthroughs addressing the key issues of how PINK1 activates Parkin in response to mitochondrial malfunction, how Parkin localizes specifically to impaired mitochondria, and how ubiquitination and deubiquitination regulate PINK1/Parkin mediated mitophagy. PMID- 25697964 TI - Time dependent analysis of assay comparability: a novel approach to understand intra- and inter-site variability over time. AB - We demonstrate here a novel use of statistical tools to study intra- and inter site assay variability of five early drug metabolism and pharmacokinetics in vitro assays over time. Firstly, a tool for process control is presented. It shows the overall assay variability but allows also the following of changes due to assay adjustments and can additionally highlight other, potentially unexpected variations. Secondly, we define the minimum discriminatory difference/ratio to support projects to understand how experimental values measured at different sites at a given time can be compared. Such discriminatory values are calculated for 3 month periods and followed over time for each assay. Again assay modifications, especially assay harmonization efforts, can be noted. Both the process control tool and the variability estimates are based on the results of control compounds tested every time an assay is run. Variability estimates for a limited set of project compounds were computed as well and found to be comparable. This analysis reinforces the need to consider assay variability in decision making, compound ranking and in silico modeling. PMID- 25697965 TI - The effect of a personalized intervention on weight gain and physical activity among pregnant women in China. AB - OBJECTIVE: To examine whether personalized interventions could improve dietary intake and physical activity among pregnant women. METHODS: A randomized controlled trial was conducted at a center in Chengdu, China, between September 2012 and February 2013. Women with a singleton pregnancy (aged >=18years, could understand written Chinese, did not have pre-existing diabetes) were enrolled at approximately 12weeks of pregnancy. They were randomly assigned (1:1) to an intervention group (received personalized educational materials) or a control group (conventional interventions only). Data for dietary intake and physical activity were recorded via questionnaires. Only pregnant women who completed the study were included in the analysis. RESULTS: Analyses included 106 women in the control group and 115 in the intervention group. After intervention, the intake of energy, protein, fruit, milk, seafood, and nuts differed significantly between groups (P<0.05), with intakes closer to the recommended amounts in the intervention group. Women in the intervention group spent significantly less time resting (P=0.033) and more time doing mild activity (P=0.016). Mean weight gain per week was significantly lower in the intervention group (P=0.023), and significantly fewer women in this group developed gestational diabetes (P=0.043). CONCLUSION: Personalized educational interventions can improve dietary behavior and physical activity levels, and reduce prevalence of gestational diabetes among pregnant women in China. Chinese Clinical Trial Register: ChiCTR-IPR-15005809. PMID- 25697967 TI - Intimate partner violence: a study in men and women from six European countries. AB - OBJECTIVES: We aimed to assess intimate partner violence (IPV) among men and women from six cities in six European countries. METHODS: Four IPV types were measured in a population-based multicentre study of adults (18-64 years; n = 3,496). Sex- and city-differences in past year prevalence were examined considering victims, perpetrators or both and considering violent acts' severity and repetition. RESULTS: Male victimization of psychological aggression ranged from 48.8 % (Porto) to 71.8 % (Athens) and female victimization from 46.4 % (Budapest) to 70.5 % (Athens). Male and female victimization of sexual coercion ranged from 5.4 and 8.9 %, respectively, in Budapest to 27.1 and 25.3 % in Stuttgart. Male and female victims of physical assault ranged from 9.7 and 8.5 %, respectively, in Porto, to 31.2 and 23.1 % in Athens. Male victims of injury were 2.7 % in Ostersund and 6.3 % in London and female victims were 1.4 % in Ostersund and 8.5 % in Stuttgart. IPV differed significantly across cities (p < 0.05). Men and women predominantly experienced IPV as both victims and perpetrators with few significant sex-differences within cities. CONCLUSIONS: Results support the need to consider men and women as both potential victims and perpetrators when approaching IPV. PMID- 25697968 TI - Will Obesity Treatment Reimbursement Benefit Those at Highest Risk? PMID- 25697969 TI - Peripherally Inserted Central Catheter-associated Deep Vein Thrombosis: A Narrative Review. AB - BACKGROUND: Although common, little is known about factors associated with peripherally inserted central catheter-related deep vein thrombosis (PICC-DVT). To better guide clinicians, we performed a comprehensive literature review to summarize best practices for this condition. METHODS: A systematic search of the literature for studies reporting epidemiology, diagnosis, treatment, and prevention of PICC-DVT was conducted. Algorithms for diagnosis and management were compiled using available evidence. RESULTS: The incidence of PICC-DVT varied between 2% and 75% according to study population, testing modality and threshold for diagnosis. Studies evaluating the diagnostic utility of clinical symptoms suggested that these were neither sensitive nor specific for PICC-DVT; conversely, ultrasonography had excellent sensitivity and specificity and is recommended as the initial diagnostic test. Although more specific, contrast venography should be reserved for cases with high clinical probability and negative ultrasound findings. Centrally positioned, otherwise functional and clinically necessary PICCs need not be removed despite concomitant DVT. Anticoagulation with low-molecular-weight heparin or warfarin for at least 3 months represents the mainstay of treatment. The role of pharmacologic prophylaxis and screening for PICC-DVT in the absence of clinical symptoms is unclear at this time. CONCLUSIONS: PICC-DVT is common, costly and morbid. Available evidence provides guidance for diagnosis, treatment and prevention of this condition. PMID- 25697970 TI - Inferences about food location in three cercopithecine species: an insight into the socioecological cognition of primates. AB - Many animal species use a variety of cognitive strategies to locate food resources. One strategy is to make inferences by exclusion, i.e., perceiving the absence of reward as a cue that another location should be investigated. The use of such advanced cognitive strategies may be more prominent in species that are known to frequently solve social challenges, and inferential reasoning has mainly been investigated in social species such as corvids, dogs, dolphins and non-human primates. In this paper, we investigate how far social intricacy may explain the disparity of reasoning performances observed in three cercopithecine species that differ in the density of their social network and the diversity of their social partners. We used standard reasoning tasks, testing the volume concept and inference by exclusion using visual and auditory modalities. We showed that Old World monkeys can infer the location of invisible food by exclusion. In addition, Tonkean macaques and olive baboons had greater performances in most tasks compared to rhesus macaques. These responses are consistent with the social complexity displayed by these three species. We suggest that the cognitive strategies required to navigate through a demanding social world are involved in the understanding of the physical domain. PMID- 25697971 TI - Habitat-dependent olfactory discrimination in three-spined sticklebacks (Gasterosteus aculeatus). AB - The ability to recognize conspecifics is indispensible for differential treatment of particular individuals in social contexts like grouping behavior. The advantages of grouping are multifarious, and there exist numerous additional benefits of joining aggregations of conspecifics. Recognition is based on different signals and transmitted via multiple channels, among others the olfactory channel. The sensory system or the combination of sensory modalities used in recognition processes is highly dependent on the availability and effectiveness of modalities, which are a function of the environmental conditions. Using F1-generations of six three-spined stickleback (Gasterosteus aculeatus) populations from two habitat types (tea-stained and clear-water lakes) from the Outer Hebrides, Scotland, we investigated whether individuals are able to recognize members of their own population solely based on olfactory cues and whether the habitat type an individual originated from had an influence on its recognition abilities. When given the choice (own vs. foreign population) sticklebacks from tea-stained lakes significantly preferred the odor of their own population, whereas fish from clear-water habitats did not show any preference. Moreover, fish from the two habitat types differed significantly in their recognition abilities, indicating that olfactory communication is better developed when visual signaling is disturbed. Thus, the observed odor preferences appear to be the consequence of different selective constraints and adaptations as a result of the differences in environmental conditions that have acted on the parental generations. These adaptations are likely genetically based as the differences are present in the F1-generation that had been reared under identical laboratory conditions. PMID- 25697972 TI - Prenatal diethylstilbestrol exposure and risk of obesity in adult women. AB - Diethylstilbestrol (DES) is a non-steroidal estrogen that was commonly prescribed during pregnancy from the late 1940s to 1971. A potent endocrine disruptor, prenatal DES exposure has been linked with reproductive tract malformations, adverse pregnancy outcomes, cancer, infertility and earlier menopause. DES was used for years as a growth promoter in animal production. Some animal studies suggest that prenatal DES exposure is associated with obesity and metabolic disturbances. Using data from the National Cancer Institute DES Follow-Up Study, we evaluated the association between DES and adult obesity, weight gain from age 20 to mid-life, central adiposity and height among 2871 prenatally exposed and 1352 unexposed women between 23 and 52 years of age (median 41.5) at baseline in 1994. DES exposure status was confirmed by prenatal medical record review. We used multivariable log-binomial models to calculate risk ratios (RRs) for obesity in 2006, and linear regression to calculate mean differences in body mass index, weight gain, waist circumference and height. The adjusted RR for DES and obesity was 1.09 [95% confidence interval (CI): 0.97, 1.22], and RRs were 1.23 (CI: 1.07, 1.42) and 1.05 (CI: 0.91, 1.20) for low and high estimated total DES dose, respectively, compared with no exposure. DES-exposed women gained slightly more weight than unexposed women [mean difference, 0.70 kg (CI: -0.27, 1.66)]. This study suggests that prenatal DES exposure may be associated with a small increase in adult obesity. PMID- 25697973 TI - Contextual effects on activity profiles of domestic field hockey during competition and training. AB - Game context is widely accepted to influence performance but most data available is 'categorical' and addresses performance rather than activity. This study assessed direct effects of opposition and team ranking in field hockey to establish influences on activity. One hundred and eight (n=108) female field hockey players (age 16-39 years) participated, giving 186 competition and 48 training analyses. Team average distance (mean +/- SD) observed in a mid-ranked team during competition ranged from 5,949 +/- 611 to 7,719 +/- 257 m demonstrating an opposition rank effect (Pearson's r=.71; adjusted R(2)=.42). However, multiple linear regression analysis demonstrated a stronger relationship in lower ranked teams (Pearson's r=.99; adjusted R(2)=.97 through 3-9). In contrast, no team rank effect was observed during randomly monitored competition where team average distance ranged from 5,177 +/- 444 to 7,316 +/- 241 m (Pearson's r=.15 and adjusted R(2)=.12). In training, however, a team rank effect was observed in distance-related performance indicators where team average distance during small-sided games ranged from 5,877 +/- 188 to 3,551 +/- 193 m drill (per 70 min) with Pearson's r=.95 and adjusted R(2)=.87. The presence of contextual effects has significant practical implications for team sports where the training load assumed from competition may be overestimated. PMID- 25697974 TI - Decreased expression of human heat shock protein 70 in the endometria and pathological lesions of women with adenomyosis and uterine myoma after GnRH agonist therapy. AB - OBJECTIVE: A prominent stress reaction in the pelvis of women with endometriosis and the role of human heat shock protein 70 (HSP70) in inflammation and the growth of endometriosis has been recently demonstrated. We report here expression of HSP70 in tissues derived from GnRH agonist (GnRHa)-untreated and -treated women with adenomyosis and uterine myoma. STUDY DESIGN: This is a case-controlled biological study. Biopsy specimens were collected from pathological lesions and eutopic endometria/autologous myometria of 30 women with adenomyosis, 35 women with uterine myoma and 15 control women during laparoscopy, laparotomy and hysteroscopy. Fourteen women with adenomyosis and 20 women with uterine myoma were treated with GnRHa for a variable period of 3-6 months before surgery. The immunoexpressions of HSP70 and CD68-positive Mphi in endometria, lesions/myometria were examined by immunohistochemistry. The immunoreactivity of HSP70 in tissues was analyzed by quantitative-histogram (Q-H) scores. RESULTS: Comparing to control women, HSP70 immunoexpression was significantly higher in endometria/myometria and pathological lesions of women with adenomyosis and myoma. A significant positive correlation between Q-H scores of HSP70 and CD68 positive Mphi numbers was found in the endometria derived from women with adenomyosis (r=0.388). Treatment with GnRHa significantly decreased Q-H scores of HSP70 in pathological lesions and endometria/myometria of women with adenomyosis and uterine myoma comparing to similar tissues derived from GnRHa-untreated women. CONCLUSION: A variable amount of tissue stress reaction occurred in endometria and pathological lesions of women adenomyosis and uterine myoma that can be effectively suppressed after GnRHa treatment. PMID- 25697975 TI - Robotic sacrocolpopexy. A review. AB - The aim of this article was to provide a contemporary reference source for robotic sacrocolpopexy. This article will discuss robotic sacrocolpopexy, in terms of its history, acceptance in modern medicine, indications, materials used, technique, outcomes, and complications. Research from our institution and others was summarized to provide a comprehensive review of robotic sacrocolpopexy. In conclusion, we found out that robotic sacrocolpopexy provides a minimally invasive approach to treatment of pelvic organ prolapse with excellent outcomes and low complication rates. PMID- 25697976 TI - Robotic management of endometriosis: where do we stand? AB - The progressive and chronic nature of this disease can have a substantial impact on both quality of life and functioning of women who suffer from the disease. While medical treatment can be sufficient therapy for many women with endometriosis, medical therapies are often inadequate for the severest cases. The anatomic changes of adhesions/fibrosis and smooth muscle metaplasia that are associated with endometriosis, however, can be substantial and surgery for this disease can be technically challenging. Historically, the severest cases of endometriosis were managed using a laparotomy approach. Traditional laparoscopy has gained popularity for the management of this disease but has limitations in the surgical treatment of the most difficult cases of endometriosis. With the introduction of the robotic surgical platform, experience has gradually accumulated regarding its application for surgical management of deeply infiltrating endometriosis (DIE). It has been suggested that the robotic platform enables more complex dissections and may be the ideal modality for the surgical management of endometriosis. As both experience and technology expand, the robotic platform is being utilized by an increasing number of surgeons and for increasingly complex minimally invasive pelvic surgery. The literature analyzing its actual performance in the management of DIE, however, is only just manifesting. This review focus on the surgical management of endometriosis by robotic laparoscopy. Specifically we describe the unique surgical challenges of this disease. We also highlight the current state of the literature that analyzes the application of robotic laparoscopy to the various anatomic and clinical manifestations of endometriosis and critique outcomes as they apply to the safety, efficacy and cost of this modality for the management of endometriosis. PMID- 25697977 TI - The role of molecular oxygen in the iron(III)-promoted oxidative dehydrogenation of amines. AB - A mechanistic study is presented of the oxidative dehydrogenation of the iron(III) complex [Fe(III)L(3)](3+), 1, (L(3) = 1,9-bis(2'-pyridyl)-5-[(ethoxy 2''-pyridyl)methyl]-2,5,8-triazanonane) in ethanol in the presence of molecular oxygen. The product of the reaction was identified by NMR spectroscopy and X-ray crystallography as the identical monoimine complex [Fe(II)L(4)](2+), 2, (L(4) = 1,9-bis(2'-pyridyl)-5-[(ethoxy-2''-pyridyl)methyl]-2,5,8-triazanon-1-ene) also formed under an inert nitrogen atmosphere. Molecular oxygen is an active player in the oxidative dehydrogenation of iron(III) complex 1. Reduced oxygen species, e.g., superoxide, (O2(-)) and peroxide (O2(2-)), are formed and undergo single electron transfer reactions with ligand-based radical intermediates. The experimental rate law can be described by the third order rate equation, d[(Fe(III)L(3))(3+)]/dt = kOD[(Fe(III)L(3))(3+)][EtO(-)][O2], with kOD = 3.80 +/- 0.09 * 10(7) M(-2) s(-1) (60 degrees C, MU = 0.01 M). The reduction O2 -> O2(-) represents the rate determining step, with superoxide becoming further reduced to peroxide as shown by a coupled heme catalase assay. In an independent study, with H2O2, replacing O2 as the oxidant, the experimental rate law depended on [H2O2]: d[(Fe(III)L(3))(3+)]/dt = kH2O2[(Fe(III)L(3))(3+)][H2O2]), with kH2O2 = 6.25 +/- 0.02 * 10(-3) M(-1) s(-1). In contrast to the reaction performed under N2, no kinetic isotope effect (KIE) or general base catalysis was found for the reaction of iron(III) complex 1 with O2. Under N2, two consecutive one-electron oxidation steps of the ligand coupled to proton removal produced the iron(II)-monoimine complex [Fe(II)L(4)](2+) and the iron(II)-amine complex [Fe(II)L(3)](2+) in a 1 : 1 ratio (disproportionation), with the amine deprotonation being the rate determining step. Notably, the reaction is almost one order of magnitude faster in the presence of O2, with kEtO(-) = 3.02 +/- 0.09 * 10(5) M(-1) s(-1) (O2) compared to kEtO(-) = 4.92 +/- 0.01 * 10(4) M(-1) s(-1) (N2), documenting the role of molecular oxygen in the dehydrogenation reaction. PMID- 25697978 TI - Laparoscopic Mitrofanoff procedure in children: critical analysis of difficulties and benefits. AB - OBJECTIVES: The Mitrofanoff principle is an accepted continent urinary diversion. We studied the feasibility and the possible benefits of using a laparoscopic approach in children with significant bladder dysfunction associated with difficulty doing efficient urethral catheterization. PATIENTS AND METHODS: A fully laparoscopic Mitrofanoff continent cystostomy was attempted in 15 children with a median age of 9 years (IQR 6), between 2003 and 2013. Before the Mitrofanoff procedure was considered, urodynamic evaluation was done for each patient, to study bladder compliance, detrusor activity, and bladder capacity. The procedure was performed using a transperitoneal four-port approach. A 30 degree down camera angle was optimal for viewing the appendix and the posterior wall of the bladder. The operative steps of the open procedure were replicated laparoscopically. The proximal end of the appendix was spatulated and anastomosed to the posterior wall of the bladder, providing an antireflux mechanism by an extramucosal tunnel. The distal end of the appendix was brought out as the cutaneous umbilical stoma. Some modifications were done because of the high rate of conversion due to early opening of the mucosa (harmonic hook) or difficult anastomosis: (a) use of 5-mm trocars to change the laparoscope position from the left to right subcostal area to better visualize the anastomosis, (b) the anastomosis was suspended at its two ends during suturing; a trans-abdominal traction suture of the bladder was inserted for better exposure of the anastomosis (hitch stitch) and to stabilize the anastomotic line during suturing, (c) use of a monopolar hook to cut the detrusor muscle fibers, to avoid incidental opening of the mucosa, and (d) the window between the appendix and the peritoneum was closed to avoid internal hernia. RESULTS: The procedure was totally completed by laparoscopy in 12 cases. Three were converted to an open procedure due to tearing of bladder mucosa (n = 2) or appendix ischemia (n = 1). Median operative time for fully laparoscopic Mitrofanoff was 255 min (IQR 52). Median follow-up was 18 months (IQR 35). No patient required stomal revision. Seven patients were continent, five experienced urinary leakage from urethra n = 1 and/or stoma n = 5. Three patients with stomal urinary leakage were successfully managed by Deflux (dextranomer-based implants) injection in the catheterizable channel. Two patients required an open revision of the appendicovesical anastomosis. The patient with both stomal and urethral urinary leakage also required the implantation of an artificial urinary sphincter 1.5 years after Mitrofanoff. One patient had bladder augmentation. CONCLUSION: Although our results of laparoscopic Mitrofanoff procedure in children are unsatisfying in cases of high-pressure bladders in terms of incontinent stoma, we still believe that it is justified to develop this challenging technique with more refinement and improvement, to provide a minimal invasive procedure that may postpone or even avoid bladder augmentation in pediatric age. PMID- 25697979 TI - Autonomic dysreflexia during urodynamics in children and adolescents with spinal cord injury or severe neurologic disease. AB - INTRODUCTION: Autonomic dysreflexia (AD) is a well-established association of high spinal cord injury (SCI), particularly in those occurring above T6. When a noxious stimulus is encountered, the body responds by stimulating an increase in blood pressure, which is then countered by vasodilation. In patients with autonomic dysreflexia, the patient is unable to vasodilate below the level of spinal injury due to interruption of the autonomic innervation below the injury. This then leads to persistently elevated blood pressure causing uncoordinated autonomic responses such as headache, flushing, sweating, and even hypertensive crisis. The noxious stimulus most commonly reported is bladder or bowel distention [1]. This potential trigger is especially important since many patients with SCI require catheterization and repeated urodynamic testing, both of which predispose them to bladder distention. In response to an incident during which a patient developed severe hypertension during UDS, institutional concern was raised about the potential risk of AD in other patients with SCI >= T8 and other severe neurological disease undergoing urodynamic testing, and a protocol was initiated in 2007 for monitoring for AD during UDS. Although no long-term complication was encountered in this incident, the need for improvement in our understanding of the detection and treatment of AD during urodynamic testing was highlighted. However, due to the potential of UDS to trigger AD and possible subsequent severe cardiovascular crisis, a protocol was established at our institution. Because of reports documenting episodes of AD for patients with severe, non-SCI neurologic disease and the unknown risk, these patients also were historically monitored at our institution as well. OBJECTIVE: Autonomic dysreflexia (AD) is an uncoordinated autonomic response seen in patients with spinal cord injury (SCI). AD is often triggered by bladder distention, which may occur during urodynamic studies (UDS), and has potentially life-threatening consequences. Our purpose is to determine the prevalence and associated factors of AD in children undergoing UDS with either SCI or other neurological disease. METHODS: We identified 13 pediatric patients with SCI at the eighth thoracic vertebrae or above (SCI >= T8) or other severe neurological disorder with urodynamic evaluations between 2007 and 2011 at our institution. We retrospectively reviewed these patients for age, gender, bladder volume, bladder compliance, detrusor instability, symptoms of AD, blood pressure, and urinary infection. RESULTS: There were a total of 13 patients with SCI >= T8 (9), transverse myelitis (2), and encephalomyelitis (2). There were a total of 41 urodynamic studies with an average of 3.2 studies per patient. One adolescent with C1/2 injury and a prepubertal child with T2/3 injury developed AD. AD was not observed in non-SCI patients. The patients who developed AD had multiple subsequent episodes with follow up UDS. No statistical associations were found for the variables evaluated. No major complications occurred, and AD was successfully managed conservatively. CONCLUSIONS: With appropriate monitoring and education, AD is easily recognized and managed conservatively. We found an increased risk of patients developing subsequent AD episodes after an initial episode. Patients who did not have autonomic dysreflexia during initial UDS did not experience autonomic dysreflexia on subsequent UDS. We did not observe autonomic dysreflexia occurring in children with transverse myelitis or encephalomyelitis. PMID- 25697980 TI - Radiological bladder characteristics in VCU for young children with high-grade VUR. AB - OBJECTIVES: It has been suggested that infants with dilating vesicoureteral reflux (VUR) often have lower urinary tract (LUT) dysfunction. Signs such as high voiding pressure levels, low bladder capacity and dyscoordination at voiding have previously been thought to be indicative of dysfunction. However, these findings have also been recognised in healthy infants and are, thus, not specific to dysfunction in this age group. The urodynamic findings of interest for LUT dysfunction in children with high-grade VUR have been shown to be high bladder capacity with incomplete emptying, and often with overactivity during filling. Because the bladders in children with VUR are often only investigated with voiding cystourethrography (VCUG) and not urodynamics, the question has arisen as to whether some of the urodynamic findings indicating dysfunction can be recognised as radiological signs. The aim of the present study was to evaluate whether cystometric signs of LUT dysfunction in infants with high-grade VUR could be recognised in VCUG. MATERIALS AND METHODS: One hundred and fifteen infants (80 boys) with Grades III-V VUR were included and investigated repeatedly with videocystometry (VCM) at a median age 6, 21 and 39 months. The sign looked for in the VCUG was bladder size (large, normal or small), according to the chosen levels in the bony pelvis. To validate the chosen levels for the different bladder sizes, bladder capacity data from a longitudinal study in healthy children were used. In addition, abnormalities in bladder wall/form and filling of the posterior urethra without voiding, as signs of bladder overactivity and detrusor-sphincter dyscoordination, were evaluated. RESULTS: Bladder size was estimated on VCUG as large, normal or small, according to pelvic landmarks. Large bladder size was mainly seen at the second and third evaluations (64% and 46%), whereas small capacity was mainly seen during the first year (33%). Corresponding cystometric capacities (ml) showed a significant difference between the groups of small, normal and large bladder size. The cystometric capacities of large and small bladder size were also compared with bladder capacity in healthy controls, where large had significantly higher bladder capacity versus age (P = 0.0001) and small had significantly lower (P = 0.011) bladder capacity versus age than in the healthy controls. Bladder shape/wall pathology was mainly seen during the first year (42%), combined with small capacity, and correlated to overactive contractions during filling. Moreover, filling of the posterior urethra without voiding, indicating detrusor/sphincter dyscoordination at voiding, was quite common during the first year (33%), and then successively decreased. CONCLUSIONS: The clinical implication from this study of small children with high-grade VUR was that a large bladder on VCUG was synonymous with a high-capacity bladder. According to earlier studies, this is a sign of LUT dysfunction in this age group and should therefore be an indicator for additional studies of bladder function. Overactive contractions could also be recognised in VCUG, but only at the infant evaluation, which should also be regarded as an indicator of LUT dysfunction. All other bladder VCUG signs mainly seen during early infancy were signs of immature bladder function and not a result of VUR dysfunction. PMID- 25697981 TI - Treatment alternatives for urinary system stone disease in preschool aged children: results of 616 cases. AB - INTRODUCTION: The treatment of stone disease is mostly similar in those adult and children. The standard treatment procedures are as follows: extracorporeal shock wave lithotripsy (ESWL), ureterorenoscopy (URS), percutaneous nephrolithotomy (PCNL), and laparoscopic surgery in selected cases. Open surgery (OS) is another option particularly in such cases with anatomic abnormalities of urinary tract. OBJECTIVE: The present study aims to provide comparative results of stone removal procedures in preschool aged patients who were diagnosed with urinary system stone disease. STUDY DESIGN: The retrospective data of 616 pediatric preschool patients consulted with urinary system stone disease between January 2009 and July 2013 were evaluated. All patients were evaluated with Kidney-Ureter-Bladder (KUB) Xray and abdomino-pelvic ultrasound. Intravenous pyelography, unenhanced computed tomography (CT), and renal scintigraphy were performed when needed. Patients were categorized according to the procedures as: Group ESWL, Group URS, Group PNL, Group micro-PNL and Group OS. Following the procedures, opaque residual stones were evaluated with KUB Xray, and non-opaque residual stones were evaluated with unenhanced CT. RESULTS: In groups (ESWL, URS, PNL, micro-PNL, OS), the stone-free rate was 68%, 66%, 85%, 100% and 94 %, respectively. The stone analysis were observed as, calcium oxalate in 377 patients (61.2%), uric acid in 106 patients (17.2%), infection stone in 73 patients (11.8 %), and cysteine in 60 patients (9.7%). There was no significant difference in stone analysis between the groups (p > 0.05) (Table). DISCUSSION: Minimally invasive procedures are frequently preferred in the pediatric age urinary system stone disease. These procedures are ESWL, PCNL, and ureteroscopy [10,11]. Open surgery is reserved only for rare cases [12]. Similarly the current literature, 18 (2.9%) patients had anatomical anomaly and had high complex stone burden were treated with open surgery in our study. ESWL is a preferred treatment method for pediatric urolithiasis patients with a stone size <20 mm, and the rate of stone-free after ESWL ranges between 57 and 92% [13]. In a study showed the effect of stone size on the success rate in ESWL, the success rate was 91% for stones <10 mm, and 75% for stones >10 mm [15]. In the present study, stone-free rate was noted as 68% on 15 mm or lower stone size. PNL is commonly used to treat stone disease in preschool children [18-20]. In the beginning, urologists hesitated to use instruments suited for adults in case of pediatric kidneys. While some authors accept a cut-off value of 24 F for tract dilatation in the pediatric age, Desai et al. recommended a threshold value <22 F [19,21]. In our study, we used adult PNL instruments in the early period, whereas mini-PERC was performed in the later years. The success rate in PNL group was found as 85%. In recent years, the micro PNL procedure has been developed to reduce/prevent the complications of standard PNL. In our study, the success rate was calculated as 100% with micro-PNL. This study has certain limitations. The major limitation of our study is its retrospective nature. In addition, sample size of micro-PNL group is fewer than other groups. CONCLUSION: The goal of kidney stone treatment is to achieve minimal kidney damage and a high success rate. Thus, the procedures are important in the pediatric age group where life expectancy is high, and particularly in the preschool age group. PMID- 25697982 TI - Surgical treatment of infective endocarditis with aortic and tricuspid valve involvement using cryopreserved aortic and mitral valve allografts. AB - Surgical treatment of infective and prosthetic endocarditis using allografts gives good results. Aortic allograft implantation is a common technique, while tricuspid valve replacement with a mitral allograft is very rare. Multiple valve disease in case of infective endocarditis is a surgical challenge as such patients are usually in a grave condition and results of surgical treatment are often unsatisfactory. In this article we describe a clinical case of successful surgical treatment in a patient with active infective endocarditis of aortic and tricuspid valve, complicated by an aortic-right ventricular fistula. The aortic valve and ascending aorta were replaced with a cryopreserved aortic allograft; the tricuspid valve was replaced with a cryopreserved mitral allograft. PMID- 25697983 TI - Trans-subxiphoid robotic thymectomy. AB - Minimally invasive surgery has replaced median sternotomy for resectable anterior mediastinal masses and is performed by various approaches. We developed a new minimally invasive surgical procedure by combining the subxiphoid approach performed through a midline camera port with the use of a robotic surgery system (Intuitive Surgical, Sunnyvale, CA, USA). A 3-cm transverse incision was made 1 cm below the xiphoid process. Then, a port designed for single-port surgery was inserted. Through this port, CO2 gas was injected at 8 mmHg. The thymus was then detached from the back of the sternum. A 1-cm skin incision was made bilaterally in the sixth intercostal space, followed by insertion of a port for the robotic system. A camera port was inserted into the subxiphoid port, to which the camera scope was mounted, and thymectomy was performed. We have performed the operation in 3 patients. In our experience, this procedure provides a good operative view in the neck region and makes verification of the phrenic nerve easy. Furthermore, with the da Vinci surgical system, which enables surgical manipulation from a correct angle due to the multijoint robotic arms, trans-subxiphoid robotic thymectomy may be a promising new thymectomy procedure. PMID- 25697984 TI - Hormonal modulation of the immune system - A spotlight on the role of progestogens. AB - This article reviews the effects of progestogens on the innate and adaptive immunity and its role in the pathogenesis of autoimmune diseases including systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis. The interplay between the sex hormones such as progestogens and the immune system is very complex. Multiple factors affect immunomodulatory effects of the progestogens including fluctuations in the endogenous sex hormone levels, stress, use of exogenous hormones (dose, route and the timing of administration), and alterations in the hormonal metabolism. Although immunomodulatory effects of progesterone, especially progesterone's effect on T cells, T cell subsets and their ratios, dose effects, and the use of synthetic progestins have been studied, there are still wide open areas for further explorations of the progestogens' multifaceted impact on the immune system. Better understanding of the intricate immunomodulatory effects of the progestins may pave the path to developing clinically meaningful therapeutic interventions in certain autoimmune diseases. PMID- 25697985 TI - Localization of the aromatase enzyme expression in the human pituitary gland and its effect on growth hormone, prolactin, and thyroid stimulating hormone axis. AB - The aim of this study is to evaluate aromatase expression in prolactin (PRL), thyroid stimulating hormone (TSH), and growth hormone (GH) secreting cells. Nontumoral human pituitary specimens were obtained from autopsy samples. Aromatase co-expression was determined by double immunohistochemical staining and assessed using H scores. H scores for GH-aromatase co-expression (GH-aromatase), TSH-aromatase co-expression (TSH-aromatase), and PRL-aromatase co-expression (PRL aromatase) were 83.1 +/- 13.1, 95.6 +/- 16.1, and 83.7 +/- 14.5, respectively. TSH producing cells exhibited the highest H score for co-expression of aromatase (p < 0.001). There was no gender difference in terms of H scores for aromatase expression and double immunohistochemical staining results (p > 0.05 for all). There was a negative correlation between the H scores for aromatase and PRL aromatase, GH-aromatase and TSH-aromatase, respectively (r = -0.592, p < 0.001; r = -0.593, p < 0.001; r = -0.650, p < 0.001, respectively). Also, H scores for aromatase co-expression of each hormone were negatively correlated with the H scores for the corresponding hormone (r = -0.503, p < 0.001 for PRL-aromatase and PRL; r = -0.470, p < 0.001 for GH-aromatase, and GH; r = -0.641, p < 0.001 for TSH-aromatase and TSH). H scores for mean aromatase, GH-aromatase, TSH-aromatase were invariant of age (p > 0.05 for all). Age was negatively correlated with PRL aromatase H score (r = -0.373, p = 0.008). Our study demonstrated significant aromatase co-expression in PRL, GH, and TSH secreting cells of the human anterior pituitary gland. The mutual paracrinal regulation between aromatase and three adenohypophyseal hormones indicates that aromatase may have a regulatory role on the synthesis and secretion of these hormones. PMID- 25697986 TI - Improvement of retinal blood vessel detection using morphological component analysis. AB - Detection and quantitative measurement of variations in the retinal blood vessels can help diagnose several diseases including diabetic retinopathy. Intrinsic characteristics of abnormal retinal images make blood vessel detection difficult. The major problem with traditional vessel segmentation algorithms is producing false positive vessels in the presence of diabetic retinopathy lesions. To overcome this problem, a novel scheme for extracting retinal blood vessels based on morphological component analysis (MCA) algorithm is presented in this paper. MCA was developed based on sparse representation of signals. This algorithm assumes that each signal is a linear combination of several morphologically distinct components. In the proposed method, the MCA algorithm with appropriate transforms is adopted to separate vessels and lesions from each other. Afterwards, the Morlet Wavelet Transform is applied to enhance the retinal vessels. The final vessel map is obtained by adaptive thresholding. The performance of the proposed method is measured on the publicly available DRIVE and STARE datasets and compared with several state-of-the-art methods. An accuracy of 0.9523 and 0.9590 has been respectively achieved on the DRIVE and STARE datasets, which are not only greater than most methods, but are also superior to the second human observer's performance. The results show that the proposed method can achieve improved detection in abnormal retinal images and decrease false positive vessels in pathological regions compared to other methods. Also, the robustness of the method in the presence of noise is shown via experimental result. PMID- 25697987 TI - An integrated breast cancer risk assessment and management model based on fuzzy cognitive maps. AB - BACKGROUND: There is a growing demand for women to be classified into different risk groups of developing breast cancer (BC). The focus of the reported work is on the development of an integrated risk prediction model using a two-level fuzzy cognitive map (FCM) model. The proposed model combines the results of the initial screening mammogram of the given woman with her demographic risk factors to predict the post-screening risk of developing BC. METHODS: The level-1 FCM models the demographic risk profile. A nonlinear Hebbian learning algorithm is used to train this model and thus to help on predicting the BC risk grade based on demographic risk factors identified by domain experts. The risk grades estimated by the proposed model are validated using two standard BC risk assessment models viz. Gail and Tyrer-Cuzick. The level-2 FCM models the features of the screening mammogram concerning normal, benign and malignant cases. The data driven Hebbian learning algorithm (DDNHL) is used to train this model in order to predict the BC risk grade based on these mammographic image features. An overall risk grade is calculated by combining the outcomes of these two FCMs. RESULTS: The main limitation of the Gail model of underestimating the risk level of women with strong family history is overcome by the proposed model. IBIS is a hard computing tool based on the Tyrer-Cuzick model that is comprehensive enough in covering a wide range of demographic risk factors including family history, but it generates results in terms of numeric risk score based on predefined formulae. Thus the outcome is difficult to interpret by naive users. Besides these models are based only on the demographic details and do not take into account the findings of the screening mammogram. The proposed integrated model overcomes the above described limitations of the existing models and predicts the risk level in terms of qualitative grades. The predictions of the proposed NHL-FCM model comply with the Tyrer-Cuzick model for 36 out of 40 patient cases. With respect to tumor grading, the overall classification accuracy of DDNHL-FCM using 70 real mammogram screening images is 94.3%. The testing accuracy of the proposed model using 10 fold cross validation technique outperforms other standard machine learning based inference engines. CONCLUSION: In the perspective of clinical oncologists, this is a comprehensive front-end medical decision support system that assists them in efficiently assessing the expected post-screening BC risk level of the given individual and hence prescribing individualized preventive interventions and more intensive surveillance for high risk women. PMID- 25697988 TI - Real-time, ultrasound-guided infraclavicular axillary vein cannulation for renal replacement therapy in the critical care unit-A prospective intervention study. AB - PURPOSE: The cannulation of the axillary vein for renal replacement therapy is a rarely performed procedure in the critical care unit. We defined the venipuncture and catheterization success rates and early mechanical complication rates of this technique in critical care patients with acute kidney injury. MATERIALS AND METHODS: Twenty-nine mechanically ventilated patients with clinical indications for insertion of temporary hemodialysis catheters enrolled in a registered trial (NCT01919528) as a pilot cohort. We performed 29 real-time, ultrasound-guided infraclavicular axillary vein cannulation attempts for renal replacement therapy. We defined the venipuncture and catheterization success rates and early mechanical complication rates for this technique. RESULTS: The puncture of the axillary vein was successful in 28 (96.5%) patients. In 22 patients (75.9%), venipuncture occurred during the first attempt and in 6 patients during the second (20.7%). The overall cannulation success rate was 93.1% (95% confidence interval, 77%-99%). We noted 6.8% potentially serious complications rate, 10.3% minor complications rate, and 0% life-threatening early mechanical complications. We achieved an 89.6% renal replacement therapy success rate and low rate of catheters malfunction. CONCLUSIONS: Real-time, ultrasound-guided, infraclavicular axillary vein cannulation for renal replacement therapy in the critical care unit is a reliable method of dual-lumen hemodialysis catheter insertion and can be considered a reasonable alternative to jugular and femoral routes in special clinical circumstances. PMID- 25697989 TI - Sound extinction by fish schools: forward scattering theory and data analysis. AB - A model used previously to study collective back scattering from fish schools [Feuillade et al., J. Acoust. Soc. Am. 99(1), 196-208 (1996)], is used to analyze the forward scattering properties of these objects. There is an essential physical difference between back and forward scattering from fish schools. Strong frequency dependent interference effects, which affect the back scattered field amplitude, are absent in the forward scattering case. This is critically important for data analysis. There is interest in using back scattering and transmission data from fish schools to study their size, the species and abundance of fish, and fish behavior. Transmission data can be processed to determine the extinction of the field by a school. The extinction of sound depends on the forward scattering characteristics of the school, and data inversion to provide information about the fish should be based upon a forward scattering paradigm. Results are presented of an analysis of transmission data obtained in September 1995 during an experiment performed in the Gulf of Lion in the Mediterranean Sea [Diachok, J. Acoust. Soc. Am. 105(4), 2107-2128 (1999)]. The analysis shows that using forward scattering leads to significantly larger estimates of fish abundance than previous analysis based upon back scattering approaches. PMID- 25697990 TI - Hearing frequency thresholds of harbor porpoises (Phocoena phocoena) temporarily affected by played back offshore pile driving sounds. AB - Harbor porpoises may suffer hearing loss when exposed to intense sounds. After exposure to playbacks of broadband pile driving sounds for 60 min, the temporary hearing threshold shift (TTS) of a porpoise was quantified at 0.5, 1, 2, 4, 8, 16, 32, 63, and 125 kHz with a psychoacoustic technique. Details of the pile driving sounds were as follows: pulse duration 124 ms, rate 2760 strikes/h, inter pulse interval 1.3 s, average received single strike unweighted sound exposure level (SEL) 146 dB re 1 MUPa(2) s (cumulative SEL: 180 dB re 1 MUPa(2) s). Statistically significant TTS only occurred at 4 and 8 kHz; mean TTS (1-4 min. after sound exposure stopped) was 2.3 dB at 4 kHz, and 3.6 dB at 8 kHz; recovery occurred within 48 min. This study shows that exposure to multiple impulsive sounds with most of their energy in the low frequencies can cause reduced hearing at higher frequencies in harbor porpoises. The porpoise's hearing threshold for the frequency in the range of its echolocation signals was not affected by the pile driving playback sounds. PMID- 25697991 TI - Duration of voicing and silence periods of continuous speech in different acoustic environments. AB - This work deals with the duration of voicing and silence periods of continuous speech in rooms with very different reverberation times (RTs). Measurements were conducted using the Ambulatory Phonation Monitoring (APM) 3200 (Kaypentax, Montvale, NJ) and Voice-Care devices (developed at the Politecnico di Torino, Italy), both of which have a contact microphone placed on the base of the neck to detect skin vibrations during phonation. Six university professors and 22 university students made short laboratory monologs in which they explained something that they knew well to a listener 6 m away. Seven students also described a map with the intention of correctly explaining directions to a listener who drew the path on a blank chart. Longer speech samples were made by 25 primary school teachers in classrooms. A tendency to increase the voicing periods as the RT increased was on average observed for the university professors, the school teachers, and the university students who described a map. These students also showed longer silence periods than the students who made short monologs. The recognized trends concerned voice professionals or subjects who were highly motivated to make themselves understood in a perturbed speaking situation. Nonparametric statistical tests, which were applied to detect the differences in distributions of voicing and silence periods, have basically supported the findings. PMID- 25697992 TI - Subjective ranking of concert halls substantiated through orthogonal objective parameters. AB - This paper studies the global subjective assessment, obtained from mean values of the results of surveys addressed to members of the audience of live concerts in Spanish auditoriums, through the mean values of the three orthogonal objective parameters (Tmid, IACCE3, and LEV), expressed in just noticeable differences (JNDs), regarding the best-valued hall. Results show that a linear combination of the relative variations of orthogonal parameters can largely explain the overall perceived quality of the sample. However, the mean values of certain orthogonal parameters are not representative, which shows that an alternative approach to the problem is necessary. Various possibilities are proposed. PMID- 25697994 TI - An approach to generating two zones of silence with application to personal sound systems. AB - An application of current interest in sound reproduction systems is the creation of multizone sound fields which produce multiple independent sound fields for multiple listeners. The challenge in producing such sound fields is the avoidance of interference between sound zones, which is dependent on the geometry of the zone and the direction of arrival of the desired sound fields. This paper provides a theoretical basis for the generation of two zones based on the creation of sound fields with nulls and the positioning of those nulls at arbitrary positions. The nulls are created by suppressing low-order mode terms in the sound field expansion. Simulations are presented for the two-dimensional case which shows that suppression of interference is possible across a broad frequency audio range. PMID- 25697993 TI - Analysis of tissue changes, measurement system effects, and motion artifacts in echo decorrelation imaging. AB - Echo decorrelation imaging, a method for mapping ablation-induced ultrasound echo changes, is analyzed. Local echo decorrelation is shown to approximate the decoherence spectrum of tissue reflectivity. Effects of the ultrasound measurement system, echo signal windowing, electronic noise, and tissue motion on echo decorrelation images are determined theoretically, leading to a method for reduction of motion and noise artifacts. Theoretical analysis is validated by simulations and experiments. Simulated decoherence of the scattering medium was recovered with root-mean-square error less than 10% with accuracy dependent on the correlation window size. Motion-induced decorrelation measured in an ex vivo pubovisceral muscle model showed similar trends to theoretical motion-induced decorrelation for a 2.1 MHz curvilinear array with decorrelation approaching unity for 3-4 mm elevational displacement or 1-1.6 mm range displacement. For in vivo imaging of porcine liver by a 7 MHz linear array, theoretical decorrelation computed using image-based motion estimates correlated significantly with measured decorrelation (r = 0.931, N = 10). Echo decorrelation artifacts incurred during in vivo radiofrequency ablation in the same porcine liver were effectively compensated based on the theoretical echo decorrelation model and measured pre treatment decorrelation. These results demonstrate the potential of echo decorrelation imaging for quantification of heat-induced changes to the scattering tissue medium during thermal ablation. PMID- 25697995 TI - Tunable effective constants of the one-dimensional piezoelectric phononic crystal with internal connected electrodes. AB - One-dimensional propagation of a longitudinal wave through an infinite piezoelectric periodically layered structure is considered. The unit cell consists, in general, of piezoelectric multilayers separated by thin electrodes which are connected through a capacitor with capacity Cj that plays the role of the external electric control providing tunability of the mechanical properties. The main focus of the present study is on the effective properties characterizing the homogenized medium. Due to the electric boundary conditions, the 4*4 transfer matrix M through the period T can be reduced to 2 * 2 dimension governing the mechanical fields only. As a result, the homogenized medium is pure elastic though its effective material parameters depend on the piezoelectric and dielectric coefficients of the actual piezoelectric medium, as well as on Cj. The effective parameters and the impedance in the low-frequency limit omega->0 and at finite frequency are obtained and analyzed. PMID- 25697996 TI - Influence of fiber orientation on the inherent acoustic nonlinearity in carbon fiber reinforced composites. AB - This paper presents the study of non-classical nonlinear response of fiber reinforced composites. Nonlinear elastic wave methods such as nonlinear resonant ultrasound spectroscopy (NRUS) and nonlinear wave modulation spectroscopy have been used earlier to detect damages in several materials. It was observed that applying these techniques to composites materials becomes difficult due to the significant inherent baseline nonlinearity. Understanding the non-classical nonlinear nature of the composites plays a vital role in implementing nonlinear acoustic techniques for material characterization as well as qualitative nondestructive testing of composites. Since fiber reinforced composites are orthotropic in nature, the baseline response variation with fiber orientation is very important. This work explores the nature of the inherent nonlinearity by performing nonlinear resonant spectroscopy (NRS) in intact unidirectional carbon/epoxy samples with different fiber orientations with respect to major axis of the sample. Factors such as frequency shifts, modal damping ratio, and higher harmonics were analyzed to explore the non-classical nonlinear nature of these materials. Conclusions were drawn based on the experimental observations. PMID- 25697997 TI - Infrasonic ray tracing applied to small-scale atmospheric structures: thermal plumes and updrafts/downdrafts. AB - A ray-tracing program is used to estimate the refraction of infrasound by the vertical structure of the atmosphere in thermal plumes, showing only weak effects, as well as in updrafts and downdrafts, which can act as vertical wave guides. Thermal plumes are ubiquitous features of the daytime atmospheric boundary layer. The effects of thermal plumes on lower frequency sound propagation are minor with the exception of major events, such as volcanoes, forest fires, or industrial explosions where quite strong temperature gradients are involved. On the other hand, when strong, organized vertical flows occur (e.g., in mature thunderstorms and microbursts), there are significant effects. For example, a downdraft surrounded by an updraft focuses sound as it travels upward, and defocuses sound as it travels downward. Such propagation asymmetry may help explain observations that balloonists can hear people on the ground; but conversely, people on the ground cannot hear balloonists aloft. These results are pertinent for those making surface measurements from acoustic sources aloft, as well as for measurements of surface sound sources using elevated receivers. PMID- 25697998 TI - Diffraction by a right-angled impedance wedge: an edge source formulation. AB - This paper concerns the frequency domain problem of diffraction of a plane wave incident on an infinite right-angled wedge on which impedance (absorbing) boundary conditions are imposed. It is demonstrated that the exact Sommerfeld Malyuzhinets contour integral solution for the diffracted field can be transformed to a line integral over a physical variable along the diffracting edge. This integral can be interpreted as a superposition of secondary point sources (with directivity) positioned along the edge, in the spirit of the edge source formulations for rigid (sound-hard) wedges derived by Svensson et al. [Acta Acust. Acust. 95, 568-572 (2009)]. However, when surface waves are present the physical interpretation of the edge source integral must be altered: it no longer represents solely the diffracted field, but rather it includes surface wave contributions. PMID- 25697999 TI - Evolution of the average steepening factor for nonlinearly propagating waves. AB - Difficulties arise in attempting to discern the effects of nonlinearity in near field jet-noise measurements due to the complicated source structure of high velocity jets. This article describes a measure that may be used to help quantify the effects of nonlinearity on waveform propagation. This measure, called the average steepening factor (ASF), is the ratio of the average positive slope in a time waveform to the average negative slope. The ASF is the inverse of the wave steepening factor defined originally by Gallagher [AIAA Paper No. 82-0416 (1982)]. An analytical description of the ASF evolution is given for benchmark cases-initially sinusoidal plane waves propagating through lossless and thermoviscous media. The effects of finite sampling rates and measurement noise on ASF estimation from measured waveforms are discussed. The evolution of initially broadband Gaussian noise and signals propagating in media with realistic absorption are described using numerical and experimental methods. The ASF is found to be relatively sensitive to measurement noise but is a relatively robust measure for limited sampling rates. The ASF is found to increase more slowly for initially Gaussian noise signals than for initially sinusoidal signals of the same level, indicating the average distortion within noise waveforms occur more slowly. PMID- 25698000 TI - Wind noise under a pine tree canopy. AB - It is well known that infrasonic wind noise levels are lower for arrays placed in forests and under vegetation than for those in open areas. In this research, the wind noise levels, turbulence spectra, and wind velocity profiles are measured in a pine forest. A prediction of the wind noise spectra from the measured meteorological parameters is developed based on recent research on wind noise above a flat plane. The resulting wind noise spectrum is the sum of the low frequency wind noise generated by the turbulence-shear interaction near and above the tops of the trees and higher frequency wind noise generated by the turbulence turbulence interaction near the ground within the tree layer. The convection velocity of the low frequency wind noise corresponds to the wind speed above the trees while the measurements showed that the wind noise generated by the turbulence-turbulence interaction is near stationary and is generated by the slow moving turbulence adjacent to the ground. Comparison of the predicted wind noise spectrum with the measured wind noise spectrum shows good agreement for four measurement sets. The prediction can be applied to meteorological estimates to predict the wind noise under other pine forests. PMID- 25698001 TI - Imaging multiple local changes in heterogeneous media with diffuse waves. AB - This study focuses on imaging local changes in heterogeneous media. The method employed is demonstrated and validated using numerical experiments of acoustic wave propagation in a multiple scattering medium. Changes are simulated by adding new scatterers of different sizes at various positions in the medium, and the induced decorrelation of the diffuse (coda) waveforms is measured for different pairs of sensors. The spatial and temporal dependences of the decorrelation are modeled through a diffuse sensitivity kernel, based on the intensity transport in the medium. The inverse problem is then solved with a linear least square algorithm, which leads to a map of scattering cross section density of the changes. PMID- 25698002 TI - Modeling of transient wave propagation in a heterogeneous solid layer coupled with fluid: application to long bones. AB - The aim of this work is to evaluate the effects of the heterogeneity and anisotropy of material properties of cortical bone on its ultrasonic response obtained by using axial transmission method. The heterogeneity and anisotropy of material properties are introduced by using a parametric probabilistic model. The geometrical configuration of the tested sample is described by a tri-layer medium composed of a heterogeneous and anisotropic solid layer sandwiched between two acoustic fluid layers of which one of these layers is excited by an acoustic linear source. The numerical results focus on studying of an interest quantity, called velocity of the first arriving signal, showing that it strongly depends on the dispersion induced by statistical fluctuations of stochastic elasticity field. PMID- 25698003 TI - Stimulus ratio dependence of low-frequency distortion-product otoacoustic emissions in humans. AB - Active amplifiers within the cochlea generate, as a by-product of their function, distortion-product otoacoustic emissions (DPOAEs) in response to specific two tone stimuli. Focus has been on invoking emissions in a mid-frequency range from ~0.5 to 4 kHz. The present study investigates stimulus parameters of the DPOAE at 2f1-f2 frequencies below 0.5 kHz. Eighteen out of 21 young human adults screened had audiometrically normal hearing for inclusion in the experiment. DPOAEs were measured with pure-tone stimuli in four configurations: f2 fixed around 2.13 kHz, f2 fixed around 0.53 kHz, 2f1-f2 fixed at 1.23 kHz and 0.25 kHz. Eight stimulus ratios, f2/f1, and three stimulus sound pressure levels, L1/L2, were measured in each configuration. Trends in ratio-magnitude responses for the mid-frequency DPOAE agree with those reported in previous literature. DPOAEs are not limited to distortion frequencies >0.5 kHz, but the stimulus ratio invoking the largest DPOAE in the mid-frequency range does not do so in the low-frequency range. Guiding the ratio according to the equivalent rectangular bandwidth of auditory filters maintains the DPOAE level. PMID- 25698004 TI - Frequency and amplitude estimation of the first peak of head-related transfer functions from individual pinna anthropometry. AB - The first (lowest) peak of head-related transfer functions (HRTFs) is known to be a concha depth resonance and a spectral cue in human sound localization. However, there is still no established model to estimate its center-frequency F1 and amplitude A1 from pinna anthropometry. Here, with geometries of 38 pinnae measured and their median-plane HRTFs calculated by numerical simulation, linear regression models were evaluated in estimating F1 and A1 from 25 concha depth and aperture measurements. F1 was best estimated (correlation coefficient r = 0.84, mean absolute error MAE = 118 Hz) by lateral distances from the base of the posterior cavum concha to the outer surface of the antitragus and antihelix (longest measures of concha depth). A1 was best estimated (r = 0.83, MAE = 0.84 dB) by the lateral distance from the ear-canal entrance to the side of the cheek near the anterior notch (shortest measure of concha depth) and by the equivalent diameter of the concha aperture. These results suggest that the first resonance's quarter-wavelength corresponds to the longest lateral extent of the concha and that its energy lost to the surrounding air depends on the concha aperture and the cavum concha's shortest lateral depth. PMID- 25698005 TI - Release from informational masking in a monaural competing-speech task with vocoded copies of the maskers presented contralaterally. AB - Single-sided deafness prevents access to the binaural cues that help normal hearing listeners extract target speech from competing voices. Little is known about how listeners with one normal-hearing ear might benefit from access to severely degraded audio signals that preserve only envelope information in the second ear. This study investigated whether vocoded masker-envelope information presented to one ear could improve performance for normal-hearing listeners in a multi-talker speech-identification task presented to the other ear. Target speech and speech or non-speech maskers were presented unprocessed to the left ear. The right ear received no signal, or either an unprocessed or eight-channel noise vocoded copy of the maskers. Presenting the vocoded maskers contralaterally yielded significant masking release from same-gender speech maskers, albeit less than in the unprocessed case, but not from opposite-gender speech, stationary noise, or modulated-noise maskers. Unmasking also occurred with as few as two vocoder channels and when an attenuated copy of the target signal was added to the maskers before vocoding. These data show that delivering masker-envelope information contralaterally generates masking release in situations where target masker similarity impedes monaural speech-identification performance. By delivering speech-envelope information to a deaf ear, cochlear implants for single-sided deafness have the potential to produce a similar effect. PMID- 25698006 TI - Spectro-temporal modulation masking patterns reveal frequency selectivity. AB - The present study investigated the possibility that the human auditory system demonstrates frequency selectivity to spectro-temporal amplitude modulations. Threshold modulation depth for detecting sinusoidal spectro-temporal modulations was measured using a generalized masked threshold pattern paradigm with narrowband masker modulations. Four target spectro-temporal modulations were examined, differing in their temporal and spectral modulation frequencies: a temporal modulation of -8, 8, or 16 Hz combined with a spectral modulation of 1 cycle/octave and a temporal modulation of 4 Hz combined with a spectral modulation of 0.5 cycles/octave. The temporal center frequencies of the masker modulation ranged from 0.25 to 4 times the target temporal modulation. The spectral masker-modulation center-frequencies were 0, 0.5, 1, 1.5, and 2 times the target spectral modulation. For all target modulations, the pattern of average thresholds for the eight normal-hearing listeners was consistent with the hypothesis of a spectro-temporal modulation filter. Such a pattern of modulation frequency sensitivity was predicted on the basis of psychoacoustical data for purely temporal amplitude modulations and purely spectral amplitude modulations. An analysis of separability indicates that, for the present data set, selectivity in the spectro-temporal modulation domain can be described by a combination of a purely spectral and a purely temporal modulation filter function. PMID- 25698007 TI - Influence of the stimulus presentation rate on medial olivocochlear system assays. AB - Click evoked otoacoustic emissions (CEOAEs) are commonly used both in research and clinics to assay the medial olivocochlear system (MOC). Clicks presented at rates >50 Hz in the contralateral ear have previously been reported to evoke contralateral MOC activity. However, in typical MOC assays, clicks are presented in the ipsilateral ear in conjunction with MOC elicitor (noise) in the contralateral ear. The effect of click rates in such an arrangement is currently unknown. A forward masking paradigm was used to emulate typical MOC assays to elucidate the influence of ipsilateral click presentation rates on MOC inhibition of CEOAEs in 28 normal hearing adults. Influence of five click rates (20.83, 25, 31.25, 41.67, and 62.5 Hz) presented at 55 dB peSPL was tested. Results indicate that click rates as low as 31.25 Hz significantly enhance contralateral MOC inhibition, possibly through the activation of ipsilateral and binaural MOC neurons with potential contributions from the middle ear muscle reflex. Therefore, click rates <=25 Hz are recommended for use in MOC assays, at least for 55 dB peSPL click level. PMID- 25698008 TI - Effects of envelope bandwidth on importance functions for cochlear implant simulations. AB - Frequency-importance functions (FIFs) quantify intelligibility contributions of spectral regions of speech. In previous work, FIFs were considered as instruments for characterizing intelligibility contributions of individual cochlear implant electrode channels. Comparisons of FIFs for natural speech and vocoder-simulated implant processed speech showed that vocoding shifted peak importance regions downward in frequency by 0.5 octaves. These shifts were attributed to voicing cue changes, and may reflect increased reliance on low-frequency information (apart from periodicity cues) for correct voicing perception. The purpose of this study was to determine whether increasing channel envelope bandwidth would reverse these shifts by improving access to voicing and pitch cues. Importance functions were measured for 48 subjects with normal hearing, who listened to vowel consonant-vowel tokens either as recorded or as output from five different vocoders that simulated implant processing. Envelopes were constructed using filters that either included or excluded pitch information. Results indicate that vocoding-based shifts are only partially counteracted by including pitch information; moreover, a substantial baseline shift is present even for vocoders with high spectral resolution. The results also suggest that vocoded speech intelligibility is most sensitive to a loss of spectral resolution in high importance regions, a finding with possible implications for cochlear implant electrode mapping. PMID- 25698010 TI - The effect of spatial separation in distance on the intelligibility of speech in rooms. AB - The influence of spatial separation in source distance on speech reception thresholds (SRTs) is investigated. In one scenario, the target was presented at 0.5 m distance, and the masker varied from 0.5 m distance up to 10 m. In a second scenario, the masker was presented at 0.5 m distance and the target distance varied. The stimuli were synthesized using convolution with binaural room impulse responses (BRIRs) measured on a dummy head in a reverberant auditorium, and were equalized to compensate for distance-dependent spectral and intensity changes. All sources were simulated directly in front of the listener. SRTs decreased monotonically when the target was at 0.5 m and the speech-masker was moved further away, resulting in a SRT improvement of up to 10 dB. When the speech masker was at 0.5 m and the target was moved away, a large variation across subjects was observed. Neither short-term signal-to-noise ratio (SNR) improvements nor cross-ear glimpsing could account for the observed improvement in intelligibility. However, the effect might be explained by an improvement in the SNR in the modulation domain and a decrease in informational masking. This study demonstrates that distance-related cues can play a significant role when listening in complex environments. PMID- 25698009 TI - Effects of age and hearing loss on the intelligibility of interrupted speech. AB - How age and hearing loss affect the perception of interrupted speech may vary based on both the physical properties of preserved or obliterated speech fragments and individual listener characteristics. To investigate perceptual processes and interruption parameters influencing intelligibility across interruption rates, participants of different age and hearing status heard sentences interrupted by silence at either a single primary rate (0.5-8 Hz; 25%, 50%, 75% duty cycle) or at an additional concurrent secondary rate (24 Hz; 50% duty cycle). Although age and hearing loss significantly affected intelligibility, the ability to integrate sub-phonemic speech fragments produced by the fast secondary rate was similar in all listener groups. Age and hearing loss interacted with rate with smallest group differences observed at the lowest and highest interruption rates of 0.5 and 24 Hz. Furthermore, intelligibility of dual-rate gated sentences was higher than single-rate gated sentences with the same proportion of retained speech. Correlations of intelligibility of interrupted speech to pure-tone thresholds, age, or measures of working memory and auditory spectro-temporal pattern discrimination were generally low-to moderate and mostly nonsignificant. These findings demonstrate rate-dependent effects of age and hearing loss on the perception of interrupted speech, suggesting complex interactions of perceptual processes across different time scales. PMID- 25698011 TI - On the spatial distribution of the reflection sources of different latency components of otoacoustic emissions. AB - The experimental observation of long- and short-latency components in both stimulus-frequency and transient-evoked otoacoustic emissions admits a comprehensive explanation within the coherent reflection mechanism, in a linear active transmission-line cochlear model. A local complex reflectivity function associated with roughness was defined and analyzed by varying the tuning factor of the model, systematically showing, for each frequency, a multiple-peak spatial structure, compatible with the observed multiple-latency structure of otoacoustic emissions. Although this spatial pattern and the peak relative intensity changes with the chosen random roughness function, the multiple-peak structure is a reproducible feature of different "digital ears," in good agreement with experimental data. If one computes the predicted transmission delays as a function of frequency and position for each source, one gets a good match to the latency-frequency patterns that are directly computed from synthesized otoacoustic spectra using time-frequency analysis. This result clarifies the role of the spatial distribution of the otoacoustic emission sources, further supporting the interpretation of different-latency otoacoustic components as due to reflection sources localized at different places along the basilar membrane. PMID- 25698012 TI - A convolution model for computing the far-field directivity of a parametric loudspeaker array. AB - This paper describes a method to compute the far-field directivity of a parametric loudspeaker array (PLA), whereby the steerable parametric loudspeaker can be implemented when phased array techniques are applied. The convolution of the product directivity and the Westervelt's directivity is suggested, substituting for the past practice of using the product directivity only. Computed directivity of a PLA using the proposed convolution model achieves significant improvement in agreement to measured directivity at a negligible computational cost. PMID- 25698013 TI - Hemispherical double-layer time reversal imaging in reverberant and noisy environments at audible frequencies. AB - Time reversal is a widely used technique in wave physics, for both imaging purposes and experimental focusing. In this paper, a complete double-layer time reversal imaging process is proposed for in situ acoustic characterization of non stationary sources, with perturbative noise sources and reverberation. The proposed method involves the use of a hemispherical array composed of pressure pressure probes. The complete set of underlying optimizations to sonic time reversal imaging is detailed, with regard to space and time reconstruction accuracy, imaging resolution and sensitivity to reverberation, and perturbative noise. The proposed technique is tested and compared to more conventional time reversal techniques through numerical simulations and experiments. Results demonstrate the ability of the proposed method to back-propagate acoustic waves radiated from non-stationary sources in the volume delimited by the measurement array with a high precision both in time and space domains. Analysis of the results also shows that the process can successfully be applied in strongly reverberant environments, even with poor signal-to-noise ratio. PMID- 25698014 TI - Blind phone segmentation based on spectral change detection using Legendre polynomial approximation. AB - Phone segmentation involves partitioning a continuous speech signal into discrete phone units. In this paper, a method for automatic phone segmentation without prior knowledge of speech content is proposed. The signal spectrum was represented by band-energies. A segment of the band-energy curve was approximated using Legendre polynomial expansion, allowing Legendre polynomial coefficients to describe the properties of the segment. The spectral changes, which imply phone boundaries in the speech signal, were then detected by monitoring the variations of Legendre polynomial coefficients. A two-step algorithm for detecting phone boundaries was derived. The first step was to detect phone boundaries using first order and second-order coefficients of the Legendre polynomial approximation. The second step was to locate slow spectral changes in the regions of concatenated voiced phones using zero-order coefficients of the Legendre polynomial approximation. This enabled the phone boundaries missed during the first step to be recovered. An evaluation using the TIMIT corpus indicated that the proposed method is comparable to or more accurate than previous methods. PMID- 25698015 TI - Locus equations and coarticulation in three Australian languages. AB - Locus equations were applied to F2 data for bilabial, alveolar, retroflex, palatal, and velar plosives in three Australian languages. In addition, F2 variance at the vowel-consonant boundary, and, by extension, consonantal coarticulatory sensitivity, was measured. The locus equation slopes revealed that there were place-dependent differences in the magnitude of vowel-to-consonant coarticulation. As in previous studies, the non-coronal (bilabial and velar) consonants tended to be associated with the highest slopes, palatal consonants tended to be associated with the lowest slopes, and alveolar and retroflex slopes tended to be low to intermediate. Similarly, F2 variance measurements indicated that non-coronals displayed greater coarticulatory sensitivity to adjacent vowels than did coronals. Thus, both the magnitude of vowel-to-consonant coarticulation and the magnitude of consonantal coarticulatory sensitivity were seen to vary inversely with the magnitude of consonantal articulatory constraint. The findings indicated that, unlike results reported previously for European languages such as English, anticipatory vowel-to-consonant coarticulation tends to exceed carryover coarticulation in these Australian languages. Accordingly, on the F2 variance measure, consonants tended to be more sensitive to the coarticulatory effects of the following vowel. Prosodic prominence of vowels was a less significant factor in general, although certain language-specific patterns were observed. PMID- 25698016 TI - Perception of glottalization and phrase-final creak. AB - American English has several linguistic sources of creaky voice. Two common sources are /t/-glottalization (where /t/ is produced as a glottal stop and/or with creaky voice, as in "button") and phrase-final creak. Both /t/ glottalization and phrase-final creak have similar acoustic properties, but they can co-occur in English. The goal of this study is to determine whether /t/ glottalization and phrase-final creak are perceived distinctly. Sixteen English listeners were asked to identify words in a two-alternative forced choice task. The auditory targets were (near-) minimal pairs, in which one word could have /t/ glottalization (e.g., "button") but the other could not (e.g., "bun"). Stimuli were presented with and without phrase-final creak. Listeners made few identification errors overall, even when /t/-glottalization co-occurred with phrase-final creak, suggesting that /t/-glottalization and phrase-final creak remain perceptually distinct to English listeners. This supports the view that creaky voice is not a single category, but one comprised of distinct voice qualities. PMID- 25698017 TI - Effects of higher order propagation modes in vocal tract like geometries. AB - In this paper, a multimodal theory accounting for higher order acoustical propagation modes is presented as an extension to the classical plane wave theory. This theoretical development is validated against experiments on vocal tract replicas, obtained using a 3D printer and finite element simulations. Simplified vocal tract geometries of increasing complexity are used to investigate the influence of some geometrical parameters on the acoustical properties of the vocal tract. It is shown that the higher order modes can produce additional resonances and anti-resonances and can also strongly affect the radiated sound. These effects appear to be dependent on the eccentricity and the cross-sectional shape of the geometries. Finally, the comparison between the simulations and the experiments points out the importance of taking visco-thermal losses into account to increase the accuracy of the resonance bandwidths prediction. PMID- 25698018 TI - Spectral and temporal resolutions of information-bearing acoustic changes for understanding vocoded sentences. AB - Short-time spectral changes in the speech signal are important for understanding noise-vocoded sentences. These information-bearing acoustic changes, measured using cochlea-scaled entropy in cochlear implant simulations [CSECI; Stilp et al. (2013). J. Acoust. Soc. Am. 133(2), EL136-EL141; Stilp (2014). J. Acoust. Soc. Am. 135(3), 1518-1529], may offer better understanding of speech perception by cochlear implant (CI) users. However, perceptual importance of CSECI for normal hearing listeners was tested at only one spectral resolution and one temporal resolution, limiting generalizability of results to CI users. Here, experiments investigated the importance of these informational changes for understanding noise-vocoded sentences at different spectral resolutions (4-24 spectral channels; Experiment 1), temporal resolutions (4-64 Hz cutoff for low-pass filters that extracted amplitude envelopes; Experiment 2), or when both parameters varied (6-12 channels, 8-32 Hz; Experiment 3). Sentence intelligibility was reduced more by replacing high-CSECI intervals with noise than replacing low-CSECI intervals, but only when sentences had sufficient spectral and/or temporal resolution. High-CSECI intervals were more important for speech understanding as spectral resolution worsened and temporal resolution improved. Trade-offs between CSECI and intermediate spectral and temporal resolutions were minimal. These results suggest that signal processing strategies that emphasize information-bearing acoustic changes in speech may improve speech perception for CI users. PMID- 25698019 TI - Stabilizing the production of nonnative consonant clusters with acoustic variability. AB - Previous research on the perception, recognition, and learning of sounds and words has identified diverse effects of phonetic variation. The present study examined how variation affects cross-language production of consonant clusters. American English speakers shadowed words beginning with nonnative clusters in low and high-variability conditions. Shadowing responses in the low-variability condition were quite sensitive to fine-grained phonetic properties that were manipulated across the stimuli. Notably, longer stop bursts led to increased rates of epenthesis, lower burst amplitudes resulted in more feature change and deletion, and intense periods of voicing at cluster onset elicited prothetic responses. Sensitivity to the acoustic manipulations was substantially attenuated in the high-variability condition, which combined stimuli from the first condition with baseline productions of the same items from two additional talkers. Detailed analyses of the response patterns indicate that more stable production targets in the high-variability condition resulted from integration, or blending, of the multiple talker stimuli. Implications of these findings for language-specific speech processing and the role of phonetic variability in second language acquisition are discussed. PMID- 25698020 TI - The effects of delayed auditory and visual feedback on speech production. AB - Monitoring the sensory consequences of articulatory movements supports speaking. For example, delaying auditory feedback of a speaker's voice disrupts speech production. Also, there is evidence that this disruption may be decreased by immediate visual feedback, i.e., seeing one's own articulatory movements. It is, however, unknown whether delayed visual feedback affects speech production in fluent speakers. Here, the effects of delayed auditory and visual feedback on speech fluency (i.e., speech rate and errors), vocal control (i.e., intensity and pitch), and speech rhythm were investigated. Participants received delayed (by 200 ms) or immediate auditory feedback, while repeating sentences. Moreover, they received either no visual feedback, immediate visual feedback, or delayed visual feedback (by 200, 400, and 600 ms). Delayed auditory feedback affected fluency, vocal control, and rhythm. Immediate visual feedback had no effect on any of the speech measures when it was combined with delayed auditory feedback. Delayed visual feedback did, however, affect speech fluency when it was combined with delayed auditory feedback. In sum, the findings show that delayed auditory feedback disrupts fluency, vocal control, and rhythm and that delayed visual feedback can strengthen the disruptive effect of delayed auditory feedback on fluency. PMID- 25698021 TI - Effects of age and hearing loss on recognition of unaccented and accented multisyllabic words. AB - The effects of age and hearing loss on recognition of unaccented and accented words of varying syllable length were investigated. It was hypothesized that with increments in length of syllables, there would be atypical alterations in syllable stress in accented compared to native English, and that these altered stress patterns would be sensitive to auditory temporal processing deficits with aging. Sets of one-, two-, three-, and four-syllable words with the same initial syllable were recorded by one native English and two Spanish-accented talkers. Lists of these words were presented in isolation and in sentence contexts to younger and older normal-hearing listeners and to older hearing-impaired listeners. Hearing loss effects were apparent for unaccented and accented monosyllabic words, whereas age effects were observed for recognition of accented multisyllabic words, consistent with the notion that altered syllable stress patterns with accent are sensitive for revealing effects of age. Older listeners also exhibited lower recognition scores for moderately accented words in sentence contexts than in isolation, suggesting that the added demands on working memory for words in sentence contexts impact recognition of accented speech. The general pattern of results suggests that hearing loss, age, and cognitive factors limit the ability to recognize Spanish-accented speech. PMID- 25698022 TI - Regulation of glottal closure and airflow in a three-dimensional phonation model: implications for vocal intensity control. AB - Maintaining a small glottal opening across a large range of voice conditions is critical to normal voice production. This study investigated the effectiveness of vocal fold approximation and stiffening in regulating glottal opening and airflow during phonation, using a three-dimensional numerical model of phonation. The results showed that with increasing subglottal pressure the vocal folds were gradually pushed open, leading to increased mean glottal opening and flow rate. A small glottal opening and a mean glottal flow rate typical of human phonation can be maintained against increasing subglottal pressure by proportionally increasing the degree of vocal fold approximation for low to medium subglottal pressures and vocal fold stiffening at high subglottal pressures. Although sound intensity was primarily determined by the subglottal pressure, the results suggest that, to maintain small glottal opening as the sound intensity increases, one has to simultaneously tighten vocal fold approximation and/or stiffen the vocal folds, resulting in increased glottal resistance, vocal efficiency, and fundamental frequency. PMID- 25698023 TI - Perceptual susceptibility to acoustic manipulations in speaker discrimination. AB - Listeners' ability to discriminate unfamiliar voices is often susceptible to the effects of manipulations of acoustic characteristics of the utterances. This vulnerability was quantified within a task in which participants determined if two utterances were spoken by the same or different speakers. Results of this task were analyzed in relation to a set of historical and novel parameters in order to hypothesize the role of those parameters in the decision process. Listener performance was first measured in a baseline task with unmodified stimuli, and then compared to responses with resynthesized stimuli under three conditions: (1) normalized mean-pitch; (2) normalized duration; and (3) normalized linear predictive coefficients (LPCs). The results of these experiments suggest that perceptual speaker discrimination is robust to acoustic changes, though mean-pitch and LPC modifications are more detrimental to a listener's ability to successfully identify same or different speaker pairings. However, this susceptibility was also found to be partially dependent on the specific speaker and utterances. PMID- 25698024 TI - Auditory, visual, and auditory-visual processing performance in typically developing children: modality independence versus dependence. AB - The study was carried out to determine whether cross-modal interactions occur during processing of auditory and/or visual signals that require separation/closure, integration, and duration pattern perception in typically developing children. Thirty typically developing children were evaluated on three auditory processing tests (speech-in-noise test in Indian-English, dichotic consonant vowel test, and duration pattern test) that tapped separation/closure, integration and duration pattern perception. The children were also evaluated on the visual and auditory-visual analogues of the auditory tests. Differences in modality were found in each of the processes that were tested. The performance when the auditory and visual modalities were tested simultaneously was significantly higher than the auditory or visual modality for tests that involved separation/closure and integration. In contrast, scores on the analogous auditory visual duration pattern test were significantly higher than the auditory test but not the visual analogous test. Further, the scores of the auditory modality were significantly poorer than the visual modality for separation/closure and duration patterning but not for integration. Findings of the study indicate that performance on higher level processing varies depending on the modality that is assessed and supports the presence of cross-modality interactions. PMID- 25698025 TI - Intraglottal velocity and pressure measurements in a hemilarynx model. AB - Determining the mechanisms of self-sustained oscillation of the vocal folds requires characterization of the pressures produced by intraglottal aerodynamics. Because most of the intraglottal aerodynamic forces cannot be measured in a tissue model of the larynx, current understanding of vocal fold vibration mechanism is derived from mechanical, analytical, and computational models. Previous studies have computed intraglottal pressures from measured intraglottal velocity fields and intraglottal geometry; however, this technique for determining pressures is not yet validated. In this study, intraglottal pressure measurements taken in a hemilarynx model are compared with pressure values that are computed from simultaneous velocity measurements. The results showed that significant negative pressure formed near the superior aspect of the folds during closing, which agrees with previous measurements in other hemilarynx models. Intraglottal velocity measurements show that the flow near the superior aspect separates from the glottal wall during closing and may develop into a vortex, which further augments the magnitude of negative pressure. Intraglottal pressure distributions, computed by solving the pressure Poisson equation, showed good agreement with pressure measurements. The match between the pressure computations and its measurements validates the current technique, which was previously used to estimate intraglottal pressure distribution in a full larynx model. PMID- 25698026 TI - Statistical properties of linear prediction analysis underlying the challenge of formant bandwidth estimation. AB - Formant bandwidth estimation is often observed to be more challenging than the estimation of formant center frequencies due to the presence of multiple glottal pulses within a period and short closed-phase durations. This study explores inherently different statistical properties between linear prediction (LP)-based estimates of formant frequencies and their corresponding bandwidths that may be explained in part by the statistical bounds on the variances of estimated LP coefficients. A theoretical analysis of the Cramer-Rao bounds on LP estimator variance indicates that the accuracy of bandwidth estimation is approximately twice as low as that of center frequency estimation. Monte Carlo simulations of all-pole vowels with stochastic and mixed-source excitation demonstrate that the distributions of estimated LP coefficients exhibit expectedly different variances for each coefficient. Transforming the LP coefficients to formant parameters results in variances of bandwidth estimates being typically larger than the variances of respective center frequency estimates, depending on vowel type and fundamental frequency. These results provide additional evidence underlying the challenge of formant bandwidth estimation due to inherent statistical properties of LP-based speech analysis. PMID- 25698027 TI - Hybrid silencers with micro-perforated panels and internal partitions. AB - A sub-structuring approach, along with a unit cell treatment, is proposed to model expansion chamber silencers with internal partitions and micro-perforated panels (MPPs) in the absence of internal flow. The side-branch of the silencer is treated as a combination of unit cells connected in series. It is shown that, by connecting multiple unit cells with varying parameters, the noise attenuation bandwidth can be enlarged. With MPPs, the hybrid noise attenuation mechanism of the silencer is revealed. Depending on the size of the perforation hole, noise attenuation can be dominated by dissipative, reactive, or combined effects together. For a broadband sound absorption, the hole size, together with the perforation ratio and other parameters, can be optimized to strike a balance between the dissipative and reactive effect, for ultimately achieving the desired noise attenuation performance within a prescribed frequency region. The modular nature of the proposed formulation allows doing this in a flexible, accurate, and cost effective manner. The accuracy of the proposed approach is validated through comparisons with finite element method and experiments. PMID- 25698028 TI - Multisource statistically optimized near-field acoustical holography. AB - This paper presents a reduced-order approach to near-field acoustical holography (NAH) that allows the user to account for sound fields generated by multiple spatially separated sources. In this method, an equivalent wave model (EWM) of a given field is formulated to include combinations of planar, cylindrical, spherical, or other elementary wave functions in contrast to an EWM restricted to a single separable coordinate system. This can alleviate the need for higher order functions, reduce the number of measurements, and decrease error. The statistically optimized near-field acoustical holography (SONAH) algorithm is utilized to perform the NAH projection after the formulation of the multisource EWM. The combined process is called multisource statistically optimized near field acoustical holography (M-SONAH). This method is used to reconstruct simulated sound fields generated by combinations of a vibrating piston in a sphere and linear arrays of monopole sources. It is shown that M-SONAH can reconstruct near-field pressures in multisource environments with lower errors and fewer measurements than a strictly plane or cylindrical-wave formulation using the same simulated measurement. PMID- 25698029 TI - A hybrid finite element-transfer matrix model for vibroacoustic systems with flat and homogeneous acoustic treatments. AB - Practical vibroacoustic systems involve passive acoustic treatments consisting of highly dissipative media such as poroelastic materials. The numerical modeling of such systems at low to mid frequencies typically relies on substructuring methodologies based on finite element models. Namely, the master subsystems (i.e., structural and acoustic domains) are described by a finite set of uncoupled modes, whereas condensation procedures are typically preferred for the acoustic treatments. However, although accurate, such methodology is computationally expensive when real life applications are considered. A potential reduction of the computational burden could be obtained by approximating the effect of the acoustic treatment on the master subsystems without introducing physical degrees of freedom. To do that, the treatment has to be assumed homogeneous, flat, and of infinite lateral extent. Under these hypotheses, simple analytical tools like the transfer matrix method can be employed. In this paper, a hybrid finite element-transfer matrix methodology is proposed. The impact of the limiting assumptions inherent within the analytical framework are assessed for the case of plate-cavity systems involving flat and homogeneous acoustic treatments. The results prove that the hybrid model can capture the qualitative behavior of the vibroacoustic system while reducing the computational effort. PMID- 25698030 TI - Target strengths of two abundant mesopelagic fish species. AB - Mesopelagic fish of the Myctophidae and Sternoptychidae families dominate the biomass of the oceanic deep scattering layers and, therefore, have important ecological roles within these ecosystems. Interest in the commercial exploitation of these fish is growing, so the development of techniques for estimating their abundance, distribution and, ultimately, sustainable exploitation are essential. The acoustic backscattering characteristics for two size classes of Maurolicus muelleri and Benthosema glaciale are reported here based on swimbladder morphology derived from digitized soft x-ray images, and empirical (in situ) measurements of target strength (TS) derived from an acoustic survey in a Norwegian Sea. A backscattering model based on a gas-filled prolate spheroid was used to predict the theoretical TS for both species across a frequency range between 0 and 250 kHz. Sensitivity analyses of the TS model to the modeling parameters indicate that TS is rather sensitive to the viscosity, swimbladder volume ratio, and tilt, which can result in substantial changes to the TS. Theoretical TS predictions close to the resonance frequency were in good agreement (+/-2 dB) with mean in situ TS derived from the areas acoustically surveyed that were spatially and temporally consistent with the trawl information for both species. PMID- 25698031 TI - Reflection of a plane wave from a two-layered seafloor with non-parallel interface between the layers. AB - This work studies the reflection coefficient of a plane wave incident on a seafloor consisting of two layers (sediment and substrate), whose interface is linear but not parallel to the water-sediment interface. This is an extension of the well-established and studied reflection coefficient concept for seafloors with parallel layers. Moreover this study introduces the concept of the Coherent Reflection Coefficient (CRC) that extends the usual Rayleigh reflection coefficient definition not only at the water-sediment interface but inside the water column as well. The mathematical formulation of the CRC is derived and its numerical implementation is explained. Based on this implementation a numerical code is developed and incorporated-among other codes-in a user-friendly graphics toolbox that was built to facilitate CRC calculations. Numerical examples for realistic seafloors are presented and the derived results are compared to similar ones for parallel layers, indicating that even for small inclination angles the reflection coefficient difference between parallel and slanted interface layers is substantial, hence cannot be ignored. An imminent application of the extended seafloor model and the CRC introduced in this work is the enhancement of geophysics inversion schemes for the estimation of the seafloor parameters. PMID- 25698032 TI - Implementation of a virtual laboratory for training on sound insulation testing and uncertainty calculations in acoustic tests. AB - This paper describes a methodology and case study for the implementation of educational virtual laboratories for practice training on acoustic tests according to international standards. The objectives of this activity are (a) to help the students understand and apply the procedures described in the standards and (b) to familiarize the students with the uncertainty in measurement and its estimation in acoustics. The virtual laboratory will not focus on the handling and set-up of real acoustic equipment but rather on procedures and uncertainty. The case study focuses on the application of the virtual laboratory for facade sound insulation tests according to ISO 140-5:1998 (International Organization for Standardization, Geneva, Switzerland, 1998), and the paper describes the causal and stochastic models and the constraints applied in the virtual environment under consideration. With a simple user interface, the laboratory will provide measurement data that the students will have to process to report the insulation results that must converge with the "virtual true values" in the laboratory. The main advantage of the virtual laboratory is derived from the customization of factors in which the student will be instructed or examined (for instance, background noise correction, the detection of sporadic corrupted observations, and the effect of instrument precision). PMID- 25698033 TI - Tuning of vocal tract model parameters for nasals using sensitivity functions. AB - Determining the cross-sectional areas of the vocal tract models from the linear predictive coding or autoregressive-moving-average analysis of speech signals from vowels has been of research interest for several decades now. To tune the shape of the vocal tract to given sets of formant frequencies, iterative methods using sensitivity functions have been developed. In this paper, the idea of sensitivity functions is expanded to a three-tube model used in connection with nasals, and the energy-based sensitivity function is compared with a Jacobian based sensitivity function for the branched-tube model. It is shown that the difference between both functions is negligible if the sensitivity is taken with respect to the formant frequency only. Results for an iterative tuning a three tube vocal tract model based on the sensitivity functions for a nasal (/m/) are given. It is shown that besides the polar angle, the absolute value of the poles and zeros of the rational transfer function also needs to be considered in the tuning process. To test the effectiveness of the iterative solver, the steepest descent method is compared with the Gauss-Newton method. It is shown, that the Gauss-Newton method converges faster if a good starting value for the iteration is given. PMID- 25698034 TI - Radiation efficiency of damped plates. AB - The radiation efficiency of damped plates is discussed in this letter. Below the critical frequency of a plate, numerical results show that the radiation efficiency is much influenced by damping. Some modifications of the classical formulas given by Cremer for an infinite plate and Leppington for a finite rectangular plate are proposed to include the influence of the damping on the radiation efficiency. PMID- 25698035 TI - Acoustic contrast control in an arc-shaped area using a linear loudspeaker array. AB - This paper proposes a method of creating acoustic contrast control in an arc shaped area using a linear loudspeaker array. The boundary of the arc-shaped area is treated as the envelope of the tangent lines that can be formed by manipulating the phase profile of the loudspeakers in the array. When compared with the existing acoustic contrast control method, the proposed method is able to generate sound field inside an arc-shaped area and achieve a trade-off between acoustic uniformity and acoustic contrast. The acoustic contrast created by the proposed method increases while the acoustic uniformity decreases with frequency. PMID- 25698036 TI - Loudness of low-frequency pure tones lateralized by interaural time differences. AB - Directional loudness is that phenomenon by which the loudness of a sound may vary according to the localization of its source. This phenomenon has been mainly observed for high-frequency sounds, for sources located in the horizontal plane. Because of the acoustic shadow of the head, the left and right ear pressures are modified depending on the source azimuth and the global loudness resulting from a summation process may vary accordingly. Directional loudness has also been reported to occur at 400 Hz, where shadowing effects are usually rather small. It might therefore be suspected that directional loudness effects could be influenced by other parameters involved in the localization process. This study assessed the loudness of low-frequency pure tones (200 and 400 Hz) lateralized with headphones by applying an interaural time difference (ITD) but no interaural level difference. It showed small but significant variations of loudness with respect to ITD at a low loudness level (40 phon): ITD values associated with virtual azimuths of +/-60 degrees and +/-90 degrees led to a small but significant increase in loudness (up to 1.25 dB). However, there was no such effect at a moderate loudness level (70 phon). PMID- 25698037 TI - On time delay estimation from a sparse linear prediction perspective. AB - This paper proposes a sparse linear prediction based algorithm to estimate time difference of arrival. This algorithm unifies the cross correlation method without prewhitening and that with prewhitening via an l2/l1 optimization process, which is solved by an augmented Lagrangian alternating direction method. It also forms a set of time delay estimators that make a tradeoff between prewhitening and non-prewhitening through adjusting a regularization parameter. The effectiveness of the proposed algorithm is demonstrated in noisy and reverberant environments. PMID- 25698038 TI - Erratum: Numerical simulation of ultrasonic wave propagation for the evaluation of dental implant biomechanical stability [J. Acoust. Soc. Am. 129, 4062-4072 (2011)]. PMID- 25698040 TI - Modelling parallel assemblies of porous materials using the equivalent circuit method. AB - Recently, the accuracy of the parallel transfer matrix method (P-TMM) and the admittance sum method (ASM) in the prediction of the absorption properties of parallel assemblies of materials was investigated [Verdiere, Panneton, Elkoun, Dupont, and Leclaire, J. Acoust. Soc. Am. 136, EL90-EL95 (2014)]. It was demonstrated that P-TMM is more versatile than ASM, as a larger variety of different backing configurations can be handled. Here it will be shown that the same universality is offered by the equivalent circuit method. PMID- 25698041 TI - The influence of pause, attack, and decay duration of the ongoing envelope on sound lateralization. AB - Klein-Hennig et al. [J. Acoust. Soc. Am. 129, 3856-3872 (2011)] introduced a class of high-frequency stimuli for which the envelope shape can be altered by independently varying the attack, hold, decay, and pause durations. These stimuli, originally employed for testing the shape dependence of human listeners' sensitivity to interaural temporal differences (ITDs) in the ongoing envelope, were used to measure the lateralization produced by fixed interaural disparities. Consistent with the threshold ITD data, a steep attack and a non-zero pause facilitate strong ITD-based lateralization. In contrast, those conditions resulted in the smallest interaural level-based lateralization. PMID- 25698042 TI - Microbubble dynamics monitoring using a dual modulation method. AB - An experimental method for characterizing microbubbles' oscillations is presented. With a Dual Frequency ultrasound excitation method, both relative and absolute microbubble size variations can be measured. Using the same experimental setup, a simple signal processing step applied to both the amplitude and the frequency modulations yields a two-fold picture of microbubbles' dynamics. In addition, assuming the occurrence of small radial oscillations, the equilibrium radius of the microbubbles can be accurately estimated. PMID- 25698043 TI - The effect of speech modification on non-native listeners for matrix-style sentences. AB - Speech can be modified to promote intelligibility in noise, but the potential benefits for non-native listeners are difficult to predict due to the additional presence of distortion introduced by speech alteration. The current study compared native and non-native listeners' keyword scores for simple sentences, unmodified and with six forms of modification. Both groups showed similar patterns of intelligibility change across conditions, with the native cohort benefiting slightly more in stationary noise. This outcome suggests that the change in masked audibility rather than distortion is the dominant factor governing listeners' responses to speech modification. PMID- 25698044 TI - Modal response of a computational vocal fold model with a substrate layer of adipose tissue. AB - This study demonstrates the effect of a substrate layer of adipose tissue on the modal response of the vocal folds, and hence, on the mechanics of voice production. Modal analysis is performed on the vocal fold structure with a lateral layer of adipose tissue. A finite element model is employed, and the first six mode shapes and modal frequencies are studied. The results show significant changes in modal frequencies and substantial variation in mode shapes depending on the strain rate of the adipose tissue. These findings highlight the importance of considering adipose tissue in computational vocal fold modeling. PMID- 25698045 TI - Disproportionate emission of bubble streams with killer whale biphonic calls: perspectives on production and function. AB - Stereotyped pulsed calls were attributed to 11 killer whales (Orcinus orca) with and without synchronous bubble streams in three datasets collected from two facilities from 1993 to 2012. Calls with and without synchronous bubble streams and divergent overlapping high frequency components ("biphonic" vs "monophonic") were compared. Subjects produced bubbles significantly more often when calls had divergent high frequency components. However, acoustic features in one biphonic call shared by five subjects provided little evidence for an acoustic effect of synchronous bubble flow. Disproportionate bubbling supported other evidence that biphonic calls form a distinct category, but suggested a function in short-range communication. PMID- 25698046 TI - Equations of motion for rays in a Snell's law medium. AB - The equations of motion for a ray in a Snell's law medium with a varying index of refraction are derived. A stratified medium is considered. Explicit expressions are given for the velocity and acceleration components of the ray. These are derived directly from Snell's law. It is further shown that the propagation of a ray can be modeled in terms of Newtonian-like equations of motion and that momentum is conserved along the interface. It is shown that Snell's law follows from this conservation law. Properties of the motion are studied and an example is given. PMID- 25698047 TI - Automatic quantitative analysis of ultrasound tongue contours via wavelet-based functional mixed models. AB - This paper illustrates the application of wavelet-based functional mixed models to automatic quantification of differences between tongue contours obtained through ultrasound imaging. The reliability of this method is demonstrated through the analysis of tongue positions recorded from a female and a male speaker at the onset of the vowels /a/ and /i/ produced in the context of the consonants /t/ and /k/. The proposed method allows detection of significant differences between configurations of the articulators that are visible in ultrasound images during the production of different speech gestures and is compatible with statistical designs containing both fixed and random terms. PMID- 25698048 TI - A corpus of noise-induced word misperceptions for Spanish. AB - Word misperceptions are valuable in designing and evaluating detailed computational models of speech perception, especially when a number of listeners agree on the misperceived word. The current paper describes the elicitation of a corpus of Spanish word misperceptions induced by different types of noise. Stimuli were presented using an adaptive procedure designed to promote the rapid discovery of misperceptions. The final corpus contains 3235 misperceptions along with speech and masker waveforms, permitting further experimental and modeling studies into the origin of each misperception. The corpus is available online as an open resource. PMID- 25698049 TI - Human cortical sensitivity to interaural level differences in low- and high frequency sounds. AB - Interaural level difference (ILD) is used as a cue in horizontal sound source localization. In free field, the magnitude of ILD depends on frequency: it is more prominent at high than low frequencies. Here, a magnetoencephalography experiment was conducted to test whether the sensitivity of the human auditory cortex to ILD is also frequency-dependent. Robust cortical sensitivity to ILD was found that could not be explained by monaural level effects, but this sensitivity did not differ between low- and high-frequency stimuli. This is consistent with previous psychoacoustical investigations showing that performance in ILD discrimination is not dependent on frequency. PMID- 25698050 TI - Dependences of ultrasonic properties on frequency and trabecular spacing in trabecular-bone-mimicking phantoms. AB - The dependences of ultrasonic properties on the frequency and the trabecular spacing were investigated in 20 trabecular-bone-mimicking phantoms consisting of cellular copper foams. The strong slow waves were consistently observed in the signals transmitted through all of the phantoms. The frequency-dependent phase velocity and attenuation coefficient of the slow wave were measured at frequencies from 0.7 to 1.3 MHz. The phase velocity decreased approximately linearly with increasing frequency while the attenuation coefficients increased with increasing frequency. The phase velocity increased monotonically with increasing trabecular spacing from 1337 to 2931 MUm while the attenuation coefficient decreased with increasing spacing. PMID- 25698051 TI - Longitudinal shear wave and transverse dilatational wave in solids. AB - Dilatation wave involves compression and extension and is known as the curl-free solution of the elastodynamic equation. Shear wave on the contrary does not involve any change in volume and is the divergence-free solution. This letter seeks to examine the elastodynamic Green's function through this definition. By separating the Green's function in divergence-free and curl-free terms, it appears first that, strictly speaking, the longitudinal wave is not a pure dilatation wave and the transverse wave is neither a pure shear wave. Second, not only a longitudinal shear wave but also a transverse dilatational wave exists. These waves are shown to be a part of the solution known as coupling terms. Their special motion is carefully described and illustrated. PMID- 25698052 TI - Mixing time prediction using spherical microphone arrays. AB - Human perception of room acoustics depends among others on the time of transition from early reflections to late reverberation in room impulse responses, which is known as mixing time. In this letter, a multi-channel mixing time prediction method is proposed, which in contrast to state-of-the-art channel-based predictors accounts for spatiotemporal properties of the sound field. The proposed diffuseness-based method is compared with existing model- and channel based prediction methods through measurements and acoustic simulations, and is shown to correlate well with the perceptual mixing time. Furthermore, insights into relations between prediction methods and mixing time definitions based on reflection density are presented. PMID- 25698053 TI - Better-ear glimpsing in hearing-impaired listeners. AB - When competing speech sounds are spatially separated, listeners can make use of the ear with the better target-to-masker ratio. Recent studies showed that listeners with normal hearing are able to efficiently make use of this "better ear," even when it alternates between left and right ears at different times in different frequency bands, which may contribute to the ability to listen in spatialized speech mixtures. In the present study, better-ear glimpsing in listeners with bilateral sensorineural hearing impairment, who perform poorly in spatialized speech mixtures, was investigated. The results suggest that this deficit is not related to better-ear glimpsing. PMID- 25698054 TI - Comparison of slope approximations used in rough surface scattering. AB - Two widely used surface slope approximations are compared to an initially exact method that treats the slopes via a differential operator acting on the characteristic function. The differential operator treatment ceases to be exact when the integrand in the scattering integrals is approximated using a Gaussian directivity approximation and Fresnel phase approximation. Analysis is restricted to the Kirchhoff approximation (single scattering). One of the simpler slope approximations agrees with the more comprehensive differential operator approximation for all backscattering geometries, as well as for specular scattering geometries down to grazing angles comparable to the source beamwidth. PMID- 25698055 TI - Structural requirements for TLR7-selective signaling by 9-(4-piperidinylalkyl)-8 oxoadenine derivatives. AB - We report the synthesis and biological evaluation of a new series of 8 oxoadenines substituted at the 9-position with a 4-piperidinylalkyl moiety. In vitro evaluation of the piperidinyl-substituted oxoadenines 3a-g in human TLR7- or TLR8-transfected HEK293 cells and in human PBMCs indicated that TLR7/8 selectivity/potency and cytokine induction can be modulated by varying the length of the alkyl linker. Oxoadenine 3f containing a 5-carbon linker was found to be the most potent TLR7 agonist and IFNalpha inducer in the series whereas 3b possessing a 1-carbon linker was the most potent TLR8 agonist. PMID- 25698056 TI - FRET study of G-quadruplex forming fluorescent oligonucleotide probes at the lipid monolayer interface. AB - Spectral properties and G-quadruplex folding ability of fluorescent oligonucleotide probes at the cationic dioctadecyldimethylammonium bromide (DODAB) monolayer interface are reported. Two oligonucleotides, a 19-mer bearing thrombin binding aptamer sequence and a 21-mer with human telomeric sequence, were end-labeled with fluorescent groups (FAM and TAMRA) to give FRET probes F19T and F21T, respectively. The probes exhibited abilities to fold into a quadruplex structure and to bind metal cations (Na(+) and K(+)). Fluorescence spectra of G quadruplex FRET probes at the monolayer interface are reported for the first time. Investigations included film balance measurements (pi-A isotherms) and fluorescence spectra recording using a fiber optic accessory interfaced with a spectrofluorimeter. The effect of the presence of DODAB monolayer, metal cations and the surface pressure of monolayer on spectral behavior of FRET probes were examined. Adsorption of probe at the cationic monolayer interface resulted in the FRET signal enhancement even in the absence of metal cations. Variation in the monolayer surface pressure exerted rather modest effect on the spectral properties of probes. The fluorescence energy transfer efficiency of monolayer adsorbed probes increased significantly in the presence of sodium or potassium ion in subphase, which indicated that the probes retained their cation binding properties when adsorbed at the monolayer interface. PMID- 25698057 TI - Evaluating anthropogenic N inputs to diverse lake basins: A case study of three Chinese lakes. AB - The environmental degradation of lakes in China has become increasingly serious over the last 30 years and eutrophication resulting from enhanced nutrient inputs is considered a top threat. In this study, a quasi-mass balance method, net anthropogenic N inputs (NANI), was introduced to assess the human influence on N input into three typical Chinese lake basins. The resultant NANI exceeded 10,000 kg N km(-2) year(-1) for all three basins, and mineral fertilizers were generally the largest sources. However, rapid urbanization and shrinking agricultural production capability may significantly increase N inputs from food and feed imports. Higher percentages of NANI were observed to be exported at urban river outlets, suggesting the acceleration of NANI transfer to rivers by urbanization. Over the last decade, the N inputs have declined in the basins dominated by the fertilizer use but have increased in the basins dominated by the food and feed import. In the foreseeable future, urban areas may arise as new hotspots for nitrogen in China while fertilizer use may decline in importance in areas of high population density. PMID- 25698058 TI - Practices, perceptions, and implications of fertilizer use in East-Central China. AB - Face-to-face interviews (n = 553) were conducted in five counties in East-Central China to study farmers' fertilizer application behaviors, decision-making processes, attitudes towards adopting better fertilizer application technologies, and environmental consciousness. The survey results revealed widespread fertilizer misapplication and highly variable application behaviors in the study regions. The lack of scientific knowledge on fertilizers and the absence of guidance from agricultural extension services have forced the farmers to rely on personal judgment and advice from fertilizer dealers and friends to make decisions in fertilizer application. Overall, farmers have been idiosyncratic in fertilizer application with limited adoption of better fertilizer application technologies. There are great potentials for reducing pollutant load from agricultural runoff through promoting scientific fertilizer application in the regions. However, farmers' diverse preferences over agricultural extension programs necessitate an integrated approach emphasizing farmer involvement throughout the development of such programs for promoting better fertilizer application practices. PMID- 25698059 TI - A highly potent human antibody neutralizes dengue virus serotype 3 by binding across three surface proteins. AB - Dengue virus (DENV) infects ~400 million people annually. There is no licensed vaccine or therapeutic drug. Only a small fraction of the total DENV-specific antibodies in a naturally occurring dengue infection consists of highly neutralizing antibodies. Here we show that the DENV-specific human monoclonal antibody 5J7 is exceptionally potent, neutralizing 50% of virus at nanogram-range antibody concentration. The 9 A resolution cryo-electron microscopy structure of the Fab 5J7-DENV complex shows that a single Fab molecule binds across three envelope proteins and engages three functionally important domains, each from a different envelope protein. These domains are critical for receptor binding and fusion to the endosomal membrane. The ability to bind to multiple domains allows the antibody to fully coat the virus surface with only 60 copies of Fab, that is, half the amount compared with other potent antibodies. Our study reveals a highly efficient and unusual mechanism of molecular recognition by an antibody. PMID- 25698060 TI - Biomarker resolution of uterine smooth muscle tumor necrosis as benign vs malignant. AB - Uterine leiomyosarcomas are rare malignant tumors with a poor prognosis while leiomyomas are common benign tumors unrelated to their malignant counterparts. Diagnostic features commonly present in leiomyosarcoma include cytologic atypia, high mitotic index, and a sarcoma-specific geographic cell death designated 'tumor cell necrosis (TCN)'. TCN has a sharp viable-nonviable boundary lacking inflammation, fibrosis or granulation tissue seen in nonspecific infarction. These characteristics are sometimes difficult to interpret on routine hematoxylin and eosin slides, and can lead to diagnostic errors. In this study, we used extracellular matrix stains to test the hypothesis that the host response which characterizes nonspecific infarction may degrade the matrix in infarcted tumor more than in TCN. A 'honeycomb' pattern of reticulin highlighted individual tumor cells in viable regions of all cases. Nonviable area of reticulin patterns differed significantly by diagnosis (P<0.001), with a honeycomb pattern maintained (91%, 20/22) in leiomyosarcoma and lost (61%, 11/18) in leiomyomas. Retention of honeycomb reticulin in nonviable areas of leiomyosarcoma occurred irrespective of the presence of inflammation, hemorrhage, fibrosis, or diffuse hyalinization. Fibrosis/hyalinization as evidenced by trichrome stain was significantly (P<0.001) more common in nonviable areas of benign leiomyomas (100%, 18/18) compared with leiomyosarcomas (36%, 8/22). In those occasions where viable tissues contained discernable polarization of mitotic activity, these decreased toward the nonviable interface in leiomyosarcoma, and had an opposite pattern in leiomyomas, increasing toward the interface. There is a significant difference in the reticulin and collagen networks of nonviable areas of leiomyosarcoma compared with leiomyoma. At the time of early injury, both retain reticulin; however, this is cleared over time in benign, but not malignant, areas of necrosis. We conclude that proliferative repair of leiomyomas at the viable nonviable interface includes remodeling of the extracellular matrix, in contrast to the static preservation of extracellular matrix ('mummification') in nonviable areas of leiomyosarcomas. PMID- 25698061 TI - DNAJB1-PRKACA is specific for fibrolamellar carcinoma. AB - Fibrolamellar carcinoma is a distinct subtype of hepatocellular carcinoma that predominantly affects young patients without underlying cirrhosis. A recurrent DNAJB1-PRKACA fusion has recently been reported in fibrolamellar carcinomas. To determine the specificity of this fusion and to develop routinely available clinical methods of detection, we developed an RT-PCR assay for paraffin-embedded tissues and a FISH probe for detection of the rearrangements of the PRKACA locus. We also developed an RNA in situ hybridization assay to assess expression levels of the total chimeric transcript and wild-type transcripts. A total of 106 primary liver tumors were studied by RT-PCR, including 26 fibrolamellar carcinomas (4 of which were metastases to the abdominal wall or lymph nodes), 25 conventional hepatocellular carcinomas, 25 cholangiocarcinomas, 25 hepatic adenomas, and 5 hepatoblastomas. RT-PCR was successful in 92% of tested fibrolamellar carcinoma cases (24/26) and the DNAJB1-PRKACA fusion transcript was found in all fibrolamellar carcinomas but not in other tumor types. FISH was tested in 19 fibrolamellar carcinomas and in 6 scirrhous hepatocellular carcinomas, which can closely mimic fibrolamellar carcinoma. Rearrangements of the PRKACA locus was seen in all 19 fibrolamellar carcinoma specimens, but in none of the scirrhous hepatocellular carcinomas. Finally, a RNA in situ hybridization strategy was positive in 7/7 successfully hybridized cases, and showed mRNA over-expression in all of the fibrolamellar carcinomas. In addition, the stromal cells embedded in the characteristic intratumoral fibrosis of fibrolamellar carcinomas and the background liver tissues were negative for the DNAJB1-PRKACA fusion by all tested methods. In conclusion, detection of DNAJB1 PRKACA is a very sensitive and specific finding in support of the diagnosis of fibrolamellar carcinoma. PMID- 25698062 TI - An international study to increase concordance in Ki67 scoring. AB - Although an important biomarker in breast cancer, Ki67 lacks scoring standardization, which has limited its clinical use. Our previous study found variability when laboratories used their own scoring methods on centrally stained tissue microarray slides. In this current study, 16 laboratories from eight countries calibrated to a specific Ki67 scoring method and then scored 50 centrally MIB-1 stained tissue microarray cases. Simple instructions prescribed scoring pattern and staining thresholds for determination of the percentage of stained tumor cells. To calibrate, laboratories scored 18 'training' and 'test' web-based images. Software tracked object selection and scoring. Success for the calibration was prespecified as Root Mean Square Error of scores compared with reference <0.6 and Maximum Absolute Deviation from reference <1.0 (log2 transformed data). Prespecified success criteria for tissue microarray scoring required intraclass correlation significantly >0.70 but aiming for observed intraclass correlation >=0.90. Laboratory performance showed non-significant but promising trends of improvement through the calibration exercise (mean Root Mean Square Error decreased from 0.6 to 0.4, Maximum Absolute Deviation from 1.6 to 0.9; paired t-test: P=0.07 for Root Mean Square Error, 0.06 for Maximum Absolute Deviation). For tissue microarray scoring, the intraclass correlation estimate was 0.94 (95% credible interval: 0.90-0.97), markedly and significantly >0.70, the prespecified minimum target for success. Some discrepancies persisted, including around clinically relevant cutoffs. After calibrating to a common scoring method via a web-based tool, laboratories can achieve high inter laboratory reproducibility in Ki67 scoring on centrally stained tissue microarray slides. Although these data are potentially encouraging, suggesting that it may be possible to standardize scoring of Ki67 among pathology laboratories, clinically important discrepancies persist. Before this biomarker could be recommended for clinical use, future research will need to extend this approach to biopsies and whole sections, account for staining variability, and link to outcomes. PMID- 25698063 TI - High fibre diet may be good alternative to complex weight loss regimen, US study finds. PMID- 25698064 TI - Long-term Safety and Antitumor Activity in the Phase 1-2 Study of Enzalutamide in Pre- and Post-docetaxel Castration-Resistant Prostate Cancer. AB - BACKGROUND: Given that some patients with castration-resistant prostate cancer (CRPC) have shown extended responses to the androgen receptor inhibitor enzalutamide, long-term safety of this drug is of interest. OBJECTIVE: To evaluate the long-term safety and antitumor activity of enzalutamide in CRPC patients. DESIGN, SETTING, AND PARTICIPANTS: This phase 1-2 study evaluated enzalutamide in 140 CRPC patients with and without prior chemotherapy. Initial findings were published in 2010. We report updated results from an additional 17 mo follow-up for antitumor activity and >4 yr for safety. INTERVENTION: Patients received 30-600mg/d oral enzalutamide. During long-term dosing, all patients were switched first to the maximum tolerated dose of 240mg/d and then to the phase 3 dose of 160mg/d. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Safety was assessed regularly. The Kaplan-Meier method was used to estimate the distributions of time to prostate-specific antigen (PSA) progression and time to radiographic progression. RESULTS AND LIMITATIONS: The safety profile of enzalutamide was consistent over time, with little change in the rates of commonly reported adverse events (AEs) or the incidence of grade 3/4 AEs. Fatigue of any grade was the most common dose-dependent AE, experienced by 70% of patients, with 14% of patients reporting grade 3/4 fatigue. The median time to PSA progression was not reached for chemotherapy-naive patients and was 45 wk for postchemotherapy patients; the corresponding median time to radiographic progression was 56 wk and 25 wk. CONCLUSIONS: Enzalutamide showed durable antitumor activity in chemotherapy-naive and postchemotherapy patients, and was well tolerated, even in patients treated for 4 yr. PATIENT SUMMARY: Enzalutamide was active against prostate cancer and was well tolerated, even for up to 4 yr of treatment, supporting its potential for long-term use in men with prostate cancer. Fatigue was the most common side effect, occurring at varying degrees of severity in most patients. PMID- 25698065 TI - Five-year analysis of a multi-institutional prospective clinical trial of delayed intervention and surveillance for small renal masses: the DISSRM registry. AB - BACKGROUND: A growing body of retrospective literature is emerging regarding active surveillance (AS) for patients with small renal masses (SRMs). There are limited prospective data evaluating the effectiveness of AS compared to primary intervention (PI). OBJECTIVE: To determine the characteristics and clinical outcomes of patients who chose AS for management of their SRM. DESIGN, SETTING, AND PARTICIPANTS: From 2009 to 2014, the multi-institutional Delayed Intervention and Surveillance for Small Renal Masses (DISSRM) registry prospectively enrolled 497 patients with solid renal masses <=4.0cm who chose PI or AS. INTERVENTION: AS versus PI. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The registry was designed and powered as a noninferiority study based on historic recurrence rates for PI. Analyses were performed in an intention-to-treat manner. Primary outcomes were overall survival (OS) and cancer-specific survival (CSS). RESULTS AND LIMITATIONS: Of the 497 patients enrolled, 274 (55%) chose PI and 223 (45%) chose AS, of whom 21 (9%) crossed over to delayed intervention. AS patients were older, had worse Eastern Cooperative Oncology Group scores, total comorbidities, and cardiovascular comorbidities, had smaller tumors, and more often had multiple and bilateral lesions. OS for PI and AS was 98% and 96% at 2 yr, and 92% and 75% at 5 yr, respectively (log rank, p=0.06). At 5 yr, CSS was 99% and 100% for PI and AS, respectively (p=0.3). AS was not predictive of OS or CSS in regression modeling with relatively short follow-up. CONCLUSIONS: In a well-selected cohort with up to 5 yr of prospective follow-up, AS was not inferior to PI. PATIENT SUMMARY: The current report is among the first prospective analyses of patients electing for active surveillance of a small renal mass. Discussion of active surveillance should become part of the standard discussion for management of small renal masses. PMID- 25698066 TI - Molecular dynamics simulations of proton-ordered water confined in low-diameter carbon nanotubes. AB - The present work deals with molecular dynamics simulations of water confined in single-walled carbon nanotubes (CNTs), with emphasis on the proton-ordering of water and its polarization. First, the water occupancy of open-ended armchair and zigzag CNTs immersed in water under ambient NPT conditions is calculated for various water models, and for varying Lennard-Jones parameters of the water carbon interaction. As a function of the CNT diameter, the water density displays several oscillations before converging to the bulk value. Based on these results, the water structures encapsulated in 10 nm long armchair CNTs (n,n) with 5 <= n <= 10, are investigated under NVT conditions. Inside the smallest nanotubes (n = 5, 6) highly ferroelectric (FE), quasi-one-dimensional water chains are found while inside the other CNTs water molecules assemble into single-walled ice nanotubes (INTs). There are several, near-degenerate minimum energy INT structures: single helical structures were found for 7 <= n <= 10, in all cases in FE arrangement. In addition, a double helical INT structure was found for n = 8 with an even higher polarization. Prism-like structures were found only for 8 <= n <= 10 with various FE, ferrielectric (FI), and antiferroelectric (AF, n = 9, 10) proton ordering. The coexistence of the nearly iso-energetic FE, FI, and AF INT structures separated by high barriers renders the molecular dynamics highly metastable, typically with nanosecond timescales at room temperature. Hence, the replica exchange simulation method is used to obtain populations of different INT states at finite temperatures. Many of the FE INT structures confined in low diameter CNTs are still prevalent at room temperature. Both helix-helix and helix prism structural transitions are detected which can be either continuous (around 470 K for n = 8) or discontinuous (at 218 K for n = 9). Also melting-like transitions are found in which the INT structures are disrupted leading to a loss of FE or FI ordering of the water orientations. Also these transitions can be either smooth (for n = 7, 8) or abrupt, first-order transitions, at T = 362 K for n = 9 and at T = 285 K for n = 10. PMID- 25698067 TI - Alpha, beta and gamma Human Papillomaviruses in the anal canal of HIV-infected and uninfected men who have sex with men. AB - OBJECTIVES: Anal infection by cutaneous Human Papillomaviruses (HPV) has been rarely investigated. We aimed to assess the prevalence, genotype diversity, and determinants of mucosal (alpha) and cutaneous (beta and gamma) anal HPV infection in men who have sex with men (MSM). METHODS: Anal samples were collected with a Dacron swab. Alpha HPVs were detected using the Linear Array HPV genotyping test, while beta and gamma HPVs using a PCR combined with Luminex technology. RESULTS: A total of 609 MSM (437 HIV-uninfected and 172 HIV-infected, most of which were undergoing cART) were enrolled. Alpha, beta, and gamma HPVs were detected in 78.0%, 27.6% and 29.3% of the participants. Only alpha HPV prevalence was significantly higher among HIV-infected compared to uninfected MSM (93.0% vs. 72.1%, p < 0.0001). Beta2 and gamma10 represented the most frequent cutaneous HPV species, with no significant differences between HIV-infected and uninfected individuals. The most common alpha, beta, and gamma genotypes were HPV16, HPV111, HPV121, respectively. Alpha HPV infection was significantly associated with lifetime number of partners, receptive anal sex, and HIV status. Beta and/or gamma HPV infection showed no significant association with HIV status, socio demographic or sexual behavioral factors. CONCLUSIONS: A wide spectrum of mucosal and cutaneous HPV types is present in the anal canal. Only mucosal HPV prevalence increased significantly in cases of concomitant HIV infection. PMID- 25698068 TI - Comparison of Single-fraction and Multi-fraction Stereotactic Radiotherapy for Patients with 18F-fluorodeoxyglucose Positron Emission Tomography-staged Pulmonary Oligometastases. AB - AIM: To compare outcomes of single-fraction and multi-fraction stereotactic ablative body radiotherapy (SABR) for pulmonary metastases. MATERIALS AND METHODS: A retrospective review from two academic institutions of patients with one to three pulmonary metastases staged with (18)F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) scans. For single-fraction SABR, 26 Gy was prescribed for peripheral targets and 18 Gy for central targets. In the multi-fraction cohort, 48 Gy/4 or 50 Gy/5 was prescribed for peripheral targets and 50 Gy/5 was prescribed for central targets. Three-dimensional conformal radiotherapy (3D-CRT), intensity-modulated radiotherapy (IMRT) and volumetric-modulated arc therapy (VMAT) plans were delivered using heterogeneity corrections. Conformity indices at an intermediate dose (R50%) and at a high dose (R100%) were used to assess a relationship with the planning target volume (PTV). Overall survival, local and distant progression and toxicity rates were analysed from the date of treatment completion. RESULTS: Between February 2010 and June 2013, 65 patients with 85 pulmonary metastases were reviewed. The median follow up was 2.1 years. Metastases most commonly originated from colorectal cancer (31%), followed by non-small cell lung cancer (25%). 3D-CRT was used in 52 targets, IMRT in 21 and VMAT in 12. 3D-CRT showed a lower median R50% (P=0.01), but a higher median R100% than IMRT/VMAT (P=0.04). The R50% index was inversely correlated to the PTV with all techniques (P=0.01). Overall survival at 1 and 2 years in all patients was 93% (95% confidence interval 87-100%) and 71% (95% confidence interval 58-86%), respectively. The 2 year freedom from local and distant progression was 93% (95% confidence interval 86-100%) and 38% (95% confidence interval 27-55%), respectively. There were no significant differences between overall survival (P=0 .14), time to distant progression (P=0.06) or toxicity rates (P=0.75) between single- and multi-fraction cohorts. CONCLUSION: We report comparable local control, overall survival and toxicity rates between single-fraction and multi-fraction SABR treatments in patients with FDG-PET staged pulmonary oligometastases. We propose a guideline for R50% conformity incorporating 3D-CRT/IMRT/VMAT techniques with heterogeneity corrected planning algorithms. PMID- 25698069 TI - The effects of verbal information and approach-avoidance training on children's fear-related responses. AB - BACKGROUND AND OBJECTIVES: This study examined the effects of verbal information and approach-avoidance training on fear-related cognitive and behavioural responses about novel animals. METHODS: One hundred and sixty children (7-11 years) were randomly allocated to receive: a) positive verbal information about one novel animal and threat information about a second novel animal (verbal information condition); b) approach-avoidance training in which they repeatedly pushed away (avoid) or pulled closer (approach) pictures of the animals (approach avoidance training), c) a combined condition in which verbal information was given prior to approach-avoidance training (verbal information + approach avoidance training) and d) a combined condition in which approach-avoidance training was given prior to verbal information (approach-avoidance training + verbal information). RESULTS: Threat and positive information significantly increased and decreased fear beliefs and avoidance behaviour respectively. Approach-avoidance training was successful in training the desired behavioural responses but had limited effects on fear-related responses. Verbal information and both combined conditions resulted in significantly larger effects than approach-avoidance training. We found no evidence for an additive effect of these pathways. LIMITATIONS: This study used a non-clinical sample and focused on novel animals rather than animals about which children already had experience or established fears. The study also compared positive information/approach with threat information/avoid training, limiting specific conclusions regarding the independent effects of these conditions. CONCLUSIONS: The present study finds little evidence in support of a possible causal role for behavioural response training in the aetiology of childhood fear. However, the provision of verbal information appears to be an important pathway involved in the aetiology of childhood fear. PMID- 25698071 TI - Conceptual framework for model-based analysis of residence time distribution in twin-screw granulation. AB - Twin-screw granulation is a promising continuous alternative for traditional batchwise wet granulation processes. The twin-screw granulator (TSG) screws consist of transport and kneading element modules. Therefore, the granulation to a large extent is governed by the residence time distribution within each module where different granulation rate processes dominate over others. Currently, experimental data is used to determine the residence time distributions. In this study, a conceptual model based on classical chemical engineering methods is proposed to better understand and simulate the residence time distribution in a TSG. The experimental data were compared with the proposed most suitable conceptual model to estimate the parameters of the model and to analyse and predict the effects of changes in number of kneading discs and their stagger angle, screw speed and powder feed rate on residence time. The study established that the kneading block in the screw configuration acts as a plug-flow zone inside the granulator. Furthermore, it was found that a balance between the throughput force and conveying rate is required to obtain a good axial mixing inside the twin-screw granulator. Although the granulation behaviour is different for other excipients, the experimental data collection and modelling methods applied in this study are generic and can be adapted to other excipients. PMID- 25698070 TI - Familiality and SNP heritability of age at onset and episodicity in major depressive disorder. AB - BACKGROUND: Strategies to dissect phenotypic and genetic heterogeneity of major depressive disorder (MDD) have mainly relied on subphenotypes, such as age at onset (AAO) and recurrence/episodicity. Yet, evidence on whether these subphenotypes are familial or heritable is scarce. The aims of this study are to investigate the familiality of AAO and episode frequency in MDD and to assess the proportion of their variance explained by common single nucleotide polymorphisms (SNP heritability). METHOD: For investigating familiality, we used 691 families with 2-5 full siblings with recurrent MDD from the DeNt study. We fitted (square root) AAO and episode count in a linear and a negative binomial mixed model, respectively, with family as random effect and adjusting for sex, age and center. The strength of familiality was assessed with intraclass correlation coefficients (ICC). For estimating SNP heritabilities, we used 3468 unrelated MDD cases from the RADIANT and GSK Munich studies. After similarly adjusting for covariates, derived residuals were used with the GREML method in GCTA (genome-wide complex trait analysis) software. RESULTS: Significant familial clustering was found for both AAO (ICC = 0.28) and episodicity (ICC = 0.07). We calculated from respective ICC estimates the maximal additive heritability of AAO (0.56) and episodicity (0.15). SNP heritability of AAO was 0.17 (p = 0.04); analysis was underpowered for calculating SNP heritability of episodicity. CONCLUSIONS: AAO and episodicity aggregate in families to a moderate and small degree, respectively. AAO is under stronger additive genetic control than episodicity. Larger samples are needed to calculate the SNP heritability of episodicity. The described statistical framework could be useful in future analyses. PMID- 25698072 TI - Monofluorophosphate is a selective inhibitor of respiratory sulfate-reducing microorganisms. AB - Despite the environmental and economic cost of microbial sulfidogenesis in industrial operations, few compounds are known as selective inhibitors of respiratory sulfate reducing microorganisms (SRM), and no study has systematically and quantitatively evaluated the selectivity and potency of SRM inhibitors. Using general, high-throughput assays to quantitatively evaluate inhibitor potency and selectivity in a model sulfate-reducing microbial ecosystem as well as inhibitor specificity for the sulfate reduction pathway in a model SRM, we screened a panel of inorganic oxyanions. We identified several SRM selective inhibitors including selenate, selenite, tellurate, tellurite, nitrate, nitrite, perchlorate, chlorate, monofluorophosphate, vanadate, molydate, and tungstate. Monofluorophosphate (MFP) was not known previously as a selective SRM inhibitor, but has promising characteristics including low toxicity to eukaryotic organisms, high stability at circumneutral pH, utility as an abiotic corrosion inhibitor, and low cost. MFP remains a potent inhibitor of SRM growing by fermentation, and MFP is tolerated by nitrate and perchlorate reducing microorganisms. For SRM inhibition, MFP is synergistic with nitrite and chlorite, and could enhance the efficacy of nitrate or perchlorate treatments. Finally, MFP inhibition is multifaceted. Both inhibition of the central sulfate reduction pathway and release of cytoplasmic fluoride ion are implicated in the mechanism of MFP toxicity. PMID- 25698073 TI - Single-crystalline In2S3 nanowire-based flexible visible-light photodetectors with an ultra-high photoresponse. AB - With a band gap of 2.28 eV, In2S3 is an excellent candidate for visible-light sensitive photodetectors. By growing single-crystalline In2S3 nanowires via a simple CVD method, we report the fabrication of high-performance single-crystal In2S3 nanowire-based flexible photodetectors. The as-fabricated flexible photodetectors exhibited an ultra-high Ion/Ioff ratio up to 10(6) and a high sensitivity to visible incident light with responsivity and quantum efficiency as high as 7.35 * 10(4) A W(-1) and 2.28 * 10(7)%, respectively. Besides, the flexible photodetectors were demonstrated to possess a robust flexibility and excellent stability. With these favorable merits, In2S3 nanowires are believed to have a promising future in the application of high performance and flexible integrated optoelectronic devices. PMID- 25698074 TI - Next-generation sequencing identified microRNAs that associate with motile aeromonad septicemia in grass carp. AB - MicroRNAs (miRNAs) modulate many biological processes and can be up-or down regulated in a variety of diseases states, including in bacterial infection. In this study, we characterized miRNAs associated with susceptibility or resistance to motile Aeromonas hydrophila in grass carp (Ctenopharyngodon idella), a commercially important farmed fish species in China. Using Illumina next generation sequencing, we detected 185 miRNAs in A. hydrophila-susceptible (SGC) and -resistant grass carp (RGC) during immune activation. Twenty-one miRNAs were found to be differentially expressed between SGC and RGC, with 23.8% (5 out 21) exhibiting elevated expression in SGC. Further investigation of a selected five miRNAs indicated differences in the timing and tissue sources of expression. Target genes likely regulated by these miRNAs were identified using computational prediction combined with transcriptome expression data. MiRNA targets of differentially expressed mRNAs included those with functions important for bacterial resistance, such as tlr4 and nfil3-6. In addition, we demonstrated that nfil3-6 and tlr4 genes are direct targets of let-7i and cid-miRn-118. The present study suggested that the multiple miRNAs, displaying diverse kinetics and tissue sources on antibacterial immune processes. PMID- 25698075 TI - Ageist attitudes block young adults' ability for compassion toward incapacitated older adults. AB - BACKGROUND: Upon encountering older adults, individuals display varying degrees of prosocial attitudes and behaviors. While some display compassion and empathy, others draw away and wish to maintain their distance from them. The current study examined if and how ageist attitudes influence the association between the sight of physical incapacity in older age and compassionate reactions toward them. We predicted that ageist attitudes would interfere with the ability to respond to them with compassion. METHODS: Young adults (N = 149, ages 19-29) were randomly distributed into two experimental conditions, each viewing a short video portraying different aspects of older adult physicality; one group viewed older adults displaying incapacitated behavior, and the other viewed fit behavior. Participants subsequently filled out scales assessing aging anxieties, and ageist and compassionate attitudes. RESULTS: Ageism was associated with reduced compassion toward the figures. Moreover, viewing incapacitated older adults led to increased concern toward them and perceived efficacy in helping them. However, significant interactions proved that higher scores of ageism in response to the videos led to increased need for distance and reduced efficacy toward incapacitated adults, an effect not observed among subjects with lower ageism scores. CONCLUSIONS: Ageism seems to be a factor which disengages individuals from older adults displaying fragility, leading them to disregard social norms which dictate compassion. The results are discussed from the framework of terror management theory, as increased mortality salience and death-related thoughts could have led to the activation of negative attitudes which, in turn, reduce compassion. PMID- 25698076 TI - Not Just Horsing Around: The Impact of Equine-Assisted Learning on Levels of Hope and Depression in At-Risk Adolescents. AB - Equine-assisted learning (EAL) is an experiential modality which utilizes horses to provide a unique learning experience for personal growth. Research by Damon et al. (Appl Dev Sci 7:119-128, 2003) suggests a positive relationship between hope and positive developmental trajectories. Hagen et al. (Am J Orthopsychiatr 75:211 219, 2005) showed hope to be a protective factor associated with adaptive functioning in at-risk youth. Ashby et al. (J Couns Dev 89:131-139, 2011) found a significant inverse relationship between hope and depression: as hope increases, depression decreases. The current study investigates the impact of a non-riding EAL curriculum entitled L.A.S.S.O. (Leading Adolescents to Successful School Outcomes) on levels of hope and depression in at-risk youth. The study uses an experimental design with longitudinal, repeated measures. Participants were randomly assigned to treatment and control groups. Participants in the treatment received 5 weeks of EAL, while participants in the control group received treatment as usual. Repeated measures ANOVA of participants' levels of hope and depression showed statistically significant improvements in the treatment group as compared with the control group. Even a brief (5-week) intervention of EAL had a positive impact on the lives and attitudes of at-risk adolescents, with increased levels of hope and decreased levels of depression. PMID- 25698077 TI - Open abdominal surgery: a risk factor for future laparoscopic surgery? AB - BACKGROUND: This study seeks to investigate the outcomes of laparoscopic procedures in patients with previous open abdominal surgery. METHODS: Using data from the National Surgical Quality Improvement Program (2005 to 2009), we identified patients who had undergone laparoscopic cholecystectomy, Nissen fundoplication, Heller myotomy, splenectomy, Roux-en-Y, sleeve gastrectomy, gastric band, appendectomy, or colectomy. Patients were then classified as to whether adhesiolysis (AD) was also carried out. Bivariate and multivariate analysis was used to compare groups. RESULTS: A total of 162,415 patients met our inclusion criteria, comprising 4,501 (3%) in the AD group and 157,913 (97%) in the nonadhesiolysis (NAD) group. Patient who had received lysis of adhesion were older, had 41% higher odds of overall complications, 17% higher adjusted mean lysis of adhesion (P < .001), and 26% higher adjusted mean operation duration (P < .001). CONCLUSIONS: A history of previous open abdominal surgery increases the potential complication rate and hospital length of stay during subsequent laparoscopic surgery. The extent of this relationship deserves further investigation. PMID- 25698078 TI - Dissolution thermodynamics and solubility of silymarin in PEG 400-water mixtures at different temperatures. AB - An isothermal method was used to measure the solubility of silymarin in binary polyethylene glycol 400 (PEG 400) + water co-solvent mixtures at temperatures T = 298.15-333.15 K and pressure p = 0.1 MPa. Apelblat and Yalkowsky models were used to correlate experimental solubility data. The mole fraction solubility of silymarin was found to increase with increasing the temperature and mass fraction of PEG 400 in co-solvent mixtures. The root mean square deviations were observed in the range of 0.48-5.32% and 1.50-9.65% for the Apelblat equation and Yalkowsky model, respectively. The highest and lowest mole fraction solubility of silymarin was observed in pure PEG 400 (0.243 at 298.15 K) and water (1.46 * 10(-5) at 298.15 K). Finally, thermodynamic parameters were determined by Van't Hoff and Krug analysis, which indicated an endothermic and spontaneous dissolution of silymarin in all co-solvent mixtures. PMID- 25698079 TI - Emotional eating and Pavlovian learning: does negative mood facilitate appetitive conditioning? AB - OBJECTIVE: Emotional eating has been suggested to be a learned behaviour; more specifically, classical conditioning processes might be involved in its development. In the present study we investigated whether a negative mood facilitates appetitive conditioning and whether trait impulsivity influences this process. METHOD: After undergoing either a negative or neutral mood induction, participants were subjected to a differential classical conditioning procedure, using neutral stimuli and appetizing food. Two initially neutral distinctive vases with flowers were (CS+) or were not (CS-) paired with chocolate mousse intake. We measured participants' expectancy and desire to eat (4 CS+ and 4 CS- trials), salivation response, and actual food intake. The BIS-11 was administered to assess trait impulsivity. RESULTS: In both mood conditions, participants showed a classically conditioned appetite. Unexpectedly, there was no evidence of facilitated appetitive learning in a negative mood with regard to expectancy, desire, salivation, or intake. However, immediately before the taste test, participants in the negative mood condition reported a stronger desire to eat in the CS+ compared to the CS- condition, while no such effect occurred in the neutral group. An effect of impulsivity was found with regard to food intake in the neutral mood condition: high-impulsive participants consumed less food when presented with the CS+ compared to the CS-, and also less than low-impulsive participants. DISCUSSION: An alternative pathway to appetitive conditioning with regard to emotions is that it is not the neutral stimuli, but the emotions themselves that become conditioned stimuli and elicit appetitive responses. PMID- 25698080 TI - An experimental field study of weight salience and food choice. AB - Laboratory research has found that individuals will consume more calories and make unhealthy food choices when in the presence of an overweight individual, sometimes even regardless of what that individual is eating. This study expanded these laboratory paradigms to the field to examine how weight salience influences eating in the real world. More specifically, we tested the threshold of the effect of weight salience of food choice to see if a more subtle weight cue (e.g., images) would be sufficient to affect food choice. Attendees (N = 262) at Obesity Week 2013, a weight-salient environment, viewed slideshows containing an image of an overweight individual, an image of a thin individual, or no image (text only), and then selected from complimentary snacks. Results of ordinal logistic regression analysis showed that participants who viewed the image of the overweight individual had higher odds of selecting the higher calorie snack compared to those who viewed the image of the thin individual (OR = 1.77, 95% CI = [1.04, 3.04]), or no image (OR = 2.42, 95% CI = [1.29, 4.54]). Perceiver BMI category did not moderate the influence of image on food choice, as these results occurred regardless of participant BMI. These findings suggest that in the context of societal weight salience, weight-related cues alone may promote unhealthy eating in the general public. PMID- 25698081 TI - Gender differences in risk factors of benign vocal fold disease in Korea: the fifth Korea National Health and Nutritional Examination Survey. AB - The aim of this study was to confirm the prevalence rate of benign vocal fold disease (BVFD) based on gender in the Korean adult population and investigate potential risk factors of BVFD. Subjects were 8,677 non-institutionalized civilian adults over the age of 19 (3,788 males and 4,899 females) who completed the laryngeal examination of the fifth Korea National Health and Nutrition Examination Survey. Poisson regression analyses were conducted to examine the potential risk factors of BVFD. The prevalence rates of BVFD were similar in men (2.7%) and women (2.6%). When adjusted for covariates, men with self-reported voice problems had a 6.7 times greater risk (RR 6.72, 95% CI 4.17-10.84) of BVFD (P < 0.01). In addition, women with self-reported voice problems (RR 4.71, 95% CI 3.01-7.37) and current smokers (RR 1.97, 95% CI 1.01-3.81) were more likely to have BVFD (P < 0.01). There are gender differences in the risk factors of BVFD. In order to prevent BVFD, the enactment of guidelines reflecting gender differences is required. PMID- 25698082 TI - Activated mutant p110alpha causes endometrial carcinoma in the setting of biallelic Pten deletion. AB - PTEN and PIK3CA mutations occur with high frequency in uterine endometrioid carcinoma (UEC). Although PTEN mutations are present in complex atypical hyperplasia and carcinoma, PIK3CA mutations are restricted to carcinoma. We generated mouse models harboring Pten loss and/or activated Pik3ca in the endometrial epithelium to investigate their respective roles in the pathogenesis of UEC. Presence of an activated mutant Pik3ca on the background of Pten loss led to aggressive disease, with 100% of mice exhibiting carcinoma. Expression of Pik3ca with E545K mutation alone was unable to cause hyperplasia or cancer in the uterus and did not activate Akt as effectively as Pten deletion in short-term cultures of mouse endometrial epithelium, likely explaining the lack of phenotype in vivo. We also report that nuclear localization of FOXO1 correlated with PTEN mutational status irrespective of the PIK3CA status in endometrial cancer cell lines. Furthermore, gene expression profiles resulting from Pten loss or activation of Pik3ca in primary mouse endometrial epithelial cells exhibit minimal overlap. Thus, Pten and Pik3ca have distinct consequences on the activation of the phosphatidylinositol 3-kinase pathway in endometrial epithelium and are likely to affect other nonoverlapping cellular mechanisms involved in the development and progression of the most common type of uterine cancer. PMID- 25698083 TI - Nose-To-Brain Delivery of PLGA-Diazepam Nanoparticles. AB - The objective of the present investigation was to optimize diazepam (Dzp)-loaded poly(lactic-co-glycolic acid) nanoparticles (NP) to achieve delivery in the brain through intranasal administration. Dzp nanoparticles (DNP) were formulated by nanoprecipitation and optimized using Box-Behnken design. The influence of various independent process variables (polymer, surfactant, aqueous to organic (w/o) phase ratio, and drug) on resulting properties of DNP (z-average and drug entrapment) was investigated. Developed DNP showed z-average 148-337 d.nm, polydispersity index 0.04-0.45, drug entrapment 69-92%, and zeta potential in the range of -15 to -29.24 mV. Optimized DNP were further analyzed by differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), ex vivo drug release, and in-vitro cytotoxicity. Ex-vivo drug release study via sheep nasal mucosa from DNP showed a controlled release of 64.4% for 24 h. 3-[4,5 Dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay performed on Vero cell line showed less toxicity for DNP as compared to Dzp suspension (DS). Gamma scintigraphy and biodistribution study of DNP and DS was performed on Sprague-Dawley rats using technetium-99m-labeled ((99m)Tc) Dzp formulations to investigate the nose-to-brain drug delivery pathway. Brain/blood uptake ratios, drug targeting efficiency, and direct nose-to-brain transport were found to be 1.23-1.45, 258, and 61% for (99m)Tc-DNP (i.n) compared to (99m)Tc-DS (i.n) (0.38 1.06, 125, and 1%). Scintigraphy images showed uptake of Dzp from nose-to-brain, and this observation was in agreement with the biodistribution results. These results suggest that the developed poly(D,L-lactide-co-glycolide) (PLGA) NP could serve as a potential carrier of Dzp for nose-to-brain delivery in outpatient management of status epilepticus. PMID- 25698084 TI - Solvent Effect on the Photolysis of Riboflavin. AB - The kinetics of photolysis of riboflavin (RF) in water (pH 7.0) and in organic solvents (acetonitrile, methanol, ethanol, 1-propanol, 1-butanol, ethyl acetate) has been studied using a multicomponent spectrometric method for the assay of RF and its major photoproducts, formylmethylflavin and lumichrome. The apparent first-order rate constants (k obs) for the reaction range from 3.19 (ethyl acetate) to 4.61 * 10(-3) min(-1) (water). The values of k obs have been found to be a linear function of solvent dielectric constant implying the participation of a dipolar intermediate along the reaction pathway. The degradation of this intermediate is promoted by the polarity of the medium. This indicates a greater stabilization of the excited-triplet states of RF with an increase in solvent polarity to facilitate its reduction. The rate constants for the reaction show a linear relation with the solvent acceptor number indicating the degree of solute solvent interaction in different solvents. It would depend on the electron donating capacity of RF molecule in organic solvents. The values of k obs are inversely proportional to the viscosity of the medium as a result of diffusion controlled processes. PMID- 25698085 TI - Facilitators, barriers and expectations in the self-management of type 2 diabetes -a qualitative study from Portugal. AB - BACKGROUND: Patients with type 2 diabetes mellitus (DM) have a central role in managing their disease, but the effective adoption of self-management behaviours is often challenging. OBJECTIVES: The main objective of this study was to assess the facilitators, barriers and expectations in the self-management of type 2 DM, as perceived by patients. METHODS: Patients with type 2 DM were recruited at the Portuguese Diabetes Association outpatient clinic, using a convenient sampling technique. Qualitative data was obtained using video-recorded focus groups. Each session had a moderator and an observer, and followed a pre-tested questioning route. Two independent researchers transcribed and analysed the focus groups. RESULTS: Three major themes were identified: diet, physical exercise, and glycaemic control. Difficulties in changing dietary habits were grouped in four main categories: decisional, food quality, food quantity, and dietary schedule. Barriers related to physical exercise also included decisional aspects, as well as fatigue, muscle and joint pain, and other co-morbidities. Information and knowledge translation, as well as family and social ties, were commonly explored aspects across the three themes and were regarded as facilitators in some situations and as barriers in others. CONCLUSION: This study provided new insight on the barriers, facilitators and expectations in type 2 DM self-management, pointing out the importance of tailored guidance. Future research should explore interventions designed to promote and facilitate behaviour change in this population. PMID- 25698086 TI - An epidemic model with a multistage vaccine. AB - Many diseases, such as the seasonal flu, tetanus, and smallpox, can be vaccinated against with a single dose of a vaccine. However, some diseases require multiple doses of a vaccine for immunity. For example, Hepatitis B requires three doses of a vaccine, with the second occurring about 1 month after the first and the third occurring about 5 months after the second, for immunity. Diseases requiring a multistage vaccine such as Hepatitis B can have extra complications with its vaccination program, as some who start the doses may forget to complete the program or could become infected before completing the program. This article concerns the setup and analysis of a model for disease spread with a multistage vaccine available to investigate how effective such a vaccine would be at establishing herd immunity for the disease as well as establishing the short-term and long-term effects of such a vaccine. PMID- 25698087 TI - The benefit of revascularization in nonagenarians with lower limb ischemia is limited by high mortality. AB - OBJECTIVE/BACKGROUND: Owing to the increased life expectancy of the population the number of very old patients referred to vascular surgical units has increased. Advanced age is a well known risk factor in patients undergoing surgical interventions for lower limb ischemia. However, amputation performed on an elderly person living independently will lead to permanent institutional care. The aim of this study was to evaluate the outcome of patients aged 90 years and older with lower limb ischemia undergoing surgical or endovascular revascularization. METHODS: Two hundred and thirty-three nonagenarians with either chronic critical limb ischemia (CLI) or acute limb ischemia (ALI) who underwent revascularization at the authors' institution between 2002 and 2013 were included in this retrospective study. Risk factors were evaluated and survival, limb salvage, and amputation free survival (AFS) assessed. RESULTS: The median age of the study population was 92 years (range 90-100 years). The majority (81.1%) of the patients were female. One in four (24.5%) patients had diabetes, and the incidence of coronary artery disease was 79.8%. Seventy-three percent of the patients had CLI and 27% of had ALI. Seventy percent of the patients underwent surgical revascularization and 30% were treated endovascularly. The majority (72.5%) of the patients maintained their independent living status; 27.5% ended up in institutional care post-operatively. Similarly, the majority (82.0%) of the patients maintained their walking ability, while 18% were not able to ambulate independently after revascularization. One year survival, limb salvage, and AFS rates were 50.9% versus 48.6% (p = .505), 85.1% versus 87.0% (p = .259), and 45.7% versus 44.4% (p = .309) in the surgical versus endovascular group, respectively. Dementia was an independent risk factor of poor AFS (odds ratio: 1.56; 95% confidence interval: 1.077-2.272; p = .019). CONCLUSION: Good limb salvage can be achieved by both surgical and endovascular revascularization, and independent living can be maintained in the majority of the patients. However, the benefit of revascularization is limited owing to high mortality, especially in patients with dementia. PMID- 25698088 TI - Identification of HPV integration and gene mutation in HeLa cell line by integrated analysis of RNA-Seq and MS/MS data. AB - HeLa cell line, which was derived from cervical carcinoma, provides an idea platform to study both the integration of human papillomavirus and the massive mutations occurring on the cancer cell genome. Proteogenomics is a field with the intersection of proteomics and genomics to perform gene annotation and identify gene mutation. In this work, we first identified the SNV/INDEL, structural variation (SV), and virus infection/integration events from RNA-Seq data of HeLa cell line; then, by applying proteogenomics strategy, we were able to detect some of the genomic events with the tandem mass spectrometry (MS/MS) data from the same sample. Furthermore, some of the mutated peptides were experimentally validated using multiple reaction monitoring technology. The integrated analysis of the RNA-Seq and MS/MS data not only renders the discovery of HeLa cell genome variations more credible but also illustrates a practical workflow for protein coding mutation discovery in cancer-related studies. PMID- 25698089 TI - A novel reduction-sensitive modified polyethylenimine oligonucleotide vector. AB - A reduction-sensitive cross-linked polyethylenimine derivative PEI-SS-OA was synthesized and evaluated for oligonucleotide delivery. PEI-SS-OA was shown to condense LOR-2501, an oligonucleotide targeting ribonucleotide reductase R1 subunit (RRM1), into positively charged complexes. The reductive degradation of the PEI-SS-OA induced by dithiothreitol was confirmed by a gel retardation assay. In vitro experiments revealed that the reduction-sensitive PEI-SS-OA was less cytotoxic and more effective in oligonucleotide delivery than the control 25kDa PEI. This study demonstrates that a reducibly degradable cationic polymer PEI-SS OA possesses both higher oligonucleotide delivery efficiency and lower cytotoxicity than PEI (25 kDa), therefore is an attractive candidate for further in vivo evaluation. PMID- 25698090 TI - Corrigendum: Targeting a portion of central European spider diversity for permanent preservation. AB - [This corrects the article DOI: 10.3897/BDJ.1.e980.]. PMID- 25698091 TI - Thoracic manifestations of paradoxical immune reconstitution inflammatory syndrome during or after antituberculous therapy in HIV-negative patients. AB - Immune reconstitution inflammatory syndrome (IRIS) is a consequence of exaggerated and dysregulated host's inflammatory response to invading microorganism, leading to uncontrolled inflammatory reactions. IRIS associated with tuberculosis (TB) is well recognized among human immunodeficiency virus (HIV)-infected patients receiving highly active antiretroviral therapy, but it is less common among HIV-negative patients. IRIS can manifest as a paradoxical worsening or recurring of preexisting tuberculous lesions or development of new lesions despite successful antituberculous treatment. Hence, the condition might be misdiagnosed as superimposed infections, treatment failure, or relapse of TB. This pictorial essay reviewed diagnostic criteria and various thoracic manifestations of the paradoxical form of TB-associated IRIS (TB-IRIS) that might aid in early recognition of this clinical entity among HIV-negative patients. The treatment and outcomes of TB-IRIS were also discussed. PMID- 25698092 TI - Percutaneous transluminal balloon angioplasty in stenosis of native hemodialysis arteriovenous fistulas: technical success and analysis of factors affecting postprocedural fistula patency. AB - PURPOSE: We aimed to determine the predictors of technical success and patency after percutaneous transluminal angioplasty (PTA) of de novo dysfunctional hemodialysis arteriovenous fistulas (AVF). METHODS: We performed a retrospective analysis of first time PTA in 228 patients (129 men, 99 women; mean age, 56.8+/ 14.6 years). Anatomical (location, length, grade, and number of stenoses) and clinical variables (sex, age, prior AVF, diabetes mellitus, AVF age, side, and location) were reviewed. RESULTS: A total of 330 stenoses were found in 228 patients. PTA was technically successful in 96.3% of the stenoses (n=319). Clinical success was achieved in 97.2% (n=321). Early dysfunction (within six months) was positively correlated with patient age (P < 0.001) and diabetes (P < 0.005). Older age (P < 0.001) and diabetes (P = 0.002) were associated with a lower primary patency rate. Patient age (P %lt; 0.001), presence of diabetes (P = 0.023), length of stenosis (P = 0.003), early recurrence (P = 0.003) and presence of residual stenosis (P = 0.014) were associated with a lower secondary patency rate. CONCLUSION: Patency of dysfunctional hemodialysis fistulas can be maintained safely with continuous follow-up and repeated interventions without shortening the venous segment by surgical revision. Percutaneous approach to hemodialysis access stenosis is an alternative to the conventional surgical approach and PTA is an effective treatment method for dysfunctional AVF. PMID- 25698093 TI - CT angiography as a confirmatory test in diagnosis of brain death: comparison between three scoring systems. AB - PURPOSE: Computed tomography (CT) angiography emerges as a viable alternative technique for confirmation of brain death. However, evaluation criteria are not well established for demonstration of cerebral circulatory arrest. This retrospective study aimed to evaluate CT angiography scoring systems in diagnosis of brain death, review the literature, and compare interobserver agreement between different scales for the diagnosis of brain death. METHODS: CT angiography examinations of 25 patients with a clinical diagnosis of brain death were reevaluated according to 10-, 7-, and 4-point scales. Exams were performed with a 64-slice CT scanner including unenhanced, arterial (20 s) and venous phase (60 s) scans. Subtraction images of both phases were obtained. Interobserver agreement was evaluated for the assessment of vessel opacification and diagnosis of brain death. RESULTS: According to 10-, 7-, and 4-point scales; 13, 16, and 22 of 25 patients had full score, respectively. Using the clinical exam as the reference standard, sensitivities obtained for 10-, 7-, and 4-point scales were 52%, 64%, and 88%, respectively. Percent agreement between readers was 100% for 10- and 7-point scales and 88% for 4-point scale. Percent agreement for opacification of scale vessels was equally high for all three scales (93.6%, 93.7%, 91% for 10-, 7-, and 4-point scales, respectively). CONCLUSION: The 4 point scale appears to be more sensitive than the 10- and 7-point scales in CT angiography evaluation for brain death. Interobserver agreement is high for all three scales when subtraction images are used. PMID- 25698094 TI - Imaging of aberrant left gastric vein and associated pseudolesions of segments II and III of the liver and mimickers. AB - We present imaging findings of aberrant left gastric vein (ALGV) and associated pseudolesions and mimickers including metastases and focal nodular hyperplasia. ALGV is formed due to interrupted involution of anastomotic omental veins, and it can drain into left portal vein or segments II and III of the liver as third inflow. Focal fat, focal fat sparing, and perfusion changes can be seen due to the presence of ALGV, which can mimic metastasis in cancer patients. ALGV may also serve as a pathway for direct tumor spread into the liver in patients with gastric cancer. Magnetic resonance imaging can be used as a problem solving tool in the presence of equivocal findings on ultrasonography and computed tomography. PMID- 25698095 TI - Region of interest demarcation for quantification of the apparent diffusion coefficient in breast lesions and its interobserver variability. AB - PURPOSE: We aimed to compare two different methods of region of interest (ROI) demarcation and determine interobserver variability on apparent diffusion coefficient (ADC) in breast lesions. METHODS: Thirty-two patients with 39 lesions were evaluated with a 3.0 Tesla scanner using a diffusion-weighted sequence with several b-values. Two observers independently performed the ADC measurements using: 1) a small fixed area of 10 mm2 ROI within the area with highest restriction; 2) a large ROI so as to include the whole lesion. Differences were assessed using the Wilcoxon-rank test. Bland-Altman method and Spearman coefficient were applied for interobserver variability and correlation analysis. RESULTS: ADC values measured using the two ROI demarcation methods were significantly different for both observers (P = 0.026; P = 0.033). There was no interobserver variability in ADC values using either method (large ROI, P = 0.21; small ROI, P = 0.64). ADC values of malignant lesions were significantly different between the two methods (P < 0.001). Variability in ADC was <=0.008*10 3 mm2/s for both methods. When using the same method, ADC values were significantly correlated between the observers (small ROI: r=0.990, P < 0.001; large ROI: r=0.985, P < 0.001). CONCLUSION: The choice of ROI demarcation method influences ADC measurements. Small ROIs show less overlap in ADC values and higher ADC reproducibility, suggesting that this method may improve lesion discrimination. Interobserver variability was low for both methods. PMID- 25698096 TI - Clinical effect of double coaxial self-expandable metallic stent in management of malignant colon obstruction. AB - PURPOSE: We aimed to evaluate the clinical effectiveness and safety of double coaxial self-expandable metallic stent (DCSEMS) in management of malignant colonic obstruction as a bridge to surgery or palliation for inoperable patients. METHODS: Between April 2006 and December 2012, 49 patients (27 males and 22 females; median age, 68 years; age range, 38-91 years) were selected to receive decompressive therapy for malignant colonic obstruction by implanting a DCSEMS. Application of DCSEMS was attempted in 49 patients under fluoroscopic guidance. The obstruction was located in the transverse colon (n=2), descending colon (n=7), sigmoid colon (n=24), rectosigmoid junction (n=6), and the rectum (n=10). The intended use of DCSEMS was as a bridge to elective surgery in 23 patients and palliation in 26 patients. RESULTS: Clinical success, defined as >50% dilatation of the stent with subsequent symptomatic improvement, was achieved in 48 of 49 patients (98%). The stent was properly inserted in all patients. No immediate major procedure-related complications occurred. One patient in the bridge-to surgery group had colon perforation three days after DCSEMS application. Four patients had late migrations of the double stent. CONCLUSION: Application of DCSEMS is safe and effective in management of malignant colonic obstruction; it prevents stent migration and tumor ingrowth and lowers perforation rate during the stent application. PMID- 25698097 TI - Distinguishing intrahepatic cholangiocarcinoma from poorly differentiated hepatocellular carcinoma using precontrast and gadoxetic acid-enhanced MRI. AB - PURPOSE: We aimed to gain further insight in magnetic resonance imaging characteristics of mass-forming intrahepatic cholangiocarcinoma (mICC), its enhancement pattern with gadoxetic acid contrast agent, and distinction from poorly differentiated hepatocellular carcinoma (pHCC). METHODS: Fourteen mICC and 22 pHCC nodules were included in this study. Two observers recorded the tumor shape, intratumoral hemorrhage, fat on chemical shift imaging, signal intensity at the center of the tumor on T2-weighted image, fibrous capsule, enhancement pattern on arterial phase of dynamic study, late enhancement three minutes after contrast injection (dynamic late phase), contrast uptake on hepatobiliary phase, apparent diffusion coefficient, vascular invasion, and intrahepatic metastasis. RESULTS: Late enhancement was more common in mICC (n=10, 71%) than in pHCC (n=3, 14%) (P < 0.001). A fat component was observed in 11 pHCC cases (50%) versus none of mICC cases (P = 0.002). Fibrous capsule was observed in 13 pHCC cases (59%) versus none of mICC cases (P < 0.001). On T2-weighted images a hypointense area was seen at the center of the tumor in 43% of mICC (6/14) and 9% of pHCC (2/22) cases (P = 0.018). Other parameters were not significantly different between the two types of nodules. CONCLUSION: The absence of fat and fibrous capsule, and presence of enhancement at three minutes appear to be most characteristic for mICC and may help its differentiation from pHCC. PMID- 25698098 TI - Titanium-titanium modular neck for primary THA. Result of a prospective series of 170 cemented THA with a minimum follow-up of 5 years. AB - BACKGROUND: Although they have been in use since the end of the 1980s, modular titanium neck components are associated with a risk of wear or fracture, and their safety has recently become a subject of debate and has never been evaluated in a consecutive series of patients. The goal of this study was to evaluate: revision-free survival of these implants after a minimum follow-up of 5 years; clinical and radiographic results; and the potential complications associated with the use of modular titanium neck components. HYPOTHESIS: The use of titanium modular neck on cemented titanium THA is safe at a minimum follow-up of 5 years. PATIENTS AND METHODS: Between January 2006 and December 2008, we prospectively followed 170 patients (170 hips) who underwent primary anatomical THA with a modular cemented titanium stem design implant. The indications were unilateral THA for primary (n=160) or secondary (n=10) hip osteoarthritis (aseptic osteonecrosis of the femoral head or hip dysplasia). Mean age of patients was 75.4+/-5.8 years old (52-85), and mean BMI was 26.1+/-4.5 kg/m(2) (16.6-42.1). Patients were operated on by a modified Watson-Jones anterolateral approach based on preoperative 2D planning. All patients underwent annual clinical and radiological follow-up by an independent observer. RESULTS: At a mean follow-up of 71+/-8 months (60-84), 5 patients died and 7 were lost to follow-up. There was no revision of THA after a maximum follow-up of 84 months. The Harris score improved significantly from 50.4+/-11.3 (0-76) preoperatively to 84.5+/-15.2 (14 100) at the final follow-up. There was no difference in postoperative femoral offset or the position of the center of rotation compared to the opposite side. On the other hand, the neck-shaft angle (NSA) and limb length were corrected (2+/ 5 degrees [-11 to +14 degrees ] and 2.16+/-3.6 mm [-7.4 to +12.7 mm]) respectively. Fifteen patients (9%) had limb length discrepancies of more than 5 mm and 4 patients (2%) of more than 10 mm. There were no complications due to the modular implant design. DISCUSSION: Our study suggests that the use of cemented titanium implants with a modular titanium stem is safe at a follow-up of 5 years. The modular design does not prevent limb length discrepancies but restores femoral offset. LEVEL OF EVIDENCE: IV: prospective, non-comparative study. PMID- 25698099 TI - Identifying critically-ill patients who will benefit most from nutritional therapy: Further validation of the "modified NUTRIC" nutritional risk assessment tool. AB - INTRODUCTION: Better tools are needed to assist in the identification of critically ill patients most likely to benefit from artificial nutrition therapy. Recently, the Nutrition Risk in Critically ill (NUTRIC) score has been developed for such purpose. The objective of this study was to externally validate a modified version of the NUTRIC score in a second database. METHODS: We conducted a post hoc analysis of a database of a randomized control trial of intensive care unit (ICU) patients with multi-organ failure. Data for all variables of the NUTRIC score with the exception of IL-6 levels were collected. These included age, APACHE II score, SOFA score, number of co-morbidities, days from hospital admission to ICU admission. The NUTRIC score was calculated using the exact same thresholds and point system as developed previously except the IL-6 item was omitted. A logistic model including the NUTRIC score, the nutritional adequacy and their interaction was estimated to assess if the NUTRIC score modified the association between nutritional adequacy and 28-day mortality. We also examined the association of elevated NUTRIC scores and 6-month month mortality and the interaction between NUTRIC score and nutritional adequacy. RESULTS: A total of 1199 patients were analyzed. The mean total calories prescribed was 1817 cal (SD 312) with total mean protein prescribed of 98.3 g (SD 23.6). The number of patients who received PN was 9.5%. The overall 28-day mortality rate in this validation sample was 29% and the mean NUTRIC score was 5.5 (SD 1.6). Based on the logistic model, the odds of mortality at 28 days was multiplied by 1.4 (95% CI, 1.3-1.5) for every point increase on the NUTRIC score. The mean (SD) nutritional adequacy was 50.2 (29.5) with an interquartile range from 24.8 to 74.1. The test for interaction confirmed that the association between nutritional adequacy and 28-day mortality is significantly modified by the NUTRIC score (test for interaction p = 0.029). In particular, there is a strong positive association between nutritional adequacy and 28 day survival in patients with a high NUTRIC score but this association diminishes with decreasing NUTRIC score. Higher NUTRIC scores are also significantly associated with higher 6-month mortality (p < 0.0001) and again the positive association between nutritional adequacy and 6 month survival was significantly stronger (and perhaps only present) in patients with higher NUTRIC score (test for interaction p = 0.038). CONCLUSION: The NUTRIC scoring system is externally validated and may be useful in identifying critically ill patients most likely to benefit from optimal amounts of macronutrients when considering mortality as an outcome. PMID- 25698100 TI - Source identification and apportionment of heavy metals in urban soil profiles. AB - Because heavy metals (HMs) occurring naturally in soils accumulate continuously due to human activities, identifying and apportioning their sources becomes a challenging task for pollution prevention in urban environments. Besides the enrichment factors (EFs) and principal component analysis (PCA) for source classification, the receptor model (Absolute Principal Component Scores-Multiple Linear Regression, APCS-MLR) and Pb isotopic mixing model were also developed to quantify the source contribution for typical HMs (Cd, Co, Cr, Cu, Mn, Ni, Pb, Zn) in urban park soils of Xiamen, a representative megacity in southeast China. Furthermore, distribution patterns of their concentrations and sources in 13 soil profiles (top 20 cm) were investigated by different depths (0-5, 5-10, 10-20 cm). Currently the principal anthropogenic source for HMs in urban soil of China is atmospheric deposition from coal combustion rather than vehicle exhaust. Specifically for Pb source by isotopic model ((206)Pb/(207)Pb and (208)Pb/(207)Pb), the average contributions were natural (49%)>coal combustion (45%)?traffic emissions (6%). Although the urban surface soils are usually more contaminated owing to recent and current human sources, leaching effects and historic vehicle emissions can also make deep soil layer contaminated by HMs. PMID- 25698101 TI - Investigation of MCHM transport mechanisms and fate: implications for coal beneficiation. AB - 4-Methyl cyclohexane methanol (MCHM) is a flotation reagent often used in fine coal beneficiation and notably involved in the January 9, 2014 Elk River chemical spill in Charleston, WV. This study investigates the mechanisms controlling the transport and fate of MCHM in coal beneficiation plants and surrounding environments. Processes such as volatilization, sorption, and leaching were evaluated through laboratory batch and column experiments. The results indicate volatilization and sorption are important mechanisms which influence the removal of MCHM from water, with sorption being the most significant removal mechanism over short time scales (<1 h). Additionally, leaching experiments show both coal and tailings have high affinity for MCHM, and this reagent does not desorb readily. Overall, the results from these experiments indicate that MCHM is either volatilized or sorbed during coal beneficiation, and it is not likely to transport out of coal beneficiation plant. Thus, use of MCHM in coal beneficiation plant is not likely to pose threat to either surface or groundwater under normal operating conditions. PMID- 25698102 TI - Mutual influence between anion-pi and pnicogen bond interactions: the enhancement of P?N and P?O interactions by an anion-pi bond. AB - In this work, the interplay between anion-pi and pnicogen bond interactions is investigated by ab initio calculations. Cooperative effects are observed in the studied complexes in which anion-pi and pnicogen bond interactions coexist. These effects are analyzed in detail in terms of the energetic, geometric, charge transfer and electron density properties of the complexes. The cooperative energy ranges from -1.8 to -4.1kcalmol(-1). The effect of an anion-pi bond on a pnicogen bond is more pronounced than that of a pnicogen bond on an anion-pi bond. The enhancing mechanism is analyzed in views with the charge-transfer, electrostatic potential and electron density analysis. PMID- 25698103 TI - Engineered single-chain variable fragment antibody for immunodiagnosis of groundnut bud necrosis virus infection. AB - Few studies have been done on engineered antibodies for diagnosis of tospovirus infections. The present study was undertaken to develop a single-chain variable fragment (scFv) for specific diagnosis of infection by groundnut bud necrosis virus (GBNV), the most prevalent serogroup IV tospovirus in India. Heavy chain (372 nucleotide [nt]) and light chain (363 nt) variable region clones obtained from a hybridoma were used to make an scFv construct that expressed a ~29-kDa protein in E. coli. The scFv specifically detected GBNV in field samples of cowpea, groundnut, mung bean, and tomato, and it did not recognize watermelon bud necrosis virus, a close relative of GBNV belonging to tospovirus serogroup IV. This study for the first time demonstrated the application of a functional scFv against a serogroup-IV tospovirus. PMID- 25698104 TI - A multiplex RT-PCR for simultaneous detection and identification of five viruses and two viroids infecting chrysanthemum. AB - Pathogens causing significant economic losses in chrysanthemum include tomato aspermy virus (TAV), chrysanthemum virus B (CVB), cucumber mosaic virus (CMV), tobacco mosaic virus (TMV), potato virus Y (PVY), chrysanthemum stunt viroid (CSVd) and chrysanthemum chlorotic mottle viroid (CChMVd). A multiplex reverse transcription polymerase chain reaction (RT-PCR) method, using specific primer sets for each virus or viroid, was developed for simultaneous detection and differentiation of TAV, CVB, CMV, TMV, PVY, CChMVd, and CSVd. The RT-PCR method was validated by testing chrysanthemum samples collected from different regions of China. In this study, CVB, TAV, TMV, PVY, CSVd, CMV, and CChMVd were detected, respectively, in 24.7 %, 17.5 %, 4.4 %, 4.4 %, 2.9 %, 2.5 %, and 1.5 % of the samples tested. These results indicate that CVB and TAV (24.7 % and 17.5 %) are common, whereas CMV, TMV, CChMVd, CSVd, and PVY (all below 5 %) are less frequently encountered. This new multiplex RT-PCR method has potential to be used routinely in large-scale virus and viroid surveys. PMID- 25698105 TI - Inside out: high-efficiency plant regeneration and Agrobacterium-mediated transformation of upland and lowland switchgrass cultivars. AB - KEY MESSAGE: Selection of pre-embryogenic callus from a core structure from mature seed-derived callus is the key for high-efficiency plant regeneration and transformation of switchgrass different cultivars. Switchgrass (Panicum virgatum L.) has been identified as a dedicated biofuel crop. For its trait improvement through biotechnological approaches, we have developed a highly efficient plant regeneration and genetic transformation protocol for both lowland and upland cultivars. We identified and separated a pre-embryogenic "core" structure from the seed-derived callus, which often leads to development of highly regenerative type II calluses. From the type II callus, plant regeneration rate of lowland cultivars Alamo and Performer reaches 95%, and upland cultivars Blackwell and Dacotah, 50 and 76%, respectively. The type II callus was also amenable for Agrobacterium-mediated transformation. Transformation efficiency of 72.8% was achieved for lowland cultivar Alamo, and 8.0% for upland cultivar Dacotah. PCR, Southern blot and GUS staining assays were performed to verify the transgenic events. High regenerative callus lines could be established in 3 months, and transgenic plants could be obtained in 2 months after Agrobacterium infection. To our knowledge, this is the first report on successful plant regeneration and recovery of transgenic plants from upland switchgrass cultivars by Agrobacterium mediated transformation. The method presented here could be helpful in breaking through the bottleneck of regeneration and transformation of lowland and upland switchgrass cultivars and probably other recalcitrant grass crops. PMID- 25698106 TI - Induction and anisotropy of fluorescence of reaction center from photosynthetic bacterium Rhodobacter sphaeroides. AB - Submillisecond dark-light changes of the yield (induction) and anisotropy of fluorescence under laser diode excitation were measured in the photosynthetic reaction center of the purple bacterium Rhodobacter sphaeroides. Narrow band (1-2 nm) laser diodes emitting at 808 and 865 nm were used to selectively excite the accessory bacteriochlorophyll (B, 800 nm) or the upper excitonic state of the bacteriochlorophyll dimer (P-, 810 nm) and the lower excitonic state of the dimer (P+, 865 nm), respectively. The fluorescence spectrum of the wild type showed two bands centered at 850 nm (B) and 910 nm (P-). While the monotonous decay of the fluorescence yield at 910 nm tracked the light-induced oxidation of the dimer, the kinetics of the fluorescence yield at 850 nm showed an initial rise before a decrease. The anisotropy of the fluorescence excited at 865 nm (P-) was very close to the limiting value (0.4) across the whole spectral range. The excitation of both B and P- at 808 nm resulted in wavelength-dependent depolarization of the fluorescence from 0.35 to 0.24 in the wild type and from 0.30 to 0.24 in the reaction center of triple mutant (L131LH-M160LH-M197FH). The additivity law of the anisotropies of the fluorescence species accounts for the wavelength dependence of the anisotropy. The measured fluorescence yields and anisotropies are interpreted in terms of very fast energy transfer from (1)B* to (1)P- (either directly or indirectly by internal conversion from (1)P+) and to the oxidized dimer. PMID- 25698107 TI - Replacement of Tyr50 stacked on the si-face of the isoalloxazine ring of the flavin adenine dinucleotide prosthetic group modulates Bacillus subtilis ferredoxin-NADP(+) oxidoreductase activity toward NADPH. AB - Ferredoxin-NAD(P)(+) oxidoreductases ([EC 1.18.1.2], [EC 1.18.1.3], FNRs) from green sulfur bacteria, purple non-sulfur bacteria and most of Firmicutes, such as Bacillus subtilis (BsFNR) are homo-dimeric flavoproteins homologous to bacterial NADPH-thioredoxin reductase. These FNRs contain two unique aromatic residues stacked on the si- and re-face of the isoalloxazine ring moiety of the FAD prosthetic group whose configurations are often found among other types of flavoproteins including plant-type FNR and flavodoxin, but not in bacterial NADPH thioredoxin reductase. To investigate the role of the si-face Tyr50 residue in BsFNR, we replaced Tyr50 with Gly, Ser, and Trp and examined its spectroscopic properties and enzymatic activities in the presence of NADPH and ferredoxin (Fd) from B. subtilis (BsFd). The replacement of Tyr50 to Gly (Y50G), Ser (Y50S), and Trp (Y50W) in BsFNR resulted in a blue shift of the FAD transition bands. The Y50G and Y50S mutations enhanced the FAD fluorescence emission, whereas those of the wild type and Y50W mutant were quenched. All three mutants decreased thermal stabilities compared to wild type. Using a diaphorase assay, the k cat values for the Y50G and Y50S mutants in the presence of NADPH and ferricyanide were decreased to less than 5 % of the wild type activity. The Y50W mutant retained approximately 20 % reactivity in the diaphorase assay and BsFd-dependent cytochrome c reduction assay relative to wild type. The present results suggest that Tyr50 modulates the electronic properties and positioning of the prosthetic group. PMID- 25698108 TI - Structural remodeling of white matter in the contralesional hemisphere is correlated with early motor recovery in patients with subcortical infarction. AB - PURPOSE: This study aimed to identify brain areas with white matter changes that contribute to motor recovery of affected limbs during acute to sub-acute phases of subcortical infarction. METHODS: Diffusion tensor imaging was performed 1, 4, and 12 weeks after stroke onset in 18 patients with acute subcortical infarct, and in 18 age- and risk factor-matched controls. Fugl-Meyer scale was used to assess levels of motor impairment, and Statistical Parametric Mapping was applied to determine fractional anisotropy (FA) changes for the entire brain in order to identify areas correlated with motor recovery. RESULTS: Fugl-Meyer scores of patients at 4 and 12 weeks were significantly higher than those at 1 week (all p < 0.01). Accompanying with the progressive decreases of FA in the corticospinal tract above and below the stroke lesion, progressive increases of FA in the contralesional medial frontal gyrus, and thalamocortical connections including projections to the somatosensory cortices, primary motor cortex, and premotor areas, were positively correlated with Fugl-Meyer scores (all p < 0.005) within 12 weeks following acute subcortical infarction. CONCLUSIONS: Remodeling of white matter in contralesional brain regions related to motor, cognition, and sensory processing may facilitate early motor recovery in patients with an acute infarct. PMID- 25698109 TI - Grey matter connectivity within and between auditory, language and visual systems in prelingually deaf adolescents. AB - PURPOSE: Previous studies have shown brain reorganizations after early deprivation of auditory sensory. However, changes of grey matter connectivity have not been investigated in prelingually deaf adolescents yet. In the present study, we aimed to investigate changes of grey matter connectivity within and between auditory, language and visual systems in prelingually deaf adolescents. METHODS: We recruited 16 prelingually deaf adolescents and 16 age-and gender matched normal controls, and extracted the grey matter volume as the structural characteristic from 14 regions of interest involved in auditory, language or visual processing to investigate the changes of grey matter connectivity within and between auditory, language and visual systems. Sparse inverse covariance estimation (SICE) was utilized to construct grey matter connectivity between these brain regions. RESULTS: The results show that prelingually deaf adolescents present weaker grey matter connectivity within auditory and visual systems, and connectivity between language and visual systems declined. Notably, significantly increased brain connectivity was found between auditory and visual systems in prelingually deaf adolescents. CONCLUSIONS: Our results indicate "cross-modal" plasticity after deprivation of the auditory input in prelingually deaf adolescents, especially between auditory and visual systems. Besides, auditory deprivation and visual deficits might affect the connectivity pattern within language and visual systems in prelingually deaf adolescents. PMID- 25698110 TI - Two-photon microscopy as a tool to investigate the therapeutic time window of methylprednisolone in a mouse spinal cord injury model. AB - PURPOSE: The aim of the present study was to explore the use of two-photon microscopy for investigating the therapeutic time window of methylprednisolone (MP) treatment after spinal cord injury (SCI). METHODS: Twenty-four YFP H-line mice were subjected to hemisection SCI and then divided into four groups. Group 1 received MP at 30 min post-injury; group 2 received MP at 8 h post-injury; group 3 received MP at 24 h post-injury; and group 4 received saline at 30 min post injury. Post-injury axonal dieback was imaged in vivo using two-photon microscopy. After all imaging sessions, histological examination of the surviving neurons and microglial/macrophage accumulation was performed. RESULTS: Two-photon imaging revealed the degree of progressive axon damage after SCI. Group 1 exhibited a shorter axonal dieback distance and slower axonal dieback speed than groups 2, 3, and 4 (p < 0.01). MAP-2 staining revealed greater neuronal survival in group 1 than in groups 2, 3, and 4 (p < 0.05). F4/80 staining revealed greater microglial/macrophage density in groups 2, 3, and 4 than in group 1 (p< 0.05). CONCLUSIONS: MP therapy may help attenuate progressive axon damage, reduce neuronal death, and inhibit microglial/macrophage accumulation, especially when initiated shortly after SCI. PMID- 25698111 TI - Tissue plasminogen activator (rt-PA) in acute ischemic stroke: Outcomes associated with ambulation. AB - PURPOSE: Several clinical trials have highlighted general favorable outcomes of intravenous tissue type plasminogen activator (rt-PA) in acute ischemic stroke using different measures including, National Institutes of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS). Findings from most of these measures indicate that the benefits of rt-PA are time dependent, thus, supporting intensive efforts to fast-track hospital thrombolytic treatment in patients with stroke. Despite the widespread benefits of rt-PA, the effectiveness of this therapy on specific functions such as ambulatory performance of the recovering stroke patient is not fully investigated. We aim to investigate this issue in the current study. METHODS: We analyzed data from a retrospective cohort of acute ischemic stroke patients admitted to Greenville Health System (GHS) between 2010 2013. We identified patients who received rt-PA within a 4.5 hour time frame following the onset of acute ischemic stroke symptoms. Our analysis compared ambulatory variables and hospital-level characteristics in proportions of patients receiving rt-PA with those not receiving rt-PA. This analysis determined whether early treatment with rt-PA is associated with favorable changes in ambulatory status from admission to discharge following acute ischemic stroke. RESULTS: Among 663 patients with ischemic stroke who were eligible to receive rt PA, 241 patients received rt-PA and 422 patients did not due to several risk factors. We found a statistically significant difference (P < 0.001) for changes in ambulation status from hospital admission to discharge between patients receiving rt-PA and patients who did not receive rt-PA. Among patients who received rt-PA, 27.8% improved in their ambulation status, 41.9% saw no change in their ambulation status, 0.4% worsened in their ambulation status, and 29.9% were unable to be determined. Of the patients who did not receive rt-PA, 20.1% improved in their ambulation status, 61.8% saw no change in their ambulation status, 1.4% worsened in their ambulation status, and 16.6% were unable to be determined. CONCLUSION: Our current study indicates that early treatment with rt PA may be associated with favorable changes in ambulatory status from admission to discharge following acute ischemic stroke. PMID- 25698112 TI - Changes of voltage-gated sodium channels in sensory nerve regeneration and neuropathic pain models. AB - PURPOSE: The present study was conducted to determine changes in the expression of voltage-gated sodium channels (VGSCs) alpha-subunits after nerve injury and their relation with development of neuropathic pain. METHODS: We used the crush injury model of regeneration of the sciatic nerve (Crush) and the spared nerve injury (SNI) model of neuropathic pain in the rat. Measurements of thermal and mechanical pain thresholds were performed until 3 months after injury. Real-time PCR and immunohistochemistry of VGSC alpha-subunits were used to evaluate the mRNA and protein expression in the DRG. RESULTS: Both nerve injuries induced similar alterations in the VGSCs expression at 7 dpi, with upregulation of Nav1.3, and downregulation of Nav1.7, Nav1.8 and Nav1.9. These changes persisted until 28 days, when hyperalgesia was still present in SNI but not in Crush rats. At 90 days, mRNA expression of all analyzed alpha-subunits returned to basal levels in the Crush group. However, SNI rats still showed altered expression of VGSCs, and neuropathic pain responses. Immunohistochemical staining revealed that Nav1.8 and Nav1.9 were widely expressed in IB4-positive neurons of the DRG, relevant in pain processing. The population of neurons coexpressing each alpha subunit and IB4 was also affected by the injury, more markedly after the Crush. CONCLUSION: Shifts in VGSCs expression occur in parallel to neuropathic pain behavior in rats early after injury, while at later times they appear to be more related to sensory nerve degeneration and regeneration processes. PMID- 25698113 TI - Bidirectional but asymmetrical sexual hybridization between Brassica carinata and Sinapis arvensis (Brassicaceae). AB - With transgenic crop development it is important to evaluate the potential for transgenes to escape into populations of wild, weedy relatives. Ethiopian mustard (Brassica carinata, BBCC) is easily transformed and is being investigated for uses from biodiesel fuels to biopharmaceuticals. However, little work has been done evaluating its ability to cross with relatives such as wild mustard (Sinapsis arvensis, SrSr), an abundant, cosmopolitan weedy relative. Here we conducted bidirectional crosses with Ethiopian mustard as a maternal parent in 997 crosses and paternal parent in 1,109 crosses. Hybrids were confirmed using flow cytometry and species-specific ITS molecular markers and indicate a high hybridization rate of 6.43 % between Ethiopian mustard (?) and wild mustard (?) and a lower, but not insignificant, hybridization rate of 0.01 % in the reverse direction. The majority of the hybrids were homoploid (BCSr) with less than 1 % of pollen production of their parents and low seed production (0.26 seeds/pollination) in crosses and backcrosses indicating a potential for advanced generation hybrids. The accession used had a significant effect on hybrid seed production with different accessions of Ethopian mustard varying in their production of hybrid offspring from 2.69 to 16.34 % and one accession of wild mustard siring almost twice as many hybrid offspring per flower as the other. One pentaploid (BBCCSr) and one hexaploid (BBCCSrSr) hybrid were produced and had higher pollen viability, though no and low seed production, respectively. As wild mustard is self-incompatible and the outcrossing rate of Ethiopian mustard has been estimated as 30 % potential for hybrid production in the wild appears to be high, though the hybridization rate found here represents a worst case scenario as it does not incorporate pre-pollination barriers. Hybridization in the wild needs to be directly evaluated as does the propensity of Ethiopian mustard to volunteer. PMID- 25698114 TI - BiP and its nucleotide exchange factors Grp170 and Sil1: mechanisms of action and biological functions. AB - BiP (immunoglobulin heavy-chain binding protein) is the endoplasmic reticulum (ER) orthologue of the Hsp70 family of molecular chaperones and is intricately involved in most functions of this organelle through its interactions with a variety of substrates and regulatory proteins. Like all Hsp70 family members, the ability of BiP to bind and release unfolded proteins is tightly regulated by a cycle of ATP binding, hydrolysis, and nucleotide exchange. As a characteristic of the Hsp70 family, multiple DnaJ-like co-factors can target substrates to BiP and stimulate its ATPase activity to stabilize the binding of BiP to substrates. However, only in the past decade have nucleotide exchange factors for BiP been identified, which has shed light not only on the mechanism of BiP-assisted folding in the ER but also on Hsp70 family members that reside throughout the cell. We will review the current understanding of the ATPase cycle of BiP in the unique environment of the ER and how it is regulated by the nucleotide exchange factors, Grp170 (glucose-regulated protein of 170kDa) and Sil1, both of which perform unanticipated roles in various biological functions and disease states. PMID- 25698116 TI - Developing pressures: fluid forces driving morphogenesis. AB - Over several decades genetic studies have unraveled many molecular mechanisms that underlie the signaling networks guiding morphogenesis, but the mechanical forces at work remain much less well understood. Accumulation of fluid within a luminal space can generate outward hydrostatic pressure capable of shaping morphogenesis at several scales, ranging from individual organs to the entire vertebrate body-plan. Here, we focus on recent work that uncovered mechanical roles for fluid secretion during morphogenesis. Identifying the roles and regulation of fluid secretion will be instrumental for understanding the mechanics of morphogenesis as well as many human diseases of complex genetic and environmental origin including secretory diarrheas and scoliosis. PMID- 25698117 TI - Subcutaneous implantable cardioverter defibrillator device malfunction: first report of a "high current" condition triggering device failure. PMID- 25698115 TI - Protein quality control under oxidative stress conditions. AB - Accumulation of reactive oxygen and chlorine species (RO/CS) is generally regarded to be a toxic and highly undesirable event, which serves as contributing factor in aging and many age-related diseases. However, it is also put to excellent use during host defense, when high levels of RO/CS are produced to kill invading microorganisms and regulate bacterial colonization. Biochemical and cell biological studies of how bacteria and other microorganisms deal with RO/CS have now provided important new insights into the physiological consequences of oxidative stress, the major targets that need protection, and the cellular strategies employed by organisms to mitigate the damage. This review examines the redox-regulated mechanisms by which cells maintain a functional proteome during oxidative stress. We will discuss the well-characterized redox-regulated chaperone Hsp33, and we will review recent discoveries demonstrating that oxidative stress-specific activation of chaperone function is a much more widespread phenomenon than previously anticipated. New members of this group include the cytosolic ATPase Get3 in yeast, the Escherichia coli protein RidA, and the mammalian protein alpha2-macroglobulin. We will conclude our review with recent evidence showing that inorganic polyphosphate (polyP), whose accumulation significantly increases bacterial oxidative stress resistance, works by a protein like chaperone mechanism. Understanding the relationship between oxidative and proteotoxic stresses will improve our understanding of both host-microbe interactions and how mammalian cells combat the damaging side effects of uncontrolled RO/CS production, a hallmark of inflammation. PMID- 25698118 TI - Event-related potential responses to letter-string comparison analogies. AB - Previous studies have used analogy completion tasks (e.g., abe is to abf as ijk is to what?) to examine the event-related potential (ERP) parameters of analogical reasoning. In the present study, ERP responses to analogies were investigated using an analogy comparison task (e.g., is abe to abf as ijk is to ijl?), with a focus on structural evaluation. The results showed that the identical match task elicited an N2 component with smaller amplitude than that of the N2 component in the zero- and one-step consistent analogies, reflecting automatic match detection. The data also showed that there were significant differences in the N400 during the consistent and inconsistent analogies, which may reflect a delayed perceptual mismatch with semantic strategies. Moreover, one step consistent analogies evoked smaller late positive component (LPC) amplitudes than that evoked by identical match or zero-step consistent analogies in the 500- to 800-ms time interval, and one-step inconsistent analogies elicited smaller amplitude LPCs than that elicited by zero-step inconsistent analogies in the 500- to 750-ms time interval, which suggested that LPCs reflected structure evaluation in analogy comparison tasks. PMID- 25698119 TI - Undergraduate baccalaureate nursing students' self-reported confidence in learning about patient safety in the classroom and clinical settings: an annual cross-sectional study (2010-2013). AB - BACKGROUND: Given the increasing incidence of adverse events and medication errors in healthcare settings, a greater emphasis is being placed on the integration of patient safety competencies into health professional education. Nurses play an important role in preventing and minimizing harm in the healthcare setting. Although patient safety concepts are generally incorporated within many undergraduate nursing programs, the level of students' confidence in learning about patient safety remains unclear. OBJECTIVES: Self-reported patient safety competence has been operationalized as confidence in learning about various dimensions of patient safety. The present study explores nursing students' self reported confidence in learning about patient safety during their undergraduate baccalaureate nursing program. DESIGN: Cross-sectional study with a nested cohort component conducted annually from 2010 to 2013. SETTING AND PARTICIPANTS: Participants were recruited from one Canadian university with a four-year baccalaureate of nursing science program. All students enrolled in the program were eligible to participate. METHODS: The Health Professional Education in Patient Safety Survey was administered annually. The Health Professional Education in Patient Safety Survey captures how the six dimensions of the Canadian Patient Safety Institute Safety Competencies Framework and broader patient safety issues are addressed in health professional education, as well as respondents' self-reported comfort in speaking up about patient safety issues. RESULTS: In general, nursing students were relatively confident in what they were learning about the clinical dimensions of patient safety, but they were less confident about the sociocultural aspects of patient safety. Confidence in what they were learning in the clinical setting about working in teams, managing adverse events and responding to adverse events declined in upper years. The majority of students did not feel comfortable speaking up about patient safety issues. The nested cohort analysis confirmed these findings. In particular, confidence in acquiring basic clinical skills, learning about adverse events, and managing safety risks improved between Year 1 and Year 2, and confidence in managing safety risks declined in upper years. CONCLUSIONS: These findings suggest nursing students are confident in what they are learning about clinical aspects of patient safety, however, their confidence in learning about sociocultural aspects declines as they are increasingly exposed to the clinical environment. This suggests a need to address the impact of the practice environment on nursing students' confidence in what they are learning about patient safety. PMID- 25698120 TI - Need-based nutritional intervention is effective in improving handgrip strength and Barthel Index scores of older people living in a nursing home: a randomized controlled trial. AB - BACKGROUND: Nutritional status is associated with physical functioning in older people. Protein-energy malnutrition can limit functional performance. OBJECTIVES: This study examined the effectiveness of a "need-based intervention" on improving the physical functioning of older adults living in nursing homes. DESIGN: A 24 week randomized, double-blind, controlled trial. SETTINGS: A privately managed geriatric nursing home in Taiwan. PARTICIPANTS: Ninety-two persons who were >=65 years old, <=25 kg/m(2), >1 month residence, non-bed-ridden, without acute infection, and able to self-feed or receive oral feeding. METHODS: Qualified participants were stratified by gender and then randomly assigned to either the control group (n=45) or the intervention group (n=47). Each participant in the intervention group would receive a 50 g/day soy-protein-based nutritional supplement when he/she was rated as undernourished, defined as Mini Nutritional Assessment score <=24 and body mass index <=24 kg/m(2). The supplement contained 9.5 g protein, 250 kcal energy, and all essential micronutrients. The supplementation would be suspended if either one of the two "at risk" conditions was not met at the next measurement (every 4 weeks). Handgrip strength and Barthel Index were measured at baseline, mid-point (week 12), and end-point (week 24) of the trial. Results were analyzed with Student's t-test and by the Generalized Estimating Equations controlled for nutritional status. RESULTS: The intervention significantly improved (a) handgrip strength of the older adults at weeks 12 and 24, and (b) the overall Barthel Index at week 24 (all p<0.05) according to the Generalized Estimating Equations. CONCLUSIONS: "Need-based intervention" can be an effective and useful strategy for improving the physical functioning of older adults living in nursing homes, without adverse effects. The results probably are the indirect results of the improved nutritional status. The study highlights the importance of routine screening and timely intervention in geriatric care. The applicability of this need-based strategy to community-living older adults is an important issue and should be evaluated. We can probably reap a greater benefit by eliminating the risk of malnutrition at the emerging stage. PMID- 25698121 TI - [Collaborative and stepped care for depression: Development of a model project within the Hamburg Network for Mental Health (psychenet.de)]. AB - BACKGROUND: Depression is one of the most widespread mental disorders in Germany and causes a great suffering and involves high costs. Guidelines recommend stepped and interdisciplinary collaborative care models for the treatment of depression. OBJECTIVES: Stepped and collaborative care models are described regarding their efficacy and cost-effectiveness. A current model project within the Hamburg Network for Mental Health exemplifies how guideline-based stepped diagnostics and treatment incorporating innovative low-intensity interventions are implemented by a large network of health care professionals and clinics. MATERIALS AND METHODS: An accompanying evaluation using a cluster randomized controlled design assesses depressive symptom reduction and cost-effectiveness for patients treated within "Health Network Depression" ("Gesundheitsnetz Depression", a subproject of psychenet.de) compared with patients treated in routine care. RESULTS: Over 90 partners from inpatient and outpatient treatment have been successfully involved in recruiting over 600 patients within the stepped care model. Communication in the network was greatly facilitated by the use of an innovative online tool for the supply and reservation of treatment capacities. The participating professionals profit from the improved infrastructure and the implementation of advanced training and quality circle work. CONCLUSIONS: New treatment models can greatly improve the treatment of depression owing to their explicit reference to guidelines, the establishment of algorithms for diagnostics and treatment, the integration of practices and clinics, in addition to the implementation of low-intensity treatment alternatives. These models could promote the development of a disease management program for depression. PMID- 25698122 TI - [The integration of telemedicine concepts in the regional care of rural areas: Possibilities, limitations, perspectives]. AB - In rural areas with a low population density and (imminent) gaps in regional health care, telemedicine concepts can be a promising option in supporting the supply of medical care.Telemedicine connections can be established between different health care providers (e.g., hospitals) or directly between health care providers and patients.Different scenarios for the implementation of telemedicine have been developed, from the monitoring of chronically ill patients to the support of acute care. Examples of frequently applied telemedicine concepts are teleradiology, telemedicine stroke networks, and the telemedicine monitoring of patients with heart failure. The development of concepts for other indications and patient groups is apparently difficult in Germany; one reason could be that research institutions are involved in only a small number of projects. However, the participation of research institutes would be of importance in creating more scientific evidence. The development of appropriate evaluation designs for analyzing the effectiveness of telemedicine concepts and economic effects is an important task and challenge for the future. Mandatory evaluation criteria should be developed to provide a basis for the translation of positively evaluated telemedicine concepts into routine care. PMID- 25698123 TI - Comparison of Type 1 D-3-phosphoglycerate dehydrogenases reveals unique regulation in pathogenic Mycobacteria. AB - D-3-phosphoglycerate dehydrogenases (PGDH) from all organisms catalyze the conversion of D-3-phosphoglycerate to phosphohydroxypyruvate as the first step in the biosynthesis of l-serine. This investigation compares the properties of Type 1 PGDHs from seven different species and demonstrates that conserved residues in the ACT and ASB domains of some allow l-serine to act as a feedback inhibitor at low micromolar concentrations. In addition, the serine sensitivity is dependent on the presence of phosphate ions. These residues are most highly conserved among PGDHs from the actinomycetales family, but only certain pathogenic mycobacteria appear to have the full complement of residues required for high sensitivity to serine. These basic residues are also responsible for the presence of dual pH optima in the acidic region that is also phosphate dependent. Analytical ultracentrifugation analysis demonstrates that the dual pH optima do not require changes in oligomeric state. This study also demonstrates that substrate inhibition is a common feature of Type 1 PGDHs and that it is suppressed by phosphate, indicating that phosphate likely interacts at both the catalytic and regulatory sites. The unique features resulting from the complement of basic residues conserved in pathogenic mycobacteria may impart important metabolic advantages to these organisms. PMID- 25698124 TI - Email for clinical communication between healthcare professionals. AB - BACKGROUND: Email is one of the most widely used methods of communication, but its use in healthcare is still uncommon. Where email communication has been utilised in health care, its purposes have included clinical communication between healthcare professionals, but the effects of using email in this way are not well known. We updated a 2012 review of the use of email for two-way clinical communication between healthcare professionals. OBJECTIVES: To assess the effects of email for clinical communication between healthcare professionals on healthcare professional outcomes, patient outcomes, health service performance, and service efficiency and acceptability, when compared to other forms of communicating clinical information. SEARCH METHODS: We searched: the Cochrane Consumers and Communication Review Group Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 9 2013), MEDLINE (OvidSP) (1946 to August 2013), EMBASE (OvidSP) (1974 to August 2013), PsycINFO (1967 to August 2013), CINAHL (EbscoHOST) (1982 to August 2013), and ERIC (CSA) (1965 to January 2010). We searched grey literature: theses/dissertation repositories, trials registers and Google Scholar (searched November 2013). We used additional search methods: examining reference lists and contacting authors. SELECTION CRITERIA: Randomised controlled trials, quasi randomised trials, controlled before and after studies, and interrupted time series studies examining interventions in which healthcare professionals used email for communicating clinical information in the form of: 1) unsecured email, 2) secure email, or 3) web messaging. All healthcare professionals, patients and caregivers in all settings were considered. DATA COLLECTION AND ANALYSIS: Two authors independently assessed studies for inclusion, assessed the included studies' risk of bias, and extracted data. We contacted study authors for additional information and have reported all measures as per the study report. MAIN RESULTS: The previous version of this review included one randomised controlled trial involving 327 patients and 159 healthcare providers at baseline. It compared an email to physicians containing patient-specific osteoporosis risk information and guidelines for evaluation and treatment versus usual care (no email). This study was at high risk of bias for the allocation concealment and blinding domains. The email reminder changed health professional actions significantly, with professionals more likely to provide guideline-recommended osteoporosis treatment (bone density measurement or osteoporosis medication, or both) when compared with usual care. The evidence for its impact on patient behaviours or actions was inconclusive. One measure found that the electronic medical reminder message impacted patient behaviour positively (patients had a higher calcium intake), and two found no difference between the two groups. The study did not assess health service outcomes or harms.No new studies were identified for this update. AUTHORS' CONCLUSIONS: Only one study was identified for inclusion, providing insufficient evidence for guiding clinical practice in regard to the use of email for clinical communication between healthcare professionals. Future research should aim to utilise high-quality study designs that use the most recent developments in information technology, with consideration of the complexity of email as an intervention. PMID- 25698125 TI - Lambert-Eaton myasthenic syndrome associated to Merkel cell carcinoma: report of a case. PMID- 25698126 TI - Moving foot dystonia in a seamstress. PMID- 25698127 TI - Occurrence and predictors of the fatigue in high-grade glioma patients. AB - A better knowledge of the fatigue could be of the greatest importance for the high-grade glioma (HGG) patients, who are a unique and vulnerable population. The aim of this study was to evaluate the occurrence and the predictors of the fatigue in HGG patients, using a specific fatigue scale. The study was designed as a cross-sectional study. The study population included sixty-seven consecutive outpatients with HGG. We used these measures: Brief Fatigue Inventory, Karnofsky Performance Scale, Functional Independence Measure, Brief Psychiatric Rating Scale and Psychological Distress Inventory and SF-36, EORTC QLQ-30 and EORTC QLQ BN20 for quality of life (QoL). Sixteen out of sixty-seven (23.9 %) patients were affected by Anaplastic Astrocytoma and 51/67 (76.1 %) by Glioblastoma Multiforme. About one-third (36.2 %) of patients had a clinically relevant fatigue (Brief Fatigue Inventory >=3). In regression analysis, physical and mental aspects of QoL were statistically significant related with fatigue (p < 0.01 and p < 0.02, respectively). Our data underlined the relevant occurrence of fatigue in HGG patients and support the development of further studies exploring a tailored rehabilitation program. PMID- 25698128 TI - Fetal surgery for myelomeningocele: history, research, clinical trials, and future directions. AB - Myelomeningocele, more commonly known as spina bifida, is the most common neural tube defect worldwide. In the United States, it is the primary cause of lifelong childhood paralysis with approximately four children born daily with this devastating disease. To minimize damage to the exposed spinal cord and prevent ascending central nervous system infections, postnatal closure of the spinal defect has been the standard of care for decades. Research into the mechanism of spinal cord injury in those with spina bifida revealed that damage continues to accrue during the gestational period. Prenatal defect closure via in utero surgery was proposed to prevent this early deterioration of the spinal cord, and early animal research demonstrated that prenatal repair was feasible and promising. This paved the way for the first human prenatal repairs in the mid-to late 1990s. Following the promising outcomes observed during the first human cases, a randomized controlled trial, the Management of Myelomeningocele Study (MOMS), was conducted comparing postnatal repair of spina bifida to prenatal repair. The MOMS trial demonstrated that to those undergoing prenatal repair of spina bifida had a decreased need for ventriculoperitoneal shunting and improved lower extremity motor function. With the success of the MOMS trial, in utero repair is now considered the standard of care in those who meet the criteria for prenatal repair. This review will provide an overview of spina bifida and its impact, highlight the historical changes in care, describe the early research and theory that made prenatal repair an option, discuss the clinical experiences with human fetal repair and briefly touch on future research directions for those with myelomeningocele. PMID- 25698130 TI - Keep it simple, surgeon. PMID- 25698131 TI - Comment on: Trocar site hernia after laparoscopic sleeve gastrectomy using a specific open laparoscopy technique. PMID- 25698132 TI - Prenatal diethylstilbestrol exposure and reproductive hormones in premenopausal women. AB - Diethylstilbestrol (DES), a synthetic estrogen widely prescribed to pregnant women in the mid-1900s, is a potent endocrine disruptor. Prenatal DES exposure has been associated with reproductive disorders in women, but little is known about its effects on endogenous hormones. We assessed the association between prenatal DES exposure and reproductive hormones among participants from the Harvard Study of Moods and Cycles (HSMC), a longitudinal study of premenopausal women aged 36-45 years from Massachusetts (1995-1999). Prenatal DES exposure was reported at baseline (43 DES exposed and 782 unexposed). Early follicular-phase concentrations of follicle-stimulating hormone (FSH), luteinizing hormone (LH) and estradiol were measured at baseline and every 6 months during 36 months of follow-up. Inhibin B concentrations were measured through 18 months. We used multivariable logistic and repeated-measures linear regression to estimate odds ratios (OR) and percent differences in mean hormone values (beta), respectively, comparing DES exposed with unexposed women, adjusted for potential confounders. DES-exposed women had lower mean concentrations of estradiol (pg/ml) (beta= 15.6%, 95% confidence interval (CI): -26.5%, -3.2%) and inhibin B (pg/ml) (beta= 20.3%, CI: -35.1%, -2.3%), and higher mean concentrations of FSH (IU/I) (beta=12.2%, CI: -1.5%, 27.9%) and LH (IU/I) (beta=10.4%, CI: -7.2%, 31.3%), than unexposed women. ORs for the association of DES with maximum FSH>10 IU/I and minimum inhibin B<45 pg/ml--indicators of low ovarian reserve--were 1.90 (CI: 0.86, 4.22) and 4.00 (CI: 0.88-18.1), respectively. Prenatal DES exposure was associated with variation in concentrations of FSH, estradiol and inhibin B among women of late reproductive age. PMID- 25698133 TI - Expression of YY1 in Differentiated Thyroid Cancer. AB - The transcription factor Yin Yang 1 (YY1) has an important regulatory role in tumorigenesis, but its implication in thyroid cancer has not been yet investigated. In the present study, we have analyzed the expression of YY1 in differentiated thyroid cancer and assessed the association of YY1 expression with clinical features. Expression of YY1 was evaluated in human thyroid cancer cell lines, a series of matched normal/tumor thyroid tissues and in a thyroid cancer tissue microarray, using real-time PCR, Western blot, and/or immunohistochemistry. YY1 was overexpressed in thyroid cancer cells, at transcription and protein levels. A significant increase of YY1 mRNA was also observed in tumor thyroid tissues. Moreover, immunohistochemical analysis of the thyroid cancer tissue microarray revealed that both papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC) present increased YY1 protein levels (48 and 19%, respectively). After stratification by the level of YY1 protein, positive YY1 expression identifies 88% of patients with PTC. The association of YY1 expression with clinicopathological features in PTC and FTC showed that YY1 expression was related with age at diagnosis. Our data indicates for the first time overexpression of YY1 in differentiated thyroid cancer, with YY1 being more frequently overexpressed in the PTC subtype. PMID- 25698135 TI - Nucleophilic substitution in ionizable Fischer thiocarbene complexes: steric effect of the alkyl substituent on the heteroatom. AB - A detailed kinetic study has been carried out for the aminolysis of ionizable Fischer thiocarbene complexes (CO)5M[double bond, length as m-dash]C(SR)CH3 (M = Cr, W; R = iPr, nBu, cHex, tBu) with five primary amines and one secondary amine in aqueous acetonitrile solutions (50% MeCN-50% water (v/v)). The observed rate constants for the reaction with primary amines showed a first-order dependence on the amine concentration, while with morpholine, the rate constant has second order dependence. The general base catalysis process was confirmed by the variation of the rate constants with the concentration of an external catalyst and the pH. The results agree with a stepwise mechanism where the nucleophilic addition to the carbene carbon to produce a tetrahedral intermediate (T+/-) is the first step, followed by a rapid deprotonation of to form the anion T- which leads to the products by general-acid catalysed leaving group (-SR) expulsion. In general, it was found that the chromium complexes are less reactive than the tungsten analogues. The obtained Bronsted parameters for the nucleophilic addition (betanuc) indicate that C-N bond formation has made little progress at the transition state. By using Charton's correlation, the role that the steric factor plays throughout the mechanism has been unraveled. The nucleophilic addition to the thiocarbenes is less sensitive to steric effects than the alkoxycarbenes regardless of the nature of the metal centre. Conversely, the steric effects on the general-base catalysis can be strong depending on the volume of the catalyst and the metal centre. On the basis of the structure reactivity coefficients beta and psi and comparison with alkoxycarbene complexes, esters and thiolesters, insights into the main factors ruling the reactivity in terms of transition state imbalances are discussed. PMID- 25698134 TI - CT screening for lung cancer: Importance of emphysema for never smokers and smokers. AB - PURPOSE: To address the prevalence of lung cancer in high and low-risk people according to their smoking history, age, and CT findings of emphysema. METHODS: We reviewed the baseline low-dose CT scans of 62,124 current, former and never smokers, aged 40-90 to determine the prevalence of lung cancer. We performed logistic regression analysis of the prevalence of lung cancer to determine the odds ratio (OR) for emphysema, conditionally on age, female gender, and ethnicity. RESULTS: The prevalence of lung cancer was 1.4% (95% CI: 1.3-1.6) for current smokers, 1.1% (95% CI: 1.0-1.2) for former smokers, and 0.4% (95% CI: 0.3 0.6) for never smokers. Emphysema was identified in 28.5% (6,684), 20.6% (5,422), and 1.6% (194) of current, former, and never smokers, respectively. The prevalence of lung cancer among current smokers was 1.1% for those without emphysema vs. 2.3% for those with emphysema (odds ratio [OR] 1.8; 95% confidence interval [CI]: 1.4-2.2) and the corresponding difference for former smokers was 0.9% vs. 1.8% (OR: 1.7; 95% CI: 1.3-2.2), and for never smokers, it was 0.4% vs. 2.6% (OR: 6.3; 95% CI: 2.4-16.9). CONCLUSIONS: Identification of emphysema in low dose CT scans increases the risk of lung cancer and is important in determining follow-up of current, former, and never smokers. PMID- 25698136 TI - Using Standardized Care Bundles in the Emergency Department to Decrease Mortality in Patients Presenting with Community-Acquired Pneumonia (CAP) and Acute Exacerbation of Chronic Obstructive Pulmonary Disease (AECOPD). AB - There is significant variability when managing community-acquired pneumonia (CAP) and exacerbation of chronic obstructive pulmonary disease (COPD) in the emergency department among doctors, hospitals, and health systems. This variability could contribute to the variable outcomes related with them. The use of standardized care bundles allows clinical teams to focus their efforts on a small number of measurable strategies aimed at improving specified outcomes. This article will review the importance of clinical care bundles when managing these diseases in the emergency department and its potential to decrease mortality. PMID- 25698137 TI - The effect of different exercise modalities on dyspnea and leg fatigue in healthy subjects. AB - BACKGROUND: This study documents the impact of different exercise modalities on dyspnea and leg fatigue during equivalent cardiopulmonary stress in healthy subjects. METHODOLOGY: Following a familiarization, 20 subjects (age 21-44 years; 8 males) performed six 5-min exercise tests, randomized among: 2 steep slope treadmill tests (25% grade), 2 lesser slope treadmill tests (12% grade) and 2 bicycle tests on 3 separate days. Subjects reported either dyspnea or leg fatigue during each test. Oxygen consumption (VO2), ventilation (VE), respiratory rate (fR) and heart rate (HR) were measured during each test. RESULTS: VO2,VE, HR, dyspnea and leg fatigue were not significantly different among the three exercise conditions (p > 0.05). CONCLUSION: These findings indicate that at equivalent levels of cardiopulmonary stress reflected by similar levels of VO2 and heart rate, the perceived level of exertional dyspnea is not influenced by different patterns of neuromuscular activity. Similarly, the intensity of leg fatigue primarily reflects whole body work and is independent of different patterns of neuromuscular activity. PMID- 25698138 TI - Is sexual reproduction of high-mountain plants endangered by heat? AB - Strong solar irradiation in combination with still air and dry soil can cause prostrate high-mountain plants to heat up considerably and ultimately suffer heat damage. Such heat damage has been repeatedly shown for vegetative structures, but not for reproductive structures, which we expected to be particularly vulnerable to heat. Heat effects on cold-adapted plants may increase with rising global temperatures and the predicted increase in heat waves. We have tested the heat tolerance of reproductive versus vegetative shoots at different reproductive stages, comparing ten common plant species from different elevation belts in the European Alps. Plant samples were exposed to temperatures in 2-K steps of 30 min each between 42 and 56 degrees C. Heat damage was assessed by visual rating and vital staining. Reproductive shoots were on average 2.5 K less heat tolerant (LT50, i.e. the mean temperature causing 50 % heat damage, 47.2 degrees C) than vegetative shoots (mean LT50 49.7 degrees C). Initial heat injuries (mean LT10) were observed at 43-45 degrees C in heat-susceptible species and at 45-47 degrees C in more heat-tolerant species, in at least one reproductive stage. Generally, heat tolerance was significantly higher during fruiting than during the bud stages and anthesis. Prostrate species with acaulescent buds and flowers tolerated heat better than those with caulescent buds and flowers. Petals were the most heat-susceptible plant structure and mature pollen the most heat tolerant. Based on these data, heat tolerance of reproductive structures appears to be adapted to the prevailing maximum temperatures which the plants experience during different reproductive stages in their environment. During hot spells, however, heat tolerance thresholds may be exceeded. More frequent heat waves would decrease the reproductive output and, consequently, the competitiveness of heat-susceptible species. PMID- 25698139 TI - Measuring feeding traits of a range of litter-consuming terrestrial snails: leaf litter consumption, faeces production and scaling with body size. AB - Plant litter decomposition is an essential ecosystem function that contributes to energy and nutrient cycling above- and belowground. Terrestrial gastropods can affect this process in various ways: they consume and fragment leaf litter and create suitable habitats for microorganisms through the production of faeces and mucus. We assessed the contributions of ten litter-feeding terrestrial snail species to leaf litter mass loss and checked whether consumption rate and faeces production scale with body size (i.e. shell size and shape), which may indicate that morphological traits can serve as proxies for consumption rate. Additionally, we compared the consumption rates of a subset of these species among litter types of two plant species which differ in resource quality (Fraxinus excelsior and Betula pendula). These snail species differed in their litter consumption rates. Consumption rates differed between the two litter types, whereas the rank order of litter consumption by the different species was independent of litter quality. Consumption rate and faeces production were positively related to shell size, whereas relative consumption rate and faeces production were related to shell shape, with more elongated snail species having lower relative consumption rates and faeces production rates. Our results show that easily measurable morphological traits scale with the feeding traits of snails, and represent useful proxies for consumption rate and faeces production, which are laborious to measure. Thus, estimated potential total consumption rates of snail communities along environmental gradients may be inferred from shell size distributions. Our study contributes to a systematic trait-based evaluation of the importance of gastropods to litter decomposition. PMID- 25698140 TI - Telomere dynamics in wild brown trout: effects of compensatory growth and early growth investment. AB - After a period of food deprivation, animals often respond with a period of faster than normal growth. Such responses have been suggested to result in decreased chromosomal maintenance, which in turn may affect the future fitness of an individual. Here, we present a field experiment in which a food deprivation period of 24 days was enforced on fish from a natural population of juvenile brown trout (Salmo trutta) at the start of the high-growth season in spring. The growth of the food-deprived fish and a non-deprived control group was then monitored in the wild during 1 year. Fin tissue samples were taken at the start of the experiment and 1 year after food deprivation to monitor the telomere dynamics, using reduced telomere length as an indicator of maintenance cost. The food-deprived fish showed partial compensatory growth in both mass and length relative to the control group. However, we found no treatment effects on telomere dynamics, suggesting that growth-compensating brown trout juveniles are able to maintain their telomeres during their second year in the stream. However, body size at the start of the experiment, reflecting growth rate during their first year of life, was negatively correlated with change in telomere length over the following year. This result raises the possibility that rapid growth early in life induces delayed costs in cellular maintenance. PMID- 25698141 TI - Body size mediates social and environmental effects on nest building behaviour in a fish with paternal care. AB - Body size, social setting, and the physical environment can all influence reproductive behaviours, but their interactions are not well understood. Here, we investigated how male body size, male-male competition, and water turbidity influence nest-building behaviour in the sand goby (Pomatoschistus minutus), a marine fish with exclusive paternal care. We found that environmental and social factors affected the nest characteristics of small and large males differently. In particular, association between male size and the level of nest elaboration (i.e. the amount of sand piled on top of the nest) was positive only under clear water conditions. Similarly, male size and nest entrance size were positively associated only in the absence of competition. Such interactions may, in turn, help to explain the persistence of variation in reproductive behaviours, which due to their importance in offspring survival-are otherwise expected to be under strong balancing selection. PMID- 25698142 TI - Experimental evidence that ptarmigan regulate willow bud production to their own advantage. AB - In some ecosystems, vertebrate herbivores increase the nutritional quality and biomass of their food source through repeated grazing, thereby manipulating their environment to support higher densities of animals. We tested whether ptarmigan (Lagopus lagopus and L. muta) are capable of regulating the nutritional quality, abundance, and availability of feltleaf willow (Salix alaxensis) buds using a simulated browsing experiment and a feeding preference study with wild birds. Simulated ptarmigan browsing resulted in smaller buds, but greater numbers of buds per shoot. Furthermore, browsing altered the morphology of willow branches such that buds were at higher densities and closer to snow level compared to unbrowsed controls. Browsing increased the number of willows with accessible buds (buds within 50 cm of snow level) from 55 to 89%, and increased total accessible bud biomass from 113 +/- 30 to 129 +/- 50 mg/ramet. Browsing did not affect bud nitrogen or carbon concentration and slightly reduced protein precipitation capacity (tannins) in buds the following winter, indicating that ptarmigan browsing does not induce a defensive response in this species. When branches of broomed (previously browsed) and unbroomed willows were placed in the snow at equal heights, ptarmigan showed no preference for either type; however, they obtained more buds from broomed willows. Increased accessibility and density of willow buds caused by browsing has the potential to increase habitat carrying capacity, thereby supporting higher densities of ptarmigan. PMID- 25698143 TI - Relationships between isotopic values and oxidative status: insights from populations of gentoo penguins. AB - Feeding strategies can affect the balance between the production of reactive oxygen species and antioxidant defences (i.e. oxidative status). This is ecologically relevant, as variation in oxidative status can in turn strongly affect fitness. However, how animals regulate their oxidative status through their feeding behaviour under natural conditions remains poorly understood. Thus, relating the isotopic values of free-ranging animals to their oxidative status may prove useful. Here, we considered three colonies of gentoo penguins (Pygoscelis papua) in which we measured (1) delta(13)C and delta(15)N values, and (2) antioxidant defences and oxidative damage. We found that colonies with the highest delta(13)C and delta(15)N values also had the highest levels of antioxidant defences and oxidative damage, resulting in positive relationships between isotopic values and markers of oxidative status. As a result, colony segregation in terms of isotopic values was reflected by segregation in terms of oxidative markers (although more markedly for oxidative damage than for antioxidant defences). Interestingly, variation in the estimated contribution of krill in the diet of penguins followed an opposite pattern to that observed for markers of oxidative status, providing evidence that inter-population differences in terms of foraging strategies can result in inter-population differences in terms of oxidative status. More studies examining simultaneously oxidative status, isotopic signature, foraging behaviour and food allocation between parents and young are, however, needed to understand better the interplay between the foraging strategies adopted by animals in their natural habitat and their oxidative status. PMID- 25698144 TI - A study on the PK and BA profiles in the mouse body for leonurine O/O microemulsion with determination by the LC-MS/MS method. AB - Leonurine (LE) has been found to have therapeutic efficacy in cerebral thrombosis, but its poor solubility in water leads to very low bioavailability. In this article, a leonurine O/O microemulsion (LE-ME) was prepared and investigated for its in vivo pharmacokinetic behavior and bioavailability in the mouse body using an aqueous suspension of leonurine (LE-SWW) for the control group. A simple, sensitive and specific method, HPLC-MS/MS, was developed for detection of the LE content in mouse plasma using n-benzoyl-L-arginine ethyl ester as an internal standard. The results demonstrated that the C max of LE-ME was 2.46-fold higher than that of the suspension following oral administration. The absolute bioavailability was 10.95 %, while that of the suspension was only 1.78 %. The T 1/2beta and MRT of LE-ME were 3.04- and 4.19-fold those of the suspension, respectively. In addition, following intramuscular administration of LE-ME, the absolute bioavailability was 37.45 %. The results indicated that LE-ME is a promising drug-delivery system to enhance the absorption and bioavailability of LE. PMID- 25698146 TI - Lurasidone: a review of its use in adult patients with bipolar I depression. AB - Lurasidone (Latuda((r))), a benzisothiazole derivative antipsychotic, is approved in the USA and Canada for the treatment of adults with major depressive episodes (MDE) associated with bipolar I disorder; this article reviews studies of lurasidone in this indication. In two 6-week, placebo-controlled trials in adults with bipolar I depression, lurasidone 20-120 mg/day reduced depressive symptoms, either as monotherapy or as an adjunct to lithium or valproate. Lurasidone reduced the mean Montgomery-Asberg Depression Rating Scale (MADRS) total score from baseline (primary endpoint) by >50 %; the reductions in scores were significantly greater than with placebo. The treatment effects were small to medium and the numbers needed to treat to obtain an additional MDE response (>=50 % reduction from baseline in the MADRS total score) were <=7 across the lurasidone groups. In a third, similarly designed trial of lurasidone 20-120 mg/day adjunctive to lithium or valproate, there was no significant between-group difference in the change in the mean MADRS total score at week 6 (primary endpoint), although significant differences favouring lurasidone were observed from week 2 to week 5. Across trials, the most frequently occurring adverse events included akathisia, extrapyramidal symptoms and somnolence. Lurasidone had a favourable profile with respect to weight gain and metabolic disturbances, known to occur with some other antipsychotics. Thus, lurasidone offers a valuable addition to the therapies available for adult patients with bipolar depression, either as monotherapy or as an adjunct to lithium or valproate. PMID- 25698145 TI - The efficacy of atomoxetine for the treatment of children and adolescents with attention-deficit/hyperactivity disorder: a comprehensive review of over a decade of clinical research. AB - Atomoxetine was first licensed to treat attention-deficit/hyperactivity disorder (ADHD) in children and adolescents in the US in 2002. The aim of this paper is to comprehensively review subsequent publications addressing the efficacy of atomoxetine in 6- to 18-year-olds with ADHD. We identified 125 eligible papers using a predefined search strategy. Overall, these papers demonstrate that atomoxetine is an effective treatment for the core ADHD symptoms (effect sizes 0.6-1.3, vs. placebo, at 6-18 weeks), and improves functional outcomes and quality of life, in various pediatric populations with ADHD (i.e., males/females, patients with co-morbidities, children/adolescents, and with/without prior exposure to other ADHD medications). Initial responses to atomoxetine may be apparent within 1 week of treatment, but can take longer (median 23 days in a 6 week study; n=72). Responses often build gradually over time, and may not be robust until after 3 months. A pooled analysis of six randomized placebo controlled trials (n=618) indicated that responses at 4 weeks may predict response at 6-9 weeks, although another pooled analysis of open-label data (n=338) suggests that the probability of a robust response to atomoxetine [>=40% decrease in ADHD-Rating Scale (ADHD-RS) scores] may continue to increase beyond 6 9 weeks. Atomoxetine may demonstrate similar efficacy to methylphenidate, particularly immediate-release methylphenidate, although randomized controlled trials are generally limited by short durations (3-12 weeks). In conclusion, notwithstanding these positive findings, before initiating treatment with atomoxetine, it is important that the clinician sets appropriate expectations for the patient and their family with regard to the likelihood of a gradual response, which often builds over time. PMID- 25698147 TI - Doctors' antibiotic prescriptions should be scrutinised, says NICE. PMID- 25698148 TI - Outcomes of Hispanic women with lymph-node positive, HER2 positive breast cancer treated with neoadjuvant chemotherapy and trastuzumab in Mexico. AB - INTRODUCTION: Evidence regarding the outcomes of Hispanic women with breast cancer is lacking. We analyzed women with HER2+ disease treated with trastuzumab based neoadjuvant chemotherapy in Mexico. METHODS: 244 patients were included. Outcomes were compared between patients who achieved pathologic complete response (pCR) (n = 119), or less than pCR (n = 125). Patients with noninvasive (ypT0/is, ypN0) residual disease were also analyzed. RESULTS: 119 (48.8%) patients achieved pCR. pCR was the only factor associated with improved 3 year survival (98.1% vs 92.3%: P = 0.02). Survival was better in patients with ypT0/is, ypN0 response than in those with residual invasive disease (p < 0.01). 3 year survival was 98.1% for patients with pCR and 92.6% for patients with ypTis, ypN0 response (p = 0.64). CONCLUSIONS: Response rates to trastuzumab based neoadjuvant chemotherapy in Hispanics mimic that of other ethnic groups. This underlines the fact that access to treatment, rather than ethnicity, is the main prognostic factor in this population. PMID- 25698149 TI - p53 status identifies triple-negative breast cancer patients who do not respond to adjuvant chemotherapy. AB - Genomic analysis and protein expression assimilate triple-negative breast cancers (TNBC) with basal-like breast tumors. TNBCs, however, have proved to encompass also tumors with normal-like phenotype and known to have favorable prognosis and to respond to chemotherapy. In a recent paper, we have provided evidence that p53 status is able to subdivide TNBCs into two distinct subgroups with different outcome, and consistent with basal- and normal-like phenotypes. Based on this finding, we explored the contribution of p53 status in predicting the response to adjuvant CMF or CMF followed doxorubicin chemotherapy of a group of TNBC patients. Results indicated that TNBC patients with a p53-positive tumor had a shorter relapse-free and overall survival than patients carrying a p53-negative TNBC, corroborating our hypothesis about the relationship between TNBC phenotype (basal-like versus normal-like) and p53 status as predictor of response to anthracycline/CMF-based chemotherapy. PMID- 25698150 TI - Electroneutrality breakdown and specific ion effects in nanoconfined aqueous electrolytes observed by NMR. AB - Ion distribution in aqueous electrolytes near the interface plays a critical role in electrochemical, biological and colloidal systems, and is expected to be particularly significant inside nanoconfined regions. Electroneutrality of the total charge inside nanoconfined regions is commonly assumed a priori in solving ion distribution of aqueous electrolytes nanoconfined by uncharged hydrophobic surfaces with no direct experimental validation. Here, we use a quantitative nuclear magnetic resonance approach to investigate the properties of aqueous electrolytes nanoconfined in graphitic-like nanoporous carbon. Substantial electroneutrality breakdown in nanoconfined regions and very asymmetric responses of cations and anions to the charging of nanoconfining surfaces are observed. The electroneutrality breakdown is shown to depend strongly on the propensity of anions towards the water-carbon interface and such ion-specific response follows, generally, the anion ranking of the Hofmeister series. The experimental observations are further supported by numerical evaluation using the generalized Poisson-Boltzmann equation. PMID- 25698151 TI - Gene therapy with the caspase activation and recruitment domain reduces the ocular inflammatory response. AB - Inflammation is a key component of chronic and acute diseases of the eye. Our goal is to test anti-inflammatory genes delivered by an adeno-associated virus (AAV) vector as potential treatments for retinal inflammation. We developed a secretable and cell penetrating form of the caspase activation and recruitment domain (CARD) from the apoptosis-associated speck-like protein containing a CARD (ASC) gene that binds caspase-1 and inhibits its activation by the inflammasome. The secretion and cell penetration characteristics of this construct were validated in vitro by measuring its effects on inflammasome signaling in a monocyte cell line and in an retinal pigmented epithelium (RPE) cell line. This vector was then packaged as AAV particles and tested in the endotoxin-induced uveitis mouse model. Gene expression was monitored one month after vector injection by fluorescence fundoscopy. Ocular inflammation was then induced by injecting lipopolysaccharide into the vitreous and was followed by enucleation 24 hours later. Eyes injected with the secretable and cell penetrating CARD AAV vector had both a significantly lower concentration of IL-1beta as well as a 64% reduction in infiltrating cells detected in histological sections. These results suggest that anti-inflammatory genes such as the CARD could be used to treat recurring inflammatory diseases like uveitis or chronic subacute inflammations of the eye. PMID- 25698152 TI - Low-lipid diet reduces frequency and severity of acute migraine attacks. AB - BACKGROUND AND AIM: There is uncertainty regarding the prevention of migraine crises by changing the lifestyle of patients. The aim of this randomized, crossover intervention trial was to evaluate the effects of a low lipid intake on the incidence and severity of migraine crises, in comparison to a diet with moderate lipid intake. METHODS AND RESULTS: After a 2-month run-in when patients received preventive medication but were left on their habitual diet, a low-lipid or a normal-lipid diet was randomly prescribed for 3 months and thereafter diets were crossed over for the following 3 months. Headache was diagnosed based on the International Classification of Headache Disorders (IHCD) III criteria. The number and severity of attacks were assessed using a self-reported calendar. Adherence to the diet was assessed by a food frequency questionnaire. An analysis was performed on the 83 episodic or chronic migraineurs (63 female and 20 male), in the age range of 18-57 years, who completed both intervention periods. Obese subjects had a significantly higher number of attacks than those overweight or with normal body weight (24.7 +/- 8, 16.3 +/- 12, and 15.6 +/- 11, respectively, p < 0.03) with a significant relationship between the body mass index (BMI) and the number of monthly attacks (r = 0.238, p < 0.03). The number (2.9 +/- 3.7 vs. 6.8 +/- 7.5, p < 0.001) and severity (1.2 + 0.9 vs. 1.7 +/- 0.9, p < 0.01) of attacks significantly decreased during both intervention periods, with a significant difference in favour of the low-lipid diet. CONCLUSIONS: In this group of patients, the low-lipid diet significantly affected the number and severity of migraine attacks in comparison to a normal-lipid diet. ClinicalTrials.gov Identifier: NCT 01917474. PMID- 25698153 TI - Cardiovascular flexibility in middle-aged overweight South Asians vs. white Caucasians: response to short-term caloric restriction. AB - BACKGROUND AND AIMS: South Asians have a higher risk of developing cardiovascular disease than white Caucasians. The underlying cause is unknown, but might be related to higher cardiac susceptibility to metabolic disorders. Short-term caloric restriction (CR) can be used as a metabolic stress test to study cardiac flexibility. We assessed whether metabolic and functional cardiovascular flexibility to CR differs between South Asians and white Caucasians. METHODS AND RESULTS: Cardiovascular function and myocardial triglycerides were assessed using a 1.5T-MRI/S-scanner in 12 middle-aged overweight male South Asians and 12 matched white Caucasians before and after an 8-day very low calorie diet (VLCD). At baseline South Asians were more insulin resistant than Caucasians. Cardiac dimensions were smaller, despite correction for body surface area, and pulse wave velocity (PWV) in the distal aorta was higher in South Asians. Systolic and diastolic function, myocardial triglycerides and pericardial fat did not differ significantly between groups. After the VLCD body weight reduced on average by 4.0 +/- 0.2 kg. Myocardial triglycerides increased in both ethnicities by 69 +/- 18%, and diastolic function decreased although this was not significant in South Asians. However, pericardial fat and PWV in the proximal and total aorta were reduced in Caucasians only. CONCLUSION: Myocardial triglyceride stores in middle aged overweight and insulin resistant South Asians are as flexible and amenable to therapeutic intervention by CR as age-, sex- and BMI-matched but less insulin resistant white Caucasians. However, paracardial fat volume and PWV showed a differential effect in response to an 8-day VLCD in favor of Caucasians. CLINICAL TRIAL REGISTRATION: NTR 2473 (URL: http://www.trialregister.nl/trialreg/admin/rctsearch.asp?Term=2473). PMID- 25698154 TI - Serum high sensitivity CRP concentrations predict the presence of carotid artery plaque in individuals without a history of cardiovascular events. PMID- 25698155 TI - Age-dependent trends in postoperative mortality and preoperative comorbidity in isolated coronary artery bypass surgery: a nationwide study. AB - OBJECTIVES: An increasing number of octogenarians are being subjected to coronary artery bypass grafting (CABG). The purpose of this study was to examine age dependent trends in postoperative mortality and preoperative comorbidity over time following CABG. METHODS: All patients who underwent isolated CABG surgery between January 1996 and December 2012 in Denmark were included. Patients were identified through nationwide administrative registers. Age was categorized into five different groups and time into three periods to see if mortality and preoperative comorbidity had changed over time. Predictors of 30-day mortality were analysed in a multivariable Cox proportional-hazard models and survival at 1 and 5 years was estimated by Kaplan-Meier curves. RESULTS: A total of 38 830 patients were included; the median age was 65.4 +/- 9.5 years, increasing over time to 66.6 +/- 9.5 years. Males comprised 80%. The number of octogenarians was 1488 (4%). The median survival was 14.7 years (60-69 years), 10.7 years (70-74 years), 8.9 years (75-79 years) and 7.2 years (>=80 years). The 30-day mortality rate was 3%, increasing with age (1% in patients <60 years, 8% in octogenarians). The long-term mortality rate at 1 and 5 years was 2 and 7% (age <60 years) and 14 and 36% (age >80 years), respectively. The proportion of patients >75 years increased from 10 to 20% during the study period as well as the proportion of patients undergoing urgent or emergency surgery. The burden of comorbidities increased over time, e.g. congestive heart failure 13-17%, diabetes 12-21%, stroke 9-11%, in all age groups. Age and emergency surgery were the main predictors of 30-day mortality: age >80 years [hazard ratio (HR): 5.75, 95% confidence interval (CI): 4.41-7.50], emergency surgery (HR: 5.23, 95% CI: 4.38 6.25). CONCLUSION: Patients are getting older at the time of surgery and have a heavier burden of comorbidities than before. The proportion of patients undergoing urgent or emergency surgery increased with age and over time. Despite this, the 30-day mortality decreased over time and long-term survival increased, except in octogenarians where it was stable. Octogenarians had substantially higher 30-day mortality compared with younger patients but surgery can be performed with acceptable risks and good long-term outcomes. PMID- 25698156 TI - Aortic arch aneurysm: short- and mid-term results comparing open arch surgery and the hybrid procedure?. AB - OBJECTIVES: Open arch surgery for aortic arch aneurysm was historically associated with a high risk of postoperative morbi-mortality. Improved operative techniques have now lowered the incidence of these complications but in parallel, hybrid arch procedures have emerged. Nowadays, very little data are available about their mid-term results compared with open surgery. METHODS: From January 2002 to January 2014, 46 patients had treatment for an exclusive aortic arch aneurysm including 25 open arch surgeries and 21 type I hybrid arch procedures in our institution. All cases involved arch aneurysms involving at least one carotid artery (Zone 0 and Zone 1). Aneurysms of the distal arch and descending aorta were excluded (Zone 2 and beyond). Results from a retrospective database are reported. There were no patients lost to the follow-up. RESULTS: There was no significant difference in preoperative comorbidities between the two groups. The incidence of in-hospital mortality was similar at 20% (5/25) for open surgery and 19% (4/21) for hybrid procedure (P = 0.830). The incidence of permanent cerebral neurological deficit was comparable at 17.4% (4/23) for open surgery and 21.1% (4/19) for hybrid procedure (P = 1). Median survival was 109.5 months for open surgery and 56.3 months for hybrid procedure. Freedom from all-cause mortality was 78, 63, 63 and 57% at 1, 3, 5 and 7 years, respectively in the open surgical group. Freedom from all-cause mortality was 74, 55, 46 and 28% at 1, 3, 5 and 7 years, respectively in the hybrid group. Survival rates and incidence of major adverse cardiac and cerebro-vascular event between open surgery and hybrid procedure were not statistically different (P = 0.530 and P = 0.325, respectively). However, incidence of reintervention was in favour of open surgery [14.5 vs 44.8% at 7 years, P = 0.045; 95% confidence interval: (0.06-0.97)]. CONCLUSIONS: The type I hybrid arch procedure fails to demonstrate better results compared with open surgery, regarding morbi-mortality at the short- and mid-term follow-up. Moreover, it increases the risk of reintervention. Patients treated by this technique must undergo a closer follow-up because of this risk. Larger randomized studies are needed to better define the exact indications of this therapy. PMID- 25698158 TI - Myogenic and neurogenic differentiation of human tooth germ stem cells (hTGSCs) are regulated by pluronic block copolymers. AB - Stem cells with high proliferation, self-renewal and differentiation capacities are promising for tissue engineering approaches. Among stem cells, human tooth germ stem cells (hTGSCs) having mesenchymal stem cell characteristics are highly proliferative and able to differentiate into several cell lineages. Researchers have recently focused on transplanting stem cells with bioconductive and/or bioinductive materials that can provide cell commitment to the desired cell lineages. In the present study, effects of pluronic block copolymers (F68, F127 and P85) on in vitro myo- and neurogenic differentiation of human tooth germ stem cells (hTGSCs) were investigated. As P85 was found to exert considerable toxicity to hTGSCs even at low concentrations, it was not evaluated for further differentiation experiments. Immunocytochemical analysis, gene and protein expression studies revealed that while F68 treatment increased lineage-specific gene expression in both myo- and neuro-genically differentiated cells, F127 did not result in any remarkable difference compared to cells treated with differentiation medium. Subsequent studies are required to explore the exact mechanisms of how F68 increases the myogenic and neurogenic differentiation of hTGSCs. The present work indicates that pluronic F68 might be used in functional skeletal and neural tissue engineering applications. PMID- 25698157 TI - Measuring the effects of aging and sex on regional brain stiffness with MR elastography in healthy older adults. AB - Changes in tissue composition and cellular architecture have been associated with neurological disease, and these in turn can affect biomechanical properties. Natural biological factors such as aging and an individual's sex also affect underlying tissue biomechanics in different brain regions. Understanding the normal changes is necessary before determining the efficacy of stiffness imaging for neurological disease diagnosis and therapy monitoring. The objective of this study was to evaluate global and regional changes in brain stiffness as a function of age and sex, using improved MRE acquisition and processing that have been shown to provide median stiffness values that are typically reproducible to within 1% in global measurements and within 2% for regional measurements. Furthermore, this is the first study to report the effects of age and sex over the entire cerebrum volume and over the full frontal, occipital, parietal, temporal, deep gray matter/white matter (insula, deep gray nuclei and white matter tracts), and cerebellum volumes. In 45 volunteers, we observed a significant linear correlation between age and brain stiffness in the cerebrum (P<.0001), frontal lobes (P<.0001), occipital lobes (P=.0005), parietal lobes (P=.0002), and the temporal lobes (P<.0001) of the brain. No significant linear correlation between brain stiffness and age was observed in the cerebellum (P=.74), and the sensory-motor regions (P=.32) of the brain, and a weak linear trend was observed in the deep gray matter/white matter (P=.075). A multiple linear regression model predicted an annual decline of 0.011 +/- 0.002 kPa in cerebrum stiffness with a theoretical median age value (76 years old) of 2.56 +/- 0.08 kPa. Sexual dimorphism was observed in the temporal (P=.03) and occipital (P=.001) lobes of the brain, but no significant difference was observed in any of the other brain regions (P>.20 for all other regions). The model predicted female occipital and temporal lobes to be 0.23 kPa and 0.09 kPa stiffer than males of the same age, respectively. This study confirms that as the brain ages, there is softening; however, the changes are dependent on region. In addition, stiffness effects due to sex exist in the occipital and temporal lobes. PMID- 25698159 TI - Effects of recombinant baculovirus AcMNPV-BmK IT on the formation of early cables and nuclear polymerization of actin in Sf9 cells. AB - Autographa californica nuclearpoly hedrosis virus (AcMNPV) is one of the most important baculoviridae. However, the application of AcMNPV as a biocontrol agent has been limited. Previously, we engineered Buthus martensii Karsch insect toxin (BmK IT) gene into the genome of AcMNPV. The bioassay data indicated that the recombinant baculovirus AcMNPV-BmK IT significantly enhanced the anti-insect efficacy of the virus. The actin cytoskeleton is the major component beneath the surface of eukaryotic cells. In this report, the effects of AcMNPV-BmK IT on the formation of early cables of actin and nuclear filamentous-actin (F-actin) were studied. The results indicated that these baculovirus induced rearrangement of the actin cytoskeleton of host cells during infection and actin might participate in the transportation of baculovirus from cytoplasm to the nuclei. AcMNPV-BmK IT delayed the formation of early cables of actin and nuclear F-actin and accelerated the clearance of actin in the nuclei. PMID- 25698160 TI - Sequential cultivation of human epidermal keratinocytes and dermal mesenchymal like stromal cells in vitro. AB - Human skin has continuous self-renewal potential throughout adult life and serves as first line of defence. Its cellular components such as human epidermal keratinocytes (HEKs) and dermal mesenchymal stromal cells (DMSCs) are valuable resources for wound healing applications and cell based therapies. Here we show a simple, scalable and cost-effective method for sequential isolation and propagation of HEKs and DMSCs under defined culture conditions. Human skin biopsy samples obtained surgically were cut into fine pieces and cultured employing explant technique. Plated skin samples attached and showed outgrowth of HEKs. Gross microscopic examination displayed polygonal cells with a granular cytoplasm and H&E staining revealed archetypal HEK morphology. RT-PCR and immunocytochemistry authenticated the presence of key HEK markers including trans membrane protein epithelial cadherin (E-cadherin), keratins and cytokeratin. After collection of HEKs by trypsin-EDTA treatment, mother explants were left intact and cultured further. Interestingly, we observed the appearance of another cell type with fibroblastic or stromal morphology which were able to grow up to 15 passages in vitro. Growth pattern, expression of cytoskeletal protein vimentin, surface proteins such as CD44, CD73, CD90, CD166 and mesodermal differentiation potential into osteocytes, adipocytes and chondrocytes confirmed their bonafide mesenchymal stem cell like status. These findings albeit preliminary may open up significant opportunities for novel applications in wound healing. PMID- 25698161 TI - The effect of superoxide dismutase mimetic and catalase on the quality of postthawed goat semen. AB - Manganese(III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin chloride (MnTE) is a cell-permeable superoxide dismutase mimetic agent which can convert superoxide to hydrogen peroxide (H2O2). Supplementation of MnTE to a commercial semen extender can protect sperm from superoxide but not H2O2. Therefore, we proposed that addition of catalase (0.0, 200, or 400 IU/mL) in combination with MnTE (0.1 MUM) may further improve the cryopreservation efficiency of goat semen in commercially optimized freezing media such as Andromed. Therefore, ejaculates were obtained from three adult bucks twice a week during the breeding season and diluted with Andromed supplemented with or without MnTE and catalase and were frozen in liquid nitrogen. Sperm parameters and reactive oxygen species contents were evaluated 2 hours after dilution (before freezing) and after freezing/thawing. The results revealed that all the treatments significantly (P <= 0.05) improved sperm motility, viability, and membrane integrity after freezing and reduced reactive oxygen species content compared with the control group, but maximum improvement was obtained in MnTE + 400 IU/mL catalase. In addition, supplementation with these antioxidants significantly (P <= 0.05) increases the cleavage rate after IVF. In conclusion, the results of present study suggest that addition of antioxidant MnTE or catalase to commercial optimized media, such as Andromed, improves total motility, membrane integrity, and viability of goat semen samples after thawing. But the degree of improvement for these parameters significantly (P <= 0.05) higher when MnTE and catalase were simultaneously added to the cryopreservation media. PMID- 25698162 TI - Children's use of gesture in ambiguous pronoun interpretation. AB - This study explores whether children can use gesture to inform their interpretation of ambiguous pronouns. Specifically, we ask whether four- to eight year-old English-speaking children are sensitive to information contained in co referential localizing gestures in video narrations. The data show that the older (7-8 years of age) but not younger (4-5 years) children integrate co-referential gestures into their interpretation of pronouns. This is the same age at which they show sensitivity to order-of-mention, the only other cue available in the stimuli. Interestingly, when children show sensitivity to the gestures, they are quite similar to adults, in that gestures consistent with order-of-mention increase first-mentioned responses as compared to stimuli with no gestures, but only slightly, while gestures inconsistent with order-of-mention have a larger effect on interpretation, decreasing first-mentioned responses and increasing second-mentioned responses. PMID- 25698163 TI - From appetitive to aversive: motivational interviewing reverses the modulation of the startle reflex by tobacco cues in smokers not ready to quit. AB - Motivational Interviewing (MI) is a treatment method that has proven effective for increasing motivation to change and decreasing the consumption of different drugs. However, the results of studies examining the impact of MI on tobacco consumption are contradictory. Moreover, evidence of the effectiveness of MI for modifying well-validated psychophysiological indices of motivational change is still lacking. The aim of the present study was to use the startle probe paradigm and self-report measures of motivational change to assess the effectiveness of MI, compared to Prescriptive Advice (PA) and no treatment, in a sample of 53 smokers (28 male) who were not ready to quit smoking. After the intervention, the MI group reported increased motivation to change compared to both the PA and control groups. MI participants also had a potentiated startle reflex in response to tobacco-related pictures compared to the other two groups. These findings provide evidence that MI reverses the underlying motivational system activated by tobacco related cues. PMID- 25698164 TI - Rape survivors' trauma-related beliefs before and after Cognitive processing therapy: associations with PTSD and depression symptoms. AB - This study examined whether cognitive distortions (i.e., assimilated and overaccommodated thoughts) and realistic (i.e., accommodated) thoughts assessed from impact statements written 5-10 years after completing cognitive processing therapy (CPT) accurately predicted posttreatment maintenance or decline in treatment gains during the same period. The sample included 50 women diagnosed with posttraumatic stress disorder (PTSD) secondary to rape who participated in a randomized clinical trial of CPT for PTSD. Cognitions were assessed via coding and analyses of participants' written impact statements at three time points: beginning of treatment, end of treatment, and at 5-10 years follow-up. Primary mental health outcomes were symptoms of PTSD (Clinician-Administered PTSD Scale) and depression (Beck Depression Inventory). Changes in trauma-related beliefs between the end of treatment and long-term follow-up were associated with concomitant changes in PTSD and depression symptoms (effect sizes ranging from r = .35-.54). Declines in accommodated thinking and increases in overaccommodated thinking were associated with elevations in symptomatology. Improvement in accommodated thinking and declines in overaccommodated thinking were associated with lower PTSD and depression symptoms during this same time period. Findings provided support for the role of changes in accommodated and overaccommodated thinking being associated with level of PTSD and depression many years after participating in CPT. PMID- 25698165 TI - How perfectionism and ineffectiveness influence growth of eating disorder risk in young adolescent girls. AB - While perfectionism is widely considered to influence risk for eating disorders, results of longitudinal studies are mixed. The goal of the current study was to investigate a more complex model of how baseline perfectionism (both high personal standards and self-critical evaluative concerns) might influence change in risk status for eating disorders in young adolescent girls, through its influence on ineffectiveness. The study was conducted with 926 girls (mean age of 13 years), and involved three waves of data (baseline, 6- and 12-month follow up). Latent growth curve modelling, incorporating the average rate at which risk changed over time, the intercept (initial status) of ineffectiveness, and baseline perfectionism, was used to explore longitudinal mediation. Personal standards was not supported as contributing to risk but results indicated that the higher mean scores on ineffectiveness over the three waves mediated the relationship between higher baseline self-critical evaluative concerns and both measures of eating disorder risk. The relationship between concern over mistakes and change in risk was small and negative. These results suggest the usefulness of interventions related to self-criticism and ineffectiveness for decreasing risk for developing an eating disorder in young adolescent girls. PMID- 25698166 TI - Sources and level of income among individuals with multiple sclerosis compared to the general population: A nationwide population-based study. AB - INTRODUCTION: Multiple sclerosis (MS) is associated with reduced work capacity, but there is limited knowledge about MS patients' sources of income. OBJECTIVES: The purpose of this study was to elucidate MS patients' earnings and social benefits compared to those of the general population. METHODS: From nationwide registers of all residents in Sweden aged 21-64 years in 2010 (n=5,291,764), those with an MS diagnosis (n=13,979) were compared to a propensity score matched reference group (n=69,895). Descriptive statistics and regression models were used to estimate the percentage difference between the MS patients and the matched references regarding the following annual incomes: earnings, disability pension, sickness absence, disability allowance, unemployment compensation and social assistance. RESULTS: Both MS patients and the matched references received most of their income from earnings followed by disability pension and sickness absence. MS patients that were diagnosed in 2010 had 15% lower earnings than the matched references, while MS patients diagnosed before 2005 had 38% lower earnings. Corresponding figures regarding summed social benefits were 33% and 130% higher for MS patients, respectively. CONCLUSION: The results indicate that MS patients are overrepresented, in relative and absolute terms, regarding health related benefits and have lower levels of earnings. However, the redistributing welfare systems appear to financially compensate the MS patients considerably. PMID- 25698167 TI - Shift work influences multiple sclerosis risk. AB - BACKGROUND: An association between working shift at a young age and subsequent risk for multiple sclerosis (MS) has been observed. OBJECTIVE: To investigate whether this finding could be replicated, and to further explore the influence of age at first exposure to shift work. METHODS: Using a Swedish population-based, case-control study (2337 cases and 4904 controls), the incidence of MS among subjects whom had worked shifts was compared with that of those whom had not, by calculating odds ratios (ORs) with 95% confidence intervals (CIs) by means of logistic regression. RESULTS: The OR of developing MS was 1.5 (95% CI 1.2-1.8) among those whom started working shifts before age 20, whereas a less pronounced association was observed among those whom started working shifts at age 20 or later (OR 1.2; 95% CI 1.1-1.4). The effect of shift work was more pronounced among subjects whom had been exposed at a young age, regardless of the duration between the start of shift work and disease onset. CONCLUSION: Some aspects of adolescence seem to be of great importance, regarding the impact of shift work on MS risk. Circadian disruption and sleep deprivation may contribute towards explaining the association; however, the exact mechanisms behind our observations remain to be elucidated. PMID- 25698169 TI - The incidence and prevalence of comorbidity in multiple sclerosis. PMID- 25698168 TI - Role of membrane complement regulators in neuromyelitis optica. AB - BACKGROUND: It is unclear why AQP4-IgG primarily causes central nervous system lesions by activating complement, but generally spares peripheral AQP4-expressing organs. OBJECTIVES: To determine whether peripheral AQP4-expressing cells are protected from complement-mediated damage by expressing complement regulators. METHODS: Human tissue and cultured human cells were immunostained for aquaporin-4 (AQP4), CD46, CD55 and CD59. We also determined the vulnerability to AQP4-IgG and complement-mediated damage of astrocytes cultured alone or co-cultured with endothelial cells. RESULTS: In normal brain, astrocyte end-feet express AQP4, but are devoid of CD46, CD55 and CD59. Immunoreactivity for CD46, CD55 and CD59 is not increased in or around neuromyelitis optica lesions. In kidney AQP4 is co expressed with CD46 and CD55, in stomach AQP4 is co-expressed with CD46 and in skeletal muscle AQP4 is co-expressed with CD46. Astrocytes cultured alone co express AQP4 and CD59 but, in astrocyte-endothelial co-cultures, AQP4 is found in cell processes devoid of CD59. Astrocytes co-cultured with endothelial cells are more vulnerable to AQP4-IgG and complement-mediated lysis than astrocytes cultured alone. CONCLUSIONS: Complement regulators protect peripheral organs, but not the central nervous system, from AQP4-IgG and complement-mediated damage. Our findings may explain why neuromyelitis optica primarily damages the central nervous system, but spares peripheral organs. PMID- 25698170 TI - The best basic science paper in multiple sclerosis in 2014: citicoline, remyelination and neuroprotection: commentary. PMID- 25698171 TI - Chitinase 3-like proteins as diagnostic and prognostic biomarkers of multiple sclerosis. AB - BACKGROUND: Despite sensitivity of MRI to diagnose multiple sclerosis (MS), prognostic biomarkers are still needed for optimized treatment. OBJECTIVE: The objective of this paper is to identify cerebrospinal fluid (CSF) diagnostic biomarkers of MS using quantitative proteomics and to analyze their expression at different disease stages. METHODS: We conducted differential analysis of the CSF proteome from control and relapsing-remitting MS (RRMS) patients followed by verification by ELISA of candidate biomarkers in CSF and serum in control, clinically isolated syndrome (CIS), RRMS and progressive MS (PMS) patients. RESULTS: Twenty-two of the 527 quantified proteins exhibited different abundances in control and RRMS CSF. These include chitinase 3-like protein 1 (CHI3L1) and 2 (CHI3L2), which showed a strong expression in brain of MS patients, especially in astrocytes and microglial cells from white matter plaques. CSF and serum CHI3L1 levels increased with the disease stage and CIS patients with high CSF (>189 ng/ml) and serum (>33 ng/ml) CHI3L1 converted more rapidly to RRMS (log rank test, p < 0.05 and p < 0.001, respectively). In contrast, CSF CHI3L2 levels were lower in PMS than in RRMS patients. Accordingly, CSF CHI3L1/CHI3L2 ratio accurately discriminated PMS from RRMS. CONCLUSIONS: CSF CHI3L1 and CHI3L2 and serum CHI3L1 might help to define MS disease stage and have a prognostic value in CIS. PMID- 25698172 TI - Cerebrospinal fluid levels of chitinase 3-like 1 and neurofilament light chain predict multiple sclerosis development and disability after optic neuritis. AB - BACKGROUND: Cerebrospinal fluid (CSF) biomarkers have been suggested to predict multiple sclerosis (MS) after clinically isolated syndromes, but studies investigating long-term prognosis are needed. OBJECTIVE: To assess the predictive ability of CSF biomarkers with regard to MS development and long-term disability after optic neuritis (ON). METHODS: Eighty-six patients with ON as a first demyelinating event were included retrospectively. Magnetic resonance imaging (MRI), CSF leukocytes, immunoglobulin G index and oligoclonal bands were registered. CSF levels of chitinase-3-like-1, osteopontin, neurofilament light chain, myelin basic protein, CCL2, CXCL10, CXCL13 and matrix metalloproteinase-9 were measured by enzyme-linked immunosorbent assay. Patients were followed up after 13.6 (range 9.6-19.4) years and 81.4% were examined, including Expanded Disability Status Scale and MS functional composite evaluation. 18.6% were interviewed by phone. Cox regression, multiple regression and Spearman correlation analyses were used. RESULTS: Forty-six (53.5%) developed clinically definite MS (CDMS) during follow-up. In a multivariate model MRI (p=0.0001), chitinase 3-like 1 (p=0.0033) and age (p=0.0194) combined predicted CDMS best. Neurofilament light-chain predicted long-term disability by the multiple sclerosis severity scale (p=0.0111) and nine-hole-peg-test (p=0.0202). Chitinase 3-like-1 predicted long-term cognitive impairment by the paced auditory serial addition test (p=0.0150). CONCLUSION: Neurofilament light-chain and chitinase-3 like-1 were significant predictors of long-term physical and cognitive disability. Furthermore, chitinase-3-like-1 predicted CDMS development. Thus, these molecules hold promise as clinically valuable biomarkers after ON as a first demyelinating event. PMID- 25698173 TI - Trichuris suis ova therapy in relapsing multiple sclerosis is safe but without signals of beneficial effect. AB - BACKGROUND: An observational study has suggested that relapsing-remitting multiple sclerosis patients with helminth infections have lower disease activity and progression than uninfected multiple sclerosis patients. OBJECTIVE: To evaluate the safety and efficacy on MRI activity of treatment with TSO in relapsing MS. METHODS: The study was an open-label, magnetic resonance imaging assessor-blinded, baseline-to-treatment study including ten patients with relapsing forms of multiple sclerosis. Median (range) age was 41 (24-55) years, disease duration 9 (4-34) years, Expanded Disability Status Scale score 2.5 (1 5.0), and number of relapses within the last two years 3 (2-5). Four patients received no disease modifying therapy, while six patients received IFN-beta. After an observational period of 8 weeks, patients received 2500 ova from the helminth Trichuris suis orally every second week for 12 weeks. Patients were followed with serial magnetic resonance imaging, neurological examinations, laboratory safety tests and expression of immunological biomarker genes. RESULTS: Treatment with Trichuris suis orally was well-tolerated apart from some gastrointestinal symptoms. Magnetic resonance imaging revealed 6 new or enlarged T2 lesions in the run-in period, 7 lesions in the early period and 21 lesions in the late treatment period. Two patients suffered a relapse before treatment and two during treatment. Eight patients developed eosinophilia. The expression of cytokines and transcription factors did not change. CONCLUSIONS: In a small group of relapsing multiple sclerosis patients, Trichuris suis oral therapy was well tolerated but without beneficial effect. PMID- 25698174 TI - Natalizumab discontinuation in patients with multiple sclerosis: Profiling risk and benefits at therapeutic crossroads. AB - OBJECTIVE: The objective of this paper is to estimate the risk of reaching well established disability milestones after withdrawal of natalizumab (NTZ) due to concern about the risk of progressive multifocal leukoencephalopathy in patients with multiple sclerosis (MS). METHODS: Data from 415 patients with MS followed-up for six years after starting NTZ were collected from seven tertiary MS centers. The risk of disability worsening, i.e. reaching Expanded Disability Status Scale (EDSS) scores of 4.0 or 6.0, and the likelihood of experiencing a disability reduction of one EDSS point (or more), were assessed by propensity score-adjusted analyses in patients who discontinued and in those still on treatment at the end of follow-up. RESULTS: A total of 318 patients who received standard NTZ treatment without experiencing evidence of disability worsening in the first two years were included in the six-year follow-up analysis, with 196 (61.6%) still on treatment and 122 (38.4%) discontinuing after a median time of 3.5 years. Patients in the discontinuing group had a more than two-fold increased risk of disability worsening (p = 0.007), and a 68% decreased likelihood of experiencing disability reduction (p = 0.009) compared with the continuing group. CONCLUSION: While discussing the overall risk/benefit profile of NTZ, patients should be advised that, in case of treatment discontinuation, the risk of disability worsening is one in three, and increases to one in two if the EDSS score at NTZ start is above 3.0. PMID- 25698175 TI - Human leukocyte antigen association with neuromyelitis optica in a south Indian population. PMID- 25698176 TI - Method for exploratory cluster analysis and visualisation of single-trial ERP ensembles. AB - BACKGROUND: The validity of ensemble averaging on event-related potential (ERP) data has been questioned, due to its assumption that the ERP is identical across trials. Thus, there is a need for preliminary testing for cluster structure in the data. NEW METHOD: We propose a complete pipeline for the cluster analysis of ERP data. To increase the signal-to-noise (SNR) ratio of the raw single-trials, we used a denoising method based on Empirical Mode Decomposition (EMD). Next, we used a bootstrap-based method to determine the number of clusters, through a measure called the Stability Index (SI). We then used a clustering algorithm based on a Genetic Algorithm (GA) to define initial cluster centroids for subsequent k-means clustering. Finally, we visualised the clustering results through a scheme based on Principal Component Analysis (PCA). RESULTS: After validating the pipeline on simulated data, we tested it on data from two experiments - a P300 speller paradigm on a single subject and a language processing study on 25 subjects. Results revealed evidence for the existence of 6 clusters in one experimental condition from the language processing study. Further, a two-way chi-square test revealed an influence of subject on cluster membership. COMPARISON WITH EXISTING METHOD(S): Our analysis operates on denoised single-trials, the number of clusters are determined in a principled manner and the results are presented through an intuitive visualisation. CONCLUSIONS: Given the cluster structure in some experimental conditions, we suggest application of cluster analysis as a preliminary step before ensemble averaging. PMID- 25698177 TI - The role of prediction and outcomes in adaptive cognitive control. AB - Humans adaptively perform actions to achieve their goals. This flexible behaviour requires two core abilities: the ability to anticipate the outcomes of candidate actions and the ability to select and implement actions in a goal-directed manner. The ability to predict outcomes has been extensively researched in reinforcement learning paradigms, but this work has often focused on simple actions that are not embedded in hierarchical and sequential structures that are characteristic of goal-directed human behaviour. On the other hand, the ability to select actions in accordance with high-level task goals, particularly in the presence of alternative responses and salient distractors, has been widely researched in cognitive control paradigms. Cognitive control research, however, has often paid less attention to the role of action outcomes. The present review attempts to bridge these accounts by proposing an outcome-guided mechanism for selection of extended actions. Our proposal builds on constructs from the hierarchical reinforcement learning literature, which emphasises the concept of reaching and evaluating informative states, i.e., states that constitute subgoals in complex actions. We develop an account of the neural mechanisms that allow outcome-guided action selection to be achieved in a network that relies on projections from cortical areas to the basal ganglia and back-projections from the basal ganglia to the cortex. These cortico-basal ganglia-thalamo-cortical 'loops' allow convergence - and thus integration - of information from non adjacent cortical areas (for example between sensory and motor representations). This integration is essential in action sequences, for which achieving an anticipated sensory state signals the successful completion of an action. We further describe how projection pathways within the basal ganglia allow selection between representations, which may pertain to movements, actions, or extended action plans. The model lastly envisages a role for hierarchical projections from the striatum to dopaminergic midbrain areas that enable more rostral frontal areas to bias the selection of inputs from more posterior frontal areas via their respective representations in the basal ganglia. PMID- 25698178 TI - Edge reconstruction in armchair phosphorene nanoribbons revealed by discontinuous Galerkin density functional theory. AB - With the help of our recently developed massively parallel DGDFT (Discontinuous Galerkin Density Functional Theory) methodology, we perform large-scale Kohn-Sham density functional theory calculations on phosphorene nanoribbons with armchair edges (ACPNRs) containing a few thousands to ten thousand atoms. The use of DGDFT allows us to systematically achieve a conventional plane wave basis set type of accuracy, but with a much smaller number (about 15) of adaptive local basis (ALB) functions per atom for this system. The relatively small number of degrees of freedom required to represent the Kohn-Sham Hamiltonian, together with the use of the pole expansion the selected inversion (PEXSI) technique that circumvents the need to diagonalize the Hamiltonian, results in a highly efficient and scalable computational scheme for analyzing the electronic structures of ACPNRs as well as their dynamics. The total wall clock time for calculating the electronic structures of large-scale ACPNRs containing 1080-10,800 atoms is only 10-25 s per self-consistent field (SCF) iteration, with accuracy fully comparable to that obtained from conventional planewave DFT calculations. For the ACPNR system, we observe that the DGDFT methodology can scale to 5000-50,000 processors. We use DGDFT based ab initio molecular dynamics (AIMD) calculations to study the thermodynamic stability of ACPNRs. Our calculations reveal that a 2 * 1 edge reconstruction appears in ACPNRs at room temperature. PMID- 25698179 TI - Concise total syntheses of (+/-)-mesembrane and (+/-)-crinane. AB - A straightforward and unified strategy to access Amaryllidaceae alkaloids comprising a cis-3a-aryloctahydroindole scaffold has been developed. The strategy features Eschenmoser-Claisen rearrangement of allylalcohol as a key step for the installation of all-carbon quaternary stereocenters present in these alkaloids. The consequent iodolactonization-reduction-oxidation sequence beautifully assembles the advanced intermediate keto-aldehyde 10a, b in synthetically viable yields. The methodology has been successfully applied in the efficient syntheses of (+/-)-mesembrane (1a) and (+/-)-crinane (2a). PMID- 25698180 TI - Effectiveness of a clinical protocol implemented to standardize snakebite management in Iran: initial evaluation. AB - OBJECTIVE: This study was designed to evaluate the effectiveness of a new protocol implemented to standardize snakebite management in Iran. METHODS: In this study, 27 patients treated according to the new protocol in 2012 (P+) were compared with 22 patients treated according to the previous modality in the year before implementation of the protocol (P-) in Mashhad Medical Toxicology Centre (MTC). Demographic characteristics and treatment details of all patients were recorded prospectively. Envenomation severity of each victim was assessed according to snakebite severity score (SSS). RESULTS: After implementation of the protocol, a smaller percentage of patients received antivenom (AV) therapy (78% vs 95%; P=.079). In spite of no significant difference in baseline severity of envenomation between the 2 groups (SSS [mean+/-SD], 34.8+/-18.1 vs 35.5+/-17.4; P=.801), the P+ group received significantly fewer AV vials (8.4+/-6.8 vs 12.1+/ 5.6 vials; P=.042) and had a significantly shorter length of hospital stay (2.2+/ 1.5 vs 3.2+/-1.8 days; P=.027). Moreover, smaller proportion of P+ patients experienced recurrence of venom-induced effects; however, the difference was not significant (18.5% vs 36%; P=.159). The reduction in use of antiallergy treatments to prevent or treat acute hypersensitivity reactions approached statistical significance (41% vs 68%; P=.051). These findings denote a reduction in AV use of approximately 4 vials and a reduction in hospital stay of 1 day for each patient, which translates to approximately $196/patient in healthcare cost savings. CONCLUSIONS: Implementation of a snakebite management protocol at MTC reduced overall antivenom usage, use of antiallergy interventions, and length of hospital stay. PMID- 25698181 TI - Retrospective study on search and rescue operations in two prealps areas of Italy. AB - OBJECTIVES: The rising number of people involved in outdoor recreation and tourism in mountain forest and wilderness areas close to urban areas has led to an increase of rescue efforts in the last decades. The study analyzes rescue operations in 2 mountain areas of the Veneto Prealps in Italy. METHODS: A retrospective review of search and rescue incident reports for a 20-year period was performed. The study also takes into consideration any differences between accidents in the 2 areas in relation to the morphology and mountain activities involved. RESULTS: There has been an increase in accidents, and the greater participation in mountain activities does not seem to be accompanied by an improvement in knowledge of the specific risks in this kind of environment. Inexperience is reflected in many reasons for callouts and is related to the remarkable rise in the number of rescued but uninjured people; the trend of fatalities and injuries is otherwise stable. Comparison of the 2 areas reveals differences in accidents mainly attributable to diversities in mountain activities involved that led to different health consequences. CONCLUSIONS: Search and rescue missions in mountain areas are dangerous for rescuers and made difficult by the severe environment. The knowledge of accident characteristics is therefore very important and is necessary to reduce risks for tourists and healthcare costs. To tackle the problem of safety there is also a need for more information in the form of preventive education and publicity about the typical hazards. PMID- 25698182 TI - Wilderness Emergency Medical Services Medical Director Course: core content developed with Delphi technique. AB - The National Association of Emergency Medical Services Physicians' (NAEMSP) position on the role of medical oversight within an operational Emergency Medical Service (EMS) program highlights the importance of integrating specially trained medical directors within the structure of these programs. In response, the NAEMSP Wilderness EMS (WEMS) Committee recognized the need for the development of an educational curriculum to provide physicians with the unique skills needed to be a medical director for a WEMS agency. This paper describes the Delphi process used to create the subject matter core content, as well as the actual core content developed. This core content was the foundation for the development of a specific WEMS medical director curriculum, the Wilderness EMS Medical Director Course. PMID- 25698183 TI - Supported depression self-care may prevent major depression in community-dwelling older adults with chronic physical conditions and co-morbid depressive symptoms. PMID- 25698184 TI - Magnetic resonance imaging in clinical medicine: current status and potential future developments in China. PMID- 25698185 TI - Challenges to the Chinese health insurance system: users' and service providers' perspectives. PMID- 25698186 TI - Semi-quantitative assessment of brain maturation by conventional magnetic resonance imaging in neonates with clinically mild hypoxic-ischemic encephalopathy. AB - BACKGROUND: Mild hypoxic-ischemic encephalopathy (HIE) injury is becoming the major type in neonatal brain diseases. The aim of this study was to assess brain maturation in mild HIE neonatal brains using total maturation score (TMS) based on conventional magnetic resonance imaging (MRI). METHODS: Totally, 45 neonates with clinically mild HIE and 45 matched control neonates were enrolled. Gestated age, birth weight, age after birth and postmenstrual age at magnetic resonance (MR) scan were homogenous in the two groups. According to MR findings, mild HIE neonates were divided into three subgroups: Pattern I, neonates with normal MR appearance; Pattern II, preterm neonates with abnormal MR appearance; Pattern III, full-term neonates with abnormal MR appearance. TMS and its parameters, progressive myelination (M), cortical infolding (C), involution of germinal matrix tissue (G), and glial cell migration bands (B), were employed to assess brain maturation and compare difference between HIE and control groups. RESULTS: The mean of TMS was significantly lower in mild HIE group than it in the control group (mean +/- standard deviation [SD] 11.62 +/- 1.53 vs. 12.36 +/- 1.26, P < 0.001). In four parameters of TMS scores, the M and C scores were significantly lower in mild HIE group. Of the three patterns of mild HIE, Pattern I (10 cases) showed no significant difference of TMS compared with control neonates, while Pattern II (22 cases), III (13 cases) all had significantly decreased TMS than control neonates (mean +/- SD 10.56 +/- 0.93 vs. 11.48 +/- 0.55, P < 0.05; 12.59 +/- 1.28 vs. 13.25 +/- 1.29, P < 0.05). It was M, C, and GM scores that significantly decreased in Pattern II, while for Pattern III, only C score significantly decreased. CONCLUSIONS: The TMS system, based on conventional MRI, is an effective method to detect delayed brain maturation in clinically mild HIE. The conventional MRI can reveal the different retardations in subtle structures and development processes among the different patterns of mild HIE. PMID- 25698187 TI - Incidence of vascular anomalies and variants associated with unilateral venous pulsatile tinnitus in 242 patients based on dual-phase contrast-enhanced computed tomography. AB - BACKGROUND: A comprehensive assessment of various vascular anomalies and variants associated with venous pulsatile tinnitus (PT) by radiography is essential for therapeutic planning and improving the clinical outcome. This study evaluated the incidence of various vascular anomalies and variants on the PT side and determined whether these lesions occurred as multiple or single entities. METHODS: The dual-phase contrast-enhanced computed tomography images of 242 patients with unilateral venous PT were retrospectively reviewed. The vascular anomalies and variants on the symptomatic and asymptomatic sides were analyzed, and the incidences of anomalies or variants on each side were compared. The number of anomalies and variants on the symptomatic side in each patient was calculated. RESULTS: (1) A total 170 patients (170/242) had more than one anomaly or variant on the symptomatic side, and 58 patients (58/242) had a single lesion on tomography. (2) There was a statistically significant difference in the incidence of dehiscent sigmoid plate (P = 0.000), lateral sinus stenosis (P = 0.014), high jugular bulb (P = 0.000), sigmoid sinus diverticulum (P = 0.000), jugular bulb diverticulum (P = 0.000), dehiscent jugular bulb (P = 0.000), and a large emissary vein (P = 0.006) between the symptomatic and asymptomatic sides. (3) Dehiscent sigmoid plate (86.4%) was the most frequent lesion on the symptomatic side, followed by lateral sinus stenosis (55.8%), high jugular bulb (47.1%), sigmoid sinus diverticulum (34.3%), jugular bulb diverticulum (13.6%), dehiscent jugular bulb (13.6%), large emissary vein (4.1%), sinus thrombosis (1.2%), and petrosquamosal sinus (0.8%). CONCLUSIONS: Various vascular anomalies and variants occur more frequently on the venous PT side. Preliminary findings suggest that venous PT patients may have multiple vascular anomalies or variants on the symptomatic side. PMID- 25698188 TI - Improved performance in differentiating benign from malignant sinonasal tumors using diffusion-weighted combined with dynamic contrast-enhanced magnetic resonance imaging. AB - BACKGROUND: Differentiating benign from malignant sinonsal lesions is essential for treatment planning as well as determining the patient's prognosis, but the differentiation is often difficult in clinical practice. The study aimed to determine whether the combination of diffusion-weighted (DW) and dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) can improve the performance in differentiating benign from malignant sinonasal tumors. METHODS: This retrospective study included 197 consecutive patients with sinonasal tumors (116 malignant tumors and 81 benign tumors). All patients underwent both DW and DCE MRI in a 3-T magnetic resonance scanner. Two different settings of b values (0,700 and 0,1000 s/mm 2 ) and two different strategies of region of interest (ROI) including whole slice (WS) and partial slice (PS) were used to calculate apparent diffusion coefficients (ADCs). A DW parameter with WS ADCs b0,1000 and two DCE-MRI parameters (time intensity curve [TIC] and time to peak enhancement [Tpeak]) were finally combined to use in differentiating the benign from the malignant tumors in this study. RESULTS: The mean ADCs of malignant sinonasal tumors (WS ADCs b0,1000 = 1.084 * 10-3 mm 2 /s) were significantly lower than those of benign tumors (WS ADCs b0,1000 = 1.617 * 10-3 mm 2 /s, P < 0.001). The accuracy using WS ADCs b0,1000 alone was 83.7% in differentiating the benign from the malignant tumors (85.3% sensitivity, 81.2% specificity, 86.4% positive predictive value [PPV], and 79.5% negative predictive value [NPV]). The accuracy using DCE with Tpeak and TIC alone was 72.1% (69.1% sensitivity, 74.1% specificity, 77.5% PPV, and 65.1% NPV). Using DW-MRI parameter was superior than using DCE parameters in differentiation between benign and malignant sinonasal tumors (P < 0.001). The accuracy was 87.3% (90.5% sensitivity, 82.7% specificity, 88.2% PPV, and 85.9% NPV) using DW-MRI combined with DCE-MRI, which was superior than that using DCE-MRI alone or using DW-MRI alone (both P < 0.001) in differentiating the benign from the malignant tumors. CONCLUSIONS: Diffusion weighted combined with DCE-MRI can improve imaging performance in differentiating benign from malignant sinonasal tumors, which has the potential to improve diagnostic accuracy and to provide added value in the management for these tumors. PMID- 25698189 TI - Amplitude of low-frequency oscillations in Parkinson's disease: a 2-year longitudinal resting-state functional magnetic resonance imaging study. AB - BACKGROUND: Neuroimaging studies have found that functional changes exist in patients with Parkinson's disease (PD). However, the majority of functional magnetic resonance imaging (fMRI) studies in patients with PD are task-related and cross-sectional. This study investigated the functional changes observed in patients with PD, at both baseline and after 2 years, using resting-state fMRI. It further investigated the relationship between whole-brain spontaneous neural activity of patients with PD and their clinical characteristics. METHODS: Seventeen patients with PD underwent an MRI procedure at both baseline and after 2 years using resting-state fMRI that was derived from the same 3T MRI. In addition, 20 age- and sex-matched, healthy controls were examined using resting state fMRI. The fractional amplitude of low-frequency fluctuation (fALFF) approach was used to analyze the fMRI data. Nonlinear registration was used to model within-subject changes over the scanning interval, as well as changes between the patients with PD and the healthy controls. A correlative analysis between the fALFF values and clinical characteristics was performed in the regions showing fALFF differences. RESULTS: Compared to the control subjects, the patients with PD showed increased fALFF values in the left inferior temporal gyrus, right inferior parietal lobule (IPL) and right middle frontal gyrus. Compared to the baseline in the 2 years follow-up, the patients with PD presented with increased fALFF values in the right middle temporal gyrus and right middle occipital gyrus while also having decreased fALFF values in the right cerebellum, right thalamus, right striatum, left superior parietal lobule, left IPL, left precentral gyrus, and left postcentral gyrus (P < 0.01, after correction with AlphaSim). In addition, the fALFF values in the right cerebellum were positively correlated with the Unified PD Rating Scale (UPDRS) motor scores (r = 0.51, P < 0.05, uncorrected) and the change in the UPDRS motor score (r = 0.61, P < 0.05, uncorrected). CONCLUSIONS: The baseline and longitudinal changes of the fALFF values in our study suggest that dysfunction in the brain may affect the regions related to cortico-striato-pallido-thalamic loops and cerebello-thalamo-cortical loops as the disease progresses and that alterations to the spontaneous neural activity of the cerebellum may also play an important role in the disease's progression in patients with PD. PMID- 25698190 TI - Frequency-specific alterations of large-scale functional brain networks in patients with Alzheimer's disease. AB - BACKGROUND: Previous studies have indicated that the cognitive deficits in patients with Alzheimer's disease (AD) may be due to topological deteriorations of the brain network. However, whether the selection of a specific frequency band could impact the topological properties is still not clear. Our hypothesis is that the topological properties of AD patients are also frequency-specific. METHODS: Resting state functional magnetic resonance imaging data from 10 right handed moderate AD patients (mean age: 64.3 years; mean mini mental state examination [MMSE]: 18.0) and 10 age and gender-matched healthy controls (mean age: 63.6 years; mean MMSE: 28.2) were enrolled in this study. The global efficiency, the clustering coefficient (CC), the characteristic path length (CpL), and "small-world" property were calculated in a wide range of thresholds and averaged within each group, at three different frequency bands (0.01-0.06 Hz, 0.06-0.11 Hz, and 0.11-0.25 Hz). RESULTS: At lower-frequency bands (0.01-0.06 Hz, 0.06-0.11 Hz), the global efficiency, the CC and the "small-world" properties of AD patients decreased compared to controls. While at higher-frequency bands (0.11 0.25 Hz), the CpL was much longer, and the "small-world" property was disrupted in AD, particularly at a higher threshold. The topological properties changed with different frequency bands, suggesting the existence of disrupted global and local functional organization associated with AD. CONCLUSIONS: This study demonstrates that the topological alterations of large-scale functional brain networks in AD patients are frequency dependent, thus providing fundamental support for optimal frequency selection in future related research. PMID- 25698191 TI - Application of computed tomography virtual noncontrast spectral imaging in evaluation of hepatic metastases: a preliminary study. AB - OBJECTIVE: The objective was to qualitatively and quantitatively evaluate hepatic metastases using computed tomography (CT) virtual noncontrast (VNC) spectral imaging in a retrospective analysis. METHODS: Forty hepatic metastases patients underwent CT scans including the conventional true noncontrast (TNC) and the tri phasic contrast-enhanced dual energy spectral scans in the hepatic arterial, portal venous, and equilibrium phases. The tri-phasic spectral CT images were used to obtain three groups of VNC images including in the arterial (VNCa), venous (VNCv), and equilibrium (VNCe) phase by the material decomposition process using water and iodine as a base material pair. The image quality and the contrast-to-noise ratio (CNR) of metastasis of the four groups were compared with ANOVA analysis. The metastasis detection rates with the four nonenhanced image groups were calculated and compared using the Chi-square test. RESULTS: There were no significant differences in image quality among TNC, VNCa and VNCv images (P > 0.05). The quality of VNCe images was significantly worse than that of other three groups (P < 0.05). The mean CNR of metastasis in the TNC and VNCs images was 1.86, 2.42, 1.92, and 1.94, respectively; the mean CNR of metastasis in VNCa images was significantly higher than that in other three groups (P < 0.05), while no statistically significant difference was observed among VNCv, VNCe and TNC images (P > 0.05). The metastasis detection rate of the four nonenhanced groups with no statistically significant difference (P > 0.05). CONCLUSIONS: The quality of VNCa and VNCv images is identical to that of TNC images, and the metastasis detection rate in VNC images is similar to that in TNC images. VNC images obtained from arterial phase show metastases more clearly. Thus, VNCa imaging may be a surrogate to TNC imaging in hepatic metastasis diagnosis. PMID- 25698192 TI - Amide proton transfer magnetic resonance imaging of Alzheimer's disease at 3.0 Tesla: a preliminary study. AB - BACKGROUND: Amide proton transfer (APT) imaging has recently emerged as an important contrast mechanism for magnetic resonance imaging (MRI) in the field of molecular and cellular imaging. The aim of this study was to evaluate the feasibility of APT imaging to detect cerebral abnormality in patients with Alzheimer's disease (AD) at 3.0 Tesla. METHODS: Twenty AD patients (9 men and 11 women; age range, 67-83 years) and 20 age-matched normal controls (11 men and 9 women; age range, 63-82 years) underwent APT and traditional MRI examination on a 3.0 Tesla MRI system. The magnetic resonance ratio asymmetry (MTR asym ) values at 3.5 ppm of bilateral hippocampi (Hc), temporal white matter regions, occipital white matter regions, and cerebral peduncles were measured on oblique axial APT images. MTR asym (3.5 ppm) values of the cerebral structures between AD patients and control subjects were compared with independent samples t-test. Controlling for age, partial correlation analysis was used to investigate the associations between mini-mental state examination (MMSE) and the various MRI measures among AD patients. RESULTS: Compared with normal controls, MTR asym (3.5 ppm) values of bilateral Hc were significantly increased in AD patients (right 1.24% +/- 0.21% vs. 0.83% +/- 0.19%, left 1.18% +/- 0.18% vs. 0.80%+/- 0.17%, t = 3.039, 3.328, P = 0.004, 0.002, respectively). MTR asym (3.5 ppm) values of bilateral Hc were significantly negatively correlated with MMSE (right r = -0.559, P = 0.013; left r = -0.461, P = 0.047). CONCLUSIONS: Increased MTR asym (3.5 ppm) values of bilateral Hc in AD patients and its strong correlations with MMSE suggest that APT imaging could potentially provide imaging biomarkers for the noninvasive molecular diagnosis of AD. PMID- 25698193 TI - Comparison of magnetic resonance elastography and diffusion-weighted imaging for staging hepatic fibrosis. AB - BACKGROUND: To compare the diagnostic values of magnetic resonance elastography (MRE) and diffusion-weighted imaging (DWI) in staging hepatic fibrosis (HF) in an animal model. METHODS: This study consisted of 44 rabbits served as HF group and 9 normal rabbits. HF group was divided into two subgroups: Group A (n = 32) and Group B (n = 12). Rabbits in Group B were served as a complementary group when rabbits in Group A suddenly died during the study. Rabbits from control and Group A underwent abdominal MR imaging (MRI), MRE, and DWI. In Group A, random eight rabbits underwent MRI examinations at 4, 5, 6, 10 weeks after carbon tetrachloride oil subcutaneous injection. Liver stiffness (LS) and apparent diffusion coefficient (ADC) values of liver parenchyma were measured. The diagnostic performance of MRE and DWI for staging HF was compared using the receiver operating characteristic curve analysis on the basis of the histopathological analysis of HF. RESULTS: Significant differences of LS and DWI values were present among HF stages (P < 0.005). The LS values measured on MRE (r = 0.838, P < 0.001) were more strongly correlated with the HF stages than with ADC values (r = -0.527, P < 0.001). The area under the receiver operating characteristic curve values of LS were significantly larger than those of DWI were for discriminating two stages of HF (0.979 vs. 0.712 for >= S1, 0.922 vs. 0.699 for >= S2). MRE showed higher specificity for predicting all stages of HF compared to DWI. CONCLUSIONS: MRE more strongly correlated with the HF stages than DWI and is more specific in predicting all HF stages. PMID- 25698194 TI - Monitoring the progression of renal fibrosis by T2-weighted signal intensity and diffusion weighted magnetic resonance imaging in cisplatin induced rat models. AB - BACKGROUND: Diffusion weighted imaging (DWI), with the applying of intravoxel incoherent motion model, has showed promising results in obtaining additional information about microperfusion and tubular flow associated with morphologic changes in chronic kidney diseases. The study aims to evaluate the potential of T2-weighted signal intensity (SI) and DWI with mono- and bi-exponential models to reflect the serial changes on cisplatin (CP) induced rat renal fibrosis models. METHODS: Magnetic resonance exams were performed prior to and 2 nd day, 4 th day, 6 th day, 8 th day, 2 nd week, 3 rd week and 4 th week after CP injection at a 3.0T with an animal coil. Besides T2-weighted images (T2WI), DWI of 13 b values from 0 to 1500 s/mm 2 was acquired. Apparent diffusion coefficient (ADC), fluid fraction f, pure diffusivity D and pseudodiffusivity DFNx01 values were calculated. The regions of interest were placed on cortex (CO), outer stripe of the outer medulla (OM) and inner stripe of the outer medulla (OM), parameters were measured and compared among different time points. Five rats were scarified at each time point for pathological examination. RESULTS: OM revealed remarkable hyperintense and broadened before it became an obscure thread, while CO demonstrated moderate hyperintense and IM didn't show significant change on T2WI. On all three stripes, ADC values decreased firstly then kept increasing since the 4 th day; f values decreased on all stripes; D values had a tendency to increase with fluctuations but the changes didn't achieve statistical significance; DFNx01 values increased at the 2 nd day then tended to be steady thereafter. Pathological findings revealed tubules epitheliums swelling followed by inflammation cells infiltration, interstitial fibrosis was observed since the 2 nd week. CONCLUSIONS: All of T2-weighted SI, ADC, and biexponential models parameters vary during fibrotic process; biexponential model is superior to monoexponential model in separating changes of microperfusion together with tubular flow from pure diffusion. PMID- 25698195 TI - How do patients and providers react to different incentives in the Chinese multiple health security systems? AB - BACKGROUND: China has achieved universal health insurance coverage. This study examined how patients and hospitals react to the different designs of the plans and to monitoring of patients by the local authority in the Chinese multiple health security schemes. METHODS: The sample for analysis consisted of 1006 orthopedic inpatients who were admitted between January and December 2011 at a tertiary teaching hospital located in Beijing. We conducted general linear regression analyses to investigate whether medical expenditure and length of stay differed according to the different incentives. RESULTS: Patients under plans with lower copayment rates consumed significantly more medication compared with those under plans with higher copayment rates. Under plans with an annual ceiling for insurance coverage, patients spent significantly more in the second half of the year than in the first half of the year. The length of stay was shorter among patients when there were government monitoring and a penalty to the hospital service provider. CONCLUSIONS: Our results indicate that the different designs and monitoring of the health security systems in China cause opportunistic behavior by patients and providers. Reformation is necessary to reduce those incentives, and improve equity and efficiency in healthcare use. PMID- 25698196 TI - Impact of body mass index on the clinical outcomes after percutaneous coronary intervention in patients >= 75 years old. AB - BACKGROUND: The impact of body mass index (BMI) on the clinical outcomes after percutaneous coronary intervention (PCI) in patients >= 75 years old remained unclear. METHODS: A total of 1098 elderly patients undergoing PCI with stent implantation were recruited. Patients were divided into four groups by the value of BMI: Underweight (<= 20.0 kg/m 2 ), normal weight (20.0-24.9 kg/m 2 ), overweight (25.0-29.9 kg/m 2 ) and obese (>= 30.0 kg/m 2 ). Major clinical outcomes after PCI were compared between the groups. The primary endpoint was defined as in-hospital major adverse cardiovascular events (MACEs), which included death, myocardial infarction (MI) and target vessel revascularization. The secondary endpoint was defined as 1 year death. Logistic regression analysis was performed to adjust for the potential confounders. RESULTS: Totally, 1077 elderly patients with available BMIs were included in the analysis. Patients of underweight, normal weight, overweight and obese accounted for 5.6%, 45.4%, 41.5% and 7.5% of the population, respectively. Underweight patients were more likely to attract ST-segment elevation MI, and get accompanied with anemia or renal dysfunction. Meanwhile, they were less likely to achieve thrombolysis in MI 3 grade flow after PCI, and receive beta-blocker, angiotensin converting enzyme inhibitor or angiotensin receptor blocker after discharge. In underweight, normal weight, overweight and obese patients, in-hospital MACE were 1.7%, 2.7%, 3.8%, and 3.7% respectively (P = 0.68), and 1 year mortality rates were 5.0%, 3.9%, 5.1% and 3.7% (P = 0.80), without significant difference between the groups. Multivariate regression analysis showed that the value of BMI was not associated with in-hospital MACE in patients at 75 years old. CONCLUSIONS: The BMI "obese paradox" was not found in patients >= 75 years old. It was suggested that BMI may not be a sensitive predictor of adverse cardiovascular events in elderly patients. PMID- 25698197 TI - Effect of desmopressin on platelet aggregation and blood loss in patients undergoing valvular heart surgery. AB - BACKGROUND: Blood loss after cardiac surgery can be caused by impaired platelet (PLT) function after cardiopulmonary bypass. Desmopressin or 1-deamino-8-D arginine vasopressin (DDAVP) is a synthetic analog of vasopressin. DDAVP can increase the level of von Willebrand factor and coagulation factor VIII, thus it may enhance PLT function and improve coagulation. In this study, we assessed the effects of DDAVP on PLT aggregation and blood loss in patients undergoing cardiac surgery. METHODS: A total of 102 patients undergoing valvular heart surgery (from October 2010 to June 2011) were divided into DDAVP group (n = 52) and control group (n = 50). A dose of DDAVP (0.3 MUg/kg) was administered to the patients intravenously when they were being re-warmed. At the same time, an equal volume of saline was given to the patients in the control group. PLT aggregation rate was measured with the AggRAM four-way PLT aggregation measurement instrument. The blood loss and transfusion, hemoglobin levels, PLT counts, and urine outputs at different time were recorded and compared. RESULTS: The postoperative blood loss in the first 6 h was significantly reduced in DDAVP group (202 +/- 119 ml vs. 258 +/- 143 ml, P = 0.023). The incidence of fresh frozen plasma (FFP) transfusion was decreased postoperatively in DDAVP group (3.8% vs. 12%, P = 0.015). There was no significant difference in the PLT aggregation, urine volumes, red blood cell transfusions and blood loss after 24 h between two groups. CONCLUSIONS: A single dose of DDAVP can reduce the first 6 h blood loss and FFP transfusion postoperatively in patients undergoing valvular heart surgery, but has no effect on PLT aggregation. PMID- 25698198 TI - Combining endometrium sampling device and SurePath preparation to screen for endometrial carcinoma: a validation study. AB - BACKGROUND: The aim of this study was to compare specimen adequacy of SAP-1 provided for cytology with that of dilation and curettage (D & C) or hysteroscopy for histology, and evaluate the accuracy of combining endometrium sampling by SAP 1 and liquid-based cytology using SurePath preparation for screening endometrial carcinoma and its precursor. METHODS: Endometrial specimens from women (n = 1514) with risk factors were obtained using an SAP-1 device for cytological analysis; histological samples were obtained from 375 of these women who underwent D & C or hysteroscopy. Cytological specimens were prepared to liquid-based smear using SurePath technology and stained by Papanicolaou. Histological samples were processed in routine pathology and stained by hematoxylin and eosin. RESULTS: Adequate specimens for cytology were obtained from 1458/1541 patients (96.3%), while adequate samples for pathology were obtained from 285/375 patients (76%). However, for postmenopausal women, 1006 of 1045 cytology (86.3%) were adequate, 153 of 238 histology (64.3%) were adequate, it was easier to collect cytological specimens than histological specimens (P < 0.05). The accuracy of endometrial cytology for detecting endometrial carcinoma and its precursor was 92.4% (sensitivity, 73%; specificity, 95.8%; positive predictive value, 75%; and negative predictive value, 95.3%). CONCLUSIONS: Endometrial cytology using SAP-1 sampling and SurePath preparation may be a reliable approach for screening patients with endometrial carcinoma and its precursor. PMID- 25698199 TI - Association between Tourette syndrome and the dopamine D3 receptor gene rs6280. AB - BACKGROUND: Tourette syndrome (TS) is a complex, heterozygous genetic disorder. The number of molecular genetic studies have investigated several candidate genes, particularly those implicated in the dopamine system. The dopamine D3 receptor (DRD3) gene has been considered as a candidate gene in TS. There was not any report about the association study of TS and DRD3 gene in Han Chinese population. We combined a case-control genetic association analysis and nuclear pedigrees transmission disequilibrium test (TDT) analysis to investigate the association between DRD3 gene rs6280 single nucleotide polymorphisms (SNPs) and TS in a Han Chinese population. METHODS: A total of 160 TS patients was diagnosed by the diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. The DRD3 gene rs6280 SNPs were genotyped by TaqMan SNP genotyping assay technique in all subjects. We used a case-control genetic association analysis to compare the difference in genotype and allele frequencies between 160 TS patients and 90 healthy controls. At the same time, we used TDT analysis to identify the DRD3 gene rs6280 transmission disequilibrium among 101 nuclear pedigrees. RESULTS: The genotype and allele frequency of DRD3 gene rs6280 SNPs had no statistical difference between control group (90) and TS group (160) (chi2 = 3.647, P = 0.161; chi2 = 0.643, P = 0.423) using Chi-squared test. At the basis of the 101 nuclear pedigrees, TDT analysis showed no transmission disequilibrium of DRD3 gene rs6280 SNPs (chi2 = 0; P = 1). CONCLUSIONS: Our findings provide no evidence for an association between DRD3 gene rs6280 and TS in the Han Chinese population. PMID- 25698200 TI - Relevant factors of estrogen changes of myopia in adolescent females. AB - BACKGROUND: Gender is one of the risk factors accounting for the high prevalence of adolescent myopia. Considerable research results have shown that myopia incidence of female is higher than that of male. This study aimed to analyze the correlation between ocular parameters and serum estrogen level and to investigate the vision changes along with estrogen change in menstrual cycle of adolescent females. METHODS: A total of 120 young females aged between 15 and 16 years, diagnosed with myopia were recruited. Spherical lens, cylindrical lens, axis, interpupillary distance (IPD), and vision in each tested eye of the same subject were measured by automatic optometry and comprehensive optometry, with repetition of all measurements in the menstrual cycle of the 2 nd or 3 rd days, 14 th days, and 28 th days, respectively. Serum estradiol (E 2 ) levels were assayed by chemiluminescence immunoassay at the same three times points of the menstrual cycle mentioned above. RESULTS: In young females with myopia, the spherical lens showed a statistically significant difference among all different time in menstrual cycle (all P < 0.0001). The cylindrical lens, axis, and IPD were changed significantly during the menstrual cycle (P < 0.05). The vision of the three different time points in menstrual cycle had a significant difference (chi2 = 6.35, P = 0.042). The vision during the 14 th and 28 th day was higher compared to that on the 2 nd or 3 rd days (P = 0.021). Serum E 2 levels were significantly different at different time points in menstrual cycle (P < 0.05). E 2 levels reached its maximum value on the 14 th day and the minimum value on the 2 nd or 3 rd day. CONCLUSIONS: In adolescent females, the spherical lens and other related ocular parameters vary sensitively with different levels of E 2 in menstrual cycle. Vision in late menstrual stage is significantly higher than that in premenstrual stage. PMID- 25698201 TI - P70S6 kinase phosphorylation: a new site to assess pharmacodynamy of sirolimus. AB - BACKGROUND: The phosphorylation of p70S6 kinase (p70S6K) represents an important target for sensitive detection on pharmacodynamic effects of sirolimus, but the methods of assessing p70S6K phosphorylation are still unclear. The aim of this study was to investigate p70S6K phosphorylation located down-stream of the mammalian target of rapamycin (mTOR) pathway in peripheral blood mononuclear cells (PBMCs) of liver transplant patients through different methods. METHODS: Seventy-five liver transplant recipients from Beijing Chaoyang Hospital of the Capital Medical University were analyzed in this study. Patients were divided into three groups, patient treated with sirolimus (n = 22), patient treated with tacrolimus (n = 30), patient treated with cyclosporine (n = 23). The p70S6K phosphorylation of PBMCs in patients and healthy control (HC, n = 12) were analyzed by phospho-flow cytometry and Western blotting. A correlation analysis of data from phospho-flow cytometry and Western blotting was performed. Intra assay variability of p70S6K phosphorylation in HC and different patients were measured. RESULTS: Intra-assay variability of p70S6K phosphorylation in phospho flow cytometry was from 4.1% to 8.4% and in Western blotting was from 8.2% to 18%. The p70S6K phosphorylation in patients receiving a sirolimus (19.5 +/- 7.7) was significantly lower than in HC (50.1 +/- 11.3, P < 0.001), tacrolimus (37.7 +/- 15.7, P < 0.001) or cyclosporine treated patients (41.7 +/- 11.7, P < 0.001). The p70S6K phosphorylation in HC (50.1 +/- 11.3) was significantly higher than in tacrolimus (37.7 +/- 15.7, P < 0.01) or cyclosporine-treated patients (41.7 +/- 11.7, P < 0.01). There was correlation between data from phospho-flow cytometry and data from Western blotting (r = 0.88, P < 0.001). CONCLUSIONS: The degree of mTOR inhibition by assessing p70S6K phosphorylation was established by phospho flow cytometry and Western blotting. Assessment of p70S6K phosphorylation may play an adjunct role to on pharmacodynamically guide and individualize sirolimus based on immunosuppression. PMID- 25698202 TI - Upregulation of miR-1280 expression in non-small cell lung cancer tissues. AB - BACKGROUND: Non-small cell lung cancer (NSCLC) is a prolific and high-mortality disease with few effective treatments. Although the detection and surgical techniques for NSCLC continue to advance, the survival rate for the patients with NSCLC remains poor. Enhanced predictive biomarkers such as microRNAs (miRNAs) are needed at the time of diagnosis to better tailor therapies for patients. This study focused on the expression of miR-1280 in NSCLC tissues and distal normal tissues in order to explore the association between miR-1280 expression and NSCLC. METHODS: A total of 72 newly diagnosed primary NSCLC patients were enrolled in this study. Quantitative real-time polymerase chain reaction (PCR) was performed to identify the expression level of miR-1280 in the NSCLC tissues and distal normal tissues of these patients. RESULTS: The miR-1280 expression was significantly higher in the NSCLC tissues (0.084 +/- 0.099) than distal normal tissues (0.014 +/- 0.015, P = 0.009). In 54 patients (75%), the miR-1280 expression in the NSCLC tissues was upregulated (2-DeltaDeltact > 2), and no case showed a downregulation of miR-1280 expression. CONCLUSIONS: The expression level of miR-1280 could be regarded as a biomarker for NSCLC. PMID- 25698203 TI - Using a surgeon-modified iliac branch device to preserve the internal iliac artery during endovascular aneurysm repair: single-center experiences and early results. AB - BACKGROUND: To evaluate the feasibility of a new surgeon-modified iliac branch device (IBD) technique to maintain pelvic perfusion in the management of common iliac artery (CIA) aneurysm during endovascular aneurysm repair (EVAR). METHODS: From January 2011 to December 2013, a new surgeon-modified IBD technique was performed in department of vascular surgery of Peking Union Medical College Hospital in five patients treated for CIA aneurysm with or without abdominal aortic aneurysm. A stent-graft limb was initially deployed in vitro, anastomosed with vascular graft, creating a modified IBD reloaded into a larger sheath, with or without a guidewire preloaded into the side branch. The reloaded IBD was then placed in the iliac artery, with a covered stent bridging internal iliac artery and the branch. Finally, a bifurcated stent-graft was deployed, and a limb device was used to connect the main body and IBD. RESULTS: Technical successes were obtained in all patients. The mean follow-up length was 24 months (range: 6-38 months). All grafts remained patent without any sign of endoleaks. There were no aneurysm ruptures, deaths, or other complications related to pelvic flow. CONCLUSIONS: Using the surgeon-modified IBD to preserve pelvic flow is a feasible endovascular technique and an appealing solution for personalized treatment of CIA aneurysm during EVAR. PMID- 25698204 TI - Effect of alemtuzumab on intestinal intraepithelial lymphocytes and intestinal barrier function in cynomolgus model. AB - BACKGROUND: Alemtuzumab has been used in organ transplantation and a variety of hematologic malignancies (especially for the treatment of B-cell chronic lymphocytic leukemia). However, serious infectious complications frequently occur after treatment. The reason for increased infections postalemtuzumab treatment is unknown at this stage. We explore the effect of alemtuzumab on intestinal intraepithelial lymphocytes (IELs) and intestinal barrier function in cynomolgus model to explain the reason of infection following alemtuzumab treatment. METHODS: Twelve male cynomolguses were randomly assigned to either a treatment or control group. The treatment group received alemtuzumab (3 mg/kg, intravenous injection) while the control group received the same volume of physiological saline. Intestinal IELs were isolated from the control group and the treatment group (on day 9, 35, and 70 after treatment) for counting and flow cytometric analysis. Moreover, intestinal permeability was monitored by enzymatic spectrophotometric technique and enzyme-linked immunosorbent assay. RESULTS: The numbers of IELs were decreased significantly on day 9 after treatment compared with the control group (0.35 +/- 0.07 * 10 8 and 1.35 +/- 0.09 * 10 8 , respectively; P < 0.05) and were not fully restored until day 70 after treatment. There were significant differences among four groups considering IELs subtypes. In addition, the proportion of apoptotic IELs after alemtuzumab treatment was significantly higher than in the control group (22.01 +/- 3.67 and 6.01 +/- 1.42, respectively; P < 0.05). Moreover, the concentration of D-lactate and endotoxin was also increased significantly on day 9 after treatment. CONCLUSIONS: Alemtuzumab treatment depletes lymphocytes in the peripheral blood and intestine of cynomolgus model. The induction of apoptosis is an important mechanism of lymphocyte depletion after alemtuzumab treatment. Notably, intestinal barrier function may be disrupted after alemtuzumab treatment. PMID- 25698205 TI - Analysis on international scientific collaboration and research focus on depression field. PMID- 25698206 TI - Laparoscopic partial splenectomy for splenic hemangioma: experience of a single center in six cases. PMID- 25698207 TI - Isthmus undivided bilateral nephrectomy in a patient with polycystic horseshoe kidney. PMID- 25698208 TI - Anticonvulsants delaying the diagnosis of Cushing's syndrome in a patient who presents with schizophrenia. PMID- 25698209 TI - Isoniazid and pulmonary fibrosis. PMID- 25698210 TI - Anastomotic pseudoaneurysm at 30 years after thoracic aorta surgery. PMID- 25698211 TI - Immunoglobulin G4-related disease with features of Mikulicz's disease and autoimmune pancreatitis which firstly presented as asymptomatic lymphadenopathy: a case report. PMID- 25698212 TI - A case of renal subcapsular hematoma caused by an accident injection from renal capsular artery. PMID- 25698213 TI - Two cases of refractory large granular lymphocytic leukemia treated by porcine anti-human thymocyte immunoglobulin. PMID- 25698214 TI - Family circumstances and survival from childhood acute lymphoblastic leukaemia in West Germany. AB - BACKGROUND: Little is known about the relationship between family characteristics and survival from childhood acute lymphoblastic leukaemia (ALL), which we studied for the first time in German children. METHODS: ALL cases were diagnosed between 1992 and 1994 and information on family characteristics was collected during a previously conducted nationwide case-control study. Children were followed for 10 years after diagnosis, as few disease-related events occur afterwards. Cox proportional hazards models estimating hazard ratios (HR) were calculated using overall as well as event-free survival methods. RESULTS: Second born children showed statistically significant better survival compared to first or later born children, with HRs ranging between 0.54 and 0.64 compared to firstborns. Somewhat poorer survival was observed for children having 3 or more siblings. A relationship was found for parental age at child's diagnosis, with poorer survival for children with younger parents (<=25 years of age at child's diagnosis), or with older fathers. The HR was statistically significant for fathers being >=41years of age (HR of 2.1). No relationship between degree of urbanization of the place of residence at diagnosis and ALL survival was observed. CONCLUSION: Family circumstances may have an impact on survival from childhood ALL in Germany. Further research is warranted to elaborate the relationship of specific family characteristics and ALL survival and to investigate possible differential adherence to therapy and interactions with physicians. PMID- 25698215 TI - Nurture is more important than nature in childhood obesity, study finds. PMID- 25698216 TI - Increasing sample size in prospective birth cohorts: back-extrapolating prenatal levels of persistent organic pollutants in newly enrolled children. AB - Study sample size in prospective birth cohorts of prenatal exposure to persistent organic pollutants (POPs) is limited by costs and logistics of follow-up. Increasing sample size at the time of health assessment would be beneficial if predictive tools could reliably back-extrapolate prenatal levels in newly enrolled children. We evaluated the performance of three approaches to back extrapolate prenatal levels of p,p'-dichlorodiphenyltrichloroethane (DDT), p,p' dichlorodiphenyldichloroethylene (DDE) and four polybrominated diphenyl ether (PBDE) congeners from maternal and/or child levels 9 years after delivery: a pharmacokinetic model and predictive models using deletion/substitution/addition or Super Learner algorithms. Model performance was assessed using the root mean squared error (RMSE), R2, and slope and intercept of the back-extrapolated versus measured levels. Super Learner outperformed the other approaches with RMSEs of 0.10 to 0.31, R2s of 0.58 to 0.97, slopes of 0.42 to 0.93 and intercepts of 0.08 to 0.60. Typically, models performed better for p,p'-DDT/E than PBDE congeners. The pharmacokinetic model performed well when back-extrapolating prenatal levels from maternal levels for compounds with longer half-lives like p,p'-DDE and BDE 153. Results demonstrate the ability to reliably back-extrapolate prenatal POP levels from levels 9 years after delivery, with Super Learner performing best based on our fit criteria. PMID- 25698217 TI - Wavelength dispersion of the local field intensity in silver-gold nanocages. AB - This study provides a combined theoretical and experimental analysis of the far field (extinction) and of the near-field (SERS enhancement) spectral distribution in hollow nanoparticles, that is, silver-gold nanocages (NCs). Chitosan protected NCs have been synthesized by a galvanic replacement-based procedure: their morphological properties and chemical composition have been characterized by TEM, STEM and ICP. NCs were then functionalized with a thiolated organic dye prior to carrying out SERS measurements. Finite Element Method simulations of a single NC have shown that the field enhancement at the excitation wavelength follows the same spectral dependence as the extinction spectrum and, consequently, the SERS enhancement profile, as a function of the excitation wavelength, peaks at higher energy with respect to extinction. The simulated extinction is remarkably narrower than the experimental spectrum of NCs in solution, indicating that the colloidal sample is substantially polydispersed. However, a simple qualitative model that we have developed would suggest that the SERS enhancement profile is blue-shifted with respect to the extinction in the presence of polydispersivity as well. In addition, NC dimers have been simulated: both their extinction and near field-spectra shift to the red when the size of the gap is reduced analogous to what happens with dimers of filled spherical nanoparticles (NPs). In addition, simulations also revealed that a NC dimer is only slightly more efficient in amplifying the field with respect to the isolated NC, and this behavior is peculiar to NCs. In fact, filled spherical NP dimers exhibit a remarkably stronger field enhancement with respect to the isolated NP. By means of Wavelength Scanned SERS, we measured the spectral distribution of the local field in a dispersion of NCs. We observed experimentally that the local field is distributed in the same spectral region as the extinction and that the absolute value of the SERS enhancement factor maintains a low value throughout the range explored (568-800 nm). We propose that the observed correlation between the SERS profile and the extinction is accidental and originates from the limited increase in amplification provided by NC aggregates with respect to isolated NCs. PMID- 25698218 TI - Colloidal particles in blue phase liquid crystals. AB - We study the effect of disorder on the phase transitions of a system already dominated by defects. Micron-sized colloidal particles are dispersed chiral nematic liquid crystals which exhibit a blue phase (BP). The colloids are a source of disorder, disrupting the liquid crystal as the system is heated from the cholesteric to the isotropic phase through the blue phase. The colloids act as a preferential site for the growth of BPI from the cholesteric; in high chirality samples BPII also forms. In both BPI and BPII the colloids lead to localised melting to the isotropic, giving rise to faceted isotropic inclusions. This is in contrast to the behaviour of a cholesteric LC where colloids lead to system spanning defects. PMID- 25698219 TI - In vitro anti-oxidant potential of new metabolites from Hypericum oblongifolium (Guttiferae). AB - Phytochemical investigations on Hypericum oblongifolium led to the isolation of a flavone named folicitin (1) and a bicyclic conjugated lactone, folenolide (2) from the ethyl acetate fraction of methanolic extract. Both metabolites were characterised as new compounds based on detailed spectroscopic analyses. In vitro anti-oxidant potential of both the compounds was evaluated by the DPPH radical scavenging assay. Compound 1 exhibited significant antioxidant activity while compound 2 was found inactive. PMID- 25698220 TI - Break-apart interphase fluorescence in situ hybridization assay in papillary thyroid carcinoma: on the road to optimizing the cut-off level for RET/PTC rearrangements. AB - OBJECTIVE: Chromosomal rearrangements of the RET proto-oncogene is one of the most common molecular events in papillary thyroid carcinoma (PTC). However, their pathogenic role and clinical significance are still debated. This study aimed to investigate the prevalence of RET/PTC rearrangement in a cohort of BRAF WT PTCs by fluorescence in situ hybridization (FISH) and to search a reliable cut-off level in order to distinguish clonal or non-clonal RET changes. DESIGN: Forty BRAF WT PTCs were analyzed by FISH for RET rearrangements. As controls, six BRAFV600E mutated PTCs, 13 follicular adenomas (FA), and ten normal thyroid parenchyma were also analyzed. METHODS: We performed FISH analysis on formalin fixed, paraffin-embedded tissue using a commercially available RET break-apart probe. A cut-off level equivalent to 10.2% of aberrant cells was accepted as significant. To validate FISH results, we analyzed the study cohort by qRT-PCR. RESULTS: Split RET signals above the cut-off level were observed in 25% (10/40) of PTCs, harboring a percentage of positive cells ranging from 12 to 50%, and in one spontaneous FA (1/13, 7.7%). Overall, the data obtained by FISH matched well with qRT-PCR results. Challenging findings were observed in five cases showing a frequency of rearrangement very close to the cut-off. CONCLUSIONS: FISH approach represents a powerful tool to estimate the ratio between broken and non-broken RET tumor cells. Establishing a precise FISH cut-off may be useful in the interpretation of the presence of RET rearrangement, primarily when this strategy is used for cytological evaluation or for targeted therapy. PMID- 25698221 TI - Comparative analyses of secreted proteins from the phytopathogenic fungus Verticillium dahliae in response to nitrogen starvation. AB - The soilborne fungus Verticillium dahliae is the major pathogen that causes the verticillium wilt disease of plants, which leads to huge economic loss worldwide. At the early stage of infection, growth of the pathogen is subject to the nutrition stress of limited nitrogen. To investigate the secreted pathogenic proteins that play indispensable roles during invasion at this stage, we compared the profiles of secreted proteins of V. dahliae under nitrogen starvation and normal conditions by using in-gel and in-solution digestion combined with liquid chromatography-nano-electrospray ionization tandem mass spectrometry (LC-nanoESI MS). In total, we identified 212 proteins from the supernatant of liquid medium, including 109 putative secreted proteins. Comparative analysis indicated that the expression of 76 proteins was induced, whereas that of 9 proteins was suppressed under nitrogen starvation. Notably, 24 proteins are constitutively expressed. Further bioinformatic exploration enabled us to classify the stress-induced proteins into seven functional groups: cell wall degradation (10.5%), reactive oxygen species (ROS) scavenging and stress response (11.8%), lipid effectors (5.3%), protein metabolism (21.1%), carbohydrate metabolism (15.8%), electron proton transport and energy metabolism (14.5%), and other (21.0%). In addition, most stress-suppressed proteins are involved in the cell-wall remodeling. Taken together, our analyses provide insights into the pathogenesis of V. dahliae and might give hints for the development of novel strategy against the verticillium wilt disease. PMID- 25698222 TI - Quantitation of permethylated N-glycans through multiple-reaction monitoring (MRM) LC-MS/MS. AB - The important biological roles of glycans and their implications in disease development and progression have created a demand for the development of sensitive quantitative glycomics methods. Quantitation of glycans existing at low abundance is still analytically challenging. In this study, an N-linked glycans quantitation method using multiple-reaction monitoring (MRM) on a triple quadrupole instrument was developed. Optimum normalized collision energy (CE) for both sialylated and fucosylated N-glycan was determined to be 30%, whereas it was found to be 35% for either fucosylated or sialylated N-glycans. The optimum CE for mannose and complex type N-glycan was determined to be 35%. Additionally, the use of three transitions was shown to facilitate reliable quantitation. A total of 88 N-glycan compositions in human blood serum were quantified using this MRM approach. Reliable detection and quantitation of these glycans was achieved when the equivalence of 0.005 MUL of blood serum was analyzed. Accordingly, N-glycans down to the 100th of a MUL level can be reliably quantified in pooled human blood serum, spanning a dynamic concentration range of three orders of magnitude. MRM was also effectively utilized to quantitatively compare the expression of N glycans derived from brain-targeting breast carcinoma cells (MDA-MB-231BR) and metastatic breast cancer cells (MDA-MB-231). Thus, the described MRM method of permethylated N-glycan enables a rapid and reliable identification and quantitation of glycans derived from glycoproteins purified or present in complex biological samples. PMID- 25698223 TI - Quantifying reversible oxidation of protein thiols in photosynthetic organisms. AB - Photosynthetic organisms use dynamic post-translational modifications to survive and adapt, which include reversible oxidative modifications of protein thiols that regulate protein structure, function, and activity. Efforts to quantify thiol modifications on a global scale have relied upon peptide derivatization, typically using isobaric tags such as TMT, ICAT, or iTRAQ that are more expensive, less accurate, and provide less proteome coverage than label-free approaches--suggesting the need for improved experimental designs for studies requiring maximal coverage and precision. Herein, we present the coverage and precision of resin-assisted thiol enrichment coupled to label-free quantitation for the characterization of reversible oxidative modifications on protein thiols. Using C. reinhardtii and Arabidopsis as model systems for algae and plants, we quantified 3662 and 1641 unique cysteinyl peptides, respectively, with median coefficient of variation (CV) of 13% and 16%. Further, our method is extendable for the detection of protein abundance changes and stoichiometries of cysteine oxidation. Finally, we demonstrate proof-of-principle for our method, and reveal that exogenous hydrogen peroxide treatment regulates the C. reinhardtii redox proteome by increasing or decreasing the level of oxidation of 501 or 67 peptides, respectively. As protein activity and function is controlled by oxidative modifications on protein thiols, resin-assisted thiol enrichment coupled to label-free quantitation can reveal how intracellular and environmental stimuli affect plant survival and fitness through oxidative stress. PMID- 25698224 TI - Molecular mechanisms of action of different concentrations of ethanol in water on ordered structures of intercellular lipids and soft keratin in the stratum corneum. AB - Ethanol (EtOH) is one of the bases in topically applied medicines that promote the skin permeation of drugs. Although the effects of EtOH have been attributed to structural modifications in the stratum corneum, the underlying mechanisms, especially the influence of different concentrations of EtOH, have not been examined extensively. Structural modifications in the stratum corneum of hairless mouse due to the application of EtOH/water mixture were herein investigated at the molecular level using synchrotron X-ray diffraction. The results revealed that all EtOH concentrations examined greatly modified the short lamellar structures containing the aqueous layer in intercellular lipids and the structure of keratin fibrils in corneocytes, which can take up hydrophilic compounds. However, the long lamellar and the hydrocarbon-chain packing structures were unaffected by EtOH. Changes to the short lamellar structures were not proportional to the concentration of EtOH. However, the keratin fibril structures changed gradually with increasing EtOH concentration. The X-ray diffraction experiments enabled the effects of different EtOH concentrations on the morphology of the stratum corneum to be assessed by using a number of experimental samples to avoid variations due to individual differences. The results indicated that alterations to the short lamellar structures appeared to be related to the skin permeability of drugs with the application of EtOH/water mixture, and monotonous structural changes in the keratin fibrils with an increase in EtOH concentration may contribute to this permeation as supplement. These results will be useful for the development of new drug formulations containing EtOH. PMID- 25698225 TI - Science communication on YouTube: Factors that affect channel and video popularity. AB - YouTube has become one of the largest websites on the Internet. Among its many genres, both professional and amateur science communicators compete for audience attention. This article provides the first overview of science communication on YouTube and examines content factors that affect the popularity of science communication videos on the site. A content analysis of 390 videos from 39 YouTube channels was conducted. Although professionally generated content is superior in number, user-generated content was significantly more popular. Furthermore, videos that had consistent science communicators were more popular than those without a regular communicator. This study represents an important first step to understand content factors, which increases the channel and video popularity of science communication on YouTube. PMID- 25698226 TI - Intraaortic balloon pump in patients with cardiogenic shock complicating myocardial infarction: a systematic review and meta-analysis of randomized trials. AB - INTRODUCTION: Cardiogenic shock is associated with significant mortality, particularly when caused by myocardial infarction. Intraaortic balloon pump (IABP) is the primary hemodynamic adjunct in patients with cardiogenic shock; however, evidence suggests that IABP may not improve mortality in this population. METHODS: We conducted an electronic search of the Medline, EMBASE, and Cochrane trial registry databases. Two reviewers independently screened citations and identified eligible trials. The same reviewers abstracted data independently. We pooled the data using a fixed effect model and reported dichotomous outcomes as risk ratios (RRs) with 95% confidence intervals (CIs). Subsequently, we used the GRADE approach to judge the quality of evidence. RESULTS: We included 4 randomized trials with 735 patients. The use of IABP did not reduce the risk of death in patients with cardiogenic shock secondary to cardiac ischemia when compared with usual care (RR, 0.94; 95% CI, 0.79-1.13; P = 0.52; I2 = 0%; moderate confidence). The use of IABP was not associated with an increased risk of stroke (RR, 0.77; 95% CI 0.22-2.69; P = 0.68; I2 = 48%; very low confidence), limb ischemia (RR, 1.24; 95% CI, 0.59-2.59; P = 0.58; I2 = 0%; low confidence), or major bleeding (RR, 0.76; 95% CI, 0.34-1.72; P = 0.52; I2 = 0%; low confidence). CONCLUSIONS: The use of IABP in patients with cardiogenic shock complicating myocardial ischemia does not reduce mortality (moderate confidence) and is not associated with a higher risk of complications (very low to low confidence). The results should be interpreted with caution owing to limitations such as imprecision, risk of bias, and clinical heterogeneity. PMID- 25698227 TI - Successful treatment with glucocorticoid for secondary Fanconi syndrome caused by sarcoidosis. AB - A 77-year-old female with renal dysfunction, hypercalcemia, and hypercalciuria was presented. Systemic investigations including renal biopsy showed that the patient had Fanconi syndrome secondary to renal sarcoidosis. Treatment with 25 mg per day of prednisolone was initiated and her condition improved. Complication of Fanconi syndrome in patients with sarcoidosis is extremely rare. Although the pathological mechanism is still unknown, corticosteroid therapy was effective for ameliorating proteinuria, glycosuria, hypercalciuria, and aminoaciduria. PMID- 25698228 TI - Ketamine as a novel treatment for major depressive disorder and bipolar depression: a systematic review and quantitative meta-analysis. AB - OBJECTIVE: Given the significant disability, morbidity and mortality associated with depression, the promising recent trials of ketamine highlight a novel intervention. A meta-analysis was conducted to assess the efficacy of ketamine in comparison with placebo for the reduction of depressive symptoms in patients who meet criteria for a major depressive episode. METHOD: Two electronic databases were searched in September 2013 for English-language studies that were randomized placebo-controlled trials of ketamine treatment for patients with major depressive disorder or bipolar depression and utilized a standardized rating scale. Studies including participants receiving electroconvulsive therapy and adolescent/child participants were excluded. Five studies were included in the quantitative meta-analysis. RESULTS: The quantitative meta-analysis showed that ketamine significantly reduced depressive symptoms. The overall effect size at day 1 was large and statistically significant with an overall standardized mean difference of 1.01 (95% confidence interval 0.69-1.34) (P<.001), with the effects sustained at 7 days postinfusion. The heterogeneity of the studies was low and not statistically significant, and the funnel plot showed no publication bias. CONCLUSIONS: The large and statistically significant effect of ketamine on depressive symptoms supports a promising, new and effective pharmacotherapy with rapid onset, high efficacy and good tolerability. PMID- 25698229 TI - Link removal for the control of stochastically evolving epidemics over networks: a comparison of approaches. AB - For many communicable diseases, knowledge of the underlying contact network through which the disease spreads is essential to determining appropriate control measures. When behavior change is the primary intervention for disease prevention, it is important to understand how to best modify network connectivity using the limited resources available to control disease spread. We describe and compare four algorithms for selecting a limited number of links to remove from a network: two "preventive" approaches (edge centrality, R0 minimization), where the decision of which links to remove is made prior to any disease outbreak and depends only on the network structure; and two "reactive" approaches (S-I edge centrality, optimal quarantining), where information about the initial disease states of the nodes is incorporated into the decision of which links to remove. We evaluate the performance of these algorithms in minimizing the total number of infections that occur over the course of an acute outbreak of disease. We consider different network structures, including both static and dynamic Erdos Renyi random networks with varying levels of connectivity, a real-world network of residential hotels connected through injection drug use, and a network exhibiting community structure. We show that reactive approaches outperform preventive approaches in averting infections. Among reactive approaches, removing links in order of S-I edge centrality is favored when the link removal budget is small, while optimal quarantining performs best when the link removal budget is sufficiently large. The budget threshold above which optimal quarantining outperforms the S-I edge centrality algorithm is a function of both network structure (higher for unstructured Erdos-Renyi random networks compared to networks with community structure or the real-world network) and disease infectiousness (lower for highly infectious diseases). We conduct a value-of information analysis of knowing which nodes are initially infected by comparing the performance improvement achieved by reactive over preventive strategies. We find that such information is most valuable for moderate budget levels, with increasing value as disease spread becomes more likely (due to either increased connectedness of the network or increased infectiousness of the disease). PMID- 25698230 TI - Modelling the vascular response to sympathetic postganglionic nerve activity. AB - This paper explores the influence of burst properties of the sympathetic nervous system on arterial contractility. Specifically, a mathematical model is constructed of the pathway from action potential generation in a sympathetic postganglionic neurone to contraction of an arterial smooth muscle cell. The differential equation model is a synthesis of models of the individual physiological processes, and is shown to be consistent with physiological data. The model is found to be unresponsive to tonic (regular) stimulation at typical frequencies recorded in sympathetic efferents. However, when stimulated at the same average frequency, but with repetitive respiratory-modulated burst patterns, it produces marked contractions. Moreover, the contractile force produced is found to be highly dependent on the number of spikes in each burst. In particular, when the model is driven by preganglionic spike trains recorded from wild-type and spontaneously hypertensive rats (which have increased spiking during each burst) the contractile force was found to be 10-fold greater in the hypertensive case. An explanation is provided in terms of the summative increased release of noradrenaline. Furthermore, the results suggest the marked effect that hypertensive spike trains had on smooth muscle cell tone can provide a significant contribution to the pathology of hypertension. PMID- 25698231 TI - The evolution of group dispersal with leaders and followers. AB - In many species, individuals disperse in groups. While there are empirical studies that explore the proximate incentives for group dispersal, theoretical research has primarily examined the consequences rather than the evolution of this phenomenon. We design a simple model to study the origin and evolution of group dispersal. We assume that like many other group activities associated with collective movement, group dispersal in our model is initiated by leaders. We use the theory of inclusive fitness to examine the incentives for leading and following in this context. High relatedness, significant reductions in the cost of dispersal due to dispersing in groups, and reproductive skew in favour of followers facilitates the emergence of group dispersal. In contrast to some previous theoretical work, which has either concluded that leadership is uniformly altruistic or that it is uniformly selfish, we find that at evolutionary equilibrium the incentives for leading can be either selfish or altruistic. The nature of result (selfish or altruistic) depends on ecological and social conditions such as the cost of dispersal and the relatedness between leaders and followers. Our model demonstrates that kin selection is sufficient and that individual differences in condition and ability are not necessary to promote the emergence and maintenance of leader-follower relationships. PMID- 25698232 TI - Effects of secretin on neuronal activity and feeding behavior in central amygdala of rats. AB - Previous studies have shown that secretin and secretin receptors are expressed in central amygdala neurons. By using both in vivo extracellular recording as well as behavioral test, we investigated the direct electrophysiological effects of secretin in the central amygdala and its involvement in feeding behavior. Micro pressure ejection of secretin increased the spontaneous firing rate by 104.22+/ 26.18% in 13 out of the 27 central amygdala neurons. In other 6 out of the 27 neurons, secretin decreased the firing rate by 68.80+/-12.10%. Firing patter analysis showed that secretin did not change the firing pattern significantly. Further electrophysiological recordings revealed that secretin decreased the firing rate of glucose-sensitive neurons. In behavioral test, microinjection of secretin into the central amygdala significantly reduced cumulative food intake through cAMP-activated protein kinase activation. Based on the present electrophysiological and behavioral findings, we hypothesized that secretin may suppress food intake by its modulation of spontaneous firing of central amygdala neurons. PMID- 25698233 TI - A structure-function study of PACAP using conformationally restricted analogs: Identification of PAC1 receptor-selective PACAP agonists. AB - Pituitary adenylate cyclase-activating polypeptide (PACAP) has widespread physiological/pathophysiological actions and there is increased interest for its use therapeutically, especially in the CNS (neuroprotection). Unfortunately, no selective PACAP-analogs exist for PACAP-preferring PAC1-receptors, primarily because of its high sequence identity to VIP and particularly, because of the inability of structure-function studies to separate the pharmacophore of PAC1-R from VPAC1-R, which has high affinity for PACAP and VIP. The present study attempted to develop PAC1-R-selective agonists primarily by making conformationally restricted PACAP-analogs in positions important for receptor selectivity/affinity. Forty-six PACAP-related-analogs were synthesized with substitutions in positions 1-4, 14-17, 20-22, 28, 34, 38 and receptor-selectivity determined in PAC1-R,VPAC1-R,VPAC2-R-transfected or native cells from binding or cAMP-generation experiments. Fifteen PACAP-analogs had 6-78-fold higher affinities for PAC1-R than VPAC1-R and 13 were agonists. Although binding affinities correlated significantly with agonist potency, the degree of receptor spareness varied markedly for the different PACAP-analogs, resulting in selective potencies for activating the PAC1 receptor over the VPAC1 receptor from 0- to 103 fold. In addition, a number of PACAP-analogs were identified that had high selectivity for PAC1-R over VPAC2-R as well as PACAP-analogs that could prove more useful therapeutically because of substitutions known to extend their half lives (substitutions at potential sites of proteolysis and attachment of long chain fatty acids). This study provides for the first time a separation of the pharmacophores for PAC1-R and VPAC1-R, resulting in PACAP-related analogs that are PAC1-R-preferring. Some of these analogs, or their modifications, could prove useful as therapeutic agents for various diseases. PMID- 25698234 TI - B-type natriuretic peptide expression and cardioprotection is regulated by Akt dependent signaling at early reperfusion. AB - Exogenously administered B-type natriuretic peptide (BNP) has been shown to offer cardioprotection through activation of particulate guanylyl cyclase (pGC), protein kinase G (PKG) and KATP channel opening. The current study explores if cardioprotection afforded by short intermittent BNP administration involves PI3K/Akt/p70s6k dependent signaling, and whether this signaling pathway may participate in regulation of BNP mRNA expression at early reperfusion. Isolated Langendorff perfused rat hearts were subjected to 30min of regional ischemia and 120min of reperfusion (IR). Applying intermittent 3*30s infusion of BNP peptide in a postconditioning like manner (BNPPost) reduced infarct size by >50% compared to controls (BNPPost 17+/-2% vs. control 42+/-4%, p<0.001). Co-treatment with inhibitors of the PI3K/Akt/p70s6k pathway (wortmannin, SH-6 and rapamycin) completely abolished the infarct-limiting effect of BNP postconditioning (BNPPost+Wi 36+/-5%, BNPPost+SH-6 41+/-4%, BNPPost+Rap 37+/-6% vs. BNPPost 17+/ 2%, p<0.001). Inhibition of natriuretic peptide receptors (NPR) by isatin also abrogated BNPPost cardioprotection (BNPPost+isatin 46+/-2% vs. BNPPost 17+/-2%, p<0.001). BNPPost also significantly phosphorylated Akt and p70s6k at early reperfusion, and Akt phosphorylation was inhibited by SH-6 and isatin. Myocardial BNP mRNA levels in the area at risk (AA) were significantly elevated at early reperfusion as compared to the non-ischemic area (ANA) (Ctr(AA) 2.7+/-0.5 vs. Ctr(ANA) 1.2+/-0.2, p<0.05) and the ischemic control tissue (Ctr(AA) 2.7+/-0.5 vs. ischemia 1.0+/-0.1, p<0.05). Additional experiments also revealed a significant higher BNP mRNA level in ischemic postconditioned (IPost) hearts as compared to ischemic controls (IPost 6.7+/-1.3 vs. ischemia 1.0+/-0.2, p<0.05), but showed no difference from controls run in parallel (Ctr 5.4+/-0.8). Akt inhibition by SH-6 completely abrogated this elevation (IPost 6.7+/-1.3 vs. IPost+SH-6 1.8+/-0.7, p<0.05) (Ctr 5.4+/-0.8 vs. SH-6 1.5+/-0.9, p<0.05). In conclusion, Akt dependent signaling is involved in mediating the cardioprotection afforded by intermittent BNP infusion at early reperfusion, and may also participate in regulation of reperfusion induced BNP expression. PMID- 25698235 TI - Can the chemotherapeutic agents perform anticancer activity through miRNA expression regulation? Proposing a new hypothesis [corrected]. AB - In the recent advancement of cancer therapy, mortality of the immortal cancer cells begins to decline, and it shows great promise for the chemotherapy regimen supported by targeted therapy. In this post-genomic era boosted by the discovery of microRNA (miRNA), it has been understood that miRNA regulates gene expression at the post-transcriptional level. On the other hand, some studies have also indicated that miRNA expression level has changed during the treatment of chemotherapy. Data based on various previous studies, we propose that the chemotherapeutic agents modulate miRNA expression that might perform anticancerous activities through cellular changes such as DNA repair, cell cycle arrest, or apoptosis. PMID- 25698236 TI - Toward patient-specific articular contact mechanics. AB - The mechanics of contacting cartilage layers is fundamentally important to understanding the development, homeostasis and pathology of diarthrodial joints. Because of the highly nonlinear nature of both the materials and the contact problem itself, numerical methods such as the finite element method are typically incorporated to obtain solutions. Over the course of five decades, we have moved from an initial qualitative understanding of articular cartilage material behavior to the ability to perform complex, three-dimensional contact analysis, including multiphasic material representations. This history includes the development of analytical and computational contact analysis methods that now provide the ability to perform highly nonlinear analyses. Numerical implementations of contact analysis based on the finite element method are rapidly advancing and will soon enable patient-specific analysis of joint contact mechanics using models based on medical image data. In addition to contact stress on the articular surfaces, these techniques can predict variations in strain and strain through the cartilage layers, providing the basis to predict damage and failure. This opens up exciting areas for future research and application to patient-specific diagnosis and treatment planning applied to a variety of pathologies that affect joint function and cartilage homeostasis. PMID- 25698237 TI - Individual limb mechanical analysis of gait following stroke. AB - The step-to-step transition of walking requires significant mechanical and metabolic energy to redirect the center of mass. Inter-limb mechanical asymmetries during the step-to-step transition may increase overall energy demands and require compensation during single-support. The purpose of this study was to compare individual limb mechanical gait asymmetries during the step-to step transitions, single-support and over a complete stride between two groups of individuals following stroke stratified by gait speed (>=0.8 m/s or <0.8 m/s). Twenty-six individuals with chronic stroke walked on an instrumented treadmill to collect ground reaction force data. Using the individual limbs method, mechanical power produced on the center of mass was calculated during the trailing double support, leading double-support, and single-support phases of a stride, as well as over a complete stride. Robust inter-limb asymmetries in mechanical power existed during walking after stroke; for both groups, the non-paretic limb produced significantly more positive net mechanical power than the paretic limb during all phases of a stride and over a complete stride. Interestingly, no differences in inter-limb mechanical power asymmetry were noted between groups based on walking speed, during any phase or over a complete stride. Paretic propulsion, however, was different between speed-based groups. The fact that paretic propulsion (calculated from anterior-posterior forces) is different between groups, but our measure of mechanical work (calculated from all three directions) is not, suggests that limb power output may be dominated by vertical components, which are required for upright support. PMID- 25698238 TI - Synchronization of regional contractions of human labor; direct effects of region size and tissue excitability. AB - The mechanisms used to coordinate organ-level contractions of human labor are not universally accepted. We previously proposed a dual mechanism, where electrical activity coordinates cellular contractions into tissue-level regional contractions, and mechanotransduction synchronizes the regional contractions into organ-level contractions. The simulation of this model successfully recapitulates the phasic pressure rises typical of human labor. In this work we extend the simulation to probe the effects of three critical parameters: electrical coupling (which defines functional regions within the uterine wall), enhancement of contractile responses during action potential bursts (action potential multiplier), and the threshold for mechanical recruitment of regional myometrial contractions (threshold). We test how changing the values of these parameters modulates the ability of the uterus to generate synchronized organ-level contractions. Simulations are performed using Mathematica and a non-classical cellular automaton program we recently published. At least 15 regions are necessary to generate physiologically relevant, synchronized contractions. Organ level synchronization was improved using higher values for the action potential multiplier. At lower values of the action potential multiplier, synchronized contractions were inhibited when the number of regions was between 32 and 44, suggesting a critical level of electrical coupling is necessary at the onset of labor. Large numbers of low threshold regions resulted in contraction patterns suggestive of hyperstimulation. This work furthers support for the electrical mechanotransduction mechanism for organ-level synchronization of uterine contractions. The mathematical simulation provides insight regarding how cellular and tissue-level physiology converge to express synchronized contractions of human labor. PMID- 25698239 TI - An optimization algorithm for individualized biomechanical analysis and simulation of tibia fractures. AB - An algorithmic strategy to determine the minimal fusion area of a tibia pseudarthrosis to achieve mechanical stability is presented. For this purpose, a workflow capable for implementation into clinical routine workup of tibia pseudarthrosis was developed using visual computing algorithms for image segmentation, that is a coarsening protocol to reduce computational effort resulting in an individualized volume-mesh based on computed tomography data. An algorithm detecting the minimal amount of fracture union necessary to allow physiological loading without subjecting the implant to stresses and strains that might result in implant failure is developed. The feasibility of the algorithm in terms of computational effort is demonstrated. Numerical finite element simulations show that the minimal fusion area of a tibia pseudarthrosis can be less than 90% of the full circumferential area given a defined maximal von Mises stress in the implant of 80% of the total stress arising in a complete pseudarthrosis of the tibia. PMID- 25698240 TI - Dynamic hydrostatic pressure enhances differentially the chondrogenesis of meniscal cells from the inner and outer zone. AB - This study analyses the influence of dynamic hydrostatic pressure on chondrogenesis of human meniscus-derived fibrochondrocytes and explores the differences in chondrogenic differentiation under loading conditions between cells derived from the avascular inner zone and vascularized outer region of the meniscus. Aggregates of human fibrochondrocytes with cell origin from the inner region or with cell origin from the outer region were generated. From the two groups of either cell origin, aggregates were treated with dynamic hydrostatic pressure (1Hz for 4h; 0.55-5.03MPa, cyclic sinusoidal) from day 1 to day 7. The other aggregates served as unloaded controls. At day 0, 7, 14 and 21 aggregates were harvested for evaluation including histology, immunostaining and ELISA analysis for glycosaminoglycan (GAG) and collagen II. Loaded aggregates were found to be macroscopically larger and revealed immunohistochemically enhanced chondrogenesis compared to the corresponding controls. Loaded or non-loaded meniscal cells from the outer zone showed a higher potential and earlier onset of chondrogenesis compared to the cells from the inner part of the meniscus. This study suggests that intrinsic factors like cell properties in the different areas of the meniscus and their reaction on mechanical load might play important roles in designing Tissue Engineering strategies for meniscal repair in vivo. PMID- 25698241 TI - Outsourcing the NHS. PMID- 25698242 TI - UPLC-QTOF-MS identification of metabolites in rat biosamples after oral administration of Dioscorea saponins: a comparative study. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Among the 49 species of the genus Dioscorea distributed in China, Dioscorea nipponica Makino (DN), Dioscorea panthaica Prain et Burkill (DP), and Dioscorea zingiberensis C. H. Wright (DZ) possess more or less similar traditional therapeutic actions, such as activating blood, relieving pain, and dispersing swelling; they have been used as folk medicine in China since 1950s. The modern pharmaceutical industry has developed these three species as herbal medicines that have been used for decades for treating cardiovascular diseases. However, there is no available information in the literature explaining how their chemical components are converted and interrelated in vivo to support their efficacies. The present study aimed to a) compare the metabolic profiles of saponins from DN, DP and DZ, which are considered to be their bioactive components, and b) to compare the changes in sustained levels of metabolites from rat biosamples. MATERIAL AND METHODS: Total saponins (TS) from each of the three species, and four individual saponins, namely protodioscin (PD), pseudoprotodioscin (PSD), dioscin (DC) and diosgenin (DG), were given to rats by oral administration. Chemical profiles of the rats' plasma, urine and feces were monitored 1-36 h. A UPLC-QTOF-MS based method was performed to identify the absorbed constituents and their metabolic products in rat biosamples (i.e., blood, urine, and feces); the ratio of peak area of major saponins to that of internal standard was calculated and plotted versus time to characterize the sustained levels of saponins in biosamples. RESULTS: Totally 10 saponin-related compounds were detected in rat plasma, 10 in rat urine and 18 in rat feces. The results indicated that formation of diosgenin by desugarization was the main pathway by which steroidal glycosides were metabolized. Other types of bio transformation were found among glycosides and aglycones, such as ring cyclization through loss of 26-O-glucosyl, substitution of beta-D-glucopyranosyl for alpha-L-rhamnopyrannosyl, hydrogenation of diosgenin at 5(6)-double bond, and hydration of 20(22)-double bond. Generally, the metabolic profiles of DN and DP were shown to be quite similar, but different from that of DZ. However, some particular similarities and connections were found among these three TS. Diosgenin was one of the main metabolites commonly found in plasma and feces (excluding urine), from all groups receiving different TS, as well as individual saponins; this is likely to be one of the bioactive constituents playing an essential role in cardioprotective efficacy. Furostane-type saponins in TS of DN, DP or DZ, such as PD, protogracillin, parvifloside, protodeltonin and protobioside, showed fast absorption into blood (<1h), but were maintained for a relatively short period (mostly<8h), while the spirostane-type saponin and sapogenin (DC and DG, respectively), were absorbed into circulation more slowly (>1h), but increased gradually and lasted longer (>36h). These two patterns suggest that the therapeutic effect of these Dioscorea saponins is achieved through a complex, multi-step process over time. In addition, it appears that PD, PSD, and DC contained in DN and DP were transformed into certain glycosides originally found in DZ but not in DN or DP (protodeltonin, deltonin, trillin, and progenin II), which might indicate another linkage among these three species. CONCLUSION: These similarities and connections described above constitute evidence supporting similarity in efficacy of these three herbs from the perspective of metabolism. The UPLC-QTOF-MS based method is accurate and efficient for analyzing metabolic changes in rat biosamples over time. PMID- 25698243 TI - Rehmannia glutinosa (Gaertn.) DC. polysaccharide ameliorates hyperglycemia, hyperlipemia and vascular inflammation in streptozotocin-induced diabetic mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Rehmannia glutinosa (Gaertn.) DC. (RG) has been widely used as traditional Chinese herbal medicine for treatment of diabetes and its complications. The polysaccharide fraction of RG has been proposed to possess hypoglycemic effect by intraperitoneal administration, however, the mechanisms responsible for the hypoglycemic effect of RG polysaccharide (RGP) remain poorly understood. Here we studied the anti-hyperglycemic and anti-hyperlipidemic effect of oral administration of a purified RGP and its underlying mechanisms in streptozotocin (STZ)-induced diabetic mice. MATERIALS AND METHODS: The preliminary structure of RGP was determined by GC and FT-IR. Mice were injected with STZ to induce type 1 diabetes. RGP at doses of 20, 40 and 80 mg/kg/day was orally administered to mice for 4 weeks, and metformin was used as positive control. After 4 weeks, the blood biochemical parameters, the pancreatic insulin contents, in vitro insulin secretion, the hepatic glycogen contents and mRNA expression of phosphoenolpyruvate carboxyl kinase (PEPCK) were assayed. RESULTS: RGP was composed of rhamnose, arabinose, mannose, glucose and galactose in the molar ratio of 1.00:1.26:0.73:16.45:30.40 with the average molecular weight of 63.5 kDa. RGP administration significantly decreased the blood levels of glucose, total cholesterol, triglycerides, low density lipoprotein-cholesterol, and increased the blood levels of high density lipoprotein-cholesterol and insulin in diabetic mice, concurrent with increases in body weights and pancreatic insulin contents. The in vitro study revealed that RGP significantly enhanced both basal and glucose-stimulated insulin secretions, as well as islet insulin contents in the pancreatic islets of diabetic mice. Moreover, RGP reversed the increased mRNA expression of PEPCK and the reduced glycogen contents in the liver of diabetic mice. Furthermore, RGP exhibited potent anti-inflammatory and anti-oxidative activities, as evidenced by the decreased blood levels of TNF-alpha, IL-6, monocyte chemoattractant protein-1, MDA, and also the elevated blood levels of SOD and GPx activities in diabetic mice. CONCLUSIONS: Taken together, RGP can effectively ameliorate hyperglycemia, hyperlipemia, vascular inflammation and oxidative stress in STZ-induced diabetic mice, and thus may be a potential therapeutic option for type 1 diabetes. PMID- 25698244 TI - The genus Litsea in traditional Chinese medicine: an ethnomedical, phytochemical and pharmacological review. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The genus Litsea, mainly distributed in the tropical and subtropical regions, has been used in traditional and indigenous Chinese medicines for the treatment of diarrhea, stomachache, dyspepsia, gastroenteritis, diabetes, edema, cold, arthritis, asthma, pain, traumatic injury, etc. for a long history. The present review aims to provide a comprehensive summary on the ethnomedical uses, phytochemistry, and pharmacology of the Litsea species used in traditional Chinese medicine (TCM). Based on these data, evidences supporting their ethnopharmacological effectiveness are illustrated, and opportunities for the future research and development as well as the therapeutic potential of this genus are analyzed to highlight the gaps in our knowledge that deserves further investigation. MATERIAL AND METHODS: Information on the Litsea species was collected via electronic search (using Pubmed, SciFinder, Google Scholar, Web of Science and CNKI) and a library search for articles published in peer-reviewed journals. Furthermore, information was also obtained from some local books on ethnopharmacology. RESULTS: Twenty plants of the genus Litsea are found to be important traditional medicines in China, and have a long medicinal application for diarrhea, stomachache, dyspepsia, gastroenteritis, diabetes, edema, cold, arthritis, asthma, pain, traumatic injury, etc. Over 200 ingredients have been identified from these 20 Litsea species used in TCM, and flavonoids, terpenoids and alkaloids are considered as the characteristic and bioactive constituents. The crude extracts and the isolated metabolites of these medicinal plants have exhibited some in vitro and in vivo pharmacological effects, including antimicrobial, hepatoprotection, anti inflammatory, antiasthmatic, immunomodulation, anti-diabetic, anticholelithogenic, as well as function on central nervous system, etc. CONCLUSIONS: The extensive literature survey reveals Litsea species to be a group of important medicinal plants used for the ethnomedical treatment of gastrointestinal diseases, diabetes, inflammatory disorders, and microbial infection in TCM. Pharmacological investigations have supported the use of some Litsea species in the traditional medicines. In addition, further researches targeting individual ingredients responsible for the pharmacological effects, as well as their mechanisms of action are necessary. The outcome of these studies will further support the therapeutic potential of the genus Litsea, and provide convincing evidences to its future clinical applications in modern medicine. PMID- 25698245 TI - Nuciferine, extracted from Nelumbo nucifera Gaertn, inhibits tumor-promoting effect of nicotine involving Wnt/beta-catenin signaling in non-small cell lung cancer. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The leaves of Nelumbo nucifera Gaertn are recorded in the earliest written documentation of traditional Chinese medicinal as "Ben Cao Gang Mu", a medicinal herb for blood clotting, dysentery and dizziness. Recently, nuciferine (NF), one of N. nucifera Gaertn leaf extracts has been shown to possess several pharmacological properties, including anti-viral and anti-cancer. The aim of this study is to investigate the underlying molecular mechanism of the anti-cancer activity of NF in NSCLC progression induced by nicotine MATERIALS AND METHODS: The effect of NF on proliferation of A549 (human lung adenocarcinoma epithelial cell line) pretreated with or without nicotine was detected by tumor cell proliferation assay. TOP-Flash reporter assay was applied to investigate the activity of Wnt/beta-catenin signaling in tumor cells in the presence of NF and/or nicotine. Apoptosis was measured using a FITC-Annexin V and PI detection kit by flow cytometry. In addition, mRNA or protein expression levels were respectively tested by quantitative RT-PCR or western blot. In vivo experiments, tumor samples were fixed in formalin and embedded in paraffin for additional analyses by immunohistochemistry and TUNEL staining. RESULTS: NF significantly inhibited the proliferation of NSCLC cells in the presence of nicotine, suppressed the activity of Wnt/beta-catenin signaling, enhanced the stabilization of Axin, and induced apoptosis. NF down-regulated the expression levels of beta-catenin and its downstream targets including c-myc, cyclin D and VEGF-A. NF also decreased the ratio of Bcl-2/Bax, which may explain the pro apoptosis effect of NF. In tumor xenograft nude mice, NF not only inhibited the growth of non-small cell lung cancer (NSCLC) cells, but also remarkably alleviated the injury induced by nicotine in liver function. CONCLUSIONS: NF has the remarkable effect to inhibit nicotine-induced NSCLC progression, which was due to its ability to reduce the activity of Wnt/beta-catenin signaling. Thus, the work stated here emphasizes the importance of this traditional medicine and presents a potential novel alternative to NSCLC prevention and therapy. PMID- 25698246 TI - Metabolomic and lipidomic study of the protective effect of Chaihuang-Yishen formula on rats with diabetic nephropathy. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Chaihuang-Yishen formula (CHYS) is a Chinese herbal formula that has been shown clinically to effectively treat chronic kidney disease including diabetic nephropathy (DN), also known as diabetic kidney disease. Our previous animal studies showed that numerous intrarenal metabolites were associated with the development of DN. In the present work, an integrated metabolomic and lipidomic analysis was used to further examine whether CHYS could attenuate the development of DN by regulating the disordered metabolic pathways. METHOD: Progressive diabetic kidney disease was induced in Wistar rats by uninephrectomy and a single intraperitoneal injection of streptozocin. Over 20 weeks, one group of animals was treated with CHYS and another group went untreated. Effects of CHYS on metabolomic and lipidomic changes in the renal cortex of diabetic rats were studied using gas chromatography/time-of-flight mass spectrometry, ultra-performance liquid chromatography/time-of-flight mass spectrometry, and tandem MS-based metabolomic and lipidomic. The well-established drug fosinopril was used as positive control throughout the experiment. RESULTS: Like fosinopril, treatment with CHYS produced a renoprotective effect against DN. Metabolomic and lipidomic analyses showed that the therapeutic effect of CHYS on DN was significantly associated with inhibition of the elevated organic toxins including several uremic toxins and glucuronides, and normalization of diminished phospholipids, especially sphingomyelins. CONCLUSION: Improved abnormal metabolic and lipidomic disorders, such as accumulation of uremic toxins and glucuronides and phospholipids, may be mechanisms by which treatment of CHYS inhibits DN. Results from this study provide new evidence for the pharmacologic characteristics of CHYS on DN. PMID- 25698247 TI - Warburgia: a comprehensive review of the botany, traditional uses and phytochemistry. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The genus Warburgia (Canellaceae) is represented by several medicinal trees found exclusively on the African continent. Traditionally, extracts and products produced from Warburgia species are regarded as important natural African antibiotics and have been used extensively as part of traditional healing practices for the treatment of fungal, bacterial and protozoal infections in both humans and animals. We here aim to collate and review the fragmented information on the ethnobotany, phytochemistry and biological activities of ethnomedicinally important Warburgia species and present recommendations for future research. MATERIALS AND METHODS: Peer-reviewed articles using "Warburgia" as search term ("all fields") were retrieved from Scopus, ScienceDirect, SciFinder and Google Scholar with no specific time frame set for the search. In addition, various books were consulted that contained botanical and ethnopharmacological information. RESULTS: The ethnopharmacology, phytochemistry and biological activity of Warburgia are reviewed. Most of the biological activities are attributed to the drimane sesquiterpenoids, including polygodial, warburganal, muzigadial, mukaadial and ugandensial, flavonoids and miscellaneous compounds present in the various species. In addition to anti infective properties, Warburgia extracts are also used to treat a wide range of ailments, including stomach aches, fever and headaches, which may also be a manifestation of infections. The need to record anecdotal evidence is emphasised and conservation efforts are highlighted to contribute to the protection and preservation of one of Africa's most coveted botanical resources. PMID- 25698248 TI - The multi-targets integrated fingerprinting for screening anti-diabetic compounds from a Chinese medicine Jinqi Jiangtang Tablet. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Jinqi Jiangtang Tablet is a traditional Chinese anti-diabetic formula containing three ingredients: Coptis chinensis Franch. (dried rhizome of C. chinensis Franch., Coptis deltoidea C. Y. Cheng et Hsiao and Coptis teeta Wall.), Astragalus membranaceus (Fisch.) Bunge. (dried root of A. membranaceus (Fisch.) Bge. var. mongholicus (Bge. ) Hsiao and A. membranaceus (Fisch.) Bge. ) and Lonicera japonica Thunb. (dried alabastrum or with nascent flowers of L. japonica Thunb. ). Free radicals, alpha-glucosidase, alpha-amylase, aldose reductase and lipase are different targets related with diabetes. However, there are no chromatographic methods employed in screening the anti-diabetic compounds from natural products basing on these targets simultaneously. The present study was aimed at the establishment of a multi-targets integrated fingerprinting to clarify the possible mechanism of the action of Traditional Chinese Medicines which simultaneously contained multiple chemical characteristics and effects of constitutions. MATERIALS AND METHODS: The multi targets integrated fingerprinting was developed and validated to screen anti diabetic compounds from natural products by using ultra-high-performance liquid chromatography/quadruple-time-of-flight mass spectrometry, fraction collector and microplate reader. Ultra performance liquid chromatography was employed to separate the components in Jinqi Jiangtang Tablet, which were identified by quadruple-time-of-flight mass spectrometry to acquire their structural information and collected by the fraction collector. Finally the active fractions were tested for scavenging 1, 1-diphenyl-2-picrylhydrazyl radical and inhibition of alpha-glucosidase, alpha-amylase, aldose reductase, and lipase activities in vitro by microplate reader. RESULTS: Our tests revealed that the Jinqi Jiangtang Tablet showed inhibitory activity against alpha-glucosidase, alpha-amylase, aldose reductase and lipase with IC50 values of 0.80 +/- 0.02 mg/mL, 1.28 +/- 0.13 mg/mL, 0.80 +/- 0.02 mg/mL, 1.90 +/- 0.18 mg/mL respectively and the scavenging activity with IC50 value of 1.71 +/- 0.178 mg/mL. The bioactive fractions were identified to be alkaloids, flavonoids and phenolic acids. The phenolic acids possessed antioxidant activities, namely the scavenging effect on 1, 1-diphenyl-2-picrylhydrazyl rull;). The alkaloids exhibited inhibitory activity against alpha-glucosidase, aldose reductase, alpha-amylase, and lipase. The flavonoids also showed mild inhibition on alpha-glucosidase, aldose reductase, alpha-amylase and lipase. CONCLUSIONS: The results demonstrate that Jinqi Jiangtang Tablet can scavenge free radicals and inhibit alpha-glucosidase, aldose reductase, alpha-amylase and lipase, which may be the possible mechanism of action of Jinqi Jiangtang Tablet for the treatment of diabetes and associated complications. Compared with conventional chromatographic separation and activity assays, the multi-targets integrated fingerprinting, which simultaneously contains the chemical characteristics and multiple effects of constitutions could comprehensively and properly reveal the activity of Jinqi Jiangtang Tablet. The results also show that the multi-targets integrated fingerprinting is a novel and powerful tool for screening and identifying active ingredients from Traditional Chinese Medicines. PMID- 25698260 TI - N2O production in the Fe(II)(EDTA)-NO reduction process: the effects of carbon source and pH. AB - Chemical absorption-biological reduction (BioDeNOx), which uses Fe(II)(EDTA) as a complexing agent for promoting the mass transfer efficiency of NO from gas to water, is a promising technology for removing nitric oxide (NO) from flue gases. The carbon source and pH are important parameters for Fe(II)(EDTA)-NO (the production of absorption) reduction and N2O emissions from BioDeNOx systems. Batch tests were performed to evaluate the effects of four different carbon sources (i.e., methanol, ethanol, sodium acetate, and glucose) on Fe(II)(EDTA)-NO reduction and N2O emissions at an initial pH of 7.2 +/- 0.2. The removal efficiency of Fe(II)(EDTA)-NO was 93.9%, with a theoretical rate of 0.77 mmol L( 1) h(-1) after 24 h of operation. The highest N2O production was 0.025 mmol L(-1) after 3 h when glucose was used as the carbon source. The capacities of the carbon sources to enhance the activity of the Fe(II)(EDTA)-NO reductase enzyme decreased in the following order based on the C/N ratio: glucose > ethanol > sodium acetate > methanol. Over the investigated pH range of 5.5-8.5, the Fe(II)(EDTA)-NO removal efficiency was highest at a pH of 7.5, with a theoretical rate of 0.88 mmol L(-1) h(-1). However, the N2O production was lowest at a pH of 8.5. The primary effect of pH on denitrification resulted from the inhibition of nosZ in acidic conditions. PMID- 25698261 TI - Effects of ciprofloxacin-containing scaffolds on enterococcus faecalis biofilms. AB - INTRODUCTION: Antibiotic-containing polymer-based nanofibers (hereafter referred to as scaffolds) have demonstrated great potential for their use in regenerative endodontics from both an antimicrobial and cytocompatibility perspective. This study sought to evaluate in vitro the effects of ciprofloxacin (CIP)-containing polymer scaffolds against Enterococcus faecalis biofilms. METHODS: Human mandibular incisors were longitudinally sectioned to prepare radicular dentin specimens. Sterile dentin specimens were distributed in 24-well plates and inoculated with E. faecalis for biofilm formation. Infected dentin specimens were exposed to 3 groups of scaffolds, namely polydioxanone (PDS) (control), PDS + 5 wt% CIP, and PDS + 25 wt% CIP for 2 days. Colony-forming units (CFU/mL) (n = 10) and scanning electron microscopy (SEM) (n = 2) were performed to quantitatively and qualitatively assess the antimicrobial effectiveness, respectively. RESULTS: PDS scaffold containing CIP at 25 wt% showed maximum bacteria elimination with no microbial growth, differing statistically (P < .05) from the control (PDS) and from PDS scaffold containing CIP at 5 wt%. Statistical differences (P < .05) were also seen for the CFU/mL data between pure PDS (5.92-6.02 log CFU/mL) and the PDS scaffold containing CIP at 5 wt% (5.39-5.87 log CFU/mL). SEM images revealed a greater concentration of bacteria on the middle third of the dentin specimen after 5 days of biofilm formation. On scaffold exposures, SEM images showed similar results when compared with the CFU/mL data. Dentin specimens exposed to PDS + 25 wt% CIP scaffolds displayed a practically bacteria-free surface. CONCLUSIONS: On the basis of the data presented, newly developed antibiotic containing electrospun scaffolds hold promise as an intracanal medicament to eliminate biofilm/infection before regenerative procedures. PMID- 25698263 TI - Association between polymorphism of dopamine D2 receptor genes and therapeutic effect of domperidone in functional dyspepsia. AB - BACKGROUND/AIMS: Functional dyspepsia (FD) is a common gastrointestinal disease, for which domperidone is one of the most commonly used drugs. This study aimed to investigate the potential causes of the varying therapeutic effects of domperidone among FD patients. MATERIALS AND METHODS: The effects of domperidone therapy in patients with FD were evaluated using a clinical symptom score combined with real-time ultrasonography examination of antral motor index. Single nucleotide polymorphism (SNP) of the dopamine D2 receptor genes 141C Ins/Del, A 241G, and TaqI, were analyzed by ligase detection reaction. RESULTS: The results of real-time ultrasonography correlated with clinical symptom scores. Single nucleotide polymorphism analysis of dopamine D2 receptor TaqI gene showed that the genotype frequencies of "C/C", "C/T", and "T/T" in the effective group were 51.35%, 31.08%, and 17.57%, respectively; the allele frequencies were 66.89% and 33.11%. In the ineffective group, the genotype frequencies of "C/C", "C/T", and "T/T" were 17.81%, 52.05%, and 30.14%, respectively; and the allele frequencies were 43.84% and 56.16%. The difference was statistically different between the two groups (p<0.01). CONCLUSION: Clinical symptom scores combined with real-time ultrasonography is effective in evaluating the therapeutic effect of domperidone in patients with functional dyspepsia. The therapeutic effect of domperidone in these patients was associated with polymorphism of dopamine D2 receptor TaqI gene. PMID- 25698262 TI - The E3 ligase synoviolin controls body weight and mitochondrial biogenesis through negative regulation of PGC-1beta. AB - Obesity is a major global public health problem, and understanding its pathogenesis is critical for identifying a cure. In this study, a gene knockout strategy was used in post-neonatal mice to delete synoviolin (Syvn)1/Hrd1/Der3, an ER-resident E3 ubiquitin ligase with known roles in homeostasis maintenance. Syvn1 deficiency resulted in weight loss and lower accumulation of white adipose tissue in otherwise wild-type animals as well as in genetically obese (ob/ob and db/db) and adipose tissue-specific knockout mice as compared to control animals. SYVN1 interacted with and ubiquitinated the thermogenic coactivator peroxisome proliferator-activated receptor coactivator (PGC)-1beta, and Syvn1 mutants showed upregulation of PGC-1beta target genes and increase in mitochondrion number, respiration, and basal energy expenditure in adipose tissue relative to control animals. Moreover, the selective SYVN1 inhibitor LS-102 abolished the negative regulation of PGC-1beta by SYVN1 and prevented weight gain in mice. Thus, SYVN1 is a novel post-translational regulator of PGC-1beta and a potential therapeutic target in obesity treatment. PMID- 25698264 TI - Effect of pantoprazole and Helicobacter pylori therapy on uninvestigated dyspeptic patients. AB - BACKGROUND/AIMS: This study aimed to test the efficacy of empirical proton pump inhibitor use and Helicobacter pylori therapy for uninvestigated dyspepsia in a population with a high prevalence of H. pylori. MATERIAL AND METHODS: The study had a two-stage design. In the first stage, the efficacy of 4-week pantoprazole treatment was compared with placebo in patients with uninvestigated dyspepsia. In the second stage, the efficacies of 2-week treatment with pantoprazole in H. pylori-negative patients and H. pylori eradication therapy (pantoprazole + amoxicillin + clarithromycin) in H. pylori-positive patients were compared. The primary endpoint was sufficient overall symptom relief (Global Overall Symptom score <=2; no or minimal symptoms) at the end of treatment. RESULTS: In the first stage, sufficient overall symptom relief was achieved by 25.2% of patients in the pantoprazole group and 15.5% of patients in the placebo group, a difference that was not statistically significant (p=0.06). In the second stage, the rate of sufficient overall symptom relief was higher in the H. pylori therapy group than in the pantoprazole group (37.1% vs. 23.4%; p=0.02). After untreated follow-up, sufficient overall symptom relief remained significantly higher in the H. pylori therapy group than in the pantoprazole group (39.7% vs. 18%; p<0.001). Almost all patients receiving pantoprazole experienced symptom relapse after treatment. CONCLUSIONS: This study validated the use of a test-and-treat strategy against H. pylori in uninvestigated dyspepsia, which may be an advisable treatment approach for uninvestigated dyspeptic patients in countries with a high prevalence of H. pylori. PMID- 25698265 TI - Visual evoked potentials and pulse wave velocity in inflammatory bowel disease. AB - BACKGROUND/AIMS: Data about the effects of inflammatory bowel disease (IBD) on various functions of the nervous and cardiovascular systems are limited. In this study, the visual neuronal and cardiovascular functions of patients with IBD were evaluated by measuring visual evoked potentials (VEP) and pulse wave velocity (PWV), respectively. MATERIALS AND METHODS: There were three study groups: the Crohn's disease (CD) group (n=25), the ulcerative colitis (UC) group (n=30), and a healthy control (C) group (n=25). The exclusion criteria were as follows: patients with IBD were in remission, had no extra-intestinal manifestations of the disease, had no additional chronic disease(s), and had been receiving medical treatment for their IBD without any previous surgical intervention. VEP amplitudes (mV) and the N2 and P2 latencies (ms) were recorded for visual neuronal analysis of all study groups. For cardiovascular assessment in all study groups, PWV was measured noninvasively as follows: the carotid-femoral PWV with the Complior Colson device (The authors have no conflict of interest.) and the PWV along the aorta with two ultrasound strain-gauge pressure-sensitive transducers (TY-306 Fukuda pressure-sensitive transducers - Fukuda Denshi Co, Tokyo, Japan) fixed transcutaneously over the course of a pair of arteries separated by a known distance. The right femoral and right common carotid arteries were the ones used. RESULTS: The PWV levels of the CD and UC groups were significantly higher than those in the C group (p<0.001). In the bilateral recording of the VEP, the N2 latencies of the CD (p<0.05) and UC (p<0.01) groups were significantly longer than those in the C group. CONCLUSION: In this study, we showed vascular and visual neuronal impairments at a subclinical stage in patients with both types of IBD. PMID- 25698267 TI - Clinical course and predictors of total colectomy in ulcerative colitis; a referral center experience from Turkey. AB - BACKGROUND/AIMS: We aimed to describe the clinical course of Ulcerative colitis (UC) and the factors that predict the need for total colectomy in Turkish patients with severe UC receiving regular follow up. MATERIALS AND METHODS: We analyzed the demographic and clinical characteristics of 612 patients with UC receiving regular follow up between 1994 and 2010 in a tertiary referral center in Ankara. RESULTS: Men accounted for 58% of patients (M:F ratio, 1.4:1), and the mean age at diagnosis was 37.9 years. Of these, 32% had distal colitis and 8.8% had further extension, and 39 patients (6.4%) had chronic active disease. Steroid dependency and steroid resistance rates were 7.5% and 17.2%, respectively. In multivariate analysis, steroid dependency (p=0.04), steroid resistance (p=0.002), further extension (p<0.001), presence of extensive disease (p=0.006), and chronic active disease (p<0.001) were independent predictors of the need for total colectomy. Patients with chronic active disease had lower total colectomy free survival (p<0.001). CONCLUSION: The predictors of total colectomy were comparable with those previously reported in the literature. However, we identified further extension in disease localization to predict the need for total colectomy. PMID- 25698266 TI - The relationship between serum adiponectin and resistin levels, insulin resistance and colorectal adenomas. AB - BACKGROUND/AIMS: The relationship between adipocytokines and the development of colorectal cancer is well-documented. Our aim was to assess the relationship among serum adiponectin and resistin levels, insulin resistance, and colorectal adenoma to evaluate whether these parameters can be used as biomarkers to predict the development of colorectal adenoma. MATERIALS AND METHODS: This is a cross sectional case-control study conducted in 32 patients with colorectal adenoma and 30 control subjects. Serum adiponectin and resistin levels, body mass index values, waist and hip circumferences and Homeostasis Model Assessment scores were measured. RESULTS: Resistin levels were slightly higher and adiponectin was slightly lower in patients with colorectal adenoma compared with controls; however, the differences in both parameters failed to reach statistical significance. The body mass index values and waist circumference of the patient group were significantly higher than controls (p=0.003 and p=0.002, respectively). Fasting serum insulin levels and Homeostasis Model Assessment scores of patients with colorectal adenoma were significantly higher than those of controls (p=0.02 and p=0.02, respectively). There was no relation between the number of colorectal adenomas and serum adiponectin or resistin levels. CONCLUSION: Our data indicate that obesity and insulin resistance may contribute to the development of colorectal adenoma and that serum adiponectin levels and insulin resistance may not have a substantial predictive value for colorectal adenoma. PMID- 25698268 TI - Comparative assessment of prognostic value for revised-Mayo risk model and Child Pugh score in patients with primary sclerosing cholangitis. AB - BACKGROUND/AIMS: The aim of this study was to compare the utility of the revised Mayo risk model (rMRM) and Child-Pugh scores (CPSs) for predicting the prognosis of disease in patients with primary sclerosing cholangitis (PSC). MATERIALS AND METHODS: Patients were divided into 2 groups: Group I (37 patients; alive and not requiring liver transplantation) and Group II (8 patients; deceased or requiring liver transplantation). rMRM suggests the possible survival percentage over a 4 year period. Thus, rMRM scores and CPSs on the first visit were calculated from the data at the time of diagnosis for patients diagnosed with PSC <4 years ago. rMRM scores and CPSs of patients with >4 years of follow-up were calculated using data from the visit 4 years prior to their last follow-up. RESULTS: Bivariate analyses showed that need for liver transplantation/mortality was correlated with either first visit CPS (r=0.481, p=0.001) or rMRM (r=0.452, p=0.002). Analysis of the area under the curve showed that both models performed similarly in terms of predicting the need for liver transplantation/mortality (rMRM: 0.780; CPS: 0.762; p=0.8). There was a significant difference in Kaplan-Meier survival rates between Group I and Group II for both risk models (rMRM: p<0.001; CPS: p<0.001) when the decisive event was death or need for liver transplantation. CONCLUSION: Both rMRM and CPSs are useful in risk assessment of patients with PSC. The ability to predict prognosis is similar for both risk models. PMID- 25698269 TI - The importance of the serum quantitative levels of hepatitis B surface antigen and hepatitis B e antigen in children with chronic hepatitis B. AB - BACKGROUND/AIMS: We aimed to investigate the clinical importance of quantitative levels of serum hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg), and to detect their correlation with hepatitis B virus (HBV) DNA load, alanine aminotransferase (ALT) levels, hepatic activity index (HAI) and fibrosis scores. MATERIALS AND METHODS: A total of 56 HBeAg-positive children with chronic hepatitis B (CHB) were included in the study. Quantification of HBsAg and HBeAg was performed using an automated chemiluminescent microparticle immunoassay. Comparisons were performed using the paired t-test, Mann-Whitney U test or t-test for independent samples. Correlations were tested using the Pearson correlation analysis. RESULTS: Significant differences were found between groups of pre- and post treatment quantitative levels of HBsAg, HBeAg, HBV DNA, and ALT. Comparison of HBsAg, HBeAg, HBV DNA, and ALT levels before the treatment and decrease ratios of these levels after treatment according to HAI and fibrosis scores did not show any statistically significant differences. There was a positive correlation between pretreatment HBV DNA load and HBeAg levels, and a negative correlation between pretreatment HBV DNA and ALT levels. There was a negative correlation between decrease ratios of HBsAg and ALT levels after treatment. Patients with post treatment HBeAg seroconversion had a lower post treatment HBV DNA load and a higher decrease ratio of HBsAg than patients who did not have HBeAg seroconversion. CONCLUSION: The present study indicated that HBsAg and HBeAg levels significantly decreased during treatment and that HBeAg correlated with HBV DNA load. Quantitative HBeAg and HBsAg assays could therefore have an important role in treatment of CHB. PMID- 25698270 TI - Diagnostic value of the JAK2 V617F mutation for latent chronic myeloproliferative disorders in patients with Budd-Chiari syndrome and/or portal vein thrombosis. AB - BACKGROUND/AIMS: The diagnosis of an underlying myeloproliferative neoplasm (MPN) is often problematic in patients with Budd Chiari syndrome (BCS) or portal vein thrombosis (PVT). This study aimed to assess the diagnostic value of the JAK2 gene V617F gain-of-function mutation for MPN in splanchnic vein thrombosis patients. MATERIALS AND METHODS: One hundred eleven patients (80 with PVT, 27 with BCS, and 4 with BCS and PVT) were investigated. The control group included 56 volunteers without any known diseases. LightCycler SNP genotyping was performed to detect the JAK2 V617F mutation in DNA extracted from peripheral blood. RESULTS: The JAK2 V617F mutation was identified in six of 28 patients (21.4%) with idiopathic PVT or BCS and in eight of 45 patients (17.8%) with PVT or BCS secondary to a known prothrombotic factor, but in only one of 38 patients (2.6%) with PVT and cirrhosis (p=0.049). CONCLUSION: The JAK2 V617F mutation is a noninvasive molecular marker for occult MPNs and can be used for the diagnosis of latent MPNs presenting with thrombotic events. Analysis of JAK2 mutation in the patients with idiopathic PVT or BCS showed that 20% had latent MPNs. In addition to this JAK2 mutation, prothrombotic events were observed in a significant number of patients with splanchnic vein thrombosis. JAK2 gene analysis should be included in the research panel for BCS and PVT patients without cirrhosis. PMID- 25698271 TI - Use of internet resources by patients awaiting gastroenterology consultation. AB - BACKGROUND/AIMS: The purpose of this study is to understand how outpatients awaiting initial gastroenterology consultation seek medical information on the Internet and how wait times affect Internet usage. MATERIALS AND METHODS: A cross sectional survey of 87 gastroenterology outpatients awaiting consultation was performed at a tertiary care center. RESULTS: Fifty-two patients (60%) utilized the Internet for medical information. The mean age of patients using the Internet was 41 years, whereas the mean age of those not using the Internet was 60 years (p<0.0001). The Internet was used by 71% of females and 47% of males (p<0.05). Regarding the educational level, the Internet was sought by 33% of the patients possessing less than secondary school education, 59% possessing secondary school education, 66% with an undergraduate degree, and 100% with a postgraduate degree (p=0.14). The mean wait time for consultation for patients who utilized the Internet was 158 days, and for patients who did not was 147 days (p=0.60). The most common websites searched were medical, 71%. The most common medical information sought was symptoms and diagnosis by 85% of patients. The reasons for Internet use were wait times for 36% of patients and recommendation by a physician for 10%. Eighty seven percent of the patients who utilized the Internet believed that they suffered from an unidentified disease, whereas 46% of patients who did not utilize the Internet believed the same (p=0.0001). CONCLUSION: Younger patients and females were more likely to use the Internet, but wait times did not affect Internet usage. The Internet is a powerful patient resource; however, further physician guidance is required to help patients identify reliable resources. PMID- 25698272 TI - Pancreatic metastasis in a case of small cell lung carcinoma diagnosed by EUS. AB - Small-cell lung carcinoma represents a group of highly malignant tumors characterized by early and widespread metastais even at the time of diagnosis. However, the pancreas is a relatively infrequent site of metastasis by this neoplasm. A 57-year-old patient was admitted with an intense cough and complaints of abdominal discomfort. A chest X-Ray showed no evidence of lung mass but did show signs of lymphadenopathy. In addition, there was little evidence for malignancy based on a transbronchial needle aspiration. In contrast, there was a mass in the head portion of the pancreas. We diagnosed a case of small-cell lung carcinoma metastasis in the pancreas by using an endoscopic ultrasound-guided fine-needle aspiration biopsy. This case demonstrates that endoscopic ultrasound guided fine-needle aspiration biopsy is an important tool in the diagnosis of metastatic pancreatic neoplasms. PMID- 25698273 TI - Gastrointestinal stromal tumor and leiomyoma of the ileum mimicking adnexal mass: a report of two cases. AB - Adnexal masses are formations seen in women of all ages; they most often include cystic elements. Medical history, physical examination, different imaging methods, and tumor marker determinations must be used together for preoperative evaluation of an adnexal mass. Both benign and malignant tumors of the small intestine are more rarely encountered than malignant tumors of other gastrointestinal system components; although advanced imaging methods and other diagnostic techniques are used, they do not always allow these tumors to be differentiated from adnexal masses. We report here on two cases operated on with the preliminary diagnosis of an adnexal mass, in which the presence of a gastrointestinal stromal tumor and a leiomyoma of the ileum, respectively, was established. PMID- 25698274 TI - Rectal diverticulitis mimicking rectal carcinoma with intestinal obstruction: case report. AB - Although diverticular disease of the colon is common, the occurrence of rectal diverticula is extremely rare with only sporadic reports in the literature since 1911. Symptomatic rectal diverticula are seen even less frequently, and surgical intervention is needed for only complicated cases. Here we report the case of a 63-year-old woman presenting with rectal diverticulitis mimicking rectal carcinoma with intestinal obstruction. PMID- 25698275 TI - Candida esophagitis mimicking esophageal malignancy on 18FDG PET/CT. PMID- 25698276 TI - Imaging findings of an isolated gastric tuberculosis case mimicking lymphoma and infiltrative gastric cancer. PMID- 25698277 TI - Acute pancreatitis due to pancreatic involvement of Burkitt's lymphoma in a child. PMID- 25698278 TI - Eosinophilic esophagitis in a girl with pollen allergy who showed trachealization. PMID- 25698279 TI - Danger in unlabeled bottles: analysis of corrosive substances. PMID- 25698280 TI - Adulthood hepatoblastoma. PMID- 25698281 TI - Swallowing-induced atrioventricular block and syncope in a patient with achalasia. PMID- 25698282 TI - Coach syndrome: the first case from Turkey. PMID- 25698283 TI - Pyogenic granuloma in differential iron deficiency diagnosis. PMID- 25698284 TI - A new technique for the removal of a transmigrated intrauterine device with rectum penetration. PMID- 25698285 TI - Primary adrenal non Hodgkin lymphoma: changing trends. PMID- 25698286 TI - Intragastric balloon and epigastric pain: beware of the pancreas. PMID- 25698287 TI - Nonoperative treatment versus appendectomy for uncomplicated acute appendicitis. PMID- 25698288 TI - Diagnostic difficulty in subepithelial gastric tumors, and the efficacy of laparoscopy-assisted distal gastrectomy in gastric cancer. PMID- 25698289 TI - Use of elafin in celiac disease. PMID- 25698290 TI - Metal detoxification and gene expression regulation after a Cd and Zn contamination: an experimental study on Danio rerio. AB - This study aimed to demonstrate the recovery potential of Danio rerio after Cd and Zn contaminations. Fish demonstrated high accumulation capacities of Cd with concentrations reaching 3716.4+/-578.6 MUg Cd/kg FW in gills after 15 d of contamination. The 75-day decontamination failed to completely eliminate Cd (93.4% and 82.2% eliminated respectively in the gills of fish exposed to Cd and Cd/Zn) whereas Zn, poorly accumulated, was quickly depurated. The fast Cd depuration in the gills likely resulted from a metal transfer to the liver. MT response was clearly correlated to the Zn contamination, while genetic responses were more pronounced in case of Cd contamination. Cd induced over-expressions of genes involved against oxidative stress (sod, sodmt), and involved in detoxification mechanisms (mt1, mt2), mitochondrial mechanisms (cox1) and DNA repair (rad51 and gadd45). Zn binary contamination with Cd was demonstrated to provide protective effects on Cd-induced toxicity in D.rerio. Results highlighted that the genetic response was metal- and tissue-dependent. The brain and the muscles showed very few genetic responses, probably due to the low bioaccumulations measured in these tissues. Conversely, genes expressed in gills and liver of fish exposed to Cd were strongly affected (sod*3 and*12, mt1*11 and *30 at T3 respectively in gills and liver). However, after 14-30 d of depuration, genes were no longer over expressed in response to Cd contamination in gills and liver of fish exposed to Cd and Cd/Zn conditions, suggesting an gene expression regulation of fish to the residual Cd contamination. PMID- 25698291 TI - The impact of a freshwater fish farm on the community of tetracycline-resistant bacteria and the structure of tetracycline resistance genes in river water. AB - The aim of this study was to assess the impact of a fish farm on the structure of antibiotic resistant bacteria and antibiotic resistance genes in water of Drweca River. Samples of upstream river waters; post-production waters and treated post production waters from fish farm; as well as downstream river waters were monitored for tetracycline resistant bacteria, tetracycline resistant genes, basic physico-chemical parameters and tetracyclines concentration. The river waters was characterized by low levels of pollution, which was determined based on water temperature, pH and concentrations of dissolved oxygen and tetracycline antibiotics. Culture-dependent (heterotrophic plate counts, counts of bacteria resistant to oxytetracycline (OTC(R)) and doxycycline (DOX(R)), minimum inhibitory concentrations for oxytetracycline and doxycycline, multidrug resistance of OTC(R) and DOX(R), qualitative composition of OTC(R) and DOX(R), prevalence of tet genes in resistant isolates) and culture-independent surveys (quantity of tet gene copies) revealed no significant differences in the abundance of antibiotic-resistant bacteria and antibiotic resistance genes between the studied samples. The only way in which the fish farm influenced water quality in the Drweca River was by increasing the diversity of tetracycline resistance genes. However, it should also be noted that the bacteria of the genera Aeromonas sp. and Acinetobacter sp. were able to transfer 6 out of 13 tested tet genes into Escherichiacoli, which can promote the spread of antibiotic resistance in the environment. PMID- 25698292 TI - Life stage-dependent susceptibility of Aphytis melinus DeBach (Hymenoptera: Aphelinidae) to two pesticides commonly used in citrus orchards. AB - The assessment of pesticides compatibility with natural enemies is recommended before including agrochemicals in integrated and organic pest management schemes. The lethal and sublethal effects of a mineral oil and a juvenile hormone mimic (pyriproxyfen), on adults and larvae of Aphytis melinus, a key ectoparasitoid of armored scale insect pests of citrus, such as Aonidiella aurantii, were evaluated. Mineral oil caused very high mortality on the adults, while a lower acute toxicity was recorded on young instars. No significant effects on their reproduction capacity and on the sex-ratio of the progeny were observed. Pyriproxyfen had neither lethal nor sublethal effects (in terms of survived female fertility) on A. melinus adults. However, parasitoid larvae exposed to this insecticide suffered strong acute toxicity and fertility reduction (progeny number and proportion of female progeny). When adults were offered the choice to parasitize treated and untreated scales they significantly preferred the control ones, and when they were exposed to only treated scaled the parasitism rate was significantly lower only with mineral oil-treated hosts. The significant differences in the susceptibility of the two parasitoid instars highlight the importance of including this aspect in pesticide risk assessment procedures and in the choice of the pesticide and of the treatment timing in the field. Overall, the results indicate potential for integrating A. melinus, both naturally present and artificially released, and these insecticides only by appropriate timing of insecticide spraying and parasitoid releases. PMID- 25698293 TI - Combined effects of larval exposure to a heat wave and chlorpyrifos in northern and southern populations of the damselfly Ischnura elegans. AB - Heat waves are generally associated with an increased energy consumption and could thus increase the vulnerability to subsequent pesticide exposure. We investigated the combined effect of a heat wave and subsequent exposure to the pesticide chlorpyrifos in Ischnura elegans damselfly larvae. To assess local thermal adaptation to heat waves, we applied these combined stressors on replicated low- and high-latitude populations in Europe. Unexpectedly, we observed positive sublethal effects of the heat wave: fat content and phenoloxidase activity increased. Chlorpyrifos had strong negative effects on survival, growth rate, and fat content, while phenoloxidase activity increased; these effects between latitudes were found similar. We found little indication of a higher ability to withstand a heat wave in southern larvae. We did detect a synergistic negative effect on AChE activity. This result highlights the importance of considering delayed effects of extreme temperature events when assessing the impact of pesticides under climate change. PMID- 25698294 TI - Inverse association between intelligence quotient and urinary retinol binding protein in Chinese school-age children with low blood lead levels: results from a cross-sectional investigation. AB - OBJECTIVES: Examine the relationship between blood lead concentration and children's intelligence quotient (IQ) in Chinese children 8-12 years old. PARTICIPANTS AND METHODS: This is a cross-sectional study, and participants included 446 children from three primary schools in Jiangsu, China. We collected environmental and genetic information from questionnaires. Blood lead (Pb), manganese (Mn), cadmium (Cd) and selenium (Se) concentrations were measured using inductively coupled plasma mass spectrometry (ICP-MS). IQ was assessed using the Combined Raven's Test and then converted to a standard IQ score according to Chinese children's norm. Morning urine samples were collected to measure retinol binding protein (RBP). RESULTS: The average blood lead concentration was 33.13 MUg L(-1) (geometric mean), and the blood lead concentration (BoxCox transform) was inversely and significantly associated with IQ (r=-0.11, p=0.02). The geometric mean of blood Mn, Cd and Se was 7.02 MUg L(-1), 0.18 MUg L(-1) and 94.77 MUg L(-1), respectively. Blood Mn, Cd and Se showed no association with IQ, but all of them associated with urinary RBP. Urinary RBP was identified as a new factor associated with IQ (beta=-6.49, p=0.011). CONCLUSIONS: Urinary RBP was recognized as a new indicated factor associated with children's IQ. Mn, Cd and Se exposure might affect urinary RBP concentration and further IQ. Findings also support that blood lead concentrations in 8-12 years old children, even <44 MUg L(-1), have a negative association with IQ. PMID- 25698296 TI - Increasing Residential Proximity of Lyme Borreliosis Cases to High-Risk Habitats: A Retrospective Study in Central Bohemia, the Czech Republic, 1987-2010. AB - An analysis of historical data on Lyme borreliosis in Central Bohemia between 1987-2010 has revealed that the rate of peri-domestic exposure, the proximity of patients' residences to high-risk habitats, and the number of disease cases have been interdependent variables and that their common upturn can be dated back to the start of the 1990s or earlier. The data indicate that the disease rise is attributable to translocation of part of the at-risk population nearer to natural environments, rather than to mere intensification of people's peri-domestic exposure at existing residential locations, or changes in the natural environment itself. PMID- 25698297 TI - Synthesis and characterization of an immobilizable photochemical molecular device for H2-generation. AB - With [Ru(II)(bpyMeP)2tpphzPtCl2](2+) (4) a molecular photocatalyst has been synthesized for visible-light-driven H2-evolution. It contains the ligand bpyMeP (4,4'-bis(diethyl-(methylene)-phosphonate)-2,2'-bipyridine) with phosphate ester groups as precursors for the highly potent phosphonate anchoring groups, which can be utilized for immobilization of the catalyst on metal-oxide semiconductor surfaces. The synthesis was optimized with regard to high yields, bpyMeP was fully characterized and a solid-state structure could be obtained. Photophysical studies showed that the photophysical properties and the localization of the excited states are not altered compared to similar Ru-complexes without anchoring group precursors. (4) was even more active in homogenous catalysis experiments than [Ru(II)(tbbpy)2tpphzPtCl2](2+) (6) with tbbpy (4,4'-bis(tbutyl)-2,2' bipyridine) as peripheral ligands. After hydrolysis (4) was successfully immobilized on NiO, suggesting that an application in photoelectrosynthesis cells is feasible. PMID- 25698298 TI - Evaluation of a positive psychotherapy group intervention for people with psychosis: pilot randomised controlled trial. AB - AIMS: Third-wave psychological interventions have gained relevance in mental health service provision but their application to people with psychosis is in its infancy and interventions targeting wellbeing in psychosis are scarce. This study tested the feasibility and preliminary effectiveness of positive psychotherapy adapted for people with psychosis (WELLFOCUS PPT) to improve wellbeing. METHODS: WELLFOCUS PPT was tested as an 11-week group intervention in a convenience sample of people with psychosis in a single centre randomised controlled trial (ISRCTN04199273) involving 94 people with psychosis. Patients were individually randomised in blocks to receive either WELLFOCUS PPT in addition to treatment as usual (TAU), or TAU only. Assessments took place before randomisation and after the therapy. The primary outcome was wellbeing (Warwick-Edinburgh Mental Well Being Scale, WEMWBS). Secondary outcomes included symptoms (Brief Psychiatric Rating Scale), depression (Short Depression-Happiness Scale), self-esteem, empowerment, hope, sense of coherence, savouring beliefs and functioning, as well as two alternative measures of wellbeing (the Positive Psychotherapy Inventory and Quality of Life). Intention-to-treat analysis was performed. This involved calculating crude changes and paired-sample t-tests for all variables, as well as ANCOVA and Complier Average Causal Effect (CACE) Analysis to estimate the main effect of group on all outcomes. RESULTS: The intervention and trial procedures proved feasible and well accepted. Crude changes between baseline and follow-up showed a significant improvement in the intervention group for wellbeing according to all three concepts assessed (i.e., WEMWBS, Positive Psychotherapy Inventory and Quality of Life), as well as for symptoms, depression, hope, self esteem and sense of coherence. No significant changes were observed in the control group. ANCOVA showed no main effect on wellbeing according to the primary outcome scale (WEMWBS) but significant effects on symptoms (p = 0.006, ES = 0.42), depression (p = 0.03, ES = 0.38) and wellbeing according to the Positive Psychotherapy Inventory (p = 0.02, ES = 0.30). Secondary analysis adapting for therapy group further improved the results for symptom reduction (p = 0.004, ES = 0.43) and depression (p = 0.03, ES = 0.41) but did not lead to any more outcomes falling below the p = 0.05 significance level. CACE analysis showed a non significant positive association between the intervention and WEMWBS scores at follow-up (b = 0.21, z = 0.9, p = 0.4). CONCLUSIONS: This study provides initial evidence on the feasibility of WELLFOCUS PPT in people with psychosis, positively affecting symptoms and depression. However, more work is needed to optimise its effectiveness. Future research might evaluate positive psychotherapy as a treatment for comorbid depression in psychosis, and consider alternative measurements of wellbeing. PMID- 25698299 TI - 3D versus 2D contrast-enhanced sonography in the evaluation of therapeutic response of hepatocellular carcinoma after locoregional therapies: preliminary findings. AB - OBJECTIVE: To investigate diagnostic performance of 3D contrast-enhanced ultrasound (CEUS) compared with 2D CEUS in the assessment of therapeutic response of hepatocellular carcinoma (HCC) treated with locoregional therapies (LRT). MATERIALS AND METHODS: Twenty-three consecutive patients (13 men and 10 women; mean age 65.5 years) with 23 HCCs (size range 1.2-7.2 cm; mean size 2.9 +/- 1.4 cm) treated by means of radiofrequency ablation (RFA n = 9), transarterial chemoembolization (TACE n = 8), combined RFA and TACE (n = 3), percutaneous alcoholization (n = 2), and wedge resection (n = 1) underwent 2D and 3D CEUS 1 month (30 +/- 2 days) after treatment. Magnetic resonance (n = 17) and computed tomography (n = 6) acted as standard of reference (SOR). Two radiologists assessed the absence (complete response CR) or presence (residual tumor RT) of any nodular arterially enhancing area within or along the margin of the treated HCC. RESULTS: Both 2D and 3D CEUS observed CR in 10/23 (43.5 %) HCCs and RT in 11/23 (47.8 %) HCCs. In 1/23 (4.3 %) HCC, RT was documented by SOR and 2D CEUS, but it was not appreciable at 3D CEUS. In 1/23 (4.3 %) HCC, the presence of peripheral residual tumor was suspected by both 2D and 3D CEUS, but it was not confirmed by SOR. No statistically significant difference between 2D and 3D CEUS in depicting either CR or RT was found (p > 0.05). Sensitivity, specificity, positive and negative predictive values, and accuracy of 3D CEUS were 91.7 % [95 % confidence interval (CI) 0.760-1.073], 90.9 % (95 % CI 0.739-1.079), 91.7, 90.9, and 91.3 %, respectively. CONCLUSION: 2D and 3D CEUS provided similar diagnostic performance in the assessment of therapeutic response of HCC treated with LRT. PMID- 25698300 TI - Endovascular management of the rectus muscle hematoma. AB - PURPOSE: Non-traumatic spontaneous hematoma of the rectus abdominal muscle is not considered a critical condition. Nevertheless, it can be a serious complication in some patients due to continuous and/or consistent bleeding. The most frequent cause of spontaneous rectus muscle hematoma is the anticoagulation therapy. The natural history of rectus muscle hematoma usually leads to a positive outcome and can be spontaneously self-limited only by conservative therapy. Nevertheless, in some patients, despite a correct and early medical therapy, the continuous bleeding requests a more radical handling. Up to now, the surgical hematoma evacuation and the bonding of blood vessels were considered the most appropriate treatment, while at present, the percutaneous management by means of selective catheters and embolization of the bleeding vessel is considered to be the most used option. Our purpose is to report our experience in the endovascular spontaneous rectus muscle bleeding treatment in the elderly patients. MATERIALS AND METHODS: From the data base and medical reports of the hospital, we selected 144 medical reports. We focused on those cases that showed the following criteria: patients with rectus muscle hematoma undergoing anticoagulation therapy and/or non-traumatic spontaneous hematoma and with persistent bleeding revealed on CT examination despite a pharmacological treatment aimed to timely reverse coagulopathy. These criteria were found in 18 patients: 15 females and 3 males, with a median age of 73 (range 64-81). In all patients, the diagnosis had been confirmed by an abdominal CT in emergency setting, performed before and after contrast medium intravenous administration. Because of clinical conditions, all patients had been moved on the angiographic room for diagnostic arteriography and embolization. The criteria for this treatment were hemodynamic instability and the continuous bleeding despite the correct medical therapy. RESULTS: CT imaging detected rectus muscle hematoma in 18/18 patients and active bleeding in 7/18 patients. Selective catheterization was applied to all 18 patients; arteriographic study confirmed the information of the CT study in all of the seven patients. The inferior epigastric artery was the main cause of the bleeding in all 18 patients. In 14 patients, one single vessel was responsible for the bleeding, while in the other four patients, more than one vessel were involved: In two patients, we also found the involvement of the superior epigastric artery; while the other two patients showed also the involvement of the deep iliac circumflex artery. The material for embolization was compatible coils with micro catheters in 17/18 patients, and glue for 1/18 patient. CONCLUSIONS: Patients with large rectus muscle hematoma, which have not yet recovered with conservative therapy, should then consider undergoing endovascular treatment. This procedure is highly recommended in patients with other coexisting pathologies that could eventually lead to a fatal outcome. It is difficult to determine when surgery is necessary when there is very poor data provided by scientific literature review, so the decision to use surgery can be suggested when embolization is unsuccessful or when it is necessary to evacuate a complex huge fluid mass in peritoneal cavity. PMID- 25698301 TI - Giant cell tumour of tendon sheath with bone invasion in extremities: analysis of clinical and imaging findings. AB - PURPOSE: The purpose of this study was to review the clinical and imaging characteristics of giant cell tumour of tendon sheath (GCTTS) with bone invasion. MATERIALS AND METHODS: Radiography (n = 9), magnetic resonance imaging (MRI) (n = 7), computed tomography (CT) (n = 4) and clinical findings of nine patients with surgically and pathologically confirmed GCTTS with bone invasion were retrospectively reviewed. Specific imaging findings including tumour site, maximum tumour size, shape, margin, density or signal intensity, bone invasion, periosteal reaction, calcification, and cystic areas were documented. RESULTS: There were five males and four females, with median age of 34 years. Presenting symptoms were painless mass in five patients, painful mass in two, intermittent pain and swelling in one and pain without mass in one. Five tumours were in the ankle-foot region, two in the hand, one in the cubital fossa and one in the patellofemoral joint. The total symptom duration ranged from 5 months to 6 years (median 12 months). The maximum tumour size ranged from 1.0 to 6.8 cm (median 3.0 cm). Radiographically, all tumours appeared as cortical destruction with well defined margins. Four patients underwent CT scanning that clearly showed an iso attenuated mass with intraosseous soft tissue. MR scanning was performed in seven patients who demonstrated a round, oval, spindle-shaped or multilobular soft tissue mass near or inside the joint with cortical destruction and intraosseous soft tissue. Five lesions were homogeneous moderate signal on T1WI. Moderate (n = 1), slightly high or high (n = 2) and low (n = 2) signal intensities were evident on T2WI. Two lesions showed heterogeneous low-to-moderate signal intensities on T1WI and mixed low signal intensities on T2WI. CONCLUSIONS: GCTTS is a benign soft tissue mass that may present as an intraosseous lesion near extremity joints and frequently occurring in foot and hand on radiological examinations. GCTTS with bone invasion should be considered when MRI shows solid mass with characteristic low signal on T2-weighted images. PMID- 25698302 TI - Age estimation from canine volumes. AB - Techniques for estimation of biological age are constantly evolving and are finding daily application in the forensic radiology field in cases concerning the estimation of the chronological age of a corpse in order to reconstruct the biological profile, or of a living subject, for example in cases of immigration of people without identity papers from a civil registry. The deposition of teeth secondary dentine and consequent decrease of pulp chamber in size are well known as aging phenomena, and they have been applied to the forensic context by the development of age estimation procedures, such as Kvaal-Solheim and Cameriere methods. The present study takes into consideration canines pulp chamber volume related to the entire teeth volume, with the aim of proposing new regression formulae for age estimation using 91 cone beam computerized scans and a freeware open-source software, in order to permit affordable reproducibility of volumes calculation. PMID- 25698303 TI - The clinical application of 320-detector row CT in transcatheter arterial chemoembolization (TACE) for hepatocellular carcinoma. AB - PURPOSE: To evaluate the clinical value of 320-detector row CT in transcatheter arterial chemoembolization (TACE) treatment for hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Sixty-four patients with HCC underwent CT perfusion scanning with a 320-detector row CT before and after TACE. With the help of built in dual-source CT perfusion software, color perfusion images of hepatic arterial perfusion (HAP), portal vein perfusion (PVP) and hepatic arterial perfusion index (HAPI) of all HCC lesions were obtained, and the above perfusion parameters were measured on the color images. The parameters obtained after TACE were compared with those obtained before TACE, and the differences were statistically analyzed. RESULTS: There were significant differences in HAP, PVP and HAPI between cancer tissues and non-cancerous tissues before TACE (P < 0.05). HCC necrotic tissues had no blood perfusion after TACE. Lower HAP and HAPI and higher PVP were observed in active cancer tissues after operation as compared with those before operation. CONCLUSIONS: The 320-row CT upper abdominal one-stop examination can display the whole liver perfusion well, especially the abnormal perfusion of HCC tissues and postoperative active tissues. Angiography can display the hepatic and nutrient arteries of tumors from three dimensions, and has important guiding significance in preoperative evaluation and postoperative follow up of TACE. PMID- 25698304 TI - Validation of the Norwegian short version of the Body Shape Questionnaire (BSQ 14). AB - BACKGROUND: The Body Shape Questionnaire (BSQ) is a widely used self-report measure of body shape dissatisfaction. AIMS: We aimed to establish psychometric properties and report normative data for the Norwegian 14-item BSQ in a clinical and non-clinical sample. METHODS: A total of 423 female students, 267 male students and 49 female inpatients [anorexia nervosa (AN) and subthreshold AN] were administered the BSQ, the Body Checking Questionnaire (BCQ), and the Eating Disorder Examination Questionnaire (EDE-Q). RESULTS: On average, the male and female controls were aged (mean+/- standard deviation) 20.98 +/- 5.68 years and 24.35 +/- 9.89 years with mean body mass indexes (BMIs) of 23.34 +/- 3.13 and 22.30 +/- 3.62 kg/m(2), respectively. Patients were 19.04 +/- 3.06 years with a mean BMI of 16.48 +/- 1.81. Divergent validity was indicated by significantly (P < 0.001) different means between the patient group versus female controls, 56.80 +/- 18.89 and 35.89 +/- 15.19, respectively. Cronbach's alpha was satisfactory for all three groups (0.91-0.96), indicating excellent internal consistency. The BSQ correlated significantly (P < 0.001) with the BCQ and EDE-Q, indicating concurrent validity. BMI and BSQ scores did not correlate significantly within the population as a whole. However, when subdividing the sample, higher BMI was associated with higher BSQ scores among females and males within the non-clinical sample. CONCLUSIONS: Our study provides psychometric support for the Norwegian version of the BSQ-14 among a clinical and non-clinical sample of both young men and women. PMID- 25698305 TI - The effects of voluntary control of respiration on the excitability of the primary motor hand area, evaluated by end-tidal CO2 monitoring. AB - OBJECTIVE: To investigate the effects of voluntary deep breathing on the excitability of the hand area in the primary motor cortex (M1). METHODS: We applied near-threshold transcranial magnetic stimulation (TMS) over M1 during the early phase of inspiration or expiration in both normal automatic and voluntary deep, but not "forced", breathing in eight healthy participants at rest. We monitored exhaled CO2 levels continuously, and recorded motor-evoked potentials (MEPs) simultaneously from the abductor pollicis brevis, first dorsal interosseous, abductor digiti minimi, flexor digitorum superficialis, and extensor incidis muscles. RESULTS: We observed that, during voluntary deep breathing, MEP amplitude increased by up to 50% for all recorded muscles and the latency of MEPs decreased by approximately 1ms, compared with normal automatic breathing. We found no difference in the amplitude or latency of MEPs between inspiratory and expiratory phases in either normal automatic or voluntary deep breathing. CONCLUSIONS: Voluntary deep breathing at rest facilitates MEPs following TMS over the hand area of M1, and MEP enhancement occurs throughout the full respiratory cycle. SIGNIFICANCE: The M1 hand region is continuously driven by top-down neural signals over the entire respiratory cycle of voluntary deep breathing. PMID- 25698306 TI - Effects of anesthetic agents on in vivo axonal HCN current in normal mice. AB - OBJECTIVE: The objective was to study the in vivo effects of anesthetic agents on peripheral nerve excitability. METHODS: Normal male mice were anesthetized by either isoflurane inhalation or a combination of medetomidine, midazolam, and butorphanol intraperitoneal injection ("triple agents"). Immediately after induction, the tail sensory nerve action potential was recorded and its excitability was monitored. RESULTS: Under both anesthetic protocols, there was an interval excitability change by long hyperpolarizing currents. There was greater threshold reduction approximately 30min post induction, in comparison to immediately post induction. Other excitability parameters were stable over time. Modeling suggested interval suppression of internodal H conductance or leak current. CONCLUSIONS: Anesthetic agents affected responses to long hyperpolarizing currents. SIGNIFICANCE: Axonal excitability during intraoperative monitoring may be affected by anesthetic agents. Interpretation of interval excitability changes under anesthesia requires caution, especially with long hyperpolarizing currents. PMID- 25698307 TI - The influence of central neuropathic pain in paraplegic patients on performance of a motor imagery based Brain Computer Interface. AB - OBJECTIVE: The aim of this study was to test how the presence of central neuropathic pain (CNP) influences the performance of a motor imagery based Brain Computer Interface (BCI). METHODS: In this electroencephalography (EEG) based study, we tested BCI classification accuracy and analysed event related desynchronisation (ERD) in 3 groups of volunteers during imagined movements of their arms and legs. The groups comprised of nine able-bodied people, ten paraplegic patients with CNP (lower abdomen and legs) and nine paraplegic patients without CNP. We tested two types of classifiers: a 3 channel bipolar montage and classifiers based on common spatial patterns (CSPs), with varying number of channels and CSPs. RESULTS: Paraplegic patients with CNP achieved higher classification accuracy and had stronger ERD than paraplegic patients with no pain for all classifier configurations. Highest 2-class classification accuracy was achieved for CSP classifier covering wider cortical area: 82+/-7% for patients with CNP, 82+/-4% for able-bodied and 78+/-5% for patients with no pain. CONCLUSION: Presence of CNP improves BCI classification accuracy due to stronger and more distinct ERD. SIGNIFICANCE: Results of the study show that CNP is an important confounding factor influencing the performance of motor imagery based BCI based on ERD. PMID- 25698308 TI - The neurobiology of psychopathy: recent developments and new directions in research and treatment. AB - Psychopathic individuals account for substantial predatory and impulsive violence. To the present, the principal intervention used to decrease the harm inflicted by psychopaths has been confinement. Nevertheless, most confined psychopathic persons return to the community. Recent advances in the understanding of the neurobiology of psychopathy hold promise for new research directions and more effective treatments. In this article, we will explore recent advances in genetics, electrophysiology, brain imaging, and psychopharmacology, as well as, in brief, their implications for new directions in research and treatment. PMID- 25698309 TI - Consequences of repeated ethanol exposure during early or late adolescence on conditioned taste aversions in rats. AB - Alcohol use is prevalent during adolescence, yet little is known about possible long-lasting consequences. Recent evidence suggests that adolescents are less sensitive than adults to ethanol's aversive effects, an insensitivity that may be retained into adulthood after repeated adolescent ethanol exposure. This study assessed whether intermittent ethanol exposure during early or late adolescence (early-AIE or late-AIE, respectively) would affect ethanol conditioned taste aversions 2 days (CTA1) and >3 weeks (CTA2) post-exposure using supersaccharin and saline as conditioning stimuli (CS), respectively. Pair-housed male Sprague Dawley rats received 4g/kg i.g. ethanol (25%) or water every 48 h from postnatal day (P) 25-45 (early AIE) or P45-65 (late AIE), or were left non-manipulated (NM). During conditioning, 30 min home cage access to the CS was followed by 0, 1, 1.5, 2 or 2.5g/kg ethanol i.p., with testing 2 days later. Attenuated CTA relative to controls was seen among early and late AIE animals at both CTA1 and CTA2, an effect particularly pronounced at CTA1 after late AIE. Thus, adolescent exposure to ethanol was found to induce an insensitivity to ethanol CTA seen soon after exposure and lasting into adulthood, and evident with ethanol exposures not only early but also later in adolescence. PMID- 25698310 TI - Performance of different culture methods and of a commercial molecular assay for the detection of carbapenemase-producing Enterobacteriaceae in nursing homes and rehabilitation centers. AB - Over the last several years, carbapenemase-producing Enterobacteriaceae (CPE) have been increasingly detected not only among patients in acute care hospitals, but also in long-term care facilities. In this point prevalence survey, residents from three nursing homes and patients in one rehabilitation center were screened for asymptomatic intestinal carriage of CPE by rectal swabs. The first objective was to evaluate the hypothesis of the establishment of a CPE reservoir in a geriatric/chronic care population. Secondly, we evaluated the comparative performances of different culture methods (chromID((r)) CARBA, chromID((r)) OXA 48, MacConkey with temocillin/meropenem, ertapenem enrichment broth) and a commercial molecular assay (Check-Direct CPE). From the 257 included residents, only one had evidence for CPE carriage. From the rectal swabs of this resident, an OXA-48-producing Klebsiella pneumoniae could be isolated and was confirmed by a molecular assay both on the strain and on the rectal swab. The specificity of the different culture methods and Check-Direct CPE was at least 97 %. Neither enrichment broth nor prolonged incubation up to 48 h increased the yield of CPE. This point prevalence survey shows a low CPE prevalence of 0.39 %. Larger scaled studies are needed in order to confirm the role of chronic care settings as secondary CPE reservoirs and to adjust the infection control and prevention recommendations. PMID- 25698311 TI - The clinical features, diagnosis, treatment, and prognosis of neuroinvasive listeriosis: a multinational study. AB - The aim of this study was to determine the independent risk factors, morbidity, and mortality of central nervous system (CNS) infections caused by Listeria monocytogenes. We retrospectively evaluated 100 episodes of neuroinvasive listeriosis in a multinational study in 21 tertiary care hospitals of Turkey, France, and Italy from 1990 to 2014. The mean age of the patients was 57 years (range, 19-92 years), and 64% were males. The all-cause immunosuppression rate was 54 % (54/100). Forty-nine (49 %) patients were referred to a hospital because of the classical triad of symptoms (fever, nuchal rigidity, and altered level of consciousness). Rhombencephalitis was detected radiologically in 9 (9 %) cases. Twenty-seven (64 %) of the patients who had cranial magnetic resonance imaging (MRI) performed had findings of meningeal and parenchymal involvement. The mean delay in the initiation of specific treatment was 6.8 +/- 7 days. Empiric treatment was appropriate in 52 (52 %) patients. The mortality rate was 25 %, while neurologic sequelae occurred in 13 % of the patients. In the multivariate analysis, delay in treatment [odds ratio (OR), 1.07 [95 % confidence interval (CI), 1.01-1.16]] and seizures (OR, 3.41 [95 % CI, 1.05-11.09]) were significantly associated with mortality. Independent risk factors for neurologic sequelae were delay in treatment (OR, 1.07 [95 % CI, 1.006-1.367]) and presence of bacteremia (OR, 45.2 [95 % CI, 2.73-748.1]). Delay in the initiation of treatment of neuroinvasive listeriosis was a poor risk factor for unfavorable outcomes. Bacteremia was one of the independent risk factors for morbidity, while the presence of seizures predicted worse prognosis. Moreover, the addition of aminoglycosides to ampicillin monotherapy did not improve patients' prognosis. PMID- 25698312 TI - Direct susceptibility testing by disk diffusion on clinical samples: a rapid and accurate tool for antibiotic stewardship. AB - We compared the accuracy of direct susceptibility testing (DST) with conventional antimicrobial susceptibility testing (AST), both using disk diffusion, on clinical samples. A total of 123 clinical samples (respiratory tract samples, urine, vaginal and abdominal abscess discharges, bile fluid and a haematoma punctate) were selected on various indications; direct inoculation on Mueller Hinton agar and antibiotic paper disks were applied. In parallel, standard culture, identification and AST on the colonies grown overnight was executed. Both AST and DST were interpreted after identification of the isolates. The results from both AST and DST for 11 antibiotics tested on 97 samples with Gram negative rods showed 93.4 % total agreement, 1.6 % minor discordances, 4.6 % major discordances and 0.4 % very major discordances. Analysing the discordant results, DST predominantly resulted in more resistant isolates than AST. This was mostly due to the presence of resistant mutants or an additional isolate. The remaining discordances were seen for isolates with inhibition zones close to the clinical breakpoint. For the 26 samples yielding staphylococci, a total agreement of 100 % was observed for the nine antibiotics tested. Overall, the highest percentage of discordant results occurred for the beta-lactam antibiotics amoxicillin-clavulanate (13.4 %) and cefuroxime (12.4 %). When used selectively and interpreted carefully, DST on clinical samples is potentially very useful in the management of critically ill patients, as the time to results is shortened by approximately 24 h. However, we recommend to communicate results with reservations and confirm by conventional AST. PMID- 25698313 TI - Identification of Hypomelanosis of Ito in Pediatric Primary Care. PMID- 25698314 TI - ADAMTS proteases in vascular biology. AB - ADAMTS (a disintegrin and metalloprotease with thrombospondin motifs) proteases comprise the most recently discovered branch of the extracellular metalloenzymes. Research during the last 15years, uncovered their association with a variety of physiological and pathological processes including blood coagulation, tissue repair, fertility, arthritis and cancer. Importantly, a frequent feature of ADAMTS enzymes relates to their effects on vascular-related phenomena, including angiogenesis. Their specific roles in vascular biology have been clarified by information on their expression profiles and substrate specificity. Through their catalytic activity, ADAMTS proteases modify rather than degrade extracellular proteins. They predominantly target proteoglycans and glycoproteins abundant in the basement membrane, therefore their broad contributions to the vasculature should not come as a surprise. Furthermore, in addition to their proteolytic functions, non-enzymatic roles for ADAMTS have also been identified expanding our understanding on the multiple activities of these enzymes in vascular-related processes. PMID- 25698315 TI - Molecular electronics under the microscope. PMID- 25698322 TI - Supramolecular catalysis: Terpenes in tight spaces. PMID- 25698323 TI - Mass spectrometry: Bound in flight. PMID- 25698324 TI - Prebiotic chemistry: Replicating towards complexity. PMID- 25698325 TI - Interfaces: Scientists strike wet gold. PMID- 25698326 TI - Graphitic nanopores: Water capture in carbon cuboids. PMID- 25698327 TI - Terpene cyclization catalysed inside a self-assembled cavity. AB - In nature, complex terpene natural products are formed by the so-called tail-to head terpene (THT) cyclization. The cationic reaction cascade is promoted efficiently in complex enzyme pockets, in which cationic intermediates and transition states are stabilized. In solution, the reaction is hard to control and man-made catalysts able to perform selective THT cyclizations are lacking. We herein report the first example of a successful THT cyclization inside a supramolecular structure. The basic mode of operation in cyclase enzymes was mimicked successfully and a catalytic non-stop THT was achieved with geranyl acetate as the substrate. The results presented have implications for the postulated reaction mechanism in cyclase enzymes. Evidence indicates that the direct isomerization of a geranyl cation to the cisoid isomer, which so far was considered unlikely, is feasible. PMID- 25698328 TI - Heat flux across an open pore enables the continuous replication and selection of oligonucleotides towards increasing length. AB - The replication of nucleic acids is central to the origin of life. On the early Earth, suitable non-equilibrium boundary conditions would have been required to surmount the effects of thermodynamic equilibrium such as the dilution and degradation of oligonucleotides. One particularly intractable experimental finding is that short genetic polymers replicate faster and outcompete longer ones, which leads to ever shorter sequences and the loss of genetic information. Here we show that a heat flux across an open pore in submerged rock concentrates replicating oligonucleotides from a constant feeding flow and selects for longer strands. Our experiments utilize the interplay of molecular thermophoresis and laminar convection, the latter driving strand separation and exponential replication. Strands of 75 nucleotides survive whereas strands half as long die out, which inverts the above dilemma of the survival of the shortest. The combined feeding, thermal cycling and positive length selection opens the door for a stable molecular evolution in the long-term microhabitat of heated porous rock. PMID- 25698329 TI - Molecular length dictates the nature of charge carriers in single-molecule junctions of oxidized oligothiophenes. AB - To develop advanced materials for electronic devices, it is of utmost importance to design organic building blocks with tunable functionality and to study their properties at the molecular level. For organic electronic and photovoltaic applications, the ability to vary the nature of charge carriers and so create either electron donors or acceptors is critical. Here we demonstrate that charge carriers in single-molecule junctions can be tuned within a family of molecules that contain electron-deficient thiophene-1,1-dioxide (TDO) building blocks. Oligomers of TDO were designed to increase electron affinity and maintain delocalized frontier orbitals while significantly decreasing the transport gap. Through thermopower measurements we show that the dominant charge carriers change from holes to electrons as the number of TDO units is increased. This results in a unique system in which the charge carrier depends on the backbone length, and provides a new means to tune p- and n-type transport in organic materials. PMID- 25698330 TI - Stereoelectronic switching in single-molecule junctions. AB - A new intersection between reaction chemistry and electronic circuitry is emerging from the ultraminiaturization of electronic devices. Over decades chemists have developed a nuanced understanding of stereoelectronics to establish how the electronic properties of molecules relate to their conformation; the recent advent of single-molecule break-junction techniques provides the means to alter this conformation with a level of control previously unimagined. Here we unite these ideas by demonstrating the first single-molecule switch that operates through a stereoelectronic effect. We demonstrate this behaviour in permethyloligosilanes with methylthiomethyl electrode linkers. The strong sigma conjugation in the oligosilane backbone couples the stereoelectronic properties of the sulfur-methylene sigma bonds that terminate the molecule. Theoretical calculations support the existence of three distinct dihedral conformations that differ drastically in their electronic character. We can shift between these three species by simply lengthening or compressing the molecular junction, and, in doing so, we can switch conductance digitally between two states. PMID- 25698331 TI - Intermediate tunnelling-hopping regime in DNA charge transport. AB - Charge transport in molecular systems, including DNA, is involved in many basic chemical and biological processes, and its understanding is critical if they are to be used in electronic devices. This important phenomenon is often described as either coherent tunnelling over a short distance or incoherent hopping over a long distance. Here, we show evidence of an intermediate regime where coherent and incoherent processes coexist in double-stranded DNA. We measure charge transport in single DNA molecules bridged to two electrodes as a function of DNA sequence and length. In general, the resistance of DNA increases linearly with length, as expected for incoherent hopping. However, for DNA sequences with stacked guanine-cytosine (GC) base pairs, a periodic oscillation is superimposed on the linear length dependence, indicating partial coherent transport. This result is supported by the finding of strong delocalization of the highest occupied molecular orbitals of GC by theoretical simulation and by modelling based on the Buttiker theory of partial coherent charge transport. PMID- 25698332 TI - Synthesis and characterization of hexaarylbenzenes with five or six different substituents enabled by programmed synthesis. AB - Since its discovery in 1825, benzene has served as one of the most used and indispensable building blocks of chemical compounds, ranging from pharmaceuticals and agrochemicals to plastics and those used in organic electronic devices. Benzene has six hydrogen atoms that can each be replaced by different substituents, which means that the structural diversity of benzene derivatives is intrinsically extraordinary. The number of possible substituted benzenes from n different substituents is (2n + 2n(2) + 4n(3) + 3n(4) + n(6))/12. However, owing to a lack of general synthetic methods for making multisubstituted benzenes, this potentially huge structural diversity has not been fully exploited. Here, we describe a programmed synthesis of hexaarylbenzenes using C-H activation, cross coupling and [4+2] cycloaddition reactions. The present method allows for the isolation and structure-property characterization of hexaarylbenzenes with distinctive aryl substituents at all positions for the first time. Moreover, the established protocol can be applied to the synthesis of tetraarylnaphthalenes and pentaarylpyridines. PMID- 25698333 TI - Atropselective syntheses of (-) and (+) rugulotrosin A utilizing point-to-axial chirality transfer. AB - Chiral, dimeric natural products containing complex structures and interesting biological properties have inspired chemists and biologists for decades. A seven step total synthesis of the axially chiral, dimeric tetrahydroxanthone natural product rugulotrosin A is described. The synthesis employs a one-pot Suzuki coupling/dimerization to generate the requisite 2,2'-biaryl linkage. Highly selective point-to-axial chirality transfer was achieved using palladium catalysis with achiral phosphine ligands. Single X-ray crystal diffraction data were obtained to confirm both the atropisomeric configuration and absolute stereochemistry of rugulotrosin A. Computational studies are described to rationalize the atropselectivity observed in the key dimerization step. Comparison of the crude fungal extract with synthetic rugulotrosin A and its atropisomer verified that nature generates a single atropisomer of the natural product. PMID- 25698334 TI - Dual-display of small molecules enables the discovery of ligand pairs and facilitates affinity maturation. AB - In contrast to standard fragment-based drug discovery approaches, dual-display DNA-encoded chemical libraries have the potential to identify fragment pairs that bind simultaneously and benefit from the chelate effect. However, the technology has been limited by the difficulty in unambiguously decoding the ligand pairs from large combinatorial libraries. Here we report a strategy that overcomes this limitation and enables the efficient identification of ligand pairs that bind to a target protein. Small organic molecules were conjugated to the 5' and 3' ends of complementary DNA strands that contain a unique identifying code. DNA hybridization followed by an inter-strand code-transfer created a stable dual display DNA-encoded chemical library of 111,100 members. Using this approach we report the discovery of a low micromolar binder to alpha-1-acid glycoprotein and the affinity maturation of a ligand to carbonic anhydrase IX, an established marker of renal cell carcinoma. The newly discovered subnanomolar carbonic anhydrase IX binder dramatically improved tumour targeting performance in vivo. PMID- 25698335 TI - Coulomb explosion during the early stages of the reaction of alkali metals with water. AB - Alkali metals can react explosively with water and it is textbook knowledge that this vigorous behaviour results from heat release, steam formation and ignition of the hydrogen gas that is produced. Here we suggest that the initial process enabling the alkali metal explosion in water is, however, of a completely different nature. High-speed camera imaging of liquid drops of a sodium/potassium alloy in water reveals submillisecond formation of metal spikes that protrude from the surface of the drop. Molecular dynamics simulations demonstrate that on immersion in water there is an almost immediate release of electrons from the metal surface. The system thus quickly reaches the Rayleigh instability limit, which leads to a 'coulomb explosion' of the alkali metal drop. Consequently, a new metal surface in contact with water is formed, which explains why the reaction does not become self-quenched by its products, but can rather lead to explosive behaviour. PMID- 25698337 TI - First there was hydrogen. PMID- 25698336 TI - A subset of annular lipids is linked to the flippase activity of an ABC transporter. AB - Lipids are critical components of membranes that could affect the properties of membrane proteins, yet the precise compositions of lipids surrounding membrane embedded protein complexes is often difficult to discern. Here we report that, for the heterodimeric ABC transporter TmrAB, the extent of delipidation can be controlled by timed exposure to detergent. We subsequently characterize the cohort of endogenous lipids that are extracted in contact with the membrane protein complex, and show that with prolonged delipidation the number of neutral lipids is reduced in favour of their negatively charged counterparts. We show that lipid A is retained by the transporter and that the extent of its binding decreases during the catalytic cycle, implying that lipid A release is linked to adenosine tri-phosphate hydrolysis. Together, these results enable us to propose that a subset of annular lipids is invariant in composition, with negatively charged lipids binding tightly to TmrAB, and imply a role for this exporter in glycolipid translocation. PMID- 25698338 TI - [Successful drug desensitization after vemurafenib-induced rash]. AB - The BRAF inhibitor vemurafenib was approved in 2011 for the treatment of inoperable or metastatic melanoma. Vemurafenib therapy is associated with several side effects, such as arthralgia, secondary skin tumors or inflammatory rashes. In particular cutaneous toxicities represent a serious threat to patients' adherence. Here, we present the case of a successful drug desensitization in a patient that presented with a vemurafenib-induced rash. Lymphocyte activation tests failed to detect drug-specific T cells, suggesting that the development of the rash was based upon a nonallergic drug hypersensitivity reaction. A program of slow desensitization was initiated and subsequently, vemurafenib was tolerated at the full effective and recommended dosage. PMID- 25698339 TI - Sleep disturbances as an evidence-based suicide risk factor. AB - Increasing research indicates that sleep disturbances may confer increased risk for suicidal behaviors, including suicidal ideation, suicide attempts, and death by suicide. Despite increased investigation, a number of methodological problems present important limitations to the validity and generalizability of findings in this area, which warrant additional focus. To evaluate and delineate sleep disturbances as an evidence-based suicide risk factor, a systematic review of the extant literature was conducted with methodological considerations as a central focus. The following methodologic criteria were required for inclusion: the report (1) evaluated an index of sleep disturbance; (2) examined an outcome measure for suicidal behavior; (3) adjusted for presence of a depression diagnosis or depression severity, as a covariate; and (4) represented an original investigation as opposed to a chart review. Reports meeting inclusion criteria were further classified and reviewed according to: study design and timeframe; sample type and size; sleep disturbance, suicide risk, and depression covariate assessment measure(s); and presence of positive versus negative findings. Based on keyword search, the following search engines were used: PubMed and PsycINFO. Search criteria generated N = 82 articles representing original investigations focused on sleep disturbances and suicide outcomes. Of these, N = 18 met inclusion criteria for review based on systematic analysis. Of the reports identified, N = 18 evaluated insomnia or poor sleep quality symptoms, whereas N = 8 assessed nightmares in association with suicide risk. Despite considerable differences in study designs, samples, and assessment techniques, the comparison of such reports indicates preliminary, converging evidence for sleep disturbances as an empirical risk factor for suicidal behaviors, while highlighting important, future directions for increased investigation. PMID- 25698340 TI - High rate and stable cycling of lithium metal anode. AB - Lithium metal is an ideal battery anode. However, dendrite growth and limited Coulombic efficiency during cycling have prevented its practical application in rechargeable batteries. Herein, we report that the use of highly concentrated electrolytes composed of ether solvents and the lithium bis(fluorosulfonyl)imide salt enables the high-rate cycling of a lithium metal anode at high Coulombic efficiency (up to 99.1%) without dendrite growth. With 4 M lithium bis(fluorosulfonyl)imide in 1,2-dimethoxyethane as the electrolyte, a lithium|lithium cell can be cycled at 10 mA cm(-2) for more than 6,000 cycles, and a copper|lithium cell can be cycled at 4 mA cm(-2) for more than 1,000 cycles with an average Coulombic efficiency of 98.4%. These excellent performances can be attributed to the increased solvent coordination and increased availability of lithium ion concentration in the electrolyte. Further development of this electrolyte may enable practical applications for lithium metal anode in rechargeable batteries. PMID- 25698341 TI - Osteoinductive potential of highly purified porous beta-TCP in mice. AB - Material-induced osteoinduction of calcium phosphate ceramics has been reported in specific animals. We previously reported that recruitment of tartrate resistant acid phosphatase (TRAP)-positive cells might be one of the main factors responsible for the difference in the occurrence of material-induced osteoinduction between dogs and rats. In this study, we evaluated the osteoinductive potential of highly purified porous beta-tricalcium phosphate materials (HPP-beta-TCP) with two different porosities, 75 and 60 % (Olympus Terumo Biomaterials, Tokyo, Japan), implanted into subcutaneous pockets of FVB and C57BL/6 mice. Twelve weeks after implantation, histological examination and gene expression analysis using reverse transcription-polymerase chain reaction were performed. We observed osteoinduction in half of the HPP-beta-TCP materials with 60 % porosity implanted into FVB mice. This group of mice also exhibited the most TRAP-positive cells. Significantly more vessels were found in FVB mice than in C57BL/6 mice, but the greatest number of vessels was counted in implants from materials with 75 % porosity implanted into FVB mice, which did not show osteoinduction. These results indicate that recruitment of TRAP-positive cells is one factor responsible for osteoinduction caused by HPP-beta-TCP materials in both FVB mice and dogs. Vessel formation seems to be necessary but appears to be less influential for osteoinduction than TRAP-positive cell recruitment. PMID- 25698342 TI - Systemic IFNgamma predicts local implant macrophage response. AB - Implantation of biomaterials can cause complications often associated with inflammatory reactions. However, repeated evaluation of the implant site would be burdening for patients. Alternatively, blood examinations with analysis of inflammatory serum markers could potentially be useful to reflect the local cellular response for detection and/or prediction of inflammation-related complications. Therefore, following intramuscular implantation of surface modified Ti implants in rats, this study aimed at examining possible associations between the post-implantation time course of pro-inflammatory (INFgamma, IL-2) and anti-inflammatory (IL-4, IL-10) cytokine serum concentrations and the local peri-implant tissue response after 56 days (pro-inflammatory CD68-positive monocytes/macrophages, anti-inflammatory CD163-positive macrophages, MHC class II positive cells, activated natural killer cells and mast cells). Multivariate correlation analysis revealed a significant interaction between serum IFNgamma and peri-implant tissue CD68-positive monocytes/macrophages (p = 0.001) while no interactions were found for other cytokines and cell types. Additional Pearson correlation analysis of IFNgamma serum concentrations on each experimental day vs. the CD68-positive monocytes/macrophages response on day 56 demonstrated a consistently positive correlation that was strongest during the first three weeks. Thus, high early pro-inflammatory IFNgamma serum concentration was associated with high late number of pro-inflammatory CD68-positive monocyte/macrophages and low early serum IFNgamma with low late CD68-positive monocyte/macrophage numbers. Further studies aimed at examination of patient samples could establish the relevance of this association to predict clinical complications. After implantation of titanium samples, high early IFNgamma serum concentrations were associated with a pronounced late pro-inflammatory CD68 positive monocyte/ macrophage (red circle) response, while no correlation was found for other investigated cytokines and inflammatory cells (green circle). In contrast, low early IFNgamma serum concentrations were correlated with low late monocyte/ macrophage numbers. PMID- 25698343 TI - Targeted survey as a method to rationalize priorities for a strategy to improve eye health in rural Uganda. PMID- 25698344 TI - Chronomedicine: a necessary concept to manage human diseases. PMID- 25698345 TI - Five isolated pentagon rule isomers of higher fullerene C94 captured as chlorides and CF3 derivatives: C94(34)Cl14, C94(61)Cl20, C94(133)Cl22, C94(42)(CF3)16, and C94(43)(CF3)18. AB - High-temperature chlorination and trifluoromethylation of C94 isomeric mixtures followed by single-crystal X-ray diffraction with the use of synchrotron radiation resulted in the structure determination of C94(34)Cl14, C94(61)Cl20, C94(133)Cl22, C94(42)(CF3)16, and C94(43)(CF3)18. Their addition patterns are stabilized by the formation of isolated C?C bonds and aromatic substructures. Four cage isomers of C94 (nos. 34, 42, 43, and 133) have been experimentally confirmed for the first time. PMID- 25698346 TI - Evolutionary adaptation to thermosensation. AB - Organisms continuously evolve to adapt to changing environmental conditions. Chief among these are daily and seasonal temperature fluctuations. Relatively small in terms of real physical values, temperature fluctuations of just a few degrees can profoundly affect organismal functions. In vertebrates, temperature is detected by primary afferents of somatosensory neurons, which express thermo gated ion channels. Most of our knowledge about temperature receptors comes from seminal studies in mice and rats. Recent work uncovered thermosensory mechanisms in other vertebrates, shedding light onto the diversity of thermosensory adaptations. Here, we summarize molecular mechanisms of thermosensation in different species and discuss the need to use the standard laboratory rodents and non-standard species side-by-side in order to understand fundamental principles of somatosensation. PMID- 25698347 TI - Empowering consumers as contributors for health product safety: lessons from the Philippines. AB - Empowering consumers to contribute to adverse drug reaction reporting seems a sensible innovation, particularly when traditional reports emanating from healthcare professionals are neither increasing nor improving. This work, inspired by an EU-FP7-funded project, describes an attempt by the Philippines to introduce a consumer reporting system through education and an online platform for reporting, and the lessons that were captured in the process. While participating consumers did not contribute to the adverse drug reporting process in the traditional sense as originally expected, the reports received by the drug regulatory agency revealed consumers' concerns regarding health product legitimacy, quality and market claims, as well as the lack of available and accessible information. These reports led regulators to take action. Initial insights on consumer behavior are proposed for regulators and industry to consider in greater depth and how this may impact on consumers providing valued information that will promote other aspects of product safety. PMID- 25698348 TI - Hyaluronan stimulates ex vivo B lymphocyte chemotaxis and cytokine production in a murine model of fungal allergic asthma. AB - Allergic asthma is a chronic inflammatory disease of the airways characterized by excessive eosinophilic and lymphocytic inflammation with associated changes in the extracellular matrix (ECM) resulting in airway wall remodeling. Hyaluronan (HA) is a nonsulfated glycosaminoglycan ECM component that functions as a structural cushion in its high molecular mass (HMM) but has been implicated in metastasis and other disease processes when it is degraded to smaller fragments. However, relatively little is known about the role HA in mediating inflammatory responses in allergy and asthma. In the present study, we used a murine Aspergillus fumigatus inhalational model to mimic human disease. After observing in vivo that a robust B cell recruitment followed a massive eosinophilic egress to the lumen of the allergic lung and corresponded with the detection of low molecular mass HA (LMM HA), we examined the effect of HA on B cell chemotaxis and cytokine production in the ex vivo studies. We found that LMM HA functioned through a CD44-mediated mechanism to elicit chemotaxis of B lymphocytes, while high molecular mass HA (HMM HA) had little effect. LMM HA, but not HMM HA, also elicited the production of IL-10 and TGF-beta1 in these cells. Taken together, these findings demonstrate a critical role for ECM components in mediating leukocyte migration and function which are critical to the maintenance of allergic inflammatory responses. PMID- 25698349 TI - Toll-like receptor 2 and 6 interdependency in the erosive stage of Staphylococcus aureus induced septic arthritis mediated by IFN-gamma and IL-6--A possible involvement of IL-17 in the progression of the disease. AB - Staphylococcus aureus induced septic arthritis has emerged as a potent disabling and life threatening disease; hence combating this malady has become an imperative need of medical science. Role of TLR-2 in innate recognition of S. aureus and activation of inflammatory cascade by the interplay of some proinflammatory cytokines, resulting in joint inflammation has been established. Variation in the reports suggesting both functional dependency and independency of TLR-2 on its heterodimeric partner TLR-6 in response to ligands exists, thus this study was postulated to observe the expression pattern of TLR-6 in synovial tissue and lymphoid organs after inducing septic arthritis by S. aureus in Swiss albino mouse model and the instigated cytokine profile could affirm its plausible role in SA. The functional relation of TLR-2 and 6 was verified by simulating an in vitro study design on synovial mononuclear cells, blocking TLR-2 and 6, and it was found that they are required to co-express for generating cytokine, NO and H2O2 on infection. IFN-gamma, IL-6 and IL-17 were identified to play a distinguished role in SA from their secretion pattern in both in vivo and in vitro study. IFN-gamma and IL-6 remained high throughout the infection possibly by the shift of response from Th1 to Th2 and Th17 and contribute in various converging pathways of inflammation. IL-17 increased with the onset of the disease but reduced on the late period. Hence IFN-gamma, IL-6, IL-17 along with TLR-6 can be a potent target for therapeutic approach because of their significant contribution in SA. PMID- 25698350 TI - Asymmetric pelvic and hip rotation in children with bilateral cerebral palsy: uni or bilateral femoral derotation osteotomy? AB - Internal rotation gait is common among children with bilateral cerebral palsy. However, despite bilaterally increased femoral anteversion asymmetric internal rotation gait is often found. Femoral derotation osteotomy (FDO) is commonly performed bilaterally. Variable functional outcomes are reported especially in cases with mild internal hip rotation during gait and abnormal preoperative pelvic rotation. A major question is if a unilateral treatment of the more involved side in asymmetric cases leads to a comparable or even superior outcome. One hundred and nine children with spastic bilateral CP treated with FDO with pre and 1-year postoperative 3D gait analysis were retrospectively collected. The asymmetry was calculated from the preoperative difference between both limbs in hip rotation obtained by 3D gait analysis. Twenty-eight children with asymmetry larger than 20 degrees were selected and classified into two groups, according to whether they obtained a unilateral or bilateral FDO. Preoperative clinical examination and pre- and postoperative hip and pelvic rotation in gait analysis on the more and the less involved side did not differ significantly between both groups. Interestingly, in both groups, hip rotation did not change significantly in less-involved limbs, although intraoperative derotation averaged 25 degrees . After unilateral FDO a significant change in pelvic rotation resulted, whereas this was not found after bilateral FDO. The results of this study suggest that unilateral FDO in children with asymmetric internal rotation gait leads to a comparable functional outcome compared to bilateral treatment. Furthermore, it was shown for the first time that considering the asymmetry has a positive effect on pelvic rotation. PMID- 25698351 TI - Gait speed and cognitive decline over 2 years in the Ibadan study of aging. AB - BACKGROUND: The evidence suggesting that gait speed may represent a sensitive marker for cognitive decline in the elderly requires support from diverse racial groups. OBJECTIVE: We investigated the relationship between gait speed and cognitive decline over 2 years in a community dwelling sample of elderly Africans. METHODS: Data are from the Ibadan study of aging (ISA) conducted among a household multi-stage probability sample of 2149 Yoruba Nigerians aged 65 years or older. Gait speed was measured as the time taken to complete a 3 or 4m distance at normal walking speed. We assessed cognitive functions with a modified version of the 10-word learning list and delay recall test, and examined the relationship between baseline gait speed, as well as gait speed changes, and follow-up cognition using multiple linear regression and longitudinal analyses using random effects. RESULTS: Approximately 71% of 1461 participants who were dementia free and who had their gait speed measured at baseline (2007) were successfully followed up in two waves (2008 and 2009). Along with increasing age, poor health and economic status, a slower baseline gait speed was independently associated with poorer follow-up cognition in both linear regression (1.2 words, 95% CI=0.48-2.0) and longitudinal analyses (0.8 words, 95% CI=0.44-1.2). Also, a greater change in gait speed between 2007 and 2009 was associated with the worst follow-up cognition (0.3 words, 95% CI=0.09-0.51). CONCLUSION: The finding that a substantial change in gait speed was associated with reduced cognitive performance is of potential importance to efforts aimed at early identification of cognitive disorders in this population. PMID- 25698352 TI - Effect of different recovery durations between bouts in 3-a-side games on youth soccer players' physiological responses and technical activities. AB - AIM: The aim of this study was to investigate the effects of the length of recovery durations between bouts in 4x4min 3-a-side small-sided games (SSG) on time-motion analysis, technical actions and physiological responses of players. METHODS: Twelve young soccer players participated in 4 different 3-a-side games in which the recovery durations between bouts were different (R1: 1 min, R2: 2 min, R3: 3 min, and R4: 4 min). Heart rate (HR), total distance covered in different speed zones, and technical performance were monitored during all SSGs, whereas the rating of perceived exertion (RPE, CR-10) and venous blood lactate were determined at the end of the last bout of each SSG. RESULTS: Results showed that SSGs-R1 induced higher %HRreserve and lower successful passes (vs. R3 and R4 conditions, P<0.05), lower total passes (vs. R4 conditions, P<0.05), and greater distance covered in walking zone (0-6.9 km.h-1) (vs. other 3 conditions, P<0.05). In addition, during the SSG-R3 players covered greater distances in high intensity running zone (>18 km.h-1), performed more tackles (vs. R1 condition, P<0.05) and had more ball contacts (vs. R1 and R2 conditions, P<0.05). CONCLUSION: According to these results, it is thought that R1 and R2 are suitable for inducing higher physiological responses, while R3 and R4 are more appropriate for training aim to improve technical skills in 4x4min 3-a-side SSGs among young soccer players. These findings provide evidence for coaches to justify the selection of recovery duration between bouts in 3-a-side SSGs among young soccer players. PMID- 25698353 TI - Evaluation of Kinetic Entropy of Breast Masses Initially Found on MRI using Whole lesion Curve Distribution Data: Comparison with the Standard Kinetic Analysis. AB - OBJECTIVES: To quantify kinetic heterogeneity of breast masses that were initially detected with dynamic contrast-enhanced MRI, using whole-lesion kinetic distribution data obtained from computer-aided evaluation (CAE), and to compare that with standard kinetic curve analysis. METHODS: Clinical MR images from 2006 to 2011 with breast masses initially detected with MRI were evaluated with CAE. The relative frequencies of six kinetic patterns (medium-persistent, medium plateau, medium-washout, rapid-persistent, rapid-plateau, rapid-washout) within the entire lesion were used to calculate kinetic entropy (KE), a quantitative measure of enhancement pattern heterogeneity. Initial uptake (IU) and signal enhancement ratio (SER) were obtained from the most-suspicious kinetic curve. Mann-Whitney U test and ROC analysis were conducted for differentiation of malignant and benign masses. RESULTS: Forty benign and 37 malignant masses comprised the case set. IU and SER were not significantly different between malignant and benign masses, whereas KE was significantly greater for malignant than benign masses (p = 0.748, p = 0.083, and p < 0.0001, respectively). Areas under ROC curve for IU, SER, and KE were 0.479, 0.615, and 0.662, respectively. CONCLUSION: Quantification of kinetic heterogeneity of whole-lesion time-curve data with KE has the potential to improve differentiation of malignant from benign breast masses on breast MRI. KEY POINTS: * Kinetic heterogeneity can be quantified by computer-aided evaluation of breast MRI * Kinetic entropy was greater in malignant masses than benign masses * Kinetic entropy has the potential to improve differentiation of breast masses. PMID- 25698354 TI - On the evolutionary origin of the adaptive immune system--the adipocyte hypothesis. AB - Jawless vertebrates utilize a form of adaptive immunity that is functionally based on molecular effectors that are completely different from those of vertebrates. This observation raises an intriguing question: why did vertebrates, representing only 5% of all animals, twice evolve a system as complex as adaptive immunity? Theories aimed at identifying a selective pressure that would 'drive' the development of an adaptive immune system (AIS) fail to explain why invertebrates would not similarly develop an AIS. We argue that an AIS can only be implemented in a certain physiological context, i.e., that an AIS represents an unevolvable trait for invertebrates. The immune system is functionally integrated with other systems; therefore a preexisting physiological innovation unique to vertebrates may have acted as the prerequisite infrastructure that allowed the development of an AIS. We propose that future efforts should be directed toward identifying the evolutionary release that allowed the development of an adaptive immune system in vertebrates. In particular, the advent of specialized adipocytes might have expanded the metabolic scope of vertebrates, allowing the opportunistic incorporation of an AIS. However, physiological innovations, unique to (or more developed in) vertebrates, support the implementation of an AIS. Thus, understanding the interaction between systems (e.g. neural-immune-adipose connection) may illuminate our understanding regarding the perplexing immunological dimorphism within the animal kingdom. PMID- 25698355 TI - Phylogeny and polyploidy: resolving the classification of cyprinine fishes (Teleostei: Cypriniformes). AB - Cyprininae is the largest subfamily (>1300 species) of the family Cyprinidae and contains more polyploid species (~400) than any other group of fishes. We examined the phylogenetic relationships of the Cyprininae based on extensive taxon, geographical, and genomic sampling of the taxa, using both mitochondrial and nuclear genes to address the phylogenetic challenges posed by polyploidy. Four datasets were analyzed in this study: two mitochondrial gene datasets (465 and 791 taxa, 5604bp), a mitogenome dataset (85 taxa, 14,771bp), and a cloned nuclear RAG1 dataset (97 taxa, 1497bp). Based on resulting trees, the subfamily Cyprininae was subdivided into 11 tribes: Probarbini (new; Probarbus+Catlocarpio), Labeonini Bleeker, 1859 (Labeo & allies), Torini Karaman, 1971 (Tor, Labeobarbus & allies), Smiliogastrini Bleeker, 1863 (Puntius, Enteromius & allies), Poropuntiini (Poropuntius & allies), Cyprinini Rafinesque, 1815 (Cyprinus & allies), Acrossocheilini (new; Acrossocheilus & allies), Spinibarbini (new; Spinibarbus), Schizothoracini McClelland, 1842 (Schizothorax & allies), Schizopygopsini Mirza, 1991 (Schizopygopsis & allies), and Barbini Bleeker, 1859 (Barbus & allies). Phylogenetic relationships within each tribe were discussed. Two or three distinct RAG1 lineages were identified for each of the following tribes Torini, Cyprinini, Spinibarbini, and Barbini, indicating their hybrid origin. The hexaploid African Labeobarbus & allies and Western Asian Capoeta are likely derived from two independent hybridization events between their respective maternal tetraploid ancestors and Cyprinion. PMID- 25698356 TI - A mitochondrial genome phylogeny of owlet moths (Lepidoptera: Noctuoidea), and examination of the utility of mitochondrial genomes for lepidopteran phylogenetics. AB - A phylogenetic hypothesis for the lepidopteran superfamily Noctuoidea was inferred based on the complete mitochondrial (mt) genomes of 12 species (six newly sequenced). The monophyly of each noctuoid family in the latest classification was well supported. Novel and robust relationships were recovered at the family level, in contrast to previous analyses using nuclear genes. Erebidae was recovered as sister to (Nolidae+(Euteliidae+Noctuidae)), while Notodontidae was sister to all these taxa (the putatively basalmost lineage Oenosandridae was not included). In order to improve phylogenetic resolution using mt genomes, various analytical approaches were tested: Bayesian inference (BI) vs. maximum likelihood (ML), excluding vs. including RNA genes (rRNA or tRNA), and Gblocks treatment. The evolutionary signal within mt genomes had low sensitivity to analytical changes. Inference methods had the most significant influence. Inclusion of tRNAs positively increased the congruence of topologies, while inclusion of rRNAs resulted in a range of phylogenetic relationships varying depending on other analytical factors. The two Gblocks parameter settings had opposite effects on nodal support between the two inference methods. The relaxed parameter (GBRA) resulted in higher support values in BI analyses, while the strict parameter (GBDH) resulted in higher support values in ML analyses. PMID- 25698357 TI - The good and bad of antioxidant foods: An immunological perspective. AB - Maintenance of redox homeostasis plays a central role in health and disease prevention, and antioxidant foods are thought to exert protective effects by counteracting oxidative stress. The term "dietary antioxidant" implies a classical reducing or radical-scavenging capacity, but more data on the in vivo bioactivity of such compounds are needed. Indeed, several dietary antioxidants activate signaling cascades that lead to effects that extend beyond radical scavenging, such as the induction of endogenous cytoprotective mechanisms and detoxification. Currently, the overall uptake of antioxidants with diet exceeds actual needs, as food additives that include vitamins, colorants, flavoring agents, and preservatives are often also relatively strong antioxidants. Chronic antioxidative stress favors adverse effects, such as the suppression of T helper (Th) type 1 immune responses and consequent activation of Th2 reactions that support the development of asthma, allergies, and obesity. In this context, we discuss the immunoregulatory pathway of tryptophan breakdown by enzyme indoleamine 2,3-dioxygenase (IDO), which represents a central regulatory hub for immune, metabolic, and neuroendocrine processes. Activation of IDO-mediated tryptophan metabolism is strongly redox-sensitive and is therefore susceptible to modulation by dietary components, phytochemicals, preservatives, and drugs. PMID- 25698358 TI - Cognitional Impairment: Is There a Role for Cognitive Assessment in the Treatment of Individuals Civilly Committed Pursuant to the Sexually Violent Predator Act? AB - Sexually Violent Predator statutes allow the involuntary treatment of individuals who are found to pose a threat to public safety. Most sex offender treatment programs rely on cognitive interventions to reduce the risk of recidivism. The purpose of this study was to examine (a) whether individuals with paraphilia diagnoses have cognitive deficits compared with the general population; (b) whether individuals diagnosed with pedophilia differed on cognitive performance when compared with individuals diagnosed with paraphilia not otherwise specified (NOS), nonconsent; and (c) whether individuals with paraphilia plus antisocial personality disorder (ASPD) differed in cognitive performance when compared with individuals with a paraphilia diagnosis only. The sample consisted of 170 males (M age = 50.21; SD = 10.22) diagnosed with pedophilia or paraphilia NOS, nonconsent, who were detained or civilly committed to a forensic psychiatric hospital. Assessments included Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Wechsler Abbreviated Scale of Intelligence (WASI), and Wide Range Achievement Test 4 (WRAT4). Individuals diagnosed with pedophilia and paraphilia NOS, nonconsent, obtained lower scores than matched controls based on the RBANS Immediate Memory, Visuospatial/Constructional, Delayed Memory indices and Total Score. In comparison with individuals with paraphilia NOS, nonconsent, those with pedophilia diagnosis had lower scores on the RBANS Delayed Memory. Individuals diagnosed with a paraphilia disorder combined with ASPD demonstrated trends toward lower IQ scores than those with a paraphilia diagnosis only. Treatment programs can improve their chance of success by assessment of cognitive processes, and offer therapy in a style that is consistent with the cognitive abilities of their clients. PMID- 25698359 TI - Treatment Progress and Behavior Following 2 Years of Inpatient Sex Offender Treatment. AB - Emerging research highlights the role of self-regulation in the treatment of sexual offenders. Safe Offender Strategies (SOS) is a manualized sex offender treatment program that emphasizes the role of self-regulation and self-regulatory skills development in sex offender treatment, particularly for offenders with serious mental illness and intellectual/developmental disabilities. The current study involves 156 adult male sexual offenders in an inpatient psychiatric setting who received SOS treatment for a period ranging from 6 months to 1 year. Participants' baseline and treatment data were obtained from archival medical records describing 1 year pre-treatment and up to 2 years of treatment participation. Dependent variables included monthly count rates of verbal and physical aggression and contact and noncontact sexual offending, as well as sexual deviancy attitudes, self-regulatory ability, and cooperation with treatment and supervision, as measured by the Sex Offender Treatment Intervention and Progress Scale (SOTIPS). Data were examined via paired-samples t tests, regression, and multilevel modeling, examining the impact of overall percentage of SOS groups attended over time, comparing participants' baseline measures to data from 2 years of treatment. The impact of predicted risk was also evaluated. Significant treatment dose effects were identified for improvements in aggression, sexual offending, and indicators of treatment compliance and change. These findings suggest that the skills-based, self-regulation approach utilized in SOS may be effective in improving clients' aggressive and sexual behaviors, attitudes toward their offenses and treatment, and self-regulatory ability over time. Implications for further research and treatment generalizability are discussed. PMID- 25698360 TI - Kinetics of glucosylated and non-glucosylated aryltetralin lignans in Linum hairy root cultures. AB - Due to their pronounced cytotoxic activity, a number of aryltetralin lignans (ATLs), such as podophyllotoxin (PTOX), are used as antitumor compounds. The production of such molecules from entire plants or plant cell-tissue-organ cultures is thus of interest to the pharmaceutical industry. Hairy root cultures constitute a good tool not only for phytochemical production but also for investigating plant secondary metabolism. This work reports on the growth and ATL biosynthesis in two hairy root cultures of Linum album Kotschy ex Boiss. and Linum flavum. The kinetics of accumulation of the intermediates of MPTOX biosynthesis and of their glucosylated forms are described over a 21-day period of growth. An accumulation of non-glucosylated forms of the ATLs during the exponential phase of the cultures is followed by an accumulation of the glucosylated forms during the stationary phase. Our results show a strong coordination of the biosynthetic paths derived from deoxypodophyllotoxin via deoxypodophyllotoxin 6-hydroxylase and deoxypodophyllotoxin 7-hydroxylase, and a coordinated glucosylation of podophyllotoxin, methoxypodophyllotoxin, and 5' demethoxymethoxypodophyllotoxin. Furthermore, our results suggest an important role of beta-peltatin-6-glucoside formation in the control of ATL accumulation in Linum hairy root cultures. PMID- 25698361 TI - Evaluating the impact of sprouting conditions on the glucosinolate content of Brassica oleracea sprouts. AB - The glucosinolates content of brassica plants is a distinctive characteristic, representing a healthy advantage as many of these compounds are associated to antioxidant and anti-carcinogenic properties. Brassica sprouts are still an underutilized source of these bioactive compounds. In this work, four varieties of brassica sprouts (red cabbage, broccoli, Galega kale and Penca cabbage), including two local varieties from the North of Portugal, were grown to evaluate the glucosinolate profile and myrosinase activity during the sprouting. Also the influence of light/darkness exposure during sprouting on the glucosinolate content was assessed. Glucosinolate content and myrosinase activity of the sprouts was evaluated by HPLC methods. All sprouts revealed a higher content of aliphatic glucosinolates than of indole glucosinolates, contrary to the profile described for most of brassica mature plants. Galega kale sprouts had the highest glucosinolate content, mainly sinigrin and glucoiberin, which are recognized for their beneficial health effects. Penca cabbage sprouts were particularly richer in glucoraphanin, who was also one of the major compounds in broccoli sprouts. Red cabbage showed a higher content of progoitrin. Regarding myrosinase activity, Galega kale sprouts showed the highest values, revealing that the use of light/dark cycles and a sprouting phase of 7-9 days could be beneficial to preserve the glucosinolate content of this variety. PMID- 25698362 TI - Comparison of LCST-transitions of homopolymer mixture, diblock and statistical copolymers of NIPAM and VCL in water. AB - The LCST-transitions of linear, well-defined polymers of N-isopropylacrylamide (NIPAM) and N-vinylcaprolactam (VCL), including a homopolymer mixture, diblock and statistical copolymers, in water are explored and compared by applying turbidity and FTIR measurements in combination with two-dimensional correlation spectroscopy (2Dcos). Only one transition is observed in all polymer systems, suggesting a dependent aggregation of poly(N-isopropylacrylamide) (PNIPAM) and poly(N-vinylcaprolactam) (PVCL) parts in the phase transition processes. With the help of 2Dcos analysis, it is discovered that the hydrophobic interaction among C H groups is the driving force for simultaneous collapse of the two distinct thermo-responsive segments. Additionally, the delicate differences within the LCST-transitions thereof have been emphasized, where the phase separation temperatures of the homopolymer mixture and the diblock copolymer are close while that of the statistical copolymer is relatively higher. Moreover, both diblock and statistical copolymers exhibit rather sharp phase transitions while the homopolymer mixture demonstrates a moderately continuous one. PMID- 25698363 TI - Pharmacists' involvement in and attitudes toward pharmacy practice research: A systematic review of the literature. AB - BACKGROUND: The role of pharmacists in health care has evolved toward patient centered care. Pharmacy practice-based research is essential to the advancement of practice; however, literature addressing attitudes and involvement of pharmacists in practice research indicates reluctance among them. An account of studies undertaken thus far is warranted. OBJECTIVE: This systematic review aims to summarize and evaluate the views and attitudes of pharmacists regarding their involvement in pharmacy practice research as well as the barriers and enablers to such research. METHODS: A systematic review of original studies published mainly in MEDLINE, PubMed, EBSCO, ScienceDirect, ProQuest, and Google Scholar was conducted to identify published studies that report pharmacists' attitudes and involvement in research as well as perceived facilitators and barriers. Data were independently extracted by two reviewers using a standardized data abstraction tool. RESULTS: Fifteen studies utilizing questionnaire-based surveys, focus groups or interviews were identified and included in the review. The majority of studies (10 of 15) involved community pharmacists, while only 6 involved hospital pharmacists. Studies were mostly conducted in the UK (5 of 15), followed by Australia and Canada (3 of 15 each). Early studies focused on pharmacists' attitudes on practice-based research, but most recently there was attention on practice-based research networks (PBRNs). Pharmacists' awareness, interest and willingness to participate in practice research, their actual involvement in research projects, and positive attitude toward research have increased over time. Pharmacists generally believed that practice-based research was needed for professional development of pharmacy and agreed with the importance of research to support evidence-based practice and to improve the quality of patient care and outcomes. The most commonly reported barriers to participation in research across the reviewed studies were: lack of time and workload; insufficient or lack of funds; and lack of research knowledge, training, mentorship and support. CONCLUSIONS: Pharmacists recognize the value of research in advancing pharmacy practice and indicate their willingness to be involved in independent research and in PBRNs. Lack of time, training and support were identified as the greatest limitations to participation in practice research. These findings have important implications on promoting research capacity building through the development of PBRNs involving academic and pharmacy practitioners as well as informal research training programs. PMID- 25698364 TI - A review of countries' pharmacist-patient communication legal requirements on prescription medications and alignment with practice: Comparison of Nordic countries. AB - BACKGROUND: Pharmacist-patient communication around prescription medications can optimize treatment outcomes. Society's expectations of pharmacist-patient communication around medications can be expressed in legislation, economic incentives, and authority control. In this study, the Nordic countries of Denmark, Finland, Iceland, Norway and Sweden provide the legislative examples and can be used as a platform to discuss how society's expectations, professional visions, and practice are aligning. OBJECTIVE: The overall aim of this study was to describe society's expectations of pharmacist-patient communication around medications as expressed by the state in Nordic legislation, economic incentives and authority control. Additionally, this study describes how the states govern Nordic pharmacists in different pharmacy systems. METHOD: A legal review was performed using online legislative databases. Regulating authorities were contacted to gather supplementary information. Thereafter, a qualitative document analysis was conducted. RESULTS: The Nordic countries regulate staff-patient communication by using broad laws. The legislation's main focus during dispensing is information on the use of medications, but also generic substitution and pricing. Pharmacies should have internal routines for this in place. Pharmacists' obligation to keep a journal on advice given during dispensing is ambiguously regulated. The economic incentives for communication on prescription medication during dispensing are included in the general pharmacy mark-up. Today's authority control focuses on the pharmacy management and appears to primarily evaluate structure indicators of communication, for example, if there is a routine method of counseling available. CONCLUSION: Various countries throughout the world differ in their requirements for pharmacy staff to communicate on the use of medicines during dispensing. The Nordic countries all require such communication, which aligns with professional visions. Regardless of the pharmacy system, the states let the employer and pharmacy professions carry out it in practice with apparently little state involvement, thus showing trust in the profession and employers. However, since Nordic communication studies show deviation from the legislation, there are reasons to reevaluate and discuss the legislation, the economic incentives and the control system. PMID- 25698365 TI - Bridging veins and autopsy findings in abusive head trauma. AB - Bridging veins are crucial for the venous drainage of the brain. They run as short and straight bridges between the brain surface and the superior sagittal sinus in the subdural compartment. Subdural bleeding is a marker for a traumatic mechanism (i.e., acceleration/deceleration, rotational and shearing forces due to violent shaking) causing rupture of the bridging veins. Demonstration of bridging vein rupture allows the unequivocal diagnosis of a traumatic mechanism and should therefore be a routine part of the postmortem in cases of subdural hemorrhage. PMID- 25698366 TI - Metaphyseal osteomyelitis in children: how often does MRI-documented joint effusion or epiphyseal extension of edema indicate coexisting septic arthritis? AB - BACKGROUND: Joint effusions identified by MRI may accompany osteomyelitis and determining whether the joint effusion is septic or reactive has important implications on patient care. OBJECTIVE: Determine the incidence of epiphyseal marrow edema, joint effusions, perisynovial edema and epiphyseal non-enhancement in the setting of pediatric metaphyseal osteomyelitis and whether this may be used to predict coexisting septic arthritis. MATERIALS AND METHODS: Following IRB approval, we retrospectively evaluated children who underwent MRI and orthopedic surgical consultation for suspected musculoskeletal infection between January 2011 and September 2013. Criteria for inclusion in the study were microbiologically/pathologically proven infection, MRI prior to surgical intervention, long bone involvement and age 0-18 years. MRI exams were independently reviewed by two faculty pediatric radiologists to confirm the presence of appendicular metaphyseal osteomyelitis, to evaluate extent of edema, to determine subjective presence of a joint effusion and to assess perisynovial edema and epiphyseal non-enhancement. Any discrepant readings were reviewed in consensus. Charts and operative notes were reviewed to confirm the diagnosis of osteomyelitis and septic arthritis. RESULTS: One hundred and three joints with metaphyseal osteomyelitis were identified (mean age: 7.1 years; M:F 1.3:1), of whom 53% (55/103) had joint effusions, and of those, 75% (41/55) had surgically confirmed septic arthritis. The incidence of coexisting septic arthritis was 40% in the setting of epiphyseal edema, 74% in epiphyseal edema and effusion, 75% with perisynovial edema, 76% with epiphyseal non-enhancement and 77% when all four variables were present. Of these, the only statistically significant variable, however, was the presence of a joint effusion with a P-value of <0.0001 via Fisher exact test. Statistical significance for coexisting septic arthritis was also encountered when cases were subdivided into intra-articular vs. extra articular metaphyses (P-value = 0.0499). No statistically significant difference was found between patients younger than 24 months and those older than 24 months. CONCLUSION: Patients with joint effusions identified by MRI, in the setting of metaphyseal osteomyelitis, should be presumed to have septic arthritis until proven otherwise. Epiphyseal extension of edema, perisynovial edema and epiphyseal non-enhancement in the setting of metaphyseal osteomyelitis are not helpful predictors in differentiating reactive and pyogenic joint effusions. Osteomyelitis at a site with an intra-articular metaphyses, however, is more likely to have concurrent septic arthritis. PMID- 25698367 TI - Reference values of MRI measurements of the common bile duct and pancreatic duct in children. AB - BACKGROUND: Magnetic resonance imaging/cholangiopancreatography (MRI/MRCP) is now an essential imaging modality for the evaluation of biliary and pancreatic pathology in children, but there are no data depicting the normal diameters of the common bile duct (CBD) and pancreatic duct. Recognition of abnormal duct size is important and the increasing use of MRCP necessitates normal MRI measurements. OBJECTIVE: To present normal MRI measurements for the common bile duct and pancreatic duct in children. MATERIALS AND METHODS: In this retrospective study we searched all children ages birth to 10 years in our MR urography (MRU) database from 2006 until 2013. We excluded children with a history of hepatobiliary or pancreatic surgery. We stratified 204 children into five age groups and retrospectively measured the CBD and the pancreatic duct on 2-D axial and 3-D coronal T2-weighted sequences. We performed statistical analysis, using logistic and linear regressions to detect the age association of the visibility and size of the duct measurements. We used non-parametric tests to detect gender and imaging plane differences. RESULTS: Our study included 204 children, 106 (52%) boys and 98 (48%) girls, with a median age of 33 months (range 0-119 months). The children were distributed into five age groups. The common bile duct was visible in all children in all age groups. The pancreatic duct was significantly less visible in the youngest children, group 1 (54/67, 80.5%; P = 0.003) than in the oldest children, group 5 (22/22, 100%). In group 2 the pancreatic duct was seen in 19/21 (90.4%), in group 3 52/55 (94.5%), and in group 4 39/39 (100%). All duct measurements increased with age (P < 0.001; r-value > 0.423), and the incremental differences between ages were significant. The measurement variations between the axial and coronal planes were statistically significant (P < 0.001); however these differences were fractions of millimeters. For example, in group 1 the mean coronal measurement of the CBD was 2.1 mm and the axial measurement was 2.0 mm; the mean coronal measurement of the pancreatic duct was 0.9 mm and the axial measurement was 0.8 mm. CONCLUSION: Our study provides normative measurements for the common bile duct and pancreatic duct for children up to age 10 years. The upper limits of the CBD and pancreatic duct increase with age, and the values range 1.1-4.0 mm for the CBD and 0.6-1.9 mm for the pancreatic duct. PMID- 25698368 TI - Successful multi-target therapy using corticosteroid, tacrolimus, cyclophosphamide, and rituximab for rapidly progressive interstitial lung disease in a patient with clinically amyopathic dermatomyositis. PMID- 25698369 TI - Juvenile polymyositis associated with anti-OJ (anti-isoleucyl-tRNA synthetase) autoantibody in a 13-year-old girl. AB - A 13-year-old girl was admitted for persistent thigh pain and remittent fever and was diagnosed as having juvenile polymyositis. Although the initial treatment with 2 cycles of methylprednisolone pulse therapy failed to achieve full remission, the second-line treatment with intravenous cyclophosphamide pulse therapy was effective. Anti-OJ antibody, which is one of anti-aminoacyl-tRNA synthetase (ARS) antibodies and is rare in adult polymyositis, was detected. Assessment of anti-ARS autoantibodies may facilitate diagnosis and management of juvenile polymyositis. PMID- 25698370 TI - Long-term safety and efficacy of treatment with subcutaneous abatacept in Japanese patients with rheumatoid arthritis who are methotrexate inadequate responders. AB - OBJECTIVE: To assess the long-term safety, immunogenicity, and efficacy of subcutaneous (SC) abatacept in combination with methotrexate (MTX) in Japanese patients with rheumatoid arthritis who were MTX inadequate responders, in a long term extension (LTE) to a double-dummy, double-blind study (NCT01001832). METHODS: Patients, who had previously received SC or intravenous (IV) abatacept with MTX (6-8 mg/week) for 24 weeks, received SC abatacept (125 mg/week) with MTX for an additional 52 weeks. Safety, immunogenicity, and efficacy were assessed. RESULTS: The LTE included 112 patients. SC abatacept was generally well tolerated in the LTE, with no new safety signals. American College of Rheumatology 20, 50, and 70 response rates, disease activity score 28 (C-reactive protein) remission rates (< 2.6), and Health Assessment Questionnaire-Disability Index response rates (>= 0.3 improvement from baseline) achieved at the end of the double-blind period were maintained over the LTE and were comparable in patients who received SC or IV abatacept in the double-blind period. Seropositivity for immunogenicity occurred in 4 (3.6%) patients. Self-injection of SC abatacept was well controlled and not associated with additional safety events. CONCLUSIONS: SC abatacept had acceptable safety and was well tolerated and effective over the LTE (76 weeks in total), with low rates of immunogenicity in Japanese patients. PMID- 25698371 TI - MRI findings of the shoulder and hip joint in patients with polymyalgia rheumatica. AB - OBJECTIVES: The purpose of this study is to evaluate magnetic resonance imaging (MRI) findings of the shoulder and hip joint in patients with polymyalgia rheumatica (PMR). METHODS: MR images of a total of 25 PMR patients (23 shoulders and 6 hips), 43 rheumatoid arthritis (RA) patients (22 shoulders and 22 hips), and 50 control patients (25 shoulders and 25 hips) were examined. The following MRI findings were evaluated: In the shoulder, thickness and abnormalities of the supraspinatus tendon, effusion around the glenohumeral joint, subacromial subdeltoid bursa, and the biceps tendon; In the hip, effusion around the acetabulofemoral joint, iliopsoas bursa, and trochanteric bursa. Periarticular soft-tissue edema and bone findings were also analyzed. RESULTS: The supraspinatus tendon was significantly thicker in PMR patients than in RA patients and control patients (p < 0.05). Severe rotator cuff tendinopathy was frequently observed in PMR patients (p = 0.002). The scores for the amount of effusions (joint, bursa, and tendon sheath in the shoulder and bursa in the hip) were much higher in PMR patients (p < 0.05). Periarticular soft tissue edema was detected more frequently in PMR patients than in RA patients and control patients (p < 0.05). CONCLUSIONS: Thick supraspinatus tendon, severe rotator cuff tendinopathy, effusion around the joints, and periarticular soft tissue edema can be good indicators for the diagnosis of PMR. PMID- 25698372 TI - A comparative study on the results of the modified Ludloff osteotomy for hallux valgus deformities with minimal erosion of the metatarsophalangeal joints in rheumatoid patients versus non-rheumatoid patients. AB - OBJECTIVES: We aimed to compare the outcomes of joint-preserving surgery for hallux valgus deformities with minimal erosion of the metatarsophalangeal joint in rheumatoid patients with non-rheumatoid controls, and to determine the prognostic factors of recurrence in rheumatoid patients. METHODS: A total of 18 rheumatoid patients (20 feet, Group I) and 35 non-rheumatoid patients (39 feet, Group II) were included. The mean follow-up was 29.6 months. Radiographic and clinical outcomes were compared. To identify the prognostic factors for recurrences in rheumatoid patients, subgroup analyses were done in Group I. RESULTS: Most of the outcomes showed favorable results in both groups. However, Group II had better results in hallux valgus angle (HVA) (15.9 degrees vs. 7.9 degrees , p < 0.001), and in sesamoid position (p = 0.040) at final follow-up. Group I showed higher recurrence rate (50% vs. 0%). The final American Orthopaedic Foot and Ankle Society score was better in Group II (82.1 vs. 90.7, p = 0.014). The large preoperative HVA, non-performance of Akin osteotomy, and insufficient reduction of sesamoid position were related to recurrence in rheumatoid patients. CONCLUSIONS: Joint-preserving surgery for hallux valgus deformities in rheumatoid forefoot deformity showed favorable results in mid-term follow-up; however, it should be warned of possible recurrent deformities. PMID- 25698373 TI - A case of anti-MDA5-positive rapidly progressive interstitial lung disease in a patient with clinically amyopathic dermatomyositis ameliorated by rituximab, in addition to standard immunosuppressive treatment. AB - Rapidly progressive interstitial lung disease (RP-ILD) in patients with clinically amyopathic dermatomyositis (CADM) associated with antibodies to melanoma differentiation-associated gene5 (MDA5) results in a high mortality rate. We experienced a case of anti-MDA5-positive RP-ILD of CADM which showed a response to rituximab, although there was no significant effect due to standard immunosuppressive treatment. This case suggests that rituximab has the potential to offer an effective agent for the treatment of anti-MDA5-positive RP-ILD of CADM. PMID- 25698374 TI - Overexpression of the adiponectin gene mimics the metabolic and stress resistance effects of calorie restriction, but not the anti-tumor effect. AB - Adiponectin (Adipoq), a peptide hormone secreted from the white adipose tissue, may play a role in the anti-aging and/or anti-tumor effects of calorie restriction (CR). We analyzed metabolic traits in Adipoq gene-overexpressing mice fed ad libitum with a regular diet (RD) or a high-fat diet (HFD), or fed 30% CR of RD initiated at 12 weeks of age. Adipoq-RD and -HFD mice at 6 months of age showed reduced blood glucose and insulin concentrations, and thus increased insulin sensitivity, compared with WT mice fed a RD or a HFD. In the epididymal white adipose tissue in Adipoq mice, senescence-like changes such as upregulation of p53 protein and of biomarkers of inflammation, Cd68 and Ccl2 mRNA, were ameliorated compared with WT-RD and WT-HFD mouse tissues. Resistance to stress induced by lipopolysaccharide was also strengthened in Adipoq mice compared with WT mice. These metabolic changes and stress resistance were also noted in the WT CR mice, suggesting that Adipoq plays a part in the effect of CR. In contrast, in an allograft tumor growth model, tumor growth was not inhibited in Adipoq mice. The present findings suggest that Adipoq plays a part in the anti-aging, but not in the anti-tumor, effects of CR. PMID- 25698375 TI - Cascade catalysis in membranes with enzyme immobilization for multi-enzymatic conversion of CO2 to methanol. AB - Facile co-immobilization of enzymes is highly desirable for bioconversion methods involving multi-enzymatic cascade reactions. Here we show for the first time that three enzymes can be immobilized in flat-sheet polymeric membranes simultaneously or separately by simple pressure-driven filtration (i.e. by directing membrane fouling formation), without any addition of organic solvent. Such co immobilization and sequential immobilization systems were examined for the production of methanol from CO2 with formate dehydrogenase (FDH), formaldehyde dehydrogenase (FaldDH) and alcohol dehydrogenase (ADH). Enzyme activity was fully retained by this non-covalent immobilization strategy. The two immobilization systems had similar catalytic efficiencies because the second reaction (formic acid->formaldehyde) catalyzed by FaldDH was found to be the cascade bottleneck (a threshold substrate concentration was required). Moreover, the trade-off between the mitigation of product inhibition and low substrate concentration for the adjacent enzymes probably made the co-immobilization meaningless. Thus, sequential immobilization could be used for multi-enzymatic cascade reactions, as it allowed the operational conditions for each single step to be optimized, not only during the enzyme immobilization but also during the reaction process, and the pressure-driven mass transfer (flow-through mode) could overcome the diffusion resistance between enzymes. This study not only offers a green and facile immobilization method for multi-enzymatic cascade systems, but also reveals the reaction bottleneck and provides possible solutions for the bioconversion of CO2 to methanol. PMID- 25698376 TI - Erratum to: quantitative assessment of subcortical atrophy and iron content in progressive supranuclear palsy and parkinsonian variant of multiple system atrophy. PMID- 25698377 TI - Fundamental movement skills proficiency in children with developmental coordination disorder: does physical self-concept matter? AB - PURPOSE: The purpose of this study was to (1) examine differences in fundamental movement skills (FMS) proficiency, physical self-concept, and physical activity in children with and without developmental coordination disorder (DCD), and (2) determine the association of FMS proficiency with physical self-concept while considering key confounding factors. METHOD: Participants included 43 children with DCD and 87 age-matched typically developing (TD) children. FMS proficiency was assessed using the Test of Gross Motor Development - second edition. Physical self-concept and physical activity were assessed using self-report questionnaires. A two-way (group by gender) ANCOVA was used to determine whether between-group differences existed in FMS proficiency, physical self-concept, and physical activity after controlling for age and BMI. Partial correlations and hierarchical multiple regression models were used to examine the relationship between FMS proficiency and physical self-concept. RESULTS: Compared with their TD peers, children with DCD displayed less proficiency in various components of FMS and viewed themselves as being less competent in physical coordination, sporting ability, and physical health. Physical coordination was a significant predictor of ability in object control skills. DCD status and gender were significant predictors of FMS proficiency. CONCLUSIONS: Future FMS interventions should target children with DCD and girls, and should emphasize improving object control skills proficiency and physical coordination. IMPLICATIONS FOR REHABILITATION: Children with DCD tend to have not only lower FMS proficiency than age-matched typically developing children but also lower physical self concept. Self-perceptions of physical coordination by children with DCD are likely to be valuable contributors to development of object control skills. This may then help to develop their confidence in performing motor skills. Children with DCD need supportive programs that facilitate the development of object control skills. Efficacy of training programs may be improved if children experience a greater sense of control and success when performing object control skills. PMID- 25698378 TI - Correlation of crystal structure and microwave dielectric properties of Nd1.02(Nb1-xTax)0.988O4 ceramic. AB - The phase structures of Nd1.02(Nb1-xTax)0.988O4 ceramics were analyzed via multiphase structure refinement. The X-ray diffraction patterns of Nd1.02(Nb1 xTax)0.988O4 showed that the monoclinic fergusonite structure of NdNbO4 and a second phase NdTa7O19 were obtained. The oxygen octahedron distortion was investigated according to the supercell of the NdNbO4 ceramic. The correlations between packing fractions, bond valences and microwave dielectric properties were discussed. For the main phase NdNbO4, as the polarizabilities increased, the epsilon increased. The Q * f value was mainly attributed to the packing fraction. With the increase of bond valence of the B-site and the oxygen octahedron distortion, the tauf value decreased. The substitution of Ta(5+) for Nb(5+) effectively influenced the microstructure and the microwave dielectric properties of NdNbO4 ceramics. Optimal microwave dielectric properties can be obtained for Nd1.02(Nb0.94Ta0.06)0.988O4 ceramics at x = 0.06. PMID- 25698379 TI - Practical opportunities to improve early detection and prevention of colorectal cancer (CRC) in members of high-risk families. AB - Colorectal cancer (CRC) incidence and mortality are steadily declining and CRC screening rates are increasing in the United States. Although this a very good news, several definable groups still have very low screening rates including younger (under age 50) members of high-risk CRC families. This opinion piece describes five strategies that could be incorporated into routine practice to improve identification and guideline-based screening in members of high-risk families. Routine incorporation of a simple family history screening tool and outreach to high-risk family members could substantially improve guideline-based screening in this population. Identification of CRCs and advanced adenomas in the endoscopy suite defines another group of high-risk families for similar outreach. Lynch syndrome families can be identified by testing CRCs and selected adenomas for microsatellite instability or loss of DNA repair protein expression. Finally, selective addition of aspirin to surveillance endoscopy can decrease the risk of new adenomas and CRCs. The rationale for these strategies as well as mechanisms for their implementation and evaluation in clinical practice is described. PMID- 25698380 TI - Network-assisted crop systems genetics: network inference and integrative analysis. AB - Although next-generation sequencing (NGS) technology has enabled the decoding of many crop species genomes, most of the underlying genetic components for economically important crop traits remain to be determined. Network approaches have proven useful for the study of the reference plant, Arabidopsis thaliana, and the success of network-based crop genetics will also require the availability of a genome-scale functional networks for crop species. In this review, we discuss how to construct functional networks and elucidate the holistic view of a crop system. The crop gene network then can be used for gene prioritization and the analysis of resequencing-based genome-wide association study (GWAS) data, the amount of which will rapidly grow in the field of crop science in the coming years. PMID- 25698381 TI - Identifying important structural features of ionic liquid stationary phases for the selective separation of nonpolar analytes by comprehensive two-dimensional gas chromatography. AB - A series of dicationic ionic liquid (IL)-based stationary phases were evaluated as secondary columns in comprehensive two-dimensional gas chromatography (GC*GC) for the separation of aliphatic hydrocarbons from kerosene. In order to understand the role that structural features of ILs play on the selectivity of nonpolar analytes, the solvation parameter model was used to probe the solvation properties of the IL-based stationary phases. It was observed that room temperature ILs containing long free alkyl side chain substituents and long linker chains between the two cations possess less cohesive forces and exhibited the highest resolution of aliphatic hydrocarbons. The anion component of the IL did not contribute significantly to the overall separation, as similar selectivities toward aliphatic hydrocarbons were observed when examining ILs with identical cations and different anions. In an attempt to further examine the separation capabilities of the IL-based GC stationary phases, columns of the best performing stationary phases were prepared with higher film thickness and resulted in enhanced selectivity of aliphatic hydrocarbons. PMID- 25698382 TI - Rapid screening and identification of multi-class substances of very high concern in textiles using liquid chromatography-hybrid linear ion trap orbitrap mass spectrometry. AB - A new analytical method was established and validated for the analysis of 19 substances of very high concern (SVHCs) in textiles, including phthalic acid esters (PAEs), organotins (OTs), perfluorochemicals (PFCs) and flame retardants (FRs). After ultrasonic extraction in methanol, the textile samples were analyzed by high performance liquid chromatography-hybrid linear ion trap Orbitrap high resolution mass spectrometry (HPLC-LTQ/Orbitrap). The values of LOQ were in the range of 2-200mg/kg. Recoveries at two levels (at the LOQ and at half the limit of regulation) ranged from 68% to 120%, and the repeatability was lower than 13%. This method was successfully applied to the screening of SVHCs in commercial textile samples and is useful for the fast screening of various SVHCs. PMID- 25698383 TI - Altered microRNA expression in folliculotropic and transformed mycosis fungoides. AB - Mycosis fungoides (MF) is a common, indolent primary cutaneous T-cell lymphoma (CTCL), with rare, more aggressive variants, such as folliculotropic MF (FMF). A minority of the MF cases may undergo large cell transformation (T-MF) associated with poor prognosis. A selection of microRNAs (miRs) contribute to the pathogenesis and progression of classic MF, and may also be useful in differential diagnostics. However, the molecular background of FMF and the mechanisms involved in large cell transformation are obscure. We analyzed the expression of 11 miRs in 9 FMF and 7 T-MF cases. Three miRs, including miR-93-5p, miR-181a and miR-34a were significantly upregulated in both FMF and T-MF. FMF also showed overexpression of miR-155 and miR-223, while miR-181b and miR-326 were overexpressed in T-MF cases compared to controls. These results by identifying a number of differentially expressed microRNAs add further insight into the molecular pathogenesis of folliculotropic MF and large cell transformation of MF. PMID- 25698384 TI - What have we learned from worldwide experiences on the management and treatment of hospital effluent? - an overview and a discussion on perspectives. AB - This study overviews lessons learned from experimental investigations on dedicated treatment systems of hospital effluent carried out worldwide in the last twenty years. It includes 48 peer reviewed papers from 1995 to 2015 assessing the efficacy of different treatment levels (preliminary, primary, secondary and polishing) of hospital wastewater in removing a wide spectrum of pharmaceutical compounds as well as conventional contaminants. Moreover, it highlights the rationale and the reasons for each study: reducing the discharge of micropollutants in surface water, improving existing wastewater treatment technologies and reducing the risk of spread of pathogens causing endemic diseases and finally, it offers a critical analysis of the conclusions and suggestions of each study. The most investigated technologies are membrane bioreactors equipped with ultrafiltration membranes in the secondary step, ozonation followed by activated carbon filtration (in powder and in granules) in the polishing step. Interesting research projects deal with photo-Fenton processes acting as primary treatments to enhance biodegradation before biological treatment, and as a polishing step, thus further reducing micro contaminant occurrence. Investment and operational costs are also presented and discussed for the different treatment technologies tested worldwide, in particular membrane bioreactors and various advanced oxidation processes. This study also discusses the need for further research to evaluate toxicity resulting from advanced oxidation processes as well as the need to develop an accurate feasibility study that encompasses technical, ecotoxicological and economic aspects to identify the best available treatment in the different situations from a global view point. PMID- 25698385 TI - Comment on Adar et al, page 106 - 114. Calcifications in the aortic arch on chest x-ray - Incidental finding or valuable surrogate marker for cardiovascular risk? PMID- 25698386 TI - Integrative therapy in patients with intermittent claudication. AB - The generally accepted first-line treatment in patients with intermittent claudication is risk factor modification, medical treatment and exercise training. In an era of reduced resources, the benefit of any further invasive intervention must be weighted against best conservative therapy for patients with claudication. According to some recent trials an integrative therapeutic concept combining best conservative treatment - including (supervised) exercise therapy - with endovascular therapy gives the best midterm results concerning walking distance and health-related quality of life. The improved mid- and long-term patency rate with use of modern technology further supports this concept. The conservative and interventional treatment strategy are more complimentary than competitive. The current main challenge is to overcome the economic barriers concerning the availability of exercise programmes. PMID- 25698387 TI - Combined and complex vascular malformations. AB - The correct diagnosis of vascular malformations is obtainable by clinical assessment and patient history in the majority of cases. Nonetheless, confusion in nomenclature, existence of multiple classifications and rarity of these lesions leads to misdiagnosis and related wrong treatment. This is especially the case in combined or complex vascular malformations or vascular malformations that are part of syndromes as these have overlapping clinical and imaging features. New entities in the field of vascular anomalies have been described recently like fibro-adipose vascular anomaly or central conducting lymphatic anomalies. PMID- 25698388 TI - Aortic arch calcification is strongly associated with coronary artery calcification. AB - BACKGROUND: We aimed to investigate the association between aortic arch and coronary artery calcification (CAC). We postulated that low- and high-risk CAC scores could be predicted with the evaluation of standard chest radiography for aortic arch calcification (AAC). PATIENTS AND METHODS: Consecutive patients who were referred for a multidetector computerized tomography (MDCT) examination were enrolled prospectively. All patients were scanned using a commercially available 64-slice MDCT scanner for the evaluation of CAC score. A four-point grading scale (0, 1, 2 and 3) was used to evaluate AAC on the standard posterior-anterior chest radiography images. RESULTS: The study group consisted of 248 patients. Median age of the study group was 52 (IQR: 10) years, and 165 (67 %) were male. AAC grades (r = 0.676, p < 0.0001) and age (r = 0.518, p < 0.0001) were significantly and positively correlated with CAC score. Presence of AAC was independently associated with the presence of CAC (OR: 11.20, 95 % CI 4.25 to 29.52). An AAC grade of >= 2 was the strongest independent predictor of a high-risk CAC score (OR: 27.42, 95 % CI 6.09 to 123.52). Receiver operating characteristics curve analysis yielded a strong predictive ability of AAC grades for a CAC score of >= 100 (AUC = 0.892, P < 0.0001), and >= 400 (AUC = 0.894, P < 0.0001). Absence of AAC had a sensitivity, specificity and accuracy of 90 %, 84 % and 89 %, respectively, for a CAC score of < 100. An AAC grade of >= 2 predicted a CAC score of >= 400 with a sensitivity, specificity and accuracy of 68 %, 98 % and 95 %, respectively. CONCLUSIONS: AAC is a strong and independent predictor of CAC. The discriminative performance of AAC is high in detecting patients with low- and high-risk CAC scores. PMID- 25698389 TI - Quality assessment of elective abdominal aortic aneurysm repair from referral to surgery. AB - BACKGROUND: The risk of rupture for a large (>= 55 mm) abdominal aortic aneurysm(AAA) is significant and therefore operative treatment should take place before possible aneurysm rupture. Timing of elective AAA surgery has rarely been investigated previously. The aim of this study is to evaluate success in the elective treatment process of large AAAs from referral to surgery in Helsinki University Central Hospital. PATIENTS AND METHODS: We retrospectively analyzed all 361 patients who were assigned for elective treatment of AAA during 2005 - 2010. We divided the patients into subgroups according to size of the aneurysm: <60 mm, 61 - 70 mm and >70 mm. The main focus was set on the preoperative period and on potential factors causing delay. End points indicating failure in the treatment process were aneurysm ruptures and deaths before surgery. RESULTS: The median time from referral to surgery for the three subgroups was 112, 91 and 45 days respectively (p < 0,001). There were no significant differences between the treatment methods: open repair (OR) with 103 days and endovascular aortic repair (EVAR) with 113 days until surgery. Twenty three (6.4 %) patients were operated on emergency basis while waiting for the operation, six of them for ruptured aneurysm. There were an additional five patients with aneurysm ruptures who all died, as did four out the six operated ones. CONCLUSIONS: The whole treatment process starting from the referral should be considered in order for elective AAA treatment to succeed. Recommendations should be established for the preoperative period to guarantee rapid preoperative evaluation. PMID- 25698390 TI - Sonography of subcutaneous tissue cannot determine causes of lower limb edema. AB - BACKGROUND: To clarify the clinical use of sonography for differentiation of edema we tried to answer the question whether a group of doctors can differentiate lymphedema from cardiac, hepatic or venous edema just by analysing sonographic images of the edema. PATIENTS AND METHODS: 38 (70 +/- 12 years, 22 (58 %) females) patients with lower limb edema were recruited according the clinical diagnosis: 10 (26 %) lymphedema, 16 (42 %) heart insufficiency, 6 (16 %) venous disorders, 6 (16 %) chronic hepatic disease. Edema was depicted sonographically at the most affected leg in a standardised way at distal and proximal calf. 38 sets of images were anonymised and send to 5 experienced doctors. They were asked whether they can see criteria for lymphedema: 1. anechoic gaps, 2. horizontal gaps and 3. echoic rims. RESULTS: Accepting an edema as lymphedema if only one doctor sees at least one of the three criteria for lymphatic edema on each single image all edema would be classified as lymphatic. Accepting lymphedema only if all doctors see at least one of the three criteria on the distal image of the same patient 80 % of the patients supposed to have lymphedema are classified as such, but also the majority of cardiac, venous and hepatic edema. Accepting lymphedema only if all doctors see all three criteria on the distal image of the same patients no edema would be classified as lymphatic. In addition we separated patients by Stemmers? sign in those with positive and negative sign. The interpretation of the images was not different between both groups. CONCLUSIONS: Our analysis shows that it is not possible to differentiate lymphedema from other lower limb edema sonographically. PMID- 25698391 TI - Health and quality of life in patients with primary and secondary lymphedema of the lower extremity. AB - BACKGROUND: Little is known about comprehensively measured health and quality of life of lower limb lymphedema (LLL). The aim of this study was to determine health and quality of life of LLL patients stratified by primary and secondary lymphedema compared to a normative population-based data stratified by age, sex and comorbidity. PATIENTS AND METHODS: A cross-sectional study of patients after treatment at the department of angiology of a rehabilitation clinic was conducted. Self-assessment was performed by the Short Form 36 (SF-36) and two condition-specific measures. RESULTS: Primary LLL (n = 52) 75 % female, mean age 47.1 years) reported health comparable to normative values, e. g. SF-36 physical functioning 80.4 (norm 84.1, p = 0.512) and SF-36 vitality 62.7 (59.7, p = 0.117) (mean scores, 100 = best). Secondary LLL (n = 60, 68 % female, mean age 60.6 years) scored 68.1 (73.9, p = 0.049) and 55.2 (56.2, p = 0.800) on the corresponding scales. Mean symptoms and function scores on the specific measures ranged from 70.0 to 83.1 for primary LLL (100 = best) and from 63.3 to 80.6 for secondary LLL. Function, vitality and both SF-36 role dimensions were higher in primary LLL than in secondary LLL, (mean SF-36 vitality 62.7 versus 55.2, p = 0.035). CONCLUSIONS: Overall health and quality of life was high and comparable to the general population norms in primary LLL. The same was true for most psycho social scales in secondary LLL whereas functionally some deficits were recorded. Cancer as the most frequent cause for secondary LLL may affect health in these dimensions. Reported negative effects of LLL seem to be well compensated, especially in primary LLL and under optimal treatment. PMID- 25698392 TI - Primitive trigeminal artery as a rare cause of trigeminal neuralgia. PMID- 25698393 TI - Saddle aortic bifurcation and iliacofemoral arteries tandem embolism in a child with dilated cardiomyopathy. PMID- 25698394 TI - Intravenous leiomyomatosis with cardiac extension. PMID- 25698395 TI - Systemic thrombolysis in pulmonary embolism - another paradigm falling? PMID- 25698396 TI - Erratum to: The use of self-gripping (ProgripTM) mesh during laparoscopic total extraperitoneal (TEP) inguinal hernia repair: a prospective feasibility and long term outcomes study. PMID- 25698397 TI - Randomized trial on the physiologic impact of NOTES. AB - BACKGROUND: Our previous work revealed significantly less acidosis in swine undergoing natural orifice translumenal endoscopic surgery (NOTES) using endoscopic air insufflation than swine undergoing standard laparoscopy. We wanted to evaluate the differential effects of CO2 versus intra-abdominal pressure as source for this finding. In addition, we investigated the endocrine stress response between swine undergoing NOTES peritoneoscopy with CO2 insufflation and animals undergoing standard diagnostic laparoscopy with CO2. MATERIALS AND METHODS: Twenty-eight (28) female 50-kg domestic pigs were randomly assigned to one of four groups using a permuted block randomization table: Group 1: NOTES using CO2 insufflation, Group 2: NOTES using air insufflation, Group 3: laparoscopy max pressure 12 mmHg and Group 4: laparoscopy with max pressure 7 mmHg. Invasive monitoring lines were placed. Pneumoperitoneum was established by the respective method and maintained for 90 min, visualizing liver, spleen and colon. Arterial blood gas was obtained at baseline and four additional time points. Serum TNF-alpha for POD (postoperative day) 1 and cumulative urine adrenaline for the procedure were determined by ELISA. ANOVA and t test were used for statistical comparison. The study was Institutional Animal Care and Use Committees approved. RESULTS: All experiments were completed as outlined. Blood pH showed a significant difference between groups. Serum TNF-alpha revealed higher levels for NOTES CO2 on POD 1 than standard laparoscopy (p = 0.03). CONCLUSION: NOTES animals with CO2 insufflation initially experienced similar pH compared to standard laparoscopy but recovered to levels seen in low-pressure laparoscopy and NOTES with air. NOTES with CO2 appears to elicit a stronger stress response in this study than standard or low-pressure laparoscopy or NOTES with air. PMID- 25698398 TI - Necroptosis-inducing rhenium(V) oxo complexes. AB - Rhenium(V) oxo complexes of general formula [ReO(OMe)(N^N)Cl2], where N^N = 4,7 diphenyl-1,10-phenanthroline, 1, or 3,4,7,8-tetramethyl-1,10-phenanthroline, 2, effectively kill cancer cells by triggering necroptosis, a non-apoptotic form of cell death. Both complexes evoke necrosome (RIP1-RIP3)-dependent intracellular reactive oxygen species (ROS) production and propidium iodide uptake. The complexes also induce mitochondrial membrane potential depletion, a possible downstream effect of ROS production. Apparently, 1 and 2 are the first rhenium complexes to evoke cellular events consistent with programmed necrosis in cancer cells. Furthermore, 1 and 2 display low acute toxicity in C57BL/6 mice and reasonable stability in fresh human blood. PMID- 25698399 TI - The role of microRNA-30c in the self-renewal and differentiation of C6 glioma cells. AB - BACKGROUND: Sphere formation, one method for identifying self-renewal ability, has been used to report that cancer stem-like cells exist in rat C6 glioma cells. Recent studies suggested that cancer stem-like cells share the stem cell properties of self-renewal and multipotent ability of neural stem cells and might be regulated by microRNAs (miRNAs). However, the mechanism of miRNA involvement in the sphere formation and neural differentiation abilities of cancer stem-like cells is poorly understood. RESULTS: We found that miRNA-30c could assist in sphere formation of C6 cells under defined conditions in neural stem cell medium DMEM/F12-bFGF-EGF-B27. Moreover, overexpression of miRNA-30c might reduce 3 isobutyl-1-methylxanthine (IBMX)-induced neural differentiation, as the expression of neural markers, especially glial fibrillary acidic protein (GFAP), decreased. Further experiments revealed that miRNA-30c inhibited the IBMX-induced astrocyte differentiation via targeting the upstream genes and inactivating phosphorylation of STAT3 of the JAK-STAT3 pathway. Subsequently, the expression of GFAP was reduced and the number of astrocyte differentiation from C6 cells decreased. CONCLUSIONS: Our findings suggest that miRNA-30c could play a regulatory role in self-renewal and neural differentiation in C6 glioma cells. PMID- 25698400 TI - Structural analysis of PseH, the Campylobacter jejuni N-acetyltransferase involved in bacterial O-linked glycosylation. AB - Campylobacter jejuni is a bacterium that uses flagella for motility and causes worldwide acute gastroenteritis in humans. The C. jejuni N-acetyltransferase PseH (cjPseH) is responsible for the third step in flagellin O-linked glycosylation and plays a key role in flagellar formation and motility. cjPseH transfers an acetyl group from an acetyl donor, acetyl coenzyme A (AcCoA), to the amino group of UDP-4-amino-4,6-dideoxy-N-acetyl-beta-L-altrosamine to produce UDP-2,4 diacetamido-2,4,6-trideoxy-beta-L-altropyranose. To elucidate the catalytic mechanism of cjPseH, crystal structures of cjPseH alone and in complex with AcCoA were determined at 1.95 A resolution. cjPseH folds into a single-domain structure of a central beta-sheet decorated by four alpha-helices with two continuously connected grooves. A deep groove (groove-A) accommodates the AcCoA molecule. Interestingly, the acetyl end of AcCoA points toward an open space in a neighboring shallow groove (groove-S), which is occupied by extra electron density that potentially serves as a pseudosubstrate, suggesting that the groove S may provide a substrate-binding site. Structure-based comparative analysis suggests that cjPseH utilizes a unique catalytic mechanism of acetylation that has not been observed in other glycosylation-associated acetyltransferases. Thus, our studies on cjPseH will provide valuable information for the design of new antibiotics to treat C. jejuni-induced gastroenteritis. PMID- 25698401 TI - Articulated minimally invasive surgical instrument based on compliant mechanism. AB - PURPOSE: In minimally invasive surgery, instruments are inserted from the exterior of the patient's body into the surgical field inside the body through the minimum incision, resulting in limited visibility, accessibility, and dexterity. To address this problem, surgical instruments with articulated joints and multiple degrees of freedom have been developed. The articulations in currently available surgical instruments use mainly wire or link mechanisms. These mechanisms are generally robust and reliable, but the miniaturization of the mechanical parts required often results in problems with size, weight, durability, mechanical play, sterilization, and assembly costs. METHODS: We thus introduced a compliant mechanism to a laparoscopic surgical instrument with multiple degrees of freedom at the tip. To show the feasibility of the concept, we developed a prototype with two degrees of freedom articulated surgical instruments that can perform the grasping and bending movements. The developed prototype is roughly the same size of the conventional laparoscopic instrument, within the diameter of 4 mm. The elastic parts were fabricated by Ni-Ti alloy and SK-85M, rigid parts ware fabricated by stainless steel, covered by 3D- printed ABS resin. The prototype was designed using iterative finite element method analysis, and has a minimal number of mechanical parts. RESULTS: The prototype showed hysteresis in grasping movement presumably due to the friction; however, the prototype showed promising mechanical characteristics and was fully functional in two degrees of freedom. In addition, the prototype was capable to exert over 15 N grasping that is sufficient for the general laparoscopic procedure. The evaluation tests thus positively showed the concept of the proposed mechanism. CONCLUSION: The prototype showed promising characteristics in the given mechanical evaluation experiments. Use of a compliant mechanism such as in our prototype may contribute to the advancement of surgical instruments in terms of simplicity, size, weight, dexterity, and affordability. PMID- 25698402 TI - A Simplified Preoperative Assessment Predicts Complete Cytoreduction and Outcomes in Patients with Low-Grade Mucinous Adenocarcinoma of the Appendix. AB - BACKGROUND: Complete cytoreduction with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) has been shown to improve survival in patients with low-grade mucinous adenocarcinoma (LGMA). However, incomplete cytoreduction exposes patients to significant morbidity without a similar survival benefit. Preoperative assessment of the ability to achieve CRS is therefore a critical step in selecting patients for CRS/HIPEC. OBJECTIVE: The aim of this study was to develop and validate a preoperative scoring system to accurately predict the ability to achieve complete cytoreduction in patients with LGMA of the appendix. METHODS: A simplified preoperative assessment for appendix tumor (SPAAT) score was developed based on computed tomography scan findings thought to predict incomplete cytoreduction. We applied the SPAAT score to patients with LGMA to determine the ability of the score to predict complete cytoreduction. This scoring system was then applied to a separate cohort of patients from a different institution. Sensitivity and specificity were determined for the SPAAT score. Survival was calculated and correlated with the SPAAT score and the completeness of cytoreduction score. RESULTS: A SPAAT score of <3 is a significant predictor of complete cytoreduction in the derivation cohort. In the validation cohort, 40 of 42 patients with a SPAAT score <3 achieved a complete cytoreduction, for a positive predictive value of 95.2 % and a negative predictive value of 100 %. Additionally, the SPAAT score was a significant predictor of disease-free survival. CONCLUSIONS: The SPAAT score is a useful tool in the preoperative assessment of patients with LGMA who are under consideration for cytoreductive surgery. Prospective analysis of this scoring system is warranted to appropriately select patients who will benefit from CRS/HIPEC. PMID- 25698403 TI - A comparative study of two anti-coagulation plans on the prevention of PVST after laparoscopic splenectomy and esophagogastric devascularization. AB - Cirrhosis and portal hypertension (PH) has a high incidence in China. Laparoscopic splenectomy and esophagogastric devascularization (LS + ED) was confirmed as an effective and safe surgical approach. But compared to open surgery (OS + ED), the rate of portal vein system thrombosis (PVST) was found to be higher after LS + ED. PVST is a common and potentially life-threatening complication after LS + ED in patients with cirrhosis and PH. Anti-coagulation therapy should be given early, but no standard plan for PSVT prophylaxis has been developed for all patients. In this study, the efficacy and safety of early use of low molecular weight heparin (LMWH) to prevent PVST were retrospectively evaluated compared with conventional anti-coagulant therapy. Of 219 patients with cirrhosis and PH undergoing LS + ED at our hospital from January 2008 to June 2013, 139 received early anti-coagulant therapy with LMWH, and 80 received conventional anti-coagulant therapy. The rates and types of PVST, perioperative coagulation function, intra-abdominal active bleeding, and esophagogastric variceal bleeding (EGVB) were compared in these two groups. Of the 139 patients in the early anti-coagulation group, 42 (30.2 %) experienced postoperative PVST, including two (1.4 %) with main trunk. Of the 80 patients in the conventional anti-coagulation group, 40 (50.0 %) experienced postoperative PVST, including 12 (15.0 %) with main trunk; three (3.8 %) experienced recurrent EGVB due to main trunk thrombosis, and one (1.3 %) underwent an immediate second laparotomy for uncontrollable active bleeding. The rates of postoperative PVST (P = 0.004), main trunk thrombosis (P = 0.000), and EGVB (P = 0.048) were significantly lower in the early than in the conventional anti-coagulant group, but all tested perioperative indices of coagulation function and rates of intraperitoneal active bleeding were similar. Early anti-coagulation with LMWH is safe and effective in patients with LS + ED for cirrhosis and PH. PMID- 25698404 TI - Anticoagulation therapy in 2015: where we are and where we are going. AB - Oral anticoagulants are a mainstay for the prevention and treatment of venous and arterial thrombosis. In 2015, the non-vitamin K oral anticoagulants (NOACs) are already replacing warfarin for many indications. Ongoing studies are focused on development of antidotes and specific reversal agents for the NOACs, and assessing their utility for prevention of cardiovascular events in patients with heart failure, coronary or peripheral artery disease, or embolic stroke of unknown source. This paper (a) lists the current indications for the NOACs; (b) reviews the current impact of the NOACs in each of these indications; PMID- 25698405 TI - Carcinosarcoma of the gallbladder with heterologous differentiation: a case report. PMID- 25698406 TI - Insomnia symptoms predict physical and mental impairments among postmenopausal women. PMID- 25698407 TI - Do Treatment Differences between Arms Affect the Main Outcome of ERSPC Rotterdam? AB - PURPOSE: We assessed differences in treatment between the screening and control arms of ERSPC Rotterdam and studied whether possible treatment differences could explain the positive study outcome. MATERIALS AND METHODS: In ERSPC Rotterdam men 55 to 74 years old were randomized to a screening arm of 21,210 and a control arm of 21,166. Treatment after diagnosis was at the discretion of the care provider chosen by the patient. Initial treatment was compared in 4 risk groups. The relation between prostate cancer incidence and prostate cancer mortality was assessed by risk group by correlating the incidence RR and the mortality RR. A direct relation would have supported a stage shift as the main cause of changes in prostate cancer mortality. RESULTS: Initial treatment differed between the arms in the low, intermediate and high risk groups but not in the metastatic group. The RRs of prostate cancer incidence and mortality per risk group were related 1:1 (regression line slope 1.00, 95% CI 0.30-1.74). Of changes in prostate cancer mortality 94% could be explained by changes in prostate cancer incidence. This made treatment differences unlikely as the reason for the observed decrease in prostate cancer mortality. CONCLUSIONS: Differences in treatment between the ERSPC Rotterdam screening and control arms were unlikely to explain the differences in prostate cancer mortality. Results are instead consistent with a decrease in prostate cancer mortality as the result of a favorable stage through screening. PMID- 25698408 TI - A review of guidelines for cross-cultural adaptation of questionnaires could not bring out a consensus. AB - OBJECTIVES: The aim of cross-cultural adaptation (CCA) of a questionnaire is to achieve equivalence between the original and adapted questionnaire. Here, we aimed to review the state of the art in CCA methods. STUDY DESIGN AND SETTING: We reviewed cross-disciplinary bibliographic databases for articles on methods and guidelines for CCA of questionnaires. Articles were first selected by their abstract and title, and then, we retrieved full-text English articles. References of selected articles were searched for additional relevant studies. RESULTS: We identified 31 guidelines and found no consensus in CCA methods. Most methods included use of committees, focus groups, and back translations. Evidence for the best methods is lacking, although clues indicate that back translation may not be mandatory. CONCLUSION: Several methods are available for CCA of questionnaires. According to experts only, most would achieve comparable results, and choosing one is a matter of preference and logistic. More evidence is needed to support recommendations. Adaptation and validation of a questionnaire are two different processes that should be distinguished and undertaken with care. PMID- 25698409 TI - Carboxylic acid production from brewer's spent grain via mixed culture fermentation. AB - This study aimed at investigating carboxylic acid production from brewer's spent grain (BSG) via mixed culture fermentation. The results showed that the distribution of fermentation products was significantly affected by pH conditions and the addition of electron donors. Lactic acid was the dominant component under acidic and alkaline conditions while volatile fatty acids (VFAs) became dominant under the neutral condition. Furthermore, the neutral condition favored the chain elongation of carboxylic acids, especially with ethanol as the electron donor. Ethanol addition enhanced valeric acid and caproic acid production by 44% and 167%, respectively. Lactic acid addition also had positive effects on VFAs production under the neutral condition but limited to C2-C4 products. As a result, propionic acid and butyric acid production was increased by 109% and 152%, respectively. These findings provide substantial evidence for regulating carboxylic acid production during mixed culture fermentation of BSG by controlling pH and adding electron donors. PMID- 25698410 TI - Life cycle assessment of swine and dairy manure: pyrolysis and combustion processes. AB - The valorization of three different manure samples via pyrolysis and combustion processes was evaluated. Dairy manure (sample Pre) was biologically pretreated by anaerobic digestion (sample Dig R) whereas swine manure (sample SW) was pretreated by a biodrying process. Thermal behavior of manure samples were studied by means of thermogravimetric analysis coupled with mass spectrometry (TGA-MS). These processes could be divided into four general stages: dehydration, devolatilization, char transformation (oxidation for combustion) and inorganic matter decomposition. The main differences observed among the samples were attributed to their different composition and pretreatment. The economic feasibility, energetic and environmental impacts of pyrolysis and combustion technologies for dairy samples were carried out by means of life cycle assessment (LCA) methodology. Four different scenarios were analyzed. The economic feasibility of the pyrolysis process was demonstrated, being sample Dig R the best environmental option. However, the combustion of sample Pre was the best energetic option. PMID- 25698411 TI - Net biomass production under complete solids retention in high organic load activated sludge process. AB - The effect of complete solids retention on net biomass production, at a slaughterhouse's activated sludge wastewater treatment process, was studied for 425 days. The process reached equilibrium after 150 days. In equilibrium phase, and until the end of the study, relative constant MLVSS to MLSS ratio, low food to microorganisms ratio (F/M), low substrate utilization rate (SUR) and negligible observed sludge yield (Y obs) were measured. Y obs fluctuated between positive and negative values (+/- 0.03 gVSS gCOD(-1)), tending zero mean values, and leading to the conclusion that zero net sludge growth can be achieved. The high BOD ultimate/COD ratio and the zero sludge accumulation, leads to the conclusion that all fractions of organic matter, including cell debris, are biodegradable. The results were verified by comparing the measured Y obs values and those predicted using a conventional activated sludge model (ASM) and a modified ASM that incorporates the slow hydrolysis concept of the unbiodegradable compounds. PMID- 25698412 TI - Co-composting of organic fraction of municipal solid waste mixed with different bulking waste: characterization of physicochemical parameters and microbial enzymatic dynamic. AB - The effect of various bulking waste such as wood shaving, agricultural and yard trimming waste combined with organic fraction of municipal solid waste (OFMSW) composting was investigated through assessing their influence on microbial enzymatic activities and quality of finished compost. All three piles of OFMSW with different bulking waste were inoculated with microbial consortium. The results revealed that OFMSW combined with wood shaving and microbial consortium (Phanerochaete chrysosporium, Trichoderma viride and Pseudomonas aeruginosa) were helpful tool to facilitate the enzymatic activity and shortened composting period within 4 weeks. Maximum enzymatic activity were observed in pile 1 and 3 during the first 3 weeks, while in pile 2 relatively very low. But phosphatase activity was relatively higher in all piles until the end of the process. Maturity parameters of compost quality also favored the pile 1 as the best formulation for OFMSW composting. PMID- 25698413 TI - Harnessing CRISPR-Cas systems for bacterial genome editing. AB - Manipulation of genomic sequences facilitates the identification and characterization of key genetic determinants in the investigation of biological processes. Genome editing via clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated (Cas) constitutes a next-generation method for programmable and high-throughput functional genomics. CRISPR-Cas systems are readily reprogrammed to induce sequence-specific DNA breaks at target loci, resulting in fixed mutations via host-dependent DNA repair mechanisms. Although bacterial genome editing is a relatively unexplored and underrepresented application of CRISPR-Cas systems, recent studies provide valuable insights for the widespread future implementation of this technology. This review summarizes recent progress in bacterial genome editing and identifies fundamental genetic and phenotypic outcomes of CRISPR targeting in bacteria, in the context of tool development, genome homeostasis, and DNA repair. PMID- 25698414 TI - St. Croix sheep produce a rapid and greater cellular immune response contributing to reduced establishment of Haemonchus contortus. AB - The objective of this study was to determine breed differences in immune response shortly following Haemonchus contortus infection. Peripheral and local cellular and humoral immune responses were evaluated in 24 St. Croix hair lambs and 24 Dorset*(Finn-Rambouillet) wool lambs at 0, 3, 5 and 7 days after infection with 10,000 L3 H. contortus larvae. Blood samples taken immediately before harvest revealed no differences in circulating effector cell populations, yet there were significant differences in levels of circulating neutrophils. Across all time points, hair lambs had a higher average circulating neutrophil concentration (3018 cells/MUl) than wool lambs (1818 cells/MUl; P<0.05). Infected hair lambs also had greater serum total-IgA compared to wool lambs (1.8 vs 0.9 mg/ml; P=0.006). Breeds did not differ in eosinophil or globule leukocyte (GL) counts in abomasal tissue, but infiltration of these cell populations increased with time. Globule leukocyte counts peaked at day 3 after infection whereas eosinophil numbers continued to increase to day 7 after infection. When averaged across all time points, abomasal neutrophil counts were higher in hair lambs (831 cells/mm(2)), than wool lambs (561 cells/mm(2); P<0.0001). Total abomasal lymph node (ALN) weight increased exponentially from 2.60 g at day 0 to 6.57 g by day 7 in hair lambs whereas ALN weight only marginally increased in wool lambs and was significantly lower than hair lambs by day 7 (P=0.0003). This result suggests a greater expansion of lymphocytes in the ALN promoting early development of antigen-specific acquired immune responses in hair lambs. Greater IgA production and infiltration of immune cells to the abomasal mucosa at an earlier stage of infection may limit establishment of adult parasites and thereby shorten the duration and severity of infection. PMID- 25698415 TI - Comment on 'Update of (40)K and (226)Ra and (232)Th series gamma-to-dose conversion factors for soil'. AB - A comment on the recent Journal of Environmental Radioactivity article titled 'Update of (40)K and (226)Ra and (232)Th series gamma-to-dose conversion factors for soil'. PMID- 25698416 TI - Periodontal-like gingival connective tissue attachment on titanium surface with nano-ordered spikes and pores created by alkali-heat treatment. AB - OBJECTIVES: Establishment of periodontal-like connective tissue attachment is one of the outstanding issues in implant dentistry. Organized nanotopographic titanium surface may acquire periodontal-like connective tissue attachment with activation of fibroblastic function. This study aimed to evaluate gingival fibroblastic function and connective tissue attachment on two types of nanotopographic titanium surface created by alkali-heat (AH) treatment. METHODS: Commercially pure titanium turned discs with or without acid-etching or two types of AH treatment, underwent scanning electron microscopic evaluation in surface topography. Rat gingival fibroblasts cultured on the discs evaluated in terms of cellular adhesion, collagen synthesis and physicochemical binding strength of deposited collagen on the surfaces. Turned or the AH-treated pure titanium mini implants were placed on the hard palatal plate of rabbits and underwent histological evaluation at 8 weeks postoperatively. RESULTS: Both AH-treated surfaces were characterized by numerous well-organized fine nanospikes with crevasses and nanoholes, and uniform shaggy-like nanotopography with a sponge like inner network, respectively. These nanotopographic surfaces enhanced cellular adhesion and collagen synthesis and toughened binding strength of deposited collagen sufficiently to resist against experimental overloading and inflammatory conditions by inclusion of collagen fibers into the surface, as compared with turned or acid-etched surfaces. The AH-treated mini-implants yielded inclusion of gingival connective tissue into the nanotopographic surface structure, with collagen fiber directions mimicking periodontal tissue in the transmucosal area. These features were not seen on turned surface implants. SIGNIFICANCE: The well-organized nanotopographic titanium surface with nanospikes and pores by the AH treatment enhanced gingival fibroblastic collagen synthesis and acquired periodontal-like connective tissue attachment with substantial detachment resistance. PMID- 25698417 TI - Seeing into the infrared: a novel IR fluorescent fingerprint powder. AB - A preliminary study demonstrates that latent fingermarks across a range of highly patterned, coloured non-porous and semi-porous substrates may be clearly developed and imaged in the near infrared following a simple dusting method using finely divided spirulina platensis powder, a naturally occurring, non-toxic algae, used widely within the food industry. Troublesome printed/multicoloured backgrounds show less interference with the fluorescence observed using this material, unlike conventional luminescent powders which fluoresce in the visible spectrum alongside the background to which they are applied. The material shows promise for use both in the field and in the laboratory. PMID- 25698419 TI - Complexity in nuclear materials. PMID- 25698420 TI - Predicting material release during a nuclear reactor accident. PMID- 25698421 TI - Long-term storage of spent nuclear fuel. PMID- 25698422 TI - Nuclear materials in Japan. PMID- 25698428 TI - Glass corrosion: Sharpened interface. PMID- 25698429 TI - Material witness: A graphene explosion. PMID- 25698430 TI - Elastic shells: Mapping curved wrinkles. PMID- 25698431 TI - Bioelectronics: Soft implants for long-term use. PMID- 25698432 TI - Cell mechanics: Hydraulic cracking. PMID- 25698433 TI - The 80-W KTP GreenLight laser vaporization of the prostate versus transurethral resection of the prostate (TURP): adjusted analysis of 5-year results of a prospective non-randomized bi-center study. AB - This study aims to compare long-term results of photoselective vaporization of the prostate (PVP) with an 80-W potassium titanyl phosphate (KTP) laser and monopolar transurethral resection of the prostate (TURP) in terms of efficacy, durability, and safety in an adjusted patient population. This prospective, non randomized bi-center study included 120 (PVP) and 68 (TURP) patients in each arm. Patients were evaluated at 60 months of follow-up. Data from 30 (PVP) and 31 (TURP) patients were available for analysis. The primary outcome measurement was the International Prostate Symptom Score (IPSS) at 5 years. Secondary outcome measurements included voiding symptoms (quality of life (QoL) score), micturition parameters (maximal flow rate, Q max), post-void residual (PVR) volume, prostate specific antigen (PSA) value, and reoperation rate. At study inclusion, voiding symptoms and micturition parameters were comparable between both groups. Age, prostate volume, and the proportion of patients with platelet aggregation inhibition or oral anticoagulation were significantly higher in the PVP group. No significant difference could be detected between patients available at 60 months and those lost to follow-up in terms of preoperative characteristics in either group. Sixty months postoperatively, the improvement of IPSS, QoL, Q max, and PVR volume showed no significant difference between both groups. PSA reduction was significantly higher after TURP. The reoperation rate due to urethral stricture (PVP, 13 %; TURP, none), bladder neck contracture (PVP, 3 %; TURP, none), and persisting or recurrent adenoma (PVP, 18 %; TURP, 3 %) was significantly higher after the 80-W PVP. Eighty-watt PVP leads to comparable functional outcomes to TURP. However, during a long-term follow-up, significantly more reoperations are necessary after PVP with the 80-W KTP laser, suggesting inferior tissue ablation capacity of the 80-W KTP laser. PMID- 25698434 TI - Evaluation of soil flushing of complex contaminated soil: an experimental and modeling simulation study. AB - The removal of heavy metals (Zn and Pb) and heavy petroleum oils (HPOs) from a soil with complex contamination was examined by soil flushing. Desorption and transport behaviors of the complex contaminants were assessed by batch and continuous flow reactor experiments and through modeling simulations. Flushing a one-dimensional flow column packed with complex contaminated soil sequentially with citric acid then a surfactant resulted in the removal of 85.6% of Zn, 62% of Pb, and 31.6% of HPO. The desorption distribution coefficients, KUbatch and KLbatch, converged to constant values as Ce increased. An equilibrium model (ADR) and nonequilibrium models (TSNE and TRNE) were used to predict the desorption and transport of complex contaminants. The nonequilibrium models demonstrated better fits with the experimental values obtained from the column test than the equilibrium model. The ranges of KUbatch and KLbatch were very close to those of KUfit and KLfit determined from model simulations. The parameters (R, beta, omega, alpha, and f) determined from model simulations were useful for characterizing the transport of contaminants within the soil matrix. The results of this study provide useful information for the operational parameters of the flushing process for soils with complex contamination. PMID- 25698435 TI - Modifiable predictors of dementia in mild cognitive impairment: a systematic review and meta-analysis. AB - OBJECTIVE: Public health campaigns encouraging early help seeking have increased rates of mild cognitive impairment (MCI) diagnosis in Western countries, but we know little about how to treat or predict dementia outcomes in persons with the condition. METHOD: The authors searched electronic databases and references for longitudinal studies reporting potentially modifiable risk factors for incident dementia after MCI. Two authors independently evaluated study quality using a checklist. Meta-analyses were conducted of three or more studies. RESULTS: There were 76 eligible articles. Diabetes and prediabetes increased risk of conversion from amnestic MCI to Alzheimer's dementia; risk in treated versus untreated diabetes was lower in one study. Diabetes was also associated with increased risk of conversion from any-type or nonamnestic MCI to all-cause dementia. Metabolic syndrome and prediabetes predicted all-cause dementia in people with amnestic and any-type MCI, respectively. Mediterranean diet decreased the risk of conversion to Alzheimer's dementia. The presence of neuropsychiatric symptoms or lower serum folate levels predicted conversion from any-type MCI to all-cause dementia, but less formal education did not. Depressive symptoms predicted conversion from any type MCI to all-cause dementia in epidemiological but not clinical studies. CONCLUSIONS: Diabetes increased the risk of conversion to dementia. Other prognostic factors that are potentially manageable are prediabetes and the metabolic syndrome, neuropsychiatric symptoms, and low dietary folate. Dietary interventions and interventions to reduce neuropsychiatric symptoms, including depression, that increase risk of conversion to dementia may decrease new incidence of dementia. PMID- 25698436 TI - Triparental families: a new genetic-epidemiological design applied to drug abuse, alcohol use disorders, and criminal behavior in a Swedish national sample. AB - OBJECTIVE: The authors sought to clarify the sources of parent-offspring resemblance for drug abuse, alcohol use disorders, and criminal behavior, using a novel genetic-epidemiological design. METHOD: Using national registries, the authors identified rates of drug abuse, alcohol use disorders, and criminal behavior in 41,360 Swedish individuals born between 1960 and 1990 and raised in triparental families comprising a biological mother who reared them, a "not-lived with" biological father, and a stepfather. RESULTS: When each syndrome was examined individually, hazard rates for drug abuse in offspring of parents with drug abuse were highest for mothers (2.80, 95% CI=2.23-3.38), intermediate for not-lived-with fathers (2.45, 95% CI=2.14-2.79), and lowest for stepfathers (1.99, 95% CI=1.55-2.56). The same pattern was seen for alcohol use disorders (2.23, 95% CI=1.93-2.58; 1.84, 95% CI=1.69-2.00; and 1.27, 95% CI=1.12-1.43) and criminal behavior (1.55, 95% CI=1.44-1.66; 1.46, 95% CI=1.40-1.52; and 1.30, 95% CI=1.23-1.37). When all three syndromes were examined together, specificity of cross-generational transmission was highest for mothers, intermediate for not lived-with fathers, and lowest for stepfathers. Analyses of intact families and other not-lived-with parents and stepparents showed similar cross-generation transmission for these syndromes in mothers and fathers, supporting the representativeness of results from triparental families. CONCLUSIONS: A major strength of the triparental design is its inclusion, within a single family, of parents who provide, to a first approximation, their offspring with genes plus rearing, genes only, and rearing only. For drug abuse, alcohol use disorders, and criminal behavior, the results of this study suggest that parent-offspring transmission involves both genetic and environmental processes, with genetic factors being somewhat more important. These results should be interpreted in the context of the strengths and limitations of national registry data. PMID- 25698437 TI - Thirty-Day Mortality After Infection Among Persons With Severe Mental Illness: A Population-Based Cohort Study in Denmark. AB - OBJECTIVE: Persons with severe mental illness die 15-20 years earlier on average than persons without severe mental illness. Although infection is one of the leading overall causes of death, no studies have evaluated whether persons with severe mental illness have a higher mortality after infection than those without. METHOD: The authors studied mortality rate ratios and cumulative mortality proportions after an admission for infection for persons with severe mental illness compared with persons without severe mental illness by linking data from Danish national registries. RESULTS: The cohort consisted of all persons hospitalized for infection during the period 1995-2011 in Denmark (N=806,835), of whom 11,343 persons had severe mental illness. Within 30 days after an infection, 1,052 (9.3%) persons with a history of severe mental illness and 58,683 (7.4%) persons without a history of severe mental illness died. Thirty-day mortality after any infection was 52% higher in persons with severe mental illness than in persons without (mortality rate ratio=1.52, 95% CI=1.43-1.61). Mortality was increased for all infections, and the mortality rate ratios ranged from 1.27 (95% CI=1.15-1.39) for persons hospitalized for sepsis to 2.61 (95% CI=1.69-4.02) for persons hospitalized for CNS infections. Depending on age, 1.7 (95% CI=1.2-2.2) to 2.9 (95% CI=2.0-3.7) more deaths were observed within 30 days after an infection per 100 persons with a history of severe mental illness compared with 100 persons without such a history. CONCLUSIONS: Persons with severe mental illness have a markedly elevated 30-day mortality after infection. Some of these excess deaths may be prevented by offering individualized and targeted interventions. PMID- 25698438 TI - Structural characterization, electrochemical, photoluminescence and thermal properties of potassium ion-mediated coordination polymer. AB - A polymeric potassium complex of p-nitrophenol was synthesized and characterized by analytical and spectroscopic techniques. Molecular structure of the complex was determined by single crystal X-ray diffraction study. X-ray structural data show that crystals contain polymeric K(+) complex of p-nitrophenol. Asymmetric unit consists of one p-nitrophenolate, one K(+) ion and one water molecule. All bond lengths and angles in the phenyl rings have normal Csp2-Csp2 values and are in the expected ranges. The p-nitrophenolate is close to planar with small distortions by some atoms. Each potassium ion in the polymeric structure is identical and eight-coordinate, bonded to four nitro, two phenolate oxygen atoms from five p-nitrophenolate ligands and two oxygen atoms from two water molecules. Electronic, electrochemical, photoluminescence and thermal properties of the complex were also investigated. PMID- 25698439 TI - Binding interaction of differently charged fluorescent probes with egg yolk phosphatidylcholine and the effect of beta-cyclodextrin on the lipid-probe complexes: a fluorometric investigation. AB - Interaction of cationic phenosafranin (PSF), anionic 8-anilino-1-naphthalene sulfonate (ANS) and non-ionic nile red (NR) have been studied with the zwitterionic phospholipid, egg yolk L-alpha-phosphatidylcholine (EYPC). The study reveals discernible binding interactions of the three fluorescent probes with the EYPC lipid vesicle. Once the binding of the probes with the lipid is established, the effect of cyclic oligosaccharide, beta-cyclodextrin (beta-CD), on these lipid bound probes has been investigated. Different fluorometric techniques suggest that addition of beta-CD to the probe-lipid complexes leads to the release of the probes from the lipid medium through the formation of probe-beta-CD inclusion complexes. A competitive binding of the probes between beta-cyclodextrin and the lipid is ascribed to be responsible for the effect. This provides an easy avenue for the removal of the probe molecules from the lipid environment. Extension of this work with drug molecules in cell membranes is expected to give rise to a strategy for the removal of adsorbed drugs from the cell membranes by the use of non-toxic beta-cyclodextrin. PMID- 25698440 TI - New bridged oligofuran for optoelectronic applications. AB - Based on density functional theory (DFT) calculations, we have investigated the structural and optoelectronic properties of oligofuran (OFu)-bridged systems via useful electron donating groups (>S, >CH2, >SiH2 and >NH) and electron accepting ones (>CC(CN)2, >CO, >CS and >CCH2). The results were then discussed and compared with those obtained with the correspondingunbridged form. It was found that the optical band gap of OFu decreases significantly when it is bridged by >NH group arranged through an alternating way with >CS or >CC(CN)2 group, which gives bridged polyfuran (PFu) with desirable opto-electronic properties. Further, an intra-molecular charge transfer for the systems was undertaken in support of time dependent DFT (TD-DFT) and semi-empirical ZINDO calculations. In this frame, we have shown that >CC(CN)2 and >S bridging groups leads to a new oligomer possessing favorable optoelectronic parameter for its use as an active layer in organic photovoltaic cells. PMID- 25698441 TI - Does the Nerium oleander extract PBI-05204 have potential for pancreatic cancer therapy? PMID- 25698442 TI - Phase I and pharmacokinetic study of the novel anthracycline derivative 5-imino 13-deoxydoxorubicin (GPX-150) in patients with advanced solid tumors. AB - PURPOSE: 5-imino-13-deoxydoxorubicin (DIDOX; GPX-150) is a doxorubicin analog modified in two locations to prevent formation of cardiotoxic metabolites and reactive oxygen species. Preclinical studies have demonstrated anti-cancer activity without cardiotoxicity. A phase I study was performed in order to determine the maximum-tolerated dose (MTD) of GPX-150 in patients with metastatic solid tumors. METHODS: GPX-150 was administered as an intravenous infusion every 21 days for up to 8 cycles. An accelerated dose escalation was used for the first three treatment groups. The dosing groups were (A) 14 mg/m(2), (B) 28 mg/m(2), (C), 56 mg/m(2), (D) 84 mg/m(2), (E) 112 mg/m(2), (F) 150 mg/m(2), (G) 200 mg/m(2), and (H) 265 mg/m(2). Pharmacokinetic samples were drawn during the first 72 h of cycle 1. RESULTS: The MTD was considered to be reached at the highest dosing level of 265 mg/m(2) since dose reduction was required in 5 of 6 patients for neutropenia. The most frequent adverse events were neutropenia, anemia, fatigue, and nausea. No patients experienced cardiotoxicity while on the study. The best overall response was stable disease in four (20 %) patients. Pharmacokinetic analysis revealed an AUC of 8.0 (+/-2.6) MUg . h/mL, a clearance of 607 (+/-210) mL/min/m(2) and a t1/2beta of 13.8 (+/-4.6) hours. CONCLUSIONS: GPX-150 administered every 21 days has an acceptable side effect profile and no cardiotoxicity was observed. Further investigation is needed to determine the efficacy of GPX-150 in anthracycline-sensitive malignancies. PMID- 25698443 TI - Stabilization and fabrication of microbubbles: applications for medical purposes and functional materials. AB - Microbubbles with diameters ranging from a few micrometers to tens of micrometers have garnered significant attention in various applications including food processing, water treatment, enhanced oil recovery, surface cleaning, medical purposes, and material preparation fields with versatile functionalities. A variety of techniques have been developed to prepare microbubbles, such as ultrasonication, excimer laser ablation, high shear emulsification, membrane emulsification, an inkjet printing method, electrohydrodynamic atomization, template layer-by-layer deposition, and microfluidics. Generated bubbles should be immediately stabilized via the adsorption of stabilizing materials (e.g., surfactants, lipids, proteins, and solid particles) onto the gas-liquid interface to lower the interfacial tension. Such adsorption of stabilizers prevents coalescence between the microbubbles and also suppresses gas dissolution and resulting disproportionation caused by the presence of the Laplace overpressure across the gas-liquid interface. Herein, we comprehensively review three important topics of microbubbles: stabilization, fabrication, and applications. PMID- 25698444 TI - The CB1 cannabinoid receptor signals striatal neuroprotection via a PI3K/Akt/mTORC1/BDNF pathway. AB - The CB1 cannabinoid receptor, the main molecular target of endocannabinoids and cannabis active components, is the most abundant G protein-coupled receptor in the mammalian brain. In particular, the CB1 receptor is highly expressed in the basal ganglia, mostly on terminals of medium-sized spiny neurons, where it plays a key neuromodulatory function. The CB1 receptor also confers neuroprotection in various experimental models of striatal damage. However, the assessment of the physiological relevance and therapeutic potential of the CB1 receptor in basal ganglia-related diseases is hampered, at least in part, by the lack of knowledge of the precise mechanism of CB1 receptor neuroprotective activity. Here, by using an array of pharmacological, genetic and pharmacogenetic (designer receptor exclusively activated by designer drug) approaches, we show that (1) CB1 receptor engagement protects striatal cells from excitotoxic death via the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin complex 1 pathway, which, in turn, (2) induces brain-derived neurotrophic factor (BDNF) expression through the selective activation of BDNF gene promoter IV, an effect that is mediated by multiple transcription factors. To assess the possible functional impact of the CB1/BDNF axis in a neurodegenerative-disease context in vivo, we conducted experiments in the R6/2 mouse, a well-established model of Huntington's disease, in which the CB1 receptor and BDNF are known to be severely downregulated in the dorsolateral striatum. Adeno-associated viral vector enforced re-expression of the CB1 receptor in the dorsolateral striatum of R6/2 mice allowed the re-expression of BDNF and the concerted rescue of the neuropathological deficits in these animals. Collectively, these findings unravel a molecular link between CB1 receptor activation and BDNF expression, and support the relevance of the CB1/BDNF axis in promoting striatal neuron survival. PMID- 25698445 TI - Slingshot-Cofilin activation mediates mitochondrial and synaptic dysfunction via Abeta ligation to beta1-integrin conformers. AB - The accumulation of amyloid-beta protein (Abeta) is an early event associated with synaptic and mitochondrial damage in Alzheimer's disease (AD). Recent studies have implicated the filamentous actin (F-actin) severing protein, Cofilin, in synaptic remodeling, mitochondrial dysfunction, and AD pathogenesis. However, whether Cofilin is an essential component of the AD pathogenic process and how Abeta impinges its signals to Cofilin from the neuronal surface are unknown. In this study, we found that Abeta42 oligomers (Abeta42O, amyloid-beta protein 1-42 oligomers) bind with high affinity to low or intermediate activation conformers of beta1-integrin, resulting in the loss of surface beta1-integrin and activation of Cofilin via Slingshot homology-1 (SSH1) activation. Specifically, conditional loss of beta1-integrin prevented Abeta42O-induced Cofilin activation, and allosteric modulation or activation of beta1-integrin significantly reduced Abeta42O binding to neurons while blocking Abeta42O-induced reactive oxygen species (ROS) production, mitochondrial dysfunction, depletion of F-actin/focal Vinculin, and apoptosis. Cofilin, in turn, was required for Abeta42O-induced loss of cell surface beta1-integrin, disruption of F-actin/focal Talin-Vinculin, and depletion of F-actin-associated postsynaptic proteins. SSH1 reduction, which mitigated Cofilin activation, prevented Abeta42O-induced mitochondrial Cofilin translocation and apoptosis, while AD brain mitochondria contained significantly increased activated/oxidized Cofilin. In mechanistic support in vivo, AD mouse model (APP (amyloid precursor protein)/PS1) brains contained increased SSH1/Cofilin and decreased SSH1/14-3-3 complexes, indicative of SSH1-Cofilin activation via release of SSH1 from 14-3-3. Finally, genetic reduction in Cofilin rescued APP/Abeta-induced synaptic protein loss and gliosis in vivo as well as deficits in long-term potentiation (LTP) and contextual memory in APP/PS1 mice. These novel findings therefore implicate the essential involvement of the beta1 integrin-SSH1-Cofilin pathway in mitochondrial and synaptic dysfunction in AD. PMID- 25698446 TI - Combined loss of the BH3-only proteins Bim and Bmf restores B-cell development and function in TACI-Ig transgenic mice. AB - Terminal differentiation of B cells depends on two interconnected survival pathways, elicited by the B-cell receptor (BCR) and the BAFF receptor (BAFF-R), respectively. Loss of either signaling pathway arrests B-cell development. Although BCR-dependent survival depends mainly on the activation of the v-AKT murine thymoma viral oncogene homolog 1 (AKT)/PI3-kinase network, BAFF/BAFF-R mediated survival engages non-canonical NF-kappaB signaling as well as MAPK/extracellular-signal regulated kinase and AKT/PI3-kinase modules to allow proper B-cell development. Plasma cell survival, however, is independent of BAFF R and regulated by APRIL that signals NF-kappaB activation via alternative receptors, that is, transmembrane activator and CAML interactor (TACI) or B-cell maturation (BCMA). All these complex signaling events are believed to secure survival by increased expression of anti-apoptotic B-cell lymphoma 2 (Bcl2) family proteins in developing and mature B cells. Curiously, how lack of BAFF- or APRIL-mediated signaling triggers B-cell apoptosis remains largely unexplored. Here, we show that two pro-apoptotic members of the 'Bcl2 homology domain 3-only' subgroup of the Bcl2 family, Bcl2 interacting mediator of cell death (Bim) and Bcl2 modifying factor (Bmf), mediate apoptosis in the context of TACI-Ig overexpression that effectively neutralizes BAFF as well as APRIL. Surprisingly, although Bcl2 overexpression triggers B-cell hyperplasia exceeding the one observed in Bim(-/-)Bmf(-/-) mice, Bcl2 transgenic B cells remain susceptible to the effects of TACI-Ig expression in vivo, leading to ameliorated pathology in Vav-Bcl2 transgenic mice. Together, our findings shed new light on the molecular machinery restricting B-cell survival during development, normal homeostasis and under pathological conditions. Our data further suggest that Bcl2 antagonists might improve the potency of BAFF/APRIL-depletion strategies in B-cell-driven pathologies. PMID- 25698447 TI - Growth differentiation factor-15 encodes a novel microRNA 3189 that functions as a potent regulator of cell death. AB - According to the latest version of miRBase, approximately 30% of microRNAs (miRNAs) are unique to primates, but the physiological function of the vast majority remains unknown. In this study, we identified miR-3189 as a novel, p53 regulated, primate-specific miRNA embedded in the intron of the p53-target gene GDF15. Antagonizing miR-3189 increased proliferation and sensitized cells to DNA damage-induced apoptosis, suggesting a tumor suppressor function for endogenous miR-3189. Identification of genome-wide miR-3189 targets revealed that miR-3189 directly inhibits the expression of a large number of genes involved in cell cycle control and cell survival. In addition, miR-3189 downregulated the expression of multiple p53 inhibitors resulting in elevated p53 levels and upregulation of several p53 targets including p21 (CDKN1A), GADD45A and the miR 3189 host gene GDF15, suggesting miR-3189 auto-regulation. Surprisingly, miR-3189 overexpression in p53-/- cells upregulated a subset of p53-targets including GDF15, GADD45A, and NOXA, but not CDKN1A. Consistent with these results, overexpression of miR-3189 potently induced apoptosis and inhibited tumorigenicity in vivo in a p53-independent manner. Collectively, our study identified miR-3189 as a novel, primate-specific miRNA whose effects are mediated by both p53-dependent and p53-independent mechanisms. miR-3189 may, therefore, represent a novel tool that can be utilized therapeutically to induce a potent proapoptotic effect even in p53-deficient tumors. PMID- 25698448 TI - JMJD3 promotes SAHF formation in senescent WI38 cells by triggering an interplay between demethylation and phosphorylation of RB protein. AB - Primary human fibroblasts undergoing oncogene-induced or replicative senescence are known to form senescence-associated heterochromatin foci (SAHF), which can stabilize the state of senescence. The retinoblastoma (RB) protein has an important role in SAHF; cells that lack active RB pathway fail to form SAHF. It has been known that the posttranslational modifications of RB, for example, phosphorylation, regulate its function. To date, whether methylation of RB impacts on the SAHF formation is unknown. Here we report that JMJD3, a histone demethylase catalyzing the tri-methylation of H3K27 (H3K27me3), can demethylate the non-histone protein RB at the lysine810 residue (K810), which is a target of the methyltransferase Set7/9. We detected a significant upregulation of JMJD3 during cellular senescence and SAHF formation in WI38 cells induced by H RasV(12), and we found that ectopic expression of JMJD3 promoted cellular senescence and SAHF formation in WI38 cells. Furthermore, during the process of SAHF assembly, JMJD3 was transported to the cytoplasm and interacted with RB through its demethylase domain JmjC. Significantly, our data demonstrated that the JMJD3-mediated demethylation of RB at K810 impeded the interaction of RB with the protein kinase CDK4 and resulted in reduced level of phosphorylation of RB at Serine807/811 (S807/811), implicating an important role of the interplay between the demethylation and phosphorylation of RB in SAHF assembly. This study highlights the role of JMJD3 as a novel inducer of SAHF formation through demethylating RB and provides new insights into the mechanisms of cellular senescence and SAHF assembly. PMID- 25698449 TI - Corrigendum: Efficient genome engineering by targeted homologous recombination in mouse embryos using transcription activator-like effector nucleases. PMID- 25698450 TI - Similar survival rates with first-line gefitinib, gemcitabine, or docetaxel in a randomized phase II trial in elderly patients with advanced non-small cell lung cancer and a poor performance status (IFCT-0301). AB - OBJECTIVES: We evaluated the impact of age in a randomized phase II trial that compared three first-line drugs in elderly patients with advanced non-small cell lung cancer (NSCLC) and a poor performance status (PS). MATERIALS AND METHODS: Patients with advanced NSCLC with a PS of 2 or 3 were enrolled into a multicenter randomized trial: arm A, gefitinib; arm B, gemcitabine; and arm C, docetaxel. We performed subgroup analyses according to age. RESULTS: Between December 2004 and June 2007, 127 patients were enrolled. Analyses were performed between the two subgroups aged <70years (younger, n=56) and >=70years (older, n=71). Patients mainly had adenocarcinoma (46% young vs. 51%: elderly), of which 62% vs. 75% had a PS of 2, respectively. Significantly more elderly patients were women and non smokers, and there was a non-significant trend towards more PS-2 among the elderly. Progression-free survival (PFS) was 1.4months (95% CI: 1.1-1.9) for younger compared to 2.3months (95% CI: 2.1-2.9) for elderly patients. Overall survival (OS) was 2.0months (95% CI: 1.5-2.4) and 3.7months (95% CI: 2.4-4.8), respectively. Toxicity did not differ between younger and older patients. NSCLC was better controlled in elderly patients after three cycles of monotherapy compared to younger patients (p=0.034). When adjusted for stratification criteria, age was the main prognostic factor for PFS. Adjusted HRs for PFS was 0.57 (95% CI: 0.38-0.85) for the elderly compared to patients aged <70years (p=0.004). CONCLUSIONS: Older patients had a decreased risk of progression/death compared to younger patients. Single-agent chemotherapy can be considered for patients aged >=70years with a PS of 2. PMID- 25698451 TI - Trends in bone mineral density in young adults with cystic fibrosis over a 15 year period. AB - BACKGROUND: Improvements in clinical care have led to increased life expectancy in patients with cystic fibrosis (CF) over the past several decades. Whether these improvements have had significant effects on bone health in patients with CF is unclear. METHODS: This is a cross-sectional study comparing clinical characteristics and bone mineral density (BMD) measured by dual energy X-ray absorptiometry (DXA) in adults with CF evaluated in 1995-1999 to age-, race-, and gender-matched patients with CF evaluated in 2011-2013 at the same center on calibrated DXA machines. RESULTS: The cohorts were similar in terms of age, BMI, pancreatic insufficiency, presence of F508del mutation, and reproductive history. In the most recent cohort, pulmonary function was superior, and fewer patients had vitamin D deficiency or secondary hyperparathyroidism. Areal BMD measures of the PA spine, lateral spine, and distal radius were similarly low in the two cohorts. CONCLUSIONS: Although pulmonary function and vitamin D status were better in patients in the present-day cohort, areal BMD of the spine was reduced in a significant number of patients and was no different in patients with CF today than in the late 1990s. Further attention to optimizing bone health may be necessary to prevent CF-related bone disease. PMID- 25698452 TI - Equivalent substrates enable simultaneous study of gastrointestinal pH and CF related diabetes. PMID- 25698453 TI - Ivacaftor as salvage therapy in a patient with cystic fibrosis genotype F508del/R117H/IVS8-5T. AB - Ivacaftor is a novel CFTR potentiator that increases CFTR activity and improves clinical outcomes in cystic fibrosis (CF) patients with at least one copy of CFTR G551D. Clinical trials have shown an improvement in lung function, weight and CF pulmonary exacerbation in adults with CFTR-G551D leading to the approval of ivacaftor as a novel CF therapy [1]. In vitro studies of ivacaftor have also shown significant improvements in CFTR chloride channel opening time in other non G551D CFTR mutations suggesting that ivacaftor may be of benefit to patients with mutations other than gating mutations [2]. R117H-CFTR is a relatively common CFTR mutation that demonstrates an in-vitro response to ivacaftor [2,3]. A clinical trial has suggested that there may be a role for ivacaftor in older patients with R117H-CFTR although this trial did not include patients with very severe CF lung disease [4]. In 2014, ivacaftor was approved in the United States as a treatment for CF subjects aged greater than 6 years old with a copy of R117H-CFTR. We present a case demonstrating a substantial therapeutic effect of ivacaftor in a CF patient with genotype F508del/R117H and advanced lung disease. PMID- 25698454 TI - Abacavir/dolutegravir/lamivudine single-tablet regimen: a review of its use in HIV-1 infection. AB - A fixed-dose, single-tablet regimen comprising the integrase strand transfer inhibitor (INSTI) dolutegravir and the nucleos(t)ide reverse transcriptase inhibitors (NRTIs) abacavir and lamivudine (abacavir/dolutegravir/lamivudine; Triumeq(r)) is now available for the treatment of HIV-1 infection. In a randomized, double-blind, phase III trial in antiretroviral therapy (ART)-naive adults (SINGLE), once-daily dolutegravir plus abacavir/lamivudine had noninferior efficacy to once-daily efavirenz/tenofovir disoproxil fumarate (tenofovir DF)/emtricitabine with regard to establishing and sustaining virological suppression over 144 weeks, and subsequent superiority testing significantly favoured dolutegravir plus abacavir/lamivudine. This outcome was predominantly driven by more favourable rates of discontinuation due to adverse events versus the efavirenz/tenofovir DF/emtricitabine group. These data were generally supported by findings from other phase III trials in ART-naive adults receiving dolutegravir plus either abacavir/lamivudine or tenofovir DF/emtricitabine (SPRING-2 and FLAMINGO). Dolutegravir plus abacavir/lamivudine is generally well tolerated, with a tolerability profile that appears to be more favourable than efavirenz/tenofovir DF/emtricitabine. In the SINGLE trial, there were no major treatment-emergent INSTI or NRTI resistance-associated mutations in dolutegravir plus abacavir/lamivudine recipients with protocol-defined virological failure, indicating a high genetic barrier to resistance. Thus, triple combination therapy with abacavir, dolutegravir and lamivudine is an effective, generally well tolerated option for the management of HIV-1 infection, with the convenient once daily fixed-dose tablet providing the first single-tablet regimen option without tenofovir DF. PMID- 25698455 TI - Early detection of melanoma: reviewing the ABCDEs. AB - Over the course of their nearly 30-year history, the ABCD(E) criteria have been used globally in medical education and in the lay press to provide simple parameters for assessment of pigmented lesions that need to be further evaluated by a dermatologist. In this article, the efficacy and limitations of the ABCDE criteria as both a clinical tool and a public message will be reviewed. PMID- 25698456 TI - An examination of prostate cancer trends in Australia, England, Canada and USA: Is the Australian death rate too high? AB - PURPOSE: To compare prostate cancer incidence and mortality rates in Australia, USA, Canada and England and quantify the gap between observed prostate cancer deaths in Australia and expected deaths, using US mortality rates. METHODS: Analysis of age-standardised prostate cancer incidence and mortality rates, using routinely available data, in four similarly developed countries and joinpoint regression to quantify the changing rates (annual percentage change: APC) and test statistical significance. Expected prostate cancer deaths, using US mortality rates, were calculated and compared with observed deaths in Australia (1994-2010). RESULTS: In all four countries, incidence rates initially peaked between 1992 and 1994, but a second, higher peak occurred in Australia in 2009 (188.9/100,000), rising at a rate of 5.8 % (1998-2008). Mortality rates in the USA (APC: -2.9 %; 2004-2010), Canada (APC: -2.9 %; 2006-2011) and England (APC: 2.6 %; 2003-2008) decreased at a faster rate compared with Australia (APC: -1.7 %; 1997-2011). In 2010, mortality rates were highest in England and Australia (23.8/100,000 in both countries). The mortality gap between Australia and USA grew from 1994 to 2010, with a total of 10,895 excess prostate cancer deaths in Australia compared with US rates over 17 preceding years. CONCLUSIONS: Prostate cancer incidence rates are likely heavily influenced by prostate-specific antigen testing, but the fall in mortality occurred too soon to be solely a result of testing. Greater emphasis should be placed on addressing system-wide differences in the management of prostate cancer to reduce the number of men dying from this disease. PMID- 25698457 TI - [Systemic lupus erythematosus and a medical history of deep vein thrombosis in a 27-year-old pregnant woman]. AB - The case of a 27-year-old pregnant woman (gravidity I, parity 0) diagnosed with systemic lupus erytematosus with SS-A-antibodies, activated protein C resistance, and a heterozygous factor V Leiden mutation is presented. Thus, the pregnancy was considered a high-risk pregnancy. Many complications are associated with these diseases, which is why the pregnant woman and her unborn baby needed increased surveillance by internists and obstetricians (laboratory values, clinical symptoms, ultrasound examination). Her current medication with hydroxychloroquine was continued. In addition, low molecular weight heparin was given for thromboprophylaxis. PMID- 25698458 TI - Relationship between work strain, need for recovery after work and cumulative cortisol among kindergarten teachers. AB - OBJECTIVES: The purpose of this study was to explore whether work strain (i.e., job demands and job control) and subjective need for recovery (NFR) after work are related to measured concentration of cumulative cortisol. METHODS: Participants were 43 teachers recruited from kindergarten. They self-reported their NFR, job demands and job control over the last month. NFR was measured with the NFR scale. Job demands and control were assessed with the Chinese version of the Job Content Questionnaire. Hair cortisol was used to represent cumulative cortisol excretion. Hair cortisol concentration (HCC) was measured with high performance liquid chromatography-tandem mass spectrometry. RESULTS: No significant correlations were found between job demands or job control and HCC. NFR was significantly and inversely correlated with HCC (r = -0.41, p = 0.006). The inverse association between NFR and HCC remained significant when age and job demands and job control were controlled for (p = 0.02). CONCLUSIONS: The activity of the hypothalamic-pituitary-adrenal axis declines with the accumulation of NFR after working time. PMID- 25698459 TI - Supraglottoplasty for sleep endoscopy diagnosed sleep dependent laryngomalacia. AB - OBJECTIVES: To evaluate the polysomnographic outcomes of supraglottoplasty (SGP) performed for sleep endoscopy diagnosed sleep dependent laryngomalacia as treatment for obstructive sleep apnea syndrome (OSAS). METHODS: Nine subjects aged 6-55 months underwent supraglottoplasty for sleep dependent laryngomalacia. All subjects underwent both pre- and post-procedural polysomnograms. RESULTS: Supraglottoplasty for sleep dependent laryngomalacia resulted in improvement of OSAS as measured by collective improvements in 8 different primary polysomnogram parameters: apnea-hypopnea index (AHI), minimum (nadir) and mean oxygen saturation, mean and maximum carbon dioxide, total sleep time, sleep efficiency, arousal index, as well as improvement in weight for length percentiles. Subjects had a significant 80% decrease in percentage change in AHI (p<0.005), with decrease in mean AHI from 23.4 to 4.8 following supraglottoplasty. Seven of 9 subjects demonstrated improvement in nadir saturations, 6 of 9 subjects had improvement in sleep efficiency, and 7 of 8 subjects under 4 years of age had improvement in weight for length percentile. CONCLUSIONS: Supraglottoplasty for sleep dependent laryngomalacia is an effective treatment of OSAS, and can be readily diagnosed using sleep endoscopy. Further investigation is warranted to increase awareness and outcomes related to sleep dependent laryngomalacia. PMID- 25698460 TI - The effectiveness of nurse-led outpatient referral triage decision making in pediatric otolaryngology. AB - OBJECTIVES: To assess the effectiveness of nurse-led triage of outpatient referrals in an academic pediatric otolaryngology practice. METHODS: Three hundred consecutive outpatient referrals were reviewed and triaged by two otolaryngology registered nurses and two attending pediatric otolaryngologists. The nurses received triage training. The referrals were triaged as 'routine' (to be seen within 2-3 months), 'semi-urgent' (to be seen within 6 weeks), or 'urgent' (to be seen within 2 weeks). Weighted Kappa statistics (correcting for chance agreement) were performed to assess for the degree of agreement. After the consultation visits, patient records were reviewed to determine whether any referrals had been inappropriately triaged by the nurses. RESULTS: Overall, there was substantial agreement between all raters. Specifically, weighted Kappa statistics were as follows: surgeon 1, nurse 1: 0.708; surgeon 1, nurse 2: 0.670; surgeon 2, nurse 1: 0.762; surgeon 2, nurse 2: 0.647; nurse 1, nurse 2: 0.756; and surgeon 1, surgeon 2: 0.784. Review of patient charts after consultation showed that no referrals were deemed to be inappropriately triaged and no urgent cases had been missed. CONCLUSIONS: Our model of nurse-led triage of outpatient referrals was found to be effective and safe. Similar systems may be considered in other areas of medicine as a viable and acceptable alternative to the traditional physician-led triage practice. PMID- 25698461 TI - Postoperative adjuvant OK-432 sclerotherapy for treatment of cervicofacial lymphatic malformations: an outcomes comparison. AB - OBJECTIVES: Surgical treatment of extensive cervicofacial lymphatic malformations is often challenging due to a high rate of postoperative fluid re-accumulation and lesion recurrence resulting from incomplete resection. This study suggests a combined treatment of surgical resection and postoperative adjuvant OK-432 sclerotherapy via closed suction drainage. Using comparative analysis, this study aims to evaluate the efficacy of adjuvant sclerotherapy. METHODS: A retrospective chart review was performed on patients who underwent surgical resection of cervicofacial lymphatic malformations between January 2009 and July 2013. Patients were divided into two groups based on whether or not adjuvant OK-432 sclerotherapy was administered via closed suction drainage after surgery. Both surgery-related and adjuvant sclerotherapy-related complications were assessed, and treatment effectiveness was measured based on the change in Cologne Disease Score (CDS) or the need for further treatment. RESULTS: A total of 17 patients underwent surgical resection. Nine of these patients underwent surgical resection only, while the other eight underwent surgical resection with adjuvant OK-432 sclerotherapy. The increase in total Cologne Disease Score (CDS) and change of progression parameters were significantly higher for the adjuvant sclerotherapy group compared to the surgery-only group. Additionally, there were no cases of postoperative lymphatic fluid retention among the adjuvant sclerotherapy group. The two groups exhibited similar complication rates with no statistically significant difference. CONCLUSIONS: Adjuvant OK-432 sclerotherapy via closed suction drainage is a safe and effective treatment modality. The combination of surgical resection and post-operative adjuvant sclerotherapy via closed suction drainage should be integrated into the treatment algorithm of extensive cervicofacial lymphatic malformation. PMID- 25698462 TI - The original SPF10 LiPA25 algorithm is more sensitive and suitable for epidemiologic HPV research than the SPF10 INNO-LiPA Extra. AB - Two commercial HPV tests target the same 65 bp fragment of the human papillomavirus genome (designated SPF10): the original HPV SPF10 PCR-DEIA-LiPA25 system, version 1, (LiPA25) and the INNO-LiPA HPV Genotyping Extra (INNO-LiPA). The original SPF10 LiPA25 system was designed to have high analytical sensitivity and applied in HPV vaccine and epidemiology studies worldwide. But due to apparent similarities, this test can be easily confused with INNO-LiPA, a more recent assay of which the intended use, i.e., epidemiological or clinical, is currently unclear. The aim was to compare the analytical sensitivity of SPF10 LiPA25 to that of INNO-LiPA on the level of general HPV detection and genotyping. HPV testing by both assays was performed on the same DNA isolated from cervical swab (n = 365) and biopsy (n = 42) specimens. In cervical swabs, SPF10 LiPA25 and INNO-LiPA identified 35.3% and 29.3% multiple infections, 52.6% and 51.5% single infections, and no HPV type in 12.1% and 19.2%, respectively. Genotyping results were 64.7% identical, 26.0% compatible and 9.3% discordant between both methods. SPF10 LiPA25 detected significantly more genotypes (p < 0.001). The higher analytical sensitivity of SPF10 LiPA25 was confirmed by the MPTS123 genotyping assay. HPV positivity by the general probes in SPF10 DEIA was significantly higher (87.9%) than by those on INNO-LiPA (77.0%) (kappa = 0.592, p < 0.001). In cervical biopsies, SPF10 LiPA25 and INNO-LiPA identified 21.4% and 9.5% multiple types, 76.2% and 81.0% single types, and no type in 2.4% and 9.5%, respectively. Between both tests, the identification of genotypes was 76.3% identical, 14.3% compatible and 9.5% discordant. Overall, significantly more genotypes were detected by SPF10 LiPA25 (kappa = 0.853, p = 0.022). HPV positivity was higher by the SPF10 DEIA (97.6%) than by the INNO-LiPA strip (92.9%). These results demonstrate that SPF10 LiPA25 is more suitable for HPV genotyping in epidemiologic and vaccine-related studies, due to its higher analytical sensitivity. PMID- 25698463 TI - Recovery of murine norovirus and feline calicivirus from plasmids encoding EMCV IRES in stable cell lines expressing T7 polymerase. AB - Reverse genetics systems constitute one of the most important and powerful tools to study the molecular biology of viruses. We developed a new strategy for the recovery of murine norovirus from a single plasmid in which a bacteriophage T7 RNA polymerase (T7pol) promoter for transcription and an EMCV IRES for efficient translation were engineered immediately upstream of the viral genome. Infectious noroviruses were recovered following transfection of the newly designed plasmid into nonpermissive BHK-21 and HEK293T cell lines that were engineered to express T7pol constitutively. Recovery of the virus did not require the presence of a ribozyme at the 3'-end of the virus genome. The strategy worked also for the efficient recovery of feline calicivirus in these normally nonpermissive cell types. This simplified reverse genetics approach may be broadly applicable to other caliciviruses. PMID- 25698464 TI - Specific rolling circle amplification of low-copy human polyomaviruses BKV, HPyV6, HPyV7, TSPyV, and STLPyV. AB - Eleven new human polyomaviruses have been recently discovered, yet for most of these viruses, little is known of their biology and clinical impact. Rolling circle amplification (RCA) is an ideal method for the amplification of the circular polyomavirus genome due to its high fidelity amplification of circular DNA. In this study, a modified RCA method was developed to selectively amplify a range of polyomavirus genomes. Initial evaluation showed a multiplexed temperature-graded reaction profile gave the best yield and sensitivity in amplifying BK polyomavirus in a background of human DNA, with up to 1 * 10(8) fold increases in viral genomes from as little as 10 genome copies per reaction. Furthermore, the method proved to be more sensitive and provided a 200-fold greater yield than that of random hexamers based standard RCA. Application of the method to other novel human polyomaviruses showed successful amplification of TSPyV, HPyV6, HPyV7, and STLPyV from low-viral load positive clinical samples, with viral genome enrichment ranging from 1 * 10(8) up to 1 * 10(10). This directed RCA method can be applied to selectively amplify other low-copy polyomaviral genomes from a background of competing non-specific DNA, and is a useful tool in further research into the rapidly expanding Polyomaviridae family. PMID- 25698465 TI - Characterization of vesicular stomatitis virus populations by tunable resistive pulse sensing. AB - Although transmission electron microscopy (TEM) has historically been the method of choice to estimate concentrations of virus and virus-like particles, these measures can often be time-consuming and labor-intensive to perform. Tunable resistive pulse sensing (TRPS) is an emerging method that applies principles of Coulter counting to nanoscale particles and may provide a simpler and higher throughput alternative to TEM for the quantitation of virus populations. To assess the performance of TRPS compared to TEM, the samples of polymer spheres at a diameter of 100nm and vesicular stomatitis virus (VSV) were characterized using both techniques. TRPS was able to quantify concentrations down to 10(7)particles/ml, providing nearly 50-fold larger measurement range, and more reproducible counts than TEM. Total-to-infectious particle ratio of VSV populations as measured by TRPS and plaque assay suggested that each VSV particle is infectious. In addition to particle counts, TRPS successfully measured particle size distributions based on hundreds of particles. Such high throughput sustained by TRPS can assist quantitative characterization of virus populations. PMID- 25698466 TI - An efficient approach for recombinant expression and purification of the viral capsid protein from beak and feather disease virus (BFDV) in Escherichia coli. AB - Structural insights into the biology of viruses such as beak and feather disease virus (BFDV) which do not replicate in cell cultures are increasingly reliant on recombinant methods for protein production and purification. Development of efficient methods for homogenous production of BFDV capsid protein is also essential for vaccine development and diagnostic purposes. In this study, two different plasmids (pMCSG21 and pMCSG24), three homologous BFDV capsid proteins, and two unique expression media (auto-induction and IPTG-induced expression) were trialled for over-expression of the BFDV in Escherichia coli. Over-expression was observed for all three recombinant targets of BFDV capsid protein using E. coli BL21 (DE3) Rosetta 2 cell lines under IPTG induction. These proteins could be purified using an optimized, two-step purification process using a buffer containing 20mM N-cyclohexyl-3-aminopropanesulfonic acid (CAPS), 500 mM NaCl and supplemented with 200 mM L-arginine at pH 10.5, to yield a soluble and stable protein of greater than 95% purity. The final concentration of purified protein was approximately fourteen-to-eighteen fold greater than that reported previously. Initial crystallization and X-ray diffraction confirm that the protein is structured in a manner consistent with icosahedral symmetry. Antigenicity of recombinant Cap was confirmed by immunoassay, verifying its validity for use in continued experimentation as a potential DNA vaccine, a reagent in diagnostic assays, and purified concentrated protein for structural and functional biology. PMID- 25698467 TI - Lanthanide derivatives comprising arylhydrazones of beta-diketones: cooperative E/Z isomerization and catalytic activity in nitroaldol reaction. AB - Two complexes [KLa(HL(1))2{(CH3)2NCHO}2(H2O)3] (1) and [Sm(H2O)9](E-H2L(2))3.2H2O (2) were synthesized by the reaction of lanthanum(III) and samarium(III) nitrates with potassium 3-(2-(2,4-dioxopentan-3-ylidene)hydrazinyl)-2-hydroxy-5 nitrobenzenesulfonate (KH2L(1)) and potassium (E,Z)-5-chloro-3-(2-(1,3-dioxo-1 phenylbutan-2-ylidene)hydrazinyl)-2-hydroxybenzenesulfonate (KH2L(2)), respectively. Both complexes were fully characterized by elemental analysis, IR, (1)H and (13)C NMR spectroscopy, ESI-MS and single-crystal X-ray diffraction. Cooperative E,Z->E isomerization of KH2L(2), induced by resonance assisted hydrogen bonding and ionic interactions, occurs upon the interaction with Sm(III). Catalytic activities of KH2L(1,2) and their lanthanide derivatives were evaluated in the Henry reaction of nitroethane with a variety of aromatic and aliphatic aldehydes. Good yields (up to 91%) and diastereoselectivities (syn/anti 3 : 1) were observed in the reactions catalyzed by 1 in water. PMID- 25698468 TI - Isolated skeletal muscle metastatic deposit in a patient with micropapillary carcinoma thyroid identified by 18F FDG PET CT. AB - Micropapillary carcinoma of thyroid is said to be low risk differentiated thyroid malignancy with excellent prognosis. We report the identification of an isolated FDG avid muscle deposit in a treated case of micropapillary carcinoma of the right lobe and widely invasive follicular carcinoma of the left lobe thyroid gland. Patient was found to have an elevated thyroglobulin level with negative iodine scan (TENIS syndrome) on follow up at 6 months. An 18F FDG PET CT (18 fluorine-fluorodeoxyglucose positron emission computed tomography) whole body study revealed a solitary FDG avid deltoid muscle deposit which was histopathologically confirmed to be metastatic papillary carcinoma. While follicular carcinoma is known to have distant metastases, this may be the first reported case of solitary skeletal metastases from micropapillary carcinoma of thyroid and probably the second reported skeletal muscle deposit from DTC detected on 18F FDG PET CT done following elevated thyroglobulin level and negative 131 iodine WB scan (TENIS). This case also assumes importance because it demonstrates possibility of metastases even from a micropapillary carcinoma in contrast to American Thyroid Association guidelines (2009) which suggests that micropapillary carcinoma of thyroid does not merit further treatment after a Total Thyroidectomy. PMID- 25698469 TI - Contextual reminders fail to trigger memory reconsolidation in aged rats and aged humans. AB - There is strong evidence that hippocampal memory returns to a labile state upon reactivation, initiating a reconsolidation process that restabilizes it and allows for its updating. Normal aging is associated with deficits in episodic memory processes. However, the effects of aging on memory reconsolidation and its neural substrate remain largely unknown, and an animal model is lacking. In this study we investigated the effects of aging on context-dependent reconsolidation using an episodic set-learning task in humans and an analogous set-learning spatial task in rats. In both tasks, young and older subjects learned a set of objects (humans) or feeder locations (rats; Set 1) in Context A on Day 1. On Day 2, a different set (Set 2) was learned in either Context A (Reminder condition) or Context B (No Reminder condition). On Day 3, subjects were instructed (humans) or cued (rats) to recall Set 1. Young rats and humans in the Reminder condition falsely recalled significantly more items from Set 2 than those in the No Reminder condition, suggesting that the reminder context triggered a reactivation of Set 1 on Day 2 and allowed the integration of Set 2 items into Set 1. In both species, older subjects displayed a different pattern of results than young subjects. In aged rats, there was no difference between conditions in the level of falsely recalled Set 2 items (intrusions). Older humans in the No Reminder condition made significantly more intrusions than those in the Reminder condition. Follow-up control experiments in aged rats suggested that intrusions in older animals reflected general interference, independent of context manipulations. We conclude that contextual reminders are not sufficient to trigger memory updating in aged rats or aged humans, unlike in younger individuals. Future studies using this animal model should further our understanding of the role of the hippocampus in memory maintenance and updating during normal aging. PMID- 25698470 TI - Linear relation between spirometric volume and the motion of cardiac structures: MRI and clinical PET study. AB - BACKGROUND: In cardiac PET, CT, and MRI respiration is major reason for impaired image quality of small targets such as coronary arteries. Strong correlations between heart motion and respiratory signals have been detected but quantitative relation between signals and motion of cardiac structures in MRI or PET is not reported . METHODS: Relation between spirometric lung volume or pressure belt signal and motion of coronary vessels in MRI was studied on nine healthy volunteers. Spirometry was further applied to (18)F-FDG cardiac PET study to determine quantitative relation between volume change and motion of center of myocardium activity (CMA) on nine CAD patients. RESULTS: Correlation coefficients (CC) between vessel motions and volume or pressure changes were 0.90-0.92 or 0.86 0.84, respectively. The linear equations based on volume or pressure changes derived 2.0-2.6 or 2.9-3.3 mm mean estimation error for vessel motions. In PET CC value of 0.93 was determined between volume changes and CMA motions. The linear equation based on volume change derived maximum estimation error of 2.5 mm for CMA motion. CONCLUSION: The spirometric volume change linearly estimates motion of myocardium in PET with good accuracy and have potential to guide selection of optimal number of respiratory gates in cardiac PET. PMID- 25698471 TI - Automatic registration of misaligned CT attenuation correction maps in Rb-82 PET/CT improves detection of angiographically significant coronary artery disease. AB - BACKGROUND: We aimed to evaluate the utility of fully automated software registration intended to improve CT attenuation correction (CTAC) map misalignments during cardiac (82)Rb PET/CT myocardial perfusion imaging (MPI). METHODS: 171 consecutive patients (108 males, mean age 69 years), undergoing both rest-stress (82)Rb PET/CT MPI and invasive coronary angiography within 6 months (mean 14 days, range 0-170), were studied. List mode data were automatically processed in batch mode to generate transaxial attenuation corrected slices with four different CTAC alignment correction strategies: (i) no alignment correction (NONE); (ii) manual correction (MANUAL); (iii) automated 6-parameter rigid correction (AUTO); and (iv) targeted use of automated correction only where PET CTAC alignment was initially judged as incorrect on either stress or rest scan (AUTO for misalignment only). Initial and final registration quality was graded (1-3) by an experienced radiologist (1: satisfactory alignment (<2 mm misalignment), 2: slight misalignment (2-5 mm in any direction), or 3: poor (>5 mm misalignment in any direction). Total perfusion deficit (TPD) and ischemic TPD (ITPD) were computed automatically, and their diagnostic accuracy to detect significant coronary artery disease with each realignment technique was assessed using receiver operating characteristic analysis. RESULTS: The diagnostic accuracy of ITPD, expressed as area under curve, was .81 +/- .03 with no alignment correction (NONE), .83 +/- .03 with MANUAL correction, .85 +/- .03 with AUTO correction (P < .05 vs. NONE and MANUAL), and .87 +/- .03 with the targeted use of AUTO correction (P < .05 vs. NONE, MANUAL and AUTO). Both manual and software corrections increased the percentage of cases with satisfactory PET-CTAC map alignment (P < .05 for all) at rest (from 55% for NONE to 80% for MANUAL and 92% for AUTO) and at stress (from 51% for NONE to 78% for MANUAL and 84% for AUTO). CONCLUSION: The diagnostic accuracy of (82)Rb PET/CT MPI with automated rigid alignment is improved compared to data with no CTAC scan alignment or with manual alignment. The optimal strategy for diagnostic performance is to apply automatic alignment only in cases which are visually identified as misaligned. PMID- 25698472 TI - Feasibility of [18F]-RGD for ex vivo imaging of atherosclerosis in detection of alphavbeta3 integrin expression. AB - BACKGROUND: Inflammation and angiogenesis play an important role in atherosclerotic plaque rupture. Therefore, molecular imaging of these processes could be used for determination of rupture-prone atherosclerotic plaques. alphavbeta3 integrin is involved in the process of angiogenesis. Targeted imaging of alphavbeta3 integrin has been shown to be possible in previous studies on tumor models, using radiolabeled arginine-glycine-aspartate (RGD). Our aim was to investigate feasibility of ex vivo detection of alphavbeta3 integrin in carotid endarterectomy (CEA) specimens. METHODS AND RESULTS: Nineteen CEA specimens were incubated in 5 MBq [18F]-RGD-K5 for 1 hour followed by 1 hour emission microPET scan. The results were quantified in 4 mm wide segments as percent incubation dose per gram (%Inc/g). Segmental-to-total ratio was calculated and presence of alphavbeta3 integrin and endothelial cells in each segment was confirmed by immunohistochemical staining for CD31 and alphavbeta3 integrin, respectively. [18F]-RGD-K5 uptake was heterogeneously distributed across CEA specimens and was localized within the vessel wall. Significant correlations were observed between segmental-to-total ratio with alphavbeta3 integrin staining score (r = 0.58, P = .038) and CD31 staining score (rho = 0.67, P < .002). CONCLUSION: This study showed the feasibility of integrin imaging by determination of alphavbeta3 integrin expression in human atherosclerotic plaques. PMID- 25698473 TI - Gated blood pool SPECT: The estimation of right ventricular volume and function is algorithm dependent in a clinical setting. AB - BACKGROUND: Gated blood pool SPECT (GBPS) requires further validation for the assessment of the right ventricle (RV). This study evaluated three algorithms: BP SPECT, QBS, and TOMPOOL (results are referred using this order). We compared (1) their "quantitative-accuracy": estimation of RV ejection fraction (EF), end diastolic volume (EDV), and cardiac output (CO); (2) their "qualitative accuracy": threshold values allowing diagnosing an impairment of the RV function; (3) their reproducibility: inter-observer relative variability (IOV). METHODS AND RESULTS: Forty-eight consecutive patients underwent GBPS. Recommended reference standards were used: cardiac magnetic resonance imaging (CMR) (EDV, EF, n = 48), catheter measurements from thermodilution (TD) (CO, n = 25). (1) "Quantitative accuracy": r = 0.42, 0.30, 0.42 for RVEF (CMR); r = 0.69, 0.77, 0.53 for RVEDV (CMR); 0.32, 0.36, 0.52 for RCO (TD). (2) "Qualitative-accuracy": optimal thresholds were 54.7%, 38.5%, 45.2% (AUC: 0.83, 0.80, 0.79) for RVEF; 229, 180, 94 mL (AUC: 0.83, 0.81, 0.81) for RVEDV; 4.1, 4.4, 2.6 L.minute(-1) (AUC: 0.73, 0.77, 0.80) for RCO. (3) Reproducibility: IOV was 5% +/- 6%, 8% +/- 12%, 17% +/- 18% for RVEF; 6% +/- 8%, 4% +/- 4%, 21% +/- 18% for RVEDV; 8% +/- 8%, 11% +/- 15%, 24% +/- 20% for RCO. CONCLUSION: Diagnostic accuracies are similar. A CMR based calibration is required for a quantitative-analysis (cautious interpretation) or an accurate qualitative analysis (thresholds must be adjusted). Automatic procedures (BP-SPECT, QBS) offer the best compromise accuracy/reproducibility. PMID- 25698474 TI - Direct visualization of regional cardiac sympathetic dysfunction in stress induced cardiomyopathy. PMID- 25698475 TI - Cardiac remodeling in a new pig model of chronic heart failure: Assessment of left ventricular functional, metabolic, and structural changes using PET, CT, and echocardiography. AB - AIMS: Large animal models are needed to study disease mechanisms in heart failure (HF). In the present study we characterized the functional, metabolic, and structural changes of myocardium in a novel pig model of chronic myocardial infarction (MI) by using multimodality imaging and histology. METHODS AND RESULTS: Male farm pigs underwent a two-step occlusion of the left anterior descending coronary artery with concurrent distal ligation and implantation of a proximal ameroid constrictor (HF group), or sham operation (control group). Three months after the operation, cardiac output and wall stress were measured by echocardiography. Left ventricle (LV) volumes and mass were measured by computed tomography (CT). Myocardial perfusion was evaluated by [(15)O]water and oxygen consumption using [(11)C]acetate positron emission tomography, and the efficiency of myocardial work was calculated. Histological examinations were conducted to detect MI, hypertrophy, and fibrosis. Animals in the HF group had a large anterior MI scar. CT showed larger LV diastolic volume and lower ejection fraction in HF pigs than in controls. Perfusion and oxygen consumption in the remote non-infarcted myocardium were preserved in HF pigs as compared to controls. Global LV work and efficiency were significantly lower in HF than control pigs and was associated with increased wall stress. Histology showed myocyte hypertrophy but not increased interstitial fibrosis in the remote segments in HF pigs. CONCLUSIONS: The chronic post-infarction model of HF is suitable for studies aimed to evaluate LV remodeling and changes in oxidative metabolism and can be useful for testing new therapies for HF. PMID- 25698476 TI - Individuals with impaired glucose tolerance demonstrate normal cardiac sympathetic innervation using I-123 mIBG scintigraphy. AB - BACKGROUND: Impaired glucose tolerance (IGT) is associated with an increased risk of type 2 diabetes (T2DM) and cardiovascular disease. Some but not all studies have reported cardiac autonomic dysfunction in subjects with IGT and there is only one direct study of cardiac innervation in subjects with IGT. The purpose of this study was to assess global and regional cardiac sympathetic innervation and cardiac autonomic function in individuals with IGT. METHODS AND RESULTS: We undertook (123)I-mIBG scintigraphy and cardiac autonomic function in 15 subjects with IGT and 15 age and sex-matched healthy controls. Early heart to mediastinum ratio (HMR) (1.71 +/- 0.17 vs 1.67 +/- 0.13, P = .49), late HMR (1.73 +/- 0.18 vs 1.73 +/- 0.16, P = .97) and washout rate (WR) (18.6 +/- 4.2 vs 19.1 +/- 7.6%, P = .84), did not differ between subjects with IGT and control subjects. More detailed regional analysis revealed reduced tracer uptake at the apex, base and inferior wall in all subjects and the anterior wall in a minority of subjects. There were no differences in total score (56.6 +/- 4.0 vs 53.3 +/- 8.4, P = .193), modified score (48.5 +/- 3.3 vs 46.2 +/- 6.0, P = .215), anterior wall score (10.2 +/- 1.3 vs 10.1 +/- 1.6, P = .898), inferior wall score (8.9 +/- 1.9 vs 7.7 +/- 2.6, P = .163), basal score (18.7 +/- 1.9 vs 18.2 +/- 3.3, P = .636) and tests of cardiac autonomic function between the groups. CONCLUSION: Global and regional measures of MIBG uptake and washout as well as cardiac autonomic function did not differ between subjects with IGT and healthy controls. PMID- 25698477 TI - A prospective evaluation of the repeatability of left ventricular ejection fraction measurement by gated SPECT. AB - BACKGROUND: Gated single-photon emission computed tomography (SPECT) is widely used for myocardial perfusion imaging and provides an automated assessment of left ventricular ejection fraction (LVEF). We prospectively tested the repeatability of serial SPECT-derived LVEF. This information is essential in order to inform the interpretation of a change in LV function on serial testing. METHODS: Consenting patients (n = 50) from among those referred for clinically indicated gated myocardial perfusion SPECT (MPs) were recruited. Following the clinical rest-stress study, patients were repositioned on the camera table for a second acquisition using identical parameters. Patient positioning, image acquisition and processing for the second scan were independently performed by a technologist blinded to the clinical scan. Quantitative LVEF was generated by Quantitative Gated SPECT and recorded as EF1 and EF2, respectively. Repeatability of serial results was assessed using the Bland-Altman method. The limits of repeatability and repeatability coefficients were generated to determine the maximum variation in LVEF that can be expected to result from test variability. Repeatability was tested across a broad range of LV systolic function and myocardial perfusion. RESULTS: The mean difference between EF1 and EF2 was 1.6% (EF units), with 95% limits of repeatability of +9.1% to -6.0% (repeatability coefficient 7.5%). Correlation between serial EF measurements was excellent (r = 0.9809). Similar results were obtained in subgroups based on normal or abnormal EF and myocardial perfusion. The largest repeatability coefficient of 8.1% was seen in patients with abnormal LV systolic function. CONCLUSION: When test protocol and acquisition parameters are kept constant, a difference of >8% EF units on serial MPs is indicative of a true change 95% of the time. PMID- 25698478 TI - More risk factors, less ischemia, and the relevance of MPI testing. PMID- 25698479 TI - Prognostication in the era of a new stressor for myocardial perfusion imaging. PMID- 25698480 TI - Multi-modality imaging: Bird's-eye view from the 2014 American Heart Association Scientific Sessions. AB - A large number of studies were presented at the 2014 American Heart Association Scientific Sessions. In this review, we will summarize key studies in nuclear cardiology, computed tomography, echocardiography, and cardiac magnetic resonance imaging. This brief review will be helpful for readers of the Journal who are interested in being updated on the latest research covering these imaging modalities. PMID- 25698482 TI - Creation of clinically relevant model of chronic heart failure: Application of multi-modality imaging to define physiology. PMID- 25698483 TI - Atheroma and the inflammasome. PMID- 25698484 TI - Has LVEF changed beyond chance? Limits of agreement of radiotracer-derived LVEF. PMID- 25698485 TI - Immunogenicity and safety of a 13-valent pneumococcal conjugate vaccine administered to older infants and children naive to pneumococcal vaccination. AB - BACKGROUND: Streptococcus pneumoniae infections are a major cause of morbidity and mortality in children <5 years old worldwide. To increase serotype coverage globally, a 13-valent pneumococcal conjugate vaccine (PCV13) has been developed and approved in many countries worldwide. OBJECTIVE: Assess the safety and immunogenicity of PCV13 in healthy older infants and children naive to previous pneumococcal vaccination. METHODS: This was a phase 3, open-label, multicenter study conducted in Polish children (N=354) who were vaccinated according to 3 age appropriate catch-up schedules: Group 1 (aged 7 to <12 months) received two PCV13 doses with a booster at 12-16 months of age; Group 2 (aged 12 to <24 months) received two vaccine doses only; and Group 3 (aged 24 to <72 months) received a single dose of PCV13. Statistical analyses were descriptive. The proportion of immunological "responders" achieving serotype-specific antipneumococcal polysaccharide concentrations >=0.35MUg/mL, 1-month after the last dose of vaccine, was determined for each vaccine serotype. In addition, antipolysaccharide immunoglobulin (Ig) G geometric mean concentrations (GMCs) were calculated. Safety assessments included systemic and local reactions, and adverse events. RESULTS: The proportion of immunological responders was >=88% across groups for all serotypes. Antipolysaccharide IgG GMCs were generally similar across groups. Each schedule elicited immune response levels against all 13 serotypes comparable to or greater than levels previously reported in infants after a 3-dose series. The 3 catch-up schedules had similar tolerability and safety profiles; a trend was present towards greater local tenderness with increasing age and subsequent dose administration. CONCLUSIONS: Immunological responses and safety results support the use of PCV13 for catch-up schedules in older infants and children naive to pneumococcal vaccination. PMID- 25698487 TI - Aluminium hydroxide potentiates a protective Th1 biased immune response against polio virus that allows for dose sparing in mice and rats. AB - BACKGROUND: The development of new low cost inactivated polio virus based vaccines (IPV) is a high priority and will be essential for the complete eradication of polio. Since the aluminium hydroxide adjuvant is widely used in humans we tested this adjuvant with IPV in two models. Our objective was twofold; to examine the IPV dose sparing effect of aluminium hydroxide and how the adjuvant effect of aluminium hydroxide affected the immunity induced by IPV. METHODS: Mice and rats were immunized with IPV formulated with Aluminium hydroxide and subjected to immunological analyses and serum polio virus neutralization titer determination. RESULTS: Addition of aluminium hydroxide to IPV led to a ten times dose sparing effect compared to IPV alone, measured by virus neutralization titers in serum. Aluminium hydroxide changed the kinetics of the response against IPV leading to a faster and stronger response, which due to IPV induced immune dominance was characterized as a strong Th1-biased cellular/humoral immune response. CONCLUSIONS: The IPV-aluminium hydroxide formulation constitutes a promising vaccine capable of generating strong Th1 immunity against infection with all three serotypes. A phase I/II clinical study was recently initiated. PMID- 25698486 TI - Comparative evaluation of the protective efficacy of two formulations of a recombinant Chlamydia abortus subunit candidate vaccine in a mouse model. AB - Chlamydia abortus (C. abortus) is the causative agent of ovine enzootic abortion (OEA) and poses a zoonotic risk to pregnant women. Current live attenuated 1B vaccines are efficacious but cause disease in vaccinated animals and inactivated vaccines are only marginally protective. We tested the ability of a new C. abortus subunit vaccine candidate based on the conserved and immunogenic polymorphic membrane protein D (Pmp18D) formulated in CpG1826+FL (Fms-like tyrosine kinase 3 Ligand; Flt3L) or Vibrio cholerae ghosts (VCG) to induce innate and cross protective immunity against genital C. abortus infection. We found that delivery of rPmp18D with VCG was more effective than with CpG+FL in up-regulating the expression of molecules critically involved in T cell activation and differentiation, including MHC II, CD40, CD80, and CD86, activation of TLRs and NLRP3 inflammasome engagement, and secretion of IL-1beta and TNF-alpha but not IL 10 and IL-4. rVCG-Pmp18D-immunized mice elicited more robust antigen-specific IFN gamma, IgA and IgG2c antibody responses compared to CpG+FL-delivered rPmp18D. Based on the number of mice with positive vaginal cultures, length of vaginal shedding, and number of inclusion forming units recovered following challenge with the heterologous C. abortus strain B577, vaccine delivery with VCG induced superior protective immunity than delivery with a combination of CpG1826 and FL, a nasal DC-targeting adjuvant. These results demonstrate that the ability of VCG to enhance protective immunity against genital C. abortus infection is superior to that of CpG+FL adjuvants. PMID- 25698488 TI - No benefit of therapeutic vaccination in clinically healthy cats persistently infected with feline leukemia virus. AB - Therapeutic vaccinations have a potential application in infections where no curative treatment is available. In contrast to HIV, efficacious vaccines for a cat retrovirus, feline leukemia virus (FeLV), are commercially available. However, the infection is still prevalent, and no effective treatment of the infection is known. By vaccinating persistently FeLV-infected cats and presenting FeLV antigens to the immune system of the host, e.g., in the form of recombinant and/or adjuvanted antigens, we intended to shift the balance toward an advantage of the host so that persistent infection could be overcome by the infected cat. Two commercially available FeLV vaccines efficacious in protecting naive cats from FeLV infection were tested in six experimentally and persistently FeLV infected cats: first, a canarypox-vectored vaccine, and second, an adjuvanted, recombinant envelope vaccine was repeatedly administered with the aim to stimulate the immune system. No beneficial effects on p27 antigen and plasma viral RNA loads, anti-FeLV antibodies, or life expectancy of the cats were detected. The cats were unable to overcome or decrease viremia. Some cats developed antibodies to FeLV antigens although not protective. Thus, we cannot recommend vaccinating persistently FeLV-infected cats as a means of improving their FeLV status, quality of life or life expectancy. We suggest testing of all cats for FeLV infection prior to FeLV vaccination. PMID- 25698489 TI - Genetic conjugation of components in two pneumococcal fusion protein vaccines enhances paediatric mucosal immune responses. AB - Streptococcus pneumoniae colonises the upper respiratory tract and can cause pneumonia, meningitis and otitis media. Existing pneumococcal conjugate vaccines are expensive to produce and only protect against 13 of the 90+ pneumococcal serotypes; hence there is an urgent need for the development of new vaccines. We have shown previously in mice that pneumolysin (Ply) and a non-toxic variant (Delta6Ply) enhance antibody responses when genetically fused to pneumococcal surface adhesin A (PsaA), a potentially valuable effect for future vaccines. We investigated this adjuvanticity in human paediatric mucosal primary immune cell cultures. Adenoidal mononuclear cells (AMNC) from children aged 0-15 years (n=46) were stimulated with conjugated, admixed or individual proteins, cell viability and CD4+ T-cell proliferative responses were assessed using flow cytometry and cytokine secretion was measured using multiplex technology. Proliferation of CD4+ T-cells in response to PsaAPly, was significantly higher than responses to individual or admixed proteins (p=0.002). In contrast, an enhanced response to PsaADelta6Ply compared to individual or admixed proteins only occurred at higher concentrations (p<0.01). Evaluation of cytotoxicity suggested that responses occurred when Ply-induced cytolysis was inhibited, either by fusion or mutation, but importantly an additional toxicity independent immune enhancing effect was also apparent as a result of fusion. Responses were MHC class II dependent and had a Th1/Th17 profile. Genetic fusion of Delta6Ply to PsaA significantly modulates and enhances pro-inflammatory CD4+ T-cell responses without the cytolytic effects of some other pneumolysoids. Membrane binding activity of such proteins may confer valuable adjuvant properties as fusion may assist Delta6Ply to deliver PsaA to the APC surface effectively, contributing to the initiation of anti-pneumococcal CD4+ T-cell immunity. PMID- 25698490 TI - The recombinant Lactococcus lactis oral vaccine induces protection against C. difficile spore challenge in a mouse model. AB - Clostridium difficile infection (CDI) causes nosocomial antibiotic-associated diarrhea and colitis in the developed world. Two potent cytotoxins, toxin A (TcdA) and toxin B (TcdB) are the virulence factors of this disease and can be a good vaccine candidate against CDI. In the present study, we genetically engineered Lactococcus lactis to express the nontoxic, recombinant fragments derived from TcdA and TcdB C-terminal receptor binding domains (Tcd-AC and Tcd BC) as an oral vaccine candidate. The immunogenicity of the genetically engineered L. lactis oral vaccine delivery system (animal groups LAC and LBC or the combination of both, LACBC) was compared with the recombinant TcdA and TcdB C terminal receptor binding domain proteins (animal groups PAC and PBC or the combination of both, PACBC), which were expressed and purified from E. coli. After the C. difficile challenge, the control groups received PBS or engineered L. lactis with empty vector, showed severe diarrhea symptoms and died within 2-3 days. However, both the oral vaccine and recombinant protein vaccine groups had significantly lower mortalities, body weight decreases and histopathologic lesions than the control sham-vaccine groups (p<0.05) except group LBC which only had a 31% survival rate after the challenge. The data of post infection survival showed that an average of 86% of animals survived in groups PAC and PACBC, 75% of animals survived in group LACBC, and 65% of animals survived in group LAC. All of the vaccinated animals produced higher titers of both IgG and IgA than the control groups (p<0.05), and the antibodies were able to neutralize the cytopathic effect of toxins in vitro. The results of this study indicate that there is a potential to use L. lactis as a delivery system to develop a cost effective oral vaccine against CDI. PMID- 25698491 TI - Prevention of perinatal hepatitis B transmission in Haimen City, China: Results of a community public health initiative. AB - In regions where hepatitis B virus (HBV) is endemic, perinatal transmission is common. Infected newborns have a 90% chance of developing chronic HBV infection, and 1 in 4 will die prematurely from HBV-related liver disease. In 2010, the Hepatitis B Foundation and the Haimen City CDC launched the Gateway to Care campaign in Haimen City, China to improve awareness, prevention, and control of HBV infection citywide. The campaign included efforts to prevent perinatal HBV transmission by screening all pregnant women for hepatitis B surface antigen (HBsAg), following those who tested positive, and administering immunoprophylaxis to their newborns at birth. Of 5407 pregnant women screened, 185 were confirmed HBsAg-positive and followed until delivery. At age one, 175 babies were available for follow up testing. Of those, 137 tested negative for HBsAg and positive for antibodies to HBsAg, indicating protection. An additional 34 HBsAg-negative babies also tested negative for antibodies to HBsAg or had indeterminate test results, were considered to have had inadequate immune responses to the vaccine, and were given a booster dose. A higher prevalence of nonresponse to HBV vaccine was observed among babies born to hepatitis B e antigen (HBeAg)-positive mothers and mothers with high HBV DNA titers. The remaining 4 babies tested positive for HBsAg and negative for antibodies, indicative of active HBV infection. The mothers of all 4 had viral loads >=8*10(6) copies/ml in the third trimester. Although inadequate response or nonresponse to HBV vaccine was more common among babies born to HBeAg-positive and/or high viral load mothers, these risk factors did not completely predict nonresponsiveness. All babies born to HBV-infected mothers should be tested upon completion of the vaccine series to ascertain adequate protection. Some babies of HBeAg-positive mothers with high viral load may still become HBV infected despite timely immunoprophylaxis with HBV vaccine and HBIG. PMID- 25698492 TI - The safety and immunogenicity of an adenovirus type 35-vectored TB vaccine in HIV infected, BCG-vaccinated adults with CD4(+) T cell counts >350 cells/mm(3). AB - BACKGROUND: The safety and immunogenicity of a replication deficient adenovirus serotype 35 tuberculosis (TB) vaccine containing gene inserts for Antigens (Ag) 85A, Ag85B and TB10.4 (AERAS-402/AD35.TB-S) was evaluated in previously BCG vaccinated, HIV-infected South African adults with baseline CD4 counts >350 cells/mm(3). METHODS: Subjects were randomized (1:1) to receive two doses of either intramuscular AERAS-402/AD35.TB-S or placebo at month 0 and at month 1. Participants were monitored for adverse events 28 days after each vaccination and for serious adverse events over 12 months. CD4(+) and CD8(+) T-cell and antibody responses to vaccine antigens were evaluated post first and second vaccination. RESULTS: 26 subjects were randomly assigned to receive AERAS-402/AD35.TB-S (N=13) or placebo (N=13). The mean age was 29.0 years, all were Black-African, 88.5% were female, 46.2% were QuantiFERON Test (QFT) positive at baseline, and the median CD4 count was 559.5 cells/mm(3), all similar by treatment group. All subjects received their first vaccination and 24 subjects received their second vaccination. Injection site reactions and some systemic reactions were reported more commonly in the AERAS-402/AD35.TB-S versus placebo recipients. AERAS 402/AD35.TB-S did not appear to influence CD4 counts and HIV-1 viral load over the course of study follow-up. AERAS-402/AD35.TB-S induced a mixed CD4(+) T-cell and CD8(+) T-cell responses to Ag85B. The CD4(+) T-cell responses peaked to Ag85A and Ag85B 14 days after the second vaccination and had declined by Day 182. AERAS 402/AD35.TB-S predominantly induced CD4(+) T-cells expressing three (IFN-gamma, TNF, IL-2) or two (IL-2 and TNF) cytokines, two weeks after the last vaccination, which did not differ by baseline Quantiferon test status. AERAS-402/AD35.TB-S induced strong Ag85A and Ag85B specific antibody responses, particularly after the second vaccination. CONCLUSION: AERAS-402/AD35.TB-S was well tolerated, safe and induced predominantly polyfunctional CD4(+) and CD8(+) T-cell responses to vaccine. PMID- 25698493 TI - Pediatric anaphylactic adverse events following immunization in Victoria, Australia from 2007 to 2013. AB - BACKGROUND: Anaphylaxis is a rare life-threatening adverse event following immunization (AEFI). Variability in presentation can make differentiation between anaphylaxis and other AEFI difficult. This study summarizes pediatric anaphylaxis AEFI reported to an Australian state-based passive surveillance system. METHODS: All suspected and reported pediatric (<18 years) anaphylaxis AEFI notified to SAEFVIC (Surveillance of Adverse Events Following Vaccination In the Community) Melbourne, Australia, between May 2007 to May 2013 were analyzed. Clinical descriptions of the AEFI, using the internationally recognized Brighton Collaboration case definition (BCCD) and final outcome were documented. RESULTS: 93% (25/27) of AEFI classified as anaphylaxis met BCCD criteria, with 36% (9/25), assessed as the highest level of diagnostic certainty (Level 1). Median age was 4.7 years (range 0.3-16.2); 48% of cases were male. The vaccine antigens administered included: diphtheria, tetanus, acellular pertussis (DTaP) alone or in combination vaccines containing other antigens in 11 of 25 cases (44%); and live attenuated measles mumps rubella (MMR) vaccine for six (five also had other vaccines concomitantly administered). The estimated incidence rate of anaphylaxis for DTaP vaccines was 0.36 cases per 100,000 doses, and 1.25 per 100,000 doses for MMR vaccines. The majority of cases had rapid onset, but in 24% (6/25) of cases, first symptoms of anaphylaxis developed >=30 min after immunization. In 60% (15/25) of cases, symptoms resolved <=60 min of presentation. Intramuscular adrenaline was administered in 90% (18/25) of cases. All cases made a full recovery with no sequelae identified. CONCLUSION: This comprehensive case series of pediatric anaphylaxis as an AEFI identified that diagnostic criteria are useful when applied to a passive vaccine surveillance system when adequate clinical information is available. Anaphylaxis as an AEFI is rare and usually begins within 30 min of vaccination. However, healthcare professionals and vaccinees/parents should be aware that onset of anaphylaxis can be delayed beyond 30 min following immunization and that medical attention should be sought promptly if anaphylaxis is suspected. PMID- 25698494 TI - Now that you want to take your HIV/AIDS vaccine/biological product research concept into the clinic: what are the "cGMP"? AB - The Division of AIDS Vaccine Research Program funds the discovery and development of HIV/AIDS vaccine candidates. Basic researchers, having discovered a potential vaccine in the laboratory, next want to take that candidate into the clinic to test the concept in humans, to see if it translates. Many of them have heard of "cGMP" and know that they are supposed to make a "GMP product" to take into the clinic, but often they are not very familiar with what "cGMP" means and why these good practices are so important. As members of the Vaccine Translational Research Branch, we frequently get asked "can't we use the material we made in the lab in the clinic?" or "aren't Phase 1 studies exempt from cGMP?" Over the years, we have had many experiences where researchers or their selected contract manufacturing organizations have not applied an appropriate degree of compliance with cGMP suitable for the clinical phase of development. We share some of these experiences and the lessons learned, along with explaining the importance of cGMP, just what cGMP means, and what they can assure, in an effort to de-mystify this subject and facilitate the rapid and safe translational development of HIV vaccines. PMID- 25698495 TI - Identifying data sources for a national population-based registry: the experience of the Spanish Rare Diseases Registry. PMID- 25698496 TI - Access to medicines in remote and rural areas: a survey of residents in the Scottish Highlands & Western Isles. AB - OBJECTIVES: Sparsely populated areas are potentially predisposed to health inequalities due to limited access to services. This study aimed to explore and describe issues of access to medicines and related advice experienced by residents of the Scottish Highlands and Western Isles. STUDY DESIGN: Cross sectional cohort study. METHODS: Anonymized questionnaires were mailed to a random sample of 6000 residents aged >=18 years identified from the electoral register. The questionnaire contained items on: access to medicines; interactions with health care services; and perceptions of the services. Results were analysed using descriptive, inferential and spatial statistics. RESULTS: Adjusted response rate was 49.5% (2913/5889). Almost two thirds (63.4%, 1847) were prescribed medicines regularly, 88.5% (1634) of whom considered the source convenient. Pharmacy (73.8%, 1364) or dispensing GP (24.0%, 443) were the most accessed sources. Prescription medicine advice was mainly obtained from the GP (55.7%, 1029). Respondents >=80 years old were significantly (P < 0.0001) more likely to live alone (45.3%, 92) compared with those <80 (15.8%, 424). Almost a fifth (16.5%, 31) of those >80 years living alone disagreed that they obtained prescribed medicines from a convenient source. The majority of respondents who felt they did not have a convenient medicines source, regardless of urban/rural classification, lived within five miles of a pharmacy or GP practice. CONCLUSIONS: Respondents accessed medicines and advice from a variety of sources. While most considered their access to medicines convenient, there were issues for those over 80 years and living alone. Perceived convenience would not appear to be solely based on geographical proximity to supply source. This requires further exploration given that these individuals are likely to have long-term conditions and be prescribed medicines on a chronic basis. PMID- 25698497 TI - The sociodemographic patterning of opposition to raising taxes on tobacco and restricting tobacco advertisements in Argentina. AB - BACKGROUND: Argentina has enacted important tobacco control initiatives in recent years. Yet little is known about the social patterning of attitudes toward tobacco control. Research is needed to explore what predicts opposition to tobacco control initiatives such as higher taxes on tobacco and the prohibition of tobacco advertising. STUDY DESIGN: Secondary analysis of Argentina's Global Adult Tobacco Survey (N = 6645). METHODS: Binary logistic regression analysis examining opposition to raising tobacco taxes and banning tobacco publicity. Models were stratified by smoking status. RESULTS: Respondents generally indicated very little opposition to either tobacco control measure, with only 15.6% of respondents opposed to increasing taxes on tobacco products and 9.6% opposed to banning tobacco advertisements. Smoking status is the most important predictor of opposition to increasing taxes (OR = 7.85, 95% CI = 6.60-9.34) and banning advertisements (OR = 1.72, 95% CI = 1.39-2.11). Opposition to these measures is most likely among young respondents (aged 15-24) and least likely among older age groups (55-64 and 65 or over), compared to the 25-34 age group. Stratified models suggest that the effect of age may be different for smokers and non-smokers. Low income is a significant predictor of opposition, but only in stratified models for smokers. CONCLUSION: There is general support for stronger tobacco control measures in Argentina. Opposition to raising taxes on tobacco products and banning tobacco advertisement appears to be concentrated among young smokers with low and medium levels of household income. PMID- 25698498 TI - A qualitative study of GPs' views towards obesity: are they fighting or giving up? AB - OBJECTIVES: Several studies indicate that general practitioners (GPs) are not taking the issue of obesity as seriously as they should. Therefore, the aim of this study was to understand GPs' views about obesity and obese people and how these professionals perceive their role in the treatment of this disease. STUDY DESIGN: Qualitative study using semi-structured interviews. METHODS: Sixteen semi structured interviews were conducted with Portuguese GPs. Data were analyzed according to thematic analysis procedures. RESULTS: GPs are negative about their own role in obesity treatment. Although they believe it is part of their job to advise obese patients on the health risks of obesity, the majority of doctors think they are not making any difference in getting their patients to make long term lifestyle changes. GPs hold negative attitudes towards these patients blaming them for being unmotivated and non-compliant and are also pessimistic about their ability to lose weight. Doctors are facing a dilemma in their practices: they want to play an active role but, due to a set of negative beliefs and perceived barriers, they are playing a relatively passive role, feeling defeated and unmotivated, which is reflected in a decrease of efforts and a willing to give up on most of the cases. CONCLUSIONS: This issue should be taken in to account during physicians' education since doctors should be aware of how their own beliefs and attitudes influence their behaviour and practices, compromising, therefore, the adherence to and the success in obesity treatment. They seem to need more precise guidelines and better tools for screening and management of obesity, more referral options, and improved coordination with other specialities. PMID- 25698499 TI - Variation in incidence and notification of Campylobacter and Salmonella by general practice in the Thames Valley area. AB - OBJECTIVES: To test whether there is unexplained variation in a) incidence of diagnosed bacterial food poisoning; and b) notification of bacterial food poisoning between general practices. STUDY DESIGN: Observational study using routine surveillance data collected between 1 January 2008 and 31 December 2009. METHODS: Poisson regression, and the pseudo-R(2) statistic, was used to test for the unexplained (i.e. after adjustment for measured confounders) variation in incidence between practices. A generalized linear model, and the pseudo-R(2) statistic, was used to test for variation in notifications between practices. Both models were adjusted for demographic factors and organisational factors (Primary Care Trust and Quality and Outcomes Framework score). RESULTS: A total of 5766 incident cases (811 Salmonella and 4955 Campylobacter) were included. The adjusted incidence of Salmonella and Campylobacter was 128.3 cases per 100,000 persons per year. The adjusted incidence by general practice ranged from 9.8 to 281 per 100,000 (IQR: 90.2-151) persons per year. The median practice notification rate for Salmonella was 25% (range: 0%-100%), and 14.3% (range: 0% 87.5%) for Campylobacter. The Poisson regression model had a pseudo-R(2) of 0.080 for the total number of Salmonella and Campylobacter cases, after adjustment for Primary Care Trust and practice deprivation, suggesting substantial variation. The Generalized Linear regression model (predicting notification by general practice) had a pseudo-R(2) of 0.040 for Salmonella and Campylobacter, after adjustment for Primary Care Trust and practice deprivation, suggesting substantial unexplained variation. CONCLUSION: Substantial variation in the diagnosed incidence and notification of Salmonella and Campylobacter by general practice in the Thames Valley area exists. Practice-level factors are likely to account for some of the difference in testing and under-notification. This is important for interpreting data from surveillance systems. Further research is needed to inform interventions designed to increase notifications or improve testing. PMID- 25698500 TI - Rabies virus phosphoprotein interacts with mitochondrial Complex I and induces mitochondrial dysfunction and oxidative stress. AB - Our previous studies in an experimental model of rabies showed neuronal process degeneration in association with severe clinical disease. Cultured adult rodent dorsal root ganglion neurons infected with challenge virus standard (CVS)-11 strain of rabies virus (RABV) showed axonal swellings and reduced axonal growth with evidence of oxidative stress. We have shown that CVS infection alters a variety of mitochondrial parameters and increases reactive oxygen species (ROS) production and mitochondrial Complex I activity vs. mock infection. We have hypothesized that a RABV protein targets mitochondria and triggers dysfunction. Mitochondrial extracts of mouse neuroblastoma cells were analyzed with a proteomics approach. We have identified peptides belonging to the RABV nucleocapsid protein (N), phosphoprotein (P), and glycoprotein (G), and our data indicate that the extract was most highly enriched with P. P was also detected by immunoblotting in RABV-infected purified mitochondrial extracts and also in Complex I immunoprecipitates from the extracts but not in mock-infected extracts. A plasmid expressing P in cells increased Complex I activity and increased ROS generation, whereas expression of other RABV proteins did not. We have analyzed recombinant plasmids encoding various P gene segments. Expression of a peptide from amino acid 139-172 increased Complex I activity and ROS generation similar to expression of the entire P protein, whereas peptides that did not contain this region did not increase Complex I activity or induce ROS generation. These results indicate that a region of the RABV P interacts with Complex I in mitochondria causing mitochondrial dysfunction, increased generation of ROS, and oxidative stress. PMID- 25698501 TI - Elasticity of liquid marbles. AB - Liquid marbles are liquid droplets covered densely with small particles. They exhibit hydrophobic properties even on hydrophilic surfaces and this behaviour is closely related to the Cassie wetting state and the phenomenon of superhydrophobicity. Typical liquid marbles are of millimetre size but their properties are analogous to smaller capsules and droplets of Pickering emulsions. We study water marbles covered with an uneven multilayer of polyethylene particles. Their elastic properties were assessed under quasi-static conditions. The liquid marbles are highly elastic and can sustain a reversible deformation of up to 30%. The spring constant is of the same order of magnitude as that for bare water droplets. Therefore the elasticity of the liquid marble is provided mainly by the liquid menisci between the particles. Upon further compression, the spring constant increases up to the point of breakage. This increase may be due to capillary attraction acting across the emerging cracks in the particle coating. The stress-strain curve for liquid marbles is similar to that obtained with liquid-filled microcapsules. A mechanical scaling description proposed for capsules is qualitatively applicable for liquid marbles. The exact mechanical role of the multilayer particle network remains elusive. PMID- 25698502 TI - In situ Raman and surface-enhanced Raman spectroscopy on working electrodes: spectroelectrochemical characterization of water oxidation electrocatalysts. AB - In situ Raman and surface-enhanced Raman scattering (SERS) are established vibrational spectroscopic techniques with a wide range of applications in the field of chemical, material and life sciences. Their particular characteristics make them especially useful when dealing with catalytic water oxidation at anodes. The in situ characterization of the fate of electrocatalysts (whether molecular or oxide materials) employed under reaction conditions is crucial to determine the chemical identity and the physical state of the actual catalytic species. Such studies also help in both, attaining mechanistic insights underlying the catalytic reaction and confirming/discarding the possibility of molecular to colloidal or heterogeneous phase conversions taking place prior or under turnover conditions. This perspective article highlights the use of in situ Raman and SERS as principal spectroscopic tools in the electrocatalysis field by means of recent contributions where they are employed to in operando characterize both molecular and oxide-based water oxidation electrocatalysts. These in situ spectroscopic measurements support in assessing both the progressive oxidation and the structural evolution of the employed catalytic species under electrochemical conditions. Therefore, this article provides an informative guideline for developing in situ spectroelectrochemical methods to study and characterize water oxidation catalysis at working anodes. PMID- 25698503 TI - Theoretical studies on mechanisms of some Mo enzymes. AB - Modeling of molybdoenzymes began even before the knowledge of the three dimensional structure of these enzymes. The theoretical and experimental knowledge on these enzymes is vast and newer investigation is regularly pursued to understand the electronic aspect of these proteins using computational means. The present review deals with some unique observation regarding the structure, function and reactivity of some models and native proteins in rationalizing the choice of diverse substrates in seemingly similar enzymes such as Nap (nitrate reductase) and Fdh (formate dehydrogenase) and the dual form of a specific substrate of an enzyme like trimethylamine N-oxide reductase (TAMOR) and providing the electronic reason for the inhibition in the oxypurinol-inhibited xanthine oxidase (XO). PMID- 25698504 TI - BBB-targeting, protein-based nanomedicines for drug and nucleic acid delivery to the CNS. AB - The increasing incidence of diseases affecting the central nervous system (CNS) demands the urgent development of efficient drugs. While many of these medicines are already available, the Blood Brain Barrier and to a lesser extent, the Blood Spinal Cord Barrier pose physical and biological limitations to their diffusion to reach target tissues. Therefore, efforts are needed not only to address drug development but specially to design suitable vehicles for delivery into the CNS through systemic administration. In the context of the functional and structural versatility of proteins, recent advances in their biological fabrication and a better comprehension of the physiology of the CNS offer a plethora of opportunities for the construction and tailoring of plain nanoconjugates and of more complex nanosized vehicles able to cross these barriers. We revise here how the engineering of functional proteins offers drug delivery tools for specific CNS diseases and more transversally, how proteins can be engineered into smart nanoparticles or 'artificial viruses' to afford therapeutic requirements through alternative administration routes. PMID- 25698505 TI - Biotechnological advances in UDP-sugar based glycosylation of small molecules. AB - Glycosylation of small molecules like specialized (secondary) metabolites has a profound impact on their solubility, stability or bioactivity, making glycosides attractive compounds as food additives, therapeutics or nutraceuticals. The subsequently growing market demand has fuelled the development of various biotechnological processes, which can be divided in the in vitro (using enzymes) or in vivo (using whole cells) production of glycosides. In this context, uridine glycosyltransferases (UGTs) have emerged as promising catalysts for the regio- and stereoselective glycosylation of various small molecules, hereby using uridine diphosphate (UDP) sugars as activated glycosyldonors. This review gives an extensive overview of the recently developed in vivo production processes using UGTs and discusses the major routes towards UDP-sugar formation. Furthermore, the use of interconverting enzymes and glycorandomization is highlighted for the production of unusual or new-to-nature glycosides. Finally, the technological challenges and future trends in UDP-sugar based glycosylation are critically evaluated and summarized. PMID- 25698506 TI - Impact of the PI3-kinase/Akt pathway on ITAM and hemITAM receptors: haemostasis, platelet activation and antithrombotic therapy. AB - Phosphoinositide 3-kinases (PI3Ks) are a family of lipid kinases that are activated in response to various stimulants, and they regulate many processes including inflammation; the stress response; gene transcription; and cell proliferation, differentiation, and death. Increasing reports have shown that the PI3Ks and their downstream effector Akt are activated by several platelet receptors that regulate platelet activation and haemostasis. Platelets express two immunoreceptor tyrosine based activation motif (ITAM) receptors, collagen receptor glycoprotein VI (GPVI) and Fcgamma receptor IIA (FcgammaRIIA), which are characterized by two YxxL sequences separated by 6-12 amino acids. Activation of an ITAM receptor initiates a reaction cascade via its YxxL sequence in which signaling molecules such as spleen tyrosine kinase (Syk), linker for activation of T cells (LAT) and phospholipase C gamma2 (PLCgamma2) become activated, leading to platelet activation. Platelets also express another receptor, C-type lectin 2 (CLEC-2), which has a single YxxL sequence, so it is appropriately called a hemITAM receptor. ITAM receptors and the hemITAM receptor share many signaling features. Here we will summarize our current knowledge about how the PI3K/Akt pathway regulates (hem)ITAM receptor-mediated platelet activation and haemostasis and discuss the possible benefits of targeting PI3K/Akt as an antithrombotic therapy. PMID- 25698507 TI - Relationship between brain accumulation of manganese and aberration of hippocampal adult neurogenesis after oral exposure to manganese chloride in mice. AB - We previously found persistent aberration of hippocampal adult neurogenesis, along with brain manganese (Mn) accumulation, in mouse offspring after developmental exposure to 800-ppm dietary Mn. Reduction of parvalbumin (Pvalb)(+) gamma-aminobutyric acid (GABA)-ergic interneurons in the hilus of the dentate gyrus along with promoter region hypermethylation are thought to be responsible for this aberrant neurogenesis. The present study was conducted to examine the relationship between the induction of aberrant neurogenesis and brain Mn accumulation after oral Mn exposure as well as the responsible mechanism in young adult animals. We used two groups of mice with 28- or 56-day exposure periods to oral MnCl2.xH2O at 800 ppm as Mn, a dose sufficient to lead to aberrant neurogenesis after developmental exposure. A third group of mice received intravenous injections of Mn at 5-mg/kg body weight once weekly for 28 days. The 28-day oral Mn exposure did not cause aberrations in neurogenesis. In contrast, 56-day oral exposure caused aberrations in neurogenesis suggestive of reductions in type 2b and type 3 progenitor cells and immature granule cells in the dentate subgranular zone. Brain Mn accumulation in 56-day exposed cases, as well as in directly Mn-injected cases occurred in parallel with reduction of Pvalb(+) GABAergic interneurons in the dentate hilus, suggesting that this may be responsible for aberrant neurogenesis. For reduction of Pvalb(+) interneurons, suppression of brain-derived neurotrophic factor-mediated signaling of mature granule cells may occur via suppression of c-Fos-mediated neuronal plasticity due to direct Mn-toxicity rather than promoter region hypermethylation of Pvalb. PMID- 25698508 TI - Current understanding of synergistic interplay of chitosan nanoparticles and anticancer drugs: merits and challenges. AB - Recent advances have been made in cancer chemotherapy through the development of conjugates for anticancer drugs. Many drugs have problems of poor stability, water insolubility, low selectivity, high toxicity, and side effects. Most of the chitosan nanoparticles showed to be good drug carriers because of their biocompatibility, biodegradability, and it can be readily modified. The anticancer drug with chitosan nanoparticles displays efficient anticancer effects with a decrease in the adverse effects of the original drug due to the predominant distribution into the tumor site and a gradual release of free drug from the conjugate which enhances drug solubility, stability, and efficiency. In this review, we discuss wider applications of numerous modified chitosan nanoparticles against different tumors and also focusing on the administration of anticancer drugs through various routes. We propose the interaction between nanosized drug carrier and tumor tissue to understand the synergistic interplay. Finally, we elaborate merits of drug delivery system at the tumor site, with emphasizing future challenges in cancer chemotherapy. PMID- 25698509 TI - Genomic analysis of Brevibacillus thermoruber 423 reveals its biotechnological and industrial potential. AB - Brevibacillus thermoruber 423 is a Gram-positive, motile, red-pigmented, spore forming, aerobic, and thermophilic bacterium that is known to produce high levels of exopolysaccharide (EPS) with many potential uses in food, feed, cosmetics, and pharmaceutical and chemical industries. This bacterium not only is among the limited number of reported thermophilic EPS producers but also exceeds other thermophilic producers in light of the high level of polymer synthesis. By a systems-based approach, whole-genome analysis of this bacterium was performed to gain more insight about the biological mechanisms and whole-genome organization of thermophilic EPS producers and hence to develop rational strategies for the genetic and metabolic optimization of EPS production. Also with this study, the first genome analysis was performed on a thermophilic Brevibacillus species. Essential genes associated with EPS biosynthesis were detected by genome annotation, and together with experimental evidences, a hypothetical mechanism for EPS biosynthesis was generated. B. thermoruber 423 was found to have many potential applications in biotechnology and industry because of its capacity to utilize xylose and to produce EPS, isoprenoids, ethanol/butanol, lipases, proteases, cellulase, and glucoamylase enzymes as well as its resistance to arsenic. PMID- 25698511 TI - Effect of S/N ratio on sulfide removal by autotrophic denitrification. AB - In this study a completely stirred tank reactor was used to study the effect of sulfide to nitrate (S/N) ratio on sulfide removal while nitrate was used as electron acceptor. Several S/N ratios were studied for this purpose ranging from 0.3 to 2.4 mol/mol. The complete sulfide removal was achieved when S/N ratio 0.85 mol/mol was used with the autotrophic denitrification efficiency up to 80 %. No nitrite accumulation was observed, and the main product of sulfide oxidation was sulfate. Dissimilatory nitrogen reduction to ammonia occurred and subsequently, elemental sulfur accumulated while S/N ratio was higher than 1.3 mol/mol. The specific autotrophic denitrification rates under S/N ratios 0.8 and 1.2 were 5 and 26 mg g(-1) h(-1) (N-NO3 (-), VSS), respectively. Thiobacillus denitrificans and Thiomicrospira denitrificans were detected in the reactor by fluorescent in situ hybridization, but their overall representation was not more than 5 % of the entire microbial populations. PMID- 25698512 TI - Improvement of acetic acid tolerance of Saccharomyces cerevisiae using a zinc finger-based artificial transcription factor and identification of novel genes involved in acetic acid tolerance. AB - Acetic acid is present in cellulosic hydrolysate as a potent inhibitor, and the superior acetic acid tolerance of Saccharomyces cerevisiae ensures good cell viability and efficient ethanol production when cellulosic raw materials are used as substrates. In this study, a mutant strain of S. cerevisiae ATCC4126 (Sc4126 M01) with improved acetic acid tolerance was obtained through screening strains transformed with an artificial zinc finger protein transcription factor (ZFP-TF) library. Further analysis indicated that improved acetic acid tolerance was associated with improved catalase (CAT) activity. The ZFP coding sequence associated with the improved phenotype was identified, and real-time RT-PCR analysis revealed that three of the possible genes involved in the enhanced acetic acid tolerance regulated by this ZFP-TF, namely YFL040W, QDR3, and IKS1, showed decreased transcription levels in Sc4126-M01 in the presence of acetic acid, compared to those in the control strain. Sc4126-M01 mutants having QDR3 and IKS1 deletion (DeltaQDR3 and DeltaIKS1) exhibited higher acetic acid tolerance than the wild-type strain under acetic acid treatment. Glucose consumption rate and ethanol productivity in the presence of 5 g/L acetic acid were improved in the DeltaQDR3 mutant compared to the wild-type strain. Our studies demonstrated that the synthetic ZFP-TF library can be used to improve acetic acid tolerance of S. cerevisiae and that the employment of an artificial transcription factor can facilitate the exploration of novel functional genes involved in stress tolerance of S. cerevisiae. PMID- 25698510 TI - Aerobic and nitrite-dependent methane-oxidizing microorganisms in sediments of freshwater lakes on the Yunnan Plateau. AB - Both aerobic methane-oxidizing bacteria (MOB) and nitrite-dependent anaerobic methane oxidation (n-damo) bacteria can play an important role in mitigating the methane emission produced in anoxic sediment layers to the atmosphere. However, the environmental factors regulating the distribution of these methane-oxidizing microorganisms in lacustrine ecosystems remain essentially unclear. The present study investigated the distribution of aerobic MOB and n-damo bacteria in sediments of various freshwater lakes on the Yunnan Plateau (China). Quantitative PCR assay and clone library analysis illustrated the spatial variations in the abundances and structures of aerobic MOB and n-damo bacterial communities. Type I MOB (Methylosoma and Methylobacter) and type II MOB (Methylocystis) were detected, while type I MOB was more abundant than type II MOB. Lake sediments n damo bacterial communities were composed of novel Methylomirabilis oxyfera-like pmoA genes. Lake sediments in the same geographic region could share a relatively similar aerobic MOB community structure. Moreover, Pearson's correlation analysis indicated that n-damo pmoA gene diversity showed a positive correlation with the ratio of organic matter to total nitrogen in lake sediment. PMID- 25698513 TI - Measuring coherence of computer-assisted likelihood ratio methods. AB - Measuring the performance of forensic evaluation methods that compute likelihood ratios (LRs) is relevant for both the development and the validation of such methods. A framework of performance characteristics categorized as primary and secondary is introduced in this study to help achieve such development and validation. Ground-truth labelled fingerprint data is used to assess the performance of an example likelihood ratio method in terms of those performance characteristics. Discrimination, calibration, and especially the coherence of this LR method are assessed as a function of the quantity and quality of the trace fingerprint specimen. Assessment of the coherence revealed a weakness of the comparison algorithm in the computer-assisted likelihood ratio method used. PMID- 25698514 TI - Two thiazolylindoles and a benzimidazole: novel compounds on the designer drug market with potential cannabinoid receptor activity. AB - In a seizure of German customauthorities two 3-([1,3]-thiazol-2-yl)indoles (N-(2 methoxyethyl),N-iso-propyl-2-(1-pentyl-1H-indol-3-yl)-4-thiazolemethanamine (1) and N,N-diethyl-2-(1-pentyl-1H-indol-3-yl)-4-thiazolemethanamine (2)) and one benzimidazole (1-(cyclohexylmethyl)-2-[(4-ethoxyphenyl)methyl]-N,N-diethyl-1H benzimidazole-5-carboxamide (6)) were seized as pure compounds. The compounds have been detected in Germany for the first time, and no analytical data had been previously published. Mass spectrometric (MS), infrared (IR) spectroscopic, and nuclear magnetic resonance (NMR) spectroscopic data are presented and the way of the structure elucidation of these rather uncommon compounds is discussed. PMID- 25698515 TI - Residual cannabis levels in blood, urine and oral fluid following heavy cannabis use. AB - An understanding of tetrahydrocannabinol (THC) kinetics and residual levels after cannabis use is essential in interpreting toxicology tests in body fluids from live subjects, particularly when used in forensic settings for drug abuse, traffic and interpersonal violence cases. However the current literature is largely based on laboratory studies using controlled cannabis dosages in experienced users, with limited research investigating the kinetics of residual THC concentrations in regular high dose cannabis users. Twenty-one dependent cannabis users were recruited at admission to two residential detoxification units in Melbourne, Australia. After being provided with information about, and consenting to, the study, subjects volunteered to provide once-daily blood, urine and oral fluid (saliva) samples for seven consecutive days following admission, involving cessation and abstinence from all cannabis use. Blood and oral fluid specimens were analysed for THC and urine specimens for the metabolite THC-COOH. In some subjects THC was detectable in blood for at least 7 days and oral fluid specimens were positive for THC up to 78 h after admission to the unit. Urinary THC-COOH concentrations exceeded 1000 ng/mL for some subjects 129 h after last use. The presented blood THC levels are higher and persist longer in some individuals than previously described, our understanding and interpretation of THC levels in long term heavy cannabis users may need to be reconsidered. PMID- 25698516 TI - Causal superseding. AB - When agents violate norms, they are typically judged to be more of a cause of resulting outcomes. In this paper, we suggest that norm violations also affect the causality attributed to other agents, a phenomenon we refer to as "causal superseding." We propose and test a counterfactual reasoning model of this phenomenon in four experiments. Experiments 1 and 2 provide an initial demonstration of the causal superseding effect and distinguish it from previously studied effects. Experiment 3 shows that this causal superseding effect is dependent on a particular event structure, following a prediction of our counterfactual model. Experiment 4 demonstrates that causal superseding can occur with violations of non-moral norms. We propose a model of the superseding effect based on the idea of counterfactual sufficiency. PMID- 25698517 TI - Synthesis of structural analogues of hexadecylphosphocholine and their antineoplastic, antimicrobial and amoebicidal activity. AB - Twelve derivatives of hexadecylphosphocholine (miltefosine) were synthesized to determine how the position and length of the alkyl chain within the molecule influence their biological activities. The prepared alkylphosphocholines have the same molecular formula as miltefosine. Activity of the compounds was studied against a spectrum of tumour cells, two species of protozoans, bacteria and yeast. Antitumour efficacy of some alkylphosphocholines measured up on MCF-7, A2780, HUT-78 and THP-1 cell lines was higher than that of miltefosine. The compounds showed antiprotozoal activity against Acanthamoeba lugdunensis and Acanthamoeba quina. Some of them also possess fungicidal activity against Candida albicans equal to miltefosine. No antibacterial activity was observed against Staphylococcus aureus and Escherichia coli. A difference in position of a long hydrocarbon chain within the structure with maximum efficacy was observed for antitumour, antiprotozoal and antifungal activity. PMID- 25698518 TI - The central cell nuclear position at the micropylar end is maintained by the balance of F-actin dynamics, but dispensable for karyogamy in Arabidopsis. AB - KEY MESSAGE: Advances in Fertilization. In flowering plants, fertilization is initiated by the delivery of immotile sperm cells to the boundary between two female gametes, the egg cell and the central cell. During female gamete development in Arabidopsis, the nucleus of the central cell becomes positioned toward this boundary. How this specific polarized nuclear position is maintained is unclear and whether it plays a role in successful fertilization remains to be determined. By disrupting and manipulating F-actin dynamics in the central cell, we identified that the balance of F-actin dynamics is important for nuclear positioning in the central cell and that the presence of intact F-actin cables in the central cell correlates with successful karyogamy regardless of the central cell nuclear position. We also report that the surface of the central cell nucleus is enriched in F-actin. Thus, the central cell nucleus might also serve as a site that organizes F-actin cytoskeleton to promote sperm cell nucleus movement and karyogamy. PMID- 25698519 TI - Using soil records with atmospheric dispersion modeling to investigate the effects of clean air regulations on 60 years of manganese deposition in Marietta, Ohio (USA). AB - Atmospheric emissions of metals from anthropogenic activities have led to deposition and contamination of soils worldwide. We quantified addition of manganese (Mn) to soils around the largest emitter of Mn in the United States (U.S.) using chemical analyses and atmospheric dispersion modeling (Second-Order Closure Integrated Puff (SCIPUFF)). Concentrations of soil-surface Mn were enriched by 9-fold relative to that of the parent material within 1 km of the facility. Elevated concentrations of Mn and chromium (Cr), another potentially toxic element that was emitted, document contamination only within 1 m of the soil surface. Total mass of Mn added per unit land area integrated over 1 m, mMn, equals ~80 mg Mn cm(-2) near the facility. Values of mMn remained above background up to tens of kilometers from the source. Air concentrations of Mn particles of 7.5-micron diameter simulated with SCIPUFF using available data for the emission rate and local meteorological conditions for 2006 were consistent with measured air concentrations. However, the Mn deposition calculated for 2006 with SCIPUFF yielded a cumulative value over the lifetime of the refinery (60 years) that is a factor of 15 lower than the Mn observed to have been added to the soils. This discrepancy can be easily explained if Mn deposition rates before 1988 were more than an order of magnitude greater than today. Such higher emissions are probable, given the changes in metal production with time and the installation of emission controls after the Clean Air Act (1970). This work shows that atmospheric dispersion models can be used with soil profiles to understand the changes in metal emissions over decadal timescales. In addition, the calculations are consistent with the Clean Air Act accounting for a 15-fold decrease in the Mn deposition to soils around the refinery per metric ton of Mn alloy produced. PMID- 25698520 TI - Comparative phytotoxicity of ZnO NPs, bulk ZnO, and ionic zinc onto the alfalfa plants symbiotically associated with Sinorhizobium meliloti in soil. AB - ZnO nanoparticles (NPs) are reported as potentially phytotoxic in hydroponic and soil media. However, studies on ZnO NPs toxicity in a plant inoculated with bacterium in soil are limited. In this study, ZnO NPs, bulk ZnO, and ZnCl2 were exposed to the symbiotic alfalfa (Medicago sativa L.)-Sinorhizobium meliloti association at concentrations ranging from 0 to 750 mg/kg soil. Plant growth, Zn bioaccumulation, dry biomass, leaf area, total protein, and catalase (CAT) activity were measured in 30 day-old plants. Results showed 50% germination reduction by bulk ZnO at 500 and 750 mg/kg and all ZnCl2 concentrations. ZnO NPs and ionic Zn reduced root and shoot biomass by 80% and 25%, respectively. Conversely, bulk ZnO at 750 mg/kg increased shoot and root biomass by 225% and 10%, respectively, compared to control. At 500 and 750 mg/kg, ZnCl2 reduced CAT activity in stems and leaves. Total leaf protein significantly decreased as external ZnCl2 concentration increased. STEM-EDX imaging revealed the presence of ZnO particles in the root, stem, leaf, and nodule tissues. ZnO NPs showed less toxicity compared to ZnCl2 and bulk ZnO found to be growth enhancing on measured traits. These findings are significant to reveal the toxicity effects of different Zn species (NPs, bulk, and ionic Zn) into environmentally important plant-bacterial system in soil. PMID- 25698521 TI - Efficacy and Safety of Posterior Versus Combined Posterior and Anterior Approach for the Treatment of Spinal Tuberculosis: A Meta-Analysis. AB - OBJECTIVE: Surgical treatment is an important strategy for the treatment of spinal tuberculosis (TB). Several approaches have been reported for the surgery. However, no single study has had a large enough sample population to definitively determine whether the single posterior approach is as effective and safe as the combined posterior and anterior approach for the treatment of spinal TB. A meta analysis was conducted to evaluate the clinical efficacy and safety of posterior versus combined posterior and anterior approach for the treatment of spinal TB. METHODS: In this meta-analysis, electronic databases, such as PubMed, MEDLINE, EMBASE, Google scholar, and Cochrane library, were searched to select the potentially relevant reports that compared the outcomes of the posterior approach (group A) with the combined posterior and anterior approach (group B) in the treatment of spinal TB. Relevant journals and references were also searched manually. Data extraction and quality assessment were according with Cochrane Collaboration guidelines. Outcome assessments were operation time, blood loss, correction of angle, loss of correction, hospital stay, fusion time of the grafting bone, neurological improvement, and complications after surgery. Results were expressed as odds ratio for dichotomous outcomes and mean difference for continuous outcomes with 95% confidence interval. RESULTS: Five controlled clinical trials published between 2012 and 2014, involving 253 patients (group A, 129; group B, 124) with spinal TB were retrieved in this study. The overall meta analysis showed that there were significant differences (P< 0.01) between groups A and B in operation time, blood loss, hospital stay, and complications after surgery. However, no significant differences (P> 0.05) were observed in correction of angle, loss of correction at the final follow-up, fusion time of the grafting bone, and neurological improvement after surgery between groups A and B. CONCLUSIONS: The posterior approach appeared to have the same clinical efficacy, but with less operation time, blood loss, hospital stay, and complications compared with the combined posterior and anterior approach in the treatment of sinal TB. However, more high-quality, randomized controlled trials are required to compare these approaches and guide clinical decision-making. PMID- 25698522 TI - Observation and modeling of deep brain stimulation electrode depth in the pallidal target of the developing brain. AB - OBJECTIVE: It is unclear how brain growth with age affects electrode position in relation to target for children undergoing deep brain stimulation surgery. We aimed to model projected change in the distance between the entry point of the electrode into the brain and target during growth to adulthood. METHODS: Modeling was performed using a neurodevelopmental magnetic resonance imaging database of age-specific templates in 6-month increments from 4 to 18 years of age. Coordinates were chosen for a set of entry points into both cerebral hemispheres and target positions within the globus pallidus internus on the youngest magnetic resonance imaging template. The youngest template was nonlinearly registered to the older templates, and the transformations generated by these registrations were applied to the original coordinates of entry and target positions, mapping these positions with increasing age. Euclidean geometry was used to calculate the distance between projected electrode entry and target with increasing age. RESULTS: A projected increase in distance between entry point and target of 5-10 mm was found from age 4 to 18 years. Most change appeared to occur before 7 years of age, after which minimal change in distance was found. CONCLUSIONS: Electrodes inserted during deep brain stimulation surgery are tethered at the point of entry to the skull. Brain growth, which could result in a relative retraction with respect to the original target position, appears to occur before 7 years of age, suggesting careful monitoring is needed for children undergoing implantation before this age. Reengineering of electrode design could avoid reimplantation surgery in young children undergoing deep brain stimulation. PMID- 25698523 TI - Subarachnoid Hemorrhage and the Pituitary. PMID- 25698524 TI - Perspective on "Modified WFNS Subarachnoid Hemorrhage Grading System". PMID- 25698525 TI - Telovelar Approach to Fourth Ventricle Tumors: Highlights and Limitations. AB - OBJECTIVE: Fourth ventricle tumors have been traditionally approached by opening the cerebellar vermis. The "telovelar" approach is an alternative approach performed through the cerebellomedullary fissure to gain access to the fourth ventricle, avoiding neural tissue damage. We describe our experience with this approach and predictive factors for the extent of resection (EOR) and for outcomes. METHODS: We retrospectively analyzed the data of patients who underwent resection of fourth ventricle lesions using a bilateral telovelar approach between June 1998 and June 2013. We evaluated EOR, clinical outcomes, complication rates, and postoperative cerebellar dysfunction. Univariate and multivariate analyses were performed to identify the predictive factors for EOR and outcomes. RESULTS: Forty-five patients were included in this series. Complete resection was obtained in 40 patients (88.9%). One patient (2.2%) had lower cranial nerve palsy and died 2 months after surgery. Two patients (4.5%) had persistent deficits of the sixth cranial nerve. Two patients (4.5%) developed shunt dependency. Brainstem attachment, tumor size >4 cm, and location in the rostral one third of the ventricle were associated with a higher rate of subtotal resection and neurological worsening. Cerebellar mutism did not occur in any patient. CONCLUSIONS: Exposure of the fourth ventricle was satisfactory in all of the patients, and the floor of the fourth ventricle could be visualized early and be protected. EOR and outcomes were satisfactory in 90% of patients, including those harboring large tumors or lesions attached to the lateral or superolateral recesses of the ventricle. Deep rostral tumor attachment was the main limitation of the telovelar approach. PMID- 25698526 TI - An Experimental-Computational Study of Catheter Induced Alterations in Pulse Wave Velocity in Anesthetized Mice. AB - Computational methods for solving problems of fluid dynamics and fluid-solid interactions have advanced to the point that they enable reliable estimates of many hemodynamic quantities, including those important for studying vascular mechanobiology or designing medical devices. In this paper, we use a customized version of the open source code SimVascular to develop a computational model of central artery hemodynamics in anesthetized mice that is informed with experimental data on regional geometries, blood flows and pressures, and biaxial wall properties. After validating a baseline model against available data, we then use the model to investigate the effects of commercially available catheters on the very parameters that they are designed to measure, namely, murine blood pressure and (pressure) pulse wave velocity (PWV). We found that a combination of two small profile catheters designed to measure pressure simultaneously in the ascending aorta and femoral artery increased the PWV due to an overall increase in pressure within the arterial system. Conversely, a larger profile dual-sensor pressure catheter inserted through a carotid artery into the descending thoracic aorta decreased the PWV due to an overall decrease in pressure. In both cases, similar reductions in cardiac output were observed due to increased peripheral vascular resistance. As might be expected, therefore, invasive transducers can alter the very quantities that are designed to measure, yet advanced computational models offer a unique method to evaluate or augment such measurements. PMID- 25698527 TI - Phenotypic assessment of THC discriminative stimulus properties in fatty acid amide hydrolase knockout and wildtype mice. AB - A number of studies have examined the ability of the endogenous cannabinoid anandamide to elicit Delta(9)-tetrahydrocannabinol (THC)-like subjective effects, as modeled through the THC discrimination paradigm. In the present study, we compared transgenic mice lacking fatty acid amide hydrolase (FAAH), the enzyme primarily responsible for anandamide catabolism, to wildtype counterparts in a THC discrimination procedure. THC (5.6 mg/kg) served as a discriminative stimulus in both genotypes, with similar THC dose-response curves between groups. Anandamide fully substituted for THC in FAAH knockout, but not wildtype, mice. Conversely, the metabolically stable anandamide analog O-1812 fully substituted in both groups, but was more potent in knockouts. The CB1 receptor antagonist rimonabant dose-dependently attenuated THC generalization in both groups and anandamide substitution in FAAH knockouts. Pharmacological inhibition of monoacylglycerol lipase (MAGL), the primary catabolic enzyme for the endocannabinoid 2-arachidonoylglycerol (2-AG), with JZL184 resulted in full substitution for THC in FAAH knockout mice and nearly full substitution in wildtypes. Quantification of brain endocannabinoid levels revealed expected elevations in anandamide in FAAH knockout mice compared to wildtypes and equipotent dose-dependent elevations in 2-AG following JZL184 administration. Dual inhibition of FAAH and MAGL with JZL195 resulted in roughly equipotent increases in THC-appropriate responding in both groups. While the notable similarity in THC's discriminative stimulus effects across genotype suggests that the increased baseline brain anandamide levels (as seen in FAAH knockout mice) do not alter THC's subjective effects, FAAH knockout mice are more sensitive to the THC-like effects of pharmacologically induced increases in anandamide and MAGL inhibition (e.g., JZL184). PMID- 25698528 TI - Pharmacological modulation of abnormal involuntary DOI-induced head twitch response movements in male DBA/2J mice: II. Effects of D3 dopamine receptor selective compounds. AB - We recently reported on the characterization of the hallucinogen 2,5-dimethoxy-4 methylamphetamine's (DOI) ability to elicit a head twitch response (HTR) in DBA/2J mice and the ability of D2 vs. D3 dopamine receptor selective compounds to modulate that response. For these studies, the ability of D3 vs. D2 dopamine receptor selective compounds to attenuate the DOI-dependent HTR was examined. WC 10, a D3 dopamine receptor weak partial agonist with 40-fold binding selectivity for D3 vs. D2 dopamine receptors, produced a dose-dependent decrease in the DOI induced HTR (IC50 = 3.7 mg/kg). WC 44, a D3 receptor selective full agonist, also inhibited the DOI-induced HTR (IC50 = 5.1 mg/kg). The effect of two D3 receptor selective partial agonists, LAX-4-136 and WW-III-55, were also evaluated. These analogs exhibit 150-fold and 800-fold D3 vs. D2 binding selectivity, respectively. Both compounds inhibited the HTR with similar potency but with different maximum efficacies. At 10 mg/kg WW-III-55 inhibited the HTR by 95%, while LAX-4-136 administration resulted in a 50% reduction. In addition, DOI (5 mg/kg) was administered at various times after LAX-4-136 or WW-III-55 administration to compare the duration of action. The homopiperazine analog LAX-4 136 exhibited greater stability. An assessment of our test compounds on motor performance and coordination was performed using a rotarod test. None of the D3 dopamine receptor selective compounds significantly altered latency to fall, suggesting that these compounds a) did not attenuate the DOI-dependent HTR due to sedative or adverse motor effects and b) may have antipsychotic/antihallucinogenic activity. PMID- 25698529 TI - Analysis of time series of cattle rabies cases in Minas Gerais, Brazil, 2006 2013. AB - Vampire bats are potential transmitters of rabies in rural areas. Cattle rabies is relevant in the state of Minas Gerais due to the increasing cattle herds and geographical features of the area, which are favorable to bat populations. This study evaluated the occurrence of rabies in state cattle by analyzing the time series of monthly values, 2006-2012, describing some aspects of the areas and species affected. The study also pointed out the disease prediction for January December 2013. We used monthly data of cases reported to the Continental Epidemiological Surveillance System (SIVCONT) of the Ministry of Agriculture, Livestock, and Supply (MAPA), January 2006-March 2013. We also collected data on municipalities and other animal species affected by rabies for a descriptive analysis of the disease. The results indicate that cattle rabies is endemic in the State, with different intensities in different regions. The variables frequency of notifications and bat shelters had a positive and regular correlation (P = 0.035; r = 0.567) between them. With respect to data series, there was a fluctuation of the number of cases (5 to 29 cases per month) over 2006 and 2013, without trend or seasonality, although there would visually appear to be a downward trend. The results also suggest that the forecasting method is suitable for predicting future cases. Bovine species had the highest number of reporting, with 1007 cases (88.88 %), followed by equine species with 112 (9.89 %). The information provided by this study may help understand disease occurrence and find the most effective measures for rabies control in endemic areas. PMID- 25698530 TI - [Aortopulmonary window]. AB - The aortopulmonary window is a rare cause of heart failure in the neonate. It must be ruled out if there are signs of pulmonary edema without the most frequent left-right shunts. We report the echocardiographic images of a newborn who was admitted with symptoms of heart failure at our institution. PMID- 25698531 TI - A phase II study of arsenic trioxide in patients with relapsed or refractory malignant lymphoma. AB - Limited data have been reported regarding the use of arsenic trioxide (ATO) in the treatment of patients with relapsed or refractory malignant lymphoma; therefore, the present phase II study evaluated the efficacy and toxicity of ATO in such patients. A total of 35 patients were treated with ATO (0.25 mg/kg) infused for 1 h daily, 5 days a week, for a 6-week cycle. Patients were evaluated for the efficacy and toxicity of this regimen. The primary outcome evaluated was the overall response rate (ORR), including the complete and partial response rates. The secondary outcomes evaluated were the overall survival (OS), progression-free survival (PFS), and toxicity. Tumor response data were obtained from all 35 enrolled patients. The ORR was 43%, including complete responses in four patients (11%) and partial responses in 11 patients (31%). The median duration of response was 16 weeks (range 11-23 weeks). The median OS was 79 weeks (range 14-171 weeks), and the median PFS was 55 weeks (range 14-135 weeks). Grade I or II hematological toxicities were the most commonly reported adverse events. The results of this study appear promising for the treatment of relapsed or refractory malignant lymphoma, with well-tolerated ATO toxicity. PMID- 25698532 TI - Improved health-related quality of life of patients with metastatic renal cell carcinoma treated with a 2 weeks on and 1 week off schedule of sunitinib. AB - The objective of this study was to investigate the significance of changes from the standard dosing schedule of sunitinib, which is 4 weeks of treatment and 2 weeks off (schedule 4/2), to an alternative schedule with 2 weeks of treatment and 1 week off (schedule 2/1), after encountering dose-limiting toxicity in 45 consecutive Japanese patients with metastatic renal cell carcinoma (mRCC). Despite a definitively improved relative dose intensity of sunitinib by changing from schedule 4/2 to 2/1, this difference was not significant. Adverse events (AEs) occurred in all patients on both schedules 4/2 and 2/1; however, the proportion of patients experiencing AEs >= grade 3 on schedule 2/1 was significantly lower than that on schedule 4/2. Quality of life (QOL) analysis using SF-36 revealed that all eight scores during schedule 2/1 were more favorable than those during schedule 4/2, and there were significant differences in 2 of the 8 scores between these two schedules. Furthermore, multivariate analyses, which were performed to evaluate the contribution of several AEs on schedule 2/1 to the improvement of each score in SF-36, revealed that fatigue had independent impacts on two scores, despite the lack of an independent association between any scores and the remaining AEs examined. These findings suggest that schedule 2/1 is the optimal dosing schedule of sunitinib against mRCC that balances efficacy and toxicity, since treatment on schedule 2/1 resulted in a markedly improved QOL compared with that on schedule 4/2 by relieving the profile of sunitinib-related AEs. PMID- 25698533 TI - Prostate stem cell antigen (PSCA) mRNA expression in peripheral blood in patients with benign prostatic hyperplasia and/or prostate cancer. AB - The aim of this study was to determine whether detection of prostate stem cell antigen (PSCA) expression in BPH might be associated with the subsequent presence of Prostate cancer (PCa) and also to determine whether detection of PSCA expression has potential for prognosis in PCa. This study was comprised of 112 PCa patients, 111 BPH patients and 120 control subjects. We employed reverse transcriptase polymerase chain reaction (RT-PCR) to detect PSCA mRNA-bearing cells in peripheral blood. PSCA mRNA was detected in the peripheral blood of 71.4% PCa patients and in 13.5% of patients with BPH by RT-PCR. PSCA was positive in 80% of high-grade diseases compared with 20% of low-grade diseases (P = 0.01). Whereas only 38.8% of prostate-confined diseases were PSCA positive, 61.2% of extraprostatic diseases were PSCA positive (P < 0.001). Patients with a lymphovascular invasion of tumor emboli tended to be PSCA positive (P = 0.02). BPH patients with RT-PCR PSCA positive were significantly more likely to develop prostate cancer (OR = 16, 95% CI = 8.1-31.6, P < 0.001). In conclusion, RT-PCR PSCA positivity is significantly associated with the Gleason score, LV tumor emboli and whether or not the tumor was organ confined. In this study, RT-PCR PSCA detection may be a promising tumor marker of diagnostic and metastasis detection for patients with prostate cancer. Also, it may be an important test for predicting BPH patients who are at high risk of subsequent cancer development. PMID- 25698534 TI - The involvement of cell surface nucleolin in the initiation of CCR6 signaling in human hepatocellular carcinoma. AB - In recent years, the chemokine CC receptor 6 (CCR6) and its ligand CCL20 were reported to play an essential role in hepatocellular carcinoma (HCC). However, the role of cell surface nucleolin in the CCR6 pathway of HCC is not well featured. Using immunohistochemistry, Western blotting, siRNA, wound healing and transwell assay, we investigated the relationships of cell surface nucleolin and CCR6 signaling in HCC. In the present study, our findings identified that cell surface nucleolin and CCR6 protein were stained in most of HCC tissues (64, 68 %, respectively) and differently expressed in HCC cell lines; meanwhile, both expression has an association with advanced stage, lymph node metastasis and poor 5-year prognosis. According to in vitro assays, we found that the silencing of either cell surface nucleolin or CCR6 inhibited the protein expression of p-ERK, p-AKT, MMP2, MMP9 and ICAM-1 in the CCL20-stimulated HCCLM6 cells. Functional analysis revealed that cell surface nucleolin or CCR6 silencing significantly hampered HCCLM6 cell motility and invasiveness ability, when compared with control. In conclusion, this work suggests that cell surface nucleolin participates in the initiation of CCR6 pathway and biological behaviors of HCC, leading to HCC cell adhesion, migration and invasive behavior. In the clinical practice, cell surface nucleolin and CCR6 are recommended to predict poor prognosis and be used as a useful target for HCC patients. PMID- 25698535 TI - Long-term outcomes and prognostic analysis of radiofrequency ablation for small hepatocellular carcinoma: 10-year follow-up in Chinese patients. AB - Radiofrequency ablation (RFA) has been used as a curative therapy for small hepatocellular carcinoma (HCC). However, relatively little is known about the long-term outcome of RFA for small HCC in a background of hepatitis B infection, which is common among the Chinese population. Between May 2001 and May 2012, 837 patients with HCC nodules <=3 cm treated with RFA were enrolled in this study. We evaluated long-term survival rates, local tumor progression rates, complications and the prognostic factors. Among 1020 tumor nodules in 837 patients, complete ablation was achieved in 98.8% (1008/1020) and the 1-, 3-,5-, and 10-year overall survival rates were 91, 71, 54, and 33%, respectively. Multivariate analysis revealed that tumor number [P = 0.003, hazard ratio (HR) 1.523, 95% confidence interval (CI) 1.158-2.004], Child-Pugh grade (P = 0.001, HR 3.089, 95% CI 2.238 4.266), and serum-glutamyltranspeptidase level (P = 0.002, HR 1.576, 95% CI 1.251 1.985) were independent predictors of overall survival. The 1-, 3-, 5-, and 10 year recurrence-free survival rates were 74, 44, 30, and 15%, respectively. Multivariate analysis revealed that serum alpha-fetoprotein level (P = 0.041, HR 1.249, 95% CI 1.028-1.517) and tumor number (P = 0002, HR 1.449, 95% CI 1.143 1.836) were independent predictors of recurrence-free survival. There were no procedure-related patient deaths and major complications occurred in 0.59% (5/837) of patients. RFA achieved comparable long-term overall survival rates to those of surgical resection with fewer major complications and could therefore be considered as an alternative option for curative treatment of patients with small liver cancer. PMID- 25698536 TI - Aprepitant as prophylaxis of chemotherapy-induced nausea and vomiting in anthracyclines and cyclophosphamide-based regimen for adjuvant breast cancer. AB - The aim of our study was to evaluate the efficacy and safety of a three-drug antiemetic prophylaxis in a single-center series treated with anthracyclines and cyclophosphamide-based regimen for BC. We collected data from 92 consecutive patients treated with routine antiemetic prophylaxis consisted of aprepitant (oral 125 mg, on day 1; oral 80 mg, on days 2 and 3), a 5-HT3 receptor antagonist (palonosetron iv 0.25 mg, on day 1), and dexamethasone (iv 12 mg, on day 1). Acute and delayed phases were defined as the first 24 h and days 2-5 after treatment, respectively. Therapy outcomes were defined as complete response (CR), in case of no vomiting, no rescue treatment; complete protection (CP), in case of no vomiting, no rescue treatment, no significant nausea; and total control (TC), in case of no vomiting, no rescue treatment, no nausea. Overall, 89.1 and 81.5% of patients showed CR in acute and delayed phase, respectively; 67.4 and 62% showed CP in acute and delayed phase, respectively; and 52.2 and 48.9% of patients showed TC in acute and delayed phase, respectively. 4.3% complained an episode of emesis during the first 24 h from treatment, while in delayed phase, only 2.2% of patients had vomiting. Our analysis confirmed that a three-drug prophylaxis is safe, effective, and consequently highly recommended in patients who undergo anthracyclines and cyclophosphamide-based regimens, though still not classified as highly emetogenic chemotherapy by all the international guidelines. PMID- 25698538 TI - PinX1 inhibits cell proliferation, migration and invasion in glioma cells. AB - PinX1 induces apoptosis and suppresses cell proliferation in some cancer cells, and the expression of PinX1 is frequently decreased in some cancer and negatively associated with metastasis and prognosis. However, the precise roles of PinX1 in gliomas have not been studied. In this study, we found that PinX1 obviously reduced the gliomas cell proliferation through regulating the expressions of cell cycle-relative molecules to arrest cell at G1 phase and down-regulating the expression of component telomerase reverse transcriptase (hTERT in human), which is the hardcore of telomerase. Moreover, PinX1 could suppress the abilities of gliomas cell wound healing, migration and invasion via suppressing MMP-2 expression and increasing TIMP-2 expression. In conclusion, our results suggested that PinX1 may be a potential suppressive gene in the progression of gliomas. PMID- 25698537 TI - BUB1B promotes multiple myeloma cell proliferation through CDC20/CCNB axis. AB - Multiple myeloma (MM) is the second most common hematopoietic malignancy characterized by plasma cell proliferative disorder. In this study, we disclosed that expression of BUB1B significantly increased in high-risk myeloma patients especially in the most aggressive myeloma genetic subgroups of proliferation. Increased BUB1B expression promotes MM cell proliferation. Mechanism study showed that BUB1B expression was highly correlated to CDC20 and CCNB1/2 expression in MM cells, leading to increased MM cell proliferation. Therefore, BUB1B may be a potential target for MM treatment especially for high-risk MM patients. PMID- 25698539 TI - C23 protein meditates bone morphogenetic protein-2-mediated EMT via up-regulation of Erk1/2 and Akt in gastric cancer. AB - In our previous study, the epithelial-to-mesenchymal transition (EMT) has been identified to be involved in gastric cancer progression. Notably, nuclear protein C23 and bone morphogenetic protein-2 (BMP2) have been linked into EMT. However, the specific mechanisms underlying BMP2 pathway-mediated EMT are not still unraveled. In this study, we adopted immunohistochemistry and immunoblotting to determine the expression of C23 and BMP2 receptor II (BMPR-II) in 90 gastric cancer samples and cell lines. Subsequently, relevant cell lines were selected to be treated with si-C23 or si-BMPRII and the detection of in vitro assay. Our results revealed that both C23 and BMPRII were aberrantly and constitutively expressed in gastric cancer specimens and cell lines, whose expression was positively associated with metastasis, stage and differentiation, and portended poor survival outcome of gastric cancer patients. In vitro assay validated the increased expression of p-Erk1/2, p-Akt, vimentin, N-cadherin, and MMP2 in BMP2 stimulated MGC803 cells, which was in a dose-dependent manner. By contrast, si C23 treatment attenuated the BMP2-stimulated expression of p-Erk1/2, p-Akt, vimentin, N-cadherin, and MMP2. Also, the treatment of either si-C23 or si-BMPRII decreased the ability of migration and invasion of MGC803 cells. In conclusion, C23 mediates BMP2-induced EMT progression via the up-regulation of Erk1/2 and Akt signaling pathway in gastric cancer, which indicated both C23 and BMPRII pathway could be recommended as prospective targets or biomarkers to antagonize the progression of gastric cancer. PMID- 25698540 TI - Brainstem cavernous malformations resected via miniature craniotomies: technique and approach selection. AB - Brainstem cavernous malformations can cause devastating neurologic disability when they hemorrhage, which occurs at a higher rate in the brainstem than in other locations. Traditional access to these lesions requires a large craniotomy with extensive exposure and manipulation of vital structures. We present a case series of patients who underwent surgical resection of brainstem cavernous malformations using minimally invasive approaches at our institution from January 2012 to August 2014, all of whom had experienced at least one hemorrhage prior to presentation. Approach choice was determined by location of the cavernous malformation in relation to the brainstem surface. Resection occurred through our described standardized method. Postoperatively, there were three instances of transient neurologic symptoms, all of which resolved at time of last follow-up. All eight patients experienced neurologic improvement after surgery, with four patients showing no deficits at last follow-up. Approach selection rationale and technical nuances are presented on a case-by-case basis. With carefully planned keyhole approaches to cavernous malformations presenting to the brainstem surface, excellent results may be achieved without the necessity of larger conventional craniotomies. We believe the nuances presented may be of use to others in the surgical treatment of these lesions. PMID- 25698541 TI - Deep brain stimulation in Huntington's disease: assessment of potential targets. AB - Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder that has very few effective therapeutic interventions. Since the disease has a defined neural circuitry abnormality, neuromodulation could be an option. Case reports, original research, and animal model studies were selected from the databases of Medline and PubMed. All related studies published up to July 2014 were included in this review. The following search terms were used: "Deep brain stimulation," "DBS," "thalamotomy," "pallidal stimulation," and "Huntington's Disease," "HD," "chorea," or "hyperkinetic movement disorders." This review examines potential nodes in the HD circuitry that could be modulated using deep brain stimulation (DBS) therapy. With rapid evolution of imaging and ability to reach difficult targets in the brain with refined DBS technology, some phenotypes of HD could potentially be treated with DBS in the near future. Further clinical studies are warranted to validate the efficacy of neuromodulation and to determine the most optimal target for HD. PMID- 25698542 TI - MKP-3 regulates PDGF-BB effects and MAPK activation in meningioma cells. AB - Autocrine platelet derived growth factor-BB (PDGF-BB) and cerebrospinal fluid, which also contains PDGF, stimulate proliferation of leptomeningeal and meningioma cells, in part, by activation of the Raf-1-MEK-1-MAPK pathway. The negative regulators of this activation are not known. However, PDGF receptors and p44/42 MAPK are regulated, in part, by mitogen activated kinase phosphatase 3 (MKP-3) and Src homology carboxyl terminus protein (SHP-2). Six fetal and one adult human leptomeninges specimens and 22 meningiomas were evaluated for MKP-3, SHP-2, and phospho-SHP-2 as well as activation/phosphorylation of MEK1/2, p44/42 MAPK, Akt and signal transducer and activator of transcription 3 (STAT3) by western blot and MKP3 expression by polymerase chain reaction. PDGF-BB and cerebrospinal fluid effects on these phosphatases and signaling were also studied in vitro. MKP-3 and phospho-p44/42 MAPK were detected in all or six of seven leptomeninges, respectively. MKP-3 was detected in six of eight World Health Organization grade I and II meningiomas. Three of four grade I and five of five grade II with no or low MKP-3 had high levels of phospho-p44/42MAPK. MKP3 was not detected in four of six grade III meningiomas. These had high levels of phospho p44/42MAPK. SHP2 was found in all leptomeninges and meningiomas while phospho-SHP 2 was found in 11 to 33% of grade I-III meningiomas. Reduced MKP-3 may facilitate PDGF-BB autocrine and paracrine mitogenic effects in a subpopulation of higher grade meningiomas by increasing phospho-p44/42 MAPK. PMID- 25698543 TI - Mouse models of glioma. AB - Gliomas are the most common primary tumour in the central nervous system in adults. The pathological hallmark of gliomas is their propensity for extensive infiltration into the surrounding brain parenchyma which results in tumour recurrence. Despite the use of optimal surgical removal and adjuvant therapies the most aggressive of these tumours, glioblastoma multiforme, has a poor patient prognosis, with median survival of less than 15 months. In this review, we discuss mouse glioma models that have been utilised to advance our basic knowledge of the processes involved in gliomagenesis and their use in the testing of novel therapies and treatment regimens in the preclinical setting. PMID- 25698544 TI - A novel literature-based approach to identify genetic and molecular predictors of survival in glioblastoma multiforme: Analysis of 14,678 patients using systematic review and meta-analytical tools. AB - Glioblastoma multiforme (GBM) has a poor prognosis despite maximal multimodal therapy. Biomarkers of relevance to prognosis which may also identify treatment targets are needed. A few hundred genetic and molecular predictors have been implicated in the literature, however with the exception of IDH1 and O6-MGMT, there is uncertainty regarding their true prognostic relevance. This study analyses reported genetic and molecular predictors of prognosis in GBM. For each, its relationship with univariate overall survival in adults with GBM is described. A systematic search of MEDLINE (1998-July 2010) was performed. Eligible papers studied the effect of any genetic or molecular marker on univariate overall survival in adult patients with histologically diagnosed GBM. Primary outcomes were median survival difference in months and univariate hazard ratios. Analyses included converting 126 Kaplan-Meier curves and 27 raw data sets into primary outcomes. Seventy-four random effects meta-analyses were performed on 39 unique genetic or molecular factors. Objective criteria were designed to classify factors into the categories of clearly prognostic, weakly prognostic, non-prognostic and promising. Included were 304 publications and 174 studies involving 14,678 unique patients from 33 countries. We identified 422 reported genetic and molecular predictors, of which 52 had ?2 studies. IDH1 mutation and O6-MGMT were classified as clearly prognostic, validating the methodology. High Ki-67/MIB-1 and loss of heterozygosity of chromosome 10/10q were classified as weakly prognostic. Four factors were classified as non-prognostic and 13 factors were classified as promising and worthy of additional investigation. Funnel plot analysis did not identify any evidence of publication bias. This study demonstrates a novel literature and meta-analytical based approach to maximise the value that can be derived from the plethora of literature reports of molecular and genetic factors in GBM. Caution is advised in over-interpreting the results due to study limitations. Further research to develop this methodology and improvements in study reporting are suggested. PMID- 25698545 TI - A multiscale decomposition approach to detect abnormal vasculature in the optic disc. AB - This paper presents a multiscale method to detect neovascularization in the optic disc (NVD) using fundus images. Our method is applied to a manually selected region of interest (ROI) containing the optic disc. All the vessels in the ROI are segmented by adaptively combining contrast enhancement methods with a vessel segmentation technique. Textural features extracted using multiscale amplitude modulation frequency-modulation, morphological granulometry, and fractal dimension are used. A linear SVM is used to perform the classification, which is tested by means of 10-fold cross-validation. The performance is evaluated using 300 images achieving an AUC of 0.93 with maximum accuracy of 88%. PMID- 25698546 TI - Watershed based intelligent scissors. AB - Watershed based modification of intelligent scissors has been developed. This approach requires a preprocessing phase with anisotropic diffusion to reduce subtle edges. Then, the watershed transform enhances the corridors. Finally, a roaming procedure, developed in this study, delineates the edge selected by a user. Due to a very restrictive set of pixels, subjected to the analysis, this approach significantly reduces the computational complexity. Moreover, the accuracy of the algorithm performance makes often one click point to be sufficient for one edge delineation. The method has been evaluated on structures as different in shape and appearance as the retina layers in OCT exams, chest and abdomen in CT and knee in MR studies. The accuracy is comparable with the traditional Life-Wire approach, whereas the analysis time decreases due to the reduction of the user interaction and number of pixels processed by the method. PMID- 25698547 TI - Mineralization-related modifications in the calcifying tendons of turkey (Meleagris gallopavo). AB - The tendons of some birds undergo a physiological process of gradual mineralization, usually limited to the central portion of the tendon and resulting in an increase of the elastic modulus and the ultimate strength. The present study was carried out by light microscopy and scanning electron microscopy and was focused on the structural and ultrastructural modifications occurring in this tissue during biomineralization. In comparison with most other tendons, turkey tendons appeared to be more finely subdivided into thinner fascicles and to contain a greater amount of cell-rich endotenon tissue. The most obvious finding, however, was the complete disappearance of the crimps in the calcified portions of the tendon, while they were present with the usual morphology in the non-mineralized portion. The electron microscopy revealed in the mineralized tendon traces of pre-existing crimps, locked in the straightened out position by the infiltrating mineral phase. This latter was composed of two different types of fine particles, respectively, growing inside and around the collagen fibrils and appearing as tightly packed platelets or as larger, flat platelets regularly arranged in phase with the D-period of collagen. The perifibrillar mineral could play a critical role in the mechanical coupling of adjoining fascicles and in the transmission of tensile loads along the tendon itself. PMID- 25698548 TI - Prevention of autologous skin graft loss. PMID- 25698549 TI - Surgical treatment of severe or moderate axillary burn scar contracture with transverse island scapular flap and expanded transverse island scapular flap in adult and pediatric patients--A clinical experience of 15 cases. AB - BACKGROUND: Axillary burn scar contracture is common and troublesome. With the aim of restoring the function of the upper extremities, a proper local flap with minor damage and preclusion from recurrence should be developed to guarantee satisfactory results. A minor webbed scar contracture was rectified by Z-plasty. However, severe or moderate contracture must be constructed by a local flap. An island scapular flap has been used in pediatric patients for repairing axillary contracture. However, no detailed description of the use of a transverse island scapular flap (TISF) was reported to correct the deformity. Moreover, an expanded transverse island scapular flap (ETISF) used for increasing the volume of skin for severe axillary contracture in adults and developing children was also not presented. METHODS: From 2006 to 2013, TISFs were harvested for 12 pediatric patients (5-12 years of age) with 15 sides of severe or moderate axillary burn scar contractures. Four ETISFs were designed for two adult patients (38 and 32 years of age). The flap size was between 10 cm*5 cm and 20 cm*10 cm. In one pediatric patient, a cicatrix was observed on the surface of the flap's donor site. Handheld Doppler was applied to detect the pedicle. RESULTS: The patients were required to lift their upper arms regularly each day after the operation. All 19 flaps survived completely. Axillary burn scar contractures were corrected successfully in 11 patients with no expander implantation. The lifting angle was enhanced considerably with 1-3 years of follow-up in the 11 patients. Only one pediatric patient with cicatrix on the donor site displayed tight skin on the back and a little restraint on the shoulder. The patient's parents were told to intensify the chin-up movement on the horizontal bar. She was in the process of a 3-month follow-up. The lifting angle was also improved significantly in the latter three cases of expander implantation although they were followed up for a short duration of 3 months. Due to poor flap design, the donor site of one adult patient was not closed directly with the help of skin grafting on the left side of her back. CONCLUSIONS: Considering the flap's negligible level of later contracture and minimal trauma, local TISF based on the transverse branch of the circumflex scapular artery is a good choice for reconstruction of axillary burn scar contractures. If the TISF is not able to meet the demand, the expander implanted in advance can be more beneficial. PMID- 25698550 TI - Prospective study of the influence of psychological and medical factors on quality of life and severity of symptoms among patients with oral squamous cell carcinoma. AB - About 400,000 people worldwide are diagnosed with oral squamous cell carcinoma (SCC) annually, and the incidence is increasing. Many advanced carcinomas of the oral cavity require radical surgical treatment that can impair patient's quality of life (QoL) and severity of symptoms. We therefore aimed to identify coping strategies and disease-specific medical factors that affect QoL and severity of symptoms. Patients with oral SCC were asked to complete the Freiburg Questionnaire on Coping with Illness (FQCI), the University of Washington Quality of life Questionnaire (UW-QOL version 4), and the Brief Symptom Inventory (BSI) to measure psychological stress. We also assessed the impact of various factors on QoL and severity of symptoms, including stage and site of tumour, method of reconstruction, time of diagnosis, and social structure (age, sex, marital status, living arrangements, level of education, and employment). We enrolled a consecutive sample of 104 patients over a period of one year. Stepwise linear regression analyses indicated that both depressive coping and size of tumour had an adverse effect on QoL and severity of symptoms. Patients with high educational attainment and those who lived alone reported impaired QoL, and women experienced increased severity of symptoms. Impaired QoL and increased severity of symptoms were associated with a depressive style of coping, size of tumour, educational attainment, and living arrangements. It is important to identify these patients during treatment as they could benefit from psycho-oncological counselling. PMID- 25698551 TI - Canada to legalise physician-assisted dying. PMID- 25698552 TI - Universal health coverage: reaching a consensus. PMID- 25698553 TI - Hollow-fiber flow field-flow fractionation and multi-angle light scattering investigation of the size, shape and metal-release of silver nanoparticles in aqueous medium for nano-risk assessment. AB - Due to the increased use of silver nanoparticles in industrial scale manufacturing, consumer products and nanomedicine reliable measurements of properties such as the size, shape and distribution of these nano particles in aqueous medium is critical. These properties indeed affect both functional properties and biological impacts especially in quantifying associated risks and identifying suitable risk-mediation strategies. The feasibility of on-line coupling of a fractionation technique such as hollow-fiber flow field flow fractionation (HF5) with a light scattering technique such as MALS (multi-angle light scattering) is investigated here for this purpose. Data obtained from such a fractionation technique and its combination thereof with MALS have been compared with those from more conventional but often complementary techniques e.g. transmission electron microscopy, dynamic light scattering, atomic absorption spectroscopy, and X-ray fluorescence. The combination of fractionation and multi angle light scattering techniques have been found to offer an ideal, hyphenated methodology for a simultaneous size-separation and characterization of silver nanoparticles. The hydrodynamic radii determined by fractionation techniques can be conveniently correlated to the mean average diameters determined by multi angle light scattering and reliable information on particle morphology in aqueous dispersion has been obtained. The ability to separate silver (Ag(+)) ions from silver nanoparticles (AgNPs) via membrane filtration during size analysis is an added advantage in obtaining quantitative insights to its risk potential. Most importantly, the methodology developed in this article can potentially be extended to similar characterization of metal-based nanoparticles when studying their functional effectiveness and hazard potential. PMID- 25698554 TI - Scavenger receptor for lipoteichoic acid is involved in the potent ability of Lactobacillus plantarum strain L-137 to stimulate production of interleukin 12p40. AB - Heat-killed Lactobacillus plantarum strain L-137 (HK L-137) is a more potent inducer of interleukin (IL)-12 than other heat-killed Lactobacillus strains. To elucidate the mechanism involved in this IL-12p40 induction, we compared HK L-137 with heat-killed L. plantarum strain JCM1149 (HK JCM1149) by nuclear magnetic resonance and mass spectrometry. Results showed that HK L-137 contained lipoteichoic acid (LTA) with a chemical structure similar to that of JCM1149, except for a lower degree of glucosyl substitution in the poly(glycerol phosphate) backbone. Lysozyme sensitivity and electrophoretic moiety analysis revealed that HK L-137 exposed more LTA on its cell surface than HK JCM1149. Phagocytosis of HK L-137 by splenic adherent cells was significantly greater than that of HK JCM1149. Anti-LTA antibody and anti-scavenger receptor-A (SR-A) antibody selectively inhibited phagocytosis of HK L-137, as well as IL-12p40 production, by splenic adherent cells. Thus, a higher efficiency of phagocytosis of HK L-137 via SR-A for LTA is responsible for the potent IL-12p40 induction. PMID- 25698555 TI - Dendritic cell immunotherapy combined with cytokine-induced killer cells promotes skewing toward Th2 cytokine profile in patients with metastatic non-small cell lung cancer. AB - Dendritic cell (DC) vaccination and cytokine-induced killer (CIK) cell therapy (DC/CIK) have shown limited success in the treatment of advanced non-small cell lung cancer (NSCLC). To investigate the reason for this limited success, the effects of DC/CIK cell therapy on the immune responses of tumor-bearing patients and patients with resected NSCLC were evaluated. In the total 50 patients studied, the serum concentrations of the Th2 cytokines (IL-4 and IL-10) in tumor bearing patients were significantly higher than those with resected NSCLC before immunotherapy. The post-therapy Th1 cytokine (IFN-gamma) level in patients with resected NSCLC significantly increased from the pre-therapy level. In contrast, significantly enhanced post-therapy Th2 cytokine (IL-4 and IL-10) levels were found in tumor-bearing patients. The intracellular staining assay revealed that DC/CIK cell therapy increased the IFN-gamma-producing T lymphocyte (CD8(+)IFN gamma(+)) frequency in patients with resected NSCLC, but these lymphocytes were not found in tumor-bearing patients. Furthermore, overproduction of vascular endothelial growth factor (VEGF) in tumor-bearing patients showed a statistically positive correlation with IL-4, suggesting that VEGF might be responsible for the predominance of serum Th2 cytokines. In a word, tumor-bearing patients developed a Th2-dominant status that could not be reversed toward Th1 following immunotherapy. A combined regiment of DC vaccination and CIK cell therapy with other treatments to overcome systemic Th2-dominant immune response might improve the current clinical benefit. PMID- 25698556 TI - Inhibitory effects of kaempferol-3-O-rhamnoside on ovalbumin-induced lung inflammation in a mouse model of allergic asthma. AB - The modification of natural flavonoid by glycosylation alters their physicochemical and pharmacokinetic properties, such as increased water solubility and stability, reduced toxicity, and sometimes enhanced or even new pharmacological activities. Kaempferol (KF), a plant flavonoid, and its glycosylated derivative, kaempferol-3-O-rhamnoside (K-3-rh), were evaluated and compared for their anti-inflammatory, anti-oxidant, and anti-asthmatic effects in an asthma model mouse. The results showed that K-3-rh fully maintained its anti inflammatory and anti-asthmatic effects compared with KF in an asthma model mouse. Both KF and K-3-rh significantly reduced the elevated inflammatory cell numbers in the bronchoalveolar lavage fluid (BALF). KF and K-3-rh also significantly inhibited the increase in Th2 cytokines (IL-4, IL-5, and IL-13) and TNF-alpha protein levels through inhibition of the phosphorylation Akt and effectively suppressed eosinophilia in a mouse model of allergic asthma. The total immunoglobulin (Ig) E levels in the serum and BALF were also blocked by KF and K-3-rh to similar extents. K-3-rh exerts similar or even slightly higher inhibitory effects on Th2 cytokines and IgE production compared with KF, whereas K-3-rh was less effective at DPPH radical scavenging and the inhibition of ROS generation in inflammatory cells compared with KF. These results suggested that the K-3-rh, as well as KF, may also be a promising candidate for the development of health beneficial foods or therapeutic agents that can prevent or treat allergic asthma. PMID- 25698557 TI - Timosaponin AIII and its metabolite sarsasapogenin ameliorate colitis in mice by inhibiting NF-kappaB and MAPK activation and restoring Th17/Treg cell balance. AB - The rhizome of Anemarrhena asphodeloides (AA, family Liliaceae), which contains furostanol and spirostanol saponins, is a typical herbal medicine that improves learning and memory in rats and inhibits inflammation. In a preliminary study, timosaponin AIII, one of AA main constituents, was metabolized to sarsasapogenin by gut microbiota and inhibited NF-kappaB activation in lipopolysaccharide (LPS) stimulated macrophages. Here we have investigated the anti-inflammatory effects of AIII and sarsasapogenin in vitro and in vivo. Both AIII and sarsasapogenin potently inhibited NF-kappaB and MAPK activation, as well as IRAK1, TAK1, and IkappaBalpha phosphorylation in LPS-stimulated macrophages. Further, AIII and sarsasapogenin inhibited the binding of LPS to macrophage Toll-like receptor 4, as well as polarization of M2 to M1 macrophages. Oral administration of AIII and sarsasapogenin inhibited 2,3,4-trinitrobenzene sulfonic acid (TNBS)-induced colon shortening and myeloperoxidase activity in mice, along with reducing NF-kappaB activation and interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha, and IL 6 levels, while simultaneously increasing IL-10. Both compounds inhibited Th17 cell differentiation in colonic lamina propria, but induced Treg cell differentiation. Further, AIII and sarsasapogenin inhibited the differentiation of splenic CD4(+) T cells into Th17 cells in vitro. The vitro and in vivo anti inflammatory effects of sarsasapogenin were more potent than AIII. These results suggest that orally administered AIII may be metabolized to sarsasapogenin by gut microbiota, which may ameliorate inflammatory diseases such as colitis by inhibiting TLR4-NF-kappaB/MAPK signaling pathway and restoring Th17/Treg cell balance. PMID- 25698558 TI - Protection against reperfusion lung injury via aborgating multiple signaling cascades by trichostatin A. AB - Trichostatin A (TSA) is a histone deacetylase inhibitor with anti-inflammatory effects. Nonetheless, little information is available about the effect of TSA in ischemia-reperfusion (IR)-induced lung injury. In a perfused rat lung model, IR was induced by 40min of ischemia followed by 60min of reperfusion. The rat lungs were randomly divided into several groups including control, control+TSA (0.1mg/kg), IR, and IR+various dosages of TSA (0.05, 0.075, 0.1mg/kg). Bronchoalveolar lavage fluids and lung tissues were obtained and examined at the end of the experiment. TSA dose-dependently diminished IR-induced increased vascular permeability and edema, pulmonary artery pressure, and histological changes in the lungs. Additionally, TSA suppressed lavage tumor necrosis factor alpha and cytokine-induced neutrophil chemoattractant concentrations, cell infiltration, and myeloperoxidase-positive cells in the lung tissue. Furthermore, TSA attenuated the phosphorylation of extracellular signal-regulated kinase, p38, and c-Jun N-terminal kinase, degradation of the inhibitor of nuclear factor (NF) kappaB, and nuclear NF-kappaB levels. TSA also decreased poly (ADP-ribose) polymerase but enhanced acetylated histone H3 acetylation, Bcl-2, and mitogen activated protein kinase phosphatase-1 (MKP-1) expression in IR lung tissue. Therefore, TSA exerted a protective effect on IR-induced lung injury via increasing histone acetylation and MKP-1 protein expression, repressing NF kappaB, mitogen-activated protein kinase, and apoptosis signaling pathways. PMID- 25698559 TI - Hypergastrinemia. AB - Gastrin is an important hormone of the digestive system, which assists gastric acid secretion. It may be pathologically elevated in conditions such as Zollinger Ellison syndrome, or due to common medications such as proton pump inhibitors. In this review we provide an overview of the pathophysiology and medical causes of hypergastrinemia, diagnostic testing and clinical consequences of chronic hypergastrinemia. PMID- 25698560 TI - A meta-analysis on efficacy and safety: single-balloon vs. double-balloon enteroscopy. AB - BACKGROUND AND AIM: Double-balloon enteroscopy (DBE) and single-balloon enteroscopy (SBE) are new techniques capable of providing deep enteroscopy. Results of individual studies comparing these techniques have not been able to identify a superior strategy. Our aim was to systematically pool all available studies to compare the efficacy and safety of DBE with SBE for evaluation of the small bowel. METHODS: Databases were searched, including PubMed, Embase, and the Cochrane Central Register of Controlled Trials. The main outcome measures were complete small-bowel visualization, diagnostic yield, therapeutic yield, and complication rate. Statistical analysis was performed using Review Manager (RevMan version 5.2). Meta-analysis was performed using fixed-effect or random effect methods, depending on the absence or presence of significant heterogeneity. We used the chi(2) and I(2) test to assess heterogeneity between trials. Results were expressed as risk ratios (RR) or mean differences with 95% confidence intervals (CI). RESULTS: Four prospective, randomized, controlled trials with a total of 375 patients were identified. DBE was superior to SBE for visualization of the entire small bowel [pooled RR = 0.37 (95% CI: 0.19-0.73; P = 0.004)]. DBE and SBE were similar in ability to provide diagnosis [pooled RR = 0.95 (95% CI: 0.77-1.17; P = 0.62)]. There was no significant difference between DBE and SBE in therapeutic yield [pooled RR = 0.78 (95% CI: 0.59-1.04; P = 0.09)] and complication rate [pooled RR = 1.08 (95% CI: 0.28-4.22); P = 0.91]. CONCLUSIONS: DBE was superior to SBE with regard to complete small bowel visualization. DBE was similar to SBE with regard to diagnostic yield, ability to provide treatment and complication rate, but these results should be interpreted with caution as they is based on very few studies and the overall quality of the evidence was rated as low to moderate, due to the small sample size. PMID- 25698561 TI - Core curriculum illustration: scapulothoracic disassociation. AB - This is the 14th installment of a series that will highlight one case per publication issue from the bank of cases available online as part of the American Society of Emergency Radiology (ASER) educational resources. Our goal is to generate more interest in and use of our online materials. To view more cases online, please visit the ASER Core Curriculum and Recommendations for Study online at: http://www.aseronline.org/curriculum/toc.htm . PMID- 25698562 TI - Skull fractures in pediatric patients on computerized tomogram: comparison between routing bone window images and 3D volume-rendered images. AB - Skull fracture is a common finding following head trauma. It has a prognostic significance and its presence points to severe trauma. Additionally, there is a greater possibility of detecting associated small underlying extra-axial hematomas and subtle injuries to the brain parenchyma. In pediatric patients, the presence of multiple open sutures often makes fracture evaluation challenging. In our experience, 3D volume (3DV)-rendered CT images complement routine axial bone window (RBW) images in detection and characterization of fractures. This is a multi-reader, multi-case, paired retrospective study to compare the sensitivity and specificity of RBW and 3DV images in detection of calvarial fractures in pediatric patients. A total of 60 cases (22 with fractures and 38 without) were analyzed. Two experienced neuroradiologists and a radiology trainee were the readers of the study. For all readers, the sensitivity was not statistically different between the RBW and the 3DV interpretations. For each reader, there was a statistically significant difference in the interpretation times between the RBW and the 3DV viewing formats. A greater number of sutural diastasis was identified on 3DV. We propose that 3DV images should be part of routine head trauma imaging, especially in the pediatric age group. It requires minimal post processing time and no additional radiation. Furthermore, 3DV images help in reducing the interpretation time and also enhance the ability of the radiologist to characterize the calvarial fractures. PMID- 25698563 TI - Core curriculum illustration: isolated fracture of the greater trochanter. AB - This is the 12th installment of a series that will highlight one case per publication issue from the bank of cases available online as part of the American Society of Emergency Radiology (ASER) educational resources. Our goal is to generate more interest in and use of our online materials. To view more cases online, please visit the ASER Core Curriculum and Recommendations for Study online at: http://www.aseronline.org/curriculum/toc.htm. PMID- 25698564 TI - Postoperative hyperkalemia. AB - Hyperkalemia occurs frequently in hospitalized patients and is of particular concern for those who have undergone surgery, with postoperative care provided by clinicians of many disciplines. This review describes the normal physiology and how multiple perioperative factors can disrupt potassium homeostasis and lead to severe elevations in plasma potassium concentration. The pathophysiologic basis of diverse causes of hyperkalemia was used to broadly classify etiologies into those with altered potassium distribution (e.g. increased potassium release from cells or other transcellular shifts), reduced urinary excretion (e.g. reduced sodium delivery, volume depletion, and hypoaldosteronism), or an exogenous potassium load (e.g. blood transfusions). Surgical conditions of particular concern involve: rhabdomyolysis from malpositioning, trauma or medications; bariatric surgery; vascular procedures with tissue ischemia; acidosis; hypovolemia; and volume or blood product resuscitation. Certain acute conditions and chronic co-morbidities present particular risk. These include chronic kidney disease, diabetes mellitus, many outpatient preoperative medications (e.g. beta blockers, salt substitutes), and inpatient agents (e.g. succinylcholine, hyperosmolar volume expanders). Clinicians need to be aware of these pathophysiologic mechanisms for developing perioperative hyperkalemia as many of the risks can be minimized or avoided. PMID- 25698565 TI - An uncommon case of post partum seizures. PMID- 25698566 TI - Calcified pulmonary nodules. PMID- 25698567 TI - Microbiome characterization of MFCs used for the treatment of swine manure. AB - Conventional swine manure treatment is performed by anaerobic digestion, but nitrogen is not treated. Microbial Fuel Cells (MFCs) allow organic matter and nitrogen removal with concomitant electricity production. MFC microbiomes treating industrial wastewaters as swine manure have not been characterized. In this study, a multidisciplinary approach allowed microbiome relation with nutrient removal capacity and electricity production. Two different MFC configurations (C-1 and C-2) were used to treat swine manure. In C-1, the nitrification and denitrification processes took place in different compartments, while in C-2, simultaneous nitrification-denitrification occurred in the cathode. Clostridium disporicum and Geobacter sulfurreducens were identified in the anode compartments of both systems. C. disporicum was related to the degradation of complex organic matter compounds and G. sulfurreducens to electricity production. Different nitrifying bacteria populations were identified in both systems because of the different operational conditions. The highest microbial diversity was detected in cathode compartments of both configurations, including members of Bacteroidetes, Chloroflexiaceae and Proteobacteria. These communities allowed similar removal rates of organic matter (2.02-2.09 kg COD m(-3)d(-1)) and nitrogen (0.11-0.16 kg Nm(-3)d(-1)) in both systems. However, they differed in the generation of electric energy (20 and 2 mW m(-3) in C-1 and C-2, respectively). PMID- 25698568 TI - Pervaporation performance of PPO membranes in dehydration of highly hazardous mmh and udmh liquid propellants. AB - Polyphenylene oxide (PPO) membranes synthesized from 2,6-dimethyl phenol monomer were subjected to pervaporation-based dehydration of the highly hazardous and hypergolic monomethyl hydrazine (MMH) and unsymmetrical dimethyl hydrazine (UDMH) liquid propellants. Membranes were characterized by TGA, DSC and SEM to study the effect of temperature besides morphologies of surface and cross-section of the films, respectively. Molecular dynamics (MD) simulation was used to study the diffusion behavior of solutions within the membrane. CFD method was employed to solve the governing mass transfer equations by considering the flux coupling. The modeling results were highlighted by the experimental data and were in good agreement. High separation factors (35-70) and reasonable water fluxes (0.1-0.2 kg/m(2)h) were observed for separation of the aqueous azeotropes of MMH (35 wt%) and UDMH (20 wt%) and their further enrichment to >90% purity. Effect of feed composition, membrane thickness and permeate pressure on separation performance of PPO membranes were investigated to determine optimum operating conditions. PMID- 25698569 TI - Structure and properties of vanadium(V)-doped hexagonal turbostratic birnessite and its enhanced scavenging of Pb2+ from solutions. AB - Vanadium(V)-doped hexagonal turbostratic birnessites were synthesized and characterized by multiple techniques and were used to remove Pb(2+) from aqueous solutions. With increasing V content, the V(V)-doped birnessites have significantly decreased crystallinity, i.e., the thickness of crystals in the c axis decreases from 9.8 nm to ~0.7 nm, and the amount of vacancies slightly increases from 0.063 to 0.089. The specific surface areas of these samples increase after doping while the Mn average oxidation sates are almost constant. V has a valence of +5 and tetrahedral symmetry, and exists as oxyanions, including V6O16(2-), and VO4(3-) on birnessite edge sites by forming monodentate corning sharing complexes. Pb LIII-edge extended X-ray absorption fine structure (EXAFS) spectra analysis shows that, at low V contents (V/Mn<=0.07) Pb(2+) mainly binds with birnessite on octahedral vacancy and especially edge sites whereas at higher V contents (V/Mn>0.07) more Pb(2+) associates with V oxyanions and form vanadinite [Pb5(VO4)3Cl]-like precipitates. With increasing V(V) content, the Pb(2+) binding affinity on the V-doped birnessites significantly increases, ascribing to both the formation of the vanadinite precipitates and decreased particle sizes of birnessite. These results are useful to design environmentally benign materials for treatment of metal-polluted water. PMID- 25698570 TI - In-situ generated H2O2 induced efficient visible light photo-electrochemical catalytic oxidation of PCP-Na with TiO2. AB - In this study, we developed a novel photo-electrochemical catalytic oxidation wastewater treatment system by interacting the cathodic in-situ generated H2O2 with TiO2 suspension to form interfacial = Ti(IV)OOH species, which endowed the PEC system with superior efficiency for degrading sodium pentachlorophenate (PCP Na) under visible light irradiation at neutral pH. The apparent PCP-Na degradation rate constant of the PEC system was more than 10 times that of the electrochemical oxidation counterpart. In the PEC system, the interfacial = Ti(IV)OOH species injected electrons to the conduction band of TiO2 to initiate the activation of O2 and the in-situ generated H2O2 adsorbed on the surface of TiO2, lead to producing reactive oxygen species of superoxide anions and hydroxyl radicals, which were responsible for the dechlorination and mineralization of PCP Na during the PEC process, respectively. The dosage of TiO2 catalyst and the current intensity applied on PCP-Na degradation were optimized. This study develops a high efficient PEC oxidation system for wastewater treatment and provides new insight into the role of cathodic in-situ generated H2O2 on PEC oxidation of PCP-Na with TiO2 under visible light irradiation. PMID- 25698571 TI - Cadmium removal by Euglena gracilis is enhanced under anaerobic growth conditions. AB - The facultative protist Euglena gracilis, a heavy metal hyper-accumulator, was grown under photo-heterotrophic and extreme conditions (acidic pH, anaerobiosis and with Cd(2+)) and biochemically characterized. High biomass (8.5*10(6)cellsmL( 1)) was reached after 10 days of culture. Under anaerobiosis, photosynthetic activity built up a microaerophilic environment of 0.7% O2, which was sufficient to allow mitochondrial respiratory activity: glutamate and malate were fully consumed, whereas 25-33% of the added glucose was consumed. In anaerobic cells, photosynthesis but not respiration was activated by Cd(2+) which induced higher oxidative stress. Malondialdehyde (MDA) levels were 20 times lower in control cells under anaerobiosis than in aerobiosis, although Cd(2+) induced a higher MDA production. Cd(2+) stress induced increased contents of chelating thiols (cysteine, glutathione and phytochelatins) and polyphosphate. Biosorption (90%) and intracellular accumulation (30%) were the mechanisms by which anaerobic cells removed Cd(2+) from medium, which was 36% higher versus aerobic cells. The present study indicated that E. gracilis has the ability to remove Cd(2+) under anaerobic conditions, which might be advantageous for metal removal in sediments from polluted water bodies or bioreactors, where the O2 concentration is particularly low. PMID- 25698572 TI - Assessment of the electronic structure and properties of trichothecene toxins using density functional theory. AB - A comprehensive quantum chemical study was carried out on 35 type A and B trichothecenes and biosynthetic precursors, including selected derivatives of deoxynivalenol and T-2 toxin. Quantum chemical properties, Natural Bond Orbital (NBO) analysis, and molecular parameters were calculated on structures geometry optimized at the B3LYP/6-311+G** level. Type B trichothecenes possessed significantly larger electrophilicity index compared to the type A trichothecenes studied. Certain hydroxyl groups of deoxynivalenol, nivalenol, and T-2 toxin exhibited considerable rotation during molecular dynamics simulations (5 ps) at the B3LYP/6-31G** level in implicit aqueous solvent. Quantitative structure activity relationship (QSAR) models were developed to evaluate toxicity and detection using genetic algorithm, principal component, and multilinear analyses. The models suggest electronegativity and several 2-dimensional topological descriptors contain important information related to trichothecene cytotoxicity, phytotoxicity, immunochemical detection, and cross-reactivity. PMID- 25698573 TI - Simultaneously photocatalytic treatment of hexavalent chromium (Cr(VI)) and endocrine disrupting compounds (EDCs) using rotating reactor under solar irradiation. AB - In this study, simultaneous treatments, reduction of hexavalent chromium (Cr(VI)) and oxidation of endocrine disrupting compounds (EDCs), such as bisphenol A (BPA), 17alpha-ethinyl estradiol (EE2) and 17beta-estradiol (E2), were investigated with a rotating photocatalytic reactor including TiO2 nanotubes formed on titanium mesh substrates under solar UV irradiation. In the laboratory tests with a rotating type I reactor, synergy effects of the simultaneous photocatalytic reduction and oxidation of inorganic (Cr(VI)) and organic (BPA) pollutants were achieved. Particularly, the concurrent photocatalytic reduction of Cr(VI) and oxidation of BPA was higher under acidic conditions. The enhanced reaction efficiency of both pollutants was attributed to a stronger charge interaction between TiO2 nanotubes (positive charge) and the anionic form of Cr(VI) (negative charge), which are prevented recombination (electron-hole pair) by the hole scavenging effect of BPA. In the extended outdoor tests with a rotating type II reactor under solar irradiation, the experiment was extended to examine the simultaneous reduction of Cr(VI) in the presence of additional EDCs, such as EE2 and E2 as well as BPA. The findings showed that synergic effect of both photocatalytic reduction and oxidation was confirmed with single-component (Cr(VI) only), two-components (Cr(VI)/BPA, Cr(VI)/EE2, and Cr(VI)/E2), and four components (Cr(VI)/BPA/EE2/E2) under various solar irradiation conditions. PMID- 25698574 TI - Photocatalytic properties of zinc sulfide nanocrystals biofabricated by metal reducing bacterium Shewanella oneidensis MR-1. AB - Accumulation and utilization of heavy metals from wastewater by biological treatment system has aroused great interest. In the present study, a metal reducing bacterium Shewanella oneidensis MR-1 was used to explore the biofabrication of ZnS nanocrystals from the artificial wastewater. The biogenic H2S produced via the reduction of thiosulfate precipitated the Zn(II) as sulfide extracellularly. Characterization by X-ray diffraction (XRD), high-resolution transmission electron microscopy (HRTEM), and field emission scanning electron microscope (FESEM) confirmed the precipitates as ZnS nanocrystals. The biogenic ZnS nanocrystals appeared spherical in shape with an average diameter of 5 nm and mainly aggregated in the medium and cell surface of S. oneidensis MR-1. UV-vis DRS spectra showed ZnS nanoparticles appeared a strong absorption below 360 nm. Thus, the photocatalytic activity of ZnS was evaluated by the photodegradation of rhodamine B (RhB) under UV irradiation. The biogenic ZnS nanocrystals showed a high level of photodegradation efficiency to RhB coupled with a significant blue shift of maximum adsorption peak. A detailed analysis indicated the photogenerated holes, rather than hydroxyl radicals, contributed to the photocatalytic decolorization of RhB. This approach of coupling biosynthesis of nanoparticles with heavy metal removal may offer a potential avenue for efficient bioremediation of heavy metal wastewater. PMID- 25698575 TI - Concentration-dependent effects on fully hydrated DNA at terahertz frequencies. AB - Using terahertz time-domain spectroscopy (THz-TDS), the frequency-dependent dielectric constant of deoxyribonucleic acid (DNA) in solution was measured. The response of the buffer solution is dominated by two Debye modes in this frequency range, and, from an analysis of the concentration dependence, the presence of the DNA increases the main relaxation time and dielectric constant. This reflects the fact that the water in the hydration layer is more tightly bound under the influence of the DNA molecule in comparison to bulk water. This dynamical slowing down with increasing DNA concentration is similar to what is observed with purine nucleotides, but opposite to the behavior of pyrimidine nucleotides. In addition, a suspension model was used with the concentration-dependent data to isolate the dielectric response of the hydrated DNA molecule. The data for the hydrated DNA molecule is still dominated by a Debye response. It is also possible to determine the thickness of the hydration layer, and the DNA molecule influences the surrounding water out to 16 or 17 A, which corresponds to about six effective hydration layers. PMID- 25698576 TI - Identification of inhibitors against the potential ligandable sites in the active cholera toxin. AB - The active cholera toxin responsible for the massive loss of water and ions in cholera patients via its ADP ribosylation activity is a heterodimer of the A1 subunit of the bacterial holotoxin and the human cytosolic ARF6 (ADP Ribosylation Factor 6). The active toxin is a potential target for the design of inhibitors against cholera. In this study we identified the potential ligandable sites of the active cholera toxin which can serve as binding sites for drug-like molecules. By employing an energy-based approach to identify ligand binding sites, and comparison with the results of computational solvent mapping, we identified two potential ligandable sites in the active toxin which can be targeted during structure-based drug design against cholera. Based on the probe affinities of the identified ligandable regions, docking-based virtual screening was employed to identify probable inhibitors against these sites. Several indole based alkaloids and phosphates showed strong interactions to the important residues of the ligandable region at the A1 active site. On the other hand, 26 top scoring hits were identified against the ligandable region at the A1 ARF6 interface which showed strong hydrogen bonding interactions, including guanidines, phosphates, Leucopterin and Aristolochic acid VIa. This study has important implications in the application of hybrid structure-based and ligand based methods against the identified ligandable sites using the identified inhibitors as reference ligands, for drug design against the active cholera toxin. PMID- 25698577 TI - The generation of sex cells. AB - Primordial germ cells (PGCs) are the earliest population of germ cells established during embryonic development and constitute the beginning of the totipotent state. A recent study provides a new protocol for the efficient generation of PGC-like cells from human embryonic stem cells, providing an in vitro platform to study human PGC differentiation and specification. PMID- 25698578 TI - miR-27b synergizes with anticancer drugs via p53 activation and CYP1B1 suppression. AB - Liver and kidney cancers are notorious for drug resistance. Due to the complexity, redundancy and interpatient heterogeneity of resistance mechanisms, most efforts targeting a single pathway were unsuccessful. Novel personalized therapies targeting multiple essential drug resistance pathways in parallel hold a promise for future cancer treatment. Exploiting the multitarget characteristic of microRNAs (miRNAs), we developed a new therapeutic strategy by the combinational use of miRNA and anticancer drugs to increase drug response. By a systems approach, we identified that miR-27b, a miRNA deleted in liver and kidney cancers, sensitizes cancer cells to a broad spectrum of anticancer drugs in vitro and in vivo. Functionally, miR-27b enhances drug response by activating p53 dependent apoptosis and reducing CYP1B1-mediated drug detoxification. Notably, miR-27b promotes drug response specifically in patients carrying p53-wild-type or CYP1B1-high signature. Together, we propose that miR-27b synergizes with anticancer drugs in a defined subgroup of liver and kidney cancer patients. PMID- 25698579 TI - p53 isoform Delta113p53/Delta133p53 promotes DNA double-strand break repair to protect cell from death and senescence in response to DNA damage. AB - The inhibitory role of p53 in DNA double-strand break (DSB) repair seems contradictory to its tumor-suppressing property. The p53 isoform Delta113p53/Delta133p53 is a p53 target gene that antagonizes p53 apoptotic activity. However, information on its functions in DNA damage repair is lacking. Here we report that Delta113p53 expression is strongly induced by gamma irradiation, but not by UV-irradiation or heat shock treatment. Strikingly, Delta113p53 promotes DNA DSB repair pathways, including homologous recombination, non-homologous end joining and single-strand annealing. To study the biological significance of Delta113p53 in promoting DNA DSB repair, we generated a zebrafish Delta113p53(M/M) mutant via the transcription activator-like effector nuclease technique and found that the mutant is more sensitive to gamma-irradiation. The human ortholog, Delta133p53, is also only induced by gamma-irradiation and functions to promote DNA DSB repair. Delta133p53-knockdown cells were arrested at the G2 phase at the later stage in response to gamma-irradiation due to a high level of unrepaired DNA DSBs, which finally led to cell senescence. Furthermore, Delta113p53/Delta133p53 promotes DNA DSB repair via upregulating the transcription of repair genes rad51, lig4 and rad52 by binding to a novel type of p53-responsive element in their promoters. Our results demonstrate that Delta113p53/Delta133p53 is an evolutionally conserved pro-survival factor for DNA damage stress by preventing apoptosis and promoting DNA DSB repair to inhibit cell senescence. Our data also suggest that the induction of Delta133p53 expression in normal cells or tissues provides an important tolerance marker for cancer patients to radiotherapy. PMID- 25698580 TI - Protein kinase D1 drives pancreatic acinar cell reprogramming and progression to intraepithelial neoplasia. AB - The transdifferentiation of pancreatic acinar cells to a ductal phenotype (acinar to-ductal metaplasia, ADM) occurs after injury or inflammation of the pancreas and is a reversible process. However, in the presence of activating Kras mutations or persistent epidermal growth factor receptor (EGF-R) signalling, cells that underwent ADM can progress to pancreatic intraepithelial neoplasia (PanIN) and eventually pancreatic cancer. In transgenic animal models, ADM and PanINs are initiated by high-affinity ligands for EGF-R or activating Kras mutations, but the underlying signalling mechanisms are not well understood. Here, using a conditional knockout approach, we show that protein kinase D1 (PKD1) is sufficient to drive the reprogramming process to a ductal phenotype and progression to PanINs. Moreover, using 3D explant culture of primary pancreatic acinar cells, we show that PKD1 acts downstream of TGFalpha and Kras, to mediate formation of ductal structures through activation of the Notch pathway. PMID- 25698586 TI - Substrate-Induced Degradation of the alpha/beta-Fold Hydrolase KARRIKIN INSENSITIVE2 Requires a Functional Catalytic Triad but Is Independent of MAX2. PMID- 25698585 TI - Elevated Monoamine Oxidase-A Distribution Volume in Borderline Personality Disorder Is Associated With Severity Across Mood Symptoms, Suicidality, and Cognition. AB - BACKGROUND: Monoamine oxidase-A (MAO-A) is a treatment target in neurodegenerative illness and mood disorders that increases oxidative stress and predisposition toward apoptosis. Increased MAO-A levels in prefrontal cortex (PFC) and anterior cingulate cortex (ACC) occur in rodent models of depressive behavior and human studies of depressed moods. Extreme dysphoria is common in borderline personality disorder (BPD), especially when severe, and the molecular underpinnings of severe BPD are largely unknown. We hypothesized that MAO-A levels in PFC and ACC would be highest in severe BPD and would correlate with symptom magnitude. METHODS: [(11)C] Harmine positron emission tomography measured MAO-A total distribution volume (MAO-A VT), an index of MAO-A density, in severe BPD subjects (n = 14), moderate BPD subjects (n = 14), subjects with a major depressive episode (MDE) only (n = 14), and healthy control subjects (n = 14). All subjects were female. RESULTS: Severe BPD was associated with greater PFC and ACC MAO-A VT compared with moderate BPD, MDE, and healthy control subjects (multivariate analysis of variance group effect: F6,102 = 5.6, p < .001). In BPD, PFC and ACC MAO-A VT were positively correlated with mood symptoms (PFC: r = .52, p = .005; ACC: r = .53, p = .004) and suicidality (PFC: r = .40, p = .037; ACC: r = .38, p = .046), while hippocampus MAO-A VT was negatively correlated with verbal memory (r = -.44, p = .023). CONCLUSIONS: These results suggest that elevated MAO-A VT is associated with multiple indicators of BPD severity, including BPD symptomatology, mood symptoms, suicidality, and neurocognitive impairment. PMID- 25698587 TI - Sinonasal angiosarcoma. AB - INTRODUCTION: Angiosarcoma is a malignant tumour arising from endothelial cells that accounts for 1% of all sarcomas. The sinonasal site of angiosarcoma is exceptional. CASE REPORT: The authors report a case of sinonasal angiosarcoma in a 53-year-old man. Despite wide resection by open surgery and postoperative chemoradiotherapy, several tumour recurrences were observed, requiring multiple operations. DISCUSSION: Only histological examination with immunohistochemistry is able to confirm the diagnosis (factor VIII, CD34 and CD31 antigens). Standard treatment consists of surgery with wide resection followed by radiotherapy. The authors discuss the treatment modalities and prognosis of this tumour. PMID- 25698588 TI - Near-infrared fluorescence imaging with intraoperative administration of indocyanine green for robotic partial nephrectomy. AB - Near-infrared fluorescence (NIRF) imaging with intraoperative administration of indocyanine green (ICG) is a technology with emerging applications in urologic surgery. ICG is a water-soluble dye that fluoresces bright green when viewed under near-infrared light (700-1000 nm). This technology has been applied to robotic partial nephrectomy, first to potentially allow for the differentiation of renal tumor from normal parenchyma. In this application, it has been hypothesized that normal kidney tissue fluoresces green, while the tumor commonly remains hypofluorescent, thereby aiding tumor excision. Secondly, NIRF imaging with ICG has been employed to facilitate selective arterial clamping during robotic partial nephrectomy, allowing for a regional perfusion deficit in the kidney to be readily identified and therefore targeted at a given tumor. Recent studies have shown the associated decrease in global ischemia to minimize resultant loss of renal function at certain time endpoints. This review presents the most recent studies and evidence on the intraoperative administration of indocyanine green for robotic partial nephrectomy. PMID- 25698589 TI - Auranofin: repurposing an old drug for a golden new age. AB - Drug discovery, development and registration is an expensive and time-consuming process associated with a high failure rate [Pessetto et al. (Mol Cancer Ther 12:1299-1309, 2013), Woodcock and Woosley (Annu Rev Med 59:1-12, 2008)]. Drug 'repurposing' is the identification of new therapeutic purposes for already approved drugs and is more affordable and achievable than novel drug discovery [Pessetto et al. (Mol Cancer Ther 12:1299-1309, 2013)]. Auranofin is a drug that is approved for the treatment of rheumatoid arthritis but is being investigated for potential therapeutic application in a number of other diseases including cancer, neurodegenerative disorders, HIV/AIDS, parasitic infections and bacterial infections [Tejman-Yarden et al. (Antimicrob Agents Chemother 57:2029-2035, 2013)]. The main mechanism of action of auranofin is through the inhibition of reduction/oxidation (redox) enzymes that are essential for maintaining intracellular levels of reactive oxygen species. Inhibition of these enzymes leads to cellular oxidative stress and intrinsic apoptosis [Pessetto et al. (Mol Cancer Ther 12:1299-1309, 2013), Fan et al. (Cell Death Dis 5:e1191, 2014), Fiskus et al. (Cancer Res 74:2520-2532, 2014), Marzano et al. (Free Radic Biol Med 42:872-881, 2007)]. Drugs such as auranofin that have already been approved for human use [Tejman-Yarden et al. (Antimicrob Agents Chemother 57:2029-2035, 2013)] can be brought into clinical use for other diseases relatively quickly and for a fraction of the cost of new drugs. PMID- 25698590 TI - [Diagnostics and treatment of primary vitreoretinal lymphoma]. AB - BACKGROUND: Primary vitreoretinal lymphoma (PVRL) is a rare ocular lymphoid malignancy, mostly a diffuse large B-cell lymphoma. The PVRL, previously called primary intraocular lymphoma (PIOL), is a subset of primary central nervous system lymphoma (PCNSL). DIAGNOSIS: The diagnosis of PVRL is often difficult as it often mimics chronic intermediate or posterior uveitis; therefore, PVRL requires various procedures for the diagnostics, e.g. immunohistochemistry, cytology, pathology, molecular pathology and cytokine analysis (interleukin 10) after surgically obtaining ocular specimens. THERAPY: Treatment forms that are effective for systemic lymphomas have not been reliably successful for PVRL and PCNSL. Current management of PVRL consists of chemotherapy, such as methotrexate or rituximab, possibly combined with external beam radiation whereby both chemotherapeutic agents are administered systemically as well as intravitreally. Intravitreal treatment alone is recommended solely in the case of monocular PVRL, which is highly controversial. A PVRL usually responds well to initial treatment; however, relapse rates and CNS involvement are high, resulting in a poor prognosis and limited survival. PMID- 25698591 TI - [Accuracy and relevance of CT volumetry in open ocular injuries with intraocular foreign bodies]. AB - BACKGROUND/OBJECTIVES: The aim of the study was to evaluate the volume of intraocular foreign bodies (IOFB) using computed tomography (CT) volumetry as a prognostic factor for clinical outcome in open ocular injuries. PATIENTS AND METHODS: This study compared the volume of 11 IOFBs more than 5 mm(3) in size based on CT volumetry with the real size determined by in vitro measurement. A retrospective evaluation of clinical data, visual acuity, complications and relation of size of IOFBs with clinical outcome in 33 patients (mean age 41.0 +/- 13.5 years) with open ocular injuries treated at our department between January 2005 and December 2010 was carried out. RESULTS: No significant differences were found between pairwise in vitro measurement and CT volumetric size (p = 0.07). All patients were surgically treated by pars plana vitrectomy. The mean follow-up time was 7.6+/- 6.2 months and the mean preoperative best corrected visual acuity (BCVA) was 0.063 +/- 0.16 (logMAR 1.2 +/- 0.79). Postoperatively, a mean BCVA of 0.25 +/- 0.2 (logMAR 0.6 +/- 0.69) could be achieved. Clinical outcomes were significantly better in injuries with small IOFBs measuring < 15 mm(3) (p = 0.0098). CONCLUSIONS: The use of CT volumetry is an accurate method for measurement of IOFBs. Exact data about the size and measurement of volume are also an important factor for the prognosis of clinical outcome in open ocular injuries with IOFBs and CT volumetry can also provide important information about the localization of IOFBs. PMID- 25698592 TI - No association between ultrasound-guided insertion of central venous catheters and bloodstream infection: a prospective observational study. PMID- 25698593 TI - New President of the European Federation of organizations in Medical Physics. PMID- 25698594 TI - Sex-specific alterations in behavioral and cognitive functions in a "three hit" animal model of schizophrenia. AB - Whereas schizophrenia affects both human sexes, there are known sex-dependent disparities. We developed a chronic animal model that shows some schizophrenia related deficits in rats by applying selective breeding after subchronic ketamine administration connected with postweaning social isolation (complex treatment). Our aim was to determine the sex-specific effects of these interventions on several processes. Sensory gating to acoustic stimulation, pain sensitivity, motor behavior, spatial learning and memory deficits on the hole-board test were assessed in the 17th generation of selectively bred Wistar rats compared to their naive counterparts with or without complex treatment. We found differences between the sexes: selectively bred males with complex treatment showed the lowest pain sensitivity; however, the results of the prepulse inhibition test indicated that female rats showed enhanced impairment of sensory gating and increased acoustic startle reaction. The cognitive performance, working and reference memory ratios were significantly decreased by selective breeding and showed sex-specific alterations, with the smallest value in male rats of the new substrain. Based on these results, the animals of the new substrain could be classified into the high-risk for schizophreniform phenotype with the highest sensitivity of males with complex treatment. Decreased cognitive performance highlighted spatial learning deficits in the selectively bred and treated rats that escalate the validity of our new and complex rat model of schizophrenia. The results indicate the same sex selectivity as observed in humans, with increased incidence of risk ratios for men to develop schizophrenia relative to women. PMID- 25698595 TI - Differential contribution of perirhinal cortex and hippocampus to taste neophobia: effect of neurotoxic lesions. AB - Although the perirhinal cortex (Prh) has been extensively related to recognition memory, little is known about its specific role in taste memories. The main aim of the present series was therefore to examine the effect of neurotoxic lesions of the Prh on taste neophobia, a phenomenon consisting of a low intake of a novel food until its postingestive consequences are determined. The results showed that Prh-lesioned rats consumed significantly more novel saccharin in trial 1 than control subjects when a saccharin solution of 0.3% (expt. 1a) and 0.5% (expt. 1b) was presented. However, when the saccharin concentration was high and qualitatively more aversive, Prh lesions did not affect the neophobic response (0.7%, expt. 1c) and the lesioned and control animals consumed a similar amount of the fluid during the first and subsequent test trials. In all three experiments, Prh-lesioned and control rats showed a comparable intake at asymptote. Experiment 2 and 3 showed that neurotoxic lesions to the dorsal hippocampus prior to or 24h after the intake of the novel taste (0.3% saccharin) had no effect on the initial occurrence of the neophobic response or on the consolidation of safe taste memory, respectively. These findings support a dissociation of functions between the Prh and the hippocampus in taste neophobia. Also, the data suggests that the Prh plays an essential role in detecting the novelty of the new tastant. PMID- 25698596 TI - A time-course study of behavioral and electrophysiological characteristics in a mouse model of different stages of Parkinson's disease using 6-hydroxydopamine. AB - Parkinson's disease (PD) is characterized by abnormal motor symptoms and increased neuronal activity in the subthalamic nucleus (STN) as the disease progresses. We investigated the behavioral and electrophysiological characteristics in a mouse model mimicking the progressive stages of human PD (early, moderate, and advanced) by injecting 6-hydroxydopamine (6-OHDA) into the right medial forebrain bundle (MFB) at three different concentrations (2, 4, and 6 MUg/2 MUl). Significant changes in motor symptoms were demonstrated between groups in association with relative TH-positive cell loss in the substantia nigra pars compacta (SNc). Moreover, electrophysiologically assessed changes in the mean neuronal firing rate in the STN neurons were comparable to those in the early to advanced stages of human PD. Thus, the mouse model presented herein replicates the unique characteristics of each progressive stage of PD, in both motor and neurophysiological aspects, and therefore can be useful for further investigations of PD pathology. PMID- 25698597 TI - Divergent effects of L-arginine-NO pathway modulators on diazepam and flunitrazepam responses in NOR task performance. AB - The goal of the study was an evaluation of the degree, in which nitric oxide (NO) is involved in the benzodiazepines (BZs)-induced recognition memory impairment in rats. The novel object recognition (NOR) test was used to examine recognition memory. The current research focused on the object memory impairing effects of diazepam (DZ; 0.5 and 1mg/kg, sc) and flunitrazepam (FNZ; 0.1 and 0.2mg/kg; sc) in 1-hour delay periods in rats. It was found that acute ip injection of L arginine (L-arg; 250 and 500 mg/kg; ip), 5 min before DZ administration (0.5mg/kg, sc) prevented DZ-induced memory deficits. On the other hand, it was also proven that L-arg (125, 250 and 500 mg/kg; ip) did not change the behaviour of rats in the NOR test, following a combined administration with FNZ at a threshold dose (0.05 mg/kg; sc). It was also found that 7-nitroindazole (7-NI; 10, 20 and 40 mg/kg; ip) induced amnesic effects in DZ in rats, submitted to the NOR test, following a combined administration of 7-NI with a threshold dose of DZ (0.25mg/kg; sc). However, following a combined administration of 7-NI (10, 20 and 40 mg/kg; ip) with FNZ (0.1mg/kg; sc), it was observed that 7-NI inhibited the amnesic effects of FNZ on rats in the NOR test. Those findings led us to hypothesize that NO synthesis suppression may induce amnesic effects of DZ, while preventing FNZ memory impairment in rats, submitted to NOR tasks. PMID- 25698598 TI - CRTH2, a prostaglandin D2 receptor, mediates depression-related behavior in mice. AB - Depression is a complex neuropsychiatric disorder with an unclear molecular etiology. Inflammatory cytokines and molecular intermediates (including prostaglandins) are suggested to be involved in depression; however, the roles of prostaglandins and their respective receptors are largely unknown in depression. Using genetic and pharmacological approaches, we show here that chemoattractant receptor-homologous molecule expressed on T helper type 2 cells (CRTH2), a second receptor for prostaglandin D2 (PGD2), mediates depression-related behavior in mice. CRTH2-deficient (CRTH2(-/-)) mice showed antidepressant-like activity in a chronic corticosterone treatment-induced depression. Consistent with this observation, the pharmacological inhibition of CRTH2 via the clinically available drug ramatroban also rescued abnormal social interaction and depression-related behavior in well-established models, including chronic corticosterone-, lipopolysaccharide-, and tumor-induced pathologically relevant depression models. Importantly, chronic stress via corticosterone treatment increased mRNA levels in PGD2-producing enzymes, such as cyclooxygenase-2 and lipocalin-type PGD2 synthase, in the brain. Furthermore, the activity of the hippocampal noradrenergic system but not the dopaminergic or serotonergic systems was increased in CRTH2(-/-) mice. Together with the observation that untreated CRTH2( /-) mice showed antidepressant-like activity in the forced swim test, these results provide evidence that central CRTH2-mediated signaling is critically involved in depression-related behavior. PMID- 25698599 TI - There is more to the picture than meets the rat: a study on rodent geometric shape and proportion preferences. AB - In rodents, the novel object preference test has been used as a behavioral parameter for evaluation of neotic exploratory behavior, and also for memory consolidation tasks. Geometric patterns of this preference are poorly understood, and may vary among species. We evaluated in Wistar rats (Rattus norvergicus) a possible exploration preference considering aluminum tripartite rounded and cylindrical objects of different proportions: 1.2; 1.618; 1.8. At the first day, animals were exposed to 1.2; 1.6 and 1.8 rounded objects. At 24h after, these animals were exposed to the same objects, together with three new steel cylindrical objects (same proportions). ANOVA and T tests were used to quantify object exploration for each animal (p<0.05). Data analysis pointed to a longer exploration time of the object 1.2 at the three different protocols indicating a preference pattern on the first day exposition. On the second day the exploration was similar in both familiar and unfamiliar objects, revealing no novel object preference for cylinders. However, we found an object preference related to the 1.2 proportion (balls plus cylinders), in two of three position protocols. In addition, on a single exposition with both cylinders and rounded objects, rats revealed a rounded object preference. The 1.2 preference disclosed by rats also reflected the proportion of their body. From nine main measures of body ratios, seven were close to 1.2 ratio. The correspondence between body ratios and object preference may be explained by habituation learning and by sexual selection, and highlight innate factors regarding aesthetic preferences among species. PMID- 25698600 TI - Neuronal marker recovery after Simvastatin treatment in dementia in the rat brain: in vivo magnetic resonance study. AB - The aim of study was to search for new biomarkers with a magnetic resonance technique to identify the early stages of dementia, induced by D-galactose, and evaluate Simvastatin therapy. Localized proton magnetic resonance spectroscopy measurements showed a significant decrease in the concentration of N acetylaspartate+N-acetylaspartylglutamate and myo-inositol in the D-galactose group compared to the control group, and, conversely, an increase of N acetylaspartate+N-acetylaspartylglutamate in the D-galactose/Simvastatin group. Using a saturation transfer experiment, with phosphorus magnetic resonance spectroscopy, we observed a significant elevation of the forward rate constant of the creatine kinase reaction in the brains of the D-galactose group compared to controls, and subsequently, a significant reduction of this reaction in the D galactose/Simvastatin group. Spatial learning and memory were evaluated using the modified Morris water maze test. The dynamics of the learning process represented by the learning index revealed a significant reduction in learning in the D galactose group, but the deficits as a consequence of the D-galactose effects were recovered in the D-galactose/Simvastatin group, in which the learning dynamics resembled those of the control group. By determining the thiobarbituric acid reactive substances and total coenzyme Q9 in plasma, we have shown that long term administration of D-galactose created conditions for oxidative stress, and that the administration of Simvastatin decreased oxidative stress in plasma. Volumetry analyses from the hippocampal area show a reduction in the segmented area in the D-galactose group, compared with the control group, and an enlarged area in the hippocampus in the d-galactose/Simvastatin group. PMID- 25698601 TI - Chronic acarbose treatment alleviates age-related behavioral and biochemical changes in SAMP8 mice. AB - The administration of maintaining the homeostasis of insulin/insulin-like growth factor 1 (IGF-1) signaling and/or glucose metabolism may reverse brain aging. In the present study, we investigated the effect of acarbose, an inhibitor of alpha glucosidase, on age-related behavioral and biochemical changes. The SAMP8 mice were randomly divided into old control group and acarbose-treatment group. The mice in the acarbose group were administered acarbose (20 mg/kg/d, dissolved in drinking water) orally from 3 to 9 months of age when a new group of 3-month-old mice was added as young controls. The results showed that the aged controls exhibited declines in sensorimotor ability, open field anxiety, spatial and non spatial memory abilities, decreased serum insulin levels, increased IGF-1 receptor and synaptotagmin 1 (Syt1) levels and decreased insulin receptor, brain derived neurotrophic factor (BDNF) and syntaxin 1 (Stx1) levels in the hippocampal layers. The age-related behavioral deficits correlated with the serological and histochemical data. Chronic acarbose treatment relieved these age related changes, especially with respect to learning and memory abilities. This protective effect of acarbose on age-related behavioral impairments might be related to changes in the insulin system and the levels of BDNF, IGF-1R, and the pre-synaptic proteins Syt1 and Stx1. In conclusion, long-term treatment with acarbose ameliorated the behavioral deficits and biochemical changes in old SAMP8 mice and promoted successful aging. This study provides insight into the potential of acarbose for the treatment of brain aging. PMID- 25698602 TI - How coordinate and categorical spatial relations combine with egocentric and allocentric reference frames in a motor task: effects of delay and stimuli characteristics. AB - This study explores how people represent spatial information in order to accomplish a visuo-motor task. To this aim we combined two fundamental components of the human visuo-spatial system: egocentric and allocentric frames of reference and coordinate and categorical spatial relations. Specifically, participants learned the position of three objects and then had to judge the distance (coordinate information) and the relation (categorical information) of a target object with respect to themselves (egocentric frame) or with respect to another object (allocentric frame). They gave spatial judgments by reaching and touching the exact position or the side previously occupied by the target object. The possible influence of stimuli characteristics (3D objects vs. 2D images) and delay between learning phase and testing phase (1.5 vs. 5s) was also assessed. Results showed an advantage of egocentric coordinate judgments over the allocentric coordinate ones independently from the kind of stimuli used and the temporal parameters of the response, whereas egocentric categorical judgments were more accurate than allocentric categorical ones only with 3D stimuli and when an immediate response was requested. This pattern of data is discussed in the light of the "perception-action" model by Milner and Goodale [13] and of neuroimaging evidence about frames of reference and spatial relations. PMID- 25698603 TI - A partial lesion model of Parkinson's disease in mice--characterization of a 6 OHDA-induced medial forebrain bundle lesion. AB - The most frequently used animal models for Parkinson's disease (PD) utilize unilateral injection of 6-hydroxydopamine (6-OHDA) in the medial forebrain bundle (MFB), which results in total denervation of the dopaminergic nigrostriatal pathway. However, neuroprotective interventions in PD require models resembling earlier stages of PD, where some dopaminergic cells and fibres remain. The aim of the present study was therefore to establish a MFB partial lesion model in mice. We tested four different 6-OHDA doses, and our results show a dose-dependent loss of nigral dopaminergic cells and striatal fibres that correlated with behavioural impairment in several behavioural tests. Specifically, doses of 0.7 MUg and 1 MUg of 6-OHDA induced a partial denervation of the nigrostriatal pathway, associated with a mild but quantifiable behavioural impairment. We identified the amphetamine-induced rotation, stepping, corridor and cylinder test to be sensitive enough to select partial lesion animals. Based on our data, we proposed a range of cut-off values for these different behavioural tests to select partial lesion mice. Using a statistical prediction model we identified two behavioural tests (the stepping test and amphetamine-induced rotation test) that with a high sensitivity and specificity predict the extent of nigral dopaminergic cell loss and select mice with a partial nigrostriatal lesion prior to further interventions. This model can serve as an important tool to study neuroprotective therapies for PD in mouse models, especially when the treatment targets the substantia nigra and/or the striatum. PMID- 25698604 TI - Effects of glutamate and its metabotropic receptors class 1 antagonist in appetitive taste memory formation. AB - Cortical glutamatergic activity is known to be important for memory formation in different learning tasks. For example, glutamate activity in the insular cortex plays an important role in aversive taste memory formation by signaling the unconditioned stimulus. However, the role of glutamate in the insular cortex in appetitive taste learning has remained poorly studied. Therefore, we considered the function of glutamate in attenuation of neophobia, a model of appetitive taste recognition memory. For this purpose, we performed infusions of vehicle, glutamate, a specific mGluR1 antagonist (AIDA) or a combination of glutamate and AIDA at 0 or 30 min, and glutamate or vehicle at 60 min after novel saccharin consumption. Glutamate infusion impaired appetitive taste recognition memory when infused at 0 or 30 min, whereas, AIDA infusions produced enhanced appetitive memory at the same infusion times. Furthermore, when glutamate and AIDA were infused together no effect on attenuation of neophobia was observed. As opposed to shorter infusion times, the administration of glutamate 60 min after the presentation of the saccharin consumption was ineffective in the impairment of the appetitive taste memory. These results are discussed in view of the effect of glutamate and its mGluR1 during the appetitive taste recognition memory formation in the insular cortex. PMID- 25698605 TI - Oral anticoagulation: a critique of recent advances and controversies. AB - There have recently been significant advances in the field of oral anticoagulation, but these have also led to many controversies. Warfarin is still the commonest drug used for clotting disorders but its use is complicated owing to wide inter-individual variability in dose requirement and its narrow therapeutic index. Warfarin dose requirement can be influenced by both genetic and environmental factors. Two recent randomized controlled trials (RCTs) came to different conclusion regarding the utility of genotype-guided dosing; we critically explore the reasons for the differences. The new generation of oral anticoagulants have been demonstrated to be as efficacious as warfarin, but further work is needed to evaluate their safety in real clinical settings. PMID- 25698606 TI - Incessant "ventricular tachycardia" in a patient with non-ischemic cardiomyopathy. What is the tachycardia mechanism? AB - We present an uncommon and unique arrhythmia in a patient with non-ischemic cardiomyopathy and dual chamber implantable cardioverter defibrillator presenting with palpitations and dyspnea. While surface electrocardiogram suggested irregular narrow complex tachycardia, evaluation of stored electrograms from implantable cardioverter defibrillator revealed incessant episodes of non sustained ventricular tachycardia. The patient underwent electrophysiological study and successful ablation of the arrhythmia with complete resolution of symptoms. We discuss the underlying tachycardia mechanism and challenges in the diagnosing and management of this unusual rhythm disorder. PMID- 25698607 TI - [Management of transient radicular pain after receiving an epidural blood patch for headaches due to spontaneous intracranial hypotension]. AB - Spontaneous intracranial hypotension headache is an uncommon disease that resolves spontaneously in most of the cases and in a short period of time. The initial treatment should be symptomatic. In some patients the symptomatology is extremely disabling, and in these cases both the diagnosis and treatment may be performed by an epidural blood patch. A 49-year-old Caucasian woman, with no previous record of epidural or intrathecal puncture, consulted in the Emergency Department complaining of a 9-day history of frontal headache and diplopia, along with nausea and vomiting. The patient was diagnosed with spontaneous intracranial hypotension headache. Considering the symptomatology and the uncontrolled pain, the Pain Unit of our hospital performed an epidural blood patch. In the first 24h the patient reported a remarkable relief of both headache and diplopia but developed a left lumbar radiculopathy that was treated successfully with supportive measures. Transient lumbar radiculopathy is a common and acceptable event secondary to the use of epidural blood patch as a treatment for spontaneous intracranial hypotension headache. PMID- 25698608 TI - Clinical evaluation of the Baska Mask laryngeal mask in adult patients in ambulatory surgery. AB - OBJECTIVE: To evaluate the clinical performance of the Baska Mask, a new second generation supraglottic airway device with a self-inflating cuff and two side suction channels for continuous aspiration. MATERIAL AND METHODS: Eighty adult patients without difficult airways were prospectively included. Ease of insertion and number of attempts needed, quality of ventilation, airway seal pressure, fibreoptic view, ease of gastric access, and complications were assessed. Sizes 3, 4, 5 were analyzed and compared. RESULTS: First attempt insertion success rate was 88% and the overall rate was 100%, although additional maneuvers were necessary in 44% of the cases. The ventilation was adequate in 96%, with 39% of them requiring adjusting maneuvers. Size 3 needed significantly less adjustments, and achieved a higher seal pressure than sizes 4 and 5 combined. The airway seal pressure was 33 +/- 7 cm H2O. Complete or partial vocal cords were visible in 90% of the 66 cases assessed. Partial obstruction, caused by distortion of the cuff free border, was seen in 5%, and no glottic structures were identified in 5%. Gastric access was easy in all cases. Complications were mild and transient. CONCLUSIONS: The Baska Mask achieves a high seal pressure, effective ventilation, and a quick access to drain gastric contents. However, additional adjustment maneuvers are frequently required to insert the mask and to optimize ventilation. PMID- 25698609 TI - Optimizing preoperative haemoglobin in major orthopaedic surgery using intravenous iron with or without erythropoietin. An epidemiologic study. AB - AIM: To evaluate the effectiveness of intravenous iron treatment, with or without associated erythropoietin (rHuEPO), measured as haemoglobin (Hb) increase. The relationships between the Hb increase and parameters used to evaluate anaemia were analysed. MATERIAL AND METHOD: Retrospective observational study carried out in two third-level hospitals between January 2005 and December 2009. The study included patients with iron deficiency anaemia scheduled for elective orthopaedic surgery and treated with intravenous iron sucrose alone or associated with rHuEPO. Treatment efficacy was analysed based on the Hb increase from baseline to just before surgery. RESULTS: A total of 412 patients who received a median of 800mg of iron sucrose were included; 125 of them (30.4%) additionally received 2.4 vials of rHuEPO. The Hb increase was 0.8 (1.1) g/dL in patients treated with intravenous iron and 1.5 (1.3) g/dL in those additionally given rHuEPO(P<.01). The percentage of hypochromic red blood cells (r=0.52) and soluble transferrin receptor (r=0.59) value were significantly correlated to the Hb increase in patients receiving iron. CONCLUSIONS: In patients with iron deficiency anaemia, the effectiveness of iron sucrose treatment to optimize Hb before surgery was moderate; adjuvant administration of erythropoietin improved the results. Determination of functional iron status parameters may improve the treatment effectiveness. PMID- 25698610 TI - [Cerebral artery thrombosis in pregnancy]. AB - A 28 year old woman, ASA I, who, in the final stages of her pregnancy presented with signs of neural deficit that consisted of distortion of the oral commissure, dysphagia, dysarthria, and weakness on the left side of the body. She was diagnosed with thrombosis in a segment of the right middle cerebral artery which led to an ischemic area in the right frontal lobe. Termination of pregnancy and conservative treatment was decided, with good resolution of the symptoms. PMID- 25698611 TI - Identification of Bacillus thuringiensis Cry3Aa toxin domain II loop 1 as the binding site of Tenebrio molitor cadherin repeat CR12. AB - Bacillus thuringiensis Cry toxins exert their toxic effect by specific recognition of larval midgut proteins leading to oligomerization of the toxin, membrane insertion and pore formation. The exposed domain II loop regions of Cry toxins have been shown to be involved in receptor binding. Insect cadherins have shown to be functionally involved in toxin binding facilitating toxin oligomerization. Here, we isolated a VHH (VHHA5) antibody by phage display that binds Cry3Aa loop 1 and competed with the binding of Cry3Aa to Tenebrio molitor brush border membranes. VHHA5 also competed with the binding of Cry3Aa to a cadherin fragment (CR12) that was previously shown to be involved in binding and toxicity of Cry3Aa, indicating that Cry3Aa binds CR12 through domain II loop 1. Moreover, we show that a loop 1 mutant, previously characterized to have increased toxicity to T. molitor, displayed a correlative enhanced binding affinity to T. molitor CR12 and to VHHA5. These results show that Cry3Aa domain II loop 1 is a binding site of CR12 T. molitor cadherin. PMID- 25698612 TI - Haploidentical hematopoietic stem cell transplantation without in vitro T cell depletion for the treatment of philadelphia chromosome-positive acute lymphoblastic leukemia. AB - The role of haploidentical related allogeneic hematopoietic stem cell transplantation (allo-HSCT) in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL) is not clear. We aimed to investigate the long term survival of Ph(+) ALL patients who underwent haploidentical donor (HID)-HSCT and to analyze the factors influencing relapse and survival after allo-HSCT. The study population included Ph(+) ALL patients who underwent haploidentical related allo-HSCT. Additionally, Ph(+) ALL patients who underwent HLA-matched related donor (MRD) transplants during the same period were included to compare outcomes. BCR-ABL transcript levels were analyzed by using real-time quantitative reverse transcription PCR. Clinical data from 139 Ph(+) ALL patients who received allo HSCT in our center were analyzed. Of these patients, 101 received HID transplants and 38 received MRD transplants. At a median follow-up of 36 months, 5-year disease-free survival (DFS) and overall survival (OS) rates in the HID transplant group were 65.8% and 74.0%, respectively. The 5-year cumulative incidence of relapse (CIR) and nonrelapse mortality (NRM) rates for the HID transplant group were 20.3% and 15.6%, respectively. In addition, there were no differences in OS, DFS, CIR, and NRM between the HID and MRD groups. Multivariate analysis showed that imatinib resistance was a significant factor influencing DFS and CIR in HID transplant patients. Haploidentical HSCT for the treatment of Ph(+) ALL achieves promising long-term survival, which is comparable with that of HLA-MRD HSCT. Imatinib resistance is a negative predictor of relapse and DFS after allo-HSCT. PMID- 25698613 TI - Isolation and structural characterization of 2R, 3R taxifolin 3-O-rhamnoside from ethyl acetate extract of Hydnocarpus alpina and its hypoglycemic effect by attenuating hepatic key enzymes of glucose metabolism in streptozotocin-induced diabetic rats. AB - Hydnocarpus alpina Wt. (Flacourtiaceae) (H. alpina) is a large tree traditionally used to treat leprosy; it also posses antidiabetic property. The present study was undertaken to isolate, characterize and to evaluate the antidiabetic effect of 2R, 3R taxifolin 3-O-rhamnoside. (rhamnoside) and its impact on carbohydrate metabolic key enzymes in control and streptozotocin (STZ)-induced diabetic rats. Diabetes mellitus was induced by a single intraperitoneal injection of streptozotocin (STZ) (40 mg/kg). Oral administration of rhamnoside for 21 days significantly reduced food intake, calorie intake, blood glucose and glycosylated hemoglobin levels, and improved plasma insulin levels. Administration of rhamnoside showed significant increase in the body weight, body composition (Lean body weight (LBW) and retro body fat), glycolytic hexokinase, glucose-6-phophate dehydrogenase and pyruvate kinase levels where as significant decrease was observed in the levels of glucose-6-phosphatase fructose-1, 6-bisphosphatase and lactate dehydrogenase in diabetic treated rats. Further, administration of rhamnoside significantly improved the glycogen content, glycogen synthase and glycogen phosphorylase, suggesting the antihyperglycemic potential of rhamnoside in diabetic rats. The results obtained were compared with glibenclamide a standard hypoglycaemic drug. Immunohistopathological study of pancreas revealed increased number of beta-cells and insulin granules in diabetes-induced rats after treatment with rhamnoside for 21 days. Furthermore, Co-administration of rhamnoside (50 mg/kg) with nifedipine (13.6 mg/kg), a Ca(2+)ion channel blocker, or nicorandil (6.8 mg/kg), an ATP-sensitive K(+) ion channel opener, reveals the insulin secretion property of rhamnoside via a K(+)-ATP channels dependent pathway in diabetic rats. In conclusion, rhamnoside normalized blood glucose, glycosylated hemoglobin, key hepatic enzymes and glycogen content by increasing insulin secretion via K(+)-ATP channels dependent signaling pathway. The results suggest that the rhamnoside from H. alpina could be used as a therapeutic agent to treat diabetes mellitus. PMID- 25698614 TI - Intravenous transplantation of bone marrow-derived mononuclear cells prevents memory impairment in transgenic mouse models of Alzheimer's disease. AB - Stem cell transplantation therapy is currently in clinical trials for the treatment of ischemic stroke, and several beneficial aspects have been reported. Similarly, in Alzheimer's disease (AD), stem cell therapy is expected to provide an efficient therapeutic approach. Indeed, the intracerebral transplantation of stem cells reduced amyloid-beta (Abeta) deposition and rescued memory deficits in AD model mice. Here, we show that intravenous transplantation of bone marrow derived mononuclear cells (BMMCs) improves cognitive function in two different AD mouse models, DAL and APP mice, and prevents neurodegeneration. GFP-positive BMMCs were isolated from tibiae and femurs of 4-week-old mice and then transplanted intravenously into DAL and APP mice. Transplantation of BMMCs suppressed neuronal loss and restored memory impairment of DAL mice to almost the same level as in wild-type mice. Transplantation of BMMCs to APP mice reduced Abeta deposition in the brain. APP mice treated with BMMCs performed significantly better on behavioral tests than vehicle-injected mice. Moreover, the effects were observed even with transplantation after the onset of cognitive impairment in DAL mice. Together, our results indicate that intravenous transplantation of BMMCs has preventive effects against the cognitive decline in AD model mice and suggest a potential therapeutic effect of BMMC transplantation therapy. PMID- 25698615 TI - Senkyunolide I protects rat brain against focal cerebral ischemia-reperfusion injury by up-regulating p-Erk1/2, Nrf2/HO-1 and inhibiting caspase 3. AB - Oxidative damage and apoptosis are critical factors contributing to neuronal death during a stroke. The aim of the present study was to evaluate the neuroprotective effects of senkyunolide I (SEI) on focal cerebral ischemia reperfusion (I/R) injury in rats, and investigate the underlying mechanisms. Male Sprague-Dawley rats were subjected to transient middle cerebral artery occlusion (tMCAO) for 2h, followed by 24h reperfusion, and then randomly assigned into four groups: Sham (sham-operated), Vehicle (tMCAO +normal saline), SEI-L (tMCAO +SEI 36 mg/kg) and SEI-H (tMCAO +SEI 72 mg/kg) groups. SEI was administered intravenously, 15 min after occlusion. Neurological deficit, brain edema and infarct volume were detected after 24h of reperfusion. Histological structures of cortices and hippocampus were observed by hematoxylin and eosin staining. Biochemical indexes in the cortex were assayed by colorimetry. The impact of SEI on the Nrf2-ARE-interaction was assayed using a luciferase reporter gene. Western blotting was performed to analysis the expressions of proteins related to anti oxidation and apoptosis. SEI administration significantly ameliorated the neurological deficit, reduced the infarct volume and brain edema, reversed the cerebral morphologic damage, decreased the levels of MDA and increased the activities of superoxide dismutase. Furthermore, the high dose SEI could significantly activate the Nrf2/ARE pathway by up-regulating the phosphorylation of Erk1/2 and inducing Nrf2 nuclear translocation with enhanced HO-1 and NQO1 expressions. Additionally, treatment with SEI remarkably promoted the ratio of Bcl-2/Bax and inhibited the expressions of cleaved caspase 3 and caspase 9. These results suggest that the neuroprotective mechanisms of SEI are associated with its anti-oxidation and anti-apoptosis properties. PMID- 25698616 TI - The amygdala central nucleus is required for acute stress-induced bladder hyperalgesia in a rat visceral pain model. AB - Chronic stress has been implicated in the pathogenesis of chronic visceral pain conditions, such as interstitial cystitis (IC), and bouts of acute stress exacerbate clinical urological pain. Studies using animal models have shown that exposure to chronic footshock stress augments reflex responses to urinary bladder distension (UBD) in animal models, however acute effects in animal models are largely unknown, as are the central nervous system mechanisms of stress-related increases in nociception. The amygdala is a salient structure for integration of sensory and cognitive/emotional factors. The present study determined the role of the central nucleus of the amygdala (CeA) in stress-related bladder hypersensitivity. We examined the effects of CeA manipulations (lesions and chemical stimulation) on visceromotor responses (abdominal muscle contractions) to UBD in adult, female Sprague-Dawley rats. We report that acute footshock stress produces bladder hyperalgesia that can be prevented by bilateral CeA lesions, despite no effect of lesions on baseline somatic sensation, as indicated by flinch/jump thresholds to electrical shock. Further, acute glucocorticoid stimulation of the CeA recapitulated stress-induced hyperalgesia. Of note is that CeA lesions, but not chemical stimulation, significantly affected HPA axis activation, as indicated by measurements of circulating corticosterone. Our findings conclusively show that the CeA is necessary for the generation of bladder hyperalgesia in response to acute stress. The CeA may play multiple stress-related roles in nociceptive modulation, i.e., via direct facilitation of the HPA axis during acute stress, or via modulation of other systems that augment acute stress responsiveness. PMID- 25698617 TI - Design, synthesis and SAR studies of GABA uptake inhibitors derived from 2 substituted pyrrolidine-2-yl-acetic acids. AB - In this paper, we disclose the design and synthesis of a series of 2-substituted pyrrolidine-2-yl-acetic acid as core structures and the N-arylalkyl derivatives thereof as potential GABA transport inhibitors. The 2-position in the side chain of pyrrolidine-2-yl-acetic acid derivatives was substituted with alkyl, hydroxy and amino groups to modulate the activity and selectivity to mGAT1 and mGAT4 proteins. SAR studies of the compounds performed for the four mouse GABA transporter proteins (mGAT1-mGAT4) implied significant potencies and subtype selectivities for 2-hydroxy-2-pyrrolidine-2-yl-acetic acid derivatives. The racemate rac-(u)-13c exhibited the highest potency (pIC50 5.67) at and selectivity for mGAT1 in GABA uptake assays. In fact, the potency of rac-(u)-13c at hGAT-1 (pIC50 6.14) was even higher than its potency at mGAT1. These uptake results for rac-(u)-13c are in line with the binding affinities to the aforesaid proteins mGAT1 (pKi 6.99) and hGAT-1 (pKi 7.18) determined by MS Binding Assay based on NO711 as marker quantified by LC-ESI-MS-MS analysis. Interestingly, the 2-hydroxy-2-pyrrolidine-2-yl-acetic acid rac-(u)-13d containing 2-{[tris(4 methoxyphenyl)]methoxy} ethyl group at the nitrogen atom of the pyrrolidine ring showed high potency at mGAT4 and a comparatively better selectivity for this protein (>15 against mGAT3) than the well known mGAT4 uptake inhibitor (S)-SNAP 5114. PMID- 25698618 TI - Design, synthesis and evaluation of XZH-5 analogues as STAT3 inhibitors. AB - Inhibition of the signaling pathways of signal transducer and activator of transcription 3 (STAT 3) has shown to be a promising strategy to combat cancer. In this paper we report the design, synthesis and evaluation of a novel class of small molecule inhibitors, that is, XZH-5 and its analogues, as promising leads for further development of STAT3 inhibitors. Preliminary SARs was established for XZH-5 and its derivatives; and the binding modes were predicted by molecular docking. Lead compounds with IC50 as low as 6.5MUM in breast cancer cell lines and 7.6MUM in pancreatic cancer cell lines were identified. PMID- 25698619 TI - An UPLC-MS/MS method coupled with automated on-line SPE for quantification of tacrolimus in peripheral blood mononuclear cells. AB - BACKGROUND: Tacrolimus is an immunosuppressor used to treat patients undergoing liver transplantation. TDM of hematic tacrolimus by liquid chromatography became standard practice, but it does not necessarily reflect its concentration at its active site. Our aim was to validate a new method for tacrolimus quantification into target cells (peripheral blood mononuclear cells, PBMCs) and testing it on 100 real samples from 37 pediatric patients. METHODS: PBMCs were collected using cell-preparation-tubes; cells number and MCV were evaluated. Tacrolimus was quantified using UPLC-MS/MS coupled with a new automated on-line SPE platform. Chromatographic run was performed on an Acquity UPLC((r)) BEH C18 1.7 MUm (2.1 mm * 50 mm) column for 5 min, with a gradient of water and methanol (both with 2 mM/L ammonium acetate and 1 mL/L formic acid). XBridge((r)) C8 10 MUm (1 mm * 10 mm) SPE cartridges were used. The internal standard was 6,7-dimethyl-2,3-di(2 pyridyl)quinoxaline. RESULTS: Full validation following FDA guidelines was performed: the method showed high sensitivity and specificity (LLOQ of 0.010 ng; LLOD of 0.005 ng). Intra- and inter-day imprecision and inaccuracy were <15%. A positive and stable matrix effect was observed, with a good recovery for tacrolimus. All drug amounts in real samples resulted within the calibration range and calibration curves were linear (r(2)=0.998). Concentrations from each patient were standardized using their evaluated MCV: intra-PBMCs concentration was meanly 12.7 times higher than the hematic one. CONCLUSION: This method might be eligible and useful for a clinical routine use, giving more reliable data on drug concentration at the active site. PMID- 25698620 TI - Reliability of measures used in radiographic evaluation of the adult hip. AB - OBJECTIVE: The reliability of radiographic measurements has been studied in pediatric hips, but less has been published on the adult hip, and none have examined the reliability of measurements for the location of the center of rotation (COR) of the hip joint. We have investigated the reliability of various radiographic variables with a focus on the COR. MATERIALS AND METHODS: The study was carried out on a standardized format for anterior-posterior radiographs of the pelvis. The measured variables were; (A) the distance from a sagittal reference line to the COR, (B) the distance from the sagittal reference line to the proximal end of the lateral cortical line of the femur, (C) the distance from the sagittal reference line to the medial rim of the acetabulum, (D) the distance from the horizontal reference line to the roof of the acetabulum, and (E) the distance from the horizontal reference line to the COR. One observer (JAB) conducted the measurements twice separated by a time interval of 45-60 days to assess intra-observer reliability, and the first measurements of JAB were compared to those performed by another observer (OR) to assess inter-observer reliability. RESULTS: Intraclass correlation coefficients were above 0.98 for all measurements, and the minimum and maximum values that statistically include 95% of the observer differences were all within -3 to +3 mm. CONCLUSIONS: These measurements proved to have high reliability and agreement of both within the same observer and between two observers. They should therefore be reproducible in a clinical setting. PMID- 25698621 TI - Origin, evolution and innate immune control of simian foamy viruses in humans. AB - Most viral pathogens that have emerged in humans have originated from various animal species. Emergence is a multistep process involving an initial spill-over of the infectious agent into single individuals and its subsequent dissemination into the human population. Similar to simian immunodeficiency viruses and simian T lymphotropic viruses, simian foamy viruses (SFV) are retroviruses that are widespread among non-human primates and can be transmitted to humans, giving rise to a persistent infection, which seems to be controlled in the case of SFV. In this review, we present current data on the discovery, cross-species transmission, and molecular evolution of SFV in human populations initially infected and thus at risk for zoonotic emergence. PMID- 25698622 TI - Dual-Energy CTA to Diagnose Subarachnoid Hemorrhage: Ready for Prime Time? PMID- 25698623 TI - SWI or T2*: which MRI sequence to use in the detection of cerebral microbleeds? The Karolinska Imaging Dementia Study. AB - BACKGROUND AND PURPOSE: Cerebral microbleeds are thought to have potentially important clinical implications in dementia and stroke. However, the use of both T2* and SWI MR imaging sequences for microbleed detection has complicated the cross-comparison of study results. We aimed to determine the impact of microbleed sequences on microbleed detection and associated clinical parameters. MATERIALS AND METHODS: Patients from our memory clinic (n = 246; 53% female; mean age, 62) prospectively underwent 3T MR imaging, with conventional thick-section T2*, thick section SWI, and conventional thin-section SWI. Microbleeds were assessed separately on thick-section SWI, thin-section SWI, and T2* by 3 raters, with varying neuroradiologic experience. Clinical and radiologic parameters from the dementia investigation were analyzed in association with the number of microbleeds in negative binomial regression analyses. RESULTS: Prevalence and number of microbleeds were higher on thick-/thin-section SWI (20/21%) compared with T2*(17%). There was no difference in microbleed prevalence/number between thick- and thin-section SWI. Interrater agreement was excellent for all raters and sequences. Univariate comparisons of clinical parameters between patients with and without microbleeds yielded no difference across sequences. In the regression analysis, only minor differences in clinical associations with the number of microbleeds were noted across sequences. CONCLUSIONS: Due to the increased detection of microbleeds, we recommend SWI as the sequence of choice in microbleed detection. Microbleeds and their association with clinical parameters are robust to the effects of varying MR imaging sequences, suggesting that comparison of results across studies is possible, despite differing microbleed sequences. PMID- 25698625 TI - Do you need a coach? I do. PMID- 25698624 TI - Fast contrast-enhanced 4D MRA and 4D flow MRI using constrained reconstruction (HYPRFlow): potential applications for brain arteriovenous malformations. AB - BACKGROUND AND PURPOSE: HYPRFlow is a novel imaging strategy that provides fast, high-resolution contrast-enhanced time-resolved images and measurement of the velocity of the entire cerebrovascular system. Our hypothesis was that the images obtained with this strategy are of adequate diagnostic image quality to delineate the major components of AVMs. MATERIALS AND METHODS: HYPRFlow and 3D TOF scans were obtained in 21 patients with AVMs with correlative DSA examinations in 14 patients. The examinations were scored for image quality and graded by using the Spetzler-Martin criteria. Mean arterial transit time and overlap integrals were calculated from the dynamic image data. Volume flow rates in normal arteries and AVM feeding arteries were measured from the phase contrast data. RESULTS: HYPRFlow was equivalent to 3D-TOF in delineating normal arterial anatomy, arterial feeders, and nidus size and was concordant with DSA for AVM grading and venous drainage in 13 of the 14 examinations. Mean arterial transit time on the AVM side was 0.49 seconds, and on the normal contralateral side, 2.53 seconds with P < .001. Across all 21 subjects, the mean arterial volume flow rate in the M1 segment ipsilateral to the AVM was 4.07 +/- 3.04 mL/s; on the contralateral M1 segment, it was 2.09 +/- 0.64 mL/s. The mean volume flow rate in the largest feeding artery to the AVM was 3.86 +/- 2.74 mL/s. CONCLUSIONS: HYPRFlow provides an alternative approach to the MRA evaluation of AVMs, with the advantages of increased coverage, 0.75-second temporal resolution, 0.68-mm isotropic spatial resolution, and quantitative measurement of flow in 6 minutes. PMID- 25698626 TI - Dilated perivascular spaces in the Basal Ganglia are a biomarker of small-vessel disease in a very elderly population with dementia. AB - BACKGROUND AND PURPOSE: Dilated perivascular spaces have been shown to be a specific biomarker of cerebral small-vessel disease in young patients with dementia. Our aim was to examine the discriminative power of dilated cerebral perivascular spaces as biomarkers of small-vessel disease in a very elderly population of patients with dementia. MATERIALS AND METHODS: We studied healthy volunteers (n = 65; mean age, 78 +/- 5.6 years) and subjects with vascular dementia (n = 39; mean age, 76.9 +/- 7.7 years) and Alzheimer disease (n = 47; mean age, 74.1 +/- 8.5 years). We compared white matter hyperintensity and 2 semiquantitative perivascular space scoring systems (perivascular space-1 and perivascular space-2). Intra- and interobserver agreement was assessed by using a weighted Cohen kappa statistic. Multinomial regression modeling was used to assess the discriminative power of imaging features to distinguish clinical groups. RESULTS: White matter hyperintensity scores were higher in vascular dementia than in Alzheimer disease (P < .05) or healthy volunteers (P < .01). The perivascular space-1 score was higher in vascular dementia and Alzheimer disease than in healthy volunteers (P < .01). The perivascular space-2 score in the centrum semiovale showed no intergroup differences. However, perivascular space-2 in the basal ganglia was higher in vascular dementia than in Alzheimer disease (P < .05) or healthy volunteers (P < .001) and higher in Alzheimer disease than in healthy volunteers (P < .001). Modeling of dementia versus healthy volunteers, Alzheimer disease versus healthy volunteers, and vascular dementia against Alzheimer disease demonstrated perivascular space-2basal ganglia as the only imaging parameter with independent significant discriminative power (P < .01, P < .01, and P < .05) with areas under the receiver operating characteristic curve of 0.855, 0.774, and 0.71, respectively. Modeling of vascular dementia versus healthy volunteers showed that perivascular space-2basal ganglia (P < .01) and the modified Scheltens score (P < .05) contributed significant, independent discriminatory power, accounting for 34% and 13% of the variance in the model respectively. CONCLUSIONS: Dilated perivascular spaces remain a valuable biomarker of small-vessel disease in an elderly population. PMID- 25698627 TI - Preface. IFPA meeting 2014. PMID- 25698628 TI - Respiratory rate extraction from single-lead ECG using homomorphic filtering. AB - In this paper a new technique for the extraction of respiratory signal from the single-lead ECG using generalized homomorphic filtering is presented. It is proposed to perform band pass filtering on the cepstrum of the ECG signal to extract the respiratory signal. For this study, transforms used in generalized homomorphic filtering are the discrete Fourier transform (DFT) and the discrete cosine transform (DCT). The performance of the ECG-derived respiration (EDR) signal obtained using the proposed method is compared with the reference respiratory signal in terms of the correlation, magnitude squared coherence coefficients and breath rate accuracy. It is observed from the comparisons that the EDR technique based on generalized homomorphic filtering using DFT performs better than the homomorphic filtering using DCT. The proposed EDR technique is also compared with the two well-known EDR techniques: principal component analysis and R peak amplitude algorithm. It is seen from the results that the proposed EDR technique (RDFT) performs significantly better than the R peak amplitude algorithm, but significant improvements are not observed when compared with the PCA based EDR technique. PMID- 25698629 TI - Review of Russian language studies on radionuclide behaviour in agricultural animals: biological half-lives. AB - Extensive studies on transfer of radionuclides to animals were carried out in the USSR from the 1950s. Few of these studies were published in the international refereed literature or taken into account in international reviews. This paper continues a series of reviews of Russian language literature on radionuclide transfer to animals, providing information on biological half-lives of radionuclides in various animal tissues. The data are compared, where possible, with those reported in other countries. The data are normally quantified using a single or double exponential accounting for different proportions of the loss. For some products, such as milk, biological half-lives tend to be rapid at 1-3 d for most radionuclides and largely described by a single exponential. However, for other animal products biological half-lives can vary widely as they are influenced by many factors such as the age and size of the animal. Experimental protocols, such as the duration of the study, radionuclide administration and/or sample collection protocol also influence the value of biological half-lives estimated. PMID- 25698630 TI - A comparison between serum carbohydrate-deficient transferrin and hair ethyl glucuronide in detecting chronic alcohol consumption in routine. AB - AIMS: In heavy alcohol consumption laboratory tests represent an objective evidence. In this study we compared older and newer biomarkers in blood and in hair. METHODS: Carbohydrate-deficient transferrin (CDT), ethyl glucuronide (EtG), AST, ALT, GGT, MCV were measured in a large sample (n = 562). All people declared no alcohol consumption within the last 3 months. Serum CDT was measured by the candidate HPLC reference method and expressed as relative amount of disialotransferrin (%DST: cutoff 1.7%). EtG was measured in hair by a validated in-house method by LC-MS/MS (cutoff 30 pg/mg). RESULTS: Respectively, 42 (7.5%) and 76 (13.5%) subjects were positive to CDT and EtG. In particular, 30 (5.3%) subjects were positive to both tests, 12 (2.1%) only to CDT, while 46 (8.2%) only to EtG. The agreement (positive and negative pairs) between CDT and EtG was 89.7%. Interestingly, 6 out of 12 (50%) CDT-positive subjects had EtG < 15 pg/mg, whereas 27 out of 46 (59%) EtG-positive subjects had CDT < 1.1%. Forty-one out of 76 (54%) EtG-positive subjects display EtG values within 30-50 pg/mg. CONCLUSION: Large variability exists between CDT and EtG in detecting chronic alcohol consumption. We suggest to use CDT, or a combination of different biomarkers, to identify alcohol abuse in a forensic context. EtG results close to the cutoff (30 50 pg/mg) should be cautiously considered before any sanction is assigned. PMID- 25698631 TI - Large-scale clinical validation of a lateral flow immunoassay for detection of cryptococcal antigen in serum and cerebrospinal fluid specimens. AB - We compared a lateral flow immunoassay (LFA) to a currently used enzyme immunoassay for detection of cryptococcal antigen in 396 sera and 651 cerebrospinal fluid specimens. We found 97% concordance between the 2 assays. The LFA detected an additional 22 positives. Overall, the LFA had sensitivity of 100% and specificity of 99.6% for the diagnosis of cryptococcosis. The LFA is rapid, accurate, and easy to perform, and it is suitable for routine patient care testing. PMID- 25698632 TI - How can we ensure effective antibiotic dosing in critically ill patients receiving different types of renal replacement therapy? AB - Determining appropriate antibiotic dosing for critically ill patients receiving renal replacement therapy (RRT) is complex. Worldwide unstandardized and heterogeneous prescribing of RRT as well as altered patient physiology and pathogen susceptibility all cause drug disposition to be much different to that seen in non-critically ill patients. Significant changes to pharmacokinetic parameters, including volume of distribution and clearance, could be expected, in particular, for antibiotics that are hydrophilic with low plasma protein binding and that are usually primarily eliminated by the renal system. Antibiotic clearance is likely to be significantly increased when higher RRT intensities are used. The combined effect of these factors that alter antibiotic disposition is that non-standard dosing strategies should be considered to achieve therapeutic exposure. In particular, an aggressive early approach to dosing should be considered and this may include administration of a 'loading dose', to rapidly achieve therapeutic concentrations and maximally reduce the inoculum of the pathogen. This approach is particularly important given the pharmacokinetic changes in the critically ill as well as the increased likelihood of less susceptible pathogens. Dose individualization that applies knowledge of the RRT and patient factors causing altered pharmacokinetics remains the key approach for ensuring effective antibiotic therapy for these patients. Where possible, therapeutic drug monitoring should also be used to ensure more accurate therapy. A lack of pharmacokinetic data for antibiotics during the prolonged intermittent RRT and intermittent hemodialysis currently limits evidence-based antibiotic dose recommendations for these patients. PMID- 25698633 TI - [Citrulline and arginine kinetics and its value as a prognostic factor in pediatric critically ill patients]. AB - INTRODUCTION: Low concentrations of plasma citrulline and arginine have been reported in children under various pathological conditions. HYPOTHESIS: Plasma citrulline and arginine levels undergo different kinetics during the early days of critical illness in children according to the severity of symptoms and can be correlated with other clinical and laboratory parameters associated with the SIR. PATIENTS AND METHODS: A single-center prospective observational study in patients 7 days to 14 years admitted to pediatric intensive care unit (PICU). Citrulline and arginine blood levels (blood in dry paper, analysis by mass spectrometry in tandem), acute phase reactants and clinical data were collected on admission, at 12 h, 24 h, 3 and 7 days. RESULTS: A total of 44 critically ill patients were included and control group was formed by 42 healthy children. The citrulline and arginine kinetic analysis showed: 1) Citrulline falls significantly (P<.05) at 12 h of admission; levels remain low until day 7 and begin progressive increase again. 2) Arginine is already lowered at 6h, although an earlier rise occurs (3rd day). 3. The decrease of citrulline in the first 3 days of admission positively correlates with arginine kinetics. Bivariate analysis showed: 1) Correlation of elevated citrulline on the 7th day with shorter duration of mechanical ventilation, lower PICU stay and lower occurrence of complications. The levels of citrulline still descended at day 7 are associated with increased CRP/procalcitonin elevation at first 24 h. 2) The greatest decrease of arginine in the first 12 h is associated with a longer PICU stay and greater number of complications and increase of acute phase reactants at 3 days. CONCLUSIONS: There are decreased levels of arginine and citrulline in the first days at PICU, with recovery at the 3rd and 7th day respectively, and a relationship between a greater decrease and a worse outcome and between a longer income and a higher serum CRP/procalcitonin. PMID- 25698634 TI - Enhanced magnetic Purcell effect in room-temperature masers. AB - Recently, the world's first room-temperature maser was demonstrated. The maser consisted of a sapphire ring housing a crystal of pentacene-doped p-terphenyl, pumped by a pulsed rhodamine-dye laser. Stimulated emission of microwaves was aided by the high quality factor and small magnetic mode volume of the maser cavity yet the peak optical pumping power was 1.4 kW. Here we report dramatic miniaturization and 2 orders of magnitude reduction in optical pumping power for a room-temperature maser by coupling a strontium titanate resonator with the spin polarized population inversion provided by triplet states in an optically excited pentacene-doped p-terphenyl crystal. We observe maser emission in a thimble-sized resonator using a xenon flash lamp as an optical pump source with peak optical power of 70 W. This is a significant step towards the goal of continuous maser operation. PMID- 25698635 TI - Extended adjuvant endocrine therapy in hormone-receptor positive early breast cancer: current and future evidence. AB - The optimal duration and regimen of adjuvant hormonal therapy for premenopausal and postmenopausal patients with hormone receptor positive early breast cancer has not yet been established. This review will give an overview of published and ongoing studies concerning extended endocrine treatment. Most of the currently published studies are based on the adjuvant treatment regime of 5 years tamoxifen, which has been proven to be inferior compared to aromatase inhibitor (AI)-containing regimes. Therefore, until today, there is no clear evidence for the extension of endocrine therapy after upfront AI-based adjuvant treatment regimes. Multiple clinical trials, which will be discussed in this review, are ongoing to elucidate on this matter. We emphasize the need for tailoring of extended adjuvant endocrine treatment. The quest for predictive biomarkers, which are currently being investigated in the context of decision-making whether or not to start adjuvant chemotherapy, should be expanded to include the feasibility of extended endocrine treatment based on these markers. By tailoring the extension of endocrine treatment, overtreatment, side effects and unnecessary costs will be prevented. PMID- 25698636 TI - Primary and secondary bone lymphomas. AB - Recent studies have contributed to the enhancement of clinical and molecular knowledge on bone lymphomas, a group of rare malignancies with particular characteristics. Nevertheless, several questions remain unanswered and the level of evidence supporting some diagnostic and therapeutic decisions remains low. Currently, three different forms of bone lymphomas can be distinguished: the primary bone lymphoma, consisting of a single bone lesion with or without regional lymphadenopathies; the polyostotic lymphoma, consisting of multifocal disease exclusively involving the skeleton; and the disseminated lymphoma with secondary infiltration of the skeleton. The first two forms exhibit a good prognosis, requiring treatments similar to those commonly used for nodal lymphomas of the same category, but several issues regarding the role of surgery and local control of the disease, the sequence of treatment, radiation volumes and doses, management of pathological fractures and prevention of late sequelae deserve particular attention. Due to its rarity, prospective trials exclusively focused on bone lymphomas appear unrealistic, thus, critical revision of our own experience and analyses of large cumulative series as well as molecular studies on archival cases remain valid alternatives to improve our knowledge on this obscure lymphoproliferative malignancy. The present review is based on the analysis of the largest available database of bone lymphomas established under the sponsorship of the International Extranodal Lymphoma Study Group (IELSG) as well as on the critical revision of related literature. We provide recommendations for diagnosis, staging, treatment, and response assessment of these patients in everyday practice as well as for the management of special conditions like pathological fractures, indolent forms and central nervous system prophylaxis. PMID- 25698637 TI - Brain structures and functional connectivity associated with individual differences in Internet tendency in healthy young adults. AB - Internet addiction (IA) incurs significant social and financial costs in the form of physical side-effects, academic and occupational impairment, and serious relationship problems. The majority of previous studies on Internet addiction disorders (IAD) have focused on structural and functional abnormalities, while few studies have simultaneously investigated the structural and functional brain alterations underlying individual differences in IA tendencies measured by questionnaires in a healthy sample. Here we combined structural (regional gray matter volume, rGMV) and functional (resting-state functional connectivity, rsFC) information to explore the neural mechanisms underlying IAT in a large sample of 260 healthy young adults. The results showed that IAT scores were significantly and positively correlated with rGMV in the right dorsolateral prefrontal cortex (DLPFC, one key node of the cognitive control network, CCN), which might reflect reduced functioning of inhibitory control. More interestingly, decreased anticorrelations between the right DLPFC and the medial prefrontal cortex/rostral anterior cingulate cortex (mPFC/rACC, one key node of the default mode network, DMN) were associated with higher IAT scores, which might be associated with reduced efficiency of the CCN and DMN (e.g., diminished cognitive control and self-monitoring). Furthermore, the Stroop interference effect was positively associated with the volume of the DLPFC and with the IA scores, as well as with the connectivity between DLPFC and mPFC, which further indicated that rGMV variations in the DLPFC and decreased anticonnections between the DLPFC and mPFC may reflect addiction-related reduced inhibitory control and cognitive efficiency. These findings suggest the combination of structural and functional information can provide a valuable basis for further understanding of the mechanisms and pathogenesis of IA. PMID- 25698638 TI - Impaired oculo-motor behaviour affects both reading and scene perception in neglect patients. AB - Unilateral spatial neglect (USN) is a common neuropsychological disorder following a right-sided brain lesion. Although USN is mostly characterized by symptoms involving the left hemispace, other symptoms are not left lateralized. Recently, it was shown that patients with neglect dyslexia, a reading disturbance that affects about 40% of USN patients, manifest a non-lateralized impairment of eye movement behaviour in association with their reading deficit when they read aloud and perform non-verbal saccadic tasks (Primativo et al., 2013). In the present paper, we aimed to demonstrate that the eye movement impairment shown by some USN patients reflects a more general oculo-motor disorder that is not confined to orthographic material, the horizontal axis or constrained saccadic tasks. We conjectured that inaccurate oculo-motor behaviour in USN patients indicates the presence of a reading deficit. With this aim we evaluated 20 patients, i.e., 10 right-sided brain-damaged patients without neglect and 10 patients affected by USN. On the basis of the patients' eye movement patterns during a scene exploration task, we found that 4 out of the 10 USN patients presented an abnormal oculo-motor pattern. These same four patients (but not the others) also failed in performing 5 different saccadic tasks and produced neglect dyslexia reading errors in both single words and texts. First, we show that a large proportion of USN patients have inaccurate eye movement behaviour in non reading tasks. Second, we demonstrate that this exploratory deficit is predictive of the reading impairment. Thus, we conclude that the eye movement deficit prevents reading and impairs the performance on many other perceptual tests, including scene exploration. The large percentage of patients with impaired eye movement pattern suggests that particular attention should be paid to eye movement behaviour during the diagnostic phase in order to program the best rehabilitation strategy for each patient. PMID- 25698639 TI - Waves of awareness for occipital and parietal phosphenes perception. AB - Transcranial magnetic stimulation (TMS) of the occipital cortex is known to induce visual sensations, i.e. phosphenes, which appear as flashes of light in the absence of an external stimulus. Recent studies have shown that TMS can produce phosphenes also when the intraparietal sulcus (IPS) is stimulated. The main question addressed in this paper is whether parietal phosphenes are generated directly by local mechanisms or emerge through indirect activation of other visual areas. Electroencephalographic (EEG) signals were recorded while stimulating left occipital or parietal cortices inducing phosphene perception in healthy participants and in a hemianopic patient who suffered from complete destruction of the early visual cortex of the left hemisphere. Results in healthy participants showed that the onset of phosphene perception induced by occipital TMS correlated with differential cortical activity in temporal sites while the onset of phosphene perception induced by parietal TMS correlated with differential cortical activity in the stimulated parietal site. Moreover, IPS-TMS of the lesioned hemisphere of the hemianopic patient with a complete lesion to V1 showed again that the onset of phosphene perception correlated with differential cortical activity in the stimulated parietal site. The present data seem thus to suggest that temporal and parietal cortices can serve as different local early gatekeepers of perceptual awareness and that activity in the occipital cortex, although being relevant for perception in general, is not part of the neural bases of the perceptual awareness of phosphenes. PMID- 25698640 TI - How does group antenatal care function within a caseload midwifery model? A critical ethnographic analysis. AB - BACKGROUND: caseload midwifery and CenteringPregnancyTM (a form of group antenatal care) are two models of maternity care that are separately associated with better clinical outcomes, maternal satisfaction scores and positive experiences compared to standard care. One study reported exclusively on younger women's experiences of caseload midwifery; none described younger women's experiences of group antenatal care. We retrieved no studies on the experiences of women who received a combination of caseload midwifery and group antenatal care. OBJECTIVE: examine younger women's experiences of caseload midwifery in a setting that incorporates group antenatal care. DESIGN: a critical, focused ethnographic approach. SETTING: the study was conducted in an Australian hospital and its associated community venue from 2011 to 2013. PARTICIPANTS: purposive sampling of younger (19-22 years) pregnant and postnatal women (n=10) and the caseload midwives (n=4) who provided group antenatal care within one midwifery group practice. METHODS: separate focus group interviews with women and caseload midwives, observations of the setting and delivery of group antenatal care, and examination of selected documents. Thematic analyses of the women's accounts have been given primary significance. Coded segments of the midwives interview data, field notes and documents were used to compare and contrast within these themes. FINDINGS: we report on women's first encounters with the group, and their interactions with peers and midwives. The group setting minimised the opportunity for the women and midwives to get to know each other. CONCLUSIONS: this study challenges the practice of combining group antenatal care with caseload midwifery and recommends further research. PMID- 25698641 TI - All Babies Count: reducing the pressure on new families. PMID- 25698642 TI - Performance characteristics of the EPR dosimetry system with table sugar in radiotherapy applications. AB - Performance characteristics of the megavoltage photon dose measurements with EPR and table sugar were analyzed. An advantage of sugar as a dosimetric material is its tissue equivalency. The minimal detectable dose was found to be 1.5Gy for both the 6 and 18MV photons. The dose response curves are linear up to at least 20Gy. The energy dependence of the dose response in the megavoltage energy range is very weak and probably statistically insignificant. Reproducibility of measurements of various doses in this range performed with the peak-to-peak and double-integral methods is reported. The method can be used in real-time dosimetry in radiation therapy. PMID- 25698643 TI - Unleashing the therapeutic potential of human kallikrein-related serine proteases. AB - Tissue kallikreins are a family of fifteen secreted serine proteases encoded by the largest protease gene cluster in the human genome. In the past decade, substantial progress has been made in characterizing the natural substrates, endogenous inhibitors and in vivo functions of kallikreins, and studies have delineated important pathophysiological roles for these proteases in a variety of tissues. Thus, kallikreins are now considered attractive targets for the development of novel therapeutics for airway, cardiovascular, tooth, brain, skin and neoplastic diseases. In this Review, we discuss recent advances in our understanding of the physiological functions and pathological implications of kallikrein proteases, and highlight progress in the identification of kallikrein inhibitors, which together are bringing us closer to therapeutically targeting kallikreins in selected disease settings. PMID- 25698645 TI - Re: "The next generation of large-scale epidemiologic research: implications for training cancer epidemiologists". PMID- 25698644 TI - Principles in the design of ligand-targeted cancer therapeutics and imaging agents. AB - Most cancer drugs are designed to interfere with one or more events in cell proliferation or survival. As healthy cells may also need to proliferate and avoid apoptosis, anticancer agents can be toxic to such cells. To minimize these toxicities, strategies have been developed wherein the therapeutic agent is targeted to tumour cells through conjugation to a tumour-cell-specific small molecule ligand, thereby reducing delivery to normal cells and the associated collateral toxicity. This Review describes the major principles in the design of ligand-targeted drugs and provides an overview of ligand-drug conjugates and ligand-imaging-agent conjugates that are currently in development. PMID- 25698646 TI - Hormone therapy and young-onset breast cancer. AB - Estrogen plus progestin hormone therapy (HT) is associated with an increased risk of postmenopausal breast cancer, but few studies have examined the impact of HT use on the risk of breast cancer in younger women. We assessed the association between estrogen plus progestin HT or unopposed estrogen HT and young-onset breast cancer using data from the Two Sister Study (2008-2010), a sister-matched study of 1,419 cases diagnosed with breast cancer before the age of 50 years and 1,665 controls. We assessed exposures up to a family-specific index age to ensure comparable opportunities for exposures and used propensity scores to control for birth cohort effects on HT use. Ever HT use was uncommon (7% and 11% in cases and controls, respectively). Use of estrogen plus progestin was not associated with an increased risk of young-onset breast cancer (odds ratio = 0.80, 95% confidence interval: 0.41, 1.59). Unopposed estrogen use was inversely associated with the risk of young-onset breast cancer (odds ratio = 0.58, 95% confidence interval: 0.34, 0.99). Duration of use, age at first use, and recency of use did not modify these associations. PMID- 25698647 TI - The authors reply. PMID- 25698648 TI - Post-transplant soluble CD30 levels are associated with early subclinical rejection in kidney transplantation. AB - Several studies have shown association of high pre- or post-transplant levels of soluble CD30 (sCD30) with acute rejection and poor late kidney transplant outcome. Our goal was to investigate whether sCD30 levels at month-3 post transplant are associated with subclinical rejection, presence of CD30(+) cells within the graft, and expression of immune response genes in peripheral blood mononuclear cells. The study comprised 118 adult first kidney graft recipients, transplanted at a single center, receiving tacrolimus in low concentration. All were submitted to a protocol biopsy at month-3. Subclinical rejection was identified in 10 biopsies and sCD30 levels >= 61.88 ng/mL (P = 0.004), younger recipient age (P = 0.030) and non-Caucasian ethnicity (P = 0.011) were independently associated with this outcome. Rare CD30(+) cells were present in only two biopsies. There was a correlation between sCD30 levels and CD30 gene expression in peripheral blood mononuclear cells (r = 0.385, P = 0.043). These results show that high sCD30 levels are independent predictors of graft dysfunction and may contribute to patient selection protocols by indicating those who could benefit from a more thorough evaluation. PMID- 25698649 TI - The unsteady eye: an information-processing stage, not a bug. AB - How is space represented in the visual system? At first glance, the answer to this fundamental question appears straightforward: spatial information is directly encoded in the locations of neurons within maps. This concept has long dominated visual neuroscience, leading to mainstream theories of how neurons encode information. However, an accumulation of evidence indicates that this purely spatial view is incomplete and that, even for static images, the representation is fundamentally spatiotemporal. The evidence for this new understanding centers on recent experimental findings concerning the functional role of fixational eye movements, the tiny movements humans and other species continually perform, even when attending to a single point. We review some of these findings and discuss their functional implications. PMID- 25698650 TI - Clinical features of primary ciliary dyskinesia in Cyprus with emphasis on lobectomized patients. AB - BACKGROUND: Despite the manifestations of primary ciliary dyskinesia (PCD) in early life, the diagnosis is often much delayed. Since 1998 in Cyprus, we have established the only national diagnostic and clinical referral center for PCD. OBJECTIVE: To review the phenotypic features at presentation of PCD patients in Cyprus in relation to age at diagnosis, with emphasis on previously lobectomised patients. METHODS: The medical records of the diagnosed PCD patients were retrospectively reviewed to obtain clinical data on presentation. RESULTS: Thirty patients, aged 13.9 years (range 0.1, 58.4 years), were diagnosed with PCD. Twelve of them presented after the age of 18. The most common manifestations were chronic cough (100%), chronic rhinorrhea (96.7%), sputum production (92.9%), laterality defects (63.3%), a history of pneumonia (53.3%) and neonatal respiratory distress (50%). A history of lobectomy in the past was recorded in 16.7% (5 patients). Patients who presented in adulthood had significantly higher frequency of lobectomy (41.7% vs 0%, p-value = 0.006) and had more frequently low FEV1 (58.3% vs 0%, p-value = 0.015) than those who presented before. Serial measurements of FEV1 and FVC indicated significantly lower intercepts in lobectomised compared to the adult non-lobectomised patients both in terms of FEV1 (-4.90 vs -1.80, p-value = 0.022) and FVC (-5.43 vs -1.91, p-value = 0.029) z-score levels. Change in FEV1 and FVC across time was not statistically significant in either group. CONCLUSIONS: PCD often remains undiagnosed up to adulthood accompanied by appearance of advanced lung disease. Performance of lobectomies seems to be a poor prognostic factor for PCD in adulthood. PMID- 25698651 TI - Changes in fatigability following intense aerobic exercise training in patients with interstitial lung disease. AB - OBJECTIVE: To determine if, in patients with interstitial lung disease (ILD), fatigue might be lessened after vigorous aerobic exercise. METHODS: 13 physically inactive patients (5 men and 8 women; age 57.2 +/- 9.1 years, BMI 28.2 +/- 4.6 kgm(-2)) with ILD of heterogeneous etiology and able to walk on a motor driven treadmill without physical limitation were enrolled. Subjects underwent cardiopulmonary exercise (CPET) and 6-min walk (6MWT) tests and completed Fatigue Severity Scale and Human Activity Profile questionnaires before and after an aerobic exercise-training regimen. The training regimen required participation in at least 24 of 30 prescribed aerobic exercise training sessions at a target heart rate of 70-80% of the heart rate reserve, 30 min per session, 3 times per week for 10 weeks. RESULTS: After training, a 55% (p < 0.001) increase in time to anaerobic threshold on the CPET, and an 11% (p = 0.045) reduction in performance fatigability index (PFI), calculated from the performance on the 6MWT were observed. Distance walked on the 6MWT (6MWD) increased by 49.7 +/- 46.9 m (p = 0.002). Significant improvements in scores on the Fatigue Severity Scale (p = 0.046) and Human Activity Profile (AAS p = 0.024; MAS p = 0.029) were also observed. No adverse events related to the training regimen were noted. CONCLUSION: After training, the decrease in fatigability appeared to result in increased 6MWD and was associated with physical activity. Since significant declines in 6MWD may be a marker for impending mortality in ILD, a better understanding of the etiological state of fatigue in patients with ILD and its reversal might provide fundamental insight into disease progression and even survival. [ClinicalTrials.gov identifier NCT00678821]. PMID- 25698652 TI - The effect of corticosteroids on quality of life in a sarcoidosis clinic: the results of a propensity analysis. AB - BACKGROUND: Both sarcoidosis and its treatment may worsen health related quality of life (HRQoL). We performed a propensity analysis of sarcoidosis-specific HRQoL patient reported outcome measures (PRO) to disentangle the effects of sarcoidosis and corticosteroid therapy on HRQoL in sarcoidosis outpatients. METHODS: Consecutive outpatient sarcoidosis patients were administered modules from two sarcoidosis-specific HRQoL PROs: the Sarcoidosis Health Questionnaire (SHQ) and the Sarcoidosis Assessment Tool (SAT). Patients were divided into those that received <=500 mg of prednisone (PRED-LOW) versus >500 mg of prednisone (PRED HIGH) over the previous year. SAT and SHQ scores were initially compared in the two corticosteroid groups. Then a multivariate analysis was performed using a propensity score analysis adjusted for race, age, gender and the severity of illness. RESULTS: In the unadjusted analysis, the PRED-HIGH group demonstrated the following worse HRQoL scores compared to the LOW-PRED group: SHQ Daily (p = 0.02), SAT satisfaction (p = 0.03), SAT daily activities (p = 0.03). In the propensity analysis, the following domains demonstrated worse HRQoL in the PRED HIGH group than the PRED-LOW group: SAT fatigue (p < 0.0001), SAT daily activities (p = 0.03), SAT satisfaction (p = 0.03). All these differences exceeded the established minimum important difference for these SAT domains. The SHQ Physical score appeared to demonstrate a borderline improved HRQoL in the PRED-HIGH versus the PRED-LOW group (p = 0.05).). In a post-hoc exploratory analysis, the presence of cardiac sarcoidosis may have explained the quality of life differences between the two corticosteroid groups. CONCLUSIONS: Our cohort of sarcoidosis clinic patients who received <=500 mg of prednisone in the previous year had an improved HRQoL compared to patients receiving >500 mg on the basis of two sarcoidosis-specific PROs after adjusting for severity of illness. These data support the need to measure HRQoL in sarcoidosis trials, and suggest that the search should continue for effective alternative medications to corticosteroids. PMID- 25698653 TI - Peptide Lv augments L-type voltage-gated calcium channels through vascular endothelial growth factor receptor 2 (VEGFR2) signaling. AB - We previously identified peptide Lv, a novel bioactive peptide that enhances the activity of L-type voltage-gated calcium channels (L-VGCCs) in cone photoreceptors. In this study, we verified that peptide Lv was able to augment L VGCC currents in cardiomyocytes, as well as promote proliferation of endothelial cells. We used a proteomics approach to determine the specific receptors and binding partners of peptide Lv and found that vascular endothelial growth factor receptor 2 (VEGFR2) interacted with peptide Lv. Peptide Lv treatment in embryonic cardiomyocytes stimulated tyrosine autophosphorylation of VEGFR2 and activated its downstream signaling. Peptide Lv activity was blocked by DMH4, a VEGFR2 specific blocker, but not by SCH202676, an allosteric inhibitor of G protein coupled receptors, suggesting that the activity of peptide Lv was mediated through VEGFR2 signaling. Inhibition of VEGFR tyrosine kinase or its downstream signaling molecules abolished the augmentation of L-VGCCs elicited by peptide Lv in cardiomyocytes. In addition, peptide Lv promoted cell proliferation of cultured human endothelial cells. Calcium entry through L-VGCCs is essential for excitation-contraction coupling in cardiomyocytes. Since peptide Lv was able to augment L-VGCCs through activation of VEGF signaling in cardiomyocytes and promote proliferation of endothelial cells, peptide Lv may play an important role in regulating the cardiovascular system. PMID- 25698654 TI - Oxygen in demand: How oxygen has shaped vertebrate physiology. AB - In response to varying environmental and physiological challenges, vertebrates have evolved complex and often overlapping systems. These systems detect changes in environmental oxygen availability and respond by increasing oxygen supply to the tissues and/or by decreasing oxygen demand at the cellular level. This suite of responses is termed the oxygen transport cascade and is comprised of several components. These components include 1) chemosensory detectors that sense changes in oxygen, carbon dioxide, and pH in the blood, and initiate changes in 2) ventilation and 3) cardiac work, thereby altering the rate of oxygen delivery to, and carbon dioxide clearance from, the tissues. In addition, changes in 4) cellular and systemic metabolism alters tissue-level metabolic demand. Thus the need for oxygen can be managed locally when increasing oxygen supply is not sufficient or possible. Together, these mechanisms provide a spectrum of responses that facilitate the maintenance of systemic oxygen homeostasis in the face of environmental hypoxia or physiological oxygen depletion (i.e. due to exercise or disease). Bill Milsom has dedicated his career to the study of these responses across phylogenies, repeatedly demonstrating the power of applying the comparative approach to physiological questions. The focus of this review is to discuss the anatomy, signalling pathways, and mechanics of each step of the oxygen transport cascade from the perspective of a Milsomite. That is, by taking into account the developmental, physiological, and evolutionary components of questions related to oxygen transport. We also highlight examples of some of the remarkable species that have captured Bill's attention through their unique adaptations in multiple components of the oxygen transport cascade, which allow them to achieve astounding physiological feats. Bill's research examining the oxygen transport cascade has provided important insight and leadership to the study of the diverse suite of adaptations that maintain cellular oxygen content across vertebrate taxa, which underscores the value of the comparative approach to the study of physiological systems. PMID- 25698655 TI - Externalizing symptoms moderate associations among interpersonal skills, parenting, and depressive symptoms in adolescents seeking mental health treatment. AB - Adolescents' interpersonal skills are associated with fewer teen depressive symptoms and more positive parenting, but little is known about how teens' externalizing problems moderate these relationships. This study examines links among teens' interpersonal skills, parenting, and withdrawn-depressed symptoms in adolescents seeking outpatient psychiatric treatment with elevated or non elevated externalizing problems. Adolescents (N = 346; 42 % female; 61 % African American) ages 12-19 years old (M = 14.9; SD = 1.8) and parents completed assessments at baseline and 6 months. At baseline parents and teens reported on teen withdrawn-depressed and externalizing symptoms, and were observed interacting to assess teen interpersonal skills. At 6 months adolescents reported on parenting, and parents and teens reported on teen withdrawn-depressed symptoms. Structural equation modeling tested two models (one with teen reported symptoms and one with parent reported symptoms). Model fit was better for youth with elevated externalizing problems regardless of reporter. For youth with elevated externalizing problems, baseline teen positive interpersonal skills were not directly associated with 6-month withdrawn-depressed symptoms, but more positive parenting was associated with fewer withdrawn-depressed symptoms. In the teen report model, more positive teen interpersonal skills were associated with more positive parenting, and there was a trend for parenting to indirectly account for the relationship between interpersonal skills and withdrawn-depressed symptoms. The findings extend research on the role of externalizing problems in teens' depression risk. Interventions for depression that target interpersonal skills may be particularly effective in youth with elevated externalizing problems. PMID- 25698656 TI - Imaging features of spinal trauma: what the radiologist needs to know. AB - Traumatic spinal fractures typically occur in a young subset of patients following a high-energy motor vehicle accident (MVA) or a fall from height. Upon recognizing the spinal injury, the radiologist should be able to describe the fracture pattern based on conventional nomenclature and to deduce the likely mechanism of injury. This will enable the provision of a more clinically relevant report and will help the radiologist to appreciate the likelihood of associated ligamentous and neurological injury. Vertebral trauma often follows a recognizable pattern based on a specific mechanism of injury. These predictable types of fracture have been referred to as the "fingerprints" of the injury.(1) This review depicts the variety of vertebral column fractures seen in a cohort of 781 patients admitted to our level 1 trauma centre over 1 year. PMID- 25698657 TI - Counterfactual thinking affects the excitability of the motor cortex. AB - Evidence suggests that monetary reward and affective experiences induce activity in the cortical motor system. Nevertheless, it is unclear whether counterfactual thinking related to wrong choices that lead to monetary loss and regret affects motor excitability. Using transcranial magnetic stimulation (TMS) of the motor cortex, we measured corticospinal excitability of 2 groups of healthy humans asked to actively guess the winning key among two possible alternatives (choice group); or passively assist to monetary outcomes randomly selected by the computer program (follow group). Results document a selective increment of the corticospinal excitability when a monetary loss outcome followed the key selection (i.e., in the choice group). On the other hand, no change in corticospinal excitability was found when participants passively assisted to a monetary loss randomly selected by the computer program (i.e., follow group). These findings suggest that counterfactual thinking and the negative emotional experiences arising from choices causing monetary loss--i.e., "I would have won instead of lost money if I'd made a different choice"--are mapped in the motor system. PMID- 25698658 TI - Risk factors and clinical outcomes of candidaemia in patients treated for Clostridium difficile infection. AB - The alterations occurring in the intestinal flora during Clostridium difficile infection (CDI) may promote the translocation of Candida to the blood and the development of candidaemia. The aim of our study was to analyse clinical findings of these patients to determine the risk factors associated with the development of candidaemia subsequent to CDI. We compared 35 patients with candidaemia subsequent to CDI with 105 patients with CDI. Patients with candidaemia showed more severe infections and higher mortality. The ribotype 027 strain and vancomycin treatment at >= 1000 mg/day were prevalent in patients developing candidaemia. CDI may predispose to the translocation of Candida. PMID- 25698659 TI - Thirty day all-cause mortality in patients with Escherichia coli bacteraemia in England. AB - Escherichia coli is the commonest cause of bacteraemia in England, with an incidence of 50.7 cases per 100 000 population in 2011. We undertook a large national study to estimate and identify risk factors for 30-day all-cause mortality in E. coli bacteraemia patients. Records for patients with E. coli bacteraemia reported to the English national mandatory surveillance system between 1 July 2011 and 30 June 2012 were linked to death registrations to determine 30-day all-cause mortality. A multivariable regression model was used to identify factors associated with 30-day all-cause mortality. There were 5220 deaths in 28 616 E. coli bacteraemia patients, a mortality rate of 18.2% (95% CI 17.8-18.7%). Three-quarters of deaths occurred within 14 days of specimen collection. Factors independently associated with increased mortality were: age < 1 year or > 44 years; an underlying respiratory or unknown infection focus; ciprofloxacin non-susceptibility; hospital-onset infection or not being admitted; and bacteraemia occurring in the winter. Female gender and a urogenital focus were associated with a reduction in mortality. This is the first national study of mortality among E. coli bacteraemia patients in England. Interventions to reduce mortality need to be multifaceted and include both primary and secondary healthcare providers. Greater awareness of the risk factors for and symptoms of E. coli bacteraemia may prompt earlier diagnosis and treatment. Changes in antimicrobial resistance patterns need to be monitored for their potential impact on infection and mortality. PMID- 25698660 TI - Diversity of human papillomavirus in the anal canal of men: the HIM Study. AB - Human papillomavirus (HPV) infections are associated with the development of anogenital lesions in men. There are no reports describing the distribution of non-alpha HPV types in the anal canal of a sexually diverse group of men. The HPV Infection in Men (HIM) Study is a multicentre study on the natural history of HPV infection in Brazil, Mexico, and the USA. At baseline, 12% of anal canal PCR HPV positive specimens were not typed by the Roche Linear Array, and were considered to be unclassified. Our goals were to characterize HPVs among these unclassified specimens at baseline, and to assess associations with participant socio demographic and behavioural characteristics. Unclassified HPVs were typed by sequencing of amplified PGMY09/11 products or cloning of PGMY/GP + nested amplicons followed by sequencing. Further analysis was conducted with FAP primers. Of men with unclassified HPV in the anal canal, most (89.1%) were men who have sex with women. Readable sequences were produced for 62.8% of unclassified specimens, of which 75.2% were characterized HPV types. Eighteen, 26 and three different alpha-HPV, beta-HPV and gamma-HPV types were detected, respectively. alpha-HPVs were more commonly detected among young men (18-30 years) than among older men (45-70 years), whereas beta-HPVs were more frequent among mid-adult men (31-44 years). beta-HPVs were more common among heterosexual men (85.0%) than among non-heterosexual men. All beta-HPVs detected among non heterosexual men were beta2-HPV types. The high prevalence of beta-HPV in the anal canal of men who do not report receptive anal sex is suggestive of other forms of transmission that do not involve penile-anal intercourse. PMID- 25698662 TI - Terminology of CCN1-6 should not be applicable for their fragments and be limited to only full length CCN1-6. PMID- 25698661 TI - The MAPK and PI3K pathways mediate CNTF-induced neuronal survival and process outgrowth in hypothalamic organotypic cultures. AB - While collateral sprouting has been shown to occur in a variety of neuronal populations, the factor or factors responsible for mediating the sprouting response remain largely un-defined. There is evidence indicating that ciliary neurotrophic factor (CNTF) may play an important role in promoting neuronal survival and process outgrowth in neuronal phenotypes tested to date. We previously demonstrated that the astrocytic Jak-STAT pathway is necessary to mediate CNTF-induced oxytocinergic (OT) neuronal survival; however, the mechanism (s) of CNTF-mediated process outgrowth remain unknown. Our working hypothesis is that CNTF mediates differential neuroprotective responses via different intracellular signal transduction pathways. In order to test this hypothesis, we utilized stationary hypothalamic organotypic cultures to assess the contribution of the MAPK-ERK and PI3-AKT pathways to OT neuron survival and process outgrowth. Our results demonstrate that the MAPK-ERK1/2 pathway mediates CNTF-induced neuronal survival. Moreover, we show that inhibition of the p38-, JNK-MAPK, and mTOR pathways prevents loss OT neurons following axotomy. We also provide quantitative evidence indicating that CNTF promotes process outgrowth of OT neurons via the PI3K-AKT pathway. Together, these data indicate that distinct intracellular signaling pathways mediate diverse neuroprotective processes in response to CNTF. PMID- 25698663 TI - Stem cell quest. AB - Chronic Myeloid Leukaemia has been a valuable model system for experimental haematologists for many years. Virtually all patients (>95 %) have the same genetic change which has driven the development of the first targeted therapies, tyrosine kinase inhibitors (TKIs). Since the introduction of TKIs in 2000 it has become clear that this approach has significantly improved the outcome for these patients. Nevertheless drug resistance inevitably develops and it is clear that the disease is controlled rather than eradicated. The recent publication by Herrmann et al. has defined a sub-population of leukaemic stem cells which are responsible for propagating the disease. CD26 now provides a new specific target for the malignant stem cells and offers the possibility of true curative therapy. PMID- 25698664 TI - Another dimension to the importance of the extracellular matrix in fibrosis. AB - The importance of the extracellular matrix (ECM) in fibrosis has been recognized for a long time, not only because ECM's increased stiffness hampers tissue function, but also because the ECM provides the mechanical tension that maintains resident cells' synthetic phenotype. A study by Parker and colleagues (Journal of Clinical Investigation 124, 1622-1635, 2014) compared the transcriptome of fibroblasts cultured on decellularized ECM from healthy vs idiopathic pulmonary fibrosis (IPF) human lungs, and revealed that the IPF matrix exerts a positive feedback loop that increases the translation of ECM genes that are enriched in the IPF ECM proteome. This study suggests that the ECM composition, in addition to ECM stiffness or the phenotype of its resident cells, might be an important factor in maintaining a fibrotic state. Targeting this feedback loop might be an efficient therapeutic strategy for IPF. PMID- 25698665 TI - Physiological changes in fruit ripening caused by overexpression of tomato SlAN2, an R2R3-MYB factor. AB - The R2R3-MYB protein SlAN2 has long been thought to be a positive regulator of anthocyanin accumulation. To investigate the role of SlAN2, we have previously overexpressed the gene in tomato. In this work, we analysed physiological characters of the transgenic plants during the fruit ripening. We show that fruits of transformants overexpressing SlAN2 displayed an orange colour, fast softening and elevated ethylene production. Overexpression of SlAN2 resulted in reduction of carotenoid levels via alteration of flux through the carotenoid pathway, elevated ethylene synthesis mainly via upregulation of ethylene biosynthesis genes, and early softening of fruits. We also found that the transcript level of SlRIN, an important ripening-related gene, was up-regulated in transgenic fruits. These results suggest that SlAN2 acts as an important regulator of fruit ripening. PMID- 25698666 TI - Simultaneous functions of the installed DAS/DAK formaldehyde-assimilation pathway and the original formaldehyde metabolic pathways enhance the ability of transgenic geranium to purify gaseous formaldehyde polluted environment. AB - The overexpression of dihydroxyacetone synthase (DAS) and dihydroxyacetone kinase (DAK) from methylotrophic yeasts in chloroplasts created a photosynthetic formaldehyde (HCHO)-assimilation pathway (DAS/DAK pathway) in transgenic tobacco. Geranium has abilities to absorb and metabolize HCHO. Results of this study showed that the installed DAS/DAK pathway functioning in chloroplasts greatly enhanced the role of the Calvin cycle in transgenic geranium under high concentrations of gaseous HCHO stress. Consequently, the yield of sugars from HCHO-assimilation increased approximately 6-fold in transgenic geranium leaves, and concomitantly, the role of three original HCHO metabolic pathways reduced, leading to a significant decrease in formic acid, citrate and glycine production from HCHO metabolism. Although the role of three metabolic pathways reduced in transgenic plants under high concentrations of gaseous HCHO stress, the installed DAS/DAK pathway could still function together with the original HCHO metabolic pathways. Consequently, the gaseous HCHO-resistance of transgenic plants was significantly improved, and the generation of H2O2 in the transgenic geranium leaves was significantly less than that in the wild type (WT) leaves. Under environmental-polluted gaseous HCHO stress for a long duration, the stomata conductance of transgenic plants remained approximately 2-fold higher than that of the WT, thereby increasing its ability to purify gaseous HCHO polluted environment. PMID- 25698667 TI - Consequences of chirality on the dynamics of a water-soluble supramolecular polymer. AB - The rational design of supramolecular polymers in water is imperative for their widespread use, but the design principles for these systems are not well understood. Herein, we employ a multi-scale (spatial and temporal) approach to differentiate two analogous water-soluble supramolecular polymers: one with and one without a stereogenic methyl. Initially aiming simply to understand the molecular behaviour of these systems in water, we find that while the fibres may look identical, the introduction of homochirality imparts a higher level of internal order to the supramolecular polymer. Although this increased order does not seem to affect the basic dimensions of the supramolecular fibres, the equilibrium dynamics of the polymers differ by almost an order of magnitude. This report represents the first observation of a structure/property relationship with regard to equilibrium dynamics in water-soluble supramolecular polymers. PMID- 25698668 TI - Angiographic findings and survival in patients undergoing coronary angiography due to sudden cardiac arrest in western Sweden. AB - AIM: Sudden cardiac arrest (SCA) accounts for more than half of all deaths from coronary heart disease. Time to return of spontaneous circulation is the most important determinant of outcome but successful resuscitation also requires percutaneous coronary intervention in selected patients. However, proper selection of patients is difficult. We describe data on angiographic finding and survival from a prospectively followed SCA patient cohort. METHODS: We merged the RIKS-HIA registry (Register of Information and Knowledge about Swedish Heart Intensive Care Admissions) and SCAAR (Swedish Coronary Angiography and Angioplasty Registry) for patients hospitalized in cardiac care units in Western Sweden between January 2005 and March 2013. We performed propensity score adjusted logistic and Cox proportional-hazards regression analyses on complete case data as well as on imputed data sets. RESULTS: 638 consecutive patients underwent coronary angiography due to SCA. Severity of coronary artery disease was similar among SCA patients and patients undergoing coronary angiography due to suspected coronary artery disease (n=37,142). An acute occlusion was reported in the majority of SCA patients and was present in 37% of patients who did not have ST-elevation on the post resuscitation ECG. 31% of SCA patients died within 30 days. Long-term risk of death among patients who survived the first 30 days was higher in patients with SCA compared to patients with acute coronary syndromes (P<0.001). CONCLUSIONS: Coronary artery disease and acute coronary occlusions are common among patients who undergo coronary angiography after sudden cardiac arrest. These patients have a substantial mortality risk both short- and long-term. PMID- 25698669 TI - A novel therapeutic approach targeting rheumatoid arthritis by combined administration of morin, a dietary flavanol and non-steroidal anti-inflammatory drug indomethacin with reference to pro-inflammatory cytokines, inflammatory enzymes, RANKL and transcription factors. AB - The present study was designed to assess the combined efficacy of morin, a dietary flavanol and non-steroidal anti-inflammatory drug indomethacin against adjuvant-induced arthritis in rats, an experimental model for rheumatoid arthritis. Arthritis was induced by intradermal injection of complete freund's adjuvant (0.1 ml) into the right hind paw of the Wistar albino rats. Morin (30 mg/kg b.wt), indomethacin (3 mg/kg b.wt) and combination of morin and indomethacin were administered intraperitoneally (from 11th to 20th day) after adjuvant injection. We have found that the activities/levels of lysosomal acid hydrolases (acid phosphatase, beta-galactosidase, N-acetyl glucosaminidase and cathepsin-D), glycoproteins (hexose and hexosamine), urinary constituents (hydroxyproline and glycosaminoglycans), reactive oxygen species (LPO and NO), elastase, inflammatory mediators (TNF-alpha, IL-1beta, MCP-1, VEGF and PGE2) and paw edema were significantly increased in arthritic rats compared to controls. Whereas, the anti-oxidant status (SOD, CAT, GPx, glutathione, and ceruloplasmin), body weight and bone collagen was found to be decreased. The mRNA expression of pro-inflammatory cytokines (TNF-alpha, IL-1beta, IL-17, IL-6 and MCP-1), inflammatory enzymes (iNOS and COX-2), RANKL, and transcription factors (NF-kB p65 and AP-1) was found upregulated in the ankle joints of arthritic rats in qRT PCR analysis. In addition, the increased protein expression of NF-kB p65 and COX 2 was also detected by immunohistochemical analysis. On the other hand, the above said imbalances were regulated back effectively to near normal as evidenced by the histopathological and radiological analysis on combined treatment with morin and indomethacin. Our study indicates that the combination therapy was more effective than either single drug alone in suppressing the pathogenesis of RA. PMID- 25698670 TI - High-resolution T2-weighted (T2W) oblique plane turbo spin-echo (TSE) MRI for rectal adenocarcinoma staging. AB - PURPOSE: The purpose of this study was to determine the frequency/significance of incorrectly planned oblique T2-weighted (T2W) MRI of rectal adenocarcinoma. METHODS: Eighty-six consecutive patients underwent MRI for rectal cancer staging. Two radiologists evaluated oblique T2W imaging and tumor stage. RESULTS: A total of 71% of middle/high tumors had correctly planned oblique T2W-MRI. Thirteen of 14 low tumors (N=7) or tumors spanning at least two rectal segments (N=7) had incorrectly planned oblique T2W-MRI. The sensitivity/specificity of staging on correct compared to incorrect oblique T2W was: 88.9/50% (R1)/77.8/60% (R2) and 80/100% (R1)/60/80% (R2), (P=.54). Agreement was substantial, K=0.67. CONCLUSIONS: Oblique T2W-MRI is incorrectly performed in low tumors and those spanning multiple rectal segments. In this study, planning errors did not impact staging accuracy. PMID- 25698671 TI - Popularity of hypoxic training methods for endurance-based professional and amateur athletes. AB - Scientific debate continues into whether hypoxic training has any performance benefit for athletes, and although this type of training seems popular, to our knowledge little empirical evidence on its popularity with endurance-based athletes exists. To quantify the usage of hypoxic training in endurance-based athletes we asked 203 athletes (amateur = 108, professional = 95) to complete a 17-question survey during 2013-2014 season. Compared to amateurs, professional athletes were 4.5 times (3.0-6.8, odds ratio, 95% confidence limits) more likely to undertake hypoxic training. Live-high train-low was the most popular hypoxic training protocol for athletes (52% professional and 80% amateur) with live-high train-high also used (38% professional, 20% amateur). Compared to amateurs, professional athletes tended to use evidence-based hypoxic training methods, seek advice on hypoxic training from reliable sources and were generally more realistic about the potential performance gains as a result of hypoxic training. Almost one third (25-30%) of all athletes suffered illness during their hypoxic training. Compared to amateurs, professional athletes are more likely to undertake hypoxic training and tend to follow current scientific guidelines. Attenuation of the ill effects that occur during hypoxic training may be accomplished if athletes give more attention to monitoring stress and training levels. PMID- 25698672 TI - TL and OSL dose response of LiF:Mg,Ti and Al2O3:C dosimeters using a PMMA phantom for IMRT technique quality assurance. AB - The principle of IMRT is to treat a patient from a number of different directions (or continuous arcs) with beams of nonuniform fluences, which have been optimized to deliver a high dose to the target volume and an acceptably low dose to the surrounding normal structures (Khan, 2010). This study intends to provide information to the physicist regarding the application of different dosimeters type, phantoms and analysis technique for Intensity Modulated Radiation Therapy (IMRT) dose distributions evaluation. The measures were performed using dosimeters of LiF:Mg,Ti and Al2O3:C evaluated by techniques of thermoluminescent (TL) and Optically Stimulated Luminescence (OSL). A polymethylmethacrylate (PMMA) phantom with five cavities, two principal target volumes considered like tumours to be treated and other three cavities to measure the scattered radiation dose was developed to carried out the measures. PMID- 25698673 TI - Innate immunity: Stressed mitochondria provide protection. PMID- 25698674 TI - Macrophages: Breaking ranks in the lymph node. PMID- 25698675 TI - B cell memory: A second chance for antibodies. PMID- 25698676 TI - Regulatory T cells: CK2: keeping TH2 cells in check. PMID- 25698677 TI - B cells: Meddling with the mind. PMID- 25698679 TI - All-trans retinoic acid prevents oxidative stress-induced loss of renal tight junction proteins in type-1 diabetic model. AB - We previously reported that diabetes decreased the expression of renal tight junction (TJ) proteins claudin-5 in glomerulus, and claudin-2 and occludin in proximal tubule through an oxidative stress dependent way. Now we investigated whether all-trans retinoic acid (atRA), a compound that plays a relevant role in kidney maintenance and that possesses antioxidant properties, prevents loss of TJ proteins in streptozotocin (STZ)-treated rats. atRA was administered daily by gavage (1mg/kg) from Days 3-21 after STZ administration. atRA attenuated loss of body weight, proteinuria and natriuresis but it did not prevent hyperglucemia. Other metabolic alterations, such as: increased kidney injury molecule (KIM)-1, oxidative stress, protein kinase C (PKC) beta 2, NADPH oxidase subunits (p47(phox) and gp91(phox)) expressions and endothelial nitric oxide synthase (eNOS) uncoupling, and decreased nitric oxide synthesis, nuclear factor-erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) expressions were also attenuated by atRA. In vitro scavenging capacity assays showed that atRA scavenged peroxyl radicals (ROO*), singlet oxygen ((1)O2) and hypochlorous acid (HOCl) in a concentration-dependent manner. Decreased expressions of occludin, claudins-2 and -5 induced by diabetes were ameliorated by atRA. We also found that diabetes induced tyrosine nitration (3-NT), SUMOylation and phosphorylation in serine residues of claudin-2 and atRA prevented these changes. In conclusion, atRA exerted nephroprotective effects by attenuating oxidative stress and preventing loss of renal TJ proteins. PMID- 25698678 TI - The generation of antibody-secreting plasma cells. AB - The regulation of antibody production is linked to the generation and maintenance of plasmablasts and plasma cells from their B cell precursors. Plasmablasts are the rapidly produced and short-lived effector cells of the early antibody response, whereas plasma cells are the long-lived mediators of lasting humoral immunity. An extraordinary number of control mechanisms, at both the cellular and molecular levels, underlie the regulation of this essential arm of the immune response. Despite this complexity, the terminal differentiation of B cells can be described as a simple probabilistic process that is governed by a central gene regulatory network and modified by environmental stimuli. PMID- 25698680 TI - Omega-3 fatty acids and inflammation: a perspective on the challenges of evaluating efficacy in clinical research. AB - Chronic inflammation is a common underpinning of many diseases. There is a strong pre-clinical evidence base demonstrating the efficacy of omega-3 fatty acids for ameliorating inflammation and thereby reducing disease burden. Clinically, C reactive protein (CRP) serves as both a reliable marker for monitoring inflammation and a modifiable endpoint for studies of anti-inflammatory pharmaceuticals. However, clinical omega-3 fatty acid supplementation trials have not replicated pre-clinical findings in terms of consistent CRP reductions. Methodological differences present numerous challenges in translating pre clinical evidence to clinical results. It is crucial that future clinical nutrition research clearly distinguish between the reversal of established inflammation and preventing the development of inflammation. Future clinical studies evaluating the ability of omega-3 fatty acids to attenuate an excessive inflammatory response, may be advanced by employing new statistical approaches and utilizing models of induced inflammation, such as low-dose human endotoxemia. PMID- 25698681 TI - Do not drown the patient: appropriate fluid management in critical illness. AB - Administering intravenous fluids to support the circulation in critically ill patients has been a mainstay of emergency medicine and critical care for decades, especially (but not exclusively) in patients with distributive or hypovolemic shock. However, in recent years, this automatic use of large fluid volumes is beginning to be questioned. Analysis from several large trials in severe sepsis and/or acute respiratory distress syndrome have shown independent links between volumes of fluid administered and outcome; conservative fluid strategies have also been associated with lower mortality in trauma patients. In addition, it is becoming ever more clear that central venous pressure, which is often used to guide fluid administration, is a completely unreliable parameter of volume status or fluid responsiveness. Furthermore, 2 recently published large multicenter trials (ARISE and ProCESS) have discredited the "early goal-directed therapy" approach, which used prespecified targets of central venous pressure and venous saturation to guide fluid and vasopressor administration. This article discusses the risks of "iatrogenic submersion" and strategies to avoid this risk while still giving our patients the fluids they need. The key lies in combining good clinical judgement, awareness of the potential harm from excessive fluid use, restraint in reflexive administration of fluids, and use of data from sophisticated monitoring tools such as echocardiography and transpulmonary thermodilution. Use of smaller volumes to perform fluid challenges, monitoring of extravascular lung water, earlier use of norepinephrine, and other strategies can help further reduce morbidity and mortality from severe sepsis. PMID- 25698682 TI - Constance Pascal's Chagrins d'amour et psychoses (1935): a French psychiatrist's views on psychoanalysis. AB - In 1935 Constance Pascal (1877-1937), France's first woman psychiatrist, published Chagrins d'amour et psychoses (The Sorrows of Love and Psychosis). My analysis of her monograph will consider: her major article leading up to Chagrins; Pascal's debts to her predecessors, particularly Morel and Kretschmer; her relationship to the French psychoanalytic movement; her co-option of psychoanalysis as a tool in her own therapeutic work with patients in the state psychiatric system; and her social/cultural interpretations of her woman patients. The literary and philosophic aspects of her work are emphasized as well as her contribution to French psychiatry. PMID- 25698683 TI - Photography and radical psychiatry in Italy in the 1960s. The case of the photobook Morire di Classe (1969). AB - In the 1960s Franco Basaglia, the Director of a Psychiatric Hospital in a small city on the edge of Italy (Gorizia), began to transform that institution from the inside. He introduced patient meetings and set up a kind of Therapeutic Community. In 1968 he asked two photographers - Carla Cerati and Gianni Berengo Gardin - to take photos inside Gorizia and other asylums. These images were then used in a photobook called Morire di Classe (To Die Because of your Class) (1969). This article re-examines in detail the content of this celebrated book and its history, and its impact on the struggle to reform and abolish large-scale psychiatric institutions. It also places the book in its social and political context and as a key text of the anti-psychiatry movement of the 1960s. PMID- 25698684 TI - From paranoia querulans to vexatious litigants: a short study on madness between psychiatry and the law. Part 2. AB - The second part of this paper examines the history of querulous paranoia and vexatious litigation in the English-speaking countries from the nineteenth century to today. This study suggests that the lack of thorough research on querulous paranoia in these countries is due to a broad cultural, legal and medical context which has caused unreasonable complainants to be considered a purely legal, rather than a medical issue. To support this hypothesis, I analyse how legal steps have been taken throughout the English-speaking world since 1896 to keep the unreasonable complainants at bay, and I present reasons why medical measures have scarcely been adopted. However, I also submit evidence that this division of responsibilities between the judges and the psychiatrists has taken a new turn since the dawn of the twenty-first century. PMID- 25698685 TI - Shell shock in Ireland: The Richmond War Hospital, Dublin (1916-19). AB - The history of mental disorders occasioned by World War I is a complex and important history, indelibly linked with social, political and cultural circumstances, and the history of the war itself. The Richmond War Hospital was a 32-bed establishment on the grounds of the large Richmond District Asylum in Dublin which, from 16 June 1916 until 23 December 1919, treated 362 soldiers with shell shock and other mental disorders, of whom more than half were considered to have recovered. Despite the limitations of the Richmond War Hospital, it was a generally forward-looking institution that pointed the way for future reform of Ireland's asylum system and, along with the other war hospitals, brought significant changes to the practice of psychiatry. PMID- 25698686 TI - Mobilizing Clouston in the colonies? General paralysis of the insane at the Auckland Mental Hospital, 1868-99. AB - This article examines the diagnosis of general paralysis of the insane (GPI) at the Auckland Mental Hospital, New Zealand, between 1868 and 1899, and changes in the identified causes of this condition. It argues that despite long-standing evidence citing the role of syphilis, asylum doctors working in New Zealand were as reluctant as their English and Scottish colleagues to blame syphilis alone for GPI. It also argues that although syphilis became a more popular cause in the aetiology of GPI by the end of the nineteenth century, medical and non-medical sources continued to cite other causes for GPI. PMID- 25698687 TI - History of leucotomies in Greece. AB - In order to present the social, scientific and institutional context which permitted the use of leucotomies in Greece, we have reviewed the Archives of the Medical Associations, the medical literature of the years 1946-56, a reader's dissertation and the memoirs of two psychiatrists. More than 250 leucotomies were done in the two public psychiatric hospitals in Athens from 1947 to 1954, as well as 40 leucotomies in the public psychiatric hospital in Thessaloniki. Although aware of the side effects, psychiatrists justified the use of the procedure. The performance of leucotomies in Greece declined because of reports of the dangers of the operation and its unpredictable outcome for the patients, but mainly because of the encouraging results with psychotropic drugs in the early 1950s. PMID- 25698688 TI - Psychological symptoms and medical responses in nineteenth-century India. AB - The article documents medical approaches to mental illness in mid- to late nineteenth-century India through examining the Indian Medical Gazette and other medical accounts. By the late nineteenth century, psychiatry in Europe moved from discussions around asylum-based care to a nuanced and informed debate about the nature of mental symptoms. This included ideas on phrenology and craniometry, biological and psycho-social causes, physical and drug treatments, many of which travelled to India. Simultaneously, indigenous socio-medical ideas were being debated. From the early to the mid-nineteenth century, not much distinction was made between the Western and the native 'mind', and consequently the diagnosis and investigation of mental symptoms did not differ. However, by the late nineteenth century Western medicine considered the 'Western mind' as more civilized and sophisticated than the 'native mind. PMID- 25698689 TI - The Jewish psychiatric hospital, Zofiowka, in Otwock, Poland. AB - The T4 euthanasia programme within Nazi Germany has been well researched, but much less is known about the extermination of psychiatric patients in Nazi occupied territories during the same period. In Poland 20,000 mentally ill patients were deliberately killed during the German occupation. This paper traces the history of one psychiatric hospital, Zofiowka, in Otwock, south-east of Warsaw. The hospital once served the Jewish population of Poland and was the largest, most prestigious neuropsychiatric centre in the country. It is now in ruins and said to be haunted by ghosts. PMID- 25698690 TI - David Hartley's views on Madness: With an introduction by GE Berrios. AB - The psychiatric aspects of David Hartley's writings have received less attention than the rest of his work. This Classic Text deals with Section VI of his Observations on Man ..., namely, the 'Imperfections of the rational Faculty'. Hartley defines madness as an imperfection of reason that can be temporary or enduring. He makes use of his model of mental functioning to differentiate between eight clinical categories of madness, each representing a different pattern of vibrations of the nerves. Hartley developed this model based on Newton's theory of vibrations and, to explain the complexity of mental acts and entities, he combined it with his own version of the mechanism of Association of Ideas borrowed from John Locke. Much work needs to be done to identify the provenance of Hartley's nosology and nosography. PMID- 25698698 TI - A specific hypoactivation of right temporo-parietal junction/posterior superior temporal sulcus in response to socially awkward situations in autism. AB - People with autism spectrum disorder (ASD) often have difficulty comprehending social situations in the complex, dynamic contexts encountered in the real world. To study the social brain under conditions which approximate naturalistic situations, we measured brain activity with FUNCTIONAL MAGNETIC RESONANCE IMAGING: while participants watched a full-length episode of the sitcom The Office. Having quantified the degree of social awkwardness at each moment of the episode, as judged by an independent sample of controls, we found that both individuals with ASD and control participants showed reliable activation of several brain regions commonly associated with social perception and cognition (e.g. those comprising the 'mentalizing network') during the more awkward moments. However, individuals with ASD showed less activity than controls in a region near right temporo-parietal junction (RTPJ) extending into the posterior end of the right superior temporal sulcus (RSTS). Further analyses suggested that, despite the free-form nature of the experimental design, this group difference was specific to this RTPJ/RSTS area of the mentalizing network; other regions of interest showed similar activity across groups with respect to both location and magnitude. These findings add support to a body of evidence suggesting that RTPJ/RSTS plays a special role in social processes across modalities and may function atypically in individuals with ASD navigating the social world. PMID- 25698699 TI - Compassion-based emotion regulation up-regulates experienced positive affect and associated neural networks. AB - Emotion regulation research has primarily focused on techniques that attenuate or modulate the impact of emotional stimuli. Recent evidence suggests that this mode regulation can be problematic in the context of regulation of emotion elicited by the suffering of others, resulting in reduced emotional connectedness. Here, we investigated the effects of an alternative emotion regulation technique based on the up-regulation of positive affect via Compassion-meditation on experiential and neural affective responses to depictions of individuals in distress, and compared these with the established emotion regulation strategy of Reappraisal. Using fMRI, we scanned 15 expert practitioners of Compassion-meditation either passively viewing, or using Compassion-meditation or Reappraisal to modulate their emotional reactions to film clips depicting people in distress. Both strategies effectively, but differentially regulated experienced affect, with Compassion primarily increasing positive and Reappraisal primarily decreasing negative affect. Imaging results showed that Compassion, relative to both passive viewing and Reappraisal increased activation in regions involved in affiliation, positive affect and reward processing including ventral striatum and medial orbitfrontal cortex. This network was shown to be active prior to stimulus presentation, suggesting that the regulatory mechanism of Compassion is the stimulus-independent endogenous generation of positive affect. PMID- 25698700 TI - Reflected glory and failure: the role of the medial prefrontal cortex and ventral striatum in self vs other relevance during advice-giving outcomes. AB - Despite the risks, people enjoy giving advice. One explanation is that giving beneficial advice can result in reflected glory, ego boosts or reputation enhancement. However, giving poor advice can be socially harmful (being perceived as incompetent or untrustworthy). In both circumstances, we have a vested interest in the advice follower's success or failure, especially when it reflects specifically on us compared with when it is diffused between multiple advisors. We examined these dynamics using an Advisor-Advisee Game, where subjects acted as an Advisor to a confederate Advisee who selected one of the three options when trying to win money: accept the subject's advice, accept the advice of a second confederate Advisor or accept both Advisors' advice. Results showed that having one's advice accepted, compared with being rejected, resulted in activity in the ventral striatum--a core reward area. Furthermore, the ventral striatum was only active when the subject's advice led to the advisee winning, and not when the advisee won based on the confederate's advice. Finally, the medial prefrontal cortex (MPFC) was more active when the Advisee won or lost money based solely on the subject's advice compared with when the second Advisor's advice was accepted. One explanation for these findings is that the MPFC monitors self-relevant social information, while the ventral striatum is active when others accept advice and when their success leads to reflected glory. PMID- 25698701 TI - Increased visual sensitivity following periods of dim illumination. AB - PURPOSE: We measured changes in the sensitivity of the human rod pathway by testing visual reaction times before and after light adaptation. We targeted a specific range of conditioning light intensities to see if a physiological adaptation recently discovered in mouse rods is observable at the perceptual level in humans. We also measured the noise spectrum of single mouse rods due to the importance of the signal-to-noise ratio in rod to rod bipolar cell signal transfer. METHODS: Using the well-defined relationship between stimulus intensity and reaction time (Pieron's law), we measured the reaction times of eight human subjects (ages 24-66) to scotopic test flashes of a single intensity before and after the presentation of a 3-minute background. We also made recordings from single mouse rods and processed the cellular noise spectrum before and after similar conditioning exposures. RESULTS: Subject reaction times to a fixed strength stimulus were fastest 5 seconds after conditioning background exposure (79% +/- 1% of the preconditioning mean, in darkness) and were significantly faster for the first 12 seconds after background exposure (P < 0.01). During the period of increased rod sensitivity, the continuous noise spectrum of individual mouse rods was not significantly increased. CONCLUSIONS: A decrease in human reaction times to a dim flash after conditioning background exposure may originate in rod photoreceptors through a transient increase in the sensitivity of the phototransduction cascade. There is no accompanying increase in rod cellular noise, allowing for reliable transmission of larger rod signals after conditioning exposures and the observed increase in perceptual sensitivity. PMID- 25698702 TI - Space perception of strabismic observers in the real world environment. AB - PURPOSE: Space perception beyond the near distance range (>2 m) is important for target localization, and for directing and guiding a variety of daily activities, including driving and walking. However, it is unclear whether the absolute (egocentric) localization of a single target in the intermediate distance range requires binocular vision, and if so, whether having subnormal stereopsis in strabismus impairs one's ability to localize the target. METHODS: We investigated this by measuring the perceived absolute location of a target by observers with normal binocular vision (n = 8; mean age, 24.5 years) and observers with strabismus (n = 8; mean age, 24.9 years) under monocular and binocular conditions. The observers used the blind walking-gesturing task to indicate the judged location of a target located at various viewing distances (2.73-6.93 m) and heights (0, 30, and 90 cm) above the floor. Near stereopsis was assessed with the Randot Stereotest. RESULTS: Both groups of observers accurately judged the absolute distance of the target on the ground (height = 0 cm) either with monocular or binocular viewing. However, when the target was suspended in midair, the normal observers accurately judged target location with binocular viewing, but not with monocular viewing (mean slant angle, 0.8 degrees +/- 0.5 degrees vs. 7.4 degrees +/- 1.4 degrees ; P < 0.001, with a slant angle of 0 degrees representing accurate localization). In contrast, the strabismic observers with poorer stereo acuity made larger errors in target localization in both viewing conditions, though with fewer errors during binocular viewing (mean slant angle, 2.7 degrees +/- 0.4 degrees vs. 9.2 degrees +/- 1.3 degrees ; P < 0.0025). Further analysis reveals the localization error, that is, slant angle, correlates positively with stereo threshold during binocular viewing (r(2) = 0.479, P < 0.005), but not during monocular viewing (r(2) = 0.0002, P = 0.963). CONCLUSIONS: Locating a single target on the ground is sufficient with monocular depth information, but binocular depth information is required when the target is suspended in midair. Since the absolute binocular disparity information of the single target is weak beyond 2 m, we suggest the visual system localizes the single target using the relative binocular disparity information between the midair target and the visible ground surface. Consequently, strabismic observers with residual stereopsis localize a target more accurately than their counterparts without stereo ability. PMID- 25698703 TI - Comparing the mode of action of intraocular lutein-based dyes with synthetic dyes. AB - PURPOSE: To investigate and compare the mechanism by which lutein-based and synthetic intraocular dyes interact with their target membranes during ophthalmic surgeries. METHODS: Surrogate membrane models were used in order to simulate the different intraocular membranes: internal limiting membrane (ILM), vitreous, anterior capsule (AC), and epiretinal membrane (ERM). Different lutein-based dyes, such as Phacodyne, Retidyne, Retidyne Plus, and Vitreodyne were tested, as well as Trypan Blue (TB), Indocyanine Green (ICG), Brilliant Blue (BB), and Triamcinolone Acetonide (TA). The interactions between the film components occurring at the air-water interface were investigated with surface pressure-area isotherms and polarization modulation infrared reflection-absorption spectroscopy (PM-IRRAS). RESULTS: With the exception of TA and ICG, none of the tested dyes revealed toxicity to the analyzed membranes. The interaction of TA with the vitreous model affected deeply the biointerface structure of the model. A significant condensation of the monolayer is noted when ICG contacted with ILM by the isotherms or even a solubilization of part of the monolayer toward the aqueous subphase. Retidyne Plus may provide the fluidization of the membrane, but maintains intact the structure of proteins present in the model. CONCLUSIONS: The present study demonstrates for the first time that lutein-based dyes interact through a physical mechanism of action with membrane models of structures present in human eye. On the other hand, the chemical interaction of synthetic dyes TA and ICG resulted in an alteration of the membrane models. PMID- 25698704 TI - Effect of myopia on the progression of primary open-angle glaucoma. AB - PURPOSE: To evaluate the effect of myopia on the progression of primary open angle glaucoma. METHODS: In this retrospective cohort study, eyes were classified into nonmyopic (NMG, >0 diopters [D]), mild to moderate (MMG, 0 to -6 D), and highly myopic glaucoma (HMG, <-6 D) groups according to the level of spherical equivalent. Glaucoma progression was determined either by optic disc/retinal nerve fiber layer (RNFL) photographs or by serial visual field (VF) data. Cox's proportional hazard models were used to detect associations between potential risk factors and glaucoma progression. RESULTS: Among 369 eyes from 369 glaucoma patients (average follow-up, 4.4 years), 54 of 178 eyes (30.3%) in the NMG, 49 of 151 eyes (32.5%) in the MMG, and 8 of 40 eyes (20.0%) in the HMG showed progression. When VF was used as a progression criterion, thinner baseline RNFL (hazard ratio [HR]: 0.942, P < 0.001) was predictive of progression. When optic disc/RNFL photographs were used, worse baseline visual field mean deviation (VF MD) and thinner RNFL were associated. The HMG category was a preventive factor for optic disc/RNFL photographic progression (HR: 0.323, P = 0.031). CONCLUSIONS: No levels of myopia were associated with glaucoma progression in our study. High myopia was a protective factor for optic disc/RNFL progression. These results may be interpreted as a lower progression detection rate because of the difficulty in detecting changes in the optic disc/RNFL in HMG, or as a consequence of some of highly myopic eyes that may not be true cases of glaucoma. PMID- 25698705 TI - Targeted Next-Generation Sequencing Improves the Diagnosis of Autosomal Dominant Retinitis Pigmentosa in Spanish Patients. AB - PURPOSE: Next-generation sequencing (NGS) has been demonstrated to be an effective strategy for the detection of mutations in retinal dystrophies, a group of inherited diseases that are highly heterogeneous. Therefore, the aim of this study is the application of an NGS-based approach in a Spanish cohort of autosomal dominant retinitis pigmentosa (RP) patients to find out causative mutations. METHODS: Index cases of 59 Spanish families with initial diagnosis of autosomal dominant RP and unsuccessfully studied for mutations in the most common RP causal genes, were selected for application of a NGS-based approach with a custom panel for 73 genes related to retinal dystrophies. Candidate variants were select based on frequency, pathogenicity, inherited model, and phenotype. Subsequently, confirmation by Sanger sequencing, cosegregation analysis, and population studies, was applied for determining the implication of those variants in the pathology. RESULTS: Overall 31 candidate variants were selected. From them, 17 variants were considered as mutations causative of the disease, 64% (11/17) of them were novel and 36% (6/17) were known RP-related mutations. Therefore, applying this technology16 families were characterized rendering a mutation detection rate of 27% (16/59). Of them, 5% (3/59) of cases displayed mutations in recessive or X-linked genes (ABCA4, RPGR, and RP2) allowing a genetic and clinical reclassification of those families. Furthermore, seven novel variants with uncertain significance and seven novel variants probably not causative of disease were also found. CONCLUSIONS: This NGS strategy is a fast, effective, and reliable tool to detect known and novel mutations in autosomal dominant RP patients allowing genetic reclassification in some cases and increasing the knowledge of pathogenesis in retinal dystrophies. PMID- 25698706 TI - Morphometry of the trabecular meshwork in vivo in a healthy population using fourier-domain optical coherence tomography. AB - PURPOSE: We measured the length, thickness, and area of the trabecular meshwork (TM) in vivo using Fourier domain optical coherence tomography (FD-OCT) in a Caucasian population of healthy subjects. METHODS: A cross-sectional study was done of 1006 healthy subjects. Left eyes were randomly selected. Age, sex, IOP, and spherical refractive error were noted. The depth and volume of the anterior chamber and the central corneal thickness were measured with Pentacam, while IOL Master was used to measure the axial length. The length, thickness, and area of the TM were measured through FD-OCT RTVue. A study was done to determine the correlation between TM size, and other demographic and ocular parameters. Finally, the reproducibility of the measurements was assessed for a subgroup of 50 eyes from 50 patients. RESULTS: We were able to measure the TM in 91.1% of the total eyes studied. The mean TM length was 496.99 +/- 92.77 MUm (range, 275-800), TM thickness was 174.16 +/- 28.14 MUm (range, 100-276), and TM area was 0.069 +/- 0.031 mm(2) (range, 0.023-0.133). No differences were found in terms of length and area for sex, although the TM was slightly thicker in men (P = 0.046). No correlation was observed between the TM measurements and any of the studied demographic or ocular parameters (R < 0.09, P < 0.001). Intra- and interobserver reproducibility of the measurements were good (intraclass correlation coefficient > 0.750, P < 0.001). CONCLUSIONS: The FD-OCT is an effective and reproducible examination technique to measure the length, thickness, and area of the TM in vivo. PMID- 25698707 TI - The zonules selectively alter the shape of the lens during accommodation based on the location of their anchorage points. AB - PURPOSE: To determine the role of anterior and posterior zonular tension on the optomechanical lens response during accommodation simulation. METHODS: Ten eyes from nine hamadryas baboons (4.9 +/- 0.7 years) and 20 eyes from 18 cynomolgus monkeys (5.4 +/- 0.3 years) were dissected, leaving the lens, zonules, ciliary body, hyaloid membrane, anterior vitreous, and a segmented scleral rim intact. The lens preparation was mounted in a lens stretcher, and the outer scleral shell was displaced radially in a stepwise fashion. The load, lens, and ciliary body diameters, lens power, lens thickness, and the anterior and posterior radius of curvature were measured during stretching. The zonular fibers attached to either the posterior or anterior lens surface were then carefully transected and the experiment was repeated. Zonular transection was confirmed in four eyes via laser scanning confocal microscopy after immunostaining. The effect of zonular transection on the tissue response to stretching was quantified. RESULTS: Without anterior zonules, 48% and 97% of the changes in anterior and posterior radii are retained. Without posterior zonules, 81% and 67% of the changes in anterior and posterior radii are retained. The changes in lens shape were reduced after transecting either the anterior or posterior zonules; however, both surfaces still changed shape. CONCLUSIONS: While either the anterior or posterior zonules alone are capable of changing the shape of both lens surfaces, the anterior zonules have a greater effect on the anterior lens surface, and the posterior zonules have a greater effect on the posterior lens surface. PMID- 25698708 TI - Applying "Lasso" Regression to Predict Future Visual Field Progression in Glaucoma Patients. AB - PURPOSE: We evaluated the usefulness of various regression models, including least absolute shrinkage and selection operator (Lasso) regression, to predict future visual field (VF) progression in glaucoma patients. METHODS: Series of 10 VFs (Humphrey Field Analyzer 24-2 SITA-standard) from each of 513 eyes in 324 open-angle glaucoma patients, obtained in 4.9 +/- 1.3 years (mean +/- SD), were investigated. For each patient, the mean of all total deviation values (mTD) in the 10th VF was predicted using varying numbers of prior VFs (ranging from the first three VFs to all previous VFs) by applying ordinary least squares linear regression (OLSLR), M-estimator robust regression (M-robust), MM-estimator robust regression (MM-robust), skipped regression (Skipped), deepest regression (Deepest), and Lasso regression. Absolute prediction errors then were compared. RESULTS: With OLSLR, prediction error varied between 5.7 +/- 6.1 (using the first three VFs) and 1.2 +/- 1.1 dB (using all nine previous VFs). Prediction accuracy was not significantly improved with M-robust, MM-robust, Skipped, or Deepest regression in almost all VF series; however, a significantly smaller prediction error was obtained with Lasso regression even with a small number of VFs (using first 3 VFs, 2.0 +/- 2.2; using all nine previous VFs, 1.2 +/- 1.1 dB). CONCLUSIONS: Prediction errors using OLSLR are large when only a small number of VFs are included in the regression. Lasso regression offers much more accurate predictions, especially in short VF series. PMID- 25698709 TI - Retinal vessel pathologies in a rat model of periventricular leukomalacia: a new model for retinopathy of prematurity? AB - PURPOSE: To characterize concurrent retinal vessel pathologies reminiscent to retinopathy of prematurity (ROP) in a rat model of periventricular leukomalacia (PVL), in order to identify uniform damage pathways in both organs, the eye and the brain. METHODS: Ischemia was induced in Long Evans rat pups on postnatal day 6 (P6) with unilateral (left side) carotid ligation (UCL) followed by exposure to different oxygen concentrations. Four different groups were studied: group A, hypoxia/ischemia (UCL + 6% O2, 1 hour); group B, hyperoxia (80% O2, 24 hours); group C, hypoxia/ischemia + hyperoxia (UCL + 6% O2, 1 hour + 80% O2, 24 hours); and group D, normoxia. In groups A and C, both retinae were examined separately (left retina, group A [A-L], right retina, group A [A-R]; left retina, group C [C L], right retina, group C [C-R]). Morphologic analysis of vessel development based on flatmounts and cryosections was performed at P11 and P21. Quantitative (q)PCR was performed at P7, P11, and P21 (VEGF-A164, HIF-1alpha, EpoR, TNFalpha, iNOS, BMP-9, and IGF-1). RESULTS: On flatmounts, distinct retardation in deeper vascular plexus development was observed, most prominent in A-L and C-L. Retinae of groups A-L and C-L displayed reduced capillary-free zones and an increased number of branching points at P11. Quantitative PCR analysis showed significantly different expression profiles of IGF-1 in A-L and B compared with D over the time course of the experiment. CONCLUSIONS: This is the first report on concurring damage to the retina that was evaluated in a rat model of white matter injury in the developing brain. The relatively mild damage to the retinal vessel system may represent the basis for a model of moderate forms of ROP and to study vascular remodeling. PMID- 25698710 TI - Traditional herbal medicine as adjunctive therapy for nasopharyngeal cancer: a systematic review and meta-analysis. AB - The effectiveness of traditional herbal medicine (THM) as treatment for nasopharyngeal cancer (NPC) has not been clearly demonstrated. The aim of this study is to assess the effectiveness of THM as adjunctive therapies for NPC using the results of randomized controlled trials (RCTs). Five electronic databases, including English and Chinese databases, were systematically searched up to February 2014. All RCTs involving traditional herbal medicine in combination with conventional cancer therapy for NPC were included. Twenty-two RCTs involving 2,298 NPC patients were systematically reviewed. Of these 22 studies, 15 on 1482 patients reported a significant increase in the number surviving patients with survivals of more than 1, 3, or 5 years. Seven studies on 595 patients reported a significant increase in immediate tumor response, and three studies on 505 patients reported a significant decrease in distant metastasis. This meta analysis of 22 studies suggests that THM combined with conventional therapy can provide an effective adjunctive therapy for NPC. More research and well-designed, rigorous, large clinical trials are required to address these issues. PMID- 25698712 TI - Corticosteroid injection of the arthritic hip: what is the indication? AB - Forty-four patients who had image-guided corticosteroid injection of the hip were reviewed as part of a service improvement project to ascertain the medium term benefit of the procedure. Injections were indicated for treatment of hip pain or as part of a diagnostic work up to differentiate hip from back pain. At 42-month review, 39 patients fulfilled the criteria for the study. Of those having therapeutic injections, 70% had gone on to hip replacement, while only 20% of those having diagnostic injections had done so. These results suggest that, for patients who are fit for surgery, hip replacement should be the intervention of choice as corticosteroid injection does not substantially delay the need for surgery. Where there is doubt about the source of pain, there seems to be a clear role for diagnostic injection. PMID- 25698711 TI - Striatal D(2/3) Binding Potential Values in Drug-Naive First-Episode Schizophrenia Patients Correlate With Treatment Outcome. AB - One of best validated findings in schizophrenia research is the association between blockade of dopamine D2 receptors and the effects of antipsychotics on positive psychotic symptoms. The aim of the present study was to examine correlations between baseline striatal D(2/3) receptor binding potential (BP(p)) values and treatment outcome in a cohort of antipsychotic-naive first-episode schizophrenia patients. Additionally, we wished to investigate associations between striatal dopamine D(2/3) receptor blockade and alterations of negative symptoms as well as functioning and subjective well-being. Twenty-eight antipsychotic-naive schizophrenia patients and 26 controls were included in the study. Single-photon emission computed tomography (SPECT) with [(123)I]iodobenzamide ([(123)I]-IBZM) was used to examine striatal D(2/3) receptor BP(p). Patients were examined before and after 6 weeks of treatment with the D(2/3) receptor antagonist amisulpride. There was a significant negative correlation between striatal D(2/3) receptor BP(p) at baseline and improvement of positive symptoms in the total group of patients. Comparing patients responding to treatment to nonresponders further showed significantly lower baseline BP(p) in the responders. At follow-up, the patients demonstrated a negative correlation between the blockade and functioning, whereas no associations between blockade and negative symptoms or subjective well-being were observed. The results show an association between striatal BP(p) of dopamine D(2/3) receptors in antipsychotic naive first-episode patients with schizophrenia and treatment response. Patients with a low BP(p) have a better treatment response than patients with a high BP(p). The results further suggest that functioning may decline at high levels of dopamine receptor blockade. PMID- 25698715 TI - Design and analysis of Bayesian adaptive crossover trials for evaluating contact lens safety and efficacy. AB - A crossover study, also referred to as a crossover trial, is a form of longitudinal study. Subjects are randomly assigned to different arms of the study and receive different treatments sequentially. While there are many frequentist methods to analyze data from a crossover study, random effects models for longitudinal data are perhaps most naturally modeled within a Bayesian framework. In this article, we introduce a Bayesian adaptive approach to crossover studies for both efficacy and safety endpoints using Gibbs sampling. Using simulation, we find our approach can detect a true difference between two treatments with a specific false-positive rate that we can readily control via the standard equal tail posterior credible interval. We then illustrate our Bayesian approaches using real data from Johnson & Johnson Vision Care, Inc. contact lens studies. We then design a variety of Bayesian adaptive predictive probability crossover studies for single and multiple continuous efficacy endpoints, indicate their extension to binary safety endpoints, and investigate their frequentist operating characteristics via simulation. The Bayesian adaptive approach emerges as a crossover trials tool that is useful yet surprisingly overlooked to date, particularly in contact lens development. PMID- 25698716 TI - Joint assessment of dependent discrete disease state processes. AB - In multiple sclerosis, the primary clinical measure of disability level is an ordinal score, the expanded disability severity scale score. In relapsing remitting multiple sclerosis, measures of relapse are additionally of interest. Multiple sclerosis patients are typically assessed with regard to both the expanded disability severity scale and relapse state at each follow-up visit. As both are discrete measures, the two can be viewed as jointly dependent Markov processes. One of the main goals of multiple sclerosis research is to accurately model, over time, both transitions between expanded disability severity scale states and change in relapse state. This objective requires a number of significant modeling decisions, including decisions about whether or not the combination of specific disease states is warranted and assessment of the dependence structure between the two disease processes. Historically, such decisions are often made in an ad hoc manner and are not formally justified. We propose novel use of Bayes factors and Bayesian variable selection in the assessment of jointly dependent Markovian processes in multiple sclerosis. Methods are assessed using both simulated data and data collected from the Partners Multiple Sclerosis Center in Boston, MA. PMID- 25698717 TI - Computer Use and Computer Anxiety in Older Korean Americans. AB - Responding to the limited literature on computer use in ethnic minority older populations, the present study examined predictors of computer use and computer anxiety in older Korean Americans. Separate regression models were estimated for computer use and computer anxiety with the common sets of predictors: (a) demographic variables (age, gender, marital status, and education), (b) physical health indicators (chronic conditions, functional disability, and self-rated health), and (c) sociocultural factors (acculturation and attitudes toward aging). Approximately 60% of the participants were computer-users, and they had significantly lower levels of computer anxiety than non-users. A higher likelihood of computer use and lower levels of computer anxiety were commonly observed among individuals with younger age, male gender, advanced education, more positive ratings of health, and higher levels of acculturation. In addition, positive attitudes toward aging were found to reduce computer anxiety. Findings provide implications for developing computer training and education programs for the target population. PMID- 25698718 TI - Shifting to Medicaid-Managed Long-Term Care: Are Vulnerable Florida Beneficiaries Properly Informed? AB - PURPOSE: To examine and assess the adequacy of informational material provided to Florida long-term care beneficiaries being required to choose a managed care provider as part of a statewide, mandatory shift to Medicaid-managed long-term care (MMLTC). DESIGN AND METHOD: Informational materials provided by the state of Florida to 90,000 Medicaid long-term care beneficiaries via print mailings and a state website were examined using established content, usability, and readability criteria. RESULTS: Overall, the presentation minimized cognitive complexity, but the information was lacking in critical areas, such as providing clear explanations of the change taking place and the significance of beneficiaries' choices, and enabling beneficiaries to assess their own needs and preferences. IMPLICATIONS: A key feature of managed care is the users' choice of plans, but amid a significant policy shift toward MMLTC in Florida, vulnerable beneficiaries may not be receiving the information necessary to make choices that best meet their needs. Our analysis offers lessons to other states shifting to MMLTC. PMID- 25698719 TI - Intergenerational Programs in Schools. AB - This study examined the prevalence, types, and perceived impact of intergenerational programs in schools. Programs involving senior volunteers assisting children, or children participating in activities with older people were considered. Of the schools reached, 47% reported intergenerational programming. Thirty-three schools in the Tel-Aviv region participated in the study. Data were collected from 85 seniors, 26 teachers, and 20 coordinators. Assessments included program characteristics, program preparation, and perceived benefits and difficulties. Both programs were reported to have beneficial effects for seniors and to benefit children in the academic, social, and emotional domains. However, programs appeared to attract different types of volunteers and different degrees of volunteer commitment. Findings suggest that there is a need to pay additional attention to both participants' specific requests and needs and to the allocation of resources to improve the design and implementation of intergenerational programs. PMID- 25698720 TI - Ownership Status and Length of Stay in Skilled Nursing Facilities: Does Endogeneity Matter? AB - In 1998, Medicare implemented the Prospective Payment System for post-acute care provided by skilled nursing facilities. This system paid a fixed price per day above the cost of care, creating an incentive to provide longer length of stays to increase revenues. In this paper, we examine whether there are systematic differences in length of stay for post-acute care patients between for-profit and not-for-profit skilled nursing facilities. Based on the financial incentives inherent in the reimbursement system, we develop a conceptual framework that argues for-profits will provide a greater number of days of care to increase profits relative to not-for-profits. We find significant differences in length of stay by ownership, but once patient selection into a facility is accounted for using two-staged residual inclusion, there is no statistical differences in length of stay between for-profit and not-for-profit facilities. PMID- 25698721 TI - The Relationship Between Subjective Falls-Risk Assessment Tools and Functional, Health-Related, and Body Composition Characteristics. AB - We sought to explore the relationship between two subjective falls-risk assessment tools (Falls Efficacy Scale-International [FES-I] and Activities Specific Balance Confidence [ABC] Scale) and functional, health-related, and body composition characteristics. A total of 245 community-dwelling people aged 60 to 88 years underwent assessments for subjective falls risk (using the FES-I and ABC Scale), health-related (cognitive; Short-Form Health Survey [SF-12]), functional (physical activity and physical function), and body composition characteristics (measured by dual X-ray absorptiometry). The FES-I and ABC Scale are strongly correlated with each other for females and males ( r = -.70, p < .001; r = -.65, p < .001), respectively. There are substantial differences between males and females when they self-assess their risk of falling as well as what characteristics contribute to explaining these self-assessments. Females are potentially more self-aware of their functional, body composition and health related characteristics to better estimate their own risk of falling. FES-I correlates better with functional, body composition, and health-related characteristics, and thus may be more appropriate for use than the ABC in community-dwelling older adults. PMID- 25698722 TI - Magnesium-containing mixed coatings on zirconia for dental implants: mechanical characterization and in vitro behavior. AB - An important challenge in the field of dental and orthopedic implantology is the preparation of implant coatings with bioactive functions that feature a high mechanical stability and at the same time mimic structural and compositional properties of native bone for a better bone ingrowth. This study investigates the influence of magnesium addition to zirconia-calcium phosphate coatings. The mixed coatings were prepared with varying additions of either magnesium oxide or magnesium fluoride to yttria-stabilized zirconia and hydroxyapatite. The coatings were deposited on zirconia discs and screw implants by wet powder spraying. Microstructure studies confirm a porous coating with similar roughness and firm adhesion not hampered by the coating composition. The coating morphology, mechanical flexural strength and calcium dissolution showed a magnesium content dependent effect. Moreover, the in vitro results obtained with human osteoblasts reveal an improved biological performance caused by the presence of Mg(2+) ions. The magnesium-containing coatings exhibited better cell proliferation and differentiation in comparison to pure zirconia-calcium phosphate coatings. In conclusion, these results demonstrate that magnesium addition increases the bioactivity potential of zirconia-calcium phosphate coatings and is thus a highly suitable candidate for bone implant coatings. PMID- 25698723 TI - KIS: synaptic plasticity's missing molecular link? PMID- 25698724 TI - Probing perceptual performance after microsaccades. PMID- 25698725 TI - New whole-body sensory-motor gradients revealed using phase-locked analysis and verified using multivoxel pattern analysis and functional connectivity. AB - Topographic organization is one of the main principles of organization in the human brain. Specifically, whole-brain topographic mapping using spectral analysis is responsible for one of the greatest advances in vision research. Thus, it is intriguing that although topography is a key feature also in the motor system, whole-body somatosensory-motor mapping using spectral analysis has not been conducted in humans outside M1/SMA. Here, using this method, we were able to map a homunculus in the globus pallidus, a key target area for deep brain stimulation, which has not been mapped noninvasively or in healthy subjects. The analysis clarifies contradictory and partial results regarding somatotopy in the caudal-cingulate zone and rostral-cingulate zone in the medial wall and in the putamen. Most of the results were confirmed at the single-subject level and were found to be compatible with results from animal studies. Using multivoxel pattern analysis, we could predict movements of individual body parts in these homunculi, thus confirming that they contain somatotopic information. Using functional connectivity, we demonstrate interhemispheric functional somatotopic connectivity of these homunculi, such that the somatotopy in one hemisphere could have been found given the connectivity pattern of the corresponding regions of interest in the other hemisphere. When inspecting the somatotopic and nonsomatotopic connectivity patterns, a similarity index indicated that the pattern of connected and nonconnected regions of interest across different homunculi is similar for different body parts and hemispheres. The results show that topographical gradients are even more widespread than previously assumed in the somatosensory motor system. Spectral analysis can thus potentially serve as a gold standard for defining somatosensory-motor system areas for basic research and clinical applications. PMID- 25698726 TI - Interleukin 1 type 1 receptor restore: a genetic mouse model for studying interleukin 1 receptor-mediated effects in specific cell types. AB - Interleukin-1 (IL-1) mediates diverse neurophysiological and neuropathological effects in the CNS through type I IL-1 receptor (IL-1R1). However, identification of IL-1R1-expressing cell types and cell-type-specific functions of IL-1R1 remains challenging. In this study, we created a novel genetic mouse model in which IL-1R1 gene expression is disrupted by an intronic insertion of a loxP flanked disruptive sequence that can be deleted by Cre recombinase, resulting in restored IL-1R1 gene expression under its endogenous promoters. A second mutation was introduced at stop codon of the IL-1R1 gene to allow tracking of the restored IL-1R1 protein by a 3HA tag and IL-1R1 mRNA by tdTomato fluorescence. These animals were designated as IL-1R1(r/r) and exhibited an IL-1R1 knock-out phenotype. We used IL-1R1 globally restored mice (IL-1R1(GR/GR)) as an IL-1R1 reporter and observed concordant labeling of IL-1R1 mRNA and protein in brain endothelial cells. Two cell-type-specific IL-1R1 restore lines were generated: Tie2Cre-IL-1R1(r/r) and LysMCre-IL-1R1(r/r). Brain endothelial COX-2 expression, CNS leukocyte infiltration, and global microglia activation induced by intracerebroventricular injection of IL-1beta were not observed in IL-1R1(r/r) or LysMCre-IL-1R1(r/r) mice, but were restored in Tie2Cre-IL-1R1(r/r) mice. These results reveal IL-1R1 expression in endothelial cells alone is sufficient to mediate these central IL-1-induced responses. In addition, ex vivo IL-1beta stimulation increased IL-1beta expression in bone marrow cells in wild-type, Tie2Cre-IL-1R1(r/r), and LysMCre-IL-1R1(r/r), but not IL-1R1(r/r) mice. These results demonstrate this IL-1R1 restore model is a valuable tool for studying cell-type-specific functions of IL-1R1. PMID- 25698727 TI - Stabilization of nontoxic Abeta-oligomers: insights into the mechanism of action of hydroxyquinolines in Alzheimer's disease. AB - The extracellular accumulation of amyloid beta (Abeta) peptides is characteristic of Alzheimer's disease (AD). However, formation of diffusible, oligomeric forms of Abeta, both on and off pathways to amyloid fibrils, is thought to include neurotoxic species responsible for synaptic loss and neurodegeneration, rather than polymeric amyloid aggregates. The 8-hydroxyquinolines (8-HQ) clioquinol (CQ) and PBT2 were developed for their ability to inhibit metal-mediated generation of reactive oxygen species from Abeta:Cu complexes and have both undergone preclinical and Phase II clinical development for the treatment of AD. Their respective modes of action are not fully understood and may include both inhibition of Abeta fibrillar polymerization and direct depolymerization of existing Abeta fibrils. In the present study, we find that CQ and PBT2 can interact directly with Abeta and affect its propensity to aggregate. Using a combination of biophysical techniques, we demonstrate that, in the presence of these 8-HQs and in the absence of metal ions, Abeta associates with two 8-HQ molecules and forms a dimer. Furthermore, 8-HQ bind Abeta with an affinity of 1 10 MUm and suppress the formation of large (>30 kDa) oligomers. The stabilized low molecular weight species are nontoxic. Treatment with 8-HQs also reduces the levels of in vivo soluble oligomers in a Caenorhabditis elegans model of Abeta toxicity. We propose that 8-HQs possess an additional mechanism of action that neutralizes neurotoxic Abeta oligomer formation through stabilization of small (dimeric) nontoxic Abeta conformers. PMID- 25698728 TI - Behavior-linked FoxP2 regulation enables zebra finch vocal learning. AB - Mutations in the FOXP2 transcription factor cause an inherited speech and language disorder, but how FoxP2 contributes to learning of these vocal communication signals remains unclear. FoxP2 is enriched in corticostriatal circuits of both human and songbird brains. Experimental knockdown of this enrichment in song control neurons of the zebra finch basal ganglia impairs tutor song imitation, indicating that adequate FoxP2 levels are necessary for normal vocal learning. In unmanipulated birds, vocal practice acutely downregulates FoxP2, leading to increased vocal variability and dynamic regulation of FoxP2 target genes. To determine whether this behavioral regulation is important for song learning, here, we used viral-driven overexpression of FoxP2 to counteract its downregulation. This manipulation disrupted the acute effects of song practice on vocal variability and caused inaccurate song imitation. Together, these findings indicate that dynamic behavior-linked regulation of FoxP2, rather than absolute levels, is critical for vocal learning. PMID- 25698729 TI - Stimulus statistics shape oscillations in nonlinear recurrent neural networks. AB - Rhythmic activity plays a central role in neural computations and brain functions ranging from homeostasis to attention, as well as in neurological and neuropsychiatric disorders. Despite this pervasiveness, little is known about the mechanisms whereby the frequency and power of oscillatory activity are modulated, and how they reflect the inputs received by neurons. Numerous studies have reported input-dependent fluctuations in peak frequency and power (as well as couplings across these features). However, it remains unresolved what mediates these spectral shifts among neural populations. Extending previous findings regarding stochastic nonlinear systems and experimental observations, we provide analytical insights regarding oscillatory responses of neural populations to stimulation from either endogenous or exogenous origins. Using a deceptively simple yet sparse and randomly connected network of neurons, we show how spiking inputs can reliably modulate the peak frequency and power expressed by synchronous neural populations without any changes in circuitry. Our results reveal that a generic, non-nonlinear and input-induced mechanism can robustly mediate these spectral fluctuations, and thus provide a framework in which inputs to the neurons bidirectionally regulate both the frequency and power expressed by synchronous populations. Theoretical and computational analysis of the ensuing spectral fluctuations was found to reflect the underlying dynamics of the input stimuli driving the neurons. Our results provide insights regarding a generic mechanism supporting spectral transitions observed across cortical networks and spanning multiple frequency bands. PMID- 25698730 TI - Vicarious reinforcement learning signals when instructing others. AB - Reinforcement learning (RL) theory posits that learning is driven by discrepancies between the predicted and actual outcomes of actions (prediction errors [PEs]). In social environments, learning is often guided by similar RL mechanisms. For example, teachers monitor the actions of students and provide feedback to them. This feedback evokes PEs in students that guide their learning. We report the first study that investigates the neural mechanisms that underpin RL signals in the brain of a teacher. Neurons in the anterior cingulate cortex (ACC) signal PEs when learning from the outcomes of one's own actions but also signal information when outcomes are received by others. Does a teacher's ACC signal PEs when monitoring a student's learning? Using fMRI, we studied brain activity in human subjects (teachers) as they taught a confederate (student) action-outcome associations by providing positive or negative feedback. We examined activity time-locked to the students' responses, when teachers infer student predictions and know actual outcomes. We fitted a RL-based computational model to the behavior of the student to characterize their learning, and examined whether a teacher's ACC signals when a student's predictions are wrong. In line with our hypothesis, activity in the teacher's ACC covaried with the PE values in the model. Additionally, activity in the teacher's insula and ventromedial prefrontal cortex covaried with the predicted value according to the student. Our findings highlight that the ACC signals PEs vicariously for others' erroneous predictions, when monitoring and instructing their learning. These results suggest that RL mechanisms, processed vicariously, may underpin and facilitate teaching behaviors. PMID- 25698731 TI - Neural activity in the medial temporal lobe reveals the fidelity of mental time travel. AB - Neural circuitry in the medial temporal lobe (MTL) is critically involved in mental time travel, which involves the vivid retrieval of the details of past experience. Neuroscientific theories propose that the MTL supports memory of the past by retrieving previously encoded episodic information, as well as by reactivating a temporal code specifying the position of a particular event within an episode. However, the neural computations supporting these abilities are underspecified. To test hypotheses regarding the computational mechanisms supported by different MTL subregions during mental time travel, we developed a computational model that linked a blood oxygenation level-dependent signal to cognitive operations, allowing us to predict human performance in a memory search task. Activity in the posterior MTL, including parahippocampal cortex, reflected how strongly one reactivates the temporal context of a retrieved memory, allowing the model to predict whether the next memory will correspond to a nearby moment in the study episode. A signal in the anterior MTL, including perirhinal cortex, indicated the successful retrieval of list items, without providing information regarding temporal organization. A hippocampal signal reflected both processes, consistent with theories that this region binds item and context information together to form episodic memories. These findings provide evidence for modern theories that describe complementary roles of the hippocampus and surrounding parahippocampal and perirhinal cortices during the retrieval of episodic memories, shaping how humans revisit the past. PMID- 25698732 TI - Identification of 12/15-lipoxygenase as a regulator of axon degeneration through high-content screening. AB - Axon degeneration is a programed process that takes place during development, in response to neuronal injury, and as a component of neurodegenerative disease pathology, yet the molecular mechanisms that drive this process remain poorly defined. In this study, we have developed a semi-automated, 384-well format axon degeneration assay in rat dorsal root ganglion (DRG) neurons using a trophic factor withdrawal paradigm. Using this setup, we have screened a library of known drugs and bioactives to identify several previously unappreciated regulators of axon degeneration, including lipoxygenases. Multiple structurally distinct lipoxygenase inhibitors as well as mouse DRG neurons lacking expression of 12/15 lipoxygenase display protection of axons in this context. Retinal ganglion cell axons from 12/15-lipoxygenase-null mice were similarly protected from degeneration following nerve crush injury. Through additional mechanistic studies, we demonstrate that lipoxygenases act cell autonomously within neurons to regulate degeneration, and are required for mitochondrial permeabilization and caspase activation in the axon. These findings suggest that these enzymes may represent an attractive target for treatment of neuropathies and provide a potential mechanism for the neuroprotection observed in various settings following lipoxygenase inhibitor treatment. PMID- 25698733 TI - DBZ regulates cortical cell positioning and neurite development by sustaining the anterograde transport of Lis1 and DISC1 through control of Ndel1 dual phosphorylation. AB - Cell positioning and neuronal network formation are crucial for proper brain function. Disrupted-in-Schizophrenia 1 (DISC1) is anterogradely transported to the neurite tips, together with Lis1, and functions in neurite extension via suppression of GSK3beta activity. Then, transported Lis1 is retrogradely transported and functions in cell migration. Here, we show that DISC1-binding zinc finger protein (DBZ), together with DISC1, regulates mouse cortical cell positioning and neurite development in vivo. DBZ hindered Ndel1 phosphorylation at threonine 219 and serine 251. DBZ depletion or expression of a double phosphorylated mimetic form of Ndel1 impaired the transport of Lis1 and DISC1 to the neurite tips and hampered microtubule elongation. Moreover, application of DISC1 or a GSK3beta inhibitor rescued the impairments caused by DBZ insufficiency or double-phosphorylated Ndel1 expression. We concluded that DBZ controls cell positioning and neurite development by interfering with Ndel1 from disproportionate phosphorylation, which is critical for appropriate anterograde transport of the DISC1-complex. PMID- 25698734 TI - Reciprocal interareal connections to corticospinal neurons in mouse M1 and S2. AB - Primary motor (M1) and secondary somatosensory (S2) cortices, although anatomically and functionally distinct, share an intriguing cellular component: corticospinal neurons (CSP) in layer 5B. Here, we investigated the long-range circuits of CSPs in mouse forelimb-M1 and S2. We found that interareal projections (S2 -> M1 and M1 -> S2) monosynaptically excited pyramidal neurons across multiple layers, including CSPs. Area-specific differences were observed in the relative strengths of inputs to subsets of CSPs and other cell types, but the general patterns were similar. Furthermore, subcellular mapping of the dendritic distributions of these corticocortical excitatory synapses onto CSPs in both areas also showed similar patterns. Because layer 5B is particularly thick in M1, but not S2, we studied M1-CSPs at different cortical depths, quantifying their dendritic morphology and mapping inputs from additional cortical (M2, contralateral M1, and local layer 2/3) and thalamic (VL nucleus) sources. These results indicated that CSPs exhibit area-specific modifications on an otherwise conserved synaptic organization, and that different afferents innervate M1-CSP dendritic domains in a source-specific manner. In the cervical spinal cord, CSP axons from S2 and M1 partly converged on middle layers, but S2-CSP axons extended further dorsally, and M1-CSP axons ventrally. Thus, our findings identify many shared features in the circuits of M1 and S2 and show that these areas communicate via mutual projections that give each area monosynaptic access to the other area's CSPs. These interareally yoked CSP circuits may enable M1 and S2 to operate in a coordinated yet differentiated manner in the service of sensorimotor integration. PMID- 25698735 TI - Mapping of functionally characterized cell classes onto canonical circuit operations in primate prefrontal cortex. AB - Microcircuits are composed of multiple cell classes that likely serve unique circuit operations. But how cell classes map onto circuit functions is largely unknown, particularly for primate prefrontal cortex during actual goal-directed behavior. One difficulty in this quest is to reliably distinguish cell classes in extracellular recordings of action potentials. Here we surmount this issue and report that spike shape and neural firing variability provide reliable markers to segregate seven functional classes of prefrontal cells in macaques engaged in an attention task. We delineate an unbiased clustering protocol that identifies four broad spiking (BS) putative pyramidal cell classes and three narrow spiking (NS) putative inhibitory cell classes dissociated by how sparse, bursty, or regular they fire. We speculate that these functional classes map onto canonical circuit functions. First, two BS classes show sparse, bursty firing, and phase synchronize their spiking to 3-7 Hz (theta) and 12-20 Hz (beta) frequency bands of the local field potential (LFP). These properties make cells flexibly responsive to network activation at varying frequencies. Second, one NS and two BS cell classes show regular firing and higher rate with only marginal synchronization preference. These properties are akin to setting tonically the excitation and inhibition balance. Finally, two NS classes fired irregularly and synchronized to either theta or beta LFP fluctuations, tuning them potentially to frequency-specific subnetworks. These results suggest that a limited set of functional cell classes emerges in macaque prefrontal cortex (PFC) during attentional engagement to not only represent information, but to subserve basic circuit operations. PMID- 25698736 TI - Cell assemblies of the basal forebrain. AB - The basal forebrain comprises several heterogeneous neuronal subgroupings having modular projection patterns to discrete sets of cortical subregions. Each cortical region forms recurrent projections, via prefrontal cortex, that reach the specific basal forebrain subgroups from which they receive afferents. This architecture enables the basal forebrain to selectively modulate cortical responsiveness according to current processing demands. Theoretically, optimal functioning of this distributed network would be enhanced by temporal coordination among coactive basal forebrain neurons, or the emergence of "cell assemblies." The present work demonstrates assembly formation in rat basal forebrain neuronal populations during a selective attention task. Neuron pairs exhibited coactivation patterns organized within beta-frequency time windows (55 ms), regardless of their membership within distinct bursting versus nonbursting basal forebrain subpopulations. Thus, the results reveal a specific temporal framework for integration of information within basal forebrain networks and for the modulation of cortical responsiveness. PMID- 25698737 TI - Loss of Clcc1 results in ER stress, misfolded protein accumulation, and neurodegeneration. AB - Folding of transmembrane and secretory proteins occurs in the lumen of the endoplasmic reticulum (ER) before transportation to the cell surface and is monitored by the unfolded protein response (UPR) signaling pathway. The accumulation of unfolded proteins in the ER activates the UPR that restores ER homeostasis by regulating gene expression that leads to an increase in the protein-folding capacity of the ER and a decrease in the ER protein-folding load. However, prolonged UPR activity has been associated with cell death in multiple pathological conditions, including neurodegeneration. Here, we report a spontaneous recessive mouse mutation that causes progressive cerebellar granule cell death and peripheral motor axon degeneration. By positional cloning, we identify the mutation in this strain as a retrotransposon insertion in the Clcc1 gene, which encodes a putative chloride channel localized to the ER. Furthermore, we demonstrate that the C3H/HeSnJ inbred strain has late onset cerebellar degeneration due to this mutation. Interestingly, acute knockdown of Clcc1 expression in cultured cells increases sensitivity to ER stress. In agreement, GRP78, the major HSP70 family chaperone in the ER, is upregulated in Clcc1 deficient granule cells in vivo, and ubiquitinated proteins accumulate in these neurons before their degeneration. These data suggest that disruption of chloride homeostasis in the ER disrupts the protein-folding capacity of the ER, leading to eventual neuron death. PMID- 25698738 TI - Controlling your impulses: electrical stimulation of the human supplementary motor complex prevents impulsive errors. AB - To err is human. However, an inappropriate urge does not always result in error. Impulsive errors thus entail both a motor system capture by an urge to act and a failed inhibition of that impulse. Here we show that neuromodulatory electrical stimulation of the supplementary motor complex in healthy humans leaves action urges unchanged but prevents them from turning into overt errors. Subjects performed a choice reaction-time task known to trigger impulsive responses, leading to fast errors that can be revealed by analyzing accuracy as a function of poststimulus time. Yet, such fast errors are only the tip of the iceberg: electromyography (EMG) revealed fast subthreshold muscle activation in the incorrect response hand in an even larger proportion of overtly correct trials, revealing covert response impulses not discernible in overt behavior. Analyzing both overt and covert response tendencies enables to gauge the ability to prevent these incorrect impulses from turning into overt action errors. Hyperpolarizing the supplementary motor complex using transcranial direct current stimulation (tDCS) preserves action impulses but prevents their behavioral expression. This new combination of detailed behavioral, EMG, and tDCS techniques clarifies the neurophysiology of impulse control, and may point to avenues for improving impulse control deficits in various neurologic and psychiatric disorders. PMID- 25698739 TI - Stimulation-evoked Ca2+ signals in astrocytic processes at hippocampal CA3-CA1 synapses of adult mice are modulated by glutamate and ATP. AB - To date, it has been difficult to reveal physiological Ca(2+) events occurring within the fine astrocytic processes of mature animals. The objective of the study was to explore whether neuronal activity evokes astrocytic Ca(2+) signals at glutamatergic synapses of adult mice. We stimulated the Schaffer collateral/commissural fibers in acute hippocampal slices from adult mice transduced with the genetically encoded Ca(2+) indicator GCaMP5E driven by the glial fibrillary acidic protein promoter. Two-photon imaging revealed global stimulation-evoked astrocytic Ca(2+) signals with distinct latencies, rise rates, and amplitudes in fine processes and somata. Specifically, the Ca(2+) signals in the processes were faster and of higher amplitude than those in the somata. A combination of P2 purinergic and group I/II metabotropic glutamate receptor (mGluR) antagonists reduced the amplitude of the Ca(2+) transients by 30-40% in both astrocytic compartments. Blockage of the mGluRs alone only modestly reduced the magnitude of the stimulation-evoked Ca(2+) signals in processes and failed to affect the somatic Ca(2+) response. Local application of group I or I/II mGluR agonists or adenosine triphosphate (ATP) elicited global astrocytic Ca(2+) signals that mimicked the stimulation-evoked astrocytic Ca(2+) responses. We conclude that stimulation-evoked Ca(2+) signals in astrocytic processes at CA3 CA1 synapses of adult mice (1) differ from those in astrocytic somata and (2) are modulated by glutamate and ATP. PMID- 25698740 TI - Microglial activation enhances associative taste memory through purinergic modulation of glutamatergic neurotransmission. AB - The cerebral innate immune system is able to modulate brain functioning and cognitive processes. During activation of the cerebral innate immune system, inflammatory factors produced by microglia, such as cytokines and adenosine triphosphate (ATP), have been directly linked to modulation of glutamatergic system on one hand and learning and memory functions on the other hand. However, the cellular mechanisms by which microglial activation modulates cognitive processes are still unclear. Here, we used taste memory tasks, highly dependent on glutamatergic transmission in the insular cortex, to investigate the behavioral and cellular impacts of an inflammation restricted to this cortical area in rats. We first show that intrainsular infusion of the endotoxin lipopolysaccharide induces a local inflammation and increases glutamatergic AMPA, but not NMDA, receptor expression at the synaptic level. This cortical inflammation also enhances associative, but not incidental, taste memory through increase of glutamatergic AMPA receptor trafficking. Moreover, we demonstrate that ATP, but not proinflammatory cytokines, is responsible for inflammation induced enhancement of both associative taste memory and AMPA receptor expression in insular cortex. In conclusion, we propose that inflammation restricted to the insular cortex enhances associative taste memory through a purinergic-dependent increase of glutamatergic AMPA receptor expression at the synapse. PMID- 25698741 TI - Dynamics of elongation factor 2 kinase regulation in cortical neurons in response to synaptic activity. AB - The rapid regulation of cell signaling in response to calcium in neurons is essential for real-time processing of large amounts of information in the brain. A vital regulatory component, and one of the most energy-intensive biochemical processes in cells, is the elongation phase of mRNA translation, which is controlled by the Ca(2+)/CaM-dependent elongation factor 2 kinase (eEF2K). However, little is known about the dynamics of eEF2K regulation in neurons despite its established role in learning and synaptic plasticity. To explore eEF2K dynamics in depth, we stimulated synaptic activity in mouse primary cortical neurons. We find that synaptic activity results in a rapid, but transient, increase in eEF2K activity that is regulated by a combination of AMPA and NMDA-type glutamate receptors and the mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) and mammalian target of rapamycin complex 1 (mTORC1) pathways. We then used computational modeling to test the hypothesis that considering Ca(2+)-coordinated MEK/ERK, mTORC1, and eEF2k activation is sufficient to describe the observed eEF2K dynamics. Although such a model could partially fit the empirical findings, it also suggested that a crucial positive regulator of eEF2K was also necessary. Through additional modeling and empirical evidence, we demonstrate that AMP kinase (AMPK) is also an important regulator of synaptic activity-driven eEF2K dynamics in neurons. Our combined modeling and experimental findings provide the first evidence that it is necessary to consider the combined interactions of Ca(2+) with MEK/ERK, mTORC1, and AMPK to adequately explain eEF2K regulation in neurons. PMID- 25698742 TI - Synchronous inhibitory potentials precede seizure-like events in acute models of focal limbic seizures. AB - Interictal spikes in models of focal seizures and epilepsies are sustained by the synchronous activation of glutamatergic and GABAergic networks. The nature of population spikes associated with seizure initiation (pre-ictal spikes; PSs) is still undetermined. We analyzed the networks involved in the generation of both interictal and PSs in acute models of limbic cortex ictogenesis induced by pharmacological manipulations. Simultaneous extracellular and intracellular recordings from both principal cells and interneurons were performed in the medial entorhinal cortex of the in vitro isolated guinea pig brain during focal interictal and ictal discharges induced in the limbic network by intracortical and brief arterial infusions of either bicuculline methiodide (BMI) or 4 aminopyridine (4AP). Local application of BMI in the entorhinal cortex did not induce seizure-like events (SLEs), but did generate periodic interictal spikes sensitive to the glutamatergic non-NMDA receptor antagonist DNQX. Unlike local applications, arterial perfusion of either BMI or 4AP induced focal limbic SLEs. PSs just ahead of SLE were associated with hyperpolarizing potentials coupled with a complete blockade of firing in principal cells and burst discharges in putative interneurons. Interictal population spikes recorded from principal neurons between two SLEs correlated with a depolarizing potential. We demonstrate in two models of acute limbic SLE that PS events are different from interictal spikes and are sustained by synchronous activation of inhibitory networks. Our findings support a prominent role of synchronous network inhibition in the initiation of a focal seizure. PMID- 25698743 TI - 7 tesla FMRI reveals systematic functional organization for binocular disparity in dorsal visual cortex. AB - The binocular disparity between the views of the world registered by the left and right eyes provides a powerful signal about the depth structure of the environment. Despite increasing knowledge of the cortical areas that process disparity from animal models, comparatively little is known about the local architecture of stereoscopic processing in the human brain. Here, we take advantage of the high spatial specificity and image contrast offered by 7 tesla fMRI to test for systematic organization of disparity representations in the human brain. Participants viewed random dot stereogram stimuli depicting different depth positions while we recorded fMRI responses from dorsomedial visual cortex. We repeated measurements across three separate imaging sessions. Using a series of computational modeling approaches, we report three main advances in understanding disparity organization in the human brain. First, we show that disparity preferences are clustered and that this organization persists across imaging sessions, particularly in area V3A. Second, we observe differences between the local distribution of voxel responses in early and dorsomedial visual areas, suggesting different cortical organization. Third, using modeling of voxel responses, we show that higher dorsal areas (V3A, V3B/KO) have properties that are characteristic of human depth judgments: a simple model that uses tuning parameters estimated from fMRI data captures known variations in human psychophysical performance. Together, these findings indicate that human dorsal visual cortex contains selective cortical structures for disparity that may support the neural computations that underlie depth perception. PMID- 25698744 TI - The PDZ-domain protein Whirlin facilitates mechanosensory signaling in mammalian proprioceptors. AB - Mechanoreception is an essential feature of many sensory modalities. Nevertheless, the mechanisms that govern the conversion of a mechanical force to distinct patterns of action potentials remain poorly understood. Proprioceptive mechanoreceptors reside in skeletal muscle and inform the nervous system of the position of body and limbs in space. We show here that Whirlin/Deafness autosomal recessive 31 (DFNB31), a PDZ-scaffold protein involved in vestibular and auditory hair cell transduction, is also expressed by proprioceptive sensory neurons (pSNs) in dorsal root ganglia in mice. Whirlin localizes to the peripheral sensory endings of pSNs and facilitates pSN afferent firing in response to muscle stretch. The requirement of Whirlin in both proprioceptors and hair cells suggests that accessory mechanosensory signaling molecules define common features of mechanoreceptive processing across sensory systems. PMID- 25698745 TI - Anticipatory anxiety disrupts neural valuation during risky choice. AB - Incidental negative emotions unrelated to the current task, such as background anxiety, can strongly influence decisions. This is most evident in psychiatric disorders associated with generalized emotional disturbances. However, the neural mechanisms by which incidental emotions may affect choices remain poorly understood. Here we study the effects of incidental anxiety on human risky decision making, focusing on both behavioral preferences and their underlying neural processes. Although observable choices remained stable across affective contexts with high and low incidental anxiety, we found a clear change in neural valuation signals: during high incidental anxiety, activity in ventromedial prefrontal cortex and ventral striatum showed a marked reduction in (1) neural coding of the expected subjective value (ESV) of risky options, (2) prediction of observed choices, (3) functional coupling with other areas of the valuation system, and (4) baseline activity. At the same time, activity in the anterior insula showed an increase in coding the negative ESV of risky lotteries, and this neural activity predicted whether the risky lotteries would be rejected. This pattern of results suggests that incidental anxiety can shift the focus of neural valuation from possible positive consequences to anticipated negative consequences of choice options. Moreover, our findings show that these changes in neural value coding can occur in the absence of changes in overt behavior. This suggest a possible pathway by which background anxiety may lead to the development of chronic reward desensitization and a maladaptive focus on negative cognitions, as prevalent in affective and anxiety disorders. PMID- 25698746 TI - SIRT1-FOXO3a regulate cocaine actions in the nucleus accumbens. AB - Previous studies have shown that chronic cocaine administration induces SIRT1, a Class III histone deacetylase, in the nucleus accumbens (NAc), a key brain reward region, and that such induction influences the gene regulation and place conditioning effects of cocaine. To determine the mechanisms by which SIRT1 mediates cocaine-induced plasticity in NAc, we used chromatin immunoprecipitation followed by massively parallel sequencing (ChIP-seq), 1 d after 7 daily cocaine (20 mg/kg) or saline injections, to map SIRT1 binding genome-wide in mouse NAc. Our unbiased results revealed two modes of SIRT1 action. First, despite its induction in NAc, chronic cocaine causes depletion of SIRT1 from most affected gene promoters in concert with enrichment of H4K16ac (itself a deacetylation target of SIRT1), which is associated with increased expression of these genes. Second, we deduced the forkhead transcription factor (FOXO) family to be a downstream mechanism through which SIRT1 regulates cocaine action. We proceeded to demonstrate that SIRT1 induction causes the deacetylation and activation of FOXO3a in NAc, which leads to the induction of several known FOXO3a gene targets in other systems. Finally, we directly establish a role for FOXO3a in promoting cocaine-elicited behavioral responses by use of viral-mediated gene transfer: we show that overexpressing FOXO3a in NAc enhances cocaine place conditioning. The discovery of these two actions of SIRT1 in NAc in the context of behavioral adaptations to cocaine represents an important step forward in advancing our understanding of the molecular adaptations underlying cocaine action. PMID- 25698747 TI - Cell-specific activity-dependent fractionation of layer 2/3->5B excitatory signaling in mouse auditory cortex. AB - Auditory cortex (AC) layer 5B (L5B) contains both corticocollicular neurons, a type of pyramidal-tract neuron projecting to the inferior colliculus, and corticocallosal neurons, a type of intratelencephalic neuron projecting to contralateral AC. Although it is known that these neuronal types have distinct roles in auditory processing and different response properties to sound, the synaptic and intrinsic mechanisms shaping their input-output functions remain less understood. Here, we recorded in brain slices of mouse AC from retrogradely labeled corticocollicular and neighboring corticocallosal neurons in L5B. Corticocollicular neurons had, on average, lower input resistance, greater hyperpolarization-activated current (Ih), depolarized resting membrane potential, faster action potentials, initial spike doublets, and less spike-frequency adaptation. In paired recordings between single L2/3 and labeled L5B neurons, the probabilities of connection, amplitude, latency, rise time, and decay time constant of the unitary EPSC were not different for L2/3->corticocollicular and L2/3->corticocallosal connections. However, short trains of unitary EPSCs showed no synaptic depression in L2/3->corticocollicular connections, but substantial depression in L2/3->corticocallosal connections. Synaptic potentials in L2/3 >corticocollicular connections decayed faster and showed less temporal summation, consistent with increased Ih in corticocollicular neurons, whereas synaptic potentials in L2/3->corticocallosal connections showed more temporal summation. Extracellular L2/3 stimulation at two different rates resulted in spiking in L5B neurons; for corticocallosal neurons the spike rate was frequency dependent, but for corticocollicular neurons it was not. Together, these findings identify cell specific intrinsic and synaptic mechanisms that divide intracortical synaptic excitation from L2/3 to L5B into two functionally distinct pathways with different input-output functions. PMID- 25698748 TI - Neural heterogeneities determine response characteristics to second-, but not first-order stimulus features. AB - Neural heterogeneities are seen ubiquitously, but how they determine neural response properties remains unclear. Here we show that heterogeneities can either strongly, or not at all, influence neural responses to a given stimulus feature. Specifically, we recorded from peripheral electroreceptor neurons, which display strong heterogeneities in their resting discharge activity, in response to naturalistic stimuli consisting of a fast time-varying waveform (i.e., first order) whose amplitude (i.e., second-order or envelope) varied slowly in the weakly electric fish Apteronotus leptorhynchus. Although electroreceptors displayed relatively homogeneous responses to first-order stimulus features, further analysis revealed two subpopulations with similar sensitivities that were excited or inhibited by increases in the envelope, respectively, for stimuli whose frequency content spanned the natural range. We further found that a linear nonlinear cascade model incorporating the known linear response characteristics to first-order features and a static nonlinearity accurately reproduced experimentally observed responses to both first- and second-order features for all stimuli tested. Importantly, this model correctly predicted that the response magnitude is independent of either the stimulus waveform's or the envelope's frequency content. Further analysis of our model led to the surprising prediction that the mean discharge activity can be used to determine whether a given neuron is excited or inhibited by increases in the envelope. This prediction was validated by our experimental data. Thus, our results provide key insight as to how neural heterogeneities can determine response characteristics to some, but not other, behaviorally relevant stimulus features. PMID- 25698749 TI - Overexpression of Sox11 promotes corticospinal tract regeneration after spinal injury while interfering with functional recovery. AB - Embryonic neurons, peripheral neurons, and CNS neurons in zebrafish respond to axon injury by initiating pro-regenerative transcriptional programs that enable axons to extend, locate appropriate targets, and ultimately contribute to behavioral recovery. In contrast, many long-distance projection neurons in the adult mammalian CNS, notably corticospinal tract (CST) neurons, display a much lower regenerative capacity. To promote CNS repair, a long-standing goal has been to activate pro-regenerative mechanisms that are normally missing from injured CNS neurons. Sox11 is a transcription factor whose expression is common to a many types of regenerating neurons, but it is unknown whether suboptimal Sox11 expression contributes to low regenerative capacity in the adult mammalian CNS. Here we show in adult mice that dorsal root ganglion neurons (DRGs) and CST neurons fail to upregulate Sox11 after spinal axon injury. Furthermore, forced viral expression of Sox11 reduces axonal dieback of DRG axons, and promotes CST sprouting and regenerative axon growth in both acute and chronic injury paradigms. In tests of forelimb dexterity, however, Sox11 overexpression in the cortex caused a modest but consistent behavioral impairment. These data identify Sox11 as a key transcription factor that can confer an elevated innate regenerative capacity to CNS neurons. The results also demonstrate an unexpected dissociation between axon growth and behavioral outcome, highlighting the need for additional strategies to optimize the functional output of stimulated neurons. PMID- 25698750 TI - Economic choices reveal probability distortion in macaque monkeys. AB - Economic choices are largely determined by two principal elements, reward value (utility) and probability. Although nonlinear utility functions have been acknowledged for centuries, nonlinear probability weighting (probability distortion) was only recently recognized as a ubiquitous aspect of real-world choice behavior. Even when outcome probabilities are known and acknowledged, human decision makers often overweight low probability outcomes and underweight high probability outcomes. Whereas recent studies measured utility functions and their corresponding neural correlates in monkeys, it is not known whether monkeys distort probability in a manner similar to humans. Therefore, we investigated economic choices in macaque monkeys for evidence of probability distortion. We trained two monkeys to predict reward from probabilistic gambles with constant outcome values (0.5 ml or nothing). The probability of winning was conveyed using explicit visual cues (sector stimuli). Choices between the gambles revealed that the monkeys used the explicit probability information to make meaningful decisions. Using these cues, we measured probability distortion from choices between the gambles and safe rewards. Parametric modeling of the choices revealed classic probability weighting functions with inverted-S shape. Therefore, the animals overweighted low probability rewards and underweighted high probability rewards. Empirical investigation of the behavior verified that the choices were best explained by a combination of nonlinear value and nonlinear probability distortion. Together, these results suggest that probability distortion may reflect evolutionarily preserved neuronal processing. PMID- 25698751 TI - Regulation of postsynaptic function by the dementia-related ESCRT-III subunit CHMP2B. AB - The charged multivesicular body proteins (Chmp1-7) are an evolutionarily conserved family of cytosolic proteins that transiently assembles into helical polymers that change the curvature of cellular membrane domains. Mutations in human CHMP2B cause frontotemporal dementia, suggesting that this protein may normally control some neuron-specific process. Here, we examined the function, localization, and interactions of neuronal Chmp2b. The protein was highly expressed in mouse brain and could be readily detected in neuronal dendrites and spines. Depletion of endogenous Chmp2b reduced dendritic branching of cultured hippocampal neurons, decreased excitatory synapse density in vitro and in vivo, and abolished activity-induced spine enlargement and synaptic potentiation. To understand the synaptic effects of Chmp2b, we determined its ultrastructural distribution by quantitative immuno-electron microscopy and its biochemical interactions by coimmunoprecipitation and mass spectrometry. In the hippocampus in situ, a subset of neuronal Chmp2b was shown to concentrate beneath the perisynaptic membrane of dendritic spines. In synaptoneurosome lysates, Chmp2b was stably bound to a large complex containing other members of the Chmp family, as well as postsynaptic scaffolds. The supramolecular Chmp assembly detected here corresponds to a stable form of the endosomal sorting complex required for transport-III (ESCRT-III), a ubiquitous cytoplasmic protein complex known to play a central role in remodeling of lipid membranes. We conclude that Chmp2b containing ESCRT-III complexes are also present at dendritic spines, where they regulate synaptic plasticity. We propose that synaptic ESCRT-III filaments may function as a novel element of the submembrane cytoskeleton of spines. PMID- 25698752 TI - Differential dynamics of spatial attention, position, and color coding within the parietofrontal network. AB - Despite an ever growing knowledge on how parietal and prefrontal neurons encode low-level spatial and color information or higher-level information, such as spatial attention, an understanding of how these cortical regions process neuronal information at the population level is still missing. A simple assumption would be that the function and temporal response profiles of these neuronal populations match that of its constituting individual cells. However, several recent studies suggest that this is not necessarily the case and that the single-cell approach overlooks dynamic changes in how information is distributed over the neuronal population. Here, we use a time-resolved population pattern analysis to explore how spatial position, spatial attention and color information are differentially encoded and maintained in the macaque monkey prefrontal (frontal eye fields) and parietal cortex (lateral intraparietal area). Overall, our work brings about three novel observations. First, we show that parietal and prefrontal populations operate in two distinct population regimens for the encoding of sensory and cognitive information: a stationary mode and a dynamic mode. Second, we show that the temporal dynamics of a heterogeneous neuronal population brings about complementary information to that of its functional subpopulations. Thus, both need to be investigated in parallel. Last, we show that identifying the neuronal configuration in which a neuronal population encodes given information can serve to reveal this same information in a different context. All together, this work challenges common views on neural coding in the parietofrontal network. PMID- 25698753 TI - The 16p11.2 deletion mouse model of autism exhibits altered cortical progenitor proliferation and brain cytoarchitecture linked to the ERK MAPK pathway. AB - Autism spectrum disorders are complex, highly heritable neurodevelopmental disorders affecting ~1 in 100 children. Copy number variations of human chromosomal region 16p11.2 are genetically linked to 1% of autism-related disorders. This interval contains the MAPK3 gene, which encodes the MAP kinase, ERK1. Mutations in upstream elements regulating the ERK pathway are genetically linked to autism and other disorders of cognition including the neuro-cardio facial cutaneous syndromes and copy number variations. We report that a murine model of human 16p11.2 deletion exhibits a reduction in brain size and perturbations in cortical cytoarchitecture. We observed enhanced progenitor proliferation and premature cell cycle exit, which are a consequence of altered levels of downstream ERK effectors cyclin D1 and p27(Kip1) during mid neurogenesis. The increased progenitor proliferation and cell cycle withdrawal resulted in premature depletion of progenitor pools, altering the number and frequency of neurons ultimately populating cortical lamina. Specifically, we found a reduced number of upper layer pyramidal neurons and an increase in layer VI corticothalamic projection neurons, reflecting the altered cortical progenitor proliferation dynamics in these mice. Importantly, we observed a paradoxical increase in ERK signaling in mid-neurogenesis in the 16p11.2del mice, which is coincident with the development of aberrant cortical cytoarchitecture. The 16p11.2del mice exhibit anxiety-like behaviors and impaired memory. Our findings provide evidence of ERK dysregulation, developmental abnormalities in neurogenesis, and behavioral impairment associated with the 16p11.2 chromosomal deletion. PMID- 25698754 TI - Depression of excitatory synapses onto parvalbumin interneurons in the medial prefrontal cortex in susceptibility to stress. AB - In response to extreme stress, individuals either show resilience or succumb to despair. The prefrontal cortex (PFC) is required for coping with stress, and PFC dysfunction has been implicated in stress-related mental disorders, including depression. Nevertheless, the mechanisms by which the PFC participates in stress responses remain unclear. Here, we investigate the role of parvalbumin (PV) interneurons in the medial PFC (mPFC) in shaping behavioral responses to stress induced by the learned helplessness procedure, in which animals are subjected to an unpredictable and inescapable stressor. PV interneurons in the mPFC were probed and manipulated in knock-in mice expressing the Cre recombinase under the endogenous parvalbumin promoter. Notably, we found that excitatory synaptic transmission onto these neurons was decreased in mice showing helplessness, a behavioral state that is thought to resemble features of human depression. Furthermore, selective suppression of PV interneurons in the mPFC using hM4Di, a DREADD (designer receptor exclusively activated by designer drug), promoted helplessness, indicating that activation of these neurons during stress promotes the establishment of resilient behavior. Our results reveal a cellular mechanism of mPFC dysfunction that may contribute to the emergence of maladaptive behavioral responses in the face of adverse life events. PMID- 25698755 TI - Influence of motivation on control hierarchy in the human frontal cortex. AB - The frontal cortex mediates cognitive control and motivation to shape human behavior. It is generally observed that medial frontal areas are involved in motivational aspects of behavior, whereas lateral frontal regions are involved in cognitive control. Recent models of cognitive control suggest a rostro-caudal gradient in lateral frontal regions, such that progressively more rostral (anterior) regions process more complex aspects of cognitive control. How motivation influences such a control hierarchy is still under debate. Although some researchers argue that both systems work in parallel, others argue in favor of an interaction between motivation and cognitive control. In the latter case it is yet unclear how motivation would affect the different levels of the control hierarchy. This was investigated in the present functional MRI study applying different levels of cognitive control under different motivational states (low vs high reward anticipation). Three levels of cognitive control were tested by varying rule complexity: stimulus-response mapping (low-level), flexible task updating (mid-level), and sustained cue-task associations (high-level). We found an interaction between levels of cognitive control and motivation in medial and lateral frontal subregions. Specifically, flexible updating (mid-level of control) showed the strongest beneficial effect of reward and only this level exhibited functional coupling between dopamine-rich midbrain regions and the lateral frontal cortex. These findings suggest that motivation differentially affects the levels of a control hierarchy, influencing recruitment of frontal cortical control regions depending on specific task demands. PMID- 25698756 TI - Valproate-induced neurodevelopmental deficits in Xenopus laevis tadpoles. AB - Autism spectrum disorder (ASD) is increasingly thought to result from low-level deficits in synaptic development and neural circuit formation that cascade into more complex cognitive symptoms. However, the link between synaptic dysfunction and behavior is not well understood. By comparing the effects of abnormal circuit formation and behavioral outcomes across different species, it should be possible to pinpoint the conserved fundamental processes that result in disease. Here we use a novel model for neurodevelopmental disorders in which we expose Xenopus laevis tadpoles to valproic acid (VPA) during a critical time point in brain development at which neurogenesis and neural circuit formation required for sensory processing are occurring. VPA is a commonly prescribed antiepileptic drug with known teratogenic effects. In utero exposure to VPA in humans or rodents results in a higher incidence of ASD or ASD-like behavior later in life. We find that tadpoles exposed to VPA have abnormal sensorimotor and schooling behavior that is accompanied by hyperconnected neural networks in the optic tectum, increased excitatory and inhibitory synaptic drive, elevated levels of spontaneous synaptic activity, and decreased neuronal intrinsic excitability. Consistent with these findings, VPA-treated tadpoles also have increased seizure susceptibility and decreased acoustic startle habituation. These findings indicate that the effects of VPA are remarkably conserved across vertebrate species and that changes in neural circuitry resulting from abnormal developmental pruning can cascade into higher-level behavioral deficits. PMID- 25698757 TI - Positively charged amino acids at the SNAP-25 C terminus determine fusion rates, fusion pore properties, and energetics of tight SNARE complex zippering. AB - SNAP-25 is a Q-SNARE protein mediating exocytosis of neurosecretory vesicles including chromaffin granules. Previous results with a SNAP-25 construct lacking the nine C terminal residues (SNAP-25Delta9) showed changed fusion pore properties (Fang et al., 2008), suggesting a model for fusion pore mechanics that couple C terminal zipping of the SNARE complex to the opening of the fusion pore. The deleted fragment contains the positively charged residues R198 and K201, adjacent to layers 7 and 8 of the SNARE complex. To determine how fusion pore conductance and dynamics depend on these residues, single exocytotic events in bovine chromaffin cells expressing R198Q, R198E, K201Q, or K201E mutants were investigated by carbon fiber amperometry and cell-attached patch capacitance measurements. Coarse grain molecular dynamics simulations revealed spontaneous transitions between a loose and tightly zippered state at the SNARE complex C terminus. The SNAP-25 K201Q mutant showed no changes compared with SNAP-25 wild type. However, K201E, R198Q, and R198E displayed reduced release frequencies, slower release kinetics, and prolonged fusion pore duration that were correlated with reduced probability to engage in the tightly zippered state. The results show that the positively charged amino acids at the SNAP-25 C terminus promote tight SNARE complex zippering and are required for high release frequency and rapid release in individual fusion events. PMID- 25698758 TI - Brain amyloid-beta burden is associated with disruption of intrinsic functional connectivity within the medial temporal lobe in cognitively normal elderly. AB - The medial temporal lobe is implicated as a key brain region involved in the pathogenesis of Alzheimer's disease (AD) and consequent memory loss. Tau tangle aggregation in this region may develop concurrently with cortical Abeta deposition in preclinical AD, but the pathological relationship between tau and Abeta remains unclear. We used task-free fMRI with a focus on the medical temporal lobe, together with Abeta PET imaging, in cognitively normal elderly human participants. We found that cortical Abeta load was related to disrupted intrinsic functional connectivity of the perirhinal cortex, which is typically the first brain region affected by tauopathies in AD. There was no concurrent association of cortical Abeta load with cognitive performance or brain atrophy. These findings suggest that dysfunction in the medial temporal lobe may represent a very early sign of preclinical AD and may predict future memory loss. PMID- 25698760 TI - Alpha phase determines successful lexical decision in noise. AB - Psychophysical target detection has been shown to be modulated by slow oscillatory brain phase. However, thus far, only low-level sensory stimuli have been used as targets. The current human electroencephalography (EEG) study examined the influence of neural oscillatory phase on a lexical-decision task performed for stimuli embedded in noise. Neural phase angles were compared for correct versus incorrect lexical decisions using a phase bifurcation index (BI), which quantifies differences in mean phase angles and phase concentrations between correct and incorrect trials. Neural phase angles in the alpha frequency range (8-12 Hz) over right anterior sensors were approximately antiphase in a prestimulus time window, and thus successfully distinguished between correct and incorrect lexical decisions. Moreover, alpha-band oscillations were again approximately antiphase across participants for correct versus incorrect trials during a later peristimulus time window (~500 ms) at left-central electrodes. Strikingly, lexical decision accuracy was not predicted by either event-related potentials (ERPs) or oscillatory power measures. We suggest that correct lexical decisions depend both on successful sensory processing, which is made possible by the alignment of stimulus onset with an optimal alpha phase, as well as integration and weighting of decisional information, which is coupled to alpha phase immediately following the critical manipulation that differentiated words from pseudowords. The current study constitutes a first step toward characterizing the role of dynamic oscillatory brain states for higher cognitive functions, such as spoken word recognition. PMID- 25698759 TI - Alcohol decreases baseline brain glucose metabolism more in heavy drinkers than controls but has no effect on stimulation-induced metabolic increases. AB - During alcohol intoxication, the human brain increases metabolism of acetate and decreases metabolism of glucose as energy substrate. Here we hypothesized that chronic heavy drinking facilitates this energy substrate shift both for baseline and stimulation conditions. To test this hypothesis, we compared the effects of alcohol intoxication (0.75 g/kg alcohol vs placebo) on brain glucose metabolism during video stimulation (VS) versus when given with no stimulation (NS), in 25 heavy drinkers (HDs) and 23 healthy controls, each of whom underwent four PET (18)FDG scans. We showed that resting whole-brain glucose metabolism (placebo-NS) was lower in HD than controls (13%, p = 0.04); that alcohol (compared with placebo) decreased metabolism more in HD (20 +/- 13%) than controls (9 +/- 11%, p = 0.005) and in proportion to daily alcohol consumption (r = 0.36, p = 0.01) but found that alcohol did not reduce the metabolic increases in visual cortex from VS in either group. Instead, VS reduced alcohol-induced decreases in whole-brain glucose metabolism (10 +/- 12%) compared with NS in both groups (15 +/- 13%, p = 0.04), consistent with stimulation-related glucose metabolism enhancement. These findings corroborate our hypothesis that heavy alcohol consumption facilitates use of alternative energy substrates (i.e., acetate) for resting activity during intoxication, which might persist through early sobriety, but indicate that glucose is still favored as energy substrate during brain stimulation. Our findings are consistent with reduced reliance on glucose as the main energy substrate for resting brain metabolism during intoxication (presumably shifting to acetate or other ketones) and a priming of this shift in HDs, which might make them vulnerable to energy deficits during withdrawal. PMID- 25698761 TI - Spiral ganglion degeneration and hearing loss as a consequence of satellite cell death in saposin B-deficient mice. AB - Saposin B (Sap B) is an essential activator protein for arylsulfatase A in the hydrolysis of sulfatide, a lipid component of myelin. To study Sap B's role in hearing and balance, a Sap B-deficient (B(-/-)) mouse was evaluated. At both light and electron microscopy (EM) levels, inclusion body accumulation was seen in satellite cells surrounding spiral ganglion (SG) neurons from postnatal month 1 onward, progressing into large vacuoles preceding satellite cell degeneration, and followed by SG degeneration. EM also revealed reduced or absent myelin sheaths in SG neurons from postnatal month 8 onwards. Hearing loss was initially seen at postnatal month 6 and progressed thereafter for frequency-specific stimuli, whereas click responses became abnormal from postnatal month 13 onward. The progressive hearing loss correlated with the accumulation of inclusion bodies in the satellite cells and their subsequent degeneration. Outer hair cell numbers and efferent function measures (distortion product otoacoustic emissions and contralateral suppression) were normal in the B(-/-) mice throughout this period. Alcian blue staining of SGs demonstrated that these inclusion bodies corresponded to sulfatide accumulation. In contrast, changes in the vestibular system were much milder, but caused severe physiologic deficits. These results demonstrate that loss of Sap B function leads to progressive sulfatide accumulation in satellite cells surrounding the SG neurons, leading to satellite cell degeneration and subsequent SG degeneration with a resultant loss of hearing. Relative sparing of the efferent auditory and vestibular neurons suggests that alternate glycosphingolipid metabolic pathways predominate in these other systems. PMID- 25698762 TI - Converging evidence for the neuroanatomic basis of combinatorial semantics in the angular gyrus. AB - Human thought and language rely on the brain's ability to combine conceptual information. This fundamental process supports the construction of complex concepts from basic constituents. For example, both "jacket" and "plaid" can be represented as individual concepts, but they can also be integrated to form the more complex representation "plaid jacket." Although this process is central to the expression and comprehension of language, little is known about its neural basis. Here we present evidence for a neuroanatomic model of conceptual combination from three experiments. We predicted that the highly integrative region of heteromodal association cortex in the angular gyrus would be critical for conceptual combination, given its anatomic connectivity and its strong association with semantic memory in functional neuroimaging studies. Consistent with this hypothesis, we found that the process of combining concepts to form meaningful representations specifically modulates neural activity in the angular gyrus of healthy adults, independent of the modality of the semantic content integrated. We also found that individual differences in the structure of the angular gyrus in healthy adults are related to variability in behavioral performance on the conceptual combination task. Finally, in a group of patients with neurodegenerative disease, we found that the degree of atrophy in the angular gyrus is specifically related to impaired performance on combinatorial processing. These converging anatomic findings are consistent with a critical role for the angular gyrus in conceptual combination. PMID- 25698763 TI - Cerebellar direct current stimulation enhances on-line motor skill acquisition through an effect on accuracy. AB - The cerebellum is involved in the update of motor commands during error-dependent learning. Transcranial direct current stimulation (tDCS), a form of noninvasive brain stimulation, has been shown to increase cerebellar excitability and improve learning in motor adaptation tasks. Although cerebellar involvement has been clearly demonstrated in adaptation paradigms, a type of task that heavily relies on error-dependent motor learning mechanisms, its role during motor skill learning, a behavior that likely involves error-dependent as well as reinforcement and strategic mechanisms, is not completely understood. Here, in humans, we delivered cerebellar tDCS to modulate its activity during novel motor skill training over the course of 3 d and assessed gains during training (on-line effects), between days (off-line effects), and overall improvement. We found that excitatory anodal tDCS applied over the cerebellum increased skill learning relative to sham and cathodal tDCS specifically by increasing on-line rather than off-line learning. Moreover, the larger skill improvement in the anodal group was predominantly mediated by reductions in error rate rather than changes in movement time. These results have important implications for using cerebellar tDCS as an intervention to speed up motor skill acquisition and to improve motor skill accuracy, as well as to further our understanding of cerebellar function. PMID- 25698764 TI - Risk of stroke among patients with post-traumatic stress disorder: nationwide longitudinal study. AB - BACKGROUND: Previous evidence has shown positive associations between post traumatic stress disorder (PTSD) and hypertension, dyslipidaemia and diabetes mellitus, which are all risk factors for stroke, but the role of PTSD in the subsequent development of stroke is still unknown. AIMS: To investigate the temporal association between PTSD and the development of stroke. METHOD: Identified from the Taiwan National Health Insurance Research Database, 5217 individuals aged >=18 years, with PTSD but with no history of stroke, and 20 868 age- and gender-matched controls were enrolled between 2002 and 2009, and followed up until the end of 2011 to identify the development of stroke. RESULTS: Individuals with PTSD had an increased risk of developing any stroke (hazard ratio (HR) 3.37, 95% CI 2.44-4.67) and ischaemic stroke (HR = 3.47, 95% CI 2.23 5.39) after adjusting for demographic data and medical comorbidities. Sensitivity tests showed consistent findings (any stroke HR = 3.02, 95% CI 2.13-4.28; ischaemic stroke HR = 2.89, 95% CI 1.79-4.66) after excluding the first year of observation. CONCLUSIONS: Individuals with PTSD have an increased risk of developing any stroke and ischaemic stroke. Further studies are required to investigate the underlying mechanisms. PMID- 25698765 TI - Religion and the risk of suicide: longitudinal study of over 1 million people. AB - BACKGROUND: Durkheim's seminal historical study demonstrated that religious affiliation reduces suicide risk, but it is unclear whether this protective effect persists in modern, more secular societies. AIMS: To examine suicide risk according to Christian religious affiliation and by inference to examine underlying mechanisms for suicide risk. If church attendance is important, risk should be lowest for Roman Catholics and highest for those with no religion; if religiosity is important, then 'conservative' Christians should fare best. METHOD: A 9-year study followed 1 106 104 people aged 16-74 years at the 2001 UK census, using Cox proportional hazards models adjusted for census-based cohort attributes. RESULTS: In fully adjusted models analysing 1119 cases of suicide, Roman Catholics, Protestants and those professing no religion recorded similar risks. The risk associated with conservative Christians was lower than that for Catholics (HR = 0.71, 95% CI 0.52-0.97). CONCLUSIONS: The relationship between religious affiliation and suicide established by Durkheim may not pertain in societies where suicide rates are highest at younger ages. Risks are similar for those with and without a religious affiliation, and Catholics (who traditionally are characterised by higher levels of church attendance) do not demonstrate lower risk of suicide. However, religious affiliation is a poor measure of religiosity, except for a small group of conservative Christians, although their lower risk of suicide may be attributable to factors such as lower risk behaviour and alcohol consumption. PMID- 25698766 TI - Cognitive-behavioural therapy for anxiety in dementia: pilot randomised controlled trial. AB - BACKGROUND: Anxiety is common and problematic in dementia, yet there is a lack of effective treatments. AIMS: To develop a cognitive-behavioural therapy (CBT) manual for anxiety in dementia and determine its feasibility through a randomised controlled trial. METHOD: A ten-session CBT manual was developed. Participants with dementia and anxiety (and their carers) were randomly allocated to CBT plus treatment as usual (TAU) (n = 25) or TAU (n = 25). Outcome and cost measures were administered at baseline, 15 weeks and 6 months. RESULTS: At 15 weeks, there was an adjusted difference in anxiety (using the Rating Anxiety in Dementia scale) of (-3.10, 95% CI -6.55 to 0.34) for CBT compared with TAU, which just fell short of statistical significance. There were significant improvements in depression at 15 weeks after adjustment (-5.37, 95% CI -9.50 to -1.25). Improvements remained significant at 6 months. CBT was cost neutral. CONCLUSIONS: CBT was feasible (in terms of recruitment, acceptability and attrition) and effective. A fully powered RCT is now required. PMID- 25698767 TI - Violent and non-violent crime against adults with severe mental illness. AB - BACKGROUND: Little is known about the relative extent of crime against people with severe mental illness (SMI). AIMS: To assess the prevalence and impact of crime among people with SMI compared with the general population. METHOD: A total of 361 psychiatric patients were interviewed using the national crime survey questionnaire, and findings compared with those from 3138 general population controls participating in the contemporaneous national crime survey. RESULTS: Past-year crime was experienced by 40% of patients v. 14% of controls (adjusted odds ratio (OR) = 2.8, 95% CI 2.0-3.8); and violent assaults by 19% of patients v. 3% of controls (adjusted OR = 5.3, 95% CI 3.1-8.8). Women with SMI had four-, ten- and four-fold increases in the odds of experiencing domestic, community and sexual violence, respectively. Victims with SMI were more likely to report psychosocial morbidity following violence than victims from the general population. CONCLUSIONS: People with SMI are at greatly increased risk of crime and associated morbidity. Violence prevention policies should be particularly focused on people with SMI. PMID- 25698768 TI - Two-photon fluorescence microscopy of corneal riboflavin absorption through an intact epithelium. PMID- 25698769 TI - Understanding the process of corneal endothelial morphological change in vitro. AB - Corneal endothelial cells often adopt a fibroblastic-like morphology in culture, a process that has been attributed to epithelial- or endothelial-to-mesenchymal transition (EMT or EndMT). Although being extensively studied in other cell types, this transition is less well characterized in the corneal endothelium. Because of their neuroectodermal origin and their in vivo mitotic arrest, corneal endothelial cells represent a particular tissue that deserves more attention. This review article presents the basic principles underlying EMT/EndMT, with emphasis on the current knowledge regarding the corneal endothelium. Furthermore, this review discusses cell culture conditions and major cell signaling pathways that have been identified as EndMT-triggering factors. Finally, it summarizes strategies that have been developed to inhibit EndMT in corneal endothelial cell culture. The review of current studies on corneal and classical EndMT highlights some research avenues to pursue in the future and underscores the need to extend our knowledge of this process in order to optimize usage of these cells in regenerative medicine. PMID- 25698770 TI - NICE is too generous in approving drugs, analysis says. PMID- 25698771 TI - Prevalence of HIV-1 drug resistance among patients failing first-line ART in Monrovia, Liberia: a cross-sectional study. AB - OBJECTIVES: To assess the prevalence of acquired drug resistance in HIV-1 infected patients living in Monrovia, Liberia, who had clinical and/or immunological failure of first-line ART according to WHO criteria. PATIENTS AND METHODS: Patients receiving ART for >1 year with clinical and/or immunological failure were included. Sequencing of protease and reverse transcriptase regions was performed using Agence Nationale de Recherche sur le SIDA et les hepatites virales (ANRS) procedures and sequences were interpreted using the ANRS resistance algorithm. RESULTS: Ninety patients were enrolled. They had been receiving ART for a median time of 42 months and half were receiving zidovudine/lamivudine/nevirapine. Seventy-five per cent of patients were infected with CRF02_AG. Twenty-seven per cent of patients displayed a plasma viral load <50 copies/mL. Among the 66 patients with detectable viraemia, the median viral load was 4.7 log10 copies/mL (IQR = 3.0-5.6). The prevalence of NRTI and NNRTI resistance-associated mutations (RAMs) was 63% and 71%, respectively; and the median number of NRTI and NNRTI RAMs was 2 and 3, respectively. Two patients (4%) displayed viruses with PI RAMs. Regarding NRTI drug resistance, 29%, 38%, 63%, 29% and 25% of patients had viruses resistant to zidovudine, stavudine, lamivudine/emtricitabine, abacavir and tenofovir, respectively. Regarding the NNRTI drug class, 56%, 65%, 33% and 42% of patients had viruses resistant to efavirenz, nevirapine, etravirine and rilpivirine, respectively. CONCLUSIONS: The high prevalence of acquired drug resistance in patients followed in two centres of the Liberian capital city, documented after a median of 3 years on a first line ART regimen, jeopardizes the activity of second-line regimens and highlights the need for virological monitoring in these settings. PMID- 25698772 TI - Extracorporeal clearance of colistin methanesulphonate and formed colistin in end stage renal disease patients receiving intermittent haemodialysis: implications for dosing. AB - OBJECTIVES: Colistin, administered intravenously as its inactive prodrug colistin methanesulphonate (CMS), is being increasingly used. However, there is very limited information available on the impact of haemodialysis (HD) on the pharmacokinetics of CMS and formed colistin. PATIENTS AND METHODS: A single 30 min intravenous dose of CMS (150 mg of colistin base activity) was administered to 10 patients undergoing HD. HD was performed from 1.5 to 5.5 h after the start of the CMS infusion. Serial blood samples were collected over 50 h, additional blood samples pre- and post-dialysis membrane at three timepoints during HD, dialysate samples at four timepoints during HD, and a cumulative urine sample over 24 h. CMS and colistin were determined by HPLC. Population modelling and determination of HD clearance by multiple methods was conducted. RESULTS: The average amount of CMS recovered in the dialysate was 30.6% of the dose administered. The concentrations of CMS and colistin in the plasma and the amounts of CMS recovered in the dialysate were well described by the population disposition model. The clearance of CMS by dialysis as estimated by population analysis based on systemic plasma concentrations and amounts in the dialysate was 4.26 L/h (26% coefficient of variation). The dialysis clearance determined from the pre- and post-membrane plasma concentrations was 5.67 L/h (21%) for CMS and 3.99 L/h (44%) for colistin. Thus, CMS clearance by dialysis from trans-cartridge extraction was ~30% higher than when calculated based on the amount in dialysate, suggesting adsorption to the membrane. CONCLUSIONS: Due to the extensive removal of CMS by dialysis, HD should be conducted at the end of a dosing interval and a supplemental dose should be administered. PMID- 25698773 TI - Antidepressants and risk of suicide. PMID- 25698774 TI - Assessment and management of alcohol use disorders. PMID- 25698775 TI - Mosquito repellents for travellers. PMID- 25698776 TI - Response to "Comparison of urine to oral fluid and the recommendation for routine drug analysis for driving under the influence cases". PMID- 25698777 TI - First reported fatalities associated with the 'research chemical' 2 methoxydiphenidine. AB - 2-Methoxydiphenidine, i.e. 1-[1-(2-methoxyphenyl)-2-phenylethyl]piperidine, also known as 'MXP' or '2-MeO-diphenidine' (or 2-MXP), has been available as a 'research chemical' since 2013 as a purported alternative to the 'dissociative anesthetics' methoxetamine and ketamine. Three deaths which involved the detection of 2-MXP in post-mortem blood and urine were encountered in forensic casework. The 2-, 3- and 4-methoxyphenyl positional isomers were synthesized to confirm the identity and concentration of 2-MXP. The 2-MXP femoral blood concentrations in the cases were found to be 24.0, 2.0 and 1.36 mg/L (the latter with an alternative cause of death). Some additional prescription drugs were encountered at therapeutic concentrations in all three cases. Analysis of the biofluids allowed the detection and characterization of various metabolites, including the suggested presence of hydroxy-2-MXP as the main metabolite with the hydroxyl group located on the piperidine rather than the phenyl or benzyl moiety. Additional metabolites included O-desmethyl-2-MXP and hydroxylated O-desmethyl-2 MXP. Diphenidine and hydroxy-diphenidine, also showing the presence of the hydroxyl group on the piperidine ring, were also detected. It was not possible to identify whether these arose from 2-MXP biotransformation or whether they represented the presence of diphenidine as a separate substance. These are the first published fatalities involving 2-MXP and presents analytical data to assist analytical toxicologists with future casework. PMID- 25698778 TI - Comparison of urine to oral fluid and the recommendation for routine drug analysis for driving under the influence cases. PMID- 25698780 TI - Metabolic PET/CT-guided lung lesion biopsies: impact on diagnostic accuracy and rate of sampling error. AB - CT-guided fine-needle aspiration (FNA) of lung lesions is subject to sampling errors. The current study assessed whether information provided by (18)F-FDG PET/CT will decrease the false-negative (FN) rate and thus improve the accuracy of CT-guided FNA. METHODS: Data from 311 consecutive patients with lung nodules who underwent (18)F-FDG PET/CT and CT-guided FNA within an interval of less than 30 d were retrospectively assessed. In-house-developed software was used to register CT images performed for the FNA procedure (CT FNA) with corresponding slices of the PET/CT study. The quality of registration was rated on a scale of 1 (excellent) to 5 (misregistration). Only cases scored 1 or 2 were further evaluated. The software provided the highest standardized uptake value (SUV) within the lesion and at the location of the tip of the aspirating needle. The distance between the tip and the area with the highest SUV within the lesion was measured. The mean distance from the tip of the needle to the focus with the highest SUV, as well as the mean difference between the maximum SUV in the whole lesion and at the needle tip, was calculated and compared for cases with true positive (TP) and FN FNA results. Anatomic and metabolic parameters of lesions included in these 2 groups were also compared. RESULTS: There were 267 patients (86%) with score 1 or 2 registration quality for CT FNA and PET/CT/CT images, including 179 TP (67%), 5 false-positive (FP, 2%), 49 true-negative (TN, 18%), and 34 FN (13%) FNA results. The distance between the location of the needle tip and the focus with the highest SUV in the lesion was significantly greater in the FN group (15.4 +/- 14 mm) than in the TP group (5.9 +/- 13.4 mm, P < 0.001). The maximum SUV at the location of the aspirating needle tip was significantly higher in the TP group, at 6.4 +/- 6.4, than in the FN group, at 4 +/- 4.7 (P < 0.05). CONCLUSION: The present results demonstrate a relationship between the degree of metabolism at the site of tissue-sampling aspiration in lung lesions and the accuracy of FNA results. Anatomy- and metabolism-based FNA guidance using information provided by both (18)F-FDG PET and CT may improve the accuracy of histologic examinations, decrease the rate of FN results, and thus increase the probability of achieving a definitive diagnosis. PMID- 25698781 TI - Aromatase imaging with [N-methyl-11C]vorozole PET in healthy men and women. AB - Aromatase, the last and obligatory enzyme catalyzing estrogen biosynthesis from androgenic precursors, can be labeled in vivo with (11)C-vorozole. Aromatase inhibitors are widely used in breast cancer and other endocrine conditions. The present study aimed to provide baseline information defining aromatase distribution in healthy men and women, against which its perturbation in pathologic situations can be studied. METHODS: (11)C-vorozole (111-296 MBq/subject) was injected intravenously in 13 men and 20 women (age range, 23-67 y). PET data were acquired over a 90-min period. Each subject had 4 scans, 2 per day separated by 2-6 wk, including brain and torso or pelvis scans. Young women were scanned at 2 discrete phases of the menstrual cycle (midcycle and late luteal). Men and postmenopausal women were also scanned after pretreatment with a clinical dose of the aromatase inhibitor letrozole. Time-activity curves were obtained, and standardized uptake values (SUV) were calculated for major organs including brain, heart, lungs, liver, kidneys, spleen, muscle, bone, and male and female reproductive organs (penis, testes, uterus, ovaries). Organ and whole-body radiation exposures were calculated using OLINDA software. RESULTS: Liver uptake was higher than uptake in any other organ but was not blocked by pretreatment with letrozole. Mean SUVs were higher in men than in women, and brain uptake was blocked by letrozole. Male brain SUVs were also higher than SUVs in any other organ (ranging from 0.48 +/- 0.05 in lungs to 1.5 +/- 0.13 in kidneys). Mean ovarian SUVs (3.08 +/- 0.7) were comparable to brain levels and higher than in any other organ. Furthermore, ovarian SUVs in young women around the time of ovulation (midcycle) were significantly higher than those measured in the late luteal phase, whereas aging and cigarette smoking reduced (11)C-vorozole uptake. CONCLUSION: PET with (11)C-vorozole is useful for assessing physiologic changes in estrogen synthesis capacity in the human body. Baseline levels in breasts, lungs, and bones are low, supporting further investigation of this tracer as a new tool for detection of aromatase-overexpressing primary tumors or metastases in these organs and optimization of treatment in cancer and other disorders in which aromatase inhibitors are useful. PMID- 25698782 TI - Biodistribution and radiation dosimetry for the chemokine receptor CXCR4 targeting probe 68Ga-pentixafor. AB - (68)Ga-pentixafor is a promising PET tracer for imaging the expression of the human chemokine receptor 4 (CXCR4) in vivo. The whole-body distribution and radiation dosimetry of (68)Ga-pentixafor were evaluated. METHODS: Five multiple myeloma patients were injected intravenously with 90-158 MBq of (68)Ga-pentixafor (mean +/- SD, 134 +/- 25 MBq), and a series of 3 rapid multiple-bed-position whole-body scans were acquired immediately afterward. Subsequently, 4 static whole-body scans followed at 30 min, 1 h, 2 h, and 4 h after administration of the radiopharmaceutical. Venous blood samples were obtained. Time-integrated activity coefficients were determined from multiexponential regression of organ region-of-interest data normalized to the administered activity, for example, the time-dependent percentages of the injected activity per organ. Mean organ absorbed doses and effective doses were calculated using OLINDA/EXM. RESULTS: The effective dose based on 150 MBq of (68)Ga-pentixafor was 2.3 mSv. The highest organ-absorbed doses (for 150 MBq injected) were found in the urinary bladder wall (12.2 mGy), spleen (8.1 mGy), kidneys (5.3 mGy), and heart wall (4.0 mGy). Other organ mean absorbed doses were as follows: 2.7 mGy, liver; 2.1 mGy, red marrow; 1.7 mGy, testes; and 1.9 mGy, ovaries. CONCLUSION: (68)Ga-pentixafor exhibits a favorable dosimetry, delivering absorbed doses to organs that are lower than those delivered by (18)F-FDG- or (68)Ga-labeled somatostatin receptor ligands. PMID- 25698783 TI - Characterization in humans of 18F-MNI-444, a PET radiotracer for brain adenosine 2A receptors. AB - PET with selective adenosine 2A receptor (A2A) radiotracers can be used to study a variety of neurodegenerative and neuropsychiatric disorders in vivo and to support drug-discovery studies targeting A2A. The aim of this study was to describe the first in vivo evaluation of (18)F-MNI-444, a novel PET radiotracer for imaging A2A, in healthy human subjects. METHODS: Ten healthy human volunteers were enrolled in this study; 6 completed the brain PET studies and 4 participated in the whole-body PET studies. Arterial blood was collected for invasive kinetic modeling of the brain PET data. Noninvasive methods of data quantification were also explored. Test-retest reproducibility was evaluated in 5 subjects. Radiotracer distribution and dosimetry was determined using serial whole-body PET images acquired over 6 h post-radiotracer injection. Urine samples were collected to calculate urinary excretion. RESULTS: After intravenous bolus injection, (18)F MNI-444 rapidly entered the brain and displayed a distribution consistent with known A2A densities in the brain. Binding potentials ranging from 2.6 to 4.9 were measured in A2A-rich regions, with an average test-retest variability of less than 10%. The estimated whole-body radiation effective dose was approximately 0.023 mSv/MBq. CONCLUSION: (18)F-MNI-444 is a useful PET radiotracer for imaging A2A in the human brain. The superior in vivo brain kinetic properties of (18)F MNI-444, compared with previously developed A2A radiotracers, provide the opportunity to foster global use of in vivo A2A PET imaging in neuroscience research. PMID- 25698784 TI - PET imaging of tenascin-C with a radiolabeled single-stranded DNA aptamer. AB - Tenascin-C is an extracellular matrix glycoprotein that is expressed by injured tissues and by various cancers. Recent publications showed that tenascin-C expression by cancer lesions predicts tumor growth, metastasis, and angiogenesis, suggesting tenascin-C as a potential therapeutic target. Currently there is no noninvasive method to determine tumoral tenascin-C expression in vivo. To address the need for an agent to image and quantify tenascin-C, we report the development of a radioactive PET tracer based on a tenascin-C-specific single-stranded DNA aptamer (tenascin-C aptamer). METHODS: Tenascin-C aptamer was radiolabeled with (18)F and (64)Cu. PET imaging studies for the evaluation of tumor uptake and pharmacokinetics of tenascin-C aptamer were performed in comparison to a nonspecific scrambled aptamer (Sc aptamer). RESULTS: The labeled tenascin-C aptamer provided clear visualization of tenascin-C-positive but not tenascin-C negative tumors. The uptake of tenascin-C aptamer was significantly higher than that of Sc aptamer in tenascin-C-positive tumors. The labeled tenascin-C aptamer had fast clearance from the blood and other nonspecific organs through the kidneys, resulting in high tumor contrast. CONCLUSION: Our data suggest that suitably labeled tenascin-C aptamer can be used as a PET tracer to image tumor expression of tenascin-C with a high tumor-to-background ratio and might provide insightful and personalized medical data that will help determine appropriate treatment and monitoring. PMID- 25698785 TI - Triple-peptide receptor targeting in vitro allows detection of all tested gut and bronchial NETs. AB - A high proportion of gut and bronchial neuroendocrine tumors (NETs) overexpresses somatostatin receptors, especially the sst2 subtype. It has also recently been observed that incretin receptors, namely glucagonlike peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) receptors, can be overexpressed in gut and bronchial NETs. However, because not all tumors can express these receptors in sufficient amounts, in vivo imaging with a single radioligand may not always be successful. We therefore evaluated with in vitro methods whether a cocktail of radioligands targeting these 3 receptors would improve tumor labeling. METHODS: In vitro receptor autoradiography was performed on 55 NETs, comparing in each successive section of tumor the binding with a single radioligand, either (125)I-Tyr(3)-octreotide, (125)I-GLP-1(7-36)amide, or (125)I GIP(1-30), with the binding using a cocktail of all 3 radioligands, given concomitantly under identical experimental conditions. RESULTS: Using the cocktail of radioligands, all tumors without exception showed moderate to very high binding, with a receptor density corresponding to 1,000-10,000 dpm/mg of tissue; conversely, single-ligand binding, although identifying most tumors as receptor-positive, failed to detect receptors or measured only a low density of receptors below 1,000 dpm/mg in a significant number of tumors. In addition, the cocktail of radioligands always provided a homogeneous labeling of the whole tumor, whereas single radioligands occasionally showed heterogeneous labeling. CONCLUSION: The study suggests that the use of a cocktail of 3 radioligands binding to somatostatin receptors, GLP-1 receptors, and GIP receptors would allow detecting virtually all NETs and labeling them homogeneously in vivo, representing a significant improvement for imaging and therapy in NETs. PMID- 25698786 TI - Countdown begins to seventh annual BMJ Awards. PMID- 25698787 TI - PF-1355, a mechanism-based myeloperoxidase inhibitor, prevents immune complex vasculitis and anti-glomerular basement membrane glomerulonephritis. AB - Small vessel vasculitis is a life-threatening condition and patients typically present with renal and pulmonary injury. Disease pathogenesis is associated with neutrophil accumulation, activation, and oxidative damage, the latter being driven in large part by myeloperoxidase (MPO), which generates hypochlorous acid among other oxidants. MPO has been associated with vasculitis, disseminated vascular inflammation typically involving pulmonary and renal microvasculature and often resulting in critical consequences. MPO contributes to vascular injury by 1) catabolizing nitric oxide, impairing vasomotor function; 2) causing oxidative damage to lipoproteins and endothelial cells, leading to atherosclerosis; and 3) stimulating formation of neutrophil extracellular traps, resulting in vessel occlusion and thrombosis. Here we report a selective 2 thiouracil mechanism-based MPO inhibitor (PF-1355 [2-(6-(2,5-dimethoxyphenyl)-4 oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamide) and demonstrate that MPO is a critical mediator of vasculitis in mouse disease models. A pharmacokinetic/pharmacodynamic response model of PF-1355 exposure in relation with MPO activity was derived from mouse peritonitis. The contribution of MPO activity to vasculitis was then examined in an immune complex model of pulmonary disease. Oral administration of PF-1355 reduced plasma MPO activity, vascular edema, neutrophil recruitment, and elevated circulating cytokines. In a model of anti-glomerular basement membrane disease, formerly known as Goodpasture disease, albuminuria and chronic renal dysfunction were completely suppressed by PF-1355 treatment. This study shows that MPO activity is critical in driving immune complex vasculitis and provides confidence in testing the hypothesis that MPO inhibition will provide benefit in treating human vasculitic diseases. PMID- 25698788 TI - Providing culturally congruent health care to older adults. PMID- 25698789 TI - Co-digestion of municipal sewage sludge and solid waste: modelling of carbohydrate, lipid and protein content influence. AB - Solid wastes from industrial, commercial and community activities are of growing concern as the total volume of waste produced continues to increase. The knowledge of the specific composition and characteristics of the waste is an important tool in the correct development of the anaerobic digestion process. The problems derived from the anaerobic digestion of sole substrates with high lipid, carbohydrate or protein content lead to the co-digestion of these substrates with another disposed waste, such as sewage sludge. The kinetic of the anaerobic digestion is especially difficult to explain adequately, although some mathematical models are able to represent the main aspects of a biological system, thus improving understanding of the parameters involved in the process. The aim of this work is to evaluate the experimental biochemical methane potential on the co-digestion of sewage sludge with different solid wastes (grease; spent grain and cow manure) through the implementation of four kinetic models. The co-digestion of grease waste and mixed sludge obtained the best improvements from the sole substrates, with additional positive synergistic effects. The Gompertz model fits the experimental biochemical methane potential to an accuracy of 99%, showing a correlation between the percentage of lipid in the substrates and co-digestions and the period of lag phase. PMID- 25698790 TI - Determination of non-gaseous and gaseous mercury fractions in unused fluorescent lamps: a study of different lamp types. AB - Since incandescent light bulbs have been phased out in the European Union from 2009, the use of fluorescent lamps has drastically increased as a reliable, more energy-efficient and cost-effective alternative. State-of-the-art fluorescent lamps are dependent on mercury/mercury alloys, posing a risk for the consumer and the environment, and appropriate waste management is challenging. Consequently analytical methods to determine possible mercury species (non-gaseous/gaseous) in these lamps are of need. Here, a straightforward and wet-chemistry-based analytical strategy for the determination of gaseous and non-gaseous mercury in commercially available fluorescent lamps is presented. It can be adapted in any analytical laboratory, without or with only minimum modifications of already installed equipment. The analytical figures of merit, as well as application of the method to a series of commercially available fluorescent lamps, are presented. Out of 14 analysed and commercially available lamp types, results from this study indicate that only one contains a slightly higher amount of mercury than set by the legislative force. In all new lamps the amount of gaseous mercury is negligible compared with the non-gaseous fraction (88%-99% of total mercury). PMID- 25698791 TI - STIF Advanced Competency. PMID- 25698792 TI - Clinical update. PMID- 25698793 TI - The relationship between violence in Northern Mexico and potentially avoidable hospitalizations in the USA-Mexico border region. AB - BACKGROUND: Substantial proportions of US residents in the USA-Mexico border region cross into Mexico for health care; increases in violence in northern Mexico may have affected this access. We quantified associations between violence in Mexico and decreases in access to care for border county residents. We also examined associations between border county residence and access. METHODS: We used hospital inpatient data for Arizona, California and Texas (2005-10) to estimate associations between homicide rates and the probability of hospitalization for ambulatory care sensitive (ACS) conditions. Hospitalizations for ACS conditions were compared with homicide rates in Mexican municipalities matched by patient residence. RESULTS: A 1 SD increase in the homicide rate of the nearest Mexican municipality was associated with a 2.2 percentage point increase in the probability of being hospitalized for an ACS condition for border county patients. Residence in a border county was associated with a 1.3 percentage point decrease in the probability of being hospitalized for an ACS condition. CONCLUSIONS: Increased homicide rates in Mexico were associated with increased hospitalizations for ACS conditions in the USA, although residence in a border county was associated with decreased probability of being hospitalized for an ACS condition. Expanding access in the border region may mitigate these effects by providing alternative sources of care. PMID- 25698794 TI - Surgical treatment of a pseudoaneurysm of mitral-aortic intervalvular fibrosa: Reply. PMID- 25698795 TI - Primary malignant tumors of the heart: Outcomes of the surgical treatment. AB - BACKGROUND: Malignant cardiac tumors are rare and have an extremely poor prognosis even when complete resection is attempted. The aim of this study was to review the experience of primary malignant cardiac tumors in 2 Italian academic hospitals. METHODS: The hospital records were searched to identify patients with primary malignant cardiac tumors who underwent surgery between January 1979 and December 2012. Secondary cardiac tumors, whether metastatic or invasive, were excluded as were primary sarcomas of the great arteries. Fourteen patients selected from our institution's surgical series were identified. Eleven (78.6%) were men and 3 (21.4%) were women, and the mean age at surgery was 47.4 years. RESULTS: The most common histological type was angiosarcoma (28.6%). The mean survival was 28.8 +/- 28 months and it was better in men than in women (30.5 +/- 8.7 vs. 21.1 +/- 3.2 months). Patients with a radical resection at the first surgery had a longer survival compared to patients with a partial resection (39.9 +/- 23.2 vs. 24 +/- 4 months). CONCLUSIONS: The treatment outcome for patients affected by primary malignant heart tumors remains poor. Aggressive surgery alone does not provide good results in terms of survival rate. A new multidisciplinary approach is mandatory to improve long-term survival. PMID- 25698796 TI - Coronary ostial compromise in aortic valve replacement: an avoidable complication. AB - BACKGROUND: We sought to determine the incidence of hospital death due to surgical compromise of the coronary ostia in aortic valve replacement. The mechanism of coronary ostium blockage was also investigated. METHODS: A retrospective review was conducted of prospectively collected clinical data and autopsy findings in 322 patients who died in hospital after aortic valve replacement with or without concomitant procedures in a single institution from January 1998 to March 2013. RESULTS: Over the 15-year period, more than 17 surgeons performed 7507 aortic valve replacements with or without other procedures. The mean age of the patients was 70.8 +/- 11.78 years and 63% were male. Bioprosthetic valves were used in 75%, mechanical valves in 24.7%, and homografts in only 0.3%. Early mortality for all patients (combined, emergency, and redo procedures) was 4.29% (mean logistic EuroSCORE 10.7). There were 322 deaths after procedures involving the aortic valve. Autopsy examinations were carried out in all patients and showed that 3.4% (n = 11) of deaths were at least partly attributed to encroachment on one or both coronary ostia. Causes of ostial compromise included the valve sutures, the valve sewing ring, and the aortotomy suture line. CONCLUSIONS: Coronary ostial compromise in aortic valve replacement is a very rare but real problem occurring in at least 0.15% of aortic valve replacements and contributing to or directly causing one in every 29 aortic valve replacement deaths. Surgeons should have a high level of awareness of the risk of this rare but fatal and avoidable complication. PMID- 25698797 TI - Editorial: tendon injuries and their repair or reconstruction. PMID- 25698798 TI - Looped suture properties: implications for multistranded flexor tendon repair. AB - Multiple-strand repair techniques are commonly used to repair cut flexor tendons to achieve initial biomechanical strength. Looped sutures achieve multiple strands with fewer passes and less technical complexity. Their biomechanical performance in comparison with an equivalent repair using a single-stranded suture is uncertain. This study examined the mechanical properties of double stranded loops of 3-0 and 4-0 braided polyester (Ticron) and polypropylene monofilament (Prolene). Double loops were generally less than twice the strength of a single loop. Ticron and Prolene had the same strengths, but Ticron was stiffer. The 4-0 double loops had significantly higher stiffness than 3-0 single loops. Increasing the size of sutures had a larger relative effect on strength than using a double-stranded suture. However, a double-strand loop had a larger effect on increasing stiffness than using a single suture of a larger equivalent size. Looped suture repairs should be compared with standard techniques using a thicker single suture. PMID- 25698799 TI - Commentary on P. C. Cavadas, A. Perez-Garcia, A. Thione and C. Lorca-Garcia, single-stage reconstruction of flexor tendons with vascularized tendon transfers. PMID- 25698800 TI - Re: Pondaag W, Malessy MJA. Intercostal and pectoral nerve transfers to re innervate the biceps muscle in obstetric brachial plexus lesions. J Hand Surg Eur. 2014, 39: 647-52. PMID- 25698801 TI - Clumsiness: a complication of trapeziectomy for thumb carpometacarpal joint arthritis? PMID- 25698802 TI - Re: Goutos et al. Extravasation injuries: a review. J Hand Surg Eur. 2014, 39: 808-18. PMID- 25698803 TI - Mondor's disease: a unique cause of penile pain. AB - Superficial dorsal penile vein thrombosis (penile Mondor's disease (MD)) is a unique and reportedly uncommon condition. Many cases of penile MD are idiopathic, but it is often precipitated by trauma, sexually transmitted infections and different sexual practices, such as vigorous sexual activity and the use of sexual devices. We describe the case of a young active duty man diagnosed with a penile MD, preceded by an intense sexual activity. Once diagnosed, a supportive care was instituted, consisting of administration of non-steroidal anti inflammatory drug, temporary sexual abstinence and proper patient reassurance with complete recovery. We believe that military physicians, who care for a majority of young and sexually active adults, must be familiar with the diagnosis of penile MD and its treatment. To the best of our knowledge, this is the first case of penile MD to be reported in a military setting. PMID- 25698804 TI - Bilateral lung transplantation from a donor with previous aortic valve surgery. AB - The British Transplantation Society states that previous chest surgery in a donor constitutes a contraindication to lung retrieval. In this report, we describe a case of successful bilateral lung harvest from a donor who had previously undergone aortic valve replacement. This case highlights that isolated valve surgery can be an addition to the extended donor criteria for lung retrieval and therefore increase the number of organs available for transplantation. PMID- 25698805 TI - A failed experiment: Substitution of acute inpatient beds by sub-acute community residential beds in South Australia. PMID- 25698806 TI - Child developmental outcomes in preschool children following antidepressant exposure in pregnancy. AB - OBJECTIVE: To examine child developmental outcomes in preschool-aged children exposed to antidepressant medication in pregnancy and compare their outcomes to children not exposed. METHOD: A prospective case-controlled study of 20 children exposed to antidepressants in pregnancy and 21 unexposed controls was available from the Victorian Psychotropic Registry. Child development outcomes at 4 years of age were assessed using the Wechsler Preschool and Primary Scale of Intelligence, third edition; the Movement Assessment Battery for Children; Behaviour Rating Inventory of Executive Functioning-Preschool; and the Child Behavior Checklist (1.5-5 years). Maternal depression was assessed using the Beck Depression Inventory-II in pregnancy and at four time points across infancy and early childhood. RESULTS: Children exposed to antidepressants in pregnancy had no statistically significant differences compared to unexposed children on any of the measures of child development undertaken. There was a trend to slightly lower scores in motor development with a small effect size for two scales of the Movement Assessment Battery for Children: balance - Cohen's d=0.36; aiming and catching - Cohen's d=0.34. CONCLUSIONS: The finding of no effect on cognition and behaviour are consistent with other previous studies conducted with younger children. Likewise, the trend towards lower motor development is similar to earlier findings from this study and a number of other similar studies. Given this trend there is a need for future research that focuses on this area of development in older children using robust measures of motor development. PMID- 25698807 TI - Chronic disease health risk behaviours amongst people with a mental illness. AB - OBJECTIVE: Amongst people with a mental illness, modifiable health risk behaviours contribute substantially to increased chronic disease morbidity and mortality. This study examined the prevalence of and interest in changing such behaviours amongst community mental health service clients in Australia. METHOD: A telephone interview was undertaken with Australian community mental health service clients. Participants reported engagement in four health risk behaviours: tobacco smoking, fruit and vegetable consumption, alcohol consumption, and physical activity. Participants were classified as at risk based upon Australian national guidelines. At-risk participants were asked whether they were considering improving their health risk behaviour within the next month. The association between psychiatric diagnosis and risk, and interest in improving health risk behaviours was examined. RESULTS: Risk prevalence was highest for inadequate vegetable consumption (78.3%), followed by inadequate fruit consumption (60%), smoking (50.7%), physical inactivity (46.8%), short-term alcohol risk (40.3%) and chronic alcohol risk (35.3%). A majority of at-risk participants were considering improving their health risk behaviour for smoking, physical inactivity and inadequate fruit and vegetable consumption (65.1%, 71.1%, and 53.3%, respectively). After adjusting for demographic factors, no diagnostic categories were associated with risk for any behaviour. Those with a diagnosis of depression were more likely to be interested in quitting smoking and increasing physical activity. CONCLUSIONS: Regardless of diagnosis, a high prevalence of chronic disease health risk behaviours was identified, with many participants expressing an interest in improving these behaviours. Such findings reinforce recommendations that preventive care addressing the chronic disease risks of clients be provided routinely by mental health clinicians. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12613000693729. URL: www.anzctr.org.au/. PMID- 25698808 TI - Is Australia in the post-traumatic stress disorder petri dish? PMID- 25698809 TI - The prevalence and correlates of chronic pain and suicidality in a nationally representative sample. AB - BACKGROUND: Research suggests that people suffering from chronic pain have elevated rates of suicidality. With an ageing population, more research is essential to gain a better understanding of this association. AIMS: To document the prevalence and correlates of chronic pain and suicide, and estimate the contribution of chronic pain to suicidality. METHOD: Data from the 2007 Australian National Survey of Mental Health and Wellbeing, a nationally representative household survey on 8841 people, aged 16-85 years, was analysed. RESULTS: The odds of lifetime and past 12-month suicidality were two to three times greater in people with chronic pain. Sixty-five percent of people who attempted suicide in the past 12 months had a history of chronic pain. Chronic pain was independently associated with lifetime suicidality after controlling for demographic, mental health and substance use disorders. CONCLUSIONS: Health care professionals need to be aware of the risk of suicidality in patients with chronic pain, even in the absence of mental health problems. PMID- 25698810 TI - Suicide-related Internet use: A review. AB - OBJECTIVE: To systematically review research on how people use the Internet for suicide-related reasons and its influence on users. This review summarises the main findings and conclusions of existing work, the nature of studies that have been conducted, their strengths and limitations, and directions for future research. METHOD: An online search was conducted through PsycINFO, PubMed, Ovid MEDLINE and CINAHL databases for papers published between 1991 and 2014. Papers were included if they examined how the Internet was used for suicide-related reasons, the influence of suicide-related Internet use, and if they presented primary data, including case studies of Internet-related suicide attempts and completions. RESULTS: Findings of significant relationships between suicide related search trends and rates of suicide suggest that search trends may be useful in monitoring suicide risk in a population. Studies that examine online communications between people who are suicidal can further our understanding of individuals' suicidal experiences. While engaging in suicide-related Internet use was associated with higher levels of suicidal ideation, evidence of its influence on suicidal ideation over time was mixed. There is a lack of studies directly recruiting suicidal Internet users. Only case studies examined the influence of suicide-related Internet use on suicidal behaviours, while no studies assessed the influence of pro-suicide or suicide prevention websites. Online professional services can be useful to suicide prevention and intervention efforts, but require more work in order to demonstrate their efficacy. CONCLUSIONS: Research has shown that individuals use the Internet to search for suicide-related information and to discuss suicide-related problems with one another. However, the causal link between suicide-related Internet use and suicidal thoughts and behaviours is still unclear. More research is needed, particularly involving direct contact with Internet users, in order to understand the impact of both informal and professionally moderated suicide-related Internet use. PMID- 25698811 TI - Towards protecting the endangered discipline of psychiatry. PMID- 25698812 TI - APHA awards contracts for TB testing in England. PMID- 25698813 TI - Final call for views on revised RCVS Practice Standards Scheme. PMID- 25698814 TI - BVA urges its members to lobby their MPs before non-stun slaughter debate. PMID- 25698815 TI - EFRACom seeks clarification on badger culling in Gloucestershire. PMID- 25698816 TI - Planning ahead for PED. PMID- 25698817 TI - Plans for a review of exotic pet trade in Scotland. PMID- 25698818 TI - Vet reprimanded for failure to provide adequate care. PMID- 25698819 TI - Army targets vets in recruitment campaign. PMID- 25698820 TI - Students get to think on their feet at the 2015 AVS congress. PMID- 25698821 TI - Postcards from the front. PMID- 25698822 TI - Bibersteinia trehalosi infection in cattle and sheep. PMID- 25698823 TI - African swine fever in wild boar in Europe: a notable challenge. PMID- 25698824 TI - Award of contracts for bovine TB testing and other OV services in England. PMID- 25698825 TI - Bovine TB in the pilot badger cull zone in Gloucestershire. PMID- 25698826 TI - Finding a home in shelter medicine. PMID- 25698827 TI - Diary of a poultry intern. PMID- 25698828 TI - Electronic properties of single Ge/Si quantum dot grown by ion beam sputtering deposition. AB - The dependence of the electronic properties of a single Ge/Si quantum dot (QD) grown by the ion-beam sputtering deposition technique on growth temperature and QD diameter is investigated by conductive atomic force microscopy (CAFM). The Si Ge intermixing effect is demonstrated to be important for the current distribution of single QDs. The current staircase induced by the Coulomb blockade effect is observed at higher growth temperatures (>700 degrees C) due to the formation of an additional barrier between dislocated QDs and Si substrate for the resonant tunneling of holes. According to the proposed single-hole-tunneling model, the fact that the intermixing effect is observed to increase as the incoherent QD size decreases may explain the increase in the starting voltage of the current staircase and the decrease in the current step width. PMID- 25698830 TI - Taking transfusion forward. PMID- 25698832 TI - A short history of Camp Bastion Hospital: the two hospitals and unit deployments. PMID- 25698836 TI - What I am learning about You, Jesus. PMID- 25698835 TI - Transmission of Ebola viruses: what we know and what we do not know. AB - Available evidence demonstrates that direct patient contact and contact with infectious body fluids are the primary modes for Ebola virus transmission, but this is based on a limited number of studies. Key areas requiring further study include (i) the role of aerosol transmission (either via large droplets or small particles in the vicinity of source patients), (ii) the role of environmental contamination and fomite transmission, (iii) the degree to which minimally or mildly ill persons transmit infection, (iv) how long clinically relevant infectiousness persists, (v) the role that "superspreading events" may play in driving transmission dynamics, (vi) whether strain differences or repeated serial passage in outbreak settings can impact virus transmission, and (vii) what role sylvatic or domestic animals could play in outbreak propagation, particularly during major epidemics such as the 2013-2015 West Africa situation. In this review, we address what we know and what we do not know about Ebola virus transmission. We also hypothesize that Ebola viruses have the potential to be respiratory pathogens with primary respiratory spread. PMID- 25698837 TI - The harmonious relationship between faith and science from the perspective of some great saints: A brief comment. AB - The objective of this editorial is to show that a harmonious relationship between science and faith is possible, as exemplified by great saints of the Catholic Church. It begins with the definitions of science and faith, followed by an explanation of the apparent conflict between them. A few saints that constitute an example that a fruitful relationship between these two seemingly opposed realities has been possible are Saint Albert the Great, Saint John of the Cross, Saint Giuseppe Moscati, and Saint Edith Stein, among others, and this editorial highlights their deep contributions to the dialogue between faith and reason. This editorial ends with a brief discussion on whether it is possible to be both a scientist and a man of faith. PMID- 25698838 TI - Lourdes: A uniquely Catholic approach to medicine. AB - As an American medical student, I spent the summer break between my first and second year in Lourdes, France, the site where the Immaculate Conception appeared eighteen times to St. Bernadette in 1858 as proclaimed approved by the Catholic Church and whose water is associated with over seven thousand unexplained cures. During this time I volunteered with St. Joseph's Service and Poste Secour, followed several medical teams taking care of large pilgrim groups, and shadowed Dr. Alessandro de Franciscis the president of Le Bureau des Constations Medicales, the office in Lourdes charged with investigating claims of miracles. Through my experiences, I found the mission of medicine in Lourdes to be twofold: to provide the critical care needed to give sick persons the chance to transform their experience of disease through their faith; and secondly, through the efforts of the Medical Bureau, to be an instrument by which we can comprehend the wonders of the work of God. I conclude that this twofold mission should inform the work of every Catholic in health care or research, and Lourdes provides the venue par excellence to cultivate this mission. Lay Summary: Lourdes is a pilgrimage site in southern France that has been associated with medical miracles for the past 150 years. The site is unique in that throughout its history, physicians, of any or no faith, have been invited to participate in the proceedings of the investigations of each claimed cure. The investigations have formalized into a process handled by the Lourdes Medical Bureau and the Lourdes International Medical Association. Travis Dichoso, an American medical student, writes about his experiences as part of this process. PMID- 25698839 TI - Formation of a Catholic physician. PMID- 25698840 TI - Mechanism of action of levonorgestrel emergency contraception. AB - There has been much debate regarding levonorgestrel emergency contraception's (LNG-EC's) method of action since 1999 when the Food and Drug Administration first approved its use. Proponents of LNG-EC have argued that they have moral certitude that LNG-EC works via a non-abortifacient mechanism of action, and claim that all the major scientific and medical data consistently support this hypothesis. However, newer medical data serve to undermine the consistency of the non-abortifacient hypothesis and instead support the hypothesis that preovulatory administration of LNG-EC has significant potential to work via abortion. The implications of the newer data have important ramifications for medical personnel, patients, and both Catholic and non-Catholic emergency room protocols. In the future, technology such as the use of early pregnancy factor may have the potential to quantify how frequently preovulatory LNG-EC works via abortion. Lay Summary: How Plan B (levonorgestrel emergency contraception) works has been vigorously debated ever since the Food and Drug Administration approved it in 1999. Many doctors and researchers claim that it has either no-or at most-an extremely small chance of working via abortion. However, the latest scientific and medical evidence now demonstrates that levonorgestrel emergency contraception theoretically works via abortion quite often. The implications of the newer data have important ramifications for medical personnel, patients, and both Catholic and non-Catholic emergency room rape protocols. PMID- 25698841 TI - Embryo adoption: Some further considerations. AB - Recent discussions of embryo adoption have sought to make sense of the teaching of the Congregation for the Doctrine of the Faith (CDF) document Dignitas personae which appeared to provide a negative judgment on such a practice. This article aims to provide a personalist account of the process of fertilization and implantation that might serve as the basis for the negative judgment of the CDF document. In doing so, it relies upon the idea that a person, including an embryo, is not to be considered in isolation, but always in relation to God and to others. This approach extends the substantialist conceptualizations commonly employed in discussions of this issue. More generally, the article seeks to highlight the value of a personalist re-framing for an understanding of the moral questions surrounding the beginning of life. Lay summary: This article seeks to make sense of what appears to be a clear-cut rejection, set out in the Congregation for the Doctrine of the Faith (CDF) document Dignitas personae, of the proposal for women to "adopt" surplus frozen embryos. It draws upon more recently developed modes of philosophical/theological reasoning to argue that, in human procreation, both fertilization and implantation represent constitutive dimensions of divine creative activity and so must be protected from manipulative technological intervention. Since embryo adoption requires this kind of technology, it makes sense for the Church document not to approve it. PMID- 25698842 TI - A template for non-religious-based discussions against euthanasia. AB - We submit this manuscript as part of the ongoing conversation in society at large about physician-assisted death (PAD) and euthanasia. This outlines an approach used by lay healthcare professionals in arguing against PAD/euthanasia during a 1 hour debate conducted on a secular medical school campus. We have included the elements chosen for the "con" side of the argument (i.e., against PAD) by the medical students and attending physician. The goal of this manuscript is to provide a focused and pithy template upon which to build an approach that honors the dignity of life in all circumstances. Lay summary: The discussion over physician assisted death and euthanasia remains ongoing in secular academic medical institutions across the United States and much of the western world. These debates have incentivized efforts to develop a framework for arguments against Euthanasia that will find traction in an environment generally hostile to religion and religious thought. In this essay, we present arguments given by the "con" side in a student-led debate over physician assisted death and euthanasia at Vanderbilt University with the hope that they will provide a foundation for future discussions promoting truth and life without alienating our secular colleagues. PMID- 25698843 TI - An unusual recovery from traumatic brain injury in a young man. AB - CONTEXT: Traumatic brain injury (TBI), a complex neurological traumatic incident where brain function is disrupted due to physical trauma, can be categorized in multiple ways and is commonly scored using the Glasgow Coma Scale. Severe closed head injury is a form of TBI with a Glasgow Coma Scale less than 8. The outcomes and prognosis are not uniform in the population but mortality is estimated at 30 50 percent. In this case of severe closed head injury, the patient was able to make a near full recovery after several neurosurgery and medical treatments and intercessory prayer to Saint Luigi Guanella. FINDINGS: A 21-year-old male patient received a severe closed head TBI and bilateral hemotympanum while rollerblading without a helmet. After imaging, a left frontal craniotomy and evacuation of epidural and subdural hematomas and resection of a left frontal contusion were performed. Intracranial pressure increased and the patient experienced a transtentorial herniation. He underwent a right frontotemporal and subtemporal craniectomy and evacuation of a frontotemporal subdural hematoma. The patient had intraventricular hemorrhage to which a ventriculostomy was performed and later converted to a ventriculo-peritoneal shunt for recurrent hydrocephalus. The patient was not expected to regain consciousness, but made a recovery after 24 days in the hospital and 10 days in rehabilitation. The patient followed up 6 months after injury for a cranioplasty and soon after returned to near baseline. CONCLUSIONS/CLINICAL RELEVANCE: In this extraordinary case, the severe closed head injury the patient sustained required intensive neurosurgical and medical treatment and the prognosis for recovery of consciousness was very poor; however, with treatment and rehabilitation and intercessory prayer to Saint Luigi Guanella, this patient was able to recover close to baseline from a Glasgow Coma Scale of 7. LAY SUMMARY: Head injuries vary in severity and traumatic brain injuries can be extremely serious leading to bleeding, loss of consciousness, and can affect verbal responses, muscles movement in motor responses, and responses with eye movement. Traumatic brain injuries require medical care to assess the severity and treat the injury. In this case report, we discuss a patient's very severe closed head injury while rollerblading without a helmet from which he was not expected to make a full recovery, but did so following intensive medical treatment, rehabilitation, and intercessory prayer to Saint Don Guanella to combat the initial injury and subsequent issues. PMID- 25698844 TI - Current Medical ResearchWinter/Spring 2014. PMID- 25698845 TI - A facile synthesis of bispyrroloquinone and bispyrroloiminoquinone ring system of marine alkaloids. AB - Bispyrroloquinone and bispyrroloiminoquinone are two important polycyclic ring systems present in biologically active marine alkaloids such as Zyzzyanones, tsitsikammamines and wakayin. A facile synthesis of these two ring systems starting from a 6-benzylamino indole-4,7-quinone or 6-benzylamino pyrroloiminoquinone is described here. This chemistry involves the construction of a pyrrole ring in a single step by treatment of the starting reagents with ethyl acetoacetate or phenylbutane-1,3-dione in the presence of ceric ammonium nitrate in MeOH/CH2Cl2 solvent. PMID- 25698846 TI - Comparing Greek-Affiliated Students and Student Athletes: An Examination of the Behavior-Intention Link, Reasons for Drinking, and Alcohol-Related Consequences. AB - While affiliation with Greek fraternities/sororities and intercollegiate athletic teams is associated with heavier drinking (Meilman et al., 1999), few studies have compared reasons for drinking among these groups. A sample of 1,541 students, identifying as either Greeks or athletes, completed an online survey. Athletes were significantly higher than Greeks on conformity reason for drinking. Tests of independent correlations indicated the magnitude of the past behavior to intention link was considerably stronger for Greeks. Greeks experienced significantly more social problems from drinking. Several group by gender ANOVA models found significant main effects with highest drinking rates, usually among Greek males, and lowest among female athletes. Understanding these specific group differences informs recommendations for group-specific and tailored educational interventions, which are discussed. PMID- 25698847 TI - Cell Permeable Au@ZnMoS4 Core-Shell Nanoparticles: Towards a Novel Cellular Copper Detoxifying Drug for Wilson's Disease. AB - A layer-by-layer self-assembly method leads to the formation of Au@ZnMoS4 core shell nanoparticles (NPs). The PEGylated Au@ZnMoS4 NPs are highly water dispersible, exhibit no cytotoxicity and can penetrate the cell membrane to selectively remove copper(I) ions from HepG2 cells in the presence of other endogenous and biologically essential metal ions including Mg(II), Ca(II), Mn(II) and Fe(II), demonstrating their potential as a novel intracellular copper detoxifying agent. PMID- 25698848 TI - ALADYN - a spatially explicit, allelic model for simulating adaptive dynamics. AB - ALADYN is a freely available cross-platform C++ modeling framework for stochastic simulation of joint allelic and demographic dynamics of spatially-structured populations. Juvenile survival is linked to the degree of match between an individual's phenotype and the local phenotypic optimum. There is considerable flexibility provided for the demography of the considered species and the genetic architecture of the traits under selection. ALADYN facilitates the investigation of adaptive processes to spatially and/or temporally changing conditions and the resulting niche and range dynamics. To our knowledge ALADYN is so far the only model that allows a continuous resolution of individuals' locations in a spatially explicit landscape together with the associated patterns of selection. PMID- 25698850 TI - Breeding strategies for tick resistance in tropical cattle: a sustainable approach for tick control. AB - About 80 % of world cattle population is under the risk of ticks and tick borne diseases (TTBDs). Losses caused by bovine tick burdens in tropical countries have a tremendous economic impact on production systems. Chemical control of disease has been found to be ineffective and also involving large cost. To reduce our reliance on these chemical products, it is necessary to embark on programs that include habitat management, genetic selection of hosts, and development of a strain capable of inducing host resistance to ticks. Selection for disease resistance provide alternate method for sustainable control of TTBDs. Domestic livestock manifests tick-resistance by skin thickness, coat type, coat color, hair density and skin secretions etc. Zebu cattle have, on average, greater tick resistance than either European cattle or African cattle. Heritability for tick burden in cattle has been shown to range about 0.30, which is sufficient to result in the success of some programs of selection for tick resistance in cattle. To select animals at younger age, to reduce generation interval and to increase genetic gain, marker assisted selection is an important tool. There are also various MHC molecules which are associated with resistance to TTBDs. PMID- 25698849 TI - NLRP3 inflammasome: activation and regulation in age-related macular degeneration. AB - Age-related macular degeneration (AMD) is the leading cause of legal blindness in the elderly in industrialized countries. AMD is a multifactorial disease influenced by both genetic and environmental risk factors. Progression of AMD is characterized by an increase in the number and size of drusen, extracellular deposits, which accumulate between the retinal pigment epithelium (RPE) and Bruch's membrane (BM) in outer retina. The major pathways associated with its pathogenesis include oxidative stress and inflammation in the early stages of AMD. Little is known about the interactions among these mechanisms that drive the transition from early to late stages of AMD, such as geographic atrophy (GA) or choroidal neovascularization (CNV). As part of the innate immune system, inflammasome activation has been identified in RPE cells and proposed to be a causal factor for RPE dysfunction and degeneration. Here, we will first review the classic model of inflammasome activation, then discuss the potentials of AMD related factors to activate the inflammasome in both nonocular immune cells and RPE cells, and finally introduce several novel mechanisms for regulating the inflammasome activity. PMID- 25698851 TI - Intestinal parasitic infection among Egyptian children with chronic liver diseases. AB - Patients with chronic liver diseases (CLD) are often highly susceptible to parasitic infection due to a depressed immune system. The objective of this study was to detect the most commonly intestinal parasites found among Egyptian children with CLD. The present study was conducted on 50 children with CLD of different etiology (25 were having different intestinal symptoms, 25 without intestinal symptoms) and 50 non-CLD children with gastrointestinal complaints served as controls. All cases were subjected to stool examination and investigated by liver function tests. Also, anthropometric measurements were taken for all children including weight and height. It was found that the most commonly intestinal protozoa identified in the patients with CLD in order of frequency were: Entamoeba histolytica/Entamoeba dispar (16 %), Giardia lamblia (14 %), Blastocystis hominis (14 %), Cryptosporidium parvum (10 %), E. histolytica and G. lamblia (2 %), E. histolytica and B. hominis (2 %), G. lamblia and B. hominis (2 %), B. hominis and Entamoeba coli (2 %), Microsporidium (2 %) and no cases were found infected with Strongyloides stercoralis. As compared to the controls, the observed incidence of these organisms in CLD patients was significantly higher (p < 0.045) as regards stool examination by unstained techniques while, there was no significant difference between both groups as regards stool examination by stained techniques (p < 0.478). In addition, this study showed that the weight and height of studied patients were affected by parasitic infection while, there was no significant correlation between parasitic infection and liver function tests. In conclusion, chronic liver diseases affect the immunity of the patients as shown in significant increase in the incidence of intestinal parasites in cases compared to controls. PMID- 25698852 TI - Seroprevalence of toxoplasmosis in mentally retarded patients in Iranian rehabilitation centers. AB - Toxoplasma gondii is one of the most common causes of latent infections in humans and animals. Although T. gondii infection is widely prevalent in the world, most acquired cases of the disease are asymptomatic. The important aspect of this parasitic infection is the probable danger of congenital transmission and its severe effects on the fetus. There have been many reports about the prevalence of anti-T. gondii antibody among different groups of people in Iran; however the epidemiological data in mentally retarded patients are rare. The present study was conducted on 158 mentally retarded persons (94 males, 64 females) in the rehabilitation centers of Khoramabad from autumn 2012 to winter 2013. The overall prevalence of anti-T. gondii antibody was 30.4 % (48 cases). There were no significant difference between sex and toxoplasmosis (p > 0.05). However, there were no statistically significant difference between age and toxoplasmosis, nevertheless the prevalence of toxoplasmosis in the patients less than 10-years old had significantly the lowest rate. The highest infection rates were found in the two age groups of 10-19 and >=30 years old. Our results showed that the prevalence of toxoplasmosis in the mentally retarded persons in the rehabilitation centers of Khorramabad was similar to the prevalence in pregnant women in this city. Therefore, the disease does not cause additional danger to this group of women. PMID- 25698853 TI - In vitro antileishmanial activity of methanolic and aqueous extracts of Eucalyptus camaldulensis against Leishmania major. AB - Pentavalent antimony compounds are expensive, toxic and drug resistance is prevalent, whereas the plant extract derivatives are safe. In the present study, the effect of methanolic and aqueous extracts of Eucalyptus camaldulensis on the promastigotes of Leishmania major was evaluated. The methanolic and aqueous extracts of E. camaldulensis leaves were prepared. The compounds were dried and powdered. Serial dilutions of the extracts and control drugs in phosphate buffer solution were prepared. The stationary phase promastigotes of L. major were incubated to the methanolic and aqueous extractions in vitro. Tartar emetic was used as the positive control drug. After 72 h of incubation the activity of the extracts was measured, using MTT method. The IC50 values (50 % inhibitory concentration) were 586.2 +/- 47.6 and 1,108.6 +/- 51.9 MUg/ml for methanolic and aqueous extracts, respectively, whereas it was 32.5 +/- 6.8 MUg/ml for tartar emetic. The results indicated that the methanolic extract was more effective than aqueous extract, although there was no significant difference. The extracts were less effective as compared to the control drug. Further investigation is required to evaluate these extracts on clinical stage in macrophage-amastigote model. PMID- 25698854 TI - Gastrointestinal parasitic infections in chickens of upper gangetic plains of India with special reference to poultry coccidiosis. AB - Studies on the prevalence of gastrointestinal parasites of chicken reared under backyard and intensive systems were carried out in two north Indian states viz., Uttar Pradesh and Uttarakhand. Out of 58 poultry farms screened for gastrointestinal parasites, 81.03 % were positive for Eimeria spp., 15.52 % for Ascaridia galli, 3.45 % for Hetarakis gallinarum, 1.72 % for Syngamus trachea, 5.17 % for Capillaria spp, 1.72 % for Raillietina spp., 1.72 % for Trichostrongylus tenuis, 1.72 % for Choanotaenia infundibulum and 1.72 % for Strongyloides avium. In broiler farms, the prevalence of Eimeria spp. was higher (88.24 %) as compared to layer farms (71.43 %) and backyard poultry (70 %). Identification of Eimeria spp. using COCCIMORPH software revealed prevalence of E. acervulina, E. tenella, E. necatrix, E. mitis and E. praecox in 94.3, 17.14, 31.44, 85.7 and 2.86 % farms, respectively. However, E. maxima and E. brunetti could not be identified in any of the farms using this software. The prevalence of helminthic infections was higher in poultry farms of Uttarakhand (40.0 %) as compared to Uttar Pradesh (11.62 %) with higher prevalence in backyard poultry (36.4 %), followed by layer farms (28.6 %) and lowest in broiler farms (9.1 %). A. galli was the most common G.I. helminth and it was recorded in free-range (backyard poultry) as well as intensive systems (broiler and layer farms). PMID- 25698855 TI - Genetic characterization of Fasciola gigantica from different geographical regions of India by ribosomal DNA markers. AB - Ribosomal DNA sequences of the second internal transcribed spacer (ITS-2) and 28S ribosomal DNA (618 bp) of Fasciola gigantica collected from cattle and buffaloes from four different geographical locations of India, were characterized for genotyping. ITS-2 sequence was analyzed in 28 worms that was typical of F. gigantica and differed at six positions, with one of these being a distinguishing deletion (T) at the 327th position in F. gigantica relative to F. hepatica. However, Fasciola specimens also showed intraspecies sequence polymorphism in the ITS-2, with two different ITS-2 sequences existing in the ribosomal DNA (rDNA) array within a single Fasciola worm. One of the sequences was identical to that of F. gigantica and the other showed extensive sequence polymorphism in the ITS 2. Using BspH1-restriction fragment length polymorphism, six variable ITS-2 sequences in F. gigantica were identified within these parasite specimens and were found distributed in these four geographical regions. 28S rDNA sequence of 24 flukes, collected from the above four geographical regions, showed a single nucleotide polymorphism at 284th nucleotide (G/A). Analyzing the sequence data of 28S rDNA of F. gigantica available from some African and Asian countries for this polymorphic 284th nucleotide position, it is proposed that there are two basic lineages of the F. gigantica for 28S rDNA existing in the fluke populations from five African and several Asian countries. PMID- 25698856 TI - First occurrence of Norileca triangulata (Crustacea: Isopoda: Cymothoidae) from Indian marine fishes. AB - An ectoparasitic isopod, Norileca triangulata was found in the branchial cavity of Sardinella gibbosa at Parangipettai coastal waters. The present findings represent the first record of N. triangulata and herein reported. Until now, this species was distributed from Tanimdao Island, Philippines and from Queensland-Eel Reef, Cape York; Michaelmas Cay, near Cairns and Mooloobah, south-eastern Queensland. The range is here extended and now includes to the Southeast coast of India. The materials examined were deposited at the Annamalai University, India (collection Ravichandran). The parasites has been found on 16 out of 16 specimens of S. gibbosa. The prevalence of N. triangulata on S. gibbosa was 7.5 % and mean intensity was 1. The host fish length ranges from 140 to 182 mm. It is further confirmed that the parasites were specific in the selection of host S. gibbosa. Previously N. triangulata was reported from two hosts Parexocoetus brachypterus. Females of N. triangulata ranges 12-18 mm but not found in males. As summarized comparative characteristic feature of two species of parasitic isopods of Norileca indica and N. triangulata. Host species were captured on pelagic region from the coast of Parangipettai. N. triangulata can be distinguished from N. indica by several characters. A related species N. indica has the head to the anterior, and the abdomen facing outwards, pressed against the gill operculum, positioned ventrally in the gill cavity. PMID- 25698857 TI - Prevalence of ixodid ticks on cattle, sheep and goats in Ilam County, Ilam Province, Iran. AB - This survey was performed to find out the infestation rate of Ixodidae ticks in domestic ruminants in Ilam County during 21 March 2009 to 23 August 2009. Sampling was performed in 25 villages and 15 animal farm from different areas of this County. A total of 1,316 ticks were collected from 416 cattle, 208 sheep and 147 goats. The overall prevalence of ticks was recorded: 43, 23.5, and 49/6 % in cattle, sheep, and goats respectively. The number of ticks that collected from cattle, sheep, and goat were 328, 573, and 415 respectively. According to the host, Hyalomma anatolicum anatolicum (71.4 %), Hyalomma asiaticum asiaticum (17.6 %) and Rhipicephalus bursa (11 %) were collected from cattle. Hy. anatolicum (32.1 %), Rh. bursa (42.2 %), Rhipicephalus sanguineus (17.3 %) and Haemaphysalis inermis (8.4 %) were collected in sheep. Rh. bursa (41.5 %), Rh. sanguineus (43.2 %) and Ha. inermis (15.3 %) were observed in goats. In this study, ticks infestation rate of cattle, sheep and goat were (43 %), (23.5 %) and (49.6 %) respectively. In this survey the ticks distribution on the body surface of infested ruminants the highest infestation was found in the udder and tail (21 %) in cattle, ear (42.5 %) and tail (30 %) in sheep and ear (63 %) and tail (17 %) in goats. The lowest number of ticks in body surface of ruminants was observed in the ear and shoulder (2 %) in cattle, head and neck (2 %) in sheep and udder (7 %) in goats. Hy. anatolicum anatolicum, Rh. Sanguineus and Rh.bursa were dominant tick in domestic ruminants of Ilam County. PMID- 25698858 TI - Haematobiochemical parameters of goats fed tannin rich Psidium guajava and Carissa spinarum against Haemonchus contortus infection in India. AB - The antihelminthic properties of tannin-rich plants are being explored as an alternative to chemical drugs to minimise the effects of gastro intestinal nematodes (GIN). The present study was, therefore, conducted to investigate the effect of condensed tannins (CT), obtained from regional tanniferous tree leaves, in the Haemonchus contortus infected goats on the heamatobiochemical parameters to assess the goat health. Twelve adult male goats were randomly divided into three equal groups, namely negative control, infected control and treatment. H. contortus infected goats were allocated into infected control and treatment groups and their feeds contained 0 and 1.96 % of CT, respectively. Feeding trial was conducted for the duration of 90 days during which haematological and serum biochemical parameters were monitored on fortnightly basis. The animals ingesting the CT-rich leaf meal mixture had increased levels of haemoglobin, packed cell volume, total protein, globulin, glucose and calcium, and decreased levels of blood urea; indicating a beneficial effect of CT supplementation at the selected level. However, the phosphorus balance, serum albumin levels and serum enzyme activity were not affected significantly. The study revealed that inclusion of CT in the diets of the adult male goats did not pose any threat to the health of the goats. Further, the CT based diet had beneficial impact on the haematological parameters and could therefore be included in small ruminant diets to minimize the impact of GIN. PMID- 25698859 TI - Detection of amitraz resistance in Rhipicephalus (Boophilus) microplus from North Gujarat, India. AB - Amitraz has become one of the most extensively used chemical acaricide for control of cattle tick due to development of resistance against most of the organophosphates and synthetic pyrethroid acaricides. The resistance status of amitraz was evaluated against Rhipicephalus (Boophilus) microplus collected from Banaskantha district, Gujarat, India by adult immersion test (AIT). The different concentrations of amitraz utilized in the AIT were 125, 250, 500, 750 and 1,000 ppm. The adult female ticks showed an upward trend in the mortality percentage with increase in drug concentration. The regression graph of probit mortality of ticks plotted against log values of progressively increasing concentrations of amitraz was utilized for the determination of slope of mortality which was 1.868 +/- 0.2068. The lethal concentration (LC95) was calculated as 3098.2 ppm and the RF was 24.78 which indicated level II resistance status. The dose response curves for egg masses, reproductive index and inhibition of oviposition of R. (B.) microplus were also validated and the slope was -0.5165 +/- 0.08287, -0.1328 +/- 0.04472 and 24.22 +/- 8.160, respectively. The current study appears to be the pioneer report of amitraz resistance in R. (B.) microplus from India and the data generated could be of immense help to develop effective control strategies against ticks. PMID- 25698860 TI - Detection of tropical bovine theileriosis by polymerase chain reaction in cattle. AB - Tropical bovine theileriosis, a tick borne disease, caused by, Theileria annulata with marked clinical signs of pyrexia (102-105 degrees F), enlargement of lymphnodes etc., causes heavy economic losses in terms of high mortality and morbidity rates. Diagnosis of theileriosis is mainly based on clinical symptoms and microscopic examination of stained blood smears and lymph node biopsy smears but limitations of these methods against Theileria sp. limits the specificity. Hence, to overcome the limitations, the present study reports the detection of T. annulata in blood samples of cattle by polymerase chain reaction. The study was conducted on 155 cattle having typical clinical symptoms and blood smear after staining with Giemsa stain was examined for the presence of T. annulata in RBC. The Primer sequences were used as per d'Oliveira et al. The assay employs primers specific for the gene encoding the 30-kDa major merozoite surface antigen of T. annulata and the amplification of 721 bp was done. Out of the total 155 animals, 34 were positive for T. annulata by blood smear method whereas 134 samples were positive by PCR. So diagnosis of blood samples by PCR is found to be the most sensitive and specific methodology as compared to cytological blood smear examination. The sensitivity was 23.88 % and specificity was 90.47 % of blood smear method considering PCR as gold standard and it was found that PCR is more sensitive than the conventional method of examination. PMID- 25698861 TI - Prevalence of Theileria annulata infection in Hyalomma anatolicum anatolicum collected from crossbred cattle of Ludhiana, Punjab. AB - The prevalence of Theileria infection in tick vector Hyalomma anatolicum anatolicum collected from healthy animals of Ludhiana district, Punjab was recorded to assess the natural infection level of theilerial parasite in the field condition. A total of 60 semi-engorged H. a. anatolicum were collected from cattle and their salivary glands were dissected out. One half of the salivary gland was stained with methyl green pyronin (MGP) and the other half was utilized for DNA isolation for molecular detection of Theileria infection. A PCR and nested PCR assays were standardized for the detection of T. annulata infection in salivary gland of H. a. anatolicum. The prevalence of T. annulata infection was recorded as 8.3, 20.0 and 60.0 % by MGP staining, primary PCR and nested PCR, respectively. Further, the prevalence was higher in female ticks (8.8 %) than male ticks (6.6 %). The results demonstrated that both primary and nested PCR assays are a valuable technique for detection of T. annulata infection in vector tick under field conditions. PMID- 25698862 TI - In vitro ovicidal assessment of methanol, ethyl acetate and chloroform extracts of Annona squamosa and Chenopodium album against caprine gastrointestinal nematodiosis. AB - The objective of this study was in vitro evaluation of the ovicidal efficacy of methanol, ethyl acetate and chloroform extracts of Annona squamosa (seeds) and Chenopodium album (whole plant) in comparison to albendazole against the GI nematodes of goats using egg hatch test. Eggs of GI nematodes were incubated at 27 degrees C in different extracts at concentration of 100-6.25 mg/ml for 2 days. Distilled water and albendazole were used as negative and positive controls, respectively. Percentage efficacy and ED50 and ED90 values were separately evaluated with upper and lower confidence limit by log probit analysis using SAS 9.2. The ED50 and ED90 values of methanolic, ethyl acetate and chloroform extracts of A. squamosa was calculated as 1.52 and 4.56; 2.48 and 10.73; 3.02 and 12.44 mg/ml, respectively against GI nematodes if goats. Similarly, the ED50 and ED90 values of methanolic, ethyl acetate and chloroform extracts of C. album was calculated as 3.86 and 7.14; 2.73 and 8.31; 4.41 and 20.11 mg/ml, respectively This study shows that C. album and A. squamosa possess in vitro anthelmintic activities. The study also suggests further large scale pharmacological and toxicological studies for their safer use in veterinary medicine. PMID- 25698863 TI - Lipid and fatty acid compositions of a trematode, Isoparorchis hypselobagri Billet, 1898 (Digenea: Isoparorchiidae) infecting swim bladder of Wallago attu in the district North 24-Parganas of West Bengal. AB - Lipid classes and fatty acid compositions of a digenetic trematode, Isoparorchis hypselobagri inhabiting swim bladder of Wallago attu were analyzed by TLC and GLC. The total lipid (TL) and percent content of neutral lipid (NL, 61.59), glycolipid (GL, 19.78) and phospholipid (PL, 18.62) were recorded. The total lipid is 3.81 % of the wet weight of the body tissue. The total percent of saturates, monoenes, dienes and polyenes in TL, NL, GL, and PL of the parasite were 52.0, 49.7, 57.9, 61.5; 31.7, 31.8, 33.1, 26.3; 5.7, 5.7, 4.7, 4.2; as well as 10.33, 12.6, 4.3, 7.4 respectively. Diunsaturated fatty acids were present in low amount. Palmitic 16:0 (among all saturates) and oleic 18:1omega9 (among all unsaturates) acids were the predominant fatty acids in the parasite recorded. PMID- 25698864 TI - Dipylidium caninum infection in dogs infested with fleas. AB - The present study pertains to the Dipylidium caninum infection in dogs infested with fleas. Twenty dogs were presented to the Divison of Surgery, SKUAST-K for different surgical procedures. Majority of the dogs had a history of pruritus, loss of weight as well as rubbing their perineal region against the wall. On external examination dogs were found infested with Ctenocephalides canis. When dogs were anesthetized, motile segments were seen coming out of their anus, which were then identified as mature segments of D. caninum. PMID- 25698865 TI - Variability of resistance in Black Bengal goats naturally infected with Haemonchus contortus. AB - A total 290 Black Bengal goats (6 buck, 109 doe and 175 kids born from 11 sires) were studied to evaluate the variability of resistance in Black Bengal goats naturally infected with Haemonchus contortus. The variability of resistance in Black Bengal goat was studied for both genetic and non-genetic factors like village, sex, age dam, sire, dam resistance group and offspring resistance group. Male kids have slightly higher resistance than female kids although it was not significant. Resistance of kids was increased as age increases and kid population showed significantly different resistance status among the offspring resistant groups. The doe population showed significantly different LEPG as per the resistance group in all the collections. The present study found that the resistance of kids under sire were varied significantly and observed that the kids under sire 1, 6-8 were significantly more resistant than the kids of the sire 2, 5 and 11 in 3rd collection and it is also noticed that maternal genetic effect has a very little impact on resistance of kids. Males (buck) were most resistant and the kids were least resistant and the resistance of dam was in between the male and kids population. PMID- 25698866 TI - Prevalence and morphological characterisation of Cysticercus tenuicollis (Taenia hydatigena cysts) in sheep and goat from north India. AB - Taenia hydatigena is an adult parasite of dogs with the metacestode (Cysticercus tenuicollis) stage residing in ruminants and pigs. Documentation and surveillance data concerning to the prevalence and risk factors associated with the disease in India is largely lacking. In this experiment, 3,199 carcasses, including 760 sheep and 2,439 goat were examined for the presence of C. tenuicollis (T. hydatigena cysts) on post-mortem inspection at different slaughter houses/shops in northern India. Morphological analysis was also conducted on five samples from each species. Out of 3199 carcasses examined, 135 were found containing cysts of T. hydatigena indicating a prevalence of 4.22 %. Most of the cysts were present in abdominal cavity, except few which were embedded in the liver. The high prevalence of 4.83 was recorded in goats as compared to 2.23 % in sheep. Principal component analysis was applied for statistical analysis. The results of morphological analysis indicated its usefulness as a valid criterion for differentiation of T. hydatigena cysts and that there might be possibility of two different strains infecting sheep and goat. PMID- 25698867 TI - Prevalence of poultry coccidiosis in Jammu region of Jammu & Kashmir State. AB - In this study prevalence of chicken coccidiosis in Jammu division were undertaken in both organized and backyard chickens during the year 2010-2011, with an overall prevalence of 39.58 % on examination of 720 faecal samples. Five Eimeria species were identified viz., E. tenella, E. necatrix, E. maxima, E. acervulina and E. mitis. E. tenella was the predominant species in both organized and unorganized farms. The highest prevalence percentage was found in July, 2011 (68.9 %) and the lowest percentage was found in May, 2011 (12.5 %). Coccidial prevalence was found to be 53.61 % in unorganized (backyard poultry birds) as compared to organized birds (25.55 %). Maximum positive cases of coccidian infection was found in monsoon season (60.55 %) and least in summer season (21.66 %). Birds of age 31-45 days showed more prevalence percentage (58.86 %). Higher oocysts count was recorded from July to September with a peak value (38973.00 +/- 3075.6) in July and lowest (12914.00 +/- 595.48) in the month of May. PMID- 25698868 TI - Assessment of cell mediated immune response in rabbits immunized with affinity purified 35 kDa midgut antigen of Rhipicephalus haemaphysaloides ticks. AB - Cell mediated immune response to immunoaffinity chromatography purified midgut antigen of Rhipicephalus haemaphysaloides ticks in rabbits was studied by using lymphocyte transformation test. This test was carried out by using 5-bromo-2' deoxy-uridine kit method. The blastogenic response of peripheral blood lymphocytes of normal rabbit to different concentrations of antigen and mitogen (Con A) showed that 2 MUg of antigen and 2 MUg of mitogen gave maximum stimulation index. The antigen specific responsiveness of immunized rabbits with affinity purified 35 kDa midgut antigen was highly significant (P <= 0.01) compared to mitogen. The maximum lymphocyte stimulation index (LSI) of 2.47 was observed on 49 day post immunization in immunized group. The lymphocytes separated from control animal cultured in RPMI1640 medium with 2 MUg of antigen and 2 MUg of mitogen (Con A) were never stimulated and their LSI values were below 2.0. PMID- 25698869 TI - Functional dynamics observations of haptoral armature in Mizelleus indicus (Jain 1957) Pandey et al. 2003. AB - The negative effect of monogenea on piscine host may vary in the host species. Genus Mizelleus (Monogenea: Ancyrocephalidae) was reported for the first time from the freshwater shark, Wallago attu (Bl. and Schn.) at Lucknow by Jain (1957). Haptor or opisthohaptor of monogenea which is more or less discoid muscular structure situated posteriorly, is the chief adhesive organ. It is usually provided with anchors and marginal hooklets. Anchors, ventral transverse bar, together with the additional supporting dorsal bars (patches) are active elements of haptor while, marginal hooklets serve as secondary supportive participants, whereas, the dorsal transverse bar can be treated as an inactive element in the whole organ of attachment. Functional dynamics detail of haptoral armature is almost unattended. The anchors in case of M. indicus (Jain 1957) Pandey et al. (2003) are disposed one against the other and used to act like four lobed grapnel like a spreader. All components of haptoral armature contribute in one way or another in the process of functional process. Interestingly the worms do not follow the same pattern of sequences during their movements. Various elements and factors are involved in the process. The authors tried to pinpoint the changes in the activity of one major element i.e., dorsal anchor. The movement and change in position/orientation of various elements with reference to dorsal anchors were observed and summarized. Present paper is rare effort in unexplored aspect in monogenea biology. PMID- 25698870 TI - Prevalence and pathological study of Paramphistomum infection in the small intestine of slaughtered ovine. AB - Paramphistomiasis, a trematode infectious disease in ruminants, has been neglected but has recently emerged as an important cause of productivity loss. The small intestine of slaughtered sheep was collected weekly from abattoirs (Kermanshah, Sanandaj, Tabriz and Urmia Slaughterhouses) to monitoring the seasonal occurrence of Paramphistomosis, 2,421 sheep carcasses (743 male (30.69 %) and 1,678 female (69.31 %)) were examined, out of which 0.041 % were positive for Paramphistomum infestation. Furthermore, upon evaluation Paramphistomum termatodes, Gastrothylax crumenifer and Cotylophoron detected as well. Overall, the small intestinal infestation by such parasite was 0.041 % which contained hyperemia, severe congestion and haemorrhage. The highest infection in the sheep infected with Paramphistomum spp. was found during the summer (July to August) (6.7, 2 %) and followed by the autumn seasons (November to October) (3.8, 2.3 %). Microscopic study of the small intestine revealed dilatation of intestinal glands, destruction of superficial glands, replacement of fibrin, diffuse infiltration of inflammatory cells and fibrinonecrotic enteritis. Other changes as congestion hemorrhage and nodules of Ostertagia were observed in total examination of small intestines. According to statistical analysis by SPSS software and Chi square test revealed that there is significant difference between pathologic changes, seasons and ecological situations of the region (p < 0.05). There was no significant difference between age, gender and sample pH of examined sheep (p > 0.05).According to the results of pathologic changes of sheep small intestines, preventive measurements in the area should be taken to decrease the damages, so applying a parasitic control program is recommended. PMID- 25698871 TI - Survival, activity and release of antigenic excretory secretory products and microfilariae of Setaria digitata maintained in artificial media. AB - The survival, activity and release of excretory secretory products from Setaria digitata, the filarial worm of cattle was studied. Adult female worms were maintained in vitro in DMEM and Tyrode solution. Worms incubated in DMEM were alive and very active for 2 days. The activity was moderate for another 2 days and after the fourth day increased mortality was observed. Antigenic excretory secretory products were also released. Worms incubated in Tyrode solution were very active without any mortality up to 4 h of incubation. Copious amount of ova and microfilaria were shed by the incubated worms in a time-dependent manner. PMID- 25698872 TI - Effect of temperature on the prevalence of different parasites in Cirrhinus mrigala Hamilton of West Bengal. AB - A study has been done to find out the prevalence of different kinds of parasites in Cirrhinus mrigala (Hamilton 1822) during 2010-2011. It has been found that the temperature variation affects some parasitic infestation over the fish species. It was found that ciliophoran and crustacean parasites are more prevalent from November to February whereas the myxozoan and monogenean parasites are more prevalent from January to April. Considering temperature variation throughout the year it has been inferred that most of the parasitic infections were found between November and April when the temperature range varies from 19 to 26 degrees C. So from the study it can be concluded that lower temperature elicits the parasitic growth in fishes while the higher temperature retards the growth. PMID- 25698873 TI - Clinico-biochemical and therapeutic studies on notoedric mange in pet rabbits. AB - Two male and two female pet rabbits of about 1 year of age, naturally infested with Notoedres cuniculi were studied in the present investigation. Clinical examination revealed presence of crustaceous lesions on the head, ear pinnae, both the limbs and external genitalia. Microscopic examination of skin scrapings confirmed presence of Notoedres mange infestation. Biochemical parameters revealed altered values of total serum protein, albumin, globulin, and activities of aspartate amino transferase, alanine amino transferase and alkaline phosphatase respectively. The affected rabbits were treated with two injections of Ivermectin (400 MUg/kg, subcutaneously, at interval of 15 days) along with supportive therapy. This treatment showed appreciable improvement in clinical signs and restoration in biochemical parameters. PMID- 25698874 TI - Occurrence of Camallanus trispinosus in a captive Indian star tortoise (Geochelone elegans). AB - Camallanoids are spirurid round worms known to occur in stomach and intestine of lower vertebrate animals such as fishes and reptiles. This paper records the occurrence of Camallanus trispinosus in a captive Indian star tortoise of Guindy snake park, Chennai, India for the first time during necropsy and identified on the basis of morphology of male and female worms, including eggs. PMID- 25698875 TI - Schistosoma spindale infection in a captive jackal (Canis aureus). AB - This report is based on the findings from a captive jackal (Canis aureus) housed in Amirthi Zoological Park, Javadu Hills, Vellore. The animal was reported to be dull, depressed and also had diarrhea. Fecal samples were collected in 10 % formalin and subjected to direct and sedimentation method of faecal examination and was examined for endoparasitic infection. Surprisingly, fecal examination revealed two spindle shaped eggs having terminal spine with a size of 250MU by 60MU. The eggs were identified as belonging to Schistosoma spindale and as per the standard keys (Soulsby 1982). PMID- 25698876 TI - A longitudinal study about the effect of practicing Yan Xin Qigong on medical care cost with medical claims data. AB - We use 7-year longitudinal medical claims data and statistical models to study the relationship between practicing Yan Xin Qigong (YXQG), a traditional advanced Chinese Qigong that has been integrated with modern science and technology, and practitioners' medical care utilization and the associated costs. We find that for the sampled practitioners, their average monthly medical visits and the associated costs are significantly lower after practicing YXQG. After controlling for other factors, the longer of practicing YXQG, the more likely there was a fall in average medical visits and medical costs. The main findings are robust to various estimation methods. PMID- 25698877 TI - Regulation of epithelial-mesenchymal transition in breast cancer cells by cell contact and adhesion. AB - Epithelial-mesenchymal transition (EMT) is a physiological program that is activated during cancer cell invasion and metastasis. We show here that EMT related processes are linked to a broad and conserved program of transcriptional alterations that are influenced by cell contact and adhesion. Using cultured human breast cancer and mouse mammary epithelial cells, we find that reduced cell density, conditions under which cell contact is reduced, leads to reduced expression of genes associated with mammary epithelial cell differentiation and increased expression of genes associated with breast cancer. We further find that treatment of cells with matrix metalloproteinase-3 (MMP-3), an inducer of EMT, interrupts a defined subset of cell contact-regulated genes, including genes encoding a variety of RNA splicing proteins known to regulate the expression of Rac1b, an activated splice isoform of Rac1 known to be a key mediator of MMP-3 induced EMT in breast, lung, and pancreas. These results provide new insights into how MMPs act in cancer progression and how loss of cell-cell interactions is a key step in the earliest stages of cancer development. PMID- 25698878 TI - Determination of Chlorophenoxy Acid Methyl Esters and Other Chlorinated Herbicides by GC High-resolution QTOFMS and Soft lonization. AB - Gas chromatography with quadrupole time-of-flight mass spectrometry (GC-QTOFMS) and soft ionization generated by a rare-gas plasma is described here for the determination of various chlorophenoxy acid methyl esters and a few chlorinated herbicides. This plasma-based, wavelength-selectable ionization source, which can use Xe, Kr, Ar, Ne, or He as the plasma gas, enables ionization of GC-amenable compounds with ionization energies below 8.4, 10, 11.6, 16.5, or 22.4 eV, respectively. The advantages of soft ionization include enhanced molecular ions, reduced fragmentation, and reduced background noise as compared to electron ionization. In the study presented here for two plasma gases, we demonstrate that Kr plasma, which is softer than Ar plasma, yields molecular ions with a relative intensity >60% for 11 of the 16 test compounds. When using this "tunable" plasma to ionize the analytes, there is the possibility for selective ionization and less fragmentation, which may lead to increased sensitivity and may help structure elucidation, especially when using high-resolution mass spectrometry that generates accurate masses within a few parts per million (ppm) mass errors. Data generated with the Ar plasma and real matrices such as a peppermint extract, a plum extract, and an orange peel extract, spiked with 16 test compounds, indicate that the test compounds can be detected at 1-10 pg/MUL of extract, and compounds such as menthone, limonene, eucalyptol, pinene, caryophylene, and other C15H24 isomers, which are present in the peppermint and the orange peel extracts at ppm to percent levels, do not appear to interfere with the determination of the chlorophenoxy acid methyl esters or the chlorinated herbicides, although there were matrix effects when the test compounds were spiked at 1-10 pg/MUL of extract. PMID- 25698879 TI - Identification and Expression Analysis of Ribosome Biogenesis Factor Co-orthologs in Solanum lycopersicum. AB - Ribosome biogenesis involves a large inventory of proteinaceous and RNA cofactors. More than 250 ribosome biogenesis factors (RBFs) have been described in yeast. These factors are involved in multiple aspects like rRNA processing, folding, and modification as well as in ribosomal protein (RP) assembly. Considering the importance of RBFs for particular developmental processes, we examined the complexity of RBF and RP (co-)orthologs by bioinformatic assignment in 14 different plant species and expression profiling in the model crop Solanum lycopersicum. Assigning (co-)orthologs to each RBF revealed that at least 25% of all predicted RBFs are encoded by more than one gene. At first we realized that the occurrence of multiple RBF co-orthologs is not globally correlated to the existence of multiple RP co-orthologs. The transcript abundance of genes coding for predicted RBFs and RPs in leaves and anthers of S. lycopersicum was determined by next generation sequencing (NGS). In combination with existing expression profiles, we can conclude that co-orthologs of RBFs by large account for a preferential function in different tissue or at distinct developmental stages. This notion is supported by the differential expression of selected RBFs during male gametophyte development. In addition, co-regulated clusters of RBF and RP coding genes have been observed. The relevance of these results is discussed. PMID- 25698880 TI - Houston's Novel Strategy to Control Hazardous Air Pollutants: A Case Study in Policy Innovation and Political Stalemate. AB - Although ambient concentrations have declined steadily over the past 30 years, Houston has recorded some of the highest levels of hazardous air pollutants in the United States. Nevertheless, federal and state regulatory efforts historically have emphasized compliance with the National Ambient Air Quality Standard for ozone, treating "air toxics" in Houston as a residual problem to be solved through application of technology-based standards. Between 2004 and 2009, Mayor Bill White and his administration challenged the well-established hierarchy of air quality management spelled out in the Clean Air Act, whereby federal and state authorities are assigned primacy over local municipalities for the purpose of designing and implementing air pollution control strategies. The White Administration believed that existing regulations were not sufficient to protect the health of Houstonians and took a diversity of both collaborative and combative policy actions to mitigate air toxic emissions from stationary sources. Opposition was substantial from a local coalition of entrenched interests satisfied with the status quo, which hindered the city's attempts to take unilateral policy actions. In the short term, the White Administration successfully raised the profile of the air toxics issue, pushed federal and state regulators to pay more attention, and induced a few polluting facilities to reduce emissions. But since White left office in 2010, air quality management in Houston has returned to the way it was before, and today there is scant evidence that his policies have had any lasting impact. PMID- 25698881 TI - Corrigendum to "effects of fibrosis morphology on reentrant ventricular tachycardia inducibility and simulation fidelity in patient-derived models". PMID- 25698882 TI - C-reactive protein and cardiovascular disease in East asians: a systematic review. AB - Elevated C-reactive protein (CRP) levels are associated with an increased risk of cardiovascular disease (CVD) in Caucasians; however, evidence is lacking for East Asians, who have low CRP levels. PubMed and Google Scholar searches were conducted (1966 through September 2014), and eight prospective studies in East Asian countries (China, Hong Kong, Japan, Korea, Macao, Mongolia, and Taiwan) that documented risk ratios of elevated CRP for CVD were included for meta analysis with random-effects models. The overall association between CRP levels and stroke was significant in six studies (risk ratio = 1.40 [95% confidence interval {CI}, 1.10-1.77], P = 0.008). The association with ischemic stroke was more evident in subgroup analyses. For coronary heart disease (CHD) and CVD, the risk ratio was 1.75 (95% CI, 0.96-3.19, P = 0.07) and 1.76 (95% CI, 1.29-2.40, P < 0.001), respectively. Although East Asians have low CRP levels, this meta analysis shows that elevated CRP levels were significantly associated with an increased risk of stroke, primarily ischemic stroke. PMID- 25698883 TI - Clinical utility of exercise training in heart failure with reduced and preserved ejection fraction. AB - Reduced exercise tolerance is an independent predictor of hospital readmission and mortality in patients with heart failure (HF). Exercise training for HF patients is well established as an adjunct therapy, and there is sufficient evidence to support the favorable role of exercise training programs for HF patients over and above the optimal medical therapy. Some of the documented benefits include improved functional capacity, quality of life (QoL), fatigue, and dyspnea. Major trials to assess exercise training in HF have, however, focused on heart failure with reduced ejection fraction (HFREF). At least half of the patients presenting with HF have heart failure with preserved ejection fraction (HFPEF) and experience similar symptoms of exercise intolerance, dyspnea, and early fatigue, and similar mortality risk and rehospitalization rates. The role of exercise training in the management of HFPEF remains less clear. This article provides a brief overview of pathophysiology of reduced exercise tolerance in HFREF and heart failure with preserved ejection fraction (HFPEF), and summarizes the evidence and mechanisms by which exercise training can improve symptoms and HF. Clinical and practical aspects of exercise training prescription are also discussed. PMID- 25698884 TI - Calibration of baroreflex equilibrium diagram based on exogenous pressor agents in chronic heart failure rats. AB - A baroreflex equilibrium diagram describes the relation between input pressure and sympathetic nerve activity (SNA) and that between SNA and arterial pressure (AP). To calibrate the SNA axis (abscissa) of the baroreflex equilibrium diagram, the AP response to intravenous bolus injections of phenylephrine (0.2-50 MUg/kg) or norepinephrine (NE, 0.02-5 MUg/kg) was examined in normal control rats (NC, n = 9) and rats with chronic heart failure (CHF, n = 6). The maximum slope of the dose-effect curve was significantly smaller in the CHF group than in the NC group (57.3 +/- 5.2 vs 80.9 +/- 6.3 mmHg/decade for phenylephrine, 60.2 +/- 7.8 vs 80.4 +/- 5.9 mmHg/decade for NE; P < 0.01). The CHF/NC ratio of the maximum slope was used to calibrate SNA. While the calibrated baroreflex equilibrium diagram showed increased maximum SNA and operating-point SNA in CHF rats compared with NC rats, the magnitude of increase was smaller than that expected from the excess plasma NE concentration in CHF rats. Plasma NE concentration in the CHF group could be disproportionally high relative to SNA. PMID- 25698885 TI - A case of tuberculous cellulitis. AB - We describe a rare case of cutaneous TB where cellulitis-like symptoms are presented. PMID- 25698886 TI - Intraperitoneal follicular dendritic cell sarcoma: role of chemotherapy and bone marrow allotransplantation in locally advanced disease? AB - We describe a case of a 44 year-old woman diagnosed with follicular dendritic cell sarcoma (FDCS). FDCS is a very rare disease affecting the dendritic antigen presenting cells and is often misdiagnosed. Surgery is considered the best treatment modality, followed by chemotherapy. In our case, surgical excision was not possible, therefore the patient received two lines of chemotherapy followed by bone marrow allotransplantation, then a third line of chemotherapy with a complete metabolic response seen on PET/computed tomography (CT) follow-up 29 months later. A review of the literature has been performed. PMID- 25698887 TI - Cyclopia: a rare condition with unusual presentation - a case report. AB - INTRODUCTION: Cyclopia (alobar holoprosencephaly) (OMIM% 236100) is a rare and lethal complex human malformation, resulting from incomplete cleavage of prosencephalon into right and left hemispheres occurring between the 18th and the 28th day of gestation. Holoprosencephaly occurs in 1/16,000 live births, and 1/250 during embryogenesis. Approximately 1.05 in 100,000 births are identified as infants with cyclopia, including stillbirths. Cyclopia typically presents with a median single eye or a partially divided eye in a single orbit, absent nose, and a proboscis above the eye. Extracranial malformations described in stillbirths with cyclopia include polydactyl, renal dysplasia, and an omphalocele. The etiology of this rare syndrome, which is incompatible with life, is still largely unknown. Most cases are sporadic. Heterogeneous risk factors have been implicated as possible causes. CASE PRESENTATION: A live full-term baby with birth weight of 2900 g, product of cesarean section because of severe fetal bradycardia, was born at Prince Hashem Military Hospital - Zarqa city/Jordan. This newborn was the first baby to a non-consanguineous family, and a healthy 18 year-old mother, with no history of drug ingestion or febrile illnesses during pregnancy. Antenatal history revealed severe hydrocephalus diagnosed early by intrauterine ultrasound but the pregnancy was not terminated because of the lack of medical legitimization in the country. On examination, the newborn was found to have a dysmorphic face, with a median single eye, absence of nose, micrognathia, and a proboscis above the eye, all of which made cyclopia the possible initial diagnosis. Multiple unusual abdominal defects were present that include a huge omphalocele containing whole liver and spleen, urinary bladder extrophy, and undefined abnormal external genitalia, which called for urgent confirmation. Brain MRI was done and revealed findings consistent with alobar holoprosencephaly (cyclopia). CONCLUSION: Presentation of cyclopia is not fully exposed and new cyclopian syndromes still can appear. The prenatal diagnosis of cyclopia can be made early by ultrasound, and the awareness of the spectrum of sonographic findings of cyclopia can improve the accuracy of prenatal diagnosis. The legitimization of pregnancy termination for indexed cases in many countries around the world should be revised. PMID- 25698889 TI - EYE MOVEMENT RECORDING AND NONLINEAR DYNAMICS ANALYSIS - THE CASE OF SACCADES. AB - Evidence of a chaotic behavioral trend in eye movement dynamics was examined in the case of a saccadic temporal series collected from a healthy human subject. Saccades are highvelocity eye movements of very short duration, their recording being relatively accessible, so that the resulting data series could be studied computationally for understanding the neural processing in a motor system. The aim of this study was to assess the complexity degree in the eye movement dynamics. To do this we analyzed the saccadic temporal series recorded with an infrared camera eye tracker from a healthy human subject in a special experimental arrangement which provides continuous records of eye position, both saccades (eye shifting movements) and fixations (focusing over regions of interest, with rapid, small fluctuations). The semi-quantitative approach used in this paper in studying the eye functioning from the viewpoint of non-linear dynamics was accomplished by some computational tests (power spectrum, portrait in the state space and its fractal dimension, Hurst exponent and largest Lyapunov exponent) derived from chaos theory. A high complexity dynamical trend was found. Lyapunov largest exponent test suggested bi-stability of cellular membrane resting potential during saccadic experiment. PMID- 25698888 TI - Intravenous lipids for preterm infants: a review. AB - Extremely low birth weight infants (ELBW) are born at a time when the fetus is undergoing rapid intrauterine brain and body growth. Continuation of this growth in the first several weeks postnatally during the time these infants are on ventilator support and receiving critical care is often a challenge. These infants are usually highly stressed and at risk for catabolism. Parenteral nutrition is needed in these infants because most cannot meet the majority of their nutritional needs using the enteral route. Despite adoption of a more aggressive approach with amino acid infusions, there still appears to be a reluctance to use early intravenous lipids. This is based on several dogmas that suggest that lipid infusions may be associated with the development or exacerbation of lung disease, displace bilirubin from albumin, exacerbate sepsis, and cause CNS injury and thrombocytopena. Several recent reviews have focused on intravenous nutrition for premature neonate, but very little exists that provides a comprehensive review of intravenous lipid for very low birth and other critically ill neonates. Here, we would like to provide a brief basic overview, of lipid biochemistry and metabolism of lipids, especially as they pertain to the preterm infant, discuss the origin of some of the current clinical practices, and provide a review of the literature, that can be used as a basis for revising clinical care, and provide some clarity in this controversial area, where clinical care is often based more on tradition and dogma than science. PMID- 25698890 TI - DYNAMICAL COMPLEXITY ANALYSIS OF SACCADIC EYE MOVEMENTS IN TWO DIFFERENT PSYCHOLOGICAL CONDITIONS. AB - Saccadic eye movements of a normal subject were assessed through semi quantitative analysis algorithms based on linear and non-linear test application in order to highlight the dynamics type characterizing saccadic neural system behavior. These movements were recorded during a simple visually-guided saccade test and one with a cognitive load involving button pressing to show a decision. Following the application of specific computational tests, chaotic dynamical trend dominancy was mostly revealed with some differences between the two saccade recording conditions: auto-correlation time was increased from 170 to 240 by cognitive task superposition and the Hurst exponent was enhanced from 0.52 to 0.76, denoting more persistence in the dynamics of saccadic system during increased neural activity related to cognitive task. PMID- 25698891 TI - Three new species of Begonia (Begoniaceae) from Bahia, Brazil. AB - The taxonomic treatment of Begoniaceae for the state of Bahia, Brazil, led to the recognition of three new species of Begonia with narrow distributions, which are described and illustrated here: Begoniadelicata Gregorio & J.A.S. Costa, sp. nov. is a herb restricted to the region of the Reconcavo; Begoniaelianeae Gregorio & J.A.S. Costa, sp. nov. is a shrub endemic to the Atlantic forest of the southern part of the state; and Begoniapaganuccii Gregorio & J.A.S. Costa, sp. nov. is a subshrub known only from the type material, collected in the Piedmont of Paraguacu. Notes on morphology, comparisons with morphologically similar species, etymology, geographic distribution, habitat and phenological data for each species are also presented. Furthermore, keys are provided as an aid to separating the new species from congeneric species that occur in their surroundings. Due to the sparse knowledge of the new species, there is as yet insufficient data to accurately assess their conservation status. PMID- 25698892 TI - Phylogenetic relationships of Zieria (Rutaceae) inferred from chloroplast, nuclear, and morphological data. AB - Zieria Sm. (Rutaceae, Boronieae) is predominantly native to eastern Australia except for one species, which is endemic to New Caledonia. For this study, sequence data of two non-coding chloroplast regions (trnL-trnF, and rpl32-trnL), one nuclear region (ITS region) and various morphological characters, based on Armstrong's (2002) taxonomic revision of Zieria, from 32 of the 42 described species of Zieria were selected to study the phylogenetic relationships within this genus. Zieria was supported as a monophyletic group in both independent and combined analyses herein (vs. Armstrong). On the basis of Armstrong's (2002) non molecular phylogenetic study, six major taxon groups were defined for Zieria. The Maximum-parsimony and the Bayesian analyses of the combined morphological and molecular datasets indicate a lack of support for any of these six major taxon groups. On the basis of the combined Bayesian analysis consisting of molecular and morphological characters, eight major taxon groups are described for Zieria: 1. Zieriacytisoides group, 2. Zieriagranulata group, 3. Zierialaevigata group, 4. Zieriasmithii group, 5. Zieriaaspalathoides group, 6. Zieriafurfuracea group, 7. Zieriamontana group, and 8. Zieriarobusta group. These informal groups, except for of the groups Zieriarobusta and Zieriacytisoides, correspond to the clades with posterior probability values of 100. PMID- 25698893 TI - Four new non-spiny Solanum (Solanaceae) species from South America. AB - Four new species of "non-spiny" Solanum from South America are described. Solanumlongifilamentum Sarkinen & P.Gonzales, sp. nov. (Morelloid clade) is widespread from Ecuador to Bolivia and is most similar to Solanummacrotonum Dunal from Central and northern South America. Solanumantisuyo Sarkinen & S.Knapp, sp. nov. (Morelloid clade) is found on the eastern Andean slopes in Ecuador, Peru and Bolivia and is most similar to the widespread lower elevation species Solanumpolytrichostylum Bitter. Solanumarenicola Sarkinen & P.Gonzales, sp. nov. (Morelloid clade) is found in low elevation habitats on the eastern Andean slopes and in Amazonia of Peru and Bolivia and is most similar to the higher elevation species Solanumaloysiifolium Dunal of Bolivia and Argentina. Solanummariae Sarkinen & S.Knapp, sp. nov. (Potato clade) is endemic to Cajamarca Department in Peru, and is most similar to the widespread Solanumcaripense Dunal. Complete descriptions, distributions and preliminary conservation assessments of all new species are given. PMID- 25698894 TI - Species delimitation and recognition in the Pediomelummegalanthum complex (Fabaceae) via multivariate morphometrics. AB - Pediomelum is a genus endemic to North America comprising about 26 species, including the megalanthum complex, which consists of Pediomelummegalanthum and its varieties retrorsum and megalanthum, Pediomelummephiticum, and the recently described Pediomelumverdiense and Pediomelumpauperitense. Historically, species of the megalanthum complex have been variably recognized at the species or variety levels, dependent upon the relative importance of morphological characters as diagnostic of species. Ten quantitative morphological characters regarded as diagnostic at the species level were analyzed using multivariate morphometrics across these taxa in order to examine the discriminatory power of these characters to delineate species and to aid in species delimitation. The analyses support the recognition of Pediomelummegalanthum, Pediomelummephiticum, and Pediomelumverdiense at the species level, Pediomelumretrorsum as a variety under Pediomelummegalanthum, and suggest the sinking of Pediomelumpauperitense into Pediomelumverdiense. The findings of the present study help quantify the power of certain characters at delimiting taxa and provide a basis for taxonomic revision of the Pediomelummegalanthum complex. PMID- 25698895 TI - Chapelieriamagna, a new species of Rubiaceae from eastern Madagascar. AB - A new species of Chapelieria was discovered during a recent field trip to the Masoala National Park in eastern Madagascar, and is described here as Chapelieriamagna Kainul., sp. nov. This species is readily distinguishable from previously described species of the genus by its quadrangular shoots, triangular calyptrate stipules, sessile leaves, pubescent styles, and ridged fruits. It also differs in the larger number of ovules and the much larger size of leaves and fruits. PMID- 25698896 TI - Psoraleaditurnerae and P.vanberkelae (Psoraleeae, Fabaceae): two new species restricted to the Core Cape Region of South Africa. AB - Two new species of Psoralea L. are described: Psoraleaditurnerae A. Bello, C.H. Stirt. & Muasya, sp. nov. and Psoraleavanberkelae C.H. Stirt., A. Bello & Muasya, sp. nov. Psoraleaditurnerae is endemic to the Outeniqua mountains (Camferskloof) and is characterised by a mass of numerous basal shoots out of which emerge 2-3 woody stems up to 2 m tall, 3-foliolate needle-like leaflets at the base of the seasonally growing shoot reducing to one towards the apex and bearing numerous 1 3-flowered axillary inflorescences along its length; each mauve to purple and white flower subtended by a trifid cupulum. Psoraleavanberkelae is characterised by its spreading mounding habit, short tightly packed fleshy leaves, with large impressed papillae, densely glandular short broadly triangular stipules, pale to intense mauve to deep blue flowers, standard with a dark purple central blotch above a M-shaped white patch situated above claw, and khaki seeds with purple flecks. PMID- 25698897 TI - Report on botanical nomenclature-Vienna 2005. XVII International Botanical Congress, Vienna: Nomenclature Section, 12-16 July 2005. PMID- 25698898 TI - Neoniphonpencei, a new species of holocentrid (Teleostei: Beryciformes) from Rarotonga, Cook Islands. AB - Neoniphonpencei, n. sp., is described from thirteen specimens, 132-197 mm standard length (SL) collected from mesophotic coral ecosystems (MCEs) at Rarotonga, Cook Islands by divers using mixed-gas closed-circuit rebreathers. It differs from all other species of the genus in number of lateral line scales, scales above and below lateral line, elements of life color, and in COI and cytochrome b DNA sequences. Of the five other known species of Neoniphon, it is most similar to the Indo-Pacific N.aurolineatus and the western Atlantic N.marianus both morphologically and genetically. PMID- 25698899 TI - New provincial records of skinks (Squamata: Scincidae) from northwestern Vietnam. AB - We report six new records of skinks from northwestern Vietnam: Eutropis macularius, Scincelladevorator , S.monticola, S.ochracea, Sphenomorphuscryptotis and S.indicus. Our new findings increase the species number of skinks (Scincidae) to nine in Dien Bien Province and to 14 in Son La Province. We also provide additional natural history data of aforementioned species. PMID- 25698900 TI - A new species of Margaromantis Piza, 1982 (Insecta: Mantodea) from Brazil. AB - A second species of the Neotropical mantid genus Margaromantis Piza, 1982, Margaromantisnigrolineata sp. n. is described from Bahia, Brazil. This new species can be recognized by the presence of a transverse black strip between compound eyes in the vertex; fore femora exhibiting black calluses on the inner face; lacking yellowish strips over the transverse veins on the metathoracic wings; left dorsal phallomere with rectangular ventral lamina, elongated and grooved lateral process, and a flattened, but not twisted apical process that is upwardly recurved. PMID- 25698901 TI - The effect of nilotinib plus arsenic trioxide on the proliferation and differentiation of primary leukemic cells from patients with chronic myoloid leukemia in blast crisis. AB - AIM: To determine the effects of arsenic trioxide (ATO) and nilotinib (AMN107, Tasigna) alone or in combination on the proliferation and differentiation of primary leukemic cells from patients with chronic myeloid leukemia in the blast crisis phase (CML-BC). METHODS: Cells were isolated from the bone marrow of CML BC patients and were treated with 1 MUM ATO and 5 nM nilotinib, either alone or in combination. Cell proliferation was evaluated using a MTT assay. Cell morphology and the content of hemoglobin were examined with Wright-Giemsa staining and benzidine staining, respectively. The expression of cell surface markers was determined using flow cytometric analysis. The levels of mRNA and protein were analyzed using RT-PCR and Western blotting, respectively. RESULTS: ATO and nilotinib alone or in combination suppressed cell proliferation in a dose and time-dependent pattern (P < 0.01 vs. control). Drug treatments promoted erythroid differentiation of CML-BC cells, with a decreased nuclei/cytoplasm ratio but increased hemoglobin content and glycophorin A (GPA) expression (P < 0.01 compared with control). In addition, macrophage and granulocyte lineage differentiation was also induced after drug treatment. The mRNA and protein levels of basic helix-loop-helix (bHLH) transcription factor T-cell acute lymphocytic leukemia protein 1 (TAL1) and B cell translocation gene 1 (BTG1) were both upregulated after 3 days of ATO and Nilotinib treatment. CONCLUSIONS: Our findings indicated that ATO and nilotinib treatment alone or in combination greatly suppressed cell proliferation but promoted the differentiation of CML-BC cells towards multiple-lineages. Nilotinib alone preferentially induced erythroid differentiation while combined treatment with ATO preferentially induced macrophage and granulocyte lineage differentiation. PMID- 25698902 TI - Galangin, a novel dietary flavonoid, attenuates metastatic feature via PKC/ERK signaling pathway in TPA-treated liver cancer HepG2 cells. AB - BACKGROUND: Galangin (3,5,7-trihydroxyflavone) is a flavonoid compound found in high concentration in lesser galangal. The objective of this study was to investigate the ability of galangin to inhibit 12-O-tetradecanoylphorbol-13 acetate (TPA)-induced the invasion and metastasis of HepG2 liver cancer cells. RESULTS: First, using a cell-matrix adhesion assay, immunofluorescence assay, transwell-chamber invasion/migration assay, and wound healing assay, we observed that galangin exerted an inhibitory effect on TPA-induced cell adhesion, morphology/actin cytoskeleton arrangement, invasion and migration. Furthermore, the results of gelatin zymography and reverse transcriptase polymerase chain reaction (RT-PCR) assays showed that galangin reduced the TPA-induced enzyme activity of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) in HepG2 cells; moreover, the messenger RNA level was downregulated. We also observed through a Western blotting assay that galangin strongly inhibited the TPA-induced protein expressions of protein kinase Calpha (PKCalpha), protein kinase Cdelta (PKCdelta), phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2), the phospho-inhibitor of kappaBalpha (phospho-IkappaBalpha), c-Fos, c-Jun, and nuclear factor kappa B (NF-kappaB). Next, galangin dose-dependently inhibited the binding ability of NF-kappaB and activator protein 1 (AP-1) to MMP 2/MMP-9 promoters, respectively, resulting in the suppression of MMP-2/MMP-9 enzyme activity. CONCLUSIONS: The results revealed that galangin effectively inhibited the TPA-induced invasion and migration of HepG2 cells through a protein kinase C/extracellular signal-regulated kinase (PKC/ERK) pathway. Thus, galangin may have widespread applications in clinical therapy as an anti-metastatic medicament. PMID- 25698903 TI - Cellular cytokine and chemokine responses to parasite antigens and fungus and mite allergens in children co-infected with helminthes and protozoa parasites. AB - BACKGROUND: In sub-Saharan Africa poly-parasite infections are frequently observed in children, and with poly-parasitism modulating immune mechanisms, mediated by cytokines and chemokines, are required to prevent overwhelming inflammation and host tissue damage. We analyzed in children co-infected with helminthes and protozoan parasites their cellular production of regulatory and pro-inflammatory cytokines and chemokines in response to parasite antigens and allergens. METHODS: Intestinal and intravascular parasite infections were detected in stool and urines samples. The in vitro cellular cytokine and chemokine responses of peripheral blood mononuclear cells (PBMC) to parasite antigens and allergens were analysed in children (n = 87) with single and poly parasite infection, and skin prick test reactivity to fungus and mite allergens was determined in singly and poly-parasitized children (n = 509). RESULTS: In children Entamoeba histolytica/dispar (62%), Necator americanus (31%), Schistosoma haematobium (28%), S. mansoni (21%), Hymenolepis nana (2%) and Strongyloides stercoralis (1%) were diagnosed. Singly infected were 37%, 47% were positive for 2 or more parasite species and 16% were infection-free. When PBMC were stimulated in vitro with parasite antigens and allergens, regulatory-type cytokine IL-27 and alarmin-type IL-33 enhanced with poly-parasite infections whilst IL-10 and pro-inflammatory MIP3-alpha/CCL20 and MIG/CXCL9 were produced in similar amounts in singly or poly-parasitized children. The co-stimulation in vitro of PBMC with mite allergens and Ascaris lumbricoides antigens depressed the allergen-induced pro-inflammatory IL-27, IL-33 and MIP3-alpha/CCL20 responses while regulatory IL-10 remained unaffected. Post albendazole and/or praziquantel treatment, the cellular release of IL-10, IL-33, MIP3-alpha/CCL20 and MIG/CXCL9 lessened significantly in all children infection groups. Skin prick test (SPT) reactivity to fungus Aspergillus fumigatus and mite Dermatophagoides pteronyssinus allergens was investigated in 509 children, and positive SPT responses were found in 23% of the infection-free, and in 47%, 53% and 56% of the singly, doubly and poly-parasite infected, respectively. CONCLUSIONS: In children co-infected with helminthes and protozoan parasites a mixed cellular response profile of both inflammatory and regulatory chemokines and cytokines was stimulated by individual antigens and allergens, pro-inflammatory cytokines and chemokines enhanced with an increasing number of parasite infections, and in poly parasitized children skin prick test reactivity to allergens extracts was highest. PMID- 25698904 TI - Pharmacokinetic and pharmacodynamic evaluation of rivaroxaban: considerations for the treatment of venous thromboembolism. AB - Patients with deep vein thrombosis or pulmonary embolism are recommended to receive anticoagulation for acute treatment and secondary prevention of venous thromboembolism (VTE). Fast-acting direct oral anticoagulants, with or without parenteral heparin, have the potential to replace vitamin K antagonists in this setting. Rivaroxaban, a direct Factor Xa inhibitor, is approved in the European Union and the United States for the single-drug treatment of deep vein thrombosis and pulmonary embolism and the secondary prevention of recurrent VTE in adults. The approved rivaroxaban dose schedule (15 mg twice daily for 3 weeks followed by 20 mg once daily) was derived based on pharmacological data from the clinical development programme to achieve a strong antithrombotic effect in the acute treatment phase and address the need to balance efficacy and bleeding risk for long-term treatment with a once-daily dose in the maintenance phase. Data from dose-ranging studies, pharmacokinetic modelling and randomised phase III trials support the use of this regimen. Other direct oral anticoagulants have also shown favourable efficacy and safety compared with standard treatment, and apixaban (European Union) and dabigatran (European Union and United States) have been approved in this indication. There are practical aspects to rivaroxaban use that must be considered, such as treatment of patients with renal and hepatic impairment, drug-drug interactions, monitoring of effect and management of bleeding. This review discusses the derivation of the VTE treatment regimen for rivaroxaban, summarises the clinical data for rivaroxaban and other direct oral anticoagulants in VTE treatment, and considers the practical aspects of rivaroxaban use in this setting. PMID- 25698905 TI - Influence of statin use on the incidence of recurrent venous thromboembolism and major bleeding in patients receiving rivaroxaban or standard anticoagulant therapy. AB - BACKGROUND: Statins may reduce the risk of first and recurrent venous thromboembolism (VTE). No data are available on their potential benefit in patients treated with the oral anticoagulant rivaroxaban. METHODS: The EINSTEIN DVT/PE and EINSTEIN Extension studies compared rivaroxaban with standard of care (n=8280) and placebo (n=1188), respectively. The incidences of recurrent VTE and major bleeding per 100 patient-years for exposure (or not) to statins were calculated. A Cox proportional hazards model was constructed, stratified by index event and intended treatment duration, with statin use as a time-dependent variable, for each treatment group (rivaroxaban vs enoxaparin/vitamin K antagonist or placebo) and adjusted for relevant variables. RESULTS: In EINSTEIN DVT/PE, 1509 (18.3%) patients used statins during the at-risk period, and 6731 (81.7%) did not. Overall, 2.6 recurrent VTEs occurred per 100 patient-years with statin use compared with 3.8 per 100 patient-years without statins (adjusted hazard ratio [HR] 0.76; 95% confidence interval [CI] 0.46-1.25). HRs for recurrent VTE were similar for concomitant use of rivaroxaban-statin and enoxaparin/VKA-statin. Major bleeding events occurred in 3.0 per 100 patient years with statin use compared with 2.3 per 100 patient-years without statins (adjusted HR 0.77; 95% CI 0.46-1.29). Due to adjustments in the Cox regression model, the direction of this HR is in contrast to the crude comparison. In EINSTEIN Extension, no recurrent VTEs occurred with statin use in the rivaroxaban group compared with 1.6 per 100 patient-years without statins. In the placebo group, 12.2 recurrent VTEs occurred per 100 patient-years with statin use compared with 13.2 per 100 patient-years without (adjusted HR 0.81; 95% CI 0.35 1.86). CONCLUSIONS: The effect of statins in this secondary analysis of the EINSTEIN VTE treatment program is consistent with other studies that suggest a reduced risk of recurrent VTE, but conclusive evidence of this benefit is lacking. Statins are simple to use, inexpensive, very safe and do not cause bleeding. Therefore, the potential effect on reducing recurrent VTE, which is in the range of that of acetylsalicylic acid, deserves evaluation in a large randomized trial. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov: EINSTEIN PE, NCT00439777; EINSTEIN DVT, NCT00440193; EINSTEIN Extension, NCT00439725. PMID- 25698906 TI - Cost-effectiveness of using a social franchise network to increase uptake of oral rehydration salts and zinc for childhood diarrhea in rural Myanmar. AB - INTRODUCTION: This paper examines the cost-effectiveness of achieving increases in the use of oral rehydration solution and zinc supplementation in the management of acute diarrhea in children under 5 years through social franchising. The study uses cost and outcome data from an initiative by Population Services International (PSI) in 3 townships of Myanmar in 2010 to promote an ORS-Zinc product called ORASEL. BACKGROUND: The objective of this study was to determine the incremental cost-effectiveness of a strategy to promote ORS-Z use through private sector franchising compared to standard government and private sector practices. METHODS: Costing from a societal perspective included program, provider, and household costs for the 2010 calendar year. Program costs including ORASEL program launch, distribution, and administration costs were obtained through a retrospective review of financial records and key informant interviews with staff in the central Yangon office. Household out of pocket payments for diarrheal episodes were obtained from a household survey conducted in the study area and additional estimates of household income lost due to parental care-giving time for a sick child were estimated. Incremental cost-effectiveness relative to status quo conditions was calculated per child death and DALY averted in 2010. Health effects included deaths and DALYs averted; the former modeled based on coverage estimates from a household survey that were entered into the Lives Saved Tool (LiST). Uncertainty was modeled with Monte Carlo methods. FINDINGS: Based on the model, the promotional strategy would translate to 2.85 (SD 0.29) deaths averted in a community population of 1 million where there would be 81,000 children under 5 expecting 48,373 cases of diarrhea. The incremental cost effectiveness of the franchised approach to improving ORASEL coverage is estimated at a median $5,955 (IQR: $3437-$7589) per death averted and $214 (IQR: $127-$287) per discounted DALY averted. INTERPRETATION: Investing in developing a network of private sector providers and keeping them stocked with ORS-Z as is done in a social franchise can be a highly cost-effective in terms of dollars per DALY averted. PMID- 25698907 TI - Model of Cation Transportation Mediated by High-Affinity Potassium Transporters (HKTs) in Higher Plants. AB - Trk/Ktr/HKT transporters probably were evolved from simple K(+) channels KcsA. HKT transporters, which mediate Na(+)-uniport or Na(+)/K(+)-symport, maintain K(+)/Na(+) homeostasis and increase salinity tolerance, can be classified into three subfamilies in higher plants. In this review, we systematically analyzed the characteristics of amino acids sequences and physiological functions of HKT transporters in higher plant. Furthermore, we depicted the hypothetical models of cations selection and transportation mediated by HKT transporters according to the highly conserved structure for the goal of better understanding the cations transportation processes. PMID- 25698908 TI - Anger and Positive Reactivity in Infancy: Effects on Maternal Report of Surgency and Attention Focusing in Early Childhood. AB - We examined two aspects of temperamental approach in early infancy, positive reactivity and anger, and their unique and combined influences on maternal reports of child surgency and attention focusing at 4 years of age. One hundred and fourteen infants were observed for their positive reactions to novel stimuli at 4 months, and their anger expressions during arm restraint at 9 months. Child surgency and attention focusing at age 4 years were assessed by maternal report. Infants who expressed more anger to restraint were rated higher in surgency during early childhood relative to infants who expressed less anger. The effects of positive reactivity to novelty on attention focusing were moderated by anger to restraint. These findings suggest that infant temperamental approach tendencies are multifaceted and have both unique and combined influences on later maternal report of attention and social behavior. PMID- 25698910 TI - Predictive Integration of Gene Ontology-Driven Similarity and Functional Interactions. AB - There is a need to develop methods to automatically incorporate prior knowledge to support the prediction and validation of novel functional associations. One such important source is represented by the Gene Ontology (GO)TM and the many model organism databases of gene products annotated to the GO. We investigated quantitative relationships between the GO-driven similarity of genes and their functional interactions by analyzing different types of associations in Saccharomyces cerevisiae and Caenorhabditis elegans. Interacting genes exhibited significantly higher levels of GO-driven similarity (GOS) in comparison to random pairs of genes used as a surrogate for negative interactions. The Biological Process hierarchy provides more reliable results for co-regulatory and protein protein interactions. GOS represent a relevant resource to support prediction of functional networks in combination with other resources. PMID- 25698909 TI - Calcium and Metabolic Oscillations in Pancreatic Islets: Who's Driving the Bus?* AB - Pancreatic islets exhibit bursting oscillations in response to elevated blood glucose. These oscillations are accompanied by oscillations in the free cytosolic Ca2+ concentration (Cac ), which drives pulses of insulin secretion. Both islet Ca2+ and metabolism oscillate, but there is some debate about their interrelationship. Recent experimental data show that metabolic oscillations in some cases persist after the addition of diazoxide (Dz), which opens K(ATP) channels, hyperpolarizing beta-cells and preventing Ca2+ entry and Ca2+ oscillations. Further, in some islets in which metabolic oscillations were eliminated with Dz, increasing the cytosolic Ca2+ concentration by the addition of KCl could restart the metabolic oscillations. Here we address why metabolic oscillations persist in some islets but not others, and why raising Cac restarts oscillations in some islets but not others. We answer these questions using the dual oscillator model (DOM) for pancreatic islets. The DOM can reproduce the experimental data and shows that the model supports two different mechanisms for slow metabolic oscillations, one that requires calcium oscillations and one that does not. PMID- 25698911 TI - Risk of hypoglycaemia in type 2 diabetes patients under different insulin regimens: a primary care database analysis. AB - AIMS: To compare rates and predictors of documented hypoglycaemia in type 2 diabetes patients treated with either basal insulin supported oral therapy (BOT), conventional therapy (CT) or supplementary insulin therapy (SIT) in primary care. METHODS: Data from 10,842 anonymous patients (mean age +/- SD: 54 +/- 8 yrs) on BOT, 2,407 subjects (56 +/- 7 yrs) on CT, and 7,480 patients (52 +/- 10 yrs) using SIT from 1,198 primary care practices were retrospectively analyzed (Disease Analyzer, Germany: 01/2005-07/2013). Stepwise logistic regression (>=1 documented hypoglycaemia: ICD code) was used to evaluate risk factors of hypoglycemia. RESULTS: The unadjusted rates (95% CI) per 100 patient-years of documented hypoglycaemia were 1.01 (0.80-1.20) (BOT), 1.68 (1.10-2.30) (CT), and 1.61 (1.30-1.90) (SIT), respectively. The odds of having >=1 hypoglycemia was increased for CT (OR; 95% CI: 1.71; 1.13-2.58) and SIT (1.55; 1.15-2.08) (reference: BOT). Previous hypoglycemia (OR: 11.24; 6.71-18.85), duration of insulin treatment (days) (1.06; 1.05-1.07), history of transient ischemic attack (TIA)/stroke (1.91; 1.04-3.50), and former salicylate prescriptions (1.44; 1.06 1.98) also showed an increased odds of having hypoglycemia. Higher age was associated with a slightly lower odds ratio (per year: 0.98; 0.97-0.99). CONCLUSIONS: Insulin naive type 2 diabetes patients in primary care, initiated with CT and SIT have an increased risk of hypoglycaemia compared to BOT, which is in line with previous randomized controlled trials. As hypoglycaemic events are associated with an increased mortality risk, this real-world finding is of clinical relevance. PMID- 25698912 TI - Evaluation of clinical trials by Ethics Committees in Germany--results and a comparison of two surveys performed among members of the German Association of Research-Based Pharmaceutical Companies (vfa). AB - OBJECTIVE: The objective of this project was to evaluate the quality and quantity of initial applications for a clinical trial according to S 7 of the German Good Clinical Practice (GCP) ordinance (German: GCP-Verordnung, GCP-V), the quality of evaluations of those applications by Ethics Committees (ECs)/Investigational Review Boards (IRBs) in Germany as well as the pattern of EC objections in their reasoned opinions (vote). In order to identify a change over time, the results of the present survey were also compared with a survey performed in 2008. METHODS: Based on reasoned opinions issued by the respective EC in charge of the coordinating principle investigator (coordinating EC) in 2011, a written survey among members of the German Association of Research-Based Pharmaceutical Companies (vfa) was conducted in 2012. The answers to the questionnaire were analyzed descriptively. Since the data set collected in 2011 was structurally identical with the data set gained in 2007 both surveys were compared. RESULTS: Of the 24 companies represented on the vfa Clinical Research/Quality Assurance Subcommittee, 75% (18) took part in the survey. Survey evaluation was based on a total of 251 applications of these 18 companies submitted to 43 ECs. These account for about 21% of 1,214 applications for authorization of commercial and non-commercial phase I-IV clinical trials submitted to the regulatory authorities (BfArM and PEI) in 2011. In comparison to 2007, a lower amount of applications (n=251 in 2011 vs. n=288 in 2007) was submitted to a slightly higher number of ECs (43 in 2011 vs. 40 in 2007). The amount of objections increased by 21% from 1,299 (2007) to 1,574 (2011) resulting in an average of 4.5 (2007) vs. 6.3 (2011) objections per application. Overall, the analysis of both formal and content related objections revealed almost the same pattern as in the previous survey. In total, the most frequent objections applied to the patient information and consent form followed in descending order by trial protocol content, miscellaneous, other application documents pursuant to S 7 (2) and (3) GCP-V, formal deficiencies pursuant to S 8 (1) GCP-V, and investigator and site qualifications. A trend towards a slightly increased rate of objections concerning patient information and consent form (+4%) and a minimal decrease in objections concerning investigator and site qualifications (-2%) was observed. As in 2007, about 1 in 6 applications was still incomplete with formal objections. Whilst the proportion of study applications with objections related to the patient information and consent form (+7.2%), the trial protocol content (+11.6%), and documents according to S 7 (2) and (3) GCP-V (+11.8%) increased in 2011 compared to 2007, the amount of study applications with objections related to the investigator and site qualifications decreased by 6.3%. CONCLUSIONS: The majority of findings with respect to quantity, quality and main focus of objections reported in the first survey in 2008 were also found in 2012, indicating a shared understanding of applicable measures and criteria by sponsors and ECs on how to ensure patient rights and well-being, data integrity, and high quality documentation in clinical trials. PMID- 25698914 TI - Switched-capacitor realization of presynaptic short-term-plasticity and stop learning synapses in 28 nm CMOS. AB - Synaptic dynamics, such as long- and short-term plasticity, play an important role in the complexity and biological realism achievable when running neural networks on a neuromorphic IC. For example, they endow the IC with an ability to adapt and learn from its environment. In order to achieve the millisecond to second time constants required for these synaptic dynamics, analog subthreshold circuits are usually employed. However, due to process variation and leakage problems, it is almost impossible to port these types of circuits to modern sub 100nm technologies. In contrast, we present a neuromorphic system in a 28 nm CMOS process that employs switched capacitor (SC) circuits to implement 128 short term plasticity presynapses as well as 8192 stop-learning synapses. The neuromorphic system consumes an area of 0.36 mm(2) and runs at a power consumption of 1.9 mW. The circuit makes use of a technique for minimizing leakage effects allowing for real-time operation with time constants up to several seconds. Since we rely on SC techniques for all calculations, the system is composed of only generic mixed signal building blocks. These generic building blocks make the system easy to port between technologies and the large digital circuit part inherent in an SC system benefits fully from technology scaling. PMID- 25698913 TI - Morphological elucidation of basal ganglia circuits contributing reward prediction. AB - Electrophysiological studies in monkeys have shown that dopaminergic neurons respond to the reward prediction error. In addition, striatal neurons alter their responsiveness to cortical or thalamic inputs in response to the dopamine signal, via the mechanism of dopamine-regulated synaptic plasticity. These findings have led to the hypothesis that the striatum exhibits synaptic plasticity under the influence of the reward prediction error and conduct reinforcement learning throughout the basal ganglia circuits. The reinforcement learning model is useful; however, the mechanism by which such a process emerges in the basal ganglia needs to be anatomically explained. The actor-critic model has been previously proposed and extended by the existence of role sharing within the striatum, focusing on the striosome/matrix compartments. However, this hypothesis has been difficult to confirm morphologically, partly because of the complex structure of the striosome/matrix compartments. Here, we review recent morphological studies that elucidate the input/output organization of the striatal compartments. PMID- 25698915 TI - An information theory analysis of spatial decisions in cognitive development. AB - Performance in a cognitive task can be considered as the outcome of a decision making process operating across various knowledge domains or aspects of a single domain. Therefore, an analysis of these decisions in various tasks can shed light on the interplay and integration of these domains (or elements within a single domain) as they are associated with specific task characteristics. In this study, we applied an information theoretic approach to assess quantitatively the gain of knowledge across various elements of the cognitive domain of spatial, relational knowledge, as a function of development. Specifically, we examined changing spatial relational knowledge from ages 5 to 10 years. Our analyses consisted of a two-step process. First, we performed a hierarchical clustering analysis on the decisions made in 16 different tasks of spatial relational knowledge to determine which tasks were performed similarly at each age group as well as to discover how the tasks clustered together. We next used two measures of entropy to capture the gradual emergence of order in the development of relational knowledge. These measures of "cognitive entropy" were defined based on two independent aspects of chunking, namely (1) the number of clusters formed at each age group, and (2) the distribution of tasks across the clusters. We found that both measures of entropy decreased with age in a quadratic fashion and were positively and linearly correlated. The decrease in entropy and, therefore, gain of information during development was accompanied by improved performance. These results document, for the first time, the orderly and progressively structured "chunking" of decisions across the development of spatial relational reasoning and quantify this gain within a formal information-theoretic framework. PMID- 25698916 TI - Patterns of myeloarchitecture in lower limb amputees: an MRI study. AB - Functional studies of cortical plasticity in humans suggest that the motor cortex reorganizes when the descending motor output pathway is disrupted as a result of limb amputation. The question thus arises if the underlying anatomical organization of the motor cortex is also altered in limb amputation. Owing to challenges involved in imaging the thin cerebral cortex in vivo, there is limited data available on the anatomical or morphological plasticity of the motor cortex in amputation. In this paper, we study the morphology of the primary motor cortex in four lower limb amputees with 37 or more years of amputation and four age and gender-matched controls using 0.7 mm isotropic, T1-weighted MRI optimized to produce enhanced intracortical contrast based on myelin content. We segment the cortex into myelinated and unmyelinated gray matter. We determine the myelinated thickness which is the thickness of the well-myelinated tissue in the deeper layers of the cortex. We compare the bilateral differences in the myelinated thickness between amputees and controls. We also compare bilateral differences in cortical thickness between the two groups. Our measurements show no statistically significant difference between the amputees and controls in the myelinated thickness and in cortical thickness, in the region of the primary motor cortex representing the lower leg. PMID- 25698917 TI - Efflux transporters in blood-brain interfaces of the developing brain. AB - The cerebral microvessel endothelium forming the blood-brain barrier (BBB) and the epithelium of the choroid plexuses forming the blood-CSF barrier (BCSFB) operate as gatekeepers for the central nervous system. Exposure of the vulnerable developing brain to chemical insults can have dramatic consequences for brain maturation and lead to life-long neurological diseases. The ability of blood brain interfaces to efficiently protect the immature brain is therefore an important pathophysiological issue. This is also key to our understanding of drug entry into the brain of neonatal and pediatric patients. Non-specific paracellular diffusion through barriers is restricted early during development, but other neuroprotective properties of these interfaces differ between the developing and adult brains. This review focuses on the developmental expression and function of various classes of efflux transporters. These include the multispecific transporters of the ATP-binding cassette transporter families ABCB, ABCC, ABCG, the organic anion and cation transporters of the solute carrier families SLC21/SLCO and SLC22, and the peptide transporters of the SLC15 family. These transporters play a key role in preventing brain entry of blood-borne molecules such as drugs, environmental toxicants, and endogenous metabolites, or else in increasing the clearance of potentially harmful organic ions from the brain. The limited data available for laboratory animals and human highlight transporter-specific developmental patterns of expression and function, which differ between blood-brain interfaces. The BCSFB achieves an adult phenotype earlier than BBB. Efflux transporters at the BBB appear to be regulated by various factors subsequently secreted by neural progenitors and astrocytes during development. Their expression is also modulated by oxidative stress, inflammation, and exposure to xenobiotic inducers. A better understanding of these regulatory pathways during development, in particular the signaling pathways triggered by oxidative stress and xenobiotics, may open new opportunities to therapeutic manipulation in view to improve or restore neuroprotective functions of the blood-brain interfaces in the context of perinatal injuries. PMID- 25698918 TI - Overweight is not associated with cortical thickness alterations in children. AB - INTRODUCTION: Several studies report an association between body mass index (BMI) and cortical thickness in adults. Some studies demonstrate diffuse cortical thinning in obesity, while others report effects in areas that are associated with self-regulation, such as lateral prefrontal cortex. METHODS: This study used multilevel modeling of data from the NIH Pediatric MRI Data Repository, a mixed longitudinal and cross-sectional database, to examine the relationship between cortical thickness and body weight in children. Cortical thickness was computed at 81,942 vertices of 716 MRI scans from 378 children aged between 4 and 18 years. Body mass index Z score for age was computed for each participant. We performed vertex-wise statistical analysis of the relationship between cortical thickness and BMI, accounting for age and gender. In addition, cortical thickness was extracted from regions of interest in prefrontal cortex and insula. RESULTS: No significant association between cortical thickness and BMI was found, either by statistical parametric mapping or by region of interest analysis. RESULTS remained negative when the analysis was restricted to children aged 12-18. CONCLUSIONS: The correlation between BMI and cortical thickness was not found in this large pediatric sample. The association between BMI and cortical thinning develops after adolescence. This has implications for the nature of the relationship between brain anatomy and weight gain. PMID- 25698919 TI - Optical triggered seizures using a caged 4-Aminopyridine. AB - Animal models of epilepsy are critical not only for understanding the fundamental mechanism of epilepsy but also for testing the efficacy of new antiepileptic drugs and novel therapeutic interventions. Photorelease of caged molecules is widely used in biological research to control pharmacologic events with high spatio-temporal resolution. We developed a technique for in vivo optical triggering of neocortical seizures using a novel caged compound based on ruthenium photochemistry (RuBi-4AP). Epileptiform events in mouse cortex were induced with blue light in both whole brain and focal illumination. Multi electrode array recording and optical techniques were used to characterize the propagation of these epileptic events, including interictal spikes, polyspikes, and ictal discharges. These results demonstrate a novel optically-triggered seizure model, with high spatio-temporal control, that could have widespread application in the investigation of ictal onset, propagation and to develop novel light-based therapeutic interventions. PMID- 25698920 TI - Highly efficient method for gene delivery into mouse dorsal root ganglia neurons. AB - The development of gene transfection technologies has greatly advanced our understanding of life sciences. While use of viral vectors has clear efficacy, it requires specific expertise and biological containment conditions. Electroporation has become an effective and commonly used method for introducing DNA into neurons and in intact brain tissue. The present study describes the use of the Neon(r) electroporation system to transfect genes into dorsal root ganglia neurons isolated from embryonic mouse Day 13.5-16. This cell type has been particularly recalcitrant and refractory to physical or chemical methods for introduction of DNA. By optimizing the culture condition and parameters including voltage and duration for this specific electroporation system, high efficiency (60-80%) and low toxicity (>60% survival) were achieved with robust differentiation in response to Nerve growth factor (NGF). Moreover, 3-50 times fewer cells are needed (6 * 10(4)) compared with other traditional electroporation methods. This approach underlines the efficacy of this type of electroporation, particularly when only limited amount of cells can be obtained, and is expected to greatly facilitate the study of gene function in dorsal root ganglia neuron cultures. PMID- 25698921 TI - Expression of ionotropic receptors in terrestrial hermit crab's olfactory sensory neurons. AB - Coenobitidae are one out of at least five crustacean lineages which independently succeeded in the transition from water to land. This change in lifestyle required adaptation of the peripheral olfactory organs, the antennules, in order to sense chemical cues in the new terrestrial habitat. Hermit crab olfactory aesthetascs are arranged in a field on the distal segment of the antennular flagellum. Aesthetascs house approximately 300 dendrites with their cell bodies arranged in spindle-like complexes of ca. 150 cell bodies each. While the aesthetascs of aquatic crustaceans have been shown to be the place of odor uptake and previous studies identified ionotropic receptors (IRs) as the putative chemosensory receptors expressed in decapod antennules, the expression of IRs besides the IR co-receptors IR25a and IR93a in olfactory sensory neurons (OSNs) has not been documented yet. Our goal was to reveal the expression and distribution pattern of non-co-receptor IRs in OSNs of Coenobita clypeatus, a terrestrial hermit crab, with RNA in situ hybridization. We expanded our previously published RNAseq dataset, and revealed 22 novel IR candidates in the Coenobita antennules. We then used RNA probes directed against three different IRs to visualize their expression within the OSN cell body complexes. Furthermore we aimed to characterize ligand spectra of single aesthetascs by recording local field potentials and responses from individual dendrites. This also allowed comparison to functional data from insect OSNs expressing antennal IRs. We show that this orphan receptor subgroup with presumably non-olfactory function in insects is likely the basis of olfaction in terrestrial hermit crabs. PMID- 25698922 TI - Pannexin2 oligomers localize in the membranes of endosomal vesicles in mammalian cells while Pannexin1 channels traffic to the plasma membrane. AB - Pannexin2 (Panx2) is the largest of three members of the pannexin proteins. Pannexins are topologically related to connexins and innexins, but serve different functional roles than forming gap junctions. We previously showed that pannexins form oligomeric channels but unlike connexins and innexins, they form only single membrane channels. High levels of Panx2 mRNA and protein in the Central Nervous System (CNS) have been documented. Whereas Pannexin1 (Panx1) is fairly ubiquitous and Pannexin3 (Panx3) is found in skin and connective tissue, both are fully glycosylated, traffic to the plasma membrane and have functions correlated with extracellular ATP release. Here, we describe trafficking and subcellular localizations of exogenous Panx2 and Panx1 protein expression in MDCK, HeLa, and HEK 293T cells as well as endogenous Panx1 and Panx2 patterns in the CNS. Panx2 was found in intracellular localizations, was partially N glycosylated, and localizations were non-overlapping with Panx1. Confocal images of hippocampal sections immunolabeled for the astrocytic protein GFAP, Panx1 and Panx2 demonstrated that the two isoforms, Panx1 and Panx2, localized at different subcellular compartments in both astrocytes and neurons. Using recombinant fusions of Panx2 with appended genetic tags developed for correlated light and electron microscopy and then expressed in different cell lines, we determined that Panx2 is localized in the membrane of intracellular vesicles and not in the endoplasmic reticulum as initially indicated by calnexin colocalization experiments. Dual immunofluorescence imaging with protein markers for specific vesicle compartments showed that Panx2 vesicles are early endosomal in origin. In electron tomographic volumes, cross-sections of these vesicles displayed fine structural details and close proximity to actin filaments. Thus, pannexins expressed at different subcellular compartments likely exert distinct functional roles, particularly in the nervous system. PMID- 25698923 TI - AMPAR interacting protein CPT1C enhances surface expression of GluA1-containing receptors. AB - AMPARs mediate the vast majority of fast excitatory synaptic transmission in the brain and their biophysical and trafficking properties depend on their subunit composition and on several posttranscriptional and posttranslational modifications. Additionally, in the brain AMPARs associate with auxiliary subunits, which modify the properties of the receptors. Despite the abundance of AMPAR partners, recent proteomic studies have revealed even more interacting proteins that could potentially be involved in AMPAR regulation. Amongst these, carnitine palmitoyltransferase 1C (CPT1C) has been demonstrated to form an integral part of native AMPAR complexes in brain tissue extracts. Thus, we aimed to investigate whether CPT1C might be able to modulate AMPAR function. Firstly, we confirmed that CPT1C is an interacting protein of AMPARs in heterologous expression systems. Secondly, CPT1C enhanced whole-cell currents of GluA1 homomeric and GluA1/GluA2 heteromeric receptors. However, CPT1C does not alter the biophysical properties of AMPARs and co-localization experiments revealed that AMPARs and CPT1C are not associated at the plasma membrane despite a strong level of co-localization at the intracellular level. We established that increased surface GluA1 receptor number was responsible for the enhanced AMPAR mediated currents in the presence of CPT1C. Additionally, we revealed that the palmitoylable residue C585 of GluA1 is important in the enhancement of AMPAR trafficking to the cell surface by CPT1C. Nevertheless, despite its potential as a depalmitoylating enzyme, CPT1C does not affect the palmitoylation state of GluA1. To sum up, this work suggests that CPT1C plays a role as a novel regulator of AMPAR surface expression in neurons. Fine modulation of AMPAR membrane trafficking is fundamental in normal synaptic activity and in plasticity processes and CPT1C is therefore a putative candidate to regulate neuronal AMPAR physiology. PMID- 25698924 TI - The Sarcoglycan complex is expressed in the cerebrovascular system and is specifically regulated by astroglial Cx30 channels. AB - Astrocytes, the most prominent glial cell type in the brain, send specialized processes called endfeet, around blood vessels and express a large molecular repertoire regulating the cerebrovascular system physiology. One of the most striking properties of astrocyte endfeet is their enrichment in gap junction proteins Connexin 43 and 30 (Cx43 and Cx30) allowing in particular for direct intercellular trafficking of ions and small signaling molecules through perivascular astroglial networks. In this study, we addressed the specific role of Cx30 at the gliovascular interface. Using an inactivation mouse model for Cx30 (Cx30(Delta/Delta); Delta means deleted allele) we showed that absence of Cx30 does not affect blood-brain barrier (BBB) organization and permeability. However, it results in the cerebrovascular fraction, in a strong upregulation of Sgcg encoding gamma-Sarcoglycan (gamma-SG), a member of the Dystrophin-associated protein complex (DAPC) connecting cytoskeleton and the extracellular matrix. The same molecular event occurs in Cx30(T5M/T5M) mutated mice, where Cx30 channels are closed, demonstrating that Sgcg regulation relied on Cx30 channel functions. We further characterized the expression of other Sarcoglycan complex (SGC) molecules in the cerebrovascular system and showed the presence of alpha-, beta-, delta-, gamma-, epsilon- and zeta- SG, as well as Sarcospan. Their expression was however not modified in Cx30(Delta/Delta). These results suggest that a full SGC might be present in the cerebrovascular system, and that expression of one of its member, gamma-SG, depends on Cx30 channels. As described in skeletal muscles, the SGC may contribute to membrane stabilization and signal transduction in the cerebrovascular system, which may therefore be regulated by Cx30 channel-mediated functions. PMID- 25698925 TI - The role of cAMP in synaptic homeostasis in response to environmental temperature challenges and hyperexcitability mutations. AB - Homeostasis is the ability of physiological systems to regain functional balance following environment or experimental insults and synaptic homeostasis has been demonstrated in various species following genetic or pharmacological disruptions. Among environmental challenges, homeostatic responses to temperature extremes are critical to animal survival under natural conditions. We previously reported that axon terminal arborization in Drosophila larval neuromuscular junctions (NMJs) is enhanced at elevated temperatures; however, the amplitude of excitatory junctional potentials (EJPs) remains unaltered despite the increase in synaptic bouton numbers. Here we determine the cellular basis of this homeostatic adjustment in larvae reared at high temperature (HT, 29 degrees C). We found that synaptic current focally recorded from individual synaptic boutons was unaffected by rearing temperature (<15 degrees C to >30 degrees C). However, HT rearing decreased the quantal size (amplitude of spontaneous miniature EJPs, or mEJPs), which compensates for the increased number of synaptic releasing sites to retain a normal EJP size. The quantal size decrease is accounted for by a decrease in input resistance of the postsynaptic muscle fiber, indicating an increase in membrane area that matches the synaptic growth at HT. Interestingly, a mutation in rutabaga (rut) encoding adenylyl cyclase (AC) exhibited no obvious changes in quantal size or input resistance of postsynaptic muscle cells after HT rearing, suggesting an important role for rut AC in temperature-induced synaptic homeostasis in Drosophila. This extends our previous finding of rut-dependent synaptic homeostasis in hyperexcitable mutants, e.g., slowpoke (slo). In slo larvae, the lack of BK channel function is partially ameliorated by upregulation of presynaptic Shaker (Sh) IA current to limit excessive transmitter release in addition to postsynaptic glutamate receptor recomposition that reduces the quantal size. PMID- 25698926 TI - Acute two-photon imaging of the neurovascular unit in the cortex of active mice. AB - In vivo two-photon scanning fluorescence imaging is a powerful technique to observe physiological processes from the millimeter to the micron scale in the intact animal. In neuroscience research, a common approach is to install an acute cranial window and head bar to explore neocortical function under anesthesia before inflammation peaks from the surgery. However, there are few detailed acute protocols for head-restrained and fully awake animal imaging of the neurovascular unit during activity. This is because acutely performed awake experiments are typically untenable when the animal is naive to the imaging apparatus. Here we detail a method that achieves acute, deep-tissue two-photon imaging of neocortical astrocytes and microvasculature in behaving mice. A week prior to experimentation, implantation of the head bar alone allows mice to train for head immobilization on an easy-to-learn air-supported ball treadmill. Following just two brief familiarization sessions to the treadmill on separate days, an acute cranial window can subsequently be installed for immediate imaging. We demonstrate how running and whisking data can be captured simultaneously with two photon fluorescence signals with acceptable movement artifacts during active motion. We also show possible applications of this technique by (1) monitoring dynamic changes to microvascular diameter and red blood cells in response to vibrissa sensory stimulation, (2) examining responses of the cerebral microcirculation to the systemic delivery of pharmacological agents using a tail artery cannula during awake imaging, and (3) measuring Ca(2+) signals from synthetic and genetically encoded Ca(2+) indicators in astrocytes. This method will facilitate acute two-photon fluorescence imaging in awake, active mice and help link cellular events within the neurovascular unit to behavior. PMID- 25698927 TI - Dopamine induces the accumulation of insoluble prion protein and affects autophagic flux. AB - Accumulation of protein aggregates is a histopathological hallmark of several neurodegenerative diseases, but in most cases the aggregation occurs without defined mutations or clinical histories, suggesting that certain endogenous metabolites can promote aggregation of specific proteins. One example that supports this hypothesis is dopamine and its metabolites. Dopamine metabolism generates several oxidative metabolites that induce aggregation of alpha synuclein, and represents the main etiology of Parkinson's diseases. Because dopamine and its metabolites are unstable and can be highly reactive, we investigated whether these molecules can also affect other proteins that are prone to aggregate, such as cellular prion protein (PrP(C)). In this study, we showed that dopamine treatment of neuronal cells reduced the number of viable cells and increased the production of reactive oxygen species (ROS) as demonstrated in previous studies. Overall PrP(C) expression level was not altered by dopamine treatment, but its unglycosylated form was consistently reduced at 100 MUM of dopamine. At the same concentration, the level of phosphorylated mTOR and 4EBP1 was also reduced. Moreover, dopamine treatment decreased the solubility of PrP(C), and increased its accumulation in autophagosomal compartments with concomitant induction of LC3-II and p62/SQSTM1 levels. In vitro oxidation of dopamine promoted formation of high-order oligomers of recombinant prion protein. These results suggest that dopamine metabolites alter the conformation of PrP(C), which in turn is sorted to degradation pathway, causing autophagosome overload and attenuation of protein synthesis. Accumulation of PrP(C) aggregates is an important feature of prion diseases. Thus, this study brings new insight into the dopamine metabolism as a source of endogenous metabolites capable of altering PrP(C) solubility and its subcellular localization. PMID- 25698928 TI - Systems biology analysis of the proteomic alterations induced by MPP(+), a Parkinson's disease-related mitochondrial toxin. AB - Parkinson's disease (PD) is a complex neurodegenerative disease whose etiology has not been completely characterized. Many cellular processes have been proposed to play a role in the neuronal damage and loss: defects in the proteosomal activity, altered protein processing, increased reactive oxygen species burden. Among them, the involvement of a decreased activity and an altered disposal of mitochondria is becoming more and more evident. The mitochondrial toxin 1-methyl 4-phenylpyridinium (MPP(+)), an inhibitor of complex I, has been widely used to reproduce biochemical alterations linked to PD in vitro and its precursor, 1 methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP), to induce a Parkinson-like syndrome in vivo. Therefore, we performed a meta-analysis of the literature of all the proteomic investigations of neuronal alterations due to MPP(+) treatment and compared it with our results obtained with a mitochondrial proteomic analysis of SH-SY5Y cells treated with MPP(+). By using open-source bioinformatics tools, we identified the biochemical pathways and the molecular functions mostly affected by MPP(+), i.e., ATP production, the mitochondrial unfolded stress response, apoptosis, autophagy, and, most importantly, the synapse funcionality. Eventually, we generated protein networks, based on physical or functional interactions, to highlight the relationships among the molecular actors involved. In particular, we identified the mitochondrial protein HSP60 as the central hub in the protein-protein interaction network. As a whole, this analysis clarified the cellular responses to MPP(+), the specific mitochondrial proteome alterations induced and how this toxic model can recapitulate some pathogenetic events of PD. PMID- 25698929 TI - Mitochondrial function in neuronal cells depends on p97/VCP/Cdc48-mediated quality control. AB - Maintaining mitochondrial function is essential for neuronal survival and offers protection against neurodegeneration. Ubiquitin-mediated, proteasome-dependent protein degradation in the form of outer mitochondrial membrane associated degradation (OMMAD) was shown to play roles in maintenance of mitochondria on the level of proteostasis, but also mitophagy and cell death. Recently, the AAA ATPase p97/VCP/Cdc48 was recognized as part of OMMAD acting as retrotranslocase of ubiquitinated mitochondrial proteins for proteasomal degradation. Thus, p97 likely plays a major role in mitochondrial maintenance. Support for this notion comes from mitochondrial dysfunction associated with amyotrophic lateral sclerosis and hereditary inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD) caused by p97 mutation. Using SH-SY5Y cells stably expressing p97 or dominant-negative p97(QQ) treated with mitochondrial toxins rotenone, 6-OHDA, or Abeta-peptide as model for neuronal cells suffering from mitochondrial dysfunction, we found mitochondrial fragmentation under normal and stress conditions was significantly increased upon inactivation of p97. Furthermore, inactivation of p97 resulted in loss of mitochondrial membrane potential and increased production of reactive oxygen species (ROS). Under additional stress conditions, loss of mitochondrial membrane potential and increased ROS production was even more pronounced. Loss of mitochondrial fidelity upon inactivation of p97 was likely due to disturbed maintenance of mitochondrial proteostasis as the employed treatments neither induced mitophagy nor cell death. This was supported by the accumulation of oxidatively-damaged proteins on mitochondria in response to p97 inactivation. Dysfunction of p97 under normal and stress conditions in neuron-like cells severely impacts mitochondrial function, thus supporting for the first time a role for p97 as a major component of mitochondrial proteostasis. PMID- 25698930 TI - The CA3 region of the hippocampus: how is it? What is it for? How does it do it? PMID- 25698931 TI - Involvement of calpains in adult neurogenesis: implications for stroke. AB - Calpains are ubiquitous proteases involved in cell proliferation, adhesion and motility. In the brain, calpains have been associated with neuronal damage in both acute and neurodegenerative disorders, but their physiological function in the nervous system remains elusive. During brain ischemia, there is a large increase in the levels of intracellular calcium, leading to the activation of calpains. Inhibition of these proteases has been shown to reduce neuronal death in a variety of stroke models. On the other hand, after stroke, neural stem cells (NSC) increase their proliferation and newly formed neuroblasts migrate towards the site of injury. However, the process of forming new neurons after injury is not efficient and finding ways to improve it may help with recovery after lesion. Understanding the role of calpains in the process of neurogenesis may therefore open a new window for the treatment of stroke. We investigated the involvement of calpains in NSC proliferation and neuroblast migration in two highly neurogenic regions in the mouse brain, the dentate gyrus (DG) and the subventricular zone (SVZ). We used mice that lack calpastatin, the endogenous calpain inhibitor, and calpains were also modulated directly, using calpeptin, a pharmacological calpain inhibitor. Calpastatin deletion impaired both NSC proliferation and neuroblast migration. Calpain inhibition increased NSC proliferation, migration speed and migration distance in cells from the SVZ. Overall, our work suggests that calpains are important for neurogenesis and encourages further research on their neurogenic role. Prospective therapies targeting calpain activity may improve the formation of new neurons following stroke, in addition to affording neuroprotection. PMID- 25698932 TI - Opportunities and limits of the one gene approach: the ability of Atoh1 to differentiate and maintain hair cells depends on the molecular context. AB - Atoh1 (Math1) was the first gene discovered in ear development that showed no hair cell (HC) differentiation when absent and could induce HC differentiation when misexpressed. These data implied that Atoh1 was both necessary and sufficient for hair cell development. However, other gene mutations also result in loss of initially forming HCs, notably null mutants for Pou4f3, Barhl1, and Gfi1. HC development and maintenance also depend on the expression of other genes (Sox2, Eya1, Gata3, Pax2) and several genes have been identified that can induce HCs when misexpressed (Jag1) or knocked out (Lmo4). In the ear Atoh1 is not only expressed in HCs but also in some supporting cells and neurons that do not differentiate into HCs. Simple removal of one gene, Neurod1, can de-repress Atoh1 and turns those neurons into HCs suggesting that Neurod1 blocks Atoh1 function in neurons. Atoh1 expression in inner pillar cells may also be blocked by too many Hes/Hey factors but conversion into HCs has only partially been achieved through Hes/Hey removal. Detailed analysis of cell cycle exit confirmed an apex to base cell cycle exit progression of HCs of the organ of Corti. In contrast, Atoh1 expression progresses from the base toward the apex with a variable delay relative to the cell cycle exit. Most HCs exit the cell cycle and are thus defined as precursors before Atoh1 is expressed. Atoh1 is a potent differentiation factor but can differentiate and maintain HCs only in the ear and when other factors are co-expressed. Upstream factors are essential to regulate Atoh1 level of expression duration while downstream, co-activated by other factors, will define the context of Atoh1 action. We suggest that these insights need to be taken into consideration and approaches beyond the simple Atoh1 expression need to be designed able to generate the radial and longitudinal variations in hair cell types for normal function of the organ of Corti. PMID- 25698934 TI - Bruchpilot and Synaptotagmin collaborate to drive rapid glutamate release and active zone differentiation. AB - The active zone (AZ) protein Bruchpilot (Brp) is essential for rapid glutamate release at Drosophila melanogaster neuromuscular junctions (NMJs). Quantal time course and measurements of action potential-waveform suggest that presynaptic fusion mechanisms are altered in brp null mutants (brp(69) ). This could account for their increased evoked excitatory postsynaptic current (EPSC) delay and rise time (by about 1 ms). To test the mechanism of release protraction at brp(69) AZs, we performed knock-down of Synaptotagmin-1 (Syt) via RNAi (syt(KD) ) in wildtype (wt), brp(69) and rab3 null mutants (rab3(rup) ), where Brp is concentrated at a small number of AZs. At wt and rab3(rup) synapses, syt(KD) lowered EPSC amplitude while increasing rise time and delay, consistent with the role of Syt as a release sensor. In contrast, syt(KD) did not alter EPSC amplitude at brp(69) synapses, but shortened delay and rise time. In fact, following syt(KD) , these kinetic properties were strikingly similar in wt and brp(69) , which supports the notion that Syt protracts release at brp(69) synapses. To gain insight into this surprising role of Syt at brp(69) AZs, we analyzed the structural and functional differentiation of synaptic boutons at the NMJ. At 'tonic' type Ib motor neurons, distal boutons contain more AZs, more Brp proteins per AZ and show elevated and accelerated glutamate release compared to proximal boutons. The functional differentiation between proximal and distal boutons is Brp-dependent and reduced after syt(KD) . Notably, syt(KD) boutons are smaller, contain fewer Brp positive AZs and these are of similar number in proximal and distal boutons. In addition, super-resolution imaging via dSTORM revealed that syt(KD) increases the number and alters the spatial distribution of Brp molecules at AZs, while the gradient of Brp proteins per AZ is diminished. In summary, these data demonstrate that normal structural and functional differentiation of Drosophila AZs requires concerted action of Brp and Syt. PMID- 25698933 TI - Systemic inflammation and the brain: novel roles of genetic, molecular, and environmental cues as drivers of neurodegeneration. AB - The nervous and immune systems have evolved in parallel from the early bilaterians, in which innate immunity and a central nervous system (CNS) coexisted for the first time, to jawed vertebrates and the appearance of adaptive immunity. The CNS feeds from, and integrates efferent signals in response to, somatic and autonomic sensory information. The CNS receives input also from the periphery about inflammation and infection. Cytokines, chemokines, and damage associated soluble mediators of systemic inflammation can also gain access to the CNS via blood flow. In response to systemic inflammation, those soluble mediators can access directly through the circumventricular organs, as well as open the blood-brain barrier. The resulting translocation of inflammatory mediators can interfere with neuronal and glial well-being, leading to a break of balance in brain homeostasis. This in turn results in cognitive and behavioral manifestations commonly present during acute infections - including anorexia, malaise, depression, and decreased physical activity - collectively known as the sickness behavior (SB). While SB manifestations are transient and self-limited, under states of persistent systemic inflammatory response the cognitive and behavioral changes can become permanent. For example, cognitive decline is almost universal in sepsis survivors, and a common finding in patients with systemic lupus erythematosus. Here, we review recent genetic evidence suggesting an association between neurodegenerative disorders and persistent immune activation; clinical and experimental evidence indicating previously unidentified immune mediated pathways of neurodegeneration; and novel immunomodulatory targets and their potential relevance for neurodegenerative disorders. PMID- 25698935 TI - A map of brain neuropils and fiber systems in the ant Cardiocondyla obscurior. AB - A wide spectrum of occupied ecological niches and spectacular morphological adaptations make social insects a prime object for comparative neuroanatomical studies. Eusocial insects have evolved complex societies based on caste polyphenism. A diverse behavioral repertoire of morphologically distinct castes of the same species requires a high degree of plasticity in the central nervous system. We have analyzed the central brain neuropils and fiber tract systems of the worker of the ant Cardiocondyla obscurior, a model for the study of social traits. Our analysis is based on whole mount preparations of adult brains labeled with an antibody against Drosophila-Synapsin, which cross-reacts strongly with synapses in Cardiocondyla. Neuropil compartments stand out as domains with a certain texture and intensity of the anti-Synapsin signal. By contrast, fiber tracts, which are composed of bundles of axons accompanied by glia and are devoid of synapses, appear as channels or sheaths with low anti-Synapsin signal. We have generated a digital 3D atlas of the Cardiocondyla brain neuropil. The atlas provides a reference for future studies of brain polymorphisms in distinct castes, brain development or localization of neurotransmitter systems. PMID- 25698936 TI - Olfactory and cortical projections to bulbar and hippocampal adult-born neurons. AB - New neurons are continually generated in the subependymal layer of the lateral ventricles and the subgranular zone of dentate gyrus during adulthood. In the subventricular zone, neuroblasts migrate a long distance to the olfactory bulb where they differentiate into granule or periglomerular interneurons. In the hippocampus, neuroblasts migrate a short distance from the subgranular zone to the granule cell layer of the dentate gyrus to become granule neurons. In addition to the short-distance inputs, bulbar interneurons receive long-distance centrifugal afferents from olfactory-recipient structures. Similarly, dentate granule cells receive differential inputs from the medial and lateral entorhinal cortices through the perforant pathway. Little is known concerning these new inputs on the adult-born cells. In this work, we have characterized afferent inputs to 21-day old newly-born neurons. Mice were intraperitoneally injected with bromodeoxyuridine. Two weeks later, rhodamine-labeled dextran-amine was injected into the anterior olfactory nucleus, olfactory tubercle, piriform cortex and lateral and medial entorhinal cortices. One week later, animals were perfused and immunofluorescences were carried out. The data show that projection neurons from the mentioned structures, establish putative synaptic contacts onto 21-day old neurons in the olfactory bulb and dentate gyrus, in some cases even before they start to express specific subpopulation proteins. Long-distance afferents reach middle and outer one-third portions of the molecular layer of the dentate gyrus and granule and, interestingly, periglomerular layers of the olfactory bulb. In the olfactory bulb, these fibers appear to establish presumptive axo somatic contacts onto newly-born granule and periglomerular cells. PMID- 25698938 TI - Brain BLAQ: Post-hoc thick-section histochemistry for localizing optogenetic constructs in neurons and their distal terminals. AB - Optogenetic constructs have revolutionized modern neuroscience, but the ability to accurately and efficiently assess their expression in the brain and associate it with prior functional measures remains a challenge. High-resolution imaging of thick, fixed brain sections would make such post-hoc assessment and association possible; however, thick sections often display autofluorescence that limits their compatibility with fluorescence microscopy. We describe and evaluate a method we call "Brain BLAQ" (Block Lipids and Aldehyde Quench) to rapidly reduce autofluorescence in thick brain sections, enabling efficient axon-level imaging of neurons and their processes in conventional tissue preparations using standard epifluorescence microscopy. Following viral-mediated transduction of optogenetic constructs and fluorescent proteins in mouse cortical pyramidal and dopaminergic neurons, we used BLAQ to assess innervation patterns in the striatum, a region in which autofluorescence often obscures the imaging of fine neural processes. After BLAQ treatment of 250-350 MUm-thick brain sections, axons and puncta of labeled afferents were visible throughout the striatum using a standard epifluorescence stereomicroscope. BLAQ histochemistry confirmed that motor cortex (M1) projections preferentially innervated the matrix component of lateral striatum, whereas medial prefrontal cortex projections terminated largely in dorsal striosomes and distinct nucleus accumbens subregions. Ventral tegmental area dopaminergic projections terminated in a similarly heterogeneous pattern within nucleus accumbens and ventral striatum. Using a minimal number of easily manipulated and visualized sections, and microscopes available in most neuroscience laboratories, BLAQ enables simple, high-resolution assessment of virally transduced optogenetic construct expression, and post-hoc association of this expression with molecular markers, physiology and behavior. PMID- 25698937 TI - Alterations in neuronal activity in basal ganglia-thalamocortical circuits in the parkinsonian state. AB - In patients with Parkinson's disease and in animal models of this disorder, neurons in the basal ganglia and related regions in thalamus and cortex show changes that can be recorded by using electrophysiologic single-cell recording techniques, including altered firing rates and patterns, pathologic oscillatory activity and increased inter-neuronal synchronization. In addition, changes in synaptic potentials or in the joint spiking activities of populations of neurons can be monitored as alterations in local field potentials (LFPs), electroencephalograms (EEGs) or electrocorticograms (ECoGs). Most of the mentioned electrophysiologic changes are probably related to the degeneration of diencephalic dopaminergic neurons, leading to dopamine loss in the striatum and other basal ganglia nuclei, although degeneration of non-dopaminergic cell groups may also have a role. The altered electrical activity of the basal ganglia and associated nuclei may contribute to some of the motor signs of the disease. We here review the current knowledge of the electrophysiologic changes at the single cell level, the level of local populations of neural elements, and the level of the entire basal ganglia-thalamocortical network in parkinsonism, and discuss the possible use of this information to optimize treatment approaches to Parkinson's disease, such as deep brain stimulation (DBS) therapy. PMID- 25698940 TI - Strain-dependent differences in corticolimbic processing of aversive or rewarding stimuli. AB - Aberrations in the elaboration of both aversive and rewarding stimuli characterize several psychopathologies including anxiety, depression and addiction. Several studies suggest that different neurotrasmitters, within the corticolimbic system, are critically involved in the processing of positive and negative stimuli. Individual differences in this system, depending on genotype, have been shown to act as a liability factor for different psychopathologies. Inbred mouse strains are commonly used in preclinical studies of normal and pathological behaviors. In particular, C57BL/6J (C57) and DBA/2J (DBA) strains have permitted to disclose the impact of different genetic backgrounds over the corticolimbic system functions. Here, we summarize the main findings collected over the years in our laboratory, showing how the genetic background plays a critical role in modulating amminergic and GABAergic neurotransmission in prefrontal-accumbal-amygdala system response to different rewarding and aversive experiences, as well as to stress response. Finally, we propose a top-down model for the response to rewarding and aversive stimuli in which amminergic transmission in prefrontal cortex (PFC) controls accumbal and amygdala neurotransmitter response. PMID- 25698939 TI - Red nucleus and rubrospinal tract disorganization in the absence of Pou4f1. AB - The red nucleus (RN) is a neuronal population that plays an important role in forelimb motor control and locomotion. Histologically it is subdivided into two subpopulations, the parvocellular RN (pRN) located in the diencephalon and the magnocellular RN (mRN) in the mesencephalon. The RN integrates signals from motor cortex and cerebellum and projects to spinal cord interneurons and motor neurons through the rubrospinal tract (RST). Pou4f1 is a transcription factor highly expressed in this nucleus that has been related to its specification. Here we profoundly analyzed consequences of Pou4f1 loss-of-function in development, maturation and axonal projection of the RN. Surprisingly, RN neurons are specified and maintained in the mutant, no cell death was detected. Nevertheless, the nucleus appeared disorganized with a strong delay in radial migration and with a wider neuronal distribution; the neurons did not form a compacted population as they do in controls, Robo1 and Slit2 were miss-expressed. Cplx1 and Npas1, expressed in the RN, are transcription factors involved in neurotransmitter release, neuronal maturation and motor function processes among others. In our mutant mice, both transcription factors are lost, suggesting an abnormal maturation of the RN. The resulting altered nucleus occupied a wider territory. Finally, we examined RST development and found that the RN neurons were able to project to the spinal cord but their axons appeared defasciculated. These data suggest that Pou4f1 is necessary for the maturation of RN neurons but not for their specification and maintenance. PMID- 25698941 TI - Comparison of the brain development trajectory between Chinese and U.S. children and adolescents. AB - This current study investigated brain development of Chinese and American children and adolescents from 8 to 16 years of age using structural magnetic resonance imaging (MRI) techniques. Analyses comparing Chinese and U.S. children brain/head MR images were performed to explore similarities and differences in the trajectory of brain development between these two groups. Our results revealed regional and age differences in both brain/head morphological and tissue level development between Chinese and U.S. children. Chinese children's brains and heads were shorter, wider, and taller than those of U.S. children. There were significant differences in the gray matter (GM) and white matter (WM) intensity between the two nationalities. Development trajectories for cerebral volume, GM, and several key brain structures were also distinct between these two populations. PMID- 25698942 TI - Functions of delay-period activity in the prefrontal cortex and mnemonic scotomas revisited. AB - Working memory (WM) is one of key concepts to understand functions of the prefrontal cortex. Delay-period activity is an important neural correlate to understand the role of WM in prefrontal functions. The importance of delay-period activity is that this activity can encode not only visuospatial information but also a variety of information including non-spatial visual features, auditory and tactile stimuli, task rules, expected reward, and numerical quantity. This activity also participates in a variety of information processing including sensory-to-motor information transformation. These mnemonic features of delay period activity enable to perform various important operations that the prefrontal cortex participates in, such as executive controls, and therefore, support the notion that WM is an important function to understand prefrontal functions. On the other hand, although experiments using manual versions of the delayed-response task had revealed many important findings, an oculomotor version of this task enabled us to use multiple cue positions, exclude postural orientation during the delay period, and further prove the importance of mnemonic functions of the prefrontal cortex. In addition, monkeys with unilateral lesions exhibited specific impairment only in the performance of memory-guided saccades directed toward visual cues in the visual field contralateral to the lesioned hemisphere. This result indicates that memories for visuospatial coordinates in each hemifield are processed primarily in the contralateral prefrontal cortex. This result further strengthened the idea of mnemonic functions of the prefrontal cortex. Thus, the mnemonic functions of the prefrontal cortex and delay-period activity may not need to be reconsidered, but should be emphasized. PMID- 25698943 TI - Enhancing multiple object tracking performance with noninvasive brain stimulation: a causal role for the anterior intraparietal sulcus. AB - Multiple object tracking (MOT) is a complex task recruiting a distributed network of brain regions. There are also marked individual differences in MOT performance. A positive causal relationship between the anterior intraparietal sulcus (AIPS), an integral region in the MOT attention network and inter individual variation in MOT performance has not been previously established. The present study used transcranial direct current stimulation (tDCS), a form of non invasive brain stimulation, in order to examine such a causal link. Active anodal stimulation was applied to the right AIPS and the left dorsolateral prefrontal cortex (DLPFC) (and sham stimulation), an area associated with working memory (but not MOT) while participants completed a MOT task. Stimulation to the right AIPS significantly improved MOT accuracy more than the other two conditions. The results confirm a causal role of the AIPS in the MOT task and illustrate that tDCS has the ability to improve MOT performance. PMID- 25698944 TI - Multifaceted effects of noisy galvanic vestibular stimulation on manual tracking behavior in Parkinson's disease. AB - Parkinson's disease (PD) is a neurodegenerative movement disorder that is characterized clinically by slowness of movement, rigidity, tremor, postural instability, and often cognitive impairments. Recent studies have demonstrated altered cortico-basal ganglia rhythms in PD, which raises the possibility of a role for non-invasive stimulation therapies such as noisy galvanic vestibular stimulation (GVS). We applied noisy GVS to 12 mild-moderately affected PD subjects (Hoehn and Yahr 1.5-2.5) off medication while they performed a sinusoidal visuomotor joystick tracking task, which alternated between 2 task conditions depending on whether the displayed cursor position underestimated the actual error by 30% ('Better') or overestimated by 200% ('Worse'). Either sham or subthreshold, noisy GVS (0.1-10 Hz, 1/f-type power spectrum) was applied in pseudorandom order. We used exploratory (linear discriminant analysis with bootstrapping) and confirmatory (robust multivariate linear regression) methods to determine if the presence of GVS significantly affected our ability to predict cursor position based on target variables. Variables related to displayed error were robustly seen to discriminate GVS in all subjects particularly in the Worse condition. If we considered higher frequency components of the cursor trajectory as "noise," the signal-to-noise ratio of cursor trajectory was significantly increased during the GVS stimulation. The results suggest that noisy GVS influenced motor performance of the PD subjects, and we speculate that they were elicited through a combination of mechanisms: enhanced cingulate activity resulting in modulation of frontal midline theta rhythms, improved signal processing in neuromotor system via stochastic facilitation and/or enhanced "vigor" known to be deficient in PD subjects. Further work is required to determine if GVS has a selective effect on corrective submovements that could not be detected by the current analyses. PMID- 25698945 TI - Multisensory perception of the six basic emotions is modulated by attentional instruction and unattended modality. AB - Previous studies have shown that the perception of facial and vocal affective expressions interacts with each other. Facial expressions usually dominate vocal expressions when we perceive the emotions of face-voice stimuli. In most of these studies, participants were instructed to pay attention to the face or voice. Few studies compared the perceived emotions with and without specific instructions regarding the modality to which attention should be directed. Also, these studies used combinations of the face and voice which expresses two opposing emotions, which limits the generalizability of the findings. The purpose of this study is to examine whether the emotion perception is modulated by instructions to pay attention to the face or voice using the six basic emotions. Also we examine the modality dominance between the face and voice for each emotion category. Before the experiment, we recorded faces and voices which expresses the six basic emotions and orthogonally combined these faces and voices. Consequently, the emotional valence of visual and auditory information was either congruent or incongruent. In the experiment, there were unisensory and multisensory sessions. The multisensory session was divided into three blocks according to whether an instruction was given to pay attention to a given modality (face attention, voice attention, and no instruction). Participants judged whether the speaker expressed happiness, sadness, anger, fear, disgust, or surprise. Our results revealed that instructions to pay attention to one modality and congruency of the emotions between modalities modulated the modality dominance, and the modality dominance is differed for each emotion category. In particular, the modality dominance for anger changed according to each instruction. Analyses also revealed that the modality dominance suggested by the congruency effect can be explained in terms of the facilitation effect and the interference effect. PMID- 25698946 TI - New approaches for the neuroimaging of gene expression. PMID- 25698947 TI - Extending peripersonal space representation without tool-use: evidence from a combined behavioral-computational approach. AB - Stimuli from different sensory modalities occurring on or close to the body are integrated in a multisensory representation of the space surrounding the body, i.e., peripersonal space (PPS). PPS dynamically modifies depending on experience, e.g., it extends after using a tool to reach far objects. However, the neural mechanism underlying PPS plasticity after tool use is largely unknown. Here we use a combined computational-behavioral approach to propose and test a possible mechanism accounting for PPS extension. We first present a neural network model simulating audio-tactile representation in the PPS around one hand. Simulation experiments showed that our model reproduced the main property of PPS neurons, i.e., selective multisensory response for stimuli occurring close to the hand. We used the neural network model to simulate the effects of a tool-use training. In terms of sensory inputs, tool use was conceptualized as a concurrent tactile stimulation from the hand, due to holding the tool, and an auditory stimulation from the far space, due to tool-mediated action. Results showed that after exposure to those inputs, PPS neurons responded also to multisensory stimuli far from the hand. The model thus suggests that synchronous pairing of tactile hand stimulation and auditory stimulation from the far space is sufficient to extend PPS, such as after tool-use. Such prediction was confirmed by a behavioral experiment, where we used an audio-tactile interaction paradigm to measure the boundaries of PPS representation. We found that PPS extended after synchronous tactile-hand stimulation and auditory-far stimulation in a group of healthy volunteers. Control experiments both in simulation and behavioral settings showed that the same amount of tactile and auditory inputs administered out of synchrony did not change PPS representation. We conclude by proposing a simple, biological plausible model to explain plasticity in PPS representation after tool-use, which is supported by computational and behavioral data. PMID- 25698948 TI - Seeking pleasant touch: neural correlates of behavioral preferences for skin stroking. AB - Affective touch is a dynamic process. In this fMRI study we investigated affective touch by exploring its effects on overt behavior. Arm and palm skin were stroked with a soft brush at five different velocities (0.3, 1, 10, 3, and 30 cm s(-1)), using a novel feedback-based paradigm. Following stimulation in each trial, participants actively chose whether the caress they would receive in the next trial would be the same speed ("repeat") or different ("change"). Since preferred stroking speeds should be sought with greater frequency than non preferred speeds, this paradigm provided a measure of such preferences in the form of active choices. The stimulation velocities were implemented with respect to the differential subjective pleasantness ratings they elicit in healthy subjects, with intermediate velocities (1, 10, and 3 cm s(-1)) considered more pleasant than very slow or very fast ones. Such pleasantness ratings linearly correlate with changes in mean firing rates of unmyelinated low-threshold C tactile (CT) afferent nerves in the skin. Here, gentle, dynamic stimulation optimal for activating CT-afferents not only affected behavioral choices, but engaged brain regions involved in reward-related behavior and decision-making. This was the case for both hairy skin of the arm, where CTs are abundant, and glabrous skin of the palm, where CTs are absent. These findings provide insights on central and behavioral mechanisms underlying the perception of affective touch, and indicate that seeking affective touch involves value-based neural processing that is ultimately reflected in behavioral preferences. PMID- 25698949 TI - Dietary intake alters behavioral recovery and gene expression profiles in the brain of juvenile rats that have experienced a concussion. AB - Concussion and mild traumatic brain injury (mTBI) research has made minimal progress diagnosing who will suffer from lingering symptomology or generating effective treatment strategies. Research demonstrates that dietary intake affects many biological systems including brain and neurological health. This study determined if exposure to a high fat diet (HFD) or caloric restriction (CR) altered post-concussion susceptibility or resiliency using a rodent model of pediatric concussion. Rats were maintained on HFD, CR, or standard diet (STD) throughout life (including the prenatal period and weaning). At postnatal day 30, male and female rats experienced a concussion or a sham injury which was followed by 17 days of testing. Prefrontal cortex and hippocampus tissue was collected for molecular profiling. Gene expression changes in BDNF, CREB, DNMT1, FGF-2, IGF1, LEP, PGC-1alpha, SIRT1, Tau, and TERT were analyzed with respect to injury and diet. Analysis of telomere length (TL) using peripheral skin cells and brain tissue found that TL in skin significantly correlated with TL in brain tissue and TL was affected by dietary intake and injury status. With respect to mTBI outcomes, diet was correlated with recovery as animals on the HFD often displayed poorer performance than animals on the CR diet. Molecular analysis demonstrated that diet induced epigenetic changes that can be associated with differences in individual predisposition and resiliency to post-concussion syndrome. PMID- 25698951 TI - Changes in gray matter volume after microsurgical lumbar discectomy: a longitudinal analysis. AB - People around the world suffer chronic lower back pain. Because spine imaging often does not explain the degree of perceived pain reported by patients, the role of the processing of nociceptor signals in the brain as the basis of pain perception is gaining increased attention. Modern neuroimaging techniques (including functional and morphometric methods) have produced results that suggest which brain areas may play a crucial role in the perception of acute and chronic pain. In this study, we examined 12 patients with chronic low back pain and sciatica, both resulting from lumbar disc herniation. Structural magnetic resonance imaging (MRI) of the brain was performed 1 day prior to and about 4 weeks after microsurgical lumbar discectomy. The subsequent MRI revealed an increase in gray matter volume in the basal ganglia but a decrease in volume in the hippocampus, which suggests the complexity of the network that involves movement, pain processing, and aspects of memory. Interestingly, volume changes in the hippocampus were significantly correlated to preoperative pain intensity but not to the duration of chronic pain. Mapping structural changes of the brain that result from lumbar disc herniation has the potential to enhance our understanding of the neuropathology of chronic low back pain and sciatica and therefore may help to optimize the decisions we make about conservative and surgical treatments in the future. The possibility of illuminating more of the details of central pain processing in lumbar disc herniation, as well as the accompanying personal and economic impact of pain relief worldwide, calls for future large-scale clinical studies. PMID- 25698952 TI - Personality and intentional binding: an exploratory study using the narcissistic personality inventory. AB - When an individual estimates the temporal interval between a voluntary action and a consequent effect, their estimates are shorter than the real duration. This perceived shortening has been termed "intentional binding", and is often due to a shift in the perception of a voluntary action forward towards the effect and a shift in the perception of the effect back towards the action. Despite much work on binding, there is virtually no consideration of individual/personality differences and how they affect it. Narcissism is a psychological trait associated with an inflated sense of self, and individuals higher in levels of subclinical narcissism tend to see themselves as highly effective agents. Conversely, lower levels of narcissism may be associated with a reduced sense of agency. In this exploratory study, to assess whether individuals with different scores on a narcissism scale are associated with differences in intentional binding, we compared perceived times of actions and effects (tones) between participants with high, middle, and low scores on the narcissistic personality inventory (NPI). We hypothesized that participants with higher scores would show increased binding compared to participants with lower scores. We found that participants in our middle and high groups showed a similar degree of binding, which was significantly greater than the level of binding shown by participants with the lowest scores. To our knowledge, these results are the first to demonstrate that different scores on a personality scale are associated with changes in the phenomenological experience of action, and therefore underscore the importance of considering individual/personality differences in the study of volition. Our results also reinforce the notion that intentional binding is related to agency experience. PMID- 25698953 TI - Cross-language activation of morphological relatives in cognates: the role of orthographic overlap and task-related processing. AB - We considered the role of orthography and task-related processing mechanisms in the activation of morphologically related complex words during bilingual word processing. So far, it has only been shown that such morphologically related words (i.e., morphological family members) are activated through the semantic and morphological overlap they share with the target word. In this study, we investigated family size effects in Dutch-English identical cognates (e.g., tent in both languages), non-identical cognates (e.g., pil and pill, in English and Dutch, respectively), and non-cognates (e.g., chicken in English). Because of their cross-linguistic overlap in orthography, reading a cognate can result in activation of family members both languages. Cognates are therefore well-suited for studying mechanisms underlying bilingual activation of morphologically complex words. We investigated family size effects in an English lexical decision task and a Dutch-English language decision task, both performed by Dutch-English bilinguals. English lexical decision showed a facilitatory effect of English and Dutch family size on the processing of English-Dutch cognates relative to English non-cognates. These family size effects were not dependent on cognate type. In contrast, for language decision, in which a bilingual context is created, Dutch and English family size effects were inhibitory. Here, the combined family size of both languages turned out to better predict reaction time than the separate family size in Dutch or English. Moreover, the combined family size interacted with cognate type: the response to identical cognates was slowed by morphological family members in both languages. We conclude that (1) family size effects are sensitive to the task performed on the lexical items, and (2) depend on both semantic and formal aspects of bilingual word processing. We discuss various mechanisms that can explain the observed family size effects in a spreading activation framework. PMID- 25698950 TI - Traumatic brain injury detection using electrophysiological methods. AB - Measuring neuronal activity with electrophysiological methods may be useful in detecting neurological dysfunctions, such as mild traumatic brain injury (mTBI). This approach may be particularly valuable for rapid detection in at-risk populations including military service members and athletes. Electrophysiological methods, such as quantitative electroencephalography (qEEG) and recording event related potentials (ERPs) may be promising; however, the field is nascent and significant controversy exists on the efficacy and accuracy of the approaches as diagnostic tools. For example, the specific measures derived from an electroencephalogram (EEG) that are most suitable as markers of dysfunction have not been clearly established. A study was conducted to summarize and evaluate the statistical rigor of evidence on the overall utility of qEEG as an mTBI detection tool. The analysis evaluated qEEG measures/parameters that may be most suitable as fieldable diagnostic tools, identified other types of EEG measures and analysis methods of promise, recommended specific measures and analysis methods for further development as mTBI detection tools, identified research gaps in the field, and recommended future research and development thrust areas. The qEEG study group formed the following conclusions: (1) Individual qEEG measures provide limited diagnostic utility for mTBI. However, many measures can be important features of qEEG discriminant functions, which do show significant promise as mTBI detection tools. (2) ERPs offer utility in mTBI detection. In fact, evidence indicates that ERPs can identify abnormalities in cases where EEGs alone are non-disclosing. (3) The standard mathematical procedures used in the characterization of mTBI EEGs should be expanded to incorporate newer methods of analysis including non-linear dynamical analysis, complexity measures, analysis of causal interactions, graph theory, and information dynamics. (4) Reports of high specificity in qEEG evaluations of TBI must be interpreted with care. High specificities have been reported in carefully constructed clinical studies in which healthy controls were compared against a carefully selected TBI population. The published literature indicates, however, that similar abnormalities in qEEG measures are observed in other neuropsychiatric disorders. While it may be possible to distinguish a clinical patient from a healthy control participant with this technology, these measures are unlikely to discriminate between, for example, major depressive disorder, bipolar disorder, or TBI. The specificities observed in these clinical studies may well be lost in real world clinical practice. (5) The absence of specificity does not preclude clinical utility. The possibility of use as a longitudinal measure of treatment response remains. However, efficacy as a longitudinal clinical measure does require acceptable test retest reliability. To date, very few test-retest reliability studies have been published with qEEG data obtained from TBI patients or from healthy controls. This is a particular concern because high variability is a known characteristic of the injured central nervous system. PMID- 25698954 TI - Risk assessment and predicting outcomes in patients with depressive symptoms: a review of potential role of peripheral blood based biomarkers. AB - Depression is one of the major global health challenges and a leading contributor of health related disability and costs. Depression is a heterogeneous disorder and current methods for assessing its severity in clinical practice rely on symptom count, however this approach is unreliable and inconsistent. The clinical evaluation of depressive symptoms is particularly challenging in primary care, where the majority of patients with depression are managed, due to the presence of co-morbidities. Current methods for risk assessment of depression do not accurately predict treatment response or clinical outcomes. Several biological pathways have been implicated in the pathophysiology of depression; however, accurate and predictive biomarkers remain elusive. We conducted a systematic review of the published evidence supporting the use of peripheral biomarkers to predict outcomes in depression, using Medline and Embase. Peripheral biomarkers in depression were found to be statistically significant predictors of mental health outcomes such as treatment response, poor outcome and symptom remission; and physical health outcomes such as increased incidence of cardiovascular events and deaths, and all-cause mortality. However, the available evidence has multiple methodological limitations which must be overcome to make any real clinical progress. Despite extensive research on the relationship of depression with peripheral biomarkers, its translational application in practice remains uncertain. In future, peripheral biomarkers identified with novel techniques and combining multiple biomarkers may have a potential role in depression risk assessment but further research is needed in this area. PMID- 25698955 TI - Altered retrieval of melodic information in congenital amusia: insights from dynamic causal modeling of MEG data. AB - Congenital amusia is a neuro-developmental disorder that primarily manifests as a difficulty in the perception and memory of pitch-based materials, including music. Recent findings have shown that the amusic brain exhibits altered functioning of a fronto-temporal network during pitch perception and short-term memory. Within this network, during the encoding of melodies, a decreased right backward frontal-to-temporal connectivity was reported in amusia, along with an abnormal connectivity within and between auditory cortices. The present study investigated whether connectivity patterns between these regions were affected during the short-term memory retrieval of melodies. Amusics and controls had to indicate whether sequences of six tones that were presented in pairs were the same or different. When melodies were different only one tone changed in the second melody. Brain responses to the changed tone in "Different" trials and to its equivalent (original) tone in "Same" trials were compared between groups using Dynamic Causal Modeling (DCM). DCM results confirmed that congenital amusia is characterized by an altered effective connectivity within and between the two auditory cortices during sound processing. Furthermore, right temporal-to-frontal message passing was altered in comparison to controls, with notably an increase in "Same" trials. An additional analysis in control participants emphasized that the detection of an unexpected event in the typically functioning brain is supported by right fronto-temporal connections. The results can be interpreted in a predictive coding framework as reflecting an abnormal prediction error sent by temporal auditory regions towards frontal areas in the amusic brain. PMID- 25698956 TI - Brain development and the attention spectrum. PMID- 25698957 TI - Brain bases of language selection: MEG evidence from Arabic-English bilingual language production. AB - Much of the world's population is bilingual, hence, language selection is a core component of language processing in a significant proportion of individuals. Though language selection has been investigated using artificial cues to language choice such as color, little is known about more ecologically valid cues. We examined with MEG the neurophysiological and behavioral effects of two natural cues: script and cultural context, hypothesizing the former to trigger more automatic language selection. Twenty Arabic-English bilinguals performed a number naming task with a Match condition, where the cue and target language of response matched, and a Mismatch condition, with opposite instruction. The latter addressed the mechanisms responsible for overriding natural cue-language associations. Early visual responses patterned according to predictions from prior object recognition literature, while at 150-300 ms, the anterior cingulate cortex showed robust sensitivity to cue-type, with enhanced amplitudes to culture trials. In contrast, a mismatch effect for both cue-types was observed at 300-400 ms in the left inferior prefrontal cortex. Our findings provide the first characterization of the spatio-temporal profile of naturally cued language selection and demonstrate that natural but less automatic language-choice, elicited by cultural cues, does not engage the same mechanisms as the clearly unnatural language-choice of our mismatch tasks. PMID- 25698958 TI - Safety and tolerability of theta burst stimulation vs. single and paired pulse transcranial magnetic stimulation: a comparative study of 165 pediatric subjects. AB - BACKGROUND: Although single- and paired-pulse (sp/pp) transcranial magnetic stimulation (TMS) studies are considered minimal risk in adults and children, the safety profile for theta-burst TMS (TBS) is unknown. OBJECTIVE: In this comparative analysis, we explored the rate, severity, and specific symptoms of TMS-related adverse effects (AEs) between sp/ppTMS and TBS in subjects between ages 6 and 18 years. METHOD: Data from 165 participants from 2009 to 2014 were analyzed. Assessment of AEs was performed based on baseline and post-TMS administration of a symptom-based questionnaire that rated AEs on a 5-level ordinal scale (minimal, mild, moderate, marked, severe). AE rates and severity were compared using Chi Square or Fisher's Exact Test depending on data characteristics. RESULT: Overall, no seizures or severe-rated AEs were reported by 165 pediatric participants. The rate of AE in all TBS sessions was 10.5% (n = 76, 95% CI: 4.7-19.7%), whereas the rate of AE in all sp/ppTMS sessions was 12.4% (n = 89, 95% CI: 6.3-21.0%). There was no statistical difference in AE rates between TBS and sp/ppTMS (p = 0.71). In all sp/ppTMS and TBS sessions, 20 subjects reported a total of 35 AEs, among these 31 (~88.6%) were rated as "minimal" or "mild". There was no difference in the severity of AE between TBS and sp/ppTMS (p = 1.0). Only one of 76 TBS participants reported an AE rated as more than minimal/mild. CONCLUSION: Our comparative analysis showed that TBS appears to be as safe as sp/ppTMS in terms of AE rate and severity. This report supports further investigation of TBS in children. PMID- 25698959 TI - Effect of foreknowledge on neural activity of primary "go" responses relates to response stopping and switching. AB - Being able to stop (or inhibit) an action rapidly as in a stop-signal task (SST) is an essential human ability. Previous studies showed that when a pre-stimulus cue warned of the possible need to stop a response in an upcoming trial, participants' response time (RT) increased if the subsequent trial required a "go" response (i.e., "go" RT cost) relative to a trial where this uncertainty was not present. This increase of the "go" RT correlated with more efficient response stopping. However, it remains a question whether foreknowledge of upcoming inhibition trials given prior to the task is sufficient to modulate neural activity associated with the primary "go" responses irrespective of whether stopping an overt response is required. We presented three task conditions with identical primary (i.e., "go") response trials but without pre-stimulus cues. Participants were informed that Condition 1 had only "go" trials (All-go condition), Condition 2 required a "stop" response for some trials (Stop condition), and Condition 3 required a response incongruent with the primary response (i.e., Switch response) for some trials (Switch condition). Participants performed the tasks during functional magnetic resonance imaging (fMRI) scans. Results showed a significant increase in the "go" RT (cost) in the Stop and Switch conditions relative to the All-go condition. The "go" RT cost was correlated with decreased inhibition time. fMRI activation in the frontal-basal ganglia regions during the "go" responses in the Stop and Switch conditions was also correlated with the efficiency of Stop and Switch responses. These results suggest that foreknowledge prior to the task is sufficient to influence neural activity associated with the primary response and modulate inhibition efficiency, irrespective of whether stopping an overt response is required. PMID- 25698961 TI - Refractoriness about adaptation. PMID- 25698960 TI - Temporal dynamics of attentional selection in adult male carriers of the fragile X premutation allele and adult controls. AB - Carriers of the fragile X premutation allele (fXPCs) have an expanded CGG trinucleotide repeat size within the FMR1 gene and are at increased risk of developing fragile x-associated tremor/ataxia syndrome (FXTAS). Previous research has shown that male fXPCs with FXTAS exhibit cognitive decline, predominantly in executive functions such as inhibitory control and working memory. Recent evidence suggests fXPCs may also exhibit impairments in processing temporal information. The attentional blink (AB) task is often used to examine the dynamics of attentional selection, but disagreements exist as to whether the AB is due to excessive or insufficient attentional control. In this study, we used a variant of the AB task and neuropsychological testing to explore the dynamics of attentional selection, relate AB performance to attentional control, and determine whether fXPCs exhibited temporal and/or attentional control impairments. Participants were adult male fXPCs, aged 18-48 years and asymptomatic for FXTAS (n = 19) and age-matched male controls (n = 20). We found that fXPCs did not differ from controls in the AB task, indicating that the temporal dynamics of attentional selection were intact. However, they were impaired in the letter-number sequencing task, a test of executive working memory. In the combined fXPC and control group, letter-number sequencing performance correlated positively with AB magnitude. This finding supports models that posit the AB is due to excess attentional control. In our two-pronged analysis approach, in control participants we replicated a previously observed effect and demonstrated that it persists under more stringent theoretical constraints, and we enhance our understanding of fXPCs by demonstrating that at least some aspects of temporal processing may be spared. PMID- 25698962 TI - Video game training and the reward system. AB - Video games contain elaborate reinforcement and reward schedules that have the potential to maximize motivation. Neuroimaging studies suggest that video games might have an influence on the reward system. However, it is not clear whether reward-related properties represent a precondition, which biases an individual toward playing video games, or if these changes are the result of playing video games. Therefore, we conducted a longitudinal study to explore reward-related functional predictors in relation to video gaming experience as well as functional changes in the brain in response to video game training. Fifty healthy participants were randomly assigned to a video game training (TG) or control group (CG). Before and after training/control period, functional magnetic resonance imaging (fMRI) was conducted using a non-video game related reward task. At pretest, both groups showed strongest activation in ventral striatum (VS) during reward anticipation. At posttest, the TG showed very similar VS activity compared to pretest. In the CG, the VS activity was significantly attenuated. This longitudinal study revealed that video game training may preserve reward responsiveness in the VS in a retest situation over time. We suggest that video games are able to keep striatal responses to reward flexible, a mechanism which might be of critical value for applications such as therapeutic cognitive training. PMID- 25698963 TI - Context-dependent memory decay is evidence of effort minimization in motor learning: a computational study. AB - Recent theoretical models suggest that motor learning includes at least two processes: error minimization and memory decay. While learning a novel movement, a motor memory of the movement is gradually formed to minimize the movement error between the desired and actual movements in each training trial, but the memory is slightly forgotten in each trial. The learning effects of error minimization trained with a certain movement are partially available in other non-trained movements, and this transfer of the learning effect can be reproduced by certain theoretical frameworks. Although most theoretical frameworks have assumed that a motor memory trained with a certain movement decays at the same speed during performing the trained movement as non-trained movements, a recent study reported that the motor memory decays faster during performing the trained movement than non-trained movements, i.e., the decay rate of motor memory is movement or context dependent. Although motor learning has been successfully modeled based on an optimization framework, e.g., movement error minimization, the type of optimization that can lead to context-dependent memory decay is unclear. Thus, context-dependent memory decay raises the question of what is optimized in motor learning. To reproduce context-dependent memory decay, I extend a motor primitive framework. Specifically, I introduce motor effort optimization into the framework because some previous studies have reported the existence of effort optimization in motor learning processes and no conventional motor primitive model has yet considered the optimization. Here, I analytically and numerically revealed that context-dependent decay is a result of motor effort optimization. My analyses suggest that context-dependent decay is not merely memory decay but is evidence of motor effort optimization in motor learning. PMID- 25698964 TI - Applying artificial vision models to human scene understanding. AB - How do we understand the complex patterns of neural responses that underlie scene understanding? Studies of the network of brain regions held to be scene-selective the parahippocampal/lingual region (PPA), the retrosplenial complex (RSC), and the occipital place area (TOS)-have typically focused on single visual dimensions (e.g., size), rather than the high-dimensional feature space in which scenes are likely to be neurally represented. Here we leverage well-specified artificial vision systems to explicate a more complex understanding of how scenes are encoded in this functional network. We correlated similarity matrices within three different scene-spaces arising from: (1) BOLD activity in scene-selective brain regions; (2) behavioral measured judgments of visually-perceived scene similarity; and (3) several different computer vision models. These correlations revealed: (1) models that relied on mid- and high-level scene attributes showed the highest correlations with the patterns of neural activity within the scene selective network; (2) NEIL and SUN-the models that best accounted for the patterns obtained from PPA and TOS-were different from the GIST model that best accounted for the pattern obtained from RSC; (3) The best performing models outperformed behaviorally-measured judgments of scene similarity in accounting for neural data. One computer vision method-NEIL ("Never-Ending-Image-Learner"), which incorporates visual features learned as statistical regularities across web scale numbers of scenes-showed significant correlations with neural activity in all three scene-selective regions and was one of the two models best able to account for variance in the PPA and TOS. We suggest that these results are a promising first step in explicating more fine-grained models of neural scene understanding, including developing a clearer picture of the division of labor among the components of the functional scene-selective brain network. PMID- 25698965 TI - Enhanced polychronization in a spiking network with metaplasticity. AB - Computational models of metaplasticity have usually focused on the modeling of single synapses (Shouval et al., 2002). In this paper we study the effect of metaplasticity on network behavior. Our guiding assumption is that the primary purpose of metaplasticity is to regulate synaptic plasticity, by increasing it when input is low and decreasing it when input is high. For our experiments we adopt a model of metaplasticity that demonstrably has this effect for a single synapse; our primary interest is in how metaplasticity thus defined affects network-level phenomena. We focus on a network-level phenomenon called polychronicity, that has a potential role in representation and memory. A network with polychronicity has the ability to produce non-synchronous but precisely timed sequences of neural firing events that can arise from strongly connected groups of neurons called polychronous neural groups (Izhikevich et al., 2004). Polychronous groups (PNGs) develop readily when spiking networks are exposed to repeated spatio-temporal stimuli under the influence of spike-timing-dependent plasticity (STDP), but are sensitive to changes in synaptic weight distribution. We use a technique we have recently developed called Response Fingerprinting to show that PNGs formed in the presence of metaplasticity are significantly larger than those with no metaplasticity. A potential mechanism for this enhancement is proposed that links an inherent property of integrator type neurons called spike latency to an increase in the tolerance of PNG neurons to jitter in their inputs. PMID- 25698966 TI - Cochlear injury and adaptive plasticity of the auditory cortex. AB - Growing evidence suggests that cochlear stressors as noise exposure and aging can induce homeostatic/maladaptive changes in the central auditory system from the brainstem to the cortex. Studies centered on such changes have revealed several mechanisms that operate in the context of sensory disruption after insult (noise trauma, drug-, or age-related injury). The oxidative stress is central to current theories of induced sensory-neural hearing loss and aging, and interventions to attenuate the hearing loss are based on antioxidant agent. The present review addresses the recent literature on the alterations in hair cells and spiral ganglion neurons due to noise-induced oxidative stress in the cochlea, as well on the impact of cochlear damage on the auditory cortex neurons. The emerging image emphasizes that noise-induced deafferentation and upward spread of cochlear damage is associated with the altered dendritic architecture of auditory pyramidal neurons. The cortical modifications may be reversed by treatment with antioxidants counteracting the cochlear redox imbalance. These findings open new therapeutic approaches to treat the functional consequences of the cortical reorganization following cochlear damage. PMID- 25698967 TI - Fornix White Matter is Correlated with Resting-State Functional Connectivity of the Thalamus and Hippocampus in Healthy Aging but Not in Mild Cognitive Impairment - A Preliminary Study. AB - In this study, we wished to examine the relationship between the structural connectivity of the fornix, a white matter (WM) tract in the limbic system, which is affected in amnestic mild cognitive impairment (aMCI) and Alzheimer's disease, and the resting-state functional connectivity (FC) of two key related subcortical structures, the thalamus, and hippocampus. Twenty-two older healthy controls (HC) and 18 older adults with aMCI underwent multi-modal MRI scanning. The fornix was reconstructed using constrained-spherical deconvolution-based tractography. The FC between the thalamus and hippocampus was calculated using a region-of-interest approach from which the mean time series were exacted and correlated. Diffusion tensor imaging measures of the WM microstructure of the fornix were correlated against the Fisher Z correlation values from the FC analysis. There was no difference between the groups in the fornix WM measures, nor in the resting-state FC of the thalamus and hippocampus. We did however find that the relationship between functional and structural connectivity differed significantly between the groups. In the HCs, there was a significant positive association between linear diffusion (CL) in the fornix and the FC of the thalamus and hippocampus, however, there was no relationship between these measures in the aMCI group. These preliminary findings suggest that in aMCI, the relationship between the functional and structural connectivity of regions of the limbic system may be significantly altered compared to healthy ageing. The combined use of diffusion weighted imaging and functional MRI may advance our understanding of neural network changes in aMCI, and elucidate subtle changes in the relationship between structural and functional brain networks. PMID- 25698969 TI - Kinin B1 receptor antagonism is equally efficient as angiotensin receptor 1 antagonism in reducing renal fibrosis in experimental obstructive nephropathy, but is not additive. AB - BACKGROUND: Renal tubulointerstitial fibrosis is the pathological hallmark of chronic kidney disease (CKD). Currently, inhibitors of the renin-angiotensin system (RAS) remain the sole therapy in human displaying antifibrotic properties. Further antifibrotic molecules are needed. We have recently reported that the delayed blockade of the bradykinin B1 receptor (B1R) reduced the development of fibrosis in two animal models of renal fibrosis. The usefulness of new drugs also resides in outperforming the gold standards and eventually being additive or complementary to existing therapies. METHODS: In this study we compared the efficacy of a B1R antagonist (B1Ra) with that of an angiotensin type 1 receptor antagonist (AT1a) in the unilateral ureteral obstruction (UUO) model of renal fibrosis and determined whether bi-therapy presented higher efficacy than any of the drugs alone. RESULTS: B1R antagonism was as efficient as the gold-standard AT1a treatment. However, bitherapy did not improve the antifibrotic effects at the protein level. We sought for the reason of the absence of this additive effect by studying the expression of a panel of genes involved in the fibrotic process. Interestingly, at the molecular level the different drugs targeted different players of fibrosis that, however, in this severe model did not result in improved reduction of fibrosis at the protein level. CONCLUSIONS: As the B1R is induced specifically in the diseased organ and thus potentially displays low side effects it might be an interesting alternative in cases of poor tolerability to RAS inhibitors. PMID- 25698968 TI - Interactions of the opioid and cannabinoid systems in reward: Insights from knockout studies. AB - The opioid system consists of three receptors, mu, delta, and kappa, which are activated by endogenous opioid peptides (enkephalins, endorphins, and dynorphins). The endogenous cannabinoid system comprises lipid neuromodulators (endocannabinoids), enzymes for their synthesis and their degradation and two well-characterized receptors, cannabinoid receptors CB1 and CB2. These systems play a major role in the control of pain as well as in mood regulation, reward processing and the development of addiction. Both opioid and cannabinoid receptors are coupled to G proteins and are expressed throughout the brain reinforcement circuitry. Extending classical pharmacology, research using genetically modified mice has provided important progress in the identification of the specific contribution of each component of these endogenous systems in vivo on reward process. This review will summarize available genetic tools and our present knowledge on the consequences of gene knockout on reinforced behaviors in both systems, with a focus on their potential interactions. A better understanding of opioid-cannabinoid interactions may provide novel strategies for therapies in addicted individuals. PMID- 25698970 TI - A genomic approach to study down syndrome and cancer inverse comorbidity: untangling the chromosome 21. AB - Down syndrome (DS), one of the most common birth defects and the most widespread genetic cause of intellectual disabilities, is caused by extra genetic material on chromosome 21 (HSA21). The increased genomic dosage of trisomy 21 is thought to be responsible for the distinct DS phenotypes, including an increased risk of developing some types of childhood leukemia and germ cell tumors. Patients with DS, however, have a strikingly lower incidence of many other solid tumors. We hypothesized that the third copy of genes located in HSA21 may have an important role on the protective effect that DS patients show against most types of solid tumors. Focusing on Copy Number Variation (CNV) array data, we have generated frequencies of deleted regions in HSA21 in four different tumor types from which DS patients have been reported to be protected. We describe three different regions of deletion pointing to a set of candidate genes that could explain the inverse comorbidity phenomenon between DS and solid tumors. In particular we found RCAN1 gene in Wilms tumors and a miRNA cluster containing miR-99A, miR 125B2 and miR-LET7C in lung, breast, and melanoma tumors as the main candidates for explaining the inverse comorbidity observed between solid tumors and DS. PMID- 25698971 TI - A1M/alpha1-microglobulin is proteolytically activated by myeloperoxidase, binds its heme group and inhibits low density lipoprotein oxidation. AB - alpha1-microglobulin (A1M) is a 26 kDa plasma and tissue protein with reductase activity and radical- and heme-binding anti-oxidative functions. In addition, exposure of A1M to hemoglobin has been shown to induce proteolytic elimination of a C-terminal tetrapeptide yielding a heme-degrading form, truncated A1M (t-A1M). Myeloperoxidase (MPO), a heme-containing enzyme that catalyzes the production of free radicals and hypochlorite, is released by neutrophils during the inflammatory response to bacterial infections. MPO-induced low density lipoprotein (LDL)-oxidation in blood has been suggested as a causative factor in atherosclerosis. In this study we have hypothesized that A1M interacts with MPO in a similar mode as with hemoglobin, and is a regulator of its activity. The results show that A1M is proteolytically cleaved, with formation of t-A1M, after exposure to MPO, and that t-A1M contains iron and heme-degradation products. The reaction is dependent of pH, time and concentration of substrates and a pH-value around 7 is shown to be optimal for cleavage. Furthermore, A1M inhibits MPO- and hydrogen peroxide-induced oxidation of LDL. The results suggest that A1M may have a role as an inhibitor of the damaging effects of the neutrophil respiratory burst on bystander tissue components. PMID- 25698972 TI - Dynamics of networks during absence seizure's on- and offset in rodents and man. AB - Network mechanisms relevant for the generation, maintenance and termination of spike-wave discharges (SWD), the neurophysiological hallmark of absence epilepsy, are still enigmatic and widely discussed. Within the last years, however, improvements in signal analytical techniques, applied to both animal and human fMRI, EEG, MEG, and ECoG data, greatly increased our understanding and challenged several, dogmatic concepts of SWD. This review will summarize these recent data, demonstrating that SWD are not primary generalized, are not sudden and unpredictable events. It will disentangle different functional contributions of structures within the cortico-thalamo-cortical system, relevant for the generation, generalization, maintenance, and termination of SWD and will present a new "network based" scenario for these oscillations. Similarities and differences between rodent and human data are presented demonstrating that in both species a local cortical onset zone of SWD exists, although with different locations; that in both some forms of cortical and thalamic precursor activity can be found, and that SWD occur through repetitive cyclic activity between cortex and thalamus. The focal onset zone in human data could differ between patients with varying spatial and temporal dynamics; in rats the latter is still poorly investigated. PMID- 25698973 TI - Ca(2+) cycling properties are conserved despite bradycardic effects of heart failure in sinoatrial node cells. AB - BACKGROUND: In animal models of heart failure (HF), heart rate decreases due to an increase in intrinsic cycle length (CL) of the sinoatrial node (SAN). Pacemaker activity of SAN cells is complex and modulated by the membrane clock, i.e., the ensemble of voltage gated ion channels and electrogenic pumps and exchangers, and the Ca(2+) clock, i.e., the ensemble of intracellular Ca(2+) ([Ca(2+)]i) dependent processes. HF in SAN cells results in remodeling of the membrane clock, but few studies have examined its effects on [Ca(2+)]i homeostasis. METHODS: SAN cells were isolated from control rabbits and rabbits with volume and pressure overload-induced HF. [Ca(2+)]i concentrations, and action potentials (APs) and Na(+)-Ca(2+) exchange current (INCX) were measured using indo-1 and patch-clamp methodology, respectively. RESULTS: The frequency of spontaneous [Ca(2+)]i transients was significantly lower in HF SAN cells (3.0 +/- 0.1 (n = 40) vs. 3.4 +/- 0.1 Hz (n = 45); mean +/- SEM), indicating that intrinsic CL was prolonged. HF slowed the [Ca(2+)]i transient decay, which could be explained by the slower frequency and reduced sarcoplasmic reticulum (SR) dependent rate of Ca(2+) uptake. Other [Ca(2+)]i transient parameters, SR Ca(2+) content, INCX density, and INCX-[Ca(2+)]i relationship were all unaffected by HF. Combined AP and [Ca(2+)]i recordings demonstrated that the slower [Ca(2+)]i transient decay in HF SAN cells may result in increased INCX during the diastolic depolarization, but that this effect is likely counteracted by the HF-induced increase in intracellular Na(+). beta-adrenergic and muscarinic stimulation were not changed in HF SAN cells, except that late diastolic [Ca(2+)]i rise, a prominent feature of the Ca(2+) clock, is lower during beta-adrenergic stimulation. CONCLUSIONS: HF SAN cells have a slower [Ca(2+)]i transient decay with limited effects on pacemaker activity. Reduced late diastolic [Ca(2+)]i rise during beta-adrenergic stimulation may contribute to an impaired increase in intrinsic frequency in HF SAN cells. PMID- 25698974 TI - Functional role of voltage gated Ca(2+) channels in heart automaticity. AB - Pacemaker activity of automatic cardiac myocytes controls the heartbeat in everyday life. Cardiac automaticity is under the control of several neurotransmitters and hormones and is constantly regulated by the autonomic nervous system to match the physiological needs of the organism. Several classes of ion channels and proteins involved in intracellular Ca(2+) dynamics contribute to pacemaker activity. The functional role of voltage-gated calcium channels (VGCCs) in heart automaticity and impulse conduction has been matter of debate for 30 years. However, growing evidence shows that VGCCs are important regulators of the pacemaker mechanisms and play also a major role in atrio-ventricular impulse conduction. Incidentally, studies performed in genetically modified mice lacking L-type Cav1.3 (Cav1.3(-/-)) or T-type Cav3.1 (Cav3.1(-/-)) channels show that genetic inactivation of these channels strongly impacts pacemaking. In cardiac pacemaker cells, VGCCs activate at negative voltages at the beginning of the diastolic depolarization and importantly contribute to this phase by supplying inward current. Loss-of-function of these channels also impairs atrio ventricular conduction. Furthermore, inactivation of Cav1.3 channels promotes also atrial fibrillation and flutter in knockout mice suggesting that these channels can play a role in stabilizing atrial rhythm. Genomic analysis demonstrated that Cav1.3 and Cav3.1 channels are widely expressed in pacemaker tissue of mice, rabbits and humans. Importantly, human diseases of pacemaker activity such as congenital bradycardia and heart block have been attributed to loss-of-function of Cav1.3 and Cav3.1 channels. In this article, we will review the current knowledge on the role of VGCCs in the generation and regulation of heart rate and rhythm. We will discuss also how loss of Ca(2+) entry through VGCCs could influence intracellular Ca(2+) handling and promote atrial arrhythmias. PMID- 25698975 TI - Age affects the contraction-induced mitochondrial redox response in skeletal muscle. AB - Compromised mitochondrial respiratory function is associated with advancing age. Damage due to an increase in reactive oxygen species (ROS) with age is thought to contribute to the mitochondrial deficits. The coenzyme nicotinamide adenine dinucleotide in its reduced (NADH) and oxidized (NAD(+)) forms plays an essential role in the cyclic sequence of reactions that result in the regeneration of ATP by oxidative phosphorylation in mitochondria. Monitoring mitochondrial NADH/NAD(+) redox status during recovery from an episode of high energy demand thus allows assessment of mitochondrial function. NADH fluoresces when excited with ultraviolet light in the UV-A band and NAD(+) does not, allowing NADH/NAD(+) to be monitored in real time using fluorescence microscopy. Our goal was to assess mitochondrial function by monitoring the NADH fluorescence response following a brief period of high energy demand in muscle from adult and old wild type mice. This was accomplished by isolating whole lumbrical muscles from the hind paws of 7- and 28-month-old mice and making simultaneous measurements of force and NADH fluorescence responses during and after a 5 s maximum isometric contraction. All muscles exhibited fluorescence oscillations that were qualitatively similar and consisted of a brief transient increase followed by a longer transient period of reduced fluorescence and, finally, an increase that included an overshoot before recovering to resting level. Compared with the adult mice, muscles from the 28 mo mice exhibited a delayed peak during the first fluorescence transient and an attenuated recovery following the second transient. These findings indicate an impaired mitochondrial capacity to maintain NADH/NAD(+) redox homeostasis during contractile activity in skeletal muscles of old mice. PMID- 25698976 TI - Myocardial electrotonic response to submaximal exercise in dogs with healed myocardial infarctions: evidence for beta-adrenoceptor mediated enhanced coupling during exercise testing. AB - INTRODUCTION: Autonomic neural activation during cardiac stress testing is an established risk-stratification tool in post-myocardial infarction (MI) patients. However, autonomic activation can also modulate myocardial electrotonic coupling, a known factor to contribute to the genesis of arrhythmias. The present study tested the hypothesis that exercise-induced autonomic neural activation modulates electrotonic coupling (as measured by myocardial electrical impedance, MEI) in post-MI animals shown to be susceptible or resistant to ventricular fibrillation (VF). METHODS: Dogs (n = 25) with healed MI instrumented for MEI measurements were trained to run on a treadmill and classified based on their susceptibility to VF (12 susceptible, 9 resistant). MEI and ECGs were recorded during 6-stage exercise tests (18 min/test; peak: 6.4 km/h @ 16%) performed under control conditions, and following complete beta-adrenoceptor (beta-AR) blockade (propranolol); MEI was also measured at rest during escalating beta-AR stimulation (isoproterenol) or overdrive-pacing. RESULTS: Exercise progressively increased heart rate (HR) and reduced heart rate variability (HRV). In parallel, MEI decreased gradually (enhanced electrotonic coupling) with exercise; at peak exercise, MEI was reduced by 5.3 +/- 0.4% (or -23 +/- 1.8Omega, P < 0.001). Notably, exercise-mediated electrotonic changes were linearly predicted by the degree of autonomic activation, as indicated by changes in either HR or in HRV (P < 0.001). Indeed, beta-AR blockade attenuated the MEI response to exercise while direct beta-AR stimulation (at rest) triggered MEI decreases comparable to those observed during exercise; ventricular pacing had no significant effects on MEI. Finally, animals prone to VF had a significantly larger MEI response to exercise. CONCLUSIONS: These data suggest that beta-AR activation during exercise can acutely enhance electrotonic coupling in the myocardium, particularly in dogs susceptible to ischemia-induced VF. PMID- 25698977 TI - Stress and the commensal microbiota: importance in parturition and infant neurodevelopment. AB - The body is colonized by an enormous array of microbes that are collectively called the microbiota. During quiescent periods, microbial communities within the gut are relatively resistant to change. However, several factors that disrupt homeostasis can also significantly change gut microbial community structure. One factor that has been shown to change the composition of the gut microbiota is exposure to psychological stressors. Studies demonstrate that the commensal microbiota are involved in stressor-induced immunomodulation, but other biological effects are not yet known. This review discusses emerging evidence that the microbiota can impact the brain and behavior and indicates that stressor induced alterations in the composition of gut microbial communities contribute to stressor-induced behavioral changes. This review will also discuss the evidence that such effects are most evident early in life, where both stress and the microbiota have been linked to birth outcomes, such as prematurity, and neurodevelopment. When considered together, a paradigm emerges in which stressor induced alterations in commensal microbial populations significantly impact parturition and infant neurodevelopment. PMID- 25698978 TI - An efficient chronic unpredictable stress protocol to induce stress-related responses in C57BL/6 mice. AB - Exposure to chronic stress can have broad effects on health ranging from increased predisposition for neuropsychiatric disorders to deregulation of immune responses. The chronic unpredictable stress (CUS) protocol has been widely used to study the impact of stress exposure in several animal models and consists in the random, intermittent, and unpredictable exposure to a variety of stressors during several weeks. CUS has consistently been shown to induce behavioral and immunological alterations typical of the chronic stress-response. Unfortunately C57BL/6 mice, one of the most widely used mouse strains, due to the great variety of genetically modified lines, seem to be resistant to the commonly used 4-week long CUS protocol. The definition of an alternative CUS protocol allowing the use of C57BL/6 mice in chronic stress experiments is a need. Here, we show that by extending the CUS protocol to 8 weeks is possible to induce a chronic stress response in C57BL/6 mice, as revealed by abrogated body weight gain, increased adrenals weight, and an overactive hypothalamic-pituitary-adrenal axis with increased levels of serum corticosterone. Moreover, we also observed stress associated behavioral alterations, including the potentiation of anxious-like and depressive-like behaviors and a reduction of exploratory behavior, as well as subtle stress-related changes in the cell population of the thymus and of the spleen. The present protocol for C57BL/6 mice consistently triggers the spectrum of CUS-induced changes observed in rats and, thus, will be highly useful to researchers that need to use this particular mouse strain as an animal model of neuropsychiatric disorders and/or immune deregulation related to CUS. PMID- 25698979 TI - Involuntary cognitions in everyday life: exploration of type, quality, content, and function. AB - Psychological research into spontaneous or intrusive cognitions has typically focused on cognitions in one predefined domain, such as obsessional thoughts in OCD, intrusive memories in posttraumatic stress disorder and depression, or involuntary autobiographical memories and daydreaming in everyday life. Such studies have resulted in a wealth of knowledge about these specific cognitions. However, by focusing on a predefined type of cognition, other subtypes of cognition that may co-occur can be missed. In this exploratory study, we aimed to assess involuntary cognitions in everyday life without a pre-determined focus on any specific subtype of cognition. Seventy unselected undergraduate student participants were administered a questionnaire that assessed the presence of any involuntary cognitions in the past month, their quality, type, content, and potential function. In addition, participants provided self-descriptions and completed measures of psychopathology. Content analyses showed that involuntary cognitions were common, predominantly visual in nature, emotional, often about social relationships, and often related to a hypothetical function of emotional processing. About two-thirds of the cognitions that participants reported were memories. Non-memories included daydreams, imaginary worst case scenarios, imaginary future events, hypothetical reconstructions, and ruminations. Memories and non-memories were strikingly similar in their subjective experience of content and emotionality. Negative (but not positive) self-descriptions were associated with negative involuntary cognitions and psychopathology, suggesting a link between involuntary cognitions and the self. Overall, the findings suggest that people experience a wide variety of subtypes of involuntary cognitions in everyday life. Moreover, the specific subtype of involuntary cognition appears to be less important than its valence or content, at least to the subjective experience of the individual. PMID- 25698980 TI - Burnout and Hypocortisolism - A Matter of Severity? A Study on ACTH and Cortisol Responses to Acute Psychosocial Stress. AB - BACKGROUND: Common consequences of long-term psychosocial stress are fatigue and burnout. It has been suggested that burnout could be associated with hypocortisolism, thus, inability to produce sufficient amounts of cortisol. This study aimed to investigate whether patients with clinical burnout exhibit aberrant ACTH and cortisol responses under acute psychosocial stress compared with healthy individuals. METHODS: Nineteen patients (9 men and 10 women) and 37 healthy subjects (20 men and 17 women), underwent the Trier Social Stress Test. Blood samples and saliva samples were collected before, after, and during the stress test for measurements of plasma ACTH, serum cortisol, and salivary cortisol. Several statistical analyses were conducted to compare the responses between patients and controls. In addition, in order to investigate the possibility that burnout patients with more severe symptoms would respond differently, sub-groups of patients reporting higher and lower burnout scores were compared. RESULTS: In both patients and healthy controls, we observed elevated levels of ACTH and cortisol after exposure to the stressor. There were no differences in responses of ACTH, serum cortisol, or salivary cortisol between patients and controls. Patients reporting higher burnout scores had lower salivary cortisol responses than controls, indicating that patients with more severe burnout symptoms may be suffering from hypocortisolism. In addition, patients with more severe burnout symptoms tended to have smaller ACTH responses than the other patients. However, there was no corresponding difference in serum cortisol. CONCLUSION: This study indicates that hypocortisolism is not present in a clinical burnout patient group as a whole but may be present in the patients with more severe burnout symptoms. PMID- 25698981 TI - The Longitudinal Course of Gross Motor Activity in Schizophrenia - Within and between Episodes. AB - Schizophrenia is associated with heterogeneous course of positive and negative symptoms. In addition, reduced motor activity as measured by wrist actigraphy has been reported. However, longitudinal studies of spontaneous motor activity are missing. We aimed to explore whether activity levels were stable within and between psychotic episodes. Furthermore, we investigated the association with the course of negative symptoms. In 45 medicated patients, we investigated motor behavior within a psychotic episode. In addition, we followed 18 medicated patients across 2 episodes. Wrist actigraphy and psychopathological ratings were applied. Within an episode symptoms changed but activity levels did not vary systematically. Activity at baseline predicted the course of negative symptoms. Between two episodes activity recordings were much more stable. Again, activity at the index episode predicted the outcome of negative symptoms. In sum, spontaneous motor activity shares trait and state characteristics, the latter are associated with negative symptom course. Actigraphy may therefore become an important ambulatory instrument to monitor negative symptoms and treatment outcome in schizophrenia. PMID- 25698982 TI - Is conflict adaptation triggered by feature repetitions? An unexpected finding. AB - For decades, cognitive adaptation to response conflict has been considered to be the hallmark of cognitive control. Notwithstanding a vast amount of evidence ruling out low-level interpretations of these findings, disbelief still exists with regard to the underlying cause of the observed effects. Especially when considering cognitive adaptation to unconscious conflict, it is still a matter of debate whether repetitions of features between trials might explain this intriguing finding rather than the involvement of unconscious control. To this purpose, we conducted two masked priming experiments in which four different responses to four different stimuli were required. This allowed us to completely eliminate repetitions of prime and target over consecutive trials. Independent of whether conflicting information was presented clearly visible or almost imperceptible, the results showed an unexpected pattern. Contrary to the regular congruency sequence effect (CSE; i.e., classic Gratton effect), in both experiments the congruency effect increased following incongruent trials. Interestingly, this reversed effect completely disappeared when we eliminated all trials with feature repetitions from the analysis. A third experiment, in which feature repetitions were excluded a priori, showed a small but regular CSE in the error rates only. Given that feature repetitions are theoretically thought to create a regular CSE, our results are not in line with an interpretation in terms of feature repetitions nor with an interpretation in terms of cognitive control. We conclude that examining cognitive adaptation with or without feature repetitions might be more difficult to conceive than is often suggested in the literature. PMID- 25698983 TI - A framework for using magic to study the mind. AB - Over the centuries, magicians have developed extensive knowledge about the manipulation of the human mind-knowledge that has been largely ignored by psychology. It has recently been argued that this knowledge could help improve our understanding of human cognition and consciousness. But how might this be done? And how much could it ultimately contribute to the exploration of the human mind? We propose here a framework outlining how knowledge about magic can be used to help us understand the human mind. Various approaches-both old and new-are surveyed, in terms of four different levels. The first focuses on the methods in magic, using these to suggest new approaches to existing issues in psychology. The second focuses on the effects that magic can produce, such as the sense of wonder induced by seeing an apparently impossible event. Third is the consideration of magic tricks-methods and effects together-as phenomena of scientific interest in their own right. Finally, there is the organization of knowledge about magic into an informative whole, including the possibility of a science centered around the experience of wonder. PMID- 25698984 TI - Are ambiguity aversion and ambiguity intolerance identical? A neuroeconomics investigation. AB - In recent years, there has been growing interest in understanding a person's reaction to ambiguous situations, and two similar constructs related to ambiguity, "ambiguity aversion" and "ambiguity intolerance," are defined in different disciplines. In the field of economic decision-making research, "ambiguity aversion" represents a preference for known risks relative to unknown risks. On the other hand, in clinical psychology, "ambiguity intolerance" describes the tendency to perceive ambiguous situations as undesirable. However, it remains unclear whether these two notions derived from different disciplines are identical or not. To clarify this issue, we combined an economic task, psychological questionnaires, and voxel-based morphometry (VBM) of structural brain magnetic resonance imaging (MRI) in a sample of healthy volunteers. The individual ambiguity aversion tendency parameter, as measured by our economic task, was negatively correlated with agreeableness scores on the self-reported version of the Revised NEO Personality Inventory. However, it was not correlated with scores of discomfort with ambiguity, one of the subscales of the Need for Closure Scale. Furthermore, the ambiguity aversion tendency parameter was negatively correlated with gray matter (GM) volume of areas in the lateral prefrontal cortex and parietal cortex, whereas ambiguity intolerance was not correlated with GM volume in any region. Our results suggest that ambiguity aversion, described in decision theory, may not necessarily be identical to ambiguity intolerance, referred to in clinical psychology. Cautious applications of decision theory to clinical neuropsychiatry are recommended. PMID- 25698985 TI - Validation of the Chinese version of the Clinical Assessment Interview for Negative Symptoms (CAINS): a preliminary report. AB - The present study aimed to examine the psychometric properties of the Chinese version of the Clinical Assessment Interview for Negative Symptoms (CAINS). We recruited 68 patients with schizophrenia from the Chinese setting. The findings showed a generally consistent two-factor structure with the original version, namely "expression" and "motivation-pleasure." There is a minor cultural variation in perceiving these items in the Chinese culture. However, the present study demonstrated that the Chinese version of the CAINS appears to be a valid and reliable clinical tool for the assessment of negative symptoms in the Chinese setting. PMID- 25698986 TI - The role of audience participation and task relevance on change detection during a card trick. AB - Magicians utilize many techniques for misdirecting audience attention away from the secret sleight of a trick. One technique is to ask an audience member to participate in a trick either physically by asking them to choose a card or cognitively by having them keep track of a card. While such audience participation is an established part of most magic the cognitive mechanisms by which it operates are unknown. Failure to detect changes to objects while passively viewing magic tricks has been shown to be conditional on the changing feature being irrelevant to the current task. How change blindness operates during interactive tasks is unclear but preliminary evidence suggests that relevance of the changing feature may also play a role (Triesch et al., 2003). The present study created a simple on-line card trick inspired by Triesch et al.'s (2003) that allowed playing cards to be instantaneously replaced without distraction or occlusion as participants were either actively sorting the cards (Doing condition) or watching another person perform the task (Watching conditions). Participants were given one of three sets of instructions. The relevance of the card color to the task increased across the three instructions. During half of the trials a card changed color (but retained its number) as it was moving to the stack. Participants were instructed to immediately report such changes. Analysis of the probability of reporting a change revealed that actively performing the sorting task led to more missed changes than passively watching the same task but only when the changing feature was irrelevant to the sorting task. If the feature was relevant during either the pick-up or put-down action change detection was as good as during the watching block. These results confirm the ability of audience participation to create subtle dynamics of attention and perception during a magic trick and hide otherwise striking changes at the center of attention. PMID- 25698987 TI - The Trier Social Stress Test as a paradigm to study how people respond to threat in social interactions. AB - In our lives, we face countless situations in which we are observed and evaluated by our social interaction partners. Social-evaluative threat is frequently associated with strong neurophysiological stress reactions, in particular, an increase in cortisol levels. Yet, social variables do not only cause stress, but they can also buffer the neurophysiological stress response. Furthermore, social variables can themselves be affected by the threat or the threat-induced neurophysiological stress response. In order to study this complex interplay of social-evaluative threat, social processes and neurophysiological stress responses, a paradigm is needed that (a) reliably induces high levels of social evaluative threat and (b) is extremely adaptable to the needs of the researcher. The Trier Social Stress Test (TSST) is a well-established paradigm in biopsychology that induces social-evaluative threat in the laboratory by subjecting participants to a mock job-interview. In this review, we aim at demonstrating the potential of the TSST for studying the complex interplay of social-evaluative threat, social processes and neurophysiological stress responses. PMID- 25698988 TI - Mindfulness training promotes upward spirals of positive affect and cognition: multilevel and autoregressive latent trajectory modeling analyses. AB - Recent theory suggests that positive psychological processes integral to health may be energized through the self-reinforcing dynamics of an upward spiral to counter emotion dysregulation. The present study examined positive emotion cognition interactions among individuals in partial remission from depression who had been randomly assigned to treatment with mindfulness-based cognitive therapy (MBCT; n = 64) or a waitlist control condition (n = 66). We hypothesized that MBCT stimulates upward spirals by increasing positive affect and positive cognition. Experience sampling assessed changes in affect and cognition during 6 days before and after treatment, which were analyzed with a series of multilevel and autoregressive latent trajectory models. Findings suggest that MBCT was associated with significant increases in trait positive affect and momentary positive cognition, which were preserved through autoregressive and cross-lagged effects driven by global emotional tone. Findings suggest that daily positive affect and cognition are maintained by an upward spiral that might be promoted by mindfulness training. PMID- 25698989 TI - Ketosis, ketogenic diet and food intake control: a complex relationship. AB - Though the hunger-reduction phenomenon reported during ketogenic diets is well known, the underlying molecular and cellular mechanisms remain uncertain. Ketosis has been demonstrated to exert an anorexigenic effect via cholecystokinin (CCK) release while reducing orexigenic signals e.g., via ghrelin. However, ketone bodies (KB) seem to be able to increase food intake through AMP-activated protein kinase (AMPK) phosphorylation, gamma-aminobutyric acid (GABA) and the release and production of adiponectin. The aim of this review is to provide a summary of our current knowledge of the effects of ketogenic diet (KD) on food control in an effort to unify the apparently contradictory data into a coherent picture. PMID- 25698990 TI - Small samples and evolution: did the law of small numbers arise as an adaptation to environmental challenges? PMID- 25698991 TI - Psychological effects of implantable cardioverter defibrillator shocks. A review of study methods. AB - BACKGROUND: The implantable cardioverter defibrillator (ICD) saves lives but clinical experience suggests that it may have detrimental effects on mental health. The ICD shock has been largely blamed as the main offender but empirical evidence is not consistent, perhaps because of methodological differences across studies. OBJECTIVE: To appraise methodologies of studies that assessed the psychological effects of ICD shock and explore associations between methods and results. DATA SOURCES: A comprehensive search of English articles that were published between 1980 and 30 June 2013 was applied to the following electronic databases: PubMed, EMBASE, NHS HTA database, PsycINFO, Sciencedirect and CINAHL. REVIEW METHODS: Only studies testing the effects of ICD shock on psychological and quality of life outcomes were included. Data were extracted according to a PICOS pre-defined sheet including methods and study quality indicators. RESULTS: Fifty-four observational studies and six randomized controlled trials met the inclusion criteria. Multiple differences in methods that were used to test the psychological effects of ICD shock were found across them. No significant association with results was observed. CONCLUSIONS: Methodological heterogeneity of study methods is too wide and limits any quantitative attempt to account for the mixed findings. Well-built and standardized research is urgently needed. PMID- 25698992 TI - Vision in schizophrenia: why it matters. PMID- 25698993 TI - Using eye tracking to test for individual differences in attention to attractive faces. AB - We assessed individual differences in visual attention toward faces in relation to their attractiveness via saccadic reaction times. Motivated by the aim to understand individual differences in attention to faces, we tested three hypotheses: (a) Attractive faces hold or capture attention more effectively than less attractive faces; (b) men show a stronger bias toward attractive opposite sex faces than women; and (c) blue-eyed men show a stronger bias toward blue-eyed than brown-eyed feminine faces. The latter test was included because prior research suggested a high effect size. Our data supported hypotheses (a) and (b) but not (c). By conducting separate tests for disengagement of attention and attention capture, we found that individual differences exist at distinct stages of attentional processing but these differences are of varying robustness and importance. In our conclusion, we also advocate the use of linear mixed effects models as the most appropriate statistical approach for studying inter-individual differences in visual attention with naturalistic stimuli. PMID- 25698994 TI - Teaching statistics using dance and movement. PMID- 25698995 TI - Processes in arithmetic strategy selection: a fMRI study. AB - This neuroimaging (functional magnetic resonance imaging) study investigated neural correlates of strategy selection. Young adults performed an arithmetic task in two different conditions. In both conditions, participants had to provide estimates of two-digit multiplication problems like 54 * 78. In the choice condition, participants had to select the better of two available rounding strategies, rounding-up (RU) strategy (i.e., doing 60 * 80 = 4,800) or rounding down (RD) strategy (i.e., doing 50 * 70 = 3,500 to estimate product of 54 * 78). In the no-choice condition, participants did not have to select strategy on each problem but were told which strategy to use; they executed RU and RD strategies each on a series of problems. Participants also had a control task (i.e., providing correct products of multiplication problems like 40 * 50). Brain activations and performance were analyzed as a function of these conditions. Participants were able to frequently choose the better strategy in the choice condition; they were also slower when they executed the difficult RU than the easier RD. Neuroimaging data showed greater brain activations in right anterior cingulate cortex (ACC), dorso-lateral prefrontal cortex (DLPFC), and angular gyrus (ANG), when selecting (relative to executing) the better strategy on each problem. Moreover, RU was associated with more parietal cortex activation than RD. These results suggest an important role of fronto-parietal network in strategy selection and have important implications for our further understanding and modeling cognitive processes underlying strategy selection. PMID- 25698996 TI - Does verbatim sentence recall underestimate the language competence of near native speakers? AB - Verbatim sentence recall is widely used to test the language competence of native and non-native speakers since it involves comprehension and production of connected speech. However, we assume that, to maintain surface information, sentence recall relies particularly on attentional resources, which differentially affects native and non-native speakers. Since even in near-natives language processing is less automatized than in native speakers, processing a sentence in a foreign language plus retaining its surface may result in a cognitive overload. We contrasted sentence recall performance of German native speakers with that of highly proficient non-natives. Non-natives recalled the sentences significantly poorer than the natives, but performed equally well on a cloze test. This implies that sentence recall underestimates the language competence of good non-native speakers in mixed groups with native speakers. The findings also suggest that theories of sentence recall need to consider both its linguistic and its attentional aspects. PMID- 25698997 TI - Children with speech sound disorder: comparing a non-linguistic auditory approach with a phonological intervention approach to improve phonological skills. AB - This study aimed to compare the effects of a non-linguistic auditory intervention approach with a phonological intervention approach on the phonological skills of children with speech sound disorder (SSD). A total of 17 children, aged 7-12 years, with SSD were randomly allocated to either the non-linguistic auditory temporal intervention group (n = 10, average age 7.7 +/- 1.2) or phonological intervention group (n = 7, average age 8.6 +/- 1.2). The intervention outcomes included auditory-sensory measures (auditory temporal processing skills) and cognitive measures (attention, short-term memory, speech production, and phonological awareness skills). The auditory approach focused on non-linguistic auditory training (e.g., backward masking and frequency discrimination), whereas the phonological approach focused on speech sound training (e.g., phonological organization and awareness). Both interventions consisted of 12 45-min sessions delivered twice per week, for a total of 9 h. Intra-group analysis demonstrated that the auditory intervention group showed significant gains in both auditory and cognitive measures, whereas no significant gain was observed in the phonological intervention group. No significant improvement on phonological skills was observed in any of the groups. Inter-group analysis demonstrated significant differences between the improvement following training for both groups, with a more pronounced gain for the non-linguistic auditory temporal intervention in one of the visual attention measures and both auditory measures. Therefore, both analyses suggest that although the non-linguistic auditory intervention approach appeared to be the most effective intervention approach, it was not sufficient to promote the enhancement of phonological skills. PMID- 25698998 TI - Controlled information integration and bayesian inference. PMID- 25698999 TI - Understanding individual resilience in the workplace: the international collaboration of workforce resilience model. AB - When not managed effectively, high levels of workplace stress can lead to several negative personal and performance outcomes. Some professional groups work in highly stressful settings and are therefore particularly at risk of conditions such as anxiety, depression, secondary traumatic stress, and burnout. However, some individuals are less affected by workplace stress and the associated negative outcomes. Such individuals have been described as "resilient." A number of studies have found relationships between levels of individual resilience and specific negative outcomes such as burnout and compassion fatigue. However, because psychological resilience is a multi-dimensional construct it is necessary to more clearly delineate it from other related and overlapping constructs. The creation of a testable theoretical model of individual workforce resilience, which includes both stable traits (e.g., neuroticism) as well as more malleable intrapersonal factors (e.g., coping style), enables information to be derived that can eventually inform interventions aimed at enhancing individual resilience in the workplace. The purpose of this paper is to introduce a new theoretical model of individual workforce resilience that includes several intrapersonal constructs known to be central in the appraisal of and response to stressors and that also overlap with the construct of psychological resilience. We propose a model in which psychological resilience is hypothesized to mediate the relationship between neuroticism, mindfulness, self-efficacy, coping, and psychological adjustment. PMID- 25699000 TI - Rats remind us what actually counts in episodic memory research. PMID- 25699001 TI - An fMRI investigation of expectation violation in magic tricks. AB - Magic tricks violate the expected causal relationships that form an implicit belief system about what is possible in the world around us. Observing a magic effect seemingly invalidates our implicit assumptions about what action causes which outcome. We aimed at identifying the neural correlates of such expectation violations by contrasting 24 video clips of magic tricks with 24 control clips in which the expected action-outcome relationship is upheld. Using fMRI, we measured the brain activity of 25 normal volunteers while they watched the clips in the scanner. Additionally, we measured the professional magician who had performed the magic tricks under the assumption that, in contrast to naive observers, the magician himself would not perceive his own magic tricks as an expectation violation. As the main effect of magic - control clips in the normal sample, we found higher activity for magic in the head of the caudate nucleus (CN) bilaterally, the left inferior frontal gyrus and the left anterior insula. As expected, the magician's brain activity substantially differed from these results, with mainly parietal areas (supramarginal gyrus bilaterally) activated, supporting our hypothesis that he did not experience any expectation violation. These findings are in accordance with previous research that has implicated the head of the CN in processing changes in the contingency between action and outcome, even in the absence of reward or feedback. PMID- 25699002 TI - Measurement equivalence in mixed mode surveys. AB - Surveys increasingly use mixed mode data collection (e.g., combining face-to-face and web) because this controls costs and helps to maintain good response rates. However, a combination of different survey modes in one study, be it cross sectional or longitudinal, can lead to different kinds of measurement errors. For example, respondents in a face-to-face survey or a web survey may interpret the same question differently, and might give a different answer, just because of the way the question is presented. This effect of survey mode on the question-answer process is called measurement mode effect. This study develops methodological and statistical tools to identify the existence and size of mode effects in a mixed mode survey. In addition, it assesses the size and importance of mode effects in measurement instruments using a specific mixed mode panel survey (Netherlands Kinship Panel Study). Most measurement instruments in the NKPS are multi-item scales, therefore confirmatory factor analysis (CFA) will be used as the main analysis tool, using propensity score methods to correct for selection effects. The results show that the NKPS scales by and large have measurement equivalence, but in most cases only partial measurement equivalence. Controlling for respondent differences on demographic variables, and on scale scores from the previous uni-mode measurement occasion, tends to improve measurement equivalence, but not for all scales. The discussion ends with a review of the implications of our results for analyses employing these scales. PMID- 25699003 TI - Coping with early stage breast cancer: examining the influence of personality traits and interpersonal closeness. AB - The study examines the influence of personality traits and close relationships on the coping style of women with breast cancer. A sample of 72 Italian patients receiving treatment for early stage breast cancer was recruited. Participants completed questionnaires measuring personality traits (Interpersonal Adaptation Questionnaire), interpersonal closeness (Inclusion of the Other in the Self Scale), and adjustment to cancer (Mini-Mental Adjustment to Cancer Scale). We hypothesized that diverse personality traits and degrees of closeness contribute to determine the coping styles shown by participants. Multiple regression analyses were conducted for each of the five coping styles (Helplessness/Hopelessness, Anxious Preoccupation, Avoidance, Fatalism, and Fighting Spirit) using personality traits and interpersonal closeness variables (Strength of Support Relations, and Number of Support Relations) as predictors. Women who rated high on assertiveness and social anxiety were more likely to utilize active coping strategies (Fighting Spirit). Perceived strength of relationships was predictive of using an active coping style while the number of supportive relationships did not correlate with any of the coping styles. Implications for assessment of breast cancer patients at risk for negative adaptation to the illness and the development of psychosocial interventions are discussed. PMID- 25699004 TI - Anticipation in turn-taking: mechanisms and information sources. AB - During conversations participants alternate smoothly between speaker and hearer roles with only brief pauses and overlaps. There are two competing types of accounts about how conversationalists accomplish this: (a) the signaling approach and (b) the anticipatory ('projection') approach. We wanted to investigate, first, the relative merits of these two accounts, and second, the relative contribution of semantic and syntactic information to the timing of next turn initiation. We performed three button-press experiments using turn fragments taken from natural conversations to address the following questions: (a) Is turn taking predominantly based on anticipation or on reaction, and (b) what is the relative contribution of semantic and syntactic information to accurate turn taking. In our first experiment we gradually manipulated the information available for anticipation of the turn end (providing information about the turn end in advance to completely removing linguistic information). The results of our first experiment show that the distribution of the participants' estimation of turn-endings for natural turns is very similar to the distribution for pure anticipation. We conclude that listeners are indeed able to anticipate a turn-end and that this strategy is predominantly used in turn-taking. In Experiment 2 we collected purely reacted responses. We used the distributions from Experiments 1 and 2 together to estimate a new dependent variable called Reaction Anticipation Proportion. We used this variable in our third experiment where we manipulated the presence vs. absence of semantic and syntactic information by low-pass filtering open-class and closed class words in the turn. The results suggest that for turn-end anticipation, both semantic and syntactic information are needed, but that the semantic information is a more important anticipation cue than syntactic information. PMID- 25699005 TI - Somatic experiencing: using interoception and proprioception as core elements of trauma therapy. AB - Here we present a theory of human trauma and chronic stress, based on the practice of Somatic Experiencing((r)) (SE), a form of trauma therapy that emphasizes guiding the client's attention to interoceptive, kinesthetic, and proprioceptive experience. SETM claims that this style of inner attention, in addition to the use of kinesthetic and interoceptive imagery, can lead to the resolution of symptoms resulting from chronic and traumatic stress. This is accomplished through the completion of thwarted, biologically based, self protective and defensive responses, and the discharge and regulation of excess autonomic arousal. We present this theory through a composite case study of SE treatment; based on this example, we offer a possible neurophysiological rationale for the mechanisms involved, including a theory of trauma and chronic stress as a functional dysregulation of the complex dynamical system formed by the subcortical autonomic, limbic, motor and arousal systems, which we term the core response network (CRN). We demonstrate how the methods of SE help restore functionality to the CRN, and we emphasize the importance of taking into account the instinctive, bodily based protective reactions when dealing with stress and trauma, as well as the effectiveness of using attention to interoceptive, proprioceptive and kinesthetic sensation as a therapeutic tool. Finally, we point out that SE and similar somatic approaches offer a supplement to cognitive and exposure therapies, and that mechanisms similar to those discussed in the paper may also be involved in the benefits of meditation and other somatic practices. PMID- 25699006 TI - The case for diet: a safe and efficacious strategy for secondary stroke prevention. AB - Diet is strongly associated with risk for first stroke. In particular, observational and experimental research suggests that a Mediterranean-type diet may reduce risk for first ischemic stroke with an effect size comparable to statin therapy. These data for first ischemic stroke suggest that diet may also be associated with risk for recurrent stroke and that diet modification might represent an effective intervention for secondary prevention. However, research on dietary pattern after stroke is limited and direct experimental evidence for a therapeutic effect in secondary prevention does not exist. The uncertain state of science in this area is reflected in recent guidelines on secondary stroke prevention from the American Heart Association, in which the Mediterranean-type diet is listed with only a class IIa recommendation (level of evidence C). To change guidelines and practice, research is needed, starting with efforts to better define current nutritional practices of stroke patients. Food frequency questionnaires and mobile applications for real-time recording of intake are available for this purpose. Dietary strategies for secondary stroke prevention are low risk, high potential, and warrant further evaluation. PMID- 25699007 TI - Is personality profile a relevant determinant of fatigue in multiple sclerosis? AB - The origin and pathophysiological background of multiple sclerosis (MS) associated fatigue is poorly understood. There is no unifying concept of its nature and its determinants to date. This paper reviews possible influences of factors determining personality profile on fatigue in MS. Likewise, the role of psychological factors and their interaction with personality to promote fatigue is discussed. Current data suggest that fatigue, especially in early MS states, may be influenced by vulnerable personality traits and personality-associated features. Among them are depressive disease coping, avoidance behavior and inhibition, irritability, less extraversion, neuroticism, lower reward responsiveness, and somatization behavior. However, among the validated personality factors, no genuine influences that are independent of depression have been documented. From a psychological perspective, depressiveness, anxiety, and somatization may be relevant mediators of fatigue. Interesting to note that in early MS, a psychiatric diagnosis is significantly more likely than on a later stage of the disease and that fatigue and motivation might share neural circuits. It is hypothesized that psychological factors promote fatigue in MS by psychological distress and sustained neuroendocrine and neurovegetative stress response. Despite the limitations of data discussed in the paper, personality research might help to disentangle specific promoting factors of fatigue in MS. Further research efforts are warranted since they might open ways to early psychological intervention of MS-associated fatigue. This is all the more important since medication is insufficient until now. PMID- 25699008 TI - Biopersistence and brain translocation of aluminum adjuvants of vaccines. AB - Aluminum oxyhydroxide (alum) is a crystalline compound widely used as an immunological adjuvant of vaccines. Concerns linked to the use of alum particles emerged following recognition of their causative role in the so-called macrophagic myofasciitis (MMF) lesion detected in patients with myalgic encephalomyelitis/chronic fatigue/syndrome. MMF revealed an unexpectedly long lasting biopersistence of alum within immune cells in presumably susceptible individuals, stressing the previous fundamental misconception of its biodisposition. We previously showed that poorly biodegradable aluminum-coated particles injected into muscle are promptly phagocytosed in muscle and the draining lymph nodes, and can disseminate within phagocytic cells throughout the body and slowly accumulate in brain. This strongly suggests that long-term adjuvant biopersistence within phagocytic cells is a prerequisite for slow brain translocation and delayed neurotoxicity. The understanding of basic mechanisms of particle biopersistence and brain translocation represents a major health challenge, since it could help to define susceptibility factors to develop chronic neurotoxic damage. Biopersistence of alum may be linked to its lysosome destabilizing effect, which is likely due to direct crystal-induced rupture of phagolysosomal membranes. Macrophages that continuously perceive foreign particles in their cytosol will likely reiterate, with variable interindividual efficiency, a dedicated form of autophagy (xenophagy) until they dispose of alien materials. Successful compartmentalization of particles within double membrane autophagosomes and subsequent fusion with repaired and re-acidified lysosomes will expose alum to lysosomal acidic pH, the sole factor that can solubilize alum particles. Brain translocation of alum particles is linked to a Trojan horse mechanism previously described for infectious particles (HIV, HCV), that obeys to CCL2, signaling the major inflammatory monocyte chemoattractant. PMID- 25699009 TI - Dissociation of Pupillary Post-Illumination Responses from Visual Function in Confirmed OPA1 c.983A > G and c.2708_2711delTTAG Autosomal Dominant Optic Atrophy. AB - PURPOSE: To test whether the melanopsin-containing, intrinsically photosensitive retinal ganglion cells (ipRGCs), as evaluated by examination of the pupillary light reflex (PLR), are preserved in genetically confirmed autosomal dominant optic atrophy (ADOA). METHOD: Twenty-nine patients with either the c.983A > G (n = 14) or the c.2708_ 2711delTTAG mutation (n = 15) were examined with monochromatic pupillometry, using isoluminant (300 cd/m(2)), red (660 nm) or blue (470 nm) light, optical coherence tomography, automated visual field analysis, and with determination of best corrected visual acuity (BCVA). Since we examined two different mutations, initially we compared all outcome variables between the two, and finding no statistically significant difference, pooled them. RESULTS: Despite a poor BCVA (56 letters, ETDRS) in the ADOA patients, their post illuminatory pupil responses did not differ significantly from those of healthy controls (blue, p = 0.45, red, p = 0.49, t-test), and no statistically significant effect was noted of peripapillary retinal nerve fiber layer thickness, ganglion cell-inner plexiform layer thickness, or age. CONCLUSION: The PLR to blue light of high luminance (300 cd/m(2)) was preserved in both c.983A > G and c.2708_2711delTTAG ADOA despite severe visual loss and optic nerve atrophy. The study confirms, in a large sample of two genetically homogenous groups, that the ipRGCs are spared in ADOA. PMID- 25699010 TI - Hormonal contraceptives and cerebral venous thrombosis risk: a systematic review and meta-analysis. AB - OBJECTIVES: Use of oral contraceptive pills (OCP) increases the risk of cerebral venous sinus thrombosis (CVST). Whether this risk varies by type, duration, and other forms of hormonal contraceptives is largely unknown. This systematic review and meta-analysis update the current state of knowledge. METHODS: We performed a search to identify all published studies on the association between hormonal contraceptive use and risk of CVST in women aged 15-50 years. RESULTS: Of 861 studies reviewed, 11 were included. The pooled odds of developing CVST in women aged 15-50 years taking OCPs was 7.59 times higher compared to women not taking OCPs (OR = 7.59, 95% CI 3.82-15.09). Data are insufficient to make conclusions about duration of use and other forms of hormonal contraceptives. CONCLUSION: Oral contraceptive pills use increases the risk of developing CVST in women of reproductive age. Future studies are required to determine if duration and type of hormonal contraceptives modify this risk. PMID- 25699011 TI - Early administration of therapeutic anticoagulation following intravenous thrombolysis for acute cardiogenic embolic stroke caused by left ventricular thrombus: case report and topic review. AB - Cardiogenic cerebral embolism represents 20% of all acute ischemic strokes (AISs) with one-third of these being caused by left ventricular thrombus (LVT). LVT is not a contraindication for treatment with intravenous recombinant tissue plasminogen activator (IV rtPA) for AIS. However, the subsequent treatment of a potentially unstable LVT is contraindicated for 24 h following the use of IV rtPA according to current guidelines. We present a 66-year-old man with AIS treated with IV rtPA. Echocardiogram shortly after treatment demonstrated both a large apical and septal thrombus in the left ventricle and at 12 h post IV rtPA infusion, therapeutic anticoagulation with heparin was started without complication. In practice, the action of IV rtPA outlasts its apparent half-life because of thrombin-binding and the prolonged effects and longer half-life of its product, plasmin; however, the pharmacokinetics do not warrant prolonged avoidance of therapeutic anticoagulation when clinically indicated. Our case demonstrates that anticoagulation for potentially unstable LVT can be safely initiated at 12 h following IV rtPA treatment for AIS. PMID- 25699012 TI - Efficacy and Tolerability of STOPAIN for a Migraine Attack. AB - OBJECTIVE: To determine whether topical menthol 6% gel will relieve a migraine attack. MATERIALS AND METHODS: A single-center, open-label pilot trial of 25 patients with at least 1 year of diagnosed episodic migraine and <15 headache days per month. Patients treated one migraine attack with STOPAIN topical menthol 6% gel to skull base within 2 h of headache onset. Headache pain severity was assessed prior to and after gel application. RESULTS: Thirty-two patients enrolled and 25 completed the study. Prior to treatment, 7 patients had mild pain, 13 moderate pain, and 5 severe pain. Two hours following gel application, 7 (28%) patients had no pain, 7 (28%) mild pain, 6 (25%) moderate pain, and 5 (20%) severe pain. The majority of patients had similar pain intensity (8; 32%) or improvement (13; 52%). At 24-h, only two non-rescued patients still had mild headache. Of the 25 completers, 2 patients took rescue medication prior to the 2 h period, and an additional 10 patients rescued between 2 and 24 h. CONCLUSION: Study results showed a significant improvement in headache intensity by 2 h after gel application. This pilot study shows STOPAIN gel may be effective in treating an acute migraine attack. PMID- 25699013 TI - Changing shapes of glycogen-autophagy nexus in neurons: perspective from a rare epilepsy. AB - In brain, glycogen metabolism is predominantly restricted to astrocytes but it also indirectly supports neuronal functions. Increased accumulation of glycogen in neurons is mysteriously pathogenic triggering neurodegeneration as seen in "Lafora disease" (LD) and in other transgenic animal models of neuronal glycogen accumulation. LD is a fatal neurodegenerative disorder with excessive glycogen inclusions in neurons. Autophagy, a pathway for bulk degradation of obsolete cellular constituents also degrades metabolites like lipid and glycogen. Recently, defects in this pathway emerged as a plausible reason for glycogen accumulation in neurons in LD, although some contradictions prevail. Albeit surprising, a reciprocal regulation of autophagy by glycogen in neurons has also just been proposed. Notably, increasing evidences of interaction between proteins of autophagy and glycogen metabolism from diverse model systems indicate a conserved, dynamic, and regulatory cross-talk between these two pathways. Concerning these findings, we herein provide certain models for the molecular basis of this cross-talk and discuss its potential implication in the pathophysiology of LD. PMID- 25699014 TI - Reconstructing SALMFamide Neuropeptide Precursor Evolution in the Phylum Echinodermata: Ophiuroid and Crinoid Sequence Data Provide New Insights. AB - The SALMFamides are a family of neuropeptides that act as muscle relaxants in echinoderms. Analysis of genome/transcriptome sequence data from the sea urchin Strongylocentrotus purpuratus (Echinoidea), the sea cucumber Apostichopus japonicus (Holothuroidea), and the starfish Patiria miniata (Asteroidea) reveals that in each species there are two types of SALMFamide precursor: an L-type precursor comprising peptides with a C-terminal LxFamide-type motif and an F-type precursor solely or largely comprising peptides with a C-terminal FxFamide-type motif. Here, we have identified transcripts encoding SALMFamide precursors in the brittle star Ophionotus victoriae (Ophiuroidea) and the feather star Antedon mediterranea (Crinoidea). We have also identified SALMFamide precursors in other species belonging to each of the five echinoderm classes. As in S. purpuratus, A. japonicus, and P. miniata, in O. victoriae there is one L-type precursor and one F-type precursor. However, in A. mediterranea only a single SALMFamide precursor was found, comprising two peptides with a LxFamide-type motif, one with a FxFamide-type motif, five with a FxLamide-type motif, and four with a LxLamide type motif. As crinoids are basal to the Echinozoa (Holothuroidea + Echinoidea) and Asterozoa (Asteroidea + Ophiuroidea) in echinoderm phylogeny, one model of SALMFamide precursor evolution would be that ancestrally there was a single SALMFamide gene encoding a variety of SALMFamides (as in crinoids), which duplicated in a common ancestor of the Echinozoa and Asterozoa and then specialized to encode L-type SALMFamides or F-type SALMFamides. Alternatively, a second SALMFamide precursor may remain to be discovered or may have been lost in crinoids. Further insights will be obtained if SALMFamide receptors are identified, which would provide a molecular basis for experimental analysis of the functional significance of the "cocktails" of SALMFamides that exist in echinoderms. PMID- 25699015 TI - Neuroendocrine Role for VGF. AB - The vgf gene (non-acronymic) is highly conserved and was identified on the basis of its rapid induction in vitro by nerve growth factor, although can also be induced by brain-derived neurotrophic factor, and glial-derived growth factor. The VGF gene gives rise to a 68 kDa precursor polypeptide, which is induced robustly, relatively selectively and is synthesized exclusively in neuronal and neuroendocrine cells. Post-translational processing by neuroendocrine specific prohormone convertases in these cells results in the production of a number of smaller peptides. The VGF gene and peptides are widely expressed throughout the brain, particularly in the hypothalamus and hippocampus, in peripheral tissues including the pituitary gland, the adrenal glands, and the pancreas, and in the gastrointestinal tract in both the myenteric plexus and in endocrine cells. VGF peptides have been associated with a number of neuroendocrine roles, and in this review, we aim to describe these roles to highlight the importance of VGF as therapeutic target for a number of disorders, particularly those associated with energy metabolism, pain, reproduction, and cognition. PMID- 25699016 TI - The multifaceted role of the vasculature in endochondral fracture repair. AB - Fracture healing is critically dependent upon an adequate vascular supply. The normal rate for fracture delayed or non-union is estimated to be between 10 and 15%, and annual fracture numbers are approximately 15 million cases per year. However, when there is decreased vascular perfusion to the fracture, incidence of impaired healing rises dramatically to 46%. Reduction in the blood supply to the fracture can be the result of traumatic injuries that physically disrupt the vasculature and damage supportive soft tissue, the result of anatomical location (i.e., distal tibia), or attributed to physiological conditions such as age, diabetes, or smoking. The role of the vasculature during repair is multifaceted and changes during the course of healing. In this article, we review recent insights into the role of the vasculature during fracture repair. Taken together these data highlight the need for an updated model for endochondral repair to facilitate improved therapeutic approaches to promote bone healing. PMID- 25699017 TI - Maintenance of homeostasis in the aging hypothalamus: the central and peripheral roles of succinate. AB - Aging is the phenotype resulting from accumulation of genetic, cellular, and molecular damages. Many factors have been identified as either the cause or consequence of age-related decline in functions and repair mechanisms. The hypothalamus is the source and a target of many of these factors and hormones responsible for the overall homeostasis in the body. With advanced age, the sensitivity of the hypothalamus to various feedback signals begins to decline. In recent years, several aging-related genes have been identified and their signaling pathways elucidated. These gene products include mTOR, IKK-beta/NF kappaB complex, and HIF-1alpha, an important cellular survival signal. All of these activators/modulators of the aging process have also been identified in the hypothalamus and shown to play crucial roles in nutrient sensing, metabolic regulation, energy balance, reproductive function, and stress adaptation. This illustrates the central role of the hypothalamus in aging. Inside the mitochondria, succinate is one of the most prominent intermediates of the Krebs cycle. Succinate oxidation in mitochondria provides the most powerful energy output per unit time. Extra-mitochondrial succinate triggers a host of succinate receptor (SUCN1 or GPR91)-mediated signaling pathways in many peripheral tissues including the hypothalamus. One of the actions of succinate is to stabilize the hypoxia and cellular stress conditions by inducing the transcriptional regulator HIF-1alpha. Through these actions, it is hypothesized that succinate has the potential to restore the gradual but significant loss in functions associated with cellular senescence and systemic aging. PMID- 25699019 TI - Oligomerization of Family B GPCRs: Exploration in Inter-Family Oligomer Formation. AB - G-protein-coupled receptors (GPCRs) are classified into A to F subfamilies in which only families A, B, and C are present in mammals. Some of these GPCRs were found to form higher ordered structures such as oligomers with the discovery of interacting receptors in the form of homomers or heteromers. The importance of these oligomers on regulating receptor functions has recently been an intense research focus. It has been proposed that receptor oligomer formation has impact on its physiological importance on receptor trafficking, signaling, ligand related regulation, and also is related to certain diseases. The present body of knowledge, however, comprises mainly intra-family oligomers formation and their consequences. Inter-family oligomers are recognized but there is limited information. This article aims to provide a current view regarding inter-family GPCR oligomerization in the subfamilies A, B, and C found in mammals. PMID- 25699018 TI - The effects of phthalates on the ovary. AB - Phthalates are commonly used as plasticizers in the manufacturing of flexible polyvinyl chloride products. Large production volumes of phthalates and their widespread use in common consumer, medical, building, and personal care products lead to ubiquitous human exposure via oral ingestion, inhalation, and dermal contact. Recently, several phthalates have been classified as reproductive toxicants and endocrine-disrupting chemicals based on their ability to interfere with normal reproductive function and hormone signaling. Therefore, exposure to phthalates represents a public health concern. Currently, the effects of phthalates on male reproduction are better understood than the effects on female reproduction. This is of concern because women are often exposed to higher levels of phthalates than men through their extensive use of personal care and cosmetic products. In the female, a primary regulator of reproductive and endocrine function is the ovary. Specifically, the ovary is responsible for folliculogenesis, the proper maturation of gametes for fertilization, and steroidogenesis, and the synthesis of necessary sex steroid hormones. Any defect in the regulation of these processes can cause complications for reproductive and non-reproductive health. For instance, phthalate-induced defects in folliculogenesis and steroidogenesis can cause infertility, premature ovarian failure, and non-reproductive disorders. Presently, there is a paucity of knowledge on the effects of phthalates on normal ovarian function; however, recent work has established the ovary as a target of phthalate toxicity. This review summarizes what is currently known about the effects of phthalates on the ovary and the mechanisms by which phthalates exert ovarian toxicity, with a particular focus on the effects on folliculogenesis and steroidogenesis. Further, this review outlines future directions, including the necessity of examining the effects of phthalates at doses that mimic human exposure. PMID- 25699020 TI - Second Attempt of Cabergoline Withdrawal in Patients with Prolactinomas after a Failed First Attempt: Is it Worthwhile? AB - Successful discontinuation of cabergoline (CAB) treatment has been reported in 31 75% of prolactinomas patients treated for at least 2 years. In contrast, it is not well established whether CAB therapy can be successfully withdrawn after a failed first attempt. This prospective open trial was designed to address this topic and to try to identify possible predictor factors. Among 180 patients with prolactinomas on CAB therapy, the authors selected those who fulfilled very strict criteria, particularly additional CAB therapy for at least 2 years, normalization of serum prolactin (PRL) levels following CAB restart, no tumor remnant >10 mm, no previous pituitary radiotherapy or surgery; and current CAB dose <=1.0 mg/week. Recurrence was defined as an increase of PRL levels above the upper limit of normal. A total of 34 patients (70.6% female) treated with CAB for 24-30 months were recruited. Ten patients (29.4%) remained without evidence of recurrence after 24-26 months of follow-up. Twenty-four patients (70.6%) recurred within 15 months (75% within 12 months) after drug withdrawal and ~80% were restarted CAB. Median time to recurrence was 10.5 months (range, 3-15). Despite overlapping values, non-recurring patients had significantly lower mean PRL levels before withdrawal. Moreover, the recurrence rate was lower in subjects without visible tumor on pituitary magnetic resonance imaging (MRI) than in those with small remnant tumor (60 vs. 79%), though the difference was not statistically significant (P = 0.20). No other characteristic could be identified as a predictor of successful CAB discontinuation. In conclusion, a second attempt of CAB withdrawal after two additional years of therapy may be successful, particularly in patients with lower PRL levels and no visible tumor on pituitary MRI. Close monitoring of PRL level is mandatory, especially within the first year after withdrawal, where most recurrences are detected. PMID- 25699021 TI - Insulin/Insulin-like growth factors in cancer: new roles for the aryl hydrocarbon receptor, tumor resistance mechanisms, and new blocking strategies. AB - The insulin-like growth factor 1 receptor (IGF1R) and the insulin receptor (IR) are receptor tyrosine kinases that are expressed in cancer cells. The results of different studies indicate that tumor proliferation and survival is dependent on the IGF1R and IR, and that their inhibition leads to reductions in proliferation and increases in cell death. Molecular targeting therapies that have been used in solid tumors include anti-IGF1R antibodies, anti-IGF1/IGF2 antibodies, and small molecule inhibitors that suppress IGF1R and IR kinase activity. New advances in the molecular basis of anti-IGF1R blocking antibodies reveal they are biased agonists and promote the binding of IGF1 to integrin beta3 receptors in some cancer cells. Our recent reports indicate that pharmacological aryl hydrocarbon receptor (AHR) ligands inhibit breast cancer cell responses to IGFs, suggesting that targeting AHR may have benefit in cancers whose proliferation and survival are dependent on insulin/IGF signaling. Novel aspects of IGF1R/IR in cancer, such as biased agonism, integrin beta3 signaling, AHR, and new therapeutic targeting strategies will be discussed. PMID- 25699022 TI - Organic extracts from Indigofera suffruticosa leaves have antimicrobial and synergic actions with erythromycin against Staphylococcus aureus. AB - A characteristic feature of Staphylococcus aureus is its ability to acquire resistance to antimicrobial agents. There is a need, therefore, for new approaches to combat this pathogen; for example, employing a combination of plant derived products and antibiotics to overcome bacterial resistance. Indigofera suffruticosa is a plant popularly used to treat infections and has verified antimicrobial action. Here, we investigate the antimicrobial activity of different extracts from I. suffruticosa against S. aureus and their synergistic effects with erythromycin. Leaves of I. suffruticosa were extracted sequentially using diethyl ether, chloroform and acetone and the antimicrobial activity of each extract then tested against nine clinical isolates of S. aureus. Minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) were determined by microdilution tests, while the fractional inhibitory concentration (FIC) was assessed by checkerboard assay. All organic solvent extracts showed antimicrobial activity against S. aureus strains. The acetone extract was the most potent inhibitor of S. aureus (MIC and MBC of 0.78 and 3.12 mg/mL), followed by the chloroform extract (MIC and MBC of 3.12 and 6.25 mg/mL). Furthermore, acetone or chloroform extracts of I. suffruticosa enhanced the activity of erythromycin against S. aureus (FIC <= 0.5). We conclude that organic extracts from leaves of I. suffruticosa, alone or combined with erythromycin, are promising natural products for the development of new anti-S. aureus formulations. PMID- 25699023 TI - Microbiota disbiosis is associated with colorectal cancer. AB - The dysbiosis of the human intestinal microbiota is linked to sporadic colorectal carcinoma (CRC). The present study was designed to investigate the gut microbiota distribution features in CRC patients. We performed pyrosequencing based analysis of the 16S rRNA gene V3 region to investigate microbiota of the cancerous tissue and adjacent non-cancerous normal tissue in proximal and distal CRC samples. The results revealed that the microbial structures of the CRC patients and healthy individuals differed significantly. Firmicutes and Fusobacteria were over represented whereas Proteobacteria was under-represented in CRC patients. In addition, Lactococcus and Fusobacterium exhibited a relatively higher abundance while Pseudomonas and Escherichia-Shigella was reduced in cancerous tissues compared to adjacent non-cancerous tissues. Meanwhile, the overall microbial structures of proximal and distal colon cancerous tissues were similar; but certain potential pro-oncogenic pathogens were different. These results suggested that the mucosa-associated microbiota is dynamically associated with CRC, which may provide evidences for microbiota-associated diagnostic, prognostic, preventive, and therapeutic strategies for CRC. PMID- 25699024 TI - The archaellum: how Archaea swim. AB - Recent studies on archaeal motility have shown that the archaeal motility structure is unique in several aspects. Although it fulfills the same swimming function as the bacterial flagellum, it is evolutionarily and structurally related to the type IV pilus. This was the basis for the recent proposal to term the archaeal motility structure the "archaellum." This review illustrates the key findings that led to the realization that the archaellum was a novel motility structure and presents the current knowledge about the structural composition, mechanism of assembly and regulation, and the posttranslational modifications of archaella. PMID- 25699026 TI - Field-based evidence for consistent responses of bacterial communities to copper contamination in two contrasting agricultural soils. AB - Copper contamination on China's arable land could pose severe economic, ecological and healthy consequences in the coming decades. As the drivers in maintaining ecosystem functioning, the responses of soil microorganisms to long term copper contamination in different soil ecosystems are still debated. This study investigated the impacts of copper gradients on soil bacterial communities in two agricultural fields with contrasting soil properties. Our results revealed consistent reduction in soil microbial biomass carbon (SMBC) with increasing copper levels in both soils, coupled by significant declines in bacterial abundance in most cases. Despite of contrasting bacterial community structures between the two soils, the bacterial diversity in the copper-contaminated soils showed considerably decreasing patterns when copper levels elevated. High throughput sequencing revealed copper selection for major bacterial guilds, in particular, Actinobacteria showed tolerance, while Acidobacteria and Chloroflexi were highly sensitive to copper. The thresholds that bacterial communities changed sharply were 800 and 200 added copper mg kg(-1) in the fluvo-aquic soil and red soil, respectively, which were similar to the toxicity thresholds (EC50 values) characterized by SMBC. Structural equation model (SEM) analysis ascertained that the shifts of bacterial community composition and diversity were closely related with the changes of SMBC in both soils. Our results provide field based evidence that copper contamination exhibits consistently negative impacts on soil bacterial communities, and the shifts of bacterial communities could have largely determined the variations of the microbial biomass. PMID- 25699025 TI - Urinary tract infections attributed to diverse ExPEC strains in food animals: evidence and data gaps. AB - Between 70 and 95% of urinary tract infections (UTI) are caused by strains of Escherichia coli. These strains, often termed Extraintestinal Pathogenic E. coli (ExPEC), possess specific virulence traits allowing them to colonize more inhospitable environments, such as the urogenital tract. Some ExPEC isolates from humans have similar virulence factor profiles to ExPEC isolates from animals, and because of the potential for these strains to cause UTI in people, these infections have been referred to as foodborne UTI, or FUTI. Finding similarities in ExPEC in animals and humans is not necessarily proof of transmission, particularly a unidirectional pathway from animals to humans; similarities in virulence factor profiles should be expected given the specific bacterial requirements for colonizing physiological compartments with similar characteristics in all animals. Many of the most important strains of human ExPEC globally, such as ST131, are highly virulent and clonal implying routes of transmission other than food. Documenting routes of transmission is particularly difficult due to the wide range of potential ExPEC sources, including the human intestinal tract, and non-human reservoirs such as food animals and retail meat products, sewage and other environmental sources, and companion animals. The significant environmental reservoir of ExPEC, including strains such as ST131, could potentially explain much more completely the global dissemination of virulent ExPEC clones and the rapid dissemination of new strains within the community. Taken in its totality, the link between ExPEC in animals and UTI in humans might exist, but studies conducted to date do not enable an estimation of the relative importance of this route of transmission. To reduce the burden of illness associated with ExPEC, the scientific community needs to push forward with ecologically-based, scientifically-sound study designs that can address the plethora of ways in which E. coli can spread. PMID- 25699027 TI - Mechanisms of antibiotic resistance. PMID- 25699028 TI - Techniques for transferring host-pathogen protein interactions knowledge to new tasks. AB - We consider the problem of building a model to predict protein-protein interactions (PPIs) between the bacterial species Salmonella Typhimurium and the plant host Arabidopsis thaliana which is a host-pathogen pair for which no known PPIs are available. To achieve this, we present approaches, which use homology and statistical learning methods called "transfer learning." In the transfer learning setting, the task of predicting PPIs between Arabidopsis and its pathogen S. Typhimurium is called the "target task." The presented approaches utilize labeled data i.e., known PPIs of other host-pathogen pairs (we call these PPIs the "source tasks"). The homology based approaches use heuristics based on biological intuition to predict PPIs. The transfer learning methods use the similarity of the PPIs from the source tasks to the target task to build a model. For a quantitative evaluation we consider Salmonella-mouse PPI prediction and some other host-pathogen tasks where known PPIs exist. We use metrics such as precision and recall and our results show that our methods perform well on the target task in various transfer settings. We present a brief qualitative analysis of the Arabidopsis-Salmonella predicted interactions. We filter the predictions from all approaches using Gene Ontology term enrichment and only those interactions involving Salmonella effectors. Thereby we observe that Arabidopsis proteins involved e.g., in transcriptional regulation, hormone mediated signaling and defense response may be affected by Salmonella. PMID- 25699029 TI - Shifts in metabolic hydrogen sinks in the methanogenesis-inhibited ruminal fermentation: a meta-analysis. AB - Maximizing the flow of metabolic hydrogen ([H]) in the rumen away from CH4 and toward volatile fatty acids (VFA) would increase the efficiency of ruminant production and decrease its environmental impact. The objectives of this meta analysis were: (i) To quantify shifts in metabolic hydrogen sinks when inhibiting ruminal methanogenesis in vitro; and (ii) To understand the variation in shifts of metabolic hydrogen sinks among experiments and between batch and continuous cultures systems when methanogenesis is inhibited. Batch (28 experiments, N = 193) and continuous (16 experiments, N = 79) culture databases of experiments with at least 50% inhibition in CH4 production were compiled. Inhibiting methanogenesis generally resulted in less fermentation and digestion in most batch culture, but not in most continuous culture, experiments. Inhibiting CH4 production in batch cultures resulted in redirection of metabolic hydrogen toward propionate and H2 but not butyrate. In continuous cultures, there was no overall metabolic hydrogen redirection toward propionate or butyrate, and H2 as a proportion of metabolic hydrogen spared from CH4 production was numerically smaller compared to batch cultures. Dihydrogen accumulation was affected by type of substrate and methanogenesis inhibitor, with highly fermentable substrates resulting in greater redirection of metabolic hydrogen toward H2 when inhibiting methanogenesis, and some oils causing small or no H2 accumulation. In both batch and continuous culture, there was a decrease in metabolic hydrogen recovered as the sum of propionate, butyrate, CH4 and H2 when inhibiting methanogenesis, and it is speculated that as CH4 production decreases metabolic hydrogen could be increasingly incorporated into formate, microbial biomass, and perhaps, reductive acetogenesis in continuous cultures. Energetic benefits of inhibiting methanogenesis depended on the inhibitor and its concentration and on the in vitro system. PMID- 25699030 TI - Animals devoid of pulmonary system as infection models in the study of lung bacterial pathogens. AB - Biological disease models can be difficult and costly to develop and use on a routine basis. Particularly, in vivo lung infection models performed to study lung pathologies use to be laborious, demand a great time and commonly are associated with ethical issues. When infections in experimental animals are used, they need to be refined, defined, and validated for their intended purpose. Therefore, alternative and easy to handle models of experimental infections are still needed to test the virulence of bacterial lung pathogens. Because non mammalian models have less ethical and cost constraints as a subjects for experimentation, in some cases would be appropriated to include these models as valuable tools to explore host-pathogen interactions. Numerous scientific data have been argued to the more extensive use of several kinds of alternative models, such as, the vertebrate zebrafish (Danio rerio), and non-vertebrate insects and nematodes (e.g., Caenorhabditis elegans) in the study of diverse infectious agents that affect humans. Here, we review the use of these vertebrate and non-vertebrate models in the study of bacterial agents, which are considered the principal causes of lung injury. Curiously none of these animals have a respiratory system as in air-breathing vertebrates, where respiration takes place in lungs. Despite this fact, with the present review we sought to provide elements in favor of the use of these alternative animal models of infection to reveal the molecular signatures of host-pathogen interactions. PMID- 25699031 TI - Chemotactic preferences govern competition and pattern formation in simulated two strain microbial communities. AB - Substrate competition is a common mode of microbial interaction in natural environments. While growth properties play an important and well-studied role in competition, we here focus on the influence of motility. In a simulated two strain community populating a homogeneous two-dimensional environment, strains competed for a common substrate and only differed in their chemotactic preference, either responding more sensitively to a chemoattractant excreted by themselves or responding more sensitively to substrate. Starting from homogeneous distributions, three possible behaviors were observed depending on the competitors' chemotactic preferences: (i) distributions remained homogeneous, (ii) patterns formed but dissolved at a later time point, resulting in a shifted community composition, and (iii) patterns emerged and led to the extinction of one strain. When patterns formed, the more aggregating strain populated the core of microbial aggregates where starving conditions prevailed, while the less aggregating strain populated the more productive zones at the fringe or outside aggregates, leading to a competitive advantage of the less aggregating strain. The presence of a competitor was found to modulate a strain's behavior, either suppressing or promoting aggregate formation. This observation provides a potential mechanism by which an aggregated lifestyle might evolve even if it is initially disadvantageous. Adverse effects can be avoided as a competitor hinders aggregate formation by a strain which has just acquired this ability. The presented results highlight both, the importance of microbial motility for competition and pattern formation, and the importance of the temporal evolution, or history, of microbial communities when trying to explain an observed distribution. PMID- 25699032 TI - Stable isotope labeling confirms mixotrophic nature of streamer biofilm communities at alkaline hot springs. AB - Streamer biofilm communities (SBC) are often observed within chemosynthetic zones of Yellowstone hot spring outflow channels, where temperatures exceed those conducive to photosynthesis. Nearest the hydrothermal source (75-88 degrees C) SBC comprise thermophilic Archaea and Bacteria, often mixed communities including Desulfurococcales and uncultured Crenarchaeota, as well as Aquificae and Thermus, each carrying diagnostic membrane lipid biomarkers. We tested the hypothesis that SBC can alternate their metabolism between autotrophy and heterotrophy depending on substrate availability. Feeding experiments were performed at two alkaline hot springs in Yellowstone National Park: Octopus Spring and "Bison Pool," using various (13)C-labeled substrates (bicarbonate, formate, acetate, and glucose) to determine the relative uptake of these different carbon sources. Highest (13)C uptake, at both sites, was from acetate into almost all bacterial fatty acids, particularly into methyl-branched C15, C17 and C19 fatty acids that are diagnostic for Thermus/Meiothermus, and some Firmicutes as well as into universally common C16:0 and C18:0 fatty acids. (13)C-glucose showed a similar, but a 10-30 times lower uptake across most fatty acids. (13)C-bicarbonate uptake, signifying the presence of autotrophic communities was only significant at "Bison Pool" and was observed predominantly in non-specific saturated C16, C18, C20, and C22 fatty acids. Incorporation of (13)C-formate occurred only at very low rates at "Bison Pool" and was almost undetectable at Octopus Spring, suggesting that formate is not an important carbon source for SBC. (13)C-uptake into archaeal lipids occurred predominantly with (13)C-acetate, suggesting also that archaeal communities at both springs have primarily heterotrophic carbon assimilation pathways. We hypothesize that these communities are energy-limited and predominantly nurtured by input of exogenous organic material, with only a small fraction being sustained by autotrophic growth. PMID- 25699033 TI - Long-term impacts of disturbance on nitrogen-cycling bacteria in a New England salt marsh. AB - Recent studies on the impacts of disturbance on microbial communities indicate communities show differential responses to disturbance, yet our understanding of how different microbial communities may respond to and recover from disturbance is still rudimentary. We investigated impacts of tidal restriction followed by tidal restoration on abundance and diversity of denitrifying bacteria, ammonia oxidizing bacteria (AOB), and ammonia-oxidizing archaea (AOA) in New England salt marshes by analyzing nirS and bacterial and archaeal amoA genes, respectively. TRFLP analysis of nirS and betaproteobacterial amoA genes revealed significant differences between restored and undisturbed marshes, with the greatest differences detected in deeper sediments. Additionally, community patterns indicated a potential recovery trajectory for denitrifiers. Analysis of archaeal amoA genes, however, revealed no differences in community composition between restored and undisturbed marshes, but we detected significantly higher gene abundance in deeper sediment at restored sites. Abundances of nirS and betaproteobacterial amoA genes were also significantly greater in deeper sediments at restored sites. Porewater ammonium was significantly higher at depth in restored sediments compared to undisturbed sediments, suggesting a possible mechanism driving some of the community differences. Our results suggest that impacts of disturbance on denitrifying and ammonia-oxidizing communities remain nearly 30 years after restoration, potentially impacting nitrogen-cycling processes in the marsh. We also present data suggesting that sampling deeper in sediments may be critical for detecting disturbance effects in coastal sediments. PMID- 25699034 TI - Antigen-driven focal inflammatory death of malaria liver stages. AB - Multiple immunizations using live irradiated sporozoites, the infectious plasmodial stage delivered into the host skin during a mosquito bite, can elicit sterile immunity to malaria. CD8(+) T cells seem to play an essential role in this protective immunity, since their depletion consistently abolishes sterilizing protection in several experimental models. So far, only a few parasite antigens are known to induce CD8(+) T cell-dependent protection, but none of them can reach the levels of protection afforded by live attenuated parasites. Systematic attempts to identify novel antigens associated with this efficient cellular protection were so far unsuccessful. In addition, the precise mechanisms involved in the recognition and elimination of parasitized hepatocytes in vivo by CD8(+) T cells still remain obscure. Recently, it has been shown that specific effector CD8(+) T cells, after recognition of parasitized hepatocytes, recruit specific and non-specific activated CD8(+) T cells to the site of infection, resulting in the formation of cellular clusters around and in the further elimination of intracellular parasites. The significance of this finding is discussed in the perspective of a general mechanism of antigen-dependent focalized inflammation and its consequences for the elimination of malaria liver stages. PMID- 25699035 TI - Heat shock proteins IbpA and IbpB are required for NlpI-participated cell division in Escherichia coli. AB - Lipoprotein NlpI of Escherichia coli is involved in the cell division, virulence, and bacterial interaction with eukaryotic host cells. To elucidate the functional mechanism of NlpI, we examined how NlpI affects cell division and found that induction of NlpI inhibits nucleoid division and halts cell growth. Consistent with these results, the cell division protein FtsZ failed to localize at the septum but diffused in the cytosol. Elevation of NlpI expression enhanced the transcription and the outer membrane localization of the heat shock protein IbpA and IbpB. Deletion of either ibpA or ibpB abolished the effects of NlpI induction, which could be restored by complementation. The C-terminus of NlpI is critical for the enhancement in IbpA and IbpB production, and the N-terminus of NlpI is required for the outer membrane localization of NlpI, IbpA, and IbpB. Furthermore, NlpI physically interacts with IbpB. These results indicate that over-expression of NlpI can interrupt the nucleoids division and the assembly of FtsZ at the septum, mediated by IbpA/IbpB, suggesting a role of the NlpI/IbpA/IbpB complex in the cell division. PMID- 25699036 TI - Co-detection of Panton-Valentine leukocidin encoding genes and cotrimoxazole resistance in Staphylococcus aureus in Gabon: implications for HIV-patients' care. AB - Patients infected with the human immunodeficiency virus (HIV) are frequently exposed to antimicrobial agents. This might have an impact on the resistance profile, genetic background and virulence factors of colonizing Staphylococcus aureus. Sub-Saharan Africa is considered to be endemic for Panton-Valentine leukocidin (PVL) positive S. aureus which can be associated with skin and soft tissue infections (SSTI). We compared S. aureus from nasal and pharyngeal swabs from HIV patients (n = 141) and healthy controls (n = 206) in Gabon in 2013, and analyzed determinants of colonization with PVL positive isolates in a cross sectional study. S. aureus isolates were screened for the presence of selected virulence factors (incl. PVL) and were subjected to antimicrobial susceptibility testing and genotyping. In HIV patients, S. aureus was more frequently detected (36.9 vs. 31.6%) and the isolates were more frequently PVL positive than in healthy controls (42.1 vs. 23.2%). The presence of PVL was associated with cotrimoxazole resistance (OR = 25.1, p < 0.001) and the use of cotrimoxazole was a risk factor for colonization with PVL positive isolates (OR = 2.5, p = 0.06). PVL positive isolates were associated with the multilocus sequence types ST15 (OR = 5.6, p < 0.001) and ST152 (OR = 62.1, p < 0.001). Participants colonized with PVL positive isolates reported more frequently SSTI in the past compared to carriers of PVL negative isolates (OR = 2.7, p = 0.01). In conclusion, the novelty of our study is that cotrimoxazole might increase the risk of SSTI in regions where cotrimoxazole resistance is high and associated with PVL. This finding needs to be confirmed in prospective studies. PMID- 25699037 TI - Threonine 286 of fatty acid desaturase 7 is essential for omega-3 fatty acid desaturation in the green microalga Chlamydomonas reinhardtii. AB - Omega-3 fatty acid desaturases catalyze the conversion of dienoic fatty acids (C18:2 and C16:2) into trienoic fatty acids (C18:3 and C16:3), accounting for more than 50% of the total fatty acids in higher plants and the green microalga Chlamydomonas reinhardtii. Here, we describe a Thr residue located in the fourth transmembrane domain of fatty acid desaturase 7 (FAD7) that is essential for the biosynthesis of omega-3 fatty acids in C. reinhardtii. The omega-3 fatty acid deficiency in strain CC-620, which contains a putative missense mutation at Thr286 of CrFAD7, was recovered by the overexpression of CC-125 CrFAD7. A Ser substitution in position 286 was able to partially complement the phenotype of the omega-3 fatty acid deficiency, but other substitution variants, such as Tyr, His, Cys, and Gly, failed to do so. Prediction of the phosphorylation target site revealed that Thr286 may be phosphorylated. Analysis of the structural conformation of CC-620 CrFAD7 via topology prediction (and bends in the helix) shows that this missense mutation may collapse the catalytic structure of CrFAD7. Taken together, this study suggests that Thr286 is essential for the maintaining the catalytic structure of CrFAD7. PMID- 25699038 TI - The Role of HLA-G Molecule and HLA-G Gene Polymorphisms in Tumors, Viral Hepatitis, and Parasitic Diseases. AB - Considering that the non-classical HLA-G molecule has well-recognized tolerogenic properties, HLA-G expression is expected to be deleterious when present in tumor cells and in cells chronically infected by viruses, whereas HLA-G expression is expected to be advantageous in autoimmune disorders. The expression of HLA-G on tissue or peripheral blood cells, the levels of soluble HLA-G and polymorphic sites along the gene have been studied in several disorders. In this study, we revised the role of the molecule and polymorphic sites along the HLA-G gene in tumors, viral hepatitis, and parasitic disorders. Overall, several lines of evidence clearly show that the induction of HLA-G expression in tumors has been associated with worse disease outcome and disease spread. In addition, the few studies conducted on hepatitis and parasitic disorders indicate that HLA-G may contribute to disease pathogenesis. Few isolated polymorphic sites, primarily located at the coding or 3' untranslated HLA-G region, have been evaluated in these disorders, and a complete HLA-G typing together with the study of gene regulatory elements may further help on the understanding of the influence of the genetic background on disease susceptibility. PMID- 25699039 TI - On the dark side of therapies with immunoglobulin concentrates: the adverse events. AB - Therapy by human immunoglobulin G (IgG) concentrates is a success story ongoing for decades with an ever increasing demand for this plasma product. The success of IgG concentrates on a clinical level is documented by the slowly increasing number of registered indication and the more rapid increase of the off-label uses, a topic dealt with in another contribution to this special issue of Frontiers in Immunology. A part of the success is the adverse event (AE) profile of IgG concentrates which is, even at life-long need for therapy, excellent. Transmission of pathogens in the last decade could be entirely controlled through the antecedent introduction by authorities of a regulatory network and installing quality standards by the plasma fractionation industry. The cornerstone of the regulatory network is current good manufacturing practice. Non-infectious AEs occur rarely and mainly are mild to moderate. However, in recent times, the increase in frequency of hemolytic and thrombotic AEs raised worrying questions on the possible background for these AEs. Below, we review elements of non infectious AEs, and particularly focus on hemolysis and thrombosis. We discuss how the introduction of plasma fractionation by ion-exchange chromatography and polishing by immunoaffinity chromatographic steps might alter repertoire of specificities and influence AE profiles and efficacy of IgG concentrates. PMID- 25699040 TI - Memory T follicular helper CD4 T cells. AB - T follicular helper (Tfh) cells are the subset of CD4 T helper cells that are required for generation and maintenance of germinal center reactions and the generation of long-lived humoral immunity. This specialized T helper subset provides help to cognate B cells via their expression of CD40 ligand, IL-21, IL 4, and other molecules. Tfh cells are characterized by their expression of the chemokine receptor CXCR5, expression of the transcriptional repressor Bcl6, and their capacity to migrate to the follicle and promote germinal center B cell responses. Until recently, it remained unclear whether Tfh cells differentiated into memory cells and whether they maintain Tfh commitment at the memory phase. This review will highlight several recent studies that support the idea of Tfh committed CD4 T cells at the memory stage of the immune response. The implication of these findings is that memory Tfh cells retain their capacity to recall their Tfh-specific effector functions upon reactivation to provide help for B cell responses and play an important role in prime and boost vaccination or during recall responses to infection. The markers that are useful for distinguishing Tfh effector and memory cells, as well as the limitations of using these markers will be discussed. Tfh effector and memory generation, lineage maintenance, and plasticity relative to other T helper lineages (Th1, Th2, Th17, etc.) will also be discussed. Ongoing discoveries regarding the maintenance and lineage stability versus plasticity of memory Tfh cells will improve strategies that utilize CD4 T cell memory to modulate antibody responses during prime and boost vaccination. PMID- 25699041 TI - The genetic regulation of infant immune responses to vaccination. AB - A number of factors are recognized to influence immune responses to vaccinations including age, gender, the dose, and quality of the antigen used, the number of doses given, the route of administration, and the nutritional status of the recipient. Additionally, several immunogenetic studies have identified associations between polymorphisms in genes encoding immune response proteins, both innate and adaptive, and variation in responses to vaccines. Variants in the genes encoding Toll-like receptors, HLA molecules, cytokines, and cytokine receptors have associated with heterogeneity of responses to a wide range of vaccines including measles, hepatitis B, influenza A, BCG, Haemophilus influenzae type b, and certain Neisseria meningitidis serotypes, amongst others. However, the vast majority of these studies have been conducted in older children and adults and there are very few data available from studies conducted in infants. This paper reviews the evidence to date that host genes influencing vaccines responses in these older population and identifies a large gap in our understanding of the genetic regulation of responses in early life. Given the high mortality from infection in early life and the challenges of developing vaccines that generate effective immune responses in the context of the developing immune system further research on infant populations is required. PMID- 25699042 TI - Analysis of the Bovine Monocyte-Derived Macrophage Response to Mycobacterium avium Subspecies Paratuberculosis Infection Using RNA-seq. AB - Johne's disease, caused by infection with Mycobacterium avium subsp. paratuberculosis, (MAP), is a chronic intestinal disease of ruminants with serious economic consequences for cattle production in the United States and elsewhere. During infection, MAP bacilli are phagocytosed and subvert host macrophage processes, resulting in subclinical infections that can lead to immunopathology and dissemination of disease. Analysis of the host macrophage transcriptome during infection can therefore shed light on the molecular mechanisms and host-pathogen interplay associated with Johne's disease. Here, we describe results of an in vitro study of the bovine monocyte-derived macrophage (MDM) transcriptome response during MAP infection using RNA-seq. MDM were obtained from seven age- and sex-matched Holstein-Friesian cattle and were infected with MAP across a 6-h infection time course with non-infected controls. We observed 245 and 574 differentially expressed (DE) genes in MAP-infected versus non-infected control samples (adjusted P value <=0.05) at 2 and 6 h post infection, respectively. Functional analyses of these DE genes, including biological pathway enrichment, highlighted potential functional roles for genes that have not been previously described in the host response to infection with MAP bacilli. In addition, differential expression of pro- and anti-inflammatory cytokine genes, such as those associated with the IL-10 signaling pathway, and other immune-related genes that encode proteins involved in the bovine macrophage response to MAP infection emphasize the balance between protective host immunity and bacilli survival and proliferation. Systematic comparisons of RNA-seq gene expression results with Affymetrix((r)) microarray data generated from the same experimental samples also demonstrated that RNA-seq represents a superior technology for studying host transcriptional responses to intracellular infection. PMID- 25699043 TI - Properdin levels in human sepsis. AB - Properdin is a normal serum protein that increases the production of complement activation products by binding C3b integral to convertase complexes and amplifying their activity at the site of activation. Thereby, it not only can aid in the resolution of infection but also contribute to tissue damage. In human sepsis, circulating complement C3 concentrations are decreased, though C3 is described as a positive acute phase reactant. However, properdin levels in human sepsis have not been reported. In this study, serum from 81 critically ill patients (predominately abdominal and respiratory sepsis) were analyzed for properdin levels at defined points of their stay in the intensive care unit (ICU) and compared with 61 age and sex-matched healthy volunteers. Properdin concentrations were significantly decreased in patients with sepsis on admission to ICU, but increased after clinical recovery to exceed levels observed in healthy volunteers. Properdin concentrations at ICU admission were decreased in non-survivors of sepsis compared to survivors, but this did not correlate with APACHE II score. However, pathologically low properdin levels (<7 MUg/ml) were related to increased duration of treatment. PMID- 25699044 TI - Complementing the Sugar Code: Role of GAGs and Sialic Acid in Complement Regulation. AB - Sugar molecules play a vital role on both microbial and mammalian cells, where they are involved in cellular communication, govern microbial virulence, and modulate host immunity and inflammatory responses. The complement cascade, as part of a host's innate immune system, is a potent weapon against invading bacteria but has to be tightly regulated to prevent inappropriate attack and damage to host tissues. A number of complement regulators, such as factor H and properdin, interact with sugar molecules, such as glycosaminoglycans (GAGs) and sialic acid, on host and pathogen membranes and direct the appropriate complement response by either promoting the binding of complement activators or inhibitors. The binding of these complement regulators to sugar molecules can vary from location to location, due to their different specificities and because distinct structural and functional subpopulations of sugars are found in different human organs, such as the brain, kidney, and eye. This review will cover recent studies that have provided important new insights into the role of GAGs and sialic acid in complement regulation and how sugar recognition may be compromised in disease. PMID- 25699045 TI - Mucosal-associated invariant T cells in inflammatory bowel diseases: bystanders, defenders, or offenders? PMID- 25699046 TI - Platelet transfusion - the new immunology of an old therapy. AB - Platelet transfusion has been a vital therapeutic approach in patients with hematologic malignancies for close to half a century. Randomized trials show that prophylactic platelet transfusions mitigate bleeding in patients with acute myeloid leukemia. However, even with prophylactic transfusions, as many as 75% of patients, experience hemorrhage. While platelet transfusion efficacy is modest, questions and concerns have arisen about the risks of platelet transfusion therapy. The acknowledged serious risks of platelet transfusion include viral transmission, bacterial sepsis, and acute lung injury. Less serious adverse effects include allergic and non-hemolytic febrile reactions. Rare hemolytic reactions have occurred due to a common policy of transfusing without regard to ABO type. In the last decade or so, new concerns have arisen; platelet-derived lipids are implicated in transfusion-related acute lung injury after transfusion. With the recognition that platelets are immune cells came the discoveries that supernatant IL-6, IL-27 sCD40L, and OX40L are closely linked to febrile reactions and sCD40L with acute lung injury. Platelet transfusions are pro-inflammatory, and may be pro-thrombotic. Anti-A and anti-B can bind to incompatible recipient or donor platelets and soluble antigens, impair hemostasis and thus increase bleeding. Finally, stored platelet supernatants contain biological mediators such as VEGF and TGF-beta1 that may compromise the host versus tumor response. This is particularly of concern in patients receiving many platelet transfusions, as for acute leukemia. New evidence suggests that removing stored supernatant will improve clinical outcomes. This new view of platelets as pro-inflammatory and immunomodulatory agents suggests that innovative approaches to improving platelet storage and pre-transfusion manipulations to reduce toxicity could substantially improve the efficacy and safety of this long-employed therapy. PMID- 25699048 TI - NKp44 and Natural Cytotoxicity Receptors as Damage-Associated Molecular Pattern Recognition Receptors. AB - Natural killer (NK) cells are a key constituent of the innate immune system, protecting against bacteria, virally infected cells, and cancer. Recognition and protective function against such cells are dictated by activating and inhibitory receptors on the surface of the NK cell, which bind to specific ligands on the surface of target cells. Among the activating receptors is a small class of specialized receptors termed the natural cytotoxicity receptors (NCRs) comprised of NKp30, NKp46, and NKp44. The NCRs are key receptors in the recognition and termination of virally infected and tumor cells. Since their discovery over 10 years ago, ligands corresponding to the NCRs have largely remained elusive. Recent identification of the cellular ligands for NKp44 and NKp30 as exosomal proliferating cell nuclear antigen (PCNA) and HLA-B-associated transcript 3 (BAT3), respectively, implicate that NCRs may function as receptors for damage associated molecular pattern (DAMP) molecules. In this review, we focus on NKp44, which surprisingly recognizes two distinct ligands resulting in either activation or inhibition of NK cell effector responses in response to tumor cells. The inhibitory function of NKp44 requires further study as it may play a pivotal role in placentation in addition to being exploited by tumors as a mechanism to escape NK cell killing. Finally, we suggest that the NCRs are a class of pattern recognition receptors, which recognize signals of genomic instability and cellular stress via interaction with the c-terminus of DAMP molecules localized to the surface of target cells by various co-ligands. PMID- 25699047 TI - Augmenting antitumor immune responses with epigenetic modifying agents. AB - Epigenetic silencing of immune-related genes is a striking feature of the cancer genome that occurs in the process of tumorigenesis. This phenomena impacts antigen processing and antigen presentation by tumor cells and facilitates evasion of immunosurveillance. Further modulation of the tumor microenvironment by altered expression of immunosuppressive cytokines impairs antigen-presenting cells and cytolytic T-cell function. The potential reversal of immunosuppression by epigenetic modulation is therefore a promising and versatile therapeutic approach to reinstate endogenous immune recognition and tumor lysis. Pre-clinical studies have identified multiple elements of the immune system that can be modulated by epigenetic mechanisms and result in improved antigen presentation, effector T-cell function, and breakdown of suppressor mechanisms. Recent clinical studies are utilizing epigenetic therapies prior to, or in combination with, immune therapies to improve clinical outcomes. PMID- 25699049 TI - Detection of impaired IgG antibody formation facilitates the decision on early immunoglobulin replacement in hypogammaglobulinemic patients. AB - Hypogammaglobulinemia (serum IgG lower than 2 SD below the age-matched mean) and clinical symptoms such as increased susceptibility to infection, autoimmune manifestations, granulomatous disease, and unexplained polyclonal lymphoproliferation are considered to be diagnostic hallmarks in patients with common variable immunodeficiency (CVID), the most frequent clinically severe primary immunodeficiency syndrome. In the present study, we investigated patients with hypogammaglobulinemia and no clinical or immunological signs of defective cell-mediated immunity and differentiated two groups on the basis of their IgG antibody formation capacity against a variety of different antigens (bacterial toxins, polysaccharide antigens, viral antigens). Patients with hypogammaglobulinemia and intact antibody production (HIAP) displayed no or only mild susceptibility to infections, while CVID patients showed marked susceptibility to bacterial infections that normalized following initiation of IVIG or subcutaneous immunoglobulin replacement therapy. There was a substantial overlap in IgG serum levels between the asymptomatic HIAP group and the CVID patients examined before immunoglobulin treatment. HIAP patients showed normal levels of switched B-memory cells (CD19(+)CD27(+)IgD(-)), while both decreased and normal levels of switched B-memory cells could be found in CVID patients. IgG antibody response to a primary antigen, tick-borne encephalitis virus (TBEV), was defective in CVID patients, thus confirming their substantial defect in IgG antibody production. Defective IgG antibody production against multiple antigens could also be demonstrated in an adult patient with recurrent infections but normal IgG levels. To facilitate early treatment before recurrent infections may lead to organ damage, the antibody formation capacity should be examined in hypogammaglobulinemic patients and the decision to treat should be based on the finding of impaired IgG antibody production. PMID- 25699050 TI - The evolution and development of the antibody repertoire. PMID- 25699051 TI - Mouse Conventional Dendritic Cells Can be Universally Classified Based on the Mutually Exclusive Expression of XCR1 and SIRPalpha. AB - Since the identification of mouse dendritic cells (DC) in the early 70s, all attempts to consistently classify the identified functional DC subpopulations according to their surface molecule expression failed. In the absence of DC lineage markers, a great variety of non-congruent surface molecules were used instead. Recent advances in the understanding of the involvement of transcription factors in the differentiation of DC subpopulations, together with the identification of a lineage marker for cross-presenting DC, have now allowed to establish a consistent and unified DC classification in the mouse. We demonstrate in the present article that all conventional DC in the mouse can be universally subdivided into either XCR1(+) ("cross-presenting") DC or SIRPalpha(+) DC, irrespective of their activation status. This advancement will greatly facilitate future work on the biology of mouse DC. We discuss this new classification in view of current DC classification systems in the mouse and the human. PMID- 25699052 TI - Review of the Results of WT1 Peptide Vaccination Strategies for Myelodysplastic Syndromes and Acute Myeloid Leukemia from Nine Different Studies. AB - We performed a systematic review of data from nine clinical trials of WT1 peptide vaccination in patients with myelodysplastic syndromes and/or acute myeloid leukemia (MDS/AML), published between 2004 and 2012. A total of 51 patients were eligible for analysis. Vaccination with WT1 peptides proved safe and feasible in patients with MDS/AML, in studies from different institutions. Additionally, clinical responses and clinical benefit were observed, with some patients achieving and maintaining remission long-term (more than 8 years). A significant correlation between induction of WT1-specific T cells and normalization/reduction of WT1 mRNA levels and progression-free survival was noted in a number of studies. However, larger studies are warranted to confirm these results. Interestingly, the majority of trials reported the presence of WT1-specific T cells with limited or absent functionality prior to vaccination, which increased in frequency and function after vaccination. In conclusion, WT1 peptide vaccination strategies were safe in this heterogeneous group of patient with MDS/AML. Larger and more homogeneous studies or randomized clinical trials are needed to quantify the contribution of WT1 peptide vaccines to clinical responses and long-term survival. PMID- 25699054 TI - Resident-Memory CD8 T Cells and mTOR: Generation, Protection, and Clinical Importance. PMID- 25699053 TI - The Jekyll and Hyde story of IL17-Producing gammadeltaT Cells. AB - In comparison to conventional alphabetaT cells, gammadeltaT cells are considered as specialized T cells based on their contributions in regulating immune response. gammadeltaT cells sense early environmental signals and initiate local immune-surveillance. The development of functional subtypes of gammadeltaT cells takes place in the thymus but they also exhibit plasticity in response to the activating signals and cytokines encountered in the extrathymic region. Thymic development of Tgammadelta1 requires strong TCR, CD27, and Skint-1 signals. However, differentiation of IL17-producing gammadeltaT cells (Tgammadelta17) is independent of Skint-1 or CD27 but requires notch signaling along with IL6 and TGFbeta cytokines in the presence of weak TCR signal. In response to cytokines like IL23, IL6, and IL1beta, Tgammadelta17 outshine Th17 cells for early activation and IL17 secretion. Despite expressing similar repertoire of lineage transcriptional factors, cytokines, and chemokine receptors, Tgammadelta17 cells differ from Th17 in spatial and temporal fashion. There are compelling reasons to consider significant role of Tgammadelta17 cells in regulating inflammation and thereby disease outcome. Tgammadelta17 cells regulate mobilization of innate immune cells and induce keratinocytes to secrete anti-microbial peptides thus exhibiting protective functions in anti-microbial immunity. In contrast, dysregulated Tgammadelta17 cells inhibit Treg cells, exacerbate autoimmunity, and are also known to support carcinogenesis by enhancing angiogenesis. The mechanism associated with this dual behavior of Tgammadelta17 is not clear. To exploit, Tgammadelta17 cells for beneficial use requires comprehensive analysis of their biology. Here, we summarize the current understanding on the characteristics, development, and functions of Tgammadelta17 cells in various pathological scenarios. PMID- 25699055 TI - Selection of IgG Variants with Increased FcRn Binding Using Random and Directed Mutagenesis: Impact on Effector Functions. AB - Despite the reasonably long half-life of immunoglogulin G (IgGs), market pressure for higher patient convenience while conserving efficacy continues to drive IgG half-life improvement. IgG half-life is dependent on the neonatal Fc receptor (FcRn), which among other functions, protects IgG from catabolism. FcRn binds the Fc domain of IgG at an acidic pH ensuring that endocytosed IgG will not be degraded in lysosomal compartments and will then be released into the bloodstream. Consistent with this mechanism of action, several Fc-engineered IgG with increased FcRn affinity and conserved pH dependency were designed and resulted in longer half-life in vivo in human FcRn-transgenic mice (hFcRn), cynomolgus monkeys, and recently in healthy humans. These IgG variants were usually obtained by in silico approaches or directed mutagenesis in the FcRn binding site. Using random mutagenesis, combined with a pH-dependent phage display selection process, we isolated IgG variants with improved FcRn-binding, which exhibited longer in vivo half-life in hFcRn mice. Interestingly, many mutations enhancing Fc/FcRn interaction were located at a distance from the FcRn binding site validating our random molecular approach. Directed mutagenesis was then applied to generate new variants to further characterize our IgG variants and the effect of the mutations selected. Since these mutations are distributed over the whole Fc sequence, binding to other Fc effectors, such as complement C1q and FcgammaRs, was dramatically modified, even by mutations distant from these effectors' binding sites. Hence, we obtained numerous IgG variants with increased FcRn-binding and different binding patterns to other Fc effectors, including variants without any effector function, providing distinct "fit-for-purpose" Fc molecules. We therefore provide evidence that half-life and effector functions should be optimized simultaneously as mutations can have unexpected effects on all Fc receptors that are critical for IgG therapeutic efficacy. PMID- 25699056 TI - Animal allergens: common protein characteristics featuring their allergenicity. PMID- 25699057 TI - Anti-rods/rings: a human model of drug-induced autoantibody generation. AB - In recent years, autoantibodies targeting subcellular structures described as the rods and rings pattern in HEp-2 ANA have been presented as a unique case of autoantibody generation. These rod and ring structures (RR) are at least partially composed of inosine monophosphate dehydrogenase type 2 (IMPDH2), and their formation can be induced in vitro by several small-molecule inhibitors, including some IMPDH2 inhibitors. Autoantibodies targeting these relatively unknown structures have been almost exclusively observed in hepatitis C virus (HCV) patients who have undergone treatment with pegylated interferon alpha/ribavirin (IFN/RBV) combination therapy. To date, anti-RR antibodies have not been found in treatment-naive HCV patients or in patients from any other disease groups, with few reported exceptions. Here, we describe recent advances in characterizing the RR structure and the strong association between anti-RR antibody response and HCV patients treated with IFN/RBV, detailing why anti-RR can be considered a human model of drug-induced autoantibody generation. PMID- 25699058 TI - Dendritic cell control of immune responses. PMID- 25699059 TI - Hyaluronan synthase 1: a mysterious enzyme with unexpected functions. AB - Hyaluronan synthase 1 (HAS1) is one of three isoenzymes responsible for cellular hyaluronan synthesis. Interest in HAS1 has been limited because its role in hyaluronan production seems to be insignificant compared to the two other isoenzymes, HAS2 and HAS3, which have higher enzymatic activity. Furthermore, in most cell types studied so far, the expression of its gene is low and the enzyme requires high concentrations of sugar precursors for hyaluronan synthesis, even when overexpressed in cell cultures. Both expression and activity of HAS1 are induced by pro-inflammatory factors like interleukins and cytokines, suggesting its involvement in inflammatory conditions. Has1 is upregulated in states associated with inflammation, like atherosclerosis, osteoarthritis, and infectious lung disease. In addition, both full length and splice variants of HAS1 are expressed in malignancies like bladder and prostate cancers, multiple myeloma, and malignant mesothelioma. Interestingly, immunostainings of tissue sections have demonstrated the role of HAS1 as a poor predictor in breast cancer, and is correlated with high relapse rate and short overall survival. Utilization of fluorescently tagged proteins has revealed the intracellular distribution pattern of HAS1, distinct from other isoenzymes. In all cell types studied so far, a high proportion of HAS1 is accumulated intracellularly, with a faint signal detected on the plasma membrane and its protrusions. Furthermore, the pericellular hyaluronan coat produced by HAS1 is usually thin without induction by inflammatory agents or glycemic stress and depends on CD44-HA interactions. These specific interactions regulate the organization of hyaluronan into a leukocyte recruiting matrix during inflammatory responses. Despite the apparently minor enzymatic activity of HAS1 under normal conditions, it may be an important factor under conditions associated with glycemic stress like metabolic syndrome, inflammation, and cancer. PMID- 25699060 TI - Brassica napus L. cultivars show a broad variability in their morphology, physiology and metabolite levels in response to sulfur limitations and to pathogen attack. AB - Under adequate sulfur supply, plants accumulate sulfate in the vacuoles and use sulfur-containing metabolites as storage compounds. Under sulfur-limiting conditions, these pools of stored sulfur-compounds are depleted in order to balance the nitrogen to sulfur ratio for protein synthesis. Stress conditions like sulfur limitation and/or pathogen attack induce changes in the sulfate pool and the levels of sulfur-containing metabolites, which often depend on the ecotypes or cultivars. We are interested in investigating the influence of the genetic background of canola (Brassica napus) cultivars in sulfur-limiting conditions on the resistance against Verticillium longisporum. Therefore, four commercially available B. napus cultivars were analyzed. These high-performing cultivars differ in some characteristics described in their cultivar pass, such as several agronomic traits, differences in the size of the root system, and resistance to certain pathogens, such as Phoma and Verticillium. The objectives of the study were to examine and explore the patterns of morphological, physiological and metabolic diversity in these B. napus cultivars at different sulfur concentrations and in the context of plant defense. Results indicate that the root systems are influenced differently by sulfur deficiency in the cultivars. Total root dry mass and length of root hairs differ not only among the cultivars but also vary in their reaction to sulfur limitation and pathogen attack. As a sensitive indicator of stress, several parameters of photosynthetic activity determined by PAM imaging showed a broad variability among the treatments. These results were supported by thermographic analysis. Levels of sulfur-containing metabolites also showed large variations. The data were interrelated to predict the specific behavior during sulfur limitation and/or pathogen attack. Advice for farming are discussed. PMID- 25699061 TI - Regulation of floral stem cell termination in Arabidopsis. AB - In Arabidopsis, floral stem cells are maintained only at the initial stages of flower development, and they are terminated at a specific time to ensure proper development of the reproductive organs. Floral stem cell termination is a dynamic and multi-step process involving many transcription factors, chromatin remodeling factors and signaling pathways. In this review, we discuss the mechanisms involved in floral stem cell maintenance and termination, highlighting the interplay between transcriptional regulation and epigenetic machinery in the control of specific floral developmental genes. In addition, we discuss additional factors involved in floral stem cell regulation, with the goal of untangling the complexity of the floral stem cell regulatory network. PMID- 25699062 TI - Polyamines in morphogenesis and development: a promising research area in seaweeds. PMID- 25699063 TI - Molecular basis of fruit development. PMID- 25699064 TI - Rhizobia and their bio-partners as novel drivers for functional remediation in contaminated soils. AB - Environmental pollutants have received considerable attention due to their serious effects on human health. There are physical, chemical, and biological means to remediate pollution; among them, bioremediation has become increasingly popular. The nitrogen-fixing rhizobia are widely distributed in the soil and root ecosystems and can increase legume growth and production by supplying nitrogen, resulting in the reduced need for fertilizer applications. Rhizobia also possess the biochemical and ecological capacity to degrade organic pollutants and are resistant to heavy metals, making them useful for rehabilitating contaminated soils. Moreover, rhizobia stimulate the survival and action of other biodegrading bacteria, thereby lowering the concentration of pollutants. The synergistic action of multiple rhizobial strains enhances both plant growth and the availability of pollutants ranging from heavy metals to persistent organic pollutants. Because phytoremediation has some restrictions, the beneficial interaction between plants and rhizobia provides a promising option for remediation. This review describes recent advances in the exploitation of rhizobia for the rehabilitation of contaminated soil and the biochemical and molecular mechanisms involved, thereby promoting further development of this novel bioremediation strategy into a widely accepted technique. PMID- 25699065 TI - Root physiological adaptations involved in enhancing P assimilation in mining and non-mining ecotypes of Polygonum hydropiper grown under organic P media. AB - It is important to seek out plant species, high in phosphorus (P) uptake, for phytoremediation of P-enriched environments with a large amount of organic P (Po). P assimilation characteristics and the related mechanisms of Polygonum hydropiper were investigated in hydroponic media containing various concentrations of Po (1-8 mmol L(-1)) supplied as phytate. The mining ecotype (ME) showed significantly higher biomass in both shoots and roots compared to the non-mining ecotype (NME) at 4, 6, and 8 m mol L(-1). Shoot P content of both ecotypes increased up to 4 mmol L(-1) while root P content increased continually up to 8 mmol L(-1) for the ME and up to 6 mmol L(-1) for the NME. Root P content of the ME exceeded 1% dry weight under 6 and 8 mmol L(-1). The ME had significantly higher P accumulation in both shoots and roots compared to the NME supplied with 6 and 8 mmol L(-1). The ME showed higher total root length, specific root length, root surface area, root volume, and displayed significantly greater root length, root surface area, and root volume of lateral roots compared to the NME grown in all Po treatments. Average diameter of lateral roots was 0.17 19 mm for the ME and 0.18-0.21 mm for the NME. Greater acid phosphatase and phytase activities were observed in the ME grown under different levels of Po relative to the NME. This indicated fine root morphology, enhanced acid phosphatase and phytase activities might be adaptations to high Po media. Results from this study establish that the ME of P. hydropiper is capable of assimilating P from Po media and is a potential material for phytoremediation of polluted area with high Po. PMID- 25699066 TI - Characterization of reference genes for RT-qPCR in the desert moss Syntrichia caninervis in response to abiotic stress and desiccation/rehydration. AB - Syntrichia caninervis is the dominant bryophyte of the biological soil crusts found in the Gurbantunggut desert. The extreme desert environment is characterized by prolonged drought, temperature extremes, high radiation and frequent cycles of hydration and dehydration. S. caninervis is an ideal organism for the identification and characterization of genes related to abiotic stress tolerance. Reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) expression analysis is a powerful analytical technique that requires the use of stable reference genes. Using available S. caninervis transcriptome data, we selected 15 candidate reference genes and analyzed their relative expression stabilities in S. caninervis gametophores exposed to a range of abiotic stresses or a hydration-desiccation-rehydration cycle. The programs geNorm, NormFinder, and RefFinder were used to assess and rank the expression stability of the 15 candidate genes. The stability ranking results of reference genes under each specific experimental condition showed high consistency using different algorithms. For abiotic stress treatments, the combination of two genes (alpha-TUB2 and CDPK) were sufficient for accurate normalization. For the hydration-desiccation-rehydration process, the combination of two genes (alpha TUB1 and CDPK) were sufficient for accurate normalization. 18S was among the least stable genes in all of the experimental sets and was unsuitable as reference gene in S. caninervis. This is the first systematic investigation and comparison of reference gene selection for RT-qPCR work in S. caninervis. This research will facilitate gene expression studies in S. caninervis, related moss species from the Syntrichia complex and other mosses. PMID- 25699067 TI - Key players of singlet oxygen-induced cell death in plants. AB - The production of reactive oxygen species (ROS) is an unavoidable consequence of oxygenic photosynthesis. Singlet oxygen ((1)O2) is a highly reactive species to which has been attributed a major destructive role during the execution of ROS induced cell death in photosynthetic tissues exposed to excess light. The study of the specific biological activity of (1)O2 in plants has been hindered by its high reactivity and short lifetime, the concurrent production of other ROS under photooxidative stress, and limited in vivo detection methods. However, during the last 15 years, the isolation and characterization of two (1)O2-overproducing mutants in Arabidopsis thaliana, flu and ch1, has allowed the identification of genetically controlled (1)O2 cell death pathways and a (1)O2 acclimation pathway that are triggered at sub-cytotoxic concentrations of (1)O2. The study of flu has revealed the control of cell death by the plastid proteins EXECUTER (EX)1 and EX2. In ch1, oxidized derivatives of beta-carotene, such as beta-cyclocitral and dihydroactinidiolide, have been identified as important upstream messengers in the (1)O2 signaling pathway that leads to stress acclimation. In both the flu and ch1 mutants, phytohormones act as important promoters or inhibitors of cell death. In particular, jasmonate has emerged as a key player in the decision between acclimation and cell death in response to (1)O2. Although the flu and ch1 mutants show many similarities, especially regarding their gene expression profiles, key differences, such as EXECUTER-independent cell death in ch1, have also been observed and will need further investigation to be fully understood. PMID- 25699068 TI - Amino acid uptake in rust fungi. AB - The plant pathogenic rust fungi colonize leaf tissue and feed off their host plants without killing them. Certain economically important species of different genera such as Melampsora, Phakopsora, Puccinia, or Uromyces are extensively studied for resolving the mechanisms of the obligate biotrophy. As obligate parasites rust fungi only can complete their life cycle on living hosts where they grow through the leaf tissue by developing an extended network of intercellular hyphae from which intracellular haustoria are differentiated. Haustoria are involved in key functions of the obligate biotrophic lifestyle: suppressing host defense responses and acquiring nutrients. This review provides a survey of rust fungi nitrogen nutrition with special emphasis on amino acid uptake. A variety of sequences of amino acid transporter genes of rust fungi have been published; however, transport activity of only three in planta highly up regulated amino acid permeases have been characterized. Functional and immunohistochemical investigations have shown the specificity and localization of these transporters. Sequence data of various genome projects allowed identification of numerous rust amino acid transporter genes. An in silico analysis reveals that these genes can be classified into different transporter families. In addition, genetic and molecular data of amino acid transporters have provided new insights in the corresponding metabolic pathways. PMID- 25699069 TI - Insight into S-RNase-based self-incompatibility in Petunia: recent findings and future directions. AB - S-RNase-based self-incompatibility in Petunia is a self/non-self recognition system that allows the pistil to reject self-pollen to prevent inbreeding and to accept non-self pollen for outcrossing. Cloning of S-RNase in 1986 marked the beginning of nearly three decades of intensive research into the mechanism of this complex system. S-RNase was shown to be the sole female determinant in 1994, and the first male determinant, S-locus F-box protein1 (SLF1), was identified in 2004. It was discovered in 2010 that additional SLF proteins are involved in pollen specificity, and recently two S-haplotypes of Petunia inflata were found to possess 17 SLF genes based on pollen transcriptome analysis, further increasing the complexity of the system. Here, we first summarize the current understanding of how the interplay between SLF proteins and S-RNase in the pollen tube allows cross-compatible pollination, but results in self-incompatible pollination. We then discuss some of the aspects that are not yet elucidated, including uptake of S-RNase into the pollen tube, nature, and assembly of SLF containing complexes, the biochemical basis for differential interactions between SLF proteins and S-RNase, and fate of non-self S-RNases in the pollen tube. PMID- 25699070 TI - Thigmomorphogenetic responses of an aquatic macrophyte to hydrodynamic stress. AB - The response of aquatic plants to abiotic factors is a crucial study topic, because the diversity of aquatic vegetation is strongly related to specific adaptations to a variety of environments. This biodiversity ensures resilience of aquatic communities to new and changing ecological conditions. In running water, hydrodynamic disturbance is one of the key factors in this context. While plant adaptations to resource stress (nutrients, light...) are well documented, adaptations to mechanical stress, particularly flow, are largely unknown. The submerged species Egeria densa was used in an experiment to detect whether the presence or absence of hydrodynamic stress causes plant thigmomorphogenetic responses (i) in terms of plant biogenic silica (BSi), cellulose and lignin concentrations, and (ii) in terms of plant strength. Plant silica concentrations, as well as lignin concentrations were significantly higher in presence of hydrodynamic stress. These physiological changes are accompanied by some significant changes in stem biomechanical traits: stem resistance to tensile forces (breaking force and breaking strength) and stiffness were higher for plants exposed to hydrodynamic stress. We conclude that the response of this aquatic plant species to mechanical stress is likely the explaining factor for a higher capacity to tolerate stress through the production of mechanically hardened shoots. PMID- 25699071 TI - Parasitic plants of the genus Cuscuta and their interaction with susceptible and resistant host plants. AB - By comparison with plant-microbe interaction, little is known about the interaction of parasitic plants with their hosts. Plants of the genus Cuscuta belong to the family of Cuscutaceae and comprise about 200 species, all of which live as stem holoparasites on other plants. Cuscuta spp. possess no roots nor fully expanded leaves and the vegetative portion appears to be a stem only. The parasite winds around plants and penetrates the host stems via haustoria, forming direct connections to the vascular bundles of their hosts to withdraw water, carbohydrates, and other solutes. Besides susceptible hosts, a few plants exist that exhibit an active resistance against infestation by Cuscuta spp. For example, cultivated tomato (Solanum lycopersicum) fends off Cuscuta reflexa by means of a hypersensitive-type response occurring in the early penetration phase. This report on the plant-plant dialog between Cuscuta spp. and its host plants focuses on the incompatible interaction of C. reflexa with tomato. PMID- 25699072 TI - Effect of IAA on in vitro growth and colonization of Nostoc in plant roots. AB - Nostoc is widely known for its ability to fix atmospheric nitrogen and the establishment of symbiotic relationship with a wide range of plants from various taxonomic groups. Several strains of Nostoc produce phytohormones that promote growth of its plant partners. Nostoc OS-1 was therefore selected for study because of the presence of putative ipdC gene that encodes a key enzyme to produce Indole-3-acetic acid (IAA). The results indicated that both cellular and released IAA was found high with increasing incubation time and reached to a peak value (i.e., 21 pmol mg(-1)ch-a) on the third week as determined by UPLC-ESI MS/MS. Also the Nostoc OS-1 strain efficiently colonized the roots and promoted the growth of rice as well as wheat under axenic conditions and induced ipdC gene that suggested the possible involvement of IAA in these phenotypes. To confirm the impact of IAA on root colonization efficiency and plant promoting phenotypes of Nostoc OS-1, an ipdC knockout mutant was generated by homologous recombinant method. The amount of releasing IAA, in vitro growth, root colonization, and plant promoting efficiency of the ipdC knockout mutant was observed significantly lower than wild type strain under axenic conditions. Importantly, these phenotypes were restored to wild-type levels when the ipdC knockout mutant was complemented with wild type ipdC gene. These results together suggested that ipdC and/or synthesized IAA of Nostoc OS-1 is required for its efficient root colonization and plant promoting activity. PMID- 25699073 TI - Pseudogene-derived lncRNAs: emerging regulators of gene expression. AB - In the more than one decade since the completion of the Human Genome Project, the prevalence of non-protein-coding functional elements in the human genome has emerged as a key revelation in post-genomic biology. Highlighted by the ENCODE (Encyclopedia of DNA Elements) and FANTOM (Functional Annotation of Mammals) consortia, these elements include tens of thousands of pseudogenes, as well as comparably numerous long non-coding RNA (lncRNA) genes. Pseudogene transcription and function remain insufficiently understood. However, the field is of great importance for human disease due to the high sequence similarity between pseudogenes and their parental protein-coding genes, which generates the potential for sequence-specific regulation. Recent case studies have established essential and coordinated roles of both pseudogenes and lncRNAs in development and disease in metazoan systems, including functional impacts of lncRNA transcription at pseudogene loci on the regulation of the pseudogenes' parental genes. This review synthesizes the nascent evidence for regulatory modalities jointly exerted by lncRNAs and pseudogenes in human disease, and for recent evolutionary origins of these systems. PMID- 25699074 TI - DNA damage response and evasion from immunosurveillance in CLL: new options for NK cell-based immunotherapies. AB - Chronic lymphocytic leukemia (CLL) is the most prominent B cell malignancy among adults in the Western world and characterized by a clonal expansion of B cells. The patients suffer from severe immune defects resulting in increased susceptibility to infections and failure to generate an antitumor immune response. Defects in both, DNA damage response (DDR) pathway and crosstalk with the tissue microenvironment have been reported to play a crucial role for the survival of CLL cells, therapy resistance and impaired immune response. To this end, major advances over the past years have highlighted several T cell immune evasion mechanisms in CLL. Here, we discuss the consequences of an impaired DDR pathway for detection and elimination of CLL cells by natural killer (NK) cells. NK cells are considered to be a major component of the immunosurveillance in leukemia but NK cell activity is impaired in CLL. Restoration of NK cell activity using immunoligands and immunoconstructs in combination with the conventional chemotherapy may provide a future perspective for CLL treatment. PMID- 25699075 TI - Portuguese crypto-Jews: the genetic heritage of a complex history. AB - The first documents mentioning Jewish people in Iberia are from the Visigothic period. It was also in this period that the first documented anti-Judaic persecution took place. Other episodes of persecution would happen again and again during the long troubled history of the Jewish people in Iberia and culminated with the Decrees of Expulsion and the establishment of the Inquisition: some Jews converted to Catholicism while others resisted and were forcedly baptized, becoming the first Iberian Crypto-Jews. In the 18th century the official discrimination and persecution carried out by the Inquisition ended and several Jewish communities emerged in Portugal. From a populational genetics point of view, the worldwide Diaspora of contemporary Jewish communities has been intensely studied. Nevertheless, very little information is available concerning Sephardic and Iberian Crypto-Jewish descendants. Data from the Iberian Peninsula, the original geographic source of Sephardic Jews, is limited to two populations in Portugal, Belmonte, and Braganca district, and the Chueta community from Mallorca. Belmonte was the first Jewish community studied for uniparental markers. The construction of a reference model for the history of the Portuguese Jewish communities, in which the genetic and classical historical data interplay dynamically, is still ongoing. Recently an enlarged sample covering a wide region in the Northeast Portugal was undertaken, allowing the genetic profiling of male and female lineages. A Jewish specific shared female lineage (HV0b) was detected between the community of Belmonte and Braganca. In contrast to what was previously described as a hallmark of the Portuguese Jews, an unexpectedly high polymorphism of lineages was found in Braganca, showing a surprising resistance to the erosion of genetic diversity typical of small-sized isolate populations, as well as signs of admixture with the Portuguese host population. PMID- 25699076 TI - Mining for viral fragments in methylation enriched sequencing data. AB - Most next generation sequencing experiments generate more data than is usable for the experimental set up. For example, methyl-CpG binding domain (MBD) affinity purification based sequencing is often used for DNA-methylation profiling, but up to 30% of the sequenced fragments cannot be mapped uniquely to the reference genome. Here we present and evaluate a methodology for the identification of viruses in these otherwise unused paired-end MBD-seq data. Viral detection is accomplished by mapping non-reference alignable reads to a comprehensive set of viral genomes. As viruses play an important role in epigenetics and cancer development, 92 (pre)malignant and benign samples, originating from two different collections of cervical samples and related cell lines, were used in this study. These samples include primary carcinomas (n = 22), low- and high-grade cervical intraepithelial neoplasia (CIN1 and CIN2/3 - n = 2/n = 30) and normal tissue (n = 20), as well as control samples (n = 17). Viruses that were detected include phages, adenoviruses, herpesviridae and HPV. HPV, which causes virtually all cervical cancers, was identified in 95% of the carcinomas, 100% of the CIN2/3 samples, both CIN1 samples and in 55% of the normal samples. Comparing the amount of mapped fragments on HPV for each HPV-infected sample yielded a significant difference between normal samples and carcinomas or CIN2/3 samples (adjusted p values resp. <10(-5), <10(-5)), reflecting different viral loads and/or methylation degrees in non-normal samples. Fragments originating from different HPV types could be distinguished and were independently validated by PCR-based assays in 71% of the detections. In conclusion, although limited by the a priori knowledge of viral reference genome sequences, the proposed methodology can provide a first confined but substantial insight into the presence, concentration and types of methylated viral sequences in MBD-seq data at low additional cost. PMID- 25699077 TI - ErbB polymorphisms: insights and implications for response to targeted cancer therapeutics. AB - Advances in high-throughput genomic-scanning have expanded the repertory of genetic variations in DNA sequences encoding ErbB tyrosine kinase receptors in humans, including single nucleotide polymorphisms (SNPs), polymorphic repetitive elements, microsatellite variations, small-scale insertions and deletions. The ErbB family members: EGFR, ErbB2, ErbB3, and ErbB4 receptors are established as drivers of many aspects of tumor initiation and progression to metastasis. This knowledge has provided rationales for the development of an arsenal of anti-ErbB therapeutics, ranging from small molecule kinase inhibitors to monoclonal antibodies. Anti-ErbB agents are becoming the cornerstone therapeutics for the management of cancers that overexpress hyperactive variants of ErbB receptors, in particular ErbB2-positive breast cancer and non-small cell lung carcinomas. However, their clinical benefit has been limited to a subset of patients due to a wide heterogeneity in drug response despite the expression of the ErbB targets, attributed to intrinsic (primary) and to acquired (secondary) resistance. Somatic mutations in ErbB tyrosine kinase domains have been extensively investigated in preclinical and clinical setting as determinants for either high sensitivity or resistance to anti-ErbB therapeutics. In contrast, only scant information is available on the impact of SNPs, which are widespread in genes encoding ErbB receptors, on receptor structure and activity, and their predictive values for drug susceptibility. This review aims to briefly update polymorphic variations in genes encoding ErbB receptors based on recent advances in deep sequencing technologies, and to address challenging issues for a better understanding of the functional impact of single versus combined SNPs in ErbB genes to receptor topology, receptor-drug interaction, and drug susceptibility. The potential of exploiting SNPs in the era of stratified targeted therapeutics is discussed. PMID- 25699078 TI - The red seaweed Plocamium brasiliense shows anti-snake venom toxic effects. AB - BACKGROUND: Snakebite is considered a neglected tropical disease by the World Health Organization. In Brazil, about 70% of the envenomation cases are caused by Bothrops snakes. Its venom may provoke hemorrhage, pain, necrosis, hemolysis, renal or cardiac failure and even death in victims. Since commercial antivenom does not efficiently neutralize the local toxic effects of venoms, natural products have been tested in order to provide alternative or complementary treatment to serum therapy. Therefore, the present study aimed to evaluate the ability of the seaweed Plocamium brasiliense and its active derivatives to neutralize hemorrhagic, edematogenic, hemolytic, coagulant and proteolytic activities of B. jararaca venom. METHODS: Specimens of P. brasiliense were collected in Rio de Janeiro state, Brazil, dried and submitted to oil extraction using four solvents of increasing polarities, n-hexane (HEX), dichloromethane (DCM), ethyl acetate (ETA) and hydroalcoholic solution (HYD). The solvents were evaporated, yielding HEX, DCM, ETA and HYD extracts. Further, all extracts were dissolved in dimethylsulfoxide. In addition, two monoterpenes (8-bromo-3,4,7 trichloro-3,7-dimethyl-1E, 5E-octadiene and 1,8-dibromo-3,4,7-trichloro-3,7 dimethyl-1E, 5E-octadiene) and a cholesterol fraction were isolated from the extract of P. brasiliense prepared in hexane. Algal samples were incubated for 30 minutes with B. jararaca venom, and then tested for lethality; hemorrhagic, edematogenic, hemolytic, coagulant and proteolytic effects. RESULTS: Most of the algal extracts inhibited the toxic effects with different potencies. The DCM extract was the most effective, since it inhibited all types of toxic activity. On the other hand, the HYD extract failed to inhibit any effect. Moreover, the isolated products inhibited proteolysis and protected mice from hemorrhage in 30% of the cases, whereas 8-bromo-3,4,7-trichloro-3,7-dimethyl-1E, 5E-octadiene inhibited 100% and 20% of the hemorrhagic and proteolytic activities, respectively. None of the algal products were toxic to mice. CONCLUSION: Seaweeds may be a promising source of inhibitors against toxic effects caused by B. jararaca envenomation, which may contribute to antivenom treatment. PMID- 25699079 TI - Nurses' experience of using an application to support new parents after early discharge: an intervention study. AB - Background. A development towards earlier postnatal discharge presents a challenge to find new ways to provide information and support to families. A possibility is the use of telemedicine. Objective. To explore how using an app in nursing practice affects the nurses' ability to offer support and information to postnatal mothers who are discharged early and their families. Design. Participatory design. An app with a chat, a knowledgebase, and automated messages was tried out between hospital and parents at home. Settings. The intervention took place on a postnatal ward with approximately 1,000 births a year. Participants. At the onset of the intervention, 17 nurses, all women, were working on the ward. At the end of the intervention, 16 nurses were employed, all women. Methods. Participant observation and two focus group interviews. The data analysis was inspired by systematic text condensation. Results. The nurses on the postnatal ward consider that the use of the app gives families easier access to timely information and support. Conclusions. The app gives the nurses the possibility to offer support and information to the parents being early discharged. The app is experienced as a lifeline that connects the homes of the new parents with the hospital. PMID- 25699080 TI - Regulation of the Human Ghrelin Promoter Activity by Transcription Factors, NF kappaB and Nkx2.2. AB - To examine the gene expression of ghrelin, a growth hormone releasing and appetite stimulating hormone from stomach, we constructed human ghrelin promoter reporter vectors and analyzed the promoter activity. The ghrelin promoter activity was high when cultured cells that express ghrelin mRNA endogenously like TT or ECC10 cells were used, indicating that these cells contain factors necessary for full expression of the human ghrelin gene. The human ghrelin promoter contains both positive and negative regulatory regions. A transient decrease of the promoter activity was found when the reporter vector with the 1600 fragment of the human ghrelin promoter was transfected into cultured cells. We then examined the effect of several transcription factors on the ghrelin promoter activity and found that NF-kappaB suppressed and that Nkx2.2, a homeodomain-containing transcription factor that is important for ghrelin cell development in pancreas, activates the promoter activity. These transcription factors may be possible targets for the control of ghrelin gene expression. PMID- 25699081 TI - Are Thyroid Hormone and Tumor Cell Proliferation in Human Breast Cancers Positive for HER2 Associated? AB - Objective. This study investigated whether thyroid hormone (TH) levels are correlated to cell proliferation (Ki67), in euthyroid breast cancer patients. Design and Methods. 86 newly diagnosed breast cancer patients with estrogen receptor (ER) positive tumors, who referred for surgery, were included in the study. Results. FT3, FT4, and TSH were within normal range. No correlation was seen between Ki67 and FT3 (r = -0.17, P = 0.15), FT4 (r = -0.13, P = 0.25), or TSH (r = -0.10, P = 0.39) in all patients studied. However, subgroup analysis showed that, in HER2(+) patients, a negative correlation existed between FT3 levels and Ki67 (r = -0.60 and P = 0.004) but not between Ki67 and FT4 (r = 0.04 and P = 0.85) or TSH (r = -0.23 and P = 0.30). In HER2(-) patients, there was no significant correlation between Ki67 and FT3 (r = -0.06, P = 0.67), FT4 (r = 0.15, P = 0.26), or TSH (r = -0.09, P = 0.49). Phospho-p44/total p44 ERK levels were found to be increased by 2-fold in HER2(+) versus HER2(-) tumors. No difference was detected in phospho-p42/total p42 ERK levels. Conclusions. TH profile is not altered in patients with newly diagnosed breast cancer. However, FT3 levels, even within normal range, are negatively correlated with cell proliferation in HER2(+) breast cancer tumors. This response may be due to the interaction between ERK and TH signaling. PMID- 25699082 TI - Role of rebiopsy in relapsed non-small cell lung cancer for directing oncology treatments. AB - Background. Currently, few rebiopsies are performed in relapses of advanced non small cell lung cancer. They are not customary in clinical practice of lung cancer. However, it is not possible to properly target treatments in cases of relapse without knowing the nature of new lesions. Design. This paper comprehensively summarizes the available literature about rebiopsy and broadly discusses the importance of rebiopsy in advanced non-small cell lung cancer. Results. Altogether 560 abstracts were used as material for further analysis. 19 articles were about clinical rebiopsy in lung cancer and were reviewed in detailed manner. Conclusions. This review shows that rebiopsy is feasible in non small cell lung cancer, and success rates can be high if rebiopsy is accompanied by adequate evaluation before biopsy. Its use may resolve the difficulties in sampling bias and detecting changes in cancer characteristics. In cases where treatment was selected based on tissue characteristics that then change, the treatment selection process must be repeated while considering new characteristics of the tumor. Rebiopsy may be used to predict therapeutic resistance and consequently redirect targeted therapies. Such knowledge may resolve the difficulties in sampling bias and also in selecting preexisting clones or formulating drug-resistant ones. Rebiopsy should be performed more often in non-small cell lung cancer. PMID- 25699083 TI - In silico conformational analysis of the short-sequence hypomurocin a peptides. AB - In this theoretical study, a conformational analysis was performed on short sequence hypomurocin A peptides, in order to identify their characteristic structural properties. For each hypomurocin A molecule, not only the backbone conformations, but also the side-chain conformations were examined. The results indicated that certain tetrapeptide units could be characterized by types I and III beta-turn structures, and considering the helical conformations, it could be concluded that the hypomurocin A peptides showed a preference for the 310-helical structure over the alpha-helical structure. Beside the backbone conformations, the side-chain conformations were investigated, and the preferred rotamer states of the side-chains of amino acids were determined. Furthermore, the occurrence of i <- i + 3 and i <- i + 4 intramolecular H-bonds was studied, which could play a role in the structural stabilization of beta-turns and helical conformations. On the whole, our theoretical study supplied a comprehensive characterization of the three-dimensional structure of short-sequence hypomurocin A peptides. PMID- 25699084 TI - Detailed reconstruction of the musculature in Limnognathia maerski (Micrognathozoa) and comparison with other Gnathifera. AB - INTRODUCTION: Limnognathia maerski is the single species of the recently described taxon, Micrognathozoa. The most conspicuous character of this animal is the complex set of jaws, which resembles an even more intricate version of the trophi of Rotifera and the jaws of Gnathostomulida. Whereas the jaws of Limnognathia maerski previously have been subject to close examinations, the related musculature and other organ systems are far less studied. Here we provide a detailed study of the body and jaw musculature of Limnognathia maerski, employing confocal laser scanning microscopy of phalloidin stained musculature as well as transmission electron microscopy (TEM). RESULTS: This study reveals a complex body wall musculature, comprising six pairs of main longitudinal muscles and 13 pairs of trunk dorso-ventral muscles. Most longitudinal muscles span the length of the body and some fibers even branch off and continue anteriorly into the head and posteriorly into the abdomen, forming a complex musculature. The musculature of the jaw apparatus shows several pairs of striated muscles largely related to the fibularium and the main jaws. The jaw articulation and function of major and minor muscle pairs are discussed. No circular muscles or intestinal musculature have been found, but some newly discovered muscles may supply the anal opening. CONCLUSIONS: The organization in Limnognathia maerski of the longitudinal and dorso-ventral muscle bundles in a loose grid is more similar to the organization found in rotifers rather than gnathostomulids. Although the dorso-ventral musculature is probably not homologous to the circular muscles of rotifers, a similar function in body extension is suggested. Additionally, a functional comparison between the jaw musculature of Limnognathia maerski, Rotifera and Gnathostomulida, emphasizes the important role of the fibularium in Limnognathia maerski, and suggests a closer functional resemblance to the jaw organization in Rotifera. PMID- 25699085 TI - Clinical Global Impression-severity score as a reliable measure for routine evaluation of remission in schizophrenia and schizoaffective disorders. AB - AIMS: This study aimed to compare the performance of Positive and Negative Syndrome Scale (PANSS) symptom severity criteria established by the Remission in Schizophrenia Working Group (RSWG) with criteria based on Clinical Global Impression (CGI) severity score. The 6-month duration criterion was not taken into consideration. METHODS: A convenience sample of 112 chronic psychotic outpatients was examined. Symptomatic remission was evaluated according to RSWG severity criterion and to a severity criterion indicated by the overall score obtained at CGI-Schizophrenia (CGI-SCH) rating scale (<=3) (CGI-S). RESULTS: Clinical remission rates of 50% and 49.1%, respectively, were given by RSWG and CGI-S, with a significant level of agreement between the two criteria in identifying remitted and non-remitted cases. Mean scores at CGI-SCH and PANSS scales were significantly higher among remitters, independent of the remission criteria adopted. Measures of cognitive functioning were largely independent of clinical remission evaluated according to both RSWG and CGI-S. When applying RSWG and CGI-S criteria, the rates of overall good functioning yielded by Personal and Social Performance scale (PSP) were 32.1% and 32.7%, respectively, while the mean scores at PSP scale differed significantly between remitted and non-remitted patients, independent of criteria adopted. The proportion of patients judged to be in a state of well-being on Social Well-Being Under Neuroleptics-Short Version scale (SWN-K) were, respectively, 66.1% and 74.5% among remitters according to RSWG and CGI-S; the mean scores at the SWN scale were significantly higher only among remitters according to CGI-S criteria. CONCLUSIONS: CGI severity criteria may represent a valid and user-friendly alternative for use in identifying patients in remission, particularly in routine clinical practice. PMID- 25699086 TI - Adjuvant low-frequency rTMS in treating auditory hallucinations in recent-onset schizophrenia: a randomized controlled study investigating the effect of high frequency priming stimulation. AB - BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) has been found to be effective in reducing frequency and duration of auditory verbal hallucinations (AVH). Priming stimulation, which involves high-frequency rTMS stimulation followed by low-frequency rTMS, has been shown to markedly enhance the neural response to the low-frequency stimulation train. However, this technique has not been investigated in recent onset schizophrenia patients. The aim of this randomized controlled study was to investigate whether the effects of rTMS on AVH can be enhanced with priming rTMS in recent onset schizophrenia patients. METHODS: Forty recent onset schizophrenia patients completed the study. Patients were randomized over two groups: one receiving low-frequency rTMS preceded by priming and another receiving low-frequency rTMS without priming. Both treatments were directed at the left temporo-parietal region. The severity of AVH and other psychotic symptoms were assessed with the auditory hallucination subscale (AHRS) of the Psychotic Symptom Rating Scales (PSYRATS), the Positive and Negative Syndrome Scale (PANSS) and the Clinical Global Impression (CGI). RESULTS: We found that all the scores of these ratings significantly reduced over time (i.e. baseline through 1, 2, 4 and 6 weeks) in both the treatment groups. We found no difference between the two groups on all measures, except for significantly greater improvement on loudness of AVH in the group with priming stimulation during the follow-ups (F = 2.72; p < .05). CONCLUSIONS: We conclude that low frequency rTMS alone and high-frequency priming of low-frequency rTMS do not elicit significant differences in treatment of overall psychopathology, particularly AVH when given in recent onset schizophrenia patients. Add on priming however, seems to be particularly better in faster reduction in loudness of AVH. PMID- 25699088 TI - Antioxidant effects of pineapple vinegar in reversing of paracetamol-induced liver damage in mice. AB - BACKGROUND: Pineapple (Ananas comosus) was demonstrated to be hepatoprotective. This study aims to investigate the reversing effects of pineapple vinegar on paracetamol-induced liver damage in murine model. METHODS: Pineapple juice was fermented via anaerobic and aerobic fermentation to produce pineapple vinegar. Male BALB/c mice (n = 70) were separated into 7 treatment groups (n = 10). Pineapple vinegar (0.08 and 2 mL/kg BW) and synthetic vinegar were used to treat paracetamol-induced liver damage in mice. The hepatoprotective effects were determined by serum biochemistry profiles (aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and triglyceride (TG)), liver antioxidant levels (ferric-reducing ability plasma (FRAP), superoxide dismutase (SOD), malondialdehyde (MDA), nitric oxide (NO), and reduced glutathione assays (GSH)) and histopathological examination with hematoxylin and eosin (H&E) staining. The effects were further evaluated by the expression levels of iNOS, NF-kappaB, and cytochrome P450 2E1 by quantitative real-time PCR and Western blot analyses. Vinegar samples were also tested for in vitro antioxidant (FRAP, 2,2-diphenyl-2-picrylhydrazyl (DPPH), and total phenolic content (TPC)). Soluble phenolic acid contents in the samples were identified by HPLC. RESULTS: Pineapple vinegar contained 169.67 +/- 0.05 MUg GAE/mL of TPC, with 862.61 +/- 4.38 MUg/mL gallic acid as the main component. Oral administration of pineapple vinegar at 2 mL/kg BW reduced serum enzyme biomarker levels, including AST (P = 0.008), ALT (P = 0.006), ALP (P = 0.002), and TG (P = 0.006) after 7 days of paracetamol treatment. Liver antioxidant levels such as hepatic glutathione (P = 0.003), SOD (P < 0.001), lipid peroxidation (P = 0.002) and FRAP (P <0.001) were restored after the treatment. Pineapple vinegar reduced the expressions of iNOS (P = 0.003) and NF-kB (P = 0.003) and the level of NO (P = 0.003) significantly. Pineapple vinegar also downregulated liver cytochrome P450 protein expression. CONCLUSIONS: Oral administration of pineapple vinegar at 0.08 and 2 mL/kg BW reduced serum enzyme biomarker levels, restored liver antioxidant levels, reduced inflammatory factor expressions, and down regulated liver cytochrome P450 protein expression in paracetamol-induced liver damage in mice. PMID- 25699090 TI - Video feedback compared to treatment as usual in families with parent-child interactions problems: a randomized controlled trial. AB - BACKGROUND: For the first time to our knowledge, short- and long-term effects of a multi-site randomized-controlled trial (RCT) of video feedback of infant-parent interaction (VIPI) intervention in naturalistic settings are published. The intervention targets families with children younger than 2 years old and parent child interactions problems. Outcome variables were 1) observed parent-child interactions and 2) parent-reported child social and emotional development. Between-group differences of the moderating effects of parental symptoms of depression, personality disorders traits, and demographic variables were investigated. METHOD: The study had a parallel-group, consecutively randomized, single-blinded design; participants were recruited by health- and social workers. Seventy-five families received VIPI, and 57 families received treatment as usual (TAU). Videotapes of each parent-child interactions were obtained before treatment, right after treatment, and at a 6-month follow-up and coded according to Biringen's Emotional Availability Scales. Parental symptoms of depression and personality disorder traits were included as possible moderators. RESULTS: Evidence of a short-term effect of VIPI treatment on parent-child interactions was established, especially among depressed parents and parents with problematic interactions-and, to some extent, among parents with dependent and paranoid personality disorder traits. A long-term positive effect of VIPI compared with TAU on child social/emotional development was also evident. In a secondary analysis, VIPI had a direct positive effect on the depressive symptoms of parents compared with TAU. CONCLUSION: The findings of the study support the use of VIPI as an intervention in families with interaction difficulties. TRIAL REGISTRATION: Current Controlled Trials ISRCTN99793905. PMID- 25699089 TI - Disruption of Bcl-2 and Bcl-xL by viral proteins as a possible cause of cancer. AB - The Bcl proteins play a critical role in apoptosis, as mutations in family members interfere with normal programmed cell death. Such events can cause cell transformation, potentially leading to cancer. Recent discoveries indicate that some viral proteins interfere with Bcl proteins either directly or indirectly; however, these data have not been systematically described. Some viruses encode proteins that reprogramme host cellular signalling pathways controlling cell differentiation, proliferation, genomic integrity, cell death, and immune system recognition. This review analyses and summarises the existing data and discusses how viral proteins interfere with normal pro- and anti-apoptotic functions of Bcl 2 and Bcl-xL. Particularly, this article focuses on how viral proteins, such as Herpesviruses, HTLV-1, HPV and HCV, block apoptosis and how accumulation of such interference predisposes cancer development. Finally, we discuss possible ways to prevent and treat cancers using a combination of traditional therapies and antiviral preparations that are effective against these viruses. PMID- 25699091 TI - Linked vaccine adverse event data from VAERS for biomedical data analysis and longitudinal studies. AB - BACKGROUND: Vaccines have been one of the most successful public health interventions to date. The use of vaccination, however, sometimes comes with possible adverse events. The U.S. FDA/CDC Vaccine Adverse Event Reporting System (VAERS) currently contains more than 200,000 reports for post-vaccination events that occur after the administration of vaccines licensed in the United States. Although the data from the VAERS has been applied to many public health and vaccine safety studies, each individual report does not necessarily indicate a casuality relationship between the vaccine and the reported symptoms. Further statistical analysis and summarization needs to be done before this data can be leveraged. METHODS: This paper introduces our efforts on representing the vaccine symptom correlations and their corresponding meta-information extracted from the VAERS database using Resource Description Framework (RDF). Numbers of occurrences of vaccine-symptom pairs reported to the VAERS were summarized with corresponding proportional reporting ratios (PRR) calculated. All the data was stored in an RDF file. We then applied network analysis approaches to the RDF data to illustrate a use case of the data for longititual studies. We further dicussed our vision on integrating the data with vaccine information from other sources using RDF linked approach to facilitate more comprehensive analyses. RESULTS: The 1990-2013 data from VAERS has been extracted from the VAERS database. There are 83,148 unique vaccine-symptom pairs with 75 vaccine types and 5,865 different reported symptoms. The yearly and over PRR values for each reported vaccine-symptom pair were calculated. The network properties of networks consisting of significant vaccine-symptom associations (i.e., PRR larger than 1) were then investigated. The results indicated that vaccine-symptom association network is a dense network, with any given node connected to all other nodes through an average of approximately two other nodes and a maximum of five nodes. PMID- 25699092 TI - High-resolution genome-wide DNA methylation maps of mouse primary female dermal fibroblasts and keratinocytes. AB - BACKGROUND: Genome-wide DNA methylation at a single nucleotide resolution in different primary cells of the mammalian genome helps to determine the characteristics and functions of tissue-specific hypomethylated regions (TS HMRs). We determined genome-wide cytosine methylation maps at 91X and 36X coverage of newborn female mouse primary dermal fibroblasts and keratinocytes and compared with mRNA-seq gene expression data. RESULTS: These high coverage methylation maps were used to identify HMRs in both cell types. A total of 2.91% of the genome are in keratinocyte HMRs, and 2.15% of the genome are in fibroblast HMRs with 1.75% being common. Half of the TS-HMRs are extensions of common HMRs, and the remaining are unique TS-HMRs. Four levels of CG methylation are observed: 1) total unmethylation for CG dinucleotides in HMRs in CGIs that are active in all tissues; 2) 10% to 40% methylation for TS-HMRs; 3) 60% methylation for TS HMRs in cells types where they are not in HMRs; and 4) 70% methylation for the nonfunctioning part of the genome. SINE elements are depleted inside the TS-HMRs, while highly enriched in the surrounding regions. Hypomethylation at the last exon shows gene repression, while demethylation toward the gene body positively correlates with gene expression. The overlapping HMRs have a more complex relationship with gene expression. The common HMRs and TS-HMRs are each enriched for distinct Transcription Factor Binding Sites (TFBS). C/EBPbeta binds to methylated regions outside of HMRs while CTCF prefers to bind in HMRs, highlighting these two parts of the genome and their potential interactions. CONCLUSIONS: Keratinocytes and fibroblasts are of epithelial and mesenchymal origin. High-resolution methylation maps in these two cell types can be used as reference methylomes for analyzing epigenetic mechanisms in several diseases including cancer. Please see related article at the following link: http://www.epigeneticsandchromatin.com/content/7/1/34. PMID- 25699093 TI - VERSE: a novel approach to detect virus integration in host genomes through reference genome customization. AB - Fueled by widespread applications of high-throughput next generation sequencing (NGS) technologies and urgent need to counter threats of pathogenic viruses, large-scale studies were conducted recently to investigate virus integration in host genomes (for example, human tumor genomes) that may cause carcinogenesis or other diseases. A limiting factor in these studies, however, is rapid virus evolution and resulting polymorphisms, which prevent reads from aligning readily to commonly used virus reference genomes, and, accordingly, make virus integration sites difficult to detect. Another confounding factor is host genomic instability as a result of virus insertions. To tackle these challenges and improve our capability to identify cryptic virus-host fusions, we present a new approach that detects Virus intEgration sites through iterative Reference SEquence customization (VERSE). To the best of our knowledge, VERSE is the first approach to improve detection through customizing reference genomes. Using 19 human tumors and cancer cell lines as test data, we demonstrated that VERSE substantially enhanced the sensitivity of virus integration site detection. VERSE is implemented in the open source package VirusFinder 2 that is available at http://bioinfo.mc.vanderbilt.edu/VirusFinder/. PMID- 25699094 TI - Aptamers: active targeting ligands for cancer diagnosis and therapy. AB - Aptamers, including DNA, RNA and peptide aptamers, are a group of promising recognition units that can specifically bind to target molecules and cells. Due to their excellent specificity and high affinity to targets, aptamers have attracted great attention in various fields in which selective recognition units are required. They have been used in biosensing, drug delivery, disease diagnosis and therapy (especially for cancer treatment). In this review, we summarized recent applications of DNA and RNA aptamers in cancer theranostics. The specific binding ability of aptamers to cancer-related markers and cancer cells ensured their high performance for early diagnosis of cancer. Meanwhile, the efficient targeting ability of aptamers to cancer cells and tissues provided a promising way to deliver imaging agents and drugs for cancer imaging and therapy. Furthermore, with the development of nanoscience and nanotechnology, the conjugation of aptamers with functional nanomaterials paved an exciting way for the fabrication of theranostic agents for different types of cancers, which might be a powerful tool for cancer treatment. PMID- 25699095 TI - Combined cancer photothermal-chemotherapy based on doxorubicin/gold nanorod loaded polymersomes. AB - Gold nanorods (GNRs) are well known in photothermal therapy based on near infrared (NIR) laser absorption of the longitudinal plasmon band. Herein, we developed an effective stimulus system -- GNRs and doxorubicin co-loaded polymersomes (P-GNRs-DOX) -- to facilitate co-therapy of photothermal and chemotherapy. DOX can be triggered to release once the polymersomes are corrupted under local hyperthermic condition of GNRs induced by NIR laser irradiation. Also, the cytotoxicity of GNRs caused by the residual cetyltrimethylacmmonium bromide (CTAB) was reduced by shielding the polymersomes. The GNRs-loaded polymersomes (P-GNRs) can be efficiently taken up by the tumor cells. The distribution of the nanomaterial was imaged by IR-820 and quantitatively analyzed by ICP-AES. We studied the ablation of tumor cells in vitro and in vivo, and found that co-therapy offers significantly improved therapeutic efficacy (tumors were eliminated without regrowth.) compared with chemotherapy or photothermal therapy alone. By TUNEL immunofluorescent staining of tumors after NIR laser irradiation, we found that the co-therapy showed more apoptotic tumor cells than the other groups. Furthermore, the toxicity study by pathologic examination of the heart tissues demonstrated a lower systematic toxicity of P-GNRs-DOX than free DOX. Thus, the chemo-photothermal treatment based on polymersomes loaded with DOX and GNRs is a useful strategy for maximizing the therapeutic efficacy and minimizing the dosage-related side effects in the treatment of solid tumors. PMID- 25699096 TI - Off to the organelles - killing cancer cells with targeted gold nanoparticles. AB - Gold nanoparticles (AuNPs) are excellent tools for cancer cell imaging and basic research. However, they have yet to reach their full potential in the clinic. At present, we are only beginning to understand the molecular mechanisms that underlie the biological effects of AuNPs, including the structural and functional changes of cancer cells. This knowledge is critical for two aspects of nanomedicine. First, it will define the AuNP-induced events at the subcellular and molecular level, thereby possibly identifying new targets for cancer treatment. Second, it could provide new strategies to improve AuNP-dependent cancer diagnosis and treatment. Our review summarizes the impact of AuNPs on selected subcellular organelles that are relevant to cancer therapy. We focus on the nucleus, its subcompartments, and mitochondria, because they are intimately linked to cancer cell survival, growth, proliferation and death. While non targeted AuNPs can damage tumor cells, concentrating AuNPs in particular subcellular locations will likely improve tumor cell killing. Thus, it will increase cancer cell damage by photothermal ablation, mechanical injury or localized drug delivery. This concept is promising, but AuNPs have to overcome multiple hurdles to perform these tasks. AuNP size, morphology and surface modification are critical parameters for their delivery to organelles. Recent strategies explored all of these variables, and surface functionalization has become crucial to concentrate AuNPs in subcellular compartments. Here, we highlight the use of AuNPs to damage cancer cells and their organelles. We discuss current limitations of AuNP-based cancer research and conclude with future directions for AuNP-dependent cancer treatment. PMID- 25699097 TI - Kinetic analysis of dynamic (11)C-acetate PET/CT imaging as a potential method for differentiation of hepatocellular carcinoma and benign liver lesions. AB - OBJECTIVE: The kinetic analysis of (11)C-acetate PET provides more information than routine one time-point static imaging. This study aims to investigate the potential of dynamic (11)C-acetate hepatic PET imaging to improve the diagnosis of hepatocellular carcinoma (HCC) and benign liver lesions by using compartmental kinetic modeling and discriminant analysis. METHODS: Twenty-two patients were enrolled in this study, 6 cases were with well-differentiated HCCs, 7 with poorly differentiated HCCs and 9 with benign pathologies. Following the CT scan, all patients underwent (11)C-acetate dynamic PET imaging. A three-compartment irreversible dual-input model was applied to the lesion time activity curves (TACs) to estimate the kinetic rate constants K1-k3, vascular fraction (VB) and the coefficient alpha representing the relative hepatic artery (HA) contribution to the hepatic blood supply on lesions and non-lesion liver tissue. The parameter Ki (=K1*k3/(k2 + k3)) was calculated to evaluate the local hepatic metabolic rate of acetate (LHMAct). The lesions were further classified by discriminant analysis with all the above parameters. RESULTS: K1 and lesion to non-lesion standardized uptake value (SUV) ratio (T/L) were found to be the parameters best characterizing the differences among well-differentiated HCC, poorly differentiated HCC and benign lesions in stepwise discriminant analysis. With discriminant functions consisting of these two parameters, the accuracy of lesion prediction was 87.5% for well-differentiated HCC, 50% for poorly-differentiated HCC and 66.7% for benign lesions. The classification was much better than that with SUV and T/L, where the corresponding classification accuracy of the three kinds of lesions was 57.1%, 33.3% and 44.4%. CONCLUSION: (11)C-acetate kinetic parameter K1 could improve the identification of HCC from benign lesions in combination with T/L in discriminant analysis. The discriminant analysis using static and kinetic parameters appears to be a very helpful method for clinical liver masses diagnosis and staging. PMID- 25699098 TI - Small sized EGFR1 and HER2 specific bifunctional antibody for targeted cancer therapy. AB - Targeting tumors using miniature antibodies is a novel and attractive therapeutic approach, as these biomolecules exhibit low immunogenicity, rapid clearance, and high targeting specificity. However, most of the small-sized antibodies in existence do not exhibit marked anti-tumor effects, which limit their use in targeted cancer immunotherapy. To overcome this difficulty in targeting multiple biomarkers by combination therapies, we designed a new bifunctional antibody, named MaAbNA (multivalent antibody comprised of nanobody and affibody moieties), capable of targeting EGFR1 and HER2, which are widely overexpressed in a variety of tumor types. The small-sized (29 kDa) MaAbNA, which was expressed in E.coli, consists of one anti-EGFR1 nanobody and two anti-HER2 affibodies, and possesses high affinity (KD) for EGFR1 (~4.1 nM) and HER2 (~4.7 nM). In order to enhance its anti-tumor activity, MaAbNA was conjugated with adriamycin (ADM) using a PEG2000 linker, forming a new complex anticancer drug, MaAbNA-PEG2000-ADM. MaAbNA exhibited high inhibitory effects on tumor cells over-expressing both EGFR1 and HER2, but displayed minimal cytotoxicity in cells expressing low levels of EGFR1 and HER2. Moreover, MaAbNA-PEG2000-ADM displayed increased tumoricidal effects than ADM or MaAbNA alone, as well exhibited greater antitumor efficacy than EGFR1 (Cetuximab) and HER2 (Herceptin) antibody drugs. The ability of MaAbNA to regulate expression of downstream oncogenes c-jun, c-fos, c-myc, as well as AEG-1 for therapeutic potential was evaluated by qPCR and western-blot analyses. The antitumor efficacy of MaAbNA and its derivative MaAbNA-PEG2000-ADM were validated in vivo, highlighting the potential for use of MaAbNA as a highly tumor-specific dual molecular imaging probe and targeted cancer therapeutic. PMID- 25699099 TI - Targeted antiangiogenesis gene therapy using targeted cationic microbubbles conjugated with CD105 antibody compared with untargeted cationic and neutral microbubbles. AB - OBJECTIVE: This study aimed to develop targeted cationic microbubbles conjugated with a CD105 antibody (CMB105) for use in targeted vascular endothelial cell gene therapy and ultrasound imaging. We compared the results with untargeted cationic microbubbles (CMB) and neutral microbubbles (NMB). METHODS: CMB105 were prepared and compared with untargeted CMB and NMB. First, the microbubbles were characterized in terms of size, zeta-potential, antibody binding ability and plasmid DNA loading capacity. A tumor model of subcutaneous breast cancer in nude mice was used for our experiments. The ability of different types of microbubbles to target HUVECs in vitro and tumor neovascularization in vivo was measured. The endostatin gene was selected for its outstanding antiangiogenesis effect. For in vitro experiments, the transfection efficiency and cell cycle were analyzed using flow cytometry, and the transcription and expression of endostatin were measured by qPCR and Western blotting, respectively. Vascular tube cavity formation and tumor cell invasion were used to evaluate the antiangiogenesis gene therapy efficiency in vitro. Tumors were exposed to ultrasound irradiation with different types of microbubbles, and the gene therapy effects were investigated by detecting apoptosis induction and changes in tumor volume. RESULTS: CMB105 and CMB differed significantly from NMB in terms of zeta-potential, and the DNA loading capacities were 16.76+/-1.75 MUg, 18.21+/-1.22 MUg, and 0.48+/-0.04 MUg per 5*10(8) microbubbles, respectively. The charge coupling of plasmid DNA to CMB105 was not affected by the presence of the CD105 antibody. Both CMB105 and CMB could target to HUVECs in vitro, whereas only CMB105 could target to tumor neovascularization in vivo. In in vitro experiments, the transfection efficiency of CMB105 was 24.7-fold higher than the transfection efficiency of NMB and 1.47 fold higher than the transfection efficiency of CMB (P<0.05). With ultrasound targeted microbubble destruction (UTMD)-mediated gene therapy, the transcription and expression of endostatin were the highest in the CMB105 group (P<0.001); the antiangiogenesis effect and inhibition of tumor cells invasion was better with CMB105 than CMB or NMB in vitro (P<0.01). After gene therapy, the tumor volumes of CMB105 group were significantly smaller than that of CMB and NMB, and many tumor cells had begun apoptosis in the CMB105 group, which had the highest apoptosis index (P<0.001). CONCLUSIONS: As a contrast agent and plasmid carrier, CMB105 can be used not only for targeted ultrasound imaging but also for targeted gene therapy both in vitro and in vivo. The plasmid DNA binding ability of the CMB was not affected by conjugation of the CMB with the CD105 antibody, and because of its targeting ability, the gene transfection efficiency and therapeutic effect were better compared with the untargeted CMB and NMB. The advantages of targeted gene therapy with CMB105 in vivo were more prominent than with CMB or NMB because neither can target the endothelia in vivo. PMID- 25699100 TI - Detection of high-risk atherosclerotic plaques with ultrasound molecular imaging of glycoprotein IIb/IIIa receptor on activated platelets. AB - OBJECTIVE: Ultrasound molecular imaging (UMI) of glycoprotein (GP) IIb/IIIa receptor on activated platelets offers a unique means of identifying high-risk atherosclerosis. We hypothesized that contrast-enhanced ultrasound with microbubbles (MBs) targeted to GP IIb/IIIa could be used to detect and quantify activated platelets on the surface of advanced plaques. METHODS AND RESULTS: A mouse model of advanced atherosclerosis was generated by maintaining apolipoprotein E-deficient (ApoE(-/-)) mice on a hypercholesterolemic diet (HCD). The three other experimental groups consisted of ApoE(-/-) and wild-type (C57BL/6) mice fed a normal chow diet and C57BL/6 mice on an HCD diet. Plaque formation was confirmed by histological and immunohistochemical methods using light, fluorescence, and electron microscopy. Mice were injected with a lipid MB conjugated cyclic Arg-Gly-Asp peptide or nonspecific control peptide, and the abdominal aorta was examined by UMI. The accumulation of GP IIb/IIIa and activated platelets on the surface of atherosclerotic plaques was highest in the ApoE(-/-)+HCD group, followed by ApoE(-/-)+chow, C57BL/6+HCD, and C57BL/6+chow groups (P<0.05). Notably, GP IIb/IIIa expression was associated with the vulnerability index and necrotic center/fiber cap ratio (P<0.05), and contrast video intensity from adhered cyclic Arg-Gly-Asp-modified MBs (MB-cRGDs) was correlated with GP IIb/IIIa expression on the plaque surface (P<0.05). CONCLUSION: GP IIb/IIIa of activated platelets on the atherosclerotic endothelium is a biomarker for high-risk plaques that can be quantified by UMI using MB cRGDs, providing a noninvasive means for detecting high-risk plaques and preventing acute cardiovascular events. PMID- 25699101 TI - Cancer cell-specific oligopeptides selected by an integrated microfluidic system from a phage display library for ovarian cancer diagnosis. AB - Ovarian cancer is one of the leading causes of female mortality worldwide. Unfortunately, there are currently few high-specificity candidate oligopeptide targeting agents that can be used for early diagnosis of this cancer. It has been suggested that cancer-specific oligopeptides could be screened from a phage display library. However, conventional methods are tedious, labor-intensive, and time consuming. Therefore, a novel, integrated microfluidic system was developed to automate the entire screening process for ovarian cancer cell-specific oligopeptides. An oligopeptide screened with microfluidic chip-based technique was demonstrated to have high affinity to ovarian cancer cells and demonstrated relatively low binding to other cancer cells, indicating a high specificity. Furthermore, the developed method consumed relatively low volumes of samples and reagents; only 70 MUL of reactant was used within the whole experimental process. Each panning process was also significantly shortened to only 7.5 hours. Therefore, the screened oligopeptide could be used to isolate ovarian cancer cells in a rapid manner, thus greatly expediting the diagnosis and its application as oligopeptide targeting agent for theranostics of this cancer. PMID- 25699102 TI - "Peer-assisted learning" (PAL) in the Skills-Lab--an inventory at the medical faculties of the Federal Republic of Germany. AB - BACKGROUND: Over multiple years, the didactic concept of "peer-assisted learning" (PAL) has proved to be valuable for medical education. Particularly in the field of the nowadays widely established Skills-Labs, the assignment of student tutors is both popular and effective. The aim of the underlying study is to assess the current status of PAL programs within German medical faculties' Skills-Labs regarding their distribution, extent, structure and content based on a nation wide survey. METHODS: All 36 medical faculties in Germany were contacted and asked for their participation (via telephone or in written form) in the survey encompassing 16 central questions as to the structure of established PAL programs. Data obtained were subject to quantitative and qualitative analysis. RESULTS: 35 of 36 (97.2%) medical faculties participated in the survey. A PAL program was shown to be established at 33 (91.7%) faculties. However, the results show distinct differences between different faculties with respect to extent and content of the PAL programs. CONCLUSIONS: Among German medical Skills-Labs, PAL has been established almost ubiquitously. Further studies on the conception and standardization of training concepts appear to be pivotal for the advancement of PAL in the context of Skills-Labs. PMID- 25699103 TI - Do medical students like communication? Validation of the German CSAS (Communication Skills Attitude Scale). AB - OBJECTIVES: Attitudes towards communication skills of medical undergraduates can be gathered using the Communication Skills Attitude Scale (CSAS). We aimed to develop a German version of the CSAS (CSAS-G) in order to explore attitudes towards communication skills in a German cohort. Additionally the potential influence of demographic factors was examined. METHODS: We realized the CSAS-G and conducted a survey with 529 participants from 3 different years of study. We then carried out an explorative as well as confirmatory factor analysis and compared the attitudinal scores. Multiple regression analysis was performed. RESULTS: The confirmatory analysis confirmed the two-subscale system revealed by the explorative factor analysis. Students indicate low levels of negative attitudes and moderate levels of positive attitudes. Attitudinal scores differ significantly in relation to gender. CONCLUSION: The CSAS-G can be used in German cohorts to evaluate attitudes towards communication skills. Medical students in our study show basically a positive approach. Further investigation is necessary to explore and understand attitudes towards communication skills of German medical students. PMID- 25699104 TI - German Medical Science--Journal for Medical Education: respectable and very much in motion. PMID- 25699105 TI - Improving teaching on the basis of student evaluation: integrative teaching consultation. AB - OBJECTIVE: Due to the development of medical education in the past decade the role of teachers has changed and requires higher didactic competence. Student evaluation of teaching alone does not lead to considerable improvement of teaching quality. We present the concept of "Integrative Teaching Consultation", which comprises both the teacher's reflection and own objectives to improve their teaching as well as data from students ratings. METHODS: Teachers in collaboration with a teaching consultant reflect on their teaching ability and set themselves improvement goals. Then the consultant himself observes a teaching session and subsequently analyses the respective student evaluation in order to give meaningful feedback to the teacher. RESULTS: The combination of student feedback with professional consultation elements can initiate and maintain improvements in teaching. CONCLUSION: Teaching consultation complements existing faculty development programs and increases the benefit of student evaluations. PMID- 25699106 TI - Symposium 'Methodology in Medical Education Research' organised by the Methodology in Medical Education Research Committee of the German Society of Medical Education May, 25th to 26th 2013 at Charite, Berlin. AB - In 2013, the Methodology in Medical Education Research Committee ran a symposium on "Research in Medical Education" as part of its ongoing faculty development activities. The symposium aimed to introduce to participants educational research methods with a specific focus on research in medical education. Thirty-five participants were able to choose from workshops covering qualitative methods, quantitative methods and scientific writing throughout the one and a half days. The symposium's evaluation showed participant satisfaction with the format as well as suggestions for future improvement. Consequently, the committee will offer the symposium again in a modified form in proximity to the next annual Congress of the German Society of Medical Education. PMID- 25699107 TI - Theory in practice instead of theory versus practice--curricular design for task based learning within a competency oriented curriculum. AB - OBJECTIVE: Already during their studies, medical students should intensively train their clinical thinking and practice skills, enhancing their clinical expertise in theoretical and practical terms. METHODS: Based on the findings of educational research, a new curriculum for clinical training was developed at Duesseldorf University, focussing on workplace-based teaching, learning and assessment. RESULTS: For students in their 3rd, 4th and 5th year of study, our curriculum is based on learning with patient complaint items in regard to multidisciplinary areas of outpatient and inpatient care. For this educational format, 123 complaint items were defined and their compatibility with diseases from various disciplines was tested. Based on the complaint of a specific case, students locate the underlying disease pattern, the differential diagnostic and therapeutical procedures and thereby deepen the required knowledge in the basic subjects. Study books have been created by the clinical departments to support this process. Learning is integrated in competence-oriented and workplace-based learning and assessment, offering a close-knit contact between students and doctors. CONCLUSION: The concept allows the integration of theory into practice and the integration of knowledge from the basic, clinical-theoretical and clinical subjects into clinical thinking and action. PMID- 25699108 TI - 5 years of experience with a large-scale mentoring program for medical students. AB - In this paper we present our 5-year-experience with a large-scale mentoring program for undergraduate medical students at the Ludwig Maximilians-Universitat Munich (LMU). We implemented a two-tiered program with a peer-mentoring concept for preclinical students and a 1:1-mentoring concept for clinical students aided by a fully automated online-based matching algorithm. Approximately 20-30% of each student cohort participates in our voluntary mentoring program. Defining ideal program evaluation strategies, recruiting mentors from beyond the academic environment and accounting for the mentoring network reality remain challenging. We conclude that a two-tiered program is well accepted by students and faculty. In addition the online-based matching seems to be effective for large-scale mentoring programs. PMID- 25699109 TI - Implementation of palliative care as a mandatory cross-disciplinary subject (QB13) at the Medical Faculty of the Heinrich-Heine-University Dusseldorf, Germany. AB - BACKGROUND: By means of the revision of the Medical Licensure Act for Physicians (AAppO) in 2009, undergraduate palliative care education (UPCE) was incorporated as a mandatory cross sectional examination subject (QB13) in medical education in Germany. Its implementation still constitutes a major challenge for German medical faculties. There is a discrepancy between limited university resources and limited patient availabilities and high numbers of medical students. Apart from teaching theoretical knowledge and skills, palliative care education is faced with the particular challenge of imparting a professional and adequate attitude towards incurably ill and dying patients and their relatives. PROJECT DESCRIPTION: Against this background, an evidence-based longitudinal UPCE curriculum was systematically developed following Kern's Cycle [1] and partly implemented and evaluated by the students participating in the pilot project. Innovative teaching methods (virtual standardised/simulated patient contacts, e learning courses, interdisciplinary and interprofessional collaborative teaching, and group sessions for reflective self-development) aim at teaching palliative care-related core competencies within the clinical context and on an interdisciplinary and interprofessional basis. RESULTS: After almost five years of development and evaluation, the UPCE curriculum comprises 60 teaching units and is being fully implemented and taught for the first time in the winter semester 2014/15. The previous pilot phases were successfully concluded. To date, the pilot phases (n=26), the subproject "E-learning in palliative care" (n=518) and the blended-learning elective course "Communication with dying patients" (n=12) have been successfully evaluated. CONCLUSION: All conducted development steps and all developed programmes are available for other palliative care educators (Open Access). The integrated teaching formats and methods (video, e learning module, interprofessional education, group sessions for reflexive self development) and their evaluations are intended to make a contribution to an evidence-based development of palliative care curricula in Germany. PMID- 25699110 TI - Self-directed e-learning at a tertiary hospital in Malawi--a qualitative evaluation and lessons learnt. AB - BACKGROUND: Malawi faces a severe lack of health workers. Despite initiatives to address this problem, a critical shortage of health care staff remains. This lack challenges the education and training of junior medical staff, especially medical interns in their final and crucial training year before they independently work as medical doctors. PROJECT DESCRIPTION: We have introduced an e-learning platform in the medical department of the Kamuzu Central Hospital (KCH) in Malawi. With the support of computer-assisted instruction, we aimed to improve the quality of medical training and education, as well as access to current medical materials, in particular for interns. METHOD: From March to April 2012, we conducted a qualitative evaluation to assess relevance and appropriateness of the e-learning platform. Data was collected via face-to-face interviews, a guided group discussion and a checklist based observation log. Evaluation data was recorded and coded using content analysis, interviewees were chosen via purposive sampling. RESULTS: E-learning proved to be technically feasible in this setting. Users considered the e-learning platform to be relevant and appropriate. Concerns were raised about sustainability, accessibility and technical infrastructure, as well as limited involvement and responsibilities of Malawian partners. Interest in e-learning was high, yet, awareness of and knowledge about the e-learning platform among potential users was low. Evaluation results indicated that further adaptions to local needs are necessary to increase usage and accessibility. CONCLUSIONS: Interview results and our project experiences showed that, in the given setting, e-learning requires commitment from local stakeholders, adequate technical infrastructure, identification and assignation of responsibilities, as well as specific adaption to local needs. PMID- 25699111 TI - Theory and practice in medical education--expectations and development of skills experienced by students of human medicine compared with students in other disciplines. AB - AIM: The aim of this article is to compare students of human medicine (HM) with students specialising in the MINT disciplines (mathematics, computer science, natural sciences and engineering), the humanities and social sciences as well as law and economic sciences with regard to their expectations of their university study and career and the areas of competence where they feel they have been supported by their education. We present in detail issues particularly relevant to prospective physicians, which are discussed with the main focus on the "theoretical and practical orientation of medical education". METHODS: We used the database in the Public Use File of the "11th Student Survey", a written survey of randomly selected students studying at 25 German tertiary institutions during the 2009/2010 winter term, which was supplied by the Tertiary Education Research working group at the University of Constance. Data on 7536 students was included, of which 488 (6.5%) were prospective physicians. RESULTS: Human medicine students have a clear career aim and want to complete their education quickly. They have a far above-average interest in working with and for people. About one student in two is interested in a career in science or research (53% in each case - close to the average for all subjects). Compared with the other disciplines, HM students are most likely to consider their university education to have practical and research relevance and are most likely to feel prepared for their profession. Yet over half of all students (O 53.3%; HM 54.5%) do not consider their education to have fostered their research skills. MINT students in particular are better able to enhance their skills through independent experimentation, while theory and practice are more likely to be communicated academically in the regular teaching of human medicine. Accordingly, the HM students feel less well supported in some areas of competence required for their later work than students in other disciplines, in developing independence, problem-solving ability, critical ability and capacity for teamwork for example. CONCLUSION: The high expectations held by human medicine students of being prepared for practical work with/on people are met to an above-average degree according to their assessments of the "practical relevance" and "career preparation" offered by their medical education. However the perceived development of skills in theory and practice does not respond sufficiently well to the demands of the complex, responsible profession they aspire to. Medical students should be better supported in developing both practical and academic independence. PMID- 25699112 TI - International medical students--a survey of perceived challenges and established support services at medical faculties. AB - INTRODUCTION: Medical students with a non-German background face several challenges during their studies. Besides support given by foreign student offices further specific projects for international students have been developed and are offered by medical faculties. However, so far, neither a systematic survey of the faculties' perceived problems nor of the offered support exists. METHOD: All study deaneries of medical faculties in Germany were contacted between April and October 2013 and asked for their participation in a telephone interview. Interview partners were asked about 1.) The percentage of non-German students at the medical faculty; 2.) The perceived difficulties and problems of foreign students; 3.) The offers for non-German students; and 4.) The specification of further possibilities of support. Given information was noted, frequencies counted and results interpreted via frequency analysis. RESULTS: Only 39% of the medical faculties could give detailed information about the percentage of non German students. They reported an average share of 3.9% of students with an EU migration background and 4.9% with a non-EU background. Most frequently cited offers are student conducted tutorials, language courses and tandem-programs. The most frequently reported problem by far is the perceived lack of language skills of foreign students at the beginning of their studies. Suggested solutions are mainly the development of tutorials and the improvement of German medical terminology. DISCUSSION: Offers of support provided by medical faculties for foreign students vary greatly in type and extent. Support offered is seen to be insufficient in coping with the needs of the international students in many cases. Hence, a better coverage of international students as well as further research efforts to the specific needs and the effectiveness of applied interventions seem to be essential. PMID- 25699113 TI - Quantitative survey of multiple CpGs from 5 genes identifies CpG methylation panel discriminating between high- and low-grade cervical intraepithelial neoplasia. AB - BACKGROUND: Studies of methylation biomarkers for cervical cancer often involved only few randomly selected CpGs per candidate gene analyzed by methylation specific PCR-based methods, with often inconsistent results from different laboratories. We evaluated the role of different CpGs from multiple genes as methylation biomarkers for high-grade cervical intraepithelial neoplasia (CIN). RESULTS: We applied a mass spectrometry-based platform to survey the quantitative methylation levels of 34 CpG units from SOX1, PAX1, NKX6-1, LMX1A, and ONECUT1 genes in 100 cervical formalin-fixed paraffin-embedded (FFPE) tissues. We then used nonparametric statistics and Random Forest algorithm to rank significant CpG methylations and support vector machine with 10-fold cross validation and 200 times bootstrap resampling to build a predictive model separating CIN II/III from CIN I/normal subjects. We found only select CpG units showed significant differences in methylation between CIN II/III and CIN I/normal groups, while mean methylation levels per gene were similar between the two groups for each gene except PAX1. An optimal classification model involving five CpG units from SOX1, PAX1, NKX6-1, and LMX1A achieved 81.2% specificity, 80.4% sensitivity, and 80.8% accuracy. CONCLUSIONS: Our study suggested that during CIN development, the methylation of CpGs within CpG islands is not uniform, with varying degrees of significance as biomarkers. Our study emphasizes the importance of not only methylated marker genes but also specific CpGs for identifying high-grade CINs. The 5-CpG classification model provides a promising biomarker panel for the early detection of cervical cancer. PMID- 25699114 TI - CpG signalling, H2A.Z/H3 acetylation and microRNA-mediated deferred self attenuation orchestrate foetal NOS3 expression. AB - BACKGROUND: An adverse intrauterine environment leads to permanent physiological changes including vascular tone regulation, potentially influencing the risk for adult vascular diseases. We therefore aimed to monitor responsive NOS3 expression in human umbilical artery endothelial cells (HUAEC) and to study the underlying epigenetic signatures involved in its regulation. RESULTS: NOS3 and STAT3 mRNA levels were elevated in HUAEC of patients who suffered from placental insufficiency. 5-hydroxymethylcytosine, H3K9ac and Histone 2A (H2A).Zac at the NOS3 transcription start site directly correlated with NOS3 mRNA levels. Concomitantly, we observed entangled histone acetylation patterns and NOS3 response upon hypoxic conditions in vitro. Knock-down of either NOS3 or STAT3 by RNAi provided evidence for a functional NOS3/STAT3 relationship. Moreover, we recognized massive turnover of Stat3 at a discrete binding site in the NOS3 promoter. Interestingly, induced hyperacetylation resulted in short-termed increase of NOS3 mRNA followed by deferred decrease indicating that NOS3 expression could become self-attenuated by co-expressed intronic 27 nt-ncRNA. Reporter assay results and phylogenetic analyses enabled us to propose a novel model for STAT3-3'-UTR targeting by this 27-nt-ncRNA. CONCLUSIONS: An adverse intrauterine environment leads to adaptive changes of NOS3 expression. Apparently, a rapid NOS3 self-limiting response upon ectopic triggers co-exists with longer termed expression changes in response to placental insufficiency involving differential epigenetic signatures. Their persistence might contribute to impaired vascular endothelial response and consequently increase the risk of cardiovascular disease later in life. PMID- 25699115 TI - Gastrointestinal complications of laparoscopic/robot-assisted urologic surgery and a review of the literature. AB - Gastrointestinal injuries that occur during or after laparoscopic and robot assisted surgery are serious side effects that affect patient outcome. In this review, we attempt to highlight the identification, incidence and management of gastrointestinal and visceral complications of laparoscopic and robot-assisted surgery. A search of Medline and PubMed databases was performed using the following terms: gastrointestinal complications of laparoscopy, laparoscopic, kidney and robotic surgery. A total of 1,072 papers related to the subject were analyzed. Forty-six of these papers were included in the present review. These papers reported high numbers of participants and had a high level of evidence. Gastrointestinal complications during laparoscopic and robot-assisted surgery are rare, but similar, and can occur at any time between access and closure. Despite their infrequency, these complications can result in mortality. The early recognition and management of gastrointestinal complications is very important. Unrecognized or delayed identification of gastrointestinal complications may cause sepsis and death. PMID- 25699116 TI - Efficacy and safety of sitagliptin in Japanese patients with type 2 diabetes. AB - BACKGROUND: The aim of this study was to investigate the clinical efficacy and safety of sitagliptin in Japanese patients with type 2 diabetes. METHODS: A total of 3,247 subjects treated with sitagliptin were retrospectively recruited. Glucose parameters were collected at baseline, and 1, 3 and 6 months after initiation of sitagliptin. In addition, we explored factors that can be used to predict sitagliptin-induced reduction in HbA1c using linear mixed effect model. Factors associated with hypoglycemic events were examined by logistic analyses. RESULTS: We analyzed the available data of 3,201 subjects (1,287 females). Treatment of sitagliptin significantly reduced HbA1c level from 7.44+/-1.20% at baseline to 6.73+/-0.99% at 6 months (P < 0.0001). Linear mixed effect model analyses demonstrated that reduction of HbA1c was associated with higher baseline HbA1c level, younger age, lower BMI and sitagliptin monotherapy. During this study, 82 cases of hypoglycemia were recorded. Logistic analyses indicated that hypoglycemic events were more frequent in female patients, and patients with low BMI, long history of type 2 diabetes, high HbA1c and on combination therapy experienced. Other adverse events were rare and mild. CONCLUSIONS: Sitagliptin is effective for diabetic management and generally well tolerated in Japanese patients with type 2 diabetes. This trial was registered with UMIN (no. 000004121). PMID- 25699117 TI - Quality evaluation of cone biopsy specimens obtained by large loop excision of the transformation zone. AB - BACKGROUND: Large loop excision of the transformation zone (LLETZ) has been used for the diagnosis and treatment of precancerous cervical lesions, and it is the first choice of treatment in the majority of cervical pathology services. The aim of this study was to evaluate the presence of thermal artifacts, the need for serial sections, the percentage of clear and involved resection margins and the relationship between endocervical gland involvement and the severity of the lesion in samples resected using LLETZ. METHODS: A retrospective study was performed at Santa Casa de Misericordia School of Science (HSCMV), Vitoria, Espirito Santo, Brazil with a sample of 52 histopathology slides from patients submitted to conization because of abnormal cytology findings and a biopsy result of cervical intraepithelial neoplasia (CIN) 2, CIN 3 and adenocarcinoma in situ. Statistical analysis was performed using Student's t-test. RESULTS: Serial sections were required to confirm diagnosis in four of 52 cases. Thermal artifacts were present in all cases, with grade I being the most common (94.2% of cases). Clear margins were found in 96.2% of cases. No association was found between glandular involvement and CIN 1 (P > 0.05); however, there was an association with CIN 2 and CIN 3 (P < 0.05). CONCLUSION: The amount of excised tissue was sufficient, thermal artifacts were slight, resection margins were clear in most of cases, and a possible association was found between glandular involvement and the severity of the lesion. PMID- 25699118 TI - Everyday memory in microsurgically treated patients after subarachnoid hemorrhage. AB - BACKGROUND: Memory declines measured by traditional tests in patients after subarachnoid hemorrhage (SAH) are well documented. Classic examinations of memory problems sometimes do not significantly correlate with memory functions in everyday life. The objective of the study was to assess the specific type of everyday memory loss in patients after microsurgical treatment of ruptured intracranial aneurysm causing SAH. METHODS: The prospective controlled, randomized study was conducted using the specific tests for everyday memory measure with high ecological validity. All patients were operated on by the same neurosurgeon (KD). Preoperatively, patients were in a good grade (Hunt-Hess I or II), with no neurological deficit and no hydrocephalus postoperatively. Patients were tested at two phases: 15 and 45 days after microsurgery with the Rivermead behavioral memory test (RBMT) and the cognitive failure questionnaire (CFQ). RESULTS: We compared the results of the tests administered in subjects that underwent microdiscectomy surgery for SAH to a control group that underwent surgery for lumbar disc herniation (DH). CONCLUSION: Neuropsychological assessment of operated patients who sustained SAH showed a decline, compared to the DH group, in everyday memory function. Also, we found failures in perception and motor function in operated SAH patients with a trend of cognitive recovery as time progresses. PMID- 25699119 TI - Comparative changes in tissue oxygenation between laparoscopic and open cholecystectomy. AB - BACKGROUND: Previous studies examined the effect of laparoscopic cholecystectomy (LC) versus open cholecystectomy (OC) on physiological variables of the respiratory system. In this study we compared changes in arterial blood gases related parameters between LC and OC to assess their comparative influence on gas exchange. METHODS: We studied 28 patients, operated under identical anesthetic protocol (LC: 18 patients, OC: 10 patients). Measurements were made on the morning before surgery (BS), the second (AS2) and the eighth (AS8) postoperative day. Studied parameters, including alveolar-arterial difference in PO2 ((A-a)DO2) and oxygen content (Oct in vol%), were statistically compared. RESULTS: On AS2 a greater increase was found in ((A-a)DO2) for the OC compared to LC (4.673 +/- 0.966 kPa versus 3.773 +/- 1.357 kPa, respectively). Between BS and AS2, Oct in vol% decreased from 17.55 +/- 1.90 to 15.69 +/- 1.88 in the LC and from 16.99 +/- 2.37 to 14.62 +/- 2.23 in the OC, whilst a reduction (P = 0.093) between AS2 and AS8 was also found for the open method. Besides, on AS2, SaO2% decrease was greater in OC compared to LC (P = 0.096). CONCLUSIONS: On AS2, the greater increase in OC-((A-a)DO2) associated with Oct in vol% and SaO2% findings also in OC group suggest that LC might be associated with lower risk for impaired tissue oxygenation. PMID- 25699120 TI - Protective effects of phosphocreatine administered post-treatment combined with ischemic post-conditioning on rat hearts with myocardial ischemia/reperfusion injury. AB - BACKGROUND: The aim of the study was to investigate the effects of phosphocreatine (PCr) post-treatment combined with ischemic post-conditioning on myocardial ischemia/reperfusion (I/R) injury in a rat model. METHODS: Forty Sprague-Dawley rats that had undergone 30 minutes ischemia and 120 minutes reperfusion were randomly divided into four groups (n = 10 in each group): the I/R group, the ischemia post-conditioning (IPost) group, the PCr group, and the IPost + PCr group. The activities of serum creatine kinase (CK), myeloperoxidase (MPO), and lactate dehydrogenase (LDH) were measured after 120 minutes of reperfusion. At the end of the experiment, serum levels of nuclear factor (NF) kappaB and tumor necrosis factor (TNF)-alpha were detected, myocardial infarct size (IS) was measured by triphenyltetrazolium chloride staining, and myocardial expression of Bcl-2 and phosphorylated Akt (p-Akt) was determined by western blot. RESULTS: The IPost, PCr, and PCr + IPost groups had significantly lower IS than the I/R group (P < 0.05). The reductions in CK, LDH, and MPO release were consistent with the decrease in the myocardial IS (P < 0.05). Serum concentrations of TNF-alpha and NF-kappaB in the IPost, PCr, and PCr + IPost groups were significantly lower than those in the I/R group (P < 0.05). The levels of p-Akt and Bcl-2 in the IPost, PCr, and PCr + IPost groups were greater than those in the I/R group (P < 0.05). CK, LDH, MPO, NF-kappaB, TNF-alpha, p Akt, Bcl-2 and IS were further enhanced in the IPost + PCr group (P < 0.05). CONCLUSIONS: Post-treatment with PCr enhanced the protective effect of IPost on rat myocardium affected by I/R injury, possibly by inhibiting the inflammatory response and activating the phosphatidylinositol 3-kinase (PI-3K)/Akt/Bcl-2 signaling pathway. PMID- 25699121 TI - Serum survivin increases in prolactinoma. AB - BACKGROUND: Prolactinoma is the most common adult pituitary adenoma. Survivin is a member of the family of inhibitors of apoptosis proteins. Its expression is observed in many tumors. Survivin expression has shown in prolactinoma tissue before but no study exists showing serum survivin level. The aim of the present study was to investigate serum survivin levels in patients with prolactinoma and demonstrate its value in diagnosis of the disease. METHODS: The group of patients consisted of 25 women, aged from 17 to 51 years. As a control group, 21 healthy women, aged from 22 to 45 years were included. Twenty patients had microprolactinoma, while five patients had macroprolactinoma. All patients had received dopamine agonist treatment. Serum survivin levels were measured in all of the groups. RESULTS: Survivin levels were significantly higher in prolactinoma patients compared to controls (19.04 (10 - 38) pg/mL; 15.05 (8 - 22) pg/mL; P = 0.042). There was no difference between microadenoma and macroadenoma patients in survivin levels (19.22 (10 - 38) pg/mL; 18.40 (16 - 22) pg/mL; P = 0.914). In correlation analysis, survivin was not correlated with other parameters. CONCLUSIONS: We consider that higher survivin levels might be a molecular marker predicting the presence of prolactinoma and may be useful for the diagnosis. But large-scale research is needed to clarify its role in diagnosis of prolactinoma patients. PMID- 25699122 TI - Lower incidence of hypo-magnesemia in surgical intensive care unit patients in 2011 versus 2001. AB - BACKGROUND: Hypo-magnesemia is described to occur in as many as 65% of intensive care unit (ICU) patients. Magnesium (Mg) is a cofactor in over 300 enzymatic reactions involving energy metabolism, protein, and nucleic acid synthesis. The membrane pump that creates the electrical gradient across the cell membrane is dependent on Mg, and it is important in the activity of electrically excitable tissues. Since Mg regulates the movement of calcium in smooth muscle cells, it is also important in peripheral vascular tone and blood pressure. Studies have linked hypo-magnesemia to multiple chronic diseases and to a higher mortality rate. METHODS: To explore trends within our own tertiary care surgical ICU, we sampled our patients' laboratory records in 2001 and in 2011. Hypo-magnesemia in our ICU is defined as an Mg less than 2.0 mg/dL. RESULTS: This retrospective review of all SICU patients from October to December revealed that there was a significant increase (P < 0.01) in the patients with their serum Mg level measured between 2001 (89%) and 2011 (95%). There was a significant decrease (P < 0.001) in patients with hypomagnesemia (< 2 mg/dL) between 2001 (47.5%) and 2011 (33.0%). On the other hand, there was a significant increase (P < 0.001) in patients with normal serum Mg level (> 2 mg/dL) between 2001 (52.5%) and 2011 (67.0%). CONCLUSIONS: There was not only more monitoring of Mg in 2011, but a lower incidence of hypo-Mg compared to 2001. Possible explanations include changing patterns of antibiotic and diuretic use, less amphotericin use, more frequent laboratory surveillance, and better trained ICU practitioners. PMID- 25699123 TI - Inflammatory bowel disease as a risk factor for premature coronary artery disease. AB - BACKGROUND: Crohn's disease and ulcerative colitis are both systemic chronic diseases that alter bowel physiology. The central process in inflammatory bowel disease (IBD) and the associated manifestations are the result of B-cell production of IgG autoantibodies directed against self-antigens in various organ systems including coronary endothelium. Previous studies have demonstrated significant micro-vascular endothelial dysfunction in patients with IBD compared to patients not affected by the disease. We sought to analyze the relation, if any, between IBD and the development of premature coronary artery disease (CAD). METHODS: We queried our hospital database to find IBD patients admitted to the hospital from January 1, 2007 to December 31, 2008. Patients with traditional cardiovascular (CV) disease risk factors including hypertension, congestive heart failure (CHF), diabetes, age >= 65, hyperlipidemia, family history, end-stage renal disease (ESRD), and greater than five pack-year smoking history were excluded from the study cohort. The charts of the remaining 300 patients with diagnosed IBD were then analyzed for the incidence of CV disease events including acute myocardial infarction (MI), unstable angina, positive stress testing, and any cardiac intervention including coronary angioplasty and/or intracoronary stent implantation. RESULTS: Of the 300 patients included, only one patient had a CV disease event. This patient had a positive exercise stress thallium test. Otherwise, the remaining 299 patients (99.7%) did not have any reported CV disease events over the 2-year follow-up period. CONCLUSION: Most of the clinical sequelae of CV disease events are the result of inflammatory changes at the vascular level. While IBD is associated with a chronic inflammatory state as reflected by high sedimentation rates, C-reactive protein (CRP), homocysteine levels, etc., our data seem to indicate that chronic inflammation in the absence of traditional risk factors is not associated with an increased risk of premature CV disease events. More wide-scale prospective studies should be performed to elucidate the relationship, if any, between chronic inflammation and CV disease risk. PMID- 25699124 TI - Tenosynovial, diffuse type giant cell tumor of the temporomandibular joint, diagnosis and management of a rare tumor. AB - The purpose of this paper was to describe a rare unusual case of primary mandibular condylar tenosynovial giant cell tumor of diffuse type with predominantly intraosseous growth and its management by resection and functional reconstruction with a vascularized costochondral graft. Clinical presentation was swelling in the right condylar area and limited mouth opening with radiological evidence of central bone destruction and magnetic resonance imaging showed central hemosiderin deposition. Fine needle aspiration did not lead to a diagnosis and an open biopsy had to be performed. Management consisted of tumor resection and reconstruction with a free vascularized costochondral graft. Tenosynovial diffuse type giant cell tumor of the temporomandibular joint is very rare. Complete resection leads to a low recurrence rate and reconstruction with a costochondral free vascularized flap leads to an excellent functional outcome. PMID- 25699125 TI - Serial lung magnetic resonance imaging to monitor disease progression in a child with a diffuse alveolar hemorrhage syndrome. AB - Serial lung magnetic resonance imaging (MRI) was performed in a child with diffuse alveolar hemorrhage (DAH). To minimize radiation exposure with conventional serial chest computerized tomography (CT), serial MRIs of the lungs were used. This effectively monitored her disease process as well as detected acute hemorrhage after 5 years remission. PMID- 25699126 TI - Atrial flutter ablation and risk of right coronary artery injury. AB - Radiofrequency ablation (RFA) of atrial flutter (AFL) is a commonly performed procedure with low risk of complications. Several case reports and animal studies cautioned about the risk of right coronary artery (RCA) injury following AFL ablation. This risk is due to the anatomic proximity of the RCA to the cavo tricuspid isthmus where ablation is performed. We present a case report that demonstrates postmortem evidence of RCA injury following RFA of AFL. PMID- 25699127 TI - Erythema Nodosum and Mycoplasma pneumoniae Infections in Childhood: Further Observations in Two Patients and a Literature Review. AB - Erythema nodosum (EN) is the most frequent panniculitis in childhood and has been associated with various conditions, such as infectious and autoimmune disorders, medications, and malignancies. The author reports on two children affected with EN associated with Mycoplasma pneumoniae infection, which occurred in one patient without pulmonary detection. The available literature on EN and M. pneumoniae infection in childhood is also reviewed. PMID- 25699128 TI - Bradyarrhythmias: first presentation of arrhythmogenic right ventricular cardiomyopathy? AB - Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a disorder characterized by progressive replacement of myocardial cells by fibro-fatty tissue giving rise to ventricular tachyarrhythmias. In this case report, we describe a pediatric patient with sinoatrial arrests and second degree atrioventricular conduction block several years before ARVC became apparent. These findings suggest that bradyarrhythmias can also be the first expression of ARVC. PMID- 25699129 TI - Improving the functionality of intra-operative nerve monitoring during thyroid surgery: is lidocaine an option? AB - Intra-operative nerve monitoring (IONM) is rapidly becoming a standard of care in many institutions across the country. In the absence of neuromuscular blocking agents to facilitate the IONM, the depth of anesthesia required to abolish the laryngo tracheal reflexes often results in profound hemodynamic instability during surgery, necessitating the use of large doses of sympathomimetic amines. The excessive alpha and beta adrenergic effects exhibited by these agents are undesirable in the presence of cardiovascular co-morbidities. Trying to strike a balance frequently results in an unsatisfactory intra-operative course. In the course of the near total thyroidectomy performed on a 60-year-old female, we employed lidocaine infusion at 1.5 mg/kg/hour following a bolus dose of 1 mg/kg. The troublesome laryngo tracheal reflexes were successfully blunted and we were able to moderate the depth of anesthesia resulting in stable hemodynamics. A bispectral index monitor was employed to guard against "recall" and a train of four monitor was used to ensure the absence of inadvertent neuromuscular blockade. During the surgery, there was loss of signal on the left recurrent laryngeal nerve (RLN). The signal strength was restored by rotating the endotracheal tube on its long axis to realign the electrode with the vocal cords under Glidescope((r)) visualization. PMID- 25699130 TI - Secondary adrenal insufficiency: an overlooked cause of hyponatremia. AB - Failure to thrive in an elderly patient is often attributed to depression, especially when a patient does not have any chronic diseases or if there is no apparent medical reason to justify poor appetite, cachexia and generalized weakness. Hyponatremia often occurs in such patients and a thorough evaluation as to its etiology should be sought before committing to a premature diagnosis, which at the time may seem more plausible. We report a patient who presented with depression, weight loss and persistent hyponatremia, evaluation of which revealed the cause to be due to secondary adrenal insufficiency, which when treated, resulted in resolution of the symptom complex. Therefore, in our case report, we elucidate the importance of pursuing further evaluation to rule out adrenal insufficiency as a medical cause of depression, especially in the presence of hyponatremia, which is often overlooked and is generally attributed to dehydration in the setting of failure to thrive or SIADH in patients who are on psychotropic medications. PMID- 25699131 TI - Low Cost Magnetic Resonance Imaging-Compatible Stepper Exercise Device for Use in Cardiac Stress Tests. AB - Cardiovascular disease is the leading cause of death worldwide. Many cardiovascular diseases are better diagnosed during a cardiac stress test. Current approaches include either exercise or pharmacological stress echocardiography and pharmacological stress magnetic resonance imaging (MRI). MRI is the most accurate noninvasive method of assessing cardiac function. Currently there are very few exercise devices that allow collection of cardiovascular MRI data during exercise. We developed a low-cost exercise device that utilizes adjustable weight resistance and is compatible with magnetic resonance (MR) imaging. It is equipped with electronics that measure power output. Our device allows subjects to exercise with a leg-stepping motion while their torso is in the MR imager. The device is easy to mount on the MRI table and can be adjusted for different body sizes. Pilot tests were conducted with 5 healthy subjects (3 male and 2 female, 29.2 +/- 3.9 yr old) showing significant exercise-induced changes in heart rate (+42%), cardiac output (+40%) and mean pulmonary artery (PA) flow (+%49) post exercise. These data demonstrate that our MR compatible stepper exercise device successfully generated a hemodynamically stressed state while allowing for high quality imaging. The adjustable weight resistance allows exercise stress testing of subjects with variable exercise capacities. This low cost device has the potential to be used in a variety of pathologies that require a cardiac stress test for diagnosis and assessment of disease progression. PMID- 25699132 TI - Covariance Matrix Estimation for the Cryo-EM Heterogeneity Problem. AB - In cryo-electron microscopy (cryo-EM), a microscope generates a top view of a sample of randomly oriented copies of a molecule. The problem of single particle reconstruction (SPR) from cryo-EM is to use the resulting set of noisy two dimensional projection images taken at unknown directions to reconstruct the three-dimensional (3D) structure of the molecule. In some situations, the molecule under examination exhibits structural variability, which poses a fundamental challenge in SPR. The heterogeneity problem is the task of mapping the space of conformational states of a molecule. It has been previously suggested that the leading eigenvectors of the covariance matrix of the 3D molecules can be used to solve the heterogeneity problem. Estimating the covariance matrix is challenging, since only projections of the molecules are observed, but not the molecules themselves. In this paper, we formulate a general problem of covariance estimation from noisy projections of samples. This problem has intimate connections with matrix completion problems and high-dimensional principal component analysis. We propose an estimator and prove its consistency. When there are finitely many heterogeneity classes, the spectrum of the estimated covariance matrix reveals the number of classes. The estimator can be found as the solution to a certain linear system. In the cryo-EM case, the linear operator to be inverted, which we term the projection covariance transform, is an important object in covariance estimation for tomographic problems involving structural variation. Inverting it involves applying a filter akin to the ramp filter in tomography. We design a basis in which this linear operator is sparse and thus can be tractably inverted despite its large size. We demonstrate via numerical experiments on synthetic datasets the robustness of our algorithm to high levels of noise. PMID- 25699133 TI - Building a Virtual Environment for Diabetes Self-Management Education and Support. AB - The authors developed an immersive diabetes community to provide diabetes self management education and support for adults with type 2 diabetes. In this article the authors describe the procedures used to develop this virtual environment (VE). Second Life Impacts Diabetes Education & Self-Management (SLIDES), the VE for our diabetes community was built in Second Life. Social Cognitive Theory, behavioral principles and key aspects of virtual environments related to usability were applied in the development in this VE. Collaboration between researchers, clinicians and information technology (IT) specialists occurred throughout the development process. An interactive community was successfully built and utilized to provide diabetes self-management education and support. VEs for health applications may be innovative and enticing, yet it must be kept in mind that there are substantial effort, expertise, and usability factors that must be considered in the development of these environments for health care consumers. PMID- 25699134 TI - Efficacy and Tolerability of Steroid-Free, Over-the-Counter Treatment Formulations in Infants and Children With Atopic Dermatitis. AB - BACKGROUND: Two steroid-free, over-the-counter skin protectant products have been developed for the care and treatment of atopic dermatitis (AD)-Eucerin Eczema Relief Body Creme (Body Cream) for daily skin moisturization and Eucerin Eczema Relief Instant Therapy cream (Instant Therapy) for treatment of AD flare-ups. We tested the efficacy and tolerability of these formulations in infants and children with AD. METHODS: Study 1: Body Cream was applied twice daily to the lower legs of 64 children with a history of AD (aged 3 months to 12 years) for 14 days. Study 2: Instant Therapy was applied to active lesions and surrounding skin of 29 children (aged 3 months to 12 years) with active atopic lesions. Assessments were performed at baseline and Days 7 and 14. Symptoms were assessed using the Atopic Dermatitis Severity Index in Study 2. RESULTS: Body Cream significantly improved skin hydration and reduced itching, burning/stinging, erythema, and tactile roughness. Instant Therapy significantly improved skin hydration and AD symptoms, notably pruritus, erythema, and lichenification. Both products were safe and well tolerated. DISCUSSION: Body Cream and Instant Therapy were effective and well tolerated in the treatment of AD in children. These products provide steroid-free, nonprescription therapy for the maintenance and treatment of acute eczema and were proven effective and safe in infants as young as 3 months. PMID- 25699135 TI - Novel inhibitors of platelet aggregation. PMID- 25699136 TI - Novel Pyridyloxadiazole Agonists of Sphingosin-1-phosphate. PMID- 25699137 TI - Conjugation and Evaluation of Small Hydrophobic Molecules to Triazole-Linked siRNAs. AB - Short interfering RNAs (siRNAs) have tremendous potential as a new class of next generation therapeutics; however, their progress is lagging due to issues related to stability, biodistribution, and cell-membrane permeability. To overcome these issues, there is widespread interest in chemically modifying siRNAs. In this study, siRNAs that contain a triazole-backbone unit with pyrimidine-modified hydrophobic substituents were synthesized and examined for their gene-silencing activity. In our study, we generated a library of siRNAs that target both a plasmid reporter system and an endogenous gene target, bcl-2. Our results indicate that these unique modifications are well tolerated within the RNA interference pathway. In addition, a cholesterol-modified triazole-linked siRNA targeting the exogenous target firefly luciferase was capable of gene-silencing at levels greater than 80% in the absence of a carrier complex. PMID- 25699138 TI - Melanocortin antagonist tetrapeptides with minimal agonist activity at the mouse melanocortin-3 receptor. AB - The melanocortin system regulates many important functions in the body. There are five melanocortin G protein-coupled receptor subtypes known to date. Herein, we report a structure-activity relationship (SAR) study of a tetrapeptide lead discovered through a double substitution strategy at the melanocortin core His Phe-Arg-Trp sequence. Several compounds were identified with micromolar agonist activity at the mouse melanocortin-1 (mMC1R) and mouse melanocortin-5 receptor (mMC5R) subtypes, weak antagonist activity at the mouse melanocortin-3 receptor (mMC3R), and potent antagonist activity at the mouse melanocortin-4 receptor (mMC4R). Two compounds (2 and 3) were nanomolar mMC4R antagonists with no mMC3R antagonist activity observed. Additionally, we identified three tetrapeptide MC3R antagonists (1, 6, and 7) that possess minimal mMC3R agonist activity only at 100 MUM, not commonly observed for mMC3R/mMC4R antagonists. These novel molecular templates have the potential as molecular probes to better differentiate the roles of the centrally expressed MC3 and MC4 receptors. PMID- 25699139 TI - Syntheses and Antituberculosis Activity of 1,3-Benzothiazinone Sulfoxide and Sulfone Derived from BTZ043. AB - The discovery of 1,3-benzothiazin-4-ones (BTZs), especially BTZ043 and PBTZ-169 as potent agents for the treatment of tuberculosis, prompted intensive research related to development of potential antituberculosis agents based on electron deficient nitroaromatic scaffolds. Herein we report the syntheses, computational and NMR studies and anti-TB activity of oxidation products, 1,3-benzothiazinone sulfoxide (BTZ-SO) and 1,3-benzothiazinone sulfone (BTZ-SO2) derived from BTZ043. The combined computational and NMR work revealed differences in the total charge densities and molecular shapes of the oxidation products. While docking studies still suggested similar interactions and binding patterns for both products with the target DprE1 enzyme, antituberculosis assays indicated remarkable differences in their activity. Interestingly, BTZ-SO possesses potent activity against nonpathogenic and pathogenic mycobacterial strains, but BTZ-SO2 is only weakly active. PMID- 25699140 TI - Diphenylpyrazoles as replication protein a inhibitors. AB - Replication Protein A is the primary eukaryotic ssDNA binding protein that has a central role in initiating the cellular response to DNA damage. RPA recruits multiple proteins to sites of DNA damage via the N-terminal domain of the 70 kDa subunit (RPA70N). Here we describe the optimization of a diphenylpyrazole carboxylic acid series of inhibitors of these RPA-protein interactions. We evaluated substituents on the aromatic rings as well as the type and geometry of the linkers used to combine fragments, ultimately leading to submicromolar inhibitors of RPA70N protein-protein interactions. PMID- 25699141 TI - Bis(aminomethyl)phosphinic Acid, a Highly Promising Scaffold for the Development of Bacterial Urease Inhibitors. AB - Inhibitors of bacterial ureases are considered to be promising compounds in the treatment of infections caused by Helicobacter pylori in the gastric tract and/or by urealytic bacteria (e.g., Proteus species) in the urinary tract. A new, extended transition state scaffold, bis(aminomethyl)phosphinic acid, was successfully explored for the construction of effective enzyme inhibitors. A reliable methodology for the synthesis of phosphinate analogues in a three component Mannich-type reaction was elaborated. The obtained molecules were assayed against ureases purified from Sporosarcina pasteurii and Proteus mirabilis, and aminomethyl(N-n-hexylaminomethyl)phosphinic acid was found to be the most potent inhibitor, with a K i = 108 nM against the S. pasteurii enzyme. PMID- 25699142 TI - SAR Studies of Diphenyl Cationic Trypanocides: Superior Activity of Phosphonium over Ammonium Salts. AB - In previous studies, we have shown that phosphonium salt diphenyl derivatives are attractive antitrypanosomal hit compounds with EC50 values against Trypanosoma brucei in the nanomolar range. To evaluate the role of the cationic center on the trypanocidal activity and extend the structure-activity relationship (SAR) of this series, trialkylammonium, pyridinium, and quinolinium salt analogues were synthesized and evaluated in vitro against T. b. brucei. Similar SARs were observed with ammonium and phosphonium salts showing that charge dispersion and lipophilic groups around the cationic center are crucial to obtain submicromolar activities. The new compounds were equally effective against wild type (T. b. brucei s427) and resistant strains (TbAT1-KO and TbB48) of trypanosomes indicating that the P2 and high affinity pentamidine transporters (HAPT) are not essential to their trypanocidal action. Similarly to phosphonium salt derivatives, diffusion seems to be the main route of entry into trypanosomes. PMID- 25699144 TI - Potent Irreversible Inhibitors of LasR Quorum Sensing in Pseudomonas aeruginosa. AB - Antagonism of quorum sensing represents a promising new antivirulence approach for the treatment of bacterial infection. The development of a novel series of non-natural irreversible antagonists of P. aeruginosa LasR is described. The lead compounds identified (25 and 28) display potent LasR antagonist activity and inhibit expression of the P. aeruginosa virulence factors pyocyanin and biofilm formation in PAO1 and PA14. PMID- 25699143 TI - Evaluation and synthesis of polar aryl- and heteroaryl spiroazetidine-piperidine acetamides as ghrelin inverse agonists. AB - Several polar heteroaromatic acetic acids and their piperidine amides were synthesized and evaluated as ghrelin or type 1a growth hormone secretagogue receptor (GHS-R1a) inverse agonists. Efforts to improve pharmacokinetic and safety profile was achieved by modulating physicochemical properties and, more specifically, emphasizing increased polarity of our chemical series. ortho Carboxamide containing compounds provided optimal physicochemical, pharmacologic, and safety profile. pH-dependent chemical stability was also assessed with our series. PMID- 25699145 TI - Development and Preliminary Evaluation of TFIB, a New Bimodal Prosthetic Group for Bioactive Molecule Labeling. AB - The new readily available prosthetic group, tetrafluorophenyl 4-fluoro-3 iodobenzoate (TFIB), designed for both molecular imaging and targeted radionuclide therapy purposes was radiolabeled either with fluorine or iodine radionuclides with excellent radiochemical yields and purities. These radiolabeled tags were conjugated to N,N-diethylethylenediamine to give melanin targeting radiotracers [ (125) I]9 and [ (18) F]9, which were successfully evaluated by PET and gamma scintigraphic imaging in B16F0 pigmented melanoma bearing C57BL/6J mice. Then, radiolabeled [ (125) I]/[ (18) F]TFIB was used to tag tumor-targeting peptides (i.e., PEG3[c(RGDyK)]2 and NDP-MSH targeting alphavbeta3 integrin and MC1R receptors, respectively) in mild conditions and with good radiochemical yields (47-83% d.c.) and purities (>99%). The resulting radiolabeled peptides were assessed both in vitro and by PET imaging in animal models. PMID- 25699146 TI - Pure Diastereomers of a Tranylcypromine-Based LSD1 Inhibitor: Enzyme Selectivity and In-Cell Studies. AB - The pure four diastereomers (11a-d) of trans-benzyl (1-((4-(2 aminocyclopropyl)phenyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate hydrochloride 11, previously described by us as LSD1 inhibitor, were obtained by enantiospecific synthesis/chiral HPLC separation method. Tested in LSD1 and MAO assays, 11b (S,1S,2R) and 11d (R,1S,2R) were the most potent isomers against LSD1 and were less active against MAO-A and practically inactive against MAO-B. In cells, all the four diastereomers induced Gfi-1b and ITGAM gene expression in NB4 cells, accordingly with their LSD1 inhibition, and 11b and 11d inhibited the colony forming potential in murine promyelocytic blasts. PMID- 25699147 TI - Interconversion of Functional Activity by Minor Structural Alterations in Nonpeptide AT2 Receptor Ligands. AB - Migration of the methylene imidazole side chain in the first reported selective drug-like AT2 receptor agonist C21/M024 (1) delivered the AT2 receptor antagonist C38/M132 (2). We now report that the AT2 receptor antagonist compound 4, a biphenyl derivative that is structurally related to 2, is transformed to the agonist 6 by migration of the isobutyl group. The importance of the relative position of the methylene imidazole and the isobutyl substituent is highlighted herein. PMID- 25699148 TI - Azepinone-Containing Tetrapeptide Analogues of Melanotropin Lead to Selective hMC4R Agonists and hMC5R Antagonist. AB - To address the need for highly potent, metabolically stable, and selective agonists, antagonists, and inverse agonists at the melanocortin receptor subtypes, conformationally constrained indolo- and benzazepinone residues were inserted into the alpha-MSH pharmacophore, His(6)-Phe(7)-Arg(8)-Trp(9)-domain. Replacement of His(6) by an aminoindoloazepinone (Aia) or aminobenzazepinone (Aba) moiety led to hMC4R and hMC5R selective agonist and antagonist ligands, respectively (tetrapeptides 1 to 3 and 4, respectively). In peptides 1 to 3 and depending on the para-substituent of the d-Phe residue in position 2, the activity goes from allosteric partial agonism (1, R = H) to allosteric full agonism (2, R = F) and finally allosteric partial agonism (3, R = Br). PMID- 25699149 TI - Conformational Restriction Leading to a Selective CB2 Cannabinoid Receptor Agonist Orally Active Against Colitis. AB - The CB2 cannabinoid receptor has been implicated in the regulation of intestinal inflammation. Following on from the promising activity of a series of 4-oxo-1,4 dihydroquinoline-3-carboxamide, we developed constrained analogues based on a 2H pyrazolo[4,3-c]quinolin-3(5H)-one scaffold, with improved affinity for the hCB2 receptor and had very high selectivity over the hCB1 receptor. Importantly, the lead of this series (26, hCB2: K i = 0.39 nM, hCB1: K i > 3000 nM) was found to protect mice against experimental colitis after oral administration. PMID- 25699150 TI - Design, synthesis, and biological evaluation of ring-constrained novobiocin analogues as hsp90 C-terminal inhibitors. AB - Hsp90 C-terminal inhibitors represent a novel and alternative chemotherapeutic approach for the treatment of cancer. Novobiocin was the first natural product identified as an Hsp90 C-terminal inhibitor; however, it manifests poor antiproliferative activity. In contrast to N-terminal inhibitors, novobiocin does not induce the pro-survival heat shock response. Structural investigations on novobiocin have elucidated some structure-activity relationships and several promising compounds. On the basis of structure-activity relationships and computational studies, a library of ring-constrained novobiocin analogues was designed, synthesized, and evaluated in antiproliferative assays. Results obtained from these studies provide insights into the Hsp90 C-terminal binding site, and new analogues that were developed manifest low micromolar to mid nanomolar antiproliferative activity resulting from Hsp90 inhibition. PMID- 25699151 TI - An Orally Available BACE1 Inhibitor That Affords Robust CNS Abeta Reduction without Cardiovascular Liabilities. AB - BACE1 inhibition to prevent Abeta peptide formation is considered to be a potential route to a disease-modifying treatment for Alzheimer's disease. Previous efforts in our laboratory using a combined structure- and property-based approach have resulted in the identification of aminooxazoline xanthenes as potent BACE1 inhibitors. Herein, we report further optimization leading to the discovery of inhibitor 15 as an orally available and highly efficacious BACE1 inhibitor that robustly reduces CSF and brain Abeta levels in both rats and nonhuman primates. In addition, compound 15 exhibited low activity on the hERG ion channel and was well tolerated in an integrated cardiovascular safety model. PMID- 25699152 TI - Improved Synthesis of Biotinol-5'-AMP: Implications for Antibacterial Discovery. AB - An improved synthesis of biotinol-5'-AMP, an acyl-AMP mimic of the natural reaction intermediate of biotin protein ligase (BPL), is reported. This compound was shown to be a pan inhibitor of BPLs from a series of clinically important bacteria, particularly Staphylococcus aureus and Mycobacterium tuberculosis, and kinetic analysis revealed it to be competitive against the substrate biotin. Biotinol-5'-AMP also exhibits antibacterial activity against a panel of clinical isolates of S. aureus and M. tuberculosis with MIC values of 1-8 and 0.5-2.5 MUg/mL, respectively, while being devoid of cytotoxicity to human HepG2 cells. PMID- 25699153 TI - Relative binding affinities of integrin antagonists by equilibrium dialysis and liquid chromatography-mass spectrometry. AB - The integrin alphavbeta6 is a potential target for treatment of idiopathic pulmonary fibrosis (IPF). Equilibrium dialysis (ED) was investigated for its ability to report ligand binding in an alphavbeta6 inhibitor screening assay. As a preliminary experiment, an established peptidomimetic inhibitor of the integrin was dialyzed against alphavbeta6, and the fraction bound (f b) and percentage saturation determined by liquid chromatography-mass spectrometry (LC-MS) analysis. Quantitation of the inhibitor in the two chambers of the ED cartridge revealed an uneven distribution in the presence of alphavbeta6, corresponding to near saturation binding to the protein (93 +/- 3%), while the control (without integrin) showed an equal partitioning of the inhibitor on either side of the dialysis membrane. A competitive ED assay with a 12 component mixture of antagonists was conducted, and the results compared with an established cell adhesion assay for quantifying alphavbeta6 inhibition of individual antagonists. Compounds clustered into three groupings: those with pIC 50 values between ca. 5.0 and 5.5, which possessed ED f b values indistinguishable from the controls, those with pIC 50s of 6.5 +/- 0.2, which exhibited detectable integrin binding (f b 13-25%) in the ED assay, and a single compound of pIC 50 7.2 possessing an f b value of 38%. A good correlation between ED-derived f b and pIC 50 was observed despite the two assays utilizing quite different outputs. These results demonstrate that ED with LC-MS detection shows promise as a rapid alphavbeta6 integrin antagonist screening assay for mixtures of putative ligands. PMID- 25699154 TI - Allosteric modulators: an emerging concept in drug discovery. PMID- 25699155 TI - The role of enhancer of zeste homologue 2 inhibitors in controlling epigenetics and their potential for cancer treatment. PMID- 25699156 TI - Treating pain with somatostatin receptor subtype 4 agonists. PMID- 25699157 TI - Discovery of autophagy inhibitors with antiproliferative activity in lung and pancreatic cancer cells. AB - The autophagy inhibitors chloroquine (CQ) and hydroxychloroquine (HCQ) have single agent antiproliferative activity against human cancer cell lines; however, low potency may limit their antitumor efficacy clinically. We synthesized a series of chloroquine analogs that retained the 4-aminoquinoline subunit and incorporated different substituted triazoles into the target structure. These compounds were tested for growth inhibition against H460 and HCC827 human lung cancer and BxPC3 pancreatic cancer cells. The most potent compound, EAD1, had an IC50 of 5.8 MUM in the BxPC3 cells and was approximately 8-fold more potent than CQ and HCQ. EAD1 inhibited autophagy, as judged by the cellular accumulation of the autophagy-related autophagosome proteins LC3-II and p62 and induced apoptosis. The increases in LC3-II levels by the analogues were highly correlated with their growth inhibitory IC50s, suggesting that autophagy blockade is closely linked to inhibition of cell proliferation. EAD1 is a viable lead compound for evaluation of the antitumor activity of autophagy inhibitors in vivo. PMID- 25699158 TI - Novel N-benzenesulfonyl sophocarpinol derivatives as coxsackie B virus inhibitors. AB - Novel N-benzenesulfonyl sophocarpinic acid/ester and sophocarpinol derivatives were synthesized and evaluated for their antienteroviral activities against coxsackievirus type B3 (CVB3) from sophocarpine (1), a natural medicine isolated from Chinese herb. Structure-activity relationship (SAR) analysis revealed that the double bond and its geometrical configuration and position at the C-11 attachment did not greatly affect the potency. Among these derivatives, sophocarpinol 24d exerted the promising activities against not only CVB3 but also CVB1, CVB2, CVB5, and CVB6 with IC50 ranging from 0.62 to 3.63 MUM (SI from 46 to 275), indicating a broad-spectrum antienteroviral characteristic. The SAR results provided the powerful information for further strategic optimization and development of a novel scaffold of broad-spectrum antiviral candidates against enteroviruses. PMID- 25699159 TI - Structural Insights for the Optimization of Dihydropyrimidin-2(1H)-one Based mPGES-1 Inhibitors. AB - The recently crystallized structure of microsomal prostaglandin E2 synthase 1 (mPGES-1) in complex with the inhibitor LVJ (PDB code: 4BPM) offered new structural information for the optimization of the previously identified lead compound 1 (IC50 = 4.16 +/- 0.47 MUM), which contains the privileged dihydropyrimidin-2-one chemical core. Systematic optimization of 1, through accurate structure-based design, provided compound 4 with a 10-fold improved mPGES-1 inhibitory activity (IC50 = 0.41 +/- 0.02 MUM). Here we highlight the optimal scaffold decoration pattern of 4 and propose a three-dimensional model for the interaction with this complex trimeric membrane protein. The reported computational insights, together with the accessible one-pot synthetic procedure, stimulate for the generation of further potent dihydropyrimidine-based mPGES-1 inhibitors. PMID- 25699160 TI - Tooth movement alterations by different low level laser protocols: a literature review. AB - Low-Level Laser Therapy (LLLT) provides several benefits for patients receiving orthodontic treatment. According to some literatures, Orthodontic Tooth Movement (OTM) can be enhanced but some investigators have reported contradictory results. This article reviews the literature regarding the different aspects of the use of LLLT on OTM and its alterations. The general data regarding the study design, sample size, wavelength (nm), power (mW), and duration were extracted and recorded independently. Electronic databases of PubMed and ScienceDirect from January 2009 to August 2014 were searched. Also Google Scholar and grey literature was searched for relevant references. Some investigators found that the amount of tooth movement in the Low-Energy Laser Irradiation (LELI) group was significantly greater than in the nonirradiation group by the end of the experimental period. Low-level laser irradiation accelerates the bone remodeling process by stimulating osteoblastic and osteoclastic cell proliferation and function during orthodontic tooth movement. But some researchers have reported that no statistical differences in the mean rate of tooth movement were noted between low energy and high energy experimental sides and their controls. Some evidence shows that low-level laser irradiation accelerates the bone remodeling process and some evidence shows that LLLT has not effect on OTM. In some investigations no statistical differences in the mean rate of tooth movement can be seen between low energy and high energy experimental sides and their controls. It has been shown by authors that laser irradiation can reduce the amount of OTM and a clinical usage for the inhibitory role of low level laser irradiation is enforcing the anchorage unit. PMID- 25699161 TI - The intravenous laser blood irradiation in chronic pain and fibromyalgia. AB - Intravenous laser blood irradiation was first introduced into therapy by the Soviet scientists EN.Meschalkin and VS.Sergiewski in 1981. Originally this method was developed for the treatment of cardiovascular diseases. Improvement of rheologic properties of the blood as well as improvement of microcirculation and reduction of the area of infarction has been proved. Further, reduction of dysrhythmia and sudden cardiac death was achieved. At first, only the Helium-Neon laser (632.8 nm) was used in this therapy. For that, a power of 1-3mW and a period of exposure of 20-60 minutes were applied. The treatments were carried out once or twice a day up to ten appointments in all1. In the years after, many, and for the most part Russian studies showed that helium-neon laser had various effects on many organs and on the hematologic and immunologic system. The studies were published mainly in Russian which were little known in the West because of decades of political separation, and were regarded with disapproval. Besides clinical research and application for patients, the cell biological basis was developed by the Estonian cell biologist Tiina Karu at the same time. An abstract is to be found in her work "The Science of Low-Power Laser-Therapy" PMID- 25699162 TI - Laser irradiation on growth of trichophyton rubrum: an in vitro study. AB - INTRODUCTION: Trichophyton rubrum is one of the most common species of dermatophytes which affects superficial keratinous tissue. It is not especially virulent but it can be responsible for considerable morbidity. Although there are different therapeutic modalities to treat fungal infections, clinicians are searching for alternative treatment because of the various side effects of the present therapeutic methods. As a new procedure, Laser therapy has brought on many advantages in clinical management of dermatophytes. Possible inhibitory potential of laser irradiation on fungal colonies was investigated invitro in this study. METHODS: A total of 240 fungal plates of standard size of trichophyton rubrum colonies that had been cultured from the lesions of different patients at the mycology laboratory, were selected. Each fungal plate was assigned as control or experimental group. Experimental plates were irradiated by a laser system (low power laser or different wavelength of high power laser). The effects of different laser wavelengths and energies on isolated colonies were assessed. After laser irradiation, final size of colonies was measured on the first, the 7th and the 14th day after laser irradiation. RESULTS: Although low power laser irradiation did not have any inhibitory effect on fungal growth, the Q-Switched Neodymium-Doped Yttrium Aluminium Garnet (Nd:YAG) laser 532nm at 8j/cm(2), Q-Switched Nd:YAG laser 1064nm at 4j/cm(2) to 8j/cm(2) and Pulsed dye laser 595nm at 8j/cm(2) to 14j/cm(2) significantly inhibited growth of trichophyton rubrum in vitro. CONCLUSION: Q-Switched Nd:YAG 532nm at 8j/cm(2), Q Switched Nd:YAG laser 1064nm at 4j/cm(2) to 8j/cm(2) and pulsed dye laser (PDL) 595nm at 8j/cm(2) to 14j/cm(2) can be effective to suppress trichophyton rubrum growth. PMID- 25699163 TI - Modulating Heat Shock Proteins 70 and 90 Expression by Low Power Laser Irradiation (635nm and 780nm) in Jurkat E6.1 T-lymphocyte Leukemia Cell Line. AB - INTRODUCTION: Heat shock proteins (HSPs) are molecular chaperones involved in protein folding, stability and turnover, and due to their role in cancer progression, the effect of low power laser irradiation (LPLI) on the expression of HSP70 and HSP90 in Jurkat E6.1 T-lymphocyte leukemia (JELT) cell line was investigated in vitro. METHODS: JETL cells were irradiated with LPLI at 635nm and 780m wavelengths (energy density 9.174 J/cm(2)), and assessed for the expression of HSP70 and HSP90 by flow cytometry after 24, 48 and 72 incubation time periods (ITPs). RESULTS: At 24 hours ITP post-irradiation, control cultures showed that 10.7% of cells expressed HSP70, while LPLI cultures at 635nm and 780nm manifested a higher expression (32.1and 21.3%, respectively), and the difference was significant (P <= 0.05). However, at 48 hours ITP, the three means were decreased but approximated (5.6, 4.9 and 6.2%, respectively), while at 72 hours ITP, they were markedly increased (45.2, 76.5 and 66.7%, respectively). In contrast, HSP90 responded differently to LPLI. At 24 hours ITP, control cultures and 780nm cultures showed a similar expression (55.9 and 55.9%, respectively), but both means were significantly higher than that of 635nm cultures (24.0%). No such difference was observed at 48 hours ITP, and at 72 hours ITP, control cultures and 635nm cultures shared approximated means (31.7 and 35.6%, respectively); but both means were significantly higher than the observed mean in 780nm cultures (15.2%). CONCLUSION: The results highlighted that HSP70 and HSP90 expression responded differently to LPLI in JETL cells; an observation that may pave the way for further investigations in malignant cells. PMID- 25699164 TI - Study of Interaction of Laser with Tissue Using Monte Carlo Method for 1064nm Neodymium-Doped Yttrium Aluminium Garnet (Nd:YAG) Laser. AB - INTRODUCTION: Liposuction using laser is now one of the most common cosmetic surgery. This new method has minimized the disadvantages of the conventional liposuction including blood loss, skin laxity and long recovery time. Benefits of the new liposuction methods which include less trauma, bleeding and skin tightening prove the superiority of these methods over the traditional mechanical methods. Interaction of laser with fat tissue has the vital role in the development of these new procedures because this interaction simultaneously results in retraction of skin layers and coagulation of small blood vessels so skin tightening and less bleeding is achieved. METHOD: Laser lipolysis uses a laser fiber inserted inside a metal cannula of 1 mm delivering the laser radiation directly to the target tissue. Laser lipolysis has a wavelength dependent mechanism, tissue heating and therefor thermal effects are achieved through absorption of radiation by the target tissue cells, causing their temperature to rise and their volumes to expand. We used Monte Carlo (MC) method to simulate the photons propagation within the tissue. This method simulates physical variables by random sampling of their probability distribution. We also simulated temperature rise and tissue heating using Comsol Multiphysics software. CONCLUSION: Because optimum and safe laser lipolysis operation highly depends on optical characteristics of both tissue and laser radiation such as laser fluence, laser power and etc. having physical understanding of these procedures is of vital importance. In this study we aim to evaluate the effects of these important parameters. RESULTS: Findings of our simulation prove that 1064 nm Neodymium Doped Yttrium Aluminium Garnet (Nd:YAG) has good penetration depth into fat tissue and can reach inside the deeper layers of fat tissue. We see that this wavelength also resulted in good temperature rise; after irradiation of fat tissue with this wavelength we observed that tissue heated in permitted values (50-65 degrees C), this is why this wavelength is widely used in laser lipolysis operations. PMID- 25699165 TI - Comparison of a CO2 (Carbon Dioxide) Laser and Tissue Glue with Conventional Surgical Techniques in Circumcision. AB - INTRODUCTION: CO2 (Carbon Dioxide) laser application in circumcision, for cutting and coagulation, has been reported to have excellent results. Also, tissue glue has been reported to have advantages over sutures for approximation of wound edges. Most previous studies focused on comparisons between CO2 laser and scalpel, or between tissue glue and sutures. This study prospectively compared the results and complications CO2 laser and tissue glue, with standard surgical techniques in circumcision. METHODS: Thirty boys were prospectively divided into two groups. Group 1 (n = 17) underwent circumcision by scalpel with approximation of the wound edges using chromic catgut sutures. Group 2 (n = 13) underwent circumcision with CO2 laser and approximation of the wound edges using tissue glue. Patient age, indications for surgery, operative time, wound swelling, bleeding, wound infection, local irritation, pain score, and cosmetic appearance were recorded. RESULTS: Group 1 had a significantly longer operative time (P= 0.011), higher rate of local irritation (P= 0.016), and poorer cosmetic appearance (P< 0.001) than group 2. Bleeding only occurred in one patient in group 1. There were no significant differences in pain score, wound infection rate, or cost of surgery between the two groups. CONCLUSIONS: CO2 laser and tissue glue have advantages over standard surgical techniques in circumcision, with a significantly shorter operative time, lower rate of local irritation, and better cosmetic appearance. The cost of surgery is similar between the two groups. PMID- 25699166 TI - Effect of Nd:YAG Laser Irradiation on the Number of Open Dentinal Tubules and Their Diameter with and without Smear of Graphite: An in Vitro Study. AB - INTRODUCTION: Dentin hypersensitivity (DH) is characterized by tooth pain arising from exposure of dental roots. In this study the efficiency of neodymium yttrium aluminum-garnet (Nd:YAG) laser in association with graphite on dentinal surface changes as the alternative to the treatment of DH was evaluated. METHODS: Sixteen noncarious human third molars were collected and sectioned into 5 parts from cementoenamel junction (CEJ) to the furcation area. The prepared samples were randomly assigned into five groups (Gs) of each 16: Control (G1), treated by Nd:YAG laser at 0.5 W (G2), irradiation of Nd:YAG with a 0.25 W output power(G3), smeared with graphite and then using Nd:YAG laser at output powers of 0.5 W (G4) and 0.25 W (G5). For all groups the parameters were 15 Hz, 60 s, at two stages and with a right angle irradiation. The number and diameter of dentinal tubules (DT) were compared and analyzed by SPSS software, One way ANOVA and Post hoc LSD tests. RESULTS: The number of open dentinal tubules varied significantly between all groups except among G1 with G3 and G2 with G5. Multiple comparison tests also exhibited significant differences regarding the diameter of tubules between the groups two by two except among G2 with G5. CONCLUSION: Nd:YAG laser used at 0.25 W and 0.5 W with application of graphite smear was able to reduce the number and diameter of dentinal tubules. PMID- 25699167 TI - Expedited removal of pyogenic granuloma by diode laser in a pediatric patient. AB - INTRODUCTION: Pyogenic granuloma (PG) is one of the inflammatory hyperplasia seen in the oral cavity. It is a reactional response to minor trauma or chronic irritation. The most common treatment of PG is surgical excision but alternative approaches such as laser excision have also been proposed especially for pediatric patients. CASE REPORT: Herein, we present a case of gingival pyogenic granuloma in a 6-year-old patient. The lesion was excised successfully with diode laser as a conservative and non-stressful method in a pediatric patient. RESULTS AND CONCLUSION: The use of laser as modern medicine offers a new tool for treatment of oral lesions as comfortable as possible in pediatric patients, which results in less stress and fear in children. PMID- 25699168 TI - Functional genetics for all: engineered nucleases, CRISPR and the gene editing revolution. AB - Developmental biology, as all experimental science, is empowered by technological advances. The availability of genetic tools in some species - designated as model organisms - has driven their use as major platforms for understanding development, physiology and behavior. Extending these tools to a wider range of species determines whether (and how) we can experimentally approach developmental diversity and evolution. During the last two decades, comparative developmental biology (evo-devo) was marked by the introduction of gene knockdown and deep sequencing technologies that are applicable to a wide range of species. These approaches allowed us to test the developmental role of specific genes in diverse species, to study biological processes that are not accessible in established models and, in some cases, to conduct genome-wide screens that overcome the limitations of the candidate gene approach. The recent discovery of CRISPR/Cas as a means of precise alterations into the genome promises to revolutionize developmental genetics. In this review we describe the development of gene editing tools, from zinc-finger nucleases to TALENs and CRISPR, and examine their application in gene targeting, their limitations and the opportunities they present for evo-devo. We outline their use in gene knock-out and knock-in approaches, and in manipulating gene functions by directing molecular effectors to specific sites in the genome. The ease-of-use and efficiency of CRISPR in diverse species provide an opportunity to close the technology gap that exists between established model organisms and emerging genetically-tractable species. PMID- 25699169 TI - A role for Galgt1 in skeletal muscle regeneration. AB - BACKGROUND: Cell surface glycans are known to play vital roles in muscle membrane stability and muscle disease, but to date, roles for glycans in muscle regeneration have been less well understood. Here, we describe a role for complex gangliosides synthesized by the Galgt1 gene in muscle regeneration. METHODS: Cardiotoxin-injected wild type (WT) and Galgt1 (-/-) muscles, and mdx and Galgt1 (-/-) mdx muscles, were used to study regeneration in response to acute and chronic injury, respectively. Muscle tissue was analyzed at various time points for morphometric measurements and for gene expression changes in satellite cell and muscle differentiation markers by quantitative real-time polymerase chain reaction (qRT-PCR). Primary cell cultures were used to measure growth rate and myotube formation and to identify Galgt1 expression changes after cardiotoxin by fluorescence-activated cell sorting (FACS). Primary cell culture and tissue sections were also used to quantify satellite cell apoptosis. RESULTS: A query of a microarray data set of cardiotoxin-induced mouse muscle gene expression changes identified Galgt1 as the most upregulated glycosylation gene immediately after muscle injury. This was validated by qRT-PCR as a 23-fold upregulation in Galgt1 expression 1 day after cardiotoxin administration and a 16-fold upregulation in 6 week-old mdx muscles. These changes correlated with increased expression of Galgt1 protein and GM1 ganglioside in mononuclear muscle cells. In the absence of Galgt1, cardiotoxin-induced injury led to significantly reduced myofiber diameters after 14 and 28 days of regeneration. Myofiber diameters were also significantly reduced in Galgt1-deficient mdx mice compared to age-matched mdx controls, and this was coupled with a significant increase in the loss of muscle tissue. Cardiotoxin-injected Galgt1 (-/-) muscles showed reduced gene expression of the satellite cell marker Pax7 and increased expression of myoblast markers MyoD, Myf5, and Myogenin after injury along with a tenfold increase in apoptosis of Pax7-positive muscle cells. Cultured primary Galgt1 (-/-) muscle cells showed a normal growth rate but demonstrated premature fusion into myofibers, resulting in an overall impairment of myofiber formation coupled with a threefold increase in muscle cell apoptosis. CONCLUSIONS: These experiments demonstrate a role for Galgt1 in skeletal muscle regeneration and suggest that complex gangliosides made by Galgt1 modulate the survival and differentiation of satellite cells. PMID- 25699170 TI - Primary Synovial Sarcoma (SS) of the digestive system: a molecular and clinicopathological study of fifteen cases. AB - BACKGROUND: Recently a few cases of synovial sarcoma (SS) of the abdominal viscera have been reported, raising awareness about the potential for confusion between this entity and KIT-negative gastrointestinal stromal tumors (GIST). We report the clinicopathological, immunophenotypical and molecular features of fifteen more SS occurring in the stomach (8 cases), epigastric region (one case), small intestine (one case), large intestine (three cases), involving both the terminal ileum and the caecum (one case) and liver (one case). METHODS: Immunostains for SMA, DESMIN, CD34, CD117, S100, EMA, CK AE1/3, TLE1, CD56, CD99, BCL2, DOG1 were performed. Rearrangement of SS18 gene region was screened in all cases: by conventional karyotype in one case, the remaining cases were screened either by interphase FISH or Q-PCR or both. RESULTS: Ten patients were male and five female, with an age range of 17-61 years (median 44). Tumor size ranged from 2 to 15 cm (median 8). Mitoses per 10 HPF ranged from 4 to 27 (median 9.5). Eleven tumors were monophasic fibrous SS, one biphasic SS and three poorly differentiated SS. SMA, Desmin, CD34, CD117 and S100 were negative in all cases, whereas EMA and/or CK AE1/AE3 were positive in all cases. TLE1, BCL2 and CD56 were positive in all tested cases. DOG1 was positive in one case. SS18 gene region rearrangement was demonstrated in all cases. A fusion transcript was amplified in eight cases: either SS18-SSX2 or SS18-SSX1 respectively in four cases each. CONCLUSIONS: SS is increasingly recognized at visceral sites. Molecular analyses play a key role when dealing with usual histotypes in unusual sites. Correct diagnosis is crucial for appropriate therapy. PMID- 25699171 TI - When is a vesicle not just a vesicle: mitochondrial spheroids and mitochondrial autophagosomes. PMID- 25699172 TI - Diagnosis and allergen immunotherapy treatment of polysensitised patients with respiratory allergy in Spain: an Allergists' Consensus. AB - BACKGROUND: Polysensitisation is common in patients with respiratory allergy in Spain. Selection of the best allergen immunotherapy (AIT) is difficult in polysensitised patients. The present study was designed to help allergists better identify relevant allergens in these patients and to improve the selection of AIT in Spain. METHODS: Sixty-two Spanish allergists answered a survey containing 88 items divided into four groups: 1) general approach to polysensitised subjects; 2) sensitisation profile involving mite, animal dander and moulds; 3) grass and olive pollen co-sensitisation, and 4) other pollen polysensitisation profile (weed and tree pollen). The Delphi method was used. RESULTS: A consensus was achieved for 83% of items (92%, 81%, 83% and 73% of the four groups analysed, respectively). Only polysensitised patients with clinical relevance should be considered polyallergic. A detailed medical history (clinical symptoms and medication) together with a profound knowledge of allergens present in the patient's environment are essential for diagnosis. Skin prick tests (SPTs) are not adequate to decide the clinical relevance of each allergen. Serum specific IgE against allergen sources adds value to SPT but molecular diagnosis, when possible, is strongly recommended, especially in pollen-allergic patients. Specific allergen challenge tests are difficult to perform and not recommended for daily practice. Regarding AIT composition, up to three allergens can be used in the same vaccine, but only related allergens may be mixed. In some cases more than one vaccine may be needed. CONCLUSION: Some criteria have been established to improve diagnosis and AIT prescription in polysensitised patients. PMID- 25699173 TI - The use of diagnostic coding in chiropractic practice. AB - BACKGROUND: Diagnostic coding has several potential benefits, including improving the feasibility of data collection for research and clinical audits and providing a common language to improve interdisciplinary collaboration. The primary aim of this study was to determine the views and perspectives of chiropractors about diagnostic coding and explore the use of it in a chiropractic setting. A secondary aim was to compare the diagnostic coding undertaken by chiropractors and an independent coder. METHOD: A codin exercise based on the International Classification of Primary Care version 2, PLUS extension (ICPC-2 PLUS) provided the 14 chiropractors with some experience in diagnostic coding, followed by an interview on the topic. The interviews were analysed thematically. The participating chiropractors and an independent coder applied ICPC-2 PLUS terms to the diagnoses of 10 patients. Then the level of agreement between the chiropractors and the coder was determined and Cohen's Kappa was used to determine the agreement beyond that expected by chance. RESULTS: From the interviews the three emerging themes were: 1) Advantages and disadvantages of using a clinical coding system in chiropractic practice, 2) ICPC-2 PLUS terminology issues for chiropractic practice and 3) Implementation of a coding system into chiropractic practice. The participating chiropractors did not uniformly support or condemn the idea of using diagnostic coding. However there was a strong agreement that the terminology in ICPC-2 PLUS would not be applicable or desirable for all practice types. In the coding exercise the chiropractors in total coded 202 diagnoses for 135 patients. The overall percentage agreement between the chiropractors and the coder was 52% (17% expected by chance) with a Kappa score of 0.4 (95% CI 0.3-0.7). Agreement was lower for more detailed coding (percentage agreement 35%; Kappa score of 0.3 (95% CI 0.2-0.5)). CONCLUSION: It appears that implementation of diagnostic coding would be possible in the majority of the chiropractic practices that participated in this study. However for those chiropractors who do not focus on symptoms in their approach to clinical care, it could be challenging to use the ICPC-2 PLUS coding system, since ICPC-2 PLUS is a symptom-based classification. PMID- 25699174 TI - Skin cancer in solid organ transplant recipients: are mTOR inhibitors a game changer? AB - While immunosuppressive agents are necessary to prevent the rejection of transplanted organs, and are a great medical success story for protecting against early allograft loss, graft and patient survival over the long term are diminished by side effects from these same drugs. One striking long-term side effect is a high rate of skin cancer development. The skin cancers that develop in transplant recipients tend to be numerous, as well as particularly aggressive, and are therefore a major contributor to morbidity and mortality in transplant recipients. An apparent reason for the high incidence of skin cancer likely relates to suppression of immune surveillance mechanisms, but other more direct effects of certain immunosuppressive drugs are also bound to contribute to cancers of UV-exposed skin. However, over the past few years, evidence has emerged to suggest that one class of immunosuppressants, mammalian target of rapamycin (mTOR) inhibitors, could potentially inhibit skin tumour formation through a number of mechanisms that are still being studied intensively today. Therefore, in light of the high skin cancer incidence in transplant recipients, it follows that clinical trials have been conducted to determine if mTOR inhibitors can significantly reduce these post-transplant skin malignancies. Here, the problem of post-transplant skin cancer will be briefly reviewed, along with the possible mechanisms contributing to this problem, followed by an overview of the relevant clinical trial results using mTOR inhibitors. PMID- 25699175 TI - Optical mapping in plant comparative genomics. AB - Optical mapping has been widely used to improve de novo plant genome assemblies, including rice, maize, Medicago, Amborella, tomato and wheat, with more genomes in the pipeline. Optical mapping provides long-range information of the genome and can more easily identify large structural variations. The ability of optical mapping to assay long single DNA molecules nicely complements short-read sequencing which is more suitable for the identification of small and short-range variants. Direct use of optical mapping to study population-level genetic diversity is currently limited to microbial strain typing and human diversity studies. Nonetheless, optical mapping shows great promise in the study of plant trait development, domestication and polyploid evolution. Here we review the current applications and future prospects of optical mapping in the field of plant comparative genomics. PMID- 25699177 TI - Sedation in non-invasive ventilation: do we know what to do (and why)? AB - This review examines some of the issues encountered in the use of sedation in patients receiving respiratory support from non-invasive ventilation (NIV). This is an area of critical and intensive care medicine where there are limited (if any) robust data to guide the development of best practice and where local custom appears to exert a strong influence on patterns of care. We examine aspects of sedation for NIV where the current lack of structure may be contributing to missed opportunities to improve standards of care and examine the existing sedative armamentarium. No single sedative agent is currently available that fulfils the criteria for an ideal agent but we offer some observations on the relative merits of different agents as they relate to considerations such as effects on respiratory drive and timing, and airways patency. The significance of agitation and delirium and the affective aspect(s) of dyspnoea are also considered. We outline an agenda for placing the use of sedation in NIV on a more systematic footing, including clearly expressed criteria and conditions for terminating NIV and structural and organizational conditions for prospective multicentre trials. PMID- 25699178 TI - Clinical efficacy and tolerability of an immune-stimulant(*) constituted by inactivated bacterial bodies in the prophylaxis of infectious episodes of airways: a double blind, placebo-controlled, randomized, multicentre study. AB - BACKGROUND: (Buccalin (r)) is a Bacterial Lysates (BL) that belongs to a family of immune-stimulators, developed more than 30 years ago and it still has a role in the prophylaxis of Recurrent Respiratory Tract Infections (RRTI). However, original studies were conducted with an approach that does not seem to be aligned with the present methodologies. In addition, concomitant therapies substantially improved in the last decades. These two reasons strongly suggested to update our knowledge on the capacity of this bacterial lysate (Buccalin (r)) to reduce the number of days with infectious episodes in patients with RRTI. METHODS: A double blind, placebo-controlled, randomized, multicentre study was programmed (EudraCT code: 2011-005187-25). The reduction of the number of days with infectious episodes (IE) was the primary endpoint. Secondary endpoints were the number of IE, the use of concomitant drugs, the efficacy on signs and symptoms of RRTI and the safety of the drug. Patients were treated according to the registered schedule and were followed up for a period of 6 months. RESULTS: From a cohort of 188 patients eligible for the study, 90 were included in the active group and 88 in the placebo group. The study was completed in 170 patients. A significant reduction of the number of days with IE was observed (6.57 days in the active group and 7.47 in the placebo group). Secondary endpoints were only partially achieved. No virtual adverse events related to the treatment were recorded. CONCLUSION: The administration of bacterial lysate (Buccalin (r)) in patients with RRTI had the capacity to significantly reduce the number of days with IE in a multicentre, randomized, placebo controlled, clinical study. The treatment was safe. Of note, all patients were free to be treated with the best concomitant therapies. In these conditions, the positive results observed demonstrated that this bacterial lysate has maintained its capacity of reducing the days with infections in patients with RRTI, also in association to the concomitant therapies available nowadays. PMID- 25699179 TI - Acute pneumonitis consequent on pleurodesis with Viscum album extract: severe chest images but benign clinical course. AB - Chemical pleurodesis is widely recommended in the treatment of pulmonary air leak of different etiologies as well as malignant pleural effusions and chylothorax. Conventional chemical pleurodesis using erythromycin, tetracycline, hydrophilic fumed silica, autologous blood and talc slurry has been standardized, and its complications, including high fever, intractable chest pain, and acute lung injury, seem to be frequent. Viscum album extract is a new chemical agent for pleurodesis, and only a few studies have reported outcomes of such chemical pleurodesis in the treatment of malignant pleural effusion. Moreover, the complications resulting from pleurodesis using Viscum album extract are very rare, and acute pneumonitis has not been reported. in this paper we report the first case of acute pneumonitis after pleurodesis using Viscum album extract in a 58-year-old man who had prolonged air leaks after a left upper lingularsegmentectomy for metastatic lung cancer. We performed repeated pleurodesis four times with 2 to 4 days intervals. While the patient had no symptoms of pneumonia, such as cough, sputum, chilling, and fatigue, a follow-up chest X-ray revealed increasing peribronchial consolidations and infiltrations in the left upper lobe. A chest tomography showed extensive parenchymal consolidations and ground-glass appearances in the left lungs, representing pneumonia with acute lung injury. The acute pneumonitis was spontaneously resolved with supportive care, and the patient was discharged ten days after the development of pneumonitis. We think that pleurodesis with Viscum album extract is effective, but repeated pleurodesis should be avoided for possible onset of acute pneumonitis. PMID- 25699180 TI - Health and social impacts of COPD and the problem of under-diagnosis. AB - This article deals with the prevalence and the possible reasons of COPD underestimation in the population and gives suggestions on how to overcome the obstacles and make the correct diagnosis in order to provide the patients with the appropriate therapy. COPD is diagnosed in later or very advanced stages. In Italy the rate of COPD under-diagnosis ranges between 25 and 50% and, as a consequence, the patient does not consult his doctor until the symptoms have worsened, mainly due to exacerbations. A missed diagnosis influences the timing of therapeutic intervention, thus contributing to the evolution into more severe stages of the illness. An incisive intervention to limit under-diagnosis cannot act only in remittance (passive diagnosis), but must be the promoter for a series of preventive actions: primary, secondary and rehabilitative. To reduce under diagnosis, some actions need to be taken, such as screening programs for smokers subjects, use of questionnaires aimed to qualify and monitor the disease severity, spirometry, early diagnosis. There is a consensus regarding diagnoses based on screening of at-risk subjects and symptoms, rather than screening of the general population. In practice, all individuals over 40 years of age with risk factors should make a spirometry test. Screening actions on a national scale can be the following: compilation of questionnaires in waiting rooms of doctor's offices or performing simple maneuvers to evaluate the expiratory force at pharmacies. It is now widely recognized that COPD is a complex syndrome with several pulmonary and extrapulmonary components; as a result, the airway obstruction as assessed by FEV1 by itself does not adequately describe the complexity of the disease and FEV1 cannot be used alone for the optimal diagnosis, assessment, and management of the disease. The identification and subsequent grouping of key elements of the COPD syndrome into clinically meaningful and useful subgroups (phenotypes) can guide therapy more effectively. In conclusion, we firmly believe that an early and correct diagnosis can influence positively the progress of the disease (lowering the lung function impairment), decrease the risk of exacerbations, relieve symptoms and increase the patients' quality of life leading also to a decrease in costs associated to the exacerbations and hospitalization of the patient. PMID- 25699181 TI - Pharmacologic rationale, efficacy and safety of the fixed-dose co-formulation of indacaterol and glycopyrronium. AB - Chronic obstructive pulmonary disease (COPD) is a widespread respiratory disorder, usually characterized by progressive and poorly reversible airflow limitation. Inhaled long-acting bronchodilators, namely LABA (long-acting beta2 adrenergic agonists) and LAMA (long-acting muscarinic receptor antagonists) are the mainstay of COPD treatment. Because the symptoms of many patients with COPD do not satisfactorily improve by using a single, either LABA or LAMA bronchodilator, the synergism of action resulting from the combination of the different bronchodilating mechanisms activated by LABA and LAMA, respectively, can significantly contribute to a better disease control. Based on these clinical and pharmacological considerations, several LABA/LAMA fixed-dose combinations have been developed and experimentally evaluated. Within such a context, the drug co-formulation containing indacaterol and glycopyrronium is probably the LABA/LAMA association which has been most extensively studied during the last few years. PMID- 25699182 TI - Acquired immunity and asymptomatic reservoir impact on frontline and airport ebola outbreak syndromic surveillance and response. AB - The number of surveillance networks for infectious disease diagnosis and response has been growing. In 2000, the World Health Organization (WHO) established the Global Outbreak Alert and Response Network, which has been endorsed by each of the 46 WHO African members since then. Yet, taming the dynamics and plague of the vicious Ebola virus disease (EVD) in African countries has been patchy and erratic due to inadequate surveillance and contact tracing, community defiance and resistance, a lack of detection and response systems, meager/weak knowledge and information on the disease, inadequacies in protective materials protocols, contact tracing nightmare and differing priorities at various levels of the public health system. Despite the widespread acceptance of syndromic surveillance (SS) systems, their ability to provide early warning alerts and notifications of outbreaks is still unverified. Information is often too limited for any outbreak, or emerging or otherwise unexpected disease, to be recognized at either the community or the national level. Indeed, little is known about the role and the interactions between the Ebola infection and exposure to other syndemics and the development of acquired immunity, asymptomatic reservoir, and Ebola seroconversion. Can lessons be learnt from smallpox, polio, and influenza immunity, and can immunization against these serve as a guide? In most endemic countries, community health centers and disease control and prevention at airports solely relies on passive routine immunization control and reactive syndromic response. The frontline and airport Ebola SS systems in West Africa have shown deficiencies in terms of responding with an alarming number of case fatalities, and suggest that more detailed insights into Ebola, and proactive actions, are needed. The quest for effective early indicators (EEE) in shifting the public and global health paradigm requires the development and implementation of a comprehensive and effective community or regional integrated pandemic preparedness and surveillance response systems tailored to local contexts. These systems must have mechanisms for early identification, rapid contact tracing and tracking, confirmation, and communication with the local population and the global community, and must endeavor to respond in a timely manner. PMID- 25699184 TI - Case report: paroxysmal cold hemoglobinuria presenting during pregnancy. AB - BACKGROUND: Paroxysmal cold hemoglobinuria is caused by a biphasic IgG autoantibody that triggers complement-mediated intravascular hemolysis. Paroxysmal cold hemoglobinuria has not previously been reported to occur in association with pregnancy. CASE PRESENTATION: We report a case of an 18 year old female who presented in early pregnancy with acute hemolytic anemia and a positive Donath-Landsteiner antibody test. She was diagnosed with paroxysmal cold hemoglobinuria and treated supportively. Her hemolysis resolved within 6 weeks. Because maternal IgG autoantibodies can cross the placenta, the patient was monitored closely throughout her pregnancy for recurrence. The outcome of the pregnancy was successful, with no evidence of neonatal anemia or hemolysis. CONCLUSION: This patient had a classic presentation of paroxysmal cold hemoglobinuria with rapid onset of hemolytic anemia that resolved spontaneously. To our knowledge, this is the first report of paroxysmal cold hemoglobinuria presenting during pregnancy. PMID- 25699185 TI - A parametric study on the decolorization and mineralization of C.I. Reactive Red 141 in water by heterogeneous Fenton-like oxidation over FeZSM-5 zeolite. AB - In this study, the heterogeneous Fenton-like degradation of Reactive Red 141 (RR141) in water was investigated over iron containing ZSM-5 zeolite (Si/Al = 42) prepared by ion-exchange (FeZSM-5 (42)). The catalyst was characterized by XRD, SEM, FTIR, TPR, and ICP-AES measurements. The effects of the initial concentrations of the dye and H2O2, the initial pH of the solution, catalyst loading, and the reaction temperature were investigated on heterogeneous Fenton like degradation of RR141. The reduction of the solution initial pH from ca. 7.0 to ca. 3.5 had a positive effect on color removal. A complete color removal was achieved with all the H2O2 concentrations in the range of 0.007 - 0.067 M over the FeZSM-5 (42) catalyst after 2 h of reaction. The COD reduction increased from 52% to 81% with an increase in the amount of the catalyst. The COD reduction was affected positively with the increase in temperature from 298 K through 313 K to 323 K and then to 333 K. The initial decolorization rate was described by the equation: -rA0 = 9.4*10(4) e(-38.8/RT) CRR141,0 CH2O2,0 (0.184) with an H2O2 concentration range of 0.007 M - 0.033 M (where R is in kJ/mol). PMID- 25699186 TI - Removal of crystal violet from water by magnetically modified activated carbon and nanomagnetic iron oxide. AB - Magnetically modified activated carbon, which synthesized by nanomagnetic iron oxide, was used for fast and effective removal of Crystal Violet from aqueous solutions. The scanning electron microscopy (SEM) images of nano-adsorbent showed that the average sizes of adsorbent are less than 100 nm. The various parameters, affecting on adsorption process, were examined including pH and temperature of dye solution, dose of adsorbent, and contact time. Then, thermodynamic parameters of sorption were calculated. Langmuir and Freundlich isotherms were used to fit the resulting data. Adsorption kinetics was consistent with a pseudo second order equation. Thermodynamic parameters of adsorption, ?H(0), and ?S(0) were calculated. Also, for further investigations, nano magnetic iron oxides was synthesized and used as adsorbent. Sorption capacities were depending on the temperature varied from 44.7 to 67.1 mg/g and from 12.7 to 16.5 mg/g for magnetically modified activated carbon and nanomagnetic iron oxide, respectively. PMID- 25699183 TI - Human Ebola virus infection in West Africa: a review of available therapeutic agents that target different steps of the life cycle of Ebola virus. AB - The recent outbreak of the human Zaire ebolavirus (EBOV) epidemic is spiraling out of control in West Africa. Human EBOV hemorrhagic fever has a case fatality rate of up to 90%. The EBOV is classified as a biosafety level 4 pathogen and is considered a category A agent of bioterrorism by Centers for Disease Control and Prevention, with no approved therapies and vaccines available for its treatment apart from supportive care. Although several promising therapeutic agents and vaccines against EBOV are undergoing the Phase I human trial, the current epidemic might be outpacing the speed at which drugs and vaccines can be produced. Like all viruses, the EBOV largely relies on host cell factors and physiological processes for its entry, replication, and egress. We have reviewed currently available therapeutic agents that have been shown to be effective in suppressing the proliferation of the EBOV in cell cultures or animal studies. Most of the therapeutic agents in this review are directed against non-mutable targets of the host, which is independent of viral mutation. These medications are approved by the Food and Drug Administration (FDA) for the treatment of other diseases. They are available and stockpileable for immediate use. They may also have a complementary role to those therapeutic agents under development that are directed against the mutable targets of the EBOV. PMID- 25699187 TI - Assessment of honking impact on traffic noise in urban traffic environment of Nagpur, India. AB - BACKGROUND: In context of increasing traffic noise in urban India, the objective of the research study is to assess noise due to heterogeneous traffic conditions and the impact of honking on it. METHOD: Traffic volume, noise levels, honking, road geometry and vehicular speed were measured on national highway, major and minor roads in Nagpur, India. RESULTS: Initial study showed lack of correlation between traffic volume and equivalent noise due to some factors, later identified as honking, road geometry and vehicular speed. Further, frequency analysis of traffic noise showed that honking contributed an additional 2 to 5 dB (A) noise, which is quite significant. Vehicular speed was also found to increase traffic noise. Statistical method of analysis of variance (ANOVA) confirms that frequent honking (p < 0.01) and vehicular speed (p < 0.05) have substantial impact on traffic noise apart from traffic volume and type of road. CONCLUSIONS: The study suggests that honking must also be a component in traffic noise assessment and to identify and monitor "No Honking" zones in urban agglomerations. PMID- 25699188 TI - Emotional labor and dysmenorrhea in women working in sales and call centers. AB - OBJECTIVES: This study was conducted to investigate the association between emotional labor and dysmenorrhea among women working in sales and call centers in Seoul, South Korea. METHODS: Working women in sales jobs and call centers in Seoul were interviewed face-to-face by well-trained interviewers. In total, 975 participants were analyzed in the final model. Emotional labor was measured using a constructed questionnaire with two components: an emotive effort component with three questions and an emotive dissonance component with five questions. To examine the association between emotional labor and dysmenorrhea, chi-squared tests and logistic regression were applied. RESULTS: The prevalence of dysmenorrhea among sales workers and call center workers were 43.0% and 61.1%, respectively. The adjusted odds ratios (OR) of emotive effort and emotive dissonance for dysmenorrhea in call center workers were 1.88 (95% confidence interval [CI], 1.07-3.28) and 1.72 (95% CI, 1.13-2.63), respectively. The adjusted OR of emotive effort and emotive dissonance for dysmenorrhea in sales workers were 1.71 (95% CI, 0.92-3.16) and 1.15 (95% CI, 0.67-1.98), respectively. CONCLUSIONS: Emotional labor was found to be associated with dysmenorrhea in call center workers. Further studies to investigate other factors, such as management strategies and the relationship between emotional labor and dysmenorrhea, are needed to support interventions to prevent dysmenorrhea that will further promote the quality of health and life of working women. PMID- 25699189 TI - Acute effect of cigarette smoking on pupil size and ocular aberrations: a pre- and postsmoking study. AB - Aim. To evaluate the acute effects of cigarette smoking on photopic and mesopic pupil sizes and wavefront aberrations. Methods. Cigarette smoker volunteers were recruited in the study. Photopic and mesopic pupil sizes and total ocular aberrations were measured before smoking and immediately after smoking. All volunteers were asked to smoke a single cigarette containing 1.0 mg nicotine. Pupil sizes and total ocular aberrations were assessed by optical path difference scanning system (OPD-Scan II ARK-10000, NIDEK). Only the right eyes were considered for statistical analysis. The changes of pupil size and total ocular aberrations after smoking were tested for significance by Wilcoxon signed ranks test. Results. Mean photopic pupil size decreased from 3.52 +/- 0.73 mm to 3.29 +/- 0.58 mm (P = 0.001) after smoking. Mean mesopic pupil size was also decreased from 6.42 +/- 0.75 mm to 6.14 +/- 0.75 mm after smoking (P = 0.001). There was a decrease in all the measured components of aberrations (total wavefront aberration, higher-order aberration, total coma, total trefoil, total tetrafoil, total spherical aberration and total higher-order aberration) after smoking; however the differences were insignificant for all (P > 0.05). Conclusion. Our results indicate that pupil constricts after smoking. On the other hand, smoking does not alter ocular aberrations. PMID- 25699190 TI - Dietary pattern and metabolic syndrome in thai adults. AB - Objectives. To determine the dietary patterns of middle-aged Thais and their association with metabolic syndrome (MetS). Methods. The Thai National Health Examination Survey IV data of 5,872 participants aged >=30-59 years were used. Dietary patterns were obtained by factor analysis and their associations with Mets were examined using multiple logistic regression. Results. Three major dietary patterns were identified. The first, meat pattern, was characterized by a high intake of red meat, processed meat, and fried food. The second, healthy pattern, equated to a high intake of beans, vegetables, wheat, and dairy products. The third, high carbohydrate pattern, had a high intake of glutinous rice, fermented fish, chili paste, and bamboo shoots. Respondents with a healthy pattern were more likely to be female, higher educated, and urban residents. The carbohydrate pattern was more common in the northeast and rural areas. Compared with the lowest quartile, the highest quartile of carbohydrate pattern was associated with MetS (adjusted odds ratio: 1.82; 95% CI 1.31, 2.55 in men and 1.60; 95% CI 1.24, 2.08 in women), particularly among those with a low level of leisure time physical activity (LTPA). Conclusion. The carbohydrate pattern with low level of LTPA increased the odds of MetS. PMID- 25699191 TI - Sativex in the management of multiple sclerosis-related spasticity: role of the corticospinal modulation. AB - Sativex is an emergent treatment option for spasticity in patients affected by multiple sclerosis (MS). This oromucosal spray, acting as a partial agonist at cannabinoid receptors, may modulate the balance between excitatory and inhibitory neurotransmitters, leading to muscle relaxation that is in turn responsible for spasticity improvement. Nevertheless, since the clinical assessment may not be sensitive enough to detect spasticity changes, other more objective tools should be tested to better define the real drug effect. The aim of our study was to investigate the role of Sativex in improving spasticity and related symptomatology in MS patients by means of an extensive neurophysiological assessment of sensory-motor circuits. To this end, 30 MS patients underwent a complete clinical and neurophysiological examination, including the following electrophysiological parameters: motor threshold, motor evoked potentials amplitude, intracortical excitability, sensory-motor integration, and Hmax/Mmax ratio. The same assessment was applied before and after one month of continuous treatment. Our data showed an increase of intracortical inhibition, a significant reduction of spinal excitability, and an improvement in spasticity and associated symptoms. Thus, we can speculate that Sativex could be effective in reducing spasticity by means of a double effect on intracortical and spinal excitability. PMID- 25699192 TI - A new case of prenatally diagnosed pentasomy x: review of the literature. AB - Pentasomy X is a rare chromosomal abnormality probably due to a nondisjunction during the meiosis. Only four cases prenatally diagnosed were described until now. Our case is the fifth one prenatally diagnosed at 20 weeks of gestational age in a 39-years-old woman. She underwent invasive prenatal diagnosis for her advanced maternal age without any other known risk factor. Amniocentesis performed at 17 weeks showed a female 49, XXXXX karyotype. The ultrasonographic examination revealed nonspecific signs of a mild early fetal growth retardation and no significant increased nuchal fold. The fetal autopsy and the X-ray excluded major malformations. Prenatal diagnosis is often difficult due to the lack of indicative ultrasonographic findings and the rarity of described cases. The influence of the mother's age on the occurrence of penta-X syndrome has not been determined. Considering the lack of correlation between advanced maternal age and increased risk for pentasomy X, as well as the absence of typical echographic signs, evaluation of the inclusion of a noninvasive prenatal test (NIPT) that expands clinical coverage to include the X and Y chromosomes in routine prenatal diagnosis should be considered as well as three-dimensional ultrasound to detect any helpful indicative prognostic signs. PMID- 25699193 TI - Delayed presentation of pharyngeal erosion after anterior cervical discectomy and fusion. AB - Dysphagia after anterior cervical discectomy and fusion (ACDF) is common, with a prevalence ranging between 28% and 57% of cases. However, nearly all cases resolve spontaneously within 2 years, thus identifying patients who require more detailed or invasive work-up is a challenging task for clinicians. A review of literature reveals a paucity of case reports detailing work-up and successful management options. The authors performed a clinical and radiographic review of a case of a 47-year-old female who presented with persistent dysphagia 3 years following anterior cervical spine surgery and was found to have an erosive pharyngeal defect with exposed spinal hardware. The diagnosis was made with direct laryngoscopy and treatment consisted of plate removal and pharyngeal repair, followed by revision fusion with deformity correction. This case and the accompanying pertinent review of the literature highlight the importance of a thorough evaluation of dysphagia, especially in the mid- and late-term postoperative period following ACDF, when most cases of dysphagia should have been resolved. Correctly identifying the underlying etiology of dysphagia may lead to improved revision of ACDF outcomes. Unresolved dysphagia should be a red flag for surgeons as it may be the presentation of erosive esophageal/pharyngeal damage, a rare but serious complication following ACDF. PMID- 25699194 TI - A bullet in the supraspinatus compartment successfully removed by arthroscopy: case report and review of the literature. AB - Arthroscopic removal of bullet from intra-articular compartment has been described for several joints. Only few reports dealing with this condition in the shoulder have been reported especially for the glenohumeral and the subacromial compartments. We report the story of a fifty-seven-year-old man presenting a bullet in the supraspinatus compartment of his left shoulder successfully removed by arthroscopy. PMID- 25699195 TI - Three cases of organized hematoma of the maxillary sinus: clinical features and immunohistological studies for vascular endothelial growth factor and vascular endothelial growth factor receptor 2 expressions. AB - Objectives. Organized hematoma (OH) is a rare, nonneoplastic, hemorrhagic lesion causing mucosal swelling and bone thinning, mainly in the maxillary sinus. We aimed to clarify the clinical presentation and treatment of OH. Methods. Three cases of maxillary sinus OH and a literature review are presented. Results. Three men aged 16-40 years complained of nasal obstruction, frequent epistaxis, and/or headache. Clinical and radiological examinations revealed a maxillary sinus OH. They were cured in a piecemeal fashion via endoscopic middle meatal antrostomy. Furthermore, vascular endothelial growth factor and its receptor were expressed in the lesion. Conclusions. The pathogenesis of OH is unclear and it presents various histological and imaging findings; however, it is not difficult to rule out malignant tumors. Minimally invasive surgery such as endoscopic sinus surgery can cure it completely. Thus, it is important to determine the diagnosis using CT and MRI and to quickly provide surgical treatment. PMID- 25699196 TI - A case of typhoid Fever with hepatic granulomas and enteritis. AB - The common histopathologic hepatic manifestations in patients infected with Salmonella include cloudy swelling and balloon degeneration with vacuolation of the hepatocytes and steatosis. Hepatic granulomas are a very rare finding, so far reported in very few cases. We report a 64-year-old patient with Salmonella enteritis who was found to have multiple 1.4 to 1.6 cm hypoechoic liver masses on ultrasound of the abdomen which on biopsy revealed hepatic granulomas. This case highlights the importance of keeping the differential diagnosis of Salmonella typhi (S. typhi) in mind in a patient with hepatic granulomas. PMID- 25699197 TI - Squamous cell carcinoma of kidney and its prognosis: a case report and review of the literature. AB - Primary squamous cell carcinoma of the renal parenchyma is an extremely rare entity. The diagnosis of squamous cell carcinoma of the renal pelvis is usually unsuspected due to the rarity and inconclusive clinical and radiological features. Most of the patients are diagnosed at an advanced stage and are with poor outcome. Radical nephrectomy is the mainstay of the treatment. We reported a case of squamous cell carcinoma of the kidney in a 50-year-old female who presented with the right sided abdomen pain. The patient was treated with radical nephrectomy. PMID- 25699198 TI - Perceptions of HIV Risk and Explanations of Sexual Risk Behavior Offered by Heterosexual Black Male Barbershop Patrons in Brooklyn, NY. AB - To describe HIV risk factors among adult heterosexual Black men recruited from four barbershops located in high HIV seroprevalent neighborhoods of Brooklyn, NY. Data on HIV-risk related behaviors and other characteristics were collected from barbershop clients. All participants (n=60) completed brief risk assessments; and a subset (n=22) also completed focus groups and/or individual interviews. Of the subset of 22 men, 68% were US born, 59% had been in jail/prison, 32% were unemployed; and during the 3 months before the interviews, 68% reported at least two partners and 45% reported unprotected vaginal or anal sex with two or more women. Emergent themes included: 1) the psychological function of multiple partnerships; 2) calculated risk taking regarding condom use; 3) the role of emotional attachment and partner trust in condom use; 4) low perceived HIV risk and community awareness; and 5) lack of relationship between HIV testing and safer sex practices. Interventions among heterosexual Black men should focus not only on increasing HIV awareness and reducing sexual risk, but also on contextual and interpersonal factors that influence sexual risk. PMID- 25699200 TI - Ultrastructural study of sperm cells in Acanthocolpidae: the case of Stephanostomum murielae and Stephanostomoides tenuis (Digenea). AB - The mature spermatozoa of Stephanostomum murielae and Stephanostomoides tenuis are described by transmission electron microscopy. They present several ultrastructural features previously reported in other digeneans. Their spermatozoa possess two axonemes of different length showing the 9 + '1' trepaxonematan pattern, four attachment zones, two mitochondria (with an anterior moniliform one in S. murielae), a nucleus, two bundles of parallel cortical microtubules, external ornamentation of the plasma membrane, spine-like bodies and granules of glycogen. The main differences between the mature spermatozoon of S. murielae and S. tenuis are the maximum number of cortical microtubules, the morphology of the anterior spermatozoon extremity and the anterior mitochondrion. This study is the first concerning members of the family Acanthocolpidae. The main ultrastructural characteristics discussed are the morphology of the anterior and posterior spermatozoon extremities, antero-lateral electron dense material, external ornamentations, spine-like bodies and number and morphology of mitochondria. In addition, the phylogenetic significance of all these ultrastructural features is discussed and compared to molecular results in order to highlight the complex relationships in the Digenea. PMID- 25699199 TI - Diversity and ecological structure of vibrios in benthic and pelagic habitats along a latitudinal gradient in the Southwest Atlantic Ocean. AB - We analyzed the diversity and population structure of the 775 Vibrio isolates from different locations of the southwestern Atlantic Ocean (SAO), including St. Peter and St. Paul Archipelago (SPSPA), Abrolhos Bank (AB) and the St. Sebastian region (SS), between 2005 and 2010. In this study, 195 novel isolates, obtained from seawater and major benthic organisms (rhodoliths and corals), were compared with a collection of 580 isolates previously characterized (available at www.taxvibrio.lncc.br). The isolates were distributed in 8 major habitat spectra according to AdaptML analysis on the basis of pyrH phylogenetic reconstruction and ecological information, such as isolation source (i.e., corals: Madracis decactis, Mussismilia braziliensis, M. hispida, Phyllogorgia dilatata, Scolymia wellsi; zoanthids: Palythoa caribaeorum, P. variabilis and Zoanthus solanderi; fireworm: Hermodice carunculata; rhodolith; water and sediment) and sampling site regions (SPSPA, AB and SS). Ecologically distinct groups were discerned through AdaptML, which finds phylogenetic groups that are significantly different in their spectra of habitat preferences. Some habitat spectra suggested ecological specialization, with habitat spectra 2, 3, and 4 corresponding to specialization on SPSPA, AB, and SS, respectively. This match between habitat and location may reflect a minor exchange of Vibrio populations between geographically isolated benthic systems. Moreover, we found several widespread Vibrio species predominantly from water column, and different populations of a single Vibrio species from H. carunculata in ecologically distinct groups (H-1 and H-8 respectively). On the other hand, AdaptML detected phylogenetic groups that are found in both the benthos and in open water. The ecological grouping observed suggests dispersal and connectivity between the benthic and pelagic systems in AB. This study is a first attempt to characterize the biogeographic distribution of vibrios in both seawater and several benthic hosts in the SAO. The benthopelagic coupling observed here stands out the importance of vibrios in the global ocean health. PMID- 25699201 TI - The effects of island forest restoration on open habitat specialists: the endangered weevil Hadramphus spinipennis Broun and its host-plant Aciphylla dieffenbachii Kirk. AB - Human alteration of islands has made restoration a key part of conservation management. As islands are restored to their original state, species interactions change and some populations may be impacted. In this study we examine the coxella weevil, (Hadramphus spinipennis Broun) and its host-plant Dieffenbach's speargrass (Aciphylla dieffenbachii Kirk), which are both open habitat specialists with populations on Mangere and Rangatira Islands, Chathams, New Zealand. Both of these islands were heavily impacted by the introduction of livestock; the majority of the forest was removed and the weevil populations declined due to the palatability of their host-plant to livestock. An intensive reforestation program was established on both islands over 50 years ago but the potential impacts of this restoration project on the already endangered H. spinipennis are poorly understood. We combined genetic and population data from 1995 and 2010-2011 to determine the health and status of these species on both islands. There was some genetic variation between the weevil populations on each island but little variation within the species as a whole. The interactions between the weevil and its host-plant populations appear to remain intact on Mangere, despite forest regeneration. A decline in weevils and host-plant on Rangatira does not appear to be caused by canopy regrowth. We recommend that (1) these populations be monitored for ongoing effects of long-term reforestation, (2) the cause of the decline on Rangatira be investigated, and (3) the two populations of weevils be conserved as separate evolutionarily significant units. PMID- 25699202 TI - The association between fluid balance and mortality in patients with ARDS was modified by serum potassium levels: a retrospective study. AB - Background and Objective. Acute respiratory distress syndrome (ARDS) is characterized by pulmonary edema and may benefit from conservative fluid management. However, conflicting results exist in the literature. The study aimed to investigate the association between mean fluid balance and mortality outcome in ARDS patients who required invasive mechanical ventilation. Methods. The study was a secondary analysis of a prospectively collected dataset obtained from the NHLBI Biologic Specimen and Data Repository Information Coordinating Center. ARDS patients with invasive mechanical ventilation were eligible. Demographic and laboratory data were extracted from the dataset. Multivariable regression model was built by stepwise selection of covariates. A fractional polynomial approach was used to test the linearity of mean fluid balance in the model. The potential interactions of mean fluid balance with other variables were tested. Main Results. A total of 282 patients were eligible for the analysis, including 61 non survivors with a mortality rate of 21.6%. After stepwise regression analysis, mean fluid balance remained to be an independent predictor of death (OR: 1.00057; 95% CI [1.00034-1.00080]). The two-term model obtained using fractional polynomial analysis was not superior to the linear model. There was significant interaction between mean fluid balance and serum potassium levels (p = 0.011). While the risk of death increased with increasing mean fluid balance at potassium levels of 1.9, 2.9 , 3.9 and 4.9 mmol/l, the risk decreased at potassium level of 5.9 mmol/l. Conclusion. The present study demonstrates that more positive fluid balance in the first 8 days is significantly associated with increased risk of death. However, the relationship between mean fluid balance and mortality can be modified by serum potassium levels. With hyperkalemia, more positive fluid balance is associated with reduced risk of death. PMID- 25699203 TI - Evidence from studies in rodents and in isolated adipocytes that agonists of the chemerin receptor CMKLR1 may be beneficial in the treatment of type 2 diabetes. AB - The literature is unclear on whether the adipokine chemerin has pro- or anti inflammatory properties or plays any role in the aetiology of type 2 diabetes or obesity. To address these questions, and in particular the potential of agonists or antagonists of the chemerin receptor CMKLR1 in the treatment of type 2 diabetes and obesity, we studied the metabolic phenotypes of both male and female, CMKLR1 knockout and heterozygote mice. We also investigated changes in plasma chemerin levels and chemerin gene mRNA content in adipose tissue in models of obesity and diabetes, and in response to fasting or administration of the insulin sensitizing drug rosiglitazone, which also has anti-inflammatory properties. The effects of murine chemerin and specific C-terminal peptides on glucose uptake in wild-type and CMKLR1 knockout adipocytes were investigated as a possible mechanism by which chemerin affects the blood glucose concentration. Both male and female CMKLR1 knockout and heterozygote mice displayed a mild tendency to obesity and impaired glucose homeostasis, but only when they were fed on a high-fat died, rather than a standard low-fat diet. Obesity and impaired glucose homeostasis did not occur concurrently, suggesting that obesity was not the sole cause of impaired glucose homeostasis. Picomolar concentrations of chemerin and its C15- and C19-terminal peptides stimulated glucose uptake in the presence of insulin by rat and mouse wild-type epididymal adipocytes, but not by murine CMKLR1 knockout adipocytes. The insulin concentration-response curve was shifted to the left in the presence of 40 pM chemerin or its C-15 terminal peptide. The plasma chemerin level was raised in diet-induced obesity and ob/ob but not db/db mice, and was reduced by fasting and, in ob/ob mice, by treatment with rosiglitazone. These findings suggest that an agonist of CMKLR1 is more likely than an antagonist to be of value in the treatment of type 2 diabetes and to have associated anti-obesity and anti-inflammatory activities. One mechanism by which an agonist of CMKLR1 might improve glucose homeostasis is by increasing insulin-stimulated glucose uptake by adipocytes. PMID- 25699204 TI - Amyloid domains in the cell nucleus controlled by nucleoskeletal protein lamin B1 reveal a new pathway of mercury neurotoxicity. AB - Mercury (Hg) is a bioaccumulating trace metal that globally circulates the atmosphere and waters in its elemental, inorganic and organic chemical forms. While Hg represents a notorious neurotoxicant, the underlying cellular pathways are insufficiently understood. We identify amyloid protein aggregation in the cell nucleus as a novel pathway of Hg-bio-interactions. By mass spectrometry of purified protein aggregates, a subset of spliceosomal components and nucleoskeletal protein lamin B1 were detected as constituent parts of an Hg induced nuclear aggregome network. The aggregome network was located by confocal imaging of amyloid-specific antibodies and dyes to amyloid cores within splicing speckles that additionally recruit components of the ubiquitin-proteasome system. Hg significantly enhances global proteasomal activity in the nucleus, suggesting that formation of amyloid speckles plays a role in maintenance of protein homeostasis. RNAi knock down showed that lamin B1 for its part regulates amyloid speckle formation and thus likewise participates in nuclear protein homeostasis. As the Hg-induced cascade of interactions between the nucleoskeleton and protein homeostasis reduces neuronal signalling, amyloid fibrillation in the cell nucleus is introduced as a feature of Hg-neurotoxicity that opens new avenues of future research. Similar to protein aggregation events in the cytoplasm that are controlled by the cytoskeleton, amyloid fibrillation of nuclear proteins may be driven by the nucleoskeleton. PMID- 25699205 TI - Requirements for data integration platforms in biomedical research networks: a reference model. AB - Biomedical research networks need to integrate research data among their members and with external partners. To support such data sharing activities, an adequate information technology infrastructure is necessary. To facilitate the establishment of such an infrastructure, we developed a reference model for the requirements. The reference model consists of five reference goals and 15 reference requirements. Using the Unified Modeling Language, the goals and requirements are set into relation to each other. In addition, all goals and requirements are described textually in tables. This reference model can be used by research networks as a basis for a resource efficient acquisition of their project specific requirements. Furthermore, a concrete instance of the reference model is described for a research network on liver cancer. The reference model is transferred into a requirements model of the specific network. Based on this concrete requirements model, a service-oriented information technology architecture is derived and also described in this paper. PMID- 25699206 TI - Pronounced and prevalent intersexuality does not impede the 'Demon Shrimp' invasion. AB - Crustacean intersexuality is widespread and often linked to infection by sex distorting parasites. However, unlike vertebrate intersexuality, its association with sexual dysfunction is unclear and remains a matter of debate. The 'Demon Shrimp,' Dikerogammarus haemobaphes, an amphipod that has invaded continental waterways, has recently become widespread in Britain. Intersexuality has been noted in D. haemobaphes but not investigated further. We hypothesise that a successful invasive population should not display a high prevalence of intersexuality if this condition represents a truly dysfunctional phenotype. In addition, experiments have indicated that particular parasite burdens in amphipods may facilitate invasions. The rapid and ongoing invasion of British waterways represents an opportunity to determine whether these hypotheses are consistent with field observations. This study investigates the parasites and sexual phenotypes of D. haemobaphes in British waterways, characterising parasite burdens using molecular screening, and makes comparisons with the threatened Gammarus pulex natives. We reveal that invasive and native populations have distinct parasitic profiles, suggesting the loss of G. pulex may have parasite mediated eco-system impacts. Furthermore, the parasite burdens are consistent with those previously proposed to facilitate biological invasions. Our study also indicates that while no intersexuality occurs in the native G. pulex, approximately 50% of D. haemobaphes males present pronounced intersexuality associated with infection by the microsporidian Dictyocoela berillonum. This unambiguously successful invasive population presents, to our knowledge, the highest reported prevalence of male intersexuality. This is the clearest evidence to date that such intersexuality does not represent a form of debilitating sexual dysfunction that negatively impacts amphipod populations. PMID- 25699207 TI - Weight-length relationships and Fulton's condition factors of skipjack tuna (Katsuwonus pelamis) in the western and central Pacific Ocean. AB - This paper describes the weight-length relationships (WLRs) and Fulton's condition factors (K) of skipjack tuna (Katsuwonus pelamis) in purse seine fisheries from three cruises in the western and central Pacific Ocean (WCPO): August-September 2009 (AS09), November-December 2012 (ND12), and June-July 2013 (JJ13). The fork length and weight of a total of 1678 specimens were measured. The results showed that the fork length of more than 70% of specimens was below 60 cm (76% in AS09, 87% in ND12, and 73% in JJ13). The coefficient b in the combined sex group was 3.367, 3.300 and 3.234 in JJ13, AS09 and ND12, respectively. The b values of WLRs when fork length was >60 cm were significantly less than 3 (P = 0.062), but when fork length was <60 cm they were significantly greater than 3 (P = 0.028). The K value ranges of JJ13, AS09 and ND12 in different fork length groups were 1.3-1.84 (1.62 +/- 0.18), 1.57-2.02 (1.86 +/- 0.15), and 1.44-1.78 (0.65 +/- 0.13), respectively. Moreover, K values in different fork length classes for each cruise had one turning point: 60-65 cm for JJ13; 60-65 cm for ND12; and 55-60 cm for AS09. The results of this study provide basic information on the WLRs and K values of skipjack tuna in different seasons and growth phases in the WCPO, which are useful for fishery biologists and fishery managers. PMID- 25699208 TI - The monophyly of Susisuchidae (Crocodyliformes) and its phylogenetic placement in Neosuchia. AB - Eusuchian crocodyliforms, which include all living crocodylians, have historically been characterized by two anatomical specializations: a ball-in socket vertebral joint and an extensive secondary hard palate with a pterygoid bound internal choana. The Early Cretaceous neosuchian clade Susisuchidae is typically regarded as phylogenetically near Eusuchia. The putative susisuchid Isisfordia duncani was initially described as a transitional form exhibiting incipient versions of these eusuchian traits. Here we examine aspects of the morphology of Isisfordia and comment on the morphology of its putative sister taxon Susisuchus. Our reexamination supports the notion of Isisfordia possessing transitional vertebral morphology but we present a new interpretation of its palate construction that shows it to be more plesiomorphic than previously thought. The secondary choana of Isisfordia is not pterygoid bound. Instead, long palatines expand distally lapping under the pterygoid to form the anterior border of the choana as is common among many advanced neosuchians. Incorporation of these observations into an expanded phylogenetic dataset of neosuchian crocodyliforms results in a new phylogenetic hypothesis for Susisuchidae. Isisfordia and Susisuchus form a monophyletic Susisuchidae that sits near the base of Neosuchia, and is not the sister taxon of Eusuchia. PMID- 25699209 TI - Testing the influence of environmental heterogeneity on fish species richness in two biogeographic provinces. AB - Environmental homogenization in coastal ecosystems impacted by human activities may be an important factor explaining the observed decline in fish species richness. We used fish community data (>200 species) from extensive surveys conducted in two biogeographic provinces (extent >1,000 km) in North America to quantify the relationship between fish species richness and local (grain <10 km(2)) environmental heterogeneity. Our analyses are based on samples collected at nearly 800 stations over a period of five years. We demonstrate that fish species richness in coastal ecosystems is associated locally with the spatial heterogeneity of environmental variables but not with their magnitude. The observed effect of heterogeneity on species richness was substantially greater than that generated by simulations from a random placement model of community assembly, indicating that the observed relationship is unlikely to arise from veil or sampling effects. Our results suggest that restoring or actively protecting areas of high habitat heterogeneity may be of great importance for slowing current trends of decreasing biodiversity in coastal ecosystems. PMID- 25699210 TI - Nephila clavata L Koch, the Joro Spider of East Asia, newly recorded from North America (Araneae: Nephilidae). AB - Nephila clavata L Koch, known as the Joro spider and native to East Asia (Japan, China, Korea, and Taiwan), is newly reported from North America. Specimens from several locations in northeast Georgia were collected from around residential properties in Barrow, Jackson, and Madison counties in late October and early November 2014. These are the first confirmed records of the species in the New World. Our collections, along with confirmed images provided by private citizens, suggest that the Joro spider is established in northeast Georgia. Genomic sequence data for the COI gene obtained from two specimens conforms to published sequences for N. clavata, providing additional confirmation of species identity. Known collection records are listed and mapped using geocoding. Our observations are summarized along with published background information on biology in Asia and we hypothesize on the invasion history and mode of introduction into North America. Recognition features are given and photographic images of the male and female are provided to aid in their differentiation from the one native species of the genus (Nephila clavipes) in North America. PMID- 25699211 TI - Effects of statins on TH1 modulating cytokines in human subjects. AB - Background. Activation of the innate immune system by cholesterol accelerates atherosclerosis. High levels or modified forms of cholesterol stimulate release of the inflammatory cytokines IL-12 and IL-18 that synergistically stimulate T lymphocytes to produce the atherogenic cytokine interferon-gamma. While activation of the innate immune system by cholesterol is well-described in animal models and human subjects with high cholesterol levels or known atherosclerotic disease, the interaction of cholesterol and lipoproteins with the innate immune system in human subjects without known atherosclerosis is less well-described. The goal of our study was to assess the TH1 modulating cytokines IL-12 p40 and IL 18, and their counter regulatory cytokines IL-18 binding protein and IL-27, to determine if their levels are linked to cholesterol levels or other factors. Methods. We performed a blinded, randomized hypothesis-generating study in human subjects without known atherosclerotic disease. We measured serum lipids, lipoprotein levels, and collected plasma samples at baseline. Subjects were randomized to two weeks of therapy with atorvastatin, pravastatin, or rosuvastatin. Lipids and cytokine levels were measured after two weeks of statin treatment. Subjects were given a four-week statin-free period. At the end of the four-week statin-free period, venous blood was sampled again to determine if serum lipids returned to within 5% of their pre-statin levels. When lipid levels returned to baseline, subjects were again treated with the next statin in the randomization scheme. IL-12, IL-18, IL-18 binding protein, and IL-27 were measured at baseline and after each statin treatment to determine effects of statin treatment on their blood levels, and identify correlations with lipids and lipoproteins. Results. Therapy with statins revealed no significant change in the levels of IL-12, IL-18, IL-18 binding protein or IL-27 levels. We found that IL 18 levels positively correlate with total cholesterol levels (r (2) = 0.15, p < 0.03), but not HDL or LDL cholesterol. In contrast, IL-12 p40 levels inversely correlated with total cholesterol (r (2) = -0.17, p < 0.008), HDL cholesterol (r (2) = -0.22, p < 0.002), and apolipoprotein A1 (r (2) = -0.21, p < 0.002). Similarly, IL-18 binding protein levels inversely correlated with apolipoprotein A1 levels (r (2) = -0.13, p < 0.02). Conclusions. Our findings suggest that total cholesterol levels positively regulate IL-18, while HDL cholesterol and apolipoprotein A1 may reduce IL-12 p40 and IL-18 binding protein levels. Additional studies in a larger patient population are needed to confirm these findings, and verify mechanistically whether HDL cholesterol can directly suppress IL-12 p40 and IL-18 binding protein levels in human subjects. PMID- 25699212 TI - Mineral derivatives in alleviating oral mucositis during cancer therapy: a systematic review. AB - Objectives. Oral mucositis (mouth ulcers) is a cancer therapy side effect. Costly treatment interventions are often neglected in favor of cost-effective agents. This review assessed the general efficacy of mineral derivatives (a cost effective agent) in alleviating oral mucositis (OM) during cancer therapy compared to the standard care, or placebo-including a decision tree to aide healthcare workers. Data Sources. Electronic searches of MEDLINE via OVID, EMBASE, CENTRAL, CANCERLIT via PubMed, and CINAHL via EBSCO (year 2000 to 11 September 2014) were undertaken for randomised controlled trials. A meta-search strategy extracted content from aggregate online databases. Review Methods. Randomized controlled trials were assessed (participants, intervention, outcome, results, and risk of bias) for inclusion. The author abstracted binary and continuous data synthesised to Hedges' g in a random effects model. The primary outcome measures were severity (incidence of peak oral mucositis, duration of oral mucositis, and time to onset); secondary outcome measures were the incidence of pain, and analgesic use. Serum mineral levels, total parenteral nutrition, and adverse events were discussed. The decision tree was mapped using sensitivity, specificity, pre-test and post-test Bayesian probability. Results. 1027 citations were identified and 16 studies were included (n = 1120; mean age 49 years). Cancer therapies consisted of chemotherapy, radiotherapy, chemo-radiotherapy, or hematopoietic stem cell transplantation. Outcome mineral derivatives were zinc (n = 549), calcium phosphate (n = 227), povidone-iodine (n = 228), or selenium (n = 116). Severity was measured across variable OM grading systems: In 13 studies, individuals in treatment groups (n = 958) experienced peak OM less than controls (g = -0.47, 95% CI -0.7 to -0.2, p = 0.0006); time to OM onset was significantly delayed in treatment than controls (g = -0.51, 95% CI-0.8 to -0.2, p = 0.0002; five studies); OM mean duration, pain incidences, or analgesics use was not significant. The decision analysis favored selenium. Conclusion. The general positive effect trend suggests individuals taking mineral derivatives during cancer therapies are less likely to experience peak OM than those without. However, significant bias and heterogeneity indicates the need for developing further methods in account of diverse protocols and include novel recordings (serum mineral levels and cell signals) in estimating a uniform true effect. PMID- 25699213 TI - Nurturing 21st century physician knowledge, skills and attitudes with medical home innovations: the Wright Center for Graduate Medical Education teaching health center curriculum experience. AB - Purpose. The effect of patient centered medical home (PCMH) curriculum interventions on residents' self-reported and demonstrated knowledge, skills and attitudes in PCMH competency arenas (KSA) is lacking in the literature. This study aimed to assess the impact of PCMH curricular innovations on the KSA of Internal Medicine residents. Methods. Twenty four (24) Internal Medicine residents-12 Traditional (TR) track residents and 12 Teaching Health Center (THC) track residents-began training in Academic Year (AY) 2011 at the Wright Center for Graduate Medical Education (WCGME). They were followed through AY2013, covering three years of training. PCMH curricular innovations were focally applied July 2011 until May 2012 to THC residents. These curricular innovations were spread program-wide in May 2012. Semi-annual, validated PCMH Clinician Assessments assessing KSA were started in AY2011 and were completed by all residents. Results. Mean KSA scores of TR residents were similar to those of THC residents at baseline for all PCMH competencies. In May 2012, mean scores of THC residents were significantly higher than TR residents for most KSA. After program wide implementation of PCMH innovations, mean scores of TR residents for all KSA improved and most became equalized to those of THC residents. Globally improved KSA scores of THC and TR residents were maintained through May 2014, with the majority of improvements above baseline and reaching statistical significance. Conclusions. PCMH curricular innovations inspired by Health Resources and Services Administration (HRSA's) Teaching Health Center funded residency program expansion quickly and consistently improved the KSA of Internal Medicine residents. PMID- 25699214 TI - A meta-analysis of plant facilitation in coastal dune systems: responses, regions, and research gaps. AB - Empirical studies in salt marshes, arid, and alpine systems support the hypothesis that facilitation between plants is an important ecological process in severe or 'stressful' environments. Coastal dunes are both abiotically stressful and frequently disturbed systems. Facilitation has been documented, but the evidence to date has not been synthesized. We did a systematic review with meta analysis to highlight general research gaps in the study of plant interactions in coastal dunes and examine if regional and local factors influence the magnitude of facilitation in these systems. The 32 studies included in the systematic review were done in coastal dunes located in 13 countries around the world but the majority was in the temperate zone (63%). Most of the studies adopt only an observational approach to make inferences about facilitative interactions, whereas only 28% of the studies used both observational and experimental approaches. Among the factors we tested, only geographic region mediates the occurrence of facilitation more broadly in coastal dune systems. The presence of a neighbor positively influenced growth and survival in the tropics, whereas in temperate and subartic regions the effect was neutral for both response variables. We found no evidence that climatic and local factors, such as life form and life stage of interacting plants, affect the magnitude of facilitation in coastal dunes. Overall, conclusions about plant facilitation in coastal dunes depend on the response variable measured and, more broadly, on the geographic region examined. However, the high variability and the limited number of studies, especially in tropical region, indicate we need to be cautious in the generalization of the conclusions. Anyway, coastal dunes provide an important means to explore topical issues in facilitation research including context dependency, local versus regional drivers of community structure, and the importance of gradients in shaping the outcome of net interactions. PMID- 25699215 TI - The impact of stress on financial decision-making varies as a function of depression and anxiety symptoms. AB - Stress can precipitate the onset of mood and anxiety disorders. This may occur, at least in part, via a modulatory effect of stress on decision-making. Some individuals are, however, more resilient to the effects of stress than others. The mechanisms underlying such vulnerability differences are nevertheless unknown. In this study we attempted to begin quantifying individual differences in vulnerability by exploring the effect of experimentally induced stress on decision-making. The threat of unpredictable shock was used to induce stress in healthy volunteers (N = 47) using a within-subjects, within-session design, and its impact on a financial decision-making task (the Iowa Gambling Task) was assessed alongside anxious and depressive symptomatology. As expected, participants learned to select advantageous decks and avoid disadvantageous decks. Importantly, we found that stress provoked a pattern of harm-avoidant behaviour (decreased selection of disadvantageous decks) in individuals with low levels of trait anxiety. By contrast, individuals with high trait anxiety demonstrated the opposite pattern: stress-induced risk-seeking (increased selection of disadvantageous decks). These contrasting influences of stress depending on mood and anxiety symptoms might provide insight into vulnerability to common mental illness. In particular, we speculate that those who adopt a more harm-avoidant strategy may be better able to regulate their exposure to further environmental stress, reducing their susceptibility to mood and anxiety disorders. PMID- 25699216 TI - Development and characterization of 47 novel microsatellite markers for Vellozia squamata (Velloziaceae). AB - * PREMISE OF THE STUDY: We developed and validated microsatellite primers for Vellozia squamata (Velloziaceae), an endemic species of the cerrado (Brazilian savannas), to investigate the influence of different fire regimes on its genetic diversity and population structure. * METHODS AND RESULTS: Using a selective hybridization method, we tested 51 SSR loci using a natural population of V. squamata and obtained 47 amplifiable loci. Among these, 26 loci were polymorphic and the average values of genetic diversity were: average number of alleles per locus ([Formula: see text]) = 6.54, average number of alleles per polymorphic locus ([Formula: see text]) = 7.13, average observed heterozygosity [Formula: see text] = 0.22, average expected heterozygosity [Formula: see text] = 0.49, and average fixation index [Formula: see text] = 0.55. * CONCLUSIONS: These 26 loci allowed us to assess the effects of distinct fire regimes on the genetic structure of V. squamata populations with the aim of establishing strategies for the conservation of this endemic species. The markers can also be useful for future pharmaceutical studies, as the species has great potential for medicinal and cosmetic applications. PMID- 25699217 TI - MatrixConverter: Facilitating construction of phenomic character matrices. AB - * PREMISE OF THE STUDY: While numerous software packages enable scientists to evaluate molecular data and transform them for phylogenetic analyses, few such tools exist for phenomic data. We introduce MatrixConverter, a program that helps expedite and facilitate the transformation of raw phenomic character data into discrete character matrices that can be used in most evolutionary inference programs. * METHODS AND RESULTS: MatrixConverter is an open source program written in Java; a platform-independent binary executable, as well as sample data sets and a user's manual, are available at https://github.com/gburleigh/MatrixConverter/tree/master/distribution. MatrixConverter has a simple, intuitive user interface that enables the user to immediately begin scoring phenomic characters. We demonstrate the performance of MatrixConverter on a phenomic data set from cycads. * CONCLUSIONS: New technologies and software make it possible to obtain phenomic data from species across the tree of life, and MatrixConverter helps to transform these new data for evolutionary or ecological inference. PMID- 25699218 TI - Development and characterization of microsatellite loci for the pseudometallophyte Commelina communis (Commelinaceae). AB - * PREMISE OF THE STUDY: Microsatellite primers were developed for the pseudometallophyte Commelina communis (Commelinaceae), an important pioneer plant for phytoremediation of copper-contaminated soil. Two wild populations collected from metalliferous and nonmetalliferous sites were used to assess the polymorphism at each locus. * METHODS AND RESULTS: Based on the Fast Isolation by AFLP of Sequences COntaining repeats (FIASCO) method, a total of 34 pairs of simple sequence repeat (SSR) markers were designed. When 40 specimens from two populations were screened, 12 microsatellite loci were found to be highly polymorphic. The number of alleles per locus ranged from one to 11 and the observed and expected heterozygosity per locus ranged from 0.000 to 1.000 and from 0.195 to 0.941, respectively. * CONCLUSIONS: These markers will be useful for examining genetic diversity, population structure, and gene flow in populations of C. communis under different edaphic conditions and guiding sustainable management plans for phytoremediation. PMID- 25699219 TI - Isolation and characterization of 22 EST-SSR markers for the genus Thujopsis (Cupressaceae). AB - * PREMISE OF THE STUDY: Expressed sequence tag-simple sequence repeat (EST-SSR) markers were developed from Thujopsis dolabrata var. hondae (Cupressaceae) using Illumina sequencing to investigate the genetic diversity and population structure of the genus Thujopsis. * METHODS AND RESULTS: Twenty-two primer pairs were developed from ESTs of T. dolabrata var. hondae. The primers amplified di- and trinucleotide repeat-containing sequences. Polymorphisms were assessed in 81 individuals from two T. dolabrata var. hondae populations and one T. dolabrata population. The number of alleles ranged from one to 17 per locus. The observed and expected heterozygosities ranged from 0.000 to 1.000 and from 0.000 to 0.926, respectively. * CONCLUSIONS: These new EST-SSR markers will be useful in analyses of the genetic diversity and population structure of the genus Thujopsis. PMID- 25699220 TI - Development and characterization of microsatellite markers for Piptadenia gonoacantha (Fabaceae). AB - * PREMISE OF THE STUDY: Microsatellite primers were designed for Piptadenia gonoacantha (Fabaceae) and characterized to estimate genetic diversity parameters. The species is a native tree from the Atlantic Forest biome commonly used in forest restoration; it has medicinal potential and the wood is economically useful. * METHODS AND RESULTS: Twenty-eight microsatellite loci were identified from an enriched genomic library. Fifteen loci resulted in successful amplifications and were characterized in a natural population of 94 individuals. Twelve loci were polymorphic, with allele numbers ranging from three to 15 per locus, and expected and observed heterozygosities ranging from 0.2142 to 0.8325 and 0.190 to 0.769, respectively. * CONCLUSIONS: The developed markers will be used in further studies of population genetics of P. gonoacantha, aimed at conservation and management of the species in natural populations and in forest restoration projects. PMID- 25699221 TI - Transcriptome sequencing and marker development for four underutilized legumes. AB - * PREMISE OF THE STUDY: Combating threats to food and nutrition security in the context of climate change and global population increase is one of the highest priorities of major international organizations. Hundreds of species are grown on a small scale in some of the most drought/flood-prone regions of the world and as such may harbor some of the most environmentally tolerant crops (and alleles). * METHODS AND RESULTS: In this study, transcriptomes were sequenced, assembled, and annotated for four underutilized legume crops. Microsatellite markers were identified in each species, as well as a conserved orthologous set of markers for cross-family phylogenetics and comparative mapping, which were ground-truthed on a panel of diverse legume germplasm. * CONCLUSIONS: An understanding of these underutilized legumes will inform crop selection and breeding by allowing the investigation of genetic variation and the genetic basis of adaptive traits to be established. PMID- 25699222 TI - Microsatellite marker development for the coastal dune shrub Prunus maritima (Rosaceae). AB - * PREMISE OF THE STUDY: Microsatellite primers were developed in the beach plum, Prunus maritima, to investigate the genetic composition of remaining populations in need of conservation and, in future studies, to determine its relation to P. maritima var. gravesii. * METHODS AND RESULTS: Fourteen primer pairs were identified and tested in four populations throughout the species' geographic range. Of these 14 loci, 12 were shown to be polymorphic among a total of 60 P. maritima individuals sampled (15 individuals sampled from four populations). Among the polymorphic loci, the number of alleles ranged from two to 10 and observed heterozygosity of loci ranged from 0.07 to 0.93 among specimens tested. * CONCLUSIONS: These microsatellites will be useful in evaluating the population genetic composition of P. maritima and in developing approaches for further conservation and management of this species within the endangered coastal dune ecosystem of the northeastern United States. PMID- 25699223 TI - Quantitative Assessment of Single-Image Super-Resolution in Myocardial Scar Imaging. AB - Single-image super resolution is a process of obtaining a high-resolution image from a set of low-resolution observations by signal processing. While super resolution has been demonstrated to improve image quality in scaled down images in the image domain, its effects on the Fourier-based image acquisition technique, such as MRI, remains unknown.We performed high-resolution ex vivo late gadolinium enhancement (LGE) magnetic resonance imaging (0.4 * 0.4 * 0.4 mm3) in postinfarction swine hearts (n = 24). The swine hearts were divided into the training set (n = 14) and the test set (n = 10), and in all hearts, low resolution images were simulated from the high-resolution images. In the training set, super-resolution dictionaries with pairs of small matching patches of the high- and low-resolution images were created. In the test set, super resolution recovered high-resolution images from low-resolution images using the dictionaries. The same algorithm was also applied to patient LGE (n = 4) to assess its effects. Compared with interpolated images, super resolution significantly improved basic image quality indices (P < 0.001). Super resolution using Fourier-based zero padding achieved the best image quality. However, the magnitude of improvement was small in images with zero padding. Super resolution substantially improved the spatial resolution of the patient LGE images by sharpening the edges of the heart and the scar. In conclusion, single-image super resolution significantly improves image errors. However, the magnitude of improvement was relatively small in images with Fourier-based zero padding. These findings provide evidence to support its potential use in myocardial scar imaging. PMID- 25699224 TI - Systemic mistakes in hand hygiene practice in Ukraine: detection, consequences and ways of elimination. AB - AIM: Every year, millions of people around the world suffer from different infectious diseases, considerable part of which are hospital-acquired infections. WHO considers hand hygiene as a priority measure aimed to reduce the level of infection. We evaluated various aspects related to the situational behavior and prioritization regarding hand hygiene measures among the healthcare workers of Ukraine. METHOD: Identification of system mistakes in hand hygiene was carried out first of all by direct and indirect observation of the activities of medical and pharmaceutical personnel in their everyday practice as well as during their participation in trainings on routine hand hygiene. Questionnaires also were used to estimate the level of hand hygiene compliance of participants of the study. During this period 112 training courses, 315 master-classes and presentations on proper hand hygiene were realized. The target audience included health care workers of medical centers, clinics, maternity hospitals, health care organizations and staff of pharmacies and pharmaceutical manufacturing enterprises in all regions of Ukraine. 638 respondents took part in anonymous survey on hand hygiene practice. RESULTS: The most common mistakes were to regard hand washing and hand disinfection equally, to wash hands before doing a hand disinfection, to neglect the five moments for hand hygiene and to ignore hand hygiene before and after wearing protective gloves. Practitioners, medical attendants, pharmacy and pharmaceutical industry workers highlighted the need for practical and understandable instructions of various hand hygiene procedures, including the clarification of the possible technical mistakes. This became a ground for us to create individual master classes on hand hygiene for each cluster of healthcare workers. CONCLUSIONS: Changing hand hygiene behavior and attitude is possible by beginning to observe clinical practice and by involving healthcare workers in teaching and training. PMID- 25699225 TI - Bacterial etiology and antibiotic susceptibility pattern of diabetic foot infections in Tabriz, Iran. AB - AIM: The aim of this study was to investigate anaerobic and aerobic bacteria profile and determination of antibiotic susceptibility pattern in aerobic bacteria. METHOD: Specimens were cultured using optimal aerobic and anaerobic microbiological techniques. Identification of bacterial isolates was performed by standard microbiological methods and antibiotic susceptibility testing was performed according to the guidelines of Clinical and Laboratory Standards Institute (CLSI). RESULT: 92 bacterial strains were isolated from 60 samples of diabetic foot ulcers. Predominant aerobic bacteria isolated from these infections were S. aureus (28%) followed by Enterobacteriaceae family (24%) including Escherichia coli (15%), Citrobacter spp. (4%), Enterobacter spp. (4%), and coagulase-negative Staphylococcus spp. (17%), Enterococcus spp. (15%), Pseudomonas aeruginosa (7%) and Acinetobacter spp. (4%). No Clostridium spp. were isolated and 4% Bacteroides fragilis obtained from anaerobic culture. All Gram positive isolates were susceptible to linezolid while all Enterobacteriaceae showed sensitivity to imipenem. CONCLUSION: Most of DFIs specimens were poly microbial infection and predominant bacteria were S. aureus and B. fragilis. These wounds may require use of combined antimicrobial therapy for initial management. PMID- 25699226 TI - Microbial contamination of mobile phones in a health care setting in Alexandria, Egypt. AB - AIM: This study aimed at investigating the microbial contamination of mobile phones in a hospital setting. METHODS: Swab samples were collected from 40 mobile phones of patients and health care workers at the Alexandria University Students' Hospital. They were tested for their bacterial contamination at the microbiology laboratory of the High Institute of Public Health. Quantification of bacteria was performed using both surface spread and pour plate methods. Isolated bacterial agents were identified using standard microbiological methods. Methicillin resistant Staphylococcus aureus was identified by disk diffusion method described by Bauer and Kirby. Isolated Gram-negative bacilli were tested for being extended spectrum beta lactamase producers using the double disk diffusion method according to the Clinical and Laboratory Standards Institute recommendations. RESULTS: All of the tested mobile phones (100%) were contaminated with either single or mixed bacterial agents. The most prevalent bacterial contaminants were methicillin-resistant S. aureus and coagulase-negative staphylococci representing 53% and 50%, respectively. The mean bacterial count was 357 CFU/ml, while the median was 13 CFU/ml using the pour plate method. The corresponding figures were 2,192 and 1,720 organisms/phone using the surface spread method. CONCLUSIONS: Mobile phones usage in hospital settings poses a risk of transmission of a variety of bacterial agents including multidrug-resistant pathogens as methicillin-resistant S. aureus. The surface spread method is an easy and useful tool for detection and estimation of bacterial contamination of mobile phones. PMID- 25699227 TI - Lesser-known or hidden reservoirs of infection and implications for adequate prevention strategies: Where to look and what to look for. AB - In developing hygiene strategies, in recent years, the major focus has been on the hands as the key route of infection transmission. However, there is a multitude of lesser-known and underestimated reservoirs for microorganisms which are the triggering sources and vehicles for outbreaks or sporadic cases of infection. Among those are water reservoirs such as sink drains, fixtures, decorative water fountains and waste-water treatment plants, frequently touched textile surfaces such as private curtains in hospitals and laundry, but also transvaginal ultrasound probes, parenteral drug products, and disinfectant wipe dispensers. The review of outbreak reports also reveals Gram-negative and multiple-drug resistant microorganisms to have become an increasingly frequent and severe threat in medical settings. In some instances, the causative organisms are particularly difficult to identify because they are concealed in biofilms or in a state referred to as viable but nonculturable, which eludes conventional culture media-based detection methods. There is an enormous preventative potential in these insights, which has not been fully tapped. New and emerging pathogens, novel pathogen detection methods, and hidden reservoirs of infection should hence be given special consideration when designing the layout of buildings and medical devices, but also when defining the core competencies for medical staff, establishing programmes for patient empowerment and education of the general public, and when implementing protocols for the prevention and control of infections in medical, community and domestic settings. PMID- 25699228 TI - The role of Octenidol((r)), Glandomed((r)) and chlorhexidine mouthwash in the prevention of mucositis and in the reduction of the oropharyngeal flora: a double blind randomized controlled trial. AB - AIM: The oropharyngeal flora is of importance for the development of oral mucositis, which is a frequent complication in oncologic practice. It also plays a role in the pathogenesis of ventilator-associated pneumonia. Mucositis is associated with significantly worse clinical and economic outcomes. The aim of our study was to assess the efficacy of Octenidol((r)), Glandomed((r)) and chlorhexidine mouthwash in the prevention of mucositis and reduction of the oropharyngeal flora. METHODS: A prospective, double-blinded RCT including two strata was conducted between October 2008 and November 2010. Stratum i consisted of ventilated cardiothoracic surgical patients. Stratum ii consisted of medical patients with haemato-oncological malignancies requiring stem cell transplantation. The primary outcome measures were development of mucositis regarding to OMAS/WHO score and reduction of the oropharyngeal flora. RESULTS: Both strata showed low OMAS/WHO scores which did not differ significantly between the groups. The overall mean reduction of colony forming units was significantly higher in the Octenidol((r)) group compared to the chlorhexidine and the Glandomed((r)) groups. CONCLUSIONS: No significant differences in the development of mucositis were found, thus all solutions proved successful in the prevention of mucositis. However, Octenidol((r)) was superior in the reduction of the oropharyngeal flora. Hence, the preventive effect on nosocomial infections might be higher in patients using Octenidol((r)) rather than chlorhexidine or Glandomed((r)). PMID- 25699229 TI - Cytomegalovirus in human brain tumors: Role in pathogenesis and potential treatment options. AB - During the last years increasing evidence implies that human cytomegalovirus (CMV) can be attributed to human malignancies arising from numerous tissues. In this perspective, we will review and discuss the potential mechanisms through which CMV infection may contribute to brain tumors by affecting tumor cell initiation, progression and metastasis formation. Recent evidence also suggests that anti-CMV treatment results in impaired tumor growth of CMV positive xenografts in animal models and potentially increased survival in CMV positive glioblastoma patients. Based on these observations and the high tumor promoting capacity of this virus, the classical and novel antiviral therapies against CMV should be revisited as they may represent a great promise for halting tumor progression and lower cancer deaths. PMID- 25699230 TI - Internal ribosome entry site-based vectors for combined gene therapy. AB - Gene therapy appears as a promising strategy to treat incurable diseases. In particular, combined gene therapy has shown improved therapeutic efficiency. Internal ribosome entry sites (IRESs), RNA elements naturally present in the 5' untranslated regions of a few mRNAs, constitute a powerful tool to co-express several genes of interest. IRESs are translational enhancers allowing the translational machinery to start protein synthesis by internal initiation. This feature allowed the design of multi-cistronic vectors expressing several genes from a single mRNA. IRESs exhibit tissue specificity, and drive translation in stress conditions when the global cell translation is blocked, which renders them useful for gene transfer in hypoxic conditions occurring in ischemic diseases and cancer. IRES-based viral and non viral vectors have been used successfully in preclinical and clinical assays of combined gene therapy and resulted in therapeutic benefits for various pathologies including cancers, cardiovascular diseases and degenerative diseases. PMID- 25699231 TI - Consolidated and emerging inflammatory markers in coronary artery disease. AB - Coronary artery disease is an event of atherosclerosis characterized by a chronic vascular inflammation. Risk factors like obesity, diabetes mellitus, hypertension, smoking, hypercholesterolemia and positive family history sometimes are not sufficiently adequate to the enhancement of cardiovascular risk assessment. In the past years numerous biomarkers, like C reactive protein, cytokines and adhesion molecules, have been observed to be related to adverse cardiovascular prognosis. Recently, several studies found an association among inflammatory biomarkers and cardiovascular diseases suggesting their utility to identify the risk of an acute ischemic event and the detection of vulnerable plaques. The emerging inflammatory markers are well divided for diagnosis and prognosis and plaque instability of coronary artery disease. Some of them, the lectin-like oxidized low density lipoprotein receptor-1 can be important both in diagnosis and in the evaluation of plaque instability, other are inserted in the above reported classification. The emerging inflammatory markers in acute-phase include amyloid A, fibrinogen and pentraxin 3 while myeloperoxidase, myeloid related protein 8/14 and pregnancy-associated plasma protein-A are recognize markers of plaque instability. Lastly, some studies demonstrated that circulating miRNAs are involved in coronary artery disease, acute myocardial infarction and heart failure. PMID- 25699232 TI - High-level disinfection of gastrointestinal endoscope reprocessing. AB - High level disinfection (HLD) of the gastrointestinal (GI) endoscope is not simply a slogan, but rather is a form of experimental monitoring-based medicine. By definition, GI endoscopy is a semicritical medical device. Hence, such medical devices require major quality assurance for disinfection. And because many of these items are temperature sensitive, low-temperature chemical methods, such as liquid chemical germicide, must be used rather than steam sterilization. In summarizing guidelines for infection prevention and control for GI endoscopy, there are three important steps that must be highlighted: manual washing, HLD with automated endoscope reprocessor, and drying. Strict adherence to current guidelines is required because compared to any other medical device, the GI endoscope is associated with more outbreaks linked to inadequate cleaning or disinfecting during HLD. Both experimental evaluation on the surveillance bacterial cultures and in-use clinical results have shown that, the monitoring of the stringent processes to prevent and control infection is an essential component of the broader strategy to ensure the delivery of safe endoscopy services, because endoscope reprocessing is a multistep procedure involving numerous factors that can interfere with its efficacy. Based on our years of experience in the surveillance of culture monitoring of endoscopic reprocessing, we aim in this study to carefully describe what details require attention in the GI endoscopy disinfection and to share our experience so that patients can be provided with high quality and safe medical practices. Quality management encompasses all aspects of pre- and post-procedural care including the efficiency of the endoscopy unit and reprocessing area, as well as the endoscopic procedure itself. PMID- 25699233 TI - Targeting neuroendocrine prostate cancer: molecular and clinical perspectives. AB - Neuroendocrine prostate carcinoma, either co-present with the local adenocarcinoma disease or as a result of transdifferentiation later in time, was described as one major process of emerging resistance to androgen deprivation therapies, and at the clinical level it is consistent with the development of rapidly progressive visceral disease, often in the absence of elevated serum prostate-specific antigen level. Until present, platinum-based chemotherapy has been the only treatment modality, able to produce a fair amount of responses but of short duration. Recently, several efforts for molecular characterization of this lethal phenotype have resulted in identification of novel signaling factors involved in microenvironment interactions, mitosis, and neural reprograming as potential therapeutic targets. Ongoing clinical testing of specific inhibitors of these targets, for example, Aurora kinase A inhibitors, in carefully selected patients and exploitation of expression changes of the target before and after manipulation is anticipated to increase the existing data and facilitate therapeutic decision making at this late stage of the disease when hormonal manipulations, even with the newest androgen-directed therapies are no longer feasible. PMID- 25699234 TI - A gender factor in shaping T-cell immunity to melanoma. PMID- 25699235 TI - Androgen-Receptor Positive Lacrimal Sac Adenocarcinoma Demonstrating Long-Lasting Response to LHRH Analog Plus Abiraterone Treatment. AB - Tumors arising at the lacrimal sac are extremely rare, as a limited number of cases have been reported worldwide. They are commonly primary and the majority of them are malignant and epithelial in origin. Adenocarcinomas account for a small percentage of these tumors. Treatment of local disease mainly includes complete surgical resection. However, metastatic disease has a poor prognosis and the development of new treatment strategies is highly important. Research efforts mainly focus on the identification of molecular targets for therapy. Herein, we describe for the first time a case of a patient with an androgen receptor expressing adenocarcinoma of the lacrimal sac that had an impressive response to abiraterone. PMID- 25699236 TI - Implications of epithelial-mesenchymal plasticity for heterogeneity in colorectal cancer. AB - Colorectal cancer (CRC) is a genetically heterogeneous disease that develops and progresses through several distinct pathways characterized by genomic instability. In recent years, it has emerged that inherent plasticity in some populations of CRC cells can contribute to heterogeneity in differentiation state, metastatic potential, therapeutic response, and disease relapse. Such plasticity is thought to arise through interactions between aberrant signaling events, including persistent activation of the APC/beta-catenin and KRAS/BRAF/ERK pathways, and the tumor microenvironment. Here, we highlight key concepts and evidence relating to the role of epithelial-mesenchymal plasticity as a driver of CRC progression and stratification of the disease into distinct molecular and clinicopathological subsets. PMID- 25699237 TI - Therapeutic Re-Activation of Protein Phosphatase 2A in Acute Myeloid Leukemia. AB - Protein phosphatase 2A (PP2A) is a serine/threonine phosphatase that is required for normal cell growth and development. PP2A is a potent tumor suppressor, which is inactivated in cancer cells as a result of genetic deletions and mutations. In myeloid leukemias, genes encoding PP2A subunits are generally intact. Instead, PP2A is functionally inhibited by post-translational modifications of its catalytic C subunit, and interactions with negative regulators by its regulatory B and scaffold A subunits. Here, we review the molecular mechanisms of genetic and functional inactivation of PP2A in human cancers, with a particular focus on human acute myeloid leukemias (AML). By analyzing expression of genes encoding PP2A subunits using transcriptome sequencing, we find that PP2A dysregulation in AML is characterized by silencing and overexpression of distinct A scaffold and B regulatory subunits, respectively. We review the mechanisms of functional PP2A activation by drugs such as fingolimod, forskolin, OP449, and perphenazine. This analysis yields two non-mutually exclusive mechanisms for therapeutic PP2A re activation: (i) allosteric activation of the phosphatase activity, and (ii) stabilization of active holo-enzyme assembly and displacement of negative regulatory factors from A and B subunits. Future studies should allow the development of specific and potent pharmacologic activators of PP2A, and definition of susceptible disease subsets based on specific mechanisms of PP2A dysregulation. PMID- 25699238 TI - A Voxel-by-Voxel Comparison of Deformable Vector Fields Obtained by Three Deformable Image Registration Algorithms Applied to 4DCT Lung Studies. AB - BACKGROUND: Commonly used methods of assessing the accuracy of deformable image registration (DIR) rely on image segmentation or landmark selection. These methods are very labor intensive and thus limited to relatively small number of image pairs. The direct voxel-by-voxel comparison can be automated to examine fluctuations in DIR quality on a long series of image pairs. METHODS: A voxel-by voxel comparison of three DIR algorithms applied to lung patients is presented. Registrations are compared by comparing volume histograms formed both with individual DIR maps and with a voxel-by-voxel subtraction of the two maps. When two DIR maps agree one concludes that both maps are interchangeable in treatment planning applications, though one cannot conclude that either one agrees with the ground truth. If two DIR maps significantly disagree one concludes that at least one of the maps deviates from the ground truth. We use the method to compare 3 DIR algorithms applied to peak inhale-peak exhale registrations of 4DFBCT data obtained from 13 patients. RESULTS: All three algorithms appear to be nearly equivalent when compared using DICE similarity coefficients. A comparison based on Jacobian volume histograms shows that all three algorithms measure changes in total volume of the lungs with reasonable accuracy, but show large differences in the variance of Jacobian distribution on contoured structures. Analysis of voxel by-voxel subtraction of DIR maps shows differences between algorithms that exceed a centimeter for some registrations. CONCLUSION: Deformation maps produced by DIR algorithms must be treated as mathematical approximations of physical tissue deformation that are not self-consistent and may thus be useful only in applications for which they have been specifically validated. The three algorithms tested in this work perform fairly robustly for the task of contour propagation, but produce potentially unreliable results for the task of DVH accumulation or measurement of local volume change. Performance of DIR algorithms varies significantly from one image pair to the next hence validation efforts, which are exhaustive but performed on a small number of image pairs may not reflect the performance of the same algorithm in practical clinical situations. Such efforts should be supplemented by validation based on a longer series of images of clinical quality. PMID- 25699239 TI - Potential applications of image-guided radiotherapy for radiation dose escalation in patients with early stage high-risk prostate cancer. AB - Patients with early stage high-risk prostate cancer (prostate specific antigen > 20, Gleason score > 7) are at high risk of recurrence following prostate cancer irradiation. Radiation dose escalation to the prostate may improve biochemical free survival for these patients. However, high rectal and bladder dose with conventional three-dimensional conformal radiotherapy may lead to excessive gastrointestinal and genitourinary toxicity. Image-guided radiotherapy (IGRT), by virtue of combining the steep dose gradient of intensity-modulated radiotherapy and daily pretreatment imaging, may allow for radiation dose escalation and decreased treatment morbidity. Reduced treatment time is feasible with hypo fractionated IGRT and it may improve patient quality of life. PMID- 25699240 TI - Estrogen receptors and their implications in colorectal carcinogenesis. AB - Upon binding their cognate receptors, ERalpha (ESR1) and ERbeta (ESR2), estrogens activate intracellular signaling cascades that have important consequences for cellular behavior. Historically linked to carcinogenesis in reproductive organs, estrogens have also been implicated in the pathogenesis of different cancer types of non-reproductive tissues including the colon. ERbeta is the predominant estrogen receptor expressed in both normal and malignant colonic epithelium. However, during colon cancer progression, ERbeta expression is lost, suggesting that estrogen signaling may play a role in disease progression. Estrogens may in fact exert an anti-tumor effect through selective activation of pro-apoptotic signaling mediated by ERbeta, inhibition of inflammatory signals and modulation of the tumor microenvironment. In this review, we analyze the estrogen pathway as a possible therapeutic avenue in colorectal cancer, we report the most recent experimental evidence to explain the cellular and molecular mechanisms of estrogen-mediated protection against colorectal tumorigenesis, and we discuss future challenges and potential avenues for targeted therapy. PMID- 25699241 TI - Impacts of activation of the mitogen-activated protein kinase pathway in pancreatic cancer. AB - Pancreatic cancer is characterized by constitutive activation of the mitogen activated protein kinase (MAPK) pathway. Mutations of KRAS or BRAF and epigenetic abrogation of DUSP6 contribute synergistically to the constitutive activation of MAPK. Active MAPK induces the expression of a variety of genes that are thought to play roles in malignant phenotypes of pancreatic cancer. By blocking the functions of such induced genes, it is possible to attenuate the malignant phenotypes. The development of drugs targeting genes downstream of MAPK may provide a novel therapeutic option for pancreatic cancer. PMID- 25699242 TI - Biofilm formation by Streptococcus agalactiae: influence of environmental conditions and implicated virulence factors. AB - Streptococcus agalactiae (Group B Streptococcus, GBS) is an important human pathogen that colonizes the urogenital and/or the lower gastro-intestinal tract of up to 40% of healthy women of reproductive age and is a leading cause of sepsis and meningitis in the neonates. GBS can also infect the elderly and immuno compromised adults, and is responsible for mastitis in bovines. Like other Gram positive bacteria, GBS can form biofilm-like three-dimensional structures that could enhance its ability to colonize and persist in the host. Biofilm formation by GBS has been investigated in vitro and appears tightly controlled by environmental conditions. Several adhesins have been shown to play a role in the formation of GBS biofilm-like structures, among which are the protein components of pili protruding outside the bacterial surface. Remarkably, antibodies directed against pilus proteins can prevent the formation of biofilms. The implications of biofilm formation in the context of GBS asymptomatic colonization and dissemination to cause invasive disease remain to be investigated in detail. PMID- 25699243 TI - Echocardiographic assessment after surgical repair of tetralogy of fallot. AB - Surgical correction of tetralogy of Fallot is still one of the most frequently performed intervention in pediatric cardiac surgery, and in many cases, it is far from being a complete and definitive correction. It is rather an excellent palliation that solves the problem of cyanosis, but predisposes the patients to medical and surgical complications during follow-up. The decision-making process regarding the treatment of late sequel is among the most discussed topics in adult congenital cardiology. In post-operative Fallot patients, echocardiography is used as the first method of diagnostic imaging and currently allows both a qualitative observation of the anatomical alterations and a detailed quantification of right ventricular volumes and function, of the right ventricular outflow tract, and of the pulmonary valve and pulmonary arteries. The literature introduced many quantitative echocardiographic criteria useful for the understanding of the pathophysiological mechanisms involving the right ventricle and those have made much more objective any decision-making processes. PMID- 25699244 TI - Biosecurity and dual-use research: gaining function - but at what cost? PMID- 25699245 TI - Epidemiological study on sand flies in an endemic focus of cutaneous leishmaniasis, bushehr city, southwestern iran. AB - Cutaneous leishmaniasis is the most important health problem in the city of Bushehr, southwestern Iran. The objective of the study was to determine some ecological aspects of sand flies in the city during 2010-2011. Sand flies were collected monthly from outdoors and indoors by sticky traps at four selected districts of the city. They were also dissected and examined by nested-PCR for identification of the parasite during August-September of 2011. A total of 1234 adult sand flies were collected and 6 species including 3 of Genus Phlebotomus and 3 of Genus Sergentomyia were identified. Four species including P. papatasi (3.98%), P. sergenti (1.14%), S. tiberiadis (87.18%), and S. baghdadis (7.7%) were found indoors. Six species including P. papatasi (3.47%), P. sergenti (3.17%), P. alexandri (0.1%), S. tiberiadis (77.74%), S. baghdadis (15.41%), and one female of S. clydei (0.11%) were collected from outdoors. Sand flies started to appear from March and disappear at the end of January. There was only one peak in the density curve in July. The study revealed that S. tiberiadis and S. baghdadis could enter indoors which 89 and 81.8% of them were found blood-fed, respectively. Moreover, P. papatasi, S. tiberiadis, and S. baghdadis were active indoors and outdoors in most months of the year. Nested-PCR of P. papatasi females was positive against kinetoplast DNA of L. major and L. turanica and also mixed natural infections were found by L. gerbilli and L. turanica. Moreover, mixed infections by L. major and L. turanica were observed in this species. Sergentomyia clydei and S. tiberiadis were found to be negative to any DNA of Leishmania species. Phlebotomus sergenti females were found infected with DNA of L. turanica and this is the first report of natural infection and detection of the parasite from this sand fly species in worldwide. PMID- 25699246 TI - Evaluation of the Effectiveness of a Novel Brain and Vestibular Rehabilitation Treatment Modality in PTSD Patients Who have Suffered Combat-Related Traumatic Brain Injuries. AB - INTRODUCTION: Blast-related head injuries are among the most prevalent injuries suffered by military personnel deployed in combat and mild traumatic brain injury (mTBI) or concussion on the battlefield in Iraq/Afghanistan has resulted in its designation as a "signature injury." Vestibular complaints are the most frequent sequelae of mTBI, and vestibular rehabilitation (VR) has been established as the most important treatment modality for this group of patients. MATERIALS AND METHODS: We studied the effectiveness of a novel brain and VR treatment post traumatic stress disorder (PTSD) in subjects who had suffered combat-related traumatic brain injuries in terms of PTSD symptom reduction. The trial was registered as ClinicalTrials.gov Identifier: NCT02003352. (http://clinicaltrials.gov/ct2/show/NCT02003352?term=carrick&rank=6). We analyzed the difference in the Clinician Administered DSM-IV PTSD Scale (CAPS) scores pre- and post-treatment using our subjects as their own matched controls. The study population consisted of 98 combat veterans maintaining an alpha of <0.05 and power of 80%. RESULTS: Prior to treatment, 75 subjects representing 76.53 % of the sample were classified in the 2 most severe categories of PTSD. Forty-one subjects, representing 41.80 % of the total sample, were classified in the extreme category of PTSD and 34 subjects, representing 34.70 % of the total sample, were classified in the severe category of PTSD. After treatment, we observed a large reduction in CAPS severity scores with both statistical and substantive significance. DISCUSSION: Treatment of PTSD as a physical injury rather than a psychiatric disorder is associated with strong statistical and substantive significant outcomes associated with a decrease of PTSD classification. The stigma associated with neuropsychiatric disorders may be lessened when PTSD is treated with brain and VR with a potential decrease in suffering of patients, family, and society. PMID- 25699247 TI - Undergraduate public health education: is there an ideal curriculum? PMID- 25699248 TI - Health department accreditation as a catalyst to foster the development of a future public health workforce. PMID- 25699249 TI - Possible influence of natural events on heavy metals exposure from shellfish consumption: a case study in the north-East of Italy. AB - The objective of this study was the estimation of the exposure over time to heavy metals (cadmium, mercury, and lead) due to shellfish consumption in the Veneto Region, Italy. Shellfish consumption was investigated by a food frequency consumption survey. Altogether, 1949 households, stratified into the five most populated areas of the Veneto Region, were involved in the study. Exposure estimation to heavy metals was carried out taking into account the level of metal measured in samples of Manila clams (Ruditapes philippinarum) and grooved carpet shell (Ruditapes decussatus), collected in the frame of the monitoring activities of mollusk production areas of Veneto Region, between January 2007 and December 2012. A general high contribution of the considered shellfish to the Tolerable Weekly Intake was noticed in the case of cadmium, especially in 2011, when a considerable increase in cadmium intake was estimated. This was probably due to a heavy rainfall event that triggered catastrophic flooding with high impact on shellfish capture areas in November 2010. The results strongly emphasize the importance of dealing with food safety in a holistic way, taking into account the potential impact of extraordinary natural events on food chain contamination, in order to identify food hazards at an early stage, before developing into a real risk for consumers. PMID- 25699250 TI - Theoretical analysis of hydrogen spillover mechanism on carbon nanotubes. AB - The spillover mechanism of molecular hydrogen on carbon nanotubes in the presence of catalytically active platinum clusters was critically and systematically investigated by using density-functional theory. Our simulation model includes a Pt4 cluster for the catalyst nanoparticle and curved and planar circumcoronene for two exemplary single-walled carbon nanotubes (CNT), the (10,10) CNT and one of large diameter, respectively. Our results show that the H2 molecule dissociates spontaneously on the Pt4 cluster. However, the dissociated H atoms have to overcome a barrier of more than 2 eV to migrate from the catalyst to the CNT, even if the Pt4 cluster is at full saturation with six adsorbed and dissociated hydrogen molecules. Previous investigations have shown that the mobility of hydrogen atoms on the CNT surface is hindered by a barrier. We find that instead the Pt4 catalyst may move along the outer surface of the CNT with activation energy of only 0.16 eV, and that this effect offers the possibility of full hydrogenation of the CNT. Thus, although we have not found a low-energy pathway to spillover onto the CNT, we suggest, based on our calculations and calculated data reported in the literature, that in the hydrogen-spillover process the observed saturation of the CNT at hydrogen background pressure occurs through mobile Pt nanoclusters, which move on the substrate more easily than the substrate-chemisorbed hydrogens, and deposit or reattach hydrogens in the process. Initial hydrogenation of the carbon substrate, however, is thermodynamically unfavoured, suggesting that defects should play a significant role. PMID- 25699251 TI - The dehydrogenase region of the NADPH oxidase component Nox2 acts as a protein disulfide isomerase (PDI) resembling PDIA3 with a role in the binding of the activator protein p67 (phox.). AB - The superoxide (O(.-) 2)-generating NADPH oxidase of phagocytes consists of a membrane component, cytochrome b 558 (a heterodimer of Nox2 and p22 (phox) ), and four cytosolic components, p47 (phox) , p67 (phox) , p40 (phox) , and Rac. The catalytic component, responsible for O(.-) 2 generation, is Nox2. It is activated by the interaction of the dehydrogenase region (DHR) of Nox2 with the cytosolic components, principally with p67 (phox) . Using a peptide-protein binding assay, we found that Nox2 peptides containing a (369)CysGlyCys(371) triad (CGC) bound p67 (phox) with high affinity, dependent upon the establishment of a disulfide bond between the two cysteines. Serially truncated recombinant Nox2 DHR proteins bound p67 (phox) only when they comprised the CGC triad. CGC resembles the catalytic motif (CGHC) of protein disulfide isomerases (PDIs). This led to the hypothesis that Nox2 establishes disulfide bonds with p67 (phox) via a thiol dilsulfide exchange reaction and, thus, functions as a PDI. Evidence for this was provided by the following: (1) Recombinant Nox2 protein, which contained the CGC triad, exhibited PDI-like disulfide reductase activity; (2) Truncation of Nox2 C terminal to the CGC triad or mutating C369 and C371 to R, resulted in loss of PDI activity; (3) Comparison of the sequence of the DHR of Nox2 with PDI family members revealed three small regions of homology with PDIA3; (4) Two monoclonal anti-Nox2 antibodies, with epitopes corresponding to regions of Nox2/PDIA3 homology, reacted with PDIA3 but not with PDIA1; (5) A polyclonal anti-PDIA3 (but not an anti-PDIA1) antibody reacted with Nox2; (6) p67 (phox) , in which all cysteines were mutated to serines, lost its ability to bind to a Nox2 peptide containing the CGC triad and had an impaired capacity to support oxidase activity in vitro. We propose a model of oxidase assembly in which binding of p67 (phox) to Nox2 via disulfide bonds, by virtue of the intrinsic PDI activity of Nox2, stabilizes the primary interaction between the two components. PMID- 25699252 TI - Nrf2 activation as target to implement therapeutic treatments. AB - A chronic increase of oxidative stress is typical of serious pathologies such as myocardial infarction, stroke, chronic limb ischemia, chronic obstructive pulmonary disease (COPD), type II-diabetes, age-related macular degeneration leads to an epic increase of morbidity and mortality in all countries of the world. The initial inflammation followed by an excessive release of reactive oxygen species (ROS) implies a diffused cellular injury that needs to be corrected by an inducible expression of the innate detoxifying and antioxidant system. The transcription factor Nrf2, when properly activated, is able to restore a redox homeostasis and possibly improve human health. PMID- 25699253 TI - Gene therapy for bone engineering. AB - Bone has an intrinsic healing capacity that may be exceeded when the fracture gap is too big or unstable. In that moment, osteogenic measures need to be taken by physicians. It is important to combine cells, scaffolds and growth factors, and the correct mechanical conditions. Growth factors are clinically administered as recombinant proteins. They are, however, expensive and needed in high supraphysiological doses. Moreover, their half-life is short when administered to the fracture. Therefore, gene therapy may be an alternative. Cells can constantly produce the protein of interest in the correct folding, with the physiological glycosylation and in the needed amounts. Genes can be delivered in vivo or ex vivo by viral or non-viral methods. Adenovirus is mostly used. For the non-viral methods, hydrogels and recently sonoporation seem to be promising means. This review will give an overview of recent advancements in gene therapy approaches for bone regeneration strategies. PMID- 25699254 TI - Novel Perfused Compression Bioreactor System as an in vitro Model to Investigate Fracture Healing. AB - Secondary bone fracture healing is a physiological process that leads to functional tissue regeneration via endochondral bone formation. In vivo studies have demonstrated that early mobilization and the application of mechanical loads enhances the process of fracture healing. However, the influence of specific mechanical stimuli and particular effects during specific phases of fracture healing remain to be elucidated. In this work, we have developed and provided proof-of-concept of an in vitro human organotypic model of physiological loading of a cartilage callus, based on a novel perfused compression bioreactor (PCB) system. We then used the fracture callus model to investigate the regulatory role of dynamic mechanical loading. Our findings provide a proof-of-principle that dynamic mechanical loading applied by the PCB can enhance the maturation process of mesenchymal stromal cells toward late hypertrophic chondrocytes and the mineralization of the deposited extracellular matrix. The PCB provides a promising tool to study fracture healing and for the in vitro assessment of alternative fracture treatments based on engineered tissue grafts or pharmaceutical compounds, allowing for the reduction of animal experiments. PMID- 25699255 TI - Induced pluripotent stem cells: applications in regenerative medicine, disease modeling, and drug discovery. AB - Recent progresses in the field of Induced Pluripotent Stem Cells (iPSCs) have opened up many gateways for the research in therapeutics. iPSCs are the cells which are reprogrammed from somatic cells using different transcription factors. iPSCs possess unique properties of self renewal and differentiation to many types of cell lineage. Hence could replace the use of embryonic stem cells (ESC), and may overcome the various ethical issues regarding the use of embryos in research and clinics. Overwhelming responses prompted worldwide by a large number of researchers about the use of iPSCs evoked a large number of peple to establish more authentic methods for iPSC generation. This would require understanding the underlying mechanism in a detailed manner. There have been a large number of reports showing potential role of different molecules as putative regulators of iPSC generating methods. The molecular mechanisms that play role in reprogramming to generate iPSCs from different types of somatic cell sources involves a plethora of molecules including miRNAs, DNA modifying agents (viz. DNA methyl transferases), NANOG, etc. While promising a number of important roles in various clinical/research studies, iPSCs could also be of great use in studying molecular mechanism of many diseases. There are various diseases that have been modeled by uing iPSCs for better understanding of their etiology which maybe further utilized for developing putative treatments for these diseases. In addition, iPSCs are used for the production of patient-specific cells which can be transplanted to the site of injury or the site of tissue degeneration due to various disease conditions. The use of iPSCs may eliminate the chances of immune rejection as patient specific cells may be used for transplantation in various engraftment processes. Moreover, iPSC technology has been employed in various diseases for disease modeling and gene therapy. The technique offers benefits over other similar techniques such as animal models. Many toxic compounds (different chemical compounds, pharmaceutical drugs, other hazardous chemicals, or environmental conditions) which are encountered by humans and newly designed drugs may be evaluated for toxicity and effects by using iPSCs. Thus, the applications of iPSCs in regenerative medicine, disease modeling, and drug discovery are enormous and should be explored in a more comprehensive manner. PMID- 25699256 TI - Lysosomal acid lipase: at the crossroads of normal and atherogenic cholesterol metabolism. AB - Unregulated cellular uptake of apolipoprotein B-containing lipoproteins in the arterial intima leads to the formation of foam cells in atherosclerosis. Lysosomal acid lipase (LAL) plays a crucial role in both lipoprotein lipid catabolism and excess lipid accumulation as it is the primary enzyme that hydrolyzes cholesteryl esters derived from both low density lipoprotein (LDL) and modified forms of LDL. Evidence suggests that as atherosclerosis progresses, accumulation of excess free cholesterol in lysosomes leads to impairment of LAL activity, resulting in accumulation of cholesteryl esters in the lysosome as well as the cytosol in foam cells. Impaired metabolism and release of cholesterol from lysosomes can lead to downstream defects in ATP-binding cassette transporter A1 regulation, needed to offload excess cholesterol from plaque foam cells. This review focuses on the role LAL plays in normal cholesterol metabolism and how the associated changes in its enzymatic activity may ultimately contribute to atherosclerosis progression. PMID- 25699257 TI - The regulation of MMP targeting to invadopodia during cancer metastasis. AB - The dissemination of cancer cells from the primary tumor to a distant site, known as metastasis, is the main cause of mortality in cancer patients. Metastasis is a very complex cellular process that involves many steps, including the breaching of the basement membrane (BM) to allow the movement of cells through tissues. The BM breach occurs via highly regulated and localized remodeling of the extracellular matrix (ECM), which is mediated by formation of structures, known as invadopodia, and targeted secretion of matrix metalloproteinases (MMPs). Recently, invadopodia have emerged as key cellular structures that regulate the metastasis of many cancers. Furthermore, targeting of various cytoskeletal modulators and MMPs has been shown to play a major role in regulating invadopodia function. Here, we highlight recent findings regarding the regulation of protein targeting during invadopodia formation and function. PMID- 25699258 TI - Ebola Virus Disease has Features of Hemophagocytic Lymphohistiocytosis Syndrome. PMID- 25699259 TI - Hernia, mesh, and topical antibiotics, especially gentamycin: seeking the evidence for the perfect outcome.... AB - Inguinal hernia repair is a clean surgical procedure and surgical site infection (SSI) rate is generally below 2%. Antibiotic prophylaxis is not routinely recommended, but it may be a good choice for institutions with high rates of wound infection (>5%). Typical prophylaxis is the intravenous application of first or second-generation cephalosporins before the skin incision. However, SSI rate remains more than 2% in many centers in spite of intravenous antibiotic prophylaxis. Even a 1% SSI rate may be unacceptable for the surgeons who specifically deal with hernia surgery. A hernia center targets to be a center of excellence not only in respect of recurrence rate but also for other postoperative outcomes, therefore a further measure is required for an excellent result regarding infection control. Topical gentamycin application in combination with preoperative single-dose intravenous antibiotic may be a useful to obtain this perfect outcome. Data about this subject are not complete and high-grade evidence has not been cumulated yet. Prospective randomized controlled trials can make our knowledge more solid about this subject and help the surgeons who seek perfect outcome regarding infection control in inguinal hernia surgery. PMID- 25699260 TI - Proposal for a new noncontact method for measuring tongue moisture to assist in tongue diagnosis and development of the tongue image analyzing system, which can separately record the gloss components of the tongue. AB - Tongue diagnosis is a noninvasive diagnosis and is traditionally one of the most important tools for physicians who practice Kampo (traditional Japanese) medicine. However, it is a subjective process, and its results can depend on the experience of the physician performing it. Previous studies have reported how to measure and evaluate the shape and color of the tongue objectively. Therefore, this study focused on the glossy component in order to quantify tongue moisture in tongue diagnosis. We hypothesized that moisture appears as a gloss in captured images and measured the amount of water on the tongue surface in 13 subjects. The results showed a high correlation between the degree of gloss and the amount of water on the tongue surface and suggested that the moisture on the tongue can be estimated by the degree of gloss in a captured image. Because the moisture level on the tongue changes during the course of taking photos, it became clear that we had to wait at least 3 minutes between photos. Based on these results, we established the tongue image analyzing system (TIAS), which can consistently record the gloss and color of the tongue surface simultaneously. PMID- 25699261 TI - Viability, apoptosis, proliferation, activation, and cytokine secretion of human keratoconus keratocytes after cross-linking. AB - PURPOSE: The purpose of this study was to determine the impact of cross-linking (CXL) on viability, apoptosis, proliferation, activation, and cytokine secretion of human keratoconus (KC) keratocytes, in vitro. METHODS: Primary KC keratocytes were cultured in DMEM/Ham's F12 medium supplemented with 10% FCS and underwent UVA illumination (370 nm, 2 J/cm(2)) during exposure to 0.1% riboflavin and 20% Dextran in PBS. Twenty-four hours after CXL, viability was assessed using Alamar blue assay; apoptosis using APO-DIRECT Kit; proliferation using ELISA-BrdU kit; and CD34 and alpha-smooth muscle actin (alpha-SMA) expression using flow cytometry. Five and 24 hours after CXL, FGFb, HGF, TGFbeta1, VEGF, KGF, IL-1beta, IL-6, and IL-8 secretion was measured using enzyme-linked-immunoabsorbent assay (ELISA). RESULTS: Following CXL, cell viability and proliferation decreased (P < 0.05; P = 0.009), the percentage of apoptotic keratocytes increased (P < 0.05) significantly, and CD34 and alpha-SMA expression remained unchanged (P > 0.06). Five hours after CXL, FGFb secretion increased significantly (P = 0.037); however no other cytokine secretion differed significantly from controls after 5 or 24 hours (P > 0.12). CONCLUSIONS: Cross-linking decreases viability, triggers apoptosis, and inhibits proliferation, without an impact on multipotent hematopoietic stem cell transformation and myofibroblastic transformation of KC keratocytes. CXL triggers FGFb secretion of KC keratocytes transiently (5 hours), normalizing after 24 hours. PMID- 25699262 TI - Investigation of Ser315 substitutions within katG gene in isoniazid-resistant clinical isolates of Mycobacterium tuberculosis from south India. AB - Mutation at codon 315 of katG gene is the major cause for isoniazid (INH) resistance in Mycobacterium tuberculosis (M. tuberculosis). Substitution at codon 315 of katG gene was analyzed in 85 phenotypically resistant isolates collected from various parts of southern India by direct sequencing method. The obtained results were interpreted in the context of minimum inhibitory concentration (MIC) of INH. Of the 85 phenotypically resistant isolates, 56 (66%) were also correlated by the presence of resistance mutations in the katG gene; 47 of these isolates had ACC, 6 had AAC, 2 had ATC, and one had CGC codon. The frequency of Ser315 substitution in katG gene was found to be higher (70%) amongst multidrug resistant (MDR) strains than among non-MDR (61%) INH-resistant isolates. Further, the frequency of mutations was found to be greater (74%) in isolates with higher MIC values in contrast to those isolates with low MIC values (58%). Therefore, the study identified high prevalence of Ser315Thr substitution in katG gene of INH-resistant isolates from south India. Also, isolates harboring this substitution were found to be associated with multidrug and high level INH resistance. PMID- 25699263 TI - Examination of the factor structure of the Schizotypal Personality Questionnaire among British and Trinidadian adults. AB - Much debate in schizotypal research has centred on the factor structure of the Schizotypal Personality Questionnaire (SPQ), with research variously showing higher-order dimensionality consisting of two to seven dimensions. In addition, cross-cultural support for the stability of those factors remains limited. Here, we examined the factor structure of the SPQ among British and Trinidadian adults. Participants from a White British subsample (n = 351) resident in the UK and from an African Caribbean subsample (n = 284) resident in Trinidad completed the SPQ. The higher-order factor structure of the SPQ was analysed through confirmatory factor analysis, followed by multiple-group analysis for the model of best fit. Between-group differences for sex and ethnicity were investigated using multivariate analysis of variance in relation to the higher-order domains. The model of best-fit was the four-factor structure, which demonstrated measurement invariance across groups. Additionally, these data had an adequate fit for two alternative models: (a) 3-factor and (b) modified 4-factor model. The British subsample had significantly higher scores across all domains than the Trinidadian group, and men scored significantly higher on the disorganised domain than women. The four-factor structure received confirmatory support and, importantly, support for use with populations varying in ethnicity and culture. PMID- 25699264 TI - Comparison and efficacy of LigaSure and rubber band ligature in closing the inflamed cecal stump in a rat model of acute appendicitis. AB - Safety of either LigaSure or rubber band in closing inflamed appendiceal stump in acute appendicitis has been less investigated. In this study, cecal ligation followed by resecting inflamed cecum was performed to mimic appendectomy in a rat model of acute appendicitis. Rats were sacrificed immediately (Group A) and 7 days (Group B) after cecal resection, respectively. The cecal stumps were closed by silk ligature (S), 5 mm LigaSure (L), or rubber band (R). Seven days after cecal resection, the LigaSure (BL) and silk subgroups (BS) had significantly less intra-abdominal adhesion and better laparotomy wound healing than rubber band subgroup (BR). The initial bursting pressure at cecal stump was comparable among the three methods; along with tissue healing process, both BL and BS provided a higher bursting pressure than BR 7 days after appendectomy. BL subgroup had more abundant hydroxyproline deposition than BS and BR subgroup. Furthermore, serum TNF-alpha in BR group kept persistently increasing along with time after cecal resection. Thus, the finding that LigaSure but not rubber band is safe in sealing off the inflamed cecal stump in rat model of acute appendicitis suggests the possibility of applying LigaSure for appendectomy via single port procedure or natural orifice transluminal endoscopic surgery (NOTES). PMID- 25699265 TI - Short-term changes in light distortion in orthokeratology subjects. AB - PURPOSE: Quantifying adaptation to light distortion of subjects undergoing orthokeratology (OK) for myopia during the first month of treatment. METHODS: Twenty-nine healthy volunteers (age: 22.34 +/- 8.08 years) with mean spherical equivalent refractive error -2.10 +/- 0.93D were evaluated at baseline and days 1, 7, 15, and 30 of OK treatment. Light distortion was determined using an experimental prototype. Corneal aberrations were derived from corneal topography for different pupil sizes. Contrast sensitivity function (CSF) was analyzed for frequencies of 1.50, 2.12, 3.00, 4.24, 6.00, 8.49, 12.00, 16.97, and 24.00 cpd under photopic conditions. RESULTS: Average monocular values of all light distortion parameters measured increased significantly on day 1, returning to baseline after 1 week (P < 0.05 in all cases). Spherical-like aberration stabilized on day 7 for all pupil diameters, while coma-like for smaller pupils only. CSF was significantly reduced on day 1 for all spatial frequencies except for 1.5 cpd, returning to baseline afterwards. Significant correlation was found between light distortion and contrast sensitivity for middle and high frequencies (P < 0.05) after 15 days. CONCLUSION: Despite consistently increased levels of corneal aberrations, light distortion tends to return to baseline after one week of treatment, suggesting that neural adaptation is capable of overcoming optical quality degradation. PMID- 25699266 TI - Functional and physical outcomes following use of a flexible CO2 laser fiber and bipolar electrocautery in close proximity to the rat sciatic nerve with correlation to an in vitro thermal profile model. AB - This study compared functional and physical collateral damage to a nerve when operating a Codman MALIS Bipolar Electrosurgical System CMC-III or a CO2 laser coupled to a laser, with correlation to an in vitro model of heating profiles created by the devices in thermochromic ink agarose. Functional damage of the rat sciatic nerve after operating the MALIS or CO2 laser at various power settings and proximities to the nerve was measured by electrically evoked nerve action potentials, and histology of the nerve was used to assess physical damage. Thermochromic ink dissolved in agarose was used to model the spatial and temporal profile of the collateral heating zone of the electrosurgical system and the laser ablation cone. We found that this laser can be operated at 2 W directly above the nerve with minimal damage, while power settings of 5 W and 10 W resulted in acute functional and physical nerve damage, correlating with the maximal heating cone in the thermochromic ink model. MALIS settings up to 40 (11 W) did not result in major functional or physical nerve damage until the nerve was between the forceps tips, correlating with the hottest zone, localized discretely between the tips. PMID- 25699267 TI - Synthesis, 68Ga-radiolabeling, and preliminary in vivo assessment of a depsipeptide-derived compound as a potential PET/CT infection imaging agent. AB - Noninvasive imaging is a powerful tool for early diagnosis and monitoring of various disease processes, such as infections. An alarming shortage of infection selective radiopharmaceuticals exists for overcoming the diagnostic limitations with unspecific tracers such as (67/68)Ga-citrate or (18)F-FDG. We report here TBIA101, an antimicrobial peptide derivative that was conjugated to DOTA and radiolabeled with (68)Ga for a subsequent in vitro assessment and in vivo infection imaging using Escherichia coli-bearing mice by targeting bacterial lipopolysaccharides with PET/CT. Following DOTA-conjugation, the compound was verified for its cytotoxic and bacterial binding behaviour and compound stability, followed by (68)Gallium-radiolabeling. uPET/CT using (68)Ga-DOTA TBIA101 was employed to detect muscular E. coli-infection in BALB/c mice, as warranted by the in vitro results. (68)Ga-DOTA-TBIA101-PET detected E. coli infected muscle tissue (SUV = 1.3-2.4) > noninfected thighs (P = 0.322) > forearm muscles (P = 0.092) > background (P = 0.021) in the same animal. Normalization of the infected thigh muscle to reference tissue showed a ratio of 3.0 +/- 0.8 and a ratio of 2.3 +/- 0.6 compared to the identical healthy tissue. The majority of the activity was cleared by renal excretion. The latter findings warrant further preclinical imaging studies of greater depth, as the DOTA-conjugation did not compromise the TBIA101's capacity as targeting vector. PMID- 25699268 TI - Phylogeny and taxonomical investigation of Trichoderma spp. from Indian region of Indo-Burma Biodiversity hot spot region with special reference to Manipur. AB - Towards assessing the genetic diversity and occurrence of Trichoderma species from the Indian region of Indo-Burma Biodiversity hotspot, a total of 193 Trichoderma strains were isolated from cultivated soils of nine different districts of Manipur comprising 4 different agroclimatic zones. The isolates were grouped based on the morphological characteristics. ITS-RFLP of the rDNA region using three restriction digestion enzymes: Mob1, Taq1, and Hinf1, showed interspecific variations among 65 isolates of Trichoderma. Based on ITS sequence data, a total of 22 different types of representative Trichoderma species were reported and phylogenetic analysis showed 4 well-separated main clades in which T. harzianum was found to be the most prevalent spp. among all the Trichoderma spp. Combined molecular and phenotypic data leads to the development of a taxonomy of all the 22 different Trichoderma spp., which was reported for the first time from this unique region. All these species were found to produce different extrolites and enzymes responsible for the biocontrol activities against the harmful fungal phytopathogens that hamper in food production. This potential indigenous Trichoderma spp. can be targeted for the development of suitable bioformulation against soil and seedborne pathogens in sustainable agricultural practice. PMID- 25699269 TI - Circulating microRNAs as clinical biomarkers in the predictions of pregnancy complications. AB - Predicting pregnancy complications is a major topic for clinicians and biologists for maternal and fetal monitoring. Noninvasive biomarkers in maternal blood such as circulating microRNAs (miRNAs) are promising molecules to predict pregnancy disorders. miRNAs are noncoding short RNAs that regulate mRNA expression by repressing the translation or cleaving the transcript. miRNAs are released to the extracellular systemic circulation via exosomes. The discovery of plasma- or serum-derived miRNAs and of free-circulating exosomes that contain miRNAs provides useful information about the physiological or pathophysiological roles of the miRNAs. Specific placental miRNAs are present in maternal plasma in different ways depending on whether the pregnancy is normal or pathological or if there is no pregnancy. This paper focuses on placental miRNAs and extracellular miRNAs to the placenta whose misregulation could lead to pregnancy complications. PMID- 25699270 TI - Preformulation studies for generic omeprazole magnesium enteric coated tablets. AB - Preformulation is an important step in the rational formulation of an active pharmaceutical ingredient (API). Micromeritics properties: bulk density (BD) and tapped density (TD), compressibility index (Carr's index), Hauser's ratio (H), and sieve analysis were performed in order to determine the best excipients to be used in the formulation development of omeprazole magnesium enteric coated tablets. Results show that omeprazole magnesium has fair flow and compressibility properties (BD 0.4 g/mL, TD 0.485 g/mL, Carr's index 17.5%, Hauser's ratio 1.2, and sieve analysis time 5 minutes). There were no significant drug excipient interactions except change in colour in all three conditions in the mixture of omeprazole and aerosil 200. Moisture content loss on drying in all three conditions was not constant and the changes were attributed to surrounding environment during the test time. Changes in the absorption spectra were noted in the mixture of omeprazole and water aerosil only in the visible region of 350 2500 nm. Omeprazole magnesium alone and with all excipients showed no significant changes in omeprazole concentration for a 30-day period. Omeprazole magnesium formulation complies with USP standards with regards to the fineness, flowability, and compressibility of which other excipients can be used in the formulation. PMID- 25699271 TI - Anti-EGFR antibody reduces lung nodules by inhibition of EGFR-pathway in a model of lymphangioleiomyomatosis. AB - EGFR belongs to the HER/ErbB family of tyrosine kinase receptors and its activation in cancer cells has been linked with increased proliferation, angiogenesis, and metastasis. Lymphangioleiomyomatosis (LAM) is a rare, low-grade neoplasm that occurs sporadically or in association with tuberous sclerosis complex (TSC), a genetic, multisystem disorder characterized by hamartomas in several organs. From chylous of a LAM/TSC patient, we previously isolated smooth muscle-like LAM/TSC cells whose proliferation depends on EGF and monoclonal anti EGFR antibodies reduced proliferation and caused cell death. We demonstrated that the dependency from EGF was caused by the absence of tuberin. To study the role of EGFR pathway in vivo, we developed a mouse model by administration of LAM/TSC cells to female nude mice. LAM/TSC cells caused pulmonary airspace enlargement and, after 30 weeks, nodule formation which express EGFR. Anti-EGFR antibody decreased the number and dimension of lung nodules likely for the inhibition of Erk and S6 signaling, reversed the pulmonary alterations, and reduced lymphatic and blood vessels. Moreover, in pulmonary nodules anti-EGFR antibody reduced the positivity to estrogen and progesterone receptors which enhance survival of LAM cells and Snail expression. These results suggest that the inhibition of EGFR signalling has a potential in treatment of LAM/TSC lung alterations. PMID- 25699272 TI - Cardiovascular diseases and women: knowledge, attitudes, and behavior in the general population in Italy. AB - BACKGROUND: The objectives of the study were to document knowledge, attitudes, and behaviors of women regarding cardiovascular diseases (CVDs) and the determinants associated. MATERIALS AND METHODS: The cross-sectional survey was conducted among a random sample of 830 women older than 18 years from the general population in Italy. RESULTS: Almost all participants reported having heard about CVDs, and among them 89.4% and 74.7% identified smoking and high cholesterol level as risk factors. Only 26.5% identified the main CVDs risk factors. Women more knowledgeable were married and better educated and self-perceived a worse health status. Only 23% knew the main CVDs preventive measures and this knowledge was significantly higher in women who are unemployed, who are more educated, who have received information about CVDs from physicians, and who know the main risk factors. Respondents with lower education, those with at least three children, those who self-perceived a worse health status, and those who need information were most likely to have a positive attitude toward the perceived risk of developing CVDs. Women with two or three children or more were at high risk profiles 49% and 56% lower than women with one child. CONCLUSIONS: Educational programs are needed among women as support to improve knowledge and appropriate behavior about CVDs. PMID- 25699273 TI - CCAAT/enhancer binding protein beta in relation to ER stress, inflammation, and metabolic disturbances. AB - The prevalence of the metabolic syndrome and underlying metabolic disturbances increase rapidly in developed countries. Various molecular targets are currently under investigation to unravel the molecular mechanisms that cause these disturbances. This is done in attempt to counter or prevent the negative health consequences of the metabolic disturbances. Here, we reviewed the current knowledge on the role of C/EBP-beta in these metabolic disturbances. C/EBP-beta deletion in mice resulted in downregulation of hepatic lipogenic genes and increased expression of beta-oxidation genes in brown adipose tissue. Furthermore, C/EBP-beta is important in the differentiation and maturation of adipocytes and is increased during ER stress and proinflammatory conditions. So far, studies were only conducted in animals and in cell systems. The results found that C/EBP-beta is an important transcription factor within the metabolic disturbances of the metabolic system. Therefore, it is interesting to examine the potential role of C/EBP-beta at molecular and physiological level in humans. PMID- 25699274 TI - Is the experience of thermal pain genetics dependent? AB - It is suggested that genetic variations explain a significant portion of the variability in pain perception; therefore, increased understanding of pain related genetic influences may identify new targets for therapies and treatments. The relative contribution of the different genes to the variance in clinical and experimental pain responses remains unknown. It is suggested that the genetic contributions to pain perception vary across pain modalities. For example, it has been suggested that more than 60% of the variance in cold pressor responses can be explained by genetic factors; in comparison, only 26% of the variance in heat pain responses is explained by these variations. Thus, the selection of pain model might markedly influence the magnitude of the association between the pain phenotype and genetic variability. Thermal pain sensation is complex with multiple molecular and cellular mechanisms operating alone and in combination within the peripheral and central nervous system. It is thus highly probable that the thermal pain experience is affected by genetic variants in one or more of the pathways involved in the thermal pain signaling. This review aims to present and discuss some of the genetic variations that have previously been associated with different experimental thermal pain models. PMID- 25699275 TI - Umbilical neutrophil gelatinase-associated lipocalin level as an early predictor of acute kidney injury in neonates with hypoplastic left heart syndrome. AB - Acute kidney injury (AKI) is a primarily described complication after unbalanced systemic perfusion in neonates with congenital heart defects, including hypoplastic left heart syndrome (HLHS). The aim of the study was to compare the umbilical NGAL concentrations between neonates born with HLHS and healthy infants, as well as to analyze whether the determination of NGAL level could predict AKI in neonates with prenatally diagnosed HLHS. Twenty-one neonates with prenatally diagnosed HLHS were enrolled as study group and 30 healthy neonates served as controls. Perinatal characteristics and postnatal parameters were extracted from the hospital neonatal database. In umbilical cord blood, we determined plasma NGAL concentrations, acid base balance, and lactate and creatinine levels. In neonates with HLHS, complications (respiratory insufficiency, circulatory failure, NEC, IVH, and AKI) were recorded until the day of cardiosurgery. We observed in neonates with HLHS higher umbilical NGAL levels compared to controls. Among 8 neonates with HLHS and diagnosed AKI stage 1, we observed elevated NGAL levels in comparison to those newborns without AKI. Umbilical NGAL could predict, with high sensitivity and specificity, AKI development in study neonates. We suggest that the umbilical blood NGAL concentration may be an early marker to predict AKI in neonates with HLHS. PMID- 25699276 TI - Label-free quantitative mass spectrometry reveals a panel of differentially expressed proteins in colorectal cancer. AB - To identify potential biomarkers involved in CRC, a shotgun proteomic method was applied to identify soluble proteins in three CRCs and matched normal mucosal tissues using high-performance liquid chromatography and mass spectrometry. Label free protein profiling of three CRCs and matched normal mucosal tissues were then conducted to quantify and compare proteins. Results showed that 67 of the 784 identified proteins were linked to CRC (28 upregulated and 39 downregulated). Gene Ontology and DAVID databases were searched to identify the location and function of differential proteins that were related to the biological processes of binding, cell structure, signal transduction, cell adhesion, and so on. Among the differentially expressed proteins, tropomyosin-3 (TPM3), endoplasmic reticulum resident protein 29 (ERp29), 18 kDa cationic antimicrobial protein (CAMP), and heat shock 70 kDa protein 8 (HSPA8) were verified to be upregulated in CRC tissue and seven cell lines through western blot analysis. Furthermore, the upregulation of TPM3, ERp29, CAMP, and HSPA8 was validated in 69 CRCs byimmunohistochemistry (IHC) analysis. Combination of TPM3, ERp29, CAMP, and HSPA8 can identify CRC from matched normal mucosal achieving an accuracy of 73.2% using IHC score. These results suggest that TPM3, ERp29, CAMP, and HSPA8 are great potential IHC diagnostic biomarkers for CRC. PMID- 25699277 TI - Diabetes-resistant NOR mice are more severely affected by streptozotocin compared to the diabetes-prone NOD mice: correlations with liver and kidney GLUT2 expressions. AB - Nonobese diabetic (NOD) mice are susceptible strains for Type 1 diabetes development, and Nonobese Diabetes-Resistant (NOR) mice are defined as suitable controls for NOD mice in non-MHC-related research. Diabetes is often accelerated in NOD mice via Streptozotocin (STZ). STZ is taken inside cells via GLUT2 transmembrane carrier proteins, the major glucose transporter isoforms in pancreatic beta cells, liver, kidneys, and the small intestine. We observed severe adverse effects in NOR mice treated with STZ compared to NOD mice that were made diabetic with a similar dose. We suggested that the underlying mechanism could be differential GLUT2 expressions in pancreatic beta cells, yet immunofluorescent and immunohistochemical studies revealed similar GLUT2 expression levels. We also detected GLUT2 expression profiles in NOD and NOR hepatic and renal tissues by western blot analysis and observed considerably higher GLUT2 expression levels in liver and kidney tissues of NOR mice. Although beta cell GLUT2 expression levels are frequently evaluated as a marker predicting STZ sensitivity in animal models, we report here very different diabetic responses to STZ in two different animal strains, in spite of similar initial GLUT2 expressions in beta cells. Furthermore, use of NOR mice in STZ-mediated experimental diabetes settings should be considered accordingly. PMID- 25699278 TI - Patient satisfaction with nursing and medical care in hospitals affiliated to arak university of medical sciences in 2009. AB - BACKGROUND: Patient satisfaction is essential and must be taken into account when decisions are being made about changes and enhancements to services. OBJECTIVES: The aim of the current study was to assess patient satisfaction with the medical and nursing services provided to patients admitted to teaching hospitals affiliated to Arak University of Medical Sciences. MATERIALS AND METHODS: This was a cross-sectional study conducted in 2009. The study population consisted of all patients admitted to the study setting. The instrument consisted of a demographic questionnaire and patient satisfaction questionnaire. Study data were analyzed using Chi-square test, Pearson's and Spearman's rho correlation coefficient. RESULTS: In terms of the medical and nursing care provided, 67% and 69% of the participants were satisfied, respectively. The 'access to opportune nursing care' and 'physician's manner' items received 82.7% and 81.7% of scores, respectively. Satisfaction with medical and nursing care was significantly correlated with the participants' education levels (P < 0.05). CONCLUSIONS: The study showed that patient satisfaction was at an average level, therefor policy makers in the organizations should consider customer-based feedback and apply various methods to improve it. PMID- 25699279 TI - The Effect of Acupressure at GB-21 and SP-6 Acupoints on Anxiety Level and Maternal-Fetal Attachment in Primiparous Women: a Randomized Controlled Clinical Trial. AB - BACKGROUND: Delivery is one of the most stressful events in women's life. Excessive anxiety, in turn, increases delivery and pregnancy complications. Mother's positive experience of delivery leads to more effective maternal-fetal attachment in the first few hours of birth. OBJECTIVES: The present study aimed to compare the effects of acupressure at two different acupoints on anxiety level and maternal-fetal attachment in primiparous women. MATERIALS AND METHODS: In this study, 150 primiparous women were allocated to acupressure at GB-21 acupoint, acupressure at SP-6 acupoint, and control group. The women in their active phase of delivery were enrolled in the study and pressure was applied to the acupoints for 20 minutes. Mother's anxiety level was assessed using Spielberger's questionnaire before and one hour after the intervention. In addition, maternal-fetal attachment behaviors were evaluated using Avant's questionnaire during the first breastfeeding. Then the data were introduced to the SPSS (v. 13) and were analyzed using t test and one way ANOVA. RESULTS: The results revealed no significant difference among the three groups regarding the anxiety level before the intervention (P > 0.05). One hour after the intervention, this measure was significantly lower in the intervention groups in comparison to the control group (P < 0.001). However, no significant difference was found between the two intervention groups in this regard (P > 0.05). Moreover, maternal-fetal attachment was higher in the intervention groups in comparison with the control group (P < 0.001). CONCLUSIONS: Acupressure at both acupoints reduced anxiety level and increased maternal-fetal attachment. This method can be easily used in the delivery room. PMID- 25699280 TI - Effect of music on postoperative pain in patients under open heart surgery. AB - BACKGROUND: Music, as a non-pharmacological and inexpensive nursing intervention, can be used easily as a complementary technique in reducing pain along with other methods. While some studies have demonstrated pain to decrease after music, others found music to be ineffective on pain. OBJECTIVES: The aim of this study was to investigate the effect of music on postoperative pain in patients under open heart surgery. PATIENTS AND METHODS: A quasi-experimental study was performed on 60 patients under open heart surgery referred to ICU of Shahid Beheshti hospital in Kashan city. Patients were randomly divided into two groups including experimental and control groups. Patients in music group listened to nonverbal music for 30 minutes after surgery by headphones. The control group did not receive any intervention other than routine care. Before and after intervention, pain intensity was measured and recorded by visual analog scale in two groups. Data was analyzed using Chi-Square and t-tests. RESULTS: Before intervention, the mean of pain intensity was 6.32 +/- 0.21 and 6.10 +/- 0.21 for experimental and control groups, respectively; and the difference was not significant (P = 0.21). After intervention, the mean of pain intensity was 3.11 +/- 0.12 and 5.81 +/- 0.38 for experimental and control groups, respectively; and the difference was significant (P = 0.04). CONCLUSIONS: Listening to the relaxant music can reduce postoperative pain. It is suggested that relaxant music be used as a complementary method in patients in order to reduce prospective pain. PMID- 25699281 TI - A New mouthwash for Chemotherapy Induced Stomatitis. AB - BACKGROUND: Stomatitis is a disturbing side-effect of chemotherapy that disturbs patients and causes difficulties in patient's drinking, eating and talking, and may results in infection and bleeding. OBJECTIVES: This study aimed to investigate the effect of Yarrow distillate in the treatment of chemotherapy induced stomatitis. PATIENTS AND METHODS: This randomized controlled trial study was conducted during 2013. The study population consisted of all cancer patients with chemotherapy-induced oral stomatitis referred to Shahid Beheshti Medical Center, Kashan, Iran. The data collection instrument had two-part; a demographic part and another part recording the severity of the stomatitis at the first, seventh, and 14th days of the intervention based on a WHO criteria checklist in 2005. In this study, 56 patients diagnosed with cancer were randomly assigned into control and experimental groups in similar blocks according to their stomatitis severity. The experimental group gargled 15 mL of a routine solution mixed with Yarrow distillate 4 times a day for 14 days while the control group gargled 15 mL of routine solution. The severity of stomatitis was assessed at the beginning of the intervention, and then after 7 and 14 days of the study. Data were analyzed using chi-square and Fisher exact test, Mann-Whitney U, Kruskal Wallis, and Friedman tests using SPSS 11.5 software. RESULTS: At first, the median score of stomatitis in the experimental group was 2.50 that significantly reduced to 1 and 0 in days 7 and 14 of the intervention, respectively (P value < 0.001). However, in the control group, the median score of stomatitis was 2.50, which significantly increased to 3 in days 7 and 14 (P value < 0.001). CONCLUSIONS: Yarrow distillate-contained solution reduced stomatitis severity more than the routine solution. Therefore, we suggest using it in patients with chemotherapy-induced stomatitis. PMID- 25699282 TI - Effect of mindfulness-based stress reduction on pain severity and mindful awareness in patients with tension headache: a randomized controlled clinical trial. AB - BACKGROUND: Programs to improve the pain and health status in illnesses with pain such as headache are still in their infancy. Mindfulness-based stress reduction (MBSR) is a new psychotherapy that appears to be effective in treating chronic pain. OBJECTIVES: This study evaluated efficacy of MBSR in improving pain severity and mindful awareness in patients with tension headache. PATIENTS AND METHODS: This study was a randomized controlled clinical trial that was conducted in 2012 in Shahid Beheshti Hospital of Kashan City. Sixty patients who were diagnosed with tension-type headache according to the International Headache Classification Subcommittee were randomly assigned to treatment as usual (TAU) or MBSR groups. The MBSR group received eight weekly treatments. Any session lasted 120 minutes. The sessions were based on MBSR protocol. Diary scale for measuring headache and Mindful Attention Awareness Scale (MAAS) were administered at pretreatment, and posttreatment, and three-month follow-up in both groups. The data was analyzed using repeated measures analysis of variance. RESULTS: The mean of pain severity was 7.36 +/- 1.25 before intervention that was significantly reduced to 5.62 +/- 1.74 and 6.07 +/- 1.08 after the intervention and follow-up (P < 0.001). In addition, the MBSR group showed higher scores in mindful awareness in comparison with the control group at posttest session. The mean of mindful awareness before intervention was 34.9 +/- 10.5 and changed to 53.8 +/- 15.5 and 40.7 +/- 10.9 after the intervention and follow-up sessions (P < 0.001). CONCLUSIONS: MBSR could reduce pain and improve mindfulness skills in patients with tension headache. It appears that MBSR is an effective psychotherapy for treatment of patients with tension headache. PMID- 25699283 TI - High-flux and low-flux membranes: efficacy in hemodialysis. AB - BACKGROUND: Inadequacy of dialysis is one of the main causes of death in hemodialysis patients. Some studies have suggested that high-flux membrane improves the removal of moderate-sized molecules while other studies indicate no significant effect on them. OBJECTIVES: This study aimed to investigate the dialysis efficacy of low-flux versus high-flux membranes in hemodialysis patients. PATIENTS AND METHODS: Forty hemodialysis patients participated in this cross-over clinical trial. Two sessions of low-flux and high-flux membrane dialysis were performed consecutively, in the first and second stage of the trial. In both stages, blood samples before and after the dialysis were taken and sent to the laboratory for assessment. Blood urea nitrogen (BUN), KT/V and the urea reduction ratio (URR) indexes were used to determine dialysis efficacy. Data were analyzed using t test and paired t test. RESULTS: The mean KT/V was 1.27 +/- 0.28 in high-flux and 1.10 +/- 0.32 in low-flux membrane which, these differences were statistically significant (P = 0.017). The mean of URR was 0.65 +/- 0.09 in high-flux and 0.61 +/- 0.14 in low-flux membrane, which these differences were not statistically significant (P = 0.221). CONCLUSIONS: The high-flux membrane had better dialysis adequacy, so we suggest using high-flux membrane in hemodialysis centers. PMID- 25699284 TI - Investigating the effect of zinc chloride to control external bleeding in rats. AB - BACKGROUND: Despite all progresses in surgical science, bleeding caused by traffic accidents is still a challenge for surgeons to save patients' lives. Therefore, introducing an effective method to control external bleeding is an important research priority. OBJECTIVES: This study aimed to compare haemostatic effect of zinc chloride and simple suturing to control external bleeding. MATERIALS AND METHODS: In this animal model study, 60 male Wistar rats were used. An incision (two cm in length and half a cm in depth) was made on shaved back of rats. The hemostasis time was measured once using zinc chloride with different concentrations (5%, 10%, 15%, 25%, and 50%) and then using simple suturing. Skin tissue was assessed for pathological changes. Due to abnormal distribution of variables in Kolmogorov-Smirnov test, the data was analyzed using Kruskal-Wallis test Mann-Whitney U tests. RESULTS: In all the groups, complete hemostasis occurred. Hemostasis times of different concentrations of zinc chloride were significantly less than that of the control group (P < 0.001). CONCLUSIONS: Zinc chloride was effective to control external bleeding in rats. PMID- 25699285 TI - The importance of spiritual care in nursing. PMID- 25699286 TI - Occupational hazards in nursing. PMID- 25699287 TI - Reasons for elective cesarean section in Iranian women. PMID- 25699288 TI - Seroprevalence of Toxoplasma gondii in women who have aborted in comparison with the women with normal delivery in Ahvaz, southwest of Iran. AB - Toxoplasma gondii is an obligate intracellular protozoan parasite causing toxoplasmosis in animals and humans. Primary maternal infection with toxoplasmosis during pregnancy is frequently associated with transplacental transmission to the fetus. However it is not certain whether Toxoplasma infection can cause recurrent abortion. The aim of this study was to determine the relationship between Toxoplasma infection and abortion via detection of anti Toxoplasma gondii antibodies in sera of women with obstetrical problems and compare the results with control group consisting of women with history of normal delivery. Sera from 130 women with abortion and sera of 130 women with normal delivery were tested for IgG and IgM anti-Toxoplasma gondii antibodies by ELISA method. The present study revealed 24.6% of the samples with abortion and 21.5% of the samples with normal delivery were positive for IgG antibodies. However, statistical analysis indicated no significant differences (P > 0.05). In addition, IgM antibody was detected in one woman who had aborted but not in women with normal childbirth. This study showed no significant difference between the case and control groups in IgG anti-Toxoplasma antibody but detected one sample with IgM antibodies in woman with abortion during the first trimester of pregnancy. In order to determine the relationship between Toxoplasma infection and abortion, anti-Toxoplasma IgG avidity and PCR to discriminate between recent and prior infections are recommended. PMID- 25699289 TI - Accuracy of Next Generation Sequencing Platforms. AB - Next-generation DNA sequencing has revolutionized genomic studies and is driving the implementation of precision diagnostics. The ability of these technologies to disentangle sequence heterogeneity, however, is limited by their relatively high error rates. A Several single molecule barcoding strategies have been propose to reduce the overall error frequency. A Duplex Sequencing additionally exploits the fact that DNA is double-strand, with one strand reciprocally encoding the sequence information of its complement, and can eliminate nearly all sequencing errors by comparing the sequence of individually tagged amplicons derived from one strand of DNA with that of its complementary strand. This method reduces errors to fewer than one per ten million nucleotides sequenced. PMID- 25699290 TI - Regenerative Medicine for the Aging Brain. AB - In the central nervous system, cholinergic and dopaminergic (DA) neurons are among the cells most susceptible to the deleterious effects of age. Thus, the basal forebrain cholinergic system is known to undergo moderate neurodegenerative changes during normal aging as well as severe atrophy in Alzheimer's disease (AD). Parkinson's disease (PD), a degeneration of nigro-striatal DA neurons is the most conspicuous reflection of the vulnerability of DA neurons to age. In this context, cell reprogramming offers novel therapeutic possibilities for the treatment of these devastating diseases. In effect, the generation of induced pluripotent stem cells (iPSCs) from somatic cells demonstrated that adult mammalian cells can be reprogrammed to a pluripotent state by the overexpression of a few embryonic transcription factors (TF). This discovery fundamentally widened the research horizon in the fields of disease modeling and regenerative medicine. Although it is possible to re-differentiate iPSCs to specific somatic cell types, the tumorigenic potential of contaminating iPSCs that failed to differentiate, increases the risk for clinical application of somatic cells generated by this procedure. Therefore, reprogramming approaches that bypass the pluripotent stem cell state are being explored. A method called lineage reprogramming has been recently documented. It consists of the direct conversion of one adult cell type into another by transgenic expression of multiple lineage specific TF or microRNAs. Another approach, termed direct reprogramming, features several advantages such as the use of universal TF system and the ability to generate a rejuvenated multipotent progenitor cell population, able to differentiate into specific cell types in response to a specific differentiation factors. These novel approaches offer a new promise for the treatment of pathologies associated with the loss of specific cell types as for instance, nigral DA neurons (in PD) or basal forebrain cholinergic neurons in the early stages of AD. The above topics are reviewed here. PMID- 25699291 TI - Semantic Predications for Complex Information Needs in Biomedical Literature. AB - Many complex information needs that arise in biomedical disciplines require exploring multiple documents in order to obtain information. While traditional information retrieval techniques that return a single ranked list of documents are quite common for such tasks, they may not always be adequate. The main issue is that ranked lists typically impose a significant burden on users to filter out irrelevant documents. Additionally, users must intuitively reformulate their search query when relevant documents have not been not highly ranked. Furthermore, even after interesting documents have been selected, very few mechanisms exist that enable document-to-document transitions. In this paper, we demonstrate the utility of assertions extracted from biomedical text (called semantic predications) to facilitate retrieving relevant documents for complex information needs. Our approach offers an alternative to query reformulation by establishing a framework for transitioning from one document to another. We evaluate this novel knowledge-driven approach using precision and recall metrics on the 2006 TREC Genomics Track. PMID- 25699292 TI - A system for optically controlling neural circuits with very high spatial and temporal resolution. AB - Optogenetics offers a powerful new approach for controlling neural circuits. It has a vast array of applications in both basic and clinical science. For basic science, it opens the door to unraveling circuit operations, since one can perturb specific circuit components with high spatial (single cell) and high temporal (millisecond) resolution. For clinical applications, it allows new kinds of selective treatments, because it provides a method to inactivate or activate specific components in a malfunctioning circuit and bring it back into a normal operating range [1-3]. To harness the power of optogenetics, though, one needs stimulating tools that work with the same high spatial and temporal resolution as the molecules themselves, the channelrhodopsins. To date, most stimulating tools require a tradeoff between spatial and temporal precision and are prohibitively expensive to integrate into a stimulating/recording setup in a laboratory or a device in a clinical setting [4, 5]. Here we describe a Digital Light Processing (DLP)-based system capable of extremely high temporal resolution (sub millisecond), without sacrificing spatial resolution. Furthermore, it is constructed using off-the-shelf components, making it feasible for a broad range of biology and bioengineering labs. Using transgenic mice that express channelrhodopsin-2 (ChR2), we demonstrate the system's capability for stimulating channelrhodopsin-expressing neurons in tissue with single cell and sub millisecond precision. PMID- 25699293 TI - Computational Modeling Reinforces that Proprioceptive Cues May Augment Compliance Discrimination When Elasticity Is Decoupled From Radius of Curvature. AB - Our capability to discriminate object compliance is based on cues both tactile and proprioceptive, in addition to visual. To understand how the mechanics of the fingertip skin and bone might encode such information, we used finite element models to simulate the task of differentiating spherical indenters of radii (4, 6 and 8 mm) and elasticity (initial shear modulus of 10, 50 and 90 kPa). In particular, we considered two response variables, the strain energy density (SED) at the epidermal-dermal interface where Merkel cell end-organs of slowly adapting type I afferents reside, and the displacement of the fingertip bone necessary to achieve certain surface contact force. The former variable ties to tactile cues while the latter ties to proprioceptive cues. The results indicate that distributions of SED are clearly distinct for most combinations of object radii and elasticity. However, for certain combinations - e.g., between 4 mm spheres of 10 kPa and 8 mm of 90 kPa - spatial distributions of SED are nearly identical. In such cases where tactile-only cues are non-differentiable, we may rely on proprioceptive cues to discriminate compliance. PMID- 25699294 TI - Using SPARQL to Test for Lattices: application to quality assurance in biomedical ontologies. AB - We present a scalable, SPARQL-based computational pipeline for testing the lattice-theoretic properties of partial orders represented as RDF triples. The use case for this work is quality assurance in biomedical ontologies, one desirable property of which is conformance to lattice structures. At the core of our pipeline is the algorithm called NuMi, for detecting the Number of Minimal upper bounds of any pair of elements in a given finite partial order. Our technical contribution is the coding of NuMi completely in SPARQL. To show its scalability, we applied NuMi to the entirety of SNOMED CT, the largest clinical ontology (over 300,000 conepts). Our experimental results have been groundbreaking: for the first time, all non-lattice pairs in SNOMED CT have been identified exhaustively from 34 million candidate pairs using over 2.5 billion queries issued to Virtuoso. The percentage of non-lattice pairs ranges from 0 to 1.66 among the 19 SNOMED CT hierarchies. These non-lattice pairs represent target areas for focused curation by domain experts. RDF, SPARQL and related tooling provide an e cient platform for implementing lattice algorithms on large data structures. PMID- 25699295 TI - Quantitative evaluation of common errors in digital impression obtained by using an LED blue light in-office CAD/CAM system. AB - OBJECTIVE: This study addresses common errors that may occur during digital impression procedures using the CEREC AC and in-office CAD/CAM systems. Error types and frequencies resulting from digital impressions of the oral cavity were investigated and their origins identified to facilitate the acquisition of more accurate digital impressions. METHOD AND MATERIALS: A total of 1,251 digital impression cases, including 163 onlays and 1,088 inlays, were constructed as restorations using the CEREC AC system. Two evaluators determined five categories of digital errors as a basis for evaluation over two sessions. The five categories were as follows: inappropriate scanner positioning (ISP), improper handling of the scanner (IHS), irregular powder arrangement (IPA), improper cavity preparation (ICP), and insufficient scanned data (ISD). RESULTS: The most frequently encountered errors were non-linear powder application (IPA), inappropriate oral cavity scanner placement (ISP), and insufficient data (ISD). ISP showed that inlays had a slightly higher frequency of errors, but this observation was not statistically significant (P > .05). CONCLUSION: Most errors are caused by incorrect operation of intraoral scanners or uneven application of powder in acquiring digital impressions. To provide optimal digital impression results, careful chairside technique procedures and operation of intraoral scanners are required. PMID- 25699296 TI - Comparison of two different xenografts in bilateral sinus augmentation: radiographic and histologic findings. AB - OBJECTIVE: The aim of this study was to evaluate the radiographic and histomorphometric results of two different xenografts in bilateral sinus augmentation in patients with posterior maxillary atrophy. METHOD AND MATERIALS: Eight patients with less than 5 mm residual alveolar bone height were included in this study. One side was augmented with bovine bone graft-1 and the other side with bovine bone graft-2. Radiographic analyses were performed before and after augmentation, and before the implant placement. After 8 months of healing period, bone biopsies were obtained during implant placement. RESULTS: No statistically significant difference was found between the groups, based on post-augmentation and pre-implantation graft heights (P > .05). Histomorphometric evaluation demonstrated 24.63% and 29.13% newly formed bone in the graft-1 and graft-2 groups, respectively. Intergroup differences were not significant for the mean percentage of new bone formation (P > .05). CONCLUSION: Within the limitations of this study, it can be concluded that xenograft materials resulted in satisfactory bone height and trabecular new bone formation, and they could be used for the rehabilitation of atrophic maxillae. PMID- 25699297 TI - Apical debris removal of CanalBrushes with different tip modifications. AB - OBJECTIVE: In this study the apical debris score regarding the rotary use of the CanalBrush (Coltene-Whaledent) with three different tip variations was compared to that of sole needle irrigation. METHOD AND MATERIALS: Sixty straight roots of human teeth with one canal were instrumented to size 45/.04. Roots were split into halves, reassembled, and embedded in model resin to form separable tooth models. Artificially manufactured dentin debris was packed into the apical 2 mm of the roots to form a relatively consistent debris challenge to be assessed. Then, the debris of each root half was evaluated apically using a modified Hulsmann-score under a light microscope. After remounting the models, root canals were irrigated with NaOCl 3% (2 mL): group 1 with sole needle irrigation, in groups 2 to 4 additionally agitated with different versions of the CanalBrush for 30 s at 600 rpm; group 2, one straight bristle ("old"); group 3, two additional diagonal bristles ("new"); group 4, central straight bristle of the new version removed ("experimental"). Following this, all root halves were reevaluated. RESULTS: Irrigation reduced debris scores in all groups (Wilcoxon tests, P < .001). Mean debris scores were reduced from a pre-irrigation score of about 4 for all groups to a score of around 2 to 3 in groups 1 and 2, and to scores around 1 in groups 3 and 4. Samples of groups 3 and 4 were significantly cleaner than of groups 1 and 2 (Mann-Whitney tests, P < .05). CONCLUSION: CanalBrushes with diagonal bristles achieved an improved apical cleaning ability. PMID- 25699298 TI - Soft tissue grafting to improve the attached mucosa at dental implants: A review of the literature and proposal of a decision tree. AB - BACKGROUND: Scientific data and clinical observations appear to indicate that an adequate width of attached mucosa may facilitate oral hygiene procedures thus preventing peri-implant inflammation and tissue breakdown (eg, biologic complications). Consequently, in order to avoid biologic complications and improve long-term prognosis, soft tissue conditions should be carefully evaluated when implant therapy is planned. At present the necessity and time-point for soft tissue grafting (eg, prior to or during implant placement or after healing) is still controversially discussed while clinical recommendations are vague. OBJECTIVES: To provide a review of the literature on the role of attached mucosa to maintain periimplant health, and to propose a decision tree which may help the clinician to select the appropriate surgical technique for increasing the width of attached mucosa. RESULTS: The available data indicate that ideally, soft tissue conditions should be optimized by various grafting procedures either before or during implant placement or as part of stage-two surgery. In cases, where, despite insufficient peri-implant soft tissue condition (ie, lack of attached mucosa or movements caused by buccal frena), implants have been uncovered and/or loaded, or in cases where biologic complications are already present (eg, mucositis, peri-implantitis), the treatment appears to be more difficult and less predictable. CONCLUSION: Soft tissue grafting may be important to prevent peri-implant tissue breakdown and should be considered when dental implants are placed. The presented decision tree may help the clinician to select the appropriate grafting technique. PMID- 25699299 TI - Metstatic papillary thyroid carcinoma to maxilla: a rare case. AB - Metastatic involvement of oral osseous and soft tissues constitutes nearly 1% of all oral malignancies. However, maxillary involvement is uncommon and this phenomenon is even less likely when the primary source is thyroid. A rare case of papillary thyroid carcinoma metastatic to maxillary right posterior alveolar process and sinus in a 43-year-old woman is described and the spectrum of metastatic oral disease is reviewed. The importance of including metastasis in the differential diagnosis of jaw lesions is also emphasized. PMID- 25699300 TI - Practice paper of the Academy of Nutrition and Dietetics abstract: nutrition and lifestyle for a healthy pregnancy outcome. AB - It is the position of the Academy of Nutrition and Dietetics that women of childbearing age should adopt a lifestyle optimizing health and reducing risk of birth defects, suboptimal fetal development, and chronic health problems in both mother and child.Components leading to healthy pregnancy outcome include healthy pre-pregnancy weight, appropriate weight gain and physical activity during pregnancy, consumption of a wide variety of foods, appropriate vitamin and mineral supplementation, avoidance of alcohol and other harmful substances, and safe food handling. Nutrition assessment needs to encompass changes in anthropometric,biochemical, and clinical indicators throughout pregnancy. Pregnant women should gain weight according to the 2009 Institute of Medicine Guidelines. Energy needs are no higher than the Estimated Energy Requirement for nonpregnant women until the second trimester; thereafter, the extra energy need per day is 340 kcal and 452 kcal in the second and third trimesters,respectively. Using the 2010 Dietary Guidelines for Americans, registered dietitian nutritionists and dietetics technicians, registered,can help pregnant women select a food plan based on age, physical activity, trimester, weight gain, and other considerations.Women are encouraged to participate in at least 150 minutes of moderate-intensity aerobic activity spread throughout the week or 30 minutes of moderately intense exercise on most days of the week.When good food choices are made, food consumption to meet extra energy needs and the increased absorption and efficiency of nutrient utilization that occurs in pregnancy are generally adequate to meet most nutrient needs. However, vitamin and mineral supplementation may be important in vulnerable cases including food insecurity; alcohol, tobacco, or other substance dependency; anemia; strict vegetarian (vegan) diet; or poor eating habits. Multiple strategies are needed to support healthy lifestyles for all women, from preconception through the postpartum period. This practice paper supports the Academy of Nutrition and Dietetics' position paper "Nutrition and Lifestyle for a Healthy Pregnancy Outcome" published in the July 2014 Journal of the Academy of Nutrition and Dietetics. PMID- 25699301 TI - ECG quiz: variation in P wave rate during AV block. PMID- 25699302 TI - Author's reply. PMID- 25699303 TI - Author's reply. PMID- 25699304 TI - Author's reply. PMID- 25699305 TI - Retraction notice to "Reconstructive, organ-preserving microsurgery in tubal infertility: still an alternative to in vitro fertilization". PMID- 25699306 TI - Influenza C virus. PMID- 25699307 TI - Workplace safety: Risky encounters. PMID- 25699308 TI - Response. PMID- 25699309 TI - The gut, intestinal permeability, and autoimmunity. PMID- 25699310 TI - Advancing the understanding of physical activity and cardiovascular risk factors in children: the European Youth Heart Study (EYHS). PMID- 25699311 TI - Method of the Year 2014. PMID- 25699312 TI - Graham Johnson. PMID- 25699313 TI - Points of significance: Sources of variation. PMID- 25699314 TI - Transparency in large tissue samples. PMID- 25699315 TI - MinION takes center stage. PMID- 25699316 TI - Bacterial recall. PMID- 25699317 TI - A bumpy, holey method to probe proteins. PMID- 25699318 TI - A global look at local translation. PMID- 25699319 TI - [Specialist competence courses in crisis--strong actions required]. PMID- 25699320 TI - [Pre-doc jumpstart for research students]. PMID- 25699321 TI - [2014 Nobel Prize in Physiology or Medicine. The Nobel laureates have explored the internal GPS of the brain]. PMID- 25699322 TI - [Narcolepsy--rare disease that has received increased attention. Pandemrix vaccination caused a higher incidence among children and adolescents]. PMID- 25699323 TI - [Treatment of pain and nausea associated with tonsil surgery. New guidelines for the pharmacological treatment of children and adolescents]. PMID- 25699324 TI - [One in five who visited a health center received help for mental illness. But only 7 percent were given a psychiatric diagnosis, as shown in a database study in Stockholm]. PMID- 25699325 TI - [Cerebral hemorrhage after ingestion of the performance enhancer "Jacked Power". Healthy woman fell ill during exercise after a single dose]. PMID- 25699326 TI - [Experiences from Lidkoping: Warfarin remains the first choice of treatment for embolic cerebral infarction]. PMID- 25699327 TI - [Fellowship success story in Lund]. PMID- 25699328 TI - [The war hospital on Gotland a refuge for war victims]. PMID- 25699329 TI - [IT in health care must be allowed to cost]. PMID- 25699330 TI - [New visions and relief on the barricades]. PMID- 25699331 TI - [Evidence-based medicine--triumphs and problems. The limitations are found in everyday clinical practice]. PMID- 25699332 TI - [IT systems in healthcare requires new ways of thinking]. PMID- 25699333 TI - [Electronic support in the medical record for drug dosage in renal failure]. PMID- 25699334 TI - [Telemedicine leads to increased patient benefit]. PMID- 25699335 TI - [Medical history taking via computer can provide better care and research]. PMID- 25699336 TI - [Clinical decision support can provide assistance in complex health care]. PMID- 25699337 TI - [When confidentiality is replaced with information sharing]. PMID- 25699338 TI - [Speak plainly about medical education outside Sweden]. PMID- 25699339 TI - [Reply on specialist competence courses, The Swedish National Board of Health and Welfare: Health care authorities have responsibility for physicians internship]. PMID- 25699340 TI - [Establish mandatory reporting of invasive infections with group C/G streptococci]. PMID- 25699341 TI - [The illness forced him to write incessantly. The story of Kierkegaards hypergraphia and death]. PMID- 25699342 TI - The role of MR cholangiopancreatography in preoperative assessment for repair of major iatrogenic biliary injury: 10-year experience. AB - BACKGROUND/AIMS: Major iatrogenic biliary injury is a potentially life threatening complication after laparoscopic cholecystectomy. Early diagnosis is essential to improve outcomes, however, to date, there is no consensus regarding the best imaging approach for preoperative assessment of these injuries. METHODOLOGY: From March 2002 to February 2012, 40 patients with postoperative major biliary injury underwent biliary reconstruction at our Institution. Mean age was 51.7 +/- 18.1 years (19-86) with 30 (75%) females. Magnetic resonance cholangiopancreatography (MRCP) were compared with different diagnostic modalities and definitive intraoperative findings. RESULTS: Of 40 patients, 10 (25%) had Bismuth type I, 10 (25%) Bismuth type II, 6 (15%) Bismuth type III injury, 10 (25%) Bismuth type IV and, 4 (10%) Bismuth type V. MRCP has similar accuracy to define injury site, but is superior in delineating proximal ductal anatomy that was often not visualized with endoscopic retrograde cholangiopancreatography (ERCP). CONCLUSION: MRCP is a reliable, accurate and readily available diagnostic tool to assess complex biliary injuries. It provides adequate visualization of the proximal and distal biliary trees and may be considered as first-line test in the management of major iatrogenic biliary injuries. Revision of current guidelines for diagnostic approach of this condition is warranted. PMID- 25699343 TI - Risk factors of morbidity and predictors of long-term survival after hepatopancreatoduodenectomy for biliary cancer. AB - BACKGROUND/AIMS: Hepatopancreatoduodenectomy (HPD) is performed to achieve radical resection of malignant biliary tumors. We reviewed clinical outcomes to evaluate the utility of HPD in terms of morbidity and mortality. METHODOLOGY: A retrospective analysis was conducted on 17 patients underwent HPD between August 1991 and May 2013; 9 bile duct cancer, 5 advanced gallbladder and 3 pancreatic tumor with liver metastasis. RESULTS: The morbidity and mortality rates were 88.3% and 0%, respectively. Univariate analysis showed that a body mass index of >=22 and preoperative total bilirubin level >=0.8 mg/dl were significantly associated with severe complications. One-, 3- and 5-year survival rate were 73.3%, 60.0% and 30.0%. In 14 patients with biliary carcinoma, univariate analysis showed that a histological grade of G1 was significantly associated with survival. Patients without pancreatic invasion or portal vein invasion tended to survive longer than patients with these types of invasion, although the difference was not significant. CONCLUSIONS: HPD can be performed with no mortality and provides a survival benefit for some patients with biliary carcinoma undergoing curative resection. In patients with grade G1 biliary carcinoma without pancreatic or portal vein invasion in particular, this aggressive surgery might offer a chance of long-term survival. PMID- 25699344 TI - The analysis of expression of CCK and IP3 receptors in gallstones patients with type 2 diabetes mellitus. AB - BACKGROUND/AIMS: Type 2 diabetes mellitus (T2DM) is correlated with gallbladder diseases. This study aimed to investigate the expression of CCK and IP3 receptors in patients with gallbladder stones and T2DM and its correlation with the hypomotility of the gallbladder. METHODOLOGY: 26 patients with gallstones and T2DM (Group 1) and 24 gallstones patients without T2DM (Group 2) were enrolled in this study. The emptying function of the gallbladder was measured by ultrasonography. The activity of CCK-R was analyzed by radioligand method and the IP3-R antibody was used to detect the IP3-R from patients in both groups. RESULTS: Gallbladder ejection volume (EV) ((11.6+/-5.1) ml3 vs (21.5+/-7.8) ml3) and gallbladder ejection fraction (GBEF2)(%)((17.2+/-11.3) ml3 vs (52.8+/-12.9) ml3) were significantly lower (P<0.01) in patients with gallstones and T2DM. The amount of CCK-R and the activity of CCK-R in Group 1 were significantly lower than that in Group 2 (P<0.01). And IP3-R in Group 1 was much lower than that in Group 2, as well (P<0.01). CONCLUSION: The expression of CCK-R and IP3-R in gallstones patients with T2DM was much lower in such patients, leading to impaired gallbladder emptying function and the formation of gallstones. PMID- 25699345 TI - The effect of endoscopic ultrasonography in treatment of distal inflammatory biliary stricture: a retrospective analysis of 165 cases. AB - BACKGROUND/AIMS: Endoscopic ultrasonography (EUS) are relatively new alternatives to surgery for the treatment of benign lesions in the biliary duct. This study was to explore the value of EUS in the treatment of distal inflammatory biliary stricture. METHODOLOGY: 165 patients with distal inflammatory biliary stricture underwent EUS, according to EUS, endoscopic retrograde cholangiopancreatography (ERCP), intraductal ultrasonography (IDUS), endoscopic retrograde biliary drainage and endoscopic biliary dilation were performed. The clinical data about therapies and recovery of 22 patients was recorded and analyzed. RESULTS: In 165 patients, 163 cases underwent ERCP and intraductal ultrasonography (IDUS) successfully following EUS. Total 356 ERCPs were performed with 87 biliary duct stents inserted. After EUS the liver function, the thickness and pressure of biliary duct were decreased compared to these before EUS. The complication rate was 5.1% (18/356). After a follow-up of 27.6+/-10.6 months, strictures had not recurred in 121 patients after stents removed. CONCLUSION: EUS for distal inflammatory biliary stricture can be selected as a safe, effective and minimally invasive therapeutic method. PMID- 25699346 TI - Anatomy of mesothyroid: value of mesothyroid excision in thyroid cancer patients. AB - BACKGROUND/AIMS: To determine the anatomic distribution of mesentery-like appearance around the thyroid and explore a potential mesothyroid excision for thyroid cancer patients. According to the concept of total mesorectal excision (TME) for rectal cancer, we perform a concept of complete mesothyroid excision for thyroid cancer. Most digestive organs have mesentery. In-depth understanding of mesentery has changed the conceptual framework of surgical treatment and improved management and better outcomes of digestive tumors. METHODOLOGY: The anatomic distribution of the fascia and fascial spaces was studied by dissection of ten specimen fixed in 10% formalin. Thyroid cancer patients (n=5) were included to verify the fascia and fascial spaces during the operation. RESULTS: The paratracheal fat tissue was found to connect to the pretracheal fat tissue with a structure embedded in two layers of fascia. The two layers of fascia combined with carotid sheath from the outside, while the inside component was connected to the thyroid and considered mesentery. CONCLUSION: The thyroid has mesentery which is located in pretracheal and paratracheal area. An adequate treatment for the patients is the systematic en bloc removal of the tumor and lymph nodes while performing mesothyroid excision. PMID- 25699347 TI - Short-term and long-term outcomes of surgical treatment for HCC within Milan criteria with cirrhotic portal hypertension. AB - BACKGROUND/AIMS: To compare and assess the outcomes of liver resection, radiofrequency ablation and liver transplantation for patients with hepatocellular carcinoma (HCC) within Milan criteria and cirrhotic portal hypertension. METHODOLOGY: 248 patients with HCC within Milan criteria and cirrhotic portal hypertension who underwent surgical treatments (liver resection, radiofrequency ablation and liver transplantation were reviewed in this study. Patients were divided into three groups according to different surgical strategies: RST Group, RFA Group and LT Group. Pre- and intra-operative parameters were statistically analyzed. Postoperative outcomes including Hematological data and tumor data, complications, long-term survival rates and recurrence-free survival rates were compared. RESULTS: The incidence of postoperative complications that were classified according to Clavien-Dido Classification were 16.22% for RST Group, 9.09% for RFA Group and 53.85% for LT Group. The 1-, 2- and 3-year recurrence-free survival rate of three groups were 88%, 74%, 68% for RST Group, 60%, 39%, 35% for RFA Group and 97%, 89%, 87% for LT Group, respectively. CONCLUSION: Although the postoperative recurrence rate following RFA was higher than that of RST and LT, the long-term survival rates of three managements for patients with HCC within Milan criteria and portal hypertension were similar. PMID- 25699348 TI - The usefulness and safety of carbon dioxide insufflation during endoscopic retrograde cholangiopancreatography in elderly patients: a prospective, double blind, randomized, controlled trial. AB - BACKGROUND/AIMS: Carbon dioxide (CO2) insufflation has been used in endoscopic retrograde cholangiopancreatography (ERCP). However, its usefulness and safety are controversial in elderly patients. Our aim was to assess the safety and usefulness of CO2 insufflation during ERCP in elderly patients. METHODOLOGY: Between April 2010 and June 2011, a total of 60 patients 75 years old or older, who underwent ERCP, were randomized into the CO2 group (n = 30) and the air group (n = 30). Main outcomes were determined by assessing abdominal symptoms according to the Wong-Baker FACES Pain Rating Scale, calculating the volume of residual gas retention within the intestines on abdominal X-ray quantitatively and observing the cardiopulmonary states. RESULTS: 30 patients in the CO2 group and 30 patients in the air group were analyzed. Abdominal distension (P < 0.01), discomfort (P < 0.01) and nausea (P < 0.01) at 2 hours after ERCP were significantly reduced in the CO2 group. The gas volume scores immediately after ERCP (P < 0.01) and at 2 hours (P < 0.01) were significantly lower in the CO2 group. CONCLUSIONS: CO2 insufflation instead of air insufflation is safe and useful for the prevention of post-ERCP abdominal symptoms in elderly patients. PMID- 25699349 TI - Acute hypervolemic hemodilution effect on oxygen metabolism and blood pharmacokinetics in patients undergoing acute laparotomy during induction of general anesthesia. AB - BACKGROUND/AIMS: To investigate acute hypervolemic hemodilution effect on oxygen metabolism and blood pharmacokinetics in patients undergoing acute laparotomy during Induction of general anesthesia. METHODOLOGY: Forty ASA I-II patients undergoing acute laparotomy were randomly divided into 2 groups (n=20 each): Patients of group A received Voluven 7 ml/kg in 20 mins before induction and 8 ml/kg after induction. Patients of group B received 6 ml/kg/h Plasmalyte A. Hemodynamic parameters MAP, HR and CVP were collected at 6 set points during the surgery: T1: before AHH; T2: before anesthesia induction; T3: right intubation; T4: 10 min after intubation; T5: 20 min after intubation; T6: skin incision. Arterial and venous blood samples were taken for blood gas analysis and determination of lactic acid, Hb and Hct: T1: before AHH, T2: right after AHH, T3: 0.5 h after AHH, T4: l h after AHH. Arterial Oxygen Content (Ca02), Central Venous Oxygen Content (Ccv02) and Oxygen Extraction Ratio (ER02) were calculated. RESULTS: The hemodynamic parameters were maintained within normal limits during operation in group A (P <0.05). CaO2, CcvO2, ERO2 and Lac between the two groups were no significant difference (P> 0.05). Compared with T1, CaO2/CcvO2 atT 2~4 reduced in both groups (P <0.05). Compared with group A, Hb and Hct in group B increased at T2~4 (P <0.05). CONCLUSIONS: Acute hypervolemic hemodilution in patients undergoing acute laparotomy during Induction of general anesthesia have some preventive hypotension effect, more conducive to the smooth blood pharmacokinetics; Voluven induced expansion of applications is safe and effective, and has no effect on the body's metabolic rate of oxygen. PMID- 25699350 TI - Acute life-threatening portal venous dilatation induced by a huge solitary fibrous tumor of the omentum. AB - An 85-year-old woman was referred to the medical oncology department because of a hypogastric mass. Contrast-enhanced CT showed a large hypervascular mass in the lower abdomen. CT angiography with volume rendering imaging revealed a vascular pedicle with an arborizing pattern of vessels. Many thick, early draining veins shunting into the portal vein were detected. Before surgery, the maximum size of the portal vein was 22 mm in diameter. Laparotomy revealed a huge, encapsulated, well-defined, hard tumor with hypervascularization, which was appended to the omentum. The mass with the omentum was curatively resected; it was 19 cm x 17 cm x 13 cm in size and 1915 g in weight. Histological features were consistent with a benign solitary fibrous tumor of the omentum, despite the tumor size and necrotic area found in the specimen. q Ultrasonography and CT performed at a 28 month follow-up revealed no evidence of tumor recurrence. Venous dilatation including that of the portal veins had diminished. PMID- 25699351 TI - Biliary strictures after cholecystectomy: long term results of a novative endoscopic treatment. AB - BACKGROUND/AIMS: In the early 1990's, we devised a novative protocol for the endoscopic treatment of post-cholecystectomy bile duct strictures: the purpose of this article is to assess the long-term outcomes of this approach. METHODOLOGY: Retrospective review of prospectively collected data from patients who underwent endoscopic stenting. Multiple stents were positioned it iterative duodenoscopies until a maximal diameter was reached. The stents were left in situ for 2 years, even if occluded. A long-term quality of life assessment using the SF-36 health status questionnaire was also performed. RESULTS: Eleven patients underwent a mean of 6 ERCP each; a mean number of 6.5 stents were inserted for a mean total French size of 62.8 F. After a mean following of 12.3 +/- 2.7 years, restenosis occurred in 1 patient. The results of the long-term quality of life assessment were similar to those of the Canadian general population. CONCLUSION: The little invasive nature and the excellent long-term results of our endoscopic protocol make it an acceptable alternative to surgery for patients who accept multiple duodenoscopies. The progressive dilatation of a stenosis by the sequential insertion of a continuously increasing number of stents without prophylactic stents changes appears as the key to success. PMID- 25699352 TI - Warm water immersion vs. standard air insufflation for colonoscopy: comparison of two techniques. AB - BACKGROUND/AIMS: Colonoscopy is associated with pain and discomfort in the majority of patients when performed without sedation. We performed a prospective and randomized study to compare warm water instillation and standard air insufflation colonoscopy techniques without any sedation. METHODOLOGY: The data of 122 patients (64 female and 58 male) were statistically analyzed. Patients were randomized into two groups by using computer generated list. In group A, standard colonoscopy with air insufflation was performed. In group B colonoscopy was performed by warm water infusion into the bowel. No analgesic, antispasmodic or sedative medications were used. After colonoscopy, the level of pain during colonoscopy experienced by the patient was measured using the visual analog scale (VAS). RESULTS: There were no statistically significant differences in gender and average age between the two groups of patients. Cecal intubation was successful in all patients (100%). All colonoscopies were performed without complications. Patients who had colonoscopy with water immersion had a significantly lower level of pain on the VAS (4.09 vs 5.06), p = 0.041. CONCLUSIONS: We confirmed the advantages of warm water instillation for colonoscope insertion in reducing pain without compromising the time to reach the cecum, success of cecum intubation or patient safety. PMID- 25699353 TI - Complete response to uracil-tegafur alone in advanced rectal cancer. AB - We report a case of a complete response to treatment with uracil-tegafur (UFT) alone in advanced rectal cancer. The patient was an 84-year-old woman referred to our hospital complaining of anal bleeding. A colonoscopy revealed a Borrmann type II tumor in the rectum, which was diagnosed as an adenocarcinoma. Therefore, best supportive care was initiated in April 2011 with oral administration of UFT. The anal bleeding stopped 2 months later, and the patient's general condition remains good at one year. A further colonoscopy at one year after initiation of treatment in April 2012 resulted in reclassification of the tumor as an Isp lesion, and the biopsy was negative for cancer. The patient was still alive with no sign of recurrence at 21 months after commencing UFT alone with no surgical treatment. These results suggest that chemotherapy with UFT alone can yield complete remission from advanced rectal cancer. PMID- 25699354 TI - Comparison analysis in synchronous and metachronous metastatic colorectal cancer based on microarray expression profile. AB - BACKGROUND/AIMS: Colorectal cancer (CRC) is one of the most common malignancies, and liver metastasis is one of the major causes of death of CRC. This study aimed to compare the genetic difference between metachronous lesions (MC) and synchronous lesions (SC) and explore the molecular pathology of CRC metastasis. METHODOLOGY: Microarray expression profile data (GSE10961) including 8 MC and 10 SC was downloaded from Gene Expression Omnibus. The differentially expressed genes (DEGs) between the two groups were identified based on T test. Furthermore, GO enrichment analysis was performed for the down-regulated DEGs using DAVID. Finally, Classify validation of known CRC genes based on previous studies between MC and SC samples was conducted. RESULTS: Total of 36 DEGs including 35 down regulated DEGs and 1 up-regulated DEGs were identified. The expressional differences of the 5 informative oncogenes: EGFr, PIK3R1, PTGS2 (COX-2), PTGS1 (COX1), and ALOX5AP between SC and MC were really tiny. CONCLUSIONS: Some DEGs, such as NFAT5, OLR1, ERAP2, HOXC6 and TWIST1 might play crucial roles in the regulation of CRC metastasis (both SC and MC) and by disrupting some pathways. However, our results indeed demand further research and experiment. PMID- 25699355 TI - Anatomical right hemicolectomy: a novel surgical method and its clinical application. AB - BACKGROUND/AIMS: Presently, the notion of traditional right hemicolectomy has not met the rapidly developed requirements for precise gastrointestinal surgical procedures. In this study, we introduced a novel surgical method, namely "anatomical right hemicolectomy," and evaluated the safety and short-term effects of this method for the treatment of right hemicolon carcinoma. METHODOLOGY: The clinical data of 10 cases with progressive right hemicolon carcinoma underwent anatomical right hemicolectomy from January 2013 to February 2014 were collected and analyzed retrospectively. RESULTS: All the operations were successfully completed. The number of cleared lymph nodes was 18.0+/-6.7, the mean operative time was 162.7+/-25.3 mins, the mean blood loss was 95.2+/-32.5 ml, time to first flatus was 4.2+/-1.9 days, and the mean size of tumor was 4.96+/-3.2 cm. In these 10 patients, there was no case of respiratory infections, intestinal obstruction, anastomotic bleeding, anastomotic stricture, anastomotic leakage and other complications. All patients recovered, and subsequently discharged. CONCLUSIONS: In summary, anatomical right hemicolectomy was a safe and feasible method for the treatment of progressive right hemicolon carcinoma; it was worth popularizing widely. PMID- 25699356 TI - Significance of KRAS mutation in patients receiving mFOLFOX6 with or without bevacizumab for metastatic colorectal cancer. AB - BACKGROUND/AIMS: KRAS mutation is an important prognostic factor for patients with metastatic colorectal cancer receiving anti-epidermal growth factor receptor therapy. However, the influence of KRAS mutation on the response to mFOLFOX6 +/- bevacizumab remains unclear. METHODOLOGY: We retrospectively analyzed 49 patients who received modified FOLFOX6 (mFOLFOX6) +/- bevacizumab as first-line therapy. Genetic analysis showed that 30 patients had wild-type (WT) KRAS and 19 patients hadKRAS mutations (MT). These two groups were compared with regard to the response rate (RR), progression-free survival (PFS), and overall survival (OS). RESULTS: The RR was not significantly different between the WT and MT groups, but PFS and OS were significantly better in the WT group than the MT group (PFS: 11.8 months vs. 8.7 months, p<0.01; OS: 37.8 months vs. 29.3 months, p<0.0385). A similar analysis of 27 patients who were treated with mFOLFOX6 + bevacizumab showed a better prognosis for WT patients. Multivariate analysis also revealed that KRAS mutation was an independent factor with a significant relation to PFS. CONCLUSIONS: These results suggest that KRAS mutation may be a useful prognostic marker for patients with metastatic colorectal cancer receiving mFOLFOX6 +/- bevacizumab therapy, especially for patients treated with mFOLFOX6 + bevacizumab. PMID- 25699357 TI - Potential tumor spread of lateral pelvic lymphatic flow in low rectal cancer. AB - BACKGROUND/AIMS: In Japan lateral pelvic lymph node dissection has been actively performed with total mesorectal excision for low rectal cancer. However, its definitive efficacy remains unclear. This study is to evaluate clinical significance of lateral pelvic lymphatic drainage in low rectal cancer patients by 99mTc-Sn colloid radioactive tracers. METHODOLOGY: Intraoperatively detecting rectal lymphatic drainage using 99mTc-Sn colloid radioactive tracer in 39 low rectal cancer patients, we performed lateral pelvic lymph node dissection in lateral pelvic lymphatic flow-positive patients. RESULTS: Lateral pelvic lymphatic flow was detected in 11 patients (28%). In four (36%) of 11 patients, tumor cells were histologically identified in lateral pelvic lymph nodes. A median size of metastatic lateral pelvic lymph nodes was 7.5 (range, 2-150) mm, and all but one overlooked patient could not be detected by routine preoperative imaging scans retrospectively. The five-year disease-free survival rate of lateral pelvic lymphatic flow-positive patients was significantly poorer (45% vs. 75%, p = 0.0044). CONCLUSIONS: Tumor cells potentially extended beyond the fascia propria recti in low rectal cancer with lateral pelvic lymphatic flow. Preoperative chemoradiation therapy and adjuvant therapy are considered to be reasonable to improve a poor prognosis of low rectal cancer patients with lateral pelvic lymphatic flow. PMID- 25699358 TI - Long-term outcome of laparoscopic resection for stage IV colorectal cancer. AB - Laparoscopic surgery is recommended as an initial stage IV colorectal cancer therapy. A 57-year-old male with sigmoid colon cancer and two hepatic metastases underwent laparoscopic sigmoidectomy with lymph adenectomy. He was orally administered postoperative Tagafur/Uracil/leucovorin therapy for 10 months. However, because of regrowth of the liver metastasis he was administered leucovorin/bolus and infusional 5-fluorouracil/irinotecan therapy for 10 months followed by extended left lobectomy of the liver and the above mentioned chemotherapy was continued for 6 months. He was diagnosed with S6 and S6/7 hepatic recurrent tumor, which were resected 14 months after the second and another 14 months after the third surgery, respectively. Forty-two months following complete response after the fourth surgery, S6 hepatic recurrent tumor was resected. Six months after the fifth surgery, he developed multiple liver metastases. He was treated successfully using leucovorin/bolus and infusional 5 fluorouracil/oxaliplatin and bevacizumab. He is alive 9 years and 3 months after initial surgery. PMID- 25699359 TI - Elevated preoperative serum C-reactive protein levels are associated with poor survival in patients with colorectal cancer. AB - BACKGROUND/AIMS: Previous studies have reported that elevated preoperative serum C-reactive protein (CRP) levels are associated with a poor prognosis in patients with various types of cancer. The aim of this study was to evaluate the prognostic significance of the preoperative serum CRP levels in patients with colorectal cancer and determine an appropriate cutoff value of the serum CRP level. METHODOLOGY: We enrolled 855 patients who underwent surgery for stage I-IV colorectal cancer. The median serum CRP level was 0.13 (range: 0.01-22.8). We set 0.6 as the cutoff value of the serum CRP level based on the receiver operating characteristic curve. The patients were classified into two groups according to the serum CRP level. The prognostic significance of an elevated serum CRP level was evaluated using a multivariate analysis. RESULTS: The cancer-specific survival was significantly worse in the patients with a high serum CRP level. In particular, more significant differences were observed in the patients with stage IV disease. The multivariate analysis indicated that a high serum CRP level was an independent risk factor for poor survival. CONCLUSIONS: The preoperative serum CRP level is a convenient biomarker and predictor of a poor prognosis after surgery for colorectal cancer. PMID- 25699360 TI - Prognostic significance of initial recurrence site in hematogenous recurrence of esophageal squamous cell carcinoma. AB - BACKGROUND/AIMS: Hematogenous recurrences of esophageal squamous cell carcinoma (ESCC) have dismal prognoses, but prognostic heterogeneity exists in this disease. The objectives of this study were to clarify the prognosis in this disease with regard to the initial recurrence site and to define the prognostic factors. METHODOLOGY: We retrospectively reviewed the cases of 67 consecutive patients with hematogenous recurrence in major organs after esophagectomy for ESCC of the thoracic esophagus and the esophagogastric junction. We analyzed clinicopathological characteristics, survival probability, and potential prognostic factors. RESULTS: Lung, liver, bone, and multiple-organ metastases occurred in 24, 19, 14, and 10 patients, respectively. Twenty-seven patients simultaneously had locoregional recurrence (combined recurrence). Among all 67 patients, the median disease-free interval (DFI) was 9.7 months, and the median survival time after the initial recurrence was 4.9 months. The patients with initial lung metastasis had most favorable prognosis with the median survival time of 9.8 months. A multivariate analysis identified that initial recurrence site, DFI, combined recurrence, and anti-cancer therapy were independent prognostic factors. CONCLUSIONS: The initial recurrence site contributes to the prognostic heterogeneity of patients with hematogenous recurrence of ESCC. The prognostic factors identified in this study are useful to optimize the management of these patients. PMID- 25699362 TI - Impact of laparoscopic surgery on survival of patients with small bowel adenocarcinoma and peritoneal metastasis. AB - The feasibility of laparoscopic surgery for peritoneal metastasis is still controversial. A 42-year-old male presenting with bloody stool underwent small intestinal fiberscopic examination. The biopsied specimens pathologically demonstrated adenocarcinoma of the upper jejunum. Laparoscopy revealed a 10-mm nodule in the omentum. Laparoscopic partial jejunal resection with regional lymph node dissection was performed with combined resection of the nodule without conversion. No other tumor was detected. The resected specimen contained an irregular ulcerative tumor measuring 52 x 33 mm. Microscopic examination revealed that the mass and peritoneal nodule comprised moderately differentiated adenocarcinoma. After surgery, the patient was treated with leucovorin/bolus and infusional 5-fluorouracil/oxaliplatin for 6 months. Eleven months after surgery, a solitary peritoneal recurrence developed near the camera port site. Six months later, positron emission tomography, computer tomography, and exploratory laparotomy revealed multiple peritoneal recurrences. The patient was then treated with leucovorin/bolus and infusional 5-fluorouracil/irinotecan. Three months and 6 months later partial remission and complete response, respectively were sequentially induced. The patient is alive 3 years and 9 months after initial surgery without any tumor recurrence. To our knowledge, this is the first report to demonstrate laparoscopic surgery combined with chemotherapy regimens, which induced a successful complete response. PMID- 25699361 TI - Knockdown of nucleostemin can inhibit the proliferation of esophageal carcinoma cells in vitro through upregulating p21. AB - BACKGROUND/AIMS: Esophageal squamous cell carcinoma is a common digestive tract cancer with poor prognosis. Nucleostemin is a nucleolar protein expressed in stem and cancer cells, involved in the regulation of cell proliferation. p21 plays an important role in negative regulation of the cell-cycle. We investigated the role of nucleostemin through regulating p21 expression in the occurrence and progression of human esophageal carcinoma. METHODOLOGY: The expression of nucleostemin and p21 protein and of nucleostemin was knocked-down by means of RNA interference (RNAi) in Eca109 cells. Then, mRNA and protein expressions of nucleostemin and p21 were determined by reverse transcriptase polymerase chain reaction and Western blotting, respectively. In addition, the effect of nucleostemin RNAi on cell proliferation and cell cycle distribution of Eca109 cells were observed. RESULTS: Nucleostemin was high expressed, but p21 was low expressed in esophageal carcinoma tissues while increased level of nucleostemin protein was associated with reduced p21. inhibition of nucleostemin resulted in an increased expression of p21 and inhibition of cell proliferation, cause G1/G0 phase cells increased and S-phase cells reduced greatly in Eca109 cells. CONCLUSION: Silence of nucleostemin inhibit cell proliferation through up regulating p21 expression and nucleostemin may be involved in the pathogenesis of esophageal squamous cell carcinoma. PMID- 25699363 TI - Upper gastrointestinal bleeding in severely burned patients: a case-control study to assess risk factors, causes, and outcome. AB - BACKGROUND/AIMS: To determine the risk factors, causes, and outcome of clinically important upper gastrointestinal bleeding that occurs in severely burned patients. METHODOLOGY: The charts of all patients admitted to the burn intensive care unit were analyzed retrospectively over a 4-year period (from January 2006 to December 2009). Cases consisted of burned patients who developed upper gastrointestinal bleeding more than 24 hours after admission to the burn intensive care unit. Controls were a set of patients, in the burn intensive care unit, without upper gastrointestinal bleeding matched with cases for age and gender. Cases and controls were compared with respect to the risk factors of upper gastrointestinal bleeding and outcomes. RESULTS: During the study period, clinically important upper gastrointestinal bleeding occurred in 20 patients out of all 964 patients. The most common cause of upper gastrointestinal bleeding was duodenal ulcer (11 of 20 cases, 55%). In the multivariate analysis, mechanical ventilation (p = 0.044) and coagulopathy (p = 0.035) were found to be the independent predictors of upper gastrointestinal bleeding in severely burned patients. CONCLUSIONS: Upper gastrointestinal hemorrhage tends to occur more frequently after having prolonged mechanical ventilation and coagulopathy. PMID- 25699364 TI - Minimizing operative time for robotic gastrectomy in cancer: analysis of the major factors for four detailed steps. AB - BACKGROUND/AIMS: We outlined the major factors for minimizing the operative time of robotic-assisted gastrectomy (RAG) during the initial learning period. METHODOLOGY: We performed correlation analysis and multivariate linear regression for detailed operation steps including preparing, docking, console and anastomosis time. RESULTS: Forty patients underwent RAG for cancer. By Pearson analysis, case number (r = -0.313; P = 0.049) and body mass index (BMI) (r = 0.368; P = 0.019) were found to be correlated with total operation time. Multivariate linear regression with backward elimination showed that BMI and case number significantly affected total operation time. A detailed four-step analysis showed that docking time was significantly affected by intraoperative complications. CONCLUSIONS: In conclusion, we recommend a V-shape port placement as an important surgical factor for preparation and docking time to avoid unnecessary intraoperative trial errors. In addition, selecting lower-BMI patients would be helpful in shortening the time to mastery of console, which is the most time consuming operative step of the robotic procedure for robotic-naive surgeons. PMID- 25699365 TI - Rescreening colonoscopy practice after a negative index colonoscopy in a clinical setting; cross-sectional study for interval and outcomes of rescreening colonoscopy. AB - BACKGROUND/AIMS: We evaluated the rescreening colonoscopy practice after negative index colonoscopy (IC) in a real clinical setting. METHODOLOGY: We reviewed the individual records of aged over 40 who had negative IC at a single center between 2003 and 2005. The quality of the IC including bowel preparation (using Boston bowel preparation scale, BBPS), cecal intubation, withdrawal time and the incidence and risk factors for advanced lesions during the rescreening colonoscopy were analyzed. RESULTS: On 1570 negative ICs, 32.6% (n = 512) had rescreen ing colonoscopy until August, 2011. The rescreened group showed significantly lower quality of the IC compared to the group not rescreened (mean BBPS 7.9 vs. 8.2, p = 0.032, mean withdrawal time 5.2 vs. 5.7 minutes, p = 0.003). Rescreening detected polyps in 33.4% (n = 171) and advanced lesions in 3.7% (n = 19, 73.7% male; p = 0.022) including cancers (0.4%, n = 2). Male gender (odds ratio, 2.995; 95% confidence interval, 1.199-7.481) was an independent risk factors for advanced lesions on rescreening. CONCLUSIONS: Advanced lesions were detected in 3.7% of rescreening group after negative IC and male was a risk factor. Following a low-quality IC, a rescreening colonoscopy was performed with short interval in a clinical practice. PMID- 25699366 TI - Monopolar soft-mode coagulation using hemostatic forceps for peptic ulcer bleeding. AB - BACKGROUND/AIMS: Upper gastrointestinal hemorrhage from bleeding peptic ulcer is sometimes difficult to treat by conventional endoscopic methods. Recently, monopolar electrocoagulation using a soft-coagulation system and hemostatic forceps (soft coagulation) has been used to prevent bleeding during endoscopic submucosal dissection. The aim of this study was to assess the safety and efficacy of soft coagulation in the treatment of bleeding peptic ulcer. METHODOLOGY: A total of 39 patients with peptic ulcers were treated using soft coagulation at our hospital between January 2005 and March 2010. Emergency treatment employed an ERBE soft-mode coagulation system using hemostatic forceps. Second-look endoscopy was performed to evaluate the efficacy of prior therapy. Initial hemostasis was defined as accomplished by soft coagulation, with or without other endoscopic therapy prior to soft coagulation. The rate of initial hemostasis, rebleeding, and ultimate hemostasis were retrospectively analyzed. RESULTS: The study subjects were 31 men and 8 women with a mean age of 68.3+/ 13.7 years, with 29 gastric ulcers and 10 duodenal ulcers. Initial hemostasis was achieved in 37 patients (95%). During follow-up, bleeding recurred in two patients, who were retreated with soft coagulation. CONCLUSIONS: The monopolar soft coagulation is feasible and safe for treating bleeding peptic ulcers. PMID- 25699367 TI - Effects of mucosal TNF-alpha levels on treatment response in Crohn's disease patients receiving anti-TNF treatment. AB - BACKGROUND/AIMS: We aimed to find out if mucosal TNF-alpha (m-TNF-alpha) levels have predictive impact on anti-TNF treatment response in Crohn's disease (CD). METHODOLOGY: TNF-alpha values were determined with immunohistochemical staining of intestinal biopsies taken from 35 subjects on anti-TNF treatment for CD and 25 controls. Correlation between m-TNF-alpha levels and anti-TNF treatment were evaluated. RESULTS: m-TNF-alpha levels were determined higher in CD group (28.0+/ 8.9 vs 5.8+/-2.1; P<0.001). m-TNF-alpha levels were lower in CD patients who were hospitalized (23.0+/-8.7 vs. 30.3+/-8.1; P=0.024). Although not to a statistically significant level, favorable parameters such as clinical remission (28.5+/-8.0 vs. 26.4+/-11.8, p=0.419) and mucosal healing (29.9+/-8.2 vs. 23.9+/ 9.2, p=0.097) were increased in patients with high m-TNF-alpha levels whereas unfavorable parameters such as relapse (26.0+/-9.4 vs. 29.7+/-8.2, P=0.107), surgery requirement (22.8+/-11.1 vs. 29.1+/-8.1, P=0.147), steroid requirement (25.9+/-9.0 vs. 28.6+/-8.9, P=0.595), and anti-TNF intensification (22.3+/-3.8 vs. 28.5+/-9.0, P=0.183) were increased in patients with low m-TNF-alpha levels. CONCLUSIONS: High mucosal TNF-alpha levels before treatment have favorable effects on anti-TNF treatment response in CD. Presence of high m-TNF-alpha levels at the diagnosis may be encouraging in early initiation of anti-TNF treatment. PMID- 25699368 TI - Effect of irinotecan on liver regeneration: an experimental study in rats. AB - BACKGROUND/AIMS: The aim of this study was to determine the histopathological changes caused by irinotecan and show the effect of these changes on liver regeneration. METHODOLOGY: In this experimental study 96 Winstar-Albino breed female rats were used. The animals were divided into two groups. Study group received intraperitoneal irinotecan weekly for four weeks. Control group received normal saline. One week after the last injection all animals had undergone 70% hepatectomy. Following 70% hepatectomy rats were sacrificed and liver tissue samples were obtained at 0, 24, 48, 72, 96 and 120 hours. Specimens were evaluated for steatosis, lobular inflammation and cellular swelling with hematoxylin and eosin staining. Liver regeneration was evaluated im munohistochemically using proliferating cell nuclear antigen activity index. RESULTS: Hepatic steatosis was significantly more in the irinotecan group. Although lobular inflammation and cellular swelling were more prominent in the irinotecan group these values were not statistically significant. In both groups, regeneration reached to peak at 48th hour and returned to baseline at 120th hour. Liver regeneration indices were not different between the groups. CONCLUSION: It was shown that irinotecan did not affect the liver regeneration adversely. In order to show the effects of irinotecan on liver regeneration in humans further clinical studies are needed. PMID- 25699369 TI - Presence of fibrosis is predictive of postoperative survival in patients with small hepatocellular carcinoma. AB - BACKGROUND/AIMS: The aim of this study was to evaluate whether liver fibrosis is predictive of survival in patients who require hepatectomy for small hepatocellular carcinoma. METHODOLOGY: In this retrospective study, we enrolled 174 patients with small HCC who underwent major or minor hepatectomy at the Changhua Christian Hospital during the period January 2001 to June 2007. Patients were classified into two subgroups depending on whether tumor recurrence after surgery. Factors influencing overall survival and recurrence were analyzed and compared between the two subgroups. Univariate and multivariate logistic regression analyses were performed to determine the most significant predictors of tumor recurrence or death. The Kaplan-Meier method and the log-rank test were used to detect differences in cumulative survival between the two subgroups based on histopathologic fibrosis scores. RESULTS: Results of the univariate analysis revealed these variables that tumor margin, type of resection, and degree of fibrosis were independent predictors of tumor recurrence or death. However, the multivariate analysis revealed that fibrosis was the only independent predictor of tumor recurrence. Survival analysis showed that low fibrotic scores were predictive of disease-free survival. CONCLUSIONS: The degree of fibrosis is an important predictor of survival among patients who undergo hepatectomy for small HCC. PMID- 25699370 TI - Usefulness of balloon-occluded retrograde transvenous obliteration for gastric varices concurrent with hepatocellular carcinoma. AB - BACKGROUND/AIMS: We performed balloon-occluded retrograde transvenous obliteration (B-RTO) before hepatocellular carcinoma (HCC) therapy in cases with HCC and gastric varices (GV) containing porto-systemic shunts. We conducted retrospective analyses on effects of B-RTO on hepatic functional reserve and HCC, as well as associated complications, and verified HCC treatment timing. METHODOLOGY: B-RTO was performed before HCC therapy after confirming disappearance or shrinkage of gastro-renal shunt with 3-dimensional computed tomography (3D-CT). Hepatic resection (HR) was performed in 7 of 12 cases, and transcatheter chemo-embolization (TACE) was used in 5 cases. RESULTS: B-RTO significantly improved GV (P=0.002). Improvement in grade/form was observed by endoscopy after 84.1 days, and that in gastro-renal shunt was observed by 3D-CT after 13.9 days. HCC size (P=0.862) and stage didn't change after B-RTO. Two cases showed improved Child-Pugh classification, and no deterioration in hepatic functional reserve was observed. B-RTO was performed 37.9 days before HCC therapy in surgical cases, and 45 days in TACE cases. CONCLUSION: Performing B-RTO before HCC therapy did not exacerbate HCC and allowed its safe performance. Evaluation with 3D-CT after B-RTO to determine HCC therapy timing was possible after 2 weeks. However, care is needed as esophageal varices worsened in some cases. PMID- 25699371 TI - Why is radiofrequency ablation therapy applied for hepatocellular carcinoma up to 3 nodules and smaller than 3 cm in tumor size? AB - BACKGROUND/AIMS: Radiofrequency ablation (RFA) has been applied for hepatocellular carcinoma (HCC) up to 3 nodules, within 3 cm in size. However, the scientific rationale of the treatment criteria for RFA has not been well analyzed. We compared the number and size of tumors with recurrence rates and survival rates. METHODOLOGY: The study participants retrospectively were enrolled 625 consecutive cases of naive HCC treated with RFA. We analyzed recurrence rates and survival of 472 for the patients with HCC <= 3 nodules, <= 3 cm in size (Group A), and 153 for the patients exceeding limits (Group B). RESULTS: Median follow-up was 2.97 years. The survival rate of Group A was significantly higher than that of Group B (5 years: 55.6% vs. 44.2%, 10 years: 27.4% vs. 15.7%; P<0.05). Multivariate analysis of predictors for prognostic factors demonstrated that meeting the RFA criteria, Child-Pugh score A, and lower levels of des-gamma carboxy prothrombin (DCP) were independent factors significantly affecting prognosis. CONCLUSIONS: The present study is the firstto elucidate the scientific rationale for RFA treatment criteria for HCC regarding tumor number and size. We confirmed that the RFA treatment criteria select patients who stand to gain the most from RFA. PMID- 25699372 TI - The distribution and resistance of pathogens causing blood stream infections following liver transplantation: a clinical analysis of 69 patients. AB - BACKGROUND/AIMS: To study the distribution and drug resistance of pathogens causing blood stream infections (BSIs) and provide the evidence for clinical therapy after liver transplantation. METHODOLOGY: Blood samples were processed by the BACTEC 9120 blood culture system. Species identification was performed using the Vitek-2 system. The drug susceptibility of pathogens was performed using the ATB FUNGUS 3 system. RESULTS: One hundred and twenty six episodes of BSIs occurred in 69 patients between January 31, 2003 and January 31, 2014. The gram positive bacteria emerged as major pathogens and constituted 48.4% of all pathogens (61/126). The most common bacilli were Enterobacter spp and Enterococcus spp followed by S. aureus. The gram-negative bacteria were relatively sensitive to carbapenems and the gram-positive bacteria were relatively sensitive to glycopeptides and oxazolidone antibiotics. The drug resistance of fungi to amphotericin B, flucytosine, voriconazole and caspofungin was not found. CONCLUSION: In liver transplantation, gram-positive bacteria caused BSls more frequently than gram-negative bacteria. The resistance rate of bacteria to antibiotics was high while the rate was low in fungi. PMID- 25699373 TI - Three-dimensional printing model of liver for operative simulation in perihilar cholangiocarcinoma. AB - 3-dimensional printed liver was constructed using 3D vascular imaging in a patient with intrahepatic cholangiocarcinoma who underwent major hepatectomy. The reproducibility of 3D modeling by the latest imaging has been clarified and future preoperative simulation should be adramatically changed. PMID- 25699374 TI - Glissonean pedicle approach in laparoscopic anatomical liver resection. AB - The remnant liver volume, its function and tumor clearance are important issues in laparoscopic liver resection (LLR). With increasing knowledge of LLR, surgical safety and oncological results after LLR are now similar to those after open liver resection. Anatomical LLR has emerged from the introduction of the Glissonean pedicle approach to open surgery. When anatomical LLR is performed with this approach, many types of resections are possible, including major resections, bisegmentectomy, and monosegmentectomy. This study provides important technical features of anatomical LLR with the Glissonean pedicle approach. PMID- 25699375 TI - Effect of acute normovolemic hemodilution combined with controlled low central venous pressure on cerebral oxygen metabolism of patients with hepalobectomy. AB - BACKGROUND/AIMS: The effect of acute normovolemic hemodilution (ANH) combined with controlled low central venous pressure (LCVP) on the cerebral oxygen metabolism of patients with hepalobectomy. METHODOLOGY: Undergoing hepatic resection operation in 60 cases, were randomly divided into control group, LCVP group (Group II) and ANH + LCVP group (Group IIl). Before hemodilution (T1), decrease of CVP (T2) and increase of CVP (T3) and at the end of surgery (T4), the blood was sampled via the jugular vein bulb and radial artery for blood gas analysis. RESULTS: Compared with group I, the CaO2 of group II at T3 and T4 was increased; in group III, CaO2 and Da-jvO2 at T2 and T3 were decreased, CjvO2 at T2 decreased, and CaO2 and CjvO2 at T4 increased. Compared with group II, CaO2, CjvO2 and Da-jvO2 of group III at T2 and T3 were decreased. CERO2 of the three groups at T3 and T4 were all decreased (P<0.05 or 0.01). The jugular venous oxygen saturation (SjvO2) and VADL of the three groups at each time point were all within the normal range. CONCLUSION: The moderate ANH combined with LCVP had no adverse effect on the cerebral oxygen metabolism of the patients with the hepalobectomy. PMID- 25699376 TI - Comparison of cellular immunity in patients with chronic hepatitis B, inactive hepatitis B surface antigen carriers and spontaneously recovered individuals. AB - Different clinical outcomes of acute HBV infection have been partially explained by individual differences in immune response. In this study we investigated interferon gamma (IFN-gamma) secretion of peripheral blood mononuclear cells (PBMC) in vitro against specific (Hepatitis B core antigen; recombinant HB-cAg) and non-specific (CMV, EBV, Influenza peptide pool; CTL CEF peptide pool "plus") antigens using enzyme linked immunospot (ELISPOT) assay in 7 patients with chronic hepatitis B (CHB group), 8 inactive carriers Of HBV (carrier group) and 8 subjects who spontaneously recovered from acute HBV infection as detected by anti HBs positivity (immune group). Phytohemaglutinin served as the positive test control. Response against recombinant HBcAg was 88+/-135, 50+/-110, 105+/-150 spot forming cell (SFC)/10(5) PBMC, in CHB, carrier and immune groups, respectively. HBcAg-specific T-cell response was slightly higher in the immune group; however, statistically there was no significant difference between the groups. Assessment of cellular immunity by IFN-gamma ELISPOT was not sufficient to explain the various outcomes of HBV infection such as resolution, chronicity and carriership. PMID- 25699377 TI - The good, the bad and the ugly: surgical resection for non-colorectal, non neuroendocrine liver metastases. AB - BACKGROUND/AIMS: The aim of this retrospective study was to analyze outcomes after partial hepatectomy for non-colorectal non-neuroendocrine metastases (mNCRNNE) and to identify prognostic factors associated with survival. METHODOLOGY: Patient demographics, tumor characteristics, treatment and outcome of 30 consecutive patients operated between January 1995 and June 2012 were analyzed. The Kaplan-Meier method was used to analyze survival and Cox regression models were applied to identify independent prognostic variables. RESULTS: NCRNNE primaries included stomach (n=13), breast (n=5), pancreas (n=3), choroid melanoma (n=2), unknown primary (n=1) and others (n=6). Thirty-day mortality. rate was 3.3% and morbidity rate was 23.3%. Following hepatectomy, median overall (OS) and disease- free survival (DFS) were 24 and 12 months, respectively. In univariate analysis, longer disease-free interval (p=0.04) was associated with better OS. Histology of the primary tumor (p=0.003) and the presence of extrahepatic disease (p=0.04) were associated with a lower DFS. Cox regression analysis identified histology as an independent prognostic factor for DFS (p=0.013). CONCLUSIONS: In selected patients, resection of mNCRNNE appears associated with prolonged survival and may be performed in a specialized environment with acceptable morbidity and mortality. Patients with a longer disease-free interval, specific primary location and histology and absence of extra-hepatic disease seem to benefit the most from this approach. PMID- 25699378 TI - High-intensity focused ultrasound ablation induced apoptosis in human hepatocellular carcinoma. AB - BACKGROUND/AIMS: To evaluate the effect of high-intensity ultrasound (HIFU) ablation on human hepatocellular carcinoma tissues and apoptotic proteins (bcl-2 and p-53). METHODOLOGY: Patients with hepatocellular carcinoma at stage B were treated with HIFU ablation. Levels of bcl-2 and p53 protein and the apoptosis rate were evaluated both in the pre-treatment and post-treatment tissue specimens using immunochemistry and TUNEL methods, respectively. RESULTS: After HIFU ablation, p53 protein levels were significantly increased around the coagulation necrosis area, whereas, the level of bcl-2 was significantly decreased. More apoptosis cells were found post ablation compared with those in the pretreatment tissues. Additionally, no significant correlation was found between p53/bcl-2 levels and apoptotic index. CONCLUSIONS: HIFU ablation may exert promote the apoptosis of hepatocellular carcinoma cells and the effect has a closely association with the change of p53 and bcl-2 expression. PMID- 25699379 TI - Fast-track program for liver resection--factors prolonging length of stay. AB - BACKGROUND/AIMS: Fast-track programs involving multi-modal measures to enhance recovery after surgery, reduce morbidity and decrease hospital length of stay (LOS) are used for different major surgical procedures. For liver resections, factors influencing LOS within a fast-track program have been studied only to a limited extent, which was the aim of the present study. METHODOLOGY: The present study comprises the first 64 patients included in a fast-track program for liver resections introduced in March 2012. Patient outcomes were compared to a historical cohort of patients (n=62) operated in 2009. Factors prolonging LOS was analyzed by uni- and multivariate analysis. RESULTS: Median LOS was 6 days (range 3-42 days) within the fast-track program as compared with 8 days (range 5-47 days) in the historical cohort (P=0.004). On multivariate analysis, factors increasing LOS in the fast-track group were found to be the presence of complication (P=0.018), extent of resection (major as compared to minor) (P=0.001) and inability to drink > 1250 ml on the day after surgery (P=0.002). CONCLUSION: Patients who can only drink limited amounts of fluid the day after liver resection represent a subset of patients that should be given special attention within a fast-track program. PMID- 25699380 TI - Anatomic variations of hepatic artery and new clinical classification based on abdominal angiographic images of 1200 cases. AB - BACKGROUND/AIMS: There is wide variation in the branches of the hepatic artery. We aimed to classify these variations clinically on the basis of abdominal angiographic images in order to find out the suitable classification. METHODOLOGY: Anatomic variations of the hepatic artery of 1200 patients were analyzed at Tokyo Women's Medical University from 2000 to 2010, and Classified into four categories: "Y", "I-I", "Y plus I", and "I-I plus I". Patients with a proper hepatic artery were categorized as "Y", and those without as "I-I", to describe the arteries morphologically. We denoted an accessory artery as "I", and described it as being to the left or right of "Y"; i.e., "I, Y" or "Y, I", respectively. RESULTS: Normal hepatic anatomy was observed in 77.2% (926 subjects), and variations were found in 22.8% (274 subjects). Of all the patients, 3.8% (45 subjects) could not be classified using Michels' classification. On the other hand, when variations were classified using our classification, all variations could be classified into either Category Y (85.6%, 1027 subjects) or Category I-I (14.4%, 173 subjects). CONCLUSIONS: Our simplified new clinical classification of hepatic artery variants would be useful for preoperative planning in hepato-biliary-pancreatic surgery and liver transplantation. PMID- 25699381 TI - The clinical manifestations and distribution and resistance of pathogens among liver transplantation with infections caused by non-fermenters: a clinical analysis of 31 patients. AB - BACKGROUND/AIMS: To investigate the clinical manifestations and determine the distribution and the characteristics of drug susceptibility of pathogens, and provide evidence for clinical anti-infection treatments among liver transplantation with infections due to non-fermenters. METHODOLOGY: Retrospective analysis to the pathogens and their drug susceptibility characteristics was carried out. We also collected these patients' clinical and laboratory data to identify the clinical manifestations. RESULTS: Fifty two episodes of infections due to non-fermenters occurred in 31 patients. The rods causing bacteremias accounted for 46.2% of all non-fermenters (24/52). The most common non-fermenter was Acinetobacter baumannii (21 isolates, 40.4%). There were 12 deaths in these 31 recipients (48.9%). A total of 12 (25%) episodes of infections were accompanied with septic shock. Antibiotic resistance rate of all non-fermenters to 8 of 12 antibiotics investigated was more than 60%. The rods were relatively sensitive to cefoperazone/sulbactam. CONCLUSIONS: The clinical manifestations of infections due to non-fermenters included high body temperature, decreased platelet count, elevated white blood cell count, onset in the early period after transplantation as well as high rates of septic shock and mortality. The antibiotic resistant rate of non-fermenters was very high among liver transplant recipients. PMID- 25699382 TI - Usefulness of preoperative C-reactive protein and alpha-fetoprotein levels for prognostication of patients with hepatocellular carcinoma after living donor liver transplantation. AB - BACKGROUND/AIMS: The C-reactive protein level has been reported as a prognostic predictor for hepatocellular carcinoma after surgery. We investigated the usefulness of preoperative C-reactive protein levels in predicting outcomes after living donor liver transplantation for hepatocellular carcinoma and identified preoperative risk factors. METHODOLOGY: We retrospectively analyzed 96 hepatocellular carcinoma patients who underwent living donor liver transplantation in March 2003-November 2009. The effect of preoperative variables on overall survival was evaluated by multivariate analysis. RESULTS: The 5-year overall survival rate was significantly lower for C-reactive protein levels >0.3 mg/dL than for C-reactive protein levels <=0.3 mg/dL (55.8% vs. 89.8%; P=0.001). In multivariate analysis, C-reactive protein levels >0.3 mg/dL (P=0.006) and alpha-fetoprotein levels >200 ng/mL (P<0.001) were significant risk factors for survival. For patients within Milan criteria (n=68), the 3-year overall survival rate with 2 risk factors (n=8) was 20%; of these patients, 63% experienced recurrence. For patients outside Milan criteria (n=28), the 5-year overall survival rate without 1-2 risk factors (n=21) was 80.9%; of these patients, 33% experienced recurrence. CONCLUSIONS: Preoperative C-reactive protein levels predicted prognosis after living donor liver transplantation for hepatocellular carcinoma. C-reactive protein and alpha-fetoprotein levels together with Milan criteria may improve hepatocellular carcinoma patient selection for liver transplantation. PMID- 25699383 TI - Radiofrequency-assisted liver resections: comparison of open and laparoscopic techniques. AB - BACKGROUND/AIMS: After the first reported laparoscopic liver resection (LLR) twenty years ago, liver surgery still remains one of the last areas of resistance to the offensive of laparoscopy. Radiofrequency assisted laparoscopic liver resection has been recently developed technique for treatment of primary and secondary liver tumors. METHODOLOGY: Over a 5-year period, a total of 134 laparoscopic and open radiofrequency assisted operations were performed in a single institution. LLR was done in 47 patients, and open liver resection (OLR) in 87 patients. RESULTS: The study selection criteria were fulfilled by 134 patients. The mean blood loss for LLR was 68.7 mL, the difference between the groups was significant with lower median of blood loss using laparoscopy (p=0.046). The mean of length of hospital stay in LLR was 7.5 days versus 8.7 days in OLR (p=0.071). The 5-year survival rate was 67.0% after LLR and 63.8% after OLR. The 5-year disease-free survival rate was 59.4% after LLR, and 62.2% after OLR. The difference between groups was not statistically significant. CONCLUSIONS: Laparoscopic liver resection is safe and feasible procedure. The hand-assisted laparoscopic radiofrequency technique can be applied effectively for selected patients. Preliminary oncological results suggest non-inferiority of laparoscopic to open procedures. PMID- 25699384 TI - Closure of the pancreas in distal pancreatectomy: comparison between bare stapler and reinforced stapler. AB - BACKGROUND/AIMS: Pancreatic fistula (PF) is a major complication after distal pancreatectomy (DP). Popularization of laparoscopic surgery for DP has promoted the use of stapler for transection and closing of the pancreas. METHODOLOGY: We reviewed the medical records of 50 consecutive patients who underwent DP with stapler. Patients were divided into 2 groups: bare stapler (n=36) and reinforced stapler (n=14). We assessed the incidence of postoperative PF, systemic inflammatory response syndrome (SIRS), and intra-abdominal fluid collection on postoperative day 7. RESULTS: The numbers of patients who developed grade A, grade B, and grade C PF were 17 (34%), 6 (12%), and 0, respectively. The incidence of postoperative PF was significantly lower in the reinforced stapler group (p=0.017). None of the patients in the reinforced stapler group developed grade B PF. Patients in the bare stapler group showed significantly higher incidence of postoperative SIRS (p=0.046), more extensive fluid collection (p=0.020), and longer postoperative hospital stay (p=0.023). CONCLUSIONS: Decreased leakage of postoperative pancreatic juice into the abdominal cavity associated with the usage of the reinforced stapler may lead to reduced inflammatory reaction, low incidence of PF, and early hospital discharge. PMID- 25699385 TI - Pancreaticoduodenectomy with right-oblique posterior dissection of superior mesenteric nerve plexus is logical procedure for pancreatic cancer with extrapancreatic nerve plexus invasion. AB - BACKGROUND/AIMS: To achieve R0 resection, pancreaticoduodenectomy with right-side half dissection of the superior mesenteric artery nerve plexus is performed for pancreatic cancer with extrapancreatic nerve plexus invasion in many facilities. However, this cancer mainly spreads behind the superior mesenteric artery. METHODOLOGY: Forty-two patients underwent pancreaticoduodenectomy with right oblique posterior dissection of the superior mesenteric artery nerve plexus from the 4 to 10 o'clock position for pancreatic ductal adenocarcinoma. The cancer spread was evaluated using preoperative multi-detector computed tomography and postoperative pathological examination. RESULTS: Thirty-one patients (73.8%) showed extrapancreatic nerve plexus invasion on multi-detector computed tomography. In 20 patients (47.6%), the tumor extended within 5 mm of the superior mesenteric artery, ranging between the 4-10 o'clock position in 19 (95.0%) patients. Although pathological examination revealed that the cancer infiltrated within 3 mm of the superior mesenteric artery margin in 17 (54.8%) patients with extrapancreatic nerve plexus invasion, R0 resection was achieved in 95.2% of cases. Six patients (14.3%) experienced postoperative diarrhea requiring administration of antidiarrheal agents. CONCLUSIONS: Pancreatic head cancer spreads mainly right-posterior of the superior mesenteric artery; and therefore, right-oblique posterior dissection is a logical procedure to achieve negative margin resection with complete clearance of nerve plexus involvement. PMID- 25699386 TI - Surgery vs. observation for liver hemangioma: a systematic review and meta analysis. AB - BACKGROUND/AIMS: To conduct a systematic review of observational studies to evaluate effectiveness of surgery for liver hemangioma. METHODOLOGY: Related studies were identified using different searching engines. Two reviewers independently extracted data on mortality, morbidity and symptoms recurrence and/or aggravation. RESULTS: Sixteen studies with a total of 1485 patients (402 in surgery and 1085 in observation group) were included in the analysis. Two deaths in surgical group (8.0%, 2/25) and two deaths in observation group (1.4%, 2/143) were reported. The RRs for mortality were not homogeneous (chi2=3.40, 1 d.f., P=0.07, I2=71 per cent). The RRs for morbidity were homogeneous across studies (x2=5.55, 12 d.f., P=0.94, I2=0 per cent). Morbidity in surgery group was significantly higher than that in observation group (RR=14.7, 95 per cent c.i. 9.56 to 45.63). Eight studies reported the symptom aggravation and RRs were heterogeneous (x2=31.03, 7 d.f., P<0.0001, I2=77 per cent), However, showed no statistical difference. CONCLUSION: The currently involved retrospective cohort studies of surgical series were likely to imply that surgery may take more risks than the benefits for non-emergency hemangioma patients. PMID- 25699387 TI - Analysis of diagnosis and treatment for pancreatic neuroendocrine neoplasms: results of 47 cases in a single institution. AB - BACKGROUND/AIMS: There are few large sample, single-center series that focus on the methods of diagnosis, treatment and long-term survival of patients with Pancreatic neuroendocrine neoplasms (pNENs). METHODOLOGY: Forty-seven patients with pNENs treated at Anhui province hospital affliated of Anhui Medical University during January 2002 to December 2013 were analyzed retrospectively. Clinical data were collected and statistically analyzed. RESULTS: The sensitivity of abdominal ultrasound, CT and MRI was 71.2% (28/39), 92.3% (38/41), and 75% (6/8), respectively. All patients received operation. 46 underwent radical surgery, pancreatic fistula in 9 patients, seroperitoneum in 4 patients, incisional infection in 4 patients. The cases of grade G1, G2, and G3 were 22, 19, and 6, respectively. The cases of stage I, II, III and IV were 32, 11, 4, and 0, respectively. The overall 1-, 3, and 5-year survival rates were 94.9%, 88.4%, and 84.4%. Univariate analysis showed that TNM, WHO classification, lymph nodes metastasis, vascular and neural invasion were risk factors of pNENs. CONCLUSION: Sprial CT was an optimal diagnostic method, while surgery was the first choice for treatment. Surgical resection in pNENs results in long-term survival. TNM, WHO classification, lymphatic metastasis, vascular and neural invasion were closely related to the prognosis of pNENs. PMID- 25699388 TI - Neoadjuvant/downstaging radiochemotherapy in marginally resectable pancreatic cancer. AB - Pancreatic cancer is a challenging disease due to the low resection rate at the time of initial diagnosis. A relatively new classification of marginally resectable pancreatic cancer has emerged and there is some evidence that this subgroup of patients may benefit from neoadjuvant radiochemotherapy. The first major definition of marginally resectable pancreatic cancer was made at M. D. Anderson Cancer Center and published in 2006. This definition was purely anatomical and CT-based and only handles the relationship of the pancreatic, tumor to its surrounding major vessels. Later on, two other subtypes have been added to this definition: suspicion or known metastasis in regional lymph nodes (N1 disease), or severe pre-existing medical comorbidities requiring prolonged evaluation or recovery and precluding immediate surgery. Other definitions (anatomical and CT-based) for marginally resectable pancreatic cancer have also been established. For systematic research on neoadjuvant therapy in marginally resectable pancreatic cancer, however, the lack of uniform definitions and randomized trials have been troublesome. Nevertheless, several small cohort studies have demonstrated that 40-80% of the marginally resectable patients could proceed to resection after neoadjuvant treatment and also reporting some promising effects on microscopic resection margins, lymph node status and survival. PMID- 25699389 TI - A randomized control study to investigate the application of Ulinastatin containing contrast medium to prevent post-ERCP pancreatitis. AB - BACKGROUND/AIMS: Ulinastatin was reported has positive effects on preventing post ERCP pancreatitis and hyperamylasemia for patients in average risk. To observe the incidence of post-ERCP pancreatitis and investigate the efficacy and feasibility of using Ulinaststin to prevent post-ERCP pancreatitis. METHODOLOGY: A total of 280 patients were randomized into two arms: an experimental arm using Ulinastatin-containing contrast medium and a control arm using the same contrast medium without Ulinastatin. Blood amylase and urine amylase-2 were measured at three and twenty-four hours after ERCP procedure. RESULTS: There were distinct differences in the incidence of post-ERCP pancreatitis and average blood amylase levels in the two arms (p < 0.05). Post-ERCP pancreatitis was observed in 20 patients (7.1%), including 7 (4.37%) patients in the experimental arm, and 13 (10.83%) patients in control arm. After 3 hours of the operation, the average blood amylase levels in control and experimental arm were 224.82+/-34.27 U/L and 189.52+/-20.94 U/L, respectively. Correspondingly, the levels were 233.59+/-35.05 U/L and 187.09+/-23.14 U/L after 24 hours. But the difference was not statistically significant in urine amylase-2 levels, hemoleukocyte count and operation time. CONCLUSIONS: The exploitation of Ulinastatin in ERCP could decrease the incidence but could not completely prevent the development of post ERCP pancreatitis. PMID- 25699390 TI - Effects of hypoxia-inducible factor-1alpha silencing on drug resistance of human pancreatic cancer cell line Patu8988/5-Fu. AB - The present study aimed to investigate the mechanism and the possible approaches of solving drug resistance by silencing hypoxia-inducible factor-1 alpha of human pancreatic cancer cell line Patu8988/5-Fu cultured in hypoxia. The effective jamming fragment screened by RT-PCR for silencing HIF-1alpha gene was transfected into pancreatic cancer cells Patu8988/5-Fu through lentivirus. RT-PCR results showed that the effective jamming fragments for HIF-1alpha in lentivirus transfection was Wtl-mus-1202(C546). Combined MTT with JC-1 fluorescence staining flow cytometric analysis, the concentration of 200 MUmol/L CoCl2 for 8 h was chosen to mimic hypoxia cell environment. The drug resistance significantly enhanced in response to hypoxia in Patu8988/5-Fu (p<0.05), and silence HIF-1alpha could reverse the multidrug resistance (P<0.05). In the Patu8988/5-Fu cells, HIF 1alpha and MDR1 significantly increased in response to hypoxia (p<0.05). The inhibition of HIF-1alpha expression synergistically downregulated the expression of the MDR1 gene in Patu8988/5-Fu cells (p<0.05). HIF-1alpha expression was positively correlated with the MDR1 expression (p<0.05). The upregulation of the HIF-1alpha and MDR1 gene expression caused by hypoxia was related with the generation of multi-drug resistance of Patu8988/5-Fu, targeted silencing HIF 1alpha may be a kind of way to reverse the chemotherapy drug resistance. PMID- 25699391 TI - Gross anatomy of pancreatic surgery related fascia and fascial spaces. AB - BACKGROUND/AIMS: The study aims to provide anatomical basis and identify surgical planes or safe routes for pancreatic surgery by studying adult or fresh cadaver specimens. METHODOLOGY: Thirty formalin-fixed adult cadavers (16 males and 14 females), provided by the Department of Anatomy at Southern Medical University, China, were perfused with red latex through the abdominal aorta, treated with antiseptic and antibacterial agents and then refrigerated. Fifteen abdomen specimens from fresh adult cadavers (Southern Medical body donation reception centers) were also perfused with red latex through the femoral artery and placed in -20 C freezer for 1 week before surgery and anatomic observation. RESULTS: The renal fascia surrounding pancreas and duodenum were mostly filled with loose connective tissues and adipose tissues. They were mutually connected with clear fascial borders but easily to be separated, suitable for surgical operations. Also, the integrating spaces were the connecting borders between different tissues without nerves or blood vessels inside. They may serve as ideal surgical planes for pancreatic surgery. CONCLUSIONS: A better understanding of the anatomy of the renal fascia and fascial spaces may provide guidance for identifying surgical landmarks and planes, and help to reduce bleeding and unnecessary side injuries in pancreatic surgery. PMID- 25699392 TI - Percutaneous endoscopic gastrostomy: cross-sectional study for Slovenia. AB - BACKGROUND/AIMS: Percutaneous endoscopic gastrostomy (PEG) is the method of choice for long-term tube feeding in patients with swallowing disorders due to the neurologic disease or cancer. First introduction of PEG in Slovenia was performed in 1995. We are presenting the results of first cross-sectional study in Slovenia. METHODOLOGY: We performed a retrospective review of medical documentation for patients in seven Slovenian hospitals who underwent PEG placement from 2004 until 2008. The aim of our study was to analyze the experience of PEG placements, evaluate patients' demographic characteristics, determine indications, measure survival after tube placement and complications. RESULTS: There were 1173 PEG placements in seven endoscopic centers: 666 in females (56,8%) and 507 in males (43,2%), mean age 72,5 years (range 14-99). Majority of patients (n=792; 67,5%) had a neurological disease. Major complications developed in 15 (1,28%) patients and four patients (0,34%) died. CONCLUSIONS: PEG is an excellent method for providing long-term enteral nutrition in patient with dysphagia. It is obviously a very simple and effective method with low morbidity and mortality. Most common indications for insertion of PEG are neurologic disorders. Multidisciplinary approach in decision who is a proper candidate for PEG tube placement is recommended. PMID- 25699393 TI - Comparison of hand-assisted laparoscopic gastrectomy vs. laparoscopy assisted gastrectomy for gastric cancer. AB - BACKGROUND/AIMS: This study aimed to compare the short and long-term outcomes of hand-assisted laparoscopic gastrectomy (HALG) to those of laparoscopy assisted gastrectomy (LAG). METHODOLOGY: From June 2009 to October 2011, fifteen pairs of patients with gastric carcinoma who underwent LAG or HALG were included for analysis retrospectively. Overall survival, morbidity and mortality, and operative variables were analyzed. RESULTS: The characteristics baselines were comparable between two groups. There was no difference in morbidity or mortality between two groups. There were also no significant differences in terms of mean number of harvested lymph nodes, postoperative hospital stay, intraoperative blood lost volume, operation time, reoperation, intraoperative conversion, mean time to first flatus and mean time to liquid diet intake between the two groups. The median survival months for patients were 28.9 and 31.7 in HALG and LAG group respectively, and the estimated 3 year overall survival rates were 73.3% in HALG group and in 80.0% LAG group without any statistic significant (P=0.779). CONCLUSIONS: There was no difference in overall morbidity and mortality, postoperative recovery or overall survival between the HALG group and LAG group. Well-designed randomized controlled trials should be needed to prove the results further. PMID- 25699394 TI - SUZ12 RNA interference inhibits the invasion of gastric carcinoma cells. AB - In order to observe the regulation effects of SUZ12 gene to the invasion of gastric carcinoma cells and the mechanisms, the expressions of SUZ12 protein in 86 patients with different infiltrating degree (Tis-T4), lymph node metastasis (N0-N3) and far metastasis (M0-M1) were detected by immunohistochemical staining. The siRNA to SUZ12 was designed and synthesized and transfected into MKN28 cells. The effects of SUZ12 siRNA to cell invasion were detected by soft agar colony forming test and Transwell cabin model. The related protein was detected by Western-Blot. We found the expression of SUZ12 in gastric carcinoma tissues (23.58+/-9.89%) was obviously higher than that in para-cancer tissue (1.12%+/ 0.12%) (p<0.01). The expression of SUZ12 was related to the infiltrating degree, and demonstrated an increasing tendency from Tis-T4, or from N0-N3. The expression of SUZ12 in M0 was obviously lower than in M1, p<0.01. The level of SUZ12 was descent obviously after transfected SUZ12 siRNA (p<0.01). The number of cell clone was reduced in dose dependent of siRNA and the cells permeated through filter membrane were decreased after transfected siRNA. Inhibition of SUZ12 caused an obviously descent of VEGF, MMP-2 and MMP-9 (0.22+/-0.06, 0.12+/-0.03, 0.08+/-0.02) compared to non transfected group (0.87+/-0.08, 0.92+/-0.16, 1.05+/ 0.18) respectively (p<0.01). We draw the conclusion that the expression of SUZ12 is increasing along with the degree of infiltrating and metastasis of gastric carcinoma. SUZ12 siRNA inhibits the invasion of gastric carcinoma cells and the expression of VEGF, MMP-2 and MMP-9. PMID- 25699395 TI - Clinical and pathological characteristics, and prognostic factors for gastric cancer survival in 155 patients in Bulgaria. AB - Almost one million new cases of gastric cancer were estimated to have occurred in 2012, making it the fifth most common malignancy in the world. It is also the third leading cause of cancer death of people of both genders worldwide. The aim of this study is to evaluate the significance of some prognostic factors for gastric cancer survival in 155 patients treated at Aleksandrovska University Hospital, Sofia, Bulgaria. This retrospective study includes patients diagnosed and treated at Department of Surgery of Aleksandrovska University Hospital for the 9-years period of time between January 2005 and December 2013. We classified the prognostic factors as patient-related (age at diagnosis specification, gender, and blood type), tumor-related (N-stage, tumor differentiation, process localization), and treatment related (patients who had radical surgery and adjuvant therapy). We found that blood type is the only statistically significant prognostic factor for overall survival from the patients-related group of factors (p = 0.030). The only prognostic factor from the ones in the tumor related group remains the N-stage according to the TNM classification (p = 0.003). Adjuvant could not prove its value for overall survival (p = 0.675). PMID- 25699396 TI - Impact of body mass index on number of lymph nodes retrieved in gastric cancer patients. AB - BACKGROUND/AIMS: The aim of this study was to assess the influence of obesity on the number of the dissected lymph nodes in patients who underwent gastrectomy for gastric adenocarcinoma. METHODOLOGY: Thirty eight Patients with gastric adenocarcinoma who underwent curative gastrectomy at one center between April 2012 and December 2012 were eligible for the study. According to their body mass index (BMI) values before surgery patients with BMI > 24.9 kg/m2 were defined as obese. Patients with BMI <= 24.9 kg/m2 were defined as normal group. The number of retrieved lymph nodes and metastatic lymph nodes were obtained from pathology reports. RESULTS: Among 38 patients there were 17 (45%) patients had BMI <= 24.9 kg/m2 (normal group), while 21 (%55) patients had BMI > 24.9 kg/m2 (obese group). The median number of retrieved lymph nodes in obese patients who underwent total gastrectomy was significantly higher compared to the normal patients underwent the same procedure. CONCLUSION: In this study we showed that the obesity affects the outcomes of surgery in gastric cancer. Furthermore, the total number of retrieved lymph nodes in obese patients who underwent total gastrectomy was higher than that in non-obese patients. PMID- 25699397 TI - Hyperthermia improves immune function and radiotherapy efficacy in patients with post-operative recurrent gastric cancer. AB - BACKGROUND/AIMS: Hyperthermia has long been used in combination with radiation for the treatment of cancers. This study aimed to investigate the efficacy safety and impact on the immune function of the abdominal hyperthermia combining with radiotherapy. METHODOLOGY: Sixty-eight patients with post-operative local recurrent gastric carcinoma were divided randomly into two groups. Patients in 3DCRT+HT group received three-dimensional conformal radio therapy combined with abdominal hyperthermia while patients from 3DCRT group only received the three dimensional conformal radiation therapy. The differences of efficacy, toxicity and the impact on immune function between two kinds of therapies were compared. RESULTS: Response rate in 3DCRT+HT group was 57.2%, which was significant higher than that in 3DCRT group (47.1%) (P=0.04). Median local progression-free survival time of 3DCRT+HT group (14 months) was significantly longer than 3DCRT group (11 months). The peripheral blood T lymphocyte subsets analyses showed that, after the treatment, CD3+, CD4+, NK level and CD4+/CD8+ ratio increased significantly, while there was no significant alterations for those immunological parameters in 3DCRT group. CONCLUSION: Abdominal hyperthermia combined with three-dimensional conformal radiotherapy could gain higher response rate, prolong median local progression-free survival time and improve immune function for the post-operative recurrentgastric cancer. PMID- 25699398 TI - Clinicopathologic characteristics and prognosis of gastric cancer patients underwent gastrectomy combined with splenectomy. AB - BACKGROUND/AIMS: This study gives insight into the effect of splenectomy in radical surgery for gastric cancer. METHODOLOGY: The study included 631 patients who underwent radical resection for gastric cancer. Of these 631 patients, 105 underwent splenectomy and 526 had splenic preservation. The clinicopathologic features of 105 patients underwent gastrectomy combined with resection of the spleen (splenectomy group) and 526 patients underwent gastrectomy (spleen preservation group) were compared. RESULTS: Gastric cancer with splenectomy was characterized by tumor located in gastric cardia (33.3%), positive lymph node metastasis (91.4%), and serosal invasion (94.3%). For age, gender, and tumor size, there was no significant difference between the patients with splenectomy and spleen-preservation. The 5-year survival of splenectomy group was 21.3% as compared with 38.6% for spleen-preservation group (P<0.001). With respect to patients with splenectomy, multivariate analysis showed that lymph node metastasis was significant factors affecting survival. CONCLUSIONS: Compared with spleen-preservation group, patients who underwent gastrectomy combined with splenectomy have a greater chance of tumor located in gastric cardia, positive lymph node metastasis, and serosal invasion and a significantly poor prognosis. PMID- 25699399 TI - The postoperative quality of life of two anastomosis methods of gastric tube reconstruction for proximal gastrectomy. AB - BACKGROUND/AIMS: Compare the postoperative quality of life between the anastomosis of anterior gastric wall to the esophagus (AGE) and posterior gastric wall to the esophagus (PGE) for gastric tube reconstruction of proximal gastrectomy. METHODOLOGY: Retrospectively matched-pair study collected patients who underwent anterior and posterior gastric wall anastomosis to the esophagus after proximal gastrectomy. Surgical related parameters and postoperative 3 month, 6-month, 9-month, 12-month quality of life were according to EORTC QLQ-C30 and EORTC QLQ-STO22 questionnaires during the out-patient visit. RESULTS: Eleven pair cases included in the study and finished postoperative quality of life evaluation. General characteristics, such as age, surgical duration, blood loss, postoperative complications existed no significant difference between the two groups. The AEG reconstruction existed advantage in the pain scale (EORTC QLQ-C30 and EORTC QLQ-STO22) and reflux symptom scale (EORTC QLQ-STO22) at the 3-month postoperative evaluation. However, there was no difference between the two groups in the assessment of quality of life in the postoperative 6-month, 9-month, 12 month. CONCLUSIONS: Although there were some subtle differences between the two reconstruction methods. Both of these two reconstruction methods can as a selection of gastric tube reconstruction. Further study and other reconstruction method are expected for the proximal gastrectomy. PMID- 25699400 TI - Obstructive jaundice by lymph node recurrence of gastric cancer: can surgical derivation still play a role? AB - BACKGROUND/AIMS: In some cases of bile duct compression by lymph node recurrence of gastric cancer, a second line chemotherapy can lead to prolonged survival; thus, a surgical derivation could represent a reasonable alternative to non surgical drainage, owing to its better long term efficacy. Our study retrospectively compares the surgical approach (SA) and percutaneous transhepatic biliary drainage (PTBD) in this particular oncological condition. METHODOLOGY: 11 patients undergoing biliary-jejunal anastomosis for obstructive jaundice by lymph node recurrence of gastric cancer at our Institution were compared with 10 patients undergoing PTBD. Clinical records and outcome parameters (success rate, complications, survival) were statistically matched in order to assess possible advantages for each technique and to evaluate any particular variable influencing survival. RESULTS: The SA patients experienced a better jaundice resolution (91% vs 50%, p.0.063), a lower major complication rate (9% vs 30%, p:0.311), and a significantly longer survival (317 days vs 85 days, p:0.001). Procedural success and complication rates were found to be correlated with survival. CONCLUSIONS: According to our experience the SA represents a valid alternative to PTBD in the case of lymph node recurrence of gastric cancer, being favoured for patients with better performance status and longer life expectancy. PMID- 25699401 TI - Subtotal gastrectomy for gastric cancer: long term outcomes of Billroth I reconstruction at a single European institute. AB - BACKGROUND/AIMS: The role of Billroth I (BI) subtotal gastrectomy (SG) for gastric cancer (GC) remains controversial in Western countries. The aim of the study is to critically analyze the long term outcomes of this procedure in a large single-institution experience. METHODOLOGY: Between 1990 and 2004, 158 patients underwent BI SG for GC at the Regina Elena Cancer Institute of Rome. Evaluation focused on cancer recurrence of the gastric stump, functional outcome and endoscopic findings. RESULTS: Actuarial survival rate 10 years after resection in stage I-II was 70.7 per cent. After curative resection, primary cancer of the gastric stump occurred in one patient seven years after resection (0.7 per cent), whereas two patients had early recurrence (1.4 per cent) one and three years postoperatively. There were no oesophageal cancers. In survivors, Visick grades I and II achieved 95 per cent, and postoperative endoscopy showed no evidence of mucosal changes in 85 per cent of the patients. Twelve per cent of the patients took acid blocker regularly, however, the incidence of functional failure was 5 per cent. CONCLUSIONS: In selected patients, Billroth I subtotal gastrectomy is a safe and effective procedure that provides long-term survival and very good functional outcome. PMID- 25699402 TI - Detection of pharmaceutical drug crystallites in solid dispersions by transmission electron microscopy. AB - We explored the use of transmission electron microscopy (TEM) to evaluate the crystallinity of griseofulvin (GF)/hydroxypropyl methylcellulose acetate succinate (HPMCAS) solid dispersions. TEM, which provides both real-space images and electron diffraction patterns, was used to unambiguously identify GF crystals in spray dried GF. Using TEM, we were also able to detect GF crystals in a physical mixture of spray dried GF particles and spray dried HPMCAS particles with an overall crystallinity of ~3 vol %, below the practical lower limit of detection for laboratory-scale wide-angle X-ray scattering (WAXS). Using TEM and WAXS, we did not find crystals in GF/HPMCAS solid dispersions with GF loadings of 5, 10, and 50 wt %. However, we detected GF crystals in annealed 5 wt % GF solid dispersion using TEM, whereas we did not detect crystals using in situ WAXS and modulated differential scanning calorimetry, thereby establishing the superior crystal detection sensitivity of TEM. We also performed TEM analysis of the in situ growth of GF crystals in a TEM sample of 50 wt % GF solid dispersion. Based on this study, TEM has significant potential for characterizing even small degrees of crystallinity in solid dispersions. PMID- 25699404 TI - Recovery Is A Reality: But What Is It? PMID- 25699403 TI - Role of biofilm roughness and hydrodynamic conditions in Legionella pneumophila adhesion to and detachment from simulated drinking water biofilms. AB - Biofilms in drinking water distribution systems (DWDS) could exacerbate the persistence and associated risks of pathogenic Legionella pneumophila (L. pneumophila), thus raising human health concerns. However, mechanisms controlling adhesion and subsequent detachment of L. pneumophila associated with biofilms remain unclear. We determined the connection between L. pneumophila adhesion and subsequent detachment with biofilm physical structure characterization using optical coherence tomography (OCT) imaging technique. Analysis of the OCT images of multispecies biofilms grown under low nutrient condition up to 34 weeks revealed the lack of biofilm deformation even when these biofilms were exposed to flow velocity of 0.7 m/s, typical flow for DWDS. L. pneumophila adhesion on these biofilm under low flow velocity (0.007 m/s) positively correlated with biofilm roughness due to enlarged biofilm surface area and local flow conditions created by roughness asperities. The preadhered L. pneumophila on selected rough and smooth biofilms were found to detach when these biofilms were subjected to higher flow velocity. At the flow velocity of 0.1 and 0.3 m/s, the ratio of detached cell from the smooth biofilm surface was from 1.3 to 1.4 times higher than that from the rough biofilm surface, presumably because of the low shear stress zones near roughness asperities. This study determined that physical structure and local hydrodynamics control L. pneumophila adhesion to and detachment from simulated drinking water biofilm, thus it is the first step toward reducing the risk of L. pneumophila exposure and subsequent infections. PMID- 25699405 TI - Discovery of potent and selective 8-fluorotriazolopyridine c-Met inhibitors. AB - The overexpression of c-Met and/or hepatocyte growth factor (HGF), the amplification of the MET gene, and mutations in the c-Met kinase domain can activate signaling pathways that contribute to cancer progression by enabling tumor cell proliferation, survival, invasion, and metastasis. Herein, we report the discovery of 8-fluorotriazolopyridines as inhibitors of c-Met activity. Optimization of the 8-fluorotriazolopyridine scaffold through the combination of structure-based drug design, SAR studies, and metabolite identification provided potent (cellular IC50 < 10 nM), selective inhibitors of c-Met with desirable pharmacokinetic properties that demonstrate potent inhibition of HGF-mediated c Met phosphorylation in a mouse liver pharmacodynamic model. PMID- 25699406 TI - Predicting the Development of Tuberculosis with the Tuberculin Skin Test and QuantiFERON Testing. AB - RATIONALE: The identification of patients with latent tuberculosis infection, who are at higher risk to develop active disease, is an important component of disease control. OBJECTIVES: We aim to compare the usefulness of the QuantiFERON TB Gold in-tube assay and the tuberculin skin test to predict the development of active tuberculosis during follow-up, using positive and negative predictive values, positive likelihood ratios, and stratified level of risk. METHODS: The study included contacts of tuberculosis cases diagnosed between 2007 and 2009. All contacts included were from the first circle of exposure. Tuberculin skin test and QuantiFERON test were performed and a chest radiograph was obtained during the contact's study. MEASUREMENTS AND MAIN RESULTS: A total of 1,335 contacts were followed up for 4 years: a smear-positive index case was identified for 937 contacts, of whom 15 developed active tuberculosis and had initially presented with positive tuberculin skin test/QuantiFERON results, a normal chest radiograph, and no symptoms. The positive predictive value was 4% for QuantiFERON and 2% for the tuberculin skin test (when >=5 mm). The probability of developing active disease was 2.36 times higher with a positive QuantiFERON, and 1.3 times higher with a positive tuberculin skin test. The positive predictive value was 17%, and the positive likelihood ratio was 7.53 for untreated contacts with a positive QuantiFERON. Stratifying according to initial QuantiFERON results showed a 6.36 times higher risk of developing active tuberculosis for patients with a QuantiFERON result greater than or equal to 10 IU/ml. Among bacillus Calmette Guerin-vaccinated patients, a tuberculin skin test induration greater than or equal to 15 mm correlated better with a positive QuantiFERON. CONCLUSIONS: QuantiFERON results were more accurate than tuberculin skin test results in predicting tuberculosis. Although all contacts with QuantiFERON-positive results are at risk of developing tuberculosis, those with a tuberculin skin test induration greater than or equal to 15 mm and QuantiFERON greater than or equal to 10 IU/ml are at highest risk. This has important implications in the clinical management of tuberculosis contacts. PMID- 25699407 TI - Vibronic spectroscopy of a nitrile/isonitrile isoelectronic pair: para diisocyanobenzene and para-isocyanobenzonitrile. AB - The ultraviolet spectroscopy of isoelectronic pair para-diisocyanobenzene (pDIB) and para-isocyanobenzonitrile (pIBN) has been studied under gas-phase, jet-cooled conditions. These molecules complete a sequence of mono and disubstituted nitrile/isonitrile benzene derivatives, enabling a comparison of the electronic effects of such substitution. Utilizing laser-induced fluorescence (LIF) and resonant two-photon ionization (R2PI) spectroscopy, the S0-S1 electronic origins of pDIB and pIBN have been identified at 35,566 and 35,443 cm(-1), respectively. In pDIB, the S0-S1 origin is very weak, with b(3g) fundamentals induced by vibronic coupling to the S2 state dominating the spectrum at 501 cm(-1) (nu17, isocyano bend) and 650 cm(-1) (nu16, ring distortion). The spectrum extends over 5000 cm(-1), remaining sharp and relatively uncongested over much of this range. Dispersed fluorescence (DFL) spectra confirm the dominating role played by vibronic coupling and identify Franck-Condon active ring modes built off the vibronically-induced bands. In pDIB, the S2 state has been tentatively observed at about 6100 cm(-1) above the S0-S1 origin. In pIBN, the S0-S1 origin is considerably stronger, but vibronic coupling still plays an important role, involving fundamentals of b2 symmetry. The bending mode of the nitrile group dominates the vibronically-induced activity. Calculations carried out at the TD DFT B3LYP/6-31+G(d) level of theory account for the extremely weak S0-S1 oscillator strength of pDIB and the larger intensity of the S0-S1 origins of pIBN and pDCB (para-dicyanobenzene) as nitrile groups are substituted for isonitrile groups. In pDIB, a nearly perfect cancellation of transition dipoles occurs due to two one-electron transitions that contribute nearly equally to the S0-S1 transition. The spectra of both molecules show no clear evidence of charge transfer interactions that play such an important role in some cyanobenzene derivatives. PMID- 25699408 TI - Development of a non-tissue adherent neurosurgical patty and an ex vivo testing system to evaluate adherent characteristics. AB - Neurosurgical patties are the most frequently used instruments during neurosurgical procedures, and their high performance is required to ensure safe operations. They must offer cushioning, water-absorbing, water-retaining, and non tissue adherent characteristics. Here, the authors describe a revised neurosurgical patty that is superior in all respects to the conventional patty available in Japan. Patty characteristics were critically and scientifically evaluated using various in vitro assays. Moreover, a novel ex vivo evaluation system focusing on the adherent characteristics of the neurosurgical patty was developed. The proposed assay could provide benchmark data for comparing different neurosurgical patties, offering neurosurgeons objective data on the performance of patties. The newly developed patty was also evaluated in real neurosurgical settings and showed superb performance during various neurosurgical procedures. PMID- 25699409 TI - Sir Victor Horsley: pioneer craniopharyngioma surgeon. AB - Sir Victor Horsley (1857-1916) is considered to be the pioneer of pituitary surgery. He is known to have performed the first surgical operation on the pituitary gland in 1889, and in 1906 he stated that he had operated on 10 patients with pituitary tumors. He did not publish the details of these procedures nor did he provide evidence of the pathology of the pituitary lesions operated on. Four of the patients underwent surgery at the National Hospital for Neurology and Neurosurgery (Queen Square, London), and the records of those cases were recently retrieved and analyzed by members of the hospital staff. The remaining cases corresponded to private operations whose records were presumably kept in Horsley's personal notebooks, most of which have been lost. In this paper, the authors have investigated the only scientific monograph providing a complete account of the pituitary surgeries that Horsley performed in his private practice, La Patologia Chirurgica dell'Ipofisi (Surgical Pathology of the Hypophysis), written in 1911 by Giovanni Verga, Italian assistant professor of anatomy at the University of Pavia. They have traced the life and work of this little-known physician who contributed to the preservation of Horsley's legacy in pituitary surgery. Within Verga's pituitary treatise, a full transcription of Horsley's notes is provided for 10 pituitary cases, including the patients' clinical symptoms, surgical techniques employed, intraoperative findings, and the outcome of surgery. The descriptions of the topographical and macroscopic features of two of the lesions correspond unmistakably to the features of craniopharyngiomas, one of the squamous-papillary type and one of the adamantinomatous type. The former lesion was found on necropsy after the patient's sudden death following a temporal osteoplastic craniectomy. Surgical removal of the lesion in the latter case, with the assumed nature of an adamantinomatous craniopharyngioma, was successful. According to the evidence provided in Giovanni Verga's monograph, it can be claimed that Sir Victor Horsley was not only the pioneer of pituitary gland surgery but also the pioneer of craniopharyngioma surgery. PMID- 25699410 TI - Role of superior hypophyseal artery in visual function impairment after paraclinoid carotid artery aneurysm surgery. AB - OBJECT: Although a number of studies have assessed the surgical treatment of paraclinoid-segment carotid artery aneurysms and resulting visual complications, less attention has been given to the results with respect to the superior hypophyseal artery (SHA). The authors evaluated the relationship between the aneurysm, the SHA itself, and postoperative visual function in patients with ruptured and unruptured SHA aneurysms. METHODS: From January 1991 through December 2013, 181 patients with 190 paraclinoid carotid artery aneurysms received treatment at Shinshu University Hospital and its affiliated hospitals. The authors retrospectively analyzed charts, operative records, operative videos, and neuroimaging findings for these patients with or without postoperative visual complications. RESULTS: The authors identified 72 SHA aneurysms in 70 patients (mean age 58 years). Of 69 patients (1 patient died) evaluated, postoperative visual complications occurred in 9 (13.0%). Although the aneurysm size and SHA sacrifice did not lead to postoperative visual impairment, simultaneous treatment of bilateral aneurysms was a risk factor for postoperative visual complications. CONCLUSIONS: Unilateral SHA impairment may be safe (i.e., it may not induce ischemia of the optic pathway) for many, but not all, patients with SHA aneurysm. PMID- 25699411 TI - Evolution of cranioplasty techniques in neurosurgery: historical review, pediatric considerations, and current trends. AB - Cranial bone repair is one of the oldest neurosurgical practices. Reconstructing the natural contours of the skull has challenged the ingenuity of surgeons from antiquity to the present day. Given the continuous improvement of neurosurgical and emergency care over the past century, more patients survive such head injuries, thus necessitating more than ever before a simple, safe, and durable means of correcting skull defects. In response, numerous techniques and materials have been devised as the art of cranioplasty has progressed. Although the goals of cranioplasty remain the same, the evolution of techniques and diversity of materials used serves as testimony to the complexity of this task. This paper highlights the evolution of these materials and techniques, with a particular focus on the implications for managing pediatric calvarial repair and emerging trends within the field. PMID- 25699412 TI - Characterization of radiation-induced cavernous malformations and comparison with a nonradiation cavernous malformation cohort. AB - OBJECT: The objective of this study was to characterize the clinical features of radiation-induced cavernous malformations (RICMs). METHODS: The authors retrospectively reviewed the clinical and radiological characteristics of patients with RICMs. The features of these RICMs were then compared with features of nonradiation cavernous malformations (CMs) in 270 patients. RESULTS: Thirty two patients with RICMs were identified (56.2% men), with a median age of 31.1 years at RICM diagnosis. The median latency from radiation treatment to RICM diagnosis was 12.0 years (interquartile range 5.0-19.6 years). RICMs were always within the previous radiation port. RICMs were symptomatic at diagnosis in 46.9%, and were associated with symptomatic intracranial hemorrhage at any time in 43.8%. Older age at the time of radiation treatment and higher radiation dose were associated with shorter latency. RICMs tended to be diagnosed at a younger age than nonradiation CMs (median 31.1 vs 42.4 years, respectively; p = 0.054) but were significantly less likely to be symptomatic at the time of diagnosis (46.9% vs 65.8%, respectively; p = 0.036). RICMs were more likely to be multiple CMs than nonradiation CMs (p = 0.0002). Prospectively, the risk of symptomatic hemorrhage was 4.2% for RICMs and 2.3% for nonradiation CMs per person-year (p = 0.556). In the absence of symptoms at presentation, the risk of hemorrhage for RICMs was higher than for nonradiation CMs (4.2% vs 0.35%, respectively; p = 0.118). CONCLUSIONS: In this patient population, RICMs occurred within the radiation port approximately 12 years after radiation treatment. Compared with nonradiation CMs, RICMs were more likely to occur as multiple CMs, to present at a younger age, and were at least as likely to cause symptomatic hemorrhage. PMID- 25699413 TI - Neurosurgical patties: adhesion and damage mitigation. AB - OBJECT: Neurosurgical patties are textile pads used during most neurosurgical operations to protect tissues, manage the fluid environment, control hemostasis, and aid tissue manipulation. Recent research has suggested that, contrary to their aim, patties adhere to brain tissue and cause damage during removal. This study aimed to characterize and quantify the degree of and consequences resulting from adhesion between neurosurgical patties and brain tissue. METHODS: Using a customized peel apparatus, the authors performed 90 degrees peel tests on 5 patty products: Policot, Telfa, Americot, Delicot, and Ray-Cot (n = 247) from American Surgical Company. They tested 4 conditions: wet patty on glass (control), wet patty on wet brain peeled at 5 mm/sec (wet), dry patty on wet brain peeled at 5 mm/sec (dry), and wet patty on wet brain peeled at 20 mm/sec (speed). The interaction between patty and tissue was analyzed using peel-force traces and pre-peel histological analysis. RESULTS: Adhesion strength differed between patty products (p < 0.001) and conditions (p < 0.001). Adhesion strength was greatest for Delicot patties under wet (2.22 mN/mm) and dry (9.88 mN/mm) conditions. For all patties, damage at the patty-tissue interface was proportional to the degree of fiber contact. When patties were irrigated, mechanical adhesion was reduced by up to 550% compared with dry usage. CONCLUSIONS: For all patty products, mechanical (destructive) and liquid-mediated (nondestructive) adhesion caused damage to neural tissue. The greatest adhesion occurred with Delicot patties. To mitigate patty adhesion and neural tissue damage, surgeons should consider regular irrigation to be essential during neurosurgical procedures. PMID- 25699414 TI - Technological innovation in neurosurgery: a quantitative study. AB - OBJECT: Technological innovation within health care may be defined as the introduction of a new technology that initiates a change in clinical practice. Neurosurgery is a particularly technology-intensive surgical discipline, and new technologies have preceded many of the major advances in operative neurosurgical techniques. The aim of the present study was to quantitatively evaluate technological innovation in neurosurgery using patents and peer-reviewed publications as metrics of technology development and clinical translation, respectively. METHODS: The authors searched a patent database for articles published between 1960 and 2010 using the Boolean search term "neurosurgeon OR neurosurgical OR neurosurgery." The top 50 performing patent codes were then grouped into technology clusters. Patent and publication growth curves were then generated for these technology clusters. A top-performing technology cluster was then selected as an exemplar for a more detailed analysis of individual patents. RESULTS: In all, 11,672 patents and 208,203 publications related to neurosurgery were identified. The top-performing technology clusters during these 50 years were image-guidance devices, clinical neurophysiology devices, neuromodulation devices, operating microscopes, and endoscopes. In relation to image-guidance and neuromodulation devices, the authors found a highly correlated rapid rise in the numbers of patents and publications, which suggests that these are areas of technology expansion. An in-depth analysis of neuromodulation-device patents revealed that the majority of well-performing patents were related to deep brain stimulation. CONCLUSIONS: Patent and publication data may be used to quantitatively evaluate technological innovation in neurosurgery. PMID- 25699415 TI - Changes in cerebrospinal fluid flow assessed using intraoperative MRI during posterior fossa decompression for Chiari malformation. AB - OBJECT The authors completed a prospective, institutional review board-approved study using intraoperative MRI (iMRI) in patients undergoing posterior fossa decompression (PFD) for Chiari I malformation. The purpose of the study was to examine the utility of iMRI in determining when an adequate decompression had been performed. METHODS Patients with symptomatic Chiari I malformations with imaging findings of obstruction of the CSF space at the foramen magnum, with or without syringomyelia, were considered candidates for surgery. All patients underwent complete T1, T2, and cine MRI studies in the supine position preoperatively as a baseline. After the patient was placed prone with the neck flexed in position for surgery, iMRI was performed. The patient then underwent a bone decompression of the foramen magnum and arch of C-1, and the MRI was repeated. If obstruction was still present, then in a stepwise fashion the patient underwent dural splitting, duraplasty, and coagulation of the tonsils, with an iMRI study performed after each step guiding the decision to proceed further. RESULTS Eighteen patients underwent PFD for Chiari I malformations between November 2011 and February 2013; 15 prone preincision iMRIs were performed. Fourteen of these patients (93%) demonstrated significant improvement of CSF flow through the foramen magnum dorsal to the tonsils with positioning only. This improvement was so notable that changes in CSF flow as a result of the bone decompression were difficult to discern. CONCLUSIONS The authors observed significant CSF flow changes when simply positioning the patient for surgery. These results put into question intraoperative flow assessments that suggest adequate decompression by PFD, whether by iMRI or intraoperative ultrasound. The use of intraoperative imaging during PFD for Chiari I malformation, whether by ultrasound or iMRI, is limited by CSF flow dynamics across the foramen magnum that change significantly when the patient is positioned for surgery. PMID- 25699416 TI - Sellar and parasellar tumor removal without discontinuing antithrombotic therapy. AB - OBJECT: Treatment with dual antiplatelet agents associated with coronary stenting procedures and long-term anticoagulant therapy is increasingly common, but the treatment carries risks during surgical procedures. Evidence-based recommendations have proposed discontinuation of antithrombotic treatment or introduction of bridging therapy in some procedures less invasive and with lower risk of bleeding. However, neurosurgical procedures without discontinuation of antithrombotic treatment and perioperative management have received little investigation. METHODS: Between October 2008 and January 2014, 15 consecutive patients (11 males and 4 females; age range 51-75 years [mean 68.2 years]), with sellar and parasellar tumors were treated through the transsphenoidal approach without discontinuation of antithrombotic therapy. Clinical data were compared with another 15 patients, who underwent transsphenoidal surgeries without preoperative antithrombotic therapy. RESULTS: Gross-total removal of the tumor or total aspiration of the content of Rathke's cleft cyst was achieved in 13 patients, and subtotal removal was achieved in 1 patient with a small remnant in the cavernous sinus. No difference was found in intraoperative bleeding between the antithrombotic agent group and the control group (mean 255 ml vs 215 ml, Mann Whitney U-test, p = 0.547), and no patient required transfusion. No difference was found in operation time between the antithrombotic agent group and the control group (167.8 minutes vs 150.0 minutes, Mann-Whitney U-test, p = 0.262). All patients were discharged on postoperative Day 12 without neurological deficits. CONCLUSIONS: The present study suggests that discontinuation of antithrombotic therapy may be unnecessary before the typical transsphenoidal surgery. Large randomized clinical trials at multiple centers are needed to confirm these findings. PMID- 25699417 TI - How benchmarking in science can lead to a reversal of priorities. PMID- 25699418 TI - Synthesis of pyrrolo[2,1,5-cd]indolizines through dehydrogenative Heck annelation of indolizines with diaryl acetylenes using dioxygen as an oxidant. AB - A dehydrogenative Heck annelation reaction of indolizine with diaryl acetylene via dual C-H bond cleavage was developed. Oxygen gas was employed as a clean oxidant in this catalysis under base-free conditions. Diarylpyrrolo[2,1,5 cd]indolizines were synthesized with high atom economy. In addition, kinetic isotope experiments provided evidence for C-H bond metalation of the 5-position of the indolizine as the rate-limiting step. PMID- 25699420 TI - Feeling Better About Self After Receiving Negative Feedback: When the Sense That Ability Can Be Improved Is Activated. AB - Past studies suggest that managers and educators often consider negative feedback as a motivator for individuals to think about their shortcomings and improve their work, but delivering negative feedback does not always achieve desired results. The present study, based on incremental theory, employed an intervention method to activate the belief that a particular ability could be improved after negative feedback. Three experiments tested the intervention effect on negative self-relevant emotion. Study 1 indicated conveying suggestions for improving ability reduced negative self-relevant emotion after negative feedback. Study 2 tested whether activating the sense of possible improvement in the ability could reduce negative self-relevant emotion. Results indicated activating the belief that ability could be improved reduced negative self-relevant emotion after failure, but delivering emotion management information alone did not yield the same effect. Study 3 extended the results by affirming the effort participants made in doing the test, and found the affirmation reduced negative self-relevant emotion. Collectively, the findings indicated focusing on the belief that the ability could be improved in the future can reduce negative self-relevant emotion after negative feedback. PMID- 25699421 TI - Editorial: soft matters. PMID- 25699419 TI - An immunosuppressive antibody-drug conjugate. AB - We have developed a novel antibody-drug conjugate (ADC) that can selectively deliver the Lck inhibitor dasatinib to human T lymphocytes. This ADC is based on a humanized antibody that selectively binds with high affinity to CXCR4, an antigen that is selectively expressed on hematopoietic cells. The resulting dasatinib-antibody conjugate suppresses T-cell-receptor (TCR)-mediated T-cell activation and cytokine expression with low nM EC50 and has minimal effects on cell viability. This ADC may lead to a new class of selective immunosuppressive drugs with improved safety and extend the ADC strategy to the targeted delivery of kinase inhibitors for indications beyond oncology. PMID- 25699422 TI - Corrections to Thomas-Fermi densities at turning points and beyond. AB - Uniform semiclassical approximations for the number and kinetic-energy densities are derived for many noninteracting fermions in one-dimensional potentials with two turning points. The resulting simple, closed-form expressions contain the leading corrections to Thomas-Fermi theory, involve neither sums nor derivatives, are spatially uniform approximations, and are exceedingly accurate. PMID- 25699423 TI - Convexity of the entanglement entropy of SU(2N)-symmetric fermions with attractive interactions. AB - The positivity of the probability measure of attractively interacting systems of 2N-component fermions enables the derivation of an exact convexity property for the ground-state energy of such systems. Using analogous arguments, applied to path-integral expressions for the entanglement entropy derived recently, we prove nonperturbative analytic relations for the Renyi entropies of those systems. These relations are valid for all subsystem sizes, particle numbers, and dimensions, and in arbitrary external trapping potentials. PMID- 25699424 TI - Testing spontaneous wave-function collapse models on classical mechanical oscillators. AB - We show that the heating effect of spontaneous wave-function collapse models implies an experimentally significant increment DeltaT(sp) of equilibrium temperature in a mechanical oscillator. The obtained new form DeltaT(sp) is linear in the oscillator's relaxation time tau and independent of the mass. The oscillator can be in a classical thermal state, also the effect DeltaT(sp) is classical for a wide range of frequencies and quality factors. We note that the test of DeltaT(sp) does not necessitate quantum state monitoring just tomography. In both the gravity-related and the continuous spontaneous localization models the strong-effect edge of their parameter range can be challenged in existing experiments on classical oscillators. For the continuous spontaneous localization theory, the conjectured highest collapse rate parameter values become immediately constrained by evidences from current experiments on extreme slow-ring-down oscillators. PMID- 25699425 TI - Zero-temperature equation of state of mass-imbalanced resonant Fermi gases. AB - We calculate the zero-temperature equation of state of mass-imbalanced resonant Fermi gases in an ab initio fashion, by implementing the recent proposal of imaginary-valued mass difference to bypass the sign problem in lattice Monte Carlo calculations. The fully nonperturbative results thus obtained are analytically continued to real mass-imbalance to yield the physical equation of state, providing predictions for upcoming experiments with mass-imbalanced atomic Fermi gases. In addition, we present an exact relation for the rate of change of the equation of state at small mass imbalances, showing that it is fully determined by the energy of the mass-balanced system. PMID- 25699426 TI - Full multipartite entanglement of frequency-comb Gaussian states. AB - An analysis is conducted of the multipartite entanglement for Gaussian states generated by the parametric down-conversion of a femtosecond frequency comb. Using a recently introduced method for constructing optimal entanglement criteria, a family of tests is formulated for mode decompositions that extends beyond the traditional bipartition analyses. A numerical optimization over this family is performed to achieve maximal significance of entanglement verification. For experimentally prepared 4-, 6-, and 10-mode states, full entanglement is certified for all of the 14, 202, and 115 974 possible nontrivial partitions, respectively. PMID- 25699427 TI - Quantum storage of orbital angular momentum entanglement in an atomic ensemble. AB - Constructing a quantum memory for a photonic entanglement is vital for realizing quantum communication and network. Because of the inherent infinite dimension of orbital angular momentum (OAM), the photon's OAM has the potential for encoding a photon in a high-dimensional space, enabling the realization of high channel capacity communication. Photons entangled in orthogonal polarizations or optical paths had been stored in a different system, but there have been no reports on the storage of a photon pair entangled in OAM space. Here, we report the first experimental realization of storing an entangled OAM state through the Raman protocol in a cold atomic ensemble. We reconstruct the density matrix of an OAM entangled state with a fidelity of 90.3%+/-0.8% and obtain the Clauser-Horne Shimony-Holt inequality parameter S of 2.41+/-0.06 after a programed storage time. All results clearly show the preservation of entanglement during the storage. PMID- 25699428 TI - Efficiency statistics at all times: Carnot limit at finite power. AB - We derive the statistics of the efficiency under the assumption that thermodynamic fluxes fluctuate with normal law, parametrizing it in terms of time, macroscopic efficiency, and a coupling parameter zeta. It has a peculiar behavior: no moments, one sub-, and one super-Carnot maxima corresponding to reverse operating regimes (engine or pump), the most probable efficiency decreasing in time. The limit zeta->0 where the Carnot bound can be saturated gives rise to two extreme situations, one where the machine works at its macroscopic efficiency, with Carnot limit corresponding to no entropy production, and one where for a transient time scaling like 1/zeta microscopic fluctuations are enhanced in such a way that the most probable efficiency approaches the Carnot limit at finite entropy production. PMID- 25699429 TI - Dark-matter decay as a complementary probe of multicomponent dark sectors. AB - In single-component theories of dark matter, the 2->2 amplitudes for dark-matter production, annihilation, and scattering can be related to each other through various crossing symmetries. The detection techniques based on these processes are thus complementary. However, multicomponent theories exhibit an additional direction for dark-matter complementarity: the possibility of dark-matter decay from heavier to lighter components. We discuss how this new detection channel may be correlated with the others, and demonstrate that the enhanced complementarity which emerges can be an important ingredient in probing and constraining the parameter spaces of such models. PMID- 25699430 TI - Does small scale structure significantly affect cosmological dynamics? AB - The large-scale homogeneity and isotropy of the Universe is generally thought to imply a well-defined background cosmological model. It may not. Smoothing over structure adds in an extra contribution, transferring power from small scales up to large. Second-order perturbation theory implies that the effect is small, but suggests that formally the perturbation series may not converge. The amplitude of the effect is actually determined by the ratio of the Hubble scales at matter radiation equality and today-which are entirely unrelated. This implies that a universe with significantly lower temperature today could have significant backreaction from more power on small scales, and so provides the ideal testing ground for understanding backreaction. We investigate this using two different N body numerical simulations-a 3D Newtonian and a 1D simulation which includes all relevant relativistic effects. We show that while perturbation theory predicts an increasing backreaction as more initial small-scale power is added, in fact the virialization of structure saturates the backreaction effect at the same level independently of the equality scale. This implies that backreaction is a small effect independently of initial conditions. Nevertheless, it may still contribute at the percent level to certain cosmological observables and therefore it cannot be neglected in precision cosmology. PMID- 25699431 TI - Glow in the dark matter: observing galactic halos with scattered light. AB - We consider the observation of diffuse halos of light around the discs of spiral galaxies, as a probe of the interaction cross section between dark matter (DM) and photons. Using the galaxy M101 as an example, we show that for a scattering cross section at the level of 10(-23)(m/GeV) cm(2) or greater dark matter in the halo will scatter light out from the more luminous center of the disc to larger radii, contributing to an effective increased surface brightness at the edges of the observed area on the sky. This allows us to set an upper limit on the DM photon cross section using data from the Dragonfly instrument. We then show how to improve this constraint, and the potential for discovery, by combining the radial profile of DM-photon scattering with measurements at multiple wavelengths. Observation of diffuse light presents a new and potentially powerful way to probe the interactions of dark matter with photons, a way that is complementary to existing searches. PMID- 25699432 TI - Exact adler function in supersymmetric QCD. AB - The Adler function D is found exactly in supersymmetric QCD. Our exact formula relates D(Q(2)) to the anomalous dimension of the matter superfields gamma(alpha(s)(Q(2))). En route we prove another theorem: the absence of the so called singlet contribution to D. While such singlet contributions are present in individual supergraphs, they cancel in the sum. PMID- 25699434 TI - Nucleon decay into a dark sector. AB - A sub-GeV dark sector fermion X can have baryon-number-violating interactions induced by high-scale physics, leading to nucleon decay into X+meson and neutron >X+photon. Such processes can mimic standard search modes containing a neutrino, but have different kinematics and may have escaped detection. If a dark force mediated by a light vector Z(d) acts on X, depending on parameters, neutron >X+Z(d) can be important. In typical scenarios, Z(d) decays into l(+)l(-), where l=e,MU, with an order unity branching fraction. Nucleon decay searches can potentially uncover new dark states that are otherwise inaccessible, due to their negligible coupling to ordinary matter or cosmological abundance. PMID- 25699436 TI - Effective field theory for lattice nuclei. AB - We show how nuclear effective field theory (EFT) and ab initio nuclear-structure methods can turn input from lattice quantum chromodynamics (LQCD) into predictions for the properties of nuclei. We argue that pionless EFT is the appropriate theory to describe the light nuclei obtained in LQCD simulations carried out at pion masses heavier than the physical pion mass. We solve the EFT using the effective-interaction hyperspherical harmonics and auxiliary-field diffusion Monte Carlo methods. Fitting the three leading-order EFT parameters to the deuteron, dineutron, and triton LQCD energies at m_{pi}~800 MeV, we reproduce the corresponding alpha-particle binding and predict the binding energies of mass-5 and mass-6 ground states. PMID- 25699437 TI - Local scaling correction for reducing delocalization error in density functional approximations. AB - Delocalization error is one of the most fundamental and dominant errors that plagues presently used density functional approximations. It is responsible for a large class of problems in the density functional theory calculations. For an effective and universal alleviation of the delocalization error, we develop a local scaling correction scheme by imposing the Perdew-Parr-Levy- Balduz linearity condition to local regions of a system. Our novel scheme is applicable to various mainstream density functional approximations. It substantially reduces the delocalization error, as exemplified by the significantly improved description of dissociating molecules, transition-state species, and charge transfer systems. The usefulness of our novel scheme affirms that the explicit treatment of fractional electron distributions is essentially important for reducing the intrinsic delocalization error associated with approximate density functionals. PMID- 25699438 TI - Induced coherence, vacuum fields, and complementarity in biphoton generation. AB - It is well established that spontaneous parametric down-conversion with induced coherence across two coupled interferometers results in high-visibility single photon interference. We describe experiments in which additional photon channels are introduced such that "which-path" information is made possible and the fringe visibility in single-photon interference is reduced in accordance with basic notions of complementarity. However, these additional pathways result in nearly perfect visibility when photons are counted in coincidence. A simplified theoretical model accounts for these observations and attributes them directly to the vacuum fields at the different crystals. PMID- 25699439 TI - Storage and retrieval of THz-bandwidth single photons using a room-temperature diamond quantum memory. AB - We report the storage and retrieval of single photons, via a quantum memory, in the optical phonons of a room-temperature bulk diamond. The THz-bandwidth heralded photons are generated by spontaneous parametric down-conversion and mapped to phonons via a Raman transition, stored for a variable delay, and released on demand. The second-order correlation of the memory output is g((2))(0)=0.65+/-0.07, demonstrating a preservation of nonclassical photon statistics throughout storage and retrieval. The memory is low noise, high speed and broadly tunable; it therefore promises to be a versatile light-matter interface for local quantum processing applications. PMID- 25699440 TI - Entangled absorption of a single photon with a single spin in diamond. AB - Quantum entanglement, a key resource for quantum information science, is inherent in a solid. It has been recently shown that entanglement between a single optical photon and a single spin qubit in a solid is generated via spontaneous emission. However, entanglement generation by measurement is rather essential for quantum operations. We here show that the physics behind the entangled emission can be time reversed to demonstrate entangled absorption mediated by an inherent spin orbit entanglement in a single nitrogen vacancy center in diamond. Optical arbitrary spin state preparation and complete spin state tomography reveal the fidelity of the entangled absorption to be 95%. With the entangled emission and absorption of a photon, materials can be spontaneously entangled or swap their quantum state based on the quantum teleportation scheme. PMID- 25699441 TI - Mode-locked ultrashort pulse generation from on-chip normal dispersion microresonators. AB - We describe generation of stable mode-locked pulse trains from on-chip normal dispersion microresonators. The excitation of hyperparametric oscillation is facilitated by the local dispersion disruptions induced by mode interactions. The system is then driven from hyperparametric oscillation to the mode-locked state with over 200 nm spectral width by controlled pump power and detuning. With the continuous-wave-driven nonlinearity, the pulses sit on a pedestal, akin to a cavity soliton. We identify the importance of pump detuning and wavelength dependent quality factors in stabilizing and shaping the pulse structure, to achieve a single pulse inside the cavity. We examine the mode-locking dynamics by numerically solving the master equation and provide analytic solutions under appropriate approximations. PMID- 25699442 TI - Magnetic-field-driven localization of light in a cold-atom gas. AB - We discover a transition from extended to localized quasimodes for light in a gas of immobile two-level atoms in a magnetic field. The transition takes place either upon increasing the number density of atoms in a strong field or upon increasing the field at a high enough density. It has many characteristic features of a disorder-driven (Anderson) transition but is strongly influenced by near-field interactions between atoms and the anisotropy of the atomic medium induced by the magnetic field. PMID- 25699443 TI - Rotating optical microcavities with broken chiral symmetry. AB - We demonstrate in open microcavities with broken chiral symmetry that quasidegenerate pairs of copropagating-wave resonances are transformed by rotation to counterpropagating ones, leading to a striking change of emission directions. The rotation-induced relative change in output intensity increases exponentially with cavity size, in contrast to the linear scaling of the Sagnac effect. By tuning the degree of spatial chirality with cavity shape, we are able to maximize the emission sensitivity to rotation without spoiling the quality factor. PMID- 25699444 TI - Strange nonchaotic stars. AB - The unprecedented light curves of the Kepler space telescope document how the brightness of some stars pulsates at primary and secondary frequencies whose ratios are near the golden mean, the most irrational number. A nonlinear dynamical system driven by an irrational ratio of frequencies generically exhibits a strange but nonchaotic attractor. For Kepler's "golden" stars, we present evidence of the first observation of strange nonchaotic dynamics in nature outside the laboratory. This discovery could aid the classification and detailed modeling of variable stars. PMID- 25699445 TI - Origin of the microbranching instability in rapid cracks. AB - The origin of the microbranching instability is a long-standing unresolved issue in the fracture of brittle amorphous materials. We investigate the onset of this instability by measuring the real-time dynamics and symmetries of the strain fields produced by rapid tensile cracks in brittle gels. We find that once a simple tensile crack is subjected to shear perturbations, cracks undergo the microbranching instability above a finite velocity-dependent threshold. We further reveal a distinct relation between the microbranching and the oscillatory instabilities of rapid cracks. PMID- 25699446 TI - From modal mixing to tunable functional switches in nonlinear phononic crystals. AB - We introduce a paradigm for spatial and modal wave manipulation based on nonlinear phononic crystals and explore its potential for engineering wave control systems with tunable, adaptive, and multifunctional characteristics. Our approach exploits nonlinear mechanisms to stretch the frequency signature of the wave response and distribute it over multiple modes, thereby activating a mixture of modal characteristics and enabling functionalities associated with high frequency optical modes, even while operating in the low-frequency regime. To elucidate the versatility of this approach, we consider different granular crystal configurations that span the available landscape of crystal topologies and wave control functionalities. The ability to switch between complementary functionalities allows rethinking nonlinear phononic crystals as programmable acoustic ports that form the building blocks of a new structural logic framework enabled by nonlinearity. PMID- 25699435 TI - Measurement of the forward-backward asymmetry in the production of B(+/-) mesons in pp collisions at ?s=1.96 TeV. AB - We present a measurement of the forward-backward asymmetry in the production of B(+/-) mesons, A(FB)(B(+/-)), using B(+/-)->J/psiK(+/-) decays in 10.4 fb(-1) of pp collisions at sqrt[s]=1.96 TeV collected by the D0 experiment during Run II of the Tevatron collider. A nonzero asymmetry would indicate a preference for a particular flavor, i.e., b quark or b antiquark, to be produced in the direction of the proton beam. We extract A(FB)(B(+/-)) from a maximum likelihood fit to the difference between the numbers of forward- and backward-produced B(+/-) mesons. We measure an asymmetry consistent with zero: A(FB)(B(+/-))=[-0.24+/-0.41 (stat)+/-0.19 (syst)]%. PMID- 25699447 TI - Detection of a dynamic cone-shaped meniscus on the surface of fluids in electric fields. AB - A cone-shaped meniscus of electrified fluids, often called a Taylor cone, is observed in rain drops and lightning and employed in various physical instruments and experimental techniques, but the way it evolves from a rounded shape to a cone is a long-standing puzzle. Earth's gravity and microgravity measurements on the meniscus whose height is just shy of droplet ejection reveal that field driven cusp evolution exhibits a universal self-similarity insensitive to the forcing field and scaled by the fluid surface tension and density. Our work paves the way for dynamic control of field-driven phenomena in fluids. PMID- 25699448 TI - Experimental demonstration of a soft x-ray self-seeded free-electron laser. AB - The Linac Coherent Light Source has added a self-seeding capability to the soft x ray range using a grating monochromator system. We report the demonstration of soft x-ray self-seeding with a measured resolving power of 2000-5000, wavelength stability of 10(-4), and an increase in peak brightness by a factor of 2-5 across the photon energy range of 500-1000 eV. By avoiding the need for a monochromator at the experimental station, the self-seeded beam can deliver as much as 50-fold higher brightness to users. PMID- 25699449 TI - New steady-state quiescent high-confinement plasma in an experimental advanced superconducting tokamak. AB - A critical challenge facing the basic long-pulse high-confinement operation scenario (H mode) for ITER is to control a magnetohydrodynamic (MHD) instability, known as the edge localized mode (ELM), which leads to cyclical high peak heat and particle fluxes at the plasma facing components. A breakthrough is made in the Experimental Advanced Superconducting Tokamak in achieving a new steady-state H mode without the presence of ELMs for a duration exceeding hundreds of energy confinement times, by using a novel technique of continuous real-time injection of a lithium (Li) aerosol into the edge plasma. The steady-state ELM-free H mode is accompanied by a strong edge coherent MHD mode (ECM) at a frequency of 35-40 kHz with a poloidal wavelength of 10.2 cm in the ion diamagnetic drift direction, providing continuous heat and particle exhaust, thus preventing the transient heat deposition on plasma facing components and impurity accumulation in the confined plasma. It is truly remarkable that Li injection appears to promote the growth of the ECM, owing to the increase in Li concentration and hence collisionality at the edge, as predicted by GYRO simulations. This new steady state ELM-free H-mode regime, enabled by real-time Li injection, may open a new avenue for next-step fusion development. PMID- 25699450 TI - Microscopic origin of shear relaxation in a model viscoelastic liquid. AB - An atomistic description of shear stress relaxation in a viscoelastic liquid is developed from first principles through accurate molecular dynamic simulations in a model Yukawa system. It is shown that the relaxation time tau(M)(ex) of the excess part of the shear stress autocorrelation function provides a correct measure of the relaxation process. Below a certain critical value Gamma(c) of the Coulomb coupling strength, the lifetime of local atomic connectivity tau(LC) converges to tau(M)(ex) and is the microscopic origin of the relaxation. At Gamma?Gamma(c), i.e., in the potential energy dominated regime, tau(M)(ex) >tau(M) (the Maxwell relaxation time) and can, therefore, fully account for the elastic or "solidlike" behavior. Our results can help provide a better fundamental understanding of viscoelastic behavior in a variety of strongly coupled systems such as dusty plasmas, colloids, and non-Newtonian fluids. PMID- 25699451 TI - Roton-maxon excitation spectrum of Bose condensates in a shaken optical lattice. AB - We present experimental evidence showing that an interacting Bose condensate in a shaken optical lattice develops a roton-maxon excitation spectrum, a feature normally associated with superfluid helium. The roton-maxon feature originates from the double-well dispersion in the shaken lattice, and can be controlled by both the atomic interaction and the lattice modulation amplitude. We determine the excitation spectrum using Bragg spectroscopy and measure the critical velocity by dragging a weak speckle potential through the condensate-both techniques are based on a digital micromirror device. Our dispersion measurements are in good agreement with a modified Bogoliubov model. PMID- 25699452 TI - Critical length limiting superlow friction. AB - Since the demonstration of superlow friction (superlubricity) in graphite at nanoscale, one of the main challenges in the field of nano- and micromechanics was to scale this phenomenon up. A key question to be addressed is to what extent superlubricity could persist, and what mechanisms could lead to its failure. Here, using an edge-driven Frenkel-Kontorova model, we establish a connection between the critical length above which superlubricity disappears and both intrinsic material properties and experimental parameters. A striking boost in dissipated energy with chain length emerges abruptly due to a high-friction stick slip mechanism caused by deformation of the slider leading to a local commensuration with the substrate lattice. We derived a parameter-free analytical model for the critical length that is in excellent agreement with our numerical simulations. Our results provide a new perspective on friction and nanomanipulation and can serve as a theoretical basis for designing nanodevices with superlow friction, such as carbon nanotubes. PMID- 25699453 TI - First-principles calculation of femtosecond symmetry-breaking atomic forces in photoexcited bismuth. AB - We present a first-principles method for the calculation of the polarization dependent atomic forces resulting from optical excitation in a solid. We calculate the induced force driving the E(g) phonon mode in bismuth immediately after absorption of polarized light. When radiation with polarization perpendicular to the c axis is absorbed, the photoexcited charge density breaks the threefold rotational symmetry, leading to an atomic force component perpendicular to the axis. We calculate the initial excited electronic distribution as a function of photon energy and polarization and find the resulting atomic force components parallel and perpendicular to the axis. The magnitude of the calculated force is in excellent agreement with that derived from recent measurements of the amplitude of E(g) atomic motion and the decay time of several femtoseconds for the driving force. PMID- 25699454 TI - Origami multistability: from single vertices to metasheets. AB - We show that the simplest building blocks of origami-based materials-rigid, degree-four vertices-are generically multistable. The existence of two distinct branches of folding motion emerging from the flat state suggests at least bistability, but we show how nonlinearities in the folding motions allow generic vertex geometries to have as many as five stable states. In special geometries with collinear folds and symmetry, more branches emerge leading to as many as six stable states. Tuning the fold energy parameters, we show how monostability is also possible. Finally, we show how to program the stability features of a single vertex into a periodic fold tessellation. The resulting metasheets provide a previously unanticipated functionality-tunable and switchable shape and size via multistability. PMID- 25699455 TI - Evolution of polytypism in GaAs nanowires during growth revealed by time-resolved in situ x-ray diffraction. AB - In III-V nanowires the energetic barriers for nucleation in the zinc blende or wurtzite arrangement are typically of a similar order of magnitude. As a result, both arrangements can occur in a single wire. Here, we investigate the evolution of this polytypism in self-catalyzed GaAs nanowires on Si(111) grown by molecular beam epitaxy with time-resolved in situ x-ray diffraction. We interpret our data in the framework of a height dependent Markov model for the stacking in the nanowires. In this way, we extract the mean sizes of faultless wurtzite and zinc blende segments-a key parameter of polytypic nanowires-and their temporal evolution during growth. Thereby, we infer quantitative information on the differences of the nucleation barriers including their evolution without requiring a model of the nucleus. PMID- 25699456 TI - Origin of an isothermal R-martensite formation in Ni-rich Ti-Ni solid solution: crystallization of strain glass. AB - We report that R martensite isothermally forms with time in a solution-treated Ti(48.7)Ni(51.3) single crystal. This abnormal formation originates from the growth of a short-range ordered R phase with time, i.e., the "crystallization" of strain glass. The established time-composition-temperature Ti-Ni diagram shows a time evolution of the R phase and composition-temperature phase diagram. The presence or absence of the R phase in this new diagram, as well as in other conditions (like doping Fe or aging), is explained in a unified framework of free energy landscape. Our finding suggests a new mechanism for the isothermal martensite formation, which could be applied to other metal and ceramic martensitic systems to find new phases and novel properties. PMID- 25699457 TI - Violation of the spin-statistics theorem and the bose-einstein condensation of particles with half-integer spin. AB - We consider the Bose condensation of bosonic particles with spin 1/2. The condensation is driven by an external magnetic field. Our work is motivated by ideas of quantum critical deconfinement and bosonic spinons in spin liquid states. We show that both the nature of the novel Bose condensate and the excitation spectrum are fundamentally different from that in the usual integer spin case. We predict two massive ("Higgs") excitations and two massless Goldstone excitations. One of the Goldstone excitations has a linear excitation spectrum and another has a quadratic spectrum. This implies that the Bose condensate does not support superfluidity, the Landau criterion is essentially violated. We formulate a "smoking gun" criterion for searches of the novel Bose condensation. PMID- 25699458 TI - Non-Gaussian spatial correlations dramatically weaken localization. AB - We perform variational studies of the interaction-localization problem to describe the interaction-induced renormalizations of the effective (screened) random potential seen by quasiparticles. Here we present results of careful finite-size scaling studies for the conductance of disordered Hubbard chains at half-filling and zero temperature. While our results indicate that quasiparticle wave functions remain exponentially localized even in the presence of moderate to strong repulsive interactions, we show that interactions produce a strong decrease of the characteristic conductance scale g^{*} signaling the crossover to strong localization. This effect, which cannot be captured by a simple renormalization of the disorder strength, instead reflects a peculiar non Gaussian form of the spatial correlations of the screened disordered potential, a hitherto neglected mechanism to dramatically reduce the impact of Anderson localization (interference) effects. PMID- 25699459 TI - Real space imaging of spin polarons in Zn-doped SrCu(2)(BO(3))(2). AB - We report on the real space profile of spin polarons in the quasi-two-dimensional frustrated dimer spin system SrCu(2)(BO(3))(2) doped with 0.16% of Zn. The (11)B nuclear magnetic resonance spectrum exhibits 15 additional boron sites near nonmagnetic Zn impurities. With the help of exact diagonalizations of finite clusters, we have deduced from the boron spectrum, the distribution of local magnetizations at the Cu sites with fine spatial resolution, providing direct evidence for an extended spin polaron. The results are confronted with those of other experiments performed on doped and undoped samples of SrCu(2)(BO(3))(2). PMID- 25699460 TI - Antiferromagnetic topological superconductor and electrically controllable Majorana fermions. AB - We investigate the realization of a topological superconductor in a generic bucked honeycomb system equipped with four types of mass-generating terms, where the superconductor gap is introduced by attaching the honeycomb system to an s wave superconductor. Constructing the topological phase diagram, we show that Majorana modes are formed in the phase boundary. In particular, we analyze the honeycomb system with antiferromagnetic order in the presence of perpendicular electric field E(z). It becomes topological for |E(z)|>E(z)(cr) and trivial for |E(z)| Ag-MnO2 > pristine alpha-MnO2. Specifically, cells with the Au-MnO2 catalyst could reduce the discharge/charge overpotentials at 100 mA g(-1) to 0.23/1.02 V and deliver discharge/charge capacities of 5784/5020 mAh g(-1). They could also be cycled for at least 60 times at the depth of discharge of 1000 mAh g(-1). The good full cell performance demonstrated the effectiveness of Au/Ag nanoclusters in promoting oxygen electrocatalysis on alpha-MnO2; forming discharge products with more reactive morphologies. It is therefore worthwhile to explore the use of Au and Ag nanoclusters in other catalyst systems for oxygen electrocatalysis in nonaqueous solutions. PMID- 25699480 TI - Isotope effects in (195)Pt NMR spectroscopy: unique (35/37)Cl- and (16/18)O resolved "fingerprints" for all [PtCl6-n(OH)n](2-) (n = 1-5) anions in an alkaline solution and the implications of the trans influence. AB - A detailed analysis of the intrinsic (1)Delta(195)Pt((37/35)Cl) and (1)Delta(195)Pt((18/16)O) isotope 128.8 MHz (195)Pt NMR profiles of the series of kinetically inert [PtCl6-n(OH)n](2-) (n = 1-5) anions generated in strongly alkaline aqueous solutions shows that each (195)Pt NMR resonance of the [Pt(35/37)Cl6-n((16/18)OH)n](2-) (n = 1-5) anions is resolved only into [(6 - n) + 1 for n = 1-5] (35/37)Cl isotopologues at 293 K. Evidently, the greater trans influence of the hydroxido ligand in the order OH(-) > Cl(-) > H2O in [PtCl6 n(OH)n](2-) (n = 1-5) complexes results in somewhat longer Pt-Cl bond displacements trans to the hydroxido ligands, resulting in the absence of isotopomer effects in the [PtCl6-n(OH)n](2-) (n = 1-5) anions in contrast to that observed in the corresponding [PtCl6-n(H2O)n]((2-n)-) (n = 1-5) complexes. In suitably (18)O-enriched sodium hydroxide solutions, additional intrinsic (1)Delta(195)Pt((18/16)O) isotope effects are remarkably well-resolved into unique isotopologue- and isotopomer-based (195)Pt NMR profiles, ascribable to the higher trans influence of the OH(-) ligand. The consequent significantly shorter Pt-OH bonds in these anions emphasize (16/18)O isotopomer effects in the (195)Pt NMR peaks of [Pt(35/37)Cl6-n((16/18)OH)n](2-) (n = 1-5) for magnetically nonequivalent (16/18)OH isotopomers statistically possible in some isotopologues. These (195)Pt NMR profiles constitute unique NMR "fingerprints", useful for the unambiguous assignment of the series of [PtCl6-n(OH)n](2-) anions including their possible cis/trans/fac/mer stereoisomers in such solutions, without a need for accurate chemical shift measurements. PMID- 25699481 TI - Exercise Enhances the Behavioral Responses to Acute Stress in an Animal Model of PTSD. AB - INTRODUCTION: This study examined the effects of endurance exercise on the behavioral response to stress and patterns of brain-derived neurotrophic factor (BDNF), neuropeptide Y (NPY), and delta-opioid receptor (phospho-DOR) expression in the hippocampus. METHODS: Animals ran on a treadmill at 15 m.min, 5 min.d gradually increasing to 20 min.d, 5 d.wk for 6 wk. After training, one group of animals was exposed to a predator scent stress (PSS) protocol for 10 min. Outcome measurements included behavior in an elevated plus-maze (EPM) and acoustic startle response (ASR) 7 d after exposure to stress. Immunohistochemical technique was used to detect the expression of the BDNF, NPY, and phospho-DOR in the hippocampus 8 d after exposure. RESULTS: Sedentary animals exposed to PSS were observed to have a greater incidence of extreme behavior responses including higher anxiety, less total activity in the EPM, and greater amplitude in the ASR than unexposed and/or trained animals. Exercise-trained animals exposed to PSS developed a resiliency to the stress, reflected by significantly greater total activity in the EPM, reduced anxiety, and reduced ASR compared to the sedentary, exposed animals. Exercise in the absence of stress significantly elevated the expression of BDNF and phospho-DOR, whereas exposure to PSS resulted in a significant decline in the expression of NPY, BDNF, and phospho-DOR. Trained animals that were exposed maintained expression of BDNF, NPY, and phospho-DOR in most subregions of the hippocampus. CONCLUSION: Results indicated that endurance training provided a mechanism to promote resilience and/or recovery from stress. In addition, exercise increased expression of BDNF, NPY, and DOR signaling in the hippocampus that was associated with the greater resiliency seen in the trained animals. PMID- 25699482 TI - Context of Physical Activity in a Representative Sample of Adults. AB - PURPOSE: The establishment of formal physical activity (PA) guidelines has led to considerable interest in quantifying participation in moderate to vigorous PA (MVPA). However, evidence on the context of MVPA at the population level is scarce. The aim of this study was to provide information on the type, location, and purpose of MVPA in a representative sample of adults. METHODS: Data from a representative sample of 1234 Iowa adults were included in this study. Each participant performed a telephone-administered 24-h PA recall method to recall PA in the previous 24 h. Self-reported data from the recall instrument included time and types of reported activities across five distinct location and purpose codes. Reported activities were matched with corresponding metabolic equivalent (MET) scores from a reduced list of compendium of physical activities. MVPA was defined as any activity with assigned MET >= 3.0. RESULTS: Of the top 30 most frequently reported MVPA, 16 were lifestyle activities involving walking, and only 4 can be regarded as traditional "exercises." Occupational activities (41% for purpose and 40% for location) and household activities (37% for purpose and 39% for location) accounted for nearly 80% of total reported MVPA time. Time allocations across purpose and location codes considerably differed by sociodemographic indicators. CONCLUSION: Lifestyle activities are more frequently reported than sports and/or recreational activities. Individuals with varying levels of sociodemographic indicators exhibit different patterns of use of time within a given day. A multidomain approach is needed to better understand and increase MVPA in diverse populations of US adults. PMID- 25699483 TI - Gender and geographic differences in the prevalence of reportable childhood speech and language disability in Taiwan. AB - Speech and language disability (SLD) is not uncommon in children. However, data at the national level are limited, and geographic differences are seldom evaluated. Starting from 1980, the local governments in Taiwan has begun to certify disabled residents for providing various services and report cases to the central government according to the law, and the central government maintains a registry of reported cases, which provides a unique opportunity for studying SLD at the national level. Using the registry data from 2004 to 2010, we calculated the prevalence of SLD by age, gender, and geographic area and assessed the changes over time. Because the government discourages the certification under 3 years of age, we excluded cases under 3 years old from the analyses. We found that from 2004 to 2010 the registered cases between 3 and 17 years old increased from 1418 to 1637 per year, and the prevalence generally increased every year in all age groups except in 12-14 years of age. In each year there were more boy cases than girl cases, and the prevalence rate ratio increased from 1.50 to 1.83 (p < 0.05 in all years), with an increasing trend over time (p < 0.01). A higher prevalence was observed in the rural areas over the years, and the prevalence rate ratio increased from 1.35 to 1.71 (p < 0.05 in all years), with an increasing trend over time (p < 0.01). Further studies identifying the risk factors contributed to the increases might help the prevention of SLD in the future. PMID- 25699484 TI - The need to differentiate the magnocellular system from the dorsal stream in connection with dyslexia. AB - A number of authors have postulated a "magnocellular-dorsal stream" deficit in dyslexia. Combining the magnocellular system and the dorsal stream into a single entity in this context faces the problem that contrast sensitivity data do not point to a magnocellular deficiency linked to dyslexia, while, on the other hand, motion perception data are largely consistent with a dorsal stream dysfunction. Thus, there are data both for and against a "magnocellular-dorsal stream" deficit in connection with dyslexia. It is here pointed out that this inconsistency is abolished once it is recognized that the magnocellular system and the dorsal stream are separate entities. PMID- 25699485 TI - The third wave: H7N9 endemic reassortant viruses and patient clusters. AB - Southern China experienced few cases of H7N9 during the first wave of human infections in the spring of 2013. The second and now the third waves of H7N9 infections have been localized mostly in Southern China with the Guangdong province an epicenter for the generation of novel H7N9 reassortants. Clusters of human infections show human-to-human transmission to be a rare but well documented event. A recent cluster of infections involving hospital health care workers stresses the importance of care givers utilizing personal protective equipment in treating H7N9 infected or suspected patients. PMID- 25699486 TI - Recommended advanced techniques for waterborne pathogen detection in developing countries. AB - The effect of human activities on water resources has expanded dramatically during the past few decades, leading to the spread of waterborne microbial pathogens. The total global health impact of human infectious diseases associated with pathogenic microorganisms from land-based wastewater pollution was estimated to be approximately three million disability-adjusted life years (DALY), with an estimated economic loss of nearly 12 billion US dollars per year. Although clean water is essential for healthy living, it is not equally granted to all humans. Indeed, people who live in developing countries are challenged every day by an inadequate supply of clean water. Polluted water can lead to health crises that in turn spread waterborne pathogens. Taking measures to assess the water quality can prevent these potential risks. Thus, a pressing need has emerged in developing countries for comprehensive and accurate assessments of water quality. This review presents current and emerging advanced techniques for assessing water quality that can be adopted by authorities in developing countries. PMID- 25699487 TI - Clostridium difficile infection: a Serbian single-center experience. AB - INTRODUCTION: Clostridium difficile infection (CDI) is the most common cause of hospital-acquired diarrhea. Severity of CDI is associated with advanced age and co-morbidities. The clinical spectrum varies from mild watery diarrhea to severe fulminant pseudomembranous colitis with complications. METHODOLOGY: This study conducted over a six-year period (2008 to 2013) included 510 patients treated at the University Hospital for Infectious and Tropical Diseases in Belgrade, Serbia. In patients with a history of previous hospitalization and/or treatment with antimicrobial agents who developed diarrhea, the diagnosis was established with rapid tests for C. difficile toxin A and B and by stool culture for C. difficile (454 patients) or by endoscopic examination and histological analyses of the biopsy samples taken from the colonic mucosa (56 patients). RESULTS: The mean age of patients was 67.71+/-13.34 years. A total of 67.8% patients were older than 65 years. Over half (58.7%) of the patients were female. 93% had been previously hospitalized and/or had surgical interventions, during which they had been treated with antibiotics. In the clinical presentation spectrum, pseudomembranous colitis occurred in 51.0%. The mean duration of illness after the introduction of specific antibiotic therapy was 7.10 +/- 4.88 days. Complications developed in 14 patients. The disease relapsed in 43 (8.4%). Thirty-two (6.3%) patients died, mostly due to co-morbidities. CONCLUSIONS: CDI is the most important cause of hospital-acquired diarrhea in Serbia. The disease mainly affects elderly patients with co-morbidities. The incidence of complications is low and prognosis is age dependent and related to pre-existing diseases. PMID- 25699488 TI - Acute Brucella melitensis M16 infection model in mice treated with tumor necrosis factor-alpha inhibitors. AB - INTRODUCTION: There is limited data in the literature about brucellosis related to an intracellular pathogen and anti-tumor necrosis factor alpha (anti-TNFalpha) medication. The aim of this study was to evaluate acute Brucella infections in mice receiving anti-TNFalpha drug treatment. METHODOLOGY: Anti-TNFalpha drugs were injected in mice on the first and fifth days of the study, after which the mice were infected with B. melitensis M16 strain. Mice were sacrificed on the fourteenth day after infection. Bacterial loads in the liver and spleen were defined, and histopathological changes were evaluated. RESULTS: Neither the liver nor the spleen showed an increased bacterial load in all anti-TNFalpha drug groups when compared to a non-treated, infected group. The most significant histopathological findings were neutrophil infiltrations in the red pulp of the spleen and apoptotic cells with hepatocellular pleomorphism in the liver. There was no significant difference among the groups in terms of previously reported histopathological findings, such as extramedullary hematopoiesis and granuloma formation. CONCLUSIONS: There were no differences in hepatic and splenic bacterial load and granuloma formation, which indicate worsening of the acute Brucella infection in mice; in other words, anti-TNFalpha treatment did not exacerbate the acute Brucella spp. infection in mice. PMID- 25699489 TI - Assessment of antibiotic- and disinfectant-resistant bacteria in hospital wastewater, south Ethiopia: a cross-sectional study. AB - INTRODUCTION: Large quantities of antimicrobials are used in hospitals for patient care and disinfection. Antibiotics are partially metabolized and residual quantities reach hospital wastewater, exposing bacteria to a wide range of biocides that could act as selective pressure for the development of resistance. METHODOLOGY: A cross-sectional study was conducted between December 2010 and February 2011 on hospital wastewater. A total of 24 composite samples were collected on a weekly basis for bacteriological analysis and susceptibility testing. Indicator organisms and pathogenic and potentially pathogenic bacteria were found and isolated on selective bacteriologic media. Disinfectant activity was evaluated by use-dilution, and minimum inhibitory concentration (MIC) was determined by the agar dilution method. Similarly, antibiotic susceptibility tests were performed using the Kirby-Bauer disk diffusion method. RESULTS: Pathogenic (Salmonella, Shigella, and S. aureus) and potentially pathogenic (E. coli) bacteria were detected from effluents of both hospitals. Dilution demonstrated tincture iodine to be the most effective agent, followed by sodium hypochlorite; the least active was 70% ethanol. MIC for ethanol against S. aureus and Gram-negative rods from Yirgalem Hospital (YAH) showed 4 and 3.5 log reduction, respectively. Salmonella isolates from YAH effluent were resistant to ceftriaxone, tetracycline, and doxycycline. Isolates from Hawassa University Referral Hospital (HURH) effluent were resistant to the above three antibiotics as well as gentamycin. CONCLUSIONS: Hospital effluents tested contained antibiotic-resistant bacteria, which are released into receiving water bodies, resulting in a threat to public health. PMID- 25699490 TI - Performance of vancomycin and teicoplanin disk diffusion test in isogenic vancomycin non-susceptible Staphylococcus aureus. AB - INTRODUCTION: Detection of heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) is currently problematic. Although the population analysis profile with area under the curve (PAP-AUC) is the gold standard for detecting hVISA strains, this method is time consuming. This study aimed to induce vancomycin non susceptible Staphylococcus aureus isolates in methicillin-resistant S. aureus (MRSA) and to determine the performance of the vancomycin and teicoplanin disk diffusion test for screening of induced and natural vancomycin non-susceptible isolates. METHODOLOGY: Vancomycin resistance was induced in vitro in methicillin resistant S. aureus by serial passage in media with increasing vancomycin concentrations. All test isolates were confirmed for their susceptibility to vancomycin by using a PAP-AUC method. The performance of the vancomycin and teicoplanin disk diffusion test for detecting both induced and natural hVISA/VISA isolates was analyzed using the MedCal program version 10.2.0. RESULTS: The induction test revealed that 42 of 78 MRSA isolates (53.8%) became hVISA and/or VISA. Using 10, 15, 20, 30 ug vancomycin disks and a 30 ug teicoplanin disk, the highest performance (88.9%) for hVISA/VISA detection (71.1%), sensitivity, 100% specificity, 100% positive predictive value, and 75% negative predictive value) was obtained when a 20 ug vancomycin disk was used at 1.0 McFarland inoculum for a 24-hour incubation. CONCLUSIONS: The results indicated that using a 20 ug vancomycin disk and bacterial inoculum of 1.0 McFarland is simple to perform and provides a primary result for hVISA/VISA screening within 24 hours. PMID- 25699491 TI - Diarrheagenic Escherichia coli pathotypes isolated from children with diarrhea in the Federal Capital Territory Abuja, Nigeria. AB - INTRODUCTION: Escherichia coli are frequently isolated from diarrheic children in the Federal Capital Territory Abuja, Nigeria, but their virulent properties are not routinely evaluated. Therefore, the etiology of childhood diarrheal disease attributable to diarrheagenic Escherichia coli (DEC) in Abuja, Nigeria remains unknown. METHODOLOGY: Stool specimens from 400 acute diarrheic children between 0 and 60 months of age were studied. E. coli strains isolated were evaluated by polymerase chain reaction (PCR) for nine virulence genes and HEp-2 cell adherence to detect and identify five distinct diarrheagenic E. coli categories. RESULTS: Diarrheagenic E.coli was detected in 51 (12.8%) of the diarrheic children. The observed DEC pathotypes were enteropathogenic E. coli (EPEC) in 18 (4.5%) children, enterotoxigenic E. coli (ETEC) in 16 (4.0%), enteroaggrative E. coli (EAEC) in 8 (2.0%), enterohaemorrhagic E. coli (EHEC) in 6 (1.5%), and enteroinvasive E. coli (EIEC) in 3 (0.8%). Four (1.0 %) EPEC strains with only the eae+ gene that adhered diffusely to HEp-2 cell were identified as atypical EPEC. All the DEC categories except atypical EPEC were identified in children between 6 and 12 months of age. CONCLUSIONS: This study underscores the need for routine evaluation of diarrheic children for virulence properties of infectious DEC. Atypical EPEC are emerging among the DEC pathotypes isolated from childhood acute gastroenteritis in Abuja, Nigeria. PMID- 25699492 TI - Ratios of CD64 expressed on neutrophils, monocytes, and lymphocytes may be a novel method for diagnosis of neonatal sepsis. AB - INTRODUCTION: Neutrophil CD64 expression has been demonstrated as an improved diagnostic marker of infection and sepsis. The purpose of this study was to develop a new method to evaluate neutrophil CD64 expression for diagnosis of neonatal sepsis. METHODOLOGY: Eighty neonates with neonatal sepsis (21 culture positive, 59 negative) were enrolled in this prospective study along with 19 neonates with no symptoms or signs of infection as controls. Expressions of CD64 on monocytes, lymphocytes, and neutrophils were evaluated with flow cytometry (FCM). Ratios were calculated with these levels of CD64 expression. Blood culture and other laboratory exams were done at the same time for the diagnosis of neonatal sepsis. Results were compared between the neonatal sepsis and control groups. RESULTS: CD64 ratios showed significant difference between the groups (p < 0.01). Receiver operating curve (ROC) analysis showed that the CD64 ratios possessed high sensitivity (90%) and specificity (89.5%) in neonatal sepsis identification. CONCLUSIONS: The novel CD64 evaluation method, CD64 ratio, can be used as a supplementary method for diagnosis of neonatal sepsis. PMID- 25699493 TI - Cost-benefit analysis of craniocerebral surgical site infection control in tertiary hospitals in China. AB - INTRODUCTION: Surgical site infection (SSI) is one of the most common postoperative complications. This study aimed to determine the cost of SSIs and to evaluate whether SSI control can reduce medical costs under the current medical payment system and wage rates in China. METHODOLOGY: Prospective surveillance of craniocerebral surgery was conducted between July 2009 and June 2012. SSI patients and non-SSI patients were matched with a ratio of 1:2. Terms such as medical costs and length of hospital stay were compared between the two groups. Based on the economic loss of hospital infection, which causes additional expenditures and a reduction in the number of patients treated, the benefits of hospital infection control were estimated. The costs of human resources and materials of hospital infection surveillance and control were also estimated. Finally, the cost-benefit rates in different medical contexts and with different SSI-case ratios were calculated. RESULTS: The incidence of SSIs in this study was 4%. SSIs significantly prolonged hospital stay by 11.75 days (95% CI: 6.24 22.52), increased medical costs by US $3,412.48 (95% CI: $1,680.65-$5,879.89). The direct economic loss was $114,903 in a 40-bed ward. The cost of implementing infection control in such a unit was calculated to be approximately $5,555.47 CONCLUSIONS: Under the current fee-for-service healthcare model in China, the control of SSIs can hardly yield direct economic benefits, but can yield social benefits. With the implementation of a total medical cost pre-payment system, SSI control will present a remarkable benefit-cost ratio for hospitals. PMID- 25699494 TI - Cytokine levels are associated with the severity of varicella infections. AB - INTRODUCTION: Varicella is a highly contagious disease. Epidemics of varicella are seen every year globally and present a threat to public health, especially in China and other developing countries. METHODOLOGY: Clinical and laboratory findings of 865 varicella patients admitted to Beijing You'an Hospital, China, between January 2011 and December 2013 were collected and analyzed. Patients with isolated complication were grouped as SI (skin infection, n = 132) and LD (liver damage, n = 89). Two hundred and one patients without complications were grouped as control (mild group). Levels of T-cell subtypes and eight serum cytokines and were also tested. Levels of IFNg and IL-6 were monitored prospectively in another 12 grouped patients. RESULTS: SI was complicated in 21.7% (188/865) of varicella cases, and LD was complicated in 16.8% (145/865). The rates of SI and LD in varicella patients increased rapidly in the past three years. No laboratory findings were associated with SI or LD (all p > 0.05). IL-6 and IFNg levels were correlated with amniotic membrane extract (AME) (p = 0.044 and p = 0.038). Their levels peaked at day 1 of admission, and then started to decline. CONCLUSIONS: The incidence of serious complications has become more common in recent years. IL 6 and IFNg may possibly be used as early serum markers for identifying patients at risk of developing complications such as skin infections in varicella. PMID- 25699495 TI - Immunogenicity to the bivalent HPV-16/18 vaccine among adolescent African students exposed to helminths and malaria. AB - INTRODUCTION: Efficacious vaccines that prevent human papillomavirus (HPV) infection, the recognized cause of cervical cancer, are now available. However, in sub-Saharan Africa, immune-modulating infections such as helminths and malaria may affect immunogenicity to the HPV vaccine. This study aimed to evaluate the effect of helminth infections and exposure to malaria on the immune response to the bivalent HPV-16/18 vaccine. METHODOLOGY: AS04-adjuvanted HPV-16/18 vaccinated students between 10 and 16 years of age from western Uganda, at 18 months-post vaccination were followed up for six months. After consent was obtained, demographic data, blood, and stool samples were collected. Multiplex HPV serology technology was used to determine HPV-16/18 antibody levels expressed as median fluorescent intensity (MFI). The malaria antibody immunoassay test was used to detect antibodies to malaria parasites. The Kato-Katz method was used to detect the presence of helminths. HPV-16/18 antibody levels among students exposed to malaria or helminths were compared with those who were not exposed using the Student's t-test. RESULTS: A total of 211 students participated in the study. There was no difference between MFI levels to HPV-16/18 antibodies at 18- and 24 month follow-ups among students who were positive and negative to malaria or helminth exposure. There was an increase in HPV-18 MFI antibody levels at month 24 among the students who were positive for malaria at enrolment (p = 0.05). CONCLUSIONS: Immune-modulating parasites (malaria/helminths) were not associated with reduced immune response to the bivalent HPV-16/18 vaccine. The data may support the use of this vaccine in sub-Saharan Africa. PMID- 25699496 TI - Changing molecular epidemiology of methicillin-resistant Staphylococcus aureus in an Algerian hospital. AB - INTRODUCTION: Methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of both hospital- and community-acquired infections worldwide. However, data about the molecular epidemiology of MRSA in North Africa are still scarce. METHODOLOGY: All MRSA isolates recovered between January 2006 and July 2011 from one Algerian hospital were genetically and phenotypically characterized. RESULTS: The predominance of a European community-associated-MRSA (CA-MRSA) clone (ST80 SCCmec IV-PVL positive) was revealed by this analysis. CONCLUSION: Our data suggest that a CA-MRSA clone recently invaded the hospital setting in Algiers and replaced a typical hospital-associated pandemic clone such as the Brazilian clone (ST239-SCCmec IIImercury-PVL negative). PMID- 25699497 TI - Multidrug resistance in Pseudomonas aeruginosa isolated from nosocomial respiratory and urinary infections in Aleppo, Syria. AB - INTRODUCTION: Pseudomonas aeruginosa represents a serious clinical challenge due to its frequent involvement in nosocomial infections and its tendency towards multidrug resistance. METHODOLOGY: This study uncovered antibiotic susceptibility patterns in 177 isolates from inpatients in three key hospitals in Aleppo, the largest city in Syria. RESULTS: Exceptionally low susceptibility to most routinely used antibiotics was uncovered; resistance to ciprofloxacin and gentamicin was 64.9% and 70.3%, respectively. Contrarily, susceptibility to colistin was the highest (89.1%). CONCLUSIONS: Multidrug resistance was rife, found at a rate of 53.67% among studied P. aeruginosa isolates. PMID- 25699498 TI - Clinical and epidemiological investigation of a fatal anthrax case in China. AB - Anthrax is a recessive infectious disease caused by the bacterium Bacillus anthracis, and is primarily a zoonotic disease. Until recently, Bacillus anthracis infections were relatively infrequent and confined to agrarian communities in underdeveloped countries. No anthrax cases were reported in Changchun City in the past few decades until a male patient from the Inner Mongolia Autonomous Region presented the anthrax disease manifestation. This paper describes an anthrax patient's diagnosis, isolation and treatment which involved institutions in two different Chinese provinces; the foci epidemiological investigation alongside with the outbreak management process, which is of great significance to control the spread of the recessive infection is also described. PMID- 25699499 TI - In vitro emergence of carbapenem resistance in extended-spectrum beta-lactamase producing Klebsiella pneumoniae clinical isolates. PMID- 25699500 TI - Synergistic effect of non-ionic surfactants Tween 80 and PEG6000 on cytotoxicity of insecticides. AB - The use of surfactants in the development of a suitable formulation for insecticides should improve the solubility behavior, the permeability and the efficiency against pests meanwhile decrease the toxic risks of insecticides on human health. Cytotoxicity of insecticides including abamectin, chlorfluazuron, hexaflumuron, chlorpyrifos, and tebufenozide was assessed on human HepG2 and lepidopteran Tn5B1-4 cells utilizing insecticide alone and in combination with nontoxic concentrations of nonionic surfactants Tween 80 and PEG6000. The results showed avermection revealed high cytotoxicity, chlorfluazuron and hexaflumuron possessed median cytotoxicity, and chlorpyrifos and tebufenozide had little cytotoxicity on HepG2 and Tn5B1-4 cells. The co-incubation with Tween 80 and PEG6000 powerfully counteracted the cytotoxicity of avermectin. Tween 80 enhanced, whereas PEG6000 compressed, the cytotoxicity of chlorfluazuron on Tn5B1 4 cells, and also improved a bit of the cytotoxicity of chlorpyrifos or tebufenozide on HepG2 cells. PEG6000 was more suitable to be used as surfactant in improving insecticide solubility and reducing the cytotoxicity. The present investigation demonstrates the necessity of utilizing surfactants to weaken the cytotoxicity of insecticides. PMID- 25699501 TI - Re: Normative values and predictors of retinal oxygen saturation. PMID- 25699502 TI - Reply: To PMID 23842102. PMID- 25699503 TI - Re: Prevalence of open angle glaucoma in vitrectomized eyes: a cross sectional study. PMID- 25699504 TI - Reply: To PMID 24608670. PMID- 25699505 TI - Re: Thrombophilic risk factors are uncommon in young patients with retinal vein occlusion. PMID- 25699506 TI - Reply: To PMID 25299970. PMID- 25699507 TI - Re: The 'pitchfork sign' a distinctive optical coherence tomography finding in inflammatory choroidal neovascularization. PMID- 25699508 TI - Reply: To PMID 23514797. PMID- 25699509 TI - Re: Impact of intravitreal dexamethasone implant (Ozurdex) on macular morphology and function. PMID- 25699510 TI - Reply: To PMID 23945638. PMID- 25699511 TI - Nanoengineered surfaces for focal adhesion guidance trigger mesenchymal stem cell self-organization and tenogenesis. AB - The initial conditions for morphogenesis trigger a cascade of events that ultimately dictate structure and functions of tissues and organs. Here we report that surface nanopatterning can control the initial assembly of focal adhesions, hence guiding human mesenchymal stem cells (hMSCs) through the process of self organization and differentiation. This process self-sustains, leading to the development of macroscopic tissues with molecular profiles and microarchitecture reminiscent of embryonic tendons. Therefore, material surfaces can be in principle engineered to set off the hMSC program toward tissuegenesis in a deterministic manner by providing adequate sets of initial environmental conditions. PMID- 25699433 TI - Study of vector boson scattering and search for new physics in events with two same-sign leptons and two jets. AB - A study of vector boson scattering in pp collisions at a center-of-mass energy of 8 TeV is presented. The data sample corresponds to an integrated luminosity of 19.4 fb(-1) collected with the CMS detector. Candidate events are selected with exactly two leptons of the same charge, two jets with large rapidity separation and high dijet mass, and moderate missing transverse energy. The signal region is expected to be dominated by electroweak same-sign W-boson pair production. The observation agrees with the standard model prediction. The observed significance is 2.0 standard deviations, where a significance of 3.1 standard deviations is expected based on the standard model. Cross section measurements for W(+/-)W(+/-) and WZ processes in the fiducial region are reported. Bounds on the structure of quartic vector-boson interactions are given in the framework of dimension-eight effective field theory operators, as well as limits on the production of doubly charged Higgs bosons. PMID- 25699512 TI - Bilateral Epidermoid Cysts of the Testes: A Characteristic Appearance on Ultrasonography. PMID- 25699513 TI - Dynamic dielectrophoresis model of multi-phase ionic fluids. AB - Ionic-based dielectrophoretic microchips have attracted significant attention due to their wide-ranging applications in electro kinetic and biological experiments. In this work, a numerical method is used to simulate the dynamic behaviors of ionic droplets in a microchannel under the effect of dielectrophoresis. When a discrete liquid dielectric is encompassed within a continuous fluid dielectric placed in an electric field, an electric force is produced due to the dielectrophoresis effect. If either or both of the fluids are ionic liquids, the magnitude and even the direction of the force will be changed because the net ionic charge induced by an electric field can affect the polarization degree of the dielectrics. However, using a dielectrophoresis model, assuming ideal dielectrics, results in significant errors. To avoid the inaccuracy caused by the model, this work incorporates the electrode kinetic equation and defines a relationship between the polarization charge and the net ionic charge. According to the simulation conditions presented herein, the electric force obtained in this work has an error exceeding 70% of the actual value if the false effect of net ionic charge is not accounted for, which would result in significant issues in the design and optimization of experimental parameters. Therefore, there is a clear motivation for developing a model adapted to ionic liquids to provide precise control for the dielectrophoresis of multi-phase ionic liquids. PMID- 25699514 TI - High prevalence of Tropheryma whipplei in Lao kindergarten children. AB - BACKGROUND: Tropheryma whipplei is a bacterium commonly found in feces of young children in Africa, but with no data from Asia. We estimated the prevalence of T. whipplei carriage in feces of children in Lao PDR (Laos). METHODS/PRINCIPAL FINDINGS: Using specific quantitative real-time PCR, followed by genotyping for each positive specimen, we estimated the prevalence of T. whipplei in 113 feces from 106 children in Vientiane, the Lao PDR (Laos). T. whipplei was detected in 48% (51/106) of children. Those aged <= 4 years were significantly less frequently positive (17/52, 33%) than older children (34/54, 63%; p< 0.001). Positive samples were genotyped. Eight genotypes were detected including 7 specific to Laos. Genotype 2, previously detected in Europe, was circulating (21% of positive children) in 2 kindergartens (Chompet and Akad). Genotypes 136 and 138 were specific to Chompet (21% and 15.8%, respectively) whereas genotype 139 was specific to Akad (10.55%). CONCLUSIONS/SIGNIFICANCE: T. whipplei is a widely distributed bacterium, highly prevalent in feces of healthy children in Laos. Further research is needed to identify the public health significance of this finding. PMID- 25699515 TI - Feasibility of a Self-Determination Theory-Based Exercise Program in Community Dwelling South Korean Older Adults: Experiences from a 13-Month Trial. AB - Little is known about the effectiveness of self-determination theory (SDT), a representative motivational theory, on exercise domain in older adults. This feasibility study used quantitative and qualitative approaches to evaluate the effectiveness of a 13-month group exercise program applying SDT-based motivational strategies on exercise adherence, physical fitness, and quality of life, and to explore factors affecting exercise adherence in South Korean older adults (N = 18). Exercise attendance rate was high (82.52%). There were significant differences in aerobic endurance (p < .001), lower body strength (p < .05), dynamic balance (p < .001), and perceived social functioning (p < .05) at 13 months compared with baseline. Factors affecting exercise adherence were related to the SDT-based motivational strategies. These results support the importance of health professionals applying SDT-based motivational strategies to exercise programs to help facilitate motivation for participation and to promote physical fitness and quality of life in older adults. PMID- 25699516 TI - The "good cop, bad cop" effect in the RT-based concealed information test: exploring the effect of emotional expressions displayed by a virtual investigator. AB - Concealing the possession of relevant information represents a complex cognitive process, shaped by contextual demands and individual differences in cognitive and socio-emotional functioning. The Reaction Time-based Concealed Information Test (RT-CIT) is used to detect concealed knowledge based on the difference in RTs between denying recognition of critical (probes) and newly encountered (irrelevant) information. Several research questions were addressed in this scenario implemented after a mock crime. First, we were interested whether the introduction of a social stimulus (facial identity) simulating a virtual investigator would facilitate the process of deception detection. Next, we explored whether his emotional displays (friendly, hostile or neutral) would have a differential impact on speed of responses to probe versus irrelevant items. We also compared the impact of introducing similar stimuli in a working memory (WM) updating context without requirements to conceal information. Finally, we explored the association between deceptive behavior and individual differences in WM updating proficiency or in internalizing problems (state / trait anxiety and depression). Results indicated that the mere presence of a neutral virtual investigator slowed down participants' responses, but not the appended lie specific time (difference between probes and irrelevants). Emotional expression was shown to differentially affect speed of responses to critical items, with positive displays from the virtual examiner enhancing lie-specific time, compared to negative facial expressions, which had an opposite impact. This valence specific effect was not visible in the WM updating context. Higher levels of trait / state anxiety were related to faster responses to probes in the negative condition (hostile facial expression) of the RT-CIT. These preliminary findings further emphasize the need to take into account motivational and emotional factors when considering the transfer of deception detection techniques from the laboratory to real-life settings. PMID- 25699517 TI - Establishment of hepatitis C virus RNA-replicating cell lines possessing ribavirin-resistant phenotype. AB - BACKGROUND: Ribavirin (RBV) is a potential partner of interferon-based therapy and recently approved therapy using direct acting antivirals for patients with chronic hepatitis C. However, the precise mechanisms underlying RBV action against hepatitis C virus (HCV) replication are not yet understood. To clarify this point, we attempted to develop RBV-resistant cells from RBV-sensitive HCV RNA-replicating cells. METHODOLOGY/PRINCIPAL FINDINGS: By repetitive RBV (100 MUM) treatment (10 weeks) of 3.5-year-cultured OL8 cells, in which genome-length HCV RNA (O strain of genotype 1b) efficiently replicates, dozens of colonies that survived RBV treatment were obtained. These colonies were mixed together and further treated with high doses of RBV (up to 200 MUM). By such RBV treatment, we successfully established 12 RBV-survived genome-length HCV RNA-replicating cell lines. Among them, three representative cell lines were characterized. HCV RNA replication in these cells resisted RBV significantly more than that in the parental OL8 cells. Genetic analysis of HCV found several common and conserved amino acid substitutions in HCV proteins among the three RBV-resistant cell species. Furthermore, using cDNA microarray and quantitative RT-PCR analyses, we identified 5 host genes whose expression levels were commonly altered by more than four-fold among these RBV-resistant cells compared with the parental cells. Moreover, to determine whether viral or host factor contributes to RBV resistance, we developed newly HCV RNA-replicating cells by introducing total RNAs isolated from RBV-sensitive parental cells or RBV-resistant cells into the HCV RNA-cured-parental or -RBV-resistant cells using an electroporation method, and evaluated the degrees of RBV resistance of these developed cells. Consequently, we found that RBV-resistant phenotype was conferred mainly by host factor and partially by viral factor. CONCLUSIONS/SIGNIFICANCE: These newly established HCV RNA-replicating cell lines should become useful tools for further understanding the anti-HCV mechanisms of RBV. PMID- 25699518 TI - Determinants of academics' job satisfaction: empirical evidence from private universities in Bangladesh. AB - The job satisfaction of academics is related to a number of variables of complex function such as demographic characters, the work itself, pay, work responsibilities, variety of tasks, promotional opportunities, relationship with co-workers and others. Academics may be simultaneously satisfied with some facets of the job and dissatisfied with others. This paper aims at determining the influential factors that contribute to the enhancement or reduction of academics' job satisfaction among private universities in Bangladesh with special reference to Dhaka, the capital city of Bangladesh. A total of 346 respondents are considered from ten private universities using non-probability sampling. A pre tested and closed-ended questionnaire using a seven-point Likert scale is used for data collection. In this study, descriptive statistics, Pearson product moment correlation, multiple regression, and factor analysis are exercised as statistical tools. A conceptual model of job satisfaction is developed and applied for academics' job satisfaction. The results reveal that compensation package, supervisory support, job security, training and development opportunities, team cohesion, career growth, working conditions, and organizational culture and policies are positively associated with the academics' job satisfaction. Amongst them, three factors stood out as significant contributors for job satisfaction of academics i.e. compensation package, job security, and working conditions. Therefore, the management of private universities should focus their effort on these areas of human resource management for maintaining academics' job satisfaction and employee retention. The study will be useful for university management in improving overall job satisfaction as it suggests some strategies for employee satisfaction practices. PMID- 25699519 TI - A novel sterol regulatory element-binding protein gene (sreA) identified in penicillium digitatum is required for prochloraz resistance, full virulence and erg11 (cyp51) regulation. AB - Penicillium digitatum is the most destructive postharvest pathogen of citrus fruits, causing fruit decay and economic loss. Additionally, control of the disease is further complicated by the emergence of drug-resistant strains due to the extensive use of triazole antifungal drugs. In this work, an orthologus gene encoding a putative sterol regulatory element-binding protein (SREBP) was identified in the genome of P. digitatum and named sreA. The putative SreA protein contains a conserved domain of unknown function (DUF2014) at its carboxyl terminus and a helix-loop-helix (HLH) leucine zipper DNA binding domain at its amino terminus, domains that are functionally associated with SREBP transcription factors. The deletion of sreA (DeltasreA) in a prochloraz-resistant strain (PdHS F6) by Agrobacterium tumefaciens-mediated transformation led to increased susceptibility to prochloraz and a significantly lower EC50 value compared with the HS-F6 wild-type or complementation strain (COsreA). A virulence assay showed that the DeltasreA strain was defective in virulence towards citrus fruits, while the complementation of sreA could restore the virulence to a large extent. Further analysis by quantitative real-time PCR demonstrated that prochloraz induced expression of cyp51A and cyp51B in PdHS-F6 was completely abolished in the DeltasreA strain. These results demonstrate that sreA is a critical transcription factor gene required for prochloraz resistance and full virulence in P. digitatum and is involved in the regulation of cyp51 expression. PMID- 25699520 TI - Topical Acyclothymidine Dinucleosides (aTds) Promote Non-UV-Mediated Endogenous Defense Mechanisms in Guinea Pig Skin. PMID- 25699521 TI - Technique for direct posterior reduction in irreducible atlantoaxial dislocation: multi-planar realignment of C1-2. AB - OBJECTIVE: Apart from the commonly seen antero-posterior subluxation of C1 over C2, the dislocation may occur in vertical, lateral or rotational plane. Desired C1-2 realignment can be achieved by corrrecting its dislocation in all planes. We describe a technique for the same. MATERIAL AND METHODS: The clinical and radiological features of 16 patients (4 - traumatic and 12 - congenital) with irreducible atlantoaxial dislocation (AAD) admitted in the last 1.5 years were studied. Specific attention was paid to vertical dislocation with lateral and rotational components, apart from anterior-posterior subluxation. They were operated through direct posterior approach. The technique using a long rod holder as lever and screw head (tulip) as fulcrum was employed to achieve C1-2 realignment in all planes. The postoperative clinical and radiological data was analyzed and compared with preoperative data. RESULTS: Patients presented with progressive myelopathy and/or progressive worsening of neck pain. Vertical dislocation was seen in 11 patients with congenital AAD in addition to the antero posterior subluxation seen in all. Three patients with traumatic AAD and 8 with congenital AAD had additional lateral dislocation or lateral tilt. Three patients with traumatic AAD and 7 with congenital AAD showed rotational component. Postoperatively, all patients showed clinical improvement. CONCLUSIONS: The antero-posterior and vertical realignment could be achieved in all except one. Similarly, rotational and lateral components could be completely corrected in 8 out of 10 patients. The technique appears to realign the C1-2 in all planes and provides good anatomical restoration. PMID- 25699522 TI - Cell-based screening identifies the active ingredients from Traditional Chinese Medicine formula Shixiao San as the inhibitors of atherosclerotic endothelial dysfunction. AB - In this study, we performed a phenotypic screening in human endothelial cells exposed to oxidized low density lipoprotein (an in vitro model of atherosclerotic endothelial dysfunction) to identify the effective compounds in Shixiao San. After investigating the suitability and reliability of the cell-based screening method using atorvastatin as the positive control drug, this method was applied in screening Shixiao San and its extracts. The treatment of n-butanol fraction on endothelial cells exhibited stronger healing effects against oxidized low density lipoprotein-induced insult when compared with other fractions. Cell viability, the level of nitric oxide, endothelial nitric oxide synthase and endothelin-1 were measured, respectively. The assays revealed n-butanol fraction significantly elevated the survival ratio of impaired cells in culture. In parallel, n-butanol fraction exhibited the highest inhibition of inflammation. The generation of prostaglandin-2 and adhesion molecule (soluble intercellular adhesion molecule-1) was obviously declined. Furthermore, n-butanol fraction suppressed the production of reactive oxygen species and malondialdehyde, and restored the activity of superoxide dismutase. Compounds identification of the n-butanol fraction was carried out by ultra high liquid chromatography coupled to quadrupole time-of flight tandem mass spectrometry. The active ingredients including quercetin-3-O (2G-alpha-l-rhamnosyl)-rutinoside, quercetin-3-O-neohesperidoside, isorhamnetin-3 O-neohesperidoside and isorhamnetin-3-O-rutinoside revealed the ability of anti atherosclerosis after exposing on endothelial cells. The current work illustrated the pharmacology effect of Shixiao San and clearly indicated the major active components in Shixiao San. More importantly, the proposed cell-based screening method might be particularly suitable for fast evaluating the anti atherosclerosis efficacy of Traditional Chinese Medicines and screening out the interesting ingredients of Traditional Chinese Medicines. PMID- 25699523 TI - Electrochemical conversion and storage systems: general discussion. PMID- 25699524 TI - A single multifunctional nanoplatform based on upconversion luminescence and gold nanorods. AB - Lanthanide-doped upconverting nanoparticles (UCNPs), which convert near-infrared (NIR) light to higher energy light have been intensively studied for theranostic applications. Here, we developed a hybrid core/shell nanocomposite with multifunctional properties using a multistep strategy consisting of a gold nanorod (GNR) core with an upconverting NaYF4:Er3+, Yb3+ shell (GNR@NaYF4:Er3+, Yb3+). To use a single excitation beam, the GNR plasmon was tuned to ~650 nm, which is resonant with the upconverted red Er3+ emission emanating from the 4F9/2 excited state. Thus, under laser irradiation at 980 nm, the intensity ratio of the upconverted green emission (arising from the 2H11/2 and 4S3/2 excited states of Er3+) showed a remarkable thermal sensitivity, which was used to calculate the temperature change due to rapid heat conversion from the GNR core. The red upconversion emission of the GNR@NaYF4:Er3+, Yb3+ core/shell nanocomposite decreased compared with the NaYF4:Er3+, Yb3+ nanoshell structure (without a GNR core), which indicates that energy transfer from NaYF4:Er3+, Yb3+ to the GNR takes place, subsequently causing a photothermal effect. The anticancer drug, doxorubicin, was loaded into the GNR@NaYF4:Er3+, Yb3+ nanocomposites and the drug release profile was evaluated. In particular, the release of doxorubicin was significantly enhanced at lower pH and higher temperature caused by the photothermal effect. This multifunctional nanocomposite, which is suitable for local heating and controlled drug release, shows strong potential for use in cancer therapy. PMID- 25699525 TI - Pigmented villonodular synovitis of the temporomandibular joint with intracranial extension. AB - Pigmented villonodular synovitis is an uncommon benign tumor-like proliferative lesion with an undetermined origin. Involvement of the temporomandibular joint is uncommon. Although pigmented villonodular synovitis is a benign lesion, it can grow with an aggressive pattern, and it extends extra-articularly in most of the reported cases, about one-third of them exhibiting intracranial involvement. The authors reported an additional case of a 47-year-old woman with intracranial extension, who had a history of joint pain and trismus. The preoperative diagnosis was made with arthroscopy. The lesion was completely excised via preauricular approach and condylotomy. The bone defect was covered by the pedicled temporalis myofascial fat flap. The patient has been symptom-free for 40 months postoperatively. PMID- 25699526 TI - Coexistence of spontaneous spinal and undiagnosed cranial subdual hematomas. AB - Spinal subdual hematoma (SDH) is an uncommon pathology, and its simultaneous occurrence with cranial SDH is even rarer. We report a unique case of spinal SDH combined with bilateral intracranial SDH, in which the cranial lesion was detected after the evacuation of spinal SDH. The undiagnosed chronic SDH developed acute-on-chronic SDH after the evacuation of spinal SDH. The patient had an uneventful clinical course, and a satisfactory outcome was achieved. The reason for reporting this case is to draw attention to the possibility of concurrent cranial SDH in patients with unexplained spinal SDH. The removal of the spinal SDH may exacerbate intracranial hemorrhage and consequently lead to the potential occurrence of tentorial herniation in patients with accompanied cranial SDH. PMID- 25699527 TI - Early-stage hemangioblastoma presenting as a small lesion with significant edema in the cerebellum. AB - Hemangioblastomas are benign tumors that are frequently associated with peritumoral cysts; however, their early characteristics before cyst formation remain unclear. In this article, the authors present a novel case of a cerebellar hemangioblastoma presenting as a small solid lesion with significant edema. Surgery was performed to resect the tumor, and a follow-up magnetic resonance imaging scan revealed complete excision of the mass and resolution of the cerebellar edema. Histological examination confirmed that the lesion was a hemangioblastoma. This is the only report in the literature to describe the imaging and histopathologic characteristics of an initial hemangioblastoma in the cerebellum. PMID- 25699528 TI - Resorbable plates for the fixation of isolated mandibular angle fracture. AB - PURPOSE: This study was designed to evaluate the results in isolated mandibular angle fractures treated with resorbable plates and to summarize experiences of the application of resorbable plates. PATIENTS AND METHODS: Ten patients (6 men and 4 women) with isolated displaced mandibular angle fracture were included in this case series. Open reduction by intraoral or extraoral approach was performed, and the fractures were fixed using single or dual resorbable plates. Postoperatively, follow-up was undertaken to evaluate the fracture healing and the degradation of resorbable plates. RESULTS: All the fractures healed without complications during the follow-up period. No screw or plate fractured during the surgery, no dislocation of the fracture segment after the fixation by resorbable plates, and no foreign body reaction related with resorbable plates were observed. CONCLUSIONS: With proper indication, resorbable plates are suitable for the fixation of isolated mandibular angle fractures. Single or dual resorbable plates by intraoral or extraoral approach can be individualized on the basis of the patients' condition. PMID- 25699529 TI - Surgical management of non-communicating hydrocephalus in patients: meta-analysis and comparison of endoscopic third ventriculostomy and ventriculoperitoneal shunt. AB - OBJECTIVE: We performed a meta-analysis of reported series of endoscopic third ventriculostomy (ETV) and ventriculoperitoneal shunt (VPS) for non-communicating hydrocephalus to determine whether comparisons between the outcomes in ETV and VPS approaches are valid. METHODS: Online databases were searched for articles reporting quantifiable outcome data published between 1990 and 2014 pertaining to the surgical treatment of non-communicating hydrocephalus, with no language restrictions. Eight articles meeting predetermined criteria were included. Data were pooled for 5 surgical outcome measures. RESULTS: Our literature search identified 5 prospective cohort studies and 3 retrospective cohort studies with a cumulative number of 652 patients that compared the ETV with VPS for non communicating hydrocephalus. Analysis of outcomes favored the approach of ETV in terms of duration of surgery (P < 0.00001), incidence of major complications (RR 0.35, 95% CI: 0.24-0.52), and reoperation rate (OR 0.22, 95% CI: 0.12-0.40), whereas it did not favor either approach in terms of length of stay in hospital (P = 0.052) and improvement of symptoms (P = 0.18, OR 0.71, 95% CI: 0.44-1.16). CONCLUSION: ETV and VPS have therapeutic equivalence for non-communicating hydrocephalus, whereas ETV can result in lower surgery time, incidence of postoperative complication, and reoperation rate of hydrocephalus. PMID- 25699530 TI - Treatment of orbital blowout fracture using porous polyethylene with embedded titanium. AB - The study was performed to evaluate the effectiveness and safety of porous polyethylene with embedded titanium in the repair of orbital blowout fracture. The study was designed as a prospective case series. Patients who were diagnosed with orbital blowout fracture from May 2012 to March 2013 were included in the study. A composite material of porous polyethylene and titanium mesh was used. Orbital volumes before and after surgery were measured, and the results of diplopia and ocular movement were recorded. The occurrence of diplopia was grouped and compared according to the time interval between injury and surgery. The incidence of other complications was also recorded. A total of 26 patients were involved in the study. The minimal follow-up time was 12 months. All surgeries were performed uneventfully. The orbital volume significantly decreased after the surgery, and the remission rate and the elimination rate of diplopia in 12 months were 85.7% and 47.6%, respectively. Postoperative diplopia was correlated with the time interval between injury and surgery. One patient presented with undercorrection of enophthalmos, and another patient presented with acute aggravation of diplopia and exophthalmos after surgery, which was resolved with treatment. In conclusion, porous polyethylene with embedded titanium was effective and safe in the repair of orbital blowout fracture, and studies with more subjects and longer follow-up period are recommended in future studies. PMID- 25699531 TI - The transforming training pathway of plastic and craniofacial surgery in China. AB - The history of plastic surgery in China dates back to about 17 centuries ago when Chinese ancestors documented a case of cleft lip repair, whereas the concepts of modern plastic surgery were imported from the West. In the last 50 years, the Chinese plastic surgeons have thrived and, through their hard work and even harder-gained experiences, witnessed the emergence of microsurgery in the 1960s, the development of craniofacial surgery during the 1970s, and cosmetic surgery becoming a trend since 1980s.With the fast renovation of treatment methods and the broadened spectrum of indications, more specialists with solid basic science knowledge and adequate clinical experience are needed for providing plastic, reconstructive, and aesthetic treatment. Attempts and efforts have been made to establish a suitable training system in China for plastic surgeons and plastic subspecialists recently, which led to the transformation of pathway for one to become a plastic surgeon and provoked thoughts upon the upcoming challenges. PMID- 25699532 TI - Correction of craniosynostosis using modified spring-assisted surgery. AB - BACKGROUND: The use of springs in craniofacial surgery was originated at Sahlgrenska University Hospital in 1997 as a way of remodeling the cranial vault postoperatively. After a decade of development, spring technology has been improved to a greater extent. However, there still exist some problems, such as the poor consistency of steel wire stretches, the wrong position of steel wire, the problem of increasing the elasticity of springs, and so on. METHOD: We have designed a spring device for external uses. This device is composed of 3 parts. The first part is the outside of the spring ring. This ring is the same as the internal spring, only a little bigger. The second part is a small U-shaped hook, which is made of titanium plates and linked to the skull portion. The U-shaped hook is approximately 1 cm long and 1 cm wide. The hang is approximately 1 cm long and 0.6 cm wide. The U-shaped level length is 1 cm, but the level width should be equal to or bigger than the thickness of the skull. The third part is a steel wire, which is placed at 1 end of hook. We first conduct a strip craniotomy, then put 2 hooks at the bone ends and, after that, fix hooks on the skull. Finally, we pull the steel wire of the hook end out of the scalp, connect it with the external spring, and draw out the external spring. We performed 24 craniofacial spring placement procedures for 12 patients with craniosynostosis. RESULTS: We used 6 springs for 3 patients who had anterior plagiocephaly, 12 springs for 6 patients who had scaphocephaly, and 3 springs for another patient who had metopic synostosis and holoprosencephaly. We also used 3 springs for 2 patients who had metopic synostosis. The 12 patients have not required further surgeries so far, and there were no major complications. Spring dislodgement had not caused any complication in early cases. We could easily change the position of the spring rings from outside the scalp, regularly correct the elasticity of the spring rings, and replace spring rings to increase the traction. The head shapes of the 12 children have been improved significantly to use external spring rings. CONCLUSIONS: This therapeutic modality in craniofacial surgery has allowed minimization of the extent of surgery without compromising clinical outcomes. The authors have shown that the use of external spring techniques is safe and, in selected situations, offer significant advantages over other methods of treatment. It makes up for a number of shortcomings of internal springs. PMID- 25699533 TI - Molding of top skull in the treatment of Apert syndrome. AB - Patients with Apert syndrome have bilateral coronal craniosynostosis, along with a distinguishing feature of their many deformity, called tower skull. Surgical correction of this deformity is the mainstay of treatment. We describe 3 patients molded top skull after front bone osteotomy orbital bar advancement. This successfully restricted growth of their top skull while allowing growth in other dimensions. Utilization of top-skull molding after cranial surgery shows promise of satisfaction in this setting. PMID- 25699534 TI - Repair lower face defect with an expanded flap from submental and submandibular region in children. AB - Scar and defect in the lower face always lead to serious facial deformity and asymmetry. Conventional method such as skin graft or free flap is hard to obtain a satisfactory outcome. In this article, we present a skin expanding technique. An expanded flap was designed to repair the lower face scar or defect on submental and submandibular regions. A tissue expander was implanted into the region and inflated for 2 to 3 months. After removing the expander, we harvested the flap as a rotation flap to repair the lower facial defect. The longest follow up period was 3 years. All of the flaps were well matched to the surrounding skin with respect to color, texture, and thickness. An expanded flap on submental and submandibular regions is suitable to repair a lower face defect. PMID- 25699535 TI - Treatment of orbital hypertelorism using inverted U-shaped osteotomy. AB - The objective of this article was to explore the effect of correction orbital hypertelorism using inverted U-shaped osteotomy by combined intracranial extracranial approach. Eleven cases of severe orbital hypertelorism were performed. The measurement of interorbital and intercanthal distance was studied preoperatively and postoperatively by 3-dimensional computed tomography. The interorbital distance of the 11 patients are significantly decreased .The intercanthal distance decreased from 6.7 and 4.8 cm to 5.0 and 3.8 cm, respectively. The inverted U-shaped osteotomy technique may be an effective and safe technique for the stability of the corrected orbital framework and the prevention of recurrence in severe cases of orbital hypertelorism. Moreover, this method has little trauma compared with box osteotomy technique. PMID- 25699536 TI - Surgical guide assistant mandibular distraction osteogenesis and sagittal split osteotomy in the treatment of hemifacial microsomia. AB - BACKGROUND: Hemifacial microsomia is the second most common congenital craniofacial malformation after cleft lip/palate with a wide variety of pathologic expression in jaws, skeletal components, ears, and soft tissues. Among the deformities, mandibular hypoplasia is the most common and is the main component that affects facial asymmetry. Mandibular distraction osteogenesis is the mainstay treatment; however, the vector of device and osteotomy lines need to be well designed. We utilized the sagittal split osteotomy for mandibular distraction with rapid prototyping surgical guide plate, making a successful outcome. METHODS: Hemifacial microsomia with unilateral Pruzansky II mandibular hypoplasia were selected in this study. Three-dimensional CT reconstructive data was put into Proplan CFM for preoperative designing and then manufacturing the surgical guide plate. The mandibular osteotomy and implantation of the internal distractor were performed through an intraoral approach aided with the prefabricated guide plate. Distraction began 7 days postoperation with a frequency of 1 mm/d and the distractor was kept in place 6 to 10 months after the first operation, then the distractor was removed. RESULTS: From July 2012 to March 2014, 6 cases of Pruzansky II hemifacial microsomia aged from 7 to 11 years were treated with the technique mentioned above. The range of distraction extends from 20 to 30 mm. The facial asymmetry deformities were improved obviously and without any complication. CONCLUSIONS: Mandibular distraction osteogenesis by sagittal split osteotomy through rapid prototyping surgical guide plate provides certain advantages in the treatment of hemifacial microsomia. PMID- 25699537 TI - Muscle tension line concept in nasolabial muscle complex--based on 3-dimensional reconstruction of nasolabial muscle fibers. AB - BACKGROUND: Plastic surgeons have attempted various ways to rebuild the aesthetic subunits of the upper lip in patients with cleft lip with less than perfect results in most cases. We propose that repairing the 3 muscle tension line groups in the nasolabial complex will have improved aesthetic results. METHODS: Micro computed tomographic scans were performed on the nasolabial tissues of 5 normal aborted fetuses and used to construct a 3-dimensional model to study the nasolabial muscle complex structure. RESULTS: The micro-computed tomographic (CT) scans showed the close relationship and interaction between the muscle fibers of nasalis, pars peripheralis, levator labii superioris, and pars marginalis. CONCLUSIONS: Based on the 2-dimensional images obtained from the micro-computed tomographic scans, we suggest the concept of nasolabial muscle complex and muscle tension line group theory: there is a close relationship among the alar part of the nasalis, depressor septi muscle, orbicularis oris muscle, and levator labii superioris alaeque nasi. The tension line groups are 3 tension line structures in the nasolabial muscle complex that interlock with each other at the intersections and maintain the specific shape and aesthetics of the lip and nose. PMID- 25699538 TI - The aesthetic proportion index of facial contour surgery. AB - An oval-shaped face is considered ideal in Chinese culture, which means not only narrow mid and low face but also appropriate proportion between them. Numerous surgical resections of the malar and mandibular angles began in the 1980s. The objective of this study was to investigate the facial proportion index before and after facial contour surgery. All 266 patients were subjected to L-shaped reduction malarplasty and reduction of mandibular angles with partial masseter muscle resection. All computed tomographic parameters (preoperative and 2 years postoperative) were conducted on facial morphometry to reveal the change of the facial proportion index of hard and soft tissue, respectively, such as the widest part of the mid face (WM), widest part of the lower face (WL), facial height (FH), WM/WL, WM/FH, and WL/FH. All patients were satisfied with the optimal outcome of the combined facial contour surgery. Morphometric analysis indicated that the ideal WM/WL ratio was 1.27 +/- 0.1 (1.21 +/- 0.09 preoperative) in hard tissue and 1.2 +/- 0.12 (1.16 +/- 0.12 preoperative) in soft tissue 2 years postoperatively. The combined facial contour surgery could acquire an ideal facial contour for Chinese patients. Furthermore, the relative proportion index can be referenced as the standard for preoperative design. PMID- 25699539 TI - Clinical feasibility and efficacy of using virtual surgical planning in bimaxillary orthognathic surgery without intermediate splint. AB - BACKGROUND: Computer-aided jaw surgery has been extensively studied recently. The purpose of this study was to determine the clinical feasibility of performing bimaxillary orthognathic surgery without intermediate splint using virtual surgical planning and rapid prototyping technology. METHODS: Twelve consecutive patients who underwent bimaxillary orthognathic surgery were included. The presented treatment plan here mainly consists of 6 procedures: (1) data acquisition from computed tomography (CT) of the skull and laser scanning of the dentition; (2) reconstruction and fusion of a virtual skull model with accurate dentition; (3) virtual surgery simulation including osteotomy and movement and repositioning of bony segments; (4) final surgical splint fabrication (no intermediate splint) using computer-aided design and rapid prototyping technology; (5) transfer of the virtual surgical plan to the operating room; and (6) comparison of the actual surgical outcome to the virtual surgical plan. RESULTS: All procedures of the treatment were successfully performed on all 12 patients. In quantification of differences between simulated and actual postoperative outcome, we found that the mean linear difference was less than 1.8 mm, and the mean angular difference was less than 2.5 degrees in all evaluated patients. CONCLUSION: Results from this study suggested that it was feasible to perform bimaxillary orthognathic surgery without intermediate splint. Virtual surgical planning and the guiding splints facilitated the diagnosis, treatment planning, accurate osteotomy, and bony segments repositioning in orthognathic surgery. PMID- 25699540 TI - Periprosthetic femur fractures. AB - Successful treatment of periprosthetic femur fractures, like all fractures, requires careful attention to understand the fracture pattern nuances, identifying and executing a rational treatment approach, and providing an appropriate postoperative recovery protocol. Unlike most other fractures, modification of standard techniques is often required to obtain a stable fixation construct, and there is a greater role for revision arthroplasty in the treatment of periprosthetic fractures. Optimal indications for surgical repair versus revision arthroplasty and optimal postoperative weight-bearing protocols remain uncertain. Reported outcomes for patients with periprosthetic femoral shaft fractures are generally good and are relatively consistent. Results for periprosthetic distal femur fractures, however, are less good and more inconsistent. Both periprosthetic femoral shaft and distal femur fractures are associated with relatively high mortality rates, approaching that of patients with hip fractures. This review should provide insight into the current solutions and challenges for the treatment of patients with periprosthetic femur fractures. PMID- 25699541 TI - Can geriatric hip fractures be managed effectively within a level 1 trauma center? AB - OBJECTIVES: To determine whether geriatric hip fractures can be managed effectively within a level 1 trauma center. DESIGN: A prospective observational cohort study with a historical control group. SETTING: Level 1 trauma center. PATIENTS: A total of 199 patients admitted under our hip fracture service were prospectively identified from 2011-2012. These were compared with 191 hip fracture patients who were admitted before the service. INTERVENTION: The hip fracture service includes coadmission under an orthopaedic and a geriatric team. A daily, consultant-led operating list was made available for hip fracture surgery. A "neck of femur" nurse was employed to coordinate patient care. MAIN OUTCOME MEASUREMENTS: Time to surgery, length of stay, discharge destination, and mortality. A cost-benefit analysis and a comparison with a lower acuity hospital were also performed. RESULTS: Since the hip fracture service, more patients underwent surgery within 48 hours (67% vs. 52%; P = 0.004), the length of stay significantly decreased from 26 to 22 days (P = 0.004), significantly more patients were admitted to the rehabilitation unit (58.7% vs. 3.5%; P < 0.001) and ultimately discharged to their own residence (51.6% vs. 40.5%; P = 0.034). Inpatient mortality rates did not change significantly (7.5% vs. 6.8%; P = 0.780). The estimated cost saving in 2011 was $981,040. CONCLUSIONS: Only minor changes are required to significantly improve the management of geriatric hip fracture patients. These patients can be managed effectively within a level 1 trauma center when an organized service prioritizing these patients is used. LEVEL OF EVIDENCE: Therapeutic level III. See Instructions for authors for a complete description of levels of evidence. PMID- 25699542 TI - Targeting a cell state common to triple-negative breast cancers. AB - Some mutations in cancer cells can be exploited for therapeutic intervention. However, for many cancer subtypes, including triple-negative breast cancer (TNBC), no frequently recurring aberrations could be identified to make such an approach clinically feasible. Characterized by a highly heterogeneous mutational landscape with few common features, many TNBCs cluster together based on their 'basal-like' transcriptional profiles. We therefore hypothesized that targeting TNBC cells on a systems level by exploiting the transcriptional cell state might be a viable strategy to find novel therapies for this highly aggressive disease. We performed a large-scale chemical genetic screen and identified a group of compounds related to the drug PKC412 (midostaurin). PKC412 induced apoptosis in a subset of TNBC cells enriched for the basal-like subtype and inhibited tumor growth in vivo. We employed a multi-omics approach and computational modeling to address the mechanism of action and identified spleen tyrosine kinase (SYK) as a novel and unexpected target in TNBC. Quantitative phosphoproteomics revealed that SYK inhibition abrogates signaling to STAT3, explaining the selectivity for basal like breast cancer cells. This non-oncogene addiction suggests that chemical SYK inhibition may be beneficial for a specific subset of TNBC patients and demonstrates that targeting cell states could be a viable strategy to discover novel treatment strategies. PMID- 25699543 TI - Improvements from a flipped classroom may simply be the fruits of active learning. AB - The "flipped classroom" is a learning model in which content attainment is shifted forward to outside of class, then followed by instructor-facilitated concept application activities in class. Current studies on the flipped model are limited. Our goal was to provide quantitative and controlled data about the effectiveness of this model. Using a quasi-experimental design, we compared an active nonflipped classroom with an active flipped classroom, both using the 5-E learning cycle, in an effort to vary only the role of the instructor and control for as many of the other potentially influential variables as possible. Results showed that both low-level and deep conceptual learning were equivalent between the conditions. Attitudinal data revealed equal student satisfaction with the course. Interestingly, both treatments ranked their contact time with the instructor as more influential to their learning than what they did at home. We conclude that the flipped classroom does not result in higher learning gains or better attitudes compared with the nonflipped classroom when both utilize an active-learning, constructivist approach and propose that learning gains in either condition are most likely a result of the active-learning style of instruction rather than the order in which the instructor participated in the learning process. PMID- 25699544 TI - Kinetic and multidimensional profiling of accelerated degradation of oil sludge by biostimulation. AB - Biostimulation, which employs nutrients to enhance the proliferation of indigenous microorganisms and therefore the degradation of contaminants, is an effective tool for treatment of oil-contaminated soil. However, the evolution of microbial ecology, which responds directly to stimulation procedures and intrinsically determines the degradation of oil contaminants, has rarely been explored, particularly in the context of biostimulation. In this study, the effects of biostimulation procedures including the regulation of the C : N : P ratio, as well as application of surfactants and electron acceptors in the degradation of crude oil contaminants and the evolution of the microbial community were examined simultaneously to provide ecological insights into the biostimulation. The real-time PCR showed that biostimulation promoted the proliferation of bacteria, with Gammaproteobacteria showing the greatest increase. However, the proliferation of fungi was inhibited by the accumulation of the degradation products. The degradation of polar compounds of crude oil contaminants was characterized by negative-ion electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry (negative-ion ESI FT-ICR MS), showing a biased increase in the relative abundance of naphthenic acids. Principal component analysis (PCA) showed that different species in oil sludge have different degradation rates during biostimulation. The addition of fertilizers with surfactants and electron acceptors profoundly stimulated the indigenous microorganisms with N1, O1 and O2 species as substrates while those with O3 and O4 species were little affected. An enriched abundance of alkB genes was observed during the degradation of saturated hydrocarbons. Monitoring the kinetics of the microbial community, functional genes and degradation offers a comprehensive view for the understanding and optimization of the biostimulation process. PMID- 25699545 TI - Metabolomics method to comprehensively analyze amino acids in different domains. AB - Amino acids play essential roles in both metabolism and the proteome. Many studies have profiled free amino acids (FAAs) or proteins; however, few have connected the measurement of FAA with individual amino acids in the proteome. In this study, we developed a metabolomics method to comprehensively analyze amino acids in different domains, using two examples of different sample types and disease models. We first examined the responses of FAAs and insoluble-proteome amino acids (IPAAs) to the Myc oncogene in Tet21N human neuroblastoma cells. The metabolic and proteomic amino acid profiles were quite different, even under the same Myc condition, and their combination provided a better understanding of the biological status. In addition, amino acids were measured in 3 domains (FAAs, free and soluble-proteome amino acids (FSPAAs), and IPAAs) to study changes in serum amino acid profiles related to colon cancer. A penalized logistic regression model based on the amino acids from the three domains had better sensitivity and specificity than that from each individual domain. To the best of our knowledge, this is the first study to perform a combined analysis of amino acids in different domains, and indicates the useful biological information available from a metabolomics analysis of the protein pellet. This study lays the foundation for further quantitative tracking of the distribution of amino acids in different domains, with opportunities for better diagnosis and mechanistic studies of various diseases. PMID- 25699546 TI - Implementation and Evaluation of a Wiki Involving Multiple Stakeholders Including Patients in the Promotion of Best Practices in Trauma Care: The WikiTrauma Interrupted Time Series Protocol. AB - BACKGROUND: Trauma is the most common cause of mortality among people between the ages of 1 and 45 years, costing Canadians 19.8 billion dollars a year (2004 data), yet half of all patients with major traumatic injuries do not receive evidence-based care, and significant regional variation in the quality of care across Canada exists. Accordingly, our goal is to lead a research project in which stakeholders themselves will adapt evidence-based trauma care knowledge tools to their own varied institutional contexts and cultures. We will do this by developing and assessing the combined impact of WikiTrauma, a free collaborative database of clinical decision support tools, and Wiki101, a training course teaching participants how to use WikiTrauma. WikiTrauma has the potential to ensure that all stakeholders (eg, patients, clinicians, and decision makers) can all contribute to, and benefit from, evidence-based clinical knowledge about trauma care that is tailored to their own needs and clinical setting. OBJECTIVE: Our main objective will be to study the combined effect of WikiTrauma and Wiki101 on the quality of care in four trauma centers in Quebec. METHODS: First, we will pilot-test the wiki with potential users to create a version ready to test in practice. A rapid, iterative prototyping process with 15 health professionals from nonparticipating centers will allow us to identify and resolve usability issues prior to finalizing the definitive version for the interrupted time series. Second, we will conduct an interrupted time series to measure the impact of our combined intervention on the quality of care in four trauma centers that will be selected-one level I, one level II, and two level III centers. Participants will be health care professionals working in the selected trauma centers. Also, five patient representatives will be recruited to participate in the creation of knowledge tools destined for their use (eg, handouts). All participants will be invited to complete the Wiki101 training and then use, and contribute to, WikiTrauma for 12 months. The primary outcome will be the change over time of a validated, composite, performance indicator score based on 15 process performance indicators found in the Quebec Trauma Registry. RESULTS: This project was funded in November 2014 by the Canadian Medical Protective Association. We expect to start this trial in early 2015 and preliminary results should be available in June 2016. Two trauma centers have already agreed to participate and two more will be recruited in the next months. CONCLUSIONS: We expect that this study will add important and unique evidence about the effectiveness, safety, and cost savings of using collaborative platforms to adapt knowledge implementation tools across jurisdictions. PMID- 25699548 TI - Spinal Cord Injury in the Child and Young Adult. PMID- 25699547 TI - Autoinhibition of Bruton's tyrosine kinase (Btk) and activation by soluble inositol hexakisphosphate. AB - Bruton's tyrosine kinase (Btk), a Tec-family tyrosine kinase, is essential for B cell function. We present crystallographic and biochemical analyses of Btk, which together reveal molecular details of its autoinhibition and activation. Autoinhibited Btk adopts a compact conformation like that of inactive c-Src and c Abl. A lipid-binding PH-TH module, unique to Tec kinases, acts in conjunction with the SH2 and SH3 domains to stabilize the inactive conformation. In addition to the expected activation of Btk by membranes containing phosphatidylinositol triphosphate (PIP3), we found that inositol hexakisphosphate (IP6), a soluble signaling molecule found in both animal and plant cells, also activates Btk. This activation is a consequence of a transient PH-TH dimerization induced by IP6, which promotes transphosphorylation of the kinase domains. Sequence comparisons with other Tec-family kinases suggest that activation by IP6 is unique to Btk. PMID- 25699549 TI - Interoperability after deployment: persistent challenges and regional strategies in Denmark. AB - QUALITY PROBLEM OR ISSUE: The European Union has identified Denmark as one of the countries who have the potential to provide leadership and inspiration for other countries in eHealth implementation and adoption. However, Denmark has historically struggled to facilitate data exchange between their public hospitals' electronic health records (EHRs). Furthermore, state-led projects failed to adequately address the challenges of interoperability after deployment. CHOICE OF SOLUTION: Changes in the organizational setup and division of responsibilities concerning the future of eHealth implementations in hospitals took place, which granted the Danish regions the full responsibility for all hospital systems, specifically the consolidation of EHRs to one system per region. IMPLEMENTATION: The regions reduced the number of different EHRs to six systems by 2014. Additionally, the first version of the National Health Record was launched to provide health care practitioners with an overview of a patient's data stored in all EHRs across the regions and within the various health sectors. EVALUATION: The governance of national eHealth implementation plays a crucial role in the development and diffusion of interoperable technologies. Changes in the organizational setup and redistribution of responsibilities between the Danish regions and the state play a pivotal role in producing viable and coherent solutions in a timely manner. LESSONS LEARNED: Interoperability initiatives are best managed on a regional level or by the authorities responsible for the provision of local health care services. Cross-regional communication is essential during the initial phases of planning in order to set a common goal for countrywide harmonization, coherence and collaboration. PMID- 25699561 TI - Aetiology and epidemiology of human cryptosporidiosis cases in Galicia (NW Spain), 2000-2008. AB - Cryptosporidium infects millions of people worldwide causing acute gastroenteritis, but despite its remarkable epidemiological and economic impact, information on the epidemiological trends of human cryptosporidiosis is still scarce in most countries. Here we investigate a panel of 486 cases collected in Galicia (NW Iberian Peninsula) between 2000 and 2008, which sheds new light on the epidemiology in this region of the South Atlantic European facade. Incidence rates in Galicia are one order of magnitude higher than those reported in other regions of Spain, suggesting that this parasite remains largely underdiagnosed in this country, and are also larger than those typical of other European countries with available data. Two species dominate our dataset, Cryptosporidium hominis (65%) and C. parvum (34%). The sex ratio of patients infected by either species was 0.5, but C. hominis was significantly more common in younger males. C. parvum infections were more acute and required more specialized medical attention, which suggests a differential adaptation of each species to human hosts. The parasites display strong seasonal and geographical variation. C. parvum incidence peaked during summer and was mainly detected in rural areas while C. hominis infections were more frequent in autumn and exhibited a more even geographical distribution. Such differences probably reflect their distinct sources of infection - C. parvum is mainly zoonotic and C. hominis anthroponotic - and the effects of climatic variables, like temperature and rainfall. PMID- 25699562 TI - Does the Transmissible Liability Index (TLI) assessed in late childhood predict suicidal symptoms at young adulthood? AB - OBJECTIVE: Our previous work demonstrated that the Transmissible Liability Index (TLI), an instrument designed as an index of liability for substance use disorder (SUD), is associated with risk of substance use disorder. This longitudinal study assessed whether TLI measured in 10-12-year-olds (late childhood) predicts suicidal behavior from age 12-14 (preadolescence) to age 25 (young adulthood). We hypothesized that TLI would predict number and severity of suicide attempts. METHODS: Subjects were sons of men who had lifetime history of SUD (n = 250), called the High Average Risk (HAR) group, and sons of men with no lifetime history of a SUD (n = 250), called the Low Average Risk (LAR) group. The TLI was delineated at baseline (age 10-12), and age-specific versions were administered at 12-14, 16, 19, 22, and 25 years of age. RESULTS: TLI was significantly associated with number and severity of lifetime suicide attempts. CONCLUSIONS: These findings confirm the hypothesis that TLI assessed at late childhood is a predictor of frequency and severity of suicidal behavior from preadolescence to young adulthood. PMID- 25699563 TI - Sudden unexpected death in infancy: aetiology, pathophysiology, epidemiology and prevention in 2015. AB - Despite the fall in numbers of unexpected infant deaths that followed the 'Back to Sleep' campaigns in the early 1990 s in the UK and many other countries, such deaths remain one of the largest single groups of deaths in the postneonatal period in many Western countries. Changes in the ways in which unexpected infant deaths are categorised by pathologists and coroners, and increasing reluctance to use the term 'sudden infant death syndrome', make assessment of nationally and internationally collected data on incidence potentially inaccurate and confusing. In this paper, we review current understanding of the epidemiology and aetiology of unexpected deaths in infancy, and current hypotheses on the pathophysiology of the processes that may lead to death. We also review interventions that have been adopted, with variable degrees of effectiveness in efforts to reduce the numbers of deaths, and new approaches that offer the possibility of prevention in the future. PMID- 25699564 TI - Large observer variation of clinical assessment of dyspnoeic wheezing children. AB - BACKGROUND: In children with acute dyspnoea, the assessment of severity of dyspnoea and response to treatment is often performed by different professionals, implying that knowledge of the interobserver variation of this clinical assessment is important. OBJECTIVE: To determine intraobserver and interobserver variation in clinical assessment of children with dyspnoea. METHODS: From September 2009 to September 2010, we recorded a convenience sample of 27 acutely wheezing children (aged 3 months-7 years) in the emergency department of a general teaching hospital in the Netherlands, on video before and after treatment with inhaled bronchodilators. These video recordings were independently assessed by nine observers scoring wheeze, prolonged expiratory phase, retractions, nasal flaring and a general assessment of dyspnoea on a Likert scale (0-10). Assessment was repeated after 2 weeks to evaluate intraobserver variation. RESULTS: We analysed 972 observations. Intraobserver reliability was the highest for supraclavicular retractions (kappa 0.84) and moderate-to-substantial for other items (kappa 0.49-0.65). Interobserver reliability was considerably worse, with kappa<0.46 for all items. The smallest detectable change of the dyspnoea score (>3 points) was larger than the minimal important change (<1 point), meaning that in 69% of observations a clinically important change after treatment cannot be distinguished from measurement error. CONCLUSIONS: Intraobserver variation is modest, and interobserver variation is large for most clinical findings in children with dyspnoea. The measurement error induced by this variation is too large to distinguish potentially clinically relevant changes in dyspnoea after treatment in two-thirds of observations. The poor interobserver reliability of clinical dyspnoea assessment in children limits its usefulness in clinical practice and research, and highlights the need to use more objective measurements in these patients. PMID- 25699565 TI - Broadening the evidence base and the mind when thinking about mixed methods research. PMID- 25699566 TI - Maternal overweight and obesity in early pregnancy are associated with an increase in infant mortality risk. PMID- 25699567 TI - Assessment of cardiovascular risk in adults with type 2 diabetes and metabolic syndrome: Framingham versus UKPDS equations. AB - PURPOSE: The purpose of this study was to assess risk of cardiovascular disease (CVD) by comparing the Framingham and United Kingdom Prospective Diabetes Study (UKPDS) risk equations in Korean adults with type 2 diabetes (T2DM) and metabolic syndrome. METHODS: The study was a cross-sectional survey enrolling a convenience sample of 110 Korean adults with T2DM and metabolic syndrome. The 10-year CVD risk scores were calculated using the Framingham risk equation and UKPDS risk engines. RESULTS: Overall participants had a moderate prevalence (average, 64.3%) of metabolic syndrome factors, with the most prevalent being abdominal obesity (86.4%) and elevated blood pressure (78.2%). A lower percentage of women were current smokers and consumed alcohol than men, whereas a higher percentage of men had their weight and stress controlled than women. The mean scores of 10-year CVD risk using the Framingham and UKPDS equations were 14.55% and 15.99%, respectively. However, there were no significant differences between results of the 2 equations. Regarding level of CVD risk, the percentage of high risk (>20%) was about 24% using both equations. Also, the area under the receiver operating characteristic curves using Framingham and UKPDS equations was similar: 0.707 and 0.696, respectively, which indicated moderate accuracy. CONCLUSIONS: About one fourth of adults with T2DM and metabolic syndrome had high level of CVD risk (>20%). In practice, people with diabetes and metabolic syndrome could be managed earlier and more intensively based on their risk estimated by the Framingham or UKPDS equations. PMID- 25699568 TI - Low Health Literacy Predicts Misperceptions of Diabetes Control in Patients With Persistently Elevated A1C. AB - PURPOSE: The purpose of this study is to identify factors associated with perceived control of diabetes in a group of poorly controlled patients. Identifying factors associated with perceived control in these patients is an important step in improving actual control as measured by A1C. As health literacy is essential for understanding complex medical information, we hypothesized that low health literacy would be associated with inaccurate perceptions of diabetes control. METHODS: A cross-sectional analysis was performed on 280 adults with type 2 diabetes whose last 2 A1C measurements were >8.0%. Participants were recruited primarily from 6 University of Pennsylvania primary care practices. Perceived control and factors potentially associated with this outcome, including health literacy, were assessed during an in-person interview. Health literacy was measured using the Rapid Estimate of Adult Literacy. RESULTS: Thirty-nine percent of patients responded that they were managing to control their diabetes well or very well. However, 57% of those at the seventh to eighth-grade health literacy level and 61% of those at the level of sixth grade and below reported that they were controlling their diabetes well or very well. CONCLUSIONS: In this population of patients with poorly controlled diabetes, a majority of those with low health literacy believed that they were controlling their disease well or very well. Patients who believe that they are already controlling their diabetes well may be less likely to make changes to improve control. Health care providers and educators should consider health literacy when discussing control of diabetes and when setting management goals with patients. PMID- 25699569 TI - Nodopathies of the peripheral nerve: an emerging concept. AB - Peripheral nerve diseases are traditionally classified as demyelinating or axonal. It has been recently proposed that microstructural changes restricted to the nodal/paranodal region may be the key to understanding the pathophysiology of antiganglioside antibody mediated neuropathies. We reviewed neuropathies with different aetiologies (dysimmune, inflammatory, ischaemic, nutritional, toxic) in which evidence from nerve conductions, excitability studies, pathology and animal models, indicate the involvement of the nodal region in the pathogenesis. For these neuropathies, the classification in demyelinating and axonal is inadequate or even misleading, we therefore propose a new category of nodopathy that has the following features: (1) it is characterised by a pathophysiological continuum from transitory nerve conduction block to axonal degeneration; (2) the conduction block may be due to paranodal myelin detachment, node lengthening, dysfunction or disruption of Na(+) channels, altered homeostasis of water and ions, or abnormal polarisation of the axolemma; (3) the conduction block may be promptly reversible without development of excessive temporal dispersion; (4) axonal degeneration, depending on the specific disorder and its severity, eventually follows the conduction block. The term nodopathy focuses to the site of primary nerve injury, avoids confusion with segmental demyelinating neuropathies and circumvents the apparent paradox that something axonal may be reversible and have a good prognosis. PMID- 25699570 TI - MRI signs of multiple system atrophy preceding the clinical diagnosis: the case for an imaging-supported probable MSA diagnostic category. PMID- 25699571 TI - Neurological picture. I cannot stand this anymore! PMID- 25699572 TI - Novel Cryptic Rearrangements in Adult B-Cell Precursor Acute Lymphoblastic Leukemia Involving the MLL Gene. AB - MLL (mixed-lineage-leukemia) gene rearrangements are typical for acute leukemia and are associated with an aggressive course of disease, with a worse outcome than comparable case, and thus require intensified treatment. Here we describe a 69-year-old female with adult B cell precursor acute lymphoblastic leukemia (BCP ALL) with hyperleukocytosis and immunophenotype CD10- and CD19+ with cryptic MLL rearrangements. G-banding at the time of diagnosis showed a normal karyotype: 46,XX. Molecular cytogenetics using multitude multicolor banding (mMCB) revealed a complex rearrangement of the two copies of chromosome 11. However, a locus specific probe additionally identified that the MLL gene at 11q23.3 was disrupted, and that the 5' region was inserted into the chromosomal sub-band 4q21; thus the aberration involved three chromosomes and five break events. Unfortunately, the patient died six months after the initial diagnosis from serious infections and severe complications. Overall, the present findings confirm that, by far not all MLL aberrations are seen by routine chromosome banding techniques and that fluorescence in situ hybridization (FISH) should be regarded as standard tool to access MLL rearrangements in patients with BCP-ALL. PMID- 25699573 TI - Levels and congener profiles of PBDEs in edible Baltic, freshwater, and farmed fish in Finland. AB - Fish is the major source of polybrominated diphenyl ethers (PBDEs) for Finnish consumers. To estimate the PBDE contamination in fish that Finns regularly consume as food, a large-scale sampling was undertaken in 2009-2010. Altogether 207 samples of 17 edible fish species were collected from commercially and recreationally important fishing areas in the Baltic Sea, freshwater lakes, and farming facilities. The analysis of 15 PBDE congeners was performed in an accredited testing laboratory with high-resolution gas chromatography mass spectrometry. In all of the samples, the Sigma15PBDE varied between 0.029 and 73 ng/g fw. The most abundant congeners were BDE-47 (average proportion 42%), -99 (8.4%), -100 (11%), -154 (5.6%), and -209 (27%). High levels of BDE-209 were observed in the Baltic Sea, off the coast of Pori, in Baltic herring, perch, pike, and pike-perch. Overall, the PBDE levels in Baltic and freshwater fish were low. The levels in farmed whitefish were slightly higher than in wild whitefish. The reasons for the high BDE-209 levels in Baltic herring in Pori and the elevated levels of PBDEs in farmed whitefish should be investigated more thoroughly. PMID- 25699574 TI - Ribifolin, an orbitide from Jatropha ribifolia, and its potential antimalarial activity. AB - A new orbitide named ribifolin was isolated and characterized from Jatropha ribifolia using mass spectrometry, NMR spectroscopy, quantitative amino acid analysis, molecular dynamics/simulated annealing, and Raman optical activity measurements and calculations. Ribifolin (1) and its linear form (1a) were synthesized by solid-phase peptide synthesis, followed by evaluation of its antiplasmodial and cytotoxicity activities. Compound 1 was moderately effective (IC50 = 42 MUM) against the Plasmodium falciparum strain 3D7. PMID- 25699575 TI - Absorption and emission spectral shapes of a prototype dye in water by combining classical/dynamical and quantum/static approaches. AB - We study the absorption and emission electronic spectra in an aqueous solution of N-methyl-6-oxyquinolinium betaine (MQ), an interesting dye characterized by a large change of polarity and H-bond ability between the ground (S0) and the excited (S1) states. To that end we compare alternative approaches based either on explicit solvent models and density functional theory (DFT)/molecular mechanics (MM) calculations or on DFT calculations on clusters models embedded in a polarizable continuum (PCM). In the first approach (ClMD), the spectrum is computed according to the classical Franck-Condon principle, from the dispersion of the time-dependent (TD)-DFT vertical transitions at selected snapshots of molecular dynamics (MD) on the initial state. In the cluster model (Qst) the spectrum is simulated by computing the quantum vibronic structure, estimating the inhomogeneous broadening from state-specific TD-DFT/PCM solvent reorganization energies. While both approaches provide absorption and emission spectral shapes in nice agreement with experiment, the Stokes shift is perfectly reproduced by Qst calculations if S0 and S1 clusters are selected on the grounds of the MD trajectory. Furthermore, Qst spectra better fit the experimental line shape, mostly in absorption. Comparison of the predictions of the two approaches is very instructive: the positions of Qst and ClMD spectra are shifted due to the different solvent models and the ClMD spectra are narrower than the Qst ones, because MD underestimates the width of the vibrational density of states of the high-frequency modes coupled to the electronic transition. On the other hand, both Qst and ClMD approaches highlight that the solvent has multiple and potentially opposite effects on the spectral width, so that the broadening due to solute-solvent vibrations and electrostatic interaction with bulk solvent is (partially) counterbalanced by a narrowing of the contribution due to the solute vibrational modes. Qst analysis evidences a pure quantum broadening effect of the spectra in water due to vibronic progressions along the solute/solvent H-bonds. PMID- 25699577 TI - Enantioselective bromocyclization of allylic amides catalyzed by BINAP derivatives. AB - A highly enantioselective bromocyclization of allylic amides with N bromosuccinimide (NBS) was developed with DTBM-BINAP as a catalyst, affording chiral oxazolines with a tetrasubstituted carbon center in high yield with up to 99% ee. By utilizing the bromo substituent as a handle, the obtained compounds were converted to synthetically useful chiral building blocks. PMID- 25699578 TI - Autophagy as a Stress Response Pathway in the Immune System. AB - Macroautophagy, hereafter, referred to as autophagy, has long been regarded as a housekeeping pathway involved in intracellular degradation and energy recycling. These housekeeping and homeostatic functions are especially important during cellular stress, such as periods of nutrient deprivation. However, importance of autophagy extends far beyond its degradative functions. Recent evidence shows that autophagy plays an essential role in development, organization and functions of the immune system, and defects in autophagy lead to several diseases, including cancer and autoimmunity. In the immune system, autophagy is important in regulation of the innate and adaptive immune responses. This review focuses on the roles of autophagy in the adaptive immune system. We first introduce the autophagy pathway and provide a brief description of the major molecular players involved in autophagy. We then discuss the importance of autophagy as a stress integrator mechanism and provide relevant examples of this role of autophagy in adaptive immune cells. Then we proceed to describe how autophagy regulates development, activation and functions of different adaptive immune cells. In these contexts, we mention both degradative and non-degradative roles of autophagy, and illustrate their importance. We also discuss role of autophagy in antigen presenting cells, which play critical roles in the activation of adaptive immune cells. Further, we describe how autophagy regulates functions of different adaptive immune cells during infection, inflammation and autoimmunity. PMID- 25699581 TI - Erratum. PMID- 25699583 TI - Ultracompressible, high-rate supercapacitors from graphene-coated carbon nanotube aerogels. AB - Emerging applications for electrochemical energy storage require devices that not only possess high power and energy, but also are capable of withstanding mechanical deformation without degradation of performance. To this end, we have constructed electric double layer capacitors (EDLCs), also referred to as supercapacitors, using thick, ultracompressible graphene-coated carbon nanotube aerogels as electrodes. These electrodes showed a high capacitance in both aqueous and room-temperature ionic liquid (RTIL) electrolytes, achieving between 60 and100 F/g, respectively, with the performance stable over hundreds of charge/discharge cycles and at high rates exceeding 1 V/s. This performance was retained fully under 90% compression of the systems, allowing us to construct cells with high volumetric capacitances of ~5-18 F/cm(3) in aqueous and RTIL electrolytes, respectively, which are 50-100 times higher than comparable compressible EDLCs (~0.1 F/cm(3)). Further, the volumetric capacitances approach values reported for compressible pseudocapacitors (~15-30 F/cm(3)) but without the degraded lifetime and reversibility that typically plague compressible pseudocapacitors. The electrodes demonstrated largely strain-invariant ion transport with no change in capacitance and high-rate performance even at 90% compressive strain. This material serves as an excellent platform for exploring the possibility for use of extremely compressible EDLCs with negligible degradation in capacitance in applications such as electric vehicles and wearable electronics. PMID- 25699579 TI - Hypersubones A and B, new polycyclic acylphloroglucinols with intriguing adamantane type cores from Hypericum subsessile. AB - Hypersubones A and B (1, 2), two adamantane type polycyclic polyprenylated acylphloroglucinols possessing an unprecedented seco-adamantane architecture and a tetracyclo-[6.3.1.1(3,10).0(4,8)]-tridecane core combined with a peroxide ring, respectively, were isolated from Hypericum subsessile together with three analogues (3-5). Their structures were determined by extensive NMR spectroscopic analysis, ECD calculations, and single-crystal X-ray diffraction. Compound 2 exhibited significant cytotoxicities against four human cancer lines in vitro (IC50 0.07-7.52 MUM). PMID- 25699584 TI - Size-controlled synthesis of Ag nanoparticles functionalized by heteroleptic dipyrrinato complexes having meso-pyridyl substituents and their catalytic applications. AB - The syntheses of heteroleptic dipyrrinato nickel(II) complexes [Ni(4 pydpm)(dedtc)] (1) and [Ni(4-pydpm)(dipdtc)] (2) [4-pydpm = 5-(4 pyridyl)dipyrromethene; dedtc = diethyldithiocarabamate; and dipdtc = diisopropyldithiocarbamate] and the thorough characterization of these complexes by satisfactory elemental analyses, electrospray ionization mass spectrometry, Fourier-transform infrared, NMR ((1)H, (13)C), and UV-vis spectroscopies, and electrochemical studies was achieved. Structure of 1 was authenticated by X-ray single-crystal analysis. Both the complexes 1 and 2 were successfully utilized as a capping agent in the preparation of silver nanoparticles. Availability of free pyridyl nitrogen on the dipyrrin core of these complexes was meticulously exploited in functionalization and stabilization of the silver nanoparticles (AgNPs). Morphological and structural investigations on colloidal nanoparticles were followed by UV-vis spectroscopy and transmission electron microscopy (TEM). Overall results revealed that average size of the silver nanoparticles (~10, 15, 20 nm, and aggregation) is strongly influenced by ratio of Ag/[1/2] (03, 06, 10, 20). Correlation between particle size and capping agents was realized by UV-vis and TEM studies. Catalytic activity of the AgNPs obtained through this route was successfully employed in the reduction of 4-nitrophenol (4-NP) to 4-aminophenol (4-AP). It was established that reduction process follows a pseudo-first-order kinetics. PMID- 25699580 TI - Three new phenanthrenone constituents from Trigonostemon lii. AB - Three new phenanthrenone constituents, trigoxyphins U-W (1, 7 and 9), together with eight known ones, trigoxyphin M (2), 6,9-O-dimethyltrigonostemone (3), trigonstemone (4), thrigonosomone B (5), trigonochinene E (6), actephiiol A (8), epiactephilol A (10) and neoboutomannin (11), were obtained from the methanol extract of the leaves and stems of Trigonostemonlii. The structures of the new metabolites were elucidated by analysing the spectroscopic data (1D NMR, 2D NMR, HR-ESI-MS and IR). Compounds 1-6 were evaluated for their cytotoxic activities on five human tumour cell lines by using the MTT method, and compound 1 exhibited inhibitory activity against HL-60, SMMC-7721, A-549, MCF-7 and SW480 with IC50 values ranging from 3.77 to 14.51 MUM. PMID- 25699576 TI - Development of novel ACK1/TNK2 inhibitors using a fragment-based approach. AB - The tyrosine kinase ACK1, a critical signal transducer regulating survival of hormone-refractory cancers, is an important therapeutic target, for which there are no selective inhibitors in clinical trials to date. This work reports the discovery of novel and potent inhibitors for ACK1 tyrosine kinase (also known as TNK2) using an innovative fragment-based approach. Focused libraries were designed and synthesized by selecting fragments from reported ACK inhibitors to create hybrid structures in a mix and match process. The hybrid library was screened by enzyme-linked immunosorbent assay-based kinase inhibition and (33)P HotSpot assays. Systematic structure-activity relationship studies led to the identification of compound (R)-9b, which shows potent in vitro (IC50 = 56 nM, n = 3, (33)P HotSpot assay) and in vivo (IC50 < 2 MUM, human cancer cell lines) ACK1 inhibition. Both (R)-9b and (S)-9b were stable in human plasma and displayed a long half-life (t(1/2) > 6 h). PMID- 25699582 TI - Correction to Using chromate to investigate the impact of natural organics on the surface reactivity of nanoparticulate magnetite. PMID- 25699585 TI - Intermolecular reaction screening as a tool for reaction evaluation. AB - Synthetic organic chemistry underpins many scientific disciplines. The development of new synthetic methods proceeds with the ultimate intention of providing access to novel structural motifs or providing safer, increasingly efficient, or more economical chemical reactions. To facilitate the identification and application of new methods in solving real synthetic problems, this Account will highlight the benefits of providing a fuller picture of both the scope and limitations of new reactions, with a primary focus on the evaluation of functional group tolerance and stability of a reaction using intermolecular screens. This Account will begin with a discussion on reaction evaluation, specifically considering the suitability of a given reaction for application in target-oriented synthesis. A comparison of desirable and essential criteria when choosing a reaction is given, and a short discussion on the value of negative and qualitative data is provided. The concept of intermolecular reaction screening will be introduced, and a direct comparison with a traditional substrate scope highlights the benefits and limitations of each and thus the complementary nature of these approaches. In recent years, a number of ad hoc applications of intermolecular screens to evaluate the functional group tolerance of a reaction or the stability of functional groups to a given set of reaction conditions have been reported, and will be discussed. More recently, we have developed a formal high-throughput intermolecular screening protocol that can be utilized to rapidly evaluate new chemical reactions. This simple and rapid protocol enables a much broader evaluation of a reaction in terms of functional group tolerance and the stability of chemical motifs to the reaction conditions than is feasible with a typical reaction scope. The development, evaluation, and application of this method within our group will be discussed in detail, with both the potential benefits and limitations highlighted and discussed. In addition, we will discuss more recent applications of intermolecular screens from both industrial and academic groups. Modifications in protocols and applications will be highlighted, including problem based evaluations, assessment of biomolecule compatibility, establishment of relative rate data, and the identification of new reactivity. Such screens have been applied in diverse chemistries including C-H functionalization reactions, frustrated Lewis-pair catalyzed hydrogenations, heterogeneous catalysis, photoredox catalysis, enantioselective organocatalysis, and polymer science. We feel that the application of intermolecular screens to such a diversity of reactions highlights the practical simplicity of such screens. A summary of the applications and potential utility of intermolecular reaction evaluation is provided. PMID- 25699586 TI - Inosine at Different Primer Positions to Study Structure and Diversity of Prokaryotic Populations. AB - Culture-independent methods, employed to study the diversity and complexity of microbial communities that are based on amplification of rRNA genes with universal primers, include gradient gel electrophoresis (denaturing or temperature), single-strand-conformation polymorphism, restriction fragment length polymorphism, qPCR and high-throughput DNA sequencing. Substituting one or more base(s) within or at the 3'-termi of the universal primers by inosine can overcome some of their shortcomings improving amplification capacity. Universal primer sets do not usually amplify sequences with nucleotide mismatch to the templates, particularly in the last three bases, whereas inosine-modified primers anneal and amplify a variety of rRNA gene sequences. Inosine-containing primers are therefore might be useful to detect more species in diverse prokaryotic populations. The article summarizes the pros and cons of using inosine especially at the 3' termini of universal primers in nucleic acid amplification for the study of microbial diversity. PMID- 25699587 TI - Phene synergism between root hair length and basal root growth angle for phosphorus acquisition. AB - Shallow basal root growth angle (BRGA) increases phosphorus acquisition efficiency by enhancing topsoil foraging because in most soils, phosphorus is concentrated in the topsoil. Root hair length and density (RHL/D) increase phosphorus acquisition by expanding the soil volume subject to phosphorus depletion through diffusion. We hypothesized that shallow BRGA and large RHL/D are synergetic for phosphorus acquisition, meaning that their combined effect is greater than the sum of their individual effects. To evaluate this hypothesis, phosphorus acquisition in the field in Mozambique was compared among recombinant inbred lines of common bean (Phaseolus vulgaris) having four distinct root phenotypes: long root hairs and shallow basal roots, long root hairs and deep basal roots, short root hairs and shallow basal roots, and short root hairs and deep basal roots. The results revealed substantial synergism between BRGA and RHL/D. Compared with short-haired, deep-rooted phenotypes, long root hairs increased shoot biomass under phosphorus stress by 89%, while shallow roots increased shoot biomass by 58%. Genotypes with both long root hairs and shallow roots had 298% greater biomass accumulation than short-haired, deep-rooted phenotypes. Therefore, the utility of shallow basal roots and long root hairs for phosphorus acquisition in combination is twice as large as their additive effects. We conclude that the anatomical phene of long, dense root hairs and the architectural phene of shallower basal root growth are synergetic for phosphorus acquisition. Phene synergism may be common in plant biology and can have substantial importance for plant fitness, as shown here. PMID- 25699588 TI - PHOTOSYSTEM II SUBUNIT R is required for efficient binding of LIGHT-HARVESTING COMPLEX STRESS-RELATED PROTEIN3 to photosystem II-light-harvesting supercomplexes in Chlamydomonas reinhardtii. AB - In Chlamydomonas reinhardtii, the LIGHT-HARVESTING COMPLEX STRESS-RELATED PROTEIN3 (LHCSR3) protein is crucial for efficient energy-dependent thermal dissipation of excess absorbed light energy and functionally associates with photosystem II-light-harvesting complex II (PSII-LHCII) supercomplexes. Currently, it is unknown how LHCSR3 binds to the PSII-LHCII supercomplex. In this study, we investigated the role of PHOTOSYSTEM II SUBUNIT R (PSBR) an intrinsic membrane-spanning PSII subunit, in the binding of LHCSR3 to PSII-LHCII supercomplexes. Down-regulation of PSBR expression diminished the efficiency of oxygen evolution and the extent of nonphotochemical quenching and had an impact on the stability of the oxygen-evolving complex as well as on PSII-LHCII-LHCSR3 supercomplex formation. Its down-regulation destabilized the PSII-LHCII supercomplex and strongly reduced the binding of LHCSR3 to PSII-LHCII supercomplexes, as revealed by quantitative proteomics. PHOTOSYSTEM II SUBUNIT P deletion, on the contrary, destabilized PHOTOSYSTEM II SUBUNIT Q binding but did not affect PSBR and LHCSR3 association with PSII-LHCII. In summary, these data provide clear evidence that PSBR is required for the stable binding of LHCSR3 to PSII-LHCII supercomplexes and is essential for efficient energy-dependent quenching and the integrity of the PSII-LHCII-LHCSR3 supercomplex under continuous high light. PMID- 25699589 TI - Arabidopsis glutaredoxin S17 and its partner, the nuclear factor Y subunit C11/negative cofactor 2alpha, contribute to maintenance of the shoot apical meristem under long-day photoperiod. AB - Glutaredoxins (GRXs) catalyze the reduction of protein disulfide bonds using glutathione as a reductant. Certain GRXs are able to transfer iron-sulfur clusters to other proteins. To investigate the function of Arabidopsis (Arabidopsis thaliana) GRXS17, we applied a strategy combining biochemical, genetic, and physiological approaches. GRXS17 was localized in the nucleus and cytosol, and its expression was elevated in the shoot meristems and reproductive tissues. Recombinant GRXS17 bound Fe2S2 clusters, a property likely contributing to its ability to complement the defects of a Baker's yeast (Saccharomyces cerevisiae) strain lacking the mitochondrial GRX5. However, a grxs17 knockout Arabidopsis mutant exhibited only a minor decrease in the activities of iron sulfur enzymes, suggesting that its primary function is as a disulfide oxidoreductase. The grxS17 plants were sensitive to high temperatures and long day photoperiods, resulting in elongated leaves, compromised shoot apical meristem, and delayed bolting. Both environmental conditions applied simultaneously led to a growth arrest. Using affinity chromatography and split Yellow Fluorescent Protein methods, a nuclear transcriptional regulator, the Nuclear Factor Y Subunit C11/Negative Cofactor 2alpha (NF-YC11/NC2alpha), was identified as a GRXS17 interacting partner. A mutant deficient in NF YC11/NC2alpha exhibited similar phenotypes to grxs17 in response to photoperiod. Therefore, we propose that GRXS17 interacts with NF-YC11/NC2alpha to relay a redox signal generated by the photoperiod to maintain meristem function. PMID- 25699590 TI - Site-specific nitrosoproteomic identification of endogenously S-nitrosylated proteins in Arabidopsis. AB - Nitric oxide (NO) regulates multiple developmental events and stress responses in plants. A major biologically active species of NO is S-nitrosoglutathione (GSNO), which is irreversibly degraded by GSNO reductase (GSNOR). The major physiological effect of NO is protein S-nitrosylation, a redox-based posttranslational modification mechanism by covalently linking an NO molecule to a cysteine thiol. However, little is known about the mechanisms of S-nitrosylation-regulated signaling, partly due to limited S-nitrosylated proteins being identified. In this study, we identified 1,195 endogenously S-nitrosylated peptides in 926 proteins from the Arabidopsis (Arabidopsis thaliana) by a site-specific nitrosoproteomic approach, which, to date, is the largest data set of S nitrosylated proteins among all organisms. Consensus sequence analysis of these peptides identified several motifs that contain acidic, but not basic, amino acid residues flanking the S-nitrosylated cysteine residues. These S-nitrosylated proteins are involved in a wide range of biological processes and are significantly enriched in chlorophyll metabolism, photosynthesis, carbohydrate metabolism, and stress responses. Consistently, the gsnor1-3 mutant shows the decreased chlorophyll content and altered photosynthetic properties, suggesting that S-nitrosylation is an important regulatory mechanism in these processes. These results have provided valuable resources and new clues to the studies on S nitrosylation-regulated signaling in plants. PMID- 25699592 TI - Congenital Meso-Rex Bypass: A Rare and Remarkable Anatomical Variation of the Portal System. PMID- 25699591 TI - FYVE1 is essential for vacuole biogenesis and intracellular trafficking in Arabidopsis. AB - The plant vacuole is a central organelle that is involved in various biological processes throughout the plant life cycle. Elucidating the mechanism of vacuole biogenesis and maintenance is thus the basis for our understanding of these processes. Proper formation of the vacuole has been shown to depend on the intracellular membrane trafficking pathway. Although several mutants with altered vacuole morphology have been characterized in the past, the molecular basis for plant vacuole biogenesis has yet to be fully elucidated. With the aim to identify key factors that are essential for vacuole biogenesis, we performed a forward genetics screen in Arabidopsis (Arabidopsis thaliana) and isolated mutants with altered vacuole morphology. The vacuolar fusion defective1 (vfd1) mutant shows seedling lethality and defects in central vacuole formation. VFD1 encodes a Fab1, YOTB, Vac1, and EEA1 (FYVE) domain-containing protein, FYVE1, that has been implicated in intracellular trafficking. FYVE1 localizes on late endosomes and interacts with Src homology-3 domain-containing proteins. Mutants of FYVE1 are defective in ubiquitin-mediated protein degradation, vacuolar transport, and autophagy. Altogether, our results show that FYVE1 is essential for plant growth and development and place FYVE1 as a key regulator of intracellular trafficking and vacuole biogenesis. PMID- 25699593 TI - Efficacy of Dietary Treatment for Inducing Disease Remission in Eosinophilic Gastroenteritis. AB - OBJECTIVES: Various dietary interventions have been used to treat patients with eosinophilic gastroenteritis (EGE). Concrete evidence as to the effectiveness of such treatments in inducing disease remission is, however, lacking. The aim of the study was to systematically review the efficacy of dietary therapies in inducing EGE remission. METHODS: We performed a systematic search for the MEDLINE, EMBASE, and SCOPUS libraries for studies investigating the efficacy of dietary interventions (in both histological and symptomatic remission) for children and adults with EGE and colitis. RESULTS: The search yielded 490 references; 30 were included in the review, with most of these references being "low-quality" individual cases or short case series. No significant publication bias was found. Elemental diets in children were linked to 75.8% of clinical improvement, but few of these patients underwent a histological evaluation. Allergy-testing results have been used scarcely in EGE. Empiric elimination of allergy-associated foods was the most commonly used option. The variable results in terms of symptom relief, however, were scarcely accompanied by histological confirmation. Clinical and methodological heterogeneity hindered the performance of quantitative summaries for the efficacy of dietary therapies in inducing disease remission. CONCLUSIONS: Symptomatic improvements reported for dietary treatment in EGE by most of the available literature are questionable because of the lack of objective evaluation of clinical changes and the very limited assessment of histological remission. Because of the relative lack of well designed, high-quality studies, the unequivocal use of dietary treatment for patients with EGE and colitis cannot be supported. Further research should be undertaken. PMID- 25699594 TI - Neferine attenuates the protein level and toxicity of mutant huntingtin in PC-12 cells via induction of autophagy. AB - Mutant huntingtin aggregation is highly associated with the pathogenesis of Huntington's disease, an adult-onset autosomal dominant disorder, which leads to a loss of motor control and decline in cognitive function. Recent literature has revealed the protective role of autophagy in neurodegenerative diseases through degradation of mutant toxic proteins, including huntingtin or a-synuclein. Through the GFP-LC3 autophagy detection platform, we have identified neferine, isolated from the lotus seed embryo of Nelumbo nucifera, which is able to induce autophagy through an AMPK-mTOR-dependent pathway. Furthermore, by overexpressing huntingtin with 74 CAG repeats (EGFP-HTT 74) in PC-12 cells, neferine reduces both the protein level and toxicity of mutant huntingtin through an autophagy-related gene 7 (Atg7)-dependent mechanism. With the variety of novel active compounds present in medicinal herbs, our current study suggests the possible protective mechanism of an autophagy inducer isolated from Chinese herbal medicine, which is crucial for its further development into a potential therapeutic agent for neurodegenerative disorders in the future. PMID- 25699595 TI - Effect of diterpenes isolated of the marine alga Canistrocarpus cervicornis against some toxic effects of the venom of the bothrops jararaca snake. AB - Snake venoms are composed of a complex mixture of active proteins and peptides which induce a wide range of toxic effects. Envenomation by Bothrops jararaca venom results in hemorrhage, edema, pain, tissue necrosis and hemolysis. In this work, the effect of a mixture of two secodolastane diterpenes (linearol/isolinearol), previously isolated from the Brazilian marine brown alga, Canistrocarpus cervicornis, was evaluated against some of the toxic effects induced by B. jararaca venom. The mixture of diterpenes was dissolved in dimethylsulfoxide and incubated with venom for 30 min at room temperature, and then several in vivo (hemorrhage, edema and lethality) and in vitro (hemolysis, plasma clotting and proteolysis) assays were performed. The diterpenes inhibited hemolysis, proteolysis and hemorrhage, but failed to inhibit clotting and edema induced by B. jararaca venom. Moreover, diterpenes partially protected mice from lethality caused by B. jararaca venom. The search for natural inhibitors of B. jararaca venom in C. cervicornis algae is a relevant subject, since seaweeds are a rich and powerful source of active molecules which are as yet but poorly explored. Our results suggest that these diterpenes have the potential to be used against Bothropic envenomation accidents or to improve traditional treatments for snake bites. PMID- 25699596 TI - The annual winter surge - why are we so surprised? PMID- 25699597 TI - Red cell discards in a large UK emergency department. PMID- 25699598 TI - A new simple bilateral eye irrigation technique. PMID- 25699599 TI - Lung ultrasound in prehospital acute cardiac pulmonary edema: a new practical tool for CPAP assessment? PMID- 25699600 TI - Psychiatric evaluation of the face transplant candidate. AB - PURPOSE OF REVIEW: There have now been a total of 32 face transplants done in the world since the first in Amien, France, in 2005. This procedure is moving from being considered experimental to being considered an accepted option for reconstruction in cases of severe facial disfigurement. RECENT FINDINGS: There have been three published reports of prospective quantitative assessments of facial transplant candidates related to psychological outcomes with face transplant recipients. Various instruments have been used in assessment, including the Beck Depression Inventory, Patient Health Questionnaire-9 (PHQ-9), and Center for Epidemiologic Studies Depression Scale for rating depressive symptoms. Quality-of-life instruments used have included the Short Form-12, the Short Form-36, the Euro-QOL-5D (EQ-5D), the WHO Quality of Life rating scale (WHO BREF), and the Psychosocial Adjustment to Illness Scale-Self-Report. SUMMARY: There have been three deaths in the first 32 cases of facial transplantation (9.4%), two cases of post-transplant lymphoproliferative disorder in the first 20 face transplant recipients (10%). This rate of post-transplant lymphoproliferative disorder is about 10 times the rate seen in solid-organ transplant recipients. Collaborative assessment protocols are needed to determine whether the improvement in quality of life with facial transplantation is justified in the face of the risk of lifelong immunosuppression. PMID- 25699601 TI - Generation and use of renal cells for replacement therapies. PMID- 25699602 TI - Phosphomimics destabilize Hsp27 oligomeric assemblies and enhance chaperone activity. AB - Serine phosphorylation of the mammalian small heat-shock protein Hsp27 at residues 15, 78, and 82 is thought to regulate its structure and chaperone function; however, the site-specific impact has not been established. We used mass spectrometry to assess the combinatorial effect of mutations that mimic phosphorylation upon the oligomeric state of Hsp27. Comprehensive dimerization yielded a relatively uncrowded spectrum, composed solely of even-sized oligomers. Modification at one or two serines decreased the average oligomeric size, while the triple mutant was predominantly a dimer. These changes were reflected in a greater propensity for oligomers to dissociate upon increased modification. The ability of Hsp27 to prevent amorphous or fibrillar aggregation of target proteins was enhanced and correlated with the amount of dissociated species present. We propose that, in vivo, phosphorylation promotes oligomer dissociation, thereby enhancing chaperone activity. Our data support a model in which dimers are the chaperone-active component of Hsp27. PMID- 25699603 TI - D-enantiomeric peptides that eradicate wild-type and multidrug-resistant biofilms and protect against lethal Pseudomonas aeruginosa infections. AB - In many infections, bacteria form surface-associated communities known as biofilms that are substantially more resistant to antibiotics than their planktonic counterparts. Based on the design features of active antibiofilm peptides, we made a series of related 12-amino acid L-, D- and retro-inverso derivatives. Specific D-enantiomeric peptides were the most potent at inhibiting biofilm development and eradicating preformed biofilms of seven species of wild type and multiply antibiotic-resistant Gram-negative pathogens. Moreover, these peptides showed strong synergy with conventional antibiotics, reducing the antibiotic concentrations required for complete biofilm inhibition by up to 64 fold. As shown previously for 1018, these D-amino acid peptides targeted the intracellular stringent response signal (p)ppGpp. The most potent peptides DJK-5 and DJK-6 protected invertebrates from lethal Pseudomonas aeruginosa infections and were considerably more active than a previously described L-amino acid peptide 1018. Thus, the protease-resistant peptides produced here were more effective both in vitro and in vivo. PMID- 25699605 TI - A standardized treatment regimen for patients with severe haemophilia A undergoing orthopaedic or trauma surgery: a single centre experience. AB - Recommendations on the administration of clotting factor concentrates in patients with severe haemophilia undergoing surgery are usually determined by monitoring target clotting factor levels. In this retrospective cohort study, we enrolled patients with severe haemophilia A who underwent major orthopaedic or trauma surgery. We wanted to evaluate the feasibility and the safety of a standardized medical treatment procedure. Further on, we wanted to assess whether our standardized treatment regimen enables surgical procedures in certain situations in which measuring clotting factor VIII (FVIII) activity is not available. We created a standardized medical treatment procedure that included a medical protocol and close cooperation with the Haemophilic Treatment Centre. Thirteen surgical procedures in nine patients were examined. The feasibility and safety of this standardized treatment concept were assessed by identifying perioperative complications and by means of a questionnaire. Depending on the surgery, the amount of FVIII administered within the first 10 days ranged between 653 and 1027 units/kg body weight. No allogeneic blood transfusion was required. The measurement of FVIII activity was performed repeatedly in five patients. In all patients activated partial thromboplastin time monitoring was performed during the hospital stays. The surgeons and patients were satisfied with our treatment concept and adhered to the medical regimen protocol. By means of a detailed, standardized medical protocol and by ensuring close cooperation between the patient, the surgeons and the Haemophilic Treatment Centre, we could show that elective and emergency operations can be safely performed even in situations in which FVIII activity could not be monitored. PMID- 25699604 TI - Identification of histone deacetylase inhibitors with benzoylhydrazide scaffold that selectively inhibit class I histone deacetylases. AB - Inhibitors of histone deacetylases (HDACi) hold considerable therapeutic promise as clinical anticancer therapies. However, currently known HDACi exhibit limited isoform specificity, off-target activity, and undesirable pharmaceutical properties. Thus, HDACi with new chemotypes are needed to overcome these limitations. Here, we identify a class of HDACi with a previously undescribed benzoylhydrazide scaffold that is selective for the class I HDACs. These compounds are competitive inhibitors with a fast-on/slow-off HDAC-binding mechanism. We show that the lead compound, UF010, inhibits cancer cell proliferation via class I HDAC inhibition. This causes global changes in protein acetylation and gene expression, resulting in activation of tumor suppressor pathways and concurrent inhibition of several oncogenic pathways. The isotype selectivity coupled with interesting biological activities in suppressing tumor cell proliferation support further preclinical development of the UF010 class of compounds for potential therapeutic applications. PMID- 25699606 TI - Pulmonary embolism as the initial clinical presentation of Kimura disease: case report and literature review. AB - Pulmonary embolism is clinically critical in that if misdiagnosed or delayed, the mortality is very high. The recognition of its risk factor or underlying disease is important for prevention of recurrence. Kimura disease is a rare, chronic inflammatory disease, which is seldom associated with thrombosis. We reported a 47-year-old male case presenting with pleural pain and dyspnoea and was found to have pulmonary embolism. After successful management of pulmonary embolism, he was noticed to have eosinophilia and lymphadenopathy. Pathologic examination of a resected lymph node has confirmed the diagnosis of Kimura disease. The patient was treated with corticosteroid and cyclosporine A, with a significant improvement of the symptoms and signs of Kimura disease and no recurrence of any thromboembolism. Associated literatures were reviewed to explore the pathogenesis underlying the thrombotic event in Kimura disease cases. It is suggested that hypereosinophilia may play a key role in thrombosis formation. The control of hypereosinophilia may contribute to the prevention of thrombosis and its recurrence in patients with Kimura disease. PMID- 25699607 TI - Endothelial nitric oxide synthase gene intron 4 variable number tandem repeat polymorphism in beta-thalassemia major: relation to cardiovascular complications. AB - Endothelial nitric oxide synthase (eNOS), an enzyme that generates nitric oxide, is a major determinant of endothelial function. Several eNOS gene polymorphisms have been reported as 'susceptibility genes' in various human diseases states, including cardiovascular, pulmonary and renal diseases. We studied the 27-base pair tandem repeat polymorphism in intron 4 of eNOS gene in 60 beta-thalassemia major (beta-TM) patients compared with 60 healthy controls and assessed its role in subclinical atherosclerosis and vascular complications. Patients were evaluated stressing on transfusion history, splenectomy, thrombotic events, echocardiography and carotid intima-media thickness (CIMT). Analysis of eNOS intron 4 gene polymorphism was performed by PCR. No significant difference was found between beta-TM patients and controls with regard to the distribution of eNOS4 alleles or genotypes. The frequency of eNOS4a allele (aa and ab genotypes) was significantly higher in beta-TM patients with pulmonary hypertension or cardiomyopathy. Logistic regression analysis revealed that eNOS4a allele was an independent risk factor for pulmonary hypertension in beta-TM patients [odds ratio (OR) 2.2, 95% confidence interval (95% CI) 1.19-5.6; P < 0.001]. We suggest that eNOS intron 4 gene polymorphism is related to endothelial dysfunction and subclinical atherosclerosis and could be a possible genetic marker for prediction of increased susceptibility to cardiovascular complications. PMID- 25699608 TI - Treatable high homocysteine alone or in concert with five other thrombophilias in 1014 patients with thrombotic events. AB - In 1014 patients with thrombotic events, we determined how often treatable high serum homocysteine alone, or in concert with five other thrombophilias, was associated with thrombotic events. We studied 1014 outpatients sequentially referred for evaluation of thrombotic events, all having six measures of thrombophilia--three PCR (methylenetetrahydrofolate reductase C677T-A1298C, factor V Leiden G506A, prothrombin G20210A), and three serologic (factors VIII, XI, homocysteine). Of the 1014 patients, 198 (20%) had atherothrombosis, 199 (20%) ocular vascular thrombosis, 211 (21%) osteonecrosis, 180 (18%) pseudotumor cerebri, and 123 (12%) recurrent miscarriage. In 434 of 1014 (43%) patients, all six thrombophilic measures were normal. High homocysteine, present in 126 of 1014 patients (12.4%), was the sole thrombophilia in 50 (5%), accompanied only by methylenetetrahydrofolate reductase homozygosity-compound heterozygosity in 22 (2.2%), and accompanied by other thrombophilias in 54 (5%). Patients were more likely than 110 healthy controls to have high homocysteine (12 vs. 5%; P = 0.02) and high factor VIII (21 vs. 7%; P = 0.0003). On treatment for a median of 18 months with L-methyl folate (5 mg), vitamin B6 (100 mg), and vitamin B12 (2 mg/day), in 74 homocysteinemic patients, median homocysteine fell from 15.6 to 10.0 MUmol/l (P < 0.0001), and in 56 (76%), homocysteine fell to normal on treatment. When homocysteinemia was the sole thrombophilia, normalization of homocysteine was accompanied by freedom from new thrombotic events in 38 of 41 patients (93%). In evaluation of 1014 patients with thrombotic events, 126 (12%) had treatable high serum homocysteine, and in 50 (5%), high homocysteine was the sole treatable thrombophilia. PMID- 25699609 TI - Adherence to guidelines for perioperative management of anticoagulation results in decreased bleeding complications: a single-centre experience. AB - Guidelines describing the perioperative management of antithrombotic therapy in patients requiring temporary interruption of vitamin K antagonists (VKAs) were first published in 2008. The objective of this study is to evaluate the perioperative management of anticoagulation of patients on chronic VKA and the incidence of bleeding and thrombotic complications pre and postpublication of the 2008 American College of Chest Physicians (ACCP) guidelines. A retrospective review of 40 patients on chronic VKA requiring temporary discontinuation of VKA due to an invasive or surgical procedure who were referred to a single haematology practice from January 2006 to June 2010. Demographics, indications of VKA, risk factors for thrombosis, type of procedure, bridging regimen and bleeding complications were recorded pre and post-2008 ACCP guidelines. Sixty-one procedures were performed in 40 patients; 60% were women. Indications for anticoagulation were secondary prevention of venous thrombosis (n = 27), arterial thrombosis (n = 8) or both arterial thrombosis and venous thrombosis (n = 4), and primary prevention of arterial thrombosis (n = 1). Twenty patients (50%) had thrombophilia. The most common surgical and invasive procedures were gastrointestinal (33%), gynaecological (15%) and orthopaedic (11%). Bridging regimen with therapeutic-dose subcutaneous low molecular heparin (LMWH) was used in 27 (67.5%) patients, prophylactic-dose LMWH in 12 (30%) and a combination of LMWH therapeutic and prophylactic-dose doses in 11 (27.5%). Three bleeding complications occurred prepublication of the 2008 ACCP practice guidelines, although no bleeding complications occurred after the guidelines were published. Adherence to the 2008 ACCP guidelines for the perioperative management of anticoagulation reduced bleeding complications in patients on chronic VKA treatment. PMID- 25699610 TI - Polymorphisms in prothrombotic genes in young stroke patients in Greece: a case controlled study. AB - Mechanisms of ischemic stroke in young adults are poorly understood. The aim of the study was to investigate and compare the frequency of common variations in prothrombotic genes between young patients with ischemic stroke and controls. Fifty-one cases of first-ever ischemic stroke and 70 community-based controls aged below 50 years were studied. In both groups, the insertion/deletion 4G/5G variation (-675 4G/5G PAI-1) as well as the single-nucleotide polymorphism-844 G/A of the PAI-1 (-844 G/A PAI-1) gene promoter, factor V Leiden (FVL) G1691Alpha, the prothrombin variant (allele 20210A, FIIG20210A), factor XIII-A Val34Leu polymorphism (FXIII-AVal34Leu) and C677T methylenotetrahydrofolate reductase (C677T MTHFR) polymorphism have been assessed. The -675 4G/5G PAI-1 allele distribution differed significantly between patients and controls (P = 0.020), but no difference was found regarding the distribution of -844 G/A PAI-1 (P = 0.493), FVL (P = 0.199), FIIG20210A (P = 0.410), FXIII-AVal34leu (P = 0.160) and C677T MTHFR (P = 0.788). A lower frequency of 5G/5G genotype and a higher frequency of the 4G/5G genotype of the PAI -675 4G/5G polymorphism was found in young ischemic stroke patients compared to healthy controls. Further epidemiological studies are needed to investigate the differences between different geographic areas, and prospective cohort studies are needed to investigate the possible protective role of 5G/5G polymorphism. PMID- 25699611 TI - Impact of CYP2C9 and VKORC1 genetic polymorphisms upon warfarin dose requirements in Egyptian patients with acute coronary syndrome. AB - Warfarin is the most widely prescribed anticoagulant drugs. Cytochrome P450-2C9 (CYP2C9) and vitamin K epoxide reductase-oxidaxe complex subunit 1 (VKORC1) contribute significantly to the variability of warfarin dose requirements among patients. We investigated the impact of CYP2C9 and VKORC1 polymorphisms on the variability of warfarin dosage requirements in Egyptian patients with acute coronary syndrome and their association with other nongenetic factors. Eighty participants with acute coronary syndrome were enrolled in this cross-sectional study. Associations between CYP2C9 and VKORC1 gene variants together with daily warfarin dose, demographic data, clinical status of patients and time to target international normalized ratio were assessed. Mean warfarin dose among patients with wild-type CYP2C91/1 genotype was significantly higher than heterozygous CYP2C91/2 and CYP2C91/3 variants (P <= 0.001). Patients with wild VKORC1 (G/G) genotype were treated with significantly higher daily warfarin dosages than homozygous (A/A) and heterozygous (G/A) genotypes. Patients carrying VKORC1 (G/G) genotype in combination with the CYP2C91/1 type alleles had the highest daily warfarin dosage, whereas the lowest daily warfarin dosage to achieve the required clinical effect was found among patients having CYP2C91/2 and CYP2C91/3 genotypes combined with VKORC1 (A/A) genotype (P <= 0.001). Regression analysis revealed that age, height, CYP2C9 and VKORC1 genotypes were significantly associated with warfarin dose. Genetic polymorphisms in VKORC1, CYP2C9 along with age and height are determinants of warfarin dose requirements in Egyptian population acute coronary syndrome. Higher warfarin loading dose is required for both wild CYP2C9 and VKORC1 gene variants which may contribute to warfarin-resistant cases. PMID- 25699612 TI - Laboratory assessment of warfarin reversal with global coagulation tests versus international normalized ratio in patients with intracranial bleeding. AB - We assess the in-vivo relationship between international normalized ratio (INR) and global coagulation tests in patients with life-threatening bleeding who received prothrombin complex concentrate (PCC) for warfarin reversal. This was a prospective pilot study in adult patients with intracranial bleeding related to anticoagulation with warfarin. Thromboelastography (TEG), thrombin generation parameters and INR were assessed at baseline, 30 min, 2 and 24 h after PCC. Changes in laboratory parameters and relationship between INR and global coagulation tests were assessed over time. Eight patients mean [standard deviation (SD)] age 72 (16) were included and received mean (SD) dose of PCC 24 (5) units/kg. Four patients died during the study, all with INR values more than 1.5 thirty minutes after PCC. Mean (SD) INR was 3.0 (1.3) and decreased significantly to 1.8 (0.48) thirty minutes after PCC (P < 0.01). Baseline endogenous thrombin potential and thrombin peak were 890 nmol/min and 123 nmol and increased significantly to 1943 nmol/min (P < 0.01) and 301 nmol (P < 0.01) 30 min after PCC administration. Reaction (R)-time decreased significantly (P = 0.02), and maximum amplitude and overall coagulation index (CI) significantly increased during treatment (P < 0.01, respectively). Thrombin generation and TEG values corrected after PCC administration; however, INR did not fully correct. Patients that died tended to be older with prolonged INR values across the study period. INR and TEG values correlated well with thrombin generation before administration of PCC, but this relationship was lost afterward. PMID- 25699613 TI - An Unexpected Intraorbital Foreign Body. PMID- 25699614 TI - Orbital Injury From Needlefish Impalement. PMID- 25699615 TI - Vision-Threatening Massive Orbital Emphysema After Infero-Medial Orbital Decompression Associated With Sneezing. PMID- 25699616 TI - Multicomponent smoking cessation treatment including mobile contingency management in homeless veterans. AB - INTRODUCTION: Smoking rates are 80% among persons who are homeless, and these smokers have decreased odds of quitting smoking. Little is known about relapse rates among homeless smokers. More information is needed regarding both quit rates and innovative methods to treat smoking cessation among homeless smokers. Web-based contingency management (CM) approaches have been found helpful in reducing smoking among other difficult-to-treat smoker populations but have been generally limited by the need for computers or frequent clinic-based carbon monoxide (CO) monitoring. This open pilot study builds on a web-based CM approach by evaluating a smartphone-based application for CM named mobile CM (mCM). The study was conducted from January 1, 2013-April 15, 2014. METHOD: Following a 1 week training period, 20 homeless veteran smokers (>= 10 cigarettes daily for 1 year or more and a CO baseline level >= 10 ppm) participated in a multicomponent smoking cessation intervention including 4 weeks of mCM. All smokers received 4 smoking cessation counseling sessions, nicotine replacement, and bupropion (if medically eligible). Participants could earn up to $815 ($480 for mCM, $100 for CO readings showing abstinence [ie, 6 ppm or less] at posttreatment and follow up, and $35 for equipment return). RESULTS: Mean compensation for the mCM component was $286 of a possible $480. Video transmission compliance was high during the 1-week training (97%) and the 4-week treatment period (87%). Bioverified 7-day point prevalence abstinence was 50% at 4 weeks. Follow-up bioverified single assessment point prevalence abstinence was 55% at 3 months and 45% at 6 months. CONCLUSIONS: Results of this open pilot study suggest that mCM may be a useful adjunctive smoking cessation treatment component for reducing smoking among homeless veterans. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01789710. PMID- 25699617 TI - An Overview of Acquired Brain Injury Rehabilitation Randomized Controlled Trials. AB - OBJECTIVE: To summarize randomized controlled trials published in the acquired brain injury rehabilitation literature. SETTING: N/A. PARTICIPANTS: N/A. DESIGN: Systematic literature review. MAIN MEASURES: A total of 143 published randomized controlled trials in acquired brain injury rehabilitation literature from January 1980 to October 2012. Measures were area of research, number of studies, sample size, methodological quality, and country of origin. RESULTS: There were no significant differences in median sample sizes (P = .212; 95% confidence interval [CI], 0.199-0.215) or PEDro scores (P = .492; 95% CI, .491-.510) between 4 research areas in acquired brain injury: sensory-motor, cognitive-communication, medical complications, and psychosocial. Between 1980 and 2012, there was no significant difference in median sample sizes (P = .202; 95% CI, 0.198-0.214). Median PEDro scores did not significantly improve between 1983-1987 (median = 4, interquartile range = 4.5) and 2008-2012 (median = 6, interquartile range = 2; P = .100; 95% CI, 0.093-0.105). CONCLUSIONS: This study demonstrates the need for more randomized controlled trials, increased sample sizes, and improved methodological quality to better guide clinical practice for acquired brain injury rehabilitation. PMID- 25699618 TI - Three Scoring Approaches to the Neurobehavioral Symptom Inventory for Measuring Clinical Change in Service Members Receiving Intensive Treatment for Combat Related mTBI. AB - OBJECTIVE: To examine the use of the Neurobehavioral Symptom Inventory to measure clinical changes over time in a population of US service members undergoing treatment of mild traumatic brain injury and comorbid psychological health conditions. SETTING: A 4-week, 8-hour per day, intensive, outpatient, interdisciplinary, comprehensive treatment program at the National Intrepid Center of Excellence in Bethesda, Maryland. PARTICIPANTS: Three hundred fourteen active-duty service members being treated for combat-related comorbid mild traumatic brain injury and psychological health conditions. DESIGN: Repeated measures, retrospective analysis of a single-group using a pretest-posttest treatment design. MAIN MEASURES: Three Neurobehavioral Symptom Inventory scoring methods: (1) a total summated score, (2) the 3-factor method, and (3) the 4 factor method (with and without orphan items). RESULTS: All 3 scoring methods yielded statistically significant within-subject changes between admission and discharge. The evaluation of effect sizes indicated that the 3 different Neurobehavioral Symptom Inventory scoring methods were comparable. CONCLUSION: Findings indicate that the different scoring methods all have potential for assessing clinical changes in symptoms for groups of patients undergoing treatment, with no clear advantage with any one method. PMID- 25699619 TI - Trajectories of Life Satisfaction Over the First 10 Years After Traumatic Brain Injury: Race, Gender, and Functional Ability. AB - OBJECTIVE: This study investigated the influence of race, gender, functional ability, and an array of preinjury, injury-related, and sociodemographic variables on life satisfaction trajectories over 10 years following moderate to severe traumatic brain injury (TBI). SETTING/PARTICIPANTS: A sample of 3157 individuals with TBI from the TBI Model Systems database was included in this study. DESIGN: Hierarchical linear modeling (HLM) analyses were conducted to examine the trajectories of life satisfaction. MAIN MEASURES: The Functional Independence Measure, Glasgow Coma Scale, and the Satisfaction With Life Scale were utilized. RESULTS: Initial models suggested that life satisfaction trajectories increased over the 10-year period and Asian/Pacific Islander participants experienced an increase in life satisfaction over time. In a comprehensive model, time was no longer a significant predictor of increased life satisfaction. Black race, however, was associated with lower life satisfaction, and significant interactions revealed that black participants' life satisfaction trajectory decreased over time while white participants' trajectory increased over the same time period. Life satisfaction trajectories did not significantly differ by gender, and greater motor and cognitive functioning were associated with increasingly positive life satisfaction trajectories over the 10 years. CONCLUSION: Individuals with more functional impairments are at risk for decreases in life satisfaction over time. Further research is needed to identify the mechanisms and factors that contribute to the lower levels of life satisfaction observed among black individuals post-TBI. This work is needed to determine strategic ways to promote optimal adjustment for these individuals. PMID- 25699620 TI - A Profile of Patients With Traumatic Brain Injury Within Home Care, Long-Term Care, Complex Continuing Care, and Institutional Mental Health Settings in a Publicly Insured Population. AB - OBJECTIVE: To describe the sociodemographic and clinical profile of people with traumatic brain injury (TBI) in home care, nursing homes, and complex continuing care settings in a national sample. METHODS: Cross-sectional study using available Resident Assessment Instrument (RAI 2.0 and RAI Home Care [HC]) national databases in Canada from 1996 to 2011. The profile of people with TBI was compared with patients with and without prespecified neurological conditions within each setting. PARTICIPANTS: Adults 18 years and older identified with TBI (n = 10 878) and adult patients with other neurological (n = 422 300) and non neurological (n = 571 567) conditions. MAIN MEASURES: Demographic and clinical characteristics, functional characteristics, mood and behavior, and treatment and medication variables. Data from Canadian home care (RAI-HC), mental health (RAI MH), nursing home, and complex continuing care facilities (RAI Minimum Data Set 2.0). RESULTS: Patients with TBI were significantly different on almost all items. They were among the youngest in care settings, and psychotropic drug use by this population was among the highest in at least 2 settings. CONCLUSION: These data can inform the planning for appropriate care and resources for patients with TBI in a range of settings. PMID- 25699621 TI - Awareness Deficits in Children and Adolescents After Traumatic Brain Injury: A Systematic Review. AB - OBJECTIVES: To systematically review empirical research on awareness deficits in children and adolescents following traumatic brain injury (TBI). METHODS: PsycINFO, MEDLINE, Cochrane Library, CINAHL (Cumulative Index to Nursing and Allied Health Literature), ERIC (Education Resources Information Centre), PsycBITE, and Web of Science were searched from inception to August 8, 2013, using key terms relating to awareness of deficits and brain injury in childhood/adolescence. Studies of children or adolescents with traumatic brain injury (TBI), systematic measurement of awareness of deficits, and reporting of quantitative data were included. Details of participants, methodology, and findings were summarized for each study, and methodological quality was rated. RESULTS: Review of 12 eligible studies yielded mixed evidence concerning the presence of awareness deficits after childhood TBI. Awareness deficits were most evident both for memory and executive function impairments and for children and adolescents with severe TBI. Methodological variability, including sampling characteristics, objects of awareness, measurement issues, and approach to statistical analysis, contributed to the mixed findings. CONCLUSIONS: Further research focusing on factors contributing to awareness deficits following pediatric TBI, the course of recovery, and relation to functional outcomes is warranted. PMID- 25699622 TI - Do Children and Adolescents With Mild Traumatic Brain Injury and Persistent Symptoms Benefit From Treatment? A Systematic Review. AB - OBJECTIVE: To review the literature on treatment interventions in children and adolescents with mild traumatic brain injury (mTBI) and persistent symptoms. DESIGN: Systematic review of the literature yielding 6 studies incorporating 421 children and adolescents with mTBI. RESULTS: A variety of medical and nonmedical interventions have been used to treat the persistent symptoms of mTBI in children and adolescents. Treatment included medications for headaches, transcranial stimulation for headaches, giving information booklets, nurse visits, cognitive and physical rest, and active rehabilitation (exercise). All 6 studies reported positive results; but none was a randomized controlled trial, only 1 included a no-treatment comparison group, and none compared different interventions. CONCLUSION: It is difficult to determine whether the positive findings resulted from intervention or reflected natural resolution of the symptoms with time. There is a need for more, higher-quality studies of interventions designed to reduce the duration and severity of persistent postconcussion symptoms. PMID- 25699623 TI - Prospective Associations Between Traumatic Brain Injury and Postdeployment Tinnitus in Active-Duty Marines. AB - OBJECTIVE: To examine whether cause, severity, and frequency of traumatic brain injury (TBI) increase risk of postdeployment tinnitus when accounting for comorbid posttraumatic stress disorder. DESIGN: Self-report and clinical assessments were done before and after an "index" deployment to Iraq or Afghanistan. SETTING, PARTICIPANTS, AND MEASURES: Assessments took place on Marine Corps bases in southern California and the VA San Diego Medical Center. Participants were 1647 active-duty enlisted Marine and Navy servicemen who completed pre- and postdeployment assessments of the Marine Resiliency Study. The main outcome was the presence of tinnitus at 3 months postdeployment. RESULTS: Predeployment TBI increased the likelihood of new-onset postdeployment tinnitus (odds ratio [OR] = 1.86; 95% confidence interval [CI], 1.28-2.70). Deployment related TBIs increased the likelihood of postdeployment tinnitus (OR = 2.65; 95% CI, 1.19-5.89). Likelihood of new-onset postdeployment tinnitus was highest for those who were blast-exposed (OR = 2.93; 95% CI, 1.82-6.17), who reported moderate-severe TBI symptoms (OR = 2.22; 95% CI, 1.22-3.40), and who sustained multiple TBIs across study visits (OR = 2.27; 95% CI, 1.44-4.24). Posttraumatic stress disorder had no effect on tinnitus outcome. CONCLUSIONS: Participants who were blast-exposed, sustained multiple TBIs, and reported moderate-severe TBI symptoms were most at risk for new-onset tinnitus. PMID- 25699624 TI - Self- and Informant Ratings of Executive Functioning After Mild Traumatic Brain Injury. AB - OBJECTIVE: To determine correlates of self- and informant reports on a standardized rating of executive functioning in persons with mild traumatic brain injury. SETTING: Outpatient clinic at a rehabilitation hospital. PARTICIPANTS: One hundred referred persons who met criteria for mild traumatic brain injury (ie, time to follow commands <30 minutes, posttraumatic amnesia <24 hours, and Glasgow Coma Scale score >12). DESIGN: Retrospective case series review. MAIN MEASURES: Participants and informants completed the Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) during outpatient neuropsychological evaluations within 30 to 360 days postinjury. RESULTS: Participant and informant BRIEF-A ratings were strongly correlated, but participants rated themselves as worse than informants did. Regression analysis revealed that higher levels of education and presence of intracranial neuroimaging findings were associated with better BRIEF-A ratings whereas worse BRIEF-A ratings were associated with longer time since injury and prior psychiatric treatment. BRIEF-A ratings were not correlated with laboratory measures of executive functioning. CONCLUSIONS: Subjective perceptions of executive dysfunction during the first year after mild TBI are driven primarily by premorbid factors and do not reflect acquired cerebral impairment. PMID- 25699625 TI - The Relation Between Injury of the Spinothalamocortical Tract and Central Pain in Chronic Patients With Mild Traumatic Brain Injury. AB - OBJECTIVES: Little is known about the pathogenetic etiology of central pain in patients with traumatic brain injury (TBI). We investigated the relation between injury of the spinothalamocortical tract (STT) and chronic central pain in patients with mild TBI. DESIGN: Retrospective survey. PARTICIPANTS: We recruited 40 consecutive chronic patients with mild TBI and 21 normal control subjects: 8 patients were excluded by the inclusion criteria and the remaining 32 patients were finally recruited. The patients were classified according to 2 groups based on the presence of central pain: the pain group (22 patients) and the nonpain group (10 patients). METHODS: Diffusion tensor tractography for the STT was performed using the Functional Magnetic Resonance Imaging of the Brain Software Library. Values of fractional anisotropy (FA), mean diffusivity (MD), and tract volume of each STT were measured. RESULTS: Lower FA value and tract volume were observed in the pain group than in the nonpain group and the control group (P < .05). By contrast, higher MD value was observed in the pain group than in the nonpain group and the control group (P < .05). However, no significant differences in all diffusion tensor imaging parameters were observed between the nonpain group and the control group (P > .05). CONCLUSIONS: Decreased FA and tract volume and increased MD of the STTs in the pain group appeared to indicate injury of the STT. As a result, we found that injury of the STT is related to the occurrence of central pain in patients with mild TBI. We believe that injury of the STT is a pathogenetic etiology of central pain following mild TBI. PMID- 25699626 TI - Polysomnographic Sleep Patterns in Children and Adolescents in Unresponsive Wakefulness Syndrome. AB - OBJECTIVES: We aimed (i) to search for qualitative sleep patterns for pediatric unresponsive wakefulness syndrome (SPPUWS) in prolonged polysomnographic (PSG) recordings in children and adolescents with subacute severe disorders of consciousness due to an acquired brain damage; (ii) to investigate the clinical relevance of SPPUWS and of possible neurophysiological markers (rapid eye movement sleep and sleep spindles) in PSG recordings of pediatric patients with unresponsive wakefulness syndrome (UWS). METHODS: We performed a PSG study in 27 children with UWS due to acquired brain damage in the subacute phase. Patients received a full neurological examination and a clinical assessment with standardized scales. In addition, outcome was assessed after 36 months. RESULTS: We identified 6 PSG patterns (SPPUWS) corresponding to increasing neuroelectrical complexity. The presence of an organized sleep pattern, as well as rapid eye movement sleep and sleep spindles, in the subacute stage appeared highly predictive of a more favorable outcome. Correlation was found between SPPUWS and recovery, as assessed by several clinical and rehabilitation scales. CONCLUSIONS: Polysomnography can be used as a prognostic tool, as it can help determine the capability to recover from a pediatric UWS and predict outcome well before the confirmation provided by suitable clinical scales. PMID- 25699627 TI - The Relationship of Health Locus of Control and Health-Related Quality of Life in the Chronic Phase After Traumatic Brain Injury. AB - OBJECTIVE: To study health locus of control (HLC) after moderate to severe traumatic brain injury (TBI) compared with norm values and in relation to health related quality of life (HR-QoL) over time. SETTING: Three level-1 trauma centers. PARTICIPANTS: Individuals with moderate to severe TBI (N = 85). DESIGN: Prospective cohort study. MAIN MEASURES: Multidimensional health locus of control scales including internal control (Internal-HLC), control attributed to physicians (Physician-HLC) or to chance (Chance-HLC) and sickness impact profile 68 including physical and psychosocial HR-QoL. RESULTS: One to 3 years after TBI, Internal-HLC, and Chance-HLC significantly declined, whereas Physician-HLC remained stable. Total and psychosocial HR-QoL did not change over time, but physical HR-QoL improved. Three years after TBI, Internal-HLC (P < .001), and Physician-HLC (P < .001) were significantly lower and Chance-HLC (P < .001) significantly higher than norm values. Chance-HLC was independently related to total (beta = .321, P < .001) and psychosocial HR-QoL (beta = .258, P < .001), adjusted for baseline characteristics, functional, and cognitive outcome. CONCLUSIONS: After TBI, HLC may change over time and may be different from healthy adults. The external Chance-HLC orientation has a negative relationship with HR-QoL. Future research focused on the effect of rehabilitation programs for improving the balance in internal and external locus of control is needed. PMID- 25699628 TI - Prescription opioid use and non-fatal overdose in a cohort of injection drug users. AB - BACKGROUND: There is growing concern regarding rising rates of prescription drug related deaths among the general North American population as well as increasing availability of illicitly obtained prescription opioids. Concurrently among people who inject drugs (IDU), illicit prescription opioid use has increased while non-fatal overdose remains a major source of morbidity. OBJECTIVES: To evaluate whether the use of prescription opioids was associated with non-fatal overdose among IDU in Vancouver, Canada. METHODS: Data was obtained from two open prospective cohorts of IDU between December 2005 and May 2013. We used generalized estimating equation (GEE) logistic regression to evaluate the association between prescription opioid use and non-fatal overdose, adjusting for various social, demographic, and behavioral factors. RESULTS: There were 1614 IDU, including 541 (33.5%) women, who were recruited and included in this analysis. At baseline, 526 (32.6%) reported using prescription opioids and 118 (7.3%) reported experiencing an overdose in the previous six months. In a multivariable analysis, prescription opioid use remained independently associated with non-fatal overdose (adjusted odds ratio: 1.61, 95% confidence interval: 1.32 1.95), after adjusting for confounders. CONCLUSION: We observed relatively high rates of prescription opioid use among IDU in this setting, and found an independent association between prescription opioid use and non-fatal overdose. Our data is likely representative of riskier substance use associated with those who use prescription opioids within our sample. Interventions to prevent and respond to overdoses should consider the higher risk profiles of IDU who use prescription opioids. PMID- 25699629 TI - Modified Protocol Decreases Surgical Site Infections after Total Knee Arthroplasty. AB - We investigate the effectiveness of a comprehensive aseptic protocol in reducing surgical site infection (SSI) after knee arthroplasty in a single medical center with a high prevalence of MRSA. A database of all patients in a single center undergoing primary knee arthroplasty between 2005 and 2011 was reviewed for SSI using Centers for Disease Control criteria and AAOS guidelines. All patients were treated with an aseptic protocol consisting of the following: preoperative 2% mupirocin nasal ointment and 0.4% chlorhexidine surgical site wipes, modified instrument care, perioperative prophylactic vancomycin and cefazolin, and surgical site skin preparation with chlorhexidine, alcohol, and iodophor. We compare our protocol total knee arthroplasty SSI rate to our institutional historical control (2001-2004) and to contemporary literature. Among 1,224 patients, 70% were ASA class >2 and 64% had a body mass index (BMI) > 30 kg/m(2). We found an overall 0.49% infection rate, significantly lower than that of our institutional historical control (0.49 vs. 2.24%, p < 0.001; odds ratio [OR], 0.21; number needed to treat [NNT], 145) and seven recently published reports (p < 0.001-0.042; OR, 0.07-0.42). Compared with these reports, significantly more of our patients were ASA class > 2, BMI > 30 kg/m(2), immunosuppressed, or had rheumatoid arthritis. Our aseptic protocol decreases SSI in a high-risk population undergoing knee arthroplasty in a medical center and community with a high prevalence of MRSA. PMID- 25699630 TI - Silver-catalyzed double-decarboxylative cross-coupling of alpha-keto acids with cinnamic acids in water: a strategy for the preparation of chalcones. AB - A silver-catalyzed double-decarboxylative protocol has been proposed for the construction of chalcone derivatives via cascade coupling of substituted alpha keto acids with cinnamic acids under the mild aqueous conditions. The developed method for constructing C-C bonds via double-decarboxylative reactions is efficient, practical, and environmentally benign by using the readily available starting materials. It should provide a promising synthesis candidate for the formation of diverse and useful chalcone derivatives in the fields of synthetic and pharmaceutical chemistry. PMID- 25699631 TI - A common late-stage intermediate in catalysis by 2-hydroxyethyl-phosphonate dioxygenase and methylphosphonate synthase. AB - 2-Hydroxyethylphosphonate dioxygenase (HEPD) and methylphosphonate synthase (MPnS) are nonheme iron oxygenases that both catalyze the carbon-carbon bond cleavage of 2-hydroxyethylphosphonate but generate different products. Substrate labeling experiments led to a mechanistic hypothesis in which the fate of a common intermediate determined product identity. We report here the generation of a bifunctional mutant of HEPD (E176H) that exhibits the activity of both HEPD and MPnS. The product distribution of the mutant is sensitive to a substrate isotope effect, consistent with an isotope-sensitive branching mechanism involving a common intermediate. The X-ray structure of the mutant was determined and suggested that the introduced histidine does not coordinate the active site metal, unlike the iron-binding glutamate it replaced. PMID- 25699633 TI - Ethylene glycol emissions from on-road vehicles. AB - Ethylene glycol (HOCH2CH2OH), used as engine coolant for most on-road vehicles, is an intermediate volatility organic compound (IVOC) with a high Henry's law coefficient. We present measurements of ethylene glycol (EG) vapor in the Caldecott Tunnel near San Francisco, using a proton transfer reaction mass spectrometer (PTR-MS). Ethylene glycol was detected at mass-to-charge ratio 45, usually interpreted as solely coming from acetaldehyde. EG concentrations in bore 1 of the Caldecott Tunnel, which has a 4% uphill grade, were characterized by infrequent (approximately once per day) events with concentrations exceeding 10 times the average concentration, likely from vehicles with malfunctioning engine coolant systems. Limited measurements in tunnels near Houston and Boston are not conclusive regarding the presence of EG in sampled air. Previous PTR-MS measurements in urban areas may have overestimated acetaldehyde concentrations at times due to this interference by ethylene glycol. Estimates of EG emission rates from the Caldecott Tunnel data are unrealistically high, suggesting that the Caldecott data are not representative of emissions on a national or global scale. EG emissions are potentially important because they can lead to the formation of secondary organic aerosol following oxidation in the atmospheric aqueous phase. PMID- 25699634 TI - Compensation effects in molecular interactions and the quantum chemical le Chatelier principle. AB - Components of molecular interactions and various changes in the components of total energy changes during molecular processes typically exhibit some degrees of compensation. This may be as prominent as the over 90% compensation of the electronic energy and nuclear repulsion energy components of the total energy in some conformational changes. Some of these compensations are enhanced by solvent effects. For various arrangements of ions in a solvent, however, not only compensation but also a formal, mutual enhancement between the electronic energy and nuclear repulsion energy components of the total energy may also occur, when the tools of nuclear charge variation are applied to establish quantum chemically rigorous energy inequalities. PMID- 25699635 TI - Enhanced preference for high-fat foods following a simulated night shift. AB - OBJECTIVES: Shift workers are prone to obesity and associated co-morbidities such as diabetes and cardiovascular disease. Sleep restriction associated with shift work results in dramatic endocrine and metabolic effects that predispose shift workers to these adverse health consequences. While sleep restriction has been associated with increased caloric intake, food preference may also play a key role in weight gain associated with shift work. This study examined the impact of an overnight simulated night shift on food preference. METHODS: Sixteen participants [mean 20.1, standard deviation (SD) 1.4 years; 8 women] underwent a simulated night shift and control condition in a counterbalanced order. On the following morning, participants were provided an opportunity for breakfast that included high- and low-fat food options (mean 64.8% and 6.4% fat, respectively). RESULTS: Participants ate significantly more high-fat breakfast items after the simulated night shift than after the control condition [167.3, standard error of the mean (SEM 28.7) g versus 211.4 (SEM 35.6) g; P=0.012]. The preference for high-fat food was apparent among the majority of individuals following the simulated night shift (81%), but not for the control condition (31%). Shift work and control conditions did not differ, however, in the total amount of food or calories consumed. CONCLUSIONS: A simulated night shift leads to preference for high-fat food during a subsequent breakfast opportunity. These results suggest that food choice may contribute to weight-related chronic health problems commonly seen among night shift workers. PMID- 25699636 TI - Impact of age-adjusted insulin-like growth factor 1 on major cardiovascular events after acute myocardial infarction: results from the fast-MI registry. AB - BACKGROUND: The GH/IGF-1 axis is being targeted for therapeutic development in diseases such as short stature, cancer, and metabolic disorders. The impact of IGF-1 in cardiovascular disease remains controversial. We therefore studied whether IGF-1 at admission for acute myocardial infarction (AMI) predicted death, recurrent AMI, and stroke over a 2-year follow-up. METHODS: Using data from the French registry of Acute ST-elevation and non-ST-elevation Myocardial Infarction registry, we measured IGF-1 among all the 1005 patients with AMI who participated in the serum data bank. Because IGF-1 decreases with age, a standardized IGF-1 score was calculated as previously described [IGF-1 score = (log [IGF-1 (micrograms per liter)] + 0.00625 * age - 2.555)/0.104]. Impact of IGF-1 score (continuous and quartiles) on outcomes were compared using Cox proportional hazards regression models. RESULTS: During follow-up, 190 patients died or had a recurrent AMI or stroke. Patients in the lowest quartile of IGF-1 were older and more frequently female and diabetic compared with patients in the other quartiles. After adjustment for known cardiovascular factors, an increase of five units of IGF-1 score was associated with a 30% decrease of the risk of events during follow-up (adjusted hazard ratio 0.70; 95% confidence interval 0.54-0.92; P = .0093). Similarly, the lowest quartile of IGF-1 was associated with an increased risk of events (adjusted hazard ratio 1.52, 95% confidence interval 1.11-2.08; compared with others quartiles, P = .010). CONCLUSIONS: Low IGF-1 score is associated with an increased risk of all-cause death, recurrent myocardial infarction, and stroke in AMI patients. Whether patients treated by IGF-1 axis inhibitors have a specific clinical course after AMI would be worth studying. PMID- 25699637 TI - 5'-C-Ethyl-tetrazolyl-N(6)-substituted adenosine and 2-chloro-adenosine derivatives as highly potent dual acting A1 adenosine receptor agonists and A3 adenosine receptor antagonists. AB - A series of N(6)-substituted-5'-C-(2-ethyl-2H-tetrazol-5-yl)-adenosine and 2 chloro-adenosine derivatives was synthesized as novel, highly potent dual acting hA1AR agonists and hA3AR antagonists, potentially useful in the treatment of glaucoma and other diseases. The best affinity and selectivity profiles were achieved by N(6)-substitution with a 2-fluoro-4-chloro-phenyl- or a methyl- group. Through an in silico receptor-driven approach, the molecular bases of the hA1- and hA3AR recognition and activation of this series of 5'-C-ethyl-tetrazolyl derivatives were explained. PMID- 25699638 TI - DiiodoBodipy-rhodamine dyads: preparation and study of the acid-activatable competing intersystem crossing and energy transfer processes. AB - Iodo-bodipy/rhodamine dyads with cyanuric chloride linker were prepared with the goal of achieving pH switching of the triplet excited state formation. The pH switching takes advantage of the acid-activated reversible cyclic lactam<->opened amide transformation of the rhodamine unit and the fluorescence resonance energy transfer (FRET). The photophysical properties of the dyads were studied with steady-state and femtosecond/nanosecond time-resolved transient absorption spectroscopies, electrochemical methods, as well as TD-DFT calculations. Our results show that the model dyad is an efficient triplet state generator under neutral condition, when the rhodamine unit adopts the closed form. The triplet generation occurs at the iodo-bodipy moiety and the triplet state is long-lived, with a lifetime of 51.7 MUs. In the presence of the acid, the rhodamine unit adopts an opened amide form, and in this case, the efficient FRET occurs from iodo-bodipy to the rhodamine moiety. The FRET is much faster (tauFRET = 81 ps) than the intersystem crossing of iodo-bodipy (tauISC = 178 ps), thus suppressing the triplet generation is assumed. However, we found that the additional energy transfer occurs at the longer timescale, which eventually converts the rhodamine based S1 state to the T1 state localized on the iodo-bodipy unit. PMID- 25699639 TI - Ambiphilic properties of SF5CF2CF2Br derived perfluorinated radical in addition reactions across carbon-carbon double bonds. AB - The extraordinary properties of the pentafluorosulfanyl (SF5) group attract attention of organic chemists. While numerous SF5-substituted compounds have been synthesized, the direct introduction of SF5(CF2)n moieties has remained almost unexplored. Our investigations revealed the ambiphilic character of the SF5CF2CF2 radical. Addition reactions to electron-rich or electron-deficient alkenes profit either from its electrophilic or nucleophilic properties. Thus, the readily available SF5CF2CF2Br proved to be a promising and versatile building block for the introduction of this perfluorinated moiety. PMID- 25699640 TI - Comparison of dietary supplement product knowledge and confidence between pharmacists and health food store employees. AB - OBJECTIVES: To determine pharmacists' and health food store employees' knowledge about the safety and efficacy of common, nonvitamin, nonmineral dietary supplements in a retail setting and confidence in discussing, recommending, and acquiring knowledge about complementary and alternative medicine (CAM). DESIGN: Cross-sectional survey. SETTING: Central and western New York in May and June 2012. MAIN OUTCOME MEASURES: Knowledge and confidence survey scores based on true/false and Likert scale responses. RESULTS: Pharmacists' mean knowledge score was significantly higher than that of health food store employees (8.42 vs. 6.15 items of 15 total knowledge questions). Adjusting for differences in experience, education, occupation, and confidence, knowledge scores were significantly higher for pharmacists and those with a higher total confidence score. Pharmacists were significantly less confident about the safety and efficacy of CAM comparatively (13 vs. 16 items of 20 total questions). CONCLUSION: Pharmacists scored significantly higher than health food store employees on a survey assessing knowledge of dietary supplements' safety and efficacy. Despite the significant difference, scores were unacceptably low for pharmacists, highlighting a knowledge deficit in subject matter. PMID- 25699641 TI - Trust-but verify-scientific findings. PMID- 25699642 TI - Adherent endotoxin on dental implant surfaces: a reappraisal. AB - Osteoimmunology is the crosstalk between cells from the immune and skeletal systems, suggesting a role of pro-inflammatory cytokines in the stimulation of osteoclast activity. Endotoxin or bacterial challenges to inflammatory cells are directly relevant to dental implant pathologies involving bone resorption, such as osseointegration failure and peri-implantitis. While the endotoxin amount on implant devices is regulated by standards, it is unknown whether commercially available dental implants elicit different levels of adherent-endotoxin stimulated cytokines. The objective of this work is to develop a model system and evaluate endotoxin-induced expression of pro-inflammatory cytokine genes relevant to osteoclast activation on commercially available dental implants. Murine J774 A1 macrophages were cultured on Ti disks with different level of lipopolysaccharide (LPS) contamination to define the time-course of the inflammatory response to endotoxin, as evaluated by reverse transcription polymerase chain reaction analysis. The developed protocol was then used to measure adherent endotoxin on commercially available packaged and sterile dental implants in the "as-implanted" condition. Results show that tested dental implants induce variable expression of endotoxin-stimulated genes, sometimes above the level expected to promote bone resorption in vivo. Results are unaffected by the specific surface treatment; rather, they likely reflect care in cleaning and packaging protocols. In conclusion, expression of genes that enhance osteoclast activity through endotoxin stimulation of inflammatory cells is widely different on commercially available dental implants. A reappraisal of the clinical impact of adherent endotoxins on dental (and bone) implant devices is required in light of increasing knowledge on crosstalk between cells from the immune and skeletal systems. PMID- 25699643 TI - Full mouth reconstruction with dental implants in the conservative treatment of bilateral condylar fractures: a clinical letter. PMID- 25699644 TI - A simple, custom-made osteotome for sinus floor elevation. PMID- 25699645 TI - Investigation of the photochemical changes of chlorogenic acids induced by ultraviolet light in model systems and in agricultural practice with Stevia rebaudiana cultivation as an example. AB - Mono- and diacyl chlorogenic acids undergo photochemical trans-cis isomerization under ultraviolet (UV) irradiation. The photochemical equilibrium composition was established for eight selected derivatives. In contrast to all other dicaffeoylquinic acid derivatives, cynarin (1,3-dicaffeoylquinic acid) undergoes a [2 + 2] photochemical cycloaddition reaction, constituting a first example of Schmidt's law in a natural product family. The relevance of photochemical isomerization in agricultural practice was investigated using 120 samples of Stevia rebaudiana leave samples grown under defined cultivation conditions. Ratios of cis to trans chlorogenic acids were determined in leaf samples and correlated with climatic and harvesting conditions. The data indicate a clear correlation between the formation of cis-caffeoyl derivatives and sunshine hours prior to harvesting and illustrate the relevance of UV exposure to plant material affecting its phytochemical composition. PMID- 25699646 TI - Maintenance of residual activity of Bt toxin by using natural and synthetic dyes: a novel approach for sustainable mosquito vector control. AB - Mosquito control protein from Bacillus thuringiensis gets inactivated with exposure to sunlight. To address this issue, the potential of synthetic and natural dye was investigated as sunlight protectants. Bt SV2 in absence of dyes when exposed to sunlight showed reduced effectiveness against the fourth instars of mosquito larvae. Whereas acriflavin, congo red and violacein were able to maintain 86.4%, 91.6% and 82.2% mosquito larvicidal efficacy of Bt SV2 against IVth instars larvae of Anopheles stephensi Meigen after exposure to sunlight. Similarly, beetroot dye, acriflavin, congo red and violacein maintained 98.4%, 97.1%, 90.8% and 70.7% larvicidal activities against Aedes aegypti Linnaeus after sunlight exposure. Prodigiosin was found to be the best photo-protectant by simultaneously protecting and enhancing Bt activity by 6.16% and 22.16% against A. stephensi and A. aegypti, respectively. Combination of dyes with Bt formulations can be a good strategy for mosquito control programmes in tropical and sub-tropical regions. PMID- 25699647 TI - Biomimetic synthesis of dendridine A. AB - Biomimetic synthesis of the bisindole natural product dendridine A is reported. Although attempts to install the hindered biaryl bond by oxidative phenolic coupling of the 7-hydroxytryptamine 6 gave the undesired ortho-ortho product, a Scholl-type oxidative coupling of the 7-isopropoxytryptamine 9 with molybdenum pentachloride proceeded through the desired para-para pathway, installing the entire carbon framework of dendridine A. PMID- 25699648 TI - Nanoscale mapping of catalytic activity using tip-enhanced Raman spectroscopy. AB - Chemical mapping of a photocatalytic reaction with nanoscale spatial resolution is demonstrated for the first time using tip-enhanced Raman spectroscopy (TERS). An ultrathin alumina film applied to the Ag-coated TERS tip blocks catalytic interference whilst maintaining near-field electromagnetic enhancement, thus enabling spectroscopic imaging of catalytic activity on nanostructured Ag surfaces. PMID- 25699649 TI - A smart approach to achieve an exceptionally high loading of metal nanoparticles supported by functionalized extended frameworks for efficient catalysis. AB - The problem associated with metal nanoparticle (NP) agglomeration when trying to achieve a high loading amount has been solved by a new method of functionalization of MOFs' pores with terminal alkyne moieties. The alkynophilicity of the Au(3+) ions has been utilized successfully for an exceptionally high loading (~50 wt%) of Au-NPs on supported functionalized MOFs. PMID- 25699650 TI - MicroRNA-138 Regulates DNA Damage Response in Small Cell Lung Cancer Cells by Directly Targeting H2AX. AB - Lung cancer is the leading cause of cancer death worldwide and small cell lung cancer (SCLC) accounts for a significant proportion of all lung cancer cases. Even so, the underlying mechanism governing SCLC development remains poorly understood and SCLC related cancer death stands high despite decades of intensive investigation. We noted that both miR-138 and H2AX have been implicated in development of various malignancies. Also, there is a recent report showing the role of miR-138 in mediating DNA damage response by targeting H2AX. In light of these data, we sought to characterize the role of miR-138 for SCLC cell growth and cell-cycle progression by regulating H2AX expression. Results showed that miR 138 is significantly down-regulated in SCLC tumor tissues as well as in three SCLC cell lines. After successfully engineering miR-138 overexpression in one of the SCLC cell lines, NCI-H2081, we observed a remarkable reduction of cell growth and a significant inhibition on cell-cycle progression. Moreover, we were able to show that miR-138 potently inhibits H2AX expression, which suggests that H2AX may serve as a downstream executor for miR-138. Consistent with this hypothesis, we found that engineered H2AX knockdown achieves a similar effect as observed for miR-138 overexpression in terms of SCLC growth and cell cycle regulation. We also showed that H2AX overexpression largely abolished miR-138-mediated SCLC cancer cell growth and cell-cycle progression inhibition, which strongly suggests, at least in vitro, that miR-138 potently regulates SCLC development by targeting H2AX. In addition, we found lower miR-138 expression confers SCLC cells with greater DNA damage repair capacity. Finally, we were able to show miR-138 overexpression inhibits DNA damage repair in SCLC cells while miR-138 knockdown further facilitates DNA damage repair in these cells after IR. To date, there has been no study showing the role of miR-138/H2AX machinery in SCLC development. Our results may shed a light to development of new lines of SCLC diagnosis and treatment approaches. PMID- 25699651 TI - Decitabine treatment could ameliorate primary iron-overload in myelodysplastic syndrome patients. AB - In order to research how does hypomethylating agents ameliorate iron metabolism in myelodysplastic syndrome (MDS), we performed methylation-specific, polymerase chain reaction (MSP), bisulfate genomic sequencing polymerase chain reaction (BSP), quantitative real-time PCR and western blot of hemojuvelin (HJV) and ELISA assay for hepcidin before and after demethylating therapy (decitabine) to determine whether the change of HJV methylation status would have an influence on hepcidin expression. Eleven of 22 MDS patients achieved CR or PR according to IWG criteria (50%). HJV mRNA was induced in decitabine responders (p = .006 comparing pre/post decitabine treatment) but not in non-responders (p = .121). Similarly, hepcidin serum expression increased from 320.77 +/- 34.8 MUg/L to 366.77 +/- 21.90 MUg/L (p = .012) in responders but did not significantly change in non responders (p = .058), while no difference of adjusted serum ferritin (ASF) was found. In conclusion, hypermethylation of HJV promoter region could silence the gene expression and demethylating therapy might ameliorate iron-overload through HJV demethylation. PMID- 25699652 TI - Natural killer cell killer immunoglobulin-like gene receptor polymorphisms in non Hodgkin lymphoma: possible association with clinical course. AB - Natural killer (NK) cell killer immunoglobulin-like receptors (KIRs) contribute to the pathogenesis of many diseases. We determined the association between polymorphisms of KIR and their ligands and susceptibility to non-Hodgkin lymphoma (NHL), clinical features and prognosis. We included 90 patients with NHL and 94 controls. In the NHL group, KIR2DS1, HLA-Bw4 (Thr80) and HLA-Bw4 (Thr80)+/Bw4 (Iso80)- ligands were significantly more frequent. Patients with early-stage NHL had more frequent KIR2DL5 and KIR2DL5B than patients with advanced-stage NHL. During a median follow-up of 27 months, 26 patients with NHL died. Poor prognostic factors in univariate analysis were KIR2DL5A, KIR2DS1 and KIR3DS1 genotypes. In multivariate Cox regression analysis, advanced age and early relapse were poor prognostic factors. KIR genes and ligands had no significant effect on survival. The activating KIR2DS1 gene might activate NK cells, contributing to the production of more lymphoma cells. In addition, KIR2DS1, KIR2DL5A and KIR3DS1 might also be associated with a poor prognosis in NHL. PMID- 25699653 TI - Serum free light chain reduction correlates with response and progression-free survival following carfilzomib therapy in relapsed/refractory multiple myeloma. PMID- 25699654 TI - Gambogic acid induces death of K562 cells through autophagy and apoptosis mechanisms. AB - This study was aimed to detect the effects of gambogic acid (GA) on the growth of chronic myelogenous leukemia (CML) K562 cells. Our results showed that GA induced the accumulation of autophagic vacuoles and up-regulation of two autophagy related proteins (Beclin 1 and LC3). GA also induced down-regulation of mRNA levels of BCR-ABL fusion gene and SQSTM1/sequestosome 1 (p62) protein levels. After treatment by chloroquine (CQ) and pan caspase inhibitor Z-VAD-FMK (PC), both GA-induced autophagy and apoptosis were inhibited. Our study demonstrates that GA may induce cell death through autophagy and apoptosis pathways in CML K562 cells. A cross-talk mechanism exists between GA-induced autophagy and apoptosis. However, the mechanism of GA for inducing autophagy and apoptosis need further clarification. PMID- 25699655 TI - Nanoscale mapping of carbon oxidation in pyrogenic black carbon from ancient Amazonian anthrosols. AB - Understanding soil organic matter is necessary for the development of soil amendments, which are important for sustaining agriculture in humid tropical climates. Ancient Amazonian anthrosols are uniquely high in black recalcitrant carbon, making them extremely fertile. In this study, we use high-resolution electron microscopy and spectroscopy to resolve the oxidation process of carbon in the nanoscale crystallites within the black carbon grains of this special soil. Most alkali and acid chemical extraction methods are known to cause chemical modifications in soil organic matter and to give poor or no information about the real spatial structure of soil aggregates. However, here we show that carbon-oxygen functional groups such as phenol, carbonyl, and carboxyl dominate over different spatial regions, with areas varying from over tens to hundreds of nm(2). The chemical maps show that in the nanoscale grain, the surface has a tendency to be less aromatic than the grain core, where higher oxidative degradation levels are indicated by the presence of carbonyl and carboxyl groups. A deep understanding of these structures could allow artificial reproduction of these natural events. PMID- 25699656 TI - Superposition of an AC field improves the discrimination between peptides in nanopore analysis. AB - In standard nanopore analysis a constant DC voltage is used to electrophoretically drive small molecules and peptides towards a pore. Superposition of an AC voltage at particular frequencies causes molecules to oscillate as they approach the pore which can alter the event parameters, the blockade current (I) and blockade time (T). Four peptides with similar structures were studied. Alpha-helical peptides A10 (FmocDDA10KK), A14, A18 and retro inverso A10. It was shown that the ratio of translocations to bumping events could be manipulated by a combination of AC voltages and frequencies. In particular, A10 could be studied without interference from retro-inverso A10. Similarly, a large, intrinsically disordered protein of 140 amino acids, alpha synuclein, which translocates the pore readily in a DC field could be prevented from doing so by application of an AC field of 200 mV at 100 MHz. PMID- 25699657 TI - Mass spectrometric sampling of a liquid surface by nanoliter droplet generation from bursting bubbles and focused acoustic pulses: application to studies of interfacial chemistry. AB - The complex chemistry occurring at the interface between liquid and vapor phases contributes significantly to the dynamics and evolution of numerous chemical systems of interest, ranging from damage to the human lung surfactant layer to the aging of atmospheric aerosols. This work presents two methodologies to eject droplets from a liquid water surface and analyze them via mass spectrometry. In bursting bubble ionization (BBI), droplet ejection is achieved via the formation of a jet following bubble rupture at the surface of a liquid to yield 250 MUm diameter droplets (10 nL volume). In interfacial sampling by an acoustic transducer (ISAT), droplets are produced by focusing pulsed piezoelectric transducer-generated acoustic waves at the surface of a liquid, resulting in the ejection of droplets of 100 MUm in diameter (500 pL volume). In both experimental methodologies, ejected droplets are aspirated into the inlet of the mass spectrometer, resulting in the facile formation of gas-phase ions. We demonstrate the ability of this technique to readily generate spectra of surface-active analytes, and we compare the spectra to those obtained by electrospray ionization. Charge measurements indicate that the ejected droplets are near neutral (<0.1% of the Rayleigh limit), suggesting that gas-phase ion generation occurs in the heated transfer capillary of the instrument in a mechanism similar to thermospray or sonic spray ionization. Finally, we present the oxidation of oleic acid by ozone as an initial demonstration of the ability of ISAT-MS to monitor heterogeneous chemistry occurring at a planar water/air interface. PMID- 25699658 TI - BODIPY-based fluorometric sensor for the simultaneous determination of Cys, Hcy, and GSH in human serum. AB - Cysteine (Cys), homocysteine (Hcy), and glutathione (GSH) are interconnected and play essential roles for regulating the redox balance of biological processes. However, finding a simple and effective method for the simultaneous determination for these three biothiols in biological systems is always a challenge. In this work, we report a method for the simultaneous quantitative determination of three biothiols in a mixture using a monochlorinated boron dipyrromethene (BODIPY) based fluorometric sensor. At a specified period of time, after reacting with excess sensor, Hcy and GSH form predominantly sulfur-substituted BODIPY, while Cys generates sulfur-amino-diBODIPY due to a fast substitution-rearrangement substitution reaction. A significant difference in polarities of these respective major products simplifies their separation by TLC, thus leading to the simultaneous determination of Cys, Hcy, and GSH readily. The sensor was successfully applied for the simultaneous quantitative detection of three biothiols in human serum, and the results were in good agreement with those obtained via high performance liquid chromatography (HPLC). PMID- 25699659 TI - Impact of ligand framework on the crystal structures and luminescent properties of Cu(I) and Ag(I) clusters and a coordination polymer derived from thiolate/iodide/dppm ligands. AB - New homoleptic hexanuclear Ag(I) and heteroleptic trinuclear Cu(I) clusters and a Cu(I) coordination polymer (CP) of the formulas [Ag6(dtc)6] 1, [Cu3I2(dppm)3(dtc)] 2, and [Cu(ttc)I]infinity 3 (dtc = N-methylbenzyl-N-methyl thiophenedithiocarbamate; dppm = 1,1-bis(diphenylphosphino)methane; and ttc = dimethyltrithiocarbonate) were synthesized and characterized by elemental analysis, IR, UV-vis, (1)H, (13)C, and (31)P NMR spectroscopies, and their structures were elucidated by X-ray crystallography. The complexes show interesting structures and luminescent properties. Complex 1, which is centrosymmetric, contains four short Ag...Ag interactions at 2 * 2.966(1) and 2 * 3.014(1) A. There are also several Ag...Ag distances of 3.3-3.4 A. The molecule shows hexagonal orientation with alternating silver and sulfur atoms of the overlapping Ag3S3 hexagons in the front and rear, along the a axis. Complex 2 is a rare trinuclear cluster complex of Cu(I); the Cu...Cu distances are 2.906(2), 3.551(2), and 3.338(2) A, the foremost representing a substantial intermetallic contact. The Cu3I2P6S2 core is comprised of three fused distorted hexagonal rings with the I1 atom located at the center participating in all three rings. Complex 3 is an iodide-bridged CP with a "staircase"-like arrangement in which the Cu(I) is tetrahedrally surrounded by a sulfur atom from the ttc ligand and three iodine atoms. Unlike 3, which is nonluminescent, 1 and 2 are strongly luminescent in the solid and solution at room temperature. The time-resolved emission spectra reveal a triexponential decay curve and short mean lifetime characteristic of fluorescence behavior. Diffuse reflectance spectroscopy revealed semiconducting behavior with band gaps of 2.12, 3.01, and 2.18 eV for 1-3, respectively. PMID- 25699660 TI - Feline immunodeficiency virus (FIV) env recombinants are common in natural infections. AB - BACKGROUND: Recombination is a common feature of retroviral biology and one of the most important factors responsible for generating viral diversity at both the intra-host and the population levels. However, relatively little is known about rates and molecular processes of recombination for retroviruses other than HIV, including important model viruses such as feline immunodeficiency virus (FIV). RESULTS: We investigated recombination in complete FIV env gene sequences (n = 355) isolated from 43 naturally infected cats. We demonstrated that recombination is abundant in natural FIV infection, with over 41% of the cats being infected with viruses containing recombinant env genes. In addition, we identified shared recombination breakpoints; the most significant hotspot occurred between the leader/signal fragment and the remainder of env. CONCLUSIONS: Our results have identified the leader/signal fragment of env as an important site for recombination and highlight potential limitations of the current phylogenetic classification of FIV based on partial env sequences. Furthermore, the presence of abundant recombinant FIV in the USA poses a significant challenge for commercial diagnostic tests and should inform the development of the next generation of FIV vaccines. PMID- 25699661 TI - Electron-transfer acceleration investigated by time resolved infrared spectroscopy. AB - Ultrafast electron transfer (ET) processes are important primary steps in natural and artificial photosynthesis, as well as in molecular electronic/photonic devices. In biological systems, ET often occurs surprisingly fast over long distances of several tens of angstroms. Laser-pulse irradiation is conveniently used to generate strongly oxidizing (or reducing) excited states whose reactions are then studied by time-resolved spectroscopic techniques. While photoluminescence decay and UV-vis absorption supply precise kinetics data, time resolved infrared absorption (TRIR) and Raman-based spectroscopies have the advantage of providing additional structural information and monitoring vibrational energy flows and dissipation, as well as medium relaxation, that accompany ultrafast ET. We will discuss three cases of photoinduced ET involving the Re(I)(CO)3(N,N) moiety (N,N = polypyridine) that occur much faster than would be expected from ET theories. [Re(4-N-methylpyridinium-pyridine)(CO)3(N,N)](2+) represents a case of excited-state picosecond ET between two different ligands that remains ultrafast even in slow-relaxing solvents, beating the adiabatic limit. This is caused by vibrational/solvational excitation of the precursor state and participation of high-frequency quantum modes in barrier crossing. The case of Re-tryptophan assemblies demonstrates that excited-state Trp -> *Re(II) ET is accelerated from nanoseconds to picoseconds when the Re(I)(CO)3(N,N) chromophore is appended to a protein, close to a tryptophan residue. TRIR in combination with DFT calculations and structural studies reveals an interaction between the N,N ligand and the tryptophan indole. It results in partial electronic delocalization in the precursor excited state and likely contributes to the ultrafast ET rate. Long-lived vibrational/solvational excitation of the protein Re(I)(CO)3(N,N)...Trp moiety, documented by dynamic IR band shifts, could be another accelerating factor. The last discussed process, back-ET in a porphyrin-Re(I)(CO)3(N,N) dyad, demonstrates that formation of a hot product accelerates highly exergonic ET in the Marcus inverted region. Overall, it follows that ET can be accelerated by enhancing the electronic interaction and by vibrational excitation of the reacting system and its medium, stressing the importance of quantum nuclear dynamics in ET reactivity. These effects are experimentally accessible by time-resolved vibrational spectroscopies (IR, Raman) in combination with quantum chemical calculations. It is suggested that structural dynamics play different mechanistic roles in light-triggered ET involving electronically excited donors or acceptors than in ground-state processes. While TRIR spectroscopy is well suitable to elucidate ET processes on a molecular-level, transient 2D-IR techniques combining optical and two IR (or terahertz) laser pulses present future opportunities for investigating, driving, and controlling ET. PMID- 25699662 TI - Injection of steroids intralesional in central giant cell granuloma cases (giant cell tumor): Is it free of systemic complications or not? A case report. AB - Central giant tumors commonly occur in long bones. In the oral and maxillofacial region, a counterpart coined with the term Central giant cell granuloma exists. Choung and Kaban classified central giant cell granulomas based on clinical and radiographic findings. The classification includes aggressive and non-aggressive variants. However, to date there has been no molecular method of distinguishing the variants. Different lines of treatment had been reported. The aggressive form showed high recurrence rates with conservative surgical treatment. Intra-lesional steroid, calcitonin, interferon, bisphosphonates and denosumab; have been administered as a treatment lines. Several reports support the injection of intra lesional steroids and its successful outcome. An Egyptian, nine years old female presented with a facial swelling affecting lower left side of the mandible. Biopsy confirmed it to be a CGCG. The treatment plan was intralesional steroid injections to avoid resection of the mandible. The treatment showed acceptable progress but was associated with cushinoid appearance of patient. This forced the operating team to halt the steroid injections and resolute to adjunctive surgical curettage yet sparing the mandible from resection. One-year follow up showed no recurrence, however, the patient still suffers mild cushinoid appearance. PMID- 25699663 TI - (210)Pb and compositional data of sediments from Rondonian lakes, Madeira River basin, Brazil. AB - Gold exploration has been intensive in Brazilian Amazon over the last 40 years, where the use of mercury as an amalgam has caused abnormal Hg concentrations in water bodies. Special attention has been directed to Madeira River due to fact it is a major tributary of Amazon River and that since 1986, gold exploration has been officially permitted along a 350km sector of the river. The (21)(0)Pb method has been used to date sediments taken from nine lakes situated in Madeira River basin, Rondonia State, and to verify where anthropogenic Hg might exist due to gold exploitation in Madeira River. Activity profiles of excess (21)(0)Pb determined in the sediment cores provided a means to evaluate the sedimentation rates using a Constant Flux: Constant Sedimentation (CF:CS) and Constant Rate of Supply (CRS) of unsupported/excess (21)(0)Pb models. A significant relationship was found between the CF:CS sedimentation rates and the mean values of the CRS sedimentation rates (Pearson correlation coefficient r=0.59). Chemical data were also determined in the sediments for identifying possible relationships with Hg occurring in the area. Significant values were found in statistical correlation tests realized among the Hg, major oxides and Total Organic Carbon (TOC) content in the sediments. The TOC increased in the sediment cores accompanied by a loss on ignition (LOI) increment, whereas silica decreased following a specific surface area raising associated to the TOC increase. The CRS model always provided ages within the permitted range of the (21)(0)Pb-method in the studied lakes, whereas the CF:CS model predicted two values above 140 years. PMID- 25699664 TI - Neutron spectra due (13)N production in a PET cyclotron. AB - Monte Carlo and experimental methods have been used to characterize the neutron radiation field around PET (Positron Emission Tomography) cyclotrons. In this work, the Monte Carlo code MCNPX was used to estimate the neutron spectra, the neutron fluence rates and the ambient dose equivalent (H*(10)) in seven locations around a PET cyclotron during (13)N production. In order to validate these calculations, H*(10) was measured in three sites and were compared with the calculated doses. All the spectra have two peaks, one above 0.1MeV due to the evaporation neutrons and another in the thermal region due to the room-return effects. Despite the relatively large difference between the measured and calculated H*(10) for one point, the agreement was considered good, compared with that obtained for (18)F production in a previous work. PMID- 25699665 TI - Design, optimization and performance of source and detector collimators for gamma ray scanning of a lab-scale distillation column. AB - When using source and detector collimators for gamma ray column scanning, it is important to obtain an acceptable density profile quality. This paper consists of two main works. The first is devoted to describing the designs used to optimize the source and detector collimators for a lab-scale distillation column, and the second is devoted to investigating the effect of designed collimators on the quality of the density profiles obtained using the gamma scanning technique. Simulations using the MCNP4C Monte Carlo code were performed to model the collimators and obtain the density profiles. The source and detector collimator designs were developed for a cylindrical volume source with the energy of 0.662MeV and 1in.*1in. NaI, respectively. The pinhole and panoramic collimator designs and the pinhole and quartic collimator designs were considered for the source and the detector, respectively. The source container, with an opening angle of 60 degrees , has the capability of substituting the collimator for high resolution, general and high sensitivity purposes. The pinhole collimator parameters for the source that were obtained were generally quite coarse and were 1.2cm in diameter and 4cm in length. Additionally, the detector pinhole collimator thickness and length obtained were 4cm and 5cm, respectively. Using the semi-quartic collimator for the detector, the weight of required lead was reduced by over 33% compared with the pinhole collimator. The simulation results of the column scanning in abnormal operation condition have been validated by experimental measurement results. The obtained results from scans demonstrated that the optimized panoramic source collimator and semi-quartic detector collimator in this study could help us to obtain an acceptable density profile quality in total count approach. PMID- 25699666 TI - Study of the continuous internal bremsstrahlung spectrum from (204)Tl by using singular value decomposition. AB - Internal bremsstrahlung (IB) accompanying the beta(-) decay of (204)Tl was measured using a 5.08*5.08cm(2) NaI(Tl) detector employing a magnetic deflection method in the range of 10-760keV. A novel approach, the Singular Value Decomposition (SVD), is applied to unfold the raw detector spectrum of (204)Tl. Unfolded IB spectrum is compared with the KUB theory. The measured spectrum is found to show fairly good agreement with the KUB theory in the energy range of 100-600keV. The distribution beyond the 600keV takes a positive deviation from the theory. PMID- 25699667 TI - Direct measurement of the half-life of (223)Ra. AB - Radioactive decay half-life measurements of (223)Ra, a member of the (235)U naturally occurring radioactive decay series, have been performed of a radiochemically pure solution with an ionisation chamber. The radioactive decay of (223)Ra was followed for 50 days, approximately 4.4 half-lives. The deduced half-life of (223)Ra was found to be 11.4358 (28) days, supporting the other published direct measurements. A detailed uncertainty budget is presented. A new evaluation of the published half-life values was performed, indicating significant variation across the existing published values, suggesting that further measurements of the half-life of (223)Ra are required. A new evaluated half-life has been calculated using a power moderated weighted mean of selected experimental values, with a new value of the recommended half-life for (223)Ra of 11.4354 (17) days. PMID- 25699668 TI - Acculturative stress negatively impacts maternal depressive symptoms in Mexican American women during pregnancy. AB - BACKGROUND: Mexican-American women exhibit high rates of prenatal maternal depressive symptoms relative to the general population. Though pregnant acculturated Mexican-American women experience cultural stressors such as acculturation, acculturative stress and discrimination that may contribute to elevated depressive symptoms, the contribution of these socio-cultural correlates to depressive symptomology is unknown. METHOD: Ninety-eight pregnant women of Mexican descent were recruited from a community hospital clinic during their first trimester. Women completed surveys about acculturation, acculturative stress, perceived discrimination, general perceived stress, and maternal depressive symptoms as well as the potential protective factor of Mexican cultural values. RESULTS: Women who experienced greater acculturative and perceived stress, but not perceived discrimination or acculturation, reported significantly elevated depressive symptoms during pregnancy. Also, women who experienced greater acculturative stress identified with a mixture of Mexican and American cultural values. However, only the Mexican cultural value of respect was protective against maternal depressive symptoms while adhering to the Anglo value of independence and self-reliance was a risk factor. LIMITATIONS: A limitation in the study is the cross-sectional and descriptive self-report nature of the work, underscoring the need for additional research. Moreover, physiological measures of stress were not analyzed in the current study. CONCLUSIONS: Results point to acculturative stress, above other cultural stressors, as a potential intervention target in culturally competent obstetric care. These findings have implications for maternal mental health treatment during pregnancy, which likely affects maternal-fetal programming and may favorably affect perinatal outcomes in the vulnerable Mexican-American population. PMID- 25699669 TI - Clinical features distinguishing grief from depressive episodes: A qualitative analysis. AB - BACKGROUND: The independence or interdependence of grief and major depression has been keenly argued in relation to recent DSM definitions and encouraged the current study. METHODS: We report a phenomenological study seeking to identify the experiential and phenomenological differences between depression and grief as judged qualitatively by those who had experienced clinical (n=125) or non clinical depressive states (n=28). RESULTS: Analyses involving the whole sample indicated that, in contrast to grief, depression involved feelings of hopelessness and helplessness, being endless and was associated with a lack of control, having an internal self-focus impacting on self-esteem, being more severe and stressful, being marked by physical symptoms and often lacking a justifiable cause. Grief was distinguished from depression by the individual viewing their experience as natural and to be expected, a consequence of a loss, and with an external focus (i.e. the loss of the other). Some identified differences may have reflected the impact of depressive "type" (e.g. melancholia) rather than depression per se, and argue for a two-tiered model differentiating normative depressive and grief states at their base level and then "clinical" depressive and 'pathological' grief states by their associated clinical features. LIMITATIONS: Comparative analyses between the clinical and non-clinical groups were limited by the latter sub-set being few in number. The provision of definitions may have shaped subjects' nominated differentiating features. CONCLUSION: The study identified a distinct number of phenomenological and clinical differences between grief and depression and few shared features, but more importantly, argued for the development of a two-tiered model defining both base states and clinical expressions. PMID- 25699670 TI - Gender differences and disabilities of perceived depression in the workplace. AB - BACKGROUND: Few studies have investigated gender difference and associated disability among workers. Comprehensive investigations concerning the occurrence and consequences of depression in workplace are scarce. The study aims to evaluate how workers perceive depression in workplace, as well as to examine depression-related disabilities by gender. METHODS: This is a cross-sectional web based survey of 1000 Brazilian workers recruited from Internet sources. Participants answered an online questionnaire about depressive symptoms and related consequences in the workplace. RESULTS: Common symptoms attributable to depression were crying, loss of interest, and sadness. Almost one in five (18.9%) participants reported had ever been "labeled" by a health professional as suffering from depression. However, the majority of ever-depressed workers (73.5%) remained working. Performance-related impairments were reported by around 60% of depressed workers who continued working. Over half of them also complained about cognitive symptoms (concentration difficulties, indecisiveness, forgetfulness), with men reporting more cognitive dysfunctions than women. One in three workers had taken off work due to depression (mean 65.7 out-of-role days), with these periods being lengthier for men than women. LIMITATIONS: Some depressive events might have occurred before working age, since the participants have self-reported the diagnosis of health professionals in past timeframe. The representativeness of recruited workers was reliant upon the availability of Internet service. CONCLUSIONS: The findings suggest that identification and management of symptoms of depression should be set as a priority in worker's health care. General and gender-related strategies to handle depression in the workplace are recommended. PMID- 25699671 TI - A forward-design approach to increase the production of poly-3-hydroxybutyrate in genetically engineered Escherichia coli. AB - Biopolymers, such as poly-3-hydroxybutyrate (P(3HB)) are produced as a carbon store in an array of organisms and exhibit characteristics which are similar to oil-derived plastics, yet have the added advantages of biodegradability and biocompatibility. Despite these advantages, P(3HB) production is currently more expensive than the production of oil-derived plastics, and therefore, more efficient P(3HB) production processes would be desirable. In this study, we describe the model-guided design and experimental validation of several engineered P(3HB) producing operons. In particular, we describe the characterization of a hybrid phaCAB operon that consists of a dual promoter (native and J23104) and RBS (native and B0034) design. P(3HB) production at 24 h was around six-fold higher in hybrid phaCAB engineered Escherichia coli in comparison to E. coli engineered with the native phaCAB operon from Ralstonia eutropha H16. Additionally, we describe the utilization of non-recyclable waste as a low-cost carbon source for the production of P(3HB). PMID- 25699672 TI - An exploration of hypotheses that explain herbivore and pathogen attack in restored plant communities. AB - Many hypotheses address the associations of plant community composition with natural enemies, including: (i) plant species diversity may reduce enemy attack, (ii) attack may increase as host abundance increases, (iii) enemy spillover may lead to increased attack on one host species due to transmission from another host species, or enemy dilution may lead to reduced attack on a host that would otherwise have more attack, (iv) physical characteristics of the plant community may influence attack, and (v) plant vigor may affect attack. Restoration experiments with replicated plant communities provide an exceptional opportunity to explore these hypotheses. To explore the relative predictive strengths of these related hypotheses and to investigate the potential effect of several restoration site preparation techniques, we surveyed arthropod herbivore and fungal pathogen attack on the six most common native plant species in a restoration experiment. Multi-model inference revealed a weak but consistent negative correlation with pathogen attack and host diversity across the plant community, and no correlation between herbivory and host diversity. Our analyses also revealed host species-specific relationships between attack and abundance of the target host species, other native plant species, introduced plant species, and physical community characteristics. We found no relationship between enemy attack and plant vigor. We found minimal differences in plant community composition among several diverse site preparation techniques, and limited effects of site preparation techniques on attack. The strongest associations of community characteristics with attack varied among plant species with no community-wide patterns, suggesting that no single hypothesis successfully predicts the dominant community-wide trends in enemy attack. PMID- 25699673 TI - Forecasting the effects of land use scenarios on farmland birds reveal a potential mitigation of climate change impacts. AB - Climate and land use changes are key drivers of current biodiversity trends, but interactions between these drivers are poorly modeled, even though they could amplify or mitigate negative impacts of climate change. Here, we attempt to predict the impacts of different agricultural change scenarios on common breeding birds within farmland included in the potential future climatic suitable areas for these species. We used the Special Report on Emissions Scenarios (SRES) to integrate likely changes in species climatic suitability, based on species distribution models, and changes in area of farmland, based on the IMAGE model, inside future climatic suitable areas. We also developed six farmland cover scenarios, based on expert opinion, which cover a wide spectrum of potential changes in livestock farming and cropping patterns by 2050. We ran generalized linear mixed models to calibrate the effects of farmland cover and climate change on bird specific abundance within 386 small agricultural regions. We used model outputs to predict potential changes in bird populations on the basis of predicted changes in regional farmland cover, in area of farmland and in species climatic suitability. We then examined the species sensitivity according to their habitat requirements. A scenario based on extensification of agricultural systems (i.e., low-intensity agriculture) showed the greatest potential to reduce reverse current declines in breeding birds. To meet ecological requirements of a larger number of species, agricultural policies accounting for regional disparities and landscape structure appear more efficient than global policies uniformly implemented at national scale. Interestingly, we also found evidence that farmland cover changes can mitigate the negative effect of climate change. Here, we confirm that there is a potential for countering negative effects of climate change by adaptive management of landscape. We argue that such studies will help inform sustainable agricultural policies for the future. PMID- 25699674 TI - Characterizing long-term patterns of weight change in China using latent class trajectory modeling. AB - BACKGROUND: Over the past three decades, obesity-related diseases have increased tremendously in China, and are now the leading causes of morbidity and mortality. Patterns of weight change can be used to predict risk of obesity-related diseases, increase understanding of etiology of disease risk, identify groups at particularly high risk, and shape prevention strategies. METHODS: Latent class trajectory modeling was used to compute weight change trajectories for adults aged 18 to 66 using the China Health and Nutrition Survey (CHNS) data (n = 12,611). Weight change trajectories were computed separately for males and females by age group at baseline due to differential age-related patterns of weight gain in China with urbanization. Generalized linear mixed effects models examined the association between weight change trajectories and baseline characteristics including urbanicity, BMI category, age, and year of study entry. RESULTS: Trajectory classes were identified for each of six age-sex subgroups corresponding to various degrees of weight loss, maintenance and weight gain. Baseline BMI status was a significant predictor of trajectory membership for all age-sex subgroups. Baseline overweight/obesity increased odds of following 'initial loss with maintenance' trajectories. We found no significant association between baseline urbanization and trajectory membership after controlling for other covariates. CONCLUSION: Trajectory analysis identified patterns of weight change for age by gender groups. Lack of association between baseline urbanization status and trajectory membership suggests that living in a rural environment at baseline was not protective. Analyses identified age-specific nuances in weight change patterns, pointing to the importance of subgroup analyses in future research. PMID- 25699675 TI - Dynamics and correlation of serum cortisol and corticosterone under different physiological or stressful conditions in mice. AB - Although plasma corticosterone is considered the main glucocorticoid involved in regulation of stress responses in rodents, the presence of plasma cortisol and whether its level can be used as an indicator for rodent activation of stress remain to be determined. In this study, effects of estrous cycle stage, circadian rhythm, and acute and chronic (repeated or unpredictable) stressors of various severities on dynamics and correlation of serum cortisol and corticosterone were examined in mice. A strong (r = 0.6-0.85) correlation between serum cortisol and corticosterone was observed throughout the estrous cycle, all day long, and during acute or repeated restraints, chronic unpredictable stress and acute forced swimming or heat stress. Both hormones increased to the highest level on day 1 of repeated-restraint or unpredictable stresses, but after that, whereas the concentration of cortisol did not change, that of corticosterone showed different dynamics. Thus, whereas corticosterone declined dramatically during repeated restraints, it remained at the high level during unpredictable stress. During forced swimming or heat stress, whereas cortisol increased to the highest level within 3 min., corticosterone did not reach maximum until 40 min. of stress. Analysis with HPLC and HPLC-MS further confirmed the presence of cortisol in mouse serum. Taken together, results (i) confirmed the presence of cortisol in mouse serum and (ii) suggested that mouse serum cortisol and corticosterone are closely correlated in dynamics under different physiological or stressful conditions, but, whereas corticosterone was a more adaptation-related biomarker than cortisol during chronic stress, cortisol was a quicker responder than corticosterone during severe acute stress. PMID- 25699676 TI - Screening and assessment of solidification/stabilization amendments suitable for soils of lead-acid battery contaminated site. AB - Lead exposure via ingestion of soil and dust generally occurs at lead-acid battery manufacturing and recycling sites. Screening solidification/stabilization (S/S) amendments suitable for lead contaminated soil in an abandoned lead-acid battery factory site was conducted based on its chemical forms and environmental risks. Twelve amendments were used to immobilize the Pb in soil and assess the solidification/stabilization efficiency by toxicity leaching tests. The results indicated that three amendments, KH2PO4 (KP), KH2PO4:oyster shell power=1:1 (by mass ratio; SPP), and KH2PO4:sintered magnesia=1:1 (by mass ratio; KPM) had higher remediation efficiencies that led to a 92% reduction in leachable Pb with the addition of 5% amendments, while the acid soluble fraction of Pb (AS-Pb) decreased by 41-46% and the residual fraction (RS-Pb) increased by 16-25%. The S/S costs of the three selected amendments KP, SPP, and KPM could be controlled to $22.3 per ton of soil when the Pb concentration in soil ranged from 2000 to 3000 mg/kg. The results of this study demonstrated that KP, SPP, and KPM can effectively decrease bioavailability of Pb. These findings could provide basis for decision-making of S/S remediation of lead-acid battery contaminated sites. PMID- 25699677 TI - The layered double hydroxide route to Bi-Zn co-doped TiO2 with high photocatalytic activity under visible light. AB - In this work, a co-doped Bi-Zn-TiO2 photocatalist is synthesized by an original synthesis route of layered double hydroxide followed by heat treatment at 670 degrees C. After characterization the photocatalyst efficiency is estimated by the photo-discoloration of an anionic dye (indigo carmine) under visible light and compare to TiO2-P25 as reference material. In this new photocatalyst, anatase and ZnO wurtzite are the only identified crystalline phase, rutile and Bi2O3 being undetected. Moreover, the binding energy of Bi determined (XPS analysis) is different from the one of Bi in Bi2O3. Compared to TiO2-P25, the absorption is red shifted (UV-vis DRS) and the Bi-Zn-TiO2 photocatalyst showed sorption capacity toward indigo carmine higher than that TiO2-P25. The kinetics of the photo-discoloration is faster with Bi-Zn-TiO2 than with TiO2-P25. Indeed, a complete discoloration is obtained after 70 min and 120 min in the presence of Bi Zn-TiO2 and TiO2-P25 respectively. The identification of the responsible species on photo-discoloration was carried out in the presence of different scavengers. The study showed that the first responsible is h(+) specie with a moderate contribution of superoxide anion radical and a minor contribution of the hydroxyl radical. The material showed high stability after five uses with the same rate of photo-discoloration. PMID- 25699678 TI - Oral lactoferrin for the prevention of sepsis and necrotizing enterocolitis in preterm infants. AB - BACKGROUND: Lactoferrin, a normal component of human colostrum and milk, can enhance host defense and may be effective in the prevention of sepsis and necrotizing enterocolitis (NEC) in preterm neonates. OBJECTIVES: Primary objective To assess the safety and effectiveness of oral lactoferrin in the prevention of sepsis and NEC in preterm neonates. Secondary objectives1. To determine the effects of oral lactoferrin used to prevent neonatal sepsis and/or NEC on duration of positive-pressure ventilation, development of chronic lung disease (CLD) or periventricular leukomalacia (PVL), length of hospital stay to discharge among survivors, and adverse neurological outcomes at two years of age or later.2. To determine the adverse effects of oral lactoferrin in the prophylaxis of neonatal sepsis and/or NEC.When data were available, we analyzed the following subgroups.1. Gestational age < 32 weeks and 32 to 36 weeks.2. Birth weight < 1000 g (extremely low birth weight (ELBW) infants) and birth weight < 1500 g (very low birth weight (VLBW) infants).3. Type of feeding: breast milk versus formula milk. SEARCH METHODS: We used the search strategy of the Cochrane Neonatal Review Group (CNRG) and updated our search in July 2014. We searched the databases Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, PREMEDLINE, EMBASE, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL), as well as trials registries and conference proceedings. SELECTION CRITERIA: Randomized controlled trials (RCTs) evaluating oral lactoferrin at any dose or duration to prevent sepsis or NEC in preterm neonates. DATA COLLECTION AND ANALYSIS: Review authors used standard methods of the CNRG. MAIN RESULTS: Four RCTs are included in this review. Oral lactoferrin supplementation decreased late-onset sepsis (typical risk ratio (RR) 0.49, 95% confidence interval (CI) 0.32 to 0.73; typical risk difference (RD) -0.09, 95% CI -0.14 to -0.04; number needed to treat for an additional beneficial outcome (NNTB) 11, 95% CI 7 to 25; four trials, 678 participants, moderate-quality evidence), NEC stage II or greater (typical RR 0.30, 95% CI 0.12 to 0.76; typical RD -0.05, 95% CI -0.08 to -0.01; NNTB 20, 95% CI 12.5 to 100; two studies, 505 participants, low-quality evidence), and "all-cause mortality" (typical RR 0.30, 95% CI 0.12 to 0.75; typical RD -0.05, 95% CI -0.08 to -0.01; NNTB 20, 95% CI 12.5 to 100; two studies, 505 participants, low-quality evidence).Oral lactoferrin supplementation with a probiotic decreased late-onset sepsis (RR 0.27, 95% CI 0.12 to 0.60; RD -0.13, 95% CI -0.19 to -0.06; NNTB 8, 95% CI 5 to 17; one study, 321 participants, low-quality evidence) and NEC stage II or greater (RR 0.04, 95% CI 0.00 to 0.62; RD -0.05, 95% CI -0.08 to -0.03; NNTB 20, 95% CI 12.5 to 33.3; one study, 496 participants, low-quality evidence), but not "all-cause mortality."Oral lactoferrin with or without probiotics decreased fungal sepsis but not chronic lung disease or length of hospital stay (from one study, low-quality evidence). No adverse effects were reported. Long-term neurological outcomes or periventricular leukomalacia was not evaluated. AUTHORS' CONCLUSIONS: Evidence of moderate to low quality suggests that oral lactoferrin prophylaxis with or without probiotics decreases late-onset sepsis and NEC stage II or greater in preterm infants without adverse effects. Completion of ongoing trials will provide evidence from more than 6000 preterm neonates and may enhance the quality of the evidence. Clarifications regarding optimum dosing regimens, type of lactoferrin (human or bovine), and long-term outcomes are still needed. PMID- 25699679 TI - Cytogenetic analysis and chromosomal characteristics of the polymorphic 18S rDNA of Haliotis discus hannai from Fujian, China. AB - We report on novel chromosomal characteristics of Haliotis discus hannai from a breeding population at Fujian, China. The karyotypes of H. discus hannai we obtained from an abalone farm include a common type 2n = 36 = 10M + 8SM (82%) and two rare types 2n = 36 = 11M + 7SM (14%) and 2n = 36 = 10M + 7SM + 1ST (4%). The results of silver staining showed that the NORs of H. discus hannai were usually located terminally on the long arms of chromosome pairs 14 and 17, NORs were also sometimes located terminally on the short arms of other chromosomes, either metacentric or submetacentric pairs. The number of Ag-nucleoli ranged from 2 to 8, and the mean number was 3.61 +/- 0.93. Among the scored interphase cells, 41% had 3 detectable nucleoli and 37% had 4 nucleoli. The 18S rDNA FISH result is the first report of the location of 18S rDNA genes in H. discus hannai. The 18S rDNA locations were highly polymorphic in this species. Copies of the gene were observed in the terminal of long or/and short arms of submetacentric or/and metacentric chromosomes. Using FISH with probe for vertebrate-like telomeric sequences (CCCTAA)3 displayed positive green FITC signals at telomere regions of all analyzed chromosome types. We found about 7% of chromosomes had breaks in prophase. A special form of nucleolus not previously described from H. discus hannai was observed in some interphase cells. It consists of many small silver stained nucleoli gathered together to form a larger nucleolus and may correspond to prenucleolar bodies. PMID- 25699680 TI - Adolescents who self-harm are at increased risk of health and social problems as young adults. PMID- 25699681 TI - Correction: A simple isothermal DNA amplification method to screen black flies for Onchocerca volvulus infection. AB - [This corrects the article DOI: 10.1371/journal.pone.0108927.]. PMID- 25699682 TI - Sexuality after surgery for diffuse low-grade glioma. AB - BACKGROUND: Although neurological and neurocognitive outcomes have previously been studied after resection of diffuse low-grade glioma (DLGG), the impact of surgery on sexual life has not been investigated. Our aim was to assess whether DLGG surgery could have consequences on sexual experience. METHODS: Anonymous standardized questionnaires concerning sexual functioning, including the Arizona Sexual Experiences Scale (ASEX) and a subjective statement, were completed by 32 patients who underwent surgery for DLGG. All patients returned to a normal social and professional life following resection, with neither neurological deficits nor depression. No radiotherapy was administered, and patients who received chemotherapy were without treatment for at least 1 year. RESULTS: Seventeen patients (53%) reported a postoperative sexual change, with subjective deterioration in 15 (88%) and improvement in 2 (12%). Sexual dysfunction according to ASEX affected 9 of 15 women (60%) and 5 of 17 men (29%). Right-sided resections were associated with more difficulties in reaching orgasm than left sided resections (P < .02). Men with temporal lobe resection displayed more reduction in sexual drive (P < .003) and sexual arousal (P < .004) than women, resulting in significant higher overall ASEX scores for temporal lobe resections in men (P = .01). Men remaining on antiepileptic drugs who underwent right-sided resection displayed higher overall ASEX scores than women (P = .031). CONCLUSIONS: This first evaluation of sexual life after surgery for DLGG suggests that sexual dysfunction is common in this population. Therefore, we suggest that sexual health should consistently be addressed during routine pre- and postoperative examination of patients with DLGG. PMID- 25699683 TI - Look before you leap: can we draw causal conclusions from breastfeeding research? PMID- 25699684 TI - Iridium-catalyzed direct synthesis of tryptamine derivatives from indoles: exploiting n-protected beta-amino alcohols as alkylating agents. AB - The selective C3-alkylation of indoles with N-protected ethanolamines involving the "borrowing hydrogen" strategy is described. This method provides convenient and sustainable access to several tryptamine derivatives. PMID- 25699685 TI - Conjugate-like immunogens produced as protein capsular matrix vaccines. AB - Capsular polysaccharides are the primary antigenic components involved in protective immunity against encapsulated bacterial pathogens. Although immunization of adolescents and adults with polysaccharide antigens has reduced pathogen disease burden, pure polysaccharide vaccines have proved ineffective at conferring protective immunity to infants and the elderly, age cohorts that are deficient in their adaptive immune responses to such antigens. However, T-cell independent polysaccharide antigens can be converted into more potent immunogens by chemically coupling to a "carrier protein" antigen. Such "conjugate vaccines" efficiently induce antibody avidity maturation, isotype switching, and immunological memory in immunized neonates. These immune responses have been attributed to T-cell recognition of peptides derived from the coupled carrier protein. The covalent attachment of polysaccharide antigens to the carrier protein is thought to be imperative to the immunological properties of conjugate vaccines. Here we provide evidence that covalent attachment to carrier proteins is not required for conversion of T-independent antigens into T-dependent immunogens. Simple entrapment of polysaccharides or a d-amino acid polymer antigen in a cross-linked protein matrix was shown to be sufficient to produce potent immunogens that possess the key characteristics of conventional conjugate vaccines. The versatility and ease of manufacture of these antigen preparations, termed protein capsular matrix vaccines (PCMVs), will likely provide improvements in the manufacture of vaccines designed to protect against encapsulated microorganisms. This in turn could improve the availability of such vaccines to the developing world, which has shown only a limited capacity to afford the cost of conventional conjugate vaccines. PMID- 25699686 TI - Conditioned pain modulation. AB - PURPOSE OF REVIEW: Conditioned pain modulation (CPM) paradigms have been increasingly used over the past few years to assess endogenous analgesia capacity in healthy individuals and pain patients. The current review concentrates on selected recent literature advancing our understanding and practice of CPM. RECENT FINDINGS: The main themes covered by the present CPM review include underlying mechanisms, approaches to experimental investigation, practicality in clinical practice, neurophysiological and psychophysiological correlates, and pharmacological solutions to pain modulation dysfunction. SUMMARY: The reviewed literature refines the methodology used for eliciting CPM responses and characterizing their physiological attributes in healthy individuals and pain patients, and exemplifies the materializing concept of individualized pain medicine through targeting impaired mechanisms of pain modulation by designated drugs for optimal pain alleviation. PMID- 25699687 TI - Prospective, multicenter, randomized, controlled pilot trial of peritoneal hypothermia in patients with ST-segment- elevation myocardial infarction. AB - BACKGROUND: Systemic hypothermia may reduce infarct size if established before reperfusion. The large surface area of the bowel may facilitate rapid hypothermia. We therefore examined the feasibility, safety, and efficacy of hypothermia induced by an automated peritoneal lavage system in patients with ST segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention. METHODS AND RESULTS: Patients with ST-segment-elevation myocardial infarction within 6 hours of symptom onset were randomized to peritoneal hypothermia before and for 3 hours after percutaneous coronary intervention versus control. The primary safety end point was the 30-day composite rate of death, reinfarction, ischemia-driven target vessel revascularization, major bleeding, sepsis, pneumonia, peritonitis, severe arrhythmia, or renal failure. The primary efficacy end point was infarct size assessed by cardiac MRI on day 3 to 5. Fifty-four patients were randomized at 7 centers to hypothermia (n=28) versus control (n=26). Hypothermia was successfully initiated in 96.3% of patients, and median [interquartile range] temperature at first balloon inflation was 34.7 [34.0-34.9] degrees C. Median door-to-balloon times in the hypothermia and control groups were 62 [51-81] and 47 [37-55] minutes, respectively (P=0.007). The primary safety end point occurred in 6 (21.4%) and 0 (0%) patients in the hypothermia and control groups, respectively (P=0.01), including 3 versus 0 stent thrombosis events. Infarct size was 17.2% [15.1-20.6] and 16.1% [10.0 22.2] in the hypothermia and control groups, respectively (P=0.54). CONCLUSIONS: Peritoneal hypothermia is feasible and achieves rapid cooling with only a modest increase in treatment times in the setting of ST-segment-elevation myocardial infarction. However, in the present randomized trial, peritoneal hypothermia was associated with an increased rate of adverse events without reducing infarct size. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01655433. PMID- 25699688 TI - Parenting in Complex Conditions: Does Preterm Birth Provide a Context for the Development of Less Optimal Parental Behavior? AB - OBJECTIVE: To examine the predictive value of parent, infant, and contextual factors related to preterm childbirth for later parenting behaviors. METHODS: Mothers (n = 217) and fathers (n = 204) of term, moderately preterm, and very preterm infants were interviewed 1 month postpartum using the Clinical Interview for Parents of high-risk infants (CLIP), to assess their experiences and perceptions related to the pregnancy, delivery, infant, hospitalization, support system, and their narratives. Their responses were factor analyzed and entered into prediction models of parental behaviors (National Institute of Child Health and Human Development observations) 6 months postpartum. RESULTS: Preterm birth was associated with negative experiences and concerns in parents. Regression analyses revealed, however, that irrespective of preterm birth, negative and unrealistic parental perceptions predicted less sensitive, more intrusive, and more withdrawn behavior. CONCLUSIONS: Not prematurity per se, but particularly the presence of negative perceptions in parents, is predictive of difficulties in parent-infant interaction. The CLIP is a potentially useful instrument to identify families at risk. PMID- 25699689 TI - Professor Einstein and the quantum mechanics. PMID- 25699690 TI - Impact of childhood life events and childhood trauma on the onset and recurrence of depressive and anxiety disorders. AB - OBJECTIVE: To investigate the effect of childhood life events and childhood trauma on the onset and recurrence of depressive and/or anxiety disorders over a 2-year period in participants without current psychopathology at baseline. METHOD: Longitudinal data in a large sample of participants without baseline DSM IV depressive or anxiety disorders (n = 1,167, aged 18 to 65 years; assessed between 2004-2007) were collected in the Netherlands Study of Depression and Anxiety (NESDA). Childhood life events and childhood trauma were assessed at baseline with a semistructured interview. The Composite International Diagnostic Interview, based on DSM-IV criteria, was used to diagnose first onset or recurrent depressive and/or anxiety disorders over a 2-year period. RESULTS: At baseline, 172 participants (14.7%) reported at least 1 childhood life event, and 412 (35.3%) reported any childhood trauma. During 2 years of follow-up, 226 participants (19.4%) developed a new (n = 58) or recurrent (n = 168) episode of a depressive and/or anxiety disorder. Childhood life events did not predict the onset and recurrence of depressive or anxiety disorders. Emotional neglect and psychological, physical, and sexual abuse were all associated with an increased risk of first onset and recurrence of either depressive or comorbid disorders (P < .001), but not of anxiety disorders. In multivariate models, emotional neglect was the only significant independent predictor of first onset and recurrence of any depressive or comorbid disorder (P = .002). These effects were primarily mediated by the severity of (subclinical) depressive symptoms at baseline and, to a lesser extent, by a prior lifetime diagnosis of a depressive and/or anxiety disorder. CONCLUSIONS: Childhood maltreatment is a key environmental risk factor, inducing vulnerability to develop new and recurrent depressive and comorbid anxiety and depressive episodes. PMID- 25699691 TI - UV-Vis spectrophotometric studies of self-oxidation/dissociation of quaternary ammonium permanganates (QAP) - impact of solvent polarity. AB - Self-oxidation/dissociation of some quaternary ammonium permanganates (QAPs), such as cetyltrimethylammonium permanganate (CTAP) and tetrabutylammonium permanganate (TBAP), have been studied spectrophotometrically in six different organic solvent media of different polarities wherein the compounds show good solubility and stability. The optical densities of the substrates at zero time (ODo) and first-order rate constants of dissociation (k1) have been determined from their successive scanning for 40min. At comparable experimental conditions, absorption capabilities of the substrates are compared from the ODo values in various organic media; the stability of the solutions is compared from the successive scan spectra in those media. The ODo values and the k1 values have been plotted against some solvent parameters to understand their effects on the absorbance and reactivity of the QAPs. These data are also subjected to multiple regression analysis to explain the influence of various solvent parameters on the ion-pairing properties of the substrates, thus elucidating their effects on the process of self-oxidation/dissociation of the substrates. PMID- 25699692 TI - Comparative study on bulk and composite fibrous samples photophysical feature: synthesis and characterization of a fluorine-containing Re(I) complex and its electrospinning fibers. AB - This paper reported a diamine ligand 2-(4-fluorophenyl)-5-(pyridin-2-yl)-1,3,4 oxadiazole (referred to as FPOZ) owing two typical electron-withdrawing moieties of an oxidiazole group and a fluorine atom, as well as its corresponding Re(I) complex Re(CO)3(FPOZ)Br. Geometric structure and electronic nature of Re(CO)3(FPOZ)Br were explored and discussed by single crystal analysis and theoretical calculation, which suggested that Re(CO)3(FPOZ)Br took a distorted octahedral coordination field. The onset electronic transitions owned a mixed character of metal-to-ligand-charge-transfer (MLCT) and ligand-to-ligand-charge transfer (LLCT). Re(CO)3(FPOZ)Br was then doped into a polymer host. Photophysical difference between resulting composite fibers and bulk Re(CO)3(FPOZ)Br was carefully performed, so that the correlation between emissive performance and electron-withdrawing group/geometric relaxation could be investigated. It was found that the immobilization in polymer matrix could repress MLCT excited state geometric relaxation, leading to improved PL parameters such as emission blue shift, longer excited state lifetime and higher photostability. PMID- 25699693 TI - A sensitive SERS substrate based on Au/TiO2/Au nanosheets. AB - Sensitive SERS substrates based on Au/TiO2/Au nanosheet have been prepared by physically sputtering Au nanoparticles onto fabricated TiO2 nanosheets. The Au/TiO2/Au nanosheets show much stronger SERS signal as compared to normal Au/Ti substrates by increasing surface area and effectively inducing plasmonic coupling between adjoining Au nanoparticles. In addition, influence factors such as concentration of probe solution and deposition time of gold nanoparticles were discussed. This study provides an easy-prepared and label-free substrate for the detection of biomolecule. PMID- 25699694 TI - Experimental and theoretical investigations of copper (I/II) complexes with triazine-pyrazole derivatives as ligands and their in situ C-N bond cleavage. AB - Two copper complexes, Cu(SCN)(Mpz(*)T-(EtO)2) (1) (Mpz(*)T-(EtO)2=L3) and CuCl(H2O)(Mpz(*)T-O2) (2) (Mpz(*)T-O2=L4) were synthesized by the reaction of 2,4,6-tri(3,5-dimethylpyrazol-1-yl)-1,3,5-triazine (L1) or 2,4,6-tri(1H-pyrazol-1 yl)-1,3,5-triazine (L2) with CuCl2.2H2O in anhydrous ethanol and methanol, respectively. The complexes were characterized by elemental analysis, IR spectroscopy, thermogravimetric analysis, single crystal X-ray diffraction and X ray powder diffraction. The structural characterizations and quantum mechanical calculations of the two complexes were analyzed in detail. It was found that an in site reaction occurred during the synthesis process of complexes 1 and 2, likely due to catalytic property of copper ions which leads to the C-N bond cleavage to generate new organic species, namely, Mpz(*)T-(EtO)2 (L3) and Mpz(*)T O2 (L4). PMID- 25699695 TI - Controllable biosynthesis of gold nanoparticles from a Eucommia ulmoides bark aqueous extract. AB - The present work reports the green synthesis of gold nanoparticles (AuNPs) by water extract of Eucommia ulmoides (E. ulmoides) bark. The effects of various parameters such as the concentration of reactants, pH of the reaction mixture, temperature and the time of incubation were explored to the controlled formation of gold nanoparticles. The characterization through high resolution-transmission electron microscopic (HRTEM), energy dispersive X-ray spectroscopy (EDX) and X ray diffraction (XRD) infer that the as-synthesized AuNPs were spherical in shape with a face cubic crystal (FCC) structure. The results from zeta potential and dynamic light scattering (DLS) suggest the good stability and narrow size distribution of the AuNPs. This method for synthesis of AuNPs is simple, economic, nontoxic and efficient. The as-synthesized AuNPs show excellent catalytic activity for the catalytic reducing decoloration of model compounds of azo-dye: reactive yellow 179 and Congo red. PMID- 25699696 TI - Differentiation of Leishmania species by FT-IR spectroscopy. AB - Leishmaniasis is a parasitic infectious disease caused by protozoa that belong to the genus Leishmania. It is transmitted by the bite of an infected female Sand fly. The disease is endemic in 88 countries Desjeux (2001) [1] (16 developed countries and 72 developing countries) on four continents. In Brazil, epidemiological data show the disease is present in all Brazilian regions, with the highest incidences in the North and Northeast. There are several methods used to diagnose leishmaniasis, but these procedures have many limitations, are time consuming, have low sensitivity, and are expensive. In this context, Fourier Transform Infrared Spectroscopy (FT-IR) analysis has the potential to provide rapid results and may be adapted for a clinical test with high sensitivity and specificity. In this work, FT-IR was used as a tool to investigate the promastigotes of Leishmaniaamazonensis, Leishmaniachagasi, and Leishmaniamajor species. The spectra were analyzed by cluster analysis and deconvolution procedure base on spectra second derivatives. RESULTS: cluster analysis found four specific regions that are able to identify the Leishmania species. The dendrogram representation clearly indicates the heterogeneity among Leishmania species. The band deconvolution done by the curve fitting in these regions quantitatively differentiated the polysaccharides, amide III, phospholipids, proteins, and nucleic acids. L. chagasi and L. major showed a greater biochemistry similarity and have three bands that were not registered in L. amazonensis. The L. amazonensis presented three specific bands that were not recorded in the other two species. It is evident that the FT-IR method is an indispensable tool to discriminate these parasites. The high sensitivity and specificity of this technique opens up the possibilities for further studies about characterization of other microorganisms. PMID- 25699697 TI - Selective colorimetric sensors based on the monitoring of an unmodified silver nanoparticles (AgNPs) reduction for a simple and rapid determination of mercury. AB - In this work, selective colorimetric sensors for simple and rapid detection of Hg(II) ions based on the monitoring of an unmodified silver nanoparticles (AgNPs) reduction were developed. The average diameter of synthesized AgNPs was 8.3+/ 1.4nm which was characterized by transmission electron microscopy (TEM). The abrupt change in absorbance of the unmodified AgNPs was observed which progressively decreased and slightly shifted to the blue wavelength as the concentration of Hg(II) increased, indicating the oxidation of Ag(0) to Ag(I) occurred. It appears that the AgNPs were oxidized by Hg(II), resulting in disintegration of the AgNPs into smaller particles as well as mediating the reduction of Hg(II) to Hg(0) adsorbed onto the surface of AgNPs. The adsorption of Hg(0) resulted in the lack of sufficient charges on AgNPs surfaces due to the decrease in the surface coverage of negatively charged citrate molecules, which then leaded to enlargement of AgNPs. The calibration curve of this technique was demonstrated from 0.5 to 7ppm (r(2)=0.995), the limit of detection (LOD) was 0.06ppm (SDblank/slope of calibration curve) with the precision (RSD, n=4) of 3.24-4.53. Interestingly, the results show a significant enhance in the Hg(II) analytical sensitivity when Cu(II) is doped onto the unmodified AgNPs, which improves the quantitative detection limit to 0.008ppm. In addition, greater selectivity toward Hg(II) compared with the other metal ions tested was observed. Furthermore, the percentage recoveries of spiked drinking water, tap water and SRM1641d (mercury in water) were in acceptable range with a good precision (RSD) which were in agreement with the values obtained from graphite furnace atomic absorption spectrometer (GFAAS). The technique proposed in this study provides a rapid, simple, sensitive and selective detection method for Hg(II) in water samples. PMID- 25699698 TI - Chiral power change upon photoisomerization in twisted nematic liquid crystals. AB - In this work, we use the photoisomerization of azobenzenes, a phenanthrospirooxazine, and a fulgide in a twisted nematic liquid crystalline phase to change the chiral twisting power of the system. The changes are probed by the rotatory power of linearly polarized light. Time resolved and steady state experiments are carried out. The chiral change and the photoisomerization process have similar characteristic recovery times and activation energy, thus probing that the change is induced by the modification in the chemical composition of the photochromic dopant system. The amplitude of the light twisting power change correlates with the order change in the liquid crystal (LC) but not with the modification in the absorption characteristics of the system. This indicates that the driving force of the chiral change is the microscopic order modification in the LC phase that affects the helical pitch of the phase. PMID- 25699699 TI - Studies on the growth, spectral, structural, electrical, optical and mechanical properties of Uronium 3-carboxy-4-hydroxybenzenesulfonate single crystal for third-order nonlinear optical applications. AB - Organic Uronium 3-carboxy-4-hydroxybenzenesulfonate (UCHBS) nonlinear optical single crystal was grown by solution growth technique. The solubility and nucleation studies were performed for UCHBS at different temperatures 30, 35, 40, 45, 50 and 55 degrees C. The crystal structure of UCHBS was elucidated from single crystal X-ray diffraction study. High resolution X-ray diffraction technique was employed to study the perfection and internal defects of UCHBS crystal. Infrared and Raman spectra were recorded to analyze the vibrational behavior of chemical bonds and its functional groups. The physico-chemical changes, stability and decomposition stages of the UCHBS compound were established by TG-DTA studies. The dielectric phenomenon of UCHBS crystal was studied at different temperatures with respect to frequency. Linear optical properties of transmittance, cut-off wavelength, band gap of UCHBS were found from UV-visible spectral studies. Third-order nonlinear optical susceptibility, nonlinear refractive index, nonlinear optical absorption coefficient values were measured by Z-scan technique. The mechanical properties of UCHBS crystal was studied by using Vicker's microhardness test. The growth features of UCHBS crystal were analyzed from etching studies. PMID- 25699700 TI - Deferiprone, a non-toxic reagent for determination of iron in samples via sequential injection analysis. AB - We present for the first time the use of deferiprone as a non-toxic complexing agent for the determination of iron by sequential injection analysis in pharmaceuticals and food samples. The method was based on the reaction of Fe(III) and deferiprone in phosphate buffer at pH 7.5 to give a Fe(III)-deferiprone complex, which showed a maximum absorption at 460nm. Under the optimum conditions, the linearity range for iron determination was found over the range of 0.05-3.0MUgmL(-1) with a correlation coefficient (r(2)) of 0.9993. The limit of detection and limit of quantitation were 0.032MUgmL(-1) and 0.055MUgmL(-1), respectively. The relative standard deviation (%RSD) of the method was less than 5.0% (n=11), and the percentage recovery was found in the range of 96.0-104.0%. The proposed method was satisfactorily applied for the determination of Fe(III) in pharmaceuticals, water and food samples with a sampling rate of 60h(-1). PMID- 25699701 TI - UV-Vis microspectrophotometry as a method of differentiation between cotton fibre evidence coloured with reactive dyes. AB - The main purposes of this study was to assess the usefulness of microspectrophotometry (MSP), both in the ultraviolet (UV) and visible (Vis) range for discriminating single cotton fibres dyed with reactive dyes coming from the same manufacturer, as well as the possibility of evaluation of the concentration of dye in an examine fibre. This study utilised woven cotton fabrics dyed with different concentrations of one-compound reactive dyes with the commercial name Cibacron(r) (at present Novacron(r)) as the focus of the MSP analysis. The spectra were recorded in the UV-Vis range between 200 and 800nm, in transmission mode. The results from this study illustrated that all of the analysed cotton samples dyed with reactive dyes were distinguishable between each other with the use of MSP, mostly in the visible, and also in ultraviolet range. The limit for applied MSP techniques was 0.18% of the concentration of a dye in the textile sample. The results indicate that based on the absorbance measurements for fibres constituting e.g. forensic traces it was not possible to estimate the concentration of the dye in the fibre because Beer's law did not obey. The intra-sample, and inter- sample variation, as well as dichroism effect in a case of a cotton fibres dyed with reactive dye were observed. On the basis of the results obtained for each analysed cotton sample, it was concluded that there was no correlation between colour uniformity in cotton fabric (changes in lightness, red/green and yellow/blue colour) and concentration of the reactive dye. PMID- 25699702 TI - Long-distance inter-hydrogen bond coupling effects in the polarized IR spectra of succinic acid crystals. AB - The spectral properties of four different crystalline succinic acid (HOOC-(CH2)2 COOH) (SAC) isotopomer systems, h6, d2, d4 and d6, were examined by means of the IR spectroscopy in polarized light aided by numerical simulations of the nuO-H and nuO-D band contour shapes on utilizing the "strong-coupling" model. The abnormal IR spectral properties of SAC crystals in relation to the corresponding properties of glutaric, pimelic and adipic acid crystals were ascribed to the hyperconjugation electronic effects in the acid associated molecules. A vibronic coupling mechanism involving the proton stretching vibrations in the (COOH)2 cycles and the electronic motions in the molecular skeletons, the isotopic "H/D self-organization" mechanisms and a long-distance vibrational exciton coupling between the adjacent (COOH)2 cycles in the molecular chains are mainly responsible for the generation of the temperature effects in the crystalline IR spectra. PMID- 25699703 TI - Isotherm and kinetics study of malachite green adsorption onto copper nanowires loaded on activated carbon: artificial neural network modeling and genetic algorithm optimization. AB - In this study, copper nanowires loaded on activated carbon (Cu-NWs-AC) was used as novel efficient adsorbent for the removal of malachite green (MG) from aqueous solution. This new material was synthesized through simple protocol and its surface properties such as surface area, pore volume and functional groups were characterized with different techniques such XRD, BET and FESEM analysis. The relation between removal percentages with variables such as solution pH, adsorbent dosage (0.005, 0.01, 0.015, 0.02 and 0.1g), contact time (1-40min) and initial MG concentration (5, 10, 20, 70 and 100mg/L) was investigated and optimized. A three-layer artificial neural network (ANN) model was utilized to predict the malachite green dye removal (%) by Cu-NWs-AC following conduction of 248 experiments. When the training of the ANN was performed, the parameters of ANN model were as follows: linear transfer function (purelin) at output layer, Levenberg-Marquardt algorithm (LMA), and a tangent sigmoid transfer function (tansig) at the hidden layer with 11 neurons. The minimum mean squared error (MSE) of 0.0017 and coefficient of determination (R(2)) of 0.9658 were found for prediction and modeling of dye removal using testing data set. A good agreement between experimental data and predicted data using the ANN model was obtained. Fitting the experimental data on previously optimized condition confirm the suitability of Langmuir isotherm models for their explanation with maximum adsorption capacity of 434.8mg/g at 25 degrees C. Kinetic studies at various adsorbent mass and initial MG concentration show that the MG maximum removal percentage was achieved within 20min. The adsorption of MG follows the pseudo second-order with a combination of intraparticle diffusion model. PMID- 25699704 TI - A new path to leukemia with WIT. AB - In this issue, Wang et al., 2015 describes that WT1 recruits TET2 to the DNA, an important feature of a new regulatory pathway linked to the development of acute myeloid leukemia (AML). This pathway consists of WT1, IDH1/2, and TET2 (WIT) genes, with exclusive mutations of the three genes inducing myeloid cell proliferation. PMID- 25699705 TI - Micro(RNA) managing by mTORC1. AB - In this issue of Molecular Cell, Ye et al. (2015) demonstrate that mTORC1 globally regulates miRNA biogenesis under nutrient-rich conditions via the E3 ubiquitin ligase Mdm2, which promotes Drosha degradation. PMID- 25699706 TI - TOPping off meiosis. AB - Double-strand breaks (DSBs) threaten chromosome integrity. The most accurate repair of DSBs is by homologous recombination (HR), catalyzed by recombination proteins such as Rad51. Three papers in this issue of Molecular Cell (Fasching et al., 2015; Kaur et al., 2015; Tang et al., 2015) now reveal the role of three of these proteins in budding yeast: Sgs1 (BLM homolog), Top3 (TOPIIIalpha homolog), and Rmi1. They demonstrate several steps where all three proteins act together, and find additional functions of the Top3-Rmi1 subcomplex that are critical for the completion of meiosis. PMID- 25699707 TI - Top3-Rmi1 DNA single-strand decatenase is integral to the formation and resolution of meiotic recombination intermediates. AB - The topoisomerase III (Top3)-Rmi1 heterodimer, which catalyzes DNA single-strand passage, forms a conserved complex with the Bloom's helicase (BLM, Sgs1 in budding yeast). This complex has been proposed to regulate recombination by disassembling double Holliday junctions in a process called dissolution. Top3 Rmi1 has been suggested to act at the end of this process, resolving hemicatenanes produced by earlier BLM/Sgs1 activity. We show here that, to the contrary, Top3-Rmi1 acts in all meiotic recombination functions previously associated with Sgs1, most notably as an early recombination intermediate chaperone, promoting regulated crossover and noncrossover recombination and preventing aberrant recombination intermediate accumulation. In addition, we show that Top3-Rmi1 has important Sgs1-independent functions that ensure complete recombination intermediate resolution and chromosome segregation. These findings indicate that Top3-Rmi1 activity is important throughout recombination to resolve strand crossings that would otherwise impede progression through both early steps of pathway choice and late steps of intermediate resolution. PMID- 25699708 TI - Top3-Rmi1 dissolve Rad51-mediated D loops by a topoisomerase-based mechanism. AB - The displacement loop (D loop) is a DNA strand invasion product formed during homologous recombination. Disruption of nascent D loops prevents recombination, and during synthesis-dependent strand annealing (SDSA), disruption of D loops extended by DNA polymerase ensures a non-crossover outcome. The proteins implicated in D loop disruption are DNA motor proteins/helicases that act by moving DNA junctions. Here we report that D loops can also be disrupted by DNA topoisomerase 3 (Top3), and this disruption depends on Top3's catalytic activity. Yeast Top3 specifically disrupts D loops mediated by yeast Rad51/Rad54; protein free D loops or D loop mediated by bacterial RecA protein or human RAD51/RAD54 resist dissolution. Also, the human Topoisomerase IIIa-RMI1-RMI2 complex is capable of dissolving D loops. Consistent with genetic data, we suggest that the extreme growth defect and hyper-recombination phenotype of Top3-deficient yeast cells is partially a result of unprocessed D loops. PMID- 25699709 TI - Pervasive and essential roles of the Top3-Rmi1 decatenase orchestrate recombination and facilitate chromosome segregation in meiosis. AB - The Bloom's helicase ortholog, Sgs1, plays central roles to coordinate the formation and resolution of joint molecule intermediates (JMs) during meiotic recombination in budding yeast. Sgs1 can associate with type-I topoisomerase Top3 and its accessory factor Rmi1 to form a conserved complex best known for its unique ability to decatenate double-Holliday junctions. Contrary to expectations, we show that the strand-passage activity of Top3-Rmi1 is required for all known functions of Sgs1 in meiotic recombination, including channeling JMs into physiological crossover and noncrossover pathways, and suppression of non-allelic recombination. We infer that Sgs1 always functions in the context of the Sgs1 Top3-Rmi1 complex to regulate meiotic recombination. In addition, we reveal a distinct late role for Top3-Rmi1 in resolving recombination-dependent chromosome entanglements to allow segregation at anaphase. Surprisingly, Sgs1 does not share this essential role of Top3-Rmi1. These data reveal an essential and pervasive role for the Top3-Rmi1 decatenase during meiosis. PMID- 25699710 TI - BRCA1 recruitment to transcriptional pause sites is required for R-loop-driven DNA damage repair. AB - The mechanisms contributing to transcription-associated genomic instability are both complex and incompletely understood. Although R-loops are normal transcriptional intermediates, they are also associated with genomic instability. Here, we show that BRCA1 is recruited to R-loops that form normally over a subset of transcription termination regions. There it mediates the recruitment of a specific, physiological binding partner, senataxin (SETX). Disruption of this complex led to R-loop-driven DNA damage at those loci as reflected by adjacent gamma-H2AX accumulation and ssDNA breaks within the untranscribed strand of relevant R-loop structures. Genome-wide analysis revealed widespread BRCA1 binding enrichment at R-loop-rich termination regions (TRs) of actively transcribed genes. Strikingly, within some of these genes in BRCA1 null breast tumors, there are specific insertion/deletion mutations located close to R-loop mediated BRCA1 binding sites within TRs. Thus, BRCA1/SETX complexes support a DNA repair mechanism that addresses R-loop-based DNA damage at transcriptional pause sites. PMID- 25699711 TI - Zic2 is an enhancer-binding factor required for embryonic stem cell specification. AB - The Zinc-finger protein of the cerebellum 2 (Zic2) is one of the vertebrate homologs of the Drosophila pair-rule gene odd-paired (opa). Our molecular and biochemical studies demonstrate that Zic2 preferentially binds to transcriptional enhancers and is required for the regulation of gene expression in embryonic stem cells. Detailed genome-wide and molecular studies reveal that Zic2 can function with Mbd3/NuRD in regulating the chromatin state and transcriptional output of genes linked to differentiation. Zic2 is required for proper differentiation of embryonic stem cells (ESCs), similar to what has been previously reported for Mbd3/NuRD. Our study identifies Zic2 as a key factor in the execution of transcriptional fine-tuning with Mbd3/NuRD in ESCs through interactions with enhancers. Our study also points to the role of the Zic family of proteins as enhancer-specific binding factors functioning in development. PMID- 25699713 TI - Identification of the molecular basis of inhibitor selectivity between the human and streptococcal type I methionine aminopeptidases. AB - The methionine aminopeptidase (MetAP) family is responsible for the cleavage of the initiator methionine from newly synthesized proteins. Currently, there are no small molecule inhibitors that show selectivity toward the bacterial MetAPs compared to the human enzyme. In our current study, we have screened 20 alpha aminophosphonate derivatives and identified a molecule (compound 15) that selectively inhibits the S. pneumonia MetAP in low micromolar range but not the human enzyme. Further bioinformatics, biochemical, and structural analyses suggested that phenylalanine (F309) in the human enzyme and methionine (M205) in the S. pneumonia MetAP at the analogous position render them with different susceptibilities against the identified inhibitor. X-ray crystal structures of various inhibitors in complex with wild type and F309M enzyme further established the molecular basis for the inhibitor selectivity. PMID- 25699712 TI - Stress induces p38 MAPK-mediated phosphorylation and inhibition of Drosha dependent cell survival. AB - MicroRNAs (miRNAs) regulate the translational potential of their mRNA targets and control many cellular processes. The key step in canonical miRNA biogenesis is the cleavage of the primary transcripts by the nuclear RNase III enzyme Drosha. Emerging evidence suggests that the miRNA biogenic cascade is tightly controlled. However, little is known whether Drosha is regulated. Here, we show that Drosha is targeted by stress. Under stress, p38 MAPK directly phosphorylates Drosha at its N terminus. This reduces its interaction with DiGeorge syndrome critical region gene 8 and promotes its nuclear export and degradation by calpain. This regulatory mechanism mediates stress-induced inhibition of Drosha function. Reduction of Drosha sensitizes cells to stress and increases death. In contrast, increase in Drosha attenuates stress-induced death. These findings reveal a critical regulatory mechanism by which stress engages p38 MAPK pathway to destabilize Drosha and inhibit Drosha-mediated cellular survival. PMID- 25699971 TI - Primary selection into shift work and change of cardiovascular risk profile. AB - OBJECTIVES: A potential "healthy shift worker effect" may bias the studied effect of shift work on health. The observed differences among shift and day workers in health behavior and health outcomes can be caused by: (i) primary selection, (ii) the influence from the shift work-related environment, and (iii) the impact of shift work. We aimed to study these potential sources. METHODS: A cohort of 4754 male trainees who had finished their professional training and started their career in production in a chemical company between 1995 and 2012 was identified. Among them, 1348 (28%) were involved in rotating shift work and 3406 (72%) in day work. Information on health behavior and risk factors for cardiovascular diseases was retrieved from the medical examinations. This information was then compared (i) at the beginning of training, (ii) at the end of training, and (iii) 3 years after the employment, in relation to the working time. RESULTS: At the beginning of the training, the prevalence of smokers was higher among future shift workers (26% versus 21%), from 1995 to 2012. During the training and the first three years of employment, a marginal decline of systolic blood pressure and an elevation of triglyceride were related with shift work. No difference was found with respect to other risk factors for cardiovascular diseases. CONCLUSIONS: Our findings do not support a primary selection in favor of shift workers. An impact of shift work on the risk profile of cardiovascular diseases was not indicated in the observation period. PMID- 25699972 TI - Structure of a zwitterionic O-polysaccharide from Photorhabdus temperata subsp. cinerea 3240. AB - A phosphorylated O-polysaccharide was isolated from the lipopolysaccharide of an entomopathogenic bacterium Photorhabdus temperata subsp. cinerea 3240 and studied by sugar analysis, dephosphorylation, and (1)H and (13)C NMR spectroscopy. The following structure of the linear trisaccharide repeating unit of the O polysaccharide was established: ->3)-beta-D-GalpNAc4PEtN-(1->4)-beta-D-GlcpA-(1 >3)-beta-D-FucpNAc4N-(1-> where GlcA indicates glucuronic acid, FucNAc4N 2 acetamido-4-amino-2,4,6-trideoxygalactose, and PEtN 2-aminoethyl phosphate. PMID- 25699973 TI - Mass spectrometry-based method to investigate the natural selectivity of sucrose as the sugar transport form for plants. AB - Sucrose is the carbon skeletons and energy vector for plants, which is important for plants growth. Among thousands of disaccharides in Nature, why chose sucrose for plants? In this paper, we analyzed the intrinsic structural characteristics of four sucrose isomers with different glycosidic linkage by mass spectrometry (MS) technique. Our results show that sucrose has the most labile glycosidic bond compared with other three isomers, which is helpful for releasing glucose and fructose unit. Besides, sucrose has the most stable integral structure, which is hard to dehydrate and degrade into fragments through losing one or three even four-carbon units, just as its three isomers. In other words, sucrose is more easily holds an integral structure during the transport process, whenever it is necessary, and sucrose can be cleaved into glucose and fructose easily. Besides, we also investigate the internal relationship of sucrose with K(+) by tandem mass spectrometry and viscosity measurement. The related results have shown that the K(+) can stabilize sucrose to a greater extent than the Na(+). Furthermore, under the same conditions, K(+) ions reduce the viscosity of sucrose-water system much more than Na(+). These results suggest that K(+) is a better co-transporter for sucrose. Of course, the transport of sucrose in plants is a very complicated process, which is involved in many proteins. This paper directly accounts for the basic structure feature of sucrose, and the results discovered could provide the novel insight for the answer why Nature chose sucrose for plants. PMID- 25699974 TI - Nuclear magnetic resonance studies of the interactions between the organic germanium compound Ge-132 and saccharides. AB - Poly-trans-[(2-carboxyethyl)germasesquioxane], Ge-132, is a water-soluble organic germanium compound with many reported physiological functions. The hydrolysate of Ge-132, 3-(trihydroxygermyl)propanoic acid, can interact with diol compounds; therefore, it can possibly interact with diol-containing sugar compounds, which have important physiological functions in sugar chains, glycoproteins, and glucolipids. In this study, we examined the interaction between sodium 3 (trihydroxygermyl)propanoate and monosaccharides using nuclear magnetic resonance. When 1,4-anhydroerythritol was mixed with sodium 3 (trihydroxygermyl)propanoate, a pattern of signals different from that obtained for each solute alone was observed. Some signals were broader, and novel signals with different chemical shifts appeared to originate from complex formation. Spectral observations for sodium 3-(trihydroxygermyl)propanoate and the sugar isomers of glucose and fructose indicated that sodium 3 (trihydroxygermyl)propanoate has a higher affinity for fructose (a ketose) than glucose (an aldose). Moreover, the beta-furanosyl conformation of fructose was the structure that interacted most with sodium 3-(trihydroxygermyl)propanoate. These results demonstrate the ability of aqueous Ge-132 to form complexes with the cis-diol structures of saccharides. Thus, interactions among 3 (trihydroxygermyl)propanoic acid and the important biological sugar compounds might be implicated in the physiological function of Ge-132. PMID- 25699975 TI - Isolation and characterization of feruloylated arabinoxylan oligosaccharides from the perennial cereal grain intermediate wheat grass (Thinopyrum intermedium). AB - In comparison to the annual grain crops dominating current agricultural production, perennial grain species require fewer chemical and energy inputs and improve soil health and erosion control. The possibility for producing sustainable grain harvests from marginal land areas is motivating research initiatives to integrate perennial grains into commercial cropping and food processing systems. In this study, the feruloylated arabinoxylans from intermediate wheat grass (Thinopyrum intermedium, IWG), a promising perennial grain candidate in agronomic screening studies, were investigated. Insoluble fiber isolated from IWG whole grain flour was subjected to either mildly acidic (50 mM TFA, 100 degrees C, 2 h) or enzymatic (Driselase) hydrolysis. The liberated feruloylated arabinoxylan oligosaccharides were concentrated with Amberlite XAD-2, separated with gel chromatography (Sephadex LH-20, water), and purified with reversed-phase HPLC (C18, water-MeOH gradient). Thirteen feruloylated oligosaccharides were isolated (including eight structures described for the first time) and identified by LC-ESI-MS and NMR. Linkage-type analysis via methylation analysis, as well as the monosaccharide and phenolic acid profiles of the IWG insoluble fiber were also determined. IWG feruloylated arabinoxylans have a relatively simple structure with only short feruloylated side chains, a lower backbone substitution rate than annual rye and wheat varieties, and a moderate phenolic acid content. PMID- 25699976 TI - Hypertension phenotypes and incident cardiovascular disease and mortality events in a decade follow-up of a Middle East cohort. AB - OBJECTIVE: To investigate the association of hypertension phenotypes, with the risk of cardiovascular disease (CVD) and mortality. METHODS: We examined the risk of hypertension phenotypes, that is, isolated systolic hypertension (ISH), isolated diastolic hypertension (IDH), systolic-diastolic hypertension (SDH), controlled blood pressure (CBP), and uncontrolled blood pressure (UBP) among 6974 middle-aged and 882 elderly participants. Cox regression analysis was used to estimate the hazard ratio for hypertension phenotypes, considering those with normotension as the reference. RESULTS: During more than 10 years of follow-up, in the middle-aged group, 490 CVD events and 152 deaths occurred; corresponding rates for the elderly group were 194 and 183, respectively. In middle-aged patients, ISH, SDH, and UBP increased the risk of CVD, whereas UBP increased the risk of mortality due to CVD and any cause (hazard ratio 5.67 and 2.95, respectively) and IDH increased only the risk of total mortality in the middle aged group (hazard ratio 2.01; all P values <0.05). In elderly patients, ISH, SDH, and UBP significantly increased the risks of CVD. IDH (hazard ratio 3.20 and 2.01), SDH (hazard ratio 3.80 and 3.23) and CBP (hazard ratio 2.86 and 1.87) increased the risks of CVD and all-cause mortality in this group, respectively (all P values <0.05). CONCLUSION: In both middle-aged and elderly population, ISH, SDH, and UBP increase the risk of CVD. Controlling of BP to less than 140/90 mmHg decreases the risk of mortality events among the middle-aged population; however, it is not suitable for the elderly as it was associated with higher risk of mortality. PMID- 25699977 TI - Immunohistochemistry in the diagnosis of cutaneous bacterial infections. AB - The identification of pathogens is of vital importance for the adequate treatment of infections. During the past 2 decades, the approach to histopathologic diagnosis has been dramatically transformed by immunohistochemistry (IHC) specifically in the diagnosis and classification of tumors and more recently in the diagnosis of infectious diseases in tissue samples. The main goals of this article were to: (1) identify by IHC the cutaneous structures where bacterial pathogens are expressed in the course of infection, (2) identify the specific cells in which bacterial pathogens are expressed in positive cases, and (3) describe the pattern of distribution of the bacterial antigens within these cells (nuclear, cytoplasmatic, or membranous). This article is an up-to-date overview of the potential uses and limitations of IHC in the histopathologic diagnosis of cutaneous bacterial infections. In conclusion, IHC is especially useful in the identification of microorganisms that are present in low numbers, stain poorly, are fastidious to grow, culture is not possible, or exhibit an atypical morphology. PMID- 25699978 TI - Transplant patient with skin nodules. Acanthamoeba spp. PMID- 25699979 TI - Transplant patient with skin nodules. PMID- 25699980 TI - Merkel cell carcinoma with glandular differentiation admixed with sweat gland carcinoma and spindle cell carcinoma: histogenesis of merkel cell carcinoma from hair follicle stem cells. AB - We describe a unique case of Merkel cell carcinoma (MCC) with a heterogeneous differentiation exhibiting distinct triphasic phenotypic differentiation features: small cells typical of MCC, sweat gland carcinoma (sweat gland Ca.) with possible decapitation secretion, and spindle cell carcinoma (spindle cell Ca.). The patient was an 84-year-old Japanese woman. We evaluated the present case immunohistochemically with various antibodies. The histological features showed a gradual transition from MCC to sweat gland Ca. and spindle cell Ca. For clarifying the histogenesis, immunophenotypic analysis of the 3 different components of the carcinoma was performed using hair follicle stem cell markers (eg, CK15, CK19, and CD200) that have been identified as biomarkers of human bulge cells. The triphasic components immunohistochemically shared the characteristic feature of CK19 and CD200 expression. We posit that the MCC arose from hair follicle stem cells residing within the bulge area where Merkel cells are preferentially situated. Based on our findings, we recommend adding this rare neoplasm to the expanding morphological spectrum of MCC. PMID- 25699981 TI - The Current Status of Tissue-Engineered Vascular Grafts. AB - Tissue-engineered vascular grafts (TEVGs) are currently being developed to overcome the limitations and complications associated with traditional synthetic grafts. This article aims to review the current status of research into the production and use of tissue-engineered grafts. TEVGs have a number of theoretical advantages over synthetic grafts. The results of animal and human studies have been promising, but more work must be done before TEVGs can replace traditional grafts. PMID- 25699982 TI - Circulating Biomarkers Predictive of Postoperative Atrial Fibrillation. AB - Postoperative atrial fibrillation (PoAF), a common complication of cardiac surgery, contributes significantly to morbidity, mortality, and increasing healthcare costs. Despite advances in surgical and medical management, the overall incidence of PoAF has not changed significantly, partly because of the limited understanding of mechanisms underlying acute surgery-related factors, such as myocardial injury, inflammation, sympathetic activation, and oxidative stress, which play an important role in the initiation of PoAF, whereas a preexisting atrial substrate appears to be more important in the maintenance of this dysrhythmia. Thus, in a majority of patients, PoAF becomes a manifestation of an underlying arrhythmogenic substrate that is unmasked after acute surgical stress. As such, the ability to identify which patients have this proarrhythmic substrate and are, therefore, at high risk for developing AF postoperatively, is important for the improved selection for prophylactic interventions, closer monitoring for complications, and establishing the probability of AF in the long term. This review highlights the role of the underlying substrate in promoting PoAF, proposed mechanisms, and the potential role of serum biomarkers to identify patients at risk for PoAF. PMID- 25699983 TI - Novel Biomarkers of Acute Kidney Injury After Contrast Coronary Angiography. AB - Acute kidney injury (AKI), defined as a rise in serum creatinine of greater than 25% from baseline measured at 48 hours after renal insult, may follow iodinated contrast coronary angiography. Termed contrast-induced nephropathy, it can result in considerable morbidity and mortality. Measurement of serum creatinine as a functional biomarker of glomerular filtration rate is widely used for detection of AKI, but it lacks sensitivity for the early diagnosis of AKI (typically rising 24 hours after functional loss) and, as a solely functional marker of glomerular filtration rate, is unable to differentiate among the various causes of AKI. These intrinsic limitations to creatinine measurement and the recognition that improved clinical outcomes are linked to a more timely diagnosis of AKI, has led investigators to search for novel biomarkers of "early" kidney injury. Several studies have investigated the utility of renal injury biomarkers in a variety of clinical settings including angiography/percutaneous coronary intervention, coronary artery bypass graft surgery, sepsis in intensive care patients, and pediatric cardiac surgery. In this article, we discuss the use of iodinated contrast for coronary procedures and the risk factors for contrast-induced nephropathy, followed by a review the potential diagnostic utility of several novel biomarkers of early AKI in the clinical settings of coronary angiography/percutaneous coronary intervention. In particular, we discuss neutrophil gelatinase associated lipocalin in depth. If validated, such biomarkers would facilitate earlier AKI diagnosis and improve clinical outcomes. PMID- 25699986 TI - Diverse Effects of Conditioned Threat Stimuli on Behavior. AB - Aversive Pavlovian memory coordinates the defensive behavioral response to learned threats. The amygdala is a key locus for the acquisition and storage of aversive associations. Information about conditioned and unconditioned stimuli converge in the lateral amygdala, which is a hot spot for the plasticity induced by associative learning. Central amygdala uses Pavlovian memory to coordinate the conditioned reaction to an aversive conditioned stimulus. Aversive associations can also access the brain networks of instrumental action. The offset of an aversive conditioned stimulus can reinforce behavior, recruiting a pathway that includes the lateral and basal amygdala, as opposed to the lateral and central amygdala circuit for Pavlovian reactions. Aversive conditioned stimuli can also modulate ongoing behavior, suppressing appetitive actions and facilitating aversive actions. Facilitation depends on an amygdalar network involving the lateral and central, as well as medial, nuclei. Thus, aversive Pavlovian memory has wide-reaching effects on defensive behavior, coordinating reactive to active responses to environmental threats. PMID- 25699984 TI - The periconceptional environment and cardiovascular disease: does in vitro embryo culture and transfer influence cardiovascular development and health? AB - Assisted Reproductive Technologies (ARTs) have revolutionised reproductive medicine; however, reports assessing the effects of ARTs have raised concerns about the immediate and long-term health outcomes of the children conceived through ARTs. ARTs include manipulations during the periconceptional period, which coincides with an environmentally sensitive period of gamete/embryo development and as such may alter cardiovascular development and health of the offspring in postnatal life. In order to identify the association between ARTs and cardiovascular health outcomes, it is important to understand the events that occur during the periconceptional period and how they are affected by procedures involved in ARTs. This review will highlight the emerging evidence implicating adverse cardiovascular outcomes before and after birth in offspring conceived through ARTs in both human and animal studies. In addition, it will identify the potential underlying causes and molecular mechanisms responsible for the congenital and adult cardiovascular dysfunctions in offspring whom were conceived through ARTs. PMID- 25699988 TI - Synthesis, structures, and photophysical properties of pi-expanded oligothiophene 8-mers and their Saturn-like C60 complexes. AB - Two isomers of a multifunctional pi-expanded macrocyclic oligothiophene 8-mer, E,E-1 and Z,Z-1, were synthesized using a McMurry coupling of a dialdehyde composed of four 2,5-thienylene and three ethynylene units under high dilution conditions. On the other hand, cyclo[8](2,5-thienylene-ethynylene) 2 was synthesized by intramolecular Sonogashira cyclization of ethynyl bromide 5. From STM measurements, both E,E-1 and Z,Z-1 formed self-assembled monolayers at the solid-liquid interface to produce porous networks, and from X-ray analyses of E,E 1 and 2, both compounds had a round shape with a honeycomb stacked structure. E,E 1 formed various fibrous polymorphs due to nanophase separation of the macrorings. E,E-1 and Z,Z-1 in solution exhibited photochromism upon irradiation with visible and UV light, respectively, and this photoisomerization was confirmed by using STM. Furthermore, amorphous films of Z,Z-1 and E,E-1 showed photoisomerization, although single crystals, fibers, and square tubes of E,E-1 remained unchanged under similar conditions. E,E-1 with a 12.5-14.7 A inner cavity incorporated fullerene C60 in the cavity in solution and the solid state to produce a Saturn-like complex, whose structure was determined by X-ray analysis. 2 also formed a Saturn-like complex with C60 in the solid state. These Saturn-like complexes are stabilized by van der Waals interactions between the sulfur atoms of 8-mer and C60. The complexes exhibited charge-transfer interactions in the solid state. Like E,E-1, Saturn-like complex E,E-1?C60 formed small cube and fiber structures depending on the solvent used, whereas those of Saturn-like complex 2?C60 were limited due to the rigidity of the macroring of 2. PMID- 25699985 TI - Arginine and citrulline and the immune response in sepsis. AB - Arginine, a semi-essential amino acid is an important initiator of the immune response. Arginine serves as a precursor in several metabolic pathways in different organs. In the immune response, arginine metabolism and availability is determined by the nitric oxide synthases and the arginase enzymes, which convert arginine into nitric oxide (NO) and ornithine, respectively. Limitations in arginine availability during inflammatory conditions regulate macrophages and T lymfocyte activation. Furthermore, over the past years more evidence has been gathered which showed that arginine and citrulline deficiencies may underlie the detrimental outcome of inflammatory conditions, such as sepsis and endotoxemia. Not only does the immune response contribute to the arginine deficiency, also the impaired arginine de novo synthesis in the kidney has a key role in the eventual observed arginine deficiency. The complex interplay between the immune response and the arginine-NO metabolism is further underscored by recent data of our group. In this review we give an overview of physiological arginine and citrulline metabolism and we address the experimental and clinical studies in which the arginine-citrulline NO pathway plays an essential role in the immune response, as initiator and therapeutic target. PMID- 25699987 TI - Internal and External Feedback Circuits for Skilled Forelimb Movement. AB - Skilled motor behavior emerges from interactions between efferent neural pathways that induce muscle contraction and feedback systems that report and refine movement. Two broad classes of feedback projections modify motor output, one from the periphery and a second that originates within the central nervous system. The mechanisms through which these pathways influence movement remain poorly understood, however. Here we discuss recent studies that delineate spinal circuitry that binds external and internal feedback pathways to forelimb motor behavior. A spinal presynaptic inhibitory circuit regulates the strength of external feedback, promoting limb stability during goal-directed reaching. A distinct excitatory propriospinal circuit conveys copies of motor commands to the cerebellum, establishing an internal feedback loop that rapidly modulates forelimb motor output. The behavioral consequences of manipulating these two circuits reveal distinct controls on motor performance and provide an initial insight into feedback strategies that underlie skilled forelimb movement. PMID- 25699989 TI - Enhanced responsibilities for pharmacy interns at a teaching hospital. AB - OBJECTIVE: To describe the implementation of a pharmacy intern distribution coordinator position and its impact on the intern's professional development. SETTING: Tertiary academic medical center. PRACTICE DESCRIPTION: In 2009, our institution implemented a pharmacy intern distribution coordinator position, which was previously staffed by a pharmacist. Interns, who are in their first through fourth professional year, take the lead in the medication distribution process while under the direct supervision of a pharmacist. The intern adjudicates the medication distribution process by ensuring proper processing, filling and timely delivery of the medications, as well as triaging inventory issues and maintaining open communication with the pharmacists about any medication issues. Additionally, the intern can make clinical interventions during the various checkpoints in the final verification process and answer drug information questions for fellow medical professionals. PRACTICE INNOVATION: Pharmacy intern resources and development are maximized via staffing in a medication distribution coordinator position previously staffed by a pharmacist. By adapting to the role of pharmacist early on in one's career, pharmacy interns are provided with a valuable opportunity to grow professionally. The position can foster the development of pharmacotherapy knowledge, communication skills, leadership experience, time management, and critical thinking by allowing pharmacy interns to practice at the top of their licensure. CONCLUSION: Our pharmacy intern distribution coordinator position provides interns with a professional development opportunity by assuming enhanced roles and responsibilities in a hospital pharmacy department. The expansion of the pharmacy intern's role can increase pharmacy department resources and provide a valuable platform for their development. Institutions should seek to maximize the opportunities for pharmacy interns to work at the peak of their licensure. PMID- 25699990 TI - Time Left for Intervention in the Suicidal Process in Borderline Personality Disorder. AB - The objective of this study was to measure the duration of the suicidal process among patients diagnosed with Borderline Personality Disorder (BPD). The sample included 110 female patients who met DSM-IV-TR criteria for BPD and were consecutively admitted after suicide-related behavior. A total of 63 patients (58%) reported that their suicidal process lasted 10 minutes or less. After being adjusted, the beta coefficient of impulsivity scales in women with a suicidal process <=10 minutes was lower compared to those observed in women with >10 min (beta = -0.03, 95% CI = -0.06 = -0.01, p < 0.01). Suicidal patients with BPD can be divided into two groups; patients who report a suicidal process less than 10 minutes show a higher degree of impulsivity. PMID- 25699991 TI - Towards graphyne molecular electronics. AB - alpha-Graphyne, a carbon-expanded version of graphene ('carbo-graphene') that was recently evidenced as an alternative zero-gap semiconductor, remains a theoretical material. Nevertheless, using specific synthesis methods, molecular units of alpha-graphyne ('carbo-benzene' macrocycles) can be inserted between two anilinyl (4-NH2-C6H4)-anchoring groups that allow these fragments to form molecular junctions between gold electrodes. Here, electrical measurements by the scanning tunnelling microscopy (STM) break junction technique and electron transport calculations are carried out on such a carbo-benzene, providing unprecedented single molecule conductance values: 106 nS through a 1.94-nm N-N distance, essentially 10 times the conductance of a shorter nanographenic hexabenzocoronene analogue. Deleting a C4 edge of the rigid C18 carbo-benzene circuit results in a flexible 'carbo-butadiene' molecule that has a conductance 40 times lower. Furthermore, carbo-benzene junctions exhibit field-effect transistor behaviour when an electrochemical gate potential is applied, opening the way for device applications. All the results are interpreted on the basis of theoretical calculations. PMID- 25699992 TI - Tracking second thoughts: continuous and discrete revision processes during visual lexical decision. AB - We studied the dynamics of lexical decisions by asking participants to categorize lexical and nonlexical stimuli and recording their mouse movements toward response buttons during the choice. In a previous report we revealed greater trajectory curvature and attraction to competitors for Low Frequency words and Pseudowords. This analysis did not clarify whether the trajectory curvature in the two conditions was due to a continuous dynamic competition between the response alternatives or if a discrete revision process (a "change of mind") took place during the choice from an initially selected response to the opposite one. To disentangle these two possibilities, here we analyse the velocity and acceleration profiles of mouse movements during the choice. Pseudowords' peak movement velocity occurred with 100 ms delay with respect to words and Letters Strings. Acceleration profile for High and Low Frequency words and Letters Strings exhibited a butterfly plot with one acceleration peak at 400 ms and one deceleration peak at 650 ms. Differently, Pseudowords' acceleration profile had double positive peaks (at 400 and 600 ms) followed by movement deceleration, in correspondence with changes in the decision from lexical to nonlexical response buttons. These results speak to different online processes during the categorization of Low Frequency words and Pseudowords, with a continuous competition process for the former and a discrete revision process for the latter. PMID- 25699993 TI - Identification and analysis of genetic variations in pri-miRNAs expressed specifically or at a high level in sheep skeletal muscle. AB - MicroRNAs (miRNAs) are key regulators in miRNA-mediated gene regulatory networks and play important roles in many biological processes, such as growth and development of mammals. In this study, we used microarrays to detect 261 miRNAs that are expressed in sheep skeletal muscle. We found 22 miRNAs that showed high levels of expression and equated to 89% of the total miRNA. Genetic variations in these 22 pri-miRNAs were further investigated using polymerase chain reaction single strand conformation polymorphism (PCR-SSCP) and sequencing. A total of 49 genetic variations, which included 41 single nucleotide polymorphisms (SNPs) and 8 deletions/insertions, were identified in four sheep breeds. Three variations were further researched in a larger sample set, including five sheep breeds with different meat production performances. We found that the genotype and allele frequencies of the CCC deletion/insertion in pri-miR-133a were significantly related to the sheep meat production trait. Finally, cell assays and quantitative reverse transcription PCR (qRT-PCR) were employed to investigate the effect of pri-miRNA genetic variation on the miRNA biogenesis process. The results confirmed that genetic variations can influence miRNA biogenesis and increase or decrease the levels of mature miRNAs, in accordance with the energy and stability change of hair-pin secondary structures. Our findings will help to further the understanding of the functions of genetic variations in sheep pri-miRNAs in skeletal muscle growth and development. PMID- 25699994 TI - Multi-regional investigation of the relationship between functional MRI blood oxygenation level dependent (BOLD) activation and GABA concentration. AB - Several recent studies have reported an inter-individual correlation between regional GABA concentration, as measured by MRS, and the amplitude of the functional blood oxygenation level dependent (BOLD) response in the same region. In this study, we set out to investigate whether this coupling generalizes across cortex. In 18 healthy participants, we performed edited MRS measurements of GABA and BOLD-fMRI experiments using regionally related activation paradigms. Regions and tasks were the: occipital cortex with a visual grating stimulus; auditory cortex with a white noise stimulus; sensorimotor cortex with a finger-tapping task; frontal eye field with a saccade task; and dorsolateral prefrontal cortex with a working memory task. In contrast to the prior literature, no correlation between GABA concentration and BOLD activation was detected in any region. The origin of this discrepancy is not clear. Subtle differences in study design or insufficient power may cause differing results; these and other potential reasons for the discrepant results are discussed. This negative result, although it should be interpreted with caution, has a larger sample size than prior positive results, and suggests that the relationship between GABA and the BOLD response may be more complex than previously thought. PMID- 25699995 TI - Echolucency of the carotid artery intima-media complex and intima-media thickness have different cardiovascular risk factor relationships: the Women's Interagency HIV Study. AB - BACKGROUND: Adults infected with HIV have increased atherosclerosis potentially associated with both HIV and non-HIV associated factors. We characterized risk factors for atherosclerosis as measured by noninvasive vascular imaging. METHODS AND RESULTS: We used B-mode ultrasound to examine levels and correlates of echogenicity and vessel wall thickness of the carotid artery intima-media complex in 1282 HIV-infected and 510 HIV-uninfected women of the Women's Interagency HIV Study. Levels of gray scale median (GSM, a measure of echogenicity) did not vary between HIV infection groups. In both groups, smokers had increased GSM, whereas age, diabetes, elevated blood pressure, and high BMI were associated with lower (rather than higher) GSM. Each of these non-lipid CVD risk factors, especially age and blood pressure, was also associated with higher levels of carotid artery intima-media thickness (cIMT). Higher serum triglyceride levels were associated with lower GSM in both HIV-infected and HIV-uninfected groups. Additional lipid risk factors for low GSM including high LDL cholesterol and low HDL cholesterol levels were identified in HIV uninfected but not in HIV infected women. In contrast to findings for GSM, among the lipid parameters only LDL cholesterol level had an association with cIMT, which was observed only in the HIV uninfected group. CONCLUSIONS: Lipid and non-lipid risk factor associations with echolucency of the carotid artery and the thickness of the common carotid artery intima-media layer suggest that these measures capture different aspects of atherosclerosis. PMID- 25699996 TI - Prehypertension and the risk of coronary heart disease in Asian and Western populations: a meta-analysis. AB - BACKGROUND: The results of studies on the association between prehypertension (blood pressure 120 to 139/80 to 89 mm Hg) and coronary heart disease (CHD) remain controversial. Furthermore, it is unclear whether prehypertension affects the risk of CHD in Asian and Western populations differently. This meta-analysis evaluated the risk of CHD associated with prehypertension and its different subgroups. METHODS AND RESULTS: The PubMed and Embase databases were searched for prospective cohort studies with data on prehypertension and the risk of CHD. Studies were included if they reported multivariate-adjusted relative risks (RRs) with 95% CIs of CHD from prehypertension. A total of 591 664 participants from 17 prospective cohort studies were included. Prehypertension increased the risk of CHD (RR 1.43, 95% CI 1.26 to 1.63, P<0.001) compared with optimal blood pressure (<120/80 mm Hg). The risk of CHD was higher in Western than in Asian participants (Western: RR 1.70, 95% CI 1.49 to 1.94; Asian: RR 1.25, 95% CI 1.12 to 1.38; ratio of RRs 1.36, 95% CI 1.15 to 1.61). The population-attributable risk indicated that 8.4% of CHD in Asian participants was attributed to prehypertension, whereas this proportion was 24.1% in Western participants. CONCLUSIONS: Prehypertension, even at the low range, is associated with an increased risk of CHD. This risk is more pronounced in Western than in Asian populations. These results supported the heterogeneity of target-organ damage caused by prehypertension and hypertension among different ethnicities and underscore the importance of prevention of CHD in Western patients with prehypertension. PMID- 25699997 TI - Is 2015 the primetime year for prehypertension? Prehypertension: a cardiovascular risk factor or simply a risk marker? PMID- 25699998 TI - A novel mathematical model describing adaptive cellular drug metabolism and toxicity in the chemoimmune system. AB - Cells cope with the threat of xenobiotic stress by activating a complex molecular network that recognizes and eliminates chemically diverse toxic compounds. This "chemoimmune system" consists of cellular Phase I and Phase II metabolic enzymes, Phase 0 and Phase III ATP Binding Cassette (ABC) membrane transporters, and nuclear receptors regulating these components. In order to provide a systems biology characterization of the chemoimmune network, we designed a reaction kinetic model based on differential equations describing Phase 0-III participants and regulatory elements, and characterized cellular fitness to evaluate toxicity. In spite of the simplifications, the model recapitulates changes associated with acquired drug resistance and allows toxicity predictions under variable protein expression and xenobiotic exposure conditions. Our simulations suggest that multidrug ABC transporters at Phase 0 significantly facilitate the defense function of successive network members by lowering intracellular drug concentrations. The model was extended with a novel toxicity framework which opened the possibility of performing in silico cytotoxicity assays. The alterations of the in silico cytotoxicity curves show good agreement with in vitro cell killing experiments. The behavior of the simplified kinetic model suggests that it can serve as a basis for more complex models to efficiently predict xenobiotic and drug metabolism for human medical applications. PMID- 25699999 TI - Asymmetric total syntheses of megacerotonic acid and shimobashiric acid A. AB - The asymmetric total syntheses of the alpha-benzylidene-gamma-butyrolactone natural products megacerotonic acid and shimobashiric acid A have been accomplished in nine and 11 steps, respectively, from simple, commercially available starting materials. The key step for each synthesis is the (arene)RuCl(monosulfonamide)-catalyzed dynamic kinetic resolution-asymmetric transfer hydrogenation (DKR-ATH) of racemic alpha,delta-diketo-beta-aryl esters to establish the absolute stereochemistry. Intramolecular diastereoselective Dieckmann cyclization forms the lactone core, and ketone reduction/alcohol elimination installs the alpha-arylidene. PMID- 25700000 TI - Simultaneous intracellular redox potential and pH measurements in live cells using SERS nanosensors. AB - Intracellular redox potential is a highly regulated cellular characteristic and is critically involved in maintaining cellular health and function. The dysregulation of redox potential can result in the initiation and progression of numerous diseases. Redox potential is determined by the balance of oxidants and reductants in the cell and also by pH. For this reason a technique for quantitative measurement of intracellular redox potential and pH is highly desirable. In this paper we demonstrate how surface enhanced Raman scattering (SERS) nanosensors can be used for multiplexed measurement of both pH and redox potential in live single cells. PMID- 25700001 TI - Global analysis reveals families of chemical motifs enriched for HERG inhibitors. AB - Promiscuous inhibition of the human ether-a-go-go-related gene (hERG) potassium channel by drugs poses a major risk for life threatening arrhythmia and costly drug withdrawals. Current knowledge of this phenomenon is derived from a limited number of known drugs and tool compounds. However, in a diverse, naive chemical library, it remains unclear which and to what degree chemical motifs or scaffolds might be enriched for hERG inhibition. Here we report electrophysiology measurements of hERG inhibition and computational analyses of >300,000 diverse small molecules. We identify chemical 'communities' with high hERG liability, containing both canonical scaffolds and structurally distinctive molecules. These data enable the development of more effective classifiers to computationally assess hERG risk. The resultant predictive models now accurately classify naive compound libraries for tendency of hERG inhibition. Together these results provide a more complete reference map of characteristic chemical motifs for hERG liability and advance a systematic approach to rank chemical collections for cardiotoxicity risk. PMID- 25700002 TI - Comparative proteomic and biochemical analyses reveal different molecular events occurring in the process of fiber initiation between wild-type allotetraploid cotton and its fuzzless-lintless mutant. AB - To explore lint fiber initiation-related proteins in allotetraploid cotton (Gossypium hirsutum L.), a comparative proteomic analysis was performed between wild-type cotton (Xu-142) and its fuzzless-lintless mutant (Xu-142-fl) at five developmental time points for lint fiber initiation from -3 to +3 days post anthesis (dpa). Using two-dimensional gel electrophoresis (2-DE) combined with mass spectrometry (MS) analyses, 91 differentially accumulated protein (DAP) species that are related to fiber initiation were successfully identified, of which 58 preferentially accumulated in the wild-type and 33 species in the fl mutant. These DAPs are involved in various cellular and metabolic processes, mainly including important energy/carbohydrate metabolism, redox homeostasis, amino acid and fatty acid biosynthesis, protein quality control, cytoskeleton dynamics, and anthocyanidin metabolism. Further physiological and biochemical experiments revealed dynamic changes in the carbohydrate flux and H2O2 levels in the cotton fiber initiation process. Compared with those in the fl mutant, the contents of glucose and fructose in wild-type ovules sharply increased after anthesis with a relatively higher rate of amino acid biosynthesis. The relative sugar starvation and lower rate of amino acid biosynthesis in the fl mutant ovules may impede the carbohydrate/energy supply and cell wall synthesis, which is consistent with the proteomic results. However, the H2O2 burst was only observed in the wild-type ovules on the day of anthesis. Cotton boll injection experiments in combination with electron microscope observation collectively indicated that H2O2 burst, which is negatively regulated by ascorbate peroxidases (APx), plays an important role in the fiber initiation process. Taken together, our study demonstrates a putative network of DAP species related to fiber initiation in cotton ovules and provides a foundation for future studies on the specific functions of these proteins in fiber development. PMID- 25700003 TI - Dynamical transitions in a pollination-herbivory interaction: a conflict between mutualism and antagonism. AB - Plant-pollinator associations are often seen as purely mutualistic, while in reality they can be more complex. Indeed they may also display a diverse array of antagonistic interactions, such as competition and victim-exploiter interactions. In some cases mutualistic and antagonistic interactions are carried-out by the same species but at different life-stages. As a consequence, population structure affects the balance of inter-specific associations, a topic that is receiving increased attention. In this paper, we developed a model that captures the basic features of the interaction between a flowering plant and an insect with a larval stage that feeds on the plant's vegetative tissues (e.g. leaves) and an adult pollinator stage. Our model is able to display a rich set of dynamics, the most remarkable of which involves victim-exploiter oscillations that allow plants to attain abundances above their carrying capacities and the periodic alternation between states dominated by mutualism or antagonism. Our study indicates that changes in the insect's life cycle can modify the balance between mutualism and antagonism, causing important qualitative changes in the interaction dynamics. These changes in the life cycle could be caused by a variety of external drivers, such as temperature, plant nutrients, pesticides and changes in the diet of adult pollinators. PMID- 25700004 TI - Response to: 'Working smarter, not harder' by Professor Iedema. PMID- 25700005 TI - Improving the efficiency of drug use disorder screening in psychiatric settings: validation of a single-item screen. AB - BACKGROUND: Co-occurring drug use disorders are under-detected in psychiatrically ill populations highlighting the need for more efficient screening tools. OBJECTIVES: This study compares a single-item screening tool, previously validated in a primary care setting, to the 10-item Drug Abuse Screening Test (DAST-10) for identifying co-occurring drug use disorders among patients with severe psychiatric illness. METHODS: A total of 395 patients attending a psychiatric partial hospital program completed both the single-item screen and DAST-10. A subsample of consecutive patients (n = 67) was also administered the Structure Clinical Interview for DSM-IV (SCID-IV) as a diagnostic reference standard. RESULTS: Concordance between screening measures was moderate (kappa = 0.4, p < 0.01). Sensitivity and specificity of the single-item screen and DAST-10 as compared to the SCID-IV were comparable, while area under the receiver operating curve showed better discriminatory power for the identification of drug use disorders with the single-item screen. CONCLUSIONS: In comparison to the DAST 10, the single-item screen appears to be a more efficient tool to identify co occurring drug use disorders in a psychiatric treatment setting among patients with a range of psychiatric diagnoses. PMID- 25700006 TI - The efficacy of computerized alcohol intervention tailored to drinking motives among college students: a quasi-experimental pilot study. AB - BACKGROUND: Although motivational processes may influence the intervention effects and help prevention programmes identify students at great risk for alcohol-related problems, no computerized alcohol intervention has yet to be tailored to drinking motives. OBJECTIVE: To describe the development and initial pilot testing of a computer-delivered intervention tailored to drinking motives, to prevent alcohol abuse and its adverse consequences among university students in general and among baseline hazardous drinkers specifically. METHODS: 124 college students attending a public university in northeastern Italy participated in this study in October of 2012 (89.2% female- mean age = 21.64-34% baseline hazardous drinkers). Two classes (one undergraduate, one graduate) were assigned to one of two conditions: intervention and control group. Both groups received profile-specific feedback and then the intervention group received profile specific online training for 4 weeks. This profile was based on their risk type (high-low) and drinking motives (enhancement-social-conformity-coping). RESULTS: Controlling for corresponding baseline alcohol measures, analyses showed a significant interaction between intervention condition and hazardous drinkers at baseline. For hazardous drinkers at baseline, the alcohol intervention results showed a significant decrease in frequency and quantity of alcohol use at follow up, while no difference was observed between intervention conditions for non hazardous drinkers at baseline. CONCLUSIONS: The results suggest that hazardous drinkers (college students) who completed the specific training and received personalized feedback seemed to do better on frequency and quantity of alcohol use than hazardous drinkers (college students) who received only personalized feedback. These results seem to provide support for a larger trial of the intervention and for more appropriate evaluations. PMID- 25700007 TI - Child abuse exposure, emotion regulation, and drinking refusal self-efficacy: an analysis of problem drinking in college students. AB - BACKGROUND: Problem drinking in college is a longstanding problem with potentially severe consequences. More recently, problem drinking has been linked to emotion regulation difficulties. However, these results are mixed and emphasize the need to examine moderating variables that may strengthen the problem drinking/emotion regulation relationship. Two such variables are child/adolescent sexual abuse (CASA) and drinking refusal self-efficacy (DRSE). OBJECTIVES: The current study hypothesized that the relations between emotion regulation difficulties and problem drinking would be most salient for college students with increased CASA exposure and decreased DRSE. Secondary analyses examined the hypothesis taking into consideration cumulative child/adolescent trauma exposure. METHODS: Undergraduate students (n = 200) completed a large survey battery for course credit. RESULTS: Three-way interactions across the CASA and cumulative trauma models were significant and in a similar direction. RESULTS indicated that for students without trauma exposure, problem drinking was the greatest for those with decreased DRSE and increased emotion regulation difficulties. As trauma exposure increased, problem drinking was the greatest for those with decreased DRSE and decreased emotion regulation difficulties (or superior perceived regulatory abilities). CONCLUSION: Discussion highlights the importance of considering DRSE and the possibility of reduced insight in trauma exposed students, who may perceive alcohol use as an adaptive regulatory strategy. PMID- 25700008 TI - Inhomogeneity in the excited-state torsional disorder of a conjugated macrocycle. AB - The photophysics of conjugated polymers has generally been explained based on the interactions between the component conjugated chromophores in a tangled chain. However, conjugated chromophores are entities with static and dynamic structural disorder, which directly affects the conjugated polymer photophysics. Here we demonstrate the impact of chain structure torsional disorder on the spectral characteristics for a macrocyclic oligothiophene 1, which is obscured in conventional linear conjugated chromophores by diverse structural disorders such as those in chromophore size and shape. We used simultaneous multiple fluorescence parameter measurement for a single molecule and quantum-mechanical calculations to show that within the fixed conjugation length across the entire ring an inhomogeneity from torsional disorder in the structure of 1 plays a crucial role in causing its energetic disorder, which affords the spectral broadening of ~220 meV. The torsional disorder in 1 fluctuated on the time scale of hundreds of milliseconds, typically accompanied by spectral drifts on the order of ~10 meV. The fluctuations could generate torsional defects and change the electronic structure of 1 associated with the ring symmetry. These findings disclose the fundamental nature of conjugated chromophore that is the most elementary spectroscopic unit in conjugated polymers and suggest the importance of engineering structural disorder to optimize polymer-based device photophysics. Additionally, we combined defocused wide-field fluorescence microscopy and linear dichroism obtained from the simultaneous measurements to show that 1 emits polarized light with a changing polarization direction based on the torsional disorder fluctuations. PMID- 25700009 TI - Three-component domino process for the pyrrolizine skeleton via [3 + 2] cycloaddition-enamine cyclization triggered by a gold catalyst. AB - Pyrrolizines are bicyclic fused azaheterocycles with a bridgehead nitrogen contained in a core skeleton and are often found in biologically active compounds. Despite their importance, there have been few reports on concise and flexible syntheses of pyrrolizines. A novel one-pot, convergent method is described for pyrrolizines by simple mixing of iminoesters, acetylenes, and dipolarophiles in the presence of a cationic gold catalyst and an acid additive. This domino process affords multisubstituted pyrrolizines without handling unstable intermediates. PMID- 25700010 TI - Exploring the conformational preferences of 20-residue peptides in isolation: Ac Ala19-Lys + H(+)vs. Ac-Lys-Ala19 + H(+) and the current reach of DFT. AB - Reliable, quantitative predictions of the structure of peptides based on their amino-acid sequence information are an ongoing challenge. We here explore the energy landscapes of two unsolvated 20-residue peptides that result from a shift of the position of one amino acid in otherwise the same sequence. Our main goal is to assess the performance of current state-of-the-art density-functional theory for predicting the structure of such large and complex systems, where weak interactions such as dispersion or hydrogen bonds play a crucial role. For validation of the theoretical results, we employ experimental gas-phase ion mobility-mass spectrometry and IR spectroscopy. While unsolvated Ac-Ala19-Lys + H(+) will be shown to be a clear helix seeker, the structure space of Ac-Lys Ala19 + H(+) is more complicated. Our first-principles structure-screening strategy using the dispersion-corrected PBE functional (PBE + vdW(TS)) identifies six distinctly different structure types competing in the low-energy regime (~16 kJ mol(-1)). For these structure types, we analyze the influence of the PBE and the hybrid PBE0 functional coupled with either a pairwise dispersion correction (PBE + vdW(TS), PBE0 + vdW(TS)) or a many-body dispersion correction (PBE + MBD*, PBE0 + MBD*). We also take harmonic vibrational and rotational free energy into account. Including this, the PBE0 + MBD* functional predicts only one unique conformer to be present at 300 K. We show that this scenario is consistent with both experiments. PMID- 25700011 TI - Theoretical analysis of [5.5.6]cyclacenes: electronic properties, strain energies and substituent effects. AB - A novel class of cyclic conjugated molecules, composed of annelated five- and six membered rings, is proposed and theoretically investigated using density functional theory and multireference methods with regards to their structures, strain energies, aromaticity (NICS values), electronic ground states, band gaps, and the effect of substituents. These [5.5.6]ncyclacenes are predicted to be low band gap materials (below 1 eV) with, depending on their size, closed-shell singlet ground states. The strain energies from n = 4 upwards lie in the range of the synthetically known [n]cycloparaphenylenes. An investigation of the effect of rim-substitution by methyl, alkynyl, thiomethyl or phenyl groups on the electronic ground states showed that thiomethyl-substitution leads to [5.5.6]ncyclacenes with closed-shell singlet ground states for all sizes n investigated. PMID- 25700012 TI - Examination of Ataxin-3 (atx-3) Aggregation by Structural Mass Spectrometry Techniques: A Rationale for Expedited Aggregation upon Polyglutamine (polyQ) Expansion. AB - Expansion of polyglutamine stretches leads to the formation of polyglutamine containing neuronal aggregates and neuronal death in nine diseases for which there currently are no treatments or cures. This is largely due to a lack in understanding of the mechanisms by which expanded polyglutamine regions contribute to aggregation and disease. To complicate matters further, several of the polyglutamine-disease related proteins, including ataxin-3, have a multistage aggregation mechanism in which flanking domain self-assembly precedes polyglutamine aggregation yet is influenced by polyglutamine expansion. How polyglutamine expansion influences flanking domain aggregation is poorly understood. Here, we use a combination of mass spectrometry and biophysical approaches to investigate this issue for ataxin-3. We show that the conformational dynamics of the flanking Josephin domain in ataxin-3 with an expanded polyglutamine tract are altered in comparison to those exhibited by its nonexpanded counterpart, specifically within the aggregation-prone region of the Josephin domain (amino acid residues 73-96). Expansion thus exposes this region more frequently in ataxin-3 containing an expanded polyglutamine tract, providing a molecular explanation of why aggregation is accelerated upon polyglutamine expansion. Here, harnessing the power of ion mobility spectrometry-mass spectrometry, oligomeric species formed during aggregation are characterized and a model for oligomer growth proposed. The results suggest that a conformational change occurs at the dimer level that initiates self-assembly. New insights into ataxin-3 fibril architecture are also described, revealing the region of the Josephin domain involved in protofibril formation and demonstrating that polyglutamine aggregation proceeds as a distinct second step after protofibril formation without requiring structural rearrangement of the protofibril core. Overall, the results enable the effect of polyglutamine expansion on every stage of ataxin-3 self-assembly, from monomer through to fibril, to be described and a rationale for expedited aggregation upon polyglutamine expansion to be provided. PMID- 25700013 TI - Examining Postsecondary Education Predictors and Participation for Students With Learning Disabilities. AB - Given the history of poor postschool outcomes for students with disabilities, researchers repeatedly sought to demonstrate the links between predictor variables and postschool outcomes for students with disabilities. This secondary data analysis used the National Longitudinal Transition Study-2 to examine the relationship between postsecondary education-related transition services and postsecondary education participation for students with learning disabilities. Logistic regression analyses indicated receiving core content area instruction in the general education classroom was positively related to postsecondary education participation. Frequency distributions indicated students with learning disabilities attended 2-year college at higher rates than other postsecondary education programs. The results suggest educators should consider inclusion in general education classroom for core content area instruction for students with learning disabilities with postsecondary education goals to the extent permitted by their least restrictive environment. PMID- 25700014 TI - Friendship Experiences and Anxiety Among Children: A Genetically Informed Study. AB - This study examined (a) whether, in line with a gene-environment correlation (rGE), a genetic disposition for anxiety puts children at risk of having anxious friends or having no reciprocal friends; (b) to what extent these friendship experiences are related to anxiety symptoms, when controlling for sex and genetic disposition for this trait; and (c) the additive and interactive predictive links of the reciprocal best friend's anxiety symptoms and of friendship quality with children's anxiety symptoms. Using a genetically informed design based on 521 monozygotic and ic twins (264 girls; 87% of European descent) assessed in Grade 4 (M age = 10.04 years, SD = .26), anxiety symptoms and perceived friendship quality were measured with self-report questionnaires. Results indicated that, in line with rGE, children with a strong genetic disposition for anxiety were more likely to have anxious friends than nonanxious friends. Moreover, controlling for their genetic risk for anxiety, children with anxious friends showed higher levels of anxiety symptoms than children with nonanxious friends but did not differ from those without reciprocal friends. Additional analyses suggested a possible contagion of anxiety symptoms between reciprocal best friends when perceived negative features of friendship were high. These results underline the importance of teaching strategies such as problem solving that enhance friendship quality to limit the potential social contagion of anxiety symptoms. PMID- 25700016 TI - Audiometry-Based Screening Procedure for Cochlear Implant Candidacy. AB - OBJECTIVE: This study defines a screening procedure for cochlear implant (CI) candidacy in hearing aid users by using simple audiometric measures. METHODS: Within this retrospective study, hearing aid performance and audiometric measures in 185 subjects (318 ears) were analyzed. By means of a linear Naive Bayes classifier, the pure-tone average and the maximum monosyllabic score (PB(max)) were used to predict the aided monosyllabic word score and CI candidacy. RESULTS: The two parameters PB(max) and four-frequency hearing threshold average can be used to predict speech perception with hearing aids with reasonable accuracy for screening purposes. The classification has a sensitivity of 87% and a specificity of 91%. The classification can be represented by a simple linear formula. CONCLUSION: CI candidacy can be predicted based on commonly used audiometric measures.Cochlear implant candidacy may be considered if the difference between the average pure-tone threshold (in decibels) and PBmax (in percent) exceeds 8. PMID- 25700015 TI - A Prospective Longitudinal Study of U.S. Children Unable to Achieve Open-Set Speech Recognition 5 Years After Cochlear Implantation. AB - OBJECTIVE: To identify characteristics associated with the inability to progress to open-set speech recognition in children 5 years after cochlear implantation. STUDY DESIGN: Prospective, longitudinal, and multidimensional assessment of auditory development for 5 years. SETTING: Six tertiary cochlear implant (CI) referral centers in the United States. PATIENTS: Children with severe-to-profound hearing loss who underwent implantation before age 5 years enrolled in the Childhood Development after Cochlear Implantation study, categorized by level of speech recognition ability. INTERVENTION(S): Cochlear implantation before 5 years of age and annual assessment of emergent speech recognition skills. MAIN OUTCOME MEASURE(S): Progression to open-set speech recognition by 5 years after implantation. RESULTS: Less functional hearing before implantation, older age at onset of amplification, lower maternal sensitivity to communication needs, minority status, and complicated perinatal history were associated with the inability to obtain open-set speech recognition by 5 years. CONCLUSION: Characteristics of a subpopulation of children with CIs associated with an inability to achieve open-set speech recognition after 5 years of CI experience were investigated. These data distinguish pediatric CI recipients at risk for poor auditory development and highlight areas for future interventions to enhance support of early implantation. PMID- 25700017 TI - Protein oxidation and protein nitration influenced by sodium nitrite in two different meat model systems. AB - The effect of NaNO2 on protein oxidation was studied in isolated myofibrillar protein isolates (100 and 1000 mg NaNO2/kg) and in porcine patties (18 and 180 mg NaNO2/kg). In addition, the potential use of 3-nitrotyrosine as a specific marker for reactive nitrogen species mediated nitration was investigated. Overall, no distinct pro- or antioxidant effect of NaNO2 against carbonyl formation was observed in the isolates or in the patties. However, in the isolates, higher protein carbonyl concentrations were found in the NaNO2-treated samples compared to the treatment without added nitrite immediately after the addition of oxidants and NaNO2. Addition of 180 mg NaNO2/kg to patties resulted in significantly lower thiol concentrations at 4 and 7 days of illuminated chilled display compared to the treatments with 0 and 18 mg/kg NaNO2, whereas no effect was observed in the isolates. No effect of NaNO2 was found on the protein solubility of either meat model. 3-Nitrotyrosine was present in all samples, but no clear effect of NaNO2 addition or oxidation time was observed. PMID- 25700018 TI - Air-processable silane-coupled polymers to modify a dielectric for solution processed organic semiconductors. AB - Poly(styrene-r-3-methacryloxypropyltrimethoxysilane) (PSMPTS) copolymers were synthesized by the free radical polymerization of styrene and 3 methacryloxypropyltrimethoxysilane (MPTS) for use as surface modifiers. PSMPTS copolymers were spun-cast onto a hydrophilic SiO2 layer and were then annealed at 150 degrees C in ambient air. The polystyrene (PS)-based copolymer, with a molecular weight of 32 700 g mol(-1) and approximately 30 MPTS coupling sites, was easily grafted onto the SiO2 surface after annealing periods longer than 1 min, yielding a physicochemically stable layer. On the untreated and polymer treated dielectrics, spin-casting of an ultrasonicated poly(3-hexyl thiophene) (P3HT) solution yielded highly interconnected crystal nanofibrils of P3HT. The resulting organic field-effect transistors (OFETs) showed similar mobility values of 0.01-0.012 cm(2) V(-1) s(-1) for all surfaces. However, the threshold voltage (Vth) drastically decreased from +13 (for bare SiO2) to 0 V by grafting the PSMPTS copolymers to the SiO2 surface. In particular, the interfacial charge traps that affect Vth were minimized by grafting the 11 mol % MPTS-loaded copolymer to the polar dielectric surface. We believe that this ambient-air processable silane-coupled copolymer can be used as a solution-based surface modifier for continuous, large-scale OFET fabrication. PMID- 25700019 TI - Photochemical charge separation at particle interfaces: the n-BiVO4-p-silicon system. AB - The charge transfer properties of interfaces are central to the function of photovoltaic and photoelectrochemical cells and photocatalysts. Here we employ surface photovoltage spectroscopy (SPS) to study photochemical charge transfer at a p-silicon/n-BiVO4 particle interface. Particle films of BiVO4 on an aluminum doped p-silicon wafer were obtained by drop-coating particle suspensions followed by thermal annealing at 353 K. Photochemical charge separation of the films was probed as a function of layer thickness and illumination intensity, and in the presence of methanol as a sacrificial electron donor. Electron injection from the BiVO4 into the p-silicon is clearly observed to occur and to result in a maximum photovoltage of 150 mV for a 1650 nm thick film under 0.3 mW cm(-2) illumination at 3.5 eV. This establishes the BiVO4-p-Si interface as a tandem-like junction. Charge separation in the BiVO4 film is limited by light absorption and by slow electron transport to the Si interface, based on time-dependent SPS measurements. These problems need to be overcome in functional tandem devices for photoelectrochemical water oxidation. PMID- 25700020 TI - Testosterone induces leucocyte migration by NADPH oxidase-driven ROS- and COX2 dependent mechanisms. AB - The mechanisms whereby testosterone increases cardiovascular risk are not clarified. However, oxidative stress and inflammation seem to be determinants. Herein, we sought to determine whether exogenous testosterone, at physiological levels, induces leucocyte migration, a central feature in immune and inflammatory responses and the mediating mechanisms. We hypothesized that testosterone induces leucocyte migration via NADPH oxidase (NADPHox)-driven reactive oxygen species (ROS) and cyclooxygenase (COX)-dependent mechanisms. Sixteen-week-old Wistar rats received an intraperitoneal injection (5 ml) of either testosterone (10(-7) mol/l) or saline. Rats were pre-treated with 5 ml of sodium salicylate (SS, non selective COX inhibitor, 1.25 * 10(-3) mol/l, 1 h prior to testosterone or saline), flutamide (androgen receptor antagonist, 10(-5) mol/l), apocynin (NADPHox inhibitor, 3 * 10(-4) mol/l), N-[2-Cyclohexyloxy-4 nitrophenyl]methanesulfonamide (NS398, COX2 inhibitor, 10(-4) mol/l) or saline, 4 h before testosterone or saline administration. Leucocyte migration was assessed 24 h after testosterone administration by intravital microscopy of the mesenteric bed. Serum levels of testosterone were measured by radioimmunoassay. NADPHox activity was assessed in membrane fractions of the mesenteric bed by dihydroethidium (DHE) fluorescence and in isolated vascular smooth muscle cells (VSMC) by HPLC. NADPHox subunits and VCAM (vascular cell adhesion molecule) expression were determined by immunoblotting. Testosterone administration did not change serum levels of endogenous testosterone, but increased venular leucocyte migration to the adventia, NADPHox activity and expression (P < 0.05). These effects were blocked by flutamide. SS inhibited testosterone-induced leucocyte migration (P<0.05). Apocynin and NS398 abolished testosterone-induced leucocyte migration and NADPHox activity (P<0.05). Testosterone induces leucocyte migration via NADPHox- and COX2-dependent mechanisms and may contribute to inflammatory processes and oxidative stress in the vasculature potentially increasing cardiovascular risk. PMID- 25700021 TI - Correction to: Point-of-care diagnostics, a major opportunity for change in traditional diagnostic approaches: potential and limitations. PMID- 25700022 TI - Analysis of organic sulfur compounds in atmospheric aerosols at the HKUST supersite in Hong Kong using HR-ToF-AMS. AB - Organic sulfur compounds have been identified in ambient secondary organic aerosols, but their contribution to organic mass is not well quantified. In this study, using a high-resolution time-of-flight aerosol mass spectrometer (AMS), concentrations of organic sulfur compounds were estimated based on the high resolution fragmentation patterns of methanesulfonic acid (MSA), and organosulfates (OS), including alkyl, phenyl, and cycloalkyl sulfates, obtained in laboratory experiments. Mass concentrations of MSA and minimum mass concentrations of OS were determined in a field campaign conducted at a coastal site of Hong Kong in September 2011. MSA and OS together accounted for at least 5% of AMS detected organics. MSA is of marine origin with its formation dominated by local photochemical activities and enhanced by aqueous phase processing. OS concentrations are better correlated with particle liquid water content (LWC) than with particle acidity. High-molecular-weight OS were detected in the continental influenced period probably because they had grown into larger molecules during long-range transport or they were formed from large anthropogenic precursors. This study highlights the importance of both aqueous phase processing and regional influence, i.e., different air mass origins, on organic sulfur compound formation in coastal cities like Hong Kong. PMID- 25700023 TI - Time-invariant measurement of time-varying bioimpedance using vector impedance analysis. AB - When stepped-sine impedance spectroscopy measurements are carried out on (periodically) time-varying bio-systems, the inherent time-variant (time periodic) parts are traditionally ignored or mitigated by filtering. The latter, however, lacks theoretical foundation and, in this paper, it is shown that it only works under certain specific conditions. Besides, we propose an alternative method, based on multisine signals, that exploits the non-stationary nature in time-varying bio-systems with a dominant periodic character, such as cardiovascular and respiratory systems, or measurements interfered with by their physiological activities. The novel method extracts the best-in a mean square sense-linear time-invariant (BLTI) impedance approximation ZBLTI(jomega) of a periodically time-varying (PTV) impedance ZPTV(jomega, t) as well as its time periodic part. Relying on the geometrical interpretation of the BLTI concept, a new impedance analysis tool, called vector impedance analysis (VIA), is also presented. The theoretical and practical aspects are validated through measurements performed on a PTV dummy circuit and on an in vivo myocardial tissue. PMID- 25700024 TI - THEMIS: a critical TCR signal regulator for ligand discrimination. AB - Genetic approaches identified THEMIS as a critical element driving positive selection of CD4(+)CD8(+) thymocytes towards maturation. THEMIS is expressed only in the T-cell lineage, and is recruited to the proximity of signaling T-cell antigen receptors (TCR) by association with the membrane scaffold LAT. However, its molecular role remained an enigma until recently. Conventionally positively selected T-cells are lacking in THEMIS-deficient mice, leading to the initial hypothesis that THEMIS positively regulates TCR signaling. Recent data show that THEMIS deficiency increases rather than decreases TCR signaling, leading to augmented apoptosis. The finding that THEMIS is constitutively bound to the tyrosine phosphatases SHP1 or SHP2, provides a mechanism for THEMIS action. When recruited onto LAT, THEMIS-SHP promotes immediate dephosphorylation of TCR proximal signaling components. This negative feedback is central in setting sharp signaling thresholds and helps explain the exquisite ligand discrimination by the TCR, particularly during thymocyte selection. PMID- 25700025 TI - Neutralisation of HIV-1 cell-cell spread by human and llama antibodies. AB - BACKGROUND: Direct cell-cell spread of HIV-1 is a very efficient mode of viral dissemination, with increasing evidence suggesting that it may pose a considerable challenge to controlling viral replication in vivo. Much current vaccine research involves the study of broadly neutralising antibodies (bNabs) that arise during natural infection with the aims of eliciting such antibodies by vaccination or incorporating them into novel therapeutics. However, whether cell cell spread of HIV-1 can be effectively targeted by bNabs remains unclear, and there is much interest in identifying antibodies capable of efficiently neutralising virus transmitted by cell-cell contact. RESULTS: In this study we have tested a panel of bNAbs for inhibition of cell-cell spread, including some not previously evaluated for inhibition of this mode of HIV-1 transmission. We found that three CD4 binding site antibodies, one from an immunised llama (J3) and two isolated from HIV-1-positive patients (VRC01 and HJ16) neutralised cell cell spread between T cells, while antibodies specific for glycan moieties (2G12, PG9, PG16) and the MPER (2F5) displayed variable efficacy. Notably, while J3 displayed a high level of potency during cell-cell spread we found that the small size of the llama heavy chain-only variable region (VHH) J3 is not required for efficient neutralisation since recombinant J3 containing a full-length human heavy chain Fc domain was significantly more potent. J3 and J3-Fc also neutralised cell-cell spread of HIV-1 from primary macrophages to CD4+ T cells. CONCLUSIONS: In conclusion, while bNabs display variable efficacy at preventing cell-cell spread of HIV-1, we find that some CD4 binding site antibodies can inhibit this mode of HIV-1 dissemination and identify the recently described llama antibody J3 as a particularly potent inhibitor. Effective neutralisation of cell-cell spread between physiologically relevant cell types by J3 and J3-Fc supports the development of VHH J3 nanobodies for therapeutic or prophylactic applications. PMID- 25700026 TI - Pt@UiO-66 heterostructures for highly selective detection of hydrogen peroxide with an extended linear range. AB - In this study, a good core-shell heterostructure of Pt NPs@UiO-66 was fabricated by encapsulating presynthesized platinum nanoparticles (Pt NPs) into the host matrix of UiO-66 which possesses the slender triangular windows with a diameter of 6 A. The transmission electron microscopy images exhibited that the number of the encapsulated Pt NPs and the crystalline morphology of as-synthesized core shell heterostructure samples had a series of changes with increasing the volume of the injected Pt NPs precursor solution. Among these samples, the Pt NPs@UiO-66 2 sample had a good crystalline morphology with several well-dispersed Pt NPs encapsulated in UiO-66 frameworks. But there were no obvious Pt NPs observed in the Pt NPs@UiO-66-1 sample, and for the Pt NPs@UiO-66-3 sample, the number of Pt NPs encapsulated in UiO-66 matrix notably reduced and the metal organic framework (MOF) crystals became small and aggregated. The electrochemical measurements showed that the Pt NPs@UiO-66-2 sample modified glass carbon electrode (GCE) presented a remarkable electrocatalytic activity toward hydrogen peroxide (H2O2) oxidation, including an excellent anti-interference performance even if the concentration of the interference species was the same as the H2O2, an extended linear range from 5 MUM to 14.75 mM, a low detection limit, as well as good stability and reproducibility. The results indicate the superiority of MOFs in H2O2 detection. And more importantly, it will provide a new opportunity to promote the anti-interference performance of the nonenzyme electrochemical sensors. PMID- 25700027 TI - Expression of Hypoxia-Inducible Factor-1alpha in the Infiltrative Belt Surrounding Hepatic Alveolar Echinococcosis in Rats. AB - Our main aims were to investigate hypoxia inducible factor-1alpha (HIF-1alpha) expression in the surrounding invasion range of hepatic alveolar echinococcosis (HAE) lesions and determine the pathological basis of angiogenesis. In total, 23 Wistar rats with hepatic echinococcus multilocularis infection were killed and their livers, which contained 27 HAE lesions, obtained. Specimen segments were generated from 119 paraffin blocks. Comparative analysis of the tissue samples containing HAE nodules and hepatic parenchyma of the surrounding region was performed with the immunohistochemical SP method in this animal experiment. Expression patterns of HIF-1alpha in the surrounding invasion range and the hepatic parenchyma were compared. The HIF-1alpha positive expression rate was 97.5% (116/119 samples). Expression of HIF-1alpha in the actively multiplying infiltrative region of the HAE lesions was significantly higher than that in hepatic parenchyma (P < 0.05). Overexpression of HIF-1alpha in the actively multiplying infiltrative region of HAE lesions in rats is closely related to angiogenesis and microvasculature. The sensitivity of HIF-1alpha facilitates its application as a representative maker of HAE. Our data indicate that the invasion range of HAE lesions is based on extrusion and compression, and induces anoxia and ischemia in hepatic tissue. Thus, HIF-1alpha provides a valuable index for evaluating HAE activity, and induces anoxia and ischemia in hepatic tissue. PMID- 25700028 TI - Non-cancer palliative care in the community needs greater interprofessional collaboration to maintain coordinated care and manage uncertainty. PMID- 25700029 TI - Professionals providing cervical screening may require training and support on how to provide safe and sensitive care for survivors of childhood sexual abuse. PMID- 25700030 TI - Enrollment bias: frequency and impact on patient selection in endovascular stroke trials. AB - BACKGROUND: Selection bias may have affected enrollment in first generation endovascular stroke trials. We investigate, evaluate, and quantify such bias for these trials at our institution. METHODS: Demographic, clinical, imaging, and angiographic data were prospectively collected on a consecutive cohort of patients with acute ischemic stroke who were enrolled in formal trials of endovascular stroke therapy (EST) or received EST in clinical practice outside of a randomized trial for acute cerebral ischemia at a single tertiary referral center from September 2004 to December 2012. RESULTS: Among patients considered appropriate for EST in practice, 47% were eligible for trials, with rates for individual trials ranging from 17% to 70%. Compared with trial ineligible patients treated with EST, trial eligible patients were younger (67 vs. 74 years; p<0.05), more often treated with intravenous tissue plasminogen activator (53% vs. 34%; p<0.01), and had shorter last known well to puncture times (328 vs. 367 min; p<0.05). Focusing on the largest trial with a non-interventional control arm, compared with trial eligible patients treated with EST outside the trial, enrolled patients presented later (274 vs. 163 min; p<0.001), had higher National Institutes of Health Stroke Scale scores (20 vs. 17; p<0.05), and larger strokes (diffusion weighted imaging volumes 49 vs. 18; p<0.001). CONCLUSIONS: The majority of patients felt suitable for EST at our institution were excluded from recent trials. Formal entry criteria succeeded in selecting patients with better prognostic features, although many of these patients were treated outside of trials. Acknowledging and mitigating these biases will be crucial to ongoing investigations. PMID- 25700031 TI - Novel receptor-derived cyclopeptides to treat heart failure caused by anti-beta1 adrenoceptor antibodies in a human-analogous rat model. AB - Despite recent therapeutic advances the prognosis of heart failure remains poor. Recent research suggests that heart failure is a heterogeneous syndrome and that many patients have stimulating auto-antibodies directed against the second extracellular loop of the beta1 adrenergic receptor (beta1EC2). In a human analogous rat model such antibodies cause myocyte damage and heart failure. Here we used this model to test a novel antibody-directed strategy aiming to prevent and/or treat antibody-induced cardiomyopathy. To generate heart failure, we immunised n = 76/114 rats with a fusion protein containing the human beta1EC2 (amino-acids 195-225) every 4 weeks; n = 38/114 rats were control-injected with 0.9% NaCl. Intravenous application of a novel cyclic peptide mimicking beta1EC2 (beta1EC2-CP, 1.0 mg/kg every 4 weeks) or administration of the beta1-blocker bisoprolol (15 mg/kg/day orally) was initiated either 6 weeks (cardiac function still normal, prevention-study, n = 24 (16 treated vs. 8 untreated)) or 8.5 months after the 1st immunisation (onset of cardiomyopathy, therapy-study, n = 52 (40 treated vs. 12 untreated)); n = 8/52 rats from the therapy-study received beta1EC2-CP/bisoprolol co-treatment. We found that beta1EC2-CP prevented and (alone or as add-on drug) treated antibody-induced cardiac damage in the rat, and that its efficacy was superior to mono-treatment with bisoprolol, a standard drug in heart failure. While bisoprolol mono-therapy was able to stop disease progression, beta1EC2-CP mono-therapy -or as an add-on to bisoprolol- almost fully reversed antibody-induced cardiac damage. The cyclo!peptide acted both by scavenging free anti-beta1EC2-antibodies and by targeting beta1EC2-specific memory B-cells involved in antibody-production. Our model provides the basis for the clinical translation of a novel double-acting therapeutic strategy that scavenges harmful anti-beta1EC2-antibodies and also selectively depletes memory B cells involved in the production of such antibodies. Treatment with immuno modulating cyclopeptides alone or as an add-on to beta1-blockade represents a promising new therapeutic option in immune-mediated heart failure. PMID- 25700032 TI - Expression of adiponectin and its receptors is altered in epithelial ovarian tumors and ascites-derived ovarian cancer cell lines. AB - OBJECTIVES: Recent evidence suggests that higher body mass index is associated with a modest increase in ovarian cancer risk. Reduced serum levels of adiponectin are correlated with obesity and increased cancer risk. The objectives of the present study are to determine if expressions of adiponectin and its receptors, AdipoR1 and AdipoR2, are altered in epithelial ovarian tumors and ascites-derived ovarian cancer cell lines and to determine if plasma adiponectin levels are altered in the chicken model of ovarian cancer. METHODS: Adiponectin, AdipoR1, and AdipoR2 mRNA concentrations in ovaries and chicken ovarian cancer (COVCAR) cell lines were determined by quantitative real-time polymerase chain reaction analysis. Existence of adiponectin isoforms in the ovaries and COVCAR cells was identified by nondenaturing gel electrophoresis. Adiponectin, AdipoR1, and AdipoR2 protein amounts were determined by Western blot analysis. Plasma total adiponectin levels were determined by an enzyme immunoassay. RESULTS: Adiponectin, AdipoR1, and AdipoR2 mRNA concentrations were significantly lower in cancerous ovaries and COVCAR cell lines compared with normal ovaries and normal ovarian surface epithelial (NOSE) cells, respectively. Adiponectin in ovary and COVCAR cell lines appeared as a heavy-molecular-weight isoform that is greater than 720-kd mass. In addition, a lower-molecular-weight adiponectin isoform was found in COVCAR cells but not in NOSE cells. Adiponectin and AdipoR1 protein concentrations were not different in COVCAR cell lines compared with NOSE cells. However, AdipoR2 protein concentrations were significantly higher in cancerous ovaries but lower in COVCAR cell lines compared with normal ovaries and NOSE cells, respectively. Plasma adiponectin concentrations were not different in chickens that had ovarian carcinoma compared with control animals. CONCLUSIONS: Expression of adiponectin in ovarian tumors and in metastatic ovarian tumor cells is likely to affect cellular metabolism and proliferation through activating AdipoR1 and/or AdipoR2. Plasma adiponectin levels may not be predictive of advanced stages of ovarian tumor in the chicken model. PMID- 25700033 TI - Factors associated with cancer-specific and overall survival among Indigenous and non-Indigenous gynecologic cancer patients in Queensland, Australia: a matched cohort study. AB - OBJECTIVE: Aboriginal and Torres Strait Islander women have a higher mortality rate due to gynecologic cancer compared with non-Indigenous women. For cervical cancer, Australian Indigenous women are less likely to survive 5 years following diagnoses than non-Indigenous women. This study investigates the factors associated with gynecologic cancer treatment and survival among Queensland indigenous and non-Indigenous women. METHODS: Australian Indigenous women diagnosed with uterine, cervical, ovarian, or other gynecologic cancers during 1998-2004 in the public hospital system were included. They were frequency matched on age (+/-5 years), residential remoteness, and cancer type to a random sample of non-Indigenous women. One- and 5-year cancer-specific survival was examined according to Indigenous status using Cox proportional hazards regression. RESULTS: Indigenous women (n = 137) compared with non-Indigenous women (n = 120) were less likely to be diagnosed with localized disease (49% vs 65%, P = 0.02) and had more comorbidities (52% vs 21%, P < 0.001). Indigenous women were less likely to receive any cancer treatment compared with non Indigenous women (91% vs 98%, P = 0.01), although when excluding those with metastatic cancer, there was no significant difference in uptake of treatment (95% vs 91%, respectively, P = 0.31). Among those who did undergo treatment, there was no difference in time to treatment (median difference 0.5 days, P = 0.98). Gynecologic cancer-specific survival differences between Indigenous and non-Indigenous women were most prominent in the first year following diagnosis (hazard ratio [HR], 1.89; 95% confidence interval [CI], 1.06-3.38) and were no longer significant 5 years after diagnosis (HR, 1.47 [95% CI, 0.97-2.25]). For cervical cancer, crude 1-year survival was poorer for Indigenous women compared with non-Indigenous women (HR, 2.46 [95% CI, 1.03-5.90]), but was no different when adjusted for stage and treatment of cancer (HR, 1.00 [95% CI, 0.45-2.24]). CONCLUSIONS: Improving the early diagnosis of cervical cancer in Indigenous women may increase cancer-specific survival in the year following diagnosis. PMID- 25700034 TI - The complexity of sequences generated by the arc-fractal system. AB - We study properties of the symbolic sequences extracted from the fractals generated by the arc-fractal system introduced earlier by Huynh and Chew. The sequences consist of only a few symbols yet possess several nontrivial properties. First using an operator approach, we show that the sequences are not periodic, even though they are constructed from very simple rules. Second by employing the epsilon-machine approach developed by Crutchfield and Young, we measure the complexity and randomness of the sequences and show that they are indeed complex, i.e. neither periodic nor random, with the value of complexity measure being significant as compared to the known example of logistic map at the edge of chaos. The complexity and randomness of the sequences are then discussed in relation with the properties of associated fractal objects, such as their fractal dimension, symmetry and orientations of the arcs. PMID- 25700035 TI - Gulypyrones A and B and Phomentrioloxins B and C Produced by Diaporthe gulyae, a Potential Mycoherbicide for Saffron Thistle (Carthamus lanatus). AB - A virulent strain of Diaporthe gulyae, isolated from stem cankers of sunflower and known to be pathogenic to saffron thistle, has been shown to produce both known and previously undescribed metabolites when grown in either static liquid culture or a bioreactor. Together with phomentrioloxin, a phytotoxic geranylcyclohexenetriol recently isolated from a strain of Phomopsis sp., two new phytotoxic trisubstituted alpha-pyrones, named gulypyrones A and B (1 and 2), and two new 1,O- and 2,O-dehydro derivatives of phomentrioloxin, named phomentrioloxins B and C (3 and 4), were isolated from the liquid culture filtrates of D. gulyae. These four metabolites were characterized as 6-[(2S)2 hydroxy-1-methylpropyl]-4-methoxy-5-methylpyran-2-one (1), 6-[(1E)-3-hydroxy-1 methylpropenyl]-4-methoxy-3-methylpyran-2-one (2), 4,6-dihydroxy-5-methoxy-2-(7 methyl-3-methyleneoct-6-en-1-ynyl)cyclohex-2-enone (3), and 2,5-dihydroxy-6 methoxy-3-(7-methyl-3-methyleneoct-6-en-1-ynyl)cyclohex-3-enone (4) using spectroscopic and chemical methods. The absolute configuration of the hydroxylated secondary carbon of the 2-hydroxy-1-methylpropyl side chain at C-6 of gulypyrone A was determined as S by applying a modified Mosher's method. Other well-known metabolites were also isolated including 3-nitropropionic, succinic, and p-hydroxy- and p-methylbenzoic acids, p-hydroxybenzaldehyde, and nectriapyrone. When assayed using a 5 mM concentration on punctured leaf disks of weedy and crop plants, apart from 3-nitropropionic acid (the main metabolite responsible for the strong phytotoxicity of the culture filtrate), phomentrioloxin B caused small, but clear, necrotic spots on a number of plant species, whereas gulypyrone A caused leaf necrosis on Helianthus annuus plantlets. All other compounds were weakly active or inactive. PMID- 25700036 TI - Higher oily fish consumption in late pregnancy is associated with reduced aortic stiffness in the child at age 9 years. AB - RATIONALE: Higher pulse wave velocity (PWV) reflects increased arterial stiffness and is an established cardiovascular risk marker associated with lower long-chain n-3 polyunsaturated fatty acid intake in adults. Experimentally, maternal fatty acid intake in pregnancy has lasting effects on offspring arterial stiffness. OBJECTIVE: To examine the association between maternal consumption of oily fish, a source of long-chain n-3 polyunsaturated fatty acids, in pregnancy and child's aortic stiffness age 9 years. METHODS AND RESULTS: In a mother-offspring study (Southampton Women's Survey), the child's descending aorta PWV was measured at the age of 9 years using velocity-encoded phase-contrast MRI and related to maternal oily fish consumption assessed prospectively during pregnancy. Higher oily fish consumption in late pregnancy was associated with lower childhood aortic PWV (sex-adjusted beta=-0.084 m/s per portion per week; 95% confidence interval, -0.137 to -0.031; P=0.002; n=226). Mother's educational attainment was independently associated with child's PWV. PWV was not associated with the child's current oily fish consumption. CONCLUSIONS: Level of maternal oily fish consumption in pregnancy may influence child's large artery development, with potential long-term consequences for later cardiovascular risk. PMID- 25700037 TI - Meta-Analysis of Cell-based CaRdiac stUdiEs (ACCRUE) in patients with acute myocardial infarction based on individual patient data. AB - RATIONALE: The meta-Analysis of Cell-based CaRdiac study is the first prospectively declared collaborative multinational database, including individual data of patients with ischemic heart disease treated with cell therapy. OBJECTIVE: We analyzed the safety and efficacy of intracoronary cell therapy after acute myocardial infarction (AMI), including individual patient data from 12 randomized trials (ASTAMI, Aalst, BOOST, BONAMI, CADUCEUS, FINCELL, REGENT, REPAIR-AMI, SCAMI, SWISS-AMI, TIME, LATE-TIME; n=1252). METHODS AND RESULTS: The primary end point was freedom from combined major adverse cardiac and cerebrovascular events (including all-cause death, AMI recurrance, stroke, and target vessel revascularization). The secondary end point was freedom from hard clinical end points (death, AMI recurrence, or stroke), assessed with random effects meta-analyses and Cox regressions for interactions. Secondary efficacy end points included changes in end-diastolic volume, end-systolic volume, and ejection fraction, analyzed with random-effects meta-analyses and ANCOVA. We reported weighted mean differences between cell therapy and control groups. No effect of cell therapy on major adverse cardiac and cerebrovascular events (14.0% versus 16.3%; hazard ratio, 0.86; 95% confidence interval, 0.63-1.18) or death (1.4% versus 2.1%) or death/AMI recurrence/stroke (2.9% versus 4.7%) was identified in comparison with controls. No changes in ejection fraction (mean difference: 0.96%; 95% confidence interval, -0.2 to 2.1), end-diastolic volume, or systolic volume were observed compared with controls. These results were not influenced by anterior AMI location, reduced baseline ejection fraction, or the use of MRI for assessing left ventricular parameters. CONCLUSIONS: This meta analysis of individual patient data from randomized trials in patients with recent AMI revealed that intracoronary cell therapy provided no benefit, in terms of clinical events or changes in left ventricular function. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01098591. PMID- 25700038 TI - Introduction to: Considerations for the use of human participants in vector biology research: a tool for investigators and regulators by Achee et al. PMID- 25700039 TI - Considerations for the use of human participants in vector biology research: a tool for investigators and regulators. AB - A thorough search of the existing literature has revealed that there are currently no published recommendations or guidelines for the interpretation of US regulations on the use of human participants in vector biology research (VBR). An informal survey of vector biologists has indicated that issues related to human participation in vector research have been largely debated by academic, national, and local Institutional Review Boards (IRBs) in the countries where the research is being conducted, and that interpretations and subsequent requirements made by these IRBs have varied widely. This document is intended to provide investigators and corresponding scientific and ethical review committee members an introduction to VBR methods involving human participation and the legal and ethical framework in which such studies are conducted with a focus on US Federal Regulations. It is also intended to provide a common perspective for guiding researchers, IRB members, and other interested parties (i.e., public health officials conducting routine entomological surveillance) in the interpretation of human subjects regulations pertaining to VBR. PMID- 25700040 TI - Assessment of prevalence and distribution of spotted fever group rickettsiae in Manitoba, Canada, in the American dog tick, Dermacentor variabilis (Acari: Ixodidae). AB - Little is known about the distribution and prevalence of the spotted fever group rickettsiae in Canada. We conducted active surveillance for tick-associated rickettsiae in 10 localities in Manitoba. A total of 1044 adult American dog ticks, Dermacentor variabilis (Acari: Ixodidae), were collected and screened for spotted fever group rickettsiae. Rickettsia montanensis was the only species of rickettsia detected. The mean prevalence of infection was 9.8% (range, 0.00 21.74% among localities). The proportion of infected male and female ticks was not significantly different; however, tick populations near the northern limit of D. variabilis distribution in Manitoba had a lower prevalence of infection compared to tick populations from more southern localities in the province. PMID- 25700041 TI - Molecular characterization of Staphylococcus aureus from nasal samples of healthy farm animals and pets in Tunisia. AB - A total of 261 healthy farm and pet animals (75 cattle, 52 goats, 100 dogs, and 34 cats) from different regions of Tunisia were screened for Staphylococcus aureus nasal carriage. Molecular typing of isolates (by spa- and multilocus sequence-typing) was performed, and their antimicrobial resistance and virulence genotypes were determined by PCR and sequencing. S. aureus isolates were detected in 17 of 261 tested samples (6.5%). All S. aureus isolates recovered were methicillin-susceptible (MSSA), and one isolate/sample was further studied. Eight different spa types were detected (t189, t279, t582, t701, t1166, t1268, t1534, and t1773), and eight different sequence types were identified (ST6, ST15, ST45, ST133, ST188, ST700 [clonal complex CC130], ST2057, and a new ST2121). MSSA from pets (six isolates) showed resistance to (number of isolates, resistance gene): penicillin (six, blaZ), tetracycline (one, tet[M]), erythromycin one, erm[A]), streptomycin (one, ant[6]-Ia), and ciprofloxacin (one). All isolates from farm animals showed susceptibility to the tested antimicrobials, except for two penicillin-resistant isolates. Five S. aureus isolates from goats and cats harbored the lukF/lukS-PV genes, encoding the Panton-Valentine leukocidin, and six isolates from goats harbored the tst virulence gene. In addition, diverse combinations of enterotoxin genes were detected, including two variants of the egc cluster. Goats and cats could represent a reservoir of important toxin genes, with potential implications in animal and human health. PMID- 25700042 TI - Demographic characteristics and infectious diseases of a population of American black bears in Humboldt County, California. AB - American black bears (Ursus americanus) are common, widely distributed, and broad ranging omnivorous mammals in northern California forests. Bears may be susceptible to pathogens infecting both domestic animals and humans. Monitoring bear populations, particularly in changing ecosystems, is important to understanding ecological features that could affect bear population health and influence the likelihood that bears may cause adverse impacts on humans. In all, 321 bears were captured between May, 2001, and October, 2003, and blood samples were collected and tested for multiple zoonotic and vector-borne diseases. We found a PCR prevalence of 10% for Anaplasma phagocytophilum, and a seroprevalence of 28% for Toxoplasma gondii, 26% for Borrelia burgdorferi, 26% for A. phagocytophilum, 8% for Trichinella spiralis, 8% for Francisella tularensis and 1% for Yersinia pestis. In addition, we tested bears for pathogens of domestic dogs and found a seroprevalence of 15% for canine distemper virus and 0.6% for canine parvovirus. Our findings show that black bears can become infected with pathogens that are an important public health concern, as well as pathogens that can affect both domestic animals and other wildlife species. PMID- 25700043 TI - Seroepidemiology of selected arboviruses in febrile patients visiting selected health facilities in the lake/river basin areas of Lake Baringo, Lake Naivasha, and Tana River, Kenya. AB - INTRODUCTION: Arboviruses cause emerging and re-emerging infections affecting humans and animals. They are spread primarily by blood-sucking insects such as mosquitoes, ticks, midges, and sandflies. Changes in climate, ecology, demographic, land-use patterns, and increasing global travel have been linked to an upsurge in arboviral disease. Outbreaks occur periodically followed by persistent low-level circulation. AIM: This study was undertaken to determine the seroepidemiology of selected arboviruses among febrile patients in selected lake/river basins of Kenya. METHODS: Using a hospital-based cross-sectional descriptive survey, febrile patients were recruited and their serum samples tested for exposure to immunoglobulin M (IgM) and IgG antibodies against Crimean Congo hemorrhagic fever virus (CCHFV), Rift Valley fever virus (RVFV), West Nile virus (WNV), and chikungunya virus (CHIKV). Samples positive for CHIKV and WNV were further confirmed by the plaque reduction neutralization test (PRNT). RESULTS: Of the 379 samples examined, 176 were IgG positive for at least one of these arboviruses (46.4%, 95% confidence interval [CI] 41.4-51.5%). Virus specific prevalence for CCHF, RVF, WN, and CHIK was 25.6%, 19.5%, 12.4%, and 2.6%, respectively. These prevalences varied significantly with geographical site (p<0.001), with Tana recording the highest overall arboviral seropositivity. PRNT results for Alphaviruses confirmed that the actual viruses circulating in Baringo were Semliki Forest virus (SFV) and CHIKV, o'nyong nyong virus (ONNV) in Naivasha, and SFV and Sindbis virus (SINDV) in Tana delta. Among the flaviviruses tested, WNV was circulating in all the three sites. CONCLUSION: There is a high burden of febrile illness in humans due to CCHFV, RVFV, WNV, and CHIKV infection in the river/lake basin regions of Kenya. PMID- 25700044 TI - Detection and isolation of Sindbis virus from mosquitoes captured during an outbreak in Sweden, 2013. AB - Mosquito-borne alphaviruses have the potential to cause large outbreaks throughout the world. Here we investigated the causative agent of an unexpected Sindbis virus (SINV) outbreak during August-September, 2013, in a previously nonendemic region of Sweden. Mosquitoes were collected using carbon dioxide baited CDC traps at locations close to human cases. The mosquitoes were initially screened as large pools by SINV-specific quantitative RT-PCR, and the SINV positive mosquitoes were species determined by single-nucleotide polymorphism (SNP) analysis, followed by sequencing the barcoding region of the cytochrome oxidase I gene. The proportion of the collected mosquitoes was determined by a metabarcoding strategy. By using novel strategies for PCR screening and genetic typing, a new SINV strain, Lovanger, was isolated from a pool of 1600 mosquitoes composed of Culex, Culiseta, and Aedes mosquitoes as determined by metabarcoding. The SINV-positive mosquito Culiseta morsitans was identified by SNP analysis and sequencing. After whole-genome sequencing and phylogenetic analysis, the SINV Lovanger isolate was shown to be most closely similar to recent Finnish SINV isolates. In conclusion, within a few weeks, we were able to detect and isolate a novel SINV strain and identify the mosquito vector during a sudden SINV outbreak. PMID- 25700045 TI - Proximity to mosquito breeding habitat and Ross River virus risk in the Peel region of Western Australia. AB - It is intuitive that vector-borne disease exposure risk is related to proximity to sources of vector breeding, but this aspect rarely receives empirical testing. The population of Western Australia (WA) is increasing rapidly, with many new residential developments proposed in close proximity to mosquito breeding habitat. However, potential mosquito-borne disease risks for future residents are given little consideration by planning authorities. The Peel region is one of the fastest growing regions in WA and regularly experiences a large number of cases of the mosquito-borne Ross River virus (RRV) disease with epidemics occuring in the region every few years. A spatial analysis of RRV disease data in the Peel region was undertaken to determine the risk associated with proximity to a mosquito breeding habitat. Geographic Information Systems (GIS) software was used to create buffers between 1 and 6 km from the breeding habitat. The number of cases per 1000 dwellings in each buffer was calculated between 2002/03 to 2011/12 for years with >100 cases across all buffers (n=5) in addition to the cumulative rate over the entire period in each buffer. Residents living within 1 km of a mosquito breeding habitat had a significantly higher rate of RRV disease compared to the background rate across the Peel region in all individual years investigated. The cumulative data over the 10-year study period showed that residents in the 1- and 2-km buffers had a significantly higher rate, whereas those living between 3 and 6 km away did not. This study demonstrates an increased mosquito-borne disease risk associated with living in close proximity to a mosquito breeding habitat in a rapidly expanding region of WA and highlights the importance of considering mosquito-borne disease risks when planning authorities assess new residential development applications. Known mosquito breeding wetlands should be incorporated into land use planning scheme maps to ensure that they are accurately delineated and the implications are considered when planning decisions are made. PMID- 25700046 TI - Comparison of the efficiency and cost of West Nile virus surveillance methods in California. AB - Surveillance systems for West Nile virus (WNV) combine several methods to determine the location and timing of viral amplification. The value of each surveillance method must be measured against its efficiency and costs to optimize integrated vector management and suppress WNV transmission to the human population. Here we extend previous comparisons of WNV surveillance methods by equitably comparing the most common methods after standardization on the basis of spatial sampling density and costs, and by estimating optimal levels of sampling effort for mosquito traps and sentinel chicken flocks. In general, testing for evidence of viral RNA in mosquitoes and public-reported dead birds resulted in detection of WNV approximately 2-5 weeks earlier than serological monitoring of sentinel chickens at equal spatial sampling density. For a fixed cost, testing of dead birds reported by the public was found to be the most cost effective of the methods, yielding the highest number of positive results per $1000. Increased spatial density of mosquito trapping was associated with more precise estimates of WNV infection prevalence in mosquitoes. Our findings also suggested that the most common chicken flock size of 10 birds could be reduced to six to seven without substantial reductions in timeliness or sensitivity. We conclude that a surveillance system that uses the testing of dead birds reported by the public complemented by strategically timed mosquito and chicken sampling as agency resources allow would detect viral activity efficiently in terms of effort and costs, so long as susceptible bird species that experience a high mortality rate from infection with WNV, such as corvids, are present in the area. PMID- 25700047 TI - Epizootiology of Tacaribe serocomplex viruses (Arenaviridae) associated with neotomine rodents (Cricetidae, Neotominae) in southern California. AB - The objective of this study was to advance our knowledge of the epizootiology of Bear Canyon virus and other Tacaribe serocomplex viruses (Arenaviridae) associated with wild rodents in California. Antibody (immunoglobulin G [IgG]) to a Tacaribe serocomplex virus was found in 145 (3.6%) of 3977 neotomine rodents (Cricetidae: Neotominae) captured in six counties in southern California. The majority (122 or 84.1%) of the 145 antibody-positive rodents were big-eared woodrats (Neotoma macrotis) or California mice (Peromyscus californicus). The 23 other antibody-positive rodents included a white-throated woodrat (N. albigula), desert woodrat (N. lepida), Bryant's woodrats (N. bryanti), brush mice (P. boylii), cactus mice (P. eremicus), and deer mice (P. maniculatus). Analyses of viral nucleocapsid protein gene sequence data indicated that Bear Canyon virus is associated with N. macrotis and/or P. californicus in Santa Barbara County, Los Angeles County, Orange County, and western Riverside County. Together, analyses of field data and antibody prevalence data indicated that N. macrotis is the principal host of Bear Canyon virus. Last, the analyses of viral nucleocapsid protein gene sequence data suggested that the Tacaribe serocomplex virus associated with N. albigula and N. lepida in eastern Riverside County represents a novel species (tentatively named "Palo Verde virus") in the genus Arenavirus. PMID- 25700048 TI - Molecular detection of the human pathogenic Rickettsia sp. strain Atlantic rainforest in Amblyomma dubitatum ticks from Argentina. AB - To date, three tick-borne pathogenic Rickettsia species have been reported in different regions of Argentina, namely, R. rickettsii, R. parkeri, and R. massiliae. However, there are no reports available for the presence of tick-borne pathogens from the northeastern region of Argentina. This study evaluated the infection with Rickettsia species of Amblyomma dubitatum ticks collected from vegetation and feeding from capybaras (Hydrochoerus hydrochaeris) in northeastern Argentina. From a total of 374 A. dubitatum ticks collected and evaluated by PCR for the presence of rickettsial DNA, 19 were positive for the presence of Rickettsia bellii DNA, two were positive for Rickettsia sp. strain COOPERI, and one was positive for the pathogenic Rickettsia sp. strain Atlantic rainforest. To our knowledge, this study is the first report of the presence of the human pathogen Rickettsia sp. strain Atlantic rainforest and Rickettsia sp. strain COOPERI in Argentina. Moreover, our findings posit A. dubitatum as a potential vector for this pathogenic strain of Rickettsia. PMID- 25700049 TI - First identification of Anaplasma platys in the blood of dogs from French Guiana. AB - Anaplasma platys is the causative agent of infectious cyclic thrombocytopenia in dogs. This infection is worldwide and reported with a higher incidence in tropical and subtropical areas such as South America. Until now, there has been no report of this bacterium in French Guiana. The aim of this study was molecular investigation of A. platys occurrence in the blood of autochthonous dogs in this region. A total 65 blood samples were taken from the shelter dogs in the cities of Cayenne and Kourou, and from dogs of private owners in the city of Cayenne. The results show that at least 15.38% (10/65) were positive to this pathogen. The strain identified in this study has been reported worldwide. These findings should be considered in the way that local veterinarians handle suspected cases of canine anaplasmosis and ehrlichiosis. PMID- 25700050 TI - Should heparin be used to treat patients with severe sepsis? PMID- 25700051 TI - ICU organization: the song, the singers, and the way the singers sing. PMID- 25700052 TI - Old drugs for bad bugs--aerosolized antibiotics in ventilator-associated pneumonia. PMID- 25700053 TI - What is old is new again: acetaminophen as a novel approach to treating sepsis. PMID- 25700054 TI - Measuring "quality": what do patient- and surrogate-perceived assessments of communication actually mean? PMID- 25700055 TI - The adrenal gland and corticosteroid therapy in sepsis: I certainly remain uncertain. PMID- 25700056 TI - SLEAP: a wake-up call to question the oversimplification of ICU delirium. PMID- 25700057 TI - Lost in translation: on lactate, hypotension, sepsis-induced tissue hypoperfusion, quantitative resuscitation and Surviving Sepsis Campaign bundles. PMID- 25700058 TI - High-flow nasal cannula oxygen therapy: innovative strategies for traditional procedures. PMID- 25700059 TI - Fluoroquinolones: another line in the long list of their collateral damage record. PMID- 25700060 TI - Seeking consent from those who cannot answer: new light on emergency research conducted under the exception from informed consent. PMID- 25700061 TI - Monday morning quarterback: the story of extubation failure. PMID- 25700062 TI - Enhancing informed decision making: is more information always better? PMID- 25700063 TI - Predicting adrenal insufficiency in severe sepsis: the role of plasma-free cortisol. PMID- 25700064 TI - Video laryngoscopy and intubation safety: the view is becoming clear. PMID- 25700065 TI - To recruit or not recruit, this is .... PMID- 25700066 TI - Finding an early warning signal for acute respiratory distress syndrome: are we getting closer? PMID- 25700067 TI - Digital decoding of pediatric traumatic brain injury. PMID- 25700068 TI - Inverse ratio ventilation: back to the future? PMID- 25700069 TI - Assessment of methodological quality for included studies is necessary in a systematic review. PMID- 25700070 TI - Serum markers of sepsis in burn patients: it takes more to convince! PMID- 25700071 TI - The authors reply. PMID- 25700072 TI - Antibiotic initiation in severe sepsis: does sequence impact outcome? PMID- 25700073 TI - Extracorporeal CO2 removal in severe chronic obstructive pulmonary disease exacerbations: a work in progress. PMID- 25700074 TI - The authors reply. PMID- 25700075 TI - Detailed characterization of a long-term rodent model of critical illness and recovery. AB - OBJECTIVE: To characterize a long-term model of recovery from critical illness, with particular emphasis on cardiorespiratory, metabolic, and muscle function. DESIGN: Randomized controlled animal study. SETTING: University research laboratory. SUBJECTS: Male Wistar rats. INTERVENTIONS: Intraperitoneal injection of the fungal cell wall constituent, zymosan or n-saline. MEASUREMENTS AND MAIN RESULTS: Following intervention, rats were followed for up to 2 weeks. Animals with zymosan peritonitis reached a clinical and biochemical nadir on day 2. Initial reductions were seen in body weight, total body protein and fat, and muscle mass. Leg muscle fiber diameter remained subnormal at 14 days with evidence of persisting myonecrosis, even though gene expression of regulators of muscle mass (e.g., MAFbx, MURF1, and myostatin) had peaked on days 2-4 but normalized by day 7. Treadmill exercise capacity, forelimb grip strength, and in vivo maximum tetanic force were also reduced. Food intake was minimal until day 4 but increased thereafter. This did not relate to appetite hormone levels with early (6 hr) rises in plasma insulin and leptin followed by persisting subnormal levels; ghrelin levels did not change. Serum interleukin-6 level peaked at 6 hours but had normalized by day 2, whereas interleukin-10 remained persistently elevated and high-density lipoprotein cholesterol persistently depressed. There was an early myocardial depression and rise in core temperature, yet reduced oxygen consumption and respiratory exchange ratio with a loss of diurnal rhythmicity that showed a gradual but incomplete recovery by day 7. CONCLUSIONS: This detailed physiological, metabolic, hormonal, functional, and histological muscle characterization of a model of critical illness and recovery reproduces many of the findings reported in human critical illness. It can be used to assess putative therapies that may attenuate loss, or enhance recovery, of muscle mass and function. PMID- 25700076 TI - Can bradycardia during therapeutic hypothermia help predicting neurologic outcome and be beneficial in post-cardiac arrest patients? PMID- 25700077 TI - The authors reply. PMID- 25700078 TI - ICU architectural design affects the delirium prevalence: is it too early to draw inference of causation from this observational study? PMID- 25700079 TI - The author replies. PMID- 25700080 TI - Seasonal variation in stable carbon and nitrogen isotope values of bats reflect environmental baselines. AB - The stable carbon and nitrogen isotope composition of animal tissues is commonly used to trace wildlife diets and analyze food chains. Changes in an animal's isotopic values over time are generally assumed to indicate diet shifts or, less frequently, physiological changes. Although plant isotopic values are known to correlate with climatic seasonality, only a few studies restricted to aquatic environments have investigated whether temporal isotopic variation in consumers may also reflect environmental baselines through trophic propagation. We modeled the monthly variation in carbon and nitrogen isotope values in whole blood of four insectivorous bat species occupying different foraging niches in southern Spain. We found a common pattern of isotopic variation independent of feeding habits, with an overall change as large as or larger than one trophic step. Physiological changes related to reproduction or to fat deposition prior to hibernation had no effect on isotopic variation, but juvenile bats had higher delta13C and delta15N values than adults. Aridity was the factor that best explained isotopic variation: bat blood became enriched in both 13C and 15N after hotter and/or drier periods. Our study is the first to show that consumers in terrestrial ecosystems reflect seasonal environmental dynamics in their isotope values. We highlight the danger of misinterpreting stable isotope data when not accounting for seasonal isotopic baselines in food web studies. Understanding how environmental seasonality is integrated in animals' isotope values will be crucial for developing reliable methods to use stable isotopes as dietary tracers. PMID- 25700081 TI - Inflammasomes in pancreatic physiology and disease. AB - In this review we summarize the role of inflammasomes in pancreatic physiology and disease with a focus on acute pancreatitis where much recent progress has been made. New findings have identified inducers of and cell specificity of inflammasome component expression in the pancreas, the contribution of inflammasome-regulated effectors to pancreatitis, and metabolic regulation of inflammasome activation, which are strong determinants of injury in pancreatitis. New areas of pancreatic biology will be highlighted in the context of our evolving understanding of gut microbiome- and injury-induced inflammasome priming, pyroptosis, and innate immune-mediated regulation of cell metabolism. PMID- 25700082 TI - Transcriptomics exposes the uniqueness of parasitic plants. AB - Parasitic plants have the ability to obtain nutrients directly from other plants, and several species are serious biological threats to agriculture by parasitizing crops of high economic importance. The uniqueness of parasitic plants is characterized by the presence of a multicellular organ called a haustorium, which facilitates plant-plant interactions, and shutting down or reducing their own photosynthesis. Current technical advances in next-generation sequencing and bioinformatics have allowed us to dissect the molecular mechanisms behind the uniqueness of parasitic plants at the genome-wide level. In this review, we summarize recent key findings mainly in transcriptomics that will give us insights into the future direction of parasitic plant research. PMID- 25700083 TI - Correction: The kSORT Assay to Detect Renal Transplant Patients at High Risk for Acute Rejection: Results of the Multicenter AART Study. PMID- 25700084 TI - Effects of N-glycosylation site removal in archaellins on the assembly and function of archaella in Methanococcus maripaludis. AB - In Methanococcus maripaludis S2, the swimming organelle, the archaellum, is composed of three archaellins, FlaB1S2, FlaB2S2 and FlaB3S2. All three are modified with an N-linked tetrasaccharide at multiple sites. Disruption of the N linked glycosylation pathway is known to cause defects in archaella assembly or function. Here, we explored the potential requirement of N-glycosylation of archaellins on archaellation by investigating the effects of eliminating the 4 N glycosylation sites in the wildtype FlaB2S2 protein in all possible combinations either by Asn to Glu (N to Q) substitution or Asn to Asp (N to D) substitutions of the N-glycosylation sequon asparagine. The ability of these mutant derivatives to complement a non-archaellated DeltaflaB2S2 strain was examined by electron microscopy (for archaella assembly) and swarm plates (for analysis of swimming). Western blot results showed that all mutated FlaB2S2 proteins were expressed and of smaller apparent molecular mass compared to wildtype FlaB2S2, consistent with the loss of glycosylation sites. In the 8 single-site mutant complements, archaella were observed on the surface of Q2, D2 and D4 (numbers after N or Q refer to the 1st to 4th glycosylation site). Of the 6 double-site mutation complementations all were archaellated except D1,3. Of the 4 triple-site mutation complements, only D2,3,4 was archaellated. Elimination of all 4 N-glycosylation sites resulted in non-archaellated cells, indicating some minimum amount of archaellin glycosylation was necessary for their incorporation into stable archaella. All complementations that led to a return of archaella also resulted in motile cells with the exception of the D4 version. In addition, a series of FlaB2S2 scanning deletions each missing 10 amino acids was also generated and tested for their ability to complement the DeltaflaB2S2 strain. While most variants were expressed, none of them restored archaellation, although FlaB2S2 harbouring a smaller 3-amino acid deletion was able to partially restore archaellation. PMID- 25700085 TI - The viability of Lactobacillus fermentum CECT5716 is not essential to exert intestinal anti-inflammatory properties. AB - Probiotics have been used as alternative therapies in intestinal inflammatory disorders. Many studies have shown that different bacterial probiotic strains possess immuno-modulatory and anti-inflammatory properties. However, there is an increasing interest in the use of non-viable bacteria to reduce the risk of microbial translocation and infection. The aim of this study was to evaluate whether the viability of L. fermentum CECT5716 is essential to exert its intestinal anti-inflammatory effect. We compared the preventative effects of viable and non-viable probiotic in the TNBS model of rat colitis. In vitro studies were also performed in Caco-2 and RAW 264.7 cells to evaluate the probiotic effects on IL-8, IL-1beta and nitrite production, and p44/42 and p38 MAP kinase protein expressions. In vitro results revealed a decrease in the stimulated production of pro-inflammatory mediators regardless of the viability of the probiotic. Likewise, both forms of the probiotic administered to colitic rats produced a significant reduction of IL-1beta and TNF-alpha levels and colonic iNOS expression. In conclusion, both live and dead L. fermentum CECT5716 have been demonstrated to attenuate the inflammatory process and diminish the production of some of the inflammatory mediators. In fact, the viability of this probiotic did not affect its immuno-modulatory and anti-inflammatory properties. PMID- 25700086 TI - Sensitizer-catalyst assemblies for water oxidation. AB - Two molecular assemblies with one Ru(II)-polypyridine photosensitizer covalently linked to one Ru(II)(bda)L2 catalyst (1) (bda = 2,2'-bipyridine-6,6' dicarboxylate) and two photosensitizers covalently linked to one catalyst (2) have been prepared using a simple C-C bond as the linkage. In the presence of sodium persulfate as a sacrificial electron acceptor, both of them show high activity for catalytic water oxidation driven by visible light, with a turnover number up to 200 for 2. The linked photocatalysts show a lower initial yield for light driven oxygen evolution but a much better photostability compared to the three component system with separate sensitizer, catalyst and acceptor, leading to a much greater turnover number. Photocatalytic experiments and time-resolved spectroscopy were carried out to probe the mechanism of this catalysis. The linked catalyst in its Ru(II) state rapidly quenches the sensitizer, predominantly by energy transfer. However, a higher stability under photocatalytic condition is shown for the linked sensitizer compared to the three component system, which is attributed to kinetic stabilization by rapid photosensitizer regeneration. Strategies for employment of the sensitizer catalyst molecules in more efficient photocatalytic systems are discussed. PMID- 25700087 TI - Activity of heat shock genes' promoters in thermally contrasting animal species. AB - Heat shock gene promoters represent a highly conserved and universal system for the rapid induction of transcription after various stressful stimuli. We chose pairs of mammalian and insect species that significantly differ in their thermoresistance and constitutive levels of Hsp70 to compare hsp promoter strength under normal conditions and after heat shock (HS). The first pair includes the HSPA1 gene promoter of camel (Camelus dromedarius) and humans. It was demonstrated that the camel HSPA1A and HSPA1L promoters function normally in vitro in human cell cultures and exceed the strength of orthologous human promoters under basal conditions. We used the same in vitro assay for Drosophila melanogaster Schneider-2 (S2) cells to compare the activity of the hsp70 and hsp83 promoters of the second species pair represented by Diptera, i.e., Stratiomys singularior and D. melanogaster, which dramatically differ in thermoresistance and the pattern of Hsp70 accumulation. Promoter strength was also monitored in vivo in D. melanogaster strains transformed with constructs containing the S. singularior hsp70 ORF driven either by its own promoter or an orthologous promoter from the D. melanogaster hsp70Aa gene. Analysis revealed low S. singularior hsp70 promoter activity in vitro and in vivo under basal conditions and after HS in comparison with the endogenous promoter in D. melanogaster cells, which correlates with the absence of canonical GAGA elements in the promoters of the former species. Indeed, the insertion of GAGA elements into the S. singularior hsp70 regulatory region resulted in a dramatic increase in promoter activity in vitro but only modestly enhanced the promoter strength in the larvae of the transformed strains. In contrast with hsp70 promoters, hsp83 promoters from both of the studied Diptera species demonstrated high conservation and universality. PMID- 25700088 TI - Rh(I)-catalyzed chemo- and stereoselective domino cycloaddition of optically active propargyl 2,4-hexadienyl ethers. AB - 1,1'-Bi-2-naphthol in combination with ZnEt2, Ti(O(i)Pr)4, and dicyclohexylamine have been employed to catalyze asymmetric alkyne addition to an ynal to synthesize optically active propargylic alcohols containing two alkyne functions with excellent yields and enantioselectivities. These chiral alcohols are readily converted to the corresponding optically active propargyl 2,4-hexadienyl ethers. These diene-diyne substrates are found to undergo a highly chemoselective and stereoselective domino Pauson-Khand and Diels-Alder cycloaddition catalyzed by [RhCl(CO)2]2 under CO to generate a class of tetracyclic compounds with high enantiomeric purity. This is a very efficient method for the asymmetric synthesis of polycyclic compounds. PMID- 25700089 TI - Phthalocyanine derivatives possessing 2-(morpholin-4-yl)ethoxy groups as potential agents for photodynamic therapy. AB - Three 2-(morpholin-4-yl)ethoxy substituted phthalocyanines were synthesized and characterized. Phthalocyanine derivatives revealed moderate to high quantum yields of singlet oxygen production depending on the solvent applied (e.g., in DMF ranging from 0.25 to 0.53). Their photosensitizing potential for photodynamic therapy was investigated in an in vitro model using cancer cell lines. Biological test results were found particularly encouraging for the zinc(II) phthalocyanine derivative possessing two 2-(morpholin-4-yl)ethoxy substituents in nonperipheral positions. Cells irradiated for 20 min at 2 mW/cm(2) revealed the lowest IC50 value at 0.25 MUM for prostate cell line (PC3), whereas 1.47 MUM was observed for human malignant melanoma (A375) cells. The cytotoxic activity in nonirradiated cells of novel phthalocyanine was found to be very low. Moreover, the cellular uptake, localization, cell cycle, apoptosis through an ELISA assay, and immunochemistry method were investigated in LNCaP cells. Our results showed that the tested photosensitizer possesses very interesting biological activity, depending on experimental conditions. PMID- 25700090 TI - Arsenic induced modulation of antioxidative defense system and brassinosteroids in Brassica juncea L. AB - Brassica juncea (Indian mustard) L. plants were exposed to different concentrations (0.0, 0.1, 0.2 and 0.3mM) of arsenic (V) and harvested after 30 and 60 days of sowing for the analysis of growth parameters, metal uptake, brassinosteroids (BRs) synthesis and oxidative stress markers. As (V) significantly hampered the growth of B. juncea plants and triggered the modulations of various stress markers like proteins, antioxidative enzymes (SOD, CAT, POD, APX, GR, MDHAR and DHAR) and MDA content. Furthermore, As (V) induced the synthesis of 4 BRs, castasterone, teasterone, 24-epibrassinolide, and typhasterol, which were isolated and characterized by gas chromatography-mass spectrometry (GC-MS). The study further highlig5895hted the significant uptake of arsenic ions by mustard plants. PMID- 25700091 TI - Fate and effect of tire rubber ash nano-particles (RANPs) in cucumber. AB - There are growing interests on effects of nano-materials on living organisms including higher plants. No report is available on positive and negative effects of rubber ash nano-particles (RANPs) on edible plants. Recently, we reported the possibility of using waste tire rubber and rubber ash as zinc (Zn) fertilizer for plants. In this nutrient solution culture study, for the first time, root uptake and the effects of RANPs on growth and Zn, cadmium (Cd), and lead (Pb) concentration in cucumber was investigated. Various Zn levels (0, 1, 5, 25, 125mgL(-1)) were applied in the form of RANPs or ZnSO4. The root RANPs uptake was visualized by light (LA), scanning electron (SEM), and transmission electron microcopies (TEM). At all Zn levels, cucumber plants supplied with RANPs produced higher shoot and root biomass compared with those supplied with ZnSO4. In addition, the RANPs resulted in higher accumulation of Zn in cucumber tissues in comparison with ZnSO4; although phytotoxicity of Zn from ZnSO4 was greater than that from RANPs. Clear evidence of the RANPs penetration into the root cells was obtained by using SEM and TEM. Filaments of RANPs were also observed at the end of roots by LM and TEM. Further research is needed to clarify the fate of the RANPs in plant cells and their possible risks for food chain. PMID- 25700092 TI - Evaluation of direct and indirect photodegradation of mianserin with high performance liquid chromatography and short-term bioassays. AB - The widespread use of pharmaceuticals has lead to their detection in surface and ground waters. In the last year antidepressants in particular have shown very high growth dynamics of consumption and numerous research shows that these pharmaceuticals are detected in the environment and even in drinking water. Drugs and their metabolites can be subject to two types of photoreaction, direct and indirect photodegradation. These pharmaceuticals even at low concentration can have adverse effects on aquatic life, and the resulting photoproducts can be more toxic than parents compounds. The aim of this study was to evaluate the direct and indirect photodegradation of mianserin. The kinetics of the process and the identification of photoproducts were investigated by HPLC-PDA and HPLC-MS/MS, respectively. Ecotoxicity of mianserin before and after irradiation was assessed with a battery of assays with bacteria, protozoa and crustacea. The results show that mianserin was not toxic to Vibrio fischeri (Microtox), but its toxicity to protozoan Spirostomum ambiguum (Spirotox) and crustacean Thamnocephalus platyurus (Thamnotoxkit F(TM)) was comparable to other antidepressants. On the basis of the results of the toxicity and HPLC before and after irradiation it can be seen that the decrease toxicity of mianserin was related only to a decrease of its concentration. The photoproducts had no impact to toxicity. The direct photodegradation of mianserin was more effective in UV/vis light than vis light. However the presence of humic acid in the indirect photodegradation increases the rate of degradation without regard to the kind of used light. PMID- 25700093 TI - Radiocaesium activity concentrations in macrofungi from Galicia (NW Spain): Influence of environmental and genetic factors. AB - Radiocaesium ((137)Cs) is an artificial radionuclide that can be captured from the soil through the mycelium of fungi. However, in Spain there are few data on its presence in edible mushrooms. (137)Cs activity concentrations were determined using 54 samples of wild and cultivated mushrooms and 18 samples of soil, all of them collected in Galicia (NW Spain) during 2010. Samples were analyzed by gamma spectroscopy with a High-Purity Germanium (HPGe) detector. The average activity concentration of (137)Cs in wild mushrooms was 249.2Bqkg(-1) dry weight (dw) and about 24.9Bqkg(-1) fresh weight (fw). Genetic factors (species) influenced the uptake of (137)Cs, highlighting Hydnum repandum as the greatest accumulator of all wild species (1016.4Bqkg(-1) dw), while cultivated species showed much lower levels (1.6Bqkg(-1) fw). Accumulation was also favored by fungal mycorrhizal ecology, whose mycelium was distributed in contaminated soil horizons. The mean levels detected in soils were 14Bqkg(-1) fw. Although some species behaved as bioexclusors of radiocaesium, the transfer factors (TF) suggest that mushrooms preferentially bioaccumulate (137)Cs. No sample reached the limit of 600Bqkg(-1) fw (about 6000Bqkg(-1) dw) indicated in the European legislation. In conclusion, the consumption of mushrooms harvested from the investigated areas poses no toxicological risk to human health due to radiocaesium. PMID- 25700094 TI - Oxidative effects, nutrients and metabolic changes in aquatic macrophyte, Elodea nuttallii, following exposure to lanthanum. AB - We investigated the phytoremediation potential of Elodea nuttallii to remove rare earth metals from contaminated water. The laboratory experiments were designed to assess the responses induced by lanthanum (5-20mgL(-1)) in E. nuttallii over a period of 7 days. The results showed that most La (approximately 85%) was associated with the cell wall. The addition of La to the culture medium reduced the concentration of K, Ca, Cu, Mg, and Mn. However, O2(.-) levels increased with a concomitant increase in the malondialdehyde (MDA) concentration as the La concentration increased, which indicated that the cells were under oxidative stress. Significant reductions in the levels of chlorophyll (Chl) a, b, and carotenoids (Car) were observed in a concentration-dependent manner. However, the levels of reduced glutathione (GSH), total non-protein thiols (TNP-SH) and phytochelatins (PCs) increased for all La concentrations. The results suggested that La was toxic to E. nuttallii because it induced oxidative stress and disturbed mineral uptake. However, E. nuttallii was able to combat La induced damage via an immobilization mechanism, which involved the cell wall and the activation of non-enzymatic antioxidant. PMID- 25700095 TI - Biosorption and biodegradation of pyrene by Brevibacillus brevis and cellular responses to pyrene treatment. AB - Biodegradation has been proposed as an effective approach to remove pyrene, however, the information regarding cellular responses to pyrene treatment is limited thus far. In this study, the biodegradation and biosorption of pyrene by Brevibacillus brevis, along with cellular responses caused by pollutant were investigated by means of flow cytometry assay and scanning electron microscopy. The experimental results showed that pyrene was initially adsorbed by B. brevis and subsequently transported and intracellularly degraded. During this process, pyrene removal was primarily dependent on biodegradation. Cell invagination and cell surface corrugation occurred due to pyrene exposure. Nevertheless, cell regrowth after 96h treatment was observed, and the proportion of necrotic cell was only 2.8% after pyrene exposure for 120h, confirming that B. brevis could utilize pyrene as a sole carbon source for growth. The removal and biodegradation amount of pyrene (1mg/L) at 168h were 0.75 and 0.69mg/L, respectively, and the biosorption amount by inactivated cells was 0.41mg/L at this time. PMID- 25700096 TI - Morphological, biochemical, molecular and ultrastructural changes induced by Cd toxicity in seedlings of Theobroma cacao L. AB - Seeds from Theobroma cacao progenies derived from the self-pollination of 'Catongo'*'Catongo' and the crossing between CCN-10*SCA-6 were immersed for 24h in different Cd solutions (2; 4; 8; 16 and 32 mgL(-1)) along with the control treatment (without Cd). Shortly after, the seeds were sown in plastic tubes containing organic substrate and were grown in a greenhouse for 60 days. The treatment with Cd was observed to cause morphological, biochemical, molecular and ultrastructural changes in both progenies of T. cacao. There has been deformation in chloroplasts, nuclear chromatin condensation, and reduction in thickness of the mesophyll. As for 'Catongo'*'Catongo', a decrease in thickness of the epidermis was noted on the abaxial face. There has been increased guaiacol peroxidase activity in the roots of CCN-10*SCA-6, as well as in the''Catongo'*'Catongo' leaves. In the presence of Cd, CCN-10*SCA-6 showed increased expression of the genes associated with the biosynthesis of phytochelatin (PCS-1) and class III peroxidases (PER-1) in leaves, and metallothionein (MT2b), in roots. In 'Catongo'*'Catongo', there has been an increase in the expression of genes associated with the biosynthesis of PER-1 and cytosolic superoxide dismutase dependent on copper and zinc (Cu-Zn SODCyt) in leaves and from MT2b and PCS-1 and roots. There was higher accumulation of Cd in the aerial parts of seedlings from both progenies, whereas the most pronounced accumulation was seen in''Catongo'*'Catongo'. The increase in Cd concentration has led to lower Zn and Fe levels in both progenies. Hence, one may conclude that the different survival strategies used by CCN-10*SCA-6 made such progeny more tolerant to Cd stress when compared to''Catongo'*'Catongo'. PMID- 25700097 TI - Congruent validity and reliability of two metabolic systems to measure resting metabolic rate. AB - Determine the congruent validity and intra- and inter-day reliability of RMR measures assessed by the ParvoMedics Trueone 2 400 hood dilution method (Parvo) and Cosmed K4b(2) (Cosmed) breath-by-breath metabolic systems. Participants underwent 6 RMR assessments over 2 consecutive mornings, 3 with the Parvo (Day 1: Parvo 1; Day 2: Parvo 2, 3), 3 with the Cosmed (Day 1: Cosmed 1; Day 2: Cosmed 2, 3). Measured VE, FEO(2), FECO(2), VO(2), VCO(2), kcal/day, and HR values were averaged over a minimum of 10 min. Intra- and inter-day reliability within each system was determined with RMANOVA, and congruent validity was assessed via paired sample t-tests.31 participants (13 females, 18 males; 27.3+/-7 years, 24.8+/-3.1 kg.m(2)) completed the study. There were no significant differences in any within or between day Parvo values or Cosmed values. When systems were compared, there was a significant difference between VE (Parvo2: 25.03 L/min, Cosmed2: 8.98 L/min) and FEO(2) (Parvo2: 19.68%, Cosmed2: 16.63%), however, there were no significant difference in device-calculated RMR (kcals/day).The Parvo and Cosmed are reliable metabolic system with no intra- or inter-day differences in RMR. Due to differences in measurement technology, FEO(2), V(E) were significantly different between systems, but the resultant RMR values were not significantly different. PMID- 25700098 TI - Ground Reaction Force and Cadence during Stationary Running Sprint in Water and on Land. AB - This study was aimed at analyzing the cadence (Cadmax) and the peak vertical ground reaction force (Fymax) during stationary running sprint on dry land and at hip and chest level of water immersion. We hypothesized that both Fymax and Cadmax depend on the level of immersion and that differences in Cadmax between immersions do not affect Fymax during stationary sprint. 32 subjects performed the exercise at maximum cadence at each immersion level and data were collected with force plates. The results show that Cadmax and Fymax decrease 17 and 58% from dry land to chest immersion respectively, with no effect of cadence on Fymax. While previous studies have shown similar neuromuscular responses between aquatic and on land stationary sprint, our results emphasize the differences in Fymax between environments and levels of immersion. Additionally, the characteristics of this exercise permit maximum movement speed in water to be close to the maximum speed on dry land. The valuable combination of reduced risk of orthopedic trauma with similar neuromuscular responses is provided by the stationary sprint exercise in water. The results of this study support the rationale behind the prescription of stationary sprinting in sports training sessions as well as rehabilitation programs. PMID- 25700099 TI - Spatiotemporal Variables of Able-bodied and Amputee Sprinters in Men's 100-m Sprint. AB - The difference in world records set by able-bodied sprinters and amputee sprinters in the men's 100-m sprint is still approximately 1 s (as of 28 March 2014). Theoretically, forward velocity in a 100-m sprint is the product of step frequency and step length. The goal of this study was to examine the hypothesis that differences in the sprint performance of able-bodied and amputee sprinters would be due to a shorter step length rather than lower step frequency. Men's elite-level 100-m races with a total of 36 able-bodied, 25 unilateral and 17 bilateral amputee sprinters were analyzed from the publicly available internet broadcasts of 11 races. For each run of each sprinter, the average forward velocity, step frequency and step length over the whole 100-m distance were analyzed. The average forward velocity of able-bodied sprinters was faster than that of the other 2 groups, but there was no significant difference in average step frequency among the 3 groups. However, the average step length of able bodied sprinters was significantly longer than that of the other 2 groups. These results suggest that the differences in sprint performance between 2 groups would be due to a shorter step length rather than lower step frequency. PMID- 25700100 TI - The Effect of Caffeine Ingestion during Evening Exercise on Subsequent Sleep Quality in Females. AB - In a randomised, double-blind, placebo-controlled crossover design, 10 females taking monophasic oral contraceptives completed 90 min intermittent treadmill running 45 min after ingestion of 6 mg?kg(-1) body mass anhydrous caffeine or artificial sweetener (placebo). Water (3 mL?kg(-1)) was provided every 15 min during exercise. Venous blood samples were taken before, during and after exercise, as well as after sleep (~15 h post-ingestion), and levels of caffeine, paraxanthine, theobromine and theophylline were measured using high-performance liquid chromatography. Sleep quality was assessed using the Leeds Sleep Evaluation Questionnaire. Plasma caffeine concentration peaked 100 min after ingestion. Caffeine clearance was 0.95+/-0.14 mL.min(-1).kg(-1) while the elimination half-life of caffeine was 17.63+/-8.06 h. Paraxanthine and theophylline levels were significantly elevated at 15 h with no significant change in theobromine. Sleep latency and subsequent quality of sleep was impaired following caffeine supplementation (P<0.05); there were no differences between trials for how participants were feeling upon awakening. This is the first controlled study to examine caffeine supplementation on sleep quality in female athletes taking a low-dose monophasic oral contraceptive steroid following an intermittent-exercise running protocol. The data shows that female athletes using monophasic oral contraceptive steroids will have impaired sleep quality following evening caffeine ingestion. PMID- 25700101 TI - Asymmetry after hamstring injury in English Premier League: issue resolved, or perhaps not? AB - Hamstring injuries constitute one of the most concerning injuries in English Premier League football, due to its high primary incidence but also its recurrence. Functional methods assessing hamstring function during high-risk performance tasks such as sprinting are vital to identify potential risk factors. The purpose of this study was to assess horizontal force deficits during maximum sprint running on a non-motorized treadmill in football players with previous history of hamstring strains as a pre-season risk-assessment in a club setting. 17 male football players from one Premier League Club were divided into 2 groups, experimental (n=6, age=24.5+/-2.3 years) and control (n=11, age=21.3+/-1.2 years), according to history of previous hamstring injury. Participants performed a protocol including a 10-s maximum sprint on a non-motorized treadmill. Force deficits during acceleration phase and steady state phases of the sprint were assessed between limbs and between groups. The main outcome measures were horizontal and vertical peak forces during the acceleration phase or steady state. There were no significant differences in peak forces between previously injured and non-injured limbs, or between groups, challenging the ideas around functional force deficits in sprint running as a diagnostic measure of hamstring re-injury risk. PMID- 25700102 TI - Physiological Responses during Cycle Ergometry at a Constant Perception of Effort. AB - 13 subjects performed an incremental test to exhaustion, 4, 8-min submaximal rides, and a 1-h ride at the rating of perceived exertion (RPE) that corresponded to the physical working capacity at the OMNI threshold (PWC(OMNI)) to examine: 1) the oxygen consumption (VO2), heart rate (HR), minute ventilation (+V(E)), respiratory frequency (FR), and power output responses during 1-h work bouts at a constant RPE that corresponded to the PWC(OMNI); and 2) the ability of current models to explain the responses for physiological and perceptual parameters during the 1-h work bouts. The RPE that corresponded to the PWC(OMNI) represented a sustainable exercise intensity (56+/-5% (VO(2Peak)) within the moderate intensity domain. The mean, normalized slope coefficients for the VO2, +V(E), and power output vs. time relationships during the 1-h rides were significantly less than zero. The mean, normalized slope coefficient for the FR vs. time relationship during the 1-h rides, however, was not significantly different from zero. Thus, RPE most clearly tracked FR responses during the 1-h rides. It was hypothesized that afferent feedback from respiratory muscles may have mediated the perception of effort during cycle ergometry at a constant RPE in the moderate intensity domain. PMID- 25700103 TI - Effect of concurrent training with blood flow restriction in the elderly. AB - The aim of this present study was to investigate on the effects of concurrent training with blood flow restriction (BFR-CT) and concurrent training (CT) on the aerobic fitness, muscle mass and muscle strength in a cohort of older individuals. 25 healthy older adults (64.7+/-4.1 years; 69.33+/-10.8 kg; 1.6+/ 0.1 m) were randomly assigned to experimental groups: CT (n=8, endurance training (ET), 2 days/week for 30-40 min, 50-80% VO(2peak) and RT, 2 days/week, leg press with 4 sets of 10 reps at 70-80% of 1-RM with 60 s rest), BFR-CT (n=10, ET, similar to CT, but resistance training with blood flow restriction: 2 days/week, leg press with 1 set of 30 and 3 sets of 15 reps at 20-30% 1-RM with 60 s rest) or control group (n=7). Quadriceps cross-sectional area (CSAq), 1-RM and VO(2peak) were assessed pre- and post-examination (12 wk). The CT and BFR-CT showed similar increases in CSAq post-test (7.3%, P<0.001; 7.6%, P<0.0001, respectively), 1-RM (38.1%, P<0.001; 35.4%, P=0.001, respectively) and VO(2peak) (9.5%, P=0.04; 10.3%, P=0.02, respectively). The BFR-CT promotes similar neuromuscular and cardiorespiratory adaptations as CT. PMID- 25700104 TI - Facial Video-Based Photoplethysmography to Detect HRV at Rest. AB - Our aim is to demonstrate the usefulness of photoplethysmography (PPG) for analyzing heart rate variability (HRV) using a standard 5-min test at rest with paced breathing, comparing the results with real RR intervals and testing supine and sitting positions. Simultaneous recordings of R-R intervals were conducted with a Polar system and a non-contact PPG, based on facial video recording on 20 individuals. Data analysis and editing were performed with individually designated software for each instrument. Agreement on HRV parameters was assessed with concordance correlations, effect size from ANOVA and Bland and Altman plots. For supine position, differences between video and Polar systems showed a small effect size in most HRV parameters. For sitting position, these differences showed a moderate effect size in most HRV parameters. A new procedure, based on the pixels that contained more heart beat information, is proposed for improving the signal-to-noise ratio in the PPG video signal. Results were acceptable in both positions but better in the supine position. Our approach could be relevant for applications that require monitoring of stress or cardio-respiratory health, such as effort/recuperation states in sports. PMID- 25700105 TI - Rehabilitation following zone II flexor tendon repairs. AB - Ongoing clinical and basic research has improved understanding of flexor tendon mechanics and physiology for surgical repair and rehabilitation after a zone II flexor tendon repair. Yet, the ideal surgical repair technique that includes sufficient strength to allow safe immediate active motion of the finger, without excessive repair stiffness, bulk or rough surfaces resulting in excessive resistance to flexion, does not exist. After optimizing the repair, the surgeon and therapist team must select a rehabilitation plan that protects the repair but helps to maintain tendon gliding. There are 3 types of rehabilitation programs for flexor tendon repairs: delayed mobilization, early passive mobilization, or an early active mobilization. No guideline for rehabilitation should be followed exactly. Many factors influence therapy decisions, including repair technique, associated tendon healing, passive versus active range of motion, edema, and tendon adhesions. These factors can assist in guiding rehabilitation progression and promote functional range of motion, safely mobilize the repaired tendon(s) and prevent gapping, rupture, and adhesions. PMID- 25700106 TI - We could be heroes: ethical issues with the pre-recruitment of research participants. AB - Pre-recruitment is the practice of recruiting potential participants to a list of potential research volunteers in general rather than to a specific research project. This is a relatively common practice in commercial medical research as it reduces the time and hence costs of recruitment and makes it possible to be more efficient by recruiting participants who may be useful for a variety of different pieces of research. It focuses on present practices in the UK although the conclusions and suggestions should be read more widely than this, applying in any situation where pre-recruitment is used as a recruitment tool for clinical trials and beyond. Current pre-recruitment practices in the UK clash significantly with what are seen as best practices and ethical guidance with regard to recruiting participants to individual trials, and insofar as this undermines these practices should be reformed. PMID- 25700107 TI - HIV-related behaviors, social support and health-related quality of life among men who have sex with men and women (MSMW): a cross-sectional study in Chongqing, China. AB - BACKGROUND: Health-related quality of life (HRQOL) has become commonly used both as a concept and as a field of research. However, little is known about the HRQOL of men who have sex with men and women (MSMW). The aim of this study was to examine HIV-related behaviors, social support, and HRQOL status and explore its predictors among MSMW. METHODS: An anonymous cross-sectional study was conducted by snowball sampling method in 2013. A total of 563 Chinese MSM completed a structured questionnaire. The HRQOL and social support were measured with the Chinese version of the World Health Organization Quality of Life Scale (WHOQOL BRFE) and the Social Support Rating Scale (SSRS), respectively. RESULTS: Of the 563 MSM analyzed, 77 (13.68%) were MSMW who had a higher proportion of in marriage and preference for an insertive role as compared with the men who have sex with men only (MSMO) (P<0.05). As high as 70.13% of MSMW had no regular sex partners and 72.73% of MSMW reported engaging in unprotected anal sex in the last six months. 36.36% had tested for HIV, while only 12.99% had accepted HIV voluntary counseling and testing (VCT) services. The scores of objective support and subjective support in MSMW were significantly higher than that of MSMO (P<0.05). No statistically significant difference was found in scores of all the four domains of the HRQOL between MSMW and MSMO. When comparing the HRQOL scores of MSMW with the Chinese general population reference group, the scores of MSMW were significantly lower in physical health domain. In a multivariate regression model, age, monthly income, sexual role, VCT acceptability, subjective support were associated with variability in HRQOL. CONCLUSIONS: To improve the HRQOL among MSMW, more attention needs to be paid to those with low social support, low income, the old and those prefer a receptive role during anal sex populations. PMID- 25700108 TI - The polysaccharide capsule of Streptococcus pneumonia partially impedes MyD88 mediated immunity during pneumonia in mice. AB - Toll-like receptors (TLR) and the downstream adaptor protein MyD88 are considered crucial for protective immunity during bacterial infections. Streptococcus (S.) pneumoniae is a human respiratory pathogen and a large majority of clinical pneumococcal isolates expresses an external polysaccharide capsule. We here sought to determine the role of pneumococcal capsule in MyD88-mediated antibacterial defense during S. pneumonia pneumonia. Wild type (WT) and Myd88(-/ ) mice were inoculated intranasally with serotype 2 S. pneumoniae D39 or with an isogenic capsule locus deletion mutant (D39?cps), and analysed for bacterial outgrowth and inflammatory responses in the lung. As compared to WT mice, Myd88( /-) mice infected with D39 demonstrated a modestly impaired bacterial clearance accompanied by decreased inflammatory responses in the lung. Strikingly, while WT mice rapidly cleared D39?cps, Myd88(-/-) mice showed 105-fold higher bacterial burdens in their lungs and dissemination to blood 24 hours after infection. These data suggest that the pneumococcal capsule impairs recognition of TLR ligands expressed by S. pneumoniae and thereby partially impedes MyD88-mediated antibacterial defense. PMID- 25700109 TI - Agromining: farming for metals in the future? AB - Phytomining technology employs hyperaccumulator plants to take up metal in harvestable plant biomass. Harvesting, drying and incineration of the biomass generates a high-grade bio-ore. We propose that "agromining" (a variant of phytomining) could provide local communities with an alternative type of agriculture on degraded lands; farming not for food crops, but for metals such as nickel (Ni). However, two decades after its inception and numerous successful experiments, commercial phytomining has not yet become a reality. To build the case for the minerals industry, a large-scale demonstration is needed to identify operational risks and provide "real-life" evidence for profitability. PMID- 25700110 TI - Roadside drug testing: comparison of two legal approaches in Belgium. AB - BACKGROUND: Internationally, urine on-site testing has been used for detecting drivers under the influence of drugs (DUID) but more and more countries, such as Belgium, are switching to oral fluid screening. OBJECTIVE: To compare the previous (published in 1999) and current (published 2009) enforcement procedures of DUID in Belgium. The two evaluated procedures differ in the way the drivers are screened by the police (signs of impairment versus signs of recent drug use), the matrix for screening (urine versus oral fluid) and the analytical cut-off concentrations in plasma. METHODS: Data on positive screening and confirmation results were gathered from 1st April 2008 to 30th September 2010, when urine screening (Dipro Druglab panels test) was performed; and from 1st October 2010 to 31st March 2013, when an on-site oral fluid test (Securetec Drugwipe 5(+)) was used. RESULTS: Approximately 4100 data sets related to urine screening and 3900 data sets related to oral fluid screening were studied. Eighty-eight percent of positive urine on-site tests yielded positive results in plasma for cannabis, 21% for cocaine, 20% for amphetamines and 7% for opiates. Sixty-six percent of the positive oral fluid on-site tests yielded positive results in plasma for cannabis, 30% for cocaine, 28% for amphetamines and 8% for opiates. For cannabis, opiates and amphetamines more negative results in plasma were observed in the period of urine screening. CONCLUSIONS: The percentage of plasma samples of tested drivers, in which none of the positive screened target drugs were present in a concentration above the legal cut-off value, has decreased from 17% to 8% since the introduction of the current legislation involving oral fluid screening. PMID- 25700111 TI - Characterization of ANFO explosive by high accuracy ESI(+/-)-FTMS with forensic identification on real samples by EASI(-)-MS. AB - Ammonium nitrate fuel oil (ANFO) is an explosive used in many civil applications. In Brazil, ANFO has unfortunately also been used in criminal attacks, mainly in automated teller machine (ATM) explosions. In this paper, we describe a detailed characterization of the ANFO composition and its two main constituents (diesel and a nitrate explosive) using high resolution and accuracy mass spectrometry performed on an FT-ICR-mass spectrometer with electrospray ionization (ESI(+/-) FTMS) in both the positive and negative ion modes. Via ESI(-)-MS, an ion marker for ANFO was characterized. Using a direct and simple ambient desorption/ionization technique, i.e., easy ambient sonic-spray ionization mass spectrometry (EASI-MS), in a simpler, lower accuracy but robust single quadrupole mass spectrometer, the ANFO ion marker was directly detected from the surface of banknotes collected from ATM explosion theft. PMID- 25700112 TI - Forensic toxicological analyses of drugs in tissues in formalin solutions and in fixatives. AB - Forensic toxicological drug analyses of human specimens are usually performed immediately after autopsy or on frozen preserved tissues. Occasionally, cases require analysis of drugs from tissues fixed in formalin solution. To improve the estimation of the level of drug in tissues following formalin fixation, we studied drug concentrations in human tissues, liver and kidney, that were collected from a drug-positive autopsy case. Parts of tissues were preserved in formalin solution for 1, 3, 6 and 13 months. Tissues obtained before and after preservation, along with tissue-exposed fixatives, were assayed using gas chromatography-mass spectrometry; all of the samples were assayed for the presence of drugs and changes in the drug concentrations both before and after preservation in formalin. Concentrations of assayed drugs decreased upon fixation in formalin; levels of these drugs did not necessarily show further decreases during subsequent storage in fixative, up to 13 months. Distinct trends in drug levels were found in liver and kidney. In liver, the levels of chlorpromazine, levomepromazine, and promethazine decreased to 23-39% at 1 month after preservation; all 3 of these drugs were detected at all tested time points of preservation. Bromazepam was not detected at 13 months after preservation. Milnacipran was the most unstable after preservation in formalin solution among all of the assayed drugs. In kidney, all assayed drugs exhibited reduced stability during preservation compared to levels in liver. Methamphetamine and methylenedioxymethamphetamine were not detected in any time points of tissues. The proportions of the drugs that remained within the tissues differed between liver and kidney. Also, S-oxide compounds of chlorpromazine and levomepromazine, which were not observed before preservation, were detected in fixed liver tissues and their fixatives at 3, 6 and 13 months of preservation. These results suggest that analyses in formalin-fixed tissues need to include analysis of various organ tissues and their fixatives at multiple time points for the duration of preservation. These analyses should include detection of chemical degradation/denaturation products, such as S-oxides of chlorpromazine and levomepromazine. PMID- 25700113 TI - Advances in chemical protein modification. PMID- 25700114 TI - Immunostaining in lung cancer for the clinician. Commonly used markers for differentiating primary and metastatic pulmonary tumors. AB - Immunohistochemical stains have become invaluable for the diagnosis of pulmonary malignancies (both primary and metastatic), particularly given the small size of transbronchial and endobronchial biopsies and the increasing need to conserve tissue for molecular studies. There are many panels of immunostains currently available to help differentiate between common types of pulmonary malignancies. It is the purpose of this review to summarize some of the most commonly used immunostains for the distinction of primary pulmonary malignancies from one another in areas with histological overlap and for distinguishing primary pulmonary malignancies from other cancers with which they may be confused. These include differentiating between poorly differentiated adenocarcinoma and poorly differentiated squamous cell carcinoma, small cell/large cell neuroendocrine carcinoma and basaloid carcinoma, and primary and metastatic adenocarcinoma involving the lung. In addition, we address the distinction between mesothelioma and pulmonary adenocarcinoma. Pitfalls in the use of these markers are also addressed. Although not aiming to be comprehensive, this review aims to guide and influence common practice by furthering the clinician's knowledge on using immunohistochemical stains for characterization of pulmonary neoplasms. This summary of frequently used immunohistochemical stains can provide usefulness by allowing accurate characterization of pulmonary tumors, thereby allowing for conservation of tissue for additional molecular testing. PMID- 25700115 TI - Finding the true spin-lattice relaxation time for half-integral nuclei with non zero quadrupole couplings. AB - Measuring true spin-lattice relaxation times T(1) of half-integral quadrupolar nuclei having non-zero nuclear quadrupole coupling constants (NQCCs) presents challenges due to the presence of satellite-transitions (STs) that may lie outside the excitation bandwidth of the central transition (CT). This leads to complications in establishing well-defined initial conditions for the population differences in these multi-level systems. In addition, experiments involving magic-angle spinning (MAS) can introduce spin exchange due to zero-crossings of the ST and CT (or possibly rotational resonance recoupling in the case of multiple sites) and greatly altered initial conditions as well. An extensive comparison of pulse sequences that have been previously used to measure T(1) in such systems is reported, using the (71)Ga (I=3/2) NMR of a Ge-doped h-GaN n-type semiconductor sample as the test case. The T(1) values were measured at the peak maximum of the Knight shift distribution. Analytical expressions for magnetization-recovery of the CT appropriate to the pulse sequences tested were used, involving contributions from both a magnetic relaxation mechanism (rate constant W) and a quadrupolar one (rate constants W(1) and W(2), approximately equal in this case). An asynchronous train of high-power saturating pulses under MAS that is able to completely saturate both CT and STs is found to be the most reliable and accurate method for obtaining the "true T(1)", defined here as (2W+2W1,2)(-)(1). All other methods studied yielded poor agreement with this "true T(1)" value or even resulted in gross errors, for reasons that are analyzed in detail. These methods involved a synchronous train of saturating pulses under MAS, an inversion-recovery sequence under MAS or static conditions, and a saturating comb of pulses on a static sample. Although the present results were obtained on a sample where the magnetic relaxation mechanism dominated the quadrupolar one, the asynchronous saturating pulse train approach is not limited to this situation. The extent to which W(1) and W(2) are unequal does affect the interpretability of the experiment however, particularly when the quadrupolar mechanism dominates. A numerically approximate solution for the I=3/2 recovery case reveals the quantitative effects of any such inequality. PMID- 25700116 TI - Magnetic resonance signal moment determination using the Earth's magnetic field. AB - We demonstrate a method to manipulate magnetic resonance data such that the moments of the signal spatial distribution are readily accessible. Usually, magnetic resonance imaging relies on data acquired in so-called k-space which is subsequently Fourier transformed to render an image. Here, via analysis of the complex signal in the vicinity of the centre of k-space we are able to access the first three moments of the signal spatial distribution, ultimately in multiple directions. This is demonstrated for biofouling of a reverse osmosis (RO) membrane module, rendering unique information and an early warning of the onset of fouling. The analysis is particularly applicable for the use of mobile magnetic resonance spectrometers; here we demonstrate it using an Earth's magnetic field system. PMID- 25700117 TI - Theoretical and experimental study of ON-Resonance Saturation, an MRI sequence for positive contrast with superparamagnetic nanoparticles. AB - Superparamagnetic iron oxide nanoparticles (SPM particles) are widely used in MRI as negative contrast agents. Their detection is sometimes difficult because negative contrast can be caused by different artifacts. To overcome this problem, MRI protocols achieving positive contrast specific to SPM particles were developed such as the ON-Resonance Saturation (ONRS) sequence. The aim of the present work is to achieve a bottom-up study of the ONRS sequence by an understanding of the physical mechanisms leading to positive contrast. A complete theoretical modeling, a novel numerical simulation approach and experiments on agarose gel phantoms on a 11.7 T MRI system were carried out for this purpose. The influence of the particle properties and concentration - as well as the effect of the sequence parameters on the contrast - were investigated. It was observed that theory and experiments were in strong agreement. The tools developed in this work allowed to predict the parameters leading to the maximum contrast. For example, particles presenting a low transverse relaxivity can provide an interesting positive contrast after optimization of their concentration in the sample. PMID- 25700118 TI - MOAtox: A comprehensive mode of action and acute aquatic toxicity database for predictive model development. AB - The mode of toxic action (MOA) has been recognized as a key determinant of chemical toxicity and as an alternative to chemical class-based predictive toxicity modeling. However, the development of quantitative structure activity relationship (QSAR) and other models has been limited by the availability of comprehensive high quality MOA and toxicity databases. The current study developed a dataset of MOA assignments for 1213 chemicals that included a diversity of metals, pesticides, and other organic compounds that encompassed six broad and 31 specific MOAs. MOA assignments were made using a combination of high confidence approaches that included international consensus classifications, QSAR predictions, and weight of evidence professional judgment based on an assessment of structure and literature information. A toxicity database of 674 acute values linked to chemical MOA was developed for fish and invertebrates. Additionally, species-specific measured or high confidence estimated acute values were developed for the four aquatic species with the most reported toxicity values: rainbow trout (Oncorhynchus mykiss), fathead minnow (Pimephales promelas), bluegill (Lepomis macrochirus), and the cladoceran (Daphnia magna). Measured acute toxicity values met strict standardization and quality assurance requirements. Toxicity values for chemicals with missing species-specific data were estimated using established interspecies correlation models and procedures (Web-ICE; http://epa.gov/ceampubl/fchain/webice/), with the highest confidence values selected. The resulting dataset of MOA assignments and paired toxicity values are provided in spreadsheet format as a comprehensive standardized dataset available for predictive aquatic toxicology model development. PMID- 25700119 TI - Low risk of male suicide and lithium in drinking water. AB - OBJECTIVE: Recently, several epidemiologic studies reported that lithium in drinking water may be associated with lower rates of suicide mortality at the population level, but other studies failed to confirm the association. The objective of the present study is to determine whether lithium in drinking water is associated with lower suicide rate after adjustment of potential confounding factors. METHOD: From 2010 to 2013, 274 mean lithium levels of 434 lithium samples in drinking water were examined in relation to suicide standardized mortality ratios (SMRs) in 274 municipalities of Kyushu Island in Japan. Weighted least squares regression analysis adjusted for the size of each population was used to investigate the association of lithium levels with suicide SMRs. The associations of lithium levels in drinking water with suicide SMRs (total, male, and female) were investigated adjusting for proportion of elderly people, proportion of 1-person households, proportion of people with college education or more, and proportion of people engaging in primary industry (adjusted model 1), and further adjustment was performed with overall unemployment rate, annual marriage rate, annual mean temperature, and annual postal savings per person (adjusted model 2). RESULTS: Lithium levels in drinking water were significantly (beta = -.169, P = .019) and inversely associated with male suicide SMRs but not total or female SMRs in the adjusted model 2. CONCLUSIONS: The present findings suggest that lithium in drinking water may be associated with the low risk of male suicide in the general population. Further studies are required to confirm these findings and investigate gender differences. PMID- 25700120 TI - The "vagal ansa": a source of complication in vagus nerve stimulation. AB - A 16-year-old boy underwent vagus nerve stimulation for treatment-resistant multifocal epilepsy. During intraoperative system diagnostics, vigorous contraction of the ipsilateral sternomastoid muscle was observed. On re exploration, a thin nerve fiber passing from the vagus to the sternomastoid was found hooked up in the upper electrode. Detailed inspection revealed an abnormal course of the superior root of the ansa cervicalis, which descended down as a single nerve trunk with the vagus and separated to join the inferior root. The authors discuss the variation in the course of the ansa cervicalis and how this could be a reason for postoperative neck muscle contractions. PMID- 25700121 TI - Recurrent craniopharyngioma after conformal radiation in children and the burden of treatment. AB - OBJECT: In this paper the authors present their experience treating children with recurrent craniopharyngioma who were initially managed with surgery followed by conformal radiation therapy (CRT). METHODS: A departmental oncology information system was queried to identify all children (< 18 years old) who received CRT for a craniopharyngioma between 1998 and 2010 (inclusive) and specifically those who experienced tumor progression. For each patient, the authors recorded the type of recurrence (solid, cystic, or both), the time interval to first progression and each subsequent progression, the associated treatment complications, and disease status at last follow-up evaluation. RESULTS: Among the 97 patients that met criteria for entry into this study, 18 (18.6%) experienced tumor progression (9 cystic, 3 solid, 6 cystic and solid). The median time to first recurrence was 4.62 years (range 1.81-9.11 years). The subgroup included 6 female and 12 male patients with a median age of 7.54 years (range 3.61-13.83 years). Ten patients experienced first progression within 5 years of CRT. The 5- and 10-year treatment free survival rates for the entire cohort were 89.0% (95% confidence interval [CI] 80.5%-93.9%) and 76.2% (95% CI 64%-85%), respectively. Seven patients had a single episode of progression and 11 had more than 1. The time interval between each subsequent progression was progressively shorter. The 18 patients underwent 38 procedures. The median follow-up duration for this group was 9.32 years (range 4.04-19.0 years). Three patients died, including 1 from perioperative complications. CONCLUSIONS: Craniopharyngioma progression after prior irradiation is exceedingly difficult to treat and local control is challenging despite repeated surgical procedures. Given our results, gross-total resection may need to be the surgical goal at the time of first recurrence, if possible. Decompressing new cyst formation alone has a low rate of long-term success. PMID- 25700122 TI - Magnetic resonance imaging as an alternative to computed tomography in select patients with traumatic brain injury: a retrospective comparison. AB - OBJECT: Traumatic head injury (THI) is a highly prevalent condition in the United States, and concern regarding excess radiation-related cancer mortality has placed focus on limiting the use of CT in the evaluation of pediatric patients with THI. Given the success of rapid-acquisition MRI in the evaluation of ventriculoperitoneal shunt malfunction in pediatric patient populations, this study sought to evaluate the sensitivity of MRI in the setting of acute THI. METHODS: Medical records of 574 pediatric admissions for THI to a Level 1 trauma center over a 10-year period were retrospectively reviewed to identify patients who underwent both CT and MRI examinations of the head within a 5-day period. Thirty-five patients were found, and diagnostic images were available for 30 patients. De-identified images were reviewed by a neuroradiologist for presence of any injury, intracranial hemorrhage, diffuse axonal injury (DAI), and skull fracture. Radiology reports were used to calculate interrater reliability scores. Baseline demographics and concordance analysis was performed with Stata version 13. RESULTS: The mean age of the 30-patient cohort was 8.5 +/- 6.7 years, and 63.3% were male. The mean Injury Severity Score was 13.7 +/- 9.2, and the mean Glasgow Coma Scale score was 9 +/- 5.7. Radiology reports noted 150 abnormal findings. CT scanning missed findings in 12 patients; the missed findings included DAI (n = 5), subarachnoid hemorrhage (n = 6), small subdural hematomas (n = 6), cerebral contusions (n = 3), and an encephalocele. The CT scan was negative in 3 patients whose subsequent MRI revealed findings. MRI missed findings in 13 patients; missed findings included skull fracture (n = 5), small subdural hematomas (n = 4), cerebral contusions (n = 3), subarachnoid hemorrhage (n = 3), and DAI (n = 1). MRI was negative in 1 patient whose preceding CT scan was read as positive for injury. Although MRI more frequently reported intracranial findings than CT scanning, there was no statistically significant difference between CT and MRI in the detection of any intracranial injury (p = 0.63), DAI (p = 0.22), or intracranial hemorrhage (p = 0.25). CT scanning tended to more frequently identify skull fractures than MRI (p = 0.06). CONCLUSIONS: MRI may be as sensitive as CT scanning in the detection of THI, DAI, and intracranial hemorrhage, but missed skull fractures in 5 of 13 patients. MRI may be a useful alternative to CT scanning in select stable patients with mild THI who warrant neuroimaging by clinical decision rules. PMID- 25700123 TI - Diagnosis and management challenge of a granular cell astrocytoma of the pineal region: case report. AB - Granular cell astrocytoma (GCA) is a rare type of infiltrative brain tumor with most reported cases occurring in the suprasellar region. A pineal localization is extremely rare, with only 4 previously reported cases in the literature. The authors describe the case of a 16-year-old boy who developed signs of increased intracranial pressure and Parinaud syndrome. Cranial CT and MRI revealed a well demarcated and enhanced mass in the pineal region accompanied by obstructive hydrocephalus. Subtotal resection was performed via a subtemporal approach. A histological diagnosis of GCA was made. Three years after surgery, the patient was alive and well without adjuvant therapy, and serial MRI showed no signs of progression of a small residual tumor. After a thorough review of the different epidemiological, clinical, and imaging features; treatments; and prognoses of GCAs in other intracranial localizations, the authors analyzed features of this tumor in the pineal region. PMID- 25700124 TI - A half-reaction alternative to water oxidation: chloride oxidation to chlorine catalyzed by silver ion. AB - Chloride oxidation to chlorine is a potential alternative to water oxidation to oxygen as a solar fuels half-reaction. Ag(I) is potentially an oxidative catalyst but is inhibited by the high potentials for accessing the Ag(II/I) and Ag(III/II) couples. We report here that the complex ions AgCl2(-) and AgCl3(2-) form in concentrated Cl(-) solutions, avoiding AgCl precipitation and providing access to the higher oxidation states by delocalizing the oxidative charge over the Cl(-) ligands. Catalysis is homogeneous and occurs at high rates and low overpotentials (10 mV at the onset) with MUM Ag(I). Catalysis is enhanced in D2O as solvent, with a significant H2O/D2O inverse kinetic isotope effect of 0.25. The results of computational studies suggest that Cl(-) oxidation occurs by 1e(-) oxidation of AgCl3(2-) to AgCl3(-) at a decreased potential, followed by Cl(-) coordination, presumably to form AgCl4(2-) as an intermediate. Adding a second Cl(-) results in "redox potential leveling", with further oxidation to {AgCl2(Cl2)}(-) followed by Cl2 release. PMID- 25700125 TI - How does a collision warning system shape driver's brake response time? The influence of expectancy and automation complacency on real-life emergency braking. AB - Brake Reaction Time (BRT) is an important parameter for road safety. Previous research has shown that drivers' expectations can impact RT when facing hazardous situations, but driving with advanced driver assistance systems, can change the way BRT are considered. The interaction with a collision warning system can help faster more efficient responses, but at the same time can require a monitoring task and evaluation process that may lead to automation complacency. The aims of the present study are to test in a real-life setting whether automation compliancy can be generated by a collision warning system and what component of expectancy can impact the different tasks involved in an assisted BRT process. More specifically four component of expectancy were investigated: presence/absence of anticipatory information, previous direct experience, reliability of the device, and predictability of the hazard determined by repeated use of the warning system. Results supply indication on perception time and mental elaboration of the collision warning system alerts. In particular reliable warning quickened the decision making process, misleading warnings generated automation complacency slowing visual search for hazard detection, lack of directed experienced slowed the overall response while unexpected failure of the device lead to inattentional blindness and potential pseudo-accidents with surprise obstacle intrusion. PMID- 25700126 TI - The effects of age, gender, and crash types on drivers' injury-related health care costs. AB - There are many studies that evaluate the effects of age, gender, and crash types on crash related injury severity. However, few studies investigate the effects of those crash factors on the crash related health care costs for drivers that are transported to hospital. The purpose of this study is to examine the relationships between drivers' age, gender, and the crash types, as well as other crash characteristics (e.g., not wearing a seatbelt, weather condition, and fatigued driving), on the crash related health care costs. The South Carolina Crash Outcome Data Evaluation System (SC CODES) from 2005 to 2007 was used to construct six separate hierarchical linear regression models based on drivers' age and gender. The results suggest that older drivers have higher health care costs than younger drivers and male drivers tend to have higher health care costs than female drivers in the same age group. Overall, single vehicle crashes had the highest health care costs for all drivers. For males older than 64-years old sideswipe crashes are as costly as single vehicle crashes. In general, not wearing a seatbelt, airbag deployment, and speeding were found to be associated with higher health care costs. Distraction-related crashes are more likely to be associated with lower health care costs in most cases. Furthermore this study highlights the value of considering drivers in subgroups, as some factors have different effects on health care costs in different driver groups. Developing an understanding of longer term outcomes of crashes and their characteristics can lead to improvements in vehicle technology, educational materials, and interventions to reduce crash-related health care costs. PMID- 25700127 TI - Effects of fog, driver experience and gender on driving behavior on S-curved road segments. AB - Driving on curved roads has been recognized as a significant safety issue for many years. However, driver behavior and the interactions among variables that affect driver performance on curves is complicated and not well understood. Previous studies have investigated various factors that influence driver performance on right- or left-turn curves, but have paid little attention to the effects of foggy weather, driver experience and gender on driver performance on complex curves. A driving simulator experiment was conducted in this study to evaluate the relationships between driving behavior on a continuous S-curve and foggy weather, driver experience and gender. The process of negotiating a curve was divided into three stages consisting of a straight segment, the transition from the straight segment to the S-curve and the S-curve. The experimental results indicated that drivers tended to drive more cautiously in heavy fog, but the driving risk was still increased, especially in the transition stage from the straight segment to the S-curve. The non-professional (NP) drivers were less sensitive to the impending change in the road geometry, and less skilled in both longitudinal and lateral vehicle control than the professional drivers. The NP female drivers in particular were found to be the most vulnerable group in S curve driving. PMID- 25700128 TI - Nickel-catalyzed decarboxylative cross-coupling of perfluorobenzoates with aryl halides and sulfonates. AB - A Ni-catalyzed method for the coupling of perfluorobenzoates with aryl halides and pseudohalides is described. Aryl iodides, bromides, chlorides, triflates, and tosylates participate in these transformations to afford the products in good yields. Penta-, tetra-, and trifluorinated biaryl compounds are obtained using these newly developed Ni-catalyzed decarboxylative cross-coupling reactions. PMID- 25700129 TI - Comment on: 'Pitfalls in microdialysis methodology: an in vitro analysis of temperature, pressure and catheter use'. PMID- 25700130 TI - Plasmon-mediated photocatalytic activity of wet-chemically prepared ZnO nanowire arrays. AB - We report on measurements and simulations of the efficient sunlight-driven and visible-active photocatalysts composed of plasmonic metal nanoparticles and ZnO nanowire (NW) arrays fabricated via an all-wet-chemical route. Because of the coupling between the ZnO dielectric response and the excitation of the Ag or Au nanoparticles, efficient electronic excitation can be induced in the vicinity of the metal-ZnO interfaces because optically-excited plasmonic particles can not only concentrate the electromagnetic field at the ZnO/particle interface, but also act as efficient sources of plasmonic hot electrons to be injected into the conduction band of the ZnO catalyst. The catalytic activities of the fabricated ZnO NWs are examined by photodegradation of methylene blue and by photocurrent measurements in a photovoltaic configuration. Numerical electromagnetic simulations were used to understand the behavior of the light on the nanometer scale to clarify the catalytic enhancement mechanisms in both the ultraviolet (UV) and visible (VIS) regions. In addition, simulation results indicated that a near-surface normal but slightly tilted ZnO NW array geometry would provide an increased optical path length and enhanced multiple scattering and absorption processes arising from the localized surface plasmon resonances of the nanoparticles. The results obtained here clarify the role of the plasmon resonance and provide us with useful knowledge for the development of metal-oxide nano-hybrid materials for solar energy conversion. PMID- 25700131 TI - Local structure of semicrystalline P3HT films probed by nanofocused coherent X rays. AB - The hidden structural properties of semicrystalline polymer films are revealed by nanofocused X-ray scattering studies. X-ray cross-correlation analysis (XCCA) is employed to diffraction patterns from blends of poly(3-hexylthiophene) (P3HT) with gold nanoparticles (AuNPs). Spatially resolved maps of orientational distribution of crystalline domains allow us to distinguish sample regions of predominant face-on morphology, with a continuous transition to edge-on morphology. The average size of crystalline domains was determined to be of the order of 10 nm. As compared to pristine P3HT film, the P3HT/AuNPs blend is characterized by substantial ordering of crystalline domains, which can be induced by Au nanoparticles. The inhomogeneous structure of the polymer film is clearly visualized on the spatially resolved nanoscale 2D maps obtained using XCCA. Our results suggest that the observed changes of the polymer matrix within crystalline regions can be attributed to nanoconfinement in the presence of gold nanoparticles. PMID- 25700132 TI - Opportunities for targeted focal treatment in Japan. AB - PURPOSE OF REVIEW: Widespread prostate-specific antigen screening has led to an increase in prostate cancer diagnoses in Asian populations, reflecting changes in socioeconomic status and epidemiological features in these countries. In this setting, the present review explores opportunities for target focal therapy in Japan. RECENT FINDINGS: Our review examines several topics relating to focal therapy in Asia, and discusses the current status of prostate cancer diagnosis and treatment in that region. First, we summarize the prevalence of prostate cancer in Asian populations. Second, we examine prostate cancer diagnosis and treatment options such as mapping biopsy and MRI fusion biopsy in Japan. Third, we review treatment strategies for localized prostate cancer, especially robotic assisted surgery, active surveillance, and high-intensity focused ultrasound. Lastly, we discuss the potential for focal therapy in Japan. SUMMARY: The number of localized prostate cancer patients is expected to increase in Asia. Accordingly, the need for precise diagnosis in terms of localization of prostate cancer foci will also expand. MRI fusion target biopsies are being performed in Asia, particularly in some Japanese academic institutions, but as pilot studies. In recent years, an increase in robotic-assisted surgery in East Asia has yielded new options in prostate cancer treatment. Although active surveillance is a practical choice for low-risk prostate cancer in some Asian countries, focal therapy is expected to see increasing interest as another alternative in Japan. PMID- 25700133 TI - Communication needs of patients with altered hearing ability: Informing pharmacists' patient care services through focus groups. AB - OBJECTIVE: The purpose of this research is to identify communication barriers and needs for Deaf and hard-of-hearing (HOH) patients when they seek pharmaceutical care, and to better understand the impact of poor communication upon medication adherence and medication errors among this underserved population. DESIGN: Focus group discussion. SETTING: Midwestern United States in September 2013 through April 2014. PARTICIPANTS: Deaf/HOH patients aged 18 years or older who used American Sign Language as their primary method of communication and were taking at least two long-term prescription medications. MAIN OUTCOME MEASURE: Qualitative themes. RESULTS: Many of the Deaf/HOH still perceived community pharmacists in a dispensing role and lacked an understanding of other services being offered in this setting. In addition, pharmacists who demonstrated a lack of sensitivity and patience towards the Deaf/HOH risk weakening the relationship between patient and provider. As a result, safe use of medications is compromised. CONCLUSION: Deaf and HOH patients have unique needs that pharmacists must understand and address. Effective communication and literacy assessment is essential to ensure safe medication use and optimal health outcomes. Pharmacist education and staff training are needed to increase awareness of this patient population's needs and to strengthen the patient-pharmacist relationship. PMID- 25700134 TI - Organization of postural coordination patterns as a function of scaling the surface of support dynamics. AB - The number and nature of the dynamical degrees of freedom (DFs) in postural coordination patterns was investigated as a function of practice over the continuously scaled frequency of the support surface dynamics. The modal number of dynamical DFs of the coordination pattern was reduced with practice particularly in the higher frequency conditions. The ankle-knee and knee-hip couplings were highly variable across the platform frequencies and practice. The findings show that practice and higher platform frequency both contribute to reducing the number of dynamical DFs of movement organization in compensatory postural control and that this is related to an increase in the strength of particularly the ankle and hip synergy. PMID- 25700135 TI - Case management directors: how to manage in a transition-focused world: part 2. AB - PURPOSE AND OBJECTIVES: Case management directors are in a dynamic position to affect the transition of care of patients across the continuum, work with all levels of providers, and support the financial well-being of a hospital. Most importantly, they can drive good patient outcomes. Although the position is critical on many different levels, there is little to help guide a new director in attending to all the "moving parts" of such a complex role.This is Part 2 of a two-part article written for case management directors, particularly new ones.Part 1 covered the first 4 of 7 tracks: (1) Staffing and Human Resources, (2) Compliance and Accreditation, (3) Discharge Planning and (4) Utilization Review and Revenue Cycle. Part 2 addresses (5) Internal Departmental Relationships (Organizational), (6) External Relationships (Community Agency), and (7) Quality and Program Outcomes.This article attempts to answer the following questions: PRIMARY PRACTICE SETTING: : The information is most meaningful to those case management directors who work in either stand-alone hospitals or integrated health systems and have frontline case managers (CMs) reporting to them. FINDINGS/CONCLUSIONS: Part 1 found that case management directors would benefit from further research and documentation of "best practices" related to their role, particularly in the areas of leadership and management. The same conclusion applies to Part 2, which addresses the director's responsibilities outside her immediate department. Leadership and management skills apply as well to building strong, productive relationships across a broad spectrum of external organizations that include payer, provider, and regulatory agencies. At the same time, they must also develop the skills to positively influence the revenue cycle and financial health of both the organization for which they work and those to whom they transition patients. IMPLICATIONS FOR CASE MANAGEMENT: A director of case management with responsibility for transitions of care has more power and influence over patient safety than is commonly known. Few of the directors who are drawn from clinical case management or other leadership positions and thrust into this role are prepared to navigate within the organization, much less across the whole spectrum of payer, provider, and monitoring organizations. Yet the external focus of the director's role continues to grow in importance as the health care industry evolves and more focus is placed on population management and relationships with payers and community providers. PMID- 25700136 TI - Acid-base speciation of carboxylate ions in the surface region of aqueous solutions in the presence of ammonium and aminium ions. AB - The acid-base speciation of surface-active carboxylate ions in the surface region of aqueous solutions was studied with synchrotron-radiation-based photoelectron spectroscopy. The protonated form was found at an extraordinarily large fraction compared to that expected from the bulk pH. When adding salts containing the weak acid NH4(+) to the solution, the fraction of the acidic form at the surface increases, and to a much greater extent than expected from the bulk pH of the solution. We show that ammonium ions also are overrepresented in the surface region, and propose that the interaction between the surface-active anionic carboxylates and cationic ammonium ions creates a carboxylate-ammonium bilayer close to the surface, which increases the probability of the protonation of the carboxylate ions. By comparing the situation when a salt of the less volatile amine diethanolamine is used, we also show that the observed evaporation of ammonia that occurs after such an event only affects the equilibrium marginally. PMID- 25700137 TI - Direct synthesis of 2-aryl-4-quinolones via transition-metal-free intramolecular oxidative C(sp(3))-H/C(sp(3))-H coupling. AB - A novel, metal-free oxidative intramolecular Mannich reaction was developed between secondary amines and unmodified ketones, affording a simple and direct access to a broad range of 2-arylquinolin-4(1H)-ones through C(sp(3))-H activation/C(sp(3))-C(sp(3)) bond formation from readily available N-arylmethyl-2 aminophenylketones, using TEMPO as the oxidant and KO(t)Bu as the base. PMID- 25700138 TI - Impaired Maturation of Cognitive Control in Adolescents Who Develop Major Depressive Disorder. AB - This study examined whether development of two forms of cognitive control (proactive and reactive) between early and midadolescence was associated with the onset of major depressive disorder (MDD) during the same period and if it prospectively predicted MDD onset between mid- and late adolescence. Adolescents (N = 165) completed 3 waves of assessments, at 12 (T1), 16 (T2), and 18 (T3) years of age. Diagnostic interviews were conducted at each time point to identify three groups of adolescents: "early MDD," those who developed MDD between early (T1) and mid- (T2) adolescence (n = 23); "late MDD," those who developed MDD between mid- (T2) and late (T3) adolescence (n = 20); and "controls," those who did not develop MDD (n = 122). A modified Stroop task was completed at T1 and T2 to examine development of proactive and reactive cognitive control. Adolescents with early MDD exhibited significant declines in reactive control, as well as a trend level decline for proactive control, during this period compared to controls. No significant differences in reactive or proactive control were identified in adolescents with late MDD compared to controls, but they did exhibit significant improvements in proactive control compared to those with early MDD. These findings suggest that normative maturation of reactive, and possibly proactive, cognitive control abilities are impaired in adolescents who develop MDD between early and midadolescence. This has implications for understanding the mechanisms underlying certain forms of behavioral dysregulation that are commonly seen in MDD. PMID- 25700139 TI - Relationship between drug dreams, affect, and craving during treatment for substance dependence. AB - OBJECTIVES: To explore the relationship between occurrence of drug dreams (DDs) and daytime negative affect and drug craving during the course of a 5-week treatment program for substance dependence. METHODS: Using the dream journal methodology, 86 participants reported occurrence of dreams, dream content, and ratings of affect and drug craving. The relationships between the experience of DD, dream content ("active" vs "passive"), and affect and craving were analyzed using mixed model methods. RESULTS: The experience of DD was associated with higher levels of negative affect (P < 0.001) and craving (P < 0.001). The occurrence of DD did not decrease significantly over the 5 weeks of the study. Cocaine/crack users reported a higher occurrence of DD (P < 0.05) than the other drug groups (opiates and alcohol), and DD involving "active" drug use was associated with larger (P < 0.05) changes in negative affect. CONCLUSIONS: These results are consistent with the hypothesis that DD can act as drug-conditioned stimuli to elevate negative affect and craving in abstaining individuals. Although correlational, such findings support the implementation of psychological and pharmacological interventions aimed at minimizing the impact of DD on individuals in recovery from drug addiction. PMID- 25700140 TI - Changes in regional cerebral blood flow are associated with endothelial dysfunction markers in cocaine-dependent patients under recent abstinence. AB - OBJECTIVES: Cocaine is a known risk factor for several vascular ischemic events. The underlying mechanisms leading to the complications are not fully understood, although thrombus formation and accelerated atherosclerosis are prominent findings. Evidence of endothelial dysfunction (ED), a key phenomenon in the pathogenesis of atherogenesis, has been demonstrated in cocaine-dependent individuals. Abnormal regional cerebral blood flow (rCBF) is a common finding among chronic cocaine users. The aim of this study was to evaluate whether brain perfusion changes were associated with ED markers in cocaine-dependent individuals. METHODS: Circulating endothelial cells (CECs), soluble intercellular cell adhesion molecule, and the chemokine regulated on activation normal T cells expressed and secreted were measured in 27 DSM-IV (Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition) cocaine-dependents patients. Regional cerebral blood flow was assessed using single-photon emission computed tomography at baseline (after recent cocaine consumption) and after 4 weeks of strict abstinence under standard benzodiazepine or antipsychotic therapy. We used statistical parametric mapping analysis to evaluate the covariates. RESULTS: Endothelial cell damage/activation markers were significantly higher in cocaine dependent individuals after recent consumption and were reduced after 1-month abstinence (P < 0.05). Global rCBF exhibited no significant difference between baseline and after abstinence. When regional perfusion was analyzed in association with ED covariates, significant differences were observed in bilateral cortical areas, including the limbic lobes. CONCLUSIONS: We demonstrated an association between systemic ED markers and rCBF in cocaine dependent patients. These findings suggest that vascular injury may play a role in the pathogenesis of abnormal rCBF. PMID- 25700141 TI - It's not always a good idea to "Pump It" up: case report on the use of a new synthetic drug. PMID- 25700142 TI - Cocaine use in individuals with schizophrenia: impact on doses of discharge antipsychotic medications. AB - OBJECTIVES: Despite the high prevalence of cocaine use disorder in schizophrenia, the impact of cocaine on antipsychotic requirement has not been studied in this population. The aim of this study was to evaluate the effect of cocaine on doses of antipsychotic medication prescribed during periods of acute exacerbation of psychotic symptoms in individuals with schizophrenia. METHODS: We reviewed the medical records of individuals with schizophrenia discharged from hospitals between 2008 and 2012. Student t tests and linear regression were used to compare doses of discharge antipsychotic medications (in chlorpromazine equivalents) between individuals with schizophrenia with cocaine positive urine drug test results (n = 180; age 42.71 +/- 10.03 years) and individuals with schizophrenia with negative urine drug test results (n = 3194; age 38.49 +/- 12.86 years). RESULTS: Unadjusted analysis revealed that individuals with schizophrenia who tested positive for cocaine were discharged on lower doses of antipsychotic medication compared with those who tested negative (449.88 +/- 2.12 vs 515.47 +/- 2.16; P = 0.021). However, after adjusting for age, sex, race, and length of stay, the 2 groups did not differ on doses of discharge antipsychotic medication (geometric mean difference 7.41; CI: 7.62-12.30; P = 0.703). CONCLUSIONS: Our preliminary result suggests that cocaine use does not impact significantly on the doses of antipsychotic medication prescribed during periods of acute exacerbation of psychosis in schizophrenia and individuals with schizophrenia with comorbid cocaine use disorder may require similar doses of antipsychotic medication as those without cocaine use disorder. PMID- 25700143 TI - Effective ligand functionalization of zirconium-based metal-organic frameworks for the adsorption and separation of benzene and toluene: a multiscale computational study. AB - The adsorption and separation properties of benzene and toluene on the zirconium based frameworks UiO-66, -67, -68, and their functional analogues UiO-Phe and UiO Me2 were studied using grand canonical Monte Carlo simulations, density functional theory, and ideal adsorbed solution theory. Remarkable higher adsorption uptakes of benzene and toluene at low pressures on UiO-Phe and -Me2 were found compared to their parent framework UiO-67. It can be ascribed to the presence of functional groups (aromatic rings and methyl groups) that significantly intensified the adsorption, majorly by reducing the effective pore size and increasing the interaction strength with the adsorbates. At high pressures, the pore volumes and accessible surfaces of the frameworks turned out to be the dominant factors governing the adsorption. In the case of toluene/benzene separation, toluene selectivities of UiOs showed a two-stage separation behavior at the measured pressure range, resulting from the greater interaction affinities of toluene at low pressures and steric hindrance effects at high pressures. Additionally, the counterbalancing factors of enhanced pi delocalization and suitable pore size of UiO-Phe gave rise to the highest toluene selectivity, suggesting the ligand functionalization strategy could reach both high adsorption capacity and separation selectivity from aromatic mixtures at low concentrations. PMID- 25700144 TI - Process evaluation of a point-of-care cluster randomised trial using a computer delivered intervention to reduce antibiotic prescribing in primary care. AB - BACKGROUND: The study aimed to conduct a process evaluation for a cluster randomised trial of a computer-delivered, point-of-care intervention to reduce antibiotic prescribing in primary care. The study aimed to evaluate both the intervention and implementation of the trial. METHODS: The intervention comprised a set of electronic educational and decision support tools that were remotely installed and activated during consultations with patients with acute respiratory infections over a 12 month intervention period. A mixed method evaluation was conducted with 103 general practitioners (GPs) who participated in the trial. Semi-structured telephone interviews were conducted with 20 GPs who had been in the intervention group of the trial and 4 members of the implementation staff. Questionnaires, consisting of both intervention evaluation and theory-based measures, were self-administered to 83 GPs (56 control group and 27 intervention group). RESULTS: Interviews suggested that a key factor influencing GPs' use of the intervention appeared to be their awareness of the implementation of the system into their practice. GPs who were aware of the implementation of the intervention reported feeling confident in using it if they chose to and understood the purpose of the intervention screens. However, GPs who were unaware that the intervention would be appearing often reported feeling confused when they saw the messages appear on the screen and not fully understanding what they were for or how they could be used. Intervention evaluation questionnaires indicated that GPs were satisfied with the usability of the prompts, and theory based measures revealed that intervention group GPs reported higher levels of self-efficacy in managing RTI patients according to recommended guidelines compared to GPs in the control group. CONCLUSIONS: Remote installation of a computer-delivered intervention for use at the point-of-care was feasible and acceptable. Additional measures to promote awareness of the intervention may be required to promote health care professionals' utilisation of the intervention and these might sometimes compromise the pragmatic intention of a trial. TRIAL REGISTRATION: ISRCTN47558792 (registered on 17 March 2010). PMID- 25700145 TI - Design of LVFFARK and LVFFARK-functionalized nanoparticles for inhibiting amyloid beta-protein fibrillation and cytotoxicity. AB - Aggregation of amyloid beta-protein (Abeta) into amyloid oligomers and fibrils is pathologically linked to Alzheimer's disease (AD). Hence, the inhibition of Abeta aggregation is essential for the prevention and treatment of AD, but the development of potent agents capable of inhibiting Abeta fibrillogenesis has posed significant challenges. Herein, we designed Ac-LVFFARK-NH2 (LK7) by incorporating two positively charged residues, R and K, into the central hydrophobic fragment of Abeta17-21 (LVFFA) and examined its inhibitory effect on Abeta42 aggregation and cytotoxicity by extensive physical, biophysical, and biological analyses. LK7 was observed to inhibit Abeta42 fibrillogenesis in a dose-dependent manner, but its strong self-assembly characteristic also resulted in high cytotoxicity. In order to prevent the cytotoxicity that resulted from the self-assembly of LK7, the peptide was then conjugated to the surface of poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) to fabricate a nanosized inhibitor, LK7@PLGA-NPs. It was found that LK7@PLGA-NPs had little cytotoxicity because the self-assembly of the LK7 conjugated on the NPs was completely inhibited. Moreover, the NPs-based inhibitor showed remarkable inhibitory capability against Abeta42 aggregation and significantly alleviated its cytotoxicity at a low LK7@PLGA-NPs concentration of 20 MUg/mL. At the same peptide concentration, free LK7 showed little inhibitory effect. It is considered that several synergetic effects contributed to the strong inhibitory ability of LK7@PLGA-NPs, including the enhanced interactions between Abeta42 and LK7@PLGA NPs brought on by inhibiting LK7 self-assembly, restricting conformational changes of Abeta42, and thus redirecting Abeta42 aggregation into unstructured, off-pathway aggregates. The working mechanisms of the inhibitory effects of LK7 and LK7@PLGA-NPs on Abeta42 aggregation were proposed based on experimental observations. This work provides new insights into the design and development of potent NPs-based inhibitors against Abeta aggregation and cytotoxicity. PMID- 25700147 TI - A Parameterised Complexity Analysis of Bi-level Optimisation with Evolutionary Algorithms. AB - Bi-level optimisation problems have gained increasing interest in the field of combinatorial optimisation in recent years. In this paper, we analyse the runtime of some evolutionary algorithms for bi-level optimisation problems. We examine two NP-hard problems, the generalised minimum spanning tree problem and the generalised travelling salesperson problem in the context of parameterised complexity. For the generalised minimum spanning tree problem, we analyse the two approaches presented by Hu and Raidl ( 2012 ) with respect to the number of clusters that distinguish each other by the chosen representation of possible solutions. Our results show that a (1+1) evolutionary algorithm working with the spanning nodes representation is not a fixed-parameter evolutionary algorithm for the problem, whereas the problem can be solved in fixed-parameter time with the global structure representation. We present hard instances for each approach and show that the two approaches are highly complementary by proving that they solve each other's hard instances very efficiently. For the generalised travelling salesperson problem, we analyse the problem with respect to the number of clusters in the problem instance. Our results show that a (1+1) evolutionary algorithm working with the global structure representation is a fixed-parameter evolutionary algorithm for the problem. PMID- 25700148 TI - Binary Image Classification: A Genetic Programming Approach to the Problem of Limited Training Instances. AB - In the computer vision and pattern recognition fields, image classification represents an important yet difficult task. It is a challenge to build effective computer models to replicate the remarkable ability of the human visual system, which relies on only one or a few instances to learn a completely new class or an object of a class. Recently we proposed two genetic programming (GP) methods, one shot GP and compound-GP, that aim to evolve a program for the task of binary classification in images. The two methods are designed to use only one or a few instances per class to evolve the model. In this study, we investigate these two methods in terms of performance, robustness, and complexity of the evolved programs. We use ten data sets that vary in difficulty to evaluate these two methods. We also compare them with two other GP and six non-GP methods. The results show that one-shot GP and compound-GP outperform or achieve results comparable to competitor methods. Moreover, the features extracted by these two methods improve the performance of other classifiers with handcrafted features and those extracted by a recently developed GP-based method in most cases. PMID- 25700146 TI - Corticostriatal synaptic adaptations in Huntington's disease. AB - Huntington's disease (HD) is a progressive neurodegenerative disorder that profoundly impairs corticostriatal information processing. While late stage pathology includes cell death, the appearance of motor symptoms parallels more subtle changes in neuronal function and synaptic integration. Because of the difficulty in modeling the disease and the complexity of the corticostriatal network, understanding the mechanisms driving pathology has been slow to develop. In recent years, advances in animal models and network analysis tools have begun to shed light on the circuit-specific deficits. These studies have revealed a progressive impairment of corticostriatal synaptic signaling in subpopulations of striatal neurons, turning classical excitotoxicity models of HD upside down. Disrupted brain derived neurotrophic factor signaling appears to be a key factor in this decline. PMID- 25700149 TI - Identification and characterization of antioxidant peptides from enzymatic hydrolysates of duck meat. AB - The objective of this study was to prepare antioxidant peptides from duck meat hydrolysate (DMH) using Protamex. The DPPH(*) scavenging activity, hydroxyl radical ((*)OH) scavenging activity, and Fe(2+)-chelating ability of DMH were investigated. DMH was separated into three groups, MWCO-1 (69.57%), MWCO-2 (9.53%), and MWCO-3 (8.21%), by ultrafiltration. MWCO-3 exhibited the highest DPPH(*) scavenging activity (83.17 +/- 0.73%) and was subsequently fractionated by using gel filtration chromatography to obtain fraction B (40.90%). Fraction B5 (6.71%) obtained from ion exchange chromatography exhibited the highest DPPH(*) scavenging activity (93.63 +/- 0.13%) and contained seven peptides which were characterized by LC-MS/MS. Among these peptides, LQAEVEELRAALE showed the highest DPPH(*) scavenging activity (93.36 +/- 0.53%) and Fe(2+)-chelating ability (87.13 +/- 0.47%) and IEDPFDQDDWGAWKK exhibited the highest (*)OH scavenging activity (46.51 +/- 0.16%). The results presented here indicated that DMH could serve as a suitable source of antioxidant peptides. PMID- 25700150 TI - T helper 9 cells induced by plasmacytoid dendritic cells regulate interleukin-17 in multiple sclerosis. AB - Multiple sclerosis (MS) is a chronic disease of the central nervous system (CNS) characterized by persistent inflammation orchestrated by cluster of differentiation (CD) 4 T helper (Th) cells. In particular, Th1 and Th17 cells amplify, whereas T regulatory (Treg) cells moderate inflammation. The role of other Th subsets in MS is not clear. In the present study, we investigated the generation of different Th responses by human dendritic cells (DCs) in MS. We compared the production of several Th cytokines by naive CD4+ T-cells polarized with myeloid and plasmacytoid DCs (mDCs and pDCs) in healthy donors (HD) and relapsing-remitting (RR)-MS patients. We found that resiquimod-stimulated mDCs were able to activate Th17 differentiation, whereas pDCs induced interleukin (IL) 10-producing Th cells. Surprisingly, resiquimod-stimulated pDCs from MS patients also significantly induced the differentiation of Th9 cells, which produce IL-9 and are known to be involved in allergic diseases. We investigated the potential role of IL-9 in MS. We found that IL-9 activated signal transducer and activator of transcription (STAT) 1 and STAT5 phosphorylation and interfered with IL-17 and interferon (IFN) regulatory transcription factor (IRF)-4 expression in Th17 polarized cells. Moreover, in the cerebrospinal fluid (CSF) of 107 RR-MS patients, IL-9 inversely correlated with indexes of inflammatory activity, neurodegeneration and disability progression of MS. High levels of IL-9 were associated with the absence of IL-17 in the CSF of RR-MS patients. Our results demonstrate a Th9-inducing potential of pDCs in MS, suggesting an immunoregulatory role leading to attenuation of the exaggerated Th17 inflammatory response. PMID- 25700151 TI - Lung cancer screening with low dose CT: experience at Campus Bio-Medico of Rome on 1500 patients. AB - AIM: The main purpose of our project was to evaluate the prevalence of lung cancer in high risk, asymptomatic individuals in addition to quantifying the rate of surgically resectable tumors, and evaluating the role of lung cancer with low dose computed tomography (LDCT) as a tool for lung cancer screening. METHODS: Between June 2011 and March 2014, 1500 volunteers at high risk for lung cancer were enrolled in our study and underwent LDCT in our institution. The subsequent diagnostic and therapeutic steps were planned in relation to the results emerging from LDCT. To evaluate speed and type of growth, solid nodules <=4 mm were reassessed with annual LDCT, those >4-6 mm or >6-8 mm were reassessed with LDCT in 6 or 3 months while nodules suspicious for malignancy were investigated with PET-CT or biopsy according to NCCN guidelines. RESULTS: Non-calcified nodules were detected in 525 subjects (35% of population): among these 42% had a diameter <=4 mm, 43% had a diameter >5 mm but <10 mm, 3% appeared as "ground glass" lesions, and 63 (12% of detected nodules) had malignant characteristics (irregular margins, retraction of the surrounding parenchyma, diameter >10 mm). Among the 63 patients who underwent PET-CT or biopsy, 25 cases resulted positive for lung cancer (1.7% of population). These patients underwent surgical treatment with histological detection of tumors in stages IA, IB or IIB. CONCLUSION: Our study confirmed the emerging data on the use of LDCT as a screening tool for lung neoplasm in individuals at risk. Due to the LDCT low rate of specificity complementary biomarkers are required to properly define patients at risk and to reduce the number of further radiological examinations. PMID- 25700152 TI - Germanium-silicon alloy and core-shell nanocrystals by gas phase synthesis. AB - In this work we present a novel route to synthesize well defined germanium silicon alloy (GexSi1-x) and core-shell nanocrystals (NCs) employing monosilane (SiH4) and monogermane (GeH4) as precursors in a continuously operated two-stage hot-wall aerosol reactor setup. The first hot-wall reactor stage (HWR I) is used to produce silicon (Si) seed particles from SiH4 pyrolysis in Argon (Ar). The resulting seeding aerosol is fed into the second reactor stage (HWR II) and a mixture of SiH4 and GeH4 is added. The ratio of the precursors in the feed, their partial pressures, the synthesis temperature in HWR II and the overall pressure are varied depending on the desired morphology and composition. Alloy particle production is achieved in the heterogeneous surface reaction regime, meaning that germanium (Ge) and Si are deposited on the seed surface simultaneously. The NCs can be synthesized with any desired composition, whilst maintaining a mean diameter around 30 nm with a geometric standard deviation (GSD) around 1.25. The absorption behavior and the related fundamental optical band gap energy in dependence on the alloy composition are exemplarily presented. They prove the possibility to tailor NC properties for electronical and opto-electronical applications. In the homogeneous gas phase reaction regime facetted Ge-Si core shell structures are accessible. The Ge deposition on the seeds precedes the Si deposition due to different gas phase reaction kinetics of the precursors. The Si layer grows epitaxially on the Ge core and is around 5 nm thick. PMID- 25700153 TI - Environmental and health benefits from designating the Marmara Sea and the Turkish Straits as an emission control area (ECA). AB - Ship emissions degrade air quality and affect human health, and are increasingly becoming a matter of concern. Sulfur emission control areas (ECA), specific coastal regions where only low-sulfur fuels may be consumed by ocean-going ships, have proven to be useful tools to reduce ship-sourced air pollution along the North American, Canadian, and European North and Baltic Sea coastlines. The present work assesses the environmental and health benefits which would derive from designating an ECA in the Marmara Sea and the Turkish Straits (50 000 ships/year; 23 million inhabitants). Results show evidence that implementing an ECA would be technically viable and that it would reduce ship-sourced PM10 and PM2.5 ambient concentrations in Istanbul by 67%, and SO2 by 90%. The reduction of the air pollution burden on health was quantified as 210 hospital admissions from exposure to PM10, 290 hospital admissions from exposure to SO2, and up to 30 premature deaths annually due to ECA emission controls. Consequently, the designation of an ECA in the Marmara Sea and the Turkish Straits is evaluated as a positive, technically viable and real-world measure to reduce air pollution from ships in Turkey. PMID- 25700154 TI - Follow-Up Study of Over Three Years of Patients with Uveitis after Cataract Phacoemulsification: Outcomes and Complications. AB - PURPOSE: To evaluate the rate and onset of intraoperative and postoperative complications post-phacoemulsification. METHODS: One hundred sixty-two eyes of 145 patients with uveitis who underwent phacoemulsification between 2006 and 2009 were identified through surgical record review. Fifty-nine eyes of 46 patients met the inclusion criteria. Hazard ratio (HR) and Kaplan-Meier survival probability were calculated for each class of uveitis. RESULTS: Macular edema (ME) resulted to be associated to chronic postoperative inflammation (r = 0.6; p = 0.00) and mostly related to patients who presented more than one postoperative relapse/year (r = 0.2; p = 0.02). Fuchs uveitis resulted to be a risk factor for posterior capsule opacification (PCO) (HR 3.36 IC95%1.0-10.5; p = 0.03). Hypotony and elevated intraocular pressure (IOP) were detected in the anterior uveitis group (0.02 EY). CONCLUSION: The HR to develop ME was significantly related to chronic anterior uveitis. PCO and elevated IOP are most frequent in Fuchs uveitis. The postoperative visual acuity result was good among all the uveitis groups. PMID- 25700155 TI - An interconverting family of coordination cages and a meso-helicate; effects of temperature, concentration, and solvent on the product distribution of a self assembly process. AB - The self-assembly between a water-soluble bis-bidentate ligand L(18w) and Co(II) salts in water affords three high-spin Co(II) products: a dinuclear meso-helicate [Co2(L(18w))3]X4; a tetrahedral cage [Co4(L(18w))6]X8; and a dodecanuclear truncated-tetrahedral cage [Co12(L(18w))18]X24 (X = BF4 or ClO4). All three products were crystallized under different conditions and structurally characterized. In [Co2(L(18w))3]X4 all three bridging ligands span a pair of metal ions; in the two larger products, there is a metal ion at each vertex of the Co4 or Co12 polyhedral cage array with a bridging ligand spanning a pair of metal ions along every edge. All three structural types are known: what is unusual here is the presence of all three from the same reaction. The assemblies Co2, Co4, and Co12 are in slow equilibrium (hours/days) in aqueous solution, and this can be conveniently monitored by (1)H NMR spectroscopy because (i) the paramagnetism of Co(II) disperses the signals over a range of ca. 200 ppm and (ii) the different symmetries of the three species give characteristically different numbers of independent (1)H NMR signals, which makes identification easy. From temperature- and concentration-dependent (1)H NMR studies it is clear that increasing temperature and increasing dilution favors fragmentation to give a larger proportion of the smaller assemblies for entropic reasons. High concentrations and low temperature favor the larger assembly despite the unfavorable entropic and electrostatic factors associated with its formation. We suggest that this arises from the hydrophobic effect: reorganization of several smaller complexes into one larger one results in a smaller proportion of the hydrophobic ligand surface being exposed to water, with a larger proportion of the ligand surface protected in the interior of the assembly. In agreement with this, (1)H NMR spectra in a nonaqueous solvent (MeNO2) show formation of only [Co2(L(18w))3]X4 because the driving force for reorganization into larger assemblies is now absent. Thus, we can identify the contributions of temperature, concentration, and solvent on the result of the metal/ligand self-assembly process and have determined the speciation behavior of the Co2/Co4/Co12 system in aqueous solution. PMID- 25700156 TI - Correction to Prenylated Flavonoids and Resveratrol Derivatives Isolated from Artocarpus communis with the Ability to Overcome TRAIL Resistance. PMID- 25700157 TI - Rumen bacterial diversity of 80 to 110-day-old goats using 16S rRNA sequencing. AB - The ability of rumen microorganisms to use fibrous plant matter plays an important role in ruminant animals; however, little information about rumen colonization by microbial populations after weaning has been reported. In this study, high-throughput sequencing was used to investigate the establishment of this microbial population in 80 to 110-day-old goats. Illumina sequencing of goat rumen samples yielded 101,356,610 nucleotides that were assembled into 256,868 reads with an average read length of 394 nucleotides. Taxonomic analysis of metagenomic reads indicated that the predominant phyla were distinct at different growth stages. The phyla Firmicutes and Synergistetes were predominant in samples taken from 80 to 100-day-old goats, but Bacteroidetes and Firmicutes became the most abundant phyla in samples from 110-day-old animals. There was a remarkable variation in the microbial populations with age; Firmicutes and Synergistetes decreased after weaning, but Bacteroidetes and Proteobacteria increased from 80 to 110 day of age. These findings suggested that colonization of the rumen by microorganisms is related to their function in the rumen digestive system. These results give a better understanding of the role of rumen microbes and the establishment of the microbial population, which help to maintain the host's health and improve animal performance. PMID- 25700158 TI - Dual Role of Acetanilides: Traceless Removal of a Directing Group through Deacetylation/Diazotation and Palladium-Catalyzed C-C-Coupling Reactions. AB - The acetamide group enables regioselective oxidative ortho-C-H activation reactions, such as Pd-catalyzed acylation. The synthetic utility of these transformations can be significantly enhanced by using the acetamide as a quasi leaving group in a subsequent conventional Pd-catalyzed coupling or cross coupling reaction. The concept is illustrated herein for the synthesis of o alkenyl- and o-arylphenones, which have potential for the synthesis of arylated aromatic heterocycles. PMID- 25700159 TI - Ferrous sulfate supplementation causes significant gastrointestinal side-effects in adults: a systematic review and meta-analysis. AB - BACKGROUND: The tolerability of oral iron supplementation for the treatment of iron deficiency anemia is disputed. OBJECTIVE: Our aim was to quantify the odds of GI side-effects in adults related to current gold standard oral iron therapy, namely ferrous sulfate. METHODS: Systematic review and meta-analysis of randomized controlled trials (RCTs) evaluating GI side-effects that included ferrous sulfate and a comparator that was either placebo or intravenous (i.v.) iron. Random effects meta-analysis modelling was undertaken and study heterogeneity was summarised using I2 statistics. RESULTS: Forty three trials comprising 6831 adult participants were included. Twenty trials (n = 3168) had a placebo arm and twenty three trials (n = 3663) had an active comparator arm of i.v. iron. Ferrous sulfate supplementation significantly increased risk of GI side-effects versus placebo with an odds ratio (OR) of 2.32 [95% CI 1.74-3.08, p<0.0001, I2 = 53.6%] and versus i.v. iron with an OR of 3.05 [95% CI 2.07-4.48, p<0.0001, I2 = 41.6%]. Subgroup analysis in IBD patients showed a similar effect versus i.v. iron (OR = 3.14, 95% CI 1.34-7.36, p = 0.008, I2 = 0%). Likewise, subgroup analysis of pooled data from 7 RCTs in pregnant women (n = 1028) showed a statistically significant increased risk of GI side-effects for ferrous sulfate although there was marked heterogeneity in the data (OR = 3.33, 95% CI 1.19-9.28, p = 0.02, I2 = 66.1%). Meta-regression did not provide significant evidence of an association between the study OR and the iron dose. CONCLUSIONS: Our meta analysis confirms that ferrous sulfate is associated with a significant increase in gastrointestinal-specific side-effects but does not find a relationship with dose. PMID- 25700160 TI - Structure-based evaluation of non-nucleoside inhibitors with improved potency and solubility that target HIV reverse transcriptase variants. AB - The development of novel non-nucleoside inhibitors (NNRTIs) with activity against variants of HIV reverse transcriptase (RT) is crucial for overcoming treatment failure. The NNRTIs bind in an allosteric pocket in RT ~10 A away from the active site. Earlier analogues of the catechol diether compound series have picomolar activity against HIV strains with wild-type RT but lose potency against variants with single Y181C and double K103N/Y181C mutations. As guided by structure-based and computational studies, removal of the 5-Cl substitution of compound 1 on the catechol aryl ring system led to a new analogue compound 2 that maintains greater potency against Y181C and K103N/Y181C variants and better solubility (510 MUg/mL). Crystal structures were determined for wild-type, Y181C, and K103N/Y181C RT in complex with both compounds 1 and 2 to understand the structural basis for these findings. Comparison of the structures reveals that the Y181C mutation destabilizes the binding mode of compound 1 and disrupts the interactions with residues in the pocket. Compound 2 maintains the same conformation in wild-type and mutant structures, in addition to several interactions with the NNRTI binding pocket. Comparison of the six crystal structures will assist in the understanding of compound binding modes and future optimization of the catechol diether series. PMID- 25700161 TI - Prevalence and correlates of physical inactivity among older adults in Rio Grande do Sul, Brazil. AB - BACKGROUND: Current information on the epidemiology of physical inactivity among older adults is lacking, making it difficult to target the inactive and to plan for interventions to ameliorate adverse effects. OBJECTIVES: To present statewide representative findings on the prevalence of physical inactivity among older community residents, its correlates and associated health service use. METHODS: A representative non-institutionalized random sample of 6963 individuals in Rio Grande do Sul, Brazil, aged >=60 years, was interviewed face-to-face. Information was obtained on demographic characteristics, social resources, health conditions and behaviors, health service use, and physical inactivity. Controlled logistic regression was used to determine the association of physical inactivity with these characteristics. RESULTS: Overall, 62% reported no regular physical activity. Physical inactivity was significantly more prevalent among women, older persons, those with lower education and income, Afro-Brazilians (73%; White: 61%; "other": 64%), those no longer married, and was associated with multiple individual health conditions and impaired activities of daily living (ADL). In adjusted analyses, associations remained for sociodemographic characteristics, social participation, impaired self-rated health, ADL, vision, and depression (odds ratios (OR) 1.2-1.7). Physically inactive respondents were less likely to report outpatient visits (OR 0.81), but more likely to be hospitalized (OR 1.41). CONCLUSIONS: Physical inactivity is highly prevalent, particularly among Afro Brazilians. It is associated with adverse sociodemographic characteristics; lack of social interaction; and poor self-rated health, ADL, vision, and depression; although not with other health conditions. Self-care may be neglected, resulting in hospitalization. PMID- 25700162 TI - Activation of NOTCH1 or NOTCH3 signaling skews human airway basal cell differentiation toward a secretory pathway. AB - Airway basal cells (BC) function as stem/progenitor cells capable of differentiating into the luminal ciliated and secretory cells to replenish the airway epithelium during physiological turnover and repair. The objective of this study was to define the role of Notch signaling in regulating human airway BC differentiation into a pseudostratified mucociliated epithelium. Notch inhibition with gamma-secretase inhibitors demonstrated Notch activation is essential for BC differentiation into secretory and ciliated cells, but more so for the secretory lineage. Sustained cell autonomous ligand independent Notch activation via lentivirus expression of the intracellular domain of each Notch receptor (NICD1 4) demonstrated that the NOTCH2 and 4 pathways have little effect on BC differentiation into secretory and ciliated cells, while activation of the NOTCH1 or 3 pathways has a major influence, with persistent expression of NICD1 or 3 resulting in a skewing toward secretory cell differentiation with a parallel decrease in ciliated cell differentiation. These observations provide insights into the control of the balance of BC differentiation into the secretory vs ciliated cell lineage, a balance that is critical for maintaining the normal function of the airway epithelium in barrier defense against the inhaled environment. PMID- 25700163 TI - Distal biceps brachii tendon repairs: a single-incision technique using a cortical button with interference screw versus a double-incision technique using suture fixation through bone tunnels. AB - BACKGROUND: Distal biceps brachii tendon repairs performed with a tension slide technique using a cortical button (CB) and interference screw are stronger than those based on suture fixation through bone tunnels (BTs) in biomechanical studies. However, clinical comparison of these 2 techniques is lacking in the literature. PURPOSE: To perform a clinical comparison of the single-incision CB and double-incision BT techniques. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Distal biceps tendon ruptures repaired through either the single incision CB or double-incision BT technique were retrospectively identified at a single institution. Patients>1 year out from surgery were assessed for range of motion, strength, and complications, and they completed a DASH questionnaire (Disabilities of the Arm, Shoulder, and Hand). RESULTS: Patients in the CB group (n=20) were older (52+/-9.5 vs 43.7+/-8.7 years; P=.008), had a shorter interval from surgery to evaluation (17.7+/-5 vs 30.8+/-16.5 months; P=.001), and were less likely to smoke (0% vs 28.5%; P=.02) compared with the BT patients (n=21). DASH scores were similar between groups (4.46+/-4.4 [CB] vs 5.7+/-7.5 [BT]; P=.65). Multivariate analysis revealed no differences in range of motion or strength between groups. More CB patients (30%; n=6) experienced a complication compared with those in the BT group (4.8%; n=1) (P=.04), and these complications were predominantly paresthesias of the superficial radial nerve that did not resolve. There were no reoperations or repair failures in either group. CONCLUSION: Both the single-incision CB and double-incision BT techniques provided excellent clinical results. Complications were more common in the single incision CB group and most commonly involved paresthesias of the superficial radial nerve. PMID- 25700164 TI - Rapid Treponema pallidum clearance from blood and ulcer samples following single dose benzathine penicillin treatment of early syphilis. AB - Currently, the efficacy of syphilis treatment is measured with anti-lipid antibody tests. These can take months to indicate cure and, as a result, syphilis treatment trials require long periods of follow-up. The causative organism, Treponema pallidum (T. pallidum), is detectable in the infectious lesions of early syphilis using DNA amplification. Bacteraemia can likewise be identified, typically in more active disease. We hypothesise that bacterial clearance from blood and ulcers will predict early the standard serology-measured treatment response and have developed a qPCR assay that could monitor this clearance directly in patients with infectious syphilis. Patients with early syphilis were given an intramuscular dose of benzathine penicillin. To investigate the appropriate sampling timeframe samples of blood and ulcer exudate were collected intensively for T. pallidum DNA (tpp047 gene) and RNA (16S rRNA) quantification. Sampling ended when two consecutive PCRs were negative. Four males were recruited. The mean peak level of T. pallidum DNA was 1626 copies/ml whole blood and the mean clearance half-life was 5.7 hours (std. dev. 0.53). The mean peak of 16S rRNA was 8879 copies/ml whole blood with a clearance half-life of 3.9 hours (std. dev. 0.84). From an ulcer, pre-treatment, 67,400 T. pallidum DNA copies and 7.08 x 107 16S rRNA copies were detected per absorbance strip and the clearance half-lives were 3.2 and 4.1 hours, respectively. Overall, T. pallidum nucleic acids were not detected in any sample collected more than 56 hours (range 20-56) after treatment. All patients achieved serologic cure. In patients with active early syphilis, measuring T. pallidum levels in blood and ulcer exudate may be a useful measure of treatment success in therapeutic trials. These laboratory findings need confirmation on a larger scale and in patients receiving different therapies. PMID- 25700165 TI - Screening the Medicines for Malaria Venture "Malaria Box" against the Plasmodium falciparum aminopeptidases, M1, M17 and M18. AB - Malaria is a parasitic disease that remains a global health burden. The ability of the parasite to rapidly develop resistance to therapeutics drives an urgent need for the delivery of new drugs. The Medicines for Malaria Venture have compounds known for their antimalarial activity, but not necessarily the molecular targets. In this study, we assess the ability of the "MMV 400" compounds to inhibit the activity of three metalloaminopeptidases from Plasmodium falciparum, PfA-M1, PfA-M17 and PfM18 AAP. We have developed a multiplex assay system to allow rapid primary screening of compounds against all three metalloaminopeptidases, followed by detailed analysis of promising compounds. Our results show that there were no PfM18AAP inhibitors, whereas two moderate inhibitors of the neutral aminopeptidases PfA-M1 and PfA-M17 were identified. Further investigation through structure-activity relationship studies and molecular docking suggest that these compounds are competitive inhibitors with novel binding mechanisms, acting through either non-classical zinc coordination or independently of zinc binding altogether. Although it is unlikely that inhibition of PfA-M1 and/or PfA-M17 is the primary mechanism responsible for the antiplasmodial activity reported for these compounds, their detailed characterization, as presented in this work, pave the way for their further optimization as a novel class of dual PfA-M1/PfA-M17 inhibitors utilising non classical zinc binding groups. PMID- 25700166 TI - Ernie. PMID- 25700167 TI - Recovery of injured lower portion of the ascending reticular activating system in a patient with traumatic brain injury. AB - The authors report on a patient with traumatic brain injury who showed recovery of an injured lower portion of the ascending reticular activating system (ARAS) between the pontine reticular formation and the thalamus. A 57-yr-old male patient experienced head trauma. After 4 mos from onset, he exhibited impaired alertness, with a score of 7 on the Glasgow Coma Scale. At 40 mos after onset, the patient had a full Glasgow Coma Scale score of 15. The lower portion of the ARAS was reconstructed using the probabilistic tractography method. On 4-mo diffusion tensor tractography, the fractional anisotropy and the tract volume of the lower portion of the right ARAS were lower by more than 2 SDs of those of control subjects. By contrast, on 40-mo diffusion tensor tractography, the fractional anisotropy and the tract volume values of the lower portion of the right ARAS were within 2 SDs of those of the control subjects. The increment fractional anisotropy and the FV value of the lower portion of the right ARAS on 40-mo diffusion tensor tractography indicated recovery of the injured lower ARAS. As a result, recovery of an injured lower portion of the ARAS in a patient with traumatic brain injury was demonstrated. PMID- 25700168 TI - Geographic inequities in liver allograft supply and demand: does it affect patient outcomes? AB - BACKGROUND: Significant geographic inequities mar the distribution of liver allografts for transplantation. METHODS: We analyzed the effect of geographic inequities on patient outcomes. During our study period (January 1 through December 31, 2010), 11,244 adult candidates were listed for liver transplantation: 5,285 adult liver allografts became available, and 5,471 adult recipients underwent transplantation. We obtained population data from the 2010 United States Census. To determine the effect of regional supply and demand disparities on patient outcomes, we performed linear regression and multivariate Cox regression analyses. RESULTS: Our proposed disparity metric, the ratio of listed candidates to liver allografts available varied from 1.3 (region 11) to 3.4 (region 1). When that ratio was used as the explanatory variable, the R(2) values for outcome measures were as follows: 1-year waitlist mortality, 0.23 and 1-year posttransplant survival, 0.27. According to our multivariate analysis, the ratio of listed candidates to liver allografts available had a significant effect on waitlist survival (hazards ratio, 1.21; 95% confidence interval, 1.04-1.40) but was not a significant risk factor for posttransplant survival. CONCLUSION: We found significant differences in liver allograft supply and demand--but these differences had only a modest effect on patient outcomes. Redistricting and allocation-sharing schemes should seek to equalize regional supply and demand rather than attempting to equalize patient outcomes. PMID- 25700169 TI - Community preferences for the allocation of donor organs for transplantation: a discrete choice study. AB - BACKGROUND: Demand for organs for transplant exceeds supply. There is an ongoing debate about the relative weighting that should be given to different allocation criteria. Little is known about the relative weight the community places on various allocation criteria. This study aims to determine community preferences for organ allocation. METHODS: Community respondents recruited from a web-based panel chose which patient received a transplant in 30 scenarios presenting two hypothetical patients. Patients were described in age, sex, previous transplants, whether they or family were registered donors, had caring responsibilities, adherence, time on waiting list, estimated survival and quality of life (QOL) with and without transplant, comorbidities, and lifestyle factors, such as smoking. Analyses were conducted in NLOGIT 5.0, using a mixed-logit model. RESULTS: Two thousand fifty-one respondents aged 18 to 83 years completed the survey. All attributes significantly influenced recipient choice except sex and having diabetes. Younger patients were preferred over older patients. Family member donor registration, having caring responsibilities, and longer time on waiting list increased priority. Pretransplant life expectancy was valued more highly than posttransplant life expectancy; 1 year less of pretransplant life expectancy required an increase of 1.49 years in posttransplant life expectancy to compensate. Posttransplant QOL was valued more highly than pretransplant QOL. CONCLUSION: Lower pretransplant life expectancy (need) was more important than higher posttransplant life expectancy (utility). Although current allocation algorithms are consistent with community preferences for prioritizing children and time on the waiting list, favoring patients with high predicted posttransplant survival as potential recipients may not be aligned with community preferences. PMID- 25700170 TI - Potential role of stabilized Criegee radicals in sulfuric acid production in a high biogenic VOC environment. AB - We present field observations made in June 2011 downwind of Dallas-Fort Worth, TX, and evaluate the role of stabilized Criegee radicals (sCIs) in gaseous sulfuric acid (H2SO4) production. Zero-dimensional model calculations show that sCI from biogenic volatile organic compounds composed the majority of the sCIs. The main uncertainty associated with an evaluation of H2SO4 production from the sCI reaction channel is the lack of experimentally determined reaction rates for sCIs formed from isoprene ozonolysis with SO2 along with systematic discrepancies in experimentally derived reaction rates between other sCIs and SO2 and water vapor. In general, the maximum of H2SO4 production from the sCI channel is found in the late afternoon as ozone increases toward the late afternoon. The sCI channel, however, contributes minor H2SO4 production compared with the conventional OH channel in the mid-day. Finally, the production and the loss rates of H2SO4 are compared. The application of the recommended mass accommodation coefficient causes significant overestimation of H2SO4 loss rates compared with H2SO4 production rates. However, the application of a lower experimental value for the mass accommodation coefficient provides good agreement between the loss and production rates of H2SO4. The results suggest that the recommended coefficient for the H2O surface may not be suitable for this relatively dry environment. PMID- 25700171 TI - Atrial-like cardiomyocytes from human pluripotent stem cells are a robust preclinical model for assessing atrial-selective pharmacology. AB - Drugs targeting atrial-specific ion channels, Kv1.5 or Kir3.1/3.4, are being developed as new therapeutic strategies for atrial fibrillation. However, current preclinical studies carried out in non-cardiac cell lines or animal models may not accurately represent the physiology of a human cardiomyocyte (CM). In the current study, we tested whether human embryonic stem cell (hESC)-derived atrial CMs could predict atrial selectivity of pharmacological compounds. By modulating retinoic acid signaling during hESC differentiation, we generated atrial-like (hESC-atrial) and ventricular-like (hESC-ventricular) CMs. We found the expression of atrial-specific ion channel genes, KCNA5 (encoding Kv1.5) and KCNJ3 (encoding Kir 3.1), in hESC-atrial CMs and further demonstrated that these ion channel genes are regulated by COUP-TF transcription factors. Moreover, in response to multiple ion channel blocker, vernakalant, and Kv1.5 blocker, XEN D0101, hESC-atrial but not hESC-ventricular CMs showed action potential (AP) prolongation due to a reduction in early repolarization. In hESC-atrial CMs, XEN R0703, a novel Kir3.1/3.4 blocker restored the AP shortening caused by CCh. Neither CCh nor XEN-R0703 had an effect on hESC-ventricular CMs. In summary, we demonstrate that hESC-atrial CMs are a robust model for pre-clinical testing to assess atrial selectivity of novel antiarrhythmic drugs. PMID- 25700172 TI - Metabolic and hypoxic adaptation to anti-angiogenic therapy: a target for induced essentiality. AB - Anti-angiogenic therapy has increased the progression-free survival of many cancer patients but has had little effect on overall survival, even in colon cancer (average 6-8 weeks) due to resistance. The current licensed targeted therapies all inhibit VEGF signalling (Table 1). Many mechanisms of resistance to anti-VEGF therapy have been identified that enable cancers to bypass the angiogenic blockade. In addition, over the last decade, there has been increasing evidence for the role that the hypoxic and metabolic responses play in tumour adaptation to anti-angiogenic therapy. The hypoxic tumour response, through the transcription factor hypoxia-inducible factors (HIFs), induces major gene expression, metabolic and phenotypic changes, including increased invasion and metastasis. Pre-clinical studies combining anti-angiogenics with inhibitors of tumour hypoxic and metabolic adaptation have shown great promise, and combination clinical trials have been instigated. Understanding individual patient response and the response timing, given the opposing effects of vascular normalisation versus reduced perfusion seen with anti-angiogenics, provides a further hurdle in the paradigm of personalised therapeutic intervention. Additional approaches for targeting the hypoxic tumour microenvironment are being investigated in pre clinical and clinical studies that have potential for producing synthetic lethality in combination with anti-angiogenic therapy as a future therapeutic strategy. PMID- 25700173 TI - Reasoning over taxonomic change: exploring alignments for the Perelleschus use case. AB - Classifications and phylogenetic inferences of organismal groups change in light of new insights. Over time these changes can result in an imperfect tracking of taxonomic perspectives through the re-/use of Code-compliant or informal names. To mitigate these limitations, we introduce a novel approach for aligning taxonomies through the interaction of human experts and logic reasoners. We explore the performance of this approach with the Perelleschus use case of Franz & Cardona-Duque (2013). The use case includes six taxonomies published from 1936 to 2013, 54 taxonomic concepts (i.e., circumscriptions of names individuated according to their respective source publications), and 75 expert-asserted Region Connection Calculus articulations (e.g., congruence, proper inclusion, overlap, or exclusion). An Open Source reasoning toolkit is used to analyze 13 paired Perelleschus taxonomy alignments under heterogeneous constraints and interpretations. The reasoning workflow optimizes the logical consistency and expressiveness of the input and infers the set of maximally informative relations among the entailed taxonomic concepts. The latter are then used to produce merge visualizations that represent all congruent and non-congruent taxonomic elements among the aligned input trees. In this small use case with 6-53 input concepts per alignment, the information gained through the reasoning process is on average one order of magnitude greater than in the input. The approach offers scalable solutions for tracking provenance among succeeding taxonomic perspectives that may have differential biases in naming conventions, phylogenetic resolution, ingroup and outgroup sampling, or ostensive (member-referencing) versus intensional (property-referencing) concepts and articulations. PMID- 25700174 TI - Brain structure. Cell types in the mouse cortex and hippocampus revealed by single-cell RNA-seq. AB - The mammalian cerebral cortex supports cognitive functions such as sensorimotor integration, memory, and social behaviors. Normal brain function relies on a diverse set of differentiated cell types, including neurons, glia, and vasculature. Here, we have used large-scale single-cell RNA sequencing (RNA-seq) to classify cells in the mouse somatosensory cortex and hippocampal CA1 region. We found 47 molecularly distinct subclasses, comprising all known major cell types in the cortex. We identified numerous marker genes, which allowed alignment with known cell types, morphology, and location. We found a layer I interneuron expressing Pax6 and a distinct postmitotic oligodendrocyte subclass marked by Itpr2. Across the diversity of cortical cell types, transcription factors formed a complex, layered regulatory code, suggesting a mechanism for the maintenance of adult cell type identity. PMID- 25700175 TI - Applied optics. Multiwavelength achromatic metasurfaces by dispersive phase compensation. AB - The replacement of bulk refractive optical elements with diffractive planar components enables the miniaturization of optical systems. However, diffractive optics suffers from large chromatic aberrations due to the dispersion of the phase accumulated by light during propagation. We show that this limitation can be overcome with an engineered wavelength-dependent phase shift imparted by a metasurface, and we demonstrate a design that deflects three wavelengths by the same angle. A planar lens without chromatic aberrations at three wavelengths is also presented. Our designs are based on low-loss dielectric resonators, which introduce a dense spectrum of optical modes to enable dispersive phase compensation. The suppression of chromatic aberrations in metasurface-based planar photonics will find applications in lightweight collimators for displays, as well as chromatically corrected imaging systems. PMID- 25700177 TI - Noninvasive Imaging of Early Venous Thrombosis by 19F Magnetic Resonance Imaging With Targeted Perfluorocarbon Nanoemulsions. AB - BACKGROUND: Noninvasive detection of deep venous thrombi and subsequent pulmonary thromboembolism is a serious medical challenge, since both incidences are difficult to identify by conventional ultrasound techniques. METHODS AND RESULTS: Here, we report a novel technique for the sensitive and specific identification of developing thrombi using background-free 19F magnetic resonance imaging, together with alpha2-antiplasmin peptide (alpha2AP)-targeted perfluorocarbon nanoemulsions (PFCs) as contrast agent, which is cross-linked to fibrin by active factor XIII. Ligand functionality was ensured by mild coupling conditions using the sterol-based postinsertion technique. Developing thrombi with a diameter<0.8 mm could be visualized unequivocally in the murine inferior vena cava as hot spots in vivo by simultaneous acquisition of anatomic matching 1H and 19F magnetic resonance images at 9.4 T with both excellent signal-to-noise and contrast-to-noise ratios (71+/-22 and 17+/-5, respectively). Furthermore, alpha2AP-PFCs could be successfully applied for the diagnosis of experimentally induced pulmonary thromboembolism. In line with the reported half-life of factor XIIIa, application of alpha2AP-PFCs>60 minutes after thrombus induction no longer resulted in detectable 19F magnetic resonance imaging signals. Corresponding results were obtained in ex vivo generated human clots. Thus, alpha2AP-PFCs can visualize freshly developed thrombi that might still be susceptible to pharmacological intervention. CONCLUSIONS: Our results demonstrate that 1H/19F magnetic resonance imaging, together with alpha2AP-PFCs, is a sensitive, noninvasive technique for the diagnosis of acute deep venous thrombi and pulmonary thromboemboli. Furthermore, ligand coupling by the sterol-based postinsertion technique represents a unique platform for the specific targeting of PFCs for in vivo 19F magnetic resonance imaging. PMID- 25700178 TI - Low cardiac index is associated with incident dementia and Alzheimer disease: the Framingham Heart Study. AB - BACKGROUND: Cross-sectional epidemiological and clinical research suggests that lower cardiac index is associated with abnormal brain aging, including smaller brain volumes, increased white matter hyperintensities, and worse cognitive performances. Lower systemic blood flow may have implications for dementia among older adults. METHODS AND RESULTS: A total of 1039 Framingham Offspring Cohort participants free of clinical stroke, transient ischemic attack, and dementia formed our sample (age, 69+/-6 years; 53% women). Multivariable-adjusted proportional hazard models adjusting for Framingham Stroke Risk Profile score (age, sex, systolic blood pressure, antihypertensive medication, diabetes mellitus, cigarette smoking, cardiovascular disease history, atrial fibrillation), education, and apolipoprotein E4 status related cardiac magnetic resonance imaging-assessed cardiac index (cardiac output divided by body surface area) to incident all-cause dementia and Alzheimer disease (AD). Over the median 7.7-year follow-up period, 32 participants developed dementia, including 26 cases of AD. Each 1-SD unit decrease in cardiac index increased the relative risk of both dementia (hazard ratio [HR]=1.66; 95% confidence interval [CI], 1.11-2.47; P=0.013) and AD (HR=1.65; 95% CI, 1.07-2.54; P=0.022). Compared with individuals with normal cardiac index, individuals with clinically low cardiac index had a higher relative risk of dementia (HR=2.07; 95% CI, 1.02-4.19; P=0.044). If participants with clinically prevalent cardiovascular disease and atrial fibrillation were excluded (n=184), individuals with clinically low cardiac index had a higher relative risk of both dementia (HR=2.92; 95% CI, 1.34-6.36; P=0.007) and AD (HR=2.87; 95% CI, 1.21-6.80; P=0.016) compared with individuals with normal cardiac index. CONCLUSION: Lower cardiac index is associated with an increased risk for the development of dementia and AD. PMID- 25700179 TI - Safety and Dose Escalation Study of Intravenous Zinc Supplementation in Pediatric Critical Illness. AB - BACKGROUND: Critically ill children have low plasma zinc (pZn), correlating with organ failure. Since Zn influences inflammation, immune function, and glucose control, Zn supplementation is a plausible therapeutic modality. We sought to determine a safe dose of intravenous (IV) Zn to restore pZn in critically ill children. METHODS: Stepwise dose escalation study of IV Zn supplementation at a tertiary children's hospital. All children (<10 years) admitted to the pediatric intensive care unit with a Pediatric Risk of Mortality III score >5, or >=1 new organ failure were eligible. After consent, patients were sequentially enrolled into 4 dosing groups: (1) no zinc, (2) Zn250: 250 mcg/kg/d ZnSO4, (3) Zn500: 500 mcg/kg/d ZnSO4, or (4) Zn750: 750 mcg/kg/d ZnSO4 ZnSO4 was administered 3 times daily for 7 days. pZn was measured at baseline, end of first ZnSO4 infusion, 1 hour postinfusion, and 7 hours postinfusion on day 1, then daily through days 2 7. Interleukin-6 (IL-6), C-reactive protein (CRP), and lymphocyte subsets were measured on days 1 and 3. Glucose was measured 3 times daily for 7 days. RESULTS: Twenty-four patients were enrolled. Baseline demographics were similar among groups. Baseline pZn was low in all patients (mean [SD], 41.8 [16.0] mcg/dL). pZn increased over the study period in supplemented groups; however, mean pZn in the Zn750 group exceeded the 50th percentile. pZn was not associated with IL-6, CRP, or lymphocyte subsets among groups. Degree of hyperglycemia did not differ among groups. No patient had a study-related adverse event. CONCLUSIONS: IV zinc supplementation at 500 mcg/kg/d restores pZn to near the 50th percentile and is well tolerated. PMID- 25700176 TI - Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways. AB - Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease with no effective treatment. We report the results of a moderate-scale sequencing study aimed at increasing the number of genes known to contribute to predisposition for ALS. We performed whole-exome sequencing of 2869 ALS patients and 6405 controls. Several known ALS genes were found to be associated, and TBK1 (the gene encoding TANK-binding kinase 1) was identified as an ALS gene. TBK1 is known to bind to and phosphorylate a number of proteins involved in innate immunity and autophagy, including optineurin (OPTN) and p62 (SQSTM1/sequestosome), both of which have also been implicated in ALS. These observations reveal a key role of the autophagic pathway in ALS and suggest specific targets for therapeutic intervention. PMID- 25700180 TI - Peripherally Inserted Central Catheters Complicated by Vascular Erosion in Neonates. AB - Peripherally inserted central catheters (PICCs) are widely used in the pediatric population, and their use continues to grow in popularity. These catheters provide a reliable source of venous access to neonatal patients but can also be the cause of life-threatening complications. There are several well-documented complications such as infections, catheter thrombosis, vascular extravasations, and fractured catheters. However, the complication of vascular erosion into the pleural space using both small and silicone-based catheters is rarely described. After obtaining institutional review board approval, we identified 4 cases to review of PICCs complicated by vascular erosions in the past 2 years. Herein, we also review the current literature of PICC complications. Getting the catheter tip as close to the atrial-caval junction as possible and confirmation of this placement are of the utmost importance. The thick wall of the vena cava near the atrium seems to be less likely to perforate; in addition, this position provides increased volume and turbulence to help dilute the hyperosmolar fluid, which seems to also be a factor in this complication. A daily screening chest x-ray in patients with upper extremity PICCs and ongoing parenteral nutrition (PN) are not necessary at this time given the overall low rate of vascular erosion and concerns regarding excessive radiation exposure in pediatric populations. However, a low threshold for chest x-ray imaging in patients with even mild respiratory symptoms in the setting of upper extremity PN is recommended. PMID- 25700181 TI - Quality of Life in a Randomized Trial of Nasogastric Tube Feeding in Acute Pancreatitis. AB - BACKGROUND: Recent clinical studies have shown that nasogastric tube feeding is safe in the majority of patients with acute pancreatitis. Patient-reported outcomes are important, but the impact of nasogastric tube feeding on the quality of life has not been investigated. This study aims to compare quality of life between nasogastric tube feeding and nil-by-mouth groups during and after hospitalization. METHODS: Patient-reported outcomes were recorded daily in a patient diary during hospitalization. The Abdominal Surgery Impact Scale questionnaire was used to determine patients' quality of life. The patients were then followed up at 1 week and 1, 3, and 6 months after discharge. RESULTS: While 17 patients were randomized to nasogastric tube feeding, 18 were put on nil-by mouth. The overall quality of life and individual domains did not differ significantly between the groups during hospitalization (P = .500) or follow-up. For the entire cohort, individual quality-of-life domains during hospitalization improved significantly, including functional impairment (P < .001), pain (P < .001), sleep (P = .035), and psychological function (P < .001). Quality of life further improved for all patients from time of hospital discharge to 3 (P = .002) and 6 months follow-up (P < .001) but not to 1 week and 1 month. CONCLUSIONS: The use of nasogastric tube feeding, in comparison with nil-by-mouth, does not impair patients' quality of life. Given the clinical benefits of nasogastric tube feeding, nasogastric feeding should be considered the first-line approach in all acute pancreatitis patients requiring enteral nutrition. PMID- 25700182 TI - Exploration of chronic kidney disease prevalence estimates using new measures of kidney function in the health survey for England. AB - BACKGROUND: Chronic kidney disease (CKD) diagnosis relies on glomerular filtration rate (eGFR) estimation, traditionally using the creatinine-based Modification of Diet in Renal Disease (MDRD) equation. The Chronic Kidney Disease Epidemiology Collaboration (CKDEPI) equation performs better in estimating eGFR and predicting mortality and CKD progression risk. Cystatin C is an alternative glomerular filtration marker less influenced by muscle mass. CKD risk stratification is improved by combining creatinine eGFR with cystatin C and urinary albumin to creatinine ratio (uACR). We aimed to identify the impact of introducing CKDEPI and cystatin C on the estimated prevalence and risk stratification of CKD in England and to describe prevalence and associations of cystatin C. METHODS AND FINDINGS: Cross sectional study of 5799 people in the nationally representative 2009 and 2010 Health Surveys for England. PRIMARY OUTCOME MEASURES: prevalence of MDRD, CKDEPI and cystatin C-defined eGFR<60 ml/min/1.73 m(2); prevalence of CKD biomarker combinations (creatinine, cystatin C, uACR). Using CKDEPI instead of MDRD reduced the prevalence of eGFR<60 ml/min/1.73 m(2) from 6.0% (95% CI 5.4-6.6%) to 5.2% (4.7-5.8%) equivalent to around 340,000 fewer individuals in England. Those reclassified as not having CKD evidenced a lower risk profile. Prevalence of cystatin C eGFR<60 ml/min/1.73 m(2) was 7.7% and independently associated with age, lack of qualifications, being an ex-smoker, BMI, hypertension, and albuminuria. Measuring cystatin C in the 3.9% people with CKDEPI-defined eGFR<60 ml/min/1.73 m(2) without albuminuria (CKD Category G3a A1) reclassified about a third into a lower risk group with one of three biomarkers and two thirds into a group with two of three. Measuring cystatin C in the 6.7% people with CKDEPI eGFR >60 ml/min/1.73 m(2) with albuminuria (CKD Category G1-2) reclassified almost a tenth into a higher risk group. LIMITATIONS: Cross sectional study, single eGFR measure, no measured ('true') GFR. CONCLUSIONS: Introducing the CKDEPI equation and targeted cystatin C measurement reduces estimated CKD prevalence and improves risk stratification. PMID- 25700183 TI - RP-HPLC analysis and in vitro identification of antimycobacterial activity of novel thiosemicarbazides and 1,2,4-triazole derivatives. AB - It has been widely recognized that chromatography can be applied to derive parameters useful for anticipation of the pharmacological properties of xenobiotics. The purpose of this study was to evaluate the use of C18 stationary phase in chromatographic experiments as to assess antimycobacterial activity of series of novel thiosemicarbazides and their cyclization products: 1,2,4-triazole derivatives. Chromatographically determined lipophilicity descriptors log k(w), S and phi0 and computer generated molecular descriptors were obtained for 32 compounds and Rifampicin as a representative anti-tuberculosis drug. As experimental parameters were not significantly related to the calculated values, the data were analyzed by the principal component analysis PCA allowing for the extraction of "dipole moment" and "energy due to solvation" as the most powerful parameters from large set of diverse data. The approach ranked the examined analytes as active and inactive against Mycobacterium strains. More significant clustering of examined compounds was achieved by construction of 3D graph relating computational (dipole moment, energy due to solvation) and experimental log k(w) (MeOH) descriptors. It was proved that lack of substituent in the C5 position in the triazole ring appears to be characteristic for active derivatives. Provided conclusions can be taken into account in planning further synthesis of new derivatives with antimycobacterial activity. PMID- 25700185 TI - Reversible potential-induced switching of alkyl chain aggregation in octyl triazatriangulenium adlayers on Au(111). AB - In situ scanning tunneling microscopy and cyclic voltammetry studies of self assembled octyl-triazatriangulenium monolayers on Au(111) electrode surfaces in 0.1 M HClO4 reveal a complex surface phase behavior, involving two fast, highly reversible transitions between different ordered adlayer phases: With decreasing potential, the preadsorbed (?19 * ?19)R23.4 degrees adlayer first is converted into a (7?3 * 7?3) and then into a (2?3 * 2?3)R30 degrees phase, corresponding to a stepwise increase in the local packing density of the molecules. The (7?3 * 7?3) -> (2?3 * 2?3)R30 degrees transition is accompanied by a reorientation of the peripheral octyl chains from a more planar to a close-packed vertical arrangement. This reversible potential-induced switching between a homogeneous adlayer of small vertical extension and a Au surface partially covered by islands of a compact hydrocarbon layer is attributed to changes in the adsorbate charge state and associated changes in the intermolecular interactions. PMID- 25700184 TI - Significance of measuring non-2,3,7,8-substituted PCDD/PCDF congeners and the identification of a new mechanism of formation for a high-temperature industrial process. AB - Many studies involving polychlorinated dibenzo-p-dioxins and dibenzofurans (Cl4 Cl8) are limited to the 17 2,3,7,8-substituted congeners, which are used for the computation of the toxic equivalent concentration (TEQ) and often are the basis for regulatory actions. The values determined for total homolog groups may also be reported in some cases, e.g., Total Tetra-Dioxins, and such results provide some additional information but do not reveal the subtle details that can be derived from the study of individual congeners. There are 136 possible structures for tetra- through octa-chlorinated dibenzo-p-dioxins and dibenzofurans, including the 17 2,3,7,8-substituted congeners. In this work, the valuable role that inclusion of the other 119 congeners plays in understanding emission deviations (upsets) compared to normal operating conditions for a secondary aluminum smelter facility is illustrated. An exponential correlation was observed between the concentrations of specific non-2,3,7,8-substituted tetrachlorinated congeners (e.g., 2,3,6,7/3,4,6,7-TCDFs vs. 1,3,6,8-TCDD and 1,3,7,9-TCDD) and the TEQ-based emissions at the outlet of a baghouse pollution control device. The correlation possibly points to the additional and occasionally essential role played by metal-catalyzed stereoselective chlorination reactions taking place during the melting-purification process, as well as (conceivably) inside the air pollution control device. This chlorination in turn highlights not only the importance of the chlorine addition step and the kinetics involved with regard to regulating emission levels but also the role of measuring all 136 PCDD/F congeners. PMID- 25700186 TI - To read or not to read: a neurophysiological study. AB - Pure alexia (PA) has been associated with visual deficits or a failure to activate the visual word form area (VWFA). We report a patient with pure alexia due to posterior cortical atrophy, in whom event-related potentials revealed a delay in the P100 component and an absent N170 compared with controls. Furthermore, there was a tendency for a larger delay in P100 latencies associated with incorrectly read words. This suggests that some cases of PA might result from deficits in visual perception, signaled by the P100 early potential which could lead to an inability to consistently activate the VWFA, marked by the absent N170. PMID- 25700187 TI - Palladium-catalyzed decarboxylative annulation of 2-arylbenzoic acids with [60]fullerene via C-H bond activation. AB - A convenient and highly efficient palladium-catalyzed decarboxylative annulation of 2-arylbenzoic acids with [60]fullerene has been exploited to synthesize the novel and scarce [60]fullerene-fused dihydrophenanthrenes. The use of Lewis acid ZnCl2 is crucial for the success of the present formal [4 + 2] annulation reaction. Plausible reaction pathways leading to the observed products have been proposed, and the electrochemistry of the fullerene products has also been investigated. PMID- 25700188 TI - Electrical transport and giant magnetoresistance in La0.75Sr0.25Mn1-xCrxO3 (0.15, 0.20 and 0.25) manganite oxide. AB - We have investigated the influence of chromium (Cr) doping on the magneto electrical properties of polycrystalline samples La0.75Sr0.25Mn1-xCrxO3 (0.15 <= x <= 0.25), prepared by the sol-gel method. Comparison of experimental data with the theoretical models shows that in the metal-ferromagnetic region, the electrical behavior of the three samples is quite well described by a theory based on electron-electron, electron-phonon and electron-magnon scattering and Kondo-like spin dependent scattering. For the high temperature paramagnetic insulating regime, the adiabatic small polaron hopping (SPH) model is found to fit well the experimental curves. PMID- 25700189 TI - Local elastic constants of LacI and implications for allostery. AB - Allostery connects subtle changes in a protein's potential energy surface, induced by perturbations like ligand-binding, to significant changes in its function. Understanding this phenomenon and predicting its occurrence are major goals of current research in biophysics and molecular biology. In this paper we introduce a novel approach for studying complex structural transformations such as those typical for allostery. We show that the calculation and analysis of atomic elastic constants of a known allosterically regulated protein, lac repressor, highlights regions that are particularly prone to suffer structural deformation and are experimentally linked to allosteric function. The calculations are based on a high resolution, all-atom description of the protein. We also show that, for the present system, modifying the description of the system from an all-atom forcefield to an elastic network model yields qualitatively different results, indicating the importance of adequately describing the local environment surrounding the different parts of the protein. PMID- 25700190 TI - Molecular dynamics simulations to calculate glass transition temperature and elastic constants of novel polyethers. AB - Molecular dynamics simulations studies are carried out on hydroxyl terminated polyethers that are useful in energetic polymeric binder applications. Energetic polymers derived from oxetanes with heterocyclic side chains with different energetic substituents are designed and simulated under the ensembles of constant particle number, pressure, temperature (NPT) and constant particle number, volume, temperature (NVT). Specific volume of different amorphous polymeric models is predicted using NPT-MD simulations as a function of temperature. Plots of specific volume versus temperature exhibited a characteristic change in slope when amorphous systems change from glassy to rubbery state. Several material properties such as Young's, shear, and bulk modulus, Poisson's ratio, etc. are predicted from equilibrated structures and established the structure-property relations among designed polymers. Energetic performance parameters of these polymers are calculated and results reveal that the performance of the designed polymers is comparable to the benchmark energetic polymers like polyNIMMO, polyAMMO and polyBAMO. Overall, it is worthy remark that this molecular simulations study on novel energetic polyethers provides a good guidance on mastering the design principles and allows us to design novel polymers of tailored properties. PMID- 25700191 TI - My crystal ball is a bit murky. PMID- 25700192 TI - Stroke and pregnancy: an integrative review with implications for neuroscience nurses. AB - Stroke in association with pregnancy is an infrequent occurrence, but there is evidence that the incidence is rising. The physiological changes of pregnancy are thought to increase stroke risk, and several conditions specific to pregnancy further increase risk. The provision of optimal care to pregnant and postpartum women who experience stroke requires awareness of how the physiological changes of pregnancy may affect the course of stroke and nursing actions. This article provides an overview of current knowledge about pregnancy-related stroke including underlying pathophysiology, risk factors unique to pregnancy, and treatment issues when stroke is a complication of pregnancy. Implications for the nursing care of women with pregnancy-related stroke and maternal child considerations are discussed. PMID- 25700193 TI - Weight reduction after severe brain injury: a challenge during the rehabilitation course. AB - BACKGROUND: There is a paucity of studies, which have described malnutrition in patients with acquired brain injury (ABI) across etiology. This study describes weight change, malnutrition, and potential associations in patients with ABI at a subacute inpatient rehabilitation hospital. METHOD: This is a descriptive cohort study. Ninety-eight patients were admitted in a 3-month period, of whom n = 76 met inclusion criteria. The Malnutrition Universal Screening Tool was used for categorizing patients according to risk of malnutrition. RESULTS: Patients had experienced weight loss of 5.59% +/- 5.89% (p < .001) at admission at the rehabilitation hospital, and patients with traumatic brain injury had experienced a greater weight loss than patients with stroke (p < .01). Thirty percent of patients were at high risk for malnutrition, and 52% of these patients received enteral or parenteral nutrition at admission at the rehabilitation hospital. No association was found between risk of malnutrition and severity of injury, complications, functional outcome, or length of stay. CONCLUSION: RESULTS underline the importance that nurses, especially in acute care, adhere to clinical guidelines to minimize weight loss. Special attention should be on patients with traumatic brain injury. Weight gain in the following course of rehabilitation may facilitate positive rehabilitation outcomes. PMID- 25700194 TI - Caring for patients with closed traumatic brain injury in rural settings. AB - The Centers for Disease Control and Prevention (CDC) has acknowledged closed traumatic brain injuries (cTBIs), a form of traumatic brain injury (TBI), as being a major public health matter in the United States. Statistical analysis, as well as public health data, has suggested that there are approximately 1,300 cases of cTBI per year in the United States alone. The standard of care for patients with a cTBI is to undergo diagnostic imaging, most commonly computerized tomography, which is considered to be a luxury and seldom exists in rural clinics. Despite increasing TBI awareness and publicity, healthcare providers, including advanced practice registered nurses, have yet to have a full understanding of the severity of damages that can result from a cTBI. The purpose of this article is to provide an understanding of cTBI and concise clinical best practice guidelines that will aid healthcare providers in rural settings to properly diagnose, treat, and provide education for patients with cTBIs. PMID- 25700195 TI - Mentoring the next generation of neuroscience nurses: a pilot study of mentor engagement within an academic-service partnership. AB - Resulting from a system-wide launch of an academic-service partnership that united a research-intensive School of Nursing and a tertiary healthcare system, neuroscience nurses used a team-based approach in mentoring undergraduate nursing students in neuroscience nursing. They linked their team approach to the Institute of Medicine's Future of Nursing report and American Association of Neuroscience Nurses' (2012) strategic plan to prepare neuroscience nurses for the future. Using case reports containing both the mentors' and students' perspective, we showcase sophomore nursing students' development in neuroscience nursing with focus on their developing skills in competency, leadership, and collaboration. Results from this implementation phase include improved reliability in performing undergraduate neurological assessments; developing competency in collaborating with the health team using a culturally sensitive approach; beginning leadership in managing a patient with seizures; and collaborating with families in patient-family-focused care. Evaluation of the effectiveness of this mentored approach to clinical undergraduate nursing education will focus on confidence building for students and mentors. PMID- 25700196 TI - The effect of nocturnal patient care interventions on patient sleep and satisfaction with nursing care in neurosurgery intensive care unit. AB - BACKGROUND: Sleep disturbance in an intensive care unit is a common problem. One of the main factors causing sleep disturbances in an intensive care unit is nocturnal patient care interventions. AIMS AND OBJECTIVES: This study aims to determine the impact of patient care interventions performed at night in a neurosurgical intensive care unit on patients' sleep and their nursing care satisfaction. METHODS: The descriptive study was conducted on 82 patients in a neurosurgical intensive care unit between January 2009 and March 2010. The data were collected by data collection instruments and Newcastle Satisfaction with Nursing Scales. The data were statistically analyzed by frequency, mean, standard deviation, chi-square, and Mann-Whitney U test. RESULTS: The study showed that 53.7% of the patients experienced sleep disturbances in the neurosurgical intensive care unit. Because of nursing interventions at night, 39.1% of these patients had their sleep affected, but this problem did not cause any negative impact on the patients' satisfaction (Newcastle Satisfaction with Nursing Scales score = 88.21 +/- 9.83). The patients received, on average, 42.21 +/- 7.45 times patient care interventions at night; however, the frequency of patient care interventions at night showed no effect on sleep disturbances in this study (p > .05). The most frequently given patient care interventions were, respectively, vital signs monitoring, neurological assessment, and repositioning in bed. These interventions were performed commonly at 6 a.m., 12 a.m., and 7 p.m. CONCLUSION: In this study, despite the patients reporting sleep disturbances in the neurosurgical intensive care unit because of nocturnal patient care interventions that prevented them from sleeping, the patients' satisfaction on the given nursing care was not negatively impacted. To reduce sleep disturbances because of nursing care initiatives and promote uninterrupted sleep in the intensive care unit, it can be useful to develop new protocols regulating night care activities. PMID- 25700198 TI - Caregivers of older persons with multiple sclerosis: determinants of health related quality of life. AB - OBJECTIVE: This study was conducted to determine which factors (clinical and demographic) are associated with mental and physical health-related quality of life (HRQOL) for caregivers of older persons with multiple sclerosis (MS). The Andersen's Healthcare Utilization Model guided this study. Knowledge of identified predictors of HRQOL may prompt nurses who care for persons with MS to address these issues and provide supportive care. METHODS: A cross-sectional descriptive design was used to examine the relationship between patient with MS and caregiver clinical and demographic factors with caregiver physical and mental HRQOL. Patients with MS aged 60 years or older and their caregivers from four MS centers on Long Island, New York, self-selected into this study (n = 102). A caregiver survey was administered that collected demographic information and included validated questionnaires measuring HRQOL, caregiver burden, and caregiver perception of risk for neuropsychological impairment of patients with MS. Patient surveys collected demographic information and validated questionnaires measuring cognition, depression, and disability. Multivariate linear regression was used to examine patient and caregiver variables to explain caregiver physical and mental HRQOL. RESULTS: The caregivers in this study were older (mean age = 61 years) with existing comorbidities. We found that caregiver mental HRQOL was negatively associated with patient depression and, surprisingly, positively associated with caregiver burden and caregiver comorbidity of heart disease. Caregiver physical HRQOL was negatively associated with caregiver comorbidities of arthritis and diabetes and lower household income. CONCLUSION: The challenges older caregivers face when caring for older persons with MS have been shown to affect their mental and physical QOL. Nurses who care for older patients with MS will increasingly rely on older caregivers to provide patient centered interventions. This descriptive study, based on the Anderson theoretical model, provides insight on factors impacting older caregivers' HRQOL. Further research is necessary to elucidate the types of interventions that support them as they care for older patients with MS. PMID- 25700199 TI - One-pot synthesis of 3,4,5-trisubstituted 1,2,4-triazoles via the addition of hydrazides to activated secondary amides. AB - A general approach has been developed for the one-pot synthesis of 3,4,5 trisubstituted 1,2,4-triazoles from secondary amides and hydrazides via triflic anhydride activation followed by microwave-induced cyclodehydration. In addition, the 1,2,4-triazole moiety is shown to be a useful directing group for Ru catalyzed C-H arylation. Access to 1,2,4-triazolophenanthridine can be achieved from the reaction products using a Pd-catalyzed intramolecular C-H functionalization reaction. PMID- 25700200 TI - Abnormal sinoatrial node development resulting from disturbed vascular endothelial growth factor signaling. AB - BACKGROUND: Sinus node dysfunction is frequently observed in patients with congenital heart disease (CHD). Variants in the Vascular Endothelial Growth Factor-A (VEGF) pathway are associated with CHD. In Vegf(120/120) mice, over expressing VEGF120, a reduced sinoatrial node (SAN) volume was suggested. Aim of the study is to assess the effect of VEGF over-expression on SAN development and function. METHODS: Heart rate was measured in Vegf(120/120) and wildtype (WT) embryos during high frequency ultrasound studies at embryonic day (E)12.5, 14.5 and 17.5 and by optical mapping at E12.5. Morphology was studied with several antibodies. SAN volume estimations were performed, and qualitative-PCR was used to quantify expression of genes in SAN tissues of WT and Vegf(120/120) embryos. RESULTS: Heart rate was reduced in Vegf(120/120) compared with WT embryos during embryonic echocardiography (52 +/- 17 versus 125 +/- 31 beats per minute (bpm) at E12.5, p<0.001; 123 +/- 37 vs 160 +/- 29 bmp at E14.5, p=0.024; and 177 +/- 30 vs 217 +/- 34 bmp, at E17.5 p=0.017) and optical mapping (81 +/- 5 vs 116 +/- 8 bpm at E12.5; p=0.003). The SAN of mutant embryos was smaller and more vascularized, and showed increased expression of the fast conducting gap junction protein, Connexin43. CONCLUSIONS: Over-expression of VEGF120 results in reduced heart rate and a smaller, less compact and hypervascularized SAN with increased expression of Connexin43. This indicates that VEGF is necessary for normal SAN development and function. PMID- 25700201 TI - The effect of mental illness and psychotropic medication on gametes and fertility: a systematic review. AB - BACKGROUND: Psychiatric disorders during the reproductive years and their treatment with psychotropic medications are increasingly common, and their effect on the reproductive system is an important area of research. OBJECTIVE: To review the effect of mental illness and psychotropic medication on gametes and fertility. DATA SOURCES: Searches of the PubMed database were conducted for English-language articles containing the keywords gametes, fertility, psychotropic, oocyte, sperm, mental illness, depression, and/or anxiety, in the title or abstract. The searches yielded 3,603 citations. STUDY SELECTION: Studies were evaluated for relevance. Those not pertinent to the clinical question, not written in English, and focusing on invertebrates were excluded. Full texts of 50 articles were obtained for further evaluation. Additional articles were identified from reference lists. Ultimately, a total of 37 studies were deemed suitable and reviewed. RESULTS: Clinical studies have not demonstrated a deleterious effect of psychotropic medication on oocytes in terms of retrieval and pregnancy rates. Clinical studies demonstrate inconclusive results regarding the effect on sperm, with several studies suggesting increased sperm motility and quantity with certain psychotropics. Decreased sperm quantity and motility are described in a number of studies, including in vitro and in vivo studies. Maternal psychiatric illness is associated with decreased reproductive success, including lower rates of oocyte retrieval, lower rates of ongoing pregnancy, and dysregulation of the stress system in a majority (n = 11) but not all (n = 3) studies reviewed. Male depression did not appear to affect sperm, but anxiety did have an effect (n = 1). CONCLUSIONS: Given the detrimental effect of untreated mental illness, current literature is not robust enough to influence the use of psychotropics in males or females who are considering reproduction. PMID- 25700202 TI - Erratum. PMID- 25700204 TI - Monoclonal antibodies to host cellular receptors for the treatment and prevention of HIV-1 infection. AB - PURPOSE OF REVIEW: Clinically relevant monoclonal antibodies (mAb) to host cellular receptors have been generated to both the CD4 receptor and the CCR5 coreceptor, cell surface proteins critical for HIV-1 entry. Ibalizumab is a novel humanized mAb that binds to a conformational epitope on CD4 and blocks entry of HIV-1. It has broad and potent antiviral activity in vitro and in vivo. PRO 140 is a humanized mAb that binds to the CCR5 coreceptor and inhibits CCR5-tropic HIV 1 by interfering with viral entry. Antiviral activity has been demonstrated both in vitro against R5 viruses and in vivo in HIV-1-infected individuals harboring CCR5-tropic virus. RECENT FINDINGS: Both antibodies have been administered intravenously in early-phase clinical trials, and current emphasis is on the development of formulations that can be administered subcutaneously. Most recently, bispecific antibodies combining either ibalizumab or PRO 140 with anti Env broadly neutralizing antibodies have been constructed with vastly improved in vitro neutralizing profiles, and may offer substantial advantages in the clinic. SUMMARY: mAb to host cellular receptors particularly when combined with broadly neutralizing antibodies in novel conformations may offer advances in both the treatment and prevention of HIV-1 infection. PMID- 25700203 TI - Broadly neutralizing antibody and the HIV reservoir in acute HIV infection: a strategy toward HIV remission? AB - PURPOSE OF REVIEW: Infection of long-lived CD4 T cells is a major obstacle to HIV remission, and antiretroviral therapy (ART) instituted during acute HIV infection restricts HIV reservoir establishment. Broadly neutralizing antibodies (bNAbs) may be employed in conjunction with early ART as strategies toward HIV remission. RECENT FINDINGS: Proof-of-concept studies in vitro and in animal models demonstrated bNAbs' ability to block viral entry into cells, suppress viremia and reduce cell-associated viral DNA. Combination bNAbs were more effective than single bNAb in suppressing viremia. When bNAb was used with ART with or without combination latency reversing agents, it prevented viral rebound after ART interruption in at least half of the animals. In one study, macaques with low baseline viral load achieved viral remission even after the blood bNAb titer was no longer detected. SUMMARY: The acute HIV infection period represents a unique opportunity to explore the use of bNAbs with ART to limit the reservoir seeding that may enhance the chance of HIV remission. This article discusses the effects of early ART and bNAbs on HIV reservoirs and proposes research strategies in acute HIV infection aiming at HIV reservoir reduction and HIV remission. PMID- 25700205 TI - Antibodies for prevention of mother-to-child transmission of HIV-1. AB - PURPOSE OF REVIEW: Although antiretroviral (ARV) prophylaxis can reduce mother-to child transmission (MTCT) of HIV-1 to less than 2%, one-quarter of a million infants continue to be infected with HIV-1 annually. ARV prophylaxis alone will fail to eliminate infant HIV-1 infection because of issues of maternal adherence, toxicities, ARV-resistant virus strains, and acute maternal infection. Effective maternal and/or infant immunization will likely be required to achieve the goal of an HIV-free generation. RECENT FINDINGS: This article describes recent studies of antibody responses that protect against vertical HIV-1 transmission. Studies have shown that maternal neutralization breadth is not a critical factor in MTCT, yet the ability of maternal plasma to neutralize autologous virus variants may be important in infant protection. There is also new evidence that infants mount robust and durable antibody responses to HIV-1 envelope following vaccination and can develop broad neutralization during infection. Finally, passive immunization of infants with highly potent and broad neutralizing antibodies may be an effective strategy to protect infants against infection with postnatally transmitted variants. SUMMARY: Defining the characteristics of maternal and infant antibody responses that protect against MTCT will inform development of effective passive and active immunization strategies that will likely be required to eliminate pediatric HIV-1. PMID- 25700206 TI - Vectored antibody gene delivery for the prevention or treatment of HIV infection. AB - PURPOSE OF REVIEW: To discuss recent progress in the use of vectors to produce antibodies in vivo as an alternative form of HIV prophylaxis or therapy. Instead of passive transfer of monoclonal antibody proteins, a transgene encoding an antibody is delivered to cells by the vector, resulting in expression and secretion by the host cell. This review will emphasize adeno-associated virus (AAV)-based strategies and summarize the evidence in support of this strategy as an alternative to traditional vaccines. We will highlight the major findings in the field and discuss the impact that this approach could have on the prevention, treatment and possibly eradication of HIV in patients. RECENT FINDINGS: In this emerging field, the emphasis has been on the use of vectors delivering antibodies as an alternative to the development of an HIV vaccine. However, recent findings suggest that AAV-delivered broadly neutralizing antibodies can suppress HIV replication. As such, a single injection of AAV could mediate long-term antibody expression to act as a long-lived therapeutic in the absence of antiretroviral drugs. SUMMARY: Vector-mediated antibody expression can both prevent transmission and inhibit the replication of established HIV infections. As such, it offers an alternative to immunogen-based vaccine design and a novel therapeutic intervention by enabling precise manipulation of humoral immunity. Success may enable not only the development of effective prevention against HIV but may also provide an alternative to a lifetime of antiretroviral drugs taken by those who are already infected. PMID- 25700207 TI - Antibodies for HIV prevention in young women. AB - PURPOSE OF REVIEW: Young women in sub-Saharan Africa bear a disproportionate HIV burden. They urgently require new HIV prevention approaches that they can use. This review provides an overview of the use of antiretrovirals for HIV preexposure prophylaxis (PrEP), highlighting some of the challenges with this technology and explores the potential role of mAbs for HIV prevention in women. RECENT FINDINGS: Recent findings on the initial steps in viral entry and establishment of a productive local infectious nidus in the vaginal epithelium has provided important clues for HIV prevention in the female genital tract. Topical and oral formulations of antiretroviral drugs have been shown to prevent HIV infection in women with varying levels of success, depending principally on adherence. Further, several new broad and potent mAbs have been isolated over the last 5 years. Nonhuman primate studies demonstrate that broadly neutralizing HIV mAbs can protect rhesus macaques from simian immunodeficiency virus-HIV chimera (SHIV) infection. These findings have created newfound enthusiasm for passive immunization as a potential prevention strategy for women. SUMMARY: If potent broadly neutralizing mAbs are effective in preventing HIV infection in women, this outcome could fill an important gap in HIV prevention technologies for young women, especially in Africa. PMID- 25700208 TI - Prospects for engineering HIV-specific antibodies for enhanced effector function and half-life. AB - PURPOSE OF REVIEW: A wealth of recent animal model data suggests that as exciting possibilities for the use of antibodies in passive immunotherapy strategies continue to develop, it will be important to broadly consider how antibodies achieve anti-HIV-1 effect in vivo. RECENT FINDINGS: Beyond neutralization breadth and potency, substantial evidence from natural infection, vaccination, and studies in animal models points to a critical role for antibody Fc receptor (FcR) engagement in reducing risk of infection, decreasing postinfection viremia, and delaying viral rebound. Supporting these findings in the setting of HIV, the clinical maturation of recombinant antibody therapeutics has reinforced the importance of Fc-driven activity in vivo across many disease settings, as well as opportunely resulted in the development and exploration of a number of engineered Fc sequence and glycosylation variants that possess differential binding to FcRs. Exploiting these variants as tools, the individual and concerted effects of antibody effector functions such as antibody-dependent cellular cytotoxicity, antibody-dependent cell-mediated virus inhibition, phagocytosis, complement dependent cytotoxicity, antibody half-life, and compartmentalization are now being explored. As exciting molecular therapies are advanced, these studies promise to provide insight into optimal in-vivo antibody activity profiles. SUMMARY: Careful consideration of recent progress in understanding protective antibody activities in vivo can point toward how tailoring antibody activity via Fc domain modification may enable optimization of HIV prevention and eradication strategies. PMID- 25700209 TI - Simulation for Skills-based Education in Pulmonary and Critical Care Medicine. AB - The clinical practice of pulmonary and critical care medicine requires procedural competence in many technical domains, including vascular access, airway management, basic and advanced bronchoscopy, pleural procedures, and critical care ultrasonography. Simulation provides opportunities for standardized training and assessment in procedures without placing patients at undue risk. A growing body of literature supports the use and effectiveness of low-fidelity and high fidelity simulators for procedural training and assessment. In this manuscript by the Skills-based Working Group of the American Thoracic Society Education Committee, we describe the background, available technology, and current evidence related to simulation-based skills training within pulmonary and critical care medicine. We outline working group recommendations for key procedural domains. PMID- 25700210 TI - Modulating the morphology and electrical properties of GaAs nanowires via catalyst stabilization by oxygen. AB - Nowadays, III-V compound semiconductor nanowires (NWs) have attracted extensive research interest because of their high carrier mobility favorable for next generation electronics. However, it is still a great challenge for the large scale synthesis of III-V NWs with well-controlled and uniform morphology as well as reliable electrical properties, especially on the low-cost noncrystalline substrates for practical utilization. In this study, high-density GaAs NWs with lengths >10 MUm and uniform diameter distribution (relative standard deviation sigma ~ 20%) have been successfully prepared by annealing the Au catalyst films (4-12 nm) in air right before GaAs NW growth, which is in distinct contrast to the ones of 2-3 MUm length and widely distributed of sigma ~ 20-60% of the conventional NWs grown by the H2-annealed film. This air-annealing process is found to stabilize the Au nanoparticle seeds and to minimize Ostwald ripening during NW growth. Importantly, the obtained GaAs NWs exhibit uniform p-type conductivity when fabricated into NW-arrayed thin-film field-effect transistors (FETs). Moreover, they can be integrated with an n-type InP NW FET into effective complementary metal oxide semiconductor inverters, capable of working at low voltages of 0.5-1.5 V. All of these results explicitly demonstrate the promise of these NW morphology and electrical property controls through the catalyst engineering for next-generation electronics. PMID- 25700211 TI - Measuring and modeling the magnetic settling of superparamagnetic nanoparticle dispersions. AB - In this paper, we present settling experiments and mathematical modeling to study the magnetic separation of superparamagnetic iron-oxide nanoparticles (SPIONs) from a brine. The experiments were performed using SPIONs suspensions of concentration between 3 and 202g/L dispersed in water and separated from the liquid under the effect of a permanent magnet. A 1D model was developed in the framework of the sedimentation theory with a conservation law for SPIONs and a mass flux function based on the Newton's law for motion in a magnetic field. The model describes both the hindering effect of suspension concentration (n) during settling due to particle collisions and the increase in settling rate due to the attraction of the SPIONs towards the magnet. The flux function was derived from the settling experiments and the numerical model validated against the analytical solution and the experimental data. Suspensions of SPIONs were of 2.8cm initial height, placed on a magnet, and monitored continuously with a digital camera. Applying a magnetic field of 0.5T of polarization, the SPION's velocity was of approximately 3.10(-5)m/s close to the magnet and decreases of two orders of magnitude across the domain. The process was characterized initially by a classical sedimentation behavior, i.e., an upper interface between the clear water and the suspension slowly moving towards the magnet and a lower interface between the sediment layer and the suspension moving away from the magnet. Subsequently, a rapid separation of nanoparticle occured suggesting a non classical settling phenomenon induced by magnetic forces which favor particle aggregation and therefore faster settling. The rate of settling decreased with n and an optimal condition for fast separation was found for an initial n of 120g/L. The model agrees well with the measurements in the early stage of the settling, but it fails to describe the upper interface movement during the later stage, probably because of particle aggregation induced by magnetization which is not accounted for in the model. PMID- 25700212 TI - Preparation of highly active and hydrothermally stable nickel catalysts. AB - The 60%Ni/AlSiO catalysts were prepared by the co-precipitation method, in which AlSiO were the composite supports with different mass ratios of Al2O3 and SiO2. It was found that the catalyst 60%Ni/AlSiO-4 with the Al2O3/SiO2 mass ratio of 4 in the support exhibited the high hydrothermal stability. The addition of proper amount of SiO2 inhibited the hydration of Al2O3 and prevented the growth of supported nickel particles during the hydrothermal treatment. The structure of the composite support in the 60%Ni/AlSiO-4 was stable and the supported nickel particles were highly dispersed. Accordingly, the hydrothermally treated catalyst maintained the high heats and uptakes for the adsorption of H2 and CO, and thus the high activity and stability for the hydrogenation of glucose to sorbitol in aqueous solution. PMID- 25700213 TI - The role of ether-functionalized ionic liquids in the sol-gel process: effects on the initial alkoxide hydrolysis steps. AB - The ether-functionalized imidazolium ionic liquids (IL) applied in the silica sol gel process demonstrated a defined coordination potential. These IL display the capacity to control the system organization from the reactions' first moments through a dynamic system-assembling ability, being the sum of ionic and physical interactions, i.e. Coulomb forces, H-bonding and London forces. The initial hydrolysis steps of tetraethyl orthosilicate (TEOS) in the presence of these IL were followed by Fourier transform infrared spectroscopy (FTIR) and dynamic light scattering (DLS), both in time-resolved experiments, in an attempt to correlate the structuring and the bonding dynamics of these systems. PMID- 25700214 TI - Calcium alginate encapsulated Ni/Fe nanoparticles beads for simultaneous removal of Cu (II) and monochlorobenzene. AB - Calcium alginate encapsulated Ni/Fe bimetallic nanoparticles beads (CA-Ni/Fe beads) were synthesized to simultaneously remove Cu (II) and monochlorobenzene (MCB) from aqueous solution. SEM, EDS, and XRD analyses confirmed that Ni/Fe bimetallic nanoparticles were not oxidized and successfully encapsulated by calcium alginate (CA). The experiments showed that the encapsulation process improved the simultaneous removal efficiency of Cu (II) and MCB, from 83.9% to 86.7% for Cu (II) and 94.7% to 99.1% for MCB compared with bare Ni/Fe nanoparticles after 120min treatment. Furthermore, the removal efficiency of Cu (II) and MCB increased with higher temperature, calcium alginate: Ni/Fe ratios and pH. Pseudo-second-order model for adsorption and pseudo-first-order model for the reduction process fitted the simultaneous removal of Cu (II) and MCB using CA Ni/Fe beads. Based on the above results, it could be concluded that the simultaneous removal was a two-step process: firstly, the adsorption of Cu (II) and MCB on the CA-Ni/Fe beads; and secondly, reduction of Cu (II) and dehalogenation of MCB by Ni/Fe in CA-Ni/Fe beads. Finally, the efficiency of regenerated CA-Ni/Fe beads was tested using synthesized wastewater which showed a satisfactory removal efficiency of Cu (II) and MCB maintained at 83.8% and 91.7% after three times' regeneration. PMID- 25700215 TI - Interfacial shear stress between a single-walled carbon nanotube and a gold surface after different physical treatments. AB - The interfacial shear stress between gold and dielectrophoretically assembled single-walled carbon nanotubes can be increased by annealing in N2, by e-beam irradiation, or by e-beam deposition of carbon. For the first time this increase has been measured, using a technique developed by this group that is based on NEMS cantilever measurements combined with modeling. Annealing increases the shear stress by more than a factor of 3 over its value of 87MPa for untreated gold surfaces, while e-beam irradiation increases the shear stress by more than a factor of 2 and carbon deposition increases the shear stress by a smaller amount. PMID- 25700216 TI - Benign fasciculation syndrome. AB - Questions from patients about pain conditions, analgesic pharmacotherapy, and responses from authors are presented to help educate patients and make them more effective self-advocates. In reply to a question about benign fasciculation syndrome, the presentation, causes, treatment, and chances of developing amyotrophic lateral sclerosis will be discussed. PMID- 25700217 TI - Minocycline Does Not Decrease Intensity of Neuropathic Pain Intensity, But Does Improve Its Affective Dimension. AB - Recent understanding of the neuron-glia communication shed light on an important role of microglia to develop neuropathic pain The analgesic effect of minocycline on neuropathic pain is promising but it remains unclear in clinical settings. This study included 20 patients with neuropathic pain of varied etiologies. We administered 100 mg/day of minocycline for 1 week and then 200 mg/day for 3 weeks, as an open-label adjunct to conventional analgesics. An 11-point numerical rating scale. (NRS) and the short-form McGill Pain Questionnaire (SF-MPQ) were used to evaluate pain severity. The data were collected at baseline and after 4 weeks of therapy and analyzed using the Wilcoxon signed-rank test. All except two of the patients tolerated the full dose of minocycline. There was no significant improvement in the scoring of NRS (5.6 +/- 1.2 at baseline vs. 5.3 +/- 1.9 at 4 weeks; P =.60). The total score of the SF-MPQ decreased significantly (17.2 +/- 7.4 vs. 13.9 +/- 9.6; P =.02), particularly in the affective subscale (4.4 +/- 2.7 vs. 3.3 +/- 3.6; P =.007) but not so in the sensory subscale (12.8 +/- 5.2 vs. 10.6 +/- 6.2; P =.06). We conclude that minocycline failed to decrease pain intensity but succeeded in reducing the affective dimension associated with neuropathic pain. PMID- 25700218 TI - Reply to Comment on 'Pitfalls in microdialysis methodology: an in vitro analysis of temperature, pressure and catheter use'. PMID- 25700219 TI - Examining Parents' Preferences for Group and Individual Parent Training for Children with ADHD Symptoms. AB - Parent training (PT) programs have been found to reduce some behavioral impairment associated with children's attention deficit hyperactivity disorder (ADHD) as well as improve parenting competence, but poor uptake and participation by parents are formidable barriers that affect service effectiveness. We used a discrete-choice experiment (DCE) to examine how parent preferences for treatment format (i.e., group vs. individual) might influence their participation in PT. Participants were 445 parents seeking mental health services for children with elevated symptoms of ADHD in Ontario, Canada. Parents completed a DCE composed of 30 choice tasks used to gauge PT format preference. Results showed that 58.7% of parents preferred individual PT; these parents were most interested in interventions that would make them feel more informed about their child's problems and in understanding-as opposed to solving-their child's problems. A minority of parents (19.4%) preferred group PT; these parents were most interested in active, skill-building services that would help them solve their child's problems. About one fifth of parents (21.9%) preferred the Minimal Information alternative (i.e., receiving neither individual or group PT); these parents reported the highest levels of depression and the most severe mental health problems in their child. Results highlight the importance of considering parent preferences for format and suggest that alternative formats to standard PT should be considered for multiply stressed families. PMID- 25700220 TI - A comparative evaluation of patient satisfaction outcomes in an interprofessional student-run free clinic. AB - As the evidence supporting the value of well-coordinated healthcare teams continues to grow, so to do the calls from medical educators and policy makers for the development of meaningful interprofessional educational experiences for health professions students. The student-run clinic has emerged as a unique venue for such experiential interprofessional learning experiences, with over 100 such clinics now in operation across North America. As the number and variety of these clinics rises, it has become increasingly important to understand the quality of care which they deliver. Here, patient satisfaction data from an interprofessional student-run free clinic are described, and these results are quantitatively compared to similar data obtained from a non-interprofessional, non-student-run clinic in a post-experience only, non-equivalent groups design. Student-run free clinic patients reported high levels of satisfaction with the patient care team and the facility quality, and lower levels of satisfaction with waiting times. When compared to the non-student-run clinic, there was no significant difference in the high levels of patient satisfaction with the patient care teams between the clinics. Student-run free clinic patients did, however, report significantly lower levels of satisfaction with the accessibility of care and with the perceived privacy of protected health information. Overall, this report provides evidence that an interprofessional student-run free clinic is capable of performing at the level of an experienced free clinic across many domains of patient satisfaction, while also identifying notable areas for improvement within the domains of clinic accessibility and the perception of the privacy of protected health information. PMID- 25700221 TI - Pigment epithelium-derived factor regulates microvascular permeability through adipose triglyceride lipase in sepsis. AB - The integrity of the vascular barrier, which is essential to blood vessel homoeostasis, can be disrupted by a variety of soluble permeability factors during sepsis. Pigment epithelium-derived factor (PEDF), a potent endogenous anti angiogenic molecule, is significantly increased in sepsis, but its role in endothelial dysfunction has not been defined. To assess the role of PEDF in the vasculature, we evaluated the effects of exogenous PEDF in vivo using a mouse model of cecal ligation and puncture (CLP)-induced sepsis and in vitro using human dermal microvascular endothelial cells (HDMECs). In addition, PEDF was inhibited using a PEDF-monoclonal antibody (PEDF-mAb) or recombinant lentivirus vectors targeting PEDF receptors, including adipose triglyceride lipase (ATGL) and laminin receptor (LR). Our results showed that exogenous PEDF induced vascular hyperpermeability, as measured by extravasation of Evan's Blue (EB), dextran and microspheres in the skin, blood, trachea and cremaster muscle, both in a normal state and under conditions of sepsis. In control and LR-shRNA-treated HDMECs, PEDF alone or in combination with inflammatory mediators resulted in activation of RhoA, which was accompanied by actin rearrangement and disassembly of intercellular junctions, impairing endothelial barrier function. But in ATGL shRNA-treated HDMECs, PEDF failed to induce the aforementioned alterations, suggesting that PEDF-induced hyperpermeability was mediated through the ATGL receptor. These results reveal a novel role for PEDF as a potential vasoactive substance in septic vascular hyperpermeability. Furthermore, our results suggest that PEDF and ATGL may serve as therapeutic targets for managing vascular hyperpermeability in sepsis. PMID- 25700222 TI - Preliminary data using computed tomography texture analysis for the classification of hypervascular liver lesions: generation of a predictive model on the basis of quantitative spatial frequency measurements--a work in progress. AB - OBJECTIVE: Computed tomography texture analysis (CTTA) is a method of quantifying lesion heterogeneity based on distribution of pixel intensities within a region of interest. This study investigates the ability of CTTA to distinguish different hypervascular liver lesions and compares CTTA parameters by creating a proof-of concept model to distinguish between different lesions. METHODS: Following institutional review board approval, CTTA software (TexRAD Ltd) was used to retrospectively analyze 17 cases of focal nodular hyperplasia, 19 hepatic adenomas, 25 hepatocellular carcinomas, and 19 cases of normal liver parenchyma using arterial phase scans. Two radiologists read the same image series used by the CTTA software and reported their best guess diagnosis. Computed tomography texture analysis parameters were computed from regions of interest using spatial band-pass filters to quantify heterogeneity. Random-forest method was used to construct a predictive model from these parameters, and a separate regression model was created using a subset of parameters. RESULTS: The random-forest model successfully distinguished the 3 lesion types and normal liver with predicted classification performance accuracy for 91.2% for adenoma, 94.4% for focal nodular hyperplasia, and 98.6% for hepatocellular carcinoma. This error prediction was generated using a subset of data points not used in generation of the model, but not on discrete prospective cases. In contrast, the 2 human readers using the same image series data analyzed by the CTTA software had lower accuracies, of 72.2% and 65.6%, respectively. The explicit regression model with a subset of image parameters had intermediate overall accuracy of 84.9%. CONCLUSIONS: Computed tomography texture analysis may prove valuable in lesion characterization. Differentiation between common hypervascular lesion types could be aided by the judicious incorporation of texture parameters into clinical analysis. PMID- 25700223 TI - Comparison of a New Integral-Based Half-Band Method for CT Measurement of Peripheral Airways in COPD With a Conventional Full-Width Half-Maximum Method Using Both Phantom and Clinical CT Images. AB - OBJECTIVES: To compare a new integral-based half-band method (IBHB) and a conventional full-width half-maximum (FWHM) method in measuring peripheral airway dimensions at airway phantoms and thin-section computed tomography of chronic obstructive pulmonary disease (COPD). METHODS: The IBHB was validated and compared using airway phantoms and 50 patients with COPD. Airway parameters (wall area percentage [WA%], mean lumen radius, and mean wall thickness) were measured at fourth to sixth generations of the right apical bronchus. Matched results from 2 methods were compared and correlated with forced expiratory volume (FEV) in 1 second (FEV1), FEV1 / forced vital capacity (FVC), and global initiative for chronic obstructive lung disease (GOLD) stage. Linear regression analysis was performed using airway dimensions and emphysema index. RESULTS: The IBHB generated more accurate measurements at phantom study. Measured airway parameters by both methods at thin-section computed tomography study were significantly different (all P < 0.05, paired t test). The IBHB method-measured WA% and wall thickness were significantly smaller. Mean WA% with IBHB also showed better correlation than that with FWHM (FEV1, r = -0.52 vs -0.28; FEV1 / FVC, r = -0.41 vs r = -0.20; GOLD, 0.52 vs 0.33, respectively). Linear regression analysis revealed fifth-generation WA% measured by IBHB was an independent variable, and addition to emphysema index increased predictability (FEV1, r = 0.63; FEV1 / FVC, r = 0.61; GOLD, r = 0.70). CONCLUSIONS: The new IBHB measured peripheral airway dimensions differently than FWHM and showed better correlations with functional parameters in COPD. PMID- 25700224 TI - Three-dimensional conformal radiation therapy in the liver: MRI findings along a time continuum. AB - Recent development of 3-dimensional conformal radiation therapies provides a concentrated radiation dose to the tumor. To achieve this goal, a complex design of multiple narrow beamlets is used to shape the radiation exposure to conform to the shape of the tumor. Imaging findings after novel radiation therapy techniques differ from those of conventional radiation therapy. This article discusses changes in the liver parenchyma and tumor after conformal radiation therapy focusing on magnetic resonance imaging. PMID- 25700225 TI - Usefulness of 18F-fluorodeoxyglucose Positron Emission Tomography-Computed Tomography in Monitoring Adhesive Capsulitis After Breast Cancer Treatment. AB - OBJECTIVES: We aimed to assess the usefulness of F-fluorodeoxyglucose (F-FDG) positron emission tomography-computed tomography (PET/CT) in the monitoring of adhesive capsulitis (AC), a joint problem commonly observed in the upper arm after breast cancer treatment. METHODS: This retrospective study included 230 patients who underwent F-FDG PET/CT before and after modified radical mastectomy of whom 22 patients were identified as having AC and categorized into 2 groups: with severely and mildly limited range of motion in the shoulder joint. The F-FDG uptake patterns and mean and maximum standardized uptake values (SUVs) were analyzed. RESULTS: The overall incidence of AC after MRM was 9.57%. The SUVs were significantly higher in patients with severely limited range of motion compared with the other group. There was no association between the SUV and radiotherapy. The F-FDG uptake pattern differed between the groups. CONCLUSIONS: F fluorodeoxyglucose PET/CT is useful in evaluating AC after breast cancer treatment. PMID- 25700226 TI - Repeatability Investigation of Reduced Field-of-View Diffusion-Weighted Magnetic Resonance Imaging on Thyroid Glands. AB - OBJECTIVE: To investigate the repeatability of the quantitative magnetic resonance imaging (MRI) metric (apparent diffusion coefficient [ADC]) derived from reduced field-of-view diffusion-weighted (rFOV DWI) on thyroid glands in a clinical setting. MATERIALS AND METHODS: Ten healthy human volunteers were enrolled in MRI studies performed on a 3-T MRI scanner. Each volunteer was designed to undergo 3 longitudinal examinations (2 weeks apart) with 2 repetitive sessions within each examination, which included rFOV and conventional full field of-view (fFOV) DWI scans. Diffusion-weighted images were assessed and scored based on image characteristics. Apparent diffusion coefficient values of thyroid glands from all participants were calculated based on regions of interest. Repeatability analysis was performed based on the framework proposed by the Quantitative Imaging Biomarker Alliance, generating 4 repeatability metrics: within-participant variance ((Equation is included in full-text article.)), repeatability coefficients, intraclass correlation coefficient, and within participant coefficient of variation. Student t test was used to compare the performance difference between rFOV and fFOV DWI. RESULTS: The overall image quality from rFOV DWI was significantly higher than that from fFOV DWI (P = 0.04). The ADC values calculated from rFOV DWI were significantly lower than corresponding values from fFOV DWI (P < 0.001). There was no significant difference in ADC values across sessions and examinations in either rFOV or fFOV DWI (P > 0.05). Reduced field-of-view DWI had lower values of (Equation is included in full-text article.), repeatability coefficient, and within participant coefficient of variation and had a higher value of intraclass correlation coefficient compared with fFOV DWI across either sessions or examinations. CONCLUSIONS: This study demonstrated that rFOV DWI produced more superior-quality DWI images and more repeatable ADC measurements compared with fFOV DWI, thus providing a feasible quantitative imaging tool for investigating thyroid glands in clinical settings. PMID- 25700227 TI - Assessment of Liver Perfusion by IntraVoxel Incoherent Motion (IVIM) Magnetic Resonance-Diffusion-Weighted Imaging: Correlation With Phase-Contrast Portal Venous Flow Measurements. AB - OBJECTIVES: To prospectively verify, in vivo, Le Bihan's model of signal decay in magnetic resonance/diffusion-weighted imaging (intravoxel incoherent motion) in healthy liver parenchyma. METHODS: Informed consent and institutional board approval were obtained. To measure both underfasting and postprandial conditions, apparent, slow, and fast diffusion (D*) coefficients and perfusion fraction of liver parenchyma, 40 healthy volunteers (19 women and 21 men) underwent a 3.0-T magnetic resonance imaging examination, including portal venous flow measurements by a 2-dimensional phase-contrast sequence, and multi-b diffusion-weighted imaging acquired before and 30 minutes after a 600-Kcal meal. Parameters were measured by fitting procedure with regions of interest drawn on the right liver lobe. Paired-sample t test was performed to search for any statistically significant difference between preprandial and postprandial values of each parameter and of portal flow. Pearson correlation coefficients were calculated to evaluate the relationship between portal flow increase and diffusion-weighted imaging parameter changes in postprandial conditions. Interobserver agreement for measurement of the intravoxel incoherent motion parameters was determined, both for preprandial and postprandial values. RESULTS: Mean increase in postprandial portal flow was 98% (P < 0.0009). The t test did not show any statistically significant difference between the preprandial and postprandial values for apparent, slow diffusion coefficients and perfusion fraction (P >= 0.05), whereas a statistically significant postprandial increase (P < 0.01) of D* was detected. Correlation with portal venous flow increase at Pearson test was statistically significant for D* (P = 0.04) and nonsignificant for the other parameters. All the parameters showed wide variability, with a higher percent coefficient of variation for D*. Interobserver agreement was always greater than 0.70. CONCLUSIONS: This study verifies Le Bihan's theory, confirming that in the liver, D* is influenced by perfusional changes related to portal venous flow. PMID- 25700228 TI - Inferior displacement of the lower belly of the lateral pterygoid muscle: a sign of temporomandibular joint lesions. AB - OBJECTIVE: The purposes of this article are to report the imaging finding of inferior displacement of the lower belly of the lateral pterygoid muscle (LPM) in patients with lesions arising from the temporomandibular joint (TMJ) and to propose that this imaging finding is suggestive of the presence of a TMJ lesion. MATERIALS AND METHODS: We reviewed computed tomographic and magnetic resonance images of 9 patients with lesions involving the TMJ. Images were evaluated for identification of an inferiorly displaced lower belly of the LPM. Pathology reports were reviewed to determine the histopathologic diagnosis of the TMJ lesion. RESULTS: Inferior displacement of the lower belly of the LPM was observed in all cases on magnetic resonance images, computed tomographic images, or both. In 2 cases, the diagnosis was calcium pyrophosphate deposition disease. The remaining cases were ganglion cyst, joint effusion due to dermatomyositis, septic arthritis, chondromyxoid fibroma, synovial chondromatosis, pigmented villonodular synovitis, and giant cell tumor of bone. CONCLUSIONS: Inferior displacement of the lower belly of the LPM is a useful radiologic sign to suggest that a lesion arises from the TMJ. PMID- 25700229 TI - Change in portal vein hemodynamics after chemoembolization for hepatocellular carcinoma: evaluation through multilevel dynamic multidetector computed tomography during arterial portography. AB - OBJECTIVE: This study aimed to clarify the effect of embolization with lipiodol on portal vein hemodynamics. METHODS: Time-density curves of the main portal vein on multilevel dynamic multidetector computed tomography during arterial portography were used to analyze peak computed tomography value (PV), time to PV (TPV), arrival time of contrast medium at the main portal vein (ATMPV), slope [(PV - 150) / (TPV - ATMPV)], and slope ratio (slope after embolization / slope before embolization). RESULTS: In 20 patients with hepatoma, ATMPV and TPV were significantly prolonged and the time-density curve slope was significantly less after embolization. The difference in TPV increased (P = 0.02) and the slope ratio decreased with increasing embolized volume rate (P < 0.001). Strong correlation (R = -0.86) was found between the slope ratio and the embolized volume rate. CONCLUSIONS: Time-density curves revealed significant portal vein flow delay after embolization; the degree of which was correlated with the extent of the embolized volume. PMID- 25700230 TI - Glutathione as a prebiotic answer to alpha-peptide based life. AB - The energetics of peptide bond formation is an important factor not only in the design of chemical peptide synthesis, but it also has a role in protein biosynthesis. In this work, quantum chemical calculations at 10 different levels of theory including G3MP2B3 were performed on the energetics of glutathione formation. The strength of the peptide bond is found to be closely related to the acid strength of the to-be N-terminal and the basicity of the to-be C-terminal amino acid. It is shown that the formation of the first peptide activates the amino acid for the next condensation step, manifested in bacterial protein synthesis where the first step is the formation of an N-formylmethionine dipeptide. The possible role of glutathione in prebiotic molecular evolution is also analyzed. The implications of the thermodynamics of peptide bond formation in prebiotic peptide formation as well as in the preference of alpha- instead of beta- or gamma-amino acids are discussed. An empirical correction is proposed for the compensation of the error due to the incapability of continuum solvation models in describing the change of the first solvation shell when a peptide bond is formed from two zwitterions accompanied by the disappearance of one ion pair. PMID- 25700231 TI - High-speed electro-optic modulator integrated with graphene-boron nitride heterostructure and photonic crystal nanocavity. AB - Nanoscale and power-efficient electro-optic (EO) modulators are essential components for optical interconnects that are beginning to replace electrical wiring for intra- and interchip communications.1-4 Silicon-based EO modulators show sufficient figures of merits regarding device footprint, speed, power consumption, and modulation depth.5-11 However, the weak electro-optic effect of silicon still sets a technical bottleneck for these devices, motivating the development of modulators based on new materials. Graphene, a two-dimensional carbon allotrope, has emerged as an alternative active material for optoelectronic applications owing to its exceptional optical and electronic properties.12-14 Here, we demonstrate a high-speed graphene electro-optic modulator based on a graphene-boron nitride (BN) heterostructure integrated with a silicon photonic crystal nanocavity. Strongly enhanced light-matter interaction of graphene in a submicron cavity enables efficient electrical tuning of the cavity reflection. We observe a modulation depth of 3.2 dB and a cutoff frequency of 1.2 GHz. PMID- 25700232 TI - Salternamides A-D from a Halophilic Streptomyces sp. Actinobacterium. AB - Salternamides A-D (1-4), the first secondary metabolites discovered from saltern derived actinomycetes, were isolated from a halophilic Streptomyces strain isolated from a saltern on Shinui Island in the Republic of Korea. The planar structures of the salternamides, which are new members of the manumycin family, were elucidated by a combination of spectroscopic analyses. The absolute configurations of the salternamides were determined by chemical and spectroscopic methods, including the modified Mosher's method, J-based configuration analysis, and circular dichroism spectroscopy. Salternamide A (1), which is the first chlorinated compound in the manumycin family, exhibited potent cytotoxicity against a human colon cancer cell line (HCT116) and a gastric cancer cell line (SNU638) with submicromolar IC50 values. Salternamides A and D were also determined to be weak Na(+)/K(+) ATPase inhibitors. PMID- 25700234 TI - Cobalt-iron (oxy)hydroxide oxygen evolution electrocatalysts: the role of structure and composition on activity, stability, and mechanism. AB - Cobalt oxides and (oxy)hydroxides have been widely studied as electrocatalysts for the oxygen evolution reaction (OER). For related Ni-based materials, the addition of Fe dramatically enhances OER activity. The role of Fe in Co-based materials is not well-documented. We show that the intrinsic OER activity of Co(1 x)Fe(x)(OOH) is ~100-fold higher for x ~ 0.6-0.7 than for x = 0 on a per-metal turnover frequency basis. Fe-free CoOOH absorbs Fe from electrolyte impurities if the electrolyte is not rigorously purified. Fe incorporation and increased activity correlate with an anodic shift in the nominally Co(2+/3+) redox wave, indicating strong electronic interactions between the two elements and likely substitutional doping of Fe for Co. In situ electrical measurements show that Co(1-x)Fe(x)(OOH) is conductive under OER conditions (~0.7-4 mS cm(-1) at ~300 mV overpotential), but that FeOOH is an insulator with measurable conductivity (2.2 * 10(-2) mS cm(-1)) only at high overpotentials >400 mV. The apparent OER activity of FeOOH is thus limited by low conductivity. Microbalance measurements show that films with x >= 0.54 (i.e., Fe-rich) dissolve in 1 M KOH electrolyte under OER conditions. For x < 0.54, the films appear chemically stable, but the OER activity decreases by 16-62% over 2 h, likely due to conversion into denser, oxide-like phases. We thus hypothesize that Fe is the most-active site in the catalyst, while CoOOH primarily provides a conductive, high-surface area, chemically stabilizing host. These results are important as Fe-containing Co- and Ni-(oxy)hydroxides are the fastest OER catalysts known. PMID- 25700233 TI - Collagen density and alignment in responsive and resistant trastuzumab-treated breast cancer xenografts. AB - Tumor collagen characteristics influence tumor malignancy, invasion, and metastasis. This study investigates the effects of trastuzumab (Tz) on the collagen of Tz-responsive (BT474) and Tz-resistant (HR6) breast cancer xenografts. Collagen content was assessed by in vivo second harmonic generation (SHG) imaging and histological trichrome staining of tumor sections. Collagen SHG imaging of control BT474 and HR6 tumors demonstrated increased collagen density after 14 days of treatment (p < 0.05). Trichrome staining revealed decreased collagen in Tz-treated BT474 and HR6 tumors at 2, 5, and 14 days of treatment, suggesting that Tz affects the tumor microenvironment independent of epithelial cell response. Additionally, collagen alignment analysis revealed significantly less aligned collagen in the Tz-treated BT474 tumors at day 14 compared with control BT474 tumors. There was no correlation between SHG endpoints (collagen density and alignment) and trichrome staining (p > 0.05), consistent with the physically distinctive nature of these measurements. There was also no correlation between tumor size and collagen endpoints (p > 0.05). These results identify changes within the collagen compartment of the tumor microenvironment following Tz treatment, which are independent from the tumor cell response to Tz, and demonstrate that intravital collagen SHG imaging is capable of measuring dynamic changes in tumor microenvironment following treatment that complements trichrome staining. PMID- 25700235 TI - The effects of visual context and individual differences on perception and evaluation of modern art and graffiti art. AB - Traditionally, artworks are seen as autonomous objects that stand (or should stand) on their own. However, at least since the emergence of Conceptual Art in the 1920s and Pop Art in the 1960s, art lacks any distinctive perceptual features that define it as such. Art, therefore, cannot be defined without reference to its context. Some studies have shown that context affects the evaluation of artworks, and that specific contexts (street for graffiti art, museum for modern art) elicit specific effects (Gartus & Leder, 2014). However, it is yet unclear how context changes perception and appreciation processes. In our study we measured eye-movements while participants (64 psychology undergraduates, 48% women) perceived and evaluated beauty, interest, emotional valence, as well as perceived style for modern art and graffiti art embedded into either museum or street contexts. For modern art, beauty and interest ratings were higher in a museum than in a street context, but context made no difference for the ratings of graffiti art. Importantly, we also found an interaction of context and individual interest in graffiti for beauty and interest ratings, as well as for number of fixations. Analyses of eye-movements also revealed that viewing times were in general significantly longer in museum than in street contexts. We conclude that context can have an important influence on aesthetic appreciation. However, some effects depend also on the style of the artworks and the individual art interests of the viewers. PMID- 25700236 TI - Expanding urban and industrial development in tropical seascapes necessitates green engineering and spatial planning thinking. PMID- 25700237 TI - Multiple failed intubation attempts are associated with decreased success rates on the first rescue intubation in the emergency department: a retrospective analysis of multicentre observational data. AB - BACKGROUND: Although the international guidelines emphasize early and systematic use of rescue intubation techniques, there is little evidence to support this notion. We aimed to test the hypothesis that preceding multiple failed intubation attempts are associated with a decreased success rate on the first rescue intubation in emergency departments (EDs). METHODS: We analysed data from two multicentre prospective registries designed to characterize current ED airway management in Japan between April 2010 and June 2013. All patients who underwent a rescue intubation after a failed attempt or a series of failed attempts were included for the analysis. Multiple failed intubation attempts were defined as >=2 consecutive failed intubation attempts before a rescue intubation. Primary outcome measure was success rate on the first rescue intubation attempt. RESULTS: Of 6,273 consecutive patients, 1,151 underwent a rescue intubation. The success rate on the first rescue intubation attempt declined as the number of preceding failed intubation attempts increased (81% [95% CI, 79%-84%] after one failed attempt; 71% [95% CI, 66%-76%] after two failed attempts; 67% [95% CI, 55%-78%] after three or more failed attempts; P(trend) <0.001). In the multivariable analysis adjusting for age, sex, principal indication, change in methods, devices, and intubator specialty, and clustering of patients within EDs, success rate on the first rescue intubation after two failed attempts was significantly lower (OR, 0.56; 95% CI, 0.41-0.77) compared to that after one failed attempt. Similarly, success rate on the first rescue intubation attempt after three or more failed attempts was significantly lower (OR, 0.49; 95% CI, 0.25-0.94) compared to that after one failed attempt. CONCLUSION: Preceding multiple failed intubation attempts was independently associated with a decreased success rate on the first rescue intubation in the ED. PMID- 25700238 TI - Comprehensive study of back and leg pain improvements after adult spinal deformity surgery: analysis of 421 patients with 2-year follow-up and of the impact of the surgery on treatment satisfaction. AB - OBJECT Back and leg pain are the primary outcomes of adult spinal deformity (ASD) and predict patients' seeking of surgical management. The authors sought to characterize changes in back and leg pain after operative or nonoperative management of ASD. Outcomes were assessed according to pain severity, type of surgical procedure, Scoliosis Research Society (SRS)-Schwab spine deformity class, and patient satisfaction. METHODS This study retrospectively reviewed data in a prospective multicenter database of ASD patients. Inclusion criteria were the following: age > 18 years and presence of spinal deformity as defined by a scoliosis Cobb angle >= 20 degrees , sagittal vertical axis length >= 5 cm, pelvic tilt angle >= 25 degrees , or thoracic kyphosis angle >= 60 degrees . Patients were grouped into nonoperated and operated subcohorts and by the type of surgical procedure, spine SRS-Schwab deformity class, preoperative pain severity, and patient satisfaction. Numerical rating scale (NRS) scores of back and leg pain, Oswestry Disability Index (ODI) scores, physical component summary (PCS) scores of the 36-Item Short Form Health Survey, minimum clinically important differences (MCIDs), and substantial clinical benefits (SCBs) were assessed. RESULTS Patients in whom ASD had been operatively managed were 6 times more likely to have an improvement in back pain and 3 times more likely to have an improvement in leg pain than patients in whom ASD had been nonoperatively managed. Patients whose ASD had been managed nonoperatively were more likely to have their back or leg pain remain the same or worsen. The incidence of postoperative leg pain was 37.0% at 6 weeks postoperatively and 33.3% at the 2 year follow-up (FU). At the 2-year FU, among patients with any preoperative back or leg pain, 24.3% and 37.8% were free of back and leg pain, respectively, and among patients with severe (NRS scores of 7-10) preoperative back or leg pain, 21.0% and 32.8% were free of back and leg pain, respectively. Decompression resulted in more patients having an improvement in leg pain and their pain scores reaching MCID. Although osteotomies improved back pain, they were associated with a higher incidence of leg pain. Patients whose spine had an SRS-Schwab coronal curve Type N deformity (sagittal malalignment only) were least likely to report improvements in back pain. Patients with a Type L deformity were most likely to report improved back or leg pain and to have reductions in pain severity scores reaching MCID and SCB. Patients with a Type D deformity were least likely to report improved leg pain and were more likely to experience a worsening of leg pain. Preoperative pain severity affected pain improvement over 2 years because patients who had higher preoperative pain severity experienced larger improvements, and their changes in pain severity were more likely to reach MCID/SCB than for those reporting lower preoperative pain. Reductions in back pain contributed to improvements in ODI and PCS scores and to patient satisfaction more than reductions in leg pain did. CONCLUSIONS The authors' results provide a valuable reference for counseling patients preoperatively about what improvements or worsening in back or leg pain they may experience after surgical intervention for ASD. PMID- 25700239 TI - Giant cell tumors of the spine: has denosumab changed the treatment paradigm? AB - OBJECT Giant cell tumors (GCTs) of the spine are rare and complex to treat. They have a propensity for local recurrence and the potential to metastasize. Treatment is currently surgical and presents unique challenges due to the proximity of neural structures and the need for reconstruction. Denosumab has been shown in clinical trials to be an effective treatment for GCT, but has not yet been studied specifically in GCT of the spine or as a surgical adjunct. To the authors' knowledge this is the first such reported series. METHODS A multicenter, prospective series of 5 patients with GCT of the spine treated with denosumab were included. Patient demographic data, oncological history, neurological status, tumor staging, treatment details and adverse events, surgical procedure, complications, radiological and histological responses, and patient outcome were analyzed. RESULTS All patients were women, with a mean age of 38 years, and presented with pain; 2 patients had additional neurological signs and symptoms. The mean duration of symptoms was 62 weeks. No patient had a prior tumor or metastatic disease at presentation. All patients had Enneking Stage III tumors and were treated with monthly cycles of 120 mg of denosumab, with initial additional loading doses on Days 8 and 15. Patients were given daily supplements of calcium (500 mg) and vitamin D (400 IU). There were no denosumab related adverse events. All patients had a radiological response to denosumab. One patient failed to have a histological response to denosumab, with > 90% of tumor cells found to be viable on histological investigation. CONCLUSIONS This study reports the early experience of using denosumab in the treatment of spinal GCT. The results demonstrate a clinically beneficial radiological response and an impressive histological response in most but not all patients. Further experience with denosumab and longer patient follow-up is required. Denosumab has the potential to change the treatment paradigm for spinal GCT. PMID- 25700240 TI - Predisposing factors for dural tear in patients undergoing lumbar spine surgery. AB - OBJECT The purpose of this prospective cohort study was to identify risk factors for incidental durotomies in lumbar spine surgery. The authors hypothesized that the incidence of durotomy would be higher in cases involving multiple operations. METHODS The authors prospectively evaluated 523 patients who underwent lumbar and thoracolumbar spine surgery. They compared data on patients in whom a dural tear occurred and those in whom a dural tear did not occur. Data from patients in whom a dural tear occurred were compared with data from patients who did not experience durotomy. The data included basic demographic information, intraoperative data, and clinical information from a medical record review. RESULTS One hundred thirty-one patients underwent discectomy and 392 patients underwent laminectomy. Among the 131 patients who underwent discectomy 6 patients had a dural tear. Among the 392 patients who underwent discectomy 49 patients had dural tear. Patients with incidental durotomy were older (mean 65 +/- 13 vs 60 +/ 14 years of age; p = 0.044, t-test), and had longer surgery (146 +/- 59 vs 110 +/- 54 minutes; p = 0.025, t-test), compared with the patients without dural tear. The incidence of dural tear was more common in patients with a history of previous spine surgery (p < 0.001). CONCLUSIONS In patients who underwent lumbar and thoracolumbar spine surgery for degenerative problems, previous surgery and older age were found to be predisposing factors for dural tear. PMID- 25700241 TI - Atlantoaxial instability and Chiari malformation. PMID- 25700242 TI - Motion characteristics and related factors of Modic changes in the lumbar spine. AB - OBJECT Most studies of Modic changes (MCs) have focused on investigating the relationship between MCs and lowback pain, whereas the kinematic characteristics and degenerative disc disease associated with MCs are not well understood. To the authors' knowledge, no previous study has reported on the kinematics of MCs. The purpose of this study was to elucidate the relationship of MCs to segmental motion and degenerative disc disease. METHODS Four hundred fifty symptomatic patients underwent weight-bearing lumbar kinematic MRI in the neutral, flexion, and extension positions. Segmental displacement and intervertebral angles were measured in 3 positions using computer analysis software. Modic changes, disc degeneration, disc bulging, spondylolisthesis, angular motion, and translational motion were recorded, and the relationship of MCs to these factors was analyzed using a logistic regression model. To control the influence of disc degeneration on segmental motion, angular and translational motion were analyzed according to mild and severe disc degeneration stages. The motion characteristics and disc degeneration among types of MCs were also evaluated. RESULTS Multivariate analysis revealed that age, disc degeneration, angular motion, and translational motion were factors significantly related to MCs. In the severe disc degeneration stage, a significant decrease of angular motion and significant increase of translational motion were found in segments with MCs, indicating that a disorder of the endplate had an additional effect on segmental motion. Disc degeneration increased and angular motion decreased significantly and gradually as the type of MC increased. Translational motion was significantly increased with Type 2 MCs. CONCLUSIONS Age, disc degeneration, angular motion, and translational motion were significantly linked to MCs in the lumbar spine. The translational motion of lumbar segments increased with Type 2 MCs, whereas angular motion decreased as the type of MC increased, indicating that Type 2 MCs may have translational instability likely due to degenerative changes. A disorder of the endplates could play an important role in spinal instability. PMID- 25700243 TI - Intraoperative and perioperative complications in minimally invasive transforaminal lumbar interbody fusion: a review of 513 patients. AB - OBJECT Transforaminal lumbar interbody fusion (TLIF) has become one of the preferred procedures for circumferential fusion in the lumbar spine. Over the last decade, advances in surgical techniques have enabled surgeons to perform the TLIF procedure through a minimally invasive approach (MI-TLIF). There are a few studies reported in the medical literature in which perioperative complication rates of MI-TLIF were evaluated; here, the authors present the largest cohort series to date. They analyzed intraoperative and perioperative complications in 513 consecutive MI-TLIF-treated patients with lumbar degenerative disc disease. METHODS The authors performed a retrospective review of prospectively collected data on 513 consecutive patients treated over a 10-year period for lumbar degenerative disc disease using MI-TLIF. All patients undergoing either a first time or revision 1- or 2-level MI-TLIF procedure were included in the study. Demographic, intraoperative, and perioperative data were collected and analyzed using bivariate analyses (Student t-test, analysis of variance, odds ratio, chi square test) and multivariate analyses (logistic regression). RESULTS A total of 513 patients underwent an MI-TLIF procedure, and the perioperative complication rate was 15.6%. The incidence of durotomy was 5.1%, and the medical and surgical infection rates were 1.4% and 0.2%, respectively. A statistically significant increase in the infection rate was seen in revision MI-TLIF cases, and the same was found for the perioperative complication rate in multilevel MI-TLIF cases. Instrumentation failure occurred in 2.3% of the cases. After analysis, no statistically significant difference was seen in the rates of durotomy during revision and multilevel surgeries. There was no significant difference between the complication rates when stratified according to presenting diagnosis. CONCLUSIONS To the authors' knowledge, this is the largest study of perioperative complications in MI-TLIF in the literature. A total of 513 patients underwent MI TLIF (perioperative complication rate 15.6%). The most common complication was a durotomy (5.1%), and there was only 1 surgical wound infection (0.2%). There were significantly more perioperative infections in revision MI-TLIF cases and more perioperative complications in multilevel MI-TLIF cases. The results of this study suggest that MI-TLIF has a similar or better perioperative complication profile than those documented in the literature for open-TLIF treatment of degenerative lumbar spine disease. PMID- 25700244 TI - Comparative measure of the electronic influence of highly substituted aryl isocyanides. AB - To assess the relative electronic influence of highly substituted aryl isocyanides on transition metal centers, a series of C4v-symmetric Cr(CNR)(CO)5 complexes featuring various alkyl, aryl, and m-terphenyl substituents have been prepared. A correlation between carbonyl-ligand (13)C{(1)H} NMR chemical shift (deltaCO) and calculated Cotton-Kraihanzel (C-K) force constant (kCO) is presented for these complexes to determine the relative changes in isocyanide sigma-donor/pi-acid ratio as a function of substituent identity and pattern. For nonfluorinated aryl isocyanides possessing alkyl or aryl substitution, minimal variation in effective sigma-donor/pi-acid ratio is observed over the series. In addition, aryl isocyanides featuring strongly electron-releasing substituents display an electronic influence that nearly matches that of nonfluorinated alkyl isocyanides. Lower sigma-donor/pi-acid ratios are displayed by polyfluorinated aryl isocyanide ligands. However, the degree of this attenuation relative to nonfluorinated aryl isocyanides is not substantial and significantly higher sigma donor/pi-acid ratios than CO are observed in all cases. Substituent patterns for polyfluorinated aryl isocyanides are identified that give rise to low relative sigma-donor/pi-acid ratios but offer synthetic convenience for coordination chemistry applications. In order to expand the range of available substitution patterns for comparison, the syntheses of the new m-terphenyl isocyanides CNAr(Tripp2), CNp-MeAr(Mes2), CNp-MeAr(DArF2), and CNp-FAr(DArF2) are also reported (Ar(Tripp2) = 2,6-(2,4,6-(i-Pr)3C6H2)2C6H3); p-MeAr(Mes2) = 2,6-(2,4,6 Me3C6H2)2-4-Me-C6H2); p-MeAr(DArF2) = 2,6-(3,5-(CF3)2C6H3)2-4-Me-C6H2); p FAr(DArF2) = 2,6-(3,5-(CF3)2C6H3)2-4-F-C6H2). PMID- 25700245 TI - Nanoparticle assembly following Langmuir-Hinshelwood kinetics on a Langmuir film and chain networks captured in LB films. AB - The Langmuir-Blodgett (LB) technique is an elegant protocol for the steered assembly of metal nanoparticles, the deposition pressure serving as a convenient parameter to tune the assembly. Adsorption of nanoparticles from the subphase to the air-water interface can provide further control of the process. Citrate stabilized gold nanoparticles in the aqueous subphase are shown to assemble into extended 2-dimensional chain networks following adsorption on a cationic amphiphile Langmuir film at the air-water interface. Kinetic investigations show that the process can be visualized as a surface-catalyzed reaction and explained in terms of the Langmuir-Hinshelwood mechanism. The LB deposition proves to be a unique route to capture the reaction product together with the amphiphile film. The deposition pressure is used to tune the density of nanoparticle chain networks in the LB film, and their optical extinction spectrum. The unusual blue shift of the extinction observed with increasing deposition pressure is attributed to the impact of the amphiphile monolayer environment. The extent of formation of the chain network is analyzed in terms of the pathways in the corresponding graph representation, and shown to scale with the deposition pressure. The current investigation highlights the use of a charged monolayer as a heterogeneous catalyst surface, provides fundamental insight into the kinetics of nanoparticle assembly at interfaces, and demonstrates the utility of the LB technique in tuning the formation of 2-dimensional nanoparticle chain networks. PMID- 25700246 TI - PD-1 expression defines two distinct T-cell sub-populations in follicular lymphoma that differentially impact patient survival. AB - To determine the biological and clinical relevance of programmed death 1 (PD-1) in follicular lymphoma (FL), we characterized PD-1(+) T-cell subsets and assessed their biological function as well as potential clinical impact. We found that PD 1 is expressed on intratumoral CD4(+) T cells with both bright and dim intensity, representing two different sub-populations of cells. By immunohistochemistry, we found that CD4(+)PD-1(high) T cells predominantly reside in the lymph node follicles, while PD-1(low) T cells are mainly located in an interfollicular pattern. Intratumoral CD4(+)PD-1(high) T cells have a TFH cell phenotype, express CXCR5, secrete IL-21 and are BCL-6 positive with no TIM-3 expression. In contrast, CD4(+)PD-1(low) T cells have an exhausted phenotype, express TIM-3 and do not express BCL-6 and CXCR5. Functionally, CD4(+)PD-1(high) T cells actively supported B-cell growth, while CD4(+)PD-1(low) T cells displayed a reduced cytokine production and cell-signal transduction. Clinically, we observed that the numbers of CD4(+) or CD8(+)PD-1(low) T cells significantly correlate with a reduced overall survival in FL patients (P=0.007 and 0.04 respectively; n=32). In contrast, the number of CD4(+)PD-1(high) T cells was not associated with patient outcome. Taken together, these results indicated that PD-1 expression defines two sub-populations with distinct functions that differentially impact patient outcome in FL. PMID- 25700247 TI - Operating principles of in-plane silicon nanowires at simple step-edges. AB - Growing silicon nanowires (SiNWs) into precise locations is a key enabling technology for SiNW-based device applications. This can be achieved via in-plane growth of SiNWs along a simple step-edge, where metal catalyst droplets absorb an amorphous Si matrix to produce c-SiNWs. However, a comprehensive understanding of this phenomenon is still lacking. We here establish an analytical model to address the driving force that dictates the growth dynamics under various droplet step contact configurations, and to identify the key control parameters for effective guided growth. These new principles were verified against a series of experimental observations and proved to be powerful in designing a stable guided growth configuration. Furthermore, we propose and demonstrate a unique ability to achieve in situ capturing, guiding and release of the in-plane SiNWs along curved step-edges. We suggest that such a new understanding and results provide a fundamental basis and a practical guide for positioning and integrating self assembled nanowires in a wide variety of material systems. PMID- 25700248 TI - Molecular dissection of itch. AB - There have been many exciting recent advances in our understanding of the molecular and cellular basis of itch. These discoveries cover diverse aspects of itch sensation, from the identification of new receptors to the characterization of spinal cord itch circuits. A common thread of these studies is that they demonstrate that itch sensory signals are segregated from input for other somatosensory modalities, such as pain, touch, and thermosensation. This specificity is achieved by the expression of dedicated receptors and transmitters in a select population of sensory neurons which detect pruritogens. Further, recent studies show that itch specificity is maintained in a spinal cord circuit by the utilization of specific neurotransmitters and cognate receptors to convey input along a distinct cellular pathway. PMID- 25700249 TI - Brominated flame retardants and seafood safety: a review. AB - Brominated flame retardants (BFRs), frequently applied to industrial and household products to make them less flammable, are highly persistent in the environment and cause multi-organ toxicity in human and wildlife. Based on the review of BFRs presence in seafood published from 2004 to 2014, it is clear that such pollutants are not ideally controlled as the surveys are too restricted, legislation inexistent for some classes, the analytical methodologies diversified, and several factors as food processing and eating habits are generally overlooked. Indeed, while a seafood rich diet presents plenty of nutritional benefits, it can also represent a potential source of these environmental contaminants. Since recent studies have shown that dietary intake constitutes a main route of human exposure to BFRs, it is of major importance to review and enhance these features, since seafood constitutes a chief pathway for human exposure and biomagnification of priority environmental contaminants. In particular, more objective studies focused on the variability factors behind contamination levels, and subsequent human exposure, are necessary to support the necessity for more restricted legislation worldwide. PMID- 25700250 TI - [Editorial]. PMID- 25700251 TI - [Physiological basis of the microcirculation: vascular adaptation]. AB - The microcirculation is the functional "business end" of the cardiovascular system. In vessels with diameters below about 300 um processes including the regulation of perfusion, exchange processes and relevant components of the immune system are localised. A large number of individual mechanisms are involved, including micro-rheology, the endothelial surface layer, vascular permeability, endothelial function, regulation of smooth muscle tone, leukocyte endothelial interaction, vascular adaptation and angiogenesis. The present article focusses mainly on the role of vascular adaptation. Much more than in large vessels, the microcirculation is characterised by constant adaptation to haemodynamic and metabolic signals. In reaction to changes in parenchymal demand, changes of the diameter of existing vessels (by changes in tone or by structural remodelling) as well as generation of new vessels (angiogenesis) or the pruning of vessels are elicited. These mechanisms are part of the so-called "angioadaptation" which is of great clinical relevance for the pathophysiological consequences of hypertension and age-related macular degeneration. PMID- 25700252 TI - [Ocular perfusion pressure and its relevance for glaucoma]. AB - Ocular perfusion pressure is defined as the difference between arterial and venous pressure in ocular vessels. In practice, mean arterial pressure is used to substitute for arterial pressure in ocular vessels while intraocular pressure gives an estimate for ocular venous pressure. This results in a value that is easy to calculate and which is of importance since several studies have shown that it is correlated to the prevalence, incidence and progression of primary open angle glaucoma. Today, ocular perfusion pressure is used to estimate individual risks. Since no target value for ocular perfusion pressure can be defined, direct therapeutic intervention is difficult. Still, it has to be kept in mind that lowering intraocular pressure automatically leads to an increase in ocular perfusion pressure. The present article also points out problems and limitations in the concept of ocular perfusion pressure and suggests possible solutions for these problems in the future. PMID- 25700253 TI - [Ocular blood flow regulation in glaucoma - examination with the ocular pressure flow analyzer (OPFA)]. AB - BACKGROUND: The results of studies of ocular blood flow (BF) regulation of patients with primary open-angle glaucoma (POAG), normal-tension glaucoma (NTG) and ocular hypertension (OH) are presented. METHODS AND PATIENTS: Examinations were carried out with the "OPFA", a newly developed ocular pressure flow analyzer (producer: tpm Luneburg) on 92 patients with newly diagnosed glaucomas, among whom 48 patients had POAG, 22 NTG and 22 OH, and compared with age-matched groups of healthy subjects. The OPFA uses pneumatic coupling through special scleral suction cups to record ocular pulses with highly sensitive transducers and a suction pump for simultaneously increasing intraocular pressure (IOP). Following local drop anaesthesia on both eyes, IOP is artificially raised to suprasystolic values. While continuously lowering IOP, the ocular pulse is then recorded with increasing ocular perfusion pressure. We obtain the relative ocular pulse blood volume by correlating the ocular pulse amplitudes with a calibration volume of 1 ul. This enables us to collect reproducible data on intra- and inter-individual pulse blood volume (PVoc). The ocular perfusion pressure pulse blood volume curve characterizes the respective individual ocular circulation as well as systolic and diastolic ocular perfusion pressures. RESULTS: In healthy subjects, the ocular pulse blood volume remains stable over a certain range of ocular perfusion pressure (ppoc) changes. After exceeding a critical point (CP), the ocular pulse blood volume drops. We refer to the difference between the CP and IOP as the autoregulatory capacity (AC). In patients with POAG and in patients with NTG, the AC was reduced significantly compared with the groups of healthy subjects. The mean AC of patients with OH remained within the normal range. The ROC curves showed at an optimal cut-off value for POAG a sensitivity of 75.0 % and a specificity of 97.9 %, for NTG a sensitivity of 77.3 % and a specificity of 100 %. In patients with POAG and OH, the ocular arterial pressures were elevated. In patients with NTG they remained unchanged compared with the healthy subjects. The ocular perfusion pressures did not change in POAG as well as in NTG and OH. CONCLUSIONS: In patients with POAG and in patients with NTG the ocular BF regulation was impaired and detected by the OPFA device with a high level of reliability. Ocular arterial blood pressures were increased as a result of vascular regulation to keep up the ocular perfusion pressure and to maintain ocular perfusion. PMID- 25700254 TI - [Role of ocular pulse amplitude in glaucoma]. AB - The ocular pulse amplitude is defined as the difference between diastolic and systolic intraocular pressure. The ocular pulse is generated by the pulsatile ocular blood flow in the choroid. It is dependent on the dynamics of the cardiovascular system, the rigidity of the ocular vessels on one side and the biomechanical properties of the eye on the other side. In addition the influence of outflow facility of the aqueous humor, the level of the intraocular pressure itself and last but not least the rigidity of the sclera on the ocular pulse amplitude is until now not clear. Dynamic contour tonometry (Pascal(r)) does not only measure intraocular pressure almost independent of corneal thickness and curvature but also allows easy and fast measurement of ocular pulse amplitude on the slit lamp. The ocular pulse amplitude in healthy subjects is between 1.2 and 4 mmHg. If the ocular pulse amplitude is larger than 1.2 mmHg spontaneous pulsations of the central retinal vein are visible on fundoscopy. In patients with ocular hypertension the ocular pulse amplitude is larger than in normal subjects but this is mainly due to higher IOP levels. In patients with manifest open-angle glaucoma the ocular pulse amplitude stays initially within the normal range. In more advanced stages of the disease and especially in patients with ocular perfusion pressure dependent optic neuropathy the ocular pulse amplitude is gradually reduced. Due to the various factors influencing ocular pulse amplitude a direct correlation between reduced ocular pulse amplitude and reduced ocular perfusion pressure has not been established as yet. New approaches investigating the variations of the ocular pressure Fourier spectral analysis are promising, especially when simultaneous analysis of the arterial blood pressure is performed. These techniques may allow a fast and easy discrimination between healthy and glaucomatous patients in the near future. If ocular pulse amplitude exhibits a massive inter-ocular asymmetry in the presence of symmetrical ocular findings of extraocular vascular pathologies (i.e. carotid stenosis) are the most likely cause and therefore should be excluded. PMID- 25700255 TI - [Ambulatory 24-h blood pressure measurement in patients with glaucoma]. AB - The arterial blood pressure is an important determinant for the development and progression of glaucoma. Some relevant information can be obtained only by ambulatory 24-h blood pressure measurement (ABPM). White-coat hypertension can be excluded by ABDM and the variability of blood pressure during 24 hours can be assessed. 24-h mean blood pressure should be < 130/80 mmHg. In contrast, diastolic blood pressure values below 60 mmHg during the night have been identified as a progression factor in glaucoma, as well as reductions of night time systolic blood pressure of less than 10 % (non-dipper) and of more than 20 % (extreme dipper). The significance of the 24-h blood pressure profile for the cooperation of ophthalmology and internal medicine is discussed. PMID- 25700256 TI - [Orbital impalement by wooden foreign bodies - an interdisciplinary challenge]. PMID- 25700257 TI - [Dietary supplements in age-related macular degeneration. Current observations of the German Ophthalmological Society, the German Retina Society and the Professional Association of German Ophthalmologists (as of October 2014)]. PMID- 25700258 TI - [Statement of the German Ophthalmological Society, the German Retina Society and the Professional Association of German Ophthalmologists: The anti-VEGF therapy in neovascular age-related macular degeneration: Therapeutic Strategies (November 2014)]. PMID- 25700259 TI - [From visual field to optic pathway lesion]. PMID- 25700260 TI - Constitutive modeling of human saphenous veins at overloading pressures. AB - In the present study, inflation tests with free axial extension of 15 human vena saphena magna were conducted ex vivo to obtain data suitable for multi-axial constitutive modeling at overloading conditions (pressures up to approximately 15kPa). Subsequently the data were fitted with a hyperelastic, nonlinear and anisotropic constitutive model based on the theory of the closed thick-walled tube. It was observed that initial highly deformable behavior (up to approximately 2.5kPa) in the pressure-circumferential stretch response is followed by progressive large strain stiffening. Contrary to that, samples were much stiffer in longitudinal direction, where the observed stretches were in the range 0.98-1.03 during the entire pressurization in most cases. The effect of possible residual stress was evaluated in a simulation of the intramural stress distribution with the opening angle prescribed to 0 degrees , 10 degrees , 20 degrees , 30 degrees , 40 degrees , and 50 degrees . The result suggests that the optimal opening angle making the stress distribution through the wall thickness uniform is about 40 degrees . The material parameters presented here are suitable for use in mechanobiological simulations describing the adaptation of the autologous vein wall after bypass surgery. PMID- 25700261 TI - Shear load transfer in high and low stress tendons. AB - BACKGROUND: Tendon is an integral part of joint movement and stability, as it functions to transmit load from muscle to bone. It has an anisotropic, fibrous hierarchical structure that is generally loaded in the direction of its fibers/fascicles. Internal load distributions are altered when joint motion rotates an insertion site or when local damage disrupts fibers/fascicles, potentially causing inter-fiber (or inter-fascicular) shear. Tendons with different microstructures (helical versus linear) may redistribute loads differently. METHOD OF APPROACH: This study explored how shear redistributes axial loads in rat tail tendon (low stress tendons with linear microstructure) and porcine flexor tendon (high stress with helical microstructure) by creating lacerations on opposite sides of the tendon, ranging from about 20% to 60% of the tendon width, to create various magnitudes of shear. Differences in fascicular orientation were quantified using polarized light microscopy. RESULTS AND CONCLUSIONS: Unexpectedly, both tendon types maintained about 20% of pre laceration stress values after overlapping cuts of 60% of tendon width (no intact fibers end to end) suggesting that shear stress transfer can contribute more to overall tendon strength and stiffness than previously reported. All structural parameters for both tendon types decreased linearly with increasing laceration depth. The tail tendon had a more rapid decline in post-laceration elastic stress and modulus parameters as well as a more linear and less tightly packed fascicular structure, suggesting that positional tendons may be less well suited to redistribute loads via a shear mechanism. PMID- 25700262 TI - Genetic diversity of the KIR/HLA system and susceptibility to hepatitis C virus related diseases. AB - BACKGROUND: The variability in the association of host innate immune response to Hepatitis C virus (HCV) infection requires ruling out the possible role of host KIR and HLA genotypes in HCV-related disorders: therefore, we therefore explored the relationships between KIR/HLA genotypes and chronic HCV infection (CHC) as they relate to the risk of HCV-related hepatocarcinoma (HCC) or lymphoproliferative disease progression. METHODS AND FINDINGS: We analyzed data from 396 HCV-positive patients with CHC (n = 125), HCC (118), and lymphoproliferative diseases (153), and 501 HCV-negative patients. All were HIV and HBV negative. KIR-SSO was used to determine the KIR typing. KIR2DL5 and KIR2DS4 variants were performed using PCR and GeneScan analysis. HLA/class-I genotyping was performed using PCR-sequence-based typing. The interaction between the KIR gene and ligand HLA molecules was investigated. Differences in frequencies were estimated using Fisher's exact test, and Cochran-Armitage trend test. The non-random association of KIR alleles was estimated using the linkage disequilibrium test. We found an association of KIR2DS2/KIR2DL2 genes, with the HCV-related lymphoproliferative disorders. Furthermore, individuals with a HLA Bw6 KIR3DL1+ combination of genes showed higher risk of developing lymphoma than cryoglobulinemia. KIR2DS3 gene was found to be the principal gene associated with chronic HCV infection, while a reduction of HLA-Bw4 + KIR3DS1+ was associated with an increased risk of developing HCC. CONCLUSIONS: Our data highlight a role of the innate-system in developing HCV-related disorders and specifically KIR2DS3 and KIR2D genes demonstrated an ability to direct HCV disease progression, and mainly towards lymphoproliferative disorders. Moreover the determination of KIR3D/HLA combination of genes direct the HCV progression towards a lymphoma rather than an hepatic disease. In this contest IFN-alpha therapy, a standard therapy for HCV-infection and lymphoproliferative diseases, known to be able to transiently enhance the cytotoxicity of NK-cells support the role of NK cells to counterstain HCV-related and lymphoproliferative diseases. PMID- 25700263 TI - The nucleocapsid protein of human coronavirus NL63. AB - Human coronavirus (HCoV) NL63 was first described in 2004 and is associated with respiratory tract disease of varying severity. At the genetic and structural level, HCoV-NL63 is similar to other members of the Coronavirinae subfamily, especially human coronavirus 229E (HCoV-229E). Detailed analysis, however, reveals several unique features of the pathogen. The coronaviral nucleocapsid protein is abundantly present in infected cells. It is a multi-domain, multi functional protein important for viral replication and a number of cellular processes. The aim of the present study was to characterize the HCoV-NL63 nucleocapsid protein. Biochemical analyses revealed that the protein shares characteristics with homologous proteins encoded in other coronaviral genomes, with the N-terminal domain responsible for nucleic acid binding and the C terminal domain involved in protein oligomerization. Surprisingly, analysis of the subcellular localization of the N protein of HCoV-NL63 revealed that, differently than homologous proteins from other coronaviral species except for SARS-CoV, it is not present in the nucleus of infected or transfected cells. Furthermore, no significant alteration in cell cycle progression in cells expressing the protein was observed. This is in stark contrast with results obtained for other coronaviruses, except for the SARS-CoV. PMID- 25700264 TI - Predominant Campylobacter jejuni sequence types persist in Finnish chicken production. AB - Consumption and handling of chicken meat are well-known risk factors for acquiring campylobacteriosis. This study aimed to describe the Campylobacter jejuni population in Finnish chickens and to investigate the distribution of C. jejuni genotypes on Finnish chicken farms over a period of several years. We included 89.8% of the total C. jejuni population recovered in Finnish poultry during 2004, 2006, 2007, 2008, and 2012 and used multilocus sequence typing (MLST) and pulsed-field gel electrophoresis (PFGE) to characterize the 380 isolates. The typing data was combined with isolate information on collection time and farm of origin. The C. jejuni prevalence in chicken slaughter batches was low (mean 3.0%, CI95% [1.8%, 4.2%]), and approximately a quarter of Finnish chicken farms delivered at least one positive chicken batch yearly. In general, the C. jejuni population was diverse as represented by a total of 63 sequence types (ST), but certain predominant MLST lineages were identified. ST-45 clonal complex (CC) accounted for 53% of the isolates while ST-21 CC and ST-677 CC covered 11% and 9% of the isolates, respectively. Less than half of the Campylobacter positive farms (40.3%) delivered C. jejuni-contaminated batches in multiple years, but the genotypes (ST and PFGE types) generally varied from year to year. Therefore, no evidence for a persistent C. jejuni source for the colonization of Finnish chickens emerged. Finnish chicken farms are infrequently contaminated with C. jejuni compared to other European Union (EU) countries, making Finland a valuable model for further epidemiological studies of the C. jejuni in poultry flocks. PMID- 25700265 TI - Epidemiology and molecular characterization of Cryptosporidium spp. in humans, wild primates, and domesticated animals in the Greater Gombe Ecosystem, Tanzania. AB - Cryptosporidium is an important zoonotic parasite globally. Few studies have examined the ecology and epidemiology of this pathogen in rural tropical systems characterized by high rates of overlap among humans, domesticated animals, and wildlife. We investigated risk factors for Cryptosporidium infection and assessed cross-species transmission potential among people, non-human primates, and domestic animals in the Gombe Ecosystem, Kigoma District, Tanzania. A cross sectional survey was designed to determine the occurrence and risk factors for Cryptosporidium infection in humans, domestic animals and wildlife living in and around Gombe National Park. Diagnostic PCR revealed Cryptosporidium infection rates of 4.3% in humans, 16.0% in non-human primates, and 9.6% in livestock. Local streams sampled were negative. DNA sequencing uncovered a complex epidemiology for Cryptosporidium in this system, with humans, baboons and a subset of chimpanzees infected with C. hominis subtype IfA12G2; another subset of chimpanzees infected with C. suis; and all positive goats and sheep infected with C. xiaoi. For humans, residence location was associated with increased risk of infection in Mwamgongo village compared to one camp (Kasekela), and there was an increased odds for infection when living in a household with another positive person. Fecal consistency and other gastrointestinal signs did not predict Cryptosporidium infection. Despite a high degree of habitat overlap between village people and livestock, our results suggest that there are distinct Cryptosporidium transmission dynamics for humans and livestock in this system. The dominance of C. hominis subtype IfA12G2 among humans and non-human primates suggest cross-species transmission. Interestingly, a subset of chimpanzees was infected with C. suis. We hypothesize that there is cross-species transmission from bush pigs (Potaochoerus larvatus) to chimpanzees in Gombe forest, since domesticated pigs are regionally absent. Our findings demonstrate a complex nature of Cryptosporidium in sympatric primates, including humans, and stress the need for further studies. PMID- 25700266 TI - Molecular characterization and hormonal regulation of tissue inhibitor of metalloproteinase 1 in goat ovarian granulosa cells. AB - Tissue inhibitor of metalloproteinase 1 (TIMP1) belongs to a group of endogenous inhibitors that control the activity of matrix metalloproteinases and other metalloproteinases. TIMP1 is ubiquitously expressed and implicated in many physiological and pathologic processes. In this study, the full-length complementary DNA of goat (Capra hircus) Timp1 was cloned from adult goat ovary for the first time to better understand the regulatory role of TIMP1. The putative TIMP1 protein shared a high amino acid sequence identity with other species. Real-time polymerase chain reaction results showed that Timp1 was widely expressed in adult goat tissues, and messenger RNA expression was higher in the ovary than in other tissues; meanwhile, increasing expression of Timp1 was also discovered during the process of follicle growth and corpus luteum. We then investigated Timp1 expression patterns in different types of ovarian follicular cells from goats. In small or large antral follicles, Timp1 expression was higher (P < 0.05) in theca cells than in granulosa cells, cumulus cells, and oocytes. Increasing expression of Timp1 in theca and granulosa cells was observed as the variation of the follicle size. Immunohistochemical analyses further revealed the presence of the TIMP1 proteins in follicles at all antral stages of development. The most intense staining for TIMP1 was observed in the theca cells and granulosa cells of large antral follicles and corpus luteum. Timp1 was highly (P < 0.05) induced in granulosa cells in vitro after treatment with the luteinizing hormone agonist, human chorionic gonadotropin. Treatments with forskolin, phorbol 12 myristate 13-acetate, or phorbol 12-myristate 13-acetate + forskolin could also stimulate Timp1 messenger RNA expression. The effects of human chorionic gonadotropin were reduced (P < 0.05) by the inhibitors of protein kinase A, protein kinase C, MAPK kinase, or p38 kinase, indicating that Timp1 expression could be adjusted by luteinizing hormone-initiated activation of these signaling mediators. Our results suggested that TIMP1 may be involved in regulating ovarian follicle development and ovulation. PMID- 25700267 TI - Effects of season, age, sex, and housing on salivary cortisol concentrations in horses. AB - Analysis of salivary cortisol is increasingly used to assess stress responses in horses. Because spontaneous or experimentally induced increases in cortisol concentrations are often relatively small for stress studies, proper controls are needed. This requires an understanding of the factors affecting salivary cortisol over longer times. In this study, we have analyzed salivary cortisol concentration for 6 mo in horses (n = 94) differing in age, sex, reproductive state, and housing. Salivary cortisol followed a diurnal rhythm with the highest concentrations in the morning and a decrease throughout the day (P < 0.001). This rhythm was disrupted in individual groups on individual days; however, alterations remained within the range of diurnal changes. Comparison between months showed highest cortisol concentrations in December (P < 0.001). Cortisol concentrations increased in breeding stallions during the breeding season (P < 0.001). No differences in salivary cortisol concentrations between nonpregnant mares with and without a corpus luteum existed. In stallions, mean daily salivary cortisol and plasma testosterone concentrations were weakly correlated (r = 0.251, P < 0.01). No differences in salivary cortisol between female and male young horses and no consistent differences between horses of different age existed. Group housing and individual stabling did not affect salivary cortisol. In conclusion, salivary cortisol concentrations in horses follow a diurnal rhythm and are increased in active breeding sires. Time of the day and reproductive state of the horses are thus important for experiments that include analysis of cortisol in saliva. PMID- 25700268 TI - Undernutrition regulates the expression of a novel splice variant of myostatin and insulin-like growth factor 1 in ovine skeletal muscle. AB - Undernutrition suppresses the growth of skeletal muscles and alters the expression of insulin-like growth factor 1 (IGF1), a key mitogen, and myostatin, a potent inhibitor of myogenesis. These changes can explain, at least in part, the reduced growth of skeletal muscles in underfed lambs. We have recently identified a myostatin splice variant (MSV) that binds to and antagonizes the canonical signaling of myostatin. In the present study, we hypothesized that the expression of MSV would be reduced in conjunction with myostatin and IGF1 in response to underfeeding in skeletal muscles of sheep. Young growing ewes were fed either ad libitum or an energy-restricted diet (30% of maintenance requirements) for 28 d. This regime of underfeeding resulted in a 24% reduction in body mass (P < 0.001) and a 36% reduction in the mass of the semitendinosus muscles relative to controls (P < 0.001) by day 28. The concentrations of MSV and IGF1 messenger RNA (mRNA) were reduced (both P < 0.001), but myostatin mRNA was not altered in semitendinosus muscles. Unlike the reduced expression of mRNA, the abundance of MSV protein was increased (P < 0.05) and there was no change in the abundance of myostatin protein. Our results suggest that undernutrition for 28 d decreases the signaling of myostatin by increasing the abundance of MSV protein. Although this action may reduce the growth inhibitory activity of myostatin, it cannot prevent the loss of growth of skeletal muscles during undernutrition. PMID- 25700269 TI - Physical forcing mechanisms controlling the variability of chlorophyll-a over the Royal-Charlotte and Abrolhos Banks-Eastern Brazilian Shelf. AB - The Abrolhos Bank is part of the so-called Eastern Brazilian Shelf and is an area of high ecological and economic importance. The bank supports the largest and richest coral reefs in the South Atlantic and the largest rhodolith bed in the world. The spatial and seasonal variation of phytoplankton concentration, however, and the dynamic processes controlling that variability have remained poorly known. The present study investigates the seasonal and spatial distributions of chlorophyll-a (Chl-a) and water conditions by analyzing nine years (2003-2011) of level-3 Moderate-resolution Imaging Spectroradiometer (MODIS) derived Chl-a, National Centers for Environmental Prediction (NCEP)/ETA model-derived winds, NCEP model-derived heat fluxes, thermohaline and velocity results from the Hybrid Circulation Ocean Model (HYCOM) 1/12o assimilated simulation. The results show that low/high concentrations occurred in austral spring-summer (wet season)/autumn-winter (dry season), with the highest values observed in the northern portion of the Abrolhos Bank. The typical meteorological and oceanographic conditions during austral summer favor the development of strong stratification. These conditions are 1) N-NE winds that favor an upwelling type Ekman circulation; 2) coupling between the open ocean and the continental shelf through the western boundary current, which promotes cooler subsurface water to rise onto the shelf break; and 3) positive net heat flux. In contrast, the S-SE winds during autumn are in the opposite direction of the predominant current system over the Abrolhos Bank, thus reducing their speed and inducing an inverse shear. The warmer ocean and a somewhat cool and dry atmosphere promote the evaporative cooling of the surface layer. The above processes drive mixed layer cooling and deepening that reaches its maximum in winter. The blooming of phytoplankton in the Abrolhos Bank waters appears to be regulated by changes in the mixed layer depth, with Chl-a levels that start to increase during autumn and reach their peak in June-July. PMID- 25700270 TI - NME2 reduces proliferation, migration and invasion of gastric cancer cells to limit metastasis. AB - Gastric cancer is one of the most common malignancies and has a high rate of metastasis. We hypothesize that NME2 (Nucleoside Diphosphate Kinase 2), which has previously been considered as an anti-metastatic gene, plays a role in the invasiveness of gastric cancer cells. Using a tissue chip technology and immunohistochemistry, we demonstrated that NME2 expression was associated with levels of differentiation of gastric cancer cells and their metastasis into the lymph nodes. When the NME2 gene product was over-expressed by ;in vitro stable transfection, cells from BGC823 and MKN45 gastric cancer cell lines had reduced rates of proliferation, migration, and invasion through the collagen matrix, suggesting an inhibitory activity of NME2 in the propagation and invasion of gastric cancer. NME2 could, therefore, severe as a risk marker for gastric cancer invasiveness and a potential new target for gene therapy to enhance or induce NME2 expression. PMID- 25700271 TI - Active surface model improvement by energy function optimization for 3D segmentation. AB - This paper proposes an optimized and efficient active surface model by improving the energy functions, searching method, neighborhood definition and resampling criterion. Extracting an accurate surface of the desired object from a number of 3D images using active surface and deformable models plays an important role in computer vision especially medical image processing. Different powerful segmentation algorithms have been suggested to address the limitations associated with the model initialization, poor convergence to surface concavities and slow convergence rate. This paper proposes a method to improve one of the strongest and recent segmentation algorithms, namely the Decoupled Active Surface (DAS) method. We consider a gradient of wavelet edge extracted image and local phase coherence as external energy to extract more information from images and we use curvature integral as internal energy to focus on high curvature region extraction. Similarly, we use resampling of points and a line search for point selection to improve the accuracy of the algorithm. We further employ an estimation of the desired object as an initialization for the active surface model. A number of tests and experiments have been done and the results show the improvements with regards to the extracted surface accuracy and computational time of the presented algorithm compared with the best and recent active surface models. PMID- 25700272 TI - Automated peroperative assessment of stents apposition from OCT pullbacks. AB - This study's aim was to control the stents apposition by automatically analyzing endovascular optical coherence tomography (OCT) sequences. Lumen is detected using threshold, morphological and gradient operators to run a Dijkstra algorithm. Wrong detection tagged by the user and caused by bifurcation, struts'presence, thrombotic lesions or dissections can be corrected using a morphing algorithm. Struts are also segmented by computing symmetrical and morphological operators. Euclidian distance between detected struts and wall artery initializes a stent's complete distance map and missing data are interpolated with thin-plate spline functions. Rejection of detected outliers, regularization of parameters by generalized cross-validation and using the one side cyclic property of the map also optimize accuracy. Several indices computed from the map provide quantitative values of malapposition. Algorithm was run on four in-vivo OCT sequences including different incomplete stent apposition's cases. Comparison with manual expert measurements validates the segmentation's accuracy and shows an almost perfect concordance of automated results. PMID- 25700273 TI - Quality control test for sequence-phenotype assignments. AB - Relating a gene mutation to a phenotype is a common task in different disciplines such as protein biochemistry. In this endeavour, it is common to find false relationships arising from mutations introduced by cells that may be depurated using a phenotypic assay; yet, such phenotypic assays may introduce additional false relationships arising from experimental errors. Here we introduce the use of high-throughput DNA sequencers and statistical analysis aimed to identify incorrect DNA sequence-phenotype assignments and observed that 10-20% of these false assignments are expected in large screenings aimed to identify critical residues for protein function. We further show that this level of incorrect DNA sequence-phenotype assignments may significantly alter our understanding about the structure-function relationship of proteins. We have made available an implementation of our method at http://bis.ifc.unam.mx/en/software/chispas. PMID- 25700274 TI - Lead-free antiferroelectric: xCaZrO3-(1 -x)NaNbO3 system (0 <=x<= 0.10). AB - This study demonstrates that antiferroelectricity can be stabilized in NaNbO(3) (NN) based ceramics by lowering the tolerance factor. Through consideration of the crystal chemistry via the Goldschmidt tolerance factor and polarizability, we show that simultaneous substitution of Zr(4+) and Ca(2+) ions in the Nb and Na sites, respectively, lowers the polarizability and tolerance factor of the (Na(1 x)Ca(x))(Nb(1-x)Zrx)O(3) (CZNN100x) solid solution, while maintaining charge neutrality. Structural investigations using both X-ray diffraction and transmission electron microscopy (TEM) indicated an enhancement of antiferroelectric (AFE) superlattice peaks with CaZrO(3) substitution. The TEM domain analysis revealed that only AFE domains existed in the CZNN4 and CZNN5 ceramics; in contrast, normal NN ceramics displayed coexistence of AFE and ferroelectric (FE) domains at room temperature. The CZNN100x (0.02 <=x<= 0.05) ceramics showed double polarization hysteresis loops, characteristic of reversible AFE<->FE phase transition switching. The field-induced polarization decreased drastically with increasing substitution, an effect of the decreases in tolerance factor. In addition, the AFE switching field was increased by the chemical substitution. First principles calculations are performed to obtain insights into the relative stability and coexistence of the AFE and FE phases in single domains. The large decrease of polarization in the CZNN system is explained by a modification of the relative stability of the relevant structures, which favours nonpolar-to-polar AFE transitions over polar-to-polar FE domain switching. PMID- 25700275 TI - Roles of proteome dynamics and cytokinin signaling in root to hypocotyl ratio changes induced by shading roots of Arabidopsis seedlings. AB - In nature, root systems of most terrestrial plants are protected from light exposure by growing in a dark soil environment. Hence, in vitro cultivation in transparent Petri dishes leads to physiological perturbations, but the mechanisms underlying root-mediated light perception and responses have not been fully elucidated. Thus, we compared Arabidopsis thaliana seedling development in transparent and darkened Petri dishes at low light intensity (20 umol m(-2) s( 1)), allowing us to follow (inter alia) hypocotyl elongation, which is an excellent process for studying interactions of signals involved in the regulation of growth and developmental responses. To obtain insights into molecular events underlying differences in seedling growth under these two conditions, we employed liquid chromatography-mass spectrometry (LC-MS) shotgun proteomics (available via the PRIDE deposit PXD001612). In total, we quantified the relative abundances of peptides representing 1,209 proteins detected in all sample replicates of LC-MS analyses. Comparison of MS spectra after manual validation revealed 48 differentially expressed proteins. Functional classification, analysis of available gene expression data and literature searches revealed alterations associated with root illumination (inter alia) in autotrophic CO2 fixation, C compound and carbohydrate metabolism, and nitrogen metabolism. The results also indicate a previously unreported role for cytokinin plant hormones in the escape tropism response to root illumination. We complemented these results with reverse transcription followed by quantitative PCR (RT-qPCR), chlorophyll fluorescence and detailed cytokinin signaling analyses, detecting in the latter a significant increase in the activity of the cytokinin two-component signaling cascade in roots and implicating the cytokinin receptor AHK3 as the major mediator of root to hypocotyl signaling in responses to root illumination. PMID- 25700278 TI - Factors Related to Job Burnout Among Community Nurses in Changchun, China. AB - BACKGROUND: Community nurses are an important component of the community health service system. Job burnout among community nurses not only leads to a decline in satisfaction and an increased turnover rate but also may seriously affect the service quality and professional development of nurses. PURPOSE: This study aims to elicit the conditions and factors that cause job burnout in community nurses in Changchun, Jilin Province, China. METHODS: A questionnaire survey was administered to 420 registered nurses in Changchun using a convenience sampling method. RESULTS: Job burnout was found in 362 community nurses (86.2%), with a total mean job burnout score of 2.27 +/- 0.65 points. Job burnout was related to marital status, educational level, job satisfaction, and interpersonal relationship difficulties. CONCLUSIONS: These results indicate that community nurses have a high rate of job burnout. Experts should be employed to train nurses in interpersonal communication skills. The community working environment should also be improved. PMID- 25700281 TI - Long-term mortality of patients with atrial fibrillation undergoing percutaneous coronary intervention with stent implantation for acute and stable coronary artery disease. AB - BACKGROUND: Patients with atrial fibrillation (AF) are of increased risk for ischemic and bleeding complications, particularly when requiring aggressive antithrombotic therapy after coronary stenting. However, data from unselected patients on long-term mortality are scarce. METHODS: We analyzed 2890 patients of a single-center registry undergoing coronary stenting between 2003 and 2012, of whom 1434 patients had stable coronary artery disease (CAD), while 1456 patients presented with acute coronary syndromes (ACS). As the primary endpoint, we compared long-term all-cause mortality between patients with AF and patients in sinus rhythm. RESULTS: History or presence of AF was found in 146 (10.2%) patients with stable CAD and 93 (6.4%) patients with ACS. The median CHA2DS2-VASc scores were similar between stable CAD and ACS patients (4[2; 5] vs. 3[2; 5], p=0.92). Patients with AF had a significantly higher atherothrombotic risk profile and more co-morbidities. Patients undergoing PCI before 2011 received triple therapy (aspirin, clopidogrel and a vitamin K antagonist) in 25% of cases, compared to 64% of cases thereafter. Patients undergoing elective or urgent revascularization and suffering from AF had a similar 2-fold increased adjusted relative risk of death after a mean follow-up of 4.8 years (HR 1.95, 95% CI 1.27; 2.99, p<0.01 for stable CAD and HR 1.95, 95% CI 1.23; 3.11, p<0.01 for ACS). CONCLUSION: In a general practice setting, patients with AF had significantly increased adjusted long-term mortality than patients without AF. After publication of the consensus document of different working groups of the European Society of Cardiology in 2010, triple therapy increased markedly. PMID- 25700280 TI - Distinct germline progenitor subsets defined through Tsc2-mTORC1 signaling. AB - Adult tissue maintenance is often dependent on resident stem cells; however, the phenotypic and functional heterogeneity existing within this self-renewing population is poorly understood. Here, we define distinct subsets of undifferentiated spermatogonia (spermatogonial progenitor cells; SPCs) by differential response to hyperactivation of mTORC1, a key growth-promoting pathway. We find that conditional deletion of the mTORC1 inhibitor Tsc2 throughout the SPC pool using Vasa-Cre promotes differentiation at the expense of self-renewal and leads to germline degeneration. Surprisingly, Tsc2 ablation within a subset of SPCs using Stra8-Cre did not compromise SPC function. SPC activity also appeared unaffected by Amh-Cre-mediated Tsc2 deletion within somatic cells of the niche. Importantly, we find that differentiation-prone SPCs have elevated mTORC1 activity when compared to SPCs with high self-renewal potential. Moreover, SPCs insensitive to Tsc2 deletion are preferentially associated with mTORC1-active committed progenitor fractions. We therefore delineate SPC subsets based on differential mTORC1 activity and correlated sensitivity to Tsc2 deletion. We propose that mTORC1 is a key regulator of SPC fate and defines phenotypically distinct SPC subpopulations with varying propensities for self-renewal and differentiation. PMID- 25700279 TI - Rational development of an attenuated recombinant cyprinid herpesvirus 3 vaccine using prokaryotic mutagenesis and in vivo bioluminescent imaging. AB - Cyprinid herpesvirus 3 (CyHV 3) is causing severe economic losses worldwide in common and koi carp industries, and a safe and efficacious attenuated vaccine compatible with mass vaccination is needed. We produced single deleted recombinants using prokaryotic mutagenesis. When producing a recombinant lacking open reading frame 134 (ORF134), we unexpectedly obtained a clone with additional deletion of ORF56 and ORF57. This triple deleted recombinant replicated efficiently in vitro and expressed an in vivo safety/efficacy profile compatible with use as an attenuated vaccine. To determine the role of the double ORF56-57 deletion in the phenotype and to improve further the quality of the vaccine candidate, a series of deleted recombinants was produced and tested in vivo. These experiments led to the selection of a double deleted recombinant lacking ORF56 and ORF57 as a vaccine candidate. The safety and efficacy of this strain were studied using an in vivo bioluminescent imaging system (IVIS), qPCR, and histopathological examination, which demonstrated that it enters fish via skin infection similar to the wild type strain. However, compared to the parental wild type strain, the vaccine candidate replicated at lower levels and spread less efficiently to secondary sites of infection. Transmission experiments allowing water contamination with or without additional physical contact between fish demonstrated that the vaccine candidate has a reduced ability to spread from vaccinated fish to naive sentinel cohabitants. Finally, IVIS analyses demonstrated that the vaccine candidate induces a protective mucosal immune response at the portal of entry. Thus, the present study is the first to report the rational development of a recombinant attenuated vaccine against CyHV 3 for mass vaccination of carp. We also demonstrated the relevance of the CyHV 3 carp model for studying alloherpesvirus transmission and mucosal immunity in teleost skin. PMID- 25700282 TI - Trends in mortality and heart failure after acute myocardial infarction in Italy from 2001 to 2011. AB - BACKGROUND: Uncertainties on long-term outcomes after acute myocardial infarction (AMI) still exist, despite the ongoing progresses in the management of patients with AMI. AIM OF THE STUDY: Our aim was to appraise both the early prognosis and prognosis at 1-year after discharge of patients hospitalized due to AMI. METHODS: This is a retrospective nationwide cohort study based on data from an administrative database on patients admitted with AMI from 2001 to 2011 in all Italian hospitals sites. Mortality and readmission rates within 30 days, 60 days and 1 year were calculated, as well as re-hospitalizations for all causes and for HF. RESULTS: A total of 1,110,822 patients were included. Index admission mortality rate (I-MR) and total in-hospital mortality rate (T-MR) at up to 1 year both decreased respectively from 11.34% to 8.99% and from 16.46% to 14.68% in the years 2001 to 2011 (both p<0.0001), while fatal readmission rate (F-RR) at 1 year increased from 4.75% to 5.28% (p=0.0019). Patients that developed HF during the index admission had significantly higher I-MR and F-RR. I-MR, F-RR, and T-MR, however, remained low at any time point considered (30 days, 60 days and 1 year) in a subgroup of low-risk optimally-treated patients. CONCLUSIONS: The risk of fatal readmission at 1 year increased slightly over time, in spite of the remarkable improvements currently achieved in overall prognosis after AMI. The identification of patients at high risk (mainly due to HF complicating AMI), and of patients at low risk is crucial to define and support management strategies. PMID- 25700284 TI - Transplant Trajectory and Relational Experience Within Living Kidney Dyads. AB - Living kidney donation is considered common practice across most Westernized countries. While extensive research has documented the experience of living donors, few studies have addressed the perspective of recipients, and even fewer have examined the experience of donor and recipient as an interactive dyad. In this study, our aim was to examine the reciprocal influence between donors and recipients across the transplantation process. We recruited a homogeneous sample of 10 donors and recipients, who were interviewed individually. Data were analyzed using interpretative phenomenological analysis. The presentation of results follows the stages of the transplantation process: the disease experience, the experience of offering and accepting a kidney, the screening period, the surgery, and the post-transplantation period. Results are discussed within the framework of Mauss's gift exchange theory, social roles, and altruism. This comprehensive description of the dyadic experience provides a way to frame and understand psychosocial aspects and relational implications of living renal transplantation. PMID- 25700283 TI - p53 and DeltaNp63alpha Coregulate the Transcriptional and Cellular Response to TGFbeta and BMP Signals. AB - The TGFbeta superfamily regulates a broad range of cellular processes, including proliferation, cell-fate specification, differentiation, and migration. Molecular mechanisms underlying this high degree of pleiotropy and cell-type specificity are not well understood. The TGFbeta family is composed of two branches: (i) TGFbetas, activins, and nodals, which signal through SMAD2/3, and (ii) bone morphogenetic proteins (BMP), which signal through SMAD1/5/8. SMADs have weak DNA binding affinity and rely on coactivators and corepressors to specify their transcriptional outputs. This report reveals that p53 and DeltaNp63alpha act as transcriptional partners for SMAD proteins and thereby influence cellular responses to TGFbeta and BMPs. Suppression of p53 or overexpression of DeltaNp63alpha synergistically enhance BMP-induced transcription. Mechanistically, p53 and DeltaNp63alpha physically interact with SMAD1/5/8 proteins and co-occupy the promoter region of inhibitor of differentiation (ID2), a prosurvival BMP target gene. Demonstrating further convergence of these pathways, TGFbeta-induced canonical BMP regulated transcription in a DeltaNp63alpha- and p53-dependent manner. Furthermore, bioinformatic analyses revealed that SMAD2/3 and DeltaNp63alpha coregulate a significant number of transcripts involved in the regulation of epithelial-to-mesenchymal transition. Thus, p53 and DeltaNp63alpha are transcriptional partners for a subset of TGFbeta and BMP-regulated SMAD target genes in the mammary epithelium. Collectively, these results establish an integrated gene network of SMADs, p53, and DeltaNp63alpha that contribute to EMT and metastasis. IMPLICATIONS: This study identifies aberrant BMP activation as a result of p53 mutation or DeltaNp63alpha expression. PMID- 25700285 TI - Stroke lesion volumes and outcome are not different in hemispheric stroke side treated with intravenous thrombolysis based on magnetic resonance imaging criteria. AB - BACKGROUND AND PURPOSE: Patients with right hemispheric stroke (RHS) have been reported to have fewer good outcomes after thrombolysis. We aimed at evaluating outcome after stroke thrombolysis with regards to the affected hemisphere controlling for stroke lesion volume as a potential confounder. METHODS: We retrospectively analyzed data from a prospective study of patients with acute stroke treated with intravenous tissue-type plasminogen activator, based on magnetic resonance imaging criteria within 6 hours of symptom onset. Neurological deficit was assessed by the National Institutes of Health Stroke Scale. Lesion volume on acute perfusion imaging, diffusion-weighted imaging (DWI) and perfusion imaging/DWI mismatch were measured. Clinical outcome was assessed after 90 days using the modified Rankin Scale, and relation to affected hemisphere was studied by multivariate analysis. RESULTS: Of 173 patients, 55 (32%) presented with RHS, whereas 118 (68%) had left HS. Baseline National Institutes of Health Stroke Scale was lower in RHS (11.7 versus 13.6; P=0.031). There were no differences in DWI lesion volume (11.0 versus 17.8 mL; P=0.519), perfusion imaging lesion volume (98.9 versus 118.3 mL; P=0.395), perfusion imaging/DWI mismatch (60 versus 85.05 mL; P=0.283). Clinical outcome was also comparable for both groups (modified Rankin Scale, 0-1; P=0.327). In multivariate analysis, DWI lesion volume (P<0.001) and age were associated with modified Rankin Scale at day 90, whereas affected hemisphere was not. CONCLUSIONS: We did not find differences between RHS and left HS with regards to stroke lesions volumes or outcome after thrombolysis. Previously reported hemisphere-related differences in stroke outcome may partly results from imbalances in stroke lesion volume between RHS and left HS. PMID- 25700287 TI - Cannabis and stroke: systematic appraisal of case reports. AB - BACKGROUND AND PURPOSE: An increasing number of case reports link cannabis consumption to cerebrovascular events. Yet these case reports have not been scrutinized using criteria for causal inference. METHODS: All case reports on cannabis and cerebrovascular events were retrieved. Four causality criteria were addressed: temporality, adequacy of stroke work-up, effects of rechallenge, and concomitant risk factors that could account for the cerebrovascular event. RESULTS: There were 34 case reports on 64 patients. Most cases (81%) exhibited a temporal relationship between cannabis exposure and the index event. In 70%, the evaluation was sufficiently comprehensive to exclude other sources for stroke. About a quarter (22%) of patients had another stroke after subsequent re-exposure to cannabis. Finally, half of patients (50%) had concomitant stroke risk factors, most commonly tobacco (34%) and alcohol (11%) consumption. CONCLUSIONS: Many case reports support a causal link between cannabis and cerebrovascular events. This accords well with epidemiological and mechanistic research on the cerebrovascular effects of cannabis. PMID- 25700286 TI - Occult anterograde flow is an under-recognized but crucial predictor of early recanalization with intravenous tissue-type plasminogen activator. AB - BACKGROUND AND PURPOSE: Thrombolysis depends on the ability of blood and thrombolytic agents to permeate thrombus. We devised a novel technique to quantify blood permeating through thrombi and determine whether this parameter predicts early recanalization with intravenous tissue-type plasminogen activator. METHODS: Intravenous tissue-type plasminogen activator-treated patients with stroke and complete occlusion on computed tomographic angiography were analyzed using perfusion computed tomography and a delay insensitive algorithm. We generated maps that measure delay in arrival time of contrast within the intracranial arterial tree (T0 maps). A positive sloped regression line of T0 values measured along artery silhouette distal to thrombus was defined as marker of permeable thrombus (occult anterograde flow). Median T0 values at proximal and distal thrombus interface were measured. Early recanalization was assessed on first angiography of subsequent intra-arterial procedure or on a 4-hour computed tomographic angiography. RESULTS: Of 66 patients, occult anterograde flow was detected in 17 (25.8%). Early recanalization was more in patients with occult anterograde flow versus not (66.7 versus 29.7%; P=0.031). Median T0 value (in s) at distal thrombus interface (1.5 versus 3.8; P=0.006) and difference in median T0 value between proximal and distal thrombus interface (1.3 versus 3.7; P=0.014) were less in early recanalizers versus in nonrecanalizers. In multivariable analysis, patients with occult anterograde flow and T0 value difference between proximal and distal thrombus interface <=2 s recanalized most (71.4%; odds ratio, 12.15; 95% confidence interval, 2.05-71.91), whereas patients with retrograde flow and T0 value difference >2 s recanalized least (25.9%; odds ratio, 1). CONCLUSIONS: Occult anterograde flow through thrombus can be assessed by perfusion computed tomography T0 maps and predicts early recanalization with intravenous tissue-type plasminogen activator robustly. PMID- 25700288 TI - Blood-brain barrier compromise does not predict perihematoma edema growth in intracerebral hemorrhage. AB - BACKGROUND AND PURPOSE: There are limited data on the extent of blood-brain barrier (BBB) compromise in acute intracerebral hemorrhage patients. We tested the hypotheses that BBB compromise measured with permeability-surface area product (PS) is increased in the perihematoma region and predicts perihematoma edema growth in acute intracerebral hemorrhage patients. METHODS: Patients were randomized within 24 hours of symptom onset to a systolic blood pressure (SBP) treatment of <150 (n=26) or <180 mm Hg (n=27). Permeability maps were generated using computed tomographic perfusion source data acquired 2 hours after randomization, and mean PS was measured in the hematoma, perihematoma, and hemispheric regions. Hematoma and edema volumes were measured on noncontrast computed tomographic scans obtained at baseline, 2 hours and 24 hours after randomization. RESULTS: Patients were randomized at a median (interquartile range) time of 9.3 hours (14.1) from symptom onset. Treatment groups were balanced with respect to baseline SBP and hematoma volume. Perihematoma PS (5.1+/ 2.4 mL/100 mL per minute) was higher than PS in contralateral regions (3.6+/-1.7 mL/100 mL per minute; P<0.001). Relative edema growth (0-24 hours) was not predicted by perihematoma PS (beta=-0.192 [-0.06 to 0.01]) or SBP change (beta= 0.092 [-0.002 to 0.001]). SBP was lower in the <150 target group (139.2+/-22.1 mm Hg) than in the <180 group (159.7+/-12.3 mm Hg; P<0.0001). Perihematoma PS was not different between groups (4.9+/-2.4 mL/100 mL per minute for the <150 group, 5.3+/-2.4 mL/100 mL per minute for the <180 group; P=0.51). CONCLUSIONS: BBB permeability is focally increased in the hematoma and perihematoma regions of acute intracerebral hemorrhage patients. BBB compromise does not predict acute perihematoma edema volume or edema growth. SBP reduction does not affect BBB permeability. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00963976. PMID- 25700290 TI - Montreal Cognitive Assessment 5-minute protocol is a brief, valid, reliable, and feasible cognitive screen for telephone administration. AB - BACKGROUND AND PURPOSE: The National Institute of Neurological Disorders and Stroke-Canadian Stroke Network Vascular Cognitive Impairment Harmonization working group proposed a brief cognitive protocol for screening of vascular cognitive impairment. We investigated the validity, reliability, and feasibility of the Montreal Cognitive Assessment 5-minute protocol (MoCA 5-minute protocol) administered over the telephone. METHODS: Four items examining attention, verbal learning and memory, executive functions/language, and orientation were extracted from the MoCA to form the MoCA 5-minute protocol. One hundred four patients with stroke or transient ischemic attack, including 53 with normal cognition (Clinical Dementia Rating, 0) and 51 with cognitive impairment (Clinical Dementia Rating, 0.5 or 1), were administered the MoCA in clinic and a month later, the MoCA 5 minute protocol over the telephone. RESULTS: Administration of the MoCA 5-minute protocol took 5 minutes over the telephone. Total score of the MoCA 5-minute protocol correlated negatively with age (r=-0.36; P<0.001) and positively with years of education (r=0.41; P<0.001) but not with sex (rho=0.03; P=0.773). Total scores of the MoCA and MoCA 5-minute protocol were highly correlated (r=0.87; P<0.001). The MoCA 5-minute protocol performed equally well as the MoCA in differentiating patients with cognitive impairment from those without (areas under receiver operating characteristics curve for MoCA 5-minute protocol, 0.78; MoCA=0.74; P>0.05 for difference; Cohen d for group difference, 0.80-1.13). It differentiated cognitively impaired patients with executive domain impairment from those without (areas under receiver operating characteristics curve, 0.89; P<0.001; Cohen d=1.7 for group difference). Thirty-day test-retest reliability was excellent (intraclass correlation coefficient, 0.89). CONCLUSIONS: The MoCA 5 minute protocol is a free, valid, and reliable cognitive screen for stroke and transient ischemic attack. It is brief and highly feasible for telephone administration. PMID- 25700289 TI - Atrial premature beats predict atrial fibrillation in cryptogenic stroke: results from the EMBRACE trial. AB - BACKGROUND AND PURPOSE: Many ischemic strokes or transient ischemic attacks are labeled cryptogenic but may have undetected atrial fibrillation (AF). We sought to identify those most likely to have subclinical AF. METHODS: We prospectively studied patients with cryptogenic stroke or transient ischemic attack aged >=55 years in sinus rhythm, without known AF, enrolled in the intervention arm of the 30 Day Event Monitoring Belt for Recording Atrial Fibrillation After a Cerebral Ischemic Event (EMBRACE) trial. Participants underwent baseline 24-hour Holter ECG poststroke; if AF was not detected, they were randomly assigned to 30-day ECG monitoring with an AF auto-detect external loop recorder. Multivariable logistic regression assessed the association between baseline variables (Holter-detected atrial premature beats [APBs], runs of atrial tachycardia, age, and left atrial enlargement) and subsequent AF detection. RESULTS: Among 237 participants, the median baseline Holter APB count/24 h was 629 (interquartile range, 142-1973) among those who subsequently had AF detected versus 45 (interquartile range, 14 250) in those without AF (P<0.001). APB count was the only significant predictor of AF detection by 30-day ECG (P<0.0001), and at 90 days (P=0.0017) and 2 years (P=0.0027). Compared with the 16% overall 90-day AF detection rate, the probability of AF increased from <9% among patients with <100 APBs/24 h to 9% to 24% in those with 100 to 499 APBs/24 h, 25% to 37% with 500 to 999 APBs/24 h, 37% to 40% with 1000 to 1499 APBs/24 h, and 40% beyond 1500 APBs/24 h. CONCLUSIONS: Among older cryptogenic stroke or transient ischemic attack patients, the number of APBs on a routine 24-hour Holter ECG was a strong dose-dependent independent predictor of prevalent subclinical AF. Those with frequent APBs have a high probability of AF and represent ideal candidates for prolonged ECG monitoring for AF detection. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00846924. PMID- 25700291 TI - Rates of ischemic stroke during warfarin treatment for atrial fibrillation. AB - BACKGROUND AND PURPOSE: Recent evidence suggests that there may be an increased risk of ischemic stroke immediately after warfarin initiation. We examined the rate of ischemic stroke among patients with atrial fibrillation newly started on warfarin therapy. METHODS: We conducted a population-based cohort study among Ontario residents aged >=66 years with atrial fibrillation who received warfarin between April 1, 1997, and March 31, 2010. Each patient was followed up for <=5 years in 30-day intervals. For each interval, we determined the rate of ischemic stroke. RESULTS: After 5 years, the cumulative incidence of ischemic stroke among new users of warfarin (n=148,446) was 4.0% (n=6006). The risk was highest during the first 30 days after initiation (6.0% per person-year; 95% confidence interval, 5.5%-6.4%) compared with the remainder of follow-up (1.6% per person year; 95% confidence interval, 1.5%-1.6%), and increased with higher baseline CHADS2 (congestive heart failure, hypertension, age >=75 years, diabetes, previous stroke) scores. Less frequent monitoring may have contributed. CONCLUSIONS: In a large cohort of older patients with atrial fibrillation, we observed the highest rate of ischemic stroke in the first 30 days after warfarin initiation. Although causation cannot be established given the observational nature of this study, our findings highlight the need for future research in this population. PMID- 25700292 TI - The nature of placebo response in clinical studies of major depressive disorder. AB - OBJECTIVE: To review factors influencing placebo response and clinical trial outcome in depression, and suggest ways to optimize trial success in mood disorders. DATA SOURCES: PubMed searches were conducted by cross-referencing the terms depression, depressive with placebo, clinical trial, and clinical trials for studies published in English between 1970 and September 2013. STUDY SELECTION: Relevant abstracts were identified in PubMed, including clinical trials, quantitative studies, and qualitative research. We obtained and reviewed relevant articles and utilized their information to synthesize the present review. DATA EXTRACTION: Included articles were grouped in the following areas of relevance: (1) biological validity of illness, (2) baseline severity of illness, (3) chronicity of the index episode of depression, (4) age of participants, (5) medical and psychiatric comorbidity, (6) probability of receiving placebo, (7) use of prospective treatment phases (lead-in) (8) dosing schedule, (9) trial duration, (10) frequency of follow-up assessments, and (11) study outcome measure. RESULTS: Several key elements emerge as critical to the ultimate success of a clinical trial, including the probability of receiving placebo, study duration, dosing schedule, visit frequency, the use of blinded lead-in phases, the use of centralized raters, illness severity and duration, and comorbid anxiety. CONCLUSIONS: Our increasing understanding of the placebo response in clinical trials of major depressive disorder lends to a, gradually, more predictable phenomenon and, hopefully, to one that becomes lesser in magnitude and variability. Several elements have emerged that seem to play a critical role in trial success, gradually reshaping the design of clinical, translational, as well as mechanistic studies in depression. PMID- 25700294 TI - Facial nerve grading scales: systematic review of the literature and suggestion for uniformity. PMID- 25700295 TI - Percentage augmentation: the more meaningful index of success in fat grafting. PMID- 25700296 TI - Illegal silicone injections create unique reconstructive challenges in transgender patients. PMID- 25700297 TI - The Effects of Whole-Vault Cranioplasty versus Strip Craniectomy on Long-Term Neuropsychological Outcomes in Sagittal Craniosynostosis. PMID- 25700298 TI - Primary intranasal lining injury: cause, deformities, and treatment plan. PMID- 25700299 TI - Simplifying the management of caudal septal deviation in rhinoplasty. PMID- 25700300 TI - Trust. PMID- 25700301 TI - The incidence of donor-site morbidity after transverse cervical artery vascularized lymph node transfers: the need for a lymphatic surgery national registry. PMID- 25700302 TI - Lymph node transplantation and quantitative clearance lymphoscintigraphy. PMID- 25700303 TI - Bevacizumab preconditioning followed by Etoposide and Cisplatin is highly effective in treating brain metastases of breast cancer progressing from whole brain radiotherapy. AB - PURPOSE: We hypothesized that a window period between bevacizumab and cytotoxic agents may enhance drug delivery into tumor tissue through bevacizumab-induced vascular normalization in patients with brain metastases of breast cancer (BMBC). EXPERIMENTAL DESIGN: A single-arm phase II study was conducted in which BMBC patients refractory to whole-brain radiotherapy (WBRT) were enrolled. In a 21-day cycle, patients received bevacizumab (15 mg/kg) on day 1, which, with a 1-day window period, was followed by etoposide (70 mg/m(2)/day; days 2-4) and cisplatin (70 mg/m(2); day 2; BEEP regimen). The BEEP regimen was administered for a maximum of 6 cycles. The primary endpoint was the central nervous system (CNS) objective response rate according to volumetric response criteria. RESULTS: A total of 35 patients were enrolled between January 2011 and January 2013. The median age was 54.3 years (range, 33-75); 19 patients (54.3%) had an Eastern Cooperative Oncology Group performance status of 2 or 3. Twenty-seven patients [77.1%; 95% confidence interval (CI), 59.9-89.6] achieved a CNS-objective response, including 13 patients (37.1%) with a >=80% volumetric reduction of CNS lesions. With a median follow-up of 16.1 months, the median CNS progression-free survival and overall survival times were 7.3 months (95% CI, 6.5-8.1) and 10.5 months (95% CI, 7.8-13.2), respectively. Common grade 3 or 4 toxicities included neutropenia (30.8%) and infection (21.3%). CONCLUSIONS: By administering bevacizumab 1 day before etoposide and cisplatin, the BEEP regimen appeared highly effective in BMBC refractory to WBRT. Further study of vascular normalization window concept is warranted. PMID- 25700304 TI - Obesity and Fatty Pancreatic Infiltration Are Risk Factors for Pancreatic Precancerous Lesions (PanIN). AB - PURPOSE: The roles of intravisceral and subcutaneous fat are unknown, and the prevalence of precancerous lesions in obese patients was never evaluated. This study aims to assess the frequency and severity of pancreatic intraepithelial neoplasia (PanIN) and to correlate pathologic findings with metabolic abnormalities, type of fat, and fatty pancreatic infiltration. EXPERIMENTAL DESIGN: Normal pancreatic tissue from surgical specimens was analyzed. Fatty infiltration and fibrosis in intra- and extralobular locations and PanIN lesions were assessed. General characteristics were collected: body mass index (BMI), diabetes, and tobacco intake. Liver steatosis and subcutaneous and intravisceral fat were assessed by CT scan (ImageJ software). RESULTS: Of note, 110 patients were included [median age, 53.8 (17-85) years]. Arterial hypertension, diabetes, and tobacco intake were found in 19%, 9%, and 23%, respectively. Median BMI was 24 (16-37; BMI < 25: 45%, 25 <= 30: 24%, >=30: 11%). Overall, PanIN lesions were found in 65% (type I, II, and III PanIN in 62%, 38%, and 1%, respectively). Fibrosis and fatty pancreas (intra- and extralobular locations) were found in 1% and 24% and in 30% and 51%, respectively. A correlation was observed between PanIN lesions and fatty pancreas [extralobular (0.01) and intralobular (<0.0001)], intralobular fibrosis (0.003), high BMI (P = 0.02), and subcutaneous (P = 0.02) and intravisceral fat (P = 0.02). The number of PanIN lesions was correlated with intravisceral fat (r = 0.22, P = 0.04), but not with subcutaneous fat (r = 0.14, P = 0.22). In multivariate analysis, PanIN lesions were associated with intralobular fibrosis [OR, 5.61; 95% confidence interval (CI), 1.18-42.99] and intralobular fat (OR, 17.86; 95% CI, 4.935-88.12). CONCLUSIONS: Obesity (especially android obesity) and pancreatic fatty infiltration are risk factors for pancreatic precancerous lesions. PMID- 25700305 TI - Relationship between female hormonal and menstrual factors and pancreatic cancer: a meta-analysis of observational studies. AB - The objective of this study was to assess the relationship between female hormone and menstrual factors and pancreatic cancer (PC) through a meta-analysis of observational studies. We undertook a systematic literature search up to July 10, 2014 in PubMed and EMBASE databases. Combined relative risks (RRs) were estimated by random-effects models. Subgroup analysis was performed by study design, source of control, and geographic regions. Sensitivity analyses and publication bias were utilized to evaluate the robustness of our results. A total of 27 case control and cohort studies were retrieved for this meta-analysis. No significant associations were observed between the risk of PC and age at menarche (RR = 0.94, 95% confidence interval [CI] 0.83-1.07), age at menopause (RR = 0.98, 95% CI 0.85 1.13), hysterectomy (RR = 0.97, 95% CI 0.84-1.11), oophorectomy (RR = 1.02, 95% CI 0.82-1.26), hormone replacement therapy (RR = 0.97, 95% CI 0.87-1.08), and oral contraceptives (RR = 1.09, 95% CI 0.96-1.23). This meta-analysis of observational studies does not support the hypothesis that exogenous hormone use and menstrual factors are associated with PC. PMID- 25700306 TI - An uncommon presentation of metastatic melanoma: a case report. AB - Metastases to the spleen are rare and are generally part of a multi-visceral metastatic disease. The most common sources of splenic metastases include breast, lung and colorectal malignancies as well as melanoma and ovarian carcinoma. Solitary splenic metastasis is very uncommon. We present a case of a 44-year-old man who presented at our department for gallstones symptoms. He had a past medical history of neck cutaneous melanoma (T3bN0M0--Stage IIb). He had not attended follow-up schedule for personal reasons. However, abdominal ultrasound revealed the presence of a solitary solid lesion in the spleen. Preoperative workup was completed with CT scan that confirmed the presence of a large splenic lesion with subcapsular fluid collection, also compatible with a post-traumatic lesion.Preoperative findings could not exclude malignancy and patient was therefore submitted to surgery. At laparoscopy, a condition of peritoneal melanosis was present. Splenectomy was carried out. Histological report confirmed the peritoneal melanosis and the diagnosis of metastatic spleen lesion from melanoma. Patient was observed, but died of metastatic disease 14 months after surgery. Splenic metastases are uncommon. Isolated metastases from melanoma are rare and could be found several months after primary diagnosis of melanoma. Surgery remains the most effective treatment, especially for metachronous disease, offering the best chance of long-term survival. Prognosis remains poor, as metachronous disease is indicative of aggressive widespread of the disease. PMID- 25700307 TI - Physician's first clinical impression of emergency department patients with nonspecific complaints is associated with morbidity and mortality. AB - The association between the physician's first clinical impression of a patient with nonspecific complaints and morbidity and mortality is unknown. The aim was to evaluate the association of the physician's first clinical impression with acute morbidity and mortality. We conducted a prospective observational study with a 30-day follow-up. This study was performed at the emergency departments (EDs) of 1 secondary and 1 tertiary care hospital, from May 2007 to February 2011. The first clinical impression ("looking ill"), expressed on a numerical rating scale from 0 to 100, age, sex, and the Charlson Comorbidity Index (CCI) were evaluated. The association was determined between these variables and acute morbidity and mortality, together with receiver operating characteristics, and validity. Of 217,699 presentations to the ED, a total of 1278 adult nontrauma patients with nonspecific complaints were enrolled by a study team. No patient was lost to follow-up. A total of 84 (6.6%) patients died during follow-up, and 742 (58.0%) patients were classified as suffering from acute morbidity. The variable "looking ill" was significantly associated with mortality and morbidity (per 10 point increase, odds ratio 1.23, 95% confidence interval [CI] 1.12-1.34, P < 0.001, and odds ratio 1.19, 95% CI 1.14-1.24, P < 0.001, respectively). The combination of the variables "looking ill," "age," "male sex," and "CCI" resulted in the best prediction of these outcomes (mortality: area under the curve [AUC] 0.77, 95% CI 0.72-0.82; morbidity: AUC 0.68, 95% CI 0.65-0.71). The physician's first impression, with or without additional variables such as age, male sex, and CCI, was associated with morbidity and mortality. This might help in the decision to perform further diagnostic tests and to hospitalize ED patients. PMID- 25700308 TI - Changes in echocardiographic parameters according to the rate of residual renal function decline in incident peritoneal dialysis patients. AB - Residual renal function (RRF) is associated with left ventricular (LV) hypertrophy as well as all-cause and cardiovascular (CV) mortality in patients with end-stage renal disease. However, no studies have yet examined the serial changes in echocardiographic findings according to the rate of RRF decline in incident dialysis patients. A total of 81 patients who started peritoneal dialysis (PD) between 2005 and 2012 at Yonsei University Health System, Seoul, South Korea, and who underwent baseline and follow-up echocardiography within the first year of PD were recruited. Patients were dichotomized into "faster" and "slower" RRF decline groups according to the median values of RRF decline slope ( 1.60 mL/min/y/1.73 m(2)). Baseline RRF and echocardiographic parameters were comparable between the 2 groups. During the first year of PD, there were no significant changes in LV end-diastolic volume index (LVEDVI), left atrial volume index (LAVI), or LV mass index (LVMI) in the "faster" RRT decline group, while these indices decreased in the "slower" RRT decline group. The rate of RRF decline was a significant determinant of 1-year changes in LVEDVI, LAVI, and LVMI. The linear mixed model further confirmed that there were significant differences in the changes in LVEDVI, LAVI, and LVMI between the 2 groups (P = 0.047, 0.048, and 0.001, respectively). During a mean follow-up duration of 31.9 months, 4 (4.9%) patients died. Compared with the "slower" RRF decline group, CV composite (20.29/100 vs 7.18/100 patient-years [PY], P = 0.098), technique failure (18.80/100 vs 4.19/100 PY, P = 0.006), and PD peritonitis (15.73/100 vs 4.95/100 PY, P = 0.064) developed more frequently in patients with "faster" RRF decline rate. On multivariate Cox regression analysis, patients with "faster" RRF decline rate showed 4.82-, 4.44-, and 7.37-fold higher risks, respectively, for each clinical outcome. Preservation of RRF is important for conserving cardiac performance, resulting in an improvement in clinical outcomes of incident PD patients. PMID- 25700309 TI - Differentially expressed miRNAs in acute wound healing of the skin: a pilot study. AB - The aim of the present study was to compare expression of microRNAs (miRNAs) from scar and normal skin areas in patients who suffered acute injuries in the skin. A total of 9 patients with acute injuries in the skin who received surgical treatment from December 2012 to March 2013 were included in this pilot study. Specimens from the hypertrophic scar and normal skin areas were obtained from the same patient during surgery. To screen for differentially expressed miRNAs, we applied 3 statistical methods, namely the traditional t test, the false discovery rate (FDR), and a novel sure independence screening procedure based on the distance correlation (DC-SIS). We examined the functional trends and metabolic and regulatory pathways for the target genes of the identified miRNAs, and explored interaction of these miRNAs in the implication of scar healing using Ingenuity Pathway Analysis. DC-SIS identified 18 differentially expressed miRNAs, 4 of which (miR-149, miR-203a, miR-222, miR-122) were also identified by FDR. The target genes of the 4 miRNAs exhibit a variety of biological functions, and are involved in various pathways such as mitogen-activated protein kinase, Wnt signaling, and focal adhesion. We identified 1 network in which 14 out of the 18 differentially expressed miRNAs were involved. Many of the miRNAs in the network target genes were involved in cell proliferation and apoptosis.In this pilot study, we identified several miRNAs exhibiting differential expression in patients who suffered acute injuries in the skin. Further studies on these miRNAs are needed to validate our findings and explore their roles in the wound healing process of the skin. PMID- 25700310 TI - A novel mutation of the HNF1B gene associated with hypoplastic glomerulocystic kidney disease and neonatal renal failure: a case report and mutation update. AB - Hepatocyte nuclear factor 1 beta (HNF1B) plays an important role in embryonic development, namely in the kidney, pancreas, liver, genital tract, and gut. Heterozygous germline mutations of HNF1B are associated with the renal cysts and diabetes syndrome (RCAD). Affected individuals may present a variety of renal developmental abnormalities and/or maturity-onset diabetes of the young (MODY). A Portuguese 19-month-old male infant was evaluated due to hypoplastic glomerulocystic kidney disease and renal dysfunction diagnosed in the neonatal period that progressed to stage 5 chronic renal disease during the first year of life. His mother was diagnosed with a solitary hypoplastic microcystic left kidney at age 20, with stage 2 chronic renal disease established at age 35, and presented bicornuate uterus, pancreatic atrophy, and gestational diabetes. DNA sequence analysis of HNF1B revealed a novel germline frameshift insertion (c.110_111insC or c.110dupC) in both the child and the mother. A review of the literature revealed a total of 106 different HNF1B mutations, in 236 mutation positive families, comprising gross deletions (34%), missense mutations (31%), frameshift deletions or insertions (15%), nonsense mutations (11%), and splice site mutations (8%). The study of this family with an unusual presentation of hypoplastic glomerulocystic kidney disease with neonatal renal dysfunction identified a previously unreported mutation of the HNF1B gene, thereby expanding the spectrum of known mutations associated with renal developmental disorders. PMID- 25700311 TI - Hepatic resection for hepatocellular carcinoma in patients with portal hypertension: a long-term benefit compared with transarterial chemoembolization and thermal ablation. AB - The optimal treatment for hepatocellular carcinoma (HCC) in cirrhotic patients with portal hypertension (PHT) is still controversial. The objective of this study is to compare HCC patients with PHT treated with hepatic resection to those treated with transarterial chemoembolization (TACE) or thermal ablation. A series of 167 cirrhotic patients with HCC undergoing hepatic resection or TACE/ablation from 2001 to 2008 were retrospectively analyzed. Cirrhotic patients with HCC were divided into 3 groups: hepatic resection in HCC patients with PHT (PHT-R group, n = 58), without PHT (NPHT-R group, n = 67), and TACE or thermal ablation in HCC patients with PHT (PHT-O group, n = 42). The short-term and long-term outcomes of liver function, operative mortality and morbidity, and survival rate were compared.Baseline characteristics were similar among the 3 groups, except for patients in the PHT-R group had larger spleen (16.0 vs 11.4 cm, P = 0.001) and smaller tumor size (4.8 vs 7.1 cm, P = 0.001) in comparison with those in the NPHT-R group. The PHT-R group had better liver function compared with those in the PHT-O group (patients had Child-Turcotte-Pugh class B liver function: 5.2% vs 31%, P = 0.001). There was no significant difference of operative mortality and morbidity in all groups. The 1-, 3-, 5-year survival rates were 80.4%, 55.6%, and 28.1% in the PHT-R group; 79.1%, 64.2%, and 39.8% in the NPHT-R group (vs PHT-R, P = 0.313); and 60.7%, 24.4%, and 7.3% in the PHT-O group (vs PHT-R, P < 0.001). Hepatic resection shows better long-term results for cirrhotic HCC patients with PHT than TACE and thermal ablation. PMID- 25700312 TI - Ex vivo liver resection followed by autotransplantation to a patient with advanced alveolar echinococcosis with a replacement of the retrohepatic inferior vena cava using autogenous vein grafting: a case report and literature review. AB - Alveolar echinococcosis (AE) of the liver is a rare disease. In advanced cases of this parasitic disease, the inferior vena cava (IVC) can be invaded; in these cases, the optimal treatment is liver transplantation and replacement of the IVC. Considering the donor shortage and the drawbacks of immunosuppressive therapy, ex vivo liver resection followed by autotransplantation may be the first choice for these patients. We report the first case of advanced AE successfully treated by an ex vivo liver resection, followed by autotransplantation with a replacement of the retrohepatic IVC using autogenous vein grafting. This graft included the following regions: the bilateral great saphenous vein, part of the retrohepatic inferior vena and the middle hepatic vein with no invasion, the inferior mesenteric vein, and part of the side wall of the infrahepatic vena cava. This patient had an uneventful postoperative recovery; currently, she has been enjoying a normal life and is 12 months postoperative with no immunosuppressive therapy or AE recurrence.In conclusion, ex vivo liver resection followed by autotransplantation with a replacement of the retrohepatic IVC using autogenous vein grafting might be a useful surgical practice for advanced AE. PMID- 25700313 TI - The effects of dementia and long-term care services on the deterioration of care needs levels of the elderly in Japan. AB - To investigate the associations between dementia, the use of long-term care (LTC) services, and the deterioration of care-needs levels of elderly persons in Japan. Using a retrospective cohort study, we analyzed 50,268 insurance beneficiaries aged 65 years and older who had utilized LTC services between 2010 and 2011 in Kyoto prefecture, Japan. Logistic regression analyses were used to identify predictors of care-needs level deterioration. Dementia, facility care services, the male sex, older age, and lower baseline care-needs levels were associated with care-needs level deterioration. The disparity between odds ratios of home care services, dementia diagnoses, and facility care services on care-needs level deterioration diminished with increasing baseline care-needs levels. The other risk factors of care-needs level deterioration showed stronger associations as care-needs levels and age increased. The effects of baseline care-needs levels and dementia should be considered when developing LTC policies. PMID- 25700314 TI - Endoscopic diagnosis of invasion depth for early colorectal carcinomas: a prospective comparative study of narrow-band imaging, acetic acid, and crystal violet. AB - Several studies have validated the effectiveness of narrow-band imaging (NBI) in estimating invasion depth of early colorectal cancers. However, comparative diagnostic accuracy between NBI and chromoendoscopy remains unclear. Other than crystal violet, use of acetic acid as a new staining method to diagnose deep submucosal invasive (SM-d) carcinomas has not been extensively evaluated. We aimed to assess the diagnostic accuracy and interobserver agreement of NBI, acetic acid enhancement, and crystal violet staining in predicting invasion depth of early colorectal cancers. A total of 112 early colorectal cancers were prospectively observed by NBI, acetic acid, and crystal violet staining in sequence by 1 expert colonoscopist. All endoscopic images of each technique were stored and reassessed. Finally, 294 images of 98 lesions were selected for evaluation by 3 less experienced endoscopists. The accuracy of NBI, acetic acid, and crystal violet for real-time diagnosis was 85.7%, 86.6%, and 92.9%, respectively. For image evaluation by novices, NBI achieved the highest accuracy of 80.6%, compared with that of 72.4% by acetic acid, and 75.8% by crystal violet. The kappa values of NBI, acetic acid, and crystal violet among the 3 trainees were 0.74 (95% CI 0.65-0.83), 0.68 (95% CI 0.59-0.77), and 0.70 (95% CI 0.61-0.79), respectively. For diagnosis of SM-d carcinoma, NBI was slightly inferior to crystal violet staining, when performed by the expert endoscopist. However, NBI yielded higher accuracy than crystal violet staining, in terms of less experienced endoscopists. Acetic acid enhancement with pit pattern analysis was capable of predicting SM-d carcinoma, comparable to the traditional crystal violet staining. PMID- 25700315 TI - A comprehensive surgical procedure in conservative management of placenta accreta: a case series. AB - We aimed to present a combined surgical procedure in conservative treatment of placenta accreta based on surgical outcomes in our cohort of patients. The study was designed as a prospective cohort series study. The setting involved two education and research hospitals in Turkey. This study included 12 patients with placenta accreta who were prenatally diagnosed and managed. We offered the patients the choice of conservative or nonconservative treatment. We then offered 2 choices for patients who had preferred conservative treatment, leaving the placenta in situ as is the classical procedure, or our surgical procedure. One patient preferred nonconservative treatment, the others opted for our procedure.We evaluated demographic and obstetric characteristics of patients, sonographic and operative parameters of patients, and surgical outcomes. We operated on 11 patients using this surgical procedure that we have developed for placenta accreta cases. We found that there was no need for hysterectomy in any patient, and we preserved the uterus for all of these patients. No patient presented any septic complication or secondary vaginal bleeding.Our surgical procedure seems to be effective and useful in the conservative treatment of placenta accreta. PMID- 25700316 TI - Giant coronary artery aneurysm with fistula to the pulmonary artery complicated by frequent ventricular premature contractions: a case report. AB - Giant coronary artery aneurysm with a fistula is a rare condition. The presence of a giant aneurysm imposes considerable health risks. We report a case of a 67 year-old woman who presented with frequent ventricular premature contractions caused by a giant coronary aneurysm arising from a branch of the left anterior descending coronary artery that had a fistulous connection to the pulmonary artery. The patient was referred for cardiac surgery. The giant aneurysm was resected, and the proximal and distal openings were closed directly. The main pulmonary artery was opened longitudinally and the fistula was also closed directly. The patient's symptoms of frequent ventricular premature contractions disappeared postoperatively as confirmed by electrocardiography. Although the standard therapeutic strategies of the disease are not well established because of the rarity of this condition, our clinical results indicate that the surgical treatment is an effective choice. PMID- 25700317 TI - Risk factors and incidence of repeat osteoporotic fractures among the elderly in Taiwan: a population-based cohort study. AB - The incidence of osteoporotic fracture (OF), a condition that leads to higher morbidity and mortality in the elderly, is increasing yearly worldwide. However, most studies of OF have focused on the epidemiology of initial fractures, mainly in female and white populations. This study aimed to explore the incidence and the risk factors for repeat osteoporotic fracture (ROF) in Taiwan.We performed a retrospective cohort study using the Taiwan National Health Insurance Database (NHIRD) from 1995 through 2011. Individuals aged 65 years or older who experienced an initial OF were included. The patients were followed until death, the end of registration in the NHIRD, ROF occurrence, or the end of the study period (December 31, 2011), whichever occurred first. The incidence of ROF over >= 5 years after the initial fracture was analyzed, and the risk factors for ROF were assessed using Cox proportional hazards models. The incidence rates of ROF were 950.5, 321.4, 158.7, 92.8, and 70.2 per 1000 person-years among subjects in their first, second, third, fourth, and fifth years after the initial OF, respectively. Nearly 45% of the subjects sustained a ROF in the first year after OF. ROF risk increased with age and Charlson Comorbidity Index (CCI) score. Greater risk for ROF was observed among female subjects and those who had suffered from hip and vertebral fracture at the first OF, had undergone OF related surgery, and had received bone-related medications. The incidence of ROF in the Taiwanese elderly is higher during the first year after the initial OF, and ROF risk increases with age, female sex, high CCI score, and in those who have undergone OF-related surgery, sustained hip or vertebral fracture, and used bone-related medications. PMID- 25700318 TI - Comparison of retroperitoneoscopic versus transperitoneoscopic resection of retroperitoneal paraganglioma: a control study of 74 cases at a single institution. AB - We aimed to compare the safety and patient outcomes of retroperitoneal paraganglioma (PG) following the retroperitoneoscopic and transperitoneoscopic approaches based on large samples.Seventy-four patients with retroperitoneal PG undergoing laparoscopic resection from June 2004 to September 2013 were retrospectively included. The patients were divided into the retroperitoneal (n = 40) and transperitoneal (n = 34) groups. Demographic and perioperative data, including the operation time, estimated blood loss, incidence of intraoperative hypertension, bowel recovery day, postoperative hospital stay, and systemic inflammatory response syndrome (SIRS) were recorded.The retroperitoneal group showed a shorter operation time and earlier postoperative exsufflation time compared with the transperitoneal group (84 +/- 28.5 minutes vs 115 +/- 35.7 minutes and 1.7 +/- 0.6 vs 2.3 +/- 0.7 day, respectively; both P < 0.001). No significant differences in the baseline data were observed between 2 groups. All patients, except for 1 case of open conversion, underwent laparoscopic surgery. There were no patient deaths. Data analysis demonstrated no significant difference in the surgical blood loss, incidence of surgical blood pressure elevation, postoperative hospital stay, or incidence of SIRS between 2 groups.The operation time for the retroperitoneoscopic resection of retroperitoneal PG is shorter, and gastrointestinal functions improve more quickly compared to the transperitoneoscopic approach. This study may provide a valuable source of clinical information for clinicians in related fields. PMID- 25700319 TI - Benefits of cardiac rehabilitation in heart failure patients according to etiology: INCARD French study. AB - We investigated the impact of heart failure (HF) etiology on the outcome of cardiac rehabilitation (CR) assessed by functional and clinical parameters. Treatment of chronic HF requires multidisciplinary approaches with a recognized role for CR. INCARD is a French study aimed at evaluating the benefits of sustainable CR in coronary (C) and noncoronary patients (NC) treated and educated during a 24-month period of follow-up. Prospective, monocentric patients with HF underwent inpatient physical training followed by a home-based program. Evaluations were performed at inclusion, discharge, 3 months after discharge, and subsequently every 6 months over the 24 months of outpatient rehabilitation.A total of 147 HF patients with left ventricular ejection fraction (LVEF) <40 were admitted to the CR center, 63 accepted to join INCARD (29 C and 34 NC). Although the C participants C having both an echocardiographic LVEF and an initially lower peak VO2, inpatient rehabilitation improved all functional parameters. Only NC showed an improved LVEF during the first 3 months of outpatient-follow-up. The main outcome of the outpatient rehabilitation was a trend toward stabilization of clinical and laboratory parameters with no significant difference between C and NC. This study confirms the benefits of initial HF inpatient rehabilitation and encourages prolonged outpatient monitoring. The results on functional parameters suggest exercise training should be conducted regardless of the HF etiology. PMID- 25700320 TI - A clinical evaluation denture adhesives used by patients with xerostomia. AB - The purpose of study was to analyze the participants' opinions concerning the effectiveness of 6 denture adhesives (DA). The study group included 60 participants. Criteria for selecting the patients were as follows: reduced retention and stabilization of maxillary complete dentures and xerostomia. These features were evaluated on basis of clinical examination and standard sialometry tests (u-SFR). Retention of maxillary dentures was scored by modified Kapur index before application of DA. All participants were divided randomly into 6 groups regarding the use of the 6 DA during a 6-month period. After this time, participants completed an HRQL questionnaire. DA noticeably improved retention and stabilization of maxillary complete dentures. DA in the glue form had the best retention effectiveness in participants with xerostomia. These materials are difficult to clean from the denture base. The data are presented in tables and figures. The results of the study collected positive influence of adhesives on retention of dentures in xerostomia patients. The cleaning dentures and denture bearing tissues was difficult. DA help in the use of prostheses, but it is also necessary for the treatment of the causes and symptoms of xerostomia. PMID- 25700321 TI - Do we really need additional contrast-enhanced abdominal computed tomography for differential diagnosis in triage of middle-aged subjects with suspected biliary pain. AB - Enhanced computed tomography (CT) is widely used for evaluating acute biliary pain in the emergency department (ED). However, concern about radiation exposure from CT has also increased. We investigated the usefulness of pre-contrast CT for differential diagnosis in middle-aged subjects with suspected biliary pain.A total of 183 subjects, who visited the ED for suspected biliary pain from January 2011 to December 2012, were included. Retrospectively, pre-contrast phase and multiphase CT findings were reviewed and the detection rate of findings suggesting disease requiring significant treatment by noncontrast CT (NCCT) was compared with cases detected by multiphase CT.Approximately 70% of total subjects had a significant condition, including 1 case of gallbladder cancer and 126 (68.8%) cases requiring intervention (122 biliary stone-related diseases, 3 liver abscesses, and 1 liver hemangioma). The rate of overlooking malignancy without contrast enhancement was calculated to be 0% to 1.5%. Biliary stones and liver space-occupying lesions were found equally on NCCT and multiphase CT. Calculated probable rates of overlooking acute cholecystitis and biliary obstruction were maximally 6.8% and 4.2% respectively. Incidental significant finding unrelated with pain consisted of 1 case of adrenal incidentaloma, which was also observed in NCCT.NCCT might be sufficient to detect life-threatening or significant disease requiring early treatment in young adults with biliary pain. PMID- 25700322 TI - Comparing characteristics of adverse drug events between older and younger adults presenting to a Taiwan emergency department. AB - To compare the proportion, seriousness, preventability of adverse drug events (ADEs) between the older adults (>= 65 years old) and younger adults (<65 years old) presenting to the emergency department (ED), we conducted a prospective observational cohort study of patients 18 years and older presenting to the ED. For all ED visits between March 1, 2009, and Feb 28, 2010, investigators identified ADEs and assessed cases using the Naranjo adverse drug reaction probability scale. Outcomes (proportion, seriousness, and preventability of ADE, length of ED stay, and hospitalization) and associated variables were measured and compared between younger and older adults. The results showed that of 58,569 ED visits, 295 older adults, and 157 younger adults were diagnosed as having an ADE and included in our analysis. The proportion of ADEs leading to ED visits in the older group, 14.3 per 1000 (295/20,628), was significantly higher than the younger group of 4.1 per 1000 (157/37,941). The older group with ADE had a longer ED stay (odds ratio [OR] 3.5, 95% confidence interval [CI] 1.9-6.4 for stay >= 24 hours) and larger proportion of preventable ADEs (OR 2.2, 95% CI 1.4 3.6) than the younger group, but there was no significant difference in terms of serious ADEs (OR 0.6, 95% CI 0.3-1.3 for fatal and life threatening) and hospitalization (OR 1.5, 95% CI 0.9-2.6) between the 2 groups. In addition, patients in the older group were more likely to be male, to have symptoms of fatigue or altered mental status, to involve cardiovascular, renal, and respiratory systems, and to have higher Charlson comorbidity index scores, higher number of prescription medications, and higher proportion of unintentional overdose. In conclusion, the proportion of ADE-related ED visits in older adults was higher than younger adults, and many of these were preventable. The most common drug categories associated with preventable ADEs in the older adults were antithrombotic agents, antidiabetic agents, and cardiovascular agents. PMID- 25700323 TI - Topical fluorometholone treatment for ocular dryness in patients with Sjogren syndrome: a randomized clinical trial in China. AB - The purpose of the study was to evaluate the efficacy of an ophthalmic solution containing 0.1% fluorometholone (FML) and 0.1% sodium hyaluronate (HA) for the treatment of ocular dryness in Sjogren syndrome (SS) patients.Forty SS patients were randomly assigned to the FML or cyclosporin A (CsA) treatment groups. The FML group was treated with 0.1% FML and 0.1% HA, and the CsA group was treated with 0.5% CsA and 0.1% HA. Primary outcomes were corneal fluorescein staining (CFS), the Ocular Surface Disease Index (OSDI) score, conjunctival goblet cell density, and the severity of conjunctival congestion. Patients were also evaluated based on tear film breakup time (TFBUT) and the Schirmer test. After 8 weeks of treatment, the mean CFS scores were significantly lower in both the groups, compared with the baseline values, and the CFS score of the FML group at week 2 was significantly lower than that of the CsA group (P = 0.042). The OSDI scores improved significantly in both the groups throughout the study, and the OSDI score in the FML group at week 4 was significantly lower than that of the CsA group (P = 0.042). After 8 weeks of therapy, the conjunctival goblet cell density was significantly higher in both the groups (P < 0.001 for both) compared with the baseline values. Conjunctival congestion was reduced in both the groups throughout the study, and the severity in the FML group was significantly less at week 4 compared with that in the CsA group (P = 0.035). The TFBUT in the FML group at week 8 was significantly longer than in the CsA group (P = 0.04). Treatment using topical 0.1% FML provided faster improvement in the symptoms of ocular dryness in SS patients compared with topical 0.5% CsA. PMID- 25700324 TI - Increased coronary artery disease severity in black women undergoing coronary bypass surgery. AB - Race and sex disparities are believed to play an important role in heart disease. The purpose of this study was to examine the association between race, sex, and number of diseased vessels at the time of coronary artery bypass grafting (CABG), and subsequent postoperative outcomes. The 13,774 patients undergoing first-time, isolated CABG between 1992 and 2011 were included. Trend in the number of diseased vessels between black and white patients, stratified by sex, were analyzed using a Cochran-Armitage trend test. Models were adjusted for age, procedural status (elective vs. nonelective), and payor type (private vs. nonprivate insurance). Black female CABG patients presented with an increasingly greater number of diseased vessels than white female CABG patients (adjusted P(trend) = 0.0021). A similar trend was not observed between black and white male CABG patients (adjusted P(trend) = 0.18). Black female CABG patients were also more likely to have longer intensive care unit and hospital lengths of stay than other race-sex groups.Our findings suggest that black female CABG patients have more advanced coronary artery disease than white female CABG patients. Further research is needed to determine the benefit of targeted preventive care and preoperative workup for this high-risk group. PMID- 25700325 TI - Association between periodontal disease and osteoporosis by gender: a nationwide population-based cohort study. AB - Periodontitis and osteoporosis are primary concerns in public health and clinical management. The aim of this study was to investigate the association between periodontitis and osteoporosis by gender.Data were retrieved from the National Health Insurance Research Database, Taiwan. A diagnosis of periodontitis was defined on the basis of subgingival curettage, periodontal flap operation, and gingivectomy (excluding those with restorative or aesthetic indications). Multiple logistic regression was used for analysis. After adjusting for age, sex, income, and geographical region, there was a significant association between periodontitis and osteoporosis among women (odds ratio: 1.96; 95% confidence interval 1.17-3.26). The association between periodontitis and osteoporosis was significant among women. PMID- 25700326 TI - The relationship between type 2 diabetic patients' early medical care-seeking consistency to the same clinician and health care system and their clinical outcomes. AB - The literature has demonstrated that the continuity of diabetes care can lower medical service utilization and expenses. However, few studies have examined the effects of patients' medical care-seeking behaviors in the early stage after the diagnosis of diabetes on their long-term prognoses. This study aimed to examine the association of medical care-seeking behavior in the first year following diabetes diagnosis on the occurrence of diabetes-related complications among patients in Taiwan. This is a retrospective data collection with follow-up analysis and a nationwide population-based dataset in Taiwan. A total of 89,428 newly diagnosed type 2 diabetes mellitus patients during the period from 2000 to 2006 were followed up until 2010. The patients' medical care-seeking behaviors were classified as follows: high consistency to a physician, high consistency to a medical setting, medium consistency to providers, and low consistency to providers. The occurrence of diabetes-related complications and all-cause mortality were the primary outcomes of this study. Chi-square tests, ANOVAs, and Cox proportional hazard models were applied to examine the relationships between the predictors and medical outcomes. Compared to the patients with high medical care-seeking consistency to a physician, the multivariate-adjusted hazard ratios of diabetes-related complications occurrence among patients in the high consistency to a medical setting, medium consistency, and low consistency categories were 1.112 (95% CI 1.089-1.136, P < 0.001), 1.226 (95% CI 1.205-1.248, P < 0.001), and 1.536 (95% CI 1.504-1.567, P < 0.001) in outpatient visits and 1.032 (95% CI 0.992-1.074, P = 0.121), 1.056 (95% CI 1.022-1.092, P = 0.001), and 1.208 (95% CI 1.164-1.254, P < 0.001) in complication-incurred hospitalizations, respectively. The monotonic trend was sustained across different strata of age, gender, and disease complexity. The findings of this study suggest that the incentives of continuity of care and physician-patient relationship management should be reinforced during the early stage of diabetes care in future medical care systems. PMID- 25700327 TI - Comparison of intranasal and intravenous diazepam on status epilepticus in stroke patients: a retrospective cohort study. AB - Administering diazepam intravenously or rectally in an adult with status epilepticus can be difficult and time consuming. The aim of this study was to examine whether intranasal diazepam is an effective alternative to intravenous diazepam when treating status epilepticus. We undertook a retrospective cohort study based on the medical records of 19 stroke patients presenting with status epilepticus to our institution. We measured the time between arrival at the hospital, the intravenous or intranasal administration of diazepam, and the seizure termination. Intranasal diazepam was administered about 9 times faster than intravenous diazepam (1 vs 9.5 minutes, P = 0.001), resulting in about 3 fold reduction in the time to termination of seizure activity after arrival at the hospital (3 minutes compared with 9.5 minutes in the intravenous group, P = 0.030). No adverse effects of intranasal diazepam were evident from the medical records. Intranasal diazepam administration is safer, easier, and quicker than intravenous administration. PMID- 25700328 TI - Evaluation of microincision vitrectomy surgery using wide-viewing system for complications with ocular sarcoidosis. AB - We evaluate the outcomes of microincision vitrectomy surgery (MIVS) using wide viewing system for complications with ocular sarcoidosis resistance to medical treatment.Consecutive clinical records of 24 eyes (19 patients) with complications of ocular sarcoidosis underwent MIVS between April 2010 and December 2013 were retrospectively reviewed. MIVS and phacoemulsification were performed in 18 eyes and MIVS only in 6 eyes. Best-corrected visual acuity (BCVA), inflammation scores in the anterior segment and in the posterior segment, and central retinal thickness (CRT) of eyes with cystoid macular edema (CME) before surgery and after 1 week, 1, 3, 6, and 12 months were evaluated.LogMAR (log of the minimum angle of resolution) converted from BCVA was improved in 83.3% after 12 months and 66.7% showed improvement of more than 2 lines. The mean LogMAR was significantly improved from 1.14 +/- 1.18 to 0.36 +/- 0.79 in all eyes and 0.83 +/- 0.86 to 0.23 +/- 0.41 in eyes with MIVS and phacoemulsification, although no improvement was observed in eyes with MIVS only. Significant decrease of the mean anterior inflammation score was observed after 1 month in eyes with MIVS only and after 12 months in eyes with MIVS and phacoemulsification, and the mean posterior inflammation scores decreased after 1 week in all eyes. In eyes with preoperative CME, mean CRT was significantly decreased from 1 week after surgery. There was no case in which ocular inflammation was exacerbated by surgical stress. Improvement of visual acuity and resolution of ocular inflammation could be achieved by MIVS using wide-viewing system for complications of ocular sarcoidosis. PMID- 25700329 TI - Anterior inferior iliac spine avulsion fracture: a series of 5 cases. AB - Avulsion fractures of the pelvic apophyses rarely occur in adolescent athletes in the course of sudden strong contraction of muscle attached to growth cartilage. This injury may usually be misdiagnosed for tendon or muscle strain. Patient's history, physical examination, and radiologic studies are important for diagnosis. The literature includes only a few case reports but no case series as yet. The aim of this study was to present the results of 5 cases of anterior inferior iliac spine (AIIS) avulsion fractures treated conservatively. The study included 5 patients (4 male, 1 female, mean age 13.6 years) who underwent conservative treatment for AIIS avulsion fractures and had an adequate follow-up. All patients were admitted to the emergency department and misdiagnosed as muscle strain. Three of them were football player, 1 skier, and 1 fighter. Each patient was treated with immobilization and nonsteroidal anti-inflammatory drugs. At follow-up, all patients showed relief from their pain and mechanical symptoms and regained full range of motion and returned to their previous levels of activity. Diagnosis requires careful attention to the physical examination and imaging. In this series, all pelvic avulsion fractures (100%) were managed successfully with a conservative approach. Good results and return to previous levels of activity can be achieved with conservative treatment. PMID- 25700330 TI - Relationship of MTHFR gene 677C -> T polymorphism, homocysteine, and estimated glomerular filtration rate levels with the risk of new-onset diabetes. AB - East Asian patients with diabetes have a higher risk for renal complications and strokes than Europeans. We aimed to evaluate the effect of methylenetetrahydrofolate reductase (MTHFR) gene 677 C -> T polymorphism, which was associated with a higher stroke risk and was common in the Chinese population, as well as homocysteine and estimated glomerular filtration rate (eGFR) levels on the risk of new-onset diabetes (NOD). A total of 2422 subjects without diabetes were followed-up for 7 years. NOD was defined as fasting plasma glucose >= 7.0 mmol/L or self-reported physician diagnosis of diabetes. Compared with subjects with MTHFR 677 CC genotype, those with TT genotype had a higher risk of NOD in females (odds ratio 2.78, 95% confidence interval 1.39-5.56) but not in males (0.80, 0.40-1.61, P for interaction = 0.008). Furthermore, MTHFR 677 C -> T polymorphism was more strongly associated with the risk of NOD among females with higher body mass index (BMI, >= 23 vs <23 kg/m(2), P for interaction = 0.009) or lower high-density lipoprotein-cholesterol (HDL-C, <1.3 vs >= 1.3 mmol/L, P for interaction = 0.015) levels. Hyperhomocysteinemia (>= 16 vs <10 MUmol/L) was not significantly associated with NOD in males (0.88, 0.42-1.85) or females (1.52, 0.65-3.57). However, mildly decreased eGFR (<90 vs 90-120 mL/min/1.73 m(2)) was associated with NOD mainly in males (1.96, 1.01-3.78; females, 0.74, 0.32-1.72, P for interaction = 0.134). Females with MTHFR 677 TT genotype had a significantly higher risk of NOD, particularly those with higher BMI or low HDL-C levels. The higher risk of NOD associated with mildly decreased eGFR also warrants more investigation. Our results provide insights into the ethnic differences of diabetic complications between East Asian patients and Europeans. PMID- 25700331 TI - Tonsillar metastasis of small cell lung cancer in a patient with idiopathic pulmonary fibrosis: a case report. AB - Small cell lung cancer (SCLC) metastasizes widely, but palatine tonsil is an extremely unusual site for metastasis. Idiopathic pulmonary fibrosis (IPF) is associated with increased risk of lung cancer. However, the most common histological findings among patients of lung cancer with IPF are known as non SCLC such as adenocarcinoma and squamous cell carcinoma. In addition, the majority of them are located in IPF-associated fibrotic peripheral lesions. A 77 year-old man visited for 1-month persistent cough and dyspnea, with inspiratory dry crackles on both lower lung fields and a large oval mass in his throat. Chest computed tomography revealed 2 masses in the left lower lobe, 1 mass in the right upper lobe, and multiple enlarged mediastinal lymph nodes of the lung accompanying with IPF, which were diagnosed as SCLC pathologically. Very interestingly, the tonsillar mass was also confirmed as the metastatic lesion of SCLC. Chemotherapy for SCLC and medical treatment for IPF were applied. However, in following-up, he expired due to respiratory failure by an acute exacerbation of IPF 3 months after the diagnosis. In this current report, we describe, for the first time, a case of tonsillar metastasis of SCLC with IPF detected simultaneously in a 77-year-old man. PMID- 25700332 TI - Hollow agarose microneedle with silver coating for intradermal surface-enhanced Raman measurements: a skin-mimicking phantom study. AB - Human intradermal components contain important clinical information beneficial to the field of immunology and disease diagnosis. Although microneedles have shown great potential to act as probes to break the human skin barrier for the minimally invasive measurement of intradermal components, metal microneedles that include stainless steel could cause the following problems: (1) sharp waste production, and (2) contamination due to reuse of microneedles especially in developing regions. In this study, we fabricate agarose microneedles coated with a layer of silver (Ag) and demonstrate their use as a probe for the realization of intradermal surface enhanced Raman scattering measurements in a set of skin mimicking phantoms. The Ag-coated agarose microneedle quantifies a range of glucose concentrations from 5 to 150 mM inside the skin phantoms with a root-mean square error of 5.1 mM within 10 s. The needle is found enlarged by 53.9% after another 6 min inside the phantom. The shape-changing capability of this agarose microneedle ensures that there use of these microneedles is impossible, thus avoiding sharp waste production and preventing needle contamination,which shows the great potential for safe and effective needle-based measurements. PMID- 25700333 TI - Why are the {Cu4N4} rings in copper(I) phosphinimide clusters [Cu{MU-N = PR3}]4 (R = NMe3 or Ph) planar? AB - The copper phosphinimide complexes [Cu{MU-N[double bond, length as m-dash]PR3}]4 (1, R = NMe2 and 2, R = Ph) were obtained in good yields from the reactions of Cu[Mes] (Mes = mesityl, C6H2Me3-2,4,6) with the corresponding iminophosphoranes, HNPR3. The molecular structures of 1 and 2 reveal the presence of planar eight membered {Cu4N4} rings which contrasts with the saddle-shaped {M4N4} rings found in related metal phosphinimide complexes. According to computations, there is negligible aromaticity in the planar {Cu4N4} rings in 1 and 2 and the saddle shape observed in related {M4N4} rings is due to steric factors. PMID- 25700334 TI - Toxic metals in children's toys and jewelry: coupling bioaccessibility with risk assessment. AB - A total of 45 children's toys and jewelry were tested for total and bioaccessible metal concentrations. Total As, Cd, Sb, Cr, Ni, and Pb concentrations were 0.22 19, 0.01-139, 0.1-189, 0.06-846, 0.14-2894 and 0.08-860,000 mg kg(-1). Metallic products had the highest concentrations, with 3-7 out of 13 samples exceeding the European Union safety limit for Cd, Pb, Cr, or Ni. However, assessment based on hazard index >1 and bioaccessible metal showed different trends. Under saliva mobilization or gastric ingestion, 11 out of 45 samples showed HI >1 for As, Cd, Sb, Cr, or Ni. Pb with the highest total concentration showed HI <1 for all samples while Ni showed the most hazard with HI up to 113. Our data suggest the importance of using bioaccessibility to evaluate health hazard of metals in children's toys and jewelry, and besides Pb and Cd, As, Ni, Cr, and Sb in children's products also deserve attention. PMID- 25700335 TI - Combined ecological risks of nitrogen and phosphorus in European freshwaters. AB - Eutrophication is a key water quality issue triggered by increasing nitrogen (N) and phosphorus (P) levels and potentially posing risks to freshwater biota. We predicted the probability that an invertebrate species within a community assemblage becomes absent due to nutrient stress as the ecological risk (ER) for European lakes and streams subjected to N and P pollution from 1985 to 2011. The ER was calculated as a function of species-specific tolerances to NO3(-) and total P concentrations and water quality monitoring data. Lake and stream ER averaged 50% in the last monitored year (i.e. 2011) and we observed a decrease by 22% and 38% in lake and stream ER (respectively) of river basins since 1985. Additionally, the ER from N stress surpassed that of P in both freshwater systems. The ER can be applied to identify river basins most subjected to eutrophication risks and the main drivers of impacts. PMID- 25700336 TI - Winter diversity and expression of proteorhodopsin genes in a polar ocean. AB - Mixotrophy is a valuable functional trait used by microbes when environmental conditions vary broadly or resources are limited. In the sunlit waters of the ocean, photoheterotrophy, a form of mixotrophy, is often mediated by proteorhodopsin (PR), a seven helices transmembrane protein binding the retinal chromophore. Altogether, they allow bacteria to capture photic energy for sensory and proton gradient formation cell functions. The seasonal occurrence and diversity of the gene coding for PR in cold oligotrophic polar oceans is not known and PR expression has not yet been reported. Here we show that PR is widely distributed among bacterial taxa, and that PR expression decreased markedly during the winter months in the Arctic Ocean. Gammaproteobacteria-like PR sequences were always dominant. However, within the second most common affiliation, there was a transition from Flavobacteria-like PR in early winter to Alphaproteobacteria-like PR in late winter. The phylogenetic shifts followed carbon dynamics, where patterns in expression were consistent with community succession, as identified by DNA community fingerprinting. Although genes for PR were always present, the trend in decreasing transcripts from January to February suggested reduced functional utility of PR during winter. Under winter darkness, sustained expression suggests that PR may continue to be useful for non-ATP forming functions, such as environmental sensing or small solute transport. The persistence of PR expression in winter among some bacterial groups may offer a competitive advantage, where its multifunctionality enhances microbial survival under harsh polar conditions. PMID- 25700337 TI - Genomic potential for nitrogen assimilation in uncultivated members of Prochlorococcus from an anoxic marine zone. AB - Cyanobacteria of the genus Prochlorococcus are the most abundant photosynthetic marine organisms and key factors in the global carbon cycle. The understanding of their distribution and ecological importance in oligotrophic tropical and subtropical waters, and their differentiation into distinct ecotypes, is based on genetic and physiological information from several isolates. Currently, all available Prochlorococcus genomes show their incapacity for nitrate utilization. However, environmental sequence data suggest that some uncultivated lineages may have acquired this capacity. Here we report that uncultivated low-light-adapted Prochlorococcus from the nutrient-rich, low-light, anoxic marine zone (AMZ) of the eastern tropical South Pacific have the genetic potential for nitrate uptake and assimilation. All genes involved in this trait were found syntenic with those present in marine Synechococcus. Genomic and phylogenetic analyses also suggest that these genes have not been aquired recently, but perhaps were retained from a common ancestor, highlighting the basal characteristics of the AMZ lineages within Prochlorococcus. PMID- 25700338 TI - Single-taxon field measurements of bacterial gene regulation controlling DMSP fate. AB - The 'bacterial switch' is a proposed regulatory point in the global sulfur cycle that routes dimethylsulfoniopropionate (DMSP) to two fundamentally different fates in seawater through genes encoding either the cleavage or demethylation pathway, and affects the flux of volatile sulfur from ocean surface waters to the atmosphere. Yet which ecological or physiological factors might control the bacterial switch remains a topic of considerable debate. Here we report the first field observations of dynamic changes in expression of DMSP pathway genes by a single marine bacterial species in its natural environment. Detection of taxon specific gene expression in Roseobacter species HTCC2255 during a month-long deployment of an autonomous ocean sensor in Monterey Bay, CA captured in situ regulation of the first gene in each DMSP pathway (dddP and dmdA) that corresponded with shifts in the taxonomy of the phytoplankton community. Expression of the demethylation pathway was relatively greater during a high-DMSP producing dinoflagellate bloom, and expression of the cleavage pathway was greater in the presence of a mixed diatom and dinoflagellate community [corrected].These field data fit the prevailing hypothesis for bacterial DMSP gene regulation based on bacterial sulfur demand, but also suggest a modification involving oxidative stress response, evidenced as upregulation of catalase via katG, when DMSP is demethylated. PMID- 25700339 TI - Porous metallic MoO2-supported MoS2 nanosheets for enhanced electrocatalytic activity in the hydrogen evolution reaction. AB - Advanced materials for electrocatalytic water splitting are central to renewable energy research. In this work, MoS2 nanosheets supported on porous metallic MoO2 (MoS2/MoO2) were produced by sulfuration treatments of porous and highly conductive MoO2 for the hydrogen evolution reaction. Porous MoO2 with one dimensional channel-like structures was prepared by calcination at elevated temperatures using phosphomolybdic acid as the precursor and mesoporous silica (SBA-15) as the template, and the subsequent hydrothermal treatment in the presence of thioacetamide led to the transformation of the top layers to MoS2 forming MoS2/MoO2 composites. Electrochemical studies showed that the obtained composites exhibited excellent electrocatalytic activity for HER with an onset potential of -104 mV (vs. RHE), a large current density (10 mA cm(-2) at -0.24 V), a small Tafel slope of 76.1 mV dec(-1) and robust electrochemical durability. The performance might be ascribed to the high electrical conductivity and porous structures of MoO2 with one-dimensional channels of 3 to 4 nm in diameter that allowed for fast charge transport and collection. PMID- 25700340 TI - Life cycle assessment of biomethane use in Argentina. AB - Renewable substitutes for natural gas, such as biogas, require adequate treatment to remove impurities. This paper presents the life cycle and environmental impact of upgrading biogas using absorption-desorption process with three different solvents: water, diglycolamine and polyethylene glycol dimethyl ether. The results showed that water produces a minor impact in most of the considered categories, and an economic analysis showed that water is the most feasible solvent for obtaining the lowest payback period. This analysis includes three different sources for biogas production and two end uses for biomethane. The use of different wastes as sources results in different environmental impacts depending on the type of energy used in the anaerobic digestion. The same situation occurs when considering the use of biomethane as a domestic fuel or for power generation. Using energy from biogas to replace conventional energy sources in production and upgrading biogas significantly reduce the environmental impacts of processes. PMID- 25700341 TI - Hydrothermal carbonization of off-specification compost: a byproduct of the organic municipal solid waste treatment. AB - The possibility to apply the hydrothermal carbonization (HTC) process to off specification compost (EWC 19.05.03) at present landfilled was investigated in this work. The aim was to produce a carbonaceous solid fuel for energy valorization, with the perspective of using HTC as a complementary technology to common organic waste treatments. Thus, samples of EWC 19.05.03 produced by a composting plant were processed through HTC in a batch reactor. Analytical activities allowed to characterize the HTC products and their yields. The hydrochar was characterized in terms of heating value, thermal stability and C, H, O, N, S and ash content. The liquid phase was characterized in terms of total organic carbon and mineral content. The composition of the gas phase was measured. Results show that the produced hydrochar has a great potentiality for use as solid fuel. PMID- 25700342 TI - Enhancing waste activated sludge digestion and power production using hypochlorite as catholyte in clayware microbial fuel cell. AB - Waste activated sludge was digested in anodic compartment of dual chambered clayware microbial fuel cell (MFC). Performance of MFC was evaluated using oxygen (MFC-1) and hypochlorite (MFC-2) as cathodic electron acceptors. Power production of 8.7 W/m(3) was achieved using hypochlorite as catholyte, which was two times higher than using oxygen (4.2 W/m(3)). Total chemical oxygen demand of sludge was reduced by 65.4% and 84.7% in MFC-1 and MFC-2, respectively. Total and volatile suspended solids reductions were higher in MFC-2 (75.8% and 80.2%, respectively) as compared to MFC-1 (66.7% and 76.4%, respectively). Use of hypochlorite demonstrated 3.8 times higher Coulombic efficiency (13.8%) than oxygen. Voltammetric and impedance analysis revealed increase in reduction peak (from 8 to 24 mA) and decreased polarization resistance (from 42.6 to 26.5 Omega). Hypochlorite proved to be better cathodic electron acceptor, supporting rapid sludge digestion within 8 days of retention time and improved power production in MFC. PMID- 25700343 TI - Bovine recombinant lipopolysaccharide binding protein (BRLBP) regulated apoptosis and inflammation response in lipopolysaccharide-challenged bovine mammary epithelial cells (BMEC). AB - Lipopolysaccharide-binding protein (LBP) is an acute-phase protein involved in host response to Gram-negative and Gram-positive pathogens. It has been reported to exert diverse biological activities, such as anti-inflammatory effects. However, what effects it has on bovine mastitis has not been investigated. The aim of this study was to verify the anti-inflammatory properties of LBP on the inflammatory response of primary bovine mammary epithelial cells (BMEC) induced by lipopolysaccharide (LPS), and to determine the underlying mechanism. Bovine mammary epithelial cells were treated with various concentrations of LPS (1, 10, 20, and 100 MUg/mL) for 3, 6, 12, and 24h. The results showed that LPS significantly inhibited cell viability in a dose-dependent manner. When cells were treated with LPS (10 MUg/mL) for 12 h, the permeability of the cell membrane increased significantly. This promoted apoptosis. Various concentrations (10 and 20 MUg/mL) of bovine recombinant lipopolysaccharide binding protein (BRLBP) could weaken the inflammation injury of BMEC induced by LPS without cytotoxicity. Toll like receptor 4 (TLR4), nuclear factor kappaB (NF-kappaB), IL-1beta, and tumor necrosis factor alpha (TNF-alpha) from BMEC were decreased. TLR4 and NF-kappaB P65 protein levels were down-regulated, and nuclear transcription factor kappaB activity was also weakened. All these results indicated that the protective effects of high concentrations of BRLBP on LPS-induced inflammation injury in BMEC were at least partially achieved by the decreased production of pro inflammatory cytokines. BRLBP was found to directly inhibit LPS/TLR4-mediated NF kappaB activation. One possible anti-inflammatory mechanism can be attributed to the negative role of BRLBP in suppressing TLR4/NF-kappaB activation mediated by LPS. These findings suggested that BRLBP may be a useful agent to treat LPS induced mastitis. PMID- 25700344 TI - Immunoglobulin kappa variable region gene selection during early human B cell development in health and systemic lupus erythematosus. AB - The unique specificity of the B cell receptor is generated by an ordered sequence of gene rearrangement events. Once IGH genes have rearranged, rearrangement at the IGK locus is initiated followed by the IGL locus if functional IGK rearrangement is not achieved. Receptor specificity can subsequently be altered by secondary light chain editing based on the features of the heavy and light chain combination. The final profile of expressed genes is not random and biases in this profile are associated with several autoimmune diseases. However, how and when biases are created is not known. To increase our understanding of the processes of selection and editing of IGK rearrangements, we compared four groups of rearrangements of IGK acquired by next generation sequencing. First, expressed rearrangements of IGK from cDNA of IGK expressing B cells. Second, productive rearrangements of IGK from DNA of the same kappa expressing B cells. Third, non productive rearrangements of IGK from DNA of IGK and IGL expressing B cells, and fourth productively rearranged IGK from DNA of IGL expressing B cells. The latter group would have been rejected during B cell development in favour of rearrangement at the IGL locus and are therefore selected against. We saw evidence that rearranged IGK segments can be selected at a checkpoint where the decision to rearrange the IGL locus is made. In addition, our data suggest that mechanisms regulating the expression or not of IGK rearrangements may also contribute to repertoire development and also that this latter component of the selection process is defective in SLE. PMID- 25700345 TI - TRAF6 is required for the GM-CSF-induced JNK, p38 and Akt activation. AB - JNK, p38 and Akt signalings have been shown to be activated by granulocyte macrophage colony-stimulating factor (GM-CSF) and are pivotal for GM-CSF-mediated survival, proliferation and differentiation of macrophages and their progenitors. However, the detailed mechanism of how these signalings is activated by GM-CSF is not fully elucidated. We report here that E3 ligase TRAF6 is required for the GM CSF-induced activation of JNK, p38 and Akt. GM-CSF triggers autoubiquitination of TRAF6 and TRAF6 knocked down results in impaired activation of JNK and p38 signaling. TRAF6 is also required for GM-CSF-induced ubiquitination and activation of Akt. These findings reveal novel roles of TRAF6 in GM-CSF signaling. PMID- 25700346 TI - MicroRNAs targeting the immunomodulatory HLA-G gene: a new survey searching for microRNAs with potential to regulate HLA-G. AB - The HLA-G gene is a non-classical class I MHC, responsible for modulating immune responses by inhibiting Natural Killer and cytotoxic T cells, presenting a crucial role in maternal tolerance to the fetus. In non-pathological conditions, its expression is restricted to certain tissues such as cornea and placenta. The HLA-G 3' untranslated region (3'UTR) has been reported to play an important role in the control of mRNA and protein levels, and polymorphisms in this region may influence mRNA stability and microRNA binding. In this study, we propose an approach to detect and classify microRNAs regarding their ability to bind the target (in this case, HLA-G 3'UTR) and the specificity of such interactions. Then, a panel of microRNAs with potential to modulate HLA-G expression is proposed, in which some microRNAs, such as miR-139-3p, would bind to non polymorphic sequences of the HLA-G 3'UTR in a stable and specific manner, while others, such as miR-608, binds to polymorphic sequences and therefore the binding might be influenced by the variant actually present. Additionally, both HLA-G 3'UTR polymorphisms and the microRNA microenvironment must be considered when studies correlating HLA-G expression profiles and polymorphisms are being conducted. These new data may provide a remarkable contribution to the understanding of the mechanisms underlying HLA-G post-transcriptional regulation, disclosing the impact of variable and non-variable regions on HLA-G biology and providing a unique microRNA repertoire for future functional studies and therapeutic use. PMID- 25700347 TI - Adenine suppresses IgE-mediated mast cell activation. AB - Nucleobase adenine is produced by dividing human lymphoblasts mainly from polyamine synthesis and inhibits immunological functions of lymphocytes. We investigated the anti-allergic effect of adenine on IgE-mediated mast cell activation in vitro and passive cutaneous anaphylaxis (PCA) in mice. Intraperitoneal injection of adenine to IgE-sensitized mice attenuated IgE mediated PCA reaction in a dose dependent manner, resulting in a median effective concentration of 4.21 mg/kg. In mast cell cultures, only adenine among cytosine, adenine, adenosine, ADP and ATP dose-dependently suppressed FcERI (a high affinity receptor for IgE)-mediated degranulation with a median inhibitory concentration of 1.6mM. It also blocked the production of LTB4, an inflammatory lipid mediator, and inflammatory cytokines TNF-alpha and IL-4. In addition, adenine blocked thapsigargin-induced degranulation which is FcERI-independent but shares FcERI-dependent signaling events. Adenine inhibited the phosphorylation of signaling molecules important to FcERI-mediated allergic reactions such as Syk, PLCgamma2, Gab2, Akt, and mitogen activated protein kinases ERK and JNK. From this result, we report for the first time that adenine inhibits PCA in mice and allergic reaction by inhibiting FcERI-mediated signaling events in mast cells. Therefore, adenine may be useful for the treatment of mast cell-mediated allergic diseases. Also, the upregulation of adenine production may provide another mechanism for suppressing mast cell activity especially at inflammatory sites. PMID- 25700348 TI - Impact of the vulcanization process on the structural characteristics and IgE recognition of two allergens, Hev b 2 and Hev b 6.02, extracted from latex surgical gloves. AB - Latex allergy is a health problem that mainly affects medical environments, causing anaphylactic shocks in extreme cases. Sensitization and reactions to this material is closely linked to the use of latex gloves. The objective of this study was to purify two of the major allergens from latex surgical gloves to study the biochemical and structural changes that could be generated during the product manufacture and to compare their IgE recognition with the non-processed allergens. Glycosylated allergen Hev b 2 (beta-1,3-glucanase) and Hev b 6.02 (hevein) were purified from glove extracts using affinity (Concanavalin A) and reversed-phase chromatographies, respectively. ELISA experiments were performed with both proteins and sera from allergic patients to assess the IgE recognition, which was heterogeneous. Crystallographic methods were used to obtain the 3D structure of Hev b 6.02 from surgical gloves, which did not show evident modification when compared with the protein from the natural non-processed form. Despite having the same crystallographic structure, the IgE from some patients showed different recognition when the glove and the natural allergen were used in ELISA. Furthermore, using electrophoretic techniques, we identified three forms of Hev b 2: one corresponding to the complete polypeptide chain with posttranslational modifications, and two glycosylated fragments. The mixture of these three forms showed stronger recognition by IgE from latex-allergic patients than the pure non-processed allergen. In conclusion, IgE from subjects sensitized to latex products showed different recognition between the allergens obtained from a natural source and the processed material, even when the structure was maintained. This demonstrates the importance of using processed allergens in further investigations of diagnosis, prevalence, product allergenicity, and therapies. PMID- 25700349 TI - T lymphocyte-derived TNF and IFN-gamma repress HFE expression in cancer cells. AB - The immune system and tumors are closely intertwined initially upon tumor development. During this period, tumors evolve to promote self-survival through immune escape, including by targeting crucial components involved in the presentation of antigens to the immune system in order to avoid recognition. Accordingly, components involved in MHC I presentation of tumor antigens are often mutated and down-regulated targets in tumors. On the other hand, the immune system has been shown to influence tumors through production of immunosuppressive cytokines, recruitment and polarization of cells favoring or impeding tumor escape or through production of anti-tumor cytokines promoting tumor rejection. We previously discovered that the hemochromatosis protein HFE, a negative regulator of iron absorption, dampens classical MHC I antigen presentation. In this study, we evaluated the impact of activated T lymphocytes purified from peripheral blood mononuclear cells (PBMC) on HFE expression in tumor cell lines. We co-cultured tumor cell lines from melanoma, lung, and kidney cancers with anti CD3-activated PBMC and established that HFE expression is increased in tumor cell lines compared to healthy tissues, whilst being down-regulated significantly upon exposure to activated PBMC. HFE down-regulation was mediated by both CD4 and CD8 T lymphocytes, through production of soluble mediators, namely TNF and IFN-gamma. These results suggest that the immune system may modulate tumor HFE expression in inflammatory conditions in order to regulate MHC I antigen presentation and promote tumor clearance. PMID- 25700350 TI - Removal of ammonium-nitrogen from groundwater using a fully passive permeable reactive barrier with oxygen-releasing compound and clinoptilolite. AB - A novel fully passive permeable reactive barrier (PRB) with oxygen-releasing compound (ORC) and clinoptilolite was proposed for the removal of ammonium nitrogen from groundwater. The PRB involves a combination of oxygen release, biological nitrification, ion exchange, and bioregeneration. A pilot-scale performance comparison experiment was carried out employing three parallel columns to assess the proposed PRB. The results showed that the PRB achieved nearly complete [Formula: see text] depletion (>99%). [Formula: see text] of 5.23 10.88 mg/L was removed, and [Formula: see text] of <1.93 mg/L and [Formula: see text] of 2.03-19.67 mg/L were generated. Ion exchange and biological nitrification both contributed to [Formula: see text] removal, and the latter played a dominant role under the condition of sufficient oxygen. Biological nitrification favored a delay in sorption saturation and a release of exchange sites. The ORC could sufficiently, efficiently supply oxygen for approximately 120 pore volumes. The clinoptilolite ensured a robust [Formula: see text] removal in case of temporary insufficient biological activities. No external alkalinity sources had to be supplied and no inhibition of aerobic metabolism occurred. The ceramicite had a negligible effect on the biomass growth. Based on the research findings, a full-scale continuous wall PRB was installed in Shenyang, China in 2012. PMID- 25700351 TI - Degradation of antibiotics norfloxacin by Fenton, UV and UV/H2O2. AB - This study aimed to evaluate the degradation of the antibiotic norfloxacin, using direct photolysis (UV), photolysis with hydrogen peroxide (UV/H2O2) and Fenton's oxidation processes. Initially, it was evaluated the behavior of the antibiotic norfloxacin on direct photolysis, in order to see if the process could be a pertinent way to eliminate the drug in water treatment stations. The results showed that the use of direct photolysis was not effective in the degradation of the antibiotic, reaching a degradation rate of 85% and a mineralization rate of 2% in 7 h of reaction; leading to the formation of intermediates products. To optimize the UV treatment, it was used the combined UV/H2O2 process. Several concentrations of hydrogen peroxide (0.7, 1.4, 2.1, 2.8, 3.5 and 4.2 mmol/L) at pH 7 were tested. The concentration of 2.1 mmol/L reached a degradation rate of 100% in 100 min of reaction. Based on this result, the speed of the reaction at pH 2, 3, 5, and 10 was evaluated for that same concentration of H2O2. The shortest reaction time (60 min) was verified at pH 2 and 3. For the treatment using Fenton oxidation, a degradation rate of 60% of the compound and a mineralization rate of 55% was obtained in 60 min. The study revealed that the Fenton oxidation and UV/H2O2 can be used for norfloxacin removal, reaching respectively degradation rates of 100% and 60%, and mineralization rates of 55% and 32%. PMID- 25700352 TI - A real time method of contaminant classification using conventional water quality sensors. AB - Early warning systems are often used to detect deliberate and accidental contamination events in a water source. After contamination detection, it is important to classify the type of contaminant quickly to provide support for implementation of remediation attempts. Conventional methods commonly rely on laboratory-based analysis or qualitative geometry analysis, which require long analysis time or suffer low true positive rate. This paper proposes a real time contaminant classification method, which discriminates contaminants based on quantitative analysis. The proposed method utilizes the Mahalanobis distance of feature vectors to classify the type of contaminant. The performance and robustness of the proposed method were evaluated using data from contaminant injection experiments and through an uncertainty analysis. An advantage of the proposed method is that it can classify the type of contaminant in minutes with no significant compromise on true positive rate. This will facilitate fast remediation response to contamination events in a water system. PMID- 25700353 TI - ENOX2 target for the anticancer isoflavone ME-143. AB - ME-143 (NV-143), a synthetic isoflavone under clinical evaluation for efficacy in the management of ovarian and other forms of human cancer, blocked the activity of a cancer-specific and growth-related cell surface ECTO-NOX protein with both oxidative (hydroquinone) and protein disulfide-thiol interchange activity designated ENOX2 (tNOX) and inhibited the growth of cultured cancer cells with EC50s in the range of 20-50 nM. Purified recombinant ENOX2 also bound ME-143 with a Kd of 43 (40-50) nM. Both the oxidative and protein disulfide-thiol interchange activities of ENOX proteins that alternate to generate a complex set of oscillations with a period length of 22 min compared to 24 min for the constitutive counterpart ENOX1 (CNOX) that characterizes ENOX proteins responded to ME-143. Oxidation of NADH or reduced coenzyme Q10 was rapidly blocked. In contrast, the protein disulfide-thiol interchange activity measured from the cleavage of dithiodipyridine (EC50 of ca. 50 nM) was inhibited progressively over an interval of 60 min that spanned three cycles of activity. Inhibition of the latter paralleled the inhibition of cell enlargement and the consequent inability of inhibited cells to initiate traverse of the cell cycle. Activities of constitutive ENOX1 (CNOX) forms of either cancer or noncancer cells were unaffected by ME-143 over the range of concentrations inhibiting ENOX2. Taken together, the findings show that ME-143 binds to ENOX2 with an affinity 4 to 10 times greater than that reported previously for the related anticancer isoflavone, phenoxodiol. PMID- 25700354 TI - Fulvestrant-mediated inhibition of estrogen receptor signaling slows lung cancer progression. AB - Estrogens are key signaling molecules that regulate various physiological processes such as cell growth, development, and differentiation. They also play a major role in many pathological conditions, such as hormone-dependent cancer. The importance of inhibiting estrogen receptor signaling in diseases of estrogen target tissues, such as breast cancer, is well documented. However, the role of estrogen signaling in diseases of nontarget tissues, such as lung cancer, is not well characterized. The aim of the current study is to examine the expression of estrogen receptor beta (ERbeta) and the roles of estradiol (E2) and fulvestrant on the progression of lung cancer. Tissue microarray (TMA) and immunohistochemistry (IHC) analyses were used to detect the expression of aromatase, ERalpha, and ERbeta in 198 patients. We performed analyses to determine if there was any correlation among these three proteins. A mouse model of urethane-induced lung adenocarcinoma was used in the study. Mice were divided into three treatment groups: blank control, E2 alone, and E2 + fulvestrant (ERbeta antagonist). Western blot analysis and fluorescence quantitative PCR (FQ PCR) were used to measure expression of ERbeta protein and mRNA levels, respectively. ERbeta, but not ERalpha, was overexpressed in NSCLC samples. Lung cancer progression in mice treated with E2 was significantly increased compared to either the control group or the E2 + fulvestrant group. Mice in the E2 treatment group had significantly increased expression of ERbeta at both the mRNA and protein levels compared to mice treated with E2 + fulvestrant or control. Our data suggest that ERbeta promotes lung cancer progression in mice and that this progression can be inhibited with fulvestrant. These findings may help elucidate the role of ERbeta in lung cancer and suggest that estrogen receptor antagonists, such as fulvestrant, may be therapeutically beneficial for the treatment of the disease. PMID- 25700355 TI - TRAF4 enhances osteosarcoma cell proliferation and invasion by Akt signaling pathway. AB - TRAF4, or tumor necrosis factor receptor-associated factor 4, is overexpressed in several cancers, suggesting a specific role in cancer progression. However, its functions in osteosarcoma are unclear. This study aimed to explore the expression of TRAF4 in osteosarcoma tissues and cells, the correlation of TRAF4 to clinical pathology of osteosarcoma, as well as the role and mechanism of TRAF4 in osteosarcoma metastasis. The protein expression levels of TRAF4 in osteosarcoma tissues and three osteosarcoma cell lines, MG-63, HOS, and U2OS, were assessed. Constructed TRAF4 overexpression vectors and established TRAF4 overexpression of the U2OS cell line. Cell proliferation, cell invasion, protein levels, and TRAF4 phosphorylations were assessed following TRAF4 transfection, as well as the effects of TRAF4 siRNA on cell proliferation and invasion. The results show that TRAF4 protein levels in osteosarcoma tissues were significantly higher than that in normal bone tissues. Importantly, an obvious upregulation of TRAF4 was found in carcinoma tissues from patients with lung metastasis compared with patients without lung metastasis. Consistently, a similar increase in TRAF4 mRNA and protein was also demonstrated in the osteosarcoma cell lines MG-63, HOS, and U2OS compared to normal bone cells, hFOB1.19. When TRAF4 was overexpressed in U2OS cells, cell proliferation was significantly enhanced, accompanied by an increase in Ki67 expression and colony formation. Compared with the control and vector treated groups, TRAF4 transfection increased the invasion potential of U2OS cells (p < 0.05). Interestingly, TRAF4 transfection significantly enhanced the phosphorylation of Akt. After blocking Akt with its specific siRNA, TRAF4-induced cell proliferation and invasion were dramatically attenuated. In summary, our findings demonstrated that TRAF4 enhances osteosarcoma cell proliferation and invasion partially by the Akt pathway. This work suggests that TRAF4 might be an important target in osteosarcoma. PMID- 25700356 TI - FOXM1 regulated by ERK pathway mediates TGF-beta1-induced EMT in NSCLC. AB - FOXM1, a member of the Forkhead transcriptional family, plays an important role in the EMT process, and transforming growth factor-beta1 (TGF-beta1) has been identified as the most potent factor that can independently induce EMT in various types of cancer cells. Here we examine the important role of FOXM1 in TGF-beta1 induced EMT and investigate the mechanism underlying the relationship between TGF beta1 and FOXM1. Lentivirus-mediated transfection was used to stably upregulate the expression of FOXM1, and a small interfering RNA (siRNA) was introduced to silence the expression of FOXM1. Transwell and wound-healing assays were then performed to assess the invasion and motility potential of non-small cell lung cancer (NSCLC) cells. The NSCLC cell lines exhibited EMT characteristics, including an elongated fibroblastoid shape, induced expression of EMT marker proteins, and increased migratory and invasive potential after induction with TGF beta1. The overexpression of FOXM1 enhanced TGF-beta1-induced EMT in NSCLC cells. Knockdown of FOXM1 reversed TGF-beta1-induced EMT in NSCLC cell lines but had no effect on the phosphorylation level of ERK. Additionally, U0126, an ERK signaling inhibitor, exerted a reversible effect on TGF-beta1-induced EMT and inhibited FOXM1 expression. FOXM1 regulated by the ERK pathway can mediate TGF-beta1 induced EMT in NSCLC and is a potential target for the treatment of NSCLC. PMID- 25700357 TI - Knockdown of tripartite motif containing 24 by lentivirus suppresses cell growth and induces apoptosis in human colorectal cancer cells. AB - Colorectal cancer remains one of the most common cancers in men and women, and it accounts for a large proportion of cancer-related deaths worldwide. Tripartite motif (TRIM) proteins are a novel class of "single protein RING finger" E3 ubiquitin ligases, which have been shown to be involved in many cancers. The aim of this study was to investigate the potential role of TRIM24 in human colorectal cancer. By using a lentivirus-mediated RNA interference system, we first explored the effect of TRIM24 knockdown on HCT116 cell proliferation and colony formation. Moreover, flow cytometry analysis was used to examine its effects on cell cycle distribution and apoptosis. Our data showed that knockdown of TRIM24 expression in HCT116 cells significantly decreased cell growth due to the induction of apoptosis. Hence, the present study provides evidence that TRIM24 functions as an oncogene in colorectal carcinogenesis. PMID- 25700358 TI - Epithelial-mesenchymal transition contributes to docetaxel resistance in human non-small cell lung cancer. AB - Lung cancer is an aggressive malignancy with high morbidity and mortality. Chemotherapy has always been the principal treatment measure, but its acquired resistance becomes a critical problem. In the current study, we established a new docetaxel-resistant human non-small lung cancer (NSCLC) cell line A549/Docetaxel. The resistance index (RI) of A549/Docetaxel cells and A549 induced by TGF-beta to docetaxel were 8.91 and 11.5, respectively. Compared to the parental A549 cells, the multiplication time of A549/Docetaxel was prolonged, the proportion of the cell cycle in the S phase decreased while that in the G1 phase increased, and apoptotic rate was much lower. The morphology of the resistant cells eventuated epithelial-mesenchymal transition (EMT), which was confirmed by the higher expression of fibronectin, vimentin (mesenchymal markers), and lower expression of E-cadherin (epithelial marker) at mRNA and proteins levels. Furthermore, the representative markers for docetaxel resistance were examined, including ABCB1 (MDR1), Bcl-2, Bax, and tubulin, to figure out the mechanisms of the resistance of A549/Docetaxel. In summary, we have established a typical docetaxel-resistant human NSCLC cell line A549/Docetaxel, and it was suggested that the multidrug resistance of A549/Docetaxel was related to EMT. PMID- 25700359 TI - Blockage of potassium channel inhibits proliferation of glioma cells via increasing reactive oxygen species. AB - The potassium (K(+)) channel plays an important role in the cell cycle and proliferation of tumor cells, while its role in brain glioma cells and the signaling pathways remains unclear. We used tetraethylammonium (TEA), a nonselective antagonist of big conductance K(+) channels, to block K(+) channels in glioma cells, and antioxidant N-acetyl-l-cysteine (NAC) to inhibit production of intracellular reactive oxygen species (ROS). TEA showed an antiproliferation effect on C6 and U87 glioma cells in a time-dependent manner, which was accompanied by an increased intracellular ROS level. Antioxidant NAC pretreatment reversed TEA-mediated antiproliferation and restored ROS level. TEA treatment also caused significant increases in mRNA and protein levels of tumor-suppressor proteins p53 and p21, and the upregulation was attenuated by pretreatment of NAC. Our results suggest that K(+) channel activity significantly contributes to brain glioma cell proliferation via increasing ROS, and it might be an upstream factor triggering the activation of the p53/p21(Cip1)-dependent signaling pathway, consequently leading to glioma cell cycle arrest. PMID- 25700360 TI - A novel cortical thickness estimation method based on volumetric Laplace-Beltrami operator and heat kernel. AB - Cortical thickness estimation in magnetic resonance imaging (MRI) is an important technique for research on brain development and neurodegenerative diseases. This paper presents a heat kernel based cortical thickness estimation algorithm, which is driven by the graph spectrum and the heat kernel theory, to capture the gray matter geometry information from the in vivo brain magnetic resonance (MR) images. First, we construct a tetrahedral mesh that matches the MR images and reflects the inherent geometric characteristics. Second, the harmonic field is computed by the volumetric Laplace-Beltrami operator and the direction of the steamline is obtained by tracing the maximum heat transfer probability based on the heat kernel diffusion. Thereby we can calculate the cortical thickness information between the point on the pial and white matter surfaces. The new method relies on intrinsic brain geometry structure and the computation is robust and accurate. To validate our algorithm, we apply it to study the thickness differences associated with Alzheimer's disease (AD) and mild cognitive impairment (MCI) on the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. Our preliminary experimental results on 151 subjects (51 AD, 45 MCI, 55 controls) show that the new algorithm may successfully detect statistically significant difference among patients of AD, MCI and healthy control subjects. Our computational framework is efficient and very general. It has the potential to be used for thickness estimation on any biological structures with clearly defined inner and outer surfaces. PMID- 25700361 TI - Determining in situ periphyton community responses to nutrient and atrazine gradients via pigment analysis. AB - Agrochemicals, including fertilizers and herbicides, are significant contributors of non-point source pollution to surface waters and have the potential to negatively affect periphyton. We characterized periphyton communities using pigment markers to assess the effects of nutrient enrichment and the herbicide atrazine with in situ experimental manipulations and by examining changes in community structure along existing agrochemical gradients. In 2008, the addition of nutrients (20 mg/L nitrate and 1.25 mg/L reactive phosphate), atrazine (20 MUg/L) and a combination of both nutrients and atrazine had no significant effect on periphyton biomass or community structure in a stream periphytometer experiment. In 2009, similar experiments with higher concentrations of atrazine (200 MUg/L) at two stream sites led to some minor effects. In contrast, at the watershed scale (2010) periphyton biomass (mg/m(2) chlorophyll a) increased significantly along correlated gradients of nitrate and atrazine but no direct effects of reactive phosphate were observed. Across the watershed, the average periphyton community was composed of Bacillariophyceae (60.9%), Chlorophyceae (28.1%), Cryptophyceae (6.9%) and Euglenophyceae (4.1%), with the Bacillariophyceae associated with high turbidity and the Chlorophyceae with nitrate enrichment. Overall, effects of nitrate on periphyton biomass and community structure superseded effects of reactive phosphate and atrazine. PMID- 25700362 TI - Phosphatase activity in relation to key litter and soil properties in mature subtropical forests in China. AB - Phosphatase-mediated phosphorus (P) mineralization is one of the critical processes in biogeochemical cycling of P and determines soil P availability in forest ecosystems; however, the regulation of soil phosphatase activity remains elusive. This study investigated the potential extracellular activities of acid phosphomonoesterase (AcPME) and phosphodiesterase (PDE) and how they were related to key edaphic properties in the L horizon (undecomposed litter) and F/H horizon (fermented and humified litter) and the underlying mineral soil at the 0-15cm depth in eight mature subtropical forests in China. AcPME activity decreased significantly in the order of F/H horizon>L horizon>mineral soil horizon, while the order for PDE activity was L horizon=F/H horizon>mineral soil horizon. AcPME (X axis) and PDE (Y axis) activities were positively correlated in all horizons with significantly higher slope in the L and F/H horizons than in the mineral soil horizon. Both AcPME and PDE activities were positively related to microbial biomass C, moisture content and water-holding capacity in the L horizon, and were positively related to soil C:P, N:P and C:N ratios and fine root (diameter<=2mm) biomass in the mineral soil horizon. Both enzyme activities were also interactively affected by forest and horizon, partly due to the interactive effect of forest and horizon on microbial biomass. Our results suggest that modulator(s) of the potential extracellular activity of phosphatases vary with horizon, depending on the relative C, P and water availability of the horizon. PMID- 25700364 TI - Comparative analysis of biofilm formation by Bacillus cereus reference strains and undomesticated food isolates and the effect of free iron. AB - Biofilm formation of Bacillus cereus reference strains ATCC 14579 and ATCC 10987 and 21 undomesticated food isolates was studied on polystyrene and stainless steel as contact surfaces. For all strains, the biofilm forming capacity was significantly enhanced when in contact with stainless steel (SS) as a surface as compared to polystyrene (PS). For a selection of strains, the total CFU and spore counts in biofilms were determined and showed a good correlation between CFU counts and total biomass of these biofilms. Sporulation was favoured in the biofilm over the planktonic state. To substantiate whether iron availability could affect B. cereus biofilm formation, the free iron availability was varied in BHI by either the addition of FeCl3 or by depletion of iron with the scavenger 2,2-Bipyridine. Addition of iron resulted in increased air-liquid interface biofilm on polystyrene but not on SS for strain ATCC 10987, while the presence of Bipyridine reduced biofilm formation for both materials. Biofilm formation was restored when excess FeCl3 was added in combination with the scavenger. Further validation of the iron effect for all 23 strains in microtiter plate showed that fourteen strains (including ATCC10987) formed a biofilm on PS. For eight of these strains biofilm formation was enhanced in the presence of added iron and for eleven strains it was reduced when free iron was scavenged. Our results show that stainless steel as a contact material provides more favourable conditions for B. cereus biofilm formation and maturation compared to polystyrene. This effect could possibly be linked to iron availability as we show that free iron availability affects B. cereus biofilm formation. PMID- 25700363 TI - Repurposing auranofin as a lead candidate for treatment of lymphatic filariasis and onchocerciasis. AB - Two major human diseases caused by filariid nematodes are onchocerciasis, or river blindness, and lymphatic filariasis, which can lead to elephantiasis. The drugs ivermectin, diethylcarbamazine (DEC), and albendazole are used in control programs for these diseases, but are mainly effective against the microfilarial stage and have minimal or no effect on adult worms. Adult Onchocerca volvulus and Brugia malayi worms (macrofilariae) can live for up to 15 years, reproducing and allowing the infection to persist in a population. Therefore, to support control or elimination of these two diseases, effective macrofilaricidal drugs are necessary, in addition to current drugs. In an effort to identify macrofilaricidal drugs, we screened an FDA-approved library with adult worms of Brugia spp. and Onchocerca ochengi, third-stage larvae (L3s) of Onchocerca volvulus, and the microfilariae of both O. ochengi and Loa loa. We found that auranofin, a gold-containing drug used for rheumatoid arthritis, was effective in vitro in killing both Brugia spp. and O. ochengi adult worms and in inhibiting the molting of L3s of O. volvulus with IC50 values in the low micromolar to nanomolar range. Auranofin had an approximately 43-fold higher IC50 against the microfilariae of L. loa compared with the IC50 for adult female O. ochengi, which may be beneficial if used in areas where Onchocerca and Brugia are co-endemic with L. loa, to prevent severe adverse reactions to the drug-induced death of L. loa microfilariae. Further testing indicated that auranofin is also effective in reducing Brugia adult worm burden in infected gerbils and that auranofin may be targeting the thioredoxin reductase in this nematode. PMID- 25700365 TI - Smokers' reactions to the new larger health warning labels on plain cigarette packs in Australia: findings from the ITC Australia project. AB - OBJECTIVES: This study examined whether larger sized Australian cigarette health warning labels (HWLs) with plain packaging (PP) were associated with increased desirable reactions towards the HWLs postimplementation. METHODS: Data were from the International Tobacco Control (ITC) longitudinal cohort survey assessing Australian smokers one wave prior to the policy change in 2011 (n=1104) and another wave after the policy change in 2013 (n=1093). We assessed initial attentional orientation (AO) to or away from warnings, plus other reactions, including cognitive reactions towards the HWLs and quit intentions. RESULTS: As expected, AO towards the HWLs and reported frequency of noticing warnings increased significantly after the policy change, but not more reading. Smokers also thought more about the harms of smoking and avoided the HWLs more after the policy change, but frequency of forgoing cigarettes did not change. The subgroup that switched from initially focusing away to focusing on the HWLs following the policy change noticed and read the HWLs more, and also thought more about the harmful effects of smoking, whereas the subgroup (5.4%) that changed to focusing away from the HWLs showed opposite effects. We tested the mediational model of Yong et al and confirmed it for predicting quit intentions, with larger effects post-policy. CONCLUSIONS: Increasing the size of HWLs and introducing them on PP in Australia appears to have led to an overall increase in desired levels and strength of some reactions, but evidence of reactance was among a small minority. PMID- 25700366 TI - Role of hepatocyte nuclear factor 4alpha (HNF4alpha) in cell proliferation and cancer. AB - Hepatocyte nuclear factor 4alpha (HNF4alpha) is an orphan nuclear receptor commonly known as the master regulator of hepatic differentiation, owing to the large number of hepatocyte-specific genes it regulates. Whereas the role of HNF4alpha in hepatocyte differentiation is well recognized and extensively studied, its role in regulation of cell proliferation is relatively less known. Recent studies have revealed that HNF4alpha inhibits proliferation not only of hepatocytes but also cells in colon and kidney. Further, a growing number of studies have demonstrated that inhibition or loss of HNF4alpha promotes tumorigenesis in the liver and colon, and reexpression of HNF4alpha results in decreased cancer growth. Studies using tissue-specific conditional knockout mice, knock-in studies, and combinatorial bioinformatics of RNA/ChIP-sequencing data indicate that the mechanisms of HNF4alpha-mediated inhibition of cell proliferation are multifold, involving epigenetic repression of promitogenic genes, significant cross talk with other cell cycle regulators including c-Myc and cyclin D1, and regulation of miRNAs. Furthermore, studies indicate that posttranslational modifications of HNF4alpha may change its activity and may be at the core of its dual role as a differentiation factor and repressor of proliferation. This review summarizes recent findings on the role of HNF4alpha in cell proliferation and highlights the newly understood function of this old receptor. PMID- 25700368 TI - The long journey of TCL1 transgenic mice: lessons learned in the last 15 years. AB - The first transgenic mouse of the TCL1 oncogene was described more than 15 years ago, and since then, the overexpression of the gene in T- and B-cells in vivo has been extensively studied to reveal the molecular details in the pathogenesis of some lymphocytic leukemias. This review discusses the main features of the original TCL1 models and the different lines of research successively developed with particular attention to genetically compound mice and the therapeutic applications in drug development. PMID- 25700369 TI - Single nucleotide polymorphisms in HIF-1alpha gene and residual ridge resorption (RRR) of mandible in Korean population. AB - Tooth extraction is a routine surgical procedure in dental treatment. As a wound healing process after tooth extraction, a saddle-shaped residual ridge forms due to bone formation in the extraction socket and localized bone resorption on the external surface of the jawbone. The residual ridge is subjected to continuous bone resorption with substantial differences among individuals. In some cases, it results in excessive bone atrophy, which complicates dental restorative treatment. This unique oral wound healing process may be influenced by factors that are specific to oral tissue. HIF expression is different in oral wound healing compared to that of skin wounds. The objective of this study was to examine a genetic association between SNP of the HIF-1alpha gene, which is known to have high genetic diversity, and the residual ridge resorption (RRR). Two hundred and two Korean subjects (70.80 +/- 9.40 years) with partially or completely edentulous mandible were recruited, and edentulous mandibular bone height was measured following the protocol of the American College of Prosthodontists. The HIF-1alpha allele was directly sequenced in 24 subjects resulting in the variants over 5% frequency in 95% likelihood, whereas tag-SNPs were selected to perform analysis for the remaining population. Student's t-test and ANOVA were used for statistical analysis to examine the association between the SNPs and the RRR. Four novel variants were discovered, and a minor allele of rs11549467 was associated with the RRR of the subjects (p = 0.028). rs11549467 increases HIF-1alpha transactivity, enhancing angiogenesis and increasing new vessel formation. Thus, rs11549467 may play an important role in the disturbed bone remodeling balance resulting in RRR. Results of this study may be useful in developing novel genetic diagnostic tests and identifying Koreans susceptible to developing excessive jawbone atrophy after dental extraction. Most importantly, early screening using genetic information will rescue susceptible patients from the vulnerable situation of excessive jawbone atrophy where no effective prosthetic treatment is available. PMID- 25700367 TI - PDGFRalpha in liver pathophysiology: emerging roles in development, regeneration, fibrosis, and cancer. AB - Platelet-derived growth factor receptor alpha (PDGFRalpha) is an isoform of the PDGFR family of tyrosine kinase receptors involved in cell proliferation, survival, differentiation, and growth. In this review, we highlight the role of PDGFRalpha and the current evidence of its expression and activities in liver development, regeneration, and pathology-including fibrosis, cirrhosis, and liver cancer. Studies elucidating PDGFRalpha signaling in processes ranging from profibrotic signaling, angiogenesis, and oxidative stress to epithelial-to mesenchymal transition point toward PDGFRalpha as a potential therapeutic target in various hepatic pathologies, including hepatic fibrosis and liver cancer. Furthermore, PDGFRalpha localization and modulation during liver development and regeneration may lend insight into its potential roles in various pathologic states. We will also briefly discuss some of the current targeted treatments for PDGFRalpha, including multi receptor tyrosine kinase inhibitors and PDGFRalpha specific inhibitors. PMID- 25700370 TI - Comprehensive analysis of the GABAergic system gene expression profile in the anterior cingulate cortex of mice with Paclitaxel-induced neuropathic pain. AB - The supraspinal pathophysiology of the painful neuropathy induced by paclitaxel, a chemotherapeutic agent, is not well understood. The gamma-aminobutyric acid (GABA) neurotransmitter system has been implicated in the pathogenesis of neuropathic pain. Gene expression of GABAergic system molecules was examined in the anterior cingulate cortex (ACC) of mice brains, by real-time PCR, during paclitaxel-induced neuropathic pain, because this area is involved in pain perception and modulation that might contribute to neuropathic pain. Paclitaxel treatment resulted in thermal hyperalgesia and in increased GABA transporter-1 (GAT-1) mRNA expression, but not that of other GABA transporters or GABA(A) ergic enzymes in the ACC compared to vehicle treatment. Among the 18 GABA(A) receptor subunits analyzed, only beta2, beta3, delta, and gamma2 had increased mRNA levels, and for the receptor subunit, only GABA(B2) had increased mRNA levels in the ACC of paclitaxel-treated mice, whereas the rest of the GABA receptor subunits were not altered. The mRNA expression of GABAA receptor subunits alpha6, theta, pi, rho1, rho2, and rho3 were not detected in the ACC. In conclusion, these data show that during paclitaxel-induced neuropathic pain there is significant increase in GAT-1 expression in the ACC. GAT-1 is the main transporter of GABA from the synapse, and thus its increased expression possibly results in less GABA at the synapse and dysregulation of the GABAergic system. GAT-1 is a potential therapeutic target for managing paclitaxel-induced neuropathic pain. PMID- 25700371 TI - Association Between Body Mass Index, Physical Activity, and Health-Related Quality of Life in Canadian Adults. AB - BACKGROUND: Obesity is associated with impairments in health-related quality of life (HRQL), whereas physical activity (PA) is a promoter of HRQL. PURPOSE: The aim of this study was to investigate the interaction between BMI and PA with HRQL in younger and older Canadian adults. METHODS: Data from the 2012 annual component of the Canadian Community Health Survey (N = 48,041; >= 30 years) were used to capture self-reported body mass index (BMI- kg/m2), PA (kcal/kg/day, KKD), and HRQL. Interactions between PA and age on the BMI and HRQL relationship were assessed using general linear models and logistic regression. RESULTS: Those younger (younger: MU = 0.79 +/- 0.02; older: MU = 0.70 +/- 0.02) and more active (active: MU = 0.82 +/- 0.02; moderately active: MU = 0.77 +/- 0.03; inactive: MU = 0.73 +/- 0.01) reported higher HRQL. Older inactive underweight, normal weight, and overweight adults have lower odds of high HRQL. CONCLUSION: PA was associated with higher HRQL in younger adults. In older adults, BMI and PA influenced HRQL. PMID- 25700372 TI - Do Advance Directives Direct? AB - Resolution of long-standing debates about the role and impact of advance directives - living wills and powers of attorney for health care - has been hampered by a dearth of appropriate data, in particular data that compare the process and outcomes of end-of-life decision making on behalf of patients with and without advance directives. Drawing on a large ethnographic study of patients in two intensive care units in a large urban teaching hospital, this article compares aspects of the medical decision-making process and outcomes by advance directive status. Controlling for demographic characteristics and severity of illness, the study finds few significant differences between patients without advance directives and those who claim to have them. Surprisingly, these few differences hold only for those whose directives are in their hospital chart. There are no significant differences between those with no directive and those claiming to have a copy at home or elsewhere. The article considers the implications if directives seemingly must be in hand to show even modest effects. Do advance directives direct? The intensive care unit data provide far more support for the growing body of literature that casts doubt on their impact than studies that promote the use of them. PMID- 25700373 TI - The ACA Medicaid Expansion Waiver in the Keystone State: Do the Medically Uninsured "Got a Friend in Pennsylvania"? AB - Medicaid is fundamental to near universal health insurance coverage under the 2010 Affordable Care Act (ACA). Its goal of broadening the program to all households with income at or below 138 percent of the federal poverty level was thwarted in 2012 by a Supreme Court decision that allowed the states to choose whether or not they would join. This essay seeks to assess the status of Pennsylvania with regard to the Medicaid expansion controversy. It briefly describes the Keystone State's existing Medicaid program and the potential impact of the ACA on its growth. It then discusses Governor Tom Corbett's market-based alternative and what he achieved in his deliberations with the Obama administration. The article also discusses some of the financial considerations facing Pennsylvania policy makers in the expansion decision, the role of three of the more influential lobby groups, and the problematic situation of the medically uninsured population. PMID- 25700374 TI - The Little State That Couldn't Could? The Politics of "Single-Payer" Health Coverage in Vermont. AB - In May 2011, a year after the passage of the Affordable Care Act (ACA), Vermont became the first state to lay the groundwork for a single-payer health care system, known as Green Mountain Care. What can other states learn from the Vermont experience? This article summarizes the findings from interviews with nearly 120 stakeholders as part of a study to inform the design of the health reform legislation. Comparing Vermont's failed effort to adopt single-payer legislation in 1994 to present efforts, we find that Vermont faced similar challenges but greater opportunities in 2010 that enabled reform. A closely contested gubernatorial election and a progressive social movement opened a window of opportunity to advance legislation to design three comprehensive health reform options for legislative consideration. With a unified Democratic government under the leadership of a single-payer proponent, a high-profile policy proposal, and relatively weak opposition, a framework for a single-payer system was adopted by the legislature - though with many details and political battles to be fought in the future. Other states looking to reform their health systems more comprehensively than national reform can learn from Vermont's design and political strategy. PMID- 25700375 TI - Introduction. PMID- 25700376 TI - An Assessment of State-Led Reform of Long-Term Services and Supports. AB - Health care in the United States is fragmented, inefficient, and rife with quality concerns. These shortcomings have particularly serious implications for adults with disabilities and functionally impaired older adults in need of long term services and supports (LTSS). Three strategies have been commonly pursued by state governments to improve LTSS: expanding noninstitutional care, integrating payment and care delivery, and realigning incentives through market-based reforms. These strategies were analyzed using an evaluation framework consisting of the following dimensions: ease of access; choice of setting/provider; quality of care/life; support for family caregivers; effective transitions among multiple providers and across settings; reductions in racial/ethnic disparities; cost effectiveness; political feasibility; and implementability. Although the analysis highlights potential benefits and drawbacks associated with each strategy, the limited breadth of the evidentiary base precludes an assessment of impact across all nine dimensions. More importantly, the analysis exposes the interdependent, complex system of care within which LTSS is situated, suggesting that policy makers will require a holistic and long-term perspective to achieve needed changes. Addressing the nation's LTSS needs will require a multipronged strategy incorporating a range of health and social services to meet the complex care needs of a diverse population in a variety of settings. PMID- 25700377 TI - Politics, Policy, Law, and Friendship: Celebrating Daniel C. Schaffer, 1938-2013. PMID- 25700378 TI - Monitoring toxicity in individuals receiving treatment for latent tuberculosis infection: a systematic review versus expert opinion. PMID- 25700379 TI - Protective role for club cell secretory protein-16 (CC16) in the development of COPD. AB - Club cell secretory protein-16 (CC16) is the major secreted product of airway club cells, but its role in the pathogenesis of chronic obstructive pulmonary disease (COPD) is unclear. We measured CC16 airway expression in humans with and without COPD and CC16 function in a cigarette smoke (CS)-induced COPD murine model. Airway CC16 expression was measured in COPD patients, smokers without COPD and non-smokers. We exposed wildtype (WT) and CC16(-/-)mice to CS or air for up to 6 months, and measured airway CC16 expression, pulmonary inflammation, alveolar septal cell apoptosis, airspace enlargement, airway mucin 5AC (MUC5AC) expression, small airway remodelling and pulmonary function. Smokers and COPD patients had reduced airway CC16 immunostaining that decreased with increasing COPD severity. Exposing mice to CS reduced airway CC16 expression. CC16(-/-) mice had greater CS-induced emphysema, airway remodelling, pulmonary inflammation, alveolar cell apoptosis, airway MUC5AC expression, and more compliant lungs than WT mice. These changes were associated with increased nuclear factor-kappaB (NF kappaB) activation in CC16(-/-) lungs. CS-induced acute pulmonary changes were reversed by adenoviral-mediated over-expression of CC16. CC16 protects lungs from CS-induced injury by reducing lung NF-kappaB activation. CS-induced airway CC16 deficiency increases CS-induced pulmonary inflammation and injury and likely contributes to the pathogenesis of COPD. PMID- 25700380 TI - Pleuroparenchymal fibroelastosis from a consecutive database: a rare disease entity? PMID- 25700382 TI - Incidence of occupational latent tuberculosis infection in South African healthcare workers. AB - The test-specific incidence of latent tuberculosis infection (LTBI) in healthcare workers from sub-Saharan Africa is unknown. 505 healthcare workers from South Africa were screened at baseline, and after 12 months, with a questionnaire, the tuberculin skin test (TST), and two T-cell assays (T-SPOT.TB and QuantiFERON-TB Gold-In-Tube). Test-specific conversion rates were calculated. The prevalence of presumed LTBI at baseline was 84, 69 and 62% using the TST, QuantiFERON-TB Gold In-Tube and T-SPOT.TB, respectively. The annual test-specific conversion rate, depending on the cut-off point used, was as follows: TST 38%; QuantiFERON-TB Gold In-Tube 13-22%; and T-SPOT.TB 18-22%. Annual reversion rates were 4, 7 and 16%, respectively. The annual TST conversion rate was significantly higher than that derived from published local community-based data (IRR 3.53, 95% CI 1.81-6.88). Factors associated with conversion (any test) included healthcare sector of employment, counselling of tuberculosis patients, and a baseline positive TST (for T-SPOT.TB). The annual rate of tuberculosis infection in South African healthcare workers was very high, irrespective of the testing method used, and may be explained by occupational exposure, as the rate was considerably higher than non-healthcare workers from the same community. Collectively, these data support the need for implementation of tuberculosis-specific infection control measures in Africa. PMID- 25700381 TI - The innate immune function of airway epithelial cells in inflammatory lung disease. AB - The airway epithelium is now considered to be central to the orchestration of pulmonary inflammatory and immune responses, and is also key to tissue remodelling. It acts as the first barrier in the defence against a wide range of inhaled challenges, and is critically involved in the regulation of both innate and adaptive immune responses to these challenges. Recent progress in our understanding of the developmental regulation of this tissue, the differentiation pathways, recognition of pathogens and antimicrobial responses is now exploited to help understand how epithelial cell function and dysfunction contributes to the pathogenesis of a variety of inflammatory lung diseases. Herein, advances in our knowledge of the biology of airway epithelium, as well as its role and (dys)function in asthma, chronic obstructive pulmonary fibrosis and cystic fibrosis will be discussed. PMID- 25700383 TI - African ancestry, lung function and the effect of genetics. AB - African-Americans have smaller lung function compared with European-Americans. The aim of this study was to disentangle the contribution of genetics from other variables on lung function. A cohort was followed from birth to 30 years of age in Brazil. Several variables were collected: genomic analysis based on DNA; forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) obtained by spirometry; height measured by anthropometrists; and thorax circumference evaluated by photonic scanner. Crude and adjusted linear regression models were calculated according to African ancestry. The sample comprised 2869 participants out of 3701 members of the cohort. Males with higher African ancestry by DNA analysis had a smaller FEV1 (-0.13 L, 95% CI -0.23- -0.03 L) and FVC (-0.21 L, 95% CI -0.32- -0.09 L) compared with those with less African ancestry, having accounted for height, sitting to standing height ratio and other confounders. Similar effects were seen in females. After adjustment, ancestry remained significantly associated with lung function, but the large effect of adjustment for confounding among males (but not females) does not allow us to exclude the possibility that residual confounding may still account for these findings. PMID- 25700384 TI - Is 1-year follow-up adequate for adult tuberculosis contacts? PMID- 25700385 TI - Long-term mortality assessment of multidrug-resistant tuberculosis patients treated with delamanid. PMID- 25700386 TI - Effects of antenatal multiple micronutrient supplementation on lung function in mid-childhood: follow-up of a double-blind randomised controlled trial in Nepal. AB - A randomised trial of prenatal multiple micronutrient supplementation in Nepalese women increased birthweight and weight at 2 years of age in offspring, compared to those born to mothers who only received iron and folic acid supplements. Further follow-up of this cohort provided an opportunity to investigate the effect of antenatal multiple micronutrients on subsequent lung function by measuring spirometry at 7-9 years of age in C: hildren born during the trial. 841 children (80% of the cohort) were seen at mean+/-sd 8.5+/-0.4 years. Technically successful spirometry results were obtained in 793 (94.3%) children, 50% of whom had been randomised to micronutrient supplementation. Background characteristics, including anthropometry, were similar in the two allocation groups. Lung function was also similar, mean (95% CI) difference in z-scores (supplementation minus control) was -0.08 (-0.19-0.04), -0.05 (-0.17-0.06) and -0.04 (-0.15-0.07) for forced expiratory volume in 1 s (FEV1), forced vital capacity and FEV1/FVC, respectively. Compared with healthy white children, FEV1 and FVC in the "healthy" Nepalese children were ~1 (~13%) z-score lower, with no difference in FEV1/FVC. We conclude that, compared with routine iron and folic acid, multiple micronutrient supplementation during pregnancy has no effect on spirometric lung function in Nepalese children at 8.5 years of age. PMID- 25700387 TI - Wedge resection and radiofrequency ablation for stage I nonsmall cell lung cancer. AB - The main aim of this study was to compare radiofrequency ablation (RFA) and wedge resection in terms of disease recurrence and survival, as intent-to-treat therapy for stage I nonsmall cell lung cancer (NSCLC) in marginal or non-surgical candidates. 121 high-risk patients, treated for stage I NSCLC with wedge resection (n=59) or RFA (n=62) in a 7-year period, were analysed. Age, sex, comorbidity score, performance status, forced expiratory volume in 1 s and forced vital capacity values, body mass index, T-stage and histology were evaluated as possible risk factors affecting disease recurrence and survival. At a median follow-up of 36 and 42 months for wedge resection and for RFA (p=0.232), local recurrence rate was 2 and 23%, respectively (p=0.002). The 1-, 2- and 5-year overall survival (disease-free interval) rates were 100% (96%), 96% (90%) and 52% (76%) for wedge resection, and 93% (87%), 72% (63%), and 35% (55%) for RFA (p=0.044 and p=0.01, respectively). None of the analysed parameters was found to be risk factor for disease recurrence and survival, except stage T2, which significantly affected disease-recurrence, overall and cancer-related survival and disease-free interval in the RFA group. Whenever possible, surgical resection, even if limited, should be preferred due to its higher disease control and survival rates. RFA can be considered a valid option for inoperable patients, especially for those with stage T1N0. PMID- 25700388 TI - Anticoagulant treatment for acute pulmonary embolism: a pathophysiology-based clinical approach. AB - The management of patients with acute pulmonary embolism is made challenging by its wide spectrum of clinical presentation and outcome, which is mainly related to patient haemodynamic status and right ventricular overload. Mechanical embolic obstruction and neurohumorally mediated pulmonary vasoconstriction are responsible for right ventricular overload. The pathophysiology of acute pulmonary embolism is the basis for risk stratification of patients as being at high, intermediate and low risk of adverse outcomes. This risk stratification has been advocated to tailor clinical management according to the severity of pulmonary embolism. Anticoagulation is the mainstay of the treatment of acute pulmonary embolism. New direct oral anticoagulants, which are easier to use than conventional anticoagulants, have been compared with conventional anticoagulation in five randomised clinical trials including >11 000 patients with pulmonary embolism. Patients at high risk of pulmonary embolism (those with haemodynamic compromise) were excluded from these studies. Direct oral anticoagulants have been shown to be as effective and at least as safe as conventional anticoagulation in patients with pulmonary embolism without haemodynamic compromise, who are the majority of patients with this disease. Whether these agents are appropriate for the acute-phase treatment of patients at intermediate high risk pulmonary embolism (those with both right ventricle dysfunction and injury) regardless of any risk stratification remains undefined. PMID- 25700389 TI - Management of EGFR mutated nonsmall cell lung carcinoma patients. AB - Tyrosine kinase inhibitors (TKIs) targeting the epidermal growth factor receptor (EGFR) are common in the therapeutic armentarium of lung cancer today. Initially tested in an unselected population, they have been of limited usefulness until the identification EGFR gene mutations. Activating mutations generate conformational changes that result in a shift toward an active state of the catalytic domain and are associated with sensitivity to first generation EGFR TKI. Other mutations have been associated with resistance to these drugs, but for rare mutations there is limited data concerning their role in predicting response to EGFR TKI. To date, four molecules have been approved for the treatment of EGFR mutated lung cancer. Gefitinib and/or erlotinib are available in almost all countries. Afatinib has been approved by the US Food and Drug Administration and by the European Medicines Agency, and icotinib has been approved only in China. Other, more active, third generation agents with a higher binding affinity for the receptor, or that are directed against specific mutations, are under development. EGFR TKIs have a favourable impact on progression-free survival when given as first line treatment in mutated patients, but may also have a moderate effect as a salvage therapy and in maintenance in an unselected population. PMID- 25700390 TI - Gait patterns in COPD: the Rotterdam Study. AB - Gait disturbances in patients with chronic obstructive pulmonary disease (COPD) may lead to disability and falls. As studies assessing gait kinematics in COPD are sparse, we investigated associations of COPD with various gait domains and explored a potential link with falling. Gait was measured within the prospective, population-based Rotterdam Study (age >=55 years) using an electronic walkway and summarised into seven gait domains: Rhythm, Variability, Phases, Pace, Tandem, Turning and Base of Support. Rhythm is a temporal gait aspect that includes cadence and reflects how quickly steps are taken. Persons with COPD (n=196) exhibited worse Rhythm (-0.21 SD, 95% CI -0.36- -0.06 SD) compared with persons with normal lung function (n=898), independent of age, sex, height, education, smoking or analgesic use, especially when dyspnoea and severe airflow limitation or frequent exacerbations (Global Initiative for Chronic Obstructive Lung Disease group D: -0.83 SD, 95% CI -1.25- -0.41 SD) were present. A lower forced expiratory volume in 1 s was associated with worse Rhythm and Pace, including lower cadence and gait velocity, respectively. Importantly, fallers with COPD had significantly worse Rhythm than nonfallers with COPD. This study demonstrates that persons with COPD exhibit worse Rhythm, especially fallers with COPD. The degree of Rhythm deterioration was associated with the degree of airflow limitation, symptoms and frequency of exacerbations. PMID- 25700391 TI - How "healthy" should children be when selecting reference samples for spirometry? AB - How "healthy" do children need to be when selecting reference samples for spirometry? Anthropometry and spirometry were measured in an unselected, multi ethnic population of school children aged 5-11 years in London, UK, with follow up assessments 12 months later. Parents provided information on children's birth data and health status. Forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) were adjusted for sex, age, height and ethnicity using the 2012 Global Lungs Initiative equations, and the effects of potential exclusion criteria on the z-score distributions were examined. After exclusions for current and chronic lung disease, acceptable data were available for 1901 children on 2767 occasions. Healthy children were defined as those without prior asthma or hospitalisation for respiratory problems, who were born at full-term with a birthweight >=2.5 kg and who were asymptomatic at testing. Mean+/-sd z-scores for FEV1 and FVC approximated 0+/-1, indicating the 2012 Global Lungs Initiative equations were appropriate for this healthy population. However, if children born preterm or with low birthweight, children with prior asthma or children mildly symptomatic at testing were included in the reference, overall results were similar to those for healthy children, while increasing the sample size by 25%. With the exception of clear-cut factors, such as current and chronic respiratory disease, paediatric reference samples for spirometry can be relatively inclusive and hence more generalisable to the target population. PMID- 25700392 TI - Genome Sequence and Annotation of Helicobacter pylori Strain Hp238, Isolated from a Taiwanese Patient with Mucosa-Associated Lymphoid Tissue Lymphoma. AB - We present the complete genome sequence of Helicobacter pylori strain Hp238, isolated from a Taiwanese patient with gastric mucosa-associated lymphoid tissue lymphoma. Importantly, H. pylori strain Hp238 can multiply in THP-1 cells after internalization through the induction of autophagosome formation. These genome data will help to identify genes associated with H. pylori intracellular multiplication and pathogenesis. PMID- 25700393 TI - Identification and Whole-Genome Sequence Analysis of Tembusu Virus GX2013G, Isolated from a Cherry Valley Duckling in Southern China. AB - A duck tembusu virus (DTMUV) was isolated from the brain of a Cherry Valley duckling that showed neurological signs by using a specific-pathogen-free chicken embryo. The isolate was named GX2013G (GenBank accession no. KM275941). The strain GX2013G was identified with reverse transcription-PCR (RT-PCR), and the amplicon was sequenced. The genome that was obtained is 10,990 nucleotides in length and contains a single open reading frame encoding a putative polyprotein of 3,425 amino acids. This study will advance the understanding of the epidemiology and molecular characteristics of tembusu virus (TMUV) in Guangxi and further studies of the mechanisms of virus replication and pathogenesis. PMID- 25700394 TI - Draft Genome Sequence of Marine-Derived Streptomyces sp. TP-A0873, a Producer of a Pyrrolizidine Alkaloid Bohemamine. AB - Streptomyces sp. TP-A0873, isolated from deep-sea water, produces three different classes of secondary metabolites: antimycin, bohemamine, and alkylated butenolides. In order to assess the biosynthetic potential of this strain, draft genome sequencing was carried out. The genome contained at least 14 gene clusters for polyketide synthase (PKS) and nonribosomal peptide synthetase (NRPS). PMID- 25700395 TI - Draft Genome Sequence of Phomopsis longicolla Type Strain TWH P74, a Fungus Causing Phomopsis Seed Decay in Soybean. AB - Phomopsis longicolla is the primary cause of Phomopsis seed decay in soybean. Here, we report the de novo assembled draft genome sequence of the P. longicolla type strain TWH P74 (ATCC 60325), which was originally isolated by Hobbs et al. from soybean seed in Ohio in 1983. PMID- 25700396 TI - Genome Sequence of Arthrobacter sp. MWB30, Isolated from a Crude Oil-Contaminated Seashore. AB - We report here the draft genome sequence of Arthrobacter sp. MWB30 strain, isolated from a crude oil-contaminated seashore in Tae-an, South Korea, which is able to degrade the crude oil and its derivatives. The draft genome sequence of 4,647,008 bp provides a resource for the identification of crude oil-degrading mechanisms in strain MWB30. PMID- 25700397 TI - Draft Genome Sequence of Stenotrophomonas maltophilia Strain B418, a Promising Agent for Biocontrol of Plant Pathogens and Root-Knot Nematode. AB - Stenotrophomonas maltophilia strain B418 was isolated from a barley rhizosphere in China. This bacterium exhibits broad-spectrum inhibitory activities against plant pathogens and root-knot nematode along with growth-promoting effects. Here, we present the draft genome sequence of S. maltophilia B418. PMID- 25700398 TI - Analysis of Quorum-Sensing Pantoea stewartii Strain M073A through Whole-Genome Sequencing. AB - Pantoea stewartii strain M073a is a Gram-negative bacterium isolated from a tropical waterfall. This strain exhibits quorum-sensing activity. Here, the assembly and annotation of its genome are presented. PMID- 25700399 TI - Erratum for Behera et al., Draft Genome Sequence of the Extremely Halophilic Bacterium Halomonas salina Strain CIFRI1, Isolated from the East Coast of India. PMID- 25700400 TI - Complete Genome Sequence of Campylobacter fetus subsp. testudinum Strain Pet-3, Isolated from a Lizard (Hydrosaurus pustulatus). AB - The whole-genome sequence for Campylobacter fetus subsp. testudinum, a pathogen isolated from humans and turtles, has been reported recently. We present another completed genome sequence of the C. fetus subsp. testudinum strain pet-3, which was isolated from a lizard in Taiwan, for further genomic comparison study. PMID- 25700401 TI - Draft Genome Sequence of Strain R13-38 from a Francisella tularensis Outbreak in Sweden. AB - We have whole-genome sequenced a Francisella tularensis subsp. holarctica (also known as type B) strain from an outbreak in Sweden in 2013, derived from a privately owned well for drinking water. PMID- 25700402 TI - Sequence Analysis of Staphylococcus hyicus ATCC 11249T, an Etiological Agent of Exudative Epidermitis in Swine, Reveals a Type VII Secretion System Locus and a Novel 116-Kilobase Genomic Island Harboring Toxin-Encoding Genes. AB - Staphylococcus hyicus is the primary etiological agent of exudative epidermitis in swine. Analysis of the complete genome sequence of the type strain revealed a locus encoding a type VII secretion system and a large chromosomal island harboring the genes encoding exfoliative toxin ExhA and an EDIN toxin homolog. PMID- 25700403 TI - Metagenomic evaluation of bacterial and archaeal diversity in the geothermal hot springs of manikaran, India. AB - Bacterial and archaeal diversity in geothermal spring water were investigated using 16S rRNA gene amplicon metagenomic sequencing. This revealed the dominance of Firmicutes, Aquificae, and the Deinococcus-Thermus group in this thermophilic environment. A number of sequences remained taxonomically unresolved, indicating the presence of potentially novel microbes in this unique habitat. PMID- 25700404 TI - Whole-Genome Sequencing Analysis of Quorum-Sensing Aeromonas hydrophila Strain M023 from Freshwater. AB - Aeromonas hydrophila is a well-known waterborne pathogen that recently was found to infect humans. Here, we report the draft genome of a freshwater isolate from a Malaysian waterfall, A. hydrophila strain M023, which portrays N-acylhomoserine lactone-dependent quorum sensing. PMID- 25700405 TI - Draft Genome Sequence of Rhodobacteraceae Strain PD-2, an Algicidal Bacterium with a Quorum-Sensing System, Isolated from the Marine Microalga Prorocentrum donghaiense. AB - Rhodobacteraceae strain PD-2 was isolated from the marine microalga Prorocentrum donghaiense. It has algicidal activity toward its host and could produce N acylhomoserine lactone signals. Here, we present the draft genome of strain PD-2, which contains 5,227,214 bp with an average GC content of 66.19%. There were 4,864 encoding gene sequences and two clusters of luxI and luxR homologues identified. PMID- 25700406 TI - Genome Sequence of Bradyrhizobium japonicum E109, One of the Most Agronomically Used Nitrogen-Fixing Rhizobacteria in Argentina. AB - We present here the complete genome sequence of Bradyrhizobium japonicum strain E109, one of the most used rhizobacteria for soybean inoculation in Argentina since the 1970s. The genome consists of a 9.22-Mbp single chromosome and contains several genes related to nitrogen fixation, phytohormone biosynthesis, and a rhizospheric lifestyle. PMID- 25700407 TI - Draft Genome Sequence of Tolypothrix boutellei Strain VB521301. AB - We report here the draft genome sequence of the filamentous nitrogen-fixing cyanobacterium Tolypothrix boutellei strain VB521301. The organism is lipid rich and hydrophobic and produces polyunsaturated fatty acids which can be harnessed for industrial purpose. The draft genome sequence assembled into 11,572,263 bp with 70 scaffolds and 7,777 protein coding genes. PMID- 25700408 TI - Genome Sequence and Annotation of a Human Infection Isolate of Escherichia coli O26:H11 Involved in a Raw Milk Cheese Outbreak. AB - The consumption of raw milk cheese can expose populations to Shiga toxin producing Escherichia coli (STEC). We report here the genome sequence of an E. coli O26:H11 strain isolated from humans during the first raw milk cheese outbreak described in France (2005). PMID- 25700409 TI - Whole-Genome Sequence of a Bordetella pertussis Brazilian Vaccine Strain. AB - Despite the reduction in incidence after vaccination, pertussis disease is still considered a public health problem worldwide, mainly due to recent and potential new outbreaks. We report here the complete genome of the Bordetella pertussis Butantan strain used in the Brazilian National Immunization Program as a whole cell pertussis antigen to compose vaccines such as DTwP (diphtheria, tetanus, and whole-cell pertussis). PMID- 25700410 TI - Draft Genome Sequence of Xanthomonas arboricola Strain 3004, a Causal Agent of Bacterial Disease on Barley. AB - We report here the annotated genome sequence of Xanthomonas arboricola strain 3004, isolated from barley leaves with symptoms of streak and capable of infecting other plant species. We sequenced the genome of X. arboricola strain 3004 to improve the understanding of molecular mechanisms of the pathogenesis and evolution of the genus Xanthomonas. PMID- 25700411 TI - Draft Genome Sequence of a Cellulase-Producing Psychrotrophic Paenibacillus Strain, IHB B 3415, Isolated from the Cold Environment of the Western Himalayas, India. AB - Paenibacillus sp. strain IHB B 3415 is a cellulase-producing psychrotrophic bacterium isolated from a soil sample from the cold deserts of Himachal Pradesh, India. Here, we report an 8.44-Mb assembly of its genome sequence with a G+C content of 50.77%. The data presented here will provide insights into the mechanisms of cellulose degradation at low temperature. PMID- 25700412 TI - Draft Genome of Pseudomonas sp. Strain 11/12A, Isolated from Lake Washington Sediment. AB - We announce here the genome sequencing of Pseudomonas sp. strain 11/12A from Lake Washington sediment. From the genome content, a versatile lifestyle is predicted but not one of bona fide methylotrophy. With the availability of its genomic sequence, Pseudomonas sp. 11/12A presents a prospective model for studying microbial communities in lake sediments. PMID- 25700413 TI - Draft Genome Sequence of an Extensively Drug-Resistant Mycobacterium tuberculosis Manu-Ancestor Spoligo-International Type 523 Isolate from Thailand. AB - We present the draft genome sequence of DS-16780, with a rare spoligo international type (SIT) 523 (777777777777771) genotype, which reveals an extensively drug-resistant Mycobacterium tuberculosis (XDR-TB) phenotype. The isolate is a representative of clonal XDR-TB from the western part of Thailand. PMID- 25700414 TI - Draft Genome Sequence of Pseudoalteromonas luteoviolacea HI1, Determined Using Roche 454 and PacBio Single-Molecule Real-Time Hybrid Sequencing. AB - We report here the 6.0-Mb draft genome assembly of Pseudoalteromonas luteoviolacea strain HI1 using Roche 454 and PacBio single-molecule real-time hybrid-sequencing analysis. This strain is of biological importance since it has the capacity to induce the settlement and metamorphosis of the serpulid polychaete Hydroides elegans and the coral Pocillopora damicornis. PMID- 25700415 TI - Complete Genome Sequence of the Nitrogen-Fixing and Solvent-Producing Clostridium pasteurianum DSM 525. AB - Here, we report on the closed genome sequence of Clostridium pasteurianum DSM 525, which is an anaerobic, Gram-positive and endospore-forming organism. C. pasteurianum can fix N2 and produce solvents such as butanol and 1,3-propanediol from carbohydrates. The genome consists of a single 4,350,673-bp replicon. PMID- 25700416 TI - Draft Genome Sequence of Hafnia paralvei Strain GTA-HAF03. AB - Hafnia paralvei is a Gram-negative member of the Enterobacteriaceae family, closely related to the opportunistic pathogen Hafnia alvei. We report here the first draft genome sequence of H. paralvei, from the beef trim isolate GTA-HAF03, consisting of a 5.0-Mbp assembly encoding 4,382 proteins and 90 predicted RNAs. PMID- 25700417 TI - Complete genome sequence and methylome analysis of bacillus strain x1. AB - Bacillus strain X1 is the source strain for the restriction enzyme BstXI. Its complete sequence and full methylome was determined using single-molecule real time (SMRT) sequencing. PMID- 25700418 TI - Complete Genome Sequence of Riemerella anatipestifer Serotype 1 Strain CH3. AB - Riemerella anatipestifer is a well-described pathogenic bacterium, which is reported worldwide as the cause of epizootic infectious polyserositis of waterfowl and other avian species. Here, we present the complete genome sequence of R. anatipestifer strain CH3, the serotype 1 prevalent in China. PMID- 25700419 TI - Closed Genome Sequence of Clostridium pasteurianum ATCC 6013. AB - We report here the closed genome of Clostridium pasteurianum ATCC 6013, a saccharolytic, nitrogen-fixing, and spore-forming Gram-positive obligate anaerobe. The organism is of biotechnological interest due to the production of solvents (butanol and 1,3-propanediol) but can be associated with food spoilage. The genome comprises a total of 4,351,223 bp. PMID- 25700420 TI - Draft genomes of two strains of flavobacterium isolated from lake washington sediment. AB - We report sequencing the genomes of two new Flavobacterium strains isolated from Lake Washington sediment. From genomic contents, versatile lifestyles were predicted but not bona fide methylotrophy. With the availability of their genomic sequences, the new Flavobacterium strains present prospective models for studying microbial communities in lake sediments. PMID- 25700421 TI - Removing a hair of doubt about BRAF targeting. AB - In this issue of Blood, Pettirossi et al, including Drs Tiacci and Falini, who led the effort in 2011 defining the BRAF-V600E driving mutation in hairy cell leukemia (HCL),provide extensive laboratory studies showing that inhibitors of BRAF-V600E and/or mitogen-activated protein kinase kinase (MEK) reach their targets and cause HCL cell death PMID- 25700422 TI - NKT-dependent B-cell activation in Gaucher disease. AB - In this issue of Blood, Nair et al describe a new population of type II natural killer T (NKT) cells with follicular helper phenotype (TFH), which is more abundant in patients and mice with Gaucher disease (GD) and is capable of regulating B-cell activity. PMID- 25700423 TI - A 2-way miRror of red blood cells and leukemia. AB - In this issue of Blood, the articles by Shaham et al and Wang et al are the first to identify microRNA 486 (miR-486) as a requisite oncomiR and credible therapeutic target in myeloid leukemia of Down syndrome (ML-DS) and chronic myeloid leukemia (CML) by showing that these 2 leukemias co-opt miR-486 functions in normal erythroid progenitor progrowth and survival activity. PMID- 25700424 TI - Bone marrow reticulocytes: a Plasmodium vivax affair? AB - In this issue of Blood, Malleret and colleagues show the importance of the bone marrow in Plasmodium vivax biology by proving the preferential infection of young reticulocytes (generally restricted to the bone marrow), which then experience accelerated maturation postinvasion. PMID- 25700425 TI - Effect of viral decontamination measures on Wright-stained blood smears. PMID- 25700426 TI - Natural killer (NK) cell function in paroxysmal nocturnal hemoglobinuria: a deficiency of NK cells, but not an NK cell deficiency. PMID- 25700427 TI - Comparison of transplantation with reduced and myeloablative conditioning for children with acute lymphoblastic leukemia. PMID- 25700429 TI - Practitioner insights on obesity prevention: the voice of South Australian OPAL workers. AB - Knowledge based on science has been central to implementing community-based childhood obesity prevention interventions. The art of practitioner wisdom is equally critical to ensure locally relevant responses. In South Australia (SA), the OPAL (Obesity Prevention and Lifestyle) program has been implemented to reduce childhood obesity across 20 communities reaching nearly one quarter of the state's population. Staff from across the State come together at regular intervals to share practice challenges and insights and refine the model of practice. Over a 3-year period 12 reflective practice workshops were held with OPAL staff (n = 46). OPAL staff were guided by an external facilitator using inquiring questions to reflect on their health promotion practice within local government. Three themes were identified as central within the reflections. The first theme is shared clarity through the OPAL obesity prevention model highlighting the importance of working to a clearly articulated, holistic obesity prevention model. The second theme is practitioner skill and sensitivity required to implement the model and deal with the 'politics' of obesity prevention. The final theme is the power of relationships as intrinsic to effective community based health promotion. Insights into the daily practices and reflections from obesity prevention practitioners are shared to shed light on the skills required to contribute to individual and social change. OPAL staff co-authored this paper. PMID- 25700430 TI - The New European Society of Cardiology guidelines on hypertrophic cardiomyopathy. PMID- 25700431 TI - Initial hospitalisation for atrial fibrillation in Aboriginal and non-Aboriginal populations in Western Australia. AB - OBJECTIVE: The epidemiology of atrial fibrillation (AF) among Aboriginal Australians is poorly described. We compared risk factors, incidence rates and mortality outcomes for first-ever hospitalised AF among Aboriginal and non Aboriginal Western Australians 20-84 years. METHODS: This retrospective cohort study used whole-of-state person-based linked hospital and deaths data. Incident hospital AF admissions (previous AF admission-free for 15 years) were identified and subsequent mortality determined. Disease-specific comorbidity histories were ascertained by 10-year look-back. Age-standardised incidence rates were estimated and the adjusted risk of 30-day and 1-year mortality calculated using regression methods. RESULTS: Aboriginal patients accounted for 923 (2.5%) of 37 097 incident AF admissions during 2000-2009. Aboriginal patients were younger (mean age 54.8 vs 69.3 years), had lower proportions of primary field AF diagnoses and higher comorbidities than non-Aboriginal patients. The Aboriginal and non-Aboriginal age standardised incidence rates per 100,000 for men 20-54 years were 197 and 55 (ratio=3.6), for women 20-54 years were 122 and 19 (ratio=6.4), for men 55-84 years were 1151 and 888 (ratio=1.3), and for women 55-84 years were 1050 and 571 (ratio=1.8). While 30-day mortality was similar, crude 1-year mortality risks in Aboriginal and non-Aboriginal patients were 20.6% and 16.3% (adjusted HR=1.24) and 14.4% and 9.9% in 30-day survivors (adjusted HR=1.58). CONCLUSIONS: The incidence (particularly at young ages) and long-term mortality following hospitalised AF is significantly higher in Aboriginal people. Better control of the antecedent risk factors for AF, improved detection and management of AF itself and prevention of its complications are needed. PMID- 25700432 TI - Three-year follow-up of treatment-naive and previously treated patients with CLL and SLL receiving single-agent ibrutinib. AB - Ibrutinib is an orally administered inhibitor of Bruton tyrosine kinase that antagonizes B-cell receptor, chemokine, and integrin-mediated signaling. In early phase studies, ibrutinib demonstrated high response rates and prolonged progression-free survival (PFS) in chronic lymphocytic leukemia (CLL). The durable responses observed with ibrutinib relate in part to a modest toxicity profile that allows the majority of patients to receive continuous therapy for an extended period. We report on median 3-year follow-up of 132 patients with symptomatic treatment-naive and relapsed/refractory CLL or small lymphocytic lymphoma. Longer treatment with ibrutinib was associated with improvement in response quality over time and durable remissions. Toxicity with longer follow-up diminished with respect to occurrence of grade 3 or greater cytopenias, fatigue, and infections. Progression remains uncommon, occurring primarily in some patients with relapsed del(17)(p13.1) and/or del(11)(q22.3) disease. Treatment related lymphocytosis remains largely asymptomatic even when persisting >1 year and does not appear to alter longer-term PFS and overall survival compared with patients with partial response or better. Collectively, these data provide evidence that ibrutinib controls CLL disease manifestations and is well tolerated for an extended period; this information can help direct potential treatment options for different subgroups to diminish the long-term risk of relapse. PMID- 25700433 TI - Cellular fibronectin containing extra domain A promotes arterial thrombosis in mice through platelet Toll-like receptor 4. AB - Cellular fibronectin containing extra domain A (Fn-EDA+), which is produced in response to tissue injury in several disease states, has prothrombotic activity and is known to interact with Toll-like-receptor 4 (TLR4). The underlying mechanism and cell types involved in mediating the prothrombotic effect of Fn EDA+ still remain unknown. Using intravital microscopy, we evaluated susceptibility to carotid artery thrombosis after FeCl3-induced injury in mice expressing Fn lacking EDA (Fn-EDA(-/-) mice) or Fn containing EDA (Fn-EDA(+/+) mice). Fn-EDA(-/-) mice exhibited prolonged times to first thrombus formation and complete occlusion and a significant decrease in the rate of thrombus growth (P < .05 vs Fn-EDA(+/+) mice). Genetic deletion of TLR4 reversed the accelerated thrombosis in Fn-EDA(+/+) mice (P < .05) but had no effect in Fn-EDA(-/-) mice. Bone marrow transplantation experiments revealed that TLR4 expressed on hematopoietic cells contributes to accelerated thrombosis in Fn-EDA(+/+) mice. In vitro studies showed that cellular Fn-EDA+ interacts with platelet TLR4 and promotes agonist-induced platelet aggregation. Finally, Fn-EDA(+/+) mice specifically lacking platelet TLR4 exhibited prolonged times to first thrombus formation and complete occlusion (P < .05 vs Fn-EDA(+/+) mice containing platelet TLR4). We conclude that platelet TLR4 contributes to the prothrombotic effect of cellular Fn-EDA+, suggesting another link between thrombosis and innate immunity. PMID- 25700435 TI - Photoacoustic-Based-Close-Loop Temperature Control for Nanoparticle Hyperthermia. AB - GOAL: Hyperthermia therapy requires tight temperature control to achieve selective killing of cancerous tissue with minimal damage on surrounding healthy tissues. METHODS: To this end, accurate temperature monitoring and subsequent heating control are critical. However, an economic, portable, and real-time temperature control solution is currently lacking. To bridge this gap, we present a novel portable close-loop system for hyperthermia temperature control, in which photoacoustic technique is proposed for noninvasive real-time temperature measurement. Exploiting the high sensitivity of photoacoustics, the temperature is monitored with an accuracy of around 0.18 degrees C and then fed back to a controller implemented on field programmable gate array (FPGA) for temperature control. Dubbed as portable hyperthermia feedback controller (pHFC), it stabilizes the temperature at preset values by regulating the hyperthermia power with a proportional-integral-derivative (PID) algorithm; and to facilitate digital implementation, the pHFC further converts the PID output into switching values (0 and 1) with the pulse width modulation (PWM) algorithm. RESULTS: Proof of-concept hyperthermia experiments demonstrate that the pHFC system is able to bring the temperature from baseline to predetermined value with an accuracy of 0.3 degrees and a negligible temperature overshoot. CONCLUSION: The pHFC can potentially be translated to clinical applications with customized hyperthermia system design. SIGNIFICANCE: This paper can facilitate future efforts in seamless integration of close-loop temperature control solution and various clinical hyperthermia systems. PMID- 25700434 TI - Plant-based oral tolerance to hemophilia therapy employs a complex immune regulatory response including LAP+CD4+ T cells. AB - Coagulation factor replacement therapy for the X-linked bleeding disorder hemophilia is severely complicated by antibody ("inhibitor") formation. We previously found that oral delivery to hemophilic mice of cholera toxin B subunit coagulation factor fusion proteins expressed in chloroplasts of transgenic plants suppressed inhibitor formation directed against factors VIII and IX and anaphylaxis against factor IX (FIX). This observation and the relatively high concentration of antigen in the chloroplasts prompted us to evaluate the underlying tolerance mechanisms. The combination of oral delivery of bioencapsulated FIX and intravenous replacement therapy induced a complex, interleukin-10 (IL-10)-dependent, antigen-specific systemic immune suppression of pathogenic antibody formation (immunoglobulin [Ig] 1/inhibitors, IgE) in hemophilia B mice. Tolerance induction was also successful in preimmune mice but required prolonged oral delivery once replacement therapy was resumed. Orally delivered antigen, initially targeted to epithelial cells, was taken up by dendritic cells throughout the small intestine and additionally by F4/80(+) cells in the duodenum. Consistent with the immunomodulatory responses, frequencies of tolerogenic CD103(+) and plasmacytoid dendritic cells were increased. Ultimately, latency-associated peptide expressing CD4(+) regulatory T cells (CD4(+)CD25( )LAP(+) cells with upregulated IL-10 and transforming growth factor-beta (TGF beta) expression) as well as conventional CD4(+)CD25(+) regulatory T cells systemically suppressed anti-FIX responses. PMID- 25700436 TI - Iterative Vessel Segmentation of Fundus Images. AB - This paper presents a novel unsupervised iterative blood vessel segmentation algorithm using fundus images. First, a vessel enhanced image is generated by tophat reconstruction of the negative green plane image. An initial estimate of the segmented vasculature is extracted by global thresholding the vessel enhanced image. Next, new vessel pixels are identified iteratively by adaptive thresholding of the residual image generated by masking out the existing segmented vessel estimate from the vessel enhanced image. The new vessel pixels are, then, region grown into the existing vessel, thereby resulting in an iterative enhancement of the segmented vessel structure. As the iterations progress, the number of false edge pixels identified as new vessel pixels increases compared to the number of actual vessel pixels. A key contribution of this paper is a novel stopping criterion that terminates the iterative process leading to higher vessel segmentation accuracy. This iterative algorithm is robust to the rate of new vessel pixel addition since it achieves 93.2-95.35% vessel segmentation accuracy with 0.9577-0.9638 area under ROC curve (AUC) on abnormal retinal images from the STARE dataset. The proposed algorithm is computationally efficient and consistent in vessel segmentation performance for retinal images with variations due to pathology, uneven illumination, pigmentation, and fields of view since it achieves a vessel segmentation accuracy of about 95% in an average time of 2.45, 3.95, and 8 s on images from three public datasets DRIVE, STARE, and CHASE_DB1, respectively. Additionally, the proposed algorithm has more than 90% segmentation accuracy for segmenting peripapillary blood vessels in the images from the DRIVE and CHASE_DB1 datasets. PMID- 25700437 TI - Independent Vector Analysis for Gradient Artifact Removal in Concurrent EEG-fMRI Data. AB - We consider the problem of removing gradient artifact from electroencephalogram (EEG) signal, recorded concurrently with functional magnetic resonance imaging (fMRI) acquisition. We estimate the artifact by exploiting its quasi-periodicity over the epochs and its similarity over the different channels by using independent vector analysis, a recent extension of independent component analysis for multiple datasets. The method fully makes use of the spatio-temporal information by using spatial dependences across channels to estimate the artifact for a particular channel. Thus, it provides robustness with respect to uncontrollable changes such as head movement and fluctuations in the B0 field during the acquisition. Results using both simulated data with gradient artifact and EEG data collected concurrently with fMRI show the desirable performance of the new method. PMID- 25700438 TI - Human Joint Angle Estimation with Inertial Sensors and Validation with A Robot Arm. AB - Traditionally, human movement has been captured primarily by motion capture systems. These systems are costly, require fixed cameras in a controlled environment, and suffer from occlusion. Recently, the availability of low-cost wearable inertial sensors containing accelerometers, gyroscopes, and magnetometers have provided an alternative means to overcome the limitations of motion capture systems. Wearable inertial sensors can be used anywhere, cannot be occluded, and are low cost. Several groups have described algorithms for tracking human joint angles. We previously described a novel approach based on a kinematic arm model and the Unscented Kalman Filter (UKF). Our proposed method used a minimal sensor configuration with one sensor on each segment. This paper reports significant improvements in both the algorithm and the assessment. The new model incorporates gyroscope and accelerometer random drift models, imposes physical constraints on the range of motion for each joint, and uses zero-velocity updates to mitigate the effect of sensor drift. A high-precision industrial robot arm precisely quantifies the performance of the tracker during slow, normal, and fast movements over continuous 15-min recording durations. The agreement between the estimated angles from our algorithm and the high-precision robot arm reference was excellent. On average, the tracker attained an RMS angle error of about 3( degrees ) for all six angles. The UKF performed slightly better than the more common Extended Kalman Filter. PMID- 25700439 TI - A Comparison of SVM and GMM-Based Classifier Configurations for Diagnostic Classification of Pulmonary Sounds. AB - GOAL: The aim of this study is to find a useful methodology to classify multiple distinct pulmonary conditions including the healthy condition and various pathological types, using pulmonary sounds data. METHODS: Fourteen-channel pulmonary sounds data of 40 subjects (healthy and pathological, where the pathologies are of obstructive and restrictive types) are modeled using a second order 250-point vector autoregressive model. The estimated model parameters are fed to support vector machine and Gaussian mixture model (GMM) classifiers which are used in various configurations, resulting in eight different methodologies in total. RESULTS: Among the eight methodologies, the hierarchical GMM classifier yields the best performance with a total correct classification rate of 85%, where the term hierarchical refers here to first classifying the data into healthy and pathological classes, then the pathological class into obstructive and restrictive types. Both the sensitivity and specificity for the healthy versus pathological classification at the first stage of hierarchy are 90%. CONCLUSION: The newly proposed methodologies provide improved results compared to the previous study. The hierarchical framework is suggested for diagnostic classification of pulmonary sounds, although the algorithms are still open for further improvements. SIGNIFICANCE: This study proposes new methodologies for diagnostic classification of pulmonary sounds, and suggests using a hierarchical framework for the first time. PMID- 25700440 TI - A Single Scatter Model for X-ray CT Energy Spectrum Estimation and Polychromatic Reconstruction. AB - To improve the quantitative accuracy of linear attenuation coefficients measured by computed tomography (CT), we used a single scatter model to estimate the Compton scatter distribution and then a polychromatic image reconstruction algorithm, namely the iterative maximum-likelihood polychromatic algorithm for CT (IMPACT), was implemented to include scatter correction (SC). To perform the IMPACT, the X-ray spectra of a tube were estimated via an expectation maximization (EM) algorithm with SC. To test the accuracy of the estimated spectra, the projection images of cubic phantoms containing different depths of polymethylmethacrylate (PMMA) were acquired. The percentage of root mean square errors (%RMSE) of the measured transmission data and calculated transmission values were used to evaluate the accuracy of the estimated spectra. In addition, a hydroxylapatite (HA) phantom was used to study streak artifacts and evaluate the accuracy of the linear attenuation coefficients estimated using the IMPACT with SC. The %RMSE of the EM-with-SC estimated spectra were all lower than 1% and were also smaller than that without SC. The error in the quantification of the HA linear attenuation was only about 3% after SC. Our results showed that the quantitative accuracy of the linear attenuation coefficients measured with a cone beam CT was improved when the IMPACT with SC was used. PMID- 25700441 TI - Localization and Segmentation of 3D Intervertebral Discs in MR Images by Data Driven Estimation. AB - This paper addresses the problem of fully-automatic localization and segmentation of 3D intervertebral discs (IVDs) from MR images. Our method contains two steps, where we first localize the center of each IVD, and then segment IVDs by classifying image pixels around each disc center as foreground (disc) or background. The disc localization is done by estimating the image displacements from a set of randomly sampled 3D image patches to the disc center. The image displacements are estimated by jointly optimizing the training and test displacement values in a data-driven way, where we take into consideration both the training data and the geometric constraint on the test image. After the disc centers are localized, we segment the discs by classifying image pixels around disc centers as background or foreground. The classification is done in a similar data-driven approach as we used for localization, but in this segmentation case we are aiming to estimate the foreground/background probability of each pixel instead of the image displacements. In addition, an extra neighborhood smooth constraint is introduced to enforce the local smoothness of the label field. Our method is validated on 3D T2-weighted turbo spin echo MR images of 35 patients from two different studies. Experiments show that compared to state of the art, our method achieves better or comparable results. Specifically, we achieve for localization a mean error of 1.6-2.0 mm, and for segmentation a mean Dice metric of 85%-88% and a mean surface distance of 1.3-1.4 mm. PMID- 25700442 TI - The Generalized Log-Ratio Transformation: Learning Shape and Adjacency Priors for Simultaneous Thigh Muscle Segmentation. AB - We present a novel probabilistic shape representation that implicitly includes prior anatomical volume and adjacency information, termed the generalized log ratio (GLR) representation. We demonstrate the usefulness of this representation in the task of thigh muscle segmentation. Analysis of the shapes and sizes of thigh muscles can lead to a better understanding of the effects of chronic obstructive pulmonary disease (COPD), which often results in skeletal muscle weakness in lower limbs. However, segmenting these muscles from one another is difficult due to a lack of distinctive features and inter-muscular boundaries that are difficult to detect. We overcome these difficulties by building a shape model in the space of GLR representations. We remove pose variability from the model by employing a presegmentation-based alignment scheme. We also design a rotationally invariant random forest boundary detector that learns common appearances of the interface between muscles from training data. We combine the shape model and the boundary detector into a fully automatic globally optimal segmentation technique. Our segmentation technique produces a probabilistic segmentation that can be used to generate uncertainty information, which can be used to aid subsequent analysis. Our experiments on challenging 3D magnetic resonance imaging data sets show that the use of the GLR representation improves the segmentation accuracy, and yields an average Dice similarity coefficient of 0.808 +/-0.074, comparable to other state-of-the-art thigh segmentation techniques. PMID- 25700443 TI - Direct Parametric Image Reconstruction in Reduced Parameter Space for Rapid Multi Tracer PET Imaging. AB - The separation of multiple PET tracers within an overlapping scan based on intrinsic differences of tracer pharmacokinetics is challenging, due to limited signal-to-noise ratio (SNR) of PET measurements and high complexity of fitting models. In this study, we developed a direct parametric image reconstruction (DPIR) method for estimating kinetic parameters and recovering single tracer information from rapid multi-tracer PET measurements. This is achieved by integrating a multi-tracer model in a reduced parameter space (RPS) into dynamic image reconstruction. This new RPS model is reformulated from an existing multi tracer model and contains fewer parameters for kinetic fitting. Ordered-subsets expectation-maximization (OSEM) was employed to approximate log-likelihood function with respect to kinetic parameters. To incorporate the multi-tracer model, an iterative weighted nonlinear least square (WNLS) method was employed. The proposed multi-tracer DPIR (MT-DPIR) algorithm was evaluated on dual-tracer PET simulations ([18F]FDG and [11C]MET) as well as on preclinical PET measurements ([18F]FLT and [18F]FDG). The performance of the proposed algorithm was compared to the indirect parameter estimation method with the original dual tracer model. The respective contributions of the RPS technique and the DPIR method to the performance of the new algorithm were analyzed in detail. For the preclinical evaluation, the tracer separation results were compared with single [18F]FDG scans of the same subjects measured two days before the dual-tracer scan. The results of the simulation and preclinical studies demonstrate that the proposed MT-DPIR method can improve the separation of multiple tracers for PET image quantification and kinetic parameter estimations. PMID- 25700444 TI - Resolution Guarantees in Electrical Impedance Tomography. AB - Electrical impedance tomography (EIT) uses current-voltage measurements on the surface of an imaging subject to detect conductivity changes or anomalies. EIT is a promising new technique with great potential in medical imaging and non destructive testing. However, in many applications, EIT suffers from inconsistent reliability due to its enormous sensitivity to modeling and measurement errors. In this work, we show that it is principally possible to give rigorous resolution guarantees in EIT even in the presence of systematic and random measurement errors. We derive a constructive criterion to decide whether a desired resolution can be achieved in a given measurement setup. Our results cover the case where anomalies of a known minimal contrast in a subject with imprecisely known background conductivity are to be detected from noisy measurements on a number of electrodes with imprecisely known contact impedances. The considered settings are still idealized in the sense that the shape of the imaging subject has to be known and the allowable amount of uncertainty is rather low. Nevertheless, we believe that this may be a starting point to identify new applications and to design and optimize measurement setups in EIT. PMID- 25700445 TI - Video tracking using learned hierarchical features. AB - In this paper, we propose an approach to learn hierarchical features for visual object tracking. First, we offline learn features robust to diverse motion patterns from auxiliary video sequences. The hierarchical features are learned via a two-layer convolutional neural network. Embedding the temporal slowness constraint in the stacked architecture makes the learned features robust to complicated motion transformations, which is important for visual object tracking. Then, given a target video sequence, we propose a domain adaptation module to online adapt the pre-learned features according to the specific target object. The adaptation is conducted in both layers of the deep feature learning module so as to include appearance information of the specific target object. As a result, the learned hierarchical features can be robust to both complicated motion transformations and appearance changes of target objects. We integrate our feature learning algorithm into three tracking methods. Experimental results demonstrate that significant improvement can be achieved using our learned hierarchical features, especially on video sequences with complicated motion transformations. PMID- 25700446 TI - Structure-sensitive saliency detection via multilevel rank analysis in intrinsic feature space. AB - This paper advocates a novel multiscale, structure-sensitive saliency detection method, which can distinguish multilevel, reliable saliency from various natural pictures in a robust and versatile way. One key challenge for saliency detection is to guarantee the entire salient object being characterized differently from nonsalient background. To tackle this, our strategy is to design a structure aware descriptor based on the intrinsic biharmonic distance metric. One benefit of introducing this descriptor is its ability to simultaneously integrate local and global structure information, which is extremely valuable for separating the salient object from nonsalient background in a multiscale sense. Upon devising such powerful shape descriptor, the remaining challenge is to capture the saliency to make sure that salient subparts actually stand out among all possible candidates. Toward this goal, we conduct multilevel low-rank and sparse analysis in the intrinsic feature space spanned by the shape descriptors defined on over segmented super-pixels. Since the low-rank property emphasizes much more on stronger similarities among super-pixels, we naturally obtain a scale space along the rank dimension in this way. Multiscale saliency can be obtained by simply computing differences among the low-rank components across the rank scale. We conduct extensive experiments on some public benchmarks, and make comprehensive, quantitative evaluation between our method and existing state-of-the-art techniques. All the results demonstrate the superiority of our method in accuracy, reliability, robustness, and versatility. PMID- 25700447 TI - A low-rank approximation-based transductive support tensor machine for semisupervised classification. AB - In the fields of machine learning, pattern recognition, image processing, and computer vision, the data are usually represented by the tensors. For the semisupervised tensor classification, the existing transductive support tensor machine (TSTM) needs to resort to iterative technique, which is very time consuming. In order to overcome this shortcoming, in this paper, we extend the concave-convex procedure-based transductive support vector machine (CCCP-TSVM) to the tensor patterns and propose a low-rank approximation-based TSTM, in which the tensor rank-one decomposition is used to compute the inner product of the tensors. Theoretically, concave-convex procedure-based TSTM (CCCP-TSTM) is an extension of the linear CCCP-TSVM to tensor patterns. When the input patterns are vectors, CCCP-TSTM degenerates into the linear CCCP-TSVM. A set of experiments is conducted on 23 semisupervised classification tasks, which are generated from seven second-order face data sets, three third-order gait data sets, and two third-order image data sets, to illustrate the performance of the CCCP-TSTM. The results show that compared with CCCP-TSVM and TSTM, CCCP-TSTM provides significant performance gain in terms of test accuracy and training speed. PMID- 25700448 TI - Query-adaptive multiple instance learning for video instance retrieval. AB - Given a query image containing the object of interest (OOI), we propose a novel learning framework for retrieving relevant frames from the input video sequence. While techniques based on object matching have been applied to solve this task, their performance would be typically limited due to the lack of capabilities in handling variations in visual appearances of the OOI across video frames. Our proposed framework can be viewed as a weakly supervised approach, which only requires a small number of (randomly selected) relevant and irrelevant frames from the input video for performing satisfactory retrieval performance. By utilizing frame-level label information of such video frames together with the query image, we propose a novel query-adaptive multiple instance learning algorithm, which exploits the visual appearance information of the OOI from the query and that of the aforementioned video frames. As a result, the derived learning model would exhibit additional discriminating abilities while retrieving relevant instances. Experiments on two real-world video data sets would confirm the effectiveness and robustness of our proposed approach. PMID- 25700449 TI - Recursive approximation of the bilateral filter. AB - This paper presents a complete proof that the bilateral filter can be implemented recursively, as long as: 1) the spatial filter can be implemented recursively and 2) the range filter can be decomposed into a recursive product. As a result, an O(ND) solution can be obtained for bilateral filtering, where N is the image size and D is the dimensionality. PMID- 25700450 TI - Cross-modal learning to rank via latent joint representation. AB - Cross-modal ranking is a research topic that is imperative to many applications involving multimodal data. Discovering a joint representation for multimodal data and learning a ranking function are essential in order to boost the cross-media retrieval (i.e., image-query-text or text-query-image). In this paper, we propose an approach to discover the latent joint representation of pairs of multimodal data (e.g., pairs of an image query and a text document) via a conditional random field and structural learning in a listwise ranking manner. We call this approach cross-modal learning to rank via latent joint representation (CML2R). In CML2R, the correlations between multimodal data are captured in terms of their sharing hidden variables (e.g., topics), and a hidden-topic-driven discriminative ranking function is learned in a listwise ranking manner. The experiments show that the proposed approach achieves a good performance in cross-media retrieval and meanwhile has the capability to learn the discriminative representation of multimodal data. PMID- 25700451 TI - Saliency region detection based on Markov absorption probabilities. AB - In this paper, we present a novel bottom-up salient object detection approach by exploiting the relationship between the saliency detection and the Markov absorption probability. First, we calculate a preliminary saliency map by the Markov absorption probability on a weighted graph via partial image borders as background prior. Unlike most of the existing background prior-based methods which treated all image boundaries as background, we only use the left and top sides as background for simplicity. The saliency of each element is defined as the sum of the corresponding absorption probability by several left and top virtual boundary nodes, which are most similar to it. Second, a better result is obtained by ranking the relevance of the image elements with foreground cues extracted from the preliminary saliency map, which can effectively emphasize the objects against the background, whose computation is processed similarly as that in the first stage and yet substantially different from the former one. At last, three optimization techniques--content-based diffusion mechanism, superpixelwise depression function, and guided filter--are utilized to further modify the saliency map generalized at the second stage, which is proved to be effective and complementary to each other. Both qualitative and quantitative evaluations on four publicly available benchmark data sets demonstrate the robustness and efficiency of the proposed method against 17 state-of-the-art methods. PMID- 25700452 TI - Hierarchical graphical models for simultaneous tracking and recognition in wide area scenes. AB - We present a unified framework to track multiple people, as well localize, and label their activities, in complex long-duration video sequences. To do this, we focus on two aspects: 1) the influence of tracks on the activities performed by the corresponding actors and 2) the structural relationships across activities. We propose a two-level hierarchical graphical model, which learns the relationship between tracks, relationship between tracks, and their corresponding activity segments, as well as the spatiotemporal relationships across activity segments. Such contextual relationships between tracks and activity segments are exploited at both the levels in the hierarchy for increased robustness. An L1 regularized structure learning approach is proposed for this purpose. While it is well known that availability of the labels and locations of activities can help in determining tracks more accurately and vice-versa, most current approaches have dealt with these problems separately. Inspired by research in the area of biological vision, we propose a bidirectional approach that integrates both bottom-up and top-down processing, i.e., bottom-up recognition of activities using computed tracks and top-down computation of tracks using the obtained recognition. We demonstrate our results on the recent and publicly available UCLA and VIRAT data sets consisting of realistic indoor and outdoor surveillance sequences. PMID- 25700453 TI - Resting-state whole-brain functional connectivity networks for MCI classification using L2-regularized logistic regression. AB - Mild cognitive impairment (MCI) has been considered as a transition phase to Alzheimer's disease (AD), and the diagnosis of MCI may help patients to carry out appropriate treatments to delay or even prevent AD. Recent advanced network analysis techniques utilizing resting-state functional Magnetic Resonance Imaging (rs-fMRI) has been widely used to get more comprehensive understanding of neurological disorders at a whole-brain connectivity level. However, how to explore effective brain functional connectivity from fMRI data is still a challenge especially when the ultimate goal is to train classifiers for discriminating patients effectively. In our research, we studied the functional connectivity of the whole brain by calculating Pearson's correlation coefficients based on rs-fMRI data, and proposed a set of novel features by applying Two Sample T-Test on the correlation coefficients matrix to identify the most discriminative correlation coefficients. We trained a L2-regularized Logistic Regression classifier based on the five novel features for the first time and evaluated the classification performance via leave-one-out cross validation. We also iterated 10-fold cross validation ten times in order to evaluate the statistical significance of our method. The experiment result demonstrates that classification accuracy and the area under receiver operating characteristic (ROC) curve in our method are 87.5% and 0.929 respectively, and the statistical results prove that our method is statistically significant better than other three algorithms, which means our method could be meaningful to assist physicians efficiently in "real-world" diagnostic situations. PMID- 25700454 TI - Design and simulation of proportional biological operational Mu-circuit. AB - It is challenging yet desirable to quantitatively control the expression of a target gene in practice. We design a device-Proportional Biological Operational Mu-circuit (P-BOM) incorporating AND/OR gate and operational amplifier into one circuit and explore its behaviors through simulation. The results imply that will be possible to regulate input-output proportionally by manipulating the RBS of hrpR, hrpS, tetR and output gene and used in the sensing of environmental weak signals such as dioxins. PMID- 25700455 TI - Peritoneal dialysis--taking the lead to promote health literacy. PMID- 25700456 TI - Introduction to point-counterpoint: Mechanisms of glomerular filtration: pores versus an electrical field. PMID- 25700457 TI - Point: Proposing the electrokinetic model. AB - It is still not fully resolved how the glomerular filter works and why it never clogs. Several models have been proposed. In this review, we will compare the most widely used "pore model" to the more recent and refined "electrokinetic model" of glomerular filtration. The pore model assumes the existence of highly ordered regular pores, but it cannot provide a mechanistic explanation for several of the inherent characteristics of the glomerular filter. The electrokinetic model assumes that streaming potentials generate an electrical field along the filter surface which repels the negatively charged plasma proteins, preventing them from passing across the filter. The electrokinetic model can provide elegant mechanistic solutions for most of the unresolved riddles about the glomerular filter. PMID- 25700458 TI - Counterpoint: Defending pore theory. PMID- 25700460 TI - Soluble VCAM-1 and E-selectin in PD patients: the additive value of the free diffusion coefficient in the assessment of local peritoneal production. PMID- 25700459 TI - Transition of mesothelial cell to fibroblast in peritoneal dialysis: EMT, stem cell or bystander? AB - Long-term peritoneal dialysis (PD) can lead to fibrotic changes in the peritoneum, characterized by loss of mesothelial cells (MCs) and thickening of the submesothelial area with an accumulation of collagen and myofibroblasts. The origin of myofibroblasts is a central question in peritoneal fibrosis that remains unanswered at present. Numerous clinical and experimental studies have suggested that MCs, through epithelial-mesenchymal transition (EMT), contribute to the pool of peritoneal myofibroblasts. However, recent work has placed significant doubts on the paradigm of EMT in organ fibrogenesis (in the kidney particularly), highlighting the need to reconsider the role of EMT in the generation of myofibroblasts in peritoneal fibrosis. In particular, selective cell isolation and lineage-tracing experiments have suggested the existence of progenitor cells in the peritoneum, which are able to switch to fibroblast-like cells when stimulated by the local environment. These findings highlight the plastic nature of MCs and its contribution to peritoneal fibrogenesis. In this review, we summarize the key findings and caveats of EMT in organ fibrogenesis, with a focus on PD-related peritoneal fibrosis, and discuss the potential of peritoneal MCs as a source of myofibroblasts. PMID- 25700461 TI - Chronic peritoneal dialysis in Lebanese children of families with low socioeconomic status. PMID- 25700462 TI - Health literacy in patients on maintenance peritoneal dialysis: prevalence and outcomes. PMID- 25700463 TI - Comparison of survival of patients with heart and lung transplants on peritoneal dialysis and hemodialysis. PMID- 25700464 TI - Correction of peritoneal catheter obstruction using a neonatal bronchoscope. PMID- 25700465 TI - Asymptomatic peritoneal leukocytosis after exteriorization of buried peritoneal dialysis catheters: a case series. PMID- 25700466 TI - A case of suppurative peritonitis by a commensal oral organism, Kingella denitrificans, in an adult peritoneal dialysis patient. PMID- 25700467 TI - Successful treatment of encapsulating peritoneal sclerosis by hemodialysis and peritoneal lavage using dialysate containing dissolved hydrogen. PMID- 25700468 TI - Migration of Tenckhoff catheter into an occult inguinal hernia. PMID- 25700469 TI - Successful treatment of Mycobacterium chelonae peritoneal dialysis-related infection by a combination regimen including local thermal therapy. PMID- 25700470 TI - Clarification of trimethoprim/sulfamethoxazole dose in CAPD. PMID- 25700471 TI - A 1.83 MUJ/Classification, 8-Channel, Patient-Specific Epileptic Seizure Classification SoC Using a Non-Linear Support Vector Machine. AB - A non-linear support vector machine (NLSVM) seizure classification SoC with 8 channel EEG data acquisition and storage for epileptic patients is presented. The proposed SoC is the first work in literature that integrates a feature extraction (FE) engine, patient specific hardware-efficient NLSVM classification engine, 96 KB SRAM for EEG data storage and low-noise, high dynamic range readout circuits. To achieve on-chip integration of the NLSVM classification engine with minimum area and energy consumption, the FE engine utilizes time division multiplexing (TDM)-BPF architecture. The implemented log-linear Gaussian basis function (LL GBF) NLSVM classifier exploits the linearization to achieve energy consumption of 0.39 MU J/operation and reduces the area by 28.2% compared to conventional GBF implementation. The readout circuits incorporate a chopper-stabilized DC servo loop to minimize the noise level elevation and achieve noise RTI of 0.81 MU Vrms for 0.5-100 Hz bandwidth with an NEF of 4.0. The 5 * 5 mm (2) SoC is implemented in a 0.18 MUm 1P6M CMOS process consuming 1.83 MU J/classification for 8-channel operation. SoC verification has been done with the Children's Hospital Boston-MIT EEG database, as well as with a specific rapid eye-blink pattern detection test, which results in an average detection rate, average false alarm rate and latency of 95.1%, 0.94% (0.27 false alarms/hour) and 2 s, respectively. PMID- 25700472 TI - Matrix variate distribution-induced sparse representation for robust image classification. AB - Sparse representation learning has been successfully applied into image classification, which represents a given image as a linear combination of an over complete dictionary. The classification result depends on the reconstruction residuals. Normally, the images are stretched into vectors for convenience, and the representation residuals are characterized by l2 -norm or l1 -norm, which actually assumes that the elements in the residuals are independent and identically distributed variables. However, it is hard to satisfy the hypothesis when it comes to some structural errors, such as illuminations, occlusions, and so on. In this paper, we represent the image data in their intrinsic matrix form rather than concatenated vectors. The representation residual is considered as a matrix variate following the matrix elliptically contoured distribution, which is robust to dependent errors and has long tail regions to fit outliers. Then, we seek the maximum a posteriori probability estimation solution of the matrix-based optimization problem under sparse regularization. An alternating direction method of multipliers (ADMMs) is derived to solve the resulted optimization problem. The convergence of the ADMM is proven theoretically. Experimental results demonstrate that the proposed method is more effective than the state-of-the-art methods when dealing with the structural errors. PMID- 25700473 TI - Adaptive Neural Network Dynamic Surface Control for a Class of Time-Delay Nonlinear Systems With Hysteresis Inputs and Dynamic Uncertainties. AB - In this paper, an adaptive neural network (NN) dynamic surface control is proposed for a class of time-delay nonlinear systems with dynamic uncertainties and unknown hysteresis. The main advantages of the developed scheme are: 1) NNs are utilized to approximately describe nonlinearities and unknown dynamics of the nonlinear time-delay systems, making it possible to deal with unknown nonlinear uncertain systems and pursue the Linfinity performance of the tracking error; 2) using the finite covering lemma together with the NNs approximators, the Krasovskii function is abandoned, which paves the way for obtaining the Linfinity performance of the tracking error; 3) by introducing an initializing technique, the Linfinity performance of the tracking error can be achieved; 4) using a generalized Prandtl-Ishlinskii (PI) model, the limitation of the traditional PI hysteresis model is overcome; and 5) by applying the Young's inequalities to deal with the weight vector of the NNs, the updated laws are needed only at the last controller design step with only two parameters being estimated, which reduces the computational burden. It is proved that the proposed scheme can guarantee semiglobal stability of the closed-loop system and achieves the Linfinity performance of the tracking error. Simulation results for general second-order time-delay nonlinear systems and the tuning metal cutting system are presented to demonstrate the efficiency of the proposed method. PMID- 25700474 TI - Carotid and Jugular Classification in ARTSENS. AB - Over past few years our group has been working on the development of a low-cost device, ARTSENS, for measurement of local arterial stiffness (AS) of the common carotid artery (CCA). This uses a single element ultrasound transducer to obtain A-mode frames from the CCA. It is designed to be fully automatic in its operation such that, a general medical practitioner can use the device without any prior knowledge of ultrasound modality. Placement of the probe over CCA and identification of echo positions corresponding to its two walls are critical steps in the process of measurement of AS. We had reported an algorithm to locate the CCA walls based on their characteristic motion. Unfortunately, in supine position, the internal jugular vein (IJV) expands in the carotid triangle and pulsates in a manner that confounds the existing algorithm and leads to wrong measurements of the AS. Jugular venous pulse (JVP), on its own right, is a very important physiological signal for diagnosis of morbidities of the right side of the heart and there is a lack of noninvasive methods for its accurate estimation. We integrated an ECG device to the existing hardware of ARTSENS and developed a method based on physiology of the vessels, which now enable us to segregate the CCA pulse (CCP) and the JVP. False identification rate is less than 4%. To retain the capabilities of ARTSENS to operate without ECG, we designed another method where the classification can be achieved without an ECG, albeit errors are a bit higher. These improvements enable ARTSENS to perform automatic measurement of AS even in the supine position and make it a unique and handy tool to perform JVP analysis. PMID- 25700475 TI - A Novel Approach to Multiple Sequence Alignment Using Multiobjective Evolutionary Algorithm Based on Decomposition. AB - Multiple sequence alignment (MSA) is a fundamental and key step for implementing other tasks in bioinformatics, such as phylogenetic analyses, identification of conserved motifs and domains, structure prediction, etc. Despite the fact that there are many methods to implement MSA, biologically perfect alignment approaches are not found hitherto. This paper proposes a novel idea to perform MSA, where MSA is treated as a multiobjective optimization problem. A famous multiobjective evolutionary algorithm framework based on decomposition is applied for solving MSA, named MOMSA. In the MOMSA algorithm, we develop a new population initialization method and a novel mutation operator. We compare the performance of MOMSA with several alignment methods based on evolutionary algorithms, including VDGA, GAPAM, and IMSA, and also with state-of-the-art progressive alignment approaches, such as MSAprobs, Probalign, MAFFT, Procons, Clustal omega, T-Coffee, Kalign2, MUSCLE, FSA, Dialign, PRANK, and CLUSTALW. These alignment algorithms are tested on benchmark datasets BAliBASE 2.0 and BAliBASE 3.0. Experimental results show that MOMSA can obtain the significantly better alignments than VDGA, GAPAM on the most of test cases by statistical analyses, produce better alignments than IMSA in terms of TC scores, and also indicate that MOMSA is comparable with the leading progressive alignment approaches in terms of quality of alignments. PMID- 25700476 TI - Lumen Segmentation in Intravascular Optical Coherence Tomography Using Backscattering Tracked and Initialized Random Walks. AB - Intravascular imaging using ultrasound or optical coherence tomography (OCT) is predominantly used to adjunct clinical information in interventional cardiology. OCT provides high-resolution images for detailed investigation of atherosclerosis induced thickening of the lumen wall resulting in arterial blockage and triggering acute coronary events. However, the stochastic uncertainty of speckles limits effective visual investigation over large volume of pullback data, and clinicians are challenged by their inability to investigate subtle variations in the lumen topology associated with plaque vulnerability and onset of necrosis. This paper presents a lumen segmentation method using OCT imaging physics-based graph representation of signals and random walks image segmentation approaches. The edge weights in the graph are assigned incorporating OCT signal attenuation physics models. Optical backscattering maxima is tracked along each A-scan of OCT and is subsequently refined using global graylevel statistics and used for initializing seeds for the random walks image segmentation. Accuracy of lumen versus tunica segmentation has been measured on 15 in vitro and 6 in vivo pullbacks, each with 150-200 frames using 1) Cohen's kappa coefficient (0.9786 +/ 0.0061) measured with respect to cardiologist's annotation and 2) divergence of histogram of the segments computed with Kullback-Leibler (5.17 +/-2.39) and Bhattacharya measures (0.56 +/-0.28). High segmentation accuracy and consistency substantiates the characteristics of this method to reliably segment lumen across pullbacks in the presence of vulnerability cues and necrotic pool and has a deterministic finite time-complexity. This paper in general also illustrates the development of methods and framework for tissue classification and segmentation incorporating cues of tissue-energy interaction physics in imaging. PMID- 25700477 TI - We feel: mapping emotion on Twitter. AB - Research data on predisposition to mental health problems, and the fluctuations and regulation of emotions, thoughts, and behaviors are traditionally collected through surveys, which cannot provide a real-time insight into the emotional state of individuals or communities. Large datasets such as World Health Organization (WHO) statistics are collected less than once per year, whereas social network platforms, such as Twitter, offer the opportunity for real-time analysis of expressed mood. Such patterns are valuable to the mental health research community, to help understand the periods and locations of greatest demand and unmet need. We describe the "We Feel" system for analyzing global and regional variations in emotional expression, and report the results of validation against known patterns of variation in mood. 2.73 *10(9) emotional tweets were collected over a 12-week period, and automatically annotated for emotion, geographic location, and gender. Principal component analysis (PCA) of the data illustrated a dominant in-phase pattern across all emotions, modulated by antiphase patterns for "positive" and "negative" emotions. The first three principal components accounted for over 90% of the variation in the data. PCA was also used to remove the dominant diurnal and weekly variations allowing identification of significant events within the data, with z-scores showing expression of emotions over 80 standard deviations from the mean. We also correlate emotional expression with WHO data at a national level and although no correlations were observed for the burden of depression, the burden of anxiety and suicide rates appeared to correlate with expression of particular emotions. PMID- 25700478 TI - Online State-Based Structured SVM Combined With Incremental PCA for Robust Visual Tracking. AB - In this paper, we propose a robust state-based structured support vector machine (SVM) tracking algorithm combined with incremental principal component analysis (PCA). Different from the current structured SVM for tracking, our method directly learns and predicts the object's states and not the 2-D translation transformation during tracking. We define the object's virtual state to combine the state-based structured SVM and incremental PCA. The virtual state is considered as the most confident state of the object in every frame. The incremental PCA is used to update the virtual feature vector corresponding to the virtual state and the principal subspace of the object's feature vectors. In order to improve the accuracy of the prediction, all the feature vectors are projected onto the principal subspace in the learning and prediction process of the state-based structured SVM. Experimental results on several challenging video sequences validate the effectiveness and robustness of our approach. PMID- 25700479 TI - Consensus of Linear Multi-Agent Systems by Distributed Event-Triggered Strategy. AB - This paper studies the consensus problem of multi-agent systems with general linear dynamics. We propose a novel event-triggered control scheme with some desirable features, namely, distributed, asynchronous, and independent. It is shown that consensus of the controlled multi-agent system can be reached asymptotically. The feasibility of the event-triggered strategy is further verified by the exclusion of both singular triggering and Zeno behavior. Moreover, a self-triggered algorithm is developed, where the next triggering time instant for each agent is determined based on its local information at the previous triggering time instant. Continuous monitoring of measurement errors is thus avoided. The effectiveness of the proposed control schemes is demonstrated by two examples. PMID- 25700480 TI - Learning Spatio-Temporal Representations for Action Recognition: A Genetic Programming Approach. AB - Extracting discriminative and robust features from video sequences is the first and most critical step in human action recognition. In this paper, instead of using handcrafted features, we automatically learn spatio-temporal motion features for action recognition. This is achieved via an evolutionary method, i.e., genetic programming (GP), which evolves the motion feature descriptor on a population of primitive 3D operators (e.g., 3D-Gabor and wavelet). In this way, the scale and shift invariant features can be effectively extracted from both color and optical flow sequences. We intend to learn data adaptive descriptors for different datasets with multiple layers, which makes fully use of the knowledge to mimic the physical structure of the human visual cortex for action recognition and simultaneously reduce the GP searching space to effectively accelerate the convergence of optimal solutions. In our evolutionary architecture, the average cross-validation classification error, which is calculated by an support-vector-machine classifier on the training set, is adopted as the evaluation criterion for the GP fitness function. After the entire evolution procedure finishes, the best-so-far solution selected by GP is regarded as the (near-)optimal action descriptor obtained. The GP-evolving feature extraction method is evaluated on four popular action datasets, namely KTH, HMDB51, UCF YouTube, and Hollywood2. Experimental results show that our method significantly outperforms other types of features, either hand-designed or machine-learned. PMID- 25700481 TI - Integrating health belief model and technology acceptance model: an investigation of health-related internet use. AB - BACKGROUND: Today, people use the Internet to satisfy health-related information and communication needs. In Malaysia, Internet use for health management has become increasingly significant due to the increase in the incidence of chronic diseases, in particular among urban women and their desire to stay healthy. Past studies adopted the Technology Acceptance Model (TAM) and Health Belief Model (HBM) independently to explain Internet use for health-related purposes. Although both the TAM and HBM have their own merits, independently they lack the ability to explain the cognition and the related mechanism in which individuals use the Internet for health purposes. OBJECTIVE: This study aimed to examine the influence of perceived health risk and health consciousness on health-related Internet use based on the HBM. Drawing on the TAM, it also tested the mediating effects of perceived usefulness of the Internet for health information and attitude toward Internet use for health purposes for the relationship between health-related factors, namely perceived health risk and health consciousness on health-related Internet use. METHODS: Data obtained for the current study were collected using purposive sampling; the sample consisted of women in Malaysia who had Internet access. The partial least squares structural equation modeling method was used to test the research hypotheses developed. RESULTS: Perceived health risk (beta=.135, t1999=2.676) and health consciousness (beta=.447, t1999=9.168) had a positive influence on health-related Internet use. Moreover, perceived usefulness of the Internet and attitude toward Internet use for health related purposes partially mediated the influence of health consciousness on health-related Internet use (beta=.025, t1999=3.234), whereas the effect of perceived health risk on health-related Internet use was fully mediated by perceived usefulness of the Internet and attitude (beta=.029, t1999=3.609). These results suggest the central role of perceived usefulness of the Internet and attitude toward Internet use for health purposes for women who were health conscious and who perceived their health to be at risk. CONCLUSIONS: The integrated model proposed and tested in this study shows that the HBM, when combined with the TAM, is able to predict Internet use for health purposes. For women who subjectively evaluate their health as vulnerable to diseases and are concerned about their health, cognition beliefs in and positive affective feelings about the Internet come into play in determining the use of health related Internet use. Furthermore, this study shows that engaging in health related Internet use is a proactive behavior rather than a reactive behavior, suggesting that TAM dimensions have a significant mediating role in Internet health management. PMID- 25700482 TI - Medical wikis dedicated to clinical practice: a systematic review. AB - BACKGROUND: Wikis may give clinician communities the opportunity to build knowledge relevant to their practice. The only previous study reviewing a set of health-related wikis, without specification of purpose or audience, globally showed a poor reliability. OBJECTIVE: Our aim was to review medical wiki websites dedicated to clinical practices. METHODS: We used Google in ten languages, PubMed, Embase, Lilacs, and Web of Science to identify websites. The review included wiki sites, accessible and operating, having a topic relevant for clinical medicine, targeting physicians or medical students. Wikis were described according to their purposes, platform, management, information framework, contributions, content, and activity. Purposes were classified as "encyclopedic" or "non-encyclopedic". The information framework quality was assessed based on the Health On the Net (HONcode) principles for collaborative websites, with additional criteria related to users' transparency and editorial policy. From a sample of five articles per wikis, we assessed the readability using the Flesch test and compared articles according to the wikis' main purpose. Annual editorial activities were estimated using the Google engine. RESULTS: Among 25 wikis included, 11 aimed at building an encyclopedia, five a textbook, three lessons, two oncology protocols, one a single article, and three at reporting clinical cases. Sixteen wikis were specialized with specific themes or disciplines. Fifteen wikis were using MediaWiki software as-is, three were hosted by online wiki farms, and seven were purpose-built. Except for one MediaWiki-based site, only purpose-built platforms managed detailed user disclosures. The owners were ten organizations, six individuals, four private companies, two universities, two scientific societies, and one unknown. Among 21 open communities, 10 required users' credentials to give editing rights. The median information framework quality score was 6 out of 16 (range 0-15). Beyond this score, only one wiki had standardized peer-reviews. Physicians contributed to 22 wikis, medical learners to nine, and lay persons to four. Among 116 sampled articles, those from encyclopedic wikis had more videos, pictures, and external resources, whereas others had more posology details and better readability. The median creation year was 2007 (1997-2011), the median number of content pages was 620.5 (3-98,039), the median of revisions per article was 17.7 (3.6-180.5) and 0.015 of talk pages per article (0-0.42). Five wikis were particularly active, whereas six were declining. Two wikis have been discontinued after the completion of the study. CONCLUSIONS: The 25 medical wikis we studied present various limitations in their format, management, and collaborative features. Professional medical wikis may be improved by using clinical cases, developing more detailed transparency and editorial policies, and involving postgraduate and continuing medical education learners. PMID- 25700483 TI - Small glycosylated lignin oligomers are stored in Arabidopsis leaf vacuoles. AB - Lignin is an aromatic polymer derived from the combinatorial coupling of monolignol radicals in the cell wall. Recently, various glycosylated lignin oligomers have been revealed in Arabidopsis thaliana. Given that monolignol oxidation and monolignol radical coupling are known to occur in the apoplast, and glycosylation in the cytoplasm, it raises questions about the subcellular localization of glycosylated lignin oligomer biosynthesis and their storage. By metabolite profiling of Arabidopsis leaf vacuoles, we show that the leaf vacuole stores a large number of these small glycosylated lignin oligomers. Their structural variety and the incorporation of alternative monomers, as observed in Arabidopsis mutants with altered monolignol biosynthesis, indicate that they are all formed by combinatorial radical coupling. In contrast to the common believe that combinatorial coupling is restricted to the apoplast, we hypothesized that the aglycones of these compounds are made within the cell. To investigate this, leaf protoplast cultures were cofed with 13C6-labeled coniferyl alcohol and a 13C4-labeled dimer of coniferyl alcohol. Metabolite profiling of the cofed protoplasts provided strong support for the occurrence of intracellular monolignol coupling. We therefore propose a metabolic pathway involving intracellular combinatorial coupling of monolignol radicals, followed by oligomer glycosylation and vacuolar import, which shares characteristics with both lignin and lignan biosynthesis. PMID- 25700484 TI - A chaperone function of NO CATALASE ACTIVITY1 is required to maintain catalase activity and for multiple stress responses in Arabidopsis. AB - Catalases are key regulators of reactive oxygen species homeostasis in plant cells. However, the regulation of catalase activity is not well understood. In this study, we isolated an Arabidopsis thaliana mutant, no catalase activity1-3 (nca1-3) that is hypersensitive to many abiotic stress treatments. The mutated gene was identified by map-based cloning as NCA1, which encodes a protein containing an N-terminal RING-finger domain and a C-terminal tetratricopeptide repeat-like helical domain. NCA1 interacts with and increases catalase activity maximally in a 240-kD complex in planta. In vitro, NCA1 interacts with CATALASE2 (CAT2) in a 1:1 molar ratio, and the NCA1 C terminus is essential for this interaction. CAT2 activity increased 10-fold in the presence of NCA1, and zinc ion binding of the NCA1 N terminus is required for this increase. NCA1 has chaperone protein activity that may maintain the folding of catalase in a functional state. NCA1 is a cytosol-located protein. Expression of NCA1 in the mitochondrion of the nca1-3 mutant does not rescue the abiotic stress phenotypes of the mutant, while expression in the cytosol or peroxisome does. Our results suggest that NCA1 is essential for catalase activity. PMID- 25700490 TI - Nanostars amplify ability to image cancer. AB - A new nanoparticle design may make cancer detection possible without the use of molecular markers of tumor cells. The star-shaped probe detected five different cancers in mouse models, according to a new study. By using nanostars to boost surface-enhanced resonance Raman scattering signals, the technique highlighted tumor margins, microscopic metastases, and even precancerous cells with high precision. PMID- 25700491 TI - Why science? Why AAAS? PMID- 25700493 TI - Water security. Drought triggers alarms in Brazil's biggest metropolis. PMID- 25700494 TI - Planetary science. Dawn probe to look for a habitable ocean on Ceres. PMID- 25700495 TI - Ancient DNA. Indo-European languages tied to herders. PMID- 25700496 TI - Biomedical research. NIH plots million-person megastudy. PMID- 25700497 TI - Arctic impact. PMID- 25700498 TI - The Siberian snow connection. PMID- 25700499 TI - Ecology. Mothers shape ecological communities. PMID- 25700500 TI - Biomolecules. The dark side of sunlight and melanoma. PMID- 25700501 TI - Neuroscience. Can oxytocin treat autism? PMID- 25700502 TI - Cell biology. Pancreas micromanages autophagy. PMID- 25700503 TI - Optics. Structured photons take it slow. PMID- 25700504 TI - Chemistry. Climbing Jacob's ladder. PMID- 25700505 TI - Geophysics. Coping with earthquakes induced by fluid injection. PMID- 25700506 TI - Editorial retraction. PMID- 25700507 TI - PETA fuels animal lab improvements. PMID- 25700508 TI - PETA undermines science and scientists. PMID- 25700509 TI - Enforcement key to China's environment. PMID- 25700510 TI - Anthropology. Comment on "Late Pleistocene human skeleton and mtDNA link Paleoamericans and modern Native Americans". AB - Chatters et al. (Reports, 16 May 2014, p. 750) reported the retrieval of DNA sequences from a 12,000- to 13,000-year-old human tooth discovered in an underwater cave in Mexico's Yucatan peninsula. They propose that this ancient human individual's mitochondrial DNA (mtDNA) belongs to haplogroup D1. However, our analysis of postmortem damage patterns finds no evidence for an ancient origin of these sequences. PMID- 25700511 TI - Anthropology. Response to Comment on "Late Pleistocene human skeleton and mtDNA link Paleoamericans and modern Native Americans". AB - Prufer and Meyer raise concerns over the mitochondrial DNA (mtDNA) results we reported for the Hoyo Negro individual, citing failure of a portion of these data to conform to their expectations of ancient DNA (aDNA). Because damage patterns in aDNA vary, outright rejection of our findings on this basis is unwarranted, especially in light of our other observations. PMID- 25700512 TI - Photochemistry. Chemiexcitation of melanin derivatives induces DNA photoproducts long after UV exposure. AB - Mutations in sunlight-induced melanoma arise from cyclobutane pyrimidine dimers (CPDs), DNA photoproducts that are typically created picoseconds after an ultraviolet (UV) photon is absorbed at thymine or cytosine. We found that in melanocytes, CPDs are generated for >3 hours after exposure to UVA, a major component of the radiation in sunlight and in tanning beds. These "dark CPDs" constitute the majority of CPDs and include the cytosine-containing CPDs that initiate UV-signature C->T mutations. Dark CPDs arise when UV-induced reactive oxygen and nitrogen species combine to excite an electron in fragments of the pigment melanin. This creates a quantum triplet state that has the energy of a UV photon but induces CPDs by energy transfer to DNA in a radiation-independent manner. Melanin may thus be carcinogenic as well as protective against cancer. These findings also validate the long-standing suggestion that chemically generated excited electronic states are relevant to mammalian biology. PMID- 25700513 TI - Structural biology. Structural basis for Notch1 engagement of Delta-like 4. AB - Notch receptors guide mammalian cell fate decisions by engaging the proteins Jagged and Delta-like (DLL). The 2.3 angstrom resolution crystal structure of the interacting regions of the Notch1-DLL4 complex reveals a two-site, antiparallel binding orientation assisted by Notch1 O-linked glycosylation. Notch1 epidermal growth factor-like repeats 11 and 12 interact with the DLL4 Delta/Serrate/Lag-2 (DSL) domain and module at the N-terminus of Notch ligands (MNNL) domains, respectively. Threonine and serine residues on Notch1 are functionalized with O fucose and O-glucose, which act as surrogate amino acids by making specific, and essential, contacts to residues on DLL4. The elucidation of a direct chemical role for O-glycans in Notch1 ligand engagement demonstrates how, by relying on posttranslational modifications of their ligand binding sites, Notch proteins have linked their functional capacity to developmentally regulated biosynthetic pathways. PMID- 25700514 TI - Quantum engineering. Confining the state of light to a quantum manifold by engineered two-photon loss. AB - Physical systems usually exhibit quantum behavior, such as superpositions and entanglement, only when they are sufficiently decoupled from a lossy environment. Paradoxically, a specially engineered interaction with the environment can become a resource for the generation and protection of quantum states. This notion can be generalized to the confinement of a system into a manifold of quantum states, consisting of all coherent superpositions of multiple stable steady states. We have confined the state of a superconducting resonator to the quantum manifold spanned by two coherent states of opposite phases and have observed a Schrodinger cat state spontaneously squeeze out of vacuum before decaying into a classical mixture. This experiment points toward robustly encoding quantum information in multidimensional steady-state manifolds. PMID- 25700515 TI - Galaxy evolution. Black hole feedback in the luminous quasar PDS 456. AB - The evolution of galaxies is connected to the growth of supermassive black holes in their centers. During the quasar phase, a huge luminosity is released as matter falls onto the black hole, and radiation-driven winds can transfer most of this energy back to the host galaxy. Over five different epochs, we detected the signatures of a nearly spherical stream of highly ionized gas in the broadband x ray spectra of the luminous quasar PDS 456. This persistent wind is expelled at relativistic speeds from the inner accretion disk, and its wide aperture suggests an effective coupling with the ambient gas. The outflow's kinetic power larger than 10(46) ergs per second is enough to provide the feedback required by models of black hole and host galaxy coevolution. PMID- 25700516 TI - Transition states. Trapping a transition state in a computationally designed protein bottle. AB - The fleeting lifetimes of the transition states (TSs) of chemical reactions make determination of their three-dimensional structures by diffraction methods a challenge. Here, we used packing interactions within the core of a protein to stabilize the planar TS conformation for rotation around the central carbon carbon bond of biphenyl so that it could be directly observed by x-ray crystallography. The computational protein design software Rosetta was used to design a pocket within threonyl-transfer RNA synthetase from the thermophile Pyrococcus abyssi that forms complementary van der Waals interactions with a planar biphenyl. This latter moiety was introduced biosynthetically as the side chain of the noncanonical amino acid p-biphenylalanine. Through iterative rounds of computational design and structural analysis, we identified a protein in which the side chain of p-biphenylalanine is trapped in the energetically disfavored, coplanar conformation of the TS of the bond rotation reaction. PMID- 25700517 TI - Animal evolution. Cope's rule in the evolution of marine animals. AB - Cope's rule proposes that animal lineages evolve toward larger body size over time. To test this hypothesis across all marine animals, we compiled a data set of body sizes for 17,208 genera of marine animals spanning the past 542 million years. Mean biovolume across genera has increased by a factor of 150 since the Cambrian, whereas minimum biovolume has decreased by less than a factor of 10, and maximum biovolume has increased by more than a factor of 100,000. Neutral drift from a small initial value cannot explain this pattern. Instead, most of the size increase reflects differential diversification across classes, indicating that the pattern does not reflect a simple scaling-up of widespread and persistent selection for larger size within populations. PMID- 25700518 TI - Spatial navigation. Disruption of the head direction cell network impairs the parahippocampal grid cell signal. AB - Navigation depends on multiple neural systems that encode the moment-to-moment changes in an animal's direction and location in space. These include head direction (HD) cells representing the orientation of the head and grid cells that fire at multiple locations, forming a repeating hexagonal grid pattern. Computational models hypothesize that generation of the grid cell signal relies upon HD information that ascends to the hippocampal network via the anterior thalamic nuclei (ATN). We inactivated or lesioned the ATN and subsequently recorded single units in the entorhinal cortex and parasubiculum. ATN manipulation significantly disrupted grid and HD cell characteristics while sparing theta rhythmicity in these regions. These results indicate that the HD signal via the ATN is necessary for the generation and function of grid cell activity. PMID- 25700519 TI - Evolutionary ecology. Cycles of species replacement emerge from locally induced maternal effects on offspring behavior in a passerine bird. AB - An important question in ecology is how mechanistic processes occurring among individuals drive large-scale patterns of community formation and change. Here we show that in two species of bluebirds, cycles of replacement of one by the other emerge as an indirect consequence of maternal influence on offspring behavior in response to local resource availability. Sampling across broad temporal and spatial scales, we found that western bluebirds, the more competitive species, bias the birth order of offspring by sex in a way that influences offspring aggression and dispersal, setting the stage for rapid increases in population density that ultimately result in the replacement of their sister species. Our results provide insight into how predictable community dynamics can occur despite the contingency of local behavioral interactions. PMID- 25700520 TI - Insulin granules. Insulin secretory granules control autophagy in pancreatic beta cells. AB - Pancreatic beta cells lower insulin release in response to nutrient depletion. The question of whether starved beta cells induce macroautophagy, a predominant mechanism maintaining energy homeostasis, remains poorly explored. We found that, in contrast to many mammalian cells, macroautophagy in pancreatic beta cells was suppressed upon starvation. Instead, starved beta cells induced lysosomal degradation of nascent secretory insulin granules, which was controlled by protein kinase D (PKD), a key player in secretory granule biogenesis. Starvation induced nascent granule degradation triggered lysosomal recruitment and activation of mechanistic target of rapamycin that suppressed macroautophagy. Switching from macroautophagy to insulin granule degradation was important to keep insulin secretion low upon fasting. Thus, beta cells use a PKD-dependent mechanism to adapt to nutrient availability and couple autophagy flux to secretory function. PMID- 25700521 TI - Kinase dynamics. Using ancient protein kinases to unravel a modern cancer drug's mechanism. AB - Macromolecular function is rooted in energy landscapes, where sequence determines not a single structure but an ensemble of conformations. Hence, evolution modifies a protein's function by altering its energy landscape. Here, we recreate the evolutionary pathway between two modern human oncogenes, Src and Abl, by reconstructing their common ancestors. Our evolutionary reconstruction combined with x-ray structures of the common ancestor and pre-steady-state kinetics reveals a detailed atomistic mechanism for selectivity of the successful cancer drug Gleevec. Gleevec affinity is gained during the evolutionary trajectory toward Abl and lost toward Src, primarily by shifting an induced-fit equilibrium that is also disrupted in the clinical T315I resistance mutation. This work reveals the mechanism of Gleevec specificity while offering insights into how energy landscapes evolve. PMID- 25700522 TI - A career's twisting road. PMID- 25700523 TI - Disease networks. Uncovering disease-disease relationships through the incomplete interactome. AB - According to the disease module hypothesis, the cellular components associated with a disease segregate in the same neighborhood of the human interactome, the map of biologically relevant molecular interactions. Yet, given the incompleteness of the interactome and the limited knowledge of disease-associated genes, it is not obvious if the available data have sufficient coverage to map out modules associated with each disease. Here we derive mathematical conditions for the identifiability of disease modules and show that the network-based location of each disease module determines its pathobiological relationship to other diseases. For example, diseases with overlapping network modules show significant coexpression patterns, symptom similarity, and comorbidity, whereas diseases residing in separated network neighborhoods are phenotypically distinct. These tools represent an interactome-based platform to predict molecular commonalities between phenotypically related diseases, even if they do not share primary disease genes. PMID- 25700524 TI - Nanomaterials. Programmable materials and the nature of the DNA bond. AB - For over half a century, the biological roles of nucleic acids as catalytic enzymes, intracellular regulatory molecules, and the carriers of genetic information have been studied extensively. More recently, the sequence-specific binding properties of DNA have been exploited to direct the assembly of materials at the nanoscale. Integral to any methodology focused on assembling matter from smaller pieces is the idea that final structures have well-defined spacings, orientations, and stereo-relationships. This requirement can be met by using DNA based constructs that present oriented nanoscale bonding elements from rigid core units. Here, we draw analogy between such building blocks and the familiar chemical concepts of "bonds" and "valency" and review two distinct but related strategies that have used this design principle in constructing new configurations of matter. PMID- 25700525 TI - Photo quiz: confusing bacteremia in a Crohn's disease patient. Weissella confusa. PMID- 25700526 TI - Chronic obstructive pulmonary disease lung microbiota diversity may be mediated by age or inhaled corticosteroid use. PMID- 25700527 TI - Reply to "chronic obstructive pulmonary disease lung microbiota diversity may be mediated by age or inhaled corticosteroid use". PMID- 25700530 TI - Incarceration and perinatal smoking: a missed public health opportunity. AB - BACKGROUND: Incarceration is simultaneously a public health opportunity and a public health concern. We examined the association between maternal/partner incarceration in the year prior to birth and perinatal smoking. METHODS: We pooled 2006-2010 data from the Centers for Disease Control and Prevention's Pregnancy Risk Assessment and Monitoring System. Controlling for age, race/ethnicity, education, marital status and other stressors, we assessed prevalence and heaviness of perinatal smoking. FINDINGS: Women who reported incarceration of themselves or their partners in the year prior to delivery were more likely to smoke during the last trimester of pregnancy (adjusted OR (AOR) 1.51 (95% CI 1.36 to 1.67)), and they were more likely to smoke more than 10 cigarettes a day compared to smokers who did not report incarceration (AOR 1.35 (95% CI 1.10 to 1.65)). Patterns were similar for the 3 months prior to pregnancy and postbirth smoking. CONCLUSIONS: Incarceration of a parent in the 12 months before birth is associated with increased risk of fetal and newborn exposure to smoking. The criminal justice system can be utilised by public health practitioners to target perinatal smoking reduction interventions. PMID- 25700531 TI - Excessive crying at 3 months of age and behavioural problems at 4 years age: a prospective cohort study. AB - BACKGROUND: Excessive crying in early infancy has been associated with behavioural problems among preschool children from high income countries but studies in low income and middle income countries are scarce. METHODS: The 2004 Pelotas Birth Cohort is a population-based study planned to enrol all live births occurring in Pelotas that year and comprises 4231 children who so far have been followed up at 3, 12, 24, 48 and 72 months of age. Several familial, maternal and child characteristics were gathered in every follow-up. At the 3-month follow-up, infants whose mothers perceived them as crying more than others of the same age were classified as 'crying babies'. Child behavioural problems were assessed through the Child Behavior Checklist (CBCL) applied to the mother at the 48-month follow-up. Crude and adjusted ORs with 95% CIs were calculated by logistic regression. RESULTS: Prevalence of excessive crying at 3 months was 11.9% (10.9% to 13.0%). Among children with excessive crying at 3 months the proportion in the clinical range for CBCL total, internalising and externalising problems at 4 years of age was 31.2%, 12.9% and 37.5%, respectively, against 20.6%, 6.8% and 29.6%, respectively, among non-crying babies. After controlling for confounders crying babies presented increased risk of being in clinical range of CBCL total (OR=1.34; 1.03 to 1.74), internalising (OR=1.55; 1.09 to 2.21) and externalising problems (OR=1.29; 1.01 to 1.64) than infants without excessive crying. CONCLUSIONS: Excessive crying in early infancy may represent one important risk factor for developing behavioural problems in later phases of early childhood. PMID- 25700532 TI - Breastfeeding duration and non-verbal IQ in children. AB - BACKGROUND: Breastfeeding has been related to better cognitive development in children. However, due to methodological challenges, such as confounding, recall bias or insufficient power, the mechanism and nature of the relation remains subject to debate. METHODS: We included 3761 participants of a population-based cohort study from fetal life onwards and examined the association of breastfeeding duration with non-verbal intelligence in children of age 6 years. Maternal and paternal lifestyle, sociodemographic factors, child factors and maternal IQ were tested for their confounding effects on the association. RESULTS: We observed an initial association between breastfeeding duration and child IQ conferring an advantage of 0.32 (0.20 to 0.44) points for each additional month of breastfeeding. This association strongly attenuated to 0.09 ( 0.03 to 0.21) points after adjustment for child factors, sociodemographic factors, parental lifestyle factors and maternal IQ. Similarly, the associations with breastfeeding duration as a categorical variable largely disappeared after confounding factors were added to the models. CONCLUSIONS: The association between breastfeeding and child IQ can be largely explained by sociodemographic factors, parental lifestyle and maternal IQ. Our results cannot confirm beneficial effects of breastfeeding on child intelligence. PMID- 25700533 TI - Male involvement and maternal health outcomes: systematic review and meta analysis. AB - BACKGROUND: The developing world accounts for 99% of global maternal deaths. Men in developing countries are the chief decision-makers, determining women's access to maternal health services and influencing their health outcomes. At present, it is unclear whether involving men in maternal health can improve maternal outcomes. This systematic review and meta-analysis aimed to investigate the impact of male involvement on maternal health outcomes of women in developing countries. METHODS: Four electronic databases and grey literature sources were searched (up to May 2013), together with reference lists of included studies. Two reviewers independently screened and assessed the quality of studies based on prespecified criteria. Measures of effects were pooled and random effect meta analysis was conducted, where possible. RESULTS: Fourteen studies met the inclusion criteria. Male involvement was significantly associated with reduced odds of postpartum depression (OR=0.36, 95% CI 0.19 to 0.68 for male involvement during pregnancy; OR=0.34, 95% CI 0.19 to 0.62 for male involvement post partum), and also with improved utilisation of maternal health services (skilled birth attendance and postnatal care). Male involvement during pregnancy and at post partum appeared to have greater benefits than male involvement during delivery. CONCLUSIONS: Male involvement is associated with improved maternal health outcomes in developing countries. Contrary to reports from developed countries, there was little evidence of positive impacts of husbands' presence in delivery rooms. However, more rigorous studies are needed to improve this area's evidence base. PMID- 25700534 TI - Relative deprivation in income and mortality by leading causes among older Japanese men and women: AGES cohort study. AB - BACKGROUND: Relative deprivation of income is hypothesised to generate frustration and stress through upward social comparison with one's peers. If psychosocial stress is the mechanism, relative deprivation should be more strongly associated with specific health outcomes, such as cardiovascular disease (compared with other health outcomes, eg, non-tobacco-related cancer). METHODS: We evaluated the association between relative income deprivation and mortality by leading causes, using a cohort of 21 031 community-dwelling adults aged 65 years or older. A baseline mail-in survey was conducted in 2003. Information on cause specific mortality was obtained from death certificates. Our relative deprivation measure was the Yitzhaki Index, derived from the aggregate income shortfall for each person, relative to individuals with higher incomes in that person's reference group. Reference groups were defined according to gender, age group and same municipality of residence. RESULTS: We identified 1682 deaths during the 4.5 years of follow-up. A Cox regression demonstrated that, after controlling for demographic, health and socioeconomic factors including income, the HR for death from cardiovascular diseases per SD increase in relative deprivation was 1.50 (95% CI 1.09 to 2.08) in men, whereas HRs for mortality by cancer and other diseases were close to the null value. Additional adjustment for depressive symptoms and health behaviours (eg, smoking and preventive care utilisation) attenuated the excess risks for mortality from cardiovascular disease by 9%. Relative deprivation was not associated with mortality for women. CONCLUSIONS: The results partially support our hypothesised mechanism: relative deprivation increases health risks via psychosocial stress among men. PMID- 25700535 TI - Elevated inflammatory biomarkers during unemployment: modification by age and country in the UK. AB - BACKGROUND: There is raised risk of mortality following unemployment, and reviews have consistently found worse psychological health among the unemployed. Inflammation is increasingly implicated as a mediating factor relating stress to physical disease and is strongly linked to depression. Inflammation may, therefore, be implicated in processes associated with excess mortality and morbidity during unemployment. This study examined associations of unemployment with inflammatory markers among working-age men and women from England and Scotland. METHODS: Cross-sectional analyses using data from the Health Survey for England and the Scottish Health Survey collected between 1998 and 2010. Systemic inflammation was indexed by serum concentrations of C reactive protein (CRP) and fibrinogen, and compared between participants currently employed/self-employed, currently unemployed and other groups. RESULTS: CRP, fibrinogen and odds of CRP >3 mg/L were all significantly raised for the unemployed, as compared to the employed participants (eg, OR for CRP >3 mg/L=1.43, CI 1.15 to 1.78 N=23 025), following adjustment for age, gender, occupational social class, housing tenure, smoking, alcohol consumption, body mass index, long-term illness and depressive/anxiety symptoms. Strengths of associations varied considerably by both age and country/region, with effects mainly driven by participants aged >=48 and participants from Scotland, which had comparatively high unemployment during this time. CONCLUSIONS: Current unemployment is associated with elevated inflammatory markers using data from two large-scale, nationally representative UK studies. Effect modification by age suggests inflammation may be particularly involved in processes leading to ill-health among the older unemployed. Country/regional effects may suggest the relationship of unemployment with inflammation is strongly influenced by contextual factors, and/or reflect life course accumulation processes. PMID- 25700536 TI - Correlation of chemical compositions of cassava varieties to their resistance to Prostephanus truncatus Horn (Coleoptera: Bostrichidae). AB - The preference of cassava as a major host by Prostephanus truncatus Horn is a major constraint to ample production of cassava, Manihot esculenta Crantz and storage. This study analyzed the nutritional and secondary metabolite compositions in 15 cassava varieties, evaluated levels of damage and reproduction by P. truncatus, and assessed their resistance to attack. One hundred grams of dried cassava chips in 250-ml Kilner jars were infested with 10 adult larger grain borerof 0-10 days old and held for 3 months. The nutritional and secondary metabolites compositions of the dry cassava chips were determined using the method of Association of Analytical Chemists . Chip perforation rates in the cassava varieties ranged from 17.7 to 71.6%. The weight of cassava powder varied by about threefold. The final number of larger grain borer in the cassava varieties varied by about sixfold with 63 in 01/0040 and 379 in 01/1368. Hydrocyanic acid content content varied by over 10-fold and correlated negatively with number of larger grain borer. Flavonoid content varied by ~10%. Tannins and saponin content of the cassava negatively correlated with number of adult P. truncatus. The cassava varieties 95/0166, 92/0326, 01/0040, 05/0024, and 34 91934 had selection index <0.8 and were classified as resistant to larger grain borer damage, while others with selection index >0.8 were classified as susceptible. The resistance to high damage in the resistant varieties was conferred by secondary metabolites such as tannins, saponins, alkaloids, and hydrocyanic acid content. The genetic variation in cassava varieties could be explored to breed resistant cassava varieties for use in larger grain borer-endemic areas. PMID- 25700537 TI - Ecotoxicological study of insecticide effects on arthropods in common bean. AB - Arthropods are an important group of macroorganisms that work to maintain ecosystem health. Despite the agricultural benefits of chemical control against arthropod pests, insecticides can cause environmental damage. We examined the effects of one and two applications of the insecticides chlorfenapyr (0.18 liters a.i. ha-1) and methamidophos (0.45 liters a.i. ha-1), both independently and in combination, on arthropods in plots of common bean. The experiment was repeated for two growing seasons. Principal response curve, richness estimator, and Shannon-Wiener diversity index analyses were performed. The insecticides generally affected the frequency, richness, diversity, and relative abundance of the arthropods. In addition, the arthropods did not experience recovery after the insecticide applications. The results suggest that the insecticide impacts were sufficiently drastic to eliminate many taxa from the studied common bean plots. PMID- 25700538 TI - Parasitism, emergence, and development of Spalangia endius (Hymenoptera: Pteromalidae) in pupae of different ages of Bactrocera cucurbitae (Diptera: Tephritidae). AB - The wasp Spalangia endius Walker (Hymenoptera: Pteromalidae) is a major parasitoid of the pupae of fruit flies, which are a common agricultural pest. An understanding of this intricate host-parasitoid interaction could provide basic information necessary for the sustainable integrated biological control of fruit flies. In this study, we investigated the effect of S. endius on different-aged pupae of the melon fly Bactrocera cucurbitae Coquillett by using choice and nonchoice tests under laboratory conditions. We showed that S. endius females oviposited, and their progeny successfully developed, in different-aged pupae of B. cucurbitae regardless of the method of exposure. There was an oviposition preference for 3-5-d-old pupa. The highest mean percentage parasitism occurred on 4- and 5-d-old hosts, followed by 2- and 3-d-old hosts. The average development time for both males and females was significantly longer in 6-7-d-old hosts than in the younger host stages. Adult females that developed from younger host pupae (2-5-d old) were significantly heavier than those from older host pupae (6-7-d old), and they also lived longer. The sex ratio (proportion of females) of the parasite progeny decreased with an increase in host age. Host mortality also decreased gradually as the pupal age increased. The differences in development time, body weight, and longevity between females and males were significant. These results suggest that S. endius is a good candidate for the biological control of B. cucurbitae. PMID- 25700539 TI - Trends in the Timing and Clinical Context of Maintenance Dialysis Initiation. AB - Whether secular trends in eGFR at dialysis initiation reflect changes in clinical presentation over time is unknown. We reviewed the medical records of a random sample of patients who initiated maintenance dialysis in the Department of Veterans Affairs (VA) in fiscal years 2000-2009 (n=1691) to characterize trends in clinical presentation in relation to eGFR at initiation. Between fiscal years 2000-2004 and 2005-2009, mean eGFR at initiation increased from 9.8+/-5.8 to 11.0+/-5.5 ml/min per 1.73 m(2) (P<0.001), the percentage of patients with an eGFR of 10-15 ml/min per 1.73 m(2) increased from 23.4% to 29.9% (P=0.002), and the percentage of patients with an eGFR>15 ml/min per 1.73 m(2) increased from 12.1% to 16.3% (P=0.01). The proportion of patients who were acutely ill at the time of initiation and the proportion of patients for whom the decision to initiate dialysis was based only on level of kidney function did not change over time. Frequencies of documented clinical signs and/or symptoms were similar during both time periods. The adjusted odds of initiating dialysis at an eGFR of 10-15 or >15 ml/min per 1.73 m(2) (versus <10 ml/min per 1.73 m(2)) during the later versus earlier time period were 1.43 (95% confidence interval [95% CI], 1.13 to 1.81) and 1.46 (95% CI, 1.09 to 1.97), respectively. In conclusion, trends in eGFR at dialysis initiation at VA medical centers do not seem to reflect changes in the clinical context in which dialysis is initiated. PMID- 25700540 TI - Prevalence and management of gastrointestinal manifestations in Silver-Russell syndrome. AB - OBJECTIVES: Silver-Russell syndrome (SRS) is an imprinted disorder characterised by intrauterine growth retardation, relative macrocephaly, failure to thrive, typical facial phenotype and frequent body asymmetry. Feeding difficulties are frequently noted, but no study described evolution of gastrointestinal signs during infancy and their management in SRS. The aim of this study was to describe these abnormalities in a large cohort of children with SRS. DESIGN: We included 75 patients (median age 24.3 months (5.1-135.2)) in the study. We retrospectively analysed nutritional status before growth hormone therapy, the frequency of gastrointestinal signs, such as gastroesophageal reflux (GER), vomiting, constipation and feeding difficulties, and nutritional management. RESULTS: Maternal uniparental disomy for chromosome 7 was found in 10 patients and 11p15 hypomethylation in 65 patients. Malnutrition (defined as a weight/expected weight for height ratio <80%) was detected in 70% of the children. Gastrointestinal signs were found in 77%, including severe vomiting before the age of 1 year in 50% of cases, persistent vomiting from the age of 1 year in 29% of cases and constipation in 20% of cases. Severe GER was diagnosed in 55% of children by 24 h oesophageal pH-metry. Feeding difficulties were described in 65% of cases, with indications for dietary enrichment in 49%. Enteral nutrition by gastrostomy was indicated in 22% of cases. CONCLUSIONS: Digestive signs (GER, constipation) and malnutrition are frequent in children with SRS. The systematic exploration and management of these signs are crucial to improve the nutritional status of these children before initiating growth hormone therapy. PMID- 25700541 TI - Eczema coxsackium. PMID- 25700542 TI - The differential diagnosis of spastic diplegia. AB - Spastic diplegia is the most common form of cerebral palsy worldwide. Many disorders mimic spastic diplegia, which can result in misdiagnosis for the child with resultant negative treatment and family counselling implications. In this paper, the authors provide a brief review of spastic diplegia and the various disorders in the differential diagnosis. We also provide a diagnostic algorithm to assist physicians in making the correct diagnosis. PMID- 25700543 TI - The potential use of lapatinib-loaded human serum albumin nanoparticles in the treatment of triple-negative breast cancer. AB - Triple-negative breast cancer (TNBC) is an aggressive cancer with limited treatment options. However, the shared feature of epidermal growth factor receptor (EGFR) expression in TNBC offers the opportunity for targeted molecular therapy for this breast cancer subtype. Previous studies have indicated that lapatinib, a selective small-molecular dual-tyrosine kinase inhibitor of HER2 and EGFR, is effective in reducing cancer progression and metastasis, indicating that it might be a candidate for TNBC treatment. However, its poor water solubility, low and variable oral absorption, and large daily dose all limit the clinical use of lapatinib. In this study, we developed human serum albumin (HSA) nanoparticles loaded with lapatinib for intravenous administration to overcome these disadvantages and enhance its efficacy against TNBC. 4T1 cells (a murine TNBC cells) were selected as the cell model because their growth and metastatic spread are very close to those of human breast cancer cells. Lapatinib-loaded HSA nanoparticles (LHNPs) were prepared by Nab technology. LHNPs displayed cytotoxicity similar to the free drug but exhibited superior capacity to induce early apoptosis in 4T1 monolayer cells. Importantly, LHNPs showed improved penetration and inhibition effects in tumor spheroids compared to lapatinib solution (LS). Pharmacokinetic investigations revealed that HSA nanoparticles (i.v.) effectively increased the accumulation of lapatinib in tumor tissue at 2.38 and 16.6 times the level of LS (i.v.) and Tykerb (p.o.), respectively. Consequently, it had markedly better suppression effects both on primary breast cancer and lung metastasis in tumor-bearing mice compared to the commercial drug Tykerb. The improved anti-tumor efficacy of LHNPs may be partly attributed to its close binding to SPARC, which is widely present in the extracellular matrix of tumor tissue. These results demonstrated that LHNPs might be a promising anti tumor agent for TNBC. PMID- 25700545 TI - Solubility product challenge. PMID- 25700544 TI - Suppression of autophagy in osteocytes does not modify the adverse effects of glucocorticoids on cortical bone. AB - Glucocorticoid excess decreases bone mass and strength in part by acting directly on osteoblasts and osteocytes, but the mechanisms remain unclear. Macroautophagy (herein referred to as autophagy) is a lysosome-based recycling pathway that promotes the turnover of intracellular components and can promote cell function and survival under stressful conditions. Recent studies have shown that glucocorticoids stimulate autophagy in osteocytes, suggesting that autophagy may oppose the negative actions of glucocorticoids on this cell type. To address this possibility, we compared the impact of prednisolone administration on the skeletons of adult mice in which autophagy was suppressed in osteocytes, via deletion of Atg7 with a Dmp1-Cre transgene, to their control littermates. In control mice, prednisolone increased autophagic flux in osteocyte-enriched bone as measured by LC3 conversion, but this change did not occur in the mice lacking Atg7 in osteocytes. Nonetheless, prednisolone reduced femoral cortical thickness, increased cortical porosity, and reduced bone strength to similar extents in mice with and without autophagy in osteocytes. Prednisolone also suppressed osteoblast number and bone formation in the cancellous bone of control mice. As shown previously, Atg7 deletion in osteocytes reduced osteoblast number and bone formation in cancellous bone, but these parameters were not further reduced by prednisolone administration. In cortical bone, prednisolone elevated osteoclast number to a similar extent in both genotypes. Taken together, these results demonstrate that although glucocorticoids stimulate autophagy in osteocytes, suppression of autophagy in this cell type does not worsen the negative impact of glucocorticoids on the skeleton. PMID- 25700546 TI - Solution to the Ariadne's thread NMR challenge. PMID- 25700547 TI - A new modeling strategy for third-order fast high-performance liquid chromatographic data with fluorescence detection. Quantitation of fluoroquinolones in water samples. AB - Matrix augmentation is regularly employed in extended multivariate curve resolution-alternating least-squares (MCR-ALS), as applied to analytical calibration based on second- and third-order data. However, this highly useful concept has almost no correspondence in parallel factor analysis (PARAFAC) of third-order data. In the present work, we propose a strategy to process third order chromatographic data with matrix fluorescence detection, based on an Augmented PARAFAC model. The latter involves decomposition of a three-way data array augmented along the elution time mode with data for the calibration samples and for each of the test samples. A set of excitation-emission fluorescence matrices, measured at different chromatographic elution times for drinking water samples, containing three fluoroquinolones and uncalibrated interferences, were evaluated using this approach. Augmented PARAFAC exploits the second-order advantage, even in the presence of significant changes in chromatographic profiles from run to run. The obtained relative errors of prediction were ca. 10 % for ofloxacin, ciprofloxacin, and danofloxacin, with a significant enhancement in analytical figures of merit in comparison with previous reports. The results are compared with those furnished by MCR-ALS. PMID- 25700548 TI - Ingredients for successful online dating are outlined in evidence based study. PMID- 25700549 TI - Procedural sedation and analgesia for adults in the emergency department. PMID- 25700550 TI - Determination of Carvedilol Enantiomers in Pharmaceutical Dosages by SBSE-HPLC Based on Diastereomer Formation. AB - A sensitive, selective and simple method for the simultaneous determination of carvedilol enantiomers in aqueous solution has been developed using stir bar sorptive extraction (SBSE) followed by high-performance liquid chromatography (HPLC) with ultraviolet (UV) detection. This method is based on the reaction of carvedilol enantiomers with (-)-menthyl chloroformate (MCF) after extraction by the SBSE method to produce diastereomeric derivatives. The separation was achieved by use of a C18 analytical column and the influence of mobile phase composition on the enantioseparation of carvedilol was studied. The applicability of two sorptive phases, poly(methyl methacrylate/ethyleneglycol dimethacrylate) (PA-EG) and polydimethylsiloxane, were tested for extraction of carvedilol enantiomers from aqueous samples. The obtained results showed excellent linear dynamic ranges and precisions for each of them. The least limit of detection for (S)- and (R)-carvedilol obtained 8 and 11 ug L(-1), respectively, using the PA-EG sorptive phase. Inter- and intra-mean recoveries were also satisfactory, ranging from 98 to 103%, with coefficient of variation in the range of 1-5% at three fortified levels using a PA-EG coated stir bar. The proposed SBSE (PA-EG)-MCF derivatization-HPLC-UV method was successfully applied to enantioselective analysis of carvedilol in water and pharmaceutical dosages, confirming the application of this method. PMID- 25700551 TI - Length of hospital stay after hip fracture and short term risk of death after discharge: a total cohort study in Sweden. AB - OBJECTIVE: To investigate relation between inpatient length of stay after hip fracture and risk of death after hospital discharge. SETTING: Population >=50 years old living in Sweden as of 31 December 2005 with a first hip fracture the years 2006-12. PARTICIPANTS: 116,111 patients with an incident hip fracture from a closed nationwide cohort. MAIN OUTCOME MEASURE: Death within 30 days of hospital discharge in relation to hospital length of stay after adjustment for multiple covariates. RESULTS: Mean inpatient length of stay after a hip fracture decreased from 14.2 days in 2006 to 11.6 days in 2012 (P<0.001). The association between length of stay and risk of death after discharge was non-linear (P<0.001), with a threshold for this non-linear effect of about 10 days. Thus, for patients with length of stay of <=10 days (n=59,154), each 1-day reduction in length of stay increased the odds of death within 30 days of discharge by 8% in 2006 (odds ratio 1.08 (95% confidence interval 1.04 to 1.12)), which increased to16% in 2012 (odds ratio 1.16 (1.12 to 1.20)). In contrast, for patients with a length of stay of >=11 days (n=56,957), a 1-day reduction in length of stay was not associated with an increased risk of death after discharge during any of the years of follow up. LIMITATIONS: No accurate evaluation of the underlying cause of death could be performed. CONCLUSION: Shorter length of stay in hospital after hip fracture is associated with increased risk of death after hospital discharge, but only among patients with length of stay of 10 days or less. This association remained robust over consecutive years. PMID- 25700552 TI - Complexity of venous symptoms. PMID- 25700553 TI - The lncRNA DRAIC/PCAT29 Locus Constitutes a Tumor-Suppressive Nexus. AB - Long noncoding RNAs (lncRNA) are emerging as major regulators of cellular phenotypes and implicated as oncogenes or tumor suppressors. Here, we report a novel tumor-suppressive locus on human chromosome 15q23 that contains two multiexonic lncRNA genes of 100 kb each: DRAIC (LOC145837) and the recently reported PCAT29. The DRAIC lncRNA was identified from RNA-seq data and is downregulated as prostate cancer cells progress from an androgen-dependent (AD) to a castration-resistant (CR) state. Prostate cancers persisting in patients after androgen deprivation therapy (ADT) select for decreased DRAIC expression, and higher levels of DRAIC in prostate cancer are associated with longer disease free survival (DFS). Androgen induced androgen receptor (AR) binding to the DRAIC locus and repressed DRAIC expression. In contrast, FOXA1 and NKX3-1 are recruited to the DRAIC locus to induce DRAIC, and FOXA1 specifically counters the repression of DRAIC by AR. The decrease of FOXA1 and NKX3-1, and aberrant activation of AR, thus accounts for the decrease of DRAIC during prostate cancer progression to the CR state. Consistent with DRAIC being a good prognostic marker, DRAIC prevents the transformation of cuboidal epithelial cells to fibroblast-like morphology and prevents cellular migration and invasion. A second tumor-suppressive lncRNA PCAT29, located 20 kb downstream of DRAIC, is regulated identically by AR and FOXA1 and also suppresses cellular migration and metastasis. Finally, based on TCGA analysis, DRAIC expression predicts good prognosis in a wide range of malignancies, including bladder cancer, low-grade gliomas, lung adenocarcinoma, stomach adenocarcinoma, renal clear cell carcinoma, hepatocellular carcinoma, skin melanoma, and stomach adenocarcinoma. IMPLICATIONS: This study reveals a novel tumor-suppressive locus encoding two hormone-regulated lncRNAs, DRAIC and PCAT29, that are prognostic for a wide variety of cancer types. PMID- 25700554 TI - Preoperative arterial microcalcification and clinical outcomes of arteriovenous fistulas for hemodialysis. AB - BACKGROUND: Arteriovenous fistulas (AVFs) often fail to mature, but the mechanism of AVF nonmaturation is poorly understood. Arterial microcalcification is common in patients with chronic kidney disease (CKD) and may limit vascular dilatation, thereby contributing to early postoperative juxta-anastomotic AVF stenosis and impaired AVF maturation. This study evaluated whether preexisting arterial microcalcification adversely affects AVF outcomes. STUDY DESIGN: Prospective study. SETTING & PARTICIPANTS: 127 patients with CKD undergoing AVF surgery at a large academic medical center. PREDICTORS: Preexisting arterial microcalcification (>=1% of media area) assessed independently by von Kossa stains of arterial specimens obtained during AVF surgery and by preoperative ultrasound. OUTCOMES: Juxta-anastomotic AVF stenosis (ascertained by ultrasound obtained 4-6 weeks postoperatively), AVF nonmaturation (inability to cannulate with 2 needles with dialysis blood flow >= 300mL/min for >=6 sessions in 1 month within 6 months of AVF creation), and duration of primary unassisted AVF survival after successful use (time to first intervention). RESULTS: Arterial microcalcification was present by histologic evaluation in 40% of patients undergoing AVF surgery. The frequency of a postoperative juxta-anastomotic AVF stenosis was similar in patients with or without preexisting arterial microcalcification (32% vs 42%; OR, 0.65; 95% CI, 0.28-1.52; P=0.3). AVF nonmaturation was observed in 29%, 33%, 33%, and 33% of patients with <1%, 1% to 4.9%, 5% to 9.9%, and >=10% arterial microcalcification, respectively (P=0.9). Sonographic arterial microcalcification was found in 39% of patients and was associated with histologic calcification (P=0.001), but did not predict AVF nonmaturation. Finally, among AVFs that matured, unassisted AVF maturation (time to first intervention) was similar for patients with and without preexisting arterial microcalcification (HR, 0.64; 95% CI, 0.35-1.21; P=0.2). LIMITATIONS: Single-center study. CONCLUSIONS: Arterial microcalcification is common in patients with advanced CKD, but does not explain postoperative AVF stenosis, AVF nonmaturation, or AVF failure after successful cannulation. PMID- 25700555 TI - CKD in HIV-Infected Patients: From the New Plague to Chronic Care Management. PMID- 25700556 TI - What clinical features precede the onset of bipolar disorder? AB - Despite a growing number of reports, there is still limited knowledge of the clinical features that precede the onset of bipolar disorder (BD). To explore this, we investigated baseline data from a prospectively evaluated longitudinal cohort of subjects aged 12-30 years to compare: first, lifetime rates of clinical features between a) subjects at increased genetic risk for developing BD ('AR'), b) participants from families without mental illness ('controls'), and c) those with established BD; and, second, prior clinical features that predict the later onset of affective disorders in these same three groups. This is the first study to report such comparisons between these three groups (though certainly not the first to compare AR and control samples). 118 AR participants with a parent or sibling with BD (including 102 with a BD parent), 110 controls, and 44 BD subjects were assessed using semi-structured interviews. AR subjects had significantly increased lifetime risks for depressive, anxiety and behavioural disorders compared to controls. Unlike prior reports, preceding anxiety and behavioural disorders were not found to increase risk for later onset of affective disorders in the AR sample, perhaps due to limited sample size. However, preceding behavioural disorders did predict later onset of affective disorders in the BD sample. The findings that i) AR subjects had higher rates of depressive, anxiety and behavioural disorders compared to controls, and ii) prior behavioural disorders increased the risk to later development of affective disorders in the BD group, suggest the possibility of therapeutic targeting for these disorders in those at high genetic risk for BD. PMID- 25700557 TI - Linking implementation process to intervention outcomes in a middle school obesity prevention curriculum, 'Choice, Control and Change'. AB - This study investigates the link between process evaluation components and the outcomes of a school-based nutrition curriculum intervention, 'Choice, Control and Change'. Ten New York City public middle schools were recruited and randomly assigned into intervention or control condition. The curriculum was to improve sixth to seventh grade students' energy balance related behaviors, based on social cognitive and self-determination theories, and implemented during the 2006 2007 school year (n = 1136). Behaviors and psychosocial variables were measured by self-reported questionnaires. Process components were evaluated with classroom observations, teacher interviews, and a student questionnaire. Using 'Teacher Implementation' (dose delivered) and 'Student Reception' (dose received) process data; intervention group was further categorized into medium- and high implementation groups. Analysis of covariance revealed that, compared with control group, only high-implementation group showed significant improvement in students' behavior and psychosocial outcomes. Hierarchical linear models showed that 'Teacher Implementation' and 'Student Reception' significantly predicted students' sweetened beverage outcomes (P < 0.05). 'Student Satisfaction' was also greater when these implementation components were higher, and significantly associated with behavior and psychosocial outcomes (P < 0.05). Implementation process influenced the effectiveness of the 'Choice, Control and Change' intervention study. It is important to take into account the process components when interpreting the results of such research. PMID- 25700558 TI - There is no correlation between peripheral inflammation and cognitive status at diagnosis in Alzheimer's disease. AB - BACKGROUND: Besides the neurofibrillary tangles and amyloid plaques, an inflammatory process is involved at central and peripheral levels in Alzheimer's disease (AD). We aimed to determine whether peripheral inflammatory parameter levels, in plasma and in peripheral blood mononuclear cells (PBMCs), could be correlated with the cognitive status at the time of AD diagnosis. METHODS: Patients were included at diagnosis with MMSE score between 16 and 25 and were naive of symptomatic treatment for AD. C-reactive protein >10 mg/L and any acute or chronic inflammation were considered as exclusion criteria. Cognitive assessment also included the ADAScog scale. Plasma interleukins (IL)-1beta, IL-6, tumor necrosis factor (TNF)-alpha and the chemokine ligand 5 (CCL5) were measured using Luminex((r)) X-MAP((r)) technology. A subgroup of patients also underwent measures of these parameters in extracellular and intracellular compartments of PBMCs (ancillary study). RESULTS: One hundred and nine patients were included; mean age 79.4 +/- 6.8 years with 37 patients in the ancillary study. The mean values of IL-1beta, TNF-alpha, IL-6 and CCL5 values were 1.49, 7.18, 3.09 and 69,615.81 pg/mL, respectively. No correlation between plasma cytokines or chemokine levels and cognitive scores was found. In PBMCs, the levels of cytokines were detectable but did not either show any correlation with cognitive scores. CONCLUSION: Our data indicate that at diagnosis, peripheral levels of cytokines and CCL5 display low values without any correlation with the cognitive status. Further results of our study will show if these circulating markers are related to the progression of AD. PMID- 25700559 TI - A new model of central lid margin apposition and tear film mixing in spontaneous blinking. AB - PURPOSE: To investigate tear film spreading and central lid position in spontaneous blinks and to propose a model of the central lid position of the closed eye in such blinks. METHOD: In vivo: lid margin position and geometry of 15 subjects (9 female; median age=45 years) were evaluated by high-speed video and slit-lamp microscope video in consecutive spontaneous blinks. Upper lid (UL) tear meniscus (TM) depth was observed in the open and almost closed eye. Eyelid geometry, position and UL TM depth were analysed by Image-J Software. Lid margin thicknesses were measured with a Scheimpflug camera. In vitro: tear film spreading and lipid layer formation were simulated on a lubricated glass plate and videoed by high-speed camera (JVC, GZ-GX1BE, Japan). RESULTS: In vivo: the median central lid margin thickness was not significantly (p=0.258) different between UL (1.8mm) and LL (1.7mm) in the opened eye. During blinking, UL remained perpendicular to the corneal surface, while LL tilted in and thinned. A scaled model diagram was created and revealed an over-blink of the UL over the LL (>0.7mm) and a height offset of the posterior lid margin of >0.7mm. In vitro: the LL TM fused with the UL TM even before full lid touch due to capillary bridge building. CONCLUSIONS: The central UL overlaps the central LL during spontaneous blinking. This provides the appearance of complete closure. The space that results from the lack of lid margin apposition influences the fusion of the upper and lower TM and ultimately tear film mixing. PMID- 25700560 TI - SIRT5 regulation of ammonia-induced autophagy and mitophagy. AB - In liver the mitochondrial sirtuin, SIRT5, controls ammonia detoxification by regulating CPS1, the first enzyme of the urea cycle. However, while SIRT5 is ubiquitously expressed, urea cycle and CPS1 are only present in the liver and, to a minor extent, in the kidney. To address the possibility that SIRT5 is involved in ammonia production also in nonliver cells, clones of human breast cancer cell lines MDA-MB-231 and mouse myoblast C2C12, overexpressing or silenced for SIRT5 were produced. Our results show that ammonia production increased in SIRT5 silenced and decreased in SIRT5-overexpressing cells. We also obtained the same ammonia increase when using a new specific inhibitor of SIRT5 called MC3482. SIRT5 regulates ammonia production by controlling glutamine metabolism. In fact, in the mitochondria, glutamine is transformed in glutamate by the enzyme glutaminase, a reaction producing ammonia. We found that SIRT5 and glutaminase coimmunoprecipitated and that SIRT5 inhibition resulted in an increased succinylation of glutaminase. We next determined that autophagy and mitophagy were increased by ammonia by measuring autophagic proteolysis of long-lived proteins, increase of autophagy markers MAP1LC3B, GABARAP, and GABARAPL2, mitophagy markers BNIP3 and the PINK1-PARK2 system as well as mitochondrial morphology and dynamics. We observed that autophagy and mitophagy increased in SIRT5-silenced cells and in WT cells treated with MC3482 and decreased in SIRT5 overexpressing cells. Moreover, glutaminase inhibition or glutamine withdrawal completely prevented autophagy. In conclusion we propose that the role of SIRT5 in nonliver cells is to regulate ammonia production and ammonia-induced autophagy by regulating glutamine metabolism. PMID- 25700561 TI - Current antiplatelet agents: place in therapy and role of genetic testing. AB - Antiplatelet therapies play a central role in reducing the risk of cardiovascular events such as myocardial infarction and stroke. While aspirin, a cyclo-oxygenase 1 inhibitor has been the cornerstone of antithrombotic treatment for several decades, P2Y12 receptor inhibitors cangrelor, clopidogrel, prasugrel, and ticagrelor and protease-activated receptor-1 antagonist vorapaxar, have emerged as additional therapies to reduce the risk of recurrent cardiovascular events in high-risk patients. Recent clinical trials evaluating the role of these agents and major society guideline updates for use of antiplatelet therapies for secondary prevention of cardiovascular events will be examined. The latest studies regarding the appropriate duration of dual antiplatelet therapy after percutaneous coronary intervention will be presented. The current state of genetic and platelet function testing will be reviewed. PMID- 25700562 TI - Preservation of high-fat diet-induced femoral trabecular bone loss through genetic target of TNF-alpha. AB - Obesity and osteoporosis are two common chronic diseases, however, the basis for the correlation between them remains largely unknown. The pro-inflammation cytokine tumor necrosis factor-alpha (TNF-alpha) plays important roles in lipid and bone metabolisms, which may be a good candidate in the correlation between obesity and osteoporosis. We investigated the pathological roles of TNF-alpha in high-fat diet (HFD)-induced bone loss. Wild-type (WT) mice and TNF-alpha knockout (TNF-alpha(-/-)) mice were fed with the standard diet or the HFD for 12 weeks. Bone marrow stromal cells (BMSCs) from both genotypes were induced to differentiate into osteoblasts and treated with palmitic acid (PA). Bone mass and microstructure of femurs were evaluated by micro-CT. Lipid and bone metabolisms were investigated by histological and plasma analyses, and real-time PCR. On the HFD, both TNF-alpha(-/-) and WT mice presented notable visceral obesity, dyslipidemia. Adipogenesis and osteoclastogenesis were enhanced, while osteoblastogenesis was reduced in both genotypes. However, the changes were significantly different between TNF-alpha(-/-) and WT mice after the HFD. The gain of body and fat-pad weight was less and adipocyte area was smaller by 22 % in TNF-alpha(-/-) mice. Osteoclast numbers and plasma CTX level were lower by 40 % and by 23 % in TNF-alpha(-/-) mice. There were more ALP positive cells in the PA-treated TNF-alpha(-/-) BMSCs. mRNA expression of PPAR-gamma was lower while that of Runx2 was higher in the bone from TNF-alpha(-/-) HFD group and in the PA treated TNF-alpha(-/-) BMSCs, compared to WT on the same treatment. Furthermore, femoral trabecular bone mass and trabecular bone number were significantly decreased in WT mice on the HFD, whereas they were increased by 1.56-fold and 1.53-fold, respectively, in TNF-alpha(-/-) mice on the same diet (P < 0.05). Our results demonstrated that TNF-alpha gene knockout retained HFD-induced femoral trabecular bone loss mainly by suppressing adipogenesis and osteoclastogenesis, and enhancing osteoblastogenesis, which suggests that TNF-alpha plays a critical role in the development of HFD-related bone metabolic disorders and it may be a new potential therapeutic target for obesity-related bone loss. PMID- 25700563 TI - Autoantibodies of beta-adrenergic and M2 cholinergic receptors: atrial fibrillation in hyperthyroidism. PMID- 25700564 TI - The changing elaboration of inhibin b in patients with unilateral testicular maldescent vs vanished testis. PMID- 25700565 TI - A Detailed Analysis of the Association Between Postoperative Phosphodiesterase Type 5 Inhibitor Use and the Risk of Biochemical Recurrence After Radical Prostatectomy. AB - A recent study reported a detrimental effect of phosphodiesterase type 5 inhibitors (PDE5-Is) on biochemical recurrence (BCR) after radical prostatectomy (RP) for prostate cancer (PCa). We tested the association between PDE5-I use, PDE5-I therapy scheme, number of PDE5-I pills taken, and BCR in 2579 patients treated with bilateral nerve-sparing RP for PCa between 2004 and 2013 at a single center. Patients were categorized according to PDE5-I use within 2 yr after surgery as on demand, rehabilitation schedule (daily PDE5-I use for at least 3 mo), and no PDE5-I use. Multivariable (MVA) Cox regression models tested the association between PDE5-I and BCR. The same analyses were repeated using the number of PDE5-I pills taken by each patient. Overall, 674 patients (26.1%) received PDE5-Is. At MVA analysis, PDE5-I use, type of administration schedule, and number of PDE5-I pills were not significantly associated with higher risk of BCR (all p >= 0.2) after accounting for multiple confounders including time from RP to PDE5-I use. While awaiting further studies, patients should not be denied PDE5-I treatment after RP. PATIENT SUMMARY: Among patients treated with radical prostatectomy, phosphodiesterase type 5 inhibitor use was not associated with an increased risk of biochemical recurrence, regardless of the therapeutic regimen used. PMID- 25700566 TI - Pharmacokinetic/pharmacodynamic analysis to evaluate ceftaroline fosamil dosing regimens for the treatment of community-acquired bacterial pneumonia and complicated skin and skin-structure infections in patients with normal and impaired renal function. AB - In this study, the probability of pharmacokinetic/pharmacodynamic target attainment (PTA) of ceftaroline against clinical isolates causing community acquired bacterial pneumonia (CABP) and complicated skin and skin-structure infection (cSSSI) in Europe was evaluated. Three dosing regimens were assessed: 600 mg every 12 h (q12 h) as a 1-h infusion (standard dose) or 600 mg every 8 h (q8 h) as a 2-h infusion in virtual patients with normal renal function; and 400 mg q12 h as a 1-h infusion in patients with moderate renal impairment. Pharmacokinetic and microbiological data were obtained from the literature. The PTA and the cumulative fraction of response (CFR) were calculated by Monte Carlo simulation. In patients with normal renal function, the ceftaroline standard dose (600 mg q12 h as a 1-h infusion) can be sufficient to treat CABP due to ceftazidime-susceptible (CAZ-S) Escherichia coli, CAZ-S Klebsiella pneumoniae, meticillin-susceptible Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis (CFR>90%). However, against meticillin-resistant S. aureus (MRSA), the CFR was 72%. In cSSSI, the CFR was also <80% for MRSA. Administration of ceftaroline 600 mg q8 h as a 2-h infusion or 400 mg q12 h as a 1-h infusion in patients with moderate renal insufficiency provided a high probability of treatment success (CFR ca. 100%) for most micro organisms causing CABP and cSSSI, including MRSA and penicillin-non-susceptible S. pneumoniae. These results suggest that in patients with normal renal function, ceftaroline 600 mg q8 h as a 2-h infusion may be a better option than the standard dose, especially if the MRSA rate is high. PMID- 25700567 TI - Effect of psychosocial environment in children having mother with schizophrenia. AB - The process of child's mental development depends heavily on the social interrelationship between the mother and her child. Schizophrenia in mothers potentially disrupts mother-infant relationship and adaptation to motherhood. Literature is limited on evaluating the emotional and behavioral problems of children of mother having schizophrenia with nearly none from the Indian subcontinent. The aim of the current study was to examine the effect of psychosocial environment in children of females with schizophrenia. Thirty children of mothers suffering with schizophrenia were evaluated with Child Behavior Checklist (CBCL) and Mini International Neuropsychiatric Interview for children and adolescents. The psychosocial environment was assessed using Parent Interview Schedule. Control group of 30 children were evaluated in the same way as the cases. The children of female patients with schizophrenia were found to score significantly higher on internalizing and externalizing behavioral problems on CBCL as compared to control group, along with significant differences in the psychosocial environment between the groups. We conclude that there is a need for screening and evaluation of children of mothers diagnosed with schizophrenia, for identifying and managing possible mental and behavioral problems in them, and to assess the psychosocial environment and provide interventions for issues related to it. PMID- 25700568 TI - Emotional intensity influences pre-implementation and implementation of distraction and reappraisal. AB - Although emotional intensity powerfully challenges regulatory strategies, its influence remains largely unexplored in affective-neuroscience. Accordingly, the present study addressed the moderating role of emotional intensity in two regulatory stages--implementation (during regulation) and pre-implementation (prior to regulation), of two major cognitive regulatory strategies--distraction and reappraisal. According to our framework, because distraction implementation involves early attentional disengagement from emotional information before it gathers force, in high-intensity it should be more effective in the short-term, relative to reappraisal, which modulates emotional processing only at a late semantic meaning phase. Supporting findings showed that in high (but not low) intensity, distraction implementation resulted in stronger modulation of negative experience, reduced neural emotional processing (centro-parietal late positive potential, LPP), with suggestive evidence for less cognitive effort (frontal LPP), relative to reappraisal. Related pre-implementation findings confirmed that anticipating regulation of high-intensity stimuli resulted in distraction (over reappraisal) preference. In contrast, anticipating regulation of low-intensity stimuli resulted in reappraisal (over distraction) preference, which is most beneficial for long-term adaptation. Furthermore, anticipating cognitively demanding regulation, either in cases of regulating counter to these preferences or via the more effortful strategy of reappraisal, enhanced neural attentional resource allocation (Stimulus Preceding Negativity). Broad implications are discussed. PMID- 25700569 TI - Special issue on circuits in metabolic engineering. PMID- 25700572 TI - Multi-gene classifiers for prediction of recurrence in breast cancer patients. AB - Accurate prediction of recurrence risk is of vital importance for tailoring adjuvant chemotherapy for individual breast cancer patients. Although recurrence risk has been assessed by means of examination of histological data and biomarkers (ER, PR, HER2, Ki67), such conventional examinations are not accurate enough to select subsets of patients who are at sufficiently low risk of recurrence to be spared adjuvant chemotherapy without comprising the prognosis. In the past two decades or so, comprehensive gene expression analysis technology has rapidly developed and made it possible to construct recurrence prediction models for breast cancer based on multi-gene expression in tumor tissues. These models include MammaPrint, Oncotype DX, PAM50 ROR, GGI, EndoPredict, BCI, and Curebest 95GC. In clinical practice, these multi-gene classifiers are mostly used for ER-positive and node-negative breast cancer patients for whom deciding the indication of adjuvant chemotherapy based on conventional histological examination findings alone is often difficult. This article briefly reviews these multi-gene expression-based classifiers with special emphasis on CurebestTM 95GC, which was developed by us for ER-positive and node-negative breast cancer patients. PMID- 25700573 TI - Use of adenylate kinase as a solubility tag for high level expression of T4 DNA ligase in Escherichia coli. AB - The discovery of T4 DNA ligase in 1960s was pivotal in the spread of molecular biotechnology. The enzyme has become ubiquitous for recombinant DNA routinely practiced in biomedical research around the globe. Great efforts have been made to express and purify T4 DNA ligase to meet the world demand, yet over-expression of soluble T4 DNA ligase in E. coli has been difficult. Here we explore the use of adenylate kinase to enhance T4 DNA ligase expression and its downstream purification. E.coli adenylate kinase, which can be expressed in active form at high level, was fused to the N-terminus of T4 DNA ligase. The resulting His tagged AK-T4 DNA ligase fusion protein was greatly over-expressed in E. coli, and readily purified to near homogeneity via two purification steps consisting of Blue Sepharose and Ni-NTA chromatography. The purified AK-T4 DNA ligase not only is fully active for DNA ligation, but also can use ADP in addition to ATP as energy source since adenylate kinase converts ADP to ATP and AMP. Thus adenylate kinase may be used as a solubility tag to facilitate recombinant protein expression as well as their downstream purification. PMID- 25700574 TI - Double incomplete aortic arch and Kommerell's Diverticulum as a cause of chronic cough. AB - Vascular rings which can cause symptoms related the trachea and esophagus compression occur in less than 1% of all cardiovascular malformations. Double incomplete aortic arch with right-sided aorta and aberrant left subclavian artery is the rarest one, and its present in 0.04-0.1% of autopsy series. A case of this malformation with a Kommerell's Diverticulum is presented. This diverticulum has risk of severe complications such as dissection and/or rupture. PMID- 25700575 TI - Transradial anterograde recanalization of a totally occluded right coronary artery using a Guideliner catheter. PMID- 25700577 TI - [Continuous assessment]. PMID- 25700576 TI - [High sensitivity C protein as an independent risk factor in people with and without history of cardiovascular disease]. AB - Among the new cardiovascular event (CVE) risk biomarkers, C-reactive protein detected using high sensitive techniques (hs-CRP) has been one of the most commonly evaluated. In this review, the available evidence on the usefulness of hs-CRP was explored as an independent risk event factor in subjects with no cardiovascular history and as prognosis in case of chronic or acute cardiovascular condition. An overview (revision of revisions) was carried out searching in the main bibliographic databases and in other general Internet search engines. During the first stage, systematic reviews, clinical practice guidelines, health technology assessments and coverage policies were found and, during the second stage primary studies published after the systematic review search dates were added. Seven hundred and seventy four quotes were found, including 36 papers assessing the role of hs-CRP in healthy populations or with cardiovascular history. High quality evidence was found pointing out hs-CRP, both as risk factor in the general population and as prognostic factor in those with CVE, in all the populations assessed. It was most useful in subjects with a history of CVE and intermediate risk of events at 10 years; where adding hs-CRP to the classical models for event risk estimation improves risk staging. There was no consensus on its clinical usefulness as a prognostic marker in subjects with chronic or acute disease. PMID- 25700578 TI - [Lung perfusion studies after percutaneous closure of patent ductus arteriosus using the Amplatzer Duct Occluder in children]. AB - OBJECTIVE: The closure of patent ductus arteriosus with multiple devices has been associated with a reduction in lung perfusion. We evaluated the pulmonary perfusion after percutaneous closure of patent ductus arteriosus with the Amplatzer Duct Occluder device using perfusion lung scan. METHODS: Thirty patients underwent successful percutaneous patent ductus arteriosus occlusions using the Amplatzer Duct Occluder device were included in this study. Lung perfusion scans were preformed 6 months after the procedure. Peak flow velocities and protrusion of the device were analyzed by Doppler echocardiography. A left lung perfusion<40% was considered abnormal. RESULTS: The device implantation was successful in all patients. Average perfusion of left lung was 44.7+/-4.9% (37.8 61.4). Five patients (16.6%) showed decreased perfusion of the left lung. Age, low weight, the length of the ductus arteriosus and the minimum and maximum diameter/length of the ductus arteriosus ratio were statistically significant in patients with abnormalities of lung perfusion. It was observed protrusion the device in 6 patients with a higher maximum flow rate in the left pulmonary artery. CONCLUSION: The left lung perfusion may be compromised after percutaneous closure of patent ductus arteriosus with the Amplatzer Duct Occluder. The increased flow velocity in the origin of the left pulmonary artery can be a poor indicator of reduction in pulmonary perfusion and can occur in the absence of protrusion of the device. PMID- 25700579 TI - [Position paper on the results of Symplicity HTN-3 trial. Grupo de estudio de la hipertension arterial resistente]. AB - Renal artery denervation has shown to be an effective treatment for resistant hypertension. Symplicity HTN 1 and 2 trials showed in small and uncontrolled groups, significant systolic blood pressure reductions down to 30 mm Hg. Symplicity HTN-3, a double blind, randomized, placebo controlled clinical trial shaded this initial enthusiasm. Surprisingly, their results showed that renal denervation has a similar effect to placebo. Pre-specified subgroup analysis showed that non-black race individuals, younger than 65 years and with normal renal function, had a statistically significant systolic blood pressure decrease. This manuscript critically appraises the Symplicity HTN-3 trial, proposing possible explanations for the results. Also declares our group position and future actions regarding renal denervation. PMID- 25700580 TI - The ACE I/D polymorphism is associated with nitric oxide metabolite and blood pressure levels in healthy Mexican men. AB - The I/D insertion/deletion polymorphism of the angiotensin-converting enzyme has been related to hypertension. This polymorphism also seems to have gender related implications. Angiotensin II contributes to the production and release of oxygen reactive species that react with nitric oxide, inactivating its effects. OBJECTIVE: To establish whether the ACE I/D polymorphism correlates with nitric oxide plasma metabolites in healthy men and women. METHODS: Among 896 subjects between 18 and 30 years of age range, 138 fulfilled inclusion criteria. The polymorphism was identified by polymerase chain reaction, and blood nitric oxide metabolites were analyzed following the method described by Bryan. RESULTS: Both systolic and diastolic arterial pressures were higher in men than in women (107/67 vs. 101/65 mm Hg, p<0.001). In terms of the ACE gene, there were differences in the concentration of nitric oxide metabolites in men with the I/D and D/D genotypes when compared to carriers of the I/I genotype (33.55 and 29.23 vs. 53.74 pmol/ml; p=<0.05), while there were no significant differences in women when compared by genotype. Men with the D/D genotype had higher systolic blood pressure than I/D carriers (111 vs. 104 mm Hg, p<0.05). We observed no arterial blood pressure differences in women when grouped by ACE genotype. CONCLUSIONS: The ACE D/D genotype was associated with nitric oxide metabolite levels and systolic blood pressure in clinically healthy men while it had no effect in women. PMID- 25700581 TI - [Giant left atrium]. AB - Woman 48 years old with progressive dyspnea, fatigue, dysphagia, lower limb edema, palpitations and decreased physical ability that made her to seek medical attention. The chest film showed severe cardiomegaly or "cor bovis" with cardiothoracic index of 0.78. The findings suggest a dilatation of both atria but mostly in the one. The echocardiogram shows severe mitral regurgitation consistent with rheumatic valve disease and "giant" left atrium. This was first described in 1938 by Semans and Taussig, is considered a rare finding and the principal cause is rheumatic mitral disease. This type of valve lesions are becoming less frequent as aneurysmal dilation. The diameters, the area and the calculated volume are shown as one of the greatest reported atrium. PMID- 25700582 TI - Screening for cancer: when to stop?: A practical guide and review of the evidence. AB - Deciding when to stop cancer screening in older adults is a complex challenge that involves multiple factors: individual health status and life expectancy; risks and benefits of screening, which vary with age and comorbidity; and individual preferences and values. This article examines current cancer screening practices and reviews the risks and benefits of cancer screening for colorectal, breast, lung, prostate, and cervical cancer, particularly in older individuals and those with multiple comorbidities. Tools for estimating life expectancy are reviewed, and a practical framework is presented to guide discussions on when the harms of screening likely outweigh the benefits. PMID- 25700583 TI - Geriatric syndromes and geriatric assessment for the generalist. AB - Geriatric assessment is an increasingly important area of outpatient medicine, given the unprecedented aging of the US population. Screening and evaluation for geriatric syndromes, particularly falls, urinary incontinence, frailty, and cognitive impairment, are crucial aspects of outpatient geriatric assessment. Innovative models of care are emerging to improve quality of care and enhance cost savings for the geriatric patient. High-value features of geriatric care systems include providing increased 24/7 access to care, a multidisciplinary team based approach to care, performing medication reconciliation and comprehensive geriatric assessments, and integrating palliative care into treatment planning. PMID- 25700584 TI - Assessment and management of fall risk in primary care settings. AB - Falls among older adults are neither purely accidental nor inevitable; research has shown that many falls are preventable. Primary care providers play a key role in preventing falls. However, fall risk assessment and management is performed infrequently in primary care settings. This article provides an overview of a clinically relevant, evidence-based approach to fall risk screening and management. It describes resources, including the STEADI (Stopping Elderly Accidents, Deaths, and Injuries) tool kit that can help providers integrate fall prevention into their practice. PMID- 25700585 TI - Appropriate prescribing and important drug interactions in older adults. AB - Polypharmacy, specifically the overuse and misuse of medications, is associated with adverse health events, increased disability, hospitalizations, and mortality. Mechanisms through which polypharmacy may increase adverse health outcomes include decreased adherence, increased drug side effects, higher use of potentially inappropriate medications, and more frequent drug-drug interactions. This article reviews clinical problems associated with polypharmacy and presents a framework to optimize prescribing for older adults. PMID- 25700587 TI - Pain management in the elderly. AB - Persistent pain in older adults is common, and associated with substantial morbidity. Optimal management starts with assessment, including pain presence, intensity, characteristics, and interference; painful conditions; pain behaviors; pain-related morbidity; pain treatments; and coping style. Treatment incorporates analgesics demonstrated to decrease pain and improve a patient's sense of well being. The World Health Organization's 3-step pain ladder is widely accepted and adopted for selecting analgesics among patients with non-cancer pain. Shared decision making is essential to balance the benefits and burdens of analgesics. This article reviews pain assessment/management for older adults, focusing on commonly used analgesics. PMID- 25700586 TI - Evaluation and management of the elderly patient presenting with cognitive complaints. AB - Cognitive complaints are common in the geriatric population. Older adults should routinely be asked about any concerns about their memory or thinking, and any cognitive complaint from the patient or an informant should be evaluated rather than be attributed to aging. Several screening instruments are available to document objective impairments and guide further evaluation. Management goals for patients with cognitive impairment are focused on maintaining function and independence, providing caregiver support, and advance care planning. There are currently no treatments to effectively prevent or treat dementia. Increasing appreciation of the heterogeneity of Alzheimer disease may lead to novel treatment approaches. PMID- 25700588 TI - Management of diabetes in the elderly. AB - Management of diabetes in the elderly necessitates careful consideration of concomitant geriatric syndromes and comorbid conditions that increase the risk of complications, including severe hypoglycemia. Whereas healthy older adults can use therapeutic approaches recommended for their younger counterparts, treatment plans for frail elderly patients need to be simplified and A1c and blood pressure goals relaxed with the development of impairments in function, cognition, vision, and dexterity. The goals of diabetes management in the elderly should be to maintain quality of life and minimize symptomatic hyperglycemia and drug side effects, including hypoglycemia. PMID- 25700589 TI - Hypertension in the geriatric population: a patient-centered approach. AB - Hypertension contributes greatly to adverse cardiovascular outcomes; the magnitude of this contribution increases with age. The most recent guideline has proposed raising the goal systolic blood pressure to less than 150 mm Hg among those over age 60; however, this recommendation is not endorsed by other organizations. There are multiple contributors to hypertension in the older individual, including increased vascular stiffness, salt sensitivity, and decreased baroreceptor responsiveness. Therapy in the hypertensive patient over age 60 should be individualized and account for patient's health, functional and cognitive status, comorbidities, frailty, and prognosis. PMID- 25700590 TI - Advance care planning in the elderly. AB - Key components of advance care planning (ACP) for the elderly include choosing a surrogate decision maker, identifying personal values, communicating with surrogates and clinicians, documenting wishes in advance directives, and translating values and preferences for future medical care into medical orders. ACP often involves multiple brief discussions over time. This article outlines common benefits and barriers to ACP in primary care, and provides practical approaches to integrating key ACP components into primary care for older adults. Opportunities for multidisciplinary teams to incorporate ACP into brief clinic visits are highlighted. PMID- 25700591 TI - Urinary incontinence and pelvic organ prolapse. AB - Urinary incontinence and pelvic organ prolapse are widely prevalent in the elderly population. The primary care physician should play a leading role in identifying the presence of incontinence in this population, as it can significantly affect quality of life and well-being. Behavioral and lifestyle modification is the cornerstone in treatment and can be initiated in the primary care setting. Frail elderly require special consideration to avoid potentially serious complications of urinary incontinence and pelvic organ prolapse. PMID- 25700592 TI - Antithrombotic management of atrial fibrillation in the elderly. AB - Older patients with atrial fibrillation have an increased risk of stroke and systemic embolism compare with younger patients. For most patients, oral anticoagulation remains the most effective way to reduce this risk. Although vitamin K antagonists have been used for decades, the more recent development of non-vitamin K-dependent oral anticoagulants provides clinicians with a broader selection of anticoagulants for stroke prevention in older patients with AF. This article discusses stroke risk-stratification tools for clinical decision making, reviews pharmacologic options for the prevention of stroke, and highlights several practical considerations to the use of these agents in older adults. PMID- 25700593 TI - Sleep problems in the elderly. AB - Epidemiologic studies have shown that approximately 50% of older adults have sleep problems, many of which carry deleterious consequences that affect physical and mental health and also social functioning. However, sleep problems in late life are often unrecognized, and are inadequately treated in clinical practice. This article focuses on the diagnosis and treatment of the 2 most common sleep problems in older patients: sleep apnea and insomnia. PMID- 25700594 TI - Medical Clinics of North America. Geriatric medicine. Foreword. PMID- 25700595 TI - Toward improving the care of older adults. PMID- 25700596 TI - Satisfaction with nursing care in the emergency department of an urban hospital in the developing world: A pilot study. AB - INTRODUCTION: Nurses form the largest group of the workforce in hospitals and as such the quality of nursing care is a critical indicator of patient satisfaction. OBJECTIVE: To determine the level of patient satisfaction with nursing care in the emergency department of an urban teaching hospital in Jamaica. METHODS: This descriptive cross-sectional study used a convenience sampling technique to recruit 142 adult patients who accessed nursing care in the emergency and intermediate areas of the emergency department. Data were collected using a 22- item questionnaire adapted from the Patient Satisfaction with Nursing Care Quality Questionnaire and managed using SPSS(r) version 19.0 for Windows(r). RESULTS: The response rate was 77.6%; most respondents (62%) were female, and educated at the secondary level (42.3%). The mean satisfaction score was 32.60 (+/- 7.11) out of a possible 42. Most (59.9%) patients reported that they were very satisfied with nursing care in the emergency department. Satisfaction with nursing care was associated with clients' education. Perceived health status and empathy of nursing care offered were associated with patient's satisfaction with care (p = 0.05). CONCLUSIONS: Patients were highly satisfied with nursing care in the emergency department studied. Client's education, perceived health status and empathy of care were predictors of satisfaction. PMID- 25700597 TI - Association of homeostasis model assessment of insulin resistance, adiponectin, and low-grade inflammation with the course of the metabolic syndrome. AB - OBJECTIVE: We examined the association between insulin resistance (IR), adiponectin, and inflammation markers and the development of metabolic syndrome (MetS). Furthermore, we aimed to establish the relationship between IR, serum adiponectin, and parameters of chronic inflammation. METHODS: MetS was assessed in 1628 Kazakh participants (768 men; 860 women) in Xinjiang, Northwestern China. RESULTS: Adiponectin, homeostasis model assessment of IR (HOMA-IR), interleukin-6 (IL-6), and C-reactive protein (CRP) remained significantly associated with MetS after further adjustment for sex, age, smoking status, low-density lipoprotein cholesterol, total cholesterol, and high-density lipoprotein cholesterol. Moreover, HOMA-IR, IL-6, and CRP increased concurrently with an increased number of MetS components, and an inverse trend between adiponectin and increased number of MetS components was found. The median of IL-6 and CRP increased with HOMA-IR from the lowest to the highest quartile. In contrast, the median of adiponectin remarkably decreased with HOMA-IR from the lowest to the highest quartile (P<0.001). According to multiple linear regression analysis, adiponectin, CRP, and IL-6 also showed a significant association with HOMA-IR. CONCLUSION: We strengthen the notion that HOMA-IR, adiponectin, and inflammatory markers can predict the course of MetS. Furthermore, our results suggest that a chronic state of inflammation and decreased serum adiponectin might be associated with IR. PMID- 25700598 TI - Pre-transplant management of valve bladder: a critical literature review. AB - OBJECTIVE: Indications, timing and problems related to augmentation cystoplasty (AC), in the context of posterior urethral valves (PUV) and renal transplantation (RT) are ill defined. Associated bladder dysfunction (BD) is not a stable condition and may cause the loss of the renal graft. Polyuria, accentuates BD and seems to improve after RT. The objective of this research is to critically review the available literature, aiming to rationalize the treatment of PUV with BD in the context of end stage renal disease (ESRD). MATERIALS AND METHODS: A thorough literature review was performed. Pertinent papers were, critically analyzed and classified according to the level of evidence. RESULTS: Data relating to PUV, RT and AC showed low levels of evidence. Results of RT in PUV cases with adequate management of BD were comparable to those suffering from other causes of ESRD. Bladder function can recover spontaneously after urinary undiversion. There were no established criteria to indicate AC in the context of ESRD and PUV or to define the ideal protocol to treat associated vesicoureteral reflux (VUR). Urinary tract infections (UTIs) were more frequent in transplanted PUV patients; this is possibly related to the inadequate control of BD, especially after AC. AC is feasible after RT with outcomes comparable to preemptive ones. CONCLUSION: AC increases the risk of UTI after RT. Preemptive AC should be constructed only if the risks associated with increased bladder pressures exceed those associated with AC. Adequate management of BD is essential to improve bladder function and to minimize UTIs. AC is feasible after RT, with complication rates similar to the ones performed beforehand. Since a considerable number of PUV patients with high pressure bladders eventually develop myogenic failure, it seems logical to postponing AC in this population, as long as they are under close surveillance. PMID- 25700599 TI - Adult Hippocampal Neurogenesis Is Regulated by the Microbiome. PMID- 25700600 TI - Inhibition of antifungal therapy by gastric acid suppressants. PMID- 25700601 TI - Acid-suppressant therapy does not influence absorption of azoles used in candidemia. PMID- 25700602 TI - Evidence about inotropes: when is enough, enough? PMID- 25700603 TI - Glucocorticoids decrease the production of glucagon-like peptide-1 at the transcriptional level in intestinal L-cells. AB - Glucocorticoids are widely used as anti-inflammatory or immunosuppressive drugs, but often induce hyperglycemia as a side effect. Glucagon-like peptide-1 (GLP-1) is secreted from intestinal L cells and plays crucial roles in maintaining glucose homeostasis. However, the direct effects of glucocorticoids on the GLP-1 production pathway in L cells remain unclear. We investigated the effects of glucocorticoids on GLP-1 production in vitro and in vivo. In L cell lines, glucocorticoids decreased GLP-1 release and expression of the precursor, proglucagon, at protein and mRNA levels, which were inhibited by mifepristone. The administration of dexamethasone or budesonide to mice significantly decreased the mRNA expression of proglucagon in the ileum and partially decreased glucose stimulated GLP-1 secretion. Compound A, a dissociated glucocorticoid receptor modulator, did not affect the expression of proglucagon in vitro. These results suggested that glucocorticoids directly reduced GLP-1 production at the transcriptional level in L cells through a glucocorticoid receptor dimerization dependent mechanism. PMID- 25700604 TI - Expression of estrogen receptor alpha in the mouse cerebral cortex. AB - Although estrogen receptor alpha (ERalpha) and 17beta-estradiol play critical roles in protecting the cerebral cortex from ischemia-induced damage, there has been some controversy about the expression of ERalpha in this region of the brain. We have examined ERalpha mRNA and protein levels in the cerebral cortices of female mice at postnatal days 5 and 17 and at 4, 13, and 18 months of age. We found that although ERalpha transcript levels declined from postnatal day 5 through 18 months of age, ERalpha protein levels remained stable. Importantly, expression of the E2-regulated progesterone receptor gene was sustained in younger and in older females suggesting that age-related changes in estrogen responsiveness in the cerebral cortex are not due to the absence of ERalpha protein. PMID- 25700605 TI - Timing of risk reducing mastectomy in breast cancer patients carrying a BRCA1/2 mutation: retrospective data from the Dutch HEBON study. AB - It is expected that rapid genetic counseling and testing (RGCT) will lead to increasing numbers of breast cancer (BC) patients knowing their BRCA1/2 carrier status before primary surgery. Considering the potential impact of knowing one's status on uptake and timing of risk-reducing contralateral mastectomy (RRCM), we aimed to evaluate trends over time in RRCM, and differences between carriers identified either before (predictively) or after (diagnostically) diagnosis. We collected data from female BRCA1/2 mutation carriers diagnosed with BC between 1995 and 2009 from four Dutch university hospitals. We compared the timing of genetic testing and RRCM in relation to diagnosis in 1995-2000 versus 2001-2009 for all patients, and predictively and diagnostically tested patients separately. Of 287 patients, 219 (76%) had a diagnostic BRCA1/2 test. In this cohort, the median time from diagnosis to DNA testing decreased from 28 months for those diagnosed between 1995 and 2000 to 14 months for those diagnosed between 2001 and 2009 (p < 0.001). Similarly, over time women in this cohort underwent RRCM sooner after diagnosis (median of 77 vs. 27 months, p = 0.05). Predictively tested women who subsequently developed BC underwent an immediate RRCM significantly more often than women who had a diagnostic test (21/61, 34%, vs. 13/170, 7.6 %, p < 0.001). Knowledge of carrying a BRCA1/2 mutation when diagnosed with BC influenced decisions concerning primary surgery. Additionally, in more recent years, women who had not undergone predictive testing were more likely to undergo diagnostic DNA testing and RRCM sooner after diagnosis. This suggests the need for RGCT to guide treatment decisions. PMID- 25700606 TI - Reprint of: Pyrolysis technologies for municipal solid waste: a review. AB - Pyrolysis has been examined as an attractive alternative to incineration for municipal solid waste (MSW) disposal that allows energy and resource recovery; however, it has seldom been applied independently with the output of pyrolysis products as end products. This review addresses the state-of-the-art of MSW pyrolysis in regards to its technologies and reactors, products and environmental impacts. In this review, first, the influence of important operating parameters such as final temperature, heating rate (HR) and residence time in the reaction zone on the pyrolysis behaviours and products is reviewed; then the pyrolysis technologies and reactors adopted in literatures and scale-up plants are evaluated. Third, the yields and main properties of the pyrolytic products from individual MSW components, refuse-derived fuel (RDF) made from MSW, and MSW are summarised. In the fourth section, in addition to emissions from pyrolysis processes, such as HCl, SO2 and NH3, contaminants in the products, including PCDD/F and heavy metals, are also reviewed, and available measures for improving the environmental impacts of pyrolysis are surveyed. It can be concluded that the single pyrolysis process is an effective waste-to-energy convertor but is not a guaranteed clean solution for MSW disposal. Based on this information, the prospects of applying pyrolysis technologies to dealing with MSW are evaluated and suggested. PMID- 25700607 TI - Low back pain affects trunk as well as lower limb movements during walking and running. AB - Up to now, most gait analyses on low back pain concentrate on changes in trunk coordination during walking on a treadmill. Locomotion on uneven ground as well as lower limb changes receives little attention in association with low back pain. The present study focuses on how chronic non-specific low back pain causes modifications in lower limb and trunk movements, in level and uneven walking and running. We found that trunk as well as lower limb movement was influenced by chronic non-specific low back pain. A consistent finding across all gaits and ground level changes is that patients with chronic non-specific low back pain show less pelvis and unchanged thorax rotation as compared to healthy controls. Furthermore, in chronic non-specific low back pain patients the trunk rotation decreased only during level and uneven running whereas the sagittal trunk inclination at touchdown increased only during uneven walking as compared to healthy controls. Besides significant changes in the upper body, in chronic non specific low back pain patients the knee joint angle at touchdown was more extended during level walking but also during uneven walking and running as compared to healthy controls. We assume that trunk movements interact with lower limb movements or vice versa. Therefore, we recommend that further investigations on low back pain should consider both trunk (primarily pelvis) and lower limb (primarily knee) movements. PMID- 25700608 TI - Individual muscle contributions to circular turning mechanics. AB - Turning is an activity of daily living that involves both the acceleration of the body center-of-mass (COM) towards the center of curvature and rotation of the pelvis towards the new heading. The purpose of this study was to understand which muscles contribute to turning using experimentation, musculoskeletal modeling and simulation. Ten healthy adults consented to walk around a 1-m radius circular path at their self-selected walking speed and then along a straight line at the same speed. Forward dynamics simulations of the individual subjects during the turning and straight-line walking tasks were generated to identify the contributions of individual muscle groups to the body mediolateral and anterior posterior COM acceleration impulse and to the pelvis angular acceleration impulse. The stance leg gluteus medius and ankle plantarflexor muscles and the swing leg adductor muscles were the primary contributors to redirect the body's COM relative to straight-line walking. In some cases, contributions to mediolateral COM acceleration were modulated through changes in leg orientation rather than through changes in muscle force. While modulation of the muscle contributions generally occurred in both the inner and outer legs, greater changes were observed during inner single-leg support than during outer single leg support. Total pelvis angular acceleration was minimal during the single support phase, but the swing leg muscles contributed significantly to balancing the internal and external rotation of the pelvis. The understanding of which muscles contribute to turning the body during walking may help guide the development of more effective locomotor therapies for those with movement impairments. PMID- 25700609 TI - Achilles tendon moment arms: the importance of measuring at constant tendon load when using the tendon excursion method. AB - Achilles tendon moment arms are commonly measured using the tendon-excursion technique and ultrasound imaging of the muscle-tendon junction. The tendon excursion technique relies on the assumption that the tendon load is constant and thus it does not stretch. However, previous studies have not enforced this constraint and thus it is not known how sensitive the estimated Achilles tendon moment arms are to varying load during the measurement process. The aim of this study was to compare estimates of Achilles tendon moment arms when calculated using the different constraints of constant force (and thus tendon stretch), constant joint torque, or contraction effort. Achilles tendon moment arms were measured for the medial and lateral gastrocnemii in 8 healthy male subjects across five different ankle angles (-5 degrees dorsiflexion to 35 degrees plantarflexion), and a range of contraction levels. Moment arms were calculated for three different constraints of constant force, torque, or effort. Moment arms were significantly greater for the lateral gastrocnemius than for the medial gastrocnemius. At low contraction levels, including the passive condition, the moment arms increased with plantarflexion, whereas the moment arms decreased with plantarflexion at higher contraction levels. There was no difference between the calculated moment arms using the constant force and the constant torque methods; however both these methods yielded significantly different moment arms when compared to the commonly used constant effort method. PMID- 25700610 TI - The effect of chemically defined medium on spontaneous calcium signaling of in situ chondrocytes during long-term culture. AB - Chemically defined serum-free medium has been shown to better maintain the mechanical integrity of articular cartilage explants than serum-supplemented medium during long-term in vitro culture, but little is known about its effect on cellular mechanisms. We hypothesized that the chemically defined culture medium could regulate the spontaneous calcium signaling of in situ chondrocytes, which may modulate the cellular metabolic activities. Bovine cartilage explants were cultured in chemically defined serum-free or serum-supplemented medium for four weeks. The spontaneous intracellular calcium ([Ca(2+)]i) signaling of in situ chondrocytes was longitudinally measured together along with the biomechanical properties of the explants. The spontaneous [Ca(2+)]i oscillations in chondrocytes were enhanced at the initial exposure of serum-supplemented medium, but were significantly dampened afterwards. In contrast, cartilage explants in chemically defined medium preserved the level of calcium signaling, and showed more responsive cells with higher and more frequent [Ca(2+)]i peaks throughout the four week culture in comparison to those in serum medium. Regardless of the culture medium that the explants were exposed, a positive correlation was detected between the [Ca(2+)]i responsive rate and the stiffness of cartilage (Spearman's rank correlation coefficient=0.762). A stable pattern of [Ca(2+)]i peaks was revealed for each chondrocyte, i.e., the spatiotemporal features of [Ca(2+)]i peaks from a cell were highly consistent during the observation period (15 min). This study showed that the beneficial effect of chemically defined culture of cartilage explants is associated with the spontaneous [Ca(2+)]i signaling of chondrocytes in cartilage. PMID- 25700611 TI - Assessing viscoelasticity of shear wave propagation in cervical tissue by multiscale computational simulation. AB - The viscoelastic properties are recently being reported to be particularly sensitive to the gestation process, and to be intimately related to the microstructure of the cervical tissue. However, this link is not fully understood yet. In this work, we explore the importance of the heterogeneous multi-scale nature of cervical tissue for quantifying both elasticity and viscosity from shear waves velocity. To this end, shear wave propagations are simulated in a microscopic cervical tissue model using the finite difference time domain technique, over a wide frequency range from 15 to 200 kHz. Three standard rheological models (Voigt, Maxwell and Zener) are evaluated regarding their ability to reproduce the simulated dispersion curves, and their plausibility to describe cervical tissue is ranked by a stochastic model-class selection formulation. It is shown that the simplest model, i.e. that with less parameters, which best describes the simulated dispersion curves in cervical tissue is the Maxwell model. Furthermore, results show that the excitation frequency determines which rheological model can be representative for the tissue. Typically, viscoelastic parameters tend to converge for excitation frequencies over 100 kHz. PMID- 25700612 TI - Investigating the microstructural and neurochemical environment within the basal ganglia of current methamphetamine abusers. AB - BACKGROUND: Methamphetamine is a highly addictive psychostimulant and the medical, social, and economic consequences associated with its use have become a major international problem. Current evidence has shown methamphetamine to be particularly neurotoxic to dopamine neurons and striatal structures within the basal ganglia. A previous study from our laboratory demonstrated larger putamen volumes in actively using methamphetamine-dependent participants. The purpose of this current study was to determine whether striatal structures in the same sample of participants also exhibit pathology on the microstructural and molecular level. METHODS: Diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MRS) were carried out in current methamphetamine users (n = 18) and healthy controls (n = 22) to investigate diffusion indices and neurometabolite levels in the basal ganglia. RESULTS: Contrary to findings from previous DTI and MRS studies, no significant differences in diffusion indices or metabolite levels were observed in the basal ganglia regions of current methamphetamine users. CONCLUSIONS: These findings differ from those reported in abstinent users and the absence of diffusion and neurochemical abnormalities may suggest that striatal enlargement in current methamphetamine use may be due to mechanisms other than edema and glial proliferation. PMID- 25700613 TI - The occipitum-dens line: the purpose of a new ultrasonographic landmark in the evaluation of the relationship between the foetal posterior fossa structures and foramen magnum. AB - PURPOSE: The aims of this study were to describe a new ultrasonographic technique to assess the normal level of the cerebellum and the brainstem in the posterior fossa in normal foetuses and to compare in pathologic cases. METHODS: We propose a new line cross between the dens cervical and the inferior portion of occipitum (occipitum-dens line-ODL). In a cross-sectional study, a single observer with experience in foetal neurosonography evaluated 54 foetuses (40 normal and 14 with open neural tube defect) between 20 and 28 weeks of gestation. The reference points for the ODL are principally the lower portion of the occipital bone (occipitum) and odontoid process of the second cervical vertebra (dens). The line was considered the level zero (near level of foramen magnum). Structures above it had a positive measurement and below it had a negative measurement. RESULTS: Moreover, in most foetuses with open neural tube defect (93 %), the end portion of cerebellum was below the ODL associated with different degrees of ventriculomegaly. CONCLUSION: The proposed innovation aims to bring to the ultrasound the most likely anatomical parameters of evaluation in normal foetuses and in foetuses with spinal dysraphism. PMID- 25700614 TI - Extradural temporopolar approach for parahypothalamic hypothalamic hamartoma and use of posterior communicating artery as resection margin pointer. AB - BACKGROUND: Hypothalamic hamartomas (HH) are malformations originating from the hypothalamus and are associated with seizures, hormonal and behavioral abnormalities. METHOD: Most patients, especially those with a typical syndrome characterized by gelastic seizures, precocious puberty, cognitive decline, and behavior problems, are diagnosed in childhood. Pedunculated and parahypothalamic types of hamartomas are attached to the floor by a narrow or wide peduncle in the absence of distortion of the overlying hypothalamus. This location is most commonly associated with a clinical presentation of precocious puberty, and surgical removal has proved curative in small case series. Enthusiastic resection of hypothalamic lesions are known to produce severe hypothalamic disturbance while under resection might mean inadequate response to surgery. CONCLUSIONS: In this article, the authors describe the use of extradural temporopolar approach to hypothalamic hamartoma as an improvisation to improve access with reduced morbidity and describe a surgical nuance of using posterior communicating artery to determine a safe but maximal resection margin. PMID- 25700615 TI - We Built This House; It's Time to Move in: Leveraging Existing DICOM Structure to More Completely Utilize Readily Available Detailed Contrast Administration Information. AB - The Digital Imaging and Communications in Medicine (DICOM) standard is the universal format for interoperability in medical imaging. In addition to imaging data, DICOM has evolved to support a wide range of imaging metadata including contrast administration data that is readily available from many modern contrast injectors. Contrast agent, route of administration, start and stop time, volume, flow rate, and duration can be recorded using DICOM attributes [1]. While this information is sparsely and inconsistently recorded in routine clinical practice, it could potentially be of significant diagnostic value. This work will describe parameters recorded by automatic contrast injectors, summarize the DICOM mechanisms available for tracking contrast injection data, and discuss the role of such data in clinical radiology. PMID- 25700616 TI - Development of Diagnostic Reference Levels Using a Real-Time Radiation Dose Monitoring System at a Cardiovascular Center in Korea. AB - Digital cardiovascular angiography accounts for a major portion of the radiation dose among the examinations performed at cardiovascular centres. However, dose related information is neither monitored nor recorded systemically. This report concerns the construction of a radiation dose monitoring system based on digital imaging and communications in medicine (DICOM) data and its use at the cardiovascular centre of the University Hospitals in Korea. The dose information was analysed according to DICOM standards for a series of procedures, and the formulation of diagnostic reference levels (DRLs) at our cardiovascular centre represents the first of its kind in Korea. We determined a dose area product (DAP) DRL for coronary angiography of 75.6 Gy cm(2) and a fluoroscopic time DRL of 318.0 s. The DAP DRL for percutaneous transluminal coronary intervention was 213.3 Gy cm(2), and the DRL for fluoroscopic time was 1207.5 s. PMID- 25700617 TI - A Feasibility Study of Real-Time Remote CT Reading for Suspected Acute Appendicitis Using an iPhone. AB - We aimed to evaluate the feasibility of an iPhone-based remote control system as a real-time remote computed tomography (CT) reading tool for suspected appendicitis using a third-generation (3G) network under suboptimal illumination. One hundred twenty abdominal CT scans were selected; 60 had no signs of appendicitis, whereas the remaining 60 had signs of appendicitis. The 16 raters reviewed the images using the liquid crystal display (LCD) monitor of a picture archiving and communication system (PACS) workstation, as well as using an iPhone connected to the PACS workstation via a remote control system. We graded the probability of the presence of acute appendicitis for each examination using a five-point Likert scale. The overall sensitivity and specificity for the diagnosis of suspected appendicitis using the iPhone and the LCD monitor were high, and they were not significantly different (sensitivity P = 1.00, specificity P = 0.14). The average areas under the receiver operating characteristic curves for all CT readings with the iPhone and LCD monitor were 0.978 (confidence interval 0.965-0.991) and 0.974 (0.960-0.988), respectively, and the two devices did not have significantly different diagnostic performances (P = 0.55). The inter-rater agreement for both devices was very good; the kappa value for the iPhone was 0.809 (0.793-0.826), and that for the LCD monitor was 0.817 (0.801-0.834). Each rater had moderate-to-very good intra-observer agreement between the two devices. We verified the feasibility of an iPhone-based remote control system as a real-time remote CT reading tool for identifying suspected appendicitis using a 3G network and suboptimal illumination. PMID- 25700618 TI - Automatic Articular Cartilage Segmentation Based on Pattern Recognition from Knee MRI Images. AB - An automatic method for cartilage segmentation using knee MRI images is described. Three binary classifiers with integral and partial pixel features are built using the Bayesian theorem to segment the femoral cartilage, tibial cartilage and patellar cartilage separately. First, an iterative procedure based on the feedback of the number of strong edges is designed to obtain an appropriate threshold for the Canny operator and to extract the bone-cartilage interface from MRI images. Second, the different edges are identified based on certain features, which allow for different cartilage to be distinguished synchronously. The cartilage is segmented preliminarily with minimum error Bayesian classifiers that have been previously trained. According to the cartilage edge and its anatomic location, the speed of segmentation is improved. Finally, morphological operations are used to improve the primary segmentation results. The cartilage edge is smooth in the automatic segmentation results and shows good consistency with manual segmentation results. The mean Dice similarity coefficient is 0.761. PMID- 25700619 TI - D-dimer for the diagnosis of upper extremity deep and superficial venous thrombosis. AB - BACKGROUND: D-dimer role is well established in the diagnostic work-up for lower limb deep vein thrombosis (DVT), however it has not been formally tested for clinically suspected upper extremity DVT and/or superficial vein thrombosis (SVT). AIM: To ascertain D-dimer diagnostic accuracy for upper extremity DVT and/or SVT. STUDY DESIGN: We performed a single centre management study in outpatients referred by emergency or primary care physicians for clinically suspected upper extremity DVT. All patients underwent D-dimer testing (cut-off value: <=500 ng/mL), and a B-mode and color Doppler ultrasonography examination. In case of either technical problems or anatomical barriers, ultrasonography was repeated after 5-7 days. All patients were followed up for three months for the occurrence of symptomatic DVT and/or SVT and/or pulmonary embolism. RESULTS: We enrolled 239 patients (F: 63.6%; mean+/-SD age: 58.3+/-16.8). At the initial diagnostic work-up, DVT was detected in 24 (10%) patients while SVT in 35 (14.6%) patients. During follow-up, one upper extremity DVT was found. D-dimer levels were higher in patients with DVT than in those without. Sensitivity and specificity of D-dimer for DVT were 92% (95%CI: 73-99%) and 60% (95%CI: 52-67%) respectively, with a negative predictive value of 98% (95%CI: 93-100%), whereas for SVT they were 77% (95%CI: 59-89%) and 60% (95%CI: 52-67%) respectively, with a negative predictive value of 93% (95%CI: 86-97%). CONCLUSIONS: D-dimer has a negative predictive value >=93% for excluding DVT in symptomatic outpatients and it can be a useful test in the diagnostic work-up of suspected upper extremity DVT. PMID- 25700620 TI - Inhibition of thiol isomerase activity diminishes endothelial activation of plasminogen, but not of protein C. AB - INTRODUCTION: Cell surface thiol isomerase enzymes, principally protein disulphide isomerase (PDI), have emerged as important regulators of platelet function and tissue factor activation via their action on allosteric disulphide bonds. Allosteric disulphides are present in other haemostasis-related proteins, and we have therefore investigated whether thiol isomerase inhibition has any influence on two endothelial activities relevant to haemostatic regulation, namely activation of protein C and activation of plasminogen, with subsequent fibrinolysis. MATERIALS AND METHODS: The study was performed using the human microvascular endothelial cell line HMEC-1. Thiol isomerase gene expression was measured by RT-PCR and activation of protein C and plasminogen by cell-based assays using chromogenic substrates S2366 and S2251, respectively. Cell mediated fibrinolysis was measured by monitoring absorbance at 405 nm following fibrin clot formation on the surface of HMEC-1 monolayers. RESULTS AND CONCLUSIONS: A variety of thiol isomerase enzymes, including PDI, were expressed by HMEC-1 cells and thiol reductase activity detectable on the cell surface was inhibited by both RL90 anti-PDI antibody and by the PDI inhibitor quercetin-3-rutinoside (rutin). In cell-based assays, activation of plasminogen, but not of protein C, was inhibited by RL90 antibody and, to a lesser extent, by rutin. Fibrin clot lysis occurring on a HMEC-1 monolayer was also significantly slowed by RL90 antibody and by rutin, but RL90-mediated inhibition was abolished in the presence of exogenous tissue plasminogen activator (tPA). We conclude that thiol isomerases, including PDI, are involved in fibrinolytic regulation at the endothelial surface, although not via a direct action on tPA. These findings broaden understanding of haemostatic regulation by PDI, and may aid in development of novel anti-thrombotic therapeutic strategies targeted via the fibrinolysis system. PMID- 25700621 TI - Clinical safety, tolerability, pharmacokinetics and pharmacodynamics of the novel factor Xa inhibitor DY-807f in healthy volunteers. AB - INTRODUCTION: Since Vitamin K antagonists are associated with various limitations such as narrow therapeutic window, slow onset and offset of effect, and numerous interactions with food and drugs, new oral anticoagulants targeted to inhibit thrombin or factor Xa (FXa) have been developed. DY-807f is a highly selective, reversible and orally bioavailable FXa inhibitor. OBJECTIVES: This article describes a first-in-human study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of single ascending oral doses of the novel direct FXa inhibitor DY-807f in healthy males. METHODS: a placebo-controlled, single-blinded, randomized, single ascending dose study with 84 subjects (10, 30, 60, 120, 240, and 360 mg). Effects of food and formulation (tablet vs solution) on bioavailability of 60 mg were also assessed as a crossover design. RESULTS: DY 807f doses were safe and well-tolerated with no dose-dependent increase in adverse events up to 360 mg. Pharmacokinetics profiles were consistent across doses with rapid absorption, biphasic elimination, and terminal elimination half life of 10.5 to 12.4 hours. Coagulation parameters (Activated Partial Thromboplastin Time (aPTT) and Prothrombin Time (PT)) were linearly correlated with plasma DY-807 (free base of DY-807f) concentrations (correlation coefficient: 0.786 for aPTT, 0.945 for PT). CONCLUSIONS: Single doses of DY-807f are safe and well-tolerated up to 360 mg with predictable pharmacokinetic and pharmacodynamic profiles. PMID- 25700622 TI - Serotonin Transporter Gene 5-HTTLPR Polymorphism as a Protective Factor Against the Progression of Post-Stroke Depression. AB - Polymorphisms in the 5-HTT and BDNF genes are shown to affect their function at the molecular and serum level. Prior work has tried to correlate the polymorphisms with post-stroke depression (PSD), the results nevertheless remain indefinitive. A plausible reason accounting for the uncertainty relates to the small sample of each published trial. In this study, we have performed a comprehensive meta-analysis in order to evaluate the effects of 5-HTT and BDNF polymorphisms (5-HTTLPR, STin2 VNTR, 5-HTR2a 102 T/C, Val66Met) on genetic risk of PSD. Human case-control trials were identified by computer-assisted and manual searches. The article search was performed until October 2014. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using the fixed effects meta analysis to measure the effects 5-HTT and BDNF polymorphisms exerted on PSD. We also performed test of heterogeneity, test of publication bias, and sensitivity analysis to examine the reliability and stability of combined effects. 5-HTTLPR was clearly associated with genetic risk of PSD. The association seemed to be more pronounced in the homozygous model (OR = 0.34, 95% CI = 0.23-0.51, P(Q-test) = 0.63). Both the heterozygous model and the recessive model showed 50% decreased risk of PSD (OR = 0.50, 95% CI = 0.37-0.67, P(Q-test) = 0.91; OR = 0.50, 95% CI = 0.36-0.70, P(Q-test) = 0.43, respectively). Such significant association was also detected for Caucasian and Asian. These results were reliable and stable based on related analyses. Taken together, 5-HTTLPR polymorphism of the 5-HTT gene seems to protect against the occurrence of PSD. Small sample size for the polymorphisms within 5-HTT and BDNF genes may have caused underestimated associations, and a larger study is required to further assess the relations. PMID- 25700623 TI - Safety and pharmacodynamics of suprachoroidal injection of triamcinolone acetonide as a controlled ocular drug release model. AB - Suprachoroidal injection is an emerging technique for drug delivery to the posterior segment, which is hard to reach by non-invasive approaches. However, the injection technique varies and the associated ocular safety is not well understood. In addition, it is not clear if drug formulation is a major factor in optimizing pharmacodynamics using this technique. The current study was designed to compare the suprachoroidal injection of different drug formulations and to characterize the safety and pharmacodynamics of triamcinolone acetonide (TA) delivered by this technique. Both indocyanine green (ICG) solution and TA suspension, at 50MUL, 100MUL, and 150MUL, were suprachoroidally injected and intraocular pressure (IOP) tonometry, fundus photography, and electroretinography were performed over multiple time points up to eight weeks. After 50MUL TA (Kenalog-40) suprachoroidal injection, 4-5 animals at 7 time points were sacrificed for aqueous, vitreous, retina, and plasma collections. TA was quantitated using ultra-performance liquid chromatography tandem mass spectrometry. For comparative efficacy study, 50MUL (2mg) suprachoroidal TA versus 20mg subtenon TA were performed 4weeks before induction of experimental uveitis with 10ng of intravitreal lipopolysaccharide. After suprachoroidal injection, IOP had an acute elevation, higher volume caused higher IOP (p<0.0001). Equivalent volume of ICG solution led to a significantly smaller IOP elevation than after TA suprachoroidal injection. This finding suggests better distribution of ICG solution than TA suspension in the suprachoroidal space. Following a 50MUL suprachoroidal injection, peak TA concentration in the aqueous was below 1ng/mL. In contrast, the posterior vitreous and retina had 1912ng/mL and 400,369ng/mL TA, respectively. Maximum TA in plasma was 11.6ng/mL. Drug exposure to the posterior retina was 523,910 times more than that to the aqueous and 29,516 times more than systemic TA exposure. In the treatment of lipopolysaccharide-induced uveitis, compared with 20mg subtenon injection, suprachoroidal 2mg TA demonstrated much better efficacy with significantly less aqueous humor cells and lower vitreous opacity scores (p<0.05). Histology showed much less vitreous inflammation in the suprachoroidal injection group (p<0.0001). It seems that a 50MUL suprachoroidal injection of TA was well tolerated in rabbit eyes and demonstrated excellent penetration into the posterior retina, providing better therapeutic effect than subtenon 20mg TA. PMID- 25700624 TI - Impact of clinical characteristics and management on the prognosis of unselected heart failure patients. AB - PURPOSE: Heart failure (HF) is a major public health issue. This study conducted a real-life analysis of the impact of clinical characteristics and medical management of HF on its prognosis. METHODS: Analysis was based on the EGB ("Echantillon Generaliste des Beneficiaires") database. A cohort comprising 1825 adult patients with a first admission for HF between 2009 and 2011 was created and followed until June 2013 (median 22.3 [7.7-34.5] months) for survival analysis. RESULTS: Mean age was 77.3 +/- 13.2 years (53 % >=80 years). The overall incidence of HF admission was 117 [112-122] per 100,000 population with a marked increase in patients >80 years (1297 [1217-1348]). At discharge, only 8 % of patients received recommended combination of angiotensin converting enzyme inhibitors/angiotensin receptor blockers (ACEi/ARB), beta-blockers (BB) and mineralocorticoid receptor antagonists (MRA). Only prescription levels of BB and vitamin K antagonists, at discharge, increased during the study period. In hospital mortality was 9 % and survival was 71.6 %[69.5-73.6] and 52.0 %[49.4 54.6] at 12 and 36 months, respectively. In multivariate analysis, female gender [HR:0.78 (0.67-0.91), p = 0.001], ACEi/ARB + BB + MRA [0.41 (0.28-0.60), p < 0.001] and ACEi/ARB + BB [0.47 (0.39-0.57) p < 0.001] treatments were associated with improved survival, conversely to age 70-79 [1.90 (1.20-3.00), p = 0.003] and >=80 [3.50 (2.30-5.40), p < 0.001], cardiogenic shock [3.00 (2.10-4.40), p < 0.001], acute pulmonary edema [1.70 (1.10-2.50), p = 0.01], denutrition [1.80 (1.45-2.24), p < 0.001], dilated cardiomyopathy [1.20 (1.00-1.40), p = 0.02] and in-hospital acute renal failure [1.36 (1.05-1.78), p = 0.002]. CONCLUSIONS: These real-life HF data provide insight into prognostic factors and "real-world" pharmacological management in this unselected HF population, confirming the benefit of ACEi/ARB + BB +/- MRAs on patient survival. PMID- 25700625 TI - Body mass index, waist circumference, hip circumference, waist-hip-ratio and waist-height-ratio: which is the better discriminator of prevalent screen detected diabetes in a Cameroonian population? AB - BACKGROUND: The link between measures of adiposity and prevalent screen-detected diabetes (SDM) in Africa has been less well investigated. We assessed and compared the strength of association and discriminatory capability of measures of adiposity including body mass index (BMI), waist circumference (WC), hip circumference (HC), waist-hip-ratio (WHR) and waist-height-ratio (WHtR) for prevalent SDM risk in a sub-Saharan African population. METHODS: Participants were 8663 adults free of diagnosed type 2 diabetes, who took part in the nationally representative Cameroon Burden of Diabetes (CAMBoD) 2006 survey. Logistic regression models were used to compute the odd ratio (OR) and 95% confidence interval (95%CI) for a standard deviation (SD) higher level of BMI (7.3), WC (12.5), HC (11.7), WHR (0.19) and WHtR (0.08) with prevalent SDM risk. Assessment and comparison of discrimination used C-statistic and relative integrated discrimination improvement (RIDI, %). RESULTS: The adjusted OR and 95%CI for prevalent SDM with each SD higher adipometric variable were: 1.05 (0.98 1.13) for BMI, 1.30 (1.16-1.46) for WC, 1.18 (1.05-1.34) for HC, 1.05 (1.00-1.16) for WHR and 1.26 (1.11-1.39) for WHtR. C-statistic comparisons and RIDI analyses showed a trend toward a significant superiority of WC over other adipometric variables in multivariable models. Combining adiposity variables did not improve discrimination beyond multivariable models with WC alone. CONCLUSION: WC was the best predictors and to some extent WHtR of prevalent SDM in this population, while BMI and WHR were less effective. PMID- 25700626 TI - Vitamin D and diabetes: Where do we stand? AB - The potential beneficial effects of supplementing vitamin D or treatment with pharmacological doses of vitamin D in the prevention or cure of diseases like type 1 (T1D) or type 2 diabetes (T2D) remains the subject of debate. Data from epidemiological and association studies clearly indicate a correlation between vitamin D deficiency and a higher prevalence of both forms of diabetes. In animal models, vitamin D deficiency predisposes to type 1 and type 2 diabetes, whereas high doses of vitamin D or its active hormonal form, 1,25-dihydroxyvitamin D, prevent disease. Large scale, randomized, blinded prospective studies however, remain lacking. Here we discuss the current literature on a role for vitamin D in diabetes. We propose, in particular, to avoid vitamin D deficiency in individuals at risk of developing T1D or T2D. Applying international guidelines on supplementation of vitamin D using small daily doses of vitamin D (500-1000IU) may contribute to reduce the burden of diabetes by preventing vitamin D deficiency. Any other recommendations are at present not supported by data. PMID- 25700627 TI - Targeted metabolomic analysis reveals the association between the postprandial change in palmitic acid, branched-chain amino acids and insulin resistance in young obese subjects. AB - Obesity is the result of a positive energy balance and often leads to difficulties in maintaining normal postprandial metabolism. The changes in postprandial metabolites after an oral glucose tolerance test (OGTT) in young obese Chinese men are unclear. In this work, the aim is to investigate the complex metabolic alterations in obesity provoked by an OGTT using targeted metabolomics. We used gas chromatography-mass spectrometry and ultra high performance liquid chromatography-triple quadrupole mass spectrometry to analyze serum fatty acids, amino acids and biogenic amines profiles from 15 control and 15 obese subjects at 0, 30, 60, 90 and 120 min during an OGTT. Metabolite profiles from 30 obese subjects as independent samples were detected in order to validate the change of metabolites. There were the decreased levels of fatty acid, amino acids and biogenic amines after OGTT in obesity. At 120 min, percent change of 20 metabolites in obesity has statistical significance when comparing with the controls. The obese parameters was positively associated with changes in arginine and histidine (P<0.05) and the postprandial change in palmitic acid (PA), branched-chain amino acids (BCAAs) and phenylalanine between 1 and 120 min were positively associated with fasting insulin and HOMA-IR (all P<0.05) in the obese group. The postprandial metabolite of PA and BCAAs may play important role in the development and onset of insulin resistance in obesity. Our findings offer new insights in the complex physiological regulation of the metabolism during an OGTT in obesity. PMID- 25700628 TI - Polymorphisms in the interleukin-10 gene and chronic periodontitis in patients with atherosclerotic and aortic aneurysmal vascular diseases. AB - BACKGROUND: Chronic periodontitis (CP), atherosclerotic and aortic aneurysmal vascular diseases (VD) are chronic inflammatory conditions with multifactorial etiologies, including involvement of predisposing genetic factors. In a previous study, polymorphisms in the gene for the anti-inflammatory interleukin-1 receptor antagonist were associated with CP in patients with VD. OBJECTIVE: This study investigates whether polymorphisms in the gene for the anti-inflammatory interleukin-10 (IL10) could be related to CP in the same manner. METHODS: Seventy two patients with VD of whom 35 had CP were genotyped for single nucleotide polymorphisms (SNPs) in the IL10 -592 (rs1800872), -819 (rs1800871), and -1,082 (rs1800896) gene by Taqman rtPCR method and by DNA sequencing. RESULTS: The C alleles and C/C genotypes of IL10 -592 and IL10 -819 frequencies were significantly higher, while the frequencies of the IL10 -592 (C/A) and IL10 -819 (C/T) heterozygote genotypes were significantly lower in the VD group with CP compared to those without CP. The IL10 haplotype ATA frequency (-1,082, -819, 592) showed a trend to a significant difference between the two groups indicating protection against CP. CONCLUSIONS: Taken together, our findings suggest an independent association of genetic polymorphisms in the IL-10 gene locus with CP in patients with VD. Development of CP and the implications on vascular disease emphasize the importance of early detection and adequate treatment of periodontitis among these patients. PMID- 25700629 TI - Association of fathers' feeding practices and feeding style on preschool age children's diet quality, eating behavior and body mass index. AB - The associations of parental feeding practices and feeding style with childhood obesity have gained more attention in the literature recently; however, fathers are rarely included within these studies. The aim of this research was to determine the relationship of paternal feeding practices on child diet quality, weight status, and eating behavior, and the moderating effect of paternal feeding style on these relationships in preschool age children. This study included a one time, one-on-one interview with biological fathers of preschoolers (n = 150) to assess feeding practices (Child Feeding Questionnaire), feeding style (Caregiver Feeding Style Questionnaire), child eating behaviors (Child Eating Behavior Questionnaire), and diet quality (24 hour recall, Healthy Eating Index). Height and weight for each father and child were also measured and Body Mass Index (BMI) or BMI z-score calculated. Linear regression was used to test the relationship between paternal feeding practices, style and child diet quality and/or body weight. Overall, the findings revealed that a father's feeding practices and feeding style are not associated with children's diet quality or weight status. However, child eating behaviors are associated with child BMI z-score and these relationships are moderated by paternal feeding practices. For example, child satiety responsiveness is inversely (beta = -.421, p = 0.031) associated with child BMI z-score only if paternal restriction scores are high. This relationship is not significant when paternal restriction scores are low (beta = -.200, p = 0.448). These results suggest that some child appetitive traits may be related to child weight status when exposed to certain paternal feeding practices. Future studies should consider the inclusion of fathers as their feeding practices and feeding style may be related to a child's eating behavior. PMID- 25700630 TI - Appetite and gut hormone responses to moderate-intensity continuous exercise versus high-intensity interval exercise, in normoxic and hypoxic conditions. AB - This study investigated the effects of continuous moderate-intensity exercise (MIE) and high-intensity interval exercise (HIIE) in combination with short exposure to hypoxia on appetite and plasma concentrations of acylated ghrelin, peptide YY (PYY), and glucagon-like peptide-1 (GLP-1). Twelve healthy males completed four, 2.6 h trials in a random order: (1) MIE-normoxia, (2) MIE hypoxia, (3) HIIE-normoxia, and (4) HIIE-hypoxia. Exercise took place in an environmental chamber. During MIE, participants ran for 50 min at 70% of altitude specific maximal oxygen uptake (VO2max) and during HIIE performed 6 * 3 min running at 90% VO2max interspersed with 6 * 3 min active recovery at 50% VO2max with a 7 min warm-up and cool-down at 70% VO2max (50 min total). In hypoxic trials, exercise was performed at a simulated altitude of 2980 m (14.5% O2). Exercise was completed after a standardised breakfast. A second meal standardised to 30% of participants' daily energy requirements was provided 45 min after exercise. Appetite was suppressed more in hypoxia than normoxia during exercise, post-exercise, and for the full 2.6 h trial period (linear mixed modelling, p <0.05). Plasma acylated ghrelin concentrations were lower in hypoxia than normoxia post-exercise and for the full 2.6 h trial period (p <0.05). PYY concentrations were higher in HIIE than MIE under hypoxic conditions during exercise (p = 0.042). No differences in GLP-1 were observed between conditions (p > 0.05). These findings demonstrate that short exposure to hypoxia causes suppressions in appetite and plasma acylated ghrelin concentrations. Furthermore, appetite responses to exercise do not appear to be influenced by exercise modality. PMID- 25700631 TI - Genomic diversity of Clostridium difficile strains. AB - Approaches to exploring Clostridium difficile genomic diversity have ranged from molecular typing methods to use of comparative genome microarrays and whole genome sequence comparisons. The C. difficile population structure is clonal and distributed into six clades, which correlate well with MLST STs (multilocus sequence types) and PCR ribotypes. However, toxigenic strains and strains with increased virulence are distributed throughout several clades. Here we summarize studies on C. difficile genomic diversity, with emphasis on phylogenetic aspects, epidemiological aspect and variability of some virulence factors. PMID- 25700632 TI - Nitric oxide metabolism and indole acetic acid biosynthesis cross-talk in Azospirillum brasilense SM. AB - Production of nitric oxide (NO) and the presence of NO metabolism genes, nitrous oxide reductase (nosZ), nitrous oxide reductase regulator (nosR) and nitric oxide reductase (norB) were identified in the plant-associated bacterium (PAB) Azospirillum brasilense SM. NO presence was confirmed in all overexpressing strains, while improvement in the plant growth response of these strains was mediated by increased NO and indole-3-acetic acid (IAA) levels in the strains. Electron microscopy showed random distribution to biofilm, with surface colonization of pleiomorphic Azospirilla. Quantitative IAA estimation highlighted a crucial role of nosR and norBC in regulating IAA biosynthesis. The NO quencher and donor reduced/blocked IAA biosynthesis by all strains, indicating their common regulatory role in IAA biosynthesis. Tryptophan (Trp) and l-Arginine (Arg) showed higher expression of NO genes tested, while in the case of ipdC, only Trp and IAA increased expression, while Arg had no significant effect. The highest nosR expression in SMnosR in the presence of IAA and Trp, along with its 2-fold IAA level, confirmed the relationship of nosR overexpression with Trp in increasing IAA. These results indicate a strong correlation between IAA and NO in A. brasilense SM and suggest the existence of cross-talk or shared signaling mechanisms in these two growth regulators. PMID- 25700633 TI - Italian Registry of Cardiac Computed Tomography. AB - PURPOSE: Cardiac CT (CCT) is an imaging modality that is becoming a standard in clinical cardiology. We evaluated indications, safety, and impact on patient management of routine CCT in a multicenter national registry. MATERIALS AND METHODS: During a period of 6 months, 47 centers in Italy enrolled 3,455 patients. RESULTS: CCT was performed mainly with 64-slice CT scanners (73.02 %). Contrast agents were administrated in 3,185 patients (92.5 %). Mean DLP changes with type of scanner and was lower in >64 row detector scanner. The most frequent indication for CCT was suspected CAD (44.8 %), followed by calcium scoring (9.6 %), post-angioplasty/stenting (8.3 %), post-CABGs (7.5 %), study of cardiac anatomy (4.22 %) and assessment in patients with known CAD (4.1 %) and acute chest pain (1.99 %). Most of the CCTs were performed in outpatient settings (2,549; 74 %) and a minority in inpatient settings (719, 20.8 %). Adverse clinical events (mild-moderate) occurred in 26 examinations (0.75 %). None of them was severe. In 45.3 % of the cases CCT findings impacted patient management. CONCLUSION: CCT is performed with different workloads in participating centers. It is a safe procedure and its results have a strong impact on patient management. PMID- 25700634 TI - Does the Incremental Shuttle Walking Test require maximal effort in healthy subjects of different ages? AB - OBJECTIVE: To evaluate if the Incremental Shuttle Walking Test (ISWT) requires maximal effort in healthy subjects of different ages. DESIGN: Cross-sectional. SETTING: University-based research laboratory. PARTICIPANTS: 331 healthy subjects separated into six groups according to age: G1, 18 to 28 years; G2, 29 to 39 years; G3, 40 to 50 years; G4, 51 to 61 years; G5, 62 to 72 years and; G6, 73 to 83 years. MAIN OUTCOME MEASURES: Two ISWTs were performed and participants were permitted to run and to exceed 12 levels during the test, if necessary. Heart rate (HR) and symptoms of dyspnoea and fatigue were recorded before and after the test, and the percentage of age-predicted maximal HR (HRmax) was calculated. Maximal effort was defined as HRmax >90% of age-predicted HRmax. RESULTS: Almost 31% of the subjects exceeded 12 levels in the ISWT. At the end of the test, all groups presented a median [interquartile range] HR greater than 90% of HRmax (G1: 100 [95 to 104]; G2: 100 [96 to 105]; G3: 103 [97 to 108]; G4: 99 [91 to 106]; G5: 96 [87 to 106] and G6: 96 [91 to 109]% HRmax). Regarding symptoms, all groups showed higher values after the test (P<0.05). A multiple logistic regression analysis identified female gender, older age and a lower HR before the test as determinants of not achieving 90% of HRmax at the end of the test. CONCLUSIONS: The ISWT requires maximal effort in healthy individuals, but for that it is necessary to extend the test beyond twelve levels. Female gender, older age and lower heart rate before the test are the determinants of not reaching maximal effort. PMID- 25700635 TI - Prevalence and impact of urinary incontinence in men with cystic fibrosis. AB - OBJECTIVES: To determine the prevalence and impact of urinary incontinence (UI) in men with cystic fibrosis (CF). DESIGN: Prospective observational study. SETTING: Adult CF clinics at tertiary referral centres. PARTICIPANTS: Men with CF (n=80) and age-matched men without lung disease (n=80). INTERVENTIONS: Validated questionnaires to identify the prevalence and impact of UI. MAIN OUTCOME MEASURES: Prevalence of UI and relationship to disease specific factors, relationship of UI with anxiety and depression. RESULTS: The prevalence of UI was higher in men with CF (15%) compared to controls (10%) (p=0.339). Men with CF and UI had higher scores for anxiety than those without UI (mean 9.1 (SD 4.8) vs 4.7 (4.1), p=0.003), with similar findings for depression (6.8 (4.6) vs 2.8 (3.4), p=0.002) using the Hospital Anxiety and Depression Scale. CONCLUSIONS: Incontinence is more prevalent in adult men with CF than age matched controls, and may have an adverse effect on mental health. The mechanisms involved are still unclear and may differ from those reported in women. PMID- 25700636 TI - Identification of the Elusive Chloroplast Ascorbate Transporter Extends the Substrate Specificity of the PHT Family. PMID- 25700637 TI - Dioxygen and nitric oxide scavenging by Treponema denticola flavodiiron protein: a mechanistic paradigm for catalysis. AB - Flavodiiron proteins (FDPs) contain a unique active site consisting of a non-heme diiron carboxylate site proximal to a flavin mononucleotide (FMN). FDPs serve as the terminal components for reductive scavenging of dioxygen (to water) or nitric oxide (to nitrous oxide), which combats oxidative or nitrosative stress in many bacteria. Characterizations of FDPs from spirochetes or from any oral microbes have not been previously reported. Here, we report characterization of an FDP from the anaerobic spirochete, Treponema (T.) denticola, which is associated with chronic periodontitis. The isolated T. denticola FDP exhibited efficient four electron dioxygen reductase activity and lower but significant anaerobic nitric oxide reductase activity. A mutant T. denticola strain containing the inactivated FDP-encoding gene was significantly more air-sensitive than the wild-type strain. Single turnover reactions of the four-electron-reduced FDP (FMNH2-Fe(II)Fe(II)) (FDPred) with O2 monitored on the milliseconds to seconds time scale indicated initial rapid formation of a spectral feature consistent with a cis-MU-1,2-peroxo diferric intermediate, which triggered two-electron oxidation of FMNH2. Reaction of FDPred with NO showed apparent cooperativity between binding of the first and second NO to the diferrous site. The resulting diferrous dinitrosyl complex triggered two-electron oxidation of the FMNH2. Our cumulative results on this and other FDPs indicate that smooth two-electron FMNH2 oxidation triggered by the FDPred/substrate complex and overall four-electron oxidation of FDPred to FDPox constitutes a mechanistic paradigm for both dioxygen and nitric oxide reductase activities of FDPs. Four-electron reductive O2 scavenging by FDPs could contribute to oxidative stress protection in many other oral bacteria. PMID- 25700639 TI - USP8 and PARK2/parkin-mediated mitophagy. AB - The Parkinson disease (PD)-associated E3-ubiquitin (Ub) ligase PARK2/parkin plays a central role in many stress response pathways, and in particular, in mitochondrial quality control. Within this pathway, PARK2 activation is accompanied by a robust increase in its autoubiquitination, followed by clearance of the damaged mitochondria by selective autophagy (mitophagy). Yet, little is known about how this auto-ubiquitination is regulated during mitophagy. In our study, we demonstrate that PARK2 forms predominantly K6-linked Ub conjugates on itself. Moreover, PARK2 interacts with the deubiquitinating enzyme USP8 that preferentially removes these K6-linked conjugates, thereby regulating the activity and function of PARK2 in the pathway. When USP8 is silenced, a persistence of K6-linked Ub conjugates on PARK2 delays both its translocation to damaged mitochondria and successful completion of mitophagy. Taken together, these findings implicate a novel role for K6-linked Ub conjugates and USP8 mediated deubiquitination in the regulation of PARK2 in mitochondrial quality control. PMID- 25700638 TI - Effect of proton-pump inhibitors on the risk of lower gastrointestinal bleeding associated with NSAIDs, aspirin, clopidogrel, and warfarin. AB - BACKGROUND: We investigated the effects of proton-pump inhibitors (PPIs) on lower gastrointestinal bleeding (LGIB) and of their interactions with nonsteroidal anti inflammatory drugs (NSAIDs), low-dose aspirin, clopidogrel, and warfarin on LGIB risk. METHODS: We prospectively studied 355 patients emergently hospitalized for LGIB and 8,221 nonbleeding patients. All patients underwent colonoscopy. Smoking, alcohol drinking, drug exposure, and the Charlson comorbidity index score were assessed before colonoscopy. Adjusted odds ratios (AOR) of LGIB were estimated. RESULTS: LGIB was significantly associated with older age, higher comorbidity index, and NSAID, aspirin, clopidogrel, or warfarin use. PPI use was significantly associated with older age, male sex, being a current alcohol drinker, higher comorbidity index, and NSAID, aspirin, clopidogrel, warfarin, acetaminophen, or corticosteroid use. Multivariate analysis adjusted by the confounding factors revealed LGIB was not significantly associated with PPI use (AOR 0.87; 95 % confidence interval 0.68-1.13; p = 0.311), or specifically with omeprazole (AOR 1.18; p = 0.408), esomeprazole (AOR 0.76; p = 0.432), lansoprazole (AOR 0.93; p = 0.669), or rabeprazole (AOR 0.63; p = 0.140). In the interaction model, no significant interactions were observed between PPIs and NSAIDs (AOR 1.40; p = 0.293), aspirin (AOR 1.09; p = 0.767), clopidogrel (AOR 0.99, p = 0.985), or warfarin (AOR 1.52; p = 0.398). CONCLUSIONS: This large case control study demonstrated that PPI use did not lead to an increased risk of LGIB, regardless of the type of PPI used. Further, LGIB risk was not affected by PPI use, irrespective of concomitant therapy with NSAIDs, low-dose aspirin, clopidogrel, or warfarin. PMID- 25700640 TI - Low rate of Propionibacterium acnes in arthritic shoulders undergoing primary total shoulder replacement surgery using a strict specimen collection technique. AB - BACKGROUND: Propionibacterium acnes is a recognized pathogen in postoperative shoulder infections. A recent study reported growth of P acnes in 42% of glenohumeral joints in primary shoulder arthroplasty, concluding that P acnes may cause shoulder osteoarthritis. Whether these results reflect true bacterial infection or specimen contamination is unclear. Our prospective study aimed to determine the rate of P acnes infection in arthritic shoulders using a strict specimen collection technique. METHODS: We used modified Oxford protocol to collect tissue specimens from the glenohumeral joint of 32 consecutive patients undergoing primary shoulder arthroplasty. Specimens were cultured specifically for P acnes. Diagnosis of P acnes infection required 2 or more positive cultures and histopathology compatible with infection. RESULTS: Three of 32 patients had a positive culture for P acnes. Overall, 3.125% of specimens grew P acnes without histologic evidence of infection. There were no patients with P acnes infection. The difference in culture rates between patients with idiopathic osteoarthritis and those with a predisposing cause for osteoarthritis was not significant. CONCLUSIONS: We found a low rate of positive cultures for P acnes, but no P acnes infection and no difference between types of osteoarthritis. These results do not support a cause-and-effect relationship between P acnes and osteoarthritis. The differing results from previous studies are likely explained by our strict specimen collection technique, reflecting different rates of contamination rather than infection. That P acnes contamination occurs in primary shoulder arthroplasty is concerning. Further studies are needed to assess the rates of contamination in shoulder surgery, its clinical effect, and to determine optimal antibiotic prophylaxis. PMID- 25700641 TI - The anterior transfer of the latissimus dorsi tendon--a difficult position to specify. PMID- 25700643 TI - Animal evolution: early emerging animals matter. PMID- 25700642 TI - Inhibition of eukaryotic elongation factor-2 confers to tumor suppression by a herbal formulation Huanglian-Jiedu decoction in human hepatocellular carcinoma. AB - ETHNOPHARMACOLOGICAL RELEVANCE: An oriental medicinal formulation, Huanglian Jiedu Decoction (HLJDD), has been well documented in few Traditional Chinese Medicine Classics 1300 years ago for treatment of heat and dampness-related diseases. Its effect is well accepted in Asian community, including China, Japan and Korea. Recent studies have postulated HLJDD as a regimen for cancer treatment, especially liver cancer, but the underlying mechanism is unknown. The aim of this study was to examine the suppressive effect of HLJDD on the growth of hepatocellular carcinoma (HCC) and its possible underlying mechanism. METHODS: Chemical composition of HLJDD was analyzed by high performance liquid chromatography. The tumor suppressive effect of HLJDD was determined on both HCC cells and xenograft model. Nascent protein synthesis was detected with Click-IT protein labeling technology; protein expression was determined by immunoblotting and imunnohistochemical analysis. RESULTS: Quality analysis revealed that HLJDD of different batches is consistent in both chemical composition and bioactivities. HLJDD inhibited HCC cell proliferation at its non-toxic doses, and suppressed growth and angiogenesis in xenografted murine model. HLJDD suppressed the synthesis of nascent protein via inactivation of eEF2 without deregulating the translation initiation factors. The major components in HLJDD, geniposide, berberine and baicalin, additively act on eEF2, and contributed to the responsible activity. HLJDD-activated eEF2 kinase (eEF2K) led to eEF2 inactivation, and activation of AMPK signaling may be responsible for the eEF2K induction. Blocked AMPK activity in HLJDD-treated HCC cells attenuated eEF2K activation as well as the inhibitory effect of the formula. In nutrient deprived HCC cells with inactivated eEF2, the inhibitory effect of HLJDD in tumor cell expansion was interfered. CONCLUSION: Our results indicate that HLJDD has potential in blocking HCC progression with involvement of eEF2 inhibition. PMID- 25700644 TI - Effects of Artemisia annua extracts on sporulation of Eimeria oocysts. AB - The present study aimed to compare the effect of different Artemisia annua extracts on sporulation rate of mixed oocysts of Eimeria acervulina, Eimeria necatrix, and Eimeria tenella. Three types of A. annua extracts including petroleum ether (PE), ethanol 96 degrees (E), and water (W) extracts were prepared. Artemisinin, a sesquiterpene lactone endoperoxide derived from the A. annua analysis of each extract was done by high-performance liquid chromatography with ultraviolet detection (HPLC-UV). Fresh fecal samples containing three Eimeria species were floated and counted, and the oocysts were transferred into 50 tubes, each containing 10(5) oocysts per milliliter. Five tubes were control. Each of the other 45 tubes contained one of three doses (1 part per thousand (ppt), 2 ppt, and 5 ppt) and one of three extracts (PE, E, and W extracts) with five replications. The tubes were incubated for 48 h at 25-29 degrees C and aerated. Sporulation inhibition assay was used to evaluate the activity of extracts. The results showed that the E and PE extracts inhibit sporulation in 2 and 5 ppt concentrations, but the W extract stimulates it in all concentrations. The proportions of oocyst inhibition relative to control were 31 % (5 ppt) and 29 % (2 ppt) for PE and 34 % (5 ppt) and 46 % (2 ppt) for E extract. Furthermore, many oocysts in PE and E groups were wrinkled and contained abnormal sporocysts. The proportions of sporulation stimulation relative to control were 22 % (5 ppt), 24 % (2 ppt), and 27 % (1 ppt) in W extract. Our study is the first to demonstrate that all types of A. annua extracts do not necessarily have a similar activity, and the interaction of all contents and their relative concentrations is an important factor for sporulation stimulation or inhibition. It seems, some parts of unmetabolized excreted PE and E extracts could inhibit oocyst sporulation and eventually affect infection transmission. PMID- 25700645 TI - Antihypertensive drugs, prevention of cognitive decline and dementia: a systematic review of observational studies, randomized controlled trials and meta analyses, with discussion of potential mechanisms. AB - BACKGROUND: Chronic hypertension, particularly midlife high blood pressure, has been associated with an increased risk for cognitive decline and dementia. In this context, antihypertensive drugs might have a preventive effect, but the association remains poorly understood. OBJECTIVES: The aim of this systematic review was to examine all published findings that investigated this relationship and discuss the mechanisms underlying the potential benefits of antihypertensive medication use. METHODS: A literature search was conducted using MEDLINE, Embase, and the Cochrane Library for publications from 1990 onwards mentioning hypertension, antihypertensive drugs, cognitive decline, and dementia. RESULTS: A total of 38 relevant publications, corresponding to 18 longitudinal studies, 11 randomized controlled trials, and nine meta-analyses were identified from the 10,251 articles retrieved in the literature search. In total, 1,346,176 subjects were included in these studies; the average age was 74 years. In the seven longitudinal studies assessing the effect of antihypertensive medication on cognitive impairment or cognitive decline, antihypertensive drugs appeared to be beneficial. Of the 11 longitudinal studies that assessed the effect of antihypertensive medication on incidence of dementia, only three did not find a significant protective effect. Antihypertensive medication could decrease the risk of not only vascular dementia but also Alzheimer's disease. Four randomized controlled trials showed a potentially preventive effect of antihypertensive drugs on the incidence of dementia or cognitive decline: SYST-EUR (Systolic Hypertension in Europe Study) I and II, with a 55% reduction in dementia risk (3.3 vs. 7.4 cases per 1,000 patient years; p<0.001); HOPE (Heart Outcomes Prevention Evaluation), with a 41% reduction in cognitive decline associated with stroke (95% confidence interval [CI] 6-63); and PROGRESS (Perindopril Protection against Recurrent Stroke Study), with a 19% reduction in cognitive decline (95% CI 4-32; p=0.01). Meta-analyses have sometimes produced conflicting results, but this may be due to methodological considerations. The lack of homogeneity across study designs, patient populations, exposition, outcomes, and duration of follow up are the most important methodological limitations that might explain the discrepancies between some of these studies. CONCLUSION: Antihypertensive drugs, particularly calcium channel blockers and renin-angiotensin system blockers, may be beneficial in preventing cognitive decline and dementia. However, further randomized controlled trials with longer periods of follow-up and cognition as the primary outcome are needed to confirm these findings. PMID- 25700646 TI - [Rare forms of hypertension : From pheochromocytoma to vasculitis]. AB - Secondary hypertension affects only 5-10 % of hypertensive patients. Screening is expensive and time-consuming and should be performed only in patients for whom there is a high clinical suspicion of secondary hypertension. Clinical signs of secondary forms of hypertension are new-onset hypertension in patients without other risk factors (i.e., family history, obesity, etc.), sudden increase of blood pressure (BP) in a previously stable patient, increased BP in prepubertal children, resistant hypertension, and severe hypertension or hypertensive emergencies. In adults, renal parenchymal and vascular diseases as well as obstructive sleep apnea are the most common causes of secondary hypertension. Medication-induced hypertension and non-adherence to medication have to be ruled out. Of the endocrine causes associated with hypertension, primary aldosteronism is the most common. Other endocrine causes of hypertension such as thyroid disease (hypo- or hyperthyroidism), hypercortisolism (Cushing's syndrome), hyperparathyroidism, and pheochromocytoma are rare. Monogenetic forms of hypertension are mostly of tubular origin and associated with alterations in mineralocorticoid handling or signaling. Rare causes of hypertension also include inflammatory vascular disease. Acute forms of vasculitis may present as "malignant" hypertension with associated thrombotic microangiopathy and organ damage/failure. It is important to diagnose these rare forms of hypertension in order to prevent acute organ damage in these patients or unnecessary invasive treatment strategies. PMID- 25700647 TI - [Myelodysplastic syndromes]. AB - Myelodysplastic syndrome (MDS) encompasses a heterogeneous group of diseases originating in hematopoietic stem cells and is characterized by inefficient hematopoiesis and dysplastic changes in the bone marrow. In peripheral blood patients show anemia (mostly macrocytic), frequently accompanied by neutropenia and thrombocytopenia. Thus, clinically the patients suffer from fatigue (anemia), increased bleeding (thrombocytopenia) and infectious complications (neutropenia). Approximately one quarter of MDS patients develop acute myeloid leukemia (AML) in the course of the disease, which is characterized by a 20 % or more increase of blasts in the bone marrow. The estimated overall survival as well as the risk for AML transformation can be calculated with the international prognostic scoring system (IPSS) as well as the revised IPSS score (IPSS-R). Novel sequencing methods (e.g. next generation sequencing) allow the detection of recurrent gene mutations in MDS patients. Genes of the splicing machinery as well as genes involved in epigenetic regulation (e.g. ASXL1 and TET2) are most frequently mutated in MDS. Therapy is selected based on the patient risk profile (IPSS). Allogeneic stem cell transplantation is a curative approach for high risk patients (i.e. IPSS int-2 and higher) with a good performance status and a biological age below 70 years. Otherwise, high risk patients are treated with demethylating agents (e.g. decitabine and azacitidine). Low risk patients (IPSS low and int-1) mainly receive supportive therapy including iron chelation. An exceptional position is presented by MDS with an isolated 5q deletion as it can be treated with lenalidomide with good success. Enrolling patients in clinical trials is strongly recommended to improve the prospects of this disease. PMID- 25700648 TI - [Modern disease-modifying antirheumatic drugs]. AB - The term modern disease-modifying antirheumatic drugs (DMARD) includes not only the constantly growing family of DMARDs for chronic inflammatory rheumatic diseases but also the repositioning of established drugs in updated and novel algorithms of the different entities. The usual precursor for these developments is rheumatoid arthritis for which completely revised and updated guidelines have been published not only in Germany but also on the European level. In addition, label extensions to existing drugs have been granted for connective tissue diseases and vasculitides, e.g. anti-CD20 antibodies for antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitides and belimumab for systemic lupus erythematosus. Moreover, several novel drugs, especially of the biologics class, have been either introduced in clinical rheumatology or are close to being licensed and include ustekinumab for psoriatic arthritis, granulocyte growth inhibitors and janus kinase inhibitors for rheumatoid arthritis and atacicept for systemic lupus erythematosus. With the termination of the patent for several biologics, a new momentum also took place: the approval of the so-called biosimilars which has already initiated intensive discussions not only with respect to "similar" effects and side effects but also with respect to their potential impact on economical aspects. PMID- 25700649 TI - [HDL and atherosclerotic cardiovascular diseases]. PMID- 25700650 TI - Pharmacological characterization of mGlu1 receptors in cerebellar granule cells reveals biased agonism. AB - The majority of existing research on the function of metabotropic glutamate (mGlu) receptor 1 focuses on G protein-mediated outcomes. However, similar to other G protein-coupled receptors (GPCR), it is becoming apparent that mGlu1 receptor signaling is multi-dimensional and does not always involve G protein activation. Previously, in transfected CHO cells, we showed that mGlu1 receptors activate a G protein-independent, beta-arrestin-dependent signal transduction mechanism and that some mGlu1 receptor ligands were incapable of stimulating this response. Here we set out to investigate the physiological relevance of these findings in a native system using primary cultures of cerebellar granule cells. We tested the ability of a panel of compounds to stimulate two mGlu1 receptor mediated outcomes: (1) protection from decreased cell viability after withdrawal of trophic support and (2) G protein-mediated phosphoinositide (PI) hydrolysis. We report that the commonly used mGlu1 receptor ligands quisqualate, DHPG, and ACPD are completely biased towards PI hydrolysis and do not induce mGlu1 receptor stimulated neuroprotection. On the other hand, endogenous compounds including glutamate, aspartate, cysteic acid, cysteine sulfinic acid, and homocysteic acid stimulate both responses. These results show that some commonly used mGlu1 receptor ligands are biased agonists, stimulating only a fraction of mGlu1 receptor-mediated responses in neurons. This emphasizes the importance of utilizing multiple agonists and assays when studying GPCR function. PMID- 25700651 TI - Predictors of human papillomavirus awareness and knowledge in 2013: gaps and opportunities for targeted communication strategies. AB - BACKGROUND: Nearly 80 million people in the U.S. are currently infected with at least one of two strains of human papillomavirus (HPV), which is associated with 70% of cervical cancers. Greater cervical cancer mortality has been observed among women of lower SES and those living in rural, versus urban, areas. African American and Hispanic women are significantly more likely to die from cervical cancer than non-Hispanic white women. PURPOSE: To assess current population awareness of and knowledge about HPV and the HPV vaccine, as well as the contribution of sociodemographic characteristics to disparities in HPV awareness and knowledge. METHODS: Cross-sectional data were obtained from the National Cancer Institute's 2013 Health Information National Trends Survey (HINTS; N=3,185). Multivariable logistic regression was employed to identify gaps in awareness and knowledge by sex, education, income, race/ethnicity, geographic area, and other important sociodemographic characteristics. Analyses were conducted in 2014. RESULTS: Sixty-eight percent of Americans had heard of HPV and the HPV vaccine. Consistent with the Knowledge Gap Hypothesis, awareness and knowledge were patterned by sex, age, education, and other important sociodemographic factors. Those in rural areas were less likely than those in urban areas to know that HPV causes cervical cancer. Less than 5% of Americans were aware that HPV often clears on its own without treatment. CONCLUSIONS: Although awareness and knowledge of HPV is increasing, there are opportunities to target communication with populations for whom knowledge gaps currently exist, in order to promote dialogue about the vaccine among patients and their providers. PMID- 25700652 TI - U.S. health professionals' views on obesity care, training, and self-efficacy. AB - BACKGROUND: Despite emphasis of recent guidelines on multidisciplinary teams for collaborative weight management, little is known about non-physician health professionals' perspectives on obesity, their weight management training, and self-efficacy for obesity care. PURPOSE: To evaluate differences in health professionals' perspectives on (1) the causes of obesity; (2) training in weight management; and (3) self-efficacy for providing obesity care. METHODS: Data were obtained from a cross-sectional Internet-based survey of 500 U.S. health professionals from nutrition, nursing, behavioral/mental health, exercise, and pharmacy (collected from January 20 through February 5, 2014). Inferences were derived using logistic regression adjusting for age and education (analyzed in 2014). RESULTS: Nearly all non-physician health professionals, regardless of specialty, cited individual-level factors, such as overconsumption of food (97%), as important causes of obesity. Nutrition professionals were significantly more likely to report high-quality training in weight management (78%) than the other professionals (nursing, 53%; behavioral/mental health, 32%; exercise, 50%; pharmacy, 47%; p<0.05). Nutrition professionals were significantly more likely to report high confidence in helping obese patients achieve clinically significant weight loss (88%) than the other professionals (nursing, 61%; behavioral/mental health, 51%; exercise, 52%; pharmacy, 61%; p<0.05), and more likely to perceive success in helping patients with obesity achieve clinically significant weight loss (nutrition, 81%; nursing, behavioral/mental health, exercise, and pharmacy, all <50%; p<0.05). CONCLUSIONS: Nursing, behavioral/mental health, exercise, and pharmacy professionals may need additional training in weight management and obesity care to effectively participate in collaborative weight management models. PMID- 25700653 TI - Medicare claims versus beneficiary self-report for influenza vaccination surveillance. AB - BACKGROUND: Although self-reported influenza vaccination status is routinely used in surveillance to estimate influenza vaccine coverage, Medicare data are becoming a promising resource for influenza surveillance to inform vaccination program management and planning. PURPOSE: To evaluate the concordance between self-reported influenza vaccination and influenza vaccination claims among Medicare beneficiaries. METHODS: This study compared influenza vaccination based upon Medicare claims and self-report among a sample of Medicare beneficiaries (N=9,378) from the 2011 Medicare Current Beneficiary Survey, which was the most recent year of data at the time of analysis (summer 2013). Sensitivity, specificity, positive predictive value, and negative predictive value were calculated using self-reported data as the referent standard. Logistic regression was used to compute the marginal mean proportions for whether a Medicare influenza vaccination claim was present among beneficiaries who reported receiving the vaccination. RESULTS: Influenza vaccination was higher for self report (69.4%) than Medicare claims (48.3%). For Medicare claims, sensitivity=67.5%, specificity=96.3%, positive predictive value=97.6%, and negative predictive value=56.7%. Among beneficiaries reporting receiving an influenza vaccination, the percentage of beneficiaries with a vaccination claim was lower for beneficiaries who were aged <65 years, male, non-Hispanic black or Hispanic, and had less than a college education. CONCLUSIONS: The classification of influenza vaccination status for Medicare beneficiaries can differ based upon survey and claims. To improve Medicare claims-based surveillance studies, further research is needed to determine the sources of discordance in self-reported and Medicare claims data, specifically for sensitivity and negative predictive value. PMID- 25700654 TI - Ensuring public health's future in a national-scale learning health system. AB - Data and information are fundamental to every function of public health and crucial to public health agencies, from outbreak investigations to environmental surveillance. Information allows for timely, relevant, and high-quality decision making by public health agencies. Evidence-based practice is an important, grounding principle within public health practice, but resources to handle and analyze public health data in a meaningful way are limited. The Learning Health System is a platform that seeks to leverage health data to allow evidence-based real-time analysis of data for a broad range of uses, including primary care decision making, public health activities, consumer education, and academic research. The Learning Health System is an emerging endeavor that is gaining support throughout the health sector and presents an important opportunity for collaboration between primary care and public health. Public health should be a key stakeholder in the development of a national-scale Learning Health System because participation presents many potential benefits, including increased workforce capacity, enhanced resources, and greater opportunities to use health information for the improvement of the public's health. This article describes the framework and progression of a national-scale Learning Health System, considers the advantages of and challenges to public health involvement in the Learning Health System, including the public health workforce, gives examples of small-scale Learning Health System projects involving public health, and discusses how public health practitioners can better engage in the Learning Health Community. PMID- 25700655 TI - Leveraging human-centered design in chronic disease prevention. AB - Bridging the knowing-doing gap in the prevention of chronic disease requires deep appreciation and understanding of the complexities inherent in behavioral change. Strategies that have relied exclusively on the implementation of evidence-based data have not yielded the desired progress. The tools of human-centered design, used in conjunction with evidence-based data, hold much promise in providing an optimal approach for advancing disease prevention efforts. Directing the focus toward wide-scale education and application of human-centered design techniques among healthcare professionals will rapidly multiply their effective ability to bring the kind of substantial results in disease prevention that have eluded the healthcare industry for decades. This, in turn, would increase the likelihood of prevention by design. PMID- 25700656 TI - Study on development of Vipera lebetina snake anti-venom in chicken egg yolk for passive immunization. AB - Chicken egg yolk antibodies against Vipera lebetina venom were evaluated for their antivenom potential. White leghorn hens were immunized with detoxified V. lebetina venom (gamma-irradiated venom). The detoxified venom (200 MUg) was mixed with an equal volume of complete Freund's adjuvant and was injected intramuscularly into the hens. The antibodies showed high activity (1.6 LD50/mL) in egg yolks after 12 d of venom injection. The eggs were collected after 12 days, and the egg yolks were removed and washed with purified water to remove any contamination with egg whites. The purification was performed using a method described by Maya Devi et al., followed by gel filtration (Sephadex G-50). The purity and molecular weight of antivenom antibodies (IgY) were determined using electrophoresis, and the molecular weight was found to be approximately 185 kDa. The potency of IgY was 6 LD50/mL (mice), i.e., 1 mL of IgY could neutralize 43.8 MUg of standard V. lebetina venom). Our results showed that chicken egg yolk antibodies were effective in neutralizing the lethality and several pharmacological effects of V. lebetina venom and could be used for developing effective antivenom. PMID- 25700657 TI - Precise engineering of dapivirine-loaded nanoparticles for the development of anti-HIV vaginal microbicides. AB - Polymeric nanoparticles (NPs) have the potential to provide effective and safe delivery of antiretroviral drugs in the context of prophylactic anti-HIV vaginal microbicides. Dapivirine-loaded poly(d,l-lactic-co-glycolic acid) (PLGA) NPs were produced by an emulsion-solvent evaporation method, optimized for colloidal properties using a 3-factor, 3-level Box-Behnken experimental design, and characterized for drug loading, production yield, morphology, thermal behavior, drug release, in vitro cellular uptake, cytotoxicity and pro-inflammatory potential. Also, drug permeability/membrane retention in well-established HEC-1-A and CaSki cell monolayer models as mediated by NPs was assessed in the absence or presence of mucin. Box-Behnken design allowed optimizing monodisperse 170nm drug loaded NPs. Drug release experiments showed an initial burst effect up to 4h, followed by sustained 24h release at pH 4.2 and 7.4. NPs were readily taken up by different genital and macrophage cell lines as assessed by fluorescence microscopy. Drug-loaded NPs presented lower or at least similar cytotoxicity as compared to the free drug, with up to around one-log increase in half-maximal cytotoxic concentration values. In all cases, no relevant changes in cell pro inflammatory cytokine/chemokine production were observed. Dapivirine transport across cell monolayers was significantly decreased when mucin was present at the donor side with either NPs or the free drug, thus evidencing the influence of this natural glycoprotein in membrane permeability. Moreover, drug retention in cell monolayers was significantly higher for NPs in comparison with the free drug. Overall, obtained dapivirine-loaded PLGA NPs possess interesting technological and biological features that may contribute to their use as novel safe and effective vaginal microbicides. PMID- 25700658 TI - Barbed suture in minimally invasive hysterectomy: a systematic review and meta analysis. AB - PURPOSE: Total laparoscopic or robotic hysterectomy represents one of the most performed gynecological procedures nowadays. Minimally invasive procedures seem to increase the risk of vaginal cuff dehiscence (VCD). Barbed suture is a new class of suture introduced to aid surgeons during laparoscopic suturing, with the aim to reduce operative time, blood loss, and vaginal dehiscence. METHODS: We identified all articles that report a series of laparoscopic or robotic-assisted hysterectomy using barbed suture compared to conventional suture for vaginal cuff closure. The main outcome measures were vaginal cuff suturing time, vaginal bleeding, and vaginal dehiscence with or without small bowel evisceration. Suturing time was meta-analyzed as the standardized mean difference, which is the difference in means of two arms divided by pooled standard deviation with 95 % confidence intervals. For vaginal bleeding and dehiscence risk difference were calculated for each study and then meta-analyzed. Fixed models were considered if heterogeneity was low (I (2) < 50 %), otherwise random models were preferred. RESULTS: We show that minor bleeding (RD = 0, 95 % CI 0.03-0.03; p value = 0.907) and VCD (RD = -0.01, 95 % CI 0.02-0.00; p value = 0.119) are comparable in minimally invasive hysterectomy with or without the use of barbed suture. The major bleeding (RD = -0.03; 95 % CI 0.05-0.00; p value = 0.047) appears borderline significant, but the difference between the two types of sutures is not high and the upper limit of 95 % IC is equal to 0 so they were considered comparable. Instead, meta-analysis on vaginal cuff suturing time demonstrates that suturing time is reduced with the use of barbed suture (SMD = -0.96, 95 % CI 1.26-0.70; p value <0.001). CONCLUSIONS: Barbed suture is safe and well tolerated as traditional sutures and is associated with reduced operative time of laparoscopic vaginal vault closure. PMID- 25700659 TI - Phytochemical analyses and effects of Alchemilla mollis (Buser) Rothm. and Alchemilla persica Rothm. in rat endometriosis model. AB - PURPOSE: The aim of the present study is to evaluate the treatment potential of Alchemilla mollis (Buser) Rothm. and Alchemilla persica Rothm. in the experimentally induced endometriosis model in rats. METHODS: Endometriosis was surgically induced in rats by autotransplanting endometrial tissue to abdominal wall. Thirty-six rats were randomly divided into six groups. The groups were orally treated with the methanol:water (80:20) extracts of aerial parts and roots of A. mollis and A. persica. Buserelin acetate (20 mg) was used as the reference drug. The phytochemical contents of the most active extracts were determined by high performance liquid chromatography. RESULTS: The cystic formation was determined to be significantly decreased with the aerial part extract of A. mollis. A reduction in the endometrioma was also determined for the aerial part extract of A. persica group. However, significant reduction on the levels of cytokine were recorded for the A. mollis aerial part extract group. Therefore, the phytochemical contents of the aerial part extracts of A. mollis. and A. persica were analyzed. CONCLUSION: The results of the present study revealed that the aerial part extracts of A. mollis and A. persica could be beneficial in the treatment of endometriosis. PMID- 25700660 TI - Phospholamban p.arg14del mutation in a Spanish family with arrhythmogenic cardiomyopathy: evidence for a European founder mutation. PMID- 25700661 TI - Inverse Correlation at the Hip Between Areal Bone Mineral Density Measured by Dual-Energy X-ray Absorptiometry and Cortical Volumetric Bone Mineral Density Measured by Quantitative Computed Tomography. AB - Quantitative computed tomography (QCT) is considered to measure true volumetric bone mineral density (vBMD; mg/cm3) and enables differentiation between cortical and trabecular bone. We aimed to determine the value of QCT by correlating areal BMD (aBMD) by dual-energy X-ray absorptiometry (DXA) with vBMD when using a fixed threshold to delineate cortical from trabecular bone. In a cross-sectional study, 98 postmenopausal women had their hip scanned by DXA and by QCT. At the total hip and the trabecular bone compartment, aBMD correlated significantly with vBMD (r=0.74 and r=0.63; p<0.01, respectively). A significant inverse correlation was found between aBMD and cortical vBMD (r=-0.57; p<0.01). Total hip volume by QCT did not change with aBMD. However, increased aBMD was associated with a decreased trabecular bone volume (r=-0.36; p<0.01) and an increased cortical volume (r=0.69; p<0.01). Changing the threshold used to delineate cortical from trabecular bone from default 350 mg/cm3 to either 300 or 400 mg/cm3 did not affect integral vBMD (p=89) but had marked effects on estimated vBMD at the cortical (p<0.001) and trabecular compartments (p<0.001). Furthermore, increasing the threshold decreased cortical thickness (p<0.001), whereas the strength parameter in terms of buckling ratio increased (p<0.001). Our results show good agreement between aBMD and integral vBMD. However, using a fixed threshold to differentiate cortical from trabecular bone causes an apparent increase in cortical volume with a decrease in cortical density as aBMD increases. This may be caused by the classification of a larger part of the transition zone as cortical bone with increased aBMD. PMID- 25700662 TI - DXA Utilization Between 2006 and 2012 in Commercially Insured Younger Postmenopausal Women. AB - Reimbursement for dual-energy X-ray absorptiometry (DXA) scans in the outpatient setting has declined significantly since 2006. Research through 2011 has suggested reimbursement reductions for DXA scans have corresponded with an overall decreased utilization of DXA. This study updates utilization estimates for DXAs through 2012 in patients with commercial insurance and compares DXA rates before and after reimbursement changes. We evaluated DXA utilization for women aged 50-64 yr from Marketscan Commercial Claims and Encounter database between January 2006 and December 2012 based on CPT codes. We estimated utilization rates per 1000 person years (PY). We also used segmented regression analysis of monthly rates to evaluate the change in utilization rates after a proposed reimbursement reduction in July 2009. In women aged 50-64 yr, 451,656 DXAs were performed in 2006, a rate of 144 DXAs per 1000 PY. This rate increased to 149 DXAs per 1000 PY in 2009 before decreasing to 110 DXAs per 1000 PY or 667,982 scans in 2012. DXA utilization increased by 2.24 per 1000 PY until July 2009 then declined by 12.98 DXAs per 1000 persons, resulting in 37.5 DXAs per PY fewer performed in 2012 compared with 2006. Since July 2009 a significant decline in DXA utilization occurred in a younger postmenopausal commercially insured population. This decline corresponds with a time period of reductions in Medicare DXA reimbursement. PMID- 25700663 TI - Comparison of different in vitro tests to detect Cryptococcus neoformans not susceptible to amphotericin B. AB - Infections due to Cryptococcus neoformans cause severe disease, mostly in AIDS patients. The antifungal drug recommended for the initial treatment of these infections is amphotericin B with or without flucytosine, but treatment failure occurs, associated with high mortality. Thus, antifungal susceptibility testing is needed. However, the in vitro susceptibility tests available for C. neoformans are not useful to detect isolates that are not susceptible to antifungal agents such as amphotericin B. The aims of the present study were: (1) to determine and compare the in vitro activity of amphotericin B against C. neoformans clinical isolates by using different dilution and diffusion methods; (2) to evaluate the concordance among the methods used and the reference method; (3) to evaluate which method could be the best to correlate with the clinical outcome. The reference method EDef 7.2 from the European Committee on Antimicrobial Susceptibility Testing and commercial Etest strips were used to determine the minimal inhibitory concentration against amphotericin B. curves, minimal fungicidal concentration, and a disk diffusion method were also developed to evaluate the cidal activity of amphotericin B. The time-kill curve assay showed correlation (p < 0.05) with clinical outcome, whereas EDef 7.2, minimal fungicidal concentration, Etest, and disk diffusion showed no correlation (p > 0.05). Thus, the time-kill curve assay could be a potential tool to guide a more efficient treatment when amphotericin B is used. PMID- 25700664 TI - Repeated sub-optimal photodynamic treatments with pheophorbide a induce an epithelial mesenchymal transition in prostate cancer cells via nitric oxide. AB - Photodynamic therapy (PDT) is a clinically approved treatment that causes a selective cytotoxic effect in cancer cells. In addition to the production of singlet oxygen and reactive oxygen species, PDT can induce the release of nitric oxide (NO) by up-regulating nitric oxide synthases (NOS). Since non-optimal PDT often causes tumor recurrence, understanding the molecular pathways involved in the photoprocess is a challenging task for scientists. The present study has examined the response of the PC3 human metastatic prostate cancer cell line following repeated low-dose pheophorbide a treatments, mimicking non-optimal PDT treatment. The analysis was focused on the NF-kB/YY1/RKIP circuitry as it is (i) dysregulated in cancer cells, (ii) modulated by NO and (iii) correlated with the epithelial to mesenchymal transition (EMT). We hypothesized that a repeated treatment of non-optimal PDT induces low levels of NO that lead to cell growth and EMT via the regulation of the above circuitry. The expressions of gene products involved in the circuitry and in EMT were analyzed by western blot. The findings demonstrate the cytoprotective role of NO following non-optimal PDT treatments that was corroborated by the use of L-NAME, an inhibitor of NOS. PMID- 25700665 TI - Efficient and sparse feature selection for biomedical text classification via the elastic net: Application to ICU risk stratification from nursing notes. AB - BACKGROUND AND SIGNIFICANCE: Sparsity is often a desirable property of statistical models, and various feature selection methods exist so as to yield sparser and interpretable models. However, their application to biomedical text classification, particularly to mortality risk stratification among intensive care unit (ICU) patients, has not been thoroughly studied. OBJECTIVE: To develop and characterize sparse classifiers based on the free text of nursing notes in order to predict ICU mortality risk and to discover text features most strongly associated with mortality. METHODS: We selected nursing notes from the first 24h of ICU admission for 25,826 adult ICU patients from the MIMIC-II database. We then developed a pair of stochastic gradient descent-based classifiers with elastic-net regularization. We also studied the performance-sparsity tradeoffs of both classifiers as their regularization parameters were varied. RESULTS: The best-performing classifier achieved a 10-fold cross-validated AUC of 0.897 under the log loss function and full L2 regularization, while full L1 regularization used just 0.00025% of candidate input features and resulted in an AUC of 0.889. Using the log loss (range of AUCs 0.889-0.897) yielded better performance compared to the hinge loss (0.850-0.876), but the latter yielded even sparser models. DISCUSSION: Most features selected by both classifiers appear clinically relevant and correspond to predictors already present in existing ICU mortality models. The sparser classifiers were also able to discover a number of informative - albeit nonclinical - features. CONCLUSION: The elastic-net regularized classifiers perform reasonably well and are capable of reducing the number of features required by over a thousandfold, with only a modest impact on performance. PMID- 25700666 TI - Early constraint-induced movement therapy promotes functional recovery and neuronal plasticity in a subcortical hemorrhage model rat. AB - Constraint-induced movement therapy (CIMT) promotes functional recovery of impaired forelimbs after hemiplegic strokes, including intracerebral hemorrhage (ICH). We used a rat model of subcortical hemorrhage to compare the effects of delivering early or late CIMT after ICH. The rat model was made by injecting collagenase into the globus pallidus near the internal capsule, and then forcing rats to use the affected forelimb for 7 days starting either 1 day (early CIMT) or 17 days (late CIMT) after the lesion. Recovery of forelimb function in the skilled reaching test and the ladder stepping test was found after early-CIMT, while no significant recovery was shown after late CIMT or in the non-CIMT controls. Early CIMT was associated with greater numbers of DeltaFosB-positive cells in the ipsi-lesional sensorimotor cortex layers II-III and V. Additionally, we found expression of the growth-related genes brain-derived neurotrophic factor (BDNF) and growth-related protein 43 (GAP-43), and abundant dendritic arborization of pyramidal neurons in the sensorimotor area. Similar results were not detected in the contra-lesional cortex. In contrast to early CIMT, late CIMT failed to induce any changes in plasticity. We conclude that CIMT induces molecular and morphological plasticity in the ipsi-lesional sensorimotor cortex and facilitates better functional recovery when initiated immediately after hemorrhage. PMID- 25700667 TI - Overcoming challenges in order to improve the management of rheumatic and musculoskeletal diseases across the globe. PMID- 25700668 TI - Attitudes Towards Gambling and Gambling Reform in Australia. AB - The Attitudes Towards Gambling Scale (ATGS) is a 14-item survey instrument examining general attitudes towards gambling (Orford et al. in Int Gambl Stud 9(1):39-54, 2009). The current study examined the validity of this scale in an Australian community sample of 1794 adults (52.8 % female). As well as considering measures of internal consistency and factor loadings, we examined the functional utility of the scale as a mediator of gambling activity, problem gambling status, and consequent opinions on national gambling-reform legislation. We found internal consistency and factor loadings of the ATGS within the Australian sample to be comparable with those observed in the original UK study. Additionally, ATGS scores were found to be a relatively robust predictor of attitudes towards gambling reform and harm minimisation. Further, the ATGS mediated the relationships between experiences with gambling and attitudes towards harm reduction. The findings suggest that the ATGS is a useful tool for examining general attitudes towards gambling within an Australian context. PMID- 25700670 TI - Team Emotional Intelligence, Team Interactions, and Gender in Medical Students During a Psychiatry Clerkship. AB - OBJECTIVE: This study examined the relationship between team emotional intelligence, quality of team interactions, and gender. METHODS: Psychiatry clerkship students participating in Team-Based Learning (TBL, n = 484) or no TBL (control, n = 265) completed the Workgroup Emotional Intelligence Profile (WEIP S) and the Team Performance Scale (TPS). RESULTS: Significant correlations (p < 0.01) existed between quality of team interactions (i.e., TPS) and team emotional intelligence (i.e., WEIP-S) subscales, but not gender. Control and TBL groups experienced significant increases in WEIP-S subscales pre to post (p < 0.01, eta (2) = .08), with the TBL group experiencing significantly higher gains in three of four subscales. Control group scored higher on TPS. CONCLUSIONS: A significant relationship exists between team emotional intelligence and quality of team interactions. Gender was unrelated to TPS or WEIP-S subscales. TBL group experienced higher gains in WEIP-S subscales while the control group experienced slightly higher TPS scores. Results suggest implications for medical educators who use TBL. PMID- 25700669 TI - Migraine and attention to visual events during mind wandering. AB - Although migraine is traditionally categorized as a primary headache disorder, the condition is also associated with abnormalities in visual attentional function in between headache events. Namely, relative to controls, migraineurs show both a heightened sensitivity to nominally unattended visual events, as well as decreased habituation responses at sensory and post-sensory (cognitive) levels. Here we used event-related potentials (ERPs) to examine whether cortical hypersensitivities in migraineurs extend to mind wandering, or periods of time wherein we transiently attenuate the processing of external stimulus inputs as our thoughts drift away from the on-going task at hand. Participants performed a sustained attention to response task while they were occasionally queried as to their attentional state-either "on-task" or "mind wandering." We then analyzed the ERP responses to task-relevant stimuli as a function of whether they immediately preceded an on-task versus mind wandering report. We found that despite the commonly reported heightened visual sensitivities in our migraine group, they nevertheless manifest a reduced cognitive response during periods of mind wandering relative to on-task attentional states, as measured via amplitude changes in the P3 ERP component. This suggests that our capacity to attenuate the processing of external stimulus inputs during mind wandering is not necessarily impaired by the class of cortical hypersensitivities characteristic of the interictal migraine brain. PMID- 25700671 TI - Elevating the behavioral and social sciences in premedical training: MCAT2015. PMID- 25700672 TI - Chaplain rounds: a chance for medical students to reflect on spirituality in patient-centered care. AB - OBJECTIVE: This study assesses the perceived impact of a required half-day with a hospital chaplain for first-year medical students, using a qualitative analysis of their written reflections. METHODS: Students shadowed chaplains at the UCLA hospital with the stated goal of increasing their awareness and understanding of the spiritual aspects of health care and the role of the chaplain in patient care. Participation in the rounds and a short written reflection on their experience with the chaplain were required as part of the first-year Doctoring course. RESULTS: The qualitative analysis of reflections from 166 students using grounded theory yielded four themes: (1) the importance of spiritual care, (2) the chaplain's role in the clinical setting, (3) personal introspection, and (4) doctors and compassion. CONCLUSIONS: Going on hospital rounds with a chaplain helps medical students understand the importance of spirituality in medicine and positively influences student perceptions of chaplains and their work. PMID- 25700673 TI - Improving smallholder food security through investigations of carcass composition and beef marketing of buffalo and cattle in northern Lao PDR. AB - This study determined the carcass composition of Lao indigenous buffalo (Bubalus bubalis) and cattle (Bos indicus), then examined trends in bovine meat marketing following review of records of beef production and prices in the two major cities of Luang Prabang (LPB) and Xieng Khoung (XK) provinces in northern Laos. Samples from 41 buffalo and 81 cattle (n = 122) were collected from animals slaughtered in May-June 2014, with live weights, carcass weights and other carcass-related variables collected. The animals were classified into four age cohort groups (<2, 2-<4, 4-6 and >6 years) with quantitative and dichotomous qualitative traits determined. There were significant differences in buffalo and cattle predicted mean carcass weights between age classification categories (p = 0.003 and 0.001) but not in dressing percentages (p = 0.1 and 0.1). The carcass weight of buffalo was 104 (+/-23.1)-176 (+/-12.0) kg compared to 65 (+/-8.7)-84 (+/-6.5) kg of cattle, with dressing percentages of 37-40 and 39-42 %, respectively. Despite an average bovine meat price increase of 42-48 % between 2011 and 2013, there was a reduction in the numbers of large ruminants slaughtered in the surveyed cities of LPB (11 %) and XK (7 %), with bovine meat availability per person of 5.2-6.6 kg (LPB) and 3.0-3.8 kg (XK). Improving the sustainability of the bovine meat supply in Laos requires a systems approach involving improvements to animal health and production, livestock marketing, plus the critical development of improved slaughterhouse facilities enabling a meat-processing sector to emerge. This development pathway is of particular importance for building the capacity of Laos to reduce food insecurity and alleviate the poverty of its largely rural smallholder community. PMID- 25700674 TI - Constraints and efficiency of cattle marketing in semiarid pastoral system in Kenya. AB - Livestock keeping is regarded as a store of wealth for pastoralists in Kenya, besides their social and cultural functions. The objective of this study was to prioritize constraints to cattle marketing in a semiarid pastoral area of Narok in Kenya and to analyze efficiency of cattle marketing in transit markets located in Garissa, Kajiado and Narok counties. Primary data collection from traders was done through participatory interviews and market surveys, while time series market price data were obtained from secondary sources. Five focus group interviews were organized with a total of 61 traders in markets from Narok County, while a total of 187 traders who purchased cattle from transit markets provided data on a number of cattle purchased, purpose of purchase, buying prices and mode of transport. Market performance was analyzed through trader's market share, gross margins, Gini coefficient and coefficient of correlation between time series price data. The marketing constraints which were ranked high included lack of market for meat, trekking of cattle to markets, lack of price information and occurrence of diseases. About 10 % of traders purchased over 50 % of cattle which were supplied in markets, revealing a high concentration index. Further, a gross marketing margin per cattle purchased was positive in all markets revealing profitability. Moderate correlation coefficients existed between time series market price data for cattle purchased from Ewaso Ngiro and Mulot markets (r = 0.5; p < 0.05), while those between Dagoretti and Garissa markets were weak (r = 0.2; p > 0.05). The integration of markets, occurrence of diseases and trekking of cattle to markets are factors which may increase a risk of infectious disease spread. These results call for support of disease surveillance activities within markets in pastoral areas so that farms and systems which are connected are protected from threats of infectious diseases. PMID- 25700675 TI - The Three NITRCs: A Guide to Neuroimaging Neuroinformatics Resources. PMID- 25700676 TI - Sagittal patellar tilt and concomitant quadriceps hypotrophy after tibial nailing. AB - PURPOSE: The aim of the study was to analyse the patellofemoral alignment in the sagittal plane following tibial fracture surgery with intramedullary nailing and its relationship to parapatellar muscle status. METHODS: The patellofemoral MRI results of 27 patients (15 males and 12 females) treated with locked intramedullary nailing following tibia shaft fracture were reviewed. The mean age of the patients was 41.8 (+/-15) years. The patella-patellar tendon angle (P-PT) and the distance between the inferior patellar pole and the tibial tubercle (DP TT) were evaluated for both the operated extremity and the contralateral normal side. MRI assessment of the infrapatellar fat pad, quadriceps, sartorius, gracilis, semi-membranosus muscles and biceps muscles was also carried out. The correlation between the changes in skeletal muscle mass, the volume of the infrapatellar fat pad and the alterations in the DP-TT distances and P-PT angles were analysed. RESULTS: The quadriceps muscle cross-sectional diameter had a mean of 157.2 mm(2) (115.6/319.5) in the operated extremity, and it was 193 mm(2) (77.6/282.2) in the non-operated normal side (p = 0.001). For the Gracilis muscle, the mean was 84.4 mm(2) (19.7/171) at the operated extremity and 75.7 mm(2) (26.9/238.2) on the normal side (p = 0.05). The cross-sectional areas of the semi-membranosus, sartorius and biceps muscles in the operated and non operated extremity were not noticeably different (n.s). The P-PT angle was 153 degrees (129.7/156.4) in the operated extremity and 145.7 degrees (137.6/163.4) in the non-operated normal extremity (p < 0.05). While DP-TT distance was 11.4 mm (9.4/20.4) in the operated extremity, it was 14.1 mm (7.3/17.1) in the non operated extremity (p = 0.001). The correlation analyses revealed that the quadriceps hypotrophy negatively correlated (r = -0.4, p = 0.02) with the P-PT angle but positively correlated with the increase in gracilis muscle volume (r = 0.4, p = 0.03). CONCLUSION: This study revealed that patellofemoral joint kinematics in the operated extremity was diminished in the sagittal plane correlating with the quadriceps muscle volume loss and gracilis muscle hypertrophy. The modalities focused on both preventing and treating the hypotrophy of the quadriceps muscle following the surgical treatment of tibial fracture, which may help to overcome this quite common pathology. PMID- 25700677 TI - Meniscal tears and articular cartilage damage in the dislocated knee. AB - PURPOSE: Knee dislocations can cause significant damage to intra-articular knee structures, but currently there are limited data reporting articular cartilage and meniscal injuries in this setting. The purpose of this study is to (1) report the rate of concomitant intra-articular injuries at the time of multiligament reconstruction for knee dislocation, (2) determine whether the pattern of ligament injury is associated with the presence of chondral and meniscal injuries, and (3) assess the relationship between timing of surgery and incidence of chondral and meniscal injuries. METHODS: The records of patients who sustained a knee dislocation between 1992 and 2013 were retrospectively reviewed. Patients included for further review had a PCL-based multiligament knee injury or a minimum of three disrupted ligaments, both indicative of knee dislocation. Patient demographics, ligament injury patterns, meniscal tears and chondral injuries at arthroscopy, and interval from injury to surgery were recorded. Early surgical intervention was defined as <3 months, delayed was between 3 and 12 months, and chronic was >12 months. Data analysis compared ligament injury pattern with chondral and meniscal injuries, as well as the rates of intra articular injury by timing of surgery. RESULTS: One-hundred and twenty-one patients (122 knees) were included (93 males, 28 females) with a median age at time of surgery of 31 years (range 15-62). Ninety-three knees (76 %) had associated chondral or meniscal injury. Sixty-seven knees (55 %) presented with meniscal tears (26 isolated medial, 27 isolated lateral, and 14 combined medial/lateral), while 52 knees (48 %) had chondral damage, most commonly in the medial compartment. Schenck classification as well as side of injury did not demonstrate consistent relationships with intra-articular injury. A higher incidence of damage to the lateral femoral condyle (20 % vs 3 %; p = 0.02), lateral tibial plateau (20 % vs 2 %; p < 0.01), and patella (40 % vs 13 %; p = 0.01) was found in the chronic group compared to the early group. The chronic group contained significantly more patients with bicompartmental and tricompartmental chondral lesions (25 % vs 6 %; p = 0.03 and 10 % vs 0 %; p = 0.02, respectively). CONCLUSION: Meniscal tears and chondral damage occur frequently in patients with a knee dislocation. A longer interval from injury to surgical reconstruction is associated with higher rates of articular cartilage lesions, especially in multiple compartments. LEVEL OF EVIDENCE: IV. PMID- 25700678 TI - Identification and utilization of donor and recipient genetic variants to predict survival after HCT: are we ready for primetime? AB - Overall survival following hematopoietic cell transplantation (HCT) has improved over the past two decades through better patient selection and advances in HLA typing, supportive care, and infection prophylaxis. Nonetheless, mortality rates are still unsatisfactory and transplant-related mortality remains a major cause of death after unrelated allogeneic HCT. Since there are no known pre-HCT, non HLA biologic predictors of survival following transplant, for over a decade, scientists have been investigating the role of non-HLA germline genetic variation in survival and treatment-related mortality after HCT. Variation in single nucleotide polymorphisms (SNPs) has the potential to impact chemotherapy, radiation, and immune responses, leading to different post-HCT survival outcomes. In this paper, we address the current knowledge of the contribution of genetic variation to survival following HCT and discuss study design and methodology for investigating HCT survival on a genomic scale. PMID- 25700679 TI - Chronic myeloid leukemia: advances in understanding disease biology and mechanisms of resistance to tyrosine kinase inhibitors. AB - The successful implementation of tyrosine kinase inhibitors (TKIs) for the treatment of chronic myeloid leukemia (CML) remains a flagship for molecularly targeted therapy in cancer. This focused review highlights critical elements of the underlying biology of CML and provides a summary of the molecular mechanisms that lead to TKI resistance: BCR-ABL1 mutation-based resistance and therapy escape through alternative pathway activation despite inhibition of BCR-ABL1 tyrosine kinase activity. We direct attention to the most current manifestations of these issues, including emergence of pan-TKI-resistant BCR-ABL1 compound mutants, new strategies for identification and therapeutic targeting of alternative pathways, and the exciting, controversial topic of cessation of TKI therapy leading to durable treatment-free remissions for a subset of patients. Further gains in our understanding of the biology of Philadelphia chromosome positive (Ph-positive) leukemia and mechanisms of resistance to BCR-ABL1 TKIs will benefit patients and also provide a blueprint for similar discovery in other cancers. PMID- 25700680 TI - A Case of Masticatory Dystonia Following Cerebellar Haemorrhage. PMID- 25700681 TI - Transplantation of Embryonic Cerebellar Grafts Improves Gait Parameters in Ataxic Lurcher Mice. AB - Hereditary cerebellar ataxias are severe diseases for which therapy is currently not sufficiently effective. One of the possible therapeutic approaches could be neurotransplantation. Lurcher mutant mice are a natural model of olivocerebellar degeneration representing a tool to investigate its pathogenesis as well as experimental therapies for hereditary cerebellar ataxias. The effect of intracerebellar transplantation of embryonic cerebellar solid tissue or cell suspension on motor performance in adult Lurcher mutant and healthy wild-type mice was studied. Brain-derived neurotrophic factor level was measured in the graft and adult cerebellar tissue. Gait analysis and rotarod, horizontal wire, and wooden beam tests were carried out 2 or 6 months after the transplantation. Higher level of the brain-derived neurotrophic factor was found in the Lurcher cerebellum than in the embryonic and adult wild-type tissue. A mild improvement of gait parameters was found in graft-treated Lurcher mice. The effect was more marked in cell suspension grafts than in solid transplants and after the longer period than after the short one. Lurcher mice treated with cell suspension and examined 6 months later had a longer hind paw stride (4.11 vs. 3.73 mm, P < 0.05) and higher swing speed for both forepaws (52.46 vs. 32.79 cm/s, P < 0.01) and hind paws (63.46 vs. 43.67 cm/s, P < 0.001) than controls. On the other hand, classical motor tests were not capable of detecting clearly the change in the motor performance. No strong long-lasting negative effect of the transplantation was seen in wild-type mice, suggesting that the treatment has no harmful impact on the healthy cerebellum. PMID- 25700682 TI - Neurodevelopmental Malformations of the Cerebellar Vermis in Genetically Engineered Rats. AB - The cerebellar vermis is particularly vulnerable to neurodevelopmental malformations in humans and rodents. Sprague-Dawley, and Long-Evans rats exhibit spontaneous cerebellar malformations consisting of heterotopic neurons and glia in the molecular layer of the vermis. Malformations are almost exclusively found along the primary fissure and are indicative of deficits of neuronal migration during cerebellar development. In the present report, we test the prediction that genetically engineered rats on Sprague-Dawley or Long-Evans backgrounds will also exhibit the same cerebellar malformations. Consistent with our hypothesis, we found that three different transgenic lines on two different backgrounds had cerebellar malformations. Heterotopia in transgenic rats had identical cytoarchitecture as that observed in wild-type rats including altered morphology of Bergmann glia. In light of the possibility that heterotopia could affect results from behavioral studies, these data suggest that histological analyses be performed in studies of cerebellar function or development when using genetically engineered rats on these backgrounds in order to have more careful interpretation of experimental findings. PMID- 25700683 TI - The unreliability of continuous postoperative lactate monitoring after extended hepatectomies: single center experience. AB - Postoperative plasma lactate clearance has been established as an important prognostic factor for liver resection morbidity and mortality. The aim of this study was to analyse continuous monitoring of plasma lactate in patients submitted to extended hepatectomy (EH) with special attention to those who received preoperative portal vein branch embolization (PVE) to augment the future remnant liver. In this single center retrospective study, a full revision of 45 medical records was performed from patients who underwent EH at ISMETT from October 1999 to August 2013. Plasma lactates from admission to ICU to day 5 were recorded. Postoperative lactate clearance (DeltaLAC) was defined as lactate at postoperative day 5 minus lactate at ICU presentation (hour 0). DeltaLAC was analysed in relation to total hospital stay and 90 days' perioperative morbidity and mortality, using Clavien-Dindo classification, and by presence or absence of PVE. Forty-one right and four left EH were performed. 17 patients underwent previous PVE with a mean of 44 +/- 28.9 days-to-surgery time and a 24 +/- 8.3% degree of hypertrophy. In 39 cases (86.7%), a malignant etiology was the indication for EH, length of surgery was 486 +/- 122 min with a median of 300 ml of blood transfusion. In 25 patients, a Clavien grade IIIa or worst complication has been experienced, and in three cases the death occurred during the first 3 months after EH. The median length of hospitalization was 11 days. In patients with preoperative PVE a significative association with an early post-resectional lactate clearance was obtained (p 0.01). Conversely, the univariate analysis measured by t test did not show any significative associations between DeltaLAC and a median time of hospital stay longer than 11 days (p 0.08), or the onset of any complications (p 0.67) and of a Clavien's grade of complications >=IIIa patients (p 0.48). After adjusting for co-variables, results of the multivariate logistic regression analyses confirmed that DeltaLAC is not independent or significant predictor for initial poor liver function following EH. In our single center experience, the continuous monitoring of postoperative lactate clearance did not work as an early marker of postoperative liver dysfunction following EH. Although lactate clearance, worked as guide having a clinical utility in the ICU statement for hemodynamic optimization and systemic fluid balance management. PMID- 25700684 TI - Association Between TSLP Polymorphisms and Eczema in Japanese Women: the Kyushu Okinawa Maternal and Child Health Study. AB - We examined the association between thymic stromal lymphopoietin (TSLP) single nucleotide polymorphisms (SNPs) and eczema in young adult Japanese women. Cases were 188 women who met the criteria of the International Study of Asthma and Allergies in Childhood (ISAAC) for eczema. Controls were 565 women without eczema according to the ISAAC criteria, who had not been diagnosed with asthma, atopic eczema, and/or allergic rhinitis by a doctor and who had no asthma as defined by the European Community Respiratory Health Survey criteria and no rhinoconjunctivitis according to the ISAAC criteria. Compared with women with the TT genotype of SNP rs1837253, those with the TC or CC genotype had a significantly increased risk of eczema after adjustment for age and smoking, although this association was not significant in crude analysis. There were no relationships between SNP rs3806933 or rs2289276 and eczema. The TC and CC genotypes combined of SNP rs1837253 may be significantly positively associated with eczema. PMID- 25700685 TI - Serum metallothionein in patients with testicular cancer. AB - PURPOSE: Metallothioneins (MTs) have been disclosed as a useful diagnostic factor for tumour progression and drug resistance in a variety of malignancies. Increased levels of MT in blood serum have been found in patients with several types of cancer, but there is no available information on serum MT levels in patients with testicular germ cell tumour (TGCT). The aim of the study was to determine MT levels in serum of patients with TGCT and to evaluate the portion of platinum (Pt) that binds to MT after cisplatin administration since MTs could be involved in drug resistance. METHODS: Concentration of total MT was determined in serum of 25 men with newly diagnosed TGCT by differential pulse voltammetry. The fractionation of serum was carried out by size exclusion high-performance liquid chromatography (SE-HPLC), while concentration of Pt in collected fractions was determined by inductively coupled plasma mass spectrometry. RESULTS: Concentration of serum MT was significantly higher in TGCT patients than in healthy volunteers. The results of SE-HPLC analysis showed that only a small amount of Pt was bound to proteins in the area of MT elution. CONCLUSIONS: Significant increase in MT levels in individuals with TGCT indicates certain health problem and, in combination with other commonly used diagnostic tools, could improve early diagnosis. PMID- 25700686 TI - Diagnostic imaging for acute appendicitis: interfacility differences in practice patterns. AB - PURPOSE: To evaluate trends and factors associated with interfacility differences in imaging modality selection in the diagnosis and management of children with suspected acute appendicitis. METHODS: We conducted a retrospective review of diagnostic imaging selection and outcomes in patients <20 years of age who underwent appendectomy at a single Children's Hospital from June 2008 to June 2013. These results were then compared with those of referring hospitals. RESULTS: A total of 232 children underwent appendectomy during the study period. Imaging results contributed to diagnostic and management decisions in 95.3 % of cases. CT scan was utilized as first-line imaging in 50 % of cases. CTs were preferentially performed at referring institutions (78 vs. 46 %, p < 0.001). Children were five times more likely to undergo CT at referring institutions (OR = 5.5, CI 3.0-10.2). Adjusting for demographics and Alvarado score, diagnostic imaging choice was independent of patient's clinical status. CONCLUSION: This study demonstrates that initial presentation to a referring hospital independently predicts the use of CT scan for suspected acute appendicitis. Further efforts should be undertaken to develop a clinical pathway that minimizes radiation exposure in the diagnosis of acute appendicitis, with focus on access to pediatric abdominal ultrasound. PMID- 25700687 TI - Unmet surgical needs in children: a household survey in Nepal. AB - PURPOSE: While an estimated two billion people lack access to surgical care, little data are available on surgical conditions for pediatric populations in low and middle-income countries. Our study aims to assess pediatric surgical needs in Nepal. METHODS: A countrywide cross-sectional study was performed in 15 randomly chosen districts; 3 clusters (2 rural; 1 urban) per district were selected. The prevalence of surgical conditions, unmet surgical needs, and barriers to care were analyzed among children (0-18 years of age). RESULTS: Overall, 1,350 households and 2,695 individuals were surveyed (response rate: 97 %); 800 respondents (29.7 %, 95 % CI 27.9-31.4 %) were pediatric; 59.8 % (95 % CI 56.3-63.2 %) were male; median age was 10 years (IQR 5-15). Of them, 84 (10.5 %, 95 % CI 8.5-12.8 %) had a surgical condition; 48 (6.0 %, 95 % CI 4.5-7.9 %) reported an unmet need for surgical care. Based on this, we estimate that 706,076 (95 % CI 529,557-929,666) children live with untreated surgical conditions. Barriers to care included limited availability of services (31.3 %), funds (22.9 %), time (4.2 %), and fear/mistrust of medical services (16.7 %). CONCLUSION: Close to 700,000 children in Nepal are estimated to need surgical consultation. Programs to address this should be developed alongside efforts by policy makers and donors to rectify the lack of care, bolster limited funds, and strengthen healthcare systems. PMID- 25700688 TI - Alterations on peripheral blood B cell subsets induced by allergic rhinitis. AB - OBJECTIVES AND DESIGN: Here we evaluated whether allergic rhinitis to Dermatophagoides pteronyssinus induces alterations on circulating B cell subsets. MATERIALS AND METHODS: Circulating B cell subsets and isotype expression on antigen-experienced B cells from allergic patients under conventional pharmacological treatment (NO-SIT, n = 15) and under subcutaneous immunotherapy (SCIT, n = 33), and non-allergic subjects (NC, n = 25) were analyzed by flow cytometry. RESULTS: In allergic patients, we found a significant decrease in IgM(+) and IgG(+) memory B cells and an increase in IgA(+) memory B cells. Additionally, the numbers of circulating IgA(+) plasmablasts in allergic patients were also increased, while those cells expressing IgM were reduced. CONCLUSIONS: Allergic patients have a disturbed B cell subsets distribution which seems to underlie rhinitis pathogenesis and remain unchanged after SCIT. PMID- 25700690 TI - Yin and Yang revisited: CCN3 as an anti-fibrotic therapeutic? AB - Fibrotic diseases are a significant cause of mortality. It is being increasingly appreciated that the cellular microenvironment plays a key role in promoting pathological fibrosis. A previous Bits and Bytes described an elegant series of experiments published by Bruce Riser and colleagues (Am J Pathol. 2009: 174:1725 34) that showed that CCN3 (nov) antagonizes the fibrogenic effects of CCN2.and hence could represent a novel anti-fibrotic therapy. They have continued their excellent work and have recently used the ob/ob mouse as a model of obesity and diabetic nephropathy to show that CCN3 could block the induction of profibrotic gene expression, fibrosis and loss of kidney function (Am J Pathol. 2014;184:2908 21). Also, reversal of fibrosis was observed. Thus this paper provides strong evidence that CCN3 may be used as a novel therapy to treat diabetes caused by obesity. PMID- 25700689 TI - Comparison of senescence-associated miRNAs in primary skin and lung fibroblasts. AB - MicroRNAs are non-coding RNAs with roles in many cellular processes. Tissue specific miRNA profiles associated with senescence have been described for several cell and tissue types. We aimed to characterise miRNAs involved in core, rather than tissue-specific, senescence pathways by assessment of common miRNA expression differences in two different cell types, with follow-up of predicted targets in human peripheral blood. MicroRNAs were profiled in early and late passage primary lung and skin fibroblasts to identify commonly-deregulated miRNAs. Expression changes of their bioinformatically-predicted mRNA targets were then assessed in both cell types and in human peripheral blood from elderly participants in the InCHIANTI study. 57/178 and 26/492 microRNAs were altered in late passage skin and lung cells respectively. Three miRNAs (miR-92a, miR-15b and miR-125a-3p) were altered in both tissues. 14 mRNA targets of the common miRNAs were expressed in lung and skin fibroblasts, of which two demonstrated up regulation in late passage skin and lung cells (LYST; p = 0.02 [skin] and 0.02 [lung] INMT; p = 0.03 [skin] and 0.04 [lung]). ZMPSTE24 and LHFPL2 demonstrated altered expression in late passage skin cells only (p = 0.01 and 0.05 respectively). LHFPL2 was also positively correlated with age in peripheral blood (p value = 6.6 * 10(-5)). We find that the majority of senescence-associated miRNAs demonstrate tissue-specific effects. However, miRNAs showing common effects across tissue types may represent those associated with core, rather than tissue-specific senescence processes. PMID- 25700691 TI - An interesting perspective on a well-studied pathway: does type III TGF-Beta receptor have therapeutic potential? AB - The type III TGF-beta receptor has potential therapeutic and prognostic potential in breast cancer. PMID- 25700692 TI - Validation of cold chain shipping environment for transport of allografts as part of a human tissue bank returns policy. AB - Human tissue is shipped to surgeons in the UK in either a freeze-dried or frozen state. To ensure quality and safety of the tissue, frozen tissue must be shipped in insulated containers such that tissue is maintained at an appropriate temperature. UK Blood Transfusion Service regulations state "Transportation systems must be validated to show maintenance of the required storage temperature" and also state that frozen, non-cryopreserved tissue "must be transported... at -20 degrees C or lower" (Guidelines for the Blood Transfusion Services in the United Kingdom, 8th Edn. 2013). To maintain an expiry date for frozen tissue longer than 6 months, the tissue must be maintained at a temperature of -40 degrees C or below. The objective of this study was to evaluate and validate the capability of a commercially available insulated polystyrene carton (XPL10), packed with dry ice, to maintain tissue temperature below -40 degrees C. Tissue temperature of a single frozen femoral head or a single frozen Achilles tendon, was recorded over a 4-day period at 37 degrees C, inside a XPL10 carton with dry ice as refrigerant. The data demonstrate that at 37 degrees C, the XPL10 carton with 9.5 kg of dry ice maintained femoral head and tendon tissue temperature below -55 degrees C for at least 48 h; tissue temperature did not rise above -40 degrees C until at least 70 h. Data also indicated that at a storage temperature lower than 37 degrees C, tissue temperature was maintained for longer periods. PMID- 25700693 TI - Human dental pulp stem cells cultured onto dentin derived scaffold can regenerate dentin-like tissue in vivo. AB - Regeneration of dentin tissues in the pulp space of teeth serves the ultimate goal of preserving teeth via endodontic approaches. In recent times, many studies suggested that human dentin scaffolds combined with dental stem cells was a potential strategy for the complete dentin tissue regeneration. In this study, human dental pulp stem cells (DPSCs) were isolated and cultured. Dentin specimens were prepared from human third molars and treated with ethylene diamine tetra acetic acid and citric acid to remove the smear layer. Then, DPSCs were cultured onto human treated dentin (hTD) and implanted in mouse model for 4, 6 and 8 weeks. The resulting grafts were assessed by hematoxylin and eosin stain and immunohistochemical stains. As a result, DPSCs were supported and induced to regenerate of dentin-like tissues which expressed specific dentin markers such as dentin sialophosphoprotein and dentin matrix protein 1 by combination with hTD in vivo. Furthermore, cells existed in the newly-formed dentin-like tissues also expressed typical human mitochondria antibodies, demonstrated that new tissues originated from human. In conclusion, the obtain results extend hopefully newly established therapy to apply in endodontics and traumatic dental hard tissues. PMID- 25700694 TI - Smoking in cars carrying children will be illegal in England from October. PMID- 25700695 TI - Successful Treatment of Myocardial Infarction in an Infant With Kawasaki Disease. AB - Although early treatment with intravenous immunoglobulin reduces the risk of coronary artery aneurysms, in refractory cases of Kawasaki disease, myocardial infarction can result from thrombosis of coronary artery aneurysms. Early recognition of myocardial infarction from Kawasaki disease myocarditis can reduce morbidity and mortality. This report describes successful treatment of myocardial infarction from coronary thrombosis in an infant with Kawasaki disease using intravenous tissue plasminogen activator and abciximab. PMID- 25700696 TI - Russia faces shortage of lifesaving drugs as rouble halves in value. PMID- 25700697 TI - Inspectors to investigate baby's death in Sicily after neonatal bed could not be found. PMID- 25700698 TI - Anatomic repair of complex transposition with en bloc rotation of the truncus arteriosus: 10-year experience?. AB - OBJECTIVES: Transposition of the great arteries, ventricular septal defect and left ventricular outflow tract obstruction are commonly called complex transposition. The traditional method of repair is the Rastelli procedure. Aortic translocation (Nikaidoh 1984) provides a more anatomic repair of this malformation. En bloc rotation of the truncus arteriosus (double root translocation, half turn truncal switch procedure) was introduced in 2003 (Yamagishi), and offers a complete anatomic repair with growth potential in all tubular structures. The aim of this study was to analyse our general experience with this method and the mid-term results concerning growth of the tubular structures as well as the function of the semilunar valves, if preserved. METHODS: Nineteen patients with transposition of the great arteries, ventricular septal defect and left ventricular outflow tract obstruction or similar cases of double outlet right ventricle (DORV) have been treated by an en bloc rotation of the truncus arteriosus in our centre since 2003. Patient age ranged between 4 days and 6.46 years. The median age was 0.39 [0.1; 2.25] years. Weight ranged between 3.1 and 18.8 kg. Median weight was 5.6 [3.6; 9] kg. Five patients had received between 1 and 4 palliative procedures prior to the definitive repair. The pulmonary valve could be preserved in 15 cases, whereas a transannular patch was necessary in 4 cases. RESULTS: One patient died of chronic left ventricular failure during the hospital stay. One patient acquired a severe cerebral haemorrhage 3 weeks after the operation. She was discharged and died 6 months later. One patient is not in a follow-up programme. Sixteen patients are now followed over a period of 153 days to 9.96 years. Aortic and pulmonary valves showed proportional growth during the follow-up period. The preserved pulmonary valves were small for age, but kept their competence satisfactorily. Three patients required a reoperation: one aortic valve repair, 1 permanent pacemaker, VSD closure. CONCLUSIONS: Up to now, reoperations had been caused by technical issues. The reoperation rate can be kept low, by understanding some important features of this procedure and avoiding these problems. Complete anatomic repair with growth potential and satisfactory preserved pulmonary valve function is possible. PMID- 25700699 TI - Comparative ergonomic workflow and user experience analysis of MRI versus fluoroscopy-guided vascular interventions: an iliac angioplasty exemplar case study. AB - PURPOSE: A methodological framework is introduced to assess and compare a conventional fluoroscopy protocol for peripheral angioplasty with a new magnetic resonant imaging (MRI)-guided protocol. Different scenarios were considered during interventions on a perfused arterial phantom with regard to time-based and cognitive task analysis, user experience and ergonomics. METHODS: Three clinicians with different expertise performed a total of 43 simulated common iliac angioplasties (9 fluoroscopic, 34 MRI-guided) in two blocks of sessions. Six different configurations for MRI guidance were tested in the first block. Four of them were evaluated in the second block and compared to the fluoroscopy protocol. Relevant stages' durations were collected, and interventions were audio visually recorded from different perspectives. A cued retrospective protocol analysis (CRPA) was undertaken, including personal interviews. In addition, ergonomic constraints in the MRI suite were evaluated. RESULTS: Significant differences were found when comparing the performance between MRI configurations versus fluoroscopy. Two configurations [with times of 8.56 (0.64) and 9.48 (1.13) min] led to reduce procedure time for MRI guidance, comparable to fluoroscopy [8.49 (0.75) min]. The CRPA pointed out the main influential factors for clinical procedure performance. The ergonomic analysis quantified musculoskeletal risks for interventional radiologists when utilising MRI. Several alternatives were suggested to prevent potential low-back injuries. CONCLUSIONS: This work presents a step towards the implementation of efficient operational protocols for MRI guided procedures based on an integral and multidisciplinary framework, applicable to the assessment of current vascular protocols. The use of first-user perspective raises the possibility of establishing new forms of clinical training and education. PMID- 25700700 TI - The importance of existential dimensions in the context of the presence of older patients at team meetings-in the light of Heidegger and Merleau-Ponty's philosophy. AB - The aim of the present study is to explore interpersonal dimensions of the presence of older patients at team meetings. The theoretical foundation of the study is grounded in caring science and lifeworld phenomenology. The results from two empirical studies, that indicated the need for a more in-depth examination of the interpersonal relationships when an older patient is present at a team meeting, were further explicated by philosophical examination in the light of Heidegger and Merleau-Ponty's philosophy. The empirical studies were performed in a hospital ward for older people, where the traditional rounds had been replaced by a team meeting, to which the patients were invited. The analysis of the general structure and philosophical examination followed the principles of reflective lifeworld research. The philosophical examination is presented in four meaning structures: mood as a force in existence; to exist in a world with others; loneliness in the presence of others; and the lived body as extending. In conclusion, professionals must consider patients' existential issues in the way they are expressed by the patients. Existence extends beyond the present situation. Accordingly, the team meeting must be seen in a larger context, including the patients' life as a whole, as well as the ontological and epistemological foundations on which healthcare is based. PMID- 25700701 TI - Effects of method of administration on oral health-related quality of life assessment using the Child Perceptions Questionnaire (CPQ-G11-14). AB - OBJECTIVES: Questionnaires that measure oral health-related quality of life (OHRQoL) in children and adolescents have emerged in recent years as an important source of patient-reported outcomes. The aim of this study was to investigate potential effects of the method of administration (face-to-face interview, telephone interview, or self-administered questionnaire) in 11- to 14-year-old children and adolescents on OHRQoL information obtained using the Child Perceptions Questionnaire (CPQ). MATERIALS AND METHODS: OHRQoL was measured using the German version of the CPQ (CPQ-G11-14). The instrument was administered to 42 children and adolescents aged 11 to 14 years using the three different methods in a randomized order with an interval of 1 week between each administration. Test retest reliability for the repeated CPQ-G11-14 assessments across the three methods of administration, internal consistency, and convergent validity were determined. RESULTS: The CPQ-G11-14 mean summary scores did not vary statistically significantly across the three administration methods (P = 0.274). Test-retest reliability was moderate to good (ICC 0.69-0.82), internal consistency was satisfactory (Cronbach's alpha 0.85-0.88), and CPQ-G11-14 mean summary scores were correlated in the expected direction with a global measure of self-reported oral health for all the three administration methods. CONCLUSION: In conclusion, the method of administration (face-to-face interview, telephone interview, or self-administered questionnaire) did not influence CPQ-G11-14 scores in 11- to 14-year-old children and adolescents to a significant extent. CLINICAL RELEVANCE: Investigators in German-speaking countries can choose between all three methods of administration to obtain valid and reliable OHRQoL information. PMID- 25700703 TI - Tumor plasma flow determined by dynamic contrast-enhanced MRI predicts response to induction chemotherapy in head and neck cancer. AB - OBJECTIVES: Non-response to induction chemotherapy (IC) occurs in 30% of head and neck squamous cell carcinoma (HNSCC) and has been predicted by tumor plasma flow (Fp) derived by perfusion computed tomography. The present study was designed to test whether baseline tumor Fp determined by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) would predict IC response. MATERIALS AND METHODS: A prospective open study powered to test the relationship between tumor Fp and response to IC (docetaxel, cisplatin, 5-fluorouracil) enrolled 50 patients with stage IV HNSCC. Response after two IC cycles was measured by MRI using Response Evaluation Criteria in Solid Tumors in 37 patients. Tumor Fp (primary end point) and multiple parameters in tumors and lymph nodes (secondary end points) were generated at baseline. Differences in baseline DCE-MRI parameters according to IC response were assessed by the Mann-Whitney U test, and predictive value by receiver operating characteristic (ROC) analysis. RESULTS: Median baseline tumor Fp was 53.2ml/100ml/min in 25 responders and 23.9 in 12 non-responders (U 82; P=0.027; area under ROC curve (AUC) 0.73). Median baseline Fp in lymph nodes was 25.8ml/100ml/min for 37 nodes in 25 responders and 17.1 for 15 nodes in 12 non responders (U 186, P=0.066; AUC 0.67). Frequency of IC response in 37 patients was 68% overall, 83% for tumor Fp above the median (40.6ml/100ml/min) and 45% below the median. Other DCE-MRI parameters were not associated with IC response. CONCLUSION: Pre-treatment tumor Fp determined by DCE-MRI predicts IC response in HNSCC. PMID- 25700702 TI - Analysis of a cardiovascular disease genetic risk score in the Diabetes Heart Study. AB - AIMS: It remains unclear whether the high cardiovascular disease (CVD) burden in people with type 2 diabetes (T2D) is associated with genetic variants that contribute to CVD in general populations. Recent studies have examined genetic risk scores of single-nucleotide polymorphisms (SNPs) identified by genome-wide association studies for their cumulative contribution to CVD-related traits. Most analyses combined SNPs associated with a single phenotypic class, e.g., lipids. In the present analysis, we examined a more comprehensive risk score comprised of SNPs associated with a broad range of CVD risk phenotypes. METHODS: The composite risk score was analyzed for potential associations with subclinical CVD, self reported CVD events, and mortality in 983 T2D-affected individuals of European descent from 466 Diabetes Heart Study (DHS) families. Genetic association was examined using marginal models with generalized estimating equations for subclinical CVD and prior CVD events and Cox proportional hazards models with sandwich-based variance estimation for mortality; analyses were adjusted for age and sex. RESULTS: An increase in genetic risk score was significantly associated with higher levels of coronary artery calcified plaque (p = 1.23 * 10(-4)); however, no significant associations with self-reported myocardial infarction and CVD events and all-cause and CVD mortality were observed. CONCLUSIONS: These results suggest that a genetic risk score of SNPs associated with CVD events and risk factors does not significantly account for CVD risk in the DHS, highlighting the limitations of applying current genetic markers for CVD in individuals with diabetes. PMID- 25700704 TI - P7170: A Novel Molecule with Unique Profile of mTORC1/C2 and Activin Receptor like Kinase 1 Inhibition Leading to Antitumor and Antiangiogenic Activity. AB - The mTOR pathway is often upregulated in cancer and thus intensively pursued as a target to design novel anticancer therapies. Approved and emerging drugs targeting the mTOR pathway have positively affected the clinical landscape. Recently, activin receptor-like kinase 1 (ALK1), belonging to the TGFbeta receptor family, has been reported as an emerging target for antiangiogenic cancer therapy. Here, we describe a novel orally efficacious compound, P7170, that inhibits mTORC1/mTORC2/ALK1 activity with a potent cell growth inhibition. In cell-based assays, P7170 strongly inhibited (IC50 < 10 nmol/L) the phosphorylation of p70S6K (T389) and pAKT (S473). In many cancer cell lines, such as prostate, ovarian, colon, and renal, P7170 treatment resulted in marked cell growth inhibition. Furthermore, it induced G1-S cell-cycle arrest and autophagy. In vitro HUVEC tube formation, in vivo Matrigel plug, and rat aorta ring assays demonstrated that P7170 exhibited significant antiangiogenic activity. In addition, ALK1 knockdown studies in HUVEC confirmed that the antiangiogenic activity of P7170 was primarily due to ALK1 inhibition. Strong inhibition of ALK1 in addition to mTORC1/mTORC2 differentiates P7170 in its mechanism of action in comparison with existing inhibitors. In vivo mouse xenograft studies revealed P7170 to exhibit a significant dose-dependent tumor growth inhibition in a broad range of human tumor types when administered orally at 10 to 20 mg/kg doses. The distinctive pharmacological profile with favorable pharmacokinetic parameters and in vivo efficacy makes P7170 an attractive candidate for clinical development. It is currently being tested in phase I clinical studies. PMID- 25700705 TI - Trifluridine Induces p53-Dependent Sustained G2 Phase Arrest with Its Massive Misincorporation into DNA and Few DNA Strand Breaks. AB - Trifluridine (FTD) is a key component of the novel oral antitumor drug TAS-102, which consists of FTD and a thymidine phosphorylase inhibitor. Like 5-fluoro-2' deoxyuridine (FdUrd), a deoxynucleoside form of 5-fluorouracil metabolite, FTD is sequentially phosphorylated and not only inhibits thymidylate synthase activity, but is also incorporated into DNA. Although TAS-102 was effective for the treatment of refractory metastatic colorectal cancer in clinical trials, the mechanism of FTD-induced cytotoxicity is not completely understood. Here, we show that FTD as well as FdUrd induce transient phosphorylation of Chk1 at Ser345, and that this is followed by accumulation of p53 and p21 proteins in p53-proficient human cancer cell lines. In particular, FTD induced p53-dependent sustained arrest at G2 phase, which was associated with a proteasome-dependent decrease in the Cyclin B1 protein level and the suppression of CCNB1 and CDK1 gene expression. In addition, a p53-dependent increase in p21 protein was associated with an FTD-induced decrease in Cyclin B1 protein. Although numerous ssDNA and dsDNA breaks were induced by FdUrd, few DNA strand breaks were detected in FTD treated HCT-116 cells despite massive FTD misincorporation into genomic DNA, suggesting that the antiproliferative effect of FTD is not due to the induction of DNA strand breaks. These distinctive effects of FTD provide insights into the cellular mechanism underlying its antitumor effect and may explain the clinical efficacy of TAS-102. PMID- 25700706 TI - Retroaortic right internal thoracic artery grafting of circumflex artery targets. AB - BACKGROUND: Retroaortic right internal thoracic artery grafting has failed to gain popularity. We aimed to delineate patient correlates of eligibility, distribution of targets, and effects of target remoteness on outcome and risk of retroaortic bleeding. METHODS: Data of 861 patients undergoing skeletonized bilateral internal thoracic artery grafting (2007-2012) were analyzed according to retroaortic (n = 300) or T-graft configuration. Retroaortic graft subgroups were categorized according to proximal (first obtuse marginal, ramus) or distal (2nd, 3rd, or sequential 1st-2nd obtuse marginal) circumflex artery targets. RESULTS: LOESS curve analyses revealed that taller patients had a higher likelihood of retroaortic grafting. The distribution of 337 retroaortic graft targets (300 patients) was first obtuse marginal in 74.5%, 2nd marginal in 12.4%, ramus in 11.2%, 3rd marginal in 1.9% and sequential 1st-2nd marginal in 12.3%. The success rate in reaching proximal and distal circumflex artery targets was 97% and 30%, respectively, 5-year survival (92.2%) and freedom from major adverse cardiac and cerebrovascular events (85.8%) were comparable between proximal and distal retroaortic graft subgroups. Distal circumflex artery targets had no effect on the occurrence of major adverse cardiac and cerebrovascular events. The incidence of retroaortic bleeding from skeletonized retroaortic grafts was 0.6%. CONCLUSIONS: Taller patients have a greater likelihood of qualifying for retroaortic grafting. This technique is highly reproducible for proximal but not distal circumflex artery targets. Distal circumflex artery targets are not independent correlates of early or late adverse outcomes. The risk of retroaortic bleeding is low despite retroaortic right internal thoracic artery skeletonization. PMID- 25700707 TI - Surgical intervention without lung resection for Pryce type I sequestration. AB - Anomalous systemic arterial supply to normal basal segments of the lower lobe is a rare congenital anomaly. Resection of the affected lung with ligation of the anomalous artery is commonly performed in these patients. We report a case of this anomaly treated surgically with interruption of the anomalous artery after placing a Hem-o-Lok vascular clip. Interruption of the anomalous artery using this vascular clip was easy and safe, and the thoracoscopic approach was minimally invasive. The patient's recovery was uneventful and he was doing well without recurrence 4 years after the operation. PMID- 25700708 TI - Bacteriological Investigation of Chronic Wounds in a Specialized Wound Healing Department: A Retrospective Analysis of 107 Cases. AB - To investigate the information of chronic wounds, especially in the aspect of microbiological profile and to explore the relationship between the wound culture result and chronic wounds infection, we retrospectively reviewed the medical records of 107 patients with chronic wounds from January 2011 to December 2013. The sociodemographic data, wound-related information, therapeutic type, and wound infection status were extracted. Microbial specimens were obtained and processed using standard hospital procedure for wound culture. The predominant pathogen isolated was Staphylococcus aureus (n = 11, 26.2%), followed by Escherichia coli (n = 6, 14.3%), Enterobacter cloacae (n = 3, 7.1%), and Pseudomonas aeruginosa (n = 3, 7.1%). Sixty percent of the infectious chronic wounds had positive culture, and 96.2% of the noninfectious wounds had negative culture. In conclusion, the microbial characteristics were mostly in the site of lower extremity, gram negative bacteria, and monopathogen, respectively. Furthermore, the relationship between the wound culture result and chronic wound infection was not exactly coincident. It may be useful for guiding the empiric therapy of chronic wounds. PMID- 25700709 TI - Transdifferentiation of Umbilical Cord-Derived Mesenchymal Stem Cells Into Epidermal-Like Cells by the Mimicking Skin Microenvironment. AB - Human umbilical cord-derived mesenchymal stem cells (UC-MSCs) are multipotent, primitive, and have been widely used for skin tissue engineering. Their transdifferentiation is determined by the local microenvironment. In this study, we investigated the potential epidermal differentiation of UC-MSCs and the formation of epidermis substitutes in a 3-dimensional (3D) microenvironment, which was fabricated by UC-MSCs embedded into collagen-chitosan scaffolds (CCSs) combined with an air-liquid interface (ALI) culture system. Using fluorescence microscope, we observed that UC-MSCs were spindle-shaped and evenly distributed in the scaffold. Methyl thiazolyl blue tetrazolium bromide assay and Live/Dead assay indicated that the CCSs have good biocompatibility with UC-MSCs. Immunohistochemistry and western blotting assay showed that UC-MSCs on the surface of the CCSs were positive for the epidermal markers cytokeratin 19 and involucrin at 14 days. In addition, hematoxylin-eosin staining indicated that multilayered epidermis substitutes were established. The constructed epidermis substitutes were applied to treat full-thickness wounds in rats and proved to promote wound healing. In conclusion, manipulating the 3D microenvironment is a novel method for inducing the epidermal differentiation of MSCs to engineer epidermal substitutes, which provides an alternative strategy for skin tissue engineering. PMID- 25700710 TI - Detection of Leishmania donovani and L. tropica in Ethiopian wild rodents. AB - Human visceral (VL, also known as Kala-azar) and cutaneous (CL) leishmaniasis are important infectious diseases affecting countries in East Africa that remain endemic in several regions of Ethiopia. The transmission and epidemiology of the disease is complicated due to the complex life cycle of the parasites and the involvement of various Leishmania spp., sand fly vectors, and reservoir animals besides human hosts. Particularly in East Africa, the role of animals as reservoirs for human VL remains unclear. Isolation of Leishmania donovani parasites from naturally infected rodents has been reported in several endemic countries; however, the status of rodents as reservoirs in Ethiopia remains unclear. Here, we demonstrated natural Leishmania infections in rodents. Animals were trapped in 41 localities of endemic and non-endemic areas in eight geographical regions of Ethiopia and DNA was isolated from spleens of 586 rodents belonging to 21 genera and 38 species. Leishmania infection was evaluated by real time PCR of kinetoplast (k)DNA and confirmed by sequencing of the PCR products. Subsequently, parasite species identification was confirmed by PCR and DNA sequencing of the 18S ribosomal RNA internal transcribed spacer one (ITS1) gene. Out of fifty (8.2%) rodent specimens positive for Leishmania kDNA-PCR and sequencing, 10 were subsequently identified by sequencing of the ITS1 showing that five belonged to the L. donovani complex and five to L. tropica. Forty nine kDNA-positive rodents were found in the endemic localities of southern and eastern Ethiopia while only one was identified from northwestern Ethiopia. Moreover, all the ten ITS1-positive rodents were captured in areas where human leishmaniasis cases have been reported and potential sand fly vectors occur. Our findings suggest the eco-epidemiological importance of rodents in these foci of leishmaniasis and indicate that rodents are likely to play a role in the transmission of leishmaniasis in Ethiopia, possibly as reservoir hosts. PMID- 25700711 TI - Schistosomiasis in a migrating population in the lake region of China and its potential impact on control operation. AB - Coverage of migrating people in schistosomiasis control program is a growing concern in China. Schistosomiasis caused by Schistosoma japonicum is still one of the major infectious diseases of public health importance in China though tremendous efforts have been made to control the transmission over the past decades. Along with the rapid social-economic development, migrant population has been remarkably increasing across the country. The infected migrants may introduce a new souse of infection to endemic areas or the areas where the transmission had been controlled or interrupted but the intermediate host Oncomelania snail is still present. Preliminary studies for surveillance on schistosomiasis prevalence in migrants were reported, but there is little basic information provided. We carried out an investigation on the prevalence in immigrants, emigrants and permanent residents in three villages of Hunan province located in the main endemic area of lake region, and analyzed the potential impact of migration on control practice. In the study villages, the migrant population accounts for 53.6% of the total. Schistosoma infection was detected by modified Kato-Katz method and miracidium hatching test. Questionnaire survey was conducted comprising knowledge of disease and its transmission, water contact, personal protective measures, and whether examined and treated after water contact. The survey indicated that the migrants and permanent residents had similar life style, and the majority of them experienced water contact in agricultural work or routine life activities. However, the infection rate in immigrants was significantly higher than that in permanent residents. It was also found that the migrants had significantly less knowledge about the disease than the permanent residents, and took no personal protective measures. This is due to that the control program could not cover the migrants when they were absent at the time the program being implemented. The present study suggested that the surveillance and intervention for migrants, immigrants in particular, should be included and strengthened in schistosomiasis control program and a feasible scheme be developed. PMID- 25700712 TI - Seroprevalence and risk factors of Chlamydia psittaci infection in domestic geese Anser domestica, in Hainan province of China. AB - Chlamydia psittaci, the agent of psittacosis in humans, infects a wide range of bird species. To assess the risk of psittacosis posed by domestic geese in China, the seroprevalence of C. psittaci infection in domestic geese in Hainan province, tropical China was examined using indirect hemagglutination assay (IHA). The overall seroprevalence was estimated at 25.6% (461/1800; 95% CI: 23.6-27.6). The C. psittaci seroprevalence ranged from 19% (95% CI: 14.6-23.4) to 34% (95% CI: 28.6-39.4) among different regions in Hainan province, and the differences were statistically significant (P<0.01). The risk factors significantly associated with C. psittaci seroprevalence were the presence of hygiene conditions, age, gender, and environment of geese in the farms. The results of the present investigation indicated the high seroprevalence of C. psittaci infection in geese in Hainan province, tropical China. Close contact with these geese is associated with a risk of zoonotic transmission of C. psittaci. Public education should be implemented to reduce the risk of avian to human transmission of such a pathogenic agent. To the best of our knowledge, this is the first report documenting the occurrence of C. psittaci seroprevalence in geese in China. PMID- 25700713 TI - First report of Babesia bigemina infection in white yaks in China. AB - White yaks, a unique yak breed and the pearl of the plateau, only live in Tianzhu Tibetan Autonomous County (TTAC), Gansu Province, northwest China, contributing significantly to local economy. However, there was no information on the prevalence of Babesia bigemina in white yaks. In this study, a total of 974 serum samples collected from white yaks in TTAC were examined for specific antibodies against B. bigemina using a commercially available ELISA kit. The overall seroprevalence of B. bigemina in white yaks was 17.76% (173/974). A multivariate logistic regression analysis was performed to determine the risk factors associated with B. bigemina seroprevalence, and the results indicated that age, gender and the numbers of pregnancies of white yaks were not the significant risk factors. However, the white yaks in spring (OR=3.523, 95% CI=1.899-6.538, P<0.001) and summer (OR=3.439, 95% CI=1.909-6.193, P<0.001) encountered higher risk of being exposed to B. bigemina than that in winter. Thus, season was considered as a risk factor associated with B. bigemina infection. This is the first survey of B. bigemina seroprevalence in white yaks in China, which extends the host range for B. bigemina and provides useful information for controlling B. bigemina infection in white yaks. PMID- 25700714 TI - Comparative safety and tolerability of anti-VEGF therapy in age-related macular degeneration. AB - Neovascular age-related macular degeneration (NVAMD) is one of the leading causes of blindness. Over the last decade, the treatment of NVAMD has been revolutionized by the development of intravitreal anti-vascular endothelial growth factor (VEGF) therapies. Several anti-VEGF medications are used for the treatment of NVAMD. The safety and tolerability of these medications deserve review given the high prevalence of NVAMD and the significant utilization of these medications. Numerous large randomized clinical trials have not shown any definitive differential safety relative to ocular or systemic safety of these medications. Intravitreal anti-VEGF therapy does appear to impact systemic VEGF levels, but the implications of these changes remain unclear. One unique safety concern relates drug compounding and the potential risks of contamination, specifically for bevacizumab. Continued surveillance for systemic safety concerns, particularly for rare events, is merited. Overall, these medications are well tolerated and effective in the treatment of NVAMD. PMID- 25700715 TI - [Psychological well-being in nursing: relationships with resilience and coping]. AB - AIMS: To determine the differences in resilience, coping, and psychological well being (PWB) among nursing professionals of different hospital services, as well as to establish a structural model in nursing staff where resilience and coping were included. METHOD: Correlational and cross-sectorial study with probabilistic sampling. A sample of 208 nursing professionals from University Hospital of Fuenlabrada (Madrid) took part in the study. This sample consisted of nurses (n = 133), nursing assistants (n = 61), and midwives (n = 14), of whom 94 worked in special units and 114 worked in wards. INSTRUMENTS: 10-Item CD-RISC (resilience), Brief-Cope (coping strategies), PWB scales (PWB dimensions), and sociodemographic variables. RESULTS: No differences were found in any assessed psychological variables as regards hospital service worked in. A structural model was found where resilience was a precursor factor of coping that determined the PWB of the nurses. Resilience favoured strategies related to engagement coping with stressful situations (beta = 0.56) that contributed to PWB (beta = 0.43) (these relationships were inverted in the case of disengagement coping). CONCLUSIONS: Resilience is an inherent feature in nursing staff whether they work in special units or wards. Coping strategies focused on engagement (or adaptive) with the stressful situation determined nursing PWB (primarily self-acceptance and environment mastery dimensions). Resilience and coping strategies more adaptives constitute two personal resources that determine PWB. PMID- 25700716 TI - [Impact on quality of life in caregivers of stroke survivors]. AB - Stroke is the first cause of disability in adults. Often, the care falls on the family and can affect their quality of life. AIM: To determine the health-related quality of life and the level of caregiver burden of a patient after a stroke. METHOD: Descriptive and cross-sectional study. Caregivers, who had cared for a patient for more than six months and without pay, were included. This study had been approved by the Ethics Committee. Variables collected: sociodemographic, EuroQol-5D questionnaire, Zarit scale, mood and sleep problems. RESULTS: Forty eight caregivers were included, with a mean age of 55.63 (SD: 13.48) and the majority were women (70.8%). The mean time of the care was 28.8 months (SD: 28.68), with 58% stated having a depressed mood, 31% had burden, and 89.6% had sleep problems. The dimensions that presented problems (moderate and severe) in the EQ-5D were pain-discomfort (66.7%) and anxiety-depression (68.8%). The score on the visual analog scale rating of quality of life was associated with a worse mood (75.5 vs. 32, p=0.0028), with the pain (81.94 vs. 38, p<0.001), and Zarit scale (r:<0.334, p=0.020). CONCLUSIONS: The role of caregivers of stroke patients often falls on women. To be a caregiver affects the quality of life, mainly in the pain-discomfort and anxiety-depression dimensions, regardless of the functional status of the patient. Nurses must identify the psychopathological needs and develop strategies on the prevention of the risk of burnout. PMID- 25700717 TI - Molecular and biochemical characterization of Entamoeba histolytica fructokinase. AB - Entamoeba histolytica is the causative agent of amoebic dysentery and liver abscess. The medium for its axenic culture contains glucose as energy source, and we addressed the question whether E. histolytica can also use fructose instead. As the amoebic hexokinases do not phosphorylate fructose, a separate fructokinase is essential. The genome project revealed a single candidate gene encoding an E. histolytica homolog of bacterial fructokinases. This gene was cloned, and the recombinant enzyme had a magnesium-dependent fructose 6-kinase activity (EC 2.7.1.4) with a K m for fructose of 0.156 mM and a V max of 131 U/mg protein. Recombinant fructokinase also showed a much weaker mannokinase activity, but no activity with glucose or galactose. The amoebae could be switched from glucose to fructose medium without any detectable consequence on doubling time. Fructokinase messenger RNA (mRNA) was modestly but significantly upregulated in amoebae switched to fructose medium as well as in fructose-adapted E. histolytica. PMID- 25700718 TI - NICTABA and UDA, two GlcNAc-binding lectins with unique antiviral activity profiles. AB - OBJECTIVES: This study aimed to assess the antiviral properties of a unique lectin (NICTABA) produced by the tobacco plant, Nicotiana tabacum. METHODS: Cellular assays were used to investigate the antiviral activity of NICTABA and Urtica dioica agglutinin (UDA). Surface plasmon resonance (SPR) studies were performed to study the sugar specificity and the interactions of both lectins with the envelope glycoproteins of HIV-1. RESULTS: The N-acetyl-d-glucosamine (GlcNAc)-binding lectins exhibited broad-spectrum activity against several families of enveloped viruses including influenza A/B, Dengue virus type 2, herpes simplex virus types 1 and 2 and HIV-1/2. The IC50 of NICTABA for various HIV-1 strains, clinical isolates and HIV-2 assessed in PBMCs ranged from 5 to 30 nM. Furthermore, NICTABA inhibited syncytium formation between persistently HIV-1 infected T cells and uninfected CD4+ T lymphocytes and prevented DC-SIGN-mediated HIV-1 transmission to CD4+ target T lymphocytes. However, unlike many other antiviral carbohydrate-binding agents (CBAs) described so far, NICTABA did not block HIV-1 capture to DC-SIGN+ cells and it did not interfere with the binding of the human monoclonal antibody 2G12 to gp120. SPR studies with HIV-1 envelope glycoproteins showed that the affinity of NICTABA for gp120 and gp41 was in the low nanomolar range. The specific binding of NICTABA to gp120 could be prevented in the presence of a GlcNAc trimer, but not in the presence of mannose trimers. NICTABA displayed no antiviral activity against non-enveloped viruses. CONCLUSIONS: Since CBAs possess a high genetic barrier for the development of viral resistance and NICTABA shows a broad antiviral activity profile, this CBA may qualify as a potential antiviral candidate with a pleiotropic mode of action aimed at targeting the entry of enveloped viruses. PMID- 25700719 TI - Virological failure of patients on maraviroc-based antiretroviral therapy. AB - OBJECTIVES: Virological failure (VF) in patients on maraviroc-based treatment has been associated with altered HIV tropism and resistance to maraviroc. This multicentre study aimed to characterize VF in patients treated with maraviroc. METHODS: We analysed 27 patients whose treatment failed between 2008 and 2011. They had been screened for HIV tropism before maraviroc initiation using population-based V3 genotyping. HIV-1 tropism and resistance of R5 viruses to maraviroc at VF and at baseline were determined retrospectively using an ultrasensitive recombinant virus assay (RVA). RESULTS: Viruses from 27 patients given maraviroc on the basis of the R5 genotype were characterized at the time of treatment failure. The RVA indicated that 12 patients harboured CXCR4-using viruses and 15 (56%) had pure R5 viruses at failure. One-third of those harbouring CXCR4-using viruses (4/12) were infected with R5X4/X4 viruses according to the RVA before maraviroc initiation. We analysed the phenotypic resistance to maraviroc of four patients harbouring R5 viruses at failure; two harboured viruses whose maximum percentage inhibition was reduced by 65%-90%, while the other two were infected with susceptible viruses. All patients had effective concentrations of drugs. CONCLUSIONS: Half of the maraviroc-treated patients who experienced VF harboured CXCR4-using viruses at failure, one-third of them were detected by a phenotypic method before maraviroc initiation. Phenotypic assessment of R5 virus resistance to CCR5 antagonists at failure could help optimize antiretroviral therapy. PMID- 25700720 TI - Circulating fibroblast growth factor 23 (FGF23) levels are associated with metabolic disturbances and fat distribution but not cardiovascular risk in HIV infected patients. AB - OBJECTIVES: Dyslipidaemia, insulin resistance, metabolic syndrome and HIV/HAART associated lipodystrophy syndrome (HALS) are common comorbidities in HIV-1 infected patients, which may increase cardiovascular risk. Fibroblast growth factor 23 (FGF23) is a bone-derived hormone with effects on metabolism and phosphate homeostasis. The aim of this study was to determine the relationship between FGF23 levels, metabolic alterations, fat distribution and cardiovascular risk. METHODS: This was a cross-sectional study. Serum FGF23 levels were analysed in 152 patients and 34 healthy control individuals. Patients belonged to three groups: HIV-1-infected, antiretroviral-treated patients who have developed HALS (n = 60); HIV-1-infected, antiretroviral-treated patients without HALS (n = 43); and untreated (naive) HIV-1-infected patients (n = 49). Serum FGF23 levels were compared with lipid and glucose homeostasis parameters, fat distribution and cardiovascular risk. RESULTS: Serum FGF23 levels were increased in HIV-1-infected patients, but the increase was most marked in those with HALS. FGF23 levels showed a strong positive correlation with age, indicators of dyslipidaemia (LDL cholesterol, polyunsaturated fatty acids and monounsaturated fatty acids), HALS parameters (trunk/appendicular fat ratio), insulin resistance (fasting insulin and homeostasis model assessment of insulin resistance) and C-reactive protein. FGF23 levels correlated with cardiovascular risk but correlation was lost after age adjustment. CONCLUSIONS: FGF23 levels are increased in HIV-1-infected patients, especially in those with HALS, and this increase is associated with dyslipidaemia, insulin resistance, metabolic syndrome, fat distribution and parameters of inflammation. FGF23 is not associated with cardiovascular risk when age is taken into account. PMID- 25700722 TI - [Cerebral amyloid angiopathy-related inflammation]. PMID- 25700721 TI - Analytical methods for kinetic studies of biological interactions: A review. AB - The rates at which biological interactions occur can provide important information concerning the mechanism and behavior of these processes in living systems. This review discusses several analytical methods that can be used to examine the kinetics of biological interactions. These techniques include common or traditional methods such as stopped-flow analysis and surface plasmon resonance spectroscopy, as well as alternative methods based on affinity chromatography and capillary electrophoresis. The general principles and theory behind these approaches are examined, and it is shown how each technique can be utilized to provide information on the kinetics of biological interactions. Examples of applications are also given for each method. In addition, a discussion is provided on the relative advantages or potential limitations of each technique regarding its use in kinetic studies. PMID- 25700723 TI - [Between Werther and Papageno effects]. AB - Research on the impact of suicide depictions in the media is traditionally focussed on two possible outcomes: on the one hand, there is ample evidence for additional copycat effects after media coverage of suicides referred to as the Werther effect but on the other hand, suicide rates decrease after appropriate media depictions of suicides referred to as the Papageno effect. It is still uncertain what exactly qualifies studies that only limitedly support an imitative or preventive media effect, i.e. studies with ambiguous findings, as they are often disregarded. The present literature review focuses on equivocal studies (n = 25) on copycat suicides that were systematically analyzed based on theoretically derived criteria. The results of the systematic analysis of all identified studies imply that media effects on suicidality are better understood and discussed as a continuum between the two extremes that were introduced as either a damaging Werther effect or a beneficial Papageno effect. Future studies must clarify what factors contribute to a shift from ambiguous findings to harmful media effects on individual suicidality. PMID- 25700724 TI - Resveratrol: Challenges in translating pre-clinical findings to improved patient outcomes. PMID- 25700725 TI - A novel ultra-high performance liquid chromatography method for the rapid determination of beta-lactoglobulin as heat load indicator in commercial milk samples. AB - The level of undenatured acid-soluble beta-lactoglobulin can be used as an indicator to assess the heat load applied to liquid milk, thus further allowing the discrimination between milk originating from different thermal production processes. In this work, a new UHPLC method for the rapid determination of bovine beta-lactoglobulin in 1.8min only (total runtime 3min) is presented using simple UV detection at 205nm. Separation selectivity for possibly co-eluting other major whey proteins (bovine serum albumin, lactoferrin, alpha-lactalbumin, immunoglobulin G) was verified, and the method validated for the analysis of liquid milk samples regarding linearity (20-560MUg/mL, R(2)>0.99), instrumentation precision (RSDs<2.8%), limits of detection and quantification (7 and 23mg/L milk), repeatability of sample work-up (RSDs<=2.6%) and method recovery (103%). In total, 71 commercial liquid milk samples produced using different preservation techniques (e.g., thermal or mechanical treatment), hence featuring different applied heat loads, were profiled for their intrinsic undenatured acid-soluble beta-lactoglobulin levels. As expected, pasteurized milk showed the highest concentrations clearly above 3000mg/L due to pasteurization being the mildest thermal treatment, while in contrast, ultra-high temperature heated milk featured the lowest amounts (<200mg/L). For extended shelf life (ESL) milk, quite diverse levels were determined ranging from ~100 up to 4000mg/L, thus clearly illustrating variable applied heat loads and impacts on the "nativeness" of milk essentially due to the fact that the production technologies used for ESL milk may differ significantly, and are currently not regulated in the EU. PMID- 25700726 TI - New reversed phase-high performance liquid chromatographic method for selective separation of yttrium from all rare earth elements employing nitrilotriacetate complexes in anion exchange mode. AB - Separation of Y from other rare earth elements (REE) is difficult because of similarity of its ionic radius to ionic radii of Tb, Dy and Ho. In the new RP HPLC system with C18 column, tetra-n-butyl ammonium hydroxide (TBAOH) as an ion interaction reagent (IIR), nitrilotriacetic acid (NTA) as a complexing agent at pH=2.8-3.5, and post column derivatization with Arsenazo III, yttrium is eluted in the region of light REE, between Nd and Sm and is base line separated from Nd and Sm and even from promethium. Simple model employing literature data on complex formation of REE with NTA and based on anion exchange mechanism was developed to foresee the order of elution of individual REE. The model correctly predicted that lanthanides up to Tb will be eluted in the order of increasing Atomic Number (At.No.) but all heavier REE will show smaller retention factors than Tb. Concurrent UV/VIS detection at 658nm and the use of radioactive tracers together with gamma-ray spectrometric measurements made possible to establish an unique elution order of elution of REE: La, Ce, Pr, Nd, Pm, Y, Sm, Er, Ho, Tm, Yb, Eu, Lu, Dy+Gd, Tb, Sc. The real place of Y however, in this elution series differs from that predicted by the model (Y between Sm and Eu). The method described in this work enables selective separation of Y from La, Ce, Pr, Nd, Pm, Sm and all heavier REE treated as a group. PMID- 25700727 TI - Comorbidity of mood and substance use disorders in patients with binge-eating disorder: Associations with personality disorder and eating disorder pathology. AB - OBJECTIVE: Binge-eating disorder (BED) is associated with elevated rates of mood and substance use disorders, but the significance of such comorbidity is ambiguous. We compared personality disorder and eating disorder psychopathology in four subgroups of BED patients: those with mood disorders, those with substance use disorders, those with both, and those with neither. METHOD: Subjects were 347 patients who met DSM-IV research criteria for BED. Semistructured interviews evaluated lifetime DSM-IV axis I disorders, DSM-IV personality disorder features, and eating disorder psychopathology. RESULTS: Among these patients, 129 had co-occurring mood disorder, 34 had substance use disorder, 60 had both, and 124 had neither. Groups differed on personality disorder features, with those having mood disorder and both mood and substance use disorders showing the highest frequencies. Although groups did not differ in body mass index or binge eating frequency, they did differ on eating disorder psychopathology-with the groups having mood disorder and both comorbidities demonstrating higher eating, weight, and shape concerns. No differences were observed between groups with respect to ages of onset for specific eating behaviors, but some differences were observed for ages of disorder onset. CONCLUSION: Mood and substance use disorders co-occur frequently among patients with BED. Compared with a previous work, the additional comparison group (those with both mood and substance use disorders) and the control group (those with neither) afforded better discrimination regarding the significance of these comorbidities. Our findings suggest approaches to subtyping BED based on psychiatric comorbidity, and may also have implications for treatment. PMID- 25700728 TI - On the correlation between perceptual inundation caused by realistic immersive environmental auditory scenes and the sensory gating inventory in schizophrenia. AB - BACKGROUND: In schizophrenia, perceptual inundation related to sensory gating deficit can be evaluated "off-line" with the sensory gating inventory (SGI) and "on-line" during listening tests. However, no study investigated the relation between "off-line evaluation" and "on-line evaluation". The present study investigates this relationship. METHODS: A sound corpus of 36 realistic environmental auditory scenes was obtained from a 3D immersive synthesizer. Twenty schizophrenic patients and twenty healthy subjects completed the SGI and evaluated the feeling of "inundation" from 1 ("null") to 5 ("maximum") for each auditory scene. Sensory gating deficit was evaluated in half of each population group with P50 suppression electrophysiological measure. RESULTS: Evaluation of inundation during sound listening was significantly higher in schizophrenia (3.25) compared to the control group (2.40, P<.001). The evaluation of inundation during the listening test correlated significantly with the perceptual modulation (n=20, rho=.52, P=.029) and the over-inclusion dimensions (n=20, rho=.59, P=.01) of the SGI in schizophrenic patients and with the P50 suppression for the entire group of controls and patients who performed ERP recordings (n=20, rho=-.49, P=.027). CONCLUSION: An evaluation of the external validity of the SGI was obtained through listening tests. The ability to control acoustic parameters of each of the realistic immersive environmental auditory scenes might in future research make it possible to identify acoustic triggers related to perceptual inundation in schizophrenia. PMID- 25700729 TI - Dynamic heterogeneity of DNA methylation and hydroxymethylation in embryonic stem cell populations captured by single-cell 3D high-content analysis. AB - Cell-surface markers and transcription factors are being used in the assessment of stem cell fate and therapeutic safety, but display significant variability in stem cell cultures. We assessed nuclear patterns of 5-hydroxymethylcytosine (5hmC, associated with pluripotency), a second important epigenetic mark, and its combination with 5-methylcytosine (5mC, associated with differentiation), also in comparison to more established markers of pluripotency (Oct-4) and endodermal differentiation (FoxA2, Sox17) in mouse embryonic stem cells (mESC) over a 10-day differentiation course in vitro: by means of confocal and super-resolution imaging together with 3D high-content analysis, an essential tool in single-cell screening. IN SUMMARY: 1) We did not measure any significant correlation of putative markers with global 5mC or 5hmC. 2) While average Oct-4 levels stagnated on a cell-population base (0.015 lnIU/day), Sox17 and FoxA2 increased 22-fold and 3-fold faster, respectively (Sox17: 0.343 lnIU/day; FoxA2: 0.046 lnIU/day). In comparison, global DNA methylation levels increased 4-fold faster (0.068 lnIU/day), and global hydroxymethylation declined at 0.046 lnIU/day, both with a better explanation of the temporal profile. 3) This progression was concomitant with the occurrence of distinct nuclear codistribution patterns that represented a heterogeneous spectrum of states in differentiation; converging to three major coexisting 5mC/5hmC phenotypes by day 10: 5hmC(+)/5mC(-), 5hmC(+)/5mC(+), and 5hmC(-)/5mC(+) cells. 4) Using optical nanoscopy we could delineate the respective topologies of 5mC/5hmC colocalization in subregions of nuclear DNA: in the majority of 5hmC(+)/5mC(+) cells 5hmC and 5mC predominantly occupied mutually exclusive territories resembling euchromatic and heterochromatic regions, respectively. Simultaneously, in a smaller subset of cells we observed a tighter colocalization of the two cytosine variants, presumably delineating chromatin domains in remodeling. We conclude that 1) 5mC emerges as the most differential marker in our model system. 2) However, the combined enrollment of the two DNA modifications provided higher-definition screening and lead to the identification of cell subpopulations based on differential 5hmC/5mC phenotypes corresponding to different 5hmC/5mC ratios. The results encourage: a) assessing the regenerative potential of early-endodermal cells enriched for the three DNA methylation/hydroxymethylation categories, and b) exploring the universality of this type of epigenetic phenotyping across other lineage-specific differentiations. PMID- 25700730 TI - From the Editor's perspective... PMID- 25700731 TI - Guest editorial: A care perspective: palliative care. PMID- 25700732 TI - "Standing still in the street": experiences, knowledge and beliefs of patients with intermittent claudication--a qualitative study. AB - OBJECTIVES: To explore the experiences of individuals living with intermittent claudication (IC) owing to peripheral artery disease (PAD), their knowledge about the condition, and their thoughts about being asked to walk more and an intervention to promote walking. METHODS: We conducted five focus group sessions with 24 people (71% male; mean age, 71 years) diagnosed with IC with no prior lower extremity revascularization. RESULTS: Two overriding themes emerged: uncertainty and lack of support/empathy. Participants expressed uncertainty about PAD and IC, how risk factors work, and whether lifestyle change, particularly walking, would help. They also expressed dissatisfaction with and lack of empathy from the medical professionals encountered, with feelings of being dismissed and left on their own. There was enthusiasm for an education program to support their self-management of the disease. CONCLUSIONS: Addressing the knowledge gaps and uncertainty around the disease process and walking will be critical to providing impetus to behavior change. A structured education approach to address these issues seems to be desirable and acceptable to those living with PAD. PRACTICE IMPLICATIONS: Those working with PAD patients should provide clear and consistent information about the disease process and specific information on walking, as well as support to enable and manage behavior change. PMID- 25700733 TI - Pharmacotherapy of heparin-induced thrombocytopenia: therapeutic options and challenges in the clinical practices. AB - Heparin-induced thrombocytopenia (HIT) is an immune response to heparin associated with significant morbidity and mortality in hospitalized patients if unidentified as soon as possible, owing to thromboembolic complications involving both arterial and venous systems. Early diagnoses based on a comprehensive interpretation of clinical and laboratory information improves clinical outcomes. Management principles of strongly suspected HIT should not be delayed for laboratory result confirmation. Treatment strategies have been introduced including new, safe, and effective agents. This review summarizes the clinical therapeutic options for HIT addressing the use of parenteral direct thrombin inhibitors and indirect factor Xa inhibitors as well as the potential non-vitamin K antagonist oral anticoagulants. PMID- 25700734 TI - Lower functional capacity is associated with higher cardiovascular risk in Brazilian patients with intermittent claudication. AB - The purpose of this study was to examine the association between cardiovascular risk estimated by the Framingham Risk Score and functional capacity in patients with peripheral artery disease using a 6-minute walk test. Fifty-six participants with intermittent claudication were recruited. The Framingham Risk Score was calculated and used to split the participants into two groups: Group A (mild and moderate risk) and group B (severe risk). The ankle-brachial index (ABI) was calculated for each leg using a handheld Doppler probe. Walking ability was verified by a 6-minute walk test. Descriptive statistics were used to describe the sample's demographic and clinical characteristics. To compare clinical data between the two groups, a t test or Mann-Whitney test was used as appropriate according to the type of variable being analyzed. The Pearson coefficient was used to verify the association between cardiovascular risk and functional capacity. Group A had 19 participants (60.5 +/- 6.3 years; 36.8% male) and group B had 37 participants (63.4 +/- 8.7 years; 73% male). No differences were observed when comparing the ABI between both groups. The total distances covered by the men in group A were shorter compared with those of group B (331.4 + 51.5 vs 257.9 + 84.0; P = .02). The cardiovascular risk score was negative and was significantly correlated with total distances for men (r = -0.53; P = .001) and with pain-free distances for women (r = -0.46; P = .03). Functional capacity, evaluated through a 6-minute walk test, seems to be associated with 10-year total mortality risk. PMID- 25700735 TI - Carotid bruit: a review. PMID- 25700736 TI - Review of article: Perioperative management with antiplatelet and statin medication is associated with reduced mortality following vascular surgery by Randall R. Martino, MD, MS, et al (J Vasc Surg 2014; 59:1615-21). PMID- 25700737 TI - A novel mechanism of autophagic cell death in dystrophic muscle regulated by P2RX7 receptor large-pore formation and HSP90. AB - P2RX7 is an ATP-gated ion channel, which can also exhibit an open state with a considerably wider permeation. However, the functional significance of the movement of molecules through the large pore (LP) and the intracellular signaling events involved are not known. Here, analyzing the consequences of P2RX7 activation in primary myoblasts and myotubes from the Dmd(mdx) mouse model of Duchenne muscular dystrophy, we found ATP-induced P2RX7-dependent autophagic flux, leading to CASP3-CASP7-independent cell death. P2RX7-evoked autophagy was triggered by LP formation but not Ca(2+) influx or MAPK1-MAPK3 phosphorylation, 2 canonical P2RX7-evoked signals. Phosphoproteomics, protein expression inference and signaling pathway prediction analysis of P2RX7 signaling mediators pointed to HSPA2 and HSP90 proteins. Indeed, specific HSP90 inhibitors prevented LP formation, LC3-II accumulation, and cell death in myoblasts and myotubes but not in macrophages. Pharmacological blockade or genetic ablation of p2rx7 also proved protective against ATP-induced death of muscle cells, as did inhibition of autophagy with 3-MA. The functional significance of the P2RX7 LP is one of the great unknowns of purinergic signaling. Our data demonstrate a novel outcome- autophagy--and show that molecules entering through the LP can be targeted to phagophores. Moreover, we show that in muscles but not in macrophages, autophagy is needed for the formation of this LP. Given that P2RX7-dependent LP and HSP90 are critically interacting in the ATP-evoked autophagic death of dystrophic muscles, treatments targeting this axis could be of therapeutic benefit in this debilitating and incurable form of muscular dystrophy. PMID- 25700739 TI - How the Atg1 complex assembles to initiate autophagy. AB - The Atg1 complex, comprising Atg1, Atg13, Atg17, Atg29, and Atg31, is a key initiator of autophagy. The Atg17-Atg31-Atg29 subcomplex is constitutively present at the phagophore assembly site (PAS), while Atg1 and Atg13 join the complex when autophagy is triggered by starvation or other signals. We sought to understand the energetics and dynamics of assembly using isothermal titration calorimetry (ITC), sedimentation velocity analytical ultracentrifugation, and hydrogen-deuterium exchange (HDX). We showed that the membrane and Atg13-binding domain of Atg1, Atg1EAT, is dynamic on its own, but is rigidified in its high affinity (~100 nM) complex with Atg13. Atg1EAT and Atg13 form a 2:2 dimeric assembly and together associate with lower affinity (~10 MUM) with the 2:2:2 Atg17-Atg31-Atg29 complex. These results lead to an overall model for the assembly pathway of the Atg1 complex. The model highlights the Atg13-Atg17 binding event as the weakest link in the assembly process and thus as a natural regulatory checkpoint. PMID- 25700738 TI - Mitochondrial damage contributes to Pseudomonas aeruginosa activation of the inflammasome and is downregulated by autophagy. AB - The nucleotide-binding domain, leucine-rich repeat containing family caspase recruitment domain containing 4 (NLRC4) inflammasome can be activated by pathogenic bacteria via products translocated through the microbial type III secretion apparatus (T3SS). Recent work has shown that activation of the NLRP3 inflammasome is downregulated by autophagy, but the influence of autophagy on NLRC4 activation is unclear. We set out to determine how autophagy might influence this process, using the bacterium Pseudomonas aeruginosa, which activates the NLRC4 inflammasome via its T3SS. Infection resulted in T3SS dependent mitochondrial damage with increased production of reactive oxygen intermediates and release of mitochondrial DNA. Inhibiting mitochondrial reactive oxygen release or degrading intracellular mitochondrial DNA abrogated NLRC4 inflammasome activation. Moreover, macrophages lacking mitochondria failed to activate NLRC4 following infection. Removal of damaged mitochondria by autophagy significantly attenuated NLRC4 inflammasome activation. Mitochondrial DNA bound specifically to NLRC4 immunoprecipitates and transfection of mitochondrial DNA directly activated the NLRC4 inflammasome; oxidation of the DNA enhanced this effect. Manipulation of autophagy altered the degree of inflammasome activation and inflammation in an in vivo model of P. aeruginosa infection. Our results reveal a novel mechanism contributing to NLRC4 activation by P. aeruginosa via mitochondrial damage and release of mitochondrial DNA triggered by the bacterial T3SS that is downregulated by autophagy. PMID- 25700740 TI - A nutrigenomic approach to detect nutritional stress from gene expression in blood samples drawn from Steller sea lions. AB - Gene expression profiles are increasingly being used as biomarkers to detect the physiological responses of a number of species to disease, nutrition, and other stressors. However, little attention has been given to using gene expression to assess the stressors and physiological status of marine mammals. We sought to develop and validate a nutrigenomic approach to quantify nutritional stress in Steller sea lions (Eumetopias jubatus). We subjected 4 female Steller sea lions to 3 feeding regimes over 70-day trials (unrestricted food intake, acute nutritional stress, and chronic nutritional stress), and drew blood samples from each animal at the end of each feeding regime. We then extracted the RNA of white blood cells and measured the response of 8 genes known to react to diet restriction in terrestrial mammals. Overall, we found that the genomic response of Steller sea lions experiencing nutritional stress was consistent with how terrestrial mammals respond to dietary restrictions. Our nutritionally stressed sea lions down-regulated some cellular processes involved in immune response and oxidative stress, and up-regulated pro-inflammatory responses and metabolic processes. Nutrigenomics appears to be a promising means to monitor nutritional status and contribute to mitigation measures needed to assist in the recovery of Steller sea lions and other at-risk species of marine mammals. PMID- 25700741 TI - Seasonal changes in body mass, serum leptin levels and hypothalamic neuropeptide gene expression in male Eothenomys olitor. AB - The present study examined seasonal changes in body mass and energy metabolism in the Chaotung vole (Eothenomys olitor) and the physiological mechanisms underpinning these changes. Seasonal changes in the following parameters were measured in male E. olitor, body mass, food intake, thermogenesis, enzyme activity, masses of tissues and organs, hormone concentrations and expression of hypothalamic arcuate nucleus energy balance genes including neuropeptide Y (NPY), agouti-related protein (AgRP), pro-opiomelanocortin (POMC), and cocaine- and amphetamine-regulated transcript (CART). Body mass was constant over the year, but the masses of tissues and organs differed significantly between seasons. There were significant changes in body fat mass and serum leptin levels over the four seasons. E. olitor showed significant seasonal changes in food intake and thermogenesis, uncoupling protein 1 (UCP1) content, enzyme activity, and serum tri-iodothyronine (T3) and thyroxine (T4) levels. Moreover, mRNA expression in the hypothalamus showed significant seasonal changes. All of our results suggested that E. olitor had constant body mass over the year, which was inconsistent with the prediction of the 'set-point' hypothesis. However, body fat mass and serum leptin levels were significantly different among the four seasons, providing support for the 'set-point' hypothesis. The changes in leptin, NPY, AgRP, POMC, and CART mRNA levels may play a role in the regulation of energy intake in E. olitor. Furthermore, the role of leptin and hypothalamic neuropeptide gene in the regulation of energy metabolism and body mass may be different in animals that are acclimated to different seasons. PMID- 25700742 TI - The role of the amygdala during emotional processing in Huntington's disease: from pre-manifest to late stage disease. AB - BACKGROUND: Deficits in emotional processing can be detected in the pre-manifest stage of Huntington's disease and negative emotion recognition has been identified as a predictor of clinical diagnosis. The underlying neuropathological correlates of such deficits are typically established using correlative structural MRI studies. This approach does not take into consideration the impact of disruption to the complex interactions between multiple brain circuits on emotional processing. Therefore, exploration of the neural substrates of emotional processing in pre-manifest HD using fMRI connectivity analysis may be a useful way of evaluating the way brain regions interrelate in the period prior to diagnosis. METHODS: We investigated the impact of predicted time to disease onset on brain activation when participants were exposed to pictures of faces with angry and neutral expressions, in 20 pre-manifest HD gene carriers and 23 healthy controls. On the basis of the results of this initial study went on to look at amygdala dependent cognitive performance in 79 Huntington's disease patients from a cross-section of disease stages (pre-manifest to late disease) and 26 healthy controls, using a validated theory of mind task: "the Reading the Mind in the Eyes Test" which has been previously been shown to be amygdala dependent. RESULTS: Psychophysiological interaction analysis identified reduced connectivity between the left amygdala and right fusiform facial area in pre-manifest HD gene carriers compared to controls when viewing angry compared to neutral faces. Change in PPI connectivity scores correlated with predicted time to disease onset (r=0.45, p<0.05). Furthermore, performance on the "Reading the Mind in the Eyes Test" correlated negatively with proximity to disease onset and became progressively worse with each stage of disease. CONCLUSION: Abnormalities in the neural networks underlying social cognition and emotional processing can be detected prior to clinical diagnosis in Huntington's disease. Connectivity between the amygdala and other brain regions is impacted by the disease process in pre-manifest HD and may therefore be a useful way of identifying participants who are approaching a clinical diagnosis. Furthermore, the "Reading the Mind in the Eyes Test" is a surrogate measure of amygdala function that is clinically useful across the entire cross-section of disease stages in HD. PMID- 25700743 TI - Intracellular trehalose and sorbitol synergistically promoting cell viability of a biocontrol yeast, Pichia anomala, for aflatoxin reduction. AB - Pichia anomala (Wickerhamomyces anomalus) WRL-076 was discovered by a visual screening bioassay for its antagonism against Aspergillus flavus. The yeast was shown to significantly inhibit aflatoxin production and the growth of A. flavus. P. anomala is a potential biocontrol agent for reduction of aflatoxin in the food chain. Maintaining the viability of biocontrol agents in formulated products is a great challenge for commercial applications. Four media, NYG, NYGS, NYGT and NYGST are described which support good growth of yeast cells and were tested as storage formulations. Post growth supplement of 5 % trehalose to NYGST resulted in 83 % viable yeast cells after 12 months in cold storage. Intracellular sorbitol and trehalose concentrations were determined by HPLC analysis at the beginning of the storage and at the end of 12 month. Correlation of cell viability to both trehalose and sorbitol suggested a synergistic effect. Bonferroni (Dunn) t Test, Tukey's Studentized Range (HSD) Test and Duncan's Multiple Range Test, all showed that yeast cell viability in samples with both intracellular trehalose and sorbitol were significantly higher than those with either or none, at a 95 % confidence level. DiBAC4(5) and CFDA-AM were used as the membrane integrity fluorescent stains to create a two-color vital staining scheme with red and green fluorescence, respectively. Yeast cells stored in formulations NYG and NYGS with no detectable trehalose, displayed mostly red fluorescence. Yeast cells in NYGST+5T showed mostly green fluorescence. PMID- 25700744 TI - Rhizobacterial communities associated with spontaneous plant species in long-term arsenic contaminated soils. AB - The microbial community composition in three soil fractions (bulk soil, rhizosphere and rhizoplane) of the root-soil system of a thistle, Cirsium arvense, and of a tufted hair grass, Deschampsia caespitosa, was investigated. The two spontaneous wild plant species were predominant in two Italian lands contaminated since centuries by arsenic and at present show high levels of arsenic (from 215 to 12,500 mg kg(-1)). In order to better understand how the rhizobacterial ecosystem responds to a long-term arsenic contamination in term of composition and functioning, culture-independent techniques (DAPI counts, fluorescence in situ hybridization and denaturing gradient gel electrophoresis analysis) along with cultivation-based methods were applied. Microbial community structure was qualitatively similar in the two root-soil systems, but some quantitative differences were observed. Bacteria of the alpha-, beta-, and gamma subclasses of the Proteobacteria were dominant in all fractions, while the subdominant groups (Cytophagaceae, gram-positive spore-forming, and filamentous bacteria) were significantly more abundant in the root-soil system of D. caespitosa. As regards to arsenic resistant strains, Firmicutes, Actinobacteria, Enterobacteria and gamma-Proteobacteria were isolated from soil system of both plants. Our results suggest that the response to a high level of arsenic contamination governed the rhizosphere microbial community structure together with the soil structure and the plant host type effects. Data from this study can provide better understanding of complex bacterial communities in metal-polluted soils, as well as useful information of indigenous bacterial strains with potential application to soil remediation. PMID- 25700745 TI - Percutaneous circulatory assist devices for high-risk coronary intervention. AB - A unifying definition of what constitutes high-risk percutaneous coronary intervention remains elusive. This reflects the existence of several recognized patient, anatomic, and procedural characteristics that, when combined, can contribute to elevating risk. The relative inability to withstand the adverse hemodynamic sequelae of dysrhythmia, transient episodes of ischemia-reperfusion injury, or distal embolization of atherogenic material associated with coronary intervention serve as a common thread to tie this patient cohort together. This enhanced susceptibility to catastrophic hemodynamic collapse has triggered the development of percutaneous cardiac assist devices such as the intra-aortic balloon pump, Impella (Abiomed Inc., Danvers, Massachusetts), TandemHeart (CardiacAssist, Inc., Pittsburgh, Pennsylvania), and extracorporeal membranous oxygenation to provide adjunctive mechanical circulatory support. In this state of-the-art review, we discuss the physiology underpinning their application. Thereafter, we examine the results of several randomized multicenter trials investigating their use in high-risk coronary intervention to determine which patients would benefit most from their implantation and whether there is a signal to delineate whether they should be used in an elective pre-procedure, standby, rescue, or routine post-procedure fashion. PMID- 25700746 TI - Procedural outcomes of chronic total occlusion percutaneous coronary intervention: a report from the NCDR (National Cardiovascular Data Registry). AB - OBJECTIVES: The aim of this study was to describe contemporary frequency, predictors, and outcomes of chronic total occlusion (CTO) percutaneous coronary intervention (PCI) in the United States. BACKGROUND: CTO PCI can provide significant clinical benefits, yet there is limited information on its success and safety in unselected patient populations. METHODS: We analyzed the frequency and outcomes of CTO PCI compared with non-CTO PCI in elective patients, and of successful versus failed CTO PCI between July 1, 2009, and March 31, 2013, in the National Cardiovascular Data Registry CathPCI Registry. Generalized estimating equations logistic regression modeling was used to generate independent variables associated with procedural success and procedural complications. RESULTS: During the study period, CTO PCI represented 3.8% of the total PCI volume for stable coronary artery disease (22,365 of 594,510). Overall, patients undergoing CTO PCI required greater contrast volume and longer fluoroscopy time and had lower procedural success (59% vs. 96%, p < 0.001) and higher major adverse cardiac event (1.6% vs. 0.8%, p < 0.001) rates than non-CTO PCI patients. On multivariable analysis, several parameters (including older age, current smoking, previous myocardial infarction, previous coronary artery bypass graft, previous peripheral arterial disease, previous cardiac arrest, right coronary artery CTO target vessel, and less operator experience) were associated with a lower likelihood of CTO PCI procedural success, whereas operators' annual CTO PCI volume was associated with improved success without a significant increase in major complications. CONCLUSIONS: CTO PCI is currently performed infrequently in the United States for stable coronary artery disease and is associated with lower procedural success and higher complication rates compared with non-CTO PCI. Procedural success was associated with several patient factors and operator experience. PMID- 25700747 TI - Percutaneous coronary intervention for chronic total occlusions: the power of negative thinking. PMID- 25700748 TI - Coronary computed tomographic prediction rule for time-efficient guidewire crossing through chronic total occlusion: insights from the CT-RECTOR multicenter registry (Computed Tomography Registry of Chronic Total Occlusion Revascularization). AB - OBJECTIVES: This study sought to establish a coronary computed tomography angiography prediction rule for grading chronic total occlusion (CTO) difficulty for percutaneous coronary intervention (PCI). BACKGROUND: The uncertainty of procedural outcome remains the strongest barrier to PCI in CTO. METHODS: Data from 4 centers involving 240 consecutive CTO lesions with pre-procedural coronary computed tomography angiography were analyzed. Successful guidewire (GW) crossing <=30 min was set as an endpoint to eliminate operator bias. The CT-RECTOR (Computed Tomography Registry of Chronic Total Occlusion Revascularization) score was developed by assigning 1 point for each independent predictor, and then summing all points accrued. Continuous distribution of scores was used to stratify CTO into 4 difficulty groups: easy (score 0); intermediate (score 1); difficult (score 2); and very difficult (score >=3). Discriminatory performance was tested by 10-fold cross-validation and compared with the angiographic J-CTO (Multicenter CTO Registry of Japan) score. RESULTS: Study endpoint was achieved in 55% of cases. Multivariable analysis yielded multiple occlusions, blunt stump, severe calcification, bending, duration of CTO >=12 months, and previously failed PCI as independent predictors for GW crossing. The probability of successful GW crossing <=30 min for each group (from easy to very difficult) was 95%, 88%, 57%, and 22%, respectively. Areas under receiver-operator characteristic curves for the CT-RECTOR and J-CTO scores were 0.83 and 0.71, respectively (p < 0.001). Both the original model fit and 10-fold cross-validation correctly classified 77.3% of lesions. CONCLUSIONS: The CT-RECTOR score represents a simple and accurate noninvasive tool for predicting time-efficient GW crossing that may aid in grading CTO difficulty before PCI. (Computed Tomography Angiography Prediction Score for Percutaneous Revascularization for Chronic Total Occlusions [CT RECTOR]; NCT02022878). PMID- 25700749 TI - Chronic total occlusion percutaneous coronary intervention in 2014 beyond the J CTO score (Japanese Multicenter CTO Registry): chance favors the prepared mind. PMID- 25700750 TI - Long-term survival benefit of revascularization compared with medical therapy in patients with coronary chronic total occlusion and well-developed collateral circulation. AB - OBJECTIVES: The purpose of this study was to compare the long-term clinical outcomes of patients with chronic total occlusion (CTO) and well-developed collateral circulation treated with revascularization versus medical therapy. BACKGROUND: Little is known about the clinical outcomes and optimal treatment strategies of CTO with well-developed collateral circulation. METHODS: We screened 2,024 consecutive patients with at least 1 CTO detected on coronary angiogram. Of these, we analyzed data from 738 patients with Rentrop 3 grade collateral circulation who were treated with medical therapy alone (n = 236), coronary artery bypass grafting (n = 170) or percutaneous coronary intervention (n = 332; 80.1% successful). Patients who underwent revascularization and medical therapy (revascularization group, n = 502) were compared with those who underwent medical therapy alone (medication group, n = 236) in terms of cardiac death and major adverse cardiac events (MACE), defined as the composite of cardiac death, myocardial infarction, and repeat revascularization. RESULTS: During a median follow-up duration of 42 months, multivariate analysis revealed a significantly lower incidence of cardiac death (hazard ratio [HR]: 0.29; 95% confidence interval [CI]: 0.15 to 0.58; p < 0.01) and MACE (HR: 0.32; 95% CI: 0.21 to 0.49; p < 0.01) in the revascularization group compared with the medication group. After propensity score matching, the incidence of cardiac death (HR: 0.27; 95% CI: 0.09 to 0.80; p = 0.02) and MACE (HR: 0.44; 95% CI: 0.23 to 0.82; p = 0.01) were still significantly lower in the revascularization group than in the medication group. CONCLUSIONS: In patients with coronary CTO and well-developed collateral circulation, aggressive revascularization may reduce the risk of cardiac mortality and MACE. PMID- 25700751 TI - Are we ready for a new paradigm shift in percutaneous revascularization of chronically occluded vessels with well-developed collaterals?: from leaving 'em all to stenting 'em all. PMID- 25700752 TI - Pre-treatment with glucagon-like Peptide-1 protects against ischemic left ventricular dysfunction and stunning without a detected difference in myocardial substrate utilization. AB - OBJECTIVES: This study sought to determine whether pre-treatment with intravenous glucagon-like peptide-1 (GLP-1)(7-36) amide could alter myocardial glucose use and protect the heart against ischemic left ventricular (LV) dysfunction during percutaneous coronary intervention. BACKGROUND: GLP-1 has been shown to have favorable cardioprotective effects, but its mechanisms of action remain unclear. METHODS: Twenty patients with preserved LV function and single-vessel left anterior descending coronary artery disease undergoing elective percutaneous coronary intervention were studied. A conductance catheter was placed into the LV, and pressure-volume loops were recorded at baseline, during 1-min low pressure balloon occlusion (BO), and at 30-min recovery. Patients were randomized to receive an infusion of either GLP-1(7-36) amide at 1.2 pmol/kg/min or saline immediately after baseline measurements. Simultaneous coronary artery and coronary sinus blood sampling was performed at baseline and after BO to assess transmyocardial glucose concentration gradients. RESULTS: BO caused both ischemic LV dysfunction and stunning in the control group but not in the GLP-1 group. Compared with control subjects, the GLP-1 group had a smaller reduction in LV performance during BO (delta dP/dTmax, -4.3 vs. -19.0%, p = 0.02; delta stroke volume, -7.8 vs. -26.4%, p = 0.05), and improved LV performance at 30-min recovery. There was no difference in transmyocardial glucose concentration gradients between the 2 groups. CONCLUSIONS: Pre-treatment with GLP-1(7-36) amide protects the heart against ischemic LV dysfunction and improves the recovery of function during reperfusion. This occurs without a detected change in myocardial glucose extraction and may indicate a mechanism of action independent of an effect on cardiac substrate use. (Effect of Glucgon-Like-Peptide-1 [GLP-1] on Left Ventricular Function During Percutaneous Coronary Intervention [PCI]; ISRCTN77442023). PMID- 25700753 TI - Prevention of myocardial stunning during percutaneous coronary interventions: novel insights from pre-treatment with glucagon-like peptide-1. PMID- 25700754 TI - Inter-core lab variability in analyzing quantitative coronary angiography for bifurcation lesions: a post-hoc analysis of a randomized trial. AB - OBJECTIVES: This study sought to evaluate inter-core lab variability in quantitative coronary angiography (QCA) analysis of bifurcation lesions. BACKGROUND: QCA of bifurcation lesions is challenging. To date there are no data available on the inter-core lab variability of bifurcation QCA analysis. METHODS: The randomized Tryton IDE (Tryton Pivotal IDE Coronary Bifurcation Trial) compared the Tryton Side Branch Stent (Tryton Medical, Durham, North Carolina) with balloon angioplasty as side branch treatment. QCA was performed in an angiographic subcohort (n = 326) at 9-month follow-up. Inter-core lab variability of QCA analysis between the Cardiovascular Research Foundation and the Cardialysis core labs was evaluated before and after alignment of the used QCA methodology using angiographic data derived from this angiographic follow-up cohort. RESULTS: In the original analysis, before alignment of QCA methodology, the mean difference between the core labs (bias) was large for all QCA parameters with wide 95% limits of agreement (1.96 * SD of the bias), indicating marked variability. The bias of the key angiographic endpoint of the Tryton trial, in segment percentage diameter stenosis (%DS) of the side branch, was 5.5% (95% limits of agreement: -26.7% to 37.8%). After reanalysis, the bias of the in segment %DS of the side branch reduced to 1.8% (95% limits of agreement: -16.7% to 20.4%). Importantly, after alignment of the 2 core labs, there was no longer a difference between both treatment groups (%DS of the side branch: treatment group A vs. group B: 34.4 +/- 19.4% vs. 32.4 +/- 16.1%, p = 0.340). CONCLUSIONS: Originally, a marked inter-core lab variability of bifurcation QCA analysis was found. After alignment of methodology, inter-core lab variability decreased considerably and impacted angiographic trial results. This latter finding emphasizes the importance of using the same methodology among different core labs worldwide. (Tryton Pivotal Prospective, Single Blind, Randomized Controlled Study to Evaluate the Safety & Effectiveness of the Tryton Side Branch Stent Used With DES in Treatment of de Novo Bifurcation Lesions in the Main Branch & Side Branch in Native Coronaries [TRYTON]; NCT01258972). PMID- 25700755 TI - Health status after transcatheter aortic valve replacement in patients at extreme surgical risk: results from the CoreValve U.S. trial. AB - OBJECTIVES: The purpose of this study was to characterize health status outcomes after transcatheter aortic valve replacement (TAVR) with a self-expanding bioprosthesis among patients at extreme surgical risk and to identify pre procedural patient characteristics associated with a poor outcome. BACKGROUND: For many patients considering TAVR, improvement in quality of life may be of even greater importance than prolonged survival. METHODS: Patients with severe, symptomatic aortic stenosis who were considered to be at prohibitive risk for surgical aortic valve replacement were enrolled in the single-arm CoreValve U.S. Extreme Risk Study. Health status was assessed at baseline and at 1, 6, and 12 months after TAVR using the Kansas City Cardiomyopathy Questionnaire (KCCQ), the Short Form-12, and the EuroQol-5D. The overall summary scale of the KCCQ (range 0 to 100; higher scores = better health) was the primary health status outcome. A poor outcome after TAVR was defined as death, a KCCQ overall summary score (OS) <45, or a decline in KCCQ-OS of 10 points at 6-month follow-up. RESULTS: A total of 471 patients underwent TAVR via the transfemoral approach, of whom 436 (93%) completed the baseline health status survey. All health status measures demonstrated considerable impairment at baseline. After TAVR, there was substantial improvement in both disease-specific and generic health status measures, with an increase in the KCCQ-OS of 23.9 points (95% confidence interval [CI]: 20.3 to 27.5 points) at 1 month, 27.4 points (95% CI: 24.2 to 30.6 points) at 6 months, 27.4 points (95% CI: 24.1 to 30.8 points) at 12 months, along with substantial increases in Short Form-12 scores and EuroQol-5D utilities (all p < 0.003 compared with baseline). Nonetheless, 39% of patients had a poor outcome after TAVR. Baseline factors independently associated with poor outcome included wheelchair dependency, lower mean aortic valve gradient, prior coronary artery bypass grafting, oxygen dependency, very high predicted mortality with surgical aortic valve replacement, and low serum albumin. CONCLUSIONS: Among patients with severe aortic stenosis, TAVR with a self-expanding bioprosthesis resulted in substantial improvements in both disease-specific and generic health-related quality of life, but there remained a large minority of patients who died or had very poor quality of life despite TAVR. Predictive models based on a combination of clinical factors as well as disability and frailty may provide insight into the optimal patient population for whom TAVR is beneficial. (Safety and Efficacy Study of the Medtronic CoreValve(r) System in the Treatment of Symptomatic Severe Aortic Stenosis in High Risk and Very High Risk Subjects Who Need Aortic Valve Replacement; NCT01240902). PMID- 25700756 TI - Outcomes of inoperable symptomatic aortic stenosis patients not undergoing aortic valve replacement: insight into the impact of balloon aortic valvuloplasty from the PARTNER trial (Placement of AoRtic TraNscathetER Valve trial). AB - OBJECTIVES: The aim of this report is to characterize the impact of balloon aortic valvuloplasty (BAV) in patients not undergoing aortic valve replacement in the PARTNER (Placement of AoRtic TraNscathetER Valves) trial. BACKGROUND: The PARTNER trial is the only randomized trial with independently adjudicated data of inoperable severe symptomatic aortic stenosis patients, allowing outcome analysis of unoperated-on patients. METHODS: The design and initial results of the PARTNER trial (Cohort B) were reported previously. After excluding patients with pre randomization BAV, we compared patients undergoing BAV within 30 days of randomization (BAV group) with those not having BAV within 30 days of randomization (no BAV group) to characterize the use and impact of BAV. RESULTS: In the PARTNER Cohort B study, 179 inoperable patients were randomized to standard treatment including 39 patients (21.8%) who had undergone a BAV before randomization (previous BAV group). Of the 140 patients who did not have BAV before enrollment in the study, 102 patients (73%) had BAV within 30 days of study randomization (BAV group). Survival at 3 months was greater in the BAV group compared with the no BAV group (88.2%; 95% confidence interval [CI]: 82.0% to 94.5% vs. 73.0%; 95% CI: 58.8% to 87.4%). However, survival was similar at 6 month follow-up (74.5%; 95% CI: 66.1% to 83.0% vs. 73.1%; 58.8% to 87.4%). There was improvement in quality of life parameters when paired comparisons were made between baseline and 30 days and 6 months between the BAV and no BAV groups, but this effect was lost at 12-month follow-up. CONCLUSIONS: BAV improves functional status and survival in the short term, but these benefits are not sustained. BAV for aortic stenosis patients who cannot undergo aortic valve replacement is a useful palliative therapy. (THE PARTNER TRIAL: Placement of AoRTic TraNscathetER Valve Trial; NCT00530894). PMID- 25700757 TI - Prosthetic valve endocarditis after transcatheter valve replacement: a systematic review. AB - OBJECTIVES: The aim of this review is to describe the incidence, features, predisposing factors, and outcomes of prosthetic valve endocarditis (PVE) after transcatheter valve replacement (TVR). BACKGROUND: Very few data exist on PVE after TVR. METHODS: Studies published between 2000 and 2013 regarding PVE in patients with transcatheter aortic valve replacement (TAVR) or transcatheter pulmonary valve replacement (TPVR) were identified through a systematic electronic search. RESULTS: A total of 28 publications describing 60 patients (32 TAVRs, 28 TPVRs) were identified. Most TAVR patients (66% male, 80 +/- 7 years of age) had a very high-risk profile (mean logistic EuroSCORE: 30.4 +/- 14.0%). In TPVR patients (90% male, 19 +/- 6 years of age), PVE was more frequent in the stenotic conduit/valve (61%). The median time between TVR and infective endocarditis was 5 months (interquartile range: 2 to 9 months). Typical microorganisms were mostly found with a higher incidence of enterococci after TAVR (34.4%), and Staphylococcus aureus after TPVR (29.4%). As many as 60% of the TAVR-PVE patients were managed medically despite related complications such as local extension, embolism, and heart failure in more than 50% of patients. The valve explantation rate was 57% and 23% in balloon- and self-expandable valves, respectively. In-hospital mortality for TAVR-PVE was 34.4%. Most TPVR-PVE patients (75%) were managed surgically, and in-hospital mortality was 7.1%. CONCLUSIONS: Most cases of PVE post-TVR involved male patients, with a very high risk profile (TAVR) or underlying stenotic conduit/valve (TPVR). Typical, but different, microorganisms of PVE were involved in one-half of the TAVR and TPVR cases. Most TPVR-PVE patients were managed surgically as opposed to TAVR patients, and the mortality rate was high, especially in the TAVR cohort. PMID- 25700758 TI - Early experimental and clinical experience with a focal implant for lower extremity post-angioplasty dissection. AB - OBJECTIVES: This study provides preliminary data on the safety and feasibility of the use of a novel focal implant for managing post-percutaneous transluminal balloon angioplasty (post-PTA) dissection. BACKGROUND: Post-PTA dissection of the lower extremity arteries is managed with stent placement. This provides an acceptable post-intervention result but has long-term disadvantages, such as in stent restenosis. Focal treatment of post-PTA dissection and avoidance of stents are the objectives of the Tack-It (Intact Vascular, Inc., Wayne, Pennsylvania) device. METHODS: A preclinical study and first-in-human data are presented. Seven swine underwent superficial femoral artery device placement, with a self expanding nitinol stent on 1 side and a series of 4 Tack-It devices on the other side. Specimens were harvested at 28 days. The clinical study included 15 limbs that underwent revascularization for critical limb ischemia (n = 9) or claudication (n = 6). Twenty-five lesions were treated in the superficial femoral (n = 8), popliteal (n = 7), and tibial (n = 10) arteries. RESULTS: The preclinical study demonstrated a reduction in stenosis with the Tack-It (16.8 +/- 2.6%) compared with stents (46.4 +/- 9.8%). Neointimal thickness and injury score decreased with the Tack-It. Clinically, Tack-It placement resulted in acute technical success with resolution of the post-PTA dissection in 100% of lesions. There were no device-related complications or major amputations. Eighteen of the 25 lesions were available for angiographic follow-up at 1-year, and patency was 83.3%. CONCLUSIONS: Preclinical data suggest that the Tack-It device causes minimal vessel injury. Clinical use of the Tack-It to manage post-PTA dissection was safe and feasible in this early study and resulted in apposition of dissection flaps without stent placement. PMID- 25700759 TI - What to do about ischemic mitral regurgitation? PMID- 25700760 TI - Valve sizing for pure aortic regurgitation during transcatheter aortic valve replacement: deformation dynamic of the aortic annulus in different valve pathology may be different. PMID- 25700761 TI - Competency-based education. PMID- 25700762 TI - Left main coronary embolization after direct current cardioversion for persistent atrial flutter in the absence of detectable intracardiac thrombi. PMID- 25700763 TI - First reported use of the repositionable lotus valve system for a failing surgical aortic bioprosthesis. PMID- 25700764 TI - Adenosine-induced vasospasticity in a myocardial bridge...endothelial dysfunction? PMID- 25700765 TI - Successful repositioning of a direct flow medical 25-mm valve due to acute occlusion of right coronary artery during transcatheter aortic valve replacement procedure. PMID- 25700766 TI - Sex, the aging immune system, and chronic disease. AB - The immune systems of men and women differ in significant ways, especially after puberty. In particular, females are generally more prone to autoimmunity, but experience lower rates of infections and chronic inflammatory disease. Sex hormones, genes encoded on the sex chromosomes, and gender-specific behaviors likely contribute to these differences. The aging process is associated with changes in the composition and function of the immune system and these changes may occur at an accelerated rate in men as compared to women. Moreover, after the age of menopause, the incidence of chronic inflammatory disease in women approaches or exceeds that observed in males. At the same time, the incidence of autoimmunity in post-menopausal women is decreased or equivalent to the rates observed in similarly-aged men. Additional studies addressing the influence of sex on the pathogenesis of chronic and autoimmune diseases in the aged are warranted. PMID- 25700767 TI - 1950-nm diode laser-assisted microanastomoses (LAMA): an innovative surgical tool for hand surgery emergencies. AB - Based on previous observations, the 1950-nm diode laser seems to be an ideal wavelength for laser microvascular anastomoses. The data presented here, part of a larger ongoing study, assess its use in emergency hand surgery. Between 2011 and 2014, 11 patients were operated on for hand trauma with laser-assisted microanastomoses (LAMA) and prospectively analysed. LAMA was performed with a 1950-nm diode laser after placement of equidistant stitches. For vessel size <1.5 mm, the following laser parameters were used: spot size 400 MUm, five spots for each wall, power 125 mW, and arterial/venous fluence 100/90 J/cm(2) (spot duration 1/0.9 s). Mean operating time for arterial and venous microanastomoses was 7.3 +/- 1.4 and 8.7 +/- 1.0 min, respectively. Three anastomoses required a secondary laser application. Arterial and venous patency rates were 100 % at the time of surgery. The success rate for the 11 procedures assessed clinically and with the Doppler was 100 %. The technique is compared to the current literature. The 1950-nm LAMA is a reliable tool with excellent results in emergency hand surgery. The system is very compact and transportable for utilization in the emergency operating room. PMID- 25700768 TI - The bactericidal effect of 470-nm light and hyperbaric oxygen on methicillin resistant Staphylococcus aureus (MRSA). AB - It has been shown that, in vitro, hyperbaric oxygen (HBO) suppresses 28 % bacterial growth, while 470-nm blue light alone suppresses up to 92 % methicillin resistant Staphylococcus aureus (MRSA) in one application in vitro. Therefore, we determined if combined 470-nm light (55 J/cm(2)) and HBO will yield 100 % bacterial suppression in experimental simulation of mild, moderate or severe MRSA infection. We cultured MRSA at 3 * 10(6), 5 * 10(6), 7 * 10(6), 8 * 10(6), or 12 * 10(6) CFU/ml and treated each concentration in four groups as follows: (1) control (no treatment) (2) photo-irradiation only, (3) photo-irradiation then HBO, (4) HBO only, and (5) HBO then photo-irradiation. Bacteria colonies were then quantified. The results showed that at each bacterial concentration, HBO alone was significantly less effective in suppressing MRSA than photo-irradiation or combined HBO and photo-irradiation (p < 0.0001). Similarly, at no bacterial concentration did combined HBO and 470-nm light treatment yield a statistically better result than 470-nm light alone (p > 0.05), neither did HBO treatment either before or after irradiation make a difference. Furthermore, at no bacterial concentration was 100 % MRSA suppression achieved. Indeed, the maximum bacterial suppression attained was in the mild infection model (3 * 10(6) CFU/ml), with blue light producing 97.3 +/- 0.2 % suppression and HBO + 55 J/cm(2) yielding 97.5 +/- 2.5 % suppression. We conclude that (1) HBO and 470-nm light individually suppress MRSA growth; (2) 470-nm blue light is more effective in suppressing MRSA than HBO; and (3) HBO did not act synergistically to heighten the bactericidal effect of 470-nm light. PMID- 25700770 TI - The role of smoking in changes in the survival curve: an empirical study in 10 European countries. AB - PURPOSE: We examined the role of smoking in the two dimensions behind the time trends in adult mortality in European countries, that is, rectangularization of the survival curve (mortality compression) and longevity extension (increase in the age-at-death). METHODS: Using data on national sex-specific populations aged 50 years and older from Denmark, Finland, France, West Germany, Italy, the Netherlands, Norway, Sweden, Switzerland, and the United Kingdom, we studied trends in life expectancy, rectangularity, and longevity from 1950 to 2009 for both all-cause and nonsmoking-related mortality and correlated them with trends in lifetime smoking prevalence. RESULTS: For all-cause mortality, rectangularization accelerated around 1980 among men in all the countries studied, and more recently among women in Denmark and the United Kingdom. Trends in lifetime smoking prevalence correlated negatively with both rectangularization and longevity extension, but more negatively with rectangularization. For nonsmoking-related mortality, rectangularization among men did not accelerate around 1980. Among women, the differences between all-cause mortality and nonsmoking-related mortality were small, but larger for rectangularization than for longevity extension. Rectangularization contributed less to the increase in life expectancy than longevity extension, especially for nonsmoking-related mortality among men. CONCLUSIONS: Smoking affects rectangularization more than longevity extension, both among men and women. PMID- 25700769 TI - Time response of increases in ATP and muscle resistance to fatigue after low level laser (light) therapy (LLLT) in mice. AB - Recently, low-level laser (light) therapy has been used to increase muscle performance in intense exercises. However, there is a lack of understanding of the time response of muscles to light therapy. The first purpose of this study was to determine the time response for light-emitting diode therapy (LEDT) mediated increase in adenosine triphosphate (ATP) in the soleus and gastrocnemius muscles in mice. Second purpose was to test whether LEDT can increase the resistance of muscles to fatigue during intense exercise. Fifty male Balb/c mice were randomly allocated into two equal groups: LEDT-ATP and LEDT-fatigue. Both groups were subdivided into five equal subgroups: LEDT-sham, LEDT-5 min, LEDT-3 h, LEDT-6 h, and LEDT-24 h. Each subgroup was analyzed for muscle ATP content or fatigue at specified time after LEDT. The fatigue test was performed by mice repeatedly climbing an inclined ladder bearing a load of 150 % of body weight until exhaustion. LEDT used a cluster of LEDs with 20 red (630 +/- 10 nm, 25 mW) and 20 infrared (850 +/- 20 nm, 50 mW) delivering 80 mW/cm(2) for 90 s (7.2 J/cm(2)) applied to legs, gluteus, and lower back muscles. LEDT-6 h was the subgroup with the highest ATP content in soleus and gastrocnemius compared to all subgroups (P < 0.001). In addition, mice in LEDT-6 h group performed more repetitions in the fatigue test (P < 0.001) compared to all subgroups: LEDT-sham and LEDT-5 min (~600 %), LEDT-3 h (~200 %), and LEDT-24 h (~300 %). A high correlation between the fatigue test repetitions and the ATP content in soleus (r = 0.84) and gastrocnemius (r = 0.94) muscles was observed. LEDT increased ATP content in muscles and fatigue resistance in mice with a peak at 6 h. Although the time response in mice and humans is not the same, athletes might consider applying LEDT at 6 h before competition. PMID- 25700771 TI - Tibial tunnel aperture location during single-bundle posterior cruciate ligament reconstruction: comparison of tibial guide positions. AB - PURPOSE: We aimed to compare posterior cruciate ligament (PCL) tibial tunnel location after tibial guide insertion medial (between the PCL remnant and the medial femoral condyle) and lateral (between the PCL remnant and the anterior cruciate ligament) to the PCL stump as determined by in vivo 3-dimensional computed tomography (3D-CT). METHODS: Tibial tunnel aperture location was analyzed by immediate postoperative in vivo CT in 66 patients who underwent single-bundle PCL reconstruction, 31 by over-the-PCL and 35 by under-the-PCL tibial guide insertion techniques. Tibial tunnel positions were measured in the medial to lateral and proximal to distal directions of the posterior proximal tibia. RESULTS: The center of the tibial tunnel aperture was located more laterally (by 2.7 mm) in the over-the-PCL group than in the under-the-PCL group (P = .040) and by a relative percentage (absolute value/tibial width) of 3.2% (P = .031). Tibial tunnel positions in the proximal to distal direction, determined by absolute value and relative percentage, were similar in the 2 groups. CONCLUSIONS: Tibial tunnel apertures were located more laterally after lateral-to the-PCL tibial guide insertion than after medial-to-the-PCL tibial guide insertion. There was, however, no significant difference between these techniques in distance from the joint line to the tibial tunnel aperture. Insertion lateral to the PCL stump may result in better placement of the PCL in its anatomic footprint. LEVEL OF EVIDENCE: Level III, retrospective comparative study. PMID- 25700772 TI - Neonatal hyperthyroidism on rat heart: interrelation with nitric oxide and sex. AB - PURPOSE: To clarify the mechanism mediating the effect of hyperthyroidism on cardiac function during the second month of life in rats. METHODS: Male and female Sprague-Dawley rats were assigned to a control or to a triiodothyronine (T3)-treated group. Treatment of each group was started on the third day after birth. Control rats (Eut) received 0.9 NaCl [0.1 ml/100 g body weight (BW)] every second day during 60 days and T3-treated rats (Hyper) received subcutaneous (SC) T3 injections every second day during 60 days. RESULTS: Hyperthyroidism decreased left ventricle volume only in male rats. Female euthyroid rats presented higher atrial nitric oxide synthase (NOS) activity than male rats and hormonal treatment decreased this enzyme's activity in both sexes. Euthyroid male and female rats had similar atrial NOS protein levels, but females had higher caveolin (cav) 3 protein levels. T3 treatment increased this protein only in males. Female rats had lower ventricular NOS activity than male rats; hyperthyroidism increased NOS activity in both sexes but this effect was associated with lower cav 3 protein levels. Hyperthyroidism did not change cav 1 protein levels in both male and female rats. CONCLUSIONS: The results of this study demonstrating clinically relevant sex-related differences in the pathophysiology of the hyperthyroid heart have raised new questions regarding the mechanisms responsible for the observed differences. This study suggests that sex-related intrinsic factors such as nitric oxide may modulate the response to hyperthyroidism that leads to cardiovascular dysfunction. PMID- 25700773 TI - Echocardiographic characteristics of annulo-leaflet mitral ring. AB - BACKGROUND: Annulo-leaflet mitral ring (ALMR) is a rare congenital cardiac anomaly caused by fibrous tissue on the atrial surface of the mitral valve, which can progress to cause severe stenosis. Because little information is available on the detailed echocardiographic features of the anomaly and their associations with surgical resection, this study was undertaken to address these questions. METHODS: A retrospective single-center study of clinical and echocardiographic data from patients with ALMR from 2004 through 2012 was conducted. Data were analyzed for associations with surgical resection. RESULTS: The median age at diagnosis of the 57 study patients was 1.8 years, and 63% were male. Isolated ALMR was found in six patients (11%). The remaining 51 patients (89%) had associated lesions: additional mitral valve abnormalities in 35 (61%), coarctation in 11 (19%), and subaortic stenosis in 15 (26%). ALMR was best visualized in the apical four-chamber view, and the lesion was indistinct from the parasternal long-axis view in 25% of patients. Seven patterns of ALMR were identified, differentiated by leaflet involvement (anterior, posterior, or both) and location (annular vs intraleaflet). Compared with other patterns, intraleaflet morphology had a higher mean mitral stenosis gradient than in patients without (8.4 vs 5.8 mm Hg, P = .01). Among the 57 patients, 32 (56%) underwent ALMR resection, at a median age of 1.5 years. Younger age at echocardiographic diagnosis (P = .02) and short chordae (P = .03) were associated with resection. CONCLUSIONS: The morphology of ALMR as evaluated by echocardiography is heterogeneous and can be classified on the basis of lesion location and leaflet involvement. Intraleaflet morphology is associated with significant mitral stenosis; younger age at diagnosis and short chordae are associated with ALMR resection. PMID- 25700774 TI - Phase I Study of Lapatinib and Pemetrexed in the Second-Line Treatment of Advanced or Metastatic Non-Small-Cell Lung Cancer With Assessment of Circulating Cell Free Thymidylate Synthase RNA as a Potential Biomarker. AB - INTRODUCTION: Lapatinib is a dual tyrosine kinase inhibitor that targets epidermal growth factor receptor and HER2. We report on a dose-escalation study of lapatinib combined with pemetrexed in second-line treatment to evaluate the safety and efficacy in advanced or metastatic non-small-cell lung cancer (NSCLC) and an exploratory study in which circulating cell-free thymidylate synthase ribonucleic acid (cfTSmRNA) was measured in all patients and compared with clinical benefit. PATIENTS AND METHODS: Eligible patients had stage IIIB or IV NSCLC after 1 previous line of chemotherapy and an Eastern Cooperative Oncology Group performance status of 0 to 2. Three dose levels (DLs) of lapatinib (daily)/pemetrexed (every 21 days) were evaluated: DL0, 1250 mg/400 mg; DL1, 1250 mg/500 mg; and DL2, 1500 mg/500 mg, respectively. The primary outcome was identification of the optimal treatment regimen. RESULTS: Eighteen patients were treated (DL0: n = 4; DL1: n = 8; DL2: n = 6). The most common adverse events (any grade) were diarrhea (61%), rash (44%), nausea (33%), anemia, and fatigue (both 28%). DL1 was determined as optimal after 3 dose-limiting toxicities (DLTs) during the first cycle of DL2 (Grade 3 diarrhea and mucositis, Grade 4 lymphocytopenia); no other DLTs were observed. Partial response was detected in 4 patients. cfTSmRNA was at the limit of detection and was not measurable in all patients. Nonsignificant trends were observed, suggesting that higher levels of cfTSmRNA are associated with poorer outcome. Confirmatory studies are required. CONCLUSION: Lapatinib and pemetrexed was well tolerated, and data suggest a similar response rate to pemetrexed monotherapy. PMID- 25700775 TI - Current and Future Approaches in the Management of Non-Small-Cell Lung Cancer Patients With Resistance to EGFR TKIs. AB - Metastatic non-small-cell lung cancer carries a dismal prognosis. However, the recognition of the predictive value of activating epidermal growth factor receptor (EGFR) mutations and the availability of tyrosine kinase inhibitors has markedly improved the prognosis of these patients, because treatment with these inhibitors induces rapid and robust responses. Unfortunately, the responses are not durable and resistance inevitably occurs after a median of 9 to 14 months. Although the management of resistant patients who harbor EGFR mutations is rapidly evolving, there are no conclusive guidelines regarding this issue. However, palliative cytotoxic chemotherapy is considered the standard of care for these patients. The elucidation of the mechanisms of acquired resistance has led to efforts to personalize the treatment approach. Promising results from early clinical trials using the third-generation inhibitors that specifically target the most common mechanism of resistance, the gatekeeper T790M mutation, provide the basis to look to the future with cautious optimism. Moreover, it has been shown that in some cases of oligoprogressive disease, aggressively treating all metastatic sites while continuing the targeted treatment could improve outcomes. Herein, we review the treatment strategies being evaluated that will shape the future management of these patients. PMID- 25700776 TI - Cancer-associated fibroblasts: a multifaceted driver of breast cancer progression. AB - Cancerous tissue is a complex mix of tumor cells, stromal cells and extracellular matrix (ECM), all of which make up a disordered and aggressive niche in comparison with organized and homeostatic normal tissue. It is well accepted that the tumor microenvironment plays an indispensable role in cancer development, and thus can be recognized as an additional cancer hallmark alongside those that are well established. In breast cancer, cancer associated fibroblasts (CAFs) are the predominant cellular components and play a centric role in the tumor microenvironment since they not only promote cancer initiation, growth, invasion, metastasis and therapeutic resistance but are also involved in microenvironmental events including angiogenesis/lymphangiogenesis, ECM remodeling, cancer associated inflammation and metabolism reprogramming, all of which are known to have pre-malignancy potency. At the molecular level, there is a sophisticated network underlying the interactions between CAFs and epithelial cells as well as other stromal components. Accordingly, targeting CAFs provides a novel strategy in cancer therapy. Herein, we summarize the current understanding of the role of CAFs in breast cancer. PMID- 25700777 TI - Circulating tumor cell thresholds and survival scores in advanced metastatic breast cancer: the observational step of the CirCe01 phase III trial. AB - The clinical validity of circulating tumor cell (CTC) count changes during chemotherapy in metastatic breast cancer patients has been validated, but its clinical utility remains to be demonstrated. We report here the non-randomized run-in phase of the CirCe01 trial which was designed to evaluate CTC changes and thresholds to other palliative prognostic scores and establish CTC thresholds to be used in the randomized part of the study. CTC count (CellSearch(r)) and other prognostic parameters (serum albumin level, lymphocyte level, LDH level, prognostic inflammatory and nutritional index (PINI) and Barbot's score) were assessed in 56 metastatic breast cancer patients before the first cycle of third line chemotherapy. Early changes of CTC count were correlated with treatment outcome. Independent prognostic markers in multivariate analysis were: low serum albumin (HR = 11.1), poor performance status (HR = 3.8), >=5 CTC/7.5 ml (HR = 3.8) and triple negative subtype (HER2+ and hormone positive vs triple negative: both HR = 0.2). Among patients with >=5 CTC/7.5 ml at baseline, a composite criteria (<5 CTC/7.5 ml or relative decrease >=-70% of the baseline CTC count) showed better prognostication for PFS (p=0.002). PMID- 25700778 TI - Personal reflections about the work of the U.S. Advisory Board on Child Abuse and Neglect. AB - Created by amendments in 1988 to the Child Abuse Treatment and Prevention Act of 1974 and first convened in 1989, the U.S. Advisory Board on Child Abuse and Neglect issued a series of passion- and research-laden reports that articulated a new neighborhood-based strategy for child protection in the United States. In so doing, the Board went far beyond the vision of its congressional creators, the most relevant federal agencies, and the field itself. The dedication, daring, collegiality, and public spirit of the drafters and ultimately the moral and intellectual power of the reports themselves were awe-inspiring, as was the level of public attention given to the Board's initial declaration of a national emergency. However, the specific effects on policy were quite limited. Possible reasons for the enormous gap between the strength of the Board's vision and the weakness of its implementation are reviewed. In the end, the history of the Board may be a case study of a single but notable step in a long process toward redemptive cultural change in the status and safety of children. PMID- 25700779 TI - Childhood maltreatment predicts allostatic load in adulthood. AB - Childhood maltreatment has been linked to numerous negative health outcomes. However, few studies have examined mediating processes using longitudinal designs or objectively measured biological data. This study sought to determine whether child abuse and neglect predicts allostatic load (a composite indicator of accumulated stress-induced biological risk) and to examine potential mediators. Using a prospective cohort design, children (ages 0-11) with documented cases of abuse and neglect were matched with non-maltreated children and followed up into adulthood with in-person interviews and a medical status exam (mean age 41). Allostatic load was assessed with nine physical health indicators. Child abuse and neglect predicted allostatic load, controlling for age, sex, and race. The direct effect of child abuse and neglect persisted despite the introduction of potential mediators of internalizing and externalizing problems in adolescence and social support and risky lifestyle in middle adulthood. These findings reveal the long-term impact of childhood abuse and neglect on physical health over 30 years later. PMID- 25700780 TI - Blocking the mitogen activated protein kinase-p38 pathway is associated with increase expression of nitric oxide synthase and higher production of nitric oxide by bovine macrophages infected with Mycobacterium avium subsp paratuberculosis. AB - This study evaluated the role of the mitogen-activated protein kinase (MAPK)-p38 pathway in the nitric oxide synthase (iNOS) expression and nitric oxide (NO) production by bovine monocyte-derived macrophages ingesting Mycobacterium avium subsp. paratuberculosis (MAP) organisms in vitro. Bovine monocyte-derived macrophages were incubated with MAP organisms with or without a specific inhibitor of the MAPKp38 pathway and activation of the MAPKp38, interleukin - (IL) IL-10, IL-12, iNOS mRNA expression and NO production were evaluated. Incubation of macrophages with MAP organisms activates the MAPKp38 pathway at early time points post infection. Chemically inhibition of MAPKp38 before incubation of bovine macrophages with MAP resulted in increased expression of IL 12 mRNA at 2, 6 and 24h, decreased expression of IL-10 mRNA at 2, 6 and 24h and increased expression of iNOS mRNA at 2 and 6h. Nitric oxide was evaluated to indirectly determine the effects of MAPKp38 pathway on the anti-microbial activity of bovine macrophages. Incubation of bovine macrophages with MAP resulted in modest increased production of NO at 4 and 6h post infection. Pretreatment of bovine macrophages with the MAPKp38 inhibitor SB203580 before addition of MAP organisms resulted in increased production of NO at 2, 4, 6 and 24h post infection. This study expanded our knowledge of the importance of the MAPKp38 pathway in limiting an appropriate macrophage response to MAP and suggested how activation of MAPKp38 pathway may be a target of this organism to disrupt earlier antimicrobial mechanisms of macrophages. These findings raises the interesting possibility that the cellular manipulation of MAPKp38 may be useful in designing novel vaccines against MAP. PMID- 25700781 TI - Russell body carditis. PMID- 25700782 TI - Comparison of immune response of Pacific white shrimp, Litopenaeus vannamei, after multiple and single infections with WSSV and Vibrio anguillarum. AB - Our previous study demonstrated that Pacific white shrimp (Litopenaeus vannamei) infected by multiple pathogens showed higher mortality and death occurred more quickly than those infected by a single pathogen (Jang et al., 2014). For better understanding the defense mechanism against white spot syndrome virus (WSSV) and Vibrio anguillarum, immune responses of shrimp were evaluated in this study. The mRNA expression levels of five immune-related genes were analyzed by quantitative reverse real-time PCR, which included proPO-activating enzyme 1 (PPAE1), PPAE2, proPO activating factor (PPAF), masquerade-like serine proteinase (Mas) and ras related nuclear gene (Ran). Results demonstrated that the transcription was suppressed more intensively in the multiple infection group than those in single infection groups. The transcriptional suppression was directly related to the higher mortality. The hypoimmunity could benefit pathogen invasion, replication and release of toxin in vivo. Results in this study will help to understand immune defense mechanism after shrimp were infected by multiple pathogens in aquaculture. PMID- 25700783 TI - Evaluation of waterborne exposure to heavy metals in innate immune defences present on skin mucus of gilthead seabream (Sparus aurata). AB - Aquatic animals are continuously exposed to chemical pollutants but the effects evoked in skin surfaces, which receive the most direct contact with them, are poorly investigated. Terminal carbohydrate composition and immunological components present in skin mucus of gilthead seabream (Sparus aurata L.) specimens exposed to waterborne sublethal dosages of heavy metals [arsenic (As2O3), cadmium (CdCl2) and mercury (CH3HgCl) at 5, 5 and 0.04 MUM, respectively for 2, 10 and 30 days were analysed. Moreover, the presence of a fucose binding lectin (FBL) was evaluated by western blot and the protein profiles were by SDS PAGE and HPLC. Results showed little effects of heavy metals in the presence of several terminal carbohydrates with few increments or decrements. Most of the enzyme activities related to immune responses were increased upon heavy metal exposure in the skin mucus including bactericidal activity. Methylmercury produced the most dramatic changes increasing all the activities. Moreover, the FBL was undetected in any of the control fish skin mucus but was evident in all the heavy metal exposed fish. In addition, As and Cd produced a clear change in the protein profile as evidenced by the lack of a protein band of around 12 kDa which is absent. These protein changes were more evident with the HPLC study showing the presence of different peaks and differences in intensity. The present results could be useful for better understanding the role and their behaviour of the mucosal immunity in skin as a key component of the innate immune system against pollutants. PMID- 25700784 TI - Role of hemoglobin from blood clam Scapharca kagoshimensis beyond oxygen transport. AB - The evolutionary race between hosts and pathogens has led to a variety of adaptations. Little is known about the immunological role of hemoglobin (Hb) in antimicrobial immune responses. Results showed that a 31.2 kDa monodimer Hb (skHbI) and a 57.8 kDa heterotetramer Hb (skHbII) from the blood clam, Scapharca kagoshimensis, had phenoloxidase (PO)-like activities and antimicrobial activities. Both were found capable of oxidizing l-DOPA, catechol and hydroquinone. Their PO-like activities were visibly greatly inhibited by oxidase inhibitors, EDTA, and divalent metal ions, and greatly enhanced by isopropanol and Fe(2+), indicating that they have the properties of a metalloenzyme and a catecholase-type PO as well. They also showed obvious anti-bacterial activities against gram-positive bacteria but not against either gram-negative bacteria nor fungi. The anti-bacterial activities levels were a result of the generation of reactive oxygen species (ROS) of superoxide anions. These results indicate that skHbI and skHbII, not only function as iron-containing oxygen carriers, but also exert anti-bacterial activities and catecholase-type oxidizing activities. The fact that skHbII exerts high level of PO-like activity indicates different roles in the innate immunodefense system. These results may improve understanding of the multiple functions of invertebrate Hbs beyond serving as oxygen carriers and may provide insight into how the fundamental and universal mode of the innate immune system has persisted in respiratory proteins throughout the course of evolution. PMID- 25700785 TI - An updated molecular basis for mussel immunity. AB - Non-self recognition with the consequent tolerance or immune reaction is a crucial process to succeed as living organisms. At the same time the interactions between host species and their microbiome, including potential pathogens and parasites, significantly contribute to animal life diversity. Marine filter feeding bivalves, mussels in particular, can survive also in heavily anthropized coastal waters despite being constantly surrounded by microorganisms. Based on the first outline of the Mytilus galloprovincialis immunome dated 2011, the continuously growing transcript data and the recent release of a draft mussel genome, we explored the available sequence data and scientific literature to reinforce our knowledge on the main gene-encoded elements of the mussel immune responses, from the pathogen recognition to its clearance. We carefully investigated molecules specialized in the sensing and targeting of potential aggressors, expected to show greater molecular diversification, and outlined, whenever relevant, the interconnected cascades of the intracellular signal transduction. Aiming to explore the diversity of extracellular, membrane-bound and intracellular pattern recognition receptors in mussel, we updated a highly complex immune system, comprising molecules which are described here in detail for the first time (e.g. NOD-like receptors) or which had only been partially characterized in bivalves (e.g. RIG-like receptors). Overall, our comparative sequence analysis supported the identification of over 70 novel full-length immunity-related transcripts in M. galloprovincialis. Nevertheless, the multiplicity of gene functions relevant to immunity, the involvement of part of them in other vital processes, and also the lack of a refined mussel genome make this work still not-exhaustive and support the development of more specific studies. PMID- 25700786 TI - Identification and functional characterization of two Bcl-2 family protein genes in Zhikong scallop Chlamys farreri. AB - Apoptosis plays significant roles in maintenance of homeostasis, immune defense and development. The Bcl-2 family proteins are important regulators of the intrinsic apoptosis. In the study, we have characterized a Bcl-2-like gene (named CfBcl-2) and a Bax-like gene (named CfBax) from the Zhikong scallop Chlamys farreri. The full-length of the CfBcl-2 cDNA is 944 nucleotides (nt) encoding a putative protein of 225 amino acid residues (aa) that contains four Bcl-2 homology (BH) domains, and the CfBax cDNA is 505 nt encoding a putative protein of 115 aa that contains three Bcl-2 BH domains. Sequence and phylogenetic analysis demonstrate that CfBcl-2 and CfBax present typical domain organization of the corresponding Bcl-2 related proteins and are more similar and clustered with their homologues of other molluscs. The two genes are ubiquitously expressed in six tissues of C. farreri, with the highest expression level of CfBcl-2 in adductor muscle and highest expression level of CfBax in gill. The expressions of CfBcl-2 and CfBax in hemocytes were both significantly up-regulated after an in vivo exposure of scallops to air, injection with lipopolysaccharide and infection with acute viral necrobiotic disease virus, and the expression patterns of the two genes after the three treatments vary in different change magnitude and up regulation timespan. Yeast two-hybrid assay reveals a direct interaction between the CfBcl-2 and CfBax proteins. These results indicate that the CfBcl-2 and CfBax may participate in the apoptosis-based stress and immune responses against noxious stimulation. PMID- 25700787 TI - Crowding of white shrimp Litopenaeus vananmei depresses their immunity to and resistance against Vibrio alginolyticus and white spot syndrome virus. AB - Immunity parameters and the expression levels of several immune-related proteins, including lipopolysaccharide and beta-glucan binding protein (LGBP), peroxinectin (PX), intergin beta (IB), prophenoloxidase (proPO) I, proPO II, alpha2 macroglobulin (alpha2-M), cytosolic mangangese superoxide dismutase (cytMnSOD), mitochondria manganese superoxide dismutase (mtMnSOD), catalase, glutathione peroxidase (GPx), lysozyme, and penaeidin 3a were examined in white shrimp Litopenaeus vannamei reared at stocking densities of 2, 10, 20, 30, and 40 shrimp L(-1) after 3, 6, and 12 h. All immune parameters including haemocyte count, phenoloxidase (PO) activity, respiratory burst (RB), superoxide dismutase (SOD) activity, lysozyme activity, and haemolymph protein were negatively related to density and time. The PO activity, SOD activity, and lysozyme activity of shrimp reared at 10 shrimp L(-1) after 12 h significantly decreased. The transcript levels of these immune-related proteins were down-regulated in shrimp reared at 20, 30, and 40 shrimp L(-1) after 12 h. Phagocytic activity and clearance efficiency to Vibrio alginolyticus were significantly lower in shrimp reared at 30 and 40 shrimp L(-1) after 12 h. The mortality rates of shrimp reared at 20 and 40 shrimp L(-1) were significantly higher than shrimp reared at 2 shrimp L(-1) over 12-144 h and 12-48 h, respectively. Shrimp reared at high densities (>10 shrimp L(-1)) exhibited decreased resistance against pathogens as evidenced by reductions in immune parameters together with decreased expression levels of immune-related proteins, indicating perturbations of the immune system. PMID- 25700788 TI - Correlates of habitual physical activity and organized sports in German primary school children. AB - OBJECTIVES: The increased prevalence of childhood obesity has also been attributed to low physical activity (PA) levels. Understanding factors affecting child PA levels is especially important considering the benefits PA offers to youth. STUDY DESIGN: This study therefore examined different correlates affecting habitual PA and sports participation in primary school children. METHODS: Height and weight were measured during a school visit in 1714 children (7.1 +/- .6 years). PA and behavioural correlates were assessed by parental questionnaire. The effect of various correlates on PA as well as participation in organized sports was assessed using logistic regression analysis. RESULTS: Significant correlates of PA and sports participation were engagement in sporting activities outside of clubs and children's weight status. Playing outdoors for more than 60 min/day was significant for PA, having well educated parents and being male. Participation in sports was influenced by children's media consumption, active travel to school and having active parents. No influence was found for migration, income, parental weight status and health consciousness. CONCLUSION: In this study, a multiplicity of independent correlates of PA and sports participation, which require a broad approach to promote an active lifestyle, have been considered. Understanding these factors might support the development of effective health-promoting interventions. PMID- 25700789 TI - A lack of vision: evidence for poor communication of visual problems and support needs in education statements/plans for children with SEN. AB - OBJECTIVE: Visual dysfunction is more common in children with neurological impairments and previous studies have recommended such children receive visual and refractive assessment. In the UK, children with neurological impairment often have educational statementing for Special Educational Needs (SEN) and the statement should detail all health care and support needs to ensure the child's needs are met during school life. STUDY DESIGN: This study examined the representation of visual information in statements of SEN and compared this to orthoptic visual information from school visual assessments for children in a special school in Northern Ireland, UK. METHODS: The parents of 115 school children in a special school were informed about the study via written information. Participation involved parents permitting the researchers to access their child's SEN educational statement and orthoptic clinical records. RESULTS: Statement information was accessed for 28 participants aged between four and 19 years; 25 contained visual information. Two participants were identified in their statements as having a certification of visual impairment. An additional 10 children had visual acuity >= 0.3 logMAR. This visual deficit was not reported in statements in eight out of these 12 cases (67%). 11 participants had significant refractive error and wore spectacles, but only five (45%) had this requirement recorded in their statement. Overall, 10 participants (55%) had either reduced visual acuity or significant refractive error which was not recorded in their statement. CONCLUSIONS: Despite additional visual needs being common, and described in clinical records, the majority of those with reduced vision and/or spectacle requirements did not have this information included in their statement. If visual limitations are not recognized by educational services, the child's needs may not be met during school life. More comprehensive eye care services, embedded with stakeholder communication and links to education are necessary to improve understanding of vision for children with neurological impairments. PMID- 25700790 TI - Assessment of Vestibular Rehabilitation Therapy Training and Practice Patterns. AB - Vestibular rehabilitation therapy (VRT) can benefit patients with a variety of balance and vestibular disorders. This expanding field requires knowledgeable and experienced therapists; however, the practice and experience of those providing this care may vary greatly. The purpose of this study was to analyze variations in training and practice patterns among practicing vestibular rehabilitation therapists. Case-controlled cohort study. Investigation of outpatient physical therapy and audiology practices that offer vestibular rehabilitation conducted by a tertiary academic referral center. Questionnaire-based investigation of level of training in vestibular disorders and therapy, practice patterns of vestibular rehabilitation, and referral sources for VRT patients. We identified 27 subjects within the state of Kentucky who practice vestibular rehabilitation and the questionnaire response rate was 63%. Responses indicated that 53% of respondents had no training in VRT during their professional degree program. Attendance of a course requiring demonstration of competence and techniques was 24% of participants. The development of VRT certification was significantly more favored by those who attended such courses compared with those who did not (p = 0.01). 50% of therapists have direct access to patients without physician referrals. There is a wide range of educational background and training among those practicing VRT. This variability in experience may affect care provided within some communities. Certification is not necessary for the practice of VRT but the development of certification is favored among some therapists to improve standardization of practice of this important specialty. PMID- 25700791 TI - Functional plasticity of GAT-3 in avian Muller cells is regulated by neurons via a glutamatergic input. AB - GABA (gamma-amino butyric acid) is the major inhibitory transmitter in the central nervous system and its action is terminated by specific transporters (GAT), found in neurons and glial cells. We have previously described that GAT-3 is responsible for GABA uptake activity in cultured avian Muller cells and that it operates in a Na(+) and Cl(-) dependent manner. Here we show that glutamate decreases [(3)H] GABA uptake in purified cultured glial cells up to 50%, without causing cell death. This effect is mediated by ionotropic glutamatergic receptors. Glutamate inhibition on GABA uptake is not reverted by inhibitors of protein kinase C or modified by agents that modulate cyclic AMP/PKA. Biotinylation experiments demonstrate that this reduction in GABA uptake correlates with a decrease in GAT-3 plasma membrane levels. Interestingly, both GAT-1 and GAT-3 mRNA levels are also decreased by glutamate. Conditioned media (CM) prepared from retinal neurons could also decrease GABA influx, and glutamate receptor antagonists (MK-801 + CNQX) were able to prevent this effect. However, glutamate levels in CM were not different from those found in fresh media, indicating that a glutamatergic co-agonist or modulator could be regulating GABA uptake by Muller cells in this scenario. In the whole avian retina, GAT-3 is present from embryonic day 5 (E5) increasing up to the end of embryonic development and post-hatch period exclusively in neuronal layers. However, this pattern may change in pathological conditions, which drive GAT-3 expression in Muller cells. Our data suggest that in purified cultures and upon extensive neuronal lesion in vivo, shown as a Brn3a reduced neuronal cells and an GFAP increased gliosis, Muller glia may change its capacity to take up GABA due to GAT 3 up regulation and suggests a regulatory interplay mediated by glutamate between neurons and glial cells in this process. PMID- 25700792 TI - Women's birth expectations, are they fulfilled? Findings from a longitudinal Swedish cohort study. AB - BACKGROUND: The importance of women's expectations on the experience of birth has shown contradictory results regarding fulfilment. The aim of this study was to describe pregnant women's expectations of birth and to investigate if these expectations were fulfilled. An additional aim was to determine if unfulfilled expectations were related to the mode of birth, use of epidural and the birth experience. METHODS: This research investigated a prospective regional cohort study of 1042 Swedish-speaking women who completed a questionnaire about birth expectations in late pregnancy and were followed up with two months after birth. Five areas were under study: support from partner, support from midwife, control, participation in decision making and the midwife's presence during labour and birth. An index combining expectations and experiences was created. RESULTS: Certain background characteristics were associated with expectations as well as experiences. Statistically significant differences were shown between expectations and experiences in support from midwife (mean 3.41 vs 3.32), support from partner (mean 3.70 vs 3.77), and midwife's presence (mean 3.00 vs 3.39). Experiences 'worse than expected' regarding decision making and control were associated with modes of birth other than vaginal and four out of five areas were associated with a less positive birth experience. CONCLUSION: Some women had high birth expectations of which some were fulfilled. An expectation on support from the midwife was less likely to be achieved, while support from partner and the midwives' presence were fulfilled. If the woman's expectations were not fulfilled, e.g. became 'worse than expected' this was associated with a less positive overall birth experience as well as with instrumental or surgical mode of birth. PMID- 25700793 TI - Evaluation of symptoms and methodology of the urodynamic study matter. PMID- 25700795 TI - Errata. PMID- 25700794 TI - Reply: To PMID 25544711. PMID- 25700796 TI - Role of miR-155 in the pathogenesis of herpetic stromal keratitis. AB - Ocular infection with herpes simplex virus 1 can result in a chronic immunoinflammatory stromal keratitis (SK) lesion that is a significant cause of human blindness. A key to controlling SK lesion severity is to identify cellular and molecular events responsible for tissue damage and to manipulate them therapeutically. Potential targets for therapy are miRNAs, but these are minimally explored especially in responses to infection. Here, we demonstrated that Mir155 expression was up-regulated after ocular herpes simplex virus 1 infection, with the increased Mir155 expression occurring mainly in macrophages and CD4(+) T cells and to a lesser extent in neutrophils. In vivo studies indicated that Mir155 knockout mice were more resistant to herpes SK with marked suppression of T helper cells type 1 and 17 responses both in the ocular lesions and the lymphoid organs. The reduced SK lesion severity was reflected by increased phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase 1 and interferon gamma receptor alpha-chain levels in activated CD4(+) T cells in the lymph nodes. Finally, in vivo silencing of miR-155 by the provision of antagomir-155 nanoparticles to herpes simplex virus 1-infected mice led to diminished SK lesions and corneal vascularization. In conclusion, our results indicate that miR 155 contributes to the pathogenesis of SK and represents a promising target to control SK severity. PMID- 25700797 TI - De novo pulmonary small cell carcinomas and large cell neuroendocrine carcinomas harboring EGFR mutations: Lack of response to EGFR inhibitors. AB - INTRODUCTION: Epidermal growth factor receptor (EGFR) mutations are present in 10 20% of all non-small-cell lung cancers and predict for response to EGFR tyrosine kinase inhibitors (TKIs). However, the incidence of these mutations and their ability to predict response to TKIs in high-grade pulmonary neuroendocrine carcinomas [i.e. small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC)] is unknown. METHODS: The presence of EGFR mutations, clinicopathologic and anti-cancer therapy response data were retrospectively compiled and analyzed from a cohort of 608 patients-lung tumors to identify EGFR mutated high-grade pulmonary neuroendocrine carcinomas. We identified 126 EGFR mutated (21.8% of 578 successful genotyped cases) lung cancers and only 2 (1.6%) were high-grade neuroendocrine carcinomas. RESULTS: Case one was of a 63 year-old white never smoker woman with extensive stage SCLC harboring EGFR delL747_P753insS but without EGFR protein expression. After progression on carboplatin/etoposide, the patient was treated with erlotinib and developed progressive disease with a survival <3 months from start of erlotinib. Case two was of a 73 year-old Asian 30 pack-year smoker man with metastatic LCNEC harboring EGFR-delL747_P753insQS and also lacking EGFR protein expression. The patient received first line therapy with erlotinib and had progressive disease with a survival of 4 months. CONCLUSIONS: The lack of response to EGFR TKIs in EGFR mutated de novo SCLC and LCNEC reported here may indicate that tumor differentiation affects tumor dependency on EGFR as a driver oncogene. PMID- 25700798 TI - Clinical Trial Designs in Amyotrophic Lateral Sclerosis: Does One Design Fit All? AB - The last 2 decades have seen a surge in the number of amyotrophic lateral sclerosis (ALS) clinical trials with the hope of finding successful treatments. Clinical trialists aim to repurpose existing drugs and test novel compounds to target potential ALS disease pathophysiology. Recent technological advancements have led to the discovery of new causative genetic agents and modes of delivering potential therapy, calling for increasingly sophisticated trial design. The standard ALS clinical trial design may be modified depending on study needs: type of therapy; route of therapy delivery; phase of therapy development; applicable subpopulation; market availability of therapy; and utility of telemedicine. Novel biomarkers of diagnostic, predictive, prognostic, and pharmacodynamic value are undergoing development and validation for use in clinical trials. Design modifications build on the traditional clinical trial design and may be employed in either the learning or confirming trial phase. Novel designs aim to minimize patient risk, study duration, and sample size, while improving efficiency and promoting statistical power to herald an exciting era for clinical research in ALS. PMID- 25700799 TI - Does the Recent Growth of Aquaculture Create Antibiotic Resistance Threats Different from those Associated with Land Animal Production in Agriculture? AB - Important antibiotics in human medicine have been used for many decades in animal agriculture for growth promotion and disease treatment. Several publications have linked antibiotic resistance development and spread with animal production. Aquaculture, the newest and fastest growing food production sector, may promote similar or new resistance mechanisms. This review of 650+ papers from diverse sources examines parallels and differences between land-based agriculture of swine, beef, and poultry and aquaculture. Among three key findings was, first, that of 51 antibiotics commonly used in aquaculture and agriculture, 39 (or 76%) are also of importance in human medicine; furthermore, six classes of antibiotics commonly used in both agriculture and aquaculture are also included on the World Health Organization's (WHO) list of critically important/highly important/important antimicrobials. Second, various zoonotic pathogens isolated from meat and seafood were observed to feature resistance to multiple antibiotics on the WHO list, irrespective of their origin in either agriculture or aquaculture. Third, the data show that resistant bacteria isolated from both aquaculture and agriculture share the same resistance mechanisms, indicating that aquaculture is contributing to the same resistance issues established by terrestrial agriculture. More transparency in data collection and reporting is needed so the risks and benefits of antibiotic usage can be adequately assessed. PMID- 25700800 TI - Stochastic models for plant microtubule self-organization and structure. AB - One of the key enablers of shape and growth in plant cells is the cortical microtubule (CMT) system, which is a polymer array that forms an appropriately structured scaffolding in each cell. Plant biologists have shown that stochastic dynamics and simple rules of interactions between CMTs can lead to a coaligned CMT array structure. However, the mechanisms and conditions that cause CMT arrays to become organized are not well understood. It is prohibitively time-consuming to use actual plants to study the effect of various genetic mutations and environmental conditions on CMT self-organization. In fact, even computer simulations with multiple replications are not fast enough due to the spatio temporal complexity of the system. To redress this shortcoming, we develop analytical models and methods for expeditiously computing CMT system metrics that are related to self-organization and array structure. In particular, we formulate a mean-field model to derive sufficient conditions for the organization to occur. We show that growth-prone dynamics itself is sufficient to lead to organization in presence of interactions in the system. In addition, for such systems, we develop predictive methods for estimation of system metrics such as expected average length and number of CMTs over time, using a stochastic fluid-flow model, transient analysis, and approximation algorithms tailored to our problem. We illustrate the effectiveness of our approach through numerical test instances and discuss biological insights. PMID- 25700801 TI - Supine or prone position for mini-PNL procedure: does it matter. AB - In this study it is aimed to compare the success and complication rates of mini PNL procedure in supine and prone positions. In this retrospective study data of 180 patients treated with MPNL either in supine (n = 54) or prone (n = 126) positions between May 2009 and August 2014 was investigated. Success was defined as no visible stones >2 mm. Perioperative complications were classified using the modified Clavien system. Groups were compared with Chi square test or Student t test and for statistical significance p value of 0.05 was accepted. Mean age of the population was 42.5 +/- 8.2 years and mean stone size was 23.9 +/- 4.1 mm. The two groups were similar with regard to demographic characteristics and stone related characteristics except the ASA status. Success rates of the supine and prone groups were 85.1 and 87.3%, respectively (p = 0.701). No statistically significant differences in terms of complications were observed. Mean operative time was the only parameter different between the two groups (55 vs 82 min, p = 0.001). Supine position for PNL seems to be promising and the complication and success rates are shown to be similar to the prone position with MPNL technique. The only significant benefit of this technique is shorter operative time. PMID- 25700802 TI - Interaction between worsening renal function and persistent congestion in acute decompensated heart failure. AB - Worsening renal function (WRF) and congestion are inextricably related pathophysiologically, suggesting that WRF occurring in conjunction with persistent congestion would be associated with worse clinical outcome. We studied the interdependence between WRF and persistent congestion in 762 patients with acute decompensated heart failure (HF). WRF was defined as >=0.3 mg/dl increase in serum creatinine above baseline at any time during hospitalization and persistent congestion as >=1 sign of congestion at discharge. The primary end point was all-cause mortality with mean follow-up of 15 +/- 9 months. Readmission for HF was a secondary end point. Persistent congestion was more common in patients with WRF than in patients with stable renal function (51.0% vs 26.6%, p <0.0001). Both persistent congestion and persistent WRF were significantly associated with mortality (both p <0.0001). There was a strong interaction (p = 0.003) between persistent WRF and congestion, such that the increased risk for mortality occurred predominantly with both WRF and persistent congestion. The adjusted hazard ratio for mortality in patients with persistent congestion as compared with those without was 4.16 (95% confidence interval [CI] 2.20 to 7.86) in patients with WRF and 1.50 (95% CI 1.16 to 1.93) in patients without WRF. In conclusion, persisted congestion is frequently associated with WRF. We have identified a substantial interaction between persistent congestion and WRF such that congestion portends increased mortality particularly when associated with WRF. PMID- 25700803 TI - A new electrocardiographic left ventricular hypertrophy prognostic score. AB - This report determines if the classic Romhilt-Estes score would predict better if points for its components were determined using a Cox hazard model and if the Cornell voltage criteria should replace the original criteria. Of the 20,903 subjects, the mean age was 43 +/- 10 years and 90.6% were men. The mean follow-up for the population was 17 years, with 881 cardiovascular deaths; they were tested from 1987 to 1999 and followed until 2013. The new score was created with multipliers based on the Cox hazards of its elements with age bracket and gender included. The Cornell criteria were analyzed individually using Cox hazards with and without adjustments for age, gender, and African-American ethnicity and subsequently incorporated into the new score for analysis. For the new score, all 7 components were significant predictors of cardiovascular mortality with gender producing the greatest hazard ratio (HR) and left axis deviation and QRS duration >110 ms producing the lowest. For the original Romhilt-Estes score, 367 patients (1.8%) met the "definite" cutoff and had an HR of 5.6 (95% confidence interval 4.3 to 7.1). For the new score, 208 patients (1.0%) met the "definite" left ventricular hypertrophy cutoff and had an HR of 13.6 (95% confidence interval 10.8 to 17.3). The Romhilt-Estes had an area under the curve of 0.63, whereas the new score and new score with Cornell voltage both had an area under the curve of 0.7. In conclusion, our modified Romhilt-Estes score with new multipliers and without voltage criteria outperformed the original score. PMID- 25700804 TI - [Diagnostic yield of video capsule endoscopy in premenopausal women with iron deficiency anemia]. AB - Clinical practice guidelines recommend video capsule endoscopy (VCE) studies in patients with iron-deficiency anemia (IDA) after conventional upper and lower endoscopies but there is a need for studies demonstrating the diagnostic yield, clinical impact, and cost in some patient subgroups. OBJECTIVES: 1.To determine the diagnostic yield of VCE in premenopausal women with IDA compared with that in men and postmenopausal women. 2. To identify the presence of VCE predictors in premenopausal women. 3. To estimate the cost-clinical impact relationship associated with VCE in this indication. MATERIAL AND METHOD: We retrospectively analyzed 408 patients who underwent VCE. Patients with IDA were enrolled (premenopausal, postmenopausal women, and men), with previous normal work-up by conventional endoscopies. RESULTS: A total of 249 patients were enrolled: 131 women (52.6%), of which 51 were premenopausal and 80 were post-menopausal, and 118 men. The mean age was 60.7+/-16 years. The diagnostic yield of VCE for the diagnosis of IDA was 44.6% (95% CI 39.9 - 50.8). Diagnostic yield was 50.8% vs 38.9% in men vs women (p=0.05) and was 55% vs 13.7% in postmenopausal vs premenopausal women (p<0.001). No predictors of small bowel lesions were found in premenopausal women. The most common findings in the postmenopausal group were angioectasias (70.5%) and erosions (57.1%) in the premenopausal group. The cost in premenopausal women was 44.727? and 86.3% of the procedures had no clinical impact. CONCLUSIONS: The diagnostic yield of VCE is low in the etiological study of IDA in premenopausal women and there is no cost-effectiveness in relation to clinical impact. No predictors of small bowel lesions were found in this group. PMID- 25700805 TI - [Ileocolic fistulas after radiotherapy for endometrial carcinoma]. PMID- 25700806 TI - A randomized, crossover study to investigate the pharmacokinetics and safety of inhaled fluticasone furoate and umeclidinium, administered separately and in combination via dry powder inhaler in healthy adult volunteers. AB - INTRODUCTION: A combination of fluticasone furoate (FF) and umeclidinium (UMEC) has been considered for development for the treatment of asthma. The primary objectives were to investigate the plasma and urine pharmacokinetics (PK) of FF/UMEC in combination compared with FF and UMEC monotherapies. METHODS: This randomized, double-blind, three-period crossover, single-center study in healthy volunteers assessed the PK of FF 400 mcg and UMEC 500 mcg administered separately and in combination (four inhalations of FF/UMEC 100/125 mcg, FF 100 mcg, or UMEC 125 mcg) via dual-strip dry powder inhaler. Subjects were randomized based on codes generated using a validated computerized system (Randall, GlaxoSmithKline). RESULTS: Eighteen subjects were enrolled; 17 received all three scheduled doses of study medication. Plasma FF and UMEC concentrations peaked at 0.5 and 0.08 h post-dose, respectively, for FF/UMEC and the monotherapies. FF and UMEC co administration resulted in slightly lower or similar systemic exposure for both drugs versus the monotherapies. In post hoc sensitivity analyses (performed because two subjects administered inhalations incorrectly), the ratio of adjusted geometric means (maximum plasma concentration and area under the curve) was closer to unity than in the planned analyses. Cumulative urinary UMEC excretion (Ae) was similar for FF/UMEC and UMEC. Post hoc sensitivity analyses on Ae(0-24) suggested a small carryover effect but results were similar to those of the population as a whole. Urinary UMEC excretion following FF/UMEC was low (~1.5% over 24 h) and unlikely to have impacted upon PK comparisons. Three adverse events were reported; none were severe or led to withdrawal. There were no clinically significant effects on electrocardiogram, vital sign, or laboratory parameters. CONCLUSION: Fluticasone furoate and umeclidinium co-administration was well tolerated and was not associated with meaningful changes in systemic or urinary PK versus the monotherapies. FUNDING: GlaxoSmithKline. PMID- 25700807 TI - Addition of ivabradine to beta-blocker improves exercise capacity in systolic heart failure patients in a prospective, open-label study. AB - INTRODUCTION: Difficulties initiating and uptitrating beta-blockers due to tolerability can complicate management of heart failure. Among other actions, beta-blockers reduce heart rate, which is an important cardiovascular risk factor in heart failure. A new therapeutic strategy is ivabradine, which reduces resting heart rate and is associated with improved outcomes. METHODS: A 5-month, prospective, open-label, nonrandomized single-center study was performed in 69 patients. All patients had chronic heart failure with left ventricular systolic dysfunction in sinus rhythm, each were initiated on 3.125 mg twice daily (bid) carvedilol alone (n = 36) or 3.125 mg bid carvedilol/5 mg bid ivabradine (n = 33), on top of background therapy including angiotensin-converting enzyme inhibitor (88%), diuretics (86%), antiplatelet agents (91%), and statins (90%). Dosages were uptitrated every 2 weeks to 25 mg bid carvedilol in both groups and 7.5 mg bid ivabradine maximum in the carvedilol/ivabradine group. Uptitration of carvedilol lasted 1.9 +/- 0.4 months with carvedilol/ivabradine and 2.8 +/- 0.6 months with carvedilol alone (P < 0.05). RESULTS: The patients receiving ivabradine had lower resting heart rate at 5 months (61.6 +/- 3.1 versus 70.2 +/- 4.4 bpm, P < 0.05). Adding ivabradine to carvedilol in patients with heart failure was associated with increases in the 6-min walk test and ejection fraction (all P < 0.05). Treatment tolerability was satisfactory. Patients receiving ivabradine and carvedilol had lower heart rates and better exercise capacity than those on carvedilol alone. CONCLUSION: Adding ivabradine to carvedilol in patients with chronic heart failure improves the uptitration of beta-blocker. The results merit further verification in a prospective double blind study. PMID- 25700808 TI - A clinical model for predicting lymph node metastasis in submucosal invasive (T1) colorectal cancer. AB - BACKGROUND: No single histopathological feature of submucosal invasive colorectal cancer (T1-CRC) can reliably predict the risk for lymph node metastasis (LNM). AIM: The purpose of the study was to develop a prediction model of LNM in T1-CRC. METHODS: Ninety-seven surgically resected T1-CRC at our institution were retrospectively evaluated. Morphology, localization, grading, mode of growth, presence of background adenoma, lymphoid infiltration, angiolymphatic invasion, budding, and depth of invasion were assessed. Mortality and morbidity related to surgery were also evaluated. Benefit-risk balance was assessed according to the presence of severe complications and to the presence of LNM. RESULTS: Fourteen cases had LNM (14%). Eight patients (8%) presented severe surgical complications and there were two deaths (2 %). Infiltrative growth pattern (OR 31.91, 95% CI 2.37-428.36; p = 0.009) and the absence of lymphoid infiltrate (OR 28.75; 95% CI 2.13-388.37; p = 0.011) were the only variables independently associated with LNM in the multivariate analysis. Both variables were included in the prediction model together with sessile morphology (OR 4.88; 95% CI 0.81-29.3; p = 0.083) and poorly differentiated carcinoma (OR 11.77; 95% CI 0.77-179.83; p = 0.076). A 0 100 score was developed (infiltrative growth pattern: no = 0, yes = 33; lymphoid infiltrate: no = 29, yes = 0; sessile morphology: no = 0, yes = 15; poorly differentiated: no = 0, yes = 23). Cutoff point to indicate additional surgery was set in 35 points (i.e., 10% risk LNM). Discrimination of the prediction model was excellent (AUC 0.90; 95% CI 0.81-0.99). CONCLUSION: Combined evaluation of infiltrative growth pattern, lymphoid infiltration, poorly differentiated carcinoma, and sessile appearance showed good performance for discriminating T1 CRC patients with LNM. The benefit-risk balance was in favor of surgery when at least two of these criteria were present. PMID- 25700809 TI - Subcutaneous vacuum drains reduce surgical site infection after primary closure of defunctioning ileostomy. AB - PURPOSE: Surgical site infection (SSI) is the most common complication after primary closure of defunctioning ileostomy. We use a subcutaneous vacuum drain (SVD) in our institution to prevent infection. This study aimed to analyze the risk factors of SSI and to assess the utility of an SVD for preventing SSI in patients undergoing primary closure of ileostomy. METHODS: Patients undergoing ileostomy closure in the Department of Colorectal Surgery, Peking University Cancer Hospital, from September 2006 to March 2013, were included in this study. The clinical features of these patients with or without a subcutaneous drain were reviewed, and the complication rate of SSI was analyzed. The primary endpoints were the incidence and risk factors of SSI, and the secondary endpoints were the rate of overall complications and their management. RESULTS: A total of 245 consecutive patients were enrolled in the study. The overall incidence of SSI was 8.6%. Eighty-five (34.7%) patients received placement of an SVD. The use of SVDs was associated with a significantly lower incidence of SSI compared with primary closure (PC) without an SVD (1.2 vs. 12.5%, p = 0.001). Multivariate analyses showed that the presence of an SVD (odds ratio (OR) 0.063, p = 0.012), total operation time >90 min (OR 4.862, p = 0.002), and postoperative complications (OR 10.576, p < 0.001) were independent risk factors of SSI. CONCLUSIONS: This study shows that an SVD is effective for reducing SSI in patients undergoing PC of ileostomy. Further randomized trials are required to confirm our findings and to compare SVDs with purse-string sutures. PMID- 25700810 TI - Dynamic magnetic resonance imaging evaluation of pelvic reconstruction with porcine dermal collagen mesh following extra-levator abdominoperineal excision for primary rectal cancer. AB - PURPOSE: Extra-levator abdominoperineal excision for rectal cancer includes resection of the levator ani muscle and therefore makes pelvic reconstruction advisable. The aim of our study was to evaluate morphologic and functional long term results of pelvic floor augmentation with porcine dermal collagen mesh by dynamic magnetic resonance imaging and clinical examination. METHODS: Twenty consecutive patients underwent perineal reconstruction with porcine dermal collagen mesh following extra-levator abdominoperineal excision for primary rectal adenocarcinoma with curative intent between 2009 and 2012. Patient perioperative and postoperative data were collected prospectively. There were one cancer-related and two noncancer-related deaths in the follow-up period, and another three patients refused the dynamic magnetic resonance imaging. RESULTS: Fourteen patients were included in the study. The median time period from surgery to dynamic magnetic resonance imaging and clinical examination was 31 months (range 19-56). Wound infections were observed in 43% (6 of 14) of these patients in the postoperative period, but no mesh had to be removed. No focal mesh defect, no damage on the suture line, and no perineal hernia were detected on dynamic magnetic resonance imaging. Clinical examination revealed no pathological findings in any patient. CONCLUSIONS: The implantation of a porcine dermal collagen mesh is an effective and reliable option for pelvic floor reconstruction after extra-levator abdominoperineal excision. Despite a high incidence of primary wound infections, the healing rate was satisfactory, no mesh had to be removed, and long-term stability could be achieved. PMID- 25700811 TI - Oxyfunctionalization with Cp*Ir(III)(NHC)(Me)(Cl) with O2: identification of a rare bimetallic Ir(IV) MU-oxo intermediate. AB - Methanol formation from [Cp*Ir(III)(NHC)Me(CD2Cl2)](+) occurs quantitatively at room temperature with air (O2) as the oxidant and ethanol as a proton source. A rare example of a diiridium bimetallic complex, [(Cp*Ir(NHC)Me)2(MU O)][(BAr(F)4)2], 3, was isolated and shown to be an intermediate in this reaction. The electronic absorption spectrum of 3 features a broad observation at ~660 nm, which is primarily responsible for its blue color. In addition, 3 is diamagnetic and can be characterized by NMR spectroscopy. Complex 3 was also characterized by X-ray crystallography and contains an Ir(IV)-O-Ir(IV) core in which two d(5) Ir(IV) centers are bridged by an oxo ligand. DFT and MCSCF calculations reveal several important features of the electronic structure of 3, most notably, that the MU-oxo bridge facilitates communication between the two Ir centers, and sigma/pi mixing yields a nonlinear arrangement of the MU-oxo core (Ir-O-Ir ~ 150 degrees ) to facilitate oxygen atom transfer. The formation of 3 results from an Ir oxo/oxyl intermediate that may be described by two competing bonding models, which are close in energy and have formal Ir-O bond orders of 2 but differ markedly in their electronic structures. The radical traps TEMPO and 1,4-cyclohexadiene do not inhibit the formation of 3; however, methanol formation from 3 is inhibited by TEMPO. Isotope labeling studies confirmed the origin of the methyl group in the methanol product is the iridium-methyl bond in the [Cp*Ir(NHC)Me(CD2Cl2)][BAr(F)4] starting material. Isolation of the diiridium containing product [(Cp*Ir(NHC)Cl)2][(BAr(F)4)2], 4, in high yields at the end of the reaction suggests that the Cp* and NHC ligands remain bound to the iridium and are not significantly degraded under reaction conditions. PMID- 25700812 TI - Managing heart failure in adults with congenital heart disease. AB - OPINION STATEMENT: The current era of cardiology has seen a significant increase in the number of adults living with congenital heart disease (CHD). Although advances in medical and surgical management have resulted in approximately 90 % of children with CHD living into adulthood, many suffer from late complications, with myocardial dysfunction as the leading cause of morbidity and mortality. The heterogeneity of the adult congenital heart disease (ACHD) population has presented a challenge, as there are only limited data regarding appropriate treatment modalities. Given the growing ACHD population and the high morbidity and mortality related to myocardial dysfunction, a comprehensive approach to heart failure (HF) care is recommended in conjunction with ACHD and HF specialty care. The field must focus on developing research strategies to leverage existing and future medical and surgical treatment options in order to improve outcomes in this diverse population. PMID- 25700813 TI - Immobilization of enzymatic extracts of Portulaca oleracea cv. roots for oxidizing aqueous bisphenol A. AB - Water pollution from the release of industrial wastewater is a serious problem for almost every industry. Enzymes from portulaca, Portulaca oleracea cv., have been investigated for their ability to degrade bisphenol A (BPA), one of the well known estrogenic pollutants. Enzymatic crude extracts from P. oleracea cv. roots were immobilized on aminopropyl-modified glass beads. They maintained BPA metabolic activity over a broad range of pH values and temperatures. The immobilized enzyme was reusable with more than 50 % of its initial activity retained after 12 batch reactions and no loss of activity after storage for 1 month at -30 degrees C. Thus, the immobilization of extracts from P. oleracea cv. roots is a useful method for removing BPA from industrial wastewater. PMID- 25700814 TI - Biotransformation of oleic acid into 10-ketostearic acid by recombinant Corynebacterium glutamicum-based biocatalyst. AB - OBJECTIVE: To produce 10-ketostearic acid from oleic acid. RESULTS: Oleic acid was converted to 10-ketostearic acid by a recombinant Corynebacterium glutamicum ATCC 13032 expressing oleate hydratase from Stenotrophomonas maltophilia and a secondary alcohol dehydrogenase from Micrococcus luteus under the control of a synthetic constitutive promoter. Optimal conditions for 10-ketostearic acid production were pH 7.5 and 30 degrees C with 5 g cells l(-1) and 2.5 g oleic acid l(-1). Under these conditions, the cells produced 1.96 g 10-ketostearic acid l(-1) from oleic acid in 6 h, with a conversion yield of 78 % (w) and a maximum volumetric productivity of 1.67 g l(-1) h(-1). CONCLUSION: This is the first report of 10-ketostearic acid production using a recombinant C. glutamicum. PMID- 25700815 TI - Metabolic and phylogenetic analyses based on nitrogen in a new poly-gamma glutamic acid-producing strain of Bacillus subtilis. AB - OBJECTIVES: Nitrogen metabolism was investigated during poly-gamma-glutamic acid (gamma-PGA) synthesis and phylogenetic analyses was used to explore glutamate dependency in Bacillus subtilis HSF1410. RESULTS: Bacillus subtilis HSF1410 was cultured with (15)NH4+ in the medium, and the gamma-PGA synthesized was then analyzed using (15)N-NMR. The gamma-PGA framework was partially labeled with (15)N, indicating that gamma-PGA was synthesized from inorganic nitrogen and carbohydrate. Assay of glutamate synthetase and glutamine synthetase activities also revealed that ammonium can be used to synthesize gamma-PGA in HSF1410. Phylogenetic trees based on gamma-PGA synthesis genes (pgsBCA) and 16S rRNA showed that HSF1410 falls within a cluster of glutamate-dependent strains, versus glutamate-independent strains, which is confirmed by HSF1410 being unable to produce gamma-PGA without glutamate in its medium CONCLUSION: we classify B. subtilis HSF1410 as a glutamate-dependent strain that can use exogenous inorganic nitrogen sources to synthesize gamma-PGA. PMID- 25700816 TI - Direct detection, cloning and characterization of a glucoside hydrolase from forest soil. AB - A glucoside hydrolase gene, egl01, was cloned from the soil DNA of Changbai Mountain forest by homologous PCR amplification. The deduced sequence of 517 amino acids included a catalytic domain of glycoside hydrolase family 5 and was homologous to a putative cellulase from Bacillus licheniformis. The recombinant enzyme, Egl01, was maximally active at pH 5 and 50 degrees C and it was stable at pH 3-9, 4-50 degrees C, and also stable in the presence of metal ions, organic solvents, surfactants and salt. Its activity was above 120 % in 2-3 M NaCl/KCl and over 70 % was retained in 1-4 M NaCl/KCl for 6d. Egl01 hydrolyzed carboxymethyl cellulose, beechwood xylan, crop stalk, laminarin, filter paper, and avicel but not pNPG, indicating its broad substrate specificity. These properties make this recombinant enzyme a promising candidate for industrial applications. PMID- 25700817 TI - Current state of genome-scale modeling in filamentous fungi. AB - The group of filamentous fungi contains important species used in industrial biotechnology for acid, antibiotics and enzyme production. Their unique lifestyle turns these organisms into a valuable genetic reservoir of new natural products and biomass degrading enzymes that has not been used to full capacity. One of the major bottlenecks in the development of new strains into viable industrial hosts is the alteration of the metabolism towards optimal production. Genome-scale models promise a reduction in the time needed for metabolic engineering by predicting the most potent targets in silico before testing them in vivo. The increasing availability of high quality models and molecular biological tools for manipulating filamentous fungi renders the model-guided engineering of these fungal factories possible with comprehensive metabolic networks. A typical fungal model contains on average 1138 unique metabolic reactions and 1050 ORFs, making them a vast knowledge-base of fungal metabolism. In the present review we focus on the current state as well as potential future applications of genome-scale models in filamentous fungi. PMID- 25700818 TI - Enhancement of L-valine production in Bacillus licheniformis by blocking three branched pathways. AB - OBJECTIVES: Bacillus licheniformis WX-02 is used for the production of many valuable chemicals. Here, we have sought to improve L-valine production by blocking the metabolic pathways related to branched-chain amino acids. RESULTS: The synthesis genes of L-leucine (leuA) and L-isoleucine (ilvA) were deleted to obtain mutant strains. L-Valine yields of WX-02DeltaleuA and WX-02DeltailvA reached 33.2 and 21.1 mmol/l, respectively, which are 22 and 14 times higher than the wild-type WX-02 (1.53 mmol/l). After further deletion of L-lactate dehydrogenase gene (ldh) from WX-02DeltaleuA, the productivity reached 0.47 mmol/l h, an increase of 19 %. CONCLUSION: We provide a possibility to over produce L-valine using genetically-modified B. licheniformis using remodeling of the biosynthetic pathway to L-valine. PMID- 25700819 TI - Heterologous biosynthesis of costunolide in Escherichia coli and yield improvement. AB - Costunolide, the main bioactive compound of the medicinal plant, Radix Aucklandiae, is a sesquiterpene lactone (SL) and has a broad range of biological activities. It is also a precursor of many biologically-active SLs and is a branching point in the biosynthesis of SLs. Here we have reconstituted the costunolide biosynthetic pathway in Escherichia coli by co-expression of three genes (GAS, GAO, LsCOS) involved in costunolide biosynthesis and eight genes involved in converting acetyl-CoA into farnesyl diphosphate from mevalonate pathway. Costunolide production was then detected. By screening and optimization of cultured medium and inducing temperature, costunolide yield was up to 100 mg l(-1) in E. coli. PMID- 25700820 TI - Well-defined differentiation of hESC-derived hemangioblasts by embryoid body formation without enzymatic treatment. AB - Human hemangioblasts exist only during the early embryonic developmental stage thereby limiting the adult cellular source from which to obtain such cells for study. To overcome this, hemangioblast studies have focused on utilizing human embryonic stem cell (hESC) derivatives but current methods are cell-line dependent. Single cell dissociation of a hESC colony quickly led to cell death in most hESC lines due to enzyme treatment which, in turn, reduced induction potential and hemangioblast differentiation efficiency. Therefore, we sought to effectively improve the process of cell dissociation that is adaptable to various hESC lines and increase the initial induction potential of embryoid body (hEB). As a result, we determined an effective cell dissociation method through a comparison study involving various reagents which demonstrated successful dissociation regardless of cell line and enhanced hemangioblast differentiation efficiency. PMID- 25700821 TI - Transient expression of rabies virus G-glycoprotein using BHK-21 cells cultured in suspension. AB - OBJECTIVE: To assess the expression of rabies virus G-glycoprotein (RVGP) expression using Semliki Forest virus as a vector in combination with BHK-21 cells cultured in suspension. RESULTS: A multilevel factorial design was used to quantify effects of temperature (33-37 degrees C), fresh medium addition after the viral adsorption step (100-200 % with respect to the initial cell suspension volume before infection) and harvest time (8-40 h) on RVGP production. Experimental runs were performed in 24-well cell culture plates at a multiplicity of infection (MOI) of 16. An additional experiment in spinner-flask was performed at MOI of 9, using the optimal conditions determined in cell culture plates. Values for temperature, fresh medium addition and harvest time of 33 degrees C, 100 % and 16 h, respectively, ensured the optimal RVGP production in culture plates. The volumetric yield (239 ng ml(-1)) in these conditions was higher than that reported previously for adherent cell culture. In spinner-flasks, the volumetric yield was improved (559 ng ml(-1)). CONCLUSION: These results establish the basis for designing bioprocess to produce RVGP. PMID- 25700822 TI - Comparison of the miRNome and piRNome of bovine blood and plasma by small RNA sequencing. AB - OBJECTIVES: The small RNAs of bovine plasma and whole blood were analysed using next-generation sequencing to quantify, profile and compare the microRNAs (miRNA) and piRNA signatures in both bio fluids. RESULTS: Evaluating read-count data resulted in a proportion of 5.0 +/- 2.9 % of miRNAs in plasma while 38.2 +/- 3.4 % were identified in whole blood. Regarding piRNAs, the percentages in both matrices were nearly the same: 1.4 +/- 0.8 % of piRNAs in plasma and 1.9 +/- 0.8 % in whole blood. Investigation of the ten most abundant miRNAs and piRNAs in both bio fluids revealed that two miRNAs and seven piRNAs were identical. Comparing the read-count values of these matching pairs highlighted that miRNA and piRNA levels in blood exceeded the abundance of their corresponding miRNAs and piRNAs in plasma, except liver-specific miR-122 and three piRNAs. CONCLUSIONS: The data strengthened evidence that the circulating small RNA signature in plasma is not only influenced by hematocytes and certain small RNAs could originate from other sources than cellular blood components. PMID- 25700823 TI - Gene chip analysis of Arabidopsis thaliana genomic DNA methylation and gene expression in response to carbendazim. AB - OBJECTIVES: To examine the effects of carbendazim on Arabidopsis genomic DNA methylation and gene expression. RESULTS: Carbendazim caused widespread changes in gene loci methylation and gene expression. With 0.1 mM (D2) and 0.2 mM (D3) carbendazim, there were, respectively, 1522 and 2278 demethylated sites and 1541 and 2790 methylated sites. A total of 279 and 505 genes were up-regulated by more than 300 % and 175 and 609 genes were down-regulated by 67 % in D2 and D3 treatments, respectively, compared with the control. Conjoint analysis showed that 20 and 39 demethylated genes were up-regulated >300 % and 21 and 24 methylated genes were down-regulated <67 % in D2 and D3, respectively. CONCLUSIONS: Carbendazim causes methylation or demethylation of certain genes and changes the expression of these genes. These findings provide a theoretical basis for novel epigenetics-based methods to detect organic food and a new interpretation for the degradation of crop varieties. PMID- 25700824 TI - Use of cell-based screening to identify small-molecule compounds that modulate claudin-4 expression. AB - Claudins constitute a family of at least 27 proteins with four transmembrane domains, and play a pivotal role in maintaining tight-junctions seals in diverse epithelial tissues. The expression of claudin-4 often changes in intestinal tissues of inflammatory bowel disease and various human cancers. Therefore, claudin-4 is a promising target for treatment of these diseases. In our previous study, we established a reporter cell line to monitor claudin-4 expression on the basis of a functional claudin-4 promoter. Using this cell line, we have performed a cell-based screen of a library containing 2642 biologically active small molecule compounds to identify modulators of claudin-4 expression. The screen identified 24 potential modulators of the claudin-4 promoter activity. Fourteen of these compounds (12 of them novel) induced endogenous claudin-4 expression. The identified compounds might serve as lead compounds targeting aberrant gene expression in inflammatory bowel disease. PMID- 25700825 TI - Efficient stabilization of recombinant human coagulation factor VIII in the milk of transgenic mice using hFVIII and vWF co-expression vector transduction. AB - OBJECTIVES: To investigate the reasons for the instability of human coagulation factor FVIII (hFVIII) in milk which is an intractable obstacle during the hFVIII production by a transgenic mammary gland bioreactor. RESULTS: We constructed P1A3 hFVIIIBDD and P1A3-hFVIIIBDD-IRES-vWF co-expression cassettes for generating transgenic mice. P1A3-hFVIII/CMV-vWF double heterozygotes were also prepared by mating P1A3-hFVIIIBDD with CMV-vWF mice. hFVIII bioactivity in milk was determined under different storage conditions. The half-life (in vitro) of hFVIII bioactivity in P1A3-hFVIIIBDD-IRES-vWF mice was significantly longer than P1A3 hFVIIIBDD mice [77 +/- 4.9 vs. 44 +/- 2.6 h at 4 degrees C, 32.5 +/- 5 vs. 19.7 +/- 0.6 h at room temperature and 7.4 +/- 1.4 vs. 3.4 +/- 0.6 at 37 degrees C, respectively (P < 0.05)]. The half-life (in vitro) of hFVIII bioactivity in milk of double heterozygotes was similar to P1A3-hFVIIIBDD-IRES-vWF ones, demonstrating that the vWF transgene expression in hFVIII transgenic mice can efficiently improve the stabilization of hFVIII bioactivity in milk. CONCLUSION: We provide a new approach of P1A3-hFVIIIBDD-IRES-vWF co-expression to generate more stable hFVIII in transgenic milk with rapid and low cost as well as valuable information for producing pharmaceutical proteins by transgenic mammary gland bioreactor. PMID- 25700826 TI - Sodium butyrate-induced histone hyperacetylation up-regulating WT1 expression in porcine kidney fibroblasts. AB - OBJECTIVES: Wilms' tumor 1 gene (WT1) is essential for the development of kidney and histone acetylation and is involved in its expression regulation in mice. However, whether WT1 expression is associated with histone acetylation in porcine kidney cells is unclear. Here, the effect of histone deacetylase inhibitor sodium butyrate (NaBu)-induced hyperacetylation on WT1 expression in porcine kidney fibroblasts (PKF) was examined. RESULTS: Treatments of NaBu (1, 3, 6 mM) for 24 h increased PKF viability, and 24, 48 h-treatments of 1 mM NaBu enhanced PKF proliferation. WT1 mRNA levels were significantly elevated in NaBu-treated (1, 3 mM for 24, 48 h, respectively) PKF samples. Consistently, strengthened expression of WT1 protein and histone acetylation level were detected in NaBu-treated PKF cells. CONCLUSION: Together, NaBu-induced hyperacetylation up-regulates WT1 expression in PKF, suggesting the involvement of histone acetylation in the transcriptional modulation of WT1 in porcine kidney cells. PMID- 25700827 TI - Preliminary findings on associations between moral emotions and social behavior in young children with normal hearing and with cochlear implants. AB - Moral emotions such as shame, guilt and pride are the result of an evaluation of the own behavior as (morally) right or wrong. The capacity to experience moral emotions is thought to be an important driving force behind socially appropriate behavior. The relationship between moral emotions and social behavior in young children has not been studied extensively in normally hearing (NH) children, let alone in those with a hearing impairment. This study compared young children with hearing impairments who have a cochlear implant (CI) to NH peers regarding the extent to which they display moral emotions, and how this relates to their social functioning and language skills. Responses of 184 NH children and 60 children with CI (14-61 months old) to shame-/guilt- and pride-inducing events were observed. Parents reported on their children's social competence and externalizing behavior, and experimenters observed children's cooperative behavior. To examine the role of communication in the development of moral emotions and social behavior, children's language skills were assessed. Results show that children with CI displayed moral emotions to a lesser degree than NH children. An association between moral emotions and social functioning was found in the NH group, but not in the CI group. General language skills were unrelated to moral emotions in the CI group, yet emotion vocabulary was related to social functioning in both groups of children. We conclude that facilitating emotion language skills has the potential to promote children's social functioning, and could contribute to a decrease in behavioral problems in children with CI specifically. Future studies should examine in greater detail which factors are associated with the development of moral emotions, particularly in children with CI. Some possible directions for future research are discussed. PMID- 25700828 TI - Hrr25: an emerging major player in selective autophagy regulation in Saccharomyces cerevisiae. AB - As with the case of the mechanism of autophagosome formation, studies in yeast have taken a leading role in elucidating the molecular basis of target recognition during selective autophagy. Degradation targets are recognized by receptor proteins, which also bind to Atg8 homologs on growing phagophore membranes, leading to the loading of the targets into autophagosomes. However, it remains to be elucidated how these processes are regulated. In yeast, receptors also interact with the scaffold/adaptor protein Atg11, which subsequently recruits core Atg proteins onto receptor-target complexes to initiate autophagosome formation. Recently, we found that Hrr25, a homolog of CSNK1D/casein kinase 1delta, regulates 3 of 4 selective autophagy-related pathways in the budding yeast Saccharomyces cerevisiae by a uniform mechanism: phosphoregulation of the receptor-scaffold interaction. PMID- 25700829 TI - Is Demirjian's original method really useful for age estimation in a forensic context? AB - PURPOSE: The suitability of Demirjian's method for forensic age estimation has been systematically questioned. The aim of this study is to further assess the reliability of Demirjian's original method in forensic age estimation using a sample of Portuguese children. METHODS: 564 panoramic radiographs of Portuguese boys and girls between 6 and 16 years of age were evaluated using Demirjian's method. Dental age (DA) was determined using the 50th percentile for the maturity score obtained for each age group. The mean difference between chronological age (CA) and dental age (DA) and the mean absolute difference between CA and DA were calculated for each age group. Paired t tests were used to test the statistical significance of mean differences between CA and DA. For each individual, a 94% confidence interval was calculated for estimated DA, using the 3rd and 97th percentiles in Demirjian's conversion tables. RESULTS: Chronological age was overestimated in boys, in every age group; mean differences between CA and DA were statistically significant, expect for age 7. In girls, chronological age was overestimated in the 10-15 year-old age group. The difference between CA and DA was highest in the 12 years olds for both sexes. The 94% confidence intervals did not include the true chronological age in all 6, 13, and 15 year-old girls, and all 14 and 15 year-old boys. Only a small portion of the individuals in the remaining age groups had their true chronological age falling within the probable age interval. CONCLUSIONS: Results show a systematic bias and consistent inaccuracy in estimating age from dental development using Demirjian's original method, making this methodology unsuitable for age estimation in the study sample. These results add to published evidence which suggests that Demirjian's method is not suitable and should be abandoned altogether for forensic age estimation purposes. PMID- 25700830 TI - Bruises: is it a case of "the more we know, the less we understand?". PMID- 25700831 TI - The inferior cochlear vein: surgical aspects in cochlear implantation. AB - The patency of the inferior cochlear vein (ICV) may be challenged in cochlear implantation (CI) due to its location near the round window (RW). This may be essential to consider during selection of different trajectories for electrode insertion aiming at preserving residual hearing. Venous blood from the human cochlea is drained through the ICV. The vein also drains blood from the modiolus containing the spiral ganglion neurons. Surgical interference with this vein could cause neural damage influencing CI outcome. We analyzed the topographical relationship between the RW and ICV bony channel and cochlear aqueduct (CA) from a surgical standpoint. Archival human temporal bones were further microdissected to visualize the CA and its accessory canals (AC1 and AC2). This was combined with examinations of plastic and silicone molds of the human labyrinth. Metric analyses were made using photo stereomicroscopy documenting the proximal portion of the AC1, the internal aperture of the CA and the RW. The mean distance between the AC1 and the anterior rim of the RW was 0.81 mm in bone specimens and 0.67 mm assessed in corrosion casts. The AC1 runs from the floor of the scala tympani through the otic capsule passing parallel to the CA to the posterior cranial fossa. The mean distance between the CA and AC1 canal was 0.31 and 0.25 mm, respectively. PMID- 25700832 TI - Management of superior subperiosteal orbital abscess. AB - A superior subperiosteal orbital abscess (SSPOA) is a collection of purulent material between the periorbit and the superior bony orbital wall, and is typically a complication of frontal sinusitis. SSPOA is characteristically managed by classic external surgical drainage. The aim of our study was to assess the role of surgical intervention in SSPOA. A retrospective medical chart review of patients diagnosed with SSPOA secondary to rhinosinusitis between the year 2005 and 2013 was conducted. Collected data included age, gender, co-morbidity, clinical presentation, prior antibiotic management, CT scans, surgical approach, outcome and complications. Six patients were included in our study, three males and three females with a mean age of 22.8 (range 9-58). Two patients were treated with amoxicillin clavulanic acid for 3 days prior to admission. Only the youngest patient with the smallest abscess responded successfully to conservative treatment, while the rest were managed surgically: three patients were treated successfully by the endonasal endoscopic approach and two patients were treated by utilizing the combined endonasal endoscopic and external approach. In patients who underwent the combined approach, the abscess was located in a more antero lateral position than those treated endonasal endoscopically only. The location of a SSPOA dictates the surgical approach. The most antero-lateral SSPOAs should be drained by the combined approach, while more posterior abscesses should be approached endoscopically. Furthermore, a small SSPOA is first to be reported to resolve with conservative treatment. Level 4 (case series). PMID- 25700833 TI - Long-term vestibulocochlear functional outcome following retro-sigmoid approach to resection of vestibular schwannoma. AB - The objective of this study was to evaluate long-term vestibulocochlear functional outcomes of patients operated for unilateral vestibular schwannoma via the retro-sigmoid approach. Patients who underwent vestibular schwannoma resection via retro-sigmoid approach between 2004 and 2008 at our institution, without prior surgical or radio-surgical therapy were considered to be eligible for this study. Preoperative auditory and vestibular symptoms were assessed retrospectively. Postoperative symptoms were prospectively assessed using a standardised questionnaire, pure tone audiometry, video-oculography, and rotary chair testing. Out of a total of 203 patients, 120 were eligible for this study, of whom 64 responded to follow-up requests and could be enrolled. Serviceable hearing was reported in 42 patients (66 %) preoperatively and was maintained in 18 (43 %) postoperatively. While no significant change in rate of tinnitus and balance impairment between pre- and postoperative periods was detected, vertigo decreased significantly (40 to 28 %, p < 0.001). Postoperative video-oculography demonstrated vestibular paresis in 80 %. Rotary chair testing demonstrated normal or central compensation in 84 %. Absence of central compensation was associated with postoperative balance disturbance (p = 0.035). Increasing tumour size and patient age, also decreasing quality of preoperative hearing were independent factors predictive of a postoperative non-serviceable hearing (p = 0.020, p = 0.039 and p = 0.002, respectively). Resection of vestibular schwannoma via the retro-sigmoid approach is associated with improvement in postoperative vertiginous symptoms. Absence of central compensation leads to increased postoperative balance disturbances. Preservation of serviceable postoperative hearing is associated with good preoperative hearing status, younger age, and smaller tumours. PMID- 25700834 TI - The role of STAT3 in tumor-mediated immune suppression. AB - The role of tumor-induced immune modulation in cancer progression is currently a focus of investigation. The signal transducer and activator of transcription 3 (STAT3) is an established molecular hub of immunosuppression, and its signaling pathways are classically overactivated within malignancies. This article will review STAT3 operational mechanisms within the immune system and the tumor microenvironment, with a focus on therapeutic strategies that may impact outcomes for patients with cancer. PMID- 25700835 TI - Evaluation of absolute and normalized apparent diffusion coefficient (ADC) values within the post-operative T2/FLAIR volume as adverse prognostic indicators in glioblastoma. AB - To evaluate the association of normalized and absolute ADC metrics with progression free survival (PFS) and overall survival (OS) in patients treated for glioblastoma multiforme (GBM). Fifty-two patients with preradiotherapy diffusion weighted imaging treated with post-operative chemoradiation for GBM were evaluated. Region of interest analysis for ADC metrics including mean and minimum ADC value (ADCmean) and (ADCmin) was performed within the T2/FLAIR volume. Normalized (N)ADC values were generated relative to contralateral white matter. PFS and OS were analyzed relative to ADC parameters using a regression model. Kaplan-Meier and Cox proportional hazards analysis with respect to (N)ADCmean, and (N)ADCmin was performed. A (N)ADC threshold <1.3 within the T2/FLAIR volume was analyzed with respect to PFS and OS. Regression analysis indicated that normalized ADC values provide the strongest association with PFS and OS. Kaplan Meier analysis revealed a non-significant trend toward inferior PFS and OS associated with (N)ADCmean <1.7, and a significant decrement to PFS and OS associated with (N)ADCmin <0.3. (N)ADCmin was a significant prognostic factor when taking into account age, performance status, and extent of resection. ADC thresholding analysis revealed that a retained volume of >0.45 cc per mL FLAIR volume was associated with a trend toward inferior PFS and OS. In the post operative, pre-radiotherapy setting, the (N)ADCmin is the strongest predictor of outcomes in patients treated for GBM. ADC thresholding analysis indicates that a large volume of normalized ADC value <1.3 may be associated with adverse outcomes. PMID- 25700836 TI - Evolution of the Karnosky Performance Status throughout life in glioblastoma patients. AB - Functional independence in glioblastoma (GBM) patients is a key factor in measuring the quality of life. Progression free survival (PFS) and overall survival (OS) have been largely described. However, the evolution over time of the performance status during the patients' life remains understudied. We thus studied the time to loss of functional independence as assessed by a Karnosky Performance Status (KPS) below 70 % in GBM patients. We analysed all GBM patients treated in our institution between 2008 and 2013 and meeting the following criteria: age >18 years, supratentorial location, post-surgical KPS >= 70 %, initially treated with concomitant radiotherapy (RT) and Temozolomide. Within the 84 patients studied, the median PFS was 9 months and the median OS was 18.7 months. The median survival time with functional independence (KPS >= 70 %) was 14.5 months. On average, the patients spent 73 % of their lifespan with a KPS >= 70 %. Surgical resection and low steroid dosage were statistically associated with increased survival time with KPS >= 70 % (p = 0.015 and p = 0.03, respectively). Sixty-two (62) patients received one or several lines of chemotherapy at recurrence. Under treatment with Bevacizumab (42 Bev-based regimens), radiological responses were seen in 35 % and improvement in KPS occurred in 24 % whereas no response and rare improvement of KPS (3 %) were seen with other type of chemotherapy (97 non Bev-based regimens). In GBM patients, median survival with KPS >= 70 % largely exceeds PFS. Surgical resection and low steroids dosage at RT-onset appeared as good prognosis factors for survival with functional independence. PMID- 25700838 TI - Single-incision laparoscopic biliary bypass for malignant obstructive jaundice. AB - Biliary bypass is a major management of resolution to malignant obstructive jaundice. Laparoscopic approach is an ideal alternative to open surgery with the less recurrence compared with endoscopic stenting. Single incision surgery approach has not been applied to biliary bypass due to technical challenge. The aim of this study is to evaluate the safety and feasibility of single-incision laparoscopic biliary bypass. Eighteen patients with periampulla tumor underwent single-incision laparoscopic cholecystojejunostomy. The preoperation and postoperation data were retrospectively analyzed. All the cases underwent surgery successfully without conversion to open or traditional laparoscopic surgery. The operation time and blood loss were 172.8 min and 101.1 ml, respectively. The postoperative hospital stay was 9.9 days. The jaundice was released, and the liver function was improved after the surgery. The mean survival of the patients was 9.5 months. The single-incision laparoscopic cholecystojejunostomy is safe and feasible with acceptable short-term outcomes in selected patients. The benefits still need to be evaluated in comparative study. PMID- 25700839 TI - Molecular mechanisms underlying PINK1 and Parkin catalyzed ubiquitylation of substrates on damaged mitochondria. AB - PINK1 and Parkin are gene products that cause genetic recessive Parkinsonism. PINK1 is a protein kinase and Parkin is a ubiquitin ligase (E3) that links ubiquitin to a substrate. Importantly, under steady state conditions, the enzymatic activity of Parkin is completely suppressed, but is activated when mitochondria become abnormal. In 2013 and 2014, biochemical and structure function analyses revealed a number of critical mechanistic insights. First, Parkin is a self-inhibitory E3 that suppresses its E3 activity via intramolecular interactions. Second, in response to a decrease in mitochondrial membrane potential, PINK1 phosphorylates Ser65 in both the Parkin ubiquitin-like domain and ubiquitin itself. These phosphorylation events cooperate to relieve the Parkin autoinhibition. Third, activated Parkin forms a ubiquitin-thioester bond at Cys431 to produce a reaction intermediate that catalyzes ubiquitylation of substrates on damaged mitochondria. While the molecular mechanism regulating Parkin enzymatic activity has largely eluded clarification, a complete picture is now emerging. PMID- 25700837 TI - Opportunistic yeast pathogens: reservoirs, virulence mechanisms, and therapeutic strategies. AB - Life-threatening invasive fungal infections are becoming increasingly common, at least in part due to the prevalence of medical interventions resulting in immunosuppression. Opportunistic fungal pathogens of humans exploit hosts that are immunocompromised, whether by immunosuppression or genetic predisposition, with infections originating from either commensal or environmental sources. Fungal pathogens are armed with an arsenal of traits that promote pathogenesis, including the ability to survive host physiological conditions and to switch between different morphological states. Despite the profound impact of fungal pathogens on human health worldwide, diagnostic strategies remain crude and treatment options are limited, with resistance to antifungal drugs on the rise. This review will focus on the global burden of fungal infections, the reservoirs of these pathogens, the traits of opportunistic yeast that lead to pathogenesis, host genetic susceptibilities, and the challenges that must be overcome to combat antifungal drug resistance and improve clinical outcome. PMID- 25700841 TI - Emory global surgery program: learning to serve the underserved well. PMID- 25700840 TI - Distinct roles of multiple isoforms of CaMKII in signaling to the nucleus. AB - Long-lasting synaptic changes following information acquisition are critical steps for memory. In this process, long-term potentiation (LTP) is widely considered as one of the major cellular mechanisms modifying synaptic strength. It can be classified into early phase LTP (E-LTP) and late phase LTP (L-LTP) based on its duration. Using genetically modified mice, investigators have recognized the critical role of CaMKII in E-LTP and memory. However, its function in L-LTP, which is strongly dependent on gene transcription and protein synthesis, is still unclear. In this review, we discuss how different isoforms of CaMKII are coordinated to regulate gene expression in an activity-dependent manner, and thus contribute to L-LTP and memory. This article is part of a Special Issue entitled: 13th European Symposium on Calcium. PMID- 25700842 TI - New onset stress urinary incontinence following laparoscopic sacrocolpopexy and its relation to anatomical outcomes. AB - INTRODUCTION AND HYPOTHESIS: The aim of this study was to assess the incidence of stress urinary incontinence (SUI) following laparoscopic sacrocolpopexy in continent women and its relation to postoperative prolapse stage. METHODS: A total of 220 continent women with symptomatic apical prolapse who underwent laparoscopic sacrocolpopexy were prospectively evaluated; 100 women had previous hysterectomy. Patients were followed up at 3 and 12 months after surgery. All subjects completed the King's Health Questionnaire (KHQ) and Prolapse Quality of Life Questionnaire (P-QOL) and were examined using the Pelvic Organ Prolapse Quantification (POP-Q) system. The primary outcome measure was the number of women who developed new onset moderate/severe SUI at 3 and 12 months postoperatively and its relation to postoperative prolapse stage. RESULTS: At 3 months, 52 women (23.6 %) developed moderate/severe SUI; 27 (12.2 %) had severe SUI. Eleven women (5.0 %) underwent surgery for SUI within 6 months of sacrocolpopexy. All surgery for SUI was in women who had post-hysterectomy sacrocolpopexy. Postoperatively, the vaginal apex (point C) was at stage 0/I in 195 cases (88.6 %). There were no differences in postoperative POP-Q stage of the anterior and apical vaginal walls between continent women and those with SUI (p = 0.45). The posterior vaginal wall was higher in women who developed de novo SUI (p = 0.03). CONCLUSIONS: The incidence of SUI following apical prolapse repair is 23.6 %. Subsequent continence procedures were performed in 5.0 % of patients. All were in women who had previous hysterectomy making the risk in this group 11 %. Higher POP-Q stage of the posterior vaginal wall was associated with SUI. PMID- 25700843 TI - Influence of smoking on perioperative oxidative stress after pulmonary resection. AB - PURPOSE: We herein investigated the influence of smoking on changes in the levels of perioperative oxidative stress after pulmonary resection. METHODS: A total of 31 patients with primary lung cancer who underwent curative pulmonary lobectomy were analyzed prospectively. The degree of perioperative oxidative stress was evaluated based on the serum levels of derivatives of reactive oxygen metabolites (d-ROM) and biological antioxidant potential (BAP). The patients were divided into two groups: group A (smoking < 40 pack-years) and group B (smoking >= 40 pack-years). The d-ROM and BAP measurements were obtained preoperatively, postoperatively and on the first, second, third and fifth postoperative days. RESULTS: In all 31 cases, the d-ROM values were higher on the third and fifth postoperative days than preoperatively. The extent of change in the d-ROM levels was greater in group A than in group B on the second, third and fifth postoperative days (1.05 +/- 0.159 vs. 0.920 +/- 0.205, p = 0.008; 1.20 +/- 0.233 vs. 1.02 +/- 0.186, p = 0.032; 1.34 +/- 0.228 vs. 1.07 +/- 0.200, p = 0.003, respectively). In contrast, there were no significant differences in the BAP values. The maximum increase in the d-ROM level and decrease in the BAP level negatively correlated with the amount of smoking (|r| = 0.428, p = 0.016 and |r| = 0.357. p = 0.049, respectively). CONCLUSIONS: Surgical stress associated with pulmonary lobectomy induces oxidative stress. In addition, smoking reduces the oxidative stress reaction, and the degree of this change is correlated with the amount of smoking. PMID- 25700844 TI - Potential mechanisms mediating improved glycemic control after bariatric/metabolic surgery. AB - Conservative medical treatment for morbid obesity generally fails to sustain weight loss. On the other hand, surgical operations, so-called bariatric surgery, have evolved due to their long-term effects. The global increase in the overweight population and the introduction of laparoscopic surgery have resulted in the use of bariatric surgery spreading quickly worldwide in recent years. Recent clinical evidence suggests that bariatric surgery not only reduces body weight, but also improves secondary serious diseases, including type 2 diabetes mellitus, in so-called metabolic surgery. Moreover, several potential mechanisms mediating the improvement in glycemic control after bariatric/metabolic surgery have been proposed based on the animal and human studies. These mechanisms include changes in the levels of gastrointestinal hormones, bacterial flora, bile acids, intestinal gluconeogenesis and gastrointestinal motility as well as adipose tissue and inflammatory mediators after surgery. The mechanisms underlying improved glycemic control are expected to accelerate the promotion of both metabolic and bariatric surgery. This article describes the current status of bariatric surgery worldwide and in Japan, reviews the accumulated data for weight loss and diabetic improvements after surgery and discusses the potential mechanisms mediating improved glycemic control. PMID- 25700845 TI - beta-Hydroxy-beta-methylbutyrate (HMB) supplementation and resistance exercise significantly reduce abdominal adiposity in healthy elderly men. AB - The effects of 12-weeks of HMB ingestion and resistance training (RT) on abdominal adiposity were examined in 48 men (66-78 yrs). All participants were randomly assigned to 1 of 4 groups: no-training placebo (NT-PL), HMB only (NT HMB), RT with PL (RT-PL), or HMB with RT (RT-HMB). DXA was used to estimate abdominal fat mass (AFM) by placing the region of interest over the L1-L4 region of the spine. Outcomes were assessed by ANCOVA, with Bonferroni-corrected pairwise comparisons. Baseline AFM values were used as the covariate. The ANCOVA indicated a significant difference (p = 0.013) between group means for the adjusted posttest AFM values (mean (kg) +/- SE: NT-PL = 2.59 +/- 0.06; NT-HMB = 2.59 +/- 0.61; RT-PL = 2.59 +/- 0.62; RT-HMB = 2.34 +/- 0.61). The pairwise comparisons indicated that AFM following the intervention period in the RT-HMB group was significantly less than NT-PL (p = 0.013), NT-HMB (p = 0.011), and RT PL (p = 0.010). These data suggested that HMB in combination with 12 weeks of RT decreased AFM in elderly men. PMID- 25700846 TI - Effects of two deep water training programs on cardiorespiratory and muscular strength responses in older adults. AB - This study aimed to investigate the effects of two deep water training programs on cardiorespiratory and muscular strength responses in older adults. Thirty-four older adults men were placed into two groups: deep water endurance training (ET; n = 16; 66 +/- 4 years) and deep water strength prior to endurance training (concurrent training: CT; n = 18; 64 +/- 4 years). The training period lasted 12 weeks, with three sessions a week. The resting heart rate and the oxygen uptake at peak (VO2peak) and at the second ventilatory threshold (VO2VT2) were evaluated during a maximal incremental test on a cycle ergometer before and after training. In addition, maximal dynamic strength (one repetition maximum test--1RM) and local muscular resistance (maximum repetitions at 60% 1RM) of the knee extensors and flexors were evaluated. After the training period, the heart rate at rest decreased significantly, while the VO2peak and VO2VT2 showed significant increases in both groups (p<0.05). Only the VO2VT2 resulted in significantly greater values for the ET compared to the CT group after the training (p<0.05). In addition, after training, there was a significant increase in the maximal dynamic strength of the knee extensors and the local muscular endurance of the knee extensors and flexors, with no difference between the groups (p > 0.05). In summary, the two training programs were effective at producing significant improvements in cardiorespiratory and muscular strength responses in older adult men. However, deep water endurance training at high intensities provides increased cardiorespiratory responses compared to CT and results in similar muscular strength responses. PMID- 25700847 TI - Leydig cell aging and hypogonadism. AB - Leydig cell testosterone (T) production is reduced with age, resulting in reduced serum T levels (hypogonadism). A number of cellular changes have been identified in the steroidogenic pathway of aged Leydig cells that are associated with reduced T formation, including reductions in luteinizing hormone (LH)-stimulated cAMP production, the cholesterol transport proteins steroidogenic acute regulatory (STAR) protein and translocator protein (TSPO), and downstream steroidogenic enzymes of the mitochondria and smooth endoplasmic reticulum. Many of the changes in steroid formation that characterize aged Leydig cells can be elicited by the experimental alteration of the redox environment of young cells, suggesting that changes in the intracellular redox balance may cause reduced T production. Hypogonadism is estimated to affect about 5 million American men, including both aged and young. This condition has been linked to mood changes, worsening cognition, fatigue, depression, decreased lean body mass, reduced bone mineral density, increased visceral fat, metabolic syndrome, decreased libido, and sexual dysfunction. Exogenous T administration is now used widely to elevate serum T levels in hypogonadal men and thus to treat symptoms of hypogonadism. However, recent evidence suggests that men who take exogenous T may face increased risk of stroke, heart attack, and prostate tumorigenesis. Moreover, it is well established that administered T can have suppressive effects on LH, resulting in lower Leydig cell T production, reduced intratesticular T concentration, and reduced spermatogenesis. This makes exogenous T administration inappropriate for men who wish to father children. There are promising new approaches to increase serum T by directly stimulating Leydig cell T production rather than by exogenous T therapy, thus potentially avoiding some of its negative consequences. PMID- 25700848 TI - Predictors and Moderators of Clinical Outcomes in Adolescents with Severe Mental Disorders After an Assertive Community Treatment. AB - Previous studies have shown that stressful life events (SLEs), gender, social functioning and pretreatment severity are some of the predictors and/or moderators of treatment outcome in psychiatric care. The current study explored the effect of these predictors and moderators on the treatment outcome related to assertive community treatment (ACT) proposed to young people with severe mental disorders. 98 patients were assessed for externalizing and emotional difficulties, at admission and then at discharge of an ACT. Analyses revealed significant improvements in terms of symptomatology. In particular, regression analyses showed that pretreatment severity is a significant predictor of the outcome on emotional symptoms and is moderated by SLE on the outcome on externalizing symptoms. Furthermore, higher social functioning proved to predict better outcome on externalizing symptoms. Our results further evidence that these factors can explain inter-individual differences in outcome related to ACT. The theoretical and clinical implications of these results are discussed. PMID- 25700849 TI - Massachusetts health reform and disparities in joint replacement use: difference in differences study. AB - OBJECTIVE: To estimate the impact of the insurance expansion in 2006 on use of knee and hip replacement procedures by race/ethnicity, area income, and the use of hospitals that predominantly serve poor people ("safety net hospitals"). DESIGN: Quasi-experimental difference in differences study examining change after reform in the share of procedures performed in safety net hospitals by race/ethnicity and area income, with adjustment for patients' residence, demographics, and comorbidity. SETTING: State of Massachusetts, United States. PARTICIPANTS: Massachusetts residents aged 40-64 as the target beneficiaries of reform and similarly aged residents of New Jersey, New York, and Pennsylvania as the comparison (control) population. MAIN OUTCOMES MEASURES: Number of knee and hip replacement procedures per 10 000 population and use of safety net hospitals. Procedure counts from state discharge data for 2.5 years before and after reform, and multivariate difference in differences. Poisson regression was used to adjust for demographics, economic conditions, secular time, and geographic factors to estimate the change in procedure rate associated with health reform by race/ethnicity and area income. RESULTS: Before reform, the number of procedures (/10 000) in Massachusetts was lower among Hispanic people (12.9, P<0.001) than black people (28.1) and white people (30.1). Overall, procedure use increased 22.4% during the 2.5 years after insurance expansion; reform in Massachusetts was associated with a 4.7% increase. The increase associated with reform was significantly higher among Hispanic people (37.9%, P<0.001) and black people (11.4%, P<0.05) than among white people (2.8%). Lower income was not associated with larger increases in procedure use. The share of knee and hip replacement procedures performed in safety net hospitals in Massachusetts decreased by 1.0% from a level of 12.7% before reform. The reduction was larger among Hispanic people (-6.4%, P<0.001) than white people (-1.0%), and among low income residents (-3.9%, p<0.001) than high income residents (0%). CONCLUSIONS: Insurance expansion can help reduce disparities by race/ethnicity but not by income in access to elective surgical care and could shift some elective surgical care away from safety net hospitals. PMID- 25700850 TI - Putting humanity back into the teaching of human biology. AB - In this paper, I draw upon debates about race in biology and philosophy as well as the concepts of ineliminable pluralism and psychological essentialism to outline the necessary subject matter knowledge that teachers should possess if they desire to: (i) increase student understanding of scientific research on genetic and behavioral variation in humans; and (ii) attenuate inegalitarian beliefs about race amongst students. PMID- 25700851 TI - Bile duct injuries following laparoscopic cholecystectomy. AB - INTRODUCTION: Bile duct injuries occur rarely but are among the most dreadful complications following cholecystectomies. METHODS: Prospective registration of bile duct injuries occurring in the period 1992-2013 at a tertiary referral hospital. RESULTS: In total, 67 patients (47 women and 20 men) with a median age of 55 (range 14-86) years had a leak or a lesion of the bile ducts during the study period. Total incidence of postoperative bile leaks or bile duct injuries was 0.9% and for bile duct injuries separately, 0.4%. Median delay from injury to repair was 5 days (range 0-68 days). In 12 patients (18%), the injury was discovered intraoperatively. Bile leak was the major symptom in 59%, and 52% had a leak from the cystic duct or from assumed aberrant ducts in the liver bed of the gall bladder. Following the Clavien-Dindo classification, 39% and 45% were classified as IIIa and IIIb, respectively, 10% as IV, and 6% as V. In all, 31 patients had injuries to the common bile duct or hepatic ducts, and in these patients, 71% were treated with a hepaticojejunostomy. Of patients treated with a hepaticojejunostomy, 56% had an uncomplicated event, whereas 14% later on developed a stricture. Out of 36 patients with injuries to the cystic duct/aberrant ducts, 30 could be treated with stents or sphincterotomies and percutaneous drainage. CONCLUSION: Half of injuries following cholecystectomies are related to the cystic duct, and most of these can be treated with endoscopic or percutaneous procedures. A considerable number of patients following hepaticojejunostomy will later on develop a stricture. PMID- 25700852 TI - Canadian professor who taught antivaccine content is put on leave. PMID- 25700853 TI - Increase general practice funding or risk "death of the family doctor," GP leader warns. PMID- 25700854 TI - [Thyroid dysfunction in pregnancy. Consensus document. Andalusian Society of Endocrinology and Nutrition (SAEN)]. AB - A position statement on the diagnosis and treatment of thyroid dysfunction in pregnancy has been agreed on behalf of The Sociedad Andaluza de Endocrinologia y Nutricion (SAEN), based on a review of the literature to date and all good clinical practice guidelines. The document is set out in different sections as regards the diagnosis and treatment of, overt and subclinical hypo- and hyperthyroidism, isolated hypothyroxinaemia and postpartum thyroiditis. It also justifies the implementation of universal screening for thyroid dysfunction in pregnancy, and provides practitioners who care for these patients with tool for rational decision making. PMID- 25700855 TI - Steroidal contraceptives: effect on bone fractures in women. PMID- 25700856 TI - Internet-delivered applied relaxation for vasomotor symptoms in postmenopausal women: lessons from a failed trial. AB - Internet-delivered therapies have a short history and promising results have been shown for several health problems, particularly for psychiatric conditions. This study was a first attempt to evaluate whether Internet-delivered applied relaxation for hot flushes in postmenopausal women may be useful. Due to a high drop-out rate the study was prematurely terminated after inclusion of approximately two thirds of calculated women. The Internet-delivered applied relaxation must probably be modified for such populations and settings before it can be used further. This article will discuss the benefits and pitfalls to learn in order to meet the challenges of future studies. Clinical trial registration number: NCT01245907. PMID- 25700857 TI - The economic burden of inpatients with type 2 diabetes: a case study in a Chinese hospital. AB - The purpose of this research was to study the components, influencing factors, and their changing trend in a Chinese hospital, so as to reduce the economic burden of inpatients with type 2 diabetes. Data were collected from 7487 cases. There were 4368 inpatients with type 2 diabetes during 2002-2012 in a Chinese hospital. Multivariate linear regression analysis was performed to explore the influencing factors of hospitalization costs. The number of inpatients and their hospitalization costs had increasing trends in the study period. The medicine, test, and examination charges were the main sources of total costs. Longer hospital stays, older ages, and more times of hospitalization led to higher medical costs. Actions should be taken on all fronts to control the rapidly increasing trend of hospitalization costs and to reduce hospital stays and the number of times of hospitalization to reduce the economic burden of diabetic inpatients. PMID- 25700858 TI - [Indication for urodynamic testing]. AB - BACKGROUND: The aim of urodynamic testing is to obtain objective information regarding urinary bladder storage and voiding function. Basic investigations provide information of the underlying incontinence form. Depending on the individual situation and findings, further urodynamic investigations are helpful or indicated. Prior to conservative therapy, a routine urodynamic investigation is not indicated. OBJECTIVES: Due to limited evidence of preoperative urodynamic investigations on postoperative results, the urodynamic results may be helpful when considering various treatment options. RESULTS: Urodynamic investigations should be performed preoperatively, especially in case of overactive bladder symptoms, prior incontinence surgery, or disordered bladder emptying. The assessment of urethral function should be considered in the urodynamic investigation of stress urinary incontinence. In patients with pelvic prolapse, urodynamic investigations should be performed during prolapse reposition. PMID- 25700859 TI - [Treatment of female stress urinary incontinence. Value of classical incontinence operations]. AB - BACKGROUND: Fascial sling and the colposuspension were considered standard operations in the therapy of female stress urinary incontinence until the mid 1990s. New surgical procedures were compared with these techniques in regard to cure rate and long-term results. RESULTS: Nowadays fascial slings are rarely performed. Colposuspension - despite comparable results - was replaced by tension free tapes as the new gold standard. This is not due to lower efficacy, but predominantly due to reduced surgical trauma, simple use, and rapid convalescence. However, in cases of recurrence and the combined treatment of prolapse, colposuspension is still used. PMID- 25700860 TI - [General and method-specific complications of sacrocolpopexy]. AB - Sacrocolpopexy has remained standard procedure for correction of pelvic organ prolapse regardless of the affected compartment. Assuming the appropriate indication, it is characterized by an excellent long-term cure rate. Asymptomatic pelvic organ prolapse is no indication for surgery and should not be corrected in view of possible complications. This article summarizes general and method specific complications of sacrocolpopexy, identifies causes, and allows error management to be tailored to each individual patient to increase treatment and outcome quality. PMID- 25700861 TI - [Tissue engineering in reconstructive urology]. AB - The term tissue engineering incorporates various techniques for the production of replacement tissues and organs. In urology tissue engineering offers many promising possibilities for the reconstruction of the urinary tract. Currently, buccal mucosa and urothelial cells are most commonly used for tissue engineering of the urinary tract. Various materials have been tested for their suitability as tissue scaffolds. The ideal scaffold, however, has not yet been found. In addition to material sciences and cell culture methods, surgical techniques play an important role in reconstructive urology for the successful implantation of tissue engineered transplants. PMID- 25700862 TI - [Intravesical gemcitabine for non-muscle invasive bladder cancer]. PMID- 25700863 TI - Nine surface plasmon resonance assays for specific protein quantitation during cell culture and process development. AB - Quantitation of protein is essential during pharmaceutical development, and a variety of methods and technologies for determination of total and specific protein concentration are available. Here we describe the development of a streamlined assay platform for specific quantitation assays using surface plasmon resonance (SPR) technology. A total of nine different assays were developed using similar conditions, of which eight assays were for quantitation of different human blood plasma proteins (IgG, IgG1-4 subclasses, IgA, transferrin, and albumin) from a chromatography-based IgG plasma process. Lastly, an assay for monitoring the concentration of a recombinant monoclonal antibody during 13 days of CHO cell culturing was developed. Assay performances were compared with enzyme linked immunosorbent assay (ELISA), nephelometry, ARCHITECT, and Cobas c501. SPR assays were shown to have higher sensitivity than analysis using nephelometry, ARCHITECT, and Cobas and to have significantly lower analysis and hands-on time compared with ELISA. Furthermore, the SPR assays were robust enough to be used for up to 12 days, allowing specific protein concentration measurement of a sample to be completed at line within 10 min. Using the same platform with only few varied parameters between different assays has saved time in the lab as well as for evaluation and presentation of results. PMID- 25700864 TI - Dissociation and reduction of covalent beta-lactoglobulin-quinone adducts by dithiothreitol, tris(2-carboxyethyl)phosphine, or sodium sulfite. AB - Covalent protein-phenol adducts, generated by reaction of protein nucleophiles with quinones, have recently attracted increased attention because the interactions change the functionality and physicochemical properties of proteins in biological and food systems. The formation of such covalent adducts between beta-lactoglobulin (beta-LG) and the quinone of 4-methylcatechol, 4 methylbenzoquinone (4MBQ), and subsequent reduction by dithiothreitol (DTT), tris(2-carboxyethyl)phosphine (TCEP), or sodium sulfite was investigated by mass spectrometry. The results showed that 19.0 +/- 8.8% of beta-LG reacted with 4MBQ when present in equimolar ratio at 20 degrees C (pH 8.0) to yield the protein phenol adduct (beta-LG-Q). Following treatment with sulfite, DTT, or TCEP, 75, 68, or 36%, respectively, of the formed beta-LG-Q adduct dissociated. Different reaction mechanisms were proposed for the reduction of beta-LG and beta-LG-Q by each of the reducing agents. These results show that on reductive sample preparation for analysis of protein samples, not only are protein polymers formed through oxidative disulfide bonds reduced into the individual protein constituents but also a large part of any protein-phenol adducts present will dissociate and, thus, give a false picture of the level of protein-protein interactions that have occurred in the sample. PMID- 25700865 TI - Electrochemical assay for the determination of nitric oxide metabolites using copper(II) chlorophyllin modified screen printed electrodes. AB - This work presents a novel electrochemical assay for the collective measurement of nitric oxide (NO) and its metabolites nitrite (NO2(-)) and nitrate (NO3(-)) in volume miniaturized sample at low cost using copper(II) chlorophyllin (CuCP) modified sensor electrode. Zinc oxide (ZnO) incorporated screen printed carbon electrode (SPCE) was used as a host matrix for the immobilization of CuCP. The morphological changes of the ZnO and CuCP modified electrodes were investigated using scanning electron microscopy. The electrochemical characterization of CuCP ZnO-SPCE exhibited the characteristic quasi-reversible redox peaks at the potential +0.06 V versus Ag/AgCl. This biosensor electrode showed a wide linear range of response over NO concentrations from 200 nM to 500 MUM with a detection limit of 100 nM and sensitivity of 85.4 nA MUM(-1). Furthermore, NO2(-) measurement showed linearity of 100 nM to 1mM with a detection limit of 100 nM for NO2(-) and sensitivity of 96.4 nA MUM(-1). Then, the concentration of NO3(-) was measured after its enzymatic conversion into NO2(-). Using this assay, the concentrations of NO, NO2(-), and NO3(-) present in human plasma samples before and after beetroot supplement were estimated using suitable membrane coated CuCP ZnO-SPCE and validated with the standard Griess method. PMID- 25700866 TI - Immobilized trypsin on hydrophobic cellulose decorated nanoparticles shows good stability and reusability for protein digestion. AB - The preparation of biocatalysts based on immobilized trypsin is of great importance for both proteomic research and industrial applications. Here, we have developed a facile method to immobilize trypsin on hydrophobic cellulose-coated silica nanoparticles by surface adsorption. The immobilization conditions for the trypsin enzyme were optimized. The as-prepared biocatalyst was characterized by Fourier transform infrared spectroscopy, transmission electron microscopy, and elemental analysis. In comparison with free enzyme, the immobilized trypsin exhibited greater resistances against thermal inactivation and denaturants. In addition, the immobilized trypsin showed good durability for multiple recycling. The general applicability of the immobilized trypsin for proteomic studies was confirmed by enzymatic digestion of two widely used protein substrates: bovine serum albumin (BSA) and cytochrome c. The surface adsorption protocols for trypsin immobilization may provide a promising strategy for enzyme immobilization in general, with great potential for a range of applications in proteomic studies. PMID- 25700867 TI - Distribution of emm types among group A Streptococcus isolates from children in Korea. AB - We analyzed 155 clinical group A Streptococcus (GAS) isolates from children at the Seoul National University Children's Hospital between 1991 and 2012 and the Seoul National University Bundang Hospital between 2006 and 2012. The erythromycin resistance rate was 10.3% (16/155), and all isolates during the recent 3 years were susceptible to erythromycin. Among isolates, emm1 (19.4%), emm12 (18.7%), and emm4 (18.1%) were the most prevalent emm types. According to clinical disease, emm1 was most common in invasive GAS infections (47.4%), and emm4, in scarlet fever (48.8%). From 2010 to 2012, an increase in invasive GAS infections and scarlet fever that correlated with an increase in emm1 and emm4 types was observed. The speC detection rate was higher in patients with scarlet fever than in those with other GAS infections (P=0.017). Recently, invasive GAS infections and scarlet fever were associated with an increase in emm1 and emm4, respectively. PMID- 25700868 TI - Night-to-Night Variability in Sleep Disordered Breathing and the Utility of Esophageal Pressure Monitoring in Suspected Obstructive Sleep Apnea. AB - STUDY OBJECTIVE: Esophageal manometry (Pes) is the gold standard to detect repetitive episodes of increased respiratory effort followed by arousal (RERAs). Because RERAs are not included in the apnea-hypopnea index (AHI), we often refer patients with symptoms of sleep disordered breathing (SDB) and AHI < 5 for a second polysomnogram (PSG) with Pes. Often, the second PSG will demonstrate AHI > 5, confirming a diagnosis of OSA. We speculate that in most cases of suspected SDB, Pes does not add further diagnostic data and that night-to-night variability in OSA severity results in a first false-negative study. METHODS: We conducted a retrospective review of PSGs between 2008 and 2012 in adults with initial PSG negative for OSA followed by a second study (with or without Pes) within 6 mo. RESULTS: Of 125 studies that met inclusion criteria, a second study was completed with Pes in 105 subjects. SDB was diagnosed in 73 subjects (68.5%) completing a second PSG with Pes: 49 (46.7%) received a diagnosis based on AHI, and 24 (22.8%) received a diagnosis based on Pes (p = 0.003). There were no statistically significant differences in the mean AHI change between the two PSGs in subjects who completed the second study with or without Pes. CONCLUSIONS: In patients with symptoms of SDB and initial PSG with AHI < 5, the majority met criteria for OSA on second PSG by AHI without additional information added by Pes. Because Pes is not widely available and is somewhat invasive, a repeat study without Pes may be sufficient to diagnose SDB. PMID- 25700869 TI - Sleep disorders in patients with multiple sclerosis. AB - OBJECTIVE: Poor sleep is a frequent symptom in patients with multiple sclerosis (MS). The objective of the study was to assess the relationship between nocturnal polysomnographic (PSG) findings and quality of sleep, fatigue, and increased daytime sleepiness among patients with MS. METHODS: Clinical characteristics were collected. Pittsburgh Sleep Quality Index (PSQI), Fatigue Severity Scale (FSS), Epworth Sleepiness Scale (ESS), and International Restless Legs Syndrome Rating Scale were used to assess quality of sleep, fatigue, excessive daytime sleepiness, and the presence of restless legs syndrome (RLS). All patients underwent nocturnal diagnostic PSG examination. RESULTS: Fifty patients with MS were enrolled into the study. Age was the only independent variable significantly determining apnea-hypopnea index and desaturation index (DI) (beta = 0.369, p = 0.010, beta 0.301, p = 0.040). PSQI and ESS score were significantly higher in a population with RLS (p = 0.004, p = 0.011). FSS significantly correlated with DI (r = 0.400, p = 0.048). Presence of RLS was the only independent variable significantly determining PSQI and ESS (p = 0.005, p = 0.025). DI and presence of RLS were independent variables determining FSS (p = 0.015, p = 0.024). CONCLUSION: Presence of RLS seems to be the main factor determining poor sleep, fatigue, and daytime somnolence. Sleep disordered breathing and its severity influences only fatigue in patients with MS. PMID- 25700870 TI - Meta-analyses of the Association of Sleep Apnea with Insulin Resistance, and the Effects of CPAP on HOMA-IR, Adiponectin, and Visceral Adipose Fat. AB - OBJECTIVE: We sought to conduct an updated meta-analysis of randomized controlled trials (RCTs) on the effect of continuous positive airway pressure (CPAP) on insulin resistance, as measured by homeostasis model assessment of insulin resistance (HOMA-IR), visceral abdominal fat (VAF), and adiponectin. Additionally, we performed a separate meta-analysis and meta-regression of studies on the association of insulin resistance and obstructive sleep apnea (OSA). METHODS: All included studies were searched from PubMed (from conception to March 15, 2014). Data were pooled across all included RCTs as the mean difference in HOMA-IR and VAF, and as the standardized mean difference in the case of adiponectin analysis. From the included case-control studies, data on the difference of HOMA-IR between cases and controls were pooled across all studies, as the standardized mean difference (SMD). RESULTS: There was a significant difference in HOMA-IR (-0.43 [95% CIs: -0.75 to -0.11], p = 0.008) between CPAP treated and non CPAP treated participants. However, there was no significant difference in VAF or adiponectin; (-47.93 [95% CI: -112.58 to 16.72], p = 0.14) and (-0.06 [95% CI: -0.28 to 0.15], p = 0.56), respectively. Meta-analysis of 16 case-control studies showed a pooled SMD in HOMA-IR of 0.51 (95% CI: 0.28 to 0.75), p <= 0.001, between cases and controls. CONCLUSIONS: The results of our meta-analyses show that CPAP has a favorable effect on insulin resistance. This effect is not associated with any significant changes in total adiponectin levels or amount of VAF. Our findings also confirm a significant association between OSA and insulin resistance. PMID- 25700871 TI - A Cost-Effectiveness Analysis of Surgery for Middle-Aged Men with Severe Obstructive Sleep Apnea Intolerant of CPAP. AB - STUDY OBJECTIVES: Obstructive sleep apnea (OSA) is associated with increased cardiovascular morbidity and mortality. Conventional OSA therapy necessitates indefinite continuous positive airway pressure (CPAP). Although CPAP is an effective treatment modality, up to 50% of OSA patients are intolerant of CPAP. We explore whether surgical modalities developed for those intolerant of CPAP are cost-effective. METHODS: We construct a lifetime semi-Markov model of OSA that accounts for observed increased risks of stroke, cardiovascular disease, and motor vehicle collisions for a 50-year-old male with untreated severe OSA. Using this model, we compare the cost-effectiveness of (1) no treatment, (2) CPAP only, and (3) CPAP followed by surgery (either palatopharyngeal reconstructive surgery [PPRS] or multilevel surgery [MLS]) for those intolerant to CPAP. RESULTS: Compared with the CPAP only strategy, CPAP followed by PPRS (CPAP-PPRS) adds 0.265 quality adjusted life years (QALYs) for an increase of $2,767 (discounted 2010 dollars) and is highly cost effective with an incremental cost-effectiveness ratio (ICER) of $10,421/QALY for a 50-year-old male with severe OSA. Compared to a CPAP-PPRS strategy, the CPAP-MLS strategy adds 0.07 QALYs at an increase of $6,213 for an ICER of $84,199/QALY. The CPAP-PPRS strategy appears cost-effective over a wide range of parameter estimates. CONCLUSIONS: Palatopharyngeal reconstructive surgery appears cost-effective in middle-aged men with severe OSA intolerant of CPAP. Further research is warranted to better define surgical candidacy as well as short-term and long-term surgical outcomes. COMMENTARY: A commentary on this article appears in this issue on page 509. PMID- 25700873 TI - Protective Effect of Long-Term CPAP Therapy on Cognitive Performance in Elderly Patients with Severe OSA: The PROOF Study. AB - OBJECTIVE: Obstructive sleep apnea syndrome (OSA) leads to a deterioration in cognitive functions, with regard to memory and executive functions. However, few studies have investigated the impact of treatment on these cognitive functions in elderly subjects. METHODS: The study was conducted in a large cohort of subjects aged 65 years or older (the PROOF cohort). Subjects were not diagnosed or treated for OSA. Subjects underwent a polygraphic recording. Cognitive performance was assessed in all OSA subjects at baseline and 10 years later, whether or not they were receiving continuous positive airway pressure (CPAP) therapy. RESULTS: A group of 126 patients were analyzed. Only 26% of them were treated, with therapy initiated at the discretion of the primary care physician. Among treated subjects, self-reported compliance with therapy was good (> 6 h/night on average), and 66% of them reported an improvement in their quality of life. Patients receiving CPAP treatment had a higher apneahypopnea index (p = 0.006), a higher oxygen desaturation index (p < 0.001), and experienced more pronounced daytime repercussions (p = 0.004). These patients showed a statistically significant improvement in mental agility (similarities test; p < 0.0001) and memory performance (Grober and Buschke delayed free recall; p = 0.02). CONCLUSION: CPAP treatment is associated with the maintenance of memory performance over time. PMID- 25700874 TI - Stability versus Transitional Changes in the EEG: From Sleep to Wakefulness. PMID- 25700872 TI - Sleep disorders in chronic obstructive pulmonary disease: etiology, impact, and management. AB - ABSTRACT: Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality and may frequently be complicated by sleep disorders. Insomnia and obstructive sleep apnea are commonly encountered in patients with COPD. Nocturnal hypoxemia is also prevalent in COPD may occur despite adequate awake oxygenation and can be especially severe in rapid eye movement sleep. Additionally, several factors--some of them unique to COPD--can contribute to sleep-related hypoventilation. Recognition of hypoventilation can be vital as supplemental oxygen therapy itself can acutely worsen hypoventilation and lead to disastrous consequences. Finally, accruing data establish an association between restless leg syndrome and COPD--an association that may be driven by hypoxemia and/or hypercapnia. Comorbid sleep disorders portend worse sleep quality, diminished quality of life, and multifarious other adverse consequences. The awareness and knowledge regarding sleep comorbidities in COPD has continued to evolve over past many years. There are still several lacunae, however, in our understanding of the etiologies, impact, and therapies of sleep disorders, specifically in patients with COPD. This review summarizes the latest concepts in prevalence, pathogenesis, diagnosis, and management of diverse sleep disorders in COPD. PMID- 25700875 TI - Sleep Disturbances in Essential Tremor and Parkinson Disease: A Polysomnographic Study. AB - OBJECTIVE: Sleep problems are a common non-motor complication of Parkinson disease (PD), and patients with essential tremor (ET) share a number of motor and non-motor features of PD. To clarify the relationship between these disorders, we evaluated the sleep problems in patients with ET and PD using assessment scales and objective polysomnographic (PSG) testing. METHOD: Twenty-one consecutive patients with PD, 16 with ET, and 14 healthy subjects participated in this study and were compared in terms of sleep related complaints, final sleep related diagnosis, and polysomnographic features. RESULTS: The results of our study have shown that patients with PD were more likely than were those with ET to have a history of REM sleep behavior disorders (RBD) (p = 0.001) and excessive daytime sleepiness (p <= 0.05). Additionally, PSG data revealed that ET patients had lower mean SpO2 values (p <= 0.05) and REM without atonia (RWA) (p = 0.032) than did patients with PD. CONCLUSION: This is the first study to use PSG to evaluate sleep problems both in ET and PD patients. The results point out different sleep problems in these two common movement disorders which should be investigated in further studies. PMID- 25700876 TI - Weighing in on a heavy subject. PMID- 25700877 TI - Letter to the Editor: Obstructive Sleep Apnea and Mandibular Advancement Splints. PMID- 25700878 TI - Quality measures for the care of adult patients with obstructive sleep apnea. AB - ABSTRACT: Obstructive sleep apnea (OSA) is a prevalent disorder associated with a multitude of adverse outcomes when left untreated. There is significant heterogeneity in the evaluation and management of OSA resulting in variation in cost and outcomes. Thus, the goal for developing these measures was to have a way to evaluate the outcomes and reliability of the processes involved with the standard care approaches used in the diagnosis and management of OSA. The OSA quality care measures presented here focus on both outcomes and processes. The AASM commissioned the Adult OSA Quality Measures Workgroup to develop quality care measures aimed at optimizing care for adult patients with OSA. These quality care measures developed by the Adult OSA Quality Measures Workgroup are an extension of the original Centers for Medicare & Medicaid Services (CMS) approved Physician Quality Reporting System (PQRS) measures group for OSA. The measures are based on the available scientific evidence, focus on public safety, and strive to improve quality of life and cardiovascular outcomes for individual OSA patients. The three outcomes that were selected were as follows: (1) improve disease detection and categorization; (2) improve quality of life; and (3) reduce cardiovascular risk. After selecting these relevant outcomes, a total of ten process measures were chosen that could be applied and assessed for the purpose of accomplishing these outcomes. In the future, the measures described in this document may be reported through the PQRS in addition to, or as a replacement for, the current OSA measures group. The overall objective for the development of these measures is that implementation of these quality measures will result in improved patient outcomes, reduce the public health burden of OSA, and provide a measurable standard for evaluating and managing OSA. PMID- 25700879 TI - Quality measures for the care of pediatric patients with obstructive sleep apnea. AB - ABSTRACT: The Board of Directors of the American Academy of Sleep Medicine (AASM) commissioned a Task Force to develop quality measures as part of its strategic plan to promote high quality patient-centered care. Among many potential dimensions of quality, the AASM requested Workgroups to develop outcome and process measures to aid in evaluating the quality of care of five common sleep disorders: insomnia, obstructive sleep apnea in adults, obstructive sleep apnea in children, restless legs syndrome, and narcolepsy. This paper describes the rationale, background, general methods development, and considerations in implementation of these quality measures in obstructive sleep apnea (OSA) in children. This document describes measurement methods for five desirable process measures: assessment of symptoms and risk factors of OSA, initiation of an evidence-based action plan, objective evaluation of high-risk children with OSA by obtaining a polysomnogram (PSG), reassessment of signs and symptoms of OSA within 12 months, and documentation of objective assessment of positive airway pressure adherence. When these five process measures are met, clinicians should be able to achieve the two defined outcomes: improve detection of childhood OSA and reduce signs and symptoms of OSA after initiation of a management plan. The AASM recommends the use of these measures as part of quality improvement programs that will enhance the ability to improve care for patients with childhood OSA. PMID- 25700880 TI - Quality measures for the care of patients with narcolepsy. AB - ABSTRACT: The American Academy of Sleep Medicine (AASM) commissioned a Workgroup to develop quality measures for the care of patients with narcolepsy. Following a comprehensive literature search, 306 publications were found addressing quality care or measures. Strength of association was graded between proposed process measures and desired outcomes. Following the AASM process for quality measure development, we identified three outcomes (including one outcome measure) and seven process measures. The first desired outcome was to reduce excessive daytime sleepiness by employing two process measures: quantifying sleepiness and initiating treatment. The second outcome was to improve the accuracy of diagnosis by employing the two process measures: completing both a comprehensive sleep history and an objective sleep assessment. The third outcome was to reduce adverse events through three steps: ensuring treatment follow-up, documenting medical comorbidities, and documenting safety measures counseling. All narcolepsy measures described in this report were developed by the Narcolepsy Quality Measures Work-group and approved by the AASM Quality Measures Task Force and the AASM Board of Directors. The AASM recommends the use of these measures as part of quality improvement programs that will enhance the ability to improve care for patients with narcolepsy. PMID- 25700881 TI - Quality measures for the care of patients with insomnia. AB - ABSTRACT: The American Academy of Sleep Medicine (AASM) commissioned five Workgroups to develop quality measures to optimize management and care for patients with common sleep disorders including insomnia. Following the AASM process for quality measure development, this document describes measurement methods for two desirable outcomes of therapy, improving sleep quality or satisfaction, and improving daytime function, and for four processes important to achieving these goals. To achieve the outcome of improving sleep quality or satisfaction, pre- and post-treatment assessment of sleep quality or satisfaction and providing an evidence-based treatment are recommended. To realize the outcome of improving daytime functioning, pre- and post-treatment assessment of daytime functioning, provision of an evidence-based treatment, and assessment of treatment-related side effects are recommended. All insomnia measures described in this report were developed by the Insomnia Quality Measures Workgroup and approved by the AASM Quality Measures Task Force and the AASM Board of Directors. The AASM recommends the use of these measures as part of quality improvement programs that will enhance the ability to improve care for patients with insomnia. PMID- 25700882 TI - Quality measures for the care of adult patients with restless legs syndrome. AB - ABSTRACT: The American Academy of Sleep Medicine (AASM) commissioned several Workgroups to develop quality measures for the care of patients with common sleep disorders, including adults with restless legs syndrome (RLS). Using the AASM process for quality measure development, the RLS Work-group developed three target outcomes for RLS management, including improving the accuracy of diagnosis, reducing symptom severity, and minimizing treatment complications. Seven processes were developed to support these outcomes. To achieve the outcome of improving accuracy of diagnosis, the use of accepted diagnostic criteria and assessment of iron stores are recommended. To realize the outcome of decreasing symptom severity, routine assessment of severity and provision of evidence-based treatment are recommended. To support the outcome of minimizing treatment complications, counseling about potential side effects and assessing for augmentation and impulse control disorders, when indicated, are recommended. Further research is needed to validate optimal practice processes to achieve best outcomes in adult patients with RLS. PMID- 25700883 TI - Measurement of quality to improve care in sleep medicine. AB - ABSTRACT: The Board of Directors of the American Academy of Sleep Medicine (AASM) commissioned a Task Force to develop quality measures as part of its strategic plan to promote high quality patient-centered care. Among many potential dimensions of quality, the AASM requested Workgroups to develop outcome and process measures to aid in evaluating the quality of care of five common sleep disorders: restless legs syndrome, insomnia, narcolepsy, obstructive sleep apnea in adults, and obstructive sleep apnea in children. This paper describes the rationale, background, general methods development, and considerations in implementation for these sleep disorder quality measures. The Workgroup papers are published in this issue under the following titles: Quality Measures for the Care of Adult Patients with Restless Legs Syndrome, Quality Measures for the Care of Patients with Insomnia, Quality Measures for the Care of Patients with Narcolepsy, Quality Measures for the Care of Adult Patients with Obstructive Sleep Apnea, and Quality Measures for the Care of Pediatric Patients with Obstructive Sleep Apnea. PMID- 25700884 TI - High-Throughput Screen of GluK1 Receptor Identifies Selective Inhibitors with a Variety of Kinetic Profiles Using Fluorescence and Electrophysiology Assays. AB - GluK1, a kainate subtype of ionotropic glutamate receptors, exhibits an expression pattern in the CNS consistent with involvement in pain processing and migraine. Antagonists of GluK1 have been shown to reduce pain signaling in the spinal cord and trigeminal nerve, and are predicted to provide pain and migraine relief. We developed an ultra-high-throughput small-molecule screen to identify antagonists of GluK1. Using the calcium indicator dye fluo-4, a multimillion member small-molecule library was screened in 1536-well plate format on the FLIPR (Fluorescent Imaging Plate Reader) Tetra against cells expressing a calcium permeable GluK1. Following confirmation in the primary assay and subsequent counter-screen against the endogenous Par-1 receptor, 6100 compounds were selected for dose titration to assess potency and selectivity. Final triage of 1000 compounds demonstrating dose-dependent inhibition with IC50 values of less than 12 uM was performed in an automated whole-cell patch clamp electrophysiology assay. Although a weak correlation between electrophysiologically active and calcium-imaging active compounds was observed, the identification of electrophysiologically active compounds with a range of kinetic profiles revealed a broad spectrum of mechanisms of action. PMID- 25700885 TI - Large-scale crystallization of proteins for purification and formulation. AB - Since about 170 years, salts were used to create supersaturated solutions and crystallize proteins. The dehydrating effect of salts as well as their kosmotropic or chaotropic character was revealed. Even the suitability of organic solvents for crystallization was already recognized. Interestingly, what was performed during the early times is still practiced today. A lot of effort was put into understanding the underlying physico-chemical interaction mechanisms leading to protein crystallization. However, it was understood that already the solvation of proteins is a highly complex process not to mention the intricate interrelation of electrostatic and hydrophobic interactions taking place. Although many basic questions are still unanswered, preparative protein crystallization was attempted as illustrated in the presented case studies. Due to the highly variable nature of crystallization, individual design of the crystallization process is needed in every single case. It was shown that preparative crystallization from impure protein solutions as a capture step is possible after applying adequate pre-treatment procedures like precipitation or extraction. Protein crystallization can replace one or more chromatography steps. It was further shown that crystallization can serve as an attractive alternative means for formulation of therapeutic proteins. Crystalline proteins can offer enhanced purity and enable highly concentrated doses of the active ingredient. Easy scalability of the proposed protein crystallization processes was shown using the maximum local energy dissipation as a suitable scale-up criterion. Molecular modeling and target-oriented protein engineering may allow protein crystallization to become part of a platform purification process in the near future. PMID- 25700886 TI - General population job exposure matrix applied to a pooled study of prevalent carpal tunnel syndrome. AB - A job exposure matrix may be useful for the study of biomechanical workplace risk factors when individual-level exposure data are unavailable. We used job title based exposure data from a public data source to construct a job exposure matrix and test exposure-response relationships with prevalent carpal tunnel syndrome (CTS). Exposures of repetitive motion and force from the Occupational Information Network were assigned to 3,452 active workers from several industries, enrolled between 2001 and 2008 from 6 studies. Repetitive motion and force exposures were combined into high/high, high/low, and low/low exposure groupings in each of 4 multivariable logistic regression models, adjusted for personal factors. Although force measures alone were not independent predictors of CTS in these data, strong associations between combined physical exposures of force and repetition and CTS were observed in all models. Consistent with previous literature, this report shows that workers with high force/high repetition jobs had the highest prevalence of CTS (odds ratio = 2.14-2.95) followed by intermediate values (odds ratio = 1.09-2.27) in mixed exposed jobs relative to the lowest exposed workers. This study supports the use of a general population job exposure matrix to estimate workplace physical exposures in epidemiologic studies of musculoskeletal disorders when measures of individual exposures are unavailable. PMID- 25700887 TI - Risk factors for falls among seniors: implications of gender. AB - Despite extensive literature on falls among seniors, little is known about gender specific risk factors. To determine the prevalence of falls by gender and sociodemographic, lifestyle/behavioral, and medical factors, we conducted a cross sectional study in a nationally representative sample of Canadian adults who were 65 years of age or older (n = 14,881) from the Canadian Community Health Survey Healthy Aging (2008-2009). Logistic regression models were applied to investigate gender-specific associations between potential risk factors and falls. In men, stroke (odds ratio (OR) = 1.91), nutritional risk (OR = 1.86), post-secondary school degree (OR = 1.68), eye disorder (OR = 1.35), widowed/separated/divorced marital status (OR = 1.28), and arthritis (OR = 1.27) were independently associated with significantly higher odds of falls. In women, significant independent correlates of falls included stroke (OR = 1.53), age of 85 years or older (OR = 1.51), nutritional risk (OR = 1.39), consumption of at least 1 alcoholic drink per week (OR = 1.39), use of 5 or more medications (OR = 1.36), arthritis (OR = 1.36), diabetes (OR = 1.31), and osteoporosis (OR = 1.22). Higher physical activity levels were protective in both genders, and higher household income was protective in women. Gender should be considered when planning fall prevention strategies. PMID- 25700888 TI - Borrelia miyamotoi infection in nature and in humans. AB - Borrelia miyamotoi is a relapsing fever Borrelia group spirochete that is transmitted by the same hard-bodied (ixodid) tick species that transmit the agents of Lyme disease. It was discovered in 1994 in Ixodes persulcatus ticks in Japan. B. miyamotoi species phylogenetically cluster with the relapsing fever group spirochetes, which usually are transmitted by soft-bodied (argasid) ticks or lice. B. miyamotoi infects at least six Ixodes tick species in North America and Eurasia that transmit Lyme disease group spirochetes and may use small rodents and birds as reservoirs. Human cases of B. miyamotoi infection were first reported in 2011 in Russia and subsequently in the United States, Europe and Japan. These reports document the public health importance of B. miyamotoi, as human B. miyamotoi infection appears to be comparable in frequency to babesiosis or human granulocytic anaplasmosis in some areas and may cause severe disease, including meningoencephalitis. The most common clinical manifestations of B. miyamotoi infection are fever, fatigue, headache, chills, myalgia, arthralgia, and nausea. Symptoms of B. miyamotoi infection generally resolve within a week of the start of antibiotic therapy. B. miyamotoi infection should be considered in patients with acute febrile illness who have been exposed to Ixodes ticks in a region where Lyme disease occurs. Because clinical manifestations are nonspecific, etiologic diagnosis requires confirmation by blood smear examination, PCR, antibody assay, in vitro cultivation, and/or isolation by animal inoculation. Antibiotics that have been used effectively include doxycycline for uncomplicated B. miyamotoi infection in adults and ceftriaxone or penicillin G for meningoencephalitis. PMID- 25700889 TI - Hepatitis B core-related antigen (HBcrAg) levels in the natural history of hepatitis B virus infection in a large European cohort predominantly infected with genotypes A and D. AB - Hepatitis B core-related antigen (HBcrAg) has been suggested as an additional marker of hepatitis B virus (HBV) infection. HBcrAg combines the antigenic reactivity resulting from denatured hepatitis B e antigen (HBeAg), HBV core antigen and an artificial core-related protein (p22cr). In Asian patients, high levels of HBcrAg have been suggested to be an independent risk factor for hepatocellular carcinoma, while low levels could guide safe cessation of treatment with nucleos(t)ide analogues. We here studied HBcrAg levels in different phases of HBV infection in a large European cohort predominantly infected with genotypes A and D: HBeAg-positive immune tolerance (n = 30), HBeAg positive immune clearance (IC) (n = 60), HBeAg-negative hepatitis (ENH) (n = 50), HBeAg-negative inactive/quiescent carrier phase (c) (n = 109) and acute hepatitis B (n = 8). Median HBcrAg levels were high in the immune tolerance and immune clearance phases (8.41 and 8.11 log U/mL, respectively), lower in ENH subjects (4.82 log U/mL) but only 2.00 log U/mL in ENQ subjects. Correlation between HBcrAg and HBV DNA varied among the different phases of HBV infection, while HBcrAg moderately correlated with hepatitis B surface antigen in all phases. ENQ patients had HBcrAg levels <3 log U/mL in 79%, in contrast to only 12% in the ENH group. HBcrAg levels vary significantly during the different phases of HBV infection. HBcrAg may serve as valuable marker for virus replication and reflect the transcriptional activity of intrahepatic cccDNA. In HBeAg-negative patients, HBcrAg may help to distinguish between inactive carriers (ENQ) and those with active disease (ENH). PMID- 25700890 TI - Case-control comparison of bacterial and protozoan microorganisms associated with gastroenteritis: application of molecular detection. AB - The introduction of molecular detection of infectious organisms has led to increased numbers of positive findings, as observed for pathogens causing gastroenteritis (GE). However, because little is known about the prevalence of these pathogens in the healthy asymptomatic population, the clinical value of these additional findings is unclear. A case-control study was carried out in a population of patients served by general practitioners in the Netherlands. A total of 2710 fecal samples from case and matched control subjects were subjected to multiplex real-time PCR for the 11 most common bacterial and four protozoal causes of GE. Of 1515 case samples, 818 (54%) were positive for one or more target organisms. A total of 49% of the controls were positive. Higher positivity rates in cases compared to controls were observed for Campylobacter spp., Salmonella spp., Clostridium difficile, enteroinvasive Escherichia coli/Shigella spp., enterotoxigenic E. coli, enteroaggregative E. coli, atypical enteropathogenic E. coli (EPEC), Cryptosporidium parvum/hominis, and Giardia lamblia. However, Dientamoeba fragilis and Shiga-like toxigenic E. coli were detected significantly less frequent in cases than in controls, while no difference in prevalence was found for typical EPEC and enterohemorrhagic E. coli. The association between the presence of microorganisms and GE was the weakest in children aged 0 to 5 years. Higher relative loads in cases further support causality. This was seen for Campylobacter spp., Salmonella spp., enterotoxigenic E. coli, and C. parvum/hominis, and for certain age categories of those infected with C. difficile, enteroaggregative E. coli, and atypical EPEC. For D. fragilis and Shiga-like toxigenic E. coli/enterohemorrhagic E. coli, pathogen loads were lower in cases. Application of molecular diagnostics in GE is rapid, sensitive and specific, but results should be interpreted with care, using clinical and additional background information. PMID- 25700891 TI - Disagreement in high-grade/low-grade intraepithelial neoplasia and high-risk/low risk HPV infection: clinical implications for anal cancer precursor lesions in HIV-positive and HIV-negative MSM. AB - Anal condylomata are common in HIV-positive individuals and among men who have sex with men (MSM). Generally attributable to infection by low-risk human papillomaviruses (HPVs), condylomata are considered benign low-grade squamous intraepithelial lesions (SILs). However, anal condylomata have occasionally been linked to high-grade SIL and to oncogenic, high-risk HPVs. Here we describe the range of intraepithelial lesions and of the associated HPVs in heterosexual men and women and MSM. Perianal and anal condylomata were collected from 243 patients (56 heterosexual women, 61 heterosexual men and 126 MSM, including 41 HIV positive MSM). We assessed lesion histology and HPV genotype. Prevalence estimates and Poisson models were used. Irrespective of HIV infection status, MSM showed a higher proportion of condylomata as high-grade SILs compared to heterosexual men/women. High-grade SILs were also more prevalent in anal than in perianal lesions in all patient groups. HIV-positive MSM exhibited increased prevalence ratio (4.6; 95% confidence interval 2.1-10.0) of perianal low-grade SILs containing only high-risk HPVs compared to HIV-negative MSM. In addition, more than 64% of anal SILs with a high-grade component, regardless of HIV infection, were exclusively associated with low-risk HPVs. In anal condylomata, both high-grade and low-grade SILs can be associated with high-risk and/or low risk HPVs. Particularly, low-grade perianal SILs associated with high-risk HPVs were common in HIV-positive MSM, while presence of only low-risk HPVs in high grade SILs were common in both MSM groups. Our findings sound a note of caution for the common clinical practice for the treatment of anal condylomata as benign lesions in MSM and HIV-positive patients. PMID- 25700892 TI - Mass gathering and globalization of respiratory pathogens during the 2013 Hajj. AB - Every year, more than 10 million pilgrims arrive in the Kingdom of Saudi Arabia for the Hajj or Umrah. Crowding conditions lead to high rates of respiratory infections among the pilgrims, representing a significant cause of morbidity and a major cause of hospitalization. Pre- and post-Hajj nasal specimens were prospectively obtained from a paired cohort (692 pilgrims) and from nonpaired cohorts (514 arriving and 470 departing pilgrims) from 13 countries. The countries of residence included Africa (44.2%), Asia (40.2%), the United States (8.4%) and Europe (7.2%). Nasal specimens were tested for 34 respiratory pathogens using RT-PCR. A total of 80 512 PCRs were performed. The prevalence of viruses and bacteria increased, from 7.4% and 15.4% before the Hajj to 45.4% and 31.0% after the Hajj, respectively, due to the acquisition of rhinovirus, coronaviruses (229E, HKU1, OC43), influenza A H1N1, Streptococcus pneumoniae, Haemophilus influenzae and Staphylococcus aureus. We did not identify Middle East respiratory coronavirus carriage. At arrival, the prevalence of several viruses was clearly dependent on the pilgrim's country of origin. After Hajj participation, these viruses were isolated among pilgrims from all countries, with few exceptions. No significant differences were observed between paired and nonpaired cohort results. Our results strongly suggest that, given the particularly crowded conditions during the rituals, an international mass gathering such as the Hajj may contribute to the globalization of respiratory pathogens after the cross-contamination of pilgrims harbouring pathogens that easily spread among participants. Influenza and pneumococcal vaccination, face mask use and hand hygiene should be considered in the context of the Hajj. PMID- 25700893 TI - Interaction of mealtime ad libitum beverage and food intake with meal advancement in healthy young men and women. AB - The objective of this study was to describe the interaction of beverage and food intake with meal advancement in healthy adults. In a randomized controlled study, 29 men and women consumed to satiation, over 20 min, a pizza meal with one of the five beverages including water, 1% milk, orange juice, regular cola and diet cola. Mealtime food and fluid intake were measured, within each of three 7-min phases of the meal. A progressive decline occurred from phase 1 to 3 in fluid intake and food intake, averaging 59 mL and 268 kcal (P < 0.0001) respectively; however, the relative intake of fluid to food (mL/kcal) increased (P < 0.0001). Beverage type was not a factor. All beverages resulted in similar fluid volume intake compared to water. However, caloric beverages led to higher mealtime total energy intake compared to water (P < 0.001) and diet cola (P < 0.0001). Baseline thirst correlated positively with both fluid (r = 0.28; P < 0.001) and food (r = 0.16; P < 0.05) intakes at the meal, whereas baseline appetite associated positively only with mealtime food intake (r = 0.23; P<0.01). In conclusion, mealtime fluid and food intakes interact, unaffected by beverage characteristics, to increase the ratio of fluid to food intake with meal progression. PMID- 25700894 TI - The role of ubiquitin/Nedd4-2 in the pathogenesis of mesial temporal lobe epilepsy. AB - Although the pathogenesis and epileptogenesis of mesial temporal lobe epilepsy (MTLE) have been studied for years, many questions remain. The ubiquitin proteasome system (UPS) is one factor that might regulate ion channels, inflammation and neuron excitability. Nedd4-2 is an E3 ubiquitin ligase linked with ion channels and synaptic vesicle recycling. Here, we explore the role of the UPS and its E3 ligase Nedd4-2 in the pathogenesis of MTLE. Our western blot results revealed that ubiquitin and Nedd4-2 were expressed differentially in different stages of MTLE. Co-immunoprecipitation and double immunostaining results indicated that Nedd4-2 was the substrate protein of ubiquitin both in vivo and in vitro. Inhibition of the UPS aggravated the epileptogenesis of MTLE, causing early and frequent spontaneous seizures, more obvious neuron loss and aberrant mossy fiber sprouting. Inhibition of ubiquitin also enhanced the activation of Nedd4-2, and switched ion channel alpha-ENaC downstream. Our study is the first to report that the UPS participates in the pathogenesis of MTLE, inhibition of UPS could aggravate the epileptogenesis, and that Nedd4-2 is a critical E3 ligase involved in this process. PMID- 25700895 TI - Transcranial non-invasive brain stimulation in swallowing rehabilitation following stroke--a review of the literature. AB - BACKGROUND: This descriptive review of the literature outlines the current evidence-base underpinning the potential of transcranial brain stimulation techniques to modulate swallowing function in healthy individuals and in treating post-stroke dysphagia. METHODS: Published research was identified by review of scientific databases (Scopus, Medline Ovid, Science Direct, AMED and Google Scholar) using relevant keywords. In addition, the reference lists of identified articles were scrutinized to identify further potentially relevant papers. Studies employing variants of transcranial magnetic or direct current stimulation for the purpose of modulating swallowing motor cortical excitability in healthy participants or dysphagia following stroke were included. Due to a significant heterogeneity in stimulation paradigms, all included studies were summarised and descriptively analysed in relation to the participants tested, cortical representations targeted by brain stimulation and outcome measures used. RESULTS: Seventeen studies met inclusion criteria (seven evaluating healthy participants, 10 evaluating participants presenting with post-stroke dysphagia). Cortical stimulation most commonly targeted pharyngeal motor representations (13/17 studies). In the 10 clinical studies, stimulation was applied contralesionally (5/10 studies), ipsilesionally (3/10 studies) or bilaterally (2/10 studies). A range of behavioural and neurophysiological outcome measures demonstrated positive effects on swallowing function across studies. CONCLUSION: There is promising proof of concept that non-invasive brain stimulation may provide a useful adjunct to post-stroke swallowing rehabilitation practice. Eventual transition of optimal paradigms into routine clinical practice will be accompanied by practical considerations in relation to local and national frameworks, e.g. the prescription and provision of treatment. PMID- 25700896 TI - Statins enhance cognitive performance in object location test in albino Swiss mice: involvement of beta-adrenoceptors. AB - Statins are inhibitors of the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, thereby inhibiting cell synthesis of cholesterol and isoprenoids. Moreover, several studies have been evaluating pleiotropic effects of statins, mainly because they present neuroprotective effects in various pathological conditions. However, knowledge about behavioral effects of statins per se is relatively scarce. Considering these facts, we aimed to analyze behavioral responses of atorvastatin or simvastatin-treated mice in the open field test, elevated plus maze and object location test. Atorvastatin treatment for 7 consecutive days at 1 mg/kg or 10 mg/kg (v.o.) or simvastatin 10 mg/kg or 20 mg/kg enhanced cognitive performance in object location test when compared to control group (saline-treated mice). Simvastatin effects on mice performance in the object location test was abolished by post-training infusion of the beta adrenoceptor antagonist propranolol. Atorvastatin and simvastatin did not change the behavioral response in open field and elevated plus-maze (EPM) tests in any of the used doses. These data demonstrate the positive effects of both statins in cognitive processes in mice, without any alteration in locomotor parameters in the open field test or anxiolytic-like behavior in EPM. In conclusion, we demonstrate that atorvastatin and simvastatin per se improve the cognitive performance in a rodent model of spatial memory and this effect is related to beta-adrenergic receptors modulation. PMID- 25700897 TI - The diverse surgeons' initiative: longitudinal assessment of a successful national program. AB - BACKGROUND: The Diverse Surgeons Initiative (DSI) is a program that was created to provide underrepresented minority surgical residents with the clinical knowledge and minimally invasive surgical skills necessary to excel in surgical residency and successfully transition into surgical practice. The early success of the graduates of the program has been published; however, a more longitudinal assessment of the program was suggested and warranted. This study provides a 5 year follow-up of the 76 physicians that participated in the DSI from 2002 to 2009 to determine if the trend toward fellowship placement and academic appointments persisted. Additionally, this extended evaluation yields an opportunity to assess these young surgeons' professional progress and contributions to the field. STUDY DESIGN: The most current professional development and employment information was obtained for the 76 physicians that completed the DSI from 2002 to 2009. The percentage of DSI graduates completing surgical residency, obtaining subspecialty fellowships, attaining board certification, receiving fellowship in the American College of Surgeons, contributing to the peer-reviewed literature, acquiring academic faculty positions, and ascending to professional leadership roles were calculated and compared with the original assessment. RESULTS: Of the 76 DSI graduates, 99% completed general surgery residency. Of those eligible, 87% completed subspecialty fellowships; 87% were board certified; 50% received fellowship in the American College of Surgeons; 76% had contributed to the peer-reviewed literature; 41% had obtained faculty positions; and 18% held local, regional, or national professional leadership positions. CONCLUSIONS: This longitudinal analysis has revealed sustained success of the DSI in preparing underrepresented minority residents to excel in their training and transition into practice, obtain postsurgical fellowships, acquire faculty appointments, and contribute to the advancement of the field of surgery. PMID- 25700898 TI - Further research required to define outcomes in neonates: in reply to Swanson. PMID- 25700899 TI - Surgical necrotizing enterocolitis: time for a definition. PMID- 25700900 TI - Assessment of tumor growth in von Hippel Lindau syndrome. PMID- 25700901 TI - Sensitivity of endoscopic ultrasound in detecting N+ disease among early gastric cancer patients needs to be underlined. PMID- 25700902 TI - Tumor growth in von Hippel Lindau syndrome: in reply to Qazi and colleagues. PMID- 25700903 TI - Endoscopic ultrasound may misclassify the nodal status of a small subset of patients with early gastric cancer: in reply to Chen and colleagues. PMID- 25700904 TI - Need for outcomes data in pain studies. PMID- 25700905 TI - Abdominal incision: the gold standard has yet to be defined. PMID- 25700906 TI - Outcomes data in pain studies: in reply to Barbul and colleagues. PMID- 25700907 TI - Fluorescence-guided laparoscopic surgery: what if we could label pancreatic cancer with biomarker-conjugated fluorescent quantum nanocrystals? PMID- 25700908 TI - Fluorescence-guided surgery: it is the cure that matters: in reply to Giorgakis and colleagues. PMID- 25700909 TI - Sub-staging colorectal cancers and adjuvant treatments. PMID- 25700911 TI - Thymoma related myasthenia gravis in humans and potential animal models. AB - Thymoma-associated Myasthenia gravis (TAMG) is one of the anti-acetylcholine receptor MG (AChR-MG) subtypes. The clinico-pathological features of TAMG and its pathogenesis are described here in comparison with pathogenetic models suggested for the more common non-thymoma AChR-MG subtypes, early onset MG and late onset MG. Emphasis is put on the role of abnormal intratumorous T cell selection and activation, lack of intratumorous myoid cells and regulatory T cells as well as deficient expression of the autoimmune regulator (AIRE) by neoplastic thymic epithelial cells. We review spontaneous and genetically engineered thymoma models in a spectrum of animals and the extensive clinical and immunological overlap between canine, feline and human TAMG. Finally, limitations and perspectives of the transplantation of human and murine thymoma tissue into nude mice, as potential models for TAMG, are addressed. PMID- 25700912 TI - Failed colonic interposition after esophagogastrectomy: What's the next step? PMID- 25700913 TI - Agreement of 3 carcass rinse sampling methods (split carcass, repeat rinse, and adjacent pair) on the detection of Salmonella contamination in broiler carcasses. AB - Whole carcass rinse is the most common method used to determine Salmonella prevalence in broiler carcasses. However, there is a need to determine the carcass rinse sampling method that best measures the Salmonella status of a broiler carcass as it proceeds through processing, thus allowing the assessment of efficacy of interventions to meet Food Safety Inspection Services (FSIS) performance standards. In this study, 3 paired carcass rinse sampling methods, namely split-carcass method (rinses of 2 halves of one carcass), repeat rinse method (rinse and rerinse of same carcass), and adjacent pair method (rinses of 2 adjacent carcasses), were evaluated during actual operations in commercial poultry processing plants in the southeastern United States. The purpose of the work was to determine which method resulted in greatest agreement of Salmonella status on paired broiler carcass rinses. The adjacent pair method showed moderate agreement consistently in 3 trials of 150 pairs per trial with kappa values of 0.46, 0.55, and 0.46. The repeat rinse method showed substantial kappa agreement (0.64) in one trial and moderate kappa agreement (0.47, 0.41) in 2 other trials. In one trial, the repeat rinse method showed a significant difference in prevalence rates between repeated rinses. Even though the split carcass method showed moderate kappa agreement (0.58, 0.45) in 150 carcasses in each of 2 trials, the disadvantages of the split carcass method were that it was more labor and time intensive and the product was damaged, when compared to the other 2 methods. Overall, although prevalence estimates were fairly consistent between pairs by each method, agreement between Salmonella status of the paired samples was less than desired, mostly moderate. This lack of agreement should be considered in the design of studies assessing the efficacy of interventions for the control of Salmonella in broilers to meet FSIS performance standards. PMID- 25700914 TI - Differences in egg nutrient availability, development, and nutrient metabolism of broiler and layer embryos. AB - Selection for production traits of broilers and layers leads to physiological differences, which may already be present during incubation. This study aimed to investigate the influence of strain (broiler vs layer) on egg nutrient availability, embryonic development and nutrient metabolism. A total of 480 eggs with an egg weight range of 62.0 to 64.0 g from Lohmann Brown Lite and Ross 308 breeder flocks of 41 or 42 weeks of age were selected in two batches of 120 eggs per batch per strain. For each batch, 30 eggs per strain were used to determine egg composition, including nutrient and energy content, and 90 eggs per strain were separately incubated in one of two climate respiration chambers at an eggshell temperature of 37.8 degrees C. The results showed that broiler eggs had a higher ratio of yolk: albumen with 2.41 g more yolk and 1.48 g less albumen than layers. The yolk energy content of broiler eggs was 46.32 kJ higher than that of layer eggs, whereas total energy content of broiler eggs was 47.85 kJ higher compared to layer eggs. Yolk-free body mass at incubation day 16 and chick weight and length at hatch were higher in broilers compared to layers. Respiration quotient of broiler embryos was higher than layer embryos during incubation day 8 to incubation day 10. A 0.24 g lower residual yolk at the hatch of broiler embryos than for the layer embryos indicated that broiler embryos used more yolk and had a higher energy utilization and energy deposition in yolk-free body mass. Heat production of broiler embryos was higher than that of layer embryos from incubation day 12 to incubation day 18, but efficiency of converting egg energy used by embryos to form yolk-free body mass was similar. In conclusion, broiler and layer embryos have different embryonic development patterns, which affect energy utilization and embryonic heat production. However, the embryos are equal in efficiency of converting the energy used to yolk-free body mass. PMID- 25700915 TI - The effect of structural modifications on the solution and interfacial properties of straight and branched aliphatic alcohols: the role of hydrophobic effects. AB - The effect of structural modifications, such as branching of the hydrocarbon chain on the solution and interfacial properties of short-chain aliphatic alcohols has been investigated. Surface tension measurements have been used to study the adsorption of the alcohols at the aqueous solution/air interface from water/alcohol mixtures, and to determine the aqueous solubilities of the alcohols. The related process of the partitioning behaviour of the alcohols between two immiscible phases has also been studied. Standard free energies of adsorption at the aqueous solution/air interface, standard free energies of transfer between water and hexane, and standard free energies of solution were obtained for the alcohols. A linear "Traube" relationship, an elegant demonstration of the hydrophobic effect, was found to exist between the various free energies for the normal alcohols and the number of carbon atoms in the alcohol molecule. The free energies showed that structurally modified alcohols have less negative free energy of adsorption, transfer or solution compared to the normal alcohol with the same number of carbon atoms. We assign effective numbers of carbon atoms for each branched alcohol for each transfer process. The position of the hydroxyl group relative to the branched part of the molecule was found to be a factor which influences the hydrophobic contribution to the free energy of each transfer process. An attempt has been made to ascertain whether there is a correlation between the molecular surface area, or the molecular volume, and the interfacial and solution thermodynamic properties of an alcohol in aqueous solution. The standard free energies of some of the branched alcohols have been found to be inconsistent with the values expected from the energetic of the adsorption and the water/hexane transfer processes. This is thought to reflect the different modes of association of the branched and normal alcohols in the liquid state as revealed by small and wide angle X-ray scattering which identifies correlation peaks attributable to intermolecular hydrogen bonding and interchain associations consistent with non-polar segmentation. PMID- 25700916 TI - Eltrombopag: a review of its use in patients with severe aplastic anaemia. AB - Eltrombopag (Promacta(r)) is an orally active thrombopoietin receptor agonist recently approved in the US for the treatment of patients with severe aplastic anaemia who have had an insufficient response to immunosuppressive therapy. This article reviews the efficacy and tolerability of eltrombopag in this indication and overviews its pharmacological properties. Eltrombopag does not compete with thrombopoietin and binds to a different site on the receptor, producing additive effects. It stimulates haematopoietic stem cells and promotes haematopoietic recovery in patients with aplastic bone marrow. Eltrombopag increased platelet counts and can also increase red blood cell and neutrophil counts. In patients with severe aplastic anaemia refractory to prior immunosuppressive therapy, oral eltrombopag at dosages <=150 mg once daily for 12-16 weeks produced a haematological response in at least one cell lineage in 40 % of patients. Trilineage responses were achieved in nearly one-half of the responders during extended treatment. In robust responders, stable haematological counts were maintained after eltrombopag discontinuation. Eltrombopag was generally well tolerated, with increased liver transaminases as the only dose-limiting toxicity. Clonal cytogenetic abnormalities were observed in 19 % of patients and dysplasia in 5 % of patients. PMID- 25700917 TI - Global tuberculosis control requires greater ambition and resources. PMID- 25700918 TI - Counselling services in prevention of mother-to-child transmission (PMTCT) in Delhi, India: an assessment through a modified version of UNICEF-PPTCT tool. AB - The study aims to assess the counselling services provided to prevent mother to child transmission of HIV (PMTCT) under the Indian programme of prevention of parent-to-child transmission of HIV (PPTCT). Five hospitals in Delhi providing PMTCT services were randomly selected. A total of 201 post-test counselled women were interviewed using a modified version of the UNICEF-PPTCT evaluation tool. Knowledge about HIV transmission from mother-to-child was low. Post-test counselling mainly helped in increasing the knowledge of HIV transmission; yet 20%-30% of the clients missed this opportunity. Discussion on window period, other sexually transmitted diseases and danger signs of pregnancy were grossly neglected. The PMTCT services during the antenatal period are feasible and agreeable to be provided; however, certain aspects, like lack of privacy, confidentiality of HIV status of the client, counsellor's 'hurried' attitude, communication skills and discriminant behaviour towards HIV-positive clients, and disinterest of clients in the counselling, remain as gaps. These issues may be addressed through refresher training to counsellors with an emphasis on social and behaviour change communication strategies. Addressing attitudinal aspects of the counsellors towards HIV positives is crucial to improve the quality of the services to prevent mother-to-child transmission of HIV. PMID- 25700919 TI - The Malay version of the brief questionnaire on smoking urge: translation and psychometric properties of the questionnaire. AB - This study aimed to evaluate the psychometric properties of Malay translated version of the brief questionnaire of smoking urges (QSU-Brief). The translation procedure was done following the standard guidelines. The reliability and validity of the Malaysian version scale were evaluated based on the data collected from 133 Malaysian smokers. The internal consistency was calculated to assess the reliability. Factor analysis and construct validity were performed to validate psychometric properties of the scale. Total Cronbach's alpha of the scale was 0.806. The exploratory factor analysis revealed two factors that accounted for 66.15% of the explained total variance. The first component consisted of items 1, 3, 6, 7, and 10, while the second component included the rest. The QSU-Brief total score had a significant positive relationship with exhaled CO level (r=0.24; P=0.005), number of cigarettes smoked per day (r=0.30; P<0.001) and other clinical factors. Items 2 and 5 loaded strongly on factor 2, whereas both items loaded ambivalently on two factors in the previous studies. This discrepancy might be clarified by language differences. The Malaysian QSU Brief is a good candidate for evaluating urge to smoke in both clinical practice and clinical trials. PMID- 25700920 TI - Evaluation of the certificate in emerging infectious disease research and the certificate in one health training programs, University of Florida. AB - In developing countries, public health professionals and scientists need targeted training and practical skills to respond to global emerging infectious disease threats. The Certificate in Emerging Infectious Disease Research was developed in 2008 to aid such professionals to respond to complex emerging disease problems. The short-course was modified slightly in 2013 and renamed the Certificate in One Health. To evaluate the immediate impact of the short-course, an online survey of 176 past participants from both the courses was conducted. The survey tool assessed the program's process, impact, and outcome measures respectively via assessing the courses' perceived strengths and weaknesses, perceived skills gained, and the participants' current position, publication status, funding status, and educational attainment; 85 (48.3%) participants completed the survey. Reported program strengths included the curriculum, expertise of lecturers, and diversity of the training cohort. The principal reported weakness was the compressed academic schedule. The most frequently reported benefits included: epidemiological and biostatistical skills, followed by One-Health knowledge, and research skills. Twenty-eight percent of the survey respondents reported publishing one or more manuscripts since completing the course and 21% reported receiving research funding. The course appears to have had a positive, immediate impact on the students' self-perceived knowledge and capabilities. PMID- 25700921 TI - Establishing a field epidemiology elective for medical students in Kenya: a strategy for increasing public health awareness and workforce capacity. AB - Medical students have limited exposure to field epidemiology, even though will assume public health roles after graduation. We established a 10-week elective in field epidemiology during medical school. Students attended one-week didactic sessions on epidemiology, and nine weeks in field placement sites. We administered pre- and post-tests to evaluate the training. We enrolled 34 students in 2011 and 2012. In 2011, we enrolled five of 24 applicants from a class of 280 medical students. In 2012, we enrolled 18 of 81 applicants from a class of 360 students; plus 11 who participated in the didactic sessions only. Among the 34 students who completed the didactic sessions, 74% were male, and their median age was 24 years (range: 22-26). The median pre-test score was 64% (range: 47-88%) and the median post-test score was 82% (range: 72-100%). Successful completion of the field projects was 100%. Six (30%) students were not aware of public health as a career option before this elective, 56% rated the field experience as outstanding, and 100% reported it increased their understanding of epidemiology. Implementing an elective in field epidemiology within the medical training is a highly acceptable strategy to increase awareness for public health among medical students. PMID- 25700922 TI - The association between development assistance for health and malaria, HIV and tuberculosis mortality: a cross-national analysis. AB - Development assistance for health (DAH) and foreign aid have been criticized for being poorly associated with health and economic outcomes on a national level. This study is an attempt to examine whether DAH targeted specifically to malaria, HIV and tuberculosis (TB) is associated with changes in malaria, HIV and TB mortality, respectively. A dataset of DAH targeted to malaria, HIV and TB and corresponding malaria-, HIV- and TB-specific mortality was compiled for 120 low- and middle-income countries. Regression analysis was performed using country and time-period fixed effects and control variables. While malaria and HIV DAH were associated with reductions in malaria and HIV mortality, respectively, TB DAH was not significantly associated with reductions in TB mortality. Estimates were consistent in various sensitivity analyses, including generalized method of moments estimation, addition of extra controls and analysis of a multiply imputed dataset. In conclusion, targeted DAH is associated with reduction of HIV and malaria mortality on a national level. PMID- 25700923 TI - Metabolic parameters and blood pressures achieved by diabetic patients at two health care facilities in south Trinidad. AB - BACKGROUND: Previous studies have demonstrated poor metabolic and blood pressure control in the diabetic population in Trinidad. The aim of this study is to compare baseline and follow-up metabolic parameters and blood pressures taken within a 16-month period to ascertain if there have been improvements. METHOD: A retrospective chart review was conducted of diabetic patients at the Siparia and Erin health facilities in 2012. To be eligible, charts had to contain two point of-care values of HbA1c, Total Cholesterol (TC), Triglycerides (TG), Low Density Lipoproteins (LDL), systolic and diastolic blood pressure (BP), and weight measurements taken within a 16-month period with at least an 8-month interval from the initial to the final testing. Comparisons were made with the Caribbean Health Research Council (CHRC) guidelines to determine clinical significance. RESULTS: 253 patients from Siparia and 68 from Erin were studied. At Siparia there was a statistically significant change in TG, LDL and diastolic BP, with TG levels actually worsening (p<0.05). At Erin there was a statistically significant change in HbA1c, LDL and diastolic BP. At neither site did these changes achieve clinical significance. There were statistically significant differences between the means of HbA1c and systolic BP by age, but not by gender or ethnicity. On comparing the outcomes between the two health facilities, there were no statistically significant differences between them. When compared with the recommendations by the CHRC, only for the TC was the guideline level achieved. CONCLUSION: Despite heavy investment in primary care centers, there continues to be little success in achieving metabolic and BP control for diabetic patients in Trinidad. PMID- 25700924 TI - The association between disability and cognitive impairment in an elderly Tanzanian population. AB - Cognitive impairment is thought to be a major cause of disability worldwide, though data from sub-Saharan Africa (SSA) are sparse. This study aimed to investigate the association between cognitive impairment and disability in a cohort of community-dwelling older adults living in Tanzania. The study cohort of 296 people aged 70years and over was recruited as part of a dementia prevalence study. Subjects were diagnosed as having dementia or mild cognitive impairment according to the DSM-IV criteria. Disability level was assessed according to the WHO Disability Assessment Schedule, version 2.0 (WHODAS). A higher WHODAS score indicates greater disability. The median WHODAS in the background population was 25.0; in those with dementia and in those with mild cognitive impairment, 72 of 78 (92.3%) and 41 of 46 (89.1%), respectively, had a WHODAS score above this level. The presence of dementia, mild cognitive impairment, hearing impairment, being unable to walk without an aid and not having attended school were independent predictors of having a WHODAS score above 25.0, though age and gender were not. In summary, cognitive impairment is a significant predictor of disability in elderly Tanzanians. Screening for early signs of cognitive decline would allow management strategies to be put in place that may reduce the associated disability burden. PMID- 25700925 TI - Does emotion and its daily fluctuation correlate with depression? A cross cultural analysis among six developing countries. AB - Utilizing a World Health Organization (WHO) multi-national dataset, the present study examined the relationships between emotion, affective variability (i.e., the fluctuation of emotional status), and depression across six developing countries, including China (N=15,050); Ghana (N=5,573); India (N=12,198); Mexico (N=5,448); South Africa (N=4,227); and Russia (N=4,947). Using moderated logistic regression and hierarchical multiple regression, the effects of emotion, affective variability, culture, and their interactions on depression and depressive symptoms were examined when statistically controlling for a number of external factors (i.e., age, gender, marital status, education level, income, smoking, alcohol drinking, physical activity, sedentary behavior, and diet). The results revealed that negative emotion was a statistically significant predictor of depressive symptoms, but the strength of association was smaller in countries with a lower incidence of depression (i.e., China and Ghana). The association between negative affective variability and the risk of depression was higher in India and lower in Ghana. Findings suggested that culture not only was associated with the incidence of depression, but it could also moderate the effects of emotion and affective variability on depression or the experience of depressive symptoms. PMID- 25700926 TI - Anaesthesia, surgery, obstetrics, and emergency care in Guyana. AB - The surgical and anaesthesia needs of low-income countries are mostly unknown due to the lack of data on surgical infrastructure and human resources. The goal of this study is to assess the surgical and anaesthesia capacity in Guyana. A survey tool adapted from the WHO Tool for Situational Analysis to Assess Emergency and Essential Surgical Care was used to survey nine regional and district hospitals within the Ministry of Health system in Guyana. In nine hospitals across Guyana, there were an average of 0.7 obstetricians/gynaecologists, 3.5 non-OB surgeons, and 1 anaesthesiologist per hospital. District and regional hospitals performed an annual total of 1520 and 10,340 surgical cases, respectively. All but 2 district hospitals reported the ability to perform surgery. An average hospital has two operating rooms; 6 out of 9 hospitals reported routine medication shortages, and 4 out of 9 hospitals reported routine water or electricity shortages. Amongst the three regional hospitals, 16.1% of pregnancies resulted in Caesarean section. Surgical capacity varies by hospital type, with district hospitals having the least surgical capacity and surgical volume. District level hospitals routinely do not perform surgery due to lack of basic infrastructure and human resources. PMID- 25700927 TI - Factors associated with incident HIV infection versus prevalent infection among youth in Rakai, Uganda. AB - Factors associated with prevalent and incident HIV infection were compared among sexually experienced Ugandans aged 15-24. Most factors were similar. However, in women, older age and current marriage were associated with prevalent, but not incident, infection. It is important to recognize the limitations of prevalence analyses for identifying at-risk youth. PMID- 25700928 TI - Global surgery: integrating an emerging sub-specialty within global health. PMID- 25700929 TI - Incidence of acute-onset atrial fibrillation correlates with air temperature. Results of a nine-year survey. PMID- 25700930 TI - Acute-onset atrial fibrillation and ambient air temperature: a linear or a non linear association? PMID- 25700932 TI - Chronic kidney disease progression is mainly associated with non-recovery of acute kidney injury. AB - BACKGROUND: Identifying individuals who are at increased risk for accelerated progressive chronic kidney disease (CKD) and who might benefit from preventive interventions is an important challenge. METHODS: The present observational study evaluated the effect of an episode of Acute Kidney Injury (AKI) on the evolution of the renal trajectory in a cohort of 311 ambulatory CKD patients. We analyzed the evolution of eGFR in this cohort within a 5-year time window around an AKI episode. The mean of the available eGFR-values over a 6 month period was calculated once at the start and once at the end of the 5-year period. Slow and fast CKD progression were defined as a decrease by respectively <= or >1 category of 15 ml/min/1.73 m(2) over the 5-year time window. The influence of AKI on progression status was analyzed. RESULTS: Median eGFR decline over the 5 year period was 11, 22 and 6 ml/min/1.73 m(2) in the total, AKI and no AKI group respectively. AKI occurred in 44/72 versus 50/239 of fast versus slow progressors (odds ratio: 5.9, 95% confidence interval: 3.4-10.5). An incomplete recovery of eGFR after an AKI episode (median in overall, fast progressors, slow progressors 11, 20 and 4 ml/min/1.73 m(2) respectively) was the major component for the overall loss of renal function over the 5-year window. Our data failed to provide evidence that the CKD progression became more accelerated once kidney function was stabilized after the AKI episode. CONCLUSIONS: Incomplete recovery of AKI was related with accelerated CKD-progression. Episodes of AKI were not associated with an accelerated decline of kidney function once the AKI episode had resolved. In the group without AKI episode, the progression was similar to that of the general population without CKD. PMID- 25700931 TI - Impact of fractional phosphate excretion on the relation of FGF23 with outcome in CKD patients. AB - BACKGROUND: Cardiovascular risk is increased in patients with chronic kidney disease (CKD). Fibroblast growth factor 23 (FGF23) has emerged as an important, independent predictor of outcome in CKD patients. High FGF23 may, however, be a reflection of renal tissue resistance to its actions, reflected by low fractional excretion of phosphate (FePi). We evaluated the modifying effect of FePi on the association between FGF23 and outcome in patients with CKD stage 3-4. METHODS: An analysis was performed in a subset of 166 adult patients of two participating centers of the MASTERPLAN trial of whom urine samples at baseline were available to calculate FePi. Outcome was defined as a composite of death, renal failure (defined as need for renal replacement therapy or doubling of serum creatinine) and cardiovascular events (myocardial infarction, cerebrovascular accident, percutaneous transluminal coronary angioplasty or coronary artery bypass graft. Patients were categorized by FGF23 and FePi. A product term was added to Cox regression and RERIs were calculated. RESULTS: Patients had a median estimated glomerular filtration rate (eGFR) of 36 ml/min/1.73 m(2) [interquartile range (IQR) 27-44], serum phosphate 1.04 mmol/l (IQR 0.92-1.20), FGF23 140 RU/ml (IQR 81-236) and FePi 0.32 (IQR 0.25-0.44). A total of 96 events occurred during 5 years of follow up. LnFGF23 was a significant, independent predictor for the composite outcome [hazard ratio (HR) 2.13, 95% confidence interval (CI) 1.53 2.95]. FePi did not modify the relation between FGF23 and outcome in these patients with CKD. CONCLUSIONS: Our study shows that FGF23 itself, but not its renal tissue resistance as reflected by FePi, is an important risk factor for clinical events in subjects with CKD stage 3-4. PMID- 25700933 TI - Intercellular bridges are essential for human parthenogenetic cell survival. AB - Parthenogenetic cells, obtained from in vitro activated mammalian oocytes, display multipolar spindles, chromosome malsegregation and a high incidence of aneuploidy, probably due to the lack of paternal contribution. Despite this, parthenogenetic cells do not show high rates of apoptosis and are able to proliferate in a way comparable to their biparental counterpart. We hypothesize that a series of adaptive mechanisms are present in parthenogenetic cells, allowing a continuous proliferation and ordinate cell differentiation both in vitro and in vivo. Here we identify the presence of intercellular bridges that contribute to the establishment of a wide communication network among human parthenogenetic cells, providing a mutual exchange of missing products. Silencing of two molecules essential for intercellular bridge formation and maintenance demonstrates the key function played by these cytoplasmic passageways that ensure normal cell functions and survival, alleviating the unbalance in cellular component composition. PMID- 25700934 TI - Prognostic impact of serum bilirubin level on long-term renal survival in IgA nephropathy. AB - BACKGROUND: Serum bilirubin has been recognized as a novel endogenous antioxidant. The aim of our study was to evaluate the impact of serum bilirubin on kidney prognosis in IgA nephropathy (IgAN). METHODS: We followed retrospectively 694 patients with IgAN diagnosed by renal biopsy between 1982 and 2010. The risk factors for developing end-stage renal disease (ESRD) were estimated using a Cox proportional hazard model. Predictive performance between models with or without serum bilirubin was evaluated by calculating the net reclassification improvement (NRI) and integrated discrimination improvement (IDI). RESULTS: Seventy-seven patients developed ESRD during the median 4.9 years of follow-up. Estimated glomerular filtration rate, proteinuria and histological severity were inversely related to bilirubin levels. In multivariate analysis, serum bilirubin was an independent risk factor for ESRD (hazard ratio for every 0.1 mg/dL decrease in serum bilirubin, 1.18; 95 % CI, 1.04-1.33). The incidence rate of ESRD decreased linearly with the increases in bilirubin levels (P for trend <0.01). When bilirubin was incorporated into a model with conventional ESRD risk factors, the NRI and IDI were 0.281 (P = 0.02) and 0.019 (P = 0.01), respectively. CONCLUSIONS: We demonstrated that lower bilirubin levels were significantly associated with higher risk of ESRD in IgAN. In addition, bilirubin provided incremental predictive value in the risk assessment for progression of IgAN beyond that provided by standard risk factors. PMID- 25700935 TI - Propofol-or regression toward the mean-increases preload dependency. PMID- 25700936 TI - Lactulose accelerates liver regeneration in rats by inducing hydrogen. AB - BACKGROUND: Oxidative stress and inflammation are implicated in the process of liver regeneration. Lactulose orally administered can be bacterially fermented and induces dramatic amounts of endogenous hydrogen. Hydrogen has been confirmed to have antioxidant and anti-inflammatory properties. This study investigated the potential influence of lactulose administration on liver regeneration. MATERIALS AND METHODS: Antibiotics were used to suppress bacterial fermentation of lactulose, and hydrogen-rich saline was used as a supplementary measure of exogenous hydrogen. The liver regeneration model was produced in Sprague-Dawley rats through 70% partial hepatectomy. RESULTS: Compared with non-lactulose treated group, lactulose administration remarkably increased the weights of remnant liver and inhibited increases in serum levels of transaminases more notably. In the lactulose-treated group, increases of markers for regeneration, such as proliferating cell nuclear antigen and cyclin D1, were highly elevated. Biochemically, lactulose administration increased liver superoxide dismutase activity and decreased malondialdehyde content. In the lactulose-treated group, excessive increases in inflammatory cytokines, such as interleukin-6 and tumor necrosis factor-alpha, were inhibited significantly. Increased heme oxygenase-1 and superoxide dismutase 2 expression were also observed after lactulose treatment. The antibiotics suppressed the regeneration-promoting effect of lactulose by reducing hydrogen production, whereas supplementing hydrogen by hydrogen-rich saline would get a similar regeneration-promoting effect as lactulose administration. CONCLUSIONS: Lactulose administration accelerates posthepatectomized liver regeneration in rats by inducing hydrogen, which may result from attenuation of the oxidative stress response and excessive inflammatory response. PMID- 25700937 TI - Dose-dependent establishment of Trichuris suis larvae in Gottingen minipigs. AB - Embryonated eggs of the pig whipworm Trichuris suis (TSOee) constitute the active pharmaceutical ingredient (API) in a medicinal product explored in human clinical trials against several immune-mediated diseases. The measurement of TSO biological potency (hatchability and infectivity) is a requirement for the assessment of TSO's pharmacological potency in human clinical trials. The present study aims to validate the dose-dependent establishment of T. suis larvae in Gottingen minipigs and eventual clinical implication of a dose range (1000-10,000 TSO). Four groups of 5 minipigs were inoculated with doses of 1000, 2500, 7500, and 10,000 TSOee, respectively, to evaluate a range of concentrations of TSOee in a minipig infectivity model. Unembryonated eggs (TSOue) were added to keep the total egg number in the inoculum constant at 10,000 eggs. Two groups received 2500 and 7500 TSOee per pig without the addition of TSOue as controls. The intestinal larval establishment at 21 days post inoculation (dpi) demonstrated a clear positive linear dose-response relationship between numbers of inoculated TSOee and recovered larvae. There was a low level of variation in larval counts in all study groups. Thus, the infectivity model in minipigs within the tested dose range offers a reliable, sensitive and accurate assay for testing biological potency of TSO. PMID- 25700938 TI - Diurnal fluctuations in nematode egg excretion in naturally and in experimentally infected chickens. AB - We investigated whether nematode egg excretion through feces of naturally or experimentally infected chickens follow certain patterns within a day, which may allow determining the most appropriate sampling time for the highest parasite egg concentration. Feces samples (n=864) from chickens (n=36) with naturally occurring mixed nematode infections (trials N1, N2) or with an experimental Ascaridia galli infection (E) were collected quantitatively every 4h for four consecutive days. Number of eggs per gram of feces (EPG) was determined, and accumulative egg output (AEO) at each sampling time as well as total number of eggs excreted within 24h (eggs per day, EPD) were then estimated. At the end of the collection period, the hens were necropsied and their worm burdens determined. Naturally infected hens harbored Heterakis gallinarum (100%), Capillaria spp. (95.7%) and A. galli (91.3%). The experimental A. galli infection produced patent infections in all the birds. In general, both fecal egg concentration (EPG) and the amount of feces increased (P<0.05) sharply from the early morning to early-noon (10:00 a.m.) and remained at a high level until evenings which thereafter decreased to their initial levels during the night both in naturally and experimentally infected birds. This resulted in a more apparent increase or a decrease in AEO at the corresponding time points, respectively, and led to much higher egg excretions during the daytime than the nights. Despite the apparent within day fluctuations in egg excretion, neither EPG (P=0.704) nor AEO (P=0.499) nor EPD (P=0.149) was significantly different among the four collection days. Similarly, there was no significant interaction (P>0.05) between effects of sampling hours and days on EPG and AEO, suggesting the existence of repeatable diurnal fluctuations within each day. Although an association between climatic parameters (e.g., ambient temperature and relative humidity) and the nematode egg excretion was quantified, a causal relationship could not be demonstrated. We conclude that nematode egg excretion through chicken feces in both natural and experimental infections shows repeatable diurnal fluctuations, which may indicate adaptive strategies by nematodes and eventually favor parasite spread. Since analytic sensitivity of fecal egg counts suffers from low egg concentrations in feces, samples taken during the daytime have a higher diagnostic value. PMID- 25700939 TI - Phenotypic and Functional Characterization of Ductal Carcinoma In Situ-Associated Myoepithelial Cells. AB - BACKGROUND: Ductal carcinoma in situ (DCIS) is contained by myoepithelial cells that are morphologically similar to normal breast tissue myoepithelial cells. However, phenotypic and functional characteristics of DCIS-associated myoepithelial cells are not known. In this study, we aimed to assess the characteristics of DCIS-associated myoepithelial cells. MATERIALS AND METHODS: Immunophenotypic and functional characteristics of myoepithelial cells of pure DCIS, the DCIS component of infiltrating duct carcinoma (IDC), and the adjacent normal breast tissue of both groups (30 cases in each group) was assessed using phenotypic (CK5/6, CK14, p63, and calponin) and functional markers (maspin and CXCL14). RESULTS: There was a decrease in expression of CK14, p63, and calponin in pure DCIS-associated myoepithelial cells compared with normal breast tissue myoepithelial cells (43.3% vs. 80.3%, 3.3% vs. 70%, 46.6 vs. 93.3%, respectively) and in the DCIS component of IDC compared with normal breast tissue myoepithelial cells (56.6% vs. 100%, 3.3% vs. 73.3%, 56.6% vs. 96.6%, respectively). CK5/6 expression was low to absent in myoepithelial cells of pure DCIS and the DCIS component of IDC as well as normal breast tissue myoepithelial cells. Maspin was expressed in all samples of normal breast tissue; however, 20% of pure DCIS and 26.6% of the DCIS component of IDC showed decreased expression. CXCL14 expression was greater in pure DCIS compared with adjacent normal breast tissue and the DCIS component of IDC. CONCLUSION: Decreased expression of myoepithelial cell markers in DCIS suggests that DCIS-associated myoepithelial cells are phenotypically different from their normal counterparts. Two or more markers, preferably p63 and calponin, should be used to distinguish in situ from invasive breast carcinomas. PMID- 25700940 TI - Developing a stroke severity index based on administrative data was feasible using data mining techniques. AB - OBJECTIVES: Case-mix adjustment is difficult for stroke outcome studies using administrative data. However, relevant prescription, laboratory, procedure, and service claims might be surrogates for stroke severity. This study proposes a method for developing a stroke severity index (SSI) by using administrative data. STUDY DESIGN AND SETTING: We identified 3,577 patients with acute ischemic stroke from a hospital-based registry and analyzed claims data with plenty of features. Stroke severity was measured using the National Institutes of Health Stroke Scale (NIHSS). We used two data mining methods and conventional multiple linear regression (MLR) to develop prediction models, comparing the model performance according to the Pearson correlation coefficient between the SSI and the NIHSS. We validated these models in four independent cohorts by using hospital-based registry data linked to a nationwide administrative database. RESULTS: We identified seven predictive features and developed three models. The k-nearest neighbor model (correlation coefficient, 0.743; 95% confidence interval: 0.737, 0.749) performed slightly better than the MLR model (0.742; 0.736, 0.747), followed by the regression tree model (0.737; 0.731, 0.742). In the validation cohorts, the correlation coefficients were between 0.677 and 0.725 for all three models. CONCLUSION: The claims-based SSI enables adjusting for disease severity in stroke studies using administrative data. PMID- 25700941 TI - Loss to follow-up was used to estimate bias in a longitudinal study: a new approach. AB - OBJECTIVES: To examine bias arising from loss to follow-up due to lack of contact. STUDY DESIGN AND SETTING: The 1973-1978 cohort of Australian Longitudinal Study on Women's Health was first surveyed in 1996 and followed up in 2000, 2003, 2006, and 2009. At the 2000 survey, 9,688 women responded (responders), 2,972 could not be contacted, of whom 1,515 responded subsequently (temporary no contact) and 1,457 did not (permanent no contact). Characteristics were compared for these groups at baseline and follow-up in 2003, 2006, or 2009. Relative risk ratios were used to estimate bias. RESULTS: No-contacts were younger, more likely to live in cities, to be less educated and stressed about money than responders. No-contacts were more likely to be in de facto relationships, separated, divorced, or widowed, to have experienced partner violence and be smokers. Compared with temporary no contact, permanent no contact were less educated, less likely to be studying or employed. Despite differences in prevalence estimates, relative odds ratios were close to one and had confidence intervals that included one, indicating little effect of bias. CONCLUSION: Although various characteristics were related to loss to follow-up, the relative risks estimates did not indicate serious bias due to loss to follow up in this cohort of young women. PMID- 25700942 TI - Trk inhibitor attenuates the BDNF/TrkB-induced protection of neuroblastoma cells from etoposide in vitro and in vivo. AB - TrkB activation by brain-derived neurotrophic factor (BDNF) contributes to chemo resistance in neuroblastoma (NB). AZD6918 is a novel potent and selective inhibitor of the Trk tyrosine kinases. In this study we evaluated the effect of AZD6918 on the sensitivity of TrkB-expressing NB cells or tumors to etoposide, a topoisomerase II inhibitor. TrkB-expressing NB cells were treated with AZD6918 and etoposide in the presence or absence of BDNF in vitro and cell survival was determined. NB xenograft tumors were treated with AZD6918 and etoposide, either alone or in combination in vivo, and the anti-tumor growth effect or mice survival advantage was evaluated. Our study showed that AZD6918 induced cell death as a single agent and attenuated BDNF/TrkB-induced protection from etoposide in vitro. Although AZD6918 alone didn't show anti-tumor growth effect or survival advantage in vivo, a combination of AZD6918 and etoposide had a statistically significant stronger anti-tumor growth effect and survival advantage compared to treatment with either agent alone. Our data indicate that as a Trk inhibitor AZD6918 increased the sensitivity of NB to etoposide. These results extend the spectrum of cytotoxic drugs whose efficacy is increased in combination with Trk inhibitors and support the combination of Trk inhibitors and cytotoxic drugs for NB treatment. PMID- 25700943 TI - Percutaneous computed tomography-guided cryoablation for renal tumor: Experience in 30 cases. AB - BACKGROUND: Percutaneous cryoablation is a minimally invasive alternative for surgical resection of a renal tumor. We report our experience with applying computed tomography-guided cryoablation in renal tumors, focusing on the technique, safety, and treatment response. METHODS: We retrospectively reviewed the medical records of patients who received cryoablation from October 2009 to August 2013 for renal tumor diagnosed by imaging studies performed at Taipei Veterans General Hospital, Taipei, Taiwan. Patient comorbidities and tumor morphology, technical success rate, tumor control rate, renal function change, and complications were recorded. RESULTS: A total of 30 patients (32 tumors) were treated, comprising 30 renal cell carcinomas and two angiomyolipomas. The mean age of the patients was 73.7 years (range, 34-89 years). The patients were referred for percutaneous cryoablation arising from old age, medical comorbidities, or preexisting malignancy. The mean follow-up period was 15.2 months (range, from 32 days to 47.4 months). According to the Clavien-Dindo classification, surgical complications included one Grade III, four Grade II, and two Grade I complications. The mean decrease in hemoglobin was 0.77 g/dL (range, from +1.1 g/dL to -3 g/dL). The mean hospital stay after cryoablation was 2.2 days (range, 1-10 days). Incomplete ablation was noted in two patients and local tumor recurrence in two patients. One of them received repeated cryoablation and achieved successful local control. Of the 22 renal cell carcinoma patients with follow-up period > 6 months, 19 patients achieved successful local tumor control (86.4%). The percentage change of glomerular filtration rate before and 3-6 months after the procedure was +1.9%, which was statistically nonsignificant (p = 0.94). CONCLUSION: Computed tomography-guided percutaneous cryoablation is a safe and effective technique for treating renal tumors with excellent renal function preservation. PMID- 25700944 TI - Effects of fatigue on cognitive control in neurosarcoidosis. AB - Fatigue is a usual reaction to prolonged performance but also a major symptom in various neuroimmunological diseases. In neurosarcoidosis fatigue is a core symptom, but little is known about the relevance of fatigue on cognitive functions in this disease. Previous results in healthy subjects suggest that fatigue strongly affects cognitive control processes. However, fatigue is not a uni-dimensional construct but consists of different facets. It is unknown which of these facets are most important for mechanisms of cognitive control. In the current study we investigate conflict monitoring and response selection processes in neurosarcoidosis patients as a 'model disease' of fatigue and healthy controls in relation to the impact of 'cognitive' and 'motor fatigue' on these processes using event-related potentials (ERPs). We focus on ERPs reflecting attentional selection (P1, N1) and conflict monitoring/response selection processes (N2). ERPs reflecting attentional selection processes were unchanged. The N2 on incompatible trials was reduced in neurosarcoidosis suggesting that response selection and conflict monitoring functions are dysfunctional. Of note, fatigue strongly modulates responses selection processes in conflicting situations (N2) in controls and neurosarcoidosis, but the effect of fatigue on these processes was stronger in neurosarcoidosis. Neuroimmunological parameters like TNF-alpha and soluble interleukin-2 receptor serum concentrations do not seem to modulate the pattern of results. Concerning fatigue it seems to be the 'cognitive' dimension and not the 'motor' dimension that is of relevance for the modulation of response selection in conflicting situations. PMID- 25700945 TI - 17alpha-hydroxyprogesterone caproate access in the Louisiana Medicaid population. AB - Preterm birth and its associated neonatal morbidities remain pertinent health care and economic issues in the United States. Progesterone supplementation in the form of 17alpha-hydroxyprogesterone caproate has been reported to reduce the risk for recurrent preterm birth in women with a prior spontaneous preterm delivery, but several barriers contribute to its underutilization. The Affordable Care Act has increased the number of women receiving insurance coverage for pre- and perinatal care. However, the increase in insurance coverage has not necessarily facilitated access to standard therapies such as progesterone for the prevention of preterm birth. Data from Louisiana illustrate this point, and the state has responded by developing educational programs and the nation's first pay for-performance strategy targeting the initiation of progesterone therapy. PMID- 25700946 TI - alphaCaMKII autophosphorylation mediates neuronal activation in the hippocampal dentate gyrus after alcohol and cocaine in mice. AB - Psychoactive drug-induced cellular activation is a key mechanism to promote neuronal plasticity and addiction. Alpha Ca(2+)/calmodulin-dependent protein kinase II (alphaCaMKII) and its autophosphorylation play a key role in the development of drug use associated behaviours. It has been suggested that alphaCaMKII autophosphorylation is necessary for drug-induced neuronal activation in the mesolimbic system. Here, we show an alcohol- and cocaine-induced increase in c-fos expression in the hippocampal dentate gyrus, which is absent in alphaCaMKII(T286A) autophosphorylation deficient mice. These findings may suggest a role in hippocampal alphaCaMKII autophosphorylation in the acute neuroplastic effects of alcohol and cocaine. PMID- 25700947 TI - Effects of acute CDP-choline treatment on resting state brain oscillations in healthy volunteers. AB - CDP-choline (cytidine-5'-diphosphocholine) is a phospholipid used to treat cognitive disorders, presumably repairing and maintaining brain cell membranes. Additional mechanisms may include enhanced cholinergic neurotransmission as the alpha7 nicotinic receptor actions of choline and increased acetylcholine synthesis accompanying CDP-choline administration may modulate brain oscillations underlying cognitive processes. This study utilizes electroencephalographic (EEG) recordings in healthy volunteers to evaluate CDP-choline induction of an oscillatory response profile associated with nicotinic stimulation. Resting state EEG was acquired in 24 male volunteers administered low (500mg) and moderate (1000mg) doses of CDP-choline in a randomized placebo-controlled, crossover trial. Consistent with nicotinic agonist treatment, spectral analysis showed dose dependent reductions in delta and increases in alpha oscillations, which were also accompanied by decreases in beta and gamma oscillatory activity. These findings support the posit that CDP-choline cognitive enhancement involves multiple mechanisms including facilitated nicotinic cholinergic action. PMID- 25700948 TI - The retino-retinal projection: Tracing retinal ganglion cells projecting to the contralateral retina. AB - We investigated the presence of a direct retino-retinal (R-R) projection between the two eyes via the optic chiasm of retinal ganglion cells (RGCs) in adult Long Evans rats. We also explored the presence of collateral projections originating from these cells to the brain. In the first group of animals, right optic nerves (ONs) were orbitally transected approximately 2mm behind the globe followed by application of fluorochrome (2% Fluorogold [FG]) to the optic nerve stump to retrogradely label the R-R projection RGCs (R-RGCs) on the contralateral side. Animals were then sacrificed after 3, 5, 7, or 21 days. Contralateral retinas were fixed, whole-mounted, and imaged for R-RGCs. In a second group of animals, RGCs were retrogradely labeled with 15% rhodamine-beta-isothiocynate (RITC) at the superior colliculi, where approximately 96% of rat RGCs synapse. Seven days later, the right ONs were transected and 2% FG applied to the proximal and distal ON stumps. Animals were then sacrificed after 5 days. Contralateral retinas were examined for co-labeled (RITC/FG) RGCs. Control rats underwent the same procedures excluding fluorescent tracer application. In the first group of animals, the number of R-RGCs in the contralateral eye ranged from 3 to 25 and did not depend on survival time. The second group of animals revealed evidence of co-labeled contralateral RGCs. Results suggest that a greater number of R-RGCs persist into adulthood than previously reported [M. Muller, H. Hollander, 1988]. Furthermore, the presence of co-labeled RGCs in the contralateral eye indicates that in adult rodents some R-R projections have a collateral projection to the brain, whereas previous reports had only found collateral projections in newborns. PMID- 25700949 TI - Functional connectivity during rested wakefulness predicts vulnerability to sleep deprivation. AB - Significant inter-individual differences in vigilance decline following sleep deprivation exist. We characterized functional connectivity in 68 healthy young adult participants in rested wakefulness and following a night of total sleep deprivation. After whole brain signal regression, functionally connected cortical networks during the well-rested state exhibited reduced correlation following sleep deprivation, suggesting that highly integrated brain regions become less integrated during sleep deprivation. In contrast, anti-correlations in the well rested state became less so following sleep deprivation, suggesting that highly segregated networks become less segregated during sleep deprivation. Subjects more resilient to vigilance decline following sleep deprivation showed stronger anti-correlations among several networks. The weaker anti-correlations overlapped with connectivity alterations following sleep deprivation. Resilient individuals thus evidence clearer separation of highly segregated cortical networks in the well-rested state. In contrast to corticocortical connectivity, subcortical cortical connectivity was comparable across resilient and vulnerable groups despite prominent state-related changes in both groups. Because sleep deprivation results in a significant elevation of whole brain signal amplitude, the aforesaid signal changes and group contrasts may be masked in analyses omitting their regression, suggesting possible value in regressing whole brain signal in certain experimental contexts. PMID- 25700950 TI - Understanding fiber mixture by simulation in 3D Polarized Light Imaging. AB - 3D Polarized Light Imaging (3D-PLI) is a neuroimaging technique that has opened up new avenues to study the complex architecture of nerve fibers in postmortem brains. The spatial orientations of the fibers are derived from birefringence measurements of unstained histological brain sections that are interpreted by a voxel-based analysis. This, however, implies that a single fiber orientation vector is obtained for each voxel and reflects the net effect of all comprised fibers. The mixture of various fiber orientations within an individual voxel is a priori not accessible by a standard 3D-PLI measurement. In order to better understand the effects of fiber mixture on the measured 3D-PLI signal and to improve the interpretation of real data, we have developed a simulation method referred to as SimPLI. By means of SimPLI, it is possible to reproduce the entire 3D-PLI analysis starting from synthetic fiber models in user-defined arrangements and ending with measurement-like tissue images. For the simulation, each synthetic fiber is considered as an optical retarder, i.e., multiple fibers within one voxel are described by multiple retarder elements. The investigation of different synthetic crossing fiber arrangements generated with SimPLI demonstrated that the derived fiber orientations are strongly influenced by the relative mixture of crossing fibers. In case of perpendicularly crossing fibers, for example, the derived fiber direction corresponds to the predominant fiber direction. The derived fiber inclination turned out to be not only influenced by myelin density but also systematically overestimated due to signal attenuation. Similar observations were made for synthetic models of optic chiasms of a human and a hooded seal which were opposed to experimental 3D-PLI data sets obtained from the chiasms of both species. Our study showed that SimPLI is a powerful method able to test hypotheses on the underlying fiber structure of brain tissue and, therefore, to improve the reliability of the extraction of nerve fiber orientations with 3D-PLI. PMID- 25700951 TI - Cortical networks dynamically emerge with the interplay of slow and fast oscillations for memory of a natural scene. AB - Neural oscillations are crucial for revealing dynamic cortical networks and for serving as a possible mechanism of inter-cortical communication, especially in association with mnemonic function. The interplay of the slow and fast oscillations might dynamically coordinate the mnemonic cortical circuits to rehearse stored items during working memory retention. We recorded simultaneous EEG-fMRI during a working memory task involving a natural scene to verify whether the cortical networks emerge with the neural oscillations for memory of the natural scene. The slow EEG power was enhanced in association with the better accuracy of working memory retention, and accompanied cortical activities in the mnemonic circuits for the natural scene. Fast oscillation showed a phase amplitude coupling to the slow oscillation, and its power was tightly coupled with the cortical activities for representing the visual images of natural scenes. The mnemonic cortical circuit with the slow neural oscillations would rehearse the distributed natural scene representations with the fast oscillation for working memory retention. The coincidence of the natural scene representations could be obtained by the slow oscillation phase to create a coherent whole of the natural scene in the working memory. PMID- 25700952 TI - Morphological covariance in anatomical MRI scans can identify discrete neural pathways in the brain and their disturbances in persons with neuropsychiatric disorders. AB - We hypothesize that coordinated functional activity within discrete neural circuits induces morphological organization and plasticity within those circuits. Identifying regions of morphological covariation that are independent of morphological covariation in other regions therefore may therefore allow us to identify discrete neural systems within the brain. Comparing the magnitude of these variations in individuals who have psychiatric disorders with the magnitude of variations in healthy controls may allow us to identify aberrant neural pathways in psychiatric illnesses. We measured surface morphological features by applying nonlinear, high-dimensional warping algorithms to manually defined brain regions. We transferred those measures onto the surface of a unit sphere via conformal mapping and then used spherical wavelets and their scaling coefficients to simplify the data structure representing these surface morphological features of each brain region. We used principal component analysis (PCA) to calculate covariation in these morphological measures, as represented by their scaling coefficients, across several brain regions. We then assessed whether brain subregions that covaried in morphology, as identified by large eigenvalues in the PCA, identified specific neural pathways of the brain. To do so, we spatially registered the subnuclei for each eigenvector into the coordinate space of a Diffusion Tensor Imaging dataset; we used these subnuclei as seed regions to track and compare fiber pathways with known fiber pathways identified in neuroanatomical atlases. We applied these procedures to anatomical MRI data in a cohort of 82 healthy participants (42 children, 18 males, age 10.5 +/- 2.43 years; 40 adults, 22 males, age 32.42 +/- 10.7 years) and 107 participants with Tourette's Syndrome (TS) (71 children, 59 males, age 11.19 +/- 2.2 years; 36 adults, 21 males, age 37.34 +/- 10.9 years). We evaluated the construct validity of the identified covariation in morphology using DTI data from a different set of 20 healthy adults (10 males, mean age 29.7 +/- 7.7 years). The PCA identified portions of structures that covaried across the brain, the eigenvalues measuring the magnitude of the covariation in morphology along the respective eigenvectors. Our results showed that the eigenvectors, and the DTI fibers tracked from their associated brain regions, corresponded with known neural pathways in the brain. In addition, the eigenvectors that captured morphological covariation across regions, and the principal components along those eigenvectors, identified neural pathways with aberrant morphological features associated with TS. These findings suggest that covariations in brain morphology can identify aberrant neural pathways in specific neuropsychiatric disorders. PMID- 25700953 TI - In vivo imaging of tau pathology using multi-parametric quantitative MRI. AB - As the number of people diagnosed with Alzheimer's disease (AD) reaches epidemic proportions, there is an urgent need to develop effective treatment strategies to tackle the social and economic costs of this fatal condition. Dozens of candidate therapeutics are currently being tested in clinical trials, and compounds targeting the aberrant accumulation of tau proteins into neurofibrillary tangles (NFTs) are the focus of substantial current interest. Reliable, translatable biomarkers sensitive to both tau pathology and its modulation by treatment along with animal models that faithfully reflect aspects of the human disease are urgently required. Magnetic resonance imaging (MRI) is well established as a valuable tool for monitoring the structural brain changes that accompany AD progression. However the descent into dementia is not defined by macroscopic brain matter loss alone: non-invasive imaging measurements sensitive to protein accumulation, white matter integrity and cerebral haemodynamics probe distinct aspects of AD pathophysiology and may serve as superior biomarkers for assessing drug efficacy. Here we employ a multi-parametric array of five translatable MRI techniques to characterise the in vivo pathophysiological phenotype of the rTg4510 mouse model of tauopathy (structural imaging, diffusion tensor imaging (DTI), arterial spin labelling (ASL), chemical exchange saturation transfer (CEST) and glucose CEST). Tau-induced pathological changes included grey matter atrophy, increased radial diffusivity in the white matter, decreased amide proton transfer and hyperperfusion. We demonstrate that the above markers unambiguously discriminate between the transgenic group and age-matched controls and provide a comprehensive profile of the multifaceted neuropathological processes underlying the rTg4510 model. Furthermore, we show that ASL and DTI techniques offer heightened sensitivity to processes believed to precede detectable structural changes and, as such, provides a platform for the study of disease mechanisms and therapeutic intervention. PMID- 25700954 TI - Quantitative tract-based white matter heritability in twin neonates. AB - Studies in adults indicate that white matter microstructure, assessed with diffusion tensor imaging (DTI), has high heritability. Little is known about genetic and environmental influences on DTI parameters, measured along fiber tracts particularly, in early childhood. In the present study, we report comprehensive heritability data of white matter microstructure fractional anisotropy (FA), radial diffusion (RD), and axial diffusion (AD) along 47 fiber tracts using the quantitative tractography in a large sample of neonatal twins (n=356). We found significant genetic influences in almost all tracts with similar heritabilities for FA, RD, and AD as well as positive relationships between these parameters and heritability. In a single tract analysis, genetic influences along the length of the tract were highly variable. These findings suggest that at birth, there is marked heterogeneity of genetic influences of white matter microstructure within white matter tracts. This study provides a basis for future studies of developmental changes in genetic and environmental influences during early childhood, a period of rapid development that likely plays a major role in individual differences in white matter structure and function. PMID- 25700955 TI - Perigenual anterior cingulate event-related potential precedes stop signal errors. AB - Momentary lapses in attention disrupt goal-directed behavior. Attentional lapse has been associated with increased "default-mode" network (DMN) activity. In our previous fMRI study of a stop signal task (SST), greater activation of the perigenual anterior cingulate cortex (pgACC) - an important node of the DMN - predicts stop signal errors. In event-related potential (ERP) studies, the amplitude of an error-preceding positivity (EPP) also predicts response error. However, it is not clear whether the EPP originates from DMN regions. Here, we combined high-density array EEG and an SST to examine response-locked ERPs of error preceding trials in twenty young adult participants. The results showed an EPP in go trials that preceded stop error than stop success trials. Importantly, source modeling identified the origin of the EPP in the pgACC. By employing a bootstrapping procedure, we further confirmed that pgACC rather than the dorsal ACC as the source provides a better fit to the EPP. Together, these results suggest that attentional lapse in association with EPP in the pgACC anticipates failure in response inhibition. PMID- 25700956 TI - Noun plural production in preschoolers with early cochlear implantation: an experimental study of Dutch and German. AB - OBJECTIVES: Studies investigating language skills of children after cochlear implantation usually present general measures of expressive/receptive vocabulary and grammar and rarely tackle the acquisition of specific language phenomena (word classes, grammatical constructions, word forms, etc.). Furthermore, research is largely restricted to children acquiring English. Cross-linguistic comparisons among children acquiring different languages are almost inexistent. The present study targets the acquisition of noun plurals (e.g., dogs, balls) by Dutch- and German-speaking children implanted before their second birthday. Given its structural complexity and irregularity, noun plural formation is a good indicator of grammatical proficiency in children at risk for a developmental delay. METHODS: The study sample consisted of 14 cochlear-implanted (CI) children (M=55 months of age), 80 age-matched normally hearing (NH) controls, and 40 normally hearing controls matched by Hearing Age (HA). The children were administered an elicitation task in which they had to provide plural forms to a set of singular nouns. The analysis focussed on the following variables: Hearing status (CI, NH), Language (Dutch, German), and Suffix Predictability/Stem Transparency of the plural words. RESULTS: There was no significant difference between children with CI and their NH peers in correct plural production. In both child groups, plural responses followed the predicted pattern of Suffix Predictability/Stem Transparency. However, children with CI significantly more frequently replied to the test item with a recast of the singular noun instead of the plural, and the probability of these responses increased with later age of CI implantation. Furthermore, Dutch-speaking children showed an overall better performance than German-speaking children. CONCLUSIONS: The findings suggest that after 3 years of implant use, preschoolers with early cochlear implantation show age-appropriate patterns of noun plural formation, but still have to catch up with respect to associating a particular singular with its plural form. PMID- 25700957 TI - Temporal characteristics of nasalization in Persian speaker children with and without cleft palate. AB - OBJECTIVES: The purpose of this study was to measure and compare temporal patterns of nasalization in Persian children with and without cleft palate in three vowel contexts. METHODS: A Sample of 14 children with repaired cleft palates with or without cleft lip with moderate to severe hyper nasality and 14 children without cleft palate was chosen as subjects. The subjects were chosen from the ages of 4 to 12 years. The nasal onset interval, nasal offset interval and total nasalization duration were obtained from acoustic waveforms and spectrograms in three vowel contexts using Praat Software. For eliminating the effect of different speed of speech in the cleft palate group and control group, the ratio of nasalization duration was calculated. RESULTS: Total nasalization duration are demonstrated by acoustic signals which shows the total significant different temporal patterns in children with cleft palate and without cleft palate and across the vowel contexts (P<0.000). CONCLUSIONS: Longer nasalization durations in children with cleft palate in comparison to children without cleft palate show the delayed or deviant temporal patterns in children with cleft palate. The duration of nasalization reflecting temporal patterns of the oral nasal acoustic impedance in children with cleft palate may have an influence on the perception of hyper nasality. PMID- 25700958 TI - [Perioperative acetylsalicylic acid and clonidine in noncardiac surgery patients (POISE-2 trial)]. PMID- 25700959 TI - [Thoracic epidural anesthesia for open cholecystectomy in severe lung disease. Description of a case and review of the literature]. AB - The incidence of chronic obstructive pulmonary disease has increased in the last decade. The anesthetic management of these patients in upper abdomen surgery is a challenge to the anesthesiologist, since general anesthesia is associated with a high possibility of severe pulmonary complications. The search for a suitable alternative has been a subject of study for years. The case is presented of a patient with chronic obstructive pulmonary disease, who required an urgent cholecystectomy. The treatment of the case and brief review of the literature is presented. PMID- 25700960 TI - The (not so) immortal strand hypothesis. AB - BACKGROUND: Non-random segregation of DNA strands during stem cell replication has been proposed as a mechanism to minimize accumulated genetic errors in stem cells of rapidly dividing tissues. According to this hypothesis, an "immortal" DNA strand is passed to the stem cell daughter and not the more differentiated cell, keeping the stem cell lineage replication error-free. After it was introduced, experimental evidence both in favor and against the hypothesis has been presented. PRINCIPAL FINDINGS: Using a novel methodology that utilizes cancer sequencing data we are able to estimate the rate of accumulation of mutations in healthy stem cells of the colon, blood and head and neck tissues. We find that in these tissues mutations in stem cells accumulate at rates strikingly similar to those expected without the protection from the immortal strand mechanism. SIGNIFICANCE: Utilizing an approach that is fundamentally different from previous efforts to confirm or refute the immortal strand hypothesis, we provide evidence against non-random segregation of DNA during stem cell replication. Our results strongly suggest that parental DNA is passed randomly to stem cell daughters and provides new insight into the mechanism of DNA replication in stem cells. PMID- 25700961 TI - Epitope-specificities of HLA antibodies: the effect of epitope structure on Luminex technique-dependent antibody reactivity. AB - The search of HLA antibodies is currently more accessible by solid-phase techniques (Luminex) in the immunized patients leading to an expansion of the antibody patterns. The aim of this study was to investigate low median fluorescence intensity value in unexpected reactivity patterns. Here, we performed HLAMatchmaker analyses to evaluate the potential functional epitopes that can elicit HLA-specific alloantibody responses in a pregnancy-sensitized woman with an epitope defined by the 82LR. Surprisingly, in according to the registry of HLA epitopes, we found that 82LR epitope covered all allelic specificities of our unexpected antibody patterns, shared between Bw4-positive HLA-B antigen and HLA-A23, -A24, -A25 and -A32. This finding is consistent with the verification of HLA ABC epitope recorded in the website-based HLA Epitope Registry and addresses the importance of determining HLA antibody epitope specificities on Luminex technique-dependent antibody reactivity. PMID- 25700962 TI - IL-36alpha induces maturation of Th1-inducing human MDDC and synergises with IFN gamma to induce high surface expression of CD14 and CD11c. AB - We show that IL-36alpha induced maturation of human MDDCs and stimulated differentiation of IFN-gamma producing (Type 1) CD3+ lymphocytes but was not as effective as IL-36beta in doing so. For the first time, we also show that IL 36alpha induced expression of CD14 by MDDCs and this was highly potentiated by co cultured with IFN-gamma. In contrast, lipopolysaccharide (LPS) did not increase CD14 expression by MDDCs, suggesting that if MDDCs represent a physiologically relevant population in vivo, they need to be stimulated by relevant inflammatory cytokines prior to CD14 expression and detection of LPS, expressed by Gram negative bacteria. IFN-gamma synergised with IL-36alpha to restore the high levels of CD11c expression by MDDCs, which was reduced by culture with these cytokines in isolation. IL-36alpha/IFN-gamma synergy also correlated with increased binding of the opsonic complement protein (iC3b) to MDDCs. However although IL-36alpha increased the phagocytic capacity of MDDCs for Salmonella Typhimurium 4/74 this was not synergistically increased by IFN-gamma (P>0.05). In conclusion we report the hitherto unknown effects of IL-36alpha on the innate cell function of human MDDCs. PMID- 25700963 TI - HLA associations and HLA sharing in recurrent miscarriage: A systematic review and meta-analysis. AB - PROBLEM: The aim of this meta-analysis was to evaluate whether specific maternal HLA alleles and HLA sharing of couples are associated with the occurrence of recurrent miscarriage (RM). METHOD OF STUDY: A systematic literature search was performed for studies that evaluated the association between HLA alleles, HLA sharing and RM. RM was defined as three or more consecutive unexplained miscarriages and a control group was included of women with at least one live birth and no miscarriages in their history. Meta-analyses were performed and the pooled odds ratio (OR) was calculated. RESULTS: We included 41 studies. Selection bias was present in 40 studies and information bias in all studies. Meta-analyses showed an increased risk of RM in mothers carrying a HLA-DRB1*4 (OR 1.41, 95% CI 1.05-1.90), HLA-DRB1*15 (OR 1.57, 95% CI 1.15-2.14), or a HLA-E*01:01 allele (OR 1.47, 95% CI 0.20-1.81), and a decreased risk with HLA-DRB1*13 (OR 0.63, 95% CI 0.45-0.89) or HLA-DRB1*14 (OR 0.54, 95% CI 0.31-0.94). Pooling results for HLA sharing showed that HLA-B sharing (OR 1.39, 95% CI 1.11-1.75) and HLA-DR sharing (OR 1.57, 95% CI 1.10-1.25) were both associated with the occurrence of RM. CONCLUSION: Although the present systematic review and meta-analysis demonstrates that specific HLA alleles and HLA sharing are associated with RM, a high degree of bias was present and therefore observed results should be interpreted carefully. PMID- 25700964 TI - Spatiotemporal expression analysis of Prdm1 and Prdm1 binding partners in early chick embryo. AB - Prdm1 is a global repressor of transcription that plays multiple important roles during embryonic development, including neural crest specification. Prdm1 acts by repressing large sets of genes via sequence-specific recruitment of co repressors, many of which are epigenetic modifiers. It is not known whether Prdm1 is expressed during neural crest development in chick embryo. Moreover, the mechanism of Prdm1 action or the nature of possible binding partners that mediate its effects in the neural crest had not yet been addressed. Prdm1 binding partners are known to play important roles during embryonic development, yet in many cases no spatiotemporal expression analysis during early vertebrate development has been performed. In this paper we report the expression patterns of Prdm1 and seven of its known or putative binding partners (Hdac1 and 2, Tle1 and 3, G9a, Prmt5, Lsd1) during early stages of chicken embryogenesis. Prdm1 is expressed in the neural plate border and premigratory neural crest during chick development. Six Prdm1 binding partners (except Tle1) are co-expressed with Prdm1 in the prospective neural plate border at HH4-HH6, and all seven show strong and specific expression in the neural plate border at HH7-HH8, suggesting all of them may cooperate with Prdm1 during neural crest development in chick embryos. PMID- 25700965 TI - Dietary sources of calcium among parents and their early adolescent children in the United States by parent race/ethnicity and place of birth. AB - Dietary calcium sources may differ by race/ethnicity and dietary acculturation. A cross-sectional, convenience sample including 587 United States (US) Asian, Hispanic and non-Hispanic White parent-child (10-13 years) pairs completed a calcium food frequency questionnaire. Calcium sources were ranked by mean percent contribution to total adjusted calcium intake, and compared by ethnic group and parents' location of birth. Five foods (fluid milk, cheese, milk on cereal, yogurt, and lattes) represented 49% of total calcium intake for parents. The same foods (except lattes) represented 55% of total calcium for early adolescent children. Fluid milk provided the largest mean percentage of intake for all race/ethnic groups among parents and children. Several food sources of calcium were greater for foreign-born versus US-born Asian or Hispanic parents and children. Understanding calcium food sources and changes in dietary patterns that affect calcium intake among parents and children is important to better promote adequate intake. PMID- 25700966 TI - Let's talk. PMID- 25700967 TI - Do initial tidal volumes impact acute respiratory distress syndrome development in patients intubated in the emergency department? PMID- 25700968 TI - "Extraoperative" MRI (eoMRI) for Brain Tumor Surgery: Initial Results at a Single Institution. AB - BACKGROUND: There is accumulating evidence that extent of resection (EOR) in intrinsic brain tumor surgery prolongs overall survival (OS) and progression-free survival (PFS). One of the strategies to increase EOR is the use of intraoperative MRI (ioMRI); however, considerable infrastructure investment is needed to establish and maintain a sophisticated ioMRI. We report the preliminary results of an extraoperative (eoMRI) protocol, with a focus on safety, feasibility, and EOR in intrinsic brain tumor surgery. METHODS: Ten patients underwent an eoMRI protocol consisting of surgical resection in a conventional operating room followed by an immediate MRI in a clinical MRI scanner while the patient was still under anesthesia. If findings of the MRI suggested residual safely resectable tumor, the patient was returned to the operating room. A retrospective volumetric analysis was undertaken to investigate the percentage of tumor resected after first resection and if applicable, after further resection. RESULTS: Six of 10 (60%) patients were thought to require no further resection after eoMRI. The EOR in these patients was 97.8% +/- 1.8%. In the 4 patients who underwent further resection, the EOR during the original surgery was 88.5% +/- 9.5% (P = 0.04). There was an average of 10.1% more tumor removed between the first and second surgery. In 3 of 4 (75%) of patients who returned for further resection, gross total resection of tumor was achieved. CONCLUSION: An eoMRI protocol appears to be a safe and practical method to ensure maximum safe resections in patients with brain tumors and can be performed readily in all centers with MRI capabilities. PMID- 25700969 TI - Intracranial Fungal Granulomas: A Single Institutional Clinicopathologic Study of 66 Patients and Review of the Literature. AB - INTRODUCTION: Fungal granulomas of the central nervous system are rare and have a high rate of mortality and morbidity, irrespective of treatment. The authors report their experience of managing 66 patients during 15 years and discuss the clinical, radiological, surgical, and pathologic findings. This series is among the largest reported. MATERIAL AND METHODS: A retrospective analysis was performed on patients with intracranial fungal granulomas (ICFGs), treated in the authors' institution, between January 1997 and May 2011. Only mass-forming histopathologically proven ICFGs were included in this study. RESULTS: The age of the patients ranged from 7 years to 67 years (mean = 32.3 years), and most patients were in the third and fourth decades of life. The study population comprised 47 male and 19 female patients. The most common symptom was headache (41 patients), followed by vomiting (16 patients) and blurring of vision (16 patients). Only 3 patients presented with fever. The duration of symptoms was less than 6 months in all cases and less than 3 months in 39 cases. Anterior cranial fossa and frontal lobe was involved in 35 cases (54.5%), followed by middle cranial fossa in 20 cases (30.3%). Three cases had granulomas in the cerebellopontine angle. Three cases had multicompartmental involvement, and 4 had multilobar involvement. Nine patients had predisposing factors for fungal infection Based on clinical and imaging data, preoperative diagnosis of a possible fungal lesion was made in 44 (some had only computed tomography imaging) patients. All the patients were treated surgically, followed by antifungal treatment with amphotericin-B and/fluconazole/itraconazole for a period of 6 weeks. Eight patients had symptomatic recurrence of lesions 3-12 weeks after treatment and underwent reoperation. Six patients were lost to follow-up. Nine patients died in the postoperative period (within 30 days postoperatively). Fifteen patients died during follow-up because of recurrent lesions, repeat surgery, renal failure, and unrelated causes. Overall mortality was 24 (36.3%). Poor neurologic status before surgery, emergency craniotomy, severe brain edema with mass effect, and opening of ventricles during surgery were associated with poor outcome. Aspergillus species were the causative organism in an overwhelming majority of patients (n = 52) followed by Mucor in 7 cases, Cladosporium in 3 cases, eumycetoma in 2 cases, and maduramycosis and blastomycosis in 1 case each. CONCLUSION: ICFGs have high rates of morbidity and mortality. Early diagnosis, radical surgery, and antifungal treatment for 6 weeks may improve outcome. Poor neurologic status of patients at the time of presentation, immunocompromised state, contamination of ventricular cerebrospinal during surgery, and renal failure (attributable to amphotericin-B) are associated with poor outcome. PMID- 25700970 TI - Which Routes for Petroclival Tumors? A Comparison Between the Anterior Expanded Endoscopic Endonasal Approach and Lateral or Posterior Routes. AB - OBJECTIVE: Petroclival tumors remain a surgical challenge. Classically, the retrosigmoid approach (RSA) has long been used to reach such tumors, whereas the anterior petrosectomy (AP) has been proposed to avoid crossing cranial nerves. More recently, the endoscopic endonasal approach has been "expanded" (i.e., EEEA) to the petroclival region. We aimed to compare these 3 approaches to help in the surgical management of petroclival tumors. METHODS: Petroclival approaches were performed on 5 specimens after they were prepared with formaldehyde colored via latex injection. RESULTS: The EEEA provides a simple straightforward route to the clivus, but reaching the petrous apex requires the surgeon to circumvent the internal carotid artery either via a medial transclival, an inferior transpterygoid, or a lateral variant through the Meckel's cave. In contrast, the AP offers a narrow direct superolateral access to the petroclival region crossed by the trigeminal nerve. Finally, the RSA provides a wide simple and quick exposure of the cerebellopontine angle, but access to the petroclival region needs the surgeon to deal with the V(th) to XI(th) cranial nerves. DISCUSSION/CONCLUSION: The EEEA should be preferred for extradural midline tumors (chordomas, chondrosarcomas) or for cystic lesions when drainage is essential. The AP could be optimal for the radical removal of intradural vascularized tumors (meningiomas) with intrapetrous or supratentorial extensions. The RSA retains an advantage for small or cystic tumors near the internal acoustic meatus. The skull base surgeon has to master all of these routes to choose the more appropriate one according to the surgical objective, the tumor characteristics, and the patient's medical status. PMID- 25700971 TI - Stereotactic Radiosurgery as the Initial Treatment for Patients with Nonfunctioning Pituitary Adenomas. AB - OBJECTIVE: The aim of this study was to confirm the efficacy and safety of stereotactic radiosurgery as the initial treatment for patients with nonfunctioning pituitary adenomas (NFPAs) and to decide the optimum dose to achieve long-term tumor control as well as preservation of pituitary endocrine function. METHODS: The study was a single-center retrospective analysis of 16 patients with primary NFPAs that were treated with gamma knife surgery (GKS). Fifteen of 16 NFPAs were growing to the suprasellar region and slightly compressing or very close to the optic apparatus. Initial GKS was selected to avoid visual disturbance caused by further tumor growth that would require surgical resection under general anesthesia. The median tumor volume was 2.0 cm(3), and the median tumor margin dose was 15 Gy. RESULTS: The median clinical follow-up period was 98 months. The last follow-up images demonstrated tumor regression in 15 patients and stable tumor in 1. No patient developed tumor progression. One patient who had pituitary apoplexy before treatment required hormone replacements 2 years after GKS. The other patients did not experience pituitary insufficiency requiring hormone-replacement therapy during the clinical follow-up period. No patient developed cranial nerve injury or radiation-induced neoplasm. CONCLUSIONS: GKS is a safe and effective treatment option in patients with primary NFPAs, especially for patients with advanced age or comorbidity. Attention should be paid to late adverse radiation effects such as hypopituitarism, optic neuropathy, and radiation-induced neoplasms. However, stereotactic radiosurgery with a conformal treatment plan sparing the normal pituitary gland will contribute to avoidance of such complications as well as achievement of long-term tumor control. PMID- 25700972 TI - Rescue Bypass for Revascularization After Ischemic Complications in the Treatment of Giant or Complex Intracranial Aneurysms. AB - BACKGROUND: Surgical trapping or endovascular deconstruction commonly is used for the treatment of giant or complex intracranial aneurysms. Preoperative balloon test occlusion and cerebral blood flow studies and intraoperative neurophysiologic monitoring can indicate whether sufficient collateralization exists or whether revascularization is needed. Hemodynamic insufficiency can occur, however, despite passing these tests, necessitating posttreatment revascularization. METHODS: We conducted a retrospective review of patients who underwent surgical or endovascular parent vessel occlusion for the management of giant or complex intracranial aneurysms and subsequently required rescue bypass for symptoms of hemodynamic insufficiency. Pre- and postrevascularization functional status was measured with the modified Rankin Scale. RESULTS: During a 15-year period from 1997 to 2012, a rescue bypass was performed in 5 patients each harboring a giant or complex intracranial internal carotid artery (ICA) aneurysm that was treated with surgical trapping or endovascular deconstruction in a previous procedure. All bypasses were extracranial-to-intracranial and included cervical ICA to middle cerebral artery, subclavian to middle cerebral artery, and cervical ICA to supraclinoid ICA anastomoses via either a saphenous vein or radial artery graft. Functional outcome at time of last follow-up was improved in each patient (improvement in modified Rankin Scale of 1-3 points). CONCLUSIONS: Ischemic complications must always be anticipated in the treatment of giant or complex intracranial aneurysms, even if pre- and intraoperative blood flow studies indicate sufficient collateralization. Here we show that extracranial-to-intracranial bypass is an effective option to rescue unanticipated hemodynamic insufficiency after parent vessel occlusion. This study emphasizes the need for cerebrovascular surgeons to maintain proficiency in complex bypass techniques. PMID- 25700973 TI - The adult murine heart has a sparse, phagocytically active macrophage population that expands through monocyte recruitment and adopts an 'M2' phenotype in response to Th2 immunologic challenge. AB - Tissue resident macrophages have vital homeostatic roles in many tissues but their roles are less well defined in the heart. The present study aimed to identify the density, polarisation status and distribution of macrophages in the healthy murine heart and to investigate their ability to respond to immune challenge. Histological analysis of hearts from CSF-1 receptor (csf1-GFP; MacGreen) and CX3CR1 (Cx3cr1(GFP/+)) reporter mice revealed a sparse population of GFP positive macrophages that were evenly distributed throughout the left and right ventricular free walls and septum. F4/80+CD11b+ cardiac macrophages, sorted from myocardial homogenates, were able to phagocytose fluorescent beads in vitro and expressed markers typical of both 'M1' (IL-1beta, TNF and CCR2) and 'M2' activation (Ym1, Arg 1, RELMalpha and IL-10), suggesting no specific polarisation in healthy myocardium. Exposure to Th2 challenge by infection of mice with helminth parasites Schistosoma mansoni, or Heligmosomoides polygyrus, resulted in an increase in cardiac macrophage density, adoption of a stellate morphology and increased expression of Ym1, RELMalpha and CD206 (mannose receptor), indicative of 'M2' polarisation. This was dependent on recruitment of Ly6ChighCCR2+ monocytes and was accompanied by an increase in collagen content. In conclusion, in the healthy heart resident macrophages are relatively sparse and have a phagocytic role. Following Th2 challenge this population expands due to monocyte recruitment and adopts an 'M2' phenotype associated with increased tissue fibrosis. PMID- 25700974 TI - The association of statin therapy with clinicopathologic outcomes and survival among patients with localized renal cell carcinoma undergoing nephrectomy. AB - OBJECTIVES: Although statins have been found to induce apoptosis and demonstrate antimetastases activity both in vitro and in vivo for renal cell carcinoma (RCC), clinical evidence of a role for these medications is limited. We evaluated the association of statin therapy with outcomes among patients with surgically treated localized RCC. METHODS AND MATERIALS: We reviewed 2,357 patients who underwent nephrectomy between 1995 and 2009 for pNx/0, M0 RCC. Of these, 630 (27%) were taking statins within 3 months of surgery. Progression-free survival, cancer-specific survival, and overall survival were estimated using the Kaplan Meier method. The associations of statin use with clinicopathologic outcomes were evaluated with multivariable logistic and proportional hazards regression models. RESULTS: Statin therapy at the time of nephrectomy was not significantly associated with the risks of locally advanced (pT3-4) pathologic tumor stage (odds ratio = 0.96; P = 0.80) or high (3-4) tumor grade (odds ratio = 1.11; P = 0.30). Median postoperative follow-up was 7.8 years. Compared with patients not on statin therapy, patients taking statins at surgery had similar 10-year progression-free survival (80% vs. 79%; P = 0.56), cancer-specific survival (85% vs. 84%; P = 0.71), and overall survival (59% vs. 64%; P = 0.11). On multivariable analysis, statin use was not significantly associated with the risks of disease progression (hazard ratio [HR] = 1.22; P = 0.10), death from RCC (HR = 1.02; P = 0.90), or all-cause mortality (HR = 0.84; P = 0.05). CONCLUSIONS: We found no independent association between preoperative statin therapy and oncologic outcomes among patients with surgically treated localized RCC. Our data thus do not support an anticancer role for statin therapy in this setting. PMID- 25700975 TI - Clinically nonmetastatic renal cell carcinoma with sarcomatoid dedifferentiation: Natural history and outcomes after surgical resection with curative intent. AB - PURPOSE: Renal cell carcinoma with sarcomatoid dedifferentiation (sRCC) is an aggressive malignancy associated with a poor prognosis. Although existing literature focuses on patients presenting with metastatic disease, characteristics and outcomes for patients with localized disease are not well described. We aimed to evaluate postnephrectomy characteristics, outcomes, and predictors of survival in patients with sRCC who presented with clinically localized disease. PATIENTS AND METHODS: An institutional review board-approved review from 1986 to 2011 identified 77 patients who presented with clinically localized disease, underwent nephrectomy, and had sRCC in their primary kidney tumor. Clinical and pathologic variables were captured for each patient. Overall survival (OS) and recurrence-free survival (RFS) were calculated for all patients and those who had no evidence of disease (NED) following nephrectomy, respectively. Comparisons were made with categorical groupings in proportional hazards regression models for univariable and multivariable analyses. RESULTS: OS for the entire cohort (n = 77) at 2 years was 50%. A total of 56 (77%) patients of the 73 who has NED following nephrectomy experienced a recurrence, with a median time to recurrence of 26.2 months. On multivariable analysis, tumor stage, pathologically positive lymph nodes, and year of nephrectomy were significant predictors of both OS and recurrence-free survival. Limitations include the retrospective nature of this study and relatively small sample size. CONCLUSIONS: Long-term survival for patients with sRCC, even in clinically localized disease, is poor. Aggressive surveillance of those who have NED following nephrectomy is essential, and further prospective studies evaluating the benefit of adjuvant systemic therapies in this cohort are warranted. PMID- 25700976 TI - MicroRNA-185 inhibits cell proliferation and induces cell apoptosis by targeting VEGFA directly in von Hippel-Lindau-inactivated clear cell renal cell carcinoma. AB - OBJECTIVES: The von Hippel-Lindau (VHL) gene acts as a tumor suppressor in most clear cell renal cell carcinomas (ccRCCs). Tumor growth in ccRCCs relies on many factors that result from the loss of VHL. This study aims to identify new microRNAs with therapeutic potential for VHL-inactivated ccRCCs. MATERIALS AND METHODS: We used 786O, A498 (VHL inactivated), and Caki-1 (VHL intact) ccRCC cell lines and 40 ccRCC samples and their adjacent nontumor tissues to measure the expression of microRNA-185 (miR-185) by real-time quantitative polymerase chain reaction. Overexpression or knockdown of VEGFA expression in renal cancer cells was fulfilled by transfecting expression plasmids or small interfering RNAs. Overexpression of miR-185 in ccRCC cell lines was fulfilled by transfecting chemically synthesized miR-185 mimics. The effects of miR-185 on ccRCC cell lines were detected by MTS assay, colony formation assay, and flow cytometric analysis. RESULTS: Compared with adjacent nontumor renal tissues, miR-185 expression levels decreased significantly in ccRCC tissues. The expression of miR-185 had a negative correlation with tumor size, Fuhrman grade, and TNM staging. Luciferase assay showed that VEGFA was a direct target gene of miR-185. The overexpression of miR-185 significantly inhibited cell proliferation and induced cell apoptosis by down-regulating VEGFA expression in VHL-inactivated ccRCC cells. CONCLUSIONS: Our results suggest that the miR-185, as a tumor suppressor, plays a pivotal role by inhibiting VEGFA in VHL-inactivated ccRCC. PMID- 25700977 TI - Population pharmacokinetic modeling of oxcarbazepine active metabolite in Chinese patients with epilepsy. AB - The aim of the study was to develop a population pharmacokinetic (PPK) model of oxcarbazepine and optimize the treatment of oxcarbazepine in Chinese patients with epilepsy. A total of 108 oxcarbazepine therapeutic drug monitoring samples from 78 patients with epilepsy were collected in this study. The pharmacologically active metabolite 10,11-dihydro-10-hydrocarbamazepine (MHD) was used as the analytical target for monitoring therapy of oxcarbazepine. Patients' clinical data were retrospectively collected. The PPK model for MHD was developed using Phoenix NLME 1.2 with a non-linear mixed-effect model. MHD pharmacokinetics obeys a one-compartment model with first-order absorption and elimination. The effect of age, gender, red blood cell count, red blood cell specific volume, hemoglobin (HGB), alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), and serum creatine were analyzed. Bootstrap and data splitting were used simultaneously to validate the final PPK models. The mean values of volume of distribution and clearance of MHD in the patients were 14.2 L and 2.38 L h(-1), respectively. BUN and HGB influenced the MHD volume of distribution according to the following equation: V = tvV * (BUN/4.76)(-0.007) * (HGB/140)(-0.001) * e (etaV) . The MHD clearance was dependent on ALT and gender as follows: CL = tvCL * (ALT/30)(0.181) * (gender) * 1.083 * e (etaCL). The final PPK model was demonstrated to be suitable and effective and it can be used to evaluate the pharmacokinetic parameters of MHD in Chinese patients with epilepsy and to choose an optimal dosage regimen of oxcarbazepine on the basis of these parameters. PMID- 25700978 TI - Stability Evaluation of Ivermectin-Loaded Biodegradable Microspheres. AB - A stability study was performed on ivermectin (IVM)-loaded biodegradable microparticles intended for injection in dogs. The rational was to evaluate the performances upon irradiation of a drug, such as IVM, with a few criticalities with respect to its stability, and toxicity. The goal was to provide valuable information for pharmaceutical scientists and manufacturers working in the veterinary area. The microspheres based on poly(D,L-lactide) and poly-(epsilon caprolactone) and loaded with IVM and with the addition of alpha-tocopherol (TCP) as antioxidant were prepared by the emulsion solvent evaporation method and sterilized by gamma irradiation. Microsphere characterization in term of size, shape, polymer, and IVM stability upon irradiation was performed. The results show that the type of polymer significantly affects microsphere characteristics and performances. Moreover, suitably stable formulations can be achieved only by TCP addition. PMID- 25700979 TI - Severity classification of acute pancreatitis: the continuing search for a better system. PMID- 25700980 TI - Analyzing serial cDNA libraries revealed reactive oxygen species and gibberellins signaling pathways in the salt response of Upland cotton (Gossypium hirsutum L.). AB - KEY MESSAGE: By comparing series full-length cDNA libraries stressed and control, the dynamic process of salt stress response in Upland cotton was studied, and reactive oxygen species and gibberellins signaling pathways were proposed. The Upland cotton is the most important fiber plant with highly salt tolerance. However, the molecular mechanism underlying salt tolerance in domesticated cotton was unclear. Here, seven full-length cDNA libraries were constructed for seedling roots of Upland cotton 'Zhong G 5' at 0, 3, 12 and 48 h after the treatment of control or 150 mM NaCl stress. About 3300 colonies in each library were selected robotically for 5'-end pyrosequencing, resulting in 20,358 expressed sequence tags (ESTs) totally. And 8516 uniESTs were then assembled, including 2914 contigs and 5602 singletons, and explored for Gene Ontology (GO) function. GO comparison between serial stress libraries and control reflected the growth regulation, stimulus response, signal transduction and biology regulation processes were conducted dynamically in response to salt stress. MYB, MYB-related, WRKY, bHLH, GRAS and ERF families of transcription factors were significantly enriched in the early response. 65 differentially expressed genes (DEGs), mainly associated with reactive oxygen species (ROS) scavenging, gibberellins (GAs) metabolism, signal transduction, transcription regulation, stress response and transmembrane transport, were identified and confirmed by quantitative real-time PCR. Overexpression of selected DEGs increased tolerance against salt stress in transgenic yeast. Results in this study supported that a ROS-GAs interacting signaling pathway of salt stress response was activated in Upland cotton. Our results provided valuable gene resources for further investigation of the molecular mechanism of salinity tolerance. PMID- 25700981 TI - Transformation of rice with large maize genomic DNA fragments containing high content repetitive sequences. AB - KEY MESSAGE: Large and complex maize BIBAC inserts, even with a length of about 164 kb and repeat sequences of 88.1%, were transferred into rice. The BIBAC vector has been established to clone large DNA fragments and directly transfer them into plants. Previously, we have constructed a maize B73 BIBAC library and demonstrated that the BIBAC clones were stable in Agrobacterium. In this study, we demonstrated that the maize BIBAC clones could be used for rice genetic transformation through Agrobacterium-mediated method, although the average transformation efficiency for the BIBAC clones (0.86%) is much lower than that for generally used binary vectors containing small DNA fragments (15.24%). The 164-kb B73 genomic DNA insert of the BIBAC clone B2-6 containing five maize gene models and 88.1% of repetitive sequences was transferred into rice. In 18.75% (3/16) of the T1, 13.79% (4/29) of the T2, and 5.26% (1/19) of the T3 generation transgenic rice plants positive for the GUS and HYG marker genes, all the five maize genes can be detected. To our knowledge, this is the largest and highest content of repeat sequence-containing DNA fragment that was successfully transferred into plants. Gene expression analysis (RT-PCR) showed that the expression of three out of five genes could be detected in the leaves of the transgenic rice plants. Our study showed a potential to massively use maize genome resource for rice breeding by mass transformation of rice with large maize genomic DNA fragment BIBAC clones. PMID- 25700982 TI - Endophytic microbes Bacillus sp. LZR216-regulated root development is dependent on polar auxin transport in Arabidopsis seedlings. AB - KEY MESSAGE: Endophytic microbes Bacillus sp. LZR216 isolated from Arabidopsis root promoted Arabidopsis seedlings growth. It may be achieved by promoting the lateral root growth and inhibiting the primary root elongation. Plant roots are colonized by an immense number of microbes, including epiphytic and endophytic microbes. It was found that they have the ability to promote plant growth and protect roots from biotic and abiotic stresses. But little is known about the mechanism of the endophytic microbes-regulated root development. We isolated and identified a Bacillus sp., named as LZR216, of endophytic bacteria from Arabidopsis root. By employing a sterile experimental system, we found that LZR216 promoted the Arabidopsis seedlings growth, which may be achieved by promoting the lateral root growth and inhibiting the primary root elongation. By testing the cell type-specific developmental markers, we demonstrated that Bacillus sp. LZR216 increases the DR5::GUS and DR5::GFP expression but decreases the CYCB1;1::GUS expression in Arabidopsis root tips. Further studies indicated that LZR216 is able to inhibit the meristematic length and decrease the cell division capability but has little effect on the quiescent center function of the root meristem. Subsequently, it was also shown that LZR216 has no significant effects on the primary root length of the pin2 and aux1-7 mutants. Furthermore, LZR216 down-regulates the levels of PIN1-GFP, PIN2-GFP, PIN3-GFP, and AUX1-YFP. In addition, the wild-type Arabidopsis seedlings in the present of 1 or 5 uM NPA (an auxin transport inhibitor) were insensitive to LZR216-inhibited primary root elongation. Collectively, LZR216 regulates the development of root system architecture depending on polar auxin transport. This study shows a new insight on the ability of beneficial endophytic bacteria in regulating postembryonic root development. PMID- 25700983 TI - Correlation of Serum Thyroid Hormones Autoantibodies with Self-Reported Exposure to Thyroid Disruptors in a Group of Nonsegmental Vitiligo Patients. AB - Vitiligo is a pigmentary disorder strongly associated with autoimmune thyroid disorders (ATD). Thyroid hormones antibodies (THAb) directed toward thyroxine (T3) and triiodothyronine (T4) (T3- and T4-Ab) are rare in the general population but are increased in individuals wit ATD and extrathyroid autoimmune disorders. Because it is known that alcohol, smoke, iodine, and some thyroid disruptors can elicit the appearance of ATD, the aim of our study was to evaluate possible correlation between T3- and T4-Ab expression and past toxic exposures in vitiligo patients. Seventy vitiligo patients were examined and self-reported exposure to thyroid disruptors (4,4'-isopropylidenediphenol, perchlorates, polychlorinated biphenyls (PCBs), hexachlorobenzene, resorcinol, dichlorodiphenyltrichloroethane, alachlor/amitriole, nitrate, thiocyanate, soy isoflavones), iodine intake, smoke, and alcohol consumption were investigated through standardized questionnaires. Immunoglobulin (Ig)M-T3-Ab, IgG-T3-Ab, IgM-T4-Ab,and IgG-T4-Ab were dosed by a radioimmunoprecipitation technique. Seventy-seven (95.7 %) patients had at least one type of THAb. Most of them had contemporarily both T3- and T4-Ab (50/70). We found a significant association between PCBs and T4-IgG-Ab (P = 0.039) and between food intake containing nitrate, thiocyanate, and soy isoflavones with (IgM + IgG)-T3-Ab (P = 0.041). Our study underlines a possible influence of diet and environment in vitiligo patients in eliciting THAb. Therefore, in the event of a positive exposure to thyroid disruptors, an evaluation of thyroid function might be useful to early detect possible associated thyroid autoantibodies such as THAb. PMID- 25700984 TI - Lessons learned about prostatic transformation from the age-related methylation of 5alpha-reductase type 2 gene. AB - This commentary highlights the article by Ge et al, which proposes the use of methylation and expression of SRD5A2 as a gene signature to tailor therapies for prostatic diseases. PMID- 25700985 TI - In vivo seeding and cross-seeding of localized amyloidosis: a molecular link between type 2 diabetes and Alzheimer disease. AB - Several proteins have been identified as amyloid forming in humans, and independent of protein origin, the fibrils are morphologically similar. Therefore, there is a potential for structures with amyloid seeding ability to induce both homologous and heterologous fibril growth; thus, molecular interaction can constitute a link between different amyloid forms. Intravenous injection with preformed fibrils from islet amyloid polypeptide (IAPP), proIAPP, or amyloid-beta (Abeta) into human IAPP transgenic mice triggered IAPP amyloid formation in pancreas in 5 of 7 mice in each group, demonstrating that IAPP amyloid could be enhanced through homologous and heterologous seeding with higher efficiency for the former mechanism. Proximity ligation assay was used for colocalization studies of IAPP and Abeta in islet amyloid in type 2 diabetic patients and Abeta deposits in brains of patients with Alzheimer disease. Abeta reactivity was not detected in islet amyloid although islet beta cells express AbetaPP and convertases necessary for Abeta production. By contrast, IAPP and proIAPP were detected in cerebral and vascular Abeta deposits, and presence of proximity ligation signal at both locations showed that the peptides were <40 nm apart. It is not clear whether IAPP present in brain originates from pancreas or is locally produced. Heterologous seeding between IAPP and Abeta shown here may represent a molecular link between type 2 diabetes and Alzheimer disease. PMID- 25700986 TI - DNA methyl transferase 1 reduces expression of SRD5A2 in the aging adult prostate. AB - 5-alpha Reductase type 2 (SRD5A2) is a critical enzyme for prostatic development and growth. Inhibition of SRD5A2 by finasteride is used commonly for the management of urinary obstruction caused by benign prostatic hyperplasia. Contrary to common belief, we have found that expression of SRD5A2 is variable and absent in one third of benign adult prostates. In human samples, absent SRD5A2 expression is associated with hypermethylation of the SRD5A2 promoter, and in vitro SRD5A2 promoter activity is suppressed by methylation. We show that methylation of SRD5A2 is regulated by DNA methyltransferase 1, and inflammatory mediators such as tumor necrosis factor alpha, NF-kappaB, and IL-6 regulate DNA methyltransferase 1 expression and thereby affect SRD5A2 promoter methylation and gene expression. Furthermore, we show that increasing age in mice and humans is associated with increased methylation of the SRD5A2 promoter and concomitantly decreased protein expression. Artificial induction of inflammation in prostate primary epithelial cells leads to hypermethylation of the SRD5A2 promoter and silencing of SRD5A2, whereas inhibition with tumor necrosis factor alpha inhibitor reactivates SRD5A2 expression. Therefore, expression of SRD5A2 is not static and ubiquitous in benign adult prostate tissues. Methylation and expression of SRD5A2 may be used as a gene signature to tailor therapies for more effective treatment of prostatic diseases. PMID- 25700987 TI - [Use of the reliable change index to evaluate the effectiveness of clinical interventions: Application of an asthma training program]. AB - OBJECTIVE: To compare two methods for the evaluation of outcomes to assess effectiveness of a therapeutic intervention of a professional education program on asthma control. DESIGN: A naturalistic, intervention study in which asthmatic patients were attended by clinicians (IG group) who Had taken part in a special education program and a control group (CG) that received medical assistance from clinicians still waiting to be trained. LOCATION: Five urban Primary Care Health Centres of the same region. PARTICIPANTS: From an initial sample of 100 patients, 76 formed the final sample for analysis. The study included 37 males and 39 females, aged between 18 and 65 years (M=41.2 years). The two study groups were found to be homogeneous except for the sex variable. INTERVENTION: Training program for clinical treatment adherence. MAIN MEASUREMENTS: Peak flow as spirometric index, and structured interview. STATISTICAL ANALYSIS: The results were initially analysed using classical techniques based on robust ANOVA models, and then by calculating the Reliable Change Index (RCI). RESULTS: ANOVA models, conducted separately for each sex, showed no significant differences, due to sample size. RCI methodology showed significant differences in the percentage of patients improved in both groups, as well as clinically relevant changes being observed individually. CONCLUSIONS: The RCI method is presented as an attractive alternative as regards the classical methods of analysis that can help in the clinical decision. PMID- 25700988 TI - Enzyme complexity in intermediary metabolism. AB - A good appraisal of the function of enzymes is essential for the understanding of inborn errors of metabolism. However, it is clear now that the 'one gene, one enzyme, one catalytic function' rule oversimplifies the actual situation. Genes often encode several related proteins, which may differ in their subcellular localisation, regulation or function. Furthermore, enzymes often show several catalytic activities. In some cases, this is because they are multifunctional, possessing two or more different active sites that catalyse different, physiologically related reactions. In enzymes with broad specificity or in multispecificity enzymes, a single type of catalytic site performs the same reaction on different physiological substrates at similar rates. Enzymes that act physiologically in only one reaction often show nonetheless substrate promiscuity: they act at low rates on compounds that resemble their physiological substrate(s), thus forming non-classical metabolites, which are in some cases eliminated by metabolite repair. In addition to their catalytic role, enzymes may have moonlighting functions, i.e. non-catalytic functions that are most often not related with their catalytic activity. Deficiency in such functions may participate in the phenotype of inborn errors of metabolism. Evolution has also made that some enzymes have lost their catalytic activity to become allosteric proteins. PMID- 25700989 TI - Effects of rapid maxillary expansion on the midpalatal suture: a systematic review. AB - OBJECTIVE: To identify and qualify the scientific evidence on the immediate and long-term effects of rapid maxillary expansion on the midpalatal suture in growing teenage or young adults, the related articles were selected. MATERIALS AND METHODS: Literatures were searched in the electronic databases, including Medline, Embase, Web of Science, and Cochrane Library. A methodologic-quality scoring (13-point) scale was used to evaluate the quality of the studies. RESULTS: Twelve relevant articles were identified. Midpalatal suture opening during orthodontic treatment with rapid maxillary expansion (RME) amounted to 12 52.5 percent of the total screw expansion. After the treatment of RME, the midpalatal suture seemed to be recalcificated, so the expansion of the midpalatal suture was stable, but there was no consistent evidence on whether the midpalatal sutural opening was parallel or triangular. LIMITATIONS: The methodologic quality of the included studies was assessed rigorously and many deficiencies were found. CONCLUSIONS: The majority of the articles were judged to be of low quality. Therefore, we could not draw any accurate conclusion on the basis of evidence in this systematic review. PMID- 25700990 TI - Regional facial asymmetries in unilateral orofacial clefts. AB - OBJECTIVES: Assess facial asymmetry in subjects with unilateral cleft lip (UCL), unilateral cleft lip and alveolus (UCLA), and unilateral cleft lip, alveolus, and palate (UCLP), and to evaluate which area of the face is most asymmetrical. METHODS: Standardized three-dimensional facial images of 58 patients (9 UCL, 21 UCLA, and 28 UCLP; age range: 8.6-12.3 years) and 121 controls (age range 9-12 years) were mirrored and distance maps were created. Absolute mean asymmetry values were calculated for the whole face, cheek, nose, lips, and chin. One-way analysis of variance, Kruskal-Wallis, and t-test were used to assess the differences between clefts and controls for the whole face and separate areas. RESULTS: Clefts and controls differ significantly for the whole face as well as in all areas. Asymmetry is distributed differently over the face for all groups. In UCLA, the nose was significantly more asymmetric compared with chin and cheek (P = 0.038 and 0.024, respectively). For UCL, significant differences in asymmetry between nose and chin and chin and cheek were present (P = 0.038 and 0.046, respectively). In the control group, the chin was the most asymmetric area compared to lip and nose (P = 0.002 and P = 0.001, respectively) followed by the nose (P = 0.004). In UCLP, the nose, followed by the lips, was the most asymmetric area compared to chin, cheek (P < 0.001 and P = 0.016, respectively). LIMITATIONS: Despite division into regional areas, the method may still exclude or underrate smaller local areas in the face, which are better visualized in a facial colour coded distance map than quantified by distance numbers. The UCL subsample is small. CONCLUSION: Each type of cleft has its own distinct asymmetry pattern. Children with unilateral clefts show more facial asymmetry than children without clefts. PMID- 25700991 TI - Impact of self-esteem and personality traits on the association between orthodontic treatment need and oral health-related quality of life in adults seeking orthodontic treatment. AB - OBJECTIVE: The aim of this study was to investigate whether an association exists between orthodontic treatment need and oral health-related quality of life (OHRQoL) and whether this association is moderated by self-esteem (SE) and/or personality traits. MATERIALS AND METHODS: In this cross-sectional study comprising 189 adults (55 males and 134 females) aged 17 or older (mean age 31.3 years), the OHRQoL was scored by the use of the shortened version of the Oral Health Impact Profile-14 (OHIP-14). The Rosenberg self-esteem scale was used to evaluate SE, and the Dutch adaptation of the Neuroticism Extraversion Openness Five-Factor Inventory was used to assess personality profiles. Need for treatment was defined by the Index of Orthodontic Treatment Need. Spearman correlations, Mann-Whitney U-tests, and regression models were used to analyse the data. RESULTS: There is a modest to weak association between treatment need (Dental Health Component and aesthetic component) and OHRQoL as measured by the total OHIP-14 score (rho = 0.21, P = 0.01216; rho = 0.18, P = 0.02960, respectively). A significant, yet modest to weak, association between SE and the total OHIP-14 score was found (rho = -0.34, P = 0.00057). Moreover, significant associations were found for the total OHIP-14 score and neuroticism and extraversion. Significant associations can be found between SE and all personality traits. CONCLUSIONS: There was a significant association between orthodontic treatment need and OHRQoL. Moreover, a significant association can be found between SE and OHRQoL, as well as certain personality traits and OHRQoL. No evidence was found that SE or personality traits moderate the association between OHRQoL and treatment need. PMID- 25700992 TI - Do the NiTi low and constant force levels remain stable in vivo? AB - OBJECTIVE: The aim was to evaluate the alteration of the deactivation forces of the most commonly used nickel-titanium wires under long-lasting oral cavity environmental influence. MATERIALS AND METHODS: Randomized in vitro and in vivo trials of 540 pieces of orthodontic archwires, NeoSentalloy(r), Copper NiTi(r) 35 degrees C and Titanol Superelastic((r)), round (0.016 inch), and rectangular (0.016 * 0.022 inch), were carried out. Randomization and blinding was achieved with 12-colour system that ensured encoding of key information on the tested specimens. Each of 270 patients (females, 18-20 years old, in the finishing stage of orthodontic treatment) received the piece of NiTi wire ligated piggyback, for a period of 4-6 weeks. Eventually, all samples were subjected to a three-point bending test. Data were statistically analysed at a 5 per cent significance level. RESULTS: In the group of the round used wires, when compared with the new ones, the deactivation force (F dav) values increased significantly for Titanol Superelastic(r); the NeoSentalloy(r) and Copper NiTi(r) 35 degrees C wires did not change their values of F dav. In the group of rectangular wires, F dav decreased for Titanol Superelastic(r), but increased for NeoSentalloy(r) wires. The F dav values of the Copper NiTi(r) 35 degrees C used wires practically did not change, but a remarkable increase of the standard deviation was noted. LIMITATIONS: No calculations concerning effectiveness of in vivo aligning of analysed wires were made. CONCLUSIONS: For the purpose of a 4-6-week aligning stage, round NeoSentalloy(r) with a diameter of 0.016 inches seems to be the wire of choice because of the low level of F dav. PMID- 25700993 TI - Extraction of the deciduous canine as an interceptive treatment in children with palatally displaced canines - part II: possible predictors of success and cut-off points for a spontaneous eruption. AB - AIM: To analyse factors affecting the success rate of palatally displaced canines (PDCs) and eruption time and to find cut-off points to predict when interceptive extraction is beneficial versus unnecessary. MATERIALS AND METHODS: Sixty-seven patients, 40 girls, 27 boys (10-13 years) with uni- (45) or bilateral (22) PDCs, persisting deciduous canine and no previous orthodontic treatment were randomly allocated for extraction or non-extraction using the block randomization method. There were no dropped out after the randomization or during the trial. Clinical examination and cone beam computed tomography was performed at 0, 6, and 12 months. Blinded measurements were done on baseline images. RESULTS: Erupted PDCs had a significantly smaller mesioangular angle, shorter distance of canine cusp tip-dental arch plane, and larger distance of canine cusp tip-midline, and the patients were younger compared to the non-erupted group. Faster eruption was noted of PDCs in the extraction group. Spontaneous eruption was achieved without prior deciduous canine extraction with cut-off points: initial canine cusp tip midline of 11mm, canine cusp tip-dental arch plane of 2.5mm, or a mesioangular angle of 103 degrees. PDCs with a less favourable position, i.e. an initial cusp tip-midline of 6mm, a canine cusp tip-dental arch plane of 5mm, or a mesioangular angle of 116 degrees, will need surgical exposure despite interceptive extraction of the deciduous canine. The canine cusp tip-midline had the best predictive measure for assessing the outcome. LIMITATIONS: Decision on where to place the cut-off points may differ from one operator to another, therefore results from several studies are needed to get average cut-off points. CONCLUSIONS: Deciduous canine extraction is the variable that affects the spontaneous eruption of the canine most. Canine cusp tip-midline, canine cusp tip-dental arch plane, and mesioangular angle might be useful for distinguishing when an interceptive extraction of the deciduous canine is beneficial or when exposure of the PDC should be implemented without previous interceptive treatment. REGISTRATION: This trial was registered in 'FoU i Sverige' (http://www.fou.nu/is/sverige), registration number: 40921. PROTOCOL: The protocol was not published before trial commencement. PMID- 25700994 TI - [Principles of biological aging]. AB - The aging process is the substrate on which aging-associated diseases develop; therefore, the scientific discipline of gerontology aims at understanding this biological aging process, which refers to the progressive increase in the risk of death caused by a loss of body functions. Studies in simple model organisms demonstrate that pharmacological substances, genetic interventions and dietary restriction can slow down the process of aging. The cell culture model of cellular senescence gives researchers the opportunity to conduct studies in a system more closely related to the human organism; therefore, cells from different human tissues are cultured in vitro until they stop proliferating. This permanent growth arrest is called cellular senescence. Recent studies have demonstrated that senescent cells also accumulate in many tissues in vivo and contribute to age-related pathologies. PMID- 25700995 TI - Editorial overview: brain rhythms and dynamic coordination. PMID- 25700996 TI - The CLAIR model: Extension of Brodmann areas based on brain oscillations and connectivity. AB - Since the beginning of the last century, the localization of brain function has been represented by Brodmann areas, maps of the anatomic organization of the brain. They are used to broadly represent cortical structures with their given sensory-cognitive functions. In recent decades, the analysis of brain oscillations has become important in the correlation of brain functions. Moreover, spectral connectivity can provide further information on the dynamic connectivity between various structures. In addition, brain responses are dynamic in nature and structural localization is almost impossible, according to Luria (1966). Therefore, brain functions are very difficult to localize; hence, a combined analysis of oscillation and event-related coherences is required. In this study, a model termed as "CLAIR" is described to enrich and possibly replace the concept of the Brodmann areas. A CLAIR model with optimum function may take several years to develop, but this study sets out to lay its foundation. PMID- 25700997 TI - BCL2L11/Bim as a dual-agent regulating autophagy and apoptosis in drug resistance. AB - A variety of anticancer agents employed in standard chemotherapy or novel targeted therapy induce autophagy. A cytoprotective autophagic response often counteracts apoptosis triggered by such agents, potentially contributing to acquired drug-resistance. It is recognized that autophagy and apoptosis share molecular regulatory mechanisms primarily governed by multidomain anti-apoptotic members (e.g., BCL2/Bcl(-)2 and BCL2L1/Bcl(-)xL) of the BCL2 family. However, the role of pro-apoptotic BH3-only proteins (e.g.,, BCL2L11/Bim), another class of BCL2 family proteins that critically determine therapeutic responses, in autophagy regulation remains largely unexplored, particularly with respect to mechanisms of acquired drug resistance. PMID- 25700998 TI - Erratum to: The sera from adult patients with suggestive signs of autoimmune diseases present antinuclear autoantibodies that cross-react with Leishmania infantum conserved proteins: crude Leishmania histone and soluble Leishmania antigens. PMID- 25700999 TI - Standard Comorbidity Measures Do Not Predict Patient-reported Outcomes 1 Year After Total Hip Arthroplasty. AB - BACKGROUND: Comorbidities influence surgical outcomes and therefore need to be included in risk adjustment when predicting patient-reported outcomes. However, there is no consensus on how best to use the available data about comorbidities in registry-based predictive models. QUESTIONS/PURPOSES: The purposes of this study were (1) to determine whether the International Classification of Diseases, 10(th) Revision (ICD-10)-based comorbidity measures (Elixhauser, Charlson, and Royal College of Surgeons Charlson) offer added value in explaining patients' health-related quality of life (HRQoL), pain, and satisfaction after total hip arthroplasty (THA) when preoperative HRQoL, pain, and Charnley classification were known; and (2) to determine the ideal timeframe for recording the different diagnoses that serves as the basis for comorbidity measure calculations. METHODS: There were 22,263 patients who had undergone THA with complete pre- and postoperative patient-reported outcome measures (PROMs) included in the Swedish Hip Arthroplasty Register between 2002 and 2007. The three comorbidity indices were calculated with ICD-10 codes identified in the Swedish National Patient Register from 1, 2, and 5 years before the patient underwent THA. The impact of the comorbidity indices on the PROM scores (EQ-5D index, EQ visual analog scale [VAS], pain VAS, and satisfaction VAS) was modeled with linear regression where the 1-year patient postoperative outcome score was the dependent variable and independent variables included patient preoperative Charnley classification, preoperative HRQoL and pain, and comorbidity indices. The partial R(2) value indicated how much each variable uniquely contributed to the predictive capacity of the model. RESULTS: The ICD-10-based comorbidity measures added little predictive value to the models for each of the outcomes of interest (EQ-5D index, EQ VAS, pain VAS, and satisfaction VAS). Charnley classification and the preoperative scores were the strongest predictors of both measures of postoperative HRQoL, of postoperative pain, and postoperative satisfaction with outcomes from surgery. Of all the predictors considered, only the Charnley classification was associated with all outcomes, irrespective of the timeframe considered. For each of the outcomes considered, there was a gradual increase in the models' predictive power with the length of the timeframe considered for calculating the comorbidity measures. CONCLUSIONS: For predicting outcomes 1 year after THA, we found that there was no added value in ICD-10-based comorbidity measures if patient Charnley classification and preoperative HRQoL and pain measures were known. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 25701000 TI - What Is the Relationship Between Depressive Symptoms and Pain During Functional Tasks in Persons Undergoing TKA? A 6-year Perioperative Cohort Study. AB - BACKGROUND: Preoperative depressive symptoms have been shown in some but not all studies to be associated with poor self-reported pain and function outcomes. In addition, depressive symptoms after surgery have been shown to improve relative to preoperative levels. QUESTIONS/PURPOSES: We hypothesized that (1) preoperative depressive symptoms would predict postoperative pain; (2) depressive symptoms would decrease after surgery; and (3) preoperative depressive symptoms would increase as the scheduled surgery date approached. METHODS: Data from the Osteoarthritis Initiative, a National Institutes of Health-funded prospective multiyear cohort study, were used in this retrospective analysis. Persons from four communities were eligible if they had radiographic knee osteoarthritis or were at risk for developing knee osteoarthritis based on occupational, medical history, or body weight risk factors. A total of 4796 persons participated and rates of followup were 80% or greater over the course of the study. Participants completed a validated depressive symptom scale and the Knee Injury and Osteoarthritis Outcome Scale pain scale each year for 3 years before and 3 years after TKA. Latent growth curve modeling was used to model intercepts and slopes of pre- and postoperative depression and pain. Preoperative trajectories and intercepts were then used to predict postoperative pain and depressive symptoms adjusting for confounding variables. RESULTS: After adjustment for potential confounding, we found no evidence that preoperative depressive symptoms predicted postoperative pain with function (estimate, 0.1; 95% confidence interval, -0.31 to 0.50; p = 0.64) or that depressive symptoms were reduced after surgery (z = 0.06, p = 0.80). We also found no evidence to indicate that preoperative depressive symptoms increased as the date of surgery approached (linear slope = 0.28, SE = 0.19, p = 0.15). CONCLUSIONS: Preoperative and postoperative depressive symptoms in patients before and after TKA did not appreciably change over a 6-year perioperative period. Patient depressive symptoms were not reduced after surgery and did not appear to be related to less pain postoperatively. Our findings of no association between preoperative depressive symptom severity and postoperative pain and no reduction in postoperative depressive symptoms run counter to other available evidence, potentially attributable, in part, to a data collection process that occurred outside of orthopaedic surgeons' offices. Future research is needed to more fully explore the potential role of social desirability, the concept that patients respond in a way that they think the researcher or clinician wants them to respond in lieu of responding in a way that truly reflects the patient's status. Social desirability may influence a TKA patient's pain and function outcome assessment. LEVEL OF EVIDENCE: Level I, prognostic study. PMID- 25701001 TI - What Is the Outcome of Allograft and Intramedullary Free Fibula (Capanna Technique) in Pediatric and Adolescent Patients With Bone Tumors? AB - BACKGROUND: After bone tumor resection, reconstruction for limb salvage surgery can be challenging because of the resultant large segmental bony defects. Structural allografts have been used to fill these voids; however, this technique is associated with high complication rates. To circumvent the complications associated with this procedure, massive bony allografts have been supplemented with an intramedullary vascularized free fibula. However, few studies have examined the outcomes using this technique in the pediatric and adolescent populations. QUESTIONS/PURPOSES: The purpose of this study was to examine the revision-free survival using he Capanna technique for limb salvage for pediatric lower limb salvage. We attempted to answer the following questions: (1) What was the overall limb salvage rate along with incidence of reoperation and complications? (2) How did pediatric and adolescent patients functionally perform after this technique? (3) What was the incidence of late complications including infection and fracture? (4) What was the incidence of limb length discrepancy? METHODS: Eighteen pediatric patients who underwent lower extremity limb salvage with the use of cadaveric allograft and intramedullary free fibular transfer (Capanna technique) were identified. There were nine boys males and nine girls with a mean age of 11 years (range, 5-18 years) and mean followup of 8 years (range, 2-15 years), respectively. All patients had at least 2 years followup. Three patients have not been seen in followup during the past 5-years; however, all had made it to their 5-year clinical followup. The patients' medical records were reviewed for clinical and functional outcomes as well as postoperative complications. Time to union was recorded through an evaluation of radiographs. Mankin functional outcome and Musculoskeletal Tumor Society (MSTS) rating scale were recorded for each patient. RESULTS: The overall limb salvage rate was 94%. Fourteen patients underwent an additional surgical procedure. Six patients underwent additional procedure(s) to treat a symptomatic nonunion. Seventeen of the patients had a good or excellent Mankin score with a mean MSTS rating of 93% at last followup. Six of the patients underwent a limb length modification procedure. CONCLUSIONS: Use of large allografts in conjunction with intramedullary vascularized free fibulas appears to be a reliable method for the reconstruction of large bony tumors of the lower extremity in this population, although we did not directly compare this with allografts alone in our study. The use of locked plates may improve union times. The proportion of patients achieving limb preservation was high and complication rates are acceptable. LEVEL OF EVIDENCE: Level IV, therapeutic study. PMID- 25701002 TI - Docosahexaenoic acid supplementation in lactating women increases breast milk and plasma docosahexaenoic acid concentrations and alters infant omega 6:3 fatty acid ratio. AB - This study investigated the effects of docosahexaenoic acid (DHA) supplementation on the fatty acid composition of breast milk and plasma concentrations in lactating women and their infants. Eighty-nine lactating women 4-6 weeks post partum received placebo, 200 mg or 400 mg DHA for 6 weeks with usual diets. Breast milk fatty acids and maternal plasma fatty acids were measured at the beginning and end of the study and infant plasma at the end of the study. Breast milk and maternal plasma DHA were significantly greater with 200 mg and 400 mg DHA compared with placebo (50% and 123% breast milk p<0.05; 71% and 101% plasma, p<0.0001), respectively. Infant plasma omega 6:3 and arachidonic acid (AA):DHA were significantly greater in the placebo group compared to both supplement groups (67% and 106%; 71% and 116%, respectively, p<0.05). DHA supplementation impacts infant fatty acids important for brain development and breast milk fatty acid composition. PMID- 25701003 TI - Liquid drop runs upward between two nonparallel plates. AB - We have recently observed an interesting phenomenon: even under gravity, a microliter-scaled silicone oil drop was still able to run upward between two nonparallel plates that were approximately vertically placed. We also saw the same phenomenon in the case of isopropyl alcohol (IPA) drops. In this work, we developed simple models to interpret this phenomenon, followed by experimental validation. We demonstrated that, by changing the locations of drops or tilt and opening angles of plates, the moving directions of silicone oil, IPA, and water drops could be controlled. In the cases of silicone oil and IPA, we also found that the speed of a drop had a linear relation with the square of the drop location when the drop was far away from the corner of two nonparallel plates and that the drop moved faster as it became closer to this corner. PMID- 25701004 TI - Impaired exercise training-induced muscle fiber hypertrophy and Akt/mTOR pathway activation in hypoxemic patients with COPD. AB - Exercise training (ExTr) is largely used to improve functional capacity in patients with chronic obstructive pulmonary disease (COPD). However, ExTr only partially restores muscle function in patients with COPD, suggesting that confounding factors may limit the efficiency of ExTr. In the present study, we hypothesized that skeletal muscle adaptations triggered by ExTr could be compromised in hypoxemic patients with COPD. Vastus lateralis muscle biopsies were obtained from patients with COPD who were either normoxemic (n = 15, resting arterial Po2 = 68.5 +/- 1.5 mmHg) or hypoxemic (n = 8, resting arterial Po2 = 57.0 +/- 1.0 mmHg) before and after a 2-mo ExTr program. ExTr induced a significant increase in exercise capacity both in normoxemic and hypoxemic patients with COPD. However, ExTr increased citrate synthase and lactate dehydrogenase enzyme activities only in skeletal muscle of normoxemic patients. Similarly, muscle fiber cross-sectional area and capillary-to-fiber ratio were increased only in patients who were normoxemic. Expression of atrogenes (MuRF1, MAFbx/Atrogin-1) and autophagy-related genes (Beclin, LC3, Bnip, Gabarapl) remained unchanged in both groups. Phosphorylation of Akt (Ser473), GSK-3beta (Ser9), and p70S6k (Thr389) was nonsignificantly increased in normoxemic patients in response to ExTr, but it was significantly decreased in hypoxemic patients. We further showed on C2C12 myotubes that hypoxia completely prevented insulin-like growth factor-1-induced phosphorylation of Akt, GSK-3beta, and p70S6K. Together, our observations suggest a role for hypoxemia in the adaptive response of skeletal muscle of patients with COPD in an ExTr program. PMID- 25701005 TI - Differential effects of age and type 2 diabetes on dynamic vs. peak response of pulmonary oxygen uptake during exercise. AB - We investigated if the magnitude of the type 2 diabetes (T2D)-induced impairments in peak oxygen uptake (Vo2) and Vo2 kinetics was affected by age. Thirty-three men with T2D (15 middle-aged, 18 older), and 21 nondiabetic (ND) men (11 middle aged, 10 older) matched by age were recruited. Participants completed four 6-min bouts of constant-load cycling at 80% ventilatory threshold for the determination of Vo2 kinetics. Cardiac output (inert-gas rebreathing) was recorded at rest and 30 and 240 s during two additional bouts. Peak Vo2 (determined from a separate graded test) was significantly (P < 0.05) reduced in middle-aged and older men with T2D compared with their respective ND counterparts (middle-aged, 3.2 +/- 0.5 vs. 2.5 +/- 0.5 l/min; older, 2.7 +/- 0.4 vs. 2.4 +/- 0.4 l/min), and the magnitude of these impairments was not affected by age. However, the time constant of phase II of the Vo2 response was only slowed (P < 0.05) in middle aged men with T2D compared with healthy counterparts, whereas it was similar among older men with and without T2D (middle-aged, 26.8 +/- 9.3 vs. 41.6 +/- 12.1 s; older, 40.5 +/- 7.8 vs. 41.1 +/- 8.5 s). Similarly, the "gains" in systemic vascular conductance (estimated from the slope between cardiac output and mean arterial pressure responses) were lower (P < 0.05) in middle-aged men with T2D than ND controls, but similar between the older groups. The results suggest that the mechanisms by which T2D induces significant reductions in peak exercise performance are linked to a slower dynamic response of Vo2 and reduced systemic vascular conductance responses in middle-aged men, whereas this is not the case in older men. PMID- 25701006 TI - Sarcolipin overexpression improves muscle energetics and reduces fatigue. AB - Sarcolipin (SLN) is a regulator of sarcoendoplasmic reticulum calcium ATPase in skeletal muscle. Recent studies using SLN-null mice have identified SLN as a key player in muscle thermogenesis and metabolism. In this study, we exploited a SLN overexpression (Sln(OE)) mouse model to determine whether increased SLN level affected muscle contractile properties, exercise capacity/fatigue, and metabolic rate in whole animals and isolated muscle. We found that Sln(OE) mice are more resistant to fatigue and can run significantly longer distances than wild-type (WT). Studies with isolated extensor digitorum longus (EDL) muscles showed that Sln(OE) EDL produced higher twitch force than WT. The force-frequency curves were not different between WT and Sln(OE) EDLs, but at lower frequencies the pyruvate induced potentiation of force was significantly higher in Sln(OE) EDL. SLN overexpression did not alter the twitch and force-frequency curve in isolated soleus muscle. However, during a 10-min fatigue protocol, both EDL and soleus from Sln(OE) mice fatigued significantly less than WT muscles. Interestingly, Sln(OE) muscles showed higher carnitine palmitoyl transferase-1 protein expression, which could enhance fatty acid metabolism. In addition, lactate dehydrogenase expression was higher in Sln(OE) EDL, suggesting increased glycolytic capacity. We also found an increase in store-operated calcium entry (SOCE) in isolated flexor digitorum brevis fibers of Sln(OE) compared with WT mice. These data allow us to conclude that increased SLN expression improves skeletal muscle performance during prolonged muscle activity by increasing SOCE and muscle energetics. PMID- 25701007 TI - Effect of skin temperature on cutaneous vasodilator response to the beta adrenergic agonist isoproterenol. AB - The vascular response to local skin cooling is dependent in part on a cold induced translocation of alpha2C-receptors and an increased alpha-adrenoreceptor function. To discover whether beta-adrenergic function might contribute, we examined whether beta-receptor sensitivity to the beta-agonist isoproterenol was affected by local skin temperature. In seven healthy volunteers, skin blood flow was measured from the forearm by laser-Doppler flowmetry and blood pressure was measured by finger photoplethysmography. Data were expressed as cutaneous vascular conductance (CVC; laser-Doppler flux/mean arterial blood pressure). Pharmacological agents were administered via intradermal microdialysis. We prepared four skin sites: one site was maintained at a thermoneutral temperature of 34 degrees C (32 +/- 10%CVCmax) one site was heated to 39 degrees C (38 +/- 11%CVCmax); and two sites were cooled, one to 29 degrees C (22 +/- 7%CVCmax) and the other 24 degrees C (16 +/- 4%CVCmax). After 20 min at these temperatures to allow stabilization of skin blood flow, isoproterenol was perfused in concentrations of 10, 30, 100, and 300 MUM. Each concentration was perfused for 15 min. Relative to the CVC responses to isoproterenol at the thermoneutral skin temperature (34 degrees C) (+21 +/- 10%max), low skin temperatures reduced (at 29 degrees C) (+17 +/- 6%max) or abolished (at 24 degrees C) (+1 +/- 5%max) the vasodilator response, and warm (39 degrees C) skin temperatures enhanced the vasodilator response (+40 +/- 9%max) to isoproterenol. These data indicate that beta-adrenergic function was influenced by local skin temperature. This finding raises the possibility that a part of the vasoconstrictor response to direct skin cooling could include reduced background beta-receptor mediated vasodilation. PMID- 25701008 TI - Alemtuzumab as rescue therapy in a cohort of 16 aggressive multiple sclerosis patients previously treated by Mitoxantrone: an observational study. AB - Our study aimed to describe safety and neurological impact of alemtuzumab as last line rescue therapy in aggressive multiple sclerosis (MS) patients, previously treated by Mitoxantrone (MITOX). Between June 2004 and October 2013, 13 patients received alemtuzumab at 20 mg/day and 3 at 12 mg/day for 5 days. EDSS, relapses, secondary progression were prospectively assessed 12 and 6 months before treatment, at baseline and every 3 months. Mean follow-up was 6.2 years [1-10]. Mean age at alemtuzumab start was 40 years [26-49] for 8 Secondary Progressive (SP) and 30 years [26-35] for 8 Relapsing-Remitting (RR) patients. MS duration was 13.7 (+/- 3) and 8.3 (+/- 4) years, respectively. During the 12 months before alemtuzumab, annual relapse rate was 0.75 and 3.14, respectively and the 16 patients accumulated 2-30 new gadolinium enhancing lesions. 4 patients (suboptimal responders) received alemtuzumab during MITOX and 12 patients 1-7.8 years after MITOX. Out of 8 SPMS, 2 were disease free up to last visit (4.7 and 8 years), 5 improved or stabilized but only transiently and 1 worsened. Out of 8 RRMS, 1 remained stable up to last visit (8.7 years) despite 1 relapse and active MRI at 18 months and 7 improved (1-4 point EDSS): 4 remained disease free up to last visit (12, 24, 38 months and 7 years), 2 were successfully retreated at 25 and 33 months and 1 worsened progressively 24 months after alemtuzumab. 2 patients developed Grave's disease and 1 hypothyroidism. Alemtuzumab controls aggressive RRMS despite previous use of MITOX. PMID- 25701009 TI - New-onset seizures in two adults with hemophagocytic lymphohistiocytosis. PMID- 25701010 TI - Key emerging issues in progressive supranuclear palsy and corticobasal degeneration. AB - It has been approximately 50 years since neurologists were introduced to the entities, "progressive supranuclear palsy" and "corticobasal degeneration". Since the two seminal publications, there have been significant advancements in our understanding of these two neurodegenerative diseases, particularly the fact that both are associated with tau. Recent advances over the past 3 years that are notable to the field are discussed in this review that covers clinical diagnosis, pathological features, neuroimaging and CSF biomarkers, genetic associations and clinical trials related to progressive supranuclear palsy and corticobasal degeneration. PMID- 25701011 TI - Evolution of knee kinematics three months after total knee replacement. AB - In patients with debilitating knee osteoarthritis, total knee replacement is the most common surgical procedure. Numerous studies have demonstrated that knee kinematics one year after total knee replacement are still altered compared to the healthy joint. However, little is known regarding impairments and functional limitations of patients several months after total knee replacement. The aim of this study was to describe the evolution of the knee gait kinematic in patients with knee osteoarthritis before and three months after a total knee replacement. Ninety patients who were to undergo total knee replacement were included in this study. Twenty-three subjects were recruited as the control group. Three dimensional gait analysis was performed before and three months after surgery. The spatio-temporal parameters and three-dimensional knee kinematics for the operated limb were evaluated during a comfortable gait and compared between groups (the before and after surgery groups and the control group). Three months after surgery, patients always walk with a slower gait velocity and lower knee flexion-extension movements compared to the control group. However, a degree of progress was observed in term of the stride and step length, gait velocity and knee alignment in the coronal plane. Our results suggest that the disability is still significant for most patients three months after total knee replacement. A better understand of the impairments and functional limitations following surgery would help clinicians design rehabilitation programs. Moreover, patients should be informed that rehabilitation after total knee replacement is a long process. PMID- 25701012 TI - Associations between iliotibial band injury status and running biomechanics in women. AB - Iliotibial band syndrome (ITBS) is a common overuse knee injury that is twice as likely to afflict women compared to men. Lower extremity and trunk biomechanics during running, as well as hip abductor strength and iliotibial band flexibility, are factors believed to be associated with ITBS. The purpose of this cross sectional study was to determine if differences in lower extremity and trunk biomechanics during running exist among runners with current ITBS, previous ITBS, and controls. Additionally, we sought to determine if isometric hip abductor strength and iliotibial band flexibility were different among groups. Twenty seven female runners participated in the study. Participants were divided into three equal groups: current ITBS, previous ITBS, and controls. Overground running trials, isometric hip abductor strength, and iliotibial band flexibility were recorded for all participants. Discrete joint and segment biomechanics, as well as hip strength and flexibility measures were analyzed using a one-way analysis of variance. Runners with current ITBS exhibited 1.8 (1.5) degrees greater trunk ipsilateral flexion and 7 (6) degrees less iliotibial band flexibility compared to runners with previous ITBS and controls. Runners with previous ITBS exhibited 2.2 (2.9) degrees less hip adduction compared to runners with current ITBS and controls. Hip abductor strength 3.3 (2.6) %BM*h was less in runners with previous ITBS but not current ITBS compared to controls. Runners with current ITBS may lean their trunk more towards the stance limb which may be associated with decreased iliotibial band flexibility. PMID- 25701013 TI - A quantitative comparison of two kinematic protocols for lumbar segment motion during gait. AB - During gait analysis, motion of the lumbar region is tracked either by means of a 2-dimensional assessment with markers placed along the spine or a 3-dimensional assessment treating the lumbar region as a rigid segment. The rigid segment assumption is necessary for inverse dynamic calculations further up the kinematic chain. In the absence of a reference standard, the choice of model is mostly based on clinical experience. However, the potential exists for large differences in kinematic output if different protocols are used. The aim of this study was to determine the influence of using two 3-dimensional lumbar segment protocols on the resultant kinematic output during gait. The first protocol was a skin surface rigid protocol with markers placed across the lumbar region while the second consisted of a rigid cluster utilizing active markers applied over the 3rd lumbar vertebra. Data from both protocols were compared through simultaneous recording during gait. Overall variability was lower in 4 out of 6 measures for the skin surface protocol. Ensemble average graphs demonstrated similar mean profiles between protocols. However, Functional Limits of Agreement demonstrated only a poor to moderate agreement. This trend was confirmed with a poor to moderate waveform similarity (CMC range 0.29-0.71). This study demonstrates that the protocol used to track lumbar segment kinematics is an important consideration for clinical and research purposes. Greater variability recorded by the rigid cluster during lumbar rotation suggests the skin surface protocol may be more suited to studies where axial rotation is a consideration. PMID- 25701014 TI - Patellar tendon shortening for flexed knee gait in spastic diplegia. AB - We evaluated the outcome of three different approaches to the management of flexed knee gait patients with spastic diplegia. The three surgical procedures were patellar tendon shortening (PTS), PTS combined with rotational osteotomies of the femur and/or tibia, and PTS combined with supracondylar extension osteotomy (SEO) of the distal femur. The primary outcome measure was gait kinematics. The knee gait variable score (GVS) and the gait profile score (GPS) were derived from gait kinematics. 24 patients (16 male and 8 female), mean age 16.1 years (SD 5.8 years), who had surgery between 2002 and 2008, were followed for a mean of 22 months. Knee extension during gait improved by a mean of 20 degrees throughout the gait cycle, with an improvement in the knee GVS of 14 degrees (p<0.001). The overall gait pattern improved with a mean decrease in GPS of 4.6 degrees . Correction of patella alta was demonstrated by an improvement in the Koshino index from 1.34 pre-operatively to 1.10 post-operatively (p<0.001). Knee and gait kinematics, physical examination measures and Koshino Index improved in all three surgical groups, suggesting that a tailored approach to the correction of flexed knee gait in spastic diplegia is both feasible and appropriate. LEVEL OF EVIDENCE: Level III. PMID- 25701015 TI - Obama is urged to support India in supplying world with generic drugs. PMID- 25701016 TI - D-ribose aids heart failure patients with preserved ejection fraction and diastolic dysfunction: a pilot study. AB - OBJECTIVES: The incidence of heart failure continues to escalate with >550,000 newly diagnosed patients annually worldwide. More than half of the patients with heart failure have preserved ejection fraction or isolated diastolic dysfunction, for which no current effective therapies for diastolic dysfunction exist. Every cell requires adequate levels of high energy phosphates to maintain integrity and function. Previous studies have demonstrated that diastolic function is energy dependent and supplemental D-ribose has shown to improve diastolic dysfunction. This study investigated what role D-ribose might play in congestive heart failure patients with preserved systolic function and diastolic dysfunction. METHODS: A total of 11 patients, New York Heart Association class II-IV, with clinical symptoms, normal left ventricular systolic function and echocardiographic evidence of diastolic dysfunction were enrolled after meeting inclusion criteria. Each patient received oral D-ribose (5 g/dose) for 6 weeks. Echocardiographic evaluation, cardiopulmonary metabolic testing and subjective questionnaire assessment were performed at baseline, 6 weeks and at 9 weeks (3 weeks after discontinuing D-ribose). RESULTS: An improvement in their tissue Doppler velocity (E'), which was maintained at 9 weeks, was demonstrated in 64% of the patients. Five patients showed an improvement in their ratio of early diastolic filling velocity (E) to early annulus relaxation velocity (E'). There was no appreciable difference in these measurements during valsalva or with leg raising and handgrip exercises. Four patients also had an improvement in their maximum predicted VO2 values; two demonstrated a worsening effect and no differences were noted in the remaining patients. Subjective assessment revealed a benefit in only one patient, worsening symptoms in one patient and no change in the remaining cohort. CONCLUSIONS: This pilot study revealed some beneficial trends with D-ribose even with this small cohort size. However, future investigations are necessary to further substantiate these observed benefits. PMID- 25701017 TI - European Primary Care Cardiovascular Society (EPCCS) consensus guidance on stroke prevention in atrial fibrillation (SPAF) in primary care. AB - BACKGROUND: Atrial fibrillation affects 1-2% of the general population and 10% of those over 75, and is responsible for around a quarter of all strokes. These strokes are largely preventable by the use of anticoagulation therapy, although many eligible patients are not treated. Recent large clinical trials have added to the evidence base on stroke prevention and international clinical guidelines have been updated. DESIGN: Consensus practical recommendations from primary care physicians with an interest in vascular disease and vascular specialists. METHODS: A focussed all-day meeting, with presentation of summary evidence under each section of this guidance and review of European guidelines on stroke prevention in atrial fibrillation, was used to generate a draft document, which then underwent three cycles of revision and debate before all panel members agreed with the consensus statements. RESULTS: Six areas were identified that included how to identify patients with atrial fibrillation, how to determine their stroke risk and whether to recommend modification of this risk, and what management options are available, with practical recommendations on maximising benefit and minimising risk if anticoagulation is recommended and the reasons why antiplatelet therapy is no longer recommended. The summary evidence is presented for each area and simple summary recommendations are highlighted, with areas of remaining uncertainty listed. CONCLUSIONS: Atrial fibrillation-related stroke is a major public health priority for most health systems. This practical guidance can assist generalist community physicians to translate the large evidence base for this cause of preventable stroke and implement this at a local level. PMID- 25701018 TI - Unexplored Brazilian oceanic island host high salt tolerant biosurfactant producing bacterial strains. AB - We aimed to isolate biosurfactant-producing bacteria in high salt conditions from uncontaminated soils on the Brazilian oceanic island, Trindade. Blood agar medium was used for the isolation of presumptive biosurfactant-producing bacteria. Confirmation and measurements of biosurfactant production were made using an oil spreading method. The isolates were identified by fatty acid profiles and partial 16S rRNA gene sequence analysis. A total of 14 isolates obtained from the 12 soil samples were found to produce biosurfactants. Among them, two isolates stood out as being able to produce biosurfactant that is increasingly active in solutions containing up to 175 g L(-1) NaCl. These high salt tolerant biosurfactant producers are affiliated to different species of the genus Bacillus. Soil organic matter showed positive correlation with the number of biosurfactant-producing bacteria isolated from our different sampling sites. The applied approach successfully recovered and identified biosurfactant-producing bacteria from non contaminated soils. Due to the elevated salt tolerance, as well as their capacity to produce biosurfactants, these isolates are promising for environmental biotechnological applications, especially in the oil production chain. PMID- 25701019 TI - Malignant mesotheliomas in textile rag sorters. AB - OBJECTIVES: To analyse the asbestos exposure characteristics and mesothelioma trend in textile workers operating in the larger Tuscan textile industrial province of Prato between 1988 and 2012. METHODS: All cases of textile workers recorded by the Tuscan mesothelioma register are considered. The demographic and clinical characteristics and asbestos exposure of cases working in the province of Prato are examined. Crude incidence rates between 1988 and 2012 and their 95% confidence intervals (CI) are calculated in rag sorters and other textile workers. The trends of standardized rates are also evaluated, as well as the sources of occupational asbestos exposure from occupational histories of cases affected by other asbestos-related diseases in rag sorters. RESULTS: One hundred and seventy-two malignant mesotheliomas (MMs) have been diagnosed in textile workers in Tuscany. Among these, 46.5% were residents in the province of Prato at the time of diagnosis, half of whom working as rag sorters. All rag sorters with MM are classified as occupationally asbestos exposed, while 71.7% are other textile workers exposed to asbestos. The estimated crude incidence rate in rag sorters in Prato ranges from 74.1*100000 (95% CI: 52.5-101.8) to 166.8*100000 (95% CI: 118.1-229.0). The standardized rates in Prato rag sorters appeared higher throughout the 1990s while in other Prato textile workers the rates increased later on, at the very end of the 1990s. Another 40 cases of asbestos related diseases in rag sorters were also collected. CONCLUSIONS: A very high incidence of MMs was observed in textile workers in Prato, especially among rag sorters. This result, together with the high number of other asbestos-related diseases in rag sorters, strongly supports the hypothesis of diffuse asbestos exposure in rag sorting, in the absence of any other relevant aetiological factor for malignant mesothelioma. PMID- 25701020 TI - Nearly a fifth of cancer patients in England miss 62 day target for starting treatment. PMID- 25701021 TI - Personalising results from large trials. PMID- 25701022 TI - Doctors are urged to encourage patients to be more active to reduce chronic ill health. PMID- 25701023 TI - Discrepancy in the diagnosis of avian Borna disease virus infection of Psittaciformes by protein analysis of feather calami and enzyme-linked immunosorbent assay of plasma antibodies. AB - The present study compares diagnosis of avian Borna disease virus (ABV) infection of psittacine birds by Western blot of bornaviral proteins in dried feather stems with the detection of anti-bornaviral protein antibodies to bornaviral proteins in plasma by enzyme-linked immunosorbent assay (ELISA). The detection of ABV proteins P40 and P24 in feather calami by Western blotting was possible even after storage of the dried feathers for several years at ambient temperature. Serological identification of anti-bornaviral antibodies may fail (e.g., in young birds, hatched from infected parents), whereas bornaviral P40 and P24 proteins were detected in feather stems. This failure can last at least 10 months after the birds are hatched. In some older birds (>5 years), ABV protein was only detectable in the brain, but not in some peripheral tissues, suggesting that the immune system had succeeded in removing the infecting ABV from tissues outside the brain. These results show that a combination of feather stem analysis for the presence of bornaviral proteins by Western blot combined with serological detection of anti-bornaviral antibodies by ELISA is the most reliable procedure for the detection of a bornaviral infection. PMID- 25701024 TI - Better surveillance and vaccine coverage are needed to eliminate measles in India by 2020. PMID- 25701025 TI - Vitamin C neuroprotection against dose-dependent glutamate-induced neurodegeneration in the postnatal brain. AB - Glutamate-induced excitotoxicity due to over-activation of glutamate receptors and associated energy depletion (phosphorylation and activation of AMPK) results in neuronal cell death in various neurological disorders. Restoration of energy balance during an excitotoxic insult is critical for neuronal survival. Ascorbic acid (vitamin C), an essential nutrient with well-known antioxidant potential, protects the brain from oxidative damage in various models of neurodegeneration. In this study, we reported the therapeutic efficacy of vitamin C in response to glutamate-induced excitation, resulting in energy depletion and apoptosis in the hippocampus of the developing rat brain. A single subcutaneous injection of glutamate at two different concentrations (5 and 10 mg/kg) in postnatal day 7 rat pups increased brain glutamate levels and increased the protein expression of neuronal apoptotic markers. Both doses of glutamate upregulated the ratio of pro apoptotic Bax to anti-apoptotic Bcl-2, cytochrome-c release, caspase-3 activation and the expression of PARP-1. However, co-treatment of vitamin C (250 mg/kg) with glutamate decreased brain glutamate levels and reversed the changes induced by glutamate in the developing hippocampus. Interestingly, only a high dose of glutamate caused the phosphorylation and activation of AMPK and induced neuronal cell death, whereas a low dose of glutamate failed to mediate these effects. Vitamin C supplementation reduced the glutamate-induced phosphorylation of AMPK and attenuated neuronal cell death, as assessed morphologically by Fluoro Jade B in the hippocampal CA1 region of the developing brain. Taken together, our results indicated that glutamate in both concentrations is toxic to the immature rat brain, whereas vitamin C is pharmacologically effective against glutamate induced neurodegeneration. PMID- 25701026 TI - Basic and aromatic residues in the C-terminal domain of PriC are involved in ssDNA and SSB binding. AB - In bacterial organisms, the oriC-independent primosome plays an essential role in replication restart after dissociation of the replication DNA-protein complex following DNA damage. PriC is a key protein component in the oriC-independent replication restart primosome. Our previous study suggested that PriC was divided into an N-terminal domain and a C-terminal domain, with the latter domain being the major contributor to single-stranded DNA (ssDNA) binding capacity. In this study, we prepared several PriC mutants in which basic and aromatic amino acid residues were mutated to alanine. Five of these residues, Arg107, Lys111, Phe118, Arg121 and Lys165 in the C-terminal domain, were shown to be involved in ssDNA binding. Moreover, we evaluated the binding of the PriC mutants to the ssDNA binding protein (SSB) complex. Five residues, Phe118, Arg121, Arg129, Tyr152 and Arg155 in the C-terminal domain of PriC, were shown to be involved in SSB binding in the presence of ssDNA. On the basis of these results, we propose a structural model of the C-terminal domain of PriC and discuss how the interactions of PriC with SSB and ssDNA may contribute to the regulation of PriC-dependent replication restart. PMID- 25701027 TI - Inhibition of metastasis and growth of breast cancer by pH-sensitive poly (beta amino ester) nanoparticles co-delivering two siRNA and paclitaxel. AB - Breast cancer is the most vicious killer for women's health, while metastasis is the main culprit, which leads to failure of treatment by increasing relapse rate. In this work, a new complexes nanoparticles loading two siRNA (Snail siRNA (siSna) and Twist siRNA (siTwi)) and paclitaxel (PTX) were designed and constructed using two new amphiphilic polymer, polyethyleneimine-block-poly[(1,4 butanediol)-diacrylate-beta-5-hydroxyamylamine] (PEI-PDHA) and polyethylene glycol-block-poly[(1,4-butanediol)-diacrylate-beta-5-hydroxyamylamine] (PEG-PDHA) by self-assembly. The experimental results showed that in the 4T1 tumor-bearing mice models, PEI-PDHA/PEG-PDHA/PTX/siSna/siTwi) complex nanoparticles (PPSTs) raised the accumulation and retention of both PTX and siRNA in tumor after administrated intravenously, resulted in the strong inhibition of the tumor growth and metastasis simultaneously. It was found that co-delivery of siSna and siTwi had more significant anti-metastasis effect than delivering a single siRNA, as a result of simultaneously inhibiting the motility of cancer cells and degradation of ECM. Therefore, PPSTs could be a promising co-delivery vector for effective therapy of metastatic breast cancer. PMID- 25701028 TI - An "imaging-biopsy" strategy for colorectal tumor reconfirmation by multipurpose paramagnetic quantum dots. AB - Glucose transporter1 (Glut1) plays important roles in treatment of colorectal cancer (CRC) involving early-stage diagnosis, subtype, TNM stage, and therapeutic schedule. Currently, in situ marking and tracking of the tumor biomarkers via clinical imaging remains great challenges in early stage CRC diagnosis. In this study, we have developed a unique cell-targeted, paramagnetic-fluorescent double signal molecular nanoprobe for CRC in vivo magnetic resonance imaging (MRI) diagnosis and subsequent biopsy. The unique molecular nanoprobe is composed of a fluorescent quantum dot (QD) core; a coating layer of paramagnetic DTPA-Gd coupled BSA ((Gd)DTPA?BSA), and a surface targeting moiety of anti-Glut1 polyclonal antibody. The engineered (Gd)DTPA?BSA@QDs-PcAb is 35 nm in diameter and colloidally stable under both basic and acidic conditions. It exhibits strong fluorescent intensities and high relaxivity (r1 and r2: 16.561 and 27.702 s(-1) per mM of Gd(3+)). Distribution and expression of Glut1 of CRC cells are investigated by in vitro cellular confocal fluorescent imaging and MR scanning upon treating with the (Gd)DTPA?BSA@QDs-PcAb nanoprobes. In vivo MRI shows real time imaging of CRC tumor on nude mice after intravenously injection of the (Gd)DTPA?BSA@QDs-PcAb nanoprobes. Ex vivo biopsy is subsequently conducted for expression of Glut1 on tumor tissues. These nanoprobes are found biocompatible in vitro and in vivo. (Gd)DTPA?BSA@QDs-PcAb targeted nanoprobe is shown to be a promising agent for CRC cancer in vivo MRI diagnosis and ex vivo biopsy analysis. The "imaging-biopsy" is a viable strategy for tumor reconfirmation with improved diagnostic accuracy and biopsy in personalized treatment. PMID- 25701029 TI - An orally administrated nucleotide-delivery vehicle targeting colonic macrophages for the treatment of inflammatory bowel disease. AB - Tumor necrosis factor-alpha (TNF-alpha) plays a central role in the pathogenesis of inflammatory bowel disease (IBD). Anti-TNF-alpha therapies have shown protective effects against colitis, but an efficient tool for target suppression of its secretion - ideally via oral administration - remains in urgent demand. In the colon tissue, TNF-alpha is mainly secreted by the colonic macrophages. Here, we report an orally-administrated microspheric vehicle that can target the colonic macrophages and suppress the local expression of TNF-alpha for IBD treatment. This vehicle is formed by cationic konjac glucomannan (cKGM), phytagel and an antisense oligonucleotide against TNF-alpha. It was given to dextran sodium sulfate (DSS) colitic mice via gastric perfusion. The unique swelling properties of cKGM enabled the spontaneous release of cKGM& antisense nucleotide (ASO) nano-complex from the phytagel scaffold into the colon lumen, where the ASO was transferred into colonic macrophages via receptor-mediated phagocytosis. The treatment significantly decreased the local level of TNF-alpha and alleviated the symptoms of colitis in the mice. In summary, our study demonstrates a convenient, orally-administrated drug delivery system that effectively targets colonic macrophages for suppression of TNF-alpha expression. It may represent a promising therapeutic approach in the treatment of IBD. PMID- 25701030 TI - Mechanism of pH-switchable peroxidase and catalase-like activities of gold, silver, platinum and palladium. AB - Despite being increasingly used as artificial enzymes, little has been known for the origin of the pH-switchable peroxidase-like and catalase-like activities of metals. Using calculations and experiments, we report the mechanisms for both activities and their pH-switchability for metals Au, Ag, Pd and Pt. The calculations suggest that both activities are intrinsic properties of metals, regardless of the surfaces and intersections of facets exposed to environments. The pre-adsorbed OH groups on the surfaces, which are only favorably formed in basic conditions, trigger the switch between both activities and render the pH switchability. The adsorption energies between H2O2 and metals can be used as convenient descriptors to predict the relative enzyme-like activities of the metals with similar surface morphologies. The results agree with the enzyme-mimic activities that have been experimentally reported for Au, Ag, Pt and predict that Pd should have the similar properties. The prediction, as well as the predicted activity order for the four metals, has been verified by the experimental tests. The results thus provide an in-depth insight into the peroxidase-like and catalase-like activities of the metals and will guide the de novo design, synthesis and application of artificial enzymes based on inorganic materials. PMID- 25701031 TI - Effects of hydrophobic core components in amphiphilic PDMAEMA nanoparticles on siRNA delivery. AB - Due to their biodegradable character, polyesters such as polycaprolactone (PCL), poly(D,L-lactide) (PDLLA), and polylactic-co-glycolic acid (PLGA) were widely used as the hydrophobic cores of amphiphilic cationic nanoparticles (NPs) for siRNA delivery. However, fewer researches focused on facilitating siRNA delivery by adjusting the polyester composition of these nanoparticles. Herein, we investigated the contribution of polyester segments in siRNA delivery in vitro by introducing different ratio of DLLA moieties in PCL segments of mPEG-block-PCL graft-poly(dimethylamino ethyl methacrylate)(PEG-b-PCL-g-PDMAEMA). It was noticed that compared with the other ratios of DLLA moieties, a certain molar ratio (about 70%) of the NPs, named mPEG45-P(CL21-co-DLLA48)-g-(PDMAEMA29)2 (PECLD-70), showed the highest gene knockdown efficiency but poorest cellular uptake ability in vitro. Further research revealed that NPs with various compositions of the polyester cores showed different physicochemical properties including particle size, zeta potential and stiffness, leading to different endocytosis mechanisms thus influencing the cellular uptake efficiency. Subsequently, we observed that the cells treated by PECLD-70 NPs/Cy5 siRNA complexes exhibited more diffuse Cy5 signal distribution than other NPs by confocal laser scanning microscope, which suggested that siRNA delivered by PECLD-70 NPs/Cy5 siRNA complexes possessed of stronger capabilities in escaping from endosome/lysosome, entering the RNA induced silencing complex (RISC) and cutting the target mRNA efficiently. The different siRNA release profile was dominated by the degradation rate of polyester segments. Therefore, it could be concluded that the adjustment of hydrophobic core of cationic nanoparticles could significantly affect their transfection behavior and appropriate polyester composition should be concerned in designing of analogous siRNA vectors. PMID- 25701032 TI - Layer-by-layer assembled cell instructive nanocoatings containing platelet lysate. AB - Great efforts have been made to introduce growth factors (GFs) onto 2D/3D constructs in order to control cell behavior. Platelet lysate (PL) presents itself as a cost-effective source of multiple GFs and other proteins. The instruction given by a construct-PL combination will depend on how its instructive cues are presented to the cells. The content, stability and conformation of the GFs affect their instruction. Strategies for a controlled incorporation of PL are needed. Herein, PL was incorporated into nanocoatings by layer-by-layer assembling with polysaccharides presenting different sulfation degrees (SD) and charges. Heparin and several marine polysaccharides were tested to evaluate their PL and GF incorporation capability. The consequent effects of those multilayers on human adipose derived stem cells (hASCs) were assessed in short-term cultures. Both nature of the polysaccharide and SD were important properties that influenced the adsorption of PL, vascular endothelial growth factor (VEGF), fibroblast growth factor b (FGFb) and platelet derived growth factor (PDGF). The sulfated polysaccharides-PL multilayers showed to be efficient in the promotion of morphological changes, serum-free adhesion and proliferation of high passage hASCs (P > 5). These biomimetic multilayers promise to be versatile platforms to fabricate instructive devices allowing a tunable incorporation of PL. PMID- 25701033 TI - A fibrin-supported myocardial organ culture for isolation of cardiac stem cells via the recapitulation of cardiac homeostasis. AB - There is great interest in the development of cardiac stem cells (CSCs) cell based therapeutics; thus, clinical translation requires an efficient method for attaining therapeutic quantities of these cells. Furthermore, an in vitro model to investigate the mechanisms regulating the cardiac homeostasis is crucial. We sought to develop a simple myocardial culture method for enabling both the recapitulation of myocardial homeostasis and the simultaneous isolation of CSCs. The intact myocardial fragments were encapsulated 3-dimensionally into the fibrin and cultured under dynamic conditions. The fibrin provided secure physical support and substratum to the myocardium, which mediated integrin-mediated cell signaling that allowed in situ renewal, outgrowth and cardiomyogenic differentiation of CSCs, mimicking myocardial homeostasis. Since our culture maintained the myocardial CSCs niches, it was possible to define the identity of in vitro renewed CSCs that situated in the interstitium between cardiomyocytes and microvessels. Lastly, the use of matrix-restricted fibrinolysis enabled the selective isolation of outgrown CSCs that retained the clonogenicity, long-term growth competency and cardiovascular commitment potential. Collectively, this myocardial culture might be used as an alternative tool for studying cardiac biology and developing cell-based therapeutics. PMID- 25701034 TI - Dual-modified liposomes with a two-photon-sensitive cell penetrating peptide and NGR ligand for siRNA targeting delivery. AB - Tumor-oriented nanocarrier drug delivery approaches with photosensitivity have drawn considerable attention over the years. However, due to its low penetrability and ability to harm tissues, the use of UV light for triggered nanocarrier release in in vivo applications has been limited. Compared with UV light, near-infrared (NIR) light deeply penetrates tissues and is less damaging to cells. In this study, we devised and tested a strategy for functional siRNA delivery to cells by loading siRNA into cationic liposomes bearing a photolabile caged cell-penetrating peptide (pcCPP) and asparagine-glycine-arginine peptide (NGR) molecules attached to the liposome surface (pcCPP/NGR-LP). Here, the positive charges of the lysine residues on the CPP were temporarily caged by the photosensitive group (PG), neutralizing its charges and thereby forming a pcCPP. This event subsequently led to conditional NIR light-dependent cell-penetrating functionality. After administration, the pcCPP/NRG-LP was inactivated in the circulatory system as it could not penetrate the tumor cell membrane. The NGR moiety selectively bound to CD13-positive tumors, which facilitated the active accumulation of pcCPP/NGR-LP in tumor tissues. Then, upon illumination using NIR light at the tumor site, the PG was uncaged, the interaction of the CPP with the cell membrane was restored and the activated dual-modified liposomes exhibited enhanced tumor cellular uptake and selectivity due to the synergistic effect of CPP-mediated cellular entry and NGR-mediated endocytosis. Subsequent research demonstrated that the pcCPP/NGR-LP showed good physicochemical properties, effective cellular uptake, endosomal escape and significant gene silencing in HT 1080 cells in vitro. Additionally, after systemic administration in mice, pcCPP/NGR-LP accumulated in the tumor, augmented c-myc silencing and delayed tumor progression. In conclusion, the combined application of these pcCPP and NGR modifications may provide a reasonable approach for the selectively targeted delivery of siRNA. PMID- 25701035 TI - Novel near-infrared BiFC systems from a bacterial phytochrome for imaging protein interactions and drug evaluation under physiological conditions. AB - Monitoring protein-protein interactions (PPIs) in live subjects is critical for understanding these fundamental biological processes. Bimolecular fluorescence complementation (BiFC) provides a good technique for imaging PPIs; however, a BiFC system with a long wavelength remains to be pursued for in vivo imaging. Here, we conducted systematic screening of split reporters from a bacterial phytochrome-based, near-infrared fluorescent protein (iRFP). Several new near infrared phytochrome BiFC systems were built based on selected split sites including the amino acids residues 97/98, 99/100, 122/123, and 123/124. These new near-infrared BiFC systems from a bacterial phytochrome were verified as powerful tools for imaging PPIs under physiological conditions in live cells and in live mice. The interaction between HIV-1 integrase (IN) and cellular cofactor protein Lens epithelium-derived growth factor (LEDGF/p75) was visualized in live cells using the newly constructed iRFP BiFC system because of its important roles in HIV-1 integration and replication. Because the HIV IN-LEDGF/p75 interaction is an attractive anti-HIV target, drug evaluation assays to inhibit the HIV IN LEDGF/p75 interaction were also performed using the newly constructed BiFC system. The results showed that compound 6 and carbidopa inhibit the HIV IN LEDGF/p75 interaction in a dose-dependent manner under physiological conditions in the BiFC assays. This study provides novel near-infrared BiFC systems for imaging protein interactions under physiological conditions and provides guidance for splitting other bacterial phytochrome-like proteins to construct BiFC systems. The study also provides a new method for drug evaluation in live cells based on iRFP BiFC systems and supplies some new information regarding candidate drugs for anti-HIV therapies. PMID- 25701036 TI - Multifunctional porous silicon nanoparticles for cancer theranostics. AB - Nanomaterials provide a unique platform for the development of theranostic systems that combine diagnostic imaging modalities with a therapeutic payload in a single probe. In this work, dual-labeled iRGD-modified multifunctional porous silicon nanoparticles (PSi NPs) were prepared from dibenzocyclooctyl (DBCO) modified PSi NPs by strain-promoted azide-alkyne cycloaddition (SPAAC) click chemistry. Hydrophobic antiangiogenic drug, sorafenib, was loaded into the modified PSi NPs to enhance the drug dissolution rate and improve cancer therapy. Radiolabeling of the developed system with (111)In enabled the monitoring of the in vivo biodistribution of the nanocarrier by single photon emission computed tomography (SPECT) in an ectopic PC3-MM2 mouse xenograft model. Fluorescent labeling with Alexa Fluor 488 was used to determine the long-term biodistribution of the nanocarrier by immunofluorescence at the tissue level ex vivo. Modification of the PSi NPs with an iRGD peptide enhanced the tumor uptake of the NPs when administered intravenously. After intratumoral delivery the NPs were retained in the tumor, resulting in efficient tumor growth suppression with particle-loaded sorafenib compared to the free drug. The presented multifunctional PSi NPs highlight the utility of constructing a theranostic nanosystems for simultaneous investigations of the in vivo behavior of the nanocarriers and their drug delivery efficiency, facilitating the selection of the most promising materials for further NP development. PMID- 25701037 TI - Cell surface modification with ssDNA-PEG-lipid for analysing intercellular interactions between different cells. AB - Intercellular interactions are important in the development, immune responses, and functions of tissues and organs. Few methods are currently available for experimentally inducing and analysing cell-cell interaction in vitro. Here I propose a method to induce cell-cell attachment by cell surface modification with single-stranded DNA (ssDNA) and poly(ethylene glycol)-conjugated phospholipid (PEG-lipid) derivatives. The incorporation of an ssDNA pair (polyA20 and polyT20) into the cell membranes of two different cells was utilized to attach distinct cells through DNA hybridization. This technique enabled induction of cell-cell attachment between the same cell lines or different cell lines by controlling the contact area of two cells. Using this method, I investigated intercellular interactions, including the cell-in-cell invasion process, without impairing the interaction. I found that the normal cells MCF-10A were internalized into the cancer cells MCF-7, and that the intercellular interactions between them mainly involved the interaction of E-cadherin. PMID- 25701038 TI - Polyaptamer DNA nanothread-anchored, reduced graphene oxide nanosheets for targeted delivery. AB - Here, we report reduced graphene oxide (rGO) nanosheets anchoring receptor specific polyaptamer nanothreads for targeted drug delivery. DNA polyaptamer nanothreads of protein tyrosine kinase 7 receptor (PTK7) were synthesized by rolling cycle amplification. To strengthen the anchoring of polyaptamer nanothreads onto rGO, oligoT bridge domain was introduced between each repeating PTK7 aptamer sequence. As compared to PTK7 polyaptamer nanothreads alone, PTK7 polyaptamer nanothreads with 22-mer oligoT bridges (PNT) showed higher anchoring capacity onto rGO nanosheets. Nanothread-coated surface morphology of PNTrGO was observed. Coating of PNT did not affect the sizes of rGO, but reduced the zeta potential. In PTK7-negative Ramos cells, the uptake of PNT-anchored rGO (PNTrGO) did not differ from that of oligoT-bridged scrambled polyaptamer-anchored rGO (SNTrGO). However, in CCRF-CEM leukemia cells overexpressing PTK7, the uptake of PNTrGO was 2.1-fold higher than that of SNTrGO after 15 min pulse. In vivo distribution to CCRF-CEM tumor tissues was 2.8-fold higher in PNTrGO than in SNTrGO at 48 h post-injection. In CCRF-CEM xenografted mice, intravenously administered doxorubicin (Dox)-loaded PNTrGO showed the higher antitumor activity than other groups, reducing the tumor weight down to 12% of tumor weights of untreated mice. These results suggest the potential of PNTrGO for target-specific drug delivery nanoplatform. PMID- 25701039 TI - Physical and biological regulation of neuron regenerative growth and network formation on recombinant dragline silks. AB - Recombinant spider silks produced in transgenic goat milk were studied as cell culture matrices for neuronal growth. Major ampullate spidroin 1 (MaSp1) supported neuronal growth, axon extension and network connectivity, with cell morphology comparable to the gold standard poly-lysine. In addition, neurons growing on MaSp1 films had increased neural cell adhesion molecule (NCAM) expression at both mRNA and protein levels. The results indicate that MaSp1 films present useful surface charge and substrate stiffness to support the growth of primary rat cortical neurons. Moreover, a putative neuron-specific surface binding sequence GRGGL within MaSp1 may contribute to the biological regulation of neuron growth. These findings indicate that MaSp1 could regulate neuron growth through its physical and biological features. This dual regulation mode of MaSp1 could provide an alternative strategy for generating functional silk materials for neural tissue engineering. PMID- 25701040 TI - Inhibition of MDR1 gene expression and enhancing cellular uptake for effective colon cancer treatment using dual-surface-functionalized nanoparticles. AB - Nanomedicine options for colon cancer therapy have been limited by the lack of suitable carriers capable of delivering sufficient drug into tumors to cause lethal toxicity. To circumvent this limitation, we fabricated a camptothecin (CPT)-loaded poly(lactic-co-glycolic acid) nanoparticle (NP) with dual-surface functionalization-Pluronic F127 and chitosan-for inhibiting multi-drug resistant gene 1 (MDR1) expression and enhancing tumor uptake. The resultant spherical NPs P/C had a desirable particle size (~268 nm), slightly positive zeta-potential, and the ability to efficiently down-regulate the expression of MDR1. In vitro cytotoxicity tests revealed that the 24 and 48 h IC50 values of NPs-P/C1 were 2.03 and 0.67 MUm, respectively, which were much lower than those for free CPT and other NPs. Interestingly, NPs-P/C1 showed the highest cellular uptake efficiency (approximately 85.5%) among the different drug formulations. Most importantly, treatment of colon tumor-bearing mice with various drug formulations confirmed that the introduction of Pluronic F127 and chitosan to the NP surface significantly enhanced the therapeutic efficacy of CPT, induced tumor cell apoptosis, and reduced systemic toxicity. Collectively, these findings suggest that our one-step-fabricated, dual-surface-functionalized NPs may hold promise as a readily scalable and effective drug carrier with clinical potential in colon cancer therapy. PMID- 25701041 TI - Cytoskeletal tension induces the polarized architecture of the nucleus. AB - The nuclear lamina is a thin filamentous meshwork that provides mechanical support to the nucleus and regulates essential cellular processes such as DNA replication, chromatin organization, cell division, and differentiation. Isolated horizontal imaging using fluorescence and electron microscopy has long suggested that the nuclear lamina is composed of structurally different A-type and B-type lamin proteins and nuclear lamin-associated membrane proteins that together form a thin layer that is spatially isotropic with no apparent difference in molecular content or density between the top and bottom of the nucleus. Chromosomes are condensed differently along the radial direction from the periphery of the nucleus to the nuclear center; therefore, chromatin accessibility for gene expression is different along the nuclear radius. However, 3D confocal reconstruction reveals instead that major lamin protein lamin A/C forms an apically polarized Frisbee-like dome structure in the nucleus of adherent cells. Here we show that both A-type lamins and transcriptionally active chromatins are vertically polarized by the tension exercised by the perinuclear actin cap (or actin cap) that is composed of highly contractile actomyosin fibers organized at the apical surface of the nucleus. Mechanical coupling between actin cap and lamina through LINC (linkers of nucleoskeleton and cytoskeleton) protein complexes induces an apical distribution of transcription-active subnucleolar compartments and epigenetic markers of transcription-active genes. This study reveals that intranuclear structures, such as nuclear lamina and chromosomal architecture, are apically polarized through the extranuclear perinuclear actin cap in a wide range of somatic adherent cells. PMID- 25701043 TI - Uncertainty over Redditch hospital's emergency department led to mass resignation, say campaigners. PMID- 25701044 TI - Microbial endocrinology: the interplay between the microbiota and the endocrine system. AB - The new field of microbiome research studies the microbes within multicellular hosts and the many effects of these microbes on the host's health and well-being. We now know that microbes influence metabolism, immunity and even behavior. Essential questions, which are just starting to be answered, are what are the mechanisms by which these bacteria affect specific host characteristics. One important but understudied mechanism appears to involve hormones. Although the precise pathways of microbiota-hormonal signaling have not yet been deciphered, specific changes in hormone levels correlate with the presence of the gut microbiota. The microbiota produces and secretes hormones, responds to host hormones and regulates expression levels of host hormones. Here, we summarize the links between the endocrine system and the gut microbiota. We categorize these interactions by the different functions of the hormones, including those affecting behavior, sexual attraction, appetite and metabolism, gender and immunity. Future research in this area will reveal additional connections, and elucidate the pathways and consequences of bacterial interactions with the host endocrine system. PMID- 25701045 TI - Macular and retinal nerve fiber thickness in recovered and persistent amblyopia. AB - The aim of this study was to investigate the presence of increased macular or retinal nerve fiber layer thickness (RNFLT) in amblyopic eyes, find if the increased macular or RNFLT is related to the lack of response in amblyopic eyes, and to explore whether the increased central macular thickness (CMT) in amblyopic eyes is purely related to the hyperopia. This is a prospective descriptive study. CMT and peripapillary RNFLT were measured by spectral-domain optical coherence tomography to evaluate 60 patients with unilateral-treated amblyopia (median age 11.00 year). Patients were divided into two groups: 33 patients in recovered amblyopia group and 27 patients in persistent amblyopia group. The mean CMT in the recovered group was 247.31 (+/-23.4) versus 246.8 (+/-32.7) um (p = 0.95) for the persistent group. The mean peripapillary RNFLT was 99.13 (+/-12.1) versus 99.9 (+/-14.9) um (p = 0.85) for the persistent group. In anisometropic amblyopia, there was no significant difference in CMT and RNFLT in either group. Also there was no relation between the type of refractive error and CMT or RNFLT. There was no significant difference in CMT and RNFLT in amblyopic eyes for both the recovered amblyopia group and the persistent amblyopia group to explain the lack of response in persistent amblyopic eyes. Additionally there was no relation between the type of refractive error and CMT or peripapillary RNFLT. PMID- 25701046 TI - Effects of lyric analysis interventions on treatment motivation in patients on a detoxification unit: a randomized effectiveness study. AB - BACKGROUND: Treatment motivation is a key component in the early rehabilitative stages for people with substance use disorders. To date, no music therapy researcher has studied how lyric analysis interventions might affect motivation in a randomized controlled design. OBJECTIVES: The primary purpose of this study was to determine the effect of lyric analysis interventions on treatment motivation in patients on a detoxification unit using a single-session wait-list control design. A secondary purpose was to determine if there were between-group differences concerning two contrasting songs used for the lyric analyses. METHODS: Participants (N=104) were cluster randomized to a group lyric analysis condition or a wait-list control condition. Participants received either a "Hurt" or a "How to Save a Life" lyric analysis treatment. The Texas Christian University Treatment Motivation Scale-Client Evaluation of Self at Intake (CESI) (Simpson, 2008[2005]) was used to measure aspects of treatment motivation: problem recognition, desire for help, treatment readiness, pressures for treatment, and total motivation. RESULTS: Results indicated significant between group differences in measures of problem recognition, desire for help, treatment readiness, and total motivation, with experimental participants having higher treatment motivation means than control participants. There was no difference between the two lyric analysis interventions. CONCLUSIONS: Although the song used for lyric analysis interventions did not affect outcome, a single group-based music therapy lyric analysis session can be an effective psychosocial treatment intervention to enhance treatment motivation in patients on a detoxification unit. Limitations, implications for clinical practice, and suggestions for future research are provided. PMID- 25701047 TI - COX-2 dependent regulation of mechanotransduction in human breast cancer cells. AB - The ability of living cells to exert physical forces upon their surrounding is a necessary prerequisite for diverse biological processes, such as local cellular migrations in wound healing to metastatic-invasion of cancer. How forces are coopted in metastasis has remained unclear, however, because the mechanical interplay between cancer cells and the various stromal components has not been experimentally accessible. Current dogma implicates inflammation in these mechanical processes. Using Fourier transform traction microscopy, we measured the force-generating capacity of human breast cancer cells occupying a spectrum of invasiveness as well as basal and inducible COX-2 expression (MCF-7 5.5 corresponded to an increased likelihood of cirrhosis (LR: 6.5, 95% CI: 4.3, 11.0) and a MCALD score < 5.5 corresponded to decreased likelihood of cirrhosis in alcoholics (LR: 0.25, 95% CI: 0.19, 0.36). Sobriety platelet count (after alcohol abstinence) at a cutoff of 160*10(3) had positive LR of 7.9 (95% CI: 4.4, 14) and negative LR of 0.42 (95% CI: 0.34, 0.52) for predicting cirrhosis in alcoholics. CONCLUSIONS: A simple model of platelet count and INR has good diagnostic accuracy for identifying cirrhosis in alcoholics. PMID- 25701050 TI - To lead or not to lead? Structure and content of leadership development programs. PMID- 25701052 TI - Bone marrow fat is increased in chronic kidney disease by magnetic resonance spectroscopy. AB - In aging, the bone marrow fills with fat and this may lead to higher fracture risk. We show that a bone marrow fat measurement by magnetic resonance spectroscopy (MRS), a newer technique not previously studied in chronic kidney disease (CKD), is useful and reproducible. CKD patients have significantly higher bone marrow fat than healthy adults. INTRODUCTION: Renal osteodystrophy leads to increased morbidity and mortality in patients with CKD. Traditional bone biopsy histomorphometry is used to study abnormalities in CKD, but the bone marrow, the source of osteoblasts, has not been well characterized in patients with CKD. METHODS: To determine the repeatability of bone marrow fat fraction assessment by MRS and water-fat imaging (WFI) at four sites in patients with CKD, testing was performed to determine the coefficients of reproducibility and intraclass coefficients (ICCs). We further determined if this noninvasive technique could be used to determine if there are differences in the percent bone marrow fat in patients with CKD compared to matched controls using paired t tests. RESULTS: The mean age of subjects with CKD was 59.8 +/- 7.2 years, and the mean eGFR was 24 +/ 8 ml/min. MRS showed good reproducibility at all sites in subjects with CKD and controls, with a coefficient of reproducibilities ranging from 2.4 to 13 %. MRS and WFI assessment of bone marrow fat showed moderate to strong agreement (ICC 0.6-0.7) at the lumbar spine, with poorer agreement at the iliac crest and no agreement at the tibia. The mean percent bone marrow fat at L2-L4 was 13.8 % (95 % CI 8.3-19.7) higher in CKD versus controls (p < 0.05). CONCLUSIONS: MRS is a useful and reproducible technique to study bone marrow fat in CKD. Patients with CKD have significantly higher bone marrow fat than healthy adults; the relationship with bone changes requires further analyses. PMID- 25701053 TI - Living every minute. PMID- 25701054 TI - Hypertrophic Pulmonary Osteoarthropathy: A Rare But Treatable Condition in Palliative Medicine. PMID- 25701055 TI - Patient and Caregiver Opinions of Motivational Interviewing Techniques In Role Played Palliative Care Conversations: A Pilot Study. AB - CONTEXT: Although many have examined the role of motivational interviewing (MI) in diverse health care encounters, no one has explored whether patients and caregivers facing serious illnesses identify specific MI techniques as helpful. OBJECTIVES: The aim of this pilot study was to describe how patients and caregivers perceived MI techniques in palliative care role-play encounters. METHODS: About 21 patients and caregivers participated in a role-play encounter where we asked the participant to act out being ambivalent or reluctant regarding the goals of care decision. The participant met with either an MI-trained physician or a physician who was not trained in MI (usual care). After the simulated encounter, we conducted cognitive interviews ("think-aloud" protocol) asking participants to identify "helpful" or "unhelpful" things physicians said. Participants also completed a perceived empathy instrument as a fidelity test of the MI training of the physician. RESULTS: Qualitative analyses revealed that participants independently identified the following helpful communication elements that are consistent with core MI techniques: reflection and validation of values, support of autonomy and flexibility, and open questions acting as catalysts for discussion. Participants rated the MI-trained physician slightly higher on the perceived empathy scale. CONCLUSION: This pilot study represents the first exploration of patient and caregiver perceptions of helpful techniques in palliative care conversations. Use of MI techniques shows promise for improving palliative care discussions. PMID- 25701056 TI - [Endocarditis due to Streptococcus tigurinus: presentation of a case and a review of the literature]. PMID- 25701057 TI - [Implementation of an automatic alarms system for early detection of patients with severe sepsis]. AB - OBJECTIVE: The objective of this study was to assess the usefulness of a software tool integrated into the medical electronic history at the time of emergency triage. The aim was the early detection of patients with severe sepsis, and the potential impact of this software tool on reducing the mortality rate in patients treated. METHOD: The study consisted of two comparative samples. Patient selection was performed retrospectively into two groups using ICD-9 codes from the hospital and emergency department discharge reports. The codes were 038.9, 995.9 and 995.92 for sepsis, and 785.52 for severe sepsis and septic shock. The sample called "alarms" consisted of patients studied after implementing the sepsis alarm system in the Emergency Department computer system. There were two types of alarms, a serious one and an alert one depending on the on vital signs defined. The historical sample called "no alarms" consisted of patients seen in the Emergency Department during the year before the introduction of the alarm system. RESULTS: The compliance rate of the sepsis treatment package was higher in the "alarms" sample, compared to the sample without alarms, with blood cultures, 96.3% versus 80.9% (P<.001), antibiotic treatment in less than one hour, 62.9% vs. 39.3% (P<.001), determination of lactic acid, 91.4% vs. 77.9% (P<.001), and applying appropriate volume, 57.7% vs 54.3% (P=.052), respectively. The hospital mortality was reduced in absolute terms from 25% in the sample without alarms to 13.6% in the sample with alarms. Survival at 30 days was higher in the sample with alarms (Log Rank=.004). CONCLUSIONS: There were no studies that evaluated the effectiveness of an alarm system in our literature search. An electronic identification system for patients with sepsis allows acting earlier, better compliance with basic measures, and a reduction in hospital stay and mortality. PMID- 25701058 TI - Minimally invasive duodenojejunostomy for superior mesenteric artery syndrome: a case series and review of the literature. AB - BACKGROUND: Superior mesenteric artery syndrome (SMAS) is a disorder characterized by vascular compression of the duodenum leading to mechanical obstruction. Surgical intervention is indicated in patients who fail standard non operative management, in which duodenojejunostomy is favored based on previous small series. Given the rarity of the condition, knowledge of the optimal indications for surgery, risk of postoperative complications, and prognosis of SMAS after minimally invasive duodenojejunostomy is limited. METHODS: A retrospective chart review was performed on patients who underwent minimally invasive duodenojejunostomy for SMAS from March 2005 to December 2013 at our "healthcare system". We analyzed patients' presentations, work-up, surgical therapy, and outcomes. RESULTS: A series of 14 patients with SMAS underwent minimally invasive duodenojejunostomy. All of these patients met clinical criteria of SMAS with radiological confirmation. Average weight loss before surgery was 10.7 kg. Depression and eating disorders were comorbid in 6/14 patients. The mean age was 39 years (19-91 years). Twelve operations were completed laparoscopically and two were performed with robotic assistance. Mean operation duration was 119 min and average length of hospital stay was 5.5 days. There were no immediate postoperative complications. One patient developed a delayed anastomotic stricture that improved with single endoscopic balloon dilation. Initial symptom improvement occurred in all patients and the improvement occurred in 11 patients (79%) during the follow-up. At a mean follow up of 20 months, two patients experienced complications, including one infection at a simultaneously placed J-tube site and one patient with dumping syndrome. Mean weight gain was 3.8 kg (p < 0.01). CONCLUSION: SMAS should be considered a potential diagnosis in patients who present with a history of persistent postprandial vomiting, epigastric pain, and weight loss and confirmatory radiographic findings. In well-selected patients, minimally invasive duodenojejunostomy is a safe and effective treatment for SMAS with excellent short-term outcomes. PMID- 25701059 TI - Serum value of procalcitonin as a marker of intestinal damages: type, extension, and prognosis. AB - BACKGROUND: Ischemic and necrotic damages are complications of digestive diseases and require emergency management. Nevertheless, the decision to surgically manage could be delayed because of no sufficiently preoperative accurate marker of ischemia diagnosis, extension, and prognosis. METHODS: The aim of this study was to assess the predictive value of serum procalcitonin (PCT) levels for diagnosing intestinal necrotic damages, their extension, and their prognosis in patients with ischemic disease including ischemic colitis and mesenteric infarction by a gray zone approach. Between January 2007 to June 2014, 128 patients with ischemic colitis and mesenteric infarction (codes K55.0 and K51.9) were operated, for whom data on PCT were available. We perform a retrospective, multicenter review of their medical records. Patients were divided into subgroups: ischemia (ID group) versus necrosis (ND group); the extension [focal (FD) vs. extended (ED)] and the vital status [deceased (D) vs. alive (A)]. RESULTS: PCT levels were higher in the ND (n = 94; p = 0.009); ED (n = 100; p = 0.02); and D (n = 70; p = 0.0003) groups. With a gray zone approach, the predictive thresholds were (i) for necrosis 2.473 ng/mL, (ii) for extension 3.884 ng/mL, and (iii) for mortality 7.87 ng/mL. CONCLUSION: In our population, PCT could be used as a marker of necrosis; especially in case of extended damages and reflects the patient's prognosis. PMID- 25701060 TI - Endoscopic full-thickness resection with defect closure using an over-the-scope clip for gastric subepithelial tumors originating from the muscularis propria. AB - BACKGROUND: Endoscopic full-thickness resection (EFTR) is a mini-invasive technique for gastric subepithelial tumors originating from the muscularis propria, which enables a full-thickness resection of tumors and can provide a complete basis for pathological diagnosis. Gastric fistula closure after EFTR is a challenge for endoscopists. In this study, we introduced EFTR with fistula closure using the over-the-scope clip (OTSC) system for gastric subepithelial tumors originating from the muscularis propria. OBJECTIVES: To evaluate the feasibility and safety of fistula closure with OTSC by a retrospective analysis on the cases of EFTR with defect closure using OTSC for gastric subepithelial tumors originating from the muscularis propria in our hospital. METHODS: The patients were selected who underwent EFTR for gastric subepithelial tumors originating from the muscularis propria (tumor diameter <=2 cm) in our hospital from October 2013 to March 2014. After a full-thickness resection of tumors, the bilateral gastric mucous membranes of defect were clamped using twin graspers and then drawn into the transparent cap of OTSC, and the OTSC was released to close the defect after full suctioning. The success rate of defect closure with OTSC was observed, and the endoscopic follow-up was performed at 1 week, 1 and 6 months after operation to check OTSC closure. RESULTS: Totally 23 patients were included into the study. The full-thickness resection rate of gastric tumors in the muscularis propria was 100 % (23/23), the success rate of defect closure was 100 %, and the average time of defect closure was 4.9 min (range 2-12 min). All patients experienced no postoperative complications such as bleeding and perforation. The postoperative follow-up time was 1-6 months (mean 3 months), and no OTSC detachment was found. CONCLUSIONS: OTSC can be used to perform EFTR with defect closure for gastric tumors in the muscularis propria (tumor diameter <=2 cm). It is simple, convenient, safe and effective. PMID- 25701061 TI - Medical SPIN: misinformation by another name. PMID- 25701062 TI - Initiating statistical process control to improve quality outcomes in colorectal surgery. AB - BACKGROUND: Unexpected variations in postoperative length of stay (LOS) negatively impact resources and patient outcomes. Statistical process control (SPC) measures performance, evaluates productivity, and modifies processes for optimal performance. The goal of this study was to initiate SPC to identify LOS outliers and evaluate its feasibility to improve outcomes in colorectal surgery. METHODS: Review of a prospective database identified colorectal procedures performed by a single surgeon. Patients were grouped into elective and emergent categories and then stratified by laparoscopic and open approaches. All followed a standardized enhanced recovery protocol. SPC was applied to identify outliers and evaluate causes within each group. RESULTS: A total of 1294 cases were analyzed--83% elective (n = 1074) and 17% emergent (n = 220). Emergent cases were 70.5% open and 29.5% laparoscopic; elective cases were 36.8% open and 63.2% laparoscopic. All groups had a wide range in LOS. LOS outliers ranged from 8.6% (elective laparoscopic) to 10.8% (emergent laparoscopic). Evaluation of outliers demonstrated patient characteristics of higher ASA scores, longer operating times, ICU requirement, and temporary nursing at discharge. Outliers had higher postoperative complication rates in elective open (57.1 vs. 20.0%) and elective lap groups (77.6 vs. 26.1%). Outliers also had higher readmission rates for emergent open (11.4 vs. 5.4%), emergent lap (14.3 vs. 9.2%), and elective lap (32.8 vs. 6.9%). Elective open outliers did not follow trends of longer LOS or higher reoperation rates. CONCLUSIONS: SPC is feasible and promising for improving colorectal surgery outcomes. SPC identified patient and process characteristics associated with increased LOS. SPC may allow real-time outlier identification, during quality improvement efforts, and reevaluation of outcomes after introducing process change. SPC has clinical implications for improving patient outcomes and resource utilization. PMID- 25701063 TI - Significant pressure differences between solid-state and water-perfused systems in lower esophageal sphincter measurement. AB - OBJECTIVE: High-resolution manometry of the esophagus has gained worldwide acceptance, using different solid-state catheters. Thus, normal values for lower esophageal sphincter (LES) resting pressure in suspected gastroesophageal reflux disease patients have been established using water-perfused manometry. These standard values are commonly applied using also solid-state techniques, although they have never been compared before. The aim of the study was to compare LES measurements obtained with water-perfused manometry with a solid-state technique. METHODS: Thirty healthy subjects were studied twice on the same day: Technique 1: Station pull through using a water-perfused catheter with ports arranged at 0 degrees , 90 degrees , 180 degrees and 270 degrees which were averaged to give a mean LES pressure. Technique 2: Solid-state circumferential probe with a single station pull through. Data were collected using the same computer system and program. The LES pressures were randomly and blindly analyzed. RESULTS: Twenty seven subjects out of 30 were analyzed. Using the solid-state system, the mean LES pressure was higher (15.0 vs. 23.3 mmHg, p = 0.003) and 19 of 27 (70%) individual measurements were higher. Two subjects had a hypertensive LES by solid state (58.6 resp. 47.5 mmHg), while their pressures were normal with water perfused manometry (21.0 resp. 23.4 mmHg). The distal esophageal pressures (mean of pressure at 3 and 8 cm above LES) were the same with the two techniques. CONCLUSION: In normal control subjects, LES measurement using circumferential solid-state transducers yields higher pressures than standard water-perfused manometry. Which system yields the "true" resting pressure of the physiologic LES remains to be determined. PMID- 25701064 TI - Reply: Cortical differences in preliterate children at familiar risk of dyslexia are similar to those observed in dyslexic readers. PMID- 25701065 TI - Cortical differences in preliterate children at familiar risk of dyslexia are similar to those observed in dyslexic readers. PMID- 25701066 TI - [Perioperative evaluation and treatment of cardiovascular risk patients for noncardiac surgery : Guidelines of the European Society of Cardiology/European Society of Anaesthesiology 2014]. AB - In late summer 2014, the joint working group of the European Society of Cardiology (ESC) and the European Society of Anaesthesiology (ESA) presented new guidelines for the evaluation and treatment of cardiovascular risk patients undergoing noncardiac surgery. In addition to the preoperative collation of patient and intervention-specific risks, the guidelines deal with anaesthesiological and cardiological aspects of the perioperative management of patients with diseases of the heart and common comorbidities. This article summarizes the essential aspects of the guidelines in a clearly arranged form. PMID- 25701067 TI - [Coping with complex medical emergency situations : Competent and successful decision-making, communication and leadership]. AB - BACKGROUND: Stress is an integral part of the daily routine among healthcare workers in anesthesiology and emergency medicine. OBJECTIVES: This article describes negative stress effects in complex emergency situations and presents helpful tools for coping with them. MATERIAL AND METHODS: Evaluation and discussion of selected medical and psychological publications and the inclusion of expert opinions are presented. RESULTS: Negative stress of healthcare providers in medical emergencies severely affects their reasoning and communication and is inadequately taken into account during routine care. CONCLUSION: Research in aviation and psychology has provided various tools to improve performance during stressful events and should be taken into consideration for routine daily use. PMID- 25701068 TI - A comparison of depression scores between aesthetic and functional rhinoplasty patients. AB - Depression is a mood state of sadness, gloom, and pessimistic ideation with loss of interest or pleasure in normal activities. This mood disorder has been reported to occur more frequently among cosmetic surgery patients. The purpose of the current study was to compare the score of depression among aesthetic rhinoplasty candidates and functional rhinoplasty patients as control group. The Beck Depression Inventory (BDI) and Depression (DE) subscale of Symptom Check List-90-Revised (SCL-90-R) were administered on a sample of aesthetic rhinoplasty patients (n=21) as well as a sample of functional rhinoplasty patients (n=21). Those with both cosmetic and functional purposes were categorized regarding their primary objective. Questionnaires were given to patients preoperatively. Cohen's d was also calculated as a measure of Effect Size (ES). BDI and SCL-90-R-DE scores were analyzed using t-test for independent groups. Statistical analyses suggested that the mean BDI and SCL-90-R-DE scores of aesthetic surgery patients were significantly higher than those of functional surgery patients (P<0.05). The results showed that age, sex, and Socio-Economic Status (SES) were not significantly different between the two groups as they can be capable of influencing the depression score. Effect size was above the moderate level: d=0.51, d=0.72 for BDI and SCL-90-R-DE, respectively. Using two different depression instruments, the findings of this study showed that aesthetic rhinoplasty patients were more depressed in comparison with functional rhinoplasty patients. The measures of ES also supported the hypothesis that aesthetic rhinoplasty candidates had higher scores in depression. PMID- 25701069 TI - Opportunities and barriers in service delivery through mobile phones (mHealth) for Severe Mental Illnesses in Rajasthan, India: A multi-site study. AB - Widespread use of mobile technology holds a lot of promise for mental health service delivery in regions where mental health resources are scarce and the treatment gap is large. The felt needs of the clients, and the patterns and barriers of mobile usage must be understood before some intervention can be planned. The study presented in this paper was designed to fill this gap in the region of Rajasthan, India. The study was conducted in three tertiary care hospitals. Clients utilizing services for Severe Mental Illnesses (SMIs) were the participants of the study. Information about ownership, usage patterns and barriers to accessing mobile technology and felt needs in terms of mental health services that could be delivered through mobile phones were sought from the participants. The typical respondents in all three centres were middle-aged, married, Hindu males belonging to lower socio-economic strata from rural background. Seventy two to 92% of participants had access to mobile phone. The most preferred mode of service delivery was through calls. Helpline for crisis resolution and telephonic follow-up of stable patients emerged as the most felt need of the participants. Barriers to mobile phones usage included affordability, lack of necessity, poor signal. In conclusion, the study shows that the access to mobile phones amongst clients receiving services for SMI is widespread and offers new opportunities in service delivery in the region. PMID- 25701070 TI - Long-term results of a randomized controlled trial analyzing the role of systematic pre-operative coronary angiography before elective carotid endarterectomy in patients with asymptomatic coronary artery disease. AB - OBJECTIVES: To evaluate the potential benefit of systematic preoperative coronary artery angiography followed by selective coronary-artery revascularization on the incidence of myocardial infarction (MI) in patients undergoing carotid endarterectomy (CEA) without a previous history of coronary artery disease (CAD). METHODS: We randomised 426 patients who were candidates for CEA, with no history of CAD, a normal electrocardiogram (ECG), and a normal cardiac ultrasound. In group A (n = 216) all patients underwent coronary angiography before CEA. In group B (n = 210) CEA was performed without coronary angiography. Patients were not blinded for relevant assessments during follow-up. Primary end-point was the occurrence of MI at 3.5 years. The secondary end-point was the overall survival rate. Median length of follow-up was 6.2 years. RESULTS: In group A, coronary angiography revealed significant coronary artery stenosis in 68 patients (31.5%). Among them, 66 underwent percutaneous Intervention (PCI) prior to CEA and 2 received combined CEA and coronary-artery bypass grafting (CABG). Postoperatively, no MI was observed in group A, whereas 6 MI occurred in group B, one of which was fatal (p = .01). During the study period, 3 MI occurred in group A (1.4%) and 33 were observed in group B (15.7%), 6 of which were fatal. The Cox model demonstrated a reduced risk of MI for patients in group A receiving coronary angiography (HR,.078; 95% CI, 0.024-0.256; p < .001). In addition, patients with diabetes and patients <70 years presented with an increased risk of MI. Survival analysis at 6 years by Kaplan-Meier estimates was 95.6 +/- 3.2% in Group A and 89.7 +/- 3.7% in group B (Log Rank = 6.54, p = .01). CONCLUSIONS: In asymptomatic coronary-artery patients, systematic coronary angiography prior to CEA followed by selective PCI or CABG significantly reduces the incidence of late MI and increases long-term survival. (ClinicalTrials.gov number, NCT02260453). PMID- 25701071 TI - Epidemiological study on chronic venous disease in Belgium and Luxembourg: prevalence, risk factors, and symptomatology. AB - OBJECTIVE: This epidemiological study measured the prevalence of chronic venous disease (CVD) in Belgium and Luxembourg. Possible risk factors and the symptomatology were evaluated. MATERIAL AND METHODS: A survey was carried out in Belgium and Luxembourg between May and September 2013. Patient recruitment was carried out by 406 general practitioners (GPs). Each GP screened 10-20 consecutive patients older than 18 years, and in total 6009 patients were included. Patient characteristics, prevalence of risk factors, symptomatology, and C-classification were noted. The GPs diagnosed CVD and measured the need for treatment. Patients with diagnosed CVD completed a questionnaire about their history of leg problems and a quality of life score (CIVIQ-14). These data were converted into a CIVIQ Global Index Score (GIS). RESULTS: The mean age of the patients was 53.4 years, and they were predominantly female (67.5%). Among the 3889 symptomatic patients, heavy legs, pain, and sensation of leg swelling were the most common complaints. Among the included patients, 61.3% of patients were classified within C1-C6; however, only 45.9% of these patients were considered by the GPs to be suffering CVD. Treatment was offered to 49.5% of patients. Age and female gender correlate with a higher C-class (p < .001). Patients with a higher C-class (C3-C6) have significantly more pain, sensation of swelling and burning, night cramps, itching, and the sensation of "pins and needles" in the legs. Patients taking regular exercise and without a family history had a lower C class. Higher BMI, age, female gender, family history, history of thrombophlebitis, and a higher C-class correlated with a lower GIS (p < .001). Of the patients with CVD, 10.4% had lost days of work because of their venous leg problems. CONCLUSION: CVD is a very common disease, which is underestimated. The prevalence increases with age, generates incapacity to work, and worsens the patients' quality of life. PMID- 25701072 TI - Elastin is a key regulator of outward remodeling in arteriovenous fistulas. AB - OBJECTIVES: Maturation failure is the major limitation of arteriovenous fistulas (AVFs) as hemodialysis access conduits. Indeed, 30-50% of AVFs fail to mature due to intimal hyperplasia and insufficient outward remodeling. Elastin has emerged as an important determinant of vascular remodeling. Here the role of elastin in AVF remodeling in elastin haplodeficient (eln(+/-)) mice undergoing AVF surgery has been studied. METHODS: Unilateral AVFs between the branch of the jugular vein and carotid artery in an end to side manner were created in wild-type (WT) C57BL/6 (n = 11) and in eln(+/-) mice (n = 9). Animals were killed at day 21 and the AVFs were analyzed histologically and at an mRNA level using real-time quantitative polymerase chain reaction. RESULTS: Before AVF surgery, a marked reduction in elastin density in the internal elastic lamina (IEL) of eln(+/-) mice was observed. AVF surgery resulted in fragmentation of the venous internal elastic lamina in both groups while the expression of the tropoelastin mRNA was 53% lower in the eln(+/-) mice than in WT mice (p < .001). At 21 days after AVF surgery, the circumference of the venous outflow tract of the AVF was 21% larger in the eln(+/-) mice than in the WT mice (p = .037), indicating enhanced outward remodeling in the eln(+/-) mice. No significant difference in intimal hyperplasia was observed. The venous lumen of the AVF in the eln(+/-) mice was 53% larger than in the WT mice, although this difference was not statistically significant (eln(+/-), 350,116 +/- 45,073 MUm(2); WT, 229,405 +/- 40,453 MUm(2); p = .064). CONCLUSIONS: In a murine model, elastin has an important role in vascular remodeling following AVF creation, in which a lower amount of elastin results in enhanced outward remodeling. Interventions targeting elastin degradation might be a viable option in order to improve AVF maturation. PMID- 25701073 TI - Phylogenetic analyses of eurotiomycetous endophytes reveal their close affinities to Chaetothyriales, Eurotiales, and a new order - Phaeomoniellales. AB - Symbiotic fungi living in plants as endophytes, and in lichens as endolichenic fungi, cause no apparent symptoms to their hosts. They are ubiquitous, ecologically important, hyperdiverse, and represent a rich source of secondary compounds for new pharmaceutical and biocontrol products. Due in part to the lack of visible reproductive structures and other distinctive phenotypic traits for many species, the diversity and phylogenetic affiliations of these cryptic fungi are often poorly known. The goal of this study was to determine the phylogenetic placement of representative endophytes within the Eurotiomycetes (Pezizomycotina, Ascomycota), one of the most diverse and evolutionarily dynamic fungal classes, and to use that information to infer processes of macroevolution in trophic modes. Sequences of a single locus marker spanning the nuclear ribosomal internal transcribed spacer region (nrITS) and 600 base pairs at the 5' end of the nuclear ribosomal large subunit (nrLSU) were obtained from previous studies of >6000 endophytic and endolichenic fungi from diverse biogeographic locations and hosts. We conducted phylum-wide phylogenetic searches using this marker to determine which fungal strains belonged to Eurotiomycetes and the results were used as the basis for a class-wide, seven-locus phylogenetic study focusing on endophytic and endolichenic Eurotiomycetes. Our cumulative supermatrix-based analyses revealed that representative endophytes within Eurotiomycetes are distributed in three main clades: Eurotiales, Chaetothyriales and Phaeomoniellales ord. nov., a clade that had not yet been described formally. This new order, described herein, is sister to the clade including Verrucariales and Chaetothyriales. It appears to consist mainly of endophytes and plant pathogens. Morphological characters of endophytic Phaeomoniellales resemble those of the pathogenic genus Phaeomoniella. This study highlights the capacity of endophytic and endolichenic fungi to expand our understanding of the ecological modes associated with particular clades, and provides a first estimation of their phylogenetic relationships in the Eurotiomycetes. PMID- 25701074 TI - Can we identify patients with high risk of osteoarthritis progression who will respond to treatment? A focus on epidemiology and phenotype of osteoarthritis. AB - Osteoarthritis is a syndrome affecting a variety of patient profiles. A European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis and the European Union Geriatric Medicine Society working meeting explored the possibility of identifying different patient profiles in osteoarthritis. The risk factors for the development of osteoarthritis include systemic factors (e.g., age, sex, obesity, genetics, race, and bone density) and local biomechanical factors (e.g., obesity, sport, joint injury, and muscle weakness); most also predict disease progression, particularly joint injury, malalignment, and synovitis/effusion. The characterization of patient profiles should help to better orientate research, facilitate trial design, and define which patients are the most likely to benefit from treatment. There are a number of profile candidates. Generalized, polyarticular osteoarthritis and local, monoarticular osteoarthritis appear to be two different profiles; the former is a feature of osteoarthritis co-morbid with inflammation or the metabolic syndrome, while the latter is more typical of post-trauma osteoarthritis, especially in cases with severe malalignment. Other biomechanical factors may also define profiles, such as joint malalignment, loss of meniscal function, and ligament injury. Early- and late-stage osteoarthritis appear as separate profiles, notably in terms of treatment response. Finally, there is evidence that there are two separate profiles related to lesions in the subchondral bone, which may determine benefit from bone-active treatments. Decisions on appropriate therapy should be made considering clinical presentation, underlying pathophysiology, and stage of disease. Identification of patient profiles may lead to more personalized healthcare, with more targeted treatment for osteoarthritis. PMID- 25701075 TI - TNFalpha is required for the production of T-type Ca(2+) channel-dependent long term potentiation in visual cortex. AB - Monocular deprivation produces depression and potentiation of visual responses evoked in visual cortical neurons by stimulation of deprived and nondeprived eyes, respectively, during the critical period of ocular dominance plasticity. Our previous studies suggested that T-type Ca(2+) channel-dependent long-term potentiation (LTP), induced by 2 Hz stimulation, mediates the potentiation of visual responses. However, it was proposed that the experience-dependent response potentiation is mediated by tumor necrosis factor-alpha (TNFalpha)-dependent homeostatic synaptic scaling but not by Hebbian synaptic plasticity, because the potentiation was absent in TNFalpha knockout (TNFalpha-KO) mice. In this study, we investigated whether TNFalpha is required for LTP induced by 2 Hz stimulation using visual cortical slices prepared from critical period mice and rats. The production of LTP was prevented by pharmacological blockade of TNFalpha in rats and mice. LTP production was also prevented by an inhibitor of TNFalpha converting enzyme that converts membrane-bound TNFalpha to soluble TNFalpha. In TNFalpha-KO mice, LTP did not occur and was rescued by exogenous soluble TNFalpha. Soluble TNFalpha was required for LTP production only during a restricted time window soon after 2 Hz stimulation. These results strengthen the view that T-type Ca(2+) channel-dependent LTP contributes to the potentiation of nondeprived eye responses following monocular deprivation. PMID- 25701076 TI - Systems biologic analysis of T regulatory cells genetic pathways in murine primary biliary cirrhosis. AB - CD4(+)Foxp3(+) regulatory T cells (Tregs) play a non-redundant role in control of excessive immune responses, and defects in Tregs have been shown both in patients and murine models of primary biliary cirrhosis (PBC), a progressive autoimmune biliary disease. Herein, we took advantage of a murine model of PBC, the dominant negative transforming growth factor beta receptor II (dnTGFbetaRII) mice, to assess Treg genetic defects and their functional effects in PBC. By using high resolution microarrays with verification by PCR and protein expression, we found profound and wide-ranging differences between dnTGFbetaRII and normal, wild type Tregs. Critical transcription factors were down-regulated including Eos, Ahr, Klf2, Foxp1 in dnTGFbetaRII Tregs. Functionally, dnTGFbetaRII Tregs expressed an activated, pro-inflammatory phenotype with upregulation of Ccl5, Granzyme B and IFN-gamma. Genetic pathway analysis suggested that the primary effect of loss of TGFbeta pathway signaling was to down regulate immune regulatory processes, with a secondary upregulation of inflammatory processes. These findings provide new insights into T regulatory genetic defects; aberrations of the identified genes or genetic pathways should be investigated in human PBC Tregs. This approach which takes advantage of biologic pathway analysis illustrates the ability to identify genes/pathways that are affected both independently and dependent on abnormalities in TGFbeta signaling. Such approaches will become increasingly useful in human autoimmunity. PMID- 25701077 TI - Working Alliance in Patients with Severe Mental Illness Who Need a Crisis Intervention Plan. AB - Working alliance has been characterized as an important predictor of positive treatment outcomes. We examined whether illness insight, psychosocial functioning, social support and locus of control were associated with working alliance as perceived by both patient and clinician. We assessed 195 outpatients with psychotic or bipolar disorders. Our findings indicated that patients rated the alliance more positively when they experienced a greater need for treatment, fewer behavioral and social problems, and more psychiatric symptoms. Clinicians rated the alliance more positively in patients who reported fewer social problems and better illness insight. Patients' demographic characteristics, including being female and married, were also positively related to the clinician-rated alliance. Our results suggest that patients and clinicians have divergent perceptions of the alliance. Clinicians may need help developing awareness of the goals and tasks of patients with certain characteristics, i.e., singles, men, those with poor illness insight and those who report poor social functioning. PMID- 25701078 TI - Quality of life in psychosis: prevalence and associated factors in a Nigerian clinical population. AB - Aim of the study was to assess sociodemographic and clinical determinants of quality of life in psychotic patients in a general hospital population in Nigeria. Information was obtained on demography, duration of untreated illness (DUI) and functioning among Schizophrenia (368), schizoaffective disorder (70), and 214 patients with affective psychosis. Functioning was assessed using GAF, severity of psychopathology with PANSS and quality of life using WHOQoL-BREF. In general, the differences in the QoL across the three psychotic disorders were small. Linear regression analysis, showed that high GAF p < 0.001, medication adherence, p = 0.007 were associated with good QoL in schizophrenia, low PANSS p < 0.001 and short DUI p = 0.001 in schizoaffective disorder and low PANSS, high GAF p < 0.001 respectively in affective psychosis. QoL and its determinants in psychosis are not absolutely different. More research is required in this area. PMID- 25701079 TI - Genome sequence of aerobic anoxygenic phototrophic bacterium Erythrobacter sp. JL475, isolated from the South China Sea. AB - Erythrobacter sp. JL475 is a bacteriochlorophyll a-containing aerobic anoxygenic photo-heterotrophic bacterium. Here, we report the draft genome sequence of Erythrobacter sp. JL475 isolated from the South China Sea. It comprises ~3.26Mbp in 7 contigs with the G+C content of 61.7%. A total of 3042 protein-coding genes were obtained, and one complete photosynthetic gene cluster (~38Kbp) was found. PMID- 25701080 TI - Do echinoderm genomes measure up? AB - Echinoderm genome sequences are a corpus of useful information about a clade of animals that serve as research models in fields ranging from marine ecology to cell and developmental biology. Genomic information from echinoids has contributed to insights into the gene interactions that drive the developmental process at the molecular level. Such insights often rely heavily on genomic information and the kinds of questions that can be asked thus depend on the quality of the sequence information. Here we describe the history of echinoderm genomic sequence assembly and present details about the quality of the data obtained. All of the sequence information discussed here is posted on the echinoderm information web system, Echinobase.org. PMID- 25701081 TI - Diverting autophagic membranes for exocytosis. AB - We have recently shown that the Epstein Barr virus (EBV) incorporates the autophagic membrane label LC3B-II into mature virus particles. Upon EBV production, autophagic membranes are stabilized and infectious viral particle production is dependent on these, because ATG protein-deficiency dampens, whereas rapamycin induces, infectious particle production. Moreover, viral DNA accumulates in the cytosol when macroautophagy is impaired. We therefore conclude that EBV needs autophagic membranes for efficient enveloping during infectious viral particle production. Here, we discuss how EBV might incorporate lipidated LC3B (LC3B-II) into the viral envelope and how other viruses as well as cellular processes customize the macroautophagy machinery for exocytosis in the context of unconventional secretion. PMID- 25701082 TI - Entheseal changes and sexual division of labor in a North-African population: The case of the pre-Hispanic period of the Gran Canaria Island (11th-15th c. CE). AB - The aim of this paper is to investigate the relationship between entheseal changes and sexual division of labor in the pre-Hispanic population of Gran Canaria Island (Spain). Ethnohistorical records from the period of contact between Europeans and the Canarian indigenous population provide rich information about the different activities performed by men and women. For this purpose, entheseal changes in a sample of 138 individuals (82 males and 56 females) buried in ten pre-Hispanic cemeteries (11th and 15th centuries cal. CE) were analyzed. Forty-one entheses located in the clavicle, humerus, ulna and radius were analyzed (fibrous and fibro-cartilaginous attachment sites). Entheses were graded using a visual and descriptive standard which summarized the entheseal changes. This method interprets the changes as a sign of robustness on a scale from low to high development and includes enthesopathies. The intra- and inter-observer error of this method was minimal. Sex differences in the degree of robustness, bilateral asymmetry, sexual dimorphism and principal components analyses were tested in this sample. The results indicate significant variance in the entheseal robustness between males and females. They also suggest the impact of certain biomechanical chains (pronosupination, shoulder rotation, etc.) in entheseal changes. These results contribute to an interdisciplinary approach to the study of the sexual division of labor in the pre-Hispanic society of Gran Canaria. PMID- 25701084 TI - Work disability after diagnosis of hand-arm vibration syndrome. AB - PURPOSE: Our aim was to study the course of vasospastic and sensorineural symptoms after the clinical diagnosis of hand-arm vibration syndrome (HAVS), and the association of current HAVS symptoms with occupational status, self evaluation of health, quality of life, and work ability. METHODS: We gathered all HAVS cases diagnosed at the Finnish Institute of Occupational Health in Helsinki and Tampere during 1990-2008. A questionnaire was sent to all these patients (n = 241). Altogether 149 of them (62 %) returned the questionnaire. Cumulative lifelong vibration exposure was evaluated on the basis of the data in the patient files. RESULTS: On average, 8.5 years after the diagnosis of HAVS, approximately one-third of the patients reported improvement in symptoms of vibration-induced white finger (VWF) and the sensorineural symptoms. Young age and shorter exposure time were associated with improvement in VWF symptoms (p = 0.033 and p < 0.001, respectively). Persistent or deteriorated symptoms of both VWF and sensorineural symptoms were associated with lowered work ability, quality of life (EQ-5D), and general health, also after adjusting for age, smoking, and diseases other than HAVS. The patients' own prediction of work ability in 2 years was more negative if the VWF symptoms or sensorineural symptoms had continued after diagnosis of HAVS (p = 0.065 and p = 0.001, respectively). CONCLUSIONS: Our results suggest that in about two-thirds of the patients, the HAVS symptoms may stabilize or deteriorate in the follow-up. Considering the effects on work ability, timely prevention measures should be taken more actively to help patients continue their working careers. PMID- 25701083 TI - Screening for Barrett's Esophagus. AB - The large increase in the incidence of esophageal adenocarcinoma in the West during the past 30 years has stimulated interest in screening for Barrett's esophagus (BE), a precursor to esophageal cancer. Effective endoscopic treatments for dysplasia and intramucosal cancer, coupled with screening programs to detect BE, could help reverse the increase in the incidence of esophageal cancer. However, there are no accurate, cost-effective, minimally invasive techniques available to screen for BE, reducing the enthusiasm of gastroenterologists. Over the past 5 years, there has been significant progress in the development of screening technologies. We review existing and developing technologies, new minimally invasive imaging techniques, nonendoscopic devices for cell collection, and biomarkers that can be measured in blood or stool samples. We discuss the status of these approaches, data from clinical studies of their effects, and their anticipated strengths and weaknesses in screening. The area is rapidly evolving, and new tools will soon be ready for prime time. PMID- 25701085 TI - The Role of Twelve-Step-Related Spirituality in Addiction Recovery. AB - This paper reviews empirical studies conducted on the role of spirituality and religiosity (S/R) characteristics in 12-step recovery among program members followed up after substance abuse treatment and those assessed independent of formal treatment. Aspects of spiritual functioning that change in relation to program participation and those S/R characteristics that were found to mediate the association between program involvement and drinking-related outcomes are discussed. In addition, a review is provided of 12-step program studies investigating S/R-related predictors of clinical outcomes relevant to risk of relapse among members in long-term recovery. To further examine the role of S/R characteristics in recovery, a study was conducted on long-term AA members to assess the relationship of S/R characteristics and AA program involvement to craving for alcohol and emotional distress after controlling for relevant demographic variables. Feeling God's presence daily, believing in a higher power as a universal spirit, and serving as an AA sponsor were all predictive of positive outcomes. PMID- 25701086 TI - Analysis of degradation mechanism of disperse orange 25 in supercritical water oxidation using molecular dynamic simulations based on the reactive force field. AB - 4-[N-(2-cyanoethyl)-N-ethylamino]-4'-nitroazo-benzene (disperse orange 25, DO25) is one of the main components in dyeing wastewater. In this work, supercritical water oxidation (SCWO) process of DO25 has been investigated using the molecular dynamic simulations based on the reactive force field (ReaxFF). For the SCWO system, the effects of temperature, the molecular ratio of DO25, O2 and H2O as well as the reaction time have been analyzed. The simulated results showed that the aromatic rings in DO25 could be attacked by hydroxyl radical, oxygen molecule, and hydroxyl radical together with oxygen molecule, respectively, which caused the aromatic ring-opening reaction to happen mainly through three different pathways. The hydroxyl radicals were mainly from water clusters and H2O2 (which was produced from oxygen molecules reacting with water clusters). However, for the SCW system as comparison, the aromatic rings in DO25 could be attacked by hydroxyl radical only, and the OH radicals just come from water clusters. During the DO25 SCWO degradation process, we also found that N elements in one DO25 molecule were difficult to be converted into environmentally friendly N2 molecules because of steric hindrance, but increasing the number of DO25 molecules could improve the possibility for the connection of N elements, thus promoting N element converting into N2. Extending reaction time could also improve N elements in DO25 to transform into N2 rather than carbonitride. PMID- 25701087 TI - Enantiomeric discrimination of chiral organic salts by chiral aza-15-crown-5 ether with C 1 symmetry: experimental and theoretical approaches. AB - The work involves an experimental ((1)H NMR) and theoretical (MD, MM-PBSA and DFT) investigation of the molecular recognition and discrimination properties of a chiral aza-15-crown-5 against methyl esters of alanine, phenylalanine and valine hydrochloride salts. The results indicate that the receptor binds enantiomers with moderate binding constants (88-1,389 M(-1)), with phenylalanine being more discriminated. The difference in experimental binding free energies (DeltaG(R) - DeltaG(S)) for alanine, phenylalanine and valine enantiomers were calculated as -0.36, -1.58 and 0.80 kcal mol(-1), respectively. The differences in theoretical binding energies were calculated by MM-PBSA (DeltaE(R)PB - DeltaE(S)PB=) as -0.30, -1.45 and 0.88, by B3LYP/6-31+G(d) as -1.17, -0.84 and 0.74 and by M06-2X/6-31+G(d) as -1.40, -3.26 and 1.66 kcal mol(-1). The data obtained give valuable information regarding the molecular recognition mode of the organoammonium complexes of chiral aza-crown ether with C 1 symmetry, which may be relevant to biological systems. PMID- 25701088 TI - The structure of adsorbed cyclic chains. AB - In order to determine the structure of polymer films formed of cyclic chains (rings) we developed and studied a simple coarse-grained model. Our main goal was to check how the percolation and jamming thresholds in such a system were related to the thresholds obtained for linear flexible chains system, i.e., how the geometry of objects influenced both thresholds. All atomic details were suppressed and polymers were represented as a sequence of identical beads and the chains were embedded to a square lattice (a strictly 2D model). The system was athermal and the excluded volume was the only potential introduced. A random sequential adsorption algorithm was chosen to determine the properties of a polymer monolayer. It was shown that the percolation threshold of cyclic chains was considerably higher than those of linear flexible chains while the jamming thresholds for both chain architectures are very similar. The shape of adsorbed cyclic chains was found to be more prolate when compared to average single chain. PMID- 25701089 TI - The DFT study on the reaction between benzaldehyde and 4-amine-4H-1,2,4-triazole and their derivatives as a source of stable hemiaminals and Schiff bases. Effect of substitution and solvation on the reaction mechanism. AB - Reaction mechanism for the benzaldehyde (ald) and 4-amine-4H-1,2,4-triazole (4at) has been investigated at the DFT (B3LYP)/6-31+G(d) computational level. Three transition states (TS) have been identified. The TS1 corresponds to hydrogen transfer from the NH2 group to the C = O bond and nucleophillic attack of the carbon atom from the aldehyde group on the nitrogen atom from the NH2 group in 4at. The result of this reaction is the hemiaminal molecule. The TS2 characterises an internal rearrangement of the benzene and triazole rings in the hemiaminal molecule. The TS3 leads to breaking of the O-H bond, the elimination reaction of the H2O molecule, and formation of the C=N bond. The final product of this reaction is a Schiff base. In order to determine the most favorable conditions for hemiaminal formation, the influence of electronic structure modification on the energetic properties during the reaction of benzaldehyde and 4-amine-4H-1,2,4-triazole has been studied. Thirteen substituents: NH2, OH, OCH3, CH3, F, I, Cl, Br, COH, COOH, CF3, CN, NO2, with different Hammett's constant values (sigma = -0.66-+0.78) have been considered. Finally, the reaction mechanism has been investigated in the presence of 1 to 5 water molecules. PMID- 25701090 TI - On the intrinsic reactivity index for electrophilicity/nucleophilicity responses. AB - We present a critical discussion related to the recent definition of the intrinsic reactivity index, IRI, (Tetrahedron Lett. 2013, 54, 339-342; Tetrahedron 2013, 69, 4247-4258) formulated to describe both, electrophilicity (charge acceptance) and nucleophilicity (charge donation) reactivities. We here stress that such an IRI model, based on the quantity MU/eta, should be properly related to theoretical approximations associated to the change in the global electronic energy of a given chemical system under interaction with a suitable electron bath (Gazquez JL et al. J Phys Chem A 2007, 111, 1966-1970). Further, the limitations of the IRI model are presented by emphasizing that the intrinsic relative scales of electrophilicity and nucleophilicity within a second-order perturbation approach must account for the further stabilization of the two interacting species (Chamorro E et al. J Phys Chem A 2013, 117, 2636-2643). PMID- 25701091 TI - Expression of suppressor of cytokine signaling 1 (SOCS1) gene dramatically increases in relapsing-remitting multiple sclerosis. AB - Suppressor of cytokine signaling 1 (SOCS1) is a key regulator of cytokines signaling and plays the most important role in the regulation of the autoimmune responses. The absence of SOCS1 leads to aberrant thymocyte development and systemic inflammation. This study was conducted to evaluate the expression level of SOCS1 mRNA in peripheral blood mononuclear cells (PBMCs) of relapsing remitting (RR)-multiple sclerosis (MS) patients. In addition, the association of rs243324 SNP with MS and the assessment of this SNP role on the expression level of SOCS1 were aimed to be evaluated. Our results revealed that, SOCS1 mRNA overexpressed (24.5 times) in MS patients versus healthy controls. The rs243324 SNP showed no association with MS susceptibility and this SNP was not in Hardy Weinberg equilibrium in MS patients. Moreover, there was a significant correlation between SOCS1 expression levels with age of female control group (r= 0.43, P=0.03). Thus, we have probably shown some new evidences for the complex role of SOCS1 gene in the pathogenesis of MS. PMID- 25701092 TI - The inverse association between serum 25-hydroxyvitamin D and mortality may be modified by vitamin A status and use of vitamin A supplements. AB - BACKGROUND: Low serum 25-hydroxyvitamin D [25(OH)D] levels have been associated with higher risk of many diseases that affect mortality, including cardiovascular disease (CVD) and cancer. The inverse association between serum 25(OH)D and mortality may be modified by excess circulating vitamin A, due to interactions of vitamin A at the level of the vitamin D nuclear receptor. In this prospective cohort study, we investigated whether the association of 25(OH)D with all-cause, cancer, and CVD mortality was modified by circulating vitamin A or preformed vitamin A intake from supplements. METHODS: We analyzed 15,998 adults in the Third National Health and Nutrition Examination Survey (NHANES III), 1988-1994. Mortality data for all-cause (n = 3890), cancer (n = 844), and CVD mortality (n = 1715) were assessed through December 2006. Serum 25(OH)D was measured using a radioimmunoassay kit, vitamin A biomarkers were measured by HPLC, and information on supplement use was obtained by self-report. Multivariable hazard ratios (HRs) and corresponding 95% confidence intervals (CI) were estimated by proportional hazards regression. RESULTS: Serum 25(OH)D was significantly inversely associated with all-cause mortality (HR 0.93, 95% CI 0.89, 0.97, per 10 ng/mL increase) and also with CVD mortality and mortality due to non-cancer/non-cardiovascular causes, but not with cancer mortality. The observed inverse associations remained statistically significant only among participants with serum retinyl esters <7.0 MUg/dL. High intake (>5000 IU/day) of preformed vitamin A from supplements attenuated the inverse association of 25(OH)D with overall mortality. The observed interactions were not statistically significant. CONCLUSIONS: 25(OH)D was inversely associated with overall mortality, CVD mortality, and mortality due to non-cancer/non-CVD causes, but not with cancer mortality. A possible interaction between vitamin A exposure and 25(OH)D concentration appears to be associated with an attenuation of the inverse association between risk of death and quartile of 25(OH)D concentration. PMID- 25701093 TI - Effect of neonatal malnutrition on expression of nitric oxide synthase enzyme, production of free radicals and in vitro viability of alveolar macrophages infected with methicillin-sensitive and methicillin-resistant Staphylococcus aureus. AB - OBJECTIVE: Evaluate the effects of neonatal malnutrition on the microbicidal response and viability of in vitro macrophages infected with Staphylococcus aureus sensitive/resistant to methicillin. METHODS: Male Wistar rats (n = 24) were divided into two distinct groups: nourished (rats breast-fed by mothers undergoing diet with 17% casein) and malnourished (rats breast-fed by mothers undergoing diet with 8% casein). Macrophages were recovered after surgical tracheostomy procedure by collecting bronchoalveolar lavage. Four systems were established: negative control, composed only by phagocytes; positive control, macrophages plus lipopolysaccharide; and two test systems, macrophages plus Staphylococcus aureus sensitive and resistant to methicillin. Plates were incubated at 37 degrees C for 24 h. After this period, tests for the analysis of cell viability and microbicidal response were performed. In the statistical analysis, the Student's t and ANOVA tests were used, accepting p < 0.05. RESULTS: The neonatal malnutrition impaired the animals' body weight. There was a lower expression of the inducible nitric oxide enzyme (iNOS), nitric oxide production, and viability of macrophages infected with methicillin-resistant Staphylococcus aureus. However, increased production of superoxide anion in the malnourished group was detected. CONCLUSION: Neonatal malnutrition focusing on critical periods of development promoted lower expression of iNOS, nitric oxide production, cell viability, and exacerbated reactive oxygen species production. The high levels of reactive oxygen species may favor the onset of serious and systemic infections with fatal outcome if associated with methicillin-resistant Staphylococcus aureus. PMID- 25701094 TI - Ionic mechanisms of arrhythmogenesis. AB - The understanding of ionic mechanisms underlying cardiac rhythm disturbances (arrhythmias) is an issue of significance in the medical science community. Several advances in molecular, cellular, and optical techniques in the past few decades have substantially increased our knowledge of ionic mechanisms that are thought to underlie arrhythmias. The application of these techniques in the study of ion channel biophysics and regulatory properties has provided a wealth of information, with some important therapeutic implications for dealing with the disease. In this review, we briefly consider the cellular and tissue manifestations of a number of cardiac rhythm disturbances, while focusing on our current understanding of the ionic current mechanisms that have been implicated in such rhythm disturbances. PMID- 25701095 TI - Validation of an isotope dilution gas chromatography-mass spectrometry method for combined analysis of oxysterols and oxyphytosterols in serum samples. AB - We describe the validation of a method for the analysis of oxysterols, i.e. oxycholesterols and oxyphytosterols, in human serum using gas chromatography-mass spectrometry selected ion monitoring (GC-MS-SIM). Concentrations of 7alpha- and 7beta-hydroxy-, and 7oxo-cholesterol, -campesterol, and -sitosterol as well as 4beta-hydroxycholesterol and side-chain oxygenated 24S-, 25-, and 27 hydroxycholesterol were determined by isotope dilution methodology. After saponification at room temperature the oxysterols were extracted, separated from their substrates, cholesterol, campesterol, and sitosterol, by solid phase extraction, and subsequently derivatised to their corresponding trimethylsilyl ethers prior to GC-MS-SIM. In order to prevent artificial autoxidation butylated hydroxytoluene and ethylenediaminetetraacetic acid were added. The validation of the method was performed according to the International Conference on Harmonisation guidance, including limits of detection and quantification, ranges, recovery and precision. Due to improved instrumental settings and work-up procedure, limits of detection and quantification ranged between 8.0-202.0pg/mL and 28.0-674pg/mL, respectively. Recovery data in five calibration points varied between 91.9% and 116.8% and in serum samples between 93.1% and 118.1%. The mean coefficient of variation (CV) for the recovery of all compounds was <10%. Well satisfying CVs for within-day precision (2.1-10.8%) and for between-day precision (2.3-12.1%) were obtained. More than 20 samples could be processed in a single routine day and test series of about 300 samples can be realised without impairment of the validation parameters during a sequence. Comparison of oxysterol and oxyphytosterol content in serum and plasma revealed no difference. A fully validated isotope dilution methodology for the quantification of oxycholesterols and oxyphytosterols from human serum or plasma is presented. PMID- 25701096 TI - Microwave (MW) irradiated Ugi four-component reaction (Ugi-4CR): Expedited synthesis of steroid-amino acid conjugates--A novel class of hybrid compounds. AB - Microwave (MW) assisted chemical reactions are currently gaining considerable importance in organic synthesis to contribute in green technology. Considering the importance of peptidomimetic steroid-amino acid conjugates - a novel class of hybrid compounds having diverse biological properties, we report here synthesis of these compounds of alanine and valine methyl esters with seco-steroids (A, B and D ring cleavage) in expedited way by MW promoted Ugi-four-component reaction (Ugi-4CR). PMID- 25701097 TI - [Medicines shortage: Moving towards "regressive" medicine?]. PMID- 25701098 TI - [Drugs: Time to put a stop to mix-ups and errors]. PMID- 25701099 TI - Serum levels of nimodipine in enteral and parenteral administration in patients with aneurysmal subarachnoid hemorrhage. AB - BACKGROUND: The aim of this study was to evaluate serum nimodipine concentrations in patients with aneurysmal subarachnoid hemorrhage (SAH) after parenteral therapy and a following course of enteral administration. METHODS: SAH patients were treated with intravenous nimodipine (2 mg/h) during the 1st week after hemorrhage, and on day 8, we switched over to enteral administration (60 mg/4 h), either orally or by gavage. Serum nimodipine concentrations were measured on days 3, 5, 8, 9 and 12. Area under the curve (AUC) was calculated during parenteral and enteral therapy. The data of 15 patients were analyzed retrospectively. RESULTS: In this study, 157 blood samples were obtained. In seven samples, during the administration by gavage to two patients with high-grade SAH, the serum nimodipine concentrations were negligible. The AUC values during parenteral administration (median 149.3 ng-h/ml) were significantly higher than during oral administration on days 9 (median 92.1 ng-h/ml) and 12 (median 44.1 ng-h/ml) in seven patients (p = 0.030 and p = 0.016, respectively). The AUC values during parenteral administration were significantly higher than during administration by gavage on day 9 in eight patients (median 87.9 and 34 ng-h/ml, respectively, p = 0.001). The AUC values during enteral administration were higher in patients who received nimodine orally than in those who received it by gavage (median 52.3 and 23.1 ng-h/ml, respectively, p = 0.006). CONCLUSIONS: Enteral administration of nimodipine showed lower bioavailability during the 2nd week after SAH compared to parenteral application during the 1st week. Negligible serum concentrations were even expected when nimodipine was given by gavage in patients with high-grade SAH, thus suggesting that parenteral administration may be the better route in these patients. PMID- 25701100 TI - Ex vivo four-dimensional lung cancer model mimics metastasis. AB - BACKGROUND: We have developed a four-dimensional (4D) lung cancer model that forms perfusable tumor nodules. We determined if the model could be modified to mimic metastasis. METHODS: We modified the 4D lung cancer model by seeding H1299, A549, or H460 cells through the trachea only to the left lobes of the acellular lung matrix. The model was modified so that the tumor cells can reach the right lobes of the acellular lung matrix only through the pulmonary artery as circulating tumor cells (CTC). We determined the gene expressions of the primary tumor, CTCs, and metastatic lesions using the Human OneArray chip. RESULTS: All cell lines formed a primary tumor in the left lobe of the ex vivo 4D lung cancer model. The CTCs were identified in the media and increased over time. All cell lines formed metastatic lesions with H460 forming significantly more metastatic lesions than H1299 and A549 cells. The CTC gene signature predicted poor survival in lung cancer patients. Unique genes were significantly expressed in CTC compared with the primary tumor and metastatic lesion. CONCLUSIONS: The 4D lung cancer model can isolate tumor cells in 3 phases of tumor progression. This 4D lung cancer model may mimic the biology of lung cancer metastasis and may be used to determine its mechanism and potential therapy in the future. PMID- 25701101 TI - Does self-efficacy mediate functional change in older adults participating in an exercise program after hip fracture? A randomized controlled trial. AB - OBJECTIVES: To examine whether self-efficacy mediated the effect of the Home based Post-Hip Fracture Rehabilitation program on activity limitations in older adults after hip fracture and whether the mediating effect was different between sex and age groups. DESIGN: Randomized controlled trial. SETTING: Community. PARTICIPANTS: Participants with hip fracture (N=232; mean age +/- SD, 79+/-9.4y) were randomly assigned to intervention (n=120, 51.7%) and attention control (n=112, 48.3%) groups. INTERVENTIONS: The 6-month intervention, the Home-based Post-Hip Fracture Rehabilitation, is a functionally oriented, home-based exercise program. Data were collected at baseline, postintervention (6mo), and follow-up (9mo). MAIN OUTCOME MEASURES: Activity Measure for Post-Acute Care. RESULTS: The mediating effect of the Home-based Post-Hip Fracture Rehabilitation program on Basic Mobility function through self-efficacy for exercise was significant at 9 months (betaindirect=.21). Similarly, the mediating effect of the intervention on Daily Activity function through self-efficacy for exercise was significant at 9 months (betaindirect=.49). In subgroup analyses, the mediating effect was significant at 9 months in the younger group (age, <=79y) in comparison to the older group and was significant in women in comparison to men. CONCLUSIONS: Self efficacy may play a partial mediating role in the effect on some longer-term functional outcomes in the Home-based Post-Hip Fracture Rehabilitation intervention. The results suggest that program components that target self efficacy should be incorporated in future hip fracture rehabilitation interventions. Age and sex of the targeted participants may also need to be considered when developing interventions. PMID- 25701102 TI - Outcomes of a health coaching intervention delivered by medical students for older adults with uncontrolled type 2 diabetes. AB - Effective strategies are needed to address the health behaviors of older patients with diabetes. One approach is health coaching, the practice of health education and health promotion through a structured partnership designed to enhance well being and facilitate the achievement of individuals' health-related goals. The aim of this study was to describe the development of a pilot health coaching curriculum, investigate its effects on geriatric patient outcomes, and examine qualitative feedback by older patients and medical students to the curriculum. This mixed-methods study involved 29 first-year medical students randomly paired with 29 older adults with uncontrolled Type 2 diabetes. Health-related quality of life (HRQoL), stage of change movement, diabetes knowledge, locus of control, Body Mass Index (BMI), and glycosylated hemoglobin (HbA1c) were assessed. Focus groups were used to evaluate patients' and medical students' experiences. Results showed significant increases in patients' HRQoL and stage of change for exercise improved significantly over time. There were no significant changes in stage of change for healthy diet and medication, diabetes knowledge, BMI, and HbA1c from baseline to end of study. Focus group data indicated positive responses by older patients and the medical students. A health coaching curriculum may improve patient outcomes and can provide medical students the skills needed to provide compassionate care for geriatric patients. PMID- 25701103 TI - Evaluation of the monoamine oxidases inhibitory activity of a small series of 5 (azole)methyl oxazolidinones. AB - Oxazolidinone class of compounds continue to generate interest as promising agents effective against sensitive and resistant Gram-positive pathogenic bacteria strains. Recent focus is to develop new potent derivatives with improved broad-spectrum activity and safety profile superior to linezolid. An important toxicity issue for this class of compounds arises from the structural similarity with toloxatone, a known MAO inhibitor. Herein, we report the evaluation of a small series of 5-(1H-1,2,3-triazolyl)-, 5-(4-methyl-1H-1,2,3-triazolyl)-, 5-(5 methyl-1H-1,2,3-triazolyl)- and 5-imidazolyl-methyl oxazolidinone analogs with and without antibacterial activity for their effects as inhibitors of monoamine-A and -B (MAO-A and -B) oxidases. Substitutions at the oxazolidinone C-5 position significantly affected antibacterial activity and MAO inhibition. The N substituted-glycinyl 1H-1,2,3-triazolyl methyl oxazolidinones with potent antibacterial activity demonstrated only weak to moderate affinity for MAO-A and B, supporting further investigation for this group of compounds. PMID- 25701104 TI - The effectiveness of screening history, physical exam, and ECG to detect potentially lethal cardiac disorders in athletes: a systematic review/meta analysis. AB - BACKGROUND: The optimal cardiovascular preparticipation screen is debated. The purpose of this study was to perform a systematic review/meta-analysis of evidence comparing screening strategies. METHODS: PRIMSA guidelines were followed. Electronic databases were searched from January 1996 to November 2014 for articles examining the efficacy of screening with history and physical exam (PE) based on the American Heart Association (AHA) or similar recommendations and electrocardiogram (ECG). Pooled data was analyzed for sensitivity, specificity, false positive rates and positive and negative likelihood ratios. Secondary outcomes included rate of potentially lethal cardiovascular conditions detected with screening and the etiology of pathology discovered. RESULTS: Fifteen articles reporting on 47,137 athletes were reviewed. After meta-analysis the sensitivity and specificity of ECG was 94%/93%, history 20%/94%, and PE 9%/97%. The overall false positive rate of ECG (6%) was less than that of history (8%), or physical exam (10%). Positive likelihood ratios were ECG 14.8, history 3.22 and PE 2.93 and negative likelihood ratios were ECG 0.055, history 0.85, and PE 0.93. There were a total of 160 potentially lethal cardiovascular conditions detected for a rate of 0.3% or 1 in 294. The most common pathology was Wolff Parkinson-White (67, 42%), Long QT Syndrome (18, 11%), hypertrophic cardiomyopathy (18, 11%), dilated cardiomyopathy (11, 7%), coronary artery disease or myocardial ischemia (9, 6%) and arrhythmogenic right ventricular cardiomyopathy (4, 3%). CONCLUSIONS: The most effective strategy for screening for cardiovascular disease in athletes is ECG. It is 5 times more sensitive than history, 10 times more sensitive than physical exam, has higher positive likelihood ratio, lower negative likelihood ratio and a lower false positive rate. 12-lead ECG interpreted using modern criteria should be considered best practice in screening for cardiovascular disease in athletes while the use of history and physical alone as a screening tool should be reevaluated. PMID- 25701105 TI - The impact of MRI scanner environment on perceptual decision-making. AB - Despite the widespread use of functional magnetic resonance imaging (fMRI), few studies have addressed scanner effects on performance. The studies that have examined this question show a wide variety of results. In this article we report analyses of three experiments in which participants performed a perceptual decision-making task both in a traditional setting as well as inside an MRI scanner. The results consistently show that response times increase inside the scanner. Error rates also increase, but to a lesser extent. To reveal the underlying mechanisms that drive the behavioral changes when performing a task inside the MRI scanner, the data were analyzed using the linear ballistic accumulator model of decision-making. These analyses show that, in the scanner, participants exhibit a slow down of the motor component of the response and have less attentional focus on the task. However, the balance between focus and motor slowing depends on the specific task requirements. PMID- 25701106 TI - Assessing perceptual change with an ambiguous figures task: Normative data for 40 standard picture sets. AB - In many research domains, researchers have employed gradually morphing pictures to study perception under ambiguity. Despite their inherent utility, only a limited number of stimulus sets are available, and those sets vary substantially in quality and perceptual complexity. Here we present normative data for 40 morphing picture series. In all sets, line drawings of pictures of common objects are morphed over 15 iterations into a completely different object. Objects are either morphed from an animate to an inanimate object (or vice versa) or morphed within the animate and inanimate object categories. These pictures, together with the normative naming data presented here, will be of value for research on a diverse range of questions, from perceptual processing to decision making. PMID- 25701107 TI - Trying to separate the wheat from the chaff: Construct- and faking-related variance on the Implicit Association Test (IAT). AB - Recent research has indicated that diffusion model analyses allow the user to decompose the traditional IAT effect (D measure) into three newly developed IAT effects: IATv, which has already been shown to be significantly related to the construct-related variance of the IAT effect, and IATa and IATt0, both of which have been assumed to provide an indication of faking. But research on the impacts of faking on IATv, IATa, and IATt0 is still warranted. By reanalyzing a data set containing both faked and unfaked IAT effects, we investigated whether diffusion model analyses could be used to separate construct-related variance from faking related variance on the IAT. Our results revealed that this separation is not yet possible. As had already been shown for the traditional IAT effect, IATv was affected by faking. Interestingly, it was affected by faking only under more difficult faking conditions (i.e., when participants were asked to fake without being given recommended strategies for how to do so, and when they were requested to fake high scores). By contrast, IATa was affected by faking only in the comparably easy faking condition (i.e., when participants had been informed about possible faking strategies and were asked to fake low scores). IATt0 was not affected by faking at all. Our results show that although diffusion model analyses cannot yet provide a clear separation between construct- and faking related variance, they allow us to peer into the black box of the faking process itself, and thus provide a useful tool for analyzing and interpreting IAT scores. PMID- 25701108 TI - Can you hear what I feel? A validated prosodic set of angry, happy, and neutral Italian pseudowords. AB - This contribution aims to establish a set of validated vocal Italian pseudowords that convey three emotional tones (angry, happy, and neutral) for prosodic emotional processing research. We elaborated the materials by following a series of specific steps. First, we tested the valence of a set of written pseudowords generated by specific software. Two Italian actors (male and female) then recorded the resulting subset of linguistically legal and neutral pseudowords in three emotional tones. Finally, on the basis of the results of independent ratings of emotional intensity, we selected a set of 30 audio stimuli expressed in each of the three different emotions. Acoustic analyses indicated that the prosodic indexes of fundamental frequency, vocal intensity, and speech rate anchored individual perceptions of the emotions expressed. Finally, the acoustic profile of the set of emotional stimuli confirmed previous findings. The happy tone stimuli showed high f0 values, high intensity, high pitch variability, and a faster speech rate. The angry tone stimuli were also characterized by high f0 and intensity, but by relatively smaller pitch variability and a lower speech rate. This last profile echoes the description of "cold anger." This new set of prosodic emotion stimuli will constitute a useful resource for future research that requires emotional prosody materials. It could be used both for Italian and for cross-language studies. PMID- 25701109 TI - Association of CYP2D6*10, OATP1B1 A388G, and OATP1B1 T521C polymorphisms and overall survival of breast cancer patients after tamoxifen therapy. AB - BACKGROUND: The global incidence of breast cancer is increasing, mainly due to the sharp rise in breast cancer incidence in Asia. The aim of this study was to evaluate the association of CYP2D6*10 (c.100C>T and c.1039C>T), OATP1B1 A388G, and OATP1B1 T521C polymorphisms with overall survival (OS) for hormone receptor (estrogen receptor or progesterone receptor)-positive tumors (ER+/PR+) breast cancer patients after adjuvant tamoxifen (TAM) therapy. MATERIAL AND METHODS: We included 296 invasive breast cancer patients with hormone receptor-positive tumors during the period 2002-2009. We collected patient data, including clinical features, TAM therapy, and survival status. Archived paraffin blocks from surgery were the source of tissue for genotyping. CYP2D6*10, OATP1B1 A388G, and T521C polymorphisms were detected by direct sequencing of genomic DNA. OS was assessed with Kaplan-Meier analysis, while the Cox proportional hazards model was used to implement multivariate tests for the prognostic significance. RESULTS: There was a significant difference in OS between OATP1B1 T521C wild-type and the mutant genotype C carrier (P=0.034). However, there was no difference in overall survival between wild-type and carrier groups for CYP2D6*10 (P=0.096) and OATP1B1 A388G (P=0.388), respectively. CONCLUSIONS: These results suggest that the OATP1B1 T521C mutation may be an independent prognostic marker for breast cancer patients using TAM therapy. PMID- 25701110 TI - Architectural plan of transcriptional regulation in Mycobacterium tuberculosis. AB - Transcriptional regulation enables adaptation in bacteria. Typically, only a few transcriptional events are well understood, leaving many others unidentified. The recent genome-wide identification of transcription factor binding sites in Mycobacterium tuberculosis has changed this by deciphering a molecular road-map of transcriptional control, indicating active events and their immediate downstream effects. PMID- 25701111 TI - Fueling type III secretion. AB - Type III secretion systems (T3SSs) are complex nanomachines that export proteins from the bacterial cytoplasm across the cell envelope in a single step. They are at the core of the machinery used to assemble the bacterial flagellum, and the needle complex many Gram-negative pathogens use to inject effector proteins into host cells and cause disease. Several models have been put forward to explain how this export is energized, and the mechanism has been the subject of considerable debate. Here we present an overview of these models and discuss their relative merits. Recent evidence suggests that the proton motive force (pmf) is the primary energy source for type III secretion, although contribution from refolding of secreted proteins has not been ruled out. The mechanism by which the pmf is converted to protein export remains enigmatic. PMID- 25701112 TI - Does chronic infection in retroviruses have a sense? AB - Over recent years, retroviral gene expression has been shown to depend on a promoter that is bidirectional. This promoter activity is likely to occur at either end of the retroviral genome and has important consequences at the level of retroviral gene expression. This review focuses on the recent discovery of retroviral antisense genes termed HBZ [in human T-cell leukemia virus type 1 (HTLV-1)] and ASP (in HIV-1) in terms of their function and the regulation of their expression, both of which are interconnected with the expression and function of other viral proteins. Emphasis is also given to the potential implication of these proteins in the maintenance of chronic infection in infected individuals. In light of recent findings, the discovery of these new genes opens a new avenue for the future treatment of HTLV-1- and HIV-1-infected individuals. PMID- 25701113 TI - Neuroimaging features of Cornelia de Lange syndrome. AB - BACKGROUND: Cornelia de Lange syndrome is a rare genetic disease characterized by distinctive facial dysmorphia and dwarfism. Multiple organ system involvement is typical. Various central nervous system (CNS) aberrations have been described in the pathology literature; however, the spectrum of neuroimaging manifestations is less well documented. OBJECTIVE: To present neuroimaging findings from a series of eight patients with Cornelia de Lange syndrome. MATERIALS AND METHODS: The CT/MR database at a single academic children's hospital was searched for the terms "Cornelia," "Brachmann" and "de Lange." The search yielded 18 exams from 16 patients. Two non-CNS and six exams without available images were excluded. Ten exams from eight patients were evaluated by a board-certified neuroradiologist. RESULTS: All patients had skull base dysplasia, most with an unusual coronal basioccipital cleft (7/8). All brain MR exams showed microcephaly, volume loss and gyral simplification (5/5). Six patients had an absent massa intermedia. Four patients had small globe anterior segments; three had optic pathway hypoplasia. Basilar artery fenestration was present in two patients; vertebrobasilar hypoplasia was present in one patient. The inner ear vestibules were dysplastic in two patients. One patient had pachymeningeal thickening. Spinal anomalies included scoliosis, segmentation anomalies, endplate irregularities, basilar invagination, foramen magnum stenosis and tethered spinal cord. CONCLUSION: Typical imaging manifestations of Cornelia de Lange syndrome include skull base dysplasia with coronal clival cleft, cerebral and brainstem volume loss, and gyral simplification. Membranous labyrinth dysplasia, anterior segment and optic pathway hypoplasia, basilar artery fenestration, absent massa intermedia and spinal anomalies may also be present. PMID- 25701114 TI - New onset frequent ventricular ectopic in a human immunodeficiency virus-infected woman after uneventful cesarean section under spinal anesthesia. PMID- 25701115 TI - Preparation and characterization of quercetin-loaded lipid liquid crystalline systems. AB - The aim of the present study was to investigate mixtures of soy phosphatidylcholine (SPC) and glycerol dioleate (GDO) as encapsulation matrices for antioxidant quercetin. The effects of quercetin loading into non-aqueous formulations, non-lamellar liquid crystalline phases and their colloidal dispersions were studied by using synchrotron small angle X-ray diffraction, dynamic light scattering, cryogenic electron microscopy and high performance liquid chromatography. Quercetin incorporation is discussed in the context of lipid aggregation behavior, self-assembled nanostructure and chemical stability. The obtained results show that SPC/GDO-based formulations can incorporate relatively high amounts of quercetin and serve as liquid crystalline delivery vehicles in the form of bulk phases or colloidal dispersions. PMID- 25701116 TI - The design of shape-tunable hairy vesicles. AB - Via the use of a mesoscopic simulation technique called dissipative particle dynamics, we design sterically stable biocompatible vehicles through the self assembly of a binary mixture composed of amphiphilic molecular species, such as PEGylated lipids, and phospholipids. We examine the factors controlling the shape of the hairy vesicle, and report the shape to change with molecular stiffness, and dissimilarity in the hydrocarbon tail groups, along with the relative concentration of the species, and the functional group length. We also draw correspondence with experimental studies on the shape transformations of the hairy vesicles through phase diagrams of the reduced volume, the ratio of the minimum and maximum radii, and the interfacial line tension, as a function of the concentration of the hairy lipids and the hydrocarbon tail molecular chain stiffness. Results from our investigations can be used for the design and prediction of novel hybrid soft materials for applications in the encapsulation and delivery of therapeutic agents. PMID- 25701117 TI - Linoleic acid binding properties of ovalbumin nanoparticles. AB - In the present work, ovalbumin (OVA) solutions (10 g/L, 50 mM NaCl, pH 7.5) were heat-treated at 75, 80 and 85 degrees C (namely, OVA-75, OVA-80 and OVA-85, respectively), from 0 to 25 min. OVA nanoparticles (OVAn) around 100 nm were obtained. For 3 min of heat treatment, OVAn sizes increased with temperature, but for a heating time longer than 10 min, OVA-75 showed the highest size values. OVAn surface hydrophobicity increased 6-8 folds in comparison with native OVA and wavelength blue shifts of 25-30 nm in maximum fluorescence intensity were registered. These results suggest that buried hydrophobic residues were exposed to the aqueous medium. Binding experiments with linoleic acid (LA) as polyunsaturated fatty acid (PUFA) model were carried out. Firstly, binding ability of OVAn was determined from LA titration curves of intrinsic fluorescence measurements. OVA-85 at 5 min presented the highest binding ability and it was used for further binding properties studies (turbidity, particle size distribution--PSD--analysis and zeta-potential measurements). Turbidity measurement and PSD analysis showed that OVAn-LA nanocomplexes were formed, avoiding LA supramolecular self-assembly formation. The union of LA to OVAn surface confers them significant lower zeta-potential and larger size. Hence, fluorescence and zeta-potential results showed that LA would bind to OVAn by mean of hydrophobic interactions. Information derived from this work could be important to potentially use OVAn as PUFA vehiculization with applications in several industrial sectors (food, pharmaceutical, cosmetics, etc.). PMID- 25701118 TI - Biogenic silver nanoparticles from Abutilon indicum: their antioxidant, antibacterial and cytotoxic effects in vitro. AB - Green synthesis of silver nanoparticles using biological entities is gaining interest because of their potential applications in nano-medicine. Herein, we report the biological synthesis of Abutilon indicum silver nanoparticles (AIAgNPs) using aqueous Abutilon indicum leaf extract (AILE) and evaluation of their biological applications. TEM analysis revealed that the spherical biogenic AIAgNPs were found to be between 5 and 25 nm in size. The bioactive phyto constituents such are condensed tannins of AILE were found to play a key role in the reduction and capping of AIAgNPs. The biological properties of AIAgNPs were premeditated as free radical scavenging activity, antibacterial effect and anti proliferative activity. AIAgNPs were found to exhibit good free radical scavenging activities and the intense zone of inhibition displayed by them in six different pathogenic species indicate the potential antibacterial effect. Further, AIAgNPs showed a dose dependant anti-proliferative effect against COLO 205 (human colon cancer) and MDCK (normal) cells with an IC50 of 3 and 4 MUg/mL and 100 and 75 MUg/mL, respectively after 24 and 48 h. The morphological changes, chromatin condensation and membrane potential loss induced by AIAgNPs were evidenced by AO/EB and AnnexinV-Cy3 staining. The mitochondrial membrane potential (MMP) loss and G1/S transition cell cycle arrest in COLO 205 cells was evidenced in rhodamine123 staining and FACS analysis. The high levels of ROS as shown in DCF-DA staining could have played a major role in DNA fragmentation and eventually lead to apoptosis. The mode of action through the induction apoptosis by AIAgNPs in COLO 205 cells is exciting with promising application of nano materials in biomedical research. PMID- 25701119 TI - The 3'UTR of the pseudogene CYP4Z2P promotes tumor angiogenesis in breast cancer by acting as a ceRNA for CYP4Z1. AB - Pseudogenes are now known to regulate their protein-coding counterparts. Additionally, disturbances of 3'UTRs could increase the risk of cancer susceptibility by acting as modulators of gene expression. The aim of this study was to investigate the roles of the pseudogene CYP4Z2P-3'UTR and functional gene CYP4Z1-3'UTR in breast cancer angiogenesis process. The levels of CYP4Z2P- and CYP4Z1-3'UTR and miRNA of interests were measured in 22 cancerous tissues paired with non-cancerous samples by qRT-PCR. The effects of CYP4Z2P- and CYP4Z1-3'UTR were studied by overexpression and RNA interference approaches in vitro and ex vivo. Insights of the mechanism of competitive endogenous RNAs were gained from bioinformatic analysis, luciferase assays, and western blot. The positive CYP4Z2P/CYP4Z1 interaction and negative interaction between predicted miRNAs and CYP4Z2P or CYP4Z1 were identified via qRT-PCR assay and bivariate correlation analysis. CYP4Z2P- and CYP4Z1-3'UTR share several miRNA-binding sites, including miR-211, miR-125a-3p, miR-197, miR-1226, and miR-204. The CYP4Z2P- and CYP4Z1 3'UTRs arrest the interference caused by of these miRNAs, resulting in increased translation of CYP4Z1. Moreover, ectopic expression of the CYP4Z2P- and CYP4Z1 3'UTRs exhibit tumor angiogenesis-promoting properties in breast cancer collectively by inducing the phosphorylation of ERK1/2 and PI3K/Akt. Co transfection with Dicer siRNA reversed the CYP4Z2P 3'UTR-mediated changes. Additionally, PI3K or ERK inhibitors reversed CYP4Z2P- and CYP4Z1-3'UTR-mediated changes in VEGF-A expression. Increased CYP4Z2P- and CYP4Z1-3'UTR expression promotes tumor angiogenesis in breast cancer partly via miRNA-dependent activation of PI3K/Akt and ERK1/2. The CYP4Z2P- and CYP4Z1-3'UTRs could thus be used as combinatorial miRNA inhibitors. PMID- 25701120 TI - The mammalian target of rapamycin complex 1 (mTORC1) in breast cancer: the impact of oestrogen receptor and HER2 pathways. AB - The mammalian target of rapamycin complex 1 (mTORC1) is a downstream of the PI3K/Akt pathway which affects cancer development. mTORC1 has many downstream signalling effectors that can enhance different cellular responses. This study aims to investigate the expression of mTORC1 in breast cancer (BC) and correlate it with key clinicopathological and molecular features of BC especially to proteins related to oestrogen receptor (ER) and HER2 pathways in different BC classes. Moreover, mTORC1 expression was assessed in 6 BC cell lines including ER+ and ER- cell lines with and without HER2 transfection. Immunohistochemistry was used to assess the expression of phospho (p) mTORC1 in a large (n = 1300) annotated BC series prepared as tissue microarray. Reverse phase protein array (RPPA) was used to assess its expression in the different BC cell lines. The expression of p-mTORC1 was cytoplasmic with moderate/high expression noted in 44 % of BC. p-mTORC1 expression was associated with clinicopathological variables characteristic of good prognosis. Positive correlation with ER, ER-related proteins AKT, PI3K and luminal differentiation markers were observed in the whole series and in the ER+HER2- subgroup. Association with HER2 was mainly observed in the ER-negative class. RPPA indicated that p-mTORC1 expression was mainly related to ER expression and with better outcome in the Akt positive tumours. p-mTORC1 is associated with good prognostic features. Its expression is related to ER and ER related proteins in addition to AKT and PI3K. Its relation with HER2 expression is mainly seen in the absence of ER expression. PMID- 25701121 TI - Antihypertensive medication use and incident breast cancer in women. AB - The purpose of this study was to evaluate whether antihypertensive medication use, including long-term use, is associated with increased breast cancer incidence in women. We studied 210,641 U.S. registered nurses participating in the Nurses' Health Study (NHS) and Nurses' Health Study II (NHS II). Information on antihypertensive medication use was collected on biennial questionnaires in both cohorts, and breast cancer cases were ascertained during this period. Multivariable-adjusted Cox proportional hazard models were used to estimate relative risks of invasive breast cancer over follow-up (1988-2012 in NHS, 1989 2011 in NHS II) across categories of overall antihypertensive medication use and use of specific classes (diuretics, beta blockers, calcium channel blockers, and angiotensin-converting enzyme inhibitors). During follow-up, 10,012 cases of invasive breast cancer developed (6718 cases in NHS and 3294 in the NHS II). Overall, current use of any antihypertensive medication was not associated with breast cancer risk compared with past/never use in NHS (multivariable-adjusted relative risk = 1.00, 95 % CI = 0.95-1.06) or NHS II (multivariable-adjusted relative risk = 0.94, 95 % CI = 0.86-1.03). Furthermore, no specific class of antihypertensive medication was consistently associated with breast cancer risk. Results were similar when we considered hypertensive women only, and when we evaluated consistency and duration of medication use over time. Overall, antihypertensive medication use was largely unrelated to the risk of invasive breast cancer among women in the NHS cohorts. PMID- 25701123 TI - Prevalence and subtype analysis of Blastocystis in healthy Indian individuals. AB - There is a growing interest in subtype (ST) analysis of the intestinal parasite Blastocystis due to its extensive genetic diversity that might reflect differences in pathogenicity. Although essential for reference, few studies are available on Blastocystis in healthy individuals. Moreover, molecular epidemiology data on Blastocystis in India still remain to emerge. In the present study we identified the prevalence and ST distribution of Blastocystis in healthy Indian individuals. A total of 220 stool samples were obtained; four of 100 samples from 100 adults were chosen randomly for construction of small subunit (SSU) rRNA gene clone libraries in order to elucidate micro-eukaryotic diversity in the human gut. From the SSU rDNA library, 64 sequences annotated to Blastocystis were used for ST analysis along with sequences obtained by direct sequencing of SSU rDNA PCR products amplified from the remaining samples and generated using primers targeting Blastocystis. Of 220 stool samples collected, 120 samples from 30 infants (aged 1week to 1year) were PCR-negative. Of the remaining 100 samples from 100 adults, 27 resulted in specific amplification. Out of these 27, four samples were suspected of mixed ST infection and so these samples were further analyzed by construction of clone libraries. Analysis of cloned sequences revealed that indeed 2 samples had mixed ST infection (ST1 and ST3) while the remaining two showed infection with two separate ST3 strains. ST3 was the most common ST present in our study group (100%) followed by ST1 (7.4%); ST1 was seen only in mixed infections. SSU rDNA clone library sequences generated by processing of pooled samples were identified as ST3. The majority of ST3 sequences exhibited allele 34 commonly found in the European population. PMID- 25701122 TI - Whole genome detection of rotavirus mixed infections in human, porcine and bovine samples co-infected with various rotavirus strains collected from sub-Saharan Africa. AB - Group A rotaviruses (RVA) are among the main global causes of severe diarrhea in children under the age of 5years. Strain diversity, mixed infections and untypeable RVA strains are frequently reported in Africa. We analysed rotavirus positive human stool samples (n=13) obtained from hospitalised children under the age of 5years who presented with acute gastroenteritis at sentinel hospital sites in six African countries, as well as bovine and porcine stool samples (n=1 each), to gain insights into rotavirus diversity and evolution. Polyacrylamide gel electrophoresis (PAGE) analysis and genotyping with G-(VP7) and P-specific (VP4) typing primers suggested that 13 of the 15 samples contained more than 11 segments and/or mixed G/P genotypes. Full-length amplicons for each segment were generated using RVA-specific primers and sequenced using the Ion Torrent and/or Illumina MiSeq next-generation sequencing platforms. Sequencing detected at least one segment in each sample for which duplicate sequences, often having distinct genotypes, existed. This supported and extended the PAGE and RT-PCR genotyping findings that suggested these samples were collected from individuals that had mixed rotavirus infections. The study reports the first porcine (MRC-DPRU1567) and bovine (MRC-DPRU3010) mixed infections. We also report a unique genome segment 9 (VP7), whose G9 genotype belongs to lineage VI and clusters with porcine reference strains. Previously, African G9 strains have all been in lineage III. Furthermore, additional RVA segments isolated from humans have a clear evolutionary relationship with porcine, bovine and ovine rotavirus sequences, indicating relatively recent interspecies transmission and reassortment. Thus, multiple RVA strains from sub-Saharan Africa are infecting mammalian hosts with unpredictable variations in their gene segment combinations. Whole-genome sequence analyses of mixed RVA strains underscore the considerable diversity of rotavirus sequences and genome segment combinations that result from a complex evolutionary history involving multiple host species. PMID- 25701124 TI - Genetic diversity and population structure in the Leishmania guyanensis vector Lutzomyia anduzei (Diptera, Psychodidae) from the Brazilian Amazon. AB - Lutzomyia (Nyssomyia) anduzei has been recognized as a secondary vector of Leishmania guyanensis in the Brazilian Amazon region. Since L. anduzei is anthropophilic, co-exists in areas of high leishmaniasis transmission and has been found infected with L. guyanensis, the understanding of the vector population structure and of the process responsible for it is paramount to the vector management and control efforts. In this study we analyzed 74 and 67 sequences of the COI and Cytb loci, respectively, from mitochondrial DNA, aiming to estimate the intra-population genetic variability and population structure in six L. anduzei samples from the Brazilian Amazon region. For COI, we found 58 haplotypes, low to high (FST=0.0310-0.4128) and significant (P=0.0033) genetic structure, and reduced gene flow among populations. The haplotype network yielded many reticulations that likely resulted from hypervariability in the locus. For Cytb, we observed 27 haplotypes, low to moderate (FST=0.0077-0.1954) and nonsignificant (P>0.05) genetic structure for the majority of comparisons and extensive gene flow among populations, in line with the haplotypes network data. AMOVA analysis indicated that most of the variation occurred within populations (83.41%, 90.94%); nevertheless, there were significant differences (PhiST=0.0906 0.1659; P=0.00098; P=0.00000) among them for both loci. The Mantel test showed that the genetic structure is not associated to an isolation-by-distance (IBD) model in either of both loci. These data suggest that L. anduzei is genetically very diverse. The genetic structure lacking IBD may be due to adaptation to local habitats and the low dispersal capacity of the sandflies, and both could lead to population fragmentation and geographic isolation. These findings have important implications for epidemiology, surveillance and vector control and may be a first step in understanding the evolutionary history of this species. PMID- 25701125 TI - Qualitatively different effect of repeated stress during adolescence on principal neuron morphology across lateral and basal nuclei of the rat amygdala. AB - Repeated stress can elicit symptoms of depression and anxiety. The amygdala is a significant contributor to the expression of emotion and the basolateral amygdala (BLA) is a major target for the effects of stress on emotion. The adolescent time period may be particularly susceptible to the effects of stress on emotion. While repeated stress has been demonstrated to modify the morphology of BLA neurons in adult rats, little is known about its effects on BLA neurons during adolescence. This study tests the effects of repeated stress during adolescence on BLA neuronal morphology, and whether these are similar to the effects of stress during adulthood. The BLA includes the basal (BA) and lateral (LAT) nuclei, which are differentially responsive to stress in adults. Therefore, effects of stress during adolescence were compared between the BA and LAT nuclei. Morphological features of reconstructed BLA neurons were examined using Golgi-Cox-stained tissue from control or repeated restraint stress-exposed rats. We found subtle dendritic growth coupled with loss of spines after repeated stress during adolescence. The magnitude and dendritic location of these differences varied between the BA and LAT nuclei in strong contrast to the stress-induced increases in spine number seen in adults. These results demonstrate that repeated stress during adolescence has markedly different effects on BLA neuronal morphology, and the extent of these changes is BLA nucleus-dependent. Moreover, altered neuroanatomy was associated with age-dependent effects of repeated stress on generalization of fear, and may point to the necessity for different approaches to target stress-induced changes in adolescents. PMID- 25701126 TI - Activity, but not mRNA expression of gelatinases correlates with susceptibility to experimental autoimmune encephalomyelitis. AB - Experimental autoimmune encephalomyelitis (EAE) is a model of multiple sclerosis (MS), inflammatory, demyelinating and neurodegenerative disease of the central nervous system (CNS). Clinically manifested EAE can be induced in Dark Agouti (DA) rats, but not in Albino Oxford (AO) rats by immunization with spinal cord homogenate (SCH) and complete Freund's adjuvant (CFA). Matrix metalloproteinases (MMP) play important roles in various steps of MS and EAE pathogenesis. Expression of gelatinases MMP2 and MMP9, their activator MMP14 and their inhibitor tissue inhibitor of MMP (TIMP)1 in the CNS of AO and DA rats immunized with SCH+CFA was determined. Expression of mRNA for MMP2, MMP9 and MMP14 was higher and expression of TIMP1 mRNA was lower in AO rats. However, gelatinase activity in spinal cords was higher in samples obtained from DA rats. Further, while there was no strain difference in MMP2 and MMP9 mRNA expression in lymph nodes of the immunized rats, gelatinase activity was higher in DA rats. This activity was reduced by antiinflammatory cytokines interleukin (IL)-10 and IL-4. Interestingly, gelatinase activity was detected in the nuclei of cells within the CNS, but not of those in lymph nodes. Our results imply that posttranscriptional regulation of MMP2 and MMP9 expression and/or function determines low gelatinase activity within the CNS and in immune cells of EAE-resistant AO rats. PMID- 25701127 TI - SIU newsletter - March 2015. PMID- 25701128 TI - Robotic-assisted pelvic lymph node dissection for prostate cancer: frequency of nodal metastases and oncological outcomes. AB - PURPOSE: Limited data are available regarding the oncologic efficacy of pelvic lymph node dissection (PLND) performed during robotic-assisted laparoscopic prostatectomy (RALP) for prostate cancer. We aimed to determine the frequency of pelvic lymph node metastasis and oncological outcomes following RALP with PLND in patients who did not receive adjuvant androgen deprivation therapy (ADT). METHODS: We retrospectively reviewed the records of 1740 consecutive patients who underwent RALP and extended PLND. The primary endpoint was biochemical recurrence (BCR). The estimated BCR probability was obtained using the Kaplan-Meier method. Cox proportional hazard regression models were used to assess for predictors of BCR. RESULTS: One hundred and eight patients (6 %) with positive LNs were identified. The median number of LNs removed was 17 (IQR 11-24), and median follow-up was 26 months (IQR 14-43). Ninety-one (84 %) patients did not receive adjuvant ADT of whom 60 % had BCR with a median time to recurrence of 8 months. The 1- and 3-year BCR-free probability was 42 and 28 %, respectively. Patients with <=2 LN+ had significantly better biochemical-free estimated probability compared to those with >2 LN+ (p = 0.002). The total number of LN+ (HR = 1.1; 95 % CI 1.01-1.2, p = 0.04) and Gleason 8-10 (HR = 1.96; 95 % CI 1.1-3.4, p = 0.02) were predictors of BCR on multivariate analysis. CONCLUSION: Among men with positive lymph nodes at time of robotic prostatectomy, those with two or fewer positive nodes and Gleason <8 exhibited favorable biochemical-free survival without adjuvant therapy. PMID- 25701129 TI - Functional outcomes of adjustable continence therapy (ACTTM) balloons in women aged >80 years and suffering from stress urinary incontinence caused by intrinsic sphincter deficiency. AB - OBJECTIVE: To determine the functional outcomes of adjustable continence therapy (ACTTM) balloons in elderly women suffering from stress urinary incontinence (SUI) caused by intrinsic sphincter deficiency (ISD). MATERIAL AND METHODS: A monocentric retrospective study included all non-neurological women aged >80 years who suffered from SUI due to ISD and undergoing ACTTM balloon placement between 2000 and 2013. Early post-operative complications were reported according to the Clavien-Dindo classification. Continence was assessed subjectively by the patients. RESULTS: A total of 52 female patients were included, median age 83 years (IQR 81-85). Among them, 35 (67.3 %) had already undergone previous surgery for SUI. Balloon implantations were achieved under local anaesthesia for 33 (63.5 %) patients. Clavien grade I-II early post-operative complications occurred in five (9.6 %) patients. Median follow-up was 10.5 months (IQR 3-24.25). Eleven patients (21.1 %) were lost to follow-up. At last follow-up, seven patients (13.5 %) declared themselves fully continent after the first implantation, 13 patients (25 %) had an >80 % improvement rate (10 patients after first implantation, two after second implantation and one after third implantation). Four patients (7.7 %) found the procedure unsuccessful even after several consecutive implantations. Ten patients (19.2 %) reported a partial result and were still having successive balloon inflations. Explantation occurred in 22 patients, caused by infection, erosion or balloon migration. In intention-to-treat analysis, the failure rate was 42.3 %. CONCLUSION: Although the success rate of ACTTM balloons in women aged >80 years is lower than that reported for younger women, it remains satisfactory because these patients would not otherwise have benefited from another surgical treatment. PMID- 25701130 TI - High rate biomethanation technology for solid waste management and rapid biogas production: An emphasis on reactor design parameters. AB - A high rate biomethanation digester was designed and fabricated to study its real field treatment efficiency and simultaneous biogas generation. The major design parameters like self mixing, delinking hydraulic retention time and solid retention time etc. were considered for efficient performance. It was operated with an organic loading rate (OLR) of 1.5kg/m(3)d(-1) with composite food waste for about one year. The maximum treatment efficiency achieved with respect to total solid (TS) reduction and volatile solids (VS) reduction was 94.5% and 89.7%, respectively. Annual mean biogas of about 0.16m(3)/kgVSd(-1) was observed with methane content varying from 56% to 60% (v/v). The high competence of high rate digester is attributed to its specific design features and intermittent mixing of the digester contents and also due to the hydrodynamic principles involved in its operation. PMID- 25701131 TI - Preclinical Comparison of the Amyloid-beta Radioligands [(11)C]Pittsburgh compound B and [(18)F]florbetaben in Aged APPPS1-21 and BRI1-42 Mouse Models of Cerebral Amyloidosis. AB - PURPOSE: The aim of this study was to compare [(11)C]Pittsburgh compound B ([(11)C]PiB) and [(18)F]florbetaben ([(18)F]FBB) for preclinical investigations of amyloid-beta pathology. PROCEDURES: We investigated two aged animal models of cerebral amyloidosis with contrasting levels of amyloid-beta relating to "high" (APPPS1-21 n = 6, wild type (WT) n = 7) and "low" (BRI1-42 n = 6, WT n = 6) target states, respectively. RESULTS: APPPS1-21 mice (high target state) demonstrated extensive fibrillar amyloid-beta deposition that translated to significantly increased retention of [(11)C]PiB and [(18)F]FBB in comparison to their wild type. The retention pattern of [(11)C]PiB and [(18)F]FBB in this cohort displayed a significant correlation. However, the relative difference in tracer uptake between diseased and healthy mice was substantially higher for [(11)C]PiB than for [(18)F]FBB. Although immunohistochemistry confirmed the high plaque load in APPPS1-21 mice, correlation between tracer uptake and ex vivo quantification of amyloid-beta was poor for both tracers. BRI1-42 mice (low target state) did not demonstrate increased tracer uptake. CONCLUSIONS: In cases of high fibrillar amyloid-beta burden, both tracers detected significant differences between diseased and healthy mice, with [(11)C]PiB showing a larger dynamic range. PMID- 25701132 TI - Generation of Integration-Free Patient Specific iPS Cells Using Episomal Plasmids Under Feeder Free Conditions. AB - Reprogramming somatic cells into a pluripotent state involves the overexpression of transcription factors leading to a series of changes that end in the formation of induced pluripotent stem cells (iPSCs). These iPSCs have a wide range of potential uses from drug testing and in vitro disease modelling to personalized cell therapies for patients. While viral methods for reprogramming factor delivery have been traditionally preferred due to their high efficiency, it is now possible to generate iPSCs using nonviral methods at similar efficiencies. We developed a robust reprogramming strategy that combines episomal plasmids and the use of commercially available animal free reagents that can be easily adapted for the GMP manufacture of clinical grade cells. PMID- 25701133 TI - Microbial community structure in the gut of the New Zealand insect Auckland tree weta (Hemideina thoracica). AB - The endemic New Zealand weta is an enigmatic insect. Although the insect is well known by its distinctive name, considerable size, and morphology, many basic aspects of weta biology remain unknown. Here, we employed cultivation-independent enumeration techniques and rRNA gene sequencing to investigate the gut microbiota of the Auckland tree weta (Hemideina thoracica). Fluorescence in situ hybridisation performed on different sections of the gut revealed a bacterial community of fluctuating density, while rRNA gene-targeted amplicon pyrosequencing revealed the presence of a microbial community containing high bacterial diversity, but an apparent absence of archaea. Bacteria were further studied using full-length 16S rRNA gene sequences, with statistical testing of bacterial community membership against publicly available termite- and cockroach derived sequences, revealing that the weta gut microbiota is similar to that of cockroaches. These data represent the first analysis of the weta microbiota and provide initial insights into the potential function of these microorganisms. PMID- 25701134 TI - Gender-specific profiles of adverse childhood experiences, past year mental and substance use disorders, and their associations among a national sample of adults in the United States. AB - PURPOSE: This study examined profiles of adverse childhood experiences (ACEs) and mental and substance use disorders (MSUDs), and associations between distinct profiles of ACEs and MSUDs. METHODS: Participants were adults (N = 34, 652) involved in the National Epidemiologic Survey on Alcohol and Related Conditions. Latent class analysis was used to examine both profiles of ten ACEs and ten past year MSUDs. Dual latent class analysis regression was used to examine associations between profiles of ACEs and MSUDs. Given gender differences in ACEs and MSUDs, analyses were conducted separately for females and males. RESULTS: Four profiles of ACEs and three profiles of MSUDs were selected for both genders. The four profiles of ACEs were characterized by the following probabilities: high multiple ACEs, high parental substance abuse, high childhood physical abuse, and low ACEs. The three profiles of MSUDs were characterized by the following probabilities: high multiple MSUDs for females and low MSUDs except alcohol use disorders for males, moderate-to-high major depressive episode, and low MSUDs. When compared to the low ACEs and MSUDs profiles, members in the higher ACEs profiles had 3.71-89.75 times greater odds of also being members in the higher MSUDs profiles. However, more than one-third of members in the high multiple ACEs profiles were also in the low MSUDs profiles. CONCLUSIONS: Study findings suggest four profiles of the ACEs widely studied as part of the Adverse Childhood Experiences study and risk and resilience for recent MSUDs among men and women nationally affected by ACEs. PMID- 25701135 TI - Analytical studies of the Alexandrovo Thracian tomb wall paintings. AB - A profound study of samples obtained from Thracian tomb wall paintings at Alexandrovo, Bulgaria (dating back to the fourth century BC) were carried out by differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR) and Attenuated Total Reflectance Fourier transform infrared spectroscopy (ATR FTIR), high-resolution transmission electron microscopy (HRTEM) and energy dispersive X-ray spectroscopy (EDS). The current work provides a glimpse of the ingenious construction and painting techniques used in Thracian tomb at Alexandrovo. The results suggest that beeswax was used as a paint binder and also revealed presence of various nano-materials. PMID- 25701136 TI - Temperature effect on the recovery process in stretched Bombyx mori silk fibers. AB - The recovery process in stretched Bombyx mori silk fibers at different strain levels from 3% to 17% was investigated at room conditions during long period of time from 5min to 20days and more. How the temperature affects the recovery process in the silk fibers stretched at room conditions was examined at temperatures from 25 to 125 degrees C. The results of the recovery process at 25 degrees C revealed that although the recovery process from strain values higher than 3% strain continued slowly which caused quite high remaining deformation, a complete recovery from 3% strain was observed after 3days. However, better recovery process was observed with increasing temperature which led to lower remaining deformations. For instance, a complete recovery from 6% strain was observed after 144h and 3h for the recovery process at 100 degrees C and 125 degrees C, respectively which indicates an important result that the deformations induced by stretching the silk fibers up to 6% strain are reversible and increasing temperature affects the velocity of this process significantly. The recovery process expressed in the strain (epsilon) and logarithm time coordinates showed a linear dependence for which a linear equation was proposed. Thus, this linear equation enables to estimate the required time for a complete recovery from different strain levels and remaining deformation at any stage of the recovery at different temperatures. The ATR-FTIR spectra of the stretched silk fibers during the recovery process revealed some changes in the absorbance ratios and shifts in the positions of the bands assigned to Calpha-C, N-H stretching vibrations, and the Amide III mode. It was suggested that new formation of the hydrogen bonds between polypeptide chains especially in amorphous regions and the changes in the intra-sheet hydrogen bonds in beta-sheet crystalline regions greatly contribute to the recovery process. PMID- 25701137 TI - Methionine enkephalin (MENK) inhibits tumor growth through regulating CD4+Foxp3+ regulatory T cells (Tregs) in mice. AB - Methionine enkephalin (MENK), an endogenous neuropeptide, plays an crucial role in both neuroendocrine and immune systems. CD4+Foxp3+ regulatory T cells (Tregs) are identified as a major subpopulation of T lymphocytes in suppressing immune system to keep balanced immunity. The aim of this research work was to elucidate the mechanisms via which MENK interacts with Tregs in cancer situation. The influence of MENK on transforming growth factor-beta (TGF-beta) mediated conversion from naive CD4+CD25- T cells to CD4+CD25+ Tregs was determined and the data from flow cytometry (FCM) analysis indicated that MENK effectively inhibited the expression of Foxp3 during the process of TGF-betainduction. Furthermore, this inhibiting process was accompanied by diminishing phosphorylation and nuclear translocation of Smad2/3, confirmed by western blot (WB) analysis and immunofluorescence (IF) at molecular level. We established sarcoma mice model with S180 to investigate whether MENK could modulate Tregs in tumor circumstance. Our findings showed that MENK delayed the development of tumor in S180 tumor bearing mice and down-regulated level of Tregs. Together, these novel findings reached a conclusion that MENK could inhibit Tregs activity directly and retard tumor development through down-regulating Tregs in mice. This work advances the deepening understanding of the influence of MENK on Tregs in cancer situation, and relation of MENK with immune system, supporting the implication of MENK as a new strategy for cancer immunotherapy. PMID- 25701138 TI - Estrogens antagonize RUNX2-mediated osteoblast-driven osteoclastogenesis through regulating RANKL membrane association. AB - In addition to its thoroughly investigated role in bone formation, the osteoblast master transcription factor RUNX2 also promotes osteoclastogenesis and bone resorption. Here we demonstrate that 17beta-estradiol (E2), strongly inhibits RUNX2-mediated osteoblast-driven osteoclastogenesis in co-cultures. Towards deciphering the underlying mechanism, we induced premature expression of RUNX2 in primary murine pre-osteoblasts, which resulted in robust differentiation of co cultured splenocytes into mature osteoclasts. This was attributable to RUNX2 mediated increase in RANKL secretion, determined by ELISA, as well as to RUNX2 mediated increase in RANKL association with the osteoblast membrane, demonstrated using confocal fluorescence microscopy. The increased association with the osteoblast membrane was recapitulated by transiently expressed GFP-RANKL. E2 abolished the RUNX2-mediated increase in membrane-associated RANKL and GFP-RANKL, as well as the concomitant osteoclastogenesis. RUNX2-mediated RANKL cellular redistribution was attributable in part to a decrease in Opg expression, but E2 did not influence Opg expression either in the presence or absence of RUNX2. Diminution of RUNX2-mediated osteoclastogenesis by E2 occurred regardless of whether the pre-osteoclasts were derived from wild type or estrogen receptor alpha (ERalpha)-knockout mice, suggesting that activated ERalpha inhibited osteoblast-driven osteoclastogenesis by acting in osteoblasts, possibly targeting RUNX2. Indeed, microarray analysis demonstrated global attenuation of the RUNX2 response by E2, including abrogation of Pstpip2 expression, which likely plays a critical role in membrane trafficking. Finally, the selective ER modulators (SERMs) tamoxifen and raloxifene mimicked E2 in abrogating the stimulatory effect of osteoblastic RUNX2 on osteoclast differentiation in the co-culture assay. Thus, E2 antagonizes RUNX2-mediated RANKL trafficking and subsequent osteoclastogenesis. Targeting RUNX2 and/or downstream mechanisms that regulate RANKL trafficking may lead to the development of improved SERMs and possibly non hormonal therapeutic approaches to high turnover bone disease. PMID- 25701139 TI - Spatial distribution of intracortical porosity varies across age and sex. AB - Cortical bone porosity is a major determinant of strength, stiffness, and fracture toughness of cortical tissue. The goal of this work was to investigate changes in spatial distribution and microstructure of cortical porosity associated with aging in men and women. The specific aims were to: 1) develop an automated technique for spatial analysis of cortical microstructure based on HR pQCT data, and; 2) apply this technique to explore sex- and age-specific spatial distribution and microstructure of porosity within the cortex. We evaluated HR pQCT images of the distal tibia from a cross-sectional cohort of 145 individuals, characterizing detectable pores as being in the endosteal, midcortical, or periosteal layers of the cortex. Metrics describing porosity, pore number, and pore size were quantified within each layer and compared across sexes, age groups, and cortical layers. The elderly cohort (65-78 years, n=22) displayed higher values than the young cohort (20-29 years, n=29) for all parameters both globally and within each layer. While all three layers displayed significant age related porosity increases, the greatest difference in porosity between the young and elderly cohort was in the midcortical layer (+344%, p<0.001). Similarly, the midcortical layer reflected the greatest differences between young and elderly cohorts in both pore number (+243%, p<0.001) and size (+28%, p<0.001). Females displayed greater age-related changes in porosity and pore number than males. Females and males displayed comparable small to non-significant changes with age in pore size. In summary, considerable variability exists in the spatial distribution of detectable cortical porosity at the distal tibia, and this variability is dependent on age and sex. Intracortical pore distribution analysis may ultimately provide insight into both mechanisms of pore network expansion and biomechanical consequences of pore distribution. PMID- 25701140 TI - Study of two strategies to induce follicular wave emergence for assisted reproductive treatments (ART)-a preliminary trial. AB - PURPOSE: This study aimed to induce follicular wave emergence (FWE) using pharmacological (recombinant hCG administration) or mechanical (aspiration of dominant follicle) interventions in infertile women. METHODS: Sixteen infertile women (<=35 years) with indications for in vitro fertilization due to tubal and/or male factor infertility were randomized into three groups: control (n = 6), pharmacological (n = 5) and mechanical (n = 5) groups. Women in both experimental groups underwent serial transvaginal sonograms (TVS) from menstrual cycle day 10 until identification of a dominant follicle >=15 mm. Women in the pharmacological group received 250 MUg of recombinant-hCG to induce ovulation, and resumed serial TVS 2 days later. In the mechanical group, dominant and subordinate follicles >=10 mm were aspirated, and daily TVS was resumed on the following day. An increased pool of follicles >=5 and <=9 mm after interventions characterized FWE. Women in the control group underwent ovulation induction (OI) with 150 IU/day of recombinant follicle-stimulating hormone started on menstrual cycle day 3 (D3). OI was started on the day of FWE in the experimental groups. Endometrial asynchrony with development of the embryo was expected in the experimental groups. Therefore, all viable embryos were cryopreserved and transferred in an endometrial-stimulated cycle. RESULTS: The number of follicles >=5 and <=9 mm increased after the interventions in both experimental groups (p < .001), indicating induction of FWE. OI outcomes were similar among the groups. CONCLUSIONS: The pharmacological and mechanical interventions are efficient in inducing FWE; outcomes of OI synchronized with FWE should be further investigated. PMID- 25701141 TI - Blood type predicts live birth in the infertile population. AB - PURPOSE: To determine if blood type in infertile women relates to the likelihood for live birth (LB) following IVF, and to the etiology for infertility. METHODS: Retrospective study of patients undergoing IVF at two academic centers in the northeast US. Relationships between blood type (A, B, AB, O) and patient characteristics, IVF cycle parameters and LB were assessed utilizing multivariable logistic regression analyses. RESULTS: In the studied population (n=626), women with type O were significantly more likely to have baseline FSH > 10 IU/L after adjusting for age, BMI and race (OR 5.09, 95 % CI 1.4-18.7, p=0.01). Conversely, women with blood type A were significantly more likely to have ovulatory infertility compared to those with blood type O after adjusting for age and BMI (OR 3.2, 95 % CI 1.7-6.2). Blood type B was associated with increased likelihood of live birth (OR 1.9, 95 % CI 1.10-3.41, p=0.03) after adjusting for factors recognized to impact IVF outcome. CONCLUSION: Ovulatory infertility and baseline FSH > 10 IU/L were more prevalent in women with blood type A and O respectively. However, those of blood type B had significantly higher odds for LB compared to other blood types after adjusting for factors recognized to impact on IVF cycle outcome. While underlying mechanisms are unclear, for infertile women, patient's blood type is seemingly relevant for IVF cycle outcome. PMID- 25701142 TI - Oocyte vitrification modifies nucleolar remodeling and zygote kinetics-a sibling study. AB - PURPOSE: Oocyte vitrification does not affect embryo quality after oocyte warming, making this method effective in the preservation of female fertility. Morphokinetic parameters can be used to predict the competence of an embryo produced from fresh oocytes. Our aim was to study the effect of oocyte vitrification on zygote-embryo kinetics (pl). METHODS: The embryo-kinetics of fresh and sibling vitrified/warmed oocytes were compared to determine the consequences of oocyte preservation on the timing of embryo development. A 44 hours time-lapse analysis, from the time of ICSI (t0), of 179 fertilized fresh oocytes was compared to 168 fertilized sibling vitrified/warmed oocytes. RESULTS: Oocyte vitrification accelerated pronuclear disappearance, one-cell stage timing and modified nucleoli activity by increasing their number and decreasing their diameter at the zygote stage. In contrast, embryo kinetics during cleavage were similar to those observed for fresh sibling oocytes based on the parameters examined in this study. CONCLUSIONS: At the zygote stage, oocyte vitrification induces changes in pronuclei stability, probably due to pronuclei envelop instability as well as modifications in nucleoli functionality. Therefore, the predictive morphokinetic parameters on embryo competence found from fresh oocytes must be revised when applied on embryos from vitrified/warmed oocytes. PMID- 25701143 TI - Chromosomal characteristics at cleavage and blastocyst stages from the same embryos. AB - PURPOSE: To investigate chromosomal characteristics in the same embryos at cleavage and blastocyst stage. METHODS: Six PGD/PGS cycles were retrospective studied, including five chromosomal translocation PGD cycles and one recurrent abortion PGS cycle. The cleavage embryos were biopsied one blastomere at day 3, followed by blastocyst culture. Trophectoderm cell biopsy was performed when embryos developed into the blastocyst stage. Whole genome amplification and 24 chromosomal analysis by CGH/SNP microarray was performed on each blastomere and trophectoderm cells. RESULTS: After PGD/PGS, only one couple had no euploid embryos to transfer. Five couples delivered a healthy, balanced-karyotype baby. A total of 18 embryos had both blastomere and trophectoderm cell reliable results available. Of the 18 embryos, eleven embryos contained identical chromosomes from cleavage stage to blastocyst stage and six embryos contained almost identical chromosomes . Only one embryo presented opposite chromosomal results for the cleavage and blastocyst stage, with abnormal chromosomes in the blastomere but normal chromosomes in trophectoderm cells. CONCLUSIONS: Most embryos maintain chromosomal stability during embryonic development. Compared to cleavage stage, blastocyst stage may provide more reliable aneuploidy results. PMID- 25701144 TI - Isolation and purification of trypsin inhibitors from the seeds of Abelmoschus moschatus L. AB - Four trypsin inhibitors, AMTI-I, AMTI-II, AMTI-III, and AMTI-IV, have been isolated and purified to homogeneity from the seeds of Abelmoschus moschatus following ammonium sulphate fractionation, DEAE-cellulose ion exchange chromatography and gel permeation on Sephadex G-100, and their molecular weights were determined to be 22.4, 21.2, 20.8 and 20.2 kDa respectively by SDS-PAGE. While all the four inhibitors were very active against bovine trypsin, two of them (AMTI-III and AMTI-IV) showed moderate activity towards bovine chymotrypsin. AMTI-I and AMTI-II were found to be glycoproteins with neutral sugar content of 2.8 and 4 %, respectively, and all the four inhibitors were devoid of free sulphhydryl groups. The inhibitors were quite stable up to 80 degrees C for 10 min and were not affected at alkaline as well as acidic conditions tested. Treating them with 8 M urea and 1 % SDS for 24 h at room temperature did not result in any loss of their antitryptic activities. However, they lost considerable antitryptic activity when treated with 6 M guanidine hydrochloride. Activities of the inhibitors were unaffected even after their reduction with DTT suggesting that disulphide bonds are not needed for their inhibitory activities. PMID- 25701145 TI - The removal of hydrogen sulfide from biogas in a microaerobic biotrickling filter using polypropylene carrier as packing material. AB - Biological removal of hydrogen sulfide in biogas is an increasingly adopted alternative to the conventional physicochemical processes, because of its economic and environmental benefits. In this study, a microaerobic biofiltration system packed with polypropylene carrier was used to investigate the removal of high concentrations of H2S contained in biogas from an anaerobic digester. The results show that H2S in biogas was removed completely under different inlet concentrations of H2S from 2065 +/- 234 to 7818 +/- 131 ppmv, and the elimination capacity of H2S in the filter achieved about 122 g H2S/m(3)/h. It was observed that the content of CH4 in biogas increased after the biogas biodesulfurization process, which was beneficial for the further utilization of biogas. The elemental sulfur and sulfate were the main sulfur species of H2S degradation, and elemental sulfur was dominant (about 80 %) under high inlet H2S concentration. The results of terminal restriction fragment length polymorphism (T-RFLP) and fluorescence in situ hybridization (FISH) show that the population of sulfide oxidizing bacteria (SOB) species in the filter changed with different concentrations of H2S. The microaerobic biofiltration system allows the potential use of biogas and the recovery of elemental sulfur resource simultaneously. PMID- 25701147 TI - Restricting Access to ART on the Basis of Criminal Record : An Ethical Analysis of a State-Enforced "Presumption Against Treatment" With Regard to Assisted Reproductive Technologies. AB - As assisted reproductive technologies (ART) become increasingly popular, debate has intensified over the ethical justification for restricting access to ART based on various medical and non-medical factors. In 2010, the Australian state of Victoria enacted world-first legislation that denies access to ART for all patients with certain criminal or child protection histories. Patients and their partners are identified via a compulsory police and child protection check prior to commencing ART and, if found to have a previous relevant conviction or child protection order, are given a "presumption against treatment." This article reviews the legislation and identifies arguments that may be used to justify restricting access to ART for various reasons. The arguments reviewed include limitations of reproductive rights, inheriting undesirable genetic traits, distributive justice, and the welfare of the future child. We show that none of these arguments justifies restricting access to ART in the context of past criminal history. We show that a "presumption against treatment" is an unjustified infringement on reproductive freedom and that it creates various inconsistencies in current social, medical, and legal policy. We argue that a state-enforced policy of restricting access to ART based on the non-medical factor of past criminal history is an example of unjust discrimination and cannot be ethically justified, with one important exception: in cases where ART treatment may be considered futile on the basis that the parents are not expected to raise the resulting child. PMID- 25701148 TI - Ethical aspects of the glasgow effect. PMID- 25701146 TI - Tissue engineering for bone regeneration and osseointegration in the oral cavity. AB - OBJECTIVE: The focus of this review is to summarize recent advances on regenerative technologies (scaffolding matrices, cell/gene therapy and biologic drug delivery) to promote reconstruction of tooth and dental implant-associated bone defects. METHODS: An overview of scaffolds developed for application in bone regeneration is presented with an emphasis on identifying the primary criteria required for optimized scaffold design for the purpose of regenerating physiologically functional osseous tissues. Growth factors and other biologics with clinical potential for osteogenesis are examined, with a comprehensive assessment of pre-clinical and clinical studies. Potential novel improvements to current matrix-based delivery platforms for increased control of growth factor spatiotemporal release kinetics are highlighting including recent advancements in stem cell and gene therapy. RESULTS: An analysis of existing scaffold materials, their strategic design for tissue regeneration, and use of growth factors for improved bone formation in oral regenerative therapies results in the identification of current limitations and required improvements to continue moving the field of bone tissue engineering forward into the clinical arena. SIGNIFICANCE: Development of optimized scaffolding matrices for the predictable regeneration of structurally and physiologically functional osseous tissues is still an elusive goal. The introduction of growth factor biologics and cells has the potential to improve the biomimetic properties and regenerative potential of scaffold-based delivery platforms for next-generation patient-specific treatments with greater clinical outcome predictability. PMID- 25701149 TI - How do we thank thee? Let us (try to) count the ways. PMID- 25701150 TI - What characterises women who eat potatoes? A cross-sectional study among 74,208 women in the Norwegian Women and Cancer cohort. AB - BACKGROUND: Studies of potato consumption have shown that age, region, socioeconomic status, and household structure are important determinants. OBJECTIVE: This study aims to map which factors influence potato consumption among women in the Norwegian Women and Cancer (NOWAC) study. DESIGN: A cross sectional study using a postal questionnaire among 74,208 NOWAC participants aged 41-70. RESULTS: RESULTS showed that 56% of the women ate at least two potatoes a day. A north-south gradient in potato consumption was observed in logistic regression models (OR: 3.41, 95% CI: 3.19-3.64 for the north compared to the capital). Women in households with children had lower odds of high potato consumption than women living only with a partner, and women who lived alone had the lowest odds of all (OR: 0.39, 95% CI: 0.37-0.41). Smokers had higher odds of high potato consumption, while diabetics had lower odds. The odds of high potato consumption were greater among older women, and among those with lower income and education. In a sub-cohort, women who were dieting had lower odds of high potato consumption. Consumption of different foods varied in the low versus the high potato consumption group, with largest effect for fish and pasta/rice. The groups had similar nutrient densities. CONCLUSIONS: In addition to lifestyle and socioeconomic factors, health-related factors like smoking and diabetes were found to influence potato consumption. The high potato consumption group had an especially high consumption of fish and a low consumption of pasta/rice, though the nutrient density in the groups was similar. PMID- 25701151 TI - CuO nanoparticles induce apoptosis by impairing the antioxidant defense and detoxification systems in the mouse hippocampal HT22 cell line: protective effect of crocetin. AB - Several studies have reported that CuO nanoparticles (CuONPs) have the capacity to cross the blood brain barrier and exert a toxic effect. The aims of our study were to investigate mechanisms underlying CuONPs-induced neurotoxicity in vitro and neuroprotective effects of crocetin. We investigated the toxicological effects of exposure of HT22 hippocampal cells to CuONPs (31 nm) in the presence or absence of crocetin. Crocetin is a carotenoid with wide spectrum of pharmacological effects and the ability to cross blood-brain barrier. Exposure of HT22 cells to CuONPs resulted in: (1) increased cell death in a time- and concentration-dependent manner, with a LC50 of 25.9 MUg/ml after 24 h; (2) decreased antioxidant/detoxification enzymes activities: glutathione peroxidase (GPx), superoxide dismutase (SOD), glutathione S-tranferase (GST), and reduced glutathione (GSH) levels; (3) decreased gene expression of GPx and SOD; (4) reactive oxygen species (ROS) generation; (5) enhanced apoptosis; and (6) up regulation of the pro-apoptotic genes Bax, and down-regulation of anti-apoptotic genes Bcl-2. Importantly, all these effects were significantly attenuated by co incubation of hippocampal cells with 5 MUM crocetin. PMID- 25701152 TI - Scene setter: the importance of taking a systems approach to person centred care. PMID- 25701153 TI - "Death by a thread"--peritonitis due to visceral perforation by a guide wire, during proximal femur osteosynthesis with DHS: a fatal case and legal implications. AB - Iatrogenic intestinal perforations in orthopaedic surgery are very rare. Reports of iatrogenic lesions caused by a guide wire during femur fracture osteosynthesis are even scarcer. There are no similar reports in recent literature. As opposed to what is normally described the lesion documented in this case report was not identified on time resulting in death by peritonitis. The forensic autopsy allowed the identification of an intestinal perforation with faecal leakage to peritoneal space in association with a vesical perforation enabling the reproduction of the guide wire path. In view of the increasing number of osteosynthesis it is essential for the surgeon to be aware of possible complications due to guide wire perforations. Cases like this go unnoticed if the forensic pathologist is not familiarized with the surgical technique which may explain the rarity of such descriptions in literature. PMID- 25701154 TI - Luminescent ecstasy tablets. Authentication tool or cunning marketing tactic? AB - Forensic Science SA (FSSA) in combination with South Australia Police (SAPOL) has detected luminescent ecstasy tablets. This paper examines the emergence of luminescent ecstasy tablets and their potential role as an extra level of authentication for the user and/or as a marketing tactic aligned with their use at glow parties. PMID- 25701155 TI - Comparison of two ordinal prediction models: A cancer staging system example. AB - BACKGROUND: Choosing to replace or maintain an existing cancer staging system is a difficult task. The system plays a critical role in patient counselling and treatment decision making because the staging system conveys prognosis. METHODS: Many issues may be considered when deciding the preferred system (i.e. old or new), such as the level of evidence for one or more factors included in the system or the general opinions of expert clinicians. However, given the major objective of estimating prognosis on an ordinal scale, we argue that the rival staging system candidates should be compared on their ability to predict outcome. We sought to outline an algorithm that would compare two rival ordinal systems on their predictive ability. RESULTS: We devised an algorithm based largely on the concordance index, which is appropriate for comparing two models in their ability to rank observations. We demonstrate our algorithm with a prostate cancer staging system example. CONCLUSION: We have provided an algorithm for selecting the preferred staging system based on prognostic accuracy. It appears to be useful for the purpose of selecting between two ordinal prediction models. PMID- 25701156 TI - Simplification improves understanding of informed consent information in clinical trials regardless of health literacy level. AB - BACKGROUND: This study evaluated the effect of a simplified informed consent form for clinical trials on the understanding and efficacy of informed consent information across health literacy levels. METHODS: A total of 150 participants were randomly assigned to one of two groups and provided with either standard or simplified consent forms for a cancer clinical trial. The features of the simplified informed consent form included plain language, short sentences, diagrams, pictures, and bullet points. RESULTS: Levels of objective and subjective understanding were significantly higher in participants provided with simplified informed consent forms relative to those provided with standard informed consent forms. The interaction effects between type of consent form and health literacy level on objective and subjective understanding were nonsignificant. CONCLUSION: Simplified informed consent was effective in enhancing participant's subjective and objective understanding regardless of health literacy. PMID- 25701157 TI - [3-D reconstruction in resection planning for central hepatocellular carcinoma]. PMID- 25701158 TI - [Euthanasia and physician-assisted suicide : Attitudes of physicians and nurses]. AB - BACKGROUND: The current debate about end-of-life decisions in Germany focuses on physician-assisted suicide (PAS). However, there is only limited information available on physicians' attitudes towards euthanasia or PAS, and no data on nurses' attitudes. OBJECTIVES: The aim is to explore attitudes of physicians and nurses with a special interest in palliative care and pain medicine using a case related questionnaire. METHODS: An anonymous questionnaire, consisting of eight questions, was distributed to all participants of a palliative care congress and a pain symposium. The questions focused on two scenarios: (1) a patient with an incurable fatal illness, (2) a patient with an incurable but nonfatal illness. The question was: Should euthanasia or physician-assisted suicide (PAS) be allowed. In addition, the participants were asked what they wanted for themselves if they were the patient concerned. RESULTS: A total of 317 questionnaires were analyzed; the return rate was 70 %. The general support for euthanasia and PAS was high: 40.5 % supported euthanasia in case of a fatal illness ("definitely...", "probably should be allowed"), 53.5 % supported PAS. The support decreased in case of a nonfatal illness; however, it increased when the participants were asked about their attitudes if they were the patient concerned. Nurses were more open towards euthanasia and PAS. In physicians the rejection of PAS was directly related to a higher level of qualification in the field of palliative care. CONCLUSION: The fact that nurses had a more positive attitude towards euthanasia and PAS and that all respondents accepted life-ending acts for themselves more than for their patients hints to still existing severe deficits in Germany. PMID- 25701159 TI - Glutamine effects on heat shock protein 70 and interleukines 6 and 10: Randomized trial of glutamine supplementation versus standard parenteral nutrition in critically ill children. AB - BACKGROUND & AIMS: To determine whether glutamine (Gln) supplementation would have a role modifying both the oxidative stress and the inflammatory response of critically ill children. METHODS: Prospective, randomized, double-blind, interventional clinical trial. Selection criteria were children requiring parenteral nutrition for at least 5 days diagnosed with severe sepsis or post major surgery. Patients were randomly assigned to standard parenteral nutrition (SPN, 49 subjects) or standard parenteral nutrition with glutamine supplementation (SPN + Gln, 49 subjects). RESULTS: Glutamine levels failed to show statistical differences between groups. At day 5, patients in the SPN + Gln group had significantly higher levels of HSP-70 (heat shock protein 70) as compared with the SPN group (68.6 vs 5.4, p = 0.014). In both groups, IL-6 (interleukine 6) levels showed a remarkable descent from baseline and day 2 (SPN: 42.24 vs 9.39, p < 0.001; SPN + Gln: 35.20 vs 13.80, p < 0.001) but only the treatment group showed a statistically significant decrease between day 2 and day 5 (13.80 vs 10.55, p = 0.013). Levels of IL-10 (interleukine 10) did not vary among visits except in the SPN between baseline and day 2 (9.55 vs 5.356, p < 0.001). At the end of the study, no significant differences between groups for PICU and hospital stay were observed. No adverse events were detected in any group. CONCLUSIONS: Glutamine supplementation in critically-ill children contributed to maintain high HSP-70 levels for longer. Glutamine supplementation had no influence on IL-10 and failed to show a significant reduction of IL-6 levels. PMID- 25701160 TI - Clinically relevant heterotopic ossification after elbow fracture surgery: a risk factors study. AB - BACKGROUND: Heterotopic ossification (HO) is a common complication of elbow fracture surgery that can significantly impair function and range of motion (ROM). Whereas numerous studies have assessed HO after hip trauma or replacement surgery, few data have been reported on the prevalence and risk factors of HO after elbow fractures. HYPOTHESIS: Our objective was to investigate the prevalence and risk factors of clinically relevant HO after elbow fracture surgery under the hypothesis that the ability to identify high-risk patients would improve treatment tailoring and assist in meeting patient expectations. MATERIALS AND METHODS: We retrospectively included consecutive patients who had surgery for elbow injuries between January 2007 and December 2011. Patient demographics, operative details, and radiographs were reviewed. RESULTS: Of 124 elbows in 122 patients, 38 (30.6%) had HO and 26 (21%) clinically relevant HO. The prevalence of clinically relevant HO was highest in floating elbow injury, followed by combined olecranon and radial head fractures, types A and B distal humerus fractures, and terrible triad injury. By multiple logistic regression, factors that independently predicted clinically relevant HO were fracture dislocation (OR, 4.87; 95%CI, 1.78-13.29; P=0.002) and longer time to surgery (P<0.05). Of the 26 patients with clinically relevant HO, 6 (23%) eventually required revision elbow surgery to improve ROM. DISCUSSION: HO of the elbow occurred in almost one-third of our patients with surgically treated elbow fractures. Fracture-dislocation of the elbow and longer time to surgery independently predicted HO responsible for ROM loss. Clinically relevant HO was associated with significant morbidity. LEVEL OF EVIDENCE: Level IV, retrospective study. PMID- 25701161 TI - Percutaneous bunionette correction: results of a 49-case retrospective study at a mean 34 months' follow-up. AB - INTRODUCTION: Bunionette consists in a lateral prominence of the head of the fifth metatarsal (M5), inducing a callus. Toe malpositioning determines the varus, supraductus or infraductus form. HYPOTHESIS: A percutaneous method without osteosynthesis was assessed in 38 patients suffering from this pathology. PATIENTS AND METHODS: A continuous single-operator multicenter series operated on between May 2005 and January 2012 was analyzed with mean follow-up of 34 months. The inclusion criterion was bunionette with or without varus deviation. All patients were operated on percutaneously without tourniquet, on a day-care basis. All were clinically assessed, preoperatively and at latest FU, by visual analog pain scale (VAS), AOFAS and Coughlin scores, and callus status. Standard radiological assessment comprised monitoring of intermetatarsal (M4M5) and metatarsophalangeal (M5P1) angles. RESULTS: VAS decreased from 8 (range, 6-9) preoperatively to 0.3 (range, 0-1) out of 10 at follow-up. AOFAS score increased from 58 (range, 52-75) to 97 (range, 80-100) out of 100. According to the Coughlin score, 97.5% of patients were satisfied or very satisfied. Deformity correction was systematic, with disappearance of preoperative callus. M4M5 and M5P1 angles decreased respectively from 10 degrees (range, 6-13 degrees ) and 16.2 degrees (range, 8-24 degrees ) preoperatively to 5.5 degrees (range, 4-8 degrees ) and 4.3 degrees (range, 2-9 degrees ). There was 1 case of complex regional pain syndrome and 1 delayed consolidation. DISCUSSION: This procedure appeared reliable for correcting all types of bunionette deformity. Other minimally invasive methods with comparable results use pin fixation. The advantages over conventional techniques are the quality of results, low morbidity and absence of osteosynthesis material. The percutaneous technique should, we believe, be widely adopted in this indication. LEVEL OF EVIDENCE: IV. PMID- 25701162 TI - The Asia proximal femoral nail antirotation versus the standard proximal femoral antirotation nail for unstable intertrochanteric fractures in elderly Chinese patients. AB - BACKGROUND: The best options of internal fixation for unstable intertrochanteric fractures in elderly Chinese patients remain controversial. The Asia proximal femoral nail antirotation (PFNA-II) was specifically designed for Asian patients, which could be more effective than the regular proximal femoral nail antirotation (PFNA). Compared to PFNA, whether PFNA-II is associated with shorter operative time and lower rates of complications is unknown. HYPOTHESIS: The rate of complications using PFNA-II is lower than PFNA for the treatment of unstable intertrochanteric fractures in elderly Chinese patients, and the operation using PFNA-II is quicker. MATERIALS AND METHODS: Between June 2008 and December 2011, 188 patients with unstable intertrochanteric fractures treated with the PFNA-II (n=118) or PFNA (n=70) were retrospectively evaluated. Follow-up evaluations were performed at 1, 3, 6, 9 and 12 months, and every year thereafter. According to residual valgus-varus deformation, the quality of the fracture reduction was graded as poor (>10 degrees deformation), acceptable (5 degrees to 10 degrees deformation), or good (<5 degrees deformation). The operative time, intraoperative blood loss, overall time of fluoroscopy, blood transfusion volume, postoperative drainage, length of hospital stay and postoperative complications were recorded. RESULTS: The mean operative time in the PFNA-II group was significantly shorter than that in the PFNA group (66.25+/-13.15 vs 79.50+/-21.12 minutes; P<0.05), intraoperative blood loss was smaller (131.86+/-69.16 vs 162.14+/-66.18 mL; P<0.05), and fewer local complications were observed (25% vs 46%; P<0.05). There was no significant difference in the postoperative blood transfusions, overall time of fluoroscopy, postoperative drainage, length of hospital stay, fracture reduction, the position of the implant and tip apex distance between the two groups. At follow-up, no significant difference was found between the two groups in Harris hip score (HHS) (86.19+/-6.53 vs 85.27+/ 5.47; P>0.05), visual analogue scale (VAS) (0.87+/-0.85 vs 0.97+/-0.87; P>0.05). DISCUSSION: Due to its special design for the Asian population, PFNA-II offers a better match with the Chinese people's proximal femur anatomic structure. This study showed that the rate of complications using PFNA-II is lower than PFNA for the treatment of unstable intertrochanteric fractures in elderly Chinese patients, and the operation time is shorter. LEVEL OF EVIDENCE: Level III, case control study. PMID- 25701163 TI - Minimally invasive posterior approach in the popliteal fossa for semitendinosus and gracilis tendon harvesting: an anatomic study. AB - INTRODUCTION: Harvesting the semitendinosus (ST) and gracilis (GR) tendons at the anteromedial side of the knee may be hampered by a conjoint tendon insertion on the tibial metaphysis and an accessory bundle between the ST and the medial gastrocnemius. Locating and sparing the terminal branches of the saphenous nerve are difficult on an anteromedial approach. The principal objective of the present anatomic study was to assess the feasibility of ST and GR harvesting from a minimally invasive posterior approach in the popliteal fossa. The secondary objective was to analyze the risk of saphenous nerve branch lesion during harvesting. METHOD: Ten cadaver knees, free of scarring, were used. The whole body was positioned supine. The tendons were located in the popliteal fossa with the knee in 30 degrees flexion. A mini-incision was performed in the fossa. The ST and GR tendons were located, and retrograde followed by anterograde stripping was performed. Tendon lengths and diameters were measured. The knees were then dissected to check for saphenous nerve branch lesions (anterior, infrapatellar and posterior branches). RESULTS: The GR and ST tendons were respectively located at 14.4 and 24 mm from the medial edge of the knee. In 90% of cases, there was an accessory ST bundle toward the medial gastrocnemius muscle, 26 mm below the posterior edge. Tendons could be harvested without deviation of the stripper. Knee dissection did not find any saphenous nerve branches, these being protected by the sartorius fascia. DISCUSSION: Posterior ST and GR tendon harvesting in the popliteal fossa is reliable and reproducible. It allows easy sectioning of the accessory ST bundle, without deviation during retrograde stripping. Unlike anterior harvesting, which leads to a rate of saphenous branch lesion of 50-78%, posterior harvesting protects the nerve branches by keeping away from the sartorius. LEVEL OF EVIDENCE: Level 4. PMID- 25701164 TI - Evaluation of a new baseplate in reverse total shoulder arthroplasty - comparison of biomechanical testing of stability with roentgenological follow up criteria. AB - BACKGROUND AND PURPOSE: To minimize notching problem associated with reversed prostheses, inferior positioning of base plate is recommended. This reduces the risk of notching, but does not eliminate it completely. Both polyethylene/PE induced osteolysis and implant-to-bone or implant-to-implant contact may still occur, contributing to the risk of screw-breakage and resulting long-term failure. Therefore, the stability and integration of a newly developed base plate without inferior screw and inversion of bearing materials was investigated. PATIENTS AND METHODS: Biomechanical assessment of primary stability of the two types of glenoid baseplate (1- and 2-pegged) was carried out according to ASTM F 2028-02 (American Society for Testing and Materials). Patients with a follow-up period of at least 2 years were clinically (n=78) and for most of them radiologically (n=61) examined. The X-rays were evaluated for loosening and scapular notching. RESULTS: The mean values of micromotions after 100,000 cycles showed no relevant differences between the 2-peg and the 1-peg base plates (47 MUm for the 2-peg design and 43 MUm for the 1-peg design), i.e. both were below the borderline for secure Osseointegration of 150 MUm. Radiologically, no signs of loosening or radiolucent lines/RLL were found for both base plates. The mean incidence of inferior scapular notching was 23.6% (42 mm glenoid sphere: 15.8%). Only grade 1 and grade 2 notching was observed. Additionally as result of absence of PE-induced osteolysis shape, size, borderline and location of notching differed from those observed with conventional reverse total shoulder arthroplasty bearing materials. CONCLUSION: In combination with modified inferior operating technique, the newly designed implant has the potential to reduce the incidence of scapular notching and to avoid both PE-induced osteolysis and metal screw contact. The new design did not compromise stability of the base plate in any way during the investigation period, as demonstrated both by the data from the biomechanical investigation and also by the radiological follow-up. LEVEL OF EVIDENCE: Level III, case-control study. PMID- 25701165 TI - "Meticulous" cleaning of duodenoscopes may not eliminate infection risk, US watchdog warns. PMID- 25701166 TI - Injury of primary afferent neurons may contribute to osteoarthritis induced pain: an experimental study using the collagenase model in rats. AB - OBJECTIVE: Pain exacerbated by movement and loading on the joint is the major symptom of osteoarthritis (OA), but the mechanisms of chronic pain in this pathology are still poorly understood. Using the intra-articular (i.a.) injection of collagenase in the knee of rats as a model of OA, we aimed at evaluating whether injury of sensory neurons may contribute to the development of OA associated nociception. DESIGN: OA was induced by i.a. injection of collagenase into the left knee joint of adult male Wistar rats. Histopathological changes and movement and loading-induced nociception were assessed for 6 weeks. A time-course analysis of the expression of the neuronal injury markers activating transcription factor-3 (ATF-3) and neuropeptide Y (NPY) and of the neuropeptide SP in the dorsal root ganglion (DRG) was performed. Gabapentin's effect on nociception was evaluated, as well as the expression of the alpha2delta-1 voltage gated calcium channel subunit. RESULTS: Collagenase induced the development of OA like histopathological changes and of movement-induced nociception. Altered expression of ATF-3, NPY and SP was observed in the DRG, correlating with the degree of articular degeneration after 6 weeks of disease progression. Repeated administration of gabapentin reversed the nociceptive responses 6 weeks after the induction of OA. alpha2delta-1 was upregulated in the DRG. CONCLUSION: By inducing nociceptive behaviours associated with relevant joint structural changes, the i.a. injection of collagenase presents itself as a pertinent model for the study of OA pain. The findings in this study support the hypothesis that injury of sensory neurons innervating OA joints may be a significant element in the mechanisms of OA-associated pain. PMID- 25701167 TI - Gene-wide identification of episodic selection. AB - We present BUSTED, a new approach to identifying gene-wide evidence of episodic positive selection, where the non-synonymous substitution rate is transiently greater than the synonymous rate. BUSTED can be used either on an entire phylogeny (without requiring an a priori hypothesis regarding which branches are under positive selection) or on a pre-specified subset of foreground lineages (if a suitable a priori hypothesis is available). Selection is modeled as varying stochastically over branches and sites, and we propose a computationally inexpensive evidence metric for identifying sites subject to episodic positive selection on any foreground branches. We compare BUSTED with existing models on simulated and empirical data. An implementation is available on www.datamonkey.org/busted, with a widget allowing the interactive specification of foreground branches. PMID- 25701168 TI - PFB0595w is a Plasmodium falciparum J protein that co-localizes with PfHsp70-1 and can stimulate its in vitro ATP hydrolysis activity. AB - Heat shock proteins, many of which function as molecular chaperones, play important roles in the lifecycle and pathogenesis of the malaria parasite, Plasmodium falciparum. The P. falciparum heat shock protein 70 (PfHsp70) family of chaperones is potentially regulated by a large complement of J proteins that localize to various intracellular compartments including the infected erythrocyte cytosol. While PfHsp70-1 has been shown to be an abundant cytosolic chaperone, its regulation by J proteins is poorly understood. In this study, we characterized the J protein PFB0595w, a homologue of the well-studied yeast cytosolic J protein, Sis1. PFB0595w, similarly to PfHsp70-1, was localized to the parasite cytosol and its expression was upregulated by heat shock. Additionally, recombinant PFB0595w was shown to be dimeric and to stimulate the in vitro ATPase activity of PfHsp70-1. Overall, the expression, localization and biochemical data for PFB0595w suggest that it may function as a cochaperone of PfHsp70-1, and advances current knowledge on the chaperone machinery of the parasite. PMID- 25701169 TI - Necitumumab for patients with non-squamous NSCLC: uninspiring results. PMID- 25701172 TI - Moving the goal posts in prostate cancer trials. PMID- 25701173 TI - Erratum to: Capturing Patient-Reported Outcome (PRO) Data Electronically: The Past, Present, and Promise of ePRO Measurement in Clinical Trials. PMID- 25701171 TI - Necitumumab plus pemetrexed and cisplatin as first-line therapy in patients with stage IV non-squamous non-small-cell lung cancer (INSPIRE): an open-label, randomised, controlled phase 3 study. AB - BACKGROUND: Necitumumab is a second-generation recombinant human immunoglobulin G1 EGFR monoclonal antibody that competitively inhibits ligand binding. We aimed to compare necitumumab plus pemetrexed and cisplatin with pemetrexed and cisplatin alone in patients with previously untreated, stage IV, non-squamous non small-cell lung cancer (NSCLC). METHODS: We did this randomised, open-label, controlled phase 3 study at 103 sites in 20 countries. Patients aged 18 years or older, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 2 and adequate organ function, were randomly assigned 1:1 to treatment with a block randomisation scheme (block size of four) via a telephone-based interactive voice-response system or interactive web-response system. Patients received either cisplatin 75 mg/m(2) and pemetrexed 500 mg/m(2) on day 1 of a 3-week cycle for a maximum of six cycles alone, or with necitumumab 800 mg on days 1 and 8. Necitumumab was continued after the end of chemotherapy until disease progression or unacceptable toxic effects. Randomisation was stratified by smoking history, ECOG performance status, disease histology, and geographical region. Patients and study investigators were not masked to group assignment. The primary endpoint was overall survival. Efficacy analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00982111. FINDINGS: Between Nov 11, 2009, and Feb 2, 2011, we randomly assigned 633 patients to receive either necitumumab plus pemetrexed and cisplatin (n=315) or pemetrexed and cisplatin alone (n=318). Enrolment was stopped on Feb 2, 2011, after a recommendation from the independent data monitoring committee. There was no significant difference in overall survival between treatment groups, with a median overall survival of 11.3 months (95% CI 9.5-13.4) in the necitumumab plus pemetrexed and cisplatin group versus 11.5 months (10.1-13.1) in the pemetrexed and cisplatin group (hazard ratio 1.01 [95% CI 0.84-1.21]; p=0.96). The incidence of grade 3 or worse adverse events, including deaths, was higher in the necitumumab plus pemetrexed and cisplatin group than in the pemetrexed and cisplatin group; in particular, deaths regarded as related to study drug were reported in 15 (5%) of 304 patients in the necitumumab group versus nine (3%) of 312 patients in the pemetrexed and cisplatin group. Serious adverse events were likewise more frequent in the necitumumab plus pemetrexed and cisplatin group than in the pemetrexed and cisplatin group (155 [51%] of 304 vs 127 [41%] of 312 patients). Patients in the necitumumab plus pemetrexed and cisplatin group had more grade 3-4 rash (45 [15%] of 304 vs one [<1%] of 312 patients in the pemetrexed and cisplatin alone group), hypomagnesaemia (23 [8%] vs seven [2%] patients), and grade 3 or higher venous thromboembolic events (23 [8%] vs 11 [4%] patients) than did those in the pemetrexed and cisplatin alone group. INTERPRETATION: Our findings show no evidence to suggest that the addition of necitumumab to pemetrexed and cisplatin increases survival of previously untreated patients with stage IV non-squamous NSCLC. Unless future studies identify potentially useful predictive biomarkers, necitumumab is unlikely to provide benefit in this patient population when combined with pemetrexed and cisplatin. FUNDING: Eli Lilly and Company. PMID- 25701170 TI - Orteronel plus prednisone in patients with chemotherapy-naive metastatic castration-resistant prostate cancer (ELM-PC 4): a double-blind, multicentre, phase 3, randomised, placebo-controlled trial. AB - BACKGROUND: Orteronel is an investigational, partially selective inhibitor of CYP 17,20-lyase in the androgen signalling pathway, a validated therapeutic target for metastatic castration-resistant prostate cancer. We assessed orteronel in chemotherapy-naive patients with metastatic castration-resistant prostate cancer. METHODS: In this phase 3, double-blind, placebo-controlled trial, we recruited patients with progressive metastatic castration-resistant prostate cancer and no previous chemotherapy from 324 study centres (ie, hospitals or large urologic or group outpatient offices) in 43 countries. Eligible patients were randomly assigned in a 1:1 ratio to receive either 400 mg orteronel plus 5 mg prednisone twice daily or placebo plus 5 mg prednisone twice daily. Randomisation was done centrally with an interactive voice response system and patients were stratified by region (Europe, North America, and not Europe or North America) and the presence or absence of radiographic disease progression at baseline. The two primary endpoints were radiographic progression-free survival and overall survival, determined in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01193244. FINDINGS: From Oct 31, 2010, to June 29, 2012, 2353 patients were assessed for eligibility. Of those, 1560 were randomly assigned to receive either orteronel plus prednisone (n=781) or placebo plus prednisone (n=779). The clinical cutoff date for the final analysis was Jan 15, 2014 (with 611 deaths). Median follow-up for radiographic progression-free survival was 8.4 months (IQR 3.7-16.6). Median radiographic progression-free survival was 13.8 months (95% CI 13.1-14.9) with orteronel plus prednisone and 8.7 months (8.3-10.9) with placebo plus prednisone (hazard ratio [HR] 0.71, 95% CI 0.63-0.80; p<0.0001). After a median follow-up of 20.7 months (IQR 14.2-25.4), median overall survival was 31.4 months (95% CI 28.6-not estimable) with orteronel plus prednisone and 29.5 months (27.0-not estimable) with placebo plus prednisone (HR 0.92, 95% CI 0.79-1.08; p=0.31). The most common grade 3 or worse adverse events were increased lipase (137 [17%] of 784 patients in the orteronel plus prednisone group vs 14 [2%] of 770 patients in the placebo plus prednisone group), increased amylase (77 [10%] vs nine [1%]), fatigue (50 [6%] vs 14 [2%]), and pulmonary embolism (40 [5%] vs 27 [4%]). Serious adverse events were reported in 358 [46%] patients receiving orteronel plus prednisone and in 292 [38%] patients receiving placebo plus prednisone. INTERPRETATION: In chemotherapy-naive patients with metastatic castration-resistant prostate cancer, radiographic progression-free survival was prolonged with orteronel plus prednisone versus placebo plus prednisone. However, no improvement was noted in the other primary endpoint, overall survival. Orteronel plus prednisone was associated with increased toxic effects compared with placebo plus prednisone. On the basis of these and other data, orteronel is not undergoing further development in metastatic castration-resistant prostate cancer. FUNDING: Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. PMID- 25701174 TI - GSK3 and KIF5 regulate activity-dependent sorting of gephyrin between axons and dendrites. AB - The kinesin KIF5 transports neuronal cargoes into axons and dendrites. Isolated KIF5 motor domains preferentially move into axons, however KIF5 binding to GRIP1 or gephyrin drives the motor into dendrites, to deliver AMPA receptors (AMPARs) or glycine receptors (GlyRs), respectively. At postsynaptic sites, gephyrin forms a multimeric scaffold to anchor GlyRs and GABAA receptors (GABAARs) in apposition to inhibitory presynaptic terminals. Here, we report the unexpected observation that increased intracellular calcium through chronic activation of AMPARs, steers a newly synthesized gephyrin fusion protein (tomato-gephyrin) to axons and interferes with its normal delivery into dendrites of cultured neurons. Axonal gephyrin clusters were not apposed to presynaptic terminals, but colocalized with GlyRs and neuroligin-2 (NLG2). Notably, functional blockade of glycogen synthase kinase-3 (GSK3) and KIF5 normalized gephyrin missorting into the axonal compartment. In contrast, mutagenesis of gephyrin S270, a GSK3 target, did not contribute to axo-dendritic sorting. Our data are consistent with previous observations, which report regulation of kinesin motility through GSK3 activity. They suggest that GSK3 regulates the sorting of GlyR/gephyrin and NLG2 complexes in a KIF5-dependent manner. PMID- 25701175 TI - Quantitative Review Finds No Evidence of Cognitive Effects in Healthy Populations From Single-session Transcranial Direct Current Stimulation (tDCS). AB - BACKGROUND: Over the last 15-years, transcranial direct current stimulation (tDCS), a relatively novel form of neuromodulation, has seen a surge of popularity in both clinical and academic settings. Despite numerous claims suggesting that a single session of tDCS can modulate cognition in healthy adult populations (especially working memory and language production), the paradigms utilized and results reported in the literature are extremely variable. To address this, we conduct the largest quantitative review of the cognitive data to date. METHODS: Single-session tDCS data in healthy adults (18-50) from every cognitive outcome measure reported by at least two different research groups in the literature was collected. Outcome measures were divided into 4 broad categories: executive function, language, memory, and miscellaneous. To account for the paradigmatic variability in the literature, we undertook a three-tier analysis system; each with less-stringent inclusion criteria than the prior. Standard mean difference values with 95% CIs were generated for included studies and pooled for each analysis. RESULTS: Of the 59 analyses conducted, tDCS was found to not have a significant effect on any - regardless of inclusion laxity. This includes no effect on any working memory outcome or language production task. CONCLUSION: Our quantitative review does not support the idea that tDCS generates a reliable effect on cognition in healthy adults. Reasons for and limitations of this finding are discussed. This work raises important questions regarding the efficacy of tDCS, state-dependency effects, and future directions for this tool in cognitive research. PMID- 25701176 TI - Complete genome sequence of the cyclohexylamine-degrading Pseudomonas plecoglossicida NyZ12. AB - Pseudomonas plecoglossicida NyZ12 (CCTCC AB 2015057), a Gram-negative bacterium isolated from soil, has the ability to degrade cyclohexylamine. The complete genome sequence of this strain (6,233,254bp of chromosome length) is presented, with information about the genes of characteristic enzymes responsible for cyclohexylamine oxidation to cyclohexanone and the integrated gene cluster for the metabolic pathway of cyclohexanone oxidation to adipate. PMID- 25701177 TI - Highly efficient and regioselective synthesis of dihydromyricetin esters by immobilized lipase. AB - Dihydromyricetin is the principle component of the Chinese herbal tea Teng-cha and a promising ingredient for functional food and nutraceuticals, but its low solubility limits its application potentials. This study explored enzymatic acylation of dihydromyricetin to improve its solubility in lipid systems. Acylation was achieved with several lipases with the synthesis of a major (>86%) product and a minor product. Isolation and purification of the products by preparative HPLC followed by LC-MS, (13)C NMR, (1)H NMR and 2 D-HSQC NMR analyses showed that the major product was a dihydromyricetin monoester with the acylation site at the 3-OH group of C ring. Quantum chemical calculations revealed that the 3-OH had the lowest antioxidant activity, and therefore acylation at this site was expected to have minimum impact on the antioxidant activity. Several factors, including solvent, acyl donor, enzyme origin, molar ratio of substrates and reaction temperature and time, exhibited significant effects on the initial rate, conversion yield and regioselectivity of the reaction. Acylation occurred only with vinyl acetate as the acyl donor, and highest conversion yields were achieved with immobilized Penicillium expansum lipase and Novozyme 435 with DMSO and acetonitrile being the best solvents. In general, the acylation results were found to be superior to previous reports on acylation of aglycone flavonoids with respects to conversion yield and regioselectivity. PMID- 25701178 TI - Pan-European longitudinal surveillance of antibiotic resistance among prevalent Clostridium difficile ribotypes. AB - Clostridium difficile infection remains a major healthcare burden. Until the recent introduction of fidaxomicin, antimicrobial treatments were limited to metronidazole and vancomycin. The emergence of epidemic C. difficile PCR ribotype 027 and its potential link to decreased antibiotic susceptibility highlight the lack of large-scale antimicrobial susceptibility and epidemiological data available. We report results of epidemiological and antimicrobial susceptibility investigations of C. difficile isolates collected prior to fidaxomicin introduction, establishing important baseline data. Thirty-nine sites in 22 countries submitted a total of 953 C. difficile isolates for PCR ribotyping, toxin testing, and susceptibility testing to metronidazole, vancomycin, fidaxomicin, rifampicin, moxifloxacin, clindamycin, imipenem, chloramphenicol, and tigecycline. Ninety-nine known ribotypes were identified. Ribotypes 027, 014, 001/072, and 078 were most frequently isolated in line with previous European studies. There was no evidence of resistance to fidaxomicin, and reduced susceptibility to metronidazole and vancomycin was also scarce. Rifampicin, moxifloxacin, and clindamycin resistance (13%, 40%, and 50% of total isolates, respectively) were evident in multiple ribotypes. There was a significant correlation between lack of ribotype diversity and greater antimicrobial resistance (measured by cumulative resistance score). Well-known epidemic ribotypes 027 and 001/072 were associated with multiple antimicrobial resistance, but high levels of resistance were also observed, particularly in 018 and closely related emergent ribotype 356 in Italy. This raises the possibility of antimicrobial exposure as the underlying reason for their appearance, and highlights the need for ongoing epidemiological and antimicrobial resistance surveillance. PMID- 25701179 TI - Periostin conditions the matrix to generate a niche for islet regeneration. PMID- 25701180 TI - Corrigendum. PMID- 25701184 TI - Safety evaluation of standardized allergen extract of Japanese cedar pollen for sublingual immunotherapy. AB - Japanese cedar (JC) pollinosis is caused by Japanese cedar pollen (JCP) and most common seasonal allergic disease in Japan. Subcutaneous immunotherapy (SCIT) with allergen extract of JCP (JCP-allergen extract) is well established for JC pollinosis treatment with improvement of symptoms. However, major drawbacks for SCIT are repeated painful injections, frequent hospital visits and anaphylactic risk. Currently, sublingual immunotherapy (SLIT) has received much attention as an advanced alternative application with lower incidence of systemic reactions because the liquid or tablet form of allergen is placed under the tongue. The aim of this study was safety evaluation of standardized JCP-allergen extract currently developed for SLIT in JC pollinosis. JCP-allergen extract showed no potential genotoxicity. No systemic effects were observed in rats administered JCP-allergen extract orally for 26 weeks followed by 4-week recovery period. Mild local reactions such as hyperplasia and increased globule leukocytes resulting from vehicle (glycerin)-induced irritation were observed in stomach. No-observed adverse-effect level was greater than 10,000 JAU/kg/day for systemic toxicity, equivalent to 300-fold the human dose. No local irritation was found in rabbits oral mucosae by 7-day sublingual administration. These results demonstrate the safe profile of standardized JCP-allergen extract, suggesting it is suitable for SLIT in JC pollinosis. PMID- 25701185 TI - Part I--Evaluation of pediatric post-traumatic headaches. AB - BACKGROUND: Brain injury is one of the most common injuries in the pediatric age group, and post-traumatic headache is one of the most common symptoms following mild traumatic brain injury in children. METHODS: This is an expert opinion-based two-part review on pediatric post-traumatic headaches. Part I will focus on an overview and approach to the evaluation of post-traumatic headache. Part II will focus on the medical management of post-traumatic headache. Relevant articles were reviewed, and an algorithm is proposed. RESULTS: We review the epidemiology, classification, pathophysiology, and clinical approach to evaluating patients with post-traumatic headache. A comprehensive history and physical examination are fundamental to identifying the headache type(s). Identifying the precise headache phenotype is important to help guide treatment. Most of the post traumatic headaches are migraine or tension type, but occipital neuralgia, cervicogenic headache, and medication overuse headache also occur. Postconcussive signs often resolve within 1 month, and individuals whose signs persist longer may benefit from an interprofessional approach. CONCLUSIONS: Rigorous evaluation and diagnosis are vital to treating post-traumatic headaches effectively. A multifaceted approach is needed to address all the possible contributing factors to the headaches and any comorbid conditions that may delay recovery or alter treatment choices. PMID- 25701186 TI - Therapeutic strategies for mitochondrial disorders. AB - OBJECTIVES: There is currently no curative therapy for mitochondrial disorders, although symptomatic measures can be highly effective and greatly improve the quality of life and outcome of these patients. This review highlights potential strategies for the therapeutic management of mitochondrial disorders. METHODS: Data for this review were identified by searches of MEDLINE, Current Contents, using various relevant search terms. RESULTS: Strategies to establish a therapeutic regimen aim to enhance respiratory chain function, eliminate noxious compounds, shift the heteroplasmy rate, alter mitochondrial dynamics, transfer cytoplasm, and promote gene therapy. Symptomatic measures rely on drugs (e.g., antiepileptics), avoidance of mitochondrion-toxic agents, substitution of blood cells, hemodialysis, invasive measures (such as a pacemaker), surgery (e.g., ptosis correction), physiotherapy, speech therapy, occupational therapy, dietary measures (e.g., ketogenic diet, anaplerotic diet), and the avoidance of mitochondrion-toxic agents (e.g., ozone). With the increasing awareness of mitochondrial disorders, the number of treatment studies is growing and its quality is improving. If high quality studies (high Jadad score) yield statistical significance for end points, a treatment is more reliable than with lower quality studies. CONCLUSIONS: Despite the lack of a proven treatment for mitochondrial disorders, a nihilistic attitude toward treatment is not justified. A number of studies are seeking targeted therapies, and highly effective symptomatic measures are available. PMID- 25701187 TI - Possible linkage between visual and motor development in children with cerebral palsy. AB - AIM: The purpose of this study was to examine ophthalmic disorders associated with neurological disorders in children with cerebral palsy. METHODS: Children clinically diagnosed as cerebral palsy with supportive abnormal magnetic resonance imaging results were included in this prospective study. All participants were recommended to have comprehensive ophthalmic exams. To assess motor function, the Gross Motor Function Classification System and the Gross Motor Function Measure were used. To assess motor and cognitive function, the Bayley Scales of Infant Development-II was used. RESULTS: Forty-seven children completed all the evaluations and the data were analyzed. Ametropia was seen in 78.7% and strabismus was seen in 44.7% of the 47 children. When subjects were divided into severely impaired and mildly impaired groups based on Gross Motor Function Classification System level, ametropia was more prevalent in the severely impaired than the mildly impaired (95.8% versus 60.9%, P < 0.05). According to quantitative analysis, the severity of gross motor impairment correlated with the degree of refractive error in the subjects older than 36 months (r = -0.65 for the Bayley Scales of Infant Development-II motor scale, P < 0.05). INTERPRETATION: Based on these findings, children with cerebral palsy with poor gross motor function have a high possibility of severe refractive disorder that becomes evident from 36 months after birth. These results suggest that brain injury and impaired motor development negatively affect ophthalmic development. Hence, an ophthalmic examination is recommended for young children with cerebral palsy to start early management. PMID- 25701188 TI - An unusual cause of daytime urinary incontinence. PMID- 25701189 TI - Genetics of brain and cognitive aging: introduction to the special issue of Neuropsychology Review. PMID- 25701191 TI - Adaptive sensor-fault tolerant control for a class of multivariable uncertain nonlinear systems. AB - This paper deals with the active fault tolerant control (AFTC) problem for a class of multiple-input multiple-output (MIMO) uncertain nonlinear systems subject to sensor faults and external disturbances. The proposed AFTC method can tolerate three additive (bias, drift and loss of accuracy) and one multiplicative (loss of effectiveness) sensor faults. By employing backstepping technique, a novel adaptive backstepping-based AFTC scheme is developed using the fact that sensor faults and system uncertainties (including external disturbances and unexpected nonlinear functions caused by sensor faults) can be on-line estimated and compensated via robust adaptive schemes. The stability analysis of the closed loop system is rigorously proven using a Lyapunov approach. The effectiveness of the proposed controller is illustrated by two simulation examples. PMID- 25701190 TI - Assessment of the in vitro cytotoxicity and in vivo anti-tumor activity of the alcoholic stem bark extract/fractions of Mimusops elengi Linn. AB - Various parts of Mimusops elengi Linn. (Sapotaceae) have been used widely in traditional Indian medicine for the treatment of pain, inflammation and wounds. The study was conducted to explore the use of stem bark of M. elengi on pharmacological grounds and to evaluate the scientific basis of cytotoxic and anti-tumor activity. Extract/fractions were prepared and in vitro cytotoxicity was assessed using SRB assay. Most effective fractions were subjected to fluorescence microscopy based acridine orange/ethidium bromide (AO/EB) and Hoechst 33342 staining to determine apoptosis induction and DNA fragmentation assay. Comet and micronuclei assay were performed to assess genotoxicity. Cell cycle analysis was also performed. In vivo anti-tumor potential was evaluated by Ehrlich ascites carcinoma (EAC) model in mice. The alcoholic stem bark extract of M. elengi along with four fractions showed potential in vitro cytotoxicity in SRB assay. Of these, dichloromethane and ethyl acetate fractions were selected for further studies. The fractions revealed apoptosis inducing potential in AO/EB and Hoechst 33342 staining, which was further confirmed by DNA fragmentation assay. Genotoxic potential was revealed by comet and micronuclei assay. Fractions also exhibited specific cell cycle inhibition in G0/G1 phase. In EAC model, ethyl acetate fraction along with the standard (cisplatin) effectively reduced the increase in body weight compared to control and improved mean survival time. Both fractions were able to restore the altered hematological and biochemical parameters. Hence, M. elengi stem bark may be a possible therapeutic candidate having cytotoxic and anti-tumor potential. PMID- 25701192 TI - Stability and stabilization studies for a class of switched nonlinear systems via vector norms approach. AB - This paper is concerned with the problems of stability analysis and stabilization with a state feedback controller through pole placement for a class of both continuous and discrete-time switched nonlinear systems. These systems are modeled by differential or difference equations. Then, a transformation under the arrow form is employed. Note that, the main contribution in this work is twofold: firstly, based on the construction of an appropriated common Lyapunov function, as well the use of the vector norms notion, the recourse to the Kotelyanski lemma, the M-matrix proprieties, the aggregation techniques and the application of the Borne-Gentina criterion, new sufficient stability conditions under arbitrary switching for the autonomous system are deduced. Secondly, this result is extended for designing a state feedback controller by using pole assignment control, which guarantee that the corresponding closed-loop system is globally asymptotically stable under arbitrary switching. The main novelties features of these obtained results are the explicitness and the simplicity in their application. Moreover, they allow us to avoid the search of a common Lyapunov function which is a difficult matter. Finally, as validation to stabilize a shunt DC motor under variable mechanical loads is performed to demonstrate the effectiveness of the proposed results. PMID- 25701193 TI - Risk Factors for Subsidence of a Modular Tapered Femoral Stem Used for Revision Total Hip Arthroplasty. AB - The purpose of this study was to determine the incidence, and the clinical and radiographic risk factors for significant subsidence of a cementless, modular tapered revision femoral stem. Femoral stem subsidence of at least 10 mm or subsidence requiring revision was considered significant subsidence. Ninety-seven patients (99 hips) were included with minimum radiographic follow-up of one year (mean 34 months; range, 12-91 months). The mean stem subsidence was 4.5 mm (range, 0-44 mm). Fourteen out of 99 (14.1%) stems had significant subsidence and 6 (6.1%) stems required revision due to subsidence. Patient weight greater than 80 kg (P=0.04) and femoral stem press-fit distance of less than 2 cm (P<0.01) were both independent risk factors for significant stem subsidence. PMID- 25701194 TI - ATM-mediated PTEN phosphorylation promotes PTEN nuclear translocation and autophagy in response to DNA-damaging agents in cancer cells. AB - PTEN (phosphatase and tensin homolog), a tumor suppressor frequently mutated in human cancer, has various cytoplasmic and nuclear functions. PTEN translocates to the nucleus from the cytoplasm in response to oxidative stress. However, the mechanism and function of the translocation are not completely understood. In this study, topotecan (TPT), a topoisomerase I inhibitor, and cisplatin (CDDP) were employed to induce DNA damage. The results indicate that TPT or CDDP activates ATM (ATM serine/threonine kinase), which phosphorylates PTEN at serine 113 and further regulates PTEN nuclear translocation in A549 and HeLa cells. After nuclear translocation, PTEN induces autophagy, in association with the activation of the p-JUN-SESN2/AMPK pathway, in response to TPT. These results identify PTEN phosphorylation by ATM as essential for PTEN nuclear translocation and the subsequent induction of autophagy in response to DNA damage. PMID- 25701195 TI - The novel multispecies Fc-specific Pseudomonas exotoxin A fusion protein alpha-Fc ETA' enables screening of antibodies for immunotoxin development. AB - Immunoconjugates that deliver cytotoxic payloads to cancer cells represent a promising class of therapeutic agents which are intensively investigated in various clinical applications. Prerequisites for the generation of effective immunoconjugates are antibodies which efficiently deliver the respective cytotoxic payload. To facilitate the selection of human or mouse antibodies that display favorable characteristics as immunotoxins, we developed a novel Pseudomonas exotoxin A (ETA)-based screening protein. The alpha-Fc-ETA' consists of a multispecies-specific Fc-binding domain antibody genetically fused to a truncated ETA version (ETA'). alpha-Fc-ETA' non-covalently bound to human and mouse antibodies but did not form immune complexes with bovine immunoglobulins. In combination with antibodies harboring human or mouse Fc domains alpha-Fc-ETA' inhibited proliferation of antigen-expressing tumor cells. The cytotoxic effects were strictly antibody dependent and were observed with low alpha-Fc-ETA' concentrations. Mouse antibodies directed against CD7 and CD317/HM1.24 that previously had been used for the generation of functional recombinant immunotoxins, also showed activity in combination with alpha-Fc-ETA' by inhibiting growth of antigen-positive myeloma and leukemia cell lines. In contrast, alpha-kappa-ETA', a similarly designed human kappa light chain-specific fusion protein, was only specifically active in combination with antibodies containing a human kappa light chain. Thus, the novel alpha-Fc-ETA' fusion protein is broadly applicable in screening antibodies and Fc-containing antibody derivatives from different species to select for candidates with favorable characteristics for immunotoxin development. PMID- 25701196 TI - Computer-assisted abdominal surgery: new technologies. AB - BACKGROUND: Computer-assisted surgery is a wide field of technologies with the potential to enable the surgeon to improve efficiency and efficacy of diagnosis, treatment, and clinical management. PURPOSE: This review provides an overview of the most important new technologies and their applications. METHODS: A MEDLINE database search was performed revealing a total of 1702 references. All references were considered for information on six main topics, namely image guidance and navigation, robot-assisted surgery, human-machine interface, surgical processes and clinical pathways, computer-assisted surgical training, and clinical decision support. Further references were obtained through cross referencing the bibliography cited in each work. Based on their respective field of expertise, the authors chose 64 publications relevant for the purpose of this review. CONCLUSION: Computer-assisted systems are increasingly used not only in experimental studies but also in clinical studies. Although computer-assisted abdominal surgery is still in its infancy, the number of studies is constantly increasing, and clinical studies start showing the benefits of computers used not only as tools of documentation and accounting but also for directly assisting surgeons during diagnosis and treatment of patients. Further developments in the field of clinical decision support even have the potential of causing a paradigm shift in how patients are diagnosed and treated. PMID- 25701197 TI - Age at Autism Spectrum Disorder (ASD) Diagnosis by Race, Ethnicity, and Primary Household Language Among Children with Special Health Care Needs, United States, 2009-2010. AB - We examined prevalence of diagnosed autism spectrum disorder (ASD) and age at diagnosis according to child's race/ethnicity and primary household language. From the 2009-2010 National Survey of Children with Special Health Care Needs, we identified 2729 3-17-year-old US children whose parent reported a current ASD diagnosis. We compared ASD prevalence, mean diagnosis age, and percentage with later diagnoses (>=5 years) across racial/ethnic/primary household language groups: non-Hispanic-white, any language (NHW); non-Hispanic-black, any language (NHB); Hispanic-any-race, English (Hispanic-English); and Hispanic-any-race, other language (Hispanic-Other). We assessed findings by parent-reported ASD severity level and adjusted for family sociodemographics. ASD prevalence estimates were 15.3 (NHW), 10.4 (NHB), 14.1 (Hispanic-English), and 5.2 (Hispanic Other) per 1000 children. Mean diagnosis age was comparable across racial/ethnic/language groups for 3-4-year-olds. For 5-17-year-olds, diagnosis age varied by race/ethnicity/language and also by ASD severity. In this group, NHW children with mild/moderate ASD had a significantly higher proportion (50.8 %) of later diagnoses than NHB (33.5 %) or Hispanic-Other children (18.0 %). However, NHW children with severe ASD had a comparable or lower (albeit non significant) proportion (16.4 %) of later diagnoses than NHB (37.8 %), Hispanic English (30.8 %), and Hispanic-Other children (12.0 %). While NHW children have comparable ASD prevalence and diagnosis age distributions as Hispanic-English children, they have both higher prevalence and proportion of later diagnoses than NHB and Hispanic-Other children. The diagnosis age findings were limited to mild/moderate cases only. Thus, the prevalence disparity might be primarily driven by under-representation (potentially under-identification) of older children with mild/moderate ASD in the two minority groups. PMID- 25701198 TI - IDH mutation status and role of WHO grade and mitotic index in overall survival in grade II-III diffuse gliomas. AB - Diffuse gliomas are up till now graded based upon morphology. Recent findings indicate that isocitrate dehydrogenase (IDH) mutation status defines biologically distinct groups of tumors. The role of tumor grade and mitotic index in patient outcome has not been evaluated following stratification by IDH mutation status. To address this, we interrogated 558 WHO grade II-III diffuse gliomas for IDH1/2 mutations and investigated the prognostic impact of WHO grade within IDH-mutant and IDH-wild type tumor subsets independently. The prognostic impact of grade was modest in IDH-mutant [hazard ratio (HR) = 1.21, 95 % confidence interval (CI) = 0.91-1.61] compared to IDH-wild type tumors (HR = 1.74, 95 % CI = 0.95-3.16). Using a dichotomized mitotic index cut-off of 4/1000 tumor cells, we found that while mitotic index was significantly associated with outcome in IDH-wild type tumors (log-rank p < 0.0001, HR = 4.41, 95 % CI = 2.55-7.63), it was not associated with outcome in IDH-mutant tumors (log-rank p = 0.5157, HR = 1.10, 95 % CI = 0.80-1.51), and could demonstrate a statistical interaction (p < 0.0001) between IDH mutation and mitotic index (i.e., suggesting that the effect of mitotic index on patient outcome is dependent on IDH mutation status). Patient age, an established prognostic factor in diffuse glioma, was significantly associated with outcome only in the IDH-wild type subset, and consistent with prior data, 1p/19q co-deletion conferred improved outcome in the IDH-mutant cohort. These findings suggest that stratification of grade II-III gliomas into subsets defined by the presence or absence of IDH mutation leads to subgroups with distinct prognostic characteristics. Further evaluation of grading criteria and prognostic markers is warranted within IDH-mutant versus IDH-wild type diffuse grade II-III gliomas as independent entities. PMID- 25701199 TI - Cyanidin and malvidin in aqueous extracts of black carrots fermented with Aspergillus oryzae prevent the impairment of energy, lipid and glucose metabolism in estrogen-deficient rats by AMPK activation. AB - Black carrots (Daucus carota L.) are rich in anthocyanins which contribute many health benefits, but are limited by bioavailability and instability when exposed to oxygen, heat and light. Fermenting black carrots may improve the stability, absorption and bioactivity of its anthocyanins. Here, we examined whether and by what mechanisms the long-term consumption of unfermented black carrot extract (BC) and its extracts fermented with Lactobacillus plantarum (BCLP) or Aspergillus oryzae (BCAO) might prevent menopausal symptoms including impaired energy, glucose and lipid metabolism in estrogen-deficient animals with diet induced obesity. Ovariectomized (OVX) rats were fed four different high-fat diets containing 2 % dextrin (OVX-control), 2 % BC, 2 % BCLP, or 2 % BCAO for 12 weeks. Sham rats were fed high-fat diets containing 2 % dextrin. The contents of total anthocyanins increased in BCAO compared to BC and BCLP, whereas the contents of cyanidin-3-rutinosides, malvidin-3,5-diglycosides and delphine-3-glucoside were lower and cyanidin and malvidin were much higher in BCLP and BCAO than BC. Fat mass and weight gain were lower in descending order of OVX-control > BC and BCLP > BCAO due to increased energy expenditure and fat oxidation. However, BC, BCLP and especially BCAO all normalized HOMA-IR, an indicator of insulin resistance and glucose intolerance, in OVX rats. OVX increased serum total and LDL cholesterol and triglycerides, but BC, BCLP and BCAO significantly prevented the increases. BCAO markedly decreased hepatic triglyceride levels by increasing gene expressions of CPT-1 and PPAR-alpha, which are involved in fatty acid oxidation, and decreasing mRNA expressions of FAS and SREBP-1c, which are associated with fatty acid synthesis. This was related to increased pAMPK -> pACC signaling and improved hepatic insulin signaling (pAkt -> pFOXO-1). Cyanidin and malvidin markedly decreased fat accumulation in 3T3-L1 adipocytes by increasing CPT-1 and decreasing FAS and SREBP-1c expression in comparison with cyanidin-3-rutinoside and malvidin-3,5-diglycosides. In conclusion, with increasing cyanidin and malvidin, BCAO prevented the exacerbation of lipid and glucose metabolism by activating hepatic insulin signaling and AMPK activation by in OVX rats. PMID- 25701200 TI - Surface EMG to assess arm function in boys with DMD: a pilot study. AB - INTRODUCTION: Preserving functional abilities of the upper extremities is a major concern in boys with Duchenne Muscular Dystrophy (DMD). To assess disease progression and treatments, good knowledge on arm function in boys with DMD is essential. Therefore, feasibility and validity of the use of surface electromyography (sEMG) to assess arm function in boys with DMD was examined. METHODS: Five boys with DMD and 6 age-matched controls participated in this study. Single joint movements and ADL activities were examined while recording sEMG of main shoulder and elbow muscles. RESULTS: All boys with DMD and controls were able to perform the non standardized movements of the measurement protocol, however one boy with DMD was not able to perform all the standardized movements. Boys with DMD used significantly more of their maximal muscle capacity for all muscles to conduct movements compared to controls. DISCUSSION/CONCLUSION: The measurement protocol was feasible to assess arm function in boys with DMD. This tool was able to discriminate between DMD patients and controls. PMID- 25701201 TI - The Primary Obesity Surgery Endolumenal (POSE) procedure: one-year patient weight loss and safety outcomes. AB - BACKGROUND: Obesity is at epidemic proportions and increasing. Bariatric surgical procedures have demonstrated better durable weight loss than diet and exercise; however, risk may limit adoption of these procedures. Endoscopic procedures may offer less risk, lower cost, and satisfactory results, but limited safety and outcome data is available. The present report describes the Primary Obesity Surgery Endolumenal (POSE(TM)) procedure, perioperative care, and 1-year safety and weight loss outcomes for a single center. METHODS: One hundred forty-seven patients undergoing the POSE procedure between July 2011 and January 2013 were followed for 1 year. Overall patient status and weight data were collected at baseline and at 3, 6, and 12 months. Outcomes included change in total weight loss (TWL), percentage of TWL (%TWL), percentage of excess weight loss (%EWL), and adverse events. RESULTS: Patients tolerated the procedure well with no serious short-term or long-term adverse events. All but 1 patient were discharged within 24 hours of the procedure. Baseline body mass index (BMI) was 38.0 +/- 4.8 kg/m(2). Initial weight (106.8 +/- 18.2 kg) was significantly reduced at 3, 6, and 12 months. At 1 year, 116 patients (79% of total) who were available for follow-up had a mean TWL of 16.6 +/- 9.7 kg, %TWL of 15.1 +/- 7.8, and %EWL of 44.9 +/- 24.4. CONCLUSION: After 1-year follow-up, POSE was considered an effective, safe and well tolerated procedure for the treatment of patients with obesity. PMID- 25701203 TI - Quaternary and tertiary aldoxime antidotes for organophosphate exposure in a zebrafish model system. AB - The zebrafish is rapidly becoming an important model system for screening of new therapeutics. Here we evaluated the zebrafish as a potential pharmacological model for screening novel oxime antidotes to organophosphate (OP)-inhibited acetylcholinesterase (AChE). The ki values determined for chlorpyrifos oxon (CPO) and dichlorvos (DDVP) showed that CPO was a more potent inhibitor of both human and zebrafish AChE, but overall zebrafish AChE was less sensitive to OP inhibition. In contrast, aldoxime antidotes, the quaternary ammonium 2-PAM and tertiary amine RS-194B, showed generally similar overall reactivation kinetics, kr, in both zebrafish and human AChE. However, differences between the Kox and k2 constants suggest that zebrafish AChE associates more tightly with oximes, but has a slower maximal reactivation rate than human AChE. Homology modeling suggests that these kinetic differences result from divergences in the amino acids lining the entrance to the active site gorge. Although 2-PAM had the more favorable in vitro reactivation kinetics, RS-194B was more effective antidote in vivo. In intact zebrafish embryos, antidotal treatment with RS-194B rescued embryos from OP toxicity, whereas 2-PAM had no effect. Dechorionation of the embryos prior to antidotal treatment allowed both 2-PAM and RS-194B to rescue zebrafish embryos from OP toxicity. Interestingly, RS-194B and 2-PAM alone increased cholinergic motor activity in dechorionated embryos possibly due to the reversible inhibition kinetics, Ki and alphaKi, of the oximes. Together these results demonstrate that the zebrafish at various developmental stages provides an excellent model for investigating membrane penetrant antidotes to OP exposure. PMID- 25701202 TI - Di(2-ethylhexyl) phthalate inhibits antral follicle growth, induces atresia, and inhibits steroid hormone production in cultured mouse antral follicles. AB - Di(2-ethylhexyl) phthalate (DEHP) is a ubiquitous environmental toxicant found in consumer products that causes ovarian toxicity. Antral follicles are the functional ovarian units and must undergo growth, survival from atresia, and proper regulation of steroidogenesis to ovulate and produce hormones. Previous studies have determined that DEHP inhibits antral follicle growth and decreases estradiol levels in vitro; however, the mechanism by which DEHP elicits these effects is unknown. The present study tested the hypothesis that DEHP directly alters regulators of the cell cycle, apoptosis, and steroidogenesis to inhibit antral follicle functionality. Antral follicles from adult CD-1 mice were cultured with vehicle control or DEHP (1-100 MUg/ml) for 24-96 h to establish the temporal effects of DEHP on the follicle. Following 24-96 h of culture, antral follicles were subjected to gene expression analysis, and media were subjected to measurements of hormone levels. DEHP increased the mRNA levels of cyclin D2, cyclin dependent kinase 4, cyclin E1, cyclin A2, and cyclin B1 and decreased the levels of cyclin-dependent kinase inhibitor 1A prior to growth inhibition. Additionally, DEHP increased the mRNA levels of BCL2-associated agonist of cell death, BCL2-associated X protein, BCL2-related ovarian killer protein, B-cell leukemia/lymphoma 2, and Bcl2-like 10, leading to an increase in atresia. Further, DEHP decreased the levels of progesterone, androstenedione, and testosterone prior to the decrease in estradiol levels, with decreased mRNA levels of side-chain cleavage, 17alpha-hydroxylase-17,20-desmolase, 17beta hydroxysteroid dehydrogenase, and aromatase. Collectively, DEHP directly alters antral follicle functionality by inhibiting growth, inducing atresia, and inhibiting steroidogenesis. PMID- 25701204 TI - The effect of new monochromatic light regimes on egg production and expression of the circadian gene BMAL1 in pigeons1. AB - We examined the effect of monochromatic light supplementation on pigeon reproductive performance and on the expression of the brain and muscle aryl hydrocarbon receptor nuclear translocator-like (BMAL1) protein in the hypothalamic-pituitary-gonadal (HPG) axis. White King pigeons were selected randomly from 4 lofts (510 pairs/loft) with 3 subgroups/loft. The lofts were exposed to one of 4 light treatments for 3 months administered in the morning and evening as follows: blue light (480 nm), green light (540 nm), red light (660 nm), and control white light. The laying rate, fertility rate, and birth rate were recorded. After 3 months, 48 birds were selected randomly from the 4 lofts (6 females and 6 males from each loft), sacrificed, and the HPG axis was isolated. Following exposure to red light, laying rate was greater than the control group (P = 0.013), but there were no significant differences in the fertility rate (P = 0.41) or birth rate (P = 0.66). Expression of BMAL1 in the hypothalamus was unaffected by the light regime but was greater in the pituitary of females exposed to red light (P = 0.046) and in the pituitary of males exposed to the control white light (P = 0.059). The change in BMAL1 expression in the pituitary of females was negatively correlated with birth rate in monochromatic light (P = 0.021). We suggest that reproductive performance of pigeons is improved by light supplementation in the morning and evening. According to these data, 100 pigeons exposed to red light could lay 26.68 more eggs per month than the control group. Additionally, BMAL1 expression in the HPG axis of pigeons exposed to monochromatic light correlated with birth rate. PMID- 25701205 TI - Nutritional characteristics of camelina meal for 3-week-old broiler chickens. AB - Limited information on nutritional characteristics on camelina meal for broiler chickens limits its use in diets of broiler chickens. The objectives of this study were to determine the ileal digestible energy (IDE), ME, and MEn contents of 2 different camelina meal (CM1 and CM2) samples for 3-wk-old broiler chickens using the regression method and to determine glucosinolate compounds in the camelina meal samples. The CM1 and CM2 were incorporated into a corn-soybean meal based reference diet at 3 levels (0, 100, or 200 g/kg) by replacing the energy yielding ingredients. These 5 diets (reference diet, and 100 and 200 g/kg camelina meal from each of CM1 and CM2) were fed to 320 male Ross 708 broilers from d 21 to 28 post hatching with 8 birds per cage and 8 replicates per treatment in a randomized complete block design. Excreta were collected twice daily from d 25 to 28, and jejunal digesta and ileal digesta from the Meckel's diverticulum to approximately 2 cm proximal to the ileocecal junction were collected on d 28. The total glucosinolate content for CM1 and CM2 were 24.2 and 22.7 nmol/mg, respectively. Jejunal digesta viscosity was linearly increased (P<0.001) from 2.2 to 4.1 cP with increasing dietary camelina meal levels. There were linear effects (P<0.001) of CM1 and CM2 substitution on final weight, weight gain, feed intake, and G:F. The inclusion of CM1 and CM2 linearly decreased (P<0.001) ileal digestibility of DM, energy, and IDE. The supplementation of CM1 and CM2 linearly decreased (P<0.001) the retention of DM, nitrogen, and energy; ME, and MEn. By regressing the CM1 and CM2-associated IDE intake in kilocalories against kilograms of CM1 and CM2 intake, the IDE regression equation was Y= 10+1,429*CM1+2,125*CM2, r2=0.55, which indicates that IDE values were 1,429 kcal/kg of DM for CM1 and 2,125 kcal/kg of DM for CM2. The ME regression was Y=5+882*CM1+925*CM2, r2=0.54, which implies ME values of 882 kcal/kg of DM for CM1 and 925 kcal/kg of DM for CM2. MEn regression was Y=2+795*CM1+844*CM2, r2=0.52, which implies MEn values of 795 kcal/kg of DM for CM1 and 844 kcal/kg of DM for CM2. Based on these results, utilization of energy and nitrogen in camelina meal by broiler chickens is low and the high viscosity observed in jejunal digesta as well as the total glucosinolate in camelina meal may have contributed to the poor energy and nitrogen utilization. PMID- 25701206 TI - Chronic welfare restrictions and adrenal gland morphology in broiler chickens. AB - Gait problems constitute an important and chronic welfare restriction for broiler chickens. The objective of the present study was to determine if adrenal gland morphology indicates chronic welfare restrictions in broiler chickens, using gait problems as the stressor. Sixty-six birds raised on a commercial unit were selected at 40 d of age and separated into groups according to gait score. One group was apparently healthy birds (AH) with gait scores of 0 to 2, and the other group had birds with gait problems (GP) that showed gait scores of 4 to 5. Birds were slaughtered and weighed, and their adrenal glands were measured and weighed; proportions of medullary and adrenocortical tissues, and lymphatic tissue and blood vessels were studied. GP birds had lower BW when compared to AH birds, and when adrenal gland weight values were adjusted to BW, a greater relative adrenal weight was observed for the GP group. Adrenals from GP birds also presented a higher proportion of blood vessels when compared to AH birds. These results might indicate increased adrenal activity and evidence of the inflammatory process as a consequence of chronic stress. Results showed that gait problems caused significant adrenal gland changes, suggesting a possible role for the study of adrenal gland morphology as an indicator of chronic welfare problems in broiler chickens. PMID- 25701207 TI - Effects of different vaccine combinations against Mycoplasma gallisepticum on the internal egg and eggshell characteristics of commercial layer chickens 1,2,3. AB - Live F-strain Mycoplasma gallisepticum (FMG) vaccines are presently being used to help control field-strain MG outbreaks. However, they may exert some adverse effects on egg production. Live strains of MG of lesser virulence as well as killed vaccines have little or no effect on egg production, but afford lower levels of protection. This has led to research investigating their use in combination with a subsequent overlay vaccination of FMG given later in the production cycle. In the present study, 2 trials were conducted to investigate the effects of prelay vaccinations of live and killed MG vaccines or their combination, in conjunction with an FMG vaccine overlay after peak production, on the egg characteristics of commercial layers. The following vaccination treatments were administered at 10 wk of age (woa): 1) unvaccinated (Control), 2) MG-Bacterin (MGBac) vaccine, 3) ts-11 strain MG (ts11MG) vaccine, and 4) MGBac and ts11MG combination (MGBac + ts11MG). At 45 woa, half of the birds were overlaid with an FMG vaccine. In each trial, internal egg and eggshell parameters including egg weight (EW), Haugh unit score (HU), eggshell breaking strength (EBS), percentage yolk weight (PYW), percentage albumen weight (PAW), percentage eggshell weight (PSW), eggshell weight per unit surface area (SWUSA), percentage yolk moisture (PYM), and percent total lipids (PYL) were determined at various time periods between 21 and 52 woa. At 28 woa, SWUSA was lower in the ts11MG and MGBac + ts11MG groups compared to the Control group. Conversely, at 43 woa, SWUSA was higher in the ts11MG than in the MGBac group. Between 23 and 43 woa, PYL was higher in the MGBac and ts11MG groups in comparison to the Control group. In conclusion, vaccination with MGBac alone or in combination with ts11MG at 10 woa with or without an FMG vaccine overlay at 45 woa does not adversely affect the internal egg or eggshell quality of commercial layers throughout lay. PMID- 25701208 TI - The effect of phytase and fructooligosaccharide supplementation on growth performance, bone quality, and phosphorus utilization in broiler chickens. AB - An experiment was conducted to investigate the effects of phytase and 2 levels of fructooligosaccharide (FOS) supplementation on growth performance, bone mineralization, and P utilization of broiler chickens. A total of 210 day-old male broiler chickens (Ross) were randomly placed into 7 dietary treatments consisting of 6 replicates with 5 birds per pen. The experiment was designed as an augmented 2 * 3 factorial arrangement with 0 or 500 U/kg of phytase and 0, 0.5% or 1% of FOS added to a reduced Ca (0.8%) and available P (0.25%) negative control diet (NC). A positive control diet (PC) that contained 1% Ca and 0.45% available P was also included. During the entire experimental period, phytase supplementation significantly improved (P < 0.05) the feed conversion ratio (FCR), BW gain (BWG), and feed intake. Birds fed the PC diet showed significantly higher bone mineral density (BMD) and bone mineral content (BMC) in both femur and tibia bones (P < 0.0001) than those fed the NC diet. Phytase supplementation increased femur BMD (P < 0.05), whereas FOS decreased femur BMD and BMC (P < 0.05). Phosphorus utilization was significantly higher for the NC diet (P < 0.0001). Phytase alone and in combination with 0.5% FOS increased P utilization significantly when compared with other treatments (P < 0.05). Fructooligosaccharides, especially at the level of 0.5%, increased P retention. In conclusion, phytase supplementation in low Ca and P diets improved growth performance, bone quality, and P utilization. However, supplementing NC diets with phytase and FOS did not result in bone mineralization values comparable with that of the PC diet. The application of dietary FOS alone had a negative effect on broiler bone quality. PMID- 25701209 TI - Characterization of quinolone resistance in Salmonella enterica serovar Indiana from chickens in China. AB - The aim of this study was to characterize the quinolone resistance of Salmonella enterica serovar Indiana isolated from chickens in China. A total of 293 Salmonella strains were isolated from chicken farms and slaughterhouses in Shandong province of China, and 130 (44.4%) were characterized as Salmonella enterica Indiana (chicken farms, n=52 strains; slaughter houses, n=78 strains). All isolate serotypes were tested with the Kauffmann-White classification system and examined for susceptibility to the quinolones: nalidixic acid, enrofloxacin, norfloxacin, and ciprofloxacin. The resistance of the Salmonella Indiana strains to nalidixic acid, enrofloxacin, norfloxacin, and ciprofloxacin were 100, 73.1, 71.2, and 82.7%, and 100, 59.0, 79.5, and 80.2%, respectively. Selected quinolone resistant strains were evaluated for mutations in genes (gyrA, gyrB, parC, and marA) by DNA sequencing. The gyrA mutation was found in all isolates, the parC mutation was only found in some isolates, and the gyrB and marA mutations were not observed. Quinolone resistance was evaluated in the representative isolates by screening for the quinolone resistance determinants, qnrA, qnrB, qnrS, qepA, and aac (6 ')-Ib-cr using PCR technology. The quinolone resistance determinants in Salmonella, qnrA, qnrB, qnrS, and qepA were negative by PCR, but aac(6 ')-Ib cr had high detection rates of 90.4 and 96.2% in chicken farms and slaughterhouses, respectively. Salmonella Indiana containing the gyrA mutation was prevalent in farms and slaughterhouses and possessed a high frequency of the quinolone resistance determinant aac(6 ')-Ib-cr. These bacteria may have originated from the same source. PMID- 25701210 TI - Identification of novel Bromus- and Trifolium-associated circular DNA viruses. AB - The genomes of a large number of highly diverse novel circular DNA viruses from a wide range of sources have been characterised in recent years, including circular single-stranded DNA (ssDNA) viruses that share similarities with plant-infecting ssDNA viruses of the family Geminiviridae. Here, we describe six novel circular DNA viral genomes that encode replication-associated (Rep) proteins that are most closely related to those of either geminiviruses or gemycircularviruses (a new group of ssDNA viruses that are closely related to geminiviruses). Four possible viral genomes were recovered from Bromus hordeaceus sampled in New Zealand, and two were recovered from B. hordeaceus and Trifolium resupinatum sampled in France. Two of the viral genomes from New Zealand (one from the North Island and one from the South Island each) share >99 % sequence identity, and two genomes recovered from B. hordeaceus and T. resupinatum sampled in France share 74 % identity. All of the viral genomes that were recovered were found to have a major open reading frame on both their complementary and virion-sense strands, one of which likely encodes a Rep and the other a capsid protein. Although future infectivity studies are needed to identify the host range of these viruses, this is the first report of circular DNA viruses associated with grasses in New Zealand. PMID- 25701211 TI - Novel rat models to study primary genital herpes simplex virus-2 infection. AB - In this study we describe that six rat models (SD, WIST, LEW, BN, F344 and DA) are susceptible to intravaginal herpes simplex virus-2 (HSV-2) infection after pre-treatment with progesterone. At a virus dose of 5 * 10(6) PFU of HSV-2, all rat models were infected presenting anti-HSV-2 antibodies, infectious virus in vaginal washes, and HSV-2 DNA genome copies in lumbosacral dorsal root ganglia and the spinal cord. Most of the LEW, BN, F344, and DA rats succumbed in systemic progressive symptoms at day 8-14 post infection, but presented no or mild genital inflammation while SD and WIST rats were mostly infected asymptomatically. Infected SD rats did not reactivate HSV-2 spontaneously or after cortisone treatment. In an HSV-2 virus dose reduction study, F344 rats were shown to be most susceptible. We also investigated whether an attenuated HSV-1 strain (KOS321) given intravaginally, could protect from a subsequent HSV-2 infection. All LEW, BN, and F344 rats survived a primary HSV-1 infection and no neuronal infection was established. In BN and F344 rats, anti-HSV-1 antibodies were readily detected while LEW rats were seronegative. In contrast to naive LEW, BN, and F344 rats where only 3 of 18 animals survived 5 * 10(6) PFU of HSV-2, 23 of 25 previously HSV-1 infected rats survived a challenge with HSV-2. The described models provide a new approach to investigate protective effects of anti-viral microbicides and vaccine candidates, as well as to study asymptomatic primary genital HSV-2 infection. PMID- 25701212 TI - Differential effects of viroporin inhibitors against feline infectious peritonitis virus serotypes I and II. AB - Feline infectious peritonitis virus (FIP virus: FIPV), a feline coronavirus of the family Coronaviridae, causes a fatal disease called FIP in wild and domestic cat species. The genome of coronaviruses encodes a hydrophobic transmembrane protein, the envelope (E) protein. The E protein possesses ion channel activity. Viral proteins with ion channel activity are collectively termed "viroporins". Hexamethylene amiloride (HMA), a viroporin inhibitor, can inhibit the ion channel activity of the E protein and replication of several coronaviruses. However, it is not clear whether HMA and other viroporin inhibitors affect replication of FIPV. We examined the effect of HMA and other viroporin inhibitors (DIDS [4,4' disothiocyano-2,2'-stilbenedisulphonic acid] and amantadine) on infection by FIPV serotypes I and II. HMA treatment drastically decreased the titers of FIPV serotype I strains Black and KU-2 in a dose-dependent manner, but it only slightly decreased the titer of FIPV serotype II strain 79-1146. In contrast, DIDS treatment decreased the titer of FIPV serotype II strain 79-1146 in dose dependent manner, but it only slightly decreased the titers of FIPV serotype I strains Black and KU-2. We investigated whether there is a difference in ion channel activity of the E protein between viral serotypes using E. coli cells expressing the E protein of FIPV serotypes I and II. No difference was observed, suggesting that a viroporin other than the E protein influences the differences in the actions of HMA and DIDS on FIPV serotypes I and II. PMID- 25701213 TI - Urgent interscalene brachial plexus block for management of traumatic luxatio erecta in the ED. AB - Trauma in the emergency department may present providers with amyriad of unforeseen clinical scenarios.We present an example of how an urgent nerve block facilitated rapid management of a luxatio erecta shoulder fracture-dislocation without sedation. A 20-year-old female pedestrian presented to our level II trauma center after being stuck bya motor vehicle. At arrival, she had clinical indications of severe blunt trauma as well as a left-sided luxatio erect a shoulder dislocation and fracture. Immediate computed tomography (CT) imaging as requestedby the trauma service; however, the patient could not tolerate any movement of her left arm, precluding entry into the scanner's narrow antrum. This scenario presented a clinical dilemma: an undifferentiated victim of severe blunt trauma requiring urgent CT scanning to exclude possible intracranial, intrathoracic, and/or intra-abdominal injury in need of immediate reduction of a dislocated joint to allow entry into the CT scanner. Conscious sedation risked loss of neurologic examination,hypotension, apnea, and further delay to definitive imaging. As an alternative, our team reduced the shoulder under regional anesthesia with an interscalene nerve block using a "stay-away" technique and chloroprocaine. Regional anesthesia presents a viable option in this scenario for rapid-onset analgesia available urgently at the bedside. In our experience, using a stay-away technique in conjunction with short-acting, low toxicity chloroprocaine provides safe, quick, and effective anesthesia. This allowed for prompt reduction of the dislocated joint and timely evaluation for potential life-threatening injuries while avoiding the risks associated with conscious sedation. PMID- 25701214 TI - Dysphagia aortica: a fatal delay in diagnosis. AB - Extrinsic esophageal compression leading to dysphagia is an uncommon and late presentation of large thoracic aortic aneurysm named dysphagia aortica. Herein, we report an 86-year-old man who presented with 1-week duration of chest pain, backache, and dysphagia and was eventually diagnosed as dysphagia aortica. Our patient developed progressive dyspnea due to tracheal compression and failed surgery. The case illustrates the importance of early identification of the rare entity of dysphagia especially in elderly cases with cardiovascular disease with complaint of undetermined dysphagia accompanied with chest pain and backache. PMID- 25701215 TI - Vomiting is not associated with poor outcomes in pediatric victims of unintentional submersions. AB - INTRODUCTION: The outcome of submersion victims depends on submersion duration and the availability of timely and effective resuscitation. The prognostic implication of vomiting during resuscitation of submersion victims is unclear. The study sought to determine whether vomiting during resuscitation in children treated for unintentional submersion injuries adversely impacts outcome. METHODS: This was a retrospective study of unintentional submersion victims under age 18 treated at an urban tertiary-care children's hospital from 2003-2009. Submersion and victim details were obtained from hospital, EMS, and fatality records. Outcomes studied were survival at 24 hours and condition (Favorable: good/mild impairment or Poor: death/severe disability) at hospital discharge. Descriptive comparisons between emesis groups (yes/no) and categorical covariates were analyzed. RESULTS: There were 281 victims. The median age was 3 years; 66% were males. Most incidents occurred at swimming pools (77%) and bathtubs (16%). Most were hospitalized (83%). The presence or absence of emesis was documented in 246 (88%). Victims with emesis were significantly less likely to have apnea or be intubated in the ED, have a low ED GCS or die. No patient who had emesis died at 24 hours or had a poor outcome at hospital discharge. Victims who had emesis post resuscitation were significantly more likely to have received CPR or chest compressions than rescue breaths. CONCLUSIONS: Emesis in pediatric submersion victims is inversely associated with death at 24 hours or poor outcome at hospital discharge. The relationship between emesis and the adequacy of resuscitation of pediatric submersion victims needs to be further studied. PMID- 25701216 TI - A comparison of acuity levels between 3 freestanding and a tertiary care ED. AB - INTRODUCTION: Freestanding emergency departments (FEDs) have grown in popularity. They often provide emergent care in areas distant from other EDs. Investigations and research to characterize the operation and dynamics of FEDs are needed. This study characterizes the severity of illness seen at FEDs and compares it with a hospital-based urban tertiary care ED using the emergency severity index (ESI), a quantification of patient acuity. METHODS: Patient ESI levels were analyzed retrospectively over 1 year for a single hospital system with 1 main urban hospital-based ED and 3 FEDs. Data analysis was completed using analysis of variance with and without time as a factor. RESULTS: The average ESI level at the main ED (3.04) was lower than the FEDs, respectively (3.42, 3.22, and 3.38) (P < .001). Patient ESI levels were significantly different between FEDs (P < .001). CONCLUSION: The main ED demonstrated lower ESI levels and thus higher acuity than the 3 affiliated FEDs. There were significantly different acuity levels between the main ED and 3 FEDs as well as between individual FEDs. PMID- 25701217 TI - Institutions housing venomous animals. PMID- 25701218 TI - Position statement: medical toxicologist participation in medication management and safety systems. PMID- 25701219 TI - Disinfection in the laboratory: theory and practice in disinfection policy in late C19th and early C20th England. AB - This article examines the relationship between theory and practice in nineteenth century English public health disinfection practice. Disinfection undertaken by local authorities and practised on objects, spaces and people became an increasingly common public health practice in the last quarter of the nineteenth century, and was part of a newly developed public health system of 'stamping out' disease as described by Hardy. Despite disinfection's key role in public health policy, it has thus far not received significant investigation or historiographical attending. This article explores the development of disinfection policy at local level, highlighting that despite commentators assumptions that increasingly exacting standards of disinfection required professional oversight rather than that of the 'amateur' public, there was a significant gap between laboratory based knowledge and evidence derived from practical experience. Laboratory conditions could not replicate those found in day-to-day disinfection, and there were myriad debates about how to create a mutually understandable scientific standard for testing. Despite increasing efforts to bring local disinfection in line with new ideas promulgated by central government and disinfection researchers, the mismatches between the two meant that there was greater divergence. This tension lay at the heart of the changes in disinfection theory and practice in the second half of the nineteenth century, and illustrate the complexities of the impact of germ theory on public health policy. PMID- 25701220 TI - Erratum to: Characterization of the dengue outbreak in Nuevo Leon state, Mexico, 2010. PMID- 25701221 TI - The impact of sporotrichosis in HIV-infected patients: a systematic review. AB - Sporotrichosis is a fungal infection of man and animals caused by Sporothrix complex. It usually presents as a lymphocutaneous form, but disseminated disease may occur. Given the paucity of data about HIV/AIDS and sporotrichosis co infection, a systematic review of reported cases of HIV-associated sporotrichosis found via Pubmed (1984-2013) was done. A total of 39 papers were included, and 58 patients' data analyzed. Thirty-three (56.9 %) cases were from Brazil and 18 (31 %) from the USA. Patients' mean age was 37.8 +/- 10.4 years; males predominated (84.5 %). The median CD4(+) cell count was 97 cells/mm(3). The most common clinical forms were disseminated and disseminated cutaneous with 33 (56.9 %) and 10 (17.5 %) patients, respectively. There was a correlation between CD4(+) count and clinical categories (p = 0.002). Mortality was 30 % and there was a correlation between central nervous system involvement and death (p < 0.001). PMID- 25701222 TI - Novel antibiotics: are we still in the pre-post-antibiotic era? AB - PURPOSE: Therapeutic efficacy and safety in infections due to multidrug-resistant bacteria can be improved by the clinical development of new compounds and devising new derivatives of already useful antibiotics. Due to a striking global increase in multidrug-resistant Gram-positive but even more Gram-negative organisms, new antibiotics are urgently needed. METHODS: This paper provides a review of novel antibiotic compounds which are already in clinical development, mainly in phase III clinical trials. CONCLUSION: Each of these new trials increases the possibility of new antibiotics receiving approval. PMID- 25701224 TI - Are children conservative, liberal, or metacognitive? Preliminary evidence for the involvement of the distinctiveness heuristic in decision making. AB - The experiment tested whether young children are able to reduce their false recognition rate after distinctive encoding by implementing a strategic metacognitive rule. The participants, 72 children aged 4, 6, and 9 years, studied two lists of unrelated items. One of these lists was visually displayed (picture condition), whereas the other was presented auditorily (word condition). After each study phase, participants completed recognition tests. Finally, they answered questions about their explicit knowledge of the distinctive encoding effect. The results revealed that even the youngest children in our sample showed a smaller proportion of intrusions in the picture condition than in the word condition. Furthermore, the results of the signal detection analyses were consistent with the hypothesis that the lower rate of false recognitions after picture encoding results from the implementation of a conservative response criterion based on metacognitive expectations (distinctiveness heuristic). Moreover, the absence of correlation between children's explicit knowledge of the distinctiveness rule and their effective use of this metacognitive heuristic seems to indicate that its involvement in memory decisions could be mediated by implicit mechanisms. PMID- 25701223 TI - Clinical management of chronic hepatitis B infection: results from a registry at a German tertiary referral center. AB - PURPOSE: We studied a cohort of adult patients with chronic hepatitis B (CHB) infection, followed at a tertiary referral liver center in Germany over 12.5 years to analyze the clinical features and impact of management on disease progression and survival of CHB patients in general and of those with CHB and HCC in particular. METHODS: We retrospectively evaluated the medical records of 242 adult (age >= 18 years) patients. CHB was defined as positive hepatitis B surface antigen (HBsAg) and/or HBV-DNA levels >10 IU/mL for at least 6 months. Patient demographics, HBV markers, antiviral treatment, laboratory parameters, liver imaging and histology were recorded for each visit. HCC patients were divided into two groups and separately analyzed (group 1: n = 24, HCC at first visit and group 2: n = 11, HCC during surveillance). RESULTS: The mean age was 44 years in CHB patients without HCC (63% male) and about 59 years in patients with HCC (77% male). Antiviral therapy was given to 59% of patients without HCC compared to only 25% in group 1 and 18% in group 2 with comparable median HBV DNA levels of approximately 36,000 IU/mL. There was no statistically significant difference concerning the HCC stages (Milan, UCSF, BCLC) at first diagnosis. Five-year survival was 19% in group 1 vs. 64% in group 2 (p = 0.019), with LTx performed in 12 vs. 45%, respectively. CONCLUSION: Surveillance of CHB patients did not result in early stage detection of HCC but in a higher likelihood to receive potentially curative treatments. PMID- 25701225 TI - Receiver operating characteristic analysis of age-related changes in lineup performance. AB - In the basic face memory literature, support has been found for the late maturation hypothesis, which holds that face recognition ability is not fully developed until at least adolescence. Support for the late maturation hypothesis in the criminal lineup identification literature, however, has been equivocal because of the analytic approach that has been used to examine age-related changes in identification performance. Recently, receiver operator characteristic (ROC) analysis was applied for the first time in the adult eyewitness memory literature to examine whether memory sensitivity differs across different types of lineup tests. ROC analysis allows for the separation of memory sensitivity from response bias in the analysis of recognition data. Here, we have made the first ROC-based comparison of adults' and children's (5- and 6-year-olds and 9- and 10-year-olds) memory performance on lineups by reanalyzing data from Humphries, Holliday, and Flowe (2012). In line with the late maturation hypothesis, memory sensitivity was significantly greater for adults compared with young children. Memory sensitivity for older children was similar to that for adults. The results indicate that the late maturation hypothesis can be generalized to account for age-related performance differences on an eyewitness memory task. The implications for developmental eyewitness memory research are discussed. PMID- 25701226 TI - Role of gelatinases in pathological and physiological processes involving the dystrophin-glycoprotein complex. AB - Dystrophin is a cytosolic protein belonging to a membrane-spanning glycoprotein complex, called dystrophin-glycoprotein complex (DGC) that is expressed in many tissues, especially in skeletal muscle and in the nervous system. The DGC connects the cytoskeleton to the extracellular matrix and, although none of the proteins of the DGC displays kinase or phosphatase activity, it is involved in many signal transduction pathways. Mutations in some components of the DGC are linked to many forms of inherited muscular dystrophies. In particular, a mutation in the dystrophin gene, leading to a complete loss of the protein, provokes one of the most prominent muscular dystrophies, the Duchenne muscular dystrophy, which affects 1 out of 3500 newborn males. What is observed in these circumstances, is a dramatic alteration of the expression levels of a multitude of metalloproteinases (MMPs), a family of extracellular Zn(2+)-dependent endopeptidases, in particular of MMP-2 and MMP-9, also called gelatinases. Indeed, the enzymatic activity of MMP-2 and MMP-9 on dystroglycan, an important member of the DGC, plays a significant role also in physiological processes taking place in the central and peripheral nervous system. This mini-review discusses the role of MMP-2 and MMP-9, in physiological as well as pathological processes involving members of the DGC. PMID- 25701228 TI - Saccharomyces cerevisiae-like 1 overexpression is frequent in prostate cancer and has markedly different effects in Ets-related gene fusion-positive and fusion negative cancers. AB - The cytosolic factor Saccharomyces cerevisiae-like 1 (SEC14L1) is a regulator of lipid metabolism and signaling pathways that has been suggested to play a role in cancer. To learn more about its relevance for prostate cancer, SEC14L1 expression was analyzed on a tissue microarray containing samples from 11152 prostate cancer patients. In benign prostate glands, SEC14L1 immunostaining was absent or weak. In prostate cancer, SEC14L1 positivity was found in 80% of 9876 interpretable tumors including 9% with strong, 38% with moderate, and 32% with weak immunostaining. SEC14L1 expression was more frequent in Transmembrane Protease, Serine 2 (TMPRSS2):Ets-related gene (ERG) fusion-positive (89%) than in TMPSSR2:ERG-negative cancers (73%, P < .0001). Comparative analysis of SEC14L1 expression in TMPSSR2:ERG-positive and -negative cancers suggested a different role of SEC14L1 in the 2 subsets: in TMPSSR2:ERG-negative cancers, strong SEC14L1 expression was associated with early prostate-specific antigen recurrence (P = .0270), advanced tumor stage (P = .0042), high Gleason score (P < .0001), and high preoperative prostate-specific antigen levels (P = .0035). In TMPSSR2:ERG positive cancers, strong SEC14L1 staining was linked to a prolonged recurrence free interval (P = .0023) and absence of lymph node metastases (P = .0002). Strong associations of high SEC14L1 levels with chromosomal deletions (5q, 6q, phosphatase and tensin homolog gene, 3p13; P < .0001) and a high Ki-67 labeling index (P < .0001) were seen in TMPSSR2:ERG-negative but not TMPSSR2:ERG-positive cancers. A direct or indirect role of SEC14L1 in maintenance of genomic integrity and regulating cell proliferation may thus exclusively exist in TMPSSR2:ERG negative cancers. In conclusion, our data suggest a markedly different role of SEC14L1 in TMPSSR2:ERG-negative and TMPSSR2:ERG-positive prostate cancers. PMID- 25701229 TI - AT-rich interactive domain 2, p110alpha, p53, and beta-catenin protein expression in hepatocellular carcinoma and clinicopathologic implications. AB - AT-rich interactive domain 2 (ARID2), catenin (cadherin-associated protein), beta 1, 88kDa (beta-catenin), tumor protein 53 (p53), and phosphatidylinositol-4,5 bisphosphate 3-kinase, catalytic subunit alpha (p110alpha) mutations are implicated in hepatocellular carcinoma (HCC); and previous work has contributed to thorough molecular characterization of these events. However, studies that assess the impact of these mutations on downstream protein expression, especially those that evaluate all 4 cancer markers simultaneously, are relatively lacking. Hence, the present study uses immunohistochemistry to assess protein expression patterns of ARID2, beta-catenin, p53, and p110alpha in HCCs and adjacent nonneoplastic cirrhotic tissues from 58 explanted livers. Notably, this study is the first to our knowledge to investigate ARID2 protein expression in the liver. The frequency of ARID2 mutations detected using our immunohistochemistry method was similar to that reported in previous molecular studies. Furthermore, we found that loss of ARID2 protein expression may be associated with recurrence, although further studies must be done to validate these findings in a larger population. We found that expression patterns of the 4 cancer markers were independent of each other, suggesting separate pathways of hepatocarcinogenesis. We also did not observe an association between viral etiology and protein expression. Consistent with previous studies, overexpression of p53 correlated with poor differentiation. Lastly, 17.5% of HCCs paradoxically had diffuse loss of the oncoprotein p110alpha compared with strong expression in background cirrhotic liver. The exact mechanism is unclear, but enigmatic loss of oncoprotein function has been described in other carcinomas and could potentially have significant implications for the use of targeted mechanistic target of rapamycin (serine/threonine kinase) drug therapies. PMID- 25701230 TI - The utility of IgM, CD21, HGAL and LMO2 in the diagnosis of pediatric follicular lymphoma. AB - Pediatric follicular lymphoma (pFL) is a rare neoplasm with features differing from follicular lymphoma arising in adults. Here, we describe a rare case of pFL that showed morphologic features partially overlapping with progressive transformation of germinal centers and reactive follicular hyperplasia. As typical of pFL, neoplastic B cells within follicles did not express B-cell leukemia/lymphoma 2 (BCL2). However, this case showed additional distinctive abnormal findings, which contributed to the diagnosis: (1) diffuse and uniform staining of immunoglobulin M (IgM) on cells within and outside of follicles, (2) abnormally dim expression of CD21 on follicular dendritic cells, and (3) expression of human germinal center-associated lymphoma (HGAL) and LIM domain only 2 (LMO2) on B cells in interfollicular and follicular areas. This case demonstrates the utility of these abnormal features, which can be seen in adult- or usual-type follicular lymphoma, in the diagnosis of pFL. Further studies are necessary to evaluate the significance of these findings in other cases of pFL. PMID- 25701231 TI - Prolactin and the dietary protein/carbohydrate ratio regulate the expression of SNAT2 amino acid transporter in the mammary gland during lactation. AB - The sodium coupled neutral amino acid transporter 2 (SNAT2/SAT2/ATA2) is expressed in the mammary gland (MG) and plays an important role in the uptake of alanine and glutamine which are the most abundant amino acids transported into this tissue during lactation. Thus, the aim of this study was to assess the amount and localization of SNAT2 before delivery and during lactation in rat MG, and to evaluate whether prolactin and the dietary protein/carbohydrate ratio might influence SNAT2 expression in the MG, liver and adipose tissue during lactation. Our results showed that SNAT2 protein abundance in the MG increased during lactation and this increase was maintained along this period, while 24 h after weaning it tended to decrease. To study the effect of prolactin on SNAT2 expression, we incubated MG explants or T47D cells transfected with the SNAT2 promoter with prolactin, and we observed in both studies an increase in the SNAT2 expression or promoter activity. Consumption of a high-protein/low carbohydrate diet increased prolactin concentration, with a concomitant increase in SNAT2 expression not only in the MG during lactation, but also in the liver and adipose tissue. There was a correlation between SNAT2 expression and serum prolactin levels depending on the amount of dietary protein/carbohydrate ratio consumed. These findings suggest that prolactin actively supports lactation providing amino acids to the gland through SNAT2 for the synthesis of milk proteins. PMID- 25701232 TI - Cationic antimicrobial peptide resistance mechanisms of streptococcal pathogens. AB - Cationic antimicrobial peptides (CAMPs) are critical front line contributors to host defense against invasive bacterial infection. These immune factors have direct killing activity toward microbes, but many pathogens are able to resist their effects. Group A Streptococcus, group B Streptococcus and Streptococcus pneumoniae are among the most common pathogens of humans and display a variety of phenotypic adaptations to resist CAMPs. Common themes of CAMP resistance mechanisms among the pathogenic streptococci are repulsion, sequestration, export, and destruction. Each pathogen has a different array of CAMP-resistant mechanisms, with invasive disease potential reflecting the utilization of several mechanisms that may act in synergy. Here we discuss recent progress in identifying the sources of CAMP resistance in the medically important Streptococcus genus. Further study of these mechanisms can contribute to our understanding of streptococcal pathogenesis, and may provide new therapeutic targets for therapy and disease prevention. This article is part of a Special Issue entitled: Bacterial Resistance to Antimicrobial Peptides. PMID- 25701227 TI - Proteoglycan form and function: A comprehensive nomenclature of proteoglycans. AB - We provide a comprehensive classification of the proteoglycan gene families and respective protein cores. This updated nomenclature is based on three criteria: Cellular and subcellular location, overall gene/protein homology, and the utilization of specific protein modules within their respective protein cores. These three signatures were utilized to design four major classes of proteoglycans with distinct forms and functions: the intracellular, cell-surface, pericellular and extracellular proteoglycans. The proposed nomenclature encompasses forty-three distinct proteoglycan-encoding genes and many alternatively-spliced variants. The biological functions of these four proteoglycan families are critically assessed in development, cancer and angiogenesis, and in various acquired and genetic diseases where their expression is aberrant. PMID- 25701233 TI - Mechanisms of resistance to antimicrobial peptides in staphylococci. AB - Staphylococci are commensal bacteria living on the epithelial surfaces of humans and other mammals. Many staphylococci, including the dangerous pathogen Staphylococcus aureus, can cause severe disease when they breach the epithelial barrier. Both during their commensal life and during infection, staphylococci need to evade mechanisms of innate host defense, of which antimicrobial peptides (AMPs) play a key role in particular on the skin. Mechanisms that staphylococci have developed to evade the bactericidal activity of AMPs are manifold, comprising repulsion of AMPs via alteration of cell wall and membrane surface charges, proteolytic inactivation, sequestration, and secretion. Furthermore, many staphylococci form biofilms, which represents an additional way of protection from antimicrobial agents, including AMPs. Finally, staphylococci can sense the presence of AMPs by sensor/regulator systems that control many of those resistance mechanisms. This article is part of a Special Issue entitled: Bacterial Resistance to Antimicrobial Peptides. PMID- 25701234 TI - On the in vivo significance of bacterial resistance to antimicrobial peptides. AB - Antimicrobial peptides (AMPs) are at the front-line of host defense during infection and play critical roles both in reducing the microbial load early during infection and in linking innate to adaptive immunity. However, successful pathogens have developed mechanisms to resist AMPs. Although considerable progress has been made in elucidating AMP-resistance mechanisms of pathogenic bacteria in vitro, less is known regarding the in vivo significance of such resistance. Nevertheless, progress has been made in this area, largely by using murine models and, in two instances, human models of infection. Herein, we review progress on the use of in vivo infection models in AMP research and discuss the AMP resistance mechanisms that have been established by in vivo studies to contribute to microbial infection. We posit that in vivo infection models are essential tools for investigators to understand the significance to pathogenesis of genetic changes that impact levels of bacterial susceptibility to AMPs. This article is part of a Special Issue entitled: Bacterial Resistance to Antimicrobial Peptides. PMID- 25701235 TI - Overview and expert assessment of off-label use of misoprostol in obstetrics and gynaecology: review and report by the College national des gynecologues obstetriciens francais. AB - The literature suggests that misoprostol can be offered to patients for off-label use as it has reasonable efficacy, risk/benefit ratio, tolerance and patient satisfaction, according to the criteria for evidence-based medicine. Both the vaginal and sublingual routes are more effective than the oral route for first trimester cervical dilatation. Vaginal misoprostol 800MUg, repeated if necessary after 24 or 48h, is a possible alternative for management after early pregnancy failure. However, misoprostol has not been demonstrated to be useful for the evacuation of an incomplete miscarriage, except for cervical dilatation before vacuum aspiration. Oral mifepristone 200mg, followed 24-48h later by vaginal, sublingual or buccal misoprostol 800MUg (followed 3-4h later, if necessary, by misoprostol 400MUg) is a less efficacious but less aggressive alternative to vacuum aspiration for elective or medically-indicated first-trimester terminations; this alternative becomes increasingly less effective as gestational age increases. In the second trimester, vaginal misoprostol 800-2400MUg in 24h, 24-48h after at least 200mg of mifepristone, is an alternative to surgery, sulprostone and gemeprost. Data for the third trimester are sparse. For women with an unripe cervix and an unscarred uterus, vaginal misoprostol 25MUg every 3 6h is an alternative to prostaglandin E2 for cervical ripening at term for a live fetus. When oxytocin is unavailable, misoprostol can be used after delivery for prevention (sublingual misoprostol 600MUg) and treatment (sublingual misoprostol 800MUg) of postpartum haemorrhage. The use of misoprostol to promote cervical dilatation before diagnostic hysteroscopy or surgical procedures is beneficial for premenopausal women but not for postmenopausal women. Nonetheless, in view of the side effects of misoprostol, its use as a first-line treatment is not indicated, and it should be reserved for difficult cases. Misoprostol is not useful for placing or removing the types of intra-uterine devices used in Europe, regardless of parity. PMID- 25701236 TI - Multimorbidity in people with type 2 diabetes in the Basque Country (Spain): Prevalence, comorbidity clusters and comparison with other chronic patients. AB - BACKGROUND: Multimorbidity is a common problem in ageing societies and has a wide range of individual and social consequences. The objective of this study was to compare multimorbidity in a population with type 2 diabetes (T2DM) with that in other chronic patients, and identify disease clusters in patients with T2DM. METHODS: We included all citizens in the Basque Health Service aged >= 35 years, and identified the population with chronic conditions (from a list of 51 diseases) and those with T2DM. We performed a descriptive analysis of both populations, including their comorbidities. The average of chronic conditions unadjusted and adjusted by socioeconomic variables was obtained. Further, among patients with T2DM, we performed agglomerative hierarchical clustering to identify clinically relevant subgroups with the same concurrent conditions. RESULTS: In 2011, out of a population of 1,473,937, 15.2% had T2DM and 48% some other type of chronic condition. Overall, 87.6% men and 92% of women with T2DM had multimorbidity, while the figures were respectively 54.2% and 57% in chronic patients without T2DM. Patients with T2DM had a higher risk than the general chronic population of having 21 of the 51 chronic conditions considered. We identified 10 relevant disease clusters in patients with T2DM. CONCLUSIONS: There are notable differences between chronic patients with and without T2DM, the prevalence of multimorbidity being greater among the former. Multimorbidity is a complex phenomenon and more research is required to establish the clinical implications of the disease clusters found, to guide the introduction of integrated care management programmes. PMID- 25701237 TI - Back pain: An old cause in a young adult. PMID- 25701238 TI - Molecular imaging of hypoxia in non-small-cell lung cancer. AB - Non-small-cell lung cancer (NSCLC) is the commonest cancer worldwide but survival remains poor with a high risk of relapse, particularly after nonsurgical treatment. Hypoxia is present in a variety of solid tumours, including NSCLC. It is associated with treatment resistance and a poor prognosis, although when recognised may be amenable to different treatment strategies. Thus, noninvasive assessment of intratumoral hypoxia could be used to stratify patients for modification of subsequent treatment to improve tumour control. Molecular imaging approaches targeting hypoxic cells have shown some early success in the clinical setting. This review evaluates the evidence for hypoxia imaging using PET in NSCLC and explores its potential clinical utility. PMID- 25701239 TI - [Structural alterations during the course of glaucoma disease]. AB - BACKGROUND: Structural changes in the course of glaucoma disease affect the trabecular meshwork and ciliary body in addition to the optic disc as the primary site of glaucoma damage. OBJECTIVES: Latest results from experimental studies, animal models and measurements in human eyes are presented and discussed. RESULTS: The presenting scenario is complex with age, biochemical and mechanical stress factors leading to subsequent, irreversible tissue change in the trabecular meshwork and cribriform plate of the optic nerve, resulting in neuronal tissue loss. CONCLUSION: Knowledge of these changes will be the key for future glaucoma therapies. PMID- 25701240 TI - [Unilateral periocular angioedema after application of contrast agent]. AB - This article presents a case report of unilateral, periocular angioedema after intravenous application of a contrast agent with a temporary increase of intraocular pressure in an eye in which trabeculectomy had been carried out 5 weeks previously. PMID- 25701241 TI - Study the toxicity to Microcystis aeruginosa induced by TiO2 nanoparticles photocatalysis under UV light. AB - In the present study, the biological effect of TiO2 nanoparticles on cyanobacteria cells was studied using Microcystis aeruginosa (M. aeruginosa) as a model. Nano-TiO2 as a photo-catalysts agent used for water treatment may pose a risk to ecosystems, especially for the water organisms such as cyanobacteria. Scanning electron microscope (SEM) images provided that with the increasing of photocatalytic time, slime layer on the cell surface was damaged and sunk. Attenuated total reflectance fourier transform infrared (ATR-FTIR) spectroscopy revealed that the vibration peaks of C-C, C-H, C=O, P=O weakened within 12 h. According to the dynamic analysis of the infrared peaks, the damage on the cell groups under nano-TiO2 photocatalysis with different time periods was analyzed. The concentrations of K(+), Ca(2+), Mg(2+) released from the cells were measured, which indicated that nano-TiO2 photocatalysis have changed the cell membrane permeability and fluidity of M. aeruginosa. PMID- 25701242 TI - Hypomagnesemic down-regulation of L-type Ca(2+) channel in cardiomyocyte as an arrhythmogenic substrate in rats. AB - The present study was designed to investigate the effect of magnesium (Mg) depletion on the expression of voltage-gated calcium (Ca(2+)) channels and Ca(2+) currents in the heart and thereby on hypomagnesemic arrhythmogenesis in adult male rats. Male Wistar rats were fed an Mg-free diet or a normal diet for up to 16 weeks. Serum Mg concentrations were significantly reduced at week 4 or later with an Mg-free diet, which experimentally represents hypomagnesemia. Myocardial Mg contents were also reduced at week 16 accompanied by myocardial hypertrophy. Telemetric ECG recordings revealed a long-term changes of ECG parameters in hypomagnesemic rats; RR shortening, QT prolongation and appreciable PR prolongation. At the same time, hypomagnesemic rats demonstrate various bradycardiac arrhythmias including ventricular premature beats, atrioventricular blocks and sinus arrest, which were never recoded in rats fed by a normal diet. Electrophysiological studies elucidated that the L-type Ca(2+) channel current was decreased in Mg-deficient cardiomyocytes, and these findings were consistent with down-regulation of CaV1.2-mRNA but not in levels of CaV1.3, CaV3.1 or CaV3.2. These findings provide novel insights into hypomagnesemic electrophysiological disorders in the heart, and should be considered when assessing the design of effective antiarrhythmic treatments in patients with hypomagnesemia. PMID- 25701243 TI - Assessing the function of mitochondria in cytosolic context in human skeletal muscle: adopting high-resolution respirometry to homogenate of needle biopsy tissue samples. AB - Using skeletal muscle homogenates for respirometry has many advantages, but the main challenge is avoiding the damage to outer mitochondrial membrane (OMM) and complex I. By optimising the amount of muscle and careful titration of substrates and inhibitors we developed a new protocol and compared it to isolated mitochondria. We found acceptable damage to OMM (~10-15% increment of oxygen flux after addition of cytochrome c) and to complex I (~70% of electron flux). Homogenate retained ~90% of phosphorylation capacity of isolated mitochondria. The use of fresh homogenate was crucial as mitochondrial function declined rapidly after 2-3h of cold storage. PMID- 25701244 TI - The role of environmental variables on the efficiency of water and sewerage companies: a case study of Chile. AB - This paper evaluates the efficiency of water and sewerage companies (WaSCs) by introducing the lack of service quality as undesirable outputs. It also investigates whether the production frontier of WaSCs is overall constant returns to scale (CRS) or variable returns to scale (VRS) by using two different data envelopment analysis models. In a second-stage analysis, we study the influence of exogenous and endogenous variables on WaSC performance by applying non parametric hypothesis tests. In a pioneering approach, the analysis covers 18 WaSCs from Chile, representing about 90% of the Chilean urban population. The results evidence that the technology of the sample studied is characterized overall by CRS. Peak water demand, the percentage of external workers, and the percentage of unbilled water are the factors affecting the efficiency of WaSCs. From a policy perspective, the integration of undesirable outputs into the assessment of WaSC performance is crucial not to penalize companies that provide high service quality to customers. PMID- 25701245 TI - Legionella detection and subgrouping in water air-conditioning cooling tower systems in Kuwait. AB - The main aim of the study was to test for the presence of Legionnaires' disease causing microorganisms in air-conditioned buildings in Kuwait using molecular technologies. For this purpose, 547 samples were collected from 38 cooling towers for the analysis of Legionella pneumophila. These samples included those from water (n = 178), air (n = 231), and swabs (n = 138). Out of the 547 samples, 226 (41%) samples were presumptive positive for L. pneumophila, with L. pneumophila viable counts in the positive water samples ranging from 1 to 88 CFU/ml. Of the Legionella culture-positive samples, 204 isolates were examined by latex agglutination. These isolates were predominately identified as L. pneumophila serogroup (sg) 2-14. Using the Dresden panel of monoclonal antibodies, 74 representatives isolates were further serogrouped. Results showed that 51% of the isolates belonged to serogroup 7 followed by 1 (18%) and 3 (18%). Serogroups 4 (4%) and 10 (7%) were isolated at a lower frequency, and two isolates could not be assigned to a serogroup. These results indicate the wide prevalence of L. pneumophila serogroup 7 as the predominant serogroup at the selected sampling sites. Furthermore, the 74 L. pneumophila (sg1 = 13; sg3 = 13; sg4 = 3; sg7 = 38; sg10 = 5; sgX = 2) isolates were genotyped using the seven gene protocol sequence based typing (SBT) scheme developed by the European Working Group for Legionella Infections (EWGLI). The results show that Legionella isolates were discriminated into nine distinct sequence typing (ST) profiles, five of which were new to the SBT database of EWGLI. Additionally, all of the ST1 serogroup 1 isolates were of the OLDA/Oxford subgroup. These baseline data will form the basis for the development of a Legionella environmental surveillance program and used for future epidemiological investigations. PMID- 25701246 TI - Association between tobacco use and the upper gastrointestinal microbiome among Chinese men. AB - PURPOSE: Tobacco causes many adverse health conditions and may alter the upper gastrointestinal (UGI) microbiome. However, the few studies that studied the association between tobacco use and the microbiome were small and underpowered. Therefore, we investigated the association between tobacco use and the UGI microbiome in Chinese men. METHODS: We included 278 men who underwent esophageal cancer screening in Henan Province, China. Men were categorized as current, former, or never smokers from questionnaire data. UGI tract bacterial cells were characterized using the Human Oral Microbial Identification Microarray. Counts of unique bacterial species and genera estimated alpha diversity. For beta diversity, principal coordinate (PCoA) vectors were generated from an unweighted UniFrac distance matrix. Polytomous logistic regression models were used for most analyses. RESULTS: Of the 278 men in this study, 46.8% were current smokers and 12.6% were former smokers. Current smokers tended to have increased alpha diversity (mean 42.3 species) compared to never smokers (mean 38.9 species). For a 10 species increase, the odds ratio (OR) for current smoking was 1.29 (95% CI 1.04-1.62). Beta diversity was also associated with current smoking. The first two PCoA vectors were strongly associated with current smoking (PCoA1 OR 0.66; 95% CI 0.51-0.87; PCoA2 OR 0.73; 95% CI 0.56-0.95). Furthermore, Dialister invisus and Megasphaera micronuciformis were more commonly detected in current smokers than in never smokers. CONCLUSIONS: Current smoking was associated with both alpha and beta diversity in the UGI tract. Future work should consider how the UGI microbiome is associated with smoking-related diseases. PMID- 25701247 TI - Identifying promising practices for evaluation: the National Breast and Cervical Cancer Early Detection Program. AB - PURPOSE: The Centers for Disease Control and Prevention conducted a systematic screening and assessment process to identify promising practices implemented by grantees of the National Breast and Cervical Cancer Early Detection Program and its partners that were appropriate for rigorous evaluation. METHODS: The systematic screening and assessment (SSA) process was conducted from September 2010 through March 2012 and included five steps: (1) nominations of promising practices; (2) a first rating by subject matter experts; (3) field-based evaluability assessments; (4) a second rating by experts; and (5) use of results. Nominations were sought in three program areas including health education and promotion, quality assurance and quality improvement, and case management/patient navigation. RESULTS: A total of 98 practices were nominated of which 54 % were eligible for the first review by the experts. Fifteen practices were selected for evaluability assessment with ten forwarded for the second review by the experts. Three practices were ultimately recommended for rigorous evaluation, and one evaluation was conducted. Most nominated practices were based on evidence-based strategies rather than representing new, innovative activities. Issues were identified through the process including inconsistent implementation and lack of implementation fidelity. CONCLUSION: While the SSA was successful in identifying several programs for evaluation, the process also revealed important shortcomings in program implementation. Training and technical assistance could help address these issues and support improved programming. PMID- 25701248 TI - Aspirin and nonsteroidal anti-inflammatory drugs after but not before diagnosis are associated with improved breast cancer survival: a meta-analysis. AB - PURPOSE: The association between nonsteroidal anti-inflammatory drugs (NSAIDs) and breast cancer survival is still controversial. The aim of our meta-analysis was to assess the survival benefit of NSAIDs. METHODS: A literature search was conducted in PubMed and EMBASE (to September 2014). A meta-analysis was performed with hazard ratios (HRs) and 95% confidence intervals (CIs) as the effect measures. Subgroup analyses were based on time of NSAID use (before and after diagnosis), medication type (aspirin and other nonaspirin NSAIDs), and study design (cohort and case-control studies). RESULTS: There were 16 eligible studies. Use of NSAIDs after diagnosis was significantly inversely associated with relapse/metastasis (HR 0.69, 95% CI 0.59-0.80) and tended toward potentially protective effects on all-cause mortality, although significance was not reached (HR 0.79, 95% CI 0.61-1.02). In cohort studies, the association between post diagnostic use of NSAIDs and breast cancer survival was stronger with reduced heterogeneity (breast-cancer-specific mortality: HR 0.65, 95% CI 0.48-0.89, I(2) = 65.3%; all-cause mortality: HR 0.73, 95% CI 0.57-0.92, I(2) = 83.2%; relapse/metastasis: HR 0.73, 95% CI 0.61-0.86, I(2) = 48.3%). Aspirin use after diagnosis was significantly associated with breast-cancer-specific mortality (HR 0.69, 95% CI 0.50-0.96) and relapse/metastasis (HR 0.75, 95% CI 0.56-1.00), and tended toward a protective effect on all-cause mortality, although significance was not reached (HR 0.79, 95% CI 0.60-1.03). Including cohort studies only, we obtained similar results and post-diagnostic use of aspirin was significantly associated with all-cause mortality (HR 0.72, 95% CI 0.56-0.93). CONCLUSIONS: NSAIDs and aspirin after but not before diagnosis were associated with improved breast cancer survival, including breast-cancer-specific mortality, all-cause mortality, and relapse/metastasis. PMID- 25701249 TI - Molecular docking and antiviral activity of N-substituted benzyl/phenyl-2-(3,4 dimethyl-5,5-dioxidopyrazolo[4,3-c][1,2]benzothiazin-2(4H)-yl)acetamides. AB - Two series of fifteen N-substituted benzyl/phenyl-2-(3,4-dimethyl-5,5 dioxidopyrazolo[4,3-c][1,2]benzothiazin-2(4H)-yl)acetamides were screened for anti-HIV-1 activity and cytotoxicity. The compounds 6a, 6d, 6e, 6g and 6i from the series 6a-i of benzylamides and 7a, 7b, 7c, 7d and 7e from the series 7a-f of anilides were identified as effective anti-HIV-1 agents with EC50 values <20MUM. Among these compounds that displayed anti-HIV-1 activity, 6a, 6e, 6g and 6i showed no toxicity in human PBM, CEM and Vero cells, with the exception of 6a which displayed toxicity in Vero cells. Molecular docking of these compounds provided insight into the molecular mechanism and it was found that 6e, 6g and 6i bound deeply in the NNRTI binding pocket of the HIV-1 reverse transcriptase, using RT-bound nevirapine X-ray data and molecular docking for validation, showing the potential of these new structures as inhibitors of this viral enzyme. PMID- 25701250 TI - Inhibition of monoamine oxidase by indole-5,6-dicarbonitrile derivatives. AB - Recent studies have found that phthalonitrile derivatives are remarkably potent inhibitors of human monoamine oxidase (MAO) A and B. In an attempt to further determine the structure-activity relationships (SARs) for MAO inhibition by this class of compounds and to discover novel potent MAO inhibitors, the present study investigated the MAO inhibition properties of a series consisting of indole-5,6 dicarbonitrile derivatives. The results document that 3-chloro-1H-indole-5,6 dicarbonitrile derivatives exhibited potent inhibition of the MAOs. For example, 3-chloro-2-(4-methylphenyl)-1H-indole-5,6-dicarbonitrile inhibited MAO-A and MAO B with IC50 values of 0.014MUM and 0.017MUM, respectively. It was further shown that this compound acts as a reversible and competitive inhibitor of both MAO isoforms. An analysis of the SARs for MAO inhibition by 3-chloro-1H-indole-5,6 dicarbonitriles showed that methylation of the indole nitrogen eliminates MAO-B inhibition activity, and replacement of the 2-phenyl ring with the thienyl results in a 9-fold reduction of MAO-B inhibition activity. A series of 3-bromo-1 hydroxy-1H-indole-5,6-dicarbonitriles are, in turn, comparatively weaker MAO inhibitors. It may be concluded that indole-5,6-dicarbonitrile derivatives are suitable leads for the design MAO inhibitors for the treatment of disorders such as Parkinson's disease and depression. PMID- 25701251 TI - Synthesis and evaluation of the diarylthiourea analogs as novel anti-cancer agents. AB - Ten p-nitrodiarylthiourea analogs were designed, synthesized and evaluated in breast (MCF-7, T-47D, MDA-MB-453) and prostate (DU-145, PC-3, LNCaP) cancer cell lines for their anticancer activities. The majority of the compounds were able to inhibit the growth of these six cancer cell lines at low micromolar concentrations. Compound 7 was found to be the most potent anticancer agent in this series with GI50 values of 3.16MUM for MCF-7, 2.53MUM for T-47D, 4.77MUM for MDA-MB-453 breast cancer lines and 3.54MUM for LNCaP prostate cancer cell line. These GI50 values were comparable to the parent compound, SHetA2. PMID- 25701252 TI - Potent and selective Bruton's tyrosine kinase inhibitors: discovery of GDC-0834. AB - SAR studies focused on improving the pharmacokinetic (PK) properties of the previously reported potent and selective Btk inhibitor CGI-1746 (1) resulted in the clinical candidate GDC-0834 (2), which retained the potency and selectivity of CGI-1746, but with much improved PK in preclinical animal models. Structure based design efforts drove this work as modifications to 1 were investigated at both the solvent exposed region as well as 'H3 binding pocket'. However, in vitro metabolic evaluation of 2 revealed a non CYP-mediated metabolic process that was more prevalent in human than preclinical species (mouse, rat, dog, cyno), leading to a high-level of uncertainly in predicting human pharmacokinetics. Due to its promising potency, selectivity, and preclinical efficacy, a single dose IND was filed and 2 was taken in to a single dose phase I trial in healthy volunteers to quickly evaluate the human pharmacokinetics. In human, 2 was found to be highly labile at the exo-cyclic amide bond that links the tetrahydrobenzothiophene moiety to the central aniline ring, resulting in insufficient parent drug exposure. This information informed the back-up program and discovery of improved inhibitors. PMID- 25701253 TI - Synthesis and SAR studies of analogues of 4-(3,3-dimethyl-butyrylamino)-3,5 difluoro-N-thiazol-2-yl-benzamide (Lu AA41063) as adenosine A2A receptor ligands with improved aqueous solubility. AB - An adenosine A2A receptor antagonist may be useful for the treatment of Parkinson's disease. Synthesis and structure-activity studies starting from 4 (3,3-dimethylbutyrylamino)-3,5-difluoro-N-thiazol-2-yl-benzamide (Lu AA41063, 4) led to a novel series of human (h) A2A receptor antagonists with improved aqueous solubility. Compound 22 was identified as a key representative from the series, displaying submicromolar hA2A receptor affinity and excellent aqueous solubility. Compound 22 also displayed good in vitro pharmacokinetic properties and is considered a good starting point for further lead optimisation toward hA2A receptor antagonists with improved druggability properties. PMID- 25701254 TI - Novel tail and head group prostamide probes. AB - We report the design and synthesis of novel prostaglandin-ethanolamide (PGE2-EA) analogs containing head and tail group modifications to aid in the characterization of a putative prostamide receptor(s). Our synthetic approach utilizes Horner-Wadsworth-Emmons and Wittig reactions to construct the head and the tail moieties of the key PGE2 precursor, which leads to the final products through a peptide coupling, Swern oxidation and HF/pyridine assisted desilylation. The synthesized analogs were shown not to interact significantly with endocannabinoid proteins and recombinant EP1, EP3 and EP4 receptors and suggest a yet to be identified prostamide receptor as their site(s) of action. PMID- 25701255 TI - Exploring the potential relationship between Notch pathway genes expression and their promoter methylation in mice hippocampal neurogenesis. AB - The Notch pathway is a highly conserved pathway that regulates hippocampal neurogenesis during embryonic development and adulthood. It has become apparent that intracellular epigenetic modification including DNA methylation is deeply involved in fate specification of neural stem cells (NSCs). However, it is still unclear whether the Notch pathway regulates hippocampal neurogenesis by changing the Notch genes' DNA methylation status. Here, we present the evidence from DNA methylation profiling of Notch1, Hes1 and Ngn2 promoters during neurogenesis in the dentate gyrus (DG) of postnatal, adult and traumatic brains. We observed the expression of Notch1, Hes1 and Ngn2 in hippocampal DG with qPCR, Western blot and immunofluorescence staining. In addition, we investigated the methylation status of Notch pathway genes using the bisulfite sequencing PCR (BSP) method. The number of Notch1 or Hes1 (+) and BrdU (+) cells decreased in the subgranular zone (SGZ) of the DG in the hippocampus following TBI. Nevertheless, the number of Ngn2-positive cells in the DG of injured mice was markedly higher than in the DG of non-TBI mice. Accordingly, the DNA methylation level of the three gene promoters changed with their expression in the DG. These findings suggest that the strict spatio-temporal expression of Notch effector genes plays an important role during hippocampal neurogenesis and suggests the possibility that Notch1, Hes1 and Ngn2 were regulated by changing some specific CpG sites of their promoters to further orchestrate neurogenesis in vivo. PMID- 25701256 TI - All-inside meniscal repair surgery: factors affecting the outcome. AB - BACKGROUND: Meniscal injury is currently a well-recognized source of knee dysfunction. While it would be ideal to repair all meniscus tears, the failure rate is significantly high, although it may be reduced by careful selection of the patients. Our objective was to assess the outcome of meniscal repair surgery and the role of simultaneous reconstruction of the anterior cruciate ligament (ACL). MATERIALS AND METHODS: Retrospectively, all consecutive patients between January 2008 and 2011 who underwent meniscal repair were included. Patients were identified using the hospital database with diagnosis and procedure codes. Patient notes were reviewed, including details of the type of tear, chronicity, location, and surgery. We used symptomatic resolution as the outcome measure. RESULTS: 136 Meniscal repairs were performed in 122 patients with a mean age of 26.8 years. Mean follow-up duration was 9 months. 63 % of the patients underwent medial and 37 % underwent lateral meniscal repair, with failure rates of 19 % for medial and 12 % for lateral menisci. Ligament injuries were found in 61 % of the patients (n = 83). Failure of meniscal repair occurred in 14.5 % (n = 12) of the patients who had early ACL reconstruction and in 27 % (n = 22) of the patients who had delayed ACL reconstruction (p = 0.0006). The failure rate was found to be 13 % in patients who were younger than 25 years (61 %) and 15 % in patients who were older than 25 years (39 %). CONCLUSION: The success rate of meniscal repair was found to be significantly better when ACL reconstruction was performed simultaneously with meniscal repair. LEVEL OF EVIDENCE: Level IV. PMID- 25701257 TI - Short uncemented stems allow greater femoral flexibility and may reduce peri prosthetic fracture risk: a dry bone and cadaveric study. AB - BACKGROUND: Short femoral stems for uncemented total hip arthroplasty have been introduced as a safe alternative to traditional longer stem designs. However, there has been little biomechanical examination of the effects of stem length on complications of surgery. This study aims to examine the effect of femoral stem length on torsional resistance to peri-prosthetic fracture. MATERIALS AND METHODS: We tested 16 synthetic and two paired cadaveric femora. Specimens were implanted and then rapidly rotated until fracture to simulate internal rotation on a planted foot, as might occur during stumbling. 3D planning software and custom-printed 3D cutting guides were used to enhance the accuracy and consistency of our stem insertion technique. RESULTS: Synthetic femora implanted with short stems fractured at a significantly higher torque (27.1 vs. 24.2 Nm, p = 0.03) and angle (30.3 degrees vs. 22.3 degrees , p = 0.002) than those implanted with long stems. Fracture patterns of the two groups were different, but showed remarkable consistency within each group. These characteristic fracture patterns were closely replicated in the pair of cadaveric femora. CONCLUSIONS: This new short-stemmed press-fit femoral component allows more femoral flexibility and confers a higher resistance to peri-prosthetic fracture from torsional forces than long stems. PMID- 25701258 TI - Dual mobility acetabular components for revision THA. PMID- 25701259 TI - FGF2 Prevents Sunitinib-Induced Cardiotoxicity in Zebrafish and Cardiomyoblast H9c2 Cells. AB - Sunitinib is used extensively in the treatment of metastatic renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumors. However, the undesirable cardiotoxic effects of sunitinib, such as congestive heart failure and hypertension, limit its use in the clinical setting. As multiple receptor tyrosine kinases are inhibited by sunitinib, it raises a question as to which target mediates sunitinib-induced cardiotoxicity. Here, we reported that the injection of fibroblast growth factor 2 (FGF2) mRNA into one- to two-cell stage embryos protected against sunitinib-induced cardiotoxicity in zebrafish. In addition, FGF2 significantly prevented sunitinib-induced cardiotoxicity in cardiomyoblast H9c2 cells, possibly via activating the PLC-gamma/c-Raf/CREB pathway. Importantly, FGF2 did not compromise the antitumor activity of sunitinib in Caki-1 and OS-RC-2 renal cell carcinoma cells. Molecular docking simulations further revealed an interaction between the tyrosine kinase domain of FGF receptor 1 (FGFR1) and sunitinib. Taken together, our results clearly demonstrated that FGF2 inhibition plays an important role in sunitinib-induced cardiotoxicity both in vitro and in vivo. This study also provided a basis for further research on sunitinib-induced cardiotoxicity and may allow rational design of new sunitinib derivatives with fewer or weak cardiotoxic effects. PMID- 25701260 TI - Primary laryngeal cryptococcosis resembling laryngeal carcinoma. AB - A case of an 82-year-old female with primary laryngeal cryptococcosis who had undergone long-term corticosteroid therapy for chronic obstructive pulmonary disease and rheumatoid arthritis is reported. She complained hoarseness with swallowing pain and irritability of the larynx for over a month. Endoscopic examination revealed a white, exudative irregular region on right arytenoid that mimicked a laryngeal carcinoma. Histological examination showed pseudoepitheliomatous hyperplasia and severe submucosal inflammation with ovoid budding yeasts by Grocott's stain. A serological study indicated a high titer of cryptococcal antigen. After treating with oral fluconazole for 3 months, her primary lesion of larynx turned to be clear. We implicate a long-term use of steroids as the significant risk factor in developing cryptococcosis of the larynx. PMID- 25701261 TI - Insulin priming effect on estradiol-induced breast cancer metabolism and growth. AB - Diabetes is a risk factor for breast cancer development and is associated with poor prognosis for breast cancer patients. However, the molecular and biochemical mechanisms underlying the association between diabetes and breast cancer have not been fully elucidated. Here, we investigated estradiol response in MCF-7 breast cancer cells with or without chronic exposure to insulin. We found that insulin priming is necessary and specific for estradiol-induced cancer cell growth, and induces anaplerotic shunting of glucose into macromolecule biosynthesis in the estradiol treated cells. Treatment with ERK or Akt specific inhibitors, U0126 or LY294002, respectively, suppressed estradiol-induced growth. Interestingly, molecular analysis revealed that estradiol treatment markedly increases expression of cyclin A and B, and decreases p21 and p27 in the insulin-primed cells. In addition, estradiol treatment activated metabolic genes in pentose phosphate (PPP) and serine biosynthesis pathways in the insulin-primed cells while insulin priming decreased metabolic gene expression associated with glucose catabolism in the breast cancer cells. Finally, we found that anti-diabetic drug metformin and AMPK ligand AICAR, but not thiazolidinediones (TZDs), specifically suppress the estradiol-induced cellular growth in the insulin-primed cells. These findings suggest that estrogen receptor (ER) activation under chronic hyperinsulinemic condition increases breast cancer growth through the modulation of cell cycle and apoptotic factors and nutrient metabolism, and further provide a mechanistic evidence for the clinical benefit of metformin use for ER-positive breast cancer patients with diabetes. PMID- 25701262 TI - 13C- and 1H-detection under fast MAS for the study of poorly available proteins: application to sub-milligram quantities of a 7 trans-membrane protein. AB - We demonstrate that (13)C-detected spectra recorded using fast (60 kHz) magic angle spinning on sub-milligram (<10 MUmol) quantities of a protonated 7 trans membrane helix protein (bacteriorhodopsin) in its native lipid environment are comparable in sensitivity and resolution to those recorded using 15-fold larger sample volumes with conventional solid state NMR methodology. We demonstrate the utility of proton-detected measurements which yield narrow (1)H linewidths under these conditions, and that no structural alterations are observed. We propose that these methods will prove useful to gain structural information on membrane proteins with poor availability, which can be studied in their native lipid environments. PMID- 25701263 TI - The impact of socio-economic status on all-cause mortality after percutaneous coronary intervention: an observational cohort study of 13,770 patients. AB - AIMS: The relation between socio-economic status (SES) and outcomes after percutaneous coronary intervention (PCI) has not been established. We sought to determine whether or not socio-economic status impacts on prognosis after PCI. METHODS AND RESULTS: This was an observational cohort study of 13,770 consecutive patients who underwent PCI at a single centre between 2005 and 2011. Patient socio-economic status was defined by the English Index of Multiple Deprivation (IMD) score, according to residential postcode. Patients were analysed by quintile of IMD score (Q1, least deprived; Q5, most deprived). Median follow-up was 3.7 (IQR: 2.0-5.1) years and the primary outcome was all-cause mortality. Patients in Q5 (most deprived) were younger, more commonly South Asian, and had higher rates of smoking, diabetes mellitus, renal impairment, previous MI, and previous PCI than patients in Q1. Rates of long-term mortality increased progressively across the five quintiles of IMD score in a linear fashion (p=0.0004), as did rates of recurrent MI, target vessel revascularisation, and CABG. The difference in mortality rates persisted after adjustment for other potential confounding factors after multivariate analysis (Q5 vs. Q1: HR 1.93, 95% CI: 1.38-2.69). CONCLUSIONS: In this large contemporary cohort of patients receiving PCI, socio-economic status was associated with prognosis in a linear fashion. PMID- 25701264 TI - How should I treat subacute stent thrombosis in the context of brain haemorrhage with abciximab? PMID- 25701266 TI - Seeking social support on Facebook for children with Autism Spectrum Disorders (ASDs). AB - PURPOSE: This study examined the types of social support messages exchanged between parents and/or caregivers of children with Autism Spectrum Disorders (ASDs) who communicate via Facebook (FB); it studies two autism support groups: Autism Malaysia (AM) and Autism Children Club (ACA). METHOD: A total of 3637 messages including both postings (381) and comments (3256) were gathered from August to November 2013. The study employed a deductive content-analysis approach. The qualitative data were analyzed for social support themes adapted from the Social Support Behavior Code (SSBC). Before collecting the data, email was sent to the FB groups' moderators to gain formal consent from the members. RESULT: The finding indicated that the highest percentage of messages offered dealt with Informational support (30.7%) followed by Emotional support (27.8%). Network and Esteem support messages were responsible for 20.97% and 20.2%, respectively. Tangible Assistance was the least frequent category (0.4%). A majority of these messages discussed and addressed challenges and difficulties associated with caring and raising ASD children, as well as issues such as children's social lives and self-care routines. CONCLUSION: Understandings of how FB is used to seek social support could impact supporting and maintaining effective communication among parents and/or caregivers of children with ASDs. This information could also improve approaches used by health professionals in developing, improving and evaluating social support systems for parents/caregivers. PMID- 25701265 TI - The effect of acute exercise on cigarette cravings while using a nicotine lozenge. AB - RATIONALE: It is imperative that smoking cessation aids effectively alleviate cigarette craving and withdrawal symptoms because their intensity has shown to predict relapse. The nicotine lozenge and a single session of exercise have both been shown to provide relief from craving for smokers who have stopped smoking. These two efficacious monotherapies have distinct mechanic pathways, and applying them concurrently may provide additive-craving relief benefit. OBJECTIVE: This study aimed to examine whether an acute bout of moderate-intensity exercise provides additional craving relief to the nicotine replacement lozenge in recently quit smokers. RESULTS: Thirty smokers who had abstained from smoking for 15 h were randomized to either the experimental (exercise and lozenge, n = 15) or control (lozenge alone, n = 15) condition. Craving was assessed before (baseline), during (10 and 20 min), and after (10, 20, 30, and 40 min) treatment. RESULT: A significant condition by time interaction effect was found for craving (F(6, 23) = 2.70, p = 0.039, Wilks' Lambda = 0.59, eta rho (2) = 0.41). While both conditions demonstrated reductions in craving, the reduction was significantly greater for the experimental group. CONCLUSION: These findings demonstrate that an acute bout of exercise provides additional craving relief to the nicotine lozenge in recently quit smokers. We recommend smokers who attempt to quit employ both cessation aids simultaneously to maximize reductions in cravings. PMID- 25701267 TI - A Retrospective Survey Studying the Impact of Fabry Disease on Pregnancy. AB - Fabry disease (FD) is a lysosomal storage disorder resulting from a deficiency of lysosomal enzyme alpha-galactosidase A (alpha-gal A). Reduced or missing alpha gal A enzyme results in the storage of globotriaosylceramide (GL3) and related glycosphingolipids in the cellular lysosomes throughout the body. The majority of GL3 buildup occurs in the body's vasculature resulting in narrowed blood vessels and an increased risk for strokes, transient ischemic attacks, and deep vein thrombosis. Theoretical concerns have been raised about increased pregnancy complications in women affected by FD as glycosphingolipid storage has been found in both maternal- and fetal-derived placental tissues. This retrospective study was conducted to better understand risks for women with FD during pregnancy. Survey questions included queries about prenatal medications, teratogenic exposures, prenatal testing, common pregnancy complications, Fabry symptoms during pregnancy, obstetrical history, and immediate neonatal history. In total, 41 affected women completed the survey. Results indicate several Fabry-related symptoms and features may worsen during pregnancy, including gastrointestinal symptoms, acroparesthesias, proteinuria, headaches, and postpartum depression. Although no life-threatening complications were reported, a statistically significant increased frequency of hypertension was observed when comparing data from this study to the general population (p < 0.05) and previous publications (p < 0.001). Limitations include sample size and recall bias. Though this survey sampling of women was small and required women to recall their past pregnancy experiences, the findings suggest that when pregnant, women with FD should be aware of potential worsening of FD symptoms and may benefit from consulting with a maternal-fetal medicine specialist. PMID- 25701268 TI - Occurrence of Malignant Tumours in the Acute Hepatic Porphyrias. AB - The porphyrias are a group of inherited metabolic diseases resulting from enzymatic deficiencies of specific haem biosynthetic enzymes. They can be classified as primarily acute and non-acute types. Clinically, the acute hepatic porphyrias (AHPs) are characterised by acute neurovisceral attacks. Patients with AHP may be at increased risk for development of hepatocellular carcinoma (HCC). However, systematic studies on the occurrence of other malignancies in patients with the AHPs have not been performed to date. Here, we studied the development of HCC and distinct malignant tumours in patients with the AHPs registered in a single European porphyria specialist centre. A questionnaire was designed and sent to all individuals (n = 122) diagnosed between 1970 and 2012 of whom a valid address was available (n = 82), requesting information on their personal and family history of cancer. Statistical analysis was performed to calculate incidence, prevalence and relative risk of HCC. To calculate confidence intervals, a Poisson distribution was assumed. Forty-nine patients (59.8%) returned a completed questionnaire. Overall, HCC was diagnosed in one female (2.1%), and the remaining patients reported on six distinct malignancies. We were able to confirm that HCC is an important complication in AHP. The patients in our cohort had an approximately 35-fold increased risk of developing HCC, similar to observations in other European countries. In addition, we detected colon, breast, uterine and thyroid cancer as well as lymphoma and a liver metastasis in patients with AHP. However, considering the small number of tumours and patients studied here, the data should be interpreted with caution, and further studies on cancer occurrence in AHP patients will require a multicentre setting. PMID- 25701269 TI - Networking Across Borders for Individuals with Organic Acidurias and Urea Cycle Disorders: The E-IMD Consortium. AB - BACKGROUND: Patients with organic acidurias (OAD) and urea cycle disorders (UCD) are at increased risk of disability, impaired quality of life and reduced life expectancy. Clinical care in any one centre is constrained by small patient numbers; and furthermore diagnostic and treatment strategies vary between metabolic centres and countries, resulting in significant inequalities and disparity in patient outcome. AIMS/METHODS: The overall objective of the EU funded activity 'European registry and network for intoxication type metabolic diseases' (E-IMD) is to collect systematic data to improve the knowledge of these diseases, to develop consensus care guidelines and to provide detailed information materials for families and professionals. RESULTS: Within three years E-IMD has (1) established a network of 87 partners in 25 countries (2) set up a patient registry of more than 1,000 individuals with OAD and UCD, (3) launched a website ( www.e-imd.org ) including detailed information materials in 11 languages, (4) developed guidelines for OAD and UCD, (5) organised two teaching courses and various scientific meetings, (6) extended the IT platform clustering with other inherited metabolic diseases (IMD) and (7) strengthened the collaboration with other international scientific consortia. CONCLUSIONS: E-IMD has made important steps towards improving and sharing knowledge on OAD and UCD and harmonisation of diagnostic and therapeutic strategies. Through the establishment of a modular patient registry, clustering with other IMD and stepwise extension of the network, E-IMD has implemented the core components of a European Reference Network for rare diseases. PMID- 25701270 TI - Conversion to modified duodenal switch for relieving intractable dumping syndrome and constipation after laparoscopic Roux-en-Y gastric bypass. AB - BACKGROUND: Dumping syndrome is not infrequent after laparoscopic Roux-en-Y gastric bypass and could result in dreaded complications, such as hypoglycemia or syncope. Those patients who failed medical therapy and diet modification, regarded as intractable dumping syndrome, may be considered as candidates for revisional surgery. Herein, we make a video presentation of laparoscopic revisional procedure for intractable dumping syndrome with unsatisfactory weight loss. METHODS: A 32-year-old, morbidly obese woman (initial body mass index, 53.3 kg/m(2)) presented with dumping syndrome 17 months after initial laparoscopic Roux-en-Y gastric bypass. She underwent nutritional counseling, strict diet modification, and medication treatment but failed. In addition, the patient complained of worsening constipation and insufficient weight loss (body mass index, 36 kg/m(2)). Laparoscopic revisional procedure with modified duodenal switch was conducted to relieve her intractable condition. RESULTS: The procedure took 260 min without any intraoperative complication. Blood loss was 100 mL The patient had an uneventful postoperative course and the postoperative hospital stay was 5 days. The uncomfortable symptoms relieved successfully after the revisional surgery. CONCLUSIONS: Though long-term follow-up is warranted to draw a definite conclusion, modified duodenal switch with pyloric restoration and shortening bowel length remains an acceptable revisional procedure to relive intractable dumping syndrome and constipation in our patient successfully. PMID- 25701271 TI - Breast Reshaping Following Bariatric Surgery. AB - BACKGROUND: Obesity is a worldwide problem that affects millions of people from a medical and psychological point of view. To solve the related complications, patients should lose weight with the consequent need to be subjected to body contouring due to the presence of a loose and redundant skin. We report our experience in the treatment of the post-bariatric breast. MATERIAL AND METHODS: We considered all the post-bariatric patients subjected to a breast reshaping, and we viewed the features of the breast, the type of surgery performed, the outcomes, and the complications. All patients filled out BREAST-Q surveys both preoperatively and after 6 months to study the rate of satisfaction. RESULTS: Ninety post-bariatric patients underwent breast reshaping in the last 5 years. The average age was 40 years old. The follow-up period ranged from 6 months to 5 years. The most represented ptosis was second grade; the favorite technique has been mastopexy with parenchymal remodelling and augmentation with autologous tissue. The mean duration of the surgery has been 3 h. The most represented complications have been delayed healing, unfavorable scarring, hematoma, and seroma. Statistically significant improvements were observed in satisfaction with breast appearance, psychological, and physical well-being. CONCLUSIONS: Breast reshaping in post-bariatric patients is a big challenge and only a careful analysis of the degree of ptosis of the breast, its volume and shape, and a clear communication with the patients about the real outcomes and complications can make the winning surgeon. PMID- 25701272 TI - Informed choice in screening needs more than information. PMID- 25701273 TI - Use of a decision aid including information on overdetection to support informed choice about breast cancer screening: a randomised controlled trial. AB - BACKGROUND: Mammography screening can reduce breast cancer mortality. However, most women are unaware that inconsequential disease can also be detected by screening, leading to overdiagnosis and overtreatment. We aimed to investigate whether including information about overdetection of breast cancer in a decision aid would help women aged around 50 years to make an informed choice about breast screening. METHODS: We did a community-based, parallel-group, randomised controlled trial in New South Wales, Australia, using a random cohort of women aged 48-50 years. Recruitment to the study was done by telephone; women were eligible if they had not had mammography in the past 2 years and did not have a personal or strong family history of breast cancer. With a computer program, we randomly assigned 879 participants to either the intervention decision aid (comprising evidence-based explanatory and quantitative information on overdetection, breast cancer mortality reduction, and false positives) or a control decision aid (including information on breast cancer mortality reduction and false positives). Participants and interviewers were masked to group assignment. The primary outcome was informed choice (defined as adequate knowledge and consistency between attitudes and screening intentions), which we assessed by telephone interview about 3 weeks after random allocation. The primary outcome was analysed in all women who completed the relevant follow-up interview questions fully. This trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12613001035718. FINDINGS: Between January, 2014, and July, 2014, 440 women were allocated to the intervention group and 439 were assigned to the control group. 21 women in the intervention group and 20 controls were lost to follow-up; a further ten women assigned to the intervention and 11 controls did not answer all questions on attitudes. Therefore, 409 women in the intervention group and 408 controls were analysed for the primary outcome. 99 (24%) of 409 women in the intervention group made an informed choice compared with 63 (15%) of 408 in the control group (difference 9%, 95% CI 3-14; p=0.0017). Compared with controls, more women in the intervention group met the threshold for adequate overall knowledge (122/419 [29%] vs 71/419 [17%]; difference 12%, 95% CI 6-18; p<0.0001), fewer women expressed positive attitudes towards screening (282/409 [69%] vs 340/408 [83%]; 14%, 9-20; p<0.0001), and fewer women intended to be screened (308/419 [74%] vs 363/419 [87%]; 13%, 8-19; p<0.0001). When conceptual knowledge alone was considered, 203 (50%) of 409 women in the intervention group made an informed choice compared with 79 (19%) of 408 in the control group (p<0.0001). INTERPRETATION: Information on overdetection of breast cancer provided within a decision aid increased the number of women making an informed choice about breast screening. Becoming better informed might mean women are less likely to choose screening. FUNDING: Australian National Health and Medical Research Council. PMID- 25701274 TI - Diabetes mellitus affects activity of calcium/calmodulin-dependent protein kinase II alpha in rat trigeminal ganglia. AB - The activity of calcium/calmodulin-dependent protein kinase II alpha (CaMKIIalpha) may play a critical role in the modulation of nociceptor activity and plasticity of primary sensory trigeminal neurons. The aim of this study was to investigate the immunoreactivity of phosphorylated CaMKIIalpha (pCaMKIIalpha) in subpopulations of trigeminal ganglion (TG) neurons in rat models of early diabetes type 1 (dm1) and 2 (dm2). DM1 model was induced with intraperitoneally (i.p.) injected streptozotocin (STZ) (55mg/kg). DM2 rats were fed with the high fat diet (HFD) for 2 weeks and then received 35mg/kg of STZ i.p. Two weeks and 2 months after the STZ-diabetes induction, rats were sacrificed and immunohistochemical analysis for detection of pCaMKIIalpha immunoreactivity and double immunofluorescence labelling with isolectin (IB4) was performed. Increased intensity of pCaMKIIalpha immunofluorescence, restricted to IB4-negative small diameter neurons, was seen in TG neurons two months after STZ-DM1 induction. DM1 model, as well as the obesity (control dm2 groups) resulted in neuronal impaired growth while dm2 model led to neuron hypertrophy in TG. Observed changes may play a critical role in the modulation of nociceptor activity and plasticity of primary sensory trigeminal neurons. In future, innovative strategies for modulation of CaMKIIalpha activity in specific subpopulations of neurons could be a novel approach in therapy of diabetic trigeminal neuropathy. PMID- 25701275 TI - [Pain in nursing homes]. AB - Elderly live in nursing homes if the necessary need for care cannot be realized in the home care setting. Dementia syndrome (60 % of nursing home residents) has a prominent role. Pain is a frequent problem in nursing homes, affecting functionality and quality of life. Studies often show inadequate pain therapy. Not only is the presentation of pain often atypical, but pharmacological and invasive pain therapy is limited by multimorbidity and increased risk of side effects. Nonpharmacological pain therapy is part of nursing therapy; however, the effect on nursing home residents has been insufficiently studied. This situation necessitates interprofessional coordination of all team members, in which the nursing pain assessment and the realization of both pharmacological and nonpharmacological pain therapy are very important. PMID- 25701276 TI - [Towards increased incorporation of the patient perspective in the design of evaluation tools for the evaluation of efficiency and quality of patient care]. PMID- 25701277 TI - Differences in community and academic practice patterns for newly diagnosed myelodysplastic syndromes (MDS) patients. AB - PURPOSE: The heterogeneous nature of myelodysplastic syndromes (MDS) complicates therapeutic decision making, particularly for newly diagnosed disease. Factors impacting the treatment plan in this early period of disease course are poorly defined. This study determines whether therapeutic choices for newly diagnosed MDS are associated with location of treatment (community or academic), prognostic risk category, and patient age. METHODS: The adults in Minnesota with myelodysplastic syndromes (AIMMS) database was utilized in this statewide, prospective population-based study conducted by the University of Minnesota (UMN), Mayo Clinic, and Minnesota Department of Health. Adult (age 20+ years) cases of MDS newly diagnosed starting in April 2010 were invited to participate. This analysis includes patients enrolled during the first study year with 1-year follow-up data. Treatment choices (supportive, active, and transplant) were stratified by the international prognostic scoring system (IPSS) and the revised IPSS (IPSS-R), then separated into groups by location of care and age (<65 or 65+ years). Academic-based care was any contact with the UMN and Mayo Clinic; community-based care was all other clinical sites. RESULTS: Stratification by IPSS and IPSS-R showed supportive care decreased and active care increased with advancing risk categories (p<0.0001). Comparing treatment setting, community based care had 77% supportive and 23% active treatment; academic-based care was 36% supportive, 41% active, and 23% transplant (p<0.0001). By age groups, patients <65 years with intermediate, high, or very high risk disease by IPSS-R received 97% active care/transplant, compared to only 52% of patients age 65+. CONCLUSIONS: Younger patients and those treated at academic centers had a more aggressive treatment approach. Whether these treatment differences convey improved disease control and mortality, and therefore should be extended more frequently to older and community-based patients, is the subject of ongoing prospective study. PMID- 25701278 TI - Not all attention orienting is created equal: recognition memory is enhanced when attention orienting involves distractor suppression. AB - Learning through visual exploration often requires orienting of attention to meaningful information in a cluttered world. Previous work has shown that attention modulates visual cortex activity, with enhanced activity for attended targets and suppressed activity for competing inputs, thus enhancing the visual experience. Here we examined the idea that learning may be engaged differentially with variations in attention orienting mechanisms that drive eye movements during visual search and exploration. We hypothesized that attention orienting mechanisms that engaged suppression of a previously attended location would boost memory encoding of the currently attended target objects to a greater extent than those that involve target enhancement alone. To test this hypothesis we capitalized on the classic spatial cueing task and the inhibition of return (IOR) mechanism (Posner, 1980; Posner, Rafal, & Choate, 1985) to demonstrate that object images encoded in the context of concurrent suppression at a previously attended location were encoded more effectively and remembered better than those encoded without concurrent suppression. Furthermore, fMRI analyses revealed that this memory benefit was driven by attention modulation of visual cortex activity, as increased suppression of the previously attended location in visual cortex during target object encoding predicted better subsequent recognition memory performance. These results suggest that not all attention orienting impacts learning and memory equally. PMID- 25701279 TI - Time trend by region of suicides and suicidal thoughts among Greenland Inuit. AB - BACKGROUND: Suicides remain a major public health problem in Greenland. Their increase coincides with the modernization since 1950. Serious suicidal thoughts are reported by a significant proportion of participants in countrywide surveys. OBJECTIVE: To analyze the time trend by region of suicides and suicidal thoughts among the Inuit in Greenland. DESIGN: Data included the Greenland registry of causes of death for 1970-2011 and 2 cross-sectional health surveys carried out in 1993-1994 and 2005-2010 with 1,580 and 3,102 Inuit participants, respectively. RESULTS: Suicide rates were higher among men than women while the prevalence of suicidal thoughts was higher among women. Suicide rates for men and women together increased from 1960 to 1980 and have remained around 100 per 100,000 person-years since then. The regional pattern of time trend for suicide rates varied with an early peak in the capital, a continued increase to very high rates in remote East and North Greenland and a slow increase in villages relative to towns on the West Coast. Suicidal thoughts followed the regional pattern for completed suicides. Especially for women there was a noticeable increasing trend in the villages. The relative risk for suicide was highest among those who reported suicidal thoughts, but most suicides happened outside this high-risk group. CONCLUSION: Suicide rates and the prevalence of suicidal thoughts remain high in Greenland but different regional trends point towards an increased marginalization between towns on the central West Coast, villages and East and North Greenland. Different temporal patterns call for different regional strategies of prevention. PMID- 25701280 TI - Effect of malocclusion among adolescents on family quality of life. AB - AIM: To evaluate the effect of malocclusion among adolescents on their families' oral health-related quality of life (OHRQoL). METHODS: A consecutive sample of 125 parents/caregivers of Brazilian adolescents was chosen. Participants were asked to answer the Brazilian version of the Family Impact Scale (FIS). The main independent variable was adolescents' malocclusion, which was measured with the Dental Aesthetic Index. Gender, age, and family monthly income were the other independent variables. Data analysis involved descriptive statistics, Mann Whitney test, and univariate and multiple logistic regression. RESULTS: Among the 125 participants initially admitted to the present study, two were excluded so that 123 parents/caregivers participated providing a response rate of 98.4 %. The overall FIS score revealed a more frequent effect for families of adolescents who presented malocclusion (P = 0.005). Significant findings were also observed for parental emotions (P = 0.022), family conflict (P = 0.010), and financial burden (P = 0.010) subscales. When the independent variables family monthly income and malocclusion were inserted together in the regression model, families with a monthly income of <5 Brazilian minimum wages (approximately US$ 325.00 per month) were more likely to have a worse OHRQoL, and families whose adolescents presented malocclusion were 3.55 more likely to have a poorer quality of life than those families whose adolescents did not present malocclusion. CONCLUSIONS: Families of adolescents with malocclusion were more likely to report a worse OHRQoL. PMID- 25701281 TI - Nanoparticle technology for treatment of Parkinson's disease: the role of surface phenomena in reaching the brain. AB - The absence of a definitive treatment for Parkinson's disease has driven the emerging investigation in the search for novel therapeutic alternatives. At present, the formulation of different drugs on nanoparticles has represented several advantages over conventional treatments. This type of multifunctional carrier, owing to its size and composition, has different interactions in biological systems that can lead to a decrease in ability to cross the blood brain barrier. Therefore, this review focuses on the latest advances in obtaining nanoparticles for Parkinson's disease and provides an overview of technical aspects in the design of brain drug delivery of nanoparticles and an analysis of surface phenomena, a key aspect in the development of functional nanoparticles for Parkinson's disease. PMID- 25701282 TI - Biopharma CRO industry in China: landscape and opportunities. AB - The pharmaceutical industry has responded to the declining research and development (R&D) productivity over the past decade by decreasing its cost base and outsourcing parts of drug research, with China increasingly being the preferred destination for such outsourced work. For this Focus article, we collected and analyzed data for 66 China-based nonclinical contract research organizations (CROs); approximately 60% of the companies were localized in the Yangtze River Delta cluster and another 20% within the Beijing cluster. Almost 25% of the companies offered services in discovery biology, the single largest service offering in the data set, with another 20% offering preclinical research (toxicology, pharmacology, and animal models) and approximately 15% offering pharmaceutical development. The biologics and pharmaceutical development services represent key future growth areas, with CROs showing an increasing appetite for risk-sharing partnerships. PMID- 25701283 TI - An analysis of FDA-approved drugs for inflammation and autoimmune diseases. AB - The term 'inflammation' captures a variety of disease processes linked with the immune system. An analysis of US Food and Drug Administration (FDA)-approved nuclear molecular entities (NMEs) reveals notable trends in terms of acute and chronic inflammatory indications. The number of NMEs peaked during the 1990s and has since declined by more than 50%. Whereas pharmaceutical companies have dominated the field, biotechnology companies now receive half of new approvals and academia has a relatively large role in terms of pivotal first patents. Another notable trend is that the relative number of NMEs targeting allergy has been decreasing, whereas those targeting autoimmune indications is increasing. Unlike other indications, NMEs for inflammation tend towards nuclear receptors and cytokines, and a disproportionate number of biologics target cytokine pathways. PMID- 25701284 TI - Tetrasomic recombination is surprisingly frequent in allotetraploid Arachis. AB - Arachis hypogaea L. (cultivated peanut) is an allotetraploid (2n = 4x = 40) with an AABB genome type. Based on cytogenetic studies it has been assumed that peanut and wild-derived induced AABB allotetraploids have classic allotetraploid genetic behavior with diploid-like disomic recombination only between homologous chromosomes, at the exclusion of recombination between homeologous chromosomes. Using this assumption, numerous linkage map and quantitative trait loci studies have been carried out. Here, with a systematic analysis of genotyping and gene expression data, we show that this assumption is not entirely valid. In fact, autotetraploid-like tetrasomic recombination is surprisingly frequent in recombinant inbred lines generated from a cross of cultivated peanut and an induced allotetraploid derived from peanut's most probable ancestral species. We suggest that a better, more predictive genetic model for peanut is that of a "segmental allotetraploid" with partly disomic, partly tetrasomic genetic behavior. This intermediate genetic behavior has probably had a previously overseen, but significant, impact on the genome and genetics of cultivated peanut. PMID- 25701285 TI - Beyond asexual development: modifications in the gene expression profile caused by the absence of the Aspergillus nidulans transcription factor FlbB. AB - In the model fungus Aspergillus nidulans, asexual development is induced from vegetative hyphae by a set of early regulators including the bZIP-type transcription factor FlbB. To determine the range of genes under the influence of the transcriptional activity of FlbB and to characterize their role in fungal development, we sequenced and compared the transcriptomes of a DeltaflbB mutant and its isogenic wild-type strain at different developmental stages. Results confirmed the activating role of FlbB on downstream regulators of conidiation such as flbD and brlA. However, FlbB has additional functions beyond the induction of asexual development. Among the changes observed, absence of a functional FlbB caused induction of the dba cluster and synthesis of a secondary metabolite with bactericidal properties. In addition, a new transcriptional target of FlbB was unveiled, urdA, that codes for a putative transcription factor that represses premature sexual development. Taken together, our results indicate that the activators of asexual development simultaneously exert a role on other cellular functions, including an inhibitory effect on the sexual cycle, and reinforce the hypothesis that mutually exclusive metabolic and cellular patterns are associated with different morphogenetic programs. PMID- 25701286 TI - A novel approach for identifying causal models of complex diseases from family data. AB - Causal models including genetic factors are important for understanding the presentation mechanisms of complex diseases. Familial aggregation and segregation analyses based on polygenic threshold models have been the primary approach to fitting genetic models to the family data of complex diseases. In the current study, an advanced approach to obtaining appropriate causal models for complex diseases based on the sufficient component cause (SCC) model involving combinations of traditional genetics principles was proposed. The probabilities for the entire population, i.e., normal-normal, normal-disease, and disease disease, were considered for each model for the appropriate handling of common complex diseases. The causal model in the current study included the genetic effects from single genes involving epistasis, complementary gene interactions, gene-environment interactions, and environmental effects. Bayesian inference using a Markov chain Monte Carlo algorithm (MCMC) was used to assess of the proportions of each component for a given population lifetime incidence. This approach is flexible, allowing both common and rare variants within a gene and across multiple genes. An application to schizophrenia data confirmed the complexity of the causal factors. An analysis of diabetes data demonstrated that environmental factors and gene-environment interactions are the main causal factors for type II diabetes. The proposed method is effective and useful for identifying causal models, which can accelerate the development of efficient strategies for identifying causal factors of complex diseases. PMID- 25701287 TI - Chromatin remodeling factors Isw2 and Ino80 regulate checkpoint activity and chromatin structure in S phase. AB - When cells undergo replication stress, proper checkpoint activation and deactivation are critical for genomic stability and cell survival and therefore must be highly regulated. Although mechanisms of checkpoint activation are well studied, mechanisms of checkpoint deactivation are far less understood. Previously, we reported that chromatin remodeling factors Isw2 and Ino80 attenuate the S-phase checkpoint activity in Saccharomyces cerevisiae, especially during recovery from hydroxyurea. In this study, we found that Isw2 and Ino80 have a more pronounced role in attenuating checkpoint activity during late S phase in the presence of methyl methanesulfonate (MMS). We therefore screened for checkpoint factors required for Isw2 and Ino80 checkpoint attenuation in the presence of MMS. Here we demonstrate that Isw2 and Ino80 antagonize checkpoint activators and attenuate checkpoint activity in S phase in MMS either through a currently unknown pathway or through RPA. Unexpectedly, we found that Isw2 and Ino80 increase chromatin accessibility around replicating regions in the presence of MMS through a novel mechanism. Furthermore, through growth assays, we provide additional evidence that Isw2 and Ino80 partially counteract checkpoint activators specifically in the presence of MMS. Based on these results, we propose that Isw2 and Ino80 attenuate S-phase checkpoint activity through a novel mechanism. PMID- 25701288 TI - The NuA4 complex promotes translesion synthesis (TLS)-mediated DNA damage tolerance. AB - Lesions in DNA can block replication fork progression, leading to its collapse and gross chromosomal rearrangements. To circumvent such outcomes, the DNA damage tolerance (DDT) pathway becomes engaged, allowing the replisome to bypass a lesion and complete S phase. Chromatin remodeling complexes have been implicated in the DDT pathways, and here we identify the NuA4 remodeler, which is a histone acetyltransferase, to function on the translesion synthesis (TLS) branch of DDT. Genetic analyses in Saccharomyces cerevisiae showed synergistic sensitivity to MMS when NuA4 alleles, esa1-L254P and yng2Delta, were combined with the error free bypass mutant ubc13Delta. The loss of viability was less pronounced when NuA4 complex mutants were disrupted in combination with error-prone/TLS factors, such as rev3Delta, suggesting an epistatic relationship between NuA4 and error prone bypass. Consistent with cellular viability measurements, replication profiles after exposure to MMS indicated that small regions of unreplicated DNA or damage were present to a greater extent in esa1-L254P/ubc13Delta mutants, which persist beyond the completion of bulk replication compared to esa1 L254P/rev3Delta. The critical role of NuA4 in error-prone bypass is functional even after the bulk of replication is complete. Underscoring this observation, when Yng2 expression is restricted specifically to G2/M of the cell cycle, viability and TLS-dependent mutagenesis rates were restored. Lastly, disruption of HTZ1, which is a target of NuA4, also resulted in mutagenic rates of reversion on level with esa1-L254P and yng2Delta mutants, indicating that the histone variant H2A.Z functions in vivo on the TLS branch of DDT. PMID- 25701289 TI - Open the VALTTM: Creation and application of a visually authentic learning tool. AB - This paper describes the process of creating and applying a Visually Authentic Learning Tool (VALTTM) in an undergraduate midwifery program. The VALT was developed to facilitate learning in the topic "bleeding in pregnancy". The VALTs objective is to open the mind of the student to facilitate learning via the visual representation of authentic real life simulations designed to enhance and bring to life the written scenario. Students were asked for their feedback of the VALTs. A descriptive analysis was performed on the collated results to determine how the students rated the VALTS in terms of satisfaction and meeting their learning needs. Overall the students seemed to value the VALTs as they present an engaging and unique opportunity to promote learning whilst acknowledging and valuing different learning style within the student group. PMID- 25701290 TI - Midwifery students first encounter with the maternity ward. AB - Considerable research has been made in order to find what promotes students' learning in general, but few studies have included midwifery students and their learning in clinical practice. The purpose of this study was to get a better understanding of the midwifery students' first encounter with the maternity ward and of what was essential to them in the learning environment. A qualitative study, based on in-depth interviews with six students during their first clinical practice at a maternity ward, was conducted. The findings show that the students needed to feel their presence desired and to be included in the activities in the ward. Learning needed to be based on the students' expectations, understanding and previous experiences. The most important factor influencing the students' well-being and learning was their relationships with their mentor. In conclusion, learning in a clinical setting required more than just motivated students. Engaged mentors, who linked the students' previous experiences and expectations to the clinical practice, were crucial to learning outcomes. Mutual engagement, shared understanding and common goals were imperative for the students' experiences of a good learning environment. PMID- 25701291 TI - Strengthening partnerships: The involvement of health care providers in the evaluation of authentic assessment within midwifery undergraduate education. AB - Collaborative partnerships between health care providers and academics are essential in the provision of quality undergraduate midwifery programs. While health care providers often contribute to clinical assessment and teaching in midwifery programs, they are rarely involved in assessment design and evaluation. This paper describes the evaluation of an assessment task designed to develop critical thinking skills in final year undergraduate midwifery students. Health care providers' involvement sought to confirm the authenticity and validity of the assessment task and facilitate further engagement. A mixed method descriptive study design was used. After reviewing a sample of student work, health care providers completed a 20 item survey and participated in a focus group. Survey items were based on the domains of Educational Acceptability, Educational Impact and Preparation for Practice. Participants gave high scores for each domain and commented positively on the innovative nature of the assessment, students' ability to undertake in-depth analysis of complex cases, and development of student's critical thinking skills. Participants also reported greater confidence in students' competence and the program. Involving health care providers in evaluation of an assessment task validated the assessment, contributed to clinicians' perceptions of student credibility, and fostered strong links between the program and industry. PMID- 25701292 TI - Management of neonatal morbidities during hypothermia treatment. AB - Although the primary goal of therapeutic hypothermia is to improve the neurodevelopmental outcome in asphyxiated infants, optimal management of the full range of multi-organ system complications typically presented by such infants during cooling treatment is necessary for improvement of the overall outcome. For this reason, adequate knowledge of how cooling affects all organ systems of asphyxiated infants with multi-organ hypoxic-ischemic injury is essential. Adequate diagnostic resources, readily available subspecialty consultant services and trained multidisciplinary staff to monitor and manage multi-organ system complications in asphyxiated infants during therapeutic cooling must be ensured during implementation of a cooling program. As therapeutic hypothermia is being used more widely, centers should consider participation in national or international benchmarking of outcomes and short-term adverse events during cooling to facilitate continuous quality improvement efforts. PMID- 25701293 TI - The safety and quality agenda could smother genuine innovation. PMID- 25701294 TI - Spousal caregivers and persons with dementia: Increasing participation in shared leisure activities among hospital-based dementia support program participants. AB - Spousal caregivers of persons with dementia often have difficulty engaging persons with dementia in leisure activities. This qualitative descriptive study identifies how caregivers perceive their spouses' participation in leisure activities since dementia onset and the professional guidance caregivers require to increase persons with dementia participation in shared leisure activities. Nine spousal caregivers from a hospital-based caregiver intervention attended one of three focus groups. Using symbolic interactionism and selective optimization with compensation theory as guiding frameworks, thematic content analysis was performed. Three major themes were identified: Recognizing and acknowledging changes, Making sense of changes and conflicts, and Embracing changes and forging ahead. Findings can be used by healthcare providers to better understand caregivers' needs for engaging persons with dementia in shared leisure activities, and inform development of feedback protocols to enhance caregiver interventions. PMID- 25701295 TI - Color-Coded Prefilled Medication Syringes Decrease Time to Delivery and Dosing Error in Simulated Emergency Department Pediatric Resuscitations. AB - STUDY OBJECTIVE: The Institute of Medicine has called on the US health care system to identify and reduce medical errors. Unfortunately, medication dosing errors remain commonplace and may result in potentially life-threatening outcomes, particularly for pediatric patients when dosing requires weight-based calculations. Novel medication delivery systems that may reduce dosing errors resonate with national health care priorities. Our goal was to evaluate novel, prefilled medication syringes labeled with color-coded volumes corresponding to the weight-based dosing of the Broselow Tape, compared with conventional medication administration, in simulated pediatric emergency department (ED) resuscitation scenarios. METHODS: We performed a prospective, block-randomized, crossover study in which 10 emergency physician and nurse teams managed 2 simulated pediatric arrest scenarios in situ, using either prefilled, color-coded syringes (intervention) or conventional drug administration methods (control). The ED resuscitation room and the intravenous medication port were video recorded during the simulations. Data were extracted from video review by blinded, independent reviewers. RESULTS: Median time to delivery of all doses for the conventional and color-coded delivery groups was 47 seconds (95% confidence interval [CI] 40 to 53 seconds) and 19 seconds (95% CI 18 to 20 seconds), respectively (difference=27 seconds; 95% CI 21 to 33 seconds). With the conventional method, 118 doses were administered, with 20 critical dosing errors (17%); with the color-coded method, 123 doses were administered, with 0 critical dosing errors (difference=17%; 95% CI 4% to 30%). CONCLUSION: A novel color coded, prefilled syringe decreased time to medication administration and significantly reduced critical dosing errors by emergency physician and nurse teams during simulated pediatric ED resuscitations. PMID- 25701296 TI - Managing atrial fibrillation. PMID- 25701297 TI - Organs at risk in the brain and their dose-constraints in adults and in children: a radiation oncologist's guide for delineation in everyday practice. AB - PURPOSE: Accurate organs at risk definition is essential for radiation treatment of brain tumors. The aim of this study is to provide a stepwise and simplified contouring guide to delineate the OARs in the brain as it would be done in the everyday practice of planning radiotherapy for brain cancer treatment. METHODS: Anatomical descriptions and neuroimaging atlases of the brain were studied. The dosimetric constraints used in literature were reviewed. RESULTS: A Computed Tomography and Magnetic Resonance Imaging based detailed atlas was developed jointly by radiation oncologists, a neuroradiologist and a neurosurgeon. For each organ brief anatomical notion, main radiological reference points and useful considerations are provided. Recommended dose-constraints both for adult and pediatric patients were also provided. CONCLUSIONS: This report provides guidelines for OARs delineation and their dose-constraints for the treatment planning of patients with brain tumors. PMID- 25701298 TI - First results of the preoperative accelerated partial breast irradiation (PAPBI) trial. AB - BACKGROUND AND PURPOSE: The aim of this study is to assess the toxicity and cosmetic outcome of preoperative accelerated partial breast irradiation (PAPBI) for breast cancer patients with low risk on local recurrence. MATERIAL AND METHODS: Women aged ?60years with an invasive, unifocal ?3cm on MRI, (non lobular) adenocarcinoma of the breast and a negative sentinel node received PAPBI (40Gray in 10 fractions over 2 weeks). Six weeks after radiotherapy a wide local excision was performed. RESULTS: 70 patients with a median follow-up of 23 months (3-44 months) were evaluated. The overall postoperative infection rate was 11%. At 1, 2 and 3 years of follow-up respectively 89%, 98% and 100% of patients had no or mild induration-fibrosis. Fibrosis was only found in a small volume of the breast. The global cosmetic outcome was good to excellent in 77% at 6 months to 100% at 3 years. Two patients developed a local recurrence. CONCLUSION: Our first results show limited fibrosis in a small volume and good to excellent cosmetic outcome. In selected patients, preoperative radiotherapy appears to be a good option for breast conserving therapy. PMID- 25701299 TI - Primary hepatic lymphoma: features of a puzzling disease. PMID- 25701301 TI - Approach to the patient: contraception in women with polycystic ovary syndrome. AB - Polycystic ovary syndrome (PCOS) is a common reproductive and metabolic disorder. Patients with PCOS present with clinical signs of androgen excess (ie, hirsutism and acne), menstrual irregularities, and infertility. Combined oral contraceptive (OC) pills are the first-line medical therapy for the long-term management of PCOS. Containing a combination of estrogen and progestin, OCs restore regular menses, improve androgen excess, and provide effective contraception and protection from endometrial cancer. The benefits of hormonal contraception outweigh the risks in the vast majority of women with PCOS. However, concerns have been raised about potential adverse cardiovascular and metabolic effects of OCs. Currently available evidence indicates an increased relative risk of venous thrombosis associated with OCs varying among different formulations. Arterial thrombosis risk attributable to OCs does not appear to be significantly increased in young nonsmoking women. OC use might be associated with increased risk of diabetes in morbidly obese women with PCOS with severe insulin resistance. A tailored clinical approach to oral contraception in women with PCOS requires individualized risk stratification and management by determination of each PCOS patient's personal cardiometabolic risk profile at baseline and during follow-up. Before prescribing an OC, clinicians should document individual risk factors including age, smoking, obesity, any degree of glucose intolerance including prediabetes and diabetes, hypertension, dyslipidemia, thrombophilia, and personal or family history of a venous thromboembolic event. PMID- 25701302 TI - Withdrawn by author. PMID- 25701305 TI - Risk factors influencing BRONJ staging in patients receiving intravenous bisphosphonates: a multivariate analysis. AB - The objective of this study was to determine, retrospectively, the influence of various risk factors on the staging of bisphosphonate-related osteonecrosis of the jaw (BRONJ) in a population attending a department of dentistry and oral surgery in Italy. Data were collected from the electronic and paper medical records of 90 patients receiving intravenous bisphosphonates. Two experienced and calibrated examiners used the American Association of Oral and Maxillofacial Surgeons updated 2009 classification to record the stage of BRONJ lesions. Multivariate ordinal logistic regression was performed to determine individual risk factors negatively affecting BRONJ staging. The factors associated with a worse BRONJ staging were high bisphosphonate cumulative dose (odds ratio (OR) 1.70, 95% confidence interval (CI) 1.02-2.82; P=0.04), smoking (OR 1.80, 95% CI 1.03-2.80; P=0.04), steroid intake (OR 1.70, 95% CI 1.00-2.87; P=0.05), and a maxillary location of the lesion (OR 3.50, 95% CI 1.81-6.77; P<0.01). Tooth extraction was the event that most negatively influenced BRONJ staging (OR 1.60, 95% CI 1.00-2.81; P=0.05), in comparison to other events such as prosthetic trauma, implant treatment, oro-dental infection, and periodontal disease. Certain clinical and medical risk factors may determine a more severe staging of BRONJ lesions. Future studies are necessary to confirm these findings. PMID- 25701306 TI - Open versus arthroscopic surgery for the management of internal derangement of the temporomandibular joint: a meta-analysis of the literature. AB - The objective of this study was to assess the clinical outcomes of the following three surgical methods for the management of internal derangement (ID) of the temporomandibular joint (TMJ): arthroscopic lysis and lavage (ALL), arthroscopic surgery (AS), and open surgery (OS). A systematic and electronic search of several databases with specific key words was performed from their inception through November 2014. Clinical human studies, including randomized controlled trials (RCTs), controlled clinical trials (CCTs), and retrospective studies, with the aim of comparing the three surgical methods for the management of ID of the TMJ were included. Seven publications were identified: three RCTs, two CCTs, and two retrospective studies. A significant difference was found between OS and AS in pain reduction (P=0.05), but no significant difference with regard to maximal inter-incisal opening (MIO>35mm), mandibular function impairment, and clinical findings (clicking, joint tenderness, and crepitation) (P=0.52, P=0.34, and P=0.19, respectively). The results of the meta-analysis showed that the use of OS is superior to AS in pain reduction, with comparable MIO, jaw function, and clinical findings. In addition, the results of the present study showed that ALL provides greater improvement in MIO and comparable pain reduction when compared to AS. PMID- 25701307 TI - Pharmacokinetics, efficacy, and safety of caspofungin in Japanese pediatric patients with invasive candidiasis and invasive aspergillosis. AB - The antifungal agents approved in Japan for pediatric use are limited and many unapproved drugs are actually used without clear instruction for dosage. We investigated the pharmacokinetics of caspofungin for the treatment of invasive candidiasis and invasive aspergillosis in 20 Japanese pediatric patients using a pediatric-specific dosage based on body surface area. Caspofungin was administered intravenously over 60 min as 70 mg/m(2) on Day 1, followed by 50 mg/m(2) per day. Five or 4 point blood sampling were done in 15 patients on Day 4 5 to calculate AUC0-24 h. The geometric means (95% confidence interval) of C24 h and AUC0-24 h in the pediatric patients were 3.3(2.5, 4.4) MUg/mL and 175.1 (139.3, 220.1) MUg hr/mL, respectively, which were comparable to those in Japanese adult patients [3.2 (2.8, 3.5) MUg/mL and 144.9 (131.7, 159.3) MUg hr/mL, respectively]. Among the 20 patients, 10 (50%) had at least 1 drug-related adverse event which was considered related to caspofungin therapy. No drug related serious adverse event and no death occurred. The most common drug-related adverse events were events relating to hepatic function (mainly increases in ALT and AST). The overall success in efficacy was observed in 13 of 20 patients. In conclusion, once daily administration of caspofungin (70 mg/m(2) on Day 1, followed by 50 mg/m(2) [maximum daily dose not to exceed 70 mg]), which is the same dosage being used in overseas, achieved sufficient drug exposure and a favorable efficacy and acceptable safety profile in Japanese pediatric patients with invasive fungal infections. PMID- 25701308 TI - Clinical and microbiological characteristics of spontaneous acute prostatitis and transrectal prostate biopsy-related acute prostatitis: Is transrectal prostate biopsy-related acute prostatitis a distinct acute prostatitis category? AB - PURPOSE: This study aimed to compare the clinical and microbiological characteristics between acute bacterial prostatitis and transrectal biopsy related acute prostatitis. MATERIALS AND METHODS: We retrospectively reviewed the records of 135 patients hospitalized for acute prostatitis in three urological centers between 2004 and 2013. Acute bacterial prostatitis was diagnosed according to typical symptoms, findings of physical examination, and laboratory test results. Clinical variables, laboratory test results, and anti-microbial susceptibility results were reviewed. Patients were classified into the spontaneous acute prostatitis group (S-ABP) or biopsy-related acute prostatitis (Bx-ABP) for comparison of their clinical, laboratory, and microbiological findings. RESULTS: The mean age of all patients was 61.7 +/- 12.9 years. Compared with S-ABP patients, Bx-ABP patients were significantly older, had larger prostate volumes, higher PSA values, higher peak fever temperatures, and higher incidence of septicemia and antibiotic-resistant bacteria. Overall, of the 135 patients, 57.8% had positive bacterial urine and/or blood cultures. Bx-ABP patients had a higher incidence of bacterial (urine and/or blood) positive cultures compared to S-ABP patients (66.7% versus 55.6%). Escherichia coli was the predominant organism in both groups, but it was more common in Bx-ABP (88.9%) than in S-ABP (66.7%). Extended spectrum beta-lactamase -producing bacteria accounted for 64.7% of culture-positive patients in the Bx-ABP group compared to 13.3% in the S-ABP group. CONCLUSIONS: Bx-ABP patients showed a higher incidence of septicemia and antibiotic-resistant bacteria than S-ABP patients. These results have important implications for the management and antimicrobial treatment of Bx-ABP, which may well deserve to be considered a distinct prostatitis category. PMID- 25701309 TI - Asialoglycoprotein receptor mediated hepatocyte targeting - strategies and applications. AB - Hepatocyte resident afflictions continue to affect the human population unabated. The asialoglycoprotein receptor (ASGPR) is primarily expressed on hepatocytes and minimally on extra-hepatic cells. This makes it specifically attractive for receptor-mediated drug delivery with minimum concerns of toxicity. ASGPR facilitates internalization by clathrin-mediated endocytosis and exhibits high affinity for carbohydrates specifically galactose, N-acetylgalactosamine and glucose. Isomeric forms of sugar, galactose density and branching, spatial geometry and galactose linkages are key factors influencing ligand-receptor binding. Popular ligands for ASGPR mediated targeting are carbohydrate polymers, arabinogalactan and pullulan. Other ligands include galactose-bearing glycoproteins, glycopeptides and galactose modified polymers and lipids. Drug ligand conjugates provide a viable strategy; nevertheless ligand-anchored nanocarriers provide an attractive option for ASGPR targeted delivery and are widely explored. The present review details various ligands and nanocarriers exploited for ASGPR mediated delivery of drugs to hepatocytes. Nanocarrier properties affecting ASGPR mediated uptake are discussed at length. The review also highlights the clinical relevance of ASGPR mediated targeting and applications in diagnostics. ASGPR mediated hepatocyte targeting provides great promise for improved therapy of hepatic afflictions. PMID- 25701310 TI - Photoacoustic-based nanomedicine for cancer diagnosis and therapy. AB - Photoacoustic imaging is the latest promising diagnostic modality that has various advantages such as high spatial resolution, deep penetration depth, and use of non-ionizing radiation. It also employs a non-invasive imaging technique and optically functionalized imaging. The goal of this study was to develop a nanomedicine for simultaneous cancer therapy and diagnosis based on photoacoustic imaging. Human serum albumin nanoparticles loaded with melanin and paclitaxel (HMP-NPs) were developed using the desolvation technique. The photoacoustic-based diagnostic and chemotherapeutic properties of HMP-NPs were evaluated through in vitro and in vivo experiments. The size and zeta potential of the HMP-NPs were found to be 192.8+/-21.11nm and -22.2+/-4.39mV, respectively. In in vitro experiments, HMP-NPs produced increased photoacoustic signal intensity because of the loaded melanin and decreased cellular viability because of the encapsulated paclitaxel, compared to the free human serum albumin nanoparticles (the control). In vivo experiments showed that the HMP-NPs efficiently accumulated inside the tumor, resulting in the enhanced photoacoustic signal intensity in the tumor site, compared to the normal tissues. The in vivo chemotherapy study demonstrated that HMP-NPs had the capability to treat cancer for an extended period. In conclusion, HMP-NPs were simultaneously capable of photoacoustic diagnostic and chemotherapy against cancer. PMID- 25701311 TI - Impact of deoxynivalenol (DON) contaminated feed on intestinal integrity and immune response in swine. AB - This study was performed to characterize the influence of consuming DON naturally contaminated feeds on pig's intestinal immune defenses, antibody response and cellular immunity. Sixteen 4-week-old piglets were randomly allocated to two dietary treatments: control diet or diet contaminated with 3.5 mg DON/kg. At days 7 and 21, animals were immunized with ovalbumin (OVA). On day 42, intestinal samples were collected for measurement of gene expression involved in immune response, oxidative status and barrier function. Primary IgG antibody response to OVA was increased in pigs fed DON diet compared to control animals. In the ileum of pigs fed DON diet, claudin, occludin, and vimentin genes involved in integrity and barrier function were down-regulated compared to controls. Results also revealed that expression of two chemokines (IL-8, CXCL10), interferon-gamma, and major antioxidant glutathione peroxidase 2 (GPX-2) were up-regulated whereas expression of genes encoding enzymatic antioxidants including GPX-3, GPX-4 and superoxide dismutase 3 (SOD-3) were down-regulated in pigs fed DON-contaminated diet. These results strongly suggest that ingestion of DON naturally contaminated feed impaired intestinal barrier and immunological functions by modulating expression of genes coding for proteins involved in tight junctions, tissue remodelling, inflammatory reaction, oxidative stress reaction and immune response. PMID- 25701312 TI - Involvement of organic cation transporters in the clearance and milk secretion of thiamine in mice. AB - PURPOSE: To investigate the role of organic cation transporters (Octs) and multidrug and toxin extrusion protein 1 (Mate1) in the disposition of thiamine. METHODS: The uptake of [(3)H]thiamine was determined in Oct1-, Oct2-, and Oct3 expressing HEK293 cells and freshly isolated hepatocytes. A pharmacokinetic study of thiamine-d3 following intravenous infusion (1 and 100 nmol/min/kg) was conducted in male Oct1/2(+/+) and Oct1/2(-/-) mice. A MATE inhibitor, pyrimethamine, (5 mg/kg) was administered intravenously. The plasma and breast milk concentrations of thiamine were determined in female mice. RESULTS: Thiamine is a substrate of Oct1 and Oct2, but not Oct3. Oct1/2 defect caused a significant reduction in the uptake of [(3)H]thiamine by hepatocytes in vitro, and elevated the plasma thiamine concentration by 5.8-fold in vivo. The plasma clearance of thiamine-d3 was significantly decreased in Oct1/2(-/-) mice. At the higher infusion rate of 100 nmol/min/kg thiamine-d3, Oct1/2 defect or pyrimethamine treatment caused a significant reduction in the renal clearance of thiamine-d3. The total thiamine and thiamine-d3 concentrations were moderately reduced in the intestine of Oct1/2(-/-) mice but were unchanged in the kidney, liver, or brain. The milk-to-plasma concentration ratio of thiamine was decreased by 28-fold in the Oct1/2(-/-) mice. CONCLUSIONS: Oct1 is possibly responsible for the plasma clearance of thiamine via tissue uptake and for milk secretion. Oct1/2 and Mate1 are involved in the renal tubular secretion of thiamine. PMID- 25701313 TI - PTD-Modified ATTEMPTS for Enhanced Toxin-based Cancer Therapy: An In Vivo Proof of-Concept Study. AB - PURPOSE: To investigate the feasibility of applying PTD-modified ATTEMPTS (Antibody Targeted Triggered Electrically Modified Prodrug-Type Strategy) for enhanced toxin therapy for the treatment of cancer. METHODS: A heparin functionalized murine anti-CEA monoclonal antibody (mAb), T84.66-heparin (T84.66 Hep), was chemically synthesized and characterized for specific binding to CEA overexpressed cells. The T84.66-Hep was then applied to the PTD-modified ATTEMPTS approach and the crucial features of the drug delivery system (DDS), 'antibody targeting' and 'heparin/protamine-based prodrug', were evaluated in vitro to examine whether it could selective delivery a PTD-modified toxin, recombinant TAT gelonin chimera (TAT-Gel), to CEA high expression cancer cells (LS174T). Furthermore, the feasibility of the drug delivery system (DDS) was assessed in vivo by biodistribution and efficacy studies using LS174T s.c. xenograft tumor bearing mice. RESULTS: T84.66-Hep displayed specific binding, but limited internalization (35% after 48 h incubation) to CEA high expression LS174T cells over low expression HCT116 cells. When mixed together with TAT-Gel, the T84.66 Hep formed a strong yet reversible complex. This complex formation provided an effective means of active tumor targeting of TAT-Gel, by 1) directing the TAT-Gel to CEA overexpressed tumor cells and 2) preventing nonspecific cell transduction to non-targeted normal cells. The cell transduction of TAT-Gel could, however, be efficiently reversed by addition of protamine. Feasibility of in vivo tumor targeting and "protamine-induced release" of TAT-Gel from the T84.66-Hep counterpart was confirmed by biodistribution and preliminary efficacy studies. CONCLUSIONS: This study successfully demonstrated in vitro and in vivo the applicability of PTD-modified ATTEMPTS for toxin-based cancer therapy. PMID- 25701314 TI - Immunogenicity and safety of 3-dose primary vaccination with combined DTPa-HBV IPV/Hib vaccine in Canadian Aboriginal and non-Aboriginal infants. AB - This study compared immune responses of healthy Aboriginal and non-Aboriginal infants to Haemophilus influenzae type b (Hib) and hepatitis B virus (HBV) components of a DTaP-HBV-IPV/Hib combination vaccine, 1 month after completing dosing at 2, 4 and 6 months of age. Of 112 infants enrolled in each group, 94 Aboriginal and 107 non-Aboriginal infants qualified for the immunogenicity analysis. Anti-PRP concentrations exceeded the protective minimum (>=0.15 MUg/ml) in >=97% of infants in both groups but geometric mean concentrations (GMCs) were higher in Aboriginal infants (6.12 MUg/ml versus 3.51 MUg/ml). All subjects were seroprotected (anti-HBs >=10 mIU/mL) against HBV, with groups having similar GMCs (1797.9 versus 1544.4 mIU/mL, Aboriginal versus non-Aboriginal, respectively). No safety concerns were identified. We conclude that 3-dose primary vaccination with DTaP-HBV-IPV/Hib combination vaccine elicited immune responses to Hib and HBV components that were at least as high in Aboriginal as in non-Aboriginal Canadian infants. Clinical Trial Registration NCT00753649. PMID- 25701315 TI - A novel dengue virus serotype-2 nanovaccine induces robust humoral and cell mediated immunity in mice. AB - Dengue virus (DENV), a member of the Flaviviridae family, can be transmitted to humans through the bite of infected Aedes mosquitoes. The incidence of dengue has increased worldwide over the past few decades. Inadequate vector control, changing global ecology, increased urbanization, and faster global travel are factors enhancing the rapid spread of the virus and its vector. In the absence of specific antiviral treatments, the search for a safe and effective vaccine grows more imperative. Many strategies have been utilized to develop dengue vaccines. Here, we demonstrate the immunogenic properties of a novel dengue nanovaccine (DNV), composed of ultraviolet radiation (UV)-inactivated DENV-2, which has been loaded into the nanoparticles containing chitosan/Mycobacterium bovis Bacillus Calmette-Guerin cell wall components (CS/BCG-NPs). We investigated the immunogenicity of DNV in a Swiss albino mouse model. Inoculation with various concentrations of vaccine (0.3, 1, 3 and 10MUg/dose) with three doses, 15-day apart, induced strong anti-dengue IgM and IgG antibodies in the mouse serum along with neutralizing antibody against DENV-2 reference strain (16681), a clinical isolate strain (00745/10) and the mouse-adapted New Guinea-C (NGC) strain. Cytokine and chemokine secretion in the serum of DNV-immunized mice showed elevated levels of IFN-gamma, IL-2, IL-5, IL-12p40, IL-12p70, IL-17, eotaxin and RANTES, all of which have varying immune functions. Furthermore, we observed a DNV dose-dependent increase in the frequencies of IFN-gamma-producing CD4(+) and CD8(+) T cells after in vitro stimulation of nucleated cells. Based on these findings, DNV has the potential to become a candidate dengue vaccine. PMID- 25701316 TI - Assessing the economic benefits of vaccines based on the health investment life course framework: a review of a broader approach to evaluate malaria vaccination. AB - BACKGROUND: Economic evaluations have routinely understated the net benefits of vaccination by not including the full range of economic benefits that accrue over the lifetime of a vaccinated person. Broader approaches for evaluating benefits of vaccination can be used to more accurately calculate the value of vaccination. METHODOLOGY: This paper reflects on the methodology of one such approach - the health investment life course approach - that looks at the impact of vaccine investment on lifetime returns. The role of this approach on vaccine decision making will be assessed using the malaria health investment life course model example. RESULTS: We describe a framework that measures the impact of a health policy decision on government accounts over many generations. The methodological issues emerging from this approach are illustrated with an example from a recently completed health investment life course analysis of malaria vaccination in Ghana. Beyond the results, various conceptual and practical challenges of applying this framework to Ghana are discussed in this paper. DISCUSSION AND CONCLUSIONS: The current framework seeks to understand how disease and available technologies can impact a range of economic parameters such as labour force participation, education, healthcare consumption, productivity, wages or economic growth, and taxation following their introduction. The framework is unique amongst previous economic models in malaria because it considers future tax revenue for governments. The framework is complementary to cost-effectiveness and budget impact analysis. The intent of this paper is to stimulate discussion on how existing and new methodology can add to knowledge regarding the benefits from investing in new and underutilized vaccines. PMID- 25701317 TI - Protection against Fasciola gigantica infection in mice by vaccination with recombinant juvenile-specific cathepsin L. AB - Fasciola gigantica cathepsin L1H (FgCatL1H) is one of the major cathepsin L released by juveniles of F. gigantica to aid in the invasion of host's tissues. Due to its high sequence similarity with other cathepsin L (CatL) isoforms of late stage F. gigantica, it was considered to be a good vaccine candidate that can block all CatL-mediated protease activities and affect juveniles as well as adult parasites. In this study, recombinant proFgCatL1H protein expressed in yeast, Pichia pastoris, system was mixed with Freund's adjuvants and used to subcutaneously immunize mice that were later challenged with metacercariae of F. gigantica. The percentage of worm protection in the rproFgCatL1H-vaccinated mice compared to the non-immunized and adjuvant control mice were approximately 62.7% and 66.1%, respectively. Anti-rproFgCatL1H antisera collected from vaccinated mice reacted specifically with rproFgCatL1H and other cathepsin L isoforms of F. gigantica, but the antibodies did not cross react with antigens from other trematode and nematode parasites, including Eurytrema pancreaticum, Opisthorchis viverrini, Fischoederius cobboldi, Cotylophoron cotylophorum, Gigantocotyle explanatum, Paramphistomum cervi, and Setaria labiato-papillosa. The levels of IgG1 and IgG2a in mouse sera increased significantly at two weeks after immunization and were highest during the sixth to eighth weeks after immunization. The IgG1 level was higher than IgG2a at all periods of immunization, implicating the dominance of the Th2 response. The levels of IgG1 and IgG2a in the immune sera were shown to be strongly correlated with the numbers of worm recovery, and the correlation coefficient was higher for IgG1. The levels of serum aspartate aminotransferase and alanine transaminase were significantly lower in the sera of rproFgCatL1H-vaccinated mice than in the infected control mice indicating a lower degree of liver damage. This study demonstrated a high potential of FgCatL1H vaccine, and its efficacy is currently being studied in the larger economic animals. PMID- 25701318 TI - Core 2 Mucin-Type O-Glycan Is Related to EPEC and EHEC O157:H7 Adherence to Human Colon Carcinoma HT-29 Epithelial Cells. AB - BACKGROUND AND AIM: The roles of host glycosylation in interactions with EPEC and EHEC O157:H7 are largely unclear; this study examined whether O-glycans are involved in EPEC and EHEC O157:H7 adherence to HT-29 cells. METHODS: Bacterial adherence to the cultured cells was determined using the direct co-staining of adherent bacteria and host cells, the adherent bacteria plating, and/or the direct fluorescent observation of the adherent GFP-labeled bacteria. RESULTS: A comparison of the adherence of EPEC and EHEC O157:H7 to HT-29-Gal and HT-29 cells indicated that the differentiation of HT-29 cells led to a reduction in the adherence of EPEC and EHEC O157:H7. EPEC and EHEC O157:H7 adhesion decreased after the abrogation of O-glycan biosynthesis mediated by benzyl-alpha-GalNAc treatment. Core 2 O-glycan-deficient HT-29 cells induced by C2GnT2 knockdown had a significant reduction in EPEC and EHEC O157:H7 adhesion in C2GnT2-sh2/HT-29 cells compared with HT-29 and shRNA-Ctr/HT-29 cells. MUC2 expression in benzyl alpha-GalNAc-treated HT-29 cells was significantly reduced but unchanged in C2GnT2-deficient HT-29 cells. EPEC or EHEC O157:H7 infection in C2GnT2-deficient HT-29 cells deteriorated the epithelial barrier function. The occludin expression in the shRNA-Ctr/HT-29 and C2GnT2-sh2/HT-29 cells after infection with EPEC or EHEC O157:H7 was pyknic and discontinuous at the cell surface compared with its continuous distribution of control cells. These data indicate that EPEC and EHEC O157:H7 adherence to HT-29 cells is related to mucin-type core 2 O-glycan. CONCLUSIONS: This study provides the concepts toward the design of carbohydrate dependent inhibition of EPEC and EHEC O157:H7 adhesion to human intestinal epithelial cells. PMID- 25701319 TI - Impact of Radiofrequency Ablation on Malignant Biliary Strictures: Results of a Collaborative Registry. AB - BACKGROUND: Radiofrequency ablation of malignant biliary strictures has been offered for the last 3 years, but only limited data have been published. AIM: To assess the safety, efficacy, and survival outcomes of patients receiving endoscopic radiofrequency ablation. METHODS: Between April 2010 and December 2013, 69 patients with unresectable neoplastic lesions and malignant biliary obstruction underwent 98 radiofrequency ablation sessions with stenting. RESULTS: A total of 69 patients (22 male, aged 66.1 +/- 13.3) were included in the registry. The etiology of malignant biliary stricture included unresectable cholangiocarcinoma (n = 45), pancreatic cancer (n = 19), gallbladder cancer (n = 2), gastric cancer (n = 1), and liver metastasis from colon cancer (n = 3). Seventy-eight percentage of patients had prior chemotherapy. All strictures were stented post-radiofrequency ablation with either plastic stents or metal stents. The mean stricture length treated was 14.3 mm. There was a statistically significant improvement in stricture diameter post-ablation (p < 0.0001). The likelihood of stricture improvement was significantly greater in pancreatic cancer-associated strictures [RR 1.8 (95 % 1.03-5.38)]. Seven patients (10 %) had adverse events, not linked directly to radiofrequency ablation. Median survival was 11.46 months (6.2-25 months). CONCLUSION: Radiofrequency ablation is effective and safe in malignant biliary obstruction and seems to be associated with improved survival. PMID- 25701320 TI - Peripheral corticotropin-releasing factor receptor type 2 activation increases colonic blood flow through nitric oxide pathway in rats. AB - BACKGROUND: Corticotropin-releasing factor (CRF) peptides exert profound effects on the secretomotor function of the gastrointestinal tract. Nevertheless, despite the presence of CRF peptides and receptors in colonic tissue, their influence on colonic blood flow (CBF) is unknown. AIM: To determine the effect and mechanism of members of the CRF peptide family on CBF in isoflurane-anesthetized rats. METHODS: Proximal CBF was measured with laser-Doppler flowmetry simultaneously with mean arterial blood pressure (MABP) measurement. Rats were injected with intravenous human/rat CRF (CRF1 > CRF2 affinity), mouse urocortin 2 (mUcn2, selective CRF2 agonist), or sauvagine (SVG, CRF2 > CRF1 affinity) at 1-30 ug/kg. The nitric oxide (NO) synthase inhibitor, L-NAME (3 mg/kg, iv), the cyclooxygenase inhibitor, indomethacin (Indo, 5 mg/kg, ip), or selective CRF2 antagonist, astressin2-B (Ast2B, 50 ug/kg, iv) was given before SVG injection (10 ug/kg, iv). RESULTS: SVG and mUcn2 dose-dependently increased CBF while decreasing MABP and colonic vascular resistance (CVR). CRF had no effect on CBF, but increased CVR. The hyperemic effect of SVG was inhibited by L-NAME but not by Indo, whereas hypotension was partially reduced by L-NAME. Sensory denervation had no effect on SVG-induced changes. Ast2B inhibited SVG-induced hyperemia and decreased CVR, and partially reduced the hypotension. CONCLUSIONS: Peripheral CRF2 activation induces colonic hyperemia through NO synthesis, without involving prostaglandin synthesis or sensory nerve activation, suggesting a direct action on the endothelium and myenteric neurons. Members of the CRF peptide family may protect the colonic mucosa via the activation of the CRF2 receptor. PMID- 25701321 TI - High C-Reactive Protein Is Associated with Poor Sleep Quality Independent of Nocturnal Symptoms in Patients with Inflammatory Bowel Disease. AB - BACKGROUND: Sleep disruption is common in inflammatory bowel diseases (IBD). However, studies demonstrating a similar prevalence in irritable bowel syndrome suggest that nighttime disruption due to diarrhea and abdominal pain may be key drivers of poor sleep quality. Whether inflammation is associated with poor sleep independently has not been examined previously. METHODS: This single-center study included subjects with IBD recruited to an ongoing prospective registry who completed a questionnaire assessing sleep quality and mood. Inflammatory marker levels [C-reactive protein (CRP), erythrocyte sedimentation rate] and clinical disease activity including nighttime disruption on the day of enrollment were obtained from the medical record. Logistic regression models were used to identify predictors of sleep quality. RESULTS: The study included 131 subjects (72 women) with a median age of IBD diagnosis of 25 years. Twenty-three subjects (19 %) had a high C-reactive protein level (>=8 mg/dL). Poor sleep was more common in those with high CRP levels than with normal values (70 vs. 39 %, p = 0.009). This association remained significant on multivariate analysis [Odds ratio (OR) 4.12, 95 % confidence interval (CI) 1.38-12.29]. Adjusting for the presence of nighttime disruption did not significant alter this association (OR 3.16, 95 % CI 1.01-9.90). High CRP correlated with poor sleep even in patients not experiencing nocturnal symptoms (n = 101, OR 4.89, 95 % CI 1.24-19.36). CONCLUSION: High CRP is associated with poor sleep quality in IBD independent of the presence of nighttime disruptions, suggesting that a relationship exists between circulating inflammatory markers and sleep. PMID- 25701322 TI - Detection of Advanced Neoplasia with FIT Versus Flexible Sigmoidoscopy Versus Colonoscopy: More Is More. PMID- 25701323 TI - Oncogenic miR-23a in Pancreatic Ductal Adenocarcinogenesis Via Inhibiting APAF1. AB - BACKGROUND: miR-23a, which participates in invasion of pancreatic ductal adenocarcinoma cells into the mesothelial barrier, is a critical regulator in many cancers. It, however, is still unknown whether miR-23a regulates pancreatic cell proliferation and apoptosis or not. AIMS: We sought to investigate the role of miR-23a in regulation of pancreatic cell proliferation and apoptosis. METHODS: miRNA, mRNA, and protein expressions were determined by qRT-PCR and Western blot, respectively. Dual-luciferase reporter assay was used in detection for binding ability of miR-23a to APAF1. Ectopic miR-23a and APAF 1 were introduced to pancreatic cells, and their roles in proliferation and apoptosis were detected by MTT, colony formation, and apoptosis assays, respectively. RESULTS: Up-regulation of miR-23a and down-regulation of APAF 1 were found in pancreatic ductal cancer, respectively. miR-23a significantly inhibited the luciferase activity by targeting APAF 1 3'UTR. Ectopic miR-23a significantly suppressed the APAF 1 gene expression in pancreatic cancer cells. Similar to siAPAF1, miR-23a significantly promoted pancreatic cancer cell proliferation and repressed apoptosis. Furthermore, miR-23a inhibitor and exogenous APAF 1 could recover the effects. CONCLUSIONS: It is suggested that miR-23a, acting as an oncogenic regulator by directly targeting APAF 1 in pancreatic cancer, is a useful potential biomarker in diagnosis and treatment of pancreatic cancer. PMID- 25701324 TI - Esophagitis Dissecans Superficialis: Clinical, Endoscopic, and Histologic Features. AB - BACKGROUND: Esophagitis dissecans superficialis (EDS) is a desquamative disorder of the esophagus, but there is a paucity of the literature regarding this condition. AIM: We examined our institution's experience to further characterize clinical outcomes, and endoscopic and histopathologic features. METHODS: Endoscopy and pathology databases were retrospectively reviewed from 2000 to 2013 at Mayo Clinic Rochester to identify potential cases of EDS. Medical records and endoscopic images were reviewed to identify cases, and original pathologic specimens were also reviewed. Clinical, endoscopic, and histologic characteristics of EDS were defined. RESULTS: Forty-one subjects were identified with a median age at diagnosis of 65.0 years (IQR 52.8-76.1) and a female preponderance (63.4 %). Many patients were taking a psychoactive agent (73.1 %) or acid-suppressive therapy (58.5 %) preceding the index endoscopy. Strips of sloughed membranes had a predilection for the distal and/or middle esophagus and resolved in 85.7 % of subjects at endoscopic follow-up. Parakeratosis and intraepithelial splitting were histologic features seen in all patients, while splitting of the connective tissue and intraepithelial bullae were seen in 46.2 and 11.1 %, respectively. There were no disease-related complications at a median follow-up of 10.4 months (IQR 1.2-17.2). CONCLUSIONS: EDS is likely under recognized. A distinct endoscopic feature of EDS is "sloughing" strips of mucosa with parakeratosis and intraepithelial splitting being sine qua non histologic findings. The use of psychoactive agents (particularly a SSRI or SNRI) was prevalent at endoscopic diagnosis, although the clinical relevance of this is uncertain. EDS appears to be a benign, incidental finding without complications. PMID- 25701325 TI - PD-1 Restrains Radiotherapy-Induced Abscopal Effect. AB - We investigated the influence of PD-1 expression on the systemic antitumor response (abscopal effect) induced by stereotactic ablative radiotherapy (SABR) in preclinical melanoma and renal cell carcinoma models. We compared the SABR induced antitumor response in PD-1-expressing wild-type (WT) and PD-1-deficient knockout (KO) mice and found that PD-1 expression compromises the survival of tumor-bearing mice treated with SABR. None of the PD-1 WT mice survived beyond 25 days, whereas 20% of the PD-1 KO mice survived beyond 40 days. Similarly, PD-1 blocking antibody in WT mice was able to recapitulate SABR-induced antitumor responses observed in PD-1 KO mice and led to increased survival. The combination of SABR plus PD-1 blockade induced near complete regression of the irradiated primary tumor (synergistic effect), as opposed to SABR alone or SABR plus control antibody. The combination of SABR plus PD-1 blockade therapy elicited a 66% reduction in size of nonirradiated, secondary tumors outside the SABR radiation field (abscopal effect). The observed abscopal effect was tumor specific and was not dependent on tumor histology or host genetic background. The CD11a(high) CD8(+) T-cell phenotype identifies a tumor-reactive population, which was associated in frequency and function with a SABR-induced antitumor immune response in PD-1 KO mice. We conclude that SABR induces an abscopal tumor specific immune response in both the irradiated and nonirradiated tumors, which is potentiated by PD-1 blockade. The combination of SABR and PD-1 blockade has the potential to translate into a potent immunotherapy strategy in the management of patients with metastatic cancer. PMID- 25701326 TI - PD-1+Tim-3+ CD8+ T Lymphocytes Display Varied Degrees of Functional Exhaustion in Patients with Regionally Metastatic Differentiated Thyroid Cancer. AB - Regional metastatic differentiated thyroid cancer (mDTC) provides a unique model in which to study the tumor-immune interface. These lymph node metastases persist for years, generally without progression to distant metastases. Although the immune system likely impedes disease progression, it is unsuccessful in eliminating disease. Our previous studies revealed that programmed death-1 (PD 1)(+) T cells were enriched in tumor-involved lymph nodes (TILN). Tumor associated leukocytes and tumor cells were collected from grossly involved lymph nodes from 12 patients to further characterize the phenotype and functional potential of mDTC-associated PD-1(+) T cells. PD-1(+)CD4(+) and PD-1(+)CD8(+) T cells were enriched in 8 of 12 TILN samples. PD-1(+) T cells coexpressed Tim-3 and CD69 and failed to downregulate CD27. CD8(+) T cells, but not CD4(+) T cells, from these samples were variably deficient in their ability to produce effector cytokines when compared with control TILNs that lacked resident PD-1(+) T cells. PD-1(+)CD8(+) T cells were capable of exocytosis but lacked intracellular perforin. Surprisingly, T-cell proliferative capacity was largely maintained in all samples. Thus, although PD-1 expression by mDTC-associated CD8(+) T cells was associated with dysfunction, exhaustion was not complete. Notably, molecular markers of exhaustion did not translate to dysfunction in all samples or in CD4(+) T cells. Regulatory T cells (Treg), PD-L1, and galectin-9 were commonly found in mDTC and likely contributed to the initiation of T-cell exhaustion and disease progression. Therapies that release the effects of PD-1 and Tim-3 and reduce the suppressive effects of Tregs may encourage tumor elimination in patients with mDTC. PMID- 25701327 TI - PolySia-Specific Retargeting of Oncolytic Viruses Triggers Tumor-Specific Immune Responses and Facilitates Therapy of Disseminated Lung Cancer. AB - Polysialic acid (polySia) is expressed on several malignant tumors of neuroendocrine origin, including small cell lung cancer. In this study, we investigated the therapeutic efficacy of tumor-directed T-cell responses, elicited by polySia-retargeted oncolytic adenovirus infection, in an orthotopic murine model of disseminated polySia-positive lung cancer. In several cell lines, we demonstrated highly polySia-selective retargeting of adenoviral infection using a bispecific adapter comprising the ectodomain of the coxsackievirus/adenovirus receptor and a polySia-recognizing single-chain antibody domain. PolySia-dependent systemic infection in vivo facilitated effective uptake of viruses in subcutaneous polySia-expressing human tumors, whereas hepatic viral load and hepatotoxicity were significantly reduced. The impact and nature of antitumoral immune responses triggered by systemic delivery of polySia-retargeted oncolytic adenoviruses were investigated in an orthotopic model of disseminated lung cancer. Interestingly, improved transduction by polySia-retargeted oncolytic adenoviruses led to CD45-positive cell infiltrates in close association with large lytic areas. Consistently, enhanced tumor regression and prolonged survival was only observed in immunocompetent mice, but not in T-cell-deficient mice. To investigate whether improved systemic infection by polySia retargeting would elicit a tumor-specific T-cell response, we screened the used lung cancer cells for mutated oncogenes by complete exon sequencing. In agreement with our other results, only retargeted oncolysis was able to induce a significant response specific for the tumor-associated neoepitope Gsta2-Y9H. In conclusion, we demonstrated that effective retargeting of oncolytic adenovirus against polySia-expressing tumors elicits an effective tumor-directed T-cell response after systemic virus delivery and facilitates therapy of disseminated lung cancer. PMID- 25701328 TI - Case report and review of immunodeficiency-associated Burkitt lymphoma. PMID- 25701329 TI - Vitamin D supplementation to reduce depression in adults: meta-analysis of randomized controlled trials. AB - OBJECTIVES: The aim of this study was to estimate the weighted mean effect of vitamin D supplementation in reducing depressive symptoms among individuals aged >=18 y diagnosed with depression or depressive symptoms. METHODS: A meta-analysis of randomized controlled trials (RCTs) in which vitamin D supplementation was used to reduce depression or depressive symptoms was conducted. Databases MEDLINE, EMBASE, psych INFO, CINAHL plus, and the Cochrane library were searched from inception to August 2013 for all publications on vitamin D and depression regardless of language. The search was further updated to May 2014 to include newer studies being published. Studies involving individuals aged >=18 y who were diagnosed with depressive disorder based on both the Diagnostic and Statistical Manual of Mental Disorders or other symptom checklist for depression were included. Meta-analysis was performed using random effects model due to differences between the individual RCTs. RESULTS: The analysis included nine trials with a total of 4923 participants. No significant reduction in depression was seen after vitamin D supplementation (standardized mean difference = 0.28; 95% confidence interval, -0.14 to 0.69; P = 0.19); however, most of the studies focused on individuals with low levels of depression and sufficient serum vitamin D at baseline. The studies included used different vitamin D doses with a varying degree of intervention duration. CONCLUSIONS: Future RCTs examining the effect of vitamin D supplementation among individuals who are both depressed and vitamin D deficient are needed. PMID- 25701330 TI - Therapeutic value of oral supplementation with melon superoxide dismutase and wheat gliadin combination. AB - Dietary antioxidant supplementation has been popular in Western countries. Various supplements have been developed in recent years, and research has been gathered from both animal and clinical research trials. In this review, the therapeutic value of oral administration of a combination of melon superoxide dismutase (SOD) and a vegetable polymer (gliadin) is evaluated. Critical examination of the effects of SOD-gliadin supplementation is carried out, with an emphasis on its impact on oxidative stress levels and on endogenous antioxidant pathways. Overall analysis of peer-reviewed published data suggests that intake of SOD-gliadin might have advantageous health effects. These conclusions are dependent on the condition or pathology under consideration. In general, the authors, who analyzed SOD-gliadin supplementation, support the use of SOD-gliadin supplementation as a complementary treatment rather than a therapeutic treatment. To further clarify the importance of dietary SOD-gliadin administration, additional large-scale clinical trials are recommended. PMID- 25701331 TI - The effect of glucomannan on body weight in overweight or obese children and adults: a systematic review of randomized controlled trials. AB - OBJECTIVE: Glucomannan (GM), a soluble fiber derived from the plant Amorphophallus konjac, is marketed as being helpful in reducing body weight. However, the data supporting this claim are scarce. The aim of this review was to systematically evaluate the effects of GM on body weight (BW) and body mass index (BMI) in otherwise healthy obese or overweight children and adults. METHODS: MEDLINE, EMBASE, CENTRAL, and Google Scholar databases were systematically searched up to June 2014 for randomized controlled trials (RCTs) assessing the effectiveness of GM versus placebo. The primary outcome measures were BW and BMI. RESULTS: Six eligible RCTs, only one of which performed in children, were included. In adults, three RCTs reported a significant reduction in BW in the GM group compared with the control group at the following different points during the intervention: At week 2 (mean difference [MD], 0.21 kg; 95% confidence interval [CI], 0.13-0.29); at week 4 (MD, 2.04; 95% CI, 0.52-3.56); at week 5 (MD, 1.3; 95% CI, 0.89-1.71); and at week 8 (MD, 3.17; 95% CI, 1.29-5.05). Only one RCT reported a beneficial effect at more than one point. None of the RCTs reported a favorable effect of GM on BMI. CONCLUSIONS: In otherwise healthy overweight or obese adults, there is some evidence that in the short term GM may help to reduce BW, but not BMI. Data in children are too limited to draw any conclusions. PMID- 25701332 TI - Elevated milk beta-carotene and lycopene after carrot and tomato paste supplementation. AB - OBJECTIVES: To measure concentrations of beta-carotene and lycopene in the breast milk of healthy, well-nourished, lactating women supplemented with fresh carrot or tomato paste. METHODS: Twelve women were given fresh carrot paste and another 14 were given fresh tomato paste once a day for 3 d with a high-lipid-content meal. The women were instructed to avoid any food containing beta-carotene or lycopene, other than the test meal. Milk carotenoid levels were measured before, during, and after the trial. The carrot and tomato meals contained 15 mg of all trans beta-carotene and 15 mg of all-trans lycopene, respectively. RESULTS: We demonstrated a significant increase in milk beta-carotene and elevated milk lycopene levels after the lipid-rich fresh carrot and tomato meals, respectively. CONCLUSIONS: We suggest that breast milk carotenoid levels reflect the mother's level of intake and can thus be raised by simple nutritional intervention. The results of this study may be relevant to breast-feeding mothers of both preterm and term infants by raising antiinflammatory and antioxidant properties in their milk. PMID- 25701333 TI - Effect of an advanced glycation end product-restricted diet and exercise on metabolic parameters in adult overweight men. AB - OBJECTIVES: The aim of this study was to review the effect of a low advanced glycation end product (AGEs) diet, exercise, and a combination of both on circulating AGE levels as well as on plasma lipids and anthropometric parameters. METHODS: Forty-three overweight or obese men (body mass index [BMI] >25 kg/m(2)), 30 to 55 y, participated in a 12-wk study and were randomly assigned to one of three groups: low AGE diet, exercise with habitual food intake, or exercise plus low AGE diet. Exercise was for 45 min at 65% to 75% of their maximum heart rate three times a week. We measured somatometric variables (BMI and waist circumference), blood glucose, lipids, and serum AGEs (N(epsilon) [Carboxymethyl]Lysine [CML] and methylglyoxal [MG]) at baseline and at 12 wk. RESULTS: Exercise alone was associated with decreased somatometric variables; the low AGE diet had the same effects and decreased serum CML and MG and when combined with exercise reproduced all these effects, but also decreased triacylglycerols and increased high-density lipoprotein. Correlation analysis showed that both changes of CML and MG correlated with changes in dietary AGEs (P < 0.020 and P < 0.038, respectively); change in maximum oxygen consumption correlated inversely with change in weight and triacylglycerols. Regression analyses, including change in dietary AGEs and in dietary calories, showed that change in dietary AGEs was the independent determinant of change in CML (P < 0.020) and MG (P < 0.038). CONCLUSIONS: An AGE-restricted diet reduces serum AGE and indices of body fat. The addition of exercise to the restricted diet has the same effects but also improves lipid profile. PMID- 25701334 TI - Prevalence of iron and zinc deficiencies among preschool children ages 3 to 5 y in Vhembe district, Limpopo province, South Africa. AB - OBJECTIVES: Children under the age of 5 y constitute the most vulnerable group for iron and zinc deficiencies and their nutritional status is a sensitive indicator of community health and nutrition. The aim of this study was to determine the prevalence of zinc and iron deficiency among preschool children aged 3 to 5 y in Vhembe district, Limpopo province, South Africa. METHODS: This study included 349 preschool children recruited from two municipalities of Vhembe district, Limpopo province, South Africa. Municipalities were purposively selected and simple random sampling was used to choose children. Body weight and height were measured using standard techniques. Serum zinc, iron, ferritin, transferrin saturation, transferrin and C-reactive protein levels were also assessed, as were hemoglobin levels. RESULTS: The prevalence of wasting, stunting, and underweight was 1.4%, 18.6%, and 0.3%, respectively; whereas 20.9% of the children were overweight and 9.7% were obese. The prevalence of zinc deficiency was 42.6% and anemia was 28%; both were higher in girls than in boys. When using serum ferritin and transferrin saturation 7 (2%) of the children had iron-deficiency anemia. Combined iron and zinc deficiencies using ferritin was found in 8 (2.3%) of the children; when using transferrin saturation these deficiencies were found in 42 (12%) of the children. CONCLUSIONS: Iron and zinc deficiencies as well as anemia, accompanied by high prevalence of stunting; and overweight and obesity, were common in preschool children. The results observed here call for interventions to combat the escalating problem of child malnutrition in the form of nutritional education for mothers and food handlers at preschools to ensure food diversification in these children. PMID- 25701335 TI - Effect of non-soy legume consumption on inflammation and serum adiponectin levels among first-degree relatives of patients with diabetes: a randomized, crossover study. AB - OBJECTIVE: First-degree relatives of patients with diabetes are at more risk for endothelial dysfunction and inflammation. The aim of the present study was to determine the effects of a non-soy legume-enriched diet on inflammatory biomarkers and serum adiponectin levels among first-degree relatives of these patients. METHODS: Twenty-six participants (14 women and 12 men) with a family history of diabetes were recruited to this randomized, crossover study. Participants were randomly assigned to a legume-enriched or a habitual diet for 6 wk that was separated by a 2-wk washout. The inflammatory markers-high sensitivity C-reactive protein (hs-CRP), interleukin-6, tumor necrosis factor alpha, and serum levels of adiponectin-were measured at the beginning and the end of each intervention period according to the standard protocol. RESULTS: Energy intake of participants was not statistically different between the two diets (1821.5 +/- 100.11 versus 1788.2 +/- 92.68 kcal/d, respectively). After consumption of a legume diet, percent change of hs-CRP reduced significantly compared with consumption of a habitual diet (-4.86% +/- 1.86% versus 3.55% +/- 1.97%, P = 0.002) and among the women in the study (-12.96% +/- 1.96% versus 3.24% +/- 2.65%, P = 0.004). The percent change of other inflammatory markers and serum concentrations of adiponectin were not significantly different between the two diet groups. CONCLUSION: The results of this study showed that a legume enriched diet significantly reduced the hs-CRP concentrations in first-degree relatives of patients with diabetes after 6 wk of intervention compared with a habitual diet. PMID- 25701336 TI - Single pyruvate intake induces blood alkalization and modification of resting metabolism in humans. AB - OBJECTIVES: Three separate studies were performed with the aim to 1) determine the effect of a single sodium pyruvate intake on the blood acid-base status in males and females; 2) compare the effect of sodium and calcium pyruvate salts and establish their role in the lipolysis rate; and 3) quantify the effect of single pyruvate intake on the resting energy metabolism. METHODS: In all, 48 individuals completed three separate studies. In all the studies, participants consumed a single dose of pyruvate 0.1 g/kg 60 min before commencing the measurements. The whole blood pH, bicarbonate concentration, base excess or plasma glycerol, free fatty acids, glucose concentrations, or resting energy expenditure and calculated respiratory exchange ratio were determined. The analysis of variance for repeated measurements was performed to examine the interaction between treatment and time. RESULTS: The single dose of sodium pyruvate induced blood alkalization, which was more marked in the male than in the female participants. Following the ingestion of sodium or calcium pyruvate, the blood acid-base parameters were higher than in the placebo trial. Furthermore, 3-h postingestion glycerol was lower in both pyruvate trials than in placebo. Resting energy expenditure did not differ between the trials; however, carbohydrate oxidation was increased after sodium pyruvate ingestion. CONCLUSION: Pyruvate intake induced mild alkalization in a sex-dependent fashion. Moreover, it accelerated carbohydrate metabolism and delayed the rate of glycerol appearance in the blood, but had no effect on the resting energy expenditure. Furthermore, sodium salt seems to have had a greater effect on the blood buffering level than calcium salt. PMID- 25701337 TI - Antiinflammatory effects of L-carnitine supplementation (1000 mg/d) in coronary artery disease patients. AB - OBJECTIVE: Inflammation mediators have been recognized as risk factors for the pathogenesis of coronary artery disease (CAD). The purpose of this study was to investigate the effect of L-carnitine supplementation (LC, 1000 mg/d) on inflammation markers in patients with CAD. METHODS: We enrolled 47 patients with CAD in the study. The patients with CAD were identified by cardiac catheterization as having <50% stenosis of one major coronary artery. The patients were randomly assigned to the placebo (n = 24) and LC (n = 23) groups and the intervention was administered for 12 wk. The levels of LC, antioxidant status (malondialdehyde and antioxidant enzymes activities), and inflammation markers (C-reactive protein [CRP], interleukin [IL]-6, and tumor necrosis factor [TNF]-alpha) were measured. RESULTS: Thirty-nine participants completed the study (19 placebo; 20 LC). After LC supplementation, the levels of inflammation markers were significantly reduced compared with the baseline (CRP, P < 0.01; IL-6, P = 0.03; TNF-alpha, P = 0.07) and those in the placebo group (CRP, P < 0.05; IL-6, P = 0.04; TNF-alpha, P = 0.03). The levels of inflammation markers were significantly negatively correlated with the levels of LC and antioxidant enzymes activities (P < 0.05). CONCLUSIONS: We suggest that LC supplementation, due to its antioxidant effects, may have potential utility to reduce inflammation in CAD. PMID- 25701338 TI - omega-3 fatty acid differentially modulated serum levels of IGF1 and IGFBP3 in men with CVD: a randomized, double-blind placebo-controlled study. AB - OBJECTIVE: Studies have reported elevated serum insulin-like growth factor (IGF) 1 levels followed by omega-3 supplementation in various groups. Considering decreased level of IGF1 in patients with cardiovascular disease (CVD) and protective effects of IGF1 against CVD progression and myocardial infarctions mortality, this study was performed with the aim of determining effects of omega 3 supplementation on serum levels and gene expression of IGF1 and IGF binding protein-3 (IGFBP3) in men with CVD. METHODS: Sixty-two middle-aged (55.9 +/- 6.5 y) non-obese men with CVD followed the study protocol in two groups of omega-3 (n = 31) or placebo (n = 31) supplementation. Participants took omega-3 supplement or placebo (edible paraffin) for 8 wk and were asked not to change their diet or physical activity plan. Anthropometric and lipid profile characteristics, serum IGF1, serum IGFBP3 and also IGF1 and IGFBP3 gene expression in peripheral blood mononuclear cells (PBMCs) were measured in all participants before and after the intervention. Statistical analyses were performed using SPSS software. RESULTS: There were no significant differences between the two study groups in age and body mass index at baseline. The groups also had no difference in baseline serum low-density lipoprotein, high-density lipoprotein, very low-density lipoprotein, triacylglycerols, and IGF1. Compared with placebo, omega-3 supplementation increased serum IGF1 levels (P = 0.01), and decreased serum level of IGFBP3 (P = 0.02). There was a trending toward an increase in IGF1 expression and nonsignificant decrease in IGFBP3 expression. CONCLUSIONS: omega-3 supplementation in patients with CVD increases serum IGF1 levels and decreases serum IGFBP3. Further research is warranted to investigate the underlying mechanisms. PMID- 25701339 TI - Increased plasma selenium is associated with better outcomes in children with systemic inflammation. AB - OBJECTIVE: The aim of this study was to assess the effects of changes in plasma selenium on the outcome of critically ill children. METHODS: Plasma selenium was prospectively measured in 99 children with acute systemic inflammation. The exposure variables were selenium level on admission and on day 5 of stay in the intensive care unit (ICU) and the difference in selenium concentrations between day 5 post-admission and the ICU admission (delta selenium). Selenium was given only as part of enteral diets. Age, malnutrition, red cell glutathione peroxidase 1 activity, serum C-reactive protein, Pediatric Index of Mortality 2, and Pediatric Logistic Organ Dysfunction scores were analyzed as covariates. The outcome variables were ventilator-free days, ICU-free days, and 28-d mortality. RESULTS: Plasma selenium concentrations increased from admission (median 23.4 MUg/L, interquartile range 12.0-30.8) to day 5 (median 25.1 MUg/L, interquartile range 16.0-39.0; P = 0.018). After adjustment for confounding factors, a delta selenium increase of 10 MUg/L was associated with reductions in ventilator days (1.3 d; 95% confidence interval [CI], 0.2-2.3; P = 0.017) and ICU days (1.4 d; 95% CI, 0.5-2.3; P < 0.01). Delta selenium >0 was associated with decreased 28-d mortality on a univariate model (odds ratio, 0.67; 95% CI, 0.46-0.97; P = 0.036). The mean daily selenium intake (6.82 MUg; range 0-48.66 MUg) was correlated with the increase in selenium concentrations on day 5. CONCLUSIONS: An increase in plasma selenium is independently associated with shorter times of ventilation and ICU stay in children with systemic inflammation. These findings raise the hypothesis that selenium supplementation could be beneficial in children with critical illnesses. PMID- 25701340 TI - Sex differences in serum leptin and its relation to markers of cardiometabolic risk in middle-aged adults: evidence from a population-based study. AB - OBJECTIVE: At elevated concentrations, circulating leptin has been associated with metabolic disturbances, namely insulin resistance, elevated blood pressure, inflammation, and endothelial dysfunction. Because women have higher leptin concentrations than men, it is possible that the effects of leptin on the metabolic profile are different between the sexes. The aim of this study was to investigate whether leptin is one of the key hormones to sex affect differences in the pathophysiology of cardiometabolic risk. METHODS: Participants were 178 men and 284 women (average age: 53.9 y), evaluated in a cross-sectional, population-based study performed in Brazil. A structural equation model was used to test a theoretic pathway for the relationship between serum leptin, obesity indicators (body weight and waist circumference), and cardiometabolic risk factors (high-sensitivity C-reactive protein; blood pressure; atherogenic dyslipidemia-total cholesterol/high-density lipoprotein cholesterol (HDL-C) ratio and triacylglycerol /HDL-C ratio; and fasting plasma glucose) stratified by sex. RESULTS: In men, increasing 1 SD in serum leptin predicted an increase in 0.731 SD in body weight and in 0.123 SD in C-reactive protein. Serum leptin had positive and significant indirect effects on men's ratios of total cholesterol to HDL-C (beta = 0.215) and triacylglycerol to HDL-C (beta = 0.209), as well as fasting glucose (beta = 0.173). In women, serum leptin predicted an increase of 0.675 SD in body weight and had positive indirect effects on all cardiometabolic risk factors evaluated. CONCLUSIONS: Serum leptin was indirectly related to cardiometabolic risk factors and its relation was modest and different between sexes. The effects of leptin through mediation of body weight and waist circumference highlight the importance of weight control to prevent cardiometabolic disorders in middle-aged adults. PMID- 25701341 TI - Sex-related effects of nutritional supplementation of Escherichia coli: relevance to eating disorders. AB - OBJECTIVES: The biological background of sex-related differences in the development of eating disorders (EDs) is unknown. Recent data showed that gut bacteria Escherichia coli induce autoantibodies against anorexigenic alpha melanocyte-stimulating hormone (alpha-MSH) associated with psychopathology in ED. The aim of this study was to compare the effects of E. coli on feeding and autoantibodies against alpha-MSH and adrenocorticotropic hormone (ACTH), between female and male rats. METHODS: Commensal E. coli K12 were given in a culture medium daily to adult Wistar rats by intragastric gavage over a 3-wk period; control rats received culture medium only. RESULTS: Before gavage, E. coli K12 DNA was detected in feces of female but not male rats. E. coli provision was accompanied by an increase in body weight gain in females, but a decrease in body weight gain and food intake in males. Independent of E. coli treatment, plasma levels of anti-alpha-MSH and ACTH immunoglobulin (Ig)G were higher in female than male rats. Females responded to E. coli by increasing alpha-MSH IgG levels and affinity, but males by increasing alpha-MSH IgM levels. Affinity of IgG for ACTH was increased in both E. coli-treated females and males, although with different kinetics. IgG from females stimulated more efficiently alpha-MSH-induced cyclic adenosine monophosphate production by melanocortin 4 receptor-expressing cells compared with IgG from males. DISCUSSION: Sex-related response to how E. coli affects feeding and anti-melanocortin hormone antibody production may depend on the presence of these bacteria in the gut before E. coli supplementation. These data suggest that sex-related presence of certain gut bacteria may represent a risk factor for ED development. PMID- 25701342 TI - Omega-3 polyunsaturated fatty acids inhibit the increase in cytokines and chemotactic factors induced in vitro by lymph fluid from an intestinal ischemia reperfusion injury model. AB - OBJECTIVE: To investigate the active factors and the intervention effect of omega 3 polyunsaturated fatty acids (PUFAs) during intestinal ischemia-reperfusion (I/R) injury, which causes the inflammation of monocytes-macrophages cultured in lymph fluid and stimulated with omega-3 PUFAs. METHODS: Forty-eight Sprague Dawley male rats were randomly divided into the following two groups: A. (N + D) group and B. (I/R + D) group. The rats in the (N + D) group were drained of lymph for 180 min; the rats in the (I/R + D) group were subjected to 60 min ischemia by clamping the superior mesenteric artery followed by 120 min reperfusion and 180 min of lymph draining. Lymph fluid from each group was further divided into 4 subgroups, respectively: lymph group (A1, B1); eicosopentaenoic acid (EPA) treated group (A2, B2); EPA + docosahexaeonic acid (DHA)-treated group (A3, B3); and DHA-treated group (A4, B4), then cultured monocyte-macrophage cell line. RESULTS: The levels of tumor necrosis factor-alpha, interleukin (IL)-1 beta, IL 6, soluble cell adhesion molecule-1, chemotactic factors macrophage chemoattractant protein-1, macrophage inflammatory protein-2, and high mobility group box protein 1 in the B1 group were significantly higher than in the A1 group. Importantly, addition of EPA, EPA + DHA, and DHA to the culture media significantly reduced the levels of the above-mentioned factors. Cell stimulation with EPA, EPA + DHA, and DHA also significantly decreased the expression of Toll like receptor 4, nuclear factor-kappaB p65, macrophage chemoattractant protein-1, and macrophage inflammatory protein-2 with the combined treatment of EPA and DHA showing the strongest effect. CONCLUSIONS: The factors induced in lymph during intestinal I/R injury can cause inflammation in vitro. These data provide in vitro evidence that omega-3 PUFAs provide a protective effect by reducing the inflammatory response caused by intestinal I/R lymph. Moreover, the synergism of EPA and DHA had the greatest effect, which is possibly mediated through Toll-like receptor 4 and nuclear factor-kappaB p65. PMID- 25701343 TI - Preweaning modulation of intestinal microbiota by oligosaccharides or amoxicillin can contribute to programming of adult microbiota in rats. AB - OBJECTIVE: Increasing evidence suggests that early nutrition has programming effects on adult health. Identifying mechanisms underlying nutritional programming would aid in the design of new disease prevention strategies. The intestinal microbiota could be a key player in this programming because it affects host metabolic homeostasis, postnatal gut colonization is sensitive to early nutrition, and initial microbial set-up is thought to shape microbiota composition for life. The aim of this study was to determine whether early manipulation of intestinal microbiota actually programs adult microbiota in rats. METHODS: Suckling rats pups were supplemented with fructo-oligosaccharides, galacto-oligosaccharides/long-chain fructan mix (GOS/lcF, 9/1), acidic oligosaccharides, amoxicillin, or vehicle from the fifth to the fourteenth day of life, and weaned to standard chow at day 21. Ceco-colonic microbiota was characterized at 14 and 131 d by real-time polymerase chain reaction analysis. RESULTS: At day 14, all treatments affected microbiota. Amoxicillin had the most significant effect. All oligosaccharides decreased Firmicutes levels, whereas only fructo-oligosaccharides and GOS/lcF increased bifidobacteria. At day 131, most of these effects had faded away but a significant, albeit minor, adult microbiota programming was observed for rats that received GOS/lcF mix before weaning, regarding Roseburia intestinalis cluster, one subdivision of the Erysipelotrichaceae family as well as butyrate kinase gene. CONCLUSIONS: As revealed by a targeted quantitative polymerase chain reaction approach, programming of adult intestinal microbiota seems to vary according to the nature of the preweaning microbiotal modulator. This suggests that intestinal microbiota may, only under specific circumstances, serve as a relay of neonatal nutrition and thus potentially contribute to nutritional programming of host physiology. PMID- 25701344 TI - Energy restriction does not prevent insulin resistance but does prevent liver steatosis in aging rats on a Western-style diet. AB - OBJECTIVE: The aim of this study was to evaluate the effects of long-term energy restriction (ER) on plasma, liver, and skeletal muscle metabolite profiles in aging rats fed a Western-style diet. METHODS: Three groups of male Sprague-Dawley rats were studied. Group 1 consisted of 2 mo old rats fed ad libitum; group 2 were 19 mo old rats also fed ad libitum; and group 3 were 19 mo old rats subjected to 40% ER for the last 11.5 mo. To imitate a Western-style diet, all rats were given a high-sucrose, very low omega-3 polyunsaturated fatty acid (PUFA) diet. High-resolution magic angle spinning-(1)H nuclear magnetic resonance spectroscopy was used for hepatic and skeletal muscle metabolite determination, and fatty acid profiles were measured by capillary gas chromatography on plasma, liver, and skeletal muscle. RESULTS: ER coupled with a Western-style diet did not prevent age-induced insulin resistance or the increase in triacylglycerol content in plasma and skeletal muscle associated with aging. However, in the liver, ER did prevent steatosis and increased the percent of saturated and monounsaturated fatty acids relative to omega-6 and omega-3 PUFA. CONCLUSIONS: Although steatosis was reduced, the beneficial effects of ER on systemic insulin resistance and plasma and skeletal muscle metabolites observed elsewhere with a balanced diet seem to be compromised by high-sucrose and low omega-3 PUFA intake. PMID- 25701345 TI - Effects of a single dose of a flavonoid-rich blueberry drink on memory in 8 to 10 y old children. AB - OBJECTIVE: Recent evidence from animals and adult humans has demonstrated potential benefits to cognition from flavonoid supplementation. The aim of this study was to investigate whether these cognitive benefits extended to a sample of school-aged children. METHOD: Using a crossover design, with a washout of at least 7 d between drinks, 14 children ages 8 to 10 y consumed either a flavonoid rich blueberry drink or a matched vehicle. Two h after consumption, the children completed a battery of five cognitive tests comprising the Go-NoGo, Stroop, Rey's Auditory Verbal Learning Task, Object Location Task, and a Visual N-back. RESULTS: In comparison to the vehicle, the blueberry drink produced significant improvements in the delayed recall of a previously learned list of words, showing for the first time a cognitive benefit for acute flavonoid intervention in children. However, performance on a measure of proactive interference indicated that the blueberry intervention led to a greater negative impact of previously memorized words on the encoding of a set of new words. There was no benefit of our blueberry intervention for measures of attention, response inhibition, or visuospatial memory. CONCLUSIONS: Although findings are mixed, the improvements in delayed recall found in this pilot study suggest that, following acute flavonoid-rich blueberry interventions, school-aged children encode memory items more effectively. PMID- 25701346 TI - Severe protein malnutrition in a morbidly obese patient after bariatric surgery. AB - The aim of this study was to describe the clinical course of a morbidly obese patient who underwent Roux-en-Y gastric bypass (RYGB) surgery and, in the late postoperative period, presented the expected loss of weight, but also presented severe protein malnutrition (PM). A patient with morbid obesity, who in March 2012, presented PM (serum albumin = 2.4 g/dL) 2 y after the completion of RYGB surgery (loss of 52.7% of usual body weight). During the hospitalization, the patient received partial volumes of commercial semi-elemental, high-protein, low fat diet by tube feeding with gastric positioning, associated with an oral low fat, low-sodium, and bland-consistency diet. The patient presented a temporary clinical improvement, however, outpatient monitoring identified the need for subsequent hospitalizations due to the recurrence of severe hypoalbuminemia (e.g., 1.39 g/dL), anasarca (increase of 15 kg in 79 d), and normocytic and normochromic anemia (e.g., hemoglobin 9.2 g/dL). In July 2013 the RYGB partial reversal technique was performed with a reduction of 100 cm in the Roux-en-Y arm. Seventy days after surgery, the patient was asymptomatic (albumin 3.7 g/dL), however, she presented rapid and progressive recovery of the body weight (increase of 10.3 kg in 60 d, without edema). The effective treatment of morbid obesity is still a major challenge in clinical practice. Restrictive, malabsorptive bariatric techniques are associated with nutritional deficiencies. Severe PM is rarely reported as a late postoperative complication of RYGB, however, due to the serious consequences associated with this, it requires early diagnosis and treatment. PMID- 25701347 TI - A glance at... glycemic index. PMID- 25701348 TI - Possible therapies for obesity: focus on the available options for its treatment. PMID- 25701349 TI - Microbiome, peptide autoantibodies, and eating disorders: a missing link between gut and brain. PMID- 25701350 TI - Comment on "Early nutritional support and physiotherapy improved long-term self sufficiency in acutely ill older patients". PMID- 25701351 TI - Smalls changes are clinically relevant: response to "Comment on 'Early nutritional support and physiotherapy improved long-term self-sufficiency in acutely ill older patients'". PMID- 25701352 TI - Personalized treatment for colorectal cancer: novel developments and putative therapeutic strategies. AB - BACKGROUND: Colorectal cancer (CRC) is the third most common cancer diagnosed worldwide and continues to be a major healthcare concern. Molecular heterogeneity of CRC is believed to be one of the main factors responsible for the considerable variability in treatment response. With the recent development of powerful genomic technologies, novel insights in tumor biology of CRC have now been provided, facilitating the recognition of new molecular subtypes with prognostic and predictive implications. PURPOSE: The purpose of this review article is to summarize current knowledge about genomic, epigenomic, and proteomic characteristics of CRC, as well as their implications for biomarker identification and individualized targeted therapy. CONCLUSION: Supplementing the findings from several previous studies, the Cancer Genome Atlas (TCGA) project recently finalized the systematic characterization of CRC resulting in the first tumor dataset with complete molecular measurements at DNA, RNA, and protein levels. The challenge now is to translate these findings into a robust and reproducible CRC classification system linking molecular features of the tumor to precision medicine. PMID- 25701353 TI - Targeting Hedgehog signaling pathway and autophagy overcomes drug resistance of BCR-ABL-positive chronic myeloid leukemia. AB - The frontline tyrosine kinase inhibitor (TKI) imatinib has revolutionized the treatment of patients with chronic myeloid leukemia (CML). However, drug resistance is the major clinical challenge in the treatment of CML. The Hedgehog (Hh) signaling pathway and autophagy are both related to tumorigenesis, cancer therapy, and drug resistance. This study was conducted to explore whether the Hh pathway could regulate autophagy in CML cells and whether simultaneously regulating the Hh pathway and autophagy could induce cell death of drug-sensitive or -resistant BCR-ABL(+) CML cells. Our results indicated that pharmacological or genetic inhibition of Hh pathway could markedly induce autophagy in BCR-ABL(+) CML cells. Autophagic inhibitors or ATG5 and ATG7 silencing could significantly enhance CML cell death induced by Hh pathway suppression. Based on the above findings, our study demonstrated that simultaneously inhibiting the Hh pathway and autophagy could markedly reduce cell viability and induce apoptosis of imatinib-sensitive or -resistant BCR-ABL(+) cells. Moreover, this combination had little cytotoxicity in human peripheral blood mononuclear cells (PBMCs). Furthermore, this combined strategy was related to PARP cleavage, CASP3 and CASP9 cleavage, and inhibition of the BCR-ABL oncoprotein. In conclusion, this study indicated that simultaneously inhibiting the Hh pathway and autophagy could potently kill imatinib-sensitive or -resistant BCR-ABL(+) cells, providing a novel concept that simultaneously inhibiting the Hh pathway and autophagy might be a potent new strategy to overcome CML drug resistance. PMID- 25701354 TI - Acute kidney injury in a Malaysian intensive care unit: Assessment of incidence, risk factors, and outcome. AB - PURPOSE: Acute kidney injury (AKI) is common and carries a high mortality rate. Most epidemiological studies were retrospective and were done in Western populations. We aim to assess its incidence using both urine output and creatinine criteria and its association with risk factors and outcome. MATERIAL AND METHODS: This was a single-center, prospective, observational study. All intensive care unit (ICU) patients older than 18 years were screened for inclusion in the study. Admission of less than 48 hours, postelective surgery, and ICU readmission were excluded. RESULTS: A total of 143 patients were recruited, of these, 65% had AKI, of which 18 (19%) were stage 1; 23 (25%), stage 2; and 52 (56%), stage 3. Independent risk factors for AKI include high Acute Physiology and Chronic Health Evaluation II score and septic shock (odds ratio of 1.20 [1.09-1.33] and 8.41 [1.49-47.6], respectively). Thirty-eight percent were classified as AKI based on creatinine and 61% as AKI based on urine output criteria, and, in 34%, both AKI based on creatinine and AKI based on urine output criteria were present. Acute kidney injury was an independent risk factor for mortality (hazard ratio of, 2.61 [1.06-6.42]). CONCLUSIONS: Acute kidney injury is common in our ICU, and almost half are of highest severity stage. Patients with high severity of illness and septic shock were at risk for AKI. The presence of AKI independently predicted mortality. PMID- 25701355 TI - Dietary supplementation of beta-guanidinopropionic acid (betaGPA) reduces whole body and skeletal muscle growth in young CD-1 mice. AB - Increased AMP-activated protein kinase (AMPK) activity leads to enhanced fatty acid utilization, while also promoting increased ubiquitin-dependent proteolysis (UDP) in mammalian skeletal muscle. beta-guanidinopropionic acid (betaGPA) is a commercially available dietary supplement that has been shown to promote an AMPK dependent increase in fatty acid utilization and aerobic capacity in mammals by compromising creatine kinase function. However, it remains unknown if continuous betaGPA supplementation can negatively impact skeletal muscle growth in a rapidly growing juvenile. The current study was conducted to examine the effect of betaGPA supplementation on whole-body and skeletal muscle growth in juvenile and young adult mice. Three-week old, post weanling CD-1 mice were fed a standard rodent chow that was supplemented with either 2% (w/w) alpha-cellulose (control) or betaGPA. Control and betaGPA-fed mice (n = 6) were sampled after 2, 4, and 8 weeks. Whole-body and hindlimb muscle masses were significantly (P < 0.05) reduced in betaGPA-fed mice by 2 weeks. The level of AMPK (T172) phosphorylation increased significantly (P < 0.05) in the gastrocnemius of betaGPA-fed versus control mice at 2 weeks, but was not significantly different at the 4- and 8-week time points. Further analysis revealed a significant (P < 0.05) increase in the skeletal muscle-specific ubiquitin ligase MAFbx/Atrogin-1 protein and total protein ubiquitination in the gastrocnemius of betaGPA versus control mice at the 8-week time point. Our data indicate that feeding juvenile mice a betaGPA supplemented diet significantly reduced whole-body and skeletal muscle growth that was due, at least in part, to an AMPK-independent increase in UDP. PMID- 25701357 TI - Association of myeloperoxidase polymorphism (G463A) with cervix cancer. AB - Cervical cancer is the fourth most common cancer affecting women worldwide, according to the latest IARC release with 528 000 new cases every year. Infection by high-risk human papillomavirus (HPV) is necessary but not sufficient for progression to cancer. Epithelial tissues, the target of HPV infection, are heavily exposed to reactive oxygen species (ROS). Hypochlorous acid (HOCl) is a very potent ROS, and it is produced by myeloperoxidase (MPO). MPO, a lysosomal enzyme expressed in polymorphonuclear neutrophils (PMN), has the potential to kill HPV transformed cells, as a component of an intercellular induced-apoptosis pathway. This enzyme catalyzes the production of HOCl in the presence of hydrogen peroxide (H2O2). The H2O2 produced by the Doderlein's bacillus will interact with MPO, contributing to the intercellular induced-apoptosis pathway. We studied a functional polymorphism in the promoter region of MPO (G463A) and how it may affect the risk of developing cervix cancer. A sample of 100 patients with invasive cervical cancer and 122 control women were genotyped for MPO polymorphism by PCR-RFLP method. The statistical method used was chi(2). We found that women with the GG genotype had lower risk for cervical cancer than the women who displayed the heterozygous genotype GA (OR = 0.546, 95 % CI = 0.315-0.939, p = 0.028, OR = 2.210, 95 % CI = 1.257-3.886, p = 0.008, respectively). The genotype that leads to a higher concentration of ROS (GG) presents itself as a protection factor in comparison to the homozygous genotype (AA). This can be explained by the interaction of HOCl and superoxide of transformed cells that will generate apoptosis-inducing hydroxyl radicals. PMID- 25701356 TI - Fibroblast growth factor (FGF21) protects mouse liver against D-galactose-induced oxidative stress and apoptosis via activating Nrf2 and PI3K/Akt pathways. AB - FGF21 is recently discovered with pleiotropic effects on glucose and lipid metabolism. However, the potential protective effect of FGF21 against D-gal induced injury in the liver has not been demonstrated. The aim of this study is to investigate the pathophysiological role of FGF21 on hepatic oxidative injury and apoptosis in mice induced by D-gal. The 3-month-old Kunming mice were subcutaneously injected with D-gal (180 mg kg(-1) d(-1)) for 8 weeks and administered simultaneously with FGF21 (5 or 1 mg kg(-1) d(-1)). Our results showed that the administration of FGF21 significantly alleviated histological lesion including structure damage, degeneration, and necrosis of hepatocytes induced by D-gal, and attenuated the elevation of liver injury markers, serum AST, and ALP in a dose-dependent manner. FGF21 treatment also suppressed D-gal induced profound elevation of ROS production and oxidative stress, as evidenced by an increase of the MDA level and depletion of the intracellular GSH level in the liver, and restored the activities of antioxidant enzymes SOD, CAT, GSH-Px, and T-AOC. Moreover, FGF21 treatment increased the nuclear abundance of Nrf2 and subsequent up regulation of several antioxidant genes. Furthermore, a TUNEL assay showed that D-gal-induced apoptosis in the mouse liver was significantly inhibited by FGF21. The expression of caspase-3 was markedly inhibited by the treatment of FGF21 in the liver of D-gal-treated mice. The levels of PI3K and PBK/Akt were also largely enhanced, which in turn inactivated pro-apoptotic signaling events, restoring the balance between pro- and anti-apoptotic Bcl-2 and Bax proteins in the liver of D-gal-treated mice. In conclusion, these results suggest that FGF21 protects the mouse liver against D-gal-induced hepatocyte oxidative stress via enhancing Nrf2-mediated antioxidant capacity and apoptosis via activating PI3K/Akt pathway. PMID- 25701358 TI - Improved survival of mesenchymal stem cells by macrophage migration inhibitory factor. AB - Macrophage migration inhibitory factor (MIF) is a critical inflammatory cytokine that was recently associated with progenitor cell survival and potently inhibits apoptosis. We examined the protective effect of MIF on hypoxia/serum deprivation (SD)-induced apoptosis of mesenchymal stem cells (MSCs), as well as the possible mechanisms. MSCs were obtained from rat bone marrow and cultured in vitro. Apoptosis was induced by culturing MSCs under hypoxia/SD conditions for up to 24 h and assessed by flow cytometry. Expression levels of c-Met, Akt, and FOXO3a were detected by Western blotting. CD74 expression was detected by qRT-PCR, Western blot, and immunofluorescence. Oxidative stress under hypoxia/SD was examined by detection of reactive oxygen species (ROS) and activity of superoxide dismutase (SOD) and malondialdehyde (MDA). Hypoxia/SD-induced apoptosis was significantly attenuated by recombinant rat MIF in a concentration-dependent manner. MIF induced CD74-asssociated c-Met activation, which was blocked by knocking down CD74 expression using siRNA. MIF also induced Akt and associated FOXO3a phosphorylation, and this effect was abolished by knocking down either CD74 or Akt. In addition, MIF decreased oxidative stress in MSCs, as shown by decreased ROS and MDA, and increased the activity of SOD. Knockdown of CD74, Akt, or FOXO3a largely attenuated the anti-apoptotic effect of MIF and its ability to protect against oxidative stress. MIF protected MSCs from hypoxia/SD-induced apoptosis by interacting with CD74 to stimulate c-Met, leading to downstream PI3K/Akt-FOXO3a signaling and decreased oxidative stress. PMID- 25701359 TI - BTG3 upregulation induces cell apoptosis and suppresses invasion in esophageal adenocarcinoma. AB - B cell translocation gene 3 (BTG3) is a tumor suppressor by inhibiting cell proliferation, migration, and regulating cell cycle progression in several tumors. However, its role in esophageal adenocarcinoma (EAC) remains unknown. Here, we detected the expression of BTG3 in EAC tissues and subsequent progression. BTG3 expression was significant decreased in EAC tissues and cell lines detected by real-time RT-PCR and Western blot. Relationships of BTG3 with EAC clinicopathology were analyzed statistically. The decrease expression of BTG3 is associated with lymph node metastases. In vitro assay demonstrated that overexpression of BTG3 significantly suppressed colony formation and proliferation of EAC cells. The suppressed migration and invasion abilities found in BTG3-overexpressing EAC cells. Our findings suggested that BTG3 is suppressor in the progression of EAC. PMID- 25701360 TI - Hydrogen sulfide decreases the plasma lipid peroxidation induced by homocysteine and its thiolactone. AB - Hydrogen sulfide (H2S) has been investigated widely in recent years. H2S plays a variety of roles in different biological systems, including cardiovascular system. It is the final product of amino acids metabolism, which contains sulfur cysteine and homocysteine (Hcy). In human plasma, there are several various forms of homocysteine: free Hcy, protein-bound Hcy (S-linked, and N-linked), and homocysteine thiolactone (HTL). Our previous works have shown that both Hcy in the reduced form and its thiolactone may modify fibrinolysis, coagulation process, and biological activity of blood platelets. Moreover, we have observed that HTL, like its precursor-Hcy stimulated the generation of superoxide anion radicals (O 2 (-*) ) in blood platelets. The aim of our study in vitro was to establish the influence of sodium hydrosulfide (NaHS, as a fast-releasing H2S donor; at tested concentrations: 10-1000 uM) on the plasma lipid peroxidation induced by the reduced Hcy (at final concentrations of 0.01-1 mM) and HTL (at final concentrations of 0.1-1 uM). Our results indicate that 10 and 100 uM NaHS decreased the lipid peroxidation in plasma treated with 1 mM Hcy or 1 uM HTL (when NaHS and Hcy/HTL were added to plasma together). The protective effect of 10 and 100 uM NaHS against the lipid peroxidation in plasma preincubated with 1 mM Hcy or 1 uM HTL was also observed. Considering the data presented in this study, we suggest that the lipid peroxidation (induced by different forms of homocysteine) may be reduced by hydrogen sulfide. PMID- 25701361 TI - Global correlation analysis for microRNA and gene expression profiles in human obesity. AB - Obesity is an increasing health problem associated with major adverse consequences for human health. MicroRNAs (miRNAs), small endogenous non-coding RNAs, regulate the expression of genes that play roles in human body via posttranscriptional inhibition. To identify the miRNAs and their target genes involved in obesity, we downloaded the miRNA and gene expression profiles from gene expression omnibus (GEO) database and analyzed the differentially expressed miRNAs (DEMs) and differentially expressed genes (DEGs) in adipose tissues from obese subjects compared to those from non-obese subjects. Then, we constructed the miRNA-target interaction network and conducted functional enrichment analysis of DEGs, and the targets negatively correlated with DEMs. We identified a total of 16 miRNAs and 192 genes that showed a significantly different expression and 3002 miRNA-target interaction pairs, including 182 regulatory pairs in obesity. Target genes of DEMs were found mainly enriched in several functions, such as collagen fibril organization, extracellular matrix part, and extracellular matrix structural constituent. Moreover, hsa-miR-425 and hsa-miR-126 had a significant number of target genes and hsa-miR-16/COL12A1 and hsa-miR-634/SLC4A4 interaction pairs are significantly co-expressed, suggesting that they might play important roles in the pathogenesis of obesity. Our study provides a bioinformatic basis for further research of molecular mechanism in obesity. PMID- 25701362 TI - Current practice in handling and reporting prostate needle biopsies: results of a Turkish survey. AB - BACKGROUND: In 2005 ISUP (International Society of Urological Pathology) consensus revised the Gleason grading system. METHOD: We conducted a web based national survey of the members of Uropathology Working Group (WG) and general pathologists (NWP) to investigate the current practice in reporting prostate needle biopsies. RESULTS: The revised system was well known and applied by the respondents. In pattern analysis major difference was detected in reporting medium sized, regular cribriform glands. In both group this pattern was reported as Gleason Pattern (GP) 3 by at least 50% of the repliers, the rest reported this pattern as GP 4. Gleason Score (GS) 2-4 was not reported by the WG. In NWP GS 2-4 was reported by 25% either frequently of infrequently. Any amount of secondary higher grade was included in GS by 92.5% of WG and 70% of NWP (p<0.05). Five percent cut off was requested for the lower secondary grade by 71.4% of WG but 64% of NWP. (p<0.05) Tertiary pattern was reported by 64.5% of WG and 34% of NWP (p<0.05). Individual GS was assigned for each core by 46.4% of WG and 26.5% of NWP (p<0.05). When measuring the extend of cancer, most included the benign tissue between cancer foci in the same core. Fat invasion was interpreted as extraprostatic invasion by 85.7% of WG and 55.9%of NWP (p<0.05). CONCLUSION: This study showed the specific points where the educational efforts should be focused to have a better and standardized practice pattern of pathologists when reporting prostate biopsies. PMID- 25701363 TI - Multiple recurrences of early-stage, endometrioid-type G2 endometrial cancer with a long-time follow-up: A case study. AB - The recurrence after a long-time free period of time, in women primarily operated on for early-stage of endometrial cancer (EC), is a unique phenomenon. Currently, we present the case of a 59-year-old woman with multiple recurrences from the moderately-differentiated, stage Ib, endometrioid-type, uterine cancer. All recurrences were pathologically proven to originate from the primary tumor, and the patient expired 12 years after the primary surgery for disseminated neoplasm. We summarize the current data to give a short overview of the role of late recurrences in women operated on for early-stage EC. PMID- 25701364 TI - Management of a ruptured pseudoaneurysm of the uterine artery using a modified percutaneous embolization technique. PMID- 25701365 TI - Journal of Artificial Organs 2014: the year in review. PMID- 25701366 TI - Lysophosphatidic acid receptor 1 antagonist ki16425 blunts abdominal and systemic inflammation in a mouse model of peritoneal sepsis. AB - Lysophosphatidic acid (LPA) is a bioactive lipid mediator of inflammation via the LPA receptors 1-6. We and others have previously described proinflammatory and profibrotic activities of LPA signaling in bleomycin- or lipopolysaccharide (LPS) induced pulmonary fibrosis or lung injury models. In this study, we investigated if LPA signaling plays a role in the pathogenesis of systemic sepsis from an abdominal source. We report here that antagonism of the LPA receptor LPA1 with the small molecule ki16425 reduces the severity of abdominal inflammation and organ damage in the setting of peritoneal endotoxin exposure. Pretreatment of mice with intraperitoneal ki16425 eliminates LPS-induced peritoneal neutrophil chemokine and cytokine production, liver oxidative stress, liver injury, and cellular apoptosis in visceral organs. Mice pretreated with ki16425 are also protected from LPS-induced mortality. Tissue myeloperoxidase activity is not affected by LPA1 antagonism. We have shown that LPA1 is associated with LPS coreceptor CD14 and the association is suppressed by ki16425. LPS-induced phosphorylation of protein kinase C delta (PKCdelta) and p38 mitogen-activated protein kinase (p38 MAPK) in liver cells and interleukin 6 production in Raw264 cells are likewise blunted by LPA1 antagonism. These studies indicate that the small molecule inhibitor of LPA1, ki16425, suppresses cytokine responses and inflammation in a peritoneal sepsis model by blunting downstream signaling through the LPA1-CD14-toll-like receptor 4 receptor complex. This anti inflammatory effect may represent a therapeutic strategy for the treatment of systemic inflammatory responses to infection of the abdominal cavity. PMID- 25701367 TI - Mediterranean diet and cardiovascular disease: a step closer to mechanisms using a precision animal model? PMID- 25701368 TI - Barrett's esophagus: recent insights into pathogenesis and cellular ontogeny. AB - Esophageal adenocarcinoma (EAC) has increased 6-fold in its incidence in the last 2 decades. Evidence supports the hypothesis of stepwise progression from normal squamous epithelium -> reflux esophagitis -> metaplasia (Barrett's esophagus, BE) -> dysplasia -> adenocarcinoma. The precursor, BE, stands as the bridge connecting the widespread but naive reflux disease and the rare but fatal EAC. The step of metaplasia from squamous to intestine-like columnar phenotype is perhaps pivotal in promoting dysplastic vulnerability. It is widely accepted that chronic inflammation because of gastroesophageal reflux disease leads to the development of metaplasia, however the precise molecular mechanism is yet to be discovered. Additionally, how this seemingly adaptive change in the cellular phenotype promotes dysplasia remains a mystery. This conceptual void is deterring further translational research and clouding clinical decision making. This article critically reviews theories on the pathogenesis of Barrett's esophagus and the various controversies surrounding its diagnosis. We further discuss unanswered questions and future directions, which are vital in formulating effective preventive and therapeutic guidelines for Barrett's esophagus. PMID- 25701369 TI - Umbilical nodule. PMID- 25701370 TI - Chylothorax linked to goiter solved by transcervical total thyroidectomy without sternotomy. PMID- 25701371 TI - Abdominal mass in the right flank. PMID- 25701372 TI - Outcome of shared care for pediatric cardiac transplantation between two nations with different health care systems. AB - BACKGROUND: No data are available for the outcome of children undergoing cardiac transplantation with shared care programs in different countries. We sought to investigate the outcome of a shared care transplant program between 2 countries given the complex immunologic, cardiac, and psychologic needs of these young people. METHODS: We investigated the results of a shared care program for children who underwent cardiac transplantation between our center in the Republic of Ireland and 2 centers in the United Kingdom over 2 decades. RESULTS: Between 1990 and 2013, 22 patients underwent 23 cardiac transplants. The median age at transplant was 3.2 years (range, 0.3-13.3 years), median age at listing was 30 months (range, 0.1-13.3 years), and the median waiting list time was 2.8 months (range, 0.3-14 months). The median time to return to the referral center from the time of transplant was 3 weeks (range, 2-8 weeks). The referral center treated 4 of 5 late rejection episodes. Angiography was undertaken in the transplant center at annual or biannual review. Outcomes for rejection, coronary vasculopathy, and survival were comparable between the referral and transplant centers. CONCLUSIONS: This report of shared care for pediatric transplant patients between 2 sovereign nations demonstrates good results, with comparable outcomes to the specialist transplant center. These data may encourage liberalization of follow up in other centers. PMID- 25701373 TI - De novo sirolimus with low-dose tacrolimus versus full-dose tacrolimus with mycophenolate mofetil after heart transplantation--8-year results. AB - BACKGROUND: Although acute cellular rejection after heart transplantation (HTX) can be controlled by full-dose calcineurin inhibitor (CNI)-based immunosuppressive regimens, cardiac allograft vasculopathy (CAV), nephrotoxicity, and malignancy remain ongoing problems. To evaluate the potential beneficial effects of sirolimus and CNI reduction, we compared de novo low-dose tacrolimus and sirolimus with standard tacrolimus and mycophenolate mofetil (MMF)-based immunosuppression after HTX. METHODS: We analyzed a long-term follow-up cohort of 126 patients who underwent HTX during the period 1998-2005 and received either de novo low-dose tacrolimus/sirolimus (lowTAC/SIR; n = 61) or full-dose tacrolimus/MMF (TAC/MMF; n = 64). RESULTS: Freedom from treatment switch was less in the low TAC/SIR group than in the TAC/MMF group (51.7% vs 73.0%, p = 0.038) 8 years after HTX. Freedom from acute rejection was 90.6% in the low TAC/SIR group vs 80.3% in the TAC/MMF group (p = 0.100). There was no difference in freedom from International Society for Heart and Lung Transplantation CAV grade >= 1 (55.4% vs 60.0%, p = 0.922), time until CAV diagnosis (4.2 +/- 2.0 years vs 3.2 +/- 2.4 years, p = 0.087), and CAV severity (p = 0.618). The benefit of reduced early maximum creatinine for low TAC/SIR treatment (1.8 +/- 0.9 mg/dl vs 2.4 +/- 1.1 mg/dl in TAC/MMF group, p < 0.001) did not continue 5 years and 8 years after HTX (1.4 +/- 0.4 mg/dl vs 1.7 +/- 1.2 mg/dl, p = 0.333, and 1.6 +/- 1.1 mg/dl vs 1.6 +/- 0.8 mg/dl, p = 0.957). The trend for superior survival at 5 years with low TAC/SIR treatment (93.1% vs 81.3% in TAC/MMF group, p = 0.051) could not be confirmed after 8 years (84.7% vs 75.0%, p = 0.138). Multivariate analysis at 8 years did not reveal any benefit of low TAC/SIR treatment. CONCLUSIONS: Reduction of de novo CNI did not result in superior long-term renal function. Low-dose mechanistic target of rapamycin inhibition did not achieve any benefit in CAV prevention compared with full-dose TAC/MMF after HTX. PMID- 25701374 TI - Assessment of Sunitinib-Induced Toxicities and Clinical Outcomes Based on Therapeutic Drug Monitoring of Sunitinib for Patients With Renal Cell Carcinoma. AB - BACKGROUND: Sunitinib has been approved for the treatment of metastatic renal cell carcinoma (RCC). Sunitinib pharmacokinetics shows a large interpatient variability. PATIENTS AND METHODS: A retrospective, observational clinical study of 21 patients with RCC was performed. Sunitinib was administered for 4 weeks of a 6-week cycle for the first cycle. We evaluated the association of sunitinib induced toxicities and clinical outcomes with the trough total sunitinib concentration in a steady state during the first cycle. RESULTS: The median total sunitinib concentration was 91.8 ng/mL (range, 49.8-205 ng/mL). There was an association between total sunitinib concentration and the severity of thrombocytopenia, anorexia, and fatigue. Patients with >= 100 ng/mL total sunitinib (n = 8), compared with patients with < 100 ng/mL (n = 13), had a greater incidence of Grade >= 3 toxicities (6 patients [75.0%] vs. 3 patients [23.1%]). Patients with < 100 ng/mL total sunitinib had significantly longer time to treatment failure (TTF) and progression-free survival (PFS) time than patients with >= 100 ng/mL (median TTF, 590 vs. 71 days; P = .04; median PFS, 748 vs. 238 days; P = .02). CONCLUSION: Results of this study suggest that therapeutic drug monitoring of sunitinib could be useful for avoiding severe toxicities. Dose reduction might be needed, especially when the total sunitinib concentration is >= 100 ng/mL, to avoid unnecessary early discontinuation of treatment. PMID- 25701375 TI - Guidelines for assessing mouse endothelial function via ultrasound imaging: a report from the International Society Of Cardiovascular Translational Research. AB - The study is to establish a novel method to determine the endothelial function in mouse carotid arteries in vivo by using high-resolution ultrasound images. Atherosclerosis in carotid arteries is induced in ApoE(-/-) mice with a Western diet. The ultrasound of the ventral neck generates clear pictures of the common carotid arteries. Acetylcholine at the range from 5 to 20 MUg/kg/min (iv) is able to induce a dose-dependent relaxation as shown by the increased diameter of these normal mouse carotid arteries, which is impaired in atherosclerotic arteries. The endothelial function determined by ultrasound images in vivo matches well with that determined in isolated carotid arterial rings in vitro. All animals survived after the endothelial function measurement. In this study, we have established a standard method to determine the mouse endothelial function in vivo. It is a reliable, safe, and survival method that could be used repetitively in mouse arteries. PMID- 25701376 TI - Insights from a decade of biophysical studies on MutL: Roles in strand discrimination and mismatch removal. AB - DNA mismatch repair (MMR) is a conserved pathway that safeguards genome integrity by correcting replication errors. The coordinated actions of two proteins (MutS and MutL) initiate the mismatch repair response and defects in the genes encoding for these proteins have been linked to sporadic and hereditary cancers. The basic steps to repair a mismatch include recognizing the mismatch, discriminating the newly synthesized from the parental strand, removing and re-synthesizing the erroneous strand. Although the DNA mismatch repair pathway has been extensively studied over the last four decades, the strand discrimination mechanism has remained elusive in most organisms. Work over the last decade has brought significant progress onto this step of the pathway, in turn ascribing new and critical roles to the MutL protein. In this review, we describe biochemical, biophysical and structural analyses that have clarified how MutL aids at discriminating the newly synthesized strand from its template and marking it for removal. PMID- 25701377 TI - Phosphopeptide interactions with BRCA1 BRCT domains: More than just a motif. AB - BRCA1 BRCT domains function as phosphoprotein-binding modules for recognition of the phosphorylated protein-sequence motif pSXXF. While the motif interaction interface provides strong anchor points for binding, protein regions outside the motif have recently been found to be important for binding affinity. In this review, we compare the available structural data for BRCA1 BRCT domains in complex with phosphopeptides in order to gain a more complete understanding of the interaction between phosphopeptides and BRCA1-BRCT domains. PMID- 25701378 TI - Celecoxib sensitizes gastric cancer to rapamycin via inhibition of the Cbl-b regulated PI3K/Akt pathway. AB - Mammalian target of rapamycin (mTOR) has emerged as a new potential therapeutic target for gastric cancer. However, a phase III clinical trial found that monotherapy with the mTOR inhibitor everolimus did not significantly improve the overall survival of patients with advanced gastric cancer. This has led to the exploration of more effective combinatorial regimens to enhance the effectiveness of mTOR inhibitors. Here, we demonstrate that Akt phosphorylation is increased in the rapamycin-resistant gastric cancer cell lines MGC803 and SGC7901. We further show that combined treatment with celecoxib and rapamycin results in an additive inhibitory effect on the growth of gastric cancer cells through suppression of rapamycin-induced Akt activation. Moreover, celecoxib upregulated the expression of the ubiquitin ligase casitas B-lineage lymphoma-b (Cbl-b). Knockdown of Cbl-b significantly attenuated celecoxib-mediated inhibition of Akt phosphorylation and impaired the additive anticancer effect of celecoxib and rapamycin. Our results suggest that celecoxib-mediated upregulation of Cbl-b is responsible, at least in part, for the additive antitumor effect of celecoxib and rapamycin via inhibition of rapamycin-induced Akt activation. PMID- 25701379 TI - Response to: Pharmacokinetic and Pharmacodynamic Drug Interactions between Antiretrovirals and Oral Contraceptives. PMID- 25701380 TI - Drugs and Diseases Interacting with Cigarette Smoking in US Prescription Drug Labelling. AB - The US Food and Drug Administration (FDA) draft guidance for industry on drug interaction studies recommends, but does not mandate, that both cigarette smokers and non-smokers can be used to study drug metabolism in clinical trials, and that important results related to smoking should be included in drug labelling to guide medication usage. This study aimed to provide a comprehensive review of drugs or diseases interacting with smoking, as presented in all US drug labelling. The 62,857 drug labels deposited in the FDA Online Label Repository were searched using the keywords 'smoke', 'smoker(s)', 'smoking', 'tobacco' and 'cigarette(s)' on 19 June 2014. The resultant records were refined to include only human prescription drug labelling, for manual examination. For 188 single active-ingredient drugs and 36 multiple-active-ingredient drugs, the labelling was found to contain smoking-related information. The pharmacokinetics of 29 and 21 single-active-ingredient drugs were affected and unaffected, respectively, by smoking. For the remaining drugs, the provided information related to smoking affecting efficacy, safety or diseases but not pharmacokinetics. Depending on the nature of specific drugs, the perturbation in pharmacokinetic parameters in smokers ranged from 13 to 500%, in comparison with non-smokers. Dosage modifications in smokers are necessary for four drugs and may be necessary for six drugs, but are unnecessary for seven drugs although the pharmacokinetic parameters of four of them are affected by smoking. Cigarette smoking is a risk factor for 16 types of diseases or adverse drug reactions. For one single-active ingredient contraceptive drug and 10 multiple-active-ingredient contraceptive drugs, a black box warning (the FDA's strongest safety warning) is included in the labelling for increased risks of heart attacks and strokes in female smokers, and "women are strongly advised not to smoke" when using these drugs. This study presents the first comprehensive overview of cigarette smoking interacting with drugs and/or diseases, as presented in US drug labelling. PMID- 25701381 TI - Formation of chloroplast protrusions and catalase activity in alpine Ranunculus glacialis under elevated temperature and different CO2/O2 ratios. AB - Chloroplast protrusions (CPs) have frequently been observed in plants, but their significance to plant metabolism remains largely unknown. We investigated in the alpine plant Ranunculus glacialis L. treated under various CO2 concentrations if CP formation is related to photorespiration, specifically focusing on hydrogen peroxide (H2O2) metabolism. Immediately after exposure to different CO2 concentrations, the formation of CPs in leaf mesophyll cells was assessed and correlated to catalase (CAT) and ascorbate peroxidase (APX) activities. Under natural irradiation, the relative proportion of chloroplasts with protrusions (rCP) was highest (58.7 %) after exposure to low CO2 (38 ppm) and was lowest (3.0 %) at high CO2 (10,000 ppm). The same relationship was found for CAT activity, which decreased from 34.7 nkat mg(-1) DW under low CO2 to 18.4 nkat mg(-1) DW under high CO2, while APX activity did not change significantly. When exposed to natural CO2 concentration (380 ppm) in darkness, CP formation was significantly lower (18.2 %) compared to natural solar irradiation (41.3 %). In summary, CP formation and CAT activity are significantly increased under conditions that favour photorespiration, while in darkness or at high CO2 concentration under light, CP formation is significantly lower, providing evidence for an association between CPs and photorespiration. PMID- 25701382 TI - HPV- and non-HPV-related subtypes of penile squamous cell carcinoma (SCC): Morphological features and differential diagnosis according to the new WHO classification (2015). AB - The majority of penile carcinomas are squamous cell carcinomas originating in the squamous mucosa covering the glans, coronal sulcus, or inner surface of the foreskin, the 3 latter sites comprising the penile anatomical compartments. There is a variegated spectrum of subtypes of penile squamous cell carcinomas according to recent classification schemes. Currently, because of etiological and prognostic considerations, 2 morphologically and molecularly distinctive groups of subtypes of penile SCCs based on the presence of HPV were delineated. The predominant cell composition of tumors associated with HPV is the basaloid cell, which is the hallmark and best tissue marker for the virus. Tumors negative for the virus, however, are preferentially of lower grade and keratinizing maturing neoplasms with the exception of sarcomatoid carcinoma. HPV is detected in research studies by PCR or in situ hybridization (ISH) technologies, but p16 immunohistochemical stain is an adequate and less-expensive surrogate that is useful in the routine practice of pathology. The aim of this review is to demonstrate the variable morphological phenotypic expression of penile tumors separating non-HPV- and HPV-related neoplasms and to add morphological information that will justify subclassifying squamous cell carcinomas in a number of special subtypes. A brief discussion of the differential diagnosis in each category is also provided. PMID- 25701383 TI - Clinicopathological features and histogenesis of penile cysts. AB - Cysts arising in the penis are uncommon and can be found anywhere from the urethral meatus to the root of the penis involving glans, foreskin, or shaft. Median raphe cysts account for the majority of penile cystic lesions reported in the literature. As their name suggests, they arise on the ventral midline of the penis that extends from the urethral meatus to the scrotum and perineum. Proposed hypotheses for their origin as well as their diverse morphology are discussed. PMID- 25701384 TI - Phylogenetic analysis and expression profiling of the pattern recognition receptors: Insights into molecular recognition of invading pathogens in Manduca sexta. AB - Pattern recognition receptors (PRRs) detect microbial pathogens and trigger innate immune responses. Previous biochemical studies have elucidated the physiological functions of eleven PRRs in Manduca sexta but our understanding of the recognition process is still limited, lacking genomic perspectives. While 34 C-type lectin-domain proteins and 16 Toll-like receptors are reported in the companion papers, we present here 120 other putative PRRs identified through the genome annotation. These include 76 leucine-rich repeat (LRR) proteins, 14 peptidoglycan recognition proteins, 6 EGF/Nim-domain proteins, 5 beta-1,3 glucanase-related proteins, 4 galectins, 4 fibrinogen-related proteins, 3 thioester proteins, 5 immunoglobulin-domain proteins, 2 hemocytins, and 1 Reeler. Sequence alignment and phylogenetic analysis reveal the evolution history of a diverse repertoire of proteins for pathogen recognition. While functions of insect LRR proteins are mostly unknown, their structure diversification is phenomenal: In addition to the Toll homologs, 22 LRR proteins with a signal peptide are expected to be secreted; 18 LRR proteins lacking signal peptides may be cytoplasmic; 36 LRRs with a signal peptide and a transmembrane segment may be non-Toll receptors on the surface of cells. Expression profiles of the 120 genes in 52 tissue samples reflect complex regulation in various developmental stages and physiological states, including some likely by Rel family transcription factors via kappaB motifs in the promoter regions. This collection of information is expected to facilitate future biochemical studies detailing their respective roles in this model insect. PMID- 25701385 TI - Multicopper oxidase-1 orthologs from diverse insect species have ascorbate oxidase activity. AB - Members of the multicopper oxidase (MCO) family of enzymes can be classified by their substrate specificity; for example, ferroxidases oxidize ferrous iron, ascorbate oxidases oxidize ascorbate, and laccases oxidize aromatic substrates such as diphenols. Our previous work on an insect multicopper oxidase, MCO1, suggested that it may function as a ferroxidase. This hypothesis was based on three lines of evidence: RNAi-mediated knock down of Drosophila melanogaster MCO1 (DmMCO1) affects iron homeostasis, DmMCO1 has ferroxidase activity, and DmMCO1 has predicted iron binding residues. In our current study, we expanded our focus to include MCO1 from Anopheles gambiae, Tribolium castaneum, and Manduca sexta. We verified that MCO1 orthologs have similar expression profiles, and that the MCO1 protein is located on the basal surface of cells where it is positioned to oxidize substrates in the hemolymph. In addition, we determined that RNAi mediated knock down of MCO1 in A. gambiae affects iron homeostasis. To further characterize the enzymatic activity of MCO1 orthologs, we purified recombinant MCO1 from all four insect species and performed kinetic analyses using ferrous iron, ascorbate and two diphenols as substrates. We found that all of the MCO1 orthologs are much better at oxidizing ascorbate than they are at oxidizing ferrous iron or diphenols. This result is surprising because ascorbate oxidases are thought to be specific to plants and fungi. An analysis of three predicted iron binding residues in DmMCO1 revealed that they are not required for ferroxidase or laccase activity, but two of the residues (His374 and Asp380) influence oxidation of ascorbate. These two residues are conserved in MCO1 orthologs from insects and crustaceans; therefore, they are likely to be important for MCO1 function. The results of this study suggest that MCO1 orthologs function as ascorbate oxidases and influence iron homeostasis through an unknown mechanism. PMID- 25701386 TI - Flame retardant emission from e-waste recycling operation in northern Vietnam: environmental occurrence of emerging organophosphorus esters used as alternatives for PBDEs. AB - Three oligomeric organophosphorus flame retardants (o-PFRs), eight monomeric PFRs (m-PFRs), tetrabromobisphenol A (TBBPA), and polybrominated diphenyl ethers (PBDEs) were identified and quantified in surface soils and river sediments around the e-waste recycling area in Bui Dau, northern Vietnam. Around the e waste recycling workshops, 1,3-phenylene bis(diphenyl phosphate) (PBDPP), bisphenol A bis(diphenyl phosphate) (BPA-BDPP), triphenyl phosphate (TPHP), TBBPA, and PBDEs were dominant among the investigated flame retardants (FRs). The respective concentrations of PBDPP, BPA-BDPP, TPHP, TBBPA and the total PBDEs were 6.6-14000 ng/g-dry, <2-1500 ng/g-dry, 11-3300 ng/g-dry, <5-2900 ng/g-dry, and 67-9200 ng/g-dry in surface soils, and 4.4-78 ng/g-dry, <2-20 ng/g-dry, 7.3 38 ng/g-dry, 6.0-44 ng/g-dry and 100-350 ng/g-dry in river sediments. Near the open burning site of e-waste, tris(methylphenyl) phosphate (TMPP), (2 ethylhexyl)diphenyl phosphate (EHDPP), TPHP, and the total PBDEs were abundantly with respective concentrations of <2-190 ng/g-dry, <2-69 ng/g-dry, <3-51 ng/g-dry and 1.7-67 ng/g-dry in surface soils. Open storage and burning of e-waste have been determined to be important factors contributing to the emissions of FRs. The environmental occurrence of emerging FRs, especially o-PFRs, indicates that the alternation of FRs addition in electronic products is shifting in response to domestic and international regulations of PBDEs. The emissions of alternatives from open storage and burning of e-waste might become greater than those of PBDEs in the following years. The presence and environmental effects of alternatives should be regarded as a risk factor along with e-waste recycling. PMID- 25701387 TI - [Prevention of periprosthetic joint infections : Not evidence-based strategies]. AB - BACKGROUND: Surgical site infections are the most common nosocomial infections in orthopedic surgery. Strategies to prevent these infections are of enormous relevance. OBJECTIVES: Evidence-based procedures such as hand disinfection, prophylactic antibiotic application, hair removal with electric clippers, or preoperative treatment of Staphyloccus aureus are listed in national and international guidelines. Beside these measures, several scientifically not confirmed methods, e.g., the administration of antibiotic prophylaxis for several days or the usage of helmets during surgery, are still practiced. These measures are not evidence-based and should not be performed anymore. CONCLUSION: Only the consequent implementation of evidence-based procedures can help prevent surgical site infections. PMID- 25701388 TI - Chinese women's preferences and concerns regarding incision location for breast augmentation surgery: a survey of 216 patients. AB - BACKGROUND: The axillary approach is the dominant incision used in China for breast augmentation. Systematic preoperative education regarding incision locations for breast augmentation is scarce in China. In this study, we surveyed Chinese patients to ascertain their preferences and concerns for incision location based on a comprehensive understanding of different incisions. METHODS: We used a literature review, patient interviews, and expert panels to develop the preoperative education material and questionnaire regarding different incision locations. The respondents were requested to choose one incision location before and after they received the preoperative education. Their initial choices and final decisions as well as the reasons for these choices were recorded and analyzed. Multinomial logistic regression was preformed to analyze the affecting factors on the incision choice. RESULTS: A total of 216 Chinese women participated in the study between 2012.5 and 2014.1. Initially, 176 (81.48%) women chose axillary incision, 27 (12.50%) chose periareolar incision, and 13 (6.02%) chose inframammary fold (IMF) incision. After they received preoperative education on incisions, the axillary and periareolar approaches decreased to 117 (54.17%) and 13 (6.02%), respectively, while IMF increased to 86 (39.81%). The easily hidden scar (43.98%), lower capsular contracture rate (23.15%), and lower possibility of injury to the breast parenchyma (17.13%) ranked as the top 3 reasons for the incision choice. Patients with a preoperative cup size of AA were 12.316 times more likely to choose the axillary approach relative to the IMF approach compared with those with a B cup (P = 0.044; 95% confidence interval [CI] 1.069-141.923). For each one-unit increase in BMI, the odds that a patient would choose the axillary versus the periareolar approach decreased by 32.4% (P = 0.049; 95% CI 0.457-0.999). CONCLUSIONS: The systematic and objective preoperative education material and questionnaire regarding different incision locations helped the Chinese patients make truly informed decisions and express their personal requirements. The axillary approach was the first option for more than half of Chinese women mainly because an easily hidden scar was considered the primary concern during the decision-making process. The patients with a low BMI and a small preoperative breast cup size were more likely to choose an axillary incision. However, a considerable number of Chinese women would choose the IMF incision and value its superiority in terms of a lower capsular contracture rate, less tissue trauma, and lower possibility of injury to the breast parenchyma. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266. PMID- 25701389 TI - A review of visual perception mechanisms that regulate rapid adaptive camouflage in cuttlefish. AB - We review recent research on the visual mechanisms of rapid adaptive camouflage in cuttlefish. These neurophysiologically complex marine invertebrates can camouflage themselves against almost any background, yet their ability to quickly (0.5-2 s) alter their body patterns on different visual backgrounds poses a vexing challenge: how to pick the correct body pattern amongst their repertoire. The ability of cuttlefish to change appropriately requires a visual system that can rapidly assess complex visual scenes and produce the motor responses-the neurally controlled body patterns-that achieve camouflage. Using specifically designed visual backgrounds and assessing the corresponding body patterns quantitatively, we and others have uncovered several aspects of scene variation that are important in regulating cuttlefish patterning responses. These include spatial scale of background pattern, background intensity, background contrast, object edge properties, object contrast polarity, object depth, and the presence of 3D objects. Moreover, arm postures and skin papillae are also regulated visually for additional aspects of concealment. By integrating these visual cues, cuttlefish are able to rapidly select appropriate body patterns for concealment throughout diverse natural environments. This sensorimotor approach of studying cuttlefish camouflage thus provides unique insights into the mechanisms of visual perception in an invertebrate image-forming eye. PMID- 25701390 TI - The association of renin-angiotensin system genes with the progression of hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Angiogenesis is reported to play a pivotal role in the occurrence, development and metastasis of HCC. The renin-angiotensin system (RAS) is involved in the regulation of angiogenesis. Here, based on the analysis of HCC datasets from Gene Expression Omnibus (GEO) database and The Cancer Genome Atlas (TCGA), we found that there was a negative correlation between the mRNA levels of angiotensin converting enzyme 2 (ACE2) and CD34. To explore the association of RAS with the progression from fibrosis to cirrhosis to HCC, liver specimens and serum samples were collected from patients with hepatic fibrosis, cirrhosis and HCC. Relative hepatic mRNA levels of CD34 and ACE2 were determined by real-time PCR, and the serum concentrations of Angiotensin II (Ang II), Ang (1-7) and vascular endothelial growth factor (VEGF) were detected by ELISA. We found that ACE2 mRNA was gradually decreased, while CD34 mRNA was progressively increased with the increasing grade of disease severity. Concentrations of Ang II, Ang (1-7) and VEGF were higher in the sera of patients than in that of healthy volunteers. These proteins' concentrations were also progressively increased with the increasing grade of disease severity. Moreover, a positive correlation was found between VEGF and Ang II or Ang (1-7), while negative correlation was observed between mRNA levels of CD34 and ACE2. More importantly, patients with higher level of ACE2 expression had longer survival time than those with lower level of ACE2 expression. Taken together, our data suggests that the low expression of ACE2 may be a useful indicator of poor prognosis in HCC. The RAS may have a role in the progression of HCC. PMID- 25701391 TI - Structure-function relationships in human d-amino acid oxidase variants corresponding to known SNPs. AB - In the brain, d-amino acid oxidase plays a key role in modulating the N-methyl-d aspartate receptor (NMDAR) activation state, catalyzing the stereospecific degradation of the coagonist d-serine. A relationship between d-serine signaling deregulation, NMDAR dysfunction, and CNS diseases is presumed. Notably, the R199W substitution in human DAAO (hDAAO) was associated with familial amyotrophic lateral sclerosis (ALS), and further coding substitutions, i.e., R199Q and W209R, were also deposited in the single nucleotide polymorphism database. Here, we investigated the biochemical properties of these different hDAAO variants. The W209R hDAAO variant shows an improved d-serine degradation ability (higher activity and affinity for the cofactor FAD) and produces a greater decrease in cellular d/(d+l) serine ratio than the wild-type counterpart when expressed in U87 cells. The production of H2O2 as result of excessive d-serine degradation by this hDAAO variant may represent the factor affecting cell viability after stable transfection. The R199W/Q substitution in hDAAO altered the protein conformation and enzymatic activity was lost under conditions resembling the cellular ones: this resulted in an abnormal increase in cellular d-serine levels. Altogether, these results indicate that substitutions that affect hDAAO functionality directly impact on d-serine cellular levels (at least in the model cell system used). The pathological effect of the expression of the R199W hDAAO, as observed in familial ALS, originates from both protein instability and a decrease in kinetic efficiency: the increase in synaptic d-serine may be mainly responsible for the neurotoxic effect. This information is expected to drive future targeted treatments. PMID- 25701392 TI - Clinical echocardiographic indices of left ventricular diastolic function correlate poorly with pulmonary capillary wedge pressure at 1 year following heart transplantation. AB - Clinical echocardiographic assessment of left ventricular (LV) systolic and diastolic function is routinely performed following orthotopic heart transplantation (OHT). The purpose of this study was to determine whether echocardiographic indices of LV diastolic function correlate with pulmonary capillary wedge pressure (PCWP) in the transplanted heart. Patients who had OHT between June 2009 and November 2011 underwent transthoracic echocardiography and right heart catheterization (RHC) at approximately 1 year post transplantation. We retrospectively assessed 33 potential parameters of LV diastolic function using 2-dimensional, spectral Doppler and tissue Doppler echocardiography. We measured PCWP by RHC. We compared echocardiographic measures with PCWP using linear regression analysis. Ninety-five patients (mean age 49 +/- 13 years, 73 males, mean LV ejection fraction 62 +/- 10%) were included in the study. Overall, echocardiographic parameters of LV diastolic function demonstrated poor correlation with PCWP. By linear regression, the parameter that most strongly correlated with PCWP was left atrial (LA) minimum area in the apical 4-chamber view (p = 0.002, r(2) = 0.1). Comparing patients with PCWP <= 12 mmHg and those with PCWP > 12 mmHg, the parameter that demonstrated the most significant difference was LA minimum area in the apical 2-chamber view (p = 0.002), and comparing patients with PCWP <= 15 mmHg and those with PCWP > 15 mmHg, the most significant difference was peak early diastolic velocity of the mitral annulus (p = 0.02). In patients with cardiac allografts, clinical echocardiographic measures of LV diastolic function correlate poorly with PCWP. PMID- 25701393 TI - Is immediate bony microsurgical reconstruction after head and neck tumor ablation associated with a higher rate of local recurrence? AB - The purpose of this retrospective study was to examine the possible effect of immediate bony microvascular free flap reconstruction of mandibular defects after radical tumor resection of oral squamous cell carcinoma (OSCC) on the rate of local relapse. Our own data regarding recurrence rates for 1-step immediate reconstruction were compared to the published recurrence rates of 2-step reconstructions. A total of 21 patients (aged 45-77 years) with OSCC who underwent a primary surgical therapy with subsequent immediate bony microvascular free flap reconstruction of mandibular defects were followed up for 18-38 months. Four local relapses (19%) were recorded, all in patients with initial tumor stage of T4. Although intraoperative histological findings were R0 in all 21 cases, definitive histology later detected R1 status in the resected bone in 2 cases (10%). Immediate bony free flap reconstruction of mandibular defects after radical surgical resection of OSCC does not seem to increase the risk of local recurrence nor affect patient survival when compared with the 2-step surgical approach. PMID- 25701394 TI - Motor imagery of gait in non-demented older community-dwellers: performance depends on serum 25-hydroxyvitamin D concentrations. AB - Hypovitaminosis D has been associated with poorer physical and cognitive performances in older adults. The objectives of this study were (1) to measure and compare the time to perform (pTUG) and to imagine (iTUG) the Timed "Up & Go" test (TUG) test, and the time difference between these two performances (i.e., TUG delta time) in non-demented community-dwelling older adults with and without lower serum 25-hydroxyvitamin D (25OHD) concentrations and (2) to examine the association between the TUG delta time and serum 25OHD concentrations. Durations of pTUG, iTUG and TUG delta time, and serum 25OHD concentrations (severe insufficiency <10 ng/mL; moderate insufficiency: 10-30 ng/mL; normal status >30 ng/mL) were measured in 359 non-demented participants (mean age 70.4 +/- 4.8 years; 40.7 % women). Participants with severe 25OHD insufficiency (15.6 %) had higher TUG delta time compared to those with moderate insufficiency (P = 0.010) and normal status (P = 0.048). TUG delta time was negatively associated with serum 25OHD concentrations (P < 0.010). Accurate motor imagery of gait was explained in part by serum 25OHD concentrations, increased discrepancy between pTUG and iTUG being associated with lower serum 25OHD concentrations. PMID- 25701395 TI - Age- and gender-dependent heterogeneous proportion of variation explained by SNPs in quantitative traits reflecting human health. AB - Age-related effects are often included as covariates in the analytical model for genome-wide association analysis of quantitative traits reflecting human health. Nevertheless, previous studies have hardly examined the effects of age on the proportion of variation explained by single nucleotide polymorphisms (PVSNP) in these traits. In this study, the PVSNP estimates of body mass index (BMI), waist to-hip ratio, pulse pressure, high-density lipoprotein cholesterol level, triglyceride level (TG), low-density lipoprotein cholesterol level, and glucose level were obtained from Korean consortium metadata partitioned by gender or by age. Restricted maximum likelihood estimates of the PVSNP were obtained in a mixed model framework. Previous studies using pedigree data suggested possible differential heritability of certain traits with regard to gender, which we observed in our current study (BMI and TG; P < 0.05). However, the PVSNP analysis based on age revealed that, with respect to every trait tested, individuals aged 40 to 49 exhibited significantly lower PVSNP estimates than individuals aged 50 to 59 or 60 to 69 (P < 0.05). The consistent heterogeneous PVSNP with respect to age may be due to degenerated genetic functions in individuals between the ages of 50 and 69. Our results suggest the genetic mechanism of age- and gender dependent PVSNP of quantitative traits related to human health should be further examined. PMID- 25701396 TI - Hedgehog signaling: From basic research to clinical applications. AB - Studies of the major signaling pathways have revealed a connection between development, regeneration, and cancer, highlighting common signaling networks in these processes. The Hedgehog (Hh) pathway plays a central role in the development of most tissues and organs in mammals. Hh signaling is also required for tissue homeostasis and regeneration in adults, while perturbed Hh signaling is associated with human cancers. A fundamental understanding of Hh signaling will not only enhance our knowledge of how the embryos are patterned but also provide tools to treat diseases related to aberrant Hh signaling. Studies have yielded a basic framework of Hh signaling, which establishes the foundation for addressing unresolved issues of Hh signaling. A detailed characterization of the biochemical interactions between Hh components will help explain the production of graded Hh responses required for tissue patterning. Additional cell biological and genetic studies will offer new insight into the role of Hh signaling in homeostasis and regeneration. Finally, drugs that are capable of manipulating the Hh pathway can be used to treat human diseases caused by disrupted Hh signaling. These investigations will serve as a paradigm for studying signal transduction/integration in homeostasis and disease, and for translating discovery from bench to bedside. PMID- 25701397 TI - Progression and variation of fatty infiltration of the thigh muscles in Duchenne muscular dystrophy, a muscle magnetic resonance imaging study. AB - The purpose of this study was to assess the progression and variation of fatty infiltration of the thigh muscles of Duchenne muscular dystrophy patients. Muscle magnetic resonance imaging was used to measure the degree of fatty infiltration of the thigh muscles of 171 boys with Duchenne muscular dystrophy (mean age, 6.09 +/- 2.30 years). Fatty infiltration was assigned using a modified Mercuri's scale 0-5 (normal-severe). The gluteus maximus and adductor magnus were affected in patients less than two years old, followed by the biceps femoris. Quadriceps and semimembranosus were first affected at the age of five to six years; the sartorius, gracilis and adductor longus remained apparently unaffected until seven years of age. Fatty infiltration of all the thigh muscles developed rapidly after seven years of age. The standard deviation of the fatty infiltration scores ranged from 2.41 to 4.87 before five years old, and from 6.84 to 11.66 between six and ten years old. This study provides evidence of highly variable degrees of fatty infiltration in children of different ages with Duchenne muscular dystrophy, and indicates that fatty infiltration progresses more quickly after seven years of age. These findings may be beneficial for the selection of therapeutic regimens and the analysis of future clinical trials. PMID- 25701398 TI - Dietary nitrite induces nitrosation of the gastric mucosa: the protective action of the mucus and the modulatory effect of red wine. AB - The stomach chemical environment promotes the production of new molecules that can induce post-translational modifications of endogenous proteins with physiological impact. The nitrate-nitrite-nitric oxide pathway is relevant in this process via production of nitric oxide ((*)NO) and nitric oxide-derived nitrogen oxides (NOx) at high concentrations. Using a highly sensitive and selective chemiluminescence approach, we found that exposure the stomach of rats to nitrite yielded S- and N-nitroso derivatives in gastric mucus cysteine-rich glycoproteins (mucins). To lesser extent, the underlying epithelial cell layers also suffered nitrite-driven S- and N-nitroso modifications which increased upon mucus removal, indicating that, under normal nitrite load, (*)NO and NOx can reach inner layers of the stomach wall and locally modify proteins. S-nitrosation was by large the predominant modification. In vitro and ex vivo experiments indicated that the gastric nitrosation pattern is triggered by dietary nitrite in a concentration dependent manner, encompassing the intermediary formation of (*)NO and is susceptible to modulation by dietary reductants, notably red wine polyphenols. Collectively, these results suggest a protective action of the mucus and potential (*)NO-dependent biochemical effects at deeper cells layers of the mucosa. PMID- 25701399 TI - John A. Schellman, 1924-2014. PMID- 25701400 TI - A labor and cost effective next generation sequencing of PKHD1 in autosomal recessive polycystic kidney disease patients. AB - The Sanger sequencing of patients with recessive polycystic kidney disease is challenging due to the length and heterogeneous mutational spectrum of the PKHD1 gene. Next generation sequencing (NGS) might thus be of special interest to search for PKHD1 mutations. The study involved a total of 22 patients with autosomal recessive polycystic kidney disease (ARPKD) and 8 parents of non available ARPKD patients. Five pools of 6 samples each were sequenced with the Personal Genome Machine (PGM, Ion Torrent). For each DNA pool, a total of 109 fragments that covered the entire PKHD1 coding sequence were amplified in only two tubes followed by library preparation and NGS with the PGM. To validate the technique, each pool contained the DNA of at least one patient with known mutation. The putative mutations identified in each pool were confirmed and assigned to specific individuals through Sanger sequencing. All but one of the 109 amplicons were successfully read, and we identified the two PKHD1 mutations in 11 of the ARPKD cases, one mutation in 9 patients, and no mutation in only 2 patients. Six of the 8 parents from non-available patients were mutation carriers. The reported procedure would facilitate the large scale analysis of PKHD1 with a significant reduction in cost and labor. PMID- 25701401 TI - Functional characterization of the mouse melanocortin 3 receptor gene promoter. AB - Melanocortin receptor 3 (MC3R) is expressed in the hypothalamus and pituitary in humans and rodents, and is involved in the control of feeding, energy metabolism, and pituitary function. In the mouse pituitary, MC3R is detected in mammotrophs. This study aimed to clarify the regulatory mechanism for Mc3r expression in the mouse pituitary. The promoter activities of reporter constructs for the MC3R gene 5'-flanking region up to -4000 bp (transcription initiation site designated as +1) were analyzed. The promoter activity significantly increased in the -86/+109 construct, but decreased in the -38/+109 construct, indicating that the minimal promoter required for basal expression of Mc3r is located in the -86/+109 region. Putative binding sites for transcription factors AP-1 and ATF4 were found in the 5'-flanking region of Mc3r. Site-directed mutation or deletion of these sites affected the promoter activities. In gel-shift assays with a nuclear extract of mouse anterior pituitary cells, band-shifts were detected for both sites after the addition of the nuclear extract, and were decreased in the presence of excess unlabeled probe competitors. These results indicated that both sites were involved in the regulation of Mc3r expression in anterior pituitary cells. Estradiol-17beta treatment increased the Mc3r promoter activity, indicating that the gene is regulated by estradiol-17beta. In conclusion, we have demonstrated the minimum promoter region required for Mc3r expression, and identified two binding sites for AP-1 and ATF4 and in the 5' upstream-flanking region of Mc3r that are essential for Mc3r expression. PMID- 25701402 TI - From Arabia to Iberia: A Y chromosome perspective. AB - At different times during recent human evolution, northern Africa has served as a conduit for migrations from the Arabian Peninsula. Although previous researchers have investigated the possibility of the Strait of Gibraltar as a pathway of migration from North Africa to Iberia, we now revisit this issue and theorize that although the Strait of Gibraltar, at the west end of this corridor, has acted as a barrier for human dispersal into Southwest Europe, it has not provided an absolute seal to gene flow. To test this hypothesis, here we use the spatial frequency distributions, STR diversity and expansion time estimates of Y chromosome haplogroups J1-P58 and E-M81 to investigate the genetic imprints left by the Arabian and Berber expansions into the Iberian Peninsula, respectively. The data generated indicate that Arabian and Berber genetic markers are detected in Iberia. We present evidence that suggest that Iberia has received gene flow from Northwest Africa during and prior to the Islamic colonization of 711A.D. It is interesting that the highest frequencies of Arabia and Berber markers are not found in southern Spain, where Islam remained the longest and was culturally most influential, but in Northwest Iberia, specifically Galicia. We propose that Moriscos' relocations to the north during the Reconquista, the migration of cryptic Muslims seeking refuge in a more lenient society and/or more geographic extensive pre-Islamic incursions may explain the higher frequencies and older time estimates of mutations in the north of the Peninsula. These scenarios are congruent with the higher diversities of some diagnostic makers observed in Northwest Iberia. PMID- 25701403 TI - Two fission yeast high mobility group box proteins in the maintenance of genomic integrity following doxorubicin insult. AB - Drug resistance is a challenge in chemotherapy, and, to date, there has been little resolution as to how it is induced. We previously isolated a host of doxorubicin resistance (DXR) genes in fission yeast and here we investigate the regulation of this resistance through two high mobility group (HMG) motif containing DXR proteins, Nht1 and Hap2. The concurrent deletion of nht1 and hap2 did not confer cumulative sensitivity to doxorubicin, indicating that these factors cooperate closely in similar epistatic groups. We show that doxorubicin treatment resulted in the subcellular reorganization of Rhp54, a homologous recombination-dependent DNA damage repair protein. The disruption of either nht1 or hap2 attenuated Rhp54-foci formation, suggesting that these factors modulate the repair of doxorubicin-induced DNA lesions via the recruitment of homologous recombination machinery. Epistatic analyses further confirmed that Nht1 and Hap2 act in similar functional groups with complexes related to DSB repair but act synergistically with factors that regulate transcription and chromosome segregation. Overall, this work shows the molecular crosstalk coordinated by HMG proteins in conferring doxorubicin resistance in fission yeast. PMID- 25701404 TI - Structural stability of myoglobin and glycomyoglobin: a comparative molecular dynamics simulation study. AB - Glycoproteins are formed as the result of enzymatic glycosylation or chemical glycation in the body, and produced in vitro in industrial processes. The covalently attached carbohydrate molecule(s) confer new properties to the protein, including modified stability. In the present study, the structural stability of a glycoprotein form of myoglobin, bearing a glucose unit in the N terminus, has been compared with its native form by the use of molecular dynamics simulation. Both structures were subjected to temperatures of 300 and 500 K in an aqueous environment for 10 ns. Changes in secondary structures and RMSD were then assessed. An overall higher stability was detected for glycomyoglobin, for which the most stable segments/residues were highlighted and compared with the native form. The simple addition of a covalently bound glucose is suggested to exert its stabilizing effect via increased contacts with surrounding water molecules, as well as a different pattern of interactions with neighbor residues. PMID- 25701405 TI - Comparative analysis of the RTFL peptide family on the control of plant organogenesis. AB - Plant peptides play important roles in various aspects of plant growth and development. The RTFL/DVL family includes small peptides that are widely conserved among land plants. Overexpression of six RTFL genes in Arabidopsis was suggestive of their functions as negative regulators of cell proliferation and as positional cues along the longitudinal axis of the plant body . At this time, few reports are available on RTFL paralogs in other species and the evolutionary relationship of RTFL members among land plants remains unclear. In this study, we compared and analyzed whole amino acid sequences of 188 RTFL members from 22 species among land plants and identified 73 motifs. All RTFL members could be grouped into four clades, and each clade exhibited specific motif patterns, indicative of unique evolutionary traits in the RTFL family. In agreement with this hypothesis, we analyzed two RTFL members from Oryza sativa and Arabidopsis by overexpressing them in Arabidopsis, revealing similar phenotypes suggestive of a conserved function of the RTFL family between eudicots and monocots, as well as different phenotypes and unique functions. PMID- 25701406 TI - Downregulation of Survivin by shRNA Inhibits Invasion and Enhances the Radiosensitivity of Laryngeal Squamous Cell Carcinoma. AB - Radiotherapy is an important treatment modality for laryngeal carcinoma, however, some patients with early stage laryngeal carcinomas showed resistance to radiotherapy. Survivin overexpression is associated with radioresistance of laryngeal squamous cell carcinoma. We speculated that the inhibition of survivin expression might improve the radiosensitivity of laryngeal carcinoma. We assessed the effect of survivin expressions by shRNA on the radiosensitivity of laryngeal squamous cell carcinoma in vitro and in vivo. After transfection of shRNA targeting survivin, MTS assay showed that the survival rates of radiation groups were reduced with the prolongation of culture time (p < 0.05). In addition, shRNA targeting survivin abrogated radiation-induced G2 phase arrest and amplified radiation-induced apoptosis. In vivo, shRNA transfection also sensitized tumor xenograft to radiotherapy. Radioresistance of laryngeal squamous cell carcinoma may be associated with increased expression of survivin, and survivin suppression may enhance the radiosensitivity of laryngeal squamous cell carcinoma. PMID- 25701407 TI - Polyphenols in Regulation of Redox Signaling and Inflammation During Cardiovascular Diseases. AB - Cardiovascular diseases remain one of the major health problems worldwide. The worldwide research against cardiovascular diseases as well as genome wide association studies were successful in indentifying the loci associated with this prominent life-threatening disease but still a substantial amount of casualty remains unexplained. Over the last decade, the thorough understanding of molecular and biochemical mechanisms of cardiac disorders lead to the knowledge of various mechanisms of action of polyphenols to target inflammation during cardiac disorders. The present review article summarizes major mechanisms of polyphenols against cardiovascular diseases. PMID- 25701408 TI - Overexpression of Hiwi Inhibits the Growth and Migration of Chronic Myeloid Leukemia Cells. AB - Chronic myeloid leukemia (CML) is a hematopoietic malignancy characterized by dysregulated growth and proliferation of hematopoietic stem/progenitor cells in bone marrow and excessive expansion of hematopoietic compartments in peripheral blood. Expression deletion of Hiwi, a human Piwi homolog, has been reported to be implicated in leukemogenesis. We here explored Hiwi's role in CML pathogenesis by determining how and whether its forced overexpression could affect CML cell growth and migration. The present results showed that lentivirus-mediated overexpression of Hiwi significantly suppressed cell proliferation and induced obvious apoptosis in K562 cells, a CML line cell line. Tumors in BALB/c nude mice generated by the K562 cells expressing Hiwi were much smaller than those formed by the control cells. Like in vitro, Hiwi upregulation induced cell apoptosis in the tumor tissues in vivo. Additionally, Hiwi elevation suppressed K562 cell migration and inhibited the activity and expression of matrix metalloproteinase-2 and -9. In summary, our study demonstrates that Hiwi overexpression inhibits CML cell growth and migration, providing insights into its role in CML pathogenesis. PMID- 25701409 TI - Deviating the level of proliferating cell nuclear antigen in Trypanosoma brucei elicits distinct mechanisms for inhibiting proliferation and cell cycle progression. AB - The DNA replication machinery is spatially and temporally coordinated in all cells to reproduce a single exact copy of the genome per division, but its regulation in the protozoan parasite Trypanosoma brucei is not well characterized. We characterized the effects of altering the levels of proliferating cell nuclear antigen, a key component of the DNA replication machinery, in bloodstream form T. brucei. This study demonstrated that tight regulation of TbPCNA levels was critical for normal proliferation and DNA replication in the parasite. Depleting TbPCNA mRNA reduced proliferation, severely diminished DNA replication, arrested the synthesis of new DNA and caused the parasites to accumulated in G2/M. Attenuating the parasite by downregulating TbPCNA caused it to become hypersensitive to hydroxyurea. Overexpressing TbPCNA in T. brucei arrested proliferation, inhibited DNA replication and prevented the parasite from exiting G2/M. These results indicate that distinct mechanisms of cell cycle arrest are associated with upregulating or downregulating TbPCNA. The findings of this study validate deregulating intra-parasite levels of TbPCNA as a potential strategy for therapeutically exploiting this target in bloodstream form T. brucei. PMID- 25701410 TI - Pelvic magnetic resonance imaging angioanatomy of the arterial blood supply to the penis in suspected prostate cancer patients. AB - PURPOSE: To describe the internal pudendal artery (IPA) and accessory pudendal artery (APA) detected by magnetic resonance (MR) angiography to help surgeons to find and preserve them during radical prostatectomy (RP). MATERIALS AND METHODS: Constrast-enhanced MR 3.0 T angiography of the pelvis were performed in 111 male patients suspected diagnosis of prostate cancer (PCa), and describe the penile arterial blood supply. RESULTS: There are three patterns of the arterial blood supply to the penis (IPA and/or APA) accounting for 51.4%, 46.8% and 1.8% of cases, respectively. About the accessory pudendal artery (APA): 54/111 (48.6%) patients had APA with five different branching patterns, they were type I (APA bilateral symmetry): 17 (31.5%); type II (APA bilateral asymmetry): 1 (1.9%); type III (APA unilateral lateral): 13 (24%); type IV (APA unilateral apical): 21 (38.9%); type V (APA unilateral mix): 2 (3.7%). APA origin were from inferior epigastric artery (IEA): 7 (9.5%); from inferior vesical artery (IVA): 32 (43.2%); from obturator artery (OA): 35 (47.3%). CONCLUSION: A precise angioanatomic evalutation of arteries destined to the penis by MR angiography pre operation for male pelvic organs will help surgeons to preserve them and contributes to reduce the erectile dysfunction after these procedures. PMID- 25701411 TI - Novel polystyrene/antibody nanoparticle-coated capillary for immunoaffinity in tube solid-phase microextraction. AB - Antibody-coated polystyrene (PS) nanoparticles (denoted as PS/IgG) were prepared and chemically immobilized for the first time onto a capillary inner wall for immunoaffinity in-tube solid-phase microextraction (SPME) of beta2-microglobin (beta2MG) and cystatin C (Cys-C). Scanning electron microscopy images of the prepared capillary showed that the nanoparticles were evenly coated onto the capillary inner surface, resulting in the undulating surface of the capillary inner wall. The extraction capacity of the nanoparticle-coated capillary was nearly five times higher than that of a monolayer antibody-immobilized capillary. The in-tube SPME recovery of beta2MG (or Cys-C) by the nanoparticle functionalized capillary was more than 97.8%, whereas that by the monolayer antibody-immobilized tube was 30.5%. In addition, the method quantitation limit obtained by using the nanoparticle-coated capillary was ten times lower than that by the monolayer capillary. Therefore, the capillary coated by PS/IgG nanoparticles is more suitable for immunoaffinity in-tube SPME compared with the commonly used monolayer antibody-immobilized capillary. PMID- 25701412 TI - Quantitative analysis of Gd@C82(OH)22 and cisplatin uptake in single cells by inductively coupled plasma mass spectrometry. AB - Cisplatin is a commonly used chemotherapeutic drug in cancer treatment, whereas Gd@C82(OH)22 is a new nanomaterial anti-tumor agent. In this study, we determined intracellular Gd@C82(OH)22 and cisplatin after treatment of Hela and 16HBE cells by single cell inductively coupled plasma-mass spectrometry (SC-ICP-MS), which could provide quantitative information at a single-cell level. The cell digestion method validated the accuracy of the SC-ICP-MS. The concentrations of Gd@C82(OH)22 and cisplatin in cells at different exposure times and doses were studied. The SC-ICP-MS is a promising complement to available methods for single cell analysis and is anticipated to be applied further to biomedical research. PMID- 25701413 TI - Ripening-dependent metabolic changes in the volatiles of pineapple (Ananas comosus (L.) Merr.) fruit: I. Characterization of pineapple aroma compounds by comprehensive two-dimensional gas chromatography-mass spectrometry. AB - Qualitative ripening-dependent changes of pineapple volatiles were studied via headspace solid-phase microextraction and analyzed by comprehensive two dimensional gas chromatography quadrupole mass spectrometry (HS-SPME-GC*GC-qMS). Early green-ripe stage, post-harvest ripened, and green-ripe fruits at the end of their commercial shelf-life were compared to air-freighted pineapples harvested at full maturity. In total, more than 290 volatiles could be identified by mass spectrometry and their linear retention indices. The majority of compounds comprise esters (methyl and ethyl esters of saturated and unsaturated fatty acids, acetates), terpenes, alcohols, aldehydes, 2-ketones, free fatty acids, and miscellaneous gamma- and delta-lactones. The structured separation space obtained by GC*GC allowed revealing various homologous series of compound classes as well as clustering of sesquiterpenes. Post-harvest ripening increased the diversity of the volatile profile compared to both early green-ripe maturity stages and on plant ripened fruits. PMID- 25701414 TI - Fragmentation studies for the structural characterization of marine dissolved organic matter. AB - High-resolution tandem mass spectrometry by collision-induced dissociation with a linear ion trap-Orbitrap has been performed on marine dissolved organic matter (DOM). Product ion spectra of selected precursor ions (m/z 359-375) have been acquired to obtain structural information, after method development. To evaluate the performance of the method, the Suwannee River fulvic acid (SRFA) reference standard was also analyzed. By reconstructing the individual product ion spectrum of marine DOM, several fragments were assigned to the different precursor ions indicating the presence of carboxyl, hydroxyl, lactones, quinones, esters, and structures more similar to lignin-degraded molecules. On the basis of these findings, coastal marine DOM molecules, although structurally homogeneous, might be more rich in diversity of functional groups than previously described. PMID- 25701415 TI - Erratum to: lateral resolution of nanoscaled images delivered by surface analytical instruments: application of the BAM-L200 certified reference material and related ISO standards. PMID- 25701416 TI - Macromolecular crowding-assisted fabrication of liquid-crystalline imprinted polymers. AB - A macromolecular crowding-assisted liquid-crystalline molecularly imprinted monolith (LC-MIM) was prepared successfully for the first time. The imprinted stationary phase was synthesized with polymethyl methacrylate (PMMA) or polystyrene (PS) as the crowding agent, 4-cyanophenyl dicyclohexyl propylene (CPCE) as the liquid-crystal monomer, and hydroquinidine as the pseudo-template for the chiral separation of cinchona alkaloids in HPLC. A low level of cross linker (26%) has been found to be sufficient to achieve molecular recognition on the crowding-assisted LC-MIM due to the physical cross-linking of mesogenic groups in place of chemical cross-linking, and baseline separation of quinidine and quinine could be achieved with good resolution (R(s) = 2.96), selectivity factor (alpha = 2.16), and column efficiency (N = 2650 plates/m). In contrast, the LC-MIM prepared without crowding agents displayed the smallest diastereoselectivity (alpha = 1.90), while the crowding-assisted MIM with high level of cross-linker (80%) obtained the greatest selectivity factor (alpha = 7.65), but the lowest column efficiency (N = 177 plates/m). PMID- 25701417 TI - Determination of the surface density of polyethylene glycol on gold nanoparticles by use of microscale thermogravimetric analysis. AB - The widespread integration of nanoparticle technologies into biomedicine will depend on the ability to repeatedly create particles with well-defined properties and predictable behaviors. For this to happen, fast, reliable, inexpensive, and widely available techniques to characterize nanomaterials are needed. Characterization of the surface molecules is particularly important since the surface, including the surface molecule density, plays a dominant role in determining how nanoparticles interact with their surroundings. Here, 10 and 30 nm gold nanoparticle NIST Standard Reference Materials were functionalized with fluorescently labeled polyethylene glycol (PEG) with either thiolate or lipoic acid anchoring groups to evaluate analytical techniques for determining surface coverage. The coating of the nanoparticles was confirmed with dynamic light scattering, microscale thermogravimetric analysis (MU-TGA), and ultraviolet visible (UV-vis) spectroscopy. A UV-vis method for determining gold nanoparticle concentrations that takes into account spectral broadening upon functionalization was developed. The amount of bound PEG was quantified with MU-TGA, a technique analogous to thermogravimetric analysis that uses quartz crystal microbalances, and fluorescence spectroscopy of displaced ligands. It is shown that MU-TGA is a convenient technique for the quantification of ligands bound to inorganic particles while sacrificing a minimal amount of sample, and the treatment of the functionalized nanoparticle dispersions with dithiothreitol may be insufficient to achieve complete displacement of the surface ligands for quantification by fluorescence measurements. The MU-TGA and fluorescence results were used to determine ligand footprint sizes-average areas occupied by each ligand on the particles' surface. The lipoic acid bound ligands had footprint sizes of 0.21 and 0.25 nm(2) on 10 and 30 nm particles, respectively while the thiolate ligands had footprint sizes of 0.085 and 0.18 nm(2). PMID- 25701418 TI - Lipidome and metabolome analysis of fresh tobacco leaves in different geographical regions using liquid chromatography-mass spectrometry. AB - The combination of the lipidome and the metabolome can provide much more information in plant metabolomics studies. A method for the simultaneous extraction of the lipidome and the metabolome of fresh tobacco leaves was developed. Method validation was performed on the basis of the optimal ratio of methanol to methyl tert-butyl ether to water (37:45:68) from the design of experiments. Good repeatability was obtained. We found that 92.2% and 91.6% of the peaks for the lipidome and the metabolome were within a relative standard deviation of 20%, accounting for 94.6% and 94.6% of the total abundance, respectively. The intraday and interday precisions were also satisfactory. A total of 230 metabolites, including 129 lipids, were identified. Significant differences were found in lipidomic and metabolomic profiles of fresh tobacco leaves in different geographical regions. Highly unsaturated galactolipids, phosphatidylethanolamines, predominant phosphatidylcholines, most of the polyphenols, amino acids, and polyamines had a higher content in Yunnan province, and low-unsaturation-degree galactolipids, triacylglycerols, glucosylceramides with trihydroxy long-chain bases, acylated sterol glucosides, and some organic acids were more abundant in Henan province. Correlation analysis between differential metabolites and climatic factors indicated the vital importance of temperature. The fatty acid unsaturation degree of galactolipids could be influenced by temperature. Accumulation of polyphenols and decreases in the ratios of stigmasterols to sitosterols and glucosylstigmasterols to glucosylsitosterols were also correlated with lower temperature in Yunnan province. Furthermore, lipids were more sensitive to climatic variations than other metabolites. PMID- 25701419 TI - Cytoskeleton dynamics in drug-treated platelets. AB - Platelet activation is a key process in blood clot formation. During activation, platelets go through both chemical and physical changes, including secretion of chemical messengers and cellular shape change. Platelet shape change is mediated by the two major cytoskeletal elements in platelets, the actin matrix and microtubule ring. Most studies to date have evaluated these structures qualitatively, whereas this paper aims to provide a quantitative method of examining changes in these structures by fluorescently labeling the element of interest and performing single cell image analysis. The method described herein tracks the diameter of the microtubule ring and the circumference of the actin matrix as they change over time. Platelets were incubated with a series of drugs that interact with tubulin or actin, and the platelets were observed for variation in shape change dynamics throughout the activation process. Differences in shape change mechanics due to drug incubation were observable in each case. PMID- 25701420 TI - Development of a rapid multiplexed assay for the direct screening of antimicrobial residues in raw milk. AB - Antimicrobial residues found to be present in milk can have both health and economic impacts. For these reasons, the widespread routine testing of milk is required. Due to delays with sample handling and test scheduling, laboratory based tests are not always suited for making decisions about raw material intake and product release, especially when samples require shipping to a central testing facility. Therefore, rapid on-site screening tests that can produce results within a matter of minutes are required to facilitate rapid intake and product release processes. Such tests must be simple for use by non-technical staff. There is increasing momentum towards the development and implementation of multiplexing tests that can detect a range of important antimicrobial residues simultaneously. A simple in situ multiplexed planar waveguide device that can simultaneously detect chloramphenicol, streptomycin and desfuroylceftiofur in raw dairy milk, without sample preparation, has been developed. Samples are simply mixed with antibody prior to an aliquot being passed through the detection cartridge for 5 min before reading on a field-deployable portable instrument. Multiplexed calibration curves were produced in both buffer and raw milk. Buffer curves, for chloramphenicol, streptomycin and desfuroylceftiofur, showed linear ranges (inhibitory concentration (IC)20-IC80) of 0.1-0.9, 3-129 and 12-26 ng/ml, whilst linear range in milk was 0.13-0.74, 11-376 and 2-12 ng/ml, respectively, thus meeting European legislated concentration requirements for both chloramphenicol and streptomycin, in milk, without the need for any sample preparation. Desfuroylceftiofur-contaminated samples require only simple sample dilution to bring positive samples within the range of quantification. Assay repeatability and reproducibility were lower than 12 coefficient of variation (%CV), whilst blank raw milk samples (n = 9) showed repeatability ranging between 4.2 and 8.1%CV when measured on all three calibration curves. Graphical Abstract MBio SnapEsi reader and cartridge. PMID- 25701421 TI - Using dielectrophoresis to study the dynamic response of single budding yeast cells to Lyticase. AB - Budding yeast cells are quick and easy to grow and represent a versatile model of eukaryotic cells for a variety of cellular studies, largely because their genome has been widely studied and links can be drawn with higher eukaryotes. Therefore, the efficient separation, immobilization, and conversion of budding yeasts into spheroplast or protoplast can provide valuable insight for many fundamentals investigations in cell biology at a single cell level. Dielectrophoresis, the induced motion of particles in non-uniform electric fields, possesses a great versatility for manipulation of cells in microfluidic platforms. Despite this, dielectrophoresis has been largely utilized for studying of non-budding yeast cells and has rarely been used for manipulation of budding cells. Here, we utilize dielectrophoresis for studying the dynamic response of budding cells to different concentrations of Lyticase. This involves separation of the budding yeasts from a background of non-budding cells and their subsequent immobilization onto the microelectrodes at desired densities down to single cell level. The immobilized yeasts are then stimulated with Lyticase to remove the cell wall and convert them into spheroplasts, in a highly dynamic process that depends on the concentration of Lyticase. We also introduce a novel method for immobilization of the cell organelles released from the lysed cells by patterning multi-walled carbon nanotubes (MWCNTs) between the microelectrodes. PMID- 25701422 TI - Rapid and sensitive LC-MS-MS determination of 2-mercaptobenzothiazole, a rubber additive, in human urine. AB - 2-Mercaptobenzothiazole (MBT) is one of the most important vulcanization accelerators in the industrial production of rubber, especially car tires. Given its wide use in household articles and industrial rubber products it has a high potential to migrate into the environment. Humans can be exposed by dermal, oral, or inhalative routes. Incorporated MBT is excreted in urine, mainly as conjugates to glucuronide, sulfate, and mercapturic acid. On the basis of these facts MBT has been selected as a substance of high interest in the large scale 10-year German project on human biomonitoring (HBM); a cooperation between the German Federal Ministry for the Environment (BMUB) and the German Chemical Industry Association (VCI) with the objective of developing new analytical methods for relevant chemicals. The presented method was developed to determine MBT in human urine to reliably investigate the internal human MBT dose. Total MBT is measured after enzymatic hydrolysis followed by application of high-pressure liquid chromatography tandem mass spectrometry (HPLC-MS-MS) in positive-electrospray ionization mode (ESI+) using isotope-dilution quantification. High sample throughput could be obtained by use of the column-switching technique. Optimization yielded an analytical method with a low and reproducible limit of detection (LOD) of 0.4 MUg L(-1) and a limit of quantification (LOQ) of 1 MUg L( 1), and low relative standard deviations in the range 1.6-5.8 %. A small biomonitoring study covering unexposed humans and occupationally exposed workers was performed to establish the feasibility and reliability of the method. MBT was found in only one urine sample from the unexposed humans, at a value of 10.8 MUg MBT per liter, whereas it was found in all samples from the tested workers at values of up to 6210 MUg MBT per liter. PMID- 25701423 TI - Identification of carbonylated lipids from different phospholipid classes by shotgun and LC-MS lipidomics. AB - Oxidized lipids play a significant role in the pathogenesis of numerous oxidative stress-related human disorders, such as atherosclerosis, obesity, inflammation, and autoimmune diseases. Lipid peroxidation, induced by reactive oxygen and nitrogen species, yields a high variety of modified lipids. Among them, carbonylated lipid peroxidation products (oxoLPP), formed by oxidation of the fatty acid moiety yielding aldehydes or ketones (carbonyl groups), are electrophilic compounds that are able to modify nucleophilic substrates like proteins, nucleic acid, and aminophospholipids. Some carbonylated phosphatidylcholines possess even pro-inflammatory activities. However, little is known about oxoLPP derived from other phospholipid (PL) classes. Here, we present a new analytical strategy based on the mass spectrometry (MS) of PL-oxoLPP derivatized with 7-(diethylamino)coumarin-3-carbohydrazide (CHH). Shotgun MS revealed many oxoLPP derived from in vitro oxidized glycerophosphatidylglycerols (PG, 31), glycerophosphatidylcholine (PC, 23), glycerophosphatidylethanolamine (PE, 34), glycerophosphatidylserines (PS, 7), glycerophosphatidic acids (PA, 17), and phosphatidylinositiolphosphates (PIP, 6) vesicles. This data were used to optimize LipidXplorer-assisted identification, and a python-based post-processing script was developed to increase both throughput and accuracy. When applied to full lipid extracts from rat primary cardiomyocytes treated with peroxynitrite donor SIN-1, ten PL-bound oxoLPP were unambiguously identified by LC-MS, including two PC-, two PE-, one PG-, two PS-, and three PA-derived species. Some of the well-known carbonylated PC were detected, while most PL-oxoLPP were shown for the first time. PMID- 25701424 TI - Localization of double bonds in triacylglycerols using high-performance liquid chromatography/atmospheric pressure chemical ionization ion-trap mass spectrometry. AB - A method for localizing double bonds in triacylglycerols using high-performance liquid chromatography-tandem mass spectrometry with atmospheric pressure chemical ionization (APCI) was developed. The technique was based on collision-induced dissociation or pulsed Q collision-induced dissociation of the C3H5N(+*) adducts ([M + 55](+*)) formed in the presence of acetonitrile in the APCI source. The spectra were investigated using a large series of standards obtained from commercial sources and prepared by randomization. The fragmentation spectra made it possible to determine (i) the total number of carbons and double bonds in the molecule, (ii) the number of carbons and double bonds in acyls, (iii) the acyl in the sn-2 position on the glycerol backbone, and (iv) the double-bond positions in acyls. The double-bond positions were determined based on two types of fragments (alpha and omega ions) formed by cleavages of C-C bonds vinylic to the original double bond. The composition of the acyls and their positions on glycerol were established from the masses and intensities of the ions formed by the elimination of fatty acids from the [M + 55](+*) precursor. The method was applied for the analysis of triacylglycerols in olive oil and vernix caseosa. PMID- 25701425 TI - Development of a LC-MS/MS method for the simultaneous screening of seven water soluble vitamins in processing semi-coarse wheat flour products. AB - Wheat is the second largest crop cultivated around the world and constitutes a major part of the daily diet in Europe. It is therefore important to determine the content of micronutrient in wheat and wheat-based food products to define the contribution of wheat-based foods to the nutrition of the consumers. The aim of the present work was to develop a simple and rapid method based on liquid chromatography tandem mass spectrometry (LC-MS/MS) for the simultaneous determination of seven water-soluble vitamins in various wheat-based food materials. The vitamins present in the test material were separated in less than 15 min by using a reverse-phase C18 column, and analyzed by positive ion electrospray selected reaction monitoring MS/MS. The MS response for all the vitamins was linear over the working range (0.05 to 9 MUg/mL) with correlation coefficients ranging between 0.991 and 1. Limits of quantification in the different food materials ranged from 0.09 to 3.5 MUg/g. Intra-day and inter-day precision were found satisfactory. The developed method was applied for the simultaneous analysis of the water-soluble vitamin natural content of different semi-coarse wheat flours and in their corresponding baking products. PMID- 25701426 TI - Clinical and radiographic outcomes of supracondylar humerus fractures treated surgically by pediatric and non-pediatric orthopedic surgeons. AB - PURPOSE: This study compares clinical and radiographic outcomes of operatively managed pediatric supracondylar humerus fractures between patients treated by pediatric orthopedists (POs) and patients treated by non-pediatric orthopedists (NPOs). PATIENTS AND METHODS: A retrospective cohort study of pediatric patients with surgically managed supracondylar humerus fractures was conducted. For clinical outcomes analyses, 3 months of clinical follow-up were required, resulting in a sample size of 90 patients (33 treated by NPOs, 57 by POs). For radiographic outcomes analyses, 3 months of both clinical and radiographic follow up were required, resulting in a sample size of 57 patients (23 treated by NPOs, 34 by POs). RESULTS: The rate of inadequate fracture fixation was higher for patients treated by NPOs (43.5 %) than for patients treated by POs (14.7 %; p = 0.030), but rates of clinical complications, malreduction, and postoperative loss of reduction did not differ. Treatment with open reduction was more common for patients treated by NPOs (33.3 %) than for patients treated by POs (3.5 %; p < 0.001). Total operating room time was longer for patients treated by NPOs (110.9 min) than for patients treated by POs (82.9 min; p < 0.001). CONCLUSIONS: While patients treated by POs differed from patients treated by NPOs with respect to several intermediate outcomes, including having a lower rate of open reduction and a lower rate of inadequate fracture fixation, there were no differences between POs and NPOs in the rates of the more meaningful and definitive outcomes, including clinical complications, malreduction, and postoperative loss of reduction. PMID- 25701427 TI - High sensitivity of contact-heat evoked potentials in "snake-eye" appearance myelopathy. AB - OBJECTIVE: To evaluate the sensitivity of dermatomal contact-heat evoked potentials (dCHEPs) compared to dermatomal somatosensory evoked potentials (dSSEPs) and clinical sensory testing in patients with focal central cord myelopathy, referred to as "snake-eye" appearance myelopathy (SEAM). METHODS: 33 patients with SEAM in neuroimaging underwent electrophysiological (dCHEPs, dSSEPs) and clinical testing of sensory function (light touch [LT] and pin prick [PP]) at segments above, at and below to the spinal cord lesion. RESULTS: In total, 151 dermatomes were tested (39 above, 112 at/below lesion). The sensitivity of dCHEPs (97.0%) was significantly higher compared to dSSEPs (23.3%, p<0.001), PP (66.7%, p=0.003) and LT (69.7%, p=0.006), respectively. The sensitivity of dCHEPs was highest when applied one to two segments caudally to the level of spinal cord lesion in MRI. CONCLUSIONS: dCHEPs are highly sensitive and superior to dSSEPs and clinical sensory testing in the diagnosis of SEAM. SIGNIFICANCE: dCHEPs may complement the diagnosis in focal central cord myelopathies where clinical testing of sensory function and dSSEPs are less sensitive to provide conclusive findings. PMID- 25701428 TI - Somatosensory high frequency oscillations: A useful tool to analyze dynamic changes in somatosensory pathways? PMID- 25701429 TI - Hysteroscopy for treating subfertility associated with suspected major uterine cavity abnormalities. AB - BACKGROUND: Observational studies suggest higher pregnancy rates after the hysteroscopic removal of endometrial polyps, submucous fibroids, uterine septum or intrauterine adhesions, which are detectable in 10% to 15% of women seeking treatment for subfertility. OBJECTIVES: To assess the effects of the hysteroscopic removal of endometrial polyps, submucous fibroids, uterine septum or intrauterine adhesions suspected on ultrasound, hysterosalpingography, diagnostic hysteroscopy or any combination of these methods in women with otherwise unexplained subfertility or prior to intrauterine insemination (IUI), in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI). SEARCH METHODS: We searched the Cochrane Menstrual Disorders and Subfertility Specialised Register (8 September 2014), the Cochrane Central Register of Controlled Trials (The Cochrane Library 2014, Issue 9), MEDLINE (1950 to 12 October 2014), EMBASE (inception to 12 October 2014), CINAHL (inception to 11 October 2014) and other electronic sources of trials including trial registers, sources of unpublished literature and reference lists. We handsearched the American Society for Reproductive Medicine (ASRM) conference abstracts and proceedings (from January 2013 to October 2014) and we contacted experts in the field. SELECTION CRITERIA: Randomised comparisons between operative hysteroscopy versus control in women with otherwise unexplained subfertility or undergoing IUI, IVF or ICSI and suspected major uterine cavity abnormalities diagnosed by ultrasonography, saline infusion/gel instillation sonography, hysterosalpingography, diagnostic hysteroscopy or any combination of these methods. Primary outcomes were live birth and hysteroscopy complications. Secondary outcomes were pregnancy and miscarriage. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion and risk of bias, and extracted data. We contacted study authors for additional information. MAIN RESULTS: We retrieved 12 randomised trials possibly addressing the research questions. Only two studies (309 women) met the inclusion criteria. Neither reported the primary outcomes of live birth or procedure related complications. In women with otherwise unexplained subfertility and submucous fibroids there was no conclusive evidence of a difference between the intervention group treated with hysteroscopic myomectomy and the control group having regular fertility oriented intercourse during 12 months for the outcome of clinical pregnancy. A large clinical benefit with hysteroscopic myomectomy cannot be excluded: if 21% of women with fibroids achieve a clinical pregnancy having timed intercourse only, the evidence suggests that 39% of women (95% CI 21% to 58%) will achieve a successful outcome following the hysteroscopic removal of the fibroids (odds ratio (OR) 2.44, 95% confidence interval (CI) 0.97 to 6.17, P = 0.06, 94 women, very low quality evidence). There is no evidence of a difference between the comparison groups for the outcome of miscarriage (OR 0.58, 95% CI 0.12 to 2.85, P = 0.50, 30 clinical pregnancies in 94 women, very low quality evidence). The hysteroscopic removal of polyps prior to IUI can increase the chance of a clinical pregnancy compared to simple diagnostic hysteroscopy and polyp biopsy: if 28% of women achieve a clinical pregnancy with a simple diagnostic hysteroscopy, the evidence suggests that 63% of women (95% CI 50% to 76%) will achieve a clinical pregnancy after the hysteroscopic removal of the endometrial polyps (OR 4.41, 95% CI 2.45 to 7.96, P < 0.00001, 204 women, moderate quality evidence). AUTHORS' CONCLUSIONS: A large benefit with the hysteroscopic removal of submucous fibroids for improving the chance of clinical pregnancy in women with otherwise unexplained subfertility cannot be excluded. The hysteroscopic removal of endometrial polyps suspected on ultrasound in women prior to IUI may increase the clinical pregnancy rate. More randomised studies are needed to substantiate the effectiveness of the hysteroscopic removal of suspected endometrial polyps, submucous fibroids, uterine septum or intrauterine adhesions in women with unexplained subfertility or prior to IUI, IVF or ICSI. PMID- 25701430 TI - Review: Annexin-A5 and cell membrane repair. AB - Annexins are soluble proteins that bind to biological membranes containing negatively charged phospholipids, principally phosphatidylserine, in a Ca(2+) dependent manner. Annexin-A5 (AnxA5), the smallest member of the annexin family, presents unique properties of membrane binding and self-assembly into ordered two dimensional (2D) arrays on membrane surfaces. We have previously reported that AnxA5 plays a central role in the machinery of membrane repair by enabling rapid resealing of plasma membrane disruption in murine perivascular cells. AnxA5 promotes membrane repair via the formation of a protective 2D bandage at membrane damaged site. Here, we review current knowledge on cell membrane repair and present recent findings on the role of AnxA5 in membrane resealing of human trophoblasts. PMID- 25701431 TI - NADPH oxidase NOX1 is involved in activation of protein kinase C and premature senescence in early stage diabetic kidney. AB - Increased oxidative stress and activation of protein kinase C (PKC) under hyperglycemia have been implicated in the development of diabetic nephropathy. Because reactive oxygen species derived from nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, NOX1 accelerate the translocation of PKC isoforms, NOX1 is postulated to play a causative role in the development of diabetic nephropathy. Hyperglycemia was induced in wild-type and Nox1-deficient mice (KO) by two doses of streptozotocin injection. At 3 weeks after the induction of hyperglycemia, glomeruli and cortical tubules were isolated from kidneys. The mRNA level of Nox1 was significantly upregulated in the renal cortex at 3 weeks of hyperglycemia. Urinary albumin and expression of inflammatory or fibrotic mediators were similarly elevated in diabetic wild-type and KO; however, increases in glomerular volume and mesangial matrix area were attenuated in diabetic KO. Nox1 deficiency significantly reduced the levels of renal thiobarbituric acid-reacting substances and 8-hydroxydeoxyguanosine, membranous translocation of PKCalpha/beta, activity of PKC, and phosphorylation of p38 mitogen-activated protein kinase in the diabetic kidney. Furthermore, increased staining of senescence-associated beta-galactosidase in glomeruli and cortical tubules of diabetic mice was significantly suppressed in KO. Whereas the levels of cyclin-dependent kinase inhibitors, p16(INK4A) and p21(Cip1), were equivalent between the genotypes, increased levels of p27(Kip1) and gamma-H2AX, a biomarker for DNA double-strand breaks, were significantly attenuated in isolated glomeruli and cortical tubules of diabetic KO. Taken together, NOX1 modulates the p38/p27(Kip1) signaling pathway by activating PKC and promotes premature senescence in early stage diabetic nephropathy. PMID- 25701432 TI - A novel function of nuclear nonmuscle myosin regulatory light chain in promotion of xanthine oxidase transcription after myocardial ischemia/reperfusion. AB - Nuclear myosin regulates gene transcription and this novel function might be modulated through phosphorylation of the myosin regulatory light chain (p-MLC20). Nonmuscle MLC20 (nmMLC20) is also present in the nuclei of cardiomyocytes and a potential nmMLC20 binding sequence has been identified in the promoter of the xanthine oxidase (XO) gene. Thus, we investigated its function in the regulation of XO transcription after myocardial ischemia/reperfusion (IR). In a rat model of myocardial IR and a cardiomyocyte model of hypoxia/reoxygenation (HR) injury, the cardiac or cell injury, myosin light chain kinase (MLCK) content, XO expression and activity, XO-derived products, and level of nuclear p-nmMLC20 were detected. Coimmunoprecipitation (co-IP), chromatin immunoprecipitation, DNA pull-down, and luciferase reporter gene assays were used to decipher the molecular mechanisms through which nmMLC20 promotes XO expression. IR or HR treatment dramatically elevated nuclear p-nmMLC20 level, accompanied by increased XO expression, activity, and products (H2O2 and uric acid), as well as the IR or HR injury; these effects were ameliorated by inhibition of MLCK or knockdown of nmMLC20. Our findings from these experiments demonstrated that nuclear p-nmMLC20 binds to the consensus sequence GTCGCC in the XO gene promoter, interacts with RNA polymerase II and transcription factor IIB to form a transcription preinitiation complex, and hence activates XO gene transcription. These results suggest that nuclear p nmMLC20 plays an important role in IR/HR injury by transcriptionally upregulating XO gene expression to increase oxidative stress in myocardium. Our findings demonstrate nuclear nmMLC20 as a potential new therapeutic target to combat cardiac IR injury. PMID- 25701433 TI - Temperature controls oxidative phosphorylation and reactive oxygen species production through uncoupling in rat skeletal muscle mitochondria. AB - Mitochondrial respiratory and phosphorylation activities, mitochondrial uncoupling, and hydrogen peroxide formation were studied in isolated rat skeletal muscle mitochondria during experimentally induced hypothermia (25 degrees C) and hyperthermia (42 degrees C) compared to the physiological temperature of resting muscle (35 degrees C). For nonphosphorylating mitochondria, increasing the temperature from 25 to 42 degrees C led to a decrease in membrane potential, hydrogen peroxide production, and quinone reduction levels. For phosphorylating mitochondria, no temperature-dependent changes in these mitochondrial functions were observed. However, the efficiency of oxidative phosphorylation decreased, whereas the oxidation and phosphorylation rates and oxidative capacities of the mitochondria increased, with increasing assay temperature. An increase in proton leak, including uncoupling protein-mediated proton leak, was observed with increasing assay temperature, which could explain the reduced oxidative phosphorylation efficiency and reactive oxygen species production. PMID- 25701434 TI - Antioxidant activity of dopamine and L-DOPA in lipid micelles and their cooperation with an analogue of alpha-tocopherol. AB - Oxidative stress contributes to the progression of neurodegenerative diseases and considerable attention has been given to the development of new antioxidant-based therapies aimed at limiting neuronal cell damage. Structural analysis of catecholamine neurotransmitters indicates that these molecules can exhibit antioxidant activity due to the presence of a catechol moiety. This hypothesis is confirmed in cell culture experiments but the mechanism of antioxidant action of catecholamines is not described. Herein, we present quantitative kinetic studies on the effect of dopamine (DA) and L-3,4-dihydroxyphenylalanine (L-DOPA) on the peroxidation of methyl linoleate dispersed in Triton X-100 micelles as a model heterogeneous lipid system. Experiments were performed at extended pH range 4.0 10.0 in order to study how protonation/deprotonation of catecholamine affect its antioxidant activity. At pH 4.0-7.0, the activity of catecholamines is limited to retardation of lipid peroxidation (caused by the reaction of catecholamines with initiating radicals in the aqueous phase). The effective suppression of lipid peroxidation can be achieved by applying catecholamines together with an analogue of alpha-tocopherol (2,2,5,7,8-pentamethyl-6-hydroxychroman, PMHC). For example, a mixture of 1 MUM PMHC with 10 MUM L-DOPA causes 18-fold elongation of suppression time as compared to 1 MUM PMHC used alone. We suggest that catecholamines together with alpha-tocopherol efficiently enhance the protection of biological systems from oxidative stress. At pH above 8.0 a prooxidative effect caused by reaction of semiquinone radical anions with molecular oxygen is observed. However, this toxic action can be completely suppressed by PMHC acting as an agent removing the potentially harmful semiquinone radicals from the reaction environment. PMID- 25701435 TI - In vivo intracerebral administration of L-2-hydroxyglutaric acid provokes oxidative stress and histopathological alterations in striatum and cerebellum of adolescent rats. AB - Patients affected by L-2-hydroxyglutaric aciduria (L-2-HGA) are biochemically characterized by elevated L-2-hydroxyglutaric acid (L-2-HG) concentrations in cerebrospinal fluid, plasma, and urine due to a blockage in the conversion of L-2 HG to alpha-ketoglutaric acid. Neurological symptoms associated with basal ganglia and cerebelar abnormalities whose pathophysiology is still unknown are typical of this neurometabolic disorder. In the present study we evaluated the early effects (30min after injection) of an acute in vivo intrastriatal and intracerebellar L-2-HG administration on redox homeostasis in rat striatum and cerebellum, respectively. Histological analyses of these brain structures were also carried out 7 days after L-2-HG treatment (long-term effects). L-2-HG significantly decreased the concentrations of reduced (GSH) and total glutathione (tGS), as well as of glutathione peroxidase (GPx) and reductase (GR) activities, but did not change the activities of superoxide dismutase and catalase in striatum. Furthermore, the concentrations of oxidized glutathione (GSSG) and malondialdehyde (MDA), as well as 2',7'-dichlorofluorescein (DCFH) oxidation and hydrogen peroxide (H2O2) production, were increased, whereas carbonyl formation and nitrate plus nitrite concentrations were not altered by L-2-HG injection. It was also found that the melatonin, ascorbic acid plus alpha-tocopherol, and creatine totally prevented most of these effects, whereas N-acetylcysteine, the noncompetitive glutamate NMDA antagonist MK-801, and the nitric oxide synthase inhibitor L-NAME were not able to normalize the redox alterations elicited by L-2 HG in striatum. L-2-HG intracerebellar injection similarly provoked a decrease of antioxidant defenses (GSH, tGS, GPx, and GR) and an increase of the concentrations of GSSG, MDA, and H2O2 in cerebellum. These results strongly indicate that the major accumulating metabolite in L-2-HGA induce oxidative stress by decreasing the antioxidant defenses and enhancing reactive oxygen species in striatum and cerebellum of adolescent rats. Regarding the histopathological findings, L-2-HG caused intense vacuolation, lymphocyte and macrophage infiltrates, eosinophilic granular bodies, and necrosis in striatum. Immunohistochemistry revealed that L-2-HG treatment provoked an increase of GFAP and a decrease of NeuN immunostaining, indicating reactive astroglyosis and reduction of neuronal population, respectively, in striatum. Similar macrophage infiltrates, associated with less intense vacuolation and lymphocytic infiltration, were observed in cerebellum. However, we did not observe necrosis, eosinophilic granular bodies, and alteration of GFAP and NeuN content in L-2-HG teated cerebellum. From the biochemical and histological findings, it is presumed that L-2-HG provokes striatal and cerebellar damage in vivo possibly through oxidative stress induction. Therefore, we postulate that antioxidants may serve as adjuvant therapy allied to the current treatment based on a protein-restricted diet and riboflavin and L-carnitine supplementation in patients affected by L-2 HGA. PMID- 25701436 TI - Does procalcitonin, C-reactive protein, or interleukin-6 test have a role in the diagnosis of severe infection in patients with febrile neutropenia? A systematic review and meta-analysis. AB - PURPOSE: The study aims to determine the usefulness of procalcitonin (PCT) and other blood markers for identification of bacterial infection among patients with febrile neutropenia (FN). METHODS: The Medline, EMBASE, and Cochrane databases were searched for articles from 1966 to December 2012. We performed a search to identify articles that examined the diagnostic accuracy of PCT in patients with FN. Statistical analyses (fixed- or random-effect models) were conducted to summarize and calculate the sensitivity, specificity, likelihood ratios, and 95 % confidence intervals (CIs). RESULTS: Twenty-seven studies were included (1960 febrile episodes) for PCT analysis, 13 (1712 febrile episodes) for C-reactive protein (CRP) analysis, and five (314 febrile episodes) for interleukin (IL)-6 analysis. Increased PCT levels (odds ratio [OR] 11.5; 95 % CI 7.6 to 17.3), raised CRP levels (3.3; 2.7 to 4.2), and raised IL-6 levels (10.0; 5.5 to 18.0) were significantly associated with bacterial infection. Overall positive likelihood ratio was 5.49 (4.04-7.45) for PCT, 1.82 (1.42-2.33) for CRP, and 3.68 (2.41-5.60) for IL-6. Overall negative likelihood ratio was 0.40 (0.31-0.51) for PCT, 0.40 (0.26-0.61) for CRP, and 0.33 (0.23-0.46) for IL-6. CONCLUSIONS: Of the three potentially useful markers, PCT had the best positive likelihood ratio and can be used to confirm the diagnosis of bacterial infections in patients with FN. Due to unacceptably high negative likelihood ratio, medical decision for stopping antibiotics based on PCT alone in this high-risk population may not be possible. PMID- 25701437 TI - Development and implementation of an online program to improve how patients communicate emotional concerns to their oncology providers. AB - PURPOSE: Patients often struggle to express their emotional concerns to their oncology providers and may therefore experience unmet needs. This paper describes the development and implementation of an online program that teaches patients how to communicate their emotions to their oncology providers. METHODS: The intervention was developed by a multidisciplinary team consisting of palliative care physicians, psychologists, and an intervention software developer and included input from patients. It incorporated elements of Social Cognitive Theory and validated cognitive behavioral strategies for communication skills training. Strategies to increase intervention adherence were implemented midway through the study. RESULTS: The intervention consists of four interactive, online modules to teach patients strategies for expressing emotional concerns to their providers and asking for support. In addition to skill-building, the intervention was designed to raise patients' expectations that expressing emotional concerns to providers would be helpful, to enhance their self-efficacy for doing so, and to help them overcome barriers to having these conversations. After implementing strategies to improve adherence, usage rates increased from 47 to 64 %. CONCLUSIONS: This intervention addresses an unmet educational need for patients with advanced cancer. Strategies to increase adherence led to improvements in usage rates in this population of older patients. We are currently evaluating the intervention in a randomized clinical trial to determine its efficacy in increasing patient expression of emotional concerns and requests for support. If successful, this intervention could serve as a model for future online patient education programs. PMID- 25701438 TI - Primary oral leishmaniasis mimicking oral cancer: a case report. AB - Primary mucosal leishmaniasis is a rare infectious disease, particularly in immunocompetent patients. We present a 50-year-old patient with a 6-week history of a painful lesion of the left buccal mucosa that mimicked cancer. The exophytic lesion looked invasive, and we took an incisional biopsy specimen to exclude cancer. The diagnosis of leishmaniasis was unexpected, and the patient was successfully treated with amphotericin B for five weeks. After five months the patient had a visceral recurrence. Chronic exophytic and ulcerated mucosal lesions that do not heal within 3-4 weeks should be regarded as the first signs of oral cancer, but primary oral leishmaniasis can easily mimic it. PMID- 25701439 TI - Conformational dynamics of nucleic acid molecules studied by PELDOR spectroscopy with rigid spin labels. AB - Nucleic acid molecules can adopt a variety of structures and exhibit a large degree of conformational flexibility to fulfill their various functions in cells. Here we describe the use of Pulsed Electron-Electron Double Resonance (PELDOR or DEER) to investigate nucleic acid molecules where two cytosine analogs have been incorporated as spin probes. Because these new types of spin labels are rigid and incorporated into double stranded DNA and RNA molecules, there is no additional flexibility of the spin label itself present. Therefore the magnetic dipole dipole interaction between both spin labels encodes for the distance as well as for the mutual orientation between the spin labels. All of this information can be extracted by multi-frequency/multi-field PELDOR experiments, which gives very precise and valuable information about the structure and conformational flexibility of the nucleic acid molecules. We describe in detail our procedure to obtain the conformational ensembles and show the accuracy and limitations with test examples and application to double-stranded DNA. PMID- 25701440 TI - Toward defining a 'lineage'--The case for dendritic cells. AB - The immune system consists of a heterogeneous ensemble of cell types that immunologists have tried to classify and order for decades. This classification has relied on varying criteria, resulting in major debates in the immunology community. Discovered in the late 1970s [1], dendritic cells (DCs) are no exception, and their membership to a distinct immune lineage is still vividly debated [2-6]. Here, we review recent work on the origin of DCs and discuss the possible definition of a separate 'DC lineage'. PMID- 25701441 TI - Eating behaviours in adolescent girls: the role of body shame and body dissatisfaction. AB - PURPOSE: Numerous studies are conducted to investigate factors influencing eating and weight-related problems, given the alarming prevalence of such behaviours among adolescents. The relationship between shame, especially body shame, and eating disorders has received increased attention in recent years. The current study contributes to this field by exploring body shame as a potential mediator of the relationship between body dissatisfaction and eating behaviours among adolescent girls, while controlling for age and body mass index (BMI). METHODS: The participants, 187 adolescent girls from three secondary schools in Zagreb, completed self-report measures of demographic, eating behaviours, body satisfaction and body shame. RESULTS: Body shame and body dissatisfaction explained statistically significant amount of eating behaviours variance, while controlling for age and BMI. Further, body shame partially mediated the relationship between body dissatisfaction and eating behaviours. CONCLUSIONS: This study provides further evidence of the experience of body shame among adolescent girls and suggests that this shame is associated with disordered eating behaviours. Future longitudinal research designed to specifically explore body shame and other potentially shared risk factors is needed, and would enhance our understanding of eating disorder aetiology. PMID- 25701442 TI - Body image perception and its association with body mass index and nutrient intakes among female college students aged 18-35 years from Tabriz, Iran. AB - PURPOSE: Recent studies have shown that body image perception is an important factor in weight management and can be influenced by several social or cultural factors in Western or non-Western societies; however, body image perception and its nutritional and demographic determinants in Iran have not been extensively studied. In the current study, we aimed to evaluate body image perception and its socio-demographic and nutritional determinants among female university students in Tabriz City of Iran. METHODS: In the current cross-sectional survey, 184 female students aged 18-35 years from Tabriz, Iran, were enrolled. Anthropometric variables including weight, height, waist and hip circumference were measured and body mass index (BMI) and waist to hip ratio (WHR) were calculated. Body image perception and distortion were assessed by Figure Rating Scale (FRS) developed by Stunkard consisting of nine silhouettes. Nutrition intake was assessed by a 3-day 24-h dietary recall method and analyzed by Nutritionist IV software. RESULTS: Most of the participants in the underweight (41.66%), normal weight (67.71%) and overweight (57.14%) categories of BMI selected the thinnest figure as their desirable or ideal body image perception. The total prevalences of body image dissatisfaction and distortion were 51.63% and 64.13%, respectively. Subjects who had undistorted body image perception consumed more time for physical activity and had more night sleeping hours compared with others (P < 0.05). Subjects who perceived themselves as being of normal weight had significantly lower intake of total fat and saturated fatty acids and higher intakes of monounsaturated fatty acids (MUFAs) compared with other groups (P < 0.05). CONCLUSIONS: According to our findings, female participants had a higher tendency to consider thinness as the preferred body image style. Persons with undistorted body image perception had healthy nutritional status compared with others. Due to high prevalence of body image dissatisfaction, the need for appropriate interventional programs to prevent the associated co-morbidities is emphasized. PMID- 25701443 TI - Re: Margins, ischaemia and complications rate after laparoscopic partial nephrectomy: impact of learning curve and tumour anatomical characteristics. PMID- 25701444 TI - Re: Cytology as an alternative to frozen section at the time of nephron-sparing surgery to evaluate surgical margin status. PMID- 25701448 TI - Preface. PMID- 25701449 TI - The use of Animal-Assisted Therapy in adolescents with acute mental disorders: A randomized controlled study. AB - OBJECTIVES: The aim of this study was to compare the effects of Animal-Assisted Therapy (AAT) with a standard treatment protocol in children and adolescents admitted to the psychiatry hospital for acute mental disorders. We used a methodology involving high quality standards for AAT research. DESIGN: A pre-post experimental design with a randomized controlled trial (RCT) in 34 hospitalized patients (17 treatment, 17 control) was carried out. MAIN OUTCOME MEASURES: The study focused on improvement in clinical status including, global functioning measured by the Children Global Assessment Scale (C GAS), format of care and ordinary school attendance measured by a rating scale. RESULTS: Our results indicate a statistically significant improvement in global functioning, reduction in format of care and increased ordinary school attendance in the treatment group, but not in the control group. CONCLUSIONS: Our results verify that AAT can have significant positive effects on therapeutic progress and the recovery process. PMID- 25701450 TI - Density-dependent speciation alters the structure and dynamics of neutral communities. AB - The neutral theory of biodiversity (NTB) provides an individual-based modeling framework to study eco-evolutionary dynamics. Previous NTB models usually assumed the same per capita rate of speciation across lineages. However, population dynamics may induce macroevolutionary feedbacks that can result in variable per capita speciation rates across lineages. In this paper, with analytical and simulation approaches, we explore how different scenarios of density-dependent speciation may impact the diversity and phylogenetic patterns of neutral communities, and compare the results to predictions of the original NTB model with an invariant speciation rate. Our results show that positive per capita speciation rate-abundance relationships could result in higher species richness and evenness, enhanced stability (evidenced by higher post-disturbance recovery rates and lower temporal variability in species diversity), and higher imbalance in phylogenetic trees. The opposite patterns are predicted when per capita speciation rates decrease with abundance. Particularly, strong negative speciation rate-abundance relationships can generate a positive correlation between phylogenetic age and abundance, which has been observed in Panamanian tree species. Our findings demonstrate the importance of eco-evolutionary feedbacks for understanding long-term diversity and phylogenetic patterns in ecological communities. PMID- 25701451 TI - Immuno-modulatory strategies for reduction of HIV reservoir cells. AB - Antiretroviral therapy is able to suppress the viral load to below the detection limit, but it is not able to eradicate HIV reservoirs. Thus, there is a critical need for a novel treatment to eradicate (or reduce) the reservoir in order to eliminate the need for a lifelong adherence to antiretroviral therapy, which is expensive and potentially toxic. In this paper, we investigate the possible pharmacological strategies or combinations of strategies that may be beneficial to reduce or possibly eradicate the latent reservoir. We do this via studies with a validated mathematical model, where the parameter values are obtained with newly acquired clinical data for HIV patients. Our findings indicate that the strategy of reactivating the reservoir combined with enhancement of the killing rate of HIV-specific CD8+ T cells is able to eradicate the reservoir. In addition, our analysis shows that a targeted suppression of the immune system is also a possible strategy to eradicate the reservoir. PMID- 25701452 TI - EVERSUN: a phase 2 trial of alternating sunitinib and everolimus as first-line therapy for advanced renal cell carcinoma. AB - BACKGROUND: We hypothesised that alternating inhibitors of the vascular endothelial growth factor receptor (VEGFR) and mammalian target of rapamycin pathways would delay the development of resistance in advanced renal cell carcinoma (aRCC). PATIENTS AND METHODS: A single-arm, two-stage, multicentre, phase 2 trial to determine the activity, feasibility, and safety of 12-week cycles of sunitinib 50 mg daily 4 weeks on / 2 weeks off, alternating with everolimus 10 mg daily for 5 weeks on / 1 week off, until disease progression or prohibitive toxicity in favourable or intermediate-risk aRCC. The primary end point was proportion alive and progression-free at 6 months (PFS6m). The secondary end points were feasibility, tumour response, overall survival (OS), and adverse events (AEs). The correlative objective was to assess biomarkers and correlate with clinical outcome. RESULTS: We recruited 55 eligible participants from September 2010 to August 2012. DEMOGRAPHICS: mean age 61, 71% male, favourable risk 16%, intermediate risk 84%. Cycle 2 commenced within 14 weeks for 80% of participants; 64% received >=22 weeks of alternating therapy; 78% received >=22 weeks of any treatment. PFS6m was 29/55 (53%; 95% confidence interval [CI] 40% to 66%). Tumour response rate was 7/55 (13%; 95% CI 4% to 22%, all partial responses). After median follow-up of 20 months, 47 of 55 (86%) had progressed with a median progression-free survival of 8 months (95% CI 5-10), and 30 of 55 (55%) had died with a median OS of 17 months (95% CI 12-undefined). AEs were consistent with those expected for each single agent. No convincing prognostic biomarkers were identified. CONCLUSIONS: The EVERSUN regimen was feasible and safe, but its activity did not meet pre-specified values to warrant further research. This supports the current approach of continuing anti-VEGF therapy until progression or prohibitive toxicity before changing treatment. AUSTRALIAN NEW ZEALAND CLINICAL TRIALS REGISTRY: ACTRN12609000643279. PMID- 25701453 TI - Phase II study of interim PET-CT-guided response-adapted therapy in advanced Hodgkin's lymphoma. AB - BACKGROUND: Combination chemotherapy ABVD (doxorubicin, bleomycin, vinblastine and dacarabazine) cures ~70% of patients with advanced Hodgkin's lymphoma (aHL, stages IIB, III and IV) while more toxic escalated BEACOPP (EB, combination of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisolone) increases cure rates to 85%. Patients with a positive interim positron emission tomography-computerized tomography (PET-CT) scan after two cycles (PET-2) of ABVD have very poor outcomes with continued ABVD. Intensifying therapy with EB in PET-2-positive patients ('response-adapted therapy') may improve cure rates, whereas the negative patients can continue ABVD alone. PATIENTS AND METHODS: Eligible patients with newly diagnosed aHL received two cycles of ABVD and underwent PET-2 (scored with semi-quantitative 5-point visual criteria, 'Deauville score'). PET-2-negative patients continued four additional cycles of ABVD, whereas PET-2-positive patients received four cycles of EB. A phase II sample size of 50 was estimated keeping the lower and higher proportion of rejection of the event-free survival (EFS) as 70% and 85%, respectively. RESULTS: Fifty patients [median age 28 (12-60) years; male : female: 39 : 11; stages: IIB-3 (6%), III-29 (58%) and IV-18 (36%); International Prognostic Score (IPS): 0-3: 34 (68%); 4-7: 16 (32%)] were enrolled; 49 underwent PET-2. Eight (16%) were PET-2-positive, whereas 41 (84%) were negative. Forty-seven were evaluable for EFS and all 50 for overall survival (OS). The 2-year EFS was 76% (95% CI: 68-83) and OS was 88% (95% CI: 82-94). PET-2 was strongly prognostic-2 year EFS, negative versus positive: 82% versus 50%; P = 0.013. CONCLUSION: PET-2 response-adapted strategy could not achieve EFS of 85% in aHL. However, escalated therapy improved outcomes in PET-2-positive patients compared with historical data. TRIAL REGISTRATION: CTRI/2012/06/002741 (http://www.ctri.nic.in) and NCT01304849 (http://www.clinicaltrials.gov). PMID- 25701454 TI - Axitinib dose titration: analyses of exposure, blood pressure and clinical response from a randomized phase II study in metastatic renal cell carcinoma. AB - BACKGROUND: In a randomized, double-blind phase II trial in patients with metastatic renal cell carcinoma (mRCC), axitinib versus placebo titration yielded a significantly higher objective response rate. We evaluated pharmacokinetic and blood pressure (BP) data from this study to elucidate relationships among axitinib exposure, BP change, and efficacy. PATIENTS AND METHODS: Patients received axitinib 5 mg twice daily during a lead-in period. Patients who met dose titration criteria were randomized 1:1 to stepwise dose increases with axitinib or placebo. Patients ineligible for randomization continued without dose increases. Serial 6-h and sparse pharmacokinetic sampling were carried out; BP was measured at clinic visits and at home in all patients, and by 24-h ambulatory BP monitoring (ABPM) in a subset of patients. RESULTS: Area under the plasma concentration-time curve from 0 to 24 h throughout the course of treatment (AUCstudy) was higher in patients with complete or partial responses than those with stable or progressive disease in the axitinib-titration arm, but comparable between these groups in the placebo-titration and nonrandomized arms. In the overall population, AUCstudy and efficacy outcomes were not strongly correlated. Mean BP across the population was similar when measured in clinic, at home, or by 24-h ABPM. Weak correlations were observed between axitinib steady-state exposure and diastolic BP. When grouped by change in diastolic BP from baseline, patients in the >=10 and >=15 mmHg groups had longer progression-free survival. CONCLUSIONS: Optimal axitinib exposure may differ among patients with mRCC. Pharmacokinetic or BP measurements cannot be used exclusively to guide axitinib dosing. Individualization of treatment with vascular endothelial growth factor receptor tyrosine kinase inhibitors, including axitinib, is thus more complex than anticipated and cannot be limited to a single clinical factor. PMID- 25701455 TI - Phase I trial of everolimus in combination with thoracic radiotherapy in non small-cell lung cancer. AB - BACKGROUND: This phase I study evaluated the safety and efficacy of the oral mTOR inhibitor everolimus in combination with thoracic radiotherapy followed by consolidation chemotherapy in locally advanced or oligometastatic untreated non small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Everolimus dose was escalated in incremental steps [sequential cohorts of three patients until the occurrence of dose-limiting toxicity (DLT)] and administered orally weekly (weekly group: dose of 10, 20 or 50 mg) or daily (daily group: 2.5, 5 or 10 mg), 1 week before, and during radiotherapy until 3.5 weeks after the end of radiotherapy. Two cycles of chemotherapy (cisplatin-navelbine) were administrated 4.5 weeks after the end of radiotherapy. RESULTS: Twenty-six patients were included in two centers, 56% had adenocarcinoma and 84% had stage III disease. In the weekly group (12 assessable patients), everolimus could be administered safely up to the maximum planned weekly dose of 50 mg; however, one patient experienced a DLT of interstitial pneumonitis at the weekly dose level of 20 mg. In the daily group (9 assessable patients): one DLT of interstitial pneumonitis with a fatal outcome was observed at the daily dose level of 2.5 mg; two other DLTs (one grade 3 esophagitis and one bilateral interstitial pneumonitis) were found at the daily dose level of 5 mg. Overall there were five patients with G3-4 interstitial pneumonitis related to treatment. Among 22 assessable patients for response, there were 9 (41%) partial response and 7 (32%) stable disease. At a median follow-up of 29 months, the 2-year overall survival and progression-free survival actuarial rates were 31% and 12%, respectively. CONCLUSION: In previously untreated and unselected NSCLC patients, the recommended phase II dose of everolimus in combination with thoracic radiotherapy is 50 mg/week. Pulmonary toxicity is of concern and should be carefully monitored to establish the potential role of mTOR inhibitor with concomitant radiotherapy. EUDRACT N: 2007 001698-27. PMID- 25701457 TI - Can we use intraoperative femoral tunnel length measurement as a clue for proper femoral tunnel placement on coronal plane during ACL reconstruction? AB - INTRODUCTION: Successful anterior cruciate ligament (ACL) reconstruction is dependent on correct placement of both tibial and femoral tunnels. The purpose of this study is to investigate whether we can use intraoperative femoral tunnel length measurement to estimate the correct femoral tunnel placement on coronal plane. METHODS: This prospective study comprised 164 consecutive patients who underwent ACL reconstruction surgery. Transtibial or anteromedial portal technique is used for drilling the femoral tunnels. The length of the femoral tunnel was measured during the operation. The femoral tunnel coronal plane angle was calculated on the postoperative tunnel radiographs. A statistical comparison was made of the lengths of the tunnel, the techniques used drilling and the femoral tunnel angles. RESULTS: The far anteromedial portal was used in 81 (49%) cases and the transtibial technique in 83 (51%) cases. The mean femoral tunnel length was 42 +/- 6.4 mm and the mean femoral tunnel coronal angle was 41.1 degrees +/- 11.6. The tunnel angle in the transtibial technique was determined as significantly low compared to the far anteromedial portal technique (32.6 degrees :49.8 degrees ) and the tunnel length was significantly longer (45.8:38.1 mm) (p < 0.001). In the statistical analysis, it was found that a patient with a tunnel length of 41 mm and above had a 92.1% likelihood of femoral tunnel angle below 45 degrees . CONCLUSION: Femoral tunnel length can be used as a clue for intraoperative evaluation of the femoral tunnel position. If the femoral tunnel length is greater than 41 mm, the coronal plane orientation of the femoral tunnel will be improper and not at a desired position. PMID- 25701458 TI - Repair and augmentation of a spontaneous patellar tendon rupture in a patient with Ehlers-Danlos syndrome: a case report. AB - INTRODUCTION: Disruption of the knee extensor mechanism is a serious disorder that requires prompt treatment. It often occurs in the form of a patellar tendon rupture. It may occur in association with systemic disease or after administration of corticosteroids or fluoroquinolones. These conditions can cause tendon weakness, and consequent ruptures usually require both repair and augmentation. This paper reports on repair and augmentation for treating patellar tendon rupture in patients with Ehlers-Danlos syndrome (EDS). CASE REPORT: We report a patellar tendon rupture in a 27-year-old man with EDS, which occurred in the midsubstance of the patella. As the patient has tendon weakness, extensive repair will increase the risk of patella baja, and the use of end-to-end suturing technique alone will not be enough to prevent a rupture recurring; however, augmentation could be used to address the tendon weakness. Repair of the rupture and augmentation with hamstring tendon was performed. One year after the surgery, the patient was able to move his knee joint without pain and had an active range of motion of 0 degrees (passive 20 degrees )-145 degrees . He was able to perform a straight leg raise without an extension lag. CONCLUSIONS: Repair and augmentation with hamstring tendon was an effective treatment option for patellar tendon rupture in a patient with EDS. PMID- 25701456 TI - First-line treatment and outcome of elderly patients with primary central nervous system lymphoma (PCNSL)--a systematic review and individual patient data meta analysis. AB - BACKGROUND: To investigate prognosis and effects of first-line therapy in elderly primary central nervous system lymphoma (PCNSL) patients. PATIENTS AND METHODS: A systematic review of studies about first-line therapy in immunocompetent patients >=60 years with PCNSL until 2014 and a meta-analysis of individual patient data from eligible studies and international collaborators were carried out. RESULTS: We identified 20 eligible studies; from 13 studies, we obtained individual data of 405 patients, which were pooled with data of 378 additional patients (N = 783). Median age and Karnofsky Performance Score (KPS) was 68 years (range: 60-90 years) and 60% (range: 10%-100%), respectively. Treatments varied greatly, 573 (73%) patients received high-dose methotrexate (HD-MTX)-based therapy. A total of 276 patients received whole-brain radiotherapy (median 36 Gy, range 28.5-70 Gy). KPS >= 70% was the strongest prognostic factor for mortality [hazard ratio (HR) 0.50, 95% confidence interval (CI) 0.41-0.62]. After a median follow-up of 40 months, HD-MTX-based therapy was associated with improved survival (HR 0.70, 95% CI 0.53-0.93). There was no difference between HD-MTX plus oral chemotherapy and more aggressive HD-MTX-based therapies (HR 1.39, 95% CI 0.90-2.15). Radiotherapy was associated with an improved survival, but correlated with an increased risk for neurological side-effects (odds ratio 5.23, 95% CI 2.33-11.74). CONCLUSIONS: Elderly PCNSL patients benefit from HD-MTX-based therapy, especially if combined with oral alkylating agents. More aggressive HD-MTX protocols do not seem to improve outcome. WBRT may improve outcome, but is associated with increased risk for neurological side-effects. Prospective trials for elderly PCNSL patients are warranted. PMID- 25701459 TI - The relationship between jugular bulb position and jugular bulb related inner ear dehiscence: a retrospective analysis. AB - OBJECTIVE: High jugular bulb (HJB) can erode inner ear structures creating a jugular bulb related inner ear dehiscence (JBID). The aim of this study was to analyze the relationship between the position of jugular bulb (JB) and JBID using high-resolution computed tomography (HRCT). MATERIAL AND METHODS: In this retrospective study HRCT images of 552 ears of 276 patients with hearing loss, otogenic vertigo, tinnitus or idiopathic peripheral facial nerve paralysis were analyzed. HJB type-1 was defined when JB dome reached above the inferior part of the round window, but was below the inferior edge of the internal acoustic meatus (IAM). HJB type-2 was defined when the dome of JB was higher than the inferior edge of IAM. The frequencies and types of HJB were evaluated. JBID for each HJB type was determined. Frequencies of JBID eroding the vestibular aqueduct (VA), the cochlear aqueduct and the posterior semicircular canal were examined. RESULTS: HJB type-1 and HJB type-2 were found in 19% (105/552) and in 15.8% (87/552) of studied ears. JBID showed to be in 3.8% (21/552) of all ears. 90.5% (19/21) of JBID revealed eroding of VA. Jugular bulb related cochlear aqueduct dehiscence and jugular bulb related posterior semicircular canal dehiscence were found in one ear each. The frequency of jugular bulb related vestibular aqueduct dehiscence (JBVAD) in patients with HJB reaching above IAM was higher than in patients with HJB lower than IAM. CONCLUSIONS: HJB is common, but JBID is rare. JBID prevalently erodes VA. HJB rising above IAM is most at risk to show JBVAD. PMID- 25701460 TI - A case of sensorineural hearing loss involving a fibroepithelial polyp of the middle ear. AB - Primary middle ear neoplasms are rare, and commonly cause conductive hearing loss. When aural masses result in sensorineural hearing loss, malignant etiologies are often suspected. Fibroepithelial polyps are benign lesions commonly found in the skin and genitourinary tract and are not commonly identified as primary lesions of the middle ear. Here, we present a case of a benign fibroepithelial polyp of the middle ear causing sensorineural hearing loss and describe its surgical management. Imaging and histologic characteristics are reviewed. PMID- 25701461 TI - VGLL4 inhibits EMT in part through suppressing Wnt/beta-catenin signaling pathway in gastric cancer. AB - VGLL4 is a member of the Vestigial-like proteins that functions as a tumor suppressor, which directly competes with YAP for binding TEADs in several cancer types. Recently, an increasing number of studies have reported that VGLL4 acts as a crucial role in regulating cell mobility, migration, and invasion. However, little is known about the signaling mechanisms in regulating epithelial mesenchymal transition (EMT) of gastric cancer. In our study, we confirmed that the expression level of VGLL4 was down-regulated in gastric cancer tissues, and reduced VGLL4 expression levels inhibited apoptosis and promoted proliferation, migration, and invasion. Additionally, we found a phenomenon that VGLL4 was associated with the change in nuclear location of beta-catenin, which suggested that beta-catenin was a significant downstream factor of VGLL4. These results suggest that VGLL4 suppressed EMT in part via negative regulation of Wnt/beta catenin signaling pathway. Taken together, our study demonstrated that VGLL4 is important in the process of suppressing tumor progression of gastric cancer and provided a potential therapeutic strategy for gastric cancer. PMID- 25701462 TI - Decreased Warburg effect induced by ATP citrate lyase suppression inhibits tumor growth in pancreatic cancer. AB - ATP citrate lyase (ACLY) is responsible for the conversion of cytosolic citrate into acetyl-CoA and oxaloacetate, and the first rate-limiting enzyme involved in de novo lipogenesis. Recent studies have demonstrated that inhibition of elevated ACLY results in growth arrest and apoptosis in a subset of cancers; however, the expression pattern and underlying biological function of ACLY in pancreatic ductal adenocarcinoma (PDAC) remains unclear. In the current study, overexpressed ACLY was more commonly observed in PDAC compared to normal pancreatic tissues. Kaplan-Meier survival analysis showed that high expression level of ACLY resulted in a poor prognosis of PDAC patients. Silencing of endogenous ACLY expression by siRNA in PANC-1 cells led to reduced cell viability and increased cell apoptosis. Furthermore, significant decrease in glucose uptake and lactate production was observed after ACLY was knocked down, and this effect was blocked by 2-deoxy-D glucose, indicating that ACLY functions in the Warburg effect affect PDAC cell growth. Collectively, this study reveals that suppression of ACLY plays an anti tumor role through decreased Warburg effect, and ACLY-related inhibitors might be potential therapeutic approaches for PDAC. PMID- 25701463 TI - Downregulation of UPK1A suppresses proliferation and enhances apoptosis of bladder transitional cell carcinoma cells. AB - Uroplakin 1A (UPK1A) is a specific marker of mammalian urothelium and one of major proteins contained in urothelial plaques. Many recent studies reported that UPK1A could be useful marker for diagnosis, detection and prognostic prediction of transitional cell carcinoma. However, relatively little is known about its exact roles in bladder transitional cell carcinoma (BTCC). We tried to explore the roles UPK1A plays in BTCC via the transfection of its antisense nucleotides (AS) into T24 cells to observe their changes of proliferation and apoptosis. After AS was successfully transfected into T24 cells, the percentages of proliferating T24 cells at 24 and 48 h after the treatment were 57.2 +/- 6.8 and 44.7 +/- 5.2%, significantly lower than that of control group, as shown by MTT (p < 0.05 and 0.01). At 24 h after transfection of AS, the percentage of apoptotic T24 cells was 26.87% measured by flow cytometry, significantly higher than that of control group (p < 0.01). Similarly, Hoechst 33258 staining showed that the percentage of apoptotic nuclei of T24 cells after 24 h treated by AS was 28.9%, significantly higher than that of control (p < 0.05). The most common and typical morphological changes of apoptosis, including shrink, pyknosis and karyorrhexis of T24 cells nuclei and DNA fragmentation were seen from Hoechst 33258 staining and DNA agarose gel electrophoresis. Taken together, inhibition of UPK1A can suppress proliferation and enhance apoptosis of BTCC T24 cells, suggesting it a potential target to treat this disease. PMID- 25701464 TI - CUGBP1 promotes cell proliferation and suppresses apoptosis via down-regulating C/EBPalpha in human non-small cell lung cancers. AB - CUGBP1, which is involved in posttranscriptional regulatory networks, may control cell growth, activation and differentiation. Meanwhile, CCAAT/enhancer-binding protein alpha (C/EBPalpha) acts as a basic leucine zipper transcription factor which controls differentiation-dependent gene expression and inhibits cell proliferation. To date, very little is known about the association between CUGBP 1 and C/EBPalpha in regulating cell proliferation and apoptosis in non-small cell lung cancer (NSCLC). CUGBP1 and C/EBPalpha mRNA expressions were analyzed in NSCLC tumor and adjacent normal tissues, and the relationship in clinicopathological parameters was evaluated. Knockdown of CUGBP1 and C/EBPalpha regulated by CUGBP1 in NSCLC cell line was identified by real-time PCR and Western blot. The effect of depletion of CUGBP1 was evaluated by MTT assay and Annexin/Propidium Iodide Apoptosis assay. CUGBP1 is highly expressed and expression of C/EBPalpha is low in NSCLC tissues. The correlation analysis revealed that there was negative correlation between the expression of CUGBP 1 and C/EBPalpha. Knockdown of CUGBP1 effectively silenced the expression of CUGBP1 and up-regulated C/EBPalpha. Also, suppression of CUGBP1 inhibits proliferation and induces apoptosis in A549 cells. These observations suggest that the first proof the overexpression of CUGBP1 in NSCLC contributes to tumorigenesis through down-regulation of C/EBPalpha. Knockdown of CUGBP1 or up-regulation C/EBPalpha might be a potential therapeutic approach for human non-small cell lung cancers. PMID- 25701465 TI - Reply to: "YAP in tumorigenesis: Friend or foe?". PMID- 25701466 TI - ACE I/D genotype-related increase in ACE plasma activity is a better predictor for schizophrenia diagnosis than the genotype alone. AB - BACKGROUND: Angiotensin-I converting enzyme (ACE) is a key component of the renin angiotensin system (RAS). Although the several contradictory data, ACE has been associated with schizophrenia (SCZ) pathophysiology. Here the ACE activity of SCZ patients and healthy controls (HCs), and its possible correlations with the ACE polymorphism genotype and symptomatic dimensions, was investigated. METHODOLOGY: ACE activity of 86 SCZ patients and 100 HCs paired by age, gender and educational level was measured, using the FRET peptide substrate and the specific inhibitor lisinopril. The ACE insertion/deletion (I/D) genotypes were assessed by the restriction fragment length polymorphism (RFLP) technique. RESULTS: Significantly higher ACE activity was observed in SCZ patients compared to HCs (t=-5.09; p<0.001). The area under the receiver operating characteristic (ROC) curve was 0.701. Mean ACE activity levels were higher for the D-allele carriers (F=5.570; p=0.005), but no significant difference was found among SCZ patients and HCs for genotypes frequencies (Chi-squared=2.08; df=2; p=0.35). Interestingly, we found that the difference between the measured ACE activity for each SCZ patient and the expected average mean value for each respective genotype group (for control subjects) was a better predictor of SCZ than the ACE dichotomized values (high/low) or ACE I/D. CONCLUSION: Our results suggest that higher levels of ACE activity are associated with SCZ with stronger impact when the genetic background of each individual is considered. This may explain the heterogeneity of the results on ACE previously reported. PMID- 25701467 TI - Longevity of class 2 direct restorations in root-filled teeth: A retrospective clinical study. AB - OBJECTIVES: To evaluate retrospectively the longevity of endodontically treated teeth restored with direct resin composite without cusp coverage, with or without the insertion of fibre posts. The null hypothesis was that direct restorations with fibre posts perform better than those without fibre posts. METHODS: Patients recruited for this study were treated in the Department of Cariology and Operative Dentistry, University of Turin, between 2008 and 2011. In total, 247 patients with 376 root treated posterior teeth, restored with direct resin composite, were recalled for a control visit. Only second-class cavities were considered. Two groups were defined based on the absence (Group A) or presence (Group B) of fibre post. Failures and complications, such as periodontal failure, endodontic failure, tooth extraction, root fracture, post fracture, post debonding, replacement of restoration, crown displacement, and coronal-tooth fracture, were noted. Functional restoration quality was evaluated following the modified USPHS criteria. Data were evaluated statistically with ANOVA. RESULTS: Group A consisted of 128 patients with 178 restorations (88 premolars, 90 molars) with a median follow-up of 34.44 months. Group B consisted of 119 patients with 198 teeth (92 premolars, 106 molars) with a median follow-up of 35.37 months. Direct restorations with fibre posts were statistically significantly more functional (95.12% success) than those without fibre posts (80% success) because of less marginal discolouration, better marginal integrity, and higher restoration integrity. CONCLUSIONS: The null hypothesis was accepted because direct post-endodontic restorations with fibre posts performed better than restorations without posts after 3 years of masticatory function. CLINICAL SIGNIFICANCE: An evaluation of the longevity of post endodontic direct restoration would seem to enhance the fiber post insertion within a composite restoration to reduce clinical failures. PMID- 25701468 TI - Gait velocity and step length at baseline predict outcome of Nordic walking training in patients with Parkinson's disease. AB - BACKGROUND: The impact of Nordic walking (NW) in Parkinson's disease (PD) has been investigated in several studies but results are inconsistent. This may be due to different cohorts studied and the heterogeneity of their PD symptoms which impact the outcome of NW. This study aimed at determining predictive factors for a positive effect of NW on PD. METHODOLOGY AND PRINCIPAL FINDINGS: Primary outcome was to define the baseline disease-associated and demographic parameters that distinguish patients who demonstrate improvement in the Unified PD rating scale (UPDRS) motor part following NW training ("U+") from those patients with no improvement after the same intervention ("U-"). The potentially predictive parameters were: age, age at onset, disease duration, gait velocity, step length, daily step number, UPDRS-motor part, Berg-Balance-Scale, Parkinson Neuropsychometric-Dementia-Assessment, verbal-fluency-test and Becks-Depression Inventory-II. Twenty-two PD patients (H&Y stage 2-2.5) performed twelve weeks of NW training. Eighteen patients were included in the final analysis. Overall, the UPDRS motor part did not improve significantly; however, eight patients had an improvement in the UPDRS motor part from baseline to end of study (U+). When comparing the potentially predictive factors of the U+ cohort with those ten patients who did not improve (U-), there was a notable difference in gait velocity and step length, and showed a significant correlation with an improvement in the UDPRS motor part scores. CONCLUSION: Gait velocity and step length can predict the outcome of NW training as determined by the UPDRS motor part, indicating that PD patients with only slightly impaired gait performance benefit most. PMID- 25701469 TI - Telomere dynamics in the lower plant Physcomitrella patens. AB - A comparative approach in biology is needed to assess the universality of rules governing this discipline. In plant telomere research, most of the key principles were established based on studies in only single model plant, Arabidopsis thaliana. These principles include the absence of telomere shortening during plant development and the corresponding activity of telomerase in dividing (meristem) plant cells. Here we examine these principles in Physcomitrella patens as a representative of lower plants. To follow telomerase expression, we first characterize the gene coding for the telomerase reverse transcriptase subunit PpTERT in P. patens, for which only incomplete prediction has been available so far. In protonema cultures of P. patens, growing by filament apical cell division, the proportion of apical (dividing) cells was quantified and telomere length, telomerase expression and activity were determined. Our results show telomere stability and demonstrate proportionality of telomerase activity and expression with the number of apical cells. In addition, we analyze telomere maintenance in mre11, rad50, nbs1, ku70 and lig4 mutants of P. patens and compare the impact of these mutations in double-strand-break (DSB) repair pathways with earlier observations in corresponding A. thaliana mutants. Telomere phenotypes are absent and DSB repair kinetics is not affected in P. patens mutants for DSB factors involved in non-homologous end joining (NHEJ). This is compliant with the overall dominance of homologous recombination over NHEJ pathways in the moss, contrary to the inverse situation in flowering plants. PMID- 25701470 TI - A method to identify estuarine water quality exceedances associated with ocean conditions. AB - Wind-driven coastal upwelling along the Pacific Northwest Coast of the USA results in oceanic water that may be periodically entrained into adjacent estuaries and which possesses high nutrients and low dissolved oxygen (DO). Measurement of water quality indicators during these upwelling water entrainment events would represent extreme values for water quality thresholds derived from typical estuarine conditions. Tools are therefore needed to distinguish upwelled waters from other causes of exceedances of water quality thresholds within estuaries of the region. We present an example application of logistic regression models to predict the probability of exceedance of a water quality threshold, using DO data from the Yaquina estuary, Oregon, USA. Models including water temperature and salinity correctly classified exceedances of DO about 80 % of the time. Inclusion of in situ fluorescence in the logistic regression model for DO improved the model performance and reduced the rate of false positives. PMID- 25701471 TI - A continuous active monitoring approach to identify cross-connections between potable water and effluent distribution systems. AB - A continuous active monitoring approach was developed for identification of cross connections between potable water supply systems and treated wastewater effluent reuse distribution systems. The approach is based on monitoring the oxidation reduction potential (ORP) at the potable water system while injecting sulfite (a reducing agent) into the effluent line. A sharp decrease in the ORP of the potable water would indicate a cross-connection event. The approach was tested in batch experiments on treated municipal wastewater effluent of varying degree of treatment, and at dilution ratios of up to 1:100 (effluent/potable). The approach was then examined under continuous flow conditions, which simulated cross connection events at various dilution ratios (up to 1:100). In the continuous runs, differences between the potable water ORP and the effluent-potable water mixture (containing sulfite as sodium bisulfite (SBS)) ORP were 450-630 mV. This suggests high potential for identifying a cross-connection event. Implementation of the approach includes adding sulfite to effluent used for agricultural irrigation; hence, possible effects on soil and on crops were studied in soil columns and pots planted with basil (Ocimum basilicum) as a model plant. No negative effects of sulfite addition to the irrigation effluent were observed in the irrigated soils and plants, and therefore, it could be safely implemented also in agricultural applications. PMID- 25701472 TI - Metal distribution in marine sediment along the Doha Bay, Qatar. AB - Concentrations of 25 heavy metals (Ag, Al, As, Ba, Be, Ca, Cd, Co, Cr, Cu, Fe, K, Li, Mg, Mn, Mo, Na, Ni, Pb, Sb, Se, Sr, V, Zn and Hg) in surface sediments along the Doha Bay from 10 transects each with five stations were studied. Significant differences were observed in metal concentrations between the sampling locations and durations. Higher concentrations were observed in areas where there are a lot of anthropological activities. The distribution of selected metals was presented in contour maps showing the variation between the two periods. In order to further study particle size effect on metal uptake, two different grinding times were administered on four randomly selected samples and the results showed no significant difference on the analysis in the inductively coupled plasma-optical emission spectrometry (ICP-OES) instrument. The overall results of metal analyses were within the international standards criteria, and the results were comparable to the previous studies conducted around Qatar. PMID- 25701473 TI - Blood levels of polychlorinated biphenlys and organochlorinated pesticides in women from Istanbul, Turkey. AB - The human body is not a chemically uncontaminated system. Every simple action that humans undertake, such as drinking water, eating, nursing, and even breathing air, puts the system under environmental xenobiotic exposure stress. Environmental chemicals have been shown to produce unwanted effects on health and remove the right to healthy living, starting from the first encounter in utero to geriatrics, throughout the lifespan. Organochlorine pesticides (OCPs) and polychlorinated biphenyl (PCB) levels, important members of the persistent organic pollutants (POPs), have been detected before in human breast milk and also in the adipose tissue of women from different regions of Turkey; however, there was no information about the blood levels of these chemicals. This study generated the first information that evaluates OCP and PCB contamination levels in the blood of the women living in Turkey. The current study measured the blood concentrations of OCPs and PCBs in 58 healthy women (age 20-41 years; mean age 28 years) who were living in Istanbul, Turkey, in the years 2010-2012. Samples were analyzed for 29 OCPs and 18 PCB congeners using high-resolution gas chromatography/high-resolution mass spectrometry (HRGC/HRMS). PCB 153 was the predominant congener (643.2 pg/g lipid), followed by PCB 138 and PCB 180. 4,4' DDE (24872.8 pg/g lipid) was the most common organochlorinated pesticide contaminant in studied blood samples. Results for analyzed chlorinated compounds were as follows: ?PCB 2682 +/- 3300 pg/g lipid; ?DDT 25,938 +/- 28,644 pg/g lipid; and ?HCH 2930 +/- 2222 pg/g lipid, respectively. The mean concentration of ?WHOPCB-TEQ was 0.037 pg/g on a lipid basis. This information will be important base data during the assessment of the general health concerns of women, as well as for studies about how endocrine disruptors affect humans for forthcoming studies. PMID- 25701474 TI - Assessment of heavy metals in sediment of Aguamilpa Dam, Mexico. AB - The Aguamilpa Dam is part of the reservoir cascade system formed by four reservoirs in the middle and lower part of the Santiago River. For decades, this system has received urban and industrial wastewater from the metropolitan area of Guadalajara and the runoff of agricultural fields located in the river basin. The present study was carried out to obtain a preliminary assessment on the concentration distribution of heavy metals (Al, Ba, Cd, Cr, Cu, Fe, Hg, Mg, Ni, Pb, and Zn) in surface sediments of the Aguamilpa reservoir collected from 10 sampling stations. The metal concentrations (mg kg(-1)) in the sampling stations ranged as follows: Al, 27,600-7760; Ba, 190.0-15.9; Cd, 0.27-0.02; Cr, 18.30 0.22; Cu, 60.80-0.79; Fe, 15,900-4740; Hg, 0.04-0.01; Mg, 7590-8.05; Ni, 189.00 0.24; Pb, 13.6-1.64; and Zn, 51.8-14.8. Significant spatial variation in concentrations was observed for Al, Fe, and Pb. Sediment pollution was evaluated using the enrichment factor, the geo-accumulation index, the pollution load index, and sediment quality guidelines. Based on geo-accumulation and pollution load indexes, Aguamilpa sediments were found, in some sampling stations, as unpolluted to moderately polluted with Ni, Cd, Cu, and Mg. Enrichment factors showed that Cd is highly related to agricultural activities that take place in the surrounding areas of the Aguamilpa reservoir. Despite these results, none of the heavy metals evaluated exceeded international concentrations limits, indicating that the Aguamilpa reservoir surface sediments are not contaminated. PMID- 25701475 TI - Chronic recurrent multifocal osteomyelitis. PMID- 25701476 TI - Imaging features of ciliated hepatic foregut cyst. PMID- 25701477 TI - Abdominopelvic ultrasonographic findings after uncomplicated delivery. AB - PURPOSE: To prospectively determine the range of abdominopelvic ultrasonographic findings, including Doppler resistance index (RI) of uterine arteries, 2 and 24 hours after uncomplicated delivery. METHOD: Women who delivered vaginally or after cesarean section without complication from January 2012 to April 2012 in a tertiary care hospital were prospectively included. Abdominopelvic ultrasonography, including uterine artery resistance index (RI) at duplex Doppler ultrasonography, was performed 2 hours and 24 hours after delivery. RESULTS: Ninety-two women (mean age, 32.7 years) were included. Sixty-one (66%) delivered vaginally and 31 (34%) had cesarean section. Twenty-four hours after vaginal delivery, endometrial and anterior wall thicknesses dropped and uterine width increased (P<0.001). No changes in uterine length and posterior wall thickness were observed between 2 and 24 hours after delivery. Transient pelvic free-fluid effusion was observed in 1/92 woman (1%). Uterine artery RI increased significantly from 2 to 24 hours (0.50 vs 0.57, respectively; P<0.001). CONCLUSION: Pelvic free-fluid effusion is exceedingly rare in the early course of uncomplicated delivery. A significant increase in uterine artery RI during the 24 hours following uncomplicated delivery is a normal finding. It can be anticipated that familiarity with these findings would result in more confident diagnosis of complications. PMID- 25701478 TI - Pseudarthrosis of the cartilaginous part of the first rib is a common incidental finding on chest CT. AB - PURPOSE: The cartilaginous parts of the first rib are usually articulating with sternal manubrium via a synchondrosis. With advancing age, there is progressive calcification of the rib cartilage. Pseudarthrosis of this calcified cartilage have been described in a study on anatomic specimen, but there are no systematically studies examining the anatomy of the cartilaginous parts of the first rib in vivo or using computed tomography (CT). MATERIAL AND METHODS: A retrospective study of 60 chest CT scans of patients without history of trauma was performed and 120 first ribs were examined. In all patients, the grade of calcifications of the first rib was determined (no calcifications/some calcifications/severe and at least on one side contiguous calcification of the cartilage) and the presence of pseudarthrosis was noted. RESULTS: Pseudarthrosis was found in 39/120 ribs (32.5%). The occurrence of pseudarthrosis was significantly more common in patients with severe calcifications (54%) in contrast to patients with no or minor calcifications (6.1%). CONCLUSIONS: Pseudarthrosis of the first rib is a common finding in patients with severe calcifications. Radiologists should be aware of this frequent incidental finding, that should not be mistaken for pathology in CT imaging after trauma. PMID- 25701479 TI - Mesenteric panniculitis: still an ambiguous condition. AB - PURPOSE: To study the possible relationship between mesenteric panniculitis (MP) visible on computed tomography (CT) and the presence of an underlying neoplastic disease. PATIENTS AND METHODS: A retrospective analysis of 158 patients with CT examinations that revealed the presence of MP was performed. CT images were analyzed by two different radiologists using morphological criteria validated in the radiological literature. The presence, frequency and type of neoplastic lesions associated with MP were assessed. RESULTS: MP was asymptomatic in 96/158 patients (61%). Fat halo sign and pseudocapsule were visible on CT in 89/158 (56%) and 93/158 (59%) patients, respectively. Underlying neoplastic disease was present in 88/158 patients (56%). The neoplastic diseases most often associated with MP were lymphoma (28%), melanoma (18%), colorectal cancer (15%) and prostate cancer (13%). CONCLUSION: MP has typical CT appearance and is associated with underlying neoplastic disease in 56% of patients. Such levels of association might suggest that MP may be considered as a paraneoplastic condition. Hence, incidental depiction of MP on CT in a patient without known neoplastic disease should incite radiologists to further scrutinize CT examination for presence of synchronous neoplastic lesions. PMID- 25701480 TI - Tumor budding in colorectal cancer revisited: results of a multicenter interobserver study. AB - Tumor budding in colorectal cancer (CRC) is recognized as a valuable prognostic factor but its translation into daily histopathology practice has been delayed by lack of agreement on the optimal method of assessment. Within the context of the Swiss Association of Gastrointestinal Pathology (SAGIP), we performed a multicenter interobserver study on tumor budding, comparing hematoxylin and eosin (H&E) with pan-cytokeratin staining using a 10 high power field (10HPF) and hotspot (1HPF) method. Two serial sections of 50 TNM stage II-IV surgically treated CRC were stained for H&E and pan-cytokeratin. Tumor buds were scored by independent observers at six participating centers in Switzerland and Austria using the 10HPF and 1HPF method on a digital pathology platform. Pearson correlation (r) and intra-class correlation coefficients (ICC) comparing scores between centers were calculated. Three to four times more tumor buds were detected in pan-cytokeratin compared to H&E slides. Correlation coefficients for tumor budding counts between centers ranged from r = 0.46 to r = 0.91 for H&E and from r = 0.73 to r = 0.95 for pan-cytokeratin slides. Interobserver agreement across all centers was excellent for pan-cytokeratin [10HPF: ICC = 0.83 and 1HPF: ICC = 0.8]. In contrast, assessment of tumor budding on H&E slides reached only moderate agreement [10HPF: ICC = 0.58 and 1HPF: ICC = 0.49]. Based on previous literature and our findings, we recommend (1) pan-cytokeratin staining whenever possible, (2) 10HPF method for resection specimens, and (3) 1HPF method for limited material (preoperative biopsy or pT1). Since tumor budding counts can be used to determine probabilities of relevant outcomes and as such more optimally complement clinical decision making, we advocate the avoidance of cutoff scores. PMID- 25701481 TI - Diagnosing cytomegalovirus in patients with inflammatory bowel disease--by immunohistochemistry or polymerase chain reaction? AB - Cytomegalovirus (CMV) reactivation is a common complication in patients with inflammatory bowel diseases (IBD), particularly in those with steroid-resistant ulcerative colitis. It is usually diagnosed by histopathologic and immunohistochemical examination of the colon biopsy. The introduction of quantitative, real-time polymerase chain reaction (qPCR) has been recommended to improve the sensitivity, but there is little consensus on how to use it. We compared the two methods in samples from resected bowel of patients with IBD. Twelve patients with IBD who had undergone bowel resection were analysed for CMV, using qPCR and immunohistochemistry. In all cases, tissue samples from the base and the edge of ulcers and from uninvolved mucosa were obtained. The highest densities of CMV-positive cells were found in samples from the base of ulcers (immunohistochemistry 0-0.47 positive cells/mm(2); qPCR 10-3809 viral copies/mg) or the edge of ulcers (immunohistochemistry 0.06-0.32 positive cells/mm(2); qPCR 35-1049 viral copies/mg). In samples of uninvolved mucosa, immunohistochemistry was negative, whereas qPCR was either negative or showed very low values (0-3 viral copies/mg). We conclude that both immunohistochemistry and qPCR can be successfully used for diagnosing CMV reactivation in patients with IBD. The base and the edge of ulcers are the optimal sites for endoscopic biopsies. The density of CMV-positive cells was low and their distribution within the colon uneven. It therefore seems that the number of sampled biopsies and/or the number of investigated levels is more important that the choice of diagnostic method. PMID- 25701483 TI - Stem cell intervention ameliorates epigallocatechin-3-gallate/lipopolysaccharide induced hepatotoxicity in mice. AB - Stem cells are identified as a novel cell therapy for regenerative medicine because of their ability to differentiate into many functional cell types. We have shown earlier a new model of hepatotoxicity in mice by administering (1500 mg/kg) epigallocatechin-3-gallate (EGCG) intragastric (IG) for 5 days after a single intraperitoneal dose (6 mg/kg) of lipopolysaccharide (LPS). In this study, we aimed to study the effect of intrahepatic (IH) injection of mouse embryonic stem cells (MESCs) on the hepatotoxicity induced by EGCG/LPS in mice. Mice were administered EGCG/LPS and rested for 3 days. MESCs were obtained from American Type Culture Collection and cultured in vitro for 4 days. Stem cells were injected IH. Seven days later, a single dose of LPS (6 mg/kg) followed by daily doses of IG administration of EGCG were re-administered for 5 days. At the end of the experiment, blood samples were collected for analysis of biochemical parameters associated with liver. Results showed that the group of mice that were administered MESCs prior to EGCG/LPS showed lower levels of alanine amino transferase, alkaline phosphatase, and bilirubin, higher albumin/globulin ratio, and less remarkable histopathological lesions. Also, that group of mice showed less expression of oxidative stress biomarkers (oxidized low-density lipoprotein Ox.LDL and chemokine CXCL16), less expression of nuclear protein receptors (retinoic acid receptor and retinoid X receptor), and less expression of inflammatory biomarkers (tumor necrosis factor alpha and transforming growth factor beta1) compared with other groups of mice that were not given MESCs. In conclusion, MESCs can ameliorate EGCG/LPS-induced hepatotoxicity in mice. PMID- 25701484 TI - Outcomes of the Haigis-L formula for calculating intraocular lens power in Asian eyes after refractive surgery. AB - PURPOSE: To report outcomes using the Haigis-L formula to calculate intraocular lens (IOL) power in Asian eyes with long axial lengths (ALs) that had previous myopic laser in situ keratomileusis (LASIK) or photorefractive keratectomy (PRK). SETTING: Singapore National Eye Centre, Singapore. DESIGN: Retrospective case series. METHODS: Patients with ALs greater than 25.0 mm and previous myopic LASIK or PRK who had phacoemulsification were analyzed. The emmetropic IOL power was back-calculated using the 1-month postoperative manifest refraction and compared with the emmetropic IOL power calculated with the Haigis-L formula. The primary outcome measure was the mean arithmetic prediction error, defined as the difference between the actual postoperative refractive error and the intended formula-derived refractive target. RESULTS: Sixty-two eyes (52 patients) were analyzed. The mean arithmetic prediction error was -0.44 diopter (D) +/- 0.98 (SD) and the mean absolute error, 0.87 +/- 0.62 D. The mean arithmetic prediction error was -0.52 +/- 0.96 D in eyes with an AL less than 27.0 mm and -0.36 +/- 1.00 D in eyes with an AL of 27.0 mm or greater (P = .463). The predictability of being within +/-0.50 D and +/-1.00 D of target was 35.7% and 63.1%, respectively, overall; 31.6% and 60.5%, respectively, in eyes with an AL less than 27.0 mm; and 39.1% and 65.2%, respectively, in eyes with an AL of 27.0 mm or greater (P = .772). CONCLUSION: The Haigis-L formula was acceptably accurate in predicting and achieving target outcomes after phacoemulsification in Asian eyes with a long AL that had previous myopic LASIK or PRK. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 25701486 TI - Scaphocapitate arthrodesis for Kienbock disease. AB - PURPOSE: To assess the effect of scaphocapitate arthrodesis (SCA) on grip strength and wrist motion for patients with advanced stages of Kienbock disease. METHODS: A retrospective review was conducted of patients with advanced stages of Kienbock disease (stages III-IV) who underwent SCA at our institution between 1991 and 2010 with a minimum of 1 year clinical follow-up. Outcome measures included preoperative and postoperative pain, range of motion, grip strength, complications, additional surgery, radiographic changes, and the modified Mayo Wrist and Lichtman Outcome scores. RESULTS: Twenty-seven patients (17 males and 10 females) with a mean age of 41 years (range, 15-66 y) at the time of SCA were included in the study. The mean follow-up period was 60 months (range, 12 mo-16 y). Union was achieved in all 27 patients. Significant loss of mean motion was noted from preoperative to postoperative in wrist flexion (14 degrees ), extension (11 degrees ), and ulnar deviation (9 degrees ). However, significant improvement in grip strength was noted (+7 kg). Modified Mayo Wrist scores were mostly fair to poor and Lichtman scores were satisfactory in 32% (n = 7) of patients, yet 74% of patients returned to regular employment. Progressive radiographic carpal collapse and ulnar translocation of the carpus occurred, particularly in patients who had lunate excisions. However, no patients had symptoms attributable to carpal collapse or ulnar translocation that necessitated additional surgery. CONCLUSIONS: SCA resulted in improved grip strength with correction of carpal alignment in patients with advanced stages of Kienbock disease in medium-term follow-up. Although radiographic carpal collapse and ulnar translocation occurred, patients were not symptomatic. Patients should be counseled that decrease in wrist range of motion will likely occur. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 25701485 TI - Single-cell analysis challenges the connection between autophagy and senescence induced by DNA damage. AB - Autophagy and senescence have been described as central features of cell biology, but the interplay between these mechanisms remains obscure. Using a therapeutically relevant model of DNA damage-induced senescence in human glioma cells, we demonstrated that acute treatment with temozolomide induces DNA damage, a transitory activation of PRKAA/AMPK-ULK1 and MAPK14/p38 and the sustained inhibition of AKT-MTOR. This produced a transient induction of autophagy, which was followed by senescence. However, at the single cell level, this coordinated transition was not observed, and autophagy and senescence were triggered in a very heterogeneous manner. Indeed, at a population level, autophagy was highly negatively correlated with senescence markers, while in single cells this correlation did not exist. The inhibition of autophagy triggered apoptosis and decreased senescence, while its activation increased temozolomide-induced senescence, showing that DNA damage-induced autophagy acts by suppressing apoptosis. PMID- 25701487 TI - Four-Corner Arthrodesis Versus Proximal Row Carpectomy: A Retrospective Study With a Mean Follow-Up of 17 Years. AB - PURPOSE: To compare the long-term outcomes of proximal row carpectomy (PRC) and 4 corner arthrodesis (FCA) in a consecutive series of patients surgically treated between 1989 and 1998 in a single teaching hospital. METHODS: We included 12 patients (14 wrists) in the PRC group and 8 patients (8 wrists) in the FCA group. Mean follow-up time was 17 years. We compared functional outcome measures (range of motion and grip strength) and patient-reported outcome measures (visual analog score for pain, Mayo Wrist Score, and Michigan Hand Questionnaire). Radiographic evaluation of joint degeneration using the Culp and Jebson scoring system and postoperative complications were assessed for both groups. RESULTS: Active range of motion was slightly better after PRC. There were no differences in grip strength and patient-reported outcomes between groups. Severity of degenerative changes did not differ between groups and was not correlated with pain scores. The FCA group showed more postoperative complications. CONCLUSIONS: Considering the objective and patient-reported outcomes of this study, both types of surgery perform well in the long run. Proximal row carpectomy seems to result in slightly better movement of the wrist with fewer surgical complications and no need for hardware removal. Moreover, postoperative immobilization time was much shorter. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic III. PMID- 25701488 TI - Hand function with touch screen technology in children with normal hand formation, congenital differences, and neuromuscular disease. AB - PURPOSE: To measure and compare hand function for children with normal hand development, congenital hand differences (CHD), and neuromuscular disease (NMD) using a function test with touch screen technology designed as an iPhone application. METHODS: We measured touch screen hand function in 201 children including 113 with normal hand formation, 43 with CHD, and 45 with NMD. The touch screen test was developed on the iOS platform using an Apple iPhone 4. We measured 4 tasks: touching dots on a 3 * 4 grid, dragging shapes, use of the touch screen camera, and typing a line of text. The test takes 60 to 120 seconds and includes a pretest to familiarize the subject with the format. Each task is timed independently and the overall time is recorded. RESULTS: Children with normal hand development took less time to complete all 4 subtests with increasing age. When comparing children with normal hand development with those with CHD or NMD, in children aged less than 5 years we saw minimal differences; those aged 5 to 6 years with CHD took significantly longer total time; those aged 7 to 8 years with NMD took significantly longer total time; those aged 9 to 11 years with CHD took significantly longer total time; and those aged 12 years and older with NMD took significantly longer total time. CONCLUSIONS: Touch screen technology has becoming increasingly relevant to hand function in modern society. This study provides standardized age norms and shows that our test discriminates between normal hand development and that in children with CHD or NMD. TYPE OF STUDY/LEVEL OF EVIDENCE: Diagnostic III. PMID- 25701489 TI - The effect of lunate morphology in Kienbock disease. AB - PURPOSE: To determine if the absence (type I lunate) or presence (type II lunate) of a medial hamate facet on the lunate affects the radiographic characteristics of patients presenting with Kienbock disease. METHODS: A retrospective review was performed on all patients evaluated at our institution from 2002 to 2010 with a diagnosis of Kienbock disease confirmed on plain radiographs in concert with magnetic resonance imaging (MRI) and/or bone scan. Study groups consisted of patients with type I versus type II lunates, as determined by radiographs, MRI, and/or computed tomography. Measured variables included the modified Lichtman stage on presentation, radioscaphoid angle, presence or absence of a coronal plane fracture of the lunate, modified carpal height, ulnar variance, and ulnar translocation of the carpus at the time of presentation. RESULTS: A total of 106 wrists were examined, of which 75 were type I (71%) and 31 were type II (29%) lunates. At the time of presentation, there was significantly more advanced disease (stage IIIA or greater) in patients with type I (N = 64, 86%) compared with those with type II lunates (N = 19, 61%). Coronal fractures of the lunate were more prevalent in patients with type I (N = 58, 75%) compared with type II lunates (N = 18, 58%). In the absence of a coronal fracture, radioscaphoid angles were greater in patients with a type I (53 degrees ) versus a type II lunate (45 degrees ). CONCLUSIONS: Lunate morphology may affect the severity of Kienbock disease at the time of initial presentation. Type II lunates appear to be protective against coronal fractures and scaphoid flexion deformities. This study provides further evidence that lunate morphology affects carpal pathology and may have implications for treatment options in Kienbock disease. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic III. PMID- 25701490 TI - Olecranon fractures with sagittal splits treated with dual fixation. AB - PURPOSE: To assess the results of olecranon fractures with an intra-articular sagittal plane fracture managed by orthogonal fixation constructs. METHODS: A retrospective chart review was performed and 14 proximal ulna fractures with intra-articular comminution resulting in separate medial and lateral fragments were identified. All fractures were classified according to the Schatzker, Mayo, and AO classification systems. Postoperative functional assessment, Disabilities of the Arm, Shoulder, and Hand (DASH) score, time to union, and complications were recorded. RESULTS: Eleven patients were treated with both dorsal and lateral plates. Three patients were managed with a single dorsal plate and cerclage wires. All fractures healed. Mean length of follow-up was 15 months (range, 4-72 mo). Mean range of motion at final follow-up was a flexion-extension arc of 24 degrees to 129 degrees with 89 degrees and 79 degrees of pronation and supination, respectively. The most common complication was symptomatic hardware, leading to removal of hardware in 5 of 14 (36%) patients. Average postoperative Disabilities of the Arm, Shoulder, and Hand score was 7. Two patients developed heterotopic ossification and 1 patient required a local pedicled flap for soft tissue coverage. CONCLUSIONS: Identification of this subset of fractures is critical to successful management. A supplemental lateral plate or cerclage wires can successfully manage these difficult fractures and achieve good outcomes. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 25701491 TI - Anti-cancer evaluation of quercetin embedded PLA nanoparticles synthesized by emulsified nanoprecipitation. AB - This study was carried out to synthesize quercetin (Qt) embedded poly(lactic acid) (PLA) nanoparticles (PLA-Qt) and to evaluate anti-cancer efficacy of PLA-Qt by using human breast cancer cells. PLA-Qt were synthesized by using novel emulsified nanoprecipitation technique with varying dimension of 32 +/- 8 to 152 +/- 9 nm of PLA-Qt with 62 +/- 3% (w/w) entrapment efficiency by varying the concentration of polymer, emulsifier, drug and preparation temperature. The dimension of PLA-Qt was measured through transmission electron microscopy indicating larger particle size at higher concentration of PLA. The release rate of Qt from PLA-Qt was found to be more sustained for larger particle dimension (152 +/- 9 nm) as compared to smaller particle dimension (32 +/- 8 nm). Interaction between Qt and PLA was verified through spectroscopic and calorimetric methods. Delayed diffusion and stronger interaction in PLA-Qt caused the sustained delivery of Qt from the polymer matrix. In vitro cytotoxicity study indicate the killing of ~ 50% breast cancer cells in two days at 100 MUg/ml of drug concentration while the ~ 40% destruction of cells require 5 days for PLA-Qt (46 +/- 6 nm; 20mg/ml of PLA). Thus our results propose anticancer efficacy of PLA-Qt nanoparticles in terms of its sustained release kinetics revealing novel vehicle for the treatment of cancer. PMID- 25701492 TI - Key mediators of intracellular amino acids signaling to mTORC1 activation. AB - Mammalian target of rapamycin complex 1 (mTORC1) is activated by amino acids to promote cell growth via protein synthesis. Specifically, Ras-related guanosine triphosphatases (Rag GTPases) are activated by amino acids, and then translocate mTORC1 to the surface of late endosomes and lysosomes. Ras homolog enriched in brain (Rheb) resides on this surface and directly activates mTORC1. Apart from the presence of intracellular amino acids, Rag GTPases and Rheb, other mediators involved in intracellular amino acid signaling to mTORC1 activation include human vacuolar sorting protein-34 (hVps34) and mitogen-activating protein kinase kinase kinase kinase-3 (MAP4K3). Those molecular links between mTORC1 and its mediators form a complicate signaling network that controls cellular growth, proliferation, and metabolism. Moreover, it is speculated that amino acid signaling to mTORC1 may start from the lysosomal lumen. In this review, we discussed the function of these mediators in mTORC1 pathway and how these mediators are regulated by amino acids in details. PMID- 25701493 TI - Marked elevation of the jugular venous pressure should raise the index of suspicion for constrictive pericarditis. PMID- 25701494 TI - Elevation of the JVP in constrictive pericarditis. PMID- 25701495 TI - Structural analysis of adventitial collagen to feature aging and aneurysm formation in human aorta. AB - OBJECTIVE: Adventitial collagen structure provides the aorta with tensile strength. Like other collagen-rich tissues, it can be affected by internal factors including aging and location. We determined whether the structural characteristics of human aortic adventitial collagen change with aging, location, and aneurysm formation. METHODS: Nonatherosclerotic nonaneurysmal (NANA) human abdominal aortas were collected from 15 individuals who had died of noncardiovascular diseases (<40 years old, NANA young, n = 5; >60 years old, NANA old, n = 5). The architecture of adventitial collagen in the aortas was assessed by scanning electron microscopy, and fiber orientation was assessed by polarized microscopy with two-dimensional fast Fourier transform. We then analyzed retardation as an anisotropic property of adventitial collagen by polarized light microscopy. The orientation and retardation of NANA aortas were compared with those of abdominal aortic specimens from patients who were surgically treated for abdominal aortic aneurysm (AAA) (>60 years old, n = 11). RESULTS: Adventitial collagen of the abdominal aortas on scanning electron microscopy images appeared as wavy, ropy fibers in aortas from young individuals (NANA young, n = 5) and were essentially flattened in those from older patents (NANA old, n = 5) and from those with AAA. Collagen fibers were thicker but sparser in the adventitia of aortas with AAA. Orientation maintained in the collagen fibers of NANA aortas (n = 15) on two-dimensional fast Fourier transform analysis was unrelated to either location or age and did not differ between NANA aortas and those with AAA. However, collagen fibrils in NANA aortas (n = 15) were significantly less retarded only at the level of the inferior mesenteric artery compared with other aortic locations. In addition, retardation was significantly reduced in abdominal aortas with AAA at the level of the inferior mesenteric artery. CONCLUSIONS: The basic structure of adventitial collagen fiber was maintained in abdominal aortas regardless of location or age. Because the molecular structure at the subfibril level changed at abdominal aorta and enhanced in aortas with AAA, alterations in the molecular structure of adventitial collagen might be associated with aneurysmal formation. PMID- 25701496 TI - Feasibility of wall stress analysis of abdominal aortic aneurysms using three dimensional ultrasound. AB - OBJECTIVE: Abdominal aortic aneurysms (AAAs) are local dilations that can lead to a fatal hemorrhage when ruptured. Wall stress analysis of AAAs is a novel tool that has proven high potential to improve risk stratification. Currently, wall stress analysis of AAAs is based on computed tomography (CT) and magnetic resonance imaging; however, three-dimensional (3D) ultrasound (US) has great advantages over CT and magnetic resonance imaging in terms of costs, speed, and lack of radiation. In this study, the feasibility of 3D US as input for wall stress analysis is investigated. Second, 3D US-based wall stress analysis was compared with CT-based results. METHODS: The 3D US and CT data were acquired in 12 patients (diameter, 35-90 mm). US data were segmented manually and compared with automatically acquired CT geometries by calculating the similarity index and Hausdorff distance. Wall stresses were simulated at P = 140 mm Hg and compared between both modalities. RESULTS: The similarity index of US vs CT was 0.75 to 0.91 (n = 12), with a median Hausdorff distance ranging from 4.8 to 13.9 mm, with the higher values found at the proximal and distal sides of the AAA. Wall stresses were in accordance with literature, and a good agreement was found between US- and CT-based median stresses and interquartile stresses, which was confirmed by Bland-Altman and regression analysis (n = 8). Wall stresses based on US were typically higher (+23%), caused by geometric irregularities due to the registration of several 3D volumes and manual segmentation. In future work, an automated US registration and segmentation approach is the essential point of improvement before pursuing large-scale patient studies. CONCLUSIONS: This study is a first step toward US-based wall stress analysis, which would be the modality of choice to monitor wall stress development over time because no ionizing radiation and contrast material are involved. PMID- 25701497 TI - p27(kip1) Knockout enhances collateralization in response to hindlimb ischemia. AB - OBJECTIVE: The natural response to arterial occlusive disease is enlargement of collaterals; however, the molecular factors that control collateralization are not well understood. The gene p27(Kip1) (p27) affects human response to arterial injury. Previous studies have shown that overexpression of p27 inhibits vascular endothelial and vascular smooth muscle cell (VSMC) proliferation and angiogenesis. To test the hypothesis that knockout of p27 would improve collateralization in reaction to ischemia, we performed in vivo and in vitro experiments using p27 knockout (p27(-/-)) and wild-type (wt) mice. METHODS: Hindlimb ischemia was induced by left femoral artery ligation in p27(-/-) and wt (C57BL/6) female mice. The mice underwent weekly laser Doppler perfusion imaging of the footpads until sacrifice on postoperative day 28 followed by microcomputed tomography scanning of both hindlimbs. VSMCs were isolated from p27(-/-) and wt mice and used in migration and gel contraction assays in the absence and presence of the nonspecific matrix metalloproteinase (MMP) inhibitor BB94. MMP-2 and MMP-9 messenger RNA (mRNA) expression was measured by quantitative reverse transcription-polymerase chain reaction in p27(-/-) and wt VSMCs. RESULTS: p27(-/ ) mice reperfused more effectively than wt mice by laser Doppler starting from day 7 (ischemic/nonischemic ratio, 0.33 +/- 0.02 vs 0.25 +/- 0.02; P < .05) and continuing through day 28 (0.45 +/- 0.04 vs 0.31 +/- 0.04; P < .05). The gracilis collateral diameter was similar for the nonischemic hindlimbs of the p27(-/-) and wt mice, and this collateral pathway increased similarly after ischemia as assessed by microcomputed tomography. However, the p27(-/-) mice significantly enlarged a novel collateral pathway that bridged directly between the femoral artery proximal to the ligation site and the saphenous or popliteal artery distal to the ligation site more than wt mice (158 +/- 18.3 vs 82 +/- 22 MUm; P < .001). p27(-/-) VSMCs migrated more (79% +/- 5% vs 56% +/- 6%; P < .05) and caused more gel contraction (18% +/- 5% of the initial area vs 43% +/- 4%; P < .05) than wt cells. Migration and collagen contraction were abolished in p27(-/-) and wt cells by MMP inhibition. p27(-/-) cells expressed significantly more MMP-2 mRNA than wt cells did. CONCLUSIONS: Knockout of p27 enhances arterial collateralization in response to hindlimb ischemia through enlargement of a new collateral pathway. In vitro, knockout of p27 increases collagen gel contraction in addition to stimulating VSMC migration. We speculate that p27 may affect collateralization through its role in regulating MMP-2 expression. PMID- 25701498 TI - From molecule to molecule and cell to cell: prion-like mechanisms in amyotrophic lateral sclerosis. AB - Prions, self-proliferating infectious agents consisting of misfolded protein, are most often associated with aggressive neurodegenerative diseases in animals and humans. Akin to the contiguous spread of a living pathogen, the prion paradigm provides a mechanism by which a mutant or wild-type misfolded protein can dominate pathogenesis through self-propagating protein misfolding, and subsequently spread from region to region through the central nervous system. The prion diseases, along with more common neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and the tauopathies belong to a larger group of protein misfolding disorders termed proteinopathies that feature aberrant misfolding and aggregation of specific proteins. Amyotrophic lateral sclerosis (ALS), a lethal disease characterized by progressive degeneration of motor neurons is currently understood as a classical proteinopathy; the disease is typified by the formation of inclusions consisting of aggregated protein within motor neurons that contribute to neurotoxicity. It is well established that misfolded/aggregated proteins such as SOD1 and TDP-43 contribute to the toxicity of motor neurons and play a prominent role in the pathology of ALS. Recent work has identified propagated protein misfolding properties in both mutant and wild-type SOD1, and to a lesser extent TDP-43, which may provide the molecular basis for the clinically observed contiguous spread of the disease through the neuroaxis. In this review we examine the current state of knowledge regarding the prion-like properties of proteins associated with ALS pathology as well as their possible mechanisms of transmission. PMID- 25701499 TI - Anti-TNFalpha treatment decreases the previously increased serum Indian Hedgehog levels in patients with ankylosing spondylitis and affects the expression of functional Hedgehog pathway target genes. AB - OBJECTIVE: Indian Hedgehog (Ihh) is the ligand that activates the Hedgehog pathway (HH) in the skeleton-the main controller of endochondral ossification. We aimed at assessing serum levels of Ihh in patients with ankylosing spondylitis (AS) and the effect of serum from patients with AS on HH pathway activation. METHODS: Serum Ihh levels were measured in 59 patients with AS, 70 patients with rheumatoid arthritis (RA), and 53 healthy subjects. The effect of serum from patients with AS on HH pathway activation was evaluated using an osteoblast-like cell line model. RESULTS: Patients with AS not on anti-TNFalpha treatment had significantly higher Ihh levels compared to patients with RA not on anti-TNFalpha treatment (mean +/- SEM of OD: 0.370 +/- 0.025 vs. 0.279 +/- 0.026 for patients with AS and RA, respectively, p = 0.027) and healthy subjects (p = 0.031). Patients with AS on anti-TNFalpha treatment had significantly lower Ihh levels compared to patients with AS not on such treatment (p = 0.028). Patients with RA on anti-TNF treatment had higher levels of Ihh compared to patients not on such treatment (p = 0.013). PTHrP levels were similar in patients with RA, AS, and healthy subjects and were not affected by anti-TNFalpha treatment. We next assessed HH pathway activation in Saos2 cells following incubation with serum from AS patients prior to and following anti-TNF treatment. The HH pathway was downregulated following treatment. CONCLUSIONS: Ihh levels are increased in patients with AS and decrease following anti-TNFalpha treatment; this finding may have pathogenic and clinical implications. PMID- 25701500 TI - Reasons for failure to receive pneumococcal and influenza vaccinations among immunosuppressed patients with systemic lupus erythematosus. AB - OBJECTIVE: To better understand why immunosuppressed individuals with systemic lupus erythematosus (SLE) fail to receive influenza and pneumococcal vaccines. METHODS: These cross-sectional data were derived from the 2009 cycle of the Lupus Outcomes Study (LOS), an annual longitudinal telephone survey of individuals with confirmed SLE. Respondents were included in the analysis if they had taken immunosuppressive medications in the past year. We assessed any prior receipt of pneumococcal vaccine and influenza vaccine in the past year, and then elicited reasons for not receiving vaccination. We used bivariate statistics and multivariate logistic regression to assess frequency and predictors of reported reasons for not obtaining influenza or pneumococcal vaccines. RESULTS: Among 508 respondents who received immunosuppressants, 485 reported whether they had received vaccines. Among the 175 respondents who did not receive an influenza vaccine, the most common reason was lack of doctor recommendation (55%), followed by efficacy or safety concerns (21%), and lack of time (19%). Reasons for not receiving pneumococcal vaccine (N = 159) were similar: lack of recommendation (87%), lack of time (7%), and efficacy or safety concerns (4%). Younger, less educated, non-white patients with shorter disease duration, as well as those immunosuppressed with steroids alone, were at the greatest risk for not receiving indicated vaccine recommendations. CONCLUSIONS: The most common reason why individuals with SLE did not receive pneumococcal and influenza vaccines was that physicians failed to recommend them. Data suggest that increasing vaccination rates in SLE will require improved process quality at the provider level, as well as addressing patient concerns and barriers. PMID- 25701501 TI - Structural and functional features of enzymes of Mycobacterium tuberculosis peptidoglycan biosynthesis as targets for drug development. AB - Tuberculosis (TB) is the second leading cause of human mortality from infectious diseases worldwide. The WHO reported 1.3 million deaths and 8.6 million new cases of TB in 2012. Mycobacterium tuberculosis (M. tuberculosis), the infectious bacteria that causes TB, is encapsulated by a thick and robust cell wall. The innermost segment of the cell wall is comprised of peptidoglycan, a layer that is required for survival and growth of the pathogen. Enzymes that catalyse biosynthesis of the peptidoglycan are essential and are therefore attractive targets for discovery of novel antibiotics as humans lack similar enzymes making it possible to selectively target bacteria only. In this paper, we have reviewed the structures and functions of enzymes GlmS, GlmM, GlmU, MurA, MurB, MurC, MurD, MurE and MurF from M. tuberculosis that are involved in peptidoglycan biosynthesis. In addition, we report homology modelled 3D structures of those key enzymes from M. tuberculosis of which the structures are still unknown. We demonstrated that natural substrates can be successfully docked into the active sites of the GlmS and GlmU respectively. It is therefore expected that the models and the data provided herein will facilitate translational research to develop new drugs to treat TB. PMID- 25701502 TI - Effects of albumin binding on photocytotoxicity of extracellular photosensitization reaction using talaporfin sodium to rat myocardial cells. AB - BACKGROUND: We previously proposed a new treatment for tachyarrhythmia using an extracellular photosensitization reaction occurring in the interstitial space of myocardia shortly after the injection of talaporfin sodium. Using myocardial cells, we studied the photocytotoxicity of this extracellular photosensitization reaction between talaporfin sodium and albumin. METHODS: The albumin concentrations tested spanned the physiological range found in the interstitial space (0-15 mg/ml) while the talaporfin sodium concentration were varied from 0 to 40 MUg/ml. The reactions were conducted in 96-well plates. To obtain the binding ratio and the amount of energy deposited into the photosensitizer, we measured the change in the absorbance spectra of talaporfin sodium solutions containing different concentrations of albumin. RESULTS: Photocytotoxicity to myocardial cell due to the reaction decreased when physiological concentrations of albumin were added to the reaction mix, and decreased sharply when the molar concentration ratio of albumin to talaporfin sodium was between 0.3 and 1.2. A monotonic binding ratio was obtained, ranging from 10 to 80%, at albumin concentrations of 0.1-1.0 mg/ml. We found that the lethality of the extracellular photosensitization reaction towards myocardial cells had a threshold albumin concentration, even though the energy deposited into the talaporfin sodium solution was calculated to be almost constant (4.23 +/- 0.19 J/well) in the presence of 0-15 mg/ml albumin. CONCLUSIONS: Based on the likely concentration of albumin in the interstitial space, we conclude that the photodynamic efficacy of talaporfin, under conditions used here, will markedly decrease if the albumin level exceeds 0.65 mg/ml. PMID- 25701503 TI - Caffeine protects against alcohol-induced liver fibrosis by dampening the cAMP/PKA/CREB pathway in rat hepatic stellate cells. AB - Alcoholic liver fibrosis (ALF) is characterized by hyperplasia of extracellular matrix under long-term alcohol stimulation. Hepatic stellate cell (HSC) activation plays an important role in promoting hepatic fibrogenesis. Caffeine, as the main active component of coffee and tea, was widely consumed in daily life. It was always a thought that caffeine can reduce the probability of suffering from liver diseases. In this study, we attempt to validate the hypothesis that caffeine inhibits activation of HSCs which were isolated from rat ALF model. The rats were gavaged by ethanol to establish ALF model and then treated with different concentrations of caffeine or colchicine. Serum was collected to measure the contents of serum alanine aminotransferase (ALT), aspartate transaminase (AST), hyaluronic acid (HA), laminin (LN), N-terminal peptide of type III procollagen (PIIINP) and type IV collagen (CIV). Then liver tissues were obtained for hematoxylin-eosin staining and Sirius-red staining. Others were treated through liver perfusion to isolate primary rat HSCs. Interestingly, we found that caffeine significantly decreased ALT, AST, HA, LN, PIIINP and CIV levels and reversed liver fibrosis in rat ALF models. Results of immunohistochemistry, real-time PCR and western blot indicated that caffeine could reduce fibrosis and inhibit cAMP/PKA/CREB signal pathway in HSC. Caffeine has a preventive effect on ALF. The mechanism may be interpreted that caffeine inhibits the cAMP/PKA/CREB signal pathway through adenosine A2A receptors in HSC. PMID- 25701504 TI - Schizandrin inhibits fibrosis and epithelial-mesenchymal transition in transforming growth factor-beta1-stimulated AML12 cells. AB - The transforming growth factor (TGF)-beta1 plays a crucial role in the induction of the epithelial-to-mesenchymal transition (EMT) in hepatocytes, which contributes to the pathogenesis of liver fibrosis. The inhibition of the TGF beta1 cascade suppresses EMT and the resultant fibrosis. Schizandrin (Sch) has various therapeutic effects on a range of medical conditions such as anti asthmatic, anti-cancer, and anti-inflammatory effects. However, the effect of Sch on TGF-beta1-stimulated hepatic fibrosis and EMT is still unknown. In the present investigation, we evaluated the anti-fibrotic and anti-EMT properties of Sch and its underlying mechanisms in murine hepatocyte AML12 cells. Overall, we found that Sch inhibited the pro-fibrotic activity of TGF-beta1 in AML12 cells; thus, it suppressed the accumulation of ECM proteins. Also, Sch inhibited the EMT as assessed by reduced expression of vimentin and fibronectin, and increased E cadherin and ZO-1 in TGF-beta1 induced AML12 cells. Sch reduced TGF-beta1 mediated phosphorylation of Smad2/3 and Smad3/4 DNA binding activity. On the other hand, Sch reduced TGF-beta1-induced ERK1/2 and PI3K/Akt phosphorylation in the non-Smad pathway. In conclusion, Sch can antagonize TGF-beta1-mediated fibrosis and EMT in AML12 cells. Sch may possess potential as an anti-fibrotic molecule in the treatment of liver fibrosis. PMID- 25701505 TI - Gamma-irradiated resveratrol negatively regulates LPS-induced MAPK and NF-kappaB signaling through TLR4 in macrophages. AB - Resveratrol was irradiated at various doses of 15, 30, 50, and 70kGy for the development of physiological functionalities through modification of the structural properties. Gamma irradiation induced a decrease in the resveratrol peak, and the appearance of several new peaks by gamma irradiation was gradually increased up to 70kGy. Gamma-irradiated resveratrol did not exert cytotoxicity to macrophages in dose ranges from 15 to 70kGy; therefore, 70kGy gamma-irradiated resveratrol was used as the maximum dose throughout subsequent experiments. Treatment of LPS-stimulated macrophages with 70kGy gamma-irradiated resveratrol resulted in a dose-dependent decrease in iNOS-mediated NO, PGE2, and pro inflammatory cytokine level, such as TNF-alpha, IL-6 and IL-1beta. 70kGy gamma irradiated resveratrol significantly inhibited cyclooxygenase-2 levels, as well as the expression of cell surface molecules, such as CD80 and CD86, in LPS induced macrophages. Furthermore, the inhibitory action of these pro-inflammatory mediators occurred through an inhibition of MAPKs (ERK1/2, p38 and JNK) and NF kappaB signaling pathways based on a toll-like receptor 4 in macrophages, which may be closely mediated with the radiolysis products of resveratrol transformed by gamma-irradiation. From these findings, it seems likely that gamma irradiation can be an effective tool for a reduction of the toxicity and play a potent role in the treatment of inflammatory disease. PMID- 25701506 TI - Hesperetin derivative-7 inhibits PDGF-BB-induced hepatic stellate cell activation and proliferation by targeting Wnt/beta-catenin pathway. AB - Liver fibrosis results from a continuous wound-healing response of the liver to repeated injury. Hesperidin (HDN) is a naturally occurring flavanone glycoside, which is extracted from fruit peels of the genus citrus. Previous studies focused on the anti-inflammation, anti-tumor and anti-oxidant roles of HDN. However, the role of HDN in hepatic fibrosis is still unknown. Here, we evaluated the role of HDND-7, a derivative of HDN which has better water solubility and bioavailability, in the activation and proliferation of PDGF-BB-induced hepatic stellate cells (HSCs), then we investigated the anti-fibrotic effect of HDND-7 in CCl4-induced mouse model of liver fibrosis. The study aimed to determine whether HDND-7 could affect the survival of HSC-T6 in vitro, while evaluating its anti fibrotic efficacy on CCl4-induced liver fibrosis in Kunming mice. Our results revealed that HDND-7 inhibited the proliferation and activation of PDGF-BB treated HSC-T6 cells in a time- and dose-dependent manner. In addition, administration of HDND-7 significantly attenuated liver fibrosis, as evident by the dramatic down-regulation of alpha-smooth muscle actin (alpha-SMA) and type I collagen alpha-1 (Col1alpha1) in both mRNA and protein levels in vivo and in vitro. Furthermore, we also found that HDND-7 decreased the expression of beta catenin and the downstream proteins, cyclind1 and C-myc, indicating that HDND-7 may inhibit the activation and proliferation of PDGF-BB-induced HSC-T6 and attenuate liver fibrosis, at least in part, through targeting the Wnt/beta catenin signaling pathway. Hence HDND-7 might be employed as a promising natural supplement for liver fibrosis drug therapy. PMID- 25701507 TI - Association of single nucleotide polymorphisms in the gene encoding GLUT1 and diabetic nephropathy in Brazilian patients with type 1 diabetes mellitus. AB - Mesangial cells subject to high extracellular glucose concentrations, as occur in hyperglycaemic states, are unable to down regulate glucose influx, resulting in intracellular activation of deleterious biochemical pathways. A high expression of GLUT1 participates in the development of diabetic glomerulopathy. Variants in the gene encoding GLUT1 (SLC2A1) have been associated to this diabetic complication. The aim of this study was to test whether polymorphisms in SLC2A1 confer susceptibility to diabetic nephropathy (DN) in Brazilian type 1 diabetes patients. Four polymorphisms (rs3820589, rs1385129, rs841847 and rs841848) were genotyped in a Brazilian cohort comprised of 452 patients. A prospective analysis was performed in 155 patients. Mean duration of follow-up was 5.6 +/- 2.4 years and the incidence of renal events was 18.0%. The rs3820589 presented an inverse association with the prevalence of incipient DN (OR: 0.36, 95% CI: 0.16 - 0.80, p=0.01) and with progression to renal events (HR: 0.20; 95% CI: 0.03 - 0.70; p=0.009). AGGT and AGAC haplotypes were associated with the prevalence of incipient DN and the AGAC haplotype was also associated with the prevalence of established/advanced DN. In conclusion, rs3820589 in the SLC2A1 gene modulates the risk to DN in Brazilian patients with inadequate type 1 diabetes control. PMID- 25701508 TI - Renal physiological regenerative medicine to prevent chronic renal failure: should we start at birth? AB - With the incidence of end-stage renal disease increasing dramatically during the last ten years, its prevalence rising about 8% per year, chronic kidney disease (CKD) represents one of the most problematic public health problems worldwide. CKD represents a growing clinical problem that, in its terminal stages, requires renal replacement therapy. Kidney transplant has been proposed as the definitive therapy able to address the growing clinical, social and economic problems related to the increasing prevalence of end-stage kidney disease (ESKD). Traditional stem cell-based regenerative medicine, when applied to kidneys disrupted by end-stage renal disease, has been shown to be unable to regenerate the damaged organ. The theme of this work is to hypothesize a new approach to the prevention of CKD, based on the management of the huge amount of stem/progenitor cells physiologically present in the kidney of preterm babies at birth. Here a new concept of primary prevention of renal disease is suggested: a true primary prevention, starting in the perinatal period aimed at increasing the number of functioning glomeruli. This approach has been defined as "physiological regenerative medicine", in order to underline the use of physiological tools, including endogenous renal stem cells and stem cell stimulators physiologically expressed in our cells. PMID- 25701509 TI - Evolutions and reflections on returning from AsiaPCR/SingLIVE 2015. PMID- 25701510 TI - Renal denervation reloaded: where to go from here? PMID- 25701511 TI - Bipolar multi-electrode balloon catheter radiofrequency renal denervation with the Vessix system: preclinical safety evaluation. AB - AIMS: A bipolar multi-electrode 7 Fr-compatible balloon-catheter radiofrequency (RF) renal denervation system (VessixTM Renal Denervation System; Boston Scientific, Marlborough, MA, USA) was evaluated for safety in domestic swine. METHODS AND RESULTS: Renal arteries of 27 swine received overlapping treatments proximally/single treatments distally to mimic balloon overlap clinically. Each histopathology cohort (30, 90, 180 days) had four RF-treated and three sham treated (no RF energy delivered) animals, with the response of artery/surrounding nerves to bilateral treatment examined (42 arteries). Scanning electron microscopy of the renal artery flow surface for endothelialisation was performed in six additional pigs (three at each of 30 and 90 days: 12 arteries) following unilateral whole artery treatment with proximal overlap: RF one side, sham the other side. Power was ~1 watt, treatment duration 30 seconds, target temperature 68 degrees C. Renal histology and assessment for off-target injury was performed in all 27 swine. Renal artery thermal injury was transmural and segmental involving <10% to >90% of the circumference (typically 30-60%) with segmental neointimal hyperplasia exceeding shams but haemodynamically trivial (maximum stenosis 17.7%). Healing of necrotic arterial media was by replacement fibrosis. Overlying nerves also became fibrotic. Endothelialisation was focally incomplete at 30 days but confluent at 90 days. No off-target injury occurred outside the renal arteries. CONCLUSIONS: Safety was demonstrated. PMID- 25701512 TI - Tools & Techniques - clinical: percutaneous catheter-based left ventricular support using the Impella CP. PMID- 25701513 TI - Does it matter how you ask? The forbid-allow asymmetry in the measurement of attitudes towards drug policies. AB - BACKGROUND: It is important to know whether the public opinion on drug policies can be measured in a reliable and valid way. One of the threats to the validity of surveys on attitudes toward drug policies are wording effects, of which the most well-known is the forbid-allow asymmetry, i.e., people are often more willing to not allow something than to forbid it. The aim of the present study was to estimate the size of the allow-forbid asymmetry when measuring attitudes toward drug policy issues in the Norwegian adult population. METHODS: The data derive from a sample of 2182 adult Norwegian, aged 18-70, drawn from a large online panel comprising more than 50,000 Norwegian citizens (55% response rate). According to a 2 (allow vs. forbid)*2 (question vs. statement) between-subjects design, participants indicated support for the following three restrictive drug policies: (i) to allow/forbid wine in grocery stores, (ii) to allow/forbid smoking in parks and other public places and (iii) to allow forbid cannabis for recreational purposes. RESULTS: There was not a significant difference between the framing conditions (forbid-allow) across the three policies, with an estimated difference of 2 percentage points (95% confidence intervals 0-5). CONCLUSION: The results suggest that survey research in the present context of drug policy is indeed more of a fact-finding enterprise than a process of constructing data. PMID- 25701514 TI - The European patient advocacy perspective on specialist breast units and accreditation. AB - Europa Donna--The European Breast Cancer Coalition has been advocating for all women to have access to care in specialist breast units since 2003. Two European Parliament Resolutions, (2003 and 2006) as well as the Written Declaration against breast cancer in the EU of 2010 called on member states to ensure that all women in the European Union have access to treatment in such units set up in accordance with the "European Guidelines for quality assurance in breast cancer screening and diagnosis," by 2016. Once mammography screening implementation according to EU Guidelines commenced, it became evident that it would be essential to have high-quality units where women would receive specialised treatment upon diagnosis. Europa Donna was a member of the revision committee for Chapter 9 of the 4th edition of these Guidelines (2006) which provided a detailed description of these services as previously defined by EUSOMA. Moreover, the 2010 Written Declaration on the fight against breast cancer in the EU called on the Commission "to develop a certification protocol for specialist breast units in accordance with EU Guidelines by 2011". The most important thing for a woman diagnosed with breast cancer to know is where to go to get the best treatment, i.e. she needs to know that the clinic or unit is accredited as having implemented appropriate quality standards that meet EU Guidelines thus ensuring provision of high level breast services, and that her national health system will pay for it. Progress on accomplishing this has not moved quickly, nor has it been accepted by all stakeholders involved. PMID- 25701515 TI - Internet-based support programs to alleviate psychosocial and physical symptoms in cancer patients: a literature analysis. AB - In this review the effect of internet-based support programs on psychosocial and physical symptoms resulting from cancer diagnosis and treatment is analyzed. Selection of studies was based on the following criteria: (non-)randomized controlled trials, performed in adult cancer patients, comparing quantitative psychosocial and/or physical outcomes of an internet-based support program with (a) comparison group(s). Literature search yielded 2032 studies of which 16 fulfilled the eligibility criteria. Three different internet-based support programs were identified: social support groups, online therapy for psychosocial/physical symptoms, and online systems integrating information, support, and coaching services. Outcomes improved by these programs in nine studies. Especially fatigue, social support, and distress improved, regardless of the program type. All online systems showed positive effects, mainly for social support and quality of life. This analysis indicates that internet-based support programs are effective in improving psychosocial and physical symptoms in cancer patients. PMID- 25701516 TI - Radiotherapy for Benign Disease: Current Evidence, Benefits and Risks. PMID- 25701517 TI - Automatic assessment of shear wave elastography quality and measurement reliability in the liver. AB - A strategy is proposed that accesses the quality of individual shear wave elastography (SWE) exams and the reliability of elasticity measurements in clinical practice. For that purpose, a confidence index based on temporal stability and SWE filling was defined to provide an automatic estimation of each scan quality: high (HG) or low (LG) grade. With this index, the intra-observer acquisition variability assessed by comparing consecutive scans of the same patient was 17% and 32% for HG and LG clips, respectively. The measurement quantification variability assessed by comparing the measurements of a radiologist with those of a trained operator and of two automatic measurements on a same clip averaged 13% and 22% for HG and LG exams, respectively. It was found that SWE measurements depend greatly on the quality of the acquired data. The proposed quality index (HG or LG) provides objective input on the accuracy and diagnostic reliability of SWE measurements. PMID- 25701518 TI - Assessment of the safety and efficacy of bedside ultrasound guidance for inferior vena cava filter placement in critically ill intensive care unit patients. AB - Inferior vena cava filters (IVCFs) have been used clinically for approximately 45 y, but only a few studies of these devices have involved intensive care unit (ICU) patients who were critically ill and had multiple-organ dysfunction or were otherwise too unstable for transport. The purpose of this research was to assess the tolerability and efficacy of bedside ultrasound-guided IVCF placement in ICU patients. A retrospective analysis of both bedside ultrasound-guided and X-ray guided ICVF placement was performed from November of 2011 to August of 2013. The total success rate for ultrasound-guided IVCF placement was 93.4%, which included a 96.0% success rate in 25 ICU patients with an average age of 69.46 y. Six-month follow-up studies revealed no significant differences in long-term complications between the ultrasound- and X-ray-guided groups. IVCFs may be safely implanted under ultrasound guidance in a monitored ICU environment. Our conclusion is that patients should be fasting and should receive an enema and that pre-operative surface marking and dynamic monitoring should be employed. Further research is needed to develop specific ultrasound guidelines. PMID- 25701519 TI - Feasibility and usefulness of using swallow contrast-enhanced ultrasound to diagnose Zenker's diverticulum: preliminary results. AB - Zenker's diverticulum (ZD) may be misdiagnosed on conventional ultrasound as a thyroid nodule or other lesion. A barium esophagram is usually used to confirm the diagnosis; however, this procedure exposes the patient to radiation. The aim of this study was to evaluate the feasibility of using swallow contrast-enhanced ultrasound (swallow-CEUS) to diagnose ZD. Ten consecutive patients with ZD (7 men and 3 women, aged 67 +/- 11 y) were included in the study. In 4 patients, ZD was incidentally found on head and neck ultrasound, and in 6 patients, ZD was suspected because of dysphagia. All lesions could be detected on conventional ultrasound before swallow-CEUS. Ten healthy volunteers (8 men and 2 women, aged 60 +/- 12 y) were chosen as a control group. Written informed consent was obtained. With the patient in the sitting or upright position, conventional ultrasound was performed first to image the lesion, then the patient was asked to swallow ultrasound contrast agent (UCA) (2-4 drops of SonoVue diluted with about 200 mL of tap water). Transity of the contrast agent in the esophagus was imaged with CEUS. Retention of the UCA in the diverticulum was monitored for at least 3 min. All patients underwent a barium esophagram as the gold standard. Swallow CEUS revealed that in all patients (100%), the UCA was transported from the pharynx to the esophagus while the patient swallowed. ZD appeared as a pouch shaped structure at the posterior pharyngo-esophageal junction that retained UCA longer than 3 min. The barium esophagram confirmed the diagnosis of ZD in all patients. For the 10 volunteers, no abnormal structure (retaining UCA) was detected during or after swallowing of UCA. With the advantages of no radiation and bedside availability, swallow-CEUS may become a method of choice in confirmation of the diagnosis of ZD, especially when ZD is suspected on conventional ultrasound. PMID- 25701520 TI - A closed-form differential formulation for ultrasound spatial calibration: single wall phantom. AB - Calibration is essential in freehand 3-D ultrasound to find the spatial transformation from the image coordinates to the sensor coordinate system. Ease of use, simplicity, precision and accuracy are among the most important factors in ultrasound calibration, especially when aiming to make calibration more reliable for day-to-day clinical use. We introduce a new mathematical framework for the simple and popular single-wall calibration phantom with a plane equation pre-determination step and the use of differential measurements to obtain accurate measurements. The proposed method provides a novel solution for ultrasound calibration that is accurate and easy to perform. This method is applicable to both radiofrequency (RF) and B-mode data, and both linear and curvilinear transducers. For a linear L14-5 transducer, the point reconstruction accuracy (PRA) of reconstructing 370 points is 0.73 +/- 0.23 mm using 100 RF images, whereas the triple N-wire PRA is 0.67 +/- 0.20 mm using 100 B-mode images. For a curvilinear C5-2 transducer, the PRA using the proposed method is 0.86 +/- 0.28 mm on 400 points using 100 RF images, whereas N-wire calibration gives a PRA of 0.80 +/- 0.46 mm using 100 B-mode images. Therefore, the accuracy of the proposed variation of the single-wall method using RF data is practically similar to the N-wire method while offering a simpler phantom with no need for accurate design and construction. PMID- 25701521 TI - Sonographic cutoff values for detection of abnormalities in small, medium and large joints: a comparative study between patients with rheumatoid arthritis and healthy volunteers. AB - To determine ultrasound measurements indicative of abnormalities in small, medium and large joints, we conducted a cross-sectional study comparing 60 patients with rheumatoid arthritis (RA) and 78 healthy volunteers. A MyLab 60 ultrasound machine (Esaote) and a linear multifrequency probe were used. Quantitative measurements of synovial recesses and semiquantitative measurements of synovial hyperplasia, power Doppler and bone erosion (scores = 0-3) were performed. The cutoff values for synovial recesses indicating RA (receiver operating characteristic curve, area under the curve >0.800) were found to be (radiocarpal) 3.78 mm and (ulnocarpal) 3.07 mm. Those measurements with the greatest chance of indicating RA (logistic regression analysis expressed as odds ratios [ORs]) were (p < 0.001) measurements of synovial hyperplasia (ulnocarpal, OR = 100, and radiocarpal, OR = 70); synovial power Doppler (radiocarpal, OR = 66); synovial bone erosion (radiocarpal, OR = 324); fifth metatarsophalangeal joint (OR = 100); and second metacarpophalangeal joint (OR = 92). We concluded that for both quantitative and semiquantitative ultrasound measurements, radiocarpal abnormalities increase the chance of detecting RA. PMID- 25701522 TI - Sonoporation of adherent cells under regulated ultrasound cavitation conditions. AB - A sonoporation device dedicated to the adherent cell monolayer has been implemented with a regulation process allowing the real-time monitoring and control of inertial cavitation activity. Use of the cavitation-regulated device revealed first that adherent cell sonoporation efficiency is related to inertial cavitation activity, without inducing additional cell mortality. Reproducibility is enhanced for the highest sonoporation rates (up to 17%); sonoporation efficiency can reach 26% when advantage is taken of the standing wave acoustic configuration by applying a frequency sweep with ultrasound frequency tuned to the modal acoustic modes of the cavity. This device allows sonoporation of adherent and suspended cells, and the use of regulation allows some environmental parameters such as the temperature of the medium to be overcome, resulting in the possibility of cell sonoporation even at ambient temperature. PMID- 25701523 TI - Hybrid algorithm for elastography to visualize both solid and fluid-filled lesions. AB - We propose a novel strain estimation technique that can produce reliable strain images of both solid and fluid-filled lesions. In our method, a kernel-based correlation coefficient technique and a speckle tracking-based strain estimation technique are combined into a single algorithm. The elegance of our algorithm is that fluid-filled lesions are first automatically identified by three selection criteria, and strain in those parts is estimated using the kernel-based correlation coefficient technique. Strain where fluid-filled lesions have not been detected is estimated using a speckle tracking-based algorithm, and then these two estimates are merged to form the final image. Any speckle tracking algorithm can be used in our proposed technique; however, we used a modified version of the direct average spectral strain estimation technique to describe our algorithm. We modified the direct average spectral strain estimation algorithm to track smaller strain variation and to facilitate strain calculation from multiple frames. We describe the performance of our proposed hybrid algorithm using in vivo patient data. Both the solid and fluid-filled lesions are clearly visible in the strain images produced by our proposed approach and are of better quality in terms of contrast-to-noise ratio and border sharpness than the strain images generated by other reported techniques. We also validate the performance of our proposed multiframe technique using experimental phantom data and in vivo patient data. The results reveal that the quality of the strain image can be improved using the multiframe technique compared with its dual-frame counterpart. PMID- 25701524 TI - Fetal ventricular interactions and wall mechanics during ductus arteriosus occlusion in a sheep model. AB - We investigated the effect of fetal sheep ductus arteriosus occlusion (DO) on the distribution of cardiac output and left and right ventricular function by tissue and pulsed Doppler at baseline; after 15 and 60 min of DO induced with a vascular occluder; and 15 min after release of DO. Ductal occlusion decreased fetal pO2. Mean left ventricular output increased (p < 0.001) from 725 to 1013 mL/min, and right ventricular (1185 mL/min vs. 552 mL/min) and systemic (1757 mL/min vs. 1013 mL/min) cardiac outputs fell (p < 0.001) after 15 min of DO, compared with baseline. Pulmonary vascular impedance decreased and volume blood flow increased more than threefold during DO, whereas foramen ovale volume blood flow remained unchanged. Left ventricular systolic function was unaffected, whereas isovolumic relaxation velocity deceleration decreased. Right ventricular functional indices remained unchanged. We conclude that DO increased pulmonary volume blood flow, not foramen ovale volume blood flow. Left ventricular output increased, although not as much as right ventricular output fell, resulting in decreased systemic cardiac output. During DO, left ventricular function exhibited diminished relaxation. PMID- 25701525 TI - Contrast-enhanced ultrasound in different stages of pyogenic liver abscess. AB - To enable sonographic classification of different stages of pyogenic liver abscesses, sonographic findings in 86 patients with 113 pyogenic liver abscesses were retrospectively analyzed and compared with established pathomorphologic descriptions of the disease. The typical findings in contrast-enhanced ultrasound were sub-segmental hyperemia (93/113, 82%) and necrosis with a hyperemic margin (109/113, 96%) in the arterial phase and a washout of liver tissue surrounding necrosis in the late phase (101/113, 89%). Four different sonomorphologic stages of pyogenic liver abscess were identified. Stage I was defined by focal inflammation without necrosis (n = 2); stage II by focal clusters of micro abscesses appearing to coalesce (n = 41); and stage III by a single cavity with or without capsule (n = 64). Stage IV was defined as numerous small abscesses scattered all over the liver (n = 6). The results indicate that contrast-enhanced ultrasound is suitable for classifying different stages of pyogenic liver abscesses. Knowledge of the described morphologic patterns influences therapeutic decisions and helps distinguish abscesses from other liver masses. PMID- 25701526 TI - Safety of intravenous application of second-generation ultrasound contrast agent in children: prospective analysis. AB - The goal of the work described here was to assess the safety profile of intravenous second-generation ultrasound contrast agents (UCAs) containing sulfur hexafluoride in pediatric contrast-enhanced ultrasound. Between 2010 and 2013, a total of 167 examinations were performed in 137 children referred by the Oncology Department. Approval by an Independent Ethical Review Board on Scientific Research for the intravenous use of an UCA containing sulfur hexafluoride in children with oncologic diseases was obtained. Consent for UCA administration was acquired from the parents or legal guardians. Severe anaphylactic reaction was observed in 0.6% (n = 1). No other adverse events during or after intravenous administration of contrast were observed in the examined group (no changes in heart rate and rhythm, blood pressure, oxygen saturation or respiratory rate). There were no reports of subjective flushing, nausea, transient headaches or altered taste. Although second-generation ultrasound contrast agents are considered potentially safe, all investigators should be prepared for the development of adverse reactions and have provisions in place for all pediatric intravenous contrast-enhanced ultrasound examinations. More multicenter studies are essential to determination of an accurate UCA safety profile. PMID- 25701527 TI - Could linear hysteresis contribute to shear wave losses in tissues? AB - For nearly 100 y in the study of cyclical motion in materials, a particular phenomenon called "linear hysteresis" or "ideal hysteretic damping" has been widely observed. More recently in the field of shear wave elastography, the basic mechanisms underlying shear wave losses in soft tissues are in question. Could linear hysteresis play a role? An underlying theoretical question must be answered: Is there a real and causal physical model that is capable of producing linear hysteresis over a band of shear wave frequencies used in diagnostic imaging schemes? One model that can approximately produce classic linear hysteresis behavior, by examining a generalized Maxwell model with a specific power law relaxation spectrum, is described here. This provides a theoretical plausibility for the phenomenon as a candidate for models of tissue behavior. PMID- 25701528 TI - Focused low-intensity pulsed ultrasound enhances bone regeneration in rat calvarial bone defect through enhancement of cell proliferation. AB - A number of studies have reported the therapeutic potential of low-intensity pulsed ultrasound (LIPUS) for induction of bone repair. This study investigated whether bone regeneration might be enhanced by application of focused LIPUS to selectively stimulate fractured calvarial bone. To accomplish this, bone defects were surgically created in the middle of the skull of rats that were subsequently exposed to focused LIPUS. Bone regeneration was assessed by repeated computed tomography imaging after the operation, as well as histologic analysis with calcein, hematoxylin and eosin and proliferating cell nuclear antigen assay. At 6 wk after surgery, bone formation in the focused LIPUS-treated group improved significantly relative to the control. Interestingly, new bone tissue sprouted from focused LIPUS target points. Histologic analysis after exposure to focused LIPUS revealed that proliferating cells were significantly increased relative to the control. Taken together, these results suggest that focused LIPUS can improve re-ossification through enhancement of cell proliferation in calvarial defect sites. PMID- 25701529 TI - Increased frequency of pathologic findings on transcranial B-mode parenchymal sonography in patients with sporadic amyotrophic lateral sclerosis. AB - Although amyotrophic lateral sclerosis (ALS) is characterized by involvement of motor neurons in the motor cortex, brainstem and spinal cord, there is accumulating evidence that it is a multisystem degenerative disease, with dysfunction of the striatonigral dopaminergic system as well. Transcranial B-mode sonography of the parenchyma enables depiction of the differing tissue echogenicity of midbrain and basal ganglia structures in various movement disorders. Transcranial B-mode sonography was performed in the standard manner in 101 patients with sporadic newly diagnosed ALS and 60 age- and gender-matched controls. Increased frequencies of pathologic substantia nigra hyper-echogenicity (p = 0.027), interrupted brainstem raphe (p = 0.003) and increased third ventricle diameter (p < 0.0001) were detected in ALS patients as compared with healthy controls. Only four ALS patients exhibited some features of parkinsonism. Pathologic findings on transcranial B-mode sonography of parenchyma did not correlate with clinical presentation, functional status or disease subtype. Our study provides additional evidence of multisystem involvement in ALS patients, particularly in subcortical areas. PMID- 25701530 TI - Contrast-enhanced ultrasound in combination with color Doppler ultrasound can improve the diagnostic performance of focal nodular hyperplasia and hepatocellular adenoma. AB - The aim of our study was to evaluate the value of combining color Doppler ultrasound (CDUS) with contrast-enhanced ultrasound (CEUS) in identifying and comparing features of focal nodular hyperplasia (FNH) and hepatocellular adenoma (HCA). Thirty-eight patients with FNH (n = 28) or HCA (n = 10), whose diagnoses were later confirmed by pathology, were examined with conventional ultrasonography and CEUS between 2010 and 2013. Two doctors blinded to the pathology results independently reviewed the conventional ultrasound and CEUS images and then reached a consensus through discussion. The following parameters evaluated for all lesions included vascularity pattern on CDUS or CEUS, enhancement characteristics on CEUS and the presence of a central scar. Statistical analysis was performed with the independent sample t-test and Fisher exact test. On CDUS, FNH was characterized by the presence of abundant blood flow signals exhibiting dendritic (53.6%, 15/28) and spoke-wheel (28.6%, 8/28) patterns, whereas blood flow signal of HCA was slightly less than FNH and often showed subcapsular short rod-like (50%, 5/10) appearance. On CEUS, the most common arterial enhancement pattern was centrifugal or homogeneous enhancement in FNH (both, 12/28, 42.9%) and homogeneous enhancement in HCA (6/10, 60%). Spoke wheel arteries, feeding artery and central scar were detected in 5 (17.9%), 8 (28.6%) and 5 (17.9%) of 28 FNHs. Hypo-echogenic pattern during delayed phase was more common in HCA (60%, 6/10) than in FNH (3/28, 10.7%) (p = 0.010). A total of 25 (25/38, 65.8%) lesions were correctly assessed using CDUS in combination with CEUS, whereas the number decreased to 15 (15/38, 39.5%) when CDUS was used alone (p = 0.038). The areas under the ROC curves before and after CEUS administration were 0.768 and 0.879, respectively. In conclusion, CEUS in combination with CDUS improve the diagnostic performance of FNH and HCA. Blood signal of HCA was less than FNH on CDUS. The differences of enhancement pattern during arterial phase and echogenicity during delayed phase may contribute to the differentiation of these lesions. PMID- 25701531 TI - Single- and multiple-track-location shear wave and acoustic radiation force impulse imaging: matched comparison of contrast, contrast-to-noise ratio and resolution. AB - Acoustic radiation force impulse imaging and shear wave elasticity imaging (SWEI) use the dynamic response of tissue to impulsive mechanical stimulus to characterize local elasticity. A variant of conventional, multiple-track-location SWEI, denoted single-track-location SWEI, offers the promise of creating speckle free shear wave images. This work compares the three imaging modalities using a high push and track beam density combined acquisition sequence to image inclusions of different sizes and contrasts. Single-track-location SWEI is found to have a significantly higher contrast-to-noise ratio than multiple-track location SWEI, allowing for operation at higher resolution. Acoustic radiation force impulse imaging and single-track-location SWEI perform similarly in the larger inclusions, with single-track-location SWEI providing better visualization of small targets <= 2.5 mm in diameter. The processing of each modality introduces different trade-offs between smoothness and resolution of edges and structures; these are discussed in detail. PMID- 25701532 TI - A set of shear wave elastography quantitative parameters combined with ultrasound BI-RADS to assess benign and malignant breast lesions. AB - The goal of this study was to determine whether a combination of shear wave elastography (SWE) quantitative parameters could improve the accuracy of ultrasonography in the differentiation of benign and malignant breast lesions. Two hundred seventy-nine breast lesions in 251 women were evaluated with ultrasonography and SWE; pathologic results of all lesions were available. Each lesion was classified according to the Breast Imaging Reporting and Data System (BI-RADS) for ultrasound. SWE quantitative parameters, including maximum elastic value (Emax), mean elastic value (E mean), standard deviation (SD) and ratio of E mean of the lesion to E mean of the surrounding parenchyma (E ratio), were recorded. A receiver operating characteristic curve was used to determine their cutoff values. When any of the four parameters was equal to or higher than the cutoff value, the set of SWE parameters was counted as positive. When both BI RADS and the set were positive, lesions were evaluated as positive for malignancy. We compared the performance of this combination with use of BI-RADS, Emax, E mean, SD or E ratio alone and also with the combination of BI-RADS and Emax for benign/malignant differentiation. The combination of Emax, E mean, SD, or E ratio with BI-RADS had a sensitivity, specificity, positive predictive value, negative predictive value, accuracy and Youden index of 0.967, 0.912, 0.908, 0.969, 0.938 and 0.879, respectively. The accuracy was the highest (p < 0.01) without loss of sensitivity. Combining a set of SWE quantitative parameters (E max, E mean, SD and E ratio) could improve the accuracy of ultrasonography in differentiation of benign from malignant breast lesions, without loss of sensitivity. PMID- 25701533 TI - Diagnostic performance of contrast-enhanced ultrasound for ovarian cancer: a meta analysis. AB - This meta-analysis is the first study aimed at assessing the overall diagnostic performance of contrast-enhanced ultrasound for ovarian cancer. PubMed, Embase and Medline databases were systematically searched for relevant articles published up to June 2014. Data were pooled to yield summary sensitivity, specificity, diagnostic odds ratio and receiver operating characteristic curves using Meta-Disc Version 1.4 software. Ten independent studies with 579 ovarian tumors were enrolled in this meta-analysis. The pooled sensitivity, specificity and diagnostic odds ratio statistics were 0.89 (0.83-0.94), 0.91 (0.88-0.93) and 91.70 (41.41-203.05), respectively, and the area under the summary receiver operating characteristic curve was 0.9619 (standard error: 0.0125), all indicating that contrast-enhanced ultrasound has high diagnostic accuracy in differentiation of malignant from benign ovarian tumors. PMID- 25701534 TI - Free-hand ultrasound guidance permits safe and efficient minimally invasive intrathymic injections in both young and aged mice. AB - The goal of this study was to evaluate whether use of an aseptic free-hand approach to ultrasound-guided injection facilitates injection into the thymic gland in mice. We used this interventional radiology technique in young, aged and immunodeficient mice and found that the thymus was visible in all cases. The mean injection period was 8 seconds in young mice and 19 seconds in aged or immunodeficient mice. Injection accuracy was confirmed by intrathymic location of an injected dye or by in vivo bioluminescence imaging of injected luciferase expressing cells. Accurate intrathymic injection was confirmed in 97% of cases. No major complications were observed. We conclude that an aseptic freehand technique for ultrasound-guided intrathymic injection is safe and accurate and reduces the time required for intrathymic injections. This method facilitates large-scale experiments and injection of individual thymic lobes and is clinically relevant. PMID- 25701535 TI - Transabdominal contrast-enhanced ultrasound imaging of the prostate. AB - Numerous age-related pathologies affect the prostate gland, the most menacing of which is prostate cancer (PCa). The diagnostic tools for prostate investigation are invasive, requiring biopsies when PCa is suspected. Novel dynamic contrast enhanced ultrasound (DCE-US) imaging approaches have been proposed recently and appear promising for minimally invasive localization of PCa. Ultrasound imaging of the prostate is traditionally performed with a transrectal probe because the location of the prostate allows for high-resolution images using high-frequency transducers. However, DCE-US imaging requires lower frequencies to induce bubble resonance and, thus, improve contrast-to-tissue ratio. For this reason, in this study we investigate the feasibility of quantitative DCE-US imaging of the prostate via the abdomen. The study included 10 patients (age = 60.7 +/- 5.7 y) referred for a needle biopsy study. After having given informed consent, patients underwent DCE-US with both transabdominal and transrectal probes. Time-intensity contrast curves were derived using both approaches and their model-fit quality was compared. Although further improvements are expected by optimization of the transabdominal settings, the results of transabdominal and transrectal DCE-US are closely comparable, confirming the feasibility of transabdominal DCE-US; transabdominal curve fitting revealed an average determination coefficient r(2) = 0.91 (r(2) > 0.75 for 78.6% of all prostate pixels) compared with r(2) = 0.91 (r(2) > 0.75 for 81.6% of all prostate pixels) by the transrectal approach. Replacing the transrectal approach with more acceptable transabdominal scanning for prostate investigation is feasible. This approach would improve patient comfort and represent a useful option for PCa localization and monitoring. PMID- 25701536 TI - Relationship of sleep quality, baseline weight status, and weight-loss responsiveness in obese adolescents in an immersion treatment program. AB - OBJECTIVE: The objective of this study was to investigate the effect of baseline sleep on baseline weight status and weight-loss responsiveness in obese adolescents. METHODS: Twenty-five obese adolescents who participated in a 19-day summer camp-based immersion treatment (IT) program completed pre-intervention measures of sleep duration and quality, and pre- and post-intervention body mass index z-scores (zBMI) and waist circumference (WC) assessments. Objective measures of sleep were obtained by actigraphy for a random subset of six participants for 1 week pre- and post-intervention. RESULTS: Shorter weekday sleep durations and more sleep debt were related to higher pre-intervention WCs (r = -0.54, p = 0.01 and r = -0.56, p = 0.01), and lower subjective sleep quality was related to higher pre-intervention zBMIs (r = -0.49, p = 0.02). Longer weekend sleep durations and more sleep debt were related to smaller reductions in pre- to post-intervention zBMIs (r = -0.47, p = 0.04 and r = -0.51, p = 0.03). For the subgroup of adolescents who wore actigraphs pre- and post-intervention, an increase in their sleep durations (d = -0.25) and a reduction in their sleep latencies (d = 0.52), zBMIs (d = 0.31), and WCs (d = 0.20) were observed. CONCLUSIONS: These results provide further evidence linking poor sleep patterns and obesity in adolescence, and suggest that sleep patterns may impact the effectiveness of pediatric obesity interventions and that IT programs may improve sleep in obese adolescents. Overall, they provide support for addressing sleep problems as part of obesity interventions. PMID- 25701537 TI - What keeps low-SES children from sleeping well: the role of presleep worries and sleep environment. AB - OBJECTIVES: Children in families of low socioeconomic status (SES) have been found to have poor sleep, yet the reasons for this finding are unclear. Two possible mediators, presleep worries and home environment conditions, were investigated as indirect pathways between SES and children's sleep. PARTICIPANTS/METHODS: The participants consisted of 271 children (M (age) = 11.33 years; standard deviation (SD) = 7.74 months) from families varying in SES as indexed by the income-to-needs ratio. Sleep was assessed with actigraphy (sleep minutes, night waking duration, and variability in sleep schedule) and child self reported sleep/wake problems (e.g., oversleeping and trouble falling asleep) and sleepiness (e.g., sleeping in class and falling asleep while doing homework). Presleep worries and home environment conditions were assessed with questionnaires. RESULTS: Lower SES was associated with more subjective sleep/wake problems and daytime sleepiness, and increased exposure to disruptive sleep conditions and greater presleep worries were mediators of these associations. In addition, environmental conditions served as an intervening variable linking SES to variability in an actigraphy-derived sleep schedule, and, similarly, presleep worry was an intervening variable linking SES to actigraphy-based night waking duration. Across sleep parameters, the model explained 5-29% of variance. CONCLUSIONS: Sleep environment and psychological factors are associated with socioeconomic disparities, which affect children's sleep. PMID- 25701538 TI - Differences in torsional performance of single- and multiple-instrument rotary systems for glide path preparation. AB - A new rotary instrument has been developed to simplify the glide path preparation in root canals before shaping procedures. The purpose of this study was to compare the peak torque and force induced by nickel-titanium PathFile multiple instrument system and the recently developed M-Wire ProGlider single instrument during glide path preparation of mesial root canals in extracted mandibular molars. Each independent canal of eight mesial roots of mandibular molars was randomly assigned to achieve a reproducible glide path with a new set of either PathFile #1 and #2 or ProGlider after negotiation with a 10 K-file. Tests were run in a standardized fashion using a torque-testing platform. Peak torque (N cm) and force (N) were registered and analysis of variance and Tukey post-hoc tests were applied. Preliminary data for stationary torque at failure were also obtained and compared with peak torque for each instrument. PathFile #1 and #2 instruments showed statistically lower peak torque (p = 0.001) and peak force (p = 0.008) than ProGlider. Torque at failure according to ADA No. 28/ISO 36030-1 was not significantly different from peak torque during glide path preparation for ProGlider instruments while it was significantly higher for PathFile #1 and #2 (p < 0.001). Under the conditions of this study, PathFile instruments developed significant lower peak torque and force during glide path preparation compared to ProGlider, which is possibly subjected to a greater contact with the canal walls due to the increase in its flute diameter at middle and coronal levels. PMID- 25701539 TI - GNA15 expression in small intestinal neuroendocrine neoplasia: functional and signalling pathway analyses. AB - Gastroenteropancreatic neuroendocrine neoplasia (GEP-NEN) comprises a heterogeneous group of tumours that exhibit widely divergent biological behaviour. The identification of new targetable GPCR-pathways involved in regulating cell function could help to identify new therapeutic strategies. We assessed the function of a haematopoietic stem cell heterotrimeric G-protein, Galpha15, in gut neuroendocrine cell models and examined the clinical implications of its over expression. Functional assays were undertaken to define the role of GNA15 in the small intestinal NEN cell line KRJ-I and in clinical samples from small intestinal NENs using quantitative polymerase chain reaction, western blot, proliferation and apoptosis assays, immunoprecipitation, immunohistochemistry (IHC) and automated quantitative analysis (AQUA). GNA15 was not expressed in normal neuroendocrine cells but was overexpressed in GEP-NEN cell lines. In KRJ-I cells, decreased expression of GNA15 was associated with inhibition of proliferation, activation of apoptosis and differential effects on pro-proliferative ERK, NFkappaB and Akt pathway signalling. Moreover, Galpha15 was demonstrated to couple to the beta1 adrenergic receptor and modulated proliferative signals through this GPCR. Transcript and protein levels of GNA15 were significantly elevated in primary and metastatic tumours compared to normal mucosa and were particularly increased in low Ki-67 expressing tumours. IHC and AQUA revealed that a higher Galpha15 expression was associated with a poorer survival. GNA15 may have a pathobiological role in SI-NENs. Targeting this signalling mediator could provide an opportunity for the development of new therapeutic strategies for this tumour type. PMID- 25701540 TI - Very rare reason of spinal cord compression: solitary fibrous tumor. PMID- 25701541 TI - A late and extreme complication of lumboperitoneal shunt. AB - BACKGROUND CONTEXT: Lumboperitoneal (LP) shunting is an effective treatment modality for commmunicating hydrocephalus, pseudotumor cerebri, postoperative pseudomeningoceles, and cerebrospinal fluid fistulas. However, LP shunts are associated with some complications. Here, we report an extreme complication resulting in the formation of granulation tissue. PURPOSE: To report a late extreme complication of LP shunt. STUDY DESIGN: A case report. METHODS: A late and unusual complication of an LP shunt with unique radiologic findings is presented. RESULTS: Spinal magnetic resonance imaging studies depicted a mass on the right anterior section of the dural sac encircling the catheter throughout its course from the L3-L4 interspinous level to the catheter tip. CONCLUSIONS: The etiopathologic mechanism, the prolonged duration, and the unusual radiologic findings in this case are unique and remarkable. PMID- 25701542 TI - The value of bone scan and pars injection in nonadjacent pars fractures. PMID- 25701543 TI - Snake eyes. PMID- 25701544 TI - An observational study on the outcome after surgery for lumbar disc herniation in adolescents compared with adults based on the Swedish Spine Register. AB - BACKGROUND CONTEXT: Disc-related sciatica has a prevalence of about 2% in adults, but is rare in adolescents. If conservative treatment is unsuccessful, surgery is an option. PURPOSE: The aim of this study was to compare the outcomes of surgery for lumbar disc herniation in adolescents with adults in the Swedish Spine Register. STUDY DESIGN/SETTING: This is a prospective observational study: National Quality Register. PATIENT SAMPLE: This study included 151 patients, 18 years or younger, 4,386 patients, 19-39 years, and 6,078 patients, 40 years or older, followed for 1-2 years after surgery. OUTCOME MEASURES: The primary outcomes were patient satisfaction and global assessment of leg and back pain. Secondary outcomes were Visual Analog Scale (VAS) leg pain, VAS back pain, Oswestry disability index (ODI), and EuroQol-5 dimensions (EQ-5D). METHODS: Statistical analyses were performed with the Welch F test, the chi-square test, and the Wilcoxon signed-rank test. RESULTS: At follow-up, 86% of the adolescents were satisfied compared with 78% in the younger adults and 76% in the older adults group (p<.001). According to the global assessment, significantly decreased leg pain was experienced by 87% of the adolescents, 78% of the younger adults, and 71% of the older adults (p<.001). Corresponding figures for back pain were 88%, 73%, and 70%, respectively (p<.001). All groups experienced significant postoperative improvement of VAS leg pain, VAS back pain, ODI, and EQ-5D (all p<.001). CONCLUSIONS: The adolescent age group was more satisfied with the treatment than the adult groups. There was a significant improvement in all age groups after surgery. PMID- 25701545 TI - Treatment persistence after initiating basal insulin in type 2 diabetes patients: A primary care database analysis. AB - AIMS: To compare persistence and its predictors in type 2 diabetes patients in primary care, initiating either basal supported oral therapy (BOT) or intensified conventional therapy (ICT) with glargine, detemir, or NPH insulin. METHODS: In the BOT cohort, 1398 glargine (mean age: 68 years), 292 detemir (66 years), and 874 NPH (65 years) users from 918 practices were retrospectively analyzed (Disease Analyzer, Germany: 2008-2012). The ICT group incorporated 866 glargine (64 years), 512 detemir (60 years), and 1794 NPH (64 years) new users. Persistence was defined as proportion of patients remaining on the initial basal insulin (glargine, detemir and NPH insulin) over 2 years. Persistence was evaluated by Kaplan-Meier curves (log-rank tests) and Cox regression adjusting for age, sex, diabetes duration, antidiabetic co-therapy, comorbidities, specialist care, and private health insurance. RESULTS: In BOT, two-year persistence was 65%, 53%, and 59% in glargine, detemir, and NPH users, respectively (p<0.001). In ICT, persistence was higher without differences between groups: 84%, 85%, 86% in glargine, detemir, and NPH, respectively (p=0.536). In BOT, detemir and NPH users were more likely to discontinue basal insulin compared with glargine (detemir vs. glargine: adjusted Hazard Ratio; 95% CI: 1.56; 1.31-1.87; NPH vs. glargine: 1.22; 1.07-1.38). Heart failure (1.39; 1.16-1.67) was another predictor of non-persistence, whereas higher age (per year: 0.99; 0.98-0.99), metformin (0.61; 0.54-0.69), and sulfonylurea co medication (0.86; 0.77-0.97) were associated with lower discontinuation. CONCLUSIONS: In BOT, treatment persistence among type 2 diabetes patients initiating basal insulin is influenced by type of insulin, antidiabetic co medication, and patient characteristics. PMID- 25701546 TI - Complications following Staged Hypospadias Repair Using Transposed Preputial Skin Flaps. AB - PURPOSE: Proximal hypospadias repair using a staged approach is a complex reconstructive operation with the potential for significant complications requiring repeat surgery. We report outcomes of staged hypospadias repair using transposed preputial skin flaps and factors predictive of postoperative complications. MATERIALS AND METHODS: We retrospectively analyzed patients who underwent staged proximal hypospadias repair using transposed preputial skin flaps between 2002 and 2013. Patient demographics, operative details, complications, reoperations and factors predictive of complications were reviewed. RESULTS: A total of 56 patients were identified with a mean age of 14.1 months (median 14.3) at first stage. Mean followup was 38.6 months (median 34.1). Complications requiring additional unplanned operation(s) were observed in 38 patients (68%), including fistulas in 32 (57%), diverticula in 8 (14%), meatal stenosis in 5 (9%), urethral stricture in 8 (14%) and glans dehiscence in 3 (5%). In addition, redo first stage repair was performed in 4 patients (7%). Since some patients had more than 1 complication, the total number of complications is greater than the number of patients undergoing a redo operation. On univariate analyses the use of small intestinal submucosa was significantly associated with an increased risk of fistula (91% vs 49%, p = 0.02) and urethral diverticulum (64% vs 24%, p = 0.04). Incision of the tunica albuginea of the corpora was associated with an increased likelihood of fistula (77% vs 44%, p = 0.03). Finally, patients with glans dehiscence were significantly younger at first stage (5.8 vs 14.8 months, p = 0.01). CONCLUSIONS: The reoperation rate for complications in children undergoing staged hypospadias repair using transposed preputial skin flaps is higher than previously reported. PMID- 25701547 TI - High degree of concordance between flow cytometry and geno2pheno methods for HIV 1 tropism determination in proviral DNA. AB - Use of CCR5 antagonists requires previous viral tropism determination. The available methods have high cost, are time-consuming, or require highly trained personnel, and sophisticated equipment. We compared a flow cytometry-based tropism assay with geno2pheno method to determine HIV-1 tropism in AIDS patients, in Bahia, Brazil. We tested peripheral blood mononuclear cells of 102 AIDS patients under antiretroviral therapy by using a cytometry-based tropism assay and geno2pheno assay. Cellular membrane receptors were identified by using CXCR4, CCR5 and CD4 monoclonal antibodies, while detection of cytoplasmic mRNAs for gag and pol HIV regions was achieved by using a labeled probe. Genotypic identification of X4 and R5 tropic viruses was attempted by geno2pheno algorithm. There was a high degree of concordance between cytometry-based tropism assay and geno2pheno algorithm in determination of HIV-1 tropism. Cytometry-based tropism assay demonstrated higher sensitivity and specificity in comparison to geno2pheno, which was used as a gold-standard. One sample could not be amplified by geno2pheno method, but was classified as duotropic by cytometry-based tropism assay. We did not find any association between CD4+ count or plasma HIV-1 RNA viral load and tropism results. The overall performances of cytometry-based tropism assay and geno2pheno assay were almost identical in determination of HIV 1 tropism. PMID- 25701548 TI - Staphylococcal scalded skin syndrome in an adult, immunocompetent patient. PMID- 25701549 TI - Ubiquitination of newly synthesized proteins at the ribosome. AB - Newly synthesized proteins can be misfolded or damaged because of errors during synthesis or environmental insults (e.g., heat shock), placing a significant burden on protein quality control systems. In addition, numerous human diseases are associated with a deficiency in eliminating aberrant proteins or accumulation of aggregated proteins. Understanding the mechanisms of protein quality control and disposal pathways for misfolded proteins is therefore crucial for therapeutic intervention in these diseases. Quality control processes function at many points in the life cycle of proteins, and a subset act at the actual site of protein synthesis, the ribosome. Here we summarize recent advances in the role of the ubiquitin proteasome system in protein quality control during the process of translation. PMID- 25701550 TI - Fragile X mental retardation protein: A paradigm for translational control by RNA binding proteins. AB - Translational control is a common mechanism used to regulate gene expression and occur in bacteria to mammals. Typically in translational control, an RNA-binding protein binds to a unique sequence in the mRNA to regulate protein synthesis by the ribosomes. Alternatively, a protein may bind to or modify a translation factor to globally regulate protein synthesis by the cell. Here, we review translational control by the fragile X mental retardation protein (FMRP), the absence of which causes the neurological disease, fragile X syndrome (FXS). PMID- 25701551 TI - The new immunosuppressant, isogarcinol, binds directly to its target enzyme calcineurin, unlike cyclosporin A and tacrolimus. AB - Isogarcinol, a bioactive polyisoprenylated benzophenone derivative isolated from Garcinia mangostana L., has been shown previously to exert a strong inhibitory effect on calcineurin and is thus a potential oral, low-toxicity immunomodulatory drug. In the present study, enzyme kinetic analysis showed that inhibition of calcineurin by isogarcinol was competitive. Fluorescence spectroscopy indicated that isogarcinol bound to calcineurin. Isothermal titration calorimetry showed that binding was mainly driven by enthalpy, and was exothermic because the enthalpy change exceeded the entropy reduction. The interaction force is either hydrogen bonding or Van der Waals forces. Fluorescence resonance energy transfer and molecular docking experiments indicated that there were two potential binding sites for isogarcinol in the catalytic domain of calcineurin. In summary, isogarcinol binds directly to calcineurin in vitro, unlike the classical calcineurin inhibitors cyclosporin A and tacrolimus. PMID- 25701552 TI - The effect of lanthanum(III) and cerium(III) ions between layers of manganese oxide on water oxidation. AB - Manganese oxide structure with lanthanum(III) or cerium(III) ions between the layers was synthesized by a simple method. The ratio of Mn to Ce or La in samples was 0.00, 0.04, 0.08, 0.16, 0.32, 0.5, 0.82, or 1.62. The compounds were characterized by scanning electron microscopy, transmission electron microscopy, X-ray diffraction studies, and atomic absorption spectroscopy. The compounds show efficient catalytic activity of water oxidation in the presence of cerium(IV) ammonium nitrate with a turnover frequency of 1.6 mmol O2/mol Mn.s. In contrast to the water-oxidizing complex in Photosystem II, calcium(II) has no specific role to enhance the water-oxidizing activity of the layered manganese oxides and other cations can be replaced without any significant decrease in water-oxidizing activities of these layered Mn oxides. Based on this and previously reported results from oxygen evolution in the presence of H 2 (18) O, we discuss the mechanism and the important factors influencing the water-oxidizing activities of the manganese oxides. PMID- 25701553 TI - Is salivary epidermal growth factor a biomarker for oral leukoplakia? A preliminary study. AB - OBJECTIVES: The aim of this study was to compare the salivary epidermal growth factor (EGF) levels between patients with oral leukoplakia (OL) and clinically healthy individuals, to evaluate the association between salivary and tissular EGF, and to correlate EGF with clinicopathologic data, including the presence of dysplasia. STUDY DESIGN: Salivary EGF levels were measured in 32 patients and 32 controls. The tissue expressions of EGF and its receptor (EGFR) were immunohistochemically evaluated. RESULTS: Salivary EGF levels were similar in patients with OL compared with controls. There was no association between the salivary levels and immunohistochemical expression of EGF. An absence of EGF detection by immunohistochemistry was associated with development of multiple lesions. Dysplastic lesions showed a tendency toward presenting higher salivary EGF levels. CONCLUSIONS: Currently, it is not possible to indicate salivary EGF as a biomarker for OL. Further studies are needed to elucidate the role of EGF in oral carcinogenesis. A follow-up study is necessary to evaluate the changes in EGF values following the surgical excision of OL. PMID- 25701554 TI - The practice of oral medicine in the United States in the twenty-first century: an update. AB - OBJECTIVE: The aim of this study was to describe the practice characteristics of Oral Medicine trained dentists in the United States. METHODS: This study was a cross-sectional survey of members of the American Academy of Oral Medicine. Patient demographic characteristics, referring providers, medical comorbidities, diagnoses, and practitioner information were collected during a 5-day practice week. The survey was open during the years 2011 and 2012. RESULTS: Information from 916 patients was entered by 74 practitioners from 20 states. The mean number of practitioners seen before consulting Oral Medicine providers was 2.2, and patients had experienced symptoms for 16.8 months before the initial encounter. Common chief complaints were nonulcerative mucosal lesions, orofacial pain, and dry mouth. Patients with cardiovascular disease were at a higher risk of developing lichenoid lesions, and those with psychiatric conditions were at higher risk of reporting burning mouth symptoms. CONCLUSIONS: Diagnoses and procedures performed by Oral Medicine practitioners complement practice characteristics of general and specialty dentists in the United States. PMID- 25701555 TI - Electronic reporting of all reference laboratory results: An important step toward a truly all-encompassing, integrated health record. AB - Results from reference laboratories are often not easily available in electronic health records. This article describes a multi-pronged, long-term approach that includes bringing send-out tests in-house, upgrading the laboratory information system, interfacing more send-out tests and more reference laboratories, utilizing the "miscellaneous assay" option offered by some reference laboratories, and scanning all remaining paper reports from reference laboratories for display in the electronic health record. This allowed all laboratory results obtained in association with a patient visit, whether performed in-house or at a reference laboratory, to be available in the integrated electronic health record. This was achieved without manual data entry of reference laboratory results, thereby avoiding the risk of transcription errors. A fully integrated electronic health record that contains all laboratory results can be achieved by maximizing the number of interfaced reference laboratory assays and making all non-interfaced results available as scanned documents. PMID- 25701556 TI - A model for the evaluation of data quality in health unit websites. AB - This article presents a research work, the goal of which was to achieve a model for the evaluation of data quality in institutional websites of health units in a broad and balanced way. We have carried out a literature review of the available approaches for the evaluation of website content quality, in order to identify the most recurrent dimensions and attributes, and we have also carried out a Delphi method process with experts in order to reach an adequate set of attributes and their respective weights for the measurement of content quality. The results obtained revealed a high level of consensus among the experts who participated in the Delphi process. In addition, the different statistical analysis and techniques implemented are robust and attach confidence to our results and consequent model obtained. PMID- 25701557 TI - [Roman ophthalmology practised by doctor Castillo-Quartiellers]. PMID- 25701558 TI - Raising the quality of rheumatology management recommendations: lessons from the EULAR process 10 years after provision of standard operating procedures. AB - OBJECTIVE: To increase understanding of how to raise the quality of rheumatology guidelines by reviewing European League Against Rheumatism (EULAR) management recommendations, using the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument, 10 years after publication of the EULAR standardized operating procedures (SOP) for the production of recommendations. It was hoped that this work could help inform improvements in guideline development by other societies and organizations. METHODS: The SOP were published in 2004 to ensure the quality of EULAR-endorsed recommendations. We reviewed 27 published EULAR recommendations for management using the AGREE II tool. This provides a framework to assess the quality of guidelines across six broad domains using 23 specific questions. RESULTS: Overall the EULAR recommendations reviewed have been performed to a high standard. There are particular strengths in the methodology and presentation of the guidelines; however, the results indicate areas for development in future recommendations: in particular, stakeholder involvement and applicability of the recommendations. Improvements in quality were evident in recent years, with patient representation in 9 of 15 (60.0%) recommendations published 2010-14 compared with 4 of 12 (33.3%) published 2000-09. CONCLUSION: In the last 10 years the overall quality of recommendations was good, with standards improving over the decade following publication of the SOP. However, this review process has identified potential areas for improvement, especially in patient representation and provision of implementation tools. The lessons from this work can be applied to the development of rheumatology guidelines by other societies and organizations. PMID- 25701559 TI - Five-drug antiretroviral therapy for primary HIV infection? PMID- 25701560 TI - Comparison of two-dose priming plus 9-month booster with a standard three-dose priming schedule for a ten-valent pneumococcal conjugate vaccine in Nepalese infants: a randomised, controlled, open-label, non-inferiority trial. AB - BACKGROUND: Use of pneumococcal conjugate vaccines (PCVs) in resource-poor countries has focused on early infant immunisation with little emphasis on protection in late infancy and beyond. Boosting of the immune response later in infancy might provide improved persistence of immunogenicity into early childhood, however data are scarce. The aim of this study was to investigate if a two-dose prime with booster at age 9 months compared with a three-dose prime-only PCV schedule provided non-inferior immunogenicity in early infancy and superior persistence of antibody responses in early childhood. METHODS: We did an open label, randomised, parallel group, controlled trial in healthy infants aged 40-60 days from Kathmandu, Nepal. Participants were randomly allocated (4:4:5 ratio) to receive PCV10 in addition to routine immunisations either as a two-dose prime and boost (2+1), three-dose prime (3+0), or two doses after completion of the initial study phase (0+2). We used a computer generated randomisation list with randomly varying block sizes. We followed up participants at age 2-4 years together with a group of unvaccinated controls. Sera were analysed for opsonophagocytic activity, protein D, and PCV10 serotype-specific IgG. Laboratory staff was masked to intervention group assignment. The primary outcome measure was to determine the proportion of participants in the 2+1 group at age 10 months with specific IgG for serotypes 1, 5, and 14 of at least 0.2 MUg/mL in the per-protocol population. The secondary outcomes were non-inferiority (within 10% levels) at age 18 weeks for the proportion of participants in the 2+1 group compared with the 3+0 group with serotypes 1, 5, and 14 specific IgG of at least 0.2 MUg/mL; the proportion of participants with PCV10 serotype-specific IgG of at least 0.2 MUg/mL and opsonophagocytic activity reciprocal titre of at least 8 at ages 18 weeks and 10 months; and nasopharyngeal pneumococcal serotype-specific carriage rates at age 9 months in each study group. In the follow-up study, the primary outcome measure was the proportion of participants with IgG of at least 0.2 MUg/mL for PCV10 serotypes at age 2-4 years in children previously immunised with a 3+0 schedule compared with a 2+1 schedule. The trial is registered with Current Controlled Trials, registration number ISRCTN56766232. FINDINGS: Between May 10, 2010, and Jan 7, 2011, 390 children were randomly assigned to each group: 119 to the 2+1 group, 120 to the 3+0 group, and 151 to the 0+2 group. At age 10 months, the proportions of 2+1 participants with IgG of at least 0.2 MUg/mL were 99.0% (95% CI 94.2-100.0) for serotype 1, 100% (96.2-100.0) for serotype 5, and 97.9% (92.5 99.7) for serotype 14. At age 18 weeks, non-inferiority (within 10% levels) of the 2+1 group was shown compared with the 3+0 group, and there was no difference between the 2+1 and 3+0 groups for the proportion with IgG of at least 0.2 MUg/mL for any of the PCV10 serotypes. At age 10 months, proportions with IgG of at least 0.2 MUg/mL for serotypes 1, 5, 6B, and 23F, were higher in the 2+1 group than in the 3+0 group. At age 18 weeks, there were no differences in opsonophagocytic activity between the 2+1 and 3+0 groups for reciprocal titres of at least 8, but at age 10 months, proportions with an opsonophagocytic reciprocal titre of at least 8 for serotypes 1, 4, 5, 6B, 18C, 19F and 23F were higher in the 2+1 group than in the 3+0 group. At age 2-4 years, there were higher proportions in the 2+1 group versus the 3+0 group with IgG of at least 0.2 MUg/mL for serotypes 1, 5, 6B, and 18C. INTERPRETATION: Use of a 2+1 PCV schedule with booster at age 9 months in a resource-poor setting improved antibody persistence through early childhood without compromising antibody responses in early infancy. This schedule is now recommended by WHO for progressive introduction across Nepal, with PCV10 introduction having commenced on Jan 18, 2015. Concurrent pre implementation and post-implementation surveillance is being done by a GAVI Alliance funded study. FUNDING: This study was supported by funding from the National Institute for Public Health and the Environment, The Netherlands; Oxford Vaccine Group, University of Oxford, UK; and GlaxoSmithKline Biologicals, Belgium. PMID- 25701562 TI - Applied public health research on the frontline. PMID- 25701563 TI - Fourth European IRPA congress (IRPAeurope2014). PMID- 25701564 TI - Haemophagocytic lymphohistiocytosis: from diagnostic challenges to predictive possibilities. PMID- 25701565 TI - Childhood-onset lupus with clinical neurocognitive dysfunction shows lower streamline density and pairwise connectivity on diffusion tensor imaging. AB - OBJECTIVES: The objective of this report is to use diffusion-tensor imaging (DTI) for investigating white-matter connectivity changes associated with neurocognitive dysfunction in childhood-onset lupus (cSLE-NCD) as measured by formal neuropsychological testing. METHODS: DTI was performed in six individuals with (cSLE-NCD) and nine without neurocognitive dysfunction (cSLE-noNCD) as well as 14 healthy controls. Presence of neurocognitive deficits was identified by formal neuropsychological testing. The brain was divided into 116 regions, and pairwise connectivity (defined as the number of streamlines with an endpoint in each of those regions) and streamline density (defined as the number of streamlines passing through a region regardless of endpoints) were evaluated. Group comparisons were made for regional and global measures of streamline density and pairwise connectivity. RESULTS: A significant decrease in global streamline density was observed in the cSLE-NCD vs. control group (1189 vs. 1305 p = 0.002) and vs. cSLE-noNCD (1189 vs 1320 p = 0.001). The cSLE-noNCD and control groups had similar streamline density. A similar pattern for pairwise connectivity was observed with a significant decrease in the cSLE-NCD group (217) versus the cSLE-noNCD (236; p = 0.013) and control group (238; p = 0.004). Regional measures of pairwise connectivity displayed mixed results. CONCLUSIONS: The analysis of DTI in this pilot study shows cSLE-NCD is associated with global loss of streamline density and pairwise connectivity, suggesting breakdown of the structural network. These results complement previously reported functional and volumetric findings that suggest cSLE-NCD is associated with measurable changes in gray and white matter. If confirmed in larger cohorts, DTI abnormalities could be used as imaging biomarkers of cSLE-NCD. PMID- 25701561 TI - Intensive five-drug antiretroviral therapy regimen versus standard triple-drug therapy during primary HIV-1 infection (OPTIPRIM-ANRS 147): a randomised, open label, phase 3 trial. AB - BACKGROUND: Early combination antiretroviral therapy (cART) initiation at the time of primary HIV-1 infection could restrict the establishment of HIV reservoirs. We aimed to assess the effect of a cART regimen intensified with raltegravir and maraviroc, compared with standard triple-drug cART, on HIV-DNA load. METHODS: In this randomised, open-label, phase 3 trial, we recruited patients from hospitals across France. Inclusion criteria were primary HIV-1 infection (an incomplete HIV-1 western blot and detectable plasma HIV-RNA), with either symptoms or a CD4+ cell count below 500 cells per MUL. Patients were randomly assigned (1:1) to an intensive, five-drug cART regimen (raltegravir 400 mg and maraviroc 150 mg twice daily, and a fixed-dose combination of tenofovir disoproxil fumarate 300 g plus emtricitabine 200 g, darunavir 800 g, and ritonavir 100 g once daily) or a standard triple-drug cART regimen (tenofovir disoproxil fumarate 300 g plus emtricitabine 200 g, darunavir 800 g, and ritonavir 100 g once daily) using a predefined randomised list generated by randomly selected variable block sizes. The primary endpoint was the median number of HIV-DNA copies per 10(6) peripheral blood mononuclear cells (PBMC) at month 24, analysed in the modified intention-to-treat population, defined as all patients who started their assigned treatment. This study is registered with ClinicalTrials.gov, number NCT01033760. FINDINGS: Between April 26, 2010, and July 13, 2011, 110 patients were enrolled, of whom 92 were randomly assigned and 90 started treatment (45 in each treatment group). Six (13%) patients in the intensive cART group and two (4%) in the standard cART group discontinued before month 24. At month 24, HIV-DNA loads were similar between groups (2.35 [IQR 2.05 2.50] log10 per 10(6) PBMC in the intensive cART group vs 2.25 [1.71-2.55] in the standard cART group; p=0.21). Eight grade 3-4 clinical adverse events were reported in seven patients in the intensive cART group and seven grade 3-4 clinical adverse events were reported in seven patients in the standard cART group. Three serious clinical adverse events occurred: two (pancreatitis and lipodystrophy) in the standard cART group, which were regarded as treatment related, and one event (suicide attempt) in the intensive cART group that was unrelated to treatment. INTERPRETATION: After 24 months, cART intensified with raltegravir and maraviroc did not have a greater effect on HIV blood reservoirs than did standard cART. These results should help to design future trials of treatments aiming to decrease the HIV reservoir in patients with primary HIV-1 infection. FUNDING: Inserm-ANRS, Gilead Sciences, Janssen Pharmaceuticals, Merck, and ViiV Laboratories. PMID- 25701566 TI - Therapeutic plasma exchange in paediatric SLE: a case series from India. AB - Therapeutic plasma exchange (TPE) has been reported to be a useful adjunct in severe systemic lupus erythematosus (SLE) but paediatric literature continues to be scanty. We hereby present three cases of refractory paediatric SLE (pSLE) with thrombotic thrombocytopenic purpura (TTP), diffuse alveolar haemorrhage (DAH) and crescentic glomerulonephritis which were treated with TPE as an adjunctive therapy. TPE was carried out in haemodialysis units using the membrane filtration technique. Demonstrable benefit of TPE was seen in all three cases. In refractory pSLE, TPE may be a useful tool and should be considered. The report additionally highlights the feasibility of undertaking TPE in haemodialysis units, which is important as haemodialysis units are more readily available than dedicated apheresis units in developing countries. PMID- 25701568 TI - AIDA: ab initio domain assembly for automated multi-domain protein structure prediction and domain-domain interaction prediction. AB - MOTIVATION: Most proteins consist of multiple domains, independent structural and evolutionary units that are often reshuffled in genomic rearrangements to form new protein architectures. Template-based modeling methods can often detect homologous templates for individual domains, but templates that could be used to model the entire query protein are often not available. RESULTS: We have developed a fast docking algorithm ab initio domain assembly (AIDA) for assembling multi-domain protein structures, guided by the ab initio folding potential. This approach can be extended to discontinuous domains (i.e. domains with 'inserted' domains). When tested on experimentally solved structures of multi-domain proteins, the relative domain positions were accurately found among top 5000 models in 86% of cases. AIDA server can use domain assignments provided by the user or predict them from the provided sequence. The latter approach is particularly useful for automated protein structure prediction servers. The blind test consisting of 95 CASP10 targets shows that domain boundaries could be successfully determined for 97% of targets. AVAILABILITY AND IMPLEMENTATION: The AIDA package as well as the benchmark sets used here are available for download at http://ffas.burnham.org/AIDA/. CONTACT: adam@sanfordburnham.org SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25701569 TI - CycleFreeFlux: efficient removal of thermodynamically infeasible loops from flux distributions. AB - MOTIVATION: Constraint-based metabolic modeling methods such as Flux Balance Analysis (FBA) are routinely used to predict metabolic phenotypes, e.g. growth rates, ATP yield or the fitness of gene knockouts. One frequent difficulty of constraint-based solutions is the inclusion of thermodynamically infeasible loops (or internal cycles), which add nonbiological fluxes to the predictions. RESULTS: We propose a simple postprocessing of constraint-based solutions, which removes internal cycles from any given flux distribution [Formula: see text] without disturbing other fluxes not involved in the loops. This new algorithm, termed CycleFreeFlux, works by minimizing the sum of absolute fluxes [Formula: see text] while (i) conserving the exchange fluxes and (ii) using the fluxes of the original solution to bound the new flux distribution. This strategy reduces internal fluxes until at least one reaction of every possible internal cycle is inactive, a necessary and sufficient condition for the thermodynamic feasibility of a flux distribution. If alternative representations of the input flux distribution in terms of elementary flux modes exist that differ in their inclusion of internal cycles, then CycleFreeFlux is biased towards solutions that maintain the direction given by [Formula: see text] and towards solutions with lower total flux [Formula: see text]. Our method requires only one additional linear optimization, making it computationally very efficient compared to alternative strategies. AVAILABILITY AND IMPLEMENTATION: We provide freely available R implementations for the enumeration of thermodynamically infeasible cycles as well as for cycle-free FBA solutions, flux variability calculations and random sampling of solution spaces. CONTACT: lercher@cs.uni-duesseldorf.de. PMID- 25701570 TI - Population-scale three-dimensional reconstruction and quantitative profiling of microglia arbors. AB - MOTIVATION: The arbor morphologies of brain microglia are important indicators of cell activation. This article fills the need for accurate, robust, adaptive and scalable methods for reconstructing 3-D microglial arbors and quantitatively mapping microglia activation states over extended brain tissue regions. RESULTS: Thick rat brain sections (100-300 um) were multiplex immunolabeled for IBA1 and Hoechst, and imaged by step-and-image confocal microscopy with automated 3-D image mosaicing, producing seamless images of extended brain regions (e.g. 5903 * 9874 * 229 voxels). An over-complete dictionary-based model was learned for the image-specific local structure of microglial processes. The microglial arbors were reconstructed seamlessly using an automated and scalable algorithm that exploits microglia-specific constraints. This method detected 80.1 and 92.8% more centered arbor points, and 53.5 and 55.5% fewer spurious points than existing vesselness and LoG-based methods, respectively, and the traces were 13.1 and 15.5% more accurate based on the DIADEM metric. The arbor morphologies were quantified using Scorcioni's L-measure. Coifman's harmonic co-clustering revealed four morphologically distinct classes that concord with known microglia activation patterns. This enabled us to map spatial distributions of microglial activation and cell abundances. AVAILABILITY AND IMPLEMENTATION: Experimental protocols, sample datasets, scalable open-source multi-threaded software implementation (C++, MATLAB) in the electronic supplement, and website (www.farsight-toolkit.org). http://www.farsight-toolkit.org/wiki/Population scale_Three-dimensional_Reconstruction_and_Quanti tative_Profiling_of_Microglia_Arbors CONTACT: broysam@central.uh.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25701571 TI - tEFMA: computing thermodynamically feasible elementary flux modes in metabolic networks. AB - : Elementary flux modes (EFMs) are important structural tools for the analysis of metabolic networks. It is known that many topologically feasible EFMs are biologically irrelevant. Therefore, tools are needed to find the relevant ones. We present thermodynamic tEFM analysis (tEFMA) which uses the cellular metabolome to avoid the enumeration of thermodynamically infeasible EFMs. Specifically, given a metabolic network and a not necessarily complete metabolome, tEFMA efficiently returns the full set of thermodynamically feasible EFMs consistent with the metabolome. Compared with standard approaches, tEFMA strongly reduces the memory consumption and the overall runtime. Thus tEFMA provides a new way to analyze unbiasedly hitherto inaccessible large-scale metabolic networks. AVAILABILITY AND IMPLEMENTATION: https://github.com/mpgerstl/tEFMA CONTACT: : christian.jungreuthmayer@boku.ac.at or juergen.zanghellini@boku.ac.at SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25701572 TI - Unified representation of genetic variants. AB - A genetic variant can be represented in the Variant Call Format (VCF) in multiple different ways. Inconsistent representation of variants between variant callers and analyses will magnify discrepancies between them and complicate variant filtering and duplicate removal. We present a software tool vt normalize that normalizes representation of genetic variants in the VCF. We formally define variant normalization as the consistent representation of genetic variants in an unambiguous and concise way and derive a simple general algorithm to enforce it. We demonstrate the inconsistent representation of variants across existing sequence analysis tools and show that our tool facilitates integration of diverse variant types and call sets. AVAILABILITY AND IMPLEMENTATION: The source code is available for download at http://github.com/atks/vt. More detailed documentation is available at http://genome.sph.umich.edu/wiki/Variant_Normalization. CONTACT: hmkang@umich.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25701573 TI - Oasis: online analysis of small RNA deep sequencing data. AB - Oasis is a web application that allows for the fast and flexible online analysis of small-RNA-seq (sRNA-seq) data. It was designed for the end user in the lab, providing an easy-to-use web frontend including video tutorials, demo data and best practice step-by-step guidelines on how to analyze sRNA-seq data. Oasis' exclusive selling points are a differential expression module that allows for the multivariate analysis of samples, a classification module for robust biomarker detection and an advanced programming interface that supports the batch submission of jobs. Both modules include the analysis of novel miRNAs, miRNA targets and functional analyses including GO and pathway enrichment. Oasis generates downloadable interactive web reports for easy visualization, exploration and analysis of data on a local system. Finally, Oasis' modular workflow enables for the rapid (re-) analysis of data. AVAILABILITY AND IMPLEMENTATION: Oasis is implemented in Python, R, Java, PHP, C++ and JavaScript. It is freely available at http://oasis.dzne.de. CONTACT: stefan.bonn@dzne.de SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25701574 TI - Annocript: a flexible pipeline for the annotation of transcriptomes able to identify putative long noncoding RNAs. AB - The eukaryotic transcriptome is composed of thousands of coding and long non coding RNAs (lncRNAs). However, we lack a software platform to identify both RNA classes in a given transcriptome. Here we introduce Annocript, a pipeline that combines the annotation of protein coding transcripts with the prediction of putative lncRNAs in whole transcriptomes. It downloads and indexes the needed databases, runs the analysis and produces human readable and standard outputs together with summary statistics of the whole analysis. AVAILABILITY AND IMPLEMENTATION: Annocript is distributed under the GNU General Public License (version 3 or later) and is freely available at https://github.com/frankMusacchia/Annocript. CONTACT: remo.sanges@szn.it. PMID- 25701575 TI - Deep sequencing analysis of viral infection and evolution allows rapid and detailed characterization of viral mutant spectrum. AB - MOTIVATION: The study of RNA virus populations is a challenging task. Each population of RNA virus is composed of a collection of different, yet related genomes often referred to as mutant spectra or quasispecies. Virologists using deep sequencing technologies face major obstacles when studying virus population dynamics, both experimentally and in natural settings due to the relatively high error rates of these technologies and the lack of high performance pipelines. In order to overcome these hurdles we developed a computational pipeline, termed ViVan (Viral Variance Analysis). ViVan is a complete pipeline facilitating the identification, characterization and comparison of sequence variance in deep sequenced virus populations. RESULTS: Applying ViVan on deep sequenced data obtained from samples that were previously characterized by more classical approaches, we uncovered novel and potentially crucial aspects of virus populations. With our experimental work, we illustrate how ViVan can be used for studies ranging from the more practical, detection of resistant mutations and effects of antiviral treatments, to the more theoretical temporal characterization of the population in evolutionary studies. AVAILABILITY AND IMPLEMENTATION: Freely available on the web at http://www.vivanbioinfo.org CONTACT: : nshomron@post.tau.ac.il SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25701576 TI - Pattern recognition methods to relate time profiles of gene expression with phenotypic data: a comparative study. AB - MOTIVATION: Comparing time courses of gene expression with time courses of phenotypic data may provide new insights in cellular mechanisms. In this study, we compared the performance of five pattern recognition methods with respect to their ability to relate genes and phenotypic data: one classical method (k-means) and four methods especially developed for time series [Short Time-series Expression Miner (STEM), Linear Mixed Model mixtures, Dynamic Time Warping for Omics and linear modeling with R/Bioconductor limma package]. The methods were evaluated using data available from toxicological studies that had the aim to relate gene expression with phenotypic endpoints (i.e. to develop biomarkers for adverse outcomes). Additionally, technical aspects (influence of noise, number of time points and number of replicates) were evaluated on simulated data. RESULTS: None of the methods outperforms the others in terms of biology. Linear modeling with limma is mostly influenced by noise. STEM is mostly influenced by the number of biological replicates in the dataset, whereas k-means and linear modeling with limma are mostly influenced by the number of time points. In most cases, the results of the methods complement each other. We therefore provide recommendations to integrate the five methods. AVAILABILITY: The Matlab code for the simulations performed in this research is available in the Supplementary Data (Word file). The microarray data analysed in this paper are available at ArrayExpress (E-TOXM-22 and E-TOXM-23) and Gene Expression Omnibus (GSE39291). The phenotypic data are available in the Supplementary Data (Excel file). Links to the pattern recognition tools compared in this paper are provided in the main text. CONTACT: d.hendrickx@maastrichtuniversity.nl SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25701577 TI - First group of CCGs for commissioning GPs' services is announced. PMID- 25701578 TI - A study of New York City obstetrics units demonstrates the potential for reducing hospital inpatient capacity. AB - Hospitals are under significant pressure from payers to reduce costs. The single largest fixed cost for a hospital is inpatient beds, yet there is significant variation in hospital capacity utilization. We study bed capacity in New York City hospital obstetrics units and find that while many hospitals have an insufficient number of beds to provide timely access to care, overall there is significant excess capacity. Our findings, coupled with current demographic and clinical practice trends, indicate that a large fraction of obstetrics units nationwide could likely reduce their bed capacity while assuring timely access to care, resulting in large savings in capital and staffing costs. Given emerging health care delivery and payment models that will likely decrease demand for other types of hospital beds, our study suggests that data-based methodologies should be used by hospitals and policy makers to identify opportunities for reducing excess bed capacity in other inpatient units as well. PMID- 25701579 TI - New evidence on the persistence of health spending. AB - Surprisingly little is known about long-term spending patterns in the under-65 population. Such information could inform efforts to improve coverage and control costs. Using the MarketScan claims database, we characterize the persistence of health care spending in the privately insured, under-65 population. Over a 6-year period, 69.8% of enrollees never had annual spending in the top 10% of the distribution and the bottom 50% of spenders accounted for less than 10% of spending. Those in the top 10% in 2003 were almost as likely (34.4%) to be in the top 10% five years later as one year later (43.4%). Many comorbid conditions retained much of their predictive power even 5 years later. The persistence at both ends of the spending distribution indicates the potential for adverse selection and cream skimming and supports the use of disease management, particularly for those with the conditions that remained strong predictors of high spending throughout the follow-up period. PMID- 25701580 TI - Migraine doctor is suspended for serious breach of professional standards. PMID- 25701587 TI - Gene regulation by H-NS as a function of growth conditions depends on chromosomal position in Escherichia coli. AB - Cellular adaptation to changing environmental conditions requires the coordinated regulation of expression of large sets of genes by global regulatory factors such as nucleoid associated proteins. Although in eukaryotic cells genomic position is known to play an important role in regulation of gene expression, it remains to be established whether in bacterial cells there is an influence of chromosomal position on the efficiency of these global regulators. Here we show for the first time that genome position can affect transcription activity of a promoter regulated by the histone-like nucleoid-structuring protein (H-NS), a global regulator of bacterial transcription and genome organization. We have used as a local reporter of H-NS activity the level of expression of a fluorescent reporter protein under control of an H-NS-regulated promoter (Phns) at different sites along the genome. Our results show that the activity of the Phns promoter depends on whether it is placed within the AT-rich regions of the genome that are known to be bound preferentially by H-NS. This modulation of gene expression moreover depends on the growth phase and the growth rate of the cells, reflecting the changes taking place in the relative abundance of different nucleoid proteins and the inherent heterogeneous organization of the nucleoid. Genomic position can thus play a significant role in the adaptation of the cells to environmental changes, providing a fitness advantage that can explain the selection of a gene's position during evolution. PMID- 25701588 TI - Role of macular xanthophylls in prevention of common neovascular retinopathies: retinopathy of prematurity and diabetic retinopathy. AB - Retinopathy of prematurity (ROP) and diabetic retinopathy (DR) are important causes of blindness among children and working-age adults, respectively. The development of both diseases involves retinal microvascular degeneration, vessel loss and consequent hypoxic and inflammatory pathologic retinal neovascularization. Mechanistic studies have shown that oxidative stress and subsequent derangement of cell signaling are important factors in disease progression. In eye and vision research, role of the dietary xanthophyll carotenoids, lutein and zeaxanthin, has been more extensively studied in adult onset macular degeneration than these other retinopathies. These carotenoids also may decrease severity of ROP in preterm infants and of DR in working-age adults. A randomized controlled clinical trial of carotenoid supplementation in preterm infants indicated that lutein has functional effects in the neonatal eye and is anti-inflammatory. Three multicenter clinical trials all showed a trend of decreased ROP severity in the lutein supplemented group. Prospective studies on patients with non-proliferative DR indicate serum levels of lutein and zeaxanthin are significantly lower in these patients compared to normal subjects. The present review describes recent advances in lutein and zeaxanthin modulation of oxidative stress and inflammation related to ROP and DR and discusses potential roles of lutein/zeaxanthin in preventing or lessening the risks of disease initiation or progression. PMID- 25701589 TI - Experimental evidence suggesting that H2O2 is produced within the thylakoid membrane in a reaction between plastoquinol and singlet oxygen. AB - Plastoquinol (PQH2-9) and plastoquinone (PQ-9) mediate photosynthetic electron transfer. We isolated PQH2-9 from thylakoid membranes, purified it with HPLC, subjected the purified PQH2-9 to singlet oxygen ((1)O2) and analyzed the products. The main reaction of (1)O2 with PQH2-9 in methanol was found to result in formation of PQ-9 and H2O2, and the amount of H2O2 produced was essentially the same as the amount of oxidized PQH2-9. Formation of H2O2 in the reaction between (1)O2 and PQH2-9 may be an important source of H2O2 within the lipophilic thylakoid membrane. PMID- 25701590 TI - Insight into conformational modification of alpha-synuclein in the presence of neuronal whole cells and of their isolated membranes. AB - A change in the conformational plasticity of alpha-Synuclein (alpha-Syn) is hypothesised to be a key step in the pathogenic mechanism of Parkinson's disease (PD). Here, we report the study of extracellular alpha-Syn interaction with whole cells and membranes isolated from the neuronal SH-SY5Y cells, exploiting NMR and CD spectroscopies. In addition, the crosslinking agent DSG was used to freeze the conformational and oligomeric state of alpha-Syn in the presence of cells. These data, in a quasi-physiological environment, confirm the protein monomeric state with a propensity to adopt a transient alpha helical following interaction with biological membranes. PMID- 25701591 TI - Volume transition analysis: a new approach to resolve reclassification of brain tissue in repeated MRI scans. AB - BACKGROUND: Variability in brain tissue volumes derived from magnetic resonance images is attributable to various sources. In quantitative comparisons it is therefore crucial to distinguish between biologically and methodically conditioned variance and to take spatial accordance into account. NEW METHOD: We introduce volume transition analysis as a method that not only provides details on numerical and spatial accordance of tissue volumes in repeated scans but also on voxel shifts between tissue types. Based on brain tissue probability maps, mono- and bidirectional voxel shifts can be examined by explicitly separating volume transitions into source and target. We apply the approach to a set of subject data from repeated intra-scanner (one week and 30 month interval) as well as inter-scanner measurements. RESULTS: In all measurement scenarios, we found similar inter-class transitions of 9.9-15.9% of intracranial volume. The percentage of monodirectional net volume transition however increases from 0.3% in short term intra-scanner to 1.6% in long term intra-scanner and 9.3% in inter scanner comparisons. COMPARISON WITH EXISTING METHODS: Unlike most routinely used variability measures volume transition analysis is able to monitor reclassifications and thus to quantify not only balanced flows but also the amount of monodirectional net flows between tissue classes. The approach is independent from group analysis and can thus be applied in as few as two images. CONCLUSIONS: The proposed method is an easily applicable tool that is useful in discovering intra-individual brain changes and assists in separating biological from technical variance in structural brain measures. PMID- 25701592 TI - Decreased interoceptive accuracy following social exclusion. AB - The need for social affiliation is one of the most important and fundamental human needs. Unsurprisingly, humans display strong negative reactions to social exclusion. In the present study, we investigated the effect of social exclusion on interoceptive accuracy - accuracy in detecting signals arising inside the body - measured with a heartbeat perception task. We manipulated exclusion using Cyberball, a widely used paradigm of a virtual ball-tossing game, with half of the participants being included during the game and the other half of participants being ostracized during the game. Our results indicated that heartbeat perception accuracy decreased in the excluded, but not in the included, participants. We discuss these results in the context of social and physical pain overlap, as well as in relation to internally versus externally oriented attention. PMID- 25701593 TI - Influenza A viruses of swine circulating in the United States during 2009-2014 are susceptible to neuraminidase inhibitors but show lineage-dependent resistance to adamantanes. AB - Antiviral drug susceptibility is one of the evaluation criteria of pandemic potential posed by an influenza virus. Influenza A viruses of swine (IAV-S) can play an important role in generating novel variants, yet limited information is available on the drug resistance profiles of IAV-S circulating in the U.S. Phenotypic analysis of the IAV-S isolated in the U.S. (2009-2011) (n=105) revealed normal inhibition by the neuraminidase (NA) inhibitors (NAIs) oseltamivir, zanamivir, and peramivir. Screening NA sequences from IAV-S collected in the U.S. (1930-2014) showed 0.03% (1/3396) sequences with clinically relevant H274Y-NA substitution. Phenotypic analysis of IAV-S isolated in the U.S. (2009-2011) confirmed amantadine resistance caused by the S31N-M2 and revealed an intermediate level of resistance caused by the I27T-M2. The majority (96.7%, 589/609) of IAV-S with the I27T-M2 in the influenza database were isolated from pigs in the U.S. The frequency of amantadine-resistant markers among IAV-S in the U.S. was high (71%), and their distribution was M-lineage dependent. All IAV-S of the Eurasian avian M lineage were amantadine-resistant and possessed either a single S31N-M2 substitution (78%, 585/747) or its combination with the V27A-M2 (22%, 162/747). The I27T-M2 substitution accounted for 43% (429/993) of amantadine resistance in classic swine M lineage. Phylogenetic analysis showed that both S31N-M2 and I27T-M2 emerged stochastically but appeared to be fixed in the U.S. IAV-S population. This study defines a drug-susceptibility profile, identifies the frequency of drug-resistant markers, and establishes a phylogenetic approach for continued antiviral-susceptibility monitoring of IAV-S in the U.S. PMID- 25701595 TI - Protective effect of microRNA-30b on hypoxia/reoxygenation-induced apoptosis in H9C2 cardiomyocytes. AB - We examined the protective role of microRNA-30b (miR-30b) in ischemia-reperfusion (I/R)-induced injury in rat H9C2 cardiomyocytes. H9C2 cells were subjected to hypoxia-reoxygenation (H/R) treatment to simulate ischemia-reperfusion (I/R) injury. H9C2 cells were divided into: vehicle control (VC) group; scrambled inhibitors (INC) group; scrambled mimics (MNC) group; H/R+VC group; H/R+INC group; H/R+mimics group. H/R induced apoptosis was detected by flow cytometry and the pathways involved in miR-30b-mediated protection were examined by analyzing the expression of miR-30b, Bcl-2, Bax, Caspase-3, KRAS, p-AKT and total AKT in H9C2 cells. Overexpression of miR-30b mimic (H/R+mimics group) significantly increased Bcl-2 and Bcl-2/Bax levels and decreased Bax and Caspase-3 levels, compared with the H/R+VC group (all P<0.05). Consistent with this, the apoptosis rate was significantly decreased in the H/R+mimics group (P<0.05) compared with the H/R+VC group. Western blot analysis revealed that overexpression of miR-30b mimic resulted in significantly increase in AKT activation and decreased KRAS, compared to the H/R+VC group (both P<0.05). In conclusion, the H/R induced apoptosis decreased miR-30b expression, but over-expression of miR-30b inhibited H/R induced apoptosis. The observed miR-30b-mediated protection against H/R induced apoptosis involved the upregulation of Ras-PI3K-Akt pathway. PMID- 25701594 TI - Metabotropic glutamate receptor-mediated signaling dampens the HPA axis response to restraint stress. AB - Glutamate is an important neurotransmitter in the regulation of the neural portion of hypothalamus-pituitary-adrenal (HPA) axis activity, and signals through ionotropic and metabotropic receptors. In the current studies we investigated the role of hypothalamic paraventricular group I metabotropic glutamate receptors in the regulation of the HPA axis response to restraint stress in rats. Direct injection of the group I metabotropic glutamate receptor agonist 3,5-dihydroxyphenylglycine (DHPG) into the PVN prior to restraint leads to blunting of the HPA axis response in awake animals. Consistent with this result, infusion of the group I receptor antagonist hexyl-homoibotenic acid (HIBO) potentiates the HPA axis response to restraint. The excitatory effect of blocking paraventricular group I metabotropic glutamate signaling is blocked by co-administration of dexamethasone into the PVN. However, the inhibitory effect of DHPG is not affected by co-administration of the cannabinoid CB1 receptor antagonist AM-251 into the PVN. Together, these results suggest that paraventricular group I metabotropic glutamate receptor signaling acts to dampen HPA axis reactivity. This effect appears to be similar to the rapid inhibitory effect of glucocorticoids at the PVN, but is not mediated by endocannabinoid signaling. PMID- 25701596 TI - Genomic and proteomic features of mycobacteriophage SWU1 isolated from China soil. AB - Mycobacteriophage SWU1 is a newly isolated phage from soil sample collected in Sichuan province, China using Mycobacterium smegmatis mc(2)155 as host. Plaque, phage morphology and one-step growth curve were characterized. The complete genomic sequence of phage SWU1 was determined by shotgun sequencing. The ends of SWU1 were determined. Structural proteins of SWU1 were analyzed by NanoLC-ESI MS/MS. Seven ORFs were identified as structural protein encoded by SWU1 genome. The genetic basis underlying the SWU1 plaque was explored using comparative genomics. Prophages homologous to SWU1 were identified in two pathogens, Segniliparus rugosus ATCC BAA-974 and Mycobacterium rhodesiae JS60. Genus Segniliparus is a member of the order Corynebacteriales. To our knowledge, this is the first report of Mycobacterium prophages in different genera. PMID- 25701597 TI - De novo sequencing analysis of the Rosa roxburghii fruit transcriptome reveals putative ascorbate biosynthetic genes and EST-SSR markers. AB - Rosa roxburghii Tratt. is a well-known ornamental rose species native to China. In addition, the fruits of this species are valued for their nutritional and medicinal characteristics, especially their high ascorbic acid (AsA) levels. Nevertheless, AsA biosynthesis in R. roxburghii fruit has not been explored in detail because of a lack of genomic resources for this species. High-throughput transcriptomic sequencing generating large volumes of transcript sequence data can aid in gene discovery and molecular marker development. In this study, we generated more than 53 million clean reads using Illumina paired-end sequencing technology. De novo assembly yielded 106,590 unigenes, with an average length of 343 bp. On the basis of sequence similarity to known proteins, 9301 and 2393 unigenes were classified into Gene Ontology and Clusters of Orthologous Group categories, respectively. There were 7480 unigenes assigned to 124 pathways in the Kyoto Encyclopedia of Gene and Genome pathway database. BLASTx searches identified 498 unique putative transcripts encoding various transcription factors, some known to regulate fruit development. qRT-PCR validated the expressions of most of the genes encoding the main enzymes involved in ascorbate biosynthesis. In addition, 9131 potential simple sequence repeat (SSR) loci were identified among the unigenes. One hundred and two primer pairs were synthesized and 71 pairs produced an amplification product during initial screening. Among the amplified products, 30 were polymorphic in the 16 R. roxburghii germplasms tested. Our study was the first to produce a large volume of transcriptome data from R. roxburghii. The resulting sequence collection is a valuable resource for gene discovery and marker-assisted selective breeding in this rose species. PMID- 25701598 TI - TGF-beta/Smad2/3 signal pathway involves in U251 cell proliferation and apoptosis. AB - TGF-beta/Smad2/3 signal pathway is regarded as a central regulator in various tumors, but its roles in brain cancer therapy remain unknown. In this study, we identify that the TGF-beta/Smad2/3 signal pathway is activated in human brain glioma cells; inhibitor (SB203580) and siRNA against Smad2/3 quickly inhibited the phosphorylation of Smad2 and 3, expression of its major downstream gene, Ki 67, arrested cells in the G2/M phase and induced apoptosis of cells. The findings suggest that TGF-beta/Smad2/3 pathway plays a key role in U251 cell growth and metastasis, which suggests its potential role in the molecular therapy of brain cancer. PMID- 25701599 TI - Cys-loop ligand-gated ion channel gene discovery in the Locusta migratoria manilensis through the neuron transcriptome. AB - As an ideal model, Locusta migratoria manilensis (Meyen) has been widely used in the study of endocrinological and neurobiological processes. Here we created a large transcriptome of the locust neurons, which enriched ion channels whose potential for functional genetic experiments is currently limited. With high throughput Illumina sequencing technology, we obtained more than 50 million raw reads, which were assembled into 61,056 unique sequences with average size of 737bp. Among the unigenes, a total 24,884 sequences had significant similarities with proteins in the five public databases (NR, SwissProt, GO, COG and KEGG) with a cut-off E-value of 10(-5) using BLASTx. Moreover, the number of potential genes of the cys-loop ligand-gated ion channels (LGICs) was manually curated, including 39 putative nicotinic acetylcholine receptors (nAChRs), 6 putative gamma aminobutyric acid (GABA) gated anion channels, 21 putative glutamate-gated chloride channels (GluCls) and 1 histamine-gated chloride channels (HisCls). In addition, the full-length of 11 nAChRs subunits (9 alpha and 2 beta) were obtained by RACE technique that would be helpful to further studies on nAChR neurochemistry and pharmacological aspects. To our knowledge, this is the first study to characterize the locust neuron transcriptome, which will provide a useful resource especially for future studies on the neuro-function and behavior of the locust. PMID- 25701600 TI - Association of RBP4 gene variants with adverse lipid profile and obesity. AB - Obesity is currently a worldwide public health problem. Retinol-binding protein4 (RBP4) is a recently discovered adipokine, which is potentially associated with insulin resistance and obesity. We aimed to investigate whether genetic variation within the RBP4 gene is correlated with the obesity and lipid profile in Iranian population. 321 samples were randomly selected from participants of Isfahan Healthy Heart Program (IHHP). Genomic DNA was isolated from peripheral blood cells (PBCs) and HRM-PCR was performed in order to investigate the presence of SNPs, and further sequencing analysis was done from selected subjects according to the differences of HRM curve pattern. Statistical analyses were performed using SPSS v16.00. The difference of the presence of rs3758539 polymorphism between controls and obese patients was significant, but not about rs10882280. We found noticeable association among genetic polymorphisms and biomedical and physical characteristics within investigated population. Our findings suggested that variations in the RBP4 gene were correlated with BMI and polymorphisms more likely could contribute to the development of obesity in our population. Also appraisal of obesity risk factors within each group might be helpful for preventing obesity initiation and could have a possible role in a predisposition to obesity in the Iranians. PMID- 25701601 TI - Genome-wide target site triplication of Alu elements in the human genome. AB - Alu elements are the most successful short interspersed elements in primate genomes and their retrotransposition is a major source of genomic expansion. Alu elements integrate into genomic regions through target-site primed reverse transcription, which generates target site duplications (TSDs). Unexpectedly, we have identified target site triplications (TSTs) at some loci, where two Alu elements in tandem share one direct repeat. Thus, the three copies of the repeat are present. We located 212 TST loci in the human genome and examined 25 putative human-specific TST loci using PCR validation. As a result, 12 human-specific TST loci were identified. These findings suggest that unequal homologous recombination between TSDs can lead to TST. Through this mechanism, the copy number of Alu elements could have increased in primate genomes without new Alu retrotransposition events. This study provides new insight into the augmentation of Alu elements in the primate genome. PMID- 25701602 TI - The role dietary of bioactive compounds on the regulation of histone acetylases and deacetylases: a review. AB - Nutrigenomics is an area of epigenomics that explores and defines the rapidly evolving field of diet-genome interactions. Lifestyle and diet can significantly influence epigenetic mechanisms, which cause heritable changes in gene expression without changes in DNA sequence. Nutrient-dependent epigenetic variations can significantly affect genome stability, mRNA and protein expression, and metabolic changes, which in turn influence food absorption and the activity of its constituents. Dietary bioactive compounds can affect epigenetic alterations, which are accumulated over time and are shown to be involved in the pathogenesis of age-related diseases such as diabetes, cancer, and cardiovascular disease. Histone acetylation is an epigenetic modification mediated by histone acetyl transferases (HATs) and histone deacetylases (HDACs) critically involved in regulating affinity binding between the histones and DNA backbone. The HDAC mediated increase in histone affinity to DNA causes DNA condensation, preventing transcription, whereas HAT-acetylated chromatin is transcriptionally active. HDAC and HAT activities are reported to be associated with signal transduction, cell growth and death, as well as with the pathogenesis of various diseases. The aim of this review was to evaluate the role of diet and dietary bioactive compounds on the regulation of HATs and HDACs in epigenetic diseases. Dietary bioactive compounds such as genistein, phenylisothiocyanate, curcumin, resveratrol, indole 3-carbinol, and epigallocatechin-3-gallate can regulate HDAC and HAT activities and acetylation of histones and non-histone chromatin proteins, and their health benefits are thought to be attributed to these epigenetic mechanisms. The intake of dietary compounds that regulate epigenetic modifications can provide significant health effects and may prevent various pathological processes involved in the development of cancer and other life-threatening diseases. PMID- 25701603 TI - Unc-51 like kinase 1 (ULK1) in silico analysis for biomarker identification: a vital component of autophagy. AB - Autophagy is a degradation pathway involving lysosomal machinery for degradation of damaged organelles like the endoplasmic reticulum and mitochondria into their building blocks to maintain homeostasis within the cell. ULK1, a serine/threonine kinase, is conserved across species, from yeasts to mammals, and plays a central role in autophagy pathway. It receives signals from upstream modulators such as TIP60, mTOR and AMPK and relays them to its downstream substrates like Ambra1 and ZIP kinase. The activity of this complex is regulated through protein-protein interactions and post-translational modifications. Applying in silico analysis we identified (i) conserved patterns of ULK1 that showed its evolutionary relationship between the species which were closely related in a family compared to others. (ii) A total of 23 TFBS distributed throughout ULK1 and nuclear factor (erythroid-derived) 2 (NFE2) is of utmost significance because of its high importance rate. NEF2 has already been shown experimentally to play a role in the autophagy pathway. Most of these were of zinc coordinating class and we suggest that this information could be utilized to modulate this pathway by modifying interactions of these TFs with ULK1. (iii) CATTT haplotype was prominently found with frequency 0.774 in the studied population and nsSNPs which could have harmful effect on ULK1 protein and these could further be tested. (iv) A total of 83 phosphorylation sites were identified; 26 are already known and 57 are new that include one at tyrosine residue which could further be studied for its involvement in ULK1 regulation and hence autophagy. Furthermore, 4 palmitoylation sites at positions 426, 927, 1003 and 1049 were also found which could further be studied for protein-protein interactions as well as in trafficking. PMID- 25701604 TI - A protein binding site in the M mitochondrial genome of Mytilus galloprovincialis may be responsible for its paternal transmission. AB - Sea mussels (genus Mytilus) have two mitochondrial genomes in obligatory co existence, one that is transmitted through the egg and the other through the sperm. The phenomenon, known as Doubly Uniparental Inheritance (DUI) of mitochondrial DNA (mtDNA), is presently known to occur in more than 40 molluscan bivalve species. Females and the somatic tissues of males contain mainly the maternal (F) genome. In contrast, the sperm contains only the paternal (M) genome. Through electrophoretic mobility shift assay (EMSA) experiments we have identified a sequence element in the control region (CR) of the M genome that acts as a binding site for the formation of a complex with a protein factor that occurs in the male gonad. An adenine tract upstream to the element is also essential for the formation of the complex. The reaction is highly specific. It does not occur with protein extracts from the female gonad or from a male or female somatic tissue. Further experiments showed that the interaction takes place in mitochondria surrounding the nucleus of the cells of male gonads, suggesting a distinct role of perinuclear mitochondria. We propose that at a certain point during spermatogenesis mitochondria are subject to degradation and that perinuclear mitochondria with the M mtDNA-protein complex are protected from this degradation with the result that mature spermatozoa contain only the paternal mitochondrial genome. PMID- 25701605 TI - Identification and characterization of methylation-dependent/independent DNA regulatory elements in the human SLC9B1 gene. AB - The human NHEDC1 (hNHEDC1) protein is thought to be essential for sperm motility and fertility however the mechanisms regulating its gene expression are largely unknown. In this study we have identified multiple DNA regulatory elements in the 5' end of the gene encoding hNHEDC1 (SLC9B1) and have explored the role that DNA methylation at these elements plays in the regulation of its expression. We first show that the full-length hNHEDC1 protein is testis-specific for the tissues that we tested and that it localizes to the cells of the seminiferous tubules. In silico analysis of the SLC9B1 gene locus identified two putative promoters (P1 and P2) and two CpG islands - CpGI (overlapping with P1) and CpGII (intragenic) - at the 5' end of the gene. By deletion analysis of P1, we show that the region from -23 bp to +200 bp relative to the transcription start site (TSS) is sufficient for optimal promoter activity in a germ cell line. Additionally, in vitro methylation of the P1 (the -500 bp to +200 bp region relative to the TSS) abolishes its activity in germ cells and somatic cells strongly suggesting that DNA methylation at this promoter could regulate SLC9B1 expression. Furthermore, bisulfite-sequencing analysis of the P1/CpGI uncovered reduced methylation in the testis vs. lung whereas CpGII displayed no differences in methylation between these two tissues. Additionally, treatment of HEK 293 cells with 5-aza-2 Deoxycytidine led to upregulation of NHEDC1 transcript and reduced methylation in the promoter CpGI. Finally, we have uncovered both enhancer and silencer functions of the intragenic SLC9B1 CpGII. In all, our data suggests that SLC9B1 gene expression could be regulated via a concerted action of DNA methylation dependent and independent mechanisms mediated by these multiple DNA regulatory elements. PMID- 25701606 TI - Genome-wide identification and characterization of teleost-specific microRNAs within zebrafish. AB - The molecular genetic basis of teleost phenotypic diversity remains poorly understood, despite the increasing availability of genome and transcriptome data. Changes in gene expression, resulting from regulatory mutations, contribute to many or even most phenotypic innovations. In this study, we performed comparative genomic analyses to identify 44 Conserved Teleost-Specific MicroRNAs (CTSMs). An analysis of the sequences of CTSMs demonstrated that their sequence variability is significantly higher than that of Evolutionarily Conserved microRNAs (ECs - microRNAs conserved throughout vertebrates), and that this difference primarily results from variation in the loop regions. We computationally predicted target genes for CTSMs and found that the targets of CTSMs show significantly lower SNP density compared with targets of ECs as well as non-targets of CTSMs. The temporal expression profile of targets of CTSMs obtained from RNA-seq data revealed that the targets of CTSMs are specifically enriched in early-stage embryos and exhibit a broader expression spectrum. Finally, functional enrichment analysis (GO and KEGG) indicated that the targets of CTSMs play diverse functional roles, with a significantly enriched category being the "immune response". Our study provides the first systematic identification and characterization of conserved teleost-specific microRNAs and their targets and presents valuable foundation for a better understanding the genomic basis for the diversification of teleosts. PMID- 25701607 TI - Myogenic regulatory factor (MRF) expression is affected by exercise in postnatal chicken skeletal muscles. AB - The MyoD1, MyoG, Myf5, and Mrf4 proteins belong to the family of muscle regulatory factors (MRFs) and play important roles in skeletal muscle hyperplasia and hypertrophy. We hypothesized that exercise would affect MRF mRNA and protein abundance in postnatal chicken skeletal muscle driving molecular changes that could ultimately lead to increased muscle fiber diameter. At day (d) 43, twelve hundred chickens with similar body weight were randomly assigned to cage, pen, and free-range groups. The MRF mRNA abundance was measured in the pectoralis major and thigh muscle at d56, d70, and d84, and the protein levels of MRFs were determined from the thigh muscle at d84. The results showed no significant difference in mRNA of the MRFs among the three groups at d56 (P>0.05). At d84, chicken in the pen and free-range group showed higher MyoD1, MyoG, Myf5, and Mrf4 mRNA abundance compared to the caged chickens (P<0.05). Free-range chickens had higher Mrf4 and MyoG expression than those in penned ones (P<0.05). Protein abundances of all four factors were lowest in the caged group, and Mrf4 and MyoG protein quantities were greatest in free-range chickens (P<0.05), but Myf5 and MyoD1 protein abundance did not differ between penned and caged groups. The results suggested that exercise up-regulated MRF expression in the postnatal skeletal muscles, which led to an increase in muscle fiber diameter, and eventually affected the meat quality of the skeletal muscles in adult chickens. PMID- 25701608 TI - A rapid and sensitive UPLC-MS/MS method for the simultaneous quantification of serum androsterone glucuronide, etiocholanolone glucuronide, and androstan 3alpha, 17beta diol 17-glucuronide in postmenopausal women. AB - Quantification of steroidal glucuronide conjugates by the indirect methods of immunoassay and GC-MS/MS may underestimate some conjugates since hydrolysis is needed in sample processing. In the present work, a sensitive and rapid liquid chromatography-tandem mass spectrometry (LC-MS/MS) method has been developed and validated for the simultaneous direct quantification of androsterone glucuronide, etiocholanolone glucuronide, and androstan-3alpha, 17beta diol 17-glucuronide in postmenopausal women's serum. The quantification limits are 0.1ng/mL for 3alpha diol-17G and 4ng/mL for both ADT-G and Etio-G, respectively, with an extraction from 200MUL serum while the total run time is less than 6min for all three glucuronides. In this method, solid phase extraction is used for sample preparation. The assay has been validated in compliance with EndoCeutics SOPs and FDA guidelines for bioanalytical method development and validation. The recovery of glucuronides in stripped serum is consistent with that in unstripped serum, where the average difference in stripped and unstripped is less than 10%. A linear regression model fits well the standard curves of all three compounds with R>=0.99 where the weighting factor is 1/X. Interday accuracy and CV for all levels of QCs are within the range of 15% in both stripped and unstripped serum while all calibration curves are within the range of 6% except for LLOQs, which are within the range of 9%. Other parameters have also been assessed such as selectivity, matrix, lipemic and hemolysis effects as well as stabilities in solution and matrix. Incurred sample reanalysis has been performed with a result of over 93% within 20% of the original values. This reliable, sensitive and fast method is ready for large-scale clinical sample assays. PMID- 25701609 TI - Increased short- and long-term mortality among patients with infectious spondylodiscitis compared with a reference population. AB - BACKGROUND CONTEXT: Information on short- and especially long-term mortality among patients with infectious spondylodiscitis is sparse. PURPOSE: To analyze mortality, factors associated with death, and cause-specific mortality rates among patients with infectious nonpostoperative spondylodiscitis. STUDY DESIGN: A case-cohort study. PATIENT SAMPLE: We identified all patients aged 18 years or older treated for infectious spondylodiscitis from January 1994 to May 2009 at hospitals in Funen County, Denmark. OUTCOME MEASURES: Overall and cause-specific mortality. METHODS: Mortality rates among patients were compared with rates among a reference population using Kaplan-Meier plots and mortality rate ratios (MRRs). Short-term mortality was defined as deaths within first year after admission and long-term mortality was deaths thereafter. Factors associated with death were determined. RESULTS: Among 298 identified patients, 61 (20%) died within the first year. Adjusted MRRs were 16.8 (95% confidence interval: 9.9-28.5) for 0 to 90 days; 4.2 (2.5-7.0) for 91 to 365 days; 2.2 (1.6-2.9) for 1 to 4 years; and 1.7 (1.2-2.5) for 5 to 14 years. Mortality rate ratios stratified on microbiological etiology were 8.8 (3.3-22.1) for 0 to 90 days; 1.4 (0.3-5.8) for 91 to 365 days; 3.2 (2.0-5.1) for 1 to 4 years; and 1.1 (0.5-2.4) for 5 to 14 years for unknown etiology and 24.0 (13.0-44.2) for 0 to 90 days; 6.0 (3.1-11.5) for 91 to 365 days; 1.9 (1.1-3.2) for 1 to 4 years; and 2.7 (1.5-4.7) for 5 to 14 years among Staphylococcus aureus infections. The main factors associated with short-term mortality were severe neurologic deficits at the time of admission, epidural abscess, and comorbidities. Long-term mortality seemed independent of microbiological etiology. CONCLUSIONS: Mortality remained high the first year after admission and thereafter decreased with time to a level close to the reference population. Short-term mortality was especially related to infection with abscess formation and neurologic deficits and long-term mortality was related to alcohol dependency. PMID- 25701610 TI - Light induced cytosolic drug delivery from liposomes with gold nanoparticles. AB - Externally triggered drug release at defined targets allows site- and time controlled drug treatment regimens. We have developed liposomal drug carriers with encapsulated gold nanoparticles for triggered drug release. Light energy is converted to heat in the gold nanoparticles and released to the lipid bilayers. Localized temperature increase renders liposomal bilayers to be leaky and triggers drug release. The aim of this study was to develop a drug releasing system capable of releasing its cargo to cell cytosol upon triggering with visible and near infrared light signals. The liposomes were formulated using either heat-sensitive or heat- and pH-sensitive lipid compositions with star or rod shaped gold nanoparticles. Encapsulated fluorescent probe, calcein, was released from the liposomes after exposure to the light. In addition, the pH sensitive formulations showed a faster drug release in acidic conditions than in neutral conditions. The liposomes were internalized into human retinal pigment epithelial cells (ARPE-19) and human umbilical vein endothelial cells (HUVECs) and did not show any cellular toxicity. The light induced cytosolic delivery of calcein from the gold nanoparticle containing liposomes was shown, whereas no cytosolic release was seen without light induction or without gold nanoparticles in the liposomes. The light activated liposome formulations showed a controlled content release to the cellular cytosol at a specific location and time. Triggering with visual and near infrared light allows good tissue penetration and safety, and the pH-sensitive liposomes may enable selective drug release in the intracellular acidic compartments (endosomes, lysosomes). Thus, light activated liposomes with gold nanoparticles are an attractive option for time- and site specific drug delivery into the target cells. PMID- 25701611 TI - Self-healing of pores in PLGAs. AB - Self-healing of pores in Poly(lactic-co-glycolic acid)s (PLGA) plays an important role in the encapsulation and controlled release of drugs from PLGA microparticles. Despite the importance of this phenomenon, neither the mechanics of the deformation nor the material properties that control it have been fully studied. In this study, the material properties of PLGA have been characterized using mechanical tests, and a finite-element model has been developed to predict how pores heal. This model assumes that the healing process occurs by viscous flow resulting from the deviatoric stress field induced by the interaction between the surface curvature and the surface tension of the PLGA. The simulations, which incorporate measured material properties, show good agreement with experimental observations. However, annealing processes that occur over prolonged times increase the viscosity and slow the healing times of PLGA films at intermediate temperatures above the glass-transition temperature. These findings may be reasonably applied towards the prediction of healing processes in PLGA and in related biomaterials for important biomedical applications such as drug delivery. PMID- 25701612 TI - Post-insertion of poloxamer 188 strengthened liposomal membrane and reduced drug irritancy and in vivo precipitation, superior to PEGylation. AB - The ultimate aim of this study was to develop asulacrine (ASL)-loaded long circulating liposomes to prevent phlebitis during intravenous (i.v.) infusion for chemotherapy. Poly(ethylene)glycol (PEG) and poloxamer 188-modified liposomes (ASL-PEGL and ASL-P188L) were developed, and ASL was loaded using a remote loading method facilitated with a low concentration of sulfobutyl ether-beta cyclodextrin as a drug solubilizer. The liposomes were characterized in terms of morphology, size, release properties and stability. Pharmacokinetics and venous tissue tolerance of the formulations were simultaneously studied in rabbits following one-hour i.v. infusion via the ear vein. The irritancy was assessed using a rat paw-lift/lick model after subplantar injections. High drug loading 9.0% w/w was achieved with no drug leakage found from ASL-PEGL or ASL-P188L suspended in a 5% glucose solution at 30days. However, a rapid release (leakage) from ASL-PEGL was observed when PBS was used as release medium, partially related to the use of cyclodextrin in drug loading. Post-insertion of poloxamer 188 to the liposomes appeared to be able to restore the drug retention possibly by increasing the packing density of phospholipids in the membrane. In rabbits (n=5), ASL-P188L had a prolonged half-life with no drug precipitation or inflammation in the rabbit ear vein in contrast to ASL solution. Following subplantar (footpad) injections in rats ASL solution induced paw-lick/lift responses in all rats whereas ASL-P188L caused no response (n=8). PEGylation showed less benefit possibly due to the drug 'leakage'. In conclusion, drug precipitation in the vein and the drug mild irritancy may both contribute to the occurrence of phlebitis caused by the ASL solution, and could both be prevented by encapsulation of the drug in liposomes. Poloxamer 188 appeared to be able to 'seal' the liposomal membrane and enhance drug retention. The study also highlighted the importance of bio-relevant in vitro release study in formulation screening. PMID- 25701613 TI - Imipramine attenuates neuroinflammatory signaling and reverses stress-induced social avoidance. AB - Psychosocial stress is associated with altered immunity, anxiety and depression. Previously we showed that repeated social defeat (RSD) promoted microglia activation and social avoidance behavior that persisted for 24days after cessation of RSD. The aim of the present study was to determine if imipramine (a tricyclic antidepressant) would reverse RSD-inducedsocial avoidance and ameliorate neuroinflammatory responses. To test this, C57BL/6 mice were divided into treatment groups. One group from RSD and controls received daily injections of imipramine for 24days, following 6 cycles of RSD. Two other groups were treated with saline. RSD mice spent significantly less time in the interaction zone when an aggressor was present in the cage. Administration of imipramine reversed social avoidance behavior, significantly increasing the interaction time, so that it was similar to that of control mice. Moreover, 24days of imipramine treatment in RSD mice significantly decreased stress-induced mRNA levels for IL-6 in brain microglia. Following ex vivo LPS stimulation, microglia from mice exposed to RSD, had higher mRNA expression of IL-6, TNF-alpha, and IL 1beta, and this was reversed by imipramine treatment. In a second experiment, imipramine was added to drinking water confirming the reversal of social avoidant behavior and decrease in mRNA expression of IL-6 in microglia. These data suggest that the antidepressant imipramine may exert its effect, in part, by down regulating microglial activation. PMID- 25701614 TI - False positive rates in Voxel-based Morphometry studies of the human brain: should we be worried? AB - Voxel-based Morphometry (VBM) is a widely used automated technique for the analysis of neuroanatomical images. Despite its popularity within the neuroimaging community, there are outstanding concerns about its potential susceptibility to false positive findings. Here we review the main methodological factors that are known to influence the results of VBM studies comparing two groups of subjects. We then use two large, open-access data sets to empirically estimate false positive rates and how these depend on sample size, degree of smoothing and modulation. Our review and investigation provide three main results: (i) when groups of equal size are compared false positive rate is not higher than expected, i.e. about 5%; (ii) the sample size, degree of smoothing and modulation do not appear to influence false positive rate; (iii) when they exist, false positive findings are randomly distributed across the brain. These results provide reassurance that VBM studies comparing groups are not vulnerable to the higher than expected false positive rates that are evident in single case VBM. PMID- 25701615 TI - Is there more than one approach to evaluating the variability of surgeons' performance? AB - INTRODUCTION: To demonstrate that the variability found to be significant between surgeons' performances within a small group does not necessarily mean that this significance applies to the entire field of that specific type of surgery. It is common for inferences and recommendations for an entire field to be based on the variability within a small group of surgeons. The variability between groups usually remains unknown. METHODS: An analysis of variance was used to assess the statistical significance of the variability among surgeons' performances of a specific type of surgery within the studied sample. The intraclass correlation coefficient was used to investigate how large a segment of this variability can be explained by a surgeon-related factor for the entire surgeon population of a specific field. The topic was illustrated using data obtained from a group of seven surgeons who operated on the penetrating rotator cuff tears of 742 patients. RESULTS: There were statistically significant differences between seven surgeons in the improvement of pain and the range of shoulder joint motion. However, only a small (<=2%) and statistically non-significant part of this variability could be explained by a difference between surgeons when the results were interpolated across the entire population of shoulder surgeons. DISCUSSION AND CONCLUSION: Variability in performance within a group of surgeons performing a specific type of surgery cannot be generalized to include the performance of all surgeons doing the same type of surgery without additional statistical analyses. PMID- 25701616 TI - Brompton Harefield Infection Score (BHIS): development and validation of a stratification tool for predicting risk of surgical site infection after coronary artery bypass grafting. AB - OBJECTIVE: Surgical site infection (SSI) following coronary artery bypass grafting (CABG) is a serious complication associated with significant morbidity and mortality. Despite the substantial impact of SSI there is lack of a specific risk stratification tool to predict this complication after CABG. This study was undertaken to develop a specific prognostic scoring system for the development of SSI that could risk-stratify patients undergoing CABG. METHODS: Between January 2009 and June 2012, continuous prospective surveillance data on SSI and a set of 41 variables were collected. Using binary logistic regression analysis we identified independent predictors of SSI. Initially we developed a predictive model in a subset of 769 patients. Dataset was expanded to 4087 cases and a final model and risk score were derived. Calibration of the scores was performed using the Hosmer-Lemeshow test. RESULTS: The model had area under Receiver Operating Characteristic curve of 0.727 (0.827 for preliminary dataset). Baseline risk score incorporated independent predictors of SSI: female gender = 2 (p < 0.0001; RR 2.1), diabetes = 1 (p = 0.0098, RR 1.4) or HbA1c >7.5% = 3 (p < 0.0001; RR 3.4), body mass index >=35 = 2 (p < 0.0001; RR 2.4), left ventricular ejection fraction < 45% = 1 (p = 0.0255; RR 1.4), and emergency surgery = 2 (p = 0.012; RR 2.4). A risk stratification system, the Brompton & Harefield Infection Score (BHIS) was developed. CONCLUSION: BHIS effectively predicts SSI risk and may help with risk stratification in relation to public reporting and reimbursement as well as targeted prevention strategies in patients undergoing CABG. PMID- 25701617 TI - Influence of the bending of the tip of elastic stable intramedullary nails on removal and associated complications in pediatric both bone forearm fractures: a pilot study. AB - OBJECTIVES: Both bone forearm fractures are efficiently treated by elastic stable intramedullary nail (ESIN). According to the original technique, the tip of the nail must be bent at 90 degrees and buried under the skin. However, skin irritation is commonly reported and may lead to early surgery to shorten the tip or remove the hardware. The purpose of this study was to investigate the influence of the bending of the tip of the nail in this procedure. METHODS: We retrospectively reviewed 72 children operated on using this technique with the tip bent either at 90 degrees or at 180 degrees . In both groups we recorded complication rates after the procedure and at the removal. RESULTS: Time until removal and duration of the removal were similar in both groups. Three complications (6.7%) that required additional surgery were recorded when the tip was bent at 90 degrees whereas no complications were found with the tip bent at 180 degrees . CONCLUSION: We advocate bending the tip of the nail at 180 degrees before burying it in order to avoid skin irritation and additional procedures. LEVEL OF EVIDENCE: Level III-retrospective comparative study. PMID- 25701618 TI - Intramedullary nail versus plate treatments for distal tibial fractures: a meta analysis. AB - INTRODUCTION: Controversy remained on whether the optimal treatment for distal tibial fractures is intramedullary nail (IMN) or plate. METHODS: Databases including PubMed, Embase, Cochrane library, Wanfang and CNKI were retrieved up to May 31, 2014 for eligible studies. Quality Assessment of Diagnostic Accuracy Studies (QUADAS) tool was used to evaluate literature qualities. Q and I(2) test were applied to estimate heterogeneities. Moreover, subgroup analyses were performed and publication bias was detected. Mean difference (MD) and relative risk (RR), with their corresponding 95% confidence interval (CI) were used to calculate the pooled results. RESULTS: Sixteen studies were included involving 1140 participants (IMN: 599; plate: 541). There were no significant differences between IMN and plate treatments in operation time (OT), hospital time (HT), union time (UT), and incidence of deep infection (DI) and union complications (UC). However, IMN achieved a significant lower superficial infection (SI) incidence (RR, 0.41; 95% CI, 0.23 to 0.71; P = 0.001) and a significant higher malunion incidence (RR, 2.27; 95% CI, 1.56 to 3.31; P < 0.001). In subgroup analyses, IMN had significant shorter OT than plate in randomized controlled trials (RCTs) (MD, -19.04; 95% CI, -24.86 to -13.21; P < 0.0001), but comparable incidence of SI to plate in non-Asia countries. No obvious publication bias was indicated in UT and malunion. CONCLUSION: For distal tibial fractures treatment, IMN might be advantageous over plate with lower SI incidence, and comparable UT, OT and HT. Meanwhile, IMN was related to higher risk of malunion. However, more RCTs are warranted. PMID- 25701619 TI - Effects of surgical procedures on the occurrence and development of postoperative portal vein thrombosis in patients with cirrhosis complicated by portal hypertension. AB - OBJECTIVE: We have compared the influences of three surgical strategies on the occurrence and development of portal vein thrombosis (PVT) in patients with liver cirrhosis complicated by portal hypertension (PHT) in this study. METHODS: Total 116 patients who respectively underwent pericardial devascularization (PCDV) with splenectomy (PDS group: n = 50), selective PCDV (SPD group: n = 28) and splenorenal shunt (SRS) combined with PCDV (combined group: n = 38) were investigated in this study. The incidence of PVT before and after operation was monitored. The incidence of Grade II-IV PVT was used to assess the severity of PVT. The liver function was assessed according to the Child-Pugh classification. RESULTS: The incidence and severity of PVT and live function were similar among the three groups before operation (P > 0.05). The incidence of PVT was significantly increased after surgery in each group (P < 0.001), but recovered to the baseline level at six months in combined group (P = 0.629). Besides, the severity of PVT was significantly aggravated in PDS (P < 0.001) and SPD (P = 0.026) groups after operation, but not in combined group (P = 0.525). Patients in combined group showed significantly lower incidence and severity of PVT than those in the other two groups at each follow-up time point (P < 0.05). In addition, the liver function in the combined group was significantly improved compared with the other two groups. CONCLUSIONS: SRS combined with PCDV is superior to PCDV with splenectomy and selective PCDV for PHT in liver cirrhotic patients in inhibiting the occurrence and development of postoperative PVT and improving liver function. PMID- 25701620 TI - Intraoperative monitoring of cerebral NIRS oximetry leads to better postoperative cognitive performance: a pilot study. AB - OBJECTIVES: The aim of this study is the assessment of the regional cerebral oximetry - NIRS (near infrared spectroscopy) as an intraoperative monitoring system to protect the patient against the incidents of brain desaturations. We hypothesize that patients monitored with NIRS present a smaller range of postoperative cognitive dysfunctions (POCD) in comparison with those without NIRS monitoring during lumbar spine surgery in a prone position. SETTINGS: This study was performed at the Clinical Department of Neurosurgery and Oncology of the Central Nervous System, Medical University of Lodz, Poland. PARTICIPANTS: The study completed 43 adult patients qualified for the surgical treatment of lumbar spondylosis. Before the procedures they were randomized into two subgroups: one monitored intraoperatively by means of NIRS cerebral oximetry (INVOS 5100), which numbered 13 patients - 30.2% (13 NIRS devices were made available to the authors) and the other without NIRS intraoperative monitoring, totaling 30 people - 69.8%. The patients who presented a history of psychiatric, neurological and cardiovascular disorders which impair cognitive processes were disqualified from the study. PRIMARY AND SECONDARY OUTCOME MEASURES: A comprehensive battery of neuropsychological tests was preoperatively performed on all patients. The subjects were then divided into two groups: with and without NIRS monitoring. Both groups were statistically homogeneous. Computerized anesthesia records were used to obtain intraoperative data: mean arterial pressure, heart rate, pulsoximetry and cerebral regional oxygenation. The depth of anesthesia monitor was not used. Besides, all the patients passed the same battery of neurocognitive tests 7 days and 1 month postoperatively. The Mann-Whitney test was performed to compare POCD and therefore assess the usefulness of NIRS as a monitoring mechanism during anesthesia in the prone position. RESULTS: There was a significant (p < 0.05) difference in the presence of cognitive deficiencies between the subgroup monitored with NIRS and the subgroup without NIRS. It included: Digit Span Test overall score and forward repetition score 7 days after operation, N- back Test results after 30 days in version 0 "back" - time, N-back Test version 1 "back" results in the number of correct answers and the number of errors. CONCLUSIONS: NIRS cerebral oximetry may be useful in reducing postoperative cognitive complications in patients operated on in the prone positioning. TRIAL REGISTRATION: RNN/556/08/KB - approval of the ethics committee at Medical University of Lodz, Poland. PMID- 25701621 TI - Sulfur-oxidizing bacteria in environmental technology. AB - Hydrogen sulfide is widely known as the most undesirable component of biogas that caused not only serious sensoric and toxic problems, but also corrosion of concrete and steel structures. Many agricultural and industrial waste used in biogas production, may contain a large amount of substances that serve as direct precursors to the formation of sulfide sulfur-sources of hydrogen sulfide in the biogas. Biological desulfurization methods are currently promoted to abiotic methods because they are less expensive and do not produce undesirable materials which must be disposed of. The final products of oxidation of sulfides are no longer hazardous. Biological removal of sulfide from a liquid or gaseous phase is based on the activity of sulfur-oxidizing bacteria. They need an oxidizing agent such as an acceptor of electrons released during the oxidation of sulfides atmospheric oxygen or oxidized forms of nitrogen. Different genera of sulfur oxidizing bacteria and their technological application are discussed. PMID- 25701622 TI - Editorial medical proteomics. PMID- 25701623 TI - Laparoscopic hysterotomy for a failed termination of pregnancy: a first case report with demonstration of a new surgical technique. AB - STUDY OBJECTIVE: To show a new technique of hysterotomy via laparoscopy for a failed termination of pregnancy as an alternative for a hysterotomy via laparotomy. DESIGN: Step-by-step explanation of the technique using parts of the original video of the procedure (Canadian Task Force classification III). SETTING: A 39-year-old woman, para 1 gravida 2, was diagnosed with a trisomy 21 pregnancy at 18 weeks' gestation. After 7 days of failed medical and mechanical induction, including misoprostol per vaginam, intravenous sulprostone , intravenous oxytocin, a transcervical Foley catheter, and a transcervical Bakri balloon (Cooke Medical, Bloomington, IN), the decision was made to perform a laparoscopic hysterotomy. INTERVENTIONS: A laparoscopic hysterotomy was performed with extraction of the fetus and placenta in an endobag. The uterus was sutured using a double layer of 2 continuous Vicryl 1 sutures (Ethicon, Cincinnati, OH). The umbilical incision was enlarged to 2.5 cm to extract the endobags. The procedure was performed using only standard reusable laparoscopic equipment. FOLLOW-UP: The patient's postoperative recovery was uneventful. On the postoperative ultrasound, we suspected that a small piece of placental tissue had been left in the uterine cavity. A hysteroscopy confirmed this and showed a normal uterine cavity. The small placental fragment regressed spontaneously on the follow-up ultrasounds. A 2-year follow-up of the patient has shown no minor or major complications. The patient has used contraception since the procedure because she has no further desire for childbearing. CONCLUSION: This new technique can help surgeons avoid a laparotomy when a hysterotomy for a failed midtrimester termination of pregnancy is required. The risk of uterine rupture in a next pregnancy needs to be taken into account. This frugally innovative technique may potentially be performed in a low-resource setting because only standard reusable laparoscopic equipment was used. PMID- 25701624 TI - Lack of seasonal and moult-related stress modulation in an opportunistically breeding bird: The white-plumed honeyeater (Lichenostomus penicillatus). AB - This article is part of a Special Issue "SBN 2014". In most vertebrate species, glucocorticoid levels and stress sensitivity vary in relation to season and life history stage. In birds, baseline corticosterone (CORT) and stress sensitivity are typically highest while breeding and decrease substantially during moult. Because elevated CORT adversely affects protein synthesis, moult-related CORT suppression is thought to be necessary for forming high-quality feathers. Surprisingly, some passerine species lack moult-related CORT suppression, but these are distinguished by having slow rates of moult and being opportunistic breeders. We examined baseline and stress-induced CORT levels in an opportunistically breeding Australian passerine, the white-plumed honeyeater (Lichenostomus penicillatus). Although this species has a slower moult rate than high-latitude breeders, it differs little from north-temperate passerines. Neither baseline nor stress-induced CORT levels varied with season (winter, spring or summer), sex or moult status in adult birds. While breeding tended to be highest in early spring through late summer, laparotomies revealed only limited reduction in testicular size in males the year round. In all but one sampling period, at least some females displayed follicular hierarchy. Breeding usually coincides with outbreaks of phytophagous insects, which can happen at any time of the year. This results in moult/breeding overlap when infestations occur in late spring or summer. The ability of this species to moult and breed at the same time while having breeding-levels of CORT demonstrates that CORT suppression is not a prerequisite for synthesis of high-quality feathers. An experimental design incorporating moulting and non-moulting phenotypes is suggested to test the functional significance of CORT suppression in other species. PMID- 25701625 TI - No-reference hair occlusion assessment for dermoscopy images based on distribution feature. AB - The presence of hair is a common quality problem for dermoscopy images, which may influence the accuracy of lesion analysis. In this paper, a novel no-reference hair occlusion assessment method is proposed according to the distribution feature of hairs in the dermoscopy image. Firstly, the image is adaptively enhanced by simple linear iterative clustering (SLIC) combined with isotropic nonlinear filtering (INF). Then, hairs are extracted from the image by an automatic threshold and meanwhile the postprocessing is used to refine the hair through re-extracting omissive hairs and filtering false hairs. Finally, the degree of hair occlusion is evaluated by an objective metric based on the hair distribution. A series of experiments was carried out on both simulated images and real images. The result shows that the proposed local adaptive hair detection method can work well on both sparse hair and dense hair, and the designed metric can effectively evaluate the degree of hair occlusion. PMID- 25701626 TI - An understanding of modified release matrix tablets behavior during drug dissolution as the key for prediction of pharmaceutical product performance - case study of multimodal characterization of quetiapine fumarate tablets. AB - Motivation for the study was the lack of dedicated and effective research and development (R&D) in vitro methods for oral, generic, modified release formulations. The purpose of the research was to assess multimodal in vitro methodology for further bioequivalence study risk minimization. Principal results of the study are as follows: (i) Pharmaceutically equivalent quetiapine fumarate extended release dosage form of Seroquel XR was developed using a quality by design/design of experiment (QbD/DoE) paradigm. (ii) The developed formulation was then compared with originator using X-ray microtomography, magnetic resonance imaging and texture analysis. Despite similarity in terms of compendial dissolution test, developed and original dosage forms differed in micro/meso structure and consequently in mechanical properties. (iii) These differences were found to be the key factors of failure of biorelevant dissolution test using the stress dissolution apparatus. Major conclusions are as follows: (i) Imaging methods allow to assess internal features of the hydrating extended release matrix and together with the stress dissolution test allow to rationalize the design of generic formulations at the in vitro level. (ii) Technological impact on formulation properties e.g., on pore formation in hydrating matrices cannot be overlooked when designing modified release dosage forms. PMID- 25701627 TI - Current trends in using polymer coated gold nanoparticles for cancer therapy. AB - The interest in using the polymer-coated gold nanoparticles (P-AuNPs) for various biomedical applications, including the delivery of chemotherapeutic in cancer has been increased in the recent years. Various biocompatible polymers, including poly(ethylene glycol), heparin, hyaluronic acid, chitosan, polystyrene sulfonate, polyethyleneimine and xanthan gum are being used for the surface decoration of AuNPs for various purposes such as to improve the stability of the NPs and the payloads, impart biocompatibility, promote long systemic circulation followed by cellular uptake to utilize the AuNPs as drug/nucleic acid delivery system for cancer therapy. This review is an attempt to elucidate various synthesis strategies explored so far, including direct synthesis, "grafting in" and "grafting from" for the preparation of the P-AuNPs. Various therapeutic applications of the P-AuNPs for cancer treatment have been illustrated. PMID- 25701628 TI - Development of anti-E6 pegylated lipoplexes for mucosal application in the context of cervical preneoplastic lesions. AB - Cervical cancer induced by human papillomavirus (HPV) is the fourth highest mortality causing cancer in women despite the use of prophylactic vaccines. E6 targeting represents an attractive strategy to treat this cancer. Indeed, oncoprotein E6 is produced by keratinocytes infected by HPV and is partially responsible for carcinogenesis. E6 interferes with the apoptosis process in stressed cells by degradation of p53 tumor suppressor gene. Our strategy consists in using E6 siRNA complexed with pegylated lipoplexes. The addition of hydrophilic polymer around the nanoparticles is crucial to use them by vaginal application on account of cervicovaginal mucus. Physicochemical characteristics were evaluated and in vitro assays were performed to evaluate transfection potential, E6 mRNA extinction and p53 re-expression. Cationic liposomes DOTAP/Cholesterol/DOPE 1/0.75/0.5 (N/P 2.5) with or without 50% DSPE-PEG2000 and associated with siE6 have demonstrated good physicochemical characteristics in terms of complexation, size, surface charge and stability. Both lipoplexes have been tested on CaSki cell line (HPV 16+) with 50 nM and 100 nM of siE6. Lipoplexes formulations induce 30-40% of E6 mRNA extinction and induce the re expression of p53. In conclusion, pegylated anti-E6 lipoplexes have demonstrated their efficiency to cross the cellular membrane and to release siRNA into the cytoplasm confirmed by final p53 protein production. PMID- 25701629 TI - The influence of residual water on the secondary structure and crystallinity of freeze-dried fibrinogen. AB - The purpose of this work was to investigate the influence of water content on the secondary structure of a freeze-dried protein (fibrinogen) after a storage period of two weeks. To that end, attenuated reflectance Fourier transformed infrared (ATR-FTIR) and Raman spectra were generated and evaluated and the crystalline state of the fibrinogen bulks was determined via X-ray diffraction. First, a PCA (principal component analysis) of the spectral data was performed. While the alpha-helix and beta-turn contents were increasing with the increasing water content, the beta-sheet content was decreasing. A partial least squares (PLS) model was developed to correlate the mid-infrared and Raman spectral changes with the degree of crystallinity. The obtained R(2) value of 0.953 confirmed a correlation between changes in the secondary structure and crystallinity of the samples. The results demonstrated that the combined ATR-FTIR and Raman approach could be used to predict the crystalline state in freeze-dried fibrinogen products. PMID- 25701630 TI - Roll compaction process modeling: transfer between equipment and impact of process parameters. AB - In this study, the roll compaction of an intermediate drug load formulation was performed using horizontally and vertically force fed roll compactors. The horizontally fed roll compactor was equipped with an instrumented roll technology allowing the direct measurement of normal stress at the roll surface, while the vertically fed roll compactor was equipped with a force gauge between the roll axes. Furthermore, characterization of ribbons, granules and tablets was also performed. Ribbon porosity was primarily found to be a function of normal stress, exhibiting a quadratic relationship thereof. A similar quadratic relationship was also observed between roll force and ribbon porosity of the vertically fed roll compactor. The predicted peak pressure (Pmax) using the Johanson model was found to be higher than the measured normal stress, however, the predicted Pmax correlated well with the ribbon relative density/porosity and the majority of downstream properties of granules and tablets, demonstrating its use as a scale independent parameter. A latent variable model was developed for both the horizontal and vertical fed roll compactors to express ribbon porosity as a function of geometric and process parameters. The model validation, performed with new data, resulted in overall good predictions. This study successfully demonstrated the scale up/transfer between two different roll compactors and revealed that the combined use of design of experiments, latent variable models and in silico predictions result in better understanding of the critical process parameters in roll compaction. PMID- 25701631 TI - Anti-angiogenic drug delivery from hydrophilic resorbable embolization microspheres: an in vitro study with sunitinib and bevacizumab. AB - Anti-angiogenic (AA) drugs are proposed as novel agents for targeted therapies in hepatocellular carcinoma (HCC). Loading of AA drugs into drug delivery systems for local delivery would reduce their side effects. The present study investigated the loading and the delivery of two AA drugs, sunitinib and bevacizumab, from one day-resorbable embolization microspheres (REM). REM were prepared with 10 or 20% of methacrylic acid (MA) as active drug binding monomer. Sterilized beads (100-300 MUm) were analyzed for cytotoxicity, AA loading and in vitro release. REM modified with MA were not cytotoxic and extemporaneous drug loading was significantly higher on REM containing 20% of MA. The drug release in saline buffer was sustained for several hours before complete REM degradation. MA content had low effect on drug release profile. When eluted from REM, sunitinib and bevacizumab reduced viability of tumoral VX2 cells, and proliferation of human endothelial cells, respectively. Deliverability of REM via microcatheter was not impaired by the loaded drugs. As conclusion, the loading values of sunitinib and bevacizumab on REM were close to those achieved for cytotoxic drugs onto non-degradable MS used in chemoembolization of HCC. Transcatheter delivery to liver tumors of anti-angiogenics could be achieved with REM. PMID- 25701632 TI - Large-scale manufacturing of GMP-compliant anti-EGFR targeted nanocarriers: production of doxorubicin-loaded anti-EGFR-immunoliposomes for a first-in-man clinical trial. AB - We describe the large-scale, GMP-compliant production process of doxorubicin loaded and anti-EGFR-coated immunoliposomes (anti-EGFR-ILs-dox) used in a first in-man, dose escalation clinical trial. 10 batches of this nanoparticle have been produced in clean room facilities. Stability data from the pre-GMP and the GMP batch indicate that the anti-EGFR-ILs-dox nanoparticle was stable for at least 18 months after release. Release criteria included visual inspection, sterility testing, as well as measurements of pH (pH 5.0-7.0), doxorubicin HCl concentration (0.45-0.55 mg/ml), endotoxin concentration (<1.21 IU/ml), leakage (<10%), particle size (Z-average of Caelyx +/- 20 nm), and particle uptake (uptake absolute: >0.50 ng doxorubicin/MUg protein; uptake relatively to PLD: >5 fold). All batches fulfilled the defined release criteria, indicating a high reproducibility as well as batch-to-batch uniformity of the main physico-chemical features of the nanoparticles in the setting of the large-scale GMP process. In the clinical trial, 29 patients were treated with this nanoparticle between 2007 and 2010. Pharmacokinetic data of anti-EGFR-ILs-dox collected during the clinical study revealed stability of the nanocarrier in vivo. Thus, reliable and GMP compliant production of anti-EGFR-targeted nanoparticles for clinical application is feasible. PMID- 25701633 TI - Diverse binding modes, same goal: The receptor recognition mechanism of botulinum neurotoxin. AB - Botulinum neurotoxins (BoNTs) are among the most deadly toxins known. They act rapidly in a highly specific manner to block neurotransmitter release by cleaving the soluble N-ethylmaleimide sensitive factor attachment protein receptor (SNARE) complex at neuromuscular junctions. The extreme toxicity of BoNTs relies predominantly on their neurotropism that is accomplished by recognition of two host receptors, a polysialo-ganglioside and in the majority of cases a synaptic vesicle protein, through their receptor-binding domains. Two proteins, synaptotagmin and synaptic vesicle glycoprotein 2, have been identified as the receptors for various serotypes of BoNTs. Here, we review recent breakthroughs in the structural studies of BoNT-protein receptor recognitions that highlight a range of diverse mechanisms by which BoNTs manipulate host neuronal proteins for highly specific uptake at neuromuscular junctions. PMID- 25701634 TI - Bacterial fitness shapes the population dynamics of antibiotic-resistant and susceptible bacteria in a model of combined antibiotic and anti-virulence treatment. AB - Bacterial resistance to antibiotic treatment is a huge concern: introduction of any new antibiotic is shortly followed by the emergence of resistant bacterial isolates in the clinic. This issue is compounded by a severe lack of new antibiotics reaching the market. The significant rise in clinical resistance to antibiotics is especially problematic in nosocomial infections, where already vulnerable patients may fail to respond to treatment, causing even greater health concern. A recent focus has been on the development of anti-virulence drugs as a second line of defence in the treatment of antibiotic-resistant infections. This treatment, which weakens bacteria by reducing their virulence rather than killing them, should allow infections to be cleared through the body's natural defence mechanisms. In this way there should be little to no selective pressure exerted on the organism and, as such, a predominantly resistant population should be less likely to emerge. However, before the likelihood of resistance to these novel drugs emerging can be predicted, we must first establish whether such drugs can actually be effective. Many believe that anti-virulence drugs would not be powerful enough to clear existing infections, restricting their potential application to prophylaxis. We have developed a mathematical model that provides a theoretical framework to reveal the circumstances under which anti-virulence drugs may or may not be successful. We demonstrate that by harnessing and combining the advantages of antibiotics with those provided by anti-virulence drugs, given infection-specific parameters, it is possible to identify treatment strategies that would efficiently clear bacterial infections, while preventing the emergence of antibiotic-resistant subpopulations. Our findings strongly support the continuation of research into anti-virulence drugs and demonstrate that their applicability may reach beyond infection prevention. PMID- 25701635 TI - Biological fitness and the Price Equation in class-structured populations. AB - Price's extended covariance selection mathematics is applied to class-structured populations with additional assumptions, to derive the 'genetic Price Equation with class structure'. Each individual belongs to a class, and there may be overlapping generations; the equation is genetic because the trait is restricted to an arbitrary weighted sum of allele frequencies. Two special cases are then considered, a demography-like case corresponding to Fisher's fundamental theorem of natural selection, and a sex-ratio-like case corresponding to Fisher's sex ratio argument: these differ in whether it is natural to assume that the per capita or the total reproductive values of each class are maintained from the parental to the descendant population. These cases also match the two existing attempts to eliminate from the effects of natural selection those passive changes in allele frequencies that are caused by the class structure, and suggest improvements in one of them. In each case a more specialised Price Equation, and a 'fundamental theorem of natural selection', are proved, which hold out of class structure equilibrium, showing that passive changes can be eliminated in more than one way, and hinting at the possibility of a more general formulation. Previous class-structured Price Equations and a 'fundamental theorem' are linked to these results. The power of Price's formal approach is vividly illustrated by this lucid conspectus of otherwise self-standing theories with confusing interconnections. PMID- 25701636 TI - Development of a walleye spleen stromal cell line sensitive to viral hemorrhagic septicemia virus (VHSV IVb) and to protection by synthetic dsRNA. AB - A cell line, WE-spleen6, has been developed from the stromal layer of primary spleen cell cultures. On conventional plastic, WE-spleen6 cells had a spindle shaped morphology at low cell density but grew to become epithelial-like at confluency. On the commercial extracellular matrix (ECM), Matrigel, the cells remained spindle-shaped and formed lumen-like structures. WE-spleen6 cells had intermediate filament protein, vimentin and the ECM protein, collagen I, but not smooth muscle alpha-actin (SMA) and von Willebrand factor (vWF) and lacked alkaline phosphatase and phagocytic activities. WE-spleen6 was more susceptible to infection with VHSV IVb than a fibroblast and epithelial cell lines from the walleye caudal fin, WE-cfin11f and WE-cfin11e, respectively. Viral transcripts and proteins appeared earlier in WE-spleen6 cultures as did cytopathic effect (CPE) and significant virus production. The synthetic double-stranded RNA (dsRNA), polyinosinic: polycytidylic acid (pIC), induced the antiviral protein Mx in both cell lines. Treating WE-spleen6 cultures with pIC prior to infection with VHSV IVb inhibited the early accumulation of viral transcripts and proteins and delayed the appearance of CPE and significant viral production. Of particular note, pIC caused the disappearance of viral P protein 2 days post infection. WE spleen6 should be useful for investigating the impact of VHSV IVb on hematopoietic organs and the actions of pIC on the rhabdovirus life cycle. PMID- 25701637 TI - Effect of an evidence-based mobility intervention on the level of function in acute intracerebral and subarachnoid hemorrhagic stroke patients on a neurointensive care unit. AB - OBJECTIVES: To explore the effect of an evidence-based mobility intervention on the level of function (LOF) achieved by patients with intracerebral hemorrhage (ICH) stroke and subarachnoid hemorrhage (SAH) stroke and to identify clinical characteristics and measures associated with walking distances >15.24m. DESIGN: Retrospective pre- and postintervention study. SETTING: Regional neurointensive care unit. PARTICIPANTS: Adult patients with ICH and SAH (N=361). INTERVENTION: Daily mobility intervention based on patient's current LOF. MAIN OUTCOME MEASURE: Walking >15.24m (LOF 5) by neurointensive care unit discharge. RESULTS: Electronic health records for 361 patients (52.6% women; mean age, 62.1y; ICH stroke, 63.2%; aphasia, 35%; hemiplegia, 33%) were included. There was a 2.3-fold increase in patients with hemorrhagic stroke achieving a LOF of 5 by neurointensive care unit discharge after introduction of a mobility intervention. In the multivariable logistic regression model including neurointensive care unit length of stay (LOS) as a covariate, the intervention, LOF of 5 at admission, SAH stroke type, third (vs lowest) quartile of neurointensive care unit LOS, and absence of aphasia and/or hemiplegia were associated with higher likelihood of achieving a LOF of 5 (odds ratio [OR]=5.28; 95% confidence interval [CI], 2.52 11.06; OR=6.02; 95% CI, 1.45-24.96; OR=3.78; 95% CI, 1.83-7.80; OR=2.94; 95% CI, 1.16-7.47; OR=17.77; 95% CI, 6.59-47.92, respectively). CONCLUSIONS: A mobility intervention was strongly associated with increased distance walked by neurointensive care unit patients with acute hemorrhage at discharge and can be applied in any intensive care unit setting to promote stroke recovery. Future studies directed at building predictive models for walking achievement in patients with acute hemorrhagic stroke may provide insight into individualized treatment goal setting and discharge planning. PMID- 25701638 TI - Receipt of physical therapy among osteoarthritis patients and its influencing factors. AB - OBJECTIVE: To explore major patient and provider characteristics influencing the receipt of physical therapy (PT) among patients newly diagnosed with osteoarthritis. DESIGN: A population-based, cross-sectional study on outpatient PT for patients newly diagnosed with osteoarthritis within the period of 2005 to 2010. SETTING: Sample of 1 million National Health Insurance enrollees. PARTICIPANTS: People aged >=18 years with an incidence of osteoarthritis and receiving initial outpatient treatment. A total of 29,012 patients were included (N=29,012). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The outcome variable of interest was the probability of receiving PT within 1 year of osteoarthritis diagnosis. Both individual and provider characteristics were investigated to determine their influence on PT receipt. RESULTS: Of the 29,012 included patients with osteoarthritis, only 24.8% of them received PT within the first year of diagnosis. Men and older adults were less likely to receive PT. In addition, low-income patients with osteoarthritis were less likely to receive PT. Furthermore, PT receipt was increased in patients treated by physicians who were women and by physicians who specialized in rehabilitation medicine. In addition, we observed a pattern indicating that the lower the accreditation level of the practice setting, the greater the probability of receiving PT. CONCLUSIONS: Because of the National Health Insurance program in Taiwan, direct medical costs of PT have been substantially reduced; however, variations are still observed among different patient and provider characteristics. The major role of providers in PT receipt for patients with osteoarthritis should not be ignored. PMID- 25701639 TI - Medical Rehabilitation in Natural Disasters: A Review. AB - OBJECTIVE: To present an evidence-based overview of the effectiveness of medical rehabilitation intervention in natural disaster survivors and outcomes that are affected. DATA SOURCES: A literature search was conducted using medical and health science electronic databases (PubMed, MEDLINE, Embase, Cumulative Index to Nursing and Allied Health Literature, Cochrane Library, PsycINFO) up to September 2014. STUDY SELECTION: Two independent reviewers selected studies reporting outcomes for natural disaster survivors after medical rehabilitation that addressed functional restoration and participation. DATA EXTRACTION: Two reviewers independently extracted data and assessed the methodologic quality of the studies using the Critical Appraisal Skills Program's appraisal tools. DATA SYNTHESIS: A meta-analysis was not possible because of heterogeneity among included trials; therefore, a narrative analysis was performed for best evidence synthesis. Ten studies (2 randomized controlled trials, 8 observational studies) investigated a variety of medical rehabilitation interventions for natural disaster survivors to evaluate best evidence to date. The interventions ranged from comprehensive multidisciplinary rehabilitation to community educational programs. Studies scored low on quality assessment because of methodologic limitations. The findings suggest some evidence for the effectiveness of inpatient rehabilitation in reducing disability and improving participation and quality of life and for community-based rehabilitation for participation. There were no data available for associated costs. CONCLUSIONS: The findings highlight the need to incorporate medical rehabilitation into response planning and disaster management for future natural catastrophes. Access to rehabilitation and investment in sustainable infrastructure and education are crucial. More methodologically robust studies are needed to build evidence for rehabilitation programs, cost-effectiveness, and outcome measurement in such settings. PMID- 25701640 TI - Barriers to activity and participation for stroke survivors in rural China. AB - OBJECTIVES: To investigate environmental barriers reported by stroke survivors in the rural areas of China and to determine the impact of environmental barriers on activity and participation relative to demographic characteristics and body functioning. DESIGN: Cross-sectional survey. SETTING: Structured interviews in the participants' homes. PARTICIPANTS: Community-dwelling stroke survivors in the rural areas of China (N=639). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Activity and participation (Chinese version of the World Health Organization Disability Assessment Schedule 2.0), environmental barriers (Craig Hospital Inventory of Environmental Factors), neurological function (Canadian Neurological Scale), cognitive function (Abbreviated Mental Test), and depression (6-item Hamilton Rating Scale for Depression). RESULTS: Physical/structural barriers are the major impediment to activity and participation for these participants (odds ratio, 1.86 and 1.99 for activity and participation, respectively; P<.01). Services/assistance barriers primarily impede participation rather than activity (odds ratio, 1.58 in participation; P<.05). CONCLUSIONS: Physical/structural and services/assistance barriers were considered the dominant barriers to activity and participation for stroke survivors in the rural areas of China. Attitudinal/support and policy barriers did not emerge as serious concerns. To generate an enabling environment, physical/structural and services/assistance barriers are the environmental barriers to be decreased and eliminated first. PMID- 25701641 TI - Predictors of long-term mortality in older people with hip fracture. AB - OBJECTIVES: To determine 1-year mortality and predisposing factors in older people who had surgery after a hip fracture. DESIGN: Prospective cohort study. SETTING: Public acute hospital, trauma service. PARTICIPANTS: Patients (N=281) aged >=65 years who were admitted to the hospital with a hip fracture from January 2009 to January 2010, and followed up for 1 year thereafter. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Cumulative survival probability up to 1 year from surgery was calculated by means of Kaplan-Meier charts, and Cox regression models were performed to analyze the factors associated with mortality. Data were collected from medical charts and by interviews. Health status was evaluated using the American Society of Anesthesiologists rating, prefracture functional level with the FIM, and cognitive status with the Pfeiffer score. RESULTS: The 1-year mortality for the 281 patients who were followed up was 21% (95% confidence interval [CI], 16.1% 25.9%). A non-weight-bearing status was associated with increased mortality in unadjusted analyses (hazard ratio [HR]=1.99; 95% CI, 1.16-3.43), but 5 other factors were identified when entered into the multiple Cox regression model: age (HR=1.05; 95% CI, 1-1.09), male sex (HR=2.92; 95% CI, 1.58-5.39), low health status (HR=2.8; 95% CI, 1.29-6.09), low prefracture function (HR=.98; 95% CI, .97 .99), and change of residence (HR=3.21; 95% CI, 1.43-7.17). CONCLUSIONS: The overall 1-year mortality rate was 21%. Change of residence is the only potentially modifiable risk factor, independent of the following other traditional risk factors that were found: age, sex, health status, and prefracture functional level. Furthermore, 2 to 4 weeks of non-weight-bearing status, which is considered modifiable, is also associated with increased mortality rates in unadjusted analyses. PMID- 25701642 TI - Oxidative stress and inflammation in mucopolysaccharidosis type IVA patients treated with enzyme replacement therapy. AB - Mucopolysaccharidosis type IVA (MPS IVA) is an inborn error of glycosaminoglycan (GAG) catabolism due to the deficient activity of N-acetylgalactosamine-6-sulfate sulfatase that leads to accumulation of the keratan sulfate and chondroitin 6 sulfate in body fluids and in lysosomes. The pathophysiology of this lysosomal storage disorder is not completely understood. The aim of this study was to investigate oxidative stress parameters, pro-inflammatory cytokine and GAG levels in MPS IVA patients. We analyzed urine and blood samples from patients under ERT (n=17) and healthy age-matched controls (n=10-15). Patients presented a reduction of antioxidant defense levels, assessed by a decrease in glutathione content and by an increase in superoxide dismutase activity in erythrocytes. Concerning lipid and protein damage, it was verified increased urine isoprostanes and di-tyrosine levels and decreased plasma sulfhydryl groups in MPS IVA patients compared to controls. MPS IVA patients showed higher DNA damage than control group and this damage had an oxidative origin in both pyrimidine and purine bases. Interleukin 6 was increased in patients and presented an inverse correlation with GSH levels, showing a possible link between inflammation and oxidative stress in MPS IVA disease. The data presented suggest that pro-inflammatory and pro-oxidant states occur in MPS IVA patients even under ERT. Taking these results into account, supplementation of antioxidants in combination with ERT can be a tentative therapeutic approach with the purpose of improving the patient's quality of life. To the best of our knowledge, this is the first study relating MPS IVA patients with oxidative stress. PMID- 25701643 TI - Authoring scientific papers: a perspective from the trenches. PMID- 25701644 TI - Identification of a DNA methylation signature in blood cells from persons with Down Syndrome. AB - Down Syndrome (DS) is characterized by a wide spectrum of clinical signs, which include segmental premature aging of central nervous and immune systems. Although it is well established that the causative defect of DS is the trisomy of chromosome 21, the molecular bases of its phenotype are still largely unknown. We used the Infinium HumanMethylation450 BeadChip to investigate DNA methylation patterns in whole blood from 29 DS persons, using their relatives (mothers and unaffected siblings) as controls. This family-based model allowed us to monitor possible confounding effects on DNA methylation patterns deriving from genetic and environmental factors. Although differentially methylated regions (DMRs) displayed a genome-wide distribution, they were enriched on chromosome 21. DMRs mapped in genes involved in developmental functions, including embryonic development (HOXA family) and haematological (RUNX1 and EBF4) and neuronal (NCAM1) development. Moreover, genes involved in the regulation of chromatin structure (PRMD8, KDM2B, TET1) showed altered methylation. The data also showed that several pathways are affected in DS, including PI3K-Akt signaling. In conclusion, we identified an epigenetic signature of DS that sustains a link between developmental defects and disease phenotype, including segmental premature aging. PMID- 25701645 TI - Post-treatment surveillance of head and neck cancer: pitfalls in the interpretation of FDG PET-CT/MRI. AB - QUESTIONS UNDER STUDY: We investigated non-malignancy-associated (18F)fluoro deoxy-D-glucose (FDG) uptake in the head and neck cancer (HNC) post-treatment follow-up with positron emission tomography - computed tomography / magnetic resonance imaging (PET-CT/MRI). A retrospective study on HNC patients undergoing follow-up or re-staging PET-CT/MRI examinations was performed. Thereby, FDG positive regions were morphologically correlated to the CT and MRI images and a statement regarding tumour persistence/recurrence. METHODS: FDG-positive lesions were assessed according to their anatomical localisation and categorised as true positive, true negative, false positive or false negative findings. The gold standard for verification of an FDG-positive lesion was the cytological or histopathological examination of the region of interest. The most likely aetiology was assessed according to the following categories: (1.) physiological uptake (2.) post-surgical, inflammatory uptake, (3.) post-irradiation, inflammatory uptake and (4.) reactive, not otherwise specified. RESULTS: Tumour recurrence / tumour persistence was found in 14/87 patients (16.1%). A total of 159 non-malignancy-associated FDG-positive lesions were found. Every PET-CT/MRI examination revealed 2.1 +/- 1.5 FDG-positive lesions in the head and neck. A total of 107 FDG-positive lesions (67.3%) were categorised as physiological, 52 FDG-positive lesions (32.7%) as inflammatory (post-surgical: n = 14, 8.8%; post irradiation: n = 9, 5.7%; reactive, not otherwise specified: n = 29, 18.2%). Eight patients (11.8%) underwent invasive diagnostic procedures to clarify indistinct findings. CONCLUSIONS: Post-treatment follow-up of HNC patients requires interdisciplinary management and familiarity with the patient's past medical history. Awareness of common confounders of FDG positivity often allows clarification of indistinct lesions. However, a substantial number of approximately 12% of FDG-positive lesions remain unclear unless invasive diagnostic procedures are performed. PMID- 25701646 TI - Combining polyethylenimine and Fe(III) for mediating pDNA transfection. AB - BACKGROUND: The potential use of Fe(III) ions in biomedical applications may predict the interest of its combination with pDNA-PEI polyplexes. The present work aims at assessing the impact of this metal on pDNA complex properties. METHODS: Variations in the formation of complexes were imposed by using two types of biological buffers at different salt conditions. The incorporation of pDNA in complexes was characterised by gel electrophoresis and dynamic light scattering. Transfection efficiency and cytotoxicity were evaluated in HeLa and HUH-7 cell lines, supported by flow cytometry assays. RESULTS: Fe(III) enhances pDNA incorporation in the complex, irrespective of the buffer used. Transfection studies reveal that the addition of Fe(III) to complexes at low ionic strength reduces gene transfection, while those prepared under high salt content do not affect or, in a specific case, increase gene transfection up to 5 times. This increase may be a consequence of a favoured interaction of polyplexes with cell membrane and uptake. At low salt conditions, results attained with chloroquine indicate that the metal may inhibit polyplex endosomal escape. A reduction on the amount of PEI (N/P 5) formed at intermediary ionic strength, complemented by Fe(III), reduces the size of complexes while maintaining a transfection efficiency similar to that obtained to N/P 6. CONCLUSIONS: Fe(III) emerges as a good supporting condensing agent to modulate pDNA-PEI properties, including condensation, size and cytotoxicity, without a large penalty on gene transfection. GENERAL SIGNIFICANCE: This study highlights important aspects that govern pDNA transfection and elucidates the benefits of incorporating the versatile Fe(III) in a gene delivery system. PMID- 25701647 TI - Influence of horizontally curved roadway section characteristics on motorcycle-to barrier crash frequency. AB - The purpose of this study was to investigate motorcycle-to-barrier crash frequency on horizontally curved roadway sections in Washington State using police-reported crash data linked with roadway data and augmented with barrier presence information. Data included 4915 horizontal curved roadway sections with 252 of these sections experiencing 329 motorcycle-to-barrier crashes between 2002 and 2011. Negative binomial regression was used to predict motorcycle-to-barrier crash frequency using horizontal curvature and other roadway characteristics. Based on the model results, the strongest predictor of crash frequency was found to be curve radius. This supports a motorcycle-to-barrier crash countermeasure placement criterion based, at the very least, on horizontal curve radius. With respect to the existing horizontal curve criterion of 820 feet or less, curves meeting this criterion were found to increase motorcycle-to-barrier crash frequency rate by a factor of 10 compared to curves not meeting this criterion. Other statistically significant predictors were curve length, traffic volume and the location of adjacent curves. Assuming curves of identical radius, the model results suggest that longer curves, those with higher traffic volume, and those that have no adjacent curved sections within 300 feet of either curve end would likely be better candidates for a motorcycle-to-barrier crash countermeasure. PMID- 25701648 TI - Causes and risk factors for fatal accidents in non-commercial twin engine piston general aviation aircraft. AB - Accidents in twin-engine aircraft carry a higher risk of fatality compared with single engine aircraft and constitute 9% of all general aviation accidents. The different flight profile (higher airspeed, service ceiling, increased fuel load, and aircraft yaw in engine failure) may make comparable studies on single-engine aircraft accident causes less relevant. The objective of this study was to identify the accident causes for non-commercial operations in twin engine aircraft. A NTSB accident database query for accidents in twin piston engine airplanes of 4-8 seat capacity with a maximum certified weight of 3000-8000lbs. operating under 14CFR Part 91 for the period spanning 2002 and 2012 returned 376 accidents. Accident causes and contributing factors were as per the NTSB final report categories. Total annual flight hour data for the twin engine piston aircraft fleet were obtained from the FAA. Statistical analyses employed Chi Square, Fisher's Exact and logistic regression analysis. Neither the combined fatal/non-fatal accident nor the fatal accident rate declined over the period spanning 2002-2012. Under visual weather conditions, the largest number, n=27, (27%) of fatal accidents was attributed to malfunction with a failure to follow single engine procedures representing the most common contributing factor. In degraded visibility, poor instrument approach procedures resulted in the greatest proportion of fatal crashes. Encountering thunderstorms was the most lethal of all accident causes with all occupants sustaining fatal injuries. At night, a failure to maintain obstacle/terrain clearance was the most common accident cause leading to 36% of fatal crashes. The results of logistic regression showed that operations at night (OR 3.7), off airport landings (OR 14.8) and post-impact fire (OR 7.2) all carried an excess risk of a fatal flight. This study indicates training areas that should receive increased emphasis for twin-engine training/recency. First, increased training should be provided on single engine procedures in the event of an engine failure. Second, more focus should be placed on instrument approaches and recovery from unusual aircraft attitude where visibility is degraded. Third, pilots should be made aware of appropriate speed selection for inadvertent flights in convective weather. Finally, emphasizing the importance of conducting night operations under instrument flight rules with its altitude restrictions should lead to a diminished proportion of accidents attributed to failure to maintain obstacle/terrain clearance. PMID- 25701649 TI - The rodent malaria lactate dehydrogenase assay provides a high throughput solution for in vivo vaccine studies. AB - Rodent malaria is a useful model for evaluating the efficacy of malaria vaccine candidates; however, labor-intensive microscopic parasite counting hampers the use of an in vivo parasite challenge in high-throughput screening. The measurement of malaria parasite lactate dehydrogenase (pLDH) activity, which is commonly used in the in vitro growth inhibition assay of Plasmodium falciparum, may be the cheapest and simplest alternative to microscopic parasite counting. However, the pLDH assay has not been applied in the in vivo rodent malaria model. Here, we showed that the pLDH assay is reliable and accurately determines parasitemia in the rodent malaria model. pLDH activity measured using a chromogenic substrate reflects the parasite number in the blood; it allows fast and easy assessment using a conventional microplate reader. To validate this approach, we synthesized recombinant PyMSP1-19 protein (rPyMSP1-19) using a wheat germ cell-free protein synthesis system and immunized mice with rPyMSP1-19. The antisera showed specific reactivity on the surface of the Plasmodium yoelii merozoite and immunized mice were protected against a lethal P. yoelii 17 XL challenge. The pLDH assay quickly and easily demonstrated a significant reduction of the parasite numbers in the immunized mice. Accordingly, the pLDH assay proved to be an efficient alternative to rodent malaria parasite counting, and may therefore accelerate in vivo vaccine candidate screening. PMID- 25701650 TI - BMP-1/tolloid-like proteinases synchronize matrix assembly with growth factor activation to promote morphogenesis and tissue remodeling. AB - Bone morphogenetic protein-1 (BMP-1)/tolloid-like proteinases, here called BTPs, include the proteases originally identified for their roles in the C-terminal maturation of fibrillar procollagens ("procollagen C-proteinase"). Though numerous other substrates have since been discovered, the BTPs remain the main proteases involved in extracellular matrix assembly with little or no implication in matrix degradation. During the same period however, the BTPs have also become established as important proteases in the activation of growth factors, including TGF-beta1, BMP-2/-4, GDF-8/-11 and IGFs, as well as the release of anti angiogenic fragments from parent proteins. The BTPs are therefore key players in many pathophysiological processes such as morphogenesis, tissue repair and tumor progression. This mini-review summarizes our current knowledge of the functions of BTPs, their substrates and unusual mechanisms of regulation, and discusses their potential as new targets for future therapies. PMID- 25701651 TI - Extracellular regulation of metalloproteinases. AB - Matrix metalloproteinases (MMPs) and adamalysin-like metalloproteinase with thrombospondin motifs (ADAMTSs) belong to the metzincin superfamily of metalloproteinases and they play key roles in extracellular matrix catabolism, activation and inactivation of cytokines, chemokines, growth factors, and other proteinases at the cell surface and within the extracellular matrix. Their activities are tightly regulated in a number of ways, such as transcriptional regulation, proteolytic activation and interaction with tissue inhibitors of metalloproteinases (TIMPs). Here, we highlight recent studies that have illustrated novel mechanisms regulating the extracellular activity of these enzymes. These include allosteric activation of metalloproteinases by molecules that bind outside the active site, modulation of location and activity by interaction with cell surface and extracellular matrix molecules, and endocytic clearance from the extracellular milieu by low-density lipoprotein receptor related protein 1 (LRP1). PMID- 25701652 TI - Establishment and development of the personalized criteria for microscopic review following multiple automated routine urinalysis systems. AB - BACKGROUND: This study intends to develop the microscopic review criteria for automated urine chemistry analyzer and integrated urine chemistry and formed element analyzer. METHODS: A total of 1058 samples were analyzed using chemistry analyzer (Siemens Atlas) for proteins (PRO), blood (BLD) and WBC. Cast, RBC and WBC were analyzed using 4 different instruments, IRIS IQ200, AVE-766, US 2026, and Sysmex UF-1000i. A phase-contrast microscopy was used as reference to evaluate false-negative rate (FNR) and review rate (RR). RESULTS: The optimized review criteria for Atlas were either PRO 2+, or BLD 2+, or WBC 2+, or specimen from nephrology department. FNR was 4.65% and RR was 40.41%. The optimized criteria for integrated Atlas and IQ200, or AVE-766 or US 2026 or UF-1000i were either BLD>=2+ (>2+ for females), or RBC count >= 2 times reference range, or different WBC results between chemistry and formed-element analysis, or PRO >= 2+ or CAST>the reference range. One additional rule for integrated Atlas and UF 1000i was different results between BLD and RBC counts. FNR was 1.94%, 2.03%, 1.74%, 1.65%, and RR was 41.09%, 40.12%, 44.86%, 50.39%, respectively. CONCLUSIONS: These specific review criteria ensured a low missed-diagnosis rate and a reasonable workload in practice. PMID- 25701653 TI - Fragment profiling of low molecular weight heparins using reversed phase ion pair liquid chromatography-electrospray mass spectrometry. AB - Low molecular weight heparins (LMWHs) are linear and highly charged carbohydrate polymers prepared by chemical or enzymatic depolymerization of heparin. Compared to unfractionated heparin (UFH), LMWHs are prevalently used as clinical anticoagulant drugs due to their lower side effects and better bioavailability. The work presented herein provides a rapid and powerful fragment mapping method for structural characterization of LMWHs. The chain fragments of two types of LMWHs, enoxaparin and nadroparin, were generated by controlled enzymatic digestion with each of heparinase I (Hep I, Enzyme Commission (EC) # 4.2.2.7), heparinase II (Hep II, no EC # assigned) and heparinase III (Hep III, EC # 4.2.2.8). Reversed phase ion pair high performance liquid chromatography (RPIP HPLC) coupled with electrospray ion trap time-of-flight mass spectrometry (ESI-IT TOF-MS) was used to profile the oligosaccharide chains ranging from disaccharides to decasaccharides. A database containing all theoretical structural compositions was established to assist the mass spectra interpretation. The six digests derived by three enzymes from two types of LMWHs exhibited distinguishable fingerprinting patterns. And a total of 94 enoxaparin fragments and 109 nadroparin fragments were detected and identified. Besides the common LMWH oligosaccharides, many components containing characteristic LMWH structures such as saturated L-idopyranosuronic acid, 2,5-anhydro-D-mannitol, 1,6-anhydro-D aminopyranose, as well as odd number oligosaccharides were also revealed. Quantitative comparison of major components derived from innovator and generic nadroparin products was presented. This approach to profile LMWHs' fragments offers a highly reproducible, high resolution and information-rich tool for evaluating the quality of this category of anticoagulant drugs or comparing structural similarities among samples from various sources. PMID- 25701654 TI - Epigallocatechin-3-gallate pretreatment attenuates doxorubicin-induced cardiotoxicity in rats: A mechanistic study. AB - Doxorubicin (DOX) is a widely used chemotherapeutic agent however its clinical use is limited by cumulative cardiotoxicity. Epigallocatechin-3-gallate (EGCG), a main catechin in green tea, possesses a potent antioxidant, anti-apoptotic and anticancer properties. The current study aimed to investigate the potential protective effect of EGCG against DOX-induced cardiotoxicity. Firstly the potential cardioprotective dose of EGCG was screened at different doses (10, 20 and 40 mg/kg/day) against a single dose of DOX (15 mg/kg; i.p.). EGCG protected against DOX-induced ECG changes, leakage of cardiac enzymes (creatine kinase isoenzyme-MB, and lactate dehydrogenase) and histopathological changes. The dose of 40 mg/kg EGCG was selected for further assessment to address the EGCG cardioprotective mechanisms. EGCG was given orally 3 times/week for 4 consecutive weeks and DOX (2.5 mg/kg; i.p.) 3 times/week on the last 2 weeks. EGCG significantly ameliorated oxidative stress injury evoked by DOX as evidenced by inhibition of reduced glutathione depletion and lipid peroxidation as well as elevation of antioxidant enzyme activities. DOX caused down-regulation of ErbB2 expression while EGCG pretreatment significantly increased ErbB2 expression indicating its effect on pro-survival pathway. Furthermore, DOX provoked apoptotic responses evidenced by increasing the expression of nuclear factor kappa-B, tumor suppressor protein p53, calpain 2, caspases 3 and 12. Additionally basal level of Hsp70 was reduced in DOX-intoxicated group. EGCG pretreatment significantly ameliorated these apoptotic signals indicating its anti inflammatory and anti-apoptotic actions. In conclusion, EGCG possesses cardioprotective action against DOX-induced cardiotoxicity by suppressing oxidative stress, inflammation and apoptotic signals as well as activation of pro survival pathways. PMID- 25701655 TI - Have recent investigations into remission from childhood asthma helped in understanding the pathogenesis of this disease? AB - Studies show that a significant proportion of young people suffering from childhood onset asthma later recovered, usually in adolescence. In this article we argue that an understanding of the differences between children who recover from asthma and those who do not would contribute to increased understanding of the pathogenic mechanisms of the disease and could provide new clues about prevention and treatment. We note that some researchers have recently published results from these kinds of investigations. This paper reports results regarding genetic determinants, distorted mechanisms of inflammation, and mind/body relationships. We also try to integrate findings from these 3 areas to formulate general conclusions about the pathogenesis of asthma. PMID- 25701656 TI - Perinatal mental health service provision in Switzerland and in the UK. AB - QUESTIONS UNDER STUDY: The epidemiology of maternal perinatal-psychiatric disorders as well as their effect on the baby is well recognised. Increasingly well researched specialised treatment methods can reduce maternal morbidity, positively affect mother-baby bonding and empower women's confidence as a mother. Here, we aimed to compare guidelines and the structure of perinatal-psychiatric service delivery in the United Kingdom and in Switzerland from the government's perspective. METHODS: Swiss cantons provided information regarding guidelines and structure of service delivery in 2000. A subsequent survey using the same questionnaire was carried out in 2007. In the UK, similar information was accessed through published reports from 2000-2012. RESULTS: Guidelines for perinatal psychiatry exist in the UK, whereas in Switzerland in 2000 none of the 26 cantons had guidelines, and in 2007 only one canton did. Joint mother-baby admissions on general psychiatric wards were offered by 92% of the Swiss cantons. In the UK, pregnant women and joint mother-baby admissions are only advised onto specialised perinatal-psychiatric units. In Switzerland, in 2007, three specialised units (max. 24 beds) were in place corresponding to 1 unit per 2.5 million people, while in the UK there were 22 mother-baby units (168 beds) in 2012 (1 unit per 2.8 million). In the UK, less than 50% of trusts provided specialised perinatal-psychiatric health care. CONCLUSIONS: The main difference between the UK and Switzerland was the absence of guidelines, regular assessment and plans for future development of perinatal psychiatry in Switzerland. There are still geographical differences in the provision of perinatal-psychiatric services in the UK. PMID- 25701657 TI - Function coupling of otoferlin with GAD65 acts to modulate GABAergic activity. AB - Otoferlin, an integral membrane protein implicated in a late stage of exocytosis, has been reported to play a critical role in hearing although the underlying mechanisms remain elusive. However, its widespread tissue distribution infers a more ubiquitous role in synaptic vesicle trafficking. Glutamate, an excitatory neurotransmitter, is converted to its inhibitory counterpart, gamma-aminobutyric acid (GABA), by L-glutamic acid decarboxylase (GAD), which exists in soluble (GAD67) and membrane-bound (GAD65) forms. For the first time, we have revealed a close association between otoferlin and GAD65 in both HEK293 and neuronal cells, including SH-SY5Y neuroblastoma and primary rat hippocampus cells, showing a direct interaction between GAD65 and otoferlin's C2 domains. In primary rat hippocampus cells, otoferlin and GAD65 co-localized in a punctate pattern within the cell body, as well as in the axon along the path of vesicular traffic. Significantly, GABA is virtually abolished in otoferlin-knockdown neuronal cells whereas otoferlin overexpression markedly increases endogenous GABA. GABA attenuation in otoferlin-knockdown primary cells is correlated with diminished L type calcium current. This previously unknown and close correlation demonstrates that otoferlin, through GAD65, modulates GABAergic activity. The discovery of otoferlin-GAD65 functional coupling provides a new avenue for understanding the molecular mechanism by which otoferlin functions in neurological pathways. PMID- 25701658 TI - Analysis of higher education policy frameworks for open and distance education in Pakistan. AB - BACKGROUND: The constant rise in demand for higher education has become the biggest challenge for educational planners. This high demand has paved a way for distance education across the globe. OBJECTIVES: This article innovatively analyzes the policy documentation of a major distance education initiative in Pakistan for validity that will identify the utility of policy linkages. RESEARCH DESIGN: The study adopted a qualitative research design that consisted of two steps. In the first step, a content analysis of distance learning policy framework was made. For this purpose, two documents were accessed titled "Framework for Launching Distance Learning Programs in HEIs of Pakistan" and "Guideline on Quality of Distance Education for External Students at the HEIs of Pakistan." In the second step, the policy guidelines mentioned in these two documents were evaluated at two levels. At the first level, the overall policy documents were assessed against a criterion proposed by Cheung, Mirzaei, and Leeder. At the second level, the proposed program of distance learning was assessed against a criterion set by Gellman-Danley and Fetzner and Berge. CONCLUSION: The distance education program initiative in Pakistan is of promising nature which needs to be assessed regularly. This study has made an initial attempt to assess the policy document against a criterion identified from literature. The analysis shows that the current policy documents do offer some strengths at this initial level, however, they cannot be considered a comprehensive policy guide. The inclusion or correction of missing or vague areas identified in this study would make this policy guideline document a treasured tool for Higher Education Commission (HEC). For distance education policy makers, this distance education policy framework model recognizes several fundamental areas with which they should be concerned. The findings of this study in the light of two different policy framework measures highlight certain opportunities that can help strengthening the distance education policies. The criteria and findings are useful for the reviewers of policy proposals to identify the gaps where policy documents can be improved to bring the desired outcomes. PMID- 25701659 TI - Glycosaminoglycan sulfation determines the biochemical properties of prion protein aggregates. AB - Prion diseases are transmissible neurodegenerative disorders associated with the conversion of the cellular prion protein, PrP(C), to a misfolded isoform called PrP(Sc). Although PrP(Sc) is a necessary component of the infectious prion, additional factors, or cofactors, have been shown to contribute to the efficient formation of transmissible PrP(Sc). Glycosaminoglycans (GAGs) are attractive cofactor candidates as they can be found associated with PrP(Sc) deposits, have been shown to enhance PrP misfolding in vitro, are found in the same cellular compartments as PrP(C) and have been shown to be disease modifying in vivo. Here we investigated the effects of the sulfated GAGs, heparin and heparan sulfate (HS), on disease associated misfolding of full-length recombinant PrP. More specifically, the degree of sulfation of these molecules was investigated for its role in modulating the disease-associated characteristics of PrP. Both heparin and HS induced a beta-sheet conformation in recombinant PrP that was associated with the formation of aggregated species; however, the biochemical properties of the aggregates formed in the presence of heparin or HS varied in solubility and protease resistance. Furthermore, these properties could be modified by changes in GAG sulfation, indicating that subtle changes in the properties of prion disease cofactors could initiate disease associated misfolding. PMID- 25701660 TI - Challenges of Providing End-of-Life Care for Homeless Veterans. AB - OBJECTIVE: To describe challenges of caring for homeless veterans at end of life (EOL) as perceived by Veterans Affairs Medical Center (VAMC) homeless and EOL care staff. DESIGN: E-mail survey. SETTING/PARTICIPANTS: Homelessness and EOL programs at VAMCs. MEASUREMENTS: Programs and their ratings of personal, structural, and clinical care challenges were described statistically. Homelessness and EOL program responses were compared in unadjusted analyses and using multivariable models. RESULTS: Of 152 VAMCs, 50 (33%) completed the survey. The VAMCs treated an average of 6.5 homeless veterans at EOL annually. Lack of appropriate housing was the most critical challenge. The EOL programs expressed somewhat more concern about lack of appropriate care site and care coordination than did homelessness programs. CONCLUSIONS: Personal, clinical, and structural challenges face care providers for veterans who are homeless at EOL. Deeper understanding of these challenges will require qualitative study of homeless veterans and care providers. PMID- 25701661 TI - Palliative Sedation at the End of Life: Patterns of Use in an Israeli Hospice. AB - Palliative sedation (PS) is indicated for refractory symptoms among dying patients. This retrospective descriptive study examines PS in an Israeli hospice. Palliative sedation was defined as PS to unconsciousness (PSU), PS proportionate to symptoms (proportional palliative sedation [PPS]), or intermittent PS (IPS). Among 179 patients who died during 2012, PS was used among 21.2% (n = 38): (PSU 34.2%, PPS 34.2%, and IPS 31.6%), using midazolam (n = 33/38), halidol (21/38), and concurrent morphine (n = 35/38). Indications included agitation (71%), pain (36.8%), and dyspnea (21%). Survival following initiation of PS was 73 +/- standard deviation 54 hours. No differences in survival were observed according to who initiated the decision to use PS (patients/medical staff/family) or type of PS (PSU/PPS/IPS). Survival following PS was longest with higher sedative doses, an observation that may help dispel fears concerning the use of PS to hasten death. PMID- 25701662 TI - Therapeutic futility in cancer patients at the time of palliative care transition: An analysis with a modified version of the Medication Appropriateness Index. AB - BACKGROUND: Palliative Care professionals are often confronted with therapeutic futility, consisting in inappropriate strategies that do not add any advantage to the patient and may actually increase adverse events. Scientific literature concerning this issue is lacking. This article is one of the first to study therapeutic futility specifically at the time of transition to the palliative care setting. AIM: To study the phenomenon of pharmacologic therapeutic futility at the time of transition of a cancer patient to palliative care. DESIGN: The pharmacological prescriptions at the time of the first appointment at an oncological palliative care unit during a time period of 2 months were prospectively collected and characterized using the Medication Appropriateness Index. PARTICIPANTS: The sample comprised 71 patients with a mean age of 68.2 years. RESULTS: The most common pharmacological groups were analgesics (n = 121; 19.2%), psychoactive drugs (n = 89; 14.1%), and antihypertensives (n = 51; 8.1%). A total of 61 patients (85.9%) consumed 5 drugs or more at the time of the first appointment. The mean number of daily medications decreased significantly after the palliative care team intervention, from 7.15 to 5.73 (p < 0.05). The principal causes of inappropriateness were absence of indication for the drug (23.0% "inappropriate"), the drugs' adverse interactions (11.1%), and inadequate dosage (9.9%). After the first consultation in the palliative care setting, 28.2% of the drugs were suspended. CONCLUSION: This article tried to evaluate the main causes of therapeutic futility at the palliative care transition. The principal causes of inappropriateness were absence of clinical indication, clinically significant drug-disease/comorbidity interactions, and incorrect dosage/posology. PMID- 25701663 TI - Mindfulness-Based Stress Reduction for lung cancer patients and their partners: Results of a mixed methods pilot study. AB - BACKGROUND: Lung cancer patients and partners show high rates of impaired quality of life and heightened distress levels. Mindfulness-Based Stress Reduction has proven to be effective in reducing psychological distress in cancer patients. However, studies barely included lung cancer patients. AIM: We examined whether Mindfulness-Based Stress Reduction might be a feasible and effective intervention for patients with lung cancer and partners. DESIGN: Mindfulness-Based Stress Reduction is a training in which mindfulness practices are combined with psycho education to help participants cope with distress. In this mixed methods pilot study, questionnaires on psychological distress and quality of life were administered before, directly after and 3 months after the Mindfulness-Based Stress Reduction training, in combination with semi-structured interviews. SETTING/PARTICIPANTS: Patients with lung cancer and partners were recruited at one tertiary care academic medical centre. A total of 19 lung cancer patients and 16 partners participated in the Mindfulness-Based Stress Reduction training. RESULTS: Most patients were diagnosed with advanced stage lung cancer. Vast majority completed the training. Those receiving anti-cancer treatment did not miss more sessions than patients who were not currently treated. Patients and partners felt positive about participating in a peer group and with their partner. Among participants no significant changes were found in psychological distress. Caregiver burden in partners decreased significantly after following Mindfulness-Based Stress Reduction. The qualitative analysis showed that the training seemed to instigate a process of change in participants. CONCLUSION: The Mindfulness-Based Stress Reduction training seemed to be feasible for patients with lung cancer and their partners. A randomized controlled trial is needed to examine the effectiveness of Mindfulness-Based Stress Reduction in reducing psychological distress in lung cancer patients and partners. PMID- 25701664 TI - Hemoglobin S and C affect protein export in Plasmodium falciparum-infected erythrocytes. AB - Malaria is a potentially deadly disease. However, not every infected person develops severe symptoms. Some people are protected by naturally occurring mechanisms that frequently involve inheritable modifications in their hemoglobin. The best studied protective hemoglobins are the sickle cell hemoglobin (HbS) and hemoglobin C (HbC) which both result from a single amino acid substitution in beta-globin: glutamic acid at position 6 is replaced by valine or lysine, respectively. How these hemoglobinopathies protect from severe malaria is only partly understood. Models currently proposed in the literature include reduced disease-mediating cytoadherence of parasitized hemoglobinopathic erythrocytes, impaired intraerythrocytic development of the parasite, dampened inflammatory responses, or a combination thereof. Using a conditional protein export system and tightly synchronized Plasmodium falciparum cultures, we now show that export of parasite-encoded proteins across the parasitophorous vacuolar membrane is delayed, slower, and reduced in amount in hemoglobinopathic erythrocytes as compared to parasitized wild type red blood cells. Impaired protein export affects proteins targeted to the host cell cytoplasm, Maurer's clefts, and the host cell plasma membrane. Impaired protein export into the host cell compartment provides a mechanistic explanation for the reduced cytoadherence phenotype associated with parasitized hemoglobinopathic erythrocytes. PMID- 25701666 TI - Plk4-dependent phosphorylation of STIL is required for centriole duplication. AB - Duplication of centrioles, namely the formation of a procentriole next to the parental centriole, is regulated by the polo-like kinase Plk4. Only a few other proteins, including STIL (SCL/TAL1 interrupting locus, SIL) and Sas-6, are required for the early step of centriole biogenesis. Following Plk4 activation, STIL and Sas-6 accumulate at the cartwheel structure at the initial stage of the centriole assembly process. Here, we show that STIL interacts with Plk4 in vivo. A STIL fragment harboring both the coiled-coil domain and the STAN motif shows the strongest binding affinity to Plk4. Furthermore, we find that STIL is phosphorylated by Plk4. We identified Plk4-specific phosphorylation sites within the C-terminal domain of STIL and show that phosphorylation of STIL by Plk4 is required to trigger centriole duplication. PMID- 25701665 TI - Characterisation of detergent-insoluble membranes in pollen tubes of Nicotiana tabacum (L.). AB - Pollen tubes are the vehicle for sperm cell delivery to the embryo sac during fertilisation of Angiosperms. They provide an intriguing model for unravelling mechanisms of growing to extremes. The asymmetric distribution of lipids and proteins in the pollen tube plasma membrane modulates ion fluxes and actin dynamics and is maintained by a delicate equilibrium between exocytosis and endocytosis. The structural constraints regulating polarised secretion and asymmetric protein distribution on the plasma membrane are mostly unknown. To address this problem, we investigated whether ordered membrane microdomains, namely membrane rafts, might contribute to sperm cell delivery. Detergent insoluble membranes, rich in sterols and sphingolipids, were isolated from tobacco pollen tubes. MALDI TOF/MS analysis revealed that actin, prohibitins and proteins involved in methylation reactions and in phosphoinositide pattern regulation are specifically present in pollen tube detergent insoluble membranes. Tubulins, voltage-dependent anion channels and proteins involved in membrane trafficking and signalling were also present. This paper reports the first evidence of membrane rafts in Angiosperm pollen tubes, opening new perspectives on the coordination of signal transduction, cytoskeleton dynamics and polarised secretion. PMID- 25701667 TI - Authorship in scientific publications: analysis and recommendations. AB - In 2008, a Swiss Academies of Arts and Sciences working group chaired by Professor Emilio Bossi issued a "Memorandum on scientific integrity and the handling of misconduct in the scientific context", together with a paper setting out principles and procedures concerning integrity in scientific research. In the Memorandum, unjustified claims of authorship in scientific publications are referred to as a form of scientific misconduct - a view widely shared in other countries. In the Principles and Procedures, the main criteria for legitimate authorship are specified, as well as the associated responsibilities. It is in fact not uncommon for disputes about authorship to arise with regard to publications in fields where research is generally conducted by teams rather than individuals. Such disputes may concern not only the question who is or is not to be listed as an author but also, frequently, the precise sequence of names, if the list is to reflect the various authors' roles and contributions. Subjective assessments of the contributions made by the individual members of a research group may differ substantially. As scientific collaboration - often across national boundaries - is now increasingly common, ensuring appropriate recognition of all parties is a complex matter and, where disagreements arise, it may not be easy to reach a consensus. In addition, customs have changed over the past few decades; for example, the practice of granting "honorary" authorship to an eminent researcher - formerly not unusual - is no longer considered acceptable. It should be borne in mind that the publications list has become by far the most important indicator of a researcher's scientific performance; for this reason, appropriate authorship credit has become a decisive factor in the careers of young researchers, and it needs to be managed and protected accordingly. At the international and national level, certain practices have therefore developed concerning the listing of authors and the obligations of authorship. The Scientific Integrity Committee of the Swiss Academies of Arts and Sciences has collated the relevant principles and regulations and formulated recommendations for authorship in scientific publications. These should help to prevent authorship disputes and offer guidance in the event of conflicts. PMID- 25701668 TI - A meta-analysis on age-associated changes in blood DNA methylation: results from an original analysis pipeline for Infinium 450k data. AB - Aging is characterized by a profound remodeling of the epigenetic architecture in terms of DNA methylation patterns. To date the most effective tool to study genome wide DNA methylation changes is Infinium HumanMethylation450 BeadChip (Infinium 450k). Despite the wealth of tools for Infinium 450k analysis, the identification of the most biologically relevant DNA methylation changes is still challenging. Here we propose an analytical pipeline to select differentially methylated regions (DMRs), tailored on microarray architecture, which is highly effective in highlighting biologically relevant results. The pipeline groups microarray probes on the basis of their localization respect to CpG islands and genic sequences and, depending on probes density, identifies DMRs through a single-probe or a region-centric approach that considers the concomitant variation of multiple adjacent CpG probes. We successfully applied this analytical pipeline on 3 independent Infinium 450k datasets that investigated age associated changes in blood DNA methylation. We provide a consensus list of genes that systematically vary in DNA methylation levels from 0 to 100 years and that have a potentially relevant role in the aging process. PMID- 25701669 TI - Promoting apoptosis of neutrophils and phagocytosis by macrophages: novel strategies in the resolution of inflammation. AB - Acute inflammation is the body's response to infection or injury, characterised by the rapid infiltration of polymorphonuclear neutrophils to the site of injury followed by monocytes, which differentiate locally into macrophages. The latter are essential for the removal of effete neutrophils and provided that the harmful agent is eliminated, removal of neutrophils will lead to the resolution of inflammation. Perturbations in this process result in the persistence of inflammation and close control of pathways associated with resolution are necessary to avoid chronic inflammation, autoimmunity, or both. As our understanding of these processes increase, drugs able to trigger pro-resolution pathways may represent an effective strategy for treating chronic inflammatory diseases. PMID- 25701670 TI - Accuracy of doctors' anthropometric measurements in general practice. AB - PURPOSE: There is increasing pressure on general practitioners (GPs) to identify patients with abdominal obesity in order to reduce the life-threatening consequences of this condition in the population. We aimed to confirm previous findings on the inaccuracy of anthropometric measurements performed by GPs in an academic primary care clinic and to assess the effect of theoretical training to improve the quality of these measurements. METHODS: This cross-sectional study involved 26 GPs from private practices in Geneva, Switzerland. They were asked to measure weight, height, waist and hip circumference on ten volunteers within their practice. Two trained research assistants repeated the measurementss after the GPs ("gold standard"). The GPs were then randomised to receive information detailing the correct method for taking measurements (intervention, 14 doctors) or simple information about obesity (control, 12 doctors). Measurements were repeated a few weeks later. Measurement error was computed by comparing the GPs' values with the average value of two measurements taken in turn by the research assistants, and agreement was examined by Bland-Altman plots. The GPs' skills were assessed through auto-questionnaire and direct observation. RESULTS: All measurements except height were prone to measurement error, the least affected being weight (and therefore body mass index [BMI]). Following training, measurement errors were slightly less prominent in the intervention group. GPs' skills in measuring waist and hip circumference were frequently assessed as inadequate, but showed improvement after training. CONCLUSIONS: Without proper training, priority should be given to using classical anthropometric measurements (i.e. weight, height and BMI determination) in daily practice. PMID- 25701671 TI - Acceptability of human papillomavirus vaccines among women older than 26 years. AB - OBJECTIVE: To examine older women's (>26 years) acceptance of the human papillomavirus (HPV) vaccine, and factors associated with this outcome. STUDY DESIGN: A convenience sample of 872 women age 26-77 years were surveyed regarding the likelihood they would accept the HPV vaccine if offered to them by their provider, and factors associated with this outcome. Binomial regression, Chi square and MacNemar's analyses were used to determine associations of this outcome with demographic, attitudinal, and experiential variables. RESULTS: The response rate was 60.8%. Half the respondents indicated they would want the vaccine, even if they had to pay for it. In multivariable analyses, the only factor associated with wanting the vaccine was higher self-reported knowledge about HPV (risk ratio 1.43, 95% Confidence Interval 1.12, 1.83). A majority of participants also believed that older women in general would want the vaccine if it were covered by insurance. However, this perspective was significantly diminished if the vaccine had to be paid for out of pocket (97% vs. 22% for 26-45 year olds; 84% vs. 20% for 46-65 year olds, 60% vs. 8% for 66+ year olds, p<0.001). Nearly all (93%) believed primary care physicians should routinely discuss the vaccine with older women. CONCLUSIONS: A high proportion of women over 26 would want the HPV vaccine if offered by their provider, even if they had to pay for it out of pocket. This suggests that if providers were to routinely offer the HPV vaccine to their older patients, many women would choose to get vaccinated. PMID- 25701672 TI - Cholera toxin-B (ctxB) antigen expressing Salmonella Typhimurium polyvalent vaccine exerts protective immune response against Vibrio cholerae infection. AB - Live attenuated vaccines are cost effective approach for preventing a broad range of infectious diseases, and thus are of great interest. However, immune-defects can predispose the patient to infections by the vaccine candidate itself. So far, few live vaccine candidates have been designed specifically for immune compromised individuals. Recently, we reported a new Salmonella Typhimurium Z234 vaccine strain (Periaswamy et al., PLoS ONE 2012;7:e45433), which was specifically attenuated in the NADPH-oxidase deficient host. In the present study, the Z234-vaccine strain was further engineered to express heterologous antigen (Vibrio cholerae toxin antigen subunit-B, i.e. CtxB) with the intention of creating a vector for simultaneous protection against Cholera and Salmonellosis. The primary aim of this study was to ensure the expression of CtxB antigen by the recombinant vaccine strain Z234-pMS101. The antigen CtxB was expressed through Z234 as a fusion protein with N-terminal signal sequence of Salmonella outer protein (SopE), an effector protein from Salmonella under the control of SopE promoter. The CtxB-expressing plasmid construct pMS101 (pM968 pSopE-ctxB) was found to be stable both in vitro and in vivo. In an oral mouse infection model, the vaccine strain Z234-pMS101 efficiently colonized the host gut. The extent of protection was confirmed after challenging the immunized hosts with live V. cholerae. Vaccinated mice showed reduced gut colonization by V. cholerae. Further assessment of immunological parameters supported the possibility of conferring effective immune response by Z234-pMS101 vaccine strain. Overall, the Z234-pMS101 vaccine strain showed potential as a promising polyvalent vaccine candidate to protect against S. Typhimurium and V. cholerae infection simultaneously. PMID- 25701673 TI - Managing population immunity to reduce or eliminate the risks of circulation following the importation of polioviruses. AB - Poliovirus importations into polio-free countries represent a major concern during the final phases of global eradication of wild polioviruses (WPVs). We extend dynamic transmission models to demonstrate the dynamics of population immunity out through 2020 for three countries that only used inactivated poliovirus vaccine (IPV) for routine immunization: the US, Israel, and The Netherlands. For each country, we explore the vulnerability to re-established transmission following an importation for each poliovirus serotype, including the impact of immunization choices following the serotype 1 WPV importation that occurred in 2013 in Israel. As population immunity declines below the threshold required to prevent transmission, countries become at risk for re-established transmission. Although importations represent stochastic events that countries cannot fully control because people cross borders and polioviruses mainly cause asymptomatic infections, countries can ensure that any importations die out. Our results suggest that the general US population will remain above the threshold for transmission through 2020. In contrast, Israel became vulnerable to re established transmission of importations of live polioviruses by the late 2000s. In Israel, the recent WPV importation and outbreak response use of bivalent oral poliovirus vaccine (bOPV) eliminated the vulnerability to an importation of poliovirus serotypes 1 and 3 for several years, but not serotype 2. The Netherlands experienced a serotype 1 WPV outbreak in 1992-1993 and became vulnerable to re-established transmission in religious communities with low vaccine acceptance around the year 2000, although the general population remains well-protected from widespread transmission. All countries should invest in active management of population immunity to avoid the potential circulation of imported live polioviruses. IPV-using countries may wish to consider prevention opportunities and/or ensure preparedness for response. Countries currently using a sequential IPV/OPV schedule should continue to use all licensed OPV serotypes until global OPV cessation to minimize vulnerability to circulation of imported polioviruses. PMID- 25701674 TI - Clinical manifestations of leprosy after BCG vaccination: an observational study in Bangladesh. AB - BACKGROUND: Although BCG is used as a vaccine against tuberculosis, it also protects against leprosy. Previous evaluation over 18 years of an intervention of two doses BCG for 3536 household contacts of leprosy patients showed that 28 (23%) out of 122 contacts diagnosed with leprosy, developed symptoms 2-10 months after vaccination. This study describes contacts of leprosy patients in Bangladesh who developed leprosy within 12 weeks after receiving a single BCG dose. METHODS: A cluster RCT in Bangladesh aims to study the effectiveness of the BCG vaccine versus BCG in combination with single dose rifampicin (SDR) given 2 to 3 months after BCG, in the prevention of leprosy among contacts of newly diagnosed leprosy patients. During the first 1,5 years of this ongoing trial we identified contacts who developed leprosy within the first 12 weeks after receiving BCG vaccination, the timeframe before SDR is given. RESULTS: We identified 21 contacts who developed leprosy within 12 weeks after BCG vaccination among 5196 vaccinated contacts (0.40%). All 21 cases presented with paucibacillary (PB) leprosy, including children and adults. About half of these cases had previously received BCG vaccination as indicated by the presence of a BCG scar; 43% presented with signs of nerve function impairment and/or Type 1 (reversal) reaction, and 56% of the index patients had multibacillary (MB) leprosy. CONCLUSION: An unexpectedly high proportion of healthy contacts of leprosy patients presented with PB leprosy within 12 weeks after receiving BCG vaccination, possibly as a result of boosted cell-mediated immunity by homologues of Mycobacterium leprae antigens in BCG. Various immunological mechanisms could underlie this phenomenon, including an immune reconstitution inflammatory syndrome (IRIS). Further studies are required to determine whether BCG vaccination merely altered the incubation period or actually changed the course of the infection from self-limiting, subclinical infection to manifest disease. PMID- 25701675 TI - Local administration of granulocyte macrophage colony-stimulating factor induces local accumulation of dendritic cells and antigen-specific CD8+ T cells and enhances dendritic cell cross-presentation. AB - Immunotherapy has emerged as a promising treatment strategy for the control of HPV-associated malignancies. Various therapeutic HPV vaccines have elicited potent antigen-specific CD8+ T cell mediated antitumor immune responses in preclinical models and are currently being tested in several clinical trials. Recent evidence indicates the importance of local immune activation, and higher number of immune cells in the site of lesion correlates with positive prognosis. Granulocyte macrophage colony-stimulating factor (GMCSF) has been reported to posses the ability to induce migration of antigen presentation cells and CD8+ T cells. Therefore, in the current study, we employ a combination of systemic therapeutic HPV DNA vaccination with local GMCSF application in the TC-1 tumor model. We show that intramuscular vaccination with CRT/E7 DNA followed by GMCSF intravaginal administration effectively controls cervicovaginal TC-1 tumors in mice. Furthermore, we observe an increase in the accumulation of E7-specific CD8+ T cells and dendritic cells in vaginal tumors following the combination treatment. In addition, we show that GMCSF induces activation and maturation in dendritic cells and promotes antigen cross-presentation. Our results support the clinical translation of the combination treatment of systemic therapeutic vaccination followed by local GMCSF administration as an effective strategy for tumor treatment. PMID- 25701676 TI - Evolution of alternative methodologies of scorpion antivenoms production. AB - Scorpionism represents a serious public health problem resulting in the death of children and debilitated individuals. Scorpion sting treatment employs various strategies including the use of specific medicines such as antiserum, especially for patients with severe symptoms. In 1909 Charles Todd described the production of an antiserum against the venom of the scorpion Buthus quinquestriatus. Based on Todd's work, researchers worldwide began producing antiserum using the same approach i.e., immunization of horses with crude venom as antigen. Despite achieving satisfactory results using this approach, researchers in this field have developed alternative approaches for the production of scorpion antivenom serum. In this review, we describe the work published by experts in toxinology to the development of scorpion venom antiserum. Methods and results describing the use of specific antigens, detoxified venom or toxins, purified toxins and or venom fractions, native toxoids, recombinant toxins, synthetic peptides, monoclonal and recombinant antibodies, and alternative animal models are presented. PMID- 25701677 TI - No blood culture examinations during off-hours? PMID- 25701678 TI - Synaptic structure and function are altered by the neddylation inhibitor MLN4924. AB - The posttranslational modification of proteins by the ubiquitin-like small molecule NEDD8 has previously been shown to be vital in a number of cell signaling pathways. In particular, conjugation of NEDD8 (neddylation) serves to regulate protein ubiquitination through modifications to E3 ubiquitin ligases. Despite the prevalence of NEDD8 in neurons, very little work has been done to characterize the role of this modifier in these cells. Here, we use the recently developed NEDD8 Activating Enzyme (NAE) inhibitor MLN4924 and report evidence of a role for NEDD8 in regulating mammalian excitatory synapses. Application of this drug to dissociated rat hippocampal neurons caused reductions in synaptic strength, surface glutamate receptor levels, dendritic spine width, and spine density, suggesting that neddylation is involved in the maintenance of synapses. PMID- 25701679 TI - The DNA methylation landscape of Chinese hamster ovary (CHO) DP-12 cells. AB - Chinese hamster ovary (CHO) cells represent the most commonly used production cell line for therapeutic proteins. By recent genome and transcriptome sequencing a basis was created for future investigations of genotype-phenotype relationships and for improvement of CHO cell productivity and product quality. In this context information is missing about DNA cytosine methylation as a crucial epigenetic modification and an important element in mammalian genome regulation and development. Here, we present the first DNA methylation map of a CHO cell line in single-base resolution that was generated by whole genome bisulfite sequencing combined with gene expression analysis by CHO microarrays. We show CHO DP-12 cells to exhibit global hypomethylation compared to a majority of mammalian methylomes and hypermethylation of CpG-dense regions at gene promoters called CpG islands. We also observed partially methylated domains that cover 62% of the CHO DP-12 cell genome and contain functional clusters of genes. Gene expression analysis showed these clusters to be either highly or weakly expressed with regard to CHO-specific characteristics and hence proves DNA methylation in CHO cells to be an important link between genomics and transcriptomics. PMID- 25701680 TI - Improving thermal stability of thermophilic L-threonine aldolase from Thermotoga maritima. AB - Threonine aldolase (TA) catalyzes a reversible reaction, in which threonine is decomposed into glycine and acetaldehyde. The same enzyme can be used to catalyze aldol reaction between glycine and a variety of aromatic and aliphatic aldehydes, thus creating various alpha-amino-alcohols. Therefore, TA is a very promising enzyme that could be used to prepare biologically active compounds or building blocks for pharmaceutical industry. Rational design was applied to thermophilic TA from Thermotoga maritima to improve thermal stability by the incorporation of salt and disulfide bridges between subunits in the functional tetramer. An activity assay together with CD analysis and Western-blot detection was used to evaluate mutants. Except one, each of the designed mutants preserved activity toward the natural substrate. One of the 10 proposed single point mutants, P56C, displayed significantly enhanced stability compared to the wild type (WT). Its initial activity was not affected and persisted longer than WT, proportionally to increased stability. Additionally one of the mutants, W86E, displayed enhanced activity, with stability similar to WT. Higher activity may be explained by a subtle change in active site availability. Salt bridge formation between glutamic acid at position 86 and arginine at position 120 in the neighboring chain may be responsible for the slight shift of the chain fragment, thus creating wider access to the active site both for the substrate and PLP. PMID- 25701681 TI - Bioenergetics profile of CD4(+) T cells in relapsing remitting multiple sclerosis subjects. AB - Multiple sclerosis (MS) is a chronic inflammatory autoimmune demyelinating disease of the central nervous system. There are four clinical forms of MS, the most common of which is characterized by a relapsing remitting course (RRMS). The etiology of MS is unknown, but many studies suggested that genetic, environmental and infectious agents may contribute to the development of this disease. In experimental autoimmune encephalomyelitis (EAE), the animal model for MS, it has been shown that CD4(+) T cells play a key role in MS pathogenesis. In fact, these cells are able to cross the blood-brain barrier and cause axonal damage with neuronal death. T cell activation critically depends on mitochondrial ATP synthesis and reactive oxygen species (ROS) production. Interestingly, lots of studies linked the oxidative damage arising from mitochondrial changes to neurodegenerative disorders, such as MS. Based on these evidences, this work focused on the metabolic reprogramming of CD4(+) T cells in MS subjects, being this cell population directly implicated in pathogenesis of disease, paying attention to mitochondrial function and response to oxidative stress. Such aspects, once clarified, may open new opportunities for a therapeutic metabolic modulation of MS disorder. PMID- 25701682 TI - Effects of intra-infralimbic prefrontal cortex injections of cannabidiol in the modulation of emotional behaviors in rats: contribution of 5HT1A receptors and stressful experiences. AB - The infralimbic (IL) and prelimbic (PL) regions of the prefrontal cortex are involved in behavioral responses observed during defensive reactions. Intra-PL or IL injections of cannabidiol (CBD), a major non-psychotomimetic cannabinoid present in the Cannabis sativa plant, result in opposite behavioral effects in the contextual fear conditioning (CFC) paradigm. The intra-PL effects of CBD are mediated by 5HT1A receptors and depend on previous stressful experiences but the mechanisms and effects of intra-IL CBD injected are unknown. To this aim the present work verified the effects of intra-IL administration of CBD on two animal models of anxiety, the elevated plus maze (EPM) and CFC. We also investigated if these effects were mediated by 5HT1A receptors and depended on previous stressful experience. Male Wistar rats received bilateral microinjections of vehicle, WAY100635 (5HT1A receptor antagonist, 0.37 nmol) and/or CBD (15, 30 or 60 nmol) before being submitted to the behavioral tests. Intra-IL CBD induced anxiolytic and anxiogenic in the EPM and CFC, respectively. To verify if these effects are influenced by the previous stressful experience (footshocks) in the CFC model, we tested the animals in the EPM 24h after a 2-h restraint period. The anxiolytic like effect of CBD in the EPM disappeared when the animals were previously stressed. Both responses, i.e., anxiolytic and anxiogenic, were prevented by WAY100635, indicating that they involve local 5HT1A-mediated neurotransmission. Together these results indicate that CBD effects in the IL depend on the nature of the animal model, being influenced by previous stressful experiences and mediated by facilitation of 5HT1A receptors-mediated neurotransmission. PMID- 25701683 TI - Critical attributes of nanofibers: preparation, drug loading, and tissue regeneration. AB - The electrospinning technique for nanofiber production has opened new and interesting opportunities for tissue regeneration and treatment, because they allow biomimetic supports for cell growth to be designed and enable simultaneous delivery of diverse drugs in a controlled manner. In this review the process of electrospinning itself and the parameters affecting the electrospinning outcome are presented in detail. Critical issues related to nanofiber composition and drug loading and analytical tools for characterization and quality assurance of electrospun nanofibers are described. Recent findings about the response of cells grown on nanofibrillar supports, including cell adhesion, morphology, proliferation, and mobility, are also introduced. This review summarizes the progress that has been made in recent years on nanofibers for biomedical use and highlights the major challenges that still remain to be solved. PMID- 25701684 TI - Reactive oxygen species activated NLRP3 inflammasomes initiate inflammation in hyperosmolarity stressed human corneal epithelial cells and environment-induced dry eye patients. AB - In studies on dry eye (DE) disease, an association has been identified between tear film hyperosmolarity and inflammation severity elicited through receptor induced increases in proinflammatory cytokine and chemokine release. These immune reactions might be mediated by inflammasomes, macromolecular complexes mounted around the NLRP3 protein and can be activated by reactive oxygen species (ROS) over-generation. Hence in this study we determine whether: a) ROS activated NLRP3 inflammasomes mediate hyperosmotic stress-induced inflammation in human corneal epithelial cells (HCECs); b) the ROS-NLRP3-IL-1beta axis activation is associated with environment-induced DE. Immortalized HCECs were exposed to 500 mOsm medium in the presence and absence of a ROS inhibitor, N-acetyl-l-cysteine (NAC). HCECs transfected with NLRP3 siRNA or a negative control (NC) siRNA. Intracellular ROS was measured by fluorometric analysis using the probe 2',7'-dichlorofluorescin diacetate (DCFH-DA). Real-time PCR evaluated NLRP3, ASC, pro-caspase-1 and pro-IL 1beta mRNA levels. Western blot analysis assessed NLRP3 protein expression whereas caspase-1 activity was determined with a fluorometric assay. Bioactive IL 1beta release was assessed by ELISA. ROS production, NLRP3 inflammasome and pro IL-1beta gene expression as well as IL-1beta secretion were also evaluated in the conjunctival epithelial cells and tear fluid samples of environment-induced DE patients and normal subjects. NAC suppressed hyperosmolarity-induced rises in ROS levels, NLRP3 inflammasome formation and activation, caspase-1 activity and IL 1beta release. On the other hand, NLRP3 siRNA knockdown inhibited hyperosmotic stress-induced NLRP3 activation, which led to ASC, pro-caspase-1 and pro-IL-1beta mRNA down-regulation followed by suppression of associated caspase-1 activity and IL-1beta secretion. In addition, in ocular surface samples of environment-induced DE patients, ROS generation, NLRP3, ASC, pro-caspase-1 and pro-IL-1beta gene expression as well as IL-1beta secretion were upregulated. Taken together, NLRP3 mediated innate immune responses triggered by rises in ROS generation induce inflammation in hyperosmotic stressed HCECs. ROS-NLRP3-IL-1beta signaling pathway might play a priming role in environment-induced DE development. PMID- 25701685 TI - A rapid event-related potential (ERP) method for point-of-care evaluation of brain function: development of the Halifax Consciousness Scanner. AB - BACKGROUND: Event-related potentials (ERPs) may provide a non-invasive index of brain function for a range of clinical applications. However, as a lab-based technique, ERPs are limited by technical challenges that prevent full integration into clinical settings. NEW METHOD: To translate ERP capabilities from the lab to clinical applications, we have developed methods like the Halifax Consciousness Scanner (HCS). HCS is essentially a rapid, automated ERP evaluation of brain functional status. The present study describes the ERP components evoked from auditory tones and speech stimuli. ERP results were obtained using a 5-min test in 100 healthy individuals. The HCS sequence was designed to evoke the N100, the mismatch negativity (MMN), P300, the early negative enhancement (ENE), and the N400. These components reflected sensation, perception, attention, memory, and language perception, respectively. Component detection was examined at group and individual levels, and evaluated across both statistical and classification approaches. RESULTS: All ERP components were robustly detected at the group level. At the individual level, nonparametric statistical analyses showed reduced accuracy relative to support vector (SVM) machine classification, particularly for speech-based ERPs. Optimized SVM results were MMN: 95.6%; P300: 99.0%; ENE: 91.8%; and N400: 92.3%. CONCLUSIONS: A spectrum of individual-level ERPs can be obtained in a very short time. Machine learning classification improved detection accuracy across a large healthy control sample. Translating ERPs into clinical applications is increasingly possible at the individual level. PMID- 25701686 TI - A method for establishing the high-altitude cerebral edema (HACE) model by acute hypobaric hypoxia in adult mice. AB - BACKGROUND: Exposure to acute hypobaric hypoxia (AHH) during ascent to high altitudes (>3500 m) is one of the main causes of acute mountain sickness (AMS) and high-altitude cerebral edema (HACE). Therefore, the aim of this study was to develop a model of HACE. NEW METHODS: We developed a model of HACE in mice using a decompression chamber with rapid ascent speed. RESULTS: Healthy male C57BL/6 mice were randomly divided into the control group and the AHH group. The AHH group was housed in a decompression chamber (at a velocity of 50 m/s within 5 min to 6000 m). Compared with the controls, brain water content was increased in the early stage (within 24 h) in the AHH group. After 72 h of exposure to AHH, there was a higher BBB permeability observed. In addition, the brain structure showed significant widening of the pericellular spaces and a dilatation of the cortical blood vessels after exposure to AHH, and some of the neurons appeared shrunken with darkly stained pyknotic nuclei, resulting in neuronal structural damage. Further, exposure to AHH also decreased cognitive function in the mice. COMPARISON WITH EXISTING METHODS: At present, there are no simple and rapid mouse models to study this syndrome in terms of its genetic basis, gene polymorphisms and susceptibility. CONCLUSION: Our findings show that AHH can increase BBB permeability and lead to cerebral edema in mice; thus, we provide an effective and stable model of HACE in mice. PMID- 25701687 TI - Coping With Existential and Emotional Challenges: Development and Validation of the Self-Competence in Death Work Scale. AB - CONTEXT: Palliative care professionals often are confronted by death in their work. They may experience challenges to self, such as aroused emotions and queries about life's meaningfulness. Assessing their level of "self-competence" in coping with these challenges is crucial in understanding their needs in death work. OBJECTIVES: This study aims to develop and validate the Self-Competence in Death Work Scale (SC-DWS). METHODS: Development of this scale involved three steps: 1) items generated from a qualitative study with palliative care professionals, (2) expert panel review, and (3) pilot test. Analysis was conducted to explore the factor structure and examine the reliability and validity of the scale. Helping professionals involved in death work were recruited to complete questionnaires comprising the SC-DWS and other scales. RESULTS: A total of 151 participants were recruited. Both one-factor and two factor structures were found. Emotional and existential coping were identified as subscales in the two-factor structure. Correlations of the whole scale and subscales with measures of death attitudes, meaning in life, burnout and depression provided evidence for the construct validity. Discriminative validity was supported by showing participants with bereavement experience and longer experience in the profession and death work possessed a significantly higher level of self-competence. Reliability analyses showed that the entire scale and subscales were internally consistent. CONCLUSION: The SC-DWS was found to be valid and reliable. This scale may facilitate helping professionals' understanding of their self-competence in death work, so appropriate professional support and training may be obtained. PMID- 25701688 TI - Palliative Care Professionals' Inner Life: Exploring the Relationships Among Awareness, Self-Care, and Compassion Satisfaction and Fatigue, Burnout, and Coping With Death. AB - CONTEXT: Professionals working in the landscape of death and dying frequently are exposed to existential issues, psychological challenges, and emotional distress associated with care at the end of life. Identifying factors that help professionals cope with frequent exposure to issues related to mortality could enhance palliative care providers' and patients' quality of life. OBJECTIVES: To improve our understanding of the factors associated with professionals' inner life, through the assessment of an adapted version of Kearney and Kearney's awareness model of self-care. The main assumptions of the study were that competence in coping with death and awareness would be positively related to compassion satisfaction and negatively to compassion fatigue and burnout; moreover, participating in a specific training program aimed at facing suffering and death, and self-care would positively predict coping with death. METHODS: A cross-sectional online survey of Spanish palliative care professionals was conducted through the member e-mail list of the Spanish Society of Palliative Care. A total of 387 professionals completed the survey, which included demographic data, and personal and professional scales on the mentioned constructs. RESULTS: Data fit reasonably well with the estimated model. Whereas the hypothesis relating spiritual training to coping with death was not supported by the data, all other aspects of the hypotheses were supported, namely self-care and awareness positively predicted professionals' competence in coping with death, and this, together with awareness, positively predicted compassion satisfaction and negatively predict compassion fatigue and burnout. CONCLUSION: The awareness-based model of self-care was successfully tested in a multidisciplinary sample of Spanish palliative care professionals. This research applies a quantitative evaluation of the model, providing evidence of a constellation of key variables for health professionals' quality of life, such as specific training, self-care, awareness and coping with death competency. PMID- 25701689 TI - Improving the Diagnostic Accuracy of the Distress Thermometer: A Potential Role for the Impact Thermometer. AB - CONTEXT: Screening for and management of distress in clinical practice is an important issue in the field of psycho-oncology. The Distress Thermometer (DT) is a common screening tool, but other methods recently have been proposed, with the aim of improving its diagnostic accuracy. OBJECTIVES: To investigate the diagnostic accuracy of the DT alone and combined with the Impact Thermometer (IT), via the use of two possible combination methods. METHODS: A heterogeneous sample of 385 adult patients with cancer completed the DT, the IT, and the Brief Symptom Inventory-18. RESULTS: The results of the DT were comparable with those found in previous studies, indicating that the DT was adequate for "screening" but had limited value for "case finding." The DT and the IT combined (summed or paired scores) showed minor differences in accuracy indexes compared with the DT alone. CONCLUSION: The results of this study suggest that the addition of the IT to the DT failed to improve its accuracy for identifying distress. PMID- 25701690 TI - Preparedness for Resident Death in Long-Term Care: The Experience of Front-Line Staff. AB - CONTEXT: Although resident death is a common occurrence in long-term care, little attention has focused on how prepared certified nursing assistants (CNAs), who provide most of residents' daily care, are for this experience. OBJECTIVES: To identify characteristics of the resident, CNA, and care context associated with CNAs' preparedness for resident death and to determine differential patterns for emotional versus informational preparedness. METHODS: One hundred forty CNAs completed semistructured, in-person interviews concerning their experiences regarding resident death. The associations of CNA characteristics (e.g., personal end-of-life [EOL] care preferences), CNAs' perceptions of resident status (e.g., knowledge of resident's condition), and the caregiving context (e.g., support from coworkers and hospice involvement) with emotional and informational preparedness were examined by the use of bivariate and multivariate analyses. RESULTS: CNAs who reported that their resident was "aware of dying" or "in pain" expressed greater levels of both emotional and informational preparedness. CNAs who endorsed an EOL care preference of wanting all possible treatments regardless of chances for recovery were likely to report lesser emotional preparedness. More senior CNAs, both in regard to age and tenure, reported greater preparedness levels. Greater support from coworkers and hospice involvement also were associated with greater levels of both facets of preparedness, the latter in particular when hospice care was viewed positively by the CNA. CONCLUSION: Having more information about resident status and more exchange opportunities within the care team around EOL-related challenges may help CNAs feel more prepared for resident death and strengthen their ability to provide good EOL care. PMID- 25701691 TI - Fatigue in HIV-Infected People: A Three-Year Observational Study. AB - CONTEXT: HIV-related fatigue remains the most frequent complaint of seropositive patients. OBJECTIVES: To describe the natural course of fatigue in HIV infection, in a sample (n=128) followed for a three-year period. METHODS: A longitudinal prospective design was used to determine what factors influenced changes in fatigue intensity and fatigue-related impairment of functioning in a community dwelling sample of HIV-infected individuals. Participants were followed every six months for a three-year period. At each study visit, we collected data on a large number of physiological and psychosocial markers that have been shown to be related to fatigue in HIV-infected people. At three month intervals between study visits, we collected data on fatigue via mailed questionnaires. RESULTS: Fatigue in HIV infection is largely a result of stressful life events, and is closely tied to the anxiety and depression that accompany such events. Fatigue did not remit spontaneously over the course of the study, indicating the need for interventions to ameliorate this debilitating symptom. CONCLUSION: Intervening to help people who are suffering from HIV-related fatigue to deal with stressful life events may help to ameliorate this debilitating symptom. PMID- 25701692 TI - Ongoing Screening and Treatment to Potentially Reduce Tyrosine Kinase Inhibitor Related Fatigue in Renal Cell Carcinoma. AB - CONTEXT: Renal cell carcinoma (RCC) represents 1% to 4% of adult malignancies, and approximately 33% of patients with RCC present with metastatic disease and have a poor prognosis. Better understanding of RCC tumor biology has led to the development of several molecularly targeted agents, such as tyrosine kinase inhibitors (TKIs), to manage advanced disease. Although evolving data suggest these drugs may be beneficial in RCC, they are associated with significant toxicities. Cancer-related fatigue (CRF) is one of the most common toxicities associated with the TKIs used in RCC. OBJECTIVES: To review the incidence, pathophysiology, and management of CRF in patients with RCC who are undergoing targeted therapy with TKIs. METHODS: A comprehensive database search was performed using PubMed, Ovid, Embase, and MEDLINE. References of all cited articles also were reviewed. Data from articles published between 1975 and June 2014 were considered. A narrative review regarding the incidence, pathophysiology, and management of CRF in patients with RCC undergoing targeted therapy with TKIs was performed. RESULTS: CRF is one of the most common TKI toxicities in patients with metastatic RCC and often is the dose-limiting toxicity. Management of TKI-related CRF can be difficult and may necessitate various nonpharmacologic and pharmacologic interventions. CONCLUSION: TKI-related CRF in patients with RCC is a highly distressing complication of cancer therapy. CRF can substantially influence drug compliance, the ability to maximally treat, and quality of life. It is important to recognize this common, yet frequently underdiagnosed complication and initiate appropriate management strategies, to increase the likelihood for optimal outcomes. PMID- 25701693 TI - No evidence for generation of alternatively spliced isoforms from the mutated Trim24 allele lacking exon 4 in mouse liver. PMID- 25701694 TI - Decreased Tim-3 expression is associated with functional abnormalities of monocytes in decompensated cirrhosis without overt bacterial infection. AB - BACKGROUND & AIMS: Patients with advanced cirrhosis usually exhibit altered monocyte function. However, the molecular mechanisms underlying the functional changes of monocytes are poorly understood. METHODS: We investigated the role of T-cell immunoglobulin domain and mucin domain-containing molecule-3 (Tim-3) in regulating monocyte function in 94 patients with decompensated liver cirrhosis (DC-LC) (decompensation was defined by ascites, hepatic encephalopathy or upper gastrointestinal bleeding), 58 with compensated liver cirrhosis (C-LC) and 52 healthy controls (HC) by characterizing the frequency of Tim-3(+) monocytes, their phagocytosis capacity, HLA-DR expression, cytokine secretion and MAP kinase activation induced by lipopolysaccharide (LPS). RESULTS: Tim-3 expression on CD14(+) monocytes in DC-LC group were significantly lower than that in C-LC and HC and were associated with increased levels of plasma endotoxin, enhanced cytokine production, decreased phagocytic capacity, and reduced HLA-DR expression. Tim-3 expression on monocytes and monocyte function did not differ between C-LC and HC group. Tim-3(+)CD14(+) cells had more potent phagocytic capacity, higher levels of HLA-DR, CD86, CD80, CD163, and CD206 expression, but lower levels of CD1a and CD83, related to that of Tim-3(-)CD14(+) monocytes. In addition, Tim-3(+)CD14(+) cells produced less TNF-alpha but higher levels of IL 10 in response to LPS. Treatment with anti-Tim-3 antibody significantly reduced phagocytic capacity, but enhanced LPS-stimulated TNF-alpha, IL-6, and IL-10 secretion. Furthermore, blocking Tim-3 signaling increased p38 MAP kinase phosphorylation in monocytes upon LPS stimulation. CONCLUSIONS: Downregulation of Tim-3 expression was associated with endotoxemia and functional alterations of monocytes in patients with decompensated cirrhosis. PMID- 25701695 TI - Endovascular repair of concomitant vertebral artery and subclavian artery iatrogenic perforations. AB - Inadvertent arterial puncture is a well-established complication of central venous catheter insertion. The carotid artery is the most frequently injured artery involved with injury to the subclavian artery and vertebral artery being much less common. When these injuries do occur, they are often treated with open surgical repair or endovascular, with stent-graft placement or embolization. Repair of acute vertebral artery injury with endovascular stent-graft repair has not been well represented in the literature to date. The present report discusses the successful treatment of concomitant injuries to the left subclavian and left vertebral arteries from acute iatrogenic puncture with endovascular stent-graft placement. PMID- 25701696 TI - Late stent migration into the right ventricle in a patient with nutcracker syndrome. AB - BACKGROUND: Stent migration into the right ventricle is rare in patients treated with endovenous stenting, but can have potentially serious complications including endocarditis, cardiac arrhythmias, and heart failure. METHODS: We present a case of stent migration into the right ventricle 5 months after stent placement in a patient with nutcracker syndrome. RESULTS: Echocardiography revealed a stent caught within the subvalvular chordal structures, with significant tricuspid regurgitation. Subsequent severe damage to the tricuspid apparatus necessitated prosthetic valve replacement, as tricuspid valvuloplasty failed after stent removal. CONCLUSIONS: Because stent migration is a potential complication in left renal vein stenting that can occur up to 5 months after intervention therapy, follow-up using ultrasonography is necessary. In addition, knowing the precise location of the stent, which is important for subsequent treatment, is essential when transabdominal ultrasonography reveals the absence of the stent in the left renal vein. PMID- 25701697 TI - Warsaw Breakage Syndrome--A further report, emphasising cutaneous findings. AB - We report a new case of Warsaw Breakage syndrome (WABS) with 2 confirmed mutations in DDX11. Like the previous reported cases [Capo-Chichi et al., 2012; Van der Lelij et al., 2010], there was evidence of pre- and postnatal growth retardation, severe microcephaly, intellectual disability and facial dysmorphism. The patient had sensorineural hearing loss with evidence of bilateral hypoplastic cochleas on imaging, another feature which has been reported in the previous cases of WABS. In our case the patient exhibited a chronic rash of livedo reticularis with telangiectasia on her legs. Abnormally pigmented lesions and cutis mamorata were reported in the original WABS case. PMID- 25701698 TI - Auditory rhythms entrain visual processes in the human brain: evidence from evoked oscillations and event-related potentials. AB - Temporal regularities in the environment are thought to guide the allocation of attention in time. Here, we explored whether entrainment of neuronal oscillations underpins this phenomenon. Participants viewed a regular stream of images in silence, or in-synchrony or out-of-synchrony with an unmarked beat position of a slow (1.3 Hz) auditory rhythm. Focusing on occipital recordings, we analyzed evoked oscillations shortly before and event-related potentials (ERPs) shortly after image onset. The phase of beta-band oscillations in the in-synchrony condition differed from that in the out-of-synchrony and silence conditions. Additionally, ERPs revealed rhythm effects for a stimulus onset potential (SOP) and the N1. Both were more negative for the in-synchrony as compared to the out of-synchrony and silence conditions and their amplitudes positively correlated with the beta phase effects. Taken together, these findings indicate that rhythmic expectations are supported by a reorganization of neural oscillations that seems to benefit stimulus processing at expected time points. Importantly, this reorganization emerges from global rhythmic cues, across modalities, and for frequencies significantly higher than the external rhythm. As such, our findings support the idea that entrainment of neuronal oscillations represents a general mechanism through which the brain uses predictive elements in the environment to optimize attention and stimulus perception. PMID- 25701699 TI - Ultra-high resolution in-vivo 7.0T structural imaging of the human hippocampus reveals the endfolial pathway. AB - The hippocampus is a very important structure in memory formation and retrieval, as well as in various neurological disorders such as Alzheimer's disease, epilepsy and depression. It is composed of many intricate subregions making it difficult to study the anatomical changes that take place during disease. The hippocampal hilus may have a unique neuroanatomy in humans compared to that in monkeys and rodents, with field CA3h greatly enlarged in humans compared to that in rodents, and a white-matter pathway, called the endfolial pathway, possibly only present in humans. In this study we have used newly developed 7.0T whole brain imaging sequence, balanced steady-state free precession (bSSFP) that can achieve 0.4mm isotropic images to study, in vivo, the anatomy of the hippocampal hilus. A detailed hippocampal subregional segmentation was performed according to anatomic atlases segmenting the following regions: CA4, CA3, CA2, CA1, SRLM (stratum radiatum lacunosum moleculare), alveus, fornix, and subiculum along with its molecular layer. We also segmented a hypointense structure centrally within the hilus that resembled the endfolial pathway. To validate that this hypointense signal represented the endfolial pathway, we acquired 0.1mm isotropic 8-phase cycle bSSFP on an excised specimen, and then sectioned and stained the specimen for myelin using an anti-myelin basic protein antibody (SMI 94). A structure tensor analysis was calculated on the myelin-stained section to show directionality of the underlying fibers. The endfolial pathway was consistently visualized within the hippocampal body in vivo in all subjects. It is a central pathway in the hippocampus, with unknown relevance in neurodegenerative disorders, but now that it can be visualized noninvasively, we can study its function and alterations in neurodegeneration. PMID- 25701700 TI - Small Amounts of Gluten in Subjects With Suspected Nonceliac Gluten Sensitivity: A Randomized, Double-Blind, Placebo-Controlled, Cross-Over Trial. AB - BACKGROUND & AIMS: There is debate over the existence of nonceliac gluten sensitivity (NCGS) intestinal and extraintestinal symptoms in response to ingestion of gluten-containing foods by people without celiac disease or wheat allergy. We performed a randomized, double-blind, placebo-controlled, cross-over trial to determine the effects of administration of low doses of gluten to subjects with suspected NCGS. METHODS: We enrolled 61 adults without celiac disease or a wheat allergy who believed ingestion of gluten-containing food to be the cause of their intestinal and extraintestinal symptoms. Participants were assigned randomly to groups given either 4.375 g/day gluten or rice starch (placebo) for 1 week, each via gastrosoluble capsules. After a 1-week gluten-free diet, participants crossed over to the other group. The primary outcome was the change in overall (intestinal and extraintestinal) symptoms, determined by established scoring systems, between gluten and placebo intake. A secondary outcome was the change in individual symptom scores between gluten vs placebo. RESULTS: According to the per-protocol analysis of data from the 59 patients who completed the trial, intake of gluten significantly increased overall symptoms compared with placebo (P = .034). Abdominal bloating (P = .040) and pain (P = .047), among the intestinal symptoms, and foggy mind (P = .019), depression (P = .020), and aphthous stomatitis (P = .025), among the extraintestinal symptoms, were significantly more severe when subjects received gluten than placebo. CONCLUSIONS: In a cross-over trial of subjects with suspected NCGS, the severity of overall symptoms increased significantly during 1 week of intake of small amounts of gluten, compared with placebo. Clinical trial no: ISRCTN72857280. PMID- 25701701 TI - Should Evidence-based Medicine Be Used to Design Clinical Practice Guidelines for the Prevention of Perinatal Transmission of Hepatitis B Virus From Hepatitis B e Antigen-Positive Mothers? PMID- 25701702 TI - Sevelamer-Induced Colitis Presenting as a Pseudotumor. PMID- 25701703 TI - Pressurized intraperitoneal aerosol chemotherapy in women with recurrent ovarian cancer: A phase 2 study. AB - OBJECTIVE: Recurrent ovarian, fallopian or peritoneal cancer with peritoneal carcinomatosis (ROCPC) is resistant to systemic chemotherapy. We assessed the safety and activity of laparoscopic pressurized intraperitoneal aerosol chemotherapy (PIPAC) in women with this cancer. METHODS: In this open-label, single-arm phase 2 study, patients underwent 3 courses q 28-42 days of PIPAC with doxorubicin 1.5 mg/m(2) followed by cisplatin 7.5 mg/m(2). A pressure of 12 mm Hg and a temperature of 37 degrees C were applied for 30 min/course. The primary endpoint was the proportion of patients who had an objective tumor response (OTR) according to RECIST version 1.1 criteria. Analysis was by intention to treat. Secondary endpoints were tumor regression on histology, PC Index improvement on repeated video-laparoscopy, and quality of life measured with the EORTC QLQ-30 questionnaire. RESULTS: Sixty-four patients were enrolled. Laparoscopic non access rate was 11/64 (17%). 53 patients were eligible for analyses. 33/53 (62%) patients had an OTR - three had a partial response and 30 patients had stable disease. Tumor regression on histology and PC Index improvement were observed in 26/34 (76%) and in 26/34 (76%) patients who underwent all 3 PIPACs. There were no treatment-related deaths. No grade 4 toxicity was observed. Grade 3 toxicities were trocar hernia (n=2), bowel obstruction (n=2), abdominal pain (n=2), hematoma (n=1), intraoperative bleeding (n=1), and cystitis with urosepsis (n=1). EORTC QLQ-30 global physical health scores, nausea/vomiting, appetite loss, diarrhea, and constipation improved during therapy. CONCLUSION: PIPAC is well tolerated and active in women with ROCPC and warrants further investigation in these patients. PMID- 25701704 TI - PIKing the type and pattern of PI3K pathway mutations in endometrioid endometrial carcinomas. AB - OBJECTIVE: The vast majority of endometrioid endometrial carcinomas (EECs) harbor mutations in the PI3K pathway. Here we sought to determine whether the type and pattern of mutations targeting different components of the PI3K pathway are distinct between microsatellite stable (MSS) and high-level microsatellite instable (MSI-H) EECs. METHODS: Whole exome massively parallel sequencing-based mutation data from EECs of The Cancer Genome Atlas (TCGA) were used to define the number, type and pattern of mutations affecting PI3K pathway-related genes, including AKT1, INPP4B, MTOR, PIK3CA, PIK3R1 and PTEN. EECs were classified as MSI-H (n=70) and MSS (n=109) based on seven MSI markers assessed by TCGA. Ultramutated cases were excluded. RESULTS: Although the mutation rates and mutational signatures of MSS and MSI-H EECs were distinct, the prevalence of PI3K pathway mutations was similar between these two groups (all p>0.05), with the exception of PTEN mutations, which were more prevalent in MSI-H (61/70; 87%) than in MSS EECs (78/109; 72%; p=0.017). The PIK3CA hotspot mutations E542K, E545K, and H1047R were found to be significantly more prevalent in PIK3CA-mutant MSS (21/58, 36%) compared to PIK3CA-mutant MSI-H EECs (5/37, 13.5%; p=0.019). CONCLUSION: Although the prevalence of mutations targeting PI3K pathway genes is similar between MSS and MSI-H EECs, PIK3CA hotspot mutations, which result in constitutive kinase activation, are significantly more prevalent in MSS than in MSI-H EECs. Our findings warrant further investigation of the role of different types of PIK3CA mutations and their predictive impact on distinct subtypes of EECs. PMID- 25701705 TI - Increased reactive oxygen species production during reductive stress: The roles of mitochondrial glutathione and thioredoxin reductases. AB - Both extremes of redox balance are known to cause cardiac injury, with mounting evidence revealing that the injury induced by both oxidative and reductive stress is oxidative in nature. During reductive stress, when electron acceptors are expected to be mostly reduced, some redox proteins can donate electrons to O2 instead, which increases reactive oxygen species (ROS) production. However, the high level of reducing equivalents also concomitantly enhances ROS scavenging systems involving redox couples such as NADPH/NADP+ and GSH/GSSG. Here our objective was to explore how reductive stress paradoxically increases net mitochondrial ROS production despite the concomitant enhancement of ROS scavenging systems. Using recombinant enzymes and isolated permeabilized cardiac mitochondria, we show that two normally antioxidant matrix NADPH reductases, glutathione reductase and thioredoxin reductase, generate H2O2 by leaking electrons from their reduced flavoprotein to O2 when electron flow is impaired by inhibitors or because of limited availability of their natural electron acceptors, GSSG and oxidized thioredoxin. The spillover of H2O2 under these conditions depends on H2O2 reduction by peroxiredoxin activity, which may regulate redox signaling in response to endogenous or exogenous factors. These findings may explain how ROS production during reductive stress overwhelms ROS scavenging capability, generating the net mitochondrial ROS spillover causing oxidative injury. These enzymes could potentially be targeted to increase cancer cell death or modulate H2O2-induced redox signaling to protect the heart against ischemia/reperfusion damage. PMID- 25701706 TI - Input clustering in the normal and learned circuits of adult barn owls. AB - Experience-dependent formation of synaptic input clusters can occur in juvenile brains. Whether this also occurs in adults is largely unknown. We previously reconstructed the normal and learned circuits of prism-adapted barn owls and found that changes in clustering of axo-dendritic contacts (putative synapses) predicted functional circuit strength. Here we asked whether comparable changes occurred in normal and prism-removed adults. Across all anatomical zones, no systematic differences in the primary metrics for within-branch or between-branch clustering were observed: 95-99% of contacts resided within clusters (<10-20 MUm from nearest neighbor) regardless of circuit strength. Bouton volumes, a proxy measure of synaptic strength, were on average larger in the functionally strong zones, indicating that changes in synaptic efficacy contributed to the differences in circuit strength. Bootstrap analysis showed that the distribution of inter-contact distances strongly deviated from random not in the functionally strong zones but in those that had been strong during the sensitive period (60 250 d), indicating that clusters formed early in life were preserved regardless of current value. While cluster formation in juveniles appeared to require the production of new synapses, cluster formation in adults did not. In total, these results support a model in which high cluster dynamics in juveniles sculpt a potential connectivity map that is refined in adulthood. We propose that preservation of clusters in functionally weak adult circuits provides a storage mechanism for disused but potentially useful pathways. PMID- 25701708 TI - In vivo analysis of neuroinflammation in the late chronic phase after experimental stroke. AB - BACKGROUND AND PURPOSE: In vivo imaging of inflammatory processes is a valuable tool in stroke research. We here investigated the combination of two imaging modalities in the chronic phase after cerebral ischemia: magnetic resonance imaging (MRI) using intravenously applied ultra small supraparamagnetic iron oxide particles (USPIO), and positron emission tomography (PET) with the tracer [(11)C]PK11195. METHODS: Rats were subjected to permanent middle cerebral artery occlusion (pMCAO) by the macrosphere model and monitored by MRI and PET for 28 or 56 days, followed by immunohistochemical endpoint analysis. To our knowledge, this is the first study providing USPIO-MRI data in the chronic phase up to 8 weeks after stroke. RESULTS: Phagocytes with internalized USPIOs induced MRI T2(*) signal alterations in the brain. Combined analysis with [(11)C]PK11195-PET allowed quantification of phagocytic activity and other neuroinflammatory processes. From 4 weeks after induction of ischemia, inflammation was dominated by phagocytes. Immunohistochemistry revealed colocalization of Iba1+ microglia with [(11)C]PK11195 and ED1/CD68 with USPIOs. USPIO-related iron was distinguished from alternatively deposited iron by assessing MRI before and after USPIO application. Tissue affected by non-phagocytic inflammation during the first week mostly remained in a viably vital but remodeled state after 4 or 8 weeks, while phagocytic activity was associated with severe injury and necrosis accordingly. CONCLUSIONS: We conclude that the combined approach of USPIO-MRI and [(11)C]PK11195-PET allows to observe post-stroke inflammatory processes in the living animal in an intraindividual and longitudinal fashion, predicting long term tissue fate. The non-invasive imaging methods do not affect the immune system and have been applied to human subjects before. Translation into clinical applications is therefore feasible. PMID- 25701707 TI - The human CHRNA7 and CHRFAM7A genes: A review of the genetics, regulation, and function. AB - The human alpha7 neuronal nicotinic acetylcholine receptor gene (CHRNA7) is ubiquitously expressed in both the central nervous system and in the periphery. CHRNA7 is genetically linked to multiple disorders with cognitive deficits, including schizophrenia, bipolar disorder, ADHD, epilepsy, Alzheimer's disease, and Rett syndrome. The regulation of CHRNA7 is complex; more than a dozen mechanisms are known, one of which is a partial duplication of the parent gene. Exons 5-10 of CHRNA7 on chromosome 15 were duplicated and inserted 1.6 Mb upstream of CHRNA7, interrupting an earlier partial duplication of two other genes. The chimeric CHRFAM7A gene product, dupalpha7, assembles with alpha7 subunits, resulting in a dominant negative regulation of function. The duplication is human specific, occurring neither in primates nor in rodents. The duplicated alpha7 sequence in exons 5-10 of CHRFAM7A is almost identical to CHRNA7, and thus is not completely queried in high throughput genetic studies (GWAS). Further, pre-clinical animal models of the alpha7nAChR utilized in drug development research do not have CHRFAM7A (dupalpha7) and cannot fully model human drug responses. The wide expression of CHRNA7, its multiple functions and modes of regulation present challenges for study of this gene in disease. This article is part of the Special Issue entitled 'The Nicotinic Acetylcholine Receptor: From Molecular Biology to Cognition'. PMID- 25701709 TI - Group II metabotropic glutamate receptor antagonism prevents the antiallodynic effects of R-isovaline. AB - We previously showed that isovaline is a peripheral analgesic which acts in vivo and in brain slices as an atypical metabotropic GABA(B) agonist. Peripheral inhibitory group II and III metabotropic glutamate receptors (mGluRs) belong to the same family C as GABA(B) receptors; therefore, we hypothesized that isovaline's analgesic effects could include their activation. We examined the effects of R-isovaline on mechanical allodynia produced by prostaglandin E2 in the mouse paw. Subcutaneous R-isovaline produced dose-dependent antiallodynia restricted to the injected hindlimb. This antiallodynia was blocked by co injection with a selective group II mGluR antagonist, LY341495, but not a group III mGluR antagonist (MAP-4). The antiallodynic effect of R-isovaline was potentiated by co-administration of a group II mGluR-positive allosteric modulator, LY487379. Injection of a group II mGluR agonist (LY354740) produced an antiallodynic effect which was completely reversed by group II antagonism, but was not affected by group III or GABA(B) (CGP35348) antagonism. Similarly, group II mGluR antagonism did not alter the antiallodynia produced by the prototypical GABA(B) agonist, baclofen. Hence, there was no apparent crosstalk between group II mGluRs and GABA(B) receptors. Previous studies have demonstrated that peripheral GABA(B) receptor activation by isovaline produces antiallodynia. In addition, the present results indicate that activation of peripheral group II mGluRs by R-isovaline produces antiallodynia. PMID- 25701710 TI - Simvastatin increases excitability in the hippocampus via a PI3 kinase-dependent mechanism. AB - Simvastatin is an HMG-CoA reductase inhibitor commonly used in the clinic to treat hypercholesterolemia. In addition, simvastatin has been shown to cross the blood-brain barrier and pleiotropic effects of simvastatin have been reported including anti-inflammatory properties, enhancement of neurite outgrowth, and memory enhancement properties. However, little has been reported on the effects of simvastatin on basal synaptic transmission and neuronal excitability. Here we report that simvastatin increases the fEPSP, the N-methyl-D-aspartate (NMDA) receptor-mediated fEPSP using extracellular recordings in the dendritic region of the CA1 of hippocampal slices taken from 8-week-old C57Black6J mice. In addition, we found that simvastatin perfusion causes a change in the input/output curve and a decrease of the paired-pulse facilitation ratio, indicating respectively an increase of the neuronal excitability and neurotransmitter release. We have also observed that acute application of simvastatin increased the amplitude of the compound action potential in the CA1 region. Notably, using LY294002, we have demonstrated that this effect was PI3K dependent and was occluded if the animals had previously received a diet supplemented with simvastatin. We have finally shown that the simvastatin-mediated increase of the compound action potential amplitude was also present in hippocampal slices from aged mice. PMID- 25701711 TI - Activation of p38 MAPK in the rostral ventromedial medulla by visceral noxious inputs transmitted via the dorsal columns may contribute to pelvic organ cross sensitization in rats with endometriosis. AB - Whether visceral organ cross-sensitization is involved in endometriosis associated pain remains elusive. Previous studies have shown that visceral noxious stimuli may trigger a cascade of signal transductions in the rostral ventromedial medulla (RVM) via the spinal dorsal column (DC) pathway and the RVM plays a critical role in the descending control of visceral nociception. In the current study, we hypothesized that the p38 mitogen-activated protein kinase (MAPK) activation in the RVM by noxious visceral inputs from ectopic growths via the DC was involved in the development of pelvic organ cross-sensitization in established endometriosis. A rat model of experimental endometriosis was established. To examine ectopic growths-to-colon cross-sensitization, graded colorectal distention (CRD) was performed and abdominal withdrawal reflex (AWR) scores were recorded in female rats at 8weeks after the uterine or fat (control) auto-transplantation. Western blot study was carried out to examine the phosphorylated form and the total level of p38 MAPK protein in the RVM. Our results showed that lesions of bilateral DCs immediately following uterine or fat auto-transplantation in female rats significantly attenuated the later development of ectopic growths-to-colon cross-sensitization and the increased p38 MAPK activation in the RVM, as compared to sham DC lesions. Furthermore, intra RVM microinjection of a p38 MAPK inhibitor (SB 203580), but not vehicle, in female rats with established endometriosis significantly attenuated ectopic growths-to-colon cross-sensitization and the increased activation of p38 MAPK in the RVM. These findings suggest that the noxious inputs from ectopic growths may activate p38 MAPK in the RVM via the DC, which may contribute to the development of ectopic growths-to-colon cross-sensitization in established endometriosis. PMID- 25701712 TI - Early applied electric field stimulation attenuates secondary apoptotic responses and exerts neuroprotective effects in acute spinal cord injury of rats. AB - Injury potential, which refers to a direct current voltage between intact and injured nerve ends, is mainly caused by injury-induced Ca2+ influx. Our previous studies revealed that injury potential increased with the onset and severity of spinal cord injury (SCI), and an application of applied electric field stimulation (EFS) with the cathode distal to the lesion could delay and attenuate injury potential formation. As Ca2+ influx is also considered as a major trigger for secondary injury after SCI, we hypothesize that EFS would protect an injured spinal cord from secondary injury and consequently improve functional and pathological outcomes. In this study, rats were divided into three groups: (1) sham group, laminectomy only; (2) control group, subjected to SCI only; and (3) EFS group, received EFS immediately post-injury with the injury potential modulated to 0+/-0.5 mV by EFS. Functional recovery of the hind limbs was assessed using the Basso, Beattie, and Bresnahan (BBB) locomotor scale. Results revealed that EFS-treated rats exhibited significantly better locomotor function recovery. Luxol fast blue staining was performed to assess the spared myelin area. Immunofluorescence was used to observe the number of myelinated nerve fibers. Ultrastructural analysis was performed to evaluate the size of myelinated nerve fibers. Findings showed that the EFS group rats exhibited significantly less myelin loss and had larger and more myelinated nerve fibers than the control group rats in dorsal corticospinal tract (dCST) 8 weeks after SCI. Furthermore, we found that EFS inhibited the activation of calpain and caspase-3, as well as the expression of Bax, as detected by Western blot analysis. Moreover, EFS decreased cellular apoptosis, as measured by TUNEL, within 4 weeks post-injury. Results suggest that early EFS could significantly reduce spinal cord degeneration and improve functional and historical recovery. Furthermore, these neuroprotective effects may be related to the inhibition of secondary apoptotic responses after SCI. These findings support further investigation of the future clinical application of EFS after SCI. PMID- 25701713 TI - Dorsomedial hindbrain catecholamine regulation of hypothalamic astrocyte glycogen metabolic enzyme protein expression: Impact of estradiol. AB - The brain astrocyte glycogen reservoir is a vital energy reserve and, in the cerebral cortex, subject among other factors to noradrenergic control. The ovarian steroid estradiol potently stimulates nerve cell aerobic respiration, but its role in glial glycogen metabolism during energy homeostasis or mismatched substrate supply/demand is unclear. This study examined the premise that estradiol regulates hypothalamic astrocyte glycogen metabolic enzyme protein expression during normo- and hypoglycemia in vivo through dorsomedial hindbrain catecholamine (CA)-dependent mechanisms. Individual astrocytes identified in situ by glial fibrillary acidic protein immunolabeling were laser-microdissected from the ventromedial hypothalamic (VMH), arcuate hypothalamic (ARH), and paraventricular hypothalamic (PVH) nuclei and the lateral hypothalamic area (LHA) of estradiol (E)- or oil (O)-implanted ovariectomized (OVX) rats after insulin or vehicle injection, and pooled within each site. Stimulation [VMH, LHA] or suppression [PVH, ARH] of basal glycogen synthase (GS) protein expression by E was reversed in the former three sites by caudal fourth ventricular pretreatment with the CA neurotoxin 6-hydroxydopamine (6-OHDA). E diminished glycogen phosphorylase (GP) protein profiles by CA-dependent [VMH, PVH] or -independent mechanisms [LHA]. Insulin-induced hypoglycemia (IIH) increased GS expression in the PVH in OVX+E, but reduced this protein in the PVH, ARH, and LHA in OVX+O. Moreover, IIH augmented GP expression in the VMH, LHA, and ARH in OVX+E and in the ARH in OVX+O, responses that normalized by 6-OHDA. Results demonstrate site specific effects of E on astrocyte glycogen metabolic enzyme expression in the female rat hypothalamus, and identify locations where dorsomedial hindbrain CA input is required for such action. Evidence that E correspondingly increases and reduces basal GS and GP in the VMH and LHA, but augments the latter protein during IIH suggests that E regulates glycogen content and turnover in these structures during glucose sufficiency and shortage. PMID- 25701714 TI - Coalescence of deep and superficial epileptic foci into larger discharge units in adult rat neocortex. AB - Epilepsy is a disease of neuronal hyper-synchrony that can involve both neocortical and hippocampal brain regions. While much is known about the network properties of the hippocampus little is known of how epileptic neocortical hyper synchrony develops. We aimed at characterizing the properties of epileptic discharges of a neocortical epileptic focus. We established a multi-electrode array method to record the spatial patterns of epileptiform potentials in acute adult rat brain slices evoked by 4-Aminopyridine in the absence of magnesium. Locations of discharges mapped to two anatomical regions over the somatosensory cortex and over the lateral convexity separated by a gap at a location matching the dysgranular zone. Focal epileptiform discharges were recorded in superficial and deep neocortical layers but over superficial layers, they exhibited larger surface areas. They were often independent even when closely spaced to one another but they became progressively coupled resulting in larger zones of coherent discharge. The gradual coupling of multiple, independent, closely spaced, spatially restricted, focal discharges between deep and superficial neocortical layers represents a possible mechanism of the development of an epileptogenic zone. PMID- 25701715 TI - RIP140 as a novel therapeutic target in the treatment of atherosclerosis. PMID- 25701716 TI - Does the ending matter? The role of gender-to-ending consistency in sentence reading. AB - In many languages, during language comprehension the cognitive system needs to recover grammatical gender features in order to identify agreement dependencies established between different sentence constituents. A two-route model proposes that gender can be retrieved either lexically or computing its correlations with the word-form. However, evidence supporting this model has been collected thus far only with metalinguistic tasks on isolated nouns or word pairs. The present ERP study was aimed at testing whether the system is sensitive to gender formal cues within a sentence context. Specifically, we investigated the time course of gender processing in sentence reading where the target nouns could show a reliable gender-related ending (i.e., transparent nouns) or an ambiguous ending (i.e., opaque nouns). The results showed a greater central-anterior negativity for transparent nouns than for opaque nouns between 200 ms and 500 ms, suggesting that the system can rapidly detect reliable formal cues to gender. In addition, gender agreement violations showed a LAN-P600 pattern that was not modulated by the gender-to-ending consistency. Taken together, these results confirm that also during sentence comprehension, distributional gender cues conveyed by noun endings can be detected. This finding is compatible with the existence of a form based route. The formal cues to gender are detected at an early stage, this probably being part of the word recognition process. Whereas this distributional information does not seem to be crucial in computing agreement dependencies within a sentence context. PMID- 25701717 TI - Neural evidence reveals the rapid effects of reward history on selective attention. AB - Selective attention is often framed as being primarily driven by two factors: task-relevance and physical salience. However, factors like selection and reward history, which are neither currently task-relevant nor physically salient, can reliably and persistently influence visual selective attention. The current study investigated the nature of the persistent effects of irrelevant, physically non salient, reward-associated features. These features affected one of the earliest reliable neural indicators of visual selective attention in humans, the P1 event related potential, measured one week after the reward associations were learned. However, the effects of reward history were moderated by current task demands. The modulation of visually evoked activity supports the hypothesis that reward history influences the innate salience of reward associated features, such that even when no longer relevant, nor physically salient, these features have a rapid, persistent, and robust effect on early visual selective attention. PMID- 25701718 TI - Measuring brain lipids. AB - The rapid development of analytical technology has made lipidomics an exciting new area and this review will focus more on modern approaches to lipidomics than on earlier technology. Although not fully comprehensive for all possible brain lipids, the intent is to at least provide a reference for the analysis of classes of lipids found in brain and nervous tissue. We will discuss problems posed by the brain because of its structural and functional heterogeneity, the development changes it undergoes (myelination, aging, pathology etc.) and its cellular heterogeneity (neurons, glia etc.). Section 2 will discuss the various ways in which brain tissue can be extracted to yield lipids for analysis and section 3 will cover a wide range of techniques used to analyze brain lipids such as chromatography and mass-spectrometry. In Section 4 we will discuss ways of analyzing some of the specific biologically active brain lipids found in very small amounts except in pathological conditions and section 5 looks to the future of experimental lipidomic modification in the brain. This article is part of a Special Issue entitled Brain Lipids. PMID- 25701719 TI - Physiological feedback regulation of cholesterol biosynthesis: Role of translational control of hepatic HMG-CoA reductase and possible involvement of oxylanosterols. AB - Feedback regulation of cholesterol biosynthesis provides a mechanism to adapt to varying cholesterol input while maintaining rather constant serum and tissue cholesterol levels. The molecular mechanisms by which this occurs have been the subject of extensive investigation. This review focuses on the physiological mechanisms by which this regulation occurs. In animals that are sensitive to dietary cholesterol such as Golden Syrian hamsters, feedback regulation occurs mainly at the level of transcription of hepatic HMG-CoA reductase (3-hydroxy-3 methylglutaryl coenzyme A reductase). In animals like the Sprague Dawley rat that are resistant to the serum cholesterol raising action of dietary cholesterol, regulation occurs mainly at the level of translation efficiency of hepatic HMG CoA reductase. Oxylanosterols were shown to effectively decrease translation of HMG-CoA reductase mRNA. Dietary cholesterol acts to significantly lower transcription of squalene epoxidase and lanosterol 14alpha demethylase favoring accumulation of the putative regulatory oxylanosterol-3beta-hydroxylanosterol-8 en-32-al. Thus, decreased transcription of enzymes occurring late in the cholesterol biosynthetic pathway appears to result in decreased translation of hepatic HMG-CoA reductase mRNA. These findings indicate that pronounced physiological feedback regulation of cholesterol biosynthesis in cholesterol resistant animals occurs at the level of translational efficiency without substantial reduction in hepatic HMG-CoA reductase transcription. PMID- 25701720 TI - Experience Sampling Methodology reveals similarities in the experience of passage of time in young and elderly adults. AB - Many people accept the idea that time seems to pass more quickly as they get older, as if this is a psychological reality. However, systematic investigations of differences in judgments of passage of time between young and elderly people are very rare and contradictory. The present study examined the experience of passage of time in daily life in young and elderly people using Experience Sampling Methodology (ESM), with 8 alerts per day for 5 days being delivered by smartphones. At each alert, a short questionnaire was filled in, asking questions about passage of present time, affective state, arousal level, and attention to current activities, among others. Our ESM study found no difference between the young and the old participants in the judgment of passage of present time. Irrespective of the participants' age, the experience of passage of time in every day life was significantly related to affective states and current activities when they captured attention. PMID- 25701721 TI - Ipragliflozin, an SGLT2 inhibitor, exhibits a prophylactic effect on hepatic steatosis and fibrosis induced by choline-deficient l-amino acid-defined diet in rats. AB - Ipragliflozin is a selective sodium glucose cotransporter 2 (SGLT2) inhibitor that increases urinary glucose excretion by inhibiting renal glucose reabsorption and thereby causes a subsequent antihyperglycemic effect. As nonalcoholic fatty liver disease (NAFLD), including nonalcoholic steatohepatitis (NASH), is closely linked to metabolic diseases such as obesity and diabetes, we investigated the effect of ipragliflozin on NAFLD in rats fed a choline-deficient l-amino acid defined (CDAA) diet. Five weeks after starting the CDAA diet, rats exhibited hepatic triglyceride (TG) accumulation, fibrosis, and mild inflammation. Repeated oral administration of ipragliflozin (3mg/g, once daily for 5 weeks) prevented both hepatic TG accumulation (188 vs.290 mg/g tissue vehicle-treated group; P<0.001) and large lipid droplet formation. Further, ipragliflozin exerted a prophylactic effect on liver fibrosis, as indicated by a marked decrease in hydroxyproline content and fibrosis score. Pioglitazone, which is known to be effective on hepatic fibrosis in CDAA diet-fed rats as well as NASH patients with type 2 diabetes mellitus (T2DM), also exerted a mild prophylactic effect on fibrosis, but not on hepatic TG accumulation or inflammation. In conclusion, ipragliflozin prevented hepatic TG accumulation and fibrosis in CDAA-diet rats. These findings suggest the therapeutic potential of ipragliflozin for patients with NAFLD. PMID- 25701722 TI - Trypsin-induced biphasic regulation of tone in the porcine lower esophageal sphincter. AB - The lower esophageal sphincter (LES) plays an important role in coordinated esophageal motility. The present study aimed to elucidate how trypsin affects LES contractility. Porcine LES circular smooth muscle strips were prepared. Contractile responses to trypsin were assessed. Trypsin (300nM) induced a transient contraction. At concentrations of 1MUM or higher, trypsin induced biphasic responses, consisting of a transient contraction followed by a transient relaxation. Pretreatment with either 1MUM tetrodotoxin or carbenoxolone had no effect on these responses. In contrast, trypsin-induced responses were completely blocked by pretreatment with the serine protease inhibitor. Pretreatment with 10MUM FSLLRY-NH2, a PAR2 antagonist, significantly inhibited trypsin-induced biphasic responses. Trypsin (1MUM)-induced contractions were partially inhibited by pretreatment with 10MUM Y-27632. In addition, trypsin (10MUM)-induced relaxation was partially inhibited by pretreatment with 10MUM Y-27632, 10MUM PD98059 or 10MUM SB203580. Trypsin-induced relaxation was abolished by increasing the extracellular K(+) concentration to 40mM, but not by pretreatment with l arginine methyl ester. Furthermore, trypsin-induced relaxation was partially inhibited by pretreatment with 10MUM glibenclamide or 1MUM 4-aminopyridine. Trypsin causes biphasic regulation of LES tone by directly acting on smooth muscle. Rho-associated protein kinase (ROK) is involved in trypsin-induced contraction, whereas ROK, ERK1/2, p38MAPK, and membrane hyperpolarization are involved in relaxation. The regulation of LES tone by trypsin may play a role in esophageal motility. PMID- 25701723 TI - Long-term imipramine treatment increases N-methyl-d-aspartate receptor activity and expression via epigenetic mechanisms. AB - Imipramine, a major antidepressant, is known to inhibit reuptake of serotonin and norepinephrine, which contributes to recovery from major depressive disorder. It has recently been reported that acute imipramine treatment inhibits N-methyl-d aspartate (NMDA) receptor activity. However, the mechanisms underlying long-term effects of imipramine have not been identified. We tested these distinct effects in mouse cortical neurons and found that acute (30s) imipramine treatment decreased Ca(2+) influx through NMDA receptors, whereas long-term treatment (48h) increased Ca(2+) influx via the same receptors. Furthermore, long-term treatment increased NMDA receptor 2B (NR2B) subunit expression via epigenetic changes, including increased acetylation of histones H3K9 and H3K27 in the NR2B promoter and decreased activity of histone deacetylase 3 (HDAC3) and HDAC4. These results suggest that the long-term effects of imipramine on NMDA receptors are quite different from its acute effects. Furthermore, increased NR2B expression via epigenetic alterations might be a part of the mechanism responsible for this long term effect. PMID- 25701724 TI - The effects of A-803467 on cardiac Nav1.5 channels. AB - A-803467 is a selective Nav1.8 blocker, but its mechanism of action at cardiac sodium channels is uncertain. Thus, we investigated the mechanistic effects of A 803467 on cardiac sodium channels in isolated mouse ventricular myocytes and in human embryonic kidney 293 (HEK293) cell lines that transiently expressed Nav1.5/SCN5A, the predominant cardiac sodium channel. At 0.3MUM and greater, A 803467 blocked cardiac sodium currents in a dose-dependent manner in both ventricular myocytes and in SCN5A-expressing HEK293 cell lines. In both models, the drug caused significant depolarizing shifts at the conductance voltage relationship midpoint, hyperpolarizing shifts in voltage-dependent channel inactivation, and slower recovery from inactivation. Also, the drug reduced sodium current amplitude in a frequency-dependent manner, and blocked late sodium currents, accelerated inactivation, and enhanced the intermediate inactivation state. Our results provide strong evidence that A-803467 affects multiple biophysical characteristics of the canonical cardiac Nav1.5 channel and our data can be used to study potential applications of A-803467 as an antiarrhythmic drug. PMID- 25701725 TI - Erythroid differentiation ability of butyric acid analogues: identification of basal chemical structures of new inducers of foetal haemoglobin. AB - Several investigations have demonstrated a mild clinical status in patients with beta-globin disorders and congenital high persistence of foetal haemoglobin. This can be mimicked by a pharmacological increase of foetal gamma-globin genes expression and foetal haemoglobin production. Our goal was to apply a multistep assay including few screening methods (benzidine staining, RT-PCR and HPLC analyses) and erythroid cellular model systems (the K562 cell line and erythroid precursors collected from peripheral blood) to select erythroid differentiation agents with foetal haemoglobin inducing potential. With this methodology, we have identified a butyric acid derivative, namely the 4174 cyclopropanecarboxylic acid compound, able to induce erythroid differentiation without antiproliferative effect in K562 cells and increase of gamma-globin gene expression in erythroid precursor cells. The results are relevant for pharmacological treatments of haemoglobinopathies, including beta-thalassaemia and sickle cell anaemia. PMID- 25701726 TI - Quercetin protects gastric epithelial cell from oxidative damage in vitro and in vivo. AB - Epithelial injury caused by reactive oxygen species (ROS) including H2O2 plays a critical role in the pathogenesis of gastric disorders. Therefore, pharmacological intervention targeting reactive oxygen species elimination has highly clinical values in therapy of gastric diseases. Although quercetin has been found to possess gastroprotective activity, whether it has a protective activity againress related injury to gastric epithelial cells remains unknown. The aim of the study is herein to investigate a possible protective effect of quercetin against oxidative stress in vitro and vivo. Human gastric epithelial GES-1 cells were pretreated with quercetin and then challenged with H2O2. In vivo reactive oxygen species production in acute gastric mocosa injury was assessed using a chemiluminescent probe L-012 (8-amino-5-chloro-7-phenylpyrido [3,4 d]pyridazine-1,4-(2H,3H)dione) after quercetin was administered to mice. In GES-1 cells, pretreatment of quercetin can significantly diminish H2O2-induced cell viability loss; decrease intracellular reactive oxygen species and Ca(2+) influx; restore H2O2-induced DeltaPsim dissipation. It also upregulates peroxisome proliferator-activated receptor-gamma coactivator (PGC-1alpha) expression under the state of oxidative stress, and the downstream cell apoptosis significantly decreased. In vivo, chemiluminescence imaging shows that quercetin attenuates reactive oxygen species production and gastric damages in acute gastric mucosal injury. We first reported the evidence that quercetin can protect gastric epithelial GES-1 cells from oxidative damage and ameliorate reactive oxygen species production during acute gastric mucosal injury in mice. This might be ascribed to its inhibition of oxidative stress, regulation of mitochondrial dysfunction, initiation of antioxidant defense and inhibition of apoptosis. PMID- 25701727 TI - Redox-responsive mesoporous silica as carriers for controlled drug delivery: a comparative study based on silica and PEG gatekeepers. AB - Hybrid mesoporous silica nanoparticles (MSNs) modified with polymer polyethylene glycol (PEG) through the biodegradable disulfide bonds were prepared to achieve 'on demand' drug release. In this system, PEG chains were chosen as the representative gatekeepers that can block drugs within the mesopores of MSNs. After the addition of glutathione (GSH), the gatekeepers were removed from the pore outlets of MSNs, followed by the release of encapsulated drugs. In this research, the effects of grafting density of gatekeepers on the drug release and biocompatibility of silica carriers were also investigated. First, PEG modified MSNs were prepared by the condensation reaction between the carboxyl groups of MSN and the hydroxyl of PEG. The structure of the resultant MSN-SS-PEG was characterized by transmission electron microscopy (TEM), nitrogen adsorption/desorption isotherms analysis and Fourier transform infrared spectroscopy (FTIR). Rhodamine B (RhB) as the model drug was loaded into MSNs. The in vitro assay results indicated that RhB was released rapidly after the addition of 10 mM GSH; M1-SS-PEG had the best capping efficiency compared with M0.5 and M1.5 groups. Moreover, hemolysis assay, serum protein adsorption and cell viability test indicated that with the increase of PEG grafting density, the biocompatibility of silica carriers increased. PMID- 25701728 TI - Mortality and morbidity in a population exposed to multiple sources of air pollution: A retrospective cohort study using air dispersion models. AB - BACKGROUND AND AIMS: A landfill, an incinerator, and a refinery plant have been operating since the early 1960s in a contaminated site located in the suburb of Rome (Italy). To evaluate their potential health effects, a population-based retrospective cohort study was conducted using dispersion modeling for exposure assessment. METHODS: A fixed cohort was enrolled in the Rome Longitudinal Study in 2001, mortality and hospitalizations were followed-up until 2010. Exposure assessments to the landfill (H2S), the incinerator (PM10), and the refinery plant (SOX) were performed for each subject using a Lagrangian dispersion model. Individual and small-area variables were available (including exposures levels to NO2 from traffic and diesel trucks). Cox regression analysis was performed (hazard ratios, HRs, 95% CI) using linear terms for the exposures (5th-95th percentiles difference). Single and bi-pollutant models were run. RESULTS: The cohort included 85,559 individuals. The estimated annual average exposures levels were correlated. H2S from the landfill was associated with cardiovascular hospital admissions in both genders (HR 1.04 95% CI 1.00-1.09 in women); PM10 from the incinerator was associated with pancreatic cancer mortality in both genders (HR 1.40 95% CI 1.03-1.90 in men, HR 1.47 95% CI 1.12-1.93 in women) and with breast morbidity in women (HR 1.13 95% CI 1.00-1.27). SOx from the refinery was associated with laryngeal cancer mortality in women (HR 4.99 95% CI 1.64 15.9) and respiratory hospital admissions (HR 1.13 95% CI 1.01-1.27). CONCLUSIONS: We found an association of the pollution sources with some cancer forms and cardio-respiratory diseases. Although there was a high correlation between the estimated exposures, an indication of specific effects from the different sources emerged. PMID- 25701729 TI - Contributions of regional air pollutant emissions to ozone and fine particulate matter-related mortalities in eastern U.S. urban areas. AB - Ground-level ozone and fine particulate matter (PM2.5) are associated with adverse human health effects such as lung structure dysfunction, inflammation and infection, asthma, and premature deaths. This study estimated contributions of emissions of anthropogenic nitrogen oxides (NOx), volatile organic compounds (VOCs) and sulfur dioxides (SO2) from four regions to summertime (i.e., June, July, and August) ozone and PM2.5-related mortalities in seven major Metropolitan Statistical Areas (MSAs with more than 4 million people) in the eastern United States (U.S.). A photochemical transport model, Community Multi-scale Air Quality (CMAQ) with sensitivity analyses, was applied to quantify the contribution of the regional anthropogenic emissions to ambient ozone and PM2.5 concentrations in the seven MSAs. The results of the sensitivity analysis, along with estimates of concentration-response from published epidemiologic studies, were used to estimate excess deaths associated with changes in ambient daily 8-h average ozone and daily PM2.5 concentrations during the summer of 2007. The results show that secondary PM2.5 (i.e., PM2.5 formed in the atmosphere) had larger effects on mortality (95% confidence interval (C.I.) ranged from 700 to 3854) than ambient ozone did (95% C.I. was 470-1353) in the seven MSAs. Emissions of anthropogenic NOx, VOCs and SO2 from the northeastern U.S. could cause up to about 2500 ozone and PM2.5-related deaths in the urban areas examined in this study. The results also show that the contributions of emissions from electrical generating units (EGUs) and anthropogenic non-EGU sources to ozone-related mortality in the MSAs were similar. However, emissions from EGUs had a more significant impact on PM2.5 related deaths than anthropogenic emissions from non-EGUs sources did. Anthropogenic NOx and VOCs emissions from the regions where the MSAs are located had the most significant contributions to ozone-related mortalities in the eastern U.S. urban areas. On the other hand, PM2.5-related mortalities in the MSAs were more likely to be affected by precursors transported from other regions. PMID- 25701730 TI - In vivo functional characterization of the transmembrane histidine kinase KinC in Bacillus subtilis. AB - In response to starvation, Bacillus subtilis cells differentiate into different subsets, undergoing cannibalism, biofilm formation or sporulation. These processes require a multiple component phosphorelay, wherein the master regulator Spo0A is activated upon phosphorylation by one or a combination of five histidine kinases (KinA-KinE) via two intermediate phosphotransferases, Spo0F and Spo0B. In this study, we focused on KinC, which was originally identified as a sporulation kinase and was later shown to regulate cannibalism and biofilm formation. First, genetic experiments using both the domesticated and undomesticated (biofilm forming) strains revealed that KinC activity and the membrane localization are independent of both the lipid raft marker proteins FloTA and cytoplasmic potassium concentration, which were previously shown to be required for the kinase activity. Next, we demonstrated that KinC controls cannibalism and biofilm formation in a manner dependent on phosphorelay. For further detailed characterization of KinC, we established an IPTG-inducible expression system in the domesticated strain, in which biofilm formation is defective, for simplicity of study. Using this system, we found that the N-terminal transmembrane domain is dispensable but the PAS domain is needed for the kinase activity. An in vivo chemical cross-linking experiment demonstrated that the soluble and functional KinC (KinC(DeltaTM1+2)) forms a tetramer. Based on these results, we propose a revised model in which KinC becomes active by forming a homotetramer via the N terminal PAS domain, but its activity is independent of both the lipid raft and the potassium leakage, which was previously suggested to be induced by surfactin. PMID- 25701731 TI - Dephosphorylated NPr is involved in an envelope stress response of Escherichia coli. AB - Besides the canonical phosphoenolpyruvate-dependent phosphotransferase system (PTS) for carbohydrate transport, most Proteobacteria possess the so-called nitrogen PTS (PTS(Ntr)) that transfers a phosphate group from phosphoenolpyruvate (PEP) over enzyme I(Ntr) (EI(Ntr)) and NPr to enzyme IIA(Ntr) (EIIA(Ntr)). The PTS(Ntr) lacks membrane-bound components and functions exclusively in a regulatory capacity. While EIIA(Ntr) has been implicated in a variety of cellular processes such as potassium homeostasis, phosphate starvation, nitrogen metabolism, carbon metabolism, regulation of ABC transporters and poly-beta hydroxybutyrate accumulation in many Proteobacteria, the only identified role of NPr is the regulation of biosynthesis of the lipopolysaccharide (LPS) layer by direct interaction with LpxD in Escherichia coli. In this study, we provide another phenotype related to NPr. Several lines of evidence demonstrate that E. coli strains with increased levels of dephosphorylated NPr are sensitive to envelope stresses, such as osmotic, ethanol and SDS stresses, and these phenotypes are independent of LpxD. The C-terminal region of NPr plays an important role in sensitivity to envelope stresses. Thus, our data suggest that the dephospho-form of NPr affects adaptation to envelope stresses through a C terminus-dependent mechanism. PMID- 25701732 TI - PinR mediates the generation of reversible population diversity in Streptococcus zooepidemicus. AB - Opportunistic pathogens must adapt to and survive in a wide range of complex ecosystems. Streptococcus zooepidemicus is an opportunistic pathogen of horses and many other animals, including humans. The assembly of different surface architecture phenotypes from one genotype is likely to be crucial to the successful exploitation of such an opportunistic lifestyle. Construction of a series of mutants revealed that a serine recombinase, PinR, inverts 114 bp of the promoter of SZO_08560, which is bordered by GTAGACTTTA and TAAAGTCTAC inverted repeats. Inversion acts as a switch, controlling the transcription of this sortase-processed protein, which may enhance the attachment of S. zooepidemicus to equine trachea. The genome of a recently sequenced strain of S. zooepidemicus, 2329 (Sz2329), was found to contain a disruptive internal inversion of 7 kb of the FimIV pilus locus, which is bordered by TAGAAA and TTTCTA inverted repeats. This strain lacks pinR and this inversion may have become irreversible following the loss of this recombinase. Active inversion of FimIV was detected in three strains of S. zooepidemicus, 1770 (Sz1770), B260863 (SzB260863) and H050840501 (SzH050840501), all of which encoded pinR. A deletion mutant of Sz1770 that lacked pinR was no longer capable of inverting its internal region of FimIV. The data highlight redundancy in the PinR sequence recognition motif around a short TAGA consensus and suggest that PinR can reversibly influence the wider surface architecture of S. zooepidemicus, providing this organism with a bet-hedging solution to survival in fluctuating environments. PMID- 25701733 TI - Human neutrophils produce extracellular traps against Paracoccidioides brasiliensis. AB - Neutrophils play an important role as effector cells and contribute to the resistance of the host against microbial pathogens. Neutrophils are able to produce extracellular traps (NETs) in response to medically important fungi, including Aspergillus spp., Candida albicans and Cryptococcus gattii. However, NET production in response to Paracoccidioides brasiliensis has yet to be studied. We have demonstrated that human neutrophils produce NETs against both conidia and yeasts of P. brasiliensis. Although the NADPH oxidase inhibitor diphenyleneiodonium chloride (DPI) did not alter NET production against conidia, it partially suppressed NET formation against P. brasiliensis yeasts. Cytochalasin D or IFN-gamma did not affect the production of NETs against the fungus. Additionally, a mutant strain of P. brasiliensis with reduced expression of an alternative oxidase induced significantly higher levels of NETs in comparison with the WT strain. Finally, c.f.u. quantification of P. brasiliensis showed no significant differences when neutrophils were treated with DPI, DNase I or cytochalasin D as compared with untreated cells. These data establish that NET formation by human neutrophils appears to be either dependent or independent of reactive oxygen species production, correlating with the fungal morphotype used for stimulation. However, this mechanism was ineffective in killing the fungus. PMID- 25701734 TI - pilS loci in Neisseria gonorrhoeae are transcriptionally active. AB - Piliation is an important virulence determinant for Neisseria gonorrhoeae. PilE polypeptide is the major protein subunit in the pilus organelle and engages in extensive antigenic variation due to recombination between pilE and a pilS locus. pilS were so-named as they are believed to be transcriptionally silent, in contrast to the pilE locus. In this study, we demonstrate the presence of a small, pil-specific RNA species. Through using a series of pilE deletion mutants, we show by Northern blotting and quantitative reverse transcriptase PCR analysis (qRT-PCR), that these smaller RNA species are not derived from the primary pilE transcript following some processing events, but rather, arose through transcription of the pilS loci. Small transcriptome analysis, in conjunction with analysis of pilS recombinants, identified both sense and anti-sense RNAs originating from most, but not all, of the pilS gene copies. Focusing on the MS11 pilS6 locus, we identified by site-directed mutagenesis a sense promoter located immediately upstream of pilS6 copy 2, as well as an anti-sense promoter immediately downstream of pilS6 copy 1. Whole transcriptome analysis also revealed the presence of pil-specific sRNA in both gonococci and meningococci. Overall, this study reveals an added layer of complexity to the pilE/pilS recombination scheme by demonstrating pil-specific transcription within genes that were previously thought to be transcriptionally silent. PMID- 25701735 TI - Identification of the light-independent phosphoserine pathway as an additional source of serine in the cyanobacterium Synechocystis sp. PCC 6803. AB - L-serine is one of the proteinogenic amino acids and participates in several essential processes in all organisms. In plants, the light-dependent photorespiratory and the light-independent phosphoserine pathways contribute to serine biosynthesis. In cyanobacteria, the light-dependent photorespiratory pathway for serine synthesis is well characterized, but the phosphoserine pathway has not been identified. Here, we investigated three candidate genes for enzymes of the phosphoserine pathway in Synechocystis sp. PCC 6803. Only the gene for the D-3-phosphoglycerate dehydrogenase is correctly annotated in the genome database, whereas the 3-phosphoserine transaminase and 3-phosphoserine phosphatase (PSP) proteins are incorrectly annotated and were identified here. All enzymes were obtained as recombinant proteins and showed the activities necessary to catalyse the three-step phosphoserine pathway. The genes coding for the phosphoserine pathway were found in most cyanobacterial genomes listed in CyanoBase. The pathway seems to be essential for cyanobacteria, because it was impossible to mutate the gene coding for PSP in Synechocystis sp. PCC 6803 or in Synechococcus elongatus PCC 7942. A model approach indicates a 30-60% contribution of the phosphoserine pathway to the overall serine pool. Hence, this study verified that cyanobacteria, similar to plants, use the phosphoserine pathway in addition to photorespiration for serine biosynthesis. PMID- 25701736 TI - Factors other than metalloprotease are required for full virulence of French Vibrio tubiashii isolates in oyster larvae. AB - Vibrio tubiashii is a marine pathogen isolated from larval and juvenile bivalve molluscs that causes bacillary necrosis. Recent studies demonstrated the isolation of this species in a French experimental hatchery/nursery affecting Crassostrea gigas spat in 2007. Here, using larvae of C. gigas as an interaction model, we showed that the French V. tubiashii is virulent to larvae and can cause bacillary necrosis symptoms with an LD50 of about 2.3 * 10(3) c.f.u. ml(-1) after 24 h. Moreover, complete or gel permeation HPLC fractionated extracellular products (ECPs) of this strain appeared toxic to larvae. MS-MS analysis of the different ECP fractions revealed the existence of an extracellular metalloprotease and other suspected virulence factors. This observation is also supported by the expression level of some potential virulence factors. The overall results suggest that the pathology caused by the French V. tubiashii in C. gigas oysters is caused by a group of toxic factors and not only the metalloprotease. PMID- 25701737 TI - Chromosome-associated protein D3 promotes bacterial clearance in human intestinal epithelial cells by repressing expression of amino acid transporters. AB - BACKGROUND & AIMS: Defects in colonic epithelial barrier defenses are associated with ulcerative colitis (UC). The proteins that regulate bacterial clearance in the colonic epithelium have not been completely identified. The Drosophila chromosome-associated protein D3 (dCAP-D3) regulates responses to bacterial infection. We examined whether CAP-D3 promotes bacterial clearance in human colonic epithelium. METHODS: Clearance of Salmonella or adherent-invasive Escherichia coli LF82 was assessed by gentamycin protection assays in HT-29 and Caco-2 cells expressing small hairpin RNAs against CAP-D3. We used immunoblot assays to measure levels of CAP-D3 in colonic epithelial cells from patients with UC and healthy individuals (controls). RNA sequencing identified genes activated by CAP-D3. We analyzed the roles of CAP-D3 target genes in bacterial clearance using gentamycin protection and immunofluorescence assays and studies with pharmacologic inhibitors. RESULTS: CAP-D3 expression was reduced in colonic epithelial cells from patients with active UC. Reduced CAP-D3 expression decreased autophagy and impaired intracellular bacterial clearance by HT-29 and Caco-2 colonic epithelial cells. Lower levels of CAP-D3 increased transcription of genes encoding SLC7A5 and SLC3A2, the products of which heterodimerize to form an amino acid transporter in HT-29 cells after bacterial infection; levels of SLC7A5-SLC3A2 were increased in tissues from patients with UC compared with controls. Reduced CAP-D3 in HT-29 cells resulted in earlier recruitment of SLC7A5 to Salmonella-containing vacuoles, increased activity of mTORC1, and increased survival of bacteria. Inhibition of SLC7A5-SLC3A2 or mTORC1 activity rescued the bacterial clearance defects of CAP-D3-deficient cells. CONCLUSIONS: CAP-D3 down regulates transcription of genes that encode amino acid transporters (SLC7A5 and SLC3A2) to promote bacterial autophagy by colon epithelial cells. Levels of CAP D3 protein are reduced in patients with active UC; strategies to increase its levels might restore mucosal homeostasis to patients with active UC. PMID- 25701738 TI - Interactions Between Nuclear Receptor SHP and FOXA1 Maintain Oscillatory Homocysteine Homeostasis in Mice. AB - BACKGROUND & AIMS: Hyperhomocysteinemia is often associated with liver and metabolic diseases. We studied nuclear receptors that mediate oscillatory control of homocysteine homeostasis in mice. METHODS: We studied mice with disruptions in Nr0b2 (called small heterodimer partner [SHP]-null mice), betaine-homocysteine S methyltransferase (Bhmt), or both genes (BHMT-null/SHP-null mice), along with mice with wild-type copies of these genes (controls). Hyperhomocysteinemia was induced by feeding mice alcohol (National Institute on Alcohol Abuse and Alcoholism binge model) or chow diets along with water containing 0.18% DL homocysteine. Some mice were placed on diets containing cholic acid (1%) or cholestyramine (2%) or high-fat diets (60%). Serum and livers were collected during a 24-hour light-dark cycle and analyzed by RNA-seq, metabolomic, and quantitative polymerase chain reaction, immunoblot, and chromatin immunoprecipitation assays. RESULTS: SHP-null mice had altered timing in expression of genes that regulate homocysteine metabolism compared with control mice. Oscillatory production of S-adenosylmethionine, betaine, choline, phosphocholine, glyceophosphocholine, cystathionine, cysteine, hydrogen sulfide, glutathione disulfide, and glutathione, differed between SHP-null mice and control mice. SHP inhibited transcriptional activation of Bhmt and cystathionine gamma-lyase by FOXA1. Expression of Bhmt and cystathionine gamma-lyase was decreased when mice were fed cholic acid but increased when they were placed on diets containing cholestyramine or high-fat content. Diets containing ethanol or homocysteine induced hyperhomocysteinemia and glucose intolerance in control, but not SHP-null, mice. In BHMT-null and BHMT-null/SHP-null mice fed a control liquid, lipid vacuoles were observed in livers. Ethanol feeding induced accumulation of macrovesicular lipid vacuoles to the greatest extent in BHMT-null and BHMT-null/SHP-null mice. CONCLUSIONS: Disruption of Shp in mice alters timing of expression of genes that regulate homocysteine metabolism and the liver responses to ethanol and homocysteine. SHP inhibits the transcriptional activation of Bhmt and cystathionine gamma-lyase by FOXA1. PMID- 25701739 TI - Characterization and expression of cDNAs encoding P450c17-II (cyp17a2) in Japanese eel during induced ovarian development. AB - Estradiol-17beta (E2) and maturation-inducing hormone (MIH) are two steroid hormones produced in the teleost ovary that are required for vitellogenic growth and final oocyte maturation and ovulation. During this transition, the main steroid hormone produced in the ovary shifts from estrogens to progestogens. In the commercially important Japanese eel (Anguilla japonica), the MIH 17alpha,20beta-dihydroxy-4-pregnen-3-one (DHP) is generated from its precursor by P450c17, which has both 17alpha-hydroxylase and C17-20 lyase activities. In order to elucidate the regulatory mechanism underlying the steroidogenic shift from E2 to DHP and the mechanistic basis for the failure of this shift in artificially matured eels, the cDNA for cyp17a2-which encodes P450c17-II-was isolated from the ovary of wild, mature Japanese eel and characterized, and the expression patterns of cyp17a1 and cyp17a2 during induced ovarian development were investigated in cultured eel ovaries. Five cDNAs (types I-V) encoding P450c17-II were identified that had minor sequence variations. HEK293T cells transfected with all but type II P450c17-II converted exogenous progesterone to 17alpha-hydroxyprogesterone (17alpha-P), providing evidence for 17alpha-hydroxylase activity; however, a failure to convert 17alpha-P to androstenedione indicated that C17-20 lyase activity was absent. Cyp17a2 mRNA was expressed mainly in the head kidney, ovary, and testis, and quantitative PCR analysis demonstrated that expression in the ovary increased during induced vitellogenesis and oocyte maturation/ovulation. In contrast, P450c17-I showed both 17alpha-hydroxylase and C17-20 lyase activities, and cyp17a1 expression increased until the mid-vitellogenic stage and remained high thereafter. Considering the high level of cyp17a2 transcript in the eel ovary at the migratory nucleus stage together with our previous report demonstrating that eel ovaries have strong 17alpha-P-to-DHP conversion activity, the failure of artificially maturing eels to produce the maturation-inducing DHP may be explained by a deficiency in 17alpha-P production due to the persistence of cyp17a1 expression after the completion of vitellogenesis. PMID- 25701740 TI - Lack of oblique astigmatism in the chicken eye. AB - Primate eyes display considerable oblique off-axis astigmatism which could provide information on the sign of defocus that is needed for emmetropization. The pattern of peripheral astigmatism is not known in the chicken eye, a common model of myopia. Peripheral astigmatism was mapped out over the horizontal visual field in three chickens, 43 days old, and in three near emmetropic human subjects, average age 34.7years, using infrared photoretinoscopy. There were no differences in astigmatism between humans and chickens in the central visual field (chicks -0.35D, humans -0.65D, n.s.) but large differences in the periphery (i.e. astigmatism at 40 degrees in the temporal visual field: humans -4.21D, chicks -0.63D, p<0.001, unpaired t-test). The lack of peripheral astigmatism in chicks was not due to differences in corneal shape. Perhaps related to their superior peripheral optics, we found that chickens had excellent visual performance also in the far periphery. Using an automated optokinetic nystagmus paradigm, no difference was observed in spatial visual performance with vision restricted to either the central 67 degrees of the visual field or to the periphery beyond 67 degrees . Accommodation was elicited by stimuli presented far out in the visual field. Transscleral images of single infrared LEDs showed no sign of peripheral astigmatism. The chick may be the first terrestrial vertebrate described to lack oblique astigmatism. Since corneal shape cannot account for the difference in astigmatism in humans and chicks, it must trace back to the design of the crystalline lens. The lack of peripheral astigmatism in chicks also excludes a role in emmetropization. PMID- 25701741 TI - Discriminating anisometropic amblyopia from myopia based on interocular inhibition. AB - Amblyopia screening during childhood is critical for early detection and successful treatment. In the current study, we develop and evaluate a screening method that exploits the imbalanced interocular inhibition between amblyopic and fellow eyes. In nineteen subjects with anisometropic amblyopia and twenty-two age matched subjects with myopia, we measured the area under the contrast sensitivity functions (AUCSFs) in eight monocular conditions defined by the tested eye (left, right), patching of the untested eye (translucent, opaque), and refractive status (corrected, uncorrected). For each tested eye, we defined the inhibition index as the ratio between the AUCSF values obtained in the translucent and opaque patching conditions of the untested eye. To evaluate the screening potential of the inhibition index, we compared results from patients with amblyopia and myopia. With and without optical correction, the index was significantly lower in the amblyopic eye than in the fellow eye of the amblyopic subjects and both eyes of the myopic subjects. No significant difference was found among the two eyes of the myopic subjects and the fellow eyes of the amblyopic subjects. With the inhibition index as the predictor, a logistic regression model successfully discriminated amblyopic eyes from myopic eyes with 100% accuracy in the uncorrected condition. In the corrected condition, with the inhibition index and interocular visual acuity difference as predictors, amblyopic eyes were likewise discriminated from myopic eyes with 100% accuracy. This pattern of CSF changes, caused by the different patching modes of the untested eye, provides a potential CSF signature to discriminate anisometropic amblyopia from myopia. PMID- 25701742 TI - Characterization of co-circulating swine influenza A viruses in North America and the identification of a novel H1 genetic clade with antigenic significance. AB - Multiple genetically and antigenically distinct hemagglutinin genes of the H1 and H3 influenza A virus (IAV) subtypes co-circulate in North American swine. This diversity has evolved by repeated transmission of IAVs from humans to swine and subsequent antigenic drift in swine. To understand the evolutionary dynamics of these diverse HA lineages in North American swine, we undertook a phylogenetic analysis of 1576 H1 and 607 H3 HA gene segments, as well as 834 N1 and 1293 N2 NA gene segments, and 2126 M gene segments. These data revealed yearly co circulation of H1N1, H1N2, and H3N2 viruses, with three HA clades representing the majority of the HA sequences: of the H1 viruses, 42% were classified as H1delta1 and 40.6% were classified as H1gamma; and of the H3 viruses 53% were classified as cluster IV-A H3N2. We detected a genetically distinct minor clade consisting of 37 H1 viruses isolated between 2003 and 2013, which we classified as H1gamma-2. We estimated that this clade circulated in swine since approximately 1995, but it was not detected in swine until 2003. Though this clade only represents 1.07% of swine H1 sequences reported over the past 10 years, hemagglutination inhibition (HI) assays demonstrated that representatives of this clade of viruses are antigenically distinct, and, when measured using antigenic cartography, were as many as 7 antigenic units from other H1gamma viruses. Therefore vaccines against the contemporary H1gamma viruses are not likely to cross-protect against gamma-2 viruses. The long-term circulation of these gamma-2 viruses suggests that minor populations of viruses may be underreported in the national dataset given the long branch lengths and gaps in detections. The identification of these gamma-2 viruses demonstrates the need for robust surveillance to capture the full diversity IAVs in swine in the USA and the importance of antigenic drift in the diversification and emergence of new antigenic variants in swine, which complicates vaccine design. PMID- 25701743 TI - Peptide display on a surface loop of human parvovirus B19 VP2: Assembly and characterization of virus-like particles. AB - Virus-like particles (VLPs) are valuable tools for nanotechnology and nanomedicine. These particles are obtained by the self-assembly, either in vivo or in vitro, of structural proteins of viral capsids. VLPs are excellent scaffolds for surface display of molecules. The N-termini of the structural proteins of human parvovirus B19 (B19V) have been already modified to display peptides or proteins. However, other surface-exposed elements have not been studied as potential locations for peptide display. In this research, we tested the potential of surface loop 62-75 of VP2 protein for the presentation of a 64 residue heterologous peptide. The chimeric protein was able to self-assemble in vitro into VLPs. Improved colloidal stability was observed for these particles, indicating that the peptide is on the surface of the particle. AFM analysis of the chimeric particles shows no obvious difference between the surfaces of particles assembled with VP2 and those assembled with the chimeric VP2. Our results indicate that loop 62-75 is a good candidate for heterologous peptide presentation on the surface of B19V VLPs. PMID- 25701744 TI - Construction and immunogenicity of a recombinant pseudorabies virus co-expressing porcine circovirus type 2 capsid protein and interleukin 18. AB - A novel recombinant pseudorabies virus (PRV) expressing porcine circovirus type 2 (PCV2) capsid protein and IL-18 was constructed. The PCV2 open reading frame 2 (ORF2) and porcine IL-18 genes were amplified by PCR and then inserted into the PRV transfer vector (pG) to produce a recombinant plasmid (pGO18). Plasmid pGO18 was transfected into porcine kidney cell (PK15) pre-infected with PRV HB98 vaccine strain to generate a recombinant virus. The recombinant virus PRV-ORF2 IL18 was purified by green fluorescent plaque purification and the inserts were confirmed by PCR, enzyme digestion, sequencing, and Western blot. The humoral and cellular responses induced by the recombinant virus were assessed in mice. Mice (n=10) were immunized with PRV-ORF2-IL18, PRV-ORF2, PRV HB98, or inactivated PCV2. PRV-ORF2-IL18 elicited high titers of ELISA and serum neutralizing antibodies and strong cell-mediated immune responses in mice as indicated by anti PCV2 ELISA, PRV-neutralizing assay, PCV2 specific lymphocyte proliferation assay, CD3(+), CD4(+) and CD8(+) T lymphocytes analysis, respectively. And PRV-ORF2-IL18 immunization protected mice against a lethal challenge of a virulent PRV Fa strain and significantly reduced the amount of PCV2 viremia. These results suggest an adjuvant effect of IL-18 on cellular immune responses. The recombinant virus might be an attractive candidate vaccine for preventing PCV2 and PRV infections in pigs. PMID- 25701745 TI - Annexin 2 is a host protein binding to classical swine fever virus E2 glycoprotein and promoting viral growth in PK-15 cells. AB - Glycoprotein E2 of classical swine fever virus (CSFV) is a key determinant and major immunogen for viral entry and immunity, but little is known about its interaction with host proteins. In a previous study, we showed by proteomic analysis that cellular membrane protein annexin 2 (Anx2) was up-regulated in PK 15 cells following CSFV infection, but its function in CSFV replication remains unknown. In the present study we observed the interaction of Anx2 with CSFV E2 following infection of PK-15 cells by co-immunoprecipitation (Co-IP), mass spectrometry, Western blot and confocal laser scanning microscopy. The interaction between CSFV E2 and Anx2 was further confirmed in an E2-expressing PK 15 cell line, in which up-regulation of Anx2 was also observed, indicating that E2 alone can interact with, and increase, the expression of Anx2 protein. Further studies showed that siRNA-mediated knock-down and plasmid-mediated over expression of Anx2 in PK-15 cells inhibited and increased CSFV replication and proliferation respectively. Remarkably, treatment of PK-15 cells with Anx2 specific polyclonal antibody prior to virus infection significantly inhibited CSFV multiplication, indicating that Anx2 is a cellular membrane protein likely associated with CSFV entry into cells. In conclusion, Anx2 is the novel host protein identified to interact with CSFV E2 and promote CSFV multiplication. These observations provide support for the potential use of Anx2 as a cellular target for the development of novel anti-CSFV therapies. PMID- 25701746 TI - Systems pharmacology-based drug discovery for marine resources: an example using sea cucumber (Holothurians). AB - ETHNOPHARMACOLOGICAL RELEVANCE: Sea cucumber, a kind of marine animal, have long been utilized as tonic and traditional remedies in the Middle East and Asia because of its effectiveness against hypertension, asthma, rheumatism, cuts and burns, impotence, and constipation. In this study, an overall study performed on sea cucumber was used as an example to show drug discovery from marine resource by using systems pharmacology model. The value of marine natural resources has been extensively considered because these resources can be potentially used to treat and prevent human diseases. However, the discovery of drugs from oceans is difficult, because of complex environments in terms of composition and active mechanisms. Thus, a comprehensive systems approach which could discover active constituents and their targets from marine resource, understand the biological basis for their pharmacological properties is necessary. MATERIALS AND METHODS: In this study, a feasible pharmacological model based on systems pharmacology was established to investigate marine medicine by incorporating active compound screening, target identification, and network and pathway analysis. RESULTS: As a result, 106 candidate components of sea cucumber and 26 potential targets were identified. Furthermore, the functions of sea cucumber in health improvement and disease treatment were elucidated in a holistic way based on the established compound-target and target-disease networks, and incorporated pathways. CONCLUSIONS: This study established a novel strategy that could be used to explore specific active mechanisms and discover new drugs from marine sources. PMID- 25701747 TI - Identification of anti-inflammatory constituents from Kalimeris indica with UHPLC ESI-Q-TOF-MS/MS and GC-MS. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Kalimeris indica is a Miao's medicinal plant in Guizhou province of China employing to treat various inflammation-related diseases in clinical. The study aims to determine the active fractions of K. indica for its anti-inflammatory activity and to identify their chemical constituents. MATERIAL AND METHODS: The dried K. indica herb was extracted with 50% aqueous ethanol and then successively separated with macroporous resin and MCI column chromatography to give five fractions (A-E). The anti-inflammatory effects were determined by measuring the NO and TNF-alpha production in murine macrophage RAW 264.7 cells after exposure to LPS. The chemical constituents of the anti-inflammatory fractions were analyzed by the method of UHPLC-ESI-Q-TOF/MS or GC-MS. RESULTS: Five fractions (A-E) of different polarities were prepared from the 50% ethanol extract. Factions C and E showed significant inhibition of NO and TNF-alpha production. Six constituents, namely 3,4-dicaffeoylquinic acid (1), 3,5-dicaffeoylquinic acid (2), 1,5-dicaffeoylquinic acid (3), rutin (4), 1 malonyl-3,5-dicaffeoylquinic acid (5), and 4,5-dicaffeoylquinic acid (6) were identified from the active fraction C by UHPLC-ESI-Q-TOF/MS. Four compounds including 13-tetradecenal (7), (Z,Z)-9,12-octadecadienoic acid (8), (3alpha)-12 oleanen-3-yl acetate (9), and (+)-3-oxo-urs-12-en-24-oic acid methyl ester (10) were identified from the active fraction E by GC-MS. CONCLUSION: K. indica possessed pronounced anti-inflammatory effect. Dicaffeoylquinic acids and their dirivatives, rutin, as well as oleanolic and fatty acid derivatives are the major constituents and possibly the anti-inflammatory principles of the active fractions of K. indica. All the compounds were identified in K. indica for the first time. The work provided evidence for further development and utilization of K. indica and formed a basis for the establishment of quality control methods and standards for K. indica and its pharmaceutical preparations. PMID- 25701748 TI - Scutellarin protects against the liver injury induced by diosbulbin B in mice and its mechanism. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Diosbulbin B (DB) is the main hepatotoxic compound distributed in Dioscorea bulbifera L., which is widely used for the treatment of cancer and thyroid disorders in Asia. Scutellarin (SC) is the main compound in medicinal herb Scutellaria barbata D. Don, which is usually combined with Dioscorea bulbifera used for cancer therapy in clinic. AIM OF THE STUDY: This study aims to investigate the protection of SC against the liver injury induced by DB and its engaged mechanism. In addition, the anti-tumor effect of DB and SC is further observed in vivo. MATERIALS AND METHODS: The protection of SC against DB-induced liver injury was evaluated by detecting serum alanine/aspartate aminotransferases (ALT/AST) and alkaline phosphatase (ALP) activities, and further liver histological observation. The inflammatory response was assessed by detecting liver myeloperoxidase (MPO) activity, and serum levels of tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), and interferon gamma (IFN-gamma). Western-blot analysis was used to detect the protein expression. The oxidative liver injury was evaluated by detecting liver malondialdehyde (MDA) and glutathione (GSH) contents, and glutathione peroxidase (GPx) enzymatic activity. In vivo anti-tumor activity was analyzed in S180 tumor bearing mice. RESULTS: SC significantly decreased the increased serum ALT/AST, and ALP activities induced by DB. Liver histological observation evidenced the protection of SC against DB-induced liver injury. SC obviously reduced the increased liver MPO activity and the number of MPO-positive staining cells induced by DB. SC also reversed the decreased expression of inhibitor of kappaB (IkappaB) and the translocation of nuclear factor kappaB (NF-kappaB) p65 from cytoplasm to nucleus induced by DB. In addition, SC significantly abrogated the increased serum levels of TNF-alpha, IL-6, and IFN-gamma induced by DB. SC decreased the increased liver MDA content induced by DB significantly, and it also increased liver GSH level. The decreased GPx protein expression and its enzymatic activity induced by DB were both obviously reversed after SC treatment. The results in S180 tumor-bearing mice showed that SC combined with DB significantly inhibited tumor growth in vivo. CONCLUSIONS: Our results demonstrate that SC prevents DB-induced liver injury by attenuating NF-kappaB mediated hepatic inflammation and ameliorating liver oxidative stress injury. Meanwhile, DB plus SC has significant anti-tumor activity in vivo. This study indicates the potential combination of DB with SC for the treatment of cancer in clinic. PMID- 25701749 TI - Chemical and biological comparison of raw and vinegar-baked Radix Bupleuri. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Radix Bupleuri (RB) is a commonly used herbal drug in Traditional Chinese Medicine (TCM), and it can be baked with vinegar to afford vinegar-baked Radix Bupleuri (VBRB), which is used in TCM for liver diseases treatment. In this study, the chemical compositions and biological effects between raw and two processed RBs by different vinegars were systematically compared. MATERIALS AND METHODS: The chemical compositions of raw and two processed RBs were analyzed by (1)H NMR spectroscopy coupled with multivariate analysis. Two different extraction procedures were used, including direct extraction and liquid-liquid partition. Then HPLC was applied to determine the changes of saikosaponin contents. In addition, their liver protective effects against CCl4 induced liver injury were also investigated, and the biochemical parameters and histopathology were measured after treatment of mice with raw RB and two processed RBs (5 g/kg/day) for 14 days. RESULTS: Multivariate analysis showed clear differences between the raw and the two processed RBs, and the vinegar-baking process induced elevated contents of ssb1, ssb2, acetic acid, malic acid, citric acid, 5-HMF, and ligustrazine, as well as the decreased contents of ssa, ssd, sucrose, glycine, succinic acid etc. In addition, both raw and processed RBs showed liver protective effects against CCl4 induced liver injury, and the vinegar-baked RBs showed better effects than that of raw RB. CONCLUSIONS: The raw and vinegar-baked RBs differed not only in the chemical compositions but also in the pharmacological effects. And two processed RBs also showed chemical differences, suggesting that the type of vinegar had an important effect on vinegar baking. In order to ensure the therapeutic effect and safety of TCM, the effect of different vinegars on processing of herbal drugs should be further studied. PMID- 25701750 TI - Insulinotropic effect of Chikusetsu saponin IVa in diabetic rats and pancreatic beta-cells. AB - ETHNOPHARMACOLOGICAL RELEVANCE: As a well-known traditional Chinese medicine the root bark of Aralia taibaiensis has traditionally been used as the medicine considered alleviating several disorders including diabetes mellitus (DM). Chikusetsu saponin IVa (CHS) has been defined as a major active ingredient of triterpenoid saponins extracted from Aralia taibaiensis. The scientific evidence of anti-diabetic effect for CHS remains unknown and the purpose of our study was to study its hypoglycemic and insulin secretagogue activities. MATERIALS AND METHODS: In vivo studies were performed on type 2 diabetic mellitus (T2DM) rats given CHS for 28 days to test the antihyperglycemic activity. The in vitro effects and possible mechanisms of CHS on the insulin secretion in pancreatic beta-cell line betaTC3 were determined. RESULTS: Oral administration of CHS dose dependently increased the level of serum insulin and decreased the rise in blood glucose level in an in vivo treatment. In vitro, CHS potently stimulated the release of insulin from betaTC3 cells at both basal and stimulatory glucose concentrations, the effect which was changed by the removal of extracellular Ca(2+). Two methods showed that CHS enhanced the intracellular calcium levels in betaTC3 cells. CHS was capable of enhancing the phosphorylation of extracellular signal-regulated protein kinases C (PKC), which could be reversed by a PKC inhibitor (RO320432), and the insulin secretion induced by CHS was also inhibited by RO320432. Further study also showed that the insulinotropic effect, intracellular calcium levels and the phosphorylation of PKC were reduced by inhibiting G protein-coupled receptor 40 (GPR40) by a GPR40 inhibitor (DC126026). CONCLUSION: These observations suggest that the signaling of CHS-induced insulin secretion from betaTC3 cells via GPR40 mediated calcium and PKC pathways and thus CHS might be developed into a new potential for therapeutic agent used in T2DM patients. PMID- 25701751 TI - Antiproliferative activity and phenotypic modification induced by selected Peruvian medicinal plants on human hepatocellular carcinoma Hep3B cells. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The high incidence of human hepatocellular carcinoma (HCC) in Peru and the wide use of medicinal plants in this country led us to study the activity against HCC cells in vitro of somes species used locally against liver and digestive disorders. MATERIALS AND METHODS: Ethnopharmacological survey: Medicinal plant species with a strong convergence of use for liver and digestive diseases were collected fresh in the wild or on markets, in two places of Peru: Chiclayo (Lambayeque department, Chiclayo province) and Huaraz (Ancash department, Huaraz province). Altogether 51 species were collected and 61 ethanol extracts were prepared to be tested. Biological assessment: All extracts were first assessed against the HCC cell line Hep3B according a 3-step multi-parametric phenotypic assay. It included 1) the evaluation of phenotypic changes on cells by light microscopy, 2) the measurement of the antiproliferative activity and 3) the analysis of the cytoskeleton and mitosis by immunofluorescence. Best extracts were further assessed against other HCC cell lines HepG2, PLC/PRF/5 and SNU-182 and their toxicity measured in vitro on primary human hepatocytes. RESULTS: Ethnopharmacological survey: Some of the species collected had a high reputation spreading over the surveyed locations for treating liver problems, i.e. Baccharis genistelloides, Bejaria aestuans, Centaurium pulchellum, Desmodium molliculum, Dipsacus fullonum, Equisetum bogotense, Gentianella spp., Krameria lapacea, Otholobium spp., Schkuhria pinnata, Taraxacum officinale. Hep3B evaluation: Fourteen extracts from 13 species (Achyrocline alata, Ambrosia arborescens, Baccharis latifolia, Hypericum laricifolium, Krameria lappacea, Niphidium crassifolium, Ophryosporus chilca, Orthrosanthus chimboracensis, Otholobium pubescens, Passiflora ligularis, Perezia coerulescens, Perezia multiflora and Schkuhria pinnata) showed a significant antiproliferative activity against Hep3B cells (IC50<= 50ug/mL). This was associated with a lack of toxicity on primary human hepatocytes in vitro. Immunofluorescence experiments on Hep3B cells showed that crude extracts of Schkuhria pinnata and Orthrosanthus chimboracensis could block Hep3B cells in mitosis with an original phenotype. Crude extracts of Perezia coerulescens, Perezia multiflora, Achyrocline alata, Ophryosporus chilca, Otholobium pubescens and Hypericum laricifolium could modify the overall microtubule cytoskeletal dynamics of Hep3B cells in interphase by an original mechanism. CONCLUSIONS: Our method allowed us to select 9 extracts which displayed antiproliferative activities associated with original cellular phenotypes on Hep3B cells, regarding known microtubule-targeting drugs. Both chemical and cellular studies are ongoing in order to elucidate natural compounds and cellular mechanisms responsible of the activities described. PMID- 25701752 TI - Expectorant, antitussive, anti-inflammatory activities and compositional analysis of Aster tataricus. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The root of Aster tataricus L. f., recorded in all versions of Chinese Pharmacopoeia, is a traditional Chinese medicine with the function of dispelling phlegm and relieving cough for more than 2000 years. This study was designed to evaluate the expectorant, antitussive, and anti inflammatory activities of the root of A. tataricus and to explore the chemical substances responsible for these activities. MATERIALS AND METHODS: The 70% ethanol extract of the root of A. tataricus (RA-70) was divided into three fractions, Fr-0, Fr-50 and Fr-95. They were all orally administrated to the mice to investigate their potential expectorant activities by a tracheal phenol red secretion method. The most effective fraction, together with shionone, was evaluated the expectorant, antitussive and anti-inflammatory activities by the mouse models of phenol red secretion, ammonia-induced cough, and xylene-induced ear swelling. Furthermore, the chemical components of the effective fraction were analyzed and identified by an HPLC-Q-TOF/MS method. RESULTS: Treatment with RA 70, Fr-0 and Fr-50 increased the amount of phenol red secretion by 65.3%, 56.5%, and 76.9%, respectively. Fr-50 was chosen for the further investigation and the results showed that Fr-50 at 40, 80 mg/kg significantly enhanced the phenol red secretion of tracheas, increased the latent period and decreased the frequency of cough and inhibited the ear edema in mice. Shionone at 80 mg/kg showed the trend of enhancing sputum secreting, but had no effect on ammonia-induced cough and xylene-induced ear edema. HPLC-Q-TOF/MS analysis indicated that Fr-50 was mainly composed of 12 caffeoylquinic acids (40.8%, in relative peak area), 7 astersaponins (12.0%) and 13 astins/asterinins (pentapeptides, 26.5%). CONCLUSIONS: The root of A. tataricus has significant expectorant, antitussive and anti-inflammatory effects. Caffeoylquinic acids, astersaponins, and aster peptides, rather than shionone, may be the main constituents responsible for the expectorant and antitussive activities of A. tataricus and act in a synergistic way. PMID- 25701753 TI - 25-O-acetyl-23,24-dihydro-cucurbitacin F induces cell cycle G2/M arrest and apoptosis in human soft tissue sarcoma cells. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Quisqualis indica is used in traditional Chinese medicine to treat cancer and related syndromes and also known for its anthelminthic effects. AIM OF THE STUDY: Soft tissue sarcomas represent a rare group of malignant tumors that frequently exhibit chemotherapeutic resistance and increased metastatic potential. In this study, we evaluated the cytotoxic, apoptosis inducing and cell cycle arresting effects of 25-O-acetyl-23,24-dihydro cucurbitacin F which has been isolated from leaves and twigs of Q. indica. MATERIAL AND METHODS: The present study investigates the effects of 25-O-acetyl 23,24-dihydro-cucurbitacin F (1) on cell viability, cell cycle distribution, and apoptotic induction of three human sarcoma cell lines of various origins by using the CellTiter 96((r)) AQueous One Solution Cell Proliferation Assay, flow cytometrical experiments, real-time RT-PCR, Western blotting, and the Caspase Glo((r)) 3/7 Assay RESULTS: We could show that 1 reduced cell viability in a dose dependent manner and arrested the cells at the G2/M interface. The accumulation of cells at the G2/M phase resulted in a significant decrease of the cell cycle checkpoint regulators cyclin B1, cyclin A, CDK1, and CDK2. Interestingly, 1 inhibited survivin expression significantly, which functions as a key regulator of mitosis and programmed cell death, and is overexpressed in many tumor types including sarcomas. Moreover, 1 induced apoptosis in liposarcoma and rhabdomyosarcoma cells caspase-3 dependently. CONCLUSION: Our data strongly support 1 as a very interesting target for further investigation and development of novel therapeutics in sarcoma research. PMID- 25701754 TI - Tetrastigma hemsleyanum (Sanyeqing) root tuber extracts induces apoptosis in human cervical carcinoma HeLa cells. AB - AIM OF THE STUDY: Tetrastigma hemsleyanum (Sanyeqing) is traditionally used as a folk medicine for the treatment of cancer. However, the underlying mechanisms remain unclear. The purpose of this study was to investigate the possible mechanisms by which petroleum ether fraction (PEF) of Sanyeqing has anti-tumor activity on HeLa cells. METHODS: The chemical components of PEF were analyzed by gas chromatography-mass spectrometry. The cytotoxicity of PEF on HeLa cells was measured by MTT assay. Apoptosis was evaluated by phosphatidylserine translocation, mitochondrial membrane potential (Deltapsim) changes and the activation of caspase-3, caspase-8 and caspase-9. The levels in T-SOD, CAT, GSH PX and MDA were measured. RESULTS: PEF of Sanyeqing inhibited the growth and induced apoptosis of HeLa cells in dose- and time-dependent manner. PEF triggered intrinsic apoptotic pathway indicated by the loss of mitochondrial membrane potential and the activation of caspase-9 and caspase-3. In addition, PEF activated extrinsic apoptotic pathway indicated by the activation of caspase-8. Furthermore, PEF decreased T-SOD, CAT, GSH-PX activities and increased MDA level. Chemical analysis revealed the presence of fatty acids and phytosterol in PEF. CONCLUSIONS: PEF of Tetrastigma hemsleyanum Diels et. Gilg (Sanyeqing) exhibits cytotoxic effects, triggers both extrinsic and intrinsic apoptotic pathways, and augments oxidative stress in cervical carcinoma HeLa cells. Sanyeqing has strong potential to be developed as an agent for the treatment of cervical cancer. PMID- 25701755 TI - Investigating herb-herb interactions: the potential attenuated toxicity mechanism of the combined use of Glycyrrhizae radix et rhizoma (Gancao) and Sophorae flavescentis radix (Kushen). AB - ETHNOPHARMACOLOGICAL RELEVANCE: Glycyrrhizae radix et rhizoma (Gancao) is often prescribed together with Sophorae flavescentis radix (Kushen) in traditional Chinese medicinal practice to increase the efficacy on the treatment of hepatitis and hepatic fibrosis. Meanwhile, long-term single used Gancao can cause adverse reactions, lead to pseudohypercorticosteroidism especially. But the side effects of Gancao are significantly reduced when combined with Kushen; the reasons are still unknown. The aim of this study was to elucidate potential pharmacokinetic interaction between Kushen and Gancao, and to provide guidance for clinical medicine safety. MATERIALS AND METHODS: A specific and rapid HPLC-MS method was established to quantify the four main activity ingredients matrine (MT), oxymatrine (OMT), glycyrrhizin (GL) and glycyrrhetinic acid (GA) in rat plasma. In this study, the pharmacokinetic parameters and the pharmacokinetic differences of the four main activity ingredients MT, OMT, GL and GA in single herb and Kushen-Gancao couple were obtained. RESULTS: Compared with oral administration of Gancao extract, K10 and Tmax of GA significantly increased to 0.43 h(-1)and 30 h after giving Kushen-Gancao (p < 0.05), but T1/2 and Vd were reduced to 0.73 L kg( 1)and 4.98 h (p < 0.05). In addition, the AUC of GA was increased, and the other three activity ingredients all decreased. CONCLUSION: GA as the main factor leading to the sodium-water retention side effects of Gancao. The result found that the absorption of GA was significantly slowed down and the metabolism rate was accelerated in Kushen-Gancao than single herb. So the attenuated toxicity mechanism may be because the accumulation of GA reduced in vivo. The conclusion has important meaning to the compatibility of Chinese med. PMID- 25701756 TI - A hundred years of change in wild vegetable use in southern Herzegovina. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Wild vegetable mixes used in southern Europe are interesting from the pharmacological point of view, as they contain many species which have considerable nutritional and medicinal value, but some are potentially toxic to humans. Although many ethnobotanical studies document the rich tradition of using wild vegetables at the turn of the 20th and 21st century in the Mediterranean region, there is a dearth of older historical studies which could help us to assess the extent of Traditional Knowledge loss. MATERIAL AND METHODS: The aim of this study was to document the use of wild foods in an area of southern Herzegovina (in Bosnia-Herzegovina) and to compare it with a list of 27 taxa of wild green vegetables used there, compiled in 1913 by Vejsil Curcic. We carried out 49 interviews in the same area to estimate the current use and knowledge of wild foods. RESULTS: Eighty-two species of wild food and herbal tea plants were recorded in the study. This includes 44 species whose wild leaves are used as salads or cooked side dishes, 17 species with edible fruits and 24 species whose leaves, shoots or flowers are used for everyday herbal teas. On average, 14.2 species (median=16.5) were listed per interview, including 9.0 species of wild vegetables. Out of 27 plant names mentioned 100 years ago - five remain unidentified. Out of the 22 species or species groups, which were identified, 18 are still used as wild vegetables (including five species used very rarely and known by very few people or only by one person). Nowadays, the most commonly used wild greens are: Dioscorea communis, Sonchus spp., Allium spp., Papaver rhoeas, Rumex pulcher, Silene latifolia, and Taraxacum spp. CONCLUSIONS: Although we observed some changes in the names and uses of plants compared to the list from a hundred years ago, around three quarters of the taxa are still used to some extent nowadays. PMID- 25701757 TI - Disruption of polyubiquitin gene Ubc leads to attenuated resistance against arsenite-induced toxicity in mouse embryonic fibroblasts. AB - The polyubiquitin gene Ubc is upregulated under oxidative stress induced by arsenite [As(III)]. However, the detailed mechanism of Ubc upregulation and the exact role of ubiquitin (Ub) to protect cells against As(III)-induced toxicity remain unknown. Here, we found that Ubc-/- mouse embryonic fibroblasts (MEFs) exhibited reduced viability under As(III) exposure, although the Nrf2-Keap1 pathway was activated as a cytoprotective response. Intriguingly, due to the reduced polyubiquitination and delayed onset of degradation of Nrf2 in Ubc-/- MEFs, the basal expression levels of Nrf2 target genes were elevated. As(III) induced accumulation of Ub conjugates occurred in an Nrf2-independent manner, probably due to cellular stress conditions, including reduced proteasomal activity. Increased cellular Ub levels were essential to polyubiquitinate misfolded proteins generated under As(III) exposure and to degrade them by the proteasome. However, when cellular Ub levels decreased, these misfolded proteins were not efficiently polyubiquitinated, but rather accumulated as large protein aggregates inside the cells, causing cytotoxicity. Furthermore, increased activity of the autophagic pathway to clear these aggregates was not observed in Ubc-/- MEFs. Therefore, reduced viability of Ubc-/- MEFs under As(III) exposure may not be due to dysregulation of the Nrf2-Keap1 pathway, but mostly to reduced efficacy to polyubiquitinate and degrade misfolded protein aggregates. PMID- 25701758 TI - The calcium-sensing receptor: A promising target for prevention of colorectal cancer. AB - The inverse correlation between dietary calcium intake and the risk of colorectal cancer (CRC) is well known, but poorly understood. Expression of the calcium sensing receptor (CaSR), a calcium-binding G protein-coupled receptor is downregulated in CRC leading us to hypothesize that the CaSR has tumor suppressive roles in the colon. The aim of this study was to understand whether restoration of CaSR expression could reduce the malignant phenotype in CRC. In human colorectal tumors, expression of the CaSR negatively correlated with proliferation markers whereas loss of CaSR correlated with poor tumor differentiation and reduced apoptotic potential. In vivo, dearth of CaSR significantly increased expression of proliferation markers and decreased levels of differentiation and apoptotic markers in the colons of CaSR/PTH double knock out mice confirming the tumor suppressive functions of CaSR. In vitro CRC cells stably overexpressing wild-type CaSR showed significant reduction in proliferation, as well as increased differentiation and apoptotic potential. The positive allosteric modulator of CaSR, NPS R-568 further enhanced these effects, whereas treatment with the negative allosteric modulator, NPS 2143 inhibited these functions. Interestingly, the dominant-negative mutant (R185Q) was able to abrogate these effects. Our results demonstrate a critical tumor suppressive role of CaSR in the colon. Restoration of CaSR expression and function is linked to regulation of the balance between proliferation, differentiation, and apoptosis and provides a rationale for novel strategies in CRC therapy. PMID- 25701759 TI - Application of a recombinant capsid polyprotein (P1) expressed in a prokaryotic system to detect antibodies against foot-and-mouth disease virus serotype O. AB - Foot-and-mouth disease (FMD) is a highly contagious epidemic disease of transboundary importance. In India, the disease is endemic in nature and is controlled primarily by prophylactic bi-annual mass vaccination. In this control programme, liquid-phase blocking ELISA (LPBE) is being used widely for post vaccination seromonitoring. In order to develop an alternative assay to LPBE, the recombinant capsid polyprotein (rP1) of FMD virus (FMDV) serotype O was expressed in Escherichia coli and used as an antigen for the detection of antibodies to FMDV. The capsid polyprotein of FMDV serotype O could be expressed successfully as a recombinant 6xHis-SUMO tagged protein in soluble form. In a Western blot assay, the rP1 protein reacted strongly with anti-FMDV serotype O guinea pig and bovine serum. Further, in this study, an rP1 protein-based solid phase competitive ELISA (rP1-SPCE) was developed and evaluated with a set of serum samples representing the various epidemiological situation of the country. The performance of the rP1-SPCE was compared with the in-house LPBE, and overall, an excellent agreement (kappa = 0.95) was observed between the two tests. This report demonstrates that the recombinant capsid polyprotein-based ELISA has the potential to be an easy-to-perform, safe alternative to the conventional LPBE for the quantitative detection of antibodies to FMDV serotype O. PMID- 25701760 TI - Use of HPLC/UPLC-spectrophotometry for detection of formazan in in vitro Reconstructed human Tissue (RhT)-based test methods employing the MTT-reduction assay to expand their applicability to strongly coloured test chemicals. AB - A number of in vitro test methods using Reconstructed human Tissues (RhT) are regulatory accepted for evaluation of skin corrosion/irritation. In such methods, test chemical corrosion/irritation potential is determined by measuring tissue viability using the photometric MTT-reduction assay. A known limitation of this assay is possible interference of strongly coloured test chemicals with measurement of formazan by absorbance (OD). To address this, Cosmetics Europe evaluated use of HPLC/UPLC-spectrophotometry as an alternative formazan measurement system. Using the approach recommended by the FDA guidance for validation of bio-analytical methods, three independent laboratories established and qualified their HPLC/UPLC-spectrophotometry systems to reproducibly measure formazan from tissue extracts. Up to 26 chemicals were then tested in RhT test systems for eye/skin irritation and skin corrosion. Results support that: (1) HPLC/UPLC-spectrophotometry formazan measurement is highly reproducible; (2) formazan measurement by HPLC/UPLC-spectrophotometry and OD gave almost identical tissue viabilities for test chemicals not exhibiting colour interference nor direct MTT reduction; (3) independent of the test system used, HPLC/UPLC spectrophotometry can measure formazan for strongly coloured test chemicals when this is not possible by absorbance only. It is therefore recommended that HPLC/UPLC-spectrophotometry to measure formazan be included in the procedures of in vitro RhT-based test methods, irrespective of the test system used and the toxicity endpoint evaluated to extend the applicability of these test methods to strongly coloured chemicals. PMID- 25701761 TI - PACAP and VIP signaling in chondrogenesis and osteogenesis. AB - Skeletal development is a complex process regulated by multifactorial signaling cascades that govern proper tissue specific cell differentiation and matrix production. The influence of certain regulatory peptides on cartilage or bone development can be predicted but are not widely studied. In this review, we aimed to assemble and overview those signaling pathways which are modulated by PACAP and VIP neuropeptides and are involved in cartilage and bone formation. We discuss recent experimental data suggesting broad spectrum functions of these neuropeptides in osteogenic and chondrogenic differentiation, including the canonical downstream targets of PACAP and VIP receptors, PKA or MAPK pathways, which are key regulators of chondro- and osteogenesis. Recent experimental data support the hypothesis that PACAP is a positive regulator of chondrogenesis, while VIP has been reported playing an important role in the inflammatory reactions of surrounding joint tissues. Regulatory function of PACAP and VIP in bone development has also been proved, although the source of the peptides is not obvious. Crosstalk and collateral connections of the discussed signaling mechanisms make the system complicated and may obscure the pure effects of VIP and PACAP. Chondro-protective properties of PACAP during oxidative stress observed in our experiments indicate a possible therapeutic application of this neuropeptide. PMID- 25701762 TI - Osmotic swelling activates a novel anionic current with VRAC-like properties in a cytoplasmic droplet membrane from Phycomyces blakesleeanus sporangiophores. AB - We describe here whole-cell currents of droplets prepared from the apical region of growing Phycomyces blakesleeanus sporangiophores. Whole-cell current recordings revealed the osmotically activated, outwardly rectifying, fast inactivating instantaneous current (ORIC) with biophysical properties closely resembling volume-regulated anionic current (VRAC). ORIC is activated under conditions of osmotically induced swelling and shows strong selectivity for anions over cations. In addition, ORIC shows voltage and time-dependent inactivation at positive potentials and recovery from inactivation at negative potentials. ORIC is blocked by anthracene-9-carboxylic acid, an anion channel blocker, in a voltage-dependent manner. This is the first report of the presence of VRAC-like current in an organism outside the chordate lineage. PMID- 25701763 TI - Web resources for stem cell research. AB - In this short review, we have presented a brief overview on major web resources relevant to stem cell research. To facilitate more efficient use of these resources, we have provided a preliminary rating based on our own user experience of the overall quality for each resource. We plan to update the information on an annual basis. PMID- 25701764 TI - Preclinical studies on the pharmacokinetics, safety, and toxicology of oxfendazole: toward first in human studies. AB - A 2-week study in rats identified target organs of oxfendazole toxicity to be bone marrow, epididymis, liver, spleen, testis, and thymus. Female rats had greater oxfendazole exposure and exhibited toxicities at lower doses than did males. Decreased white blood cell levels, a class effect of benzimidazole anthelmintics, returned to normal during the recovery period. The no observed adverse effect level was determined to be >5 but <25 mg/kg/d and the maximum tolerated dose 100 mg/kg/d. The highest dose, 200 mg/kg/d, resulted in significant toxicity and mortality, leading to euthanization of the main study animals in this group after 7 days. Oxfendazole did not exhibit genetic toxicology signals in standard Ames bacterial, mouse lymphoma, or rat micronucleus assays nor did it provoke safety concerns when evaluated for behavioral effects in rats or cardiovascular safety effects in dogs. These results support the transition of oxfendazole to First in Human safety studies preliminary to its evaluation in human helminth diseases. PMID- 25701765 TI - Platelet Aggregation Study in Patients With Hemoglobin Ebeta Thalassemia in India. AB - Hemoglobin Ebeta thalassemia is a major public health problem in India, especially in the state of West Bengal. Various thromboembolic events are common, especially in splenectomized patients. Platelet hyperactivity most likely plays a pathogenetic role. To investigate the role of platelets in hypercoagulability, platelet aggregation tests were undertaken in the present study. Platelet-rich plasma from 30 patients with Ebeta thalassemia (15 splenectomized and 15 nonsplenectomized) were studied and compared with 15 healthy participants. The 4 agonists used were adenosine 5-diphosphate, adrenaline (epinephrine), collagen, and ristocetin. The current study shows both splenectomized and nonsplenectomized patients had abnormal aggregation compared to normal healthy controls. Splenectomized patients had higher platelet aggregation than nonsplenectomized patients for all 4 agonists; but statistically significant difference among 2 groups was found only for collagen. The present study confirms a role of splenic absence in platelet hyperaggregation. PMID- 25701766 TI - Pharmacologic Management of Subarachnoid Hemorrhage. AB - Subarachnoid hemorrhage (SAH) remains a condition with suboptimal functional outcomes, especially in the young population. Pharmacotherapy has an accepted role in several aspects of the disease and an emerging role in several others. No preventive pharmacologic interventions for SAH currently exist. Antiplatelet medications as well as anticoagulation have been used to prevent thromboembolic events after endovascular coiling. However, the main focus of pharmacologic treatment of SAH is the prevention of delayed cerebral ischemia (DCI). Currently the only evidence-based medical intervention is nimodipine. Other calcium channel blockers have been evaluated without convincing efficacy. Anti-inflammatory drugs such as statins have demonstrated early potential; however, they failed to provide significant evidence for the use in preventing DCI. Similar findings have been reported for magnesium, which showed potential in experimental studies and a phase 2 trial. Clazosentane, a potent endothelin receptor antagonist, did not translate to improve functional outcomes. Various other neuroprotective agents have been used to prevent DCI; however, the results have been, at best inconclusive. The prevention of DCI and improvement in functional outcome remain the goals of pharmacotherapy after the culprit lesion has been treated in aneurysmal SAH. Therefore, further research to elucidate the exact mechanisms by which DCI is propagated is clearly needed. In this article, we review the current pharmacologic approaches that have been evaluated in SAH and highlight the areas in which further research is needed. PMID- 25701767 TI - The Impact of Neurosurgical Complications on Patients' Health Status: A Comparison Between Different Grades of Complications. AB - OBJECTIVE: The aim of this article is to investigate the frequency of neurosurgical complications according to Landriel-Ibanez Classification and their impact on patients' health status. METHODS: Patients undergoing neurosurgical procedures were enrolled in an observational longitudinal study at Neurological Institute Carlo Besta from January 2012 to September 2013. We evaluated patients' health status before surgery, at discharge, and follow-up with the Karnofsky Performance Status Scale (KPS), whereas the Landriel-Ibanez Classification was used to record complications. Descriptive statistics were performed to illustrate the distribution of sociodemographic and clinical data. We used nonparametric tests to compare KPS scores of patients with different grades of complication and to evaluate the differences between preoperative KPS scores, KPS scores at discharge and follow-up. The effect sizes were also calculated. RESULTS: We enrolled 1008 patients. We registered 228 complications (139 grade 1 complications, 63 grade 2 complications, 20 grade 3 complications, and 6 grade 4 complications). All patients with a complication showed KPS scores at discharge that were lower than preoperative scores and KPS scores at follow-up greater than scores at discharge. After patients with grade 4 complications, who had the worst outcomes, those with grade 3 complications were the most compromised after surgery whereas patients with grade 2 complications seemed to have a better health status than patients with grade 1 complication. CONCLUSIONS: Our study highlights the impact of neurosurgical complications on patients' life and contributes to the debate on how define and classify adverse events because a classification only based on treatment seems to be not adequate. PMID- 25701768 TI - Long-Term Outcomes After Small-Bone-Window Posterior Fossa Decompression and Duraplasty in Adults with Chiari Malformation Type I. AB - BACKGROUND: Small-bone-window posterior fossa decompression with duraplasty is one of the popular surgical options for Chiari malformation type I, but its efficacy is controversial and the risk factors of clinical outcome remain unclear. METHODS: The study cohort included 152 patients with Chiari malformation type I who received small-bone-window posterior fossa decompression at Beijing Tiantan hospital from January 2008 to September 2009. All patients underwent combined surgical procedures: a small-bone-window suboccipital decompression (diameter, 2.5-3 cm) and a C1 laminectomy (1.5- to 2-cm wide) followed by a duraplasty with an autologous graft. Clinical manifestations, radiologic features, and follow-up data during a 6-year span were analyzed. Risk factors associated with outcome were investigated by the use of chi(2) analysis and logistic regression analysis. RESULTS: The average follow-up duration was 74 months. Symptoms were improved in 126 patients (82.9%), remained stable in 21 patients (13.8%), and deteriorated in 5 patients (3.3%). There was no mortality. Postoperative magnetic resonance imaging scans were available for all patients. Preoperatively, 112 patients were associated with syringomyelia, and the follow up magnetic resonance images showed obvious reduction of syringomyelia in 73 patients (65.2%) and no significant change in 39 patients (34.8%). In addition, enlargement of the cistern magna was observed in 92 patients (85.2%). Regression analysis indicates preoperative motor dysfunction, brainstem herniation and basilar invagination may influence the clinical outcome (P < 0.05). CONCLUSIONS: Small-bone-window posterior fossa decompression with duraplasty is an effective and safe treatment option with a low complication rate. Motor dysfunction, brainstem herniation, and basilar invagination are predictors of poor clinical prognosis. PMID- 25701769 TI - Basilar Invagination: Case Report and Literature Review. AB - BACKGROUND: Basilar invagination is a rare clinical condition characterized by upward protrusion of the odontoid process into the intracranial space, leading to bulbomedullary compression. It is often encountered in adults with rheumatoid arthritis. Transoral microscopic or endonasal endoscopic decompression may be pursued, with or without posterior fixation. We present a case of basilar invagination with C1-C2 autofusion and discuss an algorithm for choice of anterior versus posterior approaches. CASE DESCRIPTION: A 47-year-old woman with rheumatoid arthritis presented with severe occipital and cervical pain, dysphagia, hoarseness, and arm paresthesias. Findings on magnetic resonance imaging revealed moderate cranial settling with the odontoid indenting the ventral medulla but no posterior compression. Computed tomography demonstrated bony fusion at C1-C2 without lateral sag. Given autofusion of C1-C2 in proper occipitocervical alignment and the absence of posterior compression, the patient underwent endoscopic endonasal odontoidectomy without further posterior fusion, with satisfactory resolution of symptoms. CONCLUSION: Endoscopic endonasal odontoidectomy offers a safe and effective method for anterior decompression of basilar invagination. Preoperative assessment for existing posterior fusion, absence of posterior compression, and preservation of the anterior C1 ring during operative decompression help stratify the need for lone anterior approach versus a combined anterior and posterior treatment. PMID- 25701770 TI - Growth of Primary and Remnant Vestibular Schwannomas: A Three-Year Follow-Up Study. AB - OBJECTIVE: Vestibular schwannomas (VSs) are benign, slowly growing tumors. The management strategy, however, remains unclear for both primary VS and remnant VS after subtotal or partial resection. In this study, we analyzed the radiographical tumor growth to elucidate factors possibly predicting growth or regrowth of their tumors. METHODS: We retrospectively analyzed the data of 76 patients with diagnoses of VS at a single tertiary academic referral center. The primary VS group consisted of 43 patients with conservative management, and the remnant VS group included 33 patients with tumor remnant after surgery. All patients were followed up with serial magnetic resonance imaging without intervention. The primary end point in this study was significant tumor growth at the end of the 3-year follow-up period. RESULTS: Multivariate analysis revealed that remnant VS was less likely to grow than primary VS (odds ratio: 0.27, 95% confidence interval: 0.09-0.84). Tumor volume was correlated with tumor growth; larger tumors grew more frequently than small tumors in both primary and remnant VS groups with marginal (P = 0.05) and definite (P = 0.007) significance, respectively. The receiver operating characteristic curves plotted for tumor growth identified the optimum cutoff points of tumor volumes with greater sensitivity and specificity for remnant VS than for primary VS (sensitivity: 80% vs. 59%, specificity: 87% vs. 76%, respectively). CONCLUSIONS: Small remnant VS after surgery could be conservatively managed without additional treatment, and relatively large remnant VS should be followed up with close serial imaging or might be a possible candidate for radiosurgery during the early postoperative period. PMID- 25701771 TI - A molecular phylogeny of the harriers (Circus, Accipitridae) indicate the role of long distance dispersal and migration in diversification. AB - The monophyly of the raptorial Circus genus (harriers) has never been in question, but the specific status of many, often vulnerable island endemic, taxa remains uncertain. Here we utilise one mitochondrial and three nuclear loci from all currently recognised Circus taxa (species and subspecies) to infer a robust phylogeny, to estimate the divergence date and to reconstruct the biogeographic origins of the Circus group. Our phylogeny supports both the monophyly of Circus and polyphyly of the genus Accipiter. Depending on the rate of molecular clock used, the emergence of the harrier clade took place between 4.9 and 12.2mya which coincides with the worldwide formation of open habitats which extant harriers now exploit. The sister relationship of the Northern Harrier C. cyaneus hudsonius and the Cinereous Harrier C. cinereus contradicts previous classifications that treated the former as conspecific with the Hen Harrier C. cyaneus cyaneus. Thus both should be elevated to species status: C. hudsonius and C. cyaneus. Further, the African Marsh C. ranivorus and the European Marsh C. aeruginosus Harriers emerge as sister species. The remaining marsh harriers exhibit very little genetic diversity, and are all recently diverged taxa that exhibit allopatric distributions. Considering their sister relationship and geographic proximity, we recommend treating C. approximans and C. spilonotus spilothorax as subspecies of C. approximans. For C. spilonotus spilonotus C. maillardi maillardi and C. maillardi macrosceles, their plumage and morphometric differences, phylogenetic relationship and geographic distributions make lumping of these taxa as a single species complicated. We thus propose to recognise as separate, recently evolved species: C. spilonotus, C. maillardi and C. macrosceles. Biogeographic inferences on the ancestral origin of harriers are uncertain, indicating that the harriers emerged in either the Neotropics, Palearctic or Australasia. We are, however, able to show that speciation within the harriers was driven by long range dispersal and migration events. PMID- 25701772 TI - Evidence for homologous recombination in Chikungunya Virus. AB - Chikungunya Virus (CHIKV), a mosquito-transmitted alphavirus, causes acute fever and joint pain in humans. Recently, endemic CHIKV infection outbreaks have jeopardized public health in wider geographical regions. Here, we analyze the phylogenetic associations of CHIKV and explore the potential recombination events on 152 genomic isolates deposited in GenBank database. The CHIKV genotypes [West African, Asian, East/Central/South African (ECSA)], and a clear division of ECSA clade into three sub-groups (I-II-III), were defined by Bayesian analysis; similar results were obtained using E1 gene sequences. A nucleotide identity based approach is provided to facilitate CHIKV classification within ECSA clade. Using seven methods to detect recombination, we found a statistically significant event (p-values range: 1.14*10(-7)-4.45*10(-24)) located within the nsP3 coding region. This finding was further confirmed by phylogenetic networks (PHI Test, p=0.004) and phylogenetic tree incongruence analysis. The recombinant strain, KJ679578/India/2011 (ECSA III), derives from viruses of ECSA III and ECSA I. Our study demonstrates that recombination is an additional mechanism of genetic diversity in CHIKV that might assist in the cross-species transmission process. PMID- 25701773 TI - The cardiomyocyte molecular clock regulates the circadian expression of Kcnh2 and contributes to ventricular repolarization. AB - BACKGROUND: Sudden cardiac death (SCD) follows a diurnal variation. Data suggest the timing of SCD is influenced by circadian (~24-hour) changes in neurohumoral and cardiomyocyte-specific regulation of the heart's electrical properties. The basic helix-loop-helix transcription factors brain muscle arnt-like1 (BMAL1) and circadian locomotor output control kaput (CLOCK) coordinate the circadian expression of select genes. OBJECTIVE: We sought to test whether Bmal1 expression in cardiomyocytes contributes to K(+) channel expression and diurnal changes in ventricular repolarization. METHODS: We used transgenic mice that allow for the inducible cardiomyocyte-specific deletion of Bmal1 (iCSDeltaBmal1(-/-)). We used quantitative polymerase chain reaction, voltage clamping, promoter-reporter bioluminescence assays, and electrocardiographic telemetry. RESULTS: Although several K(+) channel gene transcripts were downregulated in iCSDeltaBmal1(-/ )mouse hearts, only Kcnh2 exhibited a robust circadian pattern of expression that was disrupted in iCSDeltaBmal1(-/-) hearts. Kcnh2 underlies the rapidly activating delayed-rectifier K(+) current, and the rapidly activating delayed rectifier K(+) current recorded from iCSDeltaBmal1(-/-) ventricular cardiomyocytes was ~50% smaller than control ventricular myocytes. Promoter reporter assays demonstrated that the human Kcnh2 promoter is transactivated by the coexpression of BMAL1 and CLOCK. Electrocardiographic analysis showed that iCSDeltaBmal1(-/-) mice developed a prolongation in the heart rate-corrected QT interval during the light (resting) phase. This was secondary to an augmented circadian rhythm in the uncorrected QT interval without a corresponding change in the RR interval. CONCLUSION: The molecular clock in the heart regulates the circadian expression of Kcnh2, modifies K(+) channel gene expression, and is important for normal ventricular repolarization. Disruption of the cardiomyocyte circadian clock mechanism likely unmasks diurnal changes in ventricular repolarization that could contribute to an increased risk of cardiac arrhythmias/SCD. PMID- 25701775 TI - Regulation of SCN5A by microRNAs: miR-219 modulates SCN5A transcript expression and the effects of flecainide intoxication in mice. AB - BACKGROUND: The human cardiac action potential in atrial and ventricular cells is initiated by a fast-activating, fast-inactivating sodium current generated by the SCN5A/Nav1.5 channel in association with its beta1/SCN1B subunit. The role of Nav1.5 in the etiology of many cardiac diseases strongly suggests that proper regulation of cell biology and function of the channel is critical for normal cardiac function. Hence, numerous recent studies have focused on the regulatory mechanisms of Nav1.5 biosynthetic and degradation processes as well as its subcellular localization. OBJECTIVE: The purpose of this study was to investigate the role of microRNAs in the Scn5a/Nav1.5 posttranscriptional regulation. METHODS: Quantitative polymerase chain reaction, immunohistochemical and electrophysiological measurements of distinct microRNA gain-of-function experiments in cardiomyocytes for the assessment of Scn5a expression. RESULTS: Functional studies of HL-1 cardiomyocytes and luciferase assays in fibroblasts demonstrate that Scn5a is directly (miR-98, miR-106, miR-200, and miR-219) and indirectly (miR-125 and miR-153) regulated by multiple microRNAs displaying distinct time-dependent profiles. Cotransfection experiments demonstrated that miR-219 and miR-200 have independent opposite effects on Scn5a expression modulation. Of all the microRNAs studied, only miR-219 increases Scn5a expression levels, leading to altered contraction rhythm of HL-1 cardiomyocytes. Electrophysiological analyses in HL-1 cells revealed that miR-219 increases the sodium current. In vivo administration of miR-219 does not alter normal cardiac rhythm, but abolishes some of the effects of flecainide intoxication in mice, particularly QRS prolongation. CONCLUSION: This study demonstrates the involvement of multiple microRNAs in the regulation of Scn5a. Particularly, miR 219 increases Scn5a/Nav1.5 transcript and protein expression. Our data suggest that microRNAs, such as miR-219, constitute a promising therapeutical tool to treat sodium cardiac arrhythmias. PMID- 25701774 TI - Effects of enhanced pacing modalities on health care resource utilization and costs in bradycardia patients: An analysis of the randomized MINERVA trial. AB - BACKGROUND: Many patients who suffer from bradycardia and need cardiac pacing also have atrial fibrillation (AF). New pacemaker algorithms, such as atrial preventive pacing and atrial antitachycardia pacing (DDDRP) and managed ventricular pacing (MVP), have been specifically designed to reduce AF occurrence and duration and to minimize the detrimental effects of right ventricular pacing. The randomized MINimizE Right Ventricular pacing to prevent Atrial fibrillation and heart failure trial established that DDDRP + MVP pacing modality reduced permanent AF in bradycardia patients as compared with standard dual-chamber pacing (DDDR). OBJECTIVE: The aim of this study was to estimate the cost savings due to lower AF-related health care utilization events based on health care costs from the United States and the European Union. METHODS: Dual-chamber pacemaker patients with a history of paroxysmal or persistent AF were randomly assigned to receive DDDR (n = 385) or the advanced features (DDDRP + MVP; n = 383). We used published health care costs from the United States and the European Union (Italy, Spain, and the United Kingdom) to estimate the costs associated with AF-related hospitalizations and emergency visits. RESULTS: The rate of AF-related hospitalizations was significantly lower in the DDDRP + MVP group than in the conventional pacemaker group (DDDR group; 42% reduction; incidence rate ratio 0.58). Similarly, a significant reduction of 68% was observed for AF-related emergency department visits (incidence rate ratio 0.32; P < .001). As a consequence, DDDRP + MVP could potentially reduce health care costs by 40%-44%. Over a ten-year period, the cost savings per 100 patients ranged from $35,702 in the United Kingdom to $121,831 in the United States. CONCLUSION: New pacing algorithms such as DDDRP + MVP used in the MINimizE Right Ventricular pacing to prevent Atrial fibrillation and heart failure trial successfully reduced AF related health care utilization, resulting in significant cost savings to payers. PMID- 25701776 TI - Preparation of monolithic silica-chitin composite under extreme biomimetic conditions. AB - Chitin is a widespread renewable biopolymer that is extensively distributed in the natural world. The high thermal stability of chitin provides an opportunity to develop novel inorganic-organic composites under hydrothermal synthesis conditions in vitro. For the first time, in this work we prepared monolithic silica-chitin composite under extreme biomimetic conditions (80 degrees C and pH 1.5) using three dimensional chitinous matrices isolated from the marine sponge Aplysina cauliformis. The resulting material was studied using light and fluorescence microscopy, scanning electron microscopy, Fourier transform infrared spectroscopy. A mechanism for the silica-chitin interaction after exposure to these hydrothermal conditions is proposed and discussed. PMID- 25701777 TI - WITHDRAWN: Hypoxia-induced STAT3 contributes to chemoresistance and epithelial mesenchymal transition in prostate cancer cells. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 25701778 TI - Pr1E11, a novel anti-TROP-2 antibody isolated by adenovirus-based antibody screening, recognizes a unique epitope. AB - TROP-2 is a type I transmembrane glycoprotein that is highly expressed in various epithelial cancer cells, and its increased expression correlates with poor prognosis. Although several anti-TROP-2 antibodies have been described, they were found unsuitable for antitumor therapy use in vivo as naked antibodies. In this study, we established a novel anti-TROP-2 antibody, designated Pr1E11, from mice immunized with primary prostate cancer cells. Antibody screening was based on the infection activity of Adv-LacZ-FZ33, which displays an immunoglobulin G binding domain in the adenoviral fiber protein. We found that Pr1E11 specifically binds to TROP-2 with high affinity and recognizes diverse epithelial cancer cell lines and primary pancreatic cancer tissues. Epitope analysis using TROP-2 deletion mutants revealed that binding site of Pr1E11 is a cysteine-rich domain, a unique epitope compared with other available anti-TROP-2 antibodies. In addition, Pr1E11 exhibited low internalization activity, which may make it suitable for naked antibody therapeutics. Our results suggest that Pr1E11 may stimulate different biological activities from other anti-TROP-2 antibodies based on its unique binding epitope, and is a potential candidate for naked antibody therapeutics for various epithelial cancer treatments. PMID- 25701779 TI - A novel mutation MT-COIII m.9267G>C and MT-COI m.5913G>A mutation in mitochondrial genes in a Tunisian family with maternally inherited diabetes and deafness (MIDD) associated with severe nephropathy. AB - Mitochondrial diabetes (MD) is a heterogeneous disorder characterized by a chronic hyperglycemia, maternal transmission and its association with a bilateral hearing impairment. Several studies reported mutations in mitochondrial genes as potentially pathogenic for diabetes, since mitochondrial oxidative phosphorylation plays an important role in glucose-stimulated insulin secretion from beta cells. In the present report, we studied a Tunisian family with mitochondrial diabetes (MD) and deafness associated with nephropathy. The mutational analysis screening revealed the presence of a novel heteroplasmic mutation m.9276G>C in the mitochondrial COIII gene, detected in mtDNA extracted from leukocytes of a mother and her two daughters indicating that this mutation is maternally transmitted and suggest its implication in the observed phenotype. Bioinformatic tools showed that m.9267G>C mutation (p.A21P) is " deleterious " and it can modify the function and the stability of the MT-COIII protein by affecting the assembly of mitochondrial COX subunits and the translocation of protons then reducing the activity of the respective OXPHOS complexes of ATP synthesis. The nonsynonymous mutation (p.A21P) has not been reported before, it is the first mutation described in the COXIII gene which is related to insulin dependent mitochondrial diabetes and deafness and could be specific to the Tunisian population. The m.9267G>C mutation was present with a nonsynonymous inherited mitochondrial homoplasmic variation MT-COI m.5913 G>A (D4N) responsible of high blood pressure, a clinical feature detected in all explored patients. PMID- 25701780 TI - Computational analysis of the extracellular domain of the Ca2+-sensing receptor: an alternate model for the Ca2+ sensing region. AB - The extracellular Ca(2+) sensing receptor (CaSR) belongs to Class C G-protein coupled receptors (GPCRs) which include receptors for amino acids, gamma aminobutyric acid and glutamate neurotransmitters. CaSR has been described as having an extended sequence containing a Ca(2+) binding pocket within an extracellular amino (N)-terminal domain, called a Venus Fly Trap (VFT) module. CaSR is thought to consist of three domains: 1) a Ca(2+-)sensory domain, 2) a region containing 7 transmembrane (TM) helices, and 3) a carboxy (C)-terminal tail. We find that SPOCTOPUS (a combination of hidden Markov models and artificial neural networks) predicts that Homo sapiens CaSR contains two additional TM helices ((190)D - G(210); (262)S-E(282)), with the second TM helix containing a pore-lining region ((265)K - I(280)). This predicts that the putative Ca(2+) sensory domain is within an extracellular loop, N-terminal to the highly conserved heptahelical bundle. This loop contains both the cysteine-rich domain ((537)V - C(598)) and a 14 residue "linker" sequence ((599)I - F(612)) thought to support signal transmission to the heptahelical bundle. Thus domain 1 may contain a 189 residue N-terminal extracellular region followed successively by TM-1, a short intracellular loop, TM-2 and a 329 residue extracellular loop; rather than the proposed 620 residue VFT module based on crystallography of the N terminal region of mGluR1. Since the topologies of the two proteins differ, the published CaSR VFT model is questionable. CaSR also contains multiple caveolin binding motifs and cholesterol-binding (CRAC/CARC) domains, facilitating localization to plasma membrane lipid rafts. Ion sensing may involve combination of pore-lining regions from CaSR dimers and CaSR-bound caveolins to form ion channels capable of monitoring ionized Ca(2+) levels. PMID- 25701781 TI - Protective effects of aerobic swimming training on high-fat diet induced nonalcoholic fatty liver disease: regulation of lipid metabolism via PANDER-AKT pathway. AB - This study aimed to investigate the mechanism by which aerobic swimming training prevents high-fat-diet-induced nonalcoholic fatty liver disease (NAFLD). Forty two male C57BL/6 mice were randomized into normal-diet sedentary (ND; n = 8), ND exercised (n = 8), high-fat diet sedentary (HFD; n = 13), and HFD exercised groups (n = 13). After 2 weeks of training adaptation, the mice were subjected to an aerobic swimming protocol (60 min/day) 5 days/week for 10 weeks. The HFD group exhibited significantly higher mRNA levels of fatty acid transport-, lipogenesis , and beta-oxidation-associated gene expressions than the ND group. PANDER and FOXO1 expressions increased, whereas AKT expression decreased in the HFD group. The aerobic swimming program with the HFD reversed the effects of the HFD on the expressions of thrombospondin-1 receptor, liver fatty acid-binding protein, long chain fatty-acid elongase-6, Fas cell surface death receptor, and stearoyl coenzyme A desaturase-1, as well as PANDER, FOXO1, and AKT. In the HFD exercised group, PPARalpha and AOX expressions were much higher. Our findings suggest that aerobic swimming training can prevent NAFLD via the regulation of fatty acid transport-, lipogenesis-, and beta-oxidation-associated genes. In addition, the benefits from aerobic swimming training were achieved partly through the PANDER AKT-FOXO1 pathway. PMID- 25701782 TI - Accelerated onset of senescence of endothelial progenitor cells in patients with type 2 diabetes mellitus: role of dimethylarginine dimethylaminohydrolase 2 and asymmetric dimethylarginine. AB - The risk of cardiovascular complications in diabetic patients is mainly associated with endothelial dysfunction. Reduced number of EPCs and impaired function of EPCs in diabetes result in imbalance of endothelial homeostasis and dysfunction of vessels. In patients with diabetes mellitus, plasma levels of asymmetric dimethylarginine (ADMA) were elevated, while the expression and activity of dimethylarginine dimethylaminohydrolase (DDAH) were reduced. In the present study, we investigated the role of the DDAH2/ADMA pathway in the senescence of EPCs in type 2 diabetic patients and cultured EPCs treated with high glucose. The results showed that the percentage of senescent EPCs increased while the expression of DDAH2 decreased concomitantly with an increase in the plasma levels of ADMA in patients with type 2 diabetes mellitus (T2DM). Similar results were seen in cultured EPCs treated with high glucose. Exogenous application of ADMA accelerated the senescence of EPCs in a dose-dependent manner, and overexpression of DDAH2 inhibited high glucose-induced EPCs senescence. In addition, it has also been reported that DDAH/ADMA pathway is regulated by silent information regulator 1 (SIRT1) in endothelial cell. In the present study, we found decreased expression of SIRT1 both in T2DM patients and EPCs pretreated with high glucose. And resveratrol (activating SIRT1) inhibited high glucose-induced EPCs senescence by upregulating the expression of DDAH2 and decreasing the levels of ADMA. Taken together, we concluded that DDAH2/ADMA is involved in the accelerated senescence of EPCs in diabetes, which is associated with the activation of SIRT1. PMID- 25701783 TI - Role of tyrosine kinase-independent phosphorylation of EGFR with activating mutation in cisplatin-treated lung cancer cells. AB - Epidermal growth factor receptor (EGFR) mutation is one of the hallmarks of cancer progression and resistance to anticancer therapies, particularly non-small cell lung carcinomas (NSCLCs). In contrast to the canonical EGFR activation in which tyrosine residues are engaged, we have demonstrated that the non-canonical pathway is triggered by phosphorylation of serine and threonine residues through p38 and ERK MAPKs, respectively. The purpose of this study is to investigate the role of non-canonical EGFR pathway in resistance mechanism against cisplatin treatment. Wild type and mutated (exon 19 deletion) EGFR-expressing cells responded similarly to cisplatin by showing MAPK-mediated EGFR phosphorylation. It is interesting that internalization mechanism of EGFR was switched from tyrosine kinase-dependent to p38-dependent fashions, which is involved in a survival pathway that counteracts cisplatin treatment. We therefore introduce a potential combinatorial therapy composed of p38 inhibition and cisplatin to block the activation of EGFR, therefore inducing cancer cell death and apoptosis. PMID- 25701784 TI - RASSF4 promotes EV71 replication to accelerate the inhibition of the phosphorylation of AKT. AB - Enterovirus 71 (EV71) is a neurotropic virus that causes hand, foot and mouth disease (HFMD), occasionally leading to death. As a member of the RAS association domain family (RASSFs), RASSF4 plays important roles in cell death, tumor development and signal transduction. However, little is known about the relationship between RASSF4 and EV71. Our study reveals for the first time that RASSF4 promotes EV71 replication and then accelerates AKT phosphorylation inhibition in EV71-infected 293T cells, suggesting that RASSF4 may be a potential new target for designing therapeutic measures to prevent and control EV71 infection. PMID- 25701785 TI - CD83 and GRASP55 interact in human dendritic cells. AB - CD83 is one of the best known surface markers for mature human dendritic cells (DCs). The full-length 45 kDa type-I membrane-bound form (mbCD83) is strongly glycosylated upon DCs maturation. As co-stimulatory properties of CD83 are attributed to mbCD83 surface expression is required for efficient T-cell stimulation by mature DCs. By yeast two-hybrid screening, we were able to identify GRASP55 as interaction partner of CD83. DCs maturation induces endogenous CD83 protein expression with simultaneous regulation of CD83 glycosylation, interaction and co-localization with GRASP55 and CD83 surface exposure. GRASP55 is especially known for its role in maintaining Golgi architecture, but also plays a role in Golgi transport of specific cargo proteins bearing a C-terminal valine residue. Here we additionally demonstrate that binding of CD83 and GRASP55 rely on the C-terminal TELV-motif of CD83. Mutation of this TELV-motif not only disrupted binding to GRASP55, but also altered the glycosylation pattern of CD83 and reduced its membrane expression. Here we show for the first time that GRASP55 interacts with CD83 shortly after induction of DC maturation and that this interaction plays a role in CD83 glycosylation as well as in surface expression of CD83 on DCs. PMID- 25701786 TI - SUMO-fusion, purification, and characterization of a (+)-zizaene synthase from Chrysopogon zizanioides. AB - An uncharacterized plant cDNA coding for a polypeptide presumably having sesquiterpene synthase activity, was expressed in soluble and active form. Two expression strategies were evaluated in Escherichia coli. The enzyme was fused to a highly soluble SUMO domain, in addition to being produced in an unfused form by a cold-shock expression system. Yields up to ~325 mg/L(-1) were achieved in batch cultivations. The 6x-His-tagged enzyme was purified employing an Ni(2+)-IMAC based procedure. Identity of the protein was established by Western Blot analysis as well as peptide mass fingerprinting. A molecular mass of 64 kDa and an isoelectric point of pI 4.95 were determined by 2D gel electrophoresis. Cleavage of the fusion domain was possible by digestion with specific SUMO protease. The synthase was active in Mg(2+) containing buffer and catalyzed the production of (+)-zizaene (syn. khusimene), a precursor of khusimol, from farnesyl diphosphate. Product identity was confirmed by GC-MS and comparison of retention indices. Enzyme kinetics were determined by measuring initial reaction rates for the product, using varying substrate concentrations. By assuming a Michaelis-Menten model, kinetic parameters of KM = 1.111 MUM (+/-0.113), vmax = 0.3245 MUM min(-1) (+/-0.0035), kcat = 2.95 min(-1), as well as a catalytic efficiency kcat/KM = 4.43 * 10(4) M(-1)s(-1) were calculated. Fusion to a SUMO moiety can substantially increase soluble expression levels of certain hard to express terpene synthases in E. coli. The kinetic data determined for the recombinant synthase are comparable to other described plant sesquiterpene synthases and in the typical range of enzymes belonging to the secondary metabolism. This leaves potential for optimizing catalytic parameters through methods like directed evolution. PMID- 25701787 TI - Heterogeneous nuclear ribonucleoprotein K upregulates the kinetochore complex component NUF2 and promotes the tumorigenicity of colon cancer cells. AB - Heterogeneous nuclear ribonucleoprotein K (hnRNP K) is a multi-functional protein involved in transcription, mRNA splicing, mRNA stabilization and translation. Although hnRNP K has been suggested to play a role in the development of many cancers, its molecular function in colorectal cancer has remained elusive. Here we show that hnRNP K plays an important role in the mitotic process in HCT116 colon cancer cells. Furthermore, we demonstrate that hnRNP K directly transactivates the NUF2 gene, the product of which is a component of the NDC80 kinetochore complex and which is known to be critical for a stable spindle microtubule-kinetochore attachment. In addition, knockdown of both hnRNP K and NUF2 caused failure in metaphase chromosome alignment and drastic decrease in the growth of colon cancer cells. These results suggest that the hnRNP K-NUF2 axis is important for the mitotic process and proliferation of colon cancer cells and that this axis could be a target for the therapy of colon cancer. PMID- 25701788 TI - CTRP9 enhances carotid plaque stability by reducing pro-inflammatory cytokines in macrophages. AB - The aim of this study was to investigate whether C1q/TNF-related protein 9 (CTRP9) could stabilize the mature plaques by targeting macrophages in the apolipoprotein E knockout (ApoE KO) mice model. In vivo, the mice were subjected to high-fat diet and constrictive collars on the right carotid artery for eight weeks, a lentiviral vectors expressing CTRP9 (LV-CTRP9) or green fluorescence protein (LV-eGFP) as a control was intravenously injected into ApoE KO mice. Delivery of LV-CTRP9 resulted in low contents of macrophages and lipids, and high contents of collagen and vascular smooth muscle cells in the carotid mature plaques. In addition, CTRP9 also decreased pro-inflammatory cytokines in mature plaques. In vitro, RAW264.7 macrophages were pretreated with or without LV-CTRP9 transfection, and then stimulated with oxLDL (50 MUg/mL). We found that the expression levels of tumor necrosis factor-alpha (TNF-alpha) and monocyte chemoattractant protein 1 (MCP-1) in the LV-CTRP9 group were significantly lower than those in the LV-eGFP group after exposure to oxLDL. The present data indicate that CTRP9 overexpression enhances the plaque stability in ApoE KO mice by reducing pro-inflammatory cytokines in macrophages. Our study suggests that the therapeutic approaches to enhance CTRP9 production could be valuable for plaque stabilization. PMID- 25701789 TI - Voluntary exercise prevents colonic inflammation in high-fat diet-induced obese mice by up-regulating PPAR-gamma activity. AB - Obesity is associated with increased colonic inflammation, which elevates the risk of colon cancer. Although exercise exerts anti-inflammatory actions in multiple chronic diseases associated with inflammation, it is unknown whether this strategy prevents colonic inflammation in obesity. We hypothesized that voluntary exercise would suppress colonic inflammation in high-fat diet (HFD) induced obesity by modulation of peroxisome proliferator-activated receptor (PPAR)-gamma. Male C57Bl/6J mice fed either a control diet (6.5% fat, CON) or a high-fat diet (24% fat, HFD) were divided into sedentary, voluntary exercise or voluntary exercise with PPAR-gamma antagonist GW9662 (10 mg/kg/day). All interventions took place for 12 weeks. Compared with CON-sedentary group, HFD sedentary mice gained significantly more body weight and exhibited metabolic disorders. Molecular studies revealed that HFD-sedentary mice had increased expression of inflammatory mediators and activation of nuclear factor (NF)-kappaB in the colons, which were associated with decreased expression and activity of PPAR-gamma. Voluntary exercise markedly attenuated body weight gain, improved metabolic disorders, and normalized the expression of inflammatory mediators and activation of NF-kappaB in the colons in HFD-mice while having no effects in CON animals. Moreover, voluntary exercise significantly increased expression and activity of PPAR-gamma in the colons in both HFD- and CON-animals. However, all of these beneficial effects induced by voluntary exercise were abolished by GW9662, which inhibited expression and activity of PPAR-gamma. The results suggest that decreased PPAR-gamma activity in the colon of HFD-induced obesity may facilitate the inflammatory response and colon carcinogenesis. Voluntary exercise prevents colonic inflammation in HFD-induced obesity by up-regulating PPAR-gamma activity. PMID- 25701790 TI - An oxidative fluctuation hypothesis of aging generated by imaging H2O2 levels in live Caenorhabditis elegans with altered lifespans. AB - Reactive oxygen species (ROS) are important factors mediating aging according to the free radical theory of aging. Few studies have systematically measured ROS levels in relationship to aging, partly due to the lack of tools for detection of specific ROS in live animals. By using the H2O2-specific fluorescence probe Peroxy Orange 1, we assayed the H2O2 levels of live Caenorhabditis elegans with 41 aging-related genes being individually knocked down by RNAi. Knockdown of 14 genes extends the lifespan but increases H2O2 level or shortens the lifespan but decreases H2O2 level, contradicting the free radical theory of aging. Strikingly, a significant inverse correlation between lifespan and the normalized standard deviation of H2O2 levels was observed (p < 0.0001). Such inverse correlation was also observed in worms cultured under heat shock conditions. An oxidative fluctuation hypothesis of aging is thus proposed and suggests that the ability of animals to homeostatically maintain the ROS levels within a narrow range is more important for lifespan extension than just minimizing the ROS levels though the latter still being crucial. PMID- 25701791 TI - Myocardial regeneration in adriamycin cardiomyopathy by nuclear expression of GLP1 using ultrasound targeted microbubble destruction. AB - Recently GLP-1 was found to have cardioprotective effects independent of those attributable to tight glycemic control. METHODS AND RESULTS: We employed ultrasound targeted microbubble destruction (UTMD) to deliver piggybac transposon plasmids encoding the GLP-1 gene with a nuclear localizing signal to rat hearts with adriamycin cardiomyopathy. After a single UTMD treatment, overexpression of transgenic GLP-1 was found in nuclei of rat heart cells with evidence that transfected cardiac cells had undergone proliferation. UTMD-GLP-1 gene therapy restored LV mass, fractional shortening index, and LV posterior wall diameter to nearly normal. Nuclear overexpression of GLP-1 by inducing phosphorylation of FoxO1-S256 and translocation of FoxO1 from the nucleus to the cytoplasm significantly inactivated FoxO1 and activated the expression of cyclin D1 in nuclei of cardiac muscle cells. Reversal of adriamycin cardiomyopathy appeared to be mediated by dedifferentiation and proliferation of nuclear FoxO1-positive cardiac muscle cells with evidence of embryonic stem cell markers (OCT4, Nanog, SOX2 and c-kit), cardiac early differentiation markers (NKX2.5 and ISL-1) and cellular proliferation markers (BrdU and PHH3) after UTMD with GLP-1 gene therapy. CONCLUSIONS: Intranuclear myocardial delivery of the GLP-1gene can reverse established adriamycin cardiomyopathy by stimulating myocardial regeneration. PMID- 25701792 TI - An aquaporin protein is associated with drought stress tolerance. AB - Water channel proteins known as aquaporins (AQPs) regulate the movement of water and other small molecules across plant vacuolar and plasma membranes; they are associated with plant tolerance of biotic and abiotic stresses. In this study, a PIP type AQPs gene, designated as GoPIP1, was cloned from Galega orientalis, a high value leguminous forage crop. The GoPIP1 gene consists of an 870 bp open reading frame encoding a protein of 289 amino acids, and belongs to the PIP1 subgroup of the PIP subfamily. The transcript level of GoPIP1 was higher in the root of G. orientalis than in the leaf and stem. The level of GoPIP1 transcript increased significantly when treated with 200 mM NaCl or 20% polyethylene glycol (PEG) 6000. Transient expression of GoPIP1 in onion epidermal cells revealed that the GoPIP1 protein was localized to the plasma membrane. Over-expression of GoPIP1 increased the rosette/root ratio and increased sensitivity to drought in transgenic Arabidopsis plants. However, GoPIP1 over-expression in Arabidopsis had no significant effect under saline condition. The present data provides a gene resource that contributes to furthering our understanding of water channel protein and their application in plant stress tolerance. PMID- 25701793 TI - Identification of miR-143 as a tumour suppressor in nasopharyngeal carcinoma based on microRNA expression profiling. AB - Recent evidence has indicated that miRNAs play important roles in carcinogenesis. The identification of dysregulated miRNAs and the target genes they regulate might enhance our understanding of the molecular mechanisms of nasopharyngeal carcinoma (NPC). A microarray analysis was performed to identify dysregulated miRNAs in NPC tissue samples, and protein-coding genes targeted by three or more downregulated miRNAs were selected using miRWalk and used in a pathway enrichment analysis. Nineteen KEGG pathways were selected by DAVID, including the MAPK, focal adhesion, gap junction, ECM-receptor interaction, TGF-beta, and p53 signalling pathways, most of which are involved in NPC carcinogenesis and progression. MiR-143 was significantly downregulated in NPC cell lines and clinical samples. The ectopic expression of miR-143 suppressed NPC cell viability, colony formation, and anchorage-independent growth in vitro, and it inhibited xenograft tumour growth in vivo. Furthermore, KRAS was confirmed as a direct target of miR-143, and silencing KRAS expression suppressed NPC cell viability and proliferation. The miR-143/KRAS pathway provides new insight into the molecular mechanisms that regulate the development and progression of NPC, and it provides novel therapeutic targets for NPC. PMID- 25701794 TI - Repetition priming and cortical arousal in healthy aging and Alzheimer's disease. AB - Repetition priming refers to a form of implicit memory in which prior exposure to a stimulus facilitates the subsequent processing of the same or a related stimulus. One frequently used repetition priming task is word-stem completion priming. In this task, participants complete a series of beginning word stems with the first word that comes to mind after having viewed, in an unrelated context, words that can complete some of the stems. Patients with Alzheimer's disease (AD) exhibit a significant deficit in word-stem completion priming, but the neural mechanisms underlying this deficit have yet to be identified. The present study examined the possibility that the word-stem completion priming deficit in AD is due to disruption of ascending neuromodulatory systems that mediate cortical arousal by comparing word-stem completion priming and behavioral measures of spatial orienting and phasic alerting. Results showed that in healthy elderly controls higher levels of phasic alerting were associated with a sharpening of the temporal dynamics of priming across two delay intervals: those with higher levels of alerting showed more immediate priming but less delayed priming than those with lesser levels of alerting. In patients with AD, priming was impaired despite intact levels of phasic alerting and spatial orienting, and group status rather than individual levels of alerting or orienting predicted the magnitude of their stem-completion priming. Furthermore, the change in priming across delays they displayed was not related to level of alerting or orienting. These findings support the role of the noradrenergic projection system in modulating the level of steady-state cortical activation (or "cortical tonus") underlying both phasic alerting and the temporal dynamics of repetition priming. However, impaired priming in patients with AD does not appear to be due to disruption of this neuromodulatory system. PMID- 25701795 TI - A multimodal mapping study of conduction aphasia with impaired repetition and spared reading aloud. AB - The present study explores the functional neuroanatomy of the phonological production system in an Italian aphasic patient (SP) who developed conduction aphasia of the reproduction type following brain surgery. SP presented with two peculiar features: (1) his lesion was localized in the superior temporal gyrus, just posterior to the primary auditory cortex and anterior/inferior to and neighboring the Sylvian parietal temporal (Spt) area, and (2) he presented with severely impaired repetition and spelling from dictation of words and pseudowords but spared reading-aloud of words and pseudowords. Structural, functional, fiber tracking and intraoperative findings were combined to analyze SP's pattern of performance within a widely used sensorimotor control scheme of speech production. We found a dissociation between an interrupted sector of the arcuate fasciculus terminating in STG, known to be involved in phonological processing, and a part of the arcuate fasciculus terminating in MTG, which is held to be involved in lexical-semantic processing. We argue that this phonological deficit should be interpreted as a disorder of the feedback system, in particular of the auditory and somatosensory target maps, which are assumed to be located along the Spt area. In patient SP, the spared part of the left arcuate fasciculus originating in MTG may support an unimpaired reading performance, while the damaged part of the left arcuate fasciculus originating in STG may be responsible for his impaired repetition and spelling from dictation. PMID- 25701796 TI - Improved reading measures in adults with dyslexia following transcranial direct current stimulation treatment. AB - To better understand the contribution of the dorsal system to word reading, we explored transcranial direct current stimulation (tDCS) effects when adults with developmental dyslexia received active stimulation over the visual extrastriate area MT/V5, which is dominated by magnocellular input. Stimulation was administered in 5 sessions spread over two weeks, and reading speed and accuracy as well as reading fluency were assessed before, immediately after, and a week after the end of the treatment. A control group of adults with developmental dyslexia matched for age, gender, reading level, vocabulary and block-design WAIS III sub-tests and reading level was exposed to the same protocol but with sham stimulation. The results revealed that active, but not sham stimulation, significantly improved reading speed and fluency. This finding suggests that the dorsal stream may play a role in efficient retrieval from the orthographic input lexicon in the lexical route. It also underscores the potential of tDCS as an intervention tool for improving reading speed, at least in adults with developmental dyslexia. PMID- 25701797 TI - Antiepileptogenic effects of the selective COX-2 inhibitor etoricoxib, on the development of spontaneous absence seizures in WAG/Rij rats. AB - Different data suggest the involvement of specific inflammatory pathways in the pathogenesis of epilepsy. Cyclooxygenase (COX), which catalyses the production of pro-inflammatory prostaglandins, may play a significant role in seizure-induced neuroinflammation and neuronal hyperexcitability. COX-2 is constitutively expressed in the brain and also increased during/after seizures. COX-2 inhibitors may thus attenuate inflammation associated with brain disorders. We studied whether early long-term treatment (17 consecutive weeks starting from 45 days postnatal age) with the non-steroidal anti-inflammatory drug etoricoxib (10 mg/kg/day per os), a selective COX-2 inhibitor, was able to prevent/reduce the development of absence seizures in WAG/Rij rats, a recognized animal model of absence epilepsy and epileptogenesis. Drug effects on the incidence, duration and properties of absence seizure spike-wave discharges (SWDs) were measured both 1 and 5 months after treatment withdrawal; furthermore, the acute effects of etoricoxib on SWDs in 6-month-old WAG/Rij rats were measured. Early long-term treatment (ELTT) with etoricoxib led to an ~40% long-lasting (5 months) reduction in the development of spontaneous absence seizures in adult WAG/Rij rats thus exhibiting antiepileptogenic effects. Acutely administered etoricoxib (10 and 20mg/kg i.p.) also had anti-absence properties, significantly reducing the number and duration of SWDs by ~50%. These results confirm the antiepileptogenic effects of COX-2 inhibitors and suggest the possible role of COX-2, prostaglandin synthesis and consequent neuroinflammation in the epileptogenic process underlying the development of absence seizures in WAG/Rij rats. PMID- 25701798 TI - A hydrophobic filter confers the cation selectivity of Zygosaccharomyces rouxii plasma-membrane Na+/H+ antiporter. AB - Na(+)/H(+) antiporters may recognize all alkali-metal cations as substrates but may transport them selectively. Plasma-membrane Zygosaccharomyces rouxii Sod2-22 antiporter exports Na(+) and Li(+), but not K(+). The molecular basis of this selectivity is unknown. We combined protein structure modeling, site-directed mutagenesis, phenotype analysis and cation efflux measurements to localize and characterize the cation selectivity region. A three-dimensional model of the ZrSod2-22 transmembrane domain was generated based on the X-ray structure of the Escherichia coli NhaA antiporter and primary sequence alignments with homologous yeast antiporters. The model suggested a close proximity of Thr141, Ala179 and Val375 from transmembrane segments 4, 5 and 11, respectively, forming a hydrophobic hole in the putative cation pathway's core. A series of mutagenesis experiments verified the model and showed that structural modifications of the hole resulted in altered cation selectivity and transport activity. The triple ZrSod2-22 mutant T141S-A179T-V375I gained K(+) transport capacity. The point mutation A179T restricted the antiporter substrate specificity to Li(+) and reduced its transport activity, while serine at this position preserved the native cation selectivity. The negative effect of the A179T mutation can be eliminated by introducing a second mutation, T141S or T141A, in the preceding transmembrane domain. Our experimental results confirm that the three residues found through modeling play a central role in the determination of cation selectivity and transport activity in Z. rouxii Na(+)/H(+) antiporter and that the cation selectivity can be modulated by repositioning a single local methyl group. PMID- 25701799 TI - Influence of the cis-9, cis-12 and cis-15 double bond position in octadecenoic acid (18:1) isomers on the rat FADS2-catalyzed Delta6-desaturation. AB - Oleic (cis9-18:1), linoleic (cis9,cis12-18:2) and alpha-linolenic (cis9,cis12,cis15-18:3) acids are well described substrates of the Delta6 desaturase encoded by the mammalian fatty acid desaturase 2 (FADS2) gene. In addition, at least 9 other very structurally different fatty acids have been shown to be Delta6- or even Delta8-desaturated by the FADS2 protein. A better characterization of the substrate specificity of this enzyme is therefore needed. By using commercial cis9-18:1 and chemically synthesized cis12- and cis15-18:1 (sharing the n-6 double bond with 18:2 n-6 and the n-3 double bond with 18:3 n-3, respectively), we tried to decrypt the fatty acid structure driving the FADS2 substrate affinity. We first showed that both recombinant and native rat FADS2 were able to Delta6-desaturate not only the cis9- but also the cis12- and cis15 18:1 isomers. Next, the inhibitory effect of increasing concentrations of each 18:1 isomer was investigated in vitro on the Delta6-desaturation of alpha linolenic acid. At equimolar inhibitor/substrate ratio (60 MUM), the cis9-18:1 exhibited a significantly higher inhibition (25%) than the cis12- (8%) and cis15 18:1 (5%). This study shows that a single cis double bond in 12- or 15-position in 18:1 is enough to make them low Delta6-desaturable substrates. If a preexisting cis9-double bond is not absolutely required for the Delta6 desaturation of octadecenoic acids, its presence is however crucial to explain the higher enzyme affinity. Compared with oleic acid, the additional presence of a cis12-double bond in linoleic acid increased its inhibitory effect on the Delta6-desaturation of alpha-linolenic acid at low concentration (30 MUM) but not at higher concentrations (60 and 120 MUM). In this classification of the decreasing impact of the double bond when it comes closer to the methyl end of octadecenoic acids, the cis11-18:1 (cis-vaccenic acid) should be considered apart since it is itself not Delta6-desaturated but still a good competitive inhibitor of the alpha-linolenic acid Delta6-desaturation. PMID- 25701800 TI - Carbon monoxide-releasing molecule-A1 (CORM-A1) improves clinical signs of experimental autoimmune uveoretinitis (EAU) in rats. AB - Uveitis is a sight-threatening inflammatory disease of the eye which represents the third leading cause of blindness in the developed countries. The conventional pharmacological treatment includes corticosteroids and immunosuppressive agents, which are limited by their side effects. New therapeutic strategies are thus strongly needed. Exogenously-administered carbon monoxide (CO) may represent an effective treatment for conditions characterized by a dysregulated inflammatory response. Carbon monoxide-releasing molecules (CORMs) are a novel group of compounds capable of carrying and liberating controlled quantities of CO. Among CORMs, CORM-A1 represents the first example of water soluble CO releaser. We show here that CORM-A1 under a late prophylactic regime is able to significantly ameliorate the natural course of experimental autoimmune uveoretinitis, a rodent model of immunoinflammatory posterior uveitis. The present study strongly supports the development of CORM-A1 as a potential new drug for treatment of patients with non-infectious posterior uveitis. PMID- 25701801 TI - The effectiveness of Narrative Exposure Therapy with traumatised firefighters in Saudi Arabia: a randomized controlled study. AB - Firefighters are exposed to many traumatic events. The psychological costs of this exposure increase the risk of Post-Traumatic Stress disorder (PTSD), depression and anxiety. This study examined the effectiveness of Narrative Exposure Therapy (NET) as a short-term treatment for reducing PTSD symptoms among Saudi firefighters. A randomized waiting-list control study was conducted with 34 traumatized firefighters were randomly allocated to NET or Waiting-list Control (WLC). The NET group received four therapy sessions of 60-90 min over a three week period; those in the WLC condition received the same sessions after a three week waiting period. Participants in both groups were assessed at baseline, immediately post-intervention and at 3 and 6 month follow ups. NET led to significant reductions in PTSD symptoms, anxiety and depression compared with WLC. After the WLC group received treatment, it showed the same improvements as the NET group. This occurred immediately post-treatment in both groups, but was not sustained at 3 and 6 month follow ups. Coping strategies and social support led to significant changes only in follow up times. NET was effective in reducing PTSD symptoms in traumatised Saudi firefighters. This finding could be helpful in the management of PTSD among people who work as first responders such as firefighters, police officers and emergency medical personal, as well as security officers. PMID- 25701802 TI - Evaluation of the DSM-5 severity indicator for binge eating disorder in a community sample. AB - Research has examined various aspects of the diagnostic criteria for binge-eating disorder (BED) but has yet to evaluate the DSM-5 severity criterion. This study examined the DSM-5 severity criterion for BED based on binge-eating frequency and tested an alternative severity specifier based on overvaluation of shape/weight. 338 community volunteers categorized with DSM-5 BED completed a battery of self report instruments. Participants were categorized first using DSM-5 severity levels and second by shape/weight overvaluation and were compared on clinical variables. 264 (78.1%) participants were categorized as mild, 67 (19.8%) as moderate, 6 (1.8%) as severe, and 1 (0.3%) as extreme. Analyses comparing mild and moderate severity groups revealed no significant differences in demographic variables or BMI; the moderate severity group had greater eating-disorder psychopathology (small effect-sizes) but not depression than the mild group. Participants with overvaluation (N = 196; 60.1%) versus without (N = 130; 39.9%) did not differ significantly in age, sex, BMI, or binge-eating frequency. The overvaluation group had significantly greater eating-disorder psychopathology and depression than the non-overvaluation group. The greater eating-disorder and depression levels (medium-to-large effect-sizes) persisted after adjusting for ethnicity/race and binge-eating severity/frequency, without attenuation of effect sizes. Findings from this non-clinical community sample provide support for overvaluation of shape/weight as a specifier for BED as it provides stronger information about severity than the DSM-5 rating based on binge-eating. Future research should include treatment-seeking patients with BED to test the utility of DSM-5 severity specifiers and include broader clinical validators. PMID- 25701803 TI - Diadenosine tetraphosphate improves adrenergic anti-glaucomatous drug delivery and efficiency. AB - The effect of the dinucleotide P(1), P(4)-Di (adenosine-5') tetraphosphate (Ap4A) in improving adrenergic anti-glaucomatous delivery by modifying the tight junction proteins of the corneal epithelium was evaluated. Stratified human corneal epithelial cells (HCLE) were treated with Ap4A (100 MUM) for 5 min and TJ protein levels and barrier function were analysed by western blotting and transepithelial electrical resistance (TEER), respectively. Western blot experiments showed a significant reduction at 2 h (45% reduction of ZO-1 and 65% reduction of occludin protein levels) as compared to non-treated (control) cells. Two hours after Ap4A treatment, TEER values were significantly reduced (65% as compared to control levels (p < 0.001)), indicating an increase in corneal barrier permeability. Topical application of Ap4A in New Zealand white rabbits two hours before the instillation of the hypotensor compounds (the alpha2 adrenergic receptor agonist, brimonidine and the beta-adrenergic receptor antagonist, timolol), improved the delivery of these compounds to the anterior chamber as well as their hypotensive action on the intraocular pressure. The results obtained showed that, when Ap4A was topically applied two hours before the adrenergic compounds, the concentration of brimonidine in the aqueous humour increased from 64.3 +/- 5.3 nM to 240.6 +/- 8.6 nM and from 58.9 +/- 9.2 nM to 183.7 +/- 6.8 nM in the case of timolol, which also produces a more profound effect on IOP. Therefore, Ap4A treatment results in a better entrance of adrenergic anti-glaucomatous compounds within the eye and consequently improved therapeutic efficiency by increasing corneal epithelial barrier permeability. PMID- 25701804 TI - From neural oscillations to reasoning ability: Simulating the effect of the theta to-gamma cycle length ratio on individual scores in a figural analogy test. AB - Several existing computational models of working memory (WM) have predicted a positive relationship (later confirmed empirically) between WM capacity and the individual ratio of theta to gamma oscillatory band lengths. These models assume that each gamma cycle represents one WM object (e.g., a binding of its features), whereas the theta cycle integrates such objects into the maintained list. As WM capacity strongly predicts reasoning, it might be expected that this ratio also predicts performance in reasoning tasks. However, no computational model has yet explained how the differences in the theta-to-gamma ratio found among adult individuals might contribute to their scores on a reasoning test. Here, we propose a novel model of how WM capacity constraints figural analogical reasoning, aimed at explaining inter-individual differences in reasoning scores in terms of the characteristics of oscillatory patterns in the brain. In the model, the gamma cycle encodes the bindings between objects/features and the roles they play in the relations processed. Asynchrony between consecutive gamma cycles results from lateral inhibition between oscillating bindings. Computer simulations showed that achieving the highest WM capacity required reaching the optimal level of inhibition. When too strong, this inhibition eliminated some bindings from WM, whereas, when inhibition was too weak, the bindings became unstable and fell apart or became improperly grouped. The model aptly replicated several empirical effects and the distribution of individual scores, as well as the patterns of correlations found in the 100-people sample attempting the same reasoning task. Most importantly, the model's reasoning performance strongly depended on its theta-to-gamma ratio in same way as the performance of human participants depended on their WM capacity. The data suggest that proper regulation of oscillations in the theta and gamma bands may be crucial for both high WM capacity and effective complex cognition. PMID- 25701805 TI - Intracellular delivery of dendrimer triamcinolone acetonide conjugates into microglial and human retinal pigment epithelial cells. AB - Triamcinolone acetonide (TA) is a potent, intermediate-acting, steroid that has anti-inflammatory and anti-angiogenic activity. Intravitreal administration of TA has been used for diabetic macular edema, proliferative diabetic retinopathy and exudative age-related macular degeneration (AMD). However, the hydrophobicity, lack of solubility, and the side effects limit its effectiveness in the treatment of retinal diseases. In this study, we explore a PAMAM dendrimer-TA conjugate (D TA) as a potential strategy to improve intracellular delivery and efficacy of TA to target cells. The conjugates were prepared with a high drug payload (~ 21%) and were readily soluble in saline. Compared to free TA, D-TA demonstrated a significantly improved toxicity profile in two important target [microglial and human retinal pigment epithelium (RPE)] cells. The D-TA was ~ 100-fold more effective than free TA in its anti-inflammatory activity (measured in microglia), and in suppressing VEGF production (in hypoxic RPE cells). Dendrimer-based delivery may improve the efficacy of TA towards both its key targets of inflammation and VEGF production, with significant clinical implications. PMID- 25701806 TI - Antigen presenting cell-selective drug delivery by glycan-decorated nanocarriers. AB - Targeted drug delivery systems hold promise for selective provision of active compounds to distinct tissues or cell subsets. Thus, locally enhanced drug concentrations are obtained that would confer improved efficacy. As a consequence adverse effects should be diminished, as innocent bystander cells are less affected. Currently, several controlled drug delivery systems based on diverse materials are being developed. Some systems exhibit material-associated toxic effects and/or show low drug loading capacity. In contrast, liposomal nanocarriers are particularly favorable because they are well tolerated, poorly immunogenic, can be produced in defined sizes, and offer a reasonable payload capacity. Compared with other immune cells, professional antigen-presenting cells (APCs) demonstrate enhanced liposome uptake mediated by macropinocytosis, phagocytosis and presumably also by clathrin- and caveolae-mediated endocytosis. In order to further enhance the targeting efficacy toward APCs, receptor-mediated uptake appears advisable. Since APC subsets generally do not express single linage-specific receptors, members of the C-type lectin receptor (CLR) family are compelling targets. Examples of CLR expressed by APCs include DEC-205 (CD205) expressed by myeloid dendritic cells (DC) and monocytes, the mannose receptor C type 1 (MR, CD206) expressed by DC, monocytes and macrophages, DC-SIGN (CD209) expressed by DC, and several others. These receptors bind glycans, which are typically displayed by pathogens and thus support pathogen uptake and endocytosis. Further research will elucidate whether glycan-decorated liposomes will not only enhance APCs targeting but also enable preferential delivery of their payload to discrete subcellular compartments. PMID- 25701807 TI - Sunitinib microspheres based on [PDLLA-PEG-PDLLA]-b-PLLA multi-block copolymers for ocular drug delivery. AB - Sunitinib is a multi-targeted receptor tyrosine kinase (RTK) inhibitor that blocks several angiogenesis related pathways. The aim of this study was to develop sunitinib-loaded polymeric microspheres that can be used as intravitreal formulation for the treatment of ocular diseases. A series of novel multi-block copolymers composed of amorphous blocks of poly-(D,L-lactide) (PDLLA) and polyethylene glycol (PEG) and of semi-crystalline poly-(L-lactide) (PLLA) blocks were synthesized. Sunitinib-loaded microspheres were prepared by a single emulsion method using dichloromethane as volatile solvent and DMSO as co-solvent. SEM images showed that the prepared microspheres (~ 30 MUm) were spherical with a non-porous surface. Sunitinib-loaded microspheres were studied for their degradation and in-vitro release behavior. It was found that increasing the percentage of amorphous soft blocks from 10% to 30% accelerated the degradation of the multi-block copolymers. Sunitinib microspheres released their cargo for a period of at least 210 days by a combination of diffusion and polymer erosion. The initial burst (release in 24h) and release rate could be tailored by controlling the PEG-content of the multi-block copolymers. Sunitinib-loaded microspheres suppressed angiogenesis in a chicken chorioallantoic membrane (CAM) assay. These microspheres therefore hold promise for long-term suppression of ocular neovascularization. PMID- 25701808 TI - Nanoparticle-mediated delivery of the antimicrobial peptide plectasin against Staphylococcus aureus in infected epithelial cells. AB - A number of pathogenic bacterial strains, such as Staphylococcus aureus, are difficult to kill with conventional antibiotics due to intracellular persistence in host airway epithelium. Designing drug delivery systems to deliver potent antimicrobial peptides (AMPs) intracellularly to the airway epithelial cells might thus be a promising approach to combat such infections. In this work, plectasin, which is a cationic AMP of the defensin class, was encapsulated into poly(lactic-co-glycolic acid) (PLGA) nanoparticles using the double emulsion solvent evaporation method. The nanoparticles displayed a high plectasin encapsulation efficiency (71-90%) and mediated release of the peptide over 24h. The antimicrobial efficacy of the peptide-loaded nanoparticles was investigated using bronchial epithelial Calu-3 cell monolayers infected with S. aureus. The plectasin-loaded nanoparticles displayed improved efficacy as compared to non encapsulated plectasin, while the eukaryotic cell viability was unaffected at the assayed concentrations. Further, the subcellular localization of the nanoparticles was assessed in different relevant cell lines. The nanoparticles were distributed in punctuate patterns intracellularly in Calu-3 epithelial cells and in THP-1 macrophages, whereas A549 epithelial cells did not show significant uptake of the nanoparticles. Overall, encapsulation of plectasin into PLGA-based nanoparticles appears to be a viable strategy to improve the efficacy of plectasin against infections in epithelial tissues. PMID- 25701809 TI - Additional tricuspid annuloplasty in mitral valve surgery results in better clinical outcome. AB - OBJECTIVE: The clinical benefit of tricuspid annuloplasty (TA) in patients undergoing mitral valve surgery (MVS) is still debated. We evaluated the immediate surgical success, postoperative outcome and the medium-term effect of TA in MVS. METHODS: Patients were included between September 2003 and December 2009 and followed until September 2013 to achieve a median follow-up time of 5 years (IQR 3.7-6.9). The end point of mortality due to cardiac causes and combined end point of cardiac mortality or hospitalisation for heart failure were evaluated. Propensity score adjusted Cox regression was used to evaluate the clinical benefit of TA at the time of MVS. RESULTS: Of 150 patients (84 female; 67+/-12 years), 82 presented with tricuspid regurgitation (TR) <2/4 and underwent isolated MVS. Of 68 patients presenting with TR>=2/4, 31 underwent isolated MVS whereas 37 underwent additional TA. In patients with preoperative TR>=2/4, TR was significantly reduced until 5 years postoperatively (mean reduction 0.81+/-1.31; p=0.04) when additional TA was done. The combined end point occurred in 29% vs 6% at 1 year and in 57% vs 39% at 5 years follow-up for patients with isolated MVS and patients undergoing concomitant TA, respectively. Patients with preoperative TR>=2/4 had worse unadjusted survival than those with TR<2/4 (logrank p=0.009). In the patients with TR>=2/4, propensity score-adjusted risk for the combined end point was higher in those with isolated MVS versus MVS with additional TA (Cox HR 2.855 (1.082-7.532), p=0.035). CONCLUSIONS: Additional TA is an effective surgical measure to reduce functional TR severity. This approach results in a decreased risk of cardiac mortality and hospitalisation in patients with preoperative TR>=2/4. PMID- 25701810 TI - Effects of prenatal exposure to silver nanoparticles on spatial cognition and hippocampal neurodevelopment in rats. AB - BACKGROUND: Silver nanoparticles (Ag-NPs) are among the most commonly used nanomaterials and may be exposed to human and ecosystem. Prior in vitro study showed that Ag-NPs compromised neurodevelopment of PC12 cells. This study aims to investigate the effect of prenatal exposure to Ag-NPs on spatial cognition and hippocampal neurodevelopment in rats. METHODS: Pregnant rats were exposed by intraperitoneal injection to various solutions during pregnancy, including vehicle (water and glycerol mixture, 1:1 in volume), uncoated Ag-NPs (0.427mg Ag perg rat), polyvinylpyrrolidine (PVP)-coated Ag-NPs (0.407mg Ag perg rat), silver nitrate (0.013mg Ag(+) and 0.007mg NO3(+) per g rat) and sodium nitrate (0.007mg NO3(+) perg rat). Pregnant rats without any injection were used as blank control. Male offspring at postnatal day 35 (PND35) were randomly selected for Morris Water Maze (MWM) test. After the MWM test, the rats were decapitated and hippocampus were collected for analysis of tissue structure, silver content, GAP 43 mRNA and protein expressions. RESULTS: For the spatial learning in MWM test, since the third test day, the escape latency of rats in the uncoated Ag-NPs group was significantly higher than those in the other groups. The behaviors of rats were not significantly different among the other groups. The averaged silver content in the hippocampus of rats in the uncoated Ag-NPs group was 17.51MUg/g, significantly higher than those in the other groups. The hippocampal structure in rats of the uncoated Ag-NPs group was deformed as compared to those in the other groups. Compared with the rats in blank and vehicle controls, the levels of GAP 43 mRNA and protein in the uncoated Ag-NPs, PVP-coated Ag-NPs, silver nitrate and sodium nitrate groups were all significantly decreased. The levels of GAP-43 mRNA and protein of rats in the uncoated Ag-NPs group was significantly lower than those in the later three groups, while there was no significant difference among the later three groups. CONCLUSIONS: Maternal exposure to uncoated Ag-NPs during pregnancy impaired spatial cognition in rat offspring. GAP-43 reduction might be involved in the cognitive impairment. The toxicity was mainly associated with release of silver ion. Coating with PVP reduced the toxicity of Ag-NPs. PMID- 25701811 TI - Infant sex-specific placental cadmium and DNA methylation associations. AB - BACKGROUND: Recent evidence suggests that maternal cadmium (Cd) burden and fetal growth associations may vary by fetal sex. However, mechanisms contributing to these differences are unknown. OBJECTIVES: Among 24 maternal-infant pairs, we investigated infant sex-specific associations between placental Cd and placental genome-wide DNA methylation. METHODS: We used ANOVA models to examine sex stratified associations of placental Cd (dichotomized into high/low Cd using sex specific Cd median cutoffs) with DNA methylation at each cytosine-phosphate guanine site or region. Statistical significance was defined using a false discovery rate cutoff (<0.10). RESULTS: Medians of placental Cd among females and males were 5 and 2 ng/g, respectively. Among females, three sites (near ADP ribosylation factor-like 9 (ARL9), siah E3 ubiquitin protein ligase family member 3 (SIAH3), and heparin sulfate (glucosamine) 3-O-sulfotransferase 4 (HS3ST4) and one region on chromosome 7 (including carnitine O-octanoyltransferase (CROT) and TP5S target 1 (TP53TG1)) were hypomethylated in high Cd placentas. Among males, high placental Cd was associated with methylation of three sites, two (hypomethylated) near MDS1 and EVI1 complex locus (MECOM) and one (hypermethylated) near spalt-like transcription factor 1 (SALL1), and two regions (both hypomethylated, one on chromosome 3 including MECOM and another on chromosome 8 including rho guanine nucleotide exchange factor (GEF) 10 (ARHGEF10). Differentially methylated sites were at or close to transcription start sites of genes involved in cell damage response (SIAH3, HS3ST4, TP53TG1) in females and cell differentiation, angiogenesis and organ development (MECOM, SALL1) in males. CONCLUSIONS: Our preliminary study supports infant sex-specific placental Cd-DNA methylation associations, possibly accounting for previously reported differences in Cd-fetal growth associations across fetal sex. Larger studies are needed to replicate and extend these findings. Such investigations may further our understanding of epigenetic mechanisms underlying maternal Cd burden with suboptimal fetal growth associations. PMID- 25701812 TI - Indoor particulate matter in rural, wood stove heated homes. AB - Ambient particulate matter (PM) exposures have adverse impacts on public health, but research evaluating indoor PM concentrations in rural homes in the United States using wood as fuel for heating is limited. Our objectives were to characterize indoor PM mass and particle number concentrations (PNCs), quantify infiltration of outdoor PM into the indoor environment, and investigate potential predictors of concentrations and infiltration in 96 homes in the northwestern US and Alaska using wood stoves as the primary source of heating. During two forty eight hour sampling periods during the pre-intervention winter of a randomized trial, we assessed PM mass (<2.5MUm) and PNCs (particles/cm(3)) in six size fractions (0.30-0.49, 0.50-0.99, 1.00-2.49, 2.5-5.0, 5.0-10.0, 10.0+MUm). Daily mean (sd) PM2.5 concentrations were 28.8 (28.5)MUg/m(3) during the first sampling period and 29.1 (30.1)MUg/m(3) during the second period. In repeated measures analyses, household income was inversely associated with PM2.5 and smaller size fraction PNCs, in particular. Time of day was a significant predictor of indoor and outdoor PM2.5 concentrations, and infiltration efficiency was relatively low (Finf (sd)=0.27 (0.20)). Our findings demonstrate relatively high mean PM concentrations in these wood burning homes and suggest potential targets for interventions for improving indoor air quality and health in rural settings. PMID- 25701813 TI - The endosomal pathway in Parkinson's disease. AB - Parkinson's disease is primarily a movement disorder with predilection for the nigral dopaminergic neurons and is often associated with widespread neurodegeneration and diffuse Lewy body deposition. Recent advances in molecular genetics and studies in model organisms have transformed our understanding of Parkinson's pathogenesis and suggested unifying biochemical pathways despite the clinical heterogeneity of the disease. In this review, we summarized the evidence that a number of Parkinson's associated genetic mutations or polymorphisms (LRRK2, VPS35, GBA, ATP13A2, ATP6AP2, DNAJC13/RME-8, RAB7L1, GAK) disrupt protein trafficking and degradation via the endosomal pathway and discussed how such defects could arise from or contribute to the accumulation and misfolding of alpha-synuclein in Lewy bodies. We propose that an age-related pathological depletion of functional endolysosomes due to neuromelanin deposition in dopaminergic neurons may increase their susceptibility to stochastic molecular defects in this pathway and we discuss how enzymes that regulate ubiquitin signaling, as exemplified by the ubiquitin ligase Nedd4, could provide the missing link between genetic and acquired defects in endosomal trafficking. This article is part of a Special Issue entitled 'Neuronal Protein'. PMID- 25701814 TI - Structure-function analysis of SAP97, a modular scaffolding protein that drives dendrite growth. AB - Activation of AMPA receptors assembled with the GluA1 subunit can promote dendrite growth in a manner that depends on its direct binding partner, SAP97. SAP97 is a modular scaffolding protein that has at least seven recognizable protein-protein interaction domains. Several complementary approaches were employed to show that the dendrite branching promoting action of full length SAP97 depends on ligand(s) that bind to the PDZ3 domain. Ligand(s) to PDZ1, PDZ2 and I3 domains also contribute to dendrite growth. The ability of PDZ3 ligand(s) to promote dendrite growth depends on localization at the plasma membrane along with GluA1 and SAP97. These results suggest that the assembly of a multi-protein complex at or near synapses is vital for the translation of AMPA-R activity into dendrite growth. PMID- 25701815 TI - Trpc2-expressing sensory neurons in the mouse main olfactory epithelium of type B express the soluble guanylate cyclase Gucy1b2. AB - Chemoreception in the mouse olfactory system occurs primarily at two chemosensory epithelia in the nasal cavity: the main olfactory epithelium (MOE) and the vomeronasal epithelium. The canonical chemosensory neurons in the MOE, the olfactory sensory neurons (OSNs), express the odorant receptor (OR) gene repertoire, and depend on Adcy3 and Cnga2 for chemosensory signal transduction. The canonical chemosensory neurons in the vomeronasal epithelium, the vomeronasal sensory neurons (VSNs), express two unrelated vomeronasal receptor (VR) gene repertoires, and involve Trpc2 for chemosensory signal transduction. Recently we reported the discovery of two types of neurons in the mouse MOE that express Trcp2 in addition to Cnga2. These cell types can be distinguished at the single cell level by expression of Adcy3: positive, type A and negative, type B. Some type A cells express OR genes. Thus far there is no specific gene or marker for type B cells, hampering further analyses such as physiological recordings. Here, we show that among MOE cells, type B cells are unique in their expression of the soluble guanylate cyclase Gucy1b2. We came across Gucy1b2 in an explorative approach based on Long Serial Analysis of Gene Expression (LongSAGE) that we applied to single red-fluorescent cells isolated from whole olfactory mucosa and vomeronasal organ of mice of a novel Trcp2-IRES-taumCherry gene-targeted strain. The generation of a novel Gucy1b2-IRES-tauGFP gene-targeted strain enabled us to visualize coalescence of axons of type B cells into glomeruli in the main olfactory bulb. Our molecular and anatomical analyses define Gucy1b2 as a marker for type B cells within the MOE. The Gucy1b2-IRES-tauGFP strain will be useful for physiological, molecular, cellular, and anatomical studies of this newly described chemosensory subsystem. PMID- 25701816 TI - Enteric hyperoxaluria: an important cause of end-stage kidney disease. AB - Hyperoxaluria is a frequent complication of inflammatory bowel diseases, ileal resection and Roux-en-Y gastric bypass and is well-known to cause nephrolithiasis and nephrocalcinosis. The associated prevalence of chronic kidney disease and end stage kidney disease (ESKD) is less clear but may be more consequential than recognized. In this review, we highlight three cases of ESKD due to enteric hyperoxaluria following small bowel resections. We review current information on the pathophysiology, complications and treatment of this complex disease. PMID- 25701817 TI - Genetic characterization of epizootic hemorrhagic disease virus strains isolated from cattle in Israel. AB - Epizootic hemorrhagic disease virus (EHDV), a member of the genus Orbivirus not reported previously in Israel, was isolated from Israeli cattle during a 'bluetongue-like' disease outbreak in 2006. To ascertain the origin of this new virus, three isolates from the outbreak were fully sequenced and compared with available sequences. Whilst the L2 gene segment clustered with the Australian EHDV serotype 7 (EHDV-7) reference strain, most of the other segments were clustered with EHDV isolates of African/Middle East origin, specifically Bahrain, Nigeria and South Africa. The M6 gene had genetic relatedness to the Australian/Asian strains, but with the limited data available the significance of this relationship is unclear. Only one EHDV-7 L2 sequence was available, and as this gene encodes the serotype-specific epitope, the relationship of these EHDV-7 L2 genes to an Australian EHDV-7 reflects the serotype association, not necessarily the origin. The genetic data indicated that the strains affecting Israel in 2006 may have been related to similar outbreaks that occurred in North Africa in the same year. This finding also supports the hypothesis that EHDV entered Israel during 2006 and was not present there before this outbreak. PMID- 25701819 TI - Life-long shedding of Puumala hantavirus in wild bank voles (Myodes glareolus). AB - The knowledge of viral shedding patterns and viraemia in the reservoir host species is a key factor in assessing the human risk of zoonotic viruses. The shedding of hantaviruses (family Bunyaviridae) by their host rodents has widely been studied experimentally, but rarely in natural settings. Here we present the dynamics of Puumala hantavirus (PUUV) shedding and viraemia in naturally infected wild bank voles (Myodes glareolus). In a monthly capture-mark-recapture study, we analysed 18 bank voles for the presence and relative quantity of PUUV RNA in the excreta and blood from 2 months before up to 8 months after seroconversion. The proportion of animals shedding PUUV RNA in saliva, urine and faeces peaked during the first month after seroconversion, but continued throughout the study period with only a slight decline. The quantity of shed PUUV in reverse transcription quantitative PCR (RT-qPCR) positive excreta was constant over time. In blood, PUUV RNA was present for up to 7 months but both the probability of viraemia and the virus load declined with time. Our findings contradict the current view of a decline in virus shedding after the acute phase and a short viraemic period in hantavirus infection - an assumption widely adopted in current epidemiological models. We suggest the life-long shedding as a means of hantaviruses to survive over host population bottlenecks, and to disperse in fragmented habitats where local host and/or virus populations face temporary extinctions. Our results indicate that the kinetics of pathogens in wild hosts may differ considerably from those observed in laboratory settings. PMID- 25701818 TI - Hepatitis C virus infection of cholangiocarcinoma cell lines. AB - Hepatitis C virus (HCV) infects the liver and hepatocytes are the major cell type supporting viral replication. Hepatocytes and cholangiocytes derive from a common hepatic progenitor cell that proliferates during inflammatory conditions, raising the possibility that cholangiocytes may support HCV replication and contribute to the hepatic reservoir. We screened cholangiocytes along with a panel of cholangiocarcinoma-derived cell lines for their ability to support HCV entry and replication. While primary cholangiocytes were refractory to infection and lacked expression of several entry factors, two cholangiocarcinoma lines, CC-LP-1 and Sk ChA-1, supported efficient HCV entry; furthermore, Sk-ChA-1 cells supported full virus replication. In vivo cholangiocarcinomas expressed all of the essential HCV entry factors; however, cholangiocytes adjacent to the tumour and in normal tissue showed a similar pattern of receptor expression to ex vivo isolated cholangiocytes, lacking SR-BI expression, explaining their inability to support infection. This study provides the first report that HCV can infect cholangiocarcinoma cells and suggests that these heterogeneous tumours may provide a reservoir for HCV replication in vivo. PMID- 25701820 TI - Two conserved histidines (His490 and His621) on the E2 glycoprotein of hepatitis C virus are critical for CD81-mediated cell entry. AB - Hepatitis C virus (HCV) entry is a sequential and multi-step process that includes receptor interactions followed by pH-dependent membrane fusion. Specific and conserved histidine residues on the viral envelope proteins are involved in most pH-induced virus entries. In the case of HCV, some conserved histidines on the E1 and E2 proteins have been investigated in HCV pseudotype particle (HCVpp) systems. However, the roles of these histidines in cell-culture-derived HCV particle (HCVcc) systems remain unclear due to the different aspects of the viral life cycle emphasized by the two systems. In this study, the role of two conserved histidines (His490 and His621, located in domains II and III of E2, respectively) in HCV infection was evaluated in the context of JFH-1-based HCVcc using alanine substitutions. The infectivity of the H490A mutant decreased in spite of comparable initial RNA replication, protein expression and assembly efficiency as WT virus. The H621A mutant did not affect viral protein expression, but exhibited no obvious infectivity; there were fewer core proteins in the culture supernatant compared with WT virus, indicating the partially deficient virus assembly. The HCV receptor CD81-binding ability of the two mutant E2s was assessed further using enzyme immunoassays. The CD81-binding activity of H490A-E2 was reduced, and H621A-E2 was unable to bind to CD81. These data revealed the crucial role played by His490 and His621 in HCV infection, particularly during CD81 binding in cell entry. These results also contributed to the mechanical identification of the histidines involved in pH-dependent HCV entry. PMID- 25701821 TI - Identification of RNA helicases in human immunodeficiency virus 1 (HIV-1) replication - a targeted small interfering RNA library screen using pseudotyped and WT HIV-1. AB - Central to the development of new treatments for human immunodeficiency virus 1 (HIV-1) is a more thorough understanding of the viral life cycle and the cellular cofactors upon which this depends. Targeting cellular proteins and their interaction with HIV-1 has the potential to reduce the problem of emerging viral resistance to drugs as mutational escape is more difficult. We performed a short interfering RNA (siRNA) library screen targeting 59 cellular RNA helicases, assessing the effect on both viral capsid protein production and infectious virion formation. Five RNA helicases were identified which, when knocked down, reproducibly decreased infectious particle production: DDX5, DDX10, DDX17, DDX28 and DDX52. Two of these proteins (DDX5 and DDX17) have known roles in HIV-1 replication. A further helicase (DDX10) was a positive hit from a previous genome wide siRNA screen; however, DDX28 and DDX52 have not previously been implicated as essential cofactors for HIV-1. PMID- 25701822 TI - Parapoxvirus (PPV) of red deer reveals subclinical infection and confirms a unique species. AB - Parapoxvirus (PPV) infections are of worldwide importance, particularly in sheep and goat herds. Owing to the zoonotic potential of all PPV species, they are a permanent threat to human health as well. The virus is also known to affect wildlife, as reported for pinnipeds, red deer and several other wild ruminants. PPVs found in red deer have been claimed as a unique species according to certain genomic features. So far infection of wildlife has been recognized because of clinical manifestation such as inflammation, stomatitis or typical pox-like lesions in the skin or mucous membranes. Here we report the use of targeted molecular diagnostics for the presence of PPV genomes in tonsil swabs of apparently healthy red deer in the Bavarian Alps. Out of 1764 swabs, 0.79 % tested positive for PPV genome presence. From one sample, PPV was successfully isolated in cell culture. This virus became the subject of complete genome characterization using next generation sequencing and various subsidiary PCR protocols. Strikingly, about a quarter of all ORFs were found to be larger than the corresponding ORFs in the reference PPV genome sequences used for comparison. To our knowledge this is the first genome-wide analysis that confirms red deer PPV as a unique species within the genus Parapoxvirus in Europe. Persistence of PPV in Alpine red deer indicates a source for virus transmission to susceptible livestock and hunters. The findings provide a further example of wildlife animals playing an important role as an inconspicuous reservoir of zoonotic diseases. PMID- 25701823 TI - Identification and characterization of a novel tick-borne flavivirus subtype in goats (Capra hircus) in Spain. AB - In 2011, a neurological disease was reported in a herd of goats (Capra hircus) in Asturias, Spain. Initial sequencing identified the causative agent as louping ill virus (LIV). Subsequently, with the application of whole genome sequencing and phylogenetic analysis, empirical data demonstrates that the LIV-like virus detected is significantly divergent from LIV and Spanish sheep encephalitis virus (SSEV). This virus encoded an amino acid sequence motif at the site of a previously identified marker for differentiating tick-borne flaviviruses that was shared with a virus previously isolated in Ireland in 1968. The significance of these observations reflects the diversity of tick-borne flaviviruses in Europe. These data also contribute to our knowledge of the evolution of tick-borne flaviviruses and could reflect the movement of viruses throughout Europe. Based on these observations, the proposed name for this virus is Spanish goat encephalitis virus (SGEV), to distinguish it from SSEV. PMID- 25701824 TI - Novel paramyxoviruses in Australian flying-fox populations support host-virus co evolution. AB - Understanding the diversity of henipaviruses and related viruses is important in determining the viral ecology within flying-fox populations and assessing the potential threat posed by these agents. This study sought to identify the abundance and diversity of previously unknown paramyxoviruses (UPVs) in Australian flying-fox species (Pteropus alecto, Pteropus scapulatus, Pteropus poliocephalus and Pteropus conspicillatus) and in the Christmas Island species Pteropus melanotus natalis. Using a degenerative reverse transcription-PCR specific for the L gene of known species of the genus Henipavirus and two closely related paramyxovirus genera Respirovirus and Morbillivirus, we identified an abundance and diversity of previously UPVs, with a representative 31 UPVs clustering in eight distinct groups (100 UPVs/495 samples). No new henipaviruses were identified. The findings were consistent with a hypothesis of co-evolution of paramyxoviruses and their flying-fox hosts. Quantification of the degree of co speciation between host and virus (beyond the scope of this study) would strengthen this hypothesis. PMID- 25701825 TI - Mutation analysis of the RNA silencing suppressor NS1 encoded by avian influenza virus H9N2. AB - Non-structural protein 1 (NS1) binds small interfering RNA and suppresses RNA silencing in plants, but the underlying mechanism of this suppression is not well understood. Therefore, here we characterized NS1 encoded by the avian influenza virus H9N2. The NS1 protein was able to suppress RNA silencing induced by either sense RNA or double-stranded RNA (dsRNA). Using deletion and point mutants, we discovered that the first 70 residues of NS1 could suppress RNA silencing triggered by sense transgene, but this sequence was not sufficient to block dsRNA induced silencing. Any mutations of two arginine residues (35R and 46R) of NS1, which contribute to its homodimeric structure, caused the loss of its silencing suppression activity. These results indicate that the region after residue 70 of NS1 is essential for the repression activity on dsRNA-induced RNA silencing, and that the dimeric structure of NS1 plays a critical role in its RNA silencing suppression function. PMID- 25701826 TI - New reassortant and enzootic European swine influenza viruses transmit efficiently through direct contact in the ferret model. AB - The reverse zoonotic events that introduced the 2009 pandemic influenza virus into pigs have drastically increased the diversity of swine influenza viruses in Europe. The pandemic potential of these novel reassortments is still unclear, necessitating enhanced surveillance of European pigs with additional focus on risk assessment of these new viruses. In this study, four European swine influenza viruses were assessed for their zoonotic potential. Two of the four viruses were enzootic viruses of subtype H1N2 (with avian-like H1) and H3N2, and two were new reassortants, one with avian-like H1 and human-like N2 and one with 2009 pandemic H1 and swine-like N2. All viruses replicated to high titres in nasal wash and nasal turbinate samples from inoculated ferrets and transmitted efficiently by direct contact. Only the H3N2 virus transmitted to naive ferrets via the airborne route. Growth kinetics using a differentiated human bronchial epithelial cell line showed that all four viruses were able to replicate to high titres. Further, the viruses revealed preferential binding to the 2,6-alpha silalylated glycans and investigation of the antiviral susceptibility of the viruses revealed that all were sensitive to neuraminidase inhibitors. These findings suggested that these viruses have the potential to infect humans and further underline the need for continued surveillance as well as biological characterization of new influenza A viruses. PMID- 25701827 TI - NSP1 of human rotaviruses commonly inhibits NF-kappaB signalling by inducing beta TrCP degradation. AB - Rotavirus is a leading cause of severe gastroenteritis in infants worldwide. Rotavirus nonstructural protein 1 (NSP1) is a virulence factor that inhibits innate host immune responses. NSP1 from some rotaviruses targets host interferon response factors (IRFs), leading to inhibition of type I interferon expression. A few rotaviruses encode an NSP1 that inhibits the NF-kappaB pathway by targeting beta-TrCP, a protein required for IkappaB degradation and NF-kappaB activation. Available evidence suggests that these NSP1 properties involve proteosomal degradation of target proteins. We show here that NSP1 from several human rotaviruses and porcine rotavirus CRW-8 inhibits the NF-kappaB pathway, but cannot degrade IRF3. Furthermore, beta-TrCP levels were much reduced in cells infected with these rotaviruses. This provides strong evidence that beta-TrCP degradation is required for NF-kappaB pathway inhibition by NSP1 and demonstrates the relevance of beta-TrCP degradation to rotavirus infection. C-terminal regions of NSP1, including a serine-containing motif resembling the beta-TrCP recognition motif of IkappaB, were required for NF-kappaB inhibition. CRW-8 infection of HT 29 intestinal epithelial cells induced significant levels of IFN-beta and CCL5 but not IL-8. This contrasts with monkey rotavirus SA11-4F, whose NSP1 inhibits IRF3 but not NF-kappaB. Substantial amounts of IL-8 but not IFN-beta or CCL5 were secreted from HT-29 cells infected with SA11-4F. Our results show that human rotaviruses commonly inhibit the NF-kappaB pathway by degrading beta-TrCP and thus stabilizing IkappaB. They suggest that NSP1 plays an important role during human rotavirus infection by inhibiting the expression of NF-kappaB-dependent cytokines, such as IL-8. PMID- 25701828 TI - Metabolic differences between white and brown fat from fasting rabbits at physiological temperature. AB - It has been suggested that activated brown adipose tissue (BAT) shows increased glucose metabolic activity. However, less is known about metabolic activity of BAT under conditions of fasting and normal temperature. The aim of this study was to compare the possible differences in energetic metabolism between BAT and white adipose tissue (WAT) obtained from rabbits under the conditions of physiological temperature and 24 h after fasting conditions. The study was carried out on New Zealand rabbits (n=10) maintained for a period of 8 weeks at 23+/-2 degrees C. Food was removed 24 h before BAT and WAT were obtained. Protein expression levels of the glycolytic-related protein, glyceraldehyde-3-phosphate dehydrogenase, and pyruvate dehydrogenase were higher in WAT than that in BAT. The expression level of carnitine palmitoyltransferase 1 (CPT1) and CPT2, two fatty acid mitochondrial transporters, and the fatty acid beta-oxidation-related enzyme, acyl CoA dehydrogenase, was higher in BAT than in WAT. Cytosolic malate dehydrogenase expression and malate dehydrogenase activity were higher in WAT than in BAT. However, lactate dehydrogenase expression and lactate content were significantly higher in BAT than in WAT. In summary, this study for the first time, to our knowledge, has described how under fasting and normal temperature conditions rabbit BAT seems to use anaerobic metabolism to provide energetic fuel, as opposed to WAT, where the malate-aspartate shuttle and, therefore, the gluconeogenic pathway seem to be potentiated. PMID- 25701829 TI - Nicorandil Versus Nitroglycerin for Symptomatic Relief of Angina in Patients With Slow Coronary Flow Phenomenon: A Randomized Clinical Trial. AB - OBJECTIVE: Patients with the coronary slow flow phenomenon frequently experience angina episodes. The present study aimed to compare the efficacy of nicorandil versus nitroglycerin for alleviation of angina symptoms in slow flow patients. METHODS: In a single-center, single-blind, parallel-design, comparator controlled, randomized clinical trial (NCT02254252), 54 patients with slow flow and normal or near-normal coronary angiography who presented with frequent angina episodes were randomly assigned to 1-month treatment with nicorandil 10 mg, 2 times a day (n = 27) or sustained-release glyceryltrinitrate 6.4 mg 2 times a day (n =27). Frequency of angina episodes, pain intensity, and the Canadian Cardiovascular Society (CCS) grading of angina pectoris were assessed at baseline and after 1 month of treatment. RESULTS: In all, 25 patients in the nicorandil arm and 24 patients in the nitroglycerin arm were analyzed. After 1 month, patients treated with nicorandil had fewer angina episodes (adjusted mean number of episodes per week, nicorandil versus nitroglycerin; 1.68 +/- 0.15 vs 2.29 +/- 0.15, P = .007, effect size = 14.6%). Patients also reported greater reductions in pain intensity with nicorandil versus nitroglycerin (adjusted mean of self reported pain score; 3.03 +/- 0.29 vs 3.89 +/- 0.30, P = .046, effect size = 8.4%). A significantly higher proportion of patients in the nicorandil arm were categorized in CCS class I (76% vs 33.3%, P = .004) or class II (16.0% vs 45.8%, P = .032). CONCLUSION: In slow flow patients, nicorandil provides better symptomatic relief of angina than nitroglycerin. PMID- 25701830 TI - Nicorandil-induced colonic ulceration. AB - A 76-year-old woman with significant cardiovascular comorbidities was investigated under general surgery for weight loss and change in bowel habit. Endoscopic investigations revealed a large ulcer extending from the ileocaecal valve to the ascending colon. Histology of the biopsies from this site revealed chronic inflammation and reactive changes. However, considering the history and suspicious radiological and endoscopic findings, decision was made at a multidisciplinary meeting to offer laparoscopic right hemicolectomy. Owing to complications, the procedure was converted to an open surgery. Postoperatively, histology of resected bowel revealed chronic inflammation and no evidence of malignancy. In light of an 8-year history of nicorandil therapy, the histological changes were thought to represent nicorandil-induced colonic ulceration. PMID- 25701831 TI - Type 2 diabetes presenting with hyperglycaemic hyperosmolar state in an adolescent renal transplant patient. AB - Hyperglycaemic hyperosmolar state (HHS) is a life-threatening condition rarely seen in paediatrics. It is becoming increasingly recognised with the growing incidence of childhood type 2 diabetes mellitus (T2DM). We present a 16-year-old boy with Bardet-Biedl syndrome, with comorbidities including chronic renal impairment requiring renal transplant, isolated growth hormone (GH) deficiency and obesity, who presented on routine follow-up with new onset T2DM and in HHS. Investigations revealed hyperglycaemia (45.7 mmol/L), ketones of 0.1 mmol/L, pH 7.38 and osmolarity 311 mOsmol/kg. After acute management with fluid resuscitation and intravenous insulin, he is now stable on metformin. He has lost weight, renal function is stable and he has stopped GH therapy. We discuss the dilemmas encountered in his long-term management due to his renal transplant and comorbidities, and whether or not, given his significant T2DM risk, this case was preventable or predictable. PMID- 25701832 TI - Metastatic hepatocellular carcinoma to the pelvis and vertebrae in a patient with chronic hepatitis 'C' with unknown primary. AB - A 54-year-old man infected with hepatitis C virus presented to us with pain in the right iliac fossa radiating to the back and right thigh for the past 2 months. Imaging of the abdomen and pelvis was performed, which revealed a soft tissue mass adherent to right iliac blade and right ala of sacrum. Trucut biopsy of the mass was performed and immunohistochemical stains Glypican-3 and Hep-par 1 were used for histopathological analysis, which diagnosed the mass as hepatocellular carcinoma. This is a unique case of metastasis of hepatocellular carcinoma to the bone in which imaging of the liver did not show any primary lesion. Liver function tests showed that aspartate transaminase and alanine transaminase were twice the normal range with a high viral load and significantly raised serum alpha-fetoprotein. The patient was treated with intravenous 5 flourouracil and radiotherapy as a palliative measure with only moderate clinical improvement. PMID- 25701833 TI - An unusual relapse in acute myeloid leukaemia. AB - A 40-year-old nulliparous woman, with a history of acute myeloid leukaemia (AML), presented at a gynaecological clinic with an incidental finding of a 5 cm pelvic mass on ultrasound during workup for subfertility. Biopsies confirmed a myeloid sarcoma. The patient underwent a total abdominal hysterectomy and bilateral salpingo-oophorectomy, followed by chemotherapy and radiotherapy. She recovered well from her surgery, 21 months postsurgery with no evidence of recurrence. PMID- 25701834 TI - Thrombotic thrombocytopenic purpura as an initial presentation of systemic lupus erythematosus with acquired ADAMTS 13 antibody. AB - We report a female patient presenting with headache, fatigue, ecchymoses and recent, excessive vaginal bleeding. Prompt review of the peripheral blood smear showed evidence of microangiopathic haemolytic anaemia (MAHA) and thrombocytopenia. Thrombotic thrombocytopenic purpura (TTP) was suspected. Plasma exchange and corticosteroids were started urgently. The patient responded favourably to the treatment. Subsequently, positive serological markers returned and were compatible with systemic lupus erythematosus (SLE). A disintegrin and metalloproteinase with thrombospondin type 1 motifs, member 13 (ADAMTS 13) activity was remarkably low with a positive inhibitory ADAMTS 13 antibody. Mycophenolate and hydroxychloroquine were started along with a prolonged course and taper of corticosteroids. These medications have been maintained with an excellent response in 14 months of follow-up. PMID- 25701835 TI - Influence of fatigue on construction workers' physical and cognitive function. AB - BACKGROUND: Despite scientific evidence linking workers' fatigue to occupational safety (due to impaired physical or cognitive function), little is known about this relationship in construction workers. AIMS: To assess the association between construction workers' reported fatigue and their perceived difficulties with physical and cognitive functions. METHODS: Using data from a convenience sample of US construction workers participating in the 2010-11 National Health Interview Survey two multivariate weighted logistic regression models were built to predict difficulty with physical and with cognitive functions associated with workers' reported fatigue, while controlling for age, smoking status, alcohol consumption status, sleep hygiene, psychological distress and arthritis status. RESULTS: Of 606 construction workers surveyed, 49% reported being 'tired some days' in the past 3 months and 10% reported 'tired most days or every day'. Compared with those feeling 'never tired', workers who felt 'tired some days' were significantly more likely to report difficulty with physical function (adjusted odds ratio [AOR] = 2.03; 95% confidence interval [CI] 1.17-3.51) and cognitive function (AOR = 2.27; 95% CI 1.06-4.88) after controlling for potential confounders. CONCLUSIONS: Our results suggest an association between reported fatigue and experiencing difficulties with physical and cognitive functions in construction workers. PMID- 25701836 TI - An evaluation of the burden placed on the General Internal Medicine team at the Role 3 Hospital in Camp Bastion by UK Armed Forces personnel presenting with symptoms resulting from previously identified disease. AB - INTRODUCTION: During previous deployments of the British Armed Forces, a significant proportion of aeromedical evacuations were accounted for with recurrent symptoms from a known disease that had often triggered occupational medical downgrading. Many servicemen and women had deployed inappropriately, and by doing so became a burden on the deployed medical facilities. Commanders performing systematic medical risk assessments prior to departure might have prevented these individuals from deploying. This study was designed to assess the avoidable burden from recurrent disease during the current Afghanistan operation. METHODS: A cross-sectional study reviewing the hospital and computerised primary care medical records of consecutive patients admitted under the General Physicians to the Role 3 Hospital in Camp Bastion over 9 months from April 2011. The occupational medical grading, diagnosis, disposal and whether the disease was recurrent were recorded. RESULTS: Of 270 patients admitted, 14 (5.2%) were medically downgraded. The computerised records were unavailable for 31 (11.5%) patients. All those patients who were medically downgraded were graded 'Medically Limited Deployable'. In the downgraded group, only one patient presented with recurrent symptoms from their pre-existing condition (Crohn's disease). In the non-downgraded group, two patients presented with symptoms relating to their previous diagnoses. One presented with a second heat illness and should have been medically downgraded and not have been deployed, while the other patient had previously been investigated for recurrent syncope and was upgraded 6 months prior to deploying. All three patients underwent aeromedical evacuation but only two of these were considered to have been avoidable. DISCUSSION: The number of general medical admissions to the Role 3 Hospital due to a pre-existing disease is very low. PMID- 25701837 TI - Type 2 Endometrial Cancer is Associated With a High Density of Tumor-Associated Macrophages in the Stromal Compartment. AB - INTRODUCTION: Tumor-associated macrophages (TAMs) play a pivotal role in orchestrating the microenvironment. The TAMs differentially polarize into M1 or M2 macrophages with distinct actions. The aim of our work is to characterize density, subtype, and location of TAMs in endometrial hyperplasia and cancer. METHODS: Formalin-fixed, paraffin-embedded sections of hyperplasia (n = 5), type 1 (n = 5), and type 2 (n = 5) endometrial cancer were stained with anti-CD68 and anti-CD163 monoclonal antibodies as markers for total TAMs and M2 TAMs, respectively. Macrophages were counted at 40* magnification in 10 high-power fields (HPFs) per slide by 4 observers. Repeated measures models were constructed to determine the relationships between macrophages and lesion categories. RESULTS: Most CD68+ TAMs were located in the stromal (mean = 41.0/HPF) compared to epithelial (mean = 11.0/HPF) or luminal (mean = 11.6/HPF) compartments. Similar but reduced findings were observed for CD163+ (M2 subtype) TAMs. The CD68+ stromal TAM density was highest in patients with type 2 cancers (mean = 54.0/HPF) compared to those with type 1 cancers (mean = 35.5/HPF) and hyperplasia (mean = 29.0/HPF). Women with hyperplasia had more CD163+ (M2 subtype) TAMs (26.7/HPF) than patients with either type of cancer (type 1 = 12.5/HPF and type 2 = 11.5/HPF). Based on the repeated measures models, type 2 cancers had 38.6/HPF more CD68+ TAMs than type 1 cancers (P < .0001) and type 1 and type 2 cancers had similar numbers of CD163+ TAMs (P = .27). CONCLUSIONS: Type 2 cancers have nearly twice the TAM density of type 1 cancers. This difference may be due to M1 macrophage predominance in the stroma of type 2 cancers. PMID- 25701838 TI - Plasma miR-127 and miR-218 Might Serve as Potential Biomarkers for Cervical Cancer. AB - Cervical cancer, a second common cancer in women, represents a major health care problem. Papanicolaou test, colposcopy, and different types of useful biomarkers are current major methods for detection of cervical cancer. However, these methods have the limitation of invasion, expensive cost, manpower issues, and low accuracy. The aim of this study is to explore the application of 3 plasma micro RNAs (miRNAs; miR-127, miR-205, and miR-218) in detection of cervical cancer. Blood samples were collected from 68 patients with cervical cancer, and plasma was extracted and stored at -80 degrees C freezer until use. RUN6B was selected as an internal control to determine the relative expression levels of 3 miRNAs. Quantitative real-time polymerase chain reaction was performed. The result showed that the expression levels of miR-127 and miR-205 in cervical cancers were higher than that in controls (P < .001); however, there was no marked difference in expression of miR-218 in cervical cancers and controls (P > .05). Therefore, we conducted the receiver-operating characteristic curve analyses for miR-127 and miR-205. The sensitivity and specificity of miR-127 in distinguishing patients with cervical cancer from healthy controls were 75.51% and 83.82%, respectively, with the area under the curve (AUC) of 0.820. MiR-205 showed higher predictive value with an AUC of 0.843, sensitivity of 72.00%, and specificity of 82.35%. In conclusion, we identified the predictive power of 3 plasma miRNAs for cervical cancer, and consequence can be concluded that plasma miR-127 and miR-205 are promising tumor markers for cervical cancer. PMID- 25701839 TI - Driving Human Granulosa-Luteal Cells Recovered From In Vitro Fertilization Cycles Toward the Follicular Phase Phenotype. AB - Culture systems are available for human granulosa cells (GCs) that perpetuate luteinization. The present study examines the plating density effects and long term serum-free culture on the in vitro dynamics differentiation of luteinizing human GCs. Cells were cultured in serum-free alpha-minimum essential medium (alpha-MEM) or serum-based tissue culture medium (TCM). The time course of GCs morphology and secretion of estradiol (E2), progesterone (P4), and relaxin were analyzed after 48, 96, and 144 hours of culture. Other functional markers as follicle-stimulating hormone/luteinizing hormone receptors and steroidogenic enzymes were investigated at the end of culture. The morphology of an alpha-MEM cell rather than a TCM cell resembles more closely that seen in vivo. Compared to TCM cultures, alpha-MEM cells secreted 93.7% and 87.2% more E2 and approximately 7% and 17% of the amount of P4 when cultured at densities of 2 * 10(4) or 4 * 10(4) cells/well, respectively. Relaxin secretion was significantly reduced in alpha-MEM cultures. alpha-MEM cells were estrogenic and expressed the CYP19 gene. Levels of CYP17 increased about 8-fold in alpha-MEM cells above the levels found in TCM cells. Our results reveal new insights into human GCs differentiation in vitro and demonstrate the critical importance of the culture system and cell plating density on the establishment of estrogenic or progestogenic GC phenotypes. PMID- 25701840 TI - Resveratrol Reduces Myometrial Infiltration, Uterine Hyperactivity, and Stress Levels and Alleviates Generalized Hyperalgesia in Mice With Induced Adenomyosis. AB - In this study, we sought to determine whether resveratrol (RSV), a nonhormonal compound, would suppress the myometrial infiltration, improve pain behavior, lower stress level, improve the expression of some proteins known to be involved in adenomyosis, and reduce uterine contractility in a mice model of adenomyosis. Adenomyosis was induced in 28 female ICR mice neonatally dosed with tamoxifen, while another 12 (group C) were dosed with solvent only, serving as a blank control. Starting from 4 weeks after birth, hotplate test was administrated to all mice every 4 weeks. At the 16th week, all mice with induced adenomyosis were randomly divided into 3 groups: low-dose RSV (2 mg/kg), high-dose RSV (3 mg/kg), and untreated. Group C received no treatment. After 3 weeks of treatment, they were hotplate tested again, their uterine horns and brains were harvested, and a blood sample was taken to measure the plasma corticosterone (CORT) level by enzyme-linked immunosorbent assay. The left uterine horn was used for immunohistochemistry analysis. The brain stem nucleus raphe magnus (NRM) sections were subjected to immunofluorescence staining for glutamic acid decarboxylase isoform 65 (GAD65). The depth of myometrial infiltration and uterine contractility was evaluated. We found that RSV is well tolerated and that it dose dependently suppressed myometrial infiltration, improved generalized hyperalgesia, reduced uterine contractility and lowered plasma CORT levels, and improved the expression of some proteins known to be involved in adenomyosis. It also elevated the number of GAD65-expressing neurons in the brain stem NRM, possibly boosting the GABAergic inhibition of pain due to adenomyosis. Therefore, RSV appears to be a promising compound for treating adenomyosis. PMID- 25701841 TI - Evidence for a Hypercoagulable State in Women With Ovarian Endometriomas. AB - Endometriosis is a hormonal disease and also an inflammatory condition. Converging evidence indicates that inflammation and coagulation are 2 major host defense systems that interact with each other. This study was undertaken to test the hypothesis that women with ovarian endometriomas are in a hypercoagulable state as manifested by the altered procoagulant factors and higher percentage of activated platelets in their peripheral blood. Two sets of participants were recruited. The first set consisted of 50 premenopausal women with endometriosis and 50 age-matched healthy women, and the second set consisted of 21 women with endometriosis and 17 age-comparable women without endometriosis. For the first set, prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), fibrinogen, and other coagulation factors, along with their demographic, clinical, and anthropometric data, were measured/retrieved. For the second set, only the percentage of activated platelets in peripheral blood was evaluated. We found that women with endometriosis had a significantly shortened APTT and TT and elevated fibrinogen levels as compared with controls. They also had significantly higher percentage of circulating degranuated platelets, and the percentage was significantly reduced 1 month after surgical removal of endometriotic lesions. These findings provide evidence of a hypercoagulable state in women with endometriosis, reflecting the intimate relationship between coagulation and inflammation. They also suggest that these coagulation parameters such as APTT and fibrinogen and others could potentially be used for diagnostic or prognostic purposes. It also underpins the possibility for the use of antithrombotic therapy in the treatment of endometriosis. PMID- 25701842 TI - Notch Signaling Pathway Regulates Progesterone Secretion in Murine Luteal Cells. AB - Notch signaling is an evolutionarily conserved pathway, which involves in various cell life activities. Other studies and our report showed that the Notch signaling plays very important role in follicle development in mammalian ovaries. In luteal cells, Notch ligand, delta-like ligand 4, is involved in normal luteal vasculature. In this study, murine luteal cells were cultured in vitro and treated with Notch signaling inhibitors, L-658,458 and N-[N-(3,5 difluorophenacetyl)-l-alanyl]-S-phenylglycinet-butyl ester (DAPT). We found that L-658,458 and DAPT treatment decrease basal and human chorionic gonadotropin (hCG)-stimulated progesterone secretion. On the contrary, overexpression of intracellular domain of Notch3 increased basal and hCG-stimulated progesterone secretion. Further studies demonstrated that Notch signaling regulated the expression of steroidogenic acute regulatory protein and CYP11A, 2 key enzymes for progesterone synthesis. In conclusion, Notch signaling plays important role in regulating progesterone secretion in murine luteal cells. PMID- 25701843 TI - PGAM1 is Involved in Spermatogenic Dysfunction and Affects Cell Proliferation, Apoptosis, and Migration. AB - OBJECTIVE: To investigate the correlation between PGAM1 and spermatogenic dysfunction and to evaluate the effect of expression of PGAM1 on the function of germ cells. METHODS: Expression of PGAM1 was detected in 40 cases of infertile males with definite pathological diagnosis and 12 cases of mouse models with spermatogenic dysfunction by immunohistochemistry. Then, cell proliferation, apoptosis, and migration were evaluated when expression of PGAM1 was knocked down by a specific small interfering RNA in GC1 and TM4 cells. RESULTS: The positive rates of PGAM1 in patients with normal spermatogenesis, mild hypospermatogenesis, severe hypospermatogenesis, and Sertoli cell-only syndrome were 90%, 80%, 10%, 100%, respectively, and the difference was significant (P < .001). Meanwhile, expression of PGAM1 was found to be significantly decreased in mouse models with spermatogenic dysfunction. Moreover, when expression of PGAM1 was knocked down in GC1 cells, the proliferation and migration were significantly inhibited, but the rate of apoptosis was significantly increased. Furthermore, PGAM1 downregulation in TM4 cells significantly inhibited proliferation and promoted apoptosis but didn't affect migration. CONCLUSION: PGAM1 correlates with spermatogenic distinction and affects the function of cell proliferation, apoptosis and migration. PMID- 25701844 TI - Alteromonas gracilis sp. nov., a marine polysaccharide-producing bacterium. AB - A novel exopolysaccharide-producing bacterium, designated strain 9a2(T), was isolated from Pacific Ocean sediment. The strain was Gram-stain-negative, motile, strictly aerobic, oxidase- and catalase-positive, and required NaCl for growth. Its major isoprenoid quinone was ubiquinone-8 (Q-8), and its cellular fatty acid profile consisted mainly of C16 : 1omega7c, C18 : 1omega9c and C16 : 0. The DNA G+C content was 46.6 mol%. 16S rRNA gene sequence analysis suggested that strain 9a2(T) is a member of the genus Alteromonas . Strain 9a2(T) exhibited closest phylogenetic affinity to Alteromonas macleodii NBRC 102226(T) (99.3% 16S rRNA gene sequence similarity), A. marina SW-47(T) (99.3%), A. litorea TF-22(T) (99.0%), A. australica H17(T) (98.7%), A. simiduii BCRC 17572(T) (98.5%), A. stellipolaris LMG 21861(T) (98.3%) and A. hispanica F-32(T) (98.2%). The DNA-DNA reassociation values between strain 9a2(T) and A. macleodii JCM 20772(T), A. marina JCM 11804(T), A. litorea JCM 12188(T), A. australica CIP 109921(T), A. simiduii JCM 13896(T), A. stellipolaris LMG 21861(T) and A. hispanica LMG 22958(T) were below 70%. Strain 9a2(T) contained phosphatidylethanolamine, phosphatidylglycerol and an unidentified polar lipid. Owing to differences in phenotypic and chemotaxonomic characteristics, phylogenetic analysis based on 16S rRNA gene sequences and DNA-DNA relatedness data, the isolate merits classification as representing a novel species, for which the name Alteromonas gracilis sp. nov. is proposed. The type strain of this species is 9a2(T) ( =JCM 30236(T) =NCIMB 14947(T)). PMID- 25701845 TI - Marivirga atlantica sp. nov., isolated from seawater and emended description of the genus Marivirga. AB - A novel Gram-stain-negative, aerobic, orange-pigmented, non-flagellated, gliding, rod-shaped bacterium, designated strain SM1354(T) was isolated from surface seawater of the Atlantic Ocean. The strain hydrolysed gelatin and DNA but did not reduce nitrate. It grew at 4-40 degrees C and with 0.5-11% (w/v) NaCl. Phylogenetic analysis of the 16S rRNA gene sequences revealed that strain SM1354(T) belonged to the genus Marivirga with 96.0-96.2% sequence similarities to known species of the genus Marivirga . The major fatty acids of strain SM1354(T) were iso-C15 : 0, iso-C15 : 1 G, iso-C17 : 03-OH and summed feature 3 (C16 : 1omega7c and/or iso-C15 : 02-OH). Polar lipids of strain SM1354(T) included phosphatidylethanolamine, three unidentified lipids and one unidentified aminolipid and aminophospholipid. The major respiratory quinone of strain SM1354(T) was menaquinone 7 (MK-7). The genomic DNA G+C content of strain SM1354(T) was 33.9 +/- 0.4 mol%. On the basis of the results of the polyphasic characterization in this study, it is proposed that strain SM1354(T) represents a novel species of the genus Marivirga , namely Marivirga atlantica sp. nov. The type strain of Marivirga atlantica is SM1354(T) ( =CCTCC AB 2014242(T) =JCM 30305(T)). An emended description of the genus Marivirga is also proposed. PMID- 25701846 TI - Sulfuriferula multivorans gen. nov., sp. nov., isolated from a freshwater lake, reclassification of 'Thiobacillus plumbophilus' as Sulfuriferula plumbophilus sp. nov., and description of Sulfuricellaceae fam. nov. and Sulfuricellales ord. nov. AB - A sulfur-oxidizing bacterium, strain TTN(T), was isolated from a Thioploca sample obtained from a freshwater lake in Japan. The isolate shared 97.1% 16S rRNA gene sequence similarity with an obligately aerobic chemolithoautotroph, 'Thiobacillus plumbophilus' Gro7(T). Cells were rods, motile, and Gram-stain-negative. The G+C content of the genomic DNA was approximately 66 mol%. Strain TTN(T) grew over a temperature range of 8-32 degrees C (optimum 22-25 degrees C), an NaCl concentration range of 0-133.3 mM (optimum 0-3.3 mM) and a pH range of 5.3-8.6 (optimum pH 6.4-7.0). Strain TTN(T) was facultatively anaerobic and could utilize nitrate as an electron acceptor. The isolate oxidized tetrathionate, thiosulfate and elemental sulfur as the sole energy sources for autotrophic growth, and could also grow heterotrophically on a number of organic substrates. Based on its phylogenetic and phenotypic properties, strain TTN(T) represents a novel species of a novel genus, for which the name Sulfuriferula multivorans gen. nov., sp. nov. is proposed. The type strain is TTN(T) ( =NBRC 110683(T) =DSM 29343(T)). Along with this, the reclassification of 'Thiobacillus plumbophilus' as Sulfuriferula plumbophilus sp. nov. (type strain Gro7(T) =NBRC 107929(T) =DSM 6690(T)) is proposed. Based on the data obtained in this study, we describe the designations Sulfuricellaceae fam. nov. and Sulfuricellales ord. nov. PMID- 25701847 TI - Actinomycetospora rhizophila sp. nov., an actinomycete isolated from rhizosphere soil of a peace lily (Spathi phyllum Kochii). AB - A novel actinomycete, designated strain NEAU-B-8(T), was isolated from the rhizosphere soil of a peace lily (Spathi phyllum Kochii) collected from Heilongjiang province, north-east China. Key morphological and physiological characteristics as well as chemotaxonomic features of strain NEAU-B-8(T) were congruent with the description of the genus Actinomycetospora , such as the major fatty acids, the whole-cell hydrolysates, the predominant menaquinone and the phospholipid profile. The 16S rRNA gene sequence analysis revealed that strain NEAU-B-8(T) shared the highest sequence similarities with Actinomycetospora lutea JCM 17982(T) (99.3% 16S rRNA gene sequence similarity), Actinomycetospora chlora TT07I-57(T) (98.4 %), Actinomycetospora straminea IY07-55(T) (98.3%) and Actinomycetospora chibensis TT04-21(T) (98.2%); similarities to type strains of other species of this genus were lower than 98%. The phylogenetic tree based on 16S rRNA gene sequences showed that strain NEAU-B-8(T) formed a distinct branch with A. lutea JCM 17982(T) that was supported by a high bootstrap value of 97% in the neighbour-joining tree and was also recovered with the maximum-likelihood algorithm. However, the DNA-DNA relatedness between strain NEAU-B-8(T) and A. lutea JCM 17982(T) was found to be 50.6 +/- 1.2%. Meanwhile, strain NEAU-B-8(T) differs from other most closely related strains in phenotypic properties, such as maximum NaCl tolerance, hydrolysis of aesculin and decomposition of urea. On the basis of the morphological, physiological, chemotaxonomic, phylogenetic and DNA DNA hybridization data, we conclude that strain NEAU-B-8(T) represents a novel species of the genus Actinomycetospora , named Actinomycetospora rhizophila sp. nov. The type strain is NEAU-B-8(T). ( = CGMCC 4.7134(T) =DSM 46673(T)). PMID- 25701848 TI - Rhizobium metallidurans sp. nov., a symbiotic heavy metal resistant bacterium isolated from the Anthyllis vulneraria Zn-hyperaccumulator. AB - A Gram-stain-negative, aerobic, rod-shaped, non-spore-forming bacterium (ChimEc512(T)) was isolated from 56 host seedlings of the hyperaccumulating Anthyllis vulneraria legume, which was on an old zinc mining site at Les Avinieres, Saint-Laurent-Le-Minier, Gard, South of France. On the basis of 16S rRNA gene sequence similarities, strain ChimEc512(T) was shown to belong to the genus Rhizobium and to be most closely related to Rhizobium endophyticum CCGE 2052(T) (98.4%), Rhizobium tibeticum CCBAU 85039(T) (98.1%), Rhizobium grahamii CCGE 502(T) (98.0%) and Rhizobium mesoamericanum CCGE 501(T) (98.0%). The phylogenetic relationships of ChimEc512(T) were confirmed by sequencing and analyses of recA and atpD genes. DNA-DNA relatedness values of strain ChimEc512(T) with R. endophyticum CCGE 2052(T), R. tibeticum CCBAU 85039(T), R. mesoamericanum CCGE 52(T), Rhizobium grahamii CCGE 502(T), Rhizobium etli CCBAU 85039(T) and Rhizobium radiobacter KL09-16-8-2(T) were 27, 22, 16, 18, 19 and 11%, respectively. The DNA G+C content of strain ChimEc512(T) was 58.9 mol%. The major cellular fatty acid was C18 : 1omega7c, characteristic of the genus Rhizobium . The polar lipid profile included phosphatidylethanolamine, phosphatidylmonomethylethanolamine, phosphatidylglycerol and phosphatidylcholine and moderate amounts of aminolipids, phospholipid and sulfoquinovosyl diacylglycerol. Although ChimEc512(T) was able to nodulate A. vulneraria, the nodC and nifH genes were not detected by PCR. The rhizobial strain was tolerant to high concentrations of heavy metals: up to 35 mM Zn and up to 0.5 mM Cd and its growth kinetics was not impacted by Zn. The results of DNA-DNA hybridizations and physiological tests allowed genotypic and phenotypic differentiation of strain ChimEc512(T) from species of the genus Rhizobium with validly published names. Strain ChimEc512(T), therefore, represents a novel species, for which the name Rhizobium metallidurans sp. nov. is proposed, with the type strain ChimEc512(T) ( =DSM 26575 = CIP 110550(T)). PMID- 25701849 TI - Anaerosolibacter carboniphilus gen. nov., sp. nov., a strictly anaerobic iron reducing bacterium isolated from coal-contaminated soil. AB - A strictly anaerobic, mesophilic, iron-reducing bacterial strain, IRF19(T), was isolated from coal-contaminated soil in the Republic of Korea. IRF19(T) cells were straight, rod-shaped, Gram-staining-negative and motile by means of flagella. The optimum pH and temperature for their growth were determined to be pH 7.5-8.0 and 40 degrees C, while the optimum range was pH 6.5-10.0 and 20-45 degrees C, respectively. Strain IRF19(T) did not require NaCl for growth but it tolerated up to 2% (w/v). Growth was observed with yeast extract, D-glucose, D fructose, D-ribose, D-mannitol, D-mannose, L-serine, L-alanine and L-isoleucine. Fe(III), elemental sulfur, thiosulfate and sulfate were used as electron acceptors. Phylogenetic analysis based on the 16S rRNA gene sequences indicated that strain IRF19(T) is affiliated to the family Clostridiaceae and is most closely related to Salimesophilobacter vulgaris Zn2(T) (93.5% similarity), Geosporobacter subterraneus VNs68(T) (93.2%) and Thermotalea metallivorans B2 1(T) (92.3%). The major cellular fatty acids of strain IRF19(T) were C14 : 0, iso C15 : 0 and C16 : 0, and the profile was distinct from those of the closely related species. The major respiratory quinone of strain IRF19(T) was menaquinone MK-5 (V-H2). The main polar lipids were diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, an unknown phospholipid and two unknown polar lipids. The G+C content of the genomic DNA of strain IRF19(T) was determined to be 37.4 mol%. On the basis of phenotypic, chemotaxonomic and phylogenetic results, strain IRF19(T) is considered to represent a novel species of a novel genus of the family Clostridiaceae , for which we propose the name Anaerosolibacter carboniphilus gen. nov., sp. nov., with the type strain IRF19(T) ( =KCTC 15396(T) =JCM 19988(T)). PMID- 25701850 TI - Paracoccus panacisoli sp. nov., isolated from a forest soil cultivated with Vietnamese ginseng. AB - A novel bacterial strain, designated DCY94(T), was isolated from forest soil cultivated with ginseng in Vietnam. The strain was Gram-reaction-negative, facultatively anaerobic, non-motile, rod-shaped and catalase- and oxidase positive. 16S rRNA gene sequence analysis demonstrated that strain DCY94(T) was closely related to Paracoccus sphaerophysae Zy-3(T) (97.5% 16S rRNA gene sequence similarity) and Paracoccus caeni MJ17(T) (96.9%). The fatty acid profile of strain DCY94(T) contained a predominant amount of summed feature 8 (C18 : 1omega7c and/or C18 : 1omega6c; 88.4%) and moderate to small quantities of C8 : 0 3-OH (1.0%), C10 : 0 3-OH (2.8%) and C18 : 0 (5.2%). Phosphatidylethanolamine, phosphatidylglycerol, phosphatidylcholine and one unidentified glycolipid were major polar lipids; one unidentified aminolipid, one unidentified aminophospholipid, one unidentified phospholipid and four unidentified polar lipids were minor components. The polyamine pattern comprised the major compounds putrescine and spermidine and minor amounts of sym-homospermidine and spermine. The ubiquinone of the strain was Q-10 and the G+C content of its genomic DNA was 68.3 mol%. All these results support the placement of strain DCY94(T) within the genus Paracoccus . Levels of DNA-DNA relatedness between strain DCY94(T) and P. sphaerophysae HAMBI 3106(T) and P. caeni KCTC 22480(T) were 52 and 50%, respectively. The results of phylogenetic analysis, phenotypic tests, chemotaxonomic characterization and DNA-DNA relatedness studies distinguished strain DCY94(T) from the closest recognized species of the genus Paracoccus , suggesting that this strain represents a novel species, for which the name Paracoccus panacisoli sp. nov. is proposed. The type strain is DCY94(T) ( = KCTC 42086(T) =JCM 30337(T)). PMID- 25701851 TI - Nesterenkonia populi sp. nov., an actinobacterium isolated from Populus euphratica. AB - An alkaliphilic and moderately halophilic actinobacterium, designated strain GP10 3(T), was isolated from Populus euphratica collected from the southern edge of Taklimakan desert, Xinjiang, China. Cells of this strain were Gram-stain positive, non-motile and non-spore-forming short rods. Strain GP10-3(T) grew optimally at 37 degrees C on LB agar media in the presence of 5-10% (w/v) NaCl at pH 9.0. The menaquinones were MK-7, MK-8 and MK-9. The major fatty acids (>10%) were anteiso-C17 : 0, anteiso-C15 : 0 and iso-C16 : 0. The peptidoglycan type was variation A4alpha, L-Lys-L-Glu. The polar lipids consisted of diphosphatidylglycerol, phosphatidylglycerol, phosphatidylglycolipid, phosphatidylcholine, phosphatidylinositol, glycolipid and an unidentified phospholipid. The DNA G+C content was 67.4 mol%. Phylogenetic analysis based on 16S rRNA gene sequence showed that strain GP10-3(T) belonged to the genus Nesterenkonia , sharing 94.6-96.9% sequence similarity with the type strains of species within this genus with validly published names. Based on the evidence of the polyphasic taxonomic study, strain GP10-3(T) represents a novel species of the genus Nesterenkonia , for which the name Nesterenkonia populi sp. nov. is proposed. The type strain is GP10-3(T) ( = DSM 27959(T) = KCTC 29119(T)). PMID- 25701852 TI - Reply to Hurley. PMID- 25701853 TI - Is selective decontamination of the digestive tract safe? PMID- 25701854 TI - Impact of Infectious Disease Consultation on Quality of Care, Mortality, and Length of Stay in Staphylococcus aureus Bacteremia: Results From a Large Multicenter Cohort Study. AB - BACKGROUND: We assessed the impact of infectious disease (ID) consultation on management and outcome in patients with Staphylococcus aureus bacteremia (SAB). METHODS: A retrospective cohort study examined consecutive SAB patients from 6 academic and community hospitals between 2007 and 2010. Quality measures of management including echocardiography, repeat blood culture, removal of infectious foci, and antibiotic therapy were compared between ID consultation (IDC) and no ID consultation (NIDC) groups. A competing risk model with propensity score adjustment was used to compare in-hospital mortality and time to discharge. RESULTS: Of 847 SAB patients, 506 (60%) patients received an ID consultation and 341 (40%) patients did not. Echocardiography was done for 371 (73%) IDC and 191 (56%) NIDC patients (P < .0001) in hospital. Blood cultures were repeated within 2-4 days of bacteremia in 207 (41%) IDC and 107 (31%) NIDC patients (P = .0058). The infectious foci removal rate was not statistically different between the 2 groups. For empiric therapy, 474 (94%) IDC and 297 (87%) NIDC patients received appropriate antibiotics (P = .0013). For patients who finished the planned course of antibiotics, 285 of 422 (68%) IDC and 141 of 262 (54%) NIDC patients received the appropriate duration of antibiotic therapy (P = .0004). In hospital, 204 (24%) patients died: 104 of 506 (21%) IDC and 100 of 341 (29%) NIDC patients. Matched by propensity score, ID consultation had a subdistribution hazard ratio of 0.72 (95% confidence interval [CI], .52-.99; P = .0451) for in-hospital mortality and 1.28 (95% CI, 1.06-1.56; P = .0109) for being discharged alive. CONCLUSIONS: ID consultation is associated with better adherence to quality measures, reduced in-hospital mortality, and earlier discharge in patients with SAB. PMID- 25701855 TI - Middle East respiratory syndrome coronavirus: update for clinicians. AB - Although much recent focus has been on the recognition of Ebola virus disease among travelers from West Africa, cases of Middle East respiratory syndrome coronavirus (MERS-CoV), including travel-associated cases, continue to be reported. US clinicians need to be familiar with recommendations regarding when to suspect MERS-CoV, how to make a diagnosis, and what infection control measures need to be instituted when a case is suspected. Infection control is especially critical, given that most cases have been healthcare-associated. Two cases of MERS-CoV were identified in the United States in May 2014; because these cases were detected promptly and appropriate control measures were put in place quickly, no secondary cases occurred. This paper summarizes information that US clinicians need to know to prevent secondary cases of MERS-CoV from occurring in the United States. PMID- 25701856 TI - Public support for raising the age of sale for tobacco to 21 in the United States. AB - OBJECTIVES: The vast majority of tobacco users began before the age of 21. Raising the tobacco sales age to 21 has the potential to reduce tobacco use initiation and progression to regular smoking. Our objective was to assess the level of public support nationally for 'Tobacco 21' initiatives in the USA. METHODS: The Social Climate Survey of Tobacco Control, a cross-sectional dual frame survey representing national probability samples of adults was administered in 2013. Respondents were asked to state their agreement level with, 'The age to buy tobacco should be raised to 21.' RESULTS: Of 3245 respondents, 70.5% support raising the age to buy tobacco to 21. The majority of adults in every demographic and smoking status category supported raising the tobacco sales age to 21. In multivariable analyses, support was highest among never smokers, females, African Americans and older adults. CONCLUSIONS: This national study demonstrates broad public support for raising the sales age of tobacco to 21 and will help facilitate wide dissemination of initiatives to increase the legal purchase age at national, state and local levels. Increasing public awareness about the susceptibility and rapid addiction of youth to nicotine may further increase public support for raising the tobacco sale age to 21. PMID- 25701857 TI - Effect of cigarette tax increase in combination with mass media campaign on smoking behaviour in Mauritius: findings from the ITC Mauritius Survey. AB - BACKGROUND: Mauritius has made great strides in adopting evidence-based tobacco control measures, including an increase in its cigarette excise tax and antitobacco mass media (Sponge) campaign. The primary objective of this study is to examine the combined effect of these measures on smoking behaviour. METHODS: This study used longitudinal data from the International Tobacco Control Mauritius Survey, 2009-2011. Waves 1 and 2 were conducted before the tax increase and wave 3 was conducted shortly after the Sponge campaign and 6 months after the cigarette excise tax increase. Generalised estimating equations were used to examine the effects of these two key tobacco control measures on smoking prevalence and the quantity of cigarettes smoked. RESULTS: The results showed that the combination of cigarette tax increase and the Sponge campaign had a significantly negative effect on the prevalence of smoking in Mauritius and the number of cigarettes smoked among continuing smokers. Specifically, the measures significantly reduced the odds of being a smoker (adjusted OR 0.88, 95% CI 0.81 to 0.97). For average daily cigarettes smoked, the measures had a significant reduction in cigarettes per day by about 6% (incidence rate ratios 0.94, 95% CI 0.89 to 0.99). CONCLUSIONS: The combination of policy measures significantly reduced the consumption of cigarettes in Mauritius. While these results are encouraging, these efforts must be part of a sustained effort to further reduce the smoking prevalence in Mauritius. PMID- 25701858 TI - Gender equality and smoking: a theory-driven approach to smoking gender differences in Spain. AB - BACKGROUND: The intersection between gender and class can aid in understanding gender differences in smoking. AIM: To analyse how changes in gender inequality relate to differences in smoking prevalence by gender, education and birth cohort in Spain over the past five decades (1960-2010). METHODS: The Gender Inequality Index (GII) was calculated in 5-year intervals from 1960 to 2010. GII ranges from 0 to 1 (1=highest inequality) and encompasses three dimensions: reproductive health, empowerment and labour market. Estimates of female and male smoking prevalence were reconstructed from representative National Health Surveys and stratified by birth cohort and level of education. We calculated female-to-male smoking ratios from 1960 to 2010 stratified by education and birth cohort. RESULTS: Gender inequality in Spain decreased from 0.65 to 0.09 over the past 50 years. This rapid decline was inversely correlated (r=-0.99) to a rising female to-male smoking ratio. The youngest birth cohort of the study (born 1980-1990) and women with high education levels had similar smoking prevalences compared with men. Women with high levels of education were also the first to show a reduction in smoking prevalence, compared with less educated women. CONCLUSIONS: Gender inequality fell significantly in Spain over the past 50 years. This process was accompanied by converging trends in smoking prevalence for men and women. Smoking prevalence patterns varied greatly by birth cohort and education levels. Countries in earlier stages of the tobacco epidemic should consider gender-sensitive tobacco control measures and policies. PMID- 25701859 TI - Understanding genetics: why should vets care? PMID- 25701860 TI - DNA mutations of the cat: the good, the bad and the ugly. AB - PRACTICAL RELEVANCE: The health of the cat is a complex interaction between its environment (nurture) and its genetics (nature). Over 70 genetic mutations (variants) have been defined in the cat, many involving diseases, structural abnormalities and clinically relevant health concerns. As more of the cat's genome is deciphered, less commonly will the term 'idiopathic' be used regarding the diagnosis of diseases and unique health conditions. State-of-the-art health care will include DNA profiling of the individual cat, and perhaps its tumor, to establish the best treatment approaches. Genetic testing and eventually whole genome sequencing should become routine diagnostics for feline health care. GLOBAL IMPORTANCE: Cat breeds have disseminated around the world. Thus, practitioners should be aware of the breeds common to their region and the mutations found in those regional populations. Specific random-bred populations can also have defined genetic characteristics and mutations. AUDIENCE: This review of 'the good, the bad and the ugly' DNA variants provides the current state of knowledge for genetic testing and genetic health management for cats. It is aimed at feline and general practitioners wanting to update and review the basics of genetics, what tests are available for cats and sources for genetic testing. The tables are intended to be used as references in the clinic. Practitioners with a high proportion of cat breeder clientele will especially benefit from the review. EVIDENCE BASE: The data presented is extracted from peer reviewed publications pertaining to mutation identification, and relevant articles concerning the heritable trait and/or disease. The author also draws upon personal experience and expertise in feline genetics. PMID- 25701861 TI - Update in feline therapeutics: clinical use of 10 emerging therapies. AB - PRACTICAL RELEVANCE: The field of veterinary medicine is constantly evolving. New medications are being introduced into clinical practice, and novel uses for established medications are frequently being discovered as new information comes to light. CLINICAL CHALLENGES: Therapeutic options for our feline patients can be restricted based on inadequate clinical evidence, adverse effects and patient compliance concerns. Additionally, with the reduced availability of commonly used medications in some regions, clinicians are forced to utilize alternatives with which they may have limited experience. AUDIENCE: This review article is directed towards primary care veterinarians working with feline patients. The selection of medications discussed is based on many of the clinical challenges commonly encountered in practice. EVIDENCE BASE: The evidence for use of some of these medications is limited due to their novelty. Known mechanisms of action, pharmacokinetic and pharmacodynamics data, adverse effects and clinical uses are reviewed where possible, with clinical recommendations made based on the evidence of data available. PMID- 25701862 TI - ISFM consensus guidelines on the practical management of diabetes mellitus in cats. AB - PRACTICAL RELEVANCE: Diabetes mellitus (DM) is a common endocrinopathy in cats that appears to be increasing in prevalence. The prognosis for affected cats can be good when the disease is well managed, but clinical management presents challenges, both for the veterinary team and for the owner. These ISFM Guidelines have been developed by an independent, international expert panel of clinicians and academics to provide practical advice on the management of routine (uncomplicated) diabetic cats. CLINICAL CHALLENGES: Although the diagnosis of diabetes is usually straightforward, optimal management can be challenging. Clinical goals should be to limit or eliminate clinical signs of the disease using a treatment regimen suitable for the owner, and to avoid insulin-induced hypoglycaemia or other complications. Optimising bodyweight, feeding an appropriate diet and using a longer acting insulin preparation (eg, protamine zinc insulin, insulin glargine or insulin detemir) are all factors that are likely to result in improved glycaemic control in the majority of cats. There is also some evidence that improved glycaemic control and reversal of glucose toxicity may promote the chances of diabetic remission. Owner considerations and owner involvement are an important aspect of management. Provided adequate support is given, and owners are able to take an active role in monitoring blood glucose concentrations in the home environment, glycaemic control may be improved. Monitoring of other parameters is also vitally important in assessing the response to insulin. Insulin adjustments should always be made cautiously and not too frequently--unless hypoglycaemia is encountered. EVIDENCE BASE: The Panel has produced these Guidelines after careful review of the existing literature and of the quality of the published studies. They represent a consensus view on practical management of cats with DM based on available clinical data and experience. However, in many areas, substantial data are lacking and there is a need for better studies in the future to help inform and refine recommendations for the clinical management of this common disease. PMID- 25701863 TI - 2015 AAHA/AAFP pain management guidelines for dogs and cats. AB - RATIONALE: The robust advances in pain management for companion animals underlie the decision of the American Animal Hospital Association (AAHA) and American Association of Feline Practitioners (AAFP) to expand on the information provided in the 2007 AAHA/AAFP Pain Management Guidelines. The 2015 Guidelines summarize and offer a discriminating review of much of this new knowledge. RELEVANCE: Pain management is central to veterinary practice, alleviating pain, improving patient outcomes, and enhancing both quality of life and the veterinarian-client-patient relationship. These Guidelines support veterinarians in incorporating pain management into practice, improving patient care. APPROACHES: The management of pain requires a continuum of care that includes anticipation, early intervention, and evaluation of response on an individual patient basis. A team-oriented approach, including the owner, is essential for maximizing the recognition, prevention and treatment of pain in animals. EVIDENCE BASE: The Guidelines include both pharmacologic and non-pharmacologic modalities to manage pain; they are evidence-based insofar as possible and otherwise represent a consensus of expert opinion. Behavioral changes are currently the principal indicator of pain and its course of improvement or progression, and the basis for recently validated pain scores. Post-surgical pain is eminently predictable but a strong body of evidence exists supporting strategies to mitigate adaptive as well as maladaptive forms. Chronic pain is dominated by degenerative joint disease (DJD), which is one of the most significant and under-diagnosed diseases of cats and dogs. DJD is ubiquitous, found in pets of all ages, and inevitably progresses over time; evidence-based strategies for management are established in dogs, and emerging in cats. PMID- 25701866 TI - A Randomized Trial to Compare the Safety, Tolerability, and Effectiveness of 3 Antimalarial Regimens for the Prevention of Malaria in Nigerian Patients With Sickle Cell Disease. AB - BACKGROUND: Malaria prophylaxis is recommended for persons with sickle cell disease (SCD), but the value of this has been questioned. The aim of this study was to find out whether intermittent preventive treatment (IPT) with a fixed-dose combination of mefloquine-artesunate (MQAS) or sulfadoxine-pyrimethamine plus amodiaquine (SPAQ) was more effective than daily proguanil for malaria prevention in subjects with SCD. METHODS: Patients with SCD were randomized to receive daily treatment with proguanil or IPT with either MQAS or SPAQ once every 2 months at routine clinic visits. Patients were followed up for 14 months. FINDINGS: A total of 270 patients with SCD were studied, with 90 in each group. Adherence to the IPT regimens was excellent, but 57% of patients took <75% of their daily doses of proguanil. IPT was well tolerated; the most common side effects were vomiting and abdominal pain. Protective efficacy against malaria, compared with daily proguanil, was 61% (95% confidence interval, 3%-84%) for MQAS and 36% (40%-70%) for SPAQ. There were fewer outpatient illness episodes in children who received IPT than those who received proguanil. CONCLUSIONS: IPT with MQAS administered to patients with SCD during routine clinic visits was well tolerated and more effective in preventing malaria than daily prophylaxis with proguanil. CLINICAL TRIALS REGISTRATION: NCT01319448 and ISRCTN46158146. PMID- 25701867 TI - Norovirus Genotypes in Hospital Settings: Differences Between Nosocomial and Community-Acquired Infections. AB - BACKGROUND: Norovirus (NoV) is a major cause of gastroenteritis and hospital outbreaks, leading to substantial morbidity and direct healthcare expenses as well as indirect societal costs. The aim of the study was to estimate the proportion of nosocomial NoV infections among inpatients testing positive for NoV in Denmark, 2002-2010, and to study the distribution of NoV genotypes among inpatients with nosocomial and community-acquired NoV infections, respectively. METHODS: Admission and stool sampling dates from 3656 NoV-infected patients were used to estimate the proportion of nosocomial infections. The associations between nosocomial infection and patient age, sex, and NoV genotype GII.4 were examined. RESULTS: Of the 3656 inpatients, 63% were classified as having nosocomial infections. Among these, 9 capsid and 8 polymerase NoV genotypes were detected, whereas in the smaller group of inpatients with community-acquired infections, 12 capsid and 9 polymerase genotypes were detected. Nosocomial NoV infections were associated with age >=60 years and infections with genotype GII.4. CONCLUSIONS: The majority of NoV infections in hospitalized patients were nosocomial. Nosocomial infection was mainly associated with older age but also with the specific genotype GII.4. The genotypes in community-acquired NoV infections were more heterogeneous than in nosocomial infections. PMID- 25701868 TI - The Interplay Between Host Genetic Variation, Viral Replication, and Microbial Translocation in Untreated HIV-Infected Individuals. AB - Systemic immune activation, a major determinant of human immunodeficiency virus (HIV) disease progression, is the result of a complex interplay between viral replication, dysregulation of the immune system, and microbial translocation due to gut mucosal damage. Although human genetic variants influencing HIV load have been identified, it is unknown how much the host genetic background contributes to interindividual differences in other determinants of HIV pathogenesis such as gut damage and microbial translocation. Using samples and data from 717 untreated participants in the Swiss HIV Cohort Study and a genome-wide association study design, we searched for human genetic determinants of plasma levels of intestinal fatty acid-binding protein (I-FABP/FABP2), a marker of gut damage, and of soluble CD14 (sCD14), a marker of lipopolysaccharide bioactivity and microbial translocation. We also assessed the correlations between HIV load, sCD14, and I FABP. Although we found no genome-wide significant determinant of the tested plasma markers, we observed strong associations between sCD14 and both HIV load and I-FABP, shedding new light on the relationships between processes that drive progression of untreated HIV infection. PMID- 25701869 TI - A genetic dissection of intestinal fat-soluble vitamin and carotenoid absorption. AB - Carotenoids are currently investigated regarding their potential to lower the risk of chronic disease and to combat vitamin A deficiency. Surprisingly, responses to dietary supplementation with these compounds are quite variable between individuals. Genome-wide studies have associated common genetic polymorphisms in the BCO1 gene with this variability. The BCO1 gene encodes an enzyme that is expressed in the intestine and converts provitamin A carotenoids to vitamin A-aldehyde. However, it is not clear how this enzyme can impact the bioavailability and metabolism of other carotenoids such as xanthophyll. We here provide evidence that BCO1 is a key component of a regulatory network that controls the absorption of carotenoids and fat-soluble vitamins. In this process, conversion of beta-carotene to vitamin A by BCO1 induces via retinoid signaling the expression of the intestinal homeobox transcription factor ISX. Subsequently, ISX binds to conserved DNA-binding motifs upstream of the BCO1 and SCARB1 genes. SCARB1 encodes a membrane protein that facilitates absorption of fat-soluble vitamins and carotenoids. In keeping with its role as a transcriptional repressor, SCARB1 protein levels are significantly increased in the intestine of ISX-deficient mice. This increase results in augmented absorption and tissue accumulation of xanthophyll carotenoids and tocopherols. Our study shows that fat soluble vitamin and carotenoid absorption is controlled by a BCO1-dependent negative feedback regulation. Thus, our findings provide a molecular framework for the controversial relationship between genetics and fat-soluble vitamin status in the human population. PMID- 25701870 TI - Mutations in DCPS and EDC3 in autosomal recessive intellectual disability indicate a crucial role for mRNA decapping in neurodevelopment. AB - There are two known mRNA degradation pathways, 3' to 5' and 5' to 3'. We identified likely pathogenic variants in two genes involved in these two pathways in individuals with intellectual disability. In a large family with multiple branches, we identified biallelic variants in DCPS in three affected individuals; a splice site variant (c.636+1G>A) that results in an in-frame insertion of 45 nucleotides and a missense variant (c.947C>T; p.Thr316Met). DCPS decaps the cap structure generated by 3' to 5' exonucleolytic degradation of mRNA. In vitro decapping assays showed an ablation of decapping function for both variants in DCPS. In another family, we identified a homozygous mutation (c.161T>C; p.Phe54Ser) in EDC3 in two affected children. EDC3 stimulates DCP2, which decaps mRNAs at the beginning of the 5' to 3' degradation pathway. In vitro decapping assays showed that altered EDC3 is unable to enhance DCP2 decapping at low concentrations and even inhibits DCP2 decapping at high concentration. We show that individuals with biallelic mutations in these genes of seemingly central functions are viable and that these possibly lead to impairment of neurological functions linking mRNA decapping to normal cognition. Our results further affirm an emerging theme linking aberrant mRNA metabolism to neurological defects. PMID- 25701871 TI - A large genomic deletion leads to enhancer adoption by the lamin B1 gene: a second path to autosomal dominant adult-onset demyelinating leukodystrophy (ADLD). AB - Chromosomal rearrangements with duplication of the lamin B1 (LMNB1) gene underlie autosomal dominant adult-onset demyelinating leukodystrophy (ADLD), a rare neurological disorder in which overexpression of LMNB1 causes progressive central nervous system demyelination. However, we previously reported an ADLD family (ADLD-1-TO) without evidence of duplication or other mutation in LMNB1 despite linkage to the LMNB1 locus and lamin B1 overexpression. By custom array-CGH, we further investigated this family and report here that patients carry a large (~660 kb) heterozygous deletion that begins 66 kb upstream of the LMNB1 promoter. Lamin B1 overexpression was confirmed in further ADLD-1-TO tissues and in a postmortem brain sample, where lamin B1 was increased in the frontal lobe. Through parallel studies, we investigated both loss of genetic material and chromosomal rearrangement as possible causes of LMNB1 overexpression, and found that ADLD-1-TO plausibly results from an enhancer adoption mechanism. The deletion eliminates a genome topological domain boundary, allowing normally forbidden interactions between at least three forebrain-directed enhancers and the LMNB1 promoter, in line with the observed mainly cerebral localization of lamin B1 overexpression and myelin degeneration. This second route to LMNB1 overexpression and ADLD is a new example of the relevance of regulatory landscape modifications in determining Mendelian phenotypes. PMID- 25701872 TI - Gene therapy into photoreceptors and Muller glial cells restores retinal structure and function in CRB1 retinitis pigmentosa mouse models. AB - Mutations in the Crumbs-homologue-1 (CRB1) gene lead to severe recessive inherited retinal dystrophies. Gene transfer therapy is the most promising cure for retinal dystrophies and has primarily been applied for recessive null conditions via a viral gene expression vector transferring a cDNA encoding an enzyme or channel protein, and targeting expression to one cell type. Therapy for the human CRB1 disease will be more complex, as CRB1 is a structural and signaling transmembrane protein present in three cell classes: Muller glia, cone and rod photoreceptors. In this study, we applied CRB1 and CRB2 gene therapy vectors in Crb1-retinitis pigmentosa mouse models at mid-stage disease. We tested if CRB expression restricted to Muller glial cells or photoreceptors or co expression in both is required to recover retinal function. We show that targeting both Muller glial cells and photoreceptors with CRB2 ameliorated retinal function and structure in Crb1 mouse models. Surprisingly, targeting a single cell type or all cell types with CRB1 reduced retinal function. We show here the first pre-clinical studies for CRB1-related eye disorders using CRB2 vectors and initial elucidation of the cellular mechanisms underlying CRB1 function. PMID- 25701873 TI - The E3 ubiquitin ligase TRIM32 regulates myoblast proliferation by controlling turnover of NDRG2. AB - Limb girdle muscular dystrophy 2H is caused by mutations in the gene encoding the E3 ubiquitin ligase, TRIM32. Previously, we generated and characterized a Trim32 knockout mouse (T32KO) that displays both neurogenic and myopathic features. The myopathy in these mice is attributable to impaired muscle growth, associated with satellite cell senescence and premature sarcopenia. This satellite cell senescence is due to accumulation of the SUMO ligase PIASy, a substrate of TRIM32. The goal of this investigation was to identify additional substrates of TRIM32 using 2D fluorescence difference gel electrophoresis (2D-DIGE) in order to further explore its role in skeletal muscle. Because TRIM32 is an E3 ubiquitin ligase, we reasoned that TRIM32's substrates would accumulate in its absence. 2D DIGE identified 19 proteins that accumulate in muscles from the T32KO mouse. We focused on two of these proteins, NDRG2 and TRIM72, due to their putative roles in myoblast proliferation and myogenesis. Follow-up analysis confirmed that both proteins were ubiquitinated by TRIM32 in vitro; however, only NDRG2 accumulated in skeletal muscle and myoblasts in the absence of TRIM32. NDRG2 overexpression in myoblasts led to reduced cell proliferation and delayed cell cycle withdrawal during differentiation. Thus, we identified NDRG2 as a novel target for TRIM32; these findings further corroborate the hypothesis that TRIM32 is involved in control of myogenic cells proliferation and differentiation. PMID- 25701874 TI - Blocking hyperactive androgen receptor signaling ameliorates cardiac and renal hypertrophy in Fabry mice. AB - Fabry disease is caused by deficient activity of lysosomal enzyme alpha galactosidase A. The enzyme deficiency results in intracellular accumulation of glycosphingolipids, leading to a variety of clinical manifestations including hypertrophic cardiomyopathy and renal insufficiency. The mechanism through which glycosphingolipid accumulation causes these manifestations remains unclear. Current treatment, especially when initiated at later stage of the disease, does not produce completely satisfactory results. Elucidation of the pathogenesis of Fabry disease is therefore crucial to developing new treatments. We found increased activity of androgen receptor (AR) signaling in Fabry disease. We subsequently also found that blockade of AR signaling either through castration or AR-antagonist prevented and reversed cardiac and kidney hypertrophic phenotype in a mouse model of Fabry disease. Our findings implicate abnormal AR pathway in the pathogenesis of Fabry disease and suggest blocking AR signaling as a novel therapeutic approach. PMID- 25701875 TI - Targeted sequencing of the Paget's disease associated 14q32 locus identifies several missense coding variants in RIN3 that predispose to Paget's disease of bone. AB - Paget's disease of bone (PDB) is a common disorder with a strong genetic component characterized by increased but disorganized bone remodelling. Previous genome-wide association studies identified a locus on chromosome 14q32 tagged by rs10498635 which was significantly associated with susceptibility to PDB in several European populations. Here we conducted fine-mapping and targeted sequencing of the candidate locus to identify possible functional variants. Imputation in 741 PDB patients and 2699 controls confirmed that the association was confined to a 60 kb region in the RIN3 gene and conditional analysis adjusting for rs10498635 identified no new independent signals. Sequencing of the RIN3 gene identified a common missense variant (p.R279C) that was strongly associated with the disease (OR = 0.64; P = 1.4 * 10(-9)), and was in strong linkage disequilibrium with rs10498635. A further 13 rare missense variants were identified, seven of which were novel and detected only in PDB cases. When combined, these rare variants were over-represented in cases compared with controls (OR = 3.72; P = 8.9 * 10(-10)). Most rare variants were located in a region that encodes a proline-rich, intrinsically disordered domain of the protein and many were predicted to be pathogenic. RIN3 was expressed in bone tissue and its expression level was ~10-fold higher in osteoclasts compared with osteoblasts. We conclude that susceptibility to PDB at the 14q32 locus is mediated by a combination of common and rare coding variants in RIN3 and suggest that RIN3 may contribute to PDB susceptibility by affecting osteoclast function. PMID- 25701876 TI - FDA's toothless tiger and its "lost pleasure" analysis. PMID- 25701879 TI - The retail environment for tobacco: a barometer of progress towards the endgame. PMID- 25701880 TI - Effectiveness of pictorial health warnings on cigarette packs among Lebanese school and university students. AB - BACKGROUND: Pictorial health warnings are more effective than text warnings in enhancing motivation to quit and not to start smoking among youth. In Lebanon, packs still have only a very small text warning. The aim of this study was to evaluate the perceived effectiveness of pictorial health warnings on cigarette packs among Lebanese youth. METHODS: This was a cross-sectional study including school students (n=1412) aged 13-18 years recruited from 28 schools and university students (n=1217) aged 18-25 years recruited from 7 universities. A variety of warnings were adapted from other countries. In all, 4 warnings were tested among school students and 18 among university students. RESULTS: All pictorial warnings were considered more effective than the current text warning on message-related and impact-related variables, including intentions to quit or not to start smoking among school and university students. Selected examples related to the top-ranked pictorial warnings are: among male non-smoking school students, 81% agreed that the 'lung' warning had more impact on their intentions not to start smoking as compared to 57% for the current text warning (p<0.001) with a significant difference compared to the current text warning; among female non-smoking university students, 75% agreed that the 'economic impact' pictorial had more impact on their intentions not to start smoking with significant difference as compared to 43% for the current text warning (p value=0.001); finally, the 'heart attack' pictorial resulted in 52% of male university students smokers stating they intended to quit as opposed to 20% for the current text warning (p value=0.019). CONCLUSIONS: The results of the present study add to the general international literature on the impact of pictorial warnings on youth and young adults. This study is also the first to test a non-health pictorial warning about the negative economic consequences of smoking, and to find that such a warning was effective among specific sociodemographic groups. PMID- 25701881 TI - Assessing improvements in survival for stroke patients in the Northern Territory 1992-2013: a marginal structural analysis. AB - OBJECTIVE: The aim of the present study was to investigate changes in stroke survival among Indigenous and non-Indigenous patients in the Northern Territory (NT). METHODS: A longitudinal study was undertaken of stroke patients admitted to NT public hospitals between 1992 and 2013. The Kaplan-Meier method and proportional hazards regression were used for survival analysis. A marginal structural model was applied to adjust for time-dependent confounders and informative censoring. RESULTS; There were 4754 stroke in-patients over the period, with 3540 new cases and 837 stroke deaths. Mean age of onset for Indigenous patients (51.7 years) was 12.3 years younger than that for non Indigenous patients. After adjustments for confounders and loss to follow-up, in hospital deaths were more likely among Indigenous patients (hazard ratio (HR) = 1.56; P < 0.01) and less likely among males (HR = 0.86; P < 0.05) and patients from remote areas (HR = 0.72; P < 0.01). There was a 3% decrease annually in mortality hazard from 1992 to 2013. Renal disease, cancer and chronic obstructive pulmonary disease had deleterious effects on stroke survival. CONCLUSIONS: Stroke survival has improved in the NT over the past two decades. The marginal structural models provide a powerful methodological tool that can be applied to hospital administrative data to assess changes in quality of care and the impact of interventions. PMID- 25701882 TI - Coming into focus: computational pathology as the new big data microscope. AB - This editorial discusses the rise of computational pathology as a major driver of experimental pathology research. PMID- 25701883 TI - Disruption of collagen homeostasis can reverse established age-related myocardial fibrosis. AB - Heart failure, the leading cause of hospitalization of elderly patients, is correlated with myocardial fibrosis (ie, deposition of excess extracellular matrix proteins such as collagen). A key regulator of collagen homeostasis is lysyl oxidase (LOX), an enzyme responsible for cross-linking collagen fibers. Our objective was to ameliorate age-related myocardial fibrosis by disrupting collagen cross-linking through inhibition of LOX. The nonreversible LOX inhibitor beta-aminopropionitrile (BAPN) was administered by osmotic minipump to 38-week old C57BL/6J male mice for 2 weeks. Sirius Red staining of myocardial cross sections revealed a reduction in fibrosis, compared with age-matched controls (5.84 +/- 0.30% versus 10.17 +/- 1.34%) (P < 0.05), to a level similar to that of young mice at 8 weeks (4.9 +/- 1.2%). BAPN significantly reduced COL1A1 mRNA, compared with age-matched mice (3.5 +/- 0.3-fold versus 15.2 +/- 4.9-fold) (P < 0.05), suggesting that LOX is involved in regulation of collagen synthesis. In accord, fibrotic factor mRNA expression was reduced after BAPN. There was also a novel increase in Ly6C expression by resident macrophages. By interrupting collagen cross-linking by LOX, the BAPN treatment reduced myocardial fibrosis. A novel observation is that BAPN treatment modulated the transforming growth factor beta pathway, collagen synthesis, and the resident macrophage population. This is especially valuable in terms of potential therapeutic targeting of collagen regulation and thereby age-related myocardial fibrosis. PMID- 25701884 TI - The effect of Nrf2 knockout on ocular surface protection from acute tobacco smoke exposure: evidence from Nrf2 knockout mice. AB - Ocular surface mucosa is the first-line ocular tissue to be exposed to environmental stress. We evaluated tear functions and keratoconjunctival epithelial alterations after sidestream cigarette smoke (SCS) exposure and tried to clarify the role of the transcription factor nuclear factor erythroid 2 related factor 2 (Nfe2l2, also known as Nrf2), on the ocular surface. In wild type and Nrf2(-/-) mice, tear volume did not change after SCS exposure. Tear film breakup time (tear stability) in Nrf2(-/-) mice was significantly shorter than that in wild-type mice after SCS exposure. Vital staining scores, including fluorescein and Rose Bengal staining, showed significantly higher values in Nrf2( /-) mice than in wild-type mice after SCS exposure. Excessive oxidative stress accumulation was detected in Nrf2(-/-) mice after SCS exposure using immunohistochemical analysis. Immunohistochemical analysis also revealed decreased mucin 1 (Muc1) and Muc5ac staining in Nrf2(-/-) mice after SCS exposure. mRNA expression levels of Muc1, Muc4, and Muc5ac and of SAM-pointed domain epithelial-specific transcription factor in Nrf2(-/-) mice were lower than those in wild-type mice after SCS exposure. Mean tear IL-6 concentrations increased significantly in Nrf2(-/-) mice after SCS exposure. In conclusion, SCS exposure induced decreased tear stability, ocular surface damage, and altered conjunctival phenotype in Nrf2(-/-) mice. Nrf2 could play an important role in protection of the ocular surface against SCS exposure. PMID- 25701885 TI - Comparison of lipid-containing bacterial and archaeal viruses. AB - Lipid-containing bacteriophages were discovered late and considered to be rare. After further phage isolations and the establishment of the domain Archaea, several new prokaryotic viruses with lipids were observed. Consequently, the presence of lipids in prokaryotic viruses is reasonably common. The wealth of information about how prokaryotic viruses use their lipids comes from a few well studied model viruses (PM2, PRD1, and phi6). These bacteriophages derive their lipid membranes selectively from the host during the virion assembly process which, in the case of PM2 and PRD1, culminates in the formation of protein capsid with an inner membrane, and for phi6 an outer envelope. Several inner membrane containing viruses have been described for archaea, and their lipid acquisition models are reminiscent to those of PM2 and PRD1. Unselective acquisition of lipids has been observed for bacterial mycoplasmaviruses and archaeal pleolipoviruses, which resemble each other by size, morphology, and life style. In addition to these shared morphotypes of bacterial and archaeal viruses, archaea are infected by viruses with unique morphotypes, such as lemon-shaped, helical, and globular ones. It appears that structurally related viruses may or may not have a lipid component in the virion, suggesting that the significance of viral lipids might be to provide viruses extended means to interact with the host cell. PMID- 25701886 TI - Innate recognition of alphaherpesvirus DNA. AB - Alphaherpesviruses include human and animal pathogens, such as herpes simplex virus type 1, which establish life-long latent infections with episodes of recurrence. The immunocompetence of the infected host is an important determinant for the outcome of infections with alphaherpesviruses. Recognition of pathogen associated molecular patterns by pattern recognition receptors is an essential, early step in the innate immune response to pathogens. In recent years, it has been discovered that herpesvirus DNA is a strong inducer of the innate immune system. The viral genome can be recognized in endosomes by TLR9, as well as intracellularly by a variety of DNA sensors, the best documented being cGAS, RNA Pol III, IFI16, and AIM2. These DNA sensors use converging signaling pathways to activate transcription factors, such as IRF3 and NF-kappaB, which induce the expression of type I interferons and other inflammatory cytokines and activate the inflammasome. This review summarizes the recent literature on the innate sensing of alphaherpesvirus DNA, the mechanisms of activation of the different sensors, their mechanisms of signal transduction, their physiological role in defense against herpesvirus infection, and how alphaherpesviruses seek to evade these responses to allow establishment and maintenance of infection. PMID- 25701887 TI - Molecular biology of potyviruses. AB - Potyvirus is the largest genus of plant viruses causing significant losses in a wide range of crops. Potyviruses are aphid transmitted in a nonpersistent manner and some of them are also seed transmitted. As important pathogens, potyviruses are much more studied than other plant viruses belonging to other genera and their study covers many aspects of plant virology, such as functional characterization of viral proteins, molecular interaction with hosts and vectors, structure, taxonomy, evolution, epidemiology, and diagnosis. Biotechnological applications of potyviruses are also being explored. During this last decade, substantial advances have been made in the understanding of the molecular biology of these viruses and the functions of their various proteins. After a general presentation on the family Potyviridae and the potyviral proteins, we present an update of the knowledge on potyvirus multiplication, movement, and transmission and on potyvirus/plant compatible interactions including pathogenicity and symptom determinants. We end the review providing information on biotechnological applications of potyviruses. PMID- 25701888 TI - Immune evasion strategies of molluscum contagiosum virus. AB - Molluscum contagiosum virus (MCV) is the causative agent of molluscum contagiosum (MC), the third most common viral skin infection in children, and one of the five most prevalent skin diseases worldwide. No FDA-approved treatments, vaccines, or commercially available rapid diagnostics for MCV are available. This review discusses several aspects of this medically important virus including: physical properties of MCV, MCV pathogenesis, MCV replication, and immune responses to MCV infection. Sequencing of the MCV genome revealed novel immune evasion molecules which are highlighted here. Special attention is given to the MCV MC159 and MC160 proteins. These proteins are FLIPs with homologs in gamma herpesviruses and in the cell. They are of great interest because each protein regulates apoptosis, NF kappaB, and IRF3. However, the mechanism that each protein uses to impart its effects is different. It is important to elucidate how MCV inhibits immune responses; this knowledge contributes to our understanding of viral pathogenesis and also provides new insights into how the immune system neutralizes virus infections. PMID- 25701889 TI - Allied health: leaders in health care reform. PMID- 25701890 TI - Baseline circulating ghrelin does not predict weight regain neither maintenance of weight loss after gastric bypass at long term. AB - BACKGROUND: Predictors of weight loss (WL) or weight regain (WR) after Roux-en-Y gastric bypass (RYGBP) are not established. The aim of this study was to analyze the usefulness of some baseline peptides (leptin, insulin, and ghrelin) as biomarkers of WL and WR in morbid obese patients after RYGBP at long term. METHODS: Seventy-six morbid obese (47 women, age 41.6 +/- 9.6 years, body mass index [BMI] 52.1 +/- 8 kg/m(2)) patients were evaluated at baseline and at 1, 2, and 6 years after surgery. RESULTS: Excess body weight loss after 6 years was of 63.9%. Age, BMI, and studied hormones at baseline or their changes over time did not predict long-term excess body weight loss. WR greater than 10% was observed in 36.8% of patients between 2 and 6 years of follow-up, but it was not correlated with BMI, age, or baseline peptide concentrations. CONCLUSION: Measurement of ghrelin, insulin, and leptin before surgery is not useful as predictors of WL or WR at long term after RYGBP. PMID- 25701891 TI - Prevalence, predictors, and outcomes of methicillin-resistant Staphylococcus aureus infections in patients undergoing major surgical procedures in the United States: a population-based study. AB - BACKGROUND: National estimates of methicillin-resistant Staphylococcus aureus (MRSA) infection rates in hospitalized surgical patients and outcomes are lacking. We sought to estimate the prevalence, identify the predictors, and describe the outcomes of MRSA infections in hospitalized patients undergoing major surgical procedures (MSPs) in the United States. METHODS: We performed a retrospective analysis of the Nationwide Inpatient Sample, the largest all-payer hospital discharge database in the United States, for the years 2009 to 2010. RESULTS: Of the 22,932,948 hospitalizations that had an MSP, MRSA infection occurred in 235,636 (1.03%) patients. Factors associated with "significantly" lower risk of MRSA occurrence include women (odds ratio [OR] .68), elective procedure (OR .38), teaching institutes (OR .94), and large hospital size (OR .87). Blacks (OR 1.19), native Americans (OR 1.27), increased comorbid burden (OR 1.38), and uninsured patients were associated with higher risk of MRSA occurrence. Outcomes in MSPs "with" MRSA versus "without" MRSA include mean length of stay (14 vs 5 days) and in-hospital mortality (IHM) rate (3.7% vs 1.2%). Occurrence of an MRSA was associated with significantly longer length of stay and higher odds of IHM (OR 1.39, 95% confidence interval 1.30 to 1.48). CONCLUSIONS: Although the occurrence of MRSA infections complicating MSPs was low, it is associated with worse outcomes. Certain predictors of MRSA infection are identified. PMID- 25701892 TI - Biliary tract variations of the left liver with special reference to the left medial sectional bile duct in 500 patients. AB - BACKGROUND: Among the intrahepatic bile ducts, the biliary system of the left medial sectional bile duct (B4) is known to have relatively complex patterns. METHODS: The records of 500 patients who had been diagnosed as having hepato pancreatico-biliary disease were retrospectively studied for anatomical biliary variations of the left liver with special reference to the drainage system of B4 using magnetic resonance images. RESULTS: The left hepatic duct was present in 494 patients (98.8%), whereas it was lacking in 6 patients (1.2%), and these patients exhibited the following B4 confluence patterns: B4 drained into the common hepatic duct in 2 patients (.4%), the right anterior sectional bile duct in 3 patients (.6%), and the right posterior sectional bile duct in 1 patient (.2%). The left hepatic duct was absent more frequently in patients with portal venous variations than in patients with a common branching pattern (8.2% vs .4%, P = .0011). CONCLUSION: The presently reported data are useful for obtaining a better understanding of the surgical anatomy of the biliary system of the left liver. PMID- 25701893 TI - Long-Standing Nodule of the Nipple. PMID- 25701894 TI - Ultrasound Features of Cellular Neurothekeoma. PMID- 25701895 TI - Oncologic surgery of the eyelid and orbital region. AB - Oncologic surgery of the eyelid and orbital region is a challenge in dermatologic surgery. This region presents difficulties and possible complications that do not exist at other sites, including ectropion, epiphora, corneal exposure, keratitis, conjunctivitis, and lagophthalmos. Adequate oncologic surgery associated with the best possible functional and cosmetic result requires extensive knowledge of the anatomy, innervation, and blood supply of the eyelid and anatomy of the lacrimal apparatus. We present examples of reconstructive surgical techniques that can be used after the excision of tumors of the upper or lower eyelid, with descriptions of the different flaps and grafts employed in our department in recent years. We also review the surgical techniques according to the site and size of the lesions. PMID- 25701896 TI - Granulomatous Reactions to Red Tattoo Pigments: A Description of 5 Cases. PMID- 25701897 TI - Weekend Ciclosporin Maintenance Therapy for Moderate Psoriasis. PMID- 25701898 TI - Severe: A False Friend. PMID- 25701899 TI - Frontal Fibrosing Alopecia: An Update on Epidemiology and Treatment. PMID- 25701900 TI - Detection of Oncogenic Human Papillomavirus Genotypes: A Useful Screening Tool for High-Grade Anal Intraepithelial Neoplasia. PMID- 25701901 TI - Predicting outcome after traumatic brain injury. AB - Developing insight into which factors determine prognosis after traumatic brain injury (TBI) is useful for clinical practice, research, and policy making. Several steps can be identified in prediction research: univariate analysis, multivariable analysis, and the development of prediction models. For each step, several methodological issues should be considered, such as selection/coding of predictors and dealing with missing data. "Traditional" predictors include demographic factors (age), type of injury, clinical severity, second insults, and the presence of structural abnormalities on neuroimaging. In combination, these predictors can explain approximately 35% of the variance in outcome in populations with severe and moderate TBI. Novel and emerging predictors include genetic constitution, biomarkers, and advanced magnetic resonance (MR) imaging. To estimate prognosis for individual patients reliably, multiple predictors need to be considered jointly in prognostic models. Two prognostic models for use in TBI, developed upon large patient numbers, have been extensively validated externally: the IMPACT and CRASH prediction models. Both models showed good performance in validations across a wide range of settings. Importantly, these models were developed not only for mortality but also for functional outcome. Prognostic models can be used for providing information to relatives of individual patients, for resource allocation, and to support decisions on treatment. At the group level, prognostic models aid in the characterization of patient populations, are important to clinical trial design and analysis, and importantly, can serve as benchmarks for assessing quality of care. Continued development, refinement, and validation of prognostic models for TBI is required and this should become an ongoing process. PMID- 25701902 TI - Movement disorders secondary to craniocerebral trauma. AB - Over the past few decades it has been recognized that traumatic brain injury may result in various movement disorders. In survivors of severe head injury, post traumatic movement disorders were reported in about 20%, and they persisted in about 10% of patients. The most frequent persisting movement disorder in this population is kinetic cerebellar outflow tremor in about 9%, followed by dystonia in about 4%. While tremor is associated most frequently with cerebellar or mesencephalic lesions, patients with dystonia frequently have basal ganglia or thalamic lesions. Moderate or mild traumatic brain injury only rarely causes persistent post-traumatic movement disorders. It appears that the frequency of post-traumatic movement disorders overall has been declining which most likely is secondary to improved treatment of brain injury. In patients with disabling post traumatic movement disorders which are refractory to medical treatment, stereotactic neurosurgery can provide long-lasting benefit. While in the past the primary option for severe kinetic tremor was thalamotomy and for dystonia thalamotomy or pallidotomy, today deep brain stimulation has become the preferred treatment. Parkinsonism is a rare consequence of single head injury, but repeated head injury such as seen in boxing can result in chronic encephalopathy with parkinsonian features. While there is still controversy whether or not head injury is a risk factor for the development of Parkinson's disease, recent studies indicate that genetic susceptibility might be relevant. PMID- 25701903 TI - Language impairments in traumatic brain injury: a window into complex cognitive performance. AB - Often, standard aphasia batteries do not fully characterize higher-order cognitive-linguistic sequelae associated with a traumatic brain injury (TBI). Limited understanding and detection of complex linguistic deficits have thwarted efforts to comprehensively remediate higher-order language deficits that persist even in chronic stages of recovery post-TBI. This chapter reviews key precursor metrics that have motivated efforts to elucidate higher-order language proficiencies after a TBI. The chapter further expounds on a paradigmatic shift away from sole focus on lower level basic skills, towards a more top-down cognitive control approach to measure, retrain, and strengthen complex language abilities in TBI. The intricate relations between complex language abilities and cognitive control functions are also discussed. The concluding section offers promising directions for future research and clinical management based on new discoveries of higher-order language impairments and their modifiability in TBI populations. PMID- 25701904 TI - Connecting clinical and experimental investigations of awareness in traumatic brain injury. AB - Questionnaire-based demonstrations of impaired self-awareness (SA) after traumatic brain injury (TBI) are not always supported by experimental studies of in-the-moment or online awareness. This chapter begins by describing the clinical phenomenon of impaired SA, how it is measured, and why its interdependency with mechanisms of online awareness may provide the scaffolding from which appraisals of cognitive functioning can be accurately revised following a brain injury. We review research that has measured unawareness of errors in routine action in TBI patients and propose more rigorous methodological approaches to studying the emergent properties of awareness with greater clarity in the laboratory. We discuss how neuropsychological and electrophysiologic studies are beginning to inform our understanding of impaired error processing in TBI patients and we highlight recent theory proposing that online metacognitive processes accumulate evidence of erroneous responses in a graded fashion. Neural signals with amplitudes that scale with the strength of accruing evidence and peak latencies that mark the threshold at which awareness emerges represent important neural mechanisms to examine the breakdown of error awareness after brain injury. We also discuss how errors can be investigated in relation to different sources of evidence that contribute to aware experiences after brain injury. Finally, we explore conditions beyond error signaling, and how different "objects of insight" that require retrospective and prospective judgments of confidence need to be examined in relation to the clinical phenomenon of impaired SA. PMID- 25701905 TI - Post-traumatic epilepsy: clinical clues to pathogenesis and paths to prevention. AB - Post-traumatic epilepsy (PTE) remains one of the most intractable consequences of traumatic brain injury (TBI) and its incidence and characteristics have remained relatively constant through the past century, in spite of significant advances in medical management. Survivors of military penetrating head injury (PHI) suffer by far the highest incidence of (PTE), ranging from 32% to 55%, and they are a particularly valuable group in which to study this complication. Clues to the high incidence of PTE in PHI survivors are likely related to dural penetration with free intracerebral blood, and perhaps to retained ferric metal fragments. The failure of well-reasoned and well-conducted trials evaluating conventional anticonvulsants for prevention of PTE also offers important clues and has forced us to reconsider our approach to management. Here we briefly review the clinical characteristics of PHI patients with PTE, with an emphasis on clues to pathogenesis that can generalize to other types of head injury; followed by a discussion of the pathogenetic mechanisms common to epilepsy, PHI, and TBI in general, with an eye to future neuroprotection and PTE prophylaxis. Future studies that more directly target the basic pathogenesis of TBI, including neuroinflammation and lipid peroxidation with their consequent excitotoxic mechanisms and aberrant regeneration, may ultimately prove to be more fruitful in the struggle to understand and control this especially stubborn complication of head injury. PMID- 25701906 TI - Autonomic dysfunction syndromes after acute brain injury. AB - The central autonomic nervous system (CAN) is a multifaceted, richly connected neural network incorporating the hypothalamus, its descending tracts through the brainstem, the insular cortex and down into the spinal cord. All levels of the CAN are susceptible to injury following traumatic brain injury (TBI), whether from focal or diffuse injury. Focal injuries would be expected to produce localized damage to CAN control centers, whereas the effects of diffuse injuries are presumed to be more diverse and/or widely distributed. As the combination of focal and diffuse injury following TBI can vary widely from one individual to the next, the impact of focal injuries is best understood with reference to the focal ischemic stroke literature. Subarachnoid hemorrhage (SAH), a common complication following TBI, also has predictable effects on autonomic control that can be understood with reference to spontaneous SAH literature. Finally, paroxysmal sympathetic hyperactivity (PSH), a syndrome incorporating episodes of heightened sympathetic drive and motor overactivity following minor stimulation, is discussed as an example of what happens when central inhibitory control of spinal cord autonomics is impaired. PMID- 25701907 TI - Sleep in traumatic brain injury. AB - Sleep disturbances affect more than half of survivors of traumatic brain injury (TBI) and have the potential to undermine rehabilitation, recovery, and outcomes. Normal sleep architecture has been well-described and the neurophysiology of sleep is becoming better understood in recent years, though this complex process continues to be dissected for better appreciation. There are numerous types of sleep disorder, most of which fall under two categories: dyssomnias and parasomnias. In more challenging scenarios patients may be plagued with more than one dyssomnia and/or parasomnia simultaneously, complicating the diagnostic and therapeutic approach. Objective and subjective methods are used to evaluate sleep disorders and help distinguish them from psychiatric and environmental contributors to poor sleep. There are several pharmacologic and nonpharmacologic treatments options for sleep disturbances after TBI, many of which have been particularly helpful in restoring adequate quantity and quality of sleep for survivors. However, to date no consensus has been established regarding how to treat this entity, and it may be that a multimodal approach is ultimately best. PMID- 25701908 TI - Post-traumatic headaches. AB - Chronic pain, especially headache, is an exceedingly common complication of traumatic brain injury (TBI). In fact, paradoxically, the milder the TBI, the more likely one is to develop headaches. The environment of injury and the associated comorbidities can have a significant impact on the frequency and severity of headaches and commonly serve to direct management of the headaches. Trauma likely contributes to the development of headaches via alterations in neuronal signaling, inflammation, and musculoskeletal changes. The clinical picture of the patient with post-traumatic headaches is often that of a mixed headache disorder with features of tension-type headaches as well as migrainous headaches. Treatment of these headaches is thus often guided by the predominant characteristics of the headaches and can include pharmacologic and nonpharmacologic strategies. Pharmacologic therapies include both abortive and prophylactic agents with prophylaxis targeting comorbidities, primarily impaired sleep. Nonpharmacologic interventions for post-traumatic headaches include thermal and physical modalities as well as cognitive behavioral approaches. As with many postconcussive symptoms, headaches can lessen with time but in up to 25% of patients, chronic headaches are long-term residua. PMID- 25701909 TI - Traumatic brain injury and cognition. AB - Traumatic brain injury (TBI) is a major cause of death and disability, and therefore an important health and socioeconomic problem for our society. Individuals surviving from a moderate to severe TBI frequently suffer from long lasting cognitive deficits. Such deficits include different aspects of cognition such as memory, attention, executive functions, and awareness of their deficits. This chapter presents a review of the main neuropsychological and neuroimaging studies of patients with TBI. These studies found that patients evolve differently according to the severity of the injury, the mechanism causing the injury, and the lesion location. Further research is necessary to develop rehabilitation methods that enhance brain plasticity and recovery after TBI. In this chapter, we summarize current knowledge and controversies, focusing on cognitive sequelae after TBI. Recommendations from the Common Data Elements are provided, with an emphasis on diagnosis, outcome measures, and studies organization to make data more comparable across studies. Final considerations on neuroimaging advances, rehabilitation approaches, and genetics are described in the final section of the chapter. PMID- 25701910 TI - Mood disorders. AB - Mood disturbances, especially depressive disorders, are the most frequent neuropsychiatric complication of traumatic brain injury (TBI). These disorders have a complex clinical presentation and are highly comorbid with anxiety, substance misuse, and other behavioral alterations such as impulsivity and aggression. Furthermore, once developed, mood disorders tend to have a chronic and refractory course. Thus, the functional repercussion of these disorders is huge, affecting the rehabilitation process and the long-term outcome of TBI patients. The pathophysiology of mood disorders involves the interplay of factors that precede trauma (e.g., genetic vulnerability and previous psychiatric history), factors that pertain to the traumatic injury itself (e.g., type, extent, and location of brain damage) and factors that influence the recovery process (e.g., family and social support). It is hardly surprising that mood disorders are associated with structural and functional changes of neural circuits linking brain areas specialized in emotional processing such as the prefrontal cortex, basal ganglia, and amygdala. In turn, the onset of mood disorders may contribute to further prefrontal dysfunction among TBI patients. Finally, in spite of the prevalence and impact of these disorders, there have been relatively few rigorous studies of therapeutic options. Development of treatment strategies constitutes a priority in this field of research. PMID- 25701911 TI - Post-traumatic stress disorder and traumatic brain injury. AB - Disentangling the effects of "organic" neurologic damage and psychological distress after a traumatic brain injury poses a significant challenge to researchers and clinicians. Establishing a link between traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD) has been particularly contentious, reflecting difficulties in establishing a unique diagnosis for conditions with overlapping and sometimes contradictory symptom profiles. However, each disorder is linked to a variety of adverse health outcomes, underscoring the need to better understand how neurologic and psychiatric risk factors interact following trauma. Here, we present data showing that individuals with a TBI are more likely to develop PTSD, and that individuals with PTSD are more likely to develop persistent cognitive sequelae related to TBI. Further, we describe neurobiological models of PTSD, highlighting how patterns of neurologic damage typical in TBI may promote or protect against the development of PTSD in brain-injured populations. These data highlight the unique course of PTSD following a TBI and have important diagnostic, prognostic, and treatment implications for individuals with a dual diagnosis. PMID- 25701912 TI - Long-term functional outcomes of traumatic brain injury. AB - We review the literature on two long-term functional outcomes of traumatic brain injury (TBI) important to patients, family members, and rehabilitation treatment teams: work for pay and driving outcomes. Estimates on the percentages working after TBI have ranged widely, and few consistent prognostic indicators of long term outcomes have been identified. The few large randomized controlled treatment trials of these long-term productive outcomes have been negative, but have identified promising subgroup results that bear further investigation. Salazar et al. (2000) identified patients with loss of consciousness of 1 hour or longer as a subgroup that benefited from intensive in-hospital treatment. Vanderploeg et al. (2008) found that the cognitive treatment arm resulted in improved cognitive performance, and that younger patients benefited more from the cognitive treatment; whereas older patients (31 plus) benefited from a more functional approach to treatment. The research evidence on driving post TBI is sparse - relying upon small studies, and lacking follow-up data. This review included only published research studies of 100 or more subjects, with control groups, and outcomes 6 months or longer after injury. The inclusion of more reliable studies narrowed return to work estimates and provided evidence that type of control group affects findings about return to work after mild TBI (mTBI). Prognostic indicators remain inconsistently measured among these more reliable studies. Heeding the frequent recommendation that research in this area be more stringently conducted, well powered, and use shared measures of critical variables would improve evidence. Adequately powered treatment trials of existing and innovative treatment modalities remain a priority. PMID- 25701913 TI - Sequelae in children: developmental consequences. AB - Child traumatic brain injury (TBI) is a major cause of disability in early life. Unlike in adults, a TBI in childhood causes an insult to a brain that is developing, potentially affecting future brain maturation, neural connectivity, and the acquisition of new skills. This review considers how such early brain insult may impact children's functional abilities, and how these processes may link with differential patterns of recovery across infancy, childhood, and adolescence. We also review evidence for cognitive impairment across a range of domains (IQ, attention, processing, memory executive function) and common educational, behavioral, and social consequences associated with child TBI. While impairments in all of these domains have been reported, in fact outcomes from child TBI are surprisingly varied and difficult to predict. To assist in understanding what may contribute to outcomes, we discuss predictive factors (injury severity, child and environment status) and research reporting on their individual and combined effect on recovery. The identification of such outcome predicators has led to an emerging literature in the area of intervention and rehabilitation that we also summarize. Finally, it concludes with discussion of the future direction of pediatric TBI research. PMID- 25701914 TI - Cellular and molecular neuronal plasticity. AB - The brain has the capability to adapt to function when tissue is compromised. This capability of adaptation paves the road to recovery and allows for rehabilitation after a traumatic brain injury (TBI). This chapter addresses neuroplasticity within the context of TBI. Here neuroplasticity is defined as changes in neuronal structure and function, including synaptic changes as well as modifications in neural pathways. First, the influence of TBI pathology on neuroplasticity is addressed. Here, proteins that are important in neuroplasticity are introduced and a description given of how these are affected in a temporal and severity-dependent manner. Secondly, given that we are becoming increasingly aware that the brain's response to injury is highly influenced by the environmental milieu, the manner in which behavioral manipulations have an effect on TBI-associated neuroplasticity is addressed. A description is given of how specific environmental qualities may facilitate or hinder neuroplasticity. Finally, the long-term effects of neuroplasticity and the relevance it has to rehabilitation are described. PMID- 25701915 TI - Traumatic brain injury and reserve. AB - The potential role of brain and cognitive reserve in traumatic brain injury (TBI) is reviewed. Brain reserve capacity (BRC) refers to preinjury quantitative measures such as brain size that relate to outcome. Higher BRC implies threshold differences when clinical deficits will become apparent after injury, where those individuals with higher BRC require more pathology to reach that threshold. Cognitive reserve (CR) refers to how flexibly and efficiently the individual makes use of available brain resources. The CR model suggests the brain actively attempts to cope with brain damage by using pre-existing cognitive processing approaches or by enlisting compensatory approaches. Standard proxies for CR include education and IQ although this has expanded to include literacy, occupational attainment, engagement in leisure activities, and the integrity of social networks. Most research on BRC and CR has taken place in aging and degenerative disease but these concepts likely apply to the effects of TBI, especially with regards to recovery. Since high rates of TBI occur in those under age 35, both CR and BRC factors likely relate to how the individual copes with TBI over the lifespan. These factors may be particularly relevant to the relationship of developing dementia in the individual who has sustained a TBI earlier in life. PMID- 25701916 TI - Traumatic brain injury and late-life dementia. AB - Little is known of the impact of traumatic brain injury (TBI) on outcomes decades later when the effects of the injury interact with the aging brain. Some, but not all, epidemiologic studies have reported an association between TBI and increased risk of Alzheimer's disease (AD) and other neurodegenerative disorders years after the injury. There is evidence that this association has a dose-response pattern such that risk of dementia progressively increases as the number and severity of head injuries increase. Some studies have shown that one of the mechanisms underlying the association is that TBI may contribute to earlier onset of dementia. The APOE epsilon4 allele has been proposed as a biological link between TBI and AD because individuals with an APOE epsilon4 allele show typical AD pathology within a short period postinjury and are at increased risk of poorer cognitive outcomes. There are also likely other, yet to be identified factors that interact with the postinjury damage and aging-related brain changes leading to exacerbated cognitive decline and dementia. Given the large number of young individuals with military, sports-related, and other causes of head injuries, there is a window of opportunity and an urgency to understand the link between TBI and dementia before these TBI survivors reach the age of risk for dementia. PMID- 25701917 TI - Genetic factors in traumatic brain injury. AB - Outcome after a traumatic brain injury (TBI) can be quite variable and unpredictable. This suggests factors other than injury severity play important roles in outcome. Host genotype might be one such factor. This chapter reviews key concepts important to understanding genetic influences on the response to and recovery from TBI. As an organizing framework, four broad contexts in which individual differences could play an important role in outcome after trauma are presented: (1) genes that may modulate injury extent and serve to augment or dampen the impact of a given "dose" of neurotrauma, (2) genes that may play a role in repair and recovery from injury and thus impact the trajectory of recovery and ultimate functional outcome, (3) genes modulating preinjury traits (e.g., resilience), or cognition (cognitive reserve), (4) interactions between genetic vulnerabilities to neurobehavioral disorders and neurotrauma (i.e., role of comorbidities). Each of these four broad categories involve multiple components and thus are under complex polygenic control suggesting that functional outcome following TBI is best viewed as a complex polygenic phenotype. Although the individual contribution of a given allele might be small, the effects of multiple alleles could be quite significant. PMID- 25701918 TI - Ethical and regulatory considerations in the design of traumatic brain injury clinical studies. AB - Research is essential for improving outcomes after traumatic brain injury (TBI). However, the ubiquity, variability, and nature of TBI create many ethical issues and accompanying regulations for research. To capture the complexity and importance of designing and conducting TBI research within the framework of key ethical principles, a few highly relevant topics are highlighted. The selected topics are: (1) research conducted in emergency settings; (2) maintaining equipoise in TBI clinical trials; (3) TBI research on vulnerable populations; and (4) ethical considerations for sharing data. The topics aim to demonstrate the dynamic and multifaceted challenges of TBI research, and also to stress the value of addressing these challenges with the key ethical principles of respect, beneficence, and justice. Much has been accomplished to ensure that TBI research meets the highest ethical standards and has fair and enforceable regulations, but important challenges remain and continued efforts are needed by all members of the TBI research community. PMID- 25701919 TI - Design of acute neuroprotection studies. AB - Traumatic brain injury (TBI) is a substantial public health problem. The discovery of progressive, ongoing damage to the brain by means of complex molecular mechanisms which follow the initial injury has raised the possibility of targeted therapeutic intervention. Despite a substantial investment in trials testing dozens of therapeutics in humans, however, to date none has demonstrated robust efficacy. Deficiencies in the design of human clinical trials is likely to explain many translational failures, at least in part. Here we review secondary injury mediators and key trials which have targeted them. We provide a thorough discussion of putative reasons why trials thus far have failed and suggestions for the design of future clinical studies. Important insights from the IMPACT study are also presented in detail; in addition to providing critical insights for future trial design and analysis it suggests that reanalysis of completed studies may reveal inappropriately discarded treatments. Unfortunately limited resources are available for translational research and it is difficult to procure funds needed for well-resourced, large and definitive studies. History suggests, however, that investing in studies that are unlikely to provide a definitive answer only serves to increase required investment as they tend to mandate further study. PMID- 25701920 TI - Design of brain injury rehabilitation treatment research. AB - Rehabilitation is a key service component in the context of significant brain injury, yet many of the treatments and services employed in rehabilitation are not based on rigorous evidence. Treatment research in rehabilitation, like in other fields of healthcare, relies on a developmental sequence of studies that address different questions, including safety, proof of principle, definitive efficacy, and real-world effectiveness. Each of these steps faces challenges specific to the rehabilitation domain, where many treatments are nonpharmacologic, and outcomes of interest are highly varied and complex. This chapter frames the research questions addressed by different phases of treatment research, identifies some of the particular challenges in answering these questions, and takes a hypothetical treatment through the sequence to illustrate the process. PMID- 25701921 TI - The ebb and flow of traumatic brain injury research. AB - The purpose of this chapter is to summarize some key topics discussed in this volume and describe trends suggesting the direction of future traumatic brain injury (TBI) research. Interest in, and funding for, TBI has ebbed and flowed with the public awareness of injury risk from combat, sports, or everyday life. Advances in acute resuscitation, emergency response systems, and early management have had a major impact on survival after TBI, while recent research has emphasized underlying genetic substrates and the molecular mechanisms of brain injury, repair, and neuroplasticity. This in turn impacts not only on primary and secondary neuroprotection strategies for minimizing injury, but also on the other critical remaining challenge, that of identification and validation of optimal strategies for physical and cognitive TBI rehabilitation. New information also highlights long-term degenerative conditions associated with earlier TBI and mediated by a signature cascade of abnormal molecular processes. Thus, TBI has emerged as a recognized significant public health risk with both immediate and lifelong repercussions. The linkage of a TBI to late-life neurodegenerative diseases, the observation of persistent pathologic processes including neuroinflammation and accumulation of tau protein, as well as individual differences in the genetic predisposition for brain repair and plasticity should lead to meaningful translational research with a significant impact on the efficacy and cost-efficiency of acute and chronic treatment for TBI survivors. PMID- 25701922 TI - Preface. PMID- 25701923 TI - Foreword. PMID- 25701925 TI - Cardiopulmonary exercise testing for risk prediction in major abdominal surgery. AB - Reduced exercise capacity is associated with increased postoperative morbidity. Cardiopulmonary exercise testing variables can be used to risk stratify patients. This information can be used to help guide the choice of surgical procedure and to decide on the most appropriate postoperative care environment. Thus CPET can aid collaborative decision making and improve the process of informed consent. In the future, CPET may be combined with other risk predictors to improve outcome prediction. Furthermore early evidence suggests that CPET can be used to guide prehabilitation training programs, improving fitness and thereby reducing perioperative risk. PMID- 25701924 TI - Epidemiology of child psychopathology: major milestones. AB - Child psychiatric epidemiology has developed rapidly from descriptive, cross sectional studies in the 1960s to the current large-scale prospective cohorts that unravel aetiological mechanisms. The objective of the study was to give an overview of epidemiological studies that have influenced child psychiatry. A chronological overview of selected major milestone studies was obtained to demonstrate the development of child psychiatric epidemiology, with a more in depth discussion of findings and methodological issues exemplified in one cohort, the Generation R Study. Epidemiological studies have been successful in describing the frequency and course of child psychiatric problems. The high expectations that biological factors can be used to better explain, diagnose or predict child psychiatric problems have not been met. More ambitious large-scale child psychiatric cohort studies are needed, carefully applying genetics, neuroscience or other molecular research to better understand how the brain produces maladaptive behaviour. Progress will only be attained if the basic sciences are systematically integrated in cohorts with rigorous epidemiological designs rather than hurriedly inserted in child psychiatric studies. PMID- 25701926 TI - Prehabilitation to enhance perioperative care. AB - Patients who are elderly, malnourished, anxious, and have a low physical function before surgery are likely to have suboptimal recovery from cancer surgery. A multimodal prehabilitation program is proposed, consisting of exercise training and nutritional and psychological support, which increases physiologic reserve before the stress of surgery. This interventional approach seems to improve ability to undergo the stress of surgery and faster recovery. The integration of exercise, adequate nutrition, and psychosocial components, with medical and pharmacologic optimization in the presurgical period, deserves to receive more attention by clinicians to elucidate the most effective interventions. PMID- 25701927 TI - Monitoring needs and goal-directed fluid therapy within an enhanced recovery program. AB - Patients having major abdominal surgery need perioperative fluid supplementation; however, enhanced recovery principles mitigate against many of the factors that traditionally led to relative hypovolemia in the perioperative period. An estimate of fluid requirements for abdominal surgery can be made but individualization of fluid prescription requires consideration of clinical signs and hemodynamic variables. The literature supports goal-directed fluid therapy. Application of this evidence to justify stroke volume optimization in the setting of major surgery within an enhanced recovery program is controversial. This article places the evidence in context, reviews controversies, and suggests implications for current practice and future research. PMID- 25701928 TI - Fluid management in abdominal surgery: what, when, and when not to administer. AB - The entire team (including anesthesiologists, surgeons, and intensive care physicians) must work together (before, during, and after abdominal surgery) to determine the optimal amount (quantity) and type (quality) of fluid necessary in the perioperative period. The authors present an overview of the basic principles that underlie fluid management, including evidence-based recommendations (where tenable) and a rational approach for when and what to administer. PMID- 25701929 TI - Optimal analgesia during major open and laparoscopic abdominal surgery. AB - Optimal analgesia is a key element of enhanced recovery after surgery (ERAS), not only for humanitarian reasons but also because poorly relieved surgical pain contributes to surgical stress and impairs recovery. A multimodal analgesic approach is advised in order to provide adequate analgesia, reduce opioid consumption, reduce side effects and facilitate the achievement of ERAS milestones. For open surgery, a thoracic epidural for 48 to 72 hours, with regular acetaminophen and antiinflammatories is probably the treatment of choice. For laparoscopic surgery, intrathecal or local anesthesia in the wound combined with regular acetaminophen and antiinflammatory drugs is effective. PMID- 25701930 TI - Pathophysiology of major surgery and the role of enhanced recovery pathways and the anesthesiologist to improve outcomes. AB - Enhanced recovery pathways have been increasingly adopted into surgical specialties with the aim of reducing the stress response and improving the metabolic response to surgical insult. Enhanced recovery pathways encompass a large range of perioperative elements that together aim to restore a patient's gut function, mobility, function and well-being to preoperative levels as soon as feasible after major surgery. There is increasing evidence that rapid recovery and return to normal function reduces complications. This may not just have a benefit by reducing morbidity and mortality but also have an effect on long-term survival. There also may be additional benefits for patients with cancer. PMID- 25701931 TI - Anesthesia for colorectal surgery. AB - Anesthesiologists play a pivotal role in facilitating recovery of patients undergoing colorectal surgery, as many Enhanced Recovery After Surgery (ERAS) elements are under their direct control. Successful implementation of ERAS programs requires that anesthesiologists become more involved in perioperative care and more aware of the impact of anesthetic techniques on surgical outcomes and recovery. Key to achieving success is strict adherence to the principle of aggregation of marginal gains. This article reviews anesthetic and analgesic care of patients undergoing elective colorectal surgery in the context of an ERAS program, and also discusses anesthesia considerations for emergency colorectal surgery. PMID- 25701932 TI - Anesthesia for hepatobiliary surgery. AB - Hepatobiliary surgery outcomes have significantly improved since the early 1970s. Surgical and anesthetic advances related to patient selection, alternative surgical management options, and reduction of operative blood loss have been important. Postoperative analgesic regimens are being modified to include intrathecal opiates and to embrace enhanced recovery regimens. PMID- 25701933 TI - Anesthesia for esophagectomy. AB - Esophagectomy is a high-risk operation with significant perioperative morbidity and mortality. Attention to detail in many areas of perioperative management should lead to an aggregation of marginal gains and improvement in postoperative outcome. This review addresses preoperative assessment and patient selection, perioperative care (focusing on pulmonary prehabilitation, ventilation strategies, goal-directed fluid therapy, analgesia, and cardiovascular complications), minimally invasive surgery, and current evidence for enhanced recovery in esophagectomy. PMID- 25701934 TI - Anesthesia for major urologic surgery. AB - This article details the anesthetic management of robot-assisted and laparoscopic urologic surgery. It includes the key concerns for anesthetists and a guide template for those learning this specialist area. The emphasis is on the principles of enhanced recovery, the preoperative and risk assessments, as well as the specific management plans to reduce the incidence of complications arising as a result of the prolonged pneumoperitoneum and steep head-down positions necessary for most of these procedures. PMID- 25701935 TI - Evidence-based anesthesia for major gynecologic surgery. AB - Studies on enhanced recovery after gynecological surgery are limited but seem to report outcome benefits similar to those reported after colorectal surgery. Regional anesthesia is recommended in enhanced recovery protocols. Effective regional anesthetic techniques in gynecologic surgery include spinal anesthesia, epidural analgesia, transversus abdominis plane blocks, local anesthetic wound infusions and intraperitoneal instillation catheters. Non-opioid analgesics including pregabalin, gabapentin, NSAIDs, COX-2 inhibitors, and paracetamol reduce opioid consumption after surgery. This population is at high risk for PONV, thus, a multimodal anti-emetic strategy must be employed, including strategies to reduce the baseline risk of PONV in conjunction with combination antiemetic therapy. PMID- 25701936 TI - Anesthesia for emergency abdominal surgery. AB - Emergency abdominal surgery has a high mortality, with an incidence of around 15% for all patients. Mortality in elderly patients is up to 25%, and 1-year mortality for emergent colorectal resection for patients over 80 years is around 50%. Patients presenting to hospital are often given low priority. Definitive surgery is not always possible and it may be more important to control the septic focus and to revisit surgery later. The literature is poor for such a common procedure, but there is evidence that a standardized pathway focusing on rapid diagnosis; resuscitation; sepsis treatment; and, if appropriate, urgent surgery followed by admission to intensive care improves outcomes. PMID- 25701937 TI - Anesthetic care for abdominal surgery. PMID- 25701938 TI - Enhanced recovery and the changing landscape of major abdominal surgery. PMID- 25701939 TI - Message from the Chairperson. PMID- 25701940 TI - Uremia research and toxicity. PMID- 25701941 TI - Gene mutations in chronic kidney disease patients with secondary hyperparathyroidism and Sagliker syndrome. AB - Sagliker syndrome (SS) develops particularly before puberty while chronic kidney disease (CKD) reaches stage 3 with overt secondary hyperparathyroidism. We conducted screening for mutations in all the 13 exons of GNAS1 gene, all 3 exons of FGF23, and all 18 exons in FGFR3 genes in 23 patients. In 73.9% (17 of 23) patients, 17 genetic abnormalities in GNAS1 were detected. Seven (58.3%) of 12 nucleotide alterations comprised novel missense mutations and 3 nonsense. Mismutations were in different manner. There were also 6 heterozygous transversion polymorphisms in exons. Six were introngenic mutations (introns 65626, 70387, 70817). We found 10 mutations with different manner in FGF23 gene. Two were defined previously but remaining 8 were novel mutations. Three were in intronic region near exon 2. We sequenced all exons and intronic regions near exon-exon junction regions of FGFR3 gene. We found 22 mutations with different manner. Six were defined previously and remaining 16 were novel mutations. Eight of them were in intronic region near exon 11 and the last 2 were in noncoding exonic region of exons. One was in the exon-exon junction region between exon 11 and 12, therefore this mutation might be preventing splicing of this intron. Because the incidence of CKD late stage 3 is around 8% but the incidence of SS is around 0.5% in CKD, these gene mismutations might be responsible for bone deformities such as McCune-Albright syndrome and achondroplasias. Although our patients were not resembling any of them, they could be in between, and SS might be a combination-compulsion of bone dysplasias-hereditary osteodystrophies and CKD. PMID- 25701942 TI - Factors affecting daily physical activity and physical performance in maintenance dialysis patients. AB - Maintenance hemodialysis (MHD) patients display reduced daily physical activity (DPA) and physical performance (PP). Previous studies did not differentiate the effects of kidney failure and MHD treatments from comorbidities as causes for reduced DPA and PP. In relatively healthy MHD patients and normal adults, we evaluated DPA and PP and examined relationships between DPA and PP and possible associations between anxiety or depression and DPA and PP. DPA, 6-minute walk distance (6-MWD), sit-to-stand (STS), and stair-climbing tests were measured in 72 MHD patients (40% diabetics) with limited comorbidities and 39 normal adults of similar age and gender mix. Anxiety and depression were measured by the Beck anxiety and depression inventories. DPA, time-averaged over 7 days, and all 3 PP tests were impaired in MHD patients, to about 60% to 70% of normal values (P < .0001 for each measurement). MHD patients spent more time sleeping or physically inactive (P < .0001) and less time in >= moderate activity (P < .0001). Adjusted DPA correlated with 6-MWD but not STS or stair-climbing. Anxiety and depression were identified in 43% and 33% of MHD patients and 2.5% and 5.1% of normals (P < .0001 for each comparison). Most of the impairment in DPA and PP tests were also observed in MHD patients without anxiety or depression. However, MHD patients with both anxiety and depression generally had the most impaired DPA and PP. In MHD patients, higher adjusted anxiety scores were correlated with impaired 6-MWD and STS, whereas adjusted average DPA was negatively correlated with depression (r = -0.33, P = .006) but not anxiety. DPA on the hemodialysis day (P = .01), day after dialysis (P = .03), and day 2 after dialysis (P = .03) each correlated negatively with degree of depression but not with anxiety. MHD patients displayed negative-adjusted correlations between anxiety and 6-MWD (P = .03) and STS (P = .04). In relatively healthy MHD patients, DPA and PP are substantially impaired and correlated with each other, even in patients without evidence for anxiety or depression. Anxiety and depression are common in MHD patients and are associated with further impairment in DPA and PP. PMID- 25701943 TI - The benefits of mentoring: the mushroom hunters-how to teach your patients what to find in themselves! PMID- 25701944 TI - Genetic diversity in Monoporeia affinis at polluted and reference sites of the Baltic Bothnian Bay. AB - The amphipod Monoporeia affinis plays an important role in the Baltic Sea ecosystem as prey and as detritivore. The species is monitored for contaminant effects, but almost nothing is known about its genetics in this region. A pilot screening for genetic variation at the mitochondrial COI gene was performed in 113 individuals collected at six sites in the northern Baltic. Three coastal sites were polluted by pulp mill effluents, PAHs, and trace metals, and two coastal reference sites were without obvious connection to pollution sources. An off-coastal reference site was also included. Contaminated sites showed lower levels of genetic diversity than the coastal reference ones although the difference was not statistically significant. Divergence patterns measured as PhiST showed no significant differentiation within reference and polluted groups, but there was significant genetic divergence between them. The off-coastal sample differed significantly from all coastal sites and also showed lower genetic variation. PMID- 25701945 TI - Teaching clinical ultrasonography to undergraduates. A need for systematic training programs. PMID- 25701946 TI - Early prevention and screening of cervical cancer in a developing country. PMID- 25701947 TI - Early prevention and screening of cervical cancer in a developing country-reply. PMID- 25701948 TI - Effect of periodontal therapy on systemic diseases. PMID- 25701949 TI - Response to a letter from Dr. Timothy A. DeRouen. PMID- 25701950 TI - Gene expression in the mammary gland of the tammar wallaby during the lactation cycle reveals conserved mechanisms regulating mammalian lactation. AB - The tammar wallaby (Macropus eugenii), an Australian marsupial, has evolved a different lactation strategy compared with eutherian mammals, making it a valuable comparative model for lactation studies. The tammar mammary gland was investigated for changes in gene expression during key stages of the lactation cycle using microarrays. Differentially regulated genes were identified, annotated and subsequent gene ontologies, pathways and molecular networks analysed. Major milk-protein gene expression changes during lactation were in accord with changes in milk-protein secretion. However, other gene expression changes included changes in genes affecting mRNA stability, hormone and cytokine signalling and genes for transport and metabolism of amino acids and lipids. Some genes with large changes in expression have poorly known roles in lactation. For instance, SIM2 was upregulated at lactation initiation and may inhibit proliferation and involution of mammary epithelial cells, while FUT8 was upregulated in Phase 3 of lactation and may support the large increase in milk volume that occurs at this point in the lactation cycle. This pattern of regulation has not previously been reported and suggests that these genes may play a crucial regulatory role in marsupial milk production and are likely to play a related role in other mammals. PMID- 25701951 TI - Recent Advances in Epilepsy Management. AB - One of the most common neurological disorders is epilepsy, which, approximately affecting more than 40 million people worldwide. The situation worsens in the affected patient when the epilepsy becomes intractable, that simply means failure of anti-epileptic drugs (AED) to achieve seizure freedom. It is also associated with an increased prevalence of mental health disorders including anxiety, depression, and suicidal thoughts. The present review is focused on the recent advances being utilized world over for the effective management of epilepsy patients. The review article discusses the efficacy and importance of recent AED drugs in use for management of epilepsy on one hand and on other hand highlights the use of modern advancements like High frequency oscillations, Network analysis, Seizure localization, Epilepsy surgery in curing intractable epilepsy. PMID- 25701952 TI - Neurophysiological and Neuropsychological Correlates of Subconscious Auditory Processing During Anesthesia and Their Implications in Anesthesia Awareness. AB - Like any other unusual state of consciousness, the condition of anesthesia remains a mystery, especially regarding the information processing events of the brain. Evoked potentials are the only known way to understand the neurophysiological events of brain in this condition. Auditory evoked potentials (AEPs) have been used as a measure of the depth of anesthesia during the intra operative process. AEPs have been classically divided, on the basis of their latency, into first, fast, middle, slow, and late components. Auditory evoked potential has been advocated for the assessment of intra-operative awareness (IOA) but has not been considered seriously enough to be universalized. It is because we have not explored enough the impact of auditory perception and auditory information processing on the IOA phenomena as well as on the subsequent psychological impact of IOA on the patient. This limitation is because we have poor understanding of the subconscious auditory processing itself. This perspective is especially important because more of the IOA phenomena exist in the subconscious domain than they do in the conscious domain of explicit recall. Two important forms of these subconscious manifestations of IOA are the implicit recall phenomena and post-operative dreams related to the operation. Here we present a review of the neurophysiological and neuropsychological correlates of auditory processing during anesthesia. We start with a brief description of auditory awareness and the factors affecting it. Further, we proceed to the evaluation of conscious and subconscious information processing by auditory modality and how they interact during and after intra-operative period. Further, we show that both conscious and subconscious auditory processing affect the IOA experience and both have serious psychological implications on the patient subsequently. These effects could be prevented using auditory evoked potential during monitoring of anesthesia, especially the midlatency auditory evoked potentials. To conclude, we propose that the use of Auditory evoked potential should be universal with general anesthesia use in order to prevent the occurrences of distressing outcomes resulting from both conscious and subconscious auditory processing during anesthesia. PMID- 25701953 TI - Long-Term Efficacy of Arthroscopic Debridement on Knee Osteoarthritis in Patients with Kashin-Beck Disease. AB - Kashin-Beck Disease (KBD) is a chronic and degenerative joint disease with decreased health conditions causing major functional limitations and disability. In this study, we investigated the long-term clinical outcomes of arthroscopic debridement for knee osteoarthritis in KBD patients with Kellgren-Lawrence I-III classification. 31 KBD patients underwent arthroscopic debridement and 24 of them were followed up 8 years after the surgery. The Lysholm scores, femorotibial angle (FTA), and joint space angle (JSA) of the knees were assessed and compared preoperatively and postoperatively to evaluate the clinic outcome. Our results showed that the Lysholm scores, but not the FTA or JSA, of these patients were significantly improved 8 years after the therapy, suggesting that arthroscopic surgery has long-term efficacy in KBD patients with Kellgren-Lawrence I-III classification. PMID- 25701954 TI - Dihydroartemisinin-Induced Apoptosis is Associated with Inhibition of Sarco/Endoplasmic Reticulum Calcium ATPase Activity in Colorectal Cancer. AB - Dihydroartemisinin (DHA) is a promising anti-cancer compound capable of inhibiting proliferation and inducing apoptosis of various cancer cells, including colorectal cancer. However, the molecular mechanisms have not been well understood. This study aimed to explore the underlying mechanism of DHA-induced apoptosis in HCT-116 cells. Cell counting kit-8 assay and flow cytometry analysis confirmed that DHA inhibited proliferation, arrested cell cycle at G0/G1 phase, and enhanced apoptosis in HCT-116 cells. Fluo-3/AM-stained flow cytometry assay revealed that the intracellular Ca(2+) concentration of HCT-116 cells was increased significantly after DHA treatment. Meanwhile, the activity of sarco/endoplasmic reticulum calcium ATPase (SERCA) was appeared to be reduced in a dose-dependent manner. We further detected the upregulated expression of CAAT/enhancer binding protein homologous protein (CHOP) in DHA-treated HCT-116 cells. Conversely, silencing CHOP resulted in a decrease of DHA-induced apoptosis. In addition, the expression of Bax in cytoplasm was elevated significantly along with the sharply decline of Bcl-2 expression in DHA-treated HCT-116 cells. Moreover, the distributions of Bid on mitochondria were increased, accompanied by the activation of caspase-3 in the presence of DHA. Overall, our data indicated that DHA triggered endoplasmic reticulum (ER) stress through inhibiting SERCA activity to release intracellular Ca(2+) from ER, the upregulated expression of CHOP activated mitochondrial apoptosis pathway to induce apoptosis of HCT-116 cells. Therefore, our findings provide a theoretical foundation for DHA as a potential candidate in treatment of colorectal cancer. PMID- 25701955 TI - Overexpression of Hiwi Inhibits the Cell Growth of Chronic Myeloid Leukemia K562 Cells and Enhances Their Chemosensitivity to Daunomycin. AB - Chronic myeloid leukemia (CML) is a clonal disorder characterized by excessive accumulation of myeloid cells in the peripheral blood. In the present study, to investigate the role of Hiwi in leukemogenesis, lentivirus-mediated Hiwi overexpression was performed in a CML cell line, K562 cells. Our data revealed that Hiwi protein expression was undetectable in K562 cells, and its overexpression suppressed cell proliferation, induced cell cycle arrest at G0/G1 and G2/M phases, and promoted apoptosis in K562 cells in vitro. Expression of anti-apoptotic protein, Bcl-2, was decreased in cells expressing Hiwi, whereas that of pro-apoptotic proteins, Bax, activated caspase-3, -9, and cleaved poly (ADP-ribose) polymerase were increased. Additionally, Hiwi upregulation enhanced the chemosensitivity of CML cells to daunomycin. Our study illustrates that expression deletion of Hiwi may be involved in the pathogenesis of human CML and suggests a possible role of Hiwi in regulating the cell growth, cell cycle, and apoptosis of CML cells in vitro. PMID- 25701956 TI - Microsatellite instability: an update. AB - Deficient DNA mismatch repair (MMR) results in a strong mutator phenotype known as microsatellite instability (MSI), which is a hallmark of Lynch syndrome associated cancers. MSI is characterized by length alterations within simple repeated sequences that are called microsatellites. Lynch syndrome is primarily caused by mutations in the MMR genes, mainly MLH1 and MSH2, and less frequently in MSH6, and rarely PMS2, and large genomic rearrangements account for 5-20 % of all mutations. Germ line hemiallelic methylations of MLH1 or MSH2 are termed as epimutations and have been identified as causative of Lynch syndrome. Moreover, germ line 3' deletions of EPCAM gene is involved in MSH2 methylation. MSI is also observed in about 15 % of sporadic colorectal cancer (CRC), gastric cancer (GC), and endometrial cancer (EC), and at lower frequencies in other cancers, often in association with hypermethylation of the MLH1 gene. Trimethylation of histone H3 on Lys36 (H3K36 me3) is an epigenetic histone mark that was required for DNA MMR in vivo. Thus, mutations in the H3K36 trimethyltransferase SETD2 have been reported as a potential cause of MSI. Genetic, epigenetic, and transcriptomic differences have been identified between cancers with and without MSI. Recent comprehensive molecular characterizations of CRC, EC, and GC by The Cancer Genome Atlas indicate that MSI+ cancers are distinct biological entities. The BRAF V600E mutation is specifically associated with sporadic MSI+ CRCs with methylated MLH1, but is not associated with Lynch syndrome-related CRCs. Accumulating evidence indicates a role of interactions between MSI and microRNA (miRNA) in the pathogenesis of MSI-positive (MSI+) cancer. As another new mechanism underlying MSI, overexpression of miR-155 or miR-21 has been shown to downregulate the expression of the MMR genes. Gene targets of frameshift mutations caused by MSI are involved in various cellular functions, including DNA repair (MSH3 and MSH6), cell signaling (TGFBR2 and ACVR2A), apoptosis (BAX), epigenetic regulation (HDAC2 and ARID1A), and miRNA processing (TARBP2 and XPO5), and a subset of MSI+ CRCs reportedly shows the mutated miRNA machinery phenotype. Moreover, microsatellite repeats in miRNA genes, such as hsa-miR-1273c, may be novel MSI targets for CRC, and mutations in noncoding regulatory regions of MRE11, BAX (BaxDelta2), and HSP110 (HSP110DeltaE9) may affect the efficiency of chemotherapy. Thus, analyses of MSI and its related molecular alterations in cancers are increasingly relevant in clinical settings, and MSI is a useful screening marker for identifying patients with Lynch syndrome and a prognostic factor for chemotherapeutic interventions. In this review, we summarize recent advances in the pathogenesis of MSI and focus on genome-wide analyses that indicate the potential use of MSI and related alterations as biomarkers and novel therapeutic targets. PMID- 25701957 TI - Ethylmercury and Hg2+ induce the formation of neutrophil extracellular traps (NETs) by human neutrophil granulocytes. AB - Humans are exposed to different mercurial compounds from various sources, most frequently from dental fillings, preservatives in vaccines, or consumption of fish. Among other toxic effects, these substances interact with the immune system. In high doses, mercurials are immunosuppressive. However, lower doses of some mercurials stimulate the immune system, inducing different forms of autoimmunity, autoantibodies, and glomerulonephritis in rodents. Furthermore, some studies suggest a connection between mercury exposure and the occurrence of autoantibodies against nuclear components and granulocyte cytoplasmic proteins in humans. Still, the underlying mechanisms need to be clarified. The present study investigates the formation of neutrophil extracellular traps (NETs) in response to thimerosal and its metabolites ethyl mercury (EtHg), thiosalicylic acid, and mercuric ions (Hg(2+)). Only EtHg and Hg(2+) triggered NETosis. It was independent of PKC, ERK1/2, p38, and zinc signals and not affected by the NADPH oxidase inhibitor DPI. Instead, EtHg and Hg(2+) triggered NADPH oxidase independent production of ROS, which are likely to be involved in mercurial induced NET formation. This finding might help understanding the autoimmune potential of mercurial compounds. Some diseases, to which a connection with mercurials has been shown, such as Wegener's granulomatosis and systemic lupus erythematosus, are characterized by high prevalence of autoantibodies against neutrophil-specific auto-antigens. Externalization in the form of NETs may be a source for exposure to these self-antigens. In genetically susceptible individuals, this could be one step in the series of events leading to autoimmunity. PMID- 25701958 TI - Regarding instantaneous cerebral swelling following severe cranio-cerebral trauma with brain evisceration. PMID- 25701959 TI - Liver disease in the morbidly obese: a review of 1000 consecutive patients undergoing weight loss surgery. AB - BACKGROUND: Liver disease among the morbidly obese is increasingly prevalent, contributing to significant morbidity. Obesity-related liver pathologies including nonalcoholic steatohepatitis (NASH) have become a leading cause for liver transplant. However, risk factors for developing severe liver disease in the morbidly obese remain unknown. The objective of this study was to determine the frequency of abnormal liver pathology and any relationship to patient-related factors. METHODS: One thousand consecutive patients undergoing weight loss surgery were reviewed. All patients had a liver biopsy at the time of surgery. Frequency of benign pathology, steatosis, NASH, and fibrosis on pathologic examination of liver biopsy specimens were recorded. Pathologic findings were compared and analyzed to age and body mass index (BMI) of all patients. RESULTS: All patients in the study population had a BMI>35 kg/m2. Of these patients, 80.2% had liver disease related to obesity on pathology, including 65.9% with steatosis (grade 1-3), and 14.3% with NASH and/or fibrosis. Mean BMI of patients with liver disease was 48.1 compared to a BMI of 47.7 with benign pathology (P=.523). Mean age of patients with and without abnormal pathology was 48.3 and 47.3, respectively (P=.294). CONCLUSION: Liver disease is highly prevalent in the obese, but is not associated with increased age or BMI. Although all morbidly obese patients appear at significant risk for developing severe liver pathology, further risk factors are unknown. PMID- 25701960 TI - Emerging technologies and procedures: results of an online survey and real-time poll. AB - BACKGROUND: Many new techniques and bariatric endoluminal procedures are being developed and used for the treatment of obesity. Clear guidelines or opinions of the new techniques are not readily available. The aim of this study was to gauge the level of interest and opinions of bariatric surgeons regarding these new techniques, using online and real poll surveys. METHODS: The American Society for Metabolic and Bariatric Surgery (ASMBS) Emerging Technologies committee developed a questionnaire that was distributed among the membership and conducted a live poll of attendees at Obesity Week 2013. Opinions of new technologies and techniques by practitioners were assessed. RESULTS: A total of 134 responses to the questionnaire were returned. Most responses (79%) expressed the belief that new bariatric techniques are needed to improve the practice of bariatric and metabolic surgery. The responses describing the effects of new procedures and technology as beneficial were (1) increased interest from patients or referring physicians (94%), (2) expanded indications for intervention (93%), and (3) lower risk intervention (96%). Nearly all respondents (90.2%) identified value in informational guidelines on new technologies and procedures, and most (88.7%) agreed that the ASMBS should coordinate clinical trials or registries to evaluate these therapies. CONCLUSION: Although most bariatric and metabolic surgeons agree that new endoluminal surgical techniques are beneficial, most also are unable to offer the procedures to their patients without more clinical evidence and clear guidelines from the society. PMID- 25701961 TI - A case-matched study of the differences in bone mineral density 1 year after 3 different bariatric procedures. AB - BACKGROUND: Studies have reported decreased bone mineral density (BMD) after laparoscopic sleeve gastrectomy (LSG) and laparoscopic Roux-en-Y gastric bypass (LRYGB). Laparoscopic adjustable gastric banded plication (LAGBP) is a novel procedure resulting in a dual restrictive mechanism of weight loss without altering gastrointestinal anatomy. The objectives of this study were to compare the BMD changes at 1 year after LAGBP, LSG, and LRYGB. METHODS: The sample included 120 patients (40 patients [13 men/27 premenopausal women] each in LAGBP, LSG, and LRYGB groups). The mean preoperative age and body mass index were 30.0+/ 6.5 years and 39.5+/-3.8 kg/m2, respectively. BMD was measured using dual energy X-ray absorptiometry at the lumbar anteroposterior spine and total hip preoperatively and 1 year postoperatively. RESULTS: The mean percentage of excess weight loss was 61.9%+/-16.8%, 77.1%+/-12.3%, and 72.7%+/-17.4% at 1 year after LAGBP, LSG, and LRYGB, respectively. The mean BMD at the lumbar anteroposterior spine remained unchanged in the LSG and LRYGB groups, but significantly increased in the LAGBP group. The mean BMD at the total hip significantly decreased in all groups compared to the preoperative values. However, the mean BMD was significantly higher in the LRYGB than in the LAGBP group. CONCLUSION: Bone loss at the hips was observed in all patients, including those with adequate micronutrient supplementation. LRYGB caused significantly greater bone loss than the other procedures. PMID- 25701963 TI - Liquid chromatography tandem mass spectrometry quantitation of intracellular concentrations of ganciclovir and its phosphorylated forms. AB - Ganciclovir (GCV) is prescribed for cytomegalovirus infection which is a major issue in immunodepressed patients. It is however characterized by hematological toxicity. A better understanding of GCV concentration-effects relationships implies the measurement of intracellular forms. The objective of this study was to develop a method to measure GCV and its derivatives in cells. A four-stage procedure was developed with the following strategy: (1) to separate into different fractions the different intracellular forms of GCV (GCV itself and its phosphorylated forms) by solid-phase extraction (SPE) from blood cells, (2) to dephosphorylate the different phosphorylated forms into GCV, (3) to perform a second SPE to desalt samples and concentrate GCV, and (4) to measure GCV concentrations in the different extracts using a triple-quadrupole, linear ion trap mass spectrometer. Finally, the procedure was tested in 17 patients receiving GCV. From lysed cells, the different forms of GCV were fractionated, the phosphorylated forms were eluted with different KCl solutions, and the obtained fractions were treated with acid phosphatase to transform the phosphorylated metabolites back into GCV. The method was validated from 5 to 500 MUg L(-1) with a limit of detection of 1 MUg L(-1). The whole procedure was validated according to the US Food and Drug Administration guidelines and successfully applied in 17 patients receiving GCV. The method liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) allowing the measurement of GCV and its phosphorylated forms in blood cells was developed and can be used in developing clinical studies to explore the role of these biomarkers in the event of toxicity. PMID- 25701964 TI - Are lower levels of LDL-cholesterol really better? Looking at the results of IMPROVE-IT: opinions of three experts - I. PMID- 25701965 TI - Are lower levels of LDL-cholesterol really better? Looking at the results of IMPROVE-IT: opinions of three experts - II. PMID- 25701966 TI - Are lower levels of LDL-cholesterol really better? Looking at the results of IMPROVE-IT: opinions of three experts - III. PMID- 25701967 TI - Translation and validation of the Greek "Minnesota Living with Heart Failure" questionnaire. AB - INTRODUCTION: The Minnesota Living with Heart Failure Questionnaire (MLHFQ) is an important measurement instrument for assessing the health-related quality of life (HRQOL) among heart failure patients. The purpose of this study was to translate and validate the MLHFQ in the Greek language. METHODS: Three hundred forty-four consecutive adult patients from three General Hospitals, two in Athens and one in another part of the country, who were diagnosed with chronic heart failure, and 347 healthy controls were enrolled in the study from March 2009 to March 2010. The questionnaire instrument was translated from English, back-translated, and reviewed by a committee of experts. The psychometric measurements that were performed included reliability coefficients and Explanatory Factor Analysis (EFA), using a Varimax rotation and Principal Components Method. In a further step, confirmatory analysis (CFA)--known as structural equation modeling--of the principal components was conducted. RESULTS: The internal consistency of the Greek MLHFQ version was found to be 0.97, using Cronbach's alpha coefficient. An exploratory factor analysis identified two domains that accounted for 72.5% of the variance of MLHFQ items; the area under the ROC curve was calculated at 0.942 and the logistic estimate for the threshold score of 24.50 provided the model with 95.1% sensitivity and 99.8% specificity. Additionally, the CFA demonstrated that the two-factor model offered a very good fit to our data. CONCLUSIONS: Our data indicate that the Greek MLHFQ is a reliable and valid tool for assessing HRQOL among patients with heart failure. Health professionals can use it in their clinical practice to improve their evaluation of these patients. PMID- 25701968 TI - Dabigatran etexilate as second-line therapy in patients with a left ventricular assist device. AB - INTRODUCTION: Administration of anticoagulation is mandatory in patients with left ventricular assist devices (LVADs). Vitamin K antagonists require regular monitoring and dosage adjustment. Dabigatran administered in a standard dose twice daily is more convenient and achieves a stable anticoagulant effect, but its effectiveness and safety in patients with LVADs has not been investigated. The objective of the present study was to evaluate whether dabigatran can be used safely as a second-line anticoagulation option in patients with a HeartMate II (HMII) LVAD. METHODS: The study population consisted of 7 consecutive patients with end-stage heart failure who underwent HMII implantation and sequentially received acenocoumarol and dabigatran. Occurrence of stroke, systematic embolism, device thrombosis and major or life-threatening bleeding were included in the analysis. An acute decrease in plasma hemoglobin >2 g/dL or a need for transfusion of at least 2 units of packed red blood cells (PRBC) was defined as major bleeding, while an acute decrease in plasma hemoglobin >5 g/dL, fatal, symptomatic intracranial bleed, need for transfusion of at least 4 units PRBC, or association with hypotension requiring the use of intravenous inotropic agents or surgical intervention was defined as life-threatening bleeding. RESULTS: The duration of follow up was 1564 +/- 292 days. Patients received acenocoumarol for 855 +/- 246 days, followed by dabigatran for 708 +/- 368 days. The rates of thromboembolic events were similar under dabigatran and acenocoumarol treatment: strokes, 0.094 vs. 0 /patient-year, p=0.36; systemic embolism, no event in either group; and device thrombosis, 0.053 vs. 0.258 events/patient-year, p=0.19, respectively. Compared to an adjusted acenocoumarol dose, the standard dabigatran dose resulted in similar rates of life-threatening bleeding, but significantly lower rates of major bleeding (0.18 vs. 0.27 bleeds/patient-years, p=0.76, and 0.047 vs. 0.547, p<0.001, for dabigatran and acenocoumarol, respectively). CONCLUSIONS: The safe and effective use of dabigatran as a second-line anticoagulation therapy in patients with HMII seems feasible. However, these data must be confirmed in a randomized study. PMID- 25701969 TI - Factors associated with depression and anxiety of hospitalized patients with heart failure. AB - INTRODUCTION: Heart failure (HF) is a chronic disease associated with significant prevalence, mortality, and health care expenditure. The aim of the present study was to explore the factors associated with anxiety and depression experienced by patients hospitalized with HF. METHODS: We evaluated 190 hospitalized HF patients in four public hospitals. The data were collected using a specific questionnaire, which, apart from demographic and clinical variables, included the Hospital Anxiety and Depression Scale (HADS). RESULTS: In the total sample, 24.7% and 32.6% of patients were found to have moderate or high levels of anxiety, respectively. Simple multinomial logistic regression showed that no characteristic was significantly associated with anxiety. It also appeared that 17.4% of patients had minor and 24.2% major depression. Among the factors examined, longer disease duration was associated with a higher probability of being depressed (p=0.041). Moreover, single/divorced and widowed patients were more likely to have major depression compared to married patients (35.6% vs. 19.2%, p=0.046). Simple multinomial logistic regression revealed that married patients were 59% less likely to have major depression compared to their unmarried counterparts (OR: 0.41). Moreover, patients with short (<1 year) and moderate (2-5 years) disease duration were 69% (OR: 0.31) and 61% (OR: 0.39) less likely to have major depression compared to those with a long disease duration. Multiple multinomial logistic regression showed that only the disease duration remained statistically significantly associated with depression after controlling for the rest of factors found to be significant at a univariate level. CONCLUSIONS: Nurses and physicians must take measures for the identification, assessment and management of anxiety and depression in this clinical population. PMID- 25701970 TI - Bosentan for patients with echocardiographic evidence of pulmonary hypertension due to long-standing rheumatic mitral stenosis. AB - INTRODUCTION: Vasoconstrictive endothelin signaling is not limited to idiopathic pulmonary arterial hypertension, but has also been implicated in pulmonary hypertension due to valvular heart disease. The efficacy and safety of endothelin receptor antagonists in these patients is unknown. We investigated the effects of bosentan in patients with transthoracic echocardiographic (TTE) evidence of pulmonary hypertension due to mitral stenosis associated with rheumatic fever. METHODS: This was a prospective, single-center, open-label, uncontrolled study of bosentan in outpatients with uncorrected mitral stenosis due to rheumatic fever. The primary endpoint was exercise capacity at six months, as determined by six minute walking distance (6MWD) and maximal oxygen uptake (VO2max). Secondary endpoints were the BORG dyspnea index (BDI), echocardiographic left ventricular ejection fraction (LVEF) and pulmonary arterial pressure (PAP), serum pro-brain natriuretic peptide (proBNP), and adverse events at six months. RESULTS: Ten patients (eight females; mean age 75 years) were enrolled. Bosentan was well tolerated by nine, whereas one withdrew from treatment. By intention-to-treat analysis, bosentan resulted in a marked increase in 6MWD (+32 m, p=0.015), but a significant reduction in VO2max (-0.45 mL/min/kg, p=0.011). Peak PAP did not change significantly, but mean PAP dropped by 16% (p=0.03) and LVEF increased by 6.5% (p=0.003). Profound reductions were observed in BDI and serum proBNP (-67% and -37%, p=0.002 and p=0.011, respectively). Adverse events included minor reductions in body mass and hematocrit. CONCLUSION: The results of this pilot study suggest that endothelin receptor antagonism improves the functional status of patients with TTE evidence of pulmonary hypertension due to valvular heart disease. Randomized controlled trials are needed to confirm the results. PMID- 25701971 TI - Relationship of coronary artery disease with pericardial and periaortic adipose tissue and their volume detected by MSCT. AB - INTRODUCTION: The relationship of pericardial and periaortic adipose tissue with coronary artery disease (CAD) and the significance of this relationship were investigated. METHODS: The present study included 323 subjects, with or without cardiac symptoms, who underwent multislice computed tomography coronary angiography between May 2009 and January 2013. Patients were divided into two groups according to the mean values of pericardial adipose tissue volume (PCFV) and periaortic adipose tissue volume (PAFV). In the grouping based on PCFV, subjects with PCFV<157.7 cm3 comprised Group 1, and those with PCFV>=157.7 cm3 comprised Group 2. According to PAFV values, Group 1 consisted of subjects with PAFV<24.3 cm3, and Group 2 subjects with PAFV>=24.3 cm3. The relationship of CAD with each of PCFV and PAFV was investigated. RESULTS: Based on PCFV measurements, there were 79 (43.6%) and 113 (79.6%) patients with CAD in Groups 1 and 2, respectively. Based on PAFV measurements, Group 1 comprised 90 (48.1%) and Group 2 comprised 102 (75%) CAD patients. CONCLUSIONS: In both groupings, the prevalence of CAD was significantly higher in Group 2 versus Group 1 (p<0.01 for both). There was a significant relationship between CAD and PAFV (p<0.05), but the relation between CAD and PCFV was more significant (p<0.01). PMID- 25701972 TI - Transvenous extraction of cardiac rhythm device leads: a report of the experience from a single referral centre in Greece. AB - INTRODUCTION: As rates of implanted cardiac electronic devices continue to rise, lead extraction procedures are crucial for the management of complications. The optimal method for such procedures has been constantly debated. We sought to review our experience of lead extraction using a conventional technique. METHODS: This was a retrospective study of lead extraction procedures in a major referral centre in Greece. Leads were extracted in a series of 66 consecutive patients (69% men, age range 53-90 years) who visited our centre between August 2008 and June 2012. The extraction procedure was performed in the catheterization lab with a widely used system composed of a locking stylet and sheath. RESULTS: A total of 120 leads were extracted (51 atrial, 69 ventricular) including 19 defibrillator leads and 9 coronary sinus leads. The most frequent indication for lead extraction was infective endocarditis (28 patients, 42%), followed by generator pocket infection (22 patients, 33%), and lead malfunction (16 patients, 24%). Extraction was achieved through the venous entry-site approach in all procedures. The leads were completely extracted in 65 patients (98.5%). Only one complication was recorded: perforation of the right atrium in one patient (1.5%), who eventually underwent emergency cardiac surgery with a good outcome. CONCLUSIONS: Our data confirm that a conventional mechanical technique is highly effective for successful extraction of all types of implanted cardiac electronic device leads and is associated with very limited complications. PMID- 25701973 TI - Short-term cardiometabolic risk reduction after bariatric surgery. AB - INTRODUCTION: Clinically severe obesity, defined as a body mass index (BMI) 40 kg/m2, increases cardiovascular risk and results in elevated mortality. The objective of this study was to examine the short-term health benefits after bariatric surgery. Using commonly recognized scoring systems, we assessed the shortterm reduction of calculated cardiometabolic risk following bariatric surgery. METHODS: Short-term cardiovascular risk reduction was assessed prospectively in 50 consecutive, morbidly obese patients (45 women, 5 men, age 39.3 +/- 8.97 years, BMI 50.67 +/- 12.25 kg/m2) using the following scales: the Finnish Diabetes Risk Score, Reynolds Risk Score, Italian "Progetto Cuore" score, SCORE. The follow-up data at baseline and six months were recorded in all studied patients. Patients who did not meet the inclusion criteria of particular score systems were not included in the analysis. There were no revisions, surgical failures or deaths in the study group. RESULTS: The average weight loss six months after bariatric surgery was 35.8 +/- 10.59 kg (mean BMI 36.54 +/- 5.92 kg/m2). The most interesting result was that the median value of a 10-year risk of developing type 2 diabetes according to the FINDRISC score was 15 (IQR 15-15) at baseline vs. 13 (IQR 13-13) following surgery, p<0.001. We observed a reduction of 2 points in the majority of patients. In addition, in 29 patients it was possible to calculate the 10-year probability of developing the first major cardiovascular event using the Italian "Progetto Cuore" score; the median score decreased from 2.0 to 0.8 (p<0.001). CONCLUSIONS: Weight loss at 6 months, as a result of bariatric surgery in this group of clinically severely obese patients at a very high risk, was especially effective as concerns the reduction of the calculated risk of diabetes, cardiovascular diseases, and related mortality. PMID- 25701974 TI - Post-infarction ventricular septal defect: risk factors and early outcomes. AB - INTRODUCTION: Rupture of the ventricular septum complicates acute myocardial infarction in 0.2% of cases in the thrombolytic era. Ventricular septal defect (VSD) has a mortality of 90-95% in medically managed and 19-60% in surgically treated patients. METHODS: A retrospective analysis was performed of 41 patients, 26 females (63.4%) and 15 males (36.6%), average age 67.5 +/- 15 years, with post infarction VSD who were treated in the VUL SK intensive cardiology unit between 1991 and 2007. RESULTS: Thirty-seven patients had hypertension (90.2%); anterior wall acute myocardial infarction (AMI) was found in 27 patients (68%). VSD was more frequent in women than in men (p=0.043). In 36 patients (87%) treatment was started 24 hours or later after the development of AMI symptoms. In 34 patients (83%) the rupture occurred during the first episode of AMI and in the majority of these (19 patients, 46.3%), preoperative coronary angiography demonstrated disease of only one coronary artery. During the first 10 days after the onset of AMI, 5 patients (12.2%) were treated surgically but did not survive the operation; 33 patients (80.5%) underwent operation 3-4 weeks after the onset of AMI and all survived. CONCLUSIONS: Female sex, advanced age, arterial hypertension, anterior wall AMI, absence of previous AMI, and late arrival at hospital are associated with a higher risk of mortality from acute VSD. The most important factor that determines operative mortality and intra-hospital survival is the time from the onset of AMI to operation. PMID- 25701975 TI - Noninvasive cardiovascular imaging as a guide to cardiac resynchronization therapy. PMID- 25701976 TI - Fluid dynamics of ventricular filling in heart failure: overlooked problems of RV/LV chamber dilatation. PMID- 25701977 TI - Pulmonary embolism complicated with left-sided thrombus entrapped through patent foramen ovale. PMID- 25701978 TI - Aneurysm of the basal interventricular septum secondary to turbulent flow jet from a mitral prosthetic valve. PMID- 25701979 TI - Iatrogenic left main coronary artery dissection mimicking complete proximal occlusion of the left main branches. PMID- 25701980 TI - Attitudes of healthcare professionals involved in cardiology practice towards key points of contemporary guidelines on resuscitation. AB - Hellenic J Cardiol. 2014; 55: 378-385. At the request of the authors, the name of the second author of this Original Research article has been changed from Athanasios Patialakas to Athanasios Patialiakas. PMID- 25701981 TI - The European Society of Cardiology and the latest guidelines for "seafarers": part II. PMID- 25701982 TI - The evolving landscape of interventional cardiology: "because we should". PMID- 25701983 TI - Evaluating trends in global dietary patterns. PMID- 25701984 TI - Value of additional chemotherapy for malaria in pregnancy. PMID- 25701985 TI - Trafficking, migration, and health: complexities and future directions. PMID- 25701986 TI - Effectiveness of oral cholera vaccine in Haiti. PMID- 25701987 TI - Estimating trends in life expectancy in HIV-positive individuals. PMID- 25701988 TI - Hydroxyurea for sickle-cell anaemia in Africa: mind the gap. PMID- 25701989 TI - Attitude and the 21st century doctor. PMID- 25701990 TI - Radical changes in medical education needed globally. PMID- 25701991 TI - Dietary quality among men and women in 187 countries in 1990 and 2010: a systematic assessment. AB - BACKGROUND: Healthy dietary patterns are a global priority to reduce non communicable diseases. Yet neither worldwide patterns of diets nor their trends with time are well established. We aimed to characterise global changes (or trends) in dietary patterns nationally and regionally and to assess heterogeneity by age, sex, national income, and type of dietary pattern. METHODS: In this systematic assessment, we evaluated global consumption of key dietary items (foods and nutrients) by region, nation, age, and sex in 1990 and 2010. Consumption data were evaluated from 325 surveys (71.7% nationally representative) covering 88.7% of the global adult population. Two types of dietary pattern were assessed: one reflecting greater consumption of ten healthy dietary items and the other based on lesser consumption of seven unhealthy dietary items. The mean intakes of each dietary factor were divided into quintiles, and each quintile was assigned an ordinal score, with higher scores being equivalent to healthier diets (range 0-100). The dietary patterns were assessed by hierarchical linear regression including country, age, sex, national income, and time as exploratory variables. FINDINGS: From 1990 to 2010, diets based on healthy items improved globally (by 2.2 points, 95% uncertainty interval (UI) 0.9 to 3.5), whereas diets based on unhealthy items worsened (-2.5, -3.3 to 1.7). In 2010, the global mean scores were 44.0 (SD 10.5) for the healthy pattern and 52.1 (18.6) for the unhealthy pattern, with weak intercorrelation (r=-0.08) between countries. On average, better diets were seen in older adults compared with younger adults, and in women compared with men (p<0.0001 each). Compared with low-income nations, high-income nations had better diets based on healthy items (+2.5 points, 95% UI 0.3 to 4.1), but substantially poorer diets based on unhealthy items (-33.0, -37.8 to -28.3). Diets and their trends were very heterogeneous across the world regions. For example, both types of dietary patterns improved in high-income countries, but worsened in some low-income countries in Africa and Asia. Middle-income countries showed the largest improvement in dietary patterns based on healthy items, but the largest deterioration in dietary patterns based on unhealthy items. INTERPRETATION: Consumption of healthy items improved, while consumption of unhealthy items worsened across the world, with heterogeneity across regions and countries. These global data provide the best estimates to date of nutrition transitions across the world and inform policies and priorities for reducing the health and economic burdens of poor diet quality. FUNDING: The Bill & Melinda Gates Foundation and Medical Research Council. PMID- 25701992 TI - Cost-effectiveness of two versus three or more doses of intermittent preventive treatment for malaria during pregnancy in sub-Saharan Africa: a modelling study of meta-analysis and cost data. AB - BACKGROUND: In 2012, WHO changed its recommendation for intermittent preventive treatment of malaria during pregnancy (IPTp) from two doses to monthly doses of sulfadoxine-pyrimethamine during the second and third trimesters, but noted the importance of a cost-effectiveness analysis to lend support to the decision of policy makers. We therefore estimated the incremental cost-effectiveness of IPTp with three or more (IPTp-SP3+) versus two doses of sulfadoxine-pyrimethamine (IPTp-SP2). METHODS: For this analysis, we used data from a 2013 meta-analysis of seven studies in sub-Saharan Africa. We developed a decision tree model with a lifetime horizon. We analysed the base case from a societal perspective. We did deterministic and probabilistic sensitivity analyses with appropriate parameter ranges and distributions for settings with low, moderate, and high background risk of low birthweight, and did a separate analysis for HIV-negative women. Parameters in the model were obtained for all countries included in the original meta-analysis. We did simulations in hypothetical cohorts of 1000 pregnant women receiving either IPTp-SP3+ or IPTp-SP2. We calculated disability-adjusted life years (DALYs) for low birthweight, severe to moderate anaemia, and clinical malaria. We calculated cost estimates from data obtained in observational studies, exit surveys, and from public procurement databases. We give financial and economic costs in constant 2012 US$. The main outcome measure was the incremental cost per DALY averted. FINDINGS: The delivery of IPTp-SP3+ to 1000 pregnant women averted 113.4 DALYs at an incremental cost of $825.67 producing an incremental cost-effectiveness ratio (ICER) of $7.28 per DALY averted. The results remained robust in the deterministic sensitivity analysis. In the probabilistic sensitivity analyses, the ICER was $7.7 per DALY averted for moderate risk of low birthweight, $19.4 per DALY averted for low risk, and $4.0 per DALY averted for high risk. The ICER for HIV-negative women was $6.2 per DALY averted. INTERPRETATION: Our findings lend strong support to the WHO guidelines that recommend a monthly dose of IPTp-SP from the second trimester onwards. FUNDING: Malaria in Pregnancy Consortium and the Bill & Melinda Gates Foundation. PMID- 25701993 TI - Health of men, women, and children in post-trafficking services in Cambodia, Thailand, and Vietnam: an observational cross-sectional study. AB - BACKGROUND: Trafficking is a crime of global proportions involving extreme forms of exploitation and abuse. Yet little research has been done of the health risks and morbidity patterns for men, women, and children trafficked for various forms of forced labour. METHODS: We carried out face-to-face interviews with a consecutive sample of individuals entering 15 post-trafficking services in Cambodia, Thailand, and Vietnam. We asked participants about living and working conditions, experience of violence, and health outcomes. We measured symptoms of anxiety and depression with the Hopkins Symptoms Checklist and post-traumatic stress disorder with the Harvard Trauma Questionnaire, and used adjusted logistic regression models to estimate the effect of trafficking on these mental health outcomes, controlling for age, sector of exploitation, and time in trafficking. FINDINGS: We interviewed 1102 people, of whom 1015 reached work destinations. Participants worked in various sectors including sex work (329 [32%]), fishing (275 [27%]), and factories (136 [13%]). 481 (48%) of 1015 experienced physical violence, sexual violence, or both, with 198 (35%) of 566 women and girls reporting sexual violence. 478 (47%) of 1015 participants were threatened and 198 (20%) were locked in a room. 685 (70%) of 985 who had data available worked 7 days per week and 296 (30%) of 989 worked at least 11 hours per day. 222 (22%) of 983 had a serious injury at work. 61.2% (95% CI 58.2-64.2) of participants reported symptom of depression, 42.8% (39.8-45.9) reported symptoms of anxiety, and 38.9% (36.0-42.0) reported symptoms of post-traumatic stress disorder. 5.2% (4.0-6.8) had attempted suicide in the past month. Participants who experienced extremely excessive overtime at work, restricted freedom, bad living conditions, threats, or severe violence were more likely to report symptoms of depression, anxiety, and post-traumatic stress disorder. INTERPRETATION: This is the first health study of a large and diverse sample of men, women, and child survivors of trafficking for various forms of exploitation. Violence and unsafe working conditions were common and psychological morbidity was associated with severity of abuse. Survivors of trafficking need access to health care, especially mental health care. FUNDING: Anesvad Foundation and International Organization for Migration International Development Fund. PMID- 25701994 TI - Effectiveness of reactive oral cholera vaccination in rural Haiti: a case-control study and bias-indicator analysis. AB - BACKGROUND: Between April and June, 2012, a reactive cholera vaccination campaign was done in Haiti with an oral inactivated bivalent whole-cell vaccine. We aimed to assess the effectiveness of the vaccine in a case-control study and to assess the likelihood of bias in that study in a bias-indicator study. METHODS: Residents of Bocozel or Grand Saline who were eligible for the vaccination campaign (ie, age >=12 months, not pregnant, and living in the region at the time of the vaccine campaign) were included. In the primary case-control study, cases had acute watery diarrhoea, sought treatment at one of three participating cholera treatment units, and had a stool sample positive for cholera by culture. For each case, four control individuals who did not seek treatment for acute watery diarrhoea were matched by location of residence, enrolment time (within 2 weeks of the case), and age (1-4 years, 5-15 years, and >15 years). Cases in the bias-indicator study were individuals with acute watery diarrhoea with a negative stool sample for cholera. Controls were selected in the same manner as in the primary case-control study. Trained staff used standard laboratory procedures to do rapid tests and stool cultures from study cases. Participants were interviewed to collect data on sociodemographic characteristics, risk factors for cholera, and self-reported vaccination. Data were analysed by conditional logistic regression, adjusting for matching factors. FINDINGS: From Oct 24, 2012, to March 9, 2014, 114 eligible individuals presented with acute watery diarrhoea and were enrolled, 25 of whom were subsequently excluded. 47 participants were analysed as cases in the vaccine effectiveness case-control study and 42 as cases in the bias indicator study. 33 (70%) of 47 cholera cases self-reported vaccination versus 167 (89%) of 188 controls (vaccine effectiveness 63%, 95% CI 8-85). 27 (57%) of 47 cases had certified vaccination versus 147 (78%) of 188 controls (vaccine effectiveness 58%, 13-80). Neither self-reported nor verified vaccination was significantly associated with non-cholera diarrhoea (vaccine effectiveness 18%, 95% CI -208 to 78 by self-report and -21%, -238 to 57 by verified vaccination). INTERPRETATION: Bivalent whole-cell oral cholera vaccine effectively protected against cholera in Haiti from 4 months to 24 months after vaccination. Vaccination is an important component of efforts to control cholera epidemics. FUNDING: National Institutes of Health, Delivering Oral Vaccines Effectively project, and Department of Global Health and Social Medicine at Harvard Medical School. PMID- 25701995 TI - Life expectancy among HIV-positive patients in Rwanda: a retrospective observational cohort study. AB - BACKGROUND: Rwanda has achieved substantial progress in scaling up of antiretroviral therapy. We aimed to assess the effect of increased access to antiretroviral therapy on life expectancy among HIV-positive patients in two distinct periods of lower and higher antiretroviral therapy coverage (1997-2007 and 2008-11). METHODS: In a retrospective observational cohort study, we collected clinical and demographic data for all HIV-positive patients enrolled in care at 110 health facilities across all five provinces of Rwanda. We included patients aged 15 years or older with a known enrolment date between 1997 and 2014. We constructed abridged life tables from age-specific mortality rates and life expectancy stratified by sex, CD4 cell count, and WHO disease stage at enrolment in care and initiation of antiretroviral therapy. FINDINGS: We included 72,061 patients in this study, contributing 213,983 person-years of follow-up. The crude mortality rate was 33.4 deaths per 1000 person-years (95% CI 32.7 34.2). Life expectancy for the overall cohort was 25.6 additional years (95% CI 25.1-26.1) at 20 years of age and 23.3 additional years (95% CI 22.9-23.7) at 35 years of age. Life expectancy at 20 years of age in the period of 1997-2007 was 20.4 additional years (95% CI 19.5-21.3); for the period of 2008-11, life expectancy had increased to 25.6 additional years (95% CI 24.8-26.4). Individuals enrolling in care with CD4 cell counts of 500 cells per MUL or more, and with WHO disease stage I, had the highest life expectancies. INTERPRETATION: This study adds to the growing body of evidence showing the benefit to HIV-positive patients of early enrolment in care and initiation of antiretroviral therapy. FUNDING: Bill & Melinda Gates Foundation. PMID- 25701996 TI - Real-space quadrature: a convenient, efficient representation for multipole expansions. AB - Multipoles are central to the theory and modeling of polarizable and nonpolarizable molecular electrostatics. This has made a representation in terms of point charges a highly sought after goal, since rotation of multipoles is a bottleneck in molecular dynamics implementations. All known point charge representations are orders of magnitude less efficient than spherical harmonics due to either using too many fixed charge locations or due to nonlinear fitting of fewer charge locations. We present the first complete solution to this problem completely replacing spherical harmonic basis functions by a dramatically simpler set of weights associated to fixed, discrete points on a sphere. This representation is shown to be space optimal. It reduces the spherical harmonic decomposition of Poisson's operator to pairwise summations over the point set. As a corollary, we also shows exact quadrature-based formulas for contraction over trace-free supersymmetric 3D tensors. Moreover, multiplication of spherical harmonic basis functions translates to a direct product in this representation. PMID- 25701997 TI - Annealed importance sampling with constant cooling rate. AB - Annealed importance sampling is a simulation method devised by Neal [Stat. Comput. 11, 125 (2001)] to assign weights to configurations generated by simulated annealing trajectories. In particular, the equilibrium average of a generic physical quantity can be computed by a weighted average exploiting weights and estimates of this quantity associated to the final configurations of the annealed trajectories. Here, we review annealed importance sampling from the perspective of nonequilibrium path-ensemble averages [G. E. Crooks, Phys. Rev. E 61, 2361 (2000)]. The equivalence of Neal's and Crooks' treatments highlights the generality of the method, which goes beyond the mere thermal-based protocols. Furthermore, we show that a temperature schedule based on a constant cooling rate outperforms stepwise cooling schedules and that, for a given elapsed computer time, performances of annealed importance sampling are, in general, improved by increasing the number of intermediate temperatures. PMID- 25701998 TI - Improving the efficiency of branch-and-bound complete-search NMR assignment using the symmetry of molecules and spectra. AB - Nuclear magnetic resonance (NMR) assignment of small molecules is presented as a typical example of a combinatorial optimization problem in chemical physics. Three strategies that help improve the efficiency of solution search by the branch and bound method are presented: 1. reduction of the size of the solution space by resort to a condensed structure formula, wherein symmetric nuclei are grouped together; 2. partitioning of the solution space based on symmetry, that becomes the basis for an efficient branching procedure; and 3. a criterion of selection of input restrictions that leads to increased gaps between branches and thus faster pruning of non-viable solutions. Although the examples chosen to illustrate this work focus on small-molecule NMR assignment, the results are generic and might help solving other combinatorial optimization problems. PMID- 25701999 TI - Semiclassical quantization of nonadiabatic systems with hopping periodic orbits. AB - We present a semiclassical quantization condition, i.e., quantum-classical correspondence, for steady states of nonadiabatic systems consisting of fast and slow degrees of freedom (DOFs) by extending Gutzwiller's trace formula to a nonadiabatic form. The quantum-classical correspondence indicates that a set of primitive hopping periodic orbits, which are invariant under time evolution in the phase space of the slow DOF, should be quantized. The semiclassical quantization is then applied to a simple nonadiabatic model and accurately reproduces exact quantum energy levels. In addition to the semiclassical quantization condition, we also discuss chaotic dynamics involved in the classical limit of nonadiabatic dynamics. PMID- 25702000 TI - Correlation consistent basis sets for actinides. I. The Th and U atoms. AB - New correlation consistent basis sets based on both pseudopotential (PP) and all electron Douglas-Kroll-Hess (DKH) Hamiltonians have been developed from double- to quadruple-zeta quality for the actinide atoms thorium and uranium. Sets for valence electron correlation (5f6s6p6d), cc - pV nZ - PP and cc - pV nZ - DK3, as well as outer-core correlation (valence + 5s5p5d), cc - pwCV nZ - PP and cc - pwCV nZ - DK3, are reported (n = D, T, Q). The -PP sets are constructed in conjunction with small-core, 60-electron PPs, while the -DK3 sets utilized the 3rd-order Douglas-Kroll-Hess scalar relativistic Hamiltonian. Both series of basis sets show systematic convergence towards the complete basis set limit, both at the Hartree-Fock and correlated levels of theory, making them amenable to standard basis set extrapolation techniques. To assess the utility of the new basis sets, extensive coupled cluster composite thermochemistry calculations of ThFn (n = 2 - 4), ThO2, and UFn (n = 4 - 6) have been carried out. After accurately accounting for valence and outer-core correlation, spin-orbit coupling, and even Lamb shift effects, the final 298 K atomization enthalpies of ThF4, ThF3, ThF2, and ThO2 are all within their experimental uncertainties. Bond dissociation energies of ThF4 and ThF3, as well as UF6 and UF5, were similarly accurate. The derived enthalpies of formation for these species also showed a very satisfactory agreement with experiment, demonstrating that the new basis sets allow for the use of accurate composite schemes just as in molecular systems composed only of lighter atoms. The differences between the PP and DK3 approaches were found to increase with the change in formal oxidation state on the actinide atom, approaching 5-6 kcal/mol for the atomization enthalpies of ThF4 and ThO2. The DKH3 atomization energy of ThO2 was calculated to be smaller than the DKH2 value by ~1 kcal/mol. PMID- 25702001 TI - Perturbations in vibrational diatomic spectra: factorization of the molecular wave function. AB - The coupling between two electronic states of a diatomic molecule may lead to an erratic behaviour of the associated vibrational energies. An example is the homogeneous coupling between the valence b' state and the Rydberg c' state of the N2 molecule, both of symmetry (1)Sigmau (+). The standard treatment of such a situation is to write the wave function as a sum of two Born-Oppenheimer products. It has recently been argued [L. S. Cederbaum, J. Chem. Phys. 138, 224110 (2013); N. I. Gidopoulos and E. K. U. Gross, Philos. Trans. R. Soc., A 372, 20130059 (2014)] that even in such a case the wave function should be representable as a single product, with an electronic factor depending parametrically on nuclear positions and a nuclear factor. We setup such a representation in the case of the perturbations in the N2 molecule. PMID- 25702002 TI - Basis convergence of range-separated density-functional theory. AB - Range-separated density-functional theory (DFT) is an alternative approach to Kohn-Sham density-functional theory. The strategy of range-separated density functional theory consists in separating the Coulomb electron-electron interaction into long-range and short-range components and treating the long range part by an explicit many-body wave-function method and the short-range part by a density-functional approximation. Among the advantages of using many-body methods for the long-range part of the electron-electron interaction is that they are much less sensitive to the one-electron atomic basis compared to the case of the standard Coulomb interaction. Here, we provide a detailed study of the basis convergence of range-separated density-functional theory. We study the convergence of the partial-wave expansion of the long-range wave function near the electron-electron coalescence. We show that the rate of convergence is exponential with respect to the maximal angular momentum L for the long-range wave function, whereas it is polynomial for the case of the Coulomb interaction. We also study the convergence of the long-range second-order Moller-Plesset correlation energy of four systems (He, Ne, N2, and H2O) with cardinal number X of the Dunning basis sets cc - p(C)V XZ and find that the error in the correlation energy is best fitted by an exponential in X. This leads us to propose a three-point complete-basis-set extrapolation scheme for range-separated density-functional theory based on an exponential formula. PMID- 25702003 TI - Chemical reactions induced by oscillating external fields in weak thermal environments. AB - Chemical reaction rates must increasingly be determined in systems that evolve under the control of external stimuli. In these systems, when a reactant population is induced to cross an energy barrier through forcing from a temporally varying external field, the transition state that the reaction must pass through during the transformation from reactant to product is no longer a fixed geometric structure, but is instead time-dependent. For a periodically forced model reaction, we develop a recrossing-free dividing surface that is attached to a transition state trajectory [T. Bartsch, R. Hernandez, and T. Uzer, Phys. Rev. Lett. 95, 058301 (2005)]. We have previously shown that for single mode sinusoidal driving, the stability of the time-varying transition state directly determines the reaction rate [G. T. Craven, T. Bartsch, and R. Hernandez, J. Chem. Phys. 141, 041106 (2014)]. Here, we extend our previous work to the case of multi-mode driving waveforms. Excellent agreement is observed between the rates predicted by stability analysis and rates obtained through numerical calculation of the reactive flux. We also show that the optimal dividing surface and the resulting reaction rate for a reactive system driven by weak thermal noise can be approximated well using the transition state geometry of the underlying deterministic system. This agreement persists as long as the thermal driving strength is less than the order of that of the periodic driving. The power of this result is its simplicity. The surprising accuracy of the time dependent noise-free geometry for obtaining transition state theory rates in chemical reactions driven by periodic fields reveals the dynamics without requiring the cost of brute-force calculations. PMID- 25702004 TI - Theoretical study of a screened Hartree-Fock exchange potential using position dependent atomic dielectric constants. AB - Dielectric-dependent screened Hartree-Fock (HF) exchange potential and Slater formula have been reported, where the ratio of the HF exchange term mixed into potentials is inversely proportional to the dielectric constant of the target semiconductor. This study introduces a position-dependent dielectric constant method in which the dielectric constant is partitioned between the atoms in a semiconductor. These partitioned values differ depending on the electrostatic environment surrounding the atoms and lead to position-dependent atomic dielectric constants. These atomic dielectric constants provide atomic orbital based matrix elements for the screened exchange potentials. Energy band structures of several semiconductors and insulators are also presented to validate this approach. PMID- 25702005 TI - A localized momentum constraint for non-equilibrium molecular dynamics simulations. AB - A method which controls momentum evolution in a sub-region within a molecular dynamics simulation is derived from Gauss's principle of least constraint. The technique for localization is founded on the equations by Irving and Kirkwood [J. Chem. Phys. 18, 817 (1950)] expressed in a weak form according to the control volume (CV) procedure derived by Smith et al. [Phys. Rev. E. 85, 056705 (2012)]. A term for the advection of molecules appears in the derived constraint and is shown to be essential in order to exactly control the time evolution of momentum in the subvolume. The numerical procedure converges the total momentum in the CV to the target value to within machine precision in an iterative manner. The localized momentum constraint can prescribe essentially arbitrary flow fields in non-equilibrium molecular dynamics simulations. The methodology also forms a rigorous mathematical framework for introducing coupling constraints at the boundary between continuum and discrete systems. This functionality is demonstrated with a boundary-driven flow test case. PMID- 25702006 TI - Mapping the genome of meta-generalized gradient approximation density functionals: the search for B97M-V. AB - A meta-generalized gradient approximation density functional paired with the VV10 nonlocal correlation functional is presented. The functional form is selected from more than 10(10) choices carved out of a functional space of almost 10(40) possibilities. Raw data come from training a vast number of candidate functional forms on a comprehensive training set of 1095 data points and testing the resulting fits on a comprehensive primary test set of 1153 data points. Functional forms are ranked based on their ability to reproduce the data in both the training and primary test sets with minimum empiricism, and filtered based on a set of physical constraints and an often-overlooked condition of satisfactory numerical precision with medium-sized integration grids. The resulting optimal functional form has 4 linear exchange parameters, 4 linear same-spin correlation parameters, and 4 linear opposite-spin correlation parameters, for a total of 12 fitted parameters. The final density functional, B97M-V, is further assessed on a secondary test set of 212 data points, applied to several large systems including the coronene dimer and water clusters, tested for the accurate prediction of intramolecular and intermolecular geometries, verified to have a readily attainable basis set limit, and checked for grid sensitivity. Compared to existing density functionals, B97M-V is remarkably accurate for non-bonded interactions and very satisfactory for thermochemical quantities such as atomization energies, but inherits the demonstrable limitations of existing local density functionals for barrier heights. PMID- 25702007 TI - Local hybrid functionals with orbital-free mixing functions and balanced elimination of self-interaction error. AB - The recently introduced density overlap regions indicator (DORI) [P. de Silva and C. Corminboeuf, J. Chem. Theory Comput. 10(9), 3745-3756 (2014)] is a density dependent scalar field revealing regions of high density overlap between shells, atoms, and molecules. In this work, we exploit its properties to construct local hybrid exchange-correlation functionals aiming at balanced reduction of the self interaction error. We show that DORI can successfully replace the ratio of the von Weizsacker and exact positive-definite kinetic energy densities, which is commonly used in mixing functions of local hybrids. Additionally, we introduce several semi-empirical parameters to control the local and global admixture of exact exchange. The most promising of our local hybrids clearly outperforms the underlying semi-local functionals as well as their global hybrids. PMID- 25702008 TI - Comb-locked cavity ring-down spectrometer. AB - Extreme frequency accuracy and high sensitivity are obtained with a novel comb locked cavity-ring-down spectrometer operating in the near-infrared from 1.5 to 1.63 MUm. A key feature of our approach is the tight frequency locking of the probe laser to the comb, ensuring very high reproducibility and accuracy to the frequency axis upon scanning the comb repetition rate, as well as an efficient light injection into a length-swept high-finesse passive cavity containing the gas sample. Spectroscopic tests on the (30012) <- (00001) P14e line of CO2 at ~1.57 MUm demonstrate an accuracy of ~17 kHz on the line center frequency in a Doppler broadening regime over the time scale of about 5 min, corresponding to four consecutive spectral scans of the absorption line. Over a single scan, which consists of 1500 spectral points over 75 s, the limit of detection is as low as 5.7 * 10(-11) cm(-1). PMID- 25702009 TI - A guided-ion beam study of the collisions and reactions of I(+) and I2 (+) with I2. AB - Growing interest in developing and testing iodine Hall effect thrusters requires measurements of the cross sections of reactions that generate low energy plasma following discharge. Limited experimental and theoretical work necessitates a decisive experiment to elucidate the charge exchange and collision-induced dissociation channels. To this end, we have used guided-ion beam techniques to measure cross sections for both I(+) + I2 and I2 (+)+I2 collisions. We present total collision cross sections as well as collision-induced dissociation cross sections for center-of-mass collision energies ranging from 0.5 to 200 eV for molecular iodine cations. Similarly, we present total collision cross section and charge-exchange cross sections for atomic iodine cations for center-of-mass collision energies ranging from 0.67 to 167 eV. Time-of-flight measurements of the collision products allow determination of velocity distributions, which show evidence of complex formation of I3 (+) from the I(+) + I2 reaction at collision energies below 6 eV. PMID- 25702010 TI - Excited state non-adiabatic dynamics of pyrrole: a time-resolved photoelectron spectroscopy and quantum dynamics study. AB - The dynamics of pyrrole excited at wavelengths in the range 242-217 nm are studied using a combination of time-resolved photoelectron spectroscopy and wavepacket propagations performed using the multi-configurational time-dependent Hartree method. Excitation close to the origin of pyrrole's electronic spectrum, at 242 and 236 nm, is found to result in an ultrafast decay of the system from the ionization window on a single timescale of less than 20 fs. This behaviour is explained fully by assuming the system to be excited to the A2(pisigma(*)) state, in accord with previous experimental and theoretical studies. Excitation at shorter wavelengths has previously been assumed to result predominantly in population of the bright A1(pipi(*)) and B2(pipi(*)) states. We here present time resolved photoelectron spectra at a pump wavelength of 217 nm alongside detailed quantum dynamics calculations that, together with a recent reinterpretation of pyrrole's electronic spectrum [S. P. Neville and G. A. Worth, J. Chem. Phys. 140, 034317 (2014)], suggest that population of the B1(pisigma(*)) state (hitherto assumed to be optically dark) may occur directly when pyrrole is excited at energies in the near UV part of its electronic spectrum. The B1(pisigma(*)) state is found to decay on a timescale of less than 20 fs by both N-H dissociation and internal conversion to the A2(pisigma(*)) state. PMID- 25702011 TI - Para-hydrogen and helium cluster size distributions in free jet expansions based on Smoluchowski theory with kernel scaling. AB - The size distribution of para-H2 (pH2) clusters produced in free jet expansions at a source temperature of T0 = 29.5 K and pressures of P0 = 0.9-1.96 bars is reported and analyzed according to a cluster growth model based on the Smoluchowski theory with kernel scaling. Good overall agreement is found between the measured and predicted, Nk = A k(a) e(-bk), shape of the distribution. The fit yields values for A and b for values of a derived from simple collision models. The small remaining deviations between measured abundances and theory imply a (pH2)k magic number cluster of k = 13 as has been observed previously by Raman spectroscopy. The predicted linear dependence of b(-(a+1)) on source gas pressure was verified and used to determine the value of the basic effective agglomeration reaction rate constant. A comparison of the corresponding effective growth cross sections sigma11 with results from a similar analysis of He cluster size distributions indicates that the latter are much larger by a factor 6-10. An analysis of the three body recombination rates, the geometric sizes and the fact that the He clusters are liquid independent of their size can explain the larger cross sections found for He. PMID- 25702012 TI - Theoretical spectroscopic characterization at low temperatures of methyl hydroperoxide and three S-analogs. AB - The low temperature spectra of the detectable species methyl hydroperoxide (CH3OOH) and three sulfur analogs, the two isomers of methanesulfenic acid (CH3SOH and CH3OSH) and the methyl hydrogen disulfide (CH3SSH), are predicted from highly correlated ab initio methods (CCSD(T) and CCSD(T)-F12). Rotational parameters, anharmonic frequencies, torsional energy barriers, torsional energy levels, and their splittings are provided. Our computed parameters should help for the characterization and the identification of these organic compounds in laboratory and in the interstellar medium. PMID- 25702013 TI - The electronic characterization of biphenylene--experimental and theoretical insights from core and valence level spectroscopy. AB - In this paper, we provide detailed insights into the electronic structure of the gas phase biphenylene molecule through core and valence spectroscopy. By comparing results of X-ray Photoelectron Spectroscopy (XPS) measurements with DeltaSCF core-hole calculations in the framework of Density Functional Theory (DFT), we could decompose the characteristic contributions to the total spectra and assign them to non-equivalent carbon atoms. As a difference with similar molecules like biphenyl and naphthalene, an influence of the localized orbitals on the relative XPS shifts was found. The valence spectrum probed by photoelectron spectroscopy at a photon energy of 50 eV in conjunction with hybrid DFT calculations revealed the effects of the localization on the electronic states. Using the transition potential approach to simulate the X-ray absorption spectroscopy measurements, similar contributions from the non-equivalent carbon atoms were determined from the total spectrum, for which the slightly shifted individual components can explain the observed asymmetric features. PMID- 25702014 TI - DFT study of Fe-Ni core-shell nanoparticles: stability, catalytic activity, and interaction with carbon atom for single-walled carbon nanotube growth. AB - Metal catalysts play an important role in the nucleation and growth of single walled carbon nanotubes (SWCNTs). It is essential for probing the nucleation and growth mechanism of SWCNTs to fundamentally understand the properties of the metal catalysts and their interaction with carbon species. In this study, we systematically studied the stability of 13- and 55-atom Fe and Fe-Ni core-shell particles as well as these particles interaction with the carbon atoms using the density functional theory calculations. Icosahedral 13- and 55-atom Fe-Ni core shell bimetallic particles have higher stability than the corresponding monometallic Fe and Ni particles. Opposite charge transfer (or distribution) in these particles leads to the Fe surface-shell displays a positive charge, while the Ni surface-shell exhibits a negative charge. The opposite charge transfer would induce different chemical activities. Compared with the monometallic Fe and Ni particles, the core-shell bimetallic particles have weaker interaction with C atoms. More importantly, C atoms only prefer staying on the surface of the bimetallic particles. In contrast, C atoms prefer locating into the subsurface of the monometallic particles, which is more likely to form stable metal carbides. The difference of the mono- and bimetallic particles on this issue may result in different nucleation and growth mechanism of SWCNTs. Our findings provide useful insights for the design of bimetallic catalysts and a better understanding nucleation and growth mechanism of SWCNTs. PMID- 25702015 TI - Mechanisms for the inversion of chirality: global reaction route mapping of stereochemical pathways in a probable chiral extraterrestrial molecule, 2 aminopropionitrile. AB - 2-Aminopropionitrile (APN), a probable candidate as a chiral astrophysical molecule, is a precursor to amino-acid alanine. Stereochemical pathways in 2-APN are explored using Global Reaction Route Mapping (GRRM) method employing high level quantum-mechanical computations. Besides predicting the conventional mechanism for chiral inversion that proceeds through an achiral intermediate, a counterintuitive flipping mechanism is revealed for 2-APN through chiral intermediates explored using the GRRM. The feasibility of the proposed stereochemical pathways, in terms of the Gibbs free-energy change, is analyzed at the temperature conditions akin to the interstellar medium. Notably, the stereoinversion in 2-APN is observed to be more feasible than the dissociation of 2-APN and intermediates involved along the stereochemical pathways, and the flipping barrier is observed to be as low as 3.68 kJ/mol along one of the pathways. The pathways proposed for the inversion of chirality in 2-APN may provide significant insight into the extraterrestrial origin of life. PMID- 25702016 TI - Observation of the wavepacket dynamics on the (1)B2((1)Sigma(u)(+)) state of CS2 by sub-20 fs photoelectron imaging using 159 nm probe pulses. AB - The wavepacket dynamics of CS2 after photoexcitation to the (1)B2((1)Sigmau(+)) state at 198 nm are studied by time-resolved photoelectron imaging using sub-20 fs 159 nm pulses, which enable single photon ionization from the entire region of the (1)B2 potential energy surface. The time-energy map of the photoelectron intensity reveals vibrational motions along the symmetric stretching and bending coordinates. The time-energy map of the photoelectron anisotropy parameter exhibits time-evolution within single oscillation periods of the nu1 and nu2 modes, which is attributed to variation of the excited state electronic character along these vibrational coordinates. The initially populated (1)B2 state evolves with two time constants of 107 and 394 fs. PMID- 25702017 TI - Thermodynamics of fluid conduction through hydrophobic channel of carbon nanotubes: the exciting force for filling of nanotubes with polar and nonpolar fluids. AB - Thermodynamic properties of the fluid in the hydrophobic pores of nanotubes are known to be different not only from the bulk phase but also from other conventional confinements. Here, we use a recently developed theoretical scheme of "two phase thermodynamic (2PT)" model to understand the driving forces inclined to spontaneous filling of carbon nanotubes (CNTs) with polar (water) and nonpolar (methane) fluids. The CNT confinement is found to be energetically favorable for both water and methane, leading to their spontaneous filling inside CNT(6,6). For both the systems, the free energy of transfer from bulk to CNT confinement is favored by the increased entropy (TDeltaS), i.e., increased translational entropy and increased rotational entropy, which were found to be sufficiently high to conquer the unfavorable increase in enthalpy (DeltaE) when they are transferred inside CNT. To the best of our knowledge, this is the first time when it has been established that the increase in translational entropy during confinement in CNT(6,6) is not unique to water-like H bonding fluid but is also observed in case of nonpolar fluids such as methane. The thermodynamic results are explained in terms of density, structural rigidity, and transport of fluid molecules inside CNT. The faster diffusion of methane over water in bulk phase is found to be reversed during the confinement in CNT(6,6). Studies reveal that though hydrogen bonding plays an important role in transport of water through CNT, but it is not the solitary driving factor, as the nonpolar fluids, which do not have any hydrogen bond formation capacity can go inside CNT and also can flow through it. The associated driving force for filling and transport of water and methane is enhanced translational and rotational entropies, which are attributed mainly by the strong correlation between confined fluid molecules and availability of more free space for rotation of molecule, i.e., lower density of fluid inside CNT due to their single file-like arrangement. To the best of our information, this is perhaps the first study of nonpolar fluid within CNT using 2PT method. Furthermore, the fast flow of polar fluid (water) over nonpolar fluid (methane) has been captured for the first time using molecular dynamic simulations. PMID- 25702018 TI - Improved modeling of two-dimensional transitions in dense phases on crystalline surfaces. Krypton-graphite system. AB - This paper presents a refined technique to describe two-dimensional phase transitions in dense fluids adsorbed on a crystalline surface. Prediction of parameters of 2D liquid-solid equilibrium is known to be an extremely challenging problem, which is mainly due to a small difference in thermodynamic functions of coexisting phases and lack of accuracy of numerical experiments in case of their high density. This is a serious limitation of various attempts to circumvent this problem. To improve this situation, a new methodology based on the kinetic Monte Carlo method was applied. The methodology involves analysis of equilibrium gas liquid and gas-solid systems undergoing an external potential, which allows gradual shifting parameters of the phase coexistence. The interrelation of the chemical potential and tangential pressure for each system is then treated with the Gibbs-Duhem equation to obtain the point of intersection corresponding to the liquid/solid-solid equilibrium coexistence. The methodology is demonstrated on the krypton-graphite system below and above the 2D critical temperature. Using experimental data on the liquid-solid and the commensurate-incommensurate transitions in the krypton monolayer derived from adsorption isotherms, the Kr graphite Lennard-Jones parameters have been corrected resulting in a higher periodic potential modulation. PMID- 25702019 TI - Liquid drops on a surface: using density functional theory to calculate the binding potential and drop profiles and comparing with results from mesoscopic modelling. AB - The contribution to the free energy for a film of liquid of thickness h on a solid surface due to the interactions between the solid-liquid and liquid-gas interfaces is given by the binding potential, g(h). The precise form of g(h) determines whether or not the liquid wets the surface. Note that differentiating g(h) gives the Derjaguin or disjoining pressure. We develop a microscopic density functional theory (DFT) based method for calculating g(h), allowing us to relate the form of g(h) to the nature of the molecular interactions in the system. We present results based on using a simple lattice gas model, to demonstrate the procedure. In order to describe the static and dynamic behaviour of non-uniform liquid films and drops on surfaces, a mesoscopic free energy based on g(h) is often used. We calculate such equilibrium film height profiles and also directly calculate using DFT the corresponding density profiles for liquid drops on surfaces. Comparing quantities such as the contact angle and also the shape of the drops, we find good agreement between the two methods. We also study in detail the effect on g(h) of truncating the range of the dispersion forces, both those between the fluid molecules and those between the fluid and wall. We find that truncating can have a significant effect on g(h) and the associated wetting behaviour of the fluid. PMID- 25702020 TI - Structural, bonding, and electronic properties of the hexagonal ferroelectric and paraelectric phases of LuMnO3 compound: a density functional theory study. AB - We have investigated the structural, bonding, and electronic properties of both ferroelectric (FE) and paraelectric (PE) phases of the hexagonal LuMnO3 compound using calculations based on density functional theory. The structural properties have been determined by employing the generalized gradient approximation with Perdew-Burke-Ernzerhof and Wu-Cohen parameterization. The bonding and electronic properties have been treated by recently developed modified Becke-Johnson exchange potential, which succeeded to open a band gap for both PE and FE phases, in agreement with experimental predictions. The Bader's topological analysis of electronic density showed that the character of the Lu-O axial bonds changes when the crystal exhibits the PE -> FE structural transition. This fact is in agreement with experimental findings. The covalent character of the Lu-O bond significantly increases due to orbital hybridization between the Lu 5dz(2) and O 2pz-states. This bonding mechanism causes the ferroelectricity in the hexagonal LuMnO3 compound. PMID- 25702021 TI - Influence of the van der Waals interaction in the dissociation dynamics of N2 on W(110) from first principles. AB - Using ab initio molecular dynamics (AIMD) calculations, we investigate the role of the van der Waals (vdW) interaction in the dissociative adsorption of N2 on W(110). Hitherto, existing classical dynamics calculations performed on six dimensional potential energy surfaces based on density functional theory (DFT), and the semi-local PW91 and RPBE [Hammer et al. Phys. Rev. B 59, 7413 (1999)] exchange-correlation functionals were unable to fully describe the dependence of the initial sticking coefficient on the molecular beam incidence conditions as found in experiments. N2 dissociation on W(110) was shown to be very sensitive not only to short molecule-surface distances but also to large distances where the vdW interaction, not included in semilocal-DFT, should dominate. In this work, we perform a systematic study on the dissociative adsorption using a selection of existing non-local functionals that include the vdW interaction (vdW functionals). Clearly, the inclusion of the non-local correlation term contributes in all cases to correct the unrealistic energy barriers that were identified in the RPBE at large molecule-surface distances. Among the tested vdW functionals, the original vdW-DF by Dion et al. [Phys. Rev. Lett. 92, 246401 (2004)] and the ulterior vdW-DF2 give also an adequate description of the N2 adsorption energy and energy barrier at the transition state, i.e., of the properties that are commonly used to verify the quality of any exchange correlation functional. However, the results of our AIMD calculations, which are performed at different incidence conditions and hence extensively probe the multi configurational potential energy surface of the system, do not seem as satisfactory as the preliminary static analysis suggested. When comparing the obtained dissociation probabilities with existing experimental data, none of the used vdW-functionals seems to provide altogether an adequate description of the N2/W(110) interaction at short and large distances. PMID- 25702022 TI - Facilitating guest transport in clathrate hydrates by tuning guest-host interactions. AB - The understanding and eventual control of guest molecule transport in gas hydrates is of central importance for the efficient synthesis and processing of these materials for applications in the storage, separation, and sequestration of gases and natural gas production. Previously, some links have been established between dynamics of the host water molecules and guest-host hydrogen bonding interactions, but direct observation of transport in the form of cage-to-cage guest diffusion is still lacking. Recent calculations have suggested that pairs of different guest molecules in neighboring cages can affect guest-host hydrogen bonding and, therefore, defect injection and water lattice motions. We have chosen two sets of hydrate guest pairs, tetrahydrofuran (THF)-CO2 and isobutane CO2, that are predicted to enhance or to diminish guest-host hydrogen bonding interactions as compared to those in pure CO2 hydrate and we have studied guest dynamics in each using (13)C nuclear magnetic resonance (NMR) methods. In addition, we have obtained the crystal structure of the THF-CO2 sII hydrate using the combined single crystal X-ray diffraction and (13)C NMR powder pattern data and have performed molecular dynamics-simulation of the CO2 dynamics. The NMR powder line shape studies confirm the enhanced and delayed dynamics for the THF and isobutane containing hydrates, respectively, as compared to those in the CO2 hydrate. In addition, from line shape studies and 2D exchange spectroscopy NMR, we observe cage-to-cage exchange of CO2 molecules in the THF-CO2 hydrate, but not in the other hydrates studied. We conclude that the relatively rapid intercage guest dynamics are the result of synergistic guest A-host water-guest B interactions, thus allowing tuning of the guest transport properties in the hydrates by choice of the appropriate guest molecules. Our experimental value for inter-cage hopping is slower by a factor of 10(6) than a published calculated value. PMID- 25702023 TI - Coexistence and interfacial properties of a triangle-well mimicking the Lennard Jones fluid and a comparison with noble gases. AB - Coexistence and interfacial properties of a triangle-well (TW) fluid are obtained with the aim of mimicking the Lennard-Jones (LJ) potential and approach the properties of noble gases. For this purpose, the scope of the TW is varied to match vapor-liquid densities and surface tension. Surface tension and coexistence curves of TW systems with different ranges were calculated with replica exchange Monte Carlo and compared to those data previously reported in the literature for truncated and shifted (STS), truncated (ST), and full Lennard-Jones (full-LJ) potentials. We observed that the scope of the TW potential must be increased to approach the STS, ST, and full-LJ properties. In spite of the simplicity of TW expression, a remarkable agreement is found. Furthermore, the variable scope of the TW allows for a good match of the experimental data of argon and xenon. PMID- 25702024 TI - Crystallinity effects on scaling properties of photoinduced modes in silver nanoprisms. AB - The crystallinity effects on scaling properties of photoinduced modes in crystalline silver nanoprisms with C3v symmetry are studied using a realistic atomistic model and group theory. Among all vibrational modes, photoinduced modes can be identified as those vibrational modes which possess larger in-phase radial atomic displacement and can be projected out by the projected density of states method. We found that the properties of vibrations in silver nanoprisms strongly depend on the particle's aspect ratio (bisector length over thickness). By considering crystallinity of silver nanoprisms, the dominant modes with the in plane oscillation become several closely spaced modes, and become obvious for nanoprisms with a smaller aspect ratio. The oscillation spectra show that the dominant planar modes are insensitive to thickness change. On the contrary, the atomic displacements show significantly different patterns for nanoprisms of different thicknesses. We also found that, for nanoprisms with same aspect ratio that is larger than 4, the vibrational properties of dominant modes exhibit scaling similarity. By using a simple linear transformation, the vibration frequencies for large-sized nanoprisms of aspect ratio 6 can be obtained by a corresponding scaling factor. The calculated results are in good agreement with experimental data. PMID- 25702025 TI - Grafted nanoparticles as soft patchy colloids: self-assembly versus phase separation. AB - We investigate the thermodynamic behavior of a model polymer-grafted nanoparticle (GNP) system on a fine lattice, using grand canonical Monte Carlo simulations, to compare and contrast the validity of two different models for GNPs: "nanoparticle amphiphiles" versus "patchy particles." In the former model, continuous self assembly processes are expected to dominate the system, whereas the latter are characterized by first-order phase separation into novel equilibrium phases such as "empty liquids." We find that, in general, considering GNPs as amphiphiles within the framework of a recent mean-field theory [Pryamtisyn et al., J. Chem. Phys. 131, 221102 (2009)] provides a qualitatively accurate description of the thermodynamics of GNP systems, revealing either first-order phase separation into two isotropic phases or continuous self-assembly. Our model GNPs display no signs of empty liquid formation, suggesting that these nanoparticles do not provide a route to such phases. PMID- 25702026 TI - The glass transition of polymers with different side-chain stiffness confined in free-standing thin films. AB - The effect of confinement on the glass transition temperature Tg of polymeric glass formers with different side chain stiffness is investigated by coarse grained molecular dynamics simulations. We find that polymer with stiffer side groups exhibits much more pronounced Tg variation in confinement compared to that with relatively flexible side groups, in good agreement with experiments. Our string analysis demonstrates that the polymer species dependence of dynamics can be described by an Adam-Gibbs like relation between the size of cooperatively rearranging regions and relaxation time. However, the primary effect of changing side-group stiffness is to alter the activation barrier for rearrangement, rather than string size. We clarify that free-surface perturbation is the primary factor in determining the magnitude of Tg variation for polymers in confinement: It is more significant for polymers having higher Tg and results in much more pronounced reduction of surface Tg and then the overall Tg of the polymers. PMID- 25702027 TI - Simulation studies on architecture dependence of unentangled polymer melts. AB - The dependences of the properties of linear, ring, star, and H-shaped polymer melts on architecture are investigated by nonequilibrium molecular dynamics simulations. We find that zero-shear viscosities eta0 for various architectures follow a universal relation, eta0=Ceta, where Ceta is a constant and the equilibrium mean-square radius of gyration, in the unentangled regime. This law is also found valid for asymmetrical polymers but invalid for polymers with a hard core, such as stars with many arms and short arm lengths. In the unentangled regime, from the point of view of polymer size, the relaxation times show weak dependences on architecture, but the architecture dependence of the diffusion coefficient is still apparent. Then, we examine unentangled melts of various architectures having the same size over a wide range of shear rates covering linear and nonlinear viscoelastic regimes and find that the rheological quantities, namely, viscosity, first and second normal stress differences, are independent of architecture. In contrast, the polymer deformation shows an apparent dependence on architecture in the nonlinear regime. These findings shall shed significant light on the nature of rheological behaviors of unentangled melts. PMID- 25702028 TI - Binary mixtures of asymmetric continuous charge distributions: molecular dynamics simulations and integral equations. AB - An investigation is carried out of the association and clustering of mixtures of Gaussian charge distributions (CDs) of the form ~Qexp(-r(2)/2alpha(2)), where Q is the total charge, r is the separation between the centers of charge and alpha governs the extent of charge spreading (alpha -> 0 is the point charge limit). The general case where alpha and Q are different for the positive and negatives charges is considered. The Ewald method is extended to treat these systems and it is used in Molecular Dynamics (MD) simulations of electrically neutral CD mixtures in the number ratios of 1:1 and 1:4 (or charge ratio 4:1). The MD simulations reveal increased clustering with decreasing temperature, which goes through a state in which each large CD is overlapped by four of the oppositely signed CD in the 1:4 case. At very low reduced temperatures, these mini-clusters progressively coalesce into much larger tightly bound clusters. This is different from the 1:1 mixture case, where the low temperature limit is a random distribution of neutral dimers. At higher temperatures, the MD radial distribution functions g(r) agree well with those from the hypernetted chain solution of the Ornstein-Zernike integral equation, and (at not too high densities) a previously introduced mean field approximation extended to these charge distribution systems. PMID- 25702029 TI - Cholesterics of colloidal helices: predicting the macroscopic pitch from the particle shape and thermodynamic state. AB - Building a general theoretical framework to describe the microscopic origin of macroscopic chirality in (colloidal) liquid crystals is a long-standing challenge. Here, we combine classical density functional theory with Monte Carlo calculations of virial-type coefficients to obtain the equilibrium cholesteric pitch as a function of thermodynamic state and microscopic details. Applying the theory to hard helices, we observe both right- and left-handed cholesteric phases that depend on a subtle combination of particle geometry and system density. In particular, we find that entropy alone can even lead to a (double) inversion in the cholesteric sense of twist upon changing the packing fraction. We show how the competition between single-particle properties (shape) and thermodynamics (local alignment) dictates the macroscopic chiral behavior. Moreover, by expanding our free-energy functional, we are able to assess, quantitatively, Straley's theory of weak chirality, which is used in several earlier studies. Furthermore, by extending our theory to different lyotropic and thermotropic liquid-crystal models, we analyze the effect of an additional soft interaction on the chiral behavior of the helices. Finally, we provide some guidelines for the description of more complex chiral phases, like twist-bend nematics. Our results provide new insights into the role of entropy in the microscopic origin of this state of matter. PMID- 25702030 TI - Vibrational energy flow in the villin headpiece subdomain: master equation simulations. AB - We examine vibrational energy flow in dehydrated and hydrated villin headpiece subdomain HP36 by master equation simulations. Transition rates used in the simulations are obtained from communication maps calculated for HP36. In addition to energy flow along the main chain, we identify pathways for energy transport in HP36 via hydrogen bonding between residues quite far in sequence space. The results of the master equation simulations compare well with all-atom non equilibrium simulations to about 1 ps following initial excitation of the protein, and quite well at long times, though for some residues we observe deviations between the master equation and all-atom simulations at intermediate times from about 1-10 ps. Those deviations are less noticeable for hydrated than dehydrated HP36 due to energy flow into the water. PMID- 25702031 TI - Dynamical role of phosphorylation on serine/threonine-proline Pin1 substrates from constant force molecular dynamics simulations. AB - Cis-trans isomerization of peptidyl-prolyl bonds of the protein backbone plays an important role in numerous biological processes. Cis-trans isomerization can be the rate-limiting step due its extremely slow dynamics, compared to the millisecond time scale of many processes, and is catalyzed by a widely studied family of peptidyl-prolyl cis-trans isomerase enzymes. Also, mechanical forces along the peptide chain can speed up the rate of isomerization, resulting in "mechanical catalysis," and have been used to study peptidyl-prolyl cis-trans isomerization and other mechanical properties of proteins. Here, we use constant force molecular dynamics simulations to study the dynamical effects of phosphorylation on serine/threonine-proline protein motifs that are involved in the function of many proteins and have been implicated in many aberrant biological processes. We show that the rate of cis-trans isomerization is slowed down by phosphorylation, in excellent agreement with experiments. We use a well grounded theory to describe the force dependent rate of isomerization. The calculated rates at zero force are also in excellent agreement with experimentally measured rates, providing additional validation of the models and force field parameters. Our results suggest that the slowdown in the rate upon phosphorylation is mainly due to an increase in the friction along the peptidyl prolyl bond angle during isomerization. Our results provide a microscopic description of the dynamical effects of post-translational phosphorylation on cis trans isomerization and insights into the properties of proteins under tension. PMID- 25702032 TI - Erratum: "Sub-terahertz spectroscopy reveals that proteins influence the properties of water at greater distances than previously detected" [J. Chem. Phys. 142, 055101 (2015)]. PMID- 25702033 TI - Publisher's Note: "Geometric pumping induced by shear flow in dilute liquid crystalline polymer solutions" [J. Chem. Phys. 142, 054903 (2015)]. PMID- 25702034 TI - Neighborhood socio-economic context and emergency department visits for dental care in a U.S. Midwestern metropolis. AB - OBJECTIVE: This study was to examine the association between emergency department (ED) visits for dental complaints and neighborhood socio-economic contexts of patients in a U.S. Midwestern metropolis. STUDY DESIGN: A retrospective study. METHODS: Deidentified data of ED visits for the period 2001-2010 from all facilities serving Kansas City, Missouri and 2007-2011 American Community Survey 5-Year Estimates data were used to determine odds of visit by neighborhood socio economic characteristics at the ZIP code level. ED visits with diagnoses of International Classification of Disease 9th Revision codes related to toothache or tooth injury were included. ZIP code characteristics included percent of non white population, median family income, percent of population 25 years and older with at least a high school degree, and percent of population with a language other than English spoken at home. Each ZIP code characteristic was divided into quartiles. Chi-square tests and two-level hierarchical linear modeling (HLM) were conducted. In the HLM, the outcome variable was whether to have an ED visit for dental complaints (yes/no), the first-level variables were characteristics of individual ED visits, and the second-level variables were ZIP code characteristics. RESULTS: The study population made 1,786,939 ED visits, of which 35,136 (1.9%) were for dental complaints. Among the patients making ED visits for dental complaints, 54.8% were female, 51.9% were younger adults aged 19-35 years, 48.7% were non-Hispanic black, and 35.5% used self-pay as the source of payment. After controlling the first-level variables, the HLM showed that the risk of ED visits for dental complaints significantly increased for individuals residing in ZIP Code Tabulation Areas with lower median family income, or a higher proportion of the population with a language rather than English spoken at home. CONCLUSIONS: Among socio-economic characteristics examined, median family income and percent of population with a language other than English spoken at home are important indicators of ED visits for dental complaints. PMID- 25702035 TI - Backbone resonance assignments of the PRYSPRY domain of TRIM25. AB - TRIM25 is a member of the tripartite motif (TRIM) family and has been implicated in the regulation of innate immune signaling via the RIG-I (retinoic acid inducible gene-I) pathway for antiviral defense. As the essential first step towards the structural and functional characterization of the TRIM25/RIG-I interaction, the backbone resonance of the PRYSPRY domain of TRIM25 is assigned here based on triple-resonance experiments using uniformly [(2)H, (13)C, (15)N] labeled protein. PMID- 25702036 TI - Stretch-sensitive paresis and effort perception in hemiparesis. AB - In spastic paresis, stretch applied to the antagonist increases its inappropriate recruitment during agonist command (spastic co-contraction). It is unknown whether antagonist stretch: (1) also affects agonist recruitment; (2) alters effort perception. We quantified voluntary activation of ankle dorsiflexors, effort perception, and plantar flexor co-contraction during graded dorsiflexion efforts at two gastrocnemius lengths. Eighteen healthy (age 41 +/- 13) and 18 hemiparetic (age 54 +/- 12) subjects performed light, medium and maximal isometric dorsiflexion efforts with the knee flexed or extended. We determined dorsiflexor torque, Root Mean Square EMG and Agonist Recruitment/Co-contraction Indices (ARI/CCI) from the 500 ms peak voluntary agonist recruitment in a 5-s maximal isometric effort in tibialis anterior, soleus and medial gastrocnemius. Subjects retrospectively reported effort perception on a 10-point visual analog scale. During gastrocnemius stretch in hemiparetic subjects, we observed: (1) a 25 +/- 7 % reduction of tibialis anterior voluntary activation (maximum reduction 98 %; knee extended vs knee flexed; p = 0.007, ANOVA); (2) an increase in dorsiflexion effort perception (p = 0.03, ANCOVA). Such changes did not occur in healthy subjects. Effort perception depended on tibialis anterior recruitment only (betaARI(TA) = 0.61, p < 0.01) in healthy subjects (not on gastrocnemius medialis co-contraction) while it depended on both tibialis anterior agonist recruitment (betaARI(TA) = 0.41, p < 0.001) and gastrocnemius medialis co contraction (betaCCI(MG) = 0.43, p < 0.001) in hemiparetic subjects. In hemiparesis, voluntary ability to recruit agonist motoneurones is impaired- sometimes abolished--by antagonist stretch, a phenomenon defined here as stretch sensitive paresis. In addition, spastic co-contraction increases effort perception, an additional incentive to evaluate and treat this phenomenon. PMID- 25702037 TI - Our experience with transcanalicular laser-assisted endoscopic dacryocystorhinostomy (TCLADCR) in patients of chronic dacryocystitis with deviated nasal septum. AB - The purpose of this study is to study the operative difficulties and success rate of transcanalicular laser-assisted endoscopic dacryocystorhinostomy in patients of chronic dacryocystitis with deviated nasal septum (DNS). A prospective interventional clinical study of 36 consecutive patients suffering from chronic dacryocystitis with nasolacrimal duct obstruction with DNS undergoing primary TCLADCR from March to June 2011 was carried out. Diode laser was used to create a 16-mm(2) ostium which was enlarged to 64 mm(2) using Blakesley's forceps. Success was defined as anatomical patency and absence of symptoms at 12 months of follow up. Out of the 36 patients, 25 were females with ages 20-72 years, and 19 were left sided. There were 12 high, 12 mid and 12 basal DNS towards the side of surgery, mild to moderate in severity. Intraoperatively there was difficulty in visualising the aiming beam in the nose, tedious manipulation of endoscope and excessive bleeding in 3 patients. Increased bleeding and failures were significantly higher in high DNS (Fisher exact test-2 tailed: 0.0045). The procedure was successful in 94.4 % cases with average ostium size of 21.94 mm(2) at 12 months and no statistically significant difference in success rates between mild and moderate DNS (Fisher exact test-2 tailed: 1.000). Also there was no difference in the complication rate between mild and moderate DNS (Fisher exact test-2 tailed: 0.0841). TCLADCR is an effective procedure in patients with mild to moderate mid and basal DNS and obviates the need for multiple procedures and a cutaneous scar. PMID- 25702038 TI - An enhanced experimental procedure to rationalize on the impairment of perception of action capabilities. AB - It is well documented that changes in the physiological states of the perceiver actor influence the perception of action capabilities. However, because experimental procedures of most studies involved a limitless availability for stimuli visual encoding and perceptual strategies, it remains difficult to adopt a single position among the large range of alternative interpretations for impaired perception. A reaching-to-grasp paradigm under breathing restriction was adapted from Graydon et al. (Cogn Emot 26:1301-1305, 2012) to standardize the time for encoding of stimuli information and narrowed the involvement of perceptual strategies. In the present study, we propose a highly controlled environment where the discrete information is presented during 300 ms, congruently with neurophysiological studies focused on visuomotor transformation. An underestimation of the perception of action capabilities is found under breath restriction, suggesting that 300 ms for stimuli encoding is sufficient to induce altered visuomotor brain transformations when limiting the involvement of perceptual strategies. This result suggests that such behavior could refer to an impaired brain potentiation of the perceptual occurrence, providing strong hypotheses on the brain dynamics of sensorimotor integration that underlie impaired perception of action capabilities in stressful situations. PMID- 25702039 TI - Acute DNase1 treatment improves left ventricular remodeling after myocardial infarction by disruption of free chromatin. AB - Myocardial infarction (MI) leads to necrosis and uncontrolled release of cellular content. Binucleated and polyploid cardiomyocytes contain high amounts of chromatin, a DNA polymer of histones which are cytotoxic. We hypothesized that chromatin from necrotic cells accumulates in the non-perfused, ischemic infarct region, causing local high concentrations of cytotoxic histones, thereby potentiating damage to the heart after MI. The endonuclease DNase1 is capable of dispersing extracellular chromatin through linker DNA digestion which could lead to a decrease in local histone concentrations and cytotoxicity. It was confirmed that after permanent coronary artery ligation in mice, extracellular histones accumulated within the infarcted myocardium. In vitro, histones caused myocyte cytotoxicity. For protection against histone-mediated cytotoxicity after MI in vivo, DNase1 was administered within the first 6 h after induction. Indeed, DNase1 accumulation in the infarcted region of the heart was observed, as well as effective disruption of extracellular cytotoxic chromatin and subsequent reduction of high local histone concentrations. Functionally, acute DNase1 treatment resulted in significantly improved left ventricular remodeling in mice as measured by serial echocardiography, while mortality, infarct size and inflammatory parameters were unaffected. Notably, improved cardiomyocyte survival within the infarct region was observed and might account for the protective effects in acutely DNase1-treated animals. Disruption of extracellular cytotoxic chromatin within the infarcted heart by acute DNase1 treatment is a promising approach to protect myocytes from histone-induced cell death and subsequent left ventricular dysfunction after MI. PMID- 25702040 TI - Sleep restriction increases free fatty acids in healthy men. AB - AIMS/HYPOTHESIS: Sleep loss is associated with insulin resistance and an increased risk for type 2 diabetes, yet underlying mechanisms are not understood. Elevation of circulating non-esterified (i.e. free) fatty acid (NEFA) concentrations can lead to insulin resistance and plays a central role in the development of metabolic diseases. Circulating NEFA in healthy individuals shows a marked diurnal variation with maximum levels occurring at night, yet the impact of sleep loss on NEFA levels across the 24 h cycle remains unknown. We hypothesised that sleep restriction would alter hormones that are known to stimulate lipolysis and lead to an increase in NEFA levels. METHODS: We studied 19 healthy young men under controlled laboratory conditions with four consecutive nights of 8.5 h in bed (normal sleep) and 4.5 h in bed (sleep restriction) in randomised order. The 24 h blood profiles of NEFA, growth hormone (GH), noradrenaline (norepinephrine), cortisol, glucose and insulin were simultaneously assessed. Insulin sensitivity was estimated by a frequently sampled intravenous glucose tolerance test. RESULTS: Sleep restriction relative to normal sleep resulted in increased NEFA levels during the nocturnal and early-morning hours. The elevation in NEFA was related to prolonged nocturnal GH secretion and higher early-morning noradrenaline levels. Insulin sensitivity was decreased after sleep restriction and the reduction in insulin sensitivity was correlated with the increase in nocturnal NEFA levels. CONCLUSIONS/INTERPRETATION: Sleep restriction in healthy men results in increased nocturnal and early-morning NEFA levels, which may partly contribute to insulin resistance and the elevated diabetes risk associated with sleep loss. PMID- 25702041 TI - RNA sequencing to study gene expression and SNP variations associated with growth in zebrafish fed a plant protein-based diet. AB - The objectives of this study were to measure gene expression in zebrafish and then identify SNP to be used as potential markers in a growth association study. We developed an approach where muscle samples collected from low- and high-growth fish were analyzed using RNA-Sequencing (RNA-seq), and SNP were chosen from the genes that were differentially expressed between the low and high groups. A population of 24 families was fed a plant protein-based diet from the larval to adult stages. From a total of 440 males, 5 % of the fish from both tails of the weight gain distribution were selected. Total RNA was extracted from individual muscle of 8 low-growth and 8 high-growth fish. Two pooled RNA-Seq libraries were prepared for each phenotype using 4 fish per library. Libraries were sequenced using the Illumina GAII Sequencer and analyzed using the CLCBio genomic workbench software. One hundred and twenty-four genes were differentially expressed between phenotypes (p value < 0.05 and FDR < 0.2). From these genes, 164 SNP were selected and genotyped in 240 fish samples. Marker-trait analysis revealed 5 SNP associated with growth in key genes (Nars, Lmod2b, Cuzd1, Acta1b, and Plac8l1). These genes are good candidates for further growth studies in fish and to consider for identification of potential SNPs associated with different growth rates in response to a plant protein-based diet. PMID- 25702042 TI - Soluble Syndecan-1 Levels Are Elevated in Patients with Inflammatory Bowel Disease. AB - BACKGROUND: Syndecan-1 plays a central role in maintaining normal intestinal barrier function. Shedding of syndecan-1, reflected by soluble syndecan-1 serum concentrations, is highly regulated by inflammation. AIM: To determine soluble syndecan-1 levels in inflammatory bowel disease patients and its relationship with other inflammatory markers, disease activity, and medical treatment. METHODS: Cross-sectional, pilot study in which serum concentrations of soluble syndecan-1 were analyzed by ELISA in a cohort of 41 inflammatory bowel disease patients (22 Crohn's disease, 19 ulcerative colitis) and 16 healthy controls. Disease activity was estimated by the Crohn's disease activity index, partial Mayo score, and C-reactive protein. RESULTS: Soluble syndecan-1 levels were significantly higher in inflammatory bowel disease patients compared to healthy controls (29.5 +/- 13.4 vs. 21.1 +/- 10.4 ng/ml, respectively, P = 0.03). Soluble syndecan-1 displayed a reliable ability to discriminate inflammatory bowel disease patients from healthy controls with a sensitivity of 95 %, specificity of 50 %, and positive predictive value of 83 %. Patients treated with anti inflammatory medications demonstrated significantly lower soluble syndecan-1 levels compared to untreated patients (26.45 +/- 9.75 vs. 38 +/- 18.43 ng/ml, respectively, P = 0.008). CONCLUSIONS: Our results suggest that soluble syndecan 1 is potentially a novel diagnostic marker in the management of inflammatory bowel disease patients. Its applicability as a surrogate, prognostic biomarker remains to be determined. PMID- 25702044 TI - Using OPC technology to support the study of advanced process control. AB - OPC, originally the Object Linking and Embedding (OLE) for Process Control, brings a broad communication opportunity between different kinds of control systems. This paper investigates the use of OPC technology for the study of distributed control systems (DCS) as a cost effective and flexible research tool for the development and testing of advanced process control (APC) techniques in university research centers. Co-Simulation environment based on Matlab, LabVIEW and TCP/IP network is presented here. Several implementation issues and OPC based client/server control application have been addressed for TCP/IP network. A nonlinear boiler model is simulated as OPC server and OPC client is used for closed loop model identification, and to design a Model Predictive Controller. The MPC is able to control the NOx emissions in addition to drum water level and steam pressure. PMID- 25702043 TI - Syphilis transmission: a review of the current evidence. AB - Syphilis remains widespread worldwide, with increasing rates among men who have sex with men. This paper reviews available evidence regarding syphilis transmission, including data on: sexual transmission (transmission probability per sexual partnership), vertical transmission, transmission via blood products and organ donation, and other rare modes of transmission. In addition, host susceptibility to syphilis infection is discussed. Syphilis screening and treatment, condoms and risk-reduction counselling and how they modify syphilis transmission dynamics are considered. PMID- 25702045 TI - Survey on methods of increasing the efficiency of extended state disturbance observers. AB - This survey presents various methods of improving the overall estimation quality in the class of extended state observers (ESO), which estimate not only the conventional states of the system, but the acting disturbance as well. This type of observers is crucial in forming the active disturbance rejection control structure (ADRC), where the precision of online perturbation reconstruction and cancellation directly influences the robustness of the closed-loop control system. Various aspects of the observer-based disturbance estimation/rejection loop are covered by this work and divided into three categories, related with observer: structure, tuning, and working conditions. The survey is dedicated to researchers and practitioners who are interested in increasing the efficiency of their ADRC-based governing schemes. PMID- 25702046 TI - Delay-dependent exponential passivity of uncertain cellular neural networks with discrete and distributed time-varying delays. AB - This paper is concerned with the delay-dependent exponential passivity analysis issue for uncertain cellular neural networks with discrete and distributed time varying delays. By decomposing the delay interval into multiple equidistant subintervals and multiple nonuniform subintervals, a suitable augmented Lyapunov Krasovskii functionals are constructed on these intervals. A set of novel sufficient conditions are obtained to guarantee the exponential passivity analysis issue for the considered system. Finally, two numerical examples are provided to demonstrate the effectiveness of the proposed results. PMID- 25702047 TI - Concussion and football: a review and editorial. AB - The issue of concussion in football is of substantial interest to players, coaches, fans, and physicians. In this article, we review specific cultural hindrances to diagnosis and treatment of concussion in football. We review current trends in management and identify areas for improvement. We also discuss the obligations that physicians, particularly neurosurgeons and neurologists, have toward brain-injured football players and the larger societal role they may play in helping to minimize football-associated brain injury. PMID- 25702048 TI - Significance of global versus segmental subclassification of class III and IV lupus nephritis: a single center experience. AB - INTRODUCTION: Class III and IV are the most ominous among the classes of lupus nephritis (LN) and there are contradictory reports on whether LN class IV-G (global) differs from LN class IV-S (segmental) as envisaged by the International Society of Nephrology and the Renal Pathology Society (ISN/RPS) 2003 classification. These subcategories are not validated for LN class III. This study was designed to assess the differences between global and segmental subclasses in classes III and IV of LN. PATIENTS AND METHODS: In a retrospective analysis, the kidney biopsies of 84 patients with new-onset LN were analyzed. The Student's t-test and Mann-Whitney test were employed to compare differences between the means of continuous variables among the two groups. Fisher's exact test was used to compare the categorical variables. A p-value <0.05 was considered statitistically significant. RESULTS: Of 84 patients, 69 (82.1%) were females and 15 (17.9%) males, with the female to male ratio of 4.6:1. The mean age of all patients was 32.7+/-12.6 years. The mean serum creatinine at the time of biopsy was 1.5+/-0.94 mg/dl and the mean urinary protein excretion was 1.6+/ 1.9 g/day. Among 84 biopsies, 26(30.95%) belonged to class III and 37 (44.05%) to class IV LN. In class IV LN, serum creatinine was significantly higher in global vs. segmental subcategory (2.4+/-1 vs. 1.1+/-0.5 mg/dl; p=0.034), while. 24-h proteinuria was not significantly different between the subcategories (2.7+/-1.2 vs. 3.1+/-1.0 g/d, p=0.56). In LN class III, the mean age, serum creatinine and 24-hour proteinuria did not show significant difference between the global and segmental subcategories (37+/-17 vs. 30+/-15 years, p=0.58; 1.2+/-0.2 vs. 1.25+/ 0.6 mg/dl, p=0.66; 2.03+/-0.5 vs. 3.1+/-3.5 g/day, p=0.45, respectively). The proportion of glomeruli showing endocapillary proliferation was significantly higher in global than in segmental subclasses (94.25% vs. 5.72; p=0.026) in class IV LN. The activity and chronicity percent also revealed higher values in global subclass vs. segmental subclass of class IV LN (p=0.038 and p=0.045, respectively). These parameters were not significantly different among the global and segmental subcategories of class III LN (p>0.5 for all parameters). CONCLUSION: In conclusion, our study showed significant differences in renal function and some pathological features on renal biopsies among the global and segmental subclasses of class IV LN. There were no significant differences among these subclasses of class III LN. Further, and larger studies are needed on this subject to substantiate the above results. PMID- 25702049 TI - Preclinical pharmacokinetics, pharmacodynamics, and efficacy of RG7116: a novel humanized, glycoengineered anti-HER3 antibody. AB - PURPOSE: RG7116 is a novel anti-HER3 therapeutic antibody that inhibits HER3 signalling and induces antibody-dependent cellular cytotoxicity of tumor cells due to a glycoengineered antibody Fc moiety. We investigated the efficacy and pharmacokinetic/pharmacodynamic properties of HER3 signal inhibition by RG7116 in a murine xenograft model of human head and neck cancer. METHODS: SCID-beige mice bearing FaDu cells were treated with RG7116 at a weekly dose of 0.3-10 mg/kg, and tumor growth control and modulation of selected proteins (HER3 and AKT) were examined. RESULTS: Complete tumor stasis up to Day 46 was observed at a dose >3 mg/kg, and this dose down-modulated membrane HER3 expression and inhibited HER3 and AKT phosphorylation. Systemic RG7116 exposure was greater than dose proportional and total clearance declined with increasing dose, indicating that RG7116 elimination is target-mediated. This is consistent with the better efficacy, and the HER3 and pAKT inhibition, that was observed at doses >1 mg/kg. Tumor regrowth occurred from Day 46 onwards and was associated with HER1 and HER2 upregulation, indicating the activation of alternative HER escape pathways. Modulation of HER3 and phospho-HER3 was also demonstrated in the skin and mucosa of an RG7116-treated cynomolgus monkey, suggesting that these may be useful surrogate tissues for monitoring RG7116 activity. CONCLUSIONS: These data confirm the promising efficacy of RG7116 and highlight the value of assessing the PK behavior of the antibody and measuring target protein modulation as a marker of biological activity. Clinical development of RG7116 has now begun, and phase I trials are ongoing. PMID- 25702050 TI - Amrubicin monotherapy for patients with extrapulmonary neuroendocrine carcinoma after platinum-based chemotherapy. AB - PURPOSE: Extrapulmonary neuroendocrine carcinomas (EPNEC) are rarely observed and are associated with poor outcomes. Based on the clinicopathological similarity, treatment used for small cell lung carcinoma has also been employed for EPNEC, but the response to such therapy has not been well examined. The goal of this study was to investigate amrubicin (AMR) monotherapy as a salvage therapy for EPNEC arising from digestive organs. METHODS: Patients with EPNEC of the digestive organs who had prior platinum-based chemotherapy and were subsequently treated with AMR between July 2005 and December 2013 at any one of four institutions were retrospectively examined to characterize the safety and efficacy of AMR. RESULTS: Thirteen patients (ten males, three females; median age 64 years) were examined. Primary cancer sites included stomach (n = 6), rectum (n = 3), esophagus (n = 2), liver (n = 1) and pancreas (n = 1). Prior irinotecan- and etoposide-containing chemotherapies were used in ten and six patients, respectively. Median initial dose of AMR was 40 mg/m(2)/day for three consecutive days, and median of treatment cycles was 4 (range 1-9). The objective response rate (ORR) was 38.5%. Median progression-free survival (PFS) and overall survival (OS) were 107 (range 22-275) and 215 days (range 71-535), respectively. Common severe adverse events (grade 3/4) were neutropenia (84.6%) and febrile neutropenia (30.8%). Patient with longer platinum-free interval (>90 days) exhibited longer PFS and OS than those with shorter platinum-free interval (190 vs. 63 days and 348 vs. 145 days, respectively). CONCLUSIONS: AMR showed evidence of clinical activity and safety when used for the treatment of EPNEC. It might be especially useful for populations with sensitive relapse. PMID- 25702051 TI - Cisplatin in combination with metronomic vinorelbine as front-line treatment in advanced non-small cell lung cancer: a multicenter phase II study of the Hellenic Oncology Research Group (HORG). AB - PURPOSE: To evaluate the safety and efficacy of metronomic vinorelbine in combination with cisplatin as first-line treatment in patients with advanced non small cell lung cancer (NSCLC). PATIENTS AND METHODS: A total of 41 patients with inoperable stage IIIb or stage IV NSCLC (14 with adenocarcinomas, 19 with squamous cell carcinoma and eight with other types), PS = 0-2, were treated with cisplatin (80 mg/m(2)) in combination with oral metronomic vinorelbine (60 mg total dose, every other day) in cycles of 21 days. RESULTS: A total of 35 patients who received at least one cycle of chemotherapy were evaluable for toxicity and response. Partial response was achieved in 13 patients (ORR 37.1%; CI 21.1-53.1%) and stable disease in 10 (28.6%). After a median follow-up period of 26.2 months (range 0.5-33.4 months), the median progression-free survival was 4.2 months and the median overall survival 12.0 months. The 1-year survival rate was 52.6%. Myelosuppression was the main adverse event with grade 3 and 4 neutropenia occurring in five (14.3%) and six (17.1%) patients, respectively. Three of these patients presented with febrile neutropenia and there was one death due to sepsis. Non-hematologic toxicities were mild. CONCLUSION: Cisplatin in combination with metronomic vinorelbine is an active, although myelotoxic, therapeutic option in the first-line setting for the treatment of patients with locally advanced and metastatic non-small cell lung cancer, which merits further evaluation in randomized trials. PMID- 25702052 TI - Pedestrian Behavior at Five Dangerous and Busy Manhattan Intersections. AB - Technology-related distracted behavior is an emergent national concern. Listening to, looking at or talking into an electronic device while walking divides attention, increasing the risk of injury. The purpose of this study was to quantify technology-related distracted pedestrian behavior at five dangerous and busy Manhattan intersections. Data were collected over ten cycles of signal changes at each of the four corners of five intersections at four times of day. Data for 'Walk' and 'Don't Walk' signals were tallied separately. A total of 21,760 pedestrians were observed. Nearly one-third crossing on a 'Walk' signal (n = 5414, 27.8%), and nearly half crossing on a 'Don't Walk' signal (n = 974; 42.0%) were wearing headphones, talking on a mobile phone, and/or looking down at an electronic device. Headphone use was the most common distraction. PMID- 25702053 TI - [Ocular toxoplasmosis - seeking a strategy for treatment]. AB - AIM: To compare the effectiveness of treatment for ocular toxoplasmosis with pyrimethamine + clindamycin (or sulfadiazine) + a corticoid (Group 1), or azithromycin or a combination of azithromycin with a corticoid or a corticoid alone (Group 2). To determine the relapse rate depending on the treatment approach. MATERIAL AND METHODS: A total of 25 patients treated for ocular toxoplasmosis over the last five years (2008-2013) were analyzed. Group 1 comprised 16 patients (3 were excluded) and Group 2 consisted of 6 patients. RESULTS: Visual improvement was more rapid in Group 1 (day 10.7) than in Group 2 (significant improvement on day 29.6). There were 5 cases of relapse in Group 1; in 13 cases, no relapse was noted; all patients in Group 2 relapsed (a total of 13 relapses). Twenty-three patients were positive for specific IgG antibodies. CONCLUSION: According to our experiences, pyrimethamine + clindamycin (or sulfadiazine) + a corticoid should be the treatment of choice in patients with ocular toxoplasmosis. PMID- 25702054 TI - [Bacterial efflux pumps - their role in antibiotic resistance and potential inhibitors]. AB - Efflux pumps capable of actively draining antibiotic agents from bacterial cells may be considered one of potential mechanisms of the development of antimicrobial resistance. The most important group of efflux pumps capable of removing several types of antibiotics include RND (resistance - nodulation - division) pumps. These are three proteins that cross the bacterial cell wall, allowing direct expulsion of the agent out from the bacterial cell. The most investigated efflux pumps are the AcrAB-TolC system in Escherichia coli and the MexAB-OprM system in Pseudomonas aeruginosa. Moreover, efflux pumps are able to export other than antibacterial agents such as disinfectants, thus decreasing their effectiveness. One potential approach to inactivation of an efflux pump is to use the so-called efflux pump inhibitors (EPIs). Potential inhibitors tested in vitro involve, for example, phenylalanyl-arginyl-b-naphthylamide (PAbN), carbonyl cyanide m chlorophenylhydrazone (CCCP) or agents of the phenothiazine class. PMID- 25702055 TI - [Diagnosis and therapy of chronic hepatitis B: Czech national guidelines]. AB - The new recommendations reflect the increase in knowledge that has been reported since the release of previous Czech guidelines in April 2009. According to qualified estimates, there are 350-400 million people with chronic hepatitis B (HBV) infection worldwide. The Czech Republic is among the countries with a low prevalence of HBV infection. According to the latest seroprevalent study, 0.56 % of the Czech citizens were chronically infected with HBV in 2001. HBV infection can lead to serious life-threatening liver damage - fulminant hepatitis, liver cirrhosis and hepatocellular carcinoma (HCC). The goals of treatment are to prolong the length of life and improve its quality by preventing the progression of chronic hepatitis to cirrhosis, cirrhosis decompensation and development of HCC. The goals can be achieved if HBV replication is suppressed in a sustained manner. Then, the accompanying reduction in histological activity lowers the risk of cirrhosis and HCC, particularly in non-cirrhotic patients. Currently, two different strategies for treating chronic hepatitis B are available. Treatment of finite duration is with pegylated interferon (PEG-IFN), entecavir (ETV), or tenofovir (TDV). A 48-week course of PEG-IFN is mainly recommended for HBeAg positive patients with the best chance of anti-HBe seroconversion. Finite duration of ETV or TDV treatment is available for HBeAg-positive patients who seroconvert to anti-HBe on treatment. However, treatment duration is unpredictable prior to the therapy as it depends on the timing of anti-HBe seroconversion and the treatment continuation following anti-HBe seroconversion (therapy should be prolonged for additional 12 months after anti-HBe seroconversion). Long-term ETV or TDV therapy is necessary for HBeAg-positive patients who do not develop anti-HBe seroconversion and for HBeAg-negative patients. This strategy is also recommended for patients with cirrhosis irrespective of the initial HBeAg status or anti-HBe seroconversion on treatment. The advantage of ETV and TDV is based on their high potency and optimal resistance profile. PMID- 25702056 TI - Salutation. PMID- 25702057 TI - Treatment of dyslipidemia in HIV. AB - Patients infected with HIV have a high risk of developing dyslipidemia. Effective therapeutic strategies can be challenging due to an increase risk of drug interactions and other comorbidities. Understanding the underlying pathophysiology and the principles of pharmacological and non-pharmacological therapeutic interventions can be of value in the appropriate management of dyslipidemia in the HIV-infected patient. PMID- 25702058 TI - Sortilin, encoded by the cardiovascular risk gene SORT1, and its suggested functions in cardiovascular disease. AB - Several genome-wide association studies have linked novel loci to a wide range of cardiovascular phenotypes including low-density lipoprotein (LDL)-cholesterol, early onset myocardial infarction, coronary artery calcification, coronary artery stenosis, and abdominal aorta aneurysm. Especially, one locus, namely, 1p13.3, has attracted much attention. This locus harbors four candidate genes, CELSR2, PSRC1, MYBPHL, and SORT1. SORT1 encodes sortilin, a type I sorting receptor that has recently been implicated in LDL-cholesterol metabolism, VLDL secretion, PCSK9 secretion, and development of atherosclerotic lesions. Furthermore, sortilin also seems to be involved in the development of atherosclerosis, by mechanisms not directly involving LDL-cholesterol, but possibly resulting from the attenuated secretion of proinflammatory cytokines, such as IL6 and TNFalpha, which accompanies lack of sortilin in immune cells. Sortilin seems to play an important role in the development of cardiovascular disease and have functions beyond regulating LDL-cholesterol. PMID- 25702059 TI - The association of dietary alpha-linolenic acid with blood pressure and subclinical atherosclerosis in people born small for gestational age: the Special Turku Coronary Risk Factor Intervention Project study. AB - OBJECTIVE: To determine whether dietary alpha-linolenic (omega-3) fatty acid intake is associated with lower blood pressure and aortic intima-media thickness (IMT) in people born small for gestational age (SGA). STUDY DESIGN: Participants were recruited at age 6 months and followed up every 6-12 months until age 19 years. Blood pressure and food records were assessed at each visit. A total of 1009 participants had at least one blood pressure measure and complete birth weight and gestational age data, including 115 (11%) born SGA (birth weight<=10th percentile). Aortic IMT was assessed by ultrasound at 19 years (n=413). Analysis was by linear mixed models and multivariable linear regression. RESULTS: Children born SGA had greater systolic and pulse pressure from age 14 years onwards. In those born SGA, systolic blood pressure was 2.1 mm Hg lower ([95% CI 0.8-3.3]; P=.001) and pulse pressure 1.4 mm Hg lower ([95% CI 0.3-2.4]; P=.01), per exponential increase in alpha-linolenic acid (ALA) intake; weakened by adjustment for anthropometric measures. Long-term ALA intake was inversely associated with aortic IMT at 19 years in those born SGA (-0.30 mm [95% CI -0.52, -0.08] per exponential greater ALA intake; P=.008), independent of other dietary and anthropometric factors. CONCLUSION: Long-term dietary ALA intake during childhood is associated with improved vascular health in people born SGA. PMID- 25702060 TI - Rectal temperatures, respiratory rates, production, and reproduction performances of crossbred Girolando cows under heat stress in northeastern Brazil. AB - This study compared the two breed groups of Girolando (1/2 Holstein 1/2 Gyr vs. 3/4 Holstein 1/4 Gyr) through analysis of the percentages (stressed or non stressed cows) of rectal temperature (RT), respiratory rate (RR) and pregnancy rate (PR), and means of production and reproduction parameters to determine the group best suited to rearing in semiarid tropical climate. The experiment was conducted at the farm, in the municipality of Umirim, State of Ceara, Brazil. Two hundred and forty cows were used in a 2 * 2 factorial study; 120 of each group were kept under an intensive system during wet and dry seasons. The environmental parameters obtained were relative humidity (RH), air temperature (AT), and the temperature and humidity index (THI). Pregnancy diagnosis (PD) was determined by ultrasonography 30 days after artificial insemination (AI). The milk production of each cow was recorded with automated milkings in the farm. The variables were expressed as mean and standard error, evaluated by ANOVA at 5% probability using the GLM procedure of SAS. Chi-square test at 5% probability was applied to data of RT, RR, pregnancy rate (PR), and the number of AIs to obtain pregnancy. The majority of 1/2 Holstein cows showed mean values of RT and RR within the normal range in both periods and shifts. Most animals of the 3/4 Holstein group exhibited the RR means above normal during the afternoon in the rainy and dry periods and RT means above normal during the afternoon in the dry period. After analyses, 1/2 Holstein crossbred cows are more capable of thermoregulating than 3/4 Holstein cows under conditions of thermal stress, and the dry period was more impacting for bovine physiology with significant changes in physiological parameters, even for the first breed group. Knowledge of breed groups adapted to climatic conditions of northeastern Brazil can directly assist cattle farmers in selecting animals best adapted for forming herds. PMID- 25702061 TI - A simple, fast and convenient new method for predicting the stability of nitro compounds. AB - A new method has been proposed to understand and predict the stability of nitro compounds. This method uses the maximum electron densities at the critical points of two N-O bonds of nitro groups (rho max), and it is more simple and faster than the existing methods and applicable to bigger systems. The correlations between the rho max and total energy (E), bond lengths (R C-NO2, R N-NO2 and R )-NO2), bond dissociation energy (BDE), and impact sensitivity (h 50) reveal that the molecular stability, which can be reflected by E, R, BDE and h 50, generally decreases with the increasing rho max. The compound with the larger rho max is less stable. For the nitrating reaction, the smaller rho max of the product generally implies the easier and faster reaction and the higher occurrence ratio of the product. Therefore, rho max can be applied to predict the stability of nitro compounds and the easiness of the nitrating reaction. PMID- 25702062 TI - [Experiences of main caregivers helping patients suffering from lung cancer and position assigned to general practitioners]. AB - INTRODUCTION: Cancer turns into a chronic disease. Its impact on patient's daily life may require the assistance of caregiver. AIMS: To explore the experiences of main caregivers (MCs) helping patients suffering from lung cancer (LC), and to explore the role and the position assigned to general practitioners (GPs). METHOD: Qualitative study using semi-directive interviews with 13 PCs, recruited in Roanne's hospital and the Cancer Institute Lucien-Neuwirth (Rhone-Alpes), conducted from February to May 2014. RESULTS: MCs' life was affected on a social, family, and professional level. Despite a need of listening and support, they remained behind, by devotion. GPs' were care managers, and were found out empathic, compassionate and reassuring. Present at the cancer announcement and viewed as an actor at the end of life, their functions were variable, following MCs during the treatment phase. During this phase, some of them perceived that lack of time, expertise and/or information seemed to be an obstacle to their solicitations. CONCLUSION: GPs' regular care could improve MCs' quality of life. Telemedicine could facilitate communication between GPs and hospital staff asked by the MCs. PMID- 25702063 TI - Expanding access to medical abortion: challenges and opportunities. PMID- 25702064 TI - Women's experiences with the use of medical abortion in a legally restricted context: the case of Argentina. AB - This article presents the findings of a qualitative study exploring the experiences of women living in Buenos Aires Metropolitan Area, Argentina, with the use of misoprostol for inducing an abortion. We asked women about the range of decisions they had to make, their emotions, the physical experience, strategies they needed to use, including seeking health care advice and in dealing with a clandestine medical abortion, and their overall evaluation of the experience. An in-depth interview schedule was used. The women had either used misoprostol and sought counselling or care at a public hospital (n=24) or had used misoprostol based on the advice of a local hotline, information from the internet or from other women (n=21). Four stages in the women's experiences were identified: how the decision to terminate the pregnancy was taken, how the medication was obtained, how the tablets were used, and reflections on the outcome whether or not they sought medical advice. Safety and privacy were key in deciding to use medical abortion. Access to the medication was the main obstacle, requiring a prescription or a friendly drugstore. Correct information about the number of pills to use and dosage intervals was the least easy to obtain and caused concerns. The possibility of choosing a time of privacy and having the company of a close one was highlighted as a unique advantage of medical abortion. Efforts to improve abortion law, policy and service provision in Argentina in order to ensure the best possible conditions for use of medical abortion by women should be redoubled. PMID- 25702065 TI - Perceptions of misoprostol among providers and women seeking post-abortion care in Zimbabwe. AB - In Zimbabwe, abortions are legally restricted and complications from unsafe abortions are a major public health concern. This study in 2012 explored women's and providers' perspectives in Zimbabwe on the acceptability of the use of misoprostol as a form of treatment for complications of abortion in post-abortion care. In-depth interviews were conducted with 115 participants at seven post abortion care facilities. Participants included 73 women of reproductive age who received services for incomplete abortion and 42 providers, including physicians, nurses, midwives, general practitioners and casualty staff. Only 29 providers had previously used misoprostol with their own patients, and only 21 had received any formal training in its use. Nearly all women and providers preferred misoprostol to surgical abortion methods because it was perceived as less invasive, safer and more affordable. Women also generally preferred the non-surgical method, when given the option, as fears around surgery and risk were high. Most providers favoured removing legal restrictions on abortion, particularly medical abortion. Approving use of misoprostol for post-abortion care in Zimbabwe is important in order to reduce unsafe abortion and its related sequelae. Legal, policy and practice reforms must be accompanied by effective reproductive health curricula updates in medical, nursing and midwifery schools, as well as through updated training for current and potential providers of post-abortion care services nationwide. Our findings support the use of misoprostol in national post-abortion care programmes, as it is an acceptable and potentially life-saving treatment option. PMID- 25702066 TI - The unmet need for safe abortion in Turkey: a role for medical abortion and training of medical students. AB - Abortion has been legal and safe in Turkey since 1983, but the unmet need for safe abortion services remains high. Many medical practitioners believe that the introduction of medical abortion would address this. However, since 2012 there has been political opposition to the provision of abortion services. The government has been threatening to restrict the law, and following an administrative change in booking of appointments, some hospital clinics that provided family planning and abortion services had to stop providing abortions. Thus, the availability of safe abortion depends not only on permissive legislation but also political support and the ability of health professionals to provide it. We conducted a study among university medical school students in three provinces on their knowledge of abortion and abortion methods, to try to understand their future practice intentions. Pre-tested, structured, self administered questionnaires were answered by 209 final-year medical students. The students' level of knowledge of abortion and abortion methods was very low. More than three-quarters had heard of surgical abortion, but only 56% mentioned medical abortion. Although nearly 90% supported making abortion services available in Turkey, their willingness to provide surgical abortion (16%) or medical abortion (15%) was low, due to lack of knowledge. Abortion care, including medical abortion, needs to be included in the medical school curriculum in order to safeguard this women's health service. PMID- 25702067 TI - Physicians' and non-physicians' views about provision of medical abortion by nurses and AYUSH physicians in Maharashtra and Bihar, India. AB - There is only limited evidence on whether certified and uncertified health care providers in India support reforming the Medical Termination of Pregnancy (MTP) Act to expand the abortion provider base to allow trained nurses and AYUSH physicians (who are trained in Indian systems of medicine) to provide medical abortion. To explore their views, we conducted a survey of 1,200 physicians and other health care providers in Maharashtra and Bihar states and in-depth interviews with 34 of them who had used medical abortion in their practices. Findings indicate that obstetrician-gynaecologists and other allopathic physicians were less supportive than non-physicians of nurses and AYUSH physicians providing early medical abortion. The physicians did not think that these providers would be able to assess women's eligibility for medical abortion correctly. In contrast, the majority of non-physicians found task shifting of medical abortion provision to trained nurses and AYUSH physicians acceptable, and they were confident that these providers would be able to provide medical abortion as safely and effectively as trained physicians. Assuming the reforms are passed, efforts will need to be made by government and medical professional bodies to train these new providers to undertake this role, prepare the health infrastructure to include them, and create an environment, including among physicians, that is conducive to enabling non-physicians to provide medical abortion. PMID- 25702068 TI - Towards safe abortion access: an exploratory study of medical abortion in Cambodia. AB - In 2010, following its approval by the Ministry of Health, the medical abortion combination pack Medabon (containing mifepristone and misoprostol) was made available at pharmacies and in a restricted number of health facilities in Cambodia. The qualitative study presented in this paper was conducted in 2012 as a follow-up to longer-term ethnographical research related to reproductive health and fertility regulation between 2008 and 2012. Observations were carried out at several clinic and pharmacy sites and in-depth interviews were conducted with a purposive sample of 20 women who attended two MSI Cambodia centres and 10 women identified through social networks; six men (women's male partners); eight health care providers at the two MSI centres and four pill sellers at private or informal pharmacies (who also provided health care services in private clinics). Although the level of training among the drug sellers and providers varied, their knowledge about medical abortion regimens, correct usage and common side effects was good. Overall, women were satisfied with the services provided. Medical abortion was not always a women-only process in this study as some male partners were also involved in the care process. The study illustrates positive steps forward being taken in making abortion safe and preventing and reducing unsafe abortion practices in Cambodia. PMID- 25702069 TI - The introduction of first trimester medical abortion in Armenia. AB - In Armenia, abortion is the main means of fertility regulation; however, before research activities were initiated only surgical methods were available and the quality of services was low in some areas. Our clinical study from 2008-2011 aimed to show that early medical abortion is an acceptable and feasible option. A total of 700 eligible women with pregnancies up to 63 days LMP presenting for abortion were recruited for the study in five locations. Participants took 200 mg mifepristone and 800 MUg buccal misoprostol 24-48 hours later. They returned for a follow-up visit two weeks after mifepristone administration. 95% of the women had successful abortions and 95% were satisfied with the method. In 2012-2013, we conducted a follow-up assessment to examine the ongoing provision and quality of medical abortion services at the former research sites. Medical record reviews, interviews and observations were carried out three times approximately six months apart. The assessment found that all five sites had continued providing medical abortion, with about half of eligible women choosing the medical method. Four of the five sites were achieving high success rates. Staff turnover and the lack of trained providers likely contributed to the higher failure rate at the fifth site. These findings provide evidence that first trimester medical abortion is an acceptable and feasible option for Armenian women and providers, and that high quality services are being delivered. PMID- 25702070 TI - Increasing access to safe menstrual regulation services in Bangladesh by offering medical menstrual regulation. AB - In spite of wide availability of menstrual regulation services, women often resort to a variety of medicines for inducing abortion. The Bangladeshi Government is now supporting attempts to investigate the introduction of medical menstrual regulation in the public sector. This study examined the acceptability of medical menstrual regulation in public sector urban-based clinics, public sector rural-based clinics and urban-based clinics run by Marie Stopes, a non governmental organization. Of the 2,976 women who attended for menstrual regulation services during the eight-month study period, 68% attended urban Maternal and Child Welfare Centres and the Marie Stopes clinics, while 32% went to the rural public facilities of the Union Health and Family Welfare Centre. Women were offered both medical and manual vacuum aspiration methods of menstrual regulation; 1,875 (63%) chose the medical method and 1,101 (37%) chose manual vacuum aspiration. Around 7.1% of women at Maternal and Child Welfare centres and 11.9% at the Marie Stopes clinics knew about medical menstrual regulation before taking the service, compared to a much higher proportion (43%) at the rural facilities. Overall 61.4% of women who used medical menstrual regulation found the method satisfactory, and 34.2% were very satisfied. Of the 3.9% of women who were not satisfied, most received services from rural facilities. PMID- 25702071 TI - Safety, efficacy and acceptability of outpatient mifepristone-misoprostol medical abortion through 70 days since last menstrual period in public sector facilities in Mexico City. AB - Extensive evidence exists regarding the efficacy and acceptability of medical abortion through 63 days since last menstrual period (LMP). In Mexico City's Secretariat of Health (SSDF) outpatient facilities, mifepristone-misoprostol medical abortion is the first-line approach for abortion care in this pregnancy range. Recent research demonstrates continued high rates of complete abortion through 70 days LMP. To expand access to legal abortion services in Mexico City (where abortion is legal through 12 weeks LMP), this study sought to assess the efficacy and acceptability of the standard outpatient approach through 70 days in two SSDF points of service. One thousand and one women seeking pregnancy termination were enrolled and given 200 mg mifepristone followed by 800 MUg misoprostol 24-48 hours later. Women were asked to return to the clinic one week later for evaluation. The great majority of women (93.3%; 95% CI: 91.6-94.8) had complete abortions. Women with pregnancies <= 8 weeks LMP had significantly higher success rates than women in the 9th or 10th weeks (94.9% vs. 90.5%; p = 0.01). The difference in success rates between the 9th and 10th weeks was not significant (90.0% vs. 91.2%; p = 0.71). The majority of women found the side effects (82.9%) and the use of misoprostol (84.4%) to be very acceptable or acceptable. This study provides additional evidence supporting an extended outpatient medical abortion regimen through 10 weeks LMP. PMID- 25702072 TI - Assessment of completion of early medical abortion using a text questionnaire on mobile phones compared to a self-administered paper questionnaire among women attending four clinics, Cape Town, South Africa. AB - In-clinic follow-up to assess completion of medical abortion is no longer a requirement according to World Health Organization guidance, provided adequate counselling is given. However, timely recognition of ongoing pregnancy, complications or incomplete abortion, which require treatment, is important. As part of a larger trial, this study aimed to establish whether women having a medical abortion could self-assess whether their abortion was complete using an automated, interactive questionnaire on their mobile phones. All 469 participants received standard abortion care and all returnees filled in a self-assessment on paper at clinic follow-up 2-3 weeks later. The 234 women allocated to receive the phone messages were also asked to do a mobile phone assessment at home ten days post-misoprostol. Completion of the mobile assessment was tracked by computer and all completed assessments, paper and mobile, were compared to providers' assessments at clinic follow-up. Of the 226 women able to access the mobile phone assessment, 176 (78%) completed it; 161 of them (93%) reported it was easy to do so. Neither mobile nor paper self-assessments predicted all cases needing additional treatment at follow-up. Prediction of complete procedures was good; 71% of mobile assessments and 91% of paper assessments were accurate. We conclude that an interactive questionnaire assessing completion of medical abortion on mobile phones is feasible in the South African setting; however, it should be done later than day 10 and combined with an appropriate pregnancy test to accurately detect incomplete procedures. PMID- 25702073 TI - The role of auxiliary nurse-midwives and community health volunteers in expanding access to medical abortion in rural Nepal. AB - Medical abortion was introduced in Nepal in 2009, but rural women's access to medical abortion services remained limited. We conducted a district-level operations research study to assess the effectiveness of training 13 auxiliary nurse-midwives as medical abortion providers, and 120 female community health volunteers as communicators and referral agents for expanding access to medical abortion for rural women. Interviews with service providers and women who received medical abortion were undertaken and service statistics were analysed. Compared to a neighbouring district with no intervention, there was a significant increase in the intervention area in community health volunteers' knowledge of the legal conditions for abortion, the advantages and disadvantages of medical abortion, safe places for an abortion, medical abortion drugs, correct gestational age for home use of medical abortion, and carrying out a urine pregnancy test. In a one-year period in 2011-12, the community health volunteers did pregnancy tests for 584 women and referred 114 women to the auxiliary nurse midwives for abortion; 307 women in the intervention area received medical abortion services from auxiliary nurse-midwives. There were no complications that required referral to a higher-level facility except for one incomplete abortion. Almost all women who opted for medical abortion were happy with the services provided. The study demonstrated that auxiliary nurse-midwives can independently and confidently provide medical abortion safely and effectively at the sub-health post level, and community health volunteers are effective change agents in informing women about medical abortion. PMID- 25702074 TI - Pharmacy workers in Nepal can provide the correct information about using mifepristone and misoprostol to women seeking medication to induce abortion. AB - In Nepal, despite policy restrictions, both registered and unregistered brands of mifepristone and misoprostol can easily be obtained at pharmacies. Since many women visit pharmacies for abortion information, ensuring that they receive effective care from pharmacy workers remains an important challenge. We conducted an operations research study to examine whether trained pharmacy workers can correctly provide information on safe use of mifepristone and misoprostol for early first trimester medical abortion. Pharmacy workers in one district were given orientation and training using a harm-reduction approach, and compared with a non-equivalent comparison group in the second district. Overall, trained pharmacy workers' knowledge increased substantially, but no increase was found in the comparison group. Compared to the baseline (65%), 97% of trained pharmacy workers knew up to what stage of pregnancy and how women should use mifepristone and misoprostol. A higher percentage of pharmacy workers in the intervention group (77%) compared to the comparison group (49%) were knowledgeable at follow up about determining whether an abortion was successful, implying a need for improving this aspect of training. As many mid-level health providers run their own pharmacies and offer medical abortion pills, it is important for the government to consider training these providers and registering their pharmacies as safe medical abortion service outlets. PMID- 25702075 TI - Using a harm reduction lens to examine post-intervention results of medical abortion training among Zambian pharmacists. AB - Despite broad grounds for legal abortion in Zambia, access to abortion services remains limited. Pharmacy workers, a primary source of health care for communities, present an opportunity to bridge the gap between policy and practice. As part of a larger operations study, 80 pharmacy workers, both registered pharmacists and their assistants, participated in a training on medical abortion in 2009 and 2010. Fifty-five of the 80 pharmacy workers completed an anonymous, structured training pre-test, treated as a baseline questionnaire; 53 of the 80 trainees were interviewed 12-24 months post-training in face-to-face interviews to measure the retention of information and training effectiveness. Survey questions were selected to illustrate the principles of a harm reduction approach to unsafe abortion. Bivariate analysis was used to examine pharmacy worker knowledge, attitudes and dispensing behaviours pre training and at follow-up. A higher percentage of pharmacy workers reported referring women to a health care facility between surveys (47% to 68%, p = 0.03). The number of pharmacy workers who reported dispensing ineffective abortifacients decreased from baseline to end-line (30% to 25%) but the difference was non significant. However, study results demonstrate that Zambian pharmacy workers have a role to play in safe abortion services and some are willing to play that role. PMID- 25702076 TI - Medical abortion and manual vacuum aspiration for legal abortion protect women's health and reduce costs to the health system: findings from Colombia. AB - The majority of abortions in Colombia continue to take place outside the formal health system under a range of conditions, with the majority of women obtaining misoprostol from a thriving black market for the drug and self-administering the medication. We conducted a cost analysis to compare the costs to the health system of three approaches to the provision of abortion care in Colombia: post abortion care for complications of unsafe abortions, and for legal abortions in a health facility, misoprostol-only medical abortion and vacuum aspiration abortion. Hospital billing records from three institutions, two large maternity hospitals and one specialist reproductive health clinic, were analysed for procedure and complication rates, and costs by diagnosis. The majority of visits (94%) were to the two hospitals for post-abortion care; the other 6% were for legal abortions. Only one minor complication was found among the women having legal abortions, a complication rate of less than 1%. Among the women presenting for post-abortion care, 5% had complications during their treatment, mainly from infection or haemorrhage. Legal abortions were associated not only with far fewer complications for women, but also lower costs for the health system than for post abortion care. We calculated based on our findings that for every 1,000 women receiving post-abortion care instead of a legal abortion within the health system, 16 women experienced avoidable complications, and the health system spent US $48,000 managing them. Increasing women's access to safe abortion care would not only reduce complications for women, but would also be a cost-saving strategy for the health system. PMID- 25702077 TI - Safe, accessible medical abortion in a rural Tamil Nadu clinic, India, but what about sexual and reproductive rights? AB - Women's control over their own bodies and reproduction is a fundamental prerequisite to the achievement of sexual and reproductive health and rights. A woman's ability to terminate an unwanted pregnancy has been seen as the exercise of her reproductive rights. This study reports on interviews with 15 women in rural South India who had a medical abortion. It examines the circumstances under which they chose to have an abortion and their perspectives on medical abortion. Women in this study decided to have an abortion when multiple factors like lack of spousal support for child care or contraception, hostile in-laws, economic hardship, poor health of the woman herself, spousal violence, lack of access to suitable contraceptive methods, and societal norms regarding reproduction and sexuality converged to oppress them. The availability of an easy and affordable method like medical abortion pills helped the women get out of a difficult situation, albeit temporarily. Medical abortion also fulfilled their special needs by ensuring confidentiality, causing least disruption of their domestic schedule, and dispensing with the need for rest or a caregiver. The study concludes that medical abortion can help women in oppressive situations. However, this will not deliver gender equality or women's empowerment; social conditions need to change for that. PMID- 25702078 TI - Candidial Endocarditis: A Single-Institute Pathological Analysis. AB - Infective endocarditis is increasingly perceived as a byproduct of aggressive medications and/or invasive medical procedures. Some of the organisms are fungi, and in this situation, Candida species account for nearly half of all fungal IE. We report a single-institute pathological experience of 14 cases of candidial endocarditis among surgically excised cardiac tissues and autopsied cases in a 14 year period. Twelve of the 14 cases were seen as healthcare-associated invasive infections, and only five had been diagnosed antemortem. Candidial endocarditis was predominantly right-sided and valvular. The risk factors included underlying heart diseases, central venous catheterization and prolonged antibiotic therapy. Mortality among the autopsied patients was related to septicemia and/or embolic complications. PMID- 25702079 TI - Capillary electrophoresis fingerprinting of 8-aminopyrene-1,3,6-trisulfonate derivatized nitrocellulose after partial acid depolymerization. AB - Fine characterization of nitrocellulose (NC) remains a challenge, especially in forensic analysis, and a strategy consisting in obtaining representative fingerprints by a separation technique, as for proteins, is of prime interest. In this work, we first established that NCs (especially of high molar mass) cannot be representatively derivatized by 8-aminopyrene-1,3,6-trisulfonic acid (APTS), because of their poor solubility in the medium required for APTS derivatization. Therefore, a partial acid depolymerization step was considered, prior to derivatization by APTS, in an attempt to generate a mixture of oligosaccharides retaining information on the initial NC sample and/or on the cellulose used to prepare it. Acid depolymerization conditions (time and acid concentration) as well as APTS derivatization conditions (time, temperature, APTS/NC and reducing agent/APTS molar ratios) were investigated for lowly-nitrated NCs. The best compromise between depolymerization yields, speed, and pertinency of the resulting oligosaccharidic mixture was obtained using fuming hydrochloric acid (37%, w/w) at 50 degrees C for 30 min. The most effective procedure for APTS derivatization of oligosaccharides obtained after partial acid depolymerization of NC was achieved at 70 degrees C for 2h. The resulting APTS-derivatized oligosaccharides were then separated by capillary electrophoresis (CE) using a background electrolyte composed of 60mM 6-aminocaproic acid, pH 4.5 (adjusted with acetic acid)+0.02% hydroxypropyl methyl cellulose. Finally, for the first time, they were identified using APTS-derivatized cellodextrin standards and by matrix-assisted laser desorption-ionization time-of-flight mass spectrometry (MALDI-TOF MS). PMID- 25702080 TI - Displacement chromatography of proteins using a retained pH front in a hydrophobic charge induction chromatography column. AB - The chromatographic separation of two proteins into a displacement train of two adjoined rectangular bands was accomplished using a novel method for hydrophobic charge induction chromatography (HCIC) which employs a self-sharpening pH front as the displacer. This method exploits the fact that protein elution in HCIC is promoted by a pH change, but is relatively independent of salt effects, so that a retained pH front can be used in place of a traditional displacer in displacement chromatography. The retained pH front was produced using the two adsorbed buffering species tricine and acetic acid. The separation of lysozyme and alpha chymotrypsinogen A into adjoined, rectangular bands was accomplished with overall recoveries based on the total mass injected greater than 90 and 70%, respectively. The addition of urea to the buffer system increased the sharpness of the pH front by 36% while the yields of lysozyme and alpha-chymotrypsinogen A based on the total mass eluted increased from 76% to 99% and from 37% to 85%, respectively, when the purities of both proteins in their product fractions were fixed at 85%. The results demonstrate that the method developed in this study is a useful variant of HCIC and is also a useful alternative to other displacement chromatography methods. PMID- 25702081 TI - Multivariate analysis of chromatographic retention data as a supplementary means for grouping structurally related compounds. AB - In the present study a series of 45 metabolite standards belonging to four chemically similar metabolite classes (sugars, amino acids, nucleosides and nucleobases, and amines) was subjected to LC analysis on three HILIC columns under 21 different gradient conditions with the aim to explore whether the retention properties of these analytes are determined from the chemical group they belong. Two multivariate techniques, principal component analysis (PCA) and discriminant analysis (DA), were used for statistical evaluation of the chromatographic data and extraction similarities between chemically related compounds. The total variance explained by the first two principal components of PCA was found to be about 98%, whereas both statistical analyses indicated that all analytes are successfully grouped in four clusters of chemical structure based on the retention obtained in four or at least three chromatographic runs, which, however should be performed on two different HILIC columns. Moreover, leave-one-out cross-validation of the above retention data set showed that the chemical group in which an analyte belongs can be 95.6% correctly predicted when the analyte is subjected to LC analysis under the same four or three experimental conditions as the all set of analytes was run beforehand. That, in turn, may assist with disambiguation of analyte identification in complex biological extracts. PMID- 25702082 TI - Coupling passive sampling and time of flight mass spectrometry for a better estimation of polar pesticide freshwater contamination: Simultaneous target quantification and screening analysis. AB - The aim of this study was first to develop and validate an analytical method for the quantification of 35 polar pesticides and 9 metabolites by ultra-high performance-liquid chromatography combined with a high resolution time-of-flight mass spectrometer detector (UHPLC-(Q)-TOF). Various analytical conditions were investigated (eluent composition and mass parameters) to optimize analyte responses. Analytical performance (linearity, limit of quantification, and accuracy) was then evaluated and interference in the extract of a passive sampler exposed in freshwater (POCIS: Polar Organic Chemical Integrative Sampler) was studied. The proposed quantification method was validated for 43 compounds with variation of calibration slopes below 10% in environmental matrix. For the unvalidated compound DIA (atrazine-desisopropyl: an atrazine metabolite), interference increased the error of concentration determination (50%). The limits of quantification obtained by combining POCIS and UHPLC-(Q)-TOF for 43 target compounds were between 0.1 (terbuthylazine) and 10.7 ng/L (acetochlor). Secondly, the method was successfully applied during a 14-day POCIS river exposure, and gave concentration values similar to a more commonly used triple quadrupole detector regarding concentration, but allowed for the detection of more compounds. Additionally with the targeted compound quantification, the (Q)-TOF mass spectrometer was also used for screening non-target compounds (other pesticides and pharmaceuticals) in POCIS extracts. Moreover, the acquisition of full scan MS data allowed the identification of the polyethylene glycol (PEG) compounds which gave unresolvable interference to DIA, and thus questions the ability of DIA to be used as performance reference compound (PRC) to determine sampling rates in situ. This study therefore illustrates the potential, and proposes a pathway, of UHPLC-(Q)-TOF combined with POCIS in situ pre concentration for both quantitative and screening analyses of organic contaminants in water. PMID- 25702083 TI - Occurrence of phthalate diesters in particulate and vapor phases in indoor air and implications for human exposure in Albany, New York, USA. AB - Phthalate diesters are used as plasticizers in a wide range of consumer products. Because phthalates have been shown in laboratory animal studies to be toxic, human exposure to these chemicals is a matter of concern. Nevertheless, little is known about inhalation exposure to phthalates in the United States. In this study, occurrence of nine phthalates was determined in 60 indoor air samples collected in 2014 in Albany, New York, USA. Airborne particulate and vapor phase samples were collected from various sampling locations by use of a low-volume air sampler. The median concentrations of nine phthalates in air samples collected from homes, offices, laboratories, schools, salons (hair and nail salons), and public places were 732, 143, 170, 371, 2600, and 354 ng/m(3), respectively. Diethyl phthalate (DEP) was found at the highest concentrations, which ranged from 4.83 to 2250 ng/m(3) (median 152) followed by di-n-butyl phthalate, which ranged from 4.05 to 1170 ng/m(3) (median 63.3). The median inhalation exposure dose to phthalates was estimated at 0.845, 0.423, 0.203, 0.089, and 0.070 ug/kg bw/d for infants, toddlers, children, teenagers, and adults, respectively. Inhalation is an important pathway of human exposure to DEP. PMID- 25702084 TI - Creatine, similarly to ketamine, affords antidepressant-like effects in the tail suspension test via adenosine A1 and A2A receptor activation. AB - The benefits of creatine supplementation have been reported in a broad range of central nervous systems diseases, including depression. A previous study from our group demonstrated that creatine produces an antidepressant-like effect in the tail suspension test (TST), a predictive model of antidepressant activity. Since depression is associated with a dysfunction of the adenosinergic system, we investigated the involvement of adenosine A1 and A2A receptors in the antidepressant-like effect of creatine in the TST. The anti-immobility effect of creatine (1 mg/kg, po) or ketamine (a fast-acting antidepressant, 1 mg/kg, ip) in the TST was prevented by pretreatment of mice with caffeine (3 mg/kg, ip, nonselective adenosine receptor antagonist), 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) (2 mg/kg, ip, selective adenosine A1 receptor antagonist), and 4-(2-[7 amino-2-{2-furyl}{1,2,4}triazolo-{2,3-a}{1,3,5}triazin-5-yl-amino]ethyl)-phenol (ZM241385) (1 mg/kg, ip, selective adenosine A2A receptor antagonist). In addition, the combined administration of subeffective doses of creatine and adenosine (0.1 mg/kg, ip, nonselective adenosine receptor agonist) or inosine (0.1 mg/kg, ip, nucleoside formed by the breakdown of adenosine) reduced immobility time in the TST. Moreover, the administration of subeffective doses of creatine or ketamine combined with N-6-cyclohexyladenosine (CHA) (0.05 mg/kg, ip, selective adenosine A1 receptor agonist), N-6-[2-(3,5-dimethoxyphenyl)-2 (methylphenyl)ethyl]adenosine (DPMA) (0.1 mg/kg, ip, selective adenosine A2A receptor agonist), or dipyridamole (0.1 MUg/mouse, icv, adenosine transporter inhibitor) produced a synergistic antidepressant-like effect in the TST. These results indicate that creatine, similarly to ketamine, exhibits antidepressant like effect in the TST probably mediated by the activation of both adenosine A1 and A2A receptors, further reinforcing the potential of targeting the purinergic system to the management of mood disorders. PMID- 25702085 TI - Photoprotective capacity of non-photochemical quenching in plants acclimated to different light intensities. AB - Arabidopsis plants grown at low light were exposed to a gradually increasing actinic light routine. This method allows for the discerning of the photoprotective component of NPQ, pNPQ and photoinhibition. They exhibited lower values of Photosystem II (PSII) yield in comparison to high-light grown plants, and higher calculated dark fluorescence level (F'o calc.) than the measured one (F'o act.). As a result, in low-light grown plants, the values of qP measured in the dark appeared higher than 1. Normally, F'o act. and F'o calc. match well at moderate light intensities but F'o act. becomes higher at increasing intensities due to reaction centre (RCII) damage; this indicates the onset of photoinhibition. To explain the unusual increase of qP in the dark in low-light grown plants, we have undertaken an analysis of PSII antenna size using biochemical and spectroscopic approaches. Sucrose gradient separation of thylakoid membrane complexes and fast fluorescence induction experiments illustrated that the relative PSII cross section does not increase appreciably with the rise in PSII antenna size in the low-light grown plants. This suggests that part of the increased LHCII antenna is less efficiently coupled to the RCII. A model based upon the existence of an uncoupled population LHCII is proposed to explain the discrepancies in calculated and measured values of F'o. PMID- 25702086 TI - Cyanofuels: biofuels from cyanobacteria. Reality and perspectives. AB - Cyanobacteria are represented by a diverse group of microorganisms that, by virtue of being a part of marine and freshwater phytoplankton, significantly contribute to the fixation of atmospheric carbon via photosynthesis. It is assumed that ancient cyanobacteria participated in the formation of earth's oil deposits. Biomass of modern cyanobacteria may be converted into bio-oil by pyrolysis. Modern cyanobacteria grow fast; they do not compete for agricultural lands and resources; they efficiently convert excessive amounts of CO2 into biomass, thus participating in both carbon fixation and organic chemical production. Many cyanobacterial species are easier to genetically manipulate than eukaryotic algae and other photosynthetic organisms. Thus, the cyanobacterial photosynthesis may be directed to produce carbohydrates, fatty acids, or alcohols as renewable sources of biofuels. Here we review the recent achievements in the developments and production of cyanofuels-biofuels produced from cyanobacterial biomass. PMID- 25702087 TI - Dynamic modulation of HSV chromatin drives initiation of infection and provides targets for epigenetic therapies. AB - Upon infection, the genomes of herpesviruses undergo a striking transition from a non-nucleosomal structure to a chromatin structure. The rapid assembly and modulation of nucleosomes during the initial stage of infection results in an overlay of complex regulation that requires interactions of a plethora of chromatin modulation components. For herpes simplex virus, the initial chromatin dynamic is dependent on viral and host cell transcription factors and coactivators that mediate the balance between heterochromatic suppression of the viral genome and the euchromatin transition that allows and promotes the expression of viral immediate early genes. Strikingly similar to lytic infection, in sensory neurons this dynamic transition between heterochromatin and euchromatin governs the establishment, maintenance, and reactivation from the latent state. Chromatin dynamics in both the lytic infection and latency reactivation cycles provides opportunities to shift the balance using small molecule epigenetic modulators to suppress viral infection, shedding, and reactivation from latency. PMID- 25702089 TI - Enhanced antiproliferative and apoptosis effect of paclitaxel-loaded polymeric micelles against non-small cell lung cancers. AB - Amphiphilic copolymer monomethoxy poly(ethylene glycol)-poly(caprolactone)-D alpha-tocopheryl polyethylene glycol 1000 succinate (MPEG-PCL-TPGS) was prepared. In the present study, MPEG-PCL-TPGS was used as a novel nanovehicle for the delivery of paclitaxel (PTX) in the treatment of resistant lung cancers. The PTX loaded MPEG-PCL-TPGS (PTX/MPT) micelles exhibited sustained release profile (168 h) with accelerated drug release at acidic pH conditions. The blank polymeric micelles showed excellent biocompatibility with cell viability of >85 %, making it suitable for all in vivo applications. PTX/MPT micelles displayed superior cytotoxicity in A-549 lung cancer cells than that of free PTX. The selective delivery of PTX to cancer cells resulted in enhanced cancer cell death. The PTX/MPT micelles showed higher cellular uptake via endocytosis pathways. The PTX bound micelles preferentially arrested the cells at G2/M phase and showed a marked increase in sub G1 cell population (~ 20 %). The pharmacokinetic study revealed a long blood circulation for PTX/MPT micelles. Finally, micellar formulation showed a remarkable tumor suppression effect in resistant A549/Taxol cells bearing xenograft nude mice along with no toxicity profile. The results indicate that the PTX-loaded biocompatible polymeric nanosystem could act as a potential delivery system for the treatment of lung carcinomas. PMID- 25702088 TI - Reverse genetics of Mononegavirales: How they work, new vaccines, and new cancer therapeutics. AB - The order Mononegavirales includes five families: Bornaviridae, Filoviridae, Nyamaviridae, Paramyxoviridae, and Rhabdoviridae. The genome of these viruses is one molecule of negative-sense single strand RNA coding for five to ten genes in a conserved order. The RNA is not infectious until packaged by the nucleocapsid protein and transcribed by the polymerase and co-factors. Reverse genetics approaches have answered fundamental questions about the biology of Mononegavirales. The lack of icosahedral symmetry and modular organization in the genome of these viruses has facilitated engineering of viruses expressing fluorescent proteins, and these fluorescent proteins have provided important insights about the molecular and cellular basis of tissue tropism and pathogenesis. Studies have assessed the relevance for virulence of different receptors and the interactions with cellular proteins governing the innate immune responses. Research has also analyzed the mechanisms of attenuation. Based on these findings, ongoing clinical trials are exploring new live attenuated vaccines and the use of viruses re-engineered as cancer therapeutics. PMID- 25702090 TI - Identification of potential erythrocyte phospholipid fatty acid biomarkers of advanced lung adenocarcinoma, squamous cell lung carcinoma, and small cell lung cancer. AB - New biomarkers for lung cancer would be valuable. Our aim was to analyze the fatty acid profiles of the main phospholipid species in erythrocytes from patients with advanced squamous cell lung carcinoma (SCC), lung adenocarcinoma (ADC), and small cell lung cancer (SCLC) and benign lung diseases (chronic obstructive pulmonary disease (COPD) and asthma) to determine the fatty acids that could be use as lung cancer markers. Twenty-eight, 18, 14, 16, and 15 patients with, respectively, SCC, ADC, SCLC, asthma, and COPD and 50 healthy subjects were enrolled in the study. Fatty acid profiles were investigated using gas chromatography/mass spectrometry followed by receiver operating characteristic (ROC) curve analysis. The fatty acid profiles changed significantly in the different pathologies analyzed. Based on the diagnostic yields and operating characteristics, the most significant fatty acids that might be used as biomarkers were as follows: ADC--arachidonic acid (20:4n6) in phosphatidylcholine and oleic acid (18:1n9) in phosphatidylethanolamine (PE); SCC -eicosapentaenoic acid (20:5n3) in PE and palmitic acid (16:0) in phosphatidylserine + phosphatidylinositol (PS+PI); SCLC--eicosadienoic acid (20:2n6) in PS+PI and lignoceric acid (24:0) in sphingomyelin. In conclusion, fatty acids from erythrocyte phospholipid species might serve as biomarkers in the diagnosis, and probably in other aspects related to clinical disease management, of ADC, SCC, and SCLC. PMID- 25702091 TI - Statins augment efficacy of EGFR-TKIs in patients with advanced-stage non-small cell lung cancer harbouring KRAS mutation. AB - Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) represent novel effective agents approved for the treatment of patients with advanced-stage NSCLC. KRAS mutations have been reported as a negative prognostic and predictive factor in patients with NSCLC treated with EGFR-TKIs. Several studies have recently shown that statins can block tumour cell growth, invasion and metastatic potential. We analysed clinical data of 67 patients with locally advanced (IIIB) or metastatic stage (IV) NSCLC harbouring Kirsten rat sarcoma viral oncogene (KRAS) mutation treated with erlotinib or gefitinib. Twelve patients were treated with combination of EGFR-TKI and statin and 55 patients were treated with EGFR TKI alone. Comparison of patients' survival (progression-free survival (PFS) and overall survival (OS)) according to the treatment used was performed using the Gehan-Wilcoxon test. The median of PFS and OS for patients treated with EGFR-TKI alone was 1.0 and 5.4 months compared to 2.0 and 14.0 months for patients treated with combination of EGFR-TKI and statin (p = 0.025, p = 0.130). In conclusion, the study results suggest significant improvement of PFS for patients treated with combination of statin and EGFR-TKI, and the difference in OS was not significant. PMID- 25702092 TI - Interactions of sex and aging on spatiotemporal metrics in non-pathological gait: a descriptive meta-analysis. AB - BACKGROUND: Individual studies examining aging-related changes in gait offer conflicting information on differences between male and female spatiotemporal metrics over the course of a mature lifetime. Furthermore, these studies do not often account for a known difference in size between men and women, and thus may reach conclusions based upon size rather than sex differences. OBJECTIVE: To examine the influences of sex, height, and age on spatiotemporal metrics during non-pathological gait over the course of adult aging. DATA SOURCES: Potentially relevant articles were identified from PubMed, Web of Science, and Google Scholar using the key words 'gait,' 'walk', 'gender,' 'sex,' 'female,' 'male,' 'gait speed,' 'step length,' and 'cadence.' ELIGIBILITY CRITERIA: (1) article could be obtained in English, (2) contained information about non-pathological subjects, (3) analyzed kinematics of walking, (4) provided female and male data, (5) average female/male age difference not more than 5 years, (6) reported a measure of variance and number of subjects, and (7) no known retractions associated with the publication. RESULTS AND CONCLUSIONS: Non-dimensional gait speed analysis suggests that gait speed differences between men and women may be an artifact of size rather than sex. In both raw and dimensionless data, this analysis indicates that men may take longer step lengths than women, and women may have a higher cadence than men. This analysis also identified a possible increase in many metrics between 20 and 40 years of age, before decreasing around the fifth decade of life. Future studies should examine these trends across the entire lifespan. PMID- 25702093 TI - Understanding the barriers and enablers to implementation of a self-managed exercise intervention: a qualitative study. AB - BACKGROUND: Despite a proliferation of research evidence, there remains a 'gap' between what this evidence suggests and what happens in clinical practice. One reason why physiotherapists might not implement research evidence is because the findings do not align with their current practice preferences. OBJECTIVES: While conducting a multicentre RCT we aimed to explore possible implementation barriers and facilitators with regard to the intervention under evaluation; a self-managed loaded exercise programme for rotator cuff tendinopathy. DESIGN: A qualitative study within the framework of a mixed methods design. Data was collected using individual semi-structured interviews and analysed using the framework method. SETTING: Three NHS physiotherapy departments. PARTICIPANTS: Thirteen physiotherapists. RESULTS: Six themes were generated: (1) the physiotherapists preferred therapeutic option; (2) the role of the physiotherapist; (3) attributes of the intervention; (4) attitude to symptom response; (5) response to therapy, and (6) continuing professional development. Differences between the preferred therapeutic approach of the physiotherapists and the self-managed exercise intervention were apparent; particularly in relation to the type and number of exercises, the use of manual therapy and the extent of loading. The physiotherapists recognised their role as knowledge translators but certain attributes of the intervention appeared to serve as both a barrier and facilitator; particularly the simplicity. Opinion regarding the optimal symptom response during exercise prescription also differed. CONCLUSION: Some relevant and important physiotherapist related barriers and facilitators concerning implementation of research findings have been identified. The influence of these factors needs to be recognised and considered. PMID- 25702094 TI - Comparison of contrast-enhanced ultrasound and contrast-enhanced computed tomography in evaluating the treatment response to transcatheter arterial chemoembolization of hepatocellular carcinoma using modified RECIST. AB - PURPOSE: We aimed to compare contrast-enhanced ultrasound (CEUS) with contrast enhanced computed tomography (CECT) for evaluating the treatment response to transcatheter arterial chemoembolization (TACE) of hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Treatment responses of 130 patients who underwent TACE were evaluated by CEUS and CECT. We initially compared the abilities of CEUS and CECT to detect residual tumour, which were confirmed by histology or angiography. Then, we compared the tumour response to TACE assessed by CEUS and CECT, according to Modified Response Evaluation Criteria in Solid Tumours (mRECIST). RESULTS: The sensitivity and accuracy of detecting residual tumour by CEUS vs. CECT were 95.9 % vs. 76.2 % (p < 0.001) and 96.2 % vs. 77.7 % (p < 0.001), respectively. For target lesions, 13 patients were observed as complete response (CR) by CEUS, compared to 36 by CECT (p < 0.001). For nontarget lesions, 12 patients were observed as CR by CEUS, compared to 22 by CECT (p = 0.006). For overall response, eight patients were observed as CR by CEUS, compared to 31 by CECT (p < 0.001). CONCLUSION: The diagnostic performance of CEUS was superior to CECT for detecting residual tumour after TACE. In clinical, CEUS should be recommended as an optional procedure for assessing the tumour response to TACE. KEY POINTS: * The mRECIST are widely applied for evaluating the response of HCC. * Imaging method has been applied to assess the therapeutic response to TACE. * The diagnostic performance of CEUS was superior to CECT for residual tumours. * CEUS can be a valuable method for assessing tumour response to TACE. PMID- 25702095 TI - Effectiveness and safety of tranexamic acid for total knee arthroplasty: a prospective randomized controlled trial. AB - BACKGROUND: Total knee arthroplasty (TKA) is associated with significant perioperative blood loss and need for transfusion. This study aimed to evaluate the effectiveness and safety of tranexamic acid (TXA) to reduce perioperative blood loss in patients receiving TKA. MATERIAL AND METHODS: A total of 92 patients who accepted unilateral TKA from May 2012 to May 2013 randomly received either 15 mg/kg TXA in 100 mL normal saline solution (TXA group, n=46) or the same amount of normal saline solution (placebo group, n=46) at 15 min before the tourniquet was loosened. The following data were recorded: intraoperative blood loss; post-operative drainage at 12 h; total drainage amount; hidden blood loss; total blood loss; transfusion volumes; number of transfusions; post-operative hemoglobin at 1, 3, and 5 days; D-dimer; number of lower limb ecchymoses; and deep vein thrombosis (DVT). RESULTS: A total of 81 patients were available for analysis (TXA group, n=41; placebo group, n=40). Post-operative12-h drainage, post-operative 24-h D-dimer values, total drainage volume, hidden blood loss, total blood loss, and the rate of postoperative ecchymosis were lower in the TXA group than in the placebo group (p<0.05). The post-operative 3-day Hgb was higher in the TXA group than in the placebo group (p=0.000). The rate of transfusion and DVT was similar in both groups (n.s.). CONCLUSIONS: Perioperative blood loss could be reduced after TKA by intravenously injecting 15 mg/kg TXA at 15 min before the tourniquet was loosened. The application of TXA is not associated with increased risk of DVT. PMID- 25702096 TI - Diabetes after pancreatic surgery: novel issues. AB - In the developed world, pancreatic surgery is becoming more common, with an increasing number of patients developing diabetes because of either partial or total pancreatectomy, with a significant impact on quality of life and survival. Although these patients are expected to consume increasing health care resources in the near future, many aspects of diabetes after pancreatectomy are still not well defined. The treatment of diabetes in these patients takes advantage of the therapies used in type 1 and 2 diabetes; however, no specific guidelines for its management, both immediately after pancreatic surgery or in the long term, have been developed. In this article, on the basis of both the literature and our clinical experience, we address the open issues and discuss the most appropriate therapeutic options for patients with diabetes after pancreatectomy. PMID- 25702098 TI - Transcriptional activation of glutathione pathways and role of glucose homeostasis during copper imbalance. AB - Copper is an essential micronutrient for organism health. Dietary changes or pathologies linked to this metal induce changes in intracellular glutathione concentrations. Here, we studied the transcriptional activation of glutathione pathways in Jurkat cell lines, analyzing the effect of change in glucose homeostasis during a physiological and supra-physiological copper exposure. An immortalized line of human T lymphocyte cell line (Jurkat) was exposed to different copper and glucose conditions to mimic concentrations present in human blood. We applied treatments for 6 (acute) and 24 h (sustained) to 2 uM (physiological) or 20 uM (supra-physiological, Wilson disease scenario) of CuSO4 in combination with 25 mg/dL (hypoglycemia), 100 mg/dL (normal) and 200 mg/dL (hyperglycemia, diabetes scenario) of glucose. The results indicate that a physiological concentration of copper exposure does not induce transcriptional changes in the glutathione synthesis pathway after 6 or 24 h. The G6PDH gene (regeneration pathway), however, is induced during a supra-physiological copper condition. This data was correlated with the viability assays, where fluctuation in both glucose conditions (hypo and hyperglycemia scenario) affected Jurkat proliferation when 20 uM of CuSO4 was added to the culture media. Under a copper overload condition, the transcription of a component of glutathione regeneration pathway (G6PDH gene) is activated in cells chronically exposed to a hyperglycemia scenario, indicating that fluctuations in glucose concentration impact the resistance against the metal. Our findings illustrate the importance of glucose homeostasis during copper excess. PMID- 25702097 TI - Bariatric surgery: prevalence, predictors, and mechanisms of diabetes remission. AB - Type 2 diabetes is a chronic disease that can be treated with pharmacologic and/or lifestyle interventions, but in most cases it does not get cured. One of the few interventions, however, that can remit diabetes is the Roux-en-Y gastric bypass (RYGB) surgery. Approximately 63 % of patients undergoing RYGB surgery experience diabetes remission, but the underlying mechanisms are poorly understood. Some studies implicate enterohepatic pathways with bile acids, fibroblast growth factor 19 (FGF19), and glucagon-like peptide 1 (GLP-1) being the primary components. Here, we discuss these enterohepatic changes and highlight the roles of bile acids, FGF19, and GLP-1 in diabetes remission. We also describe how we can now actually predict, prior to surgery, the probability for remitting diabetes after RYGB surgery by using the DiaRem score. Deeper understanding of the mechanisms of diabetes remission by RYGB surgery could provide the basis for developing more effective interventions for curing the disease. PMID- 25702099 TI - Chromate induces adventitious root formation via auxin signalling and SOLITARY ROOT/IAA14 gene function in Arabidopsis thaliana. AB - Morphological root plasticity optimizes nutrient and water uptake by plants and is a promising target to improve tolerance to metal toxicity. Exposure to sublethal chromate [Cr(VI)] concentrations inhibits root growth, decreases photosynthesis and compromises plant development and productivity. Despite the increasing environmental problem that Cr(VI) represents, to date, the Cr tolerance mechanisms of plants are not well understood, and it remains to be investigated whether root architecture remodelling is important for plant adaptation to Cr(VI) stress. In this report, we analysed the growth response of Arabidopsis thaliana seedlings to concentrations of Cr(VI) that strongly repress primary and lateral root growth. Interestingly, adventitious roots started developing, branched and allowed seedlings to grow under highly growth-repressing Cr(VI) concentrations. Cr(VI) negatively regulates auxin transport and response gene expression in the primary root tip, as evidenced by decreased expression of auxin-related reporters DR5::GFP, DR5::uidA and PIN1::PIN1::GFP, and then, another auxin maximum is established at the site of adventitious root initiation that drives adventitious root organogenesis. Both primary root growth inhibition and adventitious root formation induced by high Cr(VI) levels are blocked by a gain-of-function mutation in the SOLITARY-ROOT/IAA14 gene of Arabidopsis. These data provide evidence that suggests a critical role for auxin transport and signalling via IAA14/SLR1 in the developmental program linking Cr(VI) to root architecture remodelling. PMID- 25702101 TI - Leukocyte telomere length: a novel biomarker to predict the prognosis of glioma patients. AB - PURPOSE: Epidemiological studies have demonstrated that leukocyte telomere length is associated with the developing risk of various malignancies, including glioma. However, its prognostic value in glioma patients has never been investigated. METHODS: Relative telomere length (RTL) of peripheral blood leukocytes from 301 glioma patients were examined using a real-time PCR-based method. Kaplan-Meier curves and Cox proportional hazards regression model were used to assess the association of RTL with clinical outcomes of patients. To explore the potential mechanism, the immune phenotype of peripheral blood mononuclear cells (PBMCs) and concentrations of several cytokines from another 20 glioma patients were detected by flow cytometry and enzyme-linked immunosorbent assay (ELISA), respectively. The relationship between RTL and immunological characteristics of PBMCs were further analyzed. RESULTS: Patients with short RTL showed both poorer overall survival (OS) and progression-free survival (PFS) than those with long RTL. Multivariate Cox regression analysis demonstrated that RTL was an independent prognostic factor for both OS and PFS in glioma patients. Moreover, the effects of RTL on the prognosis of patients exhibited a dose-dependent manner. Stratified analysis showed that the prognostic value of RTL was not affected by host characteristics except for age. In addition, flow cytometry and ELISA analyses indicated that there was no significant association between RTL and frequency of different immune cell subsets or plasma cytokine concentrations. CONCLUSIONS: Our study for the first time demonstrates that leukocyte RTL is an independent prognostic marker for glioma patients. The potential mechanism needs further investigation. PMID- 25702102 TI - Follicular variant of papillary thyroid carcinoma (FVPTC): histological features, BRAF V600E mutation, and lymph node status. AB - PURPOSE: Follicular variant of papillary thyroid carcinoma (FVPTC) is currently treated like conventional papillary thyroid carcinoma (cPTC). Recent reports indicate that encapsulated FVPTC behaves like follicular adenomas, while infiltrative FVPTC behaves like cPTC. This raises the possibility that histology and/or mutation status might help personalize management of FVPTC regarding extent of surgery, intensity of follow-up, and targeted therapy. This study correlates histological features, immunoreactivity for CK19, HBME, and Gal, and BRAF V600E mutation with lymph node (LN) metastasis and follow-up in FVPTC. METHODS: Forty-eight FVPTC (21 with regional lymph node metastasis [LN+] and 27 with negative lymph nodes [LN-]) were reviewed. Demographics, tumor focality, size, circumscription, follicular architecture, lymphovascular invasion, extrathyroidal extension (ETE), and margin status were charted. Macrodissected formalin-fixed paraffin-embedded sections from 47 (21 LN+ and 26 LN-) cases were analyzed for BRAF V600E (1799T>A) mutation using real-time PCR. Correlations between the variables and LN status were calculated. RESULTS: Sixty-two percent of cases with ETE demonstrated LN metastasis, while 59 % of cases with circumscribed tumors were LN-. In multivariable analysis, ETE and tumor size >=1 cm were the best predictors of LN+ status, whereas in cases without ETE, the infiltrative pattern and tumor size provided the "best fit." Immunostains and BRAF mutation status were not helpful. All four tumors that recurred were LN+, with infiltrative borders, and lacked the BRAF mutation. CONCLUSIONS: Tumor circumscription, extrathyroidal extension, and tumor size >= 1.0 cm are predictors of lymph node status in FVPTC. PMID- 25702103 TI - Perception of cancer patients of their disease, self-efficacy and locus of control and usage of complementary and alternative medicine. AB - PURPOSE: A high percentage of cancer patients use complementary and alternative medicine (CAM). The aim of our study was to learn more about the association of CAM usage, information needs, perceived impact of disease, locus of control and self-efficacy of cancer patients. METHODS: We asked patients attending a series of lectures on CAM using a standardized questionnaire which integrated questions on information needs, CAM and validated short questionnaires on self-efficacy, perception of the disease and locus of control of reinforcement. RESULTS: One hundred and eighty-five patients answered the questionnaire, from whom 45 % used CAM. Sixty percentage disclosed using CAM to the general practitioner and 57 % to the oncologist. Physicians and nurses, print media and the Internet are the most important source of information on CAM (used by 20-25 % each). Impact on neither daily life, perceived personal control nor coherence was associated with CAM usage, disclosure to physicians or sources of information. There also was no association between CAM usage and self-efficacy. In contrast, there was a significant association between CAM user rate and a high external locus of control. CONCLUSION: While CAM usage is agreed upon by many physicians due to the idea that it helps patients to become active and feel more in control of the disease, our data are in favor of the contrary. A strong perception of external locus of control seems to be a driver of CAM usage. Physicians should be aware of this association when counseling on CAM. PMID- 25702104 TI - Approach to the postoperative patient with Cushing's disease. AB - INTRODUCTION: Cushing's disease is a neuroendocrine disorder marked by hypercortisolemia secondary to overproduction of ACTH by a corticotropic pituitary adenoma. Due to the diverse and deleterious effects of hypercortisolemia including diabetes mellitus, hypertension, and cardiovascular disease, prompt and accurate diagnosis followed by surgical resection of the responsible corticotropic adenoma is critical. METHODS: In the following review, we present a focused synopsis of recently published data and management strategies for the post-operative Cushing's disease patient with a particular focus on studies examining perioperative complications, establishment of biochemical remission, factors associated with disease remission, and predictors of recurrence. CONCLUSIONS: Although no standard definition of remission exists, we suggest measurement of serum cortisol level on the morning of postoperative day 1 given the preponderance of evidence in the published literature suggesting its association with long-term remission and relatively low rates of recurrence. Nevertheless, all patients should be counseled that recurrence can occur in a delayed fashion and that annual endocrine testing should be utilized to track and confirm disease status. PMID- 25702105 TI - Intracellular parcel service: current issues in intracellular membrane trafficking. AB - Eukaryotic cells contain a multitude of membrane structures that are connected through a highly dynamic and complex exchange of their constituents. The vibrant instability of these structures challenges the classical view of defined, static compartments that are connected by different types of vesicles. Despite this astonishing complexity, proteins and lipids are accurately transported into the different intracellular membrane systems. Over the past few decades many factors have been identified that either mediate or regulate intracellular membrane trafficking. Like in a modern parcel sorting system of a logistics center, the cargo typically passes through several sequential sorting stations until it finally reaches the location that is specified by its individual address label. While each membrane system employs specific sets of factors, the transport processes typically operate on common principles. With the advent of genome- and proteome-wide screens, the availability of mutant collections, exciting new developments in microscope technology and sophisticated methods to study their dynamics, the future promises a broad and comprehensive picture of the processes by which eukaryotic cells sort their proteins. PMID- 25702106 TI - In vitro analysis of the mitochondrial preprotein import machinery using recombinant precursor polypeptides. AB - The import of proteins into mitochondria represents an essential process for the survival of eukaryotic cells. Most mitochondrial proteins are synthesized as cytosolic precursor proteins. A complex chain of reactions needs to be followed to achieve a successful transport of these precursors from the cytosol through the double membrane system to their final destination inside the mitochondria. In order to elucidate the details of the translocation process, in vitro import assays have been developed that are based on the incubation of isolated active mitochondria with natural or artificial precursor proteins containing the appropriate targeting information. Using this basic system, most of the protein components of the import machinery have been identified and functionally characterized. However, a detailed definition of the molecular mechanisms requires more specialized assay techniques. Here we describe modifications of the standard in vitro import assay technique that are based on the utilization of large amounts of recombinant preprotein constructs. The application of saturating amounts of substrate preproteins is a prerequisite for the determination of translocation kinetics and energy requirements of the import process. Accumulation of preproteins as membrane-spanning translocation intermediates further provides a basis for the functional and structural characterization of the active translocation machinery. PMID- 25702107 TI - Import of proteins into isolated yeast mitochondria. AB - Mitochondria are essential organelles of eukaryotic cells. The vast majority of mitochondrial proteins is encoded within the nuclear genome and translocated into various mitochondrial compartments after translation in the cytosol as preproteins. Even in rather primitive eukaryotes like yeasts, there are 700-1,000 different proteins that need to be recognized in the cytosol, directed to the protein translocases in the two mitochondrial membranes and sorted to their appropriate mitochondrial subcompartment. In vitro reconstituted import systems have proved to be important tools to study these processes in detail. Using isolated mitochondria and radioactively labeled precursor proteins, it was possible to identify several import machineries and pathways consisting of a large number of components during the last few decades. PMID- 25702108 TI - Evaluation of unconventional protein secretion in Saccharomyces cerevisiae. AB - Recent development of large-scale analyses such as the secretome analysis has enabled the discovery of a vast number of intracellular proteins that are secreted outside the cell. Often, these proteins do not contain any known signal sequence required for conventional protein secretion. In order to avoid misidentification of such "leaked" proteins as "secreted" proteins, reconstructing the process of protein secretion is essential. Here, we describe methods for the detection of reconstructed unconventional protein secretion and determination of regulatory proteins of secretion in Saccharomyces cerevisiae. We show that conjugating target proteins with a tag-sequence and utilizing various reagents and tools can facilitate quantitative detection of the secretion of target proteins. We expect that these methods will reveal novel unconventional secretion pathways of proteins. PMID- 25702109 TI - Fractionation of Plasmodium-infected human red blood cells to study protein trafficking. AB - Subcellular fractionation is a valuable tool to follow protein traffic between cellular compartments. Here we detail a procedure for fractionating erythrocytes infected with the human malaria parasite P. falciparum using the bacterial pore forming protein Streptolysin O (SLO). Additionally we describe an experimental protocol to determine protein topology by carrying out a protease protection assay on SLO-lysed infected erythrocytes. PMID- 25702110 TI - Investigating signaling processes in membrane trafficking. AB - Signaling and phosphorylation can be very difficult areas to explore, as there can be a lot of cross-talk between signaling pathways, and the stoichiometry of phosphorylation is often very low, and is typically transient. Here we describe an innovative assay using an immunoprecipitation approach, followed by a kinase assay, coupled with a phosphorylated substrate-specific antibody. We also indicate a database and prediction program that can be used in these situations.We apply these methods to investigate the regulation of ER-to-Golgi trafficking by protein phosphorylation of critical components in the trafficking machinery. Key components of this transport step are well known thanks to the pioneering work of the 2013 Nobel Prize winners James Rothman, Randy Schekman, and Thomas Sudhof. However, the regulation aspect of this process is relatively unexplored. PMID- 25702111 TI - Recruitment of coat proteins to liposomes and peptidoliposomes. AB - Intracellular transport within the cell is generally mediated by membrane vesicles. Their formation is typically initiated by activation of small GTPases that then recruit cytosolic proteins to the membrane surface to form a coat, interact with cargo and accessory proteins, and deform the lipid bilayer to produce a transport vesicle. Liposomes proved to be a useful tool to study the molecular mechanisms of these processes in vitro. Here we describe the use of liposomes and peptidoliposomes presenting lipid-coupled cytosolic tails of cargo proteins for the in vitro analysis of the membrane recruitment of AP-1 adaptors in the process of forming AP-1/clathrin coats. AP-1 recruitment is mediated by the GTPase Arf1 and requires specific lipids and cargo signals. Interaction with cargo induces AP-1 oligomerization already in the absence of clathrin. Without cargo peptides, accessory proteins, such as amphiphysin 2, can be identified that stabilize AP-1 binding to liposomal membranes. PMID- 25702112 TI - A beta-lactamase based assay to measure surface expression of membrane proteins. AB - Measurement of cell surface expression is an essential part of studying membrane proteins. Traditional techniques for measuring surface expression depend on the availability of appropriate radioligands or antibodies towards extracellular epitopes of a protein of interest. The current protocol outlines the use of an assay to monitor surface expression of membrane proteins tagged with a bacterial beta-lactamase in mammalian cell lines. The use of this technique allows for quick, quantitative, sensitive, and inexpensive measurement of surface expression, with the potential for high-throughput screening. PMID- 25702113 TI - Cell-free reconstitution of multivesicular body (MVB) cargo sorting. AB - The signaling activity of cell surface localized membrane proteins occurs primarily while these proteins are located on the plasma membrane but is, in some cases, not terminated until the proteins are degraded. Following internalization and movement through the endocytic pathway en route to lysosomes, membrane proteins transit a late endosomal organelle called the multivesicular body (MVB). MVBs are formed by invagination of the limiting membrane of endosomes, resulting in an organelle possessing a limiting membrane and containing internal vesicles. The fate of an internalized membrane protein depends on whether it buds outwardly from the endosomal membrane, promoting recycling and continued signaling, or is internalized into internal MVB vesicles and is ultimately degraded upon MVB lysosome fusion. The molecular machinery that regulates the separation of membrane proteins destined for degradation from those resulting in surface expression is not well understood.To elucidate the molecular mechanisms that underlie membrane protein sorting, we have reconstituted an endosomal sorting event under cell-free conditions. We took advantage of the itinerary of a prototypical membrane protein, the epidermal growth factor receptor (EGFR) and designed a biochemical monitor for cargo movement into internal MVB vesicles that is generally modifiable for other membrane proteins. Since is it not known how internal vesicle formation is related to cargo sorting, morphological examination using transmission electron microscopy (TEM) allows separate monitoring of vesicle formation. We have determined that MVB sorting is dependent on cytosolic components, adenosine triphosphate (ATP), time, temperature, and an intact proton gradient. This assay reconstitutes the maturation of late endosomes and allows the morphological and biochemical examination of vesicle formation and membrane protein sorting. PMID- 25702114 TI - Analysis of biogenesis of lipid droplets by examining Rab40c associating with lipid droplets. AB - The biogenesis of lipid droplets (LDs) is regulated by multiple proteins. Rab40c is a recently characterized small GTPase associating with LDs. Here we describe our approaches to analyze the involvement of Rab40c in the biogenesis of LDs. Co localization of Rab40c and LDs was revealed through fluorescence confocal microscopy by expressing GFP-Rab40c and labeling LDs with dyes Oil Red O, Nile Red, or BODIPY 493/503. Association of Rab40c with LDs was further confirmed by fractionation with sucrose density centrifugation. The relationship of Rab40c with adipocyte differentiation was examined by detecting the protein level of Rab40c during adipocyte differentiation of 3T3-L1 cells. The roles of Rab40c in the biogenesis of LDs were analyzed by inducing LD formation in HepG2 cells. PMID- 25702115 TI - Analysis of conventional and unconventional trafficking of CFTR and other membrane proteins. AB - The cystic fibrosis transmembrane conductance regulator (CFTR) is a polytopic transmembrane protein that functions as a cAMP-activated anion channel at the apical membrane of epithelial cells. Mutations in CFTR cause cystic fibrosis and are also associated with monosymptomatic diseases in the lung, pancreas, intestines, and vas deferens. Many disease-causing CFTR mutations, including the deletion of a single phenylalanine residue at position 508 (DeltaF508-CFTR), result in protein misfolding and trafficking defects. Therefore, intracellular trafficking of wild-type and mutant CFTR has been studied extensively, and results from these studies significantly contribute to our general understanding of mechanisms involved in the cell-surface trafficking of membrane proteins. CFTR is a glycoprotein that undergoes complex N-glycosylation as it passes through Golgi-mediated conventional exocytosis. Interestingly, results from recent studies revealed that CFTR and other membrane proteins can reach the plasma membrane via an unconventional alternative route that bypasses Golgi in specific cellular conditions. Here, we describe methods that have been used to investigate the conventional and unconventional surface trafficking of CFTR. With appropriate modifications, the protocols described in this chapter can also be applied to studies investigating the intracellular trafficking of other plasma membrane proteins. PMID- 25702116 TI - Assessing mammalian autophagy. AB - Autophagy (self-eating) is a highly conserved, vesicular pathway that cells use to eat pieces of themselves, including damaged organelles, protein aggregates or invading pathogens, for self-preservation and survival (Choi et al., N Engl J Med 368:651-662, 2013; Lamb et al., Nat Rev Mol Cell Biol 14:759-774, 2013). Autophagy can be delineated into three major vesicular compartments (the phagophore, autophagosome, autolysosome, see Fig. 1). The initial stages of the pathway involve the formation of phagophores (also called isolation membranes), which are open, cup-shaped membranes that expand and sequester the cytosolic components, including organelles and aggregated proteins or intracellular pathogens. Closure of the phagophore creates an autophagosome, which is a double membrane vesicle. Fusion of the autophagosome with the lysosome, to form an autolysosome, delivers the content of the autophagosome into the lysosomal lumen and allows degradation to occur.Autophagy is a dynamic process that is initiated within 15 min of amino acid starvation in cell culture systems (Kochl et al., Traffic 7:129-145, 2006) and is likely to occur as rapidly in vivo (Mizushima et al., J Cell Biol 152:657-668, 2001). To initiate studies on the formation of the autophagosomes, and trafficking to and from the autophagic pathway, an ideal starting approach is to do a morphological analysis in fixed cells. Additional validation of the morphological data can be obtained using simple Western blot analysis. Here we describe the most commonly used morphological technique to study autophagy, in particular, using the most reliable marker, microtubule associated protein 1A/1B-light chain 3 (LC3). In addition, we describe a second immunofluorescence assay to determine if autophagy is being induced, using an antibody to WD repeat domain, phosphoinositide interacting 2 (WIPI2), an effector of the phosphatidylinositol (3)-phosphate (PI3P) produced during autophagosome formation. PMID- 25702117 TI - Expression of functional Myc-tagged conserved oligomeric Golgi (COG) subcomplexes in mammalian cells. AB - Docking and fusion of transport carriers in eukaryotic cells are regulated by a family of multi-subunit tethering complexes (MTC) that sequentially and/or simultaneously interact with other components of vesicle fusion machinery, such as SNAREs, Rabs, coiled-coil tethers, and vesicle coat components. Probing for interactions of multi-protein complexes has relied heavily on the method of exogenously expressing individual proteins and then determining their interaction stringency. An obvious pitfall of this method is that the protein interactions are not occurring in their native multi-subunit state. Here, we describe an assay where we express all eight subunits of the conserved oligomeric Golgi (COG) complex that contain the same triple-Myc epitope tag and then an assay for the (sub) complex's interaction with known protein partners. The expression of all eight proteins allows for the assembled complex to interact with partner proteins, and by having the same tag on all eight COG subunits, we are able to very accurately quantify the interaction with each subunit. The use of this assay has highlighted a very important level of specificity of interactions between COG subcomplexes and their intracellular partners. PMID- 25702118 TI - Molecular and cellular characterization of GCC185: a tethering protein of the trans-Golgi network. AB - Transport vesicle tethers are proteins that link partner membranes together to permit subsequent SNARE protein pairing and fusion. Despite the identification of a relatively large number of tethering proteins, little is known about the precise mechanisms by which they act. Biochemical isolation of tethers permits direct analysis of their physical characteristics and molecular interactions. Here, we describe the expression and purification of GCC185, a trans-Golgi localized, 190-kDa coiled-coil tethering protein. In addition, we present a gene rescue approach to analyze the function of this tether after its depletion from cells using siRNA. PMID- 25702119 TI - Visualizing toll-like receptor-dependent phagosomal dynamics in murine dendritic cells using live cell microscopy. AB - Dendritic cells are professional phagocytes that are highly specialized to process and present antigens from internalized particles to prime naive T cells. To achieve their functions, the phagocytic machinery and membrane dynamics of these cells have been adapted to optimize presentation of antigens from phagocytosed particles that bear ligands of pattern recognition receptors, such as toll-like receptors (TLRs), and that are thus perceived of as "dangerous." We have recently shown that phagosomes that are engaged in TLR signaling in dendritic cells emit numerous long tubules that facilitate content exchange with other signaling phagosomes and favor presentation of particle-derived antigens. This chapter describes the methods used to study the formation of these tubules, which we refer to as "phagotubules," by live cell imaging of mouse dendritic cells after the phagocytosis of fluorescent latex beads. We also describe methods to assess the effect of TLR signaling on this process. PMID- 25702120 TI - Understanding of complex protein interactions with respect to anchorage independence. AB - Anchorage-independent growth of cells in soft agar is one of the hallmark characteristics of cellular transformation and uncontrolled cell growth. It may be considered as one of the most stringent assays for detecting malignant transformation of cells. Here, we describe a retroviral infection of a library of small secretory proteins and the use of the soft agar assay to obtain and study novel interacting protein combinations that cause cell transformation. PMID- 25702121 TI - Application of flow cytometry to analyze intracellular location and trafficking of cargo in cell populations. AB - Pulse shape analysis (PulSA) is a flow cytometry-based method that involves the measurement of the pulse width and height of a fluorescently labeled molecule simultaneously, enabling a multidimensional analysis of protein localization in a cell at high speed and throughput. We have used the method to detect morphological changes in organelles such as Golgi fragmentation, track protein trafficking from the cell surface, and also discriminate cells with different target protein localizations such as the Golgi, lyso-endosomal network, and the plasma membrane. Here, we describe the basic experimental setup and analytical methods for performing PulSA to examine membrane trafficking processes. We illustrate in particular the application of PulSA for monitoring the trafficking of the membrane-bound enzyme furin and morphological changes to the Golgi caused by Brefeldin A. PMID- 25702122 TI - Approaches to analyze the role of Rab GTPases in endocytic trafficking of epidermal growth factor receptor (EGFR). AB - The epidermal growth factor receptor (EGFR), a member of the erythroblastic leukemia viral oncogene homologue (ErbB) receptor tyrosine kinase family, plays key mitogenic signaling roles in development, cellular, and tissue physiology, as well as a myriad of malignancies. EGFR signaling occurs concurrently with ligand receptor binding and subsequent endocytosis, and its signaling strength and engagement of different downstream signaling components are modulated by its endocytic trafficking itinerary. Understanding the factors and mechanisms that modulate ligand-bound EGFR's endocytic trafficking is therefore important for deciphering its role in pathophysiological processes. Endocytic trafficking of EGFR is regulated by a bunch of Rab small GTPases associated with the endocytic pathway. In this chapter, we describe a suite of relatively standard protocols in dissecting the role of a particular Rab protein in EGFR endocytic trafficking steps/stages. The approach constitutes a combination of genetic/molecular manipulations, followed by confocal imaging and a range of biochemical analyses. We shall mainly focus on Rab31 in our illustrations, but the approaches would be equally applicable to any Rab and its associated regulators/effectors. PMID- 25702123 TI - Does super-resolution fluorescence microscopy obsolete previous microscopic approaches to protein co-localization? AB - Conventional microscopy techniques, namely, the confocal microscope or deconvolution processes, are resolution limited to approximately 200-250 nm by the diffraction properties of light as developed by Ernst Abbe in 1873. This diffraction limit is appreciably above the size of most multi-protein complexes, which are typically 20-50 nm in diameter. In the mid-2000s, biophysicists moved beyond the diffraction barrier by structuring the illumination pattern and then applying mathematical principles and algorithms to allow a resolution of approximately 100 nm, sufficient to address protein subcellular co-localization questions. This "breaking" of the diffraction barrier, affording resolution beyond 200 nm, is termed super-resolution microscopy. More recent approaches include single-molecule localization (such as photoactivated localization microscopy (PALM)/stochastic optical reconstruction microscopy (STORM)) and point spread function engineering (such as stimulated emission depletion (STED) microscopy). In this review, we explain basic principles behind currently commercialized super-resolution setups and address advantages and considerations in applying these techniques to protein co-localization in biological systems. PMID- 25702124 TI - Bimolecular fluorescence complementation (BiFC) technique in yeast Saccharomyces cerevisiae and mammalian cells. AB - Visualization of protein-protein interactions in vivo offers a powerful tool to resolve spatial and temporal aspects of cellular functions. The bimolecular fluorescence complementation (BiFC) makes use of nonfluorescent fragments of green fluorescent protein or its variants that are added as "tags" to target proteins under study. Only upon target protein interaction is a fluorescent protein complex assembled, and the site of interaction can be monitored by microscopy. In this chapter, we describe the method and tools for the use of BiFC in the yeast Saccharomyces cerevisiae and in mammalian cells. PMID- 25702125 TI - Microscopic and spectroscopic techniques to investigate lipid droplet formation and turnover in yeast. AB - In spite of some progress in understanding the molecular basis of lipid associated disorders, major questions about the regulation of synthesis and degradation of lipids and the interaction of these processes with other aspects of cellular physiology are still unresolved. Studies in reference organisms such as various yeast species, the fruit fly Drosophila melanogaster, or the nematode Caenorhabditis elegans complement efforts in mouse models as well as clinical studies in humans to address these questions. Imaging techniques play a pivotal role in understanding lipid droplet biology, and the implementation of imaging based high-content screens of mutant collections has led to the identification of novel molecular players. This study focuses on novel fluorescent probes as well as spectroscopic imaging techniques to investigate lipid droplet formation and turnover in yeast. The application and limitations of such techniques in understanding lipid storage and turnover are discussed. PMID- 25702126 TI - Image-based identification of nuclear export inhibitors from natural products. AB - High-content imaging with robotic microscopy has been widely used for phenotype based cellular screening research. This technology is ideally suited to monitor intracellular translocation of macromolecules. Here, we describe in detail the procedures for screening microbial natural extracts for their capability to inhibit the general nuclear export machinery. The method is based on human cells that stably express a fluorescent-tagged reporter protein that contain a nuclear export signal capable of mediating its translocation from the nucleus to the cytoplasm through the nuclear pore. In the presence of a small molecule nuclear export inhibitor, the fluorescent signal is trapped to varying degrees within the nucleus. In order to analyze complex libraries of compounds, the assay has been scaled to 96- or 384-well formats and optimized for high-throughput screening (HTS). Active microbial extracts undergo confirmation screening, bioassay-guided fractionation, chemical dereplication, and compound purification. The active purified compound is characterized in secondary assays that monitor the nuclear export of disease-relevant proteins. Nuclear export inhibitors hold promise as potential cancer and antiviral drugs. PMID- 25702127 TI - Correlative video-light-electron microscopy of mobile organelles. AB - Correlative microscopy is a method when for the analysis of the very same cell or tissue area, several different methods of light microscopy (LM) and then electron microscopy (EM) are used consecutively. The combination of LM and EM allows researchers to study phenomena at a global scale and then to look for unique or rare events for their subsequent EM examination. Unfortunately, the observation of living cells under EM is still impossible. LM provides the possibility to examine quickly many live cells, whereas EM provides the high level of resolution. On the other side, the final goal of any morphological analysis of a biological sample, whether it is an organism, organ, tissue, cell, organelle, or molecule, is to get an averaged three-dimensional model of the structure examined and to determine the chemical composition of it. This chapter describes the methodology of imaging with the help of CVLEM. The guidelines presented herein enable researchers to analyze structure of organelles and to obtain the three dimensional model of the structure examined, and in particular rare events captured by low-resolution imaging of a population or transient events captured by live imaging can now also be studied at high resolution by EM. PMID- 25702128 TI - Live cell imaging of endosomal trafficking in fungi. AB - Endosomes are multipurpose membranous carriers important for endocytosis and secretion. During membrane trafficking, endosomes transport lipids, proteins, and even RNAs. In highly polarized cells such as fungal hyphae, they shuttle bidirectionally along microtubules mediated by molecular motors like kinesins and dynein. For in vivo studies of these highly dynamic protein/membrane complexes, advanced fluorescence microscopy is instrumental. In this chapter, we describe live cell imaging of endosomes in two distantly related fungal model systems, the basidiomycete Ustilago maydis and the ascomycete Aspergillus nidulans. We provide insights into live cell imaging of dynamic endosomal proteins and RNA, dual-color detection for colocalization studies, as well as fluorescence recovery after photobleaching (FRAP) for quantification and photo-activated localization microscopy (PALM) for super-resolution. These methods described in two well studied fungal model systems are applicable to a broad range of other organisms. PMID- 25702129 TI - Quantitative analysis of transferrin cycling by automated fluorescence microscopy. AB - Surface receptors are transported between the plasma membrane and intracellular compartments by various endocytic mechanisms and by recycling via different pathways from sorting or recycling endosomes. The analysis of cellular components involved in mediating or regulating these transport steps is of high current interest and requires quantitative methods to determine rates of endocytosis and/or recycling. Various biochemical procedures to measure uptake of labeled ligand molecules or internalization and reappearance of surface-labeled receptors have been developed. Here, we describe a quantitative method based on fluorescence microscopy of adherent cells taking advantage of the transferrin (Tf) receptor as the prototype of cycling transport receptors. Tf is endocytosed with bound Fe(3+) and, upon release of the iron ion in endosomes, recycled as apo Tf together with the receptor. To follow the ligand-receptor complex, fluorescently labeled Tf is used and detected microscopically with or without releasing Tf from cell surface receptors by acid stripping. To go beyond the observation of a few individual cells, automated fluorescence microscopy is employed to image thousands of cells at different time points and in parallel with different treatments (such as chemical inhibitors, siRNA silencing, or transfection of candidate genes) in a 96-well format. Computer-assisted image analysis allows unbiased quantitation of Tf content of each cell and to distinguish between different cell populations. PMID- 25702130 TI - Identification of factors regulating MET receptor endocytosis by high-throughput siRNA screening. AB - The tyrosine kinase MET, a receptor for hepatocyte growth factor, is a key regulator for normal development and organ renewal via stem cell maintenance. Dysregulated MET signaling contributes to tumor progression and metastasis and is considered a potent therapeutic target for a growing number of malignancies. Toward that goal it is critical to develop high-throughput assays to identify candidate regulators for the termination of MET signaling. We describe here a rapid and efficient method for identifying cellular factors required for MET ubiquitination, which utilizes high-throughput RNA interference screening (HT siRNA) with a receptor internalization assay and an In-Cell ELISA in a 96-well format. The assay is amenable to a large array of cell surface proteins as well as genome-wide siRNA libraries, with high signal-to-background ratio and low well to-well variability. PMID- 25702131 TI - Large-scale analysis of membrane transport in yeast using invertase reporters. AB - Transport of membrane proteins between cellular organelles requires the concerted action of many regulatory factors, which aid in cargo recognition and vesicle formation, targeting, and fusion. The yeast Saccharomyces cerevisiae is a useful model system for studying such regulators, due to the availability of genome-wide mutant collections and reporter proteins that provide sensitive biochemical readouts of individual transport pathways. Here, we describe an enzymatic invertase assay for evaluating endocytic recycling using a chimeric GFP-Snc1-Suc2 reporter. Cell surface levels of this reporter can be measured by a colorimetric assay that monitors sucrose hydrolysis at the plasma membrane, using two different methods. The first is a semiquantitative agar overlay assay followed by image densitometry that is suitable for high-throughput screening of arrayed yeast colonies. In the second, more quantitative assay, an enzymatic solution is added to yeast cultures in a multi-well plate and the absorbance is assessed by a plate reader. Furthermore, the modular nature of the chimeric reporter allows alternate transport signals to be introduced, thereby expanding the range of transport pathways that can be evaluated by this method. Together these techniques can be used to explore the function of genes involved in a variety of cellular trafficking pathways. PMID- 25702132 TI - RNAi screens for genes involved in Golgi glycosylation. AB - RNAi screening has gained popularity in recent years, due to its usefulness in systematic investigations of biological pathways. Combined with high-content screening and advances in imaging and analysis methods, it can enable detailed genetic characterization of cellular processes such as protein glycosylation, a major function of the Golgi apparatus. Glycosylation concerns about one third of all human proteins and regulates various cellular behaviors. Yet the methods available to study it are limited and not easily accessible. In this chapter, we detail a step-by-step method to systematically and quantitatively investigate glycosylation using fluorescent lectin staining, following high-throughput RNAi based downregulation of gene activities. We also provide a workflow for downstream analysis of the data generated. PMID- 25702133 TI - Proteomic analyses of a bi-lobed structure in Trypanosoma brucei. AB - The position and function of the Golgi apparatus are tightly coupled with the microtubule-organizing centers (MTOCs) that play important roles in cell growth and polarity. In the unicellular parasite Trypanosoma brucei, the single Golgi apparatus is adjacent to a novel, bilobed structure located at the proximal base of the flagellum, near to the basal body that nucleates the flagellar axoneme. The duplication and segregation of the bilobed structure are tightly coupled to the duplication and segregation of Golgi, ER exit site, basal bodies, and flagellum, suggesting a role of this unique structure in the precise positioning, biogenesis, and inheritance of these single-copied structures during the cell cycle of procyclic T. brucei. Here, we describe in details two different isolation and proteomic methods to characterize the protein components present on or associated with the bilobed structure, which allow further understanding of its function and association with other membranous and cytoskeletal organelles in the parasite. PMID- 25702134 TI - Application of the proximity-dependent assay and fluorescence imaging approaches to study viral entry pathways. AB - Virus entry into cells is a complex, multistep process that requires the coordinated activities of a large number of cellular factors and multiple membrane compartments. Because viruses can enter cells via one or more of a large number of preexisting pathways, understanding the mechanism of virus entry and transport between various intracellular compartments is a challenging task. The arrival of "omics" technologies such as genome-wide RNA interference screens has greatly advanced our ability to study the molecular intricacies of viral entry. Bioinformatics analyses of high-throughput screen data can identify enriched gene categories and specific individual genes required for infection, which can yield important insights into the cellular compartments that viruses traverse during infection. Although there are a variety of well-established genetic and biochemical approaches to validate genome-wide screen findings, confirmation of phenotypes obtained from RNA interference studies remains an important challenge. Imaging techniques commonly used to visualize virus localization to cellular organelles are often prone to artifacts that result from the necessity of using a high multiplicity of infection. Fortunately, recent advances in microscopy-based methods for studying protein location have improved our ability to accurately pinpoint virus localization within its host cell. Here we describe in detail one such technique-the proximity ligation assay (PLA)-as a tool to validate findings from a genome-wide loss-of-function genetic screen. In addition, we discuss a number of important considerations for the utilization of immunofluorescence microscopy and RNA interference to investigate the molecular mechanisms of virus entry. PMID- 25702135 TI - Induction of NQO1 and Neuroprotection by a Novel Compound KMS04014 in Parkinson's Disease Models. AB - Parkinson's disease (PD) is a progressive neurodegenerative disorder associated with a selective loss of the neurons containing dopamine (DA) in the substantia nigra pars compacta. Lines of evidence suggest that oxidative stress is a major factor contributing to the vulnerability of DA cells and that the enzyme NAD(P)H quinone oxidoreductase (NQO1) provides protection in these cells. In the present study, we report the synthesis of a novel compound KMS04014 and show that it induces NQO1 gene expression and protects DAergic neuronal cells in both cell culture and animal models of PD. In vitro, KMS04014 increased both mRNA and protein levels of NQO1 and induced nuclear translocation of Nrf2 in the DAergic neuronal cell line CATH.a. It also protected the cells against oxidative stress generated by tetrahydrobiopterin, 1-methyl-4-phenylpyridinium (MPP(+)), and H2O2. In vivo, KMS04014 attenuated the loss of tyrosine hydroxylase-immunopositive DAergic neurons in the substantia nigra and reduced degeneration of the nigral neurons and striatal fibers in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice, an animal model of PD. Taken together, KMS04014 may be utilized toward development of neuroprotective therapy for PD. PMID- 25702136 TI - The Role of Matrix Metalloproteinase 3 and 9 in the Pathogenesis of Acute Neuroinflammation. Implications for Disease Modifying Therapy. AB - Matrix metalloproteinases (MMPs) are proteolytic enzymes that are involved in a variety of physiological and pathological processes, including those in CNS. In this study, plasma values of MMP-3 and MMP-9 have been compared in clinically isolated syndrome (CIS) and relapsing-remitting multiple sclerosis (RRMS) patients during their acute attacks, in relation to the biological activity of disease. Therefore, we compared the MMPs plasma values regarding Expanded Disability Status Scale (EDSS), progression index of disease (PID), acute brain lesion volume seen on magnetic resonance imaging (MRI) and index of blood-brain barrier (BBB) permeability destruction. The obtained results demonstrated higher plasma values of MMPs in both study groups than control values (p < 0.05). No statistical significances have been detected comparing the obtained values of both enzymes between CIS and RRMS group (p > 0.05). In both CIS and RRMS groups, the patients with higher EDSS showed higher MMPs plasma values (p < 0.05). The MMPs values were also significantly higher in both study patients with higher total number comparing to those with lower number of MRI brain lesion (p < 0.05) (beyond MMP-3 in RRMS). All obtained correlations, between MMPs and EDSS, PID, volume of MRI Gd-enhancement brain lesions, and index of BBB permeability, were positive (p < 0.05.) This study demonstrates alterations of both tested MMPs with closed correlation with the disease biological activity. Although MMPs are being implicated in the pathogenesis of acute neuroinflammation, the MMPs modulation might be useful in the future design of disease modifying therapy with the specific target profile. PMID- 25702137 TI - Lipoxin A4 Activates Nrf2 Pathway and Ameliorates Cell Damage in Cultured Cortical Astrocytes Exposed to Oxygen-Glucose Deprivation/Reperfusion Insults. AB - Lipoxin A4 (LXA4), a potent antioxidant and anti-inflammation mediator, protects brains against cerebral ischemia/reperfusion (I/R) injury in vivo. However, few reports concern its function on astrocytes during cerebral I/R injury. The pathogenesis of cerebral I/R injury involves oxidative stress caused by reactive oxygen species (ROS). Upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) is generally considered to reduce oxidative stress. Nrf2 can induce heme oxygenase-1 (HO-1) expression and glutathione (GSH) release to combat increased oxidative stress. We investigated the effects of LXA4 on astrocytic cell damage, the production of ROS, and Nrf2 pathway, especially on HO-1 expression and GSH release in cultured cortical astrocytes exposed to oxygen-glucose deprivation (OGD)/recovery (OGDR) insults. Primary astrocytes were subjected to a 4-h OGD, followed by 8-h recovery. Cell viability, the production of ROS, and GSH release were measured. Furthermore, Nrf2, HO-1, and p62 expression levels were determined by Western blot. Moreover, Nrf2 location was studied by immunofluorescence staining. Treatment of LXA4 attenuates OGDR-induced cell damage and the production of ROS in a concentration-related manner. LXA4 induced Nrf2 expression and its nuclear translocation, as well as HO-1 expression and GSH release. Moreover, LXA4 induced the excess p62 accumulation. These results indicate that LXA4 can effectively protect against OGDR-induced cell damage in astrocytes, and activation of Nrf2 pathway to reduce oxidative stress may be involved in its protective effects. p62 accumulation induced by LXA4 may be closely related to Nrf2 activation. PMID- 25702138 TI - Diagnostic value and clinical impact of complementary CT scan prior to surgery for non-localized primary hyperparathyroidism. AB - INTRODUCTION: Successful localization is mandatory for focused parathyroidectomy. If ultrasound and sestamibi scan are negative, bilateral neck exploration is necessary. We examined the contribution of complementary computed tomography (CT) scan to identify the affected parathyroid gland. METHODS: Between November 1999 and April 2014, 25 patients (20 females and 5 males; mean age 67 +/- 11 years) with negative or dubious standard imaging (ultrasound and sestamibi scan) underwent CT scan prior to parathyroidectomy and were included in this study. Fifteen patients had had previous neck surgery for parathyroidectomy (n = 11) or thyroidectomy (n = 4). Thin-slice CT (n = 9) or four-dimensional (4D) CT imaging (n = 16) was used. Cure was defined as >50 % post-excision fall of intraoperatively measured parathyroid hormone or fall into the normal range, confirmed by normocalcaemia at least 6 months after surgery. RESULTS: Preoperative CT scan provided correct localization in 13 out of 25 patients (52 %) and was false positive once. Parathyroidectomy was performed by a focused approach in 11 of these 13 patients as well as in 1 patient guided by intraoperatively measured parathyroid hormone (ioPTH). Thirteen patients required bilateral neck exploration. The cure rate was 96 % (24/25 patients). One patient has persistent primary hyperparathyroidism (pHPT) and one a recurrent disease. Six patients presented a multiglandular disease. CONCLUSION: A CT scan identifies about half of abnormal parathyroid glands missed by conventional imaging and allows focused surgery in selected cases. PMID- 25702139 TI - Totally laparoscopic 95% gastrectomy for cancer: technical considerations. AB - INTRODUCTION: Total gastrectomy is the standard treatment for tumours arising in the proximal stomach and for diffuse cancer according to the Lauren classification. Laparoscopic approach is progressively accepted and provides encouraging results. In order to reduce complications associated to the esophago jejunal anastomosis, the concept of the 95 % open gastrectomy was developed in Japan, in the early 1980s. This procedure provides the spearing of a small remnant gastric stump of 2 cm and allows performing a gastro-jejunal anastomosis. Unlike the 7/8 gastrectomy, the 95 % gastrectomy allows the complete resection of the gastric fundus and an optimized pericardial lymph node dissection (group 1 and 2). We herein describe, step-by-step, our technique of full laparoscopic 95 % gastrectomy (G95 %), with D2 lymphadenectomy, including complete lymphadenectomy of the cardial nodes. DISCUSSION: When it is possible to respect the oncologic criteria regarding proximal resection margin, 95 % gastrectomy would offer best short-term results, such as lower anastomotic leak rate and a better quality of life, limiting the effect of disruption of the eso-gastric junction. CONCLUSION: In selected patients, laparoscopic G95 % is feasible and safe; it could be performed without any additional technical difficulties. Controlled clinical trials are necessary to confirm the encouraging results of the cases series, recently reported in literature. PMID- 25702140 TI - Aortic morphometry at endograft position as assessed by 3D image analysis affects risk of type I endoleak formation after TEVAR. AB - PURPOSE: The purpose of this study was to identify morphologic factors affecting type I endoleak formation and bird-beak configuration after thoracic endovascular aortic repair (TEVAR). METHODS: Computed tomography (CT) data of 57 patients (40 males; median age, 66 years) undergoing TEVAR for thoracic aortic aneurysm (34 TAA, 19 TAAA) or penetrating aortic ulcer (n = 4) between 2001 and 2010 were retrospectively reviewed. In 28 patients, the Gore TAG(r) stent-graft was used, followed by the Medtronic Valiant(r) in 16 cases, the Medtronic Talent(r) in 8, and the Cook Zenith(r) in 5 cases. Proximal landing zone (PLZ) was in zone 1 in 13, zone 2 in 13, zone 3 in 23, and zone 4 in 8 patients. In 14 patients (25%), the procedure was urgent or emergent. In each case, pre- and postoperative CT angiography was analyzed using a dedicated image processing workstation and complimentary in-house developed software based on a 3D cylindrical intensity model to calculate aortic arch angulation and conicity of the landing zones (LZ). RESULTS: Primary type Ia endoleak rate was 12% (7/57) and subsequent re intervention rate was 86% (6/7). Left subclavian artery (LSA) coverage (p = 0.036) and conicity of the PLZ (5.9 vs. 2.6 mm; p = 0.016) were significantly associated with an increased type Ia endoleak rate. Bird-beak configuration was observed in 16 patients (28%) and was associated with a smaller radius of the aortic arch curvature (42 vs. 65 mm; p = 0.049). Type Ia endoleak was not associated with a bird-beak configuration (p = 0.388). Primary type Ib endoleak rate was 7% (4/57) and subsequent re-intervention rate was 100%. Conicity of the distal LZ was associated with an increased type Ib endoleak rate (8.3 vs. 2.6 mm; p = 0.038). CONCLUSIONS: CT-based 3D aortic morphometry helps to identify risk factors of type I endoleak formation and bird-beak configuration during TEVAR. These factors were LSA coverage and conicity within the landing zones for type I endoleak formation and steep aortic angulation for bird-beak configuration. PMID- 25702141 TI - Feasibility of Smartphone-Based Education Modules and Ecological Momentary Assessment/Intervention in Pre-bariatric Surgery Patients. AB - BACKGROUND: Bariatric surgery is the most effective means of long-term weight loss. Knowledge gaps and lack of engagement in pre-operative patients can result in suboptimal outcome after surgery. Mobile technology, utilizing ecological momentary assessment (EMA)/intervention (EMI), has shown tremendous promise in changing behaviors. The primary objective of the study is to assess feasibility of using smartphone app with EMA/EMI functionality to prepare patients for bariatric surgery. METHODS: Subjects seeking primary bariatric surgery were provided a smartphone app containing video-based education modules with linked assessments to evaluate mastery of topic. Subjects received algorithmic EMA text messages soliciting a response regarding lifestyle behavior. Upon answering, subjects received tailored EMI text messaging supporting healthy lifestyle. RESULTS: Thirty subjects (27 female and 3 male), with age of 41.3 +/- 11.4 years and BMI of 46.3 +/- 7.4 kg/m(2) were enrolled. Twenty subjects completed the study. Ten subjects withdrew. On average, seven out of nine education modules were completed (70.9 +/- 27.3%), and 37.8/123 EMA were answered (30.7 +/- 21.7%), with response time of 17.4 +/- 4.4 min. Subjects reported high satisfaction with the app. Many felt that the app fit into their routine "somewhat easily" or "very easily" (n = 12), had "perfect" amount of EMA messages (n = 8), and was very helpful in preparing for surgery (n = 7). CONCLUSIONS: This study is the first to reveal the feasibility of using a smartphone app in the education and engagement of patients prior to bariatric surgery. The app was well-received based on subject satisfaction scores and revealed trends toward positive behavior change and increased weight loss. Randomized trials are necessary to delineate true efficacy. PMID- 25702142 TI - Physical activity and sedentary behavior in bariatric patients long-term post surgery. AB - BACKGROUND: To measure sedentary behaviors and physical activity using accelerometry in participants who have undergone bariatric surgery 8.87 +/- 3.78 years earlier and to compare these results with established guidelines. METHODS: Participants' weight and height were measured, an ActivPALTM3 accelerometer and sleeping journal were used to determine day sedentary time, transitions from sitting to standing, as well as steps/day, and participants were asked to indicate if they felt that they were currently less, the same, or more active than before surgery. RESULTS: Participants averaged 48 +/- 15 transitions/day, 6375 +/- 2690 steps/day, and 9.7 +/- 2.3 h/day in sedentary positions. There was a negative correlation between steps/day and sedentary time (r = -.466, p <= .001), 11.27 % of participants achieved 10,000 steps/day. Participants who reported being more active prior to surgery averaged 6323.4 +/- 2634.79 steps/day, which was not different from the other two groups of self-perceived change in level of physical activity (F (2, 68) = .941, p <= .05) from pre- to post-surgery. CONCLUSIONS: Participants were inadequately active and overly sedentary compared to established guidelines and norms. Healthcare workers should be taking physical activity and sedentary time into account when creating post surgical guidelines for this population to ensure the best long-term weight loss maintenance and health outcomes. PMID- 25702143 TI - Synchronous Ventral Hernia Repair in Patients Undergoing Bariatric Surgery. AB - BACKGROUND: Obesity predisposes patients to abdominal wall hernias. Patients undergoing bariatric surgery are not uncommonly found to have ventral hernias. Synchronous ventral hernia repair (S-VHR) has been reported in 2-5% of patients undergoing bariatric surgery. Studies reporting on the outcomes of S-VHR are limited by sample size. The aim of this study was to assess the effect of S-VHR on surgical site infection (SSI) rate. METHODS: The American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database from 2010 to 2011 was queried using Current Procedural Terminology codes for bariatric surgery. Data on patient demographics, comorbidities, procedural events, and postoperative occurrences were analyzed. Thirty-day mortality and morbidity were assessed. Comparisons between laparoscopic Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) were performed. RESULTS: We identified 17,117 patients who underwent RYGB or SG. S-VHR was performed in 503 (2.94%) patients. S-VHR was independently associated with SSI (odds ratios (OR) 1.65, 95% confidence interval (CI) 1.06-2.58), but not overall morbidity (OR 1.33, 95% CI 0.96-1.86). Four hundred thirty-three patients with RYGB and 70 with SG had S-VHR. Serious morbidity (3.5 vs. 5.7%, p = 0.32) and overall morbidity (8.3 vs. 8.6%, p = 0.942) were similar. After controlling for baseline comorbidities, there was no significant effect of procedure type on SSI (OR 0.38, 95% CI 0.05-2.91). CONCLUSIONS: S-VHR is associated with an increase in SSI but not overall morbidity. There is no significant difference in the SSI rate between RYGB and SG. Larger studies are needed to definitively assess a potential difference in the wound infection rate between RYGB and SG. PMID- 25702144 TI - Laparoscopic Gastric Banding in Obese Patients with Sleep Apnea: A 3-Year Controlled Study and Follow-up After 10 Years. AB - BACKGROUND: The purpose of this study was to compare the effects of intensive nutritional care (INC) and laparoscopic adjustable gastric banding (LAGB) on nocturnal non-invasive ventilation (NIV) requirement in obese patients using short-, medium-, and long-term follow-up data. METHODS: This prospective randomized controlled trial included obese patients with obstructive sleep apnea (OSA) treated by NIV. Patients were randomized to the INC and LAGB groups. The primary endpoint was the theoretical rate of weaning from NIV at years 1 and 3. Data were also collected from patients 10 years after randomization. RESULTS: Sixty-three patients were randomized. The rate of weaning from NIV did not differ significantly between the LAGB and INC groups at year 1 (35 vs. 13%) or year 3 (14 vs. 21%). Percentages of excess weight loss were greater in the LAGB group than in the INC group at years 1 (33 vs. 15%, p = 0.002) and 3 (27 vs. 8%, p = 0.014). Decreases in the apnea-hypopnea index were observed in the LAGB group from baseline to year 1 (-44%, p = 0.001) and from baseline to year 3 (-26%, p = 0.044). After 10 years, the weaning rate was low and similar between groups. CONCLUSION: LAGB was not superior to INC for weaning from NIV at 1 and 3 years in obese patients with OSA. PMID- 25702145 TI - Socio-contextual Determinants of Research Evidence Use in Public-Youth Systems of Care. AB - Recent efforts have been devoted to understanding the conditions by which research evidence use (REU) is facilitated from the perspective of system leaders in the context of implementing evidence-based child mental health interventions. However, we have limited understanding of the extent to which outer contextual factors influence REU. Outer contextual factors for 37 counties in California were gathered from public records in 2008; and child welfare, juvenile justice, and mental health system leaders' perceptions of their REU were measured via a web-based survey from 2010 to 2012. Results showed that leaders with higher educational attainment and in counties with lower expenditures on inpatient mental health services were significantly associated with higher REU. Positive relationships between gathering research evidence and racial minority concentration and poverty at the county level were also detected. Results underscore the need to identify the organizational and socio-political factors by which mental health services and resources meet client demands that influence REU, and to recruit and retain providers with a graduate degree to negotiate work demands and interpret research evidence. PMID- 25702146 TI - Experiments on Socio-Technical Systems: The Problem of Control. AB - My aim is to question whether the introduction of new technologies in society may be considered to be genuine experiments. I will argue that they are not, at least not in the sense in which the notion of experiment is being used in the natural and social sciences. If the introduction of a new technology in society is interpreted as an experiment, then we are dealing with a notion of experiment that differs in an important respect from the notion of experiment as used in the natural and social sciences. This difference shows itself most prominently when the functioning of the new technological system is not only dependent on technological hardware but also on social 'software', that is, on social institutions such as appropriate laws, and actions of operators of the new technological system. In those cases we are not dealing with 'simply' the introduction of a new technology, but with the introduction of a new socio technical system. I will argue that if the introduction of a new socio-technical system is considered to be an experiment, then the relation between the experimenter and the system on which the experiment is performed differs significantly from the relation in traditional experiments in the natural and social sciences. In the latter experiments it is assumed that the experimenter is not part of the experimental system and is able to intervene in and control the experimental system from the outside. With regard to the introduction of new socio-technical systems the idea that there is an experimenter outside the socio technical system who intervenes in and controls that system becomes problematic. From that perspective we are dealing with a different kind of experiment. PMID- 25702147 TI - Inter-hospital lateral transfer does not increase length of stay. AB - OBJECTIVE: The aim of the present study was to assess the effect of an inter hospital transfer on efficiency and quality of in-patient care. METHODS: A retrospective cohort study from 2010 to 2012 inclusive was conducted in two tertiary-referral urban hospitals within a single area healthcare network. The study included 14 571 acutely unwell patients admitted to a general medical service. The main outcome measures were length of in-patient stay, relative stay index, readmission rate within 7 and 28 days of discharge and in-hospital mortality rate. RESULTS: Compared with patients who were transferred to a long stay ward within the original hospital (n = 3465), transferred patients (n = 1531) were older (71 vs 80 years, respectively; P < 0.001) but suffered less comorbidity (Charlson index 0.84 vs 1.22, respectively; P < 0.001). Transferred patients spent a shorter time in hospital (5.69 vs 6.25 days; P < 0.001) and were less likely to be re-admitted within 7 days (1.5% vs 4.0%; P < 0.001) or 28 days (6.3% vs 9.3%; P < 0.001) than patients who were not transferred. Mortality was lower in the transferred patients (1.1% vs 4.1%). CONCLUSION: Appropriate patients for inter-hospital transfer can be selected within 24 h of arrival at an index hospital. The efficiency of their care at the receiving hospital appears not to be compromised. The present study provides support for inter-hospital transfer as a strategy to optimise regional bed capacity. PMID- 25702148 TI - Integrated approach to assess the environmental impact of mining activities: estimation of the spatial distribution of soil contamination (Panasqueira mining area, Central Portugal). AB - Through the years, mining and beneficiation processes in Panasqueira Sn-W mine (Central Portugal) produced large amounts of As-rich mine wastes laid up in huge tailings and open-air impoundments (Barroca Grande and Rio tailings) that are the main source of pollution in the surrounding area once they are exposed to the weathering conditions leading to the formation of acid mine drainage (AMD) and consequently to the contamination of the surrounding environments, particularly soils. The active mine started the exploration during the nineteenth century. This study aims to look at the extension of the soil pollution due to mining activities and tailing erosion by combining data on the degree of soil contamination that allows a better understanding of the dynamics inherent to leaching, transport, and accumulation of some potential toxic elements in soil and their environmental relevance. Soil samples were collected in the surrounding soils of the mine, were digested in aqua regia, and were analyzed for 36 elements by inductively coupled plasma mass spectrometry (ICP-MS). Selected results are that (a) an association of elements like Ag, As, Bi, Cd, Cu, W, and Zn strongly correlated and controlled by the local sulfide mineralization geochemical signature was revealed; (b) the global area discloses significant concentrations of As, Bi, Cd, and W linked to the exchangeable and acid-soluble bearing phases; and (c) wind promotes the mechanical dispersion of the rejected materials, from the milled waste rocks and the mineral processing plant, with subsequent deposition on soils and waters. Arsenic- and sulfide-related heavy metals (such as Cu and Cd) are associated to the fine materials that are transported in suspension by surface waters or associated to the acidic waters, draining these sites and contaminating the local soils. Part of this fraction, especially for As, Cd, and Cu, is temporally retained in solid phases by precipitation of soluble secondary minerals (through the precipitation of hydrated metal sulfates) in warm, dry periods, but such minerals are easily dissolved during rainy periods. Climate is an important instability factor, and the hot and dry summers and cold, rainy, and windy winters in this region are physical phenomena that enhance the good receptivity of these soils to retain some of the metals present in the primary and also the secondary mineralogy. Considering the obtained results from both the sequential chemical extraction and the environmental risk assessment according to the risk assessment code, Ag, Cd, Cu, and Zn are classified with very high risk while As is classified with medium risk. PMID- 25702149 TI - Receptor-associated protein promotes t-PA expression, reduces PAI-1 expression and improves neurorecovery after acute ischemic stroke. AB - Receptor-associated protein (RAP) is a receptor antagonist that inhibits ligand interactions with the receptors that belong to the low density lipoprotein receptor gene family. The low-density lipoprotein receptor-related protein 1 (LRP1) has a crucial role in regulating tissue plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI-1) expression. Furthermore, the functional balance of these two proteins is directly associated with the initiation and development of cerebral ischemic stroke. In the present study, the effect of RAP post-treatment was investigated in a rat autologous thromboembolic model. The expression and activity of t-PA and PAI-1 were detected and the neurological function was tested. The results suggest that post-treatment with RAP is able to improve neurorecovery after ischemic stroke by decreasing vascular damage and regulating t-PA and PAI-1 expressions. Post-treatment with RAP promotes t-PA expression, suppresses PAI-1 expression, significantly improves functional outcomes and decreases the amount of TUNEL-positive cells. RAP-treated rats show lower intracranial hemoglobin levels and a smaller ischemic zone. In conclusion, post-treatment with RAP regulates t-PA and PAI-1 expressions and thereby contributes to the improvement of functional outcomes after cerebral ischemia. Our findings strongly suggest that RAP may be of value in neurorecovery after stroke. PMID- 25702150 TI - Occurrence of multiple Cerebral Cavernous Malformations in a patient with Neurofibromatosis type 1. AB - BACKGROUND: Neurofibromatosis 1 (NF1) belongs to the autosomal dominant neurocutaneous disorders' group, which mainly includes NF1 and NF2, tuberous sclerosis, von Hippel-Lindau disease and Cerebral Cavernous Malformations (CCMs). NF1 has a major impact on the nervous system, eye, skin, bone or cardiovascular system. Cerebrovascular lesions have been reported in NF1 including aneurysm, pseudoaneurysm, arteriovenous malformations, vascular stenosis or occlusion and Moya moya syndrome. OBJECTIVE: To report a case of an NF1 patient with multiple CCMs. OBSERVATION: A 47-year-old man with cafe-au-lait skin lesions, countless cutaneous neurofibromas, short stature and scoliosis was admitted for progressive spinal cord compression due to histologically proven neurofibroma. Systematic cerebral MRI screening including gradient echo sequences showed multiple asymptomatic CCMs. Screening of CCM1, CCM2 and CCM3 genes was negative while a deleterious frameshift mutation was identified in NF1 gene. CONCLUSION: While single CCM can occur in NF1 patients following radiation exposure, they are only rarely reported in non-irradiated NF1 brain. Even if it could be a fortuitous association, plausible links and explanations exist. If cerebral MRI can be systematic in NF1 to detect asymptomatic gliomas, used protocols in neuroradiology do not usually include gradient echo sequences, the most sensitive test for CCM detection, leading possibly to failure to detect these vascular lesions. More reports having this combination and further investigations of NF1 families will certainly provide a better understanding of links between these 2 phakomatoses, as recently reported with "multiple meningiomas" phenotype associated with multiple CCMs in patients with CCM3 gene mutations or cafe-au lait skin lesions in CCM1 mutation carriers. PMID- 25702151 TI - Delayed imaging abnormalities of neuro-invasive West Nile virus in cancer patients. PMID- 25702152 TI - Impact of robot-assisted laparoscopic prostatectomy on the management of general anesthesia: efficacy of blood withdrawal during a steep Trendelenburg position. AB - INTRODUCTION: Robot-assisted laparoscopic prostatectomy (RALP) is being increasingly used. However, a steep Trendelenburg position and pneumoperitoneum during RALP has an impact on the respiratory, cardiovascular and cerebrovascular systems. To prevent complications, restrictive fluid management and blood withdrawal have been utilized in our hospital. We examined differences in the anesthetic management between RALP and radical retropubic prostatectomy (RRP), and the efficacy of blood withdrawal. METHODS: Medical records of patients who underwent radical prostatectomy in our hospital between January 2012 and October 2013 were retrospectively reviewed. Demographic data, intraoperative blood and fluid administration, perioperative complications and the length of hospital stay were compared among patients receiving RRP, and those receiving RALP with and without blood withdrawal (n = 78, 46 and 68, respectively). RESULTS: Patients receiving RALP with and without blood withdrawal received a smaller volume of crystalloid during surgery than those receiving RRP (mean +/- SD, 5.8 +/- 2.3 and 4.2 +/- 1.6 vs 14.3 +/- 4.1 ml/kg/h, p < 0.001). Median estimated blood loss was 885 g (80-2,800 g) for RRP and 50 g for RALP (3-950 g and 3-550 g, respectively), p < 0.001. None of the patients undergoing RALP received red blood cells, but three patients undergoing RRP did so. RALP with blood withdrawal reduced postoperative hospital stay by 45 % (6 vs 11 days). Four patients receiving RALP without blood withdrawal had delayed extubation due to severe laryngeal edema, which did not occur in any of the patients receiving RALP who had blood withdrawal. Renal function did not differ among the groups. CONCLUSIONS: RALP was associated with less blood loss, no allogeneic transfusion and shorter postoperative hospital stay. This study indicated that blood withdrawal could prevent severe laryngeal edema. PMID- 25702153 TI - Costly chronic diseases: a retrospective analysis of Chronic Disease Dental Scheme expenditure. AB - OBJECTIVE: The aim of the present study was to investigate Medicare rebate claim trends under the Australian Chronic Disease Dental Scheme (CDDS) over time, region and type of service. METHODS: CDDS data obtained from the Department of Human Services reflected all Medicare item claims lodged under the CDDS by dental practitioners and processed by Medicare. Retrospective analysis of CDDS rebate claims was conducted. RESULTS: The CDDS rebates for the period 2008-13 totalled A$2.8 billion. Just under 81% of claims were from dental practitioners working in major cities. The most frequent rebates were for crown, bridge and implant (32.4%), removable prostheses (22.4%) and restorative services (21.3%). The rebate claims of restorative services, crown and bridge, and removable prostheses per dentist in all regional areas increased over the time of the CDDS. Per capita, the rebates for every type of dental service were lower in the more remote regions. CONCLUSIONS: Rebate claims increased in each of the last 3 full years of the CDDS across all areas. The majority of Medicare rebate claims were from major city areas and for crown and bridge, removable prostheses and restorative services. The service mix varied between regions. PMID- 25702154 TI - Lipid rafts and raft-mediated supramolecular entities in the regulation of CD95 death receptor apoptotic signaling. AB - Membrane lipid rafts are highly ordered membrane domains enriched in cholesterol, sphingolipids and gangliosides that have the property to segregate and concentrate proteins. Lipid and protein composition of lipid rafts differs from that of the surrounding membrane, thus providing sorting platforms and hubs for signal transduction molecules, including CD95 death receptor-mediated signaling. CD95 can be recruited to rafts in a reversible way through S-palmitoylation following activation of cells with its physiological cognate ligand as well as with a wide variety of inducers, including several antitumor drugs through ligand independent intracellular mechanisms. CD95 translocation to rafts can be modulated pharmacologically, thus becoming a target for the treatment of apoptosis-defective diseases, such as cancer. CD95-mediated signaling largely depends on protein-protein interactions, and the recruitment and concentration of CD95 and distinct downstream apoptotic molecules in membrane raft domains, forming raft-based supramolecular entities that act as hubs for apoptotic signaling molecules, favors the generation and amplification of apoptotic signals. Efficient CD95-mediated apoptosis involves CD95 and raft internalization, as well as the involvement of different subcellular organelles. In this review, we briefly summarize and discuss the involvement of lipid rafts in the regulation of CD95-mediated apoptosis that may provide a new avenue for cancer therapy. PMID- 25702155 TI - Tumor suppressive functions of ceramide: evidence and mechanisms. AB - Studies over the past two decades have identified ceramide as a multifunctional central molecule in the sphingolipid biosynthetic pathway. Given its diverse tumor suppressive activities, molecular understanding of ceramide action will produce fundamental insights into processes that limit tumorigenesis and may identify key molecular targets for therapeutic intervention. Ceramide can be activated by a diverse array of stresses such as heat shock, genotoxic damage, oxidative stress and anticancer drugs. Ceramide triggers a variety of tumor suppressive and anti-proliferative cellular programs such as apoptosis, autophagy, senescence, and necroptosis by activating or repressing key effector molecules. Defects in ceramide generation and metabolism in cancer contribute to tumor cell survival and resistance to chemotherapy. The potent and versatile anticancer activity profile of ceramide has motivated drug development efforts to (re-)activate ceramide in established tumors. This review focuses on our current understanding of the tumor suppressive functions of ceramide and highlights the potential downstream targets of ceramide which are involved in its tumor suppressive action. PMID- 25702156 TI - From 'sugar daddies' to 'sugar babies': exploring a pathway among age-disparate sexual relationships, condom use and adolescent pregnancy in South Africa. AB - Background Adolescent pregnancy has been linked to adverse outcomes. Most studies proposing risk pathways for adolescent pregnancy in South Africa are qualitative, hypothesising links among age-disparate relationships, reduced condom use and higher pregnancy rates. No known South African studies have quantitatively explored pathways to adolescent pregnancy. OBJECTIVES: This study aimed to: (i) identify the factors associated with adolescent pregnancy and (ii) explore a pathway of risk by assessing whether condom use mediated the relationship between age-disparate sexual relationships and adolescent pregnancy. METHODS: A cross sectional survey of 447 sexually active girls aged 10-19 years was undertaken in six health districts of South Africa. Multivariate logistic regressions controlled for confounders. Mediation tests used bootstrapping. RESULTS: Consistent condom use (beta=-2.148, odds ratio (OR)=8.566, P<=0.001) and school enrolment (beta=-1.600, OR=0.202, P<=0.001) were associated with lower pregnancy rates. Age-disparate sex (beta=1.093, OR=2.982, P<=0.001) and long-term school absences (beta=1.402, OR=4.061, P<=0.001) were associated with higher pregnancy rates. The indirect effect of age-disparate sex on adolescent pregnancy through condom use was significant, irrespective of age, age at sexual initiation, poverty and residential environment (B=0.4466, s.d.=0.1303, confidence interval: 0.2323-0.7428). CONCLUSION: This survey supports hypotheses that inability to negotiate condom use in age-disparate sexual relationships may drive adolescent pregnancy. Interventions addressing these relationships, facilitating condom use and increasing access to sexual health services among adolescents might avert unwanted pregnancies. PMID- 25702157 TI - Customisation of an instrument to assess anaesthesiologists' non-technical skills. AB - OBJECTIVE: The objectives of the study were to identify Danish anaesthesiologists' non-technical skills and to customise the Scottish-developed Anaesthetists' Non-Technical Skills instrument for Danish anaesthesiologists. METHODS: Six semi-structured group interviews were conducted with 31 operating room team members: anaes-thesiologists, nurse anaesthetists, surgeons, and scrub nurses. Interviews were transcribed verbatim and analysed using directed content analysis. Anaesthesiologists' non-technical skills were identified, coded, and sorted using the original instrument as a basis. The resulting prototype instrument was discussed with anaesthesiologists from 17 centres to ensure face validity. RESULTS: Interviews lasted 46-67 minutes. Identified examples of anaesthesiologists' good or poor non-technical skills fit the four categories in the original instrument: situation awareness; decision making; team working; and task management. Anaesthesiologists' leadership role in the operating room was emphasised: the original 'Task Management' category was named 'Leadership'. One new element, 'Demonstrating self-awareness' was added under the category 'Situation Awareness'. Compared with the original instrument, half of the behavioural markers were new, which reflected that being aware of and communicating one's own abilities to the team; working systematically; and speaking up to avoid adverse events were important skills. CONCLUSIONS: The Anaesthetists' Non-Technical Skills instrument was customised to a Danish setting using the identified non-technical skills for anaesthesiologists and the original instrument as basis. The customised instrument comprises four categories and 16 underpinning elements supported by multiple behavioural markers. Identifying non technical skills through semi-structured group interviews and analysing them using direct content analysis proved a useful method for customising an assessment instrument to another setting. PMID- 25702159 TI - Targeted Immunotherapy Designed to Treat MUC1-Expressing Solid Tumour. AB - Several approaches to antigen-specific immunotherapy of cancer antigen-specific immunotherapy of cancer have been tested clinically. In this chapter, we will describe studies done with the antigen MUC1. Tested MUC1 therapeutic vaccines include the following: monoclonal antibodies (MAbs) specific for MUC1; synthetic and recombinant polypeptides from the protein sequence of MUC1; dendritic cells carrying MUC1; RNA and DNA vaccinations; and recombinant viruses carrying the MUC1 DNA sequence. Chemotherapy of cancer aims to be toxic to the cancer cells with manageable side effects to the patient. In contrast, antigen-specific immunotherapy of cancer aims to treat the patient, such that the patient is then able to control and eventually eliminate their cancer cells. It is therefore important to know the immune status of each cancer patient prior to therapy. PMID- 25702158 TI - Cardiac fatty acid uptake and metabolism in the rat model of polycystic ovary syndrome. AB - Polycystic ovary syndrome (PCOS) is associated with an altered plasma lipid profile and increased risk for cardiovascular diseases. We hypothesized that molecular mechanisms underlying cardiac pathology in PCOS involve changes in expression and subcellular localization of several key proteins involved in cardiac lipid transport and metabolism, such as fatty acid transporter CD36, lipin 1, peroxisome proliferator-activated receptor alpha (PPARalpha), peroxisome proliferator-activated receptor gamma coactivator-1 (PGC1), and carnitine palmitoyltransferase 1 (CPT1). We used the animal model of PCOS obtained by treating female rats with dihydrotestosterone (DHT). Protein levels of CD36, lipin 1, PPARalpha, PGC1, and antioxidative enzymes were assessed by Western blot in different cardiac cell compartments. Cardiac triglycerides (TG) and lipid peroxidation were also measured. The content of CD36 was decreased in both the cardiac plasma membranes and intracellular pool. On the other hand, total content of cardiac lipin 1 in DHT-treated rats was elevated, in contrast to decreased microsomal lipin 1 content. An increase in nuclear content of lipin 1 was observed together with elevation of nuclear PPARalpha and PGC1, and an increase in CPT1 expression. However, lipid peroxidation was reduced in the heart, without alterations in antioxidative enzymes expression and cardiac TG content. The results indicate that treatment of female rats with DHT is accompanied by a decrease of fatty acid uptake and a reduction of lipid peroxidation in the heart. The observed elevation of lipin 1, PPARalpha, PGC1, and CPT1 expression suggests that cardiac fatty acid metabolism is shifted toward mitochondrial beta oxidation. PMID- 25702160 TI - Ready, set, point: the effects of alertness on prism adaptation in healthy adults. AB - Prism adaptation (PA) is a promising rehabilitation technique for visuo-spatial neglect, an attention disorder that is characterized by spatial attention deficits (i.e., deficits in orienting). PA involves visuo-motor adaptation to rightward shifting prism goggles. Following goggle removal, this adaptation results in leftward shifts in visuo-motor aiming and amelioration of spatial neglect. Even though some studies clearly support the beneficial effects of PA for spatial neglect, not all studies find benefits, thus it remains unclear how PA effects could be improved. Taking advantage of the known interactions between orienting and alerting reported in the attention literature (i.e., alerting enhances orienting function; e.g., Ishigami and Klein in J Individ Differ 30:220 237. doi: 10.1027/1614-0001.30.4.220 , 2009, in J Neurosci Methods 190:117-28. doi: 10.1016/j.jneumeth.2010.04.019 , 2010; Robertson et al. in Nature 395:169 72. doi: 10.1038/25993 , 1998), we examined the effects of alerting tones on PA with healthy young and older adults. We found that the effects of alerting on PA with young adults were negative, while there was a positive effect with older adults, specifically on a visuo-motor outcome task. Thus, enhancement of PA effects by alerting may be age specific and task specific. Therefore, we can conclude that while the impact of alerting tones is not always positive, further research in patients with neglect may be warranted. PMID- 25702161 TI - Dopamine D4 receptors linked to protein kinase G are required for changes in dopamine release followed by locomotor activity after repeated cocaine administration. AB - We previously found that the dopamine D2-type receptors (D2 and D3 receptors), coupled to protein kinase G (PKG), upregulate locomotor activity after repeated cocaine administration. In this study, D4 receptors, another type of D2 receptor also coupled to PKG, were examined to determine their requirement in the regulation of locomotor activity after repeated cocaine administration. The results demonstrated that repeated injections of cocaine (20 mg/kg), given once a day for seven consecutive days, significantly increased extracellular dopamine concentrations. Intra-caudate infusion of the D4 receptor agonist, PD168077 (10 nmol), and the PKG inhibitor, KT5823 (2 nmol), significantly decreased the repeated cocaine-induced increase in dopamine levels and locomotor activity. However, intra-caudate infusion of KT5823, but not PD168077, decreased ?FosB immunoreactivity elevated by repeated cocaine administration. These findings suggest that D4 receptors linked to PKG could be a key modulator for dopamine release required for changes in locomotor activity caused by repeated cocaine exposure. PMID- 25702162 TI - Improved in vitro assay for determining the mucin adherence of bacteria sensitive to Triton X-100 treatment. AB - Mucin-associated microbiota are in relatively close contact with the intestinal epithelium and may thus have a more pronounced effect on host health. We have previously developed a simple mucin agar assay to simulate initial mucus colonization by intestinal microbial communities. Adherence of microbiota was estimated using flow cytometry after detachment with Triton X-100. In this study, the effect of this detergent on the cultivability of both virulent and commensal strains was investigated. Mucin attachment of selected strains was evaluated using the mucin adhesion assay. Bacteria were dislodged from the mucin surface by incubation with Triton or from the whole mucin agar layer using a stomacher. Mechanical extraction resulted in 1.24 +/- 0.42, 2.69 +/- 0.44, and 1.56 +/- 0.85 log CFU/mL higher plate counts of Lactobacillus rhamnosus, Bacillus cereus, and Escherichia coli strains, respectively, than the chemical method. The sensitivity of bacteria to Triton varied among microbial species and strains. Among others, Triton inhibited the growth of Salmonella enterica LMG 10396 and Pseudomonas aeruginosa LMG 8029 on laboratory media, although these bacteria maintained their viability during this treatment. Only Gram-positive strains, Enterococcus hirae LMG 6399 and L. rhamnosus GG, were not affected by this detergent. Therefore, the mechanical method is recommended for the extraction of mucin-adhered bacteria that are sensitive to Triton, especially when followed by traditional cultivation techniques. However, this approach can also be recommended for strains that are not affected by this detergent, because it resulted in higher recovery of adhered L. rhamnosus GG compared to the chemical extraction. PMID- 25702163 TI - The Nsun7 (A11337)-deletion mutation, causes reduction of its protein rate and associated with sperm motility defect in infertile men. AB - PURPOSE: Recent studies have shown that genetic abnormalities may be responsible for most unknown cases of male infertility. Human Nsun7 gene, which is located on chromosome4, has a role in sperm motility by encoding the putative methyltransferase Nsun7 protein. The aim of the present study was to investigate the mutations of exon4 in the Nsun7 gene, which is associated with sperm motility defect. METHODS: Semen samples including those of fertile normospermic (normal), infertile oligospermic (with normal sperm motility), and infertile asthenospermic (with reduced sperm motility) men were collected from the Omid and Fatemezahra IVF centres (Babol, Iran). These samples were then analysed on the basis of World Health Organization guidelines using the general phenol-chloroform DNA extraction method. Exon4 was amplified using Sun-F/Sun-R primers. Samples from asthenospermic men, which showed different patterns of movement on single-strand conformation polymorphism compared with normal and oligospermic samples, were identified and subjected to sequencing for further identification of possible mutations. RESULTS: Analysis of extracted sperm proteins showed that the rate of Nsun7 decreased. Likewise, direct sequencing of PCR products, along with their analysis, confirmed the deletion mutation of adenine in location 11337 of the Nsun7 gene in asthenospermic men. Comparison of normal and mutant protein structures of Nsun7 indicated that the A11337-deletion of the exon4 resulted in the valine residues-157 with GTA-codon in normospermic replaced with TAG-early stop codon in asthenospermic samples, causing an abortive protein product with amino acid sequence shorter than normal. The secondary structure of the protein, the protein folding, and ligand binding sites were changed, indicating the impairment of the protein function. CONCLUSIONS: Because the Nsun7 gene products have a role in sperm motility, it will lead to impairment in the activity of the protein and motility of sperm flagella as well as male infertility if a mutation occurs in this gene. PMID- 25702164 TI - Scrotal heat stress causes sperm chromatin damage and cysteinyl aspartate spicific proteinases 3 changes in fertile men. AB - PURPOSE: To observe changes in semen parameters, sperm DNA integrity, chromatin condensation and cysteinyl aspartate-spicific proteinases (Caspase-3) in adult healthy men after scrotal heat stress (SHS). METHODS: The scrotums of 19 healthy male volunteers were exposed to the condition of 40-43 degrees C SHS belt warming 40 min each day for successive 2 days per week. The course of SHS was continuously 3 months. Routine semen analysis, hypo-osmotic swelling (HOS) test, eosin Y (EY) staining sperm HOS and chromatin dispersion (HOS/SCD) test, HOS and aniline blue (HOS/AB) staining test were carried out before, during and after SHS. The activated Caspase 3 levels of spermatozoa were determined with a microtiter plate reader. RESULTS: The mean parameters of sperm concentration, motility and normal morphological sperm were significantly decreased in groups with sperm being collected during SHS 1, 2 and 3 months when compared with those in groups of pre-SHS (P < 0.01). Statistically significant differences of sperm DNA fragmentation, normal sperm membrane and vitality, and Caspase-3 activity were observed between the groups of before SHS and after SHS 3 months and the groups of during SHS 1, 2 and 3 months (P < 0.001). Three months the SHS stopped, various parameters recovered to the level before SHS. Abnormal sperm with HOS/AB and HOS/SCD showed a negatively significant correlation with normal sperm by HOS/EY test, and WBC in semen showed a positively significant correlation with Caspase-3 activity. The percentage of abnormal sperm by using the test of HOS/SCD showed a positively significant correlation with that of HOS/AB. CONCLUSIONS: The continuously constant SHS can impact the semen quality, sperm DNA integrity, chromatin condensation and Caspase-3, and the combination of HOS plus AB test may simultaneously determine the integrity of membrane and chromatin condensation at the same spermatozoon. PMID- 25702165 TI - The role of fear in mental health service users' experiences: a qualitative exploration. AB - PURPOSE: Although studies suggest that fear plays an important role in shaping mental health service users' experiences, evidence is patchy and the contexts, conditions and consequences of fear have rarely been researched. This paper explores the role of fear in adult mental health service users' lives and describes its implications for mental health services. METHODS: Four community health service user focus groups (N32) were held. Each group was reconvened after 7-14 days. An initial thematic analysis generated a service user definition of continuity of care (reported elsewhere). A Straussian 'secondary grounded theory analysis' was conducted to gain a deeper understanding of participants' experiences. RESULTS: 'Being afraid' was identified as a core process, with power and control, and stigma and discrimination found to have explanatory power in determining how and why fear manifests. Consequences included distrusting staff, cooperating reluctantly, learning reticence, delaying help-seeking, avoiding services, feeling unsafe in the community and avoiding exposure as a service user. CONCLUSIONS: Our model suggests that fear plays a substantial role in the lives of adult mental health service users. This has particular consequences for therapeutic relationships, engagement with services and engagement with the wider community. This lack of engagement is associated with adverse outcomes. Further research into the role of fear and the factors that mediate against it is warranted. PMID- 25702166 TI - The stability and predictors of peer group deviance in university students. AB - BACKGROUND: Peer group deviance (PGD) is strongly associated with current and future externalizing behaviors. Debate remains about the degree to which this association arises from social selection. The first year of university constitutes a social experiment in which most individuals leave their home environment and recreate for themselves a new peer group. METHODS: PGD was measured in newly arrived university students and then 6 and 18 months later. Other personality and family traits were also assessed. RESULTS: PGD reported for high school friends at the start of university and university friends 6 months later were substantially correlated (+0.60). This correlation was only slightly diminished if restricted to students whose home was greater than 50 miles from the university. PGD was strongly predicted across three cohorts by male sex (+), extraversion (+), conscientiousness (-), a family history of alcohol use disorders (+) and depression (+), and religiosity (-).These predictors of PGD had a relatively stable impact over 18 months and, aside from sex, differed only modestly in males and females. CONCLUSIONS: As individuals change social groups from high school to university, the level of PGD remains relatively stable, suggesting that individuals play a strong role in selecting peer groups with consistent characteristics. PGD is also predicted cross-sectionally and longitudinally by personality, family background and religiosity. Our results suggest that the association between personal and peer deviance is due at least in part to the effects of social selection. PMID- 25702167 TI - The forum as a friend: parental mental illness and communication on open Internet forums. AB - PURPOSE: The aim of this study was to identify how daughters or sons to parents suffering from mental illness perceive their situation. The objective was to provide new knowledge based on what they communicate on open Internet forums. METHODS: The sample consisted of forum posts written by individuals who reported that they had mentally ill parents. Data collection comprised 301 comments from 35 forum threads on 5 different Swedish Internet forums, and predetermined inclusion criteria were used. Data were analyzed qualitatively using thematic analysis. RESULTS: The analysis generated four themes: "Caregiver burden," "Knowledge seeking," "Support from the forum," and "Frustration and powerlessness over health care." The results showed that parents' mental illness affected the forum writers on several levels, and they often felt stigmatized. The writers often lacked knowledge of their parents' mental illness and sought out Internet forums for information and support from peers in similar situations. The psychiatric care given to the parents was a source of dissatisfaction among the forum writers, who often felt that their parents did not receive adequate care. CONCLUSIONS: This study shows that fear of stigmatization and perceived lack of care and support caused forum writers to anonymously seek out Internet forums for information and support from others with similar experiences. The role of social support and the attractiveness of anonymity and availability typical for open Internet forums ought to be considered by health care professionals and researchers when developing new ways for providing support for children or adolescents with a mentally ill parent. PMID- 25702168 TI - Zebrafish genome instability after exposure to model genotoxicants. AB - Sublethal exposure to environmental genotoxicants may impact genome integrity in affected organisms. It is therefore necessary to develop tools to measure the extent and longevity of genotoxicant-induced DNA damage, and choose appropriate model organisms for biomonitoring. To this end, markers of DNA damage were measured in zebrafish larvae and adults following exposure to model genotoxicants (benzo[a]pyrene and ethyl methanesulfonate). Specifically, we assessed primary DNA damage and the existence of potentially persistent genomic alterations through application of the comet assay, quantitative random amplified polymorphic DNA (qRAPD) and amplified fragment length polymorphism (AFLP) assays. Furthermore, expression of genes involved in DNA repair, oxidative stress response and xenobiotic metabolism was evaluated as well. Additionally, the AFLP method was applied to adult specimens 1 year after larval exposure to the genotoxicants to evaluate the longevity of the observed DNA alterations. Large numbers of DNA alterations were detected in larval DNA using the comet assay, qRAPD and AFLP, demonstrating that zebrafish larvae are a sensitive model for revealing genotoxic effects. Furthermore, some of these genomic alterations persisted into adulthood, indicating the formation of stable genomic modifications. qRAPD and AFLP methods proved to be highly sensitive to genotoxic effects, even in cases when the comet assay indicated a lack of significant damage. These results thus support the use of zebrafish larvae as a sensitive model for monitoring the impact of genotoxic insult and give evidence of the longevity of genomic modifications induced by genotoxic agents. PMID- 25702169 TI - Chlamydia and gonorrhoea point-of-care testing in Australia: where should it be used? AB - Background Diagnoses of chlamydia and gonorrhoea have increased steadily in Australia over the past decade. Testing and treatment is central to prevention and control but in some settings treatment may be delayed. Testing at the point of care has the potential to reduce these delays. We explored the potential utility of newly available accurate point-of-care tests in various clinical settings in Australia. METHODS: In-depth qualitative interviews were conducted with a purposively selected group of 18 key informants with sexual health, primary care, remote Aboriginal health and laboratory expertise. RESULTS: Participants reported that point-of-care testing would have greatest benefit in remote Aboriginal communities where prevalence of sexually transmissible infections is high and treatment delays are common. Some suggested that point-of care testing could be useful in juvenile justice services where young Aboriginal people are over-represented and detention periods may be brief. Other suggested settings included outreach (where populations may be homeless, mobile or hard to access, such as sex workers in the unregulated sex industry and services that see gay, bisexual and other men who have sex with men). Point-of-care testing could also improve the consumer experience and facilitate increased testing for sexually transmissible infections among people with HIV infection between routine HIV-management visits. Some participants disagreed with the idea of introducing point-of-care testing to urban services with easy access to pathology facilities. CONCLUSIONS: Participants felt that point-of-care testing may enhance pathology service delivery in priority populations and in particular service settings. Further research is needed to assess test performance, cost, acceptability and impact. PMID- 25702170 TI - Increased viability but decreased culturability of Mycobacterium avium subsp. paratuberculosis in macrophages from inflammatory bowel disease patients under Infliximab treatment. AB - Mycobacterium avium subsp. paratuberculosis (MAP) has long been implicated as a triggering agent in Crohn's disease (CD). In this study, we investigated the growth/persistence of both M. avium subsp. hominissuis (MAH) and MAP, in macrophages from healthy controls (HC), CD and ulcerative colitis patients. For viability assessment, both CFU counts and a pre16SrRNA RNA/DNA ratio assay (for MAP) were used. Phagolysosome fusion was evaluated by immunofluorescence, through analysis of LAMP-1 colocalization with MAP. IBD macrophages were more permissive to MAP survival than HC macrophages (a finding not evident with MAH), but did not support MAP active growth. The lower MAP CFU counts in macrophage cultures associated with Infliximab treatment were not due to increased killing, but possibly to elevation in the proportion of intracellular dormant non-culturable MAP forms, as MAP showed higher viability in those macrophages. Increased MAP viability was not related to lack of phagolysosome maturation. The predominant induction of MAP dormant forms by Infliximab treatment may explain the lack of MAP reactivation during anti-TNF therapy of CD but does not exclude the possibility of MAP recrudescence after termination of therapy. PMID- 25702171 TI - Postoperative complications after reconstructive surgery for cloacal malformations: a systematic review. AB - The repair of cloacal malformations is most often performed using a posterior sagittal anorecto-vagino-urethroplasty (PSARVUP) or total urogenital mobilization (TUM) with or without laparotomy. The aim of this study was to systematically review the frequency and type of postoperative complication seen after cloacal repair as reported in the literature. A systematic literature search was conducted according to preferred reporting items for systematic reviews and meta analyses guidelines (PRISMA). Eight records were eligible for this study which were qualitatively analyzed according to the Rangel score. Overall complication rates reported in included studies ranged from 0 to 57 %. After meta-analysis of data, postoperative complications were seen in 99 of 327 patients (30 %). The most common reported complications were recurrent or persistent fistula (n = 29, 10 %) and rectal prolapse (n = 27, 10 %). In the PSARVUP group, the complication rate was 40 % and in the TUM group 30 % (p = 0.205). This systematic review shows that postoperative complications after cloacal repair are seen in 30 % of the patients. The complication rates after PSARVUP and TUM were not significantly different. Standardization in reporting of surgical complications would inform further development of surgical approaches. Other techniques aiming to lower postoperative complication rates may also deserve consideration. PMID- 25702172 TI - Transanal endoscopic total mesorectal excision: technical aspects of approaching the mesorectal plane from below--a preliminary report. AB - BACKGROUND: Laparoscopic total mesorectal excision (TME) for low rectal cancer can be technically challenging. This report describes our initial experience with a hybrid laparoscopic and transanal endoscopic technique for TME in low rectal cancer. METHODS: Between December 2012 and October 2013, we identified patients with rectal cancer < 5 cm from the anorectal junction (ARJ) who underwent laparoscopic-assisted TME with a transanal minimally invasive surgery (TAMIS) technique. A standardized stepwise approach was used in all patients. Resection specimens were examined for completeness and measurement of margins. Preoperative magnetic resonance imaging (MRI) characteristics and short-term postoperative outcomes were examined. All values are mean +/- standard deviation. RESULTS: Ten patients (8 males; median age: 60.5 (range 36-70) years) were included. On initial MRI, all tumors were T2 or T3, mean tumor height from the ARJ was 28.9 +/ 12.2 mm, mean circumferential resection margin was 5.3 +/- 3.1 mm , and the mean angle between the anal canal and the levator ani was 83.9 degrees +/- 9.7 degrees . All patients had had preoperative chemoradiotherapy, TME via TAMIS, and distal anastomosis. There were no intraoperative complications, anastomotic leaks, or 30-day mortality. The pathologic quality of all mesorectal specimens was excellent. The distal resection margin was 19.4 +/- 10.4 mm, the mean circumferential resection margin was 13.8 +/- 5.1 mm, and the median lymph node harvest was 10.5 (range 5-15) nodes. CONCLUSIONS: A combined laparoscopic and transanal approach can achieve a safe and oncologically complete TME dissection for low rectal tumors. This approach may improve clinical outcomes in these technically difficult cases, but larger prospective studies are needed. PMID- 25702173 TI - Risk reclassification analysis investigating the added value of fatigue to sickness absence predictions. AB - BACKGROUND: Prognostic models including age, self-rated health and prior sickness absence (SA) have been found to predict high (>= 30) SA days and high (>= 3) SA episodes during 1-year follow-up. More predictors of high SA are needed to improve these SA prognostic models. The purpose of this study was to investigate fatigue as new predictor in SA prognostic models by using risk reclassification methods and measures. METHODS: This was a prospective cohort study with 1-year follow-up of 1,137 office workers. Fatigue was measured at baseline with the 20 item checklist individual strength and added to the existing SA prognostic models. SA days and episodes during 1-year follow-up were retrieved from an occupational health service register. The added value of fatigue was investigated with Net Reclassification Index (NRI) and integrated discrimination improvement (IDI) measures. RESULTS: In total, 579 (51 %) office workers had complete data for analysis. Fatigue was prospectively associated with both high SA days and episodes. The NRI revealed that adding fatigue to the SA days model correctly reclassified workers with high SA days, but incorrectly reclassified workers without high SA days. The IDI indicated no improvement in risk discrimination by the SA days model. Both NRI and IDI showed that the prognostic model predicting high SA episodes did not improve when fatigue was added as predictor variable. CONCLUSION: In the present study, fatigue increased false-positive rates which may reduce the cost-effectiveness of interventions for preventing SA. PMID- 25702174 TI - Early-life stress increases the motility of microglia in adulthood. AB - Early-life stress may cause several neuropsychological disorders in adulthood. Such disorders may be induced as a result of instability of neuronal circuits and/or synaptic formation. However, the mechanisms underlying such instability have not yet been clearly understood. We previously reported that the mushroom spine in the somatosensory cortex (SSC) is unstable in early-life stressed mice not only in the juvenile stage but also in adulthood. In this study, we measured the number and motility of microglial processes in early-life stressed mice to understand the mechanism further. We found that the number and motility of filopodia-like protrusions of microglial processes tended to increase in the SSC of early-life stressed mice. Interestingly, the motility of protrusions correlated significantly with the nociceptive threshold level measured by the von Frey test. These results indicated that the activity of microglia affected the neuronal function in early-life stressed mice. PMID- 25702175 TI - CXCL9 and CXCL10 gene polymorphisms in patients with rheumatoid arthritis. AB - Chemokines (CXCL) and their receptors play important roles in the pathogenesis of rheumatoid arthritis (RA). The aim of this study was to examine the associations between polymorphisms in the CXCL9 (rs3733236 G>A) and CXCL10 (rs8878 A>G) genes and RA. We examined 422 RA patients and 338 subjects as a control group. Single nucleotide polymorphisms (SNPs) in the CXCL9 (rs3733236 G>A) and CXCL10 (rs8878 A>G) genes were genotyped using TaqMan genotyping assays from Life Technologies Genomic. There were no significant differences in distribution of CXCL9 genotypes and alleles between RA patients and control group. Among RA patients, the increased frequency of CXCL10 (rs8878) G allele carriers was detected AG+GG vs AA (p = 0.034; OR 1.49, 95 % CI 1.03-2.13). There were no significant associations of CXCL9 genotypes with age of disease diagnosis rheumatoid factor, erosive disease, and extra-articular manifestations. In case of CXCL10 genotypes, there was the increased frequency of extra-articular manifestations in GG genotype carriers GG vs AA+AG (p = 0.027; OR 1.82, 95 % CI 1.09-3.03). In the multivariate regression analysis, the CXCL10 GG genotype was the independent factor associated with increased probability of extra-articular manifestations development (p = 0.034; OR 1.75, 95 % CI 1.04-3.03). The results of this study suggest the association between CXCL10 gene polymorphism and rheumatoid arthritis. PMID- 25702176 TI - Exercise-induced regulation of key factors in substrate choice and gluconeogenesis in mouse liver. AB - As the demand for hepatic glucose production increases during exercise, regulation of liver substrate choice and gluconeogenic activity becomes essential. The aim of the present study was to investigate the effect of a single exercise bout on gluconeogenic protein content and regulation of enzymes involved in substrate utilization in the liver. Mice were subjected to 1 h of treadmill exercise, and livers were removed immediately, 4 or 10 h after exercise. Glucose 6-phosphatase (G6Pase) and phosphoenolpyruvate carboxylase (PEPCK) mRNA contents in the liver increased immediately after exercise, while the PEPCK protein content increased at 10 h of recovery. Furthermore, 5'AMP-activated protein kinase (AMPK), acetyl-CoA carboxylase (ACC), and pyruvate dehydrogenase (PDH) E1alpha Ser(293) phosphorylations decreased immediately after exercise. In addition, PDH kinase 4 (PDK4) mRNA and protein content increased immediately after exercise and at 10 h of recovery, respectively. These findings suggest that acute changes in PEPCK and G6Pase protein contents do not contribute to the regulation of gluconeogenic enzyme activity during 1 h of non-exhaustive exercise. In addition, the observation that PDH-E1alpha, AMPK, and ACC phosphorylation decreased immediately after exercise may indicate that carbohydrates rather than fatty acids are utilized for oxidation in the liver during non-exhaustive exercise. PMID- 25702178 TI - Bony fusion in a chronic cervical bilateral facet dislocation. AB - BACKGROUND: Cervical facet dislocation injuries typically present shortly after occurrence due to the pain and neurologic deficit that can be associated with this injury. Bilateral dislocations of the facet joint require prompt evaluation, reduction, and surgical intervention. Rare case reports present bilateral dislocations presenting in a delayed fashion. CASE REPORT: We report the case of a 60-year-old male who presented with mild neck pain 1 year after initial injury. Computed topography of the cervical spine showed healing with bony fusion of a bilateral C6-7 facet dislocation. Given the chronic healed nature of the injury and minimal symptoms, the patient is being followed without intervention. CONCLUSIONS: Although most bilateral facet dislocations present and are treated immediately after injury; this case illustrates that some may be missed during initial evaluation. Once healed, these injuries may be stable without surgical intervention. PMID- 25702177 TI - The antiatherogenic effect of bixin in hypercholesterolemic rabbits is associated to the improvement of lipid profile and to its antioxidant and anti-inflammatory effects. AB - Hypercholesterolemia and oxidative stress have been implicated in the pathophysiology of atherosclerosis and coronary artery disease. We investigated whether the carotenoid bixin (BIX) may reduce oxidative damage, inflammatory response, and the atherosclerotic lesion induced by hypercholesterolemia in rabbits. Rabbits received regular chow (control) or a hypercholesterolemic diet (0.5% cholesterol) alone or supplemented with BIX (10, 30 or 100 mg/kg body weight, b.w.) or simvastatin (15 mg/kg b.w.) for 60 days. Treatment with BIX or simvastatin reduced the atherosclerotic lesions in cholesterol-fed rabbits (up to 55 and 96% reduction, respectively). This protective effect of BIX was accompanied by decrease in the levels of tumor necrosis factor alpha by 15%, interleukin 6 by 19%, lipid peroxidation by 60%, non-high-density lipoprotein cholesterol (non-HDL-C) by 37%, and triglycerides by 41%. BIX increased by 160% the HDL-C levels and decreased by 67% the atherogenic index of hypercholesterolemic rabbits. In atherosclerotic rabbits, the non-protein thiol groups content and the activity of the antioxidant enzymes superoxide dismutase, catalase, glutathione reductase, and thioredoxin reductase were increased in the aortic tissue, whereas paraoxonase activity was reduced in the serum. All these changes were completely prevented by BIX or simvastatin treatment. These results demonstrate that BIX reduces the extent of atherosclerotic lesions and this effect was associated with the decrease in oxidative stress, inflammatory response, and improvement of dyslipidemia, which were most effectively controlled after treatment with 10-30 mg BIX/kg b.w. BIX consumption may, therefore, be an adjuvant to prevent atherosclerosis reducing risk factors for coronary diseases. PMID- 25702179 TI - Pediatric brainstem gliomas: new understanding leads to potential new treatments for two very different tumors. AB - Pediatric brainstem gliomas include low-grade focal brainstem gliomas (FBSG) and high-grade diffuse intrinsic pontine gliomas (DIPG). These tumors share a crucial and eloquent area of the brain as their location, which carries common challenges for treatment. Otherwise, though, these two diseases are very different in terms of presentation, biology, treatment, and prognosis. FBSG usually present with greater than 3 months of symptoms, while DIPG are usually diagnosed within 3 months of symptom onset. Surgery remains the preferred initial treatment for FBSG, with chemotherapy used for persistent, recurrent, or inoperable disease; conversely, radiation is the only known effective treatment for DIPG. Recent developments in biological understanding of both tumors have led to new treatment possibilities. In FBSG, two genetic changes related to BRAF characterize the majority of tumors, and key differences in their biological effects are informing strategies for targeted chemotherapy use. In DIPG, widespread histone H3 and ACVR1 mutations have led to new hope for effective targeted treatments. FBSG has an excellent prognosis, while the long-term survival rate of DIPG tragically remains near zero. In this review, we cover the epidemiology, biology, presentation, imaging characteristics, multimodality treatment, and prognosis of FBSG and DIPG, with a focus on recent biological discoveries. PMID- 25702180 TI - Images in emergency medicine. Young male with rapidly swelling jaw. Burkitt's lymphoma of the jaws. PMID- 25702181 TI - Commentary. Severe Respiratory Illness Associated With Enterovirus D68-Missouri and Illinois, 2014. PMID- 25702182 TI - Change of shift. The blanket. PMID- 25702183 TI - Change of shift. "First aid? Please? First aid?". PMID- 25702184 TI - Taking the "goal-directed" out of early goal-directed therapy for sepsis?: March 2015 Annals of Emergency Medicine Journal Club. PMID- 25702185 TI - Images in emergency medicine. Young man with shortness of breath. Uremic frost. PMID- 25702186 TI - Why does your dandruff smell like urine? PMID- 25702187 TI - In-flight emergency. PMID- 25702188 TI - Images in emergency medicine. Young man with pain in finger. Slit-lamp microscope use for soft tissue foreign body removal. PMID- 25702189 TI - Reporting issues in diagnostic accuracy studies for fine-needle aspiration cytology. PMID- 25702190 TI - Reduction in posterior semicircular canal gain by age in video head impulse testing. Observational study. AB - INTRODUCTION: and objectives: In-depth assessment of the vestibulo-ocular reflex with the new video systems available provides information on various previously unidentified characteristics in patients with peripheral vestibular disorder. The aim of this work is to quantify how often pathological gain (uni- or bilateral) in the posterior semicircular canal (PSC) gain appears in video head-impulse testing (vHIT) with preservation of the gain in the rest of the semicircular canals, and to analyse the relation of this frequency with patient age and/or diagnosis. METHODS: This was a prospective observational study on adults referred to our unit between June 2012 and February 2014. Age, sex, pathological antecedents, prior history of vestibular pathology, diagnosis and time of evolution of the clinical picture and its characteristics were recorded. Each patient underwent a complete otoneurological examination, including vHIT (Otometrics(r)). Depending on suspected diagnosis, patients also received cervical vestibular evoked myogenic potential (VEMP) testing, tonal audiometry and speech test, as well as assessment by Neurology and/or nuclear magnetic resonance or computed axial tomography scan imaging study. RESULTS: In all, 363 patients were assessed; 57 (16%) patients (33 males and 24 females; mean age, 57 +/- 15 years) showed pathological PSC gains, 46 (81%) unilateral and 11 (19%) bilateral. Meniere's Disease was the most frequent diagnosis, followed by benign paroxysmal positional vertigo (27%). Patients with unilateral involvement were younger than those with bilateral (55 vs. 68 years; p=0.03). In the patients with bilateral involvement, PSC gain and age were related (-0.7; 0.04) and the gain value was symmetrical in both ears (0.7; p=0.05). The gain in the anterior and horizontal canals tended to decrease with age, but without statistical significance in our sample. CONCLUSIONS: Of the patients referred for an otoneurological consultation, 16% showed pathological PSC gain (unilateral in 81% and bilateral in 19% of the cases). This gain involvement was attributable to age when the gain was bilateral and symmetrical. PMID- 25702191 TI - Takotsubo syndrome-induced acute myocardial infarction. PMID- 25702192 TI - Quantitative analysis of left atrial volume and function during normotensive and preeclamptic pregnancy: a real-time three-dimensional echocardiography study. AB - The changes in left atrial (LA) size and function during normotensive and preeclamptic (PE) pregnancy have rarely been previously studied and the results have been inconsistent. The aim of this study was to assess the time changes in LA volume during normal pregnancy, to determine the impact of the increased afterload occurring in PE on maternal LA, and to compare differences in LA geometry and function between early-onset and late-onset PE. Using a real time three-dimensional echocardiograph, the body surface area-indexed LA volume and emptying function (EF) were compared between nonpregnant controls (n = 30), normotensive (n = 43), and PE (36 with early-onset PE and 34 with late-onset PE) pregnant women. During normotensive pregnancy, the indexed LA maximum, pre contraction, and minimum volumes progressively increased, as well as total, passive, and active EF (P < 0.05, Trimester 3 vs. controls), as an adaption to risen cardiac preload. In the PE group, indexed LA volumes were significantly enlarged and the values of LA EF were markedly decreased (P < 0.05) resulting from elevated ventricular filling pressure and diastolic dysfunction. Compared with late-onset PE, smaller LA volume and greater atrial EF were shown in early onset PE despite a higher afterload and more hypertrophied ventricle. In conclusion, LA size and function gradually improved to maintain adequate blood volume during normotensive pregnancy, while dilated chamber and reduced action of LA occurred in PE associated with increased afterload. Less LA volume and higher LA EF were shown in early-onset PE than in late-onset PE. PMID- 25702193 TI - Hypofractionated stereotactic radiotherapy in combination with bevacizumab or fotemustine for patients with progressive malignant gliomas. AB - To evaluate the efficacy of hypofractionated stereotactic radiotherapy performed as reirradiation in combination with fotemustine or bevacizumab as salvage treatment in patients with recurrent malignant glioma. Between May 2006 and December 2013, 54 patients with recurrent malignant glioma received hypofractionated stereotactic radiotherapy (HSRT, 25 Gy in 5-Gy fractions) plus either fotemustine or bevacizumab at University of Rome Sapienza, Sant'Andrea Hospital. All patients had Karnofsky performance score (KPS) >= 60 and were previously treated with standard chemoradiotherapy. Forty-two patients had a GBM and 12 patients had an anaplastic astrocytoma (AA). The median overall survival (OS) time and 12-month OS rates after HSRT was 11 months and 30 % for patients treated with HSRT plus bevacizumab and 8.3 months and 5 % for those treated with HSRT plus fotemustine (p = 0.01). Median PFS times were 4 and 6 months for patients treated with HSRT plus fotemustine or bevacizumab, respectively (p = 0.01). KPS > 70 (p = 0.04), AA histology, and the treatment with bevacizumab were independent favourable prognostic factors for OS. In general, both treatments were well tolerated with relatively low treatment-related toxicity. HSRT combined with bevacizumab or fotemustine may represent a feasible treatment option for patients with progressive malignant gliomas, although most of the tumors recur in a few months. Efficacy of bevacizumab or alkylating agents in combination with different radiation schedules needs to be evaluated in prospective studies. PMID- 25702194 TI - Colour contrasting between tissues predicts the resection in 5-aminolevulinic acid-guided surgery of malignant gliomas. AB - Due to the various intensities of 5-aminolevulinic acid (5-ALA) fluorescence, neurosurgeons tend to be uncertain about which tissues to resect. This study aimed to reveal the shortcomings of the human visual perception of fluorescence, particularly the factors guiding the tissue removal and the correlation of fluorescence with contrast enhancement (CE) on magnetic resonance imaging (MRI). Various colour features [CIE L*a*b* colour space, colour difference described by DeltaE and contrast ratio (CR)] of total 206 noticed fluorescent areas and their surroundings were measured from the video recordings of 21 primary high grade glioma (HGG) surgeries. The position of a fluorescent region was related to the corecorded navigational image. Following early postoperative MRI, 17 additional regions of corresponding to CE remnants were identified, their colour features were compared to the resected CEs. The targeted video post-processing method was designed, based on the results. There were no complications attributed to 5-ALA use and the median survival was <10 months. 82.5 % of recognised fluorescent areas were removed. Colour spaces of the resected regions and their backgrounds did not overlap. Opposite to the separate colour components (p > 0.05), the distant background colour (p < 0.05) and higher CR and DeltaE (p < 0.01) determined the resection of a fluorescent region. Noneloquent location and CR both independently increased the resection rate in logistic regression. However, greater area under the receiver operating characteristic curve (AUC) in case of CR (AUC = 0.78; 95 % CI 0.71-0.83) determined its dominant role in neurosurgeon's fluorescence perception. CE regions presented with a significantly more saturated shade of violet (consistently higher a* and b*) than other tumour parts (p < 0.05). Regions corresponding to tumour remnants had a significantly lower a* component value (p = 0.02) as well as a lower DeltaE than the matched background (AUC = 0.73; 95 % CI 0.65-0.80). In order to increase the resection rate, DeltaE > 60 was needed. These results directed essential improvements in the 5-ALA fluorescence visualisation toward enhanced resection rate. The conventional filtering, unadjusted to the 5-ALA colour space converted some background shades to colours resembling relevant fluorescence. This is one of the first studies to demonstrate that perceived colours, their contrasting and CR are of significance in the decision-making during HGG 5-ALA fluorescence-guided surgery. Irrespective of the shortcomings of conventional video filtering, further development of a tailored post-processed contrast stretching will allow to achieve safe and radical tumour resection. PMID- 25702195 TI - Dynamics of blood flow: modeling of the Fahraeus-Lindqvist effect. AB - To model the Fahraeus-Lindqvist effect, Haynes' marginal zone theory is used, following previous works, i.e., a core layer of uniform red blood cells (RBCs) is assumed to be surrounded by an annular plasma layer in which no RBCs are present. A simplified trial-and-error solution procedure is provided to determine the size of the core region and the hematocrit level in that zone in addition to the apparent viscosity, given the (upstream) large vessel hematocrit level and the average hematocrit level in the (downstream) small vessel. To test the model, a set of experimental data is selected to provide not only apparent viscosity data but also the average hematocrit levels in small tubes of different diameters. The results are found to support Haynes' marginal theory, with no fitting parameters used in the computations. Viscous dissipation is determined. The use of the mechanical energy balance is found to lead to results that are consistent with those based on the momentum balance, while leaving the average hematocrit level undetermined and required by either experimental data or an additional equation based on further theoretical work. The present analysis is used to model bifurcation using published empirical correlations quantifying the Fahraeus effect and phase separation. The model equations are extended to microvascular networks with repeated bifurcations. PMID- 25702196 TI - Constructing a validity argument for the Objective Structured Assessment of Technical Skills (OSATS): a systematic review of validity evidence. AB - In order to construct and evaluate the validity argument for the Objective Structured Assessment of Technical Skills (OSATS), based on Kane's framework, we conducted a systematic review. We searched MEDLINE, EMBASE, CINAHL, PsycINFO, ERIC, Web of Science, Scopus, and selected reference lists through February 2013. Working in duplicate, we selected original research articles in any language evaluating the OSATS as an assessment tool for any health professional. We iteratively and collaboratively extracted validity evidence from included articles to construct and evaluate the validity argument for varied uses of the OSATS. Twenty-nine articles met the inclusion criteria, all focussed on surgical technical skills assessment. We identified three intended uses for the OSATS, namely formative feedback, high-stakes assessment and program evaluation. Following Kane's framework, four inferences in the validity argument were examined (scoring, generalization, extrapolation, decision). For formative feedback and high-stakes assessment, there was reasonable evidence for scoring and extrapolation. However, for high-stakes assessment there was a dearth of evidence for generalization aside from inter-rater reliability data and an absence of evidence linking multi-station OSATS scores to performance in real clinical settings. For program evaluation, the OSATS validity argument was supported by reasonable generalization and extrapolation evidence. There was a complete lack of evidence regarding implications and decisions based on OSATS scores. In general, validity evidence supported the use of the OSATS for formative feedback. Research to provide support for decisions based on OSATS scores is required if the OSATS is to be used for higher-stakes decisions and program evaluation. PMID- 25702197 TI - Alcohol abuse and cigarette smoking are associated with global DNA hypermethylation: results from the German Investigation on Neurobiology in Alcoholism (GINA). AB - Recent studies have shown that smoking and alcoholism may be associated with altered DNA methylation and that alcohol consumption might induce changes in DNA methylation by altering homocysteine metabolism. In this monocenter study, we included 363 consecutive patients referred for hospitalization for alcohol detoxification treatment. Blood samples were obtained on treatment days 1, 3, and 7 for measurement of global DNA methylation in leukocytes by liquid chromatography tandem mass spectrometry. Genomic DNA was used for genotyping the following seven genetic variants of homocysteine metabolism: cystathionine beta synthase (CBS) c.844_855ins68, dihydrofolate-reductase (DHFR) c.594 + 59del19bp, methylenetetrahydrofolate-reductase (MTHFR) c.677C > T and c.1298A > C, methyltetrahydrofolate-transferase (MTR) c.2756A > G, reduced folate carrier 1 (RFC1) c.80G > A, and transcobalamin 2 c.776C > G. Multivariate linear regression showed a positive correlation of global DNA methylation with alcohol consumption and smoking on day 1 of hospitalization. DNA methylation was not correlated with homocysteine or vitamin plasma levels, nor with the tested genetic variants of homocysteine metabolism. This suggests a direct effect of alcohol consumption and smoking on DNA methylation, which is not mediated by effects of alcohol on homocysteine metabolism. PMID- 25702198 TI - [Non-invasive mechanical ventilation in the pre- and intraoperative period and difficult airway]. AB - Non-invasive mechanical ventilation is a method of ventilatory assistance aimed at increasing alveolar ventilation, thus achieving, in selected subjects, the avoidance of endotracheal intubation and invasive mechanical ventilation, with the consequent improvement in survival. There has been a systematic review and study of the technical, clinical experiences, and recommendations concerning the application of non-invasive mechanical ventilation in the pre- and intraoperative period. The use of prophylactic non-invasive mechanical ventilation before surgery that involves significant alterations in the ventilatory function may decrease the incidence of postoperative respiratory complications. Its intraoperative use will mainly depend on the type of surgery, type of anaesthetic technique, and the clinical status of the patient. Its use allows greater anaesthetic depth without deterioration of oxygenation and ventilation of patients. PMID- 25702199 TI - [Perioperative management of direct oral anticoagulant in emergency surgery and bleeding. Haemostasis monitoring and treatment]. AB - There is an almost unanimous consensus on the management of the direct new oral anticoagulants, dabigatran, rivaroxaban, and apixaban in elective surgery. However, this general consensus does not exist in relation with the direct new oral anticoagulants use in emergency surgery, especially in the bleeding patient. For this reason, a literature review was performed using the MEDLINE-PubMed. An analysis was made of the journal articles, reviews, systematic reviews, and practices guidelines published between 2000 and 2014 using the terms "monitoring" and "reversal". From this review, it was shown that the routine tests of blood coagulation, such as the prothrombin time and activated partial thromboplastin time, have a limited efficacy in the perioperative control of blood coagulation in these patients. There is currently no antidote to reverse the effects of these drugs, although the possibility of using concentrated prothrombin complex and recombinant activated factor vii has been suggested for the urgent reversal of the anticoagulant effect. PMID- 25702200 TI - A narrow QRS tachycardia in a 40-year-old woman. PMID- 25702201 TI - Substantial fluctuation of acoustic intensity transmittance through a bone phantom plate and its equalization by modulation of ultrasound frequency. AB - For safe and efficient sonothrombolysis therapies, accurate estimation of ultrasound transmittance through the human skull is essential. The present study clarifies uncertainty surrounding this transmittance and experimentally verifies the equalization of transmittance through the modulation of ultrasound frequency. By changing three factors (ultrasound frequency, the thickness of a bone-phantom plate, and the distance between a transducer and a bone-phantom plate), we measured the intensity of ultrasound passing through the plate. Two activating methods, sinusoidal waves at 500 kHz and modulated waves, were compared. When we changed (1) the distance between a transducer and a bone-phantom plate and (2) the thickness of the bone-phantom plate, ultrasound transmittance through the plates substantially fluctuated. The substantial fluctuation in transmittance was observed also for a cut piece of human temporal skull bone. This fluctuation significantly declined for the modulated wave. In conclusion, modulation of ultrasound frequency can equalize the transmittance with an approximately 30-65% fluctuation drop and an approximately 40% fluctuation drop for a bone-phantom plate and for a cut piece of skull bone, respectively. By using modulated waves, we can develop safer and more effective sonothrombolysis therapies. PMID- 25702202 TI - A rare case: bioprosthetic tricuspid valvuloplasty dramatically improved hepatic encephalopathy. AB - A 51-year-old woman was diagnosed as severe stenosed tricuspid bioprosthetic valve. She had developed an encephalopathy due to elevated serum ammonia concentration caused by congestive hepatic failure. Re-tricuspid valve replacement was deemed too risky, and balloon bioprosthetic valvuloplasty was instead planned. This procedure was successfully performed using a standard mitral valvuloplasty protocol. The 30-mm INOUE-BALLOON was inflated five times. The mean pressure gradient across the bioprosthetic valve decreased from 7.8 to 3.5 mmHg, and the tricuspid valve orifice area increased from 1.09 to 3.13 cm(2), without worsening of the tricuspid valve regurgitation. Finally, her hepatic encephalopathy was dramatically improved. PMID- 25702203 TI - Two new species of Ornithodoros (Ixodida; Argasidae) from the Southern Cone of South America. AB - Two new species of the genus Ornithodoros were described from larvae collected in Argentina and Chile. Ornithodoros xerophylus n. sp. was described from specimens collected on the small rodent Graomys centralis in Argentina. The diagnostic characters for this species are a combination of dorsal plate slightly oval with a length of approximately 250 um, 16 pairs of dorsal setae, hypostome with apex rounded and dental formula 2/2 in most rows, 3/3 apically, and capsule of the Haller's organ oval in shape without reticulations. Larvae of Ornithodoros lahillei n. sp. were collected on the reptiles Philodryas chamissonis and Callopistes maculatus in Chile. The diagnostic characters for O. lahillei are a combination of dorsal plate subtriangular with margins corrugated and posterior margin convex, dorsal surface with 14 pairs of setae, absence of postcoxal setae, and hypostome with apex pointed and dental formula 3/3 in anterior third and 2/2 in the middle and basal portion. Phylogenetic analysis of 16S rDNA sequences and a Principal Component Analysis based on morphometric characters provided additional support to the description of O. lahillei and O. xerophylus as two independent lineages within the genus Ornithodoros. PMID- 25702204 TI - Ticks (Acari: Ixodidae) identified from prey-predator interactions via faecal analysis of Brazilian wild carnivores. AB - Between July 2008 and May 2010, we conducted a trophic study on 12 Brazilian wild carnivore species through their faecal analysis in a silvicultural landscape at Angatuba municipality, southern Sao Paulo state. Predator faeces was identified by morphology, predator hair, and surrounding tracks; prey remnants within faeces were used for morphological identification of the prey. Among the recovered ectoparasites, there were 89 specimens of six tick species in 21 (4.0%) out of 523 analysed samples. Ticks were identified to species level, based on external morphological characters, as following: adults of Amblyomma ovale and Amblyomma sculptum; nymphs of Amblyomma brasiliense, Amblyomma calcaratum, Amblyomma dubitatum, A. ovale, and Ixodes schulzei; and larvae of Amblyomma sp. and Ixodes sp. Generally, the recovered immature ticks were associated with consumed prey (small birds or small mammals), whereas adults were associated with the predator itself, ingested during its self-grooming. Our data show that faeces is an additional information source on ticks in Brazil and which may provide information on ectoparasite-predator-prey interactions. PMID- 25702205 TI - Thulium laser for the treatment of upper urinary tract carcinoma (UTUC)? Are we there, yet? PMID- 25702206 TI - Epidemiology of traumatic brain injury. AB - Traumatic brain injury (TBI) is a leading cause of death, and in a recent analysis it was found that nearly one-third of all injury-related deaths in the US have at least one diagnosis of TBI (CDC-Quickstats, 2010). This chapter presents the burden of TBI as regards age group, gender, costs, race, emergency department (ED) visits, hospitalizations, and deaths. Injury trends over a 15 year period are examined. Rehabilitation estimates and disability estimates are also available. Through good epidemiology we can better understand the causes of TBI and design more effective intervention programs to reduce injury. Important sources of evidence for this chapter include mostly studies from the US because of their leading work in the epidemiology of this important injury. PMID- 25702207 TI - Classification of traumatic brain injury: past, present, and future. AB - Disease classification is central to the practice of medicine; it systematizes clinical knowledge and experience. Classification is essential for diagnosis and effective treatment of human disease. Progress in classifying traumatic brain injury (TBI) for targeted treatment has lagged behind other diseases such as cancer, and has contributed to a lack of progress in the field. Today TBI is most frequently classified as mild, moderate, or severe using the Glasgow Coma Scale (GCS). However, the GCS is symptoms-based and does not allow for targeting of specific pathology. Here we review general schemas for disease classification and how they have evolved over time. We discuss the characteristics of an ideal classification system and the unique challenges inherent to achieving such a system for TBI. Current means of classifying TBI are reviewed, as are the strengths and limitations of these approaches. Generating the data required to modernize TBI classification and to perhaps facilitate a targeted, precision medicine approach to its management will require a highly collaborative international effort. Fortunately these efforts are underway and will benefit from the lessons and tools that have come from other areas of medicine that have already found success with this approach. PMID- 25702208 TI - Genetic predictors of outcome following traumatic brain injury. AB - The nature of traumatic brain injury (TBI) has acute and chronic outcomes for those who survive. Over time, the chronic process of injury impacts multiple organ systems that may lead to disease. We discuss possible mechanisms and methodological issues in the context of candidate gene association studies using TBI patient populations. Because study population sizes have been generally limited, we discussed results on genes that have been the focus of independent studies. We also present a justification for testing more speculative candidate genes in recovery from TBI, such as those involved in circadian rhythm, to outline the importance of prioritizing functional variants in genes that may modulate recovery or provide neuroprotection from TBI. Finally, we provide a perspective on how future research will integrate population level genetic findings with the biological basis of disease in order to create a resource of predictive outcome measures for individual patients. PMID- 25702210 TI - Cellular and molecular mechanisms of injury and spontaneous recovery. AB - Until recently, most have assumed that traumatic brain injury (TBI) was singularly associated with the overt destruction of brain tissue resulting in subsequent morbidity or death. More recently, experimental and clinical studies have shown that the pathobiology of TBI is more complex, involving a host of cellular and subcellular changes that impact on neuronal function and viability while also affecting vascular reactivity and the activation of multiple biological response pathways. Here we review the brain's response to injury, examining both focal and diffuse changes and their implications for post traumatic brain dysfunction and recovery. TBI-induced neuronal dysfunction and death as well as the diffuse involvement of multiple fiber projections are discussed together with considerations of how local axonal membrane changes or channelopathy translate into local ionic dysregulation and axonal disconnection. Concomitant changes in the cerebral microcirculation are also discussed and their relationship with the parallel changes in the brain's metabolism is considered. These cellular and subcellular events occurring within neurons and their blood supply are correlated with multiple biological response modifiers evoked by generalized post-traumatic inflammation and the parallel activation of oxidative stress processes. The chapter closes with considerations of recovery following focal or diffuse injury. Evidence for dynamic brain reorganization/repair is presented, with considerations of traumatically induced circuit disruption and their progression to either adaptive or in some cases, maladaptive reorganization. PMID- 25702209 TI - The neuropathology of traumatic brain injury. AB - Traumatic brain injury, a leading cause of mortality and morbidity, is divided into three grades of severity: mild, moderate, and severe, based on the Glasgow Coma Scale, the loss of consciousness, and the development of post-traumatic amnesia. Although mild traumatic brain injury, including concussion and subconcussion, is by far the most common, it is also the most difficult to diagnose and the least well understood. Proper recognition, management, and treatment of acute concussion and mild traumatic brain injury are the fundamentals of an emerging clinical discipline. It is also becoming increasingly clear that some mild traumatic brain injuries have persistent, and sometimes progressive, long-term debilitating effects. Evidence indicates that a single traumatic brain injury can precipitate or accelerate multiple age-related neurodegenerations, increase the risk of developing Alzheimer's disease, Parkinson's disease, and motor neuron disease, and that repetitive mild traumatic brain injuries can provoke the development of a tauopathy, chronic traumatic encephalopathy. Clinically, chronic traumatic encephalopathy is associated with behavioral changes, executive dysfunction, memory loss, and cognitive impairments that begin insidiously and progress slowly over decades. Pathologically, chronic traumatic encephalopathy produces atrophy of the frontal and temporal lobes, thalamus, and hypothalamus, septal abnormalities, and abnormal deposits of hyperphosphorylated tau (tau) as neurofibrillary tangles and disordered neurites throughout the brain. The incidence and prevalence of chronic traumatic encephalopathy and the genetic risk factors critical to its development are currently unknown. Chronic traumatic encephalopathy frequently occurs as a sole diagnosis, but may be associated with other neurodegenerative disorders, including Alzheimer's disease, Lewy body disease, and motor neuron disease. Currently, chronic traumatic encephalopathy can be diagnosed only at autopsy; however, promising efforts to develop imaging, spinal fluid, and peripheral blood biomarkers are underway to diagnose and monitor the course of disease in living subjects. PMID- 25702211 TI - Injury biomechanics, neuropathology, and simplified physics of explosive blast and impact mild traumatic brain injury. AB - Explosive blast shock waves and blunt impact to the head are two types of loading shown to result in mild traumatic brain injury (mTBI). While mTBI from these two causes shares some common features behaviorally, there are distinct differences in the pathophysiology of the underlying injury mechanisms. Various elucidations have been offered in the literature to explain the organic damage associated with mTBI resulting from both types of loading. The current state of understanding in this field is somewhat limited by the degree of appreciation of the physics and biomechanics governing the effects of explosive blast shock waves and blunt impact on the head, which has resulted in the various approaches to the investigation of the operative brain injury "wounding mechanisms". In this chapter we provide a simplified description of terminology associated with forces on the head from explosive blast shock waves and blunt impact, to assist readers in the field in evaluating interpretations of brain injury "wounding" processes. Remarkably, mTBI from either loading is shown generally to result in only a small loss of neurons, with hippocampal neurons appearing to be particularly vulnerable to explosive blast shock waves. Explosive blast studies in large animal models show a unique pattern of periventricular injury, which is different from the classic diffuse axonal injury. Both astrocyte and microglial activation are also seen in explosive blast as well as impact trauma, but this may be a general secondary brain injury response, nonspecific to explosive blast or blunt trauma. Additionally, while moderate to severe impact closed head injuries sometimes result in petechial hemorrhages or hematomas, they do not appear to be associated with explosive blast mTBI even with repeated exposure to blasts. PMID- 25702212 TI - Cellular biomechanics of central nervous system injury. AB - With a growing interest in how the brain responds and remodels itself following a traumatic injury, this chapter outlines the major organizing principles of how to study these injuries in the laboratory and extend these findings back into the clinic. A new repertoire of models is available to examine the response of isolated circuits of the brain in vitro, and to study precisely how mechanical forces applied to even small regions of these circuits can disrupt the entire circuit dysfunction. We review the existing knowledge garnered from these models and our current understanding of mechanically sensitive receptors and channels activated immediately following trauma. In turn, we point to the emergence of in silico models of network function that will lead to an improved understanding of the principles for the remodeling of circuit structure after traumatic, possibly pointing out new biological rules for circuit reassembly that would help guide new therapies for reconstructing brain circuits after trauma. PMID- 25702214 TI - Mild traumatic brain injury. AB - Mild traumatic brain injury (TBI) is common but accurate diagnosis and defining criteria for mild TBI and its clinical consequences have been problematic. Mild TBI causes transient neurophysiologic brain dysfunction, sometimes with structural axonal and neuronal damage. Biomarkers, such as newer imaging technologies and protein markers, are promising indicators of brain injury but are not ready for clinical use. Diagnosis relies on clinical criteria regarding depth and duration of impaired consciousness and amnesia. These criteria are particularly difficult to confirm at the least severe end of the mild TBI continuum, especially when relying on subjective, retrospective accounts. The postconcussive syndrome is a controversial concept because of varying criteria, inconsistent symptom clusters and the evidence that similar symptom profiles occur with other disorders, and even in a proportion of healthy individuals. The clinical consequences of mild TBI can be conceptualized as two multidimensional disorders: (1) a constellation of acute symptoms that might be termed early phase post-traumatic disorder (e.g., headache, dizziness, imbalance, fatigue, sleep disruption, impaired cognition), that typically resolve in days to weeks and are largely related to brain trauma and concomitant injuries; (2) a later set of symptoms, a late phase post-traumatic disorder, evolving out of the early phase in a minority of patients, with a more prolonged (months to years), sometimes worsening set of somatic, emotional, and cognitive symptoms. The later phase disorder is highly influenced by a variety of psychosocial factors and has little specificity for brain injury, although a history of multiple concussions seems to increase the risk of more severe and longer duration symptoms. Effective early phase management may prevent or limit the later phase disorder and should include education about symptoms and expectations for recovery, as well as recommendations for activity modifications. Later phase treatment should be informed by thoughtful differential diagnosis and the multiplicity of premorbid and comorbid conditions that may influence symptoms. Treatment should incorporate a hierarchical, sequential approach to symptom management, prioritizing problems with significant functional impact and effective, available interventions (e.g., headache, depression, anxiety, insomnia, vertigo). PMID- 25702215 TI - Acute sports-related traumatic brain injury and repetitive concussion. AB - Concussions are described as functional, not structural injuries, and therefore cannot be easily detected through standard diagnostic imaging. The vast differences between individual athletes makes identifying and evaluating sport related concussion one of the most complex and perplexing injuries faced by medical personnel. The literature, as well as most consensus statements, supports the use of a multifaceted approach to concussion evaluation on the sideline of the athletic field. Using a standardized clinical examination that is supported by objective measures of concussion-related symptoms, cognitive function, and balance provides clinicians with the ability to track recovery in an objective manner. When used in combination, these tests allow for more informed diagnosis and treatment plan, which should involve a graduated return to play progression. Establishing a comprehensive emergency action plan that can guide the on-field management of a more serious and potentially catastrophic brain injury is also essential. This review will address these management issues, as well as the recent concerns about the risk of long-term neurologic conditions believed to be associated with repetitive concussion. PMID- 25702213 TI - Animal models of traumatic brain injury. AB - Traumatic brain injury (TBI) is a major health issue comprising a heterogeneous and complex array of pathologies. Over the last several decades, numerous animal models have been developed to address the diverse nature of human TBI. The clinical relevance of these models has been a major point of reflection given the poor translation of pharmacologic TBI interventions to the clinic. While previously characterized broadly as either focal or diffuse, this classification is falling out of favor with increased awareness of the overlap in pathologic outcomes between models and an emerging consensus that no one model is sufficient. Moreover, an appreciation of injury biomechanics is essential in recapitulating and interpreting the spectrum of TBI neuropathology observed in various established models of dynamic closed-head TBI. While these models have replicated many specific features of human TBI, an enhanced context with clinical relevancy will facilitate the further elucidation of the mechanisms and treatment of injury. PMID- 25702216 TI - Brain injury from explosive blast: description and clinical management. AB - Accumulating clinical experience is indicating that explosive blast brain injury is becoming recognized as a disease distinct from the penetrating form of blast injury as well as the classic closed head injury (CHI). In recent US conflicts in Iraq and Afghanistan, over 60% of combat casualties were from explosive blast with the hallmark explosive weapon being the improvised explosive device (IED). Explosive blast TBI is a condition afflicting many combat injured warfighters potentially constituting another category of TBI. Clinically, it shares many features with conventional TBI but possesses some unique aspects. In its mild form, it also shares many clinical features with PTSD but here again has distinct aspects. Although military medical providers depend on civilian standard of care guidelines when managing explosive blast mTBI, they are continually adapting their medical practice in order to optimize the treatment of this disease, particularly in a theater of war. It is clear that further rigorous scientific study of explosive blast mTBI at both the basic science and clinical levels is needed. This research must include improved understanding of the causes and mechanisms of explosive blast TBI as well as comprehensive epidemiologic studies to determine the prevalence of this disease and its risk factors. A widely accepted unambiguous clinical description of explosive blast mTBI with diagnostic criteria would greatly improve diagnosis. It is hoped that through appropriate research meaningful prevention, mitigation, and treatment strategies for explosive blast mTBI can be speedily realized. PMID- 25702217 TI - Surgical management of civilian gunshot wounds to the head. AB - Each year close to 20000 Americans are involved in gunshot wounds to the head (GSWH). Over 90% of the victims of GSWH eventually fail to survive and only a meager 5% of the patients have a chance to continue with a useful life. One of the fundamental jobs of providers is to realize who the best candidate for the best possible management is. Recent evidence indicates that a good Glasgow Coma Scale (GCS) score at the time of admission puts such patients at high priority for management. Lack of abnormal pupillary response to light, trajectory of slug away for central gray, and visibility of basal cisterns upgrade the need for utmost care for such a victim. Surgical management is careful attention to involvement of air sinuses and repair of base dura. Patients with diffuse injury should have intraventricular intracranial pressure (ICP) monitoring and if needed a timely decompressive craniectomy. Since close to 2% of patients with penetrating brain injury may harbor a vascular injury, subjects with injuries close to the Sylvian fissure and those with the fragment crossing two dural compartments should have computed tomography angiography and if needed digital subtraction angiography to rule out traumatic intracranial aneurysms. In case of a positive study, these patients should have endovascular management of their vascular injuries in order to prevent catastrophic intracerebral hematomas and permanent deficit. Although supported by class III data, subjects of GSWH need to be on broad spectrum antibiotics for a period of 3-5 days. If cerebrospinal fluid (CSF) fistulas are observed at any time during the patient's hospital course, they should be taken very seriously and appropriate management is needed to prevent deep intracranial infections. PMID- 25702218 TI - Acute loss of consciousness. AB - Acute loss of consciousness poses a fascinating scenario for theoretical and clinical research. This chapter introduces a simple yet powerful framework to investigate altered states of consciousness. We then explore the different disorders of consciousness that result from acute brain injury, and techniques used in the acute phase to predict clinical outcome in different patient populations in light of models of acute loss of consciousness. We further delve into post-traumatic amnesia as a model for predicting cognitive sequels following acute loss of consciousness. We approach the study of acute loss of consciousness from a theoretical and clinical perspective to conclude that clinicians in acute care centers must incorporate new measurements and techniques besides the classic coma scales in order to assess their patients with loss of consciousness. PMID- 25702219 TI - Systemic manifestations of traumatic brain injury. AB - Traumatic brain injury (TBI) affects functioning of various organ systems in the absence of concomitant non-neurologic organ injury or systemic infection. The systemic manifestations of TBI can be mild or severe and can present in the acute phase or during the recovery phase. Non-neurologic organ dysfunction can manifest following mild TBI or severe TBI. The pathophysiology of systemic manifestations following TBI is multifactorial and involves an effect on the autonomic nervous system, involvement of the hypothalamic-pituitary axis, release of inflammatory mediators, and treatment modalities used for TBI. Endocrine dysfunction, electrolyte imbalance, and respiratory manifestations are common following TBI. The influence of TBI on systemic immune response, coagulation cascade, cardiovascular system, gastrointestinal system, and other systems is becoming more evident through animal studies and clinical trials. Systemic manifestations can independently act as risk factors for mortality and morbidity following TBI. Some conditions like neurogenic pulmonary edema and disseminated intravascular coagulation can adversely affect the outcome. Early recognition and treatment of systemic manifestations may improve the clinical outcome following TBI. Further studies are required especially in the field of neuroimmunology to establish the role of various biochemical cascades, not only in the pathophysiology of TBI but also in its systemic manifestations and outcome. PMID- 25702220 TI - Special considerations in infants and children. AB - Head injury in children is one of the most common causes of death and disability in the US and, increasingly, worldwide. This chapter reviews the causes, patterns, pathophysiology, and treatment of head injury in children across the age spectrum, and compares pediatric head injury to that in adults. Classification of head injury in children can be organized according to severity, pathoanatomic type, or mechanism. Response to injury and repair mechanisms appear to vary at different ages, and these may influence optimal treatment; however, much work is still needed before investigation leads to clearly effective clinical interventions. This is true both for the more severe injuries as well as those at the milder end of the injury spectrum, the latter of which have received increasing attention. In this chapter, neuroassessment tools for each age, newer imaging modalities including magnetic resonance imaging (MRI), and specific pediatric management issues, including intracranial pressure (ICP) monitoring and seizure prophylaxis, are reviewed. Finally, specific head injury patterns and functional outcomes relevant to pediatric patients are discussed. While head injury is common, the number of head-injured children is significantly smaller than the corresponding adult head-injured population. When divided further by specific ages, injury types, and other sources of heterogeneity, properly powered clinical research is likely to require large data sets that will allow for stratification across variables, including age. While much has been learned in the past several decades, further study will be required to determine the best management practices for optimizing recovery in individual pediatric patients. This approach is likely to depend on collaborative international head injury databases that will allow researchers to better understand the nuanced evolution of different types of head injury in patients at each age, and the pathophysiologic, treatment-related, and genetic factors that influence recovery. PMID- 25702221 TI - Biomarkers. AB - Biomarkers are key tools and can provide crucial information on the complex cascade of events and molecular mechanisms underlying traumatic brain injury (TBI) pathophysiology. Obtaining a profile of distinct classes of biomarkers reflecting core pathologic mechanisms could enable us to identify and characterize the initial injury and the secondary pathologic cascades. Thus, they represent a logical adjunct to improve diagnosis, track progression and activity, guide molecularly targeted therapy, and monitor therapeutic response in TBI. Accordingly, great effort has been put into the identification of novel biomarkers in the past 25 years. However, the role of brain injury markers in clinical practice has been long debated, due to inconsistent regulatory standards and lack of reliable evidence of analytical validity and clinical utility. We present a comprehensive overview of the markers currently available while characterizing their potential role and applications in diagnosis, monitoring, drug discovery, and clinical trials in TBI. In reviewing these concepts, we discuss the recent inclusion of brain damage biomarkers in the diagnostic guidelines and provide perspectives on the validation of such markers for their use in the clinic. PMID- 25702222 TI - Current and future diagnostic tools for traumatic brain injury: CT, conventional MRI, and diffusion tensor imaging. AB - Brain imaging plays a key role in the assessment of traumatic brain injury. In this review, we present our perspectives on the use of computed tomography (CT), conventional magnetic resonance imaging (MRI), and newer advanced modalities such as diffusion tensor imaging. Specifically, we address assessment for immediately life-threatening intracranial lesions (noncontrast head CT), assessment of progression of intracranial lesions (noncontrast head CT), documenting intracranial abnormalities for medicolegal reasons (conventional MRI with blood sensitive sequences), presurgical planning for post-traumatic epilepsy (high spatial resolution conventional MRI), early prognostic decision making (conventional MRI with diffusion-weighted imaging), prognostic assessment for rehabilitative planning (conventional MRI and possibly diffusion tensor imaging in the future), stratification of subjects and pharmacodynamic tracking of targeted therapies in clinical trials (specific MRI sequences or positron emission tomography (PET) ligands, e.g., diffusion tensor imaging for traumatic axonal injury). We would like to emphasize that all of these methods, especially the newer research approaches, require careful radiologic-pathologic validation for optimal interpretation. We have taken this approach in a mouse model of pericontusional traumatic axonal injury. We found that the extent of reduction in the diffusion tensor imaging parameter relative anisotropy directly correlated with the number of amyloid precursor protein (APP)-stained axonal varicosities (r(2)=0.81, p<0.0001, n=20 injured mice). Interestingly, however, the least severe contusional injuries did not result in APP-stained axonal varicosities, but did cause reduction in relative anisotropy. Clearly, both the imaging assessments and the pathologic assessments will require iterative refinement. PMID- 25702223 TI - Using functional magnetic resonance imaging and electroencephalography to detect consciousness after severe brain injury. AB - In recent years, rapid technological developments in the field of neuroimaging have provided new methods for revealing thoughts, actions, and intentions based solely on the pattern of activity that is observed in the brain. In specialized centres, these methods are now being employed routinely in the assessment of patients diagnosed with so-called "disorders of consciousness," mapping patterns of residual function and dysfunction and helping to reduce diagnostic errors between related conditions such as the vegetative and minimally conscious states. Both functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) have now been shown to be effective tools for detecting covert awareness in behaviorally nonresponsive patients when standard clinical approaches have been unable to provide that information. Indeed, in some patients, communication with the outside world via simple "yes" and "no" questions has been achieved, even in cases where no possibility for behavioral interaction exists. These studies have profound implications for clinical care, diagnosis, prognosis and medical-legal decision making relating to the prolongation, or otherwise, of life after severe brain injury. Moreover, the results suggest an urgent need for a re-evaluation of the existing diagnostic guidelines for behaviorally nonresponsive patients to include information derived from functional neuroimaging. PMID- 25702224 TI - Resting functional imaging tools (MRS, SPECT, PET and PCT). AB - Functional imaging includes imaging techniques that provide information about the metabolic and hemodynamic status of the brain. Most commonly applied functional imaging techniques in patients with traumatic brain injury (TBI) include magnetic resonance spectroscopy (MRS), single photon emission computed tomography (SPECT), positron emission tomography (PET) and perfusion CT (PCT). These imaging modalities are used to determine the extent of injury, to provide information for the prediction of outcome, and to assess evidence of cerebral ischemia. In TBI, secondary brain damage mainly comprises ischemia and is present in more than 80% of fatal cases with traumatic brain injury (Graham et al., 1989; Bouma et al., 1991; Coles et al., 2004). In particular, while SPECT measures cerebral perfusion and MRS determines metabolism, PET is able to assess both perfusion and cerebral metabolism. This chapter will describe the application of these techniques in traumatic brain injury separately for the major groups of severity comprising the mild and moderate to severe group. The application in TBI and potential difficulties of each technique is described. The use of imaging techniques in children will be separately outlined. PMID- 25702225 TI - Advances in imaging explosive blast mild traumatic brain injury. AB - In the past, direct physical evidence of mild traumatic brain injury (mTBI) from explosive blast has been difficult to obtain through conventional imaging modalities such as T1- and T2-weighted magnetic resonance imaging (MRI) and computed tomography (CT). Here, we review current progress in detecting evidence of brain injury from explosive blast using advanced imaging, including diffusion tensor imaging (DTI), functional MRI (fMRI), and the metabolic imaging methods such as positron emission tomography (PET) and magnetic resonance spectroscopic imaging (MRSI), where each targets different aspects of the pathology involved in mTBI. DTI provides a highly sensitive measure to detect primary changes in the microstructure of white matter tracts. fMRI enables the measurement of changes in brain activity in response to different stimuli or tasks. Remarkably, all three of these paradigms have found significant success in conventional mTBI where conventional clinical imaging frequently fails to provide definitive differences. Additionally, although used less frequently for conventional mTBI, PET has the potential to characterize a variety of neurotransmitter systems using target agents and will undoubtedly play a larger role, once the basic mechanisms of injury are better understood and techniques to identify the injury are more common. Finally, our MRSI imaging studies, although acquired at much lower spatial resolution, have demonstrated selectivity to different metabolic and physiologic processes, uncovering some of the most profound differences on an individual by individual basis, suggesting the potential for utility in the management of individual patients. PMID- 25702226 TI - Electrophysiologic recordings in traumatic brain injury. AB - Following a traumatic brain injury (TBI), the brain undergoes numerous electrophysiologic changes. The most common techniques used to evaluate these changes include electroencepalography (EEG) and evoked potentials. In animals, EEGs immediately following TBI can show either diffuse slowing or voltage attenuation, or high voltage spiking. Following a TBI, many animals display evidence of hippocampal excitability and a reduced seizure threshold. Some mice subjected to severe TBI via a fluid percussion injury will eventually develop seizures, which provides a useful potential model for studying the neurophysiology of epileptogenesis. In humans, the EEG changes associated with mild TBI are relatively subtle and may be challenging to distinguish from EEG changes seen in other conditions. Quantitative EEG (QEEG) may enhance the ability to detect post-traumatic electrophysiologic changes following a mild TBI. Some types of evoked potential (EP) and event related potential (ERP) can also be used to detect post-traumatic changes following a mild TBI. Continuous EEG monitoring (cEEG) following moderate and severe TBI is useful in detecting the presence of seizures and status epilepticus acutely following an injury, although some seizures may only be detectable using intracranial monitoring. CEEG can also be helpful for assessing prognosis after moderate or severe TBI. EPs, particularly somatosensory evoked potentials, can also be useful in assessing prognosis following severe TBI. The role for newer technologies such as magnetoencephalography and bispectral analysis (BIS) in the evaluation of patients with TBI remains unclear. PMID- 25702228 TI - The prehospital management of traumatic brain injury. AB - Traumatic brain injury (TBI) is an important cause of death and disability, particularly in younger populations. The prehospital evaluation and management of TBI is a vital link between insult and definitive care and can have dramatic implications for subsequent morbidity. Following a TBI the brain is at high risk for further ischemic injury, with prehospital interventions targeted at reducing this secondary injury while optimizing cerebral physiology. In the following chapter we discuss the prehospital assessment and management of the brain-injured patient. The initial evaluation and physical examination are discussed with a focus on interpretation of specific physical examination findings and interpretation of vital signs. We evaluate patient management strategies including indications for advanced airway management, oxygenation, ventilation, and fluid resuscitation, as well as prehospital strategies for the management of suspected or impending cerebral herniation including hyperventilation and brain directed hyperosmolar therapy. Transport decisions including the role of triage models and trauma centers are discussed. Finally, future directions in the prehospital management of traumatic brain injury are explored. PMID- 25702229 TI - Acute management of military-related injury. AB - Since the dawn of armed conflict head trauma has remained one of the most challenging afflictions for surgeons and medical personnel to treat. Interventions for head trauma from antiquity through the American Civil War were met with dismal outcomes. In the 20th century, despite greater lethality of weapons, progressive advances in management led to improved outcomes for head injured patients. A triage system consisting of appropriate levels of care from the front lines, through combat support hospitals to reconstructive and rehabilitative hospitals, has also contributed to the improved outcomes of head injured patients. This chapter examines the progressive improvement in management strategies during major conflicts, the mechanisms causing head trauma during conflict, and the current medical and surgical therapies recommended in the care of head-injured patients during armed conflict. PMID- 25702230 TI - Clinical management of the minimally conscious state. AB - The minimally conscious state (MCS) was defined as a disorder of consciousness (DoC) distinct from the vegetative state more than a decade ago. While this condition has become widely recognized, there are still no guidelines to steer the approach to assessment and treatment. The development of evidence-based practice guidelines for MCS has been hampered by ambiguity around the concept of consciousness, the lack of accurate methods of assessment, and the dearth of well designed clinical trials. This chapter provides a critical review of existing assessment procedures, critically reviews available treatment options and identifies knowledge gaps. We close with practice-based recommendations for a rational approach to clinical management of this challenging population. PMID- 25702227 TI - Neuroprotection for traumatic brain injury. AB - Traumatic brain injury (TBI) is a major cause of mortality and morbidity worldwide. Despite extensive preclinical research supporting the effectiveness of neuroprotective therapies for brain trauma, there have been no successful randomized controlled clinical trials to date. TBI results in delayed secondary tissue injury due to neurochemical, metabolic and cellular changes; modulating such effects has provided the basis for neuroprotective interventions. To establish more effective neuroprotective treatments for TBI it is essential to better understand the complex cellular and molecular events that contribute to secondary injury. Here we critically review relevant research related to causes and modulation of delayed tissue damage, with particular emphasis on cell death mechanisms and post-traumatic neuroinflammation. We discuss the concept of utilizing multipotential drugs that target multiple secondary injury pathways, rather than more specific "laser"-targeted strategies that have uniformly failed in clinical trials. Moreover, we assess data supporting use of neuroprotective drugs that are currently being evaluated in human clinical trials for TBI, as well as promising emerging experimental multipotential drug treatment strategies. Finally, we describe key challenges and provide suggestions to improve the likelihood of successful clinical translation. PMID- 25702231 TI - Rehabilitation after traumatic brain injury. AB - Traumatic brain injury (TBI) is a growing problem in the US, with significant morbidity and economic implications. This diagnosis spans a wide breath of injuries from concussion to severe TBI. Thus, rehabilitation is equally diverse in its treatment strategies targeting those symptoms that are functionally limiting with the ultimate goal of independence and community reintegration. In severe TBI, rehabilitation can be lifelong. Acute care rehabilitation focuses on emergence from coma and prognostication of recovery. Therapeutic modalities and exercise, along with pharmacologic intervention, can target long-term motor and cognitive sequelae. Complications of severe TBI that are functionally limiting and impede therapy include heterotopic ossification, agitation, dysautonomia, and spasticity. In mild TBI, most patients recover quickly but education on repeat exposure is imperative, with the implications of consecutive injuries being potentially devastating. Furthermore, rehabilitation targets lingering symptoms including sleep disturbance, visuospatial deficits, headaches, and cognitive dysfunction. As research on the entire TBI population improves, commonalities in the disease process may emerge, helping rationalize therapeutic interventions and providing more robust targets for treatment. PMID- 25702232 TI - Long-term social integration and community support. AB - TBI often results in reduced social participation. This decrease in social participation is independent of injury severity and time since injury. Thus, it is one of the many stable hallmarks of TBI. Changes in social participation have been related to many factors, including emotional dysregulation and disturbance and executive dysfunction. While there are evidenced-based treatments available to improve mood and executive functioning, none of the research has examined the impact of the various treatments on social participation or social integration. Therefore, while it is reasonable to expect that individuals who are feeling better about themselves and who improve their approach to day-to-day function will also experience increased social contact, there is no evidence to support this claim. This chapter reviews the literature on post-TBI social integration and its relationship to depression and executive dysfunction. In addition the intervention research in this area is briefly examined. PMID- 25702233 TI - Recent developments in clinical trials for the treatment of traumatic brain injury. AB - The clinical understanding of traumatic brain injury (TBI) and its manifestations is beginning to change. Both clinicians and research scientists are recognizing that TBI and related disorders such as stroke are complex, systemic inflammatory and degenerative diseases that require an approach to treatment more sophisticated than targeting a single gene, receptor, or signaling pathway. It is becoming increasingly clear that TBI is a form of degenerative disorder affecting the brain and other organs, and that its manifestations can unfold days, weeks, and years after the initial damage. Until recently, and despite numerous industry and government-sponsored clinical trials, attempts to find a safe and effective neuroprotective agent have all failed - probably because the research and development strategies have been based on an outdated early 20th century paradigm seeking a magic bullet that will affect a narrowly circumscribed target. We propose that more attention be given to the development of drugs, given alone or in combination, that are pleiotropic in their actions and that have systemic as well as central nervous system effects. We review current Phase II and Phase III trials for acute pharmacologic treatments for TBI and report on their aims, methods, status, and important associated research issues. PMID- 25702234 TI - Preface. PMID- 25702235 TI - Foreword. PMID- 25702236 TI - [Neurological complications of infective endocarditis in Burkina Faso. Clinical features, management and evolutionary profile]. AB - INTRODUCTION: Neurological complications are the most frequent extracardiac complications of infective endocarditis (IE). This study aimed to describe the epidemiological, clinical and paraclinical aspects, and outcome of neurological complications of infective endocarditis in three hospitals in the city of Ouagadougou in Burkina Faso. PATIENTS AND METHOD: From 1 January 2009 to 31 December 2012, we included all patients suffering from IE and selected those in whom a neurological complication was objectified. Neurological involvement was sought on clinical examination but especially CT brain (ischemic infarcts, hemorrhages, aneurysms and abscesses). Blood cultures were systematic. Echocardiography was done for vegetations and characteristics. RESULTS: Among 63 cases of IE, neurological complications were found in 14 patients (22.2%). The average age of patients with neurological complications was 37.4 +/- 5.8 years. The sex ratio was 1.3 for women. Neurological damage consisted of nine cases of stroke (64.3%), three cases of hemorrhagic stroke (21.4%) and two cases of brain abscess (14.3%). Neurological complications had already occurred before hospitalization in 4 cases. Blood cultures were positive in 8 cases. Germs found were predominantly Staphylococcus aureus (5 cases) and Streptococcus a- viridans (2 cases). All cases of S. aureus were complicated by stroke. At echocardiography, vegetation was found in all cases. It was found on the mitral in 7 cases, the aorta in 3 cases, the mitral and aortic in 2 cases and the mitral and tricuspid in 2 cases also. The EI had occurred on a native valve in 11 cases, prosthesis in 4 cases (2 mitral and 2 aortic). The vegetations average diameter was 11.2 +/- 2.1 mm (6.4 and 1 7.7 mm). Vegetations were mobile in 12 cases. The treatment consisted of antibiotics adapted to the antibiogram, neurological and cardiovascular monitoring. The evolution was marked by seven deaths (50%), including 5 deaths related to cerebral complication (71.4% of deaths). CONCLUSION: This study shows that neurological complications during infective endocarditis are frequent, dominated by stroke with a high mortality. PMID- 25702237 TI - Intrapericardial rupture of a mitral subannular aneurysm: A case report and review of the literature. AB - Mitral subannular aneurysm is a rare heart disease that can have many different forms of clinical presentations. It was first described in young men of African descent and was later reported in other geographical areas of the world. The etiopathogenesis as per data from the literature can be congenital, acquired or idiopathic. We report the case of a 19-year-old male in whom we made the diagnosis of mitral subannular aneurysm. The evolution was fatal following a rupture of the aneurysm into the pericardium. Through this case report, we stress the importance of echocardiography in the diagnosis of this condition. In resource-limited countries, the prognosis is unfortunately often unfavorable especially the ruptured forms. Therefore, a high degree of suspicion is needed to make a prompt diagnosis and timely surgical intervention. PMID- 25702238 TI - [Arterial hypertension and control in Brazzaville (Congo): role of ambulatory blood pressure monitoring (ABPM)]. AB - OBJECTIVES: To evaluate the rate control in the hypertensive patients and to identify the predictive factors of non-control. METHODS: It was about a cross sectional study with prospective collection of data over a period of 36 months. It has been held in Brazzaville, and included a consecutive series of 620 hypertensive patients known and treated for at least 6 weeks, having profited from an ambulatory blood pressure monitoring (ABPM) with therapeutic aiming. We used the TONOPORT V and the software Cardiosoft 6.51 of GE Health Care, respectively for the recording and the data analysis. The threshold fixed on the average of 24-hour was BP<130/80 mmHg, and the patients divided into two groups according to whether they were or not controlled. RESULTS: They were 352 men (56.8%) and 268 women (43.2%), old on average of 53.8 +/- 9.7 years (ranges: 29 and 89 years). The standard of living of the patients was average in 330 cases (53.2%), weak in 132 cases (21.3%), and high in 71 cases (11.5%). The other associated risk factors were sedentariness in 275 cases (44.4%), overweight/obesity in 134 cases (21.6%), dyslipidemia in 121 cases (19.5%), diabetes mellitus in 90 cases (14.5%), and tobacco addiction in 25 cases (4%). The hypertension, old of 5.8 +/- 5.7 years on average, was controlled among 215 patients (34.7%). The 24- hour BP average was 139 +/- 14 mmHg for the SBP and 88.2 +/- 10.2 mmHg for the DBP. The awake and asleep BP averages were respectively 141 +/- 14 mmHg and 133 +/- 16.2 mmHg for the SBP, 90.5 +/- 10.5 and 81.2 +/- 11.1 mmHg for the DBP. The antihypertensive protocol used was a monotherapy in 130 cases (21%), bitherapy in 287 cases (46.3%), tritherapy in 154 cases (24.8%), quadritherapy or more in 27 cases (4.3%). Prevalence of non dipping was 43%. Age and male gender were the significant predictors of poor control. CONCLUSION: The rate control of hypertension in our study population remains low. Its improvement passes by the education of the hypertensive patients and the improvement of their living conditions. PMID- 25702239 TI - [Screening and risk factors of cardiac calcification in hemodialysis: contribution of ultra-fast multi-slice scanner and transthoracic echocardiography]. AB - INTRODUCTION: Cardiovascular disease is the first leading cause of death in hemodialysis patients. In this population, cardiovascular calcifications occur at an earlier age and progress faster than in general population. PATIENTS AND METHODS: In order to determine the prevalence and risk factors of cardiac calcifications, 49 patients on chronic hemodialysis were screened in the coronary arteries and cardiac valves by the 64 multi-slice ultra-fast CT and the transthoracic echocardiography. Different clinical and biological parameters were studied by the SPSS 10.0 statistical software to determine risk factors. RESULT: Cardiac calcifications were identified in 81.6% of cases in at least one of the two studied sites. The coronary artery involvement was more common than valvular and concerned 69.4% of cases. The mean Agatston coronary artery calcium score (ACACS) was 331.1 and 522.2 in coronary patients and was correlated to alteration of systolic function of LV (r=-0.287, P=0.045). The severity of CACS was positively correlated with age (r=0.332, P=0.02). Coronary calcifications were associated with cardiovascular risk common to those of the general population (age, male sex, systolic blood pressure, diabetes, history of ischemic heart disease), but also to a lesser quality of dialysis. Valvular calcifications were present in 49% of cases and were correlated with left ventricular hypertrophy (P=0.006). The exclusive involvement of the aortic valve was the most common valvular abnormality. Phosphocalcic and lipid parameters, levels of hemoglobin, CRP and uric acid did not predisposed to cardiac calcifications in our patients. DISCUSSION: In hemodialysis patients, the pathogenesis of cardiovascular calcification is complex and cannot be attributed to a passive process. This process involves several factors that can promote or inhibit calcification. The new multi-slice ultra-fast scanner is a very sensitive method for topographic and quantitative assessment of coronary calcification and is a better alternative to invasive techniques. CONCLUSION: Our study confirms the high prevalence of cardiac calcification in hemodialysis, and highlights the importance of early screening and treatment of predisposing factors. PMID- 25702240 TI - [Echographic diagnosis of systolic murmur among 280 young French militaries. Implications for the expertise in military medicine]. AB - Clinically discovering a systolic murmur is frequent among the young military population. When this murmur does not sound benign, a transthoracic echocardiography (TTE) is made to detect any cardiopathy, which could cause sudden cardiac death. The aim of this study was to evaluate the interest of systematic TTE in the assessment of any cardiac systolic murmur (CSM) among militaries. METHODS: We ran a retrospective monocentric study in the "Clermont Tonnerre" military hospital in Brest. We included all patients sent for TEE, aged 15 to 30 years old, from the 1st January 2010 until the 31st July 2013. RESULTS: Two hundred and eighty TTES assessing CSM were performed. We found 28/280 (10%) echocardiographic abnormalities: 13 were bicuspid aortic valves (4.6%), 6 were ventricular septal defects (2.15%), 3 were atrial septal defects (1.07%), 4 were mild mitral regurgitations (1.43%), one mild pulmonary stenosis (0.35%) and one aortic stenosis (0.35%). No hypertrophic cardiomyopathy was found. Concerning military expertise, 11 (3.92%) patients among these 28 with abnormal TEE were considered unfit for work or "fit for work with limitations". CONCLUSION: Assessing a cardiac systolic murmur with TEE lead to the diagnosis of a cardiomyopathy in 10% of the case. This study enhances the importance of systematic TEE when a CSM is detected in the young military, in order to determine if those soldiers can still fulfill their military duty. PMID- 25702241 TI - Impact of obstructive sleep apnea in recruitment of coronary collaterality during inaugural acute myocardial infarction. AB - BACKGROUND: Obstructive sleep apnea (OSA) may lead to myocardial preconditioning by increasing coronary collateral vessel recruitment in patients with acute coronary occlusion. AIM: To determine the relationship between the severity of obstructive sleep apnea and coronary collaterality during acute myocardial infarction. METHODS: This study prospectively included 71 patients with an inaugural myocardial infarction who had undergone a coronary angiography within 24h of onset. All patients underwent an overnight polygraph before discharge and were classified according to the apnea-hypopnea index (AHI). Coronary collaterals were scored by visual analyses and according to the Rentrop grading system. RESULTS: Mean age was 59+/-11years and 83% of patients were men. All patients had complete or subtotal occlusion of the infarct-related artery. After the sleep study, patients were divided into two groups: 25 were suffering from OSA (AHI>15/h). Patients with OSA showed better collateral vessel development (Rentrop score>=1) compared to non-OSA patients (68 vs. 41%, P=0.032). AHI was significantly higher in patients with developed coronary collaterals (Rentrop>=1) compared to those without collaterality (17.74+/-13.2 vs. 12.24+/-10.9, P=0.025). CONCLUSION: Coronary collateral development may be increased in OSA patients who are presenting with a first myocardial infarction. PMID- 25702242 TI - [Study of echocardiographic parameters of rheumatoid arthritis black African without clinically evident cardiovascular manifestations: A cross-sectional study of 73 cases in Senegal]. AB - INTRODUCTION: Research of cardiac involvement in patients with rheumatoid arthritis can prevent complications and place in a logical secondary prevention. The objective of this study was to investigate the echocardiographic parameters in a population of Senegalese patients with rheumatoid arthritis without clinically evident cardiovascular manifestations. PATIENTS AND METHOD: We conducted a descriptive cross-sectional study, which included prospectively from outpatients in the internal medicine department of university hospital center Aristide Le Dantec in Dakar, Senegal, with a diagnosis of rheumatoid arthritis without clinically evident cardiovascular disease. It focused on a sample of 73 patients of both sexes aged at least 18 years. Following clinical examination, we conducted laboratory tests (CRP, fibrinogen, ESR, rheumatoid factors: Latex and Waaler-Rose, anti-CCP, antinuclear factors and anti-ENA antibodies), ECG, echocardiography standard. Data were analyzed using a descriptive study of the different variables with the calculation of proportions for categorical variables, and the positional parameters and dispersion for quantitative variables. RESULTS: A total of 73 patients with rheumatoid arthritis without obvious cardiac events and meeting the criteria of definition of the ACR 1987 were included in the study. The mean age was 44.17+/-14.43 years with extremes of 18 and 75 years. The mean duration of RA was 5.93+/-4.78 years. The concept of family inflammatory arthritis was reported in 35.60% of cases and almost one in six patients had at least a factor of cardiovascular risk (16.96%). The abnormalities found in Doppler echocardiography were dominated by diastolic LV dysfunction (42.46%), increased left ventricular mass in 35.61%. Valvular leaks of variable grades were highlighted regarding all orifices but were rarely significant. CONCLUSION: The realization of echocardiography in patients with rheumatoid arthritis without clinically evident cardiovascular manifestations helps to highlight cardiovascular abnormalities related to the natural course of the disease. PMID- 25702243 TI - [Gaceta sanitaria in 2014]. PMID- 25702244 TI - Monitoring progress in NCDs: key to accountability. PMID- 25702245 TI - The Lancet Diabetes & Endocrinology needs a more rigorous conflict of interest policy. PMID- 25702246 TI - The Lancet Diabetes & Endocrinology needs a more rigorous conflict of interest policy - Editors' reply. PMID- 25702247 TI - Moving towards a more precise treatment of diabetes. PMID- 25702249 TI - Single-cell mechanics and calcium signalling in organotypic slices of human myometrium. AB - Elucidation of cellular mechanisms regulating myometrial contractility is crucial for improvement in management of many obstetric abnormalities, such as premature delivery, uterine dystocia and post-partum haemorrhage. Myometrial contractions are triggered by periodic synchronous rises in intracellular calcium concentration ([Ca(2+)]i) elicited by spontaneously generated action potentials propagating throughout the entire myometrium. During labour, hormones like oxytocin and prostaglandins potentiate uterine contractions by increasing their duration, strength and frequency. The most informative approach to studying the mechanisms underlying hormonal modulation of uterine contractility is to record [Ca(2+)]i responses to hormones in intact myometrial samples that have not been subjected to enzymatic treatment for cell isolation or cell culture conditions. However, the spatio-temporal resolution of such recording is limited due to the motion artifacts occurring in contracting tissue. Here we describe the application of our newly developed motion correction algorithm to investigate the [Ca(2+)]i dynamics in control and oxytocin stimulated slices of human myometrium on a cellular level. We present evidence that oxytocin induces asynchronous [Ca(2+)]i oscillations in individual myocytes within intact myometrium which are similar to those observed in cultured cells. The oscillations occur between synchronous action potential-driven [Ca(2+)]i transients but appear to be unrelated to contractions. Furthermore, the oxytocin-triggered [Ca(2+)]i oscillations wane within 30-50min of hormone application, while the action potential induced [Ca(2+)]i transients remain augmented. We conclude that oxytocin-induced [Ca(2+)]i oscillations are not relevant to the acute regulation of myometrial contractility but may play a role in longer-term regulatory processes, for example, by triggering gene expression. PMID- 25702250 TI - Hemodynamic effects of long-term morphological changes in the human carotid sinus. AB - Previous investigations of morphology for human carotid artery bifurcation from infancy to young adulthood found substantial growth of the internal carotid artery with advancing age, and the development of the carotid sinus at the root of the internal carotid artery during teenage years. Although the reasons for the appearance of the carotid sinus are not clearly understood yet, it has been hypothesized that the dilation of the carotid sinus serves to support pressure sensing, and slows the blood flow to reduce pulsatility to protect the brain. In order to understand this interesting evolvement at the carotid bifurcation in the aspects of fluid mechanics, we performed in vitro phase-contrast MR flow experiments using compliant silicone replicas of age-dependent carotid artery bifurcations. The silicone models in childhood, adolescence, and adulthood were fabricated using a rapid prototyping technique, and incorporated with a bench-top flow mock circulation loop using a computer-controlled piston pump. The results of the in vitro flow study showed highly complex flow characteristics at the bifurcation in all age-dependent models. However, the highest magnitude of kinetic energy was found at the internal carotid artery in the child model. The high kinetic energy in the internal carotid artery during childhood might be one of the local hemodynamic forces that initiate morphological long-term development of the carotid sinus in the human carotid bifurcation. PMID- 25702251 TI - Digital ray reconstruction through distraction osteogenesis: a retrospective study of 82 rays with long-term follow-up. AB - PURPOSE: The aim of the present study was to present the long-term radiographic results with distraction osteogenesis in traumatic or congenital length discrepancies of long bones of the hand. METHODS: The medical records and radiographs of 65 consecutive patients (27 metacarpals and 55 phalanges) with either traumatic or congenital digital length discrepancies were retrospectively reviewed. The mean follow-up was 8.2 years. The mean distraction period was 21 days with a distraction rate of 4*0.25mm/day. Callus consolidation was obtained in all patients. RESULTS: The bones were lengthened by a mean amount of 17.5mm, with a mean increase in bone length of 68+/-17.3%. The mean healing index was 28.57 days/cm. Ray reconstruction with callus distraction can be applied effectively in skeletally immature or mature patients with congenital differences of the hand or amputated fingers. CONCLUSION: A distraction rate of 1mm/day proved to be a safe rate of lengthening in both metacarpals and phalanges. PMID- 25702252 TI - Application of 3D printed customized external fixator in fracture reduction. AB - INTRODUCTION: Long bone fracture is common in traumatic osteopathic patients. Good reduction is beneficial for bone healing, preventing the complications such as delayed union, nonunion, malunion, but is hard to achieve. Repeated attempts during the surgery would increase the operation time, cause new damage to the fracture site and excessive exposure to radiation. Robotic and navigation techniques can help improve the reduction accuracy, however, the high cost and complexity of operation have limited their clinical application. MATERIALS AND METHODS: We combined 3D printing with computer-assisted reduction technique to develop a customised external fixator with the function of fracture reduction. The original CT data obtained by scanning the fracture was imported to computer for reconstructing and reducing the 3D image of the fracture, based on which the external fixator (named as Q-Fixator) was designed and then fabricated by 3D printing techniques. The fracture reduction and fixation was achieved by connecting the pins inserted in the bones with the customised Q-Fixator. Experiments were conducted on three fracture models to demonstrate the reduction results. RESULTS: Good reduction results were obtained on all three fractured bone models, with an average rotation of 1.21 degrees (+/- 0.24), angulation of 1.84 degrees (+/- 0.28), and lateral displacement of 2.22 mm(+/- 0.62). CONCLUSIONS: A novel customised external fixator for long bone fracture reduction was readily developed using 3D printing technique. The customised external fixator had the advantages of easy manipulation, accurate reduction, minimally invasion and experience-independence. Future application of the customised external fixator can be extended to include the fixation function with stress adjustment and potentially optimise the fracture healing process. PMID- 25702253 TI - [Vaccinium myrtillus]. PMID- 25702248 TI - Multimodal manifold-regularized transfer learning for MCI conversion prediction. AB - As the early stage of Alzheimer's disease (AD), mild cognitive impairment (MCI) has high chance to convert to AD. Effective prediction of such conversion from MCI to AD is of great importance for early diagnosis of AD and also for evaluating AD risk pre-symptomatically. Unlike most previous methods that used only the samples from a target domain to train a classifier, in this paper, we propose a novel multimodal manifold-regularized transfer learning (M2TL) method that jointly utilizes samples from another domain (e.g., AD vs. normal controls (NC)) as well as unlabeled samples to boost the performance of the MCI conversion prediction. Specifically, the proposed M2TL method includes two key components. The first one is a kernel-based maximum mean discrepancy criterion, which helps eliminate the potential negative effect induced by the distributional difference between the auxiliary domain (i.e., AD and NC) and the target domain (i.e., MCI converters (MCI-C) and MCI non-converters (MCI-NC)). The second one is a semi supervised multimodal manifold-regularized least squares classification method, where the target-domain samples, the auxiliary-domain samples, and the unlabeled samples can be jointly used for training our classifier. Furthermore, with the integration of a group sparsity constraint into our objective function, the proposed M2TL has a capability of selecting the informative samples to build a robust classifier. Experimental results on the Alzheimer's Disease Neuroimaging Initiative (ADNI) database validate the effectiveness of the proposed method by significantly improving the classification accuracy of 80.1 % for MCI conversion prediction, and also outperforming the state-of-the-art methods. PMID- 25702254 TI - [Hepatitis C: diagnosis, anti-viral therapy, after-care. Hungarian consensus guideline]. AB - Approximately 70,000 people are infected with hepatitis C virus in Hungary, and more than half of them are not aware of their infection. From the point of infected individuals early recognition and effective treatment of related liver injury may prevent consequent advanced liver diseases and complications (liver cirrhosis, liver failure and liver cancer) and can increase work productivity and life expectancy. Furthermore, these could from prevent further spread of the virus as well as reduce substantially long term financial burden of related morbidity, as a socioeconomic aspect. Pegylated interferon + ribavirin dual therapy, which is available in Hungary since 2003, can clear the virus in 40-45% of previously not treated (naive), and in 5-21% of previous treatment-failure patients. Addition of a direct acting first generation protease inhibitor drug (boceprevir or telaprevir) to the dual therapy increases the chance of sustained viral response to 63-75% and 59-66%, respectively. These two protease inhibitors are available and financed for a segment of Hungarian patients since May 2013. Between 2013 and February 2015, other direct acting antivirals and interferon free combination therapies have been registered for the treatment of chronic hepatitis C with a potential efficacy over 90% and typically with a short duration of 8-12 weeks. Indication of therapy includes exclusion of contraindications to the drugs and demonstration of viral replication with consequent liver injury, i.e., inflammation and/or fibrosis in the liver. Non invasive methods (elastography and biochemical methods) are accepted and preferred for staging liver damage (fibrosis). For initiation of treatment accurate and timely molecular biology tests are mandatory. Eligibility for treatment is a subject of individual central medical review. Due to budget limitations therapy is covered only for a proportion of patients by the National Health Insurance Fund. Priority is given to those with urgent need based on a Hungarian Priority Index system reflecting primarily the stage of liver disease, and considering also additional factors, i.e., activity and progression of liver disease, predictive factors of treatment and other special issues. Approved treatments are restricted to the most cost-effective combinations based on the cost per sustained viral response value in different patient categories with consensus between professional organizations, National Health Insurance Fund and patient organizations. More expensive therapies might be available upon co financing by the patient or a third party. Interferon-free treatments and shorter therapy durations preferred as much as financially feasible. A separate budget is allocated to cover interferon-free treatments for the most-in-need interferon ineligible/intolerant patients, and for those who have no more interferon-based therapy option. PMID- 25702255 TI - [The message from heroin overdoses]. AB - Drug use can be defined as a kind of self destruction, and it is directly linked to attitudes toward death and suicide occurring in a significant number of users of different narcotics. The aim of the authors was to look for the background of this relationship between drug and death and examine the origin, development, and motives behind heroin overdose based on an analysis of previous studies. It seems clear that pure heroin overdose increased gradually over the years. The fear of the police is the inhibitory factor of the overdose prevention and notification of emergency health care service. Signs of suicide could be the own home as the chosen location for heroin overdose and the presence of partners ("moment of death companion"). Interventions should include simple techniques such as first aid, naloxone administration, resuscitation, prevention of relapse of prisoners and social network extension involving maintenance programs. PMID- 25702256 TI - [The age-related macular degeneration as a vascular disease/part of systemic vasculopathy: contributions to its pathogenesis]. AB - The wall of blood vessels including those in choroids may be harmed by several repeated and/or prolonged mechanical, physical, chemical, microbiological, immunologic, and genetic impacts (risk factors), which may trigger a protracted response, the so-called host defense response. As a consequence, pathological changes resulting in vascular injury (e. g. atherosclerosis, age-related macular degeneration) may be evolved. Risk factors can also act directly on the endothelium through an increased production of reactive oxygen species promoting an endothelial activation, which leads to endothelial dysfunction, the onset of vascular disease. Thus, endothelial dysfunction is a link between the harmful stimulus and vascular injury; any kind of harmful stimuli may trigger the defensive chain that results in inflammation that may lead to vascular injury. It has been shown that even early age-related macular degeneration is associated with the presence of diffuse arterial disease and patients with early age-related macular degeneration demonstrate signs of systemic and retinal vascular alterations. Chronic inflammation, a feature of AMD, is tightly linked to diseases associated with ED: AMD is accompanied by a general inflammatory response, in the form of complement system activation, similar to that observed in degenerative vascular diseases such as atherosclerosis. All these facts indicate that age-related macular degeneration may be a vascular disease (or part of a systemic vasculopathy). This recognition could have therapeutic implications because restoration of endothelial dysfunction may prevent the development or improve vascular disease resulting in prevention or improvement of age-related macular degeneration as well. PMID- 25702257 TI - [Professional knowledge and practice mapping among nurses regarding transfusion therapy. A pilot study on reliability and validity testing]. AB - INTRODUCTION: All people involved in transfusion therapy have professional, legal and ethical responsibility for their own actions. AIM: The aims of the authors were to evaluate competencies, knowledge and practice of nurses about transfusion therapy. METHOD: Descriptive statistical approach using observation, questionnaire survey and interview was applied. Reliability and validity of the self-made questionnaire were examined with statistical methods. Variance, standard deviation, Cronbach's alpha and Pearson correlations were calculated. RESULTS: Transfusiology-related knowledge of nurses regarding current transfusion regulations was almost 90%, and 56.2% of nurses systematized the nursing functions correctly. Significant differences were found among different institutions in transfusion therapy, transfusion practice and the use of relevant documentation. 75-77% of the institutions examined had their own protocol, and assigned transfusion care nurses worked in more than 20% of the wards. CONCLUSIONS: The authors propose a better supervision by leaders in nursing aspects of transfusion therapy, and an increased professional responsibility. PMID- 25702259 TI - Predicting the Naturalistic Course of Major Depressive Disorder Using Clinical and Multimodal Neuroimaging Information: A Multivariate Pattern Recognition Study. AB - BACKGROUND: A chronic course of major depressive disorder (MDD) is associated with profound alterations in brain volumes and emotional and cognitive processing. However, no neurobiological markers have been identified that prospectively predict MDD course trajectories. This study evaluated the prognostic value of different neuroimaging modalities, clinical characteristics, and their combination to classify MDD course trajectories. METHODS: One hundred eighteen MDD patients underwent structural and functional magnetic resonance imaging (MRI) (emotional facial expressions and executive functioning) and were clinically followed-up at 2 years. Three MDD trajectories (chronic n = 23, gradual improving n = 36, and fast remission n = 59) were identified based on Life Chart Interview measuring the presence of symptoms each month. Gaussian process classifiers were employed to evaluate prognostic value of neuroimaging data and clinical characteristics (including baseline severity, duration, and comorbidity). RESULTS: Chronic patients could be discriminated from patients with more favorable trajectories from neural responses to various emotional faces (up to 73% accuracy) but not from structural MRI and functional MRI related to executive functioning. Chronic patients could also be discriminated from remitted patients based on clinical characteristics (accuracy 69%) but not when age differences between the groups were taken into account. Combining different task contrasts or data sources increased prediction accuracies in some but not all cases. CONCLUSIONS: Our findings provide evidence that the prediction of naturalistic course of depression over 2 years is improved by considering neuroimaging data especially derived from neural responses to emotional facial expressions. Neural responses to emotional salient faces more accurately predicted outcome than clinical data. PMID- 25702260 TI - Predictive value of serum HER2 ECD in patients with HER2-positive advanced gastric cancer treated with trastuzumab plus chemotherapy. AB - BACKGROUND: The levels of serum HER2 extracellular domain (ECD) are highly correlated with tissue HER2 status in metastatic gastric cancer (AGC). We sought to explore whether serum HER2 ECD could predict the efficacy of trastuzumab treated HER2-positive AGC. MATERIALS AND METHODS: From 2011 to 2013, trastuzumab treated AGC patients were enrolled. Serum HER2 ECD was centrally measured by chemiluminescence immunoassays (CLIA) method in available samples at baseline and after two cycles of trastuzumab combined with chemotherapy. The correlation between serum HER2 ECD and overall response rate (ORR) and progression-free survival (PFS) was analyzed. RESULTS: Sixty-five patients were analyzed with a median age of 58 years (range, 27-80 years). A significant difference of serum HER2 ECD levels was found between patients with HER2 IHC 3+ and those with HER2 IHC 2+ and FISH positive (p = 0.014). There was a significantly better ORR (80.00 vs. 50.00 %, p = 0.017) and PFS (median PFS, 268 vs. 139 days, p = 0.039) for patients with abnormal baseline serum HER2 ECD than for patients with normal serum HER2 ECD. Change in serum HER2 ECD during chemotherapy was significantly correlated with response to chemotherapy (79.17 vs. 51.52 %, p = 0.033) and PFS (median PFS, 303 vs. 147 days, p = 0.005) in patients with HER2-positive tumor tissue. CONCLUSIONS: Our results support the clinical utility of measuring serum HER2 ECD levels in patients with advanced gastric cancer. Baseline and early changes in serum HER2 ECD could be useful for monitoring clinical outcome in HER2 positive AGC patients receiving trastuzumab-combined chemotherapy. PMID- 25702261 TI - Role of KRAS mutation as predictor of pathologic response after neoadjuvant chemoradiation therapy for rectal cancer. AB - Individual patient response to neoadjuvant treatment is variable and reproducible biomarkers of response are needed. The role of the V-Ki-ras2 Kirsten rat sarcoma viral oncogene (KRAS) in rectal cancer remains equivocal. The aim of the current study was to evaluate the effect of KRAS mutation on outcomes following neoadjuvant chemoradiation therapy (CRT) for rectal cancer. A total of 76 stage II-III rectal cancer patients underwent preoperative CRT followed by surgery. In every patient tumor-related features and outcome results were considered for analysis and correlation with KRAS mutations. Forty-four patients (58%) obtained a downstaging after CRT, and in 7 patients (9%) a complete pathological response was found. Twenty-six (33%) mutations of KRAS were found in 26 patients. Nineteen mutations (73%) were located in codon 12, 6 in codon 13(23%) and 1 in codon 61. T level downsizing and tumor downstaging showed no significant association with KRAS mutation status, except for mutation of codon 13(G13D). No correlation between cancer-associated mortality following CRT and surgery and KRAS mutation was observed. No correlation between pelvic recurrence and KRAS mutation was observed. KRAS mutation also failed to correlate with disease-free survival. No patients with a pCR had a local or distant failure. There appears to be no significant difference in pCR, tumor down-staging, T-downsizing or effects on cancer-associated mortality, overall survival and disease-free survival in patients with KRAS mutations except for patients with KRAS codon 13 mutations that seem to be resistant to neoadjuvant CRT and less likely to achieve a pCR. PMID- 25702262 TI - Splenic flexure colon cancers: minimally invasive treatment. AB - Optimal treatment of splenic flexure (SF) colon cancer-less than 10% of all colorectal cancers is a matter of debate, in particular with regard to the optimal extent of radical surgery, according to the oncological principles of curative resection. Aims of this study were to assess the clinicopathological characteristics and report operative data and survival of patients with SF colon cancers. Short- and mid-term outcome of patients undergoing laparoscopic curative resection for SF colon cancer between June 2005 and September 2011 was assessed. The analysis considered 16 patients: 10 underwent segmental resection, 4 left hemicolectomy and 2 subtotal colectomy. There were no intraoperative deaths or major morbidity. The median operative time was 185 min. The median number of lymph nodes harvested was 17. Disease-free survival rate at 30-month follow-up was 75%. Laparoscopic resection of SF cancer is feasible and safe. Oncological principles of disease-free margins and minimum node harvest can be respected even with segmental resection. PMID- 25702263 TI - Surgery for isolated liver metastases from pancreatic cancer. AB - The resection of liver metastases from pancreatic ductal adenocarcinoma has been discouraged because it is commonly thought that it does not improve survival. However, the role of potential prognostic factors is unclear, and universally accepted strategies have not been proposed. Between 2003 and 2014, 15 patients with isolated synchronous or metachronous metastases from pancreatic cancer underwent liver resection in our department. The role of potential prognostic factors was analyzed to predict survival. One right hepatectomy, 1 bisegmentectomy and 13 wedge resections were performed. Eleven patients underwent simultaneous pancreatic and liver resection for synchronous disease. The median overall survival (OS) was 9.1 months (95% CI 8.6-9.7). The only potential prognostic factor that significatively affected survival was the timing of metastases (metachronous vs. synchronous). Median OS in patients with metachronous disease was 11.4 months (95% CI 0-25.1) vs. 8.3 months (95% CI 6.9 9.7), p = 0.038. Surgery for liver metastases from pancreatic cancer is not suggested for most patients. If resection is considered, timing of metastatic disease could be a prognostic factor for survival after surgery. PMID- 25702264 TI - Therapeutic applications of ghrelin agonists in the treatment of gastroparesis. AB - There remains an unmet need for effective pharmacologic treatments for gastroparesis. Ghrelin is the endogenous ligand for the growth hormone secretagogue receptor and has been shown to regulate energy homeostasis and exert prokinetic effects on gastrointestinal motility. In recent years, several ghrelin receptor agonists have been studied in clinical trials of patients with diabetic gastroparesis. The intravenous macrocyclic peptidomimetic, TZP-101, initially suggested improvement in gastroparesis symptoms with intravenous administration when compared to placebo. However, in subsequent studies of oral preparations, TZP-102 failed to confirm these results. Another ghrelin receptor agonist, RM 131, was recently shown to significantly accelerate gastric emptying (GE) in patients with type 1 and type 2 diabetes and delayed GE. RM-131 reduced total Gastroparesis Cardinal Symptom Index-Daily Diary (GCSI-DD) and composite scores among type 1 diabetics. Continued development of ghrelin agonists should be explored in attempts to expand therapeutic options for the treatment of gastroparesis. PMID- 25702265 TI - Cross-cultural adaptation and psychometric assessment of the Chinese version of the comprehensive needs assessment tool for cancer caregivers (CNAT-C). AB - PURPOSE: The comprehensive needs assessment tool for cancer caregivers (CNAT-C) is a systematic and comprehensive needs assessment tool for the family caregivers. The purpose of this project was twofold: (1) to adapt the CNAT-C to Mainland China's cultural context and (2) to evaluate the psychometric properties of the newly adapted Chinese CNAT-C. METHODS: Cross-cultural adaptation of the original CNAT-C was performed according to published guidelines. A pilot study was conducted in Mainland China with 30 Chinese family cancer caregivers. A subsequent validation study was conducted with 205 Chinese cancer caregivers from Mainland China. Construct validity was determined through exploratory and confirmatory factor analyses. Reliability was determined using internal consistency and test-retest reliability. RESULTS: The split-half coefficient for the overall Chinese CNAT-C scale was 0.77. Principal component analysis resulted in an eight-factor structure explaining 68.11 % of the total variance. The comparative fit index (CFI) was 0.91 from the modified model confirmatory factor analysis. The Chi-square divided by degrees of freedom was 1.98, and the root mean squared error of approximation (RMSEA) was 0.079. In relation to the known group validation, significant differences were found in the Chinese CNAT-C scale according to various caregiver characteristics. Internal consistency was high for the Chinese CNAT-C reaching a Cronbach alpha value of 0.94. Test-retest reliability was 0.85. CONCLUSIONS: The newly adapted Chinese CNAT-C scale possesses adequate validity, test-retest reliability, and internal consistency and therefore may be used to ascertain holistic health and support needs of cancer patients' family caregivers in Mainland China. PMID- 25702266 TI - Equivalence of electronic and paper-based patient-reported outcome measures. AB - AIM: Electronic formats (ePROs) of paper-based patient-reported outcomes (PROs) should be validated before they can be reliably used. This review aimed to examine studies investigating measurement equivalence between ePROs and their paper originals to identify methodologies used and to determine the extent of such validation. METHODS: Three databases (OvidSP, Web of Science and PubMed) were searched using a set of keywords. Results were examined for compliance with inclusion criteria. Articles or abstracts that directly compared screen-based electronic versions of PROs with their validated paper-based originals, with regard to their measurement equivalence, were included. Publications were excluded if the only instruments reported were stand-alone visual analogue scales or interactive voice response formats. Papers published before 2007 were excluded, as a previous meta-analysis examined papers published before this time. RESULTS: Fifty-five studies investigating 79 instruments met the inclusion criteria. 53 % of the 79 instruments studied were condition specific. Several instruments, such as the SF-36, were reported in more than one publication. The most frequently reported formats for ePROs were Web-based versions. In 78 % of the publications, there was evidence of equivalence or comparability between the two formats as judged by study authors. Of the 30 publications that provided preference data, 87 % found that overall participants preferred the electronic format. CONCLUSIONS: When examining equivalence between paper and electronic versions of PROs, formats are usually judged by authors to be equivalent. Participants prefer electronic formats. This literature review gives encouragement to the further widespread development and use of ePROs. PMID- 25702267 TI - Assessing quality of life in Crohn's disease: development and validation of the Crohn's Life Impact Questionnaire (CLIQ). AB - PURPOSE: Despite the significant impact of Crohn's disease (CD) on patients' physical and emotional well-being, no CD-specific patient-reported outcome (PRO) measure is available for determining the efficacy of interventions. The objective of the study was to develop and validate the Crohn's Life Impact Scale (CLIQ), the first such measure. METHODS: Questionnaire content was derived from qualitative interviews with CD patients and face and content validity assessed by cognitive debriefing interviews (CDIs) with patients. A postal survey was conducted to identify the final scale, confirm its unidimensionality and determine reproducibility and construct validity. A subset of the respondents was sent a second questionnaire package 2 weeks after the first. The survey included the CLIQ, Nottingham Health Profile (NHP) and Unidimensional Fatigue Impact Scale (U-FIS). RESULTS: Content analysis was conducted on the 30 interview transcripts and a draft scale produced. The CDIs indicated that the draft scale was relevant, clear and easy to use. The questionnaire package was completed by 273 CD patients (65.6 % male; aged 16-79 (mean 43.9; SD 15.1) years). Of these, 104 also completed the second package. Rasch analysis confirmed a 27-item unidimensional QoL scale (p < 0.05). Both internal consistency and test-retest reliability were high (0.91). Scores on the CLIQ were related to both physical and emotional impairments (NHP) and to fatigue (U-FIS). CONCLUSION: The CLIQ, the first CD specific PRO, is unidimensional and has excellent psychometric properties. It should prove to be a valuable tool for evaluating the impact of CD and its treatment from the patients' perspective. PMID- 25702268 TI - Construction of a high-density DArTseq SNP-based genetic map and identification of genomic regions with segregation distortion in a genetic population derived from a cross between feral and cultivated-type watermelon. AB - Watermelon [Citrullus lanatus (Thunb.) Matsum. & Nakai] is an economically important vegetable crop grown extensively worldwide. To facilitate the identification of agronomically important traits and provide new information for genetic and genomic research on this species, a high-density genetic linkage map of watermelon was constructed using an F2 population derived from a cross between elite watermelon cultivar K3 and wild watermelon germplasm PI 189225. Based on a sliding window approach, a total of 1,161 bin markers representing 3,465 SNP markers were mapped onto 11 linkage groups corresponding to the chromosome pair number of watermelon. The total length of the genetic map is 1,099.2 cM, with an average distance between bins of 1.0 cM. The number of markers in each chromosome varies from 62 in chromosome 07 to 160 in chromosome 05. The length of individual chromosomes ranged between 61.8 cM for chromosome 07 and 140.2 cM for chromosome 05. A total of 616 SNP bin markers showed significant (P < 0.05) segregation distortion across all 11 chromosomes, and 513 (83.3 %) of these distorted loci showed distortion in favor of the elite watermelon cultivar K3 allele and 103 were skewed toward PI 189225. The number of SNPs and InDels per Mb varied considerably across the segregation distorted regions (SDRs) on each chromosome, and a mixture of dense and sparse SNPs and InDel SDRs coexisted on some chromosomes suggesting that SDRs were randomly distributed throughout the genome. Recombination rates varied greatly among each chromosome, from 2.0 to 4.2 centimorgans per megabase (cM/Mb). An inconsistency was found between the genetic and physical positions on the map for a segment on chromosome 11. The high density genetic map described in the present study will facilitate fine mapping of quantitative trait loci, the identification of candidate genes, map-based cloning, as well as marker-assisted selection (MAS) in watermelon breeding programs. PMID- 25702269 TI - A review of pulsed electrochemical detection following liquid chromatography and capillary electrophoresis. AB - Pulsed electrochemical detection (PED) has progressed as a highly sensitive and selective detection technique following aqueous-based separation systems over the past three decades. The application of on-line pulsed potential cleaning to electrocatalytic noble metal electrodes has significantly increased the number of applications formerly achieved with conventional electrochemical (EC) detection. Electrochemical cells are easily miniaturized, providing the ability to apply detection by PED at microelectrodes and onto microchips utilizing electrophoretic separations. In addition, recent advances in PED waveforms and instrumentation have enabled the detection technique to be easily coupled with high pressure separation systems which require rapid detection to maintain separation integrity. As a result, advanced applications for the determination of carbohydrates as well as the expansion of PED for the detection of other organic aliphatic compounds have been recently accomplished. This review will focus on developments and methods utilizing PED following liquid chromatography (LC) and capillary electrophoresis (CE). Publications are reviewed in chronological order to emphasize the advancement of the detection method and the sustained relevance of its applications. PMID- 25702270 TI - A novel fourth-order calibration method based on alternating quinquelinear decomposition algorithm for processing high performance liquid chromatography diode array detection- kinetic-pH data of naptalam hydrolysis. AB - Five-way high performance liquid chromatography-diode array detection (HPLC-DAD) kinetic-pH data were obtained by recording the kinetic evolution of HPLC-DAD signals of samples at different pH values and a new fourth-order calibration method, alternating quinquelinear decomposition (AQQLD) based on pseudo-fully stretched matrix forms of the quinquelinear model, was developed. Simulated data were analyzed to investigate the performance of AQQLD in comparison with five-way parallel factor analysis (PARAFAC). The tested results demonstrated that AQQLD has the advantage of faster convergence rate and being insensitive to the excess component number adopted in the model. Then, they have been successfully applied to investigate quantitatively the kinetics of naptalam (NAP) hydrolysis in two practical systems. Additionally, the serious chromatographic peak shifts were accurately corrected by means of chromatographic peak alignment method based on abstract subspace difference. The good recoveries of NAP were obtained in these samples by selecting the time region of chromatogram. The elution time, spectral, kinetic time and pH profiles resolved by the chemometric techniques were in good agreement with experimental observations. It demonstrates the potential for the utilization of fourth-order data for some complex systems, opening up a new approach to fourth-order data generation and subsequent fourth-order calibration. PMID- 25702271 TI - Facile synthesis of ultrafine Co3O4 nanocrystals embedded carbon matrices with specific skeletal structures as efficient non-enzymatic glucose sensors. AB - A facile, effective, and environmentally friendly method has been adopted for the first time to prepare tiny Co3O4 nanocrystals embedded carbon matrices without using surfactants, harmful organic reagents or extreme conditions. Structural characterizations reveal that the size-controlled Co3O4 nanocrystals are uniformly dispersed on carbon matrices. Electrochemical measurements reveal that Co3O4-ordered mesoporous carbon (OMC) can more efficiently catalyze glucose oxidation and acquire better detection parameters compared with those for the Co3O4-macroporous carbon, Co3O4-reduced graphene oxide, and free Co3O4 nanoparticles (NPs) (such as: the large sensitivity (2597.5 MUA cm(-2) mM(-1) between 0 and 0.8 mM and 955.9 MUA cm(-2) mM(-1) between 0.9 and 7.0 mM), fast response time, wide linear range, good stability, and surpassingly selective capability to electroactive molecules or Cl(-)). Such excellent performances are attributed to the synergistic effect of the following three factors: (1) the high catalytic sites provided by the uniformly dispersed and size-controlled Co3O4 nanocrystals embedded on OMC; (2) the excellent reactant transport efficiency caused by the abundant mesoporous structures of OMC matrix: (3) the improved electron transport in high electron transfer rate (confinement of the Co3O4 NPs in nanoscale spaces ensured intimate contact between Co3O4 nanocrystals and the conducting OMC matrix). The superior catalytic activity and selectivity make Co3O4-OMC very promising for application in direct detection of glucose. PMID- 25702272 TI - Preparation of magnetic chitosan and graphene oxide-functional guanidinium ionic liquid composite for the solid-phase extraction of protein. AB - A series of novel cationic functional hexaalkylguanidinium ionic liquids and anionic functional tetraalkylguanidinium ionic liquids have been synthesized, and then magnetic chitosan graphene oxide (MCGO) composite has been prepared and coated with these functional guanidinium ionic liquids to extract protein by magnetic solid-phase extraction. MCGO-functional guanidinium ionic liquid has been characterized by vibrating sample magnetometer, field emission scanning electron microscopy, X-ray diffraction spectrometer and Fourier transform infrared spectrometer. After extraction, the concentrations of protein were determined by measuring the absorbance at 278 nm using an ultra violet visible spectrophotometer. The advantages of MCGO-functional guanidinium ionic liquid in protein extraction were compared with magnetic chitosan, graphene oxide, MCGO and MCGO-ordinary imidazolium ionic liquid. The proposed method has been applied to extract trypsin, lysozyme, ovalbumin and bovine serum albumin. A comprehensive study of the adsorption conditions such as the concentration of protein, the amount of MCGO-functional guanidinium ionic liquid, the pH, the temperature and the extraction time were also presented. Moreover, the MCGO-functional guanidinium ionic liquid can be easily regenerated, and the extraction capacity was about 94% of the initial one after being used three times. PMID- 25702273 TI - Direct drug analysis from oral fluid using medical swab touch spray mass spectrometry. AB - Fourteen common drugs of abuse were identified in spiked oral fluid (ng mL(-1) levels), analyzed directly from medical swabs using touch spray mass spectrometry (TS-MS), exemplifying a rapid test for drug detection. Multiple stages of mass analysis (MS(2) and MS(3)) provided identification and detection limits sought by international forensic and toxicological societies, Delta(9)-THC and buprenorphine excluded. The measurements were made using a medical swab as both the sampling probe and means of ionization. The adaptation of medical swabs for TS-MS analysis allows non-invasive and direct sampling of neat oral fluid. Data acquisition was rapid, seconds per drug, and MS(3) ensured reliable identification of illicit drugs. The reported data were acquired to investigate (i) ionization of common drugs from commercial swabs, (ii) ion intensity over spray duration, and (iii) dynamic range, all as initial steps in development of a quantitative method. The approach outlined is intended for point-of-care drug testing using oral fluid in clinical applications as well as in situ settings, viz. in forensic applications. The proof-of-concept results presented will require extension to other controlled substances and refinement in analytical procedures to meet clinical/legal requirements. PMID- 25702274 TI - Gold nanoparticles immobilized on metal-organic frameworks with enhanced catalytic performance for DNA detection. AB - In this work, gold nanoparticles (AuNPs) assembled on the surface of iron based metal-organic frameworks (MOFs), Fe-MIL-88, are facilely prepared through electrostatic interactions using polyethyleneimine (PEI) molecules as linker. The resulting hybrid materials possess synergetic peroxidase-like activity. Because iron based metal-organic frameworks, Fe-MIL-88, exhibits highly peroxidase-like activity, and AuNPs has the distinct adsorption property to single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA). The peroxidase-like activity of Au@Fe MIL-88 exhibit excellent switchable in response to specific DNA, ssDNA is easily adsorbed on the surface of the Au@Fe-MIL-88 hybrids, resulting in the reduce of the peroxidase-like activity of the hybrids. While it is recovered by the addition of target DNA, and the recovery degree is proportional to the target DNA concentration over the range of 30-150 nM with a detection limit of 11.4 nM. Based on these unique properties, we develop a label-free colorimetric method for DNA hybridization detection. In control experiment, base-mismatched DNA cannot induce recovery of the peroxidase-like activity. This detection method is simple, cheap, rapid and colorimetric. PMID- 25702275 TI - A sensitive lateral flow biosensor for Escherichia coli O157:H7 detection based on aptamer mediated strand displacement amplification. AB - Foodborne diseases caused by pathogens are one of the major problems in food safety. Convenient and sensitive point-of-care rapid diagnostic tests for food borne pathogens have been a long-felt need of clinicians. Commonly used methods for pathogen detection rely on conventional culture-based tests, antibody-based assays and polymerase chain reaction (PCR)-based techniques. These methods are costly, laborious and time-consuming. Herein, we present a simple and sensitive aptamer based biosensor for rapid detection of Escherichia coli O157:H7 (E. coli O157:H7). In this assay, two different aptamers specific for the outmembrane of E. coli O157:H7 were used. One of the aptamers was used for magnetic bead enrichment, and the other was used as a signal reporter for this pathogen, which was amplified by isothermal strand displacement amplification (SDA) and further detected by a lateral flow biosensor. Only the captured aptamers on cell membrane were amplified, limitations of conventional DNA amplification based method such as false-positive can be largely reduced. The generated signals (red bands on the test zone of a lateral flow strip) can be unambiguously read out by the naked eye. As low as 10 colony forming units (CFU) of E. coli O157:H7 were detected in this study. Without DNA extraction, the reduced handling and simpler equipment requirement render this assay a simple and rapid alternative to conventional methods. PMID- 25702276 TI - A novel adenosine-based molecular beacon probe for room temperature nucleic acid rapid detection in cotton thread device. AB - We used cotton thread as substrate to develop a novel room temperature DNA detection device for low-cost, sensitive and rapid detection of a human genetic disease, hereditary tyrosinemia type I related DNA sequences. A novel adenosine based molecular beacon (ABMB) probe modified on gold nanoparticle was used as reporter probe. In the presence of coralyne, a small molecule which can react with adenosines, the ABMB would form a hairpin structure just like traditional molecular beacon used extensively. In the presence of target DNA sequences, the hairpin structure of ABMB modified on gold nanoparticles will be opened and the biotin group modified at one end of the DNA probes will be released and react with the streptavidin immobilized on the test zone of the cotton thread. The response of the thread based DNA test device is linear over the range of 2.5-100 nM complementary DNA. The ability of our developed device for discriminating the single base mismatched DNA related to a human genetic disease, hereditary tyrosinemia type I, was improved comparing with previous report. It is worth mentioning that the whole assay procedure for DNA test is performed under room temperature which simplified the assay procedures greatly. PMID- 25702277 TI - Facile synthesis of nitrogen-doped carbon dots for Fe(3+) sensing and cellular imaging. AB - A fast and facile approach to synthesize highly nitrogen (N)-doped carbon dots (N CDs) by microwave-assisted pyrolysis of chitosan, acetic acid and 1,2 ethylenediamine as the carbon source, condensation agent and N-dopant, respectively, is reported. The obtained N-CDs are fully characterized by elemental analysis, transmission electron microscopy, high-resolution transmission electron microscopy, Fourier transform infrared spectroscopy, Raman spectroscopy, X-ray diffraction pattern, X-ray photoelectron spectroscopy, UV-vis absorption, and photoluminescence spectroscopy. Doping N heteroatoms benefits the generation of N-CDs with stronger fluorescence emission. As the emission of N-CDs is efficiently quenched by Fe(3+), the as-prepared N-CDs are employed as a highly sensitive and selective probe for Fe(3+) detection. The detection limit can reach as low as 10 ppb, and the linear range is 0.010-1.8 ppm Fe(3+). The as synthesized N-CDs have been successfully applied for cell imaging and detecting Fe(3+) in biosystem. PMID- 25702278 TI - Dystrophin genotype-cardiac phenotype correlations in Duchenne and Becker muscular dystrophies using cardiac magnetic resonance imaging. AB - Duchenne and Becker muscular dystrophies are caused by mutations in dystrophin. Cardiac manifestations vary broadly, making prognosis difficult. Current dystrophin genotype-cardiac phenotype correlations are limited. For skeletal muscle, the reading-frame rule suggests in-frame mutations tend to yield milder phenotypes. We performed dystrophin genotype-cardiac phenotype correlations using a protein-effect model and cardiac magnetic resonance imaging. A translational model was applied to patient-specific deletion, indel, and nonsense mutations to predict exons and protein domains present within truncated dystrophin protein. Patients were dichotomized into predicted present and predicted absent groups for exons and protein domains of interest. Development of myocardial fibrosis (represented by late gadolinium enhancement [LGE]) and depressed left ventricular ejection fraction (LVEF) were compared. Patients (n = 274) with predicted present cysteine-rich domain (CRD), C-terminal domain (CTD), and both the N-terminal actin-binding and cysteine-rich domains (ABD1 + CRD) had a decreased risk of LGE and trended toward greater freedom from LGE. Patients with predicted present CTD (exactly the same as those with in-frame mutations) and ABD1 + CRD trended toward decreased risk of and greater freedom from depressed LVEF. In conclusion, genotypes previously implicated in altering the dystrophinopathic cardiac phenotype were not significantly related to LGE and depressed LVEF. Patients with predicted present CRD, CTD/in-frame mutations, and ABD1 + CRD trended toward milder cardiac phenotypes, suggesting that the reading-frame rule may be applicable to the cardiac phenotype. Genotype-phenotype correlations may help predict the cardiac phenotype for dystrophinopathic patients and guide future therapies. PMID- 25702279 TI - Structural heart disease and ST2: cross-sectional and longitudinal associations with echocardiography. AB - To further explore the potential role of sST2 in the progression of cardiac disease, this section reviews both the associations with cross-sectional findings and longitudinal changes in cardiac structure and function measured by echocardiography and cardiac magnetic resonance imaging with sST2 levels in a variety of patient populations with or at-risk for cardiovascular disease. In a Pro-Brain Natriuretic Peptide Investigation of Dyspnea in the Emergency Department substudy in patients with acute dyspnea, sST2 levels were found associated with left ventricular ejection fraction (LVEF), and both estimated right ventricular (RV) systolic pressure and RV hypokinesis. In a large cohort of ambulatory patients referred for echocardiograms, sST2 was predominantly associated with RV and not LV structural findings. In contrast, in the Framingham Heart Study, a community cohort of >3,300 participants, sST2 was not associated with either echocardiographic finding, although in the Cardiovascular Health Study, sST2 appeared strongly associated with the presence of diastolic dysfunction. Little evidence exists on the relation of sST2 levels with longitudinal change in cardiac structure and function. A substudy of Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) evaluated the association among LV remodeling (defined as an increase in LV end-systolic and -diastolic volumes), sST2, and the benefit of eplerenone and found that sST2 levels were good surrogates of left ventricular remodeling. In the same line, the ProBNP Outpatient Tailored Chronic Heart Failure (PROTECT) study found that more time spent with an sST2 level less than the cutoff of 35 ng/L identified patients with a greater probability of a decrease in LV diastolic index over 1 year. PMID- 25702281 TI - Serum fucosylated paraoxonase 1 as a potential glycobiomarker for clinical diagnosis of early hepatocellular carcinoma using ELISA Index. AB - Serum paraoxonase 1 (PON1) is highly fucosylated in hepatocellular carcinoma (HCC) compared with liver cirrhosis (LC). Herein, lectin ELISA using Aleuria aurantia lectin (AAL) was established, which specifically measured optical density (OD) value of serum fucosylated PON1. PON1 protein ELISA was applied simultaneously. ELISA Index (OD value of fucosylated PON1/OD value of protein PON1) was introduced to indicate PON1 fucosylation level on its protein level (Fuc-PON1). ELISA Index in training group (90 LC and 90 HCC) was measured and area under the ROC curve (AUROC) was 0.803 with 80 % of sensitivity and 64.4 % of specificity in distinguishing early HCC from LC. Within training group, AFP(-) HCC (20/90) exhibited better AUROC (0.850), higher sensitivity (90 %) and specificity (75 %) than AFP(+) HCC (70/90). An independent testing set (20 LC and 20 HCC) validated the model and 17 HCC patients were successfully predicted. Meanwhile, serum AFP of 43 LC and 43 HCC had an AUROC of 0.760 with sensitivity of 79.1 % and specificity of 53.5 %. Thus, Fuc-PON1 may serve as a glycan biomarker for distinguishing early HCC from LC patients even with low AFP levels. PMID- 25702282 TI - UHPLC-PDA-ESI-TOF/MS metabolic profiling of Arctostaphylos pungens and Arctostaphylos uva-ursi. A comparative study of phenolic compounds from leaf methanolic extracts. AB - The aim of this study was to get a rapid metabolic fingerprinting and to gain insight into the metabolic profiling of Arctostaphylos pungens H. B. K., a plant morphologically similar to Arctostaphylos uva-ursi (L.) Spreng. (bearberry) but with a lower arbutin (Arb) content. According to the European Pharmacopoeia the Arb content in the dried leaf of A. uva-ursi (L.) Spreng. must be at least 7% (wt/wt) but other species, like A. pungens, are unintentionally or fraudulently marketed instead of it. Therefore, methanolic leaf extracts of nine A. uva-ursi and six A. pungens samples labeled and marketed as "bearberry leaf" have been analyzed. A five-minute gradient with a UHPLC-PDA-ESI-TOF/MS on an Acquity BEH C18 (50*2.1 mm i.d.) 1.7 MUm analytical column has been used for the purpose. A comprehensive assignment of secondary metabolites has been carried out in a comparative study of the two species. Among twenty-nine standards of natural compounds analyzed, fourteen have been identified, while other fifty-five metabolites have been tentatively assigned. Moreover, differences in both metabolic fingerprinting and profiling have been evidenced by statistical multivariate analysis. Specifically, main variations have been observed in the relative content for Arb, as expected, and for some galloyl derivative like tetra and pentagalloylglucose more abundant in A. uva-ursi than in A. pungens. Furthermore, differences in flavonols profile, especially in myricetin and quercetin glycosilated derivatives, were observed. Based on principal component analysis myricetrin, together with a galloyl arbutin isomer and a disaccharide are herein proposed as distinctive metabolites for A. pungens. PMID- 25702283 TI - [Pourfour du Petit syndrome in a patient with lung mucinous adenocarcinoma]. PMID- 25702285 TI - Putative mechanisms responsible for the decline in cancer prevalence during organism senescence. AB - Most scientific literature reports that aging favors the development of cancers. Each type of cancer, however, initiates and evolves differently, and their natural history can start much earlier in life before their clinical manifestations. The incidence of cancers is spread throughout human life span, and is the result of pre- and post-natal aggressions, individual susceptibility, developmental changes that evolve continuously throughout an individual's life, and time of exposure to carcinogens. Finally, during human senescence, the incidence declines for all cancers. Frequently, the progression of cancers is also slower in aged individuals. There are several possible explanations for this decline at the tissue, cell, and molecular levels, which are described here in. It is time to ask why some tumors are characteristic of either the young, the aged, or during the time of a decline in the reproductive period, and finally, why the incidence of cancers declines late during senescence of human beings. These questions need to be addressed before the origin of cancers can be understood. PMID- 25702284 TI - Multiple internal sorting determinants can contribute to the trafficking of cruciferin to protein storage vacuoles. AB - Trafficking of seed storage proteins to protein storage vacuoles is mediated by carboxy terminal and internal sorting determinants (ISDs). Protein modelling was used to identify candidate ISDs residing near surface-exposed regions in Arabidopsis thaliana cruciferin A (AtCruA). These were verified by AtCruA fusion to yellow fluorescent protein (YFP) and expression in developing embryos of A. thaliana. As the presence of endogenous cruciferin was found to mask the effects of weaker ISDs, experiments were conducted in a line that was devoid of cruciferin. In total, nine ISDs were discovered and a core determinant defined using a series of alanine scanning and deletion mutant variants. Coupling of functional data from AtCruA ISD-YFP fusions with statistical analysis of the physiochemical properties of analogous regions from several 11/12S globulins revealed that cruciferin ISDs likely adhere to the following rules: (1) ISDs are adjacent to or within hydrophilic, surface-exposed regions that serve to present them on the protein's surface; (2) ISDs generally have a hydrophobic character; (3) ISDs tend to have Leu or Ile residues at their core; (4) ISDs are approximately eight amino acids long with the physiochemical consensus [hydrophobic][preferably charged][small or hydrophobic, but not tiny][IL][polar, preferably charged][small, but not charged][hydrophobic, not charged, preferably not polar][hydrophobic, not tiny, preferably not polar]. Microscopic evidence is also presented for the presence of an interconnected protein storage vacuolar network in embryo cells, rather than discreet, individual vacuoles. PMID- 25702286 TI - Obsessive-compulsive symptom dimensions in a population-based, cross-sectional sample of school-aged children. AB - BACKGROUND: Obsessive-compulsive disorder can be expressed as four potentially overlapping obsessive-compulsive symptom (OCS) dimensions (OCSD) ("symmetry/ordering", "contamination/cleaning", "aggressive/sexual/religious" and "collecting/hoarding"). In clinical samples, some dimensions are more familial and associated with increased psychiatric comorbidity and malfunctioning. However, data concerning OCS and OCSD are scarce in non-clinical samples, particularly among children. The present study aims to estimate: (1) the prevalence and sex/age distribution of OCS/OCSD in a community-based sample of schoolchildren; (2) the association between OCS and additional clinical factors; and (3) the degree of familial aggregation of OCS/OCSD. METHODS: OCS and OCSD were evaluated in 9937 Brazilian school-children (6-12 years-old) and their biological relatives using the Family History Screen. Data analyses included gradient estimated equations and post-hoc tests. RESULTS: We included data on 9937 index-children, 3305 siblings (13-18 years-old), and 16,218 parents. Biological mothers were the informants in 87.6% of the interviews. OCS were present in 14.7% of the index-children; 15.6% of their siblings; 34.6% of their mothers and 12.1% of their fathers. The prevalence of OCS and each of the OCSD gradually increased from ages 6 to 12 years. Overall, OCS in children were associated with the presence of other psychiatric symptoms, as well as behavioral/school impairment. OCS and each of the four OCSD aggregated significantly within families. CONCLUSIONS: OCS are prevalent and associated with psychiatric symptoms and clinical impairment among school-aged children. OCSD aggregate within families in a dimension-specific fashion. These findings suggest a natural continuum between OCS and OCD with regard to their dimensional character. PMID- 25702287 TI - [New technologies for antibiotic susceptibility testing of bacteria]. AB - The past two decades have witnessed increasing infections due to multidrug resistant bacteria. Therefore, transmission of these pathogens could limit the antibiotic therapy options. Many reports suggest that initiation of appropriate antimicrobial therapy can be lifesaving. Physicians rely on combination of clinical, epidemiological and demographic data to guide empirical therapy because results of culture and antimicrobial susceptibility testing may require 48 hours or longer. Therefore, an ongoing effort for the development of earlier and more sensitive detection of resistant bacteria is inevitable. This review presents a summary of the most advanced methods (e.g. PCR-based techniques, flow cytometry, mass spectrometry, microarrays and others) that are able to rapidly detect antibiotic resistance in bacterial pathogens which have the potential to become valuable alternatives to the existing methods (standard phenotypic resistance testing) in the very near future. PMID- 25702288 TI - [Methods of phenotypic determination of New Delhi metallo-beta-lactamase (NDM-1) in Klebsiella penumoniae isolated in Slovakia]. AB - OBJECTIVES: Reported is the first isolation and phenotypic determination of Klebsiella pneumoniae producing New Delhi metallo-beta-lactamase (NDM-1) isolated from patients in the Slovak Republic. MATERIAL AND METHODS: Between 27 October 2012 and 22 January 2013, twenty-five isolates of Klebsiella pneumoniae collected from 5 patients were identified with MIC of meropenem >= 32 mg/L and MIC of ertapenem >= 4 mg/L in screening tests. Next, all isolates were assessed with the modified Hodge test, combined disk test with EDTA, double disk synergy test with EDTA and MBL E-test. To confirm production of MBL in isolated strains of Klebsiella pneumoniae, all strains were sent to the National Reference Center for Antibiotic Resistance in Bratislava. RESULTS: All strains were positive in all phenotypic tests. In the first carbapenem-resistant isolate, NDM-1 production was confirmed by PCR amplification, sequencing and comparison with the GenBank. CONCLUSIONS: To the best of our knowledge, this is the first case of isolation of NDM-1 from Klebsiella pneumoniae in the Slovak Republic. As of 31 January 2014, with well-established and strict epidemiological and preventive measures, there was no further spread or another outbreak of NDM-1 producing Enterobacteriaceae in Louis Pasteur University Hospital in Kosice. PMID- 25702289 TI - [Guidelines for antifungal prophylaxis, diagnosis and therapy in pediatric hematology and oncology - a review of literature and expert recommendations]. AB - OBJECTIVES: Problems with importing non-registered medicines for treating rare life-threatening infectious diseases led to establishment of the Emergency Anti Infective Drug Reserve (EAIDR) for the Czech Republic. METHODS: Thirteen anti infective drugs are included in the project: antisera against rabies virus, varicella-zoster virus, and botulinum toxin; antituberculosis drugs (intravenous rifampicin and isoniazid; capreomycin, cycloserine, and clofazimine); antiparasitics (intravenous quinine, primaquine, meglumine antimoniate, and praziquantel); and pentamidine. These drugs are imported according to the Czech drug legislation (specific drug availability programs). Realization: The project, approved by the Czech Ministry of Health in September 2013, was started in January 2014. The anti-infective drugs sufficient for 2-4 patients are permanently available in the Toxicological Information Center (TIC) in Prague. The medicines can be applied in any hospital throughout the Czech Republic within several hours. CONCLUSIONS: All but three drugs are available at present; the remaining ones will be imported after new batches of these drugs are released. PMID- 25702290 TI - [Thyroid dysfunction during interferon alpha therapy for chronic hepatitis B and C - twenty years of experience]. AB - OBJECTIVE: To determine the incidence of thyroid dysfunction in patients with chronic hepatitis B and C (HBV, HCV) who were treated with interferon (IFN) alpha. PATIENTS AND METHODS: In the years 1992-2013, parameters of the thyroid gland were evaluated in 304 patients (256 with HCV, 48 with HBV) who were treated with conventional or pegylated IFN at the Department of Infectious Diseases in Ostrava. Prior to, during and after completion of antiviral treatment, levels of thyroid stimulating hormone (TSH), thyroxine (T4), triiodothyronine (T3), including their free fractions fT4 and fT3, and anti-thyroid antibodies (anti thyroglobulin, anti-microsomal fraction) were determined and clinical manifestations of thyroid dysfunction were evaluated. RESULTS: TSH changes were detected in 75 patients (25 %), of whom 68 had HCV and 7 HBV. Hypothyroidism was detected in 39 patients (34 with HCV), of whom 25 required substitute therapy which was subsequently terminated in 5 patients. Hyperthyroidism with transient suppressive therapy with carbimazole developed in 4 HCV patients. In 32 patients, TSH changes were assessed as subclinical hypothyroidism. Abnormal T3 values were found in 188 (62 %) and T4 in 49 (16 %) patients; these changes practically did not correlate with TSH changes. Autoantibodies were detected in 54 (18 %) patients of whom 30 were also found to have changes in TSH. CONCLUSIONS: In a group of 304 patients treated with IFN alpha for chronic hepatitis, thyroid disease with changes in TSH were observed in a quarter of patients; hypothyroidism clearly prevailed. Thyroid diseases developed in half of the patients with the presence of antithyroid antantibodies. PMID- 25702291 TI - [Corynebacterium imitans isolated from blood culture in a patient with suspected bacteremia - the first isolation from human clinical material in the Czech Republic]. AB - The current view of the clinical importance of nondiphtherial corynebacteria recovered from human clinical material has changed considerably in recent decades; in many cases, a direct etiological role is assumed or has already been demonstrated. Presented is a case of suspected bacteremia in a hospitalized elderly woman with isolation of the very rare species Corynebacterium imitans from blood culture. However, the etiological significance of the isolated microorganism remains unclear. The aim was not to demonstrate the etiological significance of the isolated C. imitans strain but to report the occurrence of this very rare species which is considered to be the first isolation from humans in the Czech Republic. PMID- 25702292 TI - Irritable bowel syndrome may be induced by decreased neuroplasticity. AB - Neuroplasticity is the nervous system's ability to respond to intrinsic or extrinsic stimuli by reorganizing its structure, function and connections. And the nervous system monitors and coordinates internal organ function. Thus neuroplasticity may also be associated with the pathogenesis of other diseases besides neuropsychiatric diseases, such as cardiovascular disease. The digestive system is controlled by the nervous system, mainly by the autonomic nervous system. Stress may lead to depression/anxiety and irritable bowel syndrome (IBS). IBS is commonly comorbid with depression/anxiety, which are disorders of decreased neuroplasticity. And the mechanisms of depression/anxiety and IBS are related. The hypothalamo-pituitary-adrenal axis, hippocampus, amygdala and stress related factors and hormones, such as corticotropin-releasing factor, glucocorticoids and brain-derived neurotrophic factor are involved in both neuroplasticity and the pathogenesis of depression/anxiety and IBS. So we conclude that decreased neuroplasticity causes the comorbidity of depression/anxiety and IBS, and increased neuroplasticity may be beneficial against the development of IBS. This theory provides another angle that can explain some of the reported phenomena related to IBS and neuropsychiatry, and provide a potential treatment to protect against IBS. PMID- 25702293 TI - Role of astrocytes in pathogenesis of multiple sclerosis and their participation in regulation of cerebral circulation. AB - There is about 30% higher risk of the myocardial infarction in patients diagnosed with multiple sclerosis (MS) than in people without MS. Increased risk of cardiovascular disease development positively correlates with levels of serum markers of an endothelial dysfunction, and may give rise to a global cerebral hypoperfusion. It appears that these complications precede progressive loss of axons, which mechanisms are complex and should be linked to a loss of beta2 adrenergic receptors on astrocytes of demyelinating lesions. Consequence of this deficiency, the cause of which is not known yet, is a decline in energy metabolism of axons. Moreover, the loss of these receptors is linked to a reduced redistribution of potassium ions by astrocytes, glutamate excitotoxicity and increase of calcium ion concentration in the axon with subsequent activation of necrotic processes. In addition to immunological aspects we should take into account also parameters of the functional state of endothelium when appropriate targeted therapy for patient is considered. PMID- 25702294 TI - Sigmoidal polyp with adenocarcinoma discovered by transvaginal three-dimensional ultrasonographic virtual colonoscopy. AB - Adenocarcinoma of the colon represents the third most frequent cause of death from cancer, being surpassed only by lung and stomach cancer. Early screening and diagnosis of polyps are important for a good prognosis. Based on a clinical case, a novel approach is presented for screening of sigmoidal polyps and neoplasia using transvaginal 2D, 3D mode in women. This novel and simple technique can be used to visualize the sigmoid diverticula during routine gynecological examination via 3D transvaginal ultrasound probe. PMID- 25702295 TI - Quality of life in transition phase in adolescents and young adults with severe and partial growth hormone deficiency. AB - BACKGROUND: Transition is a term used to describe the period of adolescence after which the final adult height during growth hormone (GH) treatment is achieved. According to re-evaluation results in insulin tolerance test (ITT) patients with severe and partial growth hormone deficiency (GHD) may be distinguished. OBJECTIVES: The aim of the study was to assess QoL in patients with different degrees of GHD in transition phase. METHODS: QoL was evaluated in 76 subjects aged 16-25 years with severe (SGHD, n=26), partial GHD (PGHD, n=22) and normal GH secretion (NGH, n=28) using SF-36 v.2TM Health Survey and the Quality of Life Assessment of Growth Hormone Deficiency in Adults (QoL-AGHDA) questionnaires. RESULTS: Physical Component Score (PCS), Physical Functioning (PF) and General Health (GH) results were significantly lower in patients with SGHD than in NGH group. SF-36 v.2TM Health Survey scores in PGHD were similar as in NGH patients. There were no statistically significant differences in QoL-AGHDA scores between the examined groups. We found positive correlations between peak GH in ITT and PF (r=0.29; p=0.02) or Role Emotional (r=0.37; p=0.002) scores. CONCLUSIONS: We demonstrated that the QoL in adolescents and young adults with severe GHD in transition period is disturbed mainly in terms of physical health and emotions. These changes were detected only by generic SF-36, but not by disease-specific QoL-AGHDA questionnaire. Therefore AGHDA-QoL assessment may not be applicable in GHD patients in transition period. QoL in the patients with partial GHD is unchanged in comparison to growth hormone sufficient subjects. PMID- 25702296 TI - Levothyroxine replacement therapy with vitamin E supplementation prevents the oxidative stress and apoptosis in hippocampus of hypothyroid rats. AB - OBJECTIVE: To examine the effect of levothyroxine (L-T4), vitamin E or both on oxidative stress status and hippocampal apoptosis in a propylthiouracil (PTU) induced hypothyroid rat model. METHODS: Sprague-Dawley rats were randomly divided into five groups: Control, PTU+PTU+L-T4+PTU+Vit E, PTU+Vit E+L-T4. In each group we assessed levels of serum triiodothyronine (T3), tetraiodothyronine (T4), thyroid stimulating hormone (TSH), hippocampus cellular apoptosis index (AI), hippocampus nicotinamide adenine denucleotide hydrogen (NADPH)oxidase and superoxide dismutase (SOD). RESULTS: 1) Compared with the control group, NADPH oxidase levels were significantly increased, and SOD levels were significantly reduced in the PTU groups (p<0.05). 2) Compared to the PTU group, SOD levels were significantly increased in the PTU+Vit E and PTU+L-T4+Vit E group (p<0.05). NADPH oxidase levels were significantly decreased in the PTU+L-T4, PTU+Vit E and PTU+ L T4+Vit E group (p<0.05). 3) Compared with the control group, hippocampus AI increased significantly in the PTU group (p<0.05). Compared with the PTU group, hippocampus AI was significantly reduced in the PTU+L-T4 group and PTU+L-T4+Vit E group (p<0.05). 4) Hippocampus AI was positively correlated with NADPH oxidase expression levels in hippocampus tissue (r=0.644, p<0.01). CONCLUSION: Levothyroxine replacement therapy combined with vitamin E reduces hippocampus AI by improving oxidative stress. This study suggested that the mechanisms of hippocampus tissue injury in a hypothyroid rat model is related to hippocampus apoptosis from increased oxidative stress. PMID- 25702297 TI - Diabetes, hypertension and stroke - does Alzheimer protect you? AB - OBJECTIVE: The aim of our current research project is to further evaluate the role of risk factors in the pathogenesis of Alzheimer's disease; these include genetic variations, environmental factors and lifestyle issues. METHODS: We have been conducting an association study on 373 patients with Alzheimer's disease and 286 unrelated control individuals. The occurrence and the age of onset of diabetes and cardiovascular diseases were evaluated in both groups. Apolipoprotein E genotype was analyzed in all subjects by PCR method. RESULTS: We report that, in Czech population carrying ApoE4 allele increases risk of Alzheimer's disease 2.1-fold and genotype E4E4 increases the risk 8.4-fold. We have also identified a significant association between ApoE4 allele, Alzheimer's disease and hypertension. Hypertensive subjects with the ApoE4 allele have 1.5 fold greater risk of Alzheimer's disease. Thus, hypertension together with ApoE4 allele translates into 1.5-fold higher risk of AD. The most intriguing original finding in the present study is that Alzheimer's disease patients have significantly later onset of diabetes, hypertension and stroke in comparison with control subjects. This effect was not influenced by ApoE genotype. The diabetes appeared in AD patients on average more than 10 years later than in the control subjects (p<0.0001), hypertension was diagnosed 14 years later in AD patients (p<0.00001) and stroke occurred on average 6 years later (p<0.005), compared to the control group. CONCLUSIONS: Overall, in addition to the above novel findings, our study expands the data base on risk factors that could be used in near future when testing for the genetic risk of Alzheimer's disease. PMID- 25702298 TI - White matter abnormalities in medication-naive adult patients with major depressive disorder: tract-based spatial statistical analysis. AB - OBJECTIVE: While increasing evidence suggests that major depressive disorder (MDD) is coincident with the altered white matter microstructure in many brain regions including the prefrontal cortex, parietal lobe, ventral tegmental area and limbic system, it remains controversial in the nature of white matter structural changes and in its relationship with depression syndrome. We believe that the age of patients and the antidepressant treatment to them would contribute to that controversy. Here in this study we explored the microstructural changes of the entire brain white matter of the adult patients with first-episode, antidepressant drug-naive MDD. DESIGN: We performed the diffusion tensor imaging (DTI) among a relatively large sample size of patients and age-matched control individuals (forty-one MDD patients and forty-one control subjects) and used recently developed tract-based spatial statistics to analyze the difference of mean fractional anisotropy (FA) between patients and control individuals. RESULTS: We surprisingly found that MDD patients exhibited a significantly greater mean FA, which is used to elucidate the structural organization of the neural fibers, than control subjects in the whiter matter of the left superior longitufinal fasciculus. However, this change in the white matter of MDD patient did not correlate with depressive clinical features (HMAD, illness duration and initial age) in the present study. CONCLUSION: Our data suggest that a potential compensatory regeneration of nerve fibers occurs in the early course of MDD development. Advanced understanding of the potential nerve fiber regeneration in the early course of MDD and its associated mechanisms will possibly shade light on a better strategy for MDD prevention and treatment. PMID- 25702299 TI - Anxiogenic effects of chronic exposure to nandrolone decanoate (ND) at supraphysiological dose in rats: a brief report. AB - OBJECTIVE: Nandrolone decanoate (ND) is frequently used anabolic androgenic steroid (AAS) among the athletes. Despite the health risks, there is significant increase in prevalence of AAS abuse. DESIGN: The aim of this study was to investigate the effects of chronic exposure to ND at supraphysiological dose (to mimic the doses for human AAS abusers) on anxiety levels in adult rats. SETTINGS: We performed several behavioral tests (open field test, elevated plus maze test, beam-walking test, evoked beam-walking test and tail suspension test) for estimation of anxiety in rats. Adult rats received 20 mg/kg intraperitoneal injection of ND weekly for four weeks. Behavioral test were performed on the seventh day after the last dose of ND. RESULTS: Anxiogenic-like pattern of behavior was clearly observed in several behavioral tests, such as open field test (decrease of total distance moved and cumulative duration of moving, decrease of an average velocity of the animals, decrease of frequency and total time in centre zone); elevated plus maze (decreased total time spent in open arms and the number of entries in open arms of the elevated plus maze); evoked beam walking test (decreased time to cross the beam) and tail suspension test (increased latency to first immobility and decreased total duration of immobility). MAIN FINDINGS: Results of this study show that four-week treatment with the supraphysiological dose of ND produced anxiogenic effects in sedentary male rats. CONCLUSION: Our results show that rats after chronic treatment with a supraphysiological dose of ND exhibited anxiety-like behavior. PMID- 25702300 TI - Relationship between internalized stigma and treatment efficacy in mixed neurotic spectrum and depressive disorders. AB - OBJECTIVE: Many psychiatric patients suffer from self-stigma. One consequence of these internalized prejudices is decreased treatment efficacy. Much has been written about the effects of self-stigma in patients with severe mental disorders. However, individuals with minor psychiatric disorders also suffer from self-stigma. It is therefore necessary to explore the effect of self-stigma on treatment efficacy of neurotic patients. METHOD: Aim of out study was to investigate relationship between self-stigma, severity of symptoms, and presence of comorbidit disorder and treatment outcome in neurotic patients. Patients were treated by combined psycho and pharmacotherapy. Level of self-stigma was measured by Internalized Stigma Of Mental Illness scale. Severity of anxiety and depressive symptoms was assed by Beck Anxiety Inventory, Beck Depressive Inventory and Clinical Global Impression Scale. RESULTS: Level of self-stigma was significantly correlated with the levels of anxiety, depression and global evalutions of a mental state on the beginnig of the therapy. Up to our results patients with higher level of self-stigmatization had lower improvement after combined treatmet in respect to perceived anxiety symptoms. CONCLUSION: Self stigma seems to be an important factor influencing efficacy of combined treatment. More researches focused on self-stigmatization should be done to find an optimal therapeutic strategy for patients with higher level of self stigmatization. PMID- 25702301 TI - Birth after a previous cesarean section - what is most important in making a decision? AB - OBJECTIVE: A retrospective analysis of the course of labour in patients after one caesarean section (CS) and of factors influencing successful attempt of vaginal birth after caesarean (VBAC). DESIGN: A group of 296 patients after one CS was divided into: group G1 (206 patients) - elective CS, group G2 (90) - VBAC attempt, and G2 to: G2a (35) - VBAC and G2b (55) - CS after an unsuccessful VB attempt. A comparative analysis between the groups and logistic regression analysis of factors influencing a successful VBAC was made. RESULTS: There were no differences regarding age, BMI, weight gain during pregnancy or gestational age between groups G1 and G2, as well as G2a and G2b. G2a patients had more often already given VB previously (28.6% vs 10.9%; p=0.03). The most frequent indication for a repeat elective CS was the lack of informed consent for VBAC (29.13% of all indications). The mean neonatal birthweight was highest in G1 (3 410 g), and in G2b higher than in G2a (3 275 g vs 3 098 g; p=0.009). There were no differences in newborns' general condition between the group. There were no cases of uterine rupture and 4 cases of uterine scar dehiscence in G1 and 1 in G2. Of all the analysed factors only spontaneous delivery onset (OR 7.78) and previous vaginal birth after the caesarean (OR 1.99) or before the caesarean (OR 2.03) had significant influence on successful VBAC trial. CONCLUSION: The right classification of patients is a significant factor having effect on the success of a VB attempt after CS. PMID- 25702302 TI - Effects of 17beta-estradiol and IGF-1 on L-type voltage-activated and stretch activated calcium currents in cultured rat cortical neurons. AB - INTRODUCTION: Calcium transport pathways are key factors for understanding how changes in the cytoplasmic calcium concentration are associated with neuroprotection because calcium is involved in the onset of death signaling in neurons. OBJECTIVES: This study characterized the effects of 17beta-estradiol and IGF-1 on voltage-activated and stretch-activated calcium channels in rat cultured cortical neurons. METHODS: The whole-cell patch-clamp technique, using a voltage steps protocol or by applying positive pressure into the micropipette, was used on 7-10 day cultured neurons from a Wistar rat cortex, and pharmacological characterization was performed on these neurons. RESULTS: Both 17beta-estradiol and IGF-1 inhibited the currents mediated by L-type voltage-activated calcium channels, although the IGF-1 effects were lower than those of 17beta-estradiol. The effect of both hormones together was greater than the sum of the effects of the individual agents. Unlike IGF-1, 17beta-estradiol decreased the current mediated by stretch-activated channels. The inhibition of the classical receptors of these hormones did not affect the results. CONCLUSION: Both hormones regulate voltage-activated calcium channels in a synergistic way, but only 17beta estradiol has an inhibitory effect on stretch-activated calcium channels. These effects are not mediated by classical receptors and may be relevant to the neuroprotective effects of both hormones because they diminish calcium entry into the neuron and decrease the possibility for the onset of apoptotic signaling. PMID- 25702303 TI - Shoulder dystocia in diabetic and non-diabetic pregnancies. AB - OBJECTIVES: Shoulder dystocia remains an obstetric emergency. Maternal diabetes is considered to be one of the major risk factors for shoulder dystocia. The aim of this study was to analyze antepartum and peripartum risk factors and complications of shoulder dystocia in diabetic and non-diabetic women. DESIGN: We performed a retrospective analysis of 48 shoulder dystocia cases out of 28,485 vaginal deliveries of singleton, live-born infants over a 13 year period: 13 cases were diagnosed in diabetic women and 35 cases in non-diabetic women. SETTING: The study was conducted in the 2nd Department of Obstetrics and Gynecology, Medical University of Warsaw, Poland, from January 2000 to December 2012. RESULTS: Compared to non-diabetic women, diabetic patients had significantly higher pre-pregnancy body weight (83.4+/-23.8 kg vs. 62.5+/-10.9 kg, p=0.002), higher pre-pregnancy BMI (30.2+/-6.8 kg/m2 vs. 22.9+/-4.3 kg/m2, p=0.0003), and lower gestational weight gain (11.4+/-6.2 kg vs. 16.0+/-4.7 kg, p=0.01). Diabetic women with shoulder dystocia were more likely to deliver before completion of the 38th week of gestation (30.8% vs. 5.7%, p=0.02) and had a higher incidence of 1st and 2nd stage perineal tears compared with the non diabetic group (23.1% vs. 0%, p=0.02). There were two cases of symphysis pubis dehiscence in non-diabetic women. Children of diabetic mothers had a significantly higher birth weight (4,425.4+/-561.6 g vs. 4,006.9+/-452.8 g, p=0.03). Children of diabetic mothers with dystocia were at significantly higher risk of peripartum injuries (92.3% vs. 45.7%). A significant difference was observed in the percentage of brachial plexus palsy (61.5% vs. 17.1%). Children of diabetic women experiencing shoulder dystocia were more frequently affected by Erb's brachial plexus palsy and respiratory disturbances. These children had an increased likelihood of birth weights above the 90th percentile (not necessarily reaching 4,000 g) compared to children born to non-diabetic mothers. CONCLUSIONS: Shoulder dystocia in women with diabetes mellitus during pregnancy was associated with earlier gestational age of labor, and these women were more frequently overweight. The newborns of diabetic mothers after shoulder dystocia appeared to be at an increased risk for perinatal morbidity compared to the newborns of non diabetic mothers experiencing this complication. PMID- 25702304 TI - Zinc in drug-naive patients with short-illness-duration first episode major depressive disorder: impact on psychopathological features. AB - OBJECTIVE: In major depressive disorder (MDD) hypozincaemia associated with symptoms severity, melancholia, anxiety and treatment-resistance is reported. Data linking zinc with specific psychopathological dimensions is limited. METHODS: Plasma zinc was analyzed in this cross-sectional case-control study on 20 non-late-life adult, treatment-naive MDD patients with short-illness-duration first affective episode and 20 matched healthy controls together with psychometric evaluations including Hamilton Rating Scale for Depression (HAMD-17) and Spielberger State-Trait Anxiety Inventory (STAI). RESULTS: No significant difference in zinc levels was found between MDD subjects and controls. No significant correlations were observed between zinc concentration and the total HAMD-17 score as well as with the specific core depression, insomnia, anxiety and somatic psychopathological dimensions or STAIX-1 and STAIX-2 scores. CONCLUSION: The study provides evidence for unchanged plasma zinc concentration at early stage of MDD and failed to demonstrate any correlation between plasma zinc and psychopathological features including severity of symptoms and specific psychopathological dimensions in MDD. PMID- 25702305 TI - Salivary 5-hydroxyindole acetic acid (5-HIAA) in drug-naive patients with short illness-duration first episode major depressive disorder. AB - OBJECTIVES: Central serotonergic dysfunction is reported in major depressive disorder (MDD). Serotonin is primarily metabolized to 5-hydroxyindole acetic acid (5-HIAA) and its plasma, urinary or cerebrospinal fluid concentrations were extensively studied in depression. No data is available on salivary 5-HIAA (s5 HIAA) in MDD to date. METHODS: The basal, non-stimulated s5-HIAA concentration was studied in this cross-sectional case-control study on 20 non-late-life adult, short-illness-duration first-episode, treatment-naive MDD patients and in 20 age- and sex-matched healthy controls. Depressed patients showed a score in the Hamilton Rating Scale for Depression (HAMD-17) higher than 20. RESULTS: No significant difference in s5-HIAA concentration between patients with MDD and controls was observed. In post hoc analysis significantly lower s5-HIAA was seen in non-melancholic MDD (p=0.026) as related to controls whereas no difference was seen between melancholic MDD patients and controls. The concentration of s5-HIAA was not significantly correlated neither with duration nor the severity of depressive symptoms as measured by the total HAMD-17 score. CONCLUSION: No difference was observed in baseline s5-HIAA concentration between MDD patients and healthy controls. That observation corroborates with previous MDD studies on 5-HIAA concentrations in bodily fluids where unaltered 5-HIAA concentration is seen in the absence of serotonin-related behaviours including impulsivity, suicidality, and anxiety. Salivary 5-HIAA use remains to be determined. PMID- 25702306 TI - Migration of a Kirschner Wire to the Pulmonary Parenchyma. PMID- 25702307 TI - Giant Franz Tumour. PMID- 25702308 TI - [Duodenal perforations after endoscopic retrograde cholangiopancreatography]. AB - INTRODUCTION: Duodenal perforations after endoscopic retrograde cholangiopancreatography (ERCP) are an uncommon complication. The management of this kind of perforation is controversial. The aim of this study was to analyze the results of the management of a series of 15 patients who were diagnosed with this complication. METHODS: Retrospective study of duodenal perforations after ERCP diagnosed at a tertiary level hospital, between 2001 and 2011. The variables age, sex, ERCP indication, type of perforation, time of diagnosis, clinical presentation, radiographic findings, management, surgical technique, length of stay and intrahospital mortality were recorded and analyzed. RESULTS: Out of a total of 1923 ERCP performed, 15 duodenal perforations were detected (0,78%). Perforation site was the duodenal wall (3 cases) and periampullary (12 cases). Eleven perforations were suspected during the procedure. Patients with duodenal wall perforations underwent immediate surgery. Seven of 12 periampullary perforations were managed conservatively with a favorable outcome in 5 of them. Subsequent scheduled surgery was performed in 4 cases. The mean length of hospital stay was 21,2 days (range: 3-49) and intra-hospital mortality was 20%. CONCLUSIONS: Perforations after ERCP have high mortality rates, and require a complicated therapeutic approach that needs to be individualized. Selective conservative management is a valid and safe option in selected patients. PMID- 25702309 TI - Anal squamous cell carcinoma in chronic severe perianal Crohn's disease. PMID- 25702310 TI - Phytobezoar Causing Intestinal Obstruction in a Patient With a Prior Right Colectomy. PMID- 25702311 TI - Primary retroperitoneal mucinous cystadenoma. PMID- 25702314 TI - Stenting versus surgery for significant left main disease. AB - For decades, coronary artery bypass grafting (CABG) has been the choice of revascularization strategy for significant left main coronary artery (LMCA) disease. However, with marked technological advances in less invasive percutaneous strategies, such as drug-eluting stents, and potent adjunctive pharmacology, percutaneous coronary intervention (PCI) has been increasingly accepted as an alternative to CABG for selected cases with LMCA disease. The available evidence from randomized clinical trials and adequately sized, real world registries suggest that hard clinical endpoints (death, myocardial infarction, or stroke) were comparable between two treatment strategies at short- and mid-term follow-up, while higher rate of repeat revascularization are observed after PCI. Current guidelines state that PCI for LMCA disease is reasonable in patients with low to intermediate anatomic complexity and those who are at increased surgical risk. Ongoing large-sized clinical trials comparing newer-generation drug-eluting stents and CABG would provide important clinical insights to guide optimal strategy for patients with significant LMCA disease in the (near) future. PMID- 25702313 TI - Advanced imaging of cardiac sarcoidosis. AB - Sarcoidosis with cardiac involvement is underdiagnosed and can put patients at risk of morbidity including conduction defects, arrhythmias and heart failure, as well as sudden cardiac death. In addition, cardiac sarcoidosis may have no clinical manifestations or non-specific presentation and diagnosis may be difficult on clinical criteria. Investigation for cardiac sarcoidosis should be considered in those with extra-cardiac sarcoidosis and cardiac findings as well as those under the age of 60 years presenting with atrioventricular block without a clear cause. Advanced imaging modalities including cardiac magnetic resonance and positron emission tomography may help in both the diagnosis and assessment of response to treatment for cardiac sarcoidosis. This ultimately may help to minimize associated adverse outcomes from this enigmatic disease. PMID- 25702315 TI - Description of Thalassospira lohafexi sp. nov., isolated from Southern Ocean, Antarctica. AB - A gram-negative, aerobic, obligatory halophilic, curved-to-spiral rod-shaped, uni or bi-polar flagellated motile bacterium 139Z-12(T) was isolated from water samples collected from Southern Ocean surrounding Antarctica as part of the Indo German iron fertilization experiment "LOHAFEX." The bacterium was positive for catalase, oxidase, and gelatinase, with C18:1omega7c (20.1 %), C16:0 (7.3 %), C16:1omega7c (28.9 %), and C12:0 (19.0 %) as the predominant fatty acids, phosphatidylglycerol, and phosphatidylethanolamine as major lipids and Q-10 as the major respiratory quinone. DNA G + C content (mol%) of strain 139Z-12(T) was 53.0. Both BLAST and EzTaxon identified strain 139Z-12(T) as affiliated species of the genus Thalassospira with 16S rRNA gene sequence similarities ranging from 97.9 to 99.9 %. Based on above characteristics, strain 139Z-12(T) was assigned to the genus Thalassospira. Since strain 139Z-12(T) shared a DNA-DNA similarity of <70.0 % with members of the genus Thalassospira, 139Z-12(T) was identified as a novel species of the genus and named as Thalassospira lohafexi sp. nov. In addition to this, strain 139Z-12(T), based on REP-PCR, delineated at a similarity coefficient of <0.67 from other species of the genus Thalassospira and also exhibited a MLSA distance of <95.5 %, a value less than the interspecies distance determined previously for the genus Thalassospira, further supporting the species status. In addition, species rank was further confirmed by other polyphasic characteristics. The type strain of Thalassospira lohafexi sp. nov. is 139Z-12(T) (KCTC 32347(T) = LMG 27449(T) = MCC 2233(T) = NBRC 110402(T)). PMID- 25702312 TI - Transcription factors and target genes of pre-TCR signaling. AB - Almost 30 years ago pioneering work by the laboratories of Harald von Boehmer and Susumo Tonegawa provided the first indications that developing thymocytes could assemble a functional TCRbeta chain-containing receptor complex, the pre-TCR, before TCRalpha expression. The discovery and study of the pre-TCR complex revealed paradigms of signaling pathways in control of cell survival and proliferation, and culminated in the recognition of the multifunctional nature of this receptor. As a receptor integrated in a dynamic developmental process, the pre-TCR must be viewed not only in the light of the biological outcomes it promotes, but also in context with those molecular processes that drive its expression in thymocytes. This review article focuses on transcription factors and target genes activated by the pre-TCR to drive its different outcomes. PMID- 25702316 TI - Rheinheimera japonica sp. nov., a novel bacterium with antimicrobial activity from seashore sediments of the Sea of Japan. AB - Two gram-negative, aerobic, brown-pigmented, motile rod-shaped bacteria KMM 9512 and KMM 9513(T) were isolated from a sediment sample collected from the Sea of Japan seashore, Russia. On the basis of the 16S rRNA gene sequence analysis, novel strains KMM 9512 and KMM 9513(T) positioned within the genus Rheinheimera (class Gammaproteobacteria) as a separate subline adjacent to Rheinheimera baltica DSM 14885(T) sharing highest gene sequence similarities of 98.6-97.6 % to their closest phylogenetic relatives, Rheinheimera muenzenbergensis LMG 27269(T), R. baltica DSM 14885(T), Rheinheimera aquimaris JCM 14331(T), Rheinheimera nanhaiensis KACC 14030(T), and Rheinheimera pacifica KMM 1406(T). Strains KMM 9512 and KMM 9513(T) belong to the same separate genospecies on the basis of the 16S rRNA gene sequence similarity (99.8 %) and their DNA relatedness to each other (89 %) and to closely related Rheinheimera species (25-53 %). The major isoprenoid quinone was Q-8, polar lipids consisted of phosphatidylserine, phosphatidylglycerol, phosphatidylethanolamine, unknown aminolipids, unknown aminophospholipids, unknown phospholipids, and unknown lipids, and major fatty acid were C16:0, C16:1 omega7c, C17:1 omega8c, C12:0 3-OH followed by C17:0 and C18:1 omega7c in both strains. Strains KMM 9512 and KMM 9513(T) revealed a remarkable antagonistic activity toward a number of gram-positive and gram negative microorganisms. On the basis of phylogenetic analysis, DNA-DNA hybridization results, and phenotypic differences, strains KMM 9512 and KMM 9513(T) are proposed to be classified as a novel species of the genus Rheinheimera, Rheinheimera japonica sp. nov. The type strain of this species is KMM 9513(T) = NRIC 0918(T). PMID- 25702317 TI - Accuracy and workflow of navigated spinal instrumentation with the mobile AIRO((r)) CT scanner. AB - PURPOSE: Current solutions for navigated spine surgery remain hampered by restrictions in surgical workflow as well as a limited versatility and applicability. Against this background, we report the first experience of navigated spinal instrumentation with the mobile AIRO((r)) intraoperative computed tomography (iCT) scanner. METHODS: AIRO((r)) iCT was used for navigated posterior spinal instrumentation of 170 screws in 23 consecutive patients operated on in our Department between the first use of the system in May 2014 and August 2014. The indications for AIRO((r)) were based on the surgical region, anatomical complexity and the need for >3 segment instrumentation. Following navigated screw insertion, screw positions were confirmed intraoperatively by a second iCT scan. CT data on screw placement accuracy were retrospectively reviewed and analyzed by an independent observer. RESULTS: AIRO((r))-based spinal navigation was easy to implement and successfully accomplished in all patients, adding around 18-34 min to the net surgery time. A systematic description of the authors' approach, setup in the OR and workflow integration of the AIRO((r)) is presented. Analysis of screw placement accuracy revealed 9 (5.3%) screws with minor pedicle breaches (<2 mm). A total of 7 screws (4.1%) were misplaced >2 mm, resulting in an accuracy rate of 95.9%. CONCLUSIONS: The AIRO((r)) system is an easy-to-use and versatile iCT for navigated spinal instrumentation and provides high pedicle screw accuracy rates. Although the authors' experience suggests that the learning curve associated with AIRO((r))-based spinal navigation is steep, a systematic user-based approach to the technology is required. PMID- 25702318 TI - The effect of infliximab on depressive symptoms in patients with ankylosing spondylitis. AB -

OBJECTIVES: Ankylosing spondylitis is a chronic inflammatory disease which physically, psychologically, and socially affects the patient's life. Previous studies have reported a correlation between ankylosing spondylitis and depression. In this study we investigated the effect of infliximab on depression in ankylosing spondylitis patients. METHODS: A total of 29 patients with ankylosing spondylitis were enrolled in this prospective study. Infliximab was administered intravenously at a dose of 5 mg/kg at baseline, weeks 2 and 6. The measurements of morning stiffness, modified Schober's test, chest expansion, erythrocyte sedimentation rate, C-reactive protein, Bath ankylosing spondylitis disease activity index, Bath ankylosing spondylitis functional index and Beck depression inventory scores were compared with baseline and 12th week. RESULTS: The modified Schober's test and chest expansion increased, the morning stiffness duration, erythrocyte sedimentation rate and C-reactive protein levels decreased after infliximab treatment (p < 0.001, respectively). There was statistically significant decrease in Bath ankylosing spondylitis disease activity index, Bath ankylosing spondylitis functional index and Beck depression invantory scores of patients after 12 weeks (p < 0.001, respectively). CONCLUSION: Infliximab can improve depression and its symptoms in patients with ankylosing spondylitis.

. PMID- 25702319 TI - Cone the valve be repaired? PMID- 25702320 TI - Characterization of ventricular assist device-mediated sensitization in the bridge-to-heart-transplantation patient. AB - OBJECTIVE: Ventricular assist devices (VADs) are associated with increased anti human leukocyte antigen antibody production. The purpose of this study is to characterize differences in sensitization patterns in patients receiving axial flow, implantable VADs versus pulsatile, paracorporeal biventricular assist devices (BIVADs) as bridges to transplantation. METHODS: The study is a retrospective review of 68 patients who were bridged to transplantation with either a VAD or a BIVAD, as described, from January 2007 to June 2010, at a university medical center. RESULTS: Five of 15 (33.3%) VAD patients became sensitized during treatment, compared with 30 of 53 (56.6%) BIVAD patients, P = .15. Multivariable analysis comparing BIVAD with VAD, while controlling for previous cardiac surgery, pregnancy, and packed red blood cell transfusion produced an odds ratio of 2.99, P = .14. Of sensitized patients, all 5 (100%) of the VAD patients had pre-existing antibodies before VAD placement, compared with 9 of 30 (30.0%) BIVAD patients, P = .006. Maximum cumulative mean fluorescence intensities for BIVAD were 46,259 +/- 66,349 versus 42,540 +/- 12,840 for VAD, P = .90. Time to maximum antibody expression was shorter for the VAD group (34 +/- 28 days vs 5.8 +/- 9 days, P = .04). CONCLUSIONS: Device type was not a factor in patient sensitization after implantation. However, VAD patients required pre existing sensitization before implantation to produce antibodies during their treatment interval, whereas more than two thirds of BIVAD patients developed de novo antibodies. These data suggest that the mechanism of sensitization between VAD and BIVAD patients may differ, and further mechanistic studies into the impact of device types on patient sensitization are warranted. PMID- 25702321 TI - TGA/VSD/LVOTO: Evolution of surgical therapy. PMID- 25702322 TI - Down to the wire: acquiring endovascular skills in cardiac surgery. PMID- 25702323 TI - Cone reconstruction for Ebstein's anomaly: Patient outcomes, biventricular function, and cardiopulmonary exercise capacity. AB - OBJECTIVE: Cone reconstruction is advocated to treat severe tricuspid valve (TV) regurgitation associated with Ebstein's anomaly. Data on postoperative clinical status, ventricular adaptation, and objective cardiopulmonary testing are lacking in these patients. METHODS: The clinical characteristics, echocardiography, magnetic resonance imaging, and exercise data from 27 consecutive cone reconstructions, undertaken from 2009 to 2013, were retrospectively compared between preoperative baseline and follow-up. RESULTS: There were no deaths. The cone TV functioned well in all but 1 patient with late dehiscence of inferior annuloplasty sutures that were subsequently repaired. Four patients required pacemaker insertion (3 for new complete heart block). At median follow-up of 2.7 +/- 1.5 years, tricuspid regurgitation was reduced in all patients, without causing stenosis. Global left ventricle function remained unchanged (pre operative fraction 60% +/- 4% vs postoperative fraction 61% +/- 3%; P = .96). MRI showed enhanced forward pulmonary flow (pre 26 +/- 1 mL/beat vs post 36 +/- 10 mL/beat; P < .005) and increased left ventricle filling (body surface area indexed left ventricle end-diastolic volume pre 49 +/- 14 mL/m(2) vs post 60 +/- 14 mL/m(2); P < .005). New York Heart Association functional class improved (pre 2.5 +/- 0.6 vs post 1.3 +/- 0.6; P < .0001) and there was significant improvement in peak oxygen uptake (pre 54% +/- 18% vs post 66% +/- 22%; P = .02). CONCLUSIONS: Cone reconstruction of TV offers an effective repair in patients with severe regurgitation associated with Ebstein's anomaly. The patients' clinical status improved with better left ventricle filling and objective exercise capacity. The durability of repair, and mechanisms by which the ventricles adapt to the new loading conditions, need longer-term study. PMID- 25702324 TI - Incidence and risk factors of postpericardiotomy syndrome requiring medical attention: The Finland postpericardiotomy syndrome study. AB - OBJECTIVES: Postpericardiotomy syndrome is a well-known complication after cardiac surgery. Nevertheless, little is known about the incidence and predictors of postpericardiotomy syndrome requiring medical attention or hospitalization in a contemporary set of patients undergoing isolated coronary bypass. METHODS: This retrospective analysis included 688 patients from 2008 to 2010. The median follow up time was 5.3 [4.5-6.0] years. RESULTS: The incidence of postpericardiotomy syndrome was 61 of 688 patients (8.9%), and the median time to diagnosis was 21 [11-52] days, but only 13 patients (22%) required pleural drainage and 3 patients (4.9%) required pericardiocentesis. Patients with postpericardiotomy syndrome more often had 1 or more red blood cell units transfused (61% vs 43%, P = .008) after surgery and less often had diabetes (12% vs 31% P = .002) or metformin medication (3.3% vs 20%, P = .001) compared with those without postpericardiotomy syndrome. In multivariable Cox regression model, renal insufficiency and 1 or more red blood cell units transfused remained as independent predictors of postpericardiotomy syndrome and diabetes remained as a protective factor. Incidence of recurrences was high (38%), and increasing body mass index was the only predictor of relapse. CONCLUSIONS: The incidence of symptomatic postpericardiotomy syndrome leading to medical care contact was markedly lower compared with that reported in older clinical studies. Postpericardiotomy syndrome was associated with the use of red blood cell units and was less common in patients with medically treated diabetes. PMID- 25702325 TI - No guts, no glory: Visceral ischemia and acute type B aortic dissections. PMID- 25702327 TI - [Restoration and incision on the sternum--a little innovation]. PMID- 25702326 TI - Co-expression of PD-1 and PD-L1 predicts poor outcome in nasopharyngeal carcinoma. AB - Tumor immune evasion is a hallmark of cancer. The programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) pathway has been suggested to play an important role in T cell tolerance and tumor immune escape. In this study, we aimed to evaluate the correlation between the expression of PD-1/PD-L1 and the post-treatment outcome in patients with nasopharyngeal carcinoma (NPC). Formalin-fixed, paraffin embedded tissue biopsies from 139 patients with histological diagnosis of NPC treated with conventional chemoradiotherapy were studied. By using immunohistochemistry staining, expressions of PD-1 on tumor-infiltrating lymphocyte and PD-L1 on tumor tissue were detected. The staining results were evaluated with H-score. The correlation between PD-1/PD-L1 expression and clinical characteristics and post-treatment outcome were analyzed. PD-1(+) immune cell were present in 52 of these 139 tumors (37.4%). PD-L1 expression was detected in 132 patients (95.0%), which located on tumor tissue. High expression of PD-L1 (median H-score >35) in tumor tissue significantly correlated with a poor prognosis of disease-free survival (P = 0.009). Co-expression of PD-1 and PD L1 in NPC at diagnosis correlated with the poorest prognosis of disease-free survival (P = 0.038). PD-1/PD-L1 co-expression reflected the selective suppression of cytotoxic lymphocytes in the tumor microenvironment and predicted recurrence and metastasis of NPC after conventional therapies. Blocking this pathway in patients with co-expression of PD-1/PD-L1 provides a potential therapy target for NPC. PMID- 25702328 TI - [Posterior restoration procedures (PRP) of the left ventricle in a patient with non-ischemic myocardiopathy]. PMID- 25702329 TI - [Imaging diagnosis: Q & A. Markedly dilated pulmonary artery (trunk) in association with acute pulmonary hypertension, causing extrusion of the left coronary artery and acute stenosis and unstable angina]. PMID- 25702330 TI - Meningococcal A conjugate vaccine: updated guidance, February 2015. PMID- 25702331 TI - Preparation for Ebola in Cote d'Ivoire: WHO Ebola response and preparedness support team, October 2014. PMID- 25702332 TI - Monthly report on dracunculiasis cases, January-December 2014. PMID- 25702333 TI - Usually the best title is the one with the best definition. PMID- 25702334 TI - Generic drugs, skyrocketing prices. PMID- 25702335 TI - AVMA PLIT transforms brand, expands outreach. PMID- 25702336 TI - AVMA also planning member-centered changes. PMID- 25702337 TI - Economic reports dig into the details. PMID- 25702338 TI - Hunting for novel viruses: separate groups looking for potential pathogens. PMID- 25702339 TI - Behavior pioneer inspired many to learn humane, positive techniques. PMID- 25702340 TI - Response to lead commentary. PMID- 25702341 TI - Warning about topical analgesics. PMID- 25702342 TI - Rediscovering lost values: Professor Aidan Halligan: Doolin Lecture 2014. PMID- 25702343 TI - Preconception low-dose aspirin and pregnancy outcomes: results from the EAGeR randomized trial. PMID- 25702344 TI - Preparedness of elderly long-term care facilities in HSE East for influenza outbreaks. AB - Abstract We assessed preparedness of HSE East elderly long-term care facilities for an influenza outbreak, and identified Public Health Department support needs. We surveyed 166 facilities based on the HSE checklist document for influenza outbreaks, with 58% response rate. Client flu vaccination rates were > 75%; leading barriers were client anxiety and consent issues. Target flu vaccine uptake of 40% in staff occurred in 43% of facilities and was associated with staff vaccine administration by afacility-attached GP (p = 0.035), having a facility outbreak plan (p = 0.013) and being anon-HSE run facility (p = 0.013). Leading barriers were staff personal anxiety (94%) and lack of awareness of the protective effect on clients (21%). Eighty-nine percent found Public Health helpful, and requested further educational support and advocacy. Staff vaccine uptake focus, organisational leadership, optimal vaccine provision models, outbreak plans and Public Health support are central to the influenza campaign in elderly long-term care facilities. PMID- 25702345 TI - Pedestrian deaths in children--potential for prevention. AB - The National Paediatric Mortality Database was reviewed for the six year period 1st January 2006 to 31st December 2011 and all pedestrian deaths extracted, after review of available data the deaths were categorized as either traffic or non traffic related. There were 45 child pedestrian fatalities in the period examined. Traffic related deaths accounted for 26 (58%) vs. 19 (42%) non-traffic related. Analysis of the deaths showed there was a male preponderance 28 (62%), weekend trend 22 (49%) with an evening 16 (35%) and summer peak 20 (44%). The highest proportion of deaths occurred in the 1-4 year age group 24 (53%), with 13 (28%) due to low speed vehicle rollovers, mainly occurring in residential driveways 8 (61%). Child pedestrian fatalities are highly preventable through the modification of risk factors including behavioural, social and environmental. Preventative action needs to be addressed, particularly in relation to non traffic related deaths i.e, low speed vehicle rollovers. PMID- 25702346 TI - Day-case tonsillectomy: practical solution or practical impossibility. AB - The use of day case surgery is on the rise. In order to improve efficiency and reduce cost, it has been proposed that tonsillectomy could be undertaken as a day case procedure in Ireland. A retrospective, chart-based study was carried out. The medical and social criteria of all patients who underwent tonsillectomy during a twelve-month period were evaluated. Individual, local and national factors were identified and international comparisons were made. Of 161 patients included, 43 (27%) were considered suitable for day case tonsillectomy (DCT). The distance/time criteria from hospital excluded 64% of patients. The diagnosis of obstructive sleep apnoea was the single most common medical reason for exclusion. Support structures were deficient. Local factors must be considered before any policy or targets are developed for DCT. Patient safety is the fundamental tenet. Currently, the infrastructure and the support required for a patient-focused, safe efficient DCT are deficient, and need investment. PMID- 25702347 TI - Is primary prevention of childhood obesity by education at 13-month immunisations feasible and acceptable? Results from a general practice based pilot study. AB - Abstract Prevalence of childhood overweight and obesity remains high in Ireland. In this study an intervention conducted within primary care was evaluated. This involved a structured discussion with parents at the 13 month immunisations with their general practitioner (GP), including measuring weight of the toddler and parental education regarding healthy nutrition and physical activity for their toddler. There was a telephone follow-up interview with parents three months later assessing change in toddler diet/lifestyle. Endpoints assessed included parents' reports of specific lifestyle parameters with regard to the toddler and parental assessment of the usefulness of the intervention. 39 toddlers were studied. Most lifestyle parameters had improved at follow up. Reported fruit and vegetable intake of more than 4 portions per day increased from 20.5% of toddlers at baseline 28.6% at follow up. The number of toddlers abstaining from unhealthy snacks increased from 15.4% to 21.4%. Television watching of more than 2 hours daily decreased from 12.8% to 0%. Supervised exercise of more than thirty minutes per day increased from 69.2% to 89.3%. The majority of parents reported at follow up that they found the intervention acceptable (100%, n = 28) and useful (79%, n = 22). PMID- 25702348 TI - Re-attenders to the emergency department of a major urban hospital serving a population of 290,000. AB - The national Emergency Medicine Programme (EMP) in Ireland, defines a re-attender as any patient re-presenting to the Emergency Department (ED) within 28 days with the same chief complaint. A retrospective, electronic patient record audit was carried out on all re-attenders to Connolly ED during November 2012. There were 2919 attendances made up from 2530 patients; 230 patients re-attended a total of 389 times. The re-attendance rate was 13% (389/2919). 63 (27%) were frequent presenters. There was a significantly higher admission rate at second attendance than first (89 (39%) vs 39 (17%), p < 0.001). 25% (57/230) of patients 'left before completion of treatment' (LBCT) at first attendance (significantly higher than the number at second attendance (p < 0.01)). 14/57 (25%) of those who LBCT at first attendance required admission at second attendance. 28/89 (31%) of second attendance admissions were failed discharges from first attendance. Reasons for re-attendance are multi-factorial and include both patient and departmental factors. PMID- 25702349 TI - Major cost savings associated with biologic dose reduction in patients with inflammatory arthritis. AB - The purpose of this study was to explore whether patients with Inflammatory Arthritis (IA) (Rheumatoid Arthritis (RA), Psoriatic Arthritis (PsA) or Ankylosing Spondylitis (AS)) would remain in remission following a reduction in biologic dosing frequency and to calculate the cost savings associated with dose reduction. This prospective non-blinded non-randomised study commenced in 2010. Patients with Inflammatory Arthritis being treated with a biologic agent were screened for disease activity. A cohort of those in remission according to standardized disease activity indices (DAS28 < 2.6, BASDAI < 4) was offered a reduction in dosing frequency of two commonly used biologic therapies (etanercept 50 mg once per fortnight instead of weekly, adalimumab 40 mg once per month instead of fortnightly). Patients were assessed for disease activity at 3, 6, 12, 18 and 24 months following reduction in dosing frequency. Cost saving was calculated. 79 patients with inflammatory arthritis in remission were recruited. 57% had rheumatoid arthritis (n = 45), 13% psoriatic arthritis (n = 10) and 30% ankylosing spondylitis (n = 24). 57% (n = 45) were taking etanercept and 43% (n = 34) adalimumab. The percentage of patients in remission at 24 months was 56% (n = 44). This resulted in an actual saving to the state of approximately 600,000 euro over two years. This study demonstrates the reduction in biologic dosing frequency is feasible in Inflammatory Arthritis. There was a considerable cost saving at two years. The potential for major cost savings in biologic usage should be pursued further. PMID- 25702350 TI - Locally advanced rectal cancer: a cooperative surgical approach to a complex surgical procedure. AB - Single stage en bloc abdominoperineal resection and sacrectomy, with a myocutaneous flap closure is a relatively uncommon procedure. Our case study of a 77 year old man with a locally invasive rectal adenocarcinoma highlights the complex intraoperative management of such a patient. PMID- 25702351 TI - Metachronous adenocarcinoma of the remnant oesophagus 15 years following multimodal therapy. AB - A 53-year-old man underwent neo-adjuvant chemo-radiotherapy and a 2 stage oesophagectomy for a junctional oesophageal tumour in 1996. In March 2012, a metachronous oesophageal tumour was identified, 7cm above the anastomotic margin, on a background of non-inflamed squamous mucosa. He is currently being managed with chemo-radiotherapy. Oesophageal cancer is associated with a historically poor survival rate, with primary concerns being local recurrence or death from disseminated disease. This case highlights the challenges which must be faced, as treatment strategies improve and consequently survival rates increase. PMID- 25702352 TI - In-hospital stroke: characteristics and outcomes. AB - In-hospital stroke (IS) made up 6.5% of strokes recorded in the Irish National Stroke Register in 2012. International research has demonstrated poorer outcomes post IS compared to out of hospital stroke (OS). We aimed to profile all IS and OS over a 22 month period and compare the two groups by gathering data from the HIPE portal stroke register. The study site is a primary stroke centre. IS represented 11% (50/458) of total strokes with over half (27/50, 54%) admitted initially with medical complaints. IS patients had a significantly longer length of stay (79.2 +/- 87.4 days vs. 21.9 +/- 45.9 days, p < 0.01) and higher mortality (13/50 vs. 39/408, p < 0.01). Patients in the IS group were also less likely to receive stroke unit care (1/50 vs. 136/408, p < 0.01). This study demonstrates the significant morbidity and mortality associated with IS and highlights the need for efforts to be made to optimize identification and management of acute stroke in this cohort. PMID- 25702353 TI - Mouth, head & neck cancer awareness campaign. PMID- 25702354 TI - The critical view of safety in laparoscopic cholecystectomy: towards a national consensus. PMID- 25702355 TI - Westermark's sign of pulmonary embolism--well known but frequently overlooked. PMID- 25702356 TI - Potential pitfalls with the treatment of aquired methaemoglobinaemia. PMID- 25702357 TI - Impact of changes in Canadian postgraduate training on the Irish health service. PMID- 25702358 TI - An audit of urinary tract infections in very low birth weight infants--what are we missing? PMID- 25702359 TI - For how long should we use symptomatic therapies to treat people with Alzheimer disease? PMID- 25702360 TI - Long-term efficacy and toxicity of cholinesterase inhibitors in the treatment of Alzheimer disease. AB - Though the symptoms of Alzheimer disease go on for years, the phase 3 trials of the cholinesterase inhibitors (ChEIs), the current mainstay of symptomatic pharmacotherapy for this condition, were typically of only 3- to 6-months' duration. We have limited data on long-term (that is, a year or more) therapy with these agents. In this review, we explore the available information on the biological and clinical effects of long-term ChEI therapy, what happens when these agents are discontinued, and examine what others have recommended An individualized approach to deciding on whether to carry on with a ChEI should be taken. If continued, treatment goals should be clarified and patients monitored over time, for both drug-related benefits and adverse effects. PMID- 25702361 TI - Persistence and adherence with dementia pharmacotherapy: relevance of patient, provider, and system factors. AB - This paper provides a comprehensive review of studies examining adherence and (or) persistence with dementia pharmacotherapy during the past decade, including a summary of the key patient-, drug-, system-, and provider-level factors associated with these measures. Estimates of adherence and 1-year persistence to these drugs have ranged from 34% to 94% and 35% to 60%, respectively. Though many studies reported nonsignificant associations, there are data suggesting that patient age, sex, ethnoracial background, socioeconomic status, and region specific reimbursement criteria, as well as the extent and quality of interactions among patients, caregivers, and providers, may influence persistence with pharmacotherapy. As many studies relied on administrative data, limited information was available regarding the relevance of patient's cognitive and functional status or the importance of caregiver involvement or assistive devices to adherence or persistence. PMID- 25702362 TI - An observational study of bullying as a contributing factor in youth suicide in Toronto. AB - OBJECTIVE: Bullying has been identified as a potential contributing factor in youth suicide. This issue has been highlighted in recent widely publicized media reports, worldwide, in which deceased youth were bullied. We report on an observational study conducted to determine the frequency of bullying as a contributing factor to youth suicide. METHOD: Coroner records were reviewed for all suicide deaths in youth aged between 10 and 19 in the city of Toronto from 1998 to 2011. Data abstracted were recent stressors (including bullying), clinical variables, such as the presence of mental illness, demographics, and methods of suicide. RESULTS: Ninety-four youth suicides were included in the study. The mean age was 16.8 years, and 70.2% were male. Bullying was present in 6 deaths (6.4%), and there were no deaths where online or cyberbullying was detected. Bullying was the only identified contributing factor in fewer than 5 deaths. The most common stressors identified were conflict with parents (21.3%), romantic partner problems (17.0%), academic problems (10.6%), and criminal and (or) legal problems (10.6%). Any stressor or mental and (or) physical illness was detected in 78.7% of cases. Depression was detected in 40.4% of cases. CONCLUSIONS: Our study highlights the need to view suicide in youth as arising from a complex interplay of various biological, psychological, and social factors of which bullying is only one. It challenges simple cause-and-effect models that may suggest that suicide arises from anyone factor, such as bullying. PMID- 25702363 TI - Freedom of and from religion. PMID- 25702364 TI - Neurocognitive functioning in overweight and obese patients with bipolar disorder: data from the Systematic Treatment Optimization Program for Early Mania (STOP-EM). AB - OBJECTIVE: Obesity is frequent in people with bipolar I disorder (BD I) and has a major impact on the course of the illness. Although obesity negatively influences cognitive function in patients with BD, its impact in the early phase of the disorder is unknown. We investigated the impact of overweight and obesity on cognitive functioning in clinically stable patients with BD recently recovered from their first manic episode. METHOD: Sixty-five patients with BD (25 overweight or obese and 40 normal weight) recently remitted from a first episode of mania and 37 age- and sex-matched healthy control. subjects (9 overweight or obese and 28 normal weight) were included in this analysis from the Systematic Treatment Optimization Program for Early Mania (commonly referred to as STOP-EM). All subjects had their cognitive function assessed using a standard neurocognitive battery. We compared cognitive function between normal weight patients, overweight-obese patients, and normal weight healthy control subjects. RESULTS: There was a negative affect of BD diagnosis on the domains of attention, verbal memory, nonverbal memory, working memory, and executive function, but we were unable to find an additional effect of weight on cognitive functioning in patients. There was a trend for a negative correlation between body mass index and nonverbal memory in the patient group. CONCLUSIONS: These data suggest that overweight-obesity does not negatively influence cognitive function early in the course of BD. Given that there is evidence for a negative impact of obesity later in the course of illness, there may be an opportunity to address obesity early in the course of BD. PMID- 25702365 TI - Cognitive dysfunction in major depressive disorder: effects on psychosocial functioning and implications for treatment. PMID- 25702366 TI - Relapse risk assessment in early phase psychosis: the search for a reliable and valid tool. PMID- 25702367 TI - Toward a comprehensive clinical staging model for bipolar disorder: integrating the evidence. AB - OBJECTIVES: To describe key findings relating to the natural history and heterogeneity of bipolar disorder (BD) relevant to the development of a unitary clinical staging model. Currently proposed staging models are briefly discussed, highlighting complementary findings, and a comprehensive staging model of BD is proposed integrating the relevant evidence. METHOD: A selective review of key published findings addressing the natural history, heterogeneity, and clinical staging models of BD are discussed. RESULTS: The concept of BD has broadened, resulting in an increased spectrum of disorders subsumed under this diagnostic category. Different staging models for BD have been proposed based on the early psychosis literature, studies of patients with established BD, and prospective studies of the offspring of parents with BD. The overarching finding is that there are identifiable sequential clinical phases in the development of BD that differ in important ways between classical episodic and psychotic spectrum subtypes. In addition, in the context of familial risk, early risk syndromes add important predictive value and inform the staging model for BD. CONCLUSIONS: A comprehensive clinical staging model of BD can be derived from the available evidence and should consider the natural history of BD and the heterogeneity of subtypes. This model will advance both early intervention efforts and neurobiological research. PMID- 25702368 TI - Re: Cognition in schizophrenia. PMID- 25702370 TI - Re: Rational suicide: sending the wrong message? PMID- 25702371 TI - Reconsidering our strategic priorities: enhancing quality, sharpening focus. PMID- 25702372 TI - Occupational performance coaching for stroke survivors: a pilot randomized controlled trial protocol. AB - BACKGROUND: Many stroke survivors report participation challenges. Occupational Performance Coaching for stroke survivors (OPC-Stroke) is designed to assist stroke survivors to develop the ability to plan and manage engagement in occupation. This approach combines emotional support, individualized education, and goal-focused problem solving to promote occupational engagement. PURPOSE: This study will explore the potential efficacy of OPC-Stroke and the feasibility of the research methods for use in a larger trial. METHOD: A pilot randomized controlled trial will be undertaken. Participants will be randomly assigned to receive 10 sessions of OPC-Stroke or usual care. Participation, perceived goal performance, satisfaction and self-efficacy, emotional well-being, and cognition will be measured at three time points. IMPLICATIONS: This research will test the potential usefulness of OPC-Stroke as well as the study methods, and thereby inform the continuing development of OPC-Stroke and further studies to measure its effectiveness. PMID- 25702373 TI - Empirical lessons about occupational categorization from case studies of unemployment. AB - BACKGROUND: Scrutiny regarding the typological categorization of occupation (e.g., occupation as work, rest, or leisure) has prompted interest in experiential categories as a less exclusionary alternative. Empirical research can extend the dialogue about categorization by demonstrating how people in particular situations apply and generate occupational categories. PURPOSE: This article explores how adults without work utilized typological and experiential categorizations when discussing their occupations. METHOD: Data were generated via a secondary analysis of interview transcripts from three ethnographic case studies. FINDINGS: Study consultants gravitated toward experiential rather than typological categorizations, emphasizing the social, chosen, purposeful, and temporal qualities of their occupational engagement. IMPLICATIONS: Occupational therapy practitioners and researchers must explicitly state how and why they categorize occupations with clients and research participants. Whereas typological categories can be used to initiate discussions about occupation, open questions paired with consultant-generated experiential categories may better capture occupational engagement and reveal potential injustices in situations like unemployment PMID- 25702374 TI - Social occupational therapy: conversations about a Brazilian experience. AB - BACKGROUND: Researchers and practitioners worldwide have advocated for the development of critical perspectives in occupational therapy to examine the structural influences of social exclusion and injustice experienced by individuals, groups, and communities. To take action against social exclusion and injustice, Brazilian occupational therapists have been developing "social occupational therapy," referring to practice that is focused on social issues and funded outside the health system. PURPOSE: This paper presents a Brazilian perspective on the concept and practice of social occupational therapy. Illustrations are drawn from 12 studies, developed between 2008 and 2013, which were completed with socially vulnerable youth through an ongoing university community engagement partnership in Sao Carlos, Sao Paulo State, Brazil. KEY ISSUES: The authors discuss possibilities and challenges for developing a socially committed, transformative occupational therapy outside the health system. IMPLICATIONS: Occupational therapists may wish to seize opportunities to address social issues and attract funding beyond health services. PMID- 25702375 TI - Randomized controlled trial protocol feasibility: The Wheelchair Self-Efficacy Enhanced for Use (WheelSeeU). AB - BACKGROUND: Manual wheelchairs (MWCs) can improve mobility and social participation for individuals who experience difficulty walking; however, older adults receive little training for wheelchair use. The Wheelchair Self-Efficacy Enhanced for Use (WheelSeeU) research program provides peer-led training that may positively influence wheelchair use while reducing clinician burden. PURPOSE: The purpose of this study is to evaluate the feasibility and clinical outcomes of WheelSeeU. METHOD: A randomized control trial (RCT) recruits and randomly assigns 40 MWC users (55+ years). Feasibility indicators assessing process, resource, management, and treatment issues are measured, and clinical outcomes (wheelchair skills, safety, confidence, mobility, social participation, quality of life, health utility) are collected at three time points. IMPLICATIONS: WheelSeeU provides an innovative approach for teaching wheelchair skills to an aging population that may improve wheelchair use and decrease clinician burden. Since RCTs are expensive and challenging in rehabilitation, establishing feasibility prior to larger effectiveness trials is prudent. PMID- 25702376 TI - The Accountability-Well-Being-Ethics framework: a new philosophical foundation for occupational therapy. AB - BACKGROUND: The context that supported occupational therapy's inception has been replaced with new challenges brought on by globalization and dramatic changes in health care. Thus, the profession's philosophical grounding needs to be reframed to (a) achieve balance between science-driven and holistic elements, (b) operate within larger contexts on problems brought on by sociopolitical and natural determinants of health, and (c) maintain an ethical identity across all arenas of practice. PURPOSE: This paper presents a brief discussion of the philosophical underpinnings in occupational therapy's history, outlines new global challenges for the profession, and proposes a new framework to address these challenges through education, practice, and research. KEY ISSUES: Occupational therapy finds itself practising in a growing number of middle- and low-income countries where its roles and values need to be context and culture specific. IMPLICATIONS: The Accountability-Well-Being-Ethics framework guides the three domains of education, research, and practice to be relevant in an increasingly complex world. PMID- 25702377 TI - Occupation and the process of transition from homelessness. AB - BACKGROUND: The incorporation of meaningful activity or occupation in supporting those transitioning from homelessness to being housed has been promoted by researchers; however, there is little evidence to support the promotion of initiatives encouraging its use in support models. PURPOSE: This manuscript aims to advocate for further research into the role of occupation in supporting persons transitioning from homelessness to permanent housing. KEY ISSUES: The transition from homelessness to becoming housed can be facilitated through use of occupation as a way of promoting the security of meaningful roles and a "housed identity" among persons experiencing homelessness. IMPLICATIONS: By promoting an emphasis on occupation, persons experiencing homelessness may undergo a positive change in identity. This change may improve housing tenure and the likelihood of a more permanent transition away from homelessness. More research is required to identify the relationship between occupation and the transition from homelessness. PMID- 25702378 TI - INTRODUCTION: The nature of monsters. Sketches of the history of teratology. PMID- 25702379 TI - Bone deformities and skeletal malformations in the Roman Imperial Age. AB - This paper describes some cases of individuals affected by skeletal deformities resulting in "freak" appearance. The skeletal remains were found during large archaeological excavations in the Roman territory, carried out by the Special Superintendence to the Archeological Heritage of Rome in the last years, dated back to the Imperial Age. The first cases reported are referred to two growth disorders with opposite effects: a case of dwarfism and another of gigantism. The former concerns a young man from the Collatina necropolis with very short and malformed limbs, which allowed a diagnosis of acondroplasic dwarfism, a rare congenital disorder that limits height below 130 cm. The latter case comes from the necropolis of Torre Serpentana in Fidenae, and is instead referred to a young person of very high stature, about 204 cm, suffering from Gigantism, a rare condition which in this case seems to have been linked to a hormonal dysfunction due to a pituitary adenoma. A third case regards a joint disease affecting the vertebral column and causing severe deformities. The skeleton was found in the Collatina necropolis and belongs to an old woman, suffering from ankylosing spondylitis. Finally, the last and very peculiar case is related to an individual recovered in the necropolis of Castel Malnome. The skeletal remains belong to an adult man with a complete fusion of the temporo-mandibular joint, which compromised mastication and caused severe deformation of the maxillofacial complex. These cases are described in detail together with the possible implications that these deformities could have on in the social context. PMID- 25702380 TI - The birth of a monstrous child throughout history: the example of anencephaly between the Egyptian New Empire and the 21st century. AB - Anencephaly is of special interest for the historical study of human behaviour after the birth of a monstrous child. Examples of anencephalic human births from Egyptian Antiquity to the present time allow us to create a history of teratology, revealing hiatuses in the medical and scientific interpretation of monstrosity that contrast to a relative continuity in the imaginary processes that accompany the birth of a monstrous child. PMID- 25702381 TI - Medieval monsters, in theory and practice. AB - The past two decades have witnessed a plethora of studies on the medieval monster. These studies have contributed significantly to our understanding of religion, art, literature, and science in the Middle Ages. However, a tendency to treat the medieval monster in purely symbolic and psychological terms ignores the lived experiences of impaired medieval people and their culture's attitudes toward them. With the aid of recent insights provided by disability studies, this article aims to confront "real" medieval monsters--e.g., physically impaired human beings--in both their human and monstrous aspects. PMID- 25702382 TI - Leonardo Da Vinci, the genius and the monsters. Casual encounters? AB - This article analyses Leonardo's interest in monsters and deformed reality, one of the lesser known aspects of his vast and multifaceted output. With the possible exception of his studies of physiognomy, relevant drawings, sketches and short stories represent a marginal aspect of his work, but they are nevertheless significant for historians of teratology. The purpose of this study is to provide a broad overview of the relationship between Leonardo and both the literature on mythological monsters and the reports on monstrous births that he either read about or witnessed personally. While aspects of his appreciation and attention to beauty and the pursuit of perfection and good proportions are the elements most emphasised in Leonardo's work, other no less interesting aspects related to deformity have been considered of marginal importance. My analysis will demonstrate that Leonardo approached the realm of monstrosity as if he considered abnormality a mirror of normality, deformity a mirror of harmony, and disease a mirror of health, as if to emphasise that, ultimately, it is the monster that gives the world the gift of normality. Two special cases of monstrosity are analysed: the famous monster of Ravenna, whose image was found among his papers, and a very rare case of parasitic conjoined twins (thoracopagus parasiticus) portrayed for the first time alive, probably in Florence, by Leonardo himself. PMID- 25702383 TI - The woman who gave birth to a dog Monstrosity and bestiality in Quaestiones Medico-Legales by Paolo Zacchia. AB - The Italian Paolo Zacchia (1584-1659) is considered one of the fathers of forensic medicine. From a letter sent by the physician and botanist Pietro Castelli, the article seeks to reconstruct the opinions that Zacchia expressed about monsters in his monumental Quaestiones Medico-Legales. Although he did not seem too sure about the possibility that a hybrid could be born from the union of a man and a beast, he believed that God intervened, allowing the birth so that the abomination could be discovered. The opinion of Zacchia is related to the image that people had at the time of the relationship between humans and animals. PMID- 25702384 TI - "Monstre". Etienne Geoffroy Saint-Hilaire and the science of monstrosity. AB - This article aims at analyzing the entry "Monstre", written by Etienne Geoffroy Saint-Hilaire in 1827 and included in the Dictionnaire classique d'histoire naturelle. Under Etienne Geoffroy the study of monsters brought new heuristic and theoretical approaches to the research fields of anatomy and embryology, and acquired the status of a scientific discipline having its own theoreticalfoundations and therefore its own standards for classification, seen as non-random means for revealing a groundbreaking knowledge. PMID- 25702385 TI - Semantics of monstrosity in the ninenteenth century. AB - The emphasis of the normal, the human aspect and feature in monstrosities is a leitmotif that becomes prevalent in the scientific debate on teratological phenomena in the nineteenth century. The discourse highlights the organisation of the civilising process with regard to creating an antithesis between human and animality. In this respect, anthropology establishes anthropometry as a measuring and classifying instrument, hence supporting concepts of norm and abnormity in the scientific discussion. The classification approach finally translates teratological occurrences into the "human system" with the monstrosity being transformed into a subject of knowledge. Scientific discourse poses and installs the latter as living attraction for medical and anthropological examination, thus stressing boundary permeability between man and animal. Evolutionary theory finally initiates the quest for the missing link between man and ape, with congenital disorders, such as microcephaly, becoming particularly supportive of the idea of a manifesting existence of a primitive pre-human form. PMID- 25702386 TI - Retrogressive development: transcendental anatomy and teratology in nineteenth century Britain. AB - In 1855 the leading British transcendental anatomist Robert Knox proposed a theory of retrogressive development according to which the human embryo could give rise to ancestral types or races and the animal embryo to other species within the same family. Unlike monsters attributed to the older theory of arrested development, new forms produced by retrogression were neither imperfect nor equivalent to a stage in the embryo's development. Instead, Knox postulated that embryos contained all possible specific forms in potentia. Retrogressive development could account for examples of atavism or racial throwbacks, and formed part of Knox's theory of rapid (saltatory) species change. Knox's evolutionary theorizing was soon eclipsed by the better presented and more socially acceptable Darwinian gradualism, but the concept of retrogressive development remained influential in anthropology and the social sciences, and Knox's work can be seen as the scientific basis for theories of physical, mental and cultural degeneracy. PMID- 25702387 TI - Falsehood on the move. The Aztec children and science in the second half of the 19th century. AB - Allegedly kidnapped from a secret city in Central America, the "Aztec children" began a showman's career in the early-1850s. They died around 1900, after being observed by countless pathologists and ethnologists from Europe and the US. Most of the literature on the "Aztec children" has emphasized racial theories, the imperial gaze, and the character of "ethnological shows", where monstrosity and ethnicity were practically synonymous. Less attention has been paid to the fact that scientists continuously insisted that the case was false, an argument that instead of debunking the myth of the "Aztec children", contributed to establishing the "Aztecs" as "a matter of fact". In examining the case of the "Aztec children", this essay aims to explore what can be called the shifting nature or elusiveness of falsehood. PMID- 25702388 TI - Teratology in Mexico. 19th Century. AB - It was not until the last third of the 19th century, the period in which, according to historiography, the country definitely inserted itself into modernity, that anomalies and monstrosities had a presence in Mexico. Therefore, what I present here are four moments of teratology in Mexico, four dates in which I try to recount how teratology, which still occupied a marginal place within the main themes of national science, not only reached to cover the realm of medical discussions at the time, but also laid the foundations for new disciplines like biology and anthropology. PMID- 25702389 TI - Nicola Pende (1880-1970) and his "big lazy children". Parable of a clinical syndrome. AB - In the first half of the twentieth century, more than a million young Italians were found affected by a new disease: the Pende's hyperthymic syndrome. Nicola Pende was the renowned clinician who wrote the first great Italian treatise of endocrinology and who later founded the "sciences" of biotypology and orthogenesis. The paper tells the parable of the syndrome, the story of big lazy children and their fate in radiation therapy for the greater glory of Roman Italic race. PMID- 25702390 TI - Filming the freak show. Non-normative bodies on screen. AB - The article focuses on four films that display the exhibition for profit of non- normative bodies in a context that is variously called freak show, sideshow, monster show, odditorium. Freaks (Tod Browning, 1932), The Ape Woman (La donna scimmia, Marco Ferreri, 1964), Elephant Man (David Lynch, 1980) and Black Venus (Venus noire, Abdellatif Kechiche, 2010) are reflexive movies that tell stories of abnormal bodies and of people who buy a ticket to see them. They inquire the fictional nature of "freakness"--a cultural and historical artefact, a social construction, a frame of mind and a set of practices--and draw attention to the continuity between the world of the freak shows and the scientific and medical milieus. The article finally considers the new visibility of the corporeal freak in contemporary voyeuristic television programs. PMID- 25702391 TI - The monstrous metallic in medicine and horror cinema. AB - 'This paper considers the monstrous nature of medical tools and devices through the lens of horror cinema and the art of Damien Hirst. In it I argue for a shift from the monster and the monstrous as organic to the threat of the monster as an inorganic object in tools such as the scalpel and syringe. However, the metaphorical significance of the monster is sustained in these tools where human technological creations continue the discourse of the monster as a product of human creativity. PMID- 25702392 TI - Abnormal appearances: inspection, display and the clinic. AB - We provide an examination of the field of dysmorphology, a clinical speciality that in its current form combines a long history of inspection and display with the identification and representation of associated underlying molecular changes. The recognition and description of abnormal appearances is thus increasingly accompanied by genetic and other molecular investigations. Our analysis draws on our long-term ethnographic engagement with a UK clinical genetics service and the work of two clinical genetics teams within a regional teaching hospital. We document the intersection of genetic science with clinical work to suggest that while molecular testing often identifies the genetic basis for unusual appearances and abnormal development, it does not fully supplant clinical apperception and interpretation. The two modes of knowledge--the clinical and the biomedical--co-exist in the work and the discourse of dysmorphology practice. The contemporary dysmorphology clinic thus encapsulates the epistemological systems of modern medicine, grounded in the clinical gaze and on the classificatory systems of classic nosology. Within such a system of clinical knowledge, the 'monstrous' does not escape the boundaries of knowledge. Monstrous appearances are accommodated and domesticated within the classificatory systems of normal medicine. PMID- 25702393 TI - [Gagliasso E., Memoli R., Pontecorvo M. E. (a cura di), Scienza e scienziati: colloqui interdisciplinari. FrancoAngeli, Milano, 2011]. PMID- 25702394 TI - Nestle M. and Nesheim M. (by) Why Calories Count: From Science to Politics, University of California Press. PMID- 25702395 TI - [Mazarello P., L'erba della regina. Storia di un decotto miracoloso. Torino, Bollati Boringhieri, 2013]. PMID- 25702397 TI - [The features of myocardial deformation of left ventricle in patients with ischemic heart disease defined by the two dimensional strain method]. AB - Aim of this study was to assess qualitative and quantitative features of deformation parameters of left ventricular myocardium in patients with ischemic heart disease (IHD) with and without history of myocardial infarction (MI) using two-dimensional strain imaging. We examined 30 patients with clinical IHD with (group 1, n = 15) and without (group 2, n = 15) history of MI and 20 healthy volunteers. Compared with healthy subjects IHD patients of both groups had reduced longitudinal and circular myocardial deformation. There were no significant differences between patients with IHD and controls in parameters of radial, global, and regional deformation. PMID- 25702396 TI - [Role of kidney injury molecule-1 (KIM-1) for inhospital event risk assessment after coronary artery bypass surgery]. AB - AIM: To assess value of kidney injury molecule-1 (KIM-1) for prediction of inhospital events in CAD patients undergoing coronary artery bypass graft (CABG) surgery. MATERIAL AND METHODS: We analyzed postoperative course of 719 patients subjected to CABG in Research Institute for Complex Issues of Cardiovascular Diseases between March, 2011 and April, 2012. In all patients we measured creatinine concentrations, glomerular filtration rate (GFR) by MDRD and urine KIM 1 levels before and on day 7 after CABG. Major unfavorable events (myocardial infarction, stroke or transient ischemic attack, acute or decompensated chronic renal failure or remediastinotomy) were registered during hospital stay. The EuroSCORE (European System for Cardiac Operative Risk Evaluation) risk of operative mortality was calculated for each patient. RESULTS: Patients with different EuroSCORE risk had similar serum creatinine levels while KIM-1 concentrations in urine were significantly higher in patients with moderate and high EuroSCORE risk as compared with low-risk patients. Patients who experienced postoperative events had significantly higher KIM-1 both before and after surgery while there were no differences in such renal dysfunction markers as creatinine and GFR. CONCLUSION: Preoperative elevated KIM-1 can act as a marker of complicated postoperative period after CABG. PMID- 25702398 TI - [Evaluating the effectiveness of a fixed combination of amlodipine and bisoprolol in ambulatory patients with arterial hypertension and ischemic heart disease]. AB - OBJECTIVE: To evaluate the efficacy and safety of a fixed-term combination of beta-blocker bisoprolol and the calcium antagonist amlodipine in the outpatient treatment of patients with arterial hypertension (AH) and coronary heart disease (CHD). The study involved 100 patients with hypertension 1-3 first degree and CHD, which previous antihypertensive therapy was ineffective or irregular. Inclusion in the treatment regimen of amlodipine was associated with significant decrease in blood pressure (BP) with the achievement of the target level of systolic blood pressure of 90%, diastolic blood pressure--in 97% of cases after 4 weeks treatment. Analysis of the dynamics of the heart rate during the visits to the doctor and the patient diary data revealed a significant slowing on the background of the therapy, which is important for patients with coronary artery disease. In carrying out daily monitoring of ECG Holter dynamics observed a decrease in the average duration of episodes of depression segment ST on 50.5% (p < 0.05) and the number of ischemic episodes at 54.8% (p < 0.05). The use of fixed dose combination of bisoprolol and amlodipine allowed to increase the compliance of patients with treatment 2.2 times. PMID- 25702399 TI - [Effect of dosage forms loop diuretic with a different release rate for early and delayed the prognosis of patients with circulatory decompensation]. PMID- 25702400 TI - [Efficacy and safety of allapinine and quinidine bisulphate in the treatment of patients with persistent atrial fibrillation after cardioversion]. AB - OBJECTIVE: To assess and compare the safety and efficacy of allapinine and quinidine bisulphate in the treatment of patients with persistent atrial fibrillation after cardioversion. Design--Prospective, randomised, open study. Patients--73 consecutive patients (men only, mean age 44 +/- 11 years) with persisnent atrial fibrillation and flutter. Interventions--37 patients were randomised to allapinine (ALP) (1.5 mg/kg/d), 36 to quinidine bisulphate (QUIN) (15 mg/kg/d) with subsequent successful pharmacological or electrical cardioversion. Main outcome measures--Recurrence of atrial fibrillation or side effects. RESULTS: In the ALP group 15 of the 37 patients developed atrial fibrillation up to 12 month of follow-up, while in the QUIN group 20 patients developed atrial fibrillation and 5 experienced significant side effects. Relative risk (RR) (ALP vs QUIN) 0.58 (95% CI 0.37-0.91, p < 0.02). The number needed to treat (NNT) was (-3.48) (14.2-1.97 harm). When 5 patients with significant side effects were excluded from the analysis RR was 0.62 (95% CI 0.39 1.0, p = 0.052) and NNT--(-4.1) (122.7-2.1 harm) but power of the study was too low--67%. CONCLUSION: Allapinine is as effective as quinidine bisulphate in the long term treatment of patients with persistent atrial fibrillation after successful cardioversion but causes significantly less side effects. PMID- 25702401 TI - [Corrective effect of olmesartan on parameters of the local rigidity using the echo-tracking technology]. AB - Purpose of this study was to determine clinical value of intima-media thickness (IMT) and indicators of local stiffness obtained by ultrasonography of the carotid arteries by echo-tracking technology in patients with hypertension and coronary artery disease (CAD), and to assess vasoprotective effect of 24-week treatment with olmesartan. We included into the study 22 patients with 1-2 degree hypertension, 25 patients with CAD combined with hypertension, and 44 healthy subjects. In patients with CAD and hypertension local stiffness was reassessed after 24-week treatment with olmesartan (20-40 mg/day). Patients with hypertension compared with healthy subjects had higher values of loc P sys and loc P dia, P (T1), pulse wave propagation velocity (PWPV), stiffness index, as well as lower compliance and distensibility coefficients (CC and DC). In patients with CAD and hypertension all parameters of local stiffness and IMT were significantly higher, while CC and DC were significantly lower than in control group. Therapy with olmesartan for 24-weeks was associated with reductions of IMT (-4.8%, p < 0.05), loc P sys and loc P dia (-13.5 and -11%, respectively, p < 0.05), stiffness index beta (-19.1%, p < 0.05), loc PWPV (-17%) and P (T1) (-7%, p < 0.05), and increase of CC (3.3%, p < 0.05). Conclusion. Combination of CAD and hypertension worsened the local stiffness and increased IMT. Therapy with olmesartan in this group of patients was associated with indications of vasoprotective effect. PMID- 25702402 TI - [One-stage carotid and coronary artery surgeries in the treatment of multifocal atherosclerosis]. AB - One of the most severe forms of multifocal atherosclerosis often accompanied by heart attacks and strokes is concomitant coronary and carotid artery disease. Unfortunately to date there have been no qualitative randomized trials allowing us to develop a unified optimal approach to the treatment of this pathology. We have analyzed the treatment of 128 patients with coronary artery disease and atherosclerotic carotid stenosis operated on the two vascular territories over the past 10 years in the Department of Surgery of the Aorta and its Branches of the Petrovsky National Research Center of Surgery. One-stage reconstruction in two arterial basins was performed on the majority (75%) of patients. Other patients underwent multistage procedures including the use of endovascular techniques. The absence of any significant differences in mortality and postoperative complications between groups subjected to single- and multi-stage treatment, doubtless reduction of risk of vascular complications in uncorrected arterial bed by one-stage reconstruction allows us to consider this treatment strategy the method of choice in the management of this pathology. Overall surgical mortality of patients with combined coronary and carotid artery involvement subjected to our strategy was 0.8%. PMID- 25702403 TI - [Extracellular matrix remodeling myocardium of the left ventricle rats with experimental heart failure after perindopril and melatonin administration]. AB - The aim of the study was to examine the reorganization of extracellular matrix left ventricular myocardium (LVM) rats (n = 38) with experimental heart failure (EHF) as affected by perindopril and melatonin administration. Rats LVM was studied using the methods of light microscopy, immunocytochemistry and morphometry. At day 14 of EHF, marked mosaic staining cardiomyocytes acid dyes, manifest hemodynamic disturbances: venous and capillary congestion, lymphostasis, perivascular and interstitial edema, there was a increase the volume density (OD) stroma, high activity of MMP-1 and TIMP-1. After modeling the EHF to 28 days in LVM, a further increase of hemodynamic met, cardiosclerosis areas and perivascular sclerosis, a significant increase OD stroma, observed decrease in the expression of MMP-1 and TIMP-1. In rats given perindopril and melatonin for 14 days, there was a regression of pathological changes in the balance was maintained MMP-1/TIMP-1 ratio close to the group of intact rats. Cardioprotective effects of perindopril and melatonin on extracellular matrix LVM of rats with EHF is discussed. PMID- 25702404 TI - [Heart and liver fibrosis: the components of a single equation]. AB - Myocardial fibrosis plays a key role in the pathogenesis of cardiovascular diseases. The chronic pressure overload of the heart activates collagen that leads to its excessive accumulation, fibrosis and cardiac hypertrophy. Myocardial injury is often accompanied by liver damage. These two processes are closely linked. One of the links of this chain is the activation of the renin-angiotensin aldosterone system (RAAS). There is impressive evidence base for drugs that block the RAAS, and thus break the vicious cycle of cardiovascular continuum. Fibrogenesis is nonspecific process and prospect of drug application affecting the activity of the RAAS may be useful for fibrosis prevention not only for the heart and liver, but also for other organs. PMID- 25702405 TI - [Azilsartan--new representative of the class of angiotensin receptor blockers II]. AB - The article is a review of published data on the efficacy and tolerability of a new representative of the class of angiotensin receptor blockers II (BRA) azilsartana registered for use in the Russian Federation in 2014. It is found that this drug has the advantage in comparison with several other members of the class BRA (valsartan, olmesartan, candesartan) and an ACE inhibitor ramipril in the form of more powerful antihypertensive effect. PMID- 25702406 TI - [The use of dabigatran for prevention of ischemic stroke in patiets with atrial fibrillation: special features of treatment in different clinical situations]. AB - Atrial fibrillation (AF) is extremely highly prevalent both in Russia and in the world. Ischemic stroke is a severe complication of AF often resulting in disability or death. Therefore important role is given to conduct of primary and secondary prevention of development of thromboembolic complications which is realized by means of administration of antithrombotic therapy. For a long time warfarin has been used for this purpose. However compliance of physicians to its prescription remains unsatisfactory. Recently novel oral anticoagulants (NOAC) have been elaborated. Among them dabigatran has longest period of use and has been recommended as the drug of choice for patients with non-valvular AF. At present time wide use of dabigatran is limited because of lack of clear understanding of some practical questions of the use of this drug. Aim of this review--to analyze available data on efficacy and safety of dabigatran, to study special features of its administration in various clinical situations. PMID- 25702407 TI - [The place of pharmacoinvasive management in patients with ST-elevation acute coronary syndrome in Russia]. AB - The present article reviews the issues of medical healthcare provision for acute coronary syndrome (ACS) in the Russian Federation from the perspective of benefits of pharmacoinvasive management for these patients. A brief analysis of clinical trials, promoting and defining pharmacoinvasive management as a preferred therapy that should be implemented in the Federal Health Care Program for ACS, is presented. The data of the STREAM study reported similar results in comparison with primary percutaneous coronary intervention (PCI) in immediate and long-term prognosis in patients with ST-elevation ACS after the initiation of thrombolytic therapy (TLT) with tenecteplase in the early pre-hospital period (< 3 hours from the onset of myocardial infarction). PMID- 25702408 TI - [Systematic analysis of magnesium dependent mitochondrial proteins]. AB - Magnesium is principally important for maintenance of function of cardiomyocytes. Magnesium deficit provokes asthenia of cardiomyocytes accompanying cardiovascularpathology. In this paper we present results of conducted for the first time bioinformatic analysis of magnesium dependent mitochondrial proteins. The results have principal significance for understanding pharmacodynamics effects of action of magnesium on function of mitochondria. PMID- 25702409 TI - [[Meldonium in treatment of patients with myocardial infarction]. AB - Therapy with meldonium belongs to "metabolic direction" which is developing in cardiovascular medicine. Its purpose is restoration of impaired cellular metabolism. PMID- 25702410 TI - [Conjugates of cyclooligosaccharide scaffolds and carbohydrate ligands: methods of synthesis and interaction with lectins]. AB - Main approaches to the preparation of mono- and oligodentate glycoconjugates based on cyclodextrin and cyclooligo-beta-(1 -> 6)-D-glucosamine scaffolds are surveyed in the review. The data on the biological activity of the glycoconjugates by the example of their interaction with lectins are discussed. PMID- 25702411 TI - Synthesis and activity of a cyclo-heptapeptide containing Lys-Gly-Asp-sequence as a novel anti-platelet agent. AB - Linear hepta-peptide Cys-Lys-Gly-Asp-Trp-Asp-Cys was synthesized first and then disulfide bond was formed between the Cys1 and Cys7 to develop cyclo-heptapeptide containing Lys-Gly-Asp-sequence. Structural simulation showed that Lys-Gly-Asp motif (KDG) displayed functional conformation. The cyclo-heptapeptide exhibited potent anti-platelet aggregation activity based on specific recognition and interaction with the GPIIb-IIIa receptor on platelet cell membrane. The specific and potent anti-platelet activity makes the KGD-containing cyclo-heptapeptide a possible therapeutic agent. PMID- 25702412 TI - [Structural properties and functional importance of metzincin metalloproteinases]. AB - Here wediscuss known properties of metzincin metalloproteinases, their structure, physiological roles in the cell and potential medical uses. We also present results describing a novel extracellular metzincin metalloproteinase from Bacillus pumilus with a unique combination of properties typical for both astacins and adamalysins. PMID- 25702413 TI - [Glutathione S-transferase of alpha class from pike liver]. AB - In this study, glutathione S-transferase (GST) was isolated from the liver of pike Esox lucius, which was homogenous according to SDS-PAGE and isoelectrofocusing. It is a homodimer with subunits mass 25235.36 Da (according to HPLC-MS/MS) and pI about 6.4. Substrate specificity, thermostability, some kinetic characteristics and optimum pH were determined. The enzyme was identified as Alpha class GST. PMID- 25702414 TI - [Inclusion of proteins into polyelectrolyte microcapsules by coprecipitation and adsorption]. AB - In present study microcapsules composed of synthetic (PSS and PAA) and biodegradable (DS and PAr) polyelectrolytes on calcium carbonate microparticles were obtained. The ultrastructural organization of biodegradable microcapsules was studied using transmission electron microscopy. The envelope of such capsules consisting of six polyelectrolyte layers is already well-formed, having the average thickness of 44 +/- 3.0 nm, and their internal polyelectrolyte matrix is sparser compared to the synthetic microcapsules. Spectroscopy was employed to evaluate the efficiency of incorporation of FITC-labeled BSA into synthetic microcapsules by adsorption, depending on the number of polyelectrolyte layers. It was shown that the maximal amount of protein incorporated into the capsules with 6 or 7 polyelectrolyte layers (4 and 2 pg/capsule, correspondingly). As a result we conclude that, in comparison with co-precipitation, the use of adsorption allows to completely avoid the loss of protein upon encapsulation. PMID- 25702415 TI - [Calpain system dysregulation in rat brain at beta-amyloid-induced neurodegeneration]. AB - Experimental evidences of calcium-dependent proteolysis dysregulation in brain of murine model of Alzheimer disease were obtained. Experimental treatment consisted in intra-hippocampal injection of amyloid beta-peptide (AP1-40) promoted activation of main calpain forms in murine brain along with decrease incontent of natural calpain inhibitor, calpastatin. As a result of prognostic experiment on the correction of neurodegeneration induced in murine the neuroprotective properties of steroid hormone estradiol were confirmed and one of the possible protective action mechanisms was suggested. Obtained results allow considering both biochemical modifications in protein facilities of pathology-affected brain and the mechanisms of neurodegeneration and neuroprotection. PMID- 25702416 TI - [Effects of myelopeptide-1 on functional activity of murine phagocytes treated with cyclophosphan]. AB - The effects of bone marrow derived myelopeptide-1 (MP-1) on functional activities of normal murine phagocytes and phagocytes obtained from mice treated with cytostatic agent cyclophosphan (CY) were studied in vivo and in vitro. We demonstrated immunocorrecting effect of MP-1 on functional activity of bone marrow and peripheral blood phagocytes. An optimal protocol of MP-1 injections during cytostatic therapy was developed to obtain maximal efficacy in immunocorrection. The best effect on functional activity of phagocytes of different localization (the highest effect on peripheral blood neutrophils) was found when MP-1 was injected before CY. The results demonstrated that MP-1 can be considered as a substance able to protect peripheral blood phagocytes from CY damage during cytostatic treatment. PMID- 25702417 TI - Mulberry (Morus L.) methionine sulfoxide rreductase gene cloning, sequence analysis, and expression in plant development and stress response. AB - Methionine sulfoxide reductase plays a regulatory role in plant growth and development, especially in scavenging reactive oxygen species by restoration of the oxidation of methionine in protein. A full-length cDNA sequence encoding methionine sulfoxide reductase (MSR) from mulberry, which we designated MMSR, was cloned based on mulberry expressed sequence tags (ESTs). Sequence analysis showed that the MMSR is 810 bp long, encoding 194 amino acids with a predicted molecular weight of 21.6 kDa and an isoelectric point of 6.78. The expression level of the MMSR gene under conditions of drought and salt stresses was quantified by qRT PCR. The results show that the expression level changed significantly under the stress conditions compared to the normal growth environment. It helps us to get a better understanding of the molecular basis for signal transduction mechanisms underlying the stress response in mulberry. PMID- 25702418 TI - [The arsenolysis reaction in the biotechnological method of synthesis of the ribavirin. Inhibition of reproduction of influenza A virus with the combination of ribavirin and ozeltamivir in experiments in vitro and in vivo]. AB - Improved biotechnological method of receiving the antiviral drug ribavirin by the reaction of transglycosilation by addition of catalytic amounts of sodium arsenate in the reaction mixture. Such approach allows to hydrolyze the amount of the excess natural nucleoside donor--ribose and, as a consequence, to simplify the composition of the reaction mixture and the process of separation of ribavirin. The effect of ribavirin and ozeltamivir carboxylate and their combination on the reproduction of the virus of the influenza A in cell culture and in experiments on laboratory animals (mouse Balb/C). The greatest anti influenza effect is observed when using a combination of drugs, as compared to each of them taken separately. PMID- 25702419 TI - [An expedient synthesis of fluorescent labeled ceramide-1-phosphate analogues]. AB - A synthesis for fluorescent analogs of ceramide-1-phosphate bearing 9 anthrylvinyl or 4,4-difluoro-3a,4a- diaza-s-indacene-8-yl (Me4-BODIPY) fluorophore at o-position of fatty acid residue was carried out. The key stage of the synthesis is hydrolysis of corresponding sphingomyelins catalyzed by phospholipase D from Streptomyces chromofuscus; the enzymatic yield has been raised to 50-70% by appliance of organic solvent in the incubation medium. PMID- 25702420 TI - Lipophilic prodrugs of a triazole-containing colchicine analogue in liposomes: biological effects on human tumor cells. AB - Colchicine site binders--blockers of tubulin polymerization--are potential antimitotic agents for anticancer therapy. To reduce their systemic toxicity and improve biodistribution, encapsulation in nanosized liposomes may be employed. Liposomes present a convenient means for preparation of injectable formulations of hydrophobic compounds, however colchicine as such is known to leak through the lipid bilayer. In this study, newly synthesized triazole-containing analogues of colchicine and allocolchicine, and their palmitic and oleic esters (lipophilic prodrugs) were tested for anti-proliferative activity and apoptosis-inducing potential. In contrast to colchicine conjugates, whose activities ranged with those of colchicine, allocolchicine derivatives exhibited drastically lower effects and were discarded. Liposomes of about 100 nm in diameter composed of egg phosphatidylcholine--yeast phosphatidylinositol--palmitic or oleic prodrug, 8 : 1: 1, by mol, were prepared by standard extrusion technique and tested in a panel of four human tumor cell lines. Liposome formulations preserved the biological activities of the parent colchicinoid the most towards human epithelial tumor cells. Moreover, liposomal form of the oleoyl bearing colchicinoid inhibited cell proliferation more efficiently than free lipophilic prodrug. Due to substantial loading capacity of the liposomes, the dispersions contain sufficient concentration of the active agent to test wide dose range in experiments on systemic administration to animals. PMID- 25702421 TI - Synthesis and antimicrobial activity of new heterocyclic compounds containing thieno[3,2-c] coumarin and pyrazolo[4,3-c] coumarin frameworks. AB - Reaction of 4-chlorocoumarin-3-carbonitrile with ethyl thioglycolate and ethyl glycinate hydrochloride leads to a series of title products. Hydrazinolysis of amino thienocoumarin carboxylate afforded the hydrazine derivative which underwent various reactions to build new heterocyclic rings containing thienocoumarin moiety. Chloro acetylation of aminoester compound afforded the chloro acetyl amino which underwent nucleophilic substitution reactions various amines. The following treatment with formaldehyde under Mannich conditions afforded the corresponding imidazo derivatives. Reaction of Ghloroacetylamino with potassium thiocyanate yielded ethylpyrimidothieno coumarin sulfanylacetate which was used as a versatile precursor for synthesis of other heterocycles. On the other hand, reaction of chloro coumarin carbo nitrile with hydrazine gave the aminopyrazolocoumaine which reacted with bifunctionally compounds to give the substituted pyrimido derivatives. Diazotization and coupling of aminopyrazole with ethylcyanoacetate yielded ethylaminotriazinopyrazolocoumarine carboxylate. Several of the compounds obtained demonstrated considerable antifungal and antibacterial activity in the in vitro test systems. PMID- 25702422 TI - [What are thrombophilias to-day?]. AB - Modern concepts of thrombophilia, its role in pathogenesis of arterial and venous thrombosis are discussed. The author's view of further development of this issue is expounded. PMID- 25702423 TI - [Ulcerative colitis and Crohn's disease. Modern views. Part 2. Diagnostics and differential therapy]. AB - Definitions of ulcerative colitis (UC) and Crohn's disease (CD) are given, related terminological problems are discussed, the prevalence of UC and CD in the population is considered along with their etiology, pathogenesis, clinical symptoms, complications and extraintestinal (systemic) lesions. Classification and diagnostics of UC and CD are discussed with special reference to current international recommendations on their diagnostics and differential treatment, rejuvenation and extraintestinal lesions. PMID- 25702424 TI - [Protein-synthesizing function of neutrophils and lipid-releasing ability of leukocytes in patients with atherosclerosis]. AB - Concentrations of defensins-alpha, lipoprotein(alpha), C-reactive protein, proBNP, VII- coagulation factor and von Wilebrandt factor were measured in supernatants of 3-day leukocyte cultures enriched with neutrophils in order to estimate their synthesis in patients with stable angina and atherosclerosis of lower extremities. In addition, in vitro tumor necrosis factor-alpha test was performed. Simultaneously, concentrations of serum interleukine-6, -8, defensins alpha, C-reactive protein, proBNP, VII-coagulation factor were determined. Neutrophil protein synthesis was impaired in the patients with stable angina. The same was true of defensins-alpha synthesis whereas production of lipoproteins, pro-BNP, C-reactive proteins, IL-8, and von Wilebrandt factor increased. Pathogenetic role of TNF-alpha was demonstrated. PMID- 25702425 TI - [Effect of basic therapy on clinical symptoms, quality of life and systemic inflammation in patients with chronic obstructive pulmonary disease]. AB - The study included 38 men with moderately severe chronic obstructive pulmonary disease (COPD) (mean age 60.6 +/- 10.2 yr) and 42 ones with severe COPD (mean age 61.2 +/- 7.2 yr). They were treated with tiotropium bromide, formoterol and beclomethasone dipropionate for 24 weeks (stage 1), TB alone for 12 weeks (stage 2) and TB+formoterol (long-acting bronchodilators, LABD) for another 12 weeks. Each stage was followed by evaluation of COPD symptoms using the St-George's Hospital questionnaire, daily requirements for short-acting beta-2 agonists (SABA), heart rate (HR), forced expiratory volume in the 1st second (FEV-1) before and after SABA test, hemoglobin saturation with oxygen in arterial blood during pulse oxymetry before and after 6 min walking test, blood surfactant protein D level (SP-D). The control group was comprised of 34 healthy men (mean age 62.3 +/- 5.8 yr). Patients with moderately severe COPD experienced worsening of clinical symptoms (p < 0.001), required more SABA (p < 0.001), had increased HR (p = 0.01) and SP-D levels (p = 0.01) whereas FEV-1 (p = 0.05) decreased during stage 2 as compared with stage 1. Positive dynamics of all these variables except COPD symptoms and HR was observed at stage 3. Alteration in the extent of basal therapy in patients with stage III COPD did not result in dynamics of clinical and laboratory characteristics. The data obtained suggest the necessity of combined therapy with LABD or triple basal therapy of moderately severe COPD and the possibility of therapy with one or two LABD having different sites of action in the patients with clinically stable stage II COPD. PMID- 25702426 TI - [Risk factors of coronary disease]. AB - Archival materials (medical histories, results of coronary angiography) of 307 patients with coronary artery disease (mean age 57.12 +/- 10.04 years) were analyzed. Professional activity of 59 patients was associated with prolonged exposure to industrial hazard (xenobiotics). It was shown that proximal and middle parts of the major epicardial coronary arteries were most susceptible to atherosclerosis. In these segments complete chronic occlusion most often occurred. In one of five patients with coronary artery disease changes in the coronary arteries were not visualized by angiography. Percentage of unaffected coronary arteries was significantly higher in patients who were not in contact with technogenic xenobiotics. The degree of stenosis depended primarily on the effects of harmful occupational exposures, triglyceride, HDLP and LDLP cholesterol levels and hypertension. The number of damages to coronary blood vessels was determined mainly by the age of the patients and the presence of diabetes. The results show the importance of harmful work conditions as a risk factor for atherosclerotic changes in the coronary vessels. PMID- 25702427 TI - [Proinflammatory cytokine levels depending on the stage of hepatic fibrosis in patients with metabolic syndrome and non-alcoholic fatty liver disease]. AB - AIM: To study levels of systemic inflammation markers and plasminogen activator inhibitor-1 (PAL-1) in patients with metabolic syndrome (MS) and establish their relationship with the progress of selected stages of non-alcoholic fatty liver disease (NAFLD). MATERIALS AND METHODS: 129 patients aged 18-59 yr with abdominal obesity and MS underwent elastometry for the assessment of the degree of fibrosis depending on concomitant metabolic disorders and measurement of proinflammatory cytokine levels. RESULTS: Disorders of carbohydrate metabolism in MS patients are associated with the high levels of systemic inflammation markers (CRP, TNF-alpha, IL-6) and a two-fold rise in the PAI-1 level. The progress of fibrosis is associated with the increase of cytokine levels. CONCLUSION: Patients with MS and NAFLD associated with disorders of carbohydrate metabolism need to be examined by elastometry for the detection of fibrosis with simultaneous measurement of IL-6 and PAI-1 levels as cardiovascular risk factors. PMID- 25702428 TI - [Organoprotective effects of the combination of perindopril and amlodipine depending on the renal functional state in patients with arterial hypertension]. AB - AIM: To estimate effect of combined perindopril/amlodipine therapy on structural and functional characteristics of the heart and blood vessels, intrarenal hemodynamics in patients with essential arterial hypertension (AH) depending on the degree of renal dysfunction. MATERIAL AND METHODS: 112 patients (63 men and 49 women) were included in the study; 35 of them (group 1) had the glomerular filtration rate (GFR) 90 ml/min/1.73 m2 or higher, 43 (group 2)--60-89 ml/min/1.73 m2 and 34 (group 3)--9-45 ml/min/i1.7 mi. The patients were treated with a fixed combination of dosage forms ofp erindopril and amlodipine at 10/5 mg/days or 10/10 mg/days for 24 weeks. RESULTS: Pronounced antihypertensive effect of therapy was comparable in all groups. However dynamics of structural and functional indicators of the left ventricle (LV) and a brachial artery was apparent only in group 3. Endothelium-dependent vasodilation, cardiac index and LV ejectionf raction increased significantly whereas myocardiumnmass index of L decreased .A reduction of resistance andpulsation indices was recorded in interlobar renal arteries especially in groups 2 and 3. Serunmcreatinine level and urinary albumin excretion were significantly decreased while GFR increased . CONCLUSION: Manifestations ofr emodeling ofc ardiovascular system and protective efficiencvyof the fixed combination ofp erin.opril and amlodipine correlate with the degree ofr enal dysfunction. PMID- 25702429 TI - [Comparative evaluation of subjective dyspnea sensation in patients with various diseases]. AB - Results of examination of 180 patients with various diseases (COPD, bronchial asthma, idiopathic interstitial pneumonia, chronic heart failure, obesity) are presented. They suggest qualitative and quantitative differences between dyspnea sensation that may be used for differential diagnostics of the above conditions. PMID- 25702430 TI - [Pleiotropic effects of atorvastatin and dynamics of quality of life characteristics in patients with hypertensive disease and metabolic syndrome]. AB - AIM: To study pleiotropic effects of atorvastatin during 8-week therapy of metabolic syndrome and estimate their relationship with dynamics of quality of life characteristics (QLC). MATERIAL AND METHODS: This 8-week study included 36 patients with stage II hypertensive disease associated with metabolic syndrome (MS). Comprehensive clinical, laboratory and instrumental examination was supplemented by QLC assessment using the MOS SF-36 questionnaire. RESULTS: 8-week therapy of stage II hypertensive disease associated with metabolic syndrome using individually selected doses of atorvastatin (20 to 40 mg/d) significantly reduced atherogenic cholesterol fraction and serum leptin levels; it had positive effect on carbohydrate and purine metabolism and safely maintained positive dynamics of subjective assessment of most points of the MOS SF-36 questionnaire. PMID- 25702431 TI - [Effectiveness and safety of losartan and its combination with amlodipine in therapy of arterial hypertension]. AB - AIM: To estimate effectiveness and safety of losartan and its combination with amlodipine in therapy of arterial hypertension. MATERIALS AND METHODS: The study based at 6 clinical centres was conducted in two stages. All 160 patients with grade I-II AH (103 women and 57 men aged 54 +/- 12 yr) participated in stage 1 of the study and patients of centre No 1 (n = 100) in stage 2. Losartan was used at a dose of 50-100 mg/24 h for 8 weeks (stage 1) and thereafter from week 9 to 26 (stage 2) in combination with amlodipine (5-10 mg/24 hr) if the desired AP level (< 140/90 mmHg) was not achieved. The following parameters were measured: systolic and diastolic AP (SAP and DAP) (office measurement and 24-hr monitoring), pulse wave propagation rate (PWPR), left ventricle mass index (LVMI), thickness of intima-media complex (IMT), blood biochemistry, tolerability of therapy and its side effects. RESULTS: Losartan alone decreased SAP and DAP from 150 +/- 11/91 +/- 7 to 132 +/- 12/81 +/- 8 mm Hg (office measurement) and from 144 +/- 10/86 +/- 9 to 128 +/- 12/76 +/- 10 mm Hg (24-hr monitoring); heart rate decreased fom 74 +/- 8 to 70 +/- 8/min (p < 0.05). SAP and DAP in 66 patients who completed stage 2 was 122 +/- 6/73 +/- 6 mm Hg or significantly lower than before therapy (147 +/- 9/87 +/- 9) (p < 0.001). Mean daily decrease of SAP and DAP according to 24-hr monitoring decreased from 144 +/- 10 to 128 +/- 12 and from 86 +/- 9 to 76 +/- 10 mm Hg respectively (p < 0.001). The target AP value was reached in 73% of the cases (99 out of 136 patients) after stage 1 and in 95% cases (63 out of 66) after stage 2. The values of LVMI (105 +/- 23 and 98 +/- 26 g/m2), PWPR from 16 +/- 2.1 to 13 +/- 3.5 m/s (p < 0.05), IMT (0.76 +/- 0.16 and 0.80 +/- 42 mm), and microalbuminuria (11.0 +/- 1.7 and 8.6 +/- 0.7 mg/24 hr) before and after completion of stage 2 were not significantly different in 66 patients (p > 0.05). Biochemical parameters of blood did not appreciably change. The safety profiles of both drugs were on the whole positive. Deaths and adverse reactions were absent barring clinically insignificant side effects in 28 of the 160 patients (17.5%). CONCLUSION: Losartan and amlodipine are effective and safe agents for AH therapy. PMID- 25702432 TI - [Clinical efficacy of reamberin in drug-addicts with hepatic lesions]. AB - Infusion of 1.5% reamberin solution was shown to be a safe tool for combined therapy of severe viral hepatitis in drug addicts with signs of polyorganic lesions. Reamberin had detoxicating, antioxidative, hepato- and nephroprotective effects associated with clinical improvement, reduced hospital stay and normalized biochemical characteristics. Moreover, it increased the serum antioxidative potential and non-specific resistance of the patients. PMID- 25702433 TI - [Iron deficiency anemia. Modern diagnostic and treatment strategy. Criteria for therapeutic efficacy]. AB - Modern views of epidemiology, etiology and pathogenesis of iron deficiency anemia are considered. Mechanisms of iron metabolism regulation are described based on the most important literature data and the results of the authors' research. The authors present their own and literature clinical experience of using iron containing drugs with reference to the existing recommendations on the treatment of iron deficiency anemia. Causes of low treatment efficiency are discussed and the ways to address this problem are proposed based on the published results of clinical research. PMID- 25702434 TI - [A case of multifocal fibrosis]. AB - We report a case of multifocal fibrosis extending retroperitoneally (Ormond's syndrome) with urinary tract obstruction and bilateral ureterohydronephrosis that resulted in chronic renal insufficiency. The development of mediastinal and pericardial fibrosis was accompanied by clinical symptoms of exudative and constrictive pericarditis. Fibrosis of cardiac conducting system was associated with compromised sinus node and intraventricular blockade. Paraaortic, paraorbital, and periportal extension of fibrosis was documented. Diagnosis was made based on clinical observations and results of MSCT. Duration of the disease was 20 years. Immunosuppressive therapy failed to improve the patient's condition because of irreversible structural and functional changes in the organs. PMID- 25702435 TI - [HIV infection in a patient with a referral diagnosis of sore throat]. AB - HIV infection was documented in a patient with hairy leukoplakia and oral candidiasis who had the wrong referral diagnosis of sore throat in the absence of dental complaints. Dental treatment at an infectious hospital led to regression of oral mucosa lesions, but failed to arrest the progress of severe pneumonia presumably caused by a specific pathogen. PMID- 25702436 TI - [Use of multislice spiral computed tomography to diagnose and control pulmonary complications in intensive care unit patients after neurosurgical interventions]. AB - OBJECTIVE: To perform a multifactorial analysis of the association of the development of complications in neurologic intensive care unit patients in the early (on days 1-3) postoperative period and with surgical conditions, mechanical ventilation parameters, and risk factors. SUBJECT AND METHODS: The results of multislice spiral computed tomography (MSCT) of the chest and brain were analyzed in 80 patients (34 men and 46 women; mean age, 52 +/- 13 years). RESULTS: In the study patient group, the incidence of pulmonary edema and pneumonia was not found to depend on the type of neurosurgical intervention and that of an inhaled anesthetic. There was a significant (p < 0.05) relationship of the development of pulmonary edema to anesthesia duration exceeding 6 hours and an increase in the risk of lung pathology in the presence of extrapulmonary complications in patients with high body mass index. CONCLUSION: Some pulmonary complications in neurosurgical patients are potentially preventable. Early postoperative chest MSCT in neurosurgical patients is essential to timely diagnose lung pathology. PMID- 25702437 TI - [Computed tomography in the assessment of causes of restrictive lung disorders in patients with pulmonary histiocytosis X]. AB - OBJECTIVE: To estimate the capabilities of computed tomography (CT) in revealing the anatomic causes of restrictive lung changes in patients with pulmonary histiocytosis X. SUBJECT AND METHODS: The results of examining 36 patients with pulmonary histiocytosis X, who underwent comprehensive functional study of external respiration (CRSER), CT, and high-performance CT (HPCT), were analyzed. RESULTS: According to the results of CRSER, the authors identified a group of patients with restrictive ventilation disorders, which included 7 men and 1 woman. The most common cause of restrictive disorders was generalized fibrous changes in lung tissue, which fails to result in its expansion. Multiple cysts were another cause of restrictive disorders in 2 patients. Fusion of individual cysts into large ones and the formation of a great number of paradoxically ventilated cysts were the third cause of restrictive disorders in pulmonary histiocytosis X, which was identified during HPCT. CONCLUSION: Comprehensive morphofunctional examination involving CRSER and high-resolution CT can reveal the unfavorable course of pulmonary histiocytosis X with the restrictive type of lesion. PMID- 25702438 TI - [Comparison of the data of computed tomography and bacteriological studies in the complicated forms of primary tuberculosis in children and adolescents]. AB - OBJECTIVE: To establish the causes of bacterial excretion in complicated primary tuberculosis in children and adolescents, by comparing the data of computed tomography and the results of bacteriological studies. MATERIAL AND METHODS: The material of the study was data on 36 children and adolescents with complicated primary tuberculosis, including 14 and 22 children and adolescents with and without bacterial excretion, respectively. All the children and adolescents underwent computed tomography and bacteriological studies encompassing luminescence microscopy and sputum and bronchial and gastric wash cultures for Mycobacterium tuberculosis. RESULTS: The bacterial excretion group showed a preponderance of a tuberculous process concurrent with the involvement of lung tissue and intrathoracic lymph nodes. Bacterial excretion was detected in the primary tuberculosis complex (50%), generalized tuberculosis process with the involvement of a few organs and systems (14.3%), and caseous pneumonia (7.1%). Bacterial excretion was accompanied by the tuberculous involvement of intrathoracic lymph nodes in 28.6%. In Group 1, sputum cultures and luminescence microscopy were carried out in all the children. At the same time, the most effective result was yielded by sputum culture that showed Mycobacterium tuberculosis in 78.6%; luminescence microscopy revealed mycobacteria in only 35.7% of cases. In 72.7% of the children and adolescents without bacterial excretion, the tuberculous process was located in the intrathoracic lymph nodes, without involving lung tissue in the pathological process. In the other 27.3%, the computed tomographic pattern of changes corresponded to that of the primary tuberculosis complex; in their presence, the tuberculous process ran with lymphogenic dissemination in 54.5% of cases and with bronchopulmonary involvement in 22.7%. In Group 2, a sputum culture was done in only 36.4% of the children and adolescents; microscopy was carried out in all. CONCLUSION: When computed tomography reveals the disseminated forms of primary tuberculosis with the concomitant involvement of lung tissue and intrathoracic lymph nodes in the presence of lung destructive changes, with the involvement of a few organs and systems in the pathological process, it is necessary to use all bacteriological studies, including culnolecular genetic methods, in order to establish the etiology of existing changes. PMID- 25702439 TI - [Computed tomographic semiotics of respiratory tuberculosis in HIV-infected patients]. AB - OBJECTIVE: to study the computed tomographic (CT) semiotics of respiratory tuberculosis in HIV-infected patients in relation to the degree of immunosuppression. SUBJECT AND METHODS: The study enrolled 74 patients with verified respiratory tuberculosis in the presence of HIV infection. According to the degree of immunosuppression and the Centers for Disease Control (CDC) and Prevention classification (Atlanta, USA, 1993), the patients were divided into 3 groups: (1) CD4 > or = 500 cells/microl (n = 10); 2) CD4 200-499 cells/microl (n = 28); (3) CD4 <200 cells/microl (n = 36). RESULTS: With spiral CT, focal changes with a predominance of clear-cut foci are visualized at a high frequency in the patients with pulmonary tuberculosis in the presence of HIV infection. In progressive immunosuppression, the CT pattern displays atypical syndromes (frosted glass-type foci, interstitial infiltration, and thin-walled cavities) with the lower rate of alveolar infiltration with confluent foci, as well as lung tissue decay. Enlarged intrathoracic lymph nodes are characteristic of 70.0% of the patients with HIV infection and tuberculosis regardless of the level of CD4 cells. CONCLUSION: As immunosuppression progresses, the CT pattern of respiratory tuberculosis in the presence of HIV infection shows as atypical syndromes (unclearly defined frosted glass-type focal changes, interstitial infiltrations, and thin-walled cavernous masses). A marked polymorphism in changes and a high rate of lymph node involvement are characteristic. PMID- 25702440 TI - [Diagnostic capabilities of single-photon emission computed tomography/computed tomography in the evaluation of perfusion disorders in pulmonary hypertension]. AB - OBJECTIVE: to study the diagnostic capabilities of single-photon emission computed tomography/computed tomography (SPECT/ CT) in the evaluation of lung perfusion in pulmonary hypertension (PH). SUBJECT AND METHODS: Ten patients with pulmonary hypertension were examined. Its diagnosis was verified in accordance with the Russian guidelines for the diagnosis and treatment of PH, by conducting a set of studies involving right heart catheterization. CT angiopulmonography was carried out in all the patients. At the same time all the patients underwent a radiological study on a combined SPECT/CT scanner with the intravenous injection of the radiotracer 9mTc-MAA (technetium-99m-labelled macroaggregated albumin) with an activity of 2-4 mCi. RESULTS: CT-angiopulmonography revealed no thrombi in the pulmonary artery lumen in 7 patients and confirmed the diagnosis of pulmonary thromboembolism (PTE) at the level of segmental vessels in 3. SPECT/CT examination identified 5 cases of non-thromboembolic PH and 5 cases of PTE with consideration for SPECT perfusion defects and no visible lung tissue (fibrous or other) changes on a CT scan. It should be noted that the 5 patients diagnosed as having PTE included 2 patients in whom PTE had not previously been diagnosed at CT angiopulmonography. This may be due to that this technique cannot always clearly visualize thrombi in the pulmonary vessel lumen at a subsegmental level. CONCLUSION: The inivestigations have indicated that, by clearly ivisualizing pulmonary aanatomy, morphology, and function, combined SPECT/CT imaging is a valuable diagnostic tool in detecting lung pathology. PMID- 25702441 TI - [Capabilities of radionuclide imaging study in the evaluation of pulmonary hemodynamics and right ventricular function in chronic obstructive pulmonary disease]. AB - OBJECTIVE: To assess the capabilities of radionuclide imaging studies in the evaluation of pulmonary hemodynamics and right ventricular function in chronic obstructive pulmonary disease (COPD). SUBJECT AND METHODS: Twenty-one patients aged 55.8 +/- 9.7 years with COPD (forced expiratory volume in one second (FEV1), 37.43 +/- 15.46%; BODE index, 6.30 +/- 2.66) were examined. A comparison group included 15 patients aged 56.3 +/- 8.3 years without cardiorespiratory pathology. All the patients underwent radionuclide angiopulmonography (RAPG), equilibrium radionuclide tomoventriculography (ERTVG), external respiratory function testing, and determination of the plasma levels of endothelin-1 and stable nitric oxide metabolites. RESULTS: Analysis of the results of ERTVG and RAPG in the study and comparison groups has shown that the chanrades in the lesser circucr moderate. r index and smoking intensity have demonstrated the statistically significant association with the indicators of pulmonary circulation. The plasma level of endothelin-1 was higher1in the patients with COPD than in those in the comparison group. CONCLUSION: Right dysfunction is moderate in COPD as this process is preceded by structural changes in the bronchi, parenchyma, and lung vessels. To identify lesser circulatory dysfunction in COPD, one should orient to the indicators of RAPG that can verify pulmonary hemodynamic disorders and to the data of ERTVG that shows right ventricular systolic and diastolic function and right atrial dimensions. PMID- 25702442 TI - [Inflammatory myofibroblastic tumor of the lung: problems in differential diagnosis]. AB - Inflammatory myofibroblastic tumor is a neoplasm of intermediate biological potential, a marked inflammatory component, and characteristic genetic changes. Once it was identified as an independent nosological entity from a rather heterogeneous group of inflammatory pseudotumors. This paper describes a case of inflammatory myofibroblastic tumor of the chest in a child, by discussing the criteria for differential diagnosis in the use of up-to-date radiology techniques. When thoracic neoplasms are detected, it is necessary to determine their site and the most likely origin organ as exactly as possible and to assess the X-ray pattern of the pathological process. By applying the state-of-the-art radiodiagnostic techniques, the clarification of the pattern of the disease makes it possible to choose an optimal treatment policy and a surgical procedure and scope, to avoid anesthesia overload, and to decrease the probability of resurgery. Our observation is to demonstrate possible problems in the diagnosis of inflammatory myofibroblastic tumor of the lung in childhood and to recall again the algorithm of radiological approaches to detecting mediastinal and lung masses. PMID- 25702443 TI - [Differential diagnosis of focal changes on computed tomography]. AB - The paper gives differential diagnostic signs in different pulmonary focal changes detected on computed tomography, characteristics of the major types of pulmonary foci, and a diagnostic algorithm in the detection of focal dissemination or mixed changes in lung tissue. PMID- 25702444 TI - [Reperfusion therapy for ST-segment elevation acute coronary syndrome: development trends in the Russian Federation]. AB - Based on the 2010-2012 data from the National Registry of Myocardial Infarction, the authors analyzed the scope and pattern of emergency medical care for patients with ST-segment elevation acute coronary syndrome (ACS). The proportion of patients undergoing emergency endovascular interventions of the total number of those with ST-segment elevation ACS was 22.3% in 2010, 22.1% in 2011, and 28.5% in 2012. Thrombolytic therapy rates were 27.6% in 2010, 30.2% in 2011, and 30.3% in 2012. The percentage of patients who did not receive any reperfusion was 50, 46, and 42% in 2010, 2011, and 2012, respectively. At the same time, the proportion of patients who were admitted to hospital within 12 hours after a pain attack, but received no revascularization was 25.7% in 2010, 19.3% in 2011, and 16.9% in 2012. Hospital deaths due to ST-segment ACS were 7.7, and 7.0, and 6.8% in 2010, 2011, and 2012, respectively. The reduction in hospital mortality rates of myocardial infarction was due to both the wide introduction of high technology care and the increased therapeutic window of the most available reperfusion method, such as thrombolytic therapy. PMID- 25702445 TI - [Neuroimaging of the penumbra in ischemic stroke]. AB - Brain ischemia has been recently a central problem in basic and applied studies in angioneurology. The latest investigations that give an insight into a relationship between metabolic changes and cerebral blood flow and make it possible to study ischemia at the molecular level and its changes over time have promoted the accumulation of fundamentally new facts and some reappraisal of existing ideas. Ischemic semishadow or penumbra is one of the most important presently studied phenomena. Detection of penumbra signs suggests that it is expedient to evaluate cerebral blood flow and metabolism when planning treatment (thrombolysis or neuroprotective therapy) and that it is important to predict the severity of ischemic stroke. Positron emission tomography (PET) is the reference method for detecting the penumbra; however, its application is limited in clinical practice. Computed tomography (CT) perfusion and perfusion MRI, a combination of diffusion-weighted and perfusion MRI, single-photon emission CT, and xenon-enhanced CT are most frequently used to evaluate a cerebral ischemia area and its blood flow. However, there are no standardized approaches to quantifying the thresholds for cerebral blood flow or unified algorithms for penumbra verification, which calls for further investigations. PMID- 25702446 TI - [Basic principles of optical coherence tomography in interventional cardiology]. AB - Optical coherence tomography (OCT) is a technique of visualizing biological tissues. This technique versus intravascular ultrasound study has high resolution. OCT has proved to be effective in interventional cardiology due to a resolution of 10 microm. As of now, there are two crucially new different OCT flow charts. One is tomography, the basis for which is a Michelson interferometer and an up-to-date tomography scanner, such as a Fourier transform spectral interferometer. This paper describes the brief history of OCT and the principle of its operation, compares two basically different technologies, and depicts the limitations of the technique when performed in different ways. PMID- 25702447 TI - [The first school for x-ray laboratory assistants at the A. N. Bakulev Research Center of Cardiovascular Surgery]. PMID- 25702448 TI - [Professor, academician of the Russian Academy of Medical Sciences Sergey Konstantinovich TERNOVOY: on the occasion of the 65th anniversary of his birth]. PMID- 25702449 TI - [In memory of professor, academician of the Russian Academy of Medical Sciences Anatoliy Fedorovich TSYB]. PMID- 25702450 TI - [Electrophysiological mechanisms of heart rate stability of the hibernating mammals during hypothermia]. AB - Despite more than 100 years of study, the mechanisms of natural resistance of the hibernator heart to cardiac arrhythmias during hypothermia has remained unknown. Renewed optimism in this area of research comes with recent methodological advances which enable to shed light on the hidden secrets of the hibernator's heart. This review discusses basic mechanisms of hypothermic ventricular arrhythmias and highlights some recent findings from the hibernator's heart electrophysiology, which may have an antiarrhythmic potential for the human heart as well. PMID- 25702451 TI - [Mismatch negativity and its hemodynamic equivalent (based on fMRI) in research of speech perception in healthy and in speech disorders]. AB - The review is devoted to the use of electrophysiological index of auditory discrimination, known as "mismatch negativity" (MMN), and its hemodynamic equivalent obtained by functional magnetic resonamce imaging (fMRI) to study speech perception in normal and pathological conditions. Most attention is paid to works with using MMN as a neurophysiological index of the phonemic hearing impairment in patients with sensory aphasia. The MMN applicability for examination of speech compensation degree is substantiated. Also the perspectives of simultaneous EEG-fMRI registration in exploring speech pathologe are considered. PMID- 25702452 TI - [Contribution of glucocorticoid hormones to gastroprotection]. AB - The fact that the disturbance of the normal stress reaction by the elimination of the hypothalamic-pituitary-adrenocortical (HPA) axis's functioning leads to negative effects on the body such as the development and aggravation of diseases proves that stress plays a leading role in maintaining the physical health of the body. Here we demonstrate this on the base of the results of our experimental studies related with gastric ulceration. The results show that the reduction in the stress-induced corticosterone release, or its actions, aggravates stress caused gastric erosion. The data do not support the traditional paradigm about ulcerogenic role of glucocorticoids in stress and suggest that glucocorticoids released during acute activation of the HPA axis are naturally occurring gastroprotective factors. PMID- 25702453 TI - [The acoustic characteristics of the speech signal as an indicator of the human functional state]. AB - The current review focuses on the capabilities and the efficiency of the functional state investigation based on the extralinguistic (nonsemantic) properties of the speech signal. This article provides an overview of the studies, which used such speech signal characteristics to investigate the human state during performing the operator activity, in the simulation of emotions, under emotional stress and in the presence of various mental disorders. PMID- 25702454 TI - [Event-related brain potentials when Russian verbs being conjugated: to the problem of language processing modularity]. AB - In the light of alternative conceptions of "two-system" and "single-system" models of language processing the efforts have been undertaken to study brain mechanisnis for generation of regular and irregular forms of Russian verbs. The 19 EEG channels of evoked activity were registered along with casual alternations of speech morphology operations to be compared. Verbs of imperfective aspect in the form of an infinitive, belonging either to a group of productive verbs (default, conventionally regular class), or toan unproductive group of verbs (conventionally irregular class) were presented to healthy subjects. The subjects were requested to produce first person present time forms of these verbs. Results of analysis of event related potentials (ERP) for a group of 22 persons are presented. Statistically reliable ERP amplitude distinctions between the verb groups are found onlyin the latencies 600-850 ms in central and parietal zones of the cortex. In these latencies ERP values associated with a presentation of irregular verbs are negative in relation to ERP values associated with the presentation of regular verbs. The received results are interpreted as a consequence of various complexity of mental work with verbs of these different groups and presumably don't support a hypothesis of universality of the "two system" brain mechanism for processing of the regular and irregular language forms. PMID- 25702455 TI - [Estimates of the size of inhibitory areas in crowding effects in periphery]. AB - In psychophysical experiments we studied how surround influences recognition of test objects. The tests were low-contrast Landolt rings of the size 1.1, 1.5 and 2.3 deg. Their centers were located at 13.2 deg from the fixation point. The additional objects were similar Landolt rings or rings without gaps. The distance between the centers of the test and the additional objects varied from 2.2 to 13.2 deg. Inone experiment, the task of the observer was to identify both the test objects and the surrounding objects. In the second experiment the stimulus layout was the same, but'identification of only the test stimulus was required. In both experiments, deterioration of performance was found at all distances between the test objects and the surround, but the deterioration was more significant when the observer carried out the dual task. The data showed that the size of the inhibitory areas in our case does not comply with the Bouma low which states that the size of the interaction areas are equal to half of the eccentricity where the test is presented. Further deterioration of performance in the dual task reveals the contribution of attention into peripheral crowding effects. PMID- 25702456 TI - [The comparative study of bioelectronic brain activity at the drug and Internet addiction]. AB - The comparative estimation of the bioelectric brain activities at different drug (heroin, opium, toxic organic join, home chemistry) and internet addiction are studied. These data can be interest for problem of general and specific mechanism of the influence of different factors, causing the addiction, on neirofisiological and neirochemical processes. PMID- 25702457 TI - [Neuronal mechanisms of motor signal transmission in thalamic Voi nucleus in spasmodic torticollis patients]. AB - Neural mechanisms of motor signal transmission in ventrooral (Voi) nucleus of motor thalamus during the realization-of voluntary and involuntary abnormal (dystonic) movements in patients with spasmodic torticollis were investigated by means of microelectrode technique. The high reactivity of the cellular Voi elements to various functional (mainly motor) tests was proved. Analysis of neuronal activity showed: (1) the difference of neural mechanisms of motor signal transmission in the realization of voluntary movement with and without the involvement of the pathological axial neck muscles, as well as passive and abnormal involuntary dystonic movements; (2) significance of sensory component in the mechanisms of sensorimotor interactions during realization of voluntary and involuntary dystonic head and neck movements, causing the activation of the axial neck muscles; (3) important role of the rhythmic and synchronized neuronal activity in motor signal transmission during the realization of active and passive movements. Participation of Voi nucleus in pathological mechanisms of spasmodic torticollis was shown. The data obtained can be used for identificatiori of Voi thalamic nucleus during stereotactic neurosurgical operations in patients with spasmodic torticollis for selection the optimum destruction (stimulation) target and reduction of postoperative effects. PMID- 25702458 TI - [Objective and subjective indexes of auditory motion processing]. AB - The study focused at the objective and subjective indexes of human hearing system sensitivity towards different types of moving sound stimuli. The experiment employed two methods: electrophysiological (MMN recording) and psychophysical method (two-alternative forced choice). Two types of spatial sound stimuli simulated gradual and abrupt sound motion from the head midline. MMN as an objective index of spatial discrimination has been obtained in response to the subthreshold and the suprathreshold stimuli. An increase of trajectory length of the moving stimuli resulted in an increase of the MMN amplitude and of subjective discrimination as well, although their correlation remained below the significance level. The results obtained are discussed from the point of view of preconscious perception of auditory spatial information. PMID- 25702459 TI - [Localization of brain electrical activity sources and hemodynamic activity foci during motor imagery]. AB - Studied are sources of brain activity contributing to EEG patterns which correspond to motor imagery. The accuracy of their classification determines the efficiency of brain-computer interface (BCI) allowing for controlling external technical devices directly by brain signals without involving muscle activity. Sources of brain activity are identified by Independent Component Analysis. Those independent components for which the BCI classification accuracy are at maximum are treated as relevant for motor imagery task. Two of the most relevant sources demonstrate strictly exposed event related desynchronization and synchronization of mu--rhythm during imagery of contra--and ipsilateral hands. These sources are localized by solving inverse EEG problem taking into account individual geometry of brain and its covers provided by anatomical MRI images. The sources are shown to be localized in BA 3A relating to proprioceptive sensitivity of the contralateral hand. Their positions are closed to foci of BOLD activity obtained by fMRI. PMID- 25702460 TI - [Influence of the movable support under one leg on human vertical posture during standing with asymmetric load on legs]. AB - The posture in standing subjects was studied when the legs were placed on supports of different degrees of mobility, as well as, when a part of body weight was voluntary transferred to one leg. The aim of these experiments was to explore how the mobility of support under the feet affects the balance and how this influence could be changed by the load distribution between the legs during standing. When both legs were on rigid immovable supports, the posture maintaining was accomplished by control of center of pressure (CP) of both legs. When the subject transferred the weight on one foot the posture was maintained mainly due to the control of CP of loaded leg. When the legs were on the supports of different mobility, the balance was maintained by the control of CP of the leg on the immovable support. This result was observed both when the subject stood with symmetric load on the legs and when the load was transferred to one leg. Even when the leg was unloaded but was placed on immovable support its CP moved more in comparison with the CP of loaded leg on movable support. The results show that the support mobility under the legs is a factor that determines the mechanisms of the posture maintenance, and this factor is more significant than the load distribution between the legs. So, we can conclude that the upright posture is maintained accounting the physical properties of the supports under the feet. PMID- 25702461 TI - [Tissue Doppler imaging of physiological asynchrony in intracardiac myocardium]. AB - Tissue Doppler imaging (TDI) is one of the most widely used methods of quantitative assessment of asynchrony of ventricular myocardium movements. To study the parameters physiological asynchrony using TDI, we examined 32 healthy subjects (18 male, 14 female, mean age of 35.8 +/- 11.0) with no history and signs of cardiovascular disease. The putative relative parameters of systolic and diastolic asynchrony (intra- and interventricular heterogeneity at basal and mid level of 8 myocardial segments) and traditional absolute values (septolateral S-L delay, QE, TsSD, TESD intervals) were measured and compared. We have established the range of normal values of the relative physiological myocardium asynchrony factors in healthy persons, and found that systolic and diastolic asynchrony is more evident at the midventricular level compared to basal level, and diastolic asynchrony is more apparent than systolic; this fact is discussed in terms of single-layer spiral myocardium theory. PMID- 25702462 TI - [Spinal circuit motor plasticity mechanisms in long-term sports activity adaptation]. AB - Man interacts with the environment through motor activities getting considerable sensor information from numerous internal and external sources. There is significant evidence of I-a afferents sensor information being critical in initiating of functional and morphological transformations in the periods of both development and maturation of cortex and spinal cord. Ia fibers ability to transmit sensor information, generated by muscle and motor activities, causes plastic changes in the central nervous system, enabling man to acquire new skills and movements and develop them. Therefore, understanding of activity-dependent neural plasticity mechanisms is of great importance in developing methods to perfect motor function, for example, in doing sports. This article presents the results of investigation of activity-dependent changes in spinal cord circuits in athletes. There are new data of cervical and lumbosacral motor spinal system plasticity as a result of various longterm sports activities. It is shown, in particular, that, in comparison with non-athletes, in the spinal cord of ski racers and basketball-players the representation area of upper and lower extremities muscles alpha-motorneurons with high reflex excitability is extended. Moreover,.the direction of the extension was specified by the upper segments activity. Besides, the volume of some revealed signs of cervical and lumbosacral spinal cord plasticity in the ski-racers, involved into moderate cyclic activity, was higher than that in the basketball-players, whose movements are more various. PMID- 25702463 TI - [Cardiovascular resistance to orthostatic stress in athletes after aerobic exercise]. AB - In the paper cardiovascular resistance to orthostatic stress in the athletes in the two-hour recovery period after prolonged aerobic exercise was investigated. The reaction of the cardiac (stroke volume and cardiac output) and peripheral blood volumes in the lower and upper limbs, abdominal and neck regions in response to the tilt-test before and during two hours after exercise (30 min, heart rate = 156 +/- 8 beats/min) was determined by impedance method: It is found that: (1) at baseline distribution of blood flow in favor of the neck-region in response to the tilt-test, in spite of the decrease in cardiac output, was more efficient in athletes, that was due to a large decrease in blood flow to the lower extremities, and increased blood flow in the neck region; (2) after exercise it was established symptoms of potential orthostatic intolerance: postural hypotension and tachycardia, reduced peripheral pulse blood volume, expressed in a standing position, and reduced effectiveness of the distribution of blood flow in the direction of the neck region; (3) the abilityto effectively distribute blood flow in favor of the neck region in athletes after exercise remained elevated, which was due to a large decrease in blood flow in the abdominal region at the beginning, and in the lower limbs at the end of the recovery period. PMID- 25702464 TI - [Investigation of the structure breathing pattern in competitive exercises have athletes kettlebell Lifters]. AB - The aim of the research is to determine the breathing pattern characteristics of kettlebell athletes. The main indicators were identified: breathing frequency (f), tidal volume (VT), minute ventilation (VE). We also searched for the dependence of these parameters using the weight of kettlebells and skill of the athletes.We used the spirograph SMP-21/01-"R-D" for qualitative and quantitative evaluation of the miain indicators of kettlebell athletes breathing patterns. Athletes who achieved Masters of Sports (MS) and candidate masters of sport (CMS), their changes in breathing during exercise occurs mainly on two parameters -the frequeincy of breathing and tidal yolume. We found out while the weight of the kettlebell increases the breathing frequen- cy increases and tidal volume decreases. Athletes who achieved International Masters of Sports (MSIC), they dominated the change of one parameter of breathing--on the tidalivolume, which increases from 0.7 +/- 0.11 to 1.2 +/- 0.11 (p < 001). In MSIC athletes tidal volume is approximately to level of 1.2 +/- 0.1, which invariably leads to an increase in breathing frequency. We discovered transition forms of breathing in competition exercises of Kettlebell sport. In our opinion high performance level of athletes is related to undergoing breathing regulation, trying constantly to keep same level of gas composition in functional residual capacity (FRC) at a time ofperforming competition exercises. This research highlights the importance of improving breathing patterns for Kettlebell athletes if they want to improve performance. PMID- 25702465 TI - [characteristics of the bone tissue metabolism in adolescents with the connective tissue's undifferentiated dysplasia]. AB - Examination of the markers of bone turnover (osteocalcin, N-terminal propeptide of type I collagen PINP and beta-isomerized carboxy-terminal cross-linking region of collagen type I beta-CrossLaps) was carried out in 17 adolescents at the age of 11-14 years with the connective tissue's undifferentiated dysplasia. There was the decreased content of the bone-formation markers (osteocalcin and PINP) in the blood serum compared to the control group (16 healthy adolescents at the corresponding age and gender) in the normal rate of the bone destruction marker (beta-CrossLaps), it is indicative of the process abnormality of the bone remodeling characterized by the intensity loss of the bone tissue formation with relative absorption predominance. The revealed disorders of the bone metabolism contribute to the osteopenia progression. It allows to attribute the adolescents with the connective tissue's undifferentiated dysplasia to the risk group in terms of the early osteoporosis. PMID- 25702466 TI - [Identification proteins cardiovascular system in urine healthy subjects during "dry" immersion]. AB - We analyzed the urine proteome in 14 healthy volunteers who underwent a 5-day dry immersion using proteomic analysis methods and bioinformatics approach. We identified 9 proteins related to cardiovascular system. It was shown that 5-day dry immersion modifies urine proteomic profile indicating renal, endocrine, circulatory and metabolic changes. Most of these changes are characterized by both a very rapid onset and very rapid restoration within return to normal conditions. PMID- 25702467 TI - [Ultrasound markers of the genetic pathology and early hemodynamic changes in human embryo]. AB - First trimester nuchal translucency (NT) and ductus venosus reverse blood flow (DVRBF) are used as ultrasound markers (UM) to determine the risk of fetal aneuploidy, heart defects and subsequent maternal preeclampsia. One pathophysiological explanation for these UM, encompassing both normal and pathological outcomes, is the development of transient heart failure due to increased vascular resistance (afterload). Left ventricular isovolumic relaxation time (LV IRT) was demonstrated as sensitive index of afterload increase in the second and third trimester fetus. The objective of study was to determine LV IRT in normally developing embryos and embryos with early UM of chromosomal and cardiac abnormalities and to test the hypothesis of embryonic hypertension as a cause of transient heart failure. An ultrasound study in 122 normally developing and 27 human embryos with increased NT (>3 mm) and DVRBF at gestational ages 11 14 weeks was perfomed. Mean LV IRT (41 +/- 3 ms) was 36.6 percent longer in embryos with UM as compared to the normal subset (30 +/- 2 ms) (p < 0.001). PMID- 25702468 TI - [Gender features of forced expiratory tracheal noises duration in human subjects aged between 17-25 years]. AB - In the sample consisting of 77 men and 53 women aged between 17-25 years it was shown that the duration of tracheal forced expiratory noises is significantly lower in women. However normalizing duration of tracheal forced expiratory noises to height, body mass and chest circumference neglected this difference. PMID- 25702469 TI - [Endotoxin aggression in pathogenesis of acute myocardial infarction and its origin]. AB - Endotoxin aggression of intestinal origin occurs in 89% of patients with acute myocardial infarction and may be a factor of the induction and/or progression of the disease. Sources of the development of endotoxin aggression often are Escherichia coli, Bacteroicles, Klebsiella, Proteus and Pseudomonas. PMID- 25702470 TI - [Changes in heart rate among the primary school children during the oral answers at the theoretical lessons]. AB - Studying the reaction of blood stroke volume of the children of the 1st-4th forms during oral replies revealed that the pupils who systematically do muscle training have significantly reduced stroke volume reaction during oral lessons by the 4th form. Therefore, systematic muscle training contributes to less extensive changes in stroke volume during oral answers of the primary school pupils. The children leading sedentary lifestyle have the reaction of blood stroke volume during oral replies increasing with age. Moreover, the children referred to the group of intensified physical activity, at the 4th form have stroke volume reduction to the initial values after the oral answers. It is going on much faster than within children from the test group. PMID- 25702471 TI - [Alexandr Abramovich Krasnovskii (1913-1993)]. PMID- 25702472 TI - [Hydrogen peroxide in artificial photosynthesizing systems]. AB - From the point of view of the concepts of hydrogen peroxide as a source of photosynthetic oxygen (hydrogen) coordination and photochemical properties of chlorophyll and its aggregates towards hydrogen peroxide were considered. The binding energy of H2O and H2O2 with chlorophyll and chlorophyllide depending on their form (monomers, dimers and trimers) was estimated by quantum chemical calculations. It is shown that at an increase of the degree of the pigment aggregation binding energy of H2O2 was more than the energy of H2O. Analysis of experimental results of the photochemical decomposition of hydrogen peroxide using chlorophyll was carried out. Estimates of the thermodynamic parameters (deltaG degrees and deltaH degrees) of the formation of organic compounds from CO2 with water and hydrogen peroxide were compared. The interaction of CO2 with H2O2 requires much less energy consumption than with water for all considered cases. The formation of organic products (formaldehyde, alcohols, carboxylic and carbonylic compounds) and simultaneous production of O2 under the influence of visible light in the systems of inorganic carbon--hydrogen peroxide--chlorophyll (phthalocyanine) is detected by GC/MS method, FTIR spectroscopy, and chemical analysis. PMID- 25702473 TI - [On mechanisms of fluorescence quenching by water]. AB - Mechanisms of fluorescence quenching of aromatic chromophores by water are reviewed. The mechanisms include polarity of chromophore environment, proton or electron transfer between the excited chromophore and water. A hypothesis is proposed that the quenching can be a result of chromophore-solvent hydrogen bond breaking in the excited state. PMID- 25702474 TI - [Two-dimensional model of a double-well potential: proton transfer when a hydrogen bond is deformed]. AB - The potential energy cross-section profile along a hydrogen bond may contain two minima in certain conditions; it is so-called a double well potential. The H-bond double well potential is essential for proton transfer along this hydrogen bond. We have considered the two-dimensional model of such double well potential in harmonic approximation, and we have also investigated the proton tunneling in it. In real environments thermal motion of atoms or conformational changes may cause reorientation and relative shift of molecule fragment forming the hydrogen bond and, as a result, the hydrogen bond isdeformed. This deformation is liable to change the double well potential form and, hence, the probability of the proton tunneling is changed too. As it is shown the characteristic time of proton tunneling is essentially increased by even small relative shift of heavy atoms forming the H-bond and also rotational displacement of covalent bond generated by one of heavy atoms and the proton (hydrogen atom). However, it is also shown, at the certain geometry of the H-bond deformation the opposite effect occurred, i.e., the characteristic time is not increased and even decreased. Notice that such its behavior arises from two-dimensionality of potential wells; this and other properties of our model are discussed in detail. PMID- 25702475 TI - [measurement of optical density in infrared absorption maxima of oxygen molecules based on their photochemical activity upon direct laser excitation]. AB - Generation of singlet oxygen upon excitation of oxygen molecules by infrared diode lasers has been studied in organic media (carbon tetrachloride and acetone) saturated by air under normal pressure and temperature. A new approach to analysis of the experimental data has been developed taking into account a degree of overlapping of the spectral bands of oxygen and laser radiation. Optical density, molar absorption coefficient and the cross section of light absorption were determined for the main absorption maxima of O2 at 765 and 1273 nm. The results are compared with the data of previous studies. A significance of the obtained results for elucidation of photophysics and photochemistry of oxygen molecules and investigation of biological action of laser radiation is discussed. PMID- 25702476 TI - [Investigation of tautomeric composition of cytosine by multiphoton excitation spectra. I. Resonance hyper-Raman spectra]. AB - For the first time the quantum-mechanical calculations of intensity distribution in the resonance hyper-Raman spectra of the six tautomeric forms of cytosine were performed. It has been confirmed that in the aqueous solution of cytosine (pH 3.0) there exist several molecular structures: cytosine in the canonical amino oxo tautomeric form, cation, as well as cys-imino-oxo and cys-amino-hydroxy tautomers; in the gaseous phase at 235 degrees C cys-imino-oxotautomer dominates with the presence of small amount of cys-, trans-, amino-hydroxy tautomers and the caconical form of cytosine. PMID- 25702477 TI - [Investigation of tautomeric composition of cytosine by multiphoton excitation spectra. II. Two-photon absorption spectra]. AB - For the first time the quantum-mechanical calculations of intensity distribution in the two-photon absorption spectra of the six tautomeric forms of cytosine were performed. It has been confirmed that in the aqueous solution of cytosine (pH 3.0) there exist several tauromeric forms: canonical amino-oxo tautomeric form, cation, as well as cys-imino-oxo and cys-amino-hydroxy tautomers. PMID- 25702478 TI - [On peculiarities of temperature dependences of water spectra in the terahertz frequency domain]. AB - We analyzed spectra of light and heavy water at temperatures from 4 up to 50 degrees C in a frequency range of 0.15 to 6.5 THz. It was shown that the amplitude of high-frequency relaxation absorption band with its maximum at 0.5 THz extends with increasing, temperature and this temperature dependence for light water has a marked feature at 35-40 degrees C as a sharp growth. This fact is noteworthy because this range corresponds to physiological values of a body temperature of the warm-blooded organisms. At the same time, the analogous temperature dependence for heavy water in the considered temperature range lacks this particular feature. Thus, the water with its properties differs significantly not only from other fluids, but also from its own isotopologues. PMID- 25702479 TI - [Investigation of mechanisms of interaction between inulinase from Kluyveromyces marxianus and the matrices of ion-exchange resins and fiber]. AB - It is established that ion exchange resins AV-17-2P, KU-2, AV-16-GS, AM 21A, IMAC HP, PUROLITE and fiber VION KN-1 can be applied as carriers for inulinase immobilization. The analysis of IR spectra for an enzyme, carriers and heterogeneous enzyme preparations showed that inulinase binding to matrices of various carriers occurs in general through electrostatic interactions. It is assumed that the mechanisms of interaction between inulinase from Kluyveromyces marxianus and the matrices of cation- and anion exchange polymers differ essentially from each other: different sites of protein molecule take part in adsorption that causes various conformational reorganizations in an enzyme molecule. PMID- 25702480 TI - [The Carnot efficiency and plant photosystems]. AB - The concept that the Carnot efficiency places an upper limit of 0.60-0.75 on the thermodynamic efficiency of photosynthetic primary photochemistry is examined using the PSI-LHCI preparation. The maximal quantum efficiency was determined approximately 0.99 which yielded a thermodynamic efficiency of 0.96, a value far above that predicted on the basis of the Carnot efficiency. The commonly presented reasoning leading to the Carnot efficiency idea was therefore critically examined. It is concluded that the crucial assumption that the pigment system, under illumination, is in equilibrium with the incident light field, at a black body temperature of Tr, is erroneous, as the temperature of the excited state pigments was experimentally shown to be that of the sample solvent (thermal bath), 280 K in this case. It is concluded that the classical reasoning used to describe the thermodynamics of heat systems is not applicable to "photonic" systems such as plant photosystems. PMID- 25702481 TI - [Mathematical modelling of delayed calcium deregulation in brain neurons caused by hyperstimulation of glutamate receptors]. AB - Mathematical model presented in this paper is based on the data obtained in experimental studies of the mechanism of glutamate-induced deregulation of Ca2+ homeostasis and mitochondrial depolarization in cultured nerve cells. According to our hypothesis the secondary Ca2+ increase during a prolonged glutamate challenge is mainly due to a profound mitochondrial depolarization which stops mitochondrial Ca2+ uptake in the face of continuous Ca2+ influx into the cell. It is supposed that a progressive decrease in mitochondrial NADH during glutamate exposure greatly enhances sensitivity of mitochondria to intracellular Ca neurotoxicity. A system of equations developed in this work made it possible to provide a satisfactory simulation of most of experimental events observed in the present study. PMID- 25702482 TI - [Studying the effect of Dimebon and NT-1505 on microviscosity of mice brain synaptosomal membranes in vivo by EPR spin labeling method]. AB - In this work membrane fluidity alterations in synaptosomes, isolated from mice brain tissue, at chronic administration of neuroprotectors Dimebon and NT-1505 in vivo were studied. Membrane microviscosity was measured by electron paramagnetic resonance spin labeling of 2,2,6,6-tetramet-hyl-4-capryloyl-oxylpiperidine-l-oxyl (lipid probe) and 5,6-benzo-2,2,6,6-tetramethyl-1,2,3,4-tetrahydro-gamma carboline-3-oxyl (near protein probe). It was shown that the neuroprotectors Dimebon and NT-1505 affect a membrane structure. Despite the difference in membrane structures, fluidity of the lipid bilayer in time returned to control values. PMID- 25702483 TI - [Estimation of surface potential of lymphocytes from patients with leukemia using Kelvin probe mode]. AB - The feasibilities of the Kelvin probe mode were shown to estimate a surface potential of lymphocytes from the patients with leukemia. Having compared the values of the surface potential obtained by the traditional method of microelectrophoresis and by the Kelvin probe mode, it was established that the use of the atomic force microscope made it possible to obtain data which were of specified diagnostic importance while studying lymphocyte functional status at different stages in leucopoiesis and indicated progression of the pathological process. PMID- 25702484 TI - [A role of trophoblastic cells in regulation of mouse blastocyst survival in vitro after microinjection and osmotic stress]. AB - We have evaluated the morphology of the mouse preimplantation embryos at developmental stages from morula to late-blastocyst after two different impacts: microinjection of modified Witten's medium and osmotic stress in physiological osmolarity (310 mOsM), in 5% glucose (560 mOsM) at high concentration of NaCl (614 mOsM). Results of our research showed that these stresses caused similar changes in embryo morphology: volume was reduced followed by its recovery in culture medium (osmolality was less than a physiological value, 260 MOsM). The ability of embryos to recover the volume and morphology up to the initial level depends on a stage of embryo development and consequently competence of TB cells. In this study it was revealed that a key role in regulation of volume homeostasis after microinjection and after short-time (30-60 min) osmotic stress belongs to TB cells. Both physical effects induce the further embryo development in vitro up to the formation of primary colonies of embryonic and trophoblastic cells. These data could be used to develop the morphological criteria for a prediction of blastocyst-stage embryonic implantation potential. PMID- 25702485 TI - [Zinc essentiality and toxicity. Biophysical aspects]. AB - In this review the current conceptions concerning zinc biology, its metabolism and transport into the cells, its homeostasis, a role in the functioning of the human immune and endocrine systems, participation in cell signaling and its cytotoxicity, as well as the biophysical mechanisms of action of zinc ions action at the elevated concentrations on human blood cells were analyzed. PMID- 25702486 TI - [Analysis of the mechanism of intensification of fermentation process using yeast cells in a suspension of high-dispersed oxides]. AB - The differential microcalorimetry was used to explore an influence of particles of silicon dioxide, and also other high-dispersed oxides (0.05% of masses.) in water suspension of yeast cells on intensification of the process of their fermentation in endogenous metabolic conditions. It was shown that intensification of the processes of the vital activity of yeast microorganisms was observed in the specified interval of the concentration of silicon dioxide hydrosol particles. Mechanisms of interaction between SiO2 particles and a surface of a cellular organism, as well as interaction between SiO2 particles and one of metabolism products--carbon dioxide were studied. It was found out, that Al2O3, TiO2 hydrosols also had a stimulating effect, but it is lower compared to that of SiO2. PMID- 25702487 TI - [application of the analytical transmission electron microscopy techniques for detection, identification and visualization of localization of nanoparticles of titanium and cerium oxides in mammalian cells]. AB - This work represents the results of the study on applicability of the modern methods of analytical transmission electron microscopy for detection, identification and visualization of localization of nanoparticles of titanium and cerium oxides in A549 cell, human lung adenocarcinoma cell line. A comparative analysis of images of the nanoparticles in the cells obtained in the bright field mode of transmission electron microscopy, under dark-field scanning transmission electron microscopy and high-angle annular dark field scanning transmission electron was performed. For identification of nanoparticles in the cells the analytical techniques, energy-dispersive X-ray spectroscopy and electron energy loss spectroscopy, were compared when used in the mode of obtaining energy spectrum from different particles and element mapping. It was shown that the method for electron tomography is applicable to confirm that nanoparticles are localized in the sample but not coated by contamination. The possibilities and fields of utilizing different techniques for analytical transmission electron microscopy for detection, visualization and identification of nanoparticles in the biological samples are discussed. PMID- 25702488 TI - [The influence of fibroblast growth factor (FGF2) on cardiomyocytes differentiation of mesenchymal stem cells of bone marrow ex vivo]. AB - The influence of FGF2 on the efficiency of cardiomyocytes differentiation of mesenchymal stem cells (MSC) of bone marrow induced by 5-azacetidine (5-aza) was studied. The effect of FGF2 developing by the 14th day after the combined action of a differentiating agent and growth factor was manifested in an increase in Mef2A, Mef2D and gene transcription and a rise of ionized Ca2+ concentration in cytoplasm keeping cell viability and proliferation activity. In the presence of FGF2 this approach provided cardiomyogenesis and the increase in the formation of early precursors of cardiomyocytes. PMID- 25702489 TI - [Studying the influence of some reactive oxygen species on physical and chemical parameters of blood]. AB - The aim of this work was to estimate the dynamics of blood physical and chemical parameters when blood specimens were processed by singlet oxygen in vitro. Our experiments were executed with whole blood specimens of healthy people (n=10). Each specimen was divided into five separate portions of 5 ml. The first portion was a control (without any exposures). The second one was processed by an oxygen ozone mixture (at ozone concentration of 500 mcg/l, the third portion--by oxygen, and the fourth and fifth ones were processed by a gas mixture with singlet oxygen (50 and 100% of generator power). In blood samples after processing we studied the activity of lactate dehydrogenase, aldehyde dehydrogenase and superoxide dismutase, erythrocyte and plasma levels of glucose and lactate, acid-base balance and the partial pressure of gases in blood. It was found out, that blood processing by singlet oxygen leads to optimization of energy, detoxication and antioxidant enzymes functioning with changes in plasma and erythrocyte level of glucose and lactate, normalization of blood gases level and acid-base balance. Our results show, that the effect of singlet oxygen on enzyme activity is more pronounced than exposure to an oxygen-ozone gas mixture. PMID- 25702490 TI - [Influence of mediator diffusion on trigger mode of a synapse]. AB - The model of postsynaptic membrane activation, is proposed in the paper. This model takes into account inhomogeneity of mediator's space distribution in the region of the synaptic cleft as well as nonlinear nature of interaction between the mediator and receptors on the postsynaptic membrane. Based on equations of this model stationary solutions are calculated for mediator distribution in the synaptic cleft and the number of activated receptors. Kinetics of reactions for activation and deactivation of receptors is analyzed within the concept of a trigger mode of the synapse. It is shown that activation-deactivation processes and redistribution of the mediator in the cleft can be interpreted as successive transitions between two stationary states of the system. Time of transitions between these states is found and its dependence on system parameters (in particular on the width of the synaptic cleft) is analyzed. PMID- 25702491 TI - [A new approach to analysis of participation of oxidative processes in regulation of metabolism in animal tissues]. AB - A new approach to the analysis of the oxidative processes participated in regulation of metabolism in norm and the assessment of the biological consequences under the action of damaging factors of different nature and intensity for animal groups is suggested using the analysis of interrelations between the different parameters of the physicochemical regulatory system of the lipid peroxidation in tissues of the laboratory mice (the phospholipid composition, amounts of the oxidation products in lipids). by changes of the scale and direction of interrelations between the reciprocal parameters of the lipid peroxidation system in norm. PMID- 25702492 TI - [Effect of vibratory stimulation of foot support areas in rats on the functional state of leg muscles and the content of N2A titin isoforms in gravity relief]. AB - In this work, we studied the effect of vibratory stimulation of the foot support zones on the functional state of the leg muscles and the content of N2A titin isoforms in rats under simulated microgravity (hanging model). The results of this study showed that vibratory support zones of the rat foot in a gravity discharge may reduce the incidence in amplitude of the leg muscle motor response and undesirable reduction of the titin content. PMID- 25702493 TI - [Studying the effect of heavy metals on tissue protein of an edible fish Cirrhinus mrigala under the influence of pH and water hardness]. AB - The goal of the study was to investigate the influence of pH and water hardness on protein contents of muscle tissues of Cirrhinus mrigala fingerlings by Fourier transform infrared spectroscopy. FT-IR spectra revealed significant differences in absorbance intensities between control and toxic metal-treated muscle tissues, reflecting a change in protein contents due to heavy metals, nickel and chromium, influence at different pH and water hardness. Metal toxicity is also more pronounced at pH 9.0 than in hard water. PMID- 25702494 TI - [Isotopic effects of low concentration of deuterium in water on biological systems]. AB - Isotopic effects of deuterium in water are studied in a broad range of concentrations on a number of biological objects of different organization levels. The results obtained show that biological objects are sensitive to variations of isotope composition in water. A decrease or increase in deuterium concentrations in water may cause activation or inhibition of biological functions. The values of biological isotopic effects of low deuterium concentration may even be higher than those of high deuterium concentration. No regularity in response for all the objects studied failed to find out in a range of deuterium concentration in water from 4 ppm to 1%. PMID- 25702495 TI - [Functional characteristics of yeast cells in nutrient aqueous solution enriched with ortho-H2O isomers]. AB - It has been experimentally established that cultivation of yeast cells in depleted, dietary or normal nutrient aqueous solutions enriched with ortho-H2O spin isomers is accompanied by an increase in the amount of carbon dioxide produced by the cells and an increase in their biomass. It has been revealed that the rate of metabolic processes and biological activity depends on the quality of nutrition and enhances in time in both nutrient solutions. In contrast, the reproductive function and the rate of cell division are insusceptible to the components of nutrition, but intensified in a solution enriched with ortho-H2O similar to retardation of aging. The observed effects are discussed in assumption that an increase of a portion of ortho-H2O molecules occurs in the neighborhood of water channels in the cell membrane that let through only monomers of H2O and determine the rate of metabolic processes. PMID- 25702496 TI - [Parameter identification for systems of nonlinear differential equations by the example of Lotka-Volterra model]. AB - In this article we study the inverse problem of finding coefficients of Lotka Volterra's equations on one given solution. The conditions of the uniqueness and existence of the inverse problem are found. PMID- 25702497 TI - [Multilingualism and child psychiatry: on differential diagnoses of language disorder, specific learning disorder, and selective mutism]. AB - Multilingualism poses unique psychiatric problems, especially in the field of child psychiatry. The author discusses several linguistic and transcultural issues in relation to Language Disorder, Specific Learning Disorder and Selective Mutism. Linguistic characteristics of multiple language development, including so called profile effects and code-switching, need to be understood for differential diagnosis. It is also emphasized that Language Disorder in a bilingual person is not different or worse than that in a monolingual person. Second language proficiency, cultural background and transfer from the first language all need to be considered in an evaluation for Specific Learning Disorder. Selective Mutism has to be differentiated from the silent period observed in the normal successive bilingual development. The author concludes the review by remarking on some caveats around methods of language evaluation in a multilingual person. PMID- 25702498 TI - [Trends of psychotropic medication use among children and adolescents in Japan data from the national insurance claims database between 2002 and 2010]. AB - Context: Despite evidence of an increase in the number of young patients receiving mental health treatment, most psychotropic medications have not been approved for the treatment of children and adolescents by the Ministry of Health, Labour and Welfare. There is little data available on psychotropic medication use in children and adolescents in Japan. OBJECTIVE: To establish the prevalence of psychotropic medications and multiclass psychotropic polypharmacy in outpatients aged 18 years or younger in Japan between 2002 and 2010. DESIGN: We used the national insurance claims database from the 2002-2010 Survey of Medical Care Activities in Public Health Insurance in Japan. OUTCOME MEASURES: Prevalence of psychotropic prescription and psychotropic polypharmacy. RESULTS: Our study dataset comprised 233,399 outpatient visits. Among patients aged 6-12 years between 2002-2004 and 2008-2010, there was a significant increase in the prevalence of ADHD medications (Odds Ratio [OR] 1.84; 95% Confidence Interval [CI] 1.33, 2.56) and antipsychotics (OR 1.58 95% CI 1.06, 2.34), and a significant decrease in the prevalence of sedative-hypnotics (OR 0.67; 95% CI 0.46, 0.99). Among patients aged 13-18 years, there was a significant increase in the prevalence of ADHD medications (OR 2.49; 95% CI 1.34, 4.62), anti-psychotics (OR 1.43 ; 95% CI 1.20, 1.70), and antidepressants (OR 1.37; 95% CI 1.09, 1.72). Medications that were most frequently involved used in combination of two or more psychotropic agents were mood stabilizer (93%), followed by antidepressants (77%), sedative-hypnotics (62%), antipsychotics (61%), and ADHD medications (17%). CONCLUSION: Our study revealed an increase in the use of off-label antipsychotics and antidepressants among children and adolescents. Therefore, there is an urgent need for clinical trials to evaluate the efficacy of psychotropic medications for use in children and adolescents, and the development of a clinical database to monitor the associated long-term risks and benefits. PMID- 25702499 TI - [Contributions of Catholicism, Protestantism, and Buddhism to medicine--taking into account the future of palliative medicine in Japan]. AB - It is worth recalling that Catholicism and Protestantism have each played an important role in the development of modern medicine. Before modern medicine become widely accepted, palliative care was addressed by Catholic abbes in Western Europe, as well as by Buddhist monks in Japan. Palliative medicine exceeds the capability of contemporary medicine in general, insofar as spirituality is an important dimension when doctors are caring for patients who may be facing death. Being aware of this problem, the author tries to elucidate the contributions of religion to medicine, with the intention of considering the future of palliative medicine in Japan. PMID- 25702500 TI - [Cytoarchitecture of the vitellaria of two monogenean species, parasites of the holocephalan fish Chimaera monstrosa L. with analysis of vitelline structure in the Neodermata]. AB - The ultrastructural features of the vitelline follicles of ectoparasitic monogenean Chimaericola leptogaster Leuckart, 1830 (Polyopisthocotylidea, Chimaericolidae) and endoparasitic Calicotyle affinis Scott, 1911 (Monopisthocotylidea, Monocotylidae), parasites of the gills and cloaca of a holocephalan fish, Chimaera monstrosa L., are described. The vitelline follicles of the studied monogenean species are composed of the cells of a single type, vitellocytes at various stages of development. Special isolation of the vitellarium from the surrounding tissue in C. leptogaster is absent. Instead, a close relationship between bordering vitelline cells and intestinal cells of numerous branches of the caecum diverticula is observed. However, vitelline follicles of C. affinis are enclosed in a thin fibrous sheath. Some differences in the composition of the vitelline material in mature vitellocytes of C. leptogaster and C. affinis are revealed, these include the presence of different number of vitelline globules within a cluster, up to 30 globules in C. leptogaster cluster and up to 50 globules in C. affinis, and the presence of moderately electron-dense homogeneous lipid droplets in C. affinis and heterogeneous droplets in C. leptogaster. The mature vitelline cells of C. leptogaster are recognised by the presence of clusters with granular bodies inside them, these bodies have the same size as vitelline globules. In developing vitellocytes of C. affinis, the glycan vesicles about 3.5 MUm in diameter are present; in mature vitellocytes, these vesicles are destructed; this process is accompanied by liberation of glycogen rosettes and agglomerate of the dark material. Morphological variations of vitelline cytoarchitecture in the Neodermata are discussed. PMID- 25702501 TI - [Influence of the minnow Phoxinus phoxinus L. sex on the composition of the parasite fauna and component community structure of parasites]. AB - 225 minnow specimens of the 2(+)-3+ age were collected and studied using the standard technique of the total parasitological dissection. The component parasite community in a period of studies was well-established. This state is characterized by maximum species richness and biomass values. The results showed that probable differences in the infection by parasites of minnow females and males could not be ignored and underestimated. Indeed, the differences in minnow of different sex's infestation by parasites may be absent or present. In some reservoirs females are stronger affected by the same kinds of parasites, in other reservoirs, males are affected stronger. In comparison to males, in females parasites are more commonly represented by single individuals. Discussed differences may manifest themselves only in a certain seasonal condition of a fish. The structure of parasitic communities in hosts of different sex is equal and almost identical to that obtained in mixed host samples. PMID- 25702502 TI - [Comparison of taxonomic importance of morphological and molecular-genetic characters in systematics of Microsporidia (Microsporidia) of blood-sucking mosquitoes (Diptera: Culicidae)]. AB - Comparative analysis of the taxonomic position of microsporidians from mosquitoes of the family Culicidae, for which SSU rDNA sequences data were obtained, demonstrates partial contradiction of systems based on morphological and phylogenetic characteristics. Representatives of the genera Anncaliia Issi. et al., 1993 and Vavraia Weiser, 1977 constitute separate evolutionary branches of the phylogenetic tree of microsporidians of blood-sucking mosquitoes. Representatives of other genera, for which the SSU rRNA sequences data were obtained (Amblyospora Hazard, Oldacre, 1975, Andreanna Simakova et al., 2008, Culicospora (Kudo, 1921), Weiser, 1977, Culicosporella Hazard, Savage, 1970, Edhazardia (Kudo, 1930), Sprague, Fucuda, 1989, Hazardia Weiser, 1977, Hyalinocysta Hazard, Oldacre, 1975, Novothelohania Andreadis et al., 2012, Parathelohania Codreanu, 1966, Senoma Simakova et al., 2005, and Trichoctosporea Larsson, 1994), form a separate, monophyletic group in the tree of Microsporidia. They are closely related and probably possess a common ancestor. The genera Amblyospora, Culicospora, Edhazardia, and Trichoctosporea were placed in the family Amblyosporidae with the revision of the diagnosis. On the basis of the obtained data on morphology and molecular phylogeny we placed Intrapredatorus barri Chen et al:, 1998 into the genus Amblyospora as Amblyospora barri, comb. nov., and also the species Amblyospora bakcharia Andreadis et al., 2012, A. kazankia Andreadis et al., 2012, A. mocrushinia Andreadis et al., 2012, and A. rugosa Simakova, Pankova, 2005 into the genus Trichoctosporea as Trichoctosporea bakcharia comb. nov., T. kazankia comb. nov., T. mocrushinia comb. nov., and T. rugosa comb. nov. Microsporidians of blood-sucking mosquitoes originally possessed complicated life cycles with transovarial and oral transmissions and with the presence of intermediate hosts (lower crustaceans). Later, some microsporidians had lost a part of their life cycle, either during disorganization of habitats of main and intermediate hosts, or as a result of adaptation to environmental and (or) physiological characteristics of hosts. Changes in the life cycle occurred rather rapidly in comparison with the duration of evolutionary development and had an adaptive character. Differences in the life cycle of parasites of the genera Amblyospora, Culicospora, Culicosporella, Edhazardia and Hyalinocysta possibly represent an adaptation increasing the probability of host-parasite meeting. In the process of evolution, spores formed stronger spore wall with thick exospores and endospores. The appearance of thick spore walls in mature spores promoted the development of the apparatus of extrusion process, namely the flattening of the polaroplast chambers and the emergence of long anisofilar polar filament. PMID- 25702503 TI - [Fleas of small mammals in St. Petersburg]. AB - In the territory of St. Petersburg, 26 sites situated in areas with 4 types of forest vegetation, were examined. Fleas of 16 species were collected from small mammals belonging to 13 species. The flea Ctenophthalnius agyrtes was the most abundant species. Two types of flea communities can be distinguished, including communities of fleas of forests and forest parks and communities of fleas of urban parks and cemeteries. PMID- 25702504 TI - [New records of ectoparasites of the eastern water bat Myotis petax Hollister, 1912 (Vespertilionidae, Chiroptera) and the revision of the previous material collected from Myotis daubentonii s. lato in Eastern Palaearctic]. AB - New findings of ectoparasites from the eastern water bat Myotis petax Hollister, 1912, belonging to the Siberian-Russian Far Eastern complex and earlier attributed as a subspecies of the Daubenton's bat Myotis daubentonii s. lato, is given. Fourteen species of bloodsucking arthropods feed on M. petax; these species include 4, 3, and 7 species of gamasid mites, fleas, and bloodsucking flies, respectively. PMID- 25702506 TI - [Clinical trial and evidence]. PMID- 25702505 TI - [Occurrence of helminths in amphipods Gammarus lacustris Sars, 1863 (Amphipoda: Gammaridae) from Kronotskoe Lake (Kamchatka)]. AB - Metacercariae of Crepidostomum metoecus (prevalence 2.0%), procercoids of Cyathocephalus truncatus (2.9%), and nematodes of the family Cystidicolidae (17.6%) were found in the body cavity of amphipods Gammarus lacustris from the Kronotskoe Lake. The nematodes were presented by Cystidicola farionis (third stage juvenile) and Ascarophis sp. (adult and fourth-stage juvenile). PMID- 25702507 TI - [Japan Surgical Society and Gaihoren]. PMID- 25702508 TI - [On the occasion of the 50th anniversary of Japanese Society of Pediatric Surgeons]. PMID- 25702509 TI - [Progress in and outcomes of neonatal surgery over the past 50 years]. AB - The Japanese Society of Pediatric Surgeons has performed a nationwide survey of neonatal surgery every 5 years during the 50 years since its foundation. The number of neonatal surgical cases has increased 5-fold during those 50 years, while the mortality rate has decreased from 60% to 15% for the main life threatening diseases (such as esophageal atresia, diaphragmatic hernia, omphalocele, and gastroschisis). Currently, most neonatal patients who undergo surgery for severe cardiac or chromosomal anomalies survive. Therefore, pediatric surgeons are aware of the need for cosmetic considerations. Endoscopic surgical procedures and incisions using natural skin creases have been developed to achieve good cosmetic results and improve patients' quality of life. On the other hand, severe life-threatening neonatal surgical cases are still seen, such as patients with diaphragmatic hernia accompanied by severe pulmonary hypoplasia, huge sacrococcygeal teratomas, and neonatal intestinal perforation. Fetal intervention or early delivery should be considered to improve survival. Appropriate initial treatment strategies for intestinal perforation in very low birth-weight infants are needed. PMID- 25702510 TI - [Progress in the treatment of and research on Hirschsprung's disease]. AB - Hirschsprung's disease (HD) is a relatively common cause of intestinal obstruction in the newborn. The disease is named after Harald Hirschsprung, who first described two infants with the condition in 1888. It is characterized by the absence of ganglionic cells in the distal bowel beginning at the internal sphincter and extending proximally for varying distances. The aganglionosis is confined to the rectosigmoid in 80% of patients. HD occurs in about one in 5,000 Japanese children. The most accepted theory of the cause of HD is a defect in the craniocaudal migration of neuroblasts originating from the neural crest which occurs during the first 10 weeks of gestation, as proposed by Okamoto in 1967. The RET protooncogene accounts for the highest proportion of both familial and sporadic cases. Diagnostic techniques involve anorectal manometry, barium enema, and rectal biopsy. The treatment of HD consists of surgical removal (resection) of the abnormal section of the colon, followed by reanastomosis. Definitive surgery for HD has been performed for many years using one of the techniques developed by Swenson, Duhamel, or Soave. Recently, minimally invasive laparoscopic procedures have been introduced for the treatment of HD. PMID- 25702511 TI - [Surgical and long-term problems in biliary atresia]. AB - The outcome of biliary atresia (BA) has improved after developments in hepatic portojejunostomy since the 1950s. The key to successful hepatic portojejunostomy is an optimal dissection line of the hepatic hilar remnant and anastomotic technique without microductule injury on the dissected surface. Most recent articles have reported that remnant hilar tissue should be dissected and the liver capsule preserved. The long-term problems in BA patients, such as cholangitis, became apparent after increased long-term native-liver survival. When hepatic function is preserved and the cause of cholangitis is localized, both surgical intervention and liver transplantation are viable options. The most appropriate treatment option is chosen based on efficacy, invasiveness, and ability to restore hepatic function. Digestive varices and hypersplenism due to portal hypertension are often controllable via symptomatic treatment. Long-term survivors of BA need to be closely monitored for secondary pulmonary perfusion abnormality; the condition necessitates liver transplantation and affects the outcome of the procedure. Some female survivors of BA conceive, which increases the risk of cholangitis and gastrointestinal bleeding during and after pregnancy. Such patients therefore must be monitored closely. Understanding the etiology and pathophysiology of BA is necessary for a good clinical course with native-liver survival. PMID- 25702512 TI - [Advances in pediatric thoracic surgery during the past 50 years]. AB - Surgical strategies and treatment for pediatric airway and lung diseases have advanced significantly, especially in the fields of subglottic stenosis, congenital tracheal stenosis, congenital cystic lung lesions, and endoscopic surgery, during the past 50 years. Pediatricians, pathologists, and pediatric surgeons have engaged in continuous discussions at scientific meetings to establish standard terminology and operative indications and to refine surgical techniques such as laryngoplasty, sliding tracheoplasty, lobectomy under thoracotomy and thoracoscopy. The modified Myer-Cotton grading system for subglottic stenosis was proposed and proved to be useful in selecting reconstructive operative techniques. The addition of aortopexy to sliding tracheoplasty was also confirmed to be effective in maintaining a wide postoperative tracheal lumen. The disease entities of each type of cystic lung lesion were clarified, and the clinical and etiological importance of bronchial/bronchiolar atresia was emphasized. A classification of congenital cystic lung disease was proposed based on anatomic and embryologic considerations. In this classification, congenital pulmonary airway anomaly was introduced to replace congenital cystic adenomatoid malformation of the lung. Intralobar sequestration of the lung must be located in the lower lobe in this definition and classification. PMID- 25702513 TI - [Past, present, and future of pediatric endoscopic surgery]. AB - There has been an enormous evolution in endoscopic surgery, not only in general but also in pediatric surgery. Common pediatric endoscopic procedures, such as laparoscopic appendectomy, pyloromyotomy, and Nissen fundoplication, have been developed since the early 1990s, and many advanced pediatric endoscopic surgical techniques have been developed during the last two decades. Recently, thoracoscopic repair of tracheoesophageal fistula, laparoscopic portoenterostomy (Kasai operation) for the treatment of biliary atresia, etc., have been performed in high-volume centers of pediatric endoscopic surgery even in neonates and young infants. The evolution and development of minimally invasive pediatric endosurgery depend on the equipment and instrumentation technology, while the role of education and training in the pediatric endoscopic surgical field is extremely important. The history, present status, and future development of pediatric laparoscopic and thoracoscopic surgery are reviewed. PMID- 25702514 TI - [History of organ transplantation in the field of pediatric surgery in Japan]. AB - In Japan, liver transplantation was first attempted 50 years ago, around the same time as the development of pediatric surgery. In 1989, clinical liver transplantation in Japan started with a living related-donor transplantation in a boy with biliary atresia. In the early years, the majority of recipients were children worldwide, which is why pediatric surgeons played a major role in the establishment of liver transplantation in Japan. From 1998, most of the indications for pediatric patients needing liver transplantation have been covered by governmental health insurance. Since that year, the annual number of pediatric liver transplantations, mainly living-donor transplantations, has remained stable at around 130. Biliary atresia is still the most common indication, but others like metabolic disease and hepatoblastoma have been increasing. Deceased-donor liver transplantation started in 1999 in Japan, but pediatric donors are very rare. Intestinal transplantation in Japan also started in a pediatric patient with short bowel syndrome in 1996. Deceased-donor intestinal transplantation is also performed, but the number of those on the waiting list for bowel transplantations in Japan has been very limited, probably due to financial constraints and relatively poor long-term results. With the change in the Organ Transplant Law in 2010, organ donations in Japan have increased slightly. Cadaveric split-liver transplantation has the potential to expand the benefit to pediatric recipients. A universal system for the long-term follow-up of pediatric recipients should be established to manage their transition to adulthood. PMID- 25702515 TI - [Perioperative nutrition management in maintenance dialysis patients]. PMID- 25702516 TI - [What we can learn from a case of medical malpractice-substantial awards affirmed in medical malpractice case for death after caesarean section from delayed detection of intraperitoneal hemorrhage; in contrast to damages awarded for a motor vehicle accident, damages for medical accidents was estimated to be higher in this case on the basis of a decision on liability in claimant's favor]. PMID- 25702518 TI - [New team approach of cardiovascular surgical service in Japan]. PMID- 25702517 TI - [Tips and pitfalls of Frey's procedure for chronic pancreatitis]. PMID- 25702519 TI - [Revelation of the assistance for thoracic surgeons by nurse practitioner in Takasaki General Medical Center]. AB - In 2010, "A investigating board of the team medical care" started. In 2011, Nurse Practitioner performing a specific medical practice was discussed in the promotion board of the team medical care. In 2012, the trial of Japan Nurse Practitioner (JNP) was started in NHO hospitals, and one JNP assigned to Takasaki General Medical Center. She received on-the-job training in the division of thoracic surgery. Through the thoracic operation, she gradually acquired many surgical maneuvers, such as thoracotomy and closure chest, insertion of thoracic drainage tube and perioperative management. During two years, she engaged many medical practices, including 180 cases of operative assistances, 160 cases of insertion of thoracic drainage tube. PMID- 25702520 TI - [Present status and problems of work-life balance of married female surgeons having a spouse who is a doctor]. PMID- 25702521 TI - A small multifunctional pentatricopeptide repeat protein in the chloroplast of Chlamydomonas reinhardtii. AB - Organellar biogenesis is mainly regulated by nucleus-encoded factors, which act on various steps of gene expression including RNA editing, processing, splicing, stabilization, and translation initiation. Among these regulatory factors, pentatricopeptide repeat (PPR) proteins form the largest family of RNA binding proteins, with hundreds of members in flowering plants. In striking contrast, the genome of the unicellular green alga Chlamydomonas reinhardtii encodes only 14 such proteins. In this study, we analyzed PPR7, the smallest and most highly expressed PPR protein in C. reinhardtii. Green fluorescent protein-based localization and gel-filtration analysis revealed that PPR7 forms a part of a high-molecular-weight ribonucleoprotein complex in the chloroplast stroma. RIP chip analysis of PPR7-bound RNAs demonstrated that the protein associates with a diverse set of chloroplast transcripts in vivo, i.e. rrnS, psbH, rpoC2, rbcL, atpA, cemA-atpH, tscA, and atpI-psaJ. Furthermore, the investigation of PPR7 RNAi strains revealed that depletion of PPR7 results in a light-sensitive phenotype, accompanied by altered levels of its target RNAs that are compatible with the defects in their maturation or stabilization. PPR7 is thus an unusual type of small multifunctional PPR protein, which interacts, probably in conjunction with other RNA binding proteins, with numerous target RNAs to promote a variety of post-transcriptional events. PMID- 25702522 TI - ABP1: finally docking. PMID- 25702523 TI - New recombinant chimeric antigens, P35-MAG1, MIC1-ROP1, and MAG1-ROP1, for the serodiagnosis of human toxoplasmosis. AB - The aim of the study was to evaluate the usefulness of 3 chimeric Toxoplasma gondii antigens, P35-MAG1, MIC1-ROP1 and MAG1-ROP1, in the serodiagnosis of an acute toxoplasmosis in humans. Proteins were produced as fusion proteins containing His tags ends and then further purified by metal affinity chromatography. Their application for the diagnosis of recently acquired T. gondii infection was tested in IgG and IgM enzyme-linked immunosorbent assays (ELISAs). At 100%, 77.3%, and 86.4%, respectively, the reactivity of the IgG ELISA using P35-MAG1, MIC1-ROP1, and MAG1-ROP1 for sera from patients where acute toxoplasmosis was suspected was significantly higher than for the samples from people with a chronic infection, at 26.2%, 36.1%, and 32.8%, respectively. Moreover, P35-MAG1, MIC1-ROP1, and MAG1-ROP1 detected IgM antibodies with a reactivity at 81.8%, 72.7%, and 59.1%, respectively. The results presented in the article show that, particularly, P35-MAG1 may be useful in the preliminary detection of recent T. gondii infection. PMID- 25702524 TI - Clonal and horizontal spread of the blaOXA-232 gene among Enterobacteriaceae in a Korean hospital. AB - All 16 Klebsiella pneumoniae isolates and both Escherichia coli isolates harbored the bla(OXA-232) and bla(CTX-M-15) genes. Furthermore, all 16 K. pneumoniae isolates belonged to a unique pulsed-field gel electrophoresis clone and were assigned to an identical sequence type (ST14). The 2 E. coli isolates were identified as ST131 and ST457. The bla(OXA-232) gene underwent horizontal transfer to E. coli isolates via a conjugative ColE-type plasmid. The introduction of this K. pneumoniae ST14 strain to the Korean hospital was attributed to an index patient who was likely colonized during a prior hospitalization in India. PMID- 25702525 TI - Cerebral blood volume measurement using near-infrared time-resolved spectroscopy and histopathological evaluation after hypoxic-ischemic insult in newborn piglets. AB - The aim of this study was to assess the relationship between the cerebral blood volume (CBV) measured by near-infrared time-resolved spectroscopy (TRS) and pathological change of the brain in a hypoxic-ischemic (HI) piglet model. Twenty one anesthetized newborn piglets, including three sham controls, were studied. An HI event was induced by low inspired oxygen. CBV was measured using TRS (Hamamatsu TRS-10). Data were collected before, during, and 6h after the insult. CBV was calculated as the change from the end of the insult. The piglets were allowed to recover from anesthesia for 6h after the insult. At the age of 5 days, the brains of the piglets were perfusion-fixed, and histologic evaluations of brain tissue were performed. The extent of histopathological damage was graded in 0.5-unit intervals on a 9-step scale. CBV increments were well correlated with histopathological scores, especially at 1 and 3h after resuscitation. Spearman's rank-correlation coefficients at 1, 3, and 6h after resuscitation in the gray matter were 0.9016, 0.9127, and 0.6907, respectively. We conclude that an increased CBV after HI insult indicates more marked histological brain damage. CBV measurement immediately after resuscitation provides a more precise prediction of the histological outcome. PMID- 25702526 TI - Transcriptional analysis of glial cell differentiation in the postnatal murine spinal cord. AB - Postnatal murine spinal cord represents a good model system to study mammalian central nervous system myelination in vivo as a basis for further studies in demyelinating diseases. Transcriptional changes were analyzed in SJL/J mice on postnatal day 0, 14, 49 and 231 (P0, P14, P49, P231) employing Affymetrix GeneChip Mouse Genome 430 2.0 Arrays. Additionally, marker gene signatures for astrocyte and oligodendrocyte lineage-stages were defined to study their gene expression in more detail. In addition, immunohistochemistry was used to quantify the abundance of commonly used glial cell markers. 6092 differentially regulated genes (DEGs) were identified. The up-regulated DEGs at P14, P49 and P231 compared to P0 exhibited significantly enriched associations to gene ontology terms such as myelination and lipid metabolic transport and down-regulated DEGs to neurogenesis and axonogenesis. Expression values of marker gene signatures for neural stem cells, oligodendrocyte precursor cells, and developing astrocytes were constantly decreasing, whereas myelinating oligodendrocyte and mature astrocyte markers showed a steady increase. Molecular findings were substantiated by immunohistochemical observations. The transcriptional changes observed are an important reference for future analysis of degenerative and inflammatory conditions in the spinal cord. PMID- 25702527 TI - Potential neuroprotective strategies for perinatal infection and inflammation. AB - Preterm born infants have high rates of brain injury, leading to motor and neurocognitive problems in later life. Infection and resulting inflammation of the fetus and newborn are highly associated with these disabilities. However, there are no established neuroprotective therapies. Microglial activation and expression of many cytokines play a key role in normal brain function and development, as well as being deleterious. Thus, treatment must achieve a delicate balance between possible beneficial and harmful effects. In this review, we discuss potential neuroprotective strategies targeting systemic infection or the resulting systemic and central inflammatory responses. We highlight the central importance of timing of treatment and the critical lack of studies of delayed treatment of infection/inflammation. PMID- 25702528 TI - Pyrroloquinoline quinone against glutamate-induced neurotoxicity in cultured neural stem and progenitor cells. AB - Pyrroloquinoline quinone (PQQ), as a well-known redox enzyme cofactor, has been proven to play important roles in the regulation of cellular growth and development in mammals. Numerous physiological and medicinal functions of PQQ have so far been reported although its effect on neural stem and progenitor cells (NS/PCs) and the potential mechanism were even rarely investigated. In this study, the neuroprotective effects of PQQ were observed by pretreatment of NS/PCs with PQQ before glutamate injury, and the possible mechanisms were examined. PQQ stimulated cell proliferation and markedly attenuated glutamate-induced cell damage in a dose-dependent manner. By observing the nuclear morphological changes and flow cytometric analysis, PQQ pretreatment showed its significant effect on protecting NS/PCs against glutamate-induced apoptosis/necrosis. PQQ neuroprotection was associated with the decrease of intracellular reactive oxygen species (ROS) production, the increase of glutathione (GSH) levels, and the decrease of caspase-3 activity. In addition, pretreatment with PQQ also significantly enhanced the activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) in the NS/PCs exposed to glutamate. These results suggest that PQQ can protect NS/PCs against glutamate toxicity associated with ROS-mediated mitochondrial pathway, indicating a useful chemical for the clinical application of NS/PCs. PMID- 25702529 TI - Academia-industry symbiosis in organic chemistry. AB - Collaboration between academia and industry is a growing phenomenon within the chemistry community. These sectors have long held strong ties since academia traditionally trains the future scientists of the corporate world, but the recent drastic decrease of public funding is motivating the academic world to seek more private grants. This concept of industrial "sponsoring" is not new, and in the past, some companies granted substantial amounts of money per annum to various academic institutions in exchange for prime access to all their scientific discoveries and inventions. However, academic and industrial interests were not always aligned, and therefore the investment has become increasingly difficult to justify from industry's point of view. With fluctuating macroeconomic factors, this type of unrestricted grant has become more rare and has been largely replaced by smaller and more focused partnerships. In our view, forging a partnership with industry can be a golden opportunity for both parties and can represent a true symbiosis. This type of project-specific collaboration is engendered by industry's desire to access very specific academic expertise that is required for the development of new technologies at the forefront of science. Since financial pressures do not allow companies to spend the time to acquire this expertise and even less to explore fundamental research, partnering with an academic laboratory whose research is related to the problem gives them a viable alternative. From an academic standpoint, it represents the perfect occasion to apply "pure science" research concepts to solve problems that benefit humanity. Moreover, it offers a unique opportunity for students to face challenges from the "real world" at an early stage of their career. Although not every problem in industry can be solved by research developments in academia, we argue that there is significant scientific overlap between these two seemingly disparate groups, thereby presenting an opportunity for a symbiosis. This type of partnership is challenging but can be a win-win situation if both parties agree on some general guidelines, including clearly defined goals and deliverables, biweekly meetings to track research progress, and quarterly or annual meetings to recognize overarching, common objectives. This Account summarizes our personal experience concerning collaborations with various industrial groups and the way it impacted the research programs for both sides in a symbiotic fashion. PMID- 25702530 TI - Exercise modulates the expression of IL-1beta and IL-10 in the articular cartilage of normal and osteoarthritis-induced rats. AB - After a joint lesion, high-impact exercise is a risk factor for the development of osteoarthritis (OA). The degradation of articular cartilage in OA has been associated with the activation of inflammatory cytokine signaling pathways. However, differences in cytokine expression in healthy and injured cartilage after exercise have not yet been analyzed. We used immunofluorescence and Western blot to study the expression of IL-1beta and IL-10 in the articular cartilage of normal (N), sham-operated (S), and menisectomized (OA) rats subjected or not to high-impact exercise (E) for 3, 6, and 10 days (N, NE, S, SE, and OA groups). Cartilage integrity and proteoglycan content were only affected in the OA groups. Exercise increased the amount of IL-1beta and IL-10 positive chondrocytes in NE and SE groups compared with non-exercised groups (N and S). The expression of IL 1beta was up-regulated over time in the NE and OA groups, although in the late stages the increase was higher in the OA groups. In contrast, the expression of anti-inflammatory IL-10 was low in the OA group, whereas in the NE groups expression levels were higher at each time point analyzed. These results suggest that anti- and pro-inflammatory molecules in the cartilage might be tightly regulated to maintain the integrity of the tissue and that when this equilibrium is broken (when the meniscus is removed), the pro-inflammatory cytokines take over and OA develops. PMID- 25702531 TI - Derivation of keratinocytes from chicken embryonic stem cells: establishment and characterization of differentiated proliferative cell populations. AB - A common challenge in avian cell biology is the generation of differentiated cell lines, especially in the keratinocyte lineage. Only a few avian cell-lines are available and very few of them show an interesting differentiation profile. During the last decade, mammalian embryonic stem cell-lines were shown to differentiate into almost all lineages, including keratinocytes. Although chicken embryonic stem cells had been obtained in the 1990s, few differentiation studies toward the ectodermal lineage were reported. Consequently, we explored the differentiation of chicken embryonic stem cells toward the keratinocyte lineage by using a combination of stromal induction, ascorbic acid, BMP4 and chicken serum. During the induction period, we observed a downregulation of pluripotency markers and an upregulation of epidermal markers. Three homogenous cell populations were derived, which were morphologically similar to chicken primary keratinocytes, displaying intracellular lipid droplets in almost every pavimentous cell. These cells could be serially passaged without alteration of their morphology and showed gene and protein expression profiles of epidermal markers similar to chicken primary keratinocytes. These cells represent an alternative to the isolation of chicken primary keratinocytes, being less cumbersome to handle and reducing the number of experimental animals used for the preparation of primary cells. PMID- 25702532 TI - Neighborhood crime as a predictor of individual differences in emotional processing and regulation. AB - Emerging research suggests that early exposure to environmental adversity has important implications for the development of brain regions associated with emotion regulation, yet little is known about how such adversity translates into observable differences in children's emotion-related behavior. The present study examines the relationship between geocoded neighborhood crime and urban pre adolescents' emotional attention, appraisal, and response. Results indicate that living in a high-crime neighborhood is associated with greater selective attention toward negatively valenced emotional stimuli on a dot probe task, less biased appraisal of fear on a facial identification task, and lower rates of teacher-reported internalizing behaviors in the classroom. These findings suggest that children facing particularly high levels of environmental threat may develop different regulatory processes (e.g. greater use of emotional suppression) than their peers from low-crime neighborhoods in order to manage the unique stressors and social demands of their communities. PMID- 25702533 TI - Role of ECM/peptide coatings on SDF-1alpha triggered mesenchymal stromal cell migration from microcarriers for cell therapy. AB - Many cell therapies rely on the ability of mesenchymal stromal cells (MSCs) to diffuse and localize throughout the target tissue - such as tumoral and ischemic tissues-, in response to specific cytokine signals, rather than being concentrated at the site of implantation. Therefore, it is fundamental to engineer biomaterial carriers as reservoirs, from which cells can migrate, possibly in a controlled manner. In this work, microcarriers (MUCs) made of polylactic acid are characterized as MSC delivery vehicles capable of modulating key chemotactic pathways. The effect of different functionalization strategies on MSC migratory behavior from the MUCs is studied in vitro in relation to SDF 1alpha/CXCR4 axis, - a major actor in MSC recruitment, chemotaxis and homing. Collagen and arginine-glycine-aspartic acid (RGD) peptides were either covalently grafted or physisorbed on MUC surface. While stable covalent modifications promoted better cell adhesion and higher proliferation compared to physisorption, the functionalization method of the MUCs also affected the cells migratory behavior in response to SDF-1alpha (CXCL12) stimulation. Less stable coatings (physisorbed) showed sensibly higher number of migrating cells than covalent collagen/RGD coatings. The combination of physic-chemical cues provided by protein/peptide functionalization and stimuli induced by 3D culture on MUCs improved MSC expression of CXCR4, and exerted a control over cell migration, a condition suitable to promote cell homing after transplantation in vivo. These are key findings to highlight the impact of surface modification approaches on chemokine-triggered cell release, and allow designing biomaterials for efficient and controlled cell delivery to damaged tissues. PMID- 25702534 TI - Nocebo and the potential harm of 'high risk' labelling: a scoping review. AB - AIMS: A discussion of the existence, prevalence and characteristics of the nocebo effect in health care. BACKGROUND: There is increasing but inconsistent evidence for nocebo effects (the opposite of placebo). Causal mechanisms are believed to be similar to placebo (negative effects result from suggestions of negative clinical outcomes). Risk screening in health care may produce this unintended effect through labelling some patients as high risk. Given health care's almost universal coverage this potentially affects many people. DESIGN: Discussion paper following a scoping review of the existence and frequency of nocebo. DATA SOURCES: Literature databases (PsycINFO, MEDLINE, CCTR, CINAHL and EMBASE) searched from inception dates to 2013. IMPLICATIONS FOR NURSING: Significant empirical evidence indicates that negative beliefs may impact on health outcomes (incidence estimates range from 3-27%). The nocebo effect, rooted in the complex interplay between physiological functioning and social factors, appears significantly more common among women and where prior negative knowledge or expectations exist. Pre-existing psychological characteristics (anxiety, neuroses, panic disorder or pessimism) exacerbate it. CONCLUSION: While the placebo effect is well documented, there has been no systematic attempt to synthesize primary empirical research on the role of nocebo. It is possible that nocebo outcomes may be preventable through careful consideration of information provision and the prior identification of potentially high risk individuals. This paper summarizes the scale and importance of the nocebo effect, its distribution according to a range of social and clinical variables and its known relation to psychological precursors. It identifies important gaps in the research literature. PMID- 25702535 TI - Synthesis, development, characterization and effectiveness of bovine pure platelet gel-collagen-polydioxanone bioactive graft on tendon healing. AB - Bovine platelet gel (BPG) is an accessible and cost-effective source of growth factors which may have a value in tendon regenerative medicine. We produced a collagen implant (CI) as a tendon proper, covered it with polydioxanone (PDS) sheath to simulate paratenon and finally embedded the BPG as an active source of growth factor within the bioimplant to test whether BPG would be able to accelerate and enhance tendon regeneration and repair. After in vitro characterization of the bioactive grafts, the grafts were implanted in rabbit large tendon defect model. Untreated tendons and tendons treated with either CI or CI-PDS were served as controls for the CI-PDS-BPG. The animals were investigated clinically, ultrasonographically and haematologically for 120 days. After euthanasia, dry matter content, water uptake and delivery characteristics and also gross morphological, histopathological and scanning electron microscopic features of the healing tendons were assessed. In vitro, the activated platelets in the scaffold, released their growth factors significantly more than the controls. BPG also increased cell viability, and enhanced cellular differentiation, maturation and proliferation inside the CI-PDS compared with the controls. In vivo, the BPG modulated inflammation, increased quality and rate of fibroplasia and produced a remodelled tendon that had significantly higher collagen content and superior collagen fibril and fibre differentiation than controls. Treatment also significantly improved tendon water uptake and delivery characteristics, animals' serum PDGF level, CI-PDS biocompatibility and biodegradability and reduced peritendinous adhesions, muscle fibrosis and atrophy. BPG was effective on tendon healing and CI-PDS-BPG may be a valuable bioscaffold in tendon reconstructive surgery. PMID- 25702537 TI - Utilisation, Reliability and Validity of Clinical Evaluation Exercise in Otolaryngology Training. AB - OBJECTIVES: To investigate the utilisation, reliability and validity of clinical evaluation exercise (CEX) in otolaryngology training. DESIGN: Retrospective database analysis. SETTING: Online assessment database. PARTICIPANTS: We analysed all CEXs submitted by north London core (CT) and speciality trainees (ST) in otolaryngology from 2010 to 2013. MAIN OUTCOME MEASURES: Internal consistency of the 7 CEX items rated as either O: outstanding, S: satisfactory or D: development required. Overall performance rating (pS) of 1-4 assessed against completion of training level. Receiver operating characteristic was used to describe CEX sensitivity and specificity. Overall score (cS), pS and the number of 'D'-rated items were used to investigate construct validity. RESULTS: One thousand one hundred and sixty CEXs from 45 trainees were included. CEX showed good internal consistency (Cronbach's alpha= 0.85). CEX was highly sensitive (99%), yet not specific (6%). cS and pS for ST was higher than CT (99.1% +/- 0.4 versus 96.6% +/ 0.8 and 3.06 +/- 0.05 versus 1.92 +/- 0.04, respectively P < 0.001). pS showed a significant stepwise increase from CT1 to ST6 (P < 0.001). In contrast, cS only showed improvement up to ST4 (P = 0.025). The most frequently utilised item 'management and follow-up planning' was found to be the best predictor of cS and pS (rs = +0.69 and +0.21, respectively). CONCLUSION: CEX is reliable in assessing early years otolaryngology trainees in clinical examination, but not at higher level. It has the potential to be used in a summative capacity in selecting trainees for ST positions. This would also encourage trainees to master all domains of otolaryngology clinical examination by end of CT. PMID- 25702536 TI - Citrobacter rodentium-induced colitis: A robust model to study mucosal immune responses in the gut. AB - Citrobacter rodentium is a natural mouse pathogen which reproducibly infects mice and causes intestinal disease. The C. rodentium model of infection is very useful for investigating host-pathogen immune interactions in the gut, and can also be used to understand the pathogenesis of several important human intestinal disorders, including Crohn's disease, ulcerative colitis, dysbiosis and colon tumorigenesis. Both innate and adaptive immune responses play a critical role in protection against C. rodentium. Here, we summarize the role of immune components in protection against C. rodentium and describe techniques for the analysis of innate and adaptive mucosal immune responses, including setting up the infection, analysis of colonic hyperplasia and bacterial dissemination, evaluation of antibody responses, and purification and analysis of intestinal epithelial and lymphoid cells. PMID- 25702539 TI - To morcellate or not to morcellate - is that the question? PMID- 25702540 TI - Ureteric injury: always a guilty verdict? PMID- 25702541 TI - 45 years of fetal heart rate monitoring in BJOG. PMID- 25702542 TI - Authors' reply. PMID- 25702543 TI - Re: Serum vascular endothelial growth factor levels following luteal gonadotrophin-releasing hormone antagonist administration in women with severe early ovarian hyperstimulation syndrome. PMID- 25702544 TI - Re: Intake of dairy products and calcium and prevalence of depressive symptoms during pregnancy in Japan: a cross-sectional study. PMID- 25702545 TI - Authors' reply. PMID- 25702546 TI - Author's reply: To PMID 24684695. PMID- 25702547 TI - Re: Prevalence of obstetric fistula: a population-based study in rural Pakistan. PMID- 25702548 TI - Re: Transverse vaginal septae: management and long-term outcomes. PMID- 25702549 TI - Re: Are we (mis)guided by current guidelines on intrapartum fetal heart rate monitoring? Case for a more physiological approach to interpretation. PMID- 25702550 TI - Author's reply: To PMID 24920154. PMID- 25702551 TI - Re: Are we (mis)guided by current guidelines on intrapartum fetal heart rate monitoring? Case for a more physiological approach to interpretation. PMID- 25702552 TI - Re: The effectiveness of exercise for the prevention and treatment of antenatal depression: systematic review with meta-analysis; Association and prediction of amniotic fluid measurements for adverse pregnancy outcome: systematic review and meta-analysis; Does induction of labour increase the risk of caesarean section? A systematic review and meta analysis of trials in women with intact membranes. PMID- 25702553 TI - Author's reply: To PMID 24920154. PMID- 25702554 TI - Authors' reply. PMID- 25702555 TI - Author's reply: To PMID 24738894. PMID- 25702556 TI - Author's reply: To PMID 23834460. PMID- 25702557 TI - Re: Maternal obesity and excess of fetal growth in pre-eclampsia. PMID- 25702558 TI - Editor's reply. PMID- 25702559 TI - Authors' reply. PMID- 25702560 TI - Re: The impact of supportive counselling on women's pyschological wellbeing after miscarriage - a randomised controlled trial. PMID- 25702561 TI - Author's reply: To PMID 24912398. PMID- 25702562 TI - Re: Management of women with low-grade cytology: how reassuring is a normal colposcopy examination? PMID- 25702563 TI - Re: A report from #BlueJC: Can chewing gum prevent postoperative ileus? PMID- 25702564 TI - Authors' reply. PMID- 25702565 TI - A report from #BlueJC: Does the G-spot exist? PMID- 25702566 TI - Author's comment: A report from #BlueJC: Does the G-spot exist? PMID- 25702569 TI - Phosphodiesterase-3B-cAMP pathway of leptin signalling in the hypothalamus is impaired during the development of diet-induced obesity in FVB/N mice. AB - The phosphodiesterase-3B (PDE3B)-cAMP pathway plays an important role in transducing the action of leptin in the hypothalamus. Obesity is usually associated with hyperleptinaemia and resistance to anorectic and body weight reducing effects of leptin. To determine whether the hypothalamic PDE3B-cAMP pathway of leptin signalling is impaired during the development of diet-induced obesity (DIO), we fed male FVB/N mice a high-fat diet (HFD: 58% kcal as fat) or low-fat diet (LFD: 6% kcal as fat) for 4 weeks. HFD fed mice developed DIO in association with hyperphagia, hyperleptinaemia and hyperinsulinaemia. Leptin (i.p.) significantly increased hypothalamic PDE3B activity and phosphorylated (p) Akt levels in LFD-fed but not in HFD-fed mice. However, basal p-Akt levels in hypothalamus were increased in DIO mice. Additionally, amongst six-microdissected brain nuclei examined, leptin selectively decreased cAMP levels in the arcuate nucleus (ARC) of LFD-fed mice but failed to do so in HFD-fed mice. We next tested whether both the PBE3B and Akt pathways of leptin signalling remained impaired in DIO mice on the HFD for 12 weeks (long-term). DIO mice were hyperinsulinaemic and hyperleptinaemic in association with impaired glucose and insulin tolerance. Although, in LFD-fed mice, leptin significantly increased PDE3B activity and p Akt levels in the hypothalamus, it failed to do so in HFD-fed mice. Also, basal p Akt levels in the hypothalamus were increased in DIO mice and leptin had no further effect. Similarly, immunocytochemistry showed that leptin increased the number of p-Akt-positive cells in the ARC of LFD-fed but not in HFD-fed mice, and there was an increased basal number of p-Akt positive cells in the ARC of DIO mice. These results suggest that the PDE3B-cAMP- and Akt-pathways of leptin signalling in the hypothalamus are impaired during the development of DIO. Thus, a defect in the regulation by leptin of the hypothalamic PDE3B-cAMP pathway and Akt signalling may be one of the mechanisms of central leptin resistance and the development of DIO. PMID- 25702570 TI - Can a panel of clinical, laboratory, and pathological variables pinpoint patients with sinonasal polyposis at higher risk of recurrence after surgery? AB - PURPOSE: Despite improved surgical and medical therapies, recurrence remains a significant problem in chronic rhinosinusitis with nasal polyps (CRSwNP), given a recently-reported long-term revision rate of 15%-20%. In this prospective study uni- and multivariate statistical analyses were used to identify clinical, laboratory and conventional pathological parameters for pinpointing CRSwNP patients at higher risk of recurrence after functional endoscopic sinus surgery (FESS). MATERIALS AND METHODS: The investigation concerned 179 consecutive patients undergoing FESS for CRSwNP, and 24 of them developed recurrent CRSwNP after FESS. RESULTS: A univariate statistical model disclosed significant associations between recurrent CRSwNP and serum basophil counts (p=0.03) and percentages (p=0.02). The recurrence rate was higher for patients with eosinophilic-type CRSwNP (p=0.01). In a multivariate logistic model, eosinophilic type CRSwNP (p=0.025) and serum basophil percentage (statistical trend, p=0.079) retained their independent prognostic significance in relation to CRSwNP recurrence. The discriminatory power of a three-variable panel (age <65 years, serum basophil percentage and eosinophilic type) featured an AUC (ROC) of 0.7028 (an acceptable discriminatory power according to the Hosmer-Lemeshow scale). CONCLUSIONS: Although our panel achieved an acceptable discriminatory power for CRSwNP recurrence, other parameters (including biomarkers) capable of predicting outcome and orienting postoperative treatment decisions need to be investigated in CRSwNP. PMID- 25702571 TI - Bilobe flap with auricular cartilage graft for nasal alar reconstruction. AB - OBJECTIVE: To report outcomes for reconstruction of the nasal ala using a bilobe flap in combination with an auricular cartilage graft. STUDY DESIGN: Case series with chart review. SETTING: Academic tertiary care medical center. SUBJECTS AND METHODS: Data were obtained by a retrospective review of patients treated by a single surgeon (SPM) from January 2013 to December 2014. Patients were included who underwent reconstruction of the nasal ala using a bilobe flap in combination with an auricular cartilage graft. Clinical notes and postoperative photographs were reviewed to evaluate post-operative outcomes including flap viability, presence of iatrogenic lateral nasal wall insufficiency, alar retraction, and patient and surgeon reported satisfaction with aesthetic outcome. RESULTS: A total of 7 patients (3 male, 4 female) met inclusion criteria. Patient age ranged from 34 to 71 years (mean: 55 years). Follow-up time ranged from 1 to 12 months (mean: 6.3 months). All defects were located within 5 mm of the alar margin. Defect size ranged from 6 to 15 mm in largest diameter (average 11 mm). There were no incidences of flap loss, alar retraction, or iatrogenic lateral wall insufficiency, and all patients had results deemed aesthetically satisfactory by both the patient and surgeon. CONCLUSIONS: Defects of the nasal ala can be successfully reconstructed using a bilobe flap in combination with an auricular cartilage graft with excellent aesthetic and functional outcomes. PMID- 25702572 TI - Systematic T1 improvement for hyperpolarized 129xenon. AB - The spin-lattice relaxation time T1 of hyperpolarized (HP)-(129)Xe was improved at typical storage conditions (i.e. low and homogeneous magnetic fields). Very long wall relaxation times T(1)(wall) of about 18 h were observed in uncoated, spherical GE180 glass cells of ?=10 cm which were free of rubidium and not permanently sealed but attached to a standard glass stopcock. An "aging" process of the wall relaxation was identified by repeating measurements on the same cell. This effect could be easily removed by repeating the initial cleaning procedure. In this way, a constant wall relaxation was ensured. The Xe nuclear spin relaxation rate 1/T1(Xe-Xe) due to van der Waals molecules was investigated too, by admixing three different buffer gases (N(2), SF(6) and CO(2)). Especially CO(2) exhibited an unexpected high efficiency (r) in shortening the lifetime of the Xe-Xe dimers and hence prolonging the total T1 relaxation even further. These measurements also yielded an improved accuracy for the van der Waals relaxation for pure Xe (with 85% (129)Xe) of T(1)(Xe-Xe)=(4.6+/-0.1)h. Repeating the measurements with HP (129)Xe in natural abundance in mixtures with SF6, a strong dependence of T(1)(Xe-Xe) and r on the isotopic enrichment was observed, uncovering a shorter T(1)(Xe-Xe) relaxation for the (129)Xe in natural composition as compared to the 85% isotopically enriched gas. PMID- 25702573 TI - Implementing multiplicity editing in selective HSQMBC experiments. AB - Even C/CH(2) and odd CH/CH(3) carbon-multiplicity information can be directly distinguished from the relative positive/negative phase of cross-peaks in a novel ME (Multiplicity-Edited)-selHSQMBC experiment. The method can be extended by a TOCSY propagation step, and it is fully compatible for the simultaneous and precise determination of long-range heteronuclear coupling constants. Broadband homonuclear decoupling techniques can also be incorporated to enhance sensitivity and signal resolution by effective collapse of J(HH) multiplets. PMID- 25702574 TI - Human-chimpanzee differences in a FZD8 enhancer alter cell-cycle dynamics in the developing neocortex. AB - The human neocortex differs from that of other great apes in several notable regards, including altered cell cycle, prolonged corticogenesis, and increased size [1-5]. Although these evolutionary changes most likely contributed to the origin of distinctively human cognitive faculties, their genetic basis remains almost entirely unknown. Highly conserved non-coding regions showing rapid sequence changes along the human lineage are candidate loci for the development and evolution of uniquely human traits. Several studies have identified human accelerated enhancers [6-14], but none have linked an expression difference to a specific organismal trait. Here we report the discovery of a human-accelerated regulatory enhancer (HARE5) of FZD8, a receptor of the Wnt pathway implicated in brain development and size [15, 16]. Using transgenic mice, we demonstrate dramatic differences in human and chimpanzee HARE5 activity, with human HARE5 driving early and robust expression at the onset of corticogenesis. Similar to HARE5 activity, FZD8 is expressed in neural progenitors of the developing neocortex [17-19]. Chromosome conformation capture assays reveal that HARE5 physically and specifically contacts the core Fzd8 promoter in the mouse embryonic neocortex. To assess the phenotypic consequences of HARE5 activity, we generated transgenic mice in which Fzd8 expression is under control of orthologous enhancers (Pt-HARE5::Fzd8 and Hs-HARE5::Fzd8). In comparison to Pt HARE5::Fzd8, Hs-HARE5::Fzd8 mice showed marked acceleration of neural progenitor cell cycle and increased brain size. Changes in HARE5 function unique to humans thus alter the cell-cycle dynamics of a critical population of stem cells during corticogenesis and may underlie some distinctive anatomical features of the human brain. PMID- 25702575 TI - Mechanical stress and network structure drive protein dynamics during cytokinesis. AB - Cell-shape changes associated with processes like cytokinesis and motility proceed on several-second timescales but are derived from molecular events, including protein-protein interactions, filament assembly, and force generation by molecular motors, all of which occur much faster [1-4]. Therefore, defining the dynamics of such molecular machinery is critical for understanding cell-shape regulation. In addition to signaling pathways, mechanical stresses also direct cytoskeletal protein accumulation [5-7]. A myosin-II-based mechanosensory system controls cellular contractility and shape during cytokinesis and under applied stress [6, 8]. In Dictyostelium, this system tunes myosin II accumulation by feedback through the actin network, particularly through the crosslinker cortexillin I. Cortexillin-binding IQGAPs are major regulators of this system. Here, we defined the short timescale dynamics of key cytoskeletal proteins during cytokinesis and under mechanical stress, using fluorescence recovery after photobleaching and fluorescence correlation spectroscopy, to examine the dynamic interplay between these proteins. Equatorially enriched proteins including cortexillin I, IQGAP2, and myosin II recovered much more slowly than actin and polar crosslinkers. The mobility of equatorial proteins was greatly reduced at the furrow compared to the interphase cortex, suggesting their stabilization during cytokinesis. This mobility shift did not arise from a single biochemical event, but rather from a global inhibition of protein dynamics by mechanical stress-associated changes in the cytoskeletal structure. Mechanical tuning of contractile protein dynamics provides robustness to the cytoskeletal framework responsible for regulating cell shape and contributes to cytokinesis fidelity. PMID- 25702576 TI - Genomic expansion of domain archaea highlights roles for organisms from new phyla in anaerobic carbon cycling. AB - BACKGROUND: Archaea represent a significant fraction of Earth's biodiversity, yet they remain much less well understood than Bacteria. Gene surveys, a few metagenomic studies, and some single-cell sequencing projects have revealed numerous little-studied archaeal phyla. Certain lineages appear to branch deeply and may be part of a major phylum radiation. The structure of this radiation and the physiology of the organisms remain almost unknown. RESULTS: We used genome resolved metagenomic analyses to investigate the diversity, genomes sizes, metabolic capacities, and potential roles of Archaea in terrestrial subsurface biogeochemical cycles. We sequenced DNA from complex sediment and planktonic consortia from an aquifer adjacent to the Colorado River (USA) and reconstructed the first complete genomes for Archaea using cultivation-independent methods. To provide taxonomic context, we analyzed an additional 151 newly sampled archaeal sequences. We resolved two new phyla within a major, apparently deep-branching group of phyla (a superphylum). The organisms have small genomes, and metabolic predictions indicate that their primary contributions to Earth's biogeochemical cycles involve carbon and hydrogen metabolism, probably associated with symbiotic and/or fermentation-based lifestyles. CONCLUSIONS: The results dramatically expand genomic sampling of the domain Archaea and clarify taxonomic designations within a major superphylum. This study, in combination with recently published work on bacterial phyla lacking cultivated representatives, reveals a fascinating phenomenon of major radiations of organisms with small genomes, novel proteome composition, and strong interdependence in both domains. PMID- 25702577 TI - Drosophila sugar receptors in sweet taste perception, olfaction, and internal nutrient sensing. AB - Identification of nutritious compounds is dependent on expression of specific taste receptors in appropriate taste-cell types [1]. In contrast to mammals, which rely on a single, broadly tuned heterodimeric sugar receptor [2], the Drosophila genome harbors a small subfamily of eight, closely related gustatory receptor (Gr) genes, Gr5a, Gr61a, and Gr64a-Gr64f, of which three have been proposed to mediate sweet taste [3-6]. However, expression and function of several of these putative sugar Gr genes are not known. Here, we present a comprehensive expression and functional analysis using Gr(LEXA/GAL4) alleles that were generated through homologous recombination. We show that sugar Gr genes are expressed in a combinatorial manner to yield at least eight sets of sweet-sensing neurons. Behavioral investigations show that most sugar Gr mutations affect taste responses to only a small number of sugars and that effective detection of most sugars is dependent on more than one Gr gene. Surprisingly, Gr64a, one of three Gr genes previously proposed to play a major role in sweet taste [3, 4], is not expressed in labellar taste neurons, and Gr64a mutant flies exhibit normal sugar responses elicited from the labellum. Our analysis provides a molecular rationale for distinct tuning profiles of sweet taste neurons, and it favors a model whereby all sugar Grs contribute to sweet taste. Furthermore, expression in olfactory organs and the brain implies novel roles for sugar Gr genes in olfaction and internal nutrient sensing, respectively. Thus, sugar receptors may contribute to feeding behavior via multiple sensory systems. PMID- 25702578 TI - Development of twitching in sleeping infant mice depends on sensory experience. AB - Myoclonic twitches are jerky movements that occur exclusively and abundantly during active (or REM) sleep in mammals, especially in early development [1-4]. In rat pups, limb twitches exhibit a complex spatiotemporal structure that changes across early development [5]. However, it is not known whether this developmental change is influenced by sensory experience, which is a prerequisite to the notion that sensory feedback from twitches not only activates sensorimotor circuits but modifies them [4]. Here, we investigated the contributions of proprioception to twitching in newborn ErbB2 conditional knockout mice that lack muscle spindles and grow up to exhibit dysfunctional proprioception [6-8]. High speed videography of forelimb twitches unexpectedly revealed a category of reflex like twitching-comprising an agonist twitch followed immediately by an antagonist twitch-that developed postnatally in wild-types/heterozygotes, but not in knockouts. Contrary to evidence from adults that spinal reflexes are inhibited during twitching [9-11], this finding suggests that twitches trigger the monosynaptic stretch reflex and, by doing so, contribute to its activity dependent development [12-14]. Next, we assessed developmental changes in the frequency and organization (i.e., entropy) of more-complex, multi-joint patterns of twitching; again, wild-types/heterozygotes exhibited developmental changes in twitch patterning that were not seen in knockouts. Thus, targeted deletion of a peripheral sensor alters the normal development of local and global features of twitching, demonstrating that twitching is shaped by sensory experience. These results also highlight the potential use of twitching as a uniquely informative diagnostic tool for assessing the functional status of spinal and supraspinal circuits. PMID- 25702579 TI - A neuronal pathway that controls sperm ejection and storage in female Drosophila. AB - In polyandrous females, sperm storage permits competition between sperm of different mates, and in some species females influence the relative fertilization success of competing sperm in favor of a preferred mate [1, 2]. In female Drosophila melanogaster, sperm competition is strongly influenced by the timing of sperm ejection from the uterus [3, 4]. Understanding how female behavior influences sperm competition requires knowledge of the neuronal mechanisms controlling sperm retention and storage, which is currently lacking. Here, we show that D. melanogaster females eject male ejaculates from the uterus 1-6 hr after mating with a stereotypic behavior regulated by a brain signaling pathway composed of diuretic hormone 44 (Dh44), a neuropeptide related to vertebrate corticotropin-releasing factor (CRF), and its receptor, Dh44R1. Suppression of Dh44 signals in the brain expedites sperm ejection from the uterus, resulting in marked reduction of sperm in the storage organs and decreased fecundity, whereas enhancement of Dh44 signals delays sperm expulsion. The Dh44 function was mapped to six neurons located in the pars intercerebralis of the brain together with a small subset of Dh44R1 neurons that express the sex-specific transcription factor doublesex. This study identifies a neuronal pathway by which females can control sperm retention and storage and provides new insight into how the female might exercise post-copulatory sexual selection. PMID- 25702580 TI - Attention reduces spatial uncertainty in human ventral temporal cortex. AB - Ventral temporal cortex (VTC) is the latest stage of the ventral "what" visual pathway, which is thought to code the identity of a stimulus regardless of its position or size [1, 2]. Surprisingly, recent studies show that position information can be decoded from VTC [3-5]. However, the computational mechanisms by which spatial information is encoded in VTC are unknown. Furthermore, how attention influences spatial representations in human VTC is also unknown because the effect of attention on spatial representations has only been examined in the dorsal "where" visual pathway [6-10]. Here, we fill these significant gaps in knowledge using an approach that combines functional magnetic resonance imaging and sophisticated computational methods. We first develop a population receptive field (pRF) model [11, 12] of spatial responses in human VTC. Consisting of spatial summation followed by a compressive nonlinearity, this model accurately predicts responses of individual voxels to stimuli at any position and size, explains how spatial information is encoded, and reveals a functional hierarchy in VTC. We then manipulate attention and use our model to decipher the effects of attention. We find that attention to the stimulus systematically and selectively modulates responses in VTC, but not early visual areas. Locally, attention increases eccentricity, size, and gain of individual pRFs, thereby increasing position tolerance. However, globally, these effects reduce uncertainty regarding stimulus location and actually increase position sensitivity of distributed responses across VTC. These results demonstrate that attention actively shapes and enhances spatial representations in the ventral visual pathway. PMID- 25702581 TI - Oncogenic properties of apoptotic tumor cells in aggressive B cell lymphoma. AB - BACKGROUND: Cells undergoing apoptosis are known to modulate their tissue microenvironments. By acting on phagocytes, notably macrophages, apoptotic cells inhibit immunological and inflammatory responses and promote trophic signaling pathways. Paradoxically, because of their potential to cause death of tumor cells and thereby militate against malignant disease progression, both apoptosis and tumor-associated macrophages (TAMs) are often associated with poor prognosis in cancer. We hypothesized that, in progression of malignant disease, constitutive loss of a fraction of the tumor cell population through apoptosis could yield tumor-promoting effects. RESULTS: Here, we demonstrate that apoptotic tumor cells promote coordinated tumor growth, angiogenesis, and accumulation of TAMs in aggressive B cell lymphomas. Through unbiased "in situ transcriptomics" analysis gene expression profiling of laser-captured TAMs to establish their activation signature in situ-we show that these cells are activated to signal via multiple tumor-promoting reparatory, trophic, angiogenic, tissue remodeling, and anti inflammatory pathways. Our results also suggest that apoptotic lymphoma cells help drive this signature. Furthermore, we demonstrate that, upon induction of apoptosis, lymphoma cells not only activate expression of the tumor-promoting matrix metalloproteinases MMP2 and MMP12 in macrophages but also express and process these MMPs directly. Finally, using a model of malignant melanoma, we show that the oncogenic potential of apoptotic tumor cells extends beyond lymphoma. CONCLUSIONS: In addition to its profound tumor-suppressive role, apoptosis can potentiate cancer progression. These results have important implications for understanding the fundamental biology of cell death, its roles in malignant disease, and the broader consequences of apoptosis-inducing anti cancer therapy. PMID- 25702582 TI - Development of connectivity in a motoneuronal network in Drosophila larvae. AB - BACKGROUND: Much of our understanding of how neural networks develop is based on studies of sensory systems, revealing often highly stereotyped patterns of connections, particularly as these diverge from the presynaptic terminals of sensory neurons. We know considerably less about the wiring strategies of motor networks, where connections converge onto the dendrites of motoneurons. Here, we investigated patterns of synaptic connections between identified motoneurons with sensory neurons and interneurons in the motor network of the Drosophila larva and how these change as it develops. RESULTS: We find that as animals grow, motoneurons increase the number of synapses with existing presynaptic partners. Different motoneurons form characteristic cell-type-specific patterns of connections. At the same time, there is considerable variability in the number of synapses formed on motoneuron dendrites, which contrasts with the stereotypy reported for presynaptic terminals of sensory neurons. Where two motoneurons of the same cell type contact a common interneuron partner, each postsynaptic cell can arrive at a different connectivity outcome. Experimentally changing the positioning of motoneuron dendrites shows that the geography of dendritic arbors in relation to presynaptic partner terminals is an important determinant in shaping patterns of connectivity. CONCLUSIONS: In the Drosophila larval motor network, the sets of connections that form between identified neurons manifest an unexpected level of variability. Synapse number and the likelihood of forming connections appear to be regulated on a cell-by-cell basis, determined primarily by the postsynaptic dendrites of motoneuron terminals. PMID- 25702583 TI - Inverse size scaling of the nucleolus by a concentration-dependent phase transition. AB - Just as organ size typically increases with body size, the size of intracellular structures changes as cells grow and divide. Indeed, many organelles, such as the nucleus [1, 2], mitochondria [3], mitotic spindle [4, 5], and centrosome [6], exhibit size scaling, a phenomenon in which organelle size depends linearly on cell size. However, the mechanisms of organelle size scaling remain unclear. Here, we show that the size of the nucleolus, a membraneless organelle important for cell-size homeostasis [7], is coupled to cell size by an intracellular phase transition. We find that nucleolar size directly scales with cell size in early C. elegans embryos. Surprisingly, however, when embryo size is altered, we observe inverse scaling: nucleolar size increases in small cells and decreases in large cells. We demonstrate that this seemingly contradictory result arises from maternal loading of a fixed number rather than a fixed concentration of nucleolar components, which condense into nucleoli only above a threshold concentration. Our results suggest that the physics of phase transitions can dictate whether an organelle assembles, and, if so, its size, providing a mechanistic link between organelle assembly and cell size. Since the nucleolus is known to play a key role in cell growth, this biophysical readout of cell size could provide a novel feedback mechanism for growth control. PMID- 25702584 TI - A new method of surgical margin assuring for abdominal radical trachelectomy in frozen section. AB - OBJECTIVES: The aim of this study was to introduce a new method of assuring surgical margins for abdominal radical trachelectomy (ART) and report our experience using the method. METHODS: We combined transverse and perpendicular sections to assess surgical margins of specimens from RT. All surgeries from 1st August 2012 to 1st October 2013 were performed by one surgeon. The frozen section (FS) was consistently performed by a group of gynaecologic pathologists according to the detailed protocol described in this article. All cases were prepared by the same pathologist, and the slides were reviewed by two pathologists. RESULTS: There were 53 patients treated using the new method in our institution. The patient ages ranged from 20 to 41 years old (median 32). The surgeries were performed for clinical stage IA (n = 11) with LVSI and IB (n = 42) tumours (40 squamous cell carcinoma, 11 adenocarcinoma, two adenosquamous and two others). In 20 (37.74%) cases, no residual tumour of the ART specimen on frozen section was observed in the specimens as it was cleared by the preceding loop electrical excision procedure (LEEP) or conization. The margins were initially reported as negative in 45 cases and positive in nine cases. In those nine cases, a second slice of cervix was removed and negative in six cases and positive again in two cases, the other one with positive nodes. The results of frozen sections were concordant with the final paraffin-embedded sections. There were no false negative intraoperative assessments. There were no recurrences after a median follow-up of 15.4 months (range, 6-21 months). CONCLUSIONS: Combining transverse and perpendicular sections to assess surgical margins of specimens from RT makes the protocol simple, reliable and produces accurate results. PMID- 25702585 TI - High-sensitivity human papilloma virus genotyping reveals near universal positivity in anal squamous cell carcinoma: different implications for vaccine prevention and prognosis. AB - BACKGROUND: Characterisation of human papilloma virus (HPV) infection in anal squamous cell carcinoma (ASCC) may have dual importance: first, aetiological; second, prognostic, informing outcome after chemo-radiotherapy (CRT). We undertook HPV genotyping, and allelic characterisations, to evaluate the aetiological role of HPV while simultaneously evaluating the impact of HPV genotyping on relapse-free (RFS) and overall survival (OS). METHOD: Dual-primer HPV genotyping (subtypes 6, 11, 16, 18, 31, 33, 45, 52, 58) and DNA sequencing of HPV 16 positive tumours were analysed in 151 consecutively referred ASCCs, previously characterised by immunohistochemistry for p16 expression. In 110 patients treated with CRT, factors influencing RFS and OS were evaluated using univariate and multivariate models. RESULTS: HPV positivity was observed in 95%. HPV 16 accounted for 89%; of these, 64% harboured the T350G E6 variant. HPV 16 positivity was significantly correlated with improved 5-year RFS (62% versus 40%; p = 0.027) and OS (59% versus 38%; p = 0.019). p16 expression was also significantly correlated with improved 5-year RFS (positive versus negative: 65% versus 16%; p < 0.0001) and OS (63% versus 13%; p < 0.0001). In multivariable models that included HPV 16 status, p16 status, sex, and age, p16 expression remained an independent prognostic factor for RFS (p < 0.0001) and OS (p = 0.002). CONCLUSION: In ASCC, near-universal HPV detection rates were demonstrated, higher than generally reported in the literature, and supporting the development of multivalent HPV vaccinations for prevention. By contrast, p16 negatively, but not HPV 16 genotype, is an independent adverse prognosticator after chemo-radiotherapy in patients with ASCC. PMID- 25702586 TI - Dissecting FASD through the global transcriptome. PMID- 25702587 TI - A modified bone lid for osteoplastic surgery of the maxillary sinus. AB - Major problems associated with the use of a bone lid for osteoplastic surgery of the maxillary sinus, as first described by Lindorf, are the possibility of postoperative dislocation of the bony fragment into the sinus (floating bone), as well as inflammatory resorption or fracture of the very thin removed trap door fragment. We describe a technique that prevents dislocation of the bone lid and allows for very good visualization of the entire sinus by a simple extended design and the use of resorbable pins. With the use of this extended bone lid, the removal of severely dislocated teeth, implants, sinus pathologies, or foreign bodies can be performed easily. Furthermore, this is an advantageous approach for large orbital fractures, especially those of the posterior half. PMID- 25702588 TI - The diagnostic value of high-resolution ultrasonography for the detection of anterior disc displacement of the temporomandibular joint: a meta-analysis employing the HSROC statistical model. AB - The study aimed to assess the diagnostic value of high-resolution ultrasonography (HR-US) in the detection of anterior disc displacement (ADD) of the temporomandibular joint. Relevant trials reported in MEDLINE, the Chinese National Knowledge Infrastructure Database, the Chinese Biomedical Literature Database, and Embase were identified. A manual search was also performed. The quality of retrieved data was evaluated using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) criteria. Data were extracted and cross checked, and a statistically rigorous meta-analysis was performed using a hierarchical summary receiver operating characteristic model (HSROC). The clinical utility of results was assessed using Fagan nomograms (Bayes theory). All data were evaluated using Stata software. A total 11 studies including 1096 subjects were included in the analysis; all reported the utility of HR-US for the diagnosis of ADD with reduction (ADDWR) and without reduction (ADDWoR). For ADDWR, the weighted sensitivity and specificity were 0.83 (95% confidence interval (CI) 0.78-0.88) and 0.85 (95% CI 0.76-0.92) respectively. The lambda value was 3.41 (95% CI 2.37-4.46) and the Fagan nomogram pre-test probability 58%, with a positive likelihood ratio (LR) of 6.01. The positive post-test probability was 89%, with a negative LR of 0.20. The negative post-test probability was 21%. The positive increase in diagnostic utility was 31% and the negative decrement in that value 37%. For ADDWoR, the weighted sensitivity and specificity values were 0.72 (95% CI 0.59-0.81) and 0.90 (95% CI 0.86-0.93), respectively. The lambda value was 3.69 (95% CI 2.39-4.99) and the Fagan nomogram pre-test probability 38%, with a positive LR of 7.00. The positive post-test probability was 82%, with a negative LR of 0.32. The negative post-test probability was 16%. The increase in diagnostic utility was 44% and the negative decrement in that value 22%. HR-US delivers acceptable performance when used to diagnose ADD, being superior for the detection of ADDWoR than ADDWR, and exhibiting a lower negative diagnostic value in the detection of ADDWoR than ADDWR. HR-US may serve as a new method for the rapid diagnosis of ADD. The method has the advantages of simplicity and low cost. Given the uncertainty in some of the estimated values, more high-quality studies are needed to assess that diagnostic efficacy. PMID- 25702589 TI - Facile C(sp(2))-C(sp(2)) bond cleavage in oxalic acid-derived radicals. AB - Oxalate decarboxylase (OxDC) catalyzes the Mn-dependent conversion of the oxalate monoanion into CO2 and formate. Many questions remain about the catalytic mechanism of OxDC although it has been proposed that the reaction proceeds via substrate-based radical intermediates. Using coupled cluster theory combined with implicit solvation models we have examined the effects of radical formation on the structure and reactivity of oxalic acid-derived radicals in aqueous solution. Our results show that the calculated solution-phase free-energy barrier for C-C bond cleavage to form CO2 is decreased from 34.2 kcal/mol for oxalic acid to only 9.3 kcal/mol and a maximum of 3.5 kcal/mol for the cationic and neutral oxalic acid-derived radicals, respectively. These studies also show that the C-C sigma bonding orbital of the radical cation contains only a single electron, giving rise to an elongated C-C bond distance of 1.7 A; a similar lengthening of the C-C bond is not observed for the neutral radical. This study provides new chemical insights into the structure and stability of plausible intermediates in the catalytic mechanism of OxDC, and suggests that removal of an electron to form a radical (with or without the concomitant loss of a proton) may be a general strategy for cleaving the unreactive C-C bonds between adjacent sp(2)-hybridized carbon atoms. PMID- 25702590 TI - Cytokines and clinical predictors in distinguishing pulmonary transfusion reactions. AB - BACKGROUND: Pulmonary transfusion reactions are important complications of blood transfusion, yet differentiating these clinical syndromes is diagnostically challenging. We hypothesized that biologic markers of inflammation could be used in conjunction with clinical predictors to distinguish transfusion-related acute lung injury (TRALI), transfusion-associated circulatory overload (TACO), and possible TRALI. STUDY DESIGN AND METHODS: In a nested case-control study performed at the University of California at San Francisco and Mayo Clinic, Rochester, we evaluated clinical data and blood samples drawn before and after transfusion in patients with TRALI (n = 70), possible TRALI (n = 48), TACO (n = 29), and controls (n = 147). Cytokines measured included granulocyte-macrophage colony-stimulating factor, interleukin (IL)-6, IL-8, IL-10, and tumor necrosis factor-alpha. Logistic regression and receiver operating characteristics curve analyses were used to determine the accuracy of clinical predictors and laboratory markers in differentiating TACO, TRALI, and possible TRALI. RESULTS: Before and after transfusion, IL-6 and IL-8 were elevated in patients with TRALI and possible TRALI relative to controls, and IL-10 was elevated in patients with TACO and possible TRALI relative to that of TRALI and controls. For all pulmonary transfusion reactions, the combination of clinical variables and cytokine measurements displayed optimal diagnostic performance, and the model comparing TACO and TRALI correctly classified 92% of cases relative to expert panel diagnoses. CONCLUSIONS: Before transfusion, there is evidence of systemic inflammation in patients who develop TRALI and possible TRALI but not TACO. A predictive model incorporating readily available clinical and cytokine data effectively differentiated transfusion-related respiratory complications such as TRALI and TACO. PMID- 25702591 TI - Recurrent intraluminal eosinophilic tracheal granuloma in a Siberian husky. PMID- 25702592 TI - Hip-Knee-Ankle Radiographs Are More Appropriate for Assessment of Post-Operative Mechanical Alignment of Total Knee Arthroplasties than Standard AP Knee Radiographs. AB - Weight-bearing hip-knee-ankle (HKA) radiographs are the gold standard for measuring lower limb alignment after total knee arthroplasty (TKA), however the majority of UK units use standardised anteroposterior (AP) knee radiographs. This study aimed to determine whether standardised AP knee radiographs adequately assess lower limb alignment after TKA. HKA radiographs from 50 post-operative TKAs were cropped to the size of a standardised AP knee radiograph allowing comparison of mechanical and anatomical alignment measurements between the two views. Repeatability of alignment measurements was significantly better for HKA radiographs, however, there was poor agreement of the mechanical alignment measured between the two views. Standardised AP knee radiographs are insufficient to assess the mechanical alignment of post-operative TKA and we recommend routinely using HKA radiographs. PMID- 25702593 TI - Chronic Non-Orthopedic Conditions More Common in Patients with Less Severe Degenerative Changes That Have Elected to Undergo Total Knee Arthroplasty. AB - The purpose of this study was to determine whether the prevalence of chronic non orthopedic conditions that may play a role in an abnormal pain response differs between patients based on the severity of degenerative changes at the time of surgery. Of 1020 OA knees that had undergone primary TKA with a minimum 2year follow-up, we identified 117 (11.5%) that had less severe degenerative changes. The prevalence of dissatisfaction was significantly greater in less severe group compared to those with moderate or severe changes (18.8% vs. 9.3%, P=.003). Chronic non-orthopedic conditions were significantly more prevalent in the less severe group with 41.9% reporting depression/anxiety, 30.8% with fibromyalgia or low back pathology, and 12.8% with a prior traumatic brain injury or stroke. PMID- 25702594 TI - Measuring rapid recovery program outcomes: are all patients candidates for rapid recovery. AB - Total joint arthroplasty procedures have been demonstrated to be effective in the treatment of end stage hip and knee arthritis. The purpose of this paper is to outline various processes utilized to assess the outcomes of rapid recovery programs and to outline areas where future research and metrics will be beneficial in demonstrating the effectiveness of these programs. We have highlighted the use of large databases [NIS (National Inpatient Sample) and NSQIP (National Surgical Quality Improvement Program)] to help identify patients who are candidates for the rapid recovery approach. Continued thorough investigation should not only justify rapid recovery, but also move traditional joint arthroplasty programs to more efficient cost effective care once appropriate metrics are identified that support the need for resources for rapid recovery programs. PMID- 25702595 TI - Patient-Reported Allergies Are Associated With Poorer Patient Satisfaction and Outcomes After Lower Extremity Arthroplasty: A Retrospective Cohort Study. AB - Anecdotal evidence suggests that patient-reported allergies (PRAs) may exhibit prognostic value for patient-reported outcomes after lower extremity arthroplasty. This study's purpose was to investigate associations between PRAs, patient satisfaction and outcomes after total hip arthroplasty (THA) and total knee arthroplasty (TKA). PRAs in 274 patients undergoing primary THA and 257 patients receiving primary TKA were reviewed retrospectively. Satisfaction scores, baseline Western Ontario and McMaster Universities Arthritis Index (WOMAC), 2-year postoperative WOMAC and length-of-stay (LOS) were analyzed with PRAs. Increasing number of PRAs was significantly associated with worse satisfaction scores and worse WOMAC scores for TKA and THA, and it was significantly associated with increased LOS for TKA. These results may have implications for patient counseling and risk-adjusted outcome models. PMID- 25702597 TI - Survival of children with sickle cell disease in the comprehensive newborn screening programme in Minas Gerais, Brazil. AB - Background Children in developing countries with sickle cell disease SCD have high rates of mortality, especially in some parts of Africa. Aim To compare the 5 year estimated mortality rate in children born between 1999 and 2001 with that of children born between 2009 and 2011. Methods During the period 1998-2012, sickle cell disease was diagnosed in 2591 of 3,617,919 newborns screened in Minas Gerais, Brazil (1 : 1,400). The estimated probability of death [1 - Survival] was calculated by the Kaplan-Meier method. The logrank test was used to compare groups of survival data. Results Of the 2576 children (15 were excluded), 193 died (7.4%): 153 (79.3%) had SS/Sbeta0-thalassaemia, 34 had SC (17.6%), and six (3.1%) had Sbeta+ thalassaemia. The 5-year estimated mortality was lower for children born between 2009 and 2011 (n=509) than for those born between 1999 and 2001 (n=624), although not significantly [mean (SD) 5.8% (1.1) vs 6.2% (1.0)], respectively). Conclusion Despite an effective ongoing comprehensive screening programme, mortality from SCD in Minas Gerais is still high. To decrease mortality rates, socio-economic development and SCD education programmes for health professionals and families are required. PMID- 25702596 TI - A treelet transform analysis to relate nutrient patterns to the risk of hormonal receptor-defined breast cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC). AB - OBJECTIVE: Pattern analysis has emerged as a tool to depict the role of multiple nutrients/foods in relation to health outcomes. The present study aimed at extracting nutrient patterns with respect to breast cancer (BC) aetiology. DESIGN: Nutrient patterns were derived with treelet transform (TT) and related to BC risk. TT was applied to twenty-three log-transformed nutrient densities from dietary questionnaires. Hazard ratios (HR) and 95 % confidence intervals computed using Cox proportional hazards models quantified the association between quintiles of nutrient pattern scores and risk of overall BC, and by hormonal receptor and menopausal status. Principal component analysis was applied for comparison. SETTING: The European Prospective Investigation into Cancer and Nutrition (EPIC). SUBJECTS: Women (n 334 850) from the EPIC study. RESULTS: The first TT component (TC1) highlighted a pattern rich in nutrients found in animal foods loading on cholesterol, protein, retinol, vitamins B12 and D, while the second TT component (TC2) reflected a diet rich in beta-carotene, riboflavin, thiamin, vitamins C and B6, fibre, Fe, Ca, K, Mg, P and folate. While TC1 was not associated with BC risk, TC2 was inversely associated with BC risk overall (HRQ5 v. Q1=0.89, 95 % CI 0.83, 0.95, P trend<0.01) and showed a significantly lower risk in oestrogen receptor-positive (HRQ5 v. Q1=0.89, 95 % CI 0.81, 0.98, P trend=0.02) and progesterone receptor-positive tumours (HRQ5 v. Q1=0.87, 95 % CI 0.77, 0.98, P trend<0.01). CONCLUSIONS: TT produces readily interpretable sparse components explaining similar amounts of variation as principal component analysis. Our results suggest that participants with a nutrient pattern high in micronutrients found in vegetables, fruits and cereals had a lower risk of BC. PMID- 25702598 TI - The influence of propolis on rheological properties of lipstick. AB - OBJECTIVE: The aim of this work was to study the effect of propolis on the rheological and textural properties of lipsticks. The studied lipsticks were based on raw materials and contained no synthetic compounds, preservatives, fragrances or dyes. The rheological and textural properties of the prepared lipsticks, both with and without propolis, were studied as a function of temperature and storage period. METHOD: Measurements were taken using an RS6000 rheometer (Haake, Germany) with a cone-plate sensor. The cone parameters were as follows: diameter 35 mm and angle 2 degrees . Textural tests were performed using the same cone-plate geometry. RESULTS: The research results of rheological and textural properties of lipsticks, with and without the addition of propolis, indicate the possibility of application of propolis as a beneficial additive to such type of cosmetics. The presence of propolis does not significantly alter the viscoelastic properties of the lipsticks. The courses of flow curves indicate shear thinning, which is very advantageous from an application point of view. From the rheological point of view, the properties of lipsticks tested in low deformation conditions show some structural changes, most likely due to consolidation of the structure. CONCLUSION: The analysis of textural properties indicates that lipsticks with added propolis are more brittle and prone to crushing. However, the temperature increase (30 degrees C) does not cause significant changes to the textural characteristics of these lipsticks. PMID- 25702599 TI - Letter from the editor--issue 399/1-1 March 2015. PMID- 25702600 TI - The relationship between post-stroke depression and physical recovery. AB - BACKGROUND: Post-stroke depression (PSD) is a serious and common complication of stroke. In this prospective study on the relationship between clinical PSD and physical recovery, we focused on (1) distinguishing between depression and apathy, (2) issues in assessment of PSD, and (3) timing of assessment. METHODS: Japanese stroke patients (n=117) were studied. We used self-rating scales [Zung Self-Rating Depression Scale (SDS) for depression; Apathy Scale (AS) for apathy] and observer-rating scales [Montgomery-Asberg Depression Rating Scale (MADRS) for depression; Neuropsychiatric Inventory-Nursing Home (NPI-NH) for apathy] to assess psychological state. We assessed physical disability using the Functional Independence Measurement (FIM). Two-way analysis of covariance was used to determine effects of depression and apathy on functional outcome. We evaluated PSD twice, within 10 days after hospitalization and four weeks later. RESULTS: Objective scales gave higher prevalence than subjective scales for both depression and apathy. A significant effect of apathy on FIM recovery was seen with objective scale assessment during hospitalization; there was a marginal effect of depression at the same time. LIMITATIONS: We did not consider the stroke size and location. In addition, we excluded patients with severe comprehension deficits or with a history of stroke. CONCLUSIONS: Our findings indicate that depression and apathy could occur independently after stroke and could individually influence functional recovery. We obtained more accurate estimates of functional recovery using objective measures. Furthermore, our findings suggest that depression and apathy should be assessed not only at admission but also during hospitalization to estimate and enhance the functional recovery of stroke patients. PMID- 25702601 TI - Affective temperaments in subjects with female-to-male gender dysphoria. AB - BACKGROUND: Males and females have different temperaments. In individuals with gender dysphoria (GD) there is marked incongruence between a person's expressed/experienced gender and their biological sex. The present study aimed to investigate the most common affective temperaments in individuals with female-to male (FtM) GD. METHODS: We performed a prospective and comparative study investigating affective temperaments in subjects with FtM GD. Eighty subjects with FtM GD and 68 female controls were enrolled. The Temperament Evaluation of Memphis, Pisa, Paris and San Diego Autoquestionnaire (TEMPS-A) was completed by all participants. RESULTS: TEMPS-A scores were significantly higher in subjects with FtM GD for hyperthymic temperament (p<=0.001), whereas depressive (p<=0.001), anxious (p<=0.001), and cyclothymic (p=0.028) temperament scores were significantly higher in female controls. LIMITATIONS: The study was limited by the lack of male-to-female subjects and male controls. CONCLUSIONS: The results of our study indicate that individuals with FtM GD have significantly higher scores of hyperthymic temperament, measured by TEMPS-A. Biological basis underlying the development of gender identity independent from the biological sex might be related with affective temperaments. PMID- 25702602 TI - The relationship between sleep and postpartum mental disorders: A systematic review. AB - BACKGROUND: Postpartum mental disorders (e.g., anxiety, depression, psychosis) are serious conditions that affect approximately 10-15% of women after childbirth, and up to 40% of women at risk for these disorders. Research reveals an association between poor sleep quality/quantity and symptoms of anxiety, depression and psychosis. The aim of this systematic review was to evaluate the available evidence for the relationship between sleep and postpartum mental disorders. METHODS: Searches included MEDLINE, EMBASE, and EBM Reviews - Cochrane Central Register of Controlled Trials, PsycINFO and EBSCOHost CINAHL through June 30, 2014. Manual searching was performed on reference lists of included articles. Published primary research in any language was included. RESULTS: There were 3187 unique titles/abstracts and 44 full-text articles reviewed. Thirty-one studies were included. Evidence was found for the impact of self-reported poor sleep during pregnancy and the postpartum on the development of postpartum depression, with not enough evidence for either postpartum anxiety or psychosis. The evidence for objectively assessed sleep and the development of postpartum disorders was mixed. Among the 31 studies included, 1 was strong, 13 were moderate and 17 were weak. LIMITATIONS: Research design, method of assessment, timing of assessment, recruitment strategies, representative adequacy of the samples and inclusion/exclusion criteria all varied widely. Many studies did not use tools validated for the perinatal population and had small sample sizes without power analysis. CONCLUSIONS: Sleep interventions represent a potential low-cost, non pharmacological prevention and treatment strategy for postpartum mental illness. Further high-quality research is needed on this topic area. PMID- 25702603 TI - Association between longitudinal changes in prefrontal hemodynamic responses and social adaptation in patients with bipolar disorder and major depressive disorder. AB - BACKGROUND: Patients with affective disorders exhibit changes in regional brain function and show abnormal social adaptation. However, to our knowledge, no near infrared spectroscopy (NIRS) study has examined the relationship between these two phenomena longitudinally. This study examined the region-specific functional abnormality associated with bipolar disorder (BD) and major depressive disorder (MDD), and the association between particular longitudinal changes in regional activation and social adaptation. METHODS: We evaluated frontotemporal functioning during a verbal fluency test (VFT) for patients with BD (N=18), those with MDD (N=10), and healthy controls (HCs; N=14) using NIRS. NIRS measurements and the Social Adaptation Self-evaluation Scale (SASS) were administered twice with an interval of approximately 6 months. RESULTS: The BD and MDD groups showed lesser activation than the HCs in the bilateral ventro-lateral prefrontal cortex and the anterior part of the temporal cortex (VLPFC/aTC). Longitudinal changes in SASS scores were positively associated with the extent of change in left VLPFC/aTC activation in the BD group and with right VLPFC/aTC activation in the MDD group. LIMITATIONS: Our small sample size limited statistical power, and the effect of medication and multiple comparisons cannot be excluded, although these effects were considered in the interpretation of the present results. CONCLUSION: Longitudinal increases of VLPFC/aTC activation were associated with improvement in social adaptation in patients with BD and those with MDD. NIRS measurement could be a useful tool for objective evaluation of changes in social adaptation in BD and MDD. PMID- 25702604 TI - PTSD symptom presentation across the deployment cycle. AB - BACKGROUND: Symptom-level variation in posttraumatic stress disorder (PTSD) has not yet been examined in the early post-deployment phase, but may be meaningful etiologically, prognostically, and clinically. METHODS: Using latent class analysis (LCA), we examined PTSD symptom heterogeneity in a cohort of participants from the Marine Resiliency Study (MRS), a longitudinal study of combat Marines deployed to Iraq and Afghanistan (N=892). Typologies of PTSD symptom presentation were examined at one month pre-deployment and again one, five, and eight months post-deployment. RESULTS: Heterogeneity in PTSD symptom presentation was evident at each assessment point, and the degree of symptom heterogeneity (i.e., the number of classes identified) differed by time point. Symptom patterns stabilized over time from notable symptom fluctuations during the early post-deployment period to high, medium, and low symptom severity by eight months post-deployment. Hypervigilance and exaggerated startle were frequently endorsed by participants in the initial month post-deployment. Flashbacks, amnesia, and foreshortened future were infrequently endorsed. Greater combat exposure, lifespan trauma, and avoidant coping generally predicted worse outcomes. LIMITATIONS: Data were self-report and may have limited generalizability due to our lack of women and inclusion of only combat Marines. Attrition and re-ranging of data resulted in significant missing data and affected the representativeness of the sample. CONCLUSIONS: Symptom-level variability is highest in the month following deployment and then stabilizes over time. Should post-deployment assessments occur too soon, they may capture common and transient early post-deployment reactions, particularly anxious arousal. PMID- 25702605 TI - Chemical composition, antibacterial and anticancer activities of volatile oil of Melicope denhamii leaves. AB - Melicope denhamii leaf volatile oil was isolated by hydrodistillation, and twenty six constituents comprising 95.95% of the leaf oil were characterised by gas chromatographic techniques. Sesquiterpenes, zierone (22.49%) and alpha-gurjunene (19.96%), were identified as the major components. M. denhamii leaf oil tested against Gram-positive and Gram-negative bacteria showed significant activity against Bacillus subtilis and Escherichia coli. Anticancer activity of M. denhamii leaf oil against Dalton's lymphoma ascites cells was assessed by trypan blue exclusion and MTT assays, and the oil showed significant cytotoxicity at CD50 of 12.2 MUg/mL. Induction of apoptosis on DLA cells by M. denhamii leaf oil was confirmed by morphological observation, nuclear damage and comet assays. PMID- 25702606 TI - Comparison of immunological and microbiological characteristics in children and the elderly with or without dental caries. AB - The purpose of this study was to determine the relationships among early childhood caries (ECC), root caries (RC), the quantity of Streptococcus mutans in saliva, and the concentrations of total and specific secretory IgA (sIgA). Saliva samples were collected from 70 children, 3-4 yr of age, with and without ECC, and from 43 adults, >=60 yr of age, with and without RC. The decayed, missing, and filled teeth (dmft) and decayed, missing, and filled surfaces (dmfs) scores of each child, and the root decayed and filled teeth (RDFT) and root decayed and filled surfaces (RDFS) scores of each elderly subject, were determined. The S. mutans levels, total sIgA, and specific sIgA against two virulence antigens of S. mutans in saliva were analysed using quantitative real-time PCR (qPCR) and ELISAs. The quantity of S. mutans was significantly higher in caries-positive subjects within the two populations than in the caries-free subjects; and a positive correlation was found between the quantity of S. mutans and the dmft, dmfs, RDFT, and RDFS scores. In addition, the salivary total sIgA was significantly higher in children with severe early childhood caries (SECC) and in the elderly subjects with RC. Moreover, although the S. mutans level was significantly higher, the concentrations of specific sIgA against S. mutans antigens were significantly lower in samples from elderly subjects than in samples from children. These results support the concept that S. mutans is positively associated with ECC and RC. Furthermore, the levels of S. mutans specific antibodies in saliva are too low to prevent infection with cariogenic bacteria and to inhibit development of ECC and RC. PMID- 25702607 TI - Editors' pick 2014. PMID- 25702609 TI - Traceback investigation for Salmonella contamination at egg processing plants in South Korea: prevalence, antibiotic resistance, and epidemiological tracing by rep-PCR fingerprinting. AB - We conducted a survey of Salmonella from 8 egg-breaking plants and a farm to determine the prevalence and the source of the bacteria. The contents of 2400 shell eggs (20 eggs per pool), 75 pasteurized liquid egg products, and 120 unpasteurized liquid egg products from 8 egg-breaking plants in South Korea were examined. In liquid egg samples, 4 Salmonella-positive samples from 120 unpasteurized ones (3.3%) and 5 positive samples from 75 pasteurized ones (6.7%) were identified; no eggs were positive for Salmonella among shell egg samples. To trace the source of Salmonella, we revisited the 2 Salmonella-positive plants (plants A and C). We investigated the equipment and environments of the plants and a henhouse (farm A) that supplied shell eggs to plant A, and collected additional liquid eggs and shell eggs from plants A and C. All Salmonella isolates from plant A and the associated farm A, except for a single Typhimurium strain from farm A, were serotyped as Bareilly. Three serovars, including one Bareilly, four Tennessee, and one Richmond, were isolated from plant C. Most Salmonella isolates were susceptible to tested antibiotics. To identify differences between isolates, molecular subtyping by using the automated rep-PCR system was conducted. All Salmonella Bareilly (S. Bareilly) strains from plant A exhibited high similarity, indicating possible contamination by Salmonella strains from the henhouse A. Meanwhile, 2 S. Bareilly strains from plant C, one from liquid egg at the 1st visit and the other from container at the 2nd visit, exhibited identical antibiotic resistance and similar subtyping pattern, but clearly discriminated from the ones of plant A. PMID- 25702610 TI - Probiotics in transition: novel strategies. AB - Regulations regarding health claims made for probiotics demand their proven effectiveness and limit the array of microbial species regarded as safe for live consumption. Novel strategies such as moving to postbiotics and genetically modified probiotics may be necessary to increase the effectiveness of microbial products. PMID- 25702611 TI - TCP transcription factors are critical for the coordinated regulation of isochorismate synthase 1 expression in Arabidopsis thaliana. AB - Salicylic acid (SA) plays an important role in various aspects of plant development and responses to stresses. To elucidate the sophisticated regulatory mechanism of SA synthesis and signaling, we used a yeast one-hybrid system to screen for regulators of isochorismate synthase 1 (ICS1), a gene encoding the key enzyme in SA biosynthesis in Arabidopsis thaliana. A TCP family transcription factor AtTCP8 was initially identified as a candidate regulator of ICS1. The regulation of ICS1 by TCP proteins is supported by the presence of a typical TCP binding site in the ICS1 promoter. The binding of TCP8 to this site was confirmed by in vitro and in vivo assays. Expression patterns of TCP8 and its corresponding gene TCP9 largely overlapped with ICS1 under pathogen attack. A significant reduction in the expression of ICS1 during immune responses was observed in the tcp8 tcp9 double mutant. We also detected strong interactions between TCP8 and SAR deficient 1 (SARD1), WRKY family transcription factor 28 (WRKY28), NAC (NAM/ATAF1,ATAF2/CUC2) family transcription factor 019 (NAC019), as well as among TCP8, TCP9 and TCP20, suggesting a complex coordinated regulatory mechanism underlying ICS1 expression. Our results collectively demonstrate that TCP proteins are involved in the orchestrated regulation of ICS1 expression, with TCP8 and TCP9 being verified as major representatives. PMID- 25702612 TI - Insights into molecular interactions between CaM and its inhibitors from molecular dynamics simulations and experimental data. AB - In order to contribute to the structural basis for rational design of calmodulin (CaM) inhibitors, we analyzed the interaction of CaM with 14 classic antagonists and two compounds that do not affect CaM, using docking and molecular dynamics (MD) simulations, and the data were compared to available experimental data. The Ca(2+)-CaM-Ligands complexes were simulated 20 ns, with CaM starting in the "open" and "closed" conformations. The analysis of the MD simulations provided insight into the conformational changes undergone by CaM during its interaction with these ligands. These simulations were used to predict the binding free energies (DeltaG) from contributions DeltaH and DeltaS, giving useful information about CaM ligand binding thermodynamics. The DeltaG predicted for the CaM's inhibitors correlated well with available experimental data as the r(2) obtained was 0.76 and 0.82 for the group of xanthones. Additionally, valuable information is presented here: I) CaM has two preferred ligand binding sites in the open conformation known as site 1 and 4, II) CaM can bind ligands of diverse structural nature, III) the flexibility of CaM is reduced by the union of its ligands, leading to a reduction in the Ca(2+)-CaM entropy, IV) enthalpy dominates the molecular recognition process in the system Ca(2+)-CaM-Ligand, and V) the ligands making more extensive contact with the protein have higher affinity for Ca(2+)-CaM. Despite their limitations, docking and MD simulations in combination with experimental data continue to be excellent tools for research in pharmacology, toward a rational design of new drugs. PMID- 25702613 TI - Adsorption of F127 onto single-walled carbon nanotubes characterized using small angle neutron scattering. AB - Aqueous single-walled carbon nanotube dispersions are often made using polymers from the pluronic family of amphiphilic block copolymers; however, relatively few studies have been conducted using small-angle neutron scattering techniques to discover the mechanism by which they act. SANS results reported here show that a relatively simple core-shell cylinder model can be used to fit data successfully at different contrasts. The results across all contrasts showed that the best fit gave an inner nanotube radius of 10 A, corresponding to small nanotube bundles with a small amount of water present (20%), and a polydisperse adsorbed layer thickness of 61 A, with a water content of 94% in the adsorbed layer. The data fitting is thus consistent with a small SWCNT bundle surrounded by an extended and water-swollen F127 adsorbed layer. Comparing the scattering from F127/SWCNT at different contrasts, it has been found that the polymer-decorated SWCNTs are contrast matched at a D2O/H2O volume ratio of 0.36:0.64, corresponding to a scattering-length density of 1.92 * 10(-6) A(-2). PMID- 25702614 TI - Dural Arteriovenous Fistula Mimicking a Brainstem Glioma. AB - BACKGROUND: Brainstem intracranial dural arteriovenous fistulas are extremely rare and can mimic a glioma at the time of presentation. CASE: We report a patient with an infiltrating brainstem lesion that finally revealed an intracranial dural arteriovenous fistula, with full neurological improvement after embolization. CONCLUSION: A careful radiological study looking for dilated vessels around the brainstem is necessary in the workup of an infiltrating brainstem lesion, in order to rule out intracranial dural arteriovenous fistula. PMID- 25702615 TI - Inhibitory activity of Lactobacillus plantarum TF711 against Clostridium sporogenes when used as adjunct culture in cheese manufacture. AB - Bacteriocins produced by lactic acid bacteria are of great interest to the food processing industry as natural preservatives. This work aimed to investigate the efficacy of bacteriocin-producing Lactobacillus plantarum TF711, isolated from artisanal Tenerife cheese, in controlling Clostridium sporogenes during cheese ripening. Cheeses were made from pasteurised milk artificially contaminated with 10(4) spores m/l C. sporogenes. Experimental cheeses were manufactured with Lb. plantarum TF711 added at 1% as adjunct to commercial starter culture. Cheeses made under the same conditions but without Lb. plantarum TF711 served as controls. Evolution of microbiological parameters, pH and NaCl content, as well as bacteriocin production was studied throughout 45 d of ripening. Addition of Lb. plantarum TF711 did not bring about any significant change in starter culture counts, NaCl content and pH, compared with control cheese. In contrast, clostridial spore count in experimental cheeses were significantly lower than in control cheeses from 7 d onwards, reaching a maximum reduction of 2.2 log units on day 21. Inhibition of clostridia found in experimental cheeses was mainly attributed to plantaricin activity, which in fact was recovered from these cheeses. PMID- 25702616 TI - Comparison of World Health Organization 2000/2004 and World Health Organization 2010 classifications for gastrointestinal and pancreatic neuroendocrine tumors. AB - Gastroenteropancreatic neuroendocrine tumors (GEPNETs) were divided into 4 groups based on tumor diameter and stage in World Health Organization (WHO) 2000/2004 classification as well-differentiated endocrine tumor benign (WDETB), well differentiated endocrine tumor with uncertain behavior (WDETUB), well differentiated endocrine carcinoma (WDEC), and poorly differentiated endocrine carcinoma (PDEC). World Health Organization 2000/2004 was not widely accepted because of stage-related classification and the category of "uncertain behavior." The European NET Society proposed a grading classification and site-specific staging system in 2010. Gastroenteropancreatic NETs were divided into 3 groups as NET grade 1 (G1), NET grade 2 (G2), and neuroendocrine carcinoma (NEC) grade 3 (G3) based on mitoses and the Ki-67 index. We evaluated 63 GEPNET cases according to both classifications. We compared two classifications and the tumor groups in terms of prognostic parameters (diameter, mitosis, Ki-67 index, angioinvasion, perineural invasion, necrosis, and metastasis) and pathologic stage. All 14 cases diagnosed as PDEC were included in the NEC G3 according to WHO 2010. Seventeen cases were diagnosed as WDETB, 9 as WDETUB, and 23 as WDEC. There was statistically significant difference between these groups in terms of all prognostic parameters except for necrosis, mitosis, Ki-67 index, and grade. All WDETB cases, 89% of WDETUBs, and 87% of WDECs were included in the NET G1. There were 45 cases evaluated as NET G1 and 4 cases as NET G2 according to WHO 2010. Metastasis and perineural invasion were more common in NET G2, no significant differences in other parameters. In conclusion, WHO 2010 is easier to use, whereas WHO 2000/2004 shows higher correlation with prognosis. However, it includes benign and uncertain behavior categories, although small tumors with low proliferative activity can also cause metastases. All GEPNETs should be considered potentially malignant. PMID- 25702617 TI - Pericardial fat is associated with all-cause mortality but not incident CVD: the Rancho Bernardo Study. AB - OBJECTIVE: Pericardial and intra-thoracic fat are associated with prevalent cardiovascular disease (CVD) and CVD risk factors. However, it is unclear if these fat depots predict incident CVD events and/or all-cause mortality. We examined prospective associations between areas of pericardial and intra-thoracic fat and incident CVD and mortality over a 12-year follow-up in a subset of participants without baseline clinical CVD from the Rancho Bernardo Study (RBS). METHODS: Participants were 343 community-dwelling older adults (mean baseline age = 67) who completed a clinic visit in 2001-02, including a computed tomography scan of the chest. Incident CVD and mortality were recorded through January 2013. RESULTS: Over a 12.6-year median follow-up, there were 60 incident CVD events and 49 deaths. Pericardial fat was associated with all-cause mortality, such that each standard deviation increment predicted a 34% higher chance of death after adjusting for demographics, lifestyle factors, comorbidities, and visceral fat (95% CI = 1.01-1.78). When categorized by tertile, those in the middle tertile of pericardial fat showed no increased risk of mortality, while those in the highest tertile had 2.6 times the risk (95% CI = 1.10-5.97) compared to the lowest tertile. There was a marginal association between intra-thoracic fat and mortality (p = 0.06). Neither pericardial nor intra-thoracic fat was significantly associated with incident CVD. There were no significant interactions by sex. CONCLUSIONS: Higher pericardial, but not intra-thoracic, fat was associated with earlier all-cause mortality in older adults over a 12-year follow-up. This association was primarily driven by a higher mortality rate in those in the highest tertile of pericardial fat. PMID- 25702618 TI - Rosuvastatin may stabilize atherosclerotic aortic plaque: transesophageal echocardiographic study in the EPISTEME trial. AB - OBJECTIVE: Large atheromatous aortic plaques (AAPs) have been associated with ischemic stroke. There is little evidence to guide the therapeutic strategy for ischemic stroke associated with large AAPs. This study sought to analyze the temporal profile of AAPs after rosuvastatin therapy in Japanese patients with acute ischemic stroke. METHODS: The Efficacy of Post-stroke Intensive Rosuvastatin Treatment for aortogenic Embolic stroke (EPISTEME) trial was a prospective, randomized, open-label study. Acute ischemic stroke patients with dyslipidemia and AAPs >=4-mm-thick on transesophageal echocardiography (TEE) were enrolled and randomly allocated to either the group treated with 5 mg/day rosuvastatin or the control group. The primary endpoint was the changes in volume and composition of AAPs on repeat TEE after 6 months. High-echoic plaque area was analyzed using binary images. RESULTS: A total of 24 Japanese patients (rosuvastatin 12; control 12) were included in the primary analysis. Rosuvastatin substantially reduced low-density lipoprotein cholesterol (LDL-C) compared to control (-42.1% vs. 1.4%, P < 0.001). Percent changes of high-echoic plaque areas were significantly increased in the rosuvastatin group, while they were decreased in the control group (65.8% vs -14.7%, P < 0.001). There was a significant linear correlation between percent increase in high-echoic plaque area and LDL-C decrease (r=-0.434, P=0.002). CONCLUSION: Treatment with 5-mg rosuvastatin for 6 months might induce atheromatous aortic plaque stabilization together with marked LDL-C reduction in Japanese patients with ischemic stroke, which could provide evidence on which to base the therapeutic strategy for aortogenic brain embolism. PMID- 25702619 TI - Production of Gene-Corrected Adult Beta Globin Protein in Human Erythrocytes Differentiated from Patient iPSCs After Genome Editing of the Sickle Point Mutation. AB - Human induced pluripotent stem cells (iPSCs) and genome editing provide a precise way to generate gene-corrected cells for disease modeling and cell therapies. Human iPSCs generated from sickle cell disease (SCD) patients have a homozygous missense point mutation in the HBB gene encoding adult beta-globin proteins, and are used as a model system to improve strategies of human gene therapy. We demonstrate that the CRISPR/Cas9 system designer nuclease is much more efficient in stimulating gene targeting of the endogenous HBB locus near the SCD point mutation in human iPSCs than zinc finger nucleases and TALENs. Using a specific guide RNA and Cas9, we readily corrected one allele of the SCD HBB gene in human iPSCs by homologous recombination with a donor DNA template containing the wild type HBB DNA and a selection cassette that was subsequently removed to avoid possible interference of HBB transcription and translation. We chose targeted iPSC clones that have one corrected and one disrupted SCD allele for erythroid differentiation assays, using an improved xeno-free and feeder-free culture condition we recently established. Erythrocytes from either the corrected or its parental (uncorrected) iPSC line were generated with similar efficiencies. Currently ~6%-10% of these differentiated erythrocytes indeed lacked nuclei, characteristic of further matured erythrocytes called reticulocytes. We also detected the 16-kDa beta-globin protein expressed from the corrected HBB allele in the erythrocytes differentiated from genome-edited iPSCs. Our results represent a significant step toward the clinical applications of genome editing using patient-derived iPSCs to generate disease-free cells for cell and gene therapies. Stem Cells 2015;33:1470-1479. PMID- 25702620 TI - Effect of active infection on cytochrome P450-mediated metabolism of cyclosporine in renal transplant patients. AB - BACKGROUND: Infections downregulate cytochrome-P activities and thus may alter drug disposition, especially for drugs with a narrow therapeutic index. Cyclosporine (CyA), still used for the prevention of allograft rejection in renal transplant recipients in Egypt, seems to be affected by these infectious changes, based on random clinical observations. In the present study, the effects of bacterial and fungal infection on CyA metabolism were studied in renal transplant patients and subsequent nephrotoxicity was monitored. METHODS: Twenty renal transplant patients, diagnosed with fungal or bacterial infection, were recruited from the renal transplantation outpatient clinic in Alexandria University Hospitals. No dose adjustment in CyA was performed at least 1 week before the onset of infection. Exclusion criteria were patients with acute or chronic unstable liver disease, elderly patients, and patients on concomitant drugs affecting CyA metabolism. CyA trough levels and serum creatinine (SCR) concentrations were measured by fluorescence polarization immunoassay and enzymatic assay, respectively, pre-infection, during infection and in many cases, post infection. RESULTS: CyA trough levels and SCR concentrations increased significantly during the infection (P < 0.001, P = 0.002) respectively. Of the patients, 87% experienced a concomitant rise in CyA trough level and SCR concentrations. No significant difference between pre-infection and post infection levels of CyA trough and SCR was found. CONCLUSIONS: CyA trough and SCR levels increased during bacterial and fungal infections and returned to pre infection levels once the infection was resolved. The data generated stress the importance of monitoring CyA levels during episodes of infection. Our recommendations concerning CyA dose adjustment differ according to severity and duration of infection. PMID- 25702621 TI - Induction Hedgehog pathway inhibition followed by combined-modality radiotherapy for basal cell carcinoma. AB - Basal cell carcinoma (BCC), the most common cancer in the U.S.A., is treated primarily with local excision. In some cases, lesion size, location or extent prevent complete resection. Locally advanced BCC responds to systemic therapy with the Hedgehog pathway inhibitor vismodegib, but withdrawal of treatment may result in disease relapse. Here we present a case of locally advanced auricular BCC treated with induction vismodegib and radiation, resulting in durable local control and an acceptable level of acute toxicity. PMID- 25702622 TI - Detection of Dermacentor marginatus and a possible Rickettsia slovaca case in the United Kingdom - the risk of the visiting traveller. PMID- 25702623 TI - Comparison of two treatment strategies for cows with metritis in high-risk lactating dairy cows. AB - Acute puerperal metritis (APM) and clinical metritis (CM) are uterine diseases frequently diagnosed in dairy cows. These diseases are responsible for important economic loss because of their effect not only on reproductive performance but also on milk production. The objective of this study was to assess the impact of two different treatments for metritis on dairy cows by measuring their reproductive performance in the next gestation. The end points to measure the reproductive performance included the conception rate at the first artificial insemination, the number of days at conception, and the proportion of nonpregnant cows at over 150 days after beginning milk production. The study was carried out in a high production dairy cow farm located in Lleida (northeast Spain). Recordings of 1044 parturitions of 747 Holstein cows were controlled in this farm from 2009 to 2014. Cows were diagnosed as suffering from metritis (APM or CM) if the following parameters were observed: an abnormally enlarged uterus; a fetid, watery, reddish brown uterine discharge with (APM) or without (CM) fever (>39.5 degrees C); and presence (APM) or absence (CM) of signs of systemic illness (decreased milk production, dullness, or other signs of toxemia) within 21 days postpartum. Afterwards, cows suffering from metritis (APM or CM) were randomly assigned and balanced to two groups: (1) animals receiving parenteral amoxicillin intramuscularly plus intrauterine infusion with oxytetracycline (P + I group) and (2) animals receiving only parenteral amoxicillin intramuscularly (P group). Furthermore, reproductive performance of cows without metritis was used as reference (control group). Metritis was diagnosed in 27.5% of the total parturitions included in the study (288 of 1044). In particular, metritis was diagnosed in 30.5% (118 of 387) and 25.9% (170 of 657) of parturitions from heifers and multiparous cows, respectively. Reproductive performance was not significantly affected by the parity, the season at the first artificial insemination, the season at conception, the bull, or the inseminator. The P + I treatment was able to significantly reduce the number of days at the first insemination and at conception when compared with the P treatment in heifers. In multiparous cows, this significant effect was only observed for days at conception. Additionally, the P + I treatment was able to significantly increase the percentage of pregnant animals at the first insemination and decrease the percentage of nonpregnant cows at greater than 150 days in milk production for both heifers and multiparous cows when compared with the P treatment. PMID- 25702624 TI - Emerging drugs for secondary hyperparathyroidism. AB - INTRODUCTION: Secondary hyperparathyroidism (SHPT), a common, serious, and progressive complication of chronic kidney disease (CKD), is characterized by elevated serum parathyroid hormone (PTH), parathyroid gland hyperplasia, and mineral metabolism abnormalities. These disturbances may result in CKD-mineral and bone disorder (CKD-MBD), which is associated with poor quality of life and short life expectancy. AREAS COVERED: The goal of SHPT treatment is to maintain PTH, calcium, and phosphorus within accepted targeted ranges. This review highlights the pathogenesis of SHPT and current SHPT therapeutic approaches, including the use of low-phosphate diets, phosphate binders, 1,25 dihydroxyvitamin D3 (calcitriol) and its analogs, calcimimetics, and parathyroidectomy in addition to discussing emerging drugs in development for SHPT. EXPERT OPINION: Numerous studies indicate that mineral abnormalities occur early in the course of CKD, are prevalent by the time patients enter dialysis, and foreshadow a risk of cardiovascular and all-cause mortality. Several newly developed compounds may potentially overcome the limitations of current SHPT therapies. If emerging therapies can reduce PTH, normalize mineral metabolism, promote treatment adherence, and reduce the risk of side effects, they may provide the requisite features for improving long-term outcomes in patients with SHPT receiving dialysis and reduce the risks of CKD-MBD. PMID- 25702625 TI - Shoulder pain and dysfunction in young surf lifesavers. AB - OBJECTIVES: To determine the incidence and prevalence of significantly interrupting shoulder pain (SIP) in young surf lifesavers and to determine association with training dosage and the 'combined elevation test'. PARTICIPANTS: 54 surf lifesavers aged 10-18 from the Gold Coast, Australia. METHODS AND OUTCOME MEASURES: Retrospective survey of SIP and training dosage. Cross-sectional measures of the combined elevation test. DESIGN: Retrospective. RESULTS: 56.5% of female surf lifesavers reported a history of SIP compared to males with 48.5%. Females had a higher combined elevation score compared to males, 28.32 +/- SD 8.52 cm and 26.09 +/- SD 6.64 cm, respectively. Young surf lifesavers had an incidence rate of 2.1 SIP episodes per thousand hours of training, an incidence proportion of 51.9% and prevalence of 18.5%. Combined elevation had low level positive trends with training dosages and statistically significant negative correlation with board paddling sessions per week (r = -0.287, p <= 0.05). Those with a history of SIP had a statistically significant higher number of sessions (p = 0.008), duration (p = 0.015) and distance (p = 0.005) swimming per week. CONCLUSION: Young surf lifesavers with a history of SIP have greater swimming dosage not associated with a decreased combined elevation score. More board paddling sessions per week decreased the combined elevation score of young surf lifesavers. PMID- 25702626 TI - Xanthomegnin detection does not discriminate between Trichophyton rubrum and T. mentagrophytes complexes. AB - Here, we aimed to discriminate the Trichophyton rubrum and Trichophyton mentagrophytes complexes, via detection of xanthomegnin using HPLC. We concluded that it is not a reliable technique for discriminating the two complexes, because strains belonging to both T. rubrum and T. mentagrophytes complexes displayed xanthomegnin activity. PMID- 25702627 TI - Lambert-Eaton myasthenic syndrome associated with thymic neuroendocrine carcinoma. PMID- 25702628 TI - Efficient tryptophan-catabolizing activity is consistently conserved through evolution of TDO enzymes, but not IDO enzymes. AB - Indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) enzymes have independently evolved to catalyze the first step in the catabolism of tryptophan (L-Trp) through the kynurenine pathway. TDO is found in almost all metazoan and many bacterial species, but not in fungi. We show that TDO enzymes have high catalytic-efficiency for L-Trp catabolism, regardless of their biological origin, suggesting that TDO has been an L-Trp-specific degrading enzyme throughout its evolution. Meanwhile, IDO was initially discovered in mammals, and subsequently has been found in lower vertebrates, several invertebrates, fungi and a number of bacterial species. Some lineages have independently generated multiple IDO paralogues through gene duplications. Interestingly, only mammalian IDO1s and fungal "typical" IDOs have high affinity and catalytic efficiency for L-Trp catabolism, comparable to TDOs. We show that invertebrate IDO enzymes have low affinity and catalytic efficiency for L-Trp catabolism. We suggest that the phylogenetic distribution of "low catalytic efficiency IDOs" indicates the ancestral IDO also had low affinity and catalytic efficiency for L-Trp catabolism. IDOs with high catalytic-efficiency for L-Trp catabolism may have evolved in certain lineages to fulfill particular biological roles. The low catalytic-efficiency IDOs have been well conserved in a number of lineages throughout their evolution, although it is not clear that the enzymes contribute significantly to L-Trp catabolism in these species. Investigation of other substrates and functions of the ancestral IDO and low catalytic efficiency IDOs may identify additional biological roles for these enzymes. PMID- 25702629 TI - Atmospherically relevant core-shell aerosol studied using optical trapping and Mie scattering. AB - Solid core-liquid shell aerosols have been trapped in a counter-propagating optical trap confirming potential core-shell morphology in the atmosphere. Mie spectroscopy can be used to measure the core radius and film thickness to 0.5 and 1 nm precision respectively and to measure the wavelength dependent refractive indices of silica (core) and oleic acid (shell). PMID- 25702630 TI - Outcomes of a 1-year randomized controlled trial to evaluate a behavioral 'stepped-down' weight loss intervention for adolescent patients with obesity. AB - BACKGROUND: Stepped-care approaches to weight loss have shown some success among adults. A 'stepped-down' version of the stepped-care approach to adolescent weight loss has never been evaluated. OBJECTIVES: We conducted a one-year randomized controlled trial to compare a stepped-down weight loss intervention versus enhanced usual care (EUC). METHODS: Study participants were obese adolescents age 11-13 (N = 106, 51% girls, and 82% Hispanic) recruited from primary care clinics in San Diego, California. The stepped-down intervention was delivered through clinician and health educator counseling (in-person and by phone) and mailed content. The intervention consisted of four-month 'steps' beginning with the most intensive contact followed by reduced contact if treatment goals were met. The EUC group received an initial physician visit, one session with a health counselor, and monthly mailed materials. Body mass index (BMI kg/m(2) ) was measured at baseline, 4, 8, and 12 months. Mixed-model regression analyses were stratified by sex. RESULTS: Results indicated a clinically significant treatment effect for boys on BMI (p < 0.001) but not girls. No between group differences were found for adiposity and biometric outcomes. Only 13% of intervention participants succeeded in stepping down from step 1 to step 2 or step 3. CONCLUSIONS: A stepped-down approach to weight loss showed some evidence of efficacy for weight loss in boys but not girls. The findings suggest the program as designed was not intensive enough to result in weight loss in this population segment. PMID- 25702631 TI - Probing the electronic and spintronic properties of buried interfaces by extremely low energy photoemission spectroscopy. AB - Ultraviolet photoemission spectroscopy (UPS) is a powerful tool to study the electronic spin and symmetry features at both surfaces and interfaces to ultrathin top layers. However, the very low mean free path of the photoelectrons usually prevents a direct access to the properties of buried interfaces. The latter are of particular interest since they crucially influence the performance of spintronic devices like magnetic tunnel junctions (MTJs). Here, we introduce spin-resolved extremely low energy photoemission spectroscopy (ELEPS) to provide a powerful way for overcoming this limitation. We apply ELEPS to the interface formed between the half-metallic Heusler compound Co2MnSi and the insulator MgO, prepared as in state-of-the-art Co2MnSi/MgO-based MTJs. The high accordance between the spintronic fingerprint of the free Co2MnSi surface and the Co2MnSi/MgO interface buried below up to 4 nm MgO provides clear evidence for the high interface sensitivity of ELEPS to buried interfaces. Although the absolute values of the interface spin polarization are well below 100%, the now accessible spin- and symmetry-resolved wave functions are in line with the predicted existence of non-collinear spin moments at the Co2MnSi/MgO interface, one of the mechanisms evoked to explain the controversially discussed performance loss of Heusler-based MTJs at room temperature. PMID- 25702632 TI - Icosahedral metallacarborane/carborane species derived from 1,1'-bis(o carborane). AB - Examples of singly-metallated derivatives of 1,1'-bis(o-carborane) have been prepared and spectroscopically and structurally characterised. Metallation of [7 (1'-1',2'-closo-C2B10H11)-7,8-nido-C2B9H10](2-) with a {Ru(p-cymene)}(2+) fragment affords both the unisomerised species [1-(1'-1',2'-closo-C2B10H11)-3-(p cymene)-3,1,2-closo-RuC2B9H10] (2) and the isomerised [8-(1'-1',2'-closo C2B10H11)-2-(p-cymene)-2,1,8-closo-RuC2B9H10] (3), and 2 is easily transformed into 3 with mild heating. Metallation with a preformed {CoCp}(2+) fragment also affords a 3,1,2-MC2B9-1',2'-C2B10 product [1-(1'-1',2'-closo-C2B10H11)-3-Cp-3,1,2 closo-CoC2B9H10] (4), but if CoCl2/NaCp is used followed by oxidation the result is the 2,1,8-CoC2B9-1',2'-C2B10 species [8-(1'-1',2'-closo-C2B10H11)-2-Cp-2,1,8 closo-CoC2B9H10] (5). Compound 4 does not convert into 5 in refluxing toluene, but does do so if it is reduced and then reoxidised, perhaps highlighting the importance of the basicity of the metal fragment in the isomerisation of metallacarboranes. A computational study of 1,1'-bis(o-carborane) is in excellent agreement with a recently-determined precise crystallographic study and establishes that the {1',2'-closo-C2B10H11} fragment is electron-withdrawing compared to H. PMID- 25702633 TI - Sulfates-based nanothermites: an expanding horizon for metastable interstitial composites. AB - Metal sulfates (Ba, Bi, Ca, Cu, Mg, Mn, Na, Zn, Zr) were used as oxidizers in reactive compositions with Al nanopowder. These new kinds of nanothermites have outstandingly high reaction heats (4-6 kJ g(-1) ) compared to conventional Al/metal oxides (1.5-4.8 kJ g(-1) ) and also have good combustion velocities (200 840 m s(-1) vs 100-2500 m s(-1) ). These compositions are extremely insensitive to friction making their preparation and handling easy and safe. The sulfate hydration water increases the reaction heats and has a significant effect on the sensitivity to impact and to electrostatic discharge. The reaction of Al with water is easier to initiate than the one with sulfate which leads to two possible decomposition modes for samples exposed to an open flame. The pyrotechnical properties observed with sulfates have also been found for other sulfur oxygenates (SO3 (2-) , S2 O3 (2-) , S2 O8 (2-) ) which opens up new horizons in the domain of metastable interstitial composites. PMID- 25702634 TI - The removal of caesium ions using supported clinoptilolite. AB - In this paper, the sorptive kinetic and diffusional characteristics of caesium ion removal from aqueous solution by carbon-supported clinoptilolite composites are presented. Natural clinoptilolite was supported on carbonaceous scaffolds prepared from date stones. Thermal treatment was applied to produce voids in the carbon which was conditioned using polydiallyldimethylammonium chloride to facilitate the clinoptilolite attachment. This method allowed the formation of a consistent zeolite layer on the carbon surface. The composite was applied in the removal of non-radioactive caesium ions showing an enhanced uptake from 55 mg g( 1) to 120.9 mg g(-1) when compared to clinoptilolite. Kinetic studies using Pseudo First Order model revealed an enhanced rate constant for carbon clinoptilolite (0.0252 min(-1)) in comparison with clinoptilolite (0.0189 min( 1)). The Pseudo-First Order model described the process for carbon clinoptilolite, meanwhile Pseudo Second Order model adjusted better for pure clinoptilolite. Diffusivity results suggested that mass transfer resistances involved in the Cs(+) sorption are film and intraparticle diffusion for natural clinoptilolite and intraparticle diffusion as the mechanism that controls the process for carbon-clinoptilolite composite. The most significant aspect being that the vitrified volume waste can be reduced by over 60% for encapsulation of the same quantity of caesium due to the enhanced uptake of zeolite. PMID- 25702635 TI - Effect of di-n-butyl phthalate on root physiology and rhizosphere microbial community of cucumber seedlings. AB - The authors investigated the effects of di-n-butyl phthalate (DBP) on root physiology and rhizosphere microbial communities of cucumber seedlings (sativus L. cv Jinyan No. 4). Root protein content and root activity were observed to decrease. From the ultrastructural micrographs, visible impact on the mitochondria, endoplasmic reticulum and vacuole were detected. Moreover, the number of starch grains increased, and some were adhered to other cell components which might be the most direct evidence of DBP causing cellular damage. Results of PCR-DGGE (denaturing gradient gel electrophoresis) indicated that DBP significantly changed the abundance, structure and composition of rhizosphere bacteria when the concentration was higher than 50 mg L(-1). The relative abundances of Firmicutes increased while that of Bacteroidetes decreased. Bacillus was detected as the dominant bacteria in DBP contaminated cucumber rhizospheric soil. The amount of Actinobacteridae and Pseudomonas decreased until it disappeared in the rhizosphere soil when exposed to DBP concentrations higher than 50 mg L(-1). PMID- 25702636 TI - Microwave-assisted activated carbon from cocoa shell as adsorbent for removal of sodium diclofenac and nimesulide from aqueous effluents. AB - Microwave-induced chemical activation process was used to prepare an activated carbon from cocoa shell for efficient removal of two anti-inflammatories, sodium diclofenac (DFC) and nimesulide (NM), from aqueous solutions. A paste was obtained from a mixture of cocoa shell and inorganic components; with a ratio of inorganic: organic of 1 (CSC-1.0). The mixture was pyrolyzed in a microwave oven in less than 10 min. The CSC-1.0 was acidified with a 6 mol L(-1) HCl under reflux to produce MWCS-1.0. The CSC-1.0 and MWCS-1.0 were characterized using FTIR, SEM, N2 adsorption/desorption curves, X-ray diffraction, and point of zero charge (pHpzc). Experimental variables such as initial pH of the adsorbate solutions and contact time were optimized for adsorptive characteristics of MWCS 1.0. The optimum pH for removal of anti-inflammatories ranged between 7.0 and 8.0. The kinetic of adsorption was investigated using general order, pseudo first order and pseu do-second order kinetic models. The maximum amounts of DCF and NM adsorbed onto MWCS-1.0 at 25 degrees C are 63.47 and 74.81 mg g(-1), respectively. The adsorbent was tested on two simulated hospital effluents. MWCS 1.0 is capable of efficient removal of DCF and NM from a medium that contains high sugar and salt concentrations. PMID- 25702637 TI - Autism is (also) a movement disorder. PMID- 25702639 TI - Defined conditions for the isolation and expansion of basal prostate progenitor cells of mouse and human origin. AB - Methods to isolate and culture primary prostate epithelial stem/progenitor cells (PESCs) have proven difficult and ineffective. Here, we present a method to grow and expand both murine and human basal PESCs long term in serum- and feeder-free conditions. The method enriches for adherent mouse basal PESCs with a Lin(-)SCA 1(+)CD49f(+)TROP2(high) phenotype. Progesterone and sodium selenite are additionally required for the growth of human Lin(-)CD49f(+)TROP2(high) PESCs. The gene-expression profiles of expanded basal PESCs show similarities to ESCs, and NF-kB function is critical for epithelial differentiation of sphere-cultured PESCs. When transplanted in combination with urogenital sinus mesenchyme, expanded mouse and human PESCs generate ectopic prostatic tubules, demonstrating their stem cell activity in vivo. This novel method will facilitate the molecular, genomic, and functional characterization of normal and pathologic prostate glands of mouse and human origin. PMID- 25702638 TI - The L1TD1 protein interactome reveals the importance of post-transcriptional regulation in human pluripotency. AB - The RNA-binding protein L1TD1 is one of the most specific and abundant proteins in pluripotent stem cells and is essential for the maintenance of pluripotency in human cells. Here, we identify the protein interaction network of L1TD1 in human embryonic stem cells (hESCs) and provide insights into the interactome network constructed in human pluripotent cells. Our data reveal that L1TD1 has an important role in RNA splicing, translation, protein traffic, and degradation. L1TD1 interacts with multiple stem-cell-specific proteins, many of which are still uncharacterized in the context of development. Further, we show that L1TD1 is a part of the pluripotency interactome network of OCT4, SOX2, and NANOG, bridging nuclear and cytoplasmic regulation and highlighting the importance of RNA biology in pluripotency. PMID- 25702640 TI - A transposon-mediated system for flexible control of transgene expression in stem and progenitor-derived lineages. AB - Precise methods for transgene regulation are important to study signaling pathways and cell lineages in biological systems where gene function is often recycled within and across lineages. We engineered a genetic toolset for flexible transgene regulation in these diverse cellular contexts. Specifically, we created an optimized piggyBac transposon-based system, allowing for the facile generation of stably transduced cell lineages in vivo and in vitro. The system, termed pB Tet-GOI (piggyBac-transposable tetracycline transactivator-mediated flexible expression of a genetic element of interest), incorporates the latest generation of tetracycline (Tet) transactivator and reverse Tet transactivator variants- along with engineered mutants--in order to provide regulated transgene expression upon addition or removal of doxycycline (dox). Altogether, the flexibility of the system allows for dox-induced, dox-suppressed, dox-resistant (i.e., constitutive), and dox-induced/constitutive regulation of transgenes. This versatile strategy provides reversible temporal regulation of transgenes with robust inducibility and minimal leakiness. PMID- 25702642 TI - Underappreciated opportunities for high-density lipoprotein particles in risk stratification and potential targets of therapy. AB - The inverse relationship between high-density lipoprotein cholesterol (HDL-C) concentrations and coronary heart disease risk is well established. As a result, in recent years there have been significant resources focused on identifying therapies that raise HDL-C and ultimately reduce cardiovascular events. Unfortunately, a number of trials aimed at increasing HDL-C have failed to show improved outcomes, and hence, have cast doubt on the importance of HDL-C as a therapeutic target. HDL-C, however, is only one measure of HDL. HDL levels can also been estimated by quantifying apolipoprotein A-I (apoA-I) levels using enzyme immunoassay or by measuring HDL particle number (HDL-P) using nuclear magnetic resonance spectroscopy (NMR) or ion mobility. While these surrogate measures are correlated, they are not comparable. Lipoprotein-altering therapies have been shown to have different effects on HDL-C, apoA-I and HDL-P and several studies have demonstrated that HDL-P is a stronger predictor of coronary heart disease risk than HDL-C and/or apoA-I. This paper will review available evidence supporting the use of HDL-P as the biomarker of choice to assess the contribution of HDL to cardiovascular risk and as the primary goal of HDL-raising therapies. PMID- 25702643 TI - New challenges for HDL-modifying therapies as a strategy to lower cardiovascular disease events in statin-treated patients. PMID- 25702644 TI - Melatonin promotes Bax sequestration to mitochondria reducing cell susceptibility to apoptosis via the lipoxygenase metabolite 5-hydroxyeicosatetraenoic acid. AB - Extra-neurological functions of melatonin include control of the immune system and modulation of apoptosis. We previously showed that melatonin inhibits the intrinsic apoptotic pathway in leukocytes via stimulation of high affinity MT1/MT2 receptors, thereby promoting re-localization of the anti-apoptotic Bcl-2 protein to mitochondria. Here we show that Bcl-2 sequesters pro-apoptotic Bax into mitochondria in an inactive form after melatonin treatment, thus reducing cell propensity to apoptosis. Bax translocation and the anti-apoptotic effect of melatonin are strictly dependent on the presence of Bcl-2, and on the 5 lipoxygenase (5-LOX) metabolite 5-hydroxyeicosatetraenoic acid (5-HETE), which we have previously shown to be produced as a consequence of melatonin binding to its low affinity target calmodulin. Therefore, the anti-apoptotic effect of melatonin requires the simultaneous, independent interaction with high (MT1/MT2) and low (calmodulin) affinity targets, eliciting two independent signal transduction pathways converging into Bax sequestration and inactivation. MT1/MT2 vs. lipoxygenase pathways are activated by 10(-9) vs. 10(-5)M melatonin, respectively; the anti-apoptotic effect of melatonin is achieved at 10(-5)M, but drops to 10(-9)M upon addition of exogenous 5-HETE, revealing that lipoxygenase activation is the rate-limiting pathway. Therefore, in areas of inflammation with increased 5-HETE levels, physiological nanomolar concentrations of melatonin may suffice to maintain leukocyte viability. PMID- 25702645 TI - On and off metronomic oral vinorelbine in elderly women with advanced breast cancer. AB - BACKGROUND: Elderly patients with metastatic breast cancer (MBC) have more problems receiving chemotherapy than younger patients, especially with the presence of multiple comorbidities, adverse drug events and functional decline. Low-dose oral administration of cytotoxic agents such as vinorelbine, a semisynthetic vinca alkaloid that interferes with microtubule assembly, leading to arrest of cell division, is usually effective and well tolerated. METHODS: From February 2010 to February 2014, 32 patients with MBC, median age 76 years (range 69-83) were treated with oral vinorelbine 30 mg (total dose), one day on and one day off, until disease progression or unacceptable toxicity levels were reported. Toxicity, quality of life and clinical benefit were evaluated. Matched t-tests were conducted to discern whether quality-of-life indicator (p<0.05 was considered significant) differed before and 6 months after treatment. Statistical analysis was performed using Graph Pad Prism 5.0 (GraphPad Software Inc., San Diego, CA, USA). RESULTS: No grade 3 and 4 adverse events were reported. A clinical benefit of 50% was found in our cohort. On and off metronomic vinorelbine oral administration resulted in good tolerability and safe profile in our selected elderly population, and improved patient adherence to therapy. CONCLUSIONS: The present study demonstrated that metronomic vinorelbine might be a potential treatment in elderly patients by reducing adverse effects and increasing quality of life, setting the stage for future extensive clinical trials. PMID- 25702646 TI - Radiosurgical options in neuro-oncology: a review on current tenets and future opportunities. Part II: adjuvant radiobiological tools. AB - Stereotactic radiosurgery (SRS) is currently a well-established, minimally invasive treatment for many primary and secondary tumors, especially deep-sited lesions for which traditional neurosurgical procedures were poorly satisfactory or not effective at all. The initial evolution of SRS was cautious, relying on more than 30 years of experimental and clinical work that preceded its introduction into the worldwide medical community. This path enabled a brilliant present, and the continuous pace of technological advancement holds promise for a brighter future. Part II of this review article will cover the impact of multimodal adjuvant technologies on SRS, and their input to the crucial role played by neurosurgeons, radiation oncologists and medical physicists in the management and care of fragile neuro-oncological patients. PMID- 25702647 TI - The anal canal as a risk organ in cervical cancer patients with hemorrhoids undergoing whole pelvic radiotherapy. AB - AIMS AND BACKGROUND: Tolerance of the anal canal tends to be ignored in patients with cervical cancer undergoing whole pelvic radiotherapy. However, patients with hemorrhoids may be troubled with low radiation dose. We tried to analyze the dose volume statistics of the anal canal in patients undergoing whole pelvic radiotherapy. METHODS: The records of 31 patients with cervical cancer who received definite or postoperative radiotherapy at one institution were reviewed. Acute anal symptoms, such as anal pain and bleeding, were evaluated from radiotherapy start to 1 month after radiotherapy completion. Various clinical and dosimetric factors were analyzed to characterize relations with acute anal complications. RESULTS: The anal verge was located an average of 1.2 cm (range 0.6~3.9) below the lower border of the ischial tuberosity and an average of 2.7 cm (range -0.6~5.7) behind the sacral promontory level. The presence of hemorrhoids before radiotherapy was found to be significantly associated with acute radiation-induced anal symptoms (p = 0.001), and the mean induction dose for anal symptoms was 36.9 Gy. No patient without hemorrhoids developed an anal symptom during radiotherapy. Dosimetric analyses of V30 and V40 showed marginal correlations with anal symptoms (p = 0.07). CONCLUSIONS: The present study suggests a relation between acute anal symptoms following radiotherapy and acute hemorrhoid aggravation. Furthermore, the location of the anal verge was found to be variable, and consequently doses administered to the anal canal also varied substantially. Our results caution careful radiation treatment planning for whole pelvic radiotherapy, and that proper clinical management be afforded patients with hemorrhoids during radiotherapy. PMID- 25702648 TI - Thromboembolic disease in advanced colorectal cancer treated with chemotherapy and bevacizumab: a case of real "pan-thrombosis". PMID- 25702649 TI - Hepatocellular carcinoma with peritoneal metastasis treated with cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy. AB - Peritoneal carcinomatosis from hepatocellular carcinoma is well regarded as a poorly treatable malignant disease with rapid decline. Over the past decade, new modalities that combine cytoreductive surgery with perioperative hyperthermic intraperitoneal chemotherapy have been shown to be aggressive local-regional treatments with improved survival. We present a case of a 67-year-old non cirrhotic woman with peritoneal metastases from hepatocellular caracinoma who was treated with cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy. Consideration remains individualized, but it can be considered in patients with adequate preservation of liver function, management of their primary hepatocellular caracinoma as well as the localized nature of their peritoneal metastases. PMID- 25702650 TI - Irinotecan and capecitabine combination chemotherapy in a patient with triple negative breast cancer relapsed after adjuvant chemotherapy with anthracycline and taxane. AB - The most effective regimen for taxane- and anthracycline-refractory triple negative breast cancer (TNBC) has not yet been established. Capecitabine was approved by the US Food and Drug Administration for the treatment of advanced breast cancer and has shown efficacy in advanced breast cancer refractory to anthracyclines and taxanes. Irinotecan has synergism with 5-fluorouracil and shows efficacy in advanced breast cancer. Here we report on a patient with TNBC who relapsed with widespread bone and lung metastases shortly after adjuvant anthracycline followed by taxane chemotherapy. She achieved a metabolic complete response with irinotecan and capecitabine combination therapy and had 10 months' progression-free survival and 22 months' overall survival. She relapsed with and died of brain metastasis without any definite signs of progression of the lung and bone lesions she had had before the irinotecan and capecitabine combination therapy. To validate this favorable result, larger clinical trials are warranted in patients with metastatic or relapsed TNBC. PMID- 25702651 TI - Analysis of microRNA expression profile identifies novel biomarkers for non-small cell lung cancer. AB - BACKGROUND: Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer mortality. MicroRNAs (miRNAs), small noncoding RNAs, regulate the expression of genes that play roles in human cancer via posttranscriptional inhibition. METHODS: To identify the potential miRNA biomarkers in NSCLC, we downloaded the miRNA expression profile (ID: GSE29248) of NSCLC from the Gene Expression Omnibus (GEO) database and analyzed the differentially expressed miRNAs in NSCLC tissue compared with normal control tissue. Then the targets of these differentially expressed miRNAs were screened and used in network construction and functional enrichment analysis. RESULTS: We identified a total of 17 miRNAs that showed a significantly differential expression in NSCLC tissue. We found that miR-34b and miR-520h might play important roles in the regulation of NSCLC, miR-22 might be a novel biomarker as an oncogene, and miR-448 might promote, while miR-654-3p prevents, NSCLC progression. CONCLUSIONS: Our study may provide the groundwork for further clinical molecular target therapy experiments in NSCLC.BAC PMID- 25702652 TI - Limited small cell lung cancer, an early stage cancer that should receive the attention of experts. PMID- 25702653 TI - Amphicrine carcinoma of the ampullary region. AB - Amphicrine carcinoma is a peculiar tumor in which the cells have both exocrine and neuroendocrine differentiation, with mucus and neuroendocrine granules within the cytoplasm. In the 2010 WHO classification of tumors of the digestive tract, they have been included in the intermediate-grade malignant category of mixed adenoneuroendocrine carcinomas (MANECs). These tumors are extremely rare in the gastrointestinal tract. Four cases have been reported in the stomach, three in the pancreas, and one in the liver. To the best of our knowledge, this report describes the first case of amphicrine carcinoma in the ampullary region. PMID- 25702654 TI - High-dose chemotherapy followed by autologous and allogeneic hematopoietic stem cell transplantation in patients with follicular non-Hodgkin's lymphoma in the rituximab era. AB - High-dose chemotherapy in lymphomas, and mainly non-Hodgkin's lymphomas, has been advancing since the 1970s. This therapeutic strategy is based on the supposed existence of a dose-response curve for cytotoxic agents. However, the available data are contradictory, so high-dose chemotherapy cannot be guaranteed as consolidation treatment for first-remission follicular lymphoma or diffuse large cell lymphoma. The objective of this paper is to review the current knowledge about high-dose chemotherapy followed by hematopoietic stem cell transplantation in follicular non-Hodgkin's lymphoma. The published studies on follicular lymphoma after first remission, recurrent follicular lymphoma, and transformed follicular -lymphoma were assessed together with the data available on diffuse large cell lymphoma. During analysis of the studies, difficulties were encountered in comparing studies due to the heterogeneous nature of the data. High-dose chemotherapy as consolidation treatment after first remission or in recurrent or refractory disease was also analyzed. PMID- 25702655 TI - Bilateral breast radiation delivered with static angle tomotherapy (TomoDirect): clinical feasibility and dosimetric results of a single patient. AB - We herein report on a case of synchronous bilateral breast cancer patient undergoing adjuvant intensity-modulated whole breast with static angle tomotherapy (TomoDirect). The patient was treated with a hypofractionated schedule employing a simultaneous integrated boost approach. Radiotherapy schedule was 45 Gy/20 fractions (2.25 Gy daily) to the bilateral whole breast and 50 Gy/20 fractions (2.5 Gy daily) to the 2 lumpectomy cavities. Treatment was delivered over 4 weeks. Dosimetric results were robust with consistent target coverage and adequate normal tissue avoidance. Treatment was generally well tolerated and acute toxicity profile was mild. The present report highlights the promising clinical feasibility of TomoDirect for bilateral breast irradiation. PMID- 25702656 TI - Fulminant hepatitis in a patient with hepatocellular carcinoma related to nonalcoholic steatohepatitis treated with sorafenib. AB - We describe a case of acute liver failure in a patient with advanced hepatocellular carcinoma related to nonalcoholic steatohepatitis during sorafenib treatment. A 74-year-old man with diabetes mellitus and hypertension was diagnosed with hepatocellular carcinoma associated with fatty liver. Three weeks after sorafenib therapy, at Eastern Cooperative Oncology Group performance status 3, he developed jaundice, general weakness, flapping tremor, nausea, and anorexia. Sorafenib was stopped: laboratory tests showed a relevant elevation of transaminases suggesting diagnosis of acute hepatitis. During hospital admission, the patient died of liver failure. Sorafenib is the first successful target therapy effective for advanced hepatocellular carcinoma. The most common adverse events are fatigue, hand-foot skin reaction, skin rash/desquamation, diarrhea, and hypertension, whereas liver dysfunction is uncommon. To our knowledge, this is the first patient reported in the literature with hepatocellular carcinoma related to nonalcoholic steatohepatitis who died of rapid worsening of liver function during sorafenib treatment. PMID- 25702657 TI - An individual risk prediction model for lung cancer based on a study in a Chinese population. AB - AIMS AND BACKGROUND: Early detection and diagnosis remains an effective yet challenging approach to improve the clinical outcome of patients with cancer. Low dose computed tomography screening has been suggested to improve the diagnosis of lung cancer in high-risk individuals. To make screening more efficient, it is necessary to identify individuals who are at high risk. METHODS AND STUDY DESIGN: We conducted a case-control study to develop a predictive model for identification of such high-risk individuals. Clinical data from 705 lung cancer patients and 988 population-based controls were used for the development and evaluation of the model. Associations between environmental variants and lung cancer risk were analyzed with a logistic regression model. The predictive accuracy of the model was determined by calculating the area under the receiver operating characteristic curve and the optimal operating point. RESULTS: Our results indicate that lung cancer risk factors included older age, male gender, lower education level, family history of cancer, history of chronic obstructive pulmonary disease, lower body mass index, smoking cigarettes, a diet with less seafood, vegetables, fruits, dairy products, soybean products and nuts, a diet rich in meat, and exposure to pesticides and cooking emissions. The area under the curve was 0.8851 and the optimal operating point was obtained. With a cutoff of 0.35, the false positive rate, true positive rate, and Youden index were 0.21, 0.87, and 0.66, respectively. CONCLUSIONS: The risk prediction model for lung cancer developed in this study could discriminate high-risk from low-risk individuals. PMID- 25702658 TI - Predictive factors for additional non-sentinel lymph node involvement in breast cancer patients with one positive sentinel node. AB - AIM: The aim of this study was to identify a subgroup of breast cancer patients in whom it is possible to avoid axillary lymph node dissection (ALND) when the sentinel lymph node (SLN) is positive. METHODS: A series of 292 patients treated with breast-conserving surgery or mastectomy underwent ALND after positive SLN detection. To correlate SLN metastasis with the chances of finding additional metastasis in non-SLNs we evaluated the main clinicopathological characteristics. No patients received adjuvant radiotherapy to the axillary region. RESULTS: Fifty six patients (35.4%) with positive SLNs for macrometastases (n = 158) had additional metastases upon completion ALND compared with 7 patients (5.2%) with micrometastases in the SLN (n = 132). Cases with a higher number of positive axillary lymph nodes tended to have higher pT stage (p = 0.004). In multivariate analysis, pT was confirmed as an independent predictor of non-SLN metastases (OR = 2.40; 95% CI = 1.16-4.99). No patients with micrometastases in SLN and cancer lt;10 mm had additional positive non-SLNs. CONCLUSIONS: Our results, in agreement with the major published studies, suggest that ALND can be avoided in selected patients without the need for additional treatment to the axillary region. PMID- 25702659 TI - Positive consequences of cancer: exploring relationships among posttraumatic growth, adult attachment, and quality of life. AB - AIMS AND BACKGROUND: Cancer can be a life-threatening illness; however, it can also be a source of positive life changes, the posttraumatic growth (PTG) that comes from struggling with this serious illness. This cross-sectional study examines the sociodemographic and cancer-related predictors of PTG following a diagnosis of cancer. In addition, the relationships among adult attachment, health-related quality of life, and PTG are investigated. Measuring adult attachment is important because it can greatly influence the response to a highly distressing event, like facing cancer. METHODS AND STUDY DESIGN: Immediately before undergoing radiotherapy, 152 patients with breast or prostate cancer (mean = 59.1 years old, SD = 10.7) who had received a positive diagnosis within an average of 3.5 months prior to treatment were tested for measures of PTG, adult attachment, and health-related quality of life. Patients also completed a questionnaire regarding medical and sociodemographic characteristics. Hierarchical multiple regression analyses were conducted to reveal the significant predictors of PTG total score and PTG subscale scores. RESULTS: Younger age was a significant predictor of the PTG total score and New Possibilities subscale score. Subjective severity of cancer was positively associated with the PTG total score and scores on the Appreciation of Life and New Possibilities subscales. Regarding health-related quality of life, analyses indicated that greater social/family well-being significantly predicted greater PTG total score and higher scores on the New Possibilities, Spiritual Change, Appreciation of Life, and Relating to Others subscales. Finally, dismissive attachment style predicted fewer scores on the Personal Strength and Relating to Others subscales. CONCLUSIONS: These findings suggest that in addition to quality of life and adult attachment, sociodemographic and cancer-related variables may significantly contribute to positive growth. PMID- 25702660 TI - Association of the genetic polymorphisms in XRCC6 and XRCC5 with the risk of ESCC in a high-incidence region of North China. AB - BACKGROUND: The XRCC6 and XRCC5 genes are part of the nonhomologous end-joining (NHEJ) pathway, which is the main mechanism repairing DNA double-strand breaks (DSBs) in human cells. Genetic variations of XRCC6 and XRCC5 might contribute to esophageal squamous cell carcinoma (ESCC) susceptibility. METHODS: ESCC patients (n = 189) and cancer-free controls (n = 189) were recruited in an ESCC high-risk area of north China. Then the rs2267437 (XRCC6), rs3835 (XRCC5) and rs16855458 (XRCC5) polymorphisms were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. RESULTS: A significant difference in genotype distribution and allele frequency of rs2267437 (XRCC6) was observed between the cases and controls. The CG carriers were at higher risk of ESCC (p = 0.001, odds ratio [OR] = 2.040, 95% confidence interval [95% CI], 1.323 3.147). G allele carriers were also associated with an increased ESCC risk (p = 0.003, OR = 1.868, 95% CI, 1.230-2.836). In the 2 polymorphisms of XRCC5, no significant difference was found between both groups in the distribution of either genotype or allelic frequency. But in the haplotypes established by the single nucleotide polymorphisms (SNPs) of XRCC5, the haplotype AT and CC separately increased by 4.28- and 2.31-fold the risk ratio of ESCC (p = 0.01, OR = 4.28, 95% CI, 1.40-13.05; p = 0.03, OR = 2.31, 95% CI, 1.11-4.80, respectively). In addition, gene-smoking or gene-drinking interactions, and their effect on the risk of ESCC were observed, but no significant gene-environment interaction was demonstrated. CONCLUSIONS: In conclusion, both the CG carriers/G allele carriers of rs2267437 (XRCC6) and the haplotype AT/CC established by the SNPs of XRCC5 are associated with ESCC susceptibility. PMID- 25702661 TI - Prolonged response to aflibercept in ovarian cancer relapse: a case report. AB - VEGF-targeted therapies have shown activity in ovarian cancer, and one of them, bevacizumab, has been recently approved in this disease. Aflibercept is an antiangiogenic soluble fusion protein that inhibits VEGF-mediated signaling. In ovarian cancer, phase II trials with aflibercept have shown a significant benefit in the control of malignant ascites but with a lower response rate than expected.We report the case of a patient with relapsed ovarian cancer treated with aflibercept in fourth line, who experienced a prolonged response during more than two years with good tolerance. The duration of response to aflibercept was longer than that of the three previous lines of therapy (including the initial carboplatin-paclitaxel regimen) and ascites did not reappear. Further clinical research with this drug in ovarian cancer to identify patients who benefit most is warranted. PMID- 25702662 TI - Incidence and time trends of cancer in Cyprus over 11 years (1998-2008). AB - Cyprus maintains a population-based cancer registry that allows for in-depth study of cancer in a culturally and environmentally unique setting. Using 11 years of collected data (1998-2008), we present the first comprehensive analysis of cancer in Cyprus. We calculated gender-specific, world age-adjusted incidence rates and time trends for the 26 most incident cancers. This study revealed that overall world age-standardized rates among men increased from 195.4 cases per 100,000 in 1998-2002 to 239.0 cases per 100,000 in 2006-2008. For the entire 11 year period, prostate, lung, colorectal and bladder cancers were the most incident cancers among men. Among women, the overall world age-standardized rate increased from 180.6 cases per 100,000 in 1998-2002 to 217.1 cases per 100,000 in 2006-2008. Over the entire period, breast, colorectal, uterine and thyroid cancers were the most incident cancers in women. There were 16 sex-specific cancers showing statistically significantly increasing incidence trends over the study period and no types for which the rate was significantly decreasing. Thyroid cancer illustrated rapid increases in rates. Results were compared to other Mediterranean European registries using the Cancer Incidence in 5 Continents reports for 1997-2002. Overall cancer incidence in Cyprus is lower than that of many southern Mediterranean countries, and given the known environmental risk factors in Cyprus, the low rate of lung cancer is especially interesting. The epidemiologic patterns reported in this study open the door for future etiologic studies to elucidate the role of environmental and lifestyle factors in this population and highlight opportunities for cancer prevention and control. PMID- 25702663 TI - Use of 18F-choline positron emission tomography/CT in high-risk prostate cancer: a case of solitary adrenal metastasis. AB - Computed tomography and magnetic resonance imaging detected an isolated adrenal lesion in an elderly man with high-risk prostate cancer who was undergoing radiotherapy (RT) and hormonal therapy (HT). When prostate-specific antigen (PSA) was 31.66 ng/mL, the lesion was not identified as a metastasis by 18F-choline positron emission tomography/computed tomography (18F-choline-PET/CT). When PSA was over 100 ng/mL, 18F-choline-PET/CT diagnosed the malignancy. After adrenalectomy, PSA returned to normal, and stable disease remission was obtained. This case suggests that atypical metastasis may be underdiagnosed. PMID- 25702664 TI - Efficacy of bronchoscopic therapies for bronchial mucoepidermoid carcinoma in children: results from six patients. AB - AIMS AND BACKGROUND: Bronchial mucoepidermoid carcinoma is a rare disease in children, and lobectomy is traditionally considered as a first-line treatment. As the tumor is characterized by intraluminal growth, low malignancy and superficial infiltration of bronchial walls, bronchoscopic interventional therapy may provide an alternative treatment with favorable results. The aim of the study was to evaluate the efficacy and safety of bronchoscopic therapies for bronchial mucoepidermoid carcinoma in children. METHODS AND STUDY DESIGN: Clinical manifestations, multiple bronchoscopic interventions and outcomes in 6 children with bronchial mucoepidermoid carcinoma were retrospectively analyzed. RESULTS: The median age was 8.7 years (range 4 to 12 years). All the tumors were located in the lobar bronchus and were detected by computerized tomography. Diagnoses of low-grade mucoepidermoid carcinoma were made based on biopsies obtained via bronchoscopy. Five tumors were classified as intraluminal type and successfully eradicated by carbon dioxide cryotherapy and argon plasma coagulation under bronchoscopy. The other tumor in patient 3 was classified as the mixture type and could not be removed by a bronchoscopic, so left upper lobectomy was performed. For each patient, interventional procedures were conducted on the average for 6 times. No recurrence was detected by bronchoscopic inspections or computed tomography scans during follow-ups for 16-72 months. CONCLUSIONS: Multiple bronchoscopic procedures, as alternative treatments, are effective in removing bronchial mucoepidermoid carcinoma mucoepidermoid carcinoma in children without any major complications. PMID- 25702665 TI - Nonrandomized comparison between concomitant and sequential chemoradiotherapy with anthracyclines in breast cancer. AB - PURPOSE: To evaluate the tolerance of concomitant administration of anthracycline based chemotherapy (CHT) and 3-dimensional conformal radiotherapy (RT) after breast-conserving surgery. METHODS AND MATERIALS: Sixty-seven patients, treated with conservative surgery followed by 3-dimensional whole breast RT and concomitant CHT regimens including "Canadian modified" CEF (5-fluorouracil, epirubicin, cyclophosphamide) or AC (doxorubicin, cyclophosphamide) were evaluated for toxicity. They were compared in terms in compliance and acute toxicity with 67 patients irradiated sequentially after having received anthracyclines. RESULTS: Acute grade >=2 skin toxicity was significantly higher in the concomitant group compared to the sequential group, although the incidence of Grade 3 desquamation showed no statistical difference (9% vs. 3%, p = 0.14). Haematological toxicity represented the main cause of treatment discontinuation, reporting higher rate of grade 3-4 leuco-neutropenia in the concomitant group (20.9% vs. 6%, p = 0.01). Mean RT duration was longer in the concomitant group (51 days vs. 45 days) owing to RT breaks. Late toxicity was acceptable. No symptomatic lung and heart events were reported. Radiological lung hyperdensity was detected in 27.7% of the patients in the concomitant group. Post-treatment left ventricular ejection fraction significantly decreased compared with baseline, but cardiac function remained within the normal range, without any difference between left or right-sided RT. CONCLUSIONS: Although there was more acute grade >=2 skin toxicity in the concomitant group, the rate of grade 3 dermatitis was lower than expected, suggesting some advantages of 3-D CRT over older techniques. Haematological toxicity exerted a significant impact on both RT and CHT delivery. PMID- 25702666 TI - Chronic lymphocytic leukemia-associated refractory immune thrombocytopenia successfully treated with eltrombopag. AB - Chronic lymphocytic leukemia (CLL) may be associated with immune thrombocytopenia (ITP). The standard treatment for CLL-associated ITP is steroids. For refractory cases, various treatment strategies such as rituximab, splenectomy, and thrombopoietic mimetics are available. We report a patient with CLL who developed recurrent ITP and life-threatening pulmonary hemorrhage. Platelet counts remained extremely low despite massive platelet transfusion and treatment including steroids, immunoglobulin, and single-dose rituximab infusion. The bleeding stopped and platelet counts were increased to normal range 13 days after treatment with eltrombopag 25 mg per day. Our experience suggests that eltrombopag is an effective treatment option in CLL-associated, refractory ITP, especially during major bleeding, which requires relatively rapid improvement of thrombocytopenia. PMID- 25702667 TI - Efficacy and safety of long-term tolvaptan treatment in a patient with SCLC and SIADH. AB - Hyponatremia frequently occurs in patients with cancer and is mostly due to a syndrome of inappropriate antidiuresis caused by ectopic secretion of antidiuretic hormone (SIADH). Small cell lung cancer presents with SIADH in approximately 11%-15% of cases. Recently, a new class of drugs, vasopressin V2 receptor antagonists (vaptans), emerged as a promising treatment for SIADH, but efficacy and safety data in cancer patients are lacking. We present a case of SIADH, heralding small cell lung cancer and persisting after apparent complete remission of primary tumor following chemotherapy/radiotherapy, in a patient who underwent long-term treatment with tolvaptan without any serious adverse effects. PMID- 25702668 TI - Association of vitiligo and response in patients with metastatic malignant melanoma on temozolomide. AB - Vitiligo-like lesions, although rare, are believed to be a prognostic factor in malignant melanoma. While a predictive role for such lesions was shown with immunomodulatory therapies, this relation was not demonstrated with temozolomide. We present 3 patients with metastatic malignant melanoma who developed vitiligo like skin lesions accompanying good response to treatment and prolonged survival. Onset of vitiligo-like lesions with temozolomide in metastatic malignant melanoma may predict long-term response for this treatment. PMID- 25702669 TI - Identification of new hub genes associated with bladder carcinoma via bioinformatics analysis. AB - AIMS AND BACKGROUND: Bladder carcinoma (BC) is one of the most common malignant cancers worldwide. Several genes related to the mechanism of BC have been studied in recent years, but the current understanding of BC is still rather limited. This study aimed to find new differentially expressed genes (DEGs) associated with the occurrence and development of BC. METHODS: In this work, we downloaded gene expression data from Gene Expression Omnibus under accession number GSE27448, which included 10 GeneChips from urinary BC tissues and 5 from normal tissues. DEGs were identified by the LIMMA package in R. Then the protein-protein interactions (PPIs) networks were analyzed with the database of Search Tool for the Retrieval of Interacting Genes, and gene ontology (GO) was applied to explore the underlying function of the DEGs using the Database for Annotation, Visualization and Integrated Discovery. RESULTS: A total of 2,068 DEGs were found between BC and normal tissues. These genes were involved in 49 functional clusters. The top 10 highest degree nodes, such as POLR2F/2H (DNA directed RNA polymerase II polypeptide F/polypeptide H) and RPS14/15 (ribosomal protein S14/S15), were proven to be hub nodes in the PPIs network. ITGA7 (integrin, alpha 7), GRB14 (growth factor receptor-bound protein 14), CDC20 (cell division cycle 20) and PSMB1 (proteasome subunit, beta type, 1) were significant DEGs identified in the functional clusters. CONCLUSIONS: Genes such as POLR2F/2H, RPS14/15, ITGA7, GRB14, CDC20 and PSMB1 were forecast to play important roles in the occurrence and progression of BC. PMID- 25702670 TI - Clear cell thymic carcinoma: a case report. AB - Clear cell thymic carcinoma is a rare and invasive tumor of the mediastinum for which there are no uniform treatment guidelines. The combination of carboplatin plus paclitaxel seems to be the most effective regimen for this disease. We report a case of locally advanced clear cell thymic carcinoma treated with this schedule, in which we observed a relevant and rapid tumor shrinkage. PMID- 25702671 TI - Increased dose single-agent gemcitabine in platinum-taxane resistant metastatic ovarian cancer. AB - CONCLUSION: In platinum-taxane resistant epithelial ovarian cancer (EOC), we aimed to determine the effectiveness. PATIENTS AND METHODS: Between 2004 and 2013, patients afflicted with platinum-taxane resistant EOC and who were administered a 30-minute i.v. infusion of single-agent gemcitabine at a dose of 1,250 mg/m2 on the 1st, 8th and 15th days, every 28 days, were examined retrospectively. RESULTS: Twenty-six patients with platinum-taxane resistant EOC were included in the study. The overall survival (OS) was 48 months. The median survival after becoming platinum-taxane resistant was 16 months for the study population. Median time to progression (TTP) and median survival after becoming platinum-taxane resistant for patients who received second-line treatment were 3.3 months and 16 months, respectively; for patients who received third-line treatment with gemcitabine, these were 3.7 months and 19 months, respectively. Administration of gemcitabine as second- and third-line chemotherapy in platinum taxane resistant EOC, provides similar TTP and OS outcomes (p = 0.4, p = 0.9) with a similar response and toxicity rate. CONCLUSIONS: Second- and third-line gemcitabine at a dose of 1,250 mg/m2 on days 1, 8 and 15 every 28 days as a 30 minute i.v. infusion in platinum-taxane resistant EOC is an effective treatment option with a tolerable and manageable toxicity. PMID- 25702672 TI - Long progression-free survival with afatinib in a patient with EGFR-unknown lung adenocarcinoma after erlotinib failure: a case report. AB - Important therapeutic advances for patients with advanced non-small cell lung cancer (NSCLC) have recently occurred, and the development of targeted therapy has revolutionized the treatment of these patients. We report the case of an NSCLC patient with unknown EGFR mutation status who developed resistance to erlotinib and was treated with afatinib. After 19 months of therapy with afatinib, the patient is still in treatment and maintains stable disease. Emerging resistance to reversible TKIs is a significant problem. Oral irreversible TKIs such as afatinib may offer an effective treatment option after failure with reversible TKIs. PMID- 25702673 TI - Evaluation of stereotactic body radiation therapy in the management of adrenal metastases from non-small cell lung cancer. AB - AIMS AND BACKGROUND: In this retrospective analysis, we evaluated the use of stereotactic body radiation therapy in the management of adrenal metastases from non-small cell lung cancer and report our single center experience. METHODS AND STUDY DESIGN: Fifteen non-small cell lung cancer patients (9 male, 6 female) with 17 adrenal metastases referred to Gulhane Military Medical Academy Radiation Oncology Department were treated using active breathing control-guided stereotactic body radiation therapy between December 2009 and October 2013. Dose per fraction was 10 Gy to deliver a total dose of 30 Gy over 3 consecutive days for all metastatic adrenal lesions. The mean gross tumor volume was 28.4 cc (range 6.6-101.5) and mean planning target volume was 57.4 cc (range 16.5-143.8). RESULTS: At a median follow-up of 16 months, local control was 86.7% and overall survival was 33.3%. Median disease-free survival was 10 months. Treatment response according to RECIST was categorized as complete response in 3 patients (20%), partial response in 5 patients (33.3%), stable disease in 5 patients (33.3%), and progressive disease in 2 patients (13.3%). Most common acute toxicity was grade 1 nausea (n = 7) and grade 1 fatigue (n = 12). There was no case of grade >=3 acute or late toxicity. CONCLUSIONS: Stereotactic body radiation therapy offers a safe and efficacious management strategy for adrenal metastases from non-small cell lung cancer by providing excellent local control with negligible treatment related toxicity. PMID- 25702674 TI - Bleeding after bevacizumab treatment in patients with metastatic colorectal cancer. AB - AIMS AND BACKGROUND: To evaluate the adverse events (AEs) of bleeding caused by bevacizumab/5-fluorouracil/leucovorin (5-FU/LV) combination chemotherapy with addition of irinotecan or oxaliplatin in patients with metastatic colorectal cancer (mCRC). METHODS: A retrospective study was conducted to evaluate the bleeding AEs associated with bevacizumab and to explore potential associations between bleeding and baseline patient characteristics. The National Cancer Institute Common Terminology Criteria for Adverse Events v4.0 were used to classify the severity of AEs. AEs were divided into five grades: grade 1, mild: intervention not indicated; grade 2, moderate: medical intervention or minor cauterization indicated; grade 3, severe: transfusion, radiological, endoscopic or elective surgical intervention indicated; grade 4, life threatening: urgent intervention indicated; and grade 5, death. RESULTS: Sixty-two patients were evaluated. Bleeding occurred in 26 (41%) patients; the incidence of grade 3 bleeding was 1.6% while no grade 4-5 bleeding occurred. Grade 1 epistaxis and grade 2 hemoptysis events were observed in 25.8% and 3.2% of patients, respectively. Hematochezia events occurred in 12 (19.4%) patients, one (1.6%) of whom required bevacizumab discontinuation. The incidence of hematochezia was higher in patients with unresected primary tumors, prior intestinal bleeding, and tumor response (p<0.05). CONCLUSIONS: These data provide important information about the incidence of clinically significant bleeding AEs, including minor mucocutaneous hemorrhage and major tumor-related bleeding such as hemoptysis and hematochezia in bevacizumab-treated mCRC patients. In addition, unresected primary tumor, prior bleeding, and tumor response were significant risk factors for hematochezia. PMID- 25702675 TI - Lung cancer presenting as a metastasis to the tibial bones: a case report. AB - AIMS AND BACKGROUND: Bone metastasis below the knee from primary lung cancer is rare. Discussion of such cases in a multidisciplinary team is important to establish the correct treatment approach. CASE REPORT: We analyzed the diagnostic pathway of a 53-year-old female patient with a 5-month history of pain in the right foot. The patient underwent several radiological examinations for the pain. An initial diagnosis of osteoporotic syndrome was made, followed by a diagnosis of primary sarcoma. Only when the patient continued to have pain were other radiological examinations performed and a biopsy of the right ankle taken. This revealed a metastasis from undifferentiated pulmonary adenocarcinoma. A total body computed tomography scan did not show any tumor locations apart from the primary lung cancer. The patient underwent chemotherapy and palliative therapies. This case has been reported for its rarity. PMID- 25702676 TI - The added value of bevacizumab concomitantly administered with carboplatin versus carboplatin alone in patients with recurrent glioblastomas. AB - AIMS AND BACKGROUND: Carboplatin (CBDCA) and bevacizumab (BEV) are active in glioblastoma (GBM) with different profiles of toxicity. To date, no study has compared the value of the addition of BEV to historical or traditional cytotoxic chemotherapy. We sought to determine the relative value of BEV in combination with CBDCA versus CBDCA alone in patients with recurrent GBM. METHODS AND STUDY DESIGN: Eligible patients with progressive GBM following surgery, radiotherapy and temozolomide received CBDCA either alone (group 1, n = 25) or in combination with BEV (group 2, n = 23) at 5 mg/kg once every 3 weeks between June 2010 and December 2013. Baseline characteristics and outcomes after treatment were recorded. The primary end points of this retrospective analysis were progression free survival (PFS) and objective response rate. Secondary end points included safety and overall survival (OS). RESULTS: Forty-eight patients were enrolled. The median number of cycles was 4 in group 1 and 6 in group 2. No toxicities or intracerebral bleeding were observed. The objective response rate was higher in group 2 than group 1, 66% vs 24% (p = 0.003). The estimated median PFS and OS were 3.1 vs 6.7 months (p<0.0001) and 6.1 vs 8.6 months (p = 0.09) in group 1 vs group 2, respectively. CONCLUSIONS: The combination of BEV and CBDCA is associated with improved response rates and survival compared with CBDCA alone. These results highlight the value of BEV in recurrent GBM. However, the clinical benefit of this interesting approach needs validation in a larger patient cohort. PMID- 25702677 TI - Improving physicians' communication skills and reducing cancer patients' anxiety: a quasi-experimental study. AB - AIMS AND BACKGROUND: This study is aimed at evaluating the effectiveness of a physician-centered communication skills training program on cancer patient anxiety levels. METHODS AND STUDY DESIGN: In this quasi-experimental study, physicians from 9 units of 5 general hospitals and 1 cancer research institute were recruited. The unit heads chose which physicians would attend the training program (treatment group) and which would not (control group). The effectiveness of the course was evaluated by assessing the evolution of state anxiety in a sample of cancer patients before and after clinical consultations. RESULTS: Thirty-eight physicians and 339 outpatients were assessed. Patients from the treatment and control groups did not differ in pre-examination anxiety or psychological distress levels. Patients examined by physicians from the treatment group displayed a higher decrease in state-anxiety levels compared with those examined by physicians from the control group. A higher proportion of high anxiety levels was found in women, in less educated patients, and in those with a high distress level. CONCLUSIONS: Our findings suggest the effectiveness of the communication skills training program with reference to patient anxiety levels. Given the potential gap between training and clinical impact, further studies investigating the effect of communication training on patient outcomes are needed. PMID- 25702678 TI - Small-bowel neuroendocrine tumor and retroperitoneal fibrosis: efficacy of octreotide and tamoxifen. AB - AIMS AND BACKGROUND: Neuroendocrine tumors are uncommon clinical entities and only a few cases of the co-occurrence of neuroendocrine tumors and retroperitoneal fibrosis have been described in the literature. METHODS AND STUDY DESIGN: We report the promising results achieved in a case of neuroendocrine tumor complicated by retroperitoneal fibrosis causing right ureteral obstruction treated with long-acting release octreotide and tamoxifen. RESULTS AND CONCLUSIONS: The treatment resulted in a complete response without toxicity. PMID- 25702679 TI - Pathway crosstalk analysis of non-small cell lung cancer based on microarray gene expression profiling. AB - AIMS AND BACKGROUND: Lung cancer is characterized by uncontrolled cell growth in the lung tissue. A major challenge in cancer research is the biological interpretation of the complexity of cancer somatic mutation profiles. This study examines the role of pathway crosstalk in the metastatic process of lung cancer cells based on DNA microarray analysis. METHODS: We downloaded the gene expression profile GSE10096 from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were identified and the gene functions of selected DEGs were further analyzed. After KEGG pathway analysis, dysfunctional pathways and dysfunctional crosstalk between pathways in two types of lung cancer cells (low metastasis, M1, and high metastasis, M5) were examined. RESULTS: A total of 13433 genes were filtered as DEGs, and after pathway analysis, 108 signaling pathways related to cancer signaling pathways were screened, including a host pathway hsa05223 and 79 neighbor pathways. Dysfunctional crosstalk analysis of pathways revealed that pathway crosstalk dysfunction of M1 and M5 cells mainly occurred between hsa05223 (non-small cell lung cancer) and hsa04310 (Wnt signaling pathway), and between non-small cell lung cancer and hsa04520 (adherens junction), respectively. Significant pathway crosstalk dysfunction also existed between adherens junction and other classical signaling pathways such as hsa04110 (cell cycle), hsa04310 (Wnt signaling pathway), hsa04350 (TGF-beta signaling pathway), and hsa04630 (Jak-STAT signaling pathway). CONCLUSIONS: Our discovery will help to elucidate the molecular mechanisms of the high carcinogenic and metastatic potential of lung cancer cells. In addition, it will pave the way to developing effective therapies for lung cancer. PMID- 25702680 TI - Adaptive splenic radiotherapy for symptomatic splenomegaly management in myeloproliferative disorders. AB - AIMS AND BACKGROUND: Symptomatic, massive splenomegaly is a debilitating complication of myeloproliferative disorders. In the study, we evaluated the use of a contemporary, individualized radiotherapeutic approach for splenic irradiation, including 3-dimensional computed tomography-based treatment planning, individualized treatment margins based on splenic motion assessment, online setup verification with volumetric image guidance at each fraction, and adaptive radiation treatment planning to account for changes in splenic size during the fractionated radiotherapy course. METHODS AND STUDY DESIGN: Between December 2008 and January 2014, 18 patients (13 males, 5 females) with myeloproliferative disorders referred to Gulhane Military Medical Academy Radiation Oncology Department underwent 22 courses of splenic irradiation using 3 dimensional computed tomography-based treatment planning and volumetric image guidance for palliation of symptomatic splenomegaly. RESULTS: Median age was 64 years (range 28-79). Significant pain relief was achieved in 20 of the 22 splenic irradiation courses (90.9%). Improvement in hematological parameters was achieved in 8 of the 11 splenic irradiation courses applied for cytopenia (72.7%). At least a 50% reduction in splenic size was achieved in 18 of the 22 splenic irradiation courses (81.8%). Toxicity was manageable with supportive treatment including antiemetics and platelet or red blood cell transfusions. CONCLUSIONS: Splenic irradiation with a contemporary radiotherapeutic approach offers safe and effective palliation of symptomatic splenomegaly in myeloproliferative disorders. PMID- 25702681 TI - Thymoma of the left thymic lobe with a contralateral small pleural implant successfully detected with diffusion-weighted MRI. AB - Thymoma is the most common primary neoplasm of the anterior mediastinum. At diagnosis, up to 40% of patients present with advanced disease. Because advanced thymomas receive neoadjuvant chemotherapy, diagnostic imaging is crucial to plan the correct treatment. For characterizing thymomas, CT is the first choice modality, whereas 18F-FDG/PET is reserved for questionable cases and MRI is not routinely employed. Hereby, we describe a case of thymoma with a single contralateral pleural implant in a 30-year-old woman. The small pleural thickening detected at CT was correctly interpreted as pleural seeding related to thymoma at diffusion-weighted (DW)-MRI after a negative 18F-FDG/PET scan, and was subsequently confirmed at surgery. Precise diagnosis and accurate preoperative staging are crucial in managing thymic epithelial tumours in order to design the appropriate treatment and improve prognosis. Indeed, when stage IVa for pleural seeding is diagnosed preoperatively, a multimodality approach including primary chemotherapy followed by surgery and postoperative radiotherapy/chemotherapy is recommended. This is the first report that used DW-MRI for the characterization of pleural seeding in thymoma and demonstrates that DW-MRI could be useful for the correct pre-operatory staging in thymoma patients, especially in cases with indeterminate pleural thickenings at CT, in order to define the correct management. PMID- 25702682 TI - Synthesis and characterization of a Cu14 hydride cluster supported by neutral donor ligands. AB - The copper hydride clusters [Cu14 H12 (phen)6(PPh3)4][X]2 (X=Cl or OTf; OTf=trifluoromethanesulfonate, phen=1,10-phenanthroline) are obtained in good yields by the reaction of [(Ph3P)CuH]6 with phen, in the presence of a halide or pseudohalide source. The complex [Cu14H12 (phen)6(PPh3)4][Cl]2 reacts with CO2 in CH2Cl2 , in the presence of excess Ph3 P, to form the formate complex [(Ph3P)2Cu(kappa(2)-O2CH)], along with [(phen)(Ph3 P)CuCl]. PMID- 25702683 TI - Effects of gestational age at enrollment in pregnancy exposure registries. AB - PURPOSE: This study aims to explore the influence of gestational age at enrollment, and enrollment before or after prenatal screening, on the estimation of drug effects in pregnancy exposure registries. METHODS: We assessed the associations between first trimester antiepileptic drug (AED) exposure and risk of spontaneous abortion and major congenital malformations in the North American AED Registry (1996-2013). We performed logistic regression analyses, conditional or unconditional on gestational age at enrollment, to estimate relative risk (RR) for first trimester AED users compared with non-users. We also compared first trimester users of valproic acid and lamotrigine. Analyses were repeated in women who enrolled before prenatal screening. RESULTS: Enrollment occurred earlier among 7029 AED users than among 581 non-users; it was similar among AEDs. Comparing AED users with non-users, RR (95% confidence interval) of spontaneous abortion (n = 359) decreased from 5.1 (2.3-14.1) to 2.0 (0.9-5.6) after conditioning on gestational week at enrollment and to 1.9 (0.8-5.4) upon further restriction to before-screening enrollees. RR of congenital malformations (n = 216) changed from 3.1 (1.4-8.5) to 3.2 (1.4-9.0) after conditioning on gestational week at enrollment and to 2.0 (0.7-10.1) upon further restriction to before-screening enrollees. When comparing valproic acid users and lamotrigine users, the RR of congenital malformations was not substantially changed by conditioning or restricting. CONCLUSIONS: Spontaneous abortion rates were sensitive to gestational age at enrollment. Estimates of congenital malformation risks for AED users relative to non-users were sensitive to before/after screening enrollment. This difference was not apparent between active drugs, likely due to similar gestational age at enrollment. PMID- 25702684 TI - Formation of nickel sulfide nanoframes from metal-organic frameworks with enhanced pseudocapacitive and electrocatalytic properties. AB - Nanoframe-like hollow structures with unique three-dimensional (3D) open architecture hold great promise for various applications. Current research efforts mainly focus on frame-like noble metals and metal oxides. However, metal sulfides with frame-like nanostructures have been rarely reported. Starting from metal-organic frameworks (MOFs), we demonstrate a novel structure-induced anisotropic chemical etching/anion exchange method to transform Ni-Co Prussian blue analogue (PBA) nanocubes into NiS nanoframes with tunable size. The reaction between Ni-Co PBA nanocube templates and Na2 S in solution leads to the formation of well-defined NiS nanoframes. The different reactivity between the edges and the plane surface of the Ni-Co PBA nanocubes is found to be the key factor for the formation of NiS nanoframes. Benefitting from their structural merits including 3D open structure, small size of primary nanoparticles, high specific surface area, and good structural robustness, the as-derived NiS nanoframes manifest excellent electrochemical performance for electrochemical capacitors and hydrogen evolution reaction in alkaline electrolyte. PMID- 25702687 TI - The price elasticity of demand for heroin: Matched longitudinal and experimental evidence. AB - This paper reports estimates of the price elasticity of demand for heroin based on a newly constructed dataset. The dataset has two matched components concerning the same sample of regular heroin users: longitudinal information about real world heroin demand (actual price and actual quantity at daily intervals for each heroin user in the sample) and experimental information about laboratory heroin demand (elicited by presenting the same heroin users with scenarios in a laboratory setting). Two empirical strategies are used to estimate the price elasticity of demand for heroin. The first strategy exploits the idiosyncratic variation in the price experienced by a heroin user over time that occurs in markets for illegal drugs. The second strategy exploits the experimentally induced variation in price experienced by a heroin user across experimental scenarios. Both empirical strategies result in the estimate that the conditional price elasticity of demand for heroin is approximately -0.80. PMID- 25702688 TI - [Is there an Association between Prevention Campaign Knowledge and Sun Protection Behaviour of Parents for their Children? Results of a Parent Survey]. AB - AIM: The aims of this study are to assess prevalence of awareness of sun protection campaigns among parents in Bavaria, Germany, to analyse the impact of sociodemographic factors on campaign knowledge and the association between parental campaign knowledge and sun protection behaviour in their children. METHODS: A cross-sectional survey was undertaken in 2010-2011 in Bavaria, Germany, with parents of 4,579 children aged 5-6 years (response rate 61%). RESULTS: Prevalence of knowledge of sun protection campaigns is 13% among parents in Germany and independent of sociodemographic factors. Ignorance of sun protection campaigns is associated with inadequate sun protection behaviour in children independent of sociodemographic and exposure characteristics. CONCLUSION: Awareness of sun protection campaigns is low among parents. Knowledge of adequate sun protection behaviour should be further increased at the population level in Germany independently of sociodemographic status. PMID- 25702689 TI - Self-catalysed aerobic oxidization of organic linker in porous crystal for on demand regulation of sorption behaviours. AB - Control over the structure and property of synthetic materials is crucial for practical applications. Here we report a facile, green and controllable solid-gas reaction strategy for on-demand modification of porous coordination polymer. Copper(I) and a methylene-bridged bis-triazolate ligand are combined to construct a porous crystal consisting of both enzyme-like O2-activation site and oxidizable organic substrate. Thermogravimetry, single-crystal X-ray diffraction, electron paramagnetic resonance and infrared spectroscopy showed that the methylene groups can be oxidized by O2/air even at room temperature via formation of the highly active Cu(II)-O2(-) intermediate, to form carbonyl groups with enhance rigidity and polarity, without destroying the copper(I) triazolate framework. Since the oxidation degree or reaction progress can be easily monitored by the change of sample weight, gas sorption property of the crystal can be continuously and drastically (up to 4 orders of magnitude) tuned to give very high and even invertible selectivity for CO2, CH4 and C2H6. PMID- 25702690 TI - Treatment of asymmetrical class II malocclusion in adult patients. PMID- 25702691 TI - Extraction treatment, part 2: guidelines for making the extraction decision. PMID- 25702692 TI - Biomechanical considerations in the correction of anterior open bite with maxillary skeletal plates. PMID- 25702693 TI - A modified Kilroy spring for eruption of palatally impacted canines. PMID- 25702694 TI - Analyzing clinical metrics of indirect bonding and self-ligating brackets. PMID- 25702695 TI - Modified lingual retractors as an esthetic treatment option. PMID- 25702696 TI - Bias vs. science in clinical decision-making. PMID- 25702697 TI - Association between sucrose intake and risk of overweight and obesity in a prospective sub-cohort of the European Prospective Investigation into Cancer in Norfolk (EPIC-Norfolk). AB - OBJECTIVE: The objective of the present study was to investigate associations between sugar intake and overweight using dietary biomarkers in the Norfolk cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC Norfolk). DESIGN: Prospective cohort study. SETTING: EPIC-Norfolk in the UK, recruitment between 1993 and 1997. SUBJECTS: Men and women (n 1734) aged 39-77 years. Sucrose intake was assessed using 7 d diet diaries. Baseline spot urine samples were analysed for sucrose by GC-MS. Sucrose concentration adjusted by specific gravity was used as a biomarker for intake. Regression analyses were used to investigate associations between sucrose intake and risk of BMI>25.0 kg/m2 after three years of follow-up. RESULTS: After three years of follow-up, mean BMI was 26.8 kg/m2. Self-reported sucrose intake was significantly positively associated with the biomarker. Associations between the biomarker and BMI were positive (beta=0.25; 95 % CI 0.08, 0.43), while they were inverse when using self-reported dietary data (beta=-1.40; 95 % CI -1.81, -0.99). The age- and sex-adjusted OR for BMI>25.0 kg/m2 in participants in the fifth v. first quintile was 1.54 (95 % CI 1.12, 2.12; P trend=0.003) when using biomarker and 0.56 (95 % CI 0.40, 0.77; P trend<0.001) with self-reported dietary data. CONCLUSIONS: Our results suggest that sucrose measured by objective biomarker but not self reported sucrose intake is positively associated with BMI. Future studies should consider the use of objective biomarkers of sucrose intake. PMID- 25702698 TI - Drought-resistant cereals: impact on water sustainability and nutritional quality. AB - This review uses production and climate data to examine global and local production trends that can be related to events such as drought. UK grain quality data is also available and provides an overview of trends in protein content. Literature surveys show a consistent reduction in grain size due to the effects of temperature and/or drought. A review of gene expression studies showed that most genes involved in starch synthesis are down regulated under heat stress. Net protein production is also reduced under heat and/or drought stress but apparently to a lesser degree as the reduction in grain mass is larger, resulting in an increase in protein concentration. Modelling has suggested that adaptation could be achieved by moving production to more extreme latitudes but other research suggests that simply transferring germplasm from one region to another is unlikely to be successful. Another review has identified drought tolerance phenotypes that could be used to breed more drought tolerant crops. At the time of the review, the authors concluded that phenotypic selection was generally preferable to forms of marker-assisted breeding and have used the approach to produce drought tolerant wheat cultivars. Transgenic approaches have also been shown to improve drought tolerance under controlled environment conditions but there are no results to show how well these results translate into improved crop performance under field conditions. The recent advances in genomic data and detecting marker-trait associations suggest that marker-assisted breeding will play a much more important role in breeding drought tolerant cereals in the future. PMID- 25702699 TI - A fine line separates carbocations from diradical ions in donor-unconjugated cations. AB - Carbocations are traditionally thought to be closed-shell electrophiles featuring an empty orbital rich in p character. Here, density functional theory computations indicate that when strong pi donors are not placed in direct conjugation with benzylic-type cations, alternative diradical configurations that resemble non-Kekule diradicals are possible. For certain donor-acceptor frameworks, an open-shell singlet configuration is the computed ground state for the cation, whereas for coumarin and xanthenyl cations substituted with strong donors, a triplet diradical configuration is the computed ground state. Changing the substituent nature and attachment location substantially alters the energy gaps between the different electronic configurations and can manipulate the computed ground-state electronic configuration. There are few known examples of ground-state triplet carbocations, and, to our knowledge, no other examples of open-shell singlet carbocations. The open-shell singlet and triplet "carbocations" described here may have reactivity distinct from that of typical closed-shell singlet carbocations and, if appropriately stabilized, lead to organic materials with interesting electronic and magnetic properties. PMID- 25702700 TI - N-Heterocycles from chromium aminocarbenes. AB - The initial [2 + 2]-cycloadduct between a chromium aminocarbene and a tethered alkene undergoes a beta-hydrogen elimination very efficiently when triphenylphosphine is added as a ligand. The reaction gives cyclic enamines or homoenamines depending on the substitution on the alkene. PMID- 25702701 TI - The attentional 'zoom-lens' in 8-month-old infants. AB - The spatial attention mechanisms of orienting and zooming cooperate to properly select visual information from the environment and plan eye movements accordingly. Despite the fact that orienting ability has been extensively studied in infancy, the zooming mechanism--namely, the ability to distribute the attentional resources to a small or large portion of the visual field--has never been tested before. The aim of the present study was to evaluate the attentional zooming abilities of 8-month-old infants. An eye-tracker device was employed to measure the saccadic latencies (SLs) at the onset of a visual target displayed at two eccentricities. The size of the more eccentric target was adjusted in order to counteract the effect of cortical magnification. Before the target display, attentional resources were automatically focused (zoom-in) or spread out (zoom out) by using a small or large cue, respectively. Two different cue-target intervals were also employed to measure the time course of this attentional mechanism. The results showed that infants' SLs varied as a function of the cue size. Moreover, a clear time course emerged, demonstrating that infants can rapidly adjust the attentional focus size during a pre-saccadic temporal window. These findings could serve as an early marker for neurodevelopmental disorders associated with attentional zooming dysfunction such as autism and dyslexia. PMID- 25702702 TI - Sensory and inflammatory colonic changes induced by vincristine in distinct rat models of colitis. AB - Preclinical and clinical studies show that gastrointestinal (GI) inflammation can evoke sensory changes occasionally far from the original inflammatory site. Animal models of colitis with either trinitrobenzenesulphonic acid (TNBS) or mustard oil (MO) produce distinct patterns of somatic and visceral sensory changes. We evaluated the effects of four doses of i.v. vincristine 150 MUg kg( 1) (total of 600 MUg kg(-1) ) treatment on the somatic (thermal nociceptive threshold) and colonic (morphological) changes induced by TNBS or MO in rats. TNBS and MO groups were further submitted to vincristine or saline pretreatments. TNBS induced somatic hypersensitivity, while MO induced somatic hyposensitivity (P < 0.05) when compared to the saline and ethanol control groups. Vincristine per se induced somatic hypersensitivity (P < 0.05). This effect was enhanced by TNBS and reversed by MO treatments. Although vincristine increased the colitis area (colonic weight length(-1) ratio) and the Morris' score in TNBS-treated rats, it did not alter the colitis area and even lowered the Morris' score in MO treated rats. Compared to the saline (control) group, vincristine did not alter the colonic microscopic pattern. However, such lesions scores are higher (P < 0.05) in colitis groups induced by TNBS and MO, pretreated or not with vincristine. In conclusion, the somatic changes induced by different models of experimental colitis are diverse and modulated differently by vincristine. PMID- 25702703 TI - DICER1 regulated let-7 expression levels in p53-induced cancer repression requires cyclin D1. AB - Let-7 miRNAs act as tumour suppressors by directly binding to the 3'UTRs of downstream gene products. The regulatory role of let-7 in downstream gene expression has gained much interest in the cancer research community, as it controls multiple biological functions and determines cell fates. For example, one target of the let-7 family is cyclin D1, which promotes G0/S cell cycle progression and oncogenesis, was correlated with endoribonuclease DICER1, another target of let-7. Down-regulated let-7 has been identified in many types of tumours, suggesting a feedback loop may exist between let-7 and cyclin D1. A potential player in the proposed feedback relationship is Dicer, a central regulator of miRNA expression through sequence-specific silencing. We first identified that DICER1 is the key downstream gene for cyclin D1-induced let-7 expression. In addition, we found that let-7 miRNAs expression decreased because of the p53-induced cell death response, with deregulated cyclin D1. Our results also showed that cyclin D1 is required for Nutlin-3 and TAX-induced let-7 expression in cancer repression and the cell death response. For the first time, we provide evidence that let-7 and cyclin D1 form a feedback loop in regulating therapy response of cancer cells and cancer stem cells, and importantly, that alteration of let-7 expression, mainly caused by cyclin D1, is a sensitive indicator for better chemotherapies response. PMID- 25702704 TI - Increased proliferation and adhesion properties of human dental pulp stem cells in PLGA scaffolds via simulated microgravity. AB - AIM: To explore the possibility of utilizing a rotary cell culture system (RCCS) to model simulated microgravity and investigate its effects on the proliferation, adhesion, migration and cytoskeletal organization of human dental pulp stem cells (hDPSCs) on poly (lactic-co-glycolic acid) (PLGA) scaffolds. METHODOLOGY: Isolated and identified hDPSCs grown on PLGA scaffolds were exposed to simulated microgravity (SMG) or normal gravity (NG) conditions for 3 days. MTT cell proliferation assays, BrdU incorporation assays, flow cytometry analysis and Western blotting were undertaken to identify the proliferation ability of hDPSCs under SMG conditions. Additionally, immunofluorescence detection, SEM observations and cell migration and adhesion assays were performed to compare adhesion, migration and cytoskeletal changes in hDPCSs subjected to SMG conditions. To further investigate the mechanisms, human pathway-focused matrix and adhesion PCR array analyses were performed. The Student's t-test was used for statistical analyses. RESULTS: SMG promoted proliferation and adhesion, decreased migration and reorganized the cytoskeletal organization of hDPSCs compared with the NG group. PCR array analyses revealed that following SMG treatment, ITGA6 (integrin alpha-6), ITGAV (integrin alpha-V), ITGB1 (integrin beta-1), LAMB1 (laminin beta-1) and TNC (tenascin-C) were significantly upregulated (P < 0.05). CONCLUSIONS: SMG may regulate the behaviour of hDPSCs grown in PLGA scaffolds in an integrin-mediated manner, which may contribute to tooth tissue engineering by increasing their expandability and scaffold adhesion. PMID- 25702705 TI - IQ and level of alcohol consumption-findings from a national survey of Swedish conscripts. AB - BACKGROUND: Studies of the association between IQ and alcohol consumption have shown conflicting results. The aim of this study was to investigate the association between IQ test results and alcohol consumption, measured as both total alcohol intake and pattern of alcohol use. METHODS: The study population consists of 49,321 Swedish males born 1949 to 1951 who were conscripted for Swedish military service 1969 to 1970. IQ test results were available from tests performed at conscription. Questionnaires performed at conscription provided data on total alcohol intake (consumed grams of alcohol/wk) and pattern of drinking. Multinomial and binomial logistic regressions were performed on the cross sectional data to estimate odds ratios (ORs) with 95% confidence intervals (CIs). Adjustments were made for socioeconomic position as a child, psychiatric symptoms and emotional stability, and father's alcohol habits. RESULTS: We found an increased OR of 1.20 (1.17 to 1.23) for every step decrease on the stanine scale to be a high consumer versus a light consumer of alcohol. For binge drinking, an increased OR of 1.09 (95% CI = 1.08 to 1.11) was estimated for every step decrease on the stanine scale. Adjustment for confounders attenuated the associations. Also, IQ in adolescence was found to be inversely associated with moderate/high alcohol consumption measured in middle age. CONCLUSIONS: We found that lower results on IQ tests are associated with higher consumption of alcohol measured in terms of both total alcohol intake and binge drinking in Swedish adolescent men. PMID- 25702706 TI - Lomitapide. PMID- 25702707 TI - Characterization of hospital and community-acquired respiratory syncytial virus in children with severe lower respiratory tract infections in Ho Chi Minh City, Vietnam, 2010. AB - BACKGROUND: Human respiratory syncytial virus (RSV) is an important community and nosocomial pathogen in developed countries but data regarding the importance of RSV in developing countries are relatively scarce. METHODS: During a 1-year surveillance study in 2010, we took serial samples from children admitted to the Emergency Unit of the Respiratory Ward of Children's Hospital 1 in Ho Chi Minh City, Vietnam. RSV was detected within 72 hours of admission to the ward in 26% (376/1439; RSV A: n = 320; RSV B: n = 54; and RSV A and B: n = 2). Among those negative in the first 72 hours after admission, 6.6% (25/377) acquired nosocomial RSV infection during hospitalization (RSV A: n = 22; and RSV B: n = 3). RESULTS: Children with nosocomial RSV infection were younger (P = 0.001) and had a longer duration of hospitalization (P < 0.001). The rate of incomplete recovery among children with nosocomial RSV infection was significantly higher than among those without (P < 0.001). Phylogenetic analysis of partial G gene sequences obtained from 79% (316/401) of positive specimens revealed the co-circulation of multiple genotypes with RSV A NA1 being predominant (A NA1: n = 275; A GA5: n = 5; B BA3: n = 3; B BA9: n = 26; and B BA10: n = 7). The RSV A GA5 and RSV B BA3 genotypes have not been reported from Vietnam, previously. CONCLUSION: Besides emphasizing the importance of RSV as a cause of respiratory infection leading to hospitalization in young children and as a nosocomial pathogen, data from this study extend our knowledge on the genetic diversity of RSV circulating in Vietnam. PMID- 25702708 TI - Masculinisation of the zebra finch song system: roles of oestradiol and the Z chromosome gene tubulin-specific chaperone protein A. AB - Robust sex differences in brain and behaviour exist in zebra finches. Only males sing, and forebrain song control regions are more developed in males. The factors driving these differences are not clear, although numerous experiments have shown that oestradiol (E2 ) administered to female hatchlings partially masculinises brain and behaviour. Recent studies suggest that an increased expression of Z chromosome genes in males (ZZ; females: ZW) might also play a role. The Z-gene tubulin-specific chaperone A (TBCA) exhibits increased expression in the lateral magnocellular nucleus of the anterior nidopallium (LMAN) of juvenile males compared to females; TBCA+ cells project to the robust nucleus of the arcopallium (RA). In the present study, we investigated the role of TBCA and tested hypotheses with respect to the interactive or additive effects of E2 and TBCA. We first examined whether E2 in hatchling zebra finches modulates TBCA expression in the LMAN. It affected neither the mRNA, nor protein in either sex. We then unilaterally delivered TBCA small interfering (si)RNA to the LMAN of developing females treated with E2 or vehicle and males treated with the aromatase inhibitor, fadrozole, or its control. In both sexes, decreasing TBCA in LMAN reduced RA cell number, cell size and volume. It also decreased LMAN volume in females. Fadrozole in males increased LMAN volume and RA cell size. TBCA siRNA delivered to the LMAN also decreased the projection from this brain region to the RA, as indicated by anterograde tract tracing. The results suggest that TBCA is involved in masculinising the song system. However, because no interactions between the siRNA and hormone manipulations were detected, TBCA does not appear to modulate effects of E2 in the zebra finch song circuit. PMID- 25702709 TI - An exploratory study to identify risk factors for the development of capecitabine induced Palmar Plantar Erythrodysesthesia (PPE). AB - AIMS: To identify pre-treatment risk factors for the development of Palmar Plantar Erythrodysesthesia in participants receiving capecitabine monotherapy. Specifically the hypothesis that avoidance of activities that cause friction and pressure cause Palmar Plantar Erythrodysesthesia was tested. BACKGROUND: Previous literature showed contradictory evidence on the subject of predictors of chemotherapy-induced Palmar Plantar Erythrodysesthesia. There is a lack of empirical evidence to support the theory that Palmar Plantar Erythrodysesthesia is caused by damage to the microcapillaries due to everyday activities that cause friction or pressure to the hands or feet. DESIGN: Prospective epidemiological study of risk factors. METHODS: Prospective data collection. All patients prior to commencing capecitabine monotherapy between 11 June 2009-31 December 2010, were offered recruitment into the study and followed up for six cycles of treatment (n = 174). Data were collected during semi-structured interviews, from participants' diaries, physical examination of the hands and feet and review of notes. Data relating to activities that cause friction, pressure or heat were collected. Data were analysed using bivariate (chi-square and independent groups Student's t) tests where each independent variable was analysed against Palmar Plantar Erythrodysesthesia. RESULTS: The only variables that were associated with an increased risk of Palmar Plantar Erythrodysesthesia were a tendency to have warm hands and pre-existing inflammatory disease. CONCLUSIONS: This study gives no support for the hypothesis that avoidance of activities that cause friction and pressure cause Palmar Plantar Erythrodysesthesia. PMID- 25702710 TI - Involvement of OsPht1;4 in phosphate acquisition and mobilization facilitates embryo development in rice. AB - Phosphate (Pi) transporters mediate acquisition and transportation of Pi within plants. Here, we investigated the functions of OsPht1;4 (OsPT4), one of the 13 members of the Pht1 family in rice. Quantitative real-time RT-PCR analysis revealed strong expression of OsPT4 in roots and embryos, and OsPT4 promoter analysis using reporter genes confirmed these findings. Analysis using rice protoplasts showed that OsPT4 localized to the plasma membrane. OsPT4 complemented a yeast mutant defective in Pi uptake, and also facilitated increased accumulation of Pi in Xenopus oocytes. Further, OsPT4 genetically modified (GM) rice lines were generated by knockout/knockdown or over-expression of OsPT4. Pi concentrations in roots and shoots were significantly lower and higher in knockout/knockdown and over-expressing plants, respectively, compared to wild-type under various Pi regimes. (33) Pi uptake translocation assays corroborated the altered acquisition and mobilization of Pi in OsPT4 GM plants. We also observed effects of altered expression levels of OsPT4 in GM plants on the concentration of Pi, the size of the embryo, and several attributes related to seed development. Overall, our results suggest that OsPT4 encodes a plasma membrane-localized Pi transporter that facilitates acquisition and mobilization of Pi, and also plays an important role in development of the embryo in rice. PMID- 25702711 TI - Observational study of corrected count increments after transfusion of platelets treated with riboflavin pathogen reduction technology in additive solutions. AB - BACKGROUND: Mirasol pathogen reduction technology (PRT) treatment inactivates bacteria, viruses, and parasites in plasma products and platelets (PLTs) suspended in plasma and PLT additive solutions (PAS). Few clinical studies exist documenting transfusions with PAS. This study objective was to evaluate the count increments of PRT-treated PAS-C and PAS-E buffy coat (BC) PLTs in routine use observational settings. STUDY DESIGN AND METHODS: PLT pools of five or six BCs were collected, processed, and suspended in PAS-C or PAS-E, respectively. Products were exposed to ultraviolet light in the presence of riboflavin and then transfused into 19 patients with hematologic diseases. Patients were monitored for PLT corrected count increment (CCI) at 1 and 24 hours and for any adverse events in the 72 hours after transfusion. Sterility monitoring was performed with a microbial detection system (BacT/ALERT, bioMerieux). RESULTS: The PAS-E products had significantly higher PLT concentrations and counts than the PAS-C products. The mean CCIs of per-protocol (PP) units at 1 and 24 hours were 11,900 (n=27) and 5500 (n=30), respectively. Seventy-eight percent of PP transfusions classify as successful with CCIs at 1 hour of higher than 7500, and 63% higher than 4500 at 24 hours. One patient was excluded from all analyses as she was refractory to Mirasol-treated PLT transfusions and follow-up untreated transfusion products. No adverse events were observed and no contaminated products were detected by BacT/ALERT. CONCLUSION: PRT-treated BC PLTs in PAS-C or PAS-E demonstrate PLT transfusion success rates in hematology patients with thrombocytopenia that are comparable to previous studies examining PLTs stored in plasma. PMID- 25702712 TI - Structure and reaction mechanism of a novel enone reductase. AB - Recently, a novel gut-bacterial fatty acid metabolism, saturation of polyunsaturated fatty acid, that modifies fatty acid composition of the host and is expected to improve our health by altering lipid metabolism related to the onset of metabolic syndrome, was discovered in Lactobacillus plantarum AKU 1009a. Enzymes constituting the pathway catalyze sequential reactions of free fatty acids without CoA or acyl carrier protein. Among these enzymes, CLA-ER was identified as an enone reductase that can saturate the C=C bond in the 10-oxo trans-11-octadecenoic acid (KetoB) to produce 10-oxo-octadecanoic acid (KetoC). This enzyme is the sole member of the NADH oxidase/flavin reductase family that has been identified to exert an enone reduction activity. Here, we report both the structure of holo CLA-ER with cofactor FMN and the KetoC-bound structure, which elucidate the structural basis of enone group recognition of free fatty acids and provide the unique catalytic mechanism as an enone reductase in the NADH oxidase/flavin reductase family. A 'cap' structure of CLA-ER underwent a large conformational change upon KetoC binding. The resulting binding site adopts a sandglass shape and is positively charged at one side, which is suitable to recognize a fatty acid molecule with enone group. Based on the crystal structures and enzymatic activities of several mutants, we identified C51, F126 and Y101 as the critical residues for the reaction and proposed an alternative electron transfer pathway of CLA-ER. These findings expand our understanding of the complexity of fatty acid metabolism. DATABASE: The atomic coordinates have been deposited in the Protein Data Bank (PDB), www.pdb.org (PDB ID 4QLX, 4QLY). PMID- 25702713 TI - Role of effective composition on antioxidant, anti-inflammatory, sedative hypnotic capacities of 6 common edible Lilium varieties. AB - Nine Lilium samples (belong to 6 different cultivars with different maturity stage) were qualitatively and quantitatively analyzed of total phenolics (TP), total flavonoids (TF), total saponins (TS), total carbohydrates (TC, polysaccharides), and soluble proteins contents (SP), and the monomeric components were quantified utilizing high-performance liquid chromatography with photodiode array detector (HPLC-PAD) associated with liquid chromatography-mass spectrometry (HPLC-MS). Antioxidant activity (reducing power and DPPH radical scavenging activity), anti-inflammatory (xylene-induced mouse ear edema detumescent assay and carrageenan-induced mouse paw edema detumescent assay), and sedative-hypnotic capacities (sodium pentobarbital-induced sleep assay) were comparatively evaluated in mouse model. Additionally, correlation analysis and principal component analysis were carried out to detect clustering and elucidate relationships between components' concentrations and bioactivities to clarify the role of effective composition. Lilium bulbs in later maturity stage preliminary evidenced higher saponins content, and lower phenolic acids and flavonoids content. The result demonstrated that Lilium bulbs generally had distinct antioxidant, anti-inflammatory, and sedative-hypnotic capacities. Varieties statistically differed (P < 0.05) in chemical composition and bioactivities. Lilium varieties of Dongbei and Lanzhou presented potent sedative-hypnotic effect and anti-inflammatory activity. The antioxidant capacity was related to the phenolic acids and flavonoids contents, the anti-inflammatory and sedative hypnotic capacities were related to the saponins content. This is first study presenting comprehensive description of common edible Lilium bulbs' chemical compositions, sedative-hypnotic, and anti-inflammatory capacities grown in China. It would informatively benefit the genetic selection and cultivated optimization of Lilium varieties to improve nutritional quality, and promote Lilium bulbs as a therapeutic functional food worldwide. PMID- 25702714 TI - Imaging of Primary Brain Tumors and Metastases with Fast Quantitative 3 Dimensional Magnetization Transfer. AB - BACKGROUND AND PURPOSE: This study assesses whether magnetization transfer (MT) imaging provides additive information to conventional MRI in brain tumors. METHODS: MT data of 26 patients with neoplastic and metastatic brain tumors were analyzed at 1.5 T. For the 3 largest tumor groups investigated in this study- glioblastoma multiforme (GBM), meningiomas, and metastases-statistical comparisons were performed. Analyzed MT parameters included the magnetization transfer ratio (MTR) and 4 quantitative MT parameters (qMT): Relaxation times (T1, T2), exchange rate (kf), and macromolecular content (F). Total imaging time of high-resolution whole brain MTR and qMT imaging with balanced steady-state free precession required 9 minutes. Five ROIs were chosen: Contrast-enhancing (T1W-CE), noncontrast-enhancing (T1W-non-CE), proximal hyperintensity (T2W-pSI), distal hyperintensity (T2W-dSI), and a reference (ref). RESULTS: Pathologies showed significant (P < .05) MT changes (MTR and qMT) compared to the reference. The T1W-CE, T1W-non-CE, and T2W-pSI ROIs of GBMs, meningiomas, and metastases showed significant differences in MTR and qMT estimates. Similar MTR with significant different qMT values were observed in several ROIs among different lesions. MT maps (MTR and qMT) indicated changes in tissue appearing unaffected on MRI in most glial tumors. CONCLUSIONS: MTR and qMT imaging enables a better differentiation between brain tumors and provides additive information to MRI. PMID- 25702715 TI - Psychological impact of acne on 21st-century adolescents: decoding for better care. AB - The psychological consequences of acne have been the subject of many studies. As a particularly visible skin disorder, acne complicates the daily lives of adolescents who are undergoing multiple transformations: physical, intellectual and emotional. While it is well established that acne can be responsible for depression and low self-esteem, it is likely that this impact is aggravated by the sociological evolution of adolescents in the 21st century. Understanding the codes of adolescents today (who can be characterized as being more concerned by their appearance than previous generations at the same age) allows us to optimize our medical approach to acne and facilitates treatment compliance and adherence. PMID- 25702718 TI - Pseudomelanoma follow-up of a recurrent naevus with dermoscopy and reflectance confocal microscopy. PMID- 25702719 TI - [Health Care in the German Democratic Republic (GDR) from the Patients' View: A Survey of Petitions Sent to the Socialist Unity Party of Germany (SED)]. AB - OBJECTIVE: The aim of this paper is to explore the patients' view of the health system in the German Democratic Republic (GDR) in the 1980 s. It investigates how patients experienced everyday medical care in the GDR beyond the ideals of official health policy. METHODS: A systematic analysis of patients' written petitions to the Central Committee of the Socialist Party in the GDR was undertaken. RESULTS: Patients articulated their experiences and expectations quite critically, using characteristic patterns of argumentation and, at times, successfully exerting pressure on the regime to answer their demands. Conflicts concerning disability pensions, factual or putative malpractice and complaints about run-down health facilities belong to the issues most frequently addressed. Persons who mentioned their membership in the Socialist Party had better chances to get their problems solved than those who did not disclose any affiliation to the Socialist Party. CONCLUSION: The petitions surveyed in this study provide insight into the lives of patients in the late GDR. Patients made particular demands of the socialist state and its health system. It is important to integrate the patients' perspective into historical research on medical care in the GDR. PMID- 25702720 TI - [Health Status of Persons without Health Insurance and of Undocumented Migrants: Analysis of Data from the Malteser Migranten Medizin (MMM) in Munich, Germany]. AB - INTRODUCTION: It is estimated that more than 100,000 persons are without health insurance in Germany. The number of undocumented migrants is roughly estimated to be about 40,000. There are hardly any empirical studies looking at health care provision for these population groups, it is even rarely stressed that more empirical studies are needed. There seems to be a major gap concerning perception and research. The present study aims at promoting this discussion by presenting analyses based on data from an institution providing health care for these population groups, i. e., the Malteser Migranten Medizin (MMM) in Munich. METHODS: Data were available from all patients coming to MMM between January 2009 and October 2012 (i. e., from 2,352 visits altogether). The following information is available for each visit: date, sex, age group, country of origin, residence permit status (3 groups), diagnosis (ICD-10 chapter), type of health care (4 broad groups). Multivariate analyses have been conducted for simultaneous control of these variables. In order to compare these data with information from the general population, data from a large statutory sickness fund have been included as well. RESULTS: Focusing first on the MMM patients, the analyses showed large differences concerning diagnoses by country of origin and by residence permit status. We were not able, however, to confirm the hypothesis that mental health problems are especially common among undocumented migrants. The comparison with the general population indicated, surprisingly, that MMM patients showed a very similar spectrum of diagnoses as compared with the general population. CONCLUSION: The data from MMM do not allow a precise assessment of health care need, they still indicate, though, how different the patients are who seek help. MMM offers a broad range of health care, but it is hardly possible to meet the manifold demands of all the patients; there is no psychotherapist, for example. The resources available at MMM will always just allow a very limited provision of health care. It would be important to promote the integration of persons without health insurance and for undocumented migrants into the general system of statutory sickness funds. PMID- 25702721 TI - Addressing clinician workforce shortages in underserved areas. PMID- 25702722 TI - Letter to the editor. PMID- 25702723 TI - The strategic impact of a post baccalaureate pre-medicine intervention program on medical school academic performance. AB - The purpose of this longitudinal (11-year) study of the academic impact on post baccalaureate graduates' performance profiles from years 2001-2011 is to determine whether or not post-baccalaureate program reinforcement, enrichment, and intervention efforts strategically affected the students' academic performance profile while matriculating at Meharry Medical College-School of Medicine. A second purpose of this study is to provide some predictive information to help identify 'at risk' students to ensure that proactive intervention efforts are provided early in their pursuit of a health professions career, thus avoiding the pitfall of unpreparedness and the lack of counseling. PMID- 25702725 TI - Addressing the access problem for patients with serious mental illness who require tertiary medical care. AB - There is evidence to suggest that people with serious mental illness (SMI) have lower access to tertiary care than patients without SMI, particularly when care is complex. Barriers are present at the level of the individual, providers, and the health care system. High levels of co-morbidity and the associated health care costs, along with a growing focus on facilitating equal access to quality care for all, urges health care systems to address existing gaps. Some interventions have been successful at improving access to primary care for patients with SMI, but relatively little research has focused on access to complex interventions. This paper summarizes the scope of the problem regarding access to complex tertiary medical care among people with SMI. Barriers are discussed and potential solutions are proposed. Policies and programs must be developed, implemented, and evaluated to determine cost-effectiveness and impact on outcomes. PMID- 25702724 TI - Treatment disparities among African American men with depression: implications for clinical practice. AB - A decade has passed since the National Institute of Mental Health initiated its landmark Real Men Real Depression public education campaign. Despite increased awareness, depressed African American men continue to underutilize mental health treatment and have the highest all-cause mortality rates of any racial/ethnic group in the United States. We review a complex array of socio-cultural factors, including racism and discrimination, cultural mistrust, misdiagnosis and clinician bias, and informal support networks that contribute to treatment disparities. We identify clinical and community entry points to engage African American men. We provide specific recommendations for frontline mental health workers to increase depression treatment utilization for African American men. Providers who present treatment options within a frame of holistic health promotion may enhance treatment adherence. We encourage the use of multidisciplinary, community-based participatory research approaches to test our hypotheses and engage African American men in clinical research. PMID- 25702726 TI - Remaking the American health care system: a positive reflection on the Affordable Care Act with emphasis on mental health care. AB - Health care reform under the Patient Protection and Affordable Care Act (PPACA, ACA) of 2010 may be the most significant health care-related legislation enacted since the establishment of Medicare and Medicaid several decades ago. Over two years ago the U.S. Supreme Court upheld the constitutionality of the individual mandate of the Patient Protection and Affordable Care Act. This legislation has emerged as a significant and ambitious undertaking for all levels of the U.S. government. With the need to accommodate the estimated 30 million people projected over time to become newly insured it is increasingly important to understand the necessity of reform, how the legislation has been interpreted and implemented to fit the goals of the federal, state, and local governments, and what the potential benefits and consequences of changing the system are, in particular, as it relates to mental health care. PMID- 25702727 TI - The microbiome: a contributor to health and disease. AB - As the 21st century unfolds there is substantial evidence that biological research is experiencing extraordinary scientific and technological advances. Prominent among these advances are the completion of the Human Genome Project, which laid the foundation for the second advance, the Human Microbiome Project. Emerging from these advances are two overarching conclusions: a) genomics is no longer the sole domain of the geneticist, and b) we each are hosts to trillions of microorganisms. Genomics and other technologies have enhanced efforts to characterize the structure, composition, and functions of the microbiome. This characterization has fueled progress in understanding the role of the microbiome in health and disease. In this review, we highlight developments that have helped illuminate the microbiome-health connection. This information can improve an understanding of connections and relationships among multiple factors (or determinants) of health. PMID- 25702728 TI - Practice and protest: black physicians and the evolution of race-conscious professionalism. AB - Throughout history, Black physicians have been bound by a dual obligation: to pursue excellence and success in their profession, and to leverage their professional stature to improve the condition of their communities. This paradigm of race-conscious professionalism has affected greatly the experience of Black physicians, and shaped their formulation of professional identity. This paper explores the relationship between professional life and racial activism in the Black physician community from the pre-Civil War era until the present. The nature of this negotiation has shifted according to the professional and social dynamics of the era. Before the Civil War, Black physician-activists were forced to relinquish their professional duties in order to engage in activism. In later years, activism emerged as a valuable endeavor in the Black medical community, which offered greater opportunities for activism within the profession. The implications of these findings for contemporary physicians are discussed. PMID- 25702729 TI - Food insecurity, food assistance and health status in the U.S. community health center population. AB - OBJECTIVES: This study explored the relationship between food insecurity, food assistance, and self-reported health status among community health center (CHC) clients. METHODS: Using data from the 2009 Community Health Center Patient Survey (n = 4,562), representing Federally Qualified Health Center clients, we conducted logistic regression analyses to identify the association between food insecurity and fair/poor health status, controlling for food assistance and sociodemographic factors. RESULTS: Approximately 1/3 of the sample (31.9%) reported fair/poor health status, 10.9% reported food insecurity, and 52.6% reported public food assistance. Multivariate analyses revealed that, among women, those with food insecurity had significantly higher odds of reporting fair/poor health status (AOR = 2.14, 95% CI 1.20-3.82). CONCLUSIONS: Expansion of financial access to health care via the Patient Protection and Affordable Care Act coupled with recent funding cuts to the Supplemental Nutrition Assistance Program means that CHCs play an increasingly important role in addressing food insecurity. PMID- 25702730 TI - Characteristics of traumatic brain injuries sustained among veterans seeking homeless services. AB - This hypothesis-generating research describes the characteristics of traumatic brain injuries (TBIs) sustained among 229 Veterans seeking homeless services. Nearly all participants (83%) had sustained at least one TBI prior to their first episode of homelessness. Among participants with a TBI, assaults, transportation related accidents, and falls were the most common causes of these injuries. Thirty percent of individuals sustained injuries with severity levels that would be expected to be associated with ongoing TBI-related deficits. Forty-three percent of the Veterans sustained at least one brain injury following their first episode of homelessness. Median lifetime number of TBIs was three. The severity of TBIs was similar among Veterans who sustained injuries before or after their first incident of homelessness. Findings suggest that future research should directly examine the potential bi-directional relationship between TBI and homelessness, as well as the impact of TBI-related deficits on Veterans' ability to benefit from homeless services and/or maintain stable housing. PMID- 25702731 TI - Changes in smoking-related symptoms during enforced abstinence of incarceration. AB - BACKGROUND: Tobacco use among prisoners is much higher than among the general population. Little is known about changes in smoking-related symptoms during periods of incarceration. The objective of this study is to evaluate changes in smoking-related symptoms during incarceration. METHODS: We recruited 262 inmates from a tobacco-free prison. At baseline, participants were asked about smoking related symptoms prior to incarceration and then asked about recent symptoms. RESULTS: All symptom scores on the American Thoracic Society Questionnaire (ATSQ) improved during incarceration. Higher ATSQ scores were associated with asthma, depressive symptoms, stress, higher addiction and more pack years of smoking. Greater improvement in symptoms was not associated with smoking status after release. CONCLUSION: Forced tobacco abstinence leads to significant improvements in smoking-related symptoms. However, improvements in symptoms are not associated with smoking behavior changes. Addressing changes in symptoms during incarceration will require further evaluation in smoking cessation interventions for incarcerated populations. PMID- 25702732 TI - Community-based participatory research examining the health care needs of African Americans who are homeless with mental illness. AB - African Americans with mental illness who are homeless experience significant health risks and illnesses leading to high mortality and morbidity rates. A community-based participatory research (CBPR) team conducted a qualitative study to begin to describe these problems. Results from focus groups and key informant interviews of 42 individuals yielded 98 themes which were sorted into three categories: problems, solutions, and peer navigators. Results included a review of the problems and solutions which the community or people might adopt. An additional goal was to understand and develop impact of peer navigators for addressing health problems in this group. Results yielded a list of values in hiring peer navigators as well as skills and resources they might need to successfully do their job. Findings from the study are currently being used by the CBPR team to develop a peer navigator program for this community. PMID- 25702733 TI - Development and preliminary testing of the health in community survey. AB - OBJECTIVES: Develop and pilot test the Health in Community Survey (HCS), to collect patients' perceptions of care integration between traditional care providers and community-based services that address social determinants of health. RESEARCH DESIGN: Interviews of working-age, English-or Spanish-speaking patients with multiple chronic conditions to identify survey domains; cognitive interviews and pilot test of HCS Version 1. RESULTS: Preliminary interview subjects identified diverse care concerns. From these findings, we designed six HCS domains. Cognitive interviews identified problems relating to patients' perceptions about limited function and disability. Nearly one-third of pilot test subjects reported they did not definitely have enough resources for food, transportation, doctor and hospital bills, and medications; 41.6% said their clinicians only sometimes or never knew about their resource problems. CONCLUSIONS: Although it requires further validation, the HCS offers insights into patients' perceptions of care integration between traditional health care providers and services addressing social determinants of health. PMID- 25702734 TI - Barriers to Medicaid participation among Florida dentists. AB - BACKGROUND: Finding dentists who treat Medicaid-enrolled children is a struggle for many parents. The purpose of this study was to identify non-reimbursement factors that influence the decision by dentists about whether or not to participate in the Medicaid program in Florida. METHODS: Data from a mailed survey was analyzed using a logistic regression model to test the association of Medicaid participation with the Perceived Barriers and Social Responsibility variables. RESULTS: General and pediatric dentists (n=882) who identified themselves as either Medicaid (14%) or Non-Medicaid (86%) participants responded. Five items emerged as significant predictors of Medicaid participation, with a final concordance index of 0.905. Two previously unreported barriers to participation in Medicaid emerged: 1) dentists' perception of social stigma from other dentists for participating in Medicaid, and 2) the lack of specialists to whom Medicaid patients can be referred. CONCLUSIONS: This study provides new information about non-reimbursement barriers to Medicaid participation. PMID- 25702735 TI - Religiosity, spirituality, and HIV risk behaviors among African American women from four rural counties in the southeastern U.S. AB - In a cross-sectional survey of 1,013 African American women from rural Alabama and North Carolina, we examined the relationship of (1) organizational religiosity (i.e., religious service attendance), (2) non-organizational religiosity (e.g., reading religious materials), and (3) spirituality with these outcomes: women's reports of their sexual behaviors and perceptions of their partners' risk characteristics. Women with high non-organizational religiosity, compared with low, had fewer sex partners in the past 12 months (adjusted prevalence ratio (aPR): 0.58, 95% confidence interval (CI): 0.42, 0.80) and were less likely to have concurrent partnerships (aPR: 0.47, 95% CI: 0.30, 0.73). Similar results were observed for spirituality, and protective but weaker associations were observed for organizational religiosity. Weak associations were observed between organizational religiosity, non-organizational religiosity, and spirituality with partners' risk characteristics. Further exploration of how religiosity and spirituality are associated with protective sexual behaviors is needed to promote safe sex for African American women. PMID- 25702736 TI - Prescription practices involving opioid analgesics among Americans with Medicaid, 2010. AB - Recent state-based studies have shown an increased risk of opioid overdose death in Medicaid populations. To explore one side of risk, this study examines indicators of potential opioid inappropriate use or prescribing among Medicaid enrollees. We examined claims from enrollees aged 18-64 years in the 2010 Truven Health MarketScan(r) Multi-State Medicaid database, which consisted of weighted and nationally representative data from 12 states. Pharmaceutical claims were used to identify enrollees (n=359,368) with opioid prescriptions. Indicators of potential inappropriate use or prescribing included overlapping opioid prescriptions, overlapping opioid and benzodiazepine prescriptions, long acting/extended release opioids for acute pain, and high daily doses. In 2010, Medicaid enrollees with opioid prescriptions obtained an average 6.3 opioid prescriptions, and 40% had at least one indicator of potential inappropriate use or prescribing. These indicators have been linked to opioid-related adverse health outcomes, and methods exist to detect and deter inappropriate use and prescribing of opioids. PMID- 25702737 TI - Knowledge and attitudes towards eye diseases in a rural south-eastern Nigerian population. AB - BACKGROUND: Knowledge and attitudes concerning eye disorders are important socio demographic parameters critical for eye care uptake and outcomes, especially in underserved populations. OBJECTIVES: To assess knowledge and attitudes concerning common eye disorders in a rural south-eastern Nigerian population. METHODS: The study was a population-based survey of knowledge and attitudes concerning common eye diseases conducted in Abagana community in September 2011. RESULTS: The participants comprised 263 males and 238 females. Their profile of good knowledge was eye infections: 38.9%; refractive error: 28.9%; cataracts: 18.0%; diabetic retinopathy: 8.0%; glaucoma: 5.8%; and overall good knowledge: 4.0%. Prevention and treatment of eye disorders were rated as first priorities over other major disabilities by 91.4% participants. Older age and formal education were the significant predictors of good knowledge. CONCLUSION: In Abagana, there is poor overall and disorder-specific knowledge of eye disorders. Socio-demographic factors are important determinants of knowledge. Community-based preventive eye health education is underscored. PMID- 25702738 TI - A developing framework for the development, implementation and maintenance of HIV interventions in the African American church. AB - The African American church has promoted the health of African Americans through supporting interventions that target a wide variety of diseases, and it is a crucial community partner in the development of HIV prevention interventions. Although research has described the development of church-based HIV interventions, there is a significant lack of frameworks and approaches available to guide the implementation and maintenance of HIV interventions within church based settings. A developing framework of a comprehensive church-based intervention, derived from an ethnographic study about the development, implementation, and maintenance of an HIV/AIDS Ministry within an African American church is presented. This approach can provide guidance to support the development, implementation, and maintenance of HIV interventions in faith settings. PMID- 25702739 TI - Deliberation: obtaining informed input from a diverse public. AB - OBJECTIVES: Health care decision makers require public input to incorporate diverse values into programs and policies. Deliberation, one method for obtaining input, seeks to apply inclusive principles wherein diverse groups provide perspectives to inform decisions. We evaluate whether participants of different racial, ethnic, and educational backgrounds show differences in the effect of deliberation and the value placed on deliberation participation. METHODS: We surveyed 907 participants before and after deliberation. Regression models examined associations between demographics and change in knowledge and attitudes, and perceived impact. RESULTS: Changes in knowledge about using medical evidence in decision-making were not associated with race, ethnicity, or education. Changes in attitudes were not associated with these characteristics with one exception. African American, Hispanic, and participants with lower educational attainment reported more perceived impact. CONCLUSION: Similar results across demographic groups suggest deliberation's promise for obtaining input from a diverse public to inform health programs and policies. PMID- 25702740 TI - Racial differences in iron measures and outcomes observed during an iron reduction trial in peripheral arterial disease. AB - Elevated body iron (ferritin) levels may contribute to adverse health outcomes. Racial differences in iron measures and clinical outcomes were observed during an iron reduction trial in peripheral arterial disease. At entry, Black compared with White participants had higher ferritin and lower red cell measures, as well as differing ferritin and percent transferrin saturation (%TS) responses, and HDL/LDL ratios associated with statin use. Lower hematocrit levels during follow up resulted in fewer phlebotomies, less iron unloading (ferritin reduction, p=.035) and 32% less iron removed in Black compared with White participants randomized to iron reduction. Improved primary (all-cause mortality) and secondary (death plus non-fatal myocardial infarction and stroke) outcomes among White participants correlated with lower ferritin levels (p=.005 and p=.053, respectively) and higher %TS levels (p<.001 and p=.001 respectively), associations not observed in Black participants. Variant iron homeostasis contributory to racial health disparities warrants personalized intervention strategies and race-specific clinical trial design. PMID- 25702741 TI - Attitudes and perceptions about hypertension among churchgoing Blacks. AB - PURPOSE: This study evaluates beliefs churchgoing Blacks hold about causes of hypertension and impact on adherence to non-pharmacologic treatment. METHODS: We created a 17-question survey about participants' family history, medication use, behavioral modification, causes of hypertension, intake of fruit and vegetables, salt intake and physical activity. Data came from three predominantly Black churches in Florida. We conducted statistical analyses using Microsoft Excel 2010 and Stata Version 12. RESULTS: Over 67% responded that physical activity was effective in lowering blood pressure, while greater than 53% responded that a diet high in fruits and vegetables was effective in lowering blood pressure. Over 78% responded that a low-salt diet is effective in lowering blood pressure. Respondents also felt that exercise (71%) and low-salt diet (72%) were as effective as medications in lowering blood pressure. CONCLUSIONS: Our sample believes non-pharmacological treatments are effective in lowering blood pressure, regardless of perceived cause. PMID- 25702742 TI - Factors associated with overall survival prostate cancer in Florida: a multilevel analysis. AB - OBJECTIVE: To investigate individual and contextual factors contributing to overall prostate cancer (PCa) survival in Florida. METHODS: A random sample of 6,457 PCa cases diagnosed between 10/1/2001 and 12/31/2007 was extracted from Florida Cancer Data System. Comorbidity was computed following Elixhauser Index. Survival probability curve was generated using Kaplan-Meier method. The Wei, Lin, and Weissfel model was used for the multivariate analysis. RESULTS: Older age at diagnosis was associated with shorter time to death. Current smokers had a higher hazard rate than non-current smokers. Higher hazard of overall mortality was associated with being diagnosed with advanced stage compared with localized stage and having poorly-differentiated tumor compared with well-moderately differentiated tumor. No definitive treatment, radiation alone, and hormone alone were significantly associated with elevated hazard rate compared with surgery. Fifteen comorbidities were significantly associated with shorter time-to-death. CONCLUSIONS: Effective control of comorbidity in PCa patients should help improve life expectancy and lead to prolonged survival. PMID- 25702743 TI - Building surgical capacity in developing countries: lessons from Haiti and Honduras. AB - The unmet burden of surgical disease in developing countries is large and growing. We successfully initiated two surgical field hospitals in austere environments. Similar problems were encountered in the areas of facility development, operations, and social considerations. A literature review was performed to contextualize our experience and compare it with that of others. PMID- 25702744 TI - Health disparity intervention through minority collegiate service learning. AB - In Tennessee, African Americans suffer significantly from infant morbidity, sexually transmitted diseases, and deaths from vascular disease and cancer. The Meharry Medical College Wellness Project addresses these health disparities with a service learning curriculum focused on community-based research. Trained minority undergraduates have conducted 355 Institutional Review Board-approved community intervention projects statewide. PMID- 25702745 TI - Adapting chronic disease care for the underserved: innovations in the safety-net. AB - Safety-net hospitals are resource-constrained and serve complex patients yet are innovators in chronic disease care. Their strategies include personalized care, multidisciplinary teams, and information systems yielding real-time data. Safety net providers are prime examples from which the health care community can learn to improve the delivery of chronic disease care. PMID- 25702746 TI - A patient advocacy program established through an interprofessional student-run free clinic. AB - This report describes a student-run free clinic model that exposes medical, nursing, and social work students to interprofessional care of the underserved early in their training. As a result of a new partnership with social work students, a patient advocacy program was established, which helped patients apply for an expanded Medicaid program. PMID- 25702748 TI - Note from the editor. PMID- 25702749 TI - Socio-economic differences in predictors of frequent dairy food consumption among Australian adolescents: a longitudinal study. AB - OBJECTIVE: Sufficient dairy food consumption during adolescence is necessary for preventing disease. While socio-economically disadvantaged adolescents tend to consume few dairy foods, some eat quantities more in line with dietary recommendations despite socio-economic challenges. Socio-economic variations in factors supportive of adolescents' frequent dairy consumption remain unexplored. The present study aimed to identify cross-sectional and longitudinal associations between intrapersonal, social and environmental factors and adolescents' frequent dairy consumption at baseline and two years later across socio-economic strata, and to examine whether socio-economic position moderated observed effects. DESIGN: Online surveys completed at baseline (2004-2005) and follow-up (2006 2007) included a thirty-eight-item FFQ and questions based on social ecological models examining intrapersonal, social and environmental dietary influences. SETTING: Thirty-seven secondary schools in Victoria, Australia. SUBJECTS: Australian adolescents (n 1201) aged 12-15 years, drawn from a sub-sample of 3264 adolescents (response rate=33%). RESULTS: While frequent breakfast consumption was cross-sectionally associated with frequent dairy consumption among all adolescents, additional associated factors differed by socio-economic position. Baseline dairy consumption longitudinally predicted consumption at follow-up. No further factors predicted frequent consumption among disadvantaged adolescents, while four additional factors were predictive among advantaged adolescents. Socio economic position moderated two predictors; infrequently eating dinner alone and never purchasing from school vending machines predicted frequent consumption among advantaged adolescents. CONCLUSIONS: Nutrition promotion initiatives aimed at improving adolescents' dairy consumption should employ multifactorial approaches informed by social ecological models and address socio-economic differences in influences on eating behaviours; e.g., selected intrapersonal factors among all adolescents and social factors (e.g., mealtime rules) among advantaged adolescents. PMID- 25702750 TI - Thermodynamic description of Beta amyloid formation using physicochemical scales and fractal bioinformatic scales. AB - Protein function depends on both protein structure and amino acid (aa) sequence. Here we show that modular features of both structure and function can be quantified economically from the aa sequences alone for the small (40,42 aa) plaque-forming (aggregative) amyloid beta fragments. Some edge and center features of the fragments are predicted. Bioinformatic scales based on beta strand formation propensities and the thermodynamically second order fractal hydropathicity scale based on evolutionary optimization (self-organized criticality) are contrasted with the standard first order physicochemical scale based on complete protein (water-air) unfolding. The results are consistent with previous studies of these physicochemical factors that show that aggregative properties, even of beta fragments, are driven primarily by near-equilibrium hydropathic forces. PMID- 25702751 TI - Ypt/Rab GTPases: principles learned from yeast. AB - Ypt/Rab GTPases are key regulators of all membrane trafficking events in eukaryotic cells. They act as molecular switches that attach to membranes via lipid tails to recruit their multiple downstream effectors, which mediate vesicular transport. Originally discovered in yeast as Ypts, they were later shown to be conserved from yeast to humans, where Rabs are relevant to a wide array of diseases. Major principles learned from our past studies in yeast are currently accepted in the Ypt/Rab field including: (i) Ypt/Rabs are not transport step specific, but are rather compartment specific, (ii) stimulation by nucleotide exchangers, GEFs, is critical to their function, whereas GTP hydrolysis plays a role in their cycling between membranes and the cytoplasm for multiple rounds of action, (iii) they mediate diverse functions ranging from vesicle formation to vesicle fusion and (iv) they act in GTPase cascades to regulate intracellular trafficking pathways. Our recent studies on Ypt1 and Ypt31/Ypt32 and their modular GEF complex TRAPP raise three exciting novel paradigms for Ypt/Rab function: (a) coordination of vesicular transport substeps, (b) integration of individual transport steps into pathways and (c) coordination of different transport pathways. In addition to its amenability to genetic analysis, yeast provides a superior model system for future studies on the role of Ypt/Rabs in traffic coordination due to the smaller proteome that results in a simpler traffic grid. We propose that different types of coordination are important also in human cells for fine-tuning of intracellular trafficking, and that coordination defects could result in disease. PMID- 25702752 TI - Intricate short-range ordering and strongly anisotropic transport properties of Li(1-x)Sn(2+x)As2. AB - A new ternary compound, Li(1-x)Sn(2+x)As2, 0.2 < x < 0.4, was synthesized via solid-state reaction of elements. The compound crystallizes in a layered structure in the R3m space group (No. 166) with Sn-As layers separated by layers of jointly occupied Li/Sn atoms. The Sn-As layers are comprised of Sn3As3 puckered hexagons in a chair conformation that share all edges. Li/Sn atoms in the interlayer space are surrounded by a regular As6 octahedron. Thorough investigation by synchrotron X-ray and neutron powder diffraction indicate no long-range Li/Sn ordering. In contrast, the local Li/Sn ordering was revealed by synergistic investigations via solid-state (6,7)Li NMR spectroscopy, HRTEM, STEM, and neutron and X-ray pair distribution function analyses. Due to their different chemical natures, Li and Sn atoms tend to segregate into Li-rich and Sn-rich regions, creating substantial inhomogeneity on the nanoscale. The inhomogeneous local structure has a high impact on the physical properties of the synthesized compounds: the local Li/Sn ordering and multiple nanoscale interfaces result in unexpectedly low thermal conductivity and highly anisotropic resistivity in Li(1 x)Sn(2+x)As2. PMID- 25702753 TI - Evidence that mutation accumulation does not cause aging in Saccharomyces cerevisiae. AB - The concept that mutations cause aging phenotypes could not be directly tested previously due to inability to identify age-related mutations in somatic cells and determine their impact on organismal aging. Here, we subjected Saccharomyces cerevisiae to multiple rounds of replicative aging and assessed de novo mutations in daughters of mothers of different age. Mutations did increase with age, but their low numbers, < 1 per lifespan, excluded their causal role in aging. Structural genome changes also had no role. A mutant lacking thiol peroxidases had the mutation rate well above that of wild-type cells, but this did not correspond to the aging pattern, as old wild-type cells with few or no mutations were dying, whereas young mutant cells with many more mutations continued dividing. In addition, wild-type cells lost mitochondrial DNA during aging, whereas shorter-lived mutant cells preserved it, excluding a causal role of mitochondrial mutations in aging. Thus, DNA mutations do not cause aging in yeast. These findings may apply to other damage types, suggesting a causal role of cumulative damage, as opposed to individual damage types, in organismal aging. PMID- 25702754 TI - Discourse bootstrapping: preschoolers use linguistic discourse to learn new words. AB - When children acquire language, they often learn words in the absence of direct instruction (e.g. 'This is a ball!') or even social cues to reference (e.g. eye gaze, pointing). However, there are few accounts of how children do this, especially in cases where the referent of a new word is ambiguous. Across two experiments, we test whether preschoolers (2- to 4-year-olds; n = 239) can learn new words by inferring the referent of a new word from the surrounding linguistic discourse. Across two experiments, we show that children as young as 2 can learn a new word from the linguistic discourse in which it appears. This suggests that children use the linguistic discourse in which a word appears to learn new words. PMID- 25702755 TI - Extracorporeal membrane oxygenation for inhospital cardiac arrests: the rise of the machines. PMID- 25702756 TI - Primary fluid bolus therapy for infection-associated hypotension in the emergency department. AB - OBJECTIVES: The physiological changes associated with fluid bolus therapy (FBT) for patients with infection-associated hypotension in the emergency department (ED) are poorly understood. We describe the physiological outcomes of FBT in the first 6 hours (primary FBT) for patients presenting to the ED with infection associated hypotension. METHODS: We studied 101 consecutive ED patients with infection and a systolic blood pressure (SBP)<100 mmHg who underwent FBT in the first 6 hours. RESULTS: We screened 1123 patients with infection and identified 101 eligible patients. The median primary FBT volume given was 1570 mL (interquartile range, 1000- 2490 mL). The average mean arterial pressure (MAP) did not change from admission to 6 hours in the whole cohort, or in patients who were hypotensive on arrival at the ED. However, the average MAP increased from its lowest value during the first 6 hours (66 mmHg [SD, 10 mmHg]) to its value at 6 hours (73 mmHg [SD, 12 mmHg]; P<0.001). The mean heart rate, body temperature, respiratory rate and plasma creatinine level decreased (P<0.05). In patients who were severely hypotensive (SBP<90 mmHg) on arrival at the ED, the MAP increased from 54 mmHg (SD, 8 mmHg) to 70 mmHg (SD, 14 mmHg) (P<0.001). At 6 hours, however, SBP was still <100 mmHg in 44 patients and <90 mmHg in 17 patients. When noradrenaline was used, in 10 patients, hypotension was corrected in all 10 and the MAP increased from 58 mmHg (SD, 9 mmHg) to 75 mmHg (SD, 13 mmHg). CONCLUSION: Among ED patients admitted to an Australian teaching hospital with infection, hypotension was uncommon. FBT for hypotension was limited in volumes given and failed to achieve a sustained SBP of >100 mmHg in 40% of cases. In contrast, noradrenaline therapy corrected hypotension in all patients who received it. PMID- 25702757 TI - Endotoxaemic myocardial dysfunction: the role of coronary driving pressure in subendocardial perfusion. AB - OBJECTIVE: To investigate the role of coronary driving pressure (CDP) in myocardial microcirculatory blood flow during sepsis. We hypothesised that in septic shock there is an impaired autoregulation of microcirculation, and blood flow is totally dependent on CDP. We analysed the effect of lipopolysaccharide (LPS)-induced shock on myocardial microcirculation, separating subendocardial and epicardial areas. We then studied the effect of CDP increases using noradrenaline (NOR) or metaraminol (Aramine [ARA]) on myocardial microcirculation and function, and we analysed the effect of volume infusion on CDP and myocardial function. DESIGN AND SETTING: Endotoxaemia was induced in male Wistar rats by an intraperitoneal injection of LPS 10 mg/kg. Animals were divided into a control (CT) group, an LPS-injected group, and an LPS-injected group treated with saline fluid, NOR or ARA. MAIN OUTCOME MEASURES: Ninety minutes later, a haemodynamic evaluation was performed. NOR or ARA were used to manage the mean arterial pressure (MAP) and CDP, and we inserted a catheter into the left ventricle to measure cardiac parameters. To measure blood flow in the myocardium and other organs, microspheres were introduced into the left ventricle using an infusion pump. RESULTS: After LPS treatment, left ventricular (LV) systolic function (dP/dt max) and diastolic function (dP/dt min) decreased by 34% and 15%, respectively, and load-independent indices (LV contractility in ejection phase and dP/dt max/end-diastolic volume) were reduced. The CDP was also reduced (by 58%) in the endotoxaemic rats. Myocardial blood flow was reduced (by 80%) in animals with an MAP<=65 mmHg. NOR increased the CDP (LPS, 38 mmHg [SEM, 2 mmHg]; LPS+NOR, 59 mmHg [SEM, 3 mmHg]) and microcirculatory perfusion (LPS, 2 mL/min/g tissue [SEM, 0.6 mL/min/g]; LPS+NOR, 6.2 mL/min/g [SEM, 0.8 mL/min/g]). ARA was also effective in improve microcirculation but saline volume infusion was ineffective in improving CDP or myocardial function. CDP showed a significant correlation with subendocardial blood flow. CONCLUSIONS: Myocardial blood flow in the LV subendocardium and the right ventricle decreases in endotoxaemic rats. Increasing CDP improves myocardial blood flow and function. Thus, in endotoxaemia, microcirculatory blood flow is pressure dependent, suggesting that it may be beneficial to treat patients with sepsis using a higher CDP. PMID- 25702758 TI - Sodium balance, not fluid balance, is associated with respiratory dysfunction in mechanically ventilated patients: a prospective, multicentre study. AB - BACKGROUND: Large positive sodium balances, independent of fluid balance, may lead to expanded extracellular fluid volumes and adverse clinical outcomes in the critically ill, including impaired oxygenation. OBJECTIVES: To estimate sodium and fluid balances in critically ill patients needing invasive mechanical ventilation (MV) for more than 48 hours and to evaluate the relationship between fluid balance, sodium balance and respiratory function (PaO2/FiO2 ratio and length of MV). DESIGN AND SETTING: A prospective, observational study of 50 patients on MV in four tertiary intensive care units. MAIN OUTCOME MEASURES: Daily sodium and fluid input and output, biochemistry, haemodynamic variables, oxygenation (PaO2/FiO2) and steroid and vasopressor administration were recorded for 3 days after study enrolment. Outcome data included the duration of invasive MV, ICU and hospital mortality and ICU and hospital lengths of stay. RESULTS: Fifty patients (33 men [66%]) with a mean age of 62.8 years (standard deviation, 14.6 years) and a median admission Acute Physiology and Chronic Health Evaluation III score of 82 (interquartile range [IQR], 61-99) were studied. By Day 3 after enrolment, the median cumulative fluid balance was 2668 mL (IQR, 875-3507 mL) and the cumulative sodium balance was +717 mmol (IQR, +422 to +958 mmol). Intravenous steroids and the presence of shock led to a lower daily sodium excretion (P=0.004 and P=0.01, respectively). A positive sodium balance was associated with a reduction in the next day's PaO2/FiO2 ratio (rho=-0.36, P=0.001) and an increased length of MV (linear regression analysis, P<0.01). The cumulative fluid balance was not associated with either parameter. CONCLUSIONS: The cumulative positive sodium balance, not the cumulative positive fluid balance, is associated with respiratory dysfunction and an increased length of MV. PMID- 25702759 TI - Overview of the study protocols and statistical analysis plan for the Saline versus Plasma-Lyte 148 for Intravenous Fluid Therapy (SPLIT) research program. AB - BACKGROUND: 0.9% saline is the most commonly used intravenous (IV) fluid in the world but recent data raise the possibility that, compared with buffered crystalloid fluids such as Plasma-Lyte 148, the administration of 0.9% saline might increase the risk of developing acute kidney injury. OBJECTIVE: To provide an overview of the study protocols and statistical analysis plan for the six studies making up the (0.9% Saline v Plasma-Lyte 148 for Intravenous Fluid Therapy (SPLIT) research program. METHODS: The SPLIT study consists of six integrated clinical trials, including a double-blind, cluster, randomised, double crossover study in intensive care unit patients, incorporating two nested studies within it; an open-label, before-and-after study in emergency department (ED) patients; a single-centre, double-blind, crossover trial in major surgical patients; and a randomised, double-blind study in ICU patients. All studies focus on biochemical and renal outcomes but will also provide preliminary data on patient-centred outcomes including inhospital mortality and requirements for dialysis. RESULTS AND CONCLUSION: The SPLIT study program will provide preliminary data on the comparative effectiveness of using 0.9% saline v Plasma Lyte 148 for IV fluid therapy in ED, surgical and ICU patients. PMID- 25702760 TI - Cortisol responses at baseline and after corticotropin in acute aneurysmal subarachnoid haemorrhage: a prospective study. AB - BACKGROUND: Measurements of total plasma cortisol (TPC) in the acute phase of aneurysmal subarachnoid haemorrhage (aSAH) have suggested a high incidence of adrenal insufficiency (AI). OBJECTIVE: To compare TPC and free plasma cortisol (FPC) measurements in acute aSAH and to assess whether rates of diagnosis of AI based on TPC and FPC criteria were discordant. METHODS: A prospective, observational study of 20 patients admitted within 7 days of aSAH to a tertiary intensive care unit. Cortisol binding globulin (CBG), TPC and FPC levels were measured at baseline, and cortisol profiles at 30 and 60 minutes after administration of 250_g corticotropin. RESULTS: Compared with controls, the mean baseline FPC (46 nmol/L [SD, 48 nmol/L] v 9 nmol/L [SD, 6 nmol/L], P<0.0001), and TPC (566 nmol/L [SD, 288 nmol/L] v 352 nmol/L [SD, 146 nmol/L], P=0.01) were significantly elevated with a greater proportional increase of FPC over TPC (6 v 1.2 times, P<0.0001). The relative increment of FPC compared with TPC in the patient group was 505% v 114% (P<0.0001) and in the control group was 662% v 145% (P<0.0001). The prevalence of AI, measured using TPC compared with FPC, was 30% v 0% (P=0.04). CONCLUSION: In the acute phase after aSAH, the FPC increase is fivefold greater than that of TPC. There is discordance between TPC and FPC responses to corticotropin. The prevalence of AI, as assessed by FPC measurements, is negligible. We advocate caution in the assessment of adrenal cortical function using measurements of TPC in this population. PMID- 25702761 TI - Efforts to Attenuate the Spread of Infection (EASI): a prospective, observational multicentre survey of ultrasound equipment in Australian emergency departments and intensive care units. AB - BACKGROUND AND OBJECTIVES: Ultrasound is a common and necessary part of acute care medicine, but may present an infection risk to patients secondary to transfer of infectious agents between patients. Our primary objective was to detect blood contamination on ultrasound equipment in emergency departments (EDs) and intensive care units. Secondary objectives included detection of microbial contamination and determination of factors associated with contamination. DESIGN AND SETTING: We tested ultrasound equipment used in five EDs and five ICUs for blood and microbial contamination, and collated and analysed contamination data using tables and multiple logistic regression. MAIN OUTCOME MEASURES AND RESULTS: We performed 109 tests for blood and 131 tests for microbial contamination, with 61% of samples testing positive for blood contamination (95% CI, 52%-71%) and 48% testing positive for microbiological contamination (95% CI, 40%-57%). Transducer leads and transducers had high blood contamination (88% and 57%, respectively) and microbiological contamination (62% and 46%, respectively). Equipment from ICUs was less likely to test positive (odds ratio, 0.55; 95% CI, 0.37-0.79). Only 51% of blood-contaminated samples were visibly stained, and visible staining was not associated with microbiological contamination (57%; P=1). CONCLUSION: Our results show significant contamination of ultrasound equipment, and that visual inspection of equipment is neither sufficient nor reliable in excluding contamination. Ultrasound equipment is a possible factor in the transmission of infectious diseases in EDs and ICUs. Guidelines must be formulated, disseminated and rapidly adopted to ensure the safety of the most acutely ill patients exposed to ultrasound procedures in acute care settings. PMID- 25702762 TI - Analysis of performance and predictors of success in the final fellowship examination of the College of Intensive Care Medicine. AB - OBJECTIVES: To analyse the performance and predictors of success in the final fellowship examination of the College of Intensive Care Medicine (CICM), and to compare the outcomes of international medical graduates (IMGs) attempting the CICM fellowship exam with those of local trainees, defined as those from Australia, New Zealand and Hong Kong (ANZ-HK). To compare the performance of IMGs from countries with comparable health care systems (CHS) with those from other countries (non-CHS). DESIGN, SETTING AND PARTICIPANTS: Analysis of six exam presentations collected prospectively between 2009 and 2011. MAIN OUTCOME MEASURES: Pass rates in the final fellowship exam. RESULTS: Between 2009 and 2011, 233 candidates presented to the exam 334 times, and 73% were IMGs. ANZ-HK trainees performed better at the exam (79% v 46%, P<0.0001). IMG trainees from CHS performed better than trainees from non-CHS (60% v 40%, P<0.01). Any candidate completing an ANZ primary exam performed better than non-ANZ primary candidates (74% v 41%, P<0.0001). IMG candidates successful at a postgraduate exam from a CHS country performed better than candidates from a non-CHS country (56% v 34%, P=0.005). The success rate of IMGs improved to 64% after obtaining an ANZ primary. Candidates taking the exam while working in an intensive care unit had a pass rate of 57% compared with 48% of candidates working in non-ICU posts (P=0.23). This was not statistically significant. CONCLUSIONS: A significant proportion of candidates appearing for the CICM fellowship examination are IMGs. Pass rates for trainees who have graduated from the ANZ- HK systems have a higher success rate in the fellowship examination. IMGs from a CHS country, or those who completed an ANZ primary have a much higher success rate compared with other IMGs. PMID- 25702763 TI - Automated electronic monitoring of circuit pressures during continuous renal replacement therapy: a technical report. AB - BACKGROUND: Automated electronic monitoring and analysis of circuit pressures during continuous renal replacement therapy (CRRT) has the potential to predict failure and allow intervention to optimise function. METHODS: Current CRRT machines can measure and store pressure readings for downloading into databases and for analysis. We developed a procedure to obtain such data at intervals of 1 minute and analyse them using the Prismaflex CRRT machine, and we present an example of such analysis. RESULTS: We obtained data on pressures obtained at intervals of 1 minute in a patient with acute kidney injury and sepsis treated with continuous haemofiltration at 2 L/hour of ultrafiltration and a blood flow of 200 mL/minute. Data analysis identified progressive increases in transmembrane pressure (TMP) and prefilter pressure (PFP) from time 0 until 33 hours or clotting. TMP increased from 104 mmHg to 313 mmHg and PFP increased from from 131 mmHg to 185 mmHg. Effluent pressure showed a progressive increase in the negative pressure applied to achieve ultrafiltration from 0 mmHg to -168 mmHg. The inflection point for such changes was also identified. Blood pathway pressures for access and return remained unchanged throughout. CONCLUSIONS: Automated electronic monitoring of circuit pressure during CRRT is possible and provides useful information on the evolution of circuit clotting. PMID- 25702764 TI - Intubation of child and infant manikins during resuscitation: does the Venner A.P. Advance video laryngoscope improve the performance of nurses? PMID- 25702765 TI - Central venous pressure is a stopping rule, not a target of fluid resuscitation. PMID- 25702766 TI - Review and practice guidelines for celiac disease in 2014. AB - Celiac disease, or gluten-sensitive enteropathy, is defined as a state of heightened immunologic responsiveness to ingested gluten (from wheat, barley, or rye) in genetically susceptible individuals. Ingestion of the offending proteins leads to inflammation and intestinal mucosal damage, which may result in a spectrum of gastrointestinal symptoms, nutritional abnormalities, and systemic complications ranging from anemia and osteoporosis to secondary autoimmunity and malignancy. The genetic influence in the pathogenesis of celiac disease is indicated by its familial occurrence. Celiac disease does not develop unless a person has alleles that encode for human leukocyte antigen DQ2 or DQ8 proteins. The clinical picture of celiac disease has changed considerably during the past 30 years. Diarrhea, which was the presenting symptom in > 90% of celiac disease patients before 1981, is now the chief complaint in < 40%. In contrast, the increased frequency of atypical celiac disease presentations, including anemia and bone disease, is revealed by the widespread availability of serologic testing. An association between celiac disease and autoimmune disorders, such as type 1 diabetes, autoimmune thyroid disease, and Sjogren's syndrome, has been well documented. The tissue transglutaminase immunoglobulin antibody and the endomysial immunoglobulin antibody are the most sensitive and specific serologic tests, respectively, for identifying individuals who need to undergo an intestinal biopsy. If the suspicion of celiac disease is high, intestinal biopsy should be pursued even if serologic tests are negative. The gold standard for the diagnosis of celiac disease is a small bowel biopsy showing villous atrophy. The treatment for celiac disease is lifelong adherence to a gluten-free diet (GFD). Despite the proven benefits of the GFD, it can be exceedingly difficult to completely avoid gluten-containing foods, and adherence to a GFD is estimated to be only 45% to 80%. PMID- 25702767 TI - The metabolic profile of lemon juice by proton HR-MAS NMR: the case of the PGI Interdonato Lemon of Messina. AB - We have studied by means of High Resolution Magic Angle Spinning Nuclear Magnetic Resonance (HR-MAS NMR) the metabolic profile of the famous Sicilian lemon known as 'Interdonato Lemon of Messina PGI'. The PGI Interdonato Lemon of Messina possesses high organoleptic and healthy properties and is recognised as one of the most nutrient fruits. In particular, some of its constituents are actively studied for their chemo-preventive and therapeutic properties. In this paper, we have determined by means of HR-MAS NMR spectroscopy the molar concentration of the main metabolites constituent the juice of PGI Interdonato Lemon of Messina in comparison with that of the not-PGI Interdonato Lemon of Turkey. Our aim is to develop an analytical technique, in order to determine a metabolic fingerprint able to reveal commercial frauds in national and international markets. PMID- 25702768 TI - High glucose-induced intestinal epithelial barrier damage is aggravated by syndecan-1 destruction and heparanase overexpression. AB - Syndecan-1 (Sdc1) and its endo-beta-D-glucuronidase heparanase (HPSE) are implicated in maintenance of intestinal epithelial barrier (IEB), but their alterations and roles in high-glucose/hyperglycaemia (HG) conditions have not been fully investigated. This study aimed to determine the expression pattern, the possible regulation mechanism of Sdc1 and HPSE in HG conditions, and their potential effects on IEB. Therefore, diabetic mice/cell models were developed, and tissue/serum samples, cell lysate and culture supernatants were harvested. The expression of Sdc1 and HPSE in control, HG and designated interventions groups were detected. Phosphorylations of mitogen-activated protein kinase signalling pathway (MAPK), the expressions of Occludin and ZO-1, and the levels of transepithelial electrical resistance (TEER) were measured and monitored. The results showed that in HG conditions, intestinal tissue and cellular Sdc1 were significantly decreased, but the expression of HPSE, and soluble Sdc1 in serum and culture supernatants were remarkably increased. Such alterations of Sdc1 and HPSE were associated with solely p38 MAPK activation, and were correlated with the reductions of Occludin, ZO-1 and TEER. Heparin (Sdc1 analogue) and SB203580 (a p38 MAPK inhibitor), instead of insulin, alleviated Sdc1 destruction and HPSE overexpression, and effectively prevented against the reductions of tight junctions and the abnormality of intestinal permeability in HG conditions. In conclusion, we confirm the unique alterations of Sdc1 and HPSE in HG conditions, and found their interactions with p38 MAPK activation and IEB. These indicate that Sdc1/HPSE modulation can be viewed as an important complementary treatment for relieving HG-induced gastrointestinal damage. PMID- 25702769 TI - A comprehensive evaluation of strip performance in multiple blood glucose monitoring systems. AB - Accurate self-monitoring of blood glucose is a key component of effective self management of glycemic control. Accurate self-monitoring of blood glucose results are required for optimal insulin dosing and detection of hypoglycemia. However, blood glucose monitoring systems may be susceptible to error from test strip, user, environmental and pharmacological factors. This report evaluated 5 blood glucose monitoring systems that each use Verio glucose test strips for precision, effect of hematocrit and interferences in laboratory testing, and lay user and system accuracy in clinical testing according to the guidelines in ISO15197:2013(E). Performance of OneTouch((r)) VerioVueTM met or exceeded standards described in ISO15197:2013 for precision, hematocrit performance and interference testing in a laboratory setting. Performance of OneTouch((r)) Verio IQTM, OneTouch((r)) Verio ProTM, OneTouch((r)) VerioTM, OneTouch((r)) VerioVueTM and Omni Pod each met or exceeded accuracy standards for user performance and system accuracy in a clinical setting set forth in ISO15197:2013(E). PMID- 25702770 TI - Ethnic differences in presentation and severity of alcoholic liver disease. AB - BACKGROUND: The frequency of alcoholic liver disease (ALD), including alcoholic steatosis, hepatitis, and cirrhosis, varies significantly by ethnicity. METHODS: With the goal to assess the role of ethnicity in determining the age of onset and severity of ALD and to compare the risk factors for its progression among ethnic groups, we conducted a retrospective chart review of all patients with ALD who were admitted or were followed as outpatients at University of California Davis Medical Center between 2002 and 2010. After excluding HBsAg- and HIV-positive subjects, we reviewed the charts of 791 patients with ALD including 130 with alcoholic fatty liver, 154 with alcoholic hepatitis, and 507 with alcoholic cirrhosis. RESULTS: When controlling for all variables in the model, Hispanic patients presented at significantly 4 to 10 years younger ages than White/Caucasian patients, in each of the 3 disease severity categories, and the results were confirmed after excluding HCV Ab-/RNA-positive subjects. There were more obese Hispanic patients than White/Caucasian patients, whereas the proportion of patients with hepatitis C was significantly greater in African American subjects with alcoholic hepatitis, and the proportion of patients with diabetes mellitus was significantly lower in White/Caucasian subjects than in Hispanic subjects with cirrhosis. The proportion of subjects with severe alcoholic hepatitis was similar in Hispanic and White/Caucasian patients, but lower in African American subjects. CONCLUSIONS: Ethnicity is a major factor affecting the age and severity of presentation of different subtypes of ALD. PMID- 25702771 TI - Metastatic cervical carcinoma of the jaw presenting as periapical disease. AB - AIM: To present a case report of a metastasis from cervical cancer to the maxilla, which was misdiagnosed as periapical disease and to caution clinicians that metastases could have a disguised clinical presentation that must be taken into account in the differential diagnosis of periapical disease in oncologic patients. SUMMARY: Although metastatic tumours of the jaws are uncommon, they may mimic benign inflammatory processes and reactive lesions. The ability of metastatic lesions to mimic periapical disease is discussed and a brief review of the literature is presented, emphasizing the importance of correct diagnosis to prevent delay in diagnosing cancer. Attention should therefore be given to the patient's medical history, especially of those with a previous history of cancer, and all dental practitioners should be aware of the possibility of metastases that may be confused with periapical disease. Finally, endodontists are well placed to recognize malignant and metastatic oral lesions during the initial clinical stages, given that their treatments are usually based on frequent dental appointments and long-term follow-ups. PMID- 25702772 TI - Bedaquiline. PMID- 25702773 TI - Screening for sub-threshold psychotic experiences and perceived need for psychological services. AB - AIM: Sub-threshold psychotic experiences (PEs) are common in the general population and may increase risk for psychological distress and psychosis onset, generating a need for effective community screening instruments. This study aimed to explore the utility of a brief, self-report, psychosis risk screening tool in predicting perceived need for psychological treatment among a non-clinical sample, above and beyond that accounted for by accompanying forms of psychopathology or trait neuroticism. METHODS: Construct validity, predictive validity and test-retest reliability of the brief, self-report questionnaire for screening putative prepsychotic states were determined among college students (N = 679). Multiple linear regression analyses were conducted to explore the relationship between PEs and perceived need for psychological services. RESULTS: With the exception of auditory perceptual disturbances, PEs were not significantly associated with one's need for services, or the belief from others that services are needed, after controlling for neuroticism, anxiety and depressive symptoms. Auditory perceptual disturbances were significantly associated with the perceived need for psychological services, even after accounting for these additional symptoms. CONCLUSIONS: These results confirm the usefulness of the psychosis risk screening tool in evaluating the presence of sub threshold PEs, particularly auditory perceptual disturbances. The relationship between other PEs and a perceived need for psychological services, however, was largely explained by the existence of neurotic traits and anxiety and depressive symptoms. Screening for auditory perceptual disturbances may be useful in identifying unmet clinical need among young adults. PMID- 25702774 TI - The regulation of oxytocin receptor gene expression during adipogenesis. AB - Although it has been reported that oxytocin stimulates lipolysis in adipocytes, changes in the expression of oxytocin receptor (OTR) mRNA in adipogenesis are still unknown. The present study aimed to investigate the expression of OTR mRNA during adipocyte differentiation and fat accumulation in adipocytes. OTR mRNA was highly expressed in adipocytes prepared from mouse adipose tissues compared to stromal-vascular cells. OTR mRNA expression was increased during the adipocyte differentiation of 3T3-L1 cells. OTR expression levels were higher in subcutaneous and epididymal adipose tissues of 14-week-old male mice compared to 7-week-old male mice. Levels of OTR mRNA expression were higher in adipose tissues at four different sites of mice fed a high-fat diet than in those of mice fed a normal diet. The OTR expression level was also increased by refeeding for 4 h after fasting for 16 h. Oxytocin significantly induced lipolysis in 3T3-L1 adipocytes. In conclusion, a new regulatory mechanism is demonstrated for oxytocin to control the differentiation and fat accumulation in adipocytes via activation of OTR as a part of the hypothalamic-pituitary-adipose axis. PMID- 25702775 TI - Predictors of engagement in postpartum weight self-management behaviours in the first 12 weeks after birth. AB - AIM: To explore factors that influence postpartum weight self-management behaviours. Transitions Theory and the Integrated Theory of Health Behaviour Change guided selection of variables. Transition conditions, level of patient activation and social facilitation were examined for association with postpartum weight self-management behaviours. BACKGROUND: Retention of pregnancy weight increases risk of overweight and obesity later in life. Little is known about what women do to self-manage return to pre-pregnant weight and how providers can influence their behaviours. DESIGN: Prospective, longitudinal, correlational. METHODS: Data collection occurred from March through October, 2013. One hundred and twenty-four women completed surveys during postpartum hospitalization; telephone interviews were completed by 91 women at 6 weeks and 66 women at 12 weeks. Standard and hierarchical multiple regression methods were used for analyses. RESULTS: Transition difficulty was negatively associated with patient activation and immediate postbirth patient activation was positively associated with eating behaviours at 6 weeks, eating behaviours at 12 weeks and physical activity at 12 weeks. Social support and social influence were not significant predictors in the regression models. CONCLUSION: Patients experiencing a difficult postpartum transition have lower activation levels; those less activated are less probably to engage in weight self-management behaviours in the 12 weeks following their baby's birth. Patient activation level should be considered in tailoring promotion of healthy postpartum weight management. PMID- 25702776 TI - In Vivo Characterization of Carotid Neointimal Hyperplasia by use of Optical Coherence Tomography: Before and After Cutting Balloon Angioplasty. AB - Optical coherence tomography (OCT) is a modern intravascular imaging modality that has the capability to provide detailed, in vivo characterization of the arterial wall and atherosclerotic plaque. The current understanding of the appearance of atherosclerotic plaque via OCT is largely based on coronary arterial studies where OCT information has been employed to guide therapeutic management and permits the immediate evaluation of percutaneous intervention. The clinical success of OCT in the coronary arteries has laid the foundation for investigation of the carotid artery and thus, stroke risk assessment. We report the novel use of OCT for tissue characterization of severe stenosis subsequent to carotid artery stenting (CAS), both before and after treatment with cutting balloon angioplasty. PMID- 25702777 TI - A single dose of erythropoietin reduces perioperative transfusions in cardiac surgery: results of a prospective single-blind randomized controlled trial. AB - BACKGROUND: We conducted a prospective single-blind randomized study to assess whether a single 80,000 IU dose of human recombinant erythropoietin (HRE), given just 2 days before cardiac surgery, could be effective in reducing perioperative allogeneic red blood cell transfusion (aRBCt). STUDY DESIGN AND METHODS: Six hundred patients presenting with preoperative hemoglobin (Hb) level of not more than 14.5 g/dL were randomly assigned to either HRE or control. The primary endpoint was the incidence of perioperative aRBCt. The secondary endpoints were mortality and the incidence of adverse events in the first 45 days after surgery, Hb level on Postoperative Day 4, and number of units of RBC transfusions in the first 4 days after surgery. RESULTS: A total of 17% (HRE) versus 39% (control) required transfusion (relative risk, 0.436; p<0.0005). After baseline Hb was controlled for, there was no difference in the incidence of aRBCt between HRE (0%) and control (3.5%) among the patients with baseline Hb of 13.0 g/dL or more, which included the nonanemic fraction of the study population. The mean (range) Hb level on Postoperative Day 4 was 10.2 (9.9-10.6) g/dL (HRE) versus 8.7 (8.5 9.2) g/dL (control; p<0.0005). The distribution of number of units transfused was shifted toward fewer units in HRE (p<0.0005). The all-cause mortality at 45 days was 3.00% (HRE) versus 3.33% (control). The 45-day adverse event rate was 4.33% (HRE) versus 5.67% (control; both p=NS). CONCLUSION: In anemic patients (Hb<13 g/dL), a single high dose of HRE administered 2 days before cardiac surgery is effective in reducing the incidence of aRBCt without increasing adverse events. PMID- 25702778 TI - Dynamic regulation of photosynthesis in Chlamydomonas reinhardtii. AB - Plants and algae have acquired the ability to acclimatize to ever-changing environments to survive. During photosynthesis, light energy is converted by several membrane protein supercomplexes into electrochemical energy, which is eventually used to assimilate CO2 . The efficiency of photosynthesis is modulated by many environmental factors, including temperature, drought, CO2 concentration, and the quality and quantity of light. Recently, our understanding of such regulators of photosynthesis and the underlying molecular mechanisms has increased considerably. The photosynthetic supercomplexes undergo supramolecular reorganizations within a short time after receiving environmental cues. These reorganizations include state transitions that balance the excitation of the two photosystems: qE quenching, which thermally dissipates excess energy at the level of the light-harvesting antenna, and cyclic electron flow, which supplies the increased ATP demanded by CO2 assimilation and the pH gradient to activate qE quenching. This review focuses on the recent findings regarding the environmental regulation of photosynthesis in model organisms, paying particular attention to the unicellular green alga Chlamydomonas reinhardtii, which offer a glimpse into the dynamic behavior of photosynthetic machinery in nature. PMID- 25702779 TI - Modeling the ComD/ComE/comcde interaction network using small angle X-ray scattering. AB - The ComD-ComE two-component system controls the competence state of Streptococcus pneumoniae via the phospho-regulation of ComE, which fluctuates between monomeric and dimeric states. We previously showed that the non-phosphorylatable ComE(D) (58A) mutant is monomeric in solution, whereas the ComE(D) (58E) active mimic mutant dimerizes via its REC domains. The crystal structure of ComE(D) (58A) revealed an asymmetric dimer that may represent the activated form of ComE. Here, we investigated the binding between the catalytic domain of ComD, ComE and the promoter region comcde, using small angle X-ray scattering. ComD(catdom) is a dimer that adapts two monomers of ComE, one on each side, placing (Com) (E) D58 residue in front of (Com) (D) H248, a location that is convenient for the intermolecular transfer reaction of the phosphoryl group. The LytTR, ComE(D) (58A) and ComE(D) (58E) complexed with comcde are composed of two protein molecules per DNA duplex. Modeling the complexes against small angle X-ray scattering data indicated that ComE(D) (58E) bound to comcde forms a compact dimer similar to the crystal structure, whereas ComE(D) (58A) -comcde adopts more than one conformation with or without dimer contacts. The various oligomeric states of ComE induce different bending angles of the promoter, which provides a mechanistic scenario for the activation of ComE: the phosphorylation of ComE forces additional bending of comcde, and the release of this bending strain on DNA via the disruption of the ComE dimer may signal the shut-off of the competence state. DATABASE: The molecular models and experimental SAXS data have been deposited on SASBDB (Small Angle Scattering Biological Data Bank) (see http://www.sasbdb.org/aboutSASBDB/) under the SAS codes SASDAA7, SASDAB7 and SASDAC7. PMID- 25702780 TI - Itraconazole as a continuous treatment for atopic dermatitis? A case report. PMID- 25702781 TI - An unusual case of strychnine poisoning. AB - Strychnine-related death has been described since the 19th century. This alkaloid was discovered in 1818. Historically, strychnine was used by the South-East Asian autochthones on their arrows. However, its production was modified by legislation, which was used to protect people against accidental intoxications. Here, we present the case of a 69-year-old man who was found dead at home. During the autopsy, we found a blue substance in the stomach. Toxicological analysis measured strychnine at 0.29 MUg/mL in the blood sample, which is a relatively low level in comparison with the results given in the literature. However, histologic examination and toxicological findings permitted the conclusion of strychnine poisoning. PMID- 25702782 TI - Like parent, like child? Development of prejudice and tolerance towards immigrants. AB - Although intergroup attitudes are assumed to develop due to the influence of parents, there is no longitudinal evidence supporting this claim. In addition, research on socialization of intergroup attitudes has omitted possible effects of adolescents on their parents. We also know little about the conditions under which intergroup attitudes are transmitted. This two-wave, 2 years apart, study of adolescents (N = 507) and their parents examined the relations between parents and adolescents' prejudice and tolerance from a longitudinal perspective. The study tested whether parental prejudice and tolerance would predict over-time changes in adolescents' attitudes and whether adolescents' prejudice and tolerance would elicit changes in parental attitudes. Additionally, it explored whether some of the effects would depend on perceived parental support. Results showed significant bidirectional influences between parents and adolescents' attitudes. In addition, adolescents who perceived their parents as supportive showed higher parent-adolescent correspondence in prejudice than youth with low parental support. These findings show that intergroup attitudes develop as a result of mutual influences between parents and adolescents. Hence, the unidirectional transmission model and previous research findings should be revisited. The results also suggest that parents' prejudice influence adolescents' attitudes to the extent that youth perceive their parents as supportive. PMID- 25702783 TI - Surgery for thumb (trapeziometacarpal joint) osteoarthritis. AB - BACKGROUND: Surgery is used to treat persistent pain and dysfunction at the base of the thumb when conservative management, such as splinting, or medical management, such as oral analgesics, is no longer adequate in reducing disability and pain. This is an update of a Cochrane Review first published in 2005. OBJECTIVES: To assess the effects of different surgical techniques for trapeziometacarpal (thumb) osteoarthritis. SEARCH METHODS: We searched the following sources up to 08 August 2013: CENTRAL (The Cochrane Library 2013, Issue 8), MEDLINE (1950 to August 2013), EMBASE (1974 to August 2013), CINAHL (1982 to August 2013), Clinicaltrials.gov (to August 2013) and World Health Organization (WHO) Clinical Trials Portal (to August 2013). SELECTION CRITERIA: Randomised controlled trials (RCTs) or quasi-RCTs where the intervention was surgery for people with thumb osteoarthritis. Outcomes were pain, physical function, quality of life, patient global assessment, adverse events, treatment failure or trapeziometacarpal joint imaging. We excluded trials that compared non-surgical interventions with surgery. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by the Cochrane Collaboration. Two review authors independently screened and included studies according to the inclusion criteria, assessed the risk of bias and extracted data, including adverse events. MAIN RESULTS: We included 11 studies with 670 participants. Seven surgical procedures were identified (trapeziectomy with ligament reconstruction and tendon interposition (LRTI), trapeziectomy, trapeziectomy with ligament reconstruction, trapeziectomy with interpositional arthroplasty (IA), Artelon joint resurfacing, arthrodesis and Swanson joint replacement).Most included studies had an unclear risk of most biases which raises doubt about the results. No procedure demonstrated any superiority over another in terms of pain, physical function, quality of life, patient global assessment, adverse events, treatment failure (re operation) or trapeziometacarpal joint imaging. One study demonstrated a difference in adverse events (mild-moderate swelling) between Artelon joint replacement and trapeziectomy with tendon interposition. However, the quality of evidence was very low due to a high risk of bias and imprecision of results.Low quality evidence suggests trapeziectomy with LRTI may not provide additional benefits or result in more adverse events over trapeziectomy alone. Mean pain (three studies, 162 participants) was 26 mm on a 0 to 100 mm VAS (0 is no pain) for trapeziectomy alone, trapeziectomy with LRTI reduced pain by a mean of 2.8 mm (95% confidence interval (CI) -9.8 to 4.2) or an absolute reduction of 3% (-10% to 4%). Mean physical function (three studies, 211 participants) was 31.1 points on a 0 to 100 point scale (0 is best physical function, or no disability) with trapeziectomy alone, trapeziectomy with LRTI resulted in sightly lower function scores (standardised mean difference 0.1, 95% CI -0.30 to 0.32), an equivalent to a worsening of 0.2 points (95% CI -5.8 to 6.1) on a 0 to 100 point scale (absolute decrease in function 0.03% (-0.83% to 0.88%)). Low quality evidence from four studies (328 participants) indicates that the mean number of adverse events was 10 per 100 participants for trapeziectomy alone, and 19 events per 100 participants for trapeziectomy with LRTI (RR 1.89, 95% CI 0.96 to 3.73) or an absolute risk increase of 9% (95% CI 0% to 28%). Low quality evidence from one study (42 participants) indicates that the mean scapho-metacarpal distance was 2.3 mm for the trapeziectomy alone group, trapeziectomy with LRTI resulted in a mean of 0.1 mm less distance (95% CI -0.81 to 0.61). None of the included trials reported global assessment, quality of life, and revision or re-operation rates.Low-quality evidence from two small studies (51 participants) indicated that trapeziectomy with LRTI may not improve function or slow joint degeneration, or produce additional adverse events over trapeziectomy and ligament reconstruction.We are uncertain of the benefits or harms of other surgical techniques due to the mostly low quality evidence from single studies and the low reporting rates of key outcomes. There was insufficient evidence to assess if trapeziectomy with LRTI had additional benefit over arthrodesis or trapeziectomy with IA. There was also insufficient evidence to assess if trapeziectomy with IA had any additional benefit over the Artelon joint implant, the Swanson joint replacement or trapeziectomy alone.We did not find any studies that compared any other combination of the other techniques mentioned above or any other techniques including a sham procedure. AUTHORS' CONCLUSIONS: We did not identify any studies that compared surgery to sham surgery and we excluded studies that compared surgery to non-operative treatments. We were unable to demonstrate that any technique confers a benefit over another technique in terms of pain and physical function. Furthermore, the included studies were not of high enough quality to provide conclusive evidence that the compared techniques provided equivalent outcomes. PMID- 25702785 TI - Artemisinin-naphthoquine for treating uncomplicated Plasmodium falciparum malaria. AB - BACKGROUND: The World Health Organization (WHO) recommends artemisinin-based combination therapy (ACT) for treating people with Plasmodium falciparum malaria. Five combinations are currently recommended, all administered over three days. Artemisinin-naphthoquine is a new combination developed in China, which is being marketed as a one-day treatment. Although shorter treatment courses may improve adherence, the WHO recommends at least three days of the short-acting artemisinin component to eliminate 90% P. falciparum parasites in the bloodstream, before leaving the longer-acting partner drug to clear the remaining parasites. OBJECTIVES: To evaluate the efficacy and safety of the artemisinin-naphthoquine combination for treating adults and children with uncomplicated P. falciparum malaria. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register; Cochrane Central Register of Controlled Trials (CENTRAL) published in The Cochrane Library; MEDLINE; EMBASE; and LILACS up to January 2015. We also searched the metaRegister of Controlled Trials (mRCT) using 'malaria' and 'arte* OR dihydroarte*' as search terms. SELECTION CRITERIA: Randomized controlled trials comparing artemisinin-naphthoquine combinations with established WHO-recommended ACTs for the treatment of adults and children with uncomplicated malaria due to P. falciparum. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for eligibility and risk of bias, and extracted data. We analysed primary outcomes in line with the WHO 'Protocol for assessing and monitoring antimalarial drug efficacy' and compared drugs using risk ratios (RR) and 95% confidence intervals (CI). Secondary outcomes were effects on gametocytes, haemoglobin, and adverse events. We assessed the quality of evidence using the GRADE approach. MAIN RESULTS: Four trials, enrolling 740 adults and children, met the inclusion criteria. Artemisinin-naphthoquine was administered as a single dose (two trials), as two doses given eight hours apart (one trial), and once daily for three days (one trial), and compared to three-day regimens of established ACTs. Three additional small pharmaceutical company trials have been carried out. We have requested the data but have not received a response from the company. Artemisinin-naphthoquine versus artemether lumefantrineIn three small trials from Benin, Cote d'Ivoire, and Papua New Guinea, both combinations had a very low incidence of treatment failure at Day 28, and there were no differences demonstrated in PCR-unadjusted, or PCR-adjusted treatment failure (three trials, 487 participants, low quality evidence). Only the single study from Papua New Guinea followed participants up to Day 42, and the number of treatment failures remained very low with both combinations (one trial, 186 participants, very low quality evidence). Artemisinin-naphthoquine versus dihydroartemisinin-piperaquineIn a single small trial from Indonesia, treatment failure at Day 28 and Day 42 was very low in both groups with no differences demonstrated (one trial, 144 participants, very low quality evidence). AUTHORS' CONCLUSIONS: The results of these few trials of artemisinin naphthoquine are promising, but further trials from multiple settings are required to reliably demonstrate the relative efficacy and safety compared to established ACTs. Future trials should be adequately powered to demonstrate non inferiority, and regimens incorporating three days of the artemisinin component are probably preferable to the one-day regimens. PMID- 25702786 TI - Large Individual Differences in Serum 25-Hydroxyvitamin D Response to Vitamin D Supplementation: Effects of Genetic Factors, Body Mass Index, and Baseline Concentration. Results from a Randomized Controlled Trial. AB - The main aim of the study was to determine the influence of genetic factors on the serum 25-hydroxyvitamin D response to vitamin D supplementation. The main outcome measure was an increase in serum 25-hydroxyvitamin D after vitamin D supplementation. The patients are part of a randomized controlled trial in individuals with prediabetes assigned to 20 000 IU of vitamin D3 per week or placebo for 12 months. A total of 484 subjects were included in the analyses and genotyped for single nucleotide polymorphisms in the DBP, DHCR7, CYP2R1, and CYP24A1 genes. Single nucleotide polymorphisms from all 4 selected genes were significantly related to baseline serum 25-hydroxyvitamin D concentrations with differences between major and minor homozygote genotypes ranging from 4.4 to 19.2 nmol/l. In the subjects given vitamin D, those with genotypes with the highest baseline 25-hydroxyvitamin D concentration also had the highest 25-hydroxyvitamin D concentration after 12 months, and the increase (delta) in 25-hydroxyvitamin D was significantly related to 3 of the single nucleotide polymorphisms. The increase in serum 25-hydroxyvitamin D was also higher in lean vs. obese subjects, and higher in those with low baseline 25-hydroxyvitamin D concentrations. When combining these 3 factors in a linear regression model, the predicted (and observed) difference in 25-hydroxyvitamin D increase between high and low responders to the supplementation was approximately 60 nmol/l. In conclusion, due to genetic, body mass, and baseline 25-hydroxyvitamin D differences, there are huge individual variations in the serum 25-hydroxyvitamin D response to vitamin D supplementation that could be of clinical importance. PMID- 25702787 TI - Epidermal growth factor receptor and AKT1 gene copy numbers by multi-gene fluorescence in situ hybridization impact on prognosis in breast cancer. AB - The epidermal growth factor receptor (EGFR)/PI3K/AKT signaling pathway aberrations play significant roles in breast cancer occurrence and development. However, the status of EGFR and AKT1 gene copy numbers remains unclear. In this study, we showed that the rates of EGFR and AKT1 gene copy number alterations were associated with the prognosis of breast cancer. Among 205 patients, high EGFR and AKT1 gene copy numbers were observed in 34.6% and 27.8% of cases by multi-gene fluorescence in situ hybridization, respectively. Co-heightened EGFR/AKT1 gene copy numbers were identified in 11.7% cases. No changes were found in 49.3% of patients. Although changes in EGFR and AKT1 gene copy numbers had no correlation with patients' age, tumor stage, histological grade and the expression status of other molecular makers, high EGFR (P = 0.0002) but not AKT1 (P = 0.1177) gene copy numbers correlated with poor 5-year overall survival. The patients with co-heightened EGFR/AKT1 gene copy numbers displayed a poorer prognosis than those with tumors with only high EGFR gene copy numbers (P = 0.0383). Both Univariate (U) and COX multivariate (C) analyses revealed that high EGFR and AKT1 gene copy numbers (P = 0.000 [U], P = 0.0001 [C]), similar to histological grade (P = 0.001 [U], P = 0.012 [C]) and lymph node metastasis (P = 0.046 [U], P = 0.158 [C]), were independent prognostic indicators of 5-year overall survival. These results indicate that high EGFR and AKT1 gene copy numbers were relatively frequent in breast cancer. Co-heightened EGFR/AKT1 gene copy numbers had a worse outcome than those with only high EGFR gene copy numbers, suggesting that evaluation of these two genes together may be useful for selecting patients for anti-EGFR-targeted therapy or anti-EGFR/AKT1-targeted therapy and for predicting outcomes. PMID- 25702788 TI - Variability in the reported energy, total fat and saturated fat contents in fast food products across ten countries. AB - OBJECTIVE: Fast foods are often energy dense and offered in large serving sizes. Observational data have linked the consumption of fast foods to an increased risk of obesity and related diseases. DESIGN: We surveyed the reported energy, total fat and saturated fat contents, and serving sizes, of fast-food items from five major chains across ten countries, comparing product categories as well as specific food items available in most countries. SETTING: MRC Human Nutrition Research, Cambridge, UK. SUBJECTS: Data for 2961 food and drink products were collected, with most from Canada (n 550) and fewest from the United Arab Emirates (n 106). RESULTS: There was considerable variability in energy and fat contents of fast foods across countries, reflecting both the portfolio of products and serving size variability. Differences in total energy between countries were particularly noted for chicken dishes (649-1197 kJ/100 g) and sandwiches (552 1050 kJ/100g). When comparing the same product between countries variations were consistently observed in total energy and fat contents (g/100 g); for example, extreme variation in McDonald's Chicken McNuggets with 12 g total fat/100 g in Germany compared with 21.1 g/100 g in New Zealand. CONCLUSIONS: These cross country variations highlight the possibility for further product reformulation in many countries to reduce nutrients of concern and improve the nutritional profiles of fast-food products around the world. Standardisation of serving sizes towards the lower end of the range would also help to reduce the risk of overconsumption. PMID- 25702789 TI - Factors associated with adherence to antiretroviral therapy among adolescents living with HIV/AIDS in low- and middle-income countries: a systematic review. AB - Adolescents living in low- and middle-income countries (LMICs) are disproportionately burdened by the global HIV/AIDS pandemic. Maintaining medication adherence is vital to ensuring that adolescents living with HIV/AIDS receive the benefits of antiretroviral therapy (ART), although this group faces unique challenges to adherence. Knowledge of the factors influencing adherence among people during this unique developmental period is needed to develop more targeted and effective adherence-promoting strategies. This systematic review summarizes the literature on quantitative observational studies examining correlates, including risk and resilience-promoting factors, of ART adherence among adolescents living with HIV/AIDS in LMICs. A systematic search of major electronic databases, conference-specific databases, gray literature, and reference lists of relevant reviews and documents was conducted in May 2014. Included studies examined relationships between at least one factor and ART adherence as an outcome and were conducted in primarily an adolescent population (age 10-19) in LMICs. The search identified 7948 unique citations from which 15 studies fit the inclusion criteria. These 15 studies identified 35 factors significantly associated with ART adherence representing a total of 4363 participants across nine different LMICs. Relevant studies revealed few consistent relationships between measured factors and adherence while highlighting potentially important themes for ART adherence including the impact of (1) adolescent factors such as gender and knowledge of serostatus, (2) family structure, (3) the burdensome ART regimens, route of administration, and attitudes about medication, and (4) health care and environmental factors, such as rural versus urban location and missed clinic appointments. Rates of adherence across studies ranged from 16% to 99%. This review identifies unique factors significantly related to ART adherence among adolescents living in LMICs. More research using longitudinal designs and rigorous measures of adherence is required in order to identify the range of factors influencing ART adherence as adolescents living with HIV/AIDS in LMICs grow into adulthood. PMID- 25702790 TI - Epidemiological investigation of a norovirus GII.4 Sydney outbreak in a China elder care facility. AB - An outbreak of norovirus GII.4/Sydney_2012 affected a China elder care facility in December 2012. A total of 39 elderly people and staff met the outbreak case definition. The attack rates in the elderly and the staff were 15.9% (31/195) and 23.2% (19/82), respectively, including 13 asymptomatic cases in the staff. The result of gene sequencing revealed that the outbreak was caused by norovirus GII.4 Sydney. The mode of transmission of this outbreak was proven to be person to-person. The first case (a self-cared elder) was affected outside the elder care facility and was not isolated after returning. Norovirus was transmitted via close contact among the self-cared elderly. Then, through service-related close contact, the attendants promoted the cross-transmission between the self-cared elderly and the nursed elderly. The virus was also spread among the staff via daily contact. In the elder care facility, the asymptomatic cases in the attendants played an important role in the transmission of norovirus, which deserves high attention. PMID- 25702791 TI - Emergence of Salmonella strain that produces IMP-1-type metallo-beta-lactamase in a Japanese patient. PMID- 25702792 TI - Molecular typing of Mycoplasma pneumoniae isolated from pediatric patients in Tokyo, Japan. PMID- 25702793 TI - Picornavirus-like cytopathic effects on RD-18S cell lines were induced by human coronavirus 229E not picornaviruses. PMID- 25702794 TI - Impact of population size on incidence of rubella and measles in comparison with that of other infectious diseases. PMID- 25702795 TI - Patient characteristics influencing the variability of distributed parameter based models in DCE-CT kinetic analysis. AB - Kinetic parameter variability may be sensitive to kinetic model choice, kinetic model implementation or patient-specific effects. The purpose of this study was to assess their impact on the variability of dynamic contrast-enhanced computed tomography (DCE-CT) kinetic parameters. A total of 11 canine patients with sinonasal tumours received high signal-to-noise ratio, test-double retest DCE-CT scans. The variability for three distributed parameter (DP)-based models was assessed by analysis of variance. Mixed-effects modelling evaluated patient specific effects. Inter-model variability (CVinter ) was comparable to or lower than intra-model variability (CVintra ) for blood flow (CVinter :[4-28%], CVintra :[28-31%]), fractional vascular volume (CVinter :[3-17%], CVintra :[16-19%]) and permeability-surface area product (CVinter :[5-12%], CVintra :[14-15%]). The kinetic models were significantly (P<0.05) impacted by patient characteristics for patient size, area underneath the curve of the artery and of the tumour. In conclusion, DP-based models demonstrated good agreement with similar differences between models and scans. However, high variability in the kinetic parameters and their sensitivity to patient size may limit certain quantitative applications. PMID- 25702796 TI - The sexual dimorphic association of cardiorespiratory fitness to working memory in children. AB - The present investigation examined the sexual dimorphic patterns of cardiorespiratory fitness to working memory in preadolescent children (age range: 7.7-10.9). Data were collected in three separate studies (Study 1: n = 97, 42 females; Study 2: n = 95, 45 females; Study 3: n = 84, 37 females). All participants completed a cardiorespiratory fitness assessment in addition to a specific measure of working memory (i.e. the operation span task, the n-back task, or the Sternberg task). Results from all three samples revealed that higher cardiorespiratory fitness levels were associated with better working memory performance only for males with no such relation observed for females. In addition, the sexually dimorphic pattern was selective for the most challenging working memory conditions in each task. Together, these findings reveal new evidence that cardiorespiratory fitness is selectively related to better working memory performance for male children. This investigation provides additional insight into how interventions aimed at improving fitness may influence cognitive development differentially among preadolescent children. PMID- 25702797 TI - Direct, indirect and pleiotropic effects of candidate genes on internalizing disorder psychopathology. AB - BACKGROUND: Twin studies of internalizing disorders suggest that their high co morbidity is partially explained by shared genetic risk. Few studies have investigated pleiotropic effects of well-validated candidate genes across phenotypes. METHOD: Subjects were 928 Caucasian patients who presented to an out patient clinic specializing in the assessment and treatment of anxiety and mood disorders. We constructed latent dimensional phenotypes across the internalizing spectrum (neuroticism, extraversion, depression, generalized anxiety, panic/agoraphobia, social phobia, post-traumatic stress, and obsessions compulsions) by combining diagnostic criteria with other clinical indicators. We selected multiple variants in four evidence-based candidate genes (SLC6A4, COMT, GAD1, RGS2) with previously reported effects on several of these phenotypes. We conducted genetic association testing of their direct and indirect effects as well as gene * stress interactions (G * E). RESULTS: We detected 19 nominally significant main effect associations for the 10 polymorphisms tested among the eight phenotypes (24%). These were generally phenotype non-specific, showing pleiotropic effects across multiple domains. The majority of observed sharing was between depression, panic disorder, and post-traumatic stress disorder. Some of these were best explained by mediational models in which genes increase liability for disorders indirectly via their effects on temperament. Limited G * E effects were detected between variants in SLC6A4 and both panic/agoraphobia and post traumatic stress. CONCLUSIONS: Examining just a few candidate genes for their potential roles in internalizing phenotypes, we found moderate support for the shared effects of several polymorphisms. These findings highlight the richness and complexity by which genes potentially contribute to psychopathology via pleiotropy, moderation by stress, and mediation by temperament. PMID- 25702798 TI - Silencing efficacy prediction: a retrospective study on target mRNA features. AB - Post-transcriptional gene silencing is a widely used method to suppress gene expression. Unfortunately only a portion of siRNAs do successfully reduce gene expression. Target mRNA secondary structures and siRNA-mRNA thermodynamic features are believed to contribute to the silencing activity. However, there is still an open discussion as to what determines siRNA efficacy. In this retrospective study, we analysed the target accessibility comparing very high (VH) compared with low (L) efficacy siRNA sequences obtained from the siRecords Database. We determined the contribution of mRNA target local secondary structures on silencing efficacy. Both the univariable and the multivariable logistic regression evidenced no relationship between siRNA efficacy and mRNA target secondary structures. Moreover, none of the thermodynamic and sequence base parameters taken into consideration (H-b index, DeltaG degrees overall, DeltaG degrees duplex, DeltaG degrees break-target and GC%) was associated with siRNA efficacy. We found that features believed to be predictive of silencing efficacy are not confirmed to be so when externally evaluated in a large heterogeneous sample. Although it was proposed that silencing efficacy could be influenced by local target accessibility we show that this could be not generalizable because of the diversity of experimental setting that may not be representative of biological systems especially in view of the many local protein factors, usually not taken into consideration, which could hamper the silencing process. PMID- 25702799 TI - Asthma in pregnancy: Physiology, diagnosis, and management. AB - Asthma is a common, potentially serious, medical condition that affects an estimated 8% of pregnant patients, with 4% of all pregnant patients experiencing an exacerbation in the past year. Practitioners must be able to diagnose, educate, and treat such patients as they undergo significant physiological and immunologic change. But staying current can be challenging given over 3000 citations for "asthma and pregnancy" in a recent PubMed search, with 750 described as review articles. Patients have even more difficulty navigating information, with 29 million Google search results for this same query and 1.2 million alone for the question whether asthma medications are safe during pregnancy. This review provides brief answers to important management questions followed by supporting background literature. PMID- 25702800 TI - Genome modification leads to phenotype reversal in human myotonic dystrophy type 1 induced pluripotent stem cell-derived neural stem cells. AB - Myotonic dystrophy type 1 (DM1) is caused by expanded CTG repeats in the 3' untranslated region (3' UTR) of the DMPK gene. Correcting the mutation in DM1 stem cells would be an important step toward autologous stem cell therapy. The objective of this study is to demonstrate in vitro genome editing to prevent production of toxic mutant transcripts and reverse phenotypes in DM1 stem cells. Genome editing was performed in DM1 neural stem cells (NSCs) derived from human DM1 induced pluripotent stem (iPS) cells. An editing cassette containing SV40/bGH polyA signals was integrated upstream of the CTG repeats by TALEN-mediated homologous recombination (HR). The expression of mutant CUG repeats transcript was monitored by nuclear RNA foci, the molecular hallmarks of DM1, using RNA fluorescence in situ hybridization. Alternative splicing of microtubule associated protein tau (MAPT) and muscleblind-like (MBNL) proteins were analyzed to further monitor the phenotype reversal after genome modification. The cassette was successfully inserted into DMPK intron 9 and this genomic modification led to complete disappearance of nuclear RNA foci. MAPT and MBNL 1, 2 aberrant splicing in DM1 NSCs were reversed to normal pattern in genome-modified NSCs. Genome modification by integration of exogenous polyA signals upstream of the DMPK CTG repeat expansion prevents the production of toxic RNA and leads to phenotype reversal in human DM1 iPS-cells derived stem cells. Our data provide proof-of principle evidence that genome modification may be used to generate genetically modified progenitor cells as a first step toward autologous cell transfer therapy for DM1. PMID- 25702801 TI - Lipocalin-2 released in response to cerebral ischaemia mediates reperfusion injury in mice. AB - Thrombolysis remains the only effective therapy to reverse acute ischaemic stroke. However, delayed treatment may cause serious complications including hemorrhagic transformation and reperfusion injury. The level of lipocalin-2 (LCN2) is elevated in the plasma of ischaemic stroke patients, but its role in stroke is unknown. Here, we show that LCN2 was acutely induced in mice after ischaemic stroke and is an important mediator of reperfusion injury. Increased levels of LCN2 were observed in mouse serum as early as 1 hr after transient middle cerebral artery occlusion (tMCAO), reaching peak levels at 23 hrs. LCN2 was also detected in neutrophils infiltrating into the ipsilateral hemisphere, as well as a subset of astrocytes after tMCAO, but not in neurons and microglia. Stroke injury, neurological deficits and infiltration of immune cells were markedly diminished in LCN2 null mice after tMCAO, but not after permanent MCAO (pMCAO). In vitro, recombinant LCN2 protein induced apoptosis in primary cultured neurons in a dose-dependent manner. Our results demonstrate that LCN2 is a neurotoxic factor secreted rapidly in response to cerebral ischaemia, suggesting its potential usage as an early stroke biomarker and a novel therapeutic target to reduce stroke-reperfusion injury. PMID- 25702802 TI - 'Women are supposed to be the leaders': intersections of gender, race and colonisation in HIV prevention with Indigenous young people. AB - Focusing on gender, race and colonialism, this paper foregrounds the voices of Indigenous young people, their histories of oppression, their legacies of resistance and the continuing strengths rooted in Indigenous peoples, their cultures and their communities. Exploring the relationship between gender and colonialism, the paper speaks to the lived realities of young people from Indigenous communities across Canada. Over 85 young people participated in six different Indigenous community workshops to create artistic pieces that explored the connections between HIV, individual risk and structural inequalities. In the course of the research, Indigenous young people, and young Indigenous women in particular, talked about how gender intersects with race and colonisation to create experiences that are, at times, especially difficult for them. In this paper, young people discuss the ways in which colonialism has demeaned women's roles and degraded women's sexuality, and how continuing cultural erasure and assimilationist policies impact on their lives and on their bodies. PMID- 25702803 TI - Novel sequence types of non-O157 Shiga toxin-producing Escherichia coli isolated from cattle. AB - The objective of this study was to assess the genetic diversity of non-O157 Shiga toxin-producing Escherichia coli (STEC) isolates from cattle. Multi-locus sequence typing (MLST) was used to identify and compare the sequence types (STs) of 43 non-O157 STEC cattle isolates using the EcMLST database curated by the STEC Center at Michigan State University. For the 43 isolates, 19 STs were identified and 10 of those STs were novel compared to those in EcMLST. For the 43 isolates, 19 different serotypes were identified. STEC O22:H8, O174:H28 and O8:H19 were most common, and STEC O8 isolates were the most diverse, with seven different STs for isolates with that O group. STEC strains with O types identified in this study have been isolated from cattle by other researchers, as well as from cases of human gastroenteritis. Of the 10 novel STs identified, six were found to be closely related to previously identified STs, indicating that populations of non O157 STEC in cattle are similar to those from other sources, including human clinical cases. Significance and impact of the study: The foodborne pathogen Shiga toxin-producing Escherichia coli (STEC) is a significant public health concern. One of the main reservoirs for STEC are cattle, which can directly or indirectly contribute to STEC in the food supply. The genetic subtype data presented here highlight the diversity of STEC that can be isolated from cattle. These results further our understanding of the ecology of STEC in the primary production environment, which is important for developing effective control measures to reduce this pathogen in the food supply. PMID- 25702805 TI - Butyrolactones derivatives from the fermentation products of a plant entophytic fungus Penicillium oxalicum. AB - Two new butyrolactone derivatives, terrelactones A and B (1 and 2), together with four known butyrolactone derivatives (3-6), were isolated from the fermentation products of the fungus Penicillium oxalicum 0403. Their structures were elucidated by spectroscopic methods, including extensive 1D and 2D NMR techniques. The anti-tobacco mosaic virus (anti-TMV) activities of 1 and 2 were evaluated. The results showed that compounds 1 and 2 exhibited high anti-TMV activity with inhibition rates of 25.5% and 27.4%, respectively. The inhibition rate is close to that of positive control (28.9%). PMID- 25702806 TI - Electrical impedance myography in Duchenne muscular dystrophy and healthy controls: A multicenter study of reliability and validity. AB - INTRODUCTION: Electrical impedance myography (EIM) is a non-invasive, painless, objective technique to quantify muscle pathology. METHODS: We measured EIM in 8 arm and leg muscles in 61 boys with Duchenne muscular dystrophy (DMD) and 31 healthy boys, ages 3-12 years, at 5 centers. We determined the reliability of EIM and compared results in boys with DMD to controls and to 6-minute walk distance (6MWD), North Star Ambulatory Assessment (NSAA), timed functional tests (TFTs), and strength (hand-held dynamometry). RESULTS: EIM was well tolerated and had good inter- and intrarater reliability (intraclass correlation coefficient 0.81 0.96). The averaged EIM phase value from all muscles was higher (P < 0.001) in controls (10.45 +/- 2.29) than boys with DMD (7.31 +/- 2.23), and correlated (P <= 0.001) with 6MWD (r = 0.55), NSAA (r = 0.66), TFTs (r = -0.56), and strength (r = 0.44). CONCLUSION: EIM is a reliable and valid measure of disease severity in DMD. Longitudinal studies comparing EIM with other assessments over time in DMD are warranted. PMID- 25702807 TI - USP30: a new promising target for Parkinson's disease? PMID- 25702815 TI - [Oral immunotherapy in food allergy: present and future]. PMID- 25702814 TI - Nanomolar inhibitors of the transcription factor STAT5b with high selectivity over STAT5a. AB - Src homology 2 (SH2) domains play a central role in signal transduction. Although many SH2 domains have been validated as drug targets, their structural similarity makes development of specific inhibitors difficult. The cancer-relevant transcription factors STAT5a and STAT5b are particularly challenging small molecule targets because their SH2 domains are 93% identical on the amino acid level. Here we present the natural product-inspired development of the low nanomolar inhibitor Stafib-1, as the first small molecule which inhibits the STAT5b SH2 domain (K(i)=44 nM) with more than 50-fold selectivity over STAT5a. The binding site of the core moiety of Stafib-1 was validated by functional analysis of point mutants. A prodrug of Stafib-1 was shown to inhibit STAT5b with high selectivity over STAT5a in tumor cells. Stafib-1 provides the first demonstration that naturally occurring SH2 domains with more than 90% sequence identity can be selectively targeted with small organic molecules. PMID- 25702816 TI - [Recommendations for the prevention of poisoning]. AB - Poisoning is the fifth leading cause of death from unintentional injury in the WHO European region, while Spain is in the group with a lower rate. Most involuntary poisonings occur in young children while they are at the home, due to unintentional ingestion of therapeutic drugs or household products. Of these, a large percentage is stored in non-original containers and/or within reach of children. In this article, the Committee on Safety and Non-Intentional Injury Prevention in Childhood of the Spanish Association of Pediatrics provides a series of recommendations, educational as well as legal, to prevent such cases. PMID- 25702817 TI - Platelet-rich plasma enhances the differentiation of dental pulp progenitor cells into odontoblasts. AB - AIM: To investigate the effects of PRP on odontoblastic differentiation using dental pulp progenitor cells derived from the dental papilla of rat incisors. METHODOLOGY: Monolayer cultures of odontoblastic lineage KN-3 cells were incubated with PRP for various time periods. The expression of dentine sialophosphoprotein (DSPP) and dentine matrix protein-1 (DMP-1) was determined using real-time reverse transcription-polymerase chain reaction and Western blot analyses. To further clarify the role of PRP in odontogenesis, KN-3 cells were stimulated with PRP in the presence of ascorbic acid and beta-glycerophosphate. The cells were stained for alkaline phosphatase (ALP), and ALP activity was quantified in cell lysates. The formation of mineralized nodules was assessed by alizarin red staining. Statistical analysis was performed by one-way analysis of variance. RESULTS: PRP increased the mRNA and protein expressions of odontoblastic markers, such as DSPP and DMP-1. Furthermore, PRP stimulated the ALP activity and mineralized nodule formation induced by ascorbic acid and beta glycerophosphate in a time-dependent manner. CONCLUSIONS: PRP enhances odontoblastic differentiation of KN-3 cells. These results indicate that PRP could be a potential candidate for use in the regeneration of dentine-pulp complex. PMID- 25702818 TI - Economic and clinical benefits of radiofrequency ablation versus hysterectomy in patients suffering from menorrhagia: a retrospective analysis with German health claims data. AB - OBJECTIVE: To assess clinical and economic benefits of radiofrequency ablation (RFA) compared to hysterectomy when treating patients suffering from menorrhagia. METHODS: Based on German health claims data, a retrospective, longitudinal, observational analysis was performed. Patients having continuously statutory health insurance coverage during the study and being coded for menorrhagia and a relevant treatment option were included in the analysis. The control group was created using propensity score matching. RESULTS: We discovered that using RFA generates cost savings of ?1844 during the quarter of performance. As direct costs during a 2-year follow-up show similar levels in both groups, these initial savings can be preserved. This is partly because even if more patients in the RFA group were re-coded for menorrhagia after initial therapy, just a small proportion of these patients required another surgical intervention. CONCLUSION: RFA should more often be considered a relevant treatment option both from an economic and a medical point of view. PMID- 25702819 TI - CYP2B6*6 allele and age substantially reduce steady-state ketamine clearance in chronic pain patients: impact on adverse effects. AB - AIMS: Ketamine analgesia is limited by low intrinsic efficacy compounded by large interindividual variability in drug responses, possibly due to the heterogeneity in drug concentration. The CYP2B6*6 allele is associated with substantially reduced ketamine metabolism in vitro and, therefore, may affect ketamine clearance. Our aims were to examine the impact of the CYP2B6*6 allele on ketamine plasma clearance and on adverse effects in chronic pain patients. METHODS: CYP2B6 genotypes were identified in 49 chronic pain patients who received 24 h continuous subcutaneous infusions of ketamine. Steady-state plasma concentrations of ketamine (Css,k ) and norketamine (Css,nk ) were determined using HPLC. RESULTS: The median plasma clearance of ketamine after 100 mg 24 h(-1) dose was significantly lower in patients with the CYP2B6*6/*6 (21.6 l h(-1) ) and CYP2B6*1/*6 (40.6 l h(-1) ) genotypes compared with patients with the CYP2B6*1/*1 genotype (68.1 l h(-1) , P < 0.001). The ketamine : norketamine plasma metabolic ratio was significantly higher in patients with the CYP2B6*6/*6 genotype than in those with the CYP2B6*1/*6 and the CYP2B6*1/*1 genotypes (P < 0.001). Patients who experienced adverse effects had lower plasma clearance (45.6 l h(-1) ) than those who did not (52.6 l h(-1) , P = 0.04). The CYP2B6*6 genotype and age, and their combined impact explained 40%, 30% and 60% of the variation in Css,k , respectively. Similar results were observed after higher doses. CONCLUSIONS: The CYP2B6*6 allele is associated with a substantial decrease in steady-state ketamine plasma clearance in chronic pain patients. The decreased clearance and resultant higher plasma concentrations may be associated with a higher incidence of ketamine adverse effects. PMID- 25702821 TI - Measuring Healthcare Providers' Performances Within Managed Competition Using Multidimensional Quality and Cost Indicators. AB - BACKGROUND AND OBJECTIVES: The Dutch healthcare system is in transition towards managed competition. In theory, a system of managed competition involves incentives for quality and efficiency of provided care. This is mainly because health insurers contract on behalf of their clients with healthcare providers on, potentially, quality and costs. The paper develops a strategy to comprehensively analyse available multidimensional data on quality and costs to assess and report on the relative performance of healthcare providers within managed competition. DATA AND METHODS: We had access to individual information on 2409 clients of 19 Dutch diabetes care groups on a broad range of (outcome and process related) quality and cost indicators. We carried out a cost-consequences analysis and corrected for differences in case mix to reduce incentives for risk selection by healthcare providers. RESULTS AND CONCLUSION: There is substantial heterogeneity between diabetes care groups' performances as measured using multidimensional indicators on quality and costs. Better quality diabetes care can be achieved with lower or higher costs. Routine monitoring using multidimensional data on quality and costs merged at the individual level would allow a systematic and comprehensive analysis of healthcare providers' performances within managed competition. PMID- 25702820 TI - Histone acetylation inhibitors promote axon growth in adult dorsal root ganglia neurons. AB - Intrinsic mechanisms that guide damaged axons to regenerate following spinal cord injury remain poorly understood. Manipulation of posttranslational modifications of key proteins in mature neurons could reinvigorate growth machinery after injury. One such modification is acetylation, a reversible process controlled by two enzyme families, the histone deacetylases (HDACs) and the histone acetyl transferases (HATs), acting in opposition. Whereas acetylated histones in the nucleus are associated with upregulation of growth-promoting genes, deacetylated tubulin in the axoplasm is associated with more labile microtubules, conducive to axon growth. This study investigates the effects of HAT and HDAC inhibitors on cultured adult dorsal root ganglia (DRG) neurons and shows that inhibition of HATs by anacardic acid or CPTH2 improves axon outgrowth, whereas inhibition of HDACs by TSA or tubacin inhibits axon growth. Anacardic acid increased the number of axons able to cross an inhibitory chondroitin sulfate proteoglycan border. Histone acetylation but not tubulin acetylation level was affected by HAT inhibitors, whereas tubulin acetylation levels were increased in the presence of the HDAC inhibitor tubacin. Although the microtubule-stabilizing drug taxol did not have an effect on the lengths of DRG axons, nocodazole decreased axon lengths. Determining the mechanistic basis will require future studies, but this study shows that inhibitors of HAT can augment axon growth in adult DRG neurons, with the potential of aiding axon growth over inhibitory substrates produced by the glial scar. PMID- 25702822 TI - Morphology-controlled self-assembly of an organic/inorganic hybrid porphyrin derivative containing polyhedral oligomeric silsesquioxane (POSS). AB - An organic/inorganic hybrid porphyrin derivative, namely, metal-free tetrakisphenyl porphyrin-polyhedral oligomeric silsesquioxanes (H2 TPP-POSS) was synthesized by azide-alkyne click chemistry. The self-assembly behavior of H2 TPP POSS was systematically studied in CHCl3 at different concentrations and in solvents with different polarities. Novel nanovesicles could be obtained through the self-assembly of H2 TPP-POSS in CHCl3 at a concentration lower than 10(-4) m. Diffuse microrods formed at a concentration higher than 10(-4) M. Additionally, the polarity of the solvent also greatly influenced the assembled morphologies, and a series of assembled morphologies, including crescent-shaped micelles, spherical micelles, doughnut-shaped vesicles, and ordered square sheets, could form in solvents with different polarities. PMID- 25702823 TI - A qualitative study of older and middle-aged adults' perception and attitudes towards dementia and dementia risk reduction. AB - AIM: To investigate perceptions of dementia and dementia risk reduction held by people without dementia. BACKGROUND: Dementia does not only affect individuals with dementia, but also has an impact on family and friends, society and healthcare professionals. Recent research has identified modifiable risk and protective factors for dementia. However, it is unclear what knowledge people without dementia have about these risk factors and their attitudes towards addressing these risk factors to achieve dementia risk reduction are not known. DESIGN: Qualitative descriptive study using focus group methodology. METHOD: A focus group study was conducted in February 2011 with 34 older adults aged between 52-90 years. The long-table approach was used to identify themes and categorize data on dementia knowledge, risk and attitudes. FINDINGS: Participants correctly identified dementia risk factors as a group. Participants' responses about their perceived likelihood of developing dementia could be classified into three distinctive themes; fear, rational and cynical perceptions. Both fear of developing dementia and the need to improve dementia knowledge were considered major motivators towards adopting healthier lifestyle and health behaviours. Lack of knowledge on risk factors for dementia was identified as a major barrier for behavioural and lifestyle change. CONCLUSION: These findings can be used to develop effective and personalized interventions that increase motivators and reduce barriers by tailoring interventions to individual's dementia risk reduction literacy and motivations to change behaviours. Greater public-health promotion and education about risk and protective factors for dementia are also necessary to increase dementia health literacy and to reduce overall dementia prevalence. PMID- 25702824 TI - Early Blood Brain Barrier Changes in Acute Ischemic Stroke: A Sequential MRI Study. AB - BACKGROUND AND PURPOSE: We sought to identify MRI factors associated with BBB changes at the acute stage of ischemic stroke. METHODS: We analyzed BBB changes on admission and within 3 hours after the first scan. BBB changes was defined as the presence of leptomeningeal and parenchymal contrast enhancement on T1 weighted imaging. Tmax , CBV, and DWI lesion volume were assessed on baseline MRI. Clinical and MRI factors associated with BBB changes were assessed by univariate and multivariate logistic regressions analyses. RESULTS: Forty-four patients were included. BBB changes on baseline MRI was observed in 2 of 44 patients (3%). BBB disruption on H3-MRI was present in 19 of 44 patients (43%). Hemodynamic status and baseline ischemic core size were not different between patients with or without BBB changes. BBB alteration on H3 MRI was strongly associated with FLAIR MRI sequence positivity, 16/19 patients (83%) P = .001. CONCLUSION: BBB changes are exceptional during the first 3 hours after stroke onset. Delayed BBB alteration was associated with FLAIR positivity mainly reflecting vasogenic edema. PMID- 25702825 TI - Pedicled adipose tissue for treatment of chronic digital osteomyelitis. AB - PURPOSE: To describe a surgical technique (pedicled vascularized tissue transfer) for treating chronic digital osteomyelitis. METHODS: Adipose tissue was obtained at the level of the proximal phalanx based on anterograde or retrograde flow. After bone debridement, we inserted the vascularized adipose tissue into the dead space. Eight patients were treated with this procedure from 2009 to 2012. One patient had chronic osteomyelitis in the thumb, 4 in the index finger, 2 in the middle finger, and 1 in the ring finger. Foci of chronic osteomyelitis were located at the distal phalanx in 2 patients, at the distal to middle phalanx across the distal interphalangeal joint in 4, at the middle phalanx in 1, and at the proximal phalanx in 1. Mean duration of follow-up was 41 months. We assessed the efficacy of the technique by clinical symptoms and imaging. RESULTS: We used retrograde pedicled adipose tissue transfer in 7 patients and anterograde pedicled adipose tissue transfer in 1. The pedicled adipose tissue was successfully transferred from the digit tip to its base. The postoperative courses were uneventful; no additional treatments were required. Postoperative physical data and follow-up images showed no evidence of chronic osteomyelitis. No functional loss was caused by procuring vascularized adipose tissue from the digits. CONCLUSIONS: Pedicled vascularized tissue transfer based on the digital artery was a reliable and reproducible technique. We recommend it as a treatment option for chronic digital osteomyelitis. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 25702826 TI - Social media and suicide prevention: a systematic review. AB - AIM: Social media platforms are commonly used for the expression of suicidal thoughts and feelings, particularly by young people. Despite this, little is known about the ways in which social media can be used for suicide prevention. The aim of this study was to conduct a systematic review to identify current evidence pertaining to the ways in which social media are currently used as a tool for suicide prevention. METHODS: Medline, PsycInfo, Embase, CINHAL and the Cochrane Library were searched for articles published between 1991 and April 2014. English language articles with a focus on suicide-related behaviour and social media were included. No exclusion was placed on study design. RESULTS: Thirty studies were included; 4 described the development of social media sites designed for suicide prevention, 6 examined the potential of social media in terms of its ability to reach or identify people at risk of suicide, 15 examined the ways in which people used social media for suicide prevention-related purposes, and 5 examined the experiences of people who had used social media sites for suicide prevention purposes. No intervention studies were identified. CONCLUSION: Social media platforms can reach large numbers of otherwise hard-to engage individuals, may allow others to intervene following an expression of suicidal ideation online, and provide an anonymous, accessible and non-judgmental forum for sharing experiences. Challenges include difficulties controlling user behaviour and accurately assessing risk, issues relating to privacy and confidentiality and the possibility of contagion. Social media appears to hold significant potential for suicide prevention; however, additional research into its safety and efficacy is required. PMID- 25702827 TI - Taste discriminating capability to different bitter compounds by the larval styloconic sensilla in the insect herbivore Papilio hospiton (Gene). AB - Herbivorous animals may benefit from the capability to discriminate the taste of bitter compounds since plants produce noxious compounds, some of which toxic, while others are only unpalatable. Our goal was to investigate the contribution of the peripheral taste system in the discrimination of different bitter compounds by an herbivorous insect using the larvae of Papilio hospiton Gene as the experimental model, showing a narrow choice range of host plants. The spike activity from the lateral and medial styloconic sensilla, housing two and one bitter-sensitive gustatory receptor neurons (GRNs), respectively, was recorded following stimulation with nicotine, caffeine, salicin and quercitrin and the time course of the discharges was analyzed. Nicotine and caffeine activated all three bitter-sensitive GRNs, while salicin and quercitrin affected only two of them. In feeding behavior bioassays, intact larvae ate glass-fiber disks moistened with salicin and quercitrin, but rejected those with nicotine and caffeine, while lateral sensillum-ablated insects also ate the disks with the two latter compounds. The capability to discriminate bitter taste stimuli and the neural codes involved are discussed. PMID- 25702828 TI - The ejaculatory biology of leafcutter ants. AB - The eusocial ants are unique in that females (queens) acquire and store sperm on a single mating flight early in adult life. This event largely determines the size (possibly millions of workers), longevity (possibly decades) and genetic variation of the colonies that queens found, but our understanding of the fundamental biology of ejaculate production, transfer and physiological function remains extremely limited. We studied the ejaculation process in the leafcutter ant Atta colombica and found that it starts with the appearance of a clear pre ejaculatory fluid (PEF) at the tip of the endophallus that is followed by the joint expulsion of the remainder of accessory gland (AG) secretion, sperm, accessory testes (AT) secretion, and a small mating plug. PEF, AG secretion and AT secretion all contribute to sperm survival, but PEF and AG secretion also reduce the survival of sperm from other males. We show that PEF is produced in the AGs and is likely identical to AG secretion because protein-banding patterns of PEF and AG secretion were similar on 1D electrophoresis gels, but differed from the protein-banding pattern of AT secretion. We show that proteins in AG secretion are responsible for the incapacitation of rival sperm and infer that transfer of AG secretion prior to sperm may allow these components to interact with rival sperm, while at the same time providing a supportive biochemical environment for the arrival of own sperm. PMID- 25702829 TI - Designing new analogs for streamlining the structure of cytotoxic lamellarin natural products. AB - Despite the therapeutic potential of marine-derived lamellarin natural products, their preclinical development has been hampered by their lipophilic nature, causing very poor aqueous solubility. In order to develop more drug-like analogs, their structure was streamlined in this study from both the cytotoxic activity and lipophilicity standpoints. First, a modified total synthetic route was successfully devised to construct a library of 59 systematically designed lamellarin analogs, which were then subjected to cytotoxicity and log P determinations. Along with the 25 first-generation lamellarins previously synthesized in our laboratory, the structure-activity and structure-lipophilicity relationships were extensively evaluated. Our results clearly indicated the additional structural requirements around the lamellarin skeleton which, when combined with those reported previously, can provide invaluable guidance for further modifications to increase the aqueous solubility of these compounds. PMID- 25702830 TI - IgE responses to Ascaris and mite tropomyosins are risk factors for asthma. AB - BACKGROUND: The relationship between helminthiases and allergy is a matter of considerable interest and research. In the tropics, house dust mite exposure, a known risk factor for asthma, is frequently concurrent with helminth infections. It remains to be defined whether infection with the common roundworm Ascaris or its bystander immunological effects influence the prevalence and pathogenesis of asthma independently of mite sensitization. OBJECTIVE: To investigate the relationship between the IgE responses to Ascaris and its purified allergens and the risk of asthma in a tropical country. METHODS: A nested case-control study was performed in 356 subjects who reported current and past asthma symptoms (asthmatics) and 435 controls that had never experienced such symptoms. They were tested for serum levels of total IgE and specific IgE to Ascaris extract, Asc s 1 (ABA-1), Asc l 3 (tropomyosin) and GST (glutathione transferase). In addition, specific IgE to Dermatophagoides pteronyssinus, Blomia tropicalis and their tropomyosins Der p 10 and Blo t 10 was measured. Sensitization was defined as a positive specific IgE result to any extract or recombinant allergen. RESULTS: Sensitization to Ascaris and D. pteronyssinus was independently associated with asthma after adjustment for age, gender, socio-economic stratum, city and other IgE levels (adjusted ORs: 2.17; 95% CI 1.37-3.42 and 2.46; 95% CI 1.54-3.92), respectively. There was also a significant association with sensitization to the highly allergenic and cross-reactive tropomyosins Asc l 3, Blo t 10 and Der p10 (aORs: 1.76; 95% CI 1.21-2.57, 1.64; 95% CI 1.14-2.35 and 1.51; 95% CI 1.02 2.24), respectively. CONCLUSION AND CLINICAL RELEVANCE: IgE responses to Ascaris are associated with asthma symptoms in a population living in the tropics. Sensitization to the cross-reactive Ascaris and mite tropomyosins partially underlies this finding. These results have potential relevance in asthma diagnosis and management. PMID- 25702831 TI - Hydroxylated histidine of human ribosomal protein uL2 is involved in maintaining the local structure of 28S rRNA in the ribosomal peptidyl transferase center. AB - Protein uL2 is essential for the catalytic activity of the ribosome and has a conserved shape in ribosomes from all domains of life. However, the sequence of its unstructured C-terminal loop apex that contacts the conserved 23S/28S rRNA helix (H) 93 near the ribosomal peptidyl transferase center differs in bacteria, archaea and eukaryotes. Eukaryote-specific residue His216 located in this loop in mammalian uL2 is hydroxylated in ribosomes. We used a set of chemical probes to explore the structure of an RNA that mimicked a segment of 28S rRNA domain V containing part of the uL2 binding site including H93, complexed with either natural (hydroxylated) or recombinant (unmodified) human uL2. It was found that both protein forms engage H93 during binding, but only natural uL2 (uL2n) protects it from hydroxyl radicals. The association of uL2n with RNA leads to changes in its structure at U4532 adjacent to the universally conserved U4531 (U2585, Escherichia coli numbering) involved in peptidyl transferase center formation, and at the universally conserved C4447 (2501) located in the ribosome near A4397 (2451) and C3909 (2063) belonging to the peptidyl transferase center. As a result, both nucleotides become strongly exposed to hydroxyl radicals. Our data argue that the hydroxyl group at His216 in the C-terminal loop apex of mammalian uL2 contributes to stabilization of a protein conformation that is favorable for binding to H93 of 28S rRNA and that this binding induces structural rearrangement in the regions close to the peptidyl transferase center in the mature ribosome. PMID- 25702832 TI - Fat removal during cell salvage: a comparison of four different cell salvage devices. AB - BACKGROUND: Fat embolism is a possible risk factor for pulmonic and cerebral dysfunction after orthopedic and heart surgery. It is unknown whether fat occasionally observed during cell salvage adds to the risk of fat embolism after retransfusion. We have examined the fat removal capacities of different cell salvage devices including discontinuous and a continuous system under various conditions. STUDY DESIGN AND METHODS: In an experimental study ABO-matched banked blood was adjusted to a hematocrit of 20%, and 1.25% of human fat was added. This blood was processed with the cell salvage devices XTRA and Electa, CATS, or Cell Saver 5 plus. Fat in the blood samples was quantified by volumetric measurement after centrifugation in Pasteur pipettes and by gravimetric measurement after extraction of fat in organic solvents and phase partition. Performance in fat removal was tested with different programs, bowl sizes, and additional filtration. RESULTS: The continuous system consistently showed a high fat removal rate of 99.8 +/- 0.2%. Fat accumulated in the wash disposal, but not in the product. In the Latham bowl-based discontinuous systems, fat removal varied from 69.2 to 92.8 +/- 4.4% depending on the program mode, but not on the bowl size. Additional filtration increased fat removal to 96.7 +/- 2.2%, but also increased red blood cell loss. CONCLUSIONS: Fat contamination of wound blood can be detected by volumetric and gravimetric measurements. Continuous salvage systems remove fat to a higher extent than discontinuous systems. The fat removal capacities of discontinuous systems depend on the program mode and can be improved by filtration. PMID- 25702833 TI - Gold-catalyzed cycloaddition reactions of ethyl diazoacetate, nitrosoarenes, and vinyldiazo carbonyl compounds: synthesis of isoxazolidine and benzo[b]azepine derivatives. AB - Gold-catalyzed cycloadditions of ethyl diazoacetate, nitrosoarenes, and vinyldiazo carbonyl species to yield isoxazolidine derivatives stereoselectively are described. Treatment of these isoxazolidine products with the same catalyst results in a novel 1,2-H shift/[3,3] rearrangement to give benzo[b]azepine compounds. The mechanism of this skeletal rearrangement is elucidated with deuterium-labeling experiments. PMID- 25702834 TI - Discovery of genes related to formothion resistance in oriental fruit fly (Bactrocera dorsalis) by a constrained functional genomics analysis. AB - Artificial selection can provide insights into how insecticide resistance mechanisms evolve in populations. The underlying basis of such phenomena can involve complex interactions of multiple genes, and the resolution of this complexity first necessitates confirmation that specific genes are involved in resistance mechanisms. Here, we used a novel approach invoking a constrained RNA sequencing analysis to refine the discovery of specific genes involved in insecticide resistance. Specifically, for gene discovery, an additional constraint was added to the traditional comparisons of susceptible vs. resistant flies by the incorporation of a line in which insecticide susceptibility was 'recovered' within a resistant line by the removal of insecticide stress. In our analysis, the criterion for the classification of any gene as related to insecticide resistance was based on evidence for differential expression in the resistant line as compared with both the susceptible and recovered lines. The incorporation of this additional constraint reduced the number of differentially expressed genes putatively involved in resistance to 464, compared with more than 1000 that had been identified previously using this same species. In addition, our analysis identified several key genes involved in metabolic detoxification processes that showed up-regulated expression. Furthermore, the involvement of acetylcholinesterase, a known target for modification in insecticide resistance, was associated with three key nonsynonymous amino acid substitutions within our data. In conclusion, the incorporation of an additional constraint using a 'recovered' line for gene discovery provides a higher degree of confidence in genes identified to be involved in insecticide resistance phenomena. PMID- 25702835 TI - Investigating the potential of fluorescent fingerprint powders as a marker for blow fly larvae (Diptera: calliphoridae). AB - Four fluorescent fingerprint powders (RedWop(TM) , GreenWop(TM) , Basic Yellow(TM) , and Yellow Powder(TM) ) were evaluated as a marker for blow fly larvae. Administration methods included ingestion (high vs. low concentration) or topical. Ingestion of high concentrations of Basic Yellow(TM) and RedWop(TM) caused higher larval mortality. Basic Yellow(TM) delayed development and adult emergence while RedWop(TM) and Yellow Powder(TM) had a significant effect on particular stages of development, however, emergence time was not altered. Optimal administration is through ingestion at low concentration levels (<10%) or topically, with GreenWop(TM) demonstrating minimal adverse effects. Optimum wavelength for discrimination between powders was 450 nm. This research can aid in investigative training to increase visibility of larval and pupal blow flies. It can also be used in entomological studies to differentiate between larval blow flies (or other dipteran) species or individuals to further understand complex interactions and behavior during larval development. PMID- 25702836 TI - T-cell Acute Lymphoblastic Leukaemia presenting as multiple scalp tumours in a child. PMID- 25702838 TI - beta2-Microglobulin deficiency causes a complex immunodeficiency of the innate and adaptive immune system. AB - BACKGROUND: Most patients with MHC class I (MHC-I) deficiency carry genetic defects in transporter associated with antigen processing 1 (TAP1) or TAP2. The clinical presentation can vary, and about half of the patients have severe skin disease. Previously, one report described beta2-microglobulin (beta2m) deficiency as another monogenetic cause of MHC-I deficiency, but no further immunologic evaluation was performed. OBJECTIVE: We sought to describe the molecular and immunologic features of beta2m deficiency in 2 Turkish siblings with new diagnoses. METHODS: Based on clinical and serologic findings, the genetic defect was detected by means of candidate gene analysis. The immunologic characterization comprises flow cytometry, ELISA, functional assays, and immunohistochemistry. RESULTS: Here we provide the first extensive clinical and immunologic description of beta2m deficiency in 2 siblings. The sister had recurrent respiratory tract infections and severe skin disease, whereas the brother was fairly asymptomatic but had bronchiectasis. Not only polymorphic MHC I but also the related CD1a, CD1b, CD1c, and neonatal Fc receptor molecules were absent from the surfaces of beta2m-deficient cells. Absent neonatal Fc receptor surface expression led to low serum IgG and albumin levels in both siblings, whereas the heterozygous parents had normal results for all tested parameters except beta2m mRNA (B2M) expression. Similar to TAP deficiency in the absence of a regular CD8 T-cell compartment, CD8(+) gammadelta T cells were strongly expanded. Natural killer cells were normal in number but not "licensed to kill." CONCLUSION: The clinical presentation of patients with beta2m deficiency resembles that of patients with other forms of MHC-I deficiency, but because of the missing stabilizing effect of beta2m on other members of the MHC-I family, the immunologic defect is more extensive than in patients with TAP deficiency. PMID- 25702839 TI - Bids for joint attention by parent-child dyads and by dyads of young peers in interaction. AB - Before they are 3;0-3;6, children typically do not engage with peers in focused interaction, although they do with adults. With parents, children interact around the 'here-and-now'. We hypothesize that young peers do not attempt to establish joint attention to present objects. Using the CHILDES database, we compared attention-directives produced by parents to children, children to peers, and children to parents. Of 391 English-speaking parents, 88% generated attention directives, mostly Look!, See!, and Watch! Of 15 children (2;10-3;7) engaging in dyadic peer-interaction, only 26% produced such utterances. By comparison, 62% of 268 children (1;2-3;3) addressed such directives to parents. Interaction with peers in young children does not involve joint attention to a shared environmental focus, although it does with parents. The reason may be pragmatic: shared attention in parent-child dyads is a means to get information or help; it may seem pointless for a child to address such directives to a peer. PMID- 25702837 TI - Inherited CARD9 deficiency in otherwise healthy children and adults with Candida species-induced meningoencephalitis, colitis, or both. AB - BACKGROUND: Invasive infections of the central nervous system (CNS) or digestive tract caused by commensal fungi of the genus Candida are rare and life threatening. The known risk factors include acquired and inherited immunodeficiencies, with patients often displaying a history of multiple infections. Cases of meningoencephalitis, colitis, or both caused by Candida species remain unexplained. OBJECTIVE: We studied 5 previously healthy children and adults with unexplained invasive disease of the CNS, digestive tract, or both caused by Candida species. The patients were aged 39, 7, 17, 37, and 26 years at the time of infection and were unrelated, but each was born to consanguineous parents of Turkish (2 patients), Iranian, Moroccan, or Pakistani origin. Meningoencephalitis was reported in 3 patients, meningoencephalitis associated with colitis was reported in a fourth patient, and the fifth patient had colitis only. METHODS: Inherited caspase recruitment domain family, member 9 (CARD9) deficiency was recently reported in otherwise healthy patients with other forms of severe disease caused by Candida, Trichophyton, Phialophora, and Exophiala species, including meningoencephalitis but not colitis caused by Candida and Exophiala species. Therefore we sequenced CARD9 in the 5 patients. RESULTS: All patients were found to be homozygous for rare and deleterious mutant CARD9 alleles: R70W and Q289* for the 3 patients with Candida albicans-induced meningoencephalitis, R35Q for the patient with meningoencephalitis and colitis caused by Candida glabrata, and Q295* for the patient with Candida albicans induced colitis. Regardless of their levels of mutant CARD9 protein, the patients' monocyte-derived dendritic cells responded poorly to CARD9-dependent fungal agonists (curdlan, heat-killed C albicans, Saccharomyces cerevisiae, and Exophiala dermatitidis). CONCLUSION: Invasive infections of the CNS or digestive tract caused by Candida species in previously healthy children and even adults might be caused by inherited CARD9 deficiency. PMID- 25702840 TI - Diagnostic accuracy of fluorescence microlymphography for detecting limb lymphedema. AB - OBJECTIVES: Fluorescence microlymphography (FML) is a minimally invasive technique for visualization of the cutaneous lymphatic network. The aim of the study was to assess the accuracy and safety of FML in patients with unilateral lymphedema. METHODS: This was a cross sectional study. Patients with unilateral leg swelling were assessed and compared with the unaffected contralateral limb. FML was performed in all index legs and the contralateral leg by injecting 0.1 mL of fluorescein isothiocyanate (FITC)-labeled dextran intradermally in both limbs at the same level. The most prominent swelling of the affected limb was the anatomical reference. The spread of the dye in the lymphatic capillaries of the skin was measured in all dimensions by epiluminator intravital microscopy and the maximum dye spread value 10 min after injection was used for statistical analysis. The contralateral leg served as control. Test accuracy and receiver operator characteristic (ROC) analysis was performed to assess threshold values that best predict lymphedema. RESULTS: Between March 2008 and February 2014 seventy patients with unilateral chronic leg swelling were clinically diagnosed with lymphedema. The median age was 45 (IQR 27-56) years. Of those, 46 (65.7%) were female and 71.4% had primary and 28.6% secondary lymphedema. Sensitivity, specificity, positive and negative likelihood ratio, and positive and negative predictive value were 94.3%, 78.6%, 4.40, 0.07, 81.5%, and 93.2% for the 12 mm cut off level and 91.4%, 85.7%, 6.40, 0.10, 86.5%, and 90.9% for the 14 mm cut off level, respectively. The area under the ROC curve was 0.89 (95% CI: 0.83 0.95). No major adverse events were observed. CONCLUSIONS: FML is an almost atraumatic and safe technique for detecting lymphedema in patients with leg swelling. In this series the greatest accuracy was observed at a cut off level of >=14 mm maximum spread. PMID- 25702841 TI - The role of branch vessels in aortic type B dissection: an in vitro study. AB - OBJECTIVES: In acute type B aortic dissection (ABAD) a patent false lumen portends a poor outcome. Patent branch vessels originating from the false lumen in a type B aortic dissection are assumed to contribute to persistent blood flow and patent false lumen. Therefore, the morphologic changes of the false lumen generated by different outflow rates in an in vitro model were investigated. METHODS: An artificial dissection was created in two ex vivo porcine aortas. A thin cannula was placed in the false lumen, simulating a branch vessel originating from it. The aorta was positioned in a validated in vitro circulatory system with physiological pulsatile flow (1,500-2,700 mL/minute) and pressure characteristics (130/70 mm Hg). The cannula was attached to a small silicone tube with an adjustable valve mechanism. Three different valve settings were used for creating outflow from the false lumen (fully closed, opened at 50%, and fully opened at 100%). Measurements of lumen areas and flow rates were assessed with time-resolved magnetic resonance imaging. In order to study reproducibility, the experiment was performed twice in two different porcine aortas with a similar morphology. RESULTS: Increasing antegrade outflow through the branch vessel of the false lumen resulted in a significant (p < .01) increase of the mean false lumen area at the proximal and distal location in both models. The distal false lumen expanded up to 107% in the case of high outflow via the false lumen through the branch vessel. CONCLUSIONS: Increasing antegrade outflow through a branch vessel originating from the false lumen when no distal re-entry tear is present results in an expansion of the cross sectional false lumen area. PMID- 25702842 TI - Group B Streptococcus: compliance with the information in prenatal card records and knowledge of pregnant women. AB - This study aimed to determine the rate of compliance on prenatal cards and the women's knowledge and feelings regarding Group B Streptococcus (GBS) screening in a maternity ward in Sao Paulo City, Brazil. Structured interviews and a review of prenatal card records of 391 women were performed. The GBS screening was not recorded in more than half of prenatal cards (51.4%, n = 201); 169 women reported no knowledge or not remembering the GBS screening. PMID- 25702843 TI - Innovative strategies in critical care education. AB - The cadre of information pertinent to critical care medicine continues to expand at a tremendous pace, and we must adapt our strategies of medical education to keep up with the expansion. Differences in learners' characteristics can contribute to a mismatch with historical teaching strategies. Simulation is increasingly popular, but still far from universal. Emerging technology has the potential to improve our knowledge translation, but there is currently sparse literature describing these resources or their benefits and limitations. Directed strategies of assessment and feedback are often suboptimal. Even strategies of accreditation are evolving. This review attempts to summarize salient concepts, suggest resources, and highlight novel strategies to enhance practice and education in the challenging critical care environment. PMID- 25702844 TI - Decreased serum level of lipoprotein cholesterol is a poor prognostic factor for patients with severe community-acquired pneumonia that required intensive care unit admission. AB - PURPOSE: The purpose of this study is to investigate the prognostic values of the serum levels of lipids in patients with severe community-acquired pneumonia (CAP) that required intensive care unit (ICU) admission. MATERIALS AND METHODS: Patients who had severe CAP that required ICU admission were included. Serum lipid level was collected on the days 1 and 7 of ICU stay. Clinical outcome, including length of ICU stay, hospital stay, and death, were monitored prospectively. RESULTS: A total of 40 patients were enrolled in this study. Lower high-density lipoprotein (HDL) and low-density lipoprotein (LDL) were found in nonsurvival group on ICU admission day 7 (survivors vs nonsurvivors; mean HDL, 41.8 vs 13.0 mg/dL, P = .002; LDL, 62.3 vs 30.3 mg/dL, P = 0.006, respectively). High-density lipoprotein cholesterol level of less than or equal to 17 mg/dL on day 7 (odds ratio, 1.23) and LDL cholesterol level of less than or equal to 21 mg/dL on day 7 (odds ratio, 1.10) could be a predictor of hospital mortality. The mean change in levels of HDL cholesterol in nonsurvivors decreased significantly than those in survivors from days 1 to 7 (8.5 vs -17.4 mg/dL, P = .04) but not LDL cholesterol. CONCLUSIONS: Decreased serum HDL cholesterol level from days 1 to 7 may be of prognostic value. PMID- 25702845 TI - Intravenous immunoglobulin in critically ill adults: When and what is the evidence? AB - Intravenous immunoglobulin (IVIg) use is growing dramatically internationally due to the increasing numbers of acute and chronic conditions that may benefit from IVIg. Patients with conditions that may benefit from IVIg might require intensive care unit (ICU) admission, supporting the need to review IVIg use in the critical care setting. The most common clinical indications for IVIg in adults that may require ICU admission and are commonly supported under clinical practice guidelines are Guillain-Barre syndrome, myasthenia gravis and Lambert-Eaton myasthenic syndrome, inflammatory myopathies, and primary or secondary immunodeficiency diseases complicated by severe bacterial sepsis. Other emerging indications include necrotizing fasciitis, toxic epidermal necrolysis/Stevens Johnson syndrome, and toxic shock syndrome. The evidence for IVIg use in sepsis and septic shock remains controversial and insufficient to recommend its routine use. Intravenous immunoglobulin is expensive and also carries risks of adverse effects, including common and benign infusion-related reactions, as well as relatively rare and more serious problems, such as thromboembolic events, renal failure, and aseptic meningitis. In this article, we review the literature on conditions requiring ICU admission and IVIg, and we classify them as supported, emerging, or unsupported indications based on the available evidence and guidelines for clinical use of IVIg. PMID- 25702846 TI - Non-invasive molecular imaging of vulnerable atherosclerotic plaques. AB - The growing discoveries coming from clinical and basic research during the past decades have revolutionized our knowledge regarding pathophysiologic mechanisms underlying the atherosclerotic process and its thrombotic complications. The traditional view focusing on the severity of stenosis of atherosclerotic plaque has given way to the evidence that the clinical complications of atherosclerotic vascular disease, particularly the propensity to develop thrombotic complications, are determined mainly by the biological composition of the plaque. This paradigm shift has reinforced the need to move from the sole anatomical assessment toward combined anatomic and functional imaging modalities enabling the molecular and cellular characterization of the disease on top of its structural properties. Together, the progress to identify molecular targets related to plaque vulnerability and the improvement of imaging techniques for the detection of such molecular targets have allowed us to obtain new important pathophysiological information. This might allow better patient stratification for the identification of subjects at high risk to develop premature atherosclerosis who might need an aggressive therapeutic approach. Nuclear techniques, magnetic resonance imaging, computed tomography angiography, and contrast-enhanced ultrasound represent the currently available non-invasive imaging modalities for molecular imaging which can provide different and complementary insights into the biological features of the atherosclerotic process. This clinical review will discuss the evidence and potential translational applications of the individual imaging techniques particularly concerning their ability to detect the main atherosclerotic features related to plaque vulnerability, such as plaque inflammation and intertwined neovascularization. PMID- 25702847 TI - Negative life events and school adjustment among Chinese nursing students: The mediating role of psychological capital. AB - BACKGROUND: Adjustment difficulties of college students are common and their school adjustment has gained wide concern in recent years. Negative life events and psychological capital (PsyCap) have been associated with school adjustment. However, the potential impact of negative life events on PsyCap, and whether PsyCap mediates the relationship between negative life events and school adjustment among nursing students have not been studied. OBJECTIVES: To investigate the relationship among negative life events, PsyCap, and school adjustment among five-year vocational high school nursing students in China and the mediating role of PsyCap between negative life events and school adjustment. DESIGN: A cross-sectional survey design was conducted. PARTICIPANTS AND SETTINGS: 643 five-year vocational high school nursing students were recruited from three public high vocational colleges in Shandong of China. METHODS: Adolescent Self Rating Life Event Checklist (ASLEC), the Psychological Capital Questionnaire for Adolescent Students scale (PCQAS), and the Chinese College Student Adjustment Scale (CCSAS) were used in this study. Hierarchical linear regression analyses were performed to explore the mediating role of PsyCap. RESULTS: Negative life events were negatively associated with the dimensions of school adjustment (interpersonal relationship adaptation, learning adaptation, campus life adaptation, career adaptation, emotional adaptation, self-adaptation, and degree of satisfaction). PsyCap was positively associated with the dimensions of school adjustment and negatively associated with negative life events. PsyCap partially mediated the relationship between negative life events and school adjustment. CONCLUSIONS: Negative life events may increase the risk of school maladjustment in individuals with low PsyCap. Interventions designed to increase nursing students' PsyCap might buffer the stress of adverse life events, and thereby, enhance students' positive adjustment to school. PMID- 25702848 TI - Well-being and self-efficacy in a sample of undergraduate nurse students: A small survey study. AB - This paper reports findings from a survey which aimed to explore well-being and self-efficacy and test measures of those constructs with a sample of nurse students in a University setting in the United Kingdom. Evidence indicates that undergraduate nurse programmes combine academic work and clinical placement experience in a mix that can potentially lead to stress and impact on health and well-being. Self-efficacy is known to be a resource that contributes to well being, resilience and academic achievement and therefore relevant for investigation. A cross-sectional survey approach was used to obtain data using a paper questionnaire including the BBC Well-being Scale and Generalised Self efficacy Scale. A total of n=108 undergraduate preregistration nurse students participated in this small study from a potential population of 450. The majority of participants (86%) were female, and the majority (75%) were aged 17-35years old. Mean and subscale scores were calculated for both instruments and inferential analyses were carried out using non-parametric techniques. Exploratory factor analyses of the BBC Well-being Scale indicated a three factor structure consistent with validation study findings. Cronbach's alpha was alpha=.92 for the BBC Well-being Scale and alpha=.85 for the GSE suggesting that the instruments are valid and reliable measures for nurse education research. Nurse students indicated higher scores on the BBC Well-being Scale and the GSE compared with previously studied populations and a small but significant positive correlation was found between psychological well-being and self-efficacy. Cluster analysis indicated discrete student communities in this sample that varied in their Well-being and GSE scale and subscale scores. Self-efficacy and general well-being in nurse students are worthy of further study and relevant to contemporary nurse education given current interest in interventions to promote student retention and resilience post-registration. PMID- 25702849 TI - Novel fused tetrathiocines as antivirals that target the nucleocapsid zinc finger containing protein of the feline immunodeficiency virus (FIV) as a model of HIV infection. AB - A novel series of fused tetrathiocines were prepared for evaluation of activity against the nucleocapsid protein of the feline immunodeficiency virus (FIV) in an in vitro cell culture approach. The results demonstrated that the compounds display potent nanomolar activity and low toxicity against this key model of HIV infection. PMID- 25702850 TI - Synthesis and biological evaluation of pyrazolylthiazole carboxylic acids as potent anti-inflammatory-antimicrobial agents. AB - Current Letter presents design, synthesis and biological evaluation of a novel series of pyrazolylthiazole carboxylates 1a-1p and corresponding acid derivatives 2a-2p. All 32 novel compounds were tested for their in vivo anti-inflammatory activity by carrageenan-induced rat paw edema method as well as for in vitro antimicrobial activity. All the tested compounds exhibited excellent AI activity profile. Three compounds 1p (R=Cl, R(1)=Cl), 2c (R=H, R(1)=F) and 2n (R=Cl, R(1)=OCH3) were identified as potent anti-inflammatory agents exhibiting edema inhibition of 93.06-89.59% which is comparable to the reference drug indomethacin (91.32%) after 3h of carrageenan injection while most of the other compounds displayed inhibition ?80%. In addition, pyrazolylthiazole carboxylic acids (2a 2p) also showed good antimicrobial profile. Compound 2h (R=OCH3, R(1)=Cl) showed excellent antimicrobial activity (MIC 6.25MUg/mL) against both Gram positive bacteria comparable with the reference drug ciprofloxacin (MIC 6.25MUg/mL). PMID- 25702851 TI - The SCENIC consensus statement on surveillance and management of dysplasia in inflammatory bowel disease: praise and words of caution. PMID- 25702852 TI - SCENIC international consensus statement on surveillance and management of dysplasia in inflammatory bowel disease. PMID- 25702854 TI - In vitro production and antifungal activity of peptide ABP-dHC-cecropin A. AB - The antimicrobial peptide ABP-dHC-cecropin A is a small cationic peptide with potent activity against a wide range of bacterial species. Evidence of antifungal activity has also been suggested; however, testing of this peptide has been limited due to the low expression of cecropin proteins in Escherichia coli. To improve expression of this peptide in E. coli, ABP-dHC-cecropin A was cloned into a pSUMO vector and transformed into E. coli, resulting in the production of a pSUMO-ABP-dHC-cecropin A fusion protein. The soluble form of this protein was then purified by Ni-IDA chromatography, yielding a total of 496-mg protein per liter of fermentation culture. The SUMO-ABP-dHC-cecropin A fusion protein was then cleaved using a SUMO protease and re-purified by Ni-IDA chromatography, yielding a total of 158-mg recombinant ABP-dHC-cecropin A per liter of fermentation culture at a purity of >=94%, the highest yield reported to date. Antifungal activity assays performed using this purified recombinant peptide revealed strong antifungal activity against both Candida albicans and Neurospora crassa, as well as Rhizopus, Fusarium, Alternaria, and Mucor species. Combined with previous analyses demonstrating strong antibacterial activity against a number of important bacterial pathogens, these results confirm the use of ABP-dHC cecropin A as a broad-spectrum antimicrobial peptide, with significant therapeutic potential. PMID- 25702855 TI - Outcome of orthograde retreatment after failed apicoectomy: use of a mineral trioxide aggregate apical plug. AB - INTRODUCTION: This controlled, single-center historic cohort study project evaluates treatment outcomes of a nonsurgical treatment approach after failed apicoectomy. METHODS: The treatment outcomes of nonsurgical retreatment after a failed apicoectomy were evaluated clinically and radiographically. The study cohort consisted of teeth that had received primary root canal treatment and subsequent apicoectomy elsewhere before the patients presented with post treatment disease. Orthograde retreatment and obturation using an apical mineral trioxide aggregate plug was performed by postgraduate students and endodontic specialists in 25 cases between 2004 and 2012. Pre-, intra-, and postoperative information and the potential effect on the retreatment outcome were evaluated and statistically analyzed using the chi-square test. RESULTS: Twenty-two patients with 23 teeth attended the follow-up examinations (recall rate = 92%). The follow-up periods ranged from 12 to 102 months (median = 35 months). Twenty teeth (87%) were classified as "success," and 3 teeth were considered (17%) "failure." The chi-square test confirmed that the preoperative factor "number of roots" had a statistically significant effect on treatment outcome (odds ratio = 0.08; 95% confidence interval, 0-1.76; P = .03). The factor "tooth location" was of borderline significance (odds ratio = 0.1; 95% confidence interval, 0-2.14; P = .05). CONCLUSIONS: The results of the present study suggest that orthograde retreatment combined with orthograde placement of an apical mineral trioxide aggregate plug is a promising long-term treatment option for teeth with postsurgical pathosis. The success rates were higher for single-rooted teeth. The use of cone-beam computed tomographic imaging in cases of inconclusive periapical radiographs is recommended to minimize the risk of misinterpretation when assessing treatment outcome. PMID- 25702856 TI - The influence of brushing motion on the cutting behavior of 3 reciprocating files in oval-shaped canals. AB - INTRODUCTION: The purpose of this study was to compare the cutting efficiency of 3 reciprocating single-file systems used with a brushing motion in oval-shaped canals. METHODS: Sixty premolars with single oval canals were selected and randomly assigned to 3 groups according to the file used in canal instrumentation: R25 Reciproc (VDW, Munich, Germany), Primary WaveOne ((Dentsply Maillefer, Ballaigues, Switzerland), and a novel prototype instrument (UFile; MicoMega, Besancon, France). Instrumentation was performed in 4 consecutive steps; according to manufacturers' instructions, 5 brushing strokes against the buccal wall with a nonworking instrument followed by another 5 and 15 brushing strokes with a working file. Cone-beam computed tomographic scans were taken after each step of preparation. Pre- and postinstrumentation images were superimposed at the apical and midroot levels and then evaluated in terms of changes in the maximum buccolingual (DeltaBL) and mesiodistal dimensions (DeltaMD). RESULTS: Instrumentation with a brushing motion resulted in the following findings. At the apical levels, no significant difference was found in DeltaBL for the 3 groups (P > .05). However, DeltaMD was significantly less for the Reciproc (P = .006) and UFile (P = .03) groups. At the midroot levels, the UFile group showed the highest significance in terms of DeltaBL (P < .0001) but the lowest in terms of DeltaMD (P = .003). DeltaMD was significantly the highest for the WaveOne group at the midroot levels (P = .05). CONCLUSIONS: The prototype file was more efficient than the other files at the midroot levels, whereas all systems acted the same at the apical levels. The increase in the number of brushing strokes resulted in more dentinal cutting in the direction of those strokes. PMID- 25702853 TI - Longitudinal Correlates of Health Risk Behaviors in Children and Adolescents with Type 2 Diabetes. AB - OBJECTIVES: To characterize, during a 2-year period, the proportion of youth with type 2 diabetes (T2D) enrolled in the Treatment Options for Type 2 Diabetes in Adolescents and Youth study that reported ever at least trying smoking cigarettes and/or drinking alcohol. STUDY DESIGN: Longitudinal data were examined for participants with T2D ages 10-18 years at baseline. Youth psychosocial, parent/family, environmental, and biological correlates of trying health risk behaviors were tested via cross-sectional multivariate models at each time point. Longitudinal models were explored for selected factors. RESULTS: Data were obtained from the Treatment Options for Type 2 Diabetes in Adolescents and Youth study's ethnically diverse participants at baseline (N=644), 6-month (N=616), and 24-month (N=543) assessments. The percentage of youth ever trying only smoking remained stable at 4%; only drinking alcohol increased from 17% to 26%, and both smoking and drinking increased from 10% to 18% during the 2-year period. Factors related to trying health risk behaviors were older age, male sex, non-Hispanic white race-ethnicity, lower grades, more depressive symptoms, and stressful life events. Depressive symptoms, stressful life events, and body mass index Z-score (the latter with smoking only) were related to engagement in health risk behaviors over time. CONCLUSIONS: Youth with T2D who are already at risk for health complications and who reported engaging in activities that further increase the likelihood of life-threatening morbidities were characterized. Although most correlates of trying these risk behaviors are nonmodifiable, intervention efforts may need to focus on potentially modifiable factors, such as depressive symptoms and lower grades. PMID- 25702857 TI - Sympathetic Regulation of Tertiary Dentinogenesis via Beta-2 Adrenergic Receptor on Rat Odontoblasts. AB - INTRODUCTION: Beta-2 adrenergic receptor has been found within the osteoblast membrane meditating bone remodeling. Propranolol is a sympatholytic beta antagonist commonly used as long-term medication for the management of many common diseases such as hypertension. This study was performed to verify the presence of this receptor on odontoblasts in rats and, if present, to investigate its possible association with tertiary dentinogenesis. METHODS: Twenty male Sprague-Dawley rats (9 weeks old) were randomly assigned to 4 groups: CP0.8 group, cavity preparation + propranolol treatment (0.8 mg/day, n = 5); CP4 group, cavity preparation + propranolol treatment (4.0 mg/day, n = 7); CON group, cavity preparation + saline treatment (0.2 mL/day, n = 5); and NT group, no treatment (n = 3). Cavity preparation was performed on the mesial aspect of the maxillary first molars bilaterally. After 2 weeks, the tertiary dentinogenesis (CP0.8, CP4, and CON) was examined by hematoxylin-eosin staining, and the localization of beta 2 adrenergic receptor (NT) was examined by immunohistochemistry. RESULTS: The beta-2 adrenergic receptor immunoreactivity was observed in the odontoblastic layer in normal rat molar dental pulp. The tertiary dentinogenesis beneath the prepared cavity was significantly higher in the rats receiving 2-week systemic administration of propranolol than in those without the propranolol treatment. The higher-dose treatment of propranolol (P < .001) presented more effective up regulation of tertiary dentinogenesis than the lower-dose treatment (P < .01). CONCLUSIONS: These results indicate that the sympathetic nervous system decreases tertiary dentin formation via beta-2 adrenergic receptors located on rat odontoblasts. It suggests that adrenergic beta antagonist is expected to use in the treatment of inducing tertiary dentin formation to protect dental pulp. PMID- 25702858 TI - Phenotypic analysis of immunocompetent cells in healthy human dental pulp. AB - INTRODUCTION: Like other tissues in the body, the human dental pulp is equipped with a network of immune cells that can be mobilized against pathogens when they invade the tooth. Very little data, mostly obtained with classic histologic methods, have reported their quantities and relative percentages. The objective of this study was to characterize and precisely quantify immunocompetent cells in healthy human dental pulp by using fluorescence-activated cell sorting, together with identifying specific cell subsets in the leukocyte (CD45(+)) cells. METHODS: Healthy human third molars were collected from 42 young patients. Dental pulps were separated from the hard tissues and prepared for flow cytometry or immunostaining analyses. RESULTS: CD45(+) cells represented 0.94% +/- 0.65% of cells obtained from the enzymatic digestion of whole dental pulps (n = 34). CD16(+)CD14(+) granulocytes/neutrophils (50.01% +/- 9.08%, n = 7) were found to represent the major subpopulation in CD45(+) cells followed by CD3(+) T lymphocytes (32.58% +/- 11%, n = 17), CD14(+) monocytes (8.93% +/- 5.8%, n = 7), and HLA-DR(high) Lin1(-) dendritic cells (4.51% +/- 1.12%, n = 7). Minor subpopulations included CD3(-)CD56(+) natural killer cells (2.63% +/- 1.15%, n = 7) and CD19(+) B lymphocytes (1.65% +/- 0.89%, n = 17). We further identified cells harboring a phenotype compatible with Foxp3/CD25-expressing regulatory T lymphocytes (CD45(+)CD3(+)CD4(+)CD127(low)). Fluorescence-activated cell sorting analysis and confocal microscopy also revealed expression of HO-1 in HLA-DR(+) cells. CONCLUSIONS: For the first time, this study identifies and precisely quantifies the relative proportion of immunocompetent cells potentially involved in tissue homeostasis of healthy human dental pulp. PMID- 25702859 TI - Clinical outcome of endodontic microsurgery that uses EndoSequence BC root repair material as the root-end filling material. AB - INTRODUCTION: The purpose of this retrospective study was to determine the clinical and radiographic outcome of root-end surgery when EndoSequence BC Root Repair (ES-BCRR) was used as the root-end filling material and to identify any possible prognostic factors that may have affected the healing outcome. METHODS: Clinical records and periapical radiographs were collected from patients who had undergone endodontic microsurgery between 2009 and 2013 in a private endodontic office and had a minimum 1-year follow-up. All surgical procedures were performed by a single endodontist. ES-BCRR was used as the root-end filling material in all cases. Outcome was categorized into healed, healing, and non-healing on the basis of clinical and radiographic findings. The healed and healing cases were pooled and considered as success, and non-healing cases were considered failure. For statistical analysis of the prognostic factors, the dependent variable was the dichotomous outcome (ie, success versus failure). RESULTS: Ninety-four patients with 113 teeth met the inclusion criteria and were included in the study. The overall success rate was 92.0%. None of the prognostic factors, including age, sex, tooth position, size of periapical radiolucency, presence of a sinus tract, preoperative symptoms, and retreatment previous to surgery, appeared to have any significant effects on the outcome (P > .05). CONCLUSIONS: This current study suggests that ES-BCRR is a suitable root-end filling material to be used in endodontic surgery. PMID- 25702860 TI - Rock with me: the role of movement synchrony in infants' social and nonsocial choices. AB - Matching the timing of one's movements to the movements of others has been proposed to increase affiliation and prosociality. Although coordinated movements facilitate early social interactions, not much is known about the mechanisms and effects of movement synchrony throughout development. Two studies investigated 12 month-olds' (Study 1, N = 40) and 9-month-olds' (Study 2, N = 41) preferences for synchronous others in a social as opposed to a nonsocial context. It was found that movement synchrony exclusively guides infants' social choices at 12 months. In contrast, 9-month-olds did not show any preferences for synchronous movements in social or nonsocial contexts. Results suggest that movement synchrony is important in guiding infants' social preferences and its effects emerge toward the end of the 1st year of life. PMID- 25702861 TI - Recommendations for obesity management and prevention have come a long way. PMID- 25702862 TI - Calcifications in low-dose rate prostate seed brachytherapy treatment: post planning dosimetry and predictive factors. AB - BACKGROUND AND PURPOSE: The brachytherapy dose algorithm of the American Association of Physicists in Medicine Task Group (TG) Report 43 overrides all tissue materials with water. In reality, dose discrepancies will occur around tissue calcifications. This study investigates these perturbations in low dose rate prostate brachytherapy dosimetry. MATERIALS AND METHODS: 43 cancer patients with prostatic calcifications are identified. Geant4 Monte Carlo (MC) simulations are made with materials assigned based on TG186 recommendations. Five dose calculation scenarios are presented: MC in water (MCW), MCW with calcifications, (MCCA), MCCA with seeds (MCCASEED) and full tissue definition and seeds with dose to medium in medium (FMC) and dose to water in medium (FMC-Dw,m). RESULTS: The mean FMC prostate D90 (V100) difference relative to TG43 is -6.4% (range [-1.8, 14.1]) (-2.6% [-0.3, -6.7]). For MCCA we obtained -3.9% [-1.0, -8.7] (-1.5% [ 0.2, -4.1]). The mean urethra D10 difference is -4.5% [-1.3, -9.9] for FMC, -2.4% [-0.7, -5.1] with MCCA. FMC-Dw,m D90 has a -0.45% smaller dose difference than FMC on average. The calcification/prostate volume ratio is a good predictor of dose perturbation (R(2)=0.75). CONCLUSION: Based on these results, calcifications alter the dose coverage and may have severe dose perturbation that requires recalculation. PMID- 25702863 TI - A simulated SNP experiment indicates a high risk of over-fitting and false positive results when a predictive multiple SNP model is established and tested within the same dataset. AB - Several relatively small studies have established predictive models for normal tissue radiosensitivity based on multiple SNPs. Even though these models yielded statistically significant results, the models were often inconsistent with each other. This can presumably be attributed to certain methodological problems related to the way these models were established and tested. In order to explore this potential problem, we conducted 10 simulated SNP experiments based on randomly assigned 'SNP genotypes' applied to a set of real clinical data. In 8 out of 10 times, a significant result was found for the model. This clearly demonstrates that the process of fitting the model to the dataset is indeed per se capable of producing nominally significant results. Thus, great caution should be taken when a multiple SNP model is established and tested within the same patient cohort. PMID- 25702864 TI - Long-term outcome after highly advanced single-dose or fractionated radiotherapy in patients with vestibular schwannomas - pooled results from 3 large German centers. AB - PURPOSE: To evaluate long-term clinical outcome and determine prognostic factors for local-control, hearing preservation and cranial nerve toxicity in 449 patients treated for 451 vestibular schwannomas (VS) with radiosurgery (n=169; 38%) or fractionated stereotactic radiotherapy (FSRT; n=291; 62%). METHODS AND MATERIALS: 245 patients were male (55%), and 204 were female (45%). Median age was 60 years (range 17-88 years). Median tumor diameter was 15mm. For FSRT, a median dose of 57.6Gy in median single doses of 1.8Gy was applied. For SRS, median dose was 13Gy. The median follow-up time was 67 months. RESULTS: Local control was 97% at 36 months, 95% at 60 months, and 94% at 120 months with no difference between FSRT and SRS (p=0.39). "Useful hearing" was present 46%. After RT, "useful hearing" was preserved in 85% of the patients. Loss of useful hearing was observed in the FSRT group in 14%, and in the SRS group in 16% of the patients. For patients treated with SRS ?13Gy, useful hearing deterioration was 13%. For trigeminal and facial nerve toxicity, there was no difference between FSRT and SRS. CONCLUSION: Supported by this large multicentric series, both SRS and FSRT can be recommended for the treatment of VS. SRS application is limited by tumor size, and is associated with a steep dose-response-curve. When chosen diligently based on tumor volume, pre-treatment characteristics and volume dependent dose-prescription in SRS (?13Gy), both treatments may be considered equally effective. PMID- 25702866 TI - Fluorescent magnetic nanoparticles for cell labeling: flux synthesis of manganite particles and novel functionalization of silica shell. AB - Novel synthetic approaches for the development of multimodal imaging agents with high chemical stability are demonstrated. The magnetic cores are based on La0.63Sr0.37MnO3 manganite prepared as individual grains using a flux method followed by additional thermal treatment in a protective silica shell allowing to enhance their magnetic properties. The cores are then isolated and covered de novo with a hybrid silica layer formed through the hydrolysis and polycondensation of tetraethoxysilane and a fluorescent silane synthesized from rhodamine, piperazine spacer, and 3-iodopropyltrimethoxysilane. The aminoalkyltrialkoxysilanes are strictly avoided and the resulting particles are hydrolytically stable and do not release dye. The high colloidal stability of the material and the long durability of the fluorescence are reinforced by an additional silica layer on the surface of the particles. Structural and magnetic studies of the products using XRD, TEM, and SQUID magnetometry confirm the importance of the thermal treatment and demonstrate that no mechanical treatment is required for the flux-synthesized manganite. Detailed cell viability tests show negligible or very low toxicity at concentrations at which excellent labeling is achieved. Predominant localization of nanoparticles in lysosomes is confirmed by immunofluorescence staining. Relaxometric and biological studies suggest that the functionalized nanoparticles are suitable for imaging applications. PMID- 25702867 TI - Suspended crystalline films of protein hydrophobin I (HFBI). AB - Protein interfaces play an essential role in both natural and man-made materials as stabilizers, sensors, catalysts, and selective channels for ions and small molecules. Probing the molecular arrangement within such interfaces is of prime importance to understand the relation between structure and functionality. Here we report on the preparation and characterization of large area suspended crystalline films of class II hydrophobin HFBI. This small, amphiphilic globular protein readily self-assembles at the air-water interface into a 2D hexagonal lattice which can be transferred onto a holey carbon electron microscopy grid yielding large areas of hundreds of square micrometers intact hydrophobin film spun across micron-sized holes. Fourier transform analysis of low-dose electron microscopy images and selected area electron diffraction profiles reveal a unit cell dimension a=5.6+/-0.1nm, in agreement with reported atomic force microscopy studies on solid substrates and grazing incidence X-ray scattering experiments at the air-water interface. These findings constitute the first step towards the utilization of large-area suspended crystalline hydrophobin films as membranes for ultrapurification and chiral separation or as biological substrates for ultrafast electron diffraction. PMID- 25702868 TI - Effect of cationic polyacrylamide on the processing and properties of nanocellulose films. AB - The use of high molecular weight cationic polyacrylamide (CPAM) was investigated to accelerate the drainage of nanocellulose (Microfibrillated Cellulose) suspensions into films. The mechanism was quantified and optimized by measuring the gel point, the lowest solids concentration at which a continuous network is formed. The flocculation of MFC was analysed as a function of the polyelectrolyte dosage, charge density and molecular weight as well as process parameters (drainage time) and material properties. The adsorption isotherms of CPAMs on nanocellulose and their zeta potential curves were also analysed as a function of CPAM charge and dosage. Measured CPAM adsorption capacities for the 50% and 10% charged 13MDa CPAM onto MFC were 5mg/g and 8mg/g, respectively, corresponding to adsorption coverage on cellulose of 0.14mg/m(2) and 0.22mg/m(2). The floc strength and drainability of MFC suspensions were quantified with the gel point as a function of CPAM properties. For all combinations of polyelectrolyte molecular weight and charge density, the gel point of a nanocellulose suspension goes through a minimum with increasing polymer dosage. The minimum gel point was independent of the polyelectrolyte charge density at constant molecular weight. However, it reduced with decreasing CPAM molecular weight, at a constant addition rate. The drainage time of a nanocellulose suspension into a film is reduced by 2/3 by halving the gel point from 0.2 to 0.1kg/m(3); this is due to the more flocculated suspension facilitating drainage between flocs. Nanocellulose films of increased porosity also result from reducing the gel point, signifying that the more open 3D structure of the flocculated cellulose suspension is retained upon drying the 2D film cellulose film structure. PMID- 25702865 TI - Quality control systems in cardiac aging. AB - Cardiac aging is an intrinsic process that results in impaired cardiac function, along with cellular and molecular changes. These degenerative changes are intimately associated with quality control mechanisms. This review provides a general overview of the clinical and cellular changes which manifest in cardiac aging, and the quality control mechanisms involved in maintaining homeostasis and retarding aging. These mechanisms include autophagy, ubiquitin-mediated turnover, apoptosis, mitochondrial quality control and cardiac matrix homeostasis. Finally, we discuss aging interventions that have been observed to impact cardiac health outcomes. These include caloric restriction, rapamycin, resveratrol, GDF11, mitochondrial antioxidants and cardiolipin-targeted therapeutics. A greater understanding of the quality control mechanisms that promote cardiac homeostasis will help to understand the benefits of these interventions, and hopefully lead to further improved therapeutic modalities. PMID- 25702869 TI - Adsorption of ciprofloxacin, bisphenol and 2-chlorophenol on electrospun carbon nanofibers: in comparison with powder activated carbon. AB - Carbon nanofibers (CNFs) were prepared by electrospun polyacrylonitrile (PAN) polymer solutions followed by thermal treatment. For the first time, the influence of stabilization procedure on the structure properties of CNFs was explored to improve the adsorption capacity of CNFs towards the environmental pollutants from aqueous solution. The adsorption of three organic chemicals including ciprofloxacin (CIP), bisphenol (BPA) and 2-chlorophenol (2-CP) on electrospun CNFs with high surface area of 2326m(2)/g and micro/mesoporous structure characteristics were investigated. The adsorption affinities were compared with that of the commercial powder activated carbon (PAC). The adsorption kinetics and isotherms showed that the maximum adsorption capacities (qm) of CNFs towards the three pollutants are sequenced in the order of CIP>BPA>2 CP, which are 2.6-fold (CIP), 1.6-fold (BPA) and 1.1-fold (2-CP) increase respectively in comparison with that of PAC adsorption. It was assumed that the micro/mesoporous structure of CNFs, molecular size of the pollutants and the pi electron interaction play important roles on the high adsorption capacity exhibited by CNFs. In addition, electrostatic interaction and hydrophobic interaction also contribute to the adsorption of CNFs. This study demonstrates that the electrospun CNFs are promising adsorbents for the removal of pollutants from aqueous solutions. PMID- 25702870 TI - Mechanism of UCH-L5 activation and inhibition by DEUBAD domains in RPN13 and INO80G. AB - Deubiquitinating enzymes (DUBs) control vital processes in eukaryotes by hydrolyzing ubiquitin adducts. Their activities are tightly regulated, but the mechanisms remain elusive. In particular, the DUB UCH-L5 can be either activated or inhibited by conserved regulatory proteins RPN13 and INO80G, respectively. Here we show how the DEUBAD domain in RPN13 activates UCH-L5 by positioning its C terminal ULD domain and crossover loop to promote substrate binding and catalysis. The related DEUBAD domain in INO80G inhibits UCH-L5 by exploiting similar structural elements in UCH-L5 to promote a radically different conformation, and employs molecular mimicry to block ubiquitin docking. In this process, large conformational changes create small but highly specific interfaces that mediate activity modulation of UCH-L5 by altering the affinity for substrates. Our results establish how related domains can exploit enzyme conformational plasticity to allosterically regulate DUB activity. These allosteric sites may present novel insights for pharmaceutical intervention in DUB activity. PMID- 25702871 TI - Molecular architecture of 4E-BP translational inhibitors bound to eIF4E. AB - The eIF4E-binding proteins (4E-BPs) represent a diverse class of translation inhibitors that are often deregulated in cancer cells. 4E-BPs inhibit translation by competing with eIF4G for binding to eIF4E through an interface that consists of canonical and non-canonical eIF4E-binding motifs connected by a linker. The lack of high-resolution structures including the linkers, which contain phosphorylation sites, limits our understanding of how phosphorylation inhibits complex formation. Furthermore, the binding mechanism of the non-canonical motifs is poorly understood. Here, we present structures of human eIF4E bound to 4E-BP1 and fly eIF4E bound to Thor, 4E-T, and eIF4G. These structures reveal architectural elements that are unique to 4E-BPs and provide insight into the consequences of phosphorylation. Guided by these structures, we designed and crystallized a 4E-BP mimic that shows increased repressive activity. Our studies pave the way for the rational design of 4E-BP mimics as therapeutic tools to decrease translation during oncogenic transformation. PMID- 25702872 TI - Structural basis for the activation and inhibition of the UCH37 deubiquitylase. AB - The UCH37 deubiquitylase functions in two large and very different complexes, the 26S proteasome and the INO80 chromatin remodeler. We have performed biochemical characterization and determined crystal structures of UCH37 in complexes with RPN13 and NFRKB, which mediate its recruitment to the proteasome and INO80, respectively. RPN13 and NFRKB make similar contacts to the UCH37 C-terminal domain but quite different contacts to the catalytic UCH domain. RPN13 can activate UCH37 by disrupting dimerization, although physiologically relevant activation likely results from stabilization of a surface competent for ubiquitin binding and modulation of the active-site crossover loop. In contrast, NFRKB inhibits UCH37 by blocking the ubiquitin-binding site and by disrupting the enzyme active site. These findings reveal remarkable commonality in mechanisms of recruitment, yet very different mechanisms of regulating enzyme activity, and provide a foundation for understanding the roles of UCH37 in the unrelated proteasome and INO80 complexes. PMID- 25702873 TI - Limited mitochondrial permeabilization causes DNA damage and genomic instability in the absence of cell death. AB - During apoptosis, the mitochondrial outer membrane is permeabilized, leading to the release of cytochrome c that activates downstream caspases. Mitochondrial outer membrane permeabilization (MOMP) has historically been thought to occur synchronously and completely throughout a cell, leading to rapid caspase activation and apoptosis. Using a new imaging approach, we demonstrate that MOMP is not an all-or-nothing event. Rather, we find that a minority of mitochondria can undergo MOMP in a stress-regulated manner, a phenomenon we term "minority MOMP." Crucially, minority MOMP leads to limited caspase activation, which is insufficient to trigger cell death. Instead, this caspase activity leads to DNA damage that, in turn, promotes genomic instability, cellular transformation, and tumorigenesis. Our data demonstrate that, in contrast to its well-established tumor suppressor function, apoptosis also has oncogenic potential that is regulated by the extent of MOMP. These findings have important implications for oncogenesis following either physiological or therapeutic engagement of apoptosis. PMID- 25702874 TI - Hypoxic preconditioning of mesenchymal stromal cells induces metabolic changes, enhances survival, and promotes cell retention in vivo. AB - Mesenchymal stem cells/multipotent stromal cells (MSCs) are promising therapeutics for a variety of conditions. However, after transplantation, cell retention remains extremely challenging. Given that many hypoxic signals are transitory and that the therapeutic administration of MSCs is typically into tissues that are normally hypoxic, we studied the effect of hypoxic preconditioning (HP) prior to new exposure to hypoxia. We show that preincubation for 2 days or more in 1% oxygen reduces serum deprivation-mediated cell death, as observed by higher cell numbers and lower incorporation of EthD-III and Annexin V. Consistently, HP-MSCs expressed significantly lower levels of cytochrome c and heme oxygenase 1 as compared to controls. Most importantly, HP-MSCs showed enhanced survival in vivo after intramuscular injection into immune deficient NOD/SCID-IL2Rgamma(-/-) mice. Interestingly, HP-MSCs consume glucose and secrete lactate at a slower rate than controls, possibly promoting cell survival, as glucose remains available to the cells for longer periods of time. In addition, we compared the metabolome of HP-MSCs to controls, before and after hypoxia and serum deprivation, and identified several possible mediators for HP-mediated cell survival. Overall, our findings suggest that preincubation of MSCs for 2 days or more in hypoxia induces metabolic changes that yield higher retention after transplantation. PMID- 25702875 TI - Energy-related catalytic and other materials: general discussion. PMID- 25702877 TI - Androgen deprivation with radiotherapy: how long is long enough? PMID- 25702876 TI - High-dose radiotherapy with short-term or long-term androgen deprivation in localised prostate cancer (DART01/05 GICOR): a randomised, controlled, phase 3 trial. AB - BACKGROUND: The optimum duration of androgen deprivation combined with high-dose radiotherapy in prostate cancer remains undefined. We aimed to determine whether long-term androgen deprivation was superior to short-term androgen deprivation when combined with high-dose radiotherapy. METHODS: In this open-label, multicentre, phase 3 randomised controlled trial, patients were recruited from ten university hospitals throughout Spain. Eligible patients had clinical stage T1c-T3b N0M0 prostate adenocarcinoma with intermediate-risk and high-risk factors according to 2005 National Comprehensive Cancer Network criteria. Patients were randomly assigned (1:1) using a computer-generated randomisation schedule to receive either 4 months of androgen deprivation combined with three-dimensional conformal radiotherapy at a minimum dose of 76 Gy (range 76-82 Gy; short-term androgen deprivation group) or the same treatment followed by 24 months of adjuvant androgen deprivation (long-term androgen deprivation group), stratified by prostate cancer risk group (intermediate risk vs high risk) and participating centre. Patients assigned to the short-term androgen deprivation group received 4 months of neoadjuvant and concomitant androgen deprivation with subcutaneous goserelin (2 months before and 2 months combined with high-dose radiotherapy). Anti-androgen therapy (flutamide 750 mg per day or bicalutamide 50 mg per day) was added during the first 2 months of treatment. Patients assigned to long-term suppression continued with the same luteinising hormone-releasing hormone analogue every 3 months for another 24 months. The primary endpoint was biochemical disease-free survival. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT02175212. FINDINGS: Between Nov 7, 2005, and Dec 20, 2010, 178 patients were randomly assigned to receive short term androgen deprivation and 177 to receive long-term androgen deprivation. After a median follow-up of 63 months (IQR 50-82), 5-year biochemical disease free survival was significantly better among patients receiving long-term androgen deprivation than among those receiving short-term treatment (90% [95% CI 87-92] vs 81% [78-85]; hazard ratio [HR] 1.88 [95% CI 1.12-3.15]; p=0.01). 5-year overall survival (95% [95% CI 93-97] vs 86% [83-89]; HR 2.48 [95% CI 1.31-4.68]; p=0.009) and 5-year metastasis-free survival (94% [95% CI 92-96] vs 83% [80-86]; HR 2.31 [95% CI 1.23-3.85]; p=0.01) were also significantly better in the long term androgen deprivation group than in the short-term androgen deprivation group. The effect of long-term androgen deprivation on biochemical disease-free survival, metastasis-free survival, and overall survival was more evident in patients with high-risk disease than in those with low-risk disease. Grade 3 late rectal toxicity was noted in three (2%) of 177 patients in the long-term androgen deprivation group and two (1%) of 178 in the short-term androgen deprivation group; grade 3-4 late urinary toxicity was noted in five (3%) patients in each group. No deaths related to treatment were reported. INTERPRETATION: Compared with short-term androgen deprivation, 2 years of adjuvant androgen deprivation combined with high-dose radiotherapy improved biochemical control and overall survival in patients with prostate cancer, particularly those with high-risk disease, with no increase in late radiation toxicity. Longer follow-up is needed to determine whether men with intermediate-risk disease benefit from more than 4 months of androgen deprivation. FUNDING: Spanish National Health Investigation Fund, AstraZeneca. PMID- 25702878 TI - Update on paroxysmal nocturnal haemoglobinuria: on the long way to understand the principles of the disease. AB - The understanding of the clinical manifestations in paroxysmal nocturnal haemoglobinuria (PNH) has made great progress. The main symptoms of this disease such as abdominal pain, renal failure or pulmonary hypertension and even the basis of the dramatic thrombophilia can be related to intravascular haemolysis and liberation of free haemoglobin resulting in NO depletion. In addition, there has been a recent great progress in elucidating the pathophysiology of clonal expansion within PNH bone marrow. In the majority of patients with haemolytic PNH, there are additional mutations within genes beyond PIG-A and rather affecting growth and differentiation of clonal bone marrow cells. In contrast to the formerly proposed single mechanism hypotheses such as immune selection or intrinsic gain of clonal dominance, this appears to follow a pattern of a complex clonal hierarchy putatively integrating both earlier anticipated mechanisms. Treatment of PNH is mainly supportive. The only curative approach as allogeneic stem cell transplantation should only be applied to patients with complications such as secondary bone marrow aplasia or transformation into MDS or AML. Symptomatic haemolytic PNH will be treated with eculizumab, an inhibitor of the terminal complement cascade. Treatment with eculizumab can significantly prevent PNH-related symptoms including the abnormal thrombophilia. Recently, it was demonstrated that in contrast to untreated historic PNH patients, meanwhile a normal life expectancy is observed in eculizumab-treated patients. The recently approved vaccine against meningococci type B by the European Medical Agency (EMA) could probably further help to prevent meningococcal sepsis due to the induced complement deficiency by eculizumab. PMID- 25702879 TI - p-values should not be used for evaluating the strength of DNA evidence. AB - Recently, p-values have been suggested to explain the strength of a likelihood ratio that evaluates DNA evidence. It has been argued that likelihood ratios would be difficult to explain in court and that p-values would offer an alternative that is easily explained. In this article, we argue that p-values should not be used in this context. p-Values do not directly relate to the strength of the evidence. The likelihood ratio measures the strength of the evidence, while the p-value measures how rare it is to find evidence that is equally strong or stronger, which is something fundamentally different. In addition, a p-value is not always unambiguous. To illustrate our arguments, we present several examples from forensic genetics. PMID- 25702880 TI - Effects of sublethal doses of silver nanoparticles on Bacillus subtilis planktonic and sessile cells. AB - AIMS: Due to their antimicrobial activity, silver nanoparticles (Ag-NPs) are being increasingly used in a number of industrial products. The accumulation of Ag-NPs in the soil might affect plant growth-promoting rhizobacteria and, in turn, the plants. We describe the effects of Ag-NPs on the soil bacteria Azotobacter vinelandii and Bacillus subtilis. METHODS AND RESULTS: In growth inhibition studies, A. vinelandii showed extreme sensitivity to Ag-NPs, compared to B. subtilis. We investigated the effects of Ag-NPs at subinhibitory concentrations, both on planktonic and sessile B. subtilis cells. As determined by 2,7-dichlorofluorescein-diacetate assays, Ag-NPs increase the formation of reactive oxygen species in planktonic cells, but not in sessile cells, suggesting the activation of scavenging systems in biofilms. Consistently, proteomic analysis in B. subtilis Ag-NPs-treated biofilms showed increased production of proteins related to quorum sensing and involved in stress responses and redox sensing. Extracellular polysaccharides production and inorganic phosphate solubilization were also increased, possibly as part of a coordinated response to stress. CONCLUSIONS: At low concentrations, Ag-NPs killed A. vinelandii and affected cellular processes in planktonic and sessile B. subtilis cells. SIGNIFICANCE AND IMPACT OF THE STUDY: Re-direction of gene expression, linked to selective toxicity, suggests a strong impact of Ag-NPs on soil bacterial communities. PMID- 25702881 TI - Development of species-specific PCR primers and polyphasic characterization of Lactobacillus sanfranciscensis isolated from Korean sourdough. AB - Lactobacillus sanfranciscensis is a bacterium used in sourdough that provides desirable properties such as better flavor and texture to the sourdough bread. Here, the intra-species diversity of L. sanfranciscensis strains isolated from Korean sourdough was studied using genotypic (multiplex-RAPD-PCR: multiplex Randomly Amplified Polymorphic DNA-polymerase chain reaction) and phenotypic (VITEK2 Compact system) analyses. For this, a novel species-specific set of PCR primers was developed to identify L. sanfranciscensis using the recently published genome database. The primers were able to detect L. sanfranciscensis isolated from Korean sourdough with 100% accuracy. Genotyping and phenotyping analyses at the strain level demonstrated that Korean sourdough possesses various biotypes of L. sanfranciscensis strains. These strains were clustered into 5 subtypes (genotyping) or 7 subtypes (phenotyping). In summary, this strategy to construct novel primers reduced the chance of cross amplification and was able to identify the desired strain. The various strains isolated in this study can be used to develop a sourdough starter after the analysis of their fermentation characteristics. PMID- 25702882 TI - A comparison for acid production, proteolysis, autolysis and inhibitory properties of lactic acid bacteria from fresh and mature Feta PDO Greek cheese, made at three different mountainous areas. AB - Isolates of NSLAB were obtained from fresh (58 isolates) and mature (38) Feta cheese made at household level in three different mountainous areas, in order to study the effect of the area of production on NSLAB composition and their technological characteristics. Results obtained by SDS-PAGE of whole-cell proteins indicated that the microflora of the fresh cheese was composed of either lactococci (areas 1, 2), or lactococci and enterococci (area 3). The NSLAB microflora of mature cheese was composed almost entirely of lactobacilli species, differing according to the area of production. Species allocation by the SDS-PAGE method was confirmed by sequencing representative strains. Lactococci of cheese made in area 1 exhibited a narrow spectrum of antibacterial activity compared to isolates from areas 2 and 3, while for lactobacilli from all three areas a similar spectrum was noticed. Lactococci from area 2 exhibited higher (P<0.05) mean acidifying activity than lactococci from area 1. The isolates from the three areas also differed in respect of their caseinolytic activity, with preferences towards beta-CN (areas 1 and 2) or alphas-CN (area 3). Mean proteolytic activity of lactococci from area 1 was stronger (P<0.05) than that of lactococci from area 2 and the same was observed for their mean aminopeptidase activity, as well as their extent of autolysis at pH5.1. Mean acidifying activity of lactobacilli after 6h was for strains of area 3>2=1. The strains from areas 1 and 3 degraded preferentially alphas-CN, while a clear preference towards beta-CN was noticed for strains of area 2; their mean proteolytic activity was for strains of area 1 higher (P<0.05) than strains from area 3. The above results suggest that cheeses from the three areas differ in species composition of NSLAB and their technological properties. Principal component analysis of results on acidifying and proteolytic activities as well as autolysis allowed the distinction of lactococci according to their derivation area enabling the selection of appropriate strains as starters for cheese production in each area. PMID- 25702883 TI - Biofilms of Enterococcus faecalis and Enterococcus faecium isolated from the processing of ricotta and the control of these pathogens through cleaning and sanitization procedures. AB - The biofilm formation of Enterococcus faecalis and Enterococcus faecium isolated from the processing of ricotta on stainless steel coupons was evaluated, and the effect of cleaning and sanitization procedures in the control of these biofilms was determined. The formation of biofilms was observed while varying the incubation temperature (7, 25 and 39 degrees C) and time (0, 1, 2, 4, 6 and 8 days). At 7 degrees C, the counts of E. faecalis and E. faecium were below 2 log10 CFU/cm(2). For the temperatures of 25 and 39 degrees C, after 1 day, the counts of E. faecalis and E. faecium were 5.75 and 6.07 log10 CFU/cm(2), respectively, which is characteristic of biofilm formation. The tested sanitation procedures a) acid-anionic tensioactive cleaning, b) anionic tensioactive cleaning+sanitizer and c) acid-anionic tensioactive cleaning+sanitizer were effective in removing the biofilms, reducing the counts to levels below 0.4 log10 CFU/cm(2). The sanitizer biguanide was the least effective, and peracetic acid was the most effective. These studies revealed the ability of enterococci to form biofilms and the importance of the cleaning step and the type of sanitizer used in sanitation processes for the effective removal of biofilms. PMID- 25702884 TI - In vitro evaluation of the activity of thiosemicarbazone derivatives against mycotoxigenic fungi affecting cereals. AB - With a steadily increasing world population, a more efficient system of food production is of paramount importance. One of the major causes of food spoilage is the presence of fungal pathogens and the production and accumulation of mycotoxins. In the present work we report a study on the activity of a series of functionalized thiosemicarbazones (namely cuminaldehyde, trans-cinnamaldehyde, quinoline-2-carboxyaldehyde, 5-fluoroisatin thiosemicarbazone and 5-fluoroisatin N(4)-methylthiosemicarbazone), as antifungal and anti-mycotoxin agents, against the two major genera of cereal mycotoxigenic fungi, i.e. Fusarium and Aspergillus. These thiosemicarbazones display different patterns of efficacy on fungal growth and on mycotoxin accumulation depending on the fungal species. Some of the molecules display a greater effect on mycotoxin synthesis than on fungal growth. PMID- 25702885 TI - A new hypercrosslinked supermicroporous polymer, with scope for sulfonation, and its catalytic potential for the efficient synthesis of biodiesel at room temperature. AB - We have designed a new hypercrosslinked supermicroporous polymer (HMP-1) with a BET surface area of 913 m(2) g(-1) by FeCl3 via a catalyzed Friedel-Crafts alkylation reaction between carbazole and alpha,alpha'-dibromo-p-xylene. Upon sulfonation HMP-1 yielded a very efficient solid acid catalyst for the production of biodiesels via esterification/transesterification of free fatty acids (FFA)/esters at room temperature. PMID- 25702886 TI - Ketamine-Xylazine Anesthesia in Rats: Intraperitoneal versus Intravenous Administration Using a Microsurgical Femoral Vein Access. AB - BACKGROUND: Ketamine-xylazine is a frequently used combination for anesthesia in microsurgically operated rats and can be administered by intraperitoneal (IP) or intravenous (IV) injection. Both methods are associated with relatively high misadministration rates. In the present study, we want to introduce a femoral vein access that requires microsurgical cannulation but enables a 100% administration rate. METHODS: In this study, the maximal time of anesthesia was analyzed, time to response, latency time, and the total need for anesthetic agents in IP (n = 200) and IV (n = 40) anesthesia in Wistar rats for the purpose of microvascular operations. IV injections were achieved with an inserted microcatheter that was applied via a microsurgical femoral vein access. RESULTS: The time needed for the placement of the microcatheter was 5.76 +/- 0.89 minutes. Maximal time of anesthesia (IP vs. IV) was 7.02 +/- 1.92 versus 21.78 +/- 5.77 hours (p < 0.0001), time to response was 137.5 +/- 3.91 versus 18 +/- 2.18 seconds (p < 0.0001), latency time 35.53 +/- 3.21 versus 27.8 +/- 2.88 minutes (p < 0.0001), and total volume of anesthetic 1.42 +/- 0.39 versus 2.78 +/- 0.73 mL (p < 0.0001), respectively. CONCLUSION: IV administration using the microsurgical femoral vein access is a feasible method with a quicker response rate and a 100% administration rate. Furthermore, it enables longer anesthesia, for example, complex microsurgical or other experimental procedures in the rat. PMID- 25702887 TI - Preclinical evaluation of (99m)Tc labeled gefitinib as a potential scintigraphic probe for the detection of tumors expressing epidermal growth factor receptors. AB - In the present study, we successfully radiolabeled gefitinib with (99m)Tc by direct labeling method. The radio-ligand had radiolabeling efficiency of >95.0% and in vitro stability of >80.0% at 24h. The radiotracer cleared from blood bi exponentially. Animal organ biodistribution data indicated hepato-renal excretion of the radiotracer. Scintigraphy carried out in tumor bearing mice (induced by EGFR expressing EAT cell lines) demonstrated that the radiotracer accumulated in the tumor site with T/NT ratio of 3.3+/-0.2 at 1h. PMID- 25702888 TI - Collisional, radiative and total electron interaction in compound semiconductor detectors and solid state nuclear track detectors: effective atomic number and electron density. AB - Effective atomic numbers, Zeff and electron densities, Ne are widely used for characterization of interaction processes in radiation related studies. A variety of detectors are employed to detect different types of radiations i.e. photons and charged particles. In the present work, some compound semiconductor detectors (CSCD) and solid state nuclear track detectors (SSNTD) were investigated with respect to the partial as well as total electron interactions. Zeff and Ne of the given detectors were calculated for collisional, radiative and total electron interactions in the kinetic energy region 10keV-1GeV. Maximum values of Zeff and Ne were observed at higher kinetic energies of electrons. Significant variations in Zeff and Ne up to ~20-25% were noticed for the detectors, GaN, ZnO, Amber and CR-39 for total electron interaction. Moreover, the obtained Zeff and Ne for electrons were compared to those obtained for photons in the entire energy region. Significant variations in Zeff were also noted not only for photons (up to ~40% for GaN) but also between photons and electrons (up to ~60% for CR-39) especially at lower energies. Except for the lower energies, Zeff and Ne keep more or less constant values for the given materials. The energy regions where Zeff and Ne keep constant clearly show the availability of using these parameters for characterization of the materials with respect to the radiation interaction processes. PMID- 25702889 TI - The relationships among social support and quality of life in persons living with HIV/AIDS in Jiangxi and Zhejiang provinces, China. AB - Several empirical studies, particularly those conducted in developed countries, have linked social support to quality of life among persons living with HIV/AIDS (PLWA). However, few studies have been conducted in developing countries, such as China; therefore, the question of any association being present between social support and quality of life in PLWA in China remains unanswered. This retrospective cross-sectional study was conducted to examine the relationships between social support and quality of life among PLWA in the Jiangxi and Zhejiang provinces of China. A total of 377 PLWA participated in this study, and questionnaires used included demographics, the Chinese Medical Outcomes Study Short Form-36, and a Social Support Rating Scale, all of which were collected through face-to-face interviews between 1 March and 15 April 2013 in six different County Centers of Disease Control and Prevention in Jiangxi and Zhejiang provinces, and one hospital in the Jiangxi. The health-related quality of life score was 64.7+/-13.5 (out of a total score of 100), which was significantly lower than the national norm level of 78.2+/-15.9. The total score of social support was 29.4+/-7.8 (full score 66). The canonical correlation between social support and quality of participants' lives was shown to be statistically significant (p<0.0001). The relationship between subjective support and quality of life among PLWA was also significant (p=0.004). Subjective support and the use of social support showed a positive correlation with vitality, role physical, and role-emotional, and a negative correlation with body pain. The current study suggests that PLWA with lower social support have diminished quality of life. PMID- 25702890 TI - High expression of interleukin-11 is an independent indicator of poor prognosis in clear-cell renal cell carcinoma. AB - Interleukin-11 (IL-11), a member of the IL-6 family of cytokines, exerts pleiotropic oncogenic activities by stimulating angiogenesis and metastasis in many cancer types. The present study aims to evaluate the impact of IL-11 expression on recurrence and mortality of patients with clear-cell renal cell carcinoma (ccRCC). We retrospectively enrolled 193 ccRCC patients undergoing nephrectomy at a single center. Clinicopathologic features, recurrence-free survival (RFS) and overall survival (OS) were recorded. IL-11 intensity was assessed by immunohistochemistry in tumor specimens. The Kaplan-Meier method was applied to compare survival curves. Cox regression models were used to analyze the impact of prognostic factors on RFS and OS. The concordance index (C-index) was calculated to assess predictive accuracy. High IL-11 expression is associated with increased risk of recurrence and poor survival for ccRCC patients (P < 0.001 and P < 0.001, respectively), especially those with early-stage disease (TNM stage I + II). Multivariate analyses confirmed that IL-11 expression was an independent prognostic factor for RFS and OS (P = 0.006 and P = 0.008, respectively). The predictive accuracy of well-established prognostic models was improved when IL-11 expression was integrated. In conclusion, high IL-11 expression is an independent predictor of poor prognosis in ccRCC patients. It may help identify patients who could benefit from additional treatments and closer follow up. PMID- 25702895 TI - Cell surface receptors: rapid quantification of live cell receptors using bioluminescence in a flow-based microfluidic device (small 8/2015). AB - C. T. Lim and co-workers describe a rapid and sensitive bioluminescence-based microfluidic method for quantifying receptor numbers on live cells. On page 943, this integrated, lens-free optical platform allows the determination of signals from the cell surface with high sensitivity. Compared to conventional approaches, the combined use of bioluminescence and microfluidics makes it safe to use, reduces background noise, improves sensitivity, requires smaller sample volumes, and allows high-throughput sampling over thousands of cells. PMID- 25702897 TI - Epidemiology of otologic diagnoses in United States emergency departments. AB - OBJECTIVES/HYPOTHESIS: Otologic complaints may place a significant burden on emergency departments (EDs) in the United States; however, few studies have comprehensively examined this discrete patient population. We aimed to identify utilization of EDs by patients with primary otologic complaints. STUDY DESIGN: Retrospective analysis of the Nationwide Emergency Department Sample (NEDS) from 2009 through 2011. METHODS: The NEDS database was queried for patient encounters with a primary otologic diagnosis based on International Classification of Diseases, Ninth Revision codes (380-389). Weighted estimates for demographics, diagnostic characteristics, socioeconomic status, and trends over time were extracted. Predictors of mortality and admission were determined by multivariable logistic regression. RESULTS: A weighted total of 8,611,282 visits between 2009 and 2011 were attributed to otologic diagnoses, representing 2.21% of all ED visits. Stratified by patient age, otologic diagnoses encompassed 1.01% and 6.79% of all adult and pediatric ED visits, respectively. The majority of patients were treated and released (98.17%). The average age of patients presenting with an otologic complaint was 17.9 years (standard error = 0.23). Overall, 62.7% of patients who presented with an otologic complaint were 0 to 17 years old. The most common diagnoses among all age groups included otitis media not otherwise specified (NOS) (60.6%), infected otitis externa NOS (11.8%), and otalgia NOS (6.8%). CONCLUSIONS: We provide a comprehensive overview of otologic complaints that are an overlooked diagnostic category in public health research. NEDS data demonstrate a significant number of visits related to otologic complaints, especially in the pediatric population, that are nonemergent. LEVEL OF EVIDENCE: 4 PMID- 25702899 TI - Development of an Automated Column Solid-Phase Extraction Cleanup of QuEChERS Extracts, Using a Zirconia-Based Sorbent, for Pesticide Residue Analyses by LC MS/MS. AB - A new, automated, high-throughput, mini-column solid-phase extraction (c-SPE) cleanup method for QuEChERS extracts was developed, using a robotic X-Y-Z instrument autosampler, for analysis of pesticide residues in fruits and vegetables by LC-MS/MS. Removal of avocado matrix and recoveries of 263 pesticides and metabolites were studied, using various stationary phase mixtures, including zirconia-based sorbents, and elution with acetonitrile. These experiments allowed selection of a sorbent mixture consisting of zirconia, C18, and carbon-coated silica, that effectively retained avocado matrix but also retained 53 pesticides with <70% recoveries. Addition of MeOH to the elution solvent improved pesticide recoveries from zirconia, as did citrate ions in CEN QuEChERS extracts. Finally, formate buffer in acetonitrile/MeOH (1:1) was required to give >70% recoveries of all 263 pesticides. Analysis of avocado extracts by LC-Q-Orbitrap-MS showed that the method developed was removing >90% of di- and triacylglycerols. The method was validated for 269 pesticides (including homologues and metabolites) in avocado and citrus. Spike recoveries were within 70-120% and 20% RSD for 243 of these analytes in avocado and 254 in citrus, when calibrated against solvent-only standards, indicating effective matrix removal and minimal electrospray ionization suppression. PMID- 25702898 TI - Dual islet transplantation modeling of the instant blood-mediated inflammatory reaction. AB - Islet xenotransplantation is a potential treatment for diabetes without the limitations of tissue availability. Although successful experimentally, early islet loss remains substantial and attributed to an instant blood-mediated inflammatory reaction (IBMIR). This syndrome of islet destruction has been incompletely defined and characterization in pig-to-primate models has been hampered by logistical and statistical limitations of large animal studies. To further investigate IBMIR, we developed a novel in vivo dual islet transplant model to precisely characterize IBMIR as proof-of-concept that this model can serve to properly control experiments comparing modified xenoislet preparations. WT and alpha1,3-galactosyltransferase knockout (GTKO) neonatal porcine islets were studied in nonimmunosuppressed rhesus macaques. Inert polyethylene microspheres served as a control for the effects of portal embolization. Digital analysis of immunohistochemistry targeting IBMIR mediators was performed at 1 and 24 h after intraportal islet infusion. Early findings observed in transplanted islets include complement and antibody deposition, and infiltration by neutrophils, macrophages and platelets. Insulin, complement, antibody, neutrophils, macrophages and platelets were similar between GTKO and WT islets, with increasing macrophage infiltration at 24 h in both phenotypes. This model provides an objective and internally controlled study of distinct islet preparations and documents the temporal histology of IBMIR. PMID- 25702900 TI - Bioassay-guided isolation of antibacterial constituents from Diospyros lotus roots. AB - The aim of this study was to explore the extract/fractions and compounds of Diospyros lotus against various Gram-positive and Gram-negative bacteria strain. The results showed marked susceptibility of extract and its fractions against test pathogens. Among them, chloroform fraction was most dominant and effective against all tested bacteria. The chloroform fraction was subjected to column chromatography which led to the isolation of lupeol (1), 7-methyljuglone (2), beta-sitosterol (3), stigmasterol (4), betulinic acid (5), diospyrin (6) and 8 hydroxyisodiospyrin (7). Among the isolated compounds, betulinic acid (5) showed significant activity against most of the tested pathogen. In conclusion, our study validated the traditional uses of the plant in the treatment of infectious diseases which was also strongly supported by the isolated compound, betulinic acid (5). PMID- 25702901 TI - Hurdle technology applied to prickly pear beverages for inhibiting Saccharomyces cerevisiae and Escherichia coli. AB - The effect of pH reduction (from 6.30-6.45 to 4.22-4.46) and the addition of antimicrobial compounds (sodium benzoate and potassium sorbate) on the inhibition of Saccharomyces cerevisiae and Escherichia coli in prickly pear beverages formulated with the pulp and peel of Villanueva (V, Opuntia albicarpa) and Rojo Vigor (RV, Opuntia ficus-indica) varieties during 14 days of storage at 25 degrees C, was evaluated. RV variety presented the highest microbial inhibition. By combining pH reduction and preservatives, reductions of 6.2-log10 and 2.3 log10 for E. coli and S. cerevisiae were achieved respectively. Due to the low reduction of S. cerevisiae, pulsed electric fields (PEF) (11-15 MUs/25-50 Hz/27 36 kV cm(-1)) was applied as another preservation factor. The combination of preservatives, pH reduction and PEF at 13-15 MUs/25-50 Hz for V variety, and 11 MUs/50 Hz, 13-15 MUs/25-50 Hz for RV, had a synergistic effect on S. cerevisiae inhibition, achieving at least 3.4-log10 of microbial reduction immediately after processing, and more than 5-log10 at fourth day of storage at 25 degrees C maintained this reduction during 21 days of storage (P > 0.05). Hurdle technology using PEF in combination with other factors is adequate to maintain stable prickly pear beverages during 21 days/25 degrees C. Significance and impact of the study: Prickly pear is a fruit with functional value, with high content of nutraceuticals and antioxidant activity. Functional beverages formulated with the pulp and peel of this fruit represent an alternative for its consumption. Escherichia coli and Saccharomyces cerevisiae are micro-organisms that typically affect fruit beverage quality and safety. The food industry is looking for processing technologies that maintain quality without compromising safety. Hurdle technology, including pulsed electric fields (PEF) could be an option to achieve this. The combination of PEF, pH reduction and preservatives is an alternative to obtain safe and minimally processed prickly pear beverages with convenient shelf life. PMID- 25702902 TI - Etiology-based classification--the way forward for psychiatry. PMID- 25702903 TI - Ameliorative effect of methanol extract of Rumex vesicarius on CCl4-induced liver damage in Wistar albino rats. AB - CONTEXT: Rumex vesicarius L. (Polygonaceae), an edible plant, is reported to have many bioactive phytochemicals, especially flavonoids and anthraquinones with antioxidant and detoxifying properties. OBJECTIVE: This study evaluated the methanolic extract of R. vasicarius (MERV) for hepatoprotective activity in rats against CCl4-induced liver damage. MATERIALS AND METHODS: The whole plant extract was prepared and investigated for its hepatoprotective activity. Rats were pretreated with MERV (100 and 200 mg/kg, p.o.) for 7 d prior to the induction of liver damage by CCl4. Animals were then sacrificed 24 h after CCl4 administration for the biochemical (AST, ALT, and ALP activity in serum; lipid peroxidation (LPO) and glutathione (GSH) levels in liver tissue) and histological analyses. RESULTS: CCl4-induced hepatotoxicity was confirmed by an increase (p < 0.05) in serum AST (4.55-fold), ALT (3.51-fold), and ALP (1.82-fold) activities. CCl4 induced hepatotoxicity was also manifested by an increase (p < 0.05) in LPO (3.88 fold) and depletion of reduced glutathione (3.14-fold) activity in liver tissue. The multiple dose MERV administration at 200 mg/kg showed promising hepatoprotective activity as evident from significant decrease levels of serum AST (230.01 +/- 13.21), serum ALT (82.15 +/- 5.01), serum ALP (504.75 +/- 19.72), hepatic LPO (3.38 +/- 0.33), and increased levels of hepatic glutathione (0.34 +/ 0.04) towards near normal. Further, biochemical results were confirmed by histopathological changes as compared with CCl4-intoxicated rats. DISCUSSION AND CONCLUSION: The results obtained from this study indicate hepatoprotective activity of Rumex plant against CCl4-induced liver toxicity; hence, it can be used as a hepatoprotective agent. PMID- 25702904 TI - Investigation on vitamin D knowledge, attitude and practice of university students in Nanjing, China. AB - OBJECTIVE: To investigate university students' knowledge, attitudes and practice (KAP) regarding vitamin D. DESIGN: The students were requested to answer a questionnaire related to vitamin D and sun exposure. The consumption frequency of foods rich in vitamin D was assessed. Additionally, the intake of vitamin D containing supplements was recorded. SETTING: A medical university in Nanjing, China. SUBJECTS: Five hundred and fifteen medical students were included. RESULTS: The highest rate of correct responses for the quiz was 68.0 %, while the lowest was 9.6 %. Most students lacked sun exposure because they did not want to get tanned; 82.7 % of students used some sun protection and sunscreen use was more popular in the female group. The consumption frequency of foods rich in vitamin D was low and 5.6 % of the students used vitamin D supplements. The students' knowledge on vitamin D was derived mainly from the media and health professionals. Most of the students were interested to know more about vitamin D. CONCLUSIONS: The present study suggested that medical students had little knowledge and unfavourable behaviours. They should get more health education through the media and health professionals. It is advisable to increase their consumption of foods rich in vitamin D. PMID- 25702905 TI - Generations: the old gives way to the new, and the new is too soon the old. PMID- 25702906 TI - Another challenge for the presumed safety advantage of bare metal stents: noncardiac surgery. PMID- 25702907 TI - In-stent neoatherosclerosis and distal embolization: lesion architecture, composition, and PCI compression. PMID- 25702908 TI - Inhibition of thrombus formation inside the stent during PCI. PMID- 25702909 TI - The relationship between fractional flow reserve and index of microcirculatory resistance: be careful with whom you associate. PMID- 25702910 TI - Fractional flow reserve for the evaluation of coronary stenoses: limitations and alternatives. PMID- 25702911 TI - Evolving TAVR, and the need for intelligent design. PMID- 25702912 TI - The peculiar behavior of the glass transition temperature of amorphous drug polymer films coated on inert sugar spheres. AB - Fluid bed coating has been proposed in the past as an alternative technology for manufacturing of drug-polymer amorphous solid dispersions, or so-called glass solutions. It has the advantage of being a one-step process, and thus omitting separate drying steps, addition of excipients, or manipulation of the dosage form. In search of an adequate sample preparation method for modulated differential scanning calorimetry analysis of beads coated with glass solutions, glass transition broadening and decrease of the glass transition temperature (Tg ) were observed with increasing particle size of crushed coated beads and crushed isolated films of indomethacin (INDO) and polyvinylpyrrolidone (PVP). Substituting INDO with naproxen gave comparable results. When ketoconazole was probed or the solvent in INDO-PVP films was switched to dichloromethane (DCM) or a methanol-DCM mixture, two distinct Tg regions were observed. Small particle sizes had a glass transition in the high Tg region, and large particle sizes had a glass transition in the low Tg region. This particle size-dependent glass transition was ascribed to different residual solvent amounts in the bulk and at the surface of the particles. A correlation was observed between the deviation of the Tg from that calculated from the Gordon-Taylor equation and the amount of residual solvent at the Tg of particles with different sizes. PMID- 25702914 TI - Tattoo conductive polymer nanosheets for skin-contact applications. AB - Conductive tattoo nanosheets are fabricated on top of decal transfer paper and transferred on target surfaces as temporary transfer tattoos. Circuits are patterned with ink-jet printing. Tattoo nanosheets are envisioned as unperceivable human-device interfaces because of conformal adhesion to complex surfaces including skin. They are tested as dry electrodes for surface electromyography (sEMG), which permits the control of a robotic hand. PMID- 25702915 TI - Surgery for deep venous incompetence. AB - BACKGROUND: Chronic deep venous incompetence (DVI) is caused by incompetent vein valves and/or blockage of large-calibre leg veins and causes a range of symptoms including recurrent ulcers, pain and swelling. Most surgeons accept that well fitted graduated compression stockings (GCS) and local care of wounds serve as adequate treatment for most patients, but sometimes symptoms are not controlled and ulcers recur frequently, or they do not heal despite compliance with conservative measures. In these situations, in the presence of severe venous dysfunction, surgery has been advocated by some vascular surgeons. This is an update of the review first published in 2000. OBJECTIVES: To assess the effects of surgical management of deep venous incompetence in terms of ulcer healing, ulcer recurrence and alleviation of symptoms. SEARCH METHODS: For this update, the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched October 2014) and the Cochrane Central Register of Controlled Trials (CENTRAL) (2014, Issue 9). SELECTION CRITERIA: Randomised controlled trials of surgical treatment for patients with DVI. DATA COLLECTION AND ANALYSIS: For this update, two review authors (RRG and SCH) extracted data independently. All included studies required full risk of bias assessment in line with current procedures of The Cochrane Collaboration. Two review authors (RRG and SCH) independently assessed risk of bias and consulted with a third review author (AA) when necessary. MAIN RESULTS: Four studies with 273 participants were included. All included studies reported clinical outcomes following valvuloplasty. We found no studies investigating other surgical procedures for the treatment of patients with DVI. All included studies investigated primary valve incompetence. We found no trials that investigated the results of surgery for secondary valvular incompetence or the obstructive form of DVI. Because different outcome measures were used, it was not possible to pool the results of included studies. The methodological quality of the included studies was low, mainly because information regarding randomisation and blinding was missing, or because data were incomplete or were presented poorly. Ulcer healing and ulcer recurrence were not reported in one study, and the remaining three studies did not include participants with ulcers or with active ulceration. Three studies reported no significant complications of surgery and no incidence of DVT during follow-up. One study did not report on the occurrence of complications. Clinical changes were assessed by subjective and objective measurements, as specified in the clinical, aetiological, anatomical, and pathophysiological (CEAP) classification score. This requires vascular laboratory measurements of lower limb haemodynamics before and after surgery. Tests include an overall evaluation of venous function with venous refilling time (VRT) or ambulatory venous pressure (AVP). Two small trials comparing external valvuloplasty using limited anterior plication in combination with ligation of incompetent superficial veins against ligation alone (L) showed that ligation plus limited anterior plication produced significant improvement in AVP: The mean difference was -15 mm Hg (95% confidence interval (CI) -20.9 to -9.0) at one year and -15 mm Hg (95% CI -21 to -8.9) at two years. Sustainable statistically significant improvement in AVP and VRT was achieved by ligation and limited anterior plication at 10 years in one study. However, AVP values after surgery remained relatively high, causing its benefit to be questioned. Similarly, another study including participants who were deteriorating preoperatively showed sustained mild clinical improvement for seven years in those subjected to valvuloplasty compared with participants undergoing superficial venous surgery alone. However, this benefit was lost when the condition of participants was stable preoperatively. One small study (n = 40) with grade 3 reflux and no participants with ulcers reported that external valvuloplasty of the femoral vein combined with surgical repair of the superficial venous system improved the haemodynamic status of the lower limbs, restored valvular function more effectively and achieved better outcomes than surgical repair of the superficial venous system alone. AUTHORS' CONCLUSIONS: No evidence was found for benefit or harm of valvuloplasty in the treatment of patients with DVI secondary to primary valvular incompetence. The individual trials included in this review were small; they used different methods of assessment and overall were of poor quality. They did not include participants with severe DVI. Trials investigating the effects of other surgical procedures on deep veins are needed. Until the findings of such trials become available, the benefit of valvuloplasty remains uncertain. PMID- 25702916 TI - In memoriam: Paul J. Bedard, MD PhD: January 19, 1942-December 26, 2014. PMID- 25702917 TI - Postoperative complications after common femoral endarterectomy. AB - BACKGROUND: Common femoral endarterectomy (CFE) for limited arterial occlusive disease is considered a fairly low-risk operation of short duration. This study investigated the timing of 30-day outcomes as they related to hospital discharge and predicted the risk of operative mortality of this procedure. METHODS: All patients in the National Surgical Quality Improvement Program database who underwent isolated CFE between 2005 and 2010 were selected for the test sample. We identified postoperative mortality and morbidities occurring before and after hospital discharge. A risk calculator for 30-day mortality, developed in the test sample using logistic regression, was validated in a new sample of cases from 2011 to 2012. RESULTS: A total of 1843 CFEs reported from 2005 to 2010 met the inclusion and exclusion criteria. The average operative time was 146 +/- 69.5 minutes (median, 133; interquartile range, 98-179 minutes), and 10% of patients needed to return to the operating room. The average length of stay was 4 +/- 7.5 days (median, 3; interquartile range, 2-5 days); 91% of patients were discharged <= 1 week of surgery. Occurrences of cardiovascular events, renal dysfunction, and pulmonary complication were relatively low. There was 3.4% mortality and 8% wound-related complications, 30% and 86% of which occurred after hospital discharge, respectively. Overall, there was a 15% risk of combined mortality/morbidity, and >60% of these events occurred after discharge. The independent predictors of 30-day mortality were age, nonindependent functional status, preoperative dialysis, sepsis, emergency status, and American Society of Anesthesiologists Physical Status Classification 4 or 5, and the association between risk strata and death in the validation sample was strong (phi = 0.29) and significant (P < .001). CONCLUSIONS: CFE is not as "benign" a procedure as previously believed. The risks of death and wound complications are not insignificant, and a high percentage of these complications occurred after patients were discharged from the hospital. Patients should be carefully selected, especially in the elderly population, and close postoperative follow-up should be considered. PMID- 25702918 TI - Endovascular treatment of isolated abdominal aortic dissection and postoperative aortic remodeling. AB - OBJECTIVE: We report our experience of endovascular management and postoperative aortic remodeling of all types of isolated abdominal aortic dissection (IAAD). METHODS: This was retrospective study of 28 IAAD patients treated by endovascular means in our department between January 2007 and July 2013. We reviewed the risk factors, clinical features, computed tomography images, follow-up results, and aortic remodeling of these IAAD patients and propose a new morphologic classification into three types-supraceliac, paravisceral, and infrarenal according to the location of the primary entry site. RESULTS: There were four supraceliac IAADs, one paravisceral IAAD, and 23 infrarenal IAADs in our case series. Suprarenal (supraceliac + paravisceral) IAAD patients were relatively younger than infrarenal patients (45.2 +/- 8.6 years vs 60.6 +/- 15.5 years; P < .05). No difference was observed between suprarenal and infrarenal IAADs with respect to true lumen, false lumen, and dissection length on imaging (P > .05). All patients received endovascular treatment. The primary technical success rate was 100%. During a follow-up of 35.7 +/- 19.9 months, only one infrarenal patient needed an endovascular reintervention. All patients with supraceliac or infrarenal IAADs were alive at the time of follow-up; however, a paravisceral patient died of a dissecting abdominal aortic aneurysm rupture 21 months after endovascular treatment. In the suprarenal and infrarenal groups, endovascular treatment was associated with a significant decrease in the false lumen size and increase in the true lumen size (P < .05). The maximum abdominal aorta diameter decreased after endovascular treatment in both groups but was statistically significant only in the infrarenal group (P < .05). CONCLUSIONS: IAAD is a rare vascular disease. We propose it should be categorized as supraceliac, paravisceral, and infrarenal IAAD according to the location of the primary entry site. Endovascular treatment for supraceliac and infrarenal IAADs is a safe method with a high technical success rate and promising aortic remodeling, whereas endovascular treatment for paravisceral IAADs remains difficult. PMID- 25702919 TI - Morphological changes in the cervical muscles of women with chronic whiplash can be modified with exercise-A pilot study. AB - INTRODUCTION: In this preliminary study we determined whether MRI markers of cervical muscle degeneration [elevated muscle fatty infiltration (MFI), cross sectional area (CSA), and reduced relative muscle CSA (rmCSA)] could be modified with exercise in patients with chronic whiplash. METHODS: Five women with chronic whiplash undertook 10 weeks of neck exercise. MRI measures of the cervical multifidus (posterior) and longus capitus/colli (anterior) muscles, neck muscle strength, and self-reported neck disability were recorded at baseline and at completion of the exercise program. RESULTS: Overall significant increases in CSA and rmCSA were observed for both muscles, but significant reductions in MFI were only evident in the cervical multifidus muscle. These changes coincided with increased muscle strength and reduced neck disability. CONCLUSIONS: MRI markers of muscle morphology in individuals with chronic whiplash appear to be modifiable with exercise. PMID- 25702920 TI - Operant self-administration of sweetened ethanol and time course of blood ethanol levels in adolescent and adult male Long-Evans rats. AB - BACKGROUND: Little is known regarding mechanisms regulating ethanol (EtOH) self administration during adolescence or if the mechanisms differ from adults. One of the best models of abuse liability is operant self-administration. Therefore, we characterized operant sweetened EtOH self-administration behavior in adolescent and adult rats. METHODS: Adolescent (36 days old at first EtOH exposure) and adult male Long-Evans rats were first trained to self-administer 10% sucrose (10S) in an appetitive/consummatory operant model for 1 week, and then the drinking solution was switched to 10% sucrose plus 10% EtOH (10S10E) for 2 weeks. Next, rats were switched to a fixed ratio 2 schedule, and this was followed by 1 session using a progressive ratio schedule of reinforcement. Last, rats were tested for cue-induced reinstatement of lever-pressing behavior under extinction conditions after 13 days of abstinence. Blood EtOH concentration (BEC) of sweetened EtOH (self-administered or intragastric [IG] administration of 1 g/kg) was determined via gas chromatography. Control rats drank only 10S. RESULTS: Consumption of sweetened EtOH was not different between adolescents and adults under any schedule tested, reaching 1 g/kg in 20 minutes in the appetitive/consummatory model. Appetitive behavior directed at sweetened EtOH was less focused in adolescents versus adults. No age differences were found in motivation for sweetened EtOH. Cue-induced reinstatement of EtOH-seeking behavior after abstinence also did not differ by age. In control groups, no age difference was found in appetitive behavior or the amount of sucrose consumed, although adults exhibited greater cue-induced reinstatement. BEC after self-administration or IG administration of sweetened EtOH was higher in adults than adolescents. CONCLUSIONS: Consumption and motivation for sweetened EtOH are similar in adolescents and adults, although adolescents are more vulnerable to the effects of EtOH consumption on appetitive behavior. The IG results suggest larger volume of distribution and higher first-pass metabolism of sweetened EtOH in adolescents versus adults, which may limit the reinforcing effects of EtOH in some adolescents. Overall, we have begun to establish an operant sweetened EtOH self administration model in adolescent rats. PMID- 25702921 TI - Potentially inappropriate drug use in older people: a nationwide comparison of different explicit criteria for population-based estimates. AB - AIMS: The aim was to investigate the prevalence of potentially inappropriate medication use among older people in Sweden according to five different published sets of explicit criteria from Europe and the US. METHODS: This was a nationwide cross-sectional, register-based study across the whole of Sweden in 2008. All individuals aged 65 years and older were included (n = 1 346 709, both community dwelling and institutionalized persons). We applied all drug-specific criteria included in the 2012 Beers Criteria, the Laroche's list, the PRISCUS list, the NORGEP criteria and the Swedish National Board of Health and Welfare criteria. The main outcome was the potentially inappropriate drug use according to each set of criteria, separately and combined. Multivariate logistic regression models were used to identify individual factors associated with the use of potentially inappropriate drugs. RESULTS: The prevalence of potentially inappropriate medication use varied between the explicit criteria from 16% (NORGEP criteria) to 24% (2012 Beers criteria). Overall, 38% of the older people were exposed to potentially inappropriate drug use by at least one of the five sets of criteria. While controlling for other possible covariates, female gender, institutionalization and polypharmacy were systematically associated with inappropriate drug use, regardless of the set of explicit criteria we considered. CONCLUSION: Although explicit criteria for inappropriate drug use among older people have been reported to be quite different in their content, they provide similar measures of the prevalence of potentially inappropriate drug use at the population level. PMID- 25702922 TI - Nanomechanical behavior of MoS2 and WS2 multi-walled nanotubes and carbon nanohorns. AB - Nano-objects have been investigated for drug delivery, oil detection, contaminant removal, and tribology applications. In some applications, they are subjected to friction and deformation during contact with each other and their surfaces on which they slide. Experimental studies directly comparing local and global deformation are lacking. This research performs nanoindentation (local deformation) and compression tests (global deformation) with a nanoindenter (sharp tip and flat punch, respectively) on molybdenum disulfide (MoS2) multi walled nanotubes (MWNTs), ~500 nm in diameter. Hardness of the MoS2 nanotube was similar to bulk and does not follow the "smaller is stronger" phenomenon as previously reported for other nano-objects. Tungsten disulfide (WS2) MWNTs, ~300 nm in diameter and carbon nanohorns (CNHs) 80-100 nm in diameter were of interest and also selected for compression studies. These studies aid in understanding the mechanisms involved during global deformation when nano-objects are introduced to reduce friction and wear. For compression, highest loads were required for WS2 nanotubes, then MoS2 nanotubes and CNHs to achieve the same displacement. This was due to the greater number of defects with the MoS2 nanotubes and the flexibility of the CNHs. Repeat compression tests of nano-objects were performed showing a hardening effect for all three nano-objects. PMID- 25702923 TI - 4-hydroxy-3-methoxy-acetophenone-mediated long-lasting memory recovery, hippocampal neuroprotection, and reduction of glial cell activation after transient global cerebral ischemia in rats. AB - 4-Hydroxy-3-methoxy-acetophenone (apocynin) is a naturally occurring methoxy substitute catechol that is isolated from the roots of Apocynin cannabinum (Canadian hemp) and Picrorhiza kurroa (Scrophulariaceae). It has been previously shown to have antioxidant and neuroprotective properties in several models of neurodegenerative disease, including cerebral ischemia. The present study investigates the effects of apocynin on transient global cerebral ischemia (TGCI) induced retrograde memory deficits in rats. The protective effects of apocynin on neurodegeneration and the glial response to TGCI are also evaluated. Rats received a single intraperitoneal injection of apocynin (5 mg/kg) 30 min before TGCI and were tested 7, 14, and 21 days later in the eight-arm aversive radial maze (AvRM). After behavioral testing, the hippocampi were removed for histological evaluation. The present results confirm that TGCI causes memory impairment in the AvRM and that apocynin prevents these memory deficits and attenuates hippocampal neuronal death in a sustained way. Apocynin also decreases OX-42 and glial fibrillary acidic protein immunoreactivity induced by TGCI. These findings support the potential role of apocynin in preventing neurodegeneration and cognitive impairments following TGCI in rats. The long-term protective effects of apocynin may involve inhibition of the glial response. PMID- 25702924 TI - A mechanically sensitive cell layer regulates the physical properties of the Arabidopsis seed coat. AB - Endogenous mechanical stresses regulate plant growth and development. Tensile stress in epidermal cells affects microtubule reorientation and anisotropic cell wall deposition, and mechanical stimulus at the meristem regulates trafficking and polar localization of auxin transporters. However, the mechanical regulation of other plant growth regulators has not been demonstrated. Here we propose that during seed growth, mechanical stress exerted by the expanding embryo and endosperm is perceived by a specific mechanosensitive cell layer in the seed coat. We show that the adaxial epidermis of the outer integument thickens its cell wall in a mechanosensitive fashion, demonstrates microtubule dynamics consistent with mechanical stress perception and shows mechanosensitive expression of ELA1, a regulator of seed size and gibberellic acid (GA) metabolism. By exploiting physical and genetic compartmentalization, and combining genetic and surgical techniques, we propose a mechanistic link between mechanical stress and GA accumulation that regulates seed development. PMID- 25702925 TI - Anatomical Variations of the Blood Vascular System in Veterinary Medicine. The Internal Iliac Artery of the Dog. Part Two. AB - The aim of this study was to investigate the variability of the internal pudendal artery. Two hundred and thirty-two pelvic halves from 116 adult dogs were examined. Twenty-six anatomical variations were found, thirteen occurring in more than 5% of the dogs. Anatomical variations were grouped in relation to the origin of the prostatic/vaginal arteries, middle rectal artery, urethral artery, ventral perineal and caudal rectal arteries. The chi-squared test was used to analyse differences in sex, side of the body, profile and size, and the results were considered statistically significant when P <= 0.05. An identical vascular pattern in both hemipelvises was found for most of the anatomical variations described. PMID- 25702926 TI - Fluoxetine-induced transactivation of the platelet-derived growth factor type beta receptor reveals a novel heterologous desensitization process. AB - Many G protein-coupled receptors (GPCRs), including serotonin (5-HT) receptors promote the activity of receptor tyrosine kinases (RTKs) via intracellular signaling pathways in a process termed transactivation. Although transactivation pathways are commonly initiated by a GPCR, a recent report demonstrated that serotonin-selective reuptake inhibitors (SSRIs) were able to block 5-HT-induced transactivation of the platelet-derived growth factor (PDGF) type beta receptor. We show that a 45 min pretreatment of SH-SY5Y cells with the SSRI fluoxetine indeed blocked 5-HT-induced transactivation of the PDGFbeta receptor. However, upon further examination, we discovered that during the pretreatment period, fluoxetine itself was transiently transactivating the PDGFbeta receptor via 5-HT2 receptor activation. After 45min, the increase in PDGFbeta receptor phosphorylation induced by fluoxetine had returned to baseline, but a subsequent transactivating stimulus (5-HT) failed to "re-transactivate" the PDGFbeta receptor. We further demonstrate that 45min, but not 3h, 5-HT pretreatment blocks dopamine-induced PDGFbeta receptor transactivation. This did not involve changes in PDGF receptor function, since ligand (PDGF)-induced PDGFbeta receptor activation was not inhibited by 5-HT pretreatment. To our knowledge this is the first demonstration of the heterologous desensitization of an RTK transactivation pathway and reveals a previously unknown short-term "blackout" period where no additional transactivation signaling is possible. PMID- 25702927 TI - Stimulus-Driven Attention, Threat Bias, and Sad Bias in Youth with a History of an Anxiety Disorder or Depression. AB - Attention biases towards threatening and sad stimuli are associated with pediatric anxiety and depression, respectively. The basic cognitive mechanisms associated with attention biases in youth, however, remain unclear. Here, we tested the hypothesis that threat bias (selective attention for threatening versus neutral stimuli) but not sad bias relies on stimulus-driven attention. We collected measures of stimulus-driven attention, threat bias, sad bias, and current clinical symptoms in youth with a history of an anxiety disorder and/or depression (ANX/DEP; n = 40) as well as healthy controls (HC; n = 33). Stimulus driven attention was measured with a non-emotional spatial orienting task, while threat bias and sad bias were measured at a short time interval (150 ms) with a spatial orienting task using emotional faces and at a longer time interval (500 ms) using a dot-probe task. In ANX/DEP but not HC, early attention bias towards threat was negatively correlated with later attention bias to threat, suggesting that early threat vigilance was associated with later threat avoidance. Across all subjects, stimulus-driven orienting was not correlated with early threat bias but was negatively correlated with later threat bias, indicating that rapid stimulus-driven orienting is linked to later threat avoidance. No parallel relationships were detected for sad bias. Current symptoms of depression but not anxiety were related to decreased stimulus-driven attention. Together, these results are consistent with the hypothesis that threat bias but not sad bias relies on stimulus-driven attention. These results inform the design of attention bias modification programs that aim to reverse threat biases and reduce symptoms associated with pediatric anxiety and depression. PMID- 25702928 TI - Sterically hindered luminescent Pt(II) -phosphite complexes for electroluminescent devices. AB - Pt(II) complexes with one bulky, sterically demanding, tertiary phosphite ancillary ligand and a coordinating chromophore are herein presented. The phosphite ligand, tris(2,4-di-tert-butylphenyl) acts as a bidentate ligand coordinating the platinum ion through the central phosphorus atom and a cyclometalating carbon atom of one of the substituents. The two free phenoxy moieties lie above and below the coordination plane, leading to steric hindrance that avoids aggregation and provides solubility in organic solvents. The other two coordination sites on the central metal ion are occupied by a chromophoric ligand, which is responsible for the energy of the luminescent excited state. This separation of functions, on the two coordinated ligands, allows the use of a wider range of luminophores with good luminescent properties, maintaining the control of the intermolecular interactions with the non-chromophoric ligand. Based on this approach we were able to achieve a bright deep blue emission (lambda=444 nm, Phiem =0.38) from a complex with a tailored ligand, which was then used for the fabrication of an electroluminescent device. In addition commercially available luminophores were also employed to synthesize green emitters. PMID- 25702929 TI - The Relationship Between Self-Rated Health and Hospital Records. AB - This paper investigates whether self-rated health (SRH) covaries with individual hospital records. By linking the Danish Longitudinal Survey on Ageing with individual hospital records covering all hospital admissions from 1995 to 2006, I show that SRH is correlated to historical, current, and future hospital records. I use both measures separately to control for health in a regression of mortality on wealth. Using only historical and current hospitalization controls for health yields the common result that SRH is a stronger predictor of mortality than objective health measures. The addition of future hospitalizations as controls shows that the estimated gradient on wealth is similar to one in which SRH is the control. The results suggest that with a sufficiently long time series of individual records, objective health measures can predict mortality to the same extent as global self-rated measures. PMID- 25702930 TI - Sample selection bias in an international DNA panel: does Native American haplogroup Q-M3 has the b2/b3 deletion? PMID- 25702931 TI - Genome-wide SNP discovery and identification of QTL associated with agronomic traits in oil palm using genotyping-by-sequencing (GBS). AB - Oil palm has become one of the most important oil crops in the world. Marker assisted selections have played a pivotal role in oil palm breeding programs. Here, we report the use of genotyping-by-sequencing (GBS) approach for a large scale SNP discovery and genotyping of a mapping population. Reduced representation libraries of 108 F2 progeny were sequenced and a total of 524 million reads were obtained. We detected 21,471 single nucleotide substitutions, most of which (62.6%) represented transition events. Of 3417 fully informative SNP markers, we were able to place 1085 on a linkage map, which spanned 1429.6 cM and had an average of one marker every 1.26 cM. Three QTL affecting trunk height were detected on LG 10, 14 and 15, whereas a single QTL associated with fruit bunch weight was identified on LG 3. The use of GBS approach proved to be rapid, cost-effective and highly reproducible in this species. PMID- 25702932 TI - Brain Magnetic Resonance Spectroscopy Findings in the Stroke-like Migraine Attacks after Radiation Therapy (SMART) Syndrome. AB - A 41-year-old male presented with an acute onset of headache, confusion, seizures, and unilateral focal neurological deficit 25 years after receiving whole-brain radiation therapy to treat a cerebellar medulloblastoma. Brain magnetic resonance imaging (MRI) demonstrated a thick unilateral parieto occipital cortical contrast enhancement. A diagnosis of "Stroke-like Migraine Attacks after Radiation Therapy" (SMART) syndrome was made. Here, we describe the brain MR spectroscopy findings of SMART, showing a decrease in N-acetyl-aspartate and increased levels of creatine and choline, corresponding with neuronal destruction or transient neuronal impairment with mild nonspecific gliosis. The absence of a lactate peak suggests that mitochondrial dysfunction, vasospasm or ischemic mechanisms were not involved. PMID- 25702933 TI - Powder cocaine and crack use in the United States: an examination of risk for arrest and socioeconomic disparities in use. AB - BACKGROUND: In light of the current sentencing disparity (18:1) between crack and powder cocaine possession in the United States, we examined socioeconomic correlates of use of each, and relations between use and arrest, to determine who may be at highest risk for arrest and imprisonment. METHODS: We conducted secondary data analyses on the National Survey on Drug Use and Health, 2009-2012. Data were analyzed for adults age >= 18 to determine associations between use and arrest. Socioeconomic correlates of lifetime and annual use of powder cocaine and of crack were delineated using multivariable logistic regression and correlates of frequency of recent use were examined using generalized negative binomial regression. RESULTS: Crack users were at higher risk than powder cocaine users for reporting a lifetime arrest or multiple recent arrests. Racial minorities were at low risk for powder cocaine use and Hispanics were at low risk for crack use. Blacks were at increased risk for lifetime and recent crack use, but not when controlling for other socioeconomic variables. However, blacks who did use either powder cocaine or crack tended to use at higher frequencies. Higher education and higher family income were negatively associated with crack use although these factors were sometimes risk factors for powder cocaine use. CONCLUSIONS: Crack users are at higher risk of arrest and tend to be of lower socioeconomic status compared to powder cocaine users. These findings can inform US Congress as they review bills (e.g., The Smarter Sentencing Act), which would help eliminate cocaine-related sentencing disparities. PMID- 25702934 TI - Testosterone suppression in opioid users: a systematic review and meta-analysis. AB - BACKGROUND: Whether used for pain management or recreation, opioids have a number of adverse effects including hormonal imbalances. These imbalances have been reported to primarily involve testosterone and affect both males and females to the point of interfering with successful treatment and recovery. We conducted a systematic review and meta-analysis to determine the extent that opioids affect testosterone levels in both men and women, which may be relevant to improved treatment outcomes for opioid dependence and for pain management. METHODS: We searched PubMed, EMBASE, PsycINFO, and CINAHL for relevant articles and included studies that examined testosterone levels in men and women while on opioids. Data collection was completed in duplicate. RESULTS: Seventeen studies with 2769 participants (800 opioid users and 1969 controls) fulfilled the review inclusion criteria; 10 studies were cross-sectional and seven were cohort studies. Results showed a significant difference in mean testosterone level in men with opioid use compared to controls (MD=-164.78; 95% CI: -245.47, -84.08; p<0.0001). Methadone did not affect testosterone differently than other opioids. Testosterone levels in women were not affected by opioids. Generalizability of results was limited due to high heterogeneity among studies and overall low quality of evidence. CONCLUSIONS: Our findings demonstrated that testosterone level is suppressed in men with regular opioid use regardless of opioid type. We found that opioids affect testosterone levels differently in men than women. This suggests that opioids, including methadone, may have different endocrine disruption mechanisms in men and women, which should be considered when treating opioid dependence. PMID- 25702935 TI - Review of polyoxymethylene passive sampling methods for quantifying freely dissolved porewater concentrations of hydrophobic organic contaminants. AB - Meth ods involving polyoxymethylene (POM) as a passive sampler are increasing in popularity to assess contaminant freely dissolved porewater concentrations in soils and sediments. These methods require contaminant-specific POM-water partition coefficients, KPOM . Certain methods for determining KPOM perform reproducibly (within 0.2 log units). However, other methods can give highly varying KPOM values (up to 2 log units), especially for polycyclic aromatic hydrocarbons (PAHs). To account for this variation, the authors tested the influence of key methodological components in KPOM determinations, including POM thickness, extraction procedures, and environmental temperature and salinity, as well as uptake kinetics in mixed and static systems. All inconsistencies in the peer-reviewed literature can be accounted for by the likelihood that thick POM materials (500 MUm or thicker) do not achieve equilibrium (causing negative biases up to 1 log unit), or that certain POM extraction procedures do not ensure quantitative extraction (causing negative biases up to 2 log units). Temperature can also influence KPOM , although all previous literature studies were carried out at room temperature. The present study found that KPOM values at room temperature are independent (within 0.2 log units) of POM manufacture method, of thickness between 17 MUm and 80 MUm, and of salinity between 0% and 10%. Regarding kinetics, monochloro- to hexachloro-polychlorinated biphenyls (PCBs) were within 0.2 log units of equilibrium after 28 d in the mixed system, but only dichloro-PCBs achieved near equilibrium after 126 d in the static system. Based on these insights, recommended methods and KPOM values to facilitate interlaboratory reproducibility are presented. PMID- 25702936 TI - Incidence of hospitalization and its associated factors in first-episode psychosis in Hong Kong. AB - AIM: This study examined the incidence of hospitalization and its associated factors in patients with first-episode psychosis in Hong Kong. METHOD: From 2009 to 2011, 360 patients were recruited consecutively as part of a controlled study of an early psychosis intervention service (the Jockey Club Early Psychosis project) in Hong Kong. Demographic and clinical information were obtained from face-to-face interviews and was reconfirmed using medical records. Factors relating to hospitalization during first episode were explored. RESULTS: The incidence of hospitalization during first-episode psychosis was 57.2%. Patients who were hospitalized had higher antipsychotics chlorpromazine equivalent dosage, higher positive and negative syndrome scale total score, higher Udvalg for Kliniske Undersogelser others mean score and were more likely to have an acute mode of onset compared with those who were not hospitalized. CONCLUSIONS: Hospitalization was common in first-episode psychosis. Future studies are needed to explore possible programmes to prevent hospitalization in patients with first episode psychosis. PMID- 25702937 TI - Evolution of dispersal under a fecundity-dispersal trade-off. AB - Resources invested in dispersal structures as well as time and energy spent during transfer may often decrease fecundity. Here we analyse an extended version of the Hamilton-May model of dispersal evolution, where we include a fecundity dispersal trade-off and also mortality between competition and reproduction. With adaptive dynamics and critical function analysis we investigate the evolution of dispersal strategies and ask whether adaptive diversification is possible. We exclude evolutionary branching for concave trade-offs and show that for convex trade-offs diversification is promoted in a narrow parameter range. We provide theoretical evidence that dispersal strategies can monotonically decrease with increasing survival during dispersal. Moreover, we illustrate the existence of two alternative attracting dispersal strategies. The model exhibits fold bifurcation points where slight changes in survival can lead to evolutionary catastrophes. PMID- 25702938 TI - Plant reproduction and environmental noise: how do plants do it? AB - Plant populations exhibit a wide continuum of reproductive behavior, ranging from nearly constant reproductive output on one end to the extreme of masting (synchronized, highly variable reproduction) on the other. Here, we show that including variability (noise) in density-dependent pollen limitation in current models for pollen-limited plant reproduction may produce any behavior on this continuum. We previously showed that (large) variability in pollination efficiency (a related phenomenon) may induce masting in non-pollen-limited plant populations. Other modeling studies have shown that including variability in accumulated resources (and/or the threshold for reproduction) may induce masting, but do account for masting in non-pollen-limited plant populations. Thus, our results suggest that the range of plant reproductive behavior may be explained with the simple resource budget model combined with the biological realism of variability in density-dependent pollen limitation. This is a specific example of an important functional consequence of the interactions between stochasticity and nonlinearity, and highlights the importance of carefully considering both the biological basis and the mathematical effects of the noise term. PMID- 25702939 TI - Phenotypic plasticity, the Baldwin effect, and the speeding up of evolution: the computational roots of an illusion. AB - An increasing number of dissident voices claim that the standard neo-Darwinian view of genes as 'leaders' and phenotypes as 'followers' during the process of adaptive evolution should be turned on its head. This idea is older than the rediscovery of Mendel's laws of inheritance, with the turn-of-the-twentieth century notion eventually labeled as the 'Baldwin effect' as one of the many ways in which the standard neo-Darwinian view can be turned around. A condition for this effect is that environmentally induced variation such as phenotypic plasticity or learning is crucial for the initial establishment of a trait. This gives the additional time for natural selection to act on genetic variation and the adaptive trait can be eventually encoded in the genotype. An influential paper published in the late 1980s claimed the Baldwin effect to happen in computer simulations, and avowed that it was crucial to solve a difficult adaptive task. This generated much excitement among scholars in various disciplines that regard neo-Darwinian accounts to explain the evolutionary emergence of high-order phenotypic traits such as consciousness or language almost hopeless. Here, we use analytical and computational approaches to show that a standard population genetics treatment can easily crack what the scientific community has granted as an unsolvable adaptive problem without learning. Evolutionary psychologists and linguists have invoked the (claimed) Baldwin effect to make wild assertions that should not be taken seriously. What the Baldwin effect needs are plausible case-histories. PMID- 25702940 TI - Modelling the risk of airborne infectious disease using exhaled air. AB - In this paper we develop and demonstrate a flexible mathematical model that predicts the risk of airborne infectious diseases, such as tuberculosis under steady state and non-steady state conditions by monitoring exhaled air by infectors in a confined space. In the development of this model, we used the rebreathed air accumulation rate concept to directly determine the average volume fraction of exhaled air in a given space. From a biological point of view, exhaled air by infectors contains airborne infectious particles that cause airborne infectious diseases such as tuberculosis in confined spaces. Since not all infectious particles can reach the target infection site, we took into account that the infectious particles that commence the infection are determined by respiratory deposition fraction, which is the probability of each infectious particle reaching the target infection site of the respiratory tracts and causing infection. Furthermore, we compute the quantity of carbon dioxide as a marker of exhaled air, which can be inhaled in the room with high likelihood of causing airborne infectious disease given the presence of infectors. We demonstrated mathematically and schematically the correlation between TB transmission probability and airborne infectious particle generation rate, ventilation rate, average volume fraction of exhaled air, TB prevalence and duration of exposure to infectors in a confined space. PMID- 25702941 TI - Micro- and nano-technologies for lipid bilayer-based ion-channel functional assays. AB - Ion channel proteins provide gated pores that allow ions to passively flow across cell membranes. Owing to their crucial roles in regulating transmembrane ion flow, ion channel proteins have attracted the attention of pharmaceutical investigators as drug targets for use in the studies of both therapeutics and side effects. In this review, we discuss the current technologies that are used in the formation of ion channel-integrated bilayer lipid membranes (BLMs) in microfabricated devices as a potential platform for next-generation drug screening systems. Advances in BLM fabrication methodology have allowed the preparation of BLMs in sophisticated formats, such as microfluidic, automated, and/or array systems, which can be combined with channel current recordings. A much more critical step is the integration of the target channels into BLMs. Current technologies for the functional reconstitution of ion channel proteins are presented and discussed. Finally, the remaining issues of the BLM-based methods for recording ion channel activities and their potential applications as drug screening systems are discussed. PMID- 25702942 TI - Effects of hyperglycemia on lonidamine-induced acidification and de-energization of human melanoma xenografts and sensitization to melphalan. AB - We seek to exploit the natural tendency of melanomas and other tumors to convert glucose to lactate as a method for the selective intracellular acidification of cancer cells and for the potentiation of the activity of nitrogen-mustard antineoplastic agents. We performed this study to evaluate whether the induction of hyperglycemia (26 mM) could enhance the effects of lonidamine (LND, 100 mg/kg; intraperitoneally) on the induction of intracellular acidification, bioenergetic decline and potentiation of the activity of melphalan (LPAM) against DB-1 melanoma xenografts in mice. Intracellular pH (pHi ), extracellular pH (pHe ) and bioenergetics (beta-nucleoside triphosphate to inorganic phosphate ratio, beta NTP/Pi) were reduced by 0.7 units (p < 0.001), 0.3 units (p > 0.05) and 51.4% (p < 0.05), respectively. The therapeutic response to LPAM (7.5 mg/kg; intravenously) + LND (100 mg/kg; intraperitoneally) was reduced by about a factor of three under hyperglycemic conditions relative to normoglycemia, producing a growth delay of 7.76 days (tumor doubling time, 5.31 days; cell kill, 64%) compared with LND alone of 1.70 days and LPAM alone of 0.29 days. Under normoglycemic conditions, LND plus LPAM produced a growth delay of 17.75 days, corresponding to a cell kill of 90% at the same dose for each of these agents. The decrease in tumor cell kill under hyperglycemic conditions correlates with an increase in tumor ATP levels resulting from increased glycolytic activity. However, hyperglycemia substantially increases lactic acid production in tumors by a factor of approximately six (p < 0.05), but hyperglycemia did not increase the effects of LND on acidification of the tumor, most probably because of the strong buffering action of carbon dioxide (the pKa of carbonic acid is 6.4). Therefore, this study demonstrates that the addition of glucose during treatment with LND diminishes the activity of this agent. PMID- 25702943 TI - Evidence in chronic fatigue syndrome for severity-dependent upregulation of prefrontal myelination that is independent of anxiety and depression. AB - White matter (WM) involvement in chronic fatigue syndrome (CFS) was assessed using voxel-based regressions of brain MRI against CFS severity scores and CFS duration in 25 subjects with CFS and 25 normal controls (NCs). As well as voxel based morphometry, a novel voxel-based quantitative analysis of T1 - and T2 weighted spin-echo (T1w and T2w) MRI signal level was performed. Severity scores included the Bell CFS disability scale and scores based on the 10 most common CFS symptoms. Hospital Anxiety and Depression Scale (HADS) depression and anxiety scores were included as nuisance covariates. By relaxing the threshold for cluster formation, we showed that the T1w signal is elevated with increasing CFS severity in the ventrolateral thalamus, internal capsule and prefrontal WM. Earlier reports of WM volume losses and neuroinflammation in the midbrain, together with the upregulated prefrontal myelination suggested here, are consistent with the midbrain changes being associated with impaired nerve conduction which stimulates a plastic response on the cortical side of the thalamic relay in the same circuits. The T2w signal versus CFS duration and comparison of T2w signal in the CFS group with the NC group revealed changes in the right middle temporal lobe WM, where impaired communication can affect cognitive function. Adjustment for depression markedly strengthened cluster statistics and increased cluster size in both T1w severity regressions, but adjustment for anxiety less so. Thus, depression and anxiety are statistical confounders here, meaning that they contribute variance to the T1w signal in prefrontal WM but this does not correlate with the co-located variance from CFS severity. MRI regressions with depression itself only detected associations with WM volume, also located in prefrontal WM. We propose that impaired reciprocal brain-body and brain-brain communication through the midbrain provokes peripheral and central responses which contribute to CFS symptoms. Although anxiety, depression and CFS may share biological features, the present evidence indicates that CFS is a distinct disorder. PMID- 25702944 TI - Imaging of prolonged BOLD response in the somatosensory cortex of the rat. AB - Blood oxygenation level-dependent (BOLD) functional MRI is a widely employed methodology in experimental and clinical neuroscience, although its nature is not fully understood. To gain insights into BOLD mechanisms and take advantage of the new functional methods, it is of interest to investigate prolonged paradigms of activation suitable for long experimental protocols and to observe any long-term modifications induced by these functional challenges. While different types of sustained stimulation paradigm have been explored in human studies, the BOLD response is typically limited to a few minutes in animal models, due to fatigue, anesthesia effects and physiological instability. In the present study, the rat forepaw was electrically stimulated for 2 h, which resulted in a prolonged and localized cortical BOLD response over that period. The stimulation paradigm, including an inter-stimulus interval (ISI) of 10 s, that is 25% of the total time, was applied at constant or variable frequency over 2 h. The steady-state level of the BOLD response was reached after 15-20 min of stimulation and was maintained until the end of the stimulation. On average, no substantial loss in activated volume was observed at the end of the stimulation, but less variability in the fraction of remaining activated volume and higher steady-state BOLD amplitude were observed when stimulation frequency was varied between 2 and 3 Hz every 5 min. We conclude that the combination of ISI and variable stimulus frequency reproducibly results in robust, prolonged and localized BOLD activation. PMID- 25702946 TI - Raised immunoglobulin A and circulating T follicular helper cells are linked to the development of food allergy in paediatric liver transplant patients. AB - BACKGROUND: Post-transplant food allergy (LTFA) is increasingly observed after paediatric liver transplantation (LT). Although the immunopathology of LTFA remains unclear, immunoglobulin (Ig) E seems to be implicated. OBJECTIVE: To study humoral and cellular immunity in paediatric LT patients in search for factors associated with LTFA, and compare with healthy controls (HC) and non transplant food-allergic children (FA). METHODS: We studied serum Ig levels in 29 LTFA, 43 non-food-allergic LT patients (LTnoFA), 21 FA patients and 36 HC. Serum specific IgA and IgE against common food allergens in LTFA, IgA1 , IgA2 and joining-chain-containing polymeric IgA (pIgA) were measured. Peripheral blood mononuclear cells were analysed by flow cytometry for B and T cell populations of interest. RESULTS: Serum IgA and specific IgA were higher in LTFA compared to LTnoFA. LTFA patients had the highest proportion of circulating T follicular helper cells (cTfh). The percentage of cTfh correlated positively with serum IgA. Unique in LTFA was also the significant increase in serum markers of mucosal IgA and the decrease in the Th17 subset of CXCR5(-) CD4(+) cells compared to HC. Both LT patients exhibited a rise in IgA(+) memory B cells and plasmablasts compared to HC and FA. CONCLUSIONS: LT has an impact on humoral immunity, remarkably in those patients developing FA. The increase in serum markers of mucosal IgA, food allergen-specific IgA and cTfh cells observed in LTFA, point towards a disturbance in intestinal immune homoeostasis in this patient group. PMID- 25702947 TI - Spine and test skeletal matrices of the Mediterranean sea urchin Arbacia lixula- a comparative characterization of their sugar signature. AB - Calcified structures of sea urchins are biocomposite materials that comprise a minor fraction of organic macromolecules, such as proteins, glycoproteins and polysaccharides. These macromolecules are thought to collectively regulate mineral deposition during the process of calcification. When occluded, they modify the properties of the mineral. In the present study, the organic matrices (both soluble and insoluble in acetic acid) of spines and tests from the Mediterranean black sea urchin Arbacia lixula were extracted and characterized, in order to determine whether they exhibit similar biochemical signatures. Bulk characterizations were performed by mono-dimensional SDS/PAGE, FT-IR spectroscopy, and an in vitro crystallization assay. We concentrated our efforts on characterization of the sugar moieties. To this end, we determined the monosaccharide content of the soluble and insoluble organic matrices of A. lixula spines and tests by HPAE-PAD, together with their respective lectin-binding profiles via enzyme-linked lectin assay. Finally, we performed in situ localization of N-acetyl glucosamine-containing saccharides on spines and tests using gold-conjugated wheatgerm agglutinin. Our data show that the test and spine matrices exhibit different biochemical signatures with regard to their saccharidic fraction, suggesting that future studies should analyse the regulation of mineral deposition by the matrix in these two mineralized structures in detail. This study re-emphasizes the importance of non-protein moieties, i.e. sugars, in calcium carbonate systems, and highlights the need to clearly identify their function in the biomineralization process. PMID- 25702949 TI - Genetic conditions of joint Nordic genetic evaluations of lifetime competition performance in warmblood sport horses. AB - Breeding programmes for warmblood sport horses are similar in the Nordic countries Sweden, Denmark, Finland and Norway, and stallions of same origin are used. The aim was to investigate whether a joint Nordic genetic evaluation based on lifetime competition performance is feasible and beneficial for breeding competitive sport horses in the Nordic countries. Results for almost 45,000 horses in show jumping and 30,000 horses in dressage were available. The larger populations in Sweden and Denmark contributed with 85% of the results. Heritabilities and genetic correlations between performances in the different countries were estimated, and comparisons of accuracies of estimated breeding values (EBVs) and number of stallions with EBVs based on national or joint data were studied. The heritabilities ranged between 0.25 and 0.42 for show jumping and between 0.14 and 0.55 for dressage. The genetic correlations between competition performances in the Nordic countries were estimated to 0.63-1.00. EBVs based on joint data increased accuracies for EBVs for stallions by 38-81% and increased the number of available stallions with EBVs by 40-288%, compared to EBVs based on national data only. A joint Nordic genetic evaluation for sport horses is recommended. PMID- 25702950 TI - A rare case of pneumocephalus and pneumorrhachis after epidural anesthesia. AB - Both pneumocephalus and pneumorrhachis are rare but serious complications following epidural anesthesia. We report a rare case of simultaneous pneumocephalus and pneumorrhachis in a patient after undergoing epidural anesthesia. The patient lost consciousness and received emergent external ventricular drainage for pneumocephalus in another medical center. The patient was clear after external ventricular drain placement until 4 days later, when sudden onset of subdural hemorrhage occurred and an emergent craniectomy was performed. The patient passed away 2 days after craniectomy, due to multiorgan failure. Pneumocephalus with or without pneumorrhachis should be kept in mind when there is a sudden change of consciousness or persistent convulsions after epidural anesthesia. PMID- 25702951 TI - Recovery of DNA from latent fingerprint tape lifts archived against matte acetate. AB - This study was driven by court order to examine methods to remove, extract, and STR-type potential DNA entrapped between latent fingerprint lifting tape and matte acetate that was collected from a 1977 crime scene. Results indicate that recovery of appreciable quantities of DNA is more challenging once adhesive is attached to matte acetate cards and even more difficult when fixed following black powder enhancement. STR amplification of extracts from entrapped fingermarks collected following the dusting/lifting procedure did not produce robust profiles, and extraneous peaks not expressed by print donors were detected for some samples. A hearing was set to argue whether there was DNA remaining to be tested, and if so, whether that DNA could be exculpatory in this postconviction matter. The studies herein provided the basis for the court's decision to not require the testing. PMID- 25702952 TI - Platelet transfusion and catheter insertion for plasma exchange in patients with thrombotic thrombocytopenic purpura and a low platelet count. AB - BACKGROUND: In thrombotic thrombocytopenic purpura (TTP), platelet (PLT) transfusion is contraindicated unless a life-threatening hemorrhage occurs. However, when PLT count is low (<20 * 10(9) /L), their benefit-risk balance before central venous catheter (CVC) insertion for plasma exchange (PE) has not specifically been addressed in guidelines. CASE REPORTS: We report two cases in which PLTs were transfused before CVC insertion for PE, resulting in fatal myocardial infarction or neurologic complications. DISCUSSION: To date, there is a paucity of high-quality, evidence-based information on prophylactic PLT transfusion for CVC placement in TTP. Several monocenter series report that CVC could be inserted safely without PLT transfusion by experienced teams under ultrasound guidance. Uncertainty makes most physicians uncomfortable with this decision and this is a common reason why PLT transfusion remains a "precautionary" albeit misguided position. CONCLUSION: We propose a practical algorithm to avoid unnecessary PLT transfusion before CVC insertion for rapid PE in the initial management of TTP patients. We recommend no prophylactic PLT transfusion but CVC insertion in a compressible vein under ultrasound guidance by an experienced team or quick PE started on two peripheral veins if possible. PLTs should only be transfused in case of severe bleeding in association with plasma infusion and CVC insertion for immediate PE. PMID- 25702953 TI - Effects of Lysiphlebia japonica (Ashmead) on cotton-melon aphid Aphis gossypii Glover lipid synthesis. AB - The cotton-melon aphid, Aphis gossypii Glover, is a major insect pest worldwide. The wasp Lysiphlebia japonica (Ashmead) is the predominant parasitoid of cotton melon aphids in north China. Parasitization has been reported to affect host lipids in several systems, but the lipid synthesis-related genes and transcription changes in the cotton-melon aphid-parasitoid interaction are not clear. In this study, 36 lipid synthesis-related genes were cloned and their transcription changes in parasitized aphids were studied by quantitative real time PCR. In parasitized cotton-melon aphids, almost all key genes in the glycerolipid synthesis pathway were up-regulated, the rate-limiting enzyme diacylglycerol o-acyltransferase by 3.24-fold. The rate-limiting enzyme of the glycolytic pathway, pyruvate kinase, and the pace-making enzyme in citrate synthesis were 1.69-fold and 1.75-fold less in parasitized aphids than in unparasitized aphids, respectively. These results suggest increased glycerolipid synthesis in parasitized aphids but that citrate production from sucrose was decreased. Aconitate hydratase (aco), in the pathway that converts amino acids into citrate, was up-regulated. The number of fragments per kilobase per million mapped reads of the mitochondrial aco2 gene was only 4.6, whereas that of the cytoplasmic aco1 was 41.5, indicating that the citrate comes from amino acids in the cytoplasm of parasitized cotton-melon aphids. PMID- 25702954 TI - Dynamic decomposition of motion in essential and parkinsonian tremor. AB - BACKGROUND: Treatment options for essential (ET) and Parkinson disease (PD) tremor are suboptimal, with significant side effects. Botulinum toxin type A (BoNT A) is successfully used in management of various focal movement disorders but is not widely used for tremor. METHOD: This study examines complexity of wrist tremor in terms of involvement of its three anatomical degrees of freedom (DOF) in two common situations of rest and posture. The study examines tremor in 11 ET and 17 PD participants by kinematic decomposition of motion in 3-DOF. RESULTS: Tremor decomposition showed the motion involved more than one DOF (<70% contribution in one DOF) in most ET (rest: 100%, posture: 64%) and PD (rest: 77%, posture: 77%) patients. Task variation resulted in change in both amplitude and composition in ET, but not in PD. Amplitude significantly increased from rest to posture in ET. Directional bias was observed at the wrist for ET (pronation), and PD (extension, ulnar deviation, pronation). Average agreement between clinical visual and kinematic selection of muscles was 55% across all subjects. CONCLUSION: This study shows the complexity of tremor and the difficulty in visual judgment of tremor, which may be key to the success of targeted focal treatments such as BoNT A. PMID- 25702955 TI - Tumour infiltrating lymphocytes (TILs) in breast cancer during pregnancy. AB - BACKGROUND: Tumour infiltrating lymphocytes (TILs) is one of the most exciting breast cancer biomarkers, yet no data is available on its prevalence in tumours diagnosed during pregnancy. METHODS: We evaluated the prevalence of TILs (stromal and intratumoural) in pregnant and non-pregnant young breast cancer patients. RESULTS: 11/116 (9.6%) of the non-pregnant and 2/86 (2.3%) pregnant patients had TILs >= 50% (p < 0.001) with highest prevalence observed in triple negative tumours (p = 0.01). CONCLUSIONS: This is the first report on TILs in tumours diagnosed during pregnancy. The low prevalence could reflect the state of low host immunity associated with pregnancy. PMID- 25702956 TI - Basal cell carcinoma vs basaloid squamous cell carcinoma of the skin: an immunohistochemical reappraisal. AB - Typical cutaneous basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are morphologically dissimilar. It is well known, however, that poorly differentiated SCC may assume a basaloid phenotype, complicating the histologic distinction between these 2 neoplasms. Selected immunohistochemical stains have been used in the past to aid in that differential diagnosis. In the current study, additional markers were evaluated to determine whether they would be helpful in that regard. Twenty-nine cases of metatypical (squamoid) BCC (MBCC) and 25 examples of basaloid SCC (BSCC) were studied using the antibodies Ber-EP4 and MOC-31 as well as a plant lectin preparation from Ulex europaeus I (UEA-1). The resulting immunostains were interpreted independently by 3 pathologists, and the results showed that MBCCs demonstrated strong and diffuse staining for Ber EP4 (25/29) and MOC-31 (29/29). In contrast, BSCCs tended to be only sporadically reactive for both markers (4/25 and 1/25 cases, respectively). Labeling for UEA-1 was observed in almost all BSCCs (24/25), but only 6 of 29 cases of MBCC showed limited, focal staining with that lectin. These data suggest that MOC-31 is a useful marker in the specified differential diagnosis, especially when used together with UEA-1. PMID- 25702957 TI - Regional cerebral blood flow estimated by early PiB uptake is reduced in mild cognitive impairment and associated with age in an amyloid-dependent manner. AB - Early uptake of [(11)C]-Pittsburgh Compound B (ePiB, 0-6 minutes) estimates cerebral blood flow. We studied ePiB in 13 PiB-negative and 10 PiB-positive subjects with mild cognitive impairment (MCI, n = 23) and 11 PiB-positive and 74 PiB-negative cognitively healthy elderly control subjects (HCS, n = 85) in 6 bilateral volumes of interest: posterior cingulate cortex (PCC), hippocampus (hipp), temporoparietal region, superior parietal gyrus, parahippocampal gyrus (parahipp), and inferior frontal gyrus (IFG) for the associations with cognitive status, age, amyloid deposition, and apolipoprotein E epsilon4-allele. We observed no difference in ePiB between PiB-positive and -negative subjects and carriers and noncarriers. EPiB decreased with age in PiB-positive subjects in bilateral superior parietal gyrus, bilateral temporoparietal region, right IFG, right PCC, and left parahippocampal gyrus but not in PiB-negative subjects. MCI had lower ePiB than HCS (left PCC, left IFG, and left and right hipp). Lowest ePiB values were found in MCI of 70 years and older, who also displayed high cortical PiB binding. This suggests that lowered regional cerebral blood flow indicated by ePiB is associated with age in the presence but not in the absence of amyloid pathology. PMID- 25702958 TI - Muscle strength gains during resistance exercise training are attenuated with soy compared with dairy or usual protein intake in older adults: A randomized controlled trial. AB - BACKGROUND & AIMS: Maintenance of muscle mass and strength into older age is critical to maintain health. The aim was to determine whether increased dairy or soy protein intake combined with resistance training enhanced strength gains in older adults. METHODS: 179 healthy older adults (age 61.5 +/- 7.4 yrs, BMI 27.6 +/- 3.6 kg/m(2)) performed resistance training three times per week for 12 weeks and were randomized to one of three eucaloric dietary treatments which delivered >20 g of protein at each main meal or immediately after resistance training: high dairy protein (HP-D, >1.2 g of protein/kg body weight/d; ~27 g/d dairy protein); high soy protein (HP-S, >1.2 g of protein/kg body weight/d; ~27 g/d soy protein); usual protein intake (UP, <1.2 g of protein/kg body weight/d). Muscle strength, body composition, physical function and quality of life were assessed at baseline and 12 weeks. Treatments effects were analyzed using two-way ANOVA. RESULTS: 83 participants completed the intervention per protocol (HP-D = 34, HP-S = 26, UP = 23). Protein intake was higher in HP-D and HP-S compared with UP (HP-D 1.41 +/- 0.14 g/kg/d, HP-S 1.42 +/- 0.61 g/kg/d, UP 1.10 +/- 0.10 g/kg/d; P < 0.001 treatment effect). Strength increased less in HP-S compared with HP-D and UP (HP D 92.1 +/- 40.8%, HP-S 63.0 +/- 23.8%,UP 92.3 +/- 35.4%; P = 0.002 treatment effect). Lean mass, physical function and mental health scores increased and fat mass decreased (P <= 0.006), with no treatment effect (P > 0.06). CONCLUSIONS: Increased soy protein intake attenuated gains in muscle strength during resistance training in older adults compared with increased intake of dairy protein or usual protein intake. CLINICAL TRIAL REGISTRATION: ACTRN12612000177853 www.anzctr.org.au. PMID- 25702959 TI - Angiotensin processing activities in the venom of Thalassophryne nattereri. AB - The venom of marine animals is a rich source of compounds with remarkable functional specificity and diversity. Thalassophryne nattereri is a small venomous fish inhabiting the northern and northeastern coast of Brazil, and represents a relatively frequent cause of injuries. Its venom causes severe inflammatory response followed frequently by the necrosis of the affected area. This venom presents characterized components such as proteases (Natterins 1-4) and a lectin (Nattectin) with complex effects on the human organism. A specific inhibitor of tissue kallikrein (TKI) reduces the nociception and the edema caused by the venom in mice. Our study sought to investigate the proteolytic activities against vasopeptides Angiotensin I, Angiotensin II, Angiotensin 1-9 and Bradykinin. The venom indicated angiotensin conversion against angiotensin I, as well as kininase against bradykinin. Captopril conducted the total inhibition of the converting activity, featuring the first report of ACE activity in fish venoms. PMID- 25702960 TI - Distribution of DTX-3 in edible and non-edible parts of Crenomytilus grayanus from the Sea of Japan. AB - Seasonal dynamics and the distribution of dinophysistoxin-3 (DTX-3) in organs of mussel Crenomytilus grayanus, collected in 2013 in Peter the Great Bay, Sea of Japan, were determined. Active toxin forms (OA, DTX-1/2) concentrated in digestive glands (60-80%), whereas non-active 7-O-acyl derivatives (DTX-3) were more abundant in edible soft tissues (more than 80%). Possible mechanism of fast removing of DTX-3 from the digestive gland and accumulation of DTX-3 in the soft tissues is supposed. PMID- 25702961 TI - Occurrence of sulfated fucose branches in fucosylated chondroitin sulfate are essential for the polysaccharide effect preventing muscle damage induced by toxins and crude venom from Bothrops jararacussu snake. AB - Snake envenoming is an important public health problem around the world, particularly in tropics. Beyond deaths, morbidity induced by snake venoms, such as myotoxicity, is of pivotal consequence to population. Bothrops jararacussu is the main venomous snake in southeast region of Brazil, and particularly presents strong myotoxic effect. The only available therapy, antibothropic antivenom, poorly affects venom-induced myotoxicity. The aim of this study is to assess the ability of fucosylated chondroitin sulfate (fucCS), a glycosaminoglycan with anticoagulant and antithrombotic properties, and its derivatives to inhibit toxic activities of B. jararacussu crude venom and its isolated toxins, named bothropstoxins (BthTX-I and BthTX-II). The in vitro myotoxic activities induced by crude venom, by BthTX-I alone and by toxins together were abolished by fucCS. Carboxyl reduction (fucCS-CR) kept this ability whereas defucosilation (defucCS) abrogates myoprotection. We observed the same pattern in the response of these polysaccharides in antagonizing the increase in plasma creatine kinase (CK) levels, the reduction of skeletal muscle CK content and the rise of myeloperoxidase (MPO) activity induced by crude venom and isolated toxins. FucCS inhibited edematogenic activity and partially prevented the reduction of total leukocytes in blood when pre-incubated with crude venom. Furthermore, the venom procoagulant effect was completely antagonized by increasing concentrations of fucCS, although this polyanion could stop neither the tail bleeding nor the skin hemorrhage induced by Bothrops jararaca venom. The B. jararacussu phospholipase, hyaluronidase, proteolytic and collagenase activities were inhibited in vitro. The results suggest that fucCS could be able to interact with both toxins, and it is able to inhibit BthTX-II phospholipase activity. Light microscopy of extensor digitorum longus muscle (EDL) muscle showed myoprotection by fucCS, once necrotic areas, edema and inflammatory cells were all decreased as compared to venom injection alone. Altogether, data show that fucCS was able to inhibit myotoxicity and inflammation induced by B. jararacussu venom and its phospholipase toxins, BthTX-I and BthTX-II. Thus, fucosylated chondroitin sulfate is a new polyanion with potential to be used as an adjuvant in the treatment of snakebites in the future. PMID- 25702962 TI - Rebels with a cause? Adolescent defiance from the perspective of reactance theory and self-determination theory. AB - The present investigation focused on adolescents' defiance against parents by drawing upon psychological reactance theory (Brehm, 1966) and self-determination theory (Ryan & Deci, 2000). Psychological reactance would be elicited when freedom is taken away, thereby motivating individuals to engage in oppositional behavior. Throughout four studies (total N = 1,472, age ranging between 12 and 21 years), it was examined whether a controlling parenting style related to adolescents' experiences of autonomy need frustration (i.e., pressure) and reactance. Reactance, in turn, would relate to more externalizing and internalizing problems. Support was obtained for these associations in community and clinical samples, making use of different informants, and controlling for responsiveness and rule setting. A vignette-based study provided further support. The discussion highlights theoretical and clinical implications. PMID- 25702963 TI - Calcium-siRNA nanocomplexes: what reversibility is all about. AB - Gene silencing using small interfering RNA (siRNA) relies on the critical need for a safe and effective carrier, capable of strong but reversible complexation, siRNA protection, cellular uptake, and cytoplasmatic unloading of its cargo. We hypothesized that a delivery platform based on the eletrostatic interactions of siRNA with calcium ions in solution would fulfill these needs, ultimately leading to effective gene silencing. Physical characterization of the calcium-siRNA complexes, using high resolution microscopy and dynamic light scattering (DLS), showed the formation of stable nanosized complexes ~80nm in diameter, bearing mild (~-7mV) negative surface charge. The complexes were extremely stable in the presence of serum proteins or high concentrations of heparin; they maintained their nanosized features in suspension for days; and effectively protected the siRNA from enzymatic degradation. The Ca-siRNA complexes were disintegrated in the presence of Ca-chelating ion exchange resin, thus proving their reversibility. Excellent cytocompatibility of calcium-siRNA complexes was achieved using physiological calcium ion concentrations. The calcium-siRNA complexes successfully induced a very high (~80%) level of gene silencing in several cell types, at both mRNA and protein levels, associated with efficient cellular uptake. Collectively, our results show that the developed delivery platform based on reversible calcium-siRNA interactions offers a simple and versatile method for enhancing the therapeutic efficiency of siRNA. PMID- 25702964 TI - Intranasal PRGF-Endoret enhances neuronal survival and attenuates NF-kappaB dependent inflammation process in a mouse model of Parkinson's disease. AB - Parkinson's disease is a common neurodegenerative disorder of unknown pathogenesis characterized by the loss of nigrostriatal dopaminergic neurons. Oxidative stress, microglial activation and inflammatory responses seem to contribute to the pathogenesis. Recent data showed that growth factors mediate neuroprotection in rodent models of Parkinson's disease, modulating pro inflammatory processes. Based on our recent studies showing that plasma rich in growth factors (PRGF-Endoret) mediates neuroprotection as inflammatory moderator in Alzheimer's disease, in the present study we examined the effects of plasma rich in growth factors (PRGF-Endoret) in the 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP)-lesioned mouse as a translational therapeutic approach for Parkinson's disease. We found substantial neuroprotection by PRGF-Endoret in our model of Parkinson's disease, which resulted in diminished inflammatory responses and improved motor performance. Additionally, these effects were associated with robust reduction in nuclear transcription factor-kappaB (NF kappaB) activation, and nitric oxide (NO), cyclooxygenase-2 (COX-2), and tumor necrosis factor-alpha (TNF-alpha) expression in the substantia nigra. We propose that PRGF-Endoret can prevent dopaminergic degeneration via an NF-kappaB dependent signaling process. As the clinical safety profile of PRGF-Endoret is already established, these data suggest that PRGF-Endoret provides a novel neuroprotective strategy for Parkinson's disease. PMID- 25702965 TI - Immediate placement of a porous-tantalum, trabecular metal-enhanced titanium dental implant with demineralized bone matrix into a socket with deficient buccal bone: a clinical report. AB - A missing or deficient buccal alveolar bone plate is often an important limiting factor for immediate implant placement. Titanium dental implants enhanced with porous tantalum-based trabecular metal material (PTTM) are designed for osseoincorporation, a combination of vascularized bone ingrowth and osseointegration (bone on-growth). Demineralized bone matrix (DBM) contains growth factors with good handling characteristics. However, the combination of these 2 materials in facial alveolar bone regeneration associated with immediate implant therapy has not been reported. A 65-year-old Asian woman presented with a failing central incisor. Most of the buccal alveolar bone plate of the socket was missing. A PTTM enhanced implant was immediately placed with DBM. Cone beam computed tomography scans 12 months after the insertion of the definitive restoration showed regeneration of buccal alveolar bone. A combination of a PTTM enhanced implant, DBM, and a custom healing abutment may have an advantage in retaining biologically active molecules and form a scaffold for neovascularization and osteogenesis. This treatment protocol may be a viable option for immediate implant therapy in a failed tooth with deficient buccal alveolar bone. PMID- 25702966 TI - Resin-bonded restorations: a strategy for managing anterior tooth loss in adolescence. AB - In children or adolescents with anterior tooth loss, space closure with the patient's own teeth should be considered as the first choice to avoid lifelong restorative needs. Thorough diagnostics and treatment planning are required when autotransplantation or orthodontic space closure is considered. If these options are not indicated and a single tooth implant restoration is considered, implant placement should be postponed until adulthood, particularly in young women and in patients with hyperdivergent skeletal growth pattern. A ceramic resin-bonded fixed dental prosthesis with 1 retainer is an excellent treatment solution for the interim period; it may also serve as a long-term restoration, providing that sound enamel structure is present, sufficient framework dimensions have been provided, adhesive cementation techniques have been meticulously applied, and functional contacts of the cantilever pontic avoided. In contrast, a resin-bonded fixed dental prosthesis with a metal framework and retentive preparation is indicated if the palatal enamel structure is compromised, interocclusal clearance is limited, splinting (such as after orthodontic treatment) is required, or more than 1 tooth has to be replaced. PMID- 25702967 TI - Comments regarding Pieger S, Salman A, Bidra AS. Clinical outcomes of lithium disilicate single crowns and partial fixed dental prostheses: a systematic review. J Prosthet Dent 2014;112:22-30. PMID- 25702968 TI - Outcome of zirconia single crowns made by predoctoral dental students: a clinical retrospective study after 2 to 6 years of clinical service. AB - STATEMENT OF PROBLEM: Zirconia has established its role as a reliable ceramic material for fixed prostheses. PURPOSE: The purpose of this retrospective study was to evaluate the outcome of zirconia single crowns made by predoctoral students after 2 to 6 years of clinical service. MATERIAL AND METHODS: A cohort of 88 patients treated with zirconia single crowns (mean 3 crowns per patient, range 1 to 12 crowns) from 2007 to 2010 by predoctoral dental students was identified. The patients were invited to attend a clinical examination. RESULTS: Sixty-six participants (75%) took part in the clinical follow-up (30 women and 36 men; mean age 60.4 years, range 19 to 81 years). Altogether, 190 teeth with single crowns were examined, and the mean follow-up time was 3.88 years (1.85 to 6.04 years). The most common complications were chipping of veneering porcelain (4%) and loss of cementation (4%). The success rate of the zirconia single crowns after 2 to 6 years was 80% and the survival rate 89%. CONCLUSIONS: Zirconia crowns can be successfully used in predoctoral dental education. The success rate of zirconia single crowns after 2 to 6 years was 80% and the survival rate was 89%, in accordance with previous studies. PMID- 25702969 TI - A response to M. Kern regarding Pieger S, Salman A, Bidra AS. Clinical outcomes of lithium disilicate single crowns and partial fixed dental prostheses: a systematic review. J Prosthet Dent 2014;112:22-30. PMID- 25702970 TI - Radiopaque dental impression method for radiographic interpretation, digital alignment, and surgical guide fabrication for dental implant placement. AB - Adequate visualization of existing/proposed tooth position, denture base contours, and prosthetic space is critical to treatment planning of dental implants. Multiple techniques exist for fabricating radiographic guides; many involve duplicating the patient's existing prosthesis or fabricating a new diagnostic template. This article describes a technique that provides anatomic and restorative information by using an existing prosthesis and a radiographic impression method without the need to fabricate a duplicate or new template. PMID- 25702971 TI - Obesity in pregnancy. AB - The prevalence of obesity has reached alarming proportions globally, and continues to rise in both developed and developing countries. Maternal obesity has become one of the most commonly occurring risk factors in obstetric practice. The 2003-2005 report of the Confidential Enquiries into Maternal Deaths in the United Kingdom highlighted obesity as a significant risk for maternal death [1]. More than half of all women who died from direct or indirect causes were either overweight or obese. For the mother, obesity increases the risk of obstetric complications during the antenatal, intrapartum and postnatal period, as well as contributing to technical difficulties with fetal assessment. The offspring of obese mothers also have a higher rate of perinatal morbidity and an increased risk of long-term health problems. PMID- 25702972 TI - Caffeine consumption in a long-term psychiatric hospital: Tobacco smoking may explain in large part the apparent association between schizophrenia and caffeine use. AB - This study further explores the association between schizophrenia and caffeine use by combining two prior published Spanish samples (250 schizophrenia outpatients and 290 controls from the general population) with two Spanish long term inpatient samples from the same hospital (145 with schizophrenia and 64 with other severe mental illnesses). The specific aims were to establish whether or not, after controlling for confounders including tobacco smoking, the association between schizophrenia and caffeine is consistent across schizophrenia samples and across different definitions of caffeine use. The frequency of caffeine use in schizophrenia inpatients was not significantly higher than that in non schizophrenia inpatients (77%, 111/145 vs. 75%, 48/64) or controls but was significantly higher than in schizophrenia outpatients. The frequency of high caffeine users among caffeine users in schizophrenia inpatients was not significantly higher than in non-schizophrenia inpatients (45%, 50/111 vs. 52%, 25/48) or controls, but was significantly lower than in schizophrenia outpatients. Smoking was significantly associated with caffeine use across all samples and definitions. Between 2 and 3% of schizophrenia inpatients, schizophrenia outpatients and non-schizophrenia inpatients showed caffeinism (>700 mg/day in smokers). Several of these smoking patients with caffeinism were also taking other inducers, particularly omeprazole. The lack of consistent association between schizophrenia and caffeine use is surprising when compared with the very consistent association between tobacco smoking and caffeine use across all of our analyses (use and high use in users) and all our samples. The confounding effects of tobacco smoking may explain in large part the apparent association between schizophrenia and caffeine use. PMID- 25702973 TI - Integration of gene expression and GWAS results supports involvement of calcium signaling in Schizophrenia. AB - The number of Genome Wide Association Studies (GWAS) of schizophrenia is rapidly growing. However, the small effect of individual genes limits the number of reliably implicated genes, which are too few and too diverse to perform reliable pathway analysis; hence the biological roles of the genes implicated in schizophrenia are unclear. To overcome these limitations we combine GWAS with genome-wide expression data from human post-mortem brain samples of schizophrenia patients and controls, taking these steps: 1) Identify 36 GWAS-based genes which are expressed in our dataset. 2) Find a cluster of 19 genes with highly correlated expression. We show that this correlation pattern is robust and statistically significant. 3) GO-enrichment analysis of these 19 genes reveals significant enrichment of ion channels and calcium-related processes. This finding (based on analyzing a small number of coherently expressed genes) is validated and enhanced in two ways: First, the emergence of calcium channels and calcium signaling is corroborated by identifying proteins that interact with those encoded by the cluster of 19. Second, extend the 19 cluster genes into 1028 genes, whose expression is highly correlated with the cluster's average profile. When GO-enrichment analysis is performed on this extended set, many schizophrenia related pathways appear, with calcium-related processes enriched with high statistical significance. Our results give further, expression-based validation to GWAS results, support a central role of calcium-signaling in the pathogenesis of schizophrenia, and point to additional pathways potentially related to the disease. PMID- 25702975 TI - 3D volumetric displacement and strain analysis of composite polymerization. AB - OBJECTIVE: The present study aimed at a better understanding of the internal shrinkage patterns within different cavity sizes. METHODS: Ten cylindrical cavities in two sizes were filled with a flowable composite and scanned using X ray micro-computed tomography (MU-CT) before filling, before and after polymerization. Three-dimensional (3D) non-rigid image registration was applied to sets of two subsequent MU-CT images, before and after polymerization in order to calculate the displacements and strains caused by polymerization shrinkage. RESULTS: 3D volumetric displacement analysis disclosed a main vertical component for both the small and large cavities, however in the latter the downward direction reversed to an upward direction from a depth of approximately 2mm due to debonding at the bottom. Air bubbles and voids in the restorations increased upon polymerization, causing a reverse in strain in the surrounding areas. SIGNIFICANCE: Polymerization-induced shrinkage stress in composite restorations cannot be measured directly. This exploratory study revealed more information on cavity-size dependent shrinkage patterns and opens the way to more extensive studies using different composite materials and varying geometric cavity configurations. PMID- 25702974 TI - Disease implications of the Hippo/YAP pathway. AB - The Hippo signaling pathway is important for controlling organ size and tissue homeostasis. Originally identified in Drosophila melanogaster, the core components of the Hippo pathway are highly conserved in mammals. The Hippo pathway can be modulated by a wide range of stimuli, including G protein-coupled receptor (GPCR) signaling, changes in the actin cytoskeleton, cell-cell contact, and cell polarity. When activated, the Hippo pathway functions as a tumor suppressor to limit cell growth. However, dysregulation by genetic inactivation of core pathway components or amplification or gene fusion of its downstream effectors results in increased cell proliferation and decreased apoptosis and differentiation. Unsurprisingly, this can lead to tissue overgrowth, tumorigenesis, and many other diseases. PMID- 25702976 TI - Clinical outcome after failure of hypomethylating therapy for myelodysplastic syndromes. PMID- 25702977 TI - Gold nanorod biochip functionalization by antibody thiolation. AB - Conjugation of biomolecules on gold nanorod (GNR) surfaces is the basis for successful applications in biosensing, imaging, and drug delivery. Current functionalization methods are often problematic, involving multi-step nanoparticle modification to replace surfactant bilayer, delicate nanoparticle protection during surfactant exchange, and material loss due to inevitable aggregation. Instead of intensive surface modification of GNRs, we describe herein a facile method to functionalize gold nanorod surfaces via covalent Au-S bonds by thiolating receptors. The resulting GNR-bioconjugates showed superior dispersion and stability in buffer for months without morphology change and aggregation. ELISA tests confirmed the high biofunctionality of the thiolated anti-IgG moieties immobilized on the GNR surfaces. Furthermore, this simple method facilitated a straightforward functionalization of GNR assembly on glass substrate to construct a specific biochip, which can detect human IgG targets in a label-free fashion with high sensitivity and specificity. Compared to electropolymeric coating to functionalize the GNR, our method exhibited a five fold enhancement in the spectral sensitivity to refractive index change caused by the target binding. This universal GNR bioconjugation method can be extended to bind different proteins and antibodies for development of biosensors or drug delivery. PMID- 25702978 TI - Determination of the maleic acid in rat urine and serum samples by isotope dilution-liquid chromatography-tandem mass spectrometry with on-line solid phase extraction. AB - A rapid and simple on-line solid-phase extraction coupled with isotope dilution liquid chromatography-tandem mass spectrometry (SPE-ID-LC-MS/MS) method was developed to quantitate maleic acid in serum and urine of SpragueDawley (SD) rats. The aforementioned biological samples were spiked with (13)C2-maleic acid, vigorously vortexed, added with acetonitrile to precipitate proteins, and then injected into the on-line SPE-LC-MS/MS system for quantification. Upon validation, this method demonstrated excellent feasibility and sensitivity: calibration curves for maleic acid in serum and urine display excellent linearity with the coefficient of determination (R(2)) greater than 0.999; the limits of detection and quantitation (LOD and LOQ) for maleic acid were determined at 0.2 and 0.5MUg L(-1), respectively. Additionally, intra-day accuracy for maleic acid in serum and urine samples ranged from 94.0% to 100.2% and 101.3% to 104.4%, respectively. Furthermore, inter-day accuracy ranged from 93.6% to 101.0% and from 102.3% to 111.4% in serum and urine samples, respectively. Intra-day precision %RSD of maleic acid in serum and urine samples was 13.8% or less, whereas the inter-day precision was 6.1% or less. The matrix effects were not found to be statistically significant (p=0.9145 and p=0.5378, correspondingly) based on the calculations of recovery functions. The collected serum and urine samples were analyzed using SPE-ID-LC-MS/MS. Our results reveal trace levels of maleic acid in the control rats, demonstrating that this method is capable of analyzing background levels of contaminants in biofluids with excellent sensitivity and specificity at part-per-billion levels concentrations in complex matrices. PMID- 25702979 TI - Development and application of a microfluidic in-situ analyzer for dissolved Fe and Mn in natural waters. AB - The redox sensitive trace metals iron and manganese are two important elements that help shape the biogeochemistry of aquatic systems and thus their measurement is important. Current laboratory methods are expensive, time consuming and cannot provide the spatial and temporal resolution needed to characterize these elements in natural waters. Here we describe the first autonomous analyzer capable of providing vertical profiles as well as routine in-situ determinations of dissolved Fe(II) and Mn in aquatic environments. The spectrophotometric sensor uses microfluidic methods (Lab-on-a-chip technology) and mixes reagents and samples using a novel in-cell diffusion process. Fe(II) and Mn can be measured with a frequency of up to 12 and 6 samples per hour respectively with limits of detection of 27nM for Fe(II), 2.1% precision (n=20), and 28nM for Mn, 2.4% precision (n=19). The device combines relatively low cost, low power usage, low reagent consumption, portability, and tolerance to pressures up to at least 170 bars, with high precision and accuracy. We present data from a successful demonstration of the sensor during a cruise to the Gotland and Landsort Deep Basins of the Baltic Sea. PMID- 25702980 TI - Pilot study on the identification of silver in skin layers and urine after dermal exposure to a functionalized textile. AB - Silver (Ag) is increasingly used in consumer products like functionalized textiles and medical devices owing to its strong antimicrobial activity which is largely assigned to Ag ions released after oxidation of metallic Ag. To increase generation of Ag ions, in various products Ag is often present as nanoparticles. Ideally, Ag ions would remain on the surface of the skin to combat the bacteria and the uptake of Ag into the body should be limited. However, the Ag ions might penetrate across the skin into the body leading to adverse health effects. Data on in vivo uptake of Ag due to dermal exposure are scarce partly caused by the lack of suitable analytical approaches for the determination of Ag in biological matrices, but strongly needed to enable risk assessment of skin exposure to (nano) Ag containing products. With the developed approach, the presence of Ag in a functionalized textile is confirmed by using scanning electron microscopy (SEM). After in vivo dermal exposure to Ag containing textile material under ''in use'' exposure scenarios, the outermost layers of the skin (Stratum Corneum, SC) were sampled by using adhesive tapes with a size of 3.8cm(2). Different leaching and dissolution procedures of Ag from biological samples prior analysis by inductively coupled plasma mass spectrometry (ICPMS) have been evaluated. The developed method results in a limit of detection (LOD) of 2ng Ag per removed SC layer. The method allows the measurement of the Ag concentrations at different depths of the SC enabling the deduction of the percutaneous penetration kinetics. Due to the possible bio distribution within the whole body, an indirect exposure matrix (urine) was studied too. The detection power of the method permits measuring the ultra-trace concentrations of Ag in urine before and after dermal exposure; LOD is 0.010ug Ag/L urine. PMID- 25702981 TI - Preparation of 4-butylaniline-bonded attapulgite for pre-concentration of bisphenol A in trace quantity. AB - Ring-opening reaction with synchronous hydrolysis was used to prepare 4 butylaniline-modified attapulgite (abbreviated as BA-ATP) for pre-concentration of bisphenol A (BPA) in trace quantity. The preparation was achieved under mild condition, and the material was characterized by Fourier transform infrared spectroscopy (FT-IR), elemental analysis, nuclear magnetic resonance (NMR) and scanning electron microscopy. BA-ATP was used in solid phase extraction (SPE), and SPE was performed in a neutral condition without regard to ionic strength. The results indicate that BA-ATP has high affinity to BPA with a maximum adsorption amount of 44mg g(-1), and the adsorption can be described by Langmuir isotherm model. The content of bisphenol A in water samples was analyzed by HPLC method with the pre-concentration using BA-ATP. The limit of detection (LOD) can be as low as 3.9ng mL(-1), and the average recoveries are in a range of 93-97% with relative standard deviation (RSD) of less than 2%. PMID- 25702982 TI - Determination of perfluorinated carboxylic acids in water using liquid chromatography coupled to a corona-charged aerosol detector. AB - Perfluorocarboxylic acids (PFCAs) are persistent pollutants being widely detected in the environment. In order to quantitatively determine PFCAs, a simple and rapid method for the simultaneous determination of five PFCAs was developed by coupling high performance liquid chromatographic (HPLC) separation and corona charged aerosol detector (CAD). The PFCAs were separated on a Symmerry((r)) C8 analytical column (150mm*3.9mm) under isocratic conditions with a mobile phase consisting of 5mM ammonium acetate (pH4.9+/-0.2) and methanol (30:70 (v/v)) at the flow rate 1mL min(-1). Ammonium acetate as ion pairing agent was added to the mobile phase for better separation and peak shapes. The elaborated method was validated for linearity, precision and accuracy. The detection limits ranged from 1.5 to 4.4MUg L(-1) for PFCAs with C atoms of C4 to C8, which were decreased further to 75 to 220ng L(-1) after 20-fold preconcentration. The method was confirmed to have good precision with relative standard deviation of 0.9%-4.2% for intraday measurements and 0.9%-4.1% for interday measurements. The optimized method was applied to analyze practical wastewater samples with satisfactory results. PMID- 25702983 TI - Disposable immunosensor for human cytomegalovirus glycoprotein B detection. AB - Combining the advantages of the biosensor field with the problem of detecting Human Cytomegalovirus (HCMV) in human samples, an inexpensive, simple and disposable electrochemical immunosensor for glycoprotein B detection in urine is proposed. Glycoprotein B has been chosen once is the dominant antigen of HCMV. The approach is based on a sandwich-type immunoassay, with the HCMV glycoprotein B sandwiched between the Anti-HCMV antibody adsorbed onto the working electrode, and the Anti-HCMV labeled with gold nanoparticles. Glycoprotein B detection was carried out through electrochemical stripping analysis of silver nanoparticles quantitatively deposited on the immunosensor through catalysis by the nanogold labels. The influence of different steps in the immunosensor construction, namely the silver deposition time, silver enhancer concentration, antibody concentration, BSA concentration and glycoprotein B incubation time, were examined and optimized. The method showed a linear dependence between glycoprotein B concentration and the corresponding anodic stripping peak current, resulting in detection limits of 3.3+/-1.7ng/mL for samples prepared in buffer and 3.2+/-0.2ng/mL for urine samples, suggesting that the biological matrix does not interfere with the immunosensor detection capability. Given its mode of preparation, by physical adsorption of the capture antibody in the working electrode, the immunosensor also exhibited an acceptable reproducibility, with a residual standard deviation of 13.5% for samples prepared in buffer and 11.2% for urine samples, thereby presenting a promising development potential for clinical applications. PMID- 25702984 TI - An upconversion fluorescence resonance energy transfer nanosensor for one step detection of melamine in raw milk. AB - Here we report a nanosensor based on fluorescence resonance energy transfer (FRET) between upconversion nanoparticles (UCNPs) and gold nanoparticles (AuNPs) for melamine detection. The positively charged UCNPs as donor and the negatively charged AuNPs as acceptor bound together through electrostatic interaction, which caused the fluorescence quenching of UCNPs. Upon addition of melamine, AuNPs were released from the surface of UCNPs and aggregation due to the N-Au interaction between melamine and AuNPs, which results in the fluorescence of UCNPs gradually recovered. Under the optimal conditions including media pH (7.0), the concentration of AuNPs (1.23nM) and incubation time (12min), the fluorescence enhanced efficiency shows a linear response to the melamine concentration ranging from 32.0 to 500nM with a detection limit of 18.0nM. Compared with other fluorescence methods, the fluorimetric nanosensor shows high sensitivity of 0.968, ease of operation and can be used for the determination of melamine in raw milk samples. PMID- 25702985 TI - Determination of hexanal and heptanal in human urine using magnetic solid phase extraction coupled with in-situ derivatization by high performance liquid chromatography. AB - In this study, magnetic solid phase extraction coupled with in-situ derivatization (MSPE-ISD) was established for the determination of hexanal and heptanal in human urine. 2,4-Dinitrophenylhydrazine (DNPH) was used as the derivatization reagent that was adsorbed onto the surface of magnetite/silica/poly(methacrylic acid-co-ethylene glycol dimethacrylate) (Fe3O4/SiO2/P(MAA-co-EGDMA)). And then simultaneous extraction and derivatization of the aldehydes were performed on the DNPH-adsorbed Fe3O4/SiO2/P(MAA-co-EGDMA). The simple, rapid and sensitive determination of hexanal and heptanal can be accomplished within 9min. Under optimized conditions, the limits of detection (LODs) were 1.7 and 2.5nmol/L for hexanal and heptanal, respectively. The relative recoveries ranged from 72.8% to 91.4% with the intra- and inter-day relative standard deviations (RSDs) being less than 9.6%. Furthermore, the proposed method was successfully applied to determine endogenous hexanal and heptanal in human urine from healthy persons and lung cancer patients. The results showed the higher concentrations of hexanal and heptanal were observed in lung cancer patients compared to healthy controls. Thus, the developed MSPE-ISD method is suitable for the determination of aldehydes in urines. PMID- 25702986 TI - Systematic evaluation of mobile phase additives for the LC-MS characterization of therapeutic proteins. AB - Trifluoroacetic acid (TFA) is commonly used as mobile phase additive for the analysis of proteins in reversed phase liquid chromatography (RPLC). Due to its interesting features, it provides symmetrical and narrow peak shapes for proteins, but decreases mass spectrometric sensitivity through ion-pairing and spray destabilizing. Since RPLC-MS is an important technique for the characterization of proteins, some alternative MS-compatible mobile phases may be required. The aim of this study was to evaluate various acidic and basic mobile phase additives for the LC-MS analysis of therapeutic proteins possessing molecular weight between 5 and 150kDa. At the end, 10mM formate buffer pH 3 was found to be the most promising alternative, since it provided acceptable peak shapes in most cases, together with an average improvement of MS sensitivity by 5 times, compared to TFA. PMID- 25702987 TI - Development of rolling circle amplification based surface-enhanced Raman spectroscopy method for 35S promoter gene detection. AB - In this study, we developed the genetically modified organism detection method by using the combination of rolling circle amplification (RCA) and surface-enhanced Raman spectroscopy (SERS). An oligonucleotide probe which is specific for 35S DNA promoter target was immobilised onto the gold slide and a RCA reaction was performed. A self-assembled monolayer was formed on gold nanorods using 5,5' dithiobis(2-nitrobenzoic acid) (DTNB) and the second probe of the 35S DNA promoter target was immobilised on the activated gold coated slide surfaces. Probes on the nanoparticles were hybridised with the target oligonucleotide. Quantification of the target concentration was performed via SERS spectra of DTNB on the nanorods. SERS spectra of target molecules were enhanced through the RCA reaction and the detection limit was found to be 6.3fM. The sensitivity of the developed RCA-SERS method was compared with another method which had been performed without using RCA reaction, and the detection limit was found to be 0.1pM. The correlation between the target concentration and the SERS signal was found to be linear, within the range of 1pM to 10nM for the traditional assay and 100fM to 100nM for the RCA assay. For the developed RCA-SERS assay, the specificity tests were performed using the 35S promoter of Bt-176 maize gene. It was found out that the developed RCA-SERS sandwich assay method is quite sensitive, selective and specific for target sequences in model and real systems. PMID- 25702988 TI - Sequential injection chromatography with post-column reaction/derivatization for the determination of transition metal cations in natural water samples. AB - In this work, the applicability of Sequential Injection Chromatography for the determination of transition metals in water is evaluated for the separation of copper(II), zinc(II), and iron(II) cations. Separations were performed using a Dionex IonPACTM guard column (50mm*2mm i.d., 9 um). Mobile phase composition and post-column reaction were optimized by modified SIMPLEX method with subsequent study of the concentration of each component. The mobile phase consisted of 2,6 pyridinedicarboxylic acid as analyte-selective compound, sodium sulfate, and formic acid/sodium formate buffer. Post-column addition of 4-(2 pyridylazo)resorcinol was carried out for spectrophotometric detection of the analytes' complexes at 530nm. Approaches to achieve higher robustness, baseline stability, and detection sensitivity by on-column stacking of the analytes and initial gradient implementation as well as air-cushion pressure damping for post column reagent addition were studied. The method allowed the rapid separation of copper(II), zinc(II), and iron(II) within 6.5min including pump refilling and aspiration of sample and 1mmol HNO3 for analyte stacking on the separation column. High sensitivity was achieved applying an injection volume of up to 90uL. A signal repeatability of<2% RSD of peak height was found. Analyte recovery evaluated by spiking of different natural water samples was well suited for routine analysis with sub-micromolar limits of detection. PMID- 25702989 TI - Applications of everyday IT and communications devices in modern analytical chemistry: A review. AB - This paper reviews the development and recent use of everyday communications and IT equipment (mobile phones, digital cameras, scanners, webcams, etc) as detection devices for colorimetric chemistries. Such devices can readily be applied for visible detection using reaction formats such as microfluidic paper based analytical devices (uPADs), indicator papers, and well plate reaction vessels. Their use is highly advantageous with respect to cost, simplicity and portability, and offers many opportunities in the areas of point of care diagnosis, and at-site monitoring of environmental, agricultural, food and beverage parameters. PMID- 25702990 TI - DNA polymorphism sensitive impedimetric detection on gold-nanoislands modified electrodes. AB - Nanocomposite materials are being increasingly used in biosensing applications as they can significantly improve biosensor performance. Here we report the use of a novel impedimetric genosensor based on gold nanoparticles graphite-epoxy nanocomposite (nanoAu-GEC) for the detection of triple base mutation deletion in a cystic-fibrosis (CF) related human DNA sequence. The developed platform consists of chemisorbing gold nano-islands surrounded by rigid, non-chemisorbing, and conducting graphite-epoxy composite. The ratio of the gold nanoparticles in the composite was carefully optimized by electrochemical and microscopy studies. Such platform allows the very fast and stable thiol immobilization of DNA probes on the gold islands, thus minimizing the steric and electrostatic repulsion among the DNA probes and improving the detection of DNA polymorphism down to 2.25fmol by using electrochemical impedance spectroscopy. These findings are very important in order to develop new and renewable platforms to be used in point-of care devices for the detection of biomolecules. PMID- 25702991 TI - Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) coupled to XAD fractionation: Method to algal organic matter characterization. AB - This work is focused on the development of an analytical procedure for the improvement of the Organic Matter structure characterization, particularly the algal matter. Two fractions of algal organic matter from laboratory cultures of algae (Euglena gracilis) and cyanobacteria (Microcystis aeruginosa) were extracted with XAD resins. The fractions were studied using laser desorption ionization (LDI) and Matrix-Assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF). A comparison with the natural organic matter characteristics from commercial humic acids and fulvic acids extracted from Suwannee River was performed. Results show that algal and natural organic matters have unique quasi-polymeric structures. Significant repeating patterns were identified. Different fractions extracted from organic matter with common origin had common structures. Thus, 44, 114 and 169Da peaks separation for fractions from E. gracilis organic matter and 28, 58 and 100Da for M. aeruginosa ones were clearly observed. Using the developed protocol, a structural scheme and organic matter composition were obtained. The range 600-2000Da contained more architectural composition differences than the range 100-600Da, suggesting that organic matter is composed of an assembly of common small molecules. Associated to specific monomers, particular patterns were common to all samples but assembly and resulting structure were unique for each organic matter. Thus, XAD fractionation coupled to mass spectroscopy allowed determining a specific fingerprint for each organic matter. PMID- 25702992 TI - Ultra high vacuum high precision low background setup with temperature control for thermal desorption mass spectroscopy (TDA-MS) of hydrogen in metals. AB - In this work, a newly developed UHV-based high precision low background setup for hydrogen thermal desorption analysis (TDA) of metallic samples is presented. Using an infrared heating with a low thermal capacity enables a precise control of the temperature and rapid cool down of the measurement chamber. This novel TDA set up is superior in sensitivity to almost every standard hydrogen analyzer available commercially due to the special design of the measurement chamber, resulting in a very low hydrogen background. No effects of background drift characteristic as for carrier gas based TDA instruments were observed, ensuring linearity and reproducibility of the analysis. This setup will prove to be valuable for detailed investigations of hydrogen trapping sites in steels and other alloys. With a determined limit of detection of 5.9*10(-3)ug g(-1) hydrogen the developed instrument is able to determine extremely low hydrogen amounts even at very low hydrogen desorption rates. This work clearly demonstrates the great potential of ultra-high vacuum thermal desorption mass spectroscopy instrumentation. PMID- 25702993 TI - Peptide-based biosensors. AB - Peptides have been used as components in biological analysis and fabrication of novel biosensors for a number of reasons, including mature synthesis protocols, diverse structures and as highly selective substrates for enzymes. Bio conjugation strategies can provide an efficient way to convert interaction information between peptides and analytes into a measurable signal, which can be used for fabrication of novel peptide-based biosensors. Many sensitive fluorophores can respond rapidly to environmental changes and stimuli manifest as a change in spectral characteristics, hence environmentally-sensitive fluorophores have been widely used as signal markers to conjugate to peptides to construct peptide-based molecular sensors. Additionally, nanoparticles, fluorescent polymers, graphene and near infrared dyes are also used as peptide conjugated signal markers. On the other hand, peptides may play a generalist role in peptide-based biosensors. Peptides have been utilized as bio-recognition elements to bind various analytes including proteins, nucleic acid, bacteria, metal ions, enzymes and antibodies in biosensors. The selectivity of peptides as an enzymatic substrate has thus been utilized to construct enzyme sensors or enzyme-activity sensors. In addition, progress on immobilization and microarray techniques of peptides has facilitated the progress and commercial application of chip-based peptide biosensors in clinical diagnosis. PMID- 25702994 TI - Data visualization of Salmonella Typhimurium contamination in packaged fresh alfalfa sprouts using a Kohonen network. AB - Class visualization of multi-dimensional data from analysis of volatile metabolic compounds monitored using an electronic nose based on metal oxide sensor array was attained using a Kohonen network. An array of 12 metal oxide based chemical sensors was used to monitor changes in the volatile compositions from the headspace of packaged fresh sprouts with and without Salmonella Typhimurium contamination. Kohonen's self-organizing map (SOM) was then created for learning different patterns of volatile metabolites. The Kohonen network comprising 225 nodes arranged into a two-dimensional hexagonal map was used to locate the samples on the map to facilitate sample classification. Graphical maps including the unified matrix, component planes, and hit histograms were described to characterize the relation between samples. The clustering of samples with different levels of S. Typhimurium contamination could be visually distinguishable on the SOM. The Kohonen network proved to be advantageous in visualization of multi-dimensional nonlinear data and provided a clearer separation of different sample groups than a conventional linear principal component analysis (PCA) approach. The sensor array integrated with the Kohonen network could be used as a rapid and nondestructive method to distinguish samples with different levels of S. Typhimurium contamination. Although the analyses were performed on samples with natural background microbiota of about 7 Log(CFU/g), this microbiota did not affect the S. Typhimurium detection. The proposed method has potential to rapidly detect a target foodborne pathogen in real-life food samples instantaneously without subsequently culturing stages. PMID- 25702995 TI - Improvement in thallium hydride generation using iodide and Rhodamine B. AB - A continuous flow hydride generation atomic absorption spectrometry (CF-HG-AAS) system was used to study the enhancement effect of different substances for conventional chemical HG of thallium. At room temperature, the acidified sample solution containing the respective enhancement reagent merged with the aqueous NaBH4 solution. The generated thallium hydride was stripped from the eluent solution by the addition of a nitrogen flow and thereafter the bulk phases were separated in a gas-liquid separator. The main factors under study were concentration and type of enhancement reagent (Te, iodide added as KI, Rhodamine B, malachite green and crystal violet) and acid (HCl, H2SO4 or HNO3). Other parameters affecting the thallium hydride generation, such as: NaBH4 concentration, carrier gas flow rate, length of reaction-mixing coil and reagents flow rates, were studied and optimized. Among the enhancement reagents tested, the combination of Rhodamine B and iodide produced the best results. A linear response was obtained between the detection limit (LOD (3sigma)) of 1.5MUg L(-1) and 1000MUg L(-1). The RSD% (n=10) for a solution containing 15MUg L(-1) of Tl was 2.9%. The recoveries of thallium in environmental water samples by spiking the samples with 10 and 20ug L(-1) of Tl were in the 97.0-102.5% range. The accuracy for Tl determination was further confirmed by the analysis of a water standard reference material (1643e form NIST, USA). Finally, it was demonstrated that malachite green and crystal violet showed similar enhancement effect like Rhodamine B for thallium HG. PMID- 25702996 TI - Determination of steroid sex hormones in real matrices by bar adsorptive microextraction (BAMUE). AB - In the present work, the development of a novel analytical approach which combines a miniaturized bar adsorptive microextraction device with a micro-liquid desorption in one single step, followed by high performance liquid chromatography with diode array detection (BAuE-uLD/HPLC-DAD), is proposed for the determination of trace levels of nine steroid hormones (estriol, 17beta-estradiol, 17alpha estradiol, 19-northisterone, 17alpha-ethynylestradiol, estrone, D-(-)-norgestrel, progesterone and mestranol) in environmental and biological matrices. From the comparison of ten different coating phases (five polymeric and five activated carbon sorbents), the modified pyrrolidone polymer (P2) showed the best compromise between selectivity and efficiency. Assays performed through BAuE(P2, 1.3mg)-uLD(100uL)/HPLC-DAD on 25mL of ultrapure water samples spiked at the 6.0MUg/L level, yielded recoveries ranging from 93+/-9% to 101+/-8%, under optimized experimental conditions. The analytical performance showed convenient detection (50.0-100.0ng/L) and quantification limits (165.0-330.0ng/L), as well as good linear dynamic ranges (0.2-24.0ug/L) with remarkable determination coefficients (r(2)>0.9968). Excellent repeatability were also achieved through intraday (RSD<14%) and interday (RSD<12%) experiments. The application of the proposed analytical approach on environmental water and urine samples, using the standard addition methodology (SAM), revealed good linearity and sensitivity at trace level, with the detection of some of the target compounds. In short, the miniaturization of the analytical device for microextraction combined with the minimization of the solvent volume for back-extraction in one single step demonstrated remarkable performance, increasing the enrichment factor, being simultaneously more easier to implement and environment friendly. PMID- 25702997 TI - Review of advances in coupling electrochemistry and liquid state NMR. AB - The coupling of electrochemistry and NMR spectroscopy (EC-NMR) may present an interesting approach in the environmental oxidative degradation or metabolism studies. This review presents experimental advances in the field of EC-NMR and highlights the main advantages and drawbacks of in situ and on line of NMR spectroelectrochemistry. The analysis of NMR spectra recorded in situ or on line EC-NMR permits to elucidate the reaction pathway of the electrochemical oxidation reactions and could constitute a fast way for monitoring unstable species as for instance quinone and quinone imine structures without using any coupling agents. The use of 1D and 2D NMR coupled with electrochemistry may leads to the elucidation of the major species produced from the electrochemical oxidation process. The present review gives an overview about the development of the electrochemical cells which can operate on line or in situ with NMR measurements. Future developments and potential applications of EC-NMR are also discussed. PMID- 25702998 TI - Study and determination of elemental impurities by ICP-MS in active pharmaceutical ingredients using single reaction chamber digestion in compliance with USP requirements. AB - In this work a method for active pharmaceutical ingredients (APIs) digestion using the single reaction chamber (SRC-UltraWaveTM) system was proposed following the new recommendations of United States Pharmacopeia (USP). Levodope (LEVO), primaquine diphosphate (PRIM), propranolol hydrochloride (PROP) and sulfamethoxazole (SULF) were used to evaluate the digestion efficiency of the proposed method. A comparison of digestion efficiency was performed by measuring the carbon content and residual acidity in digests obtained using SRC and in digests obtained using conventional microwave-assisted digestion system (Multiwave(TM)). Three digestion solutions (concentrated HNO3, aqua regia or inverse aqua regia) were evaluated for digestion of APIs. The determination of Cd, Ir, Mn, Mo, Ni, Os, Pb, Pd, Pt, Rh, Ru was performed using inductively coupled plasma mass spectrometry (ICP-MS) in standard mode. Dynamic reaction cell (DRC) mode was used for the determination of (51)V, (52)Cr, (53)Cr, (63)Cu and (65)Cu in order to solve polyatomic ion interferences. Arsenic and Hg were determined using chemical vapor generation coupled to ICP-MS (FI-CVG-ICP-MS). Masses of 500mg of APIs were efficiently digested in a SRC-UltraWaveTM system using only HNO3 and allowing a carbon content lower than 250mg L(-1) in final digests. Inverse aqua regia was suitable for digestion of sample masses up to 250mg allowing the determination of Ir, Pd, Pt, Rh and Ru. By using HNO3 or inverse aqua regia, suitable recoveries were obtained (between 91 and 109%) for all analytes (exception for Os). Limits of quantification were in agreement with USP requirements and they ranged from 0.001 to 0.015ug g(-1) for all elemental impurities (exception for Os). The proposed method was suitable for elemental impurities determination in APIs and it can be used in routine analysis for quality control in pharmaceutical industries. PMID- 25702999 TI - Ultrasound assisted-deep eutectic solvent extraction of iron from sheep, bovine and chicken liver samples. AB - A green, novel and effective ultrasound assisted-deep eutectic solvent (DES) extraction (UA-DES-E) procedure was developed for extraction of iron from sheep, bovine and chicken liver samples. The analytical parameters including type and composition DES, volume of DES, ultrasonication time and ratio of sample to DES were optimized by using 50mg of the NIST SRM 1577b bovine liver certified reference material. The limit of detection (LOD) and the limit of quantification (LOQ) were found as 0.026ug mL(-1) and 0.085ug mL(-1), respectively. The relative standard deviation (RSD) as a result of 7 replicates of 50mg of certified reference material was 1.4%. The accuracy of proposed method was checked by the addition/recovery tests to NIST SRM 1577b bovine liver and a sheep liver. The extraction method was applied to extraction of iron from bovine, sheep and chicken liver samples retail from markets at Kayseri, Turkey with satisfactory results (recoveries higher than 95%). PMID- 25703000 TI - Multi-residue method for the analysis of pharmaceuticals and some of their metabolites in bivalves. AB - A fast, simple and robust method has been developed for the simultaneous determination of 23 pharmaceuticals (including some major metabolites) in bivalve mollusks. The analytes belong to eight different therapeutic groups: antibiotics, psychiatric drugs, analgesics/anti-inflammatories, tranquilizer, calcium channel blockers, diuretic, and prostatic hyperplasia. The method is based on pressurized liquid extraction (PLE) followed by solid phase extraction clean-up (SPE), and ultra performance liquid chromatography-triple quadrupole mass spectrometry (UHPL MS/MS) for the identification and quantification of the target analytes. It has been developed and validated in three different species of bivalves: Crassostrea gigas (Pacific oyster), Mytilus galloprovincialis (Mediterranean mussel), and Chamelea gallina (striped venus clam). The majority of the compounds were extracted with a recovery between 40 and 115%. The developed analytical method allowed the determination of the compounds in the lower ng/g concentration levels. The relative standard deviation was under 12% for the intra-day and 20% inter-day analyses, respectively. Finally, the method was applied to oyster, clam and mussel samples collected from the Ebro delta, Spain. The most ubiquitous compounds detected were the psychiatric drug venlanfaxine and the antibiotic azithromycin, with the highest concentrations found in mussel (2.7ng/g dw) and oyster (3.0ng/g dw), respectively. To the best of our knowledge, this is the first time that azithromycin has been reported in environmental samples of marine biota. PMID- 25703001 TI - An LC-MS/MS method for determination of novel fungicide pyraoxystrobin in rat plasma and tissues: Toxicokinetics and tissue distribution study. AB - A simple, specific and reproducible liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for the determination of pyraoxystrobin in rat plasma and tissues. Chromatographic separation was achieved on a Zorbax Extend-C18 column (50*2.1mm I. D., 3.5um), using a gradient mobile phase consisting of acetonitrile and 0.1% aqueous formic acid (v/v) at a flow rate of 0.5mL min(-1). Pyraoxystrobin and picoxystrobin (internal standard) were detected without interference in the selected reaction monitoring (SRM) mode with positive electrospray ionization. Further, the method was validated following FDA guideline. The calibration curves for plasma and tissues were linear over a concentration range of 1.00-200ng mL(-1), with lower limits of quantitation of 1.00ng mL(-1). Mean extraction recoveries in plasma and tissues ranged from 101.4% to 108.2% and from 49.1% to 59.4%, respectively. The intra-day and inter day precision in plasma and tissues were within 9.9% and 8.9%, and the intra-day and inter-day accuracy ranged from 88.7% to 110.7% and 93.2% to 108.7%, respectively. Finally, the validated method was successfully applied to toxicokinetics and tissue distribution studies after oral administration of pyraoxystrobin to rats. PMID- 25703002 TI - Pulsed electromembrane extraction for analysis of derivatized amino acids: A powerful technique for determination of animal source of gelatin samples. AB - Differentiation of animal sources of gelatin is required for many reasons such as some anxieties about bovine spongiform encephalopathy or a ban on consuming porcine gelatin in some religions. In the present work, an efficient method is introduced for determination of animal origin of gelatin samples. The basis of this procedure is the application of pulsed electric field for extraction, preconcentration, and analysis of derivatized amino acids in gelatin. To this end, after derivatization of amino acids of interest by means of o-phthalaldehyde (OPA) for enhancing their ultraviolet (UV) absorbance as well as increasing their lipophilicities, a 137V electric field was applied for 20min with 10min(-1) frequency to make the analytes migrate through a 200um organic liquid membrane into an aqueous acceptor phase. Finally, the acceptor phase was analyzed by HPLC UV. The proposed technique offered a high efficiency for analysis of amino acids, regarding 43% and 79% as extraction recoveries and 25ng mL(-1) and 50ng mL(-1) as limits of detection (LODs) for asparagine and glutamine, respectively. Therefore, due to sample cleanup ability of the proposed method and obtained preconcentration factors (29 and 53 for asparagine and glutamine, respectively), it could be carried out for differentiation of animal origins of gelatin samples, even if only small amounts of samples are available or in complicated media of foodstuffs and medicament. PMID- 25703003 TI - Determination of eight pharmaceuticals in an aqueous sample using automated derivatization solid-phase microextraction combined with gas chromatography-mass spectrometry. AB - An automated aqueous derivatization solid-phase microextraction (SPME) coupled with a gas chromatography/mass spectrometry (GC/MS) method was developed for simultaneous determination of eight pharmaceuticals in water samples. Dimethyl sulfate and tetrabutylammonium hydrogen sulfate were selected as derivatization and activation reagents for the esterification reaction. An experimental design approach, central composition design (CCD), was employed to investigate and optimize the operative factors influencing the extraction efficiency, including extraction time, extraction temperature and ionic strength. The other parameters such as type of fiber coating, pH and derivatization conditions were also evaluated. SPME was finally carried out in headspace mode at 80 degrees C for 60min with the presence of 3.00g Na2SO4, using a home-made 44MUm PDMS fiber. Wide linear ranges and low limits of detection (0.06-1.24ng L(-1)) were obtained under the optimized conditions. The relative standard deviations (RSDs) and recoveries ranged from 0.5% to 12.3% and 85% to 110%, respectively. The proposed method was successfully applied to the analysis of the real surface water samples from the Pearl River Estuary. PMID- 25703004 TI - Colorimetric analyzer based on mobile phone camera for determination of available phosphorus in soil. AB - A field deployable colorimetric analyzer based on an "Android mobile phone" was developed for the determination of available phosphorus content in soil. An inexpensive mobile phone embedded with digital camera was used for taking photograph of the chemical solution under test. The method involved a reaction of the phosphorus (orthophosphate form), ammonium molybdate and potassium antimonyl tartrate to form phosphomolybdic acid which was reduced by ascorbic acid to produce the intense colored molybdenum blue. The software program was developed to use with the phone for recording and analyzing RGB color of the picture. A light tight box with LED light to control illumination was fabricated to improve precision and accuracy of the measurement. Under the optimum conditions, the calibration graph was created by measuring blue color intensity of a series of standard phosphorus solution (0.0-1.0mgPL(-1)), then, the calibration equation obtained was retained by the program for the analysis of sample solution. The results obtained from the proposed method agreed well with the spectrophotometric method, with a detection limit of 0.01mgPL(-1) and a sample throughput about 40h( 1) was achieved. The developed system provided good accuracy (RE<5%) and precision (RSD<2%, intra- and inter-day), fast and cheap analysis, and especially convenient to use in crop field for soil analysis of phosphorus nutrient. PMID- 25703005 TI - A colorimetric lead (II) ions sensor based on selective recognition of G quadruplexes by a clip-like cyanine dye. AB - A probe for colorimetric detecting lead ion (Pb(2+)) has been designed by using a newly synthesized clip-like cyanine dye and G-quadruplex. The unique structure of the clip-like cyanine dye endowed the probe with a high selectivity towards Pb(2+). Significant changes in absorption spectra of the cyanine dye recognizing the Pb(2+)-induced conformational transition of G-quadruplexes made the probe show a high sensitivity towards Pb(2+) with a detection limit of 1nM. The excellent performance enabled the probe to be practically applied in measuring the Pb(2+) pollution in freshwater system. PMID- 25703006 TI - Developmental changes and the effect of self-generated feedback in metacognitive controlled spacing strategies in 7-year-olds, 10-year-olds, and adults. AB - The current study investigated the development of metacognitive monitoring-based control of spacing choices in children and adults. Moreover, we assessed whether metacognitive learning decisions are influenced by the effects of previous metacognitive decisions. We tested groups of 7-year-olds, 10-year-olds, and adults in a task with two learning blocks in which they needed to monitor their learning through judgments of learning (JoL) and in which they then needed to decide whether to space their study, mass it, or terminate it. Extending previous findings, our study provides the first evidence that already by 7 years of age children can make metacognitive controlled scheduling decisions. The results also revealed that adults had more clearly differentiated strategies related to their JoL. Furthermore, our study provides evidence that participants of all age groups improved their relative monitoring accuracy in the second learning block and adjusted their JoL. However, only adults changed their strategy choices. PMID- 25703007 TI - Global transcriptional analysis of Escherichia coli expressing IrrE, a regulator from Deinococcus radiodurans, in response to NaCl shock. AB - Improving the microbial tolerance to stresses is very important for bioprocesses. Our previous study showed that IrrE, a global regulator from the extremely radioresistant bacterium Deinococcus radiodurans, dramatically enhanced the multi stress tolerance of Escherichia coli when expressed exogenously. However, the function of IrrE is still unclear. In this study, we used whole-genome microarray assays to profile the global gene expression of the IrrE-expressing E. coli strain MGE and the control strain MGT with or without salt shock. The analysis showed that IrrE expression led to many differentially expressed genes in E. coli, which were responsible for the transport and metabolism of trehalose and glycerol, nucleotide biosynthesis, carbon source utilization, amino acid utilization, and acid resistance, including many RpoS-dependent genes, e.g., the trehalose biosynthesis genes otsAB, the acid-resistance genes gadABC and uspB, the osmotic and oxidative stress response genes katE (response to DNA damage stimulus and stress) and osmBC (response to stress), and gadWX (which controls the transcription of pH-inducible genes). The intracellular content of trehalose and glycerol increased significantly in the IrrE-expressing strain after NaCl treatment for 0 and 60 min as determined by HPLC. These results indicated the possibility that IrrE regulates the global regulator RpoS. Interestingly, we found that although IrrE did not affect the level of the rpoS transcript, it enhanced the accumulation of the RpoS protein by increasing the expression of the antiadaptors, AppY, IraM and IraD, which inhibit RpoS degradation, suggesting that the accumulation of RpoS due to IrrE regulation is an important way to improve tolerance to salt and other stresses in E. coli. PMID- 25703008 TI - Chondroitin Sulfate Proteoglycans Negatively Modulate Spinal Cord Neural Precursor Cells by Signaling Through LAR and RPTPsigma and Modulation of the Rho/ROCK Pathway. AB - Multipotent adult neural precursor cells (NPCs) have tremendous intrinsic potential to repair the damaged spinal cord. However, evidence shows that the regenerative capabilities of endogenous and transplanted NPCs are limited in the microenvironment of spinal cord injury (SCI). We previously demonstrated that injury-induced upregulation of matrix chondroitin sulfate proteoglycans (CSPGs) restricts the survival, migration, integration, and differentiation of NPCs following SCI. CSPGs are long-lasting components of the astroglial scar that are formed around the lesion. Our recent in vivo studies demonstrated that removing CSPGs from the SCI environment enhances the potential of transplanted and endogenous adult NPCs for spinal cord repair; however, the mechanisms by which CSPGs regulate NPCs remain unclear. In this study, using in vitro models recapitulating the extracellular matrix of SCI, we investigated the direct role of CSPGs in modulating the properties of adult spinal cord NPCs. We show that CSPGs significantly decrease NPCs growth, attachment, survival, proliferation, and oligodendrocytes differentiation. Moreover, using genetic models, we show that CSPGs regulate NPCs by signaling on receptor protein tyrosine phosphate sigma (RPTPsigma) and leukocyte common antigen-related phosphatase (LAR). Intracellularly, CSPGs inhibitory effects are mediated through Rho/ROCK pathway and inhibition of Akt and Erk1/2 phosphorylation. Downregulation of RPTPsigma and LAR and blockade of ROCK in NPCs attenuates the inhibitory effects of CSPGS. Our work provide novel evidence uncovering how upregulation of CSPGs challenges the response of NPCs in their post-SCI niche and identifies new therapeutic targets for enhancing NPC-based therapies for SCI repair. PMID- 25703009 TI - Radioprotective activity of neutral polysaccharides isolated from the fruiting bodies of Hohenbuehelia serotina. AB - In this study, the radioprotective effect of neutral polysaccharides from Hohenbuehelia serotina (NTHSP) against the damages induced by (60)Co-gamma radiation was investigated. The results showed that NTHSP could significantly improve the activity of glutathione peroxidase (GSH-Px) and increase the contents of glutathione (GSH) and ceruloplasmin in plasma after treated with 6 Gy radiation compared with the radiation controls (p < 0.05). Furthermore, administration with NTHSP could effectively increase the quantity of marrow DNA (p < 0.05) and reduce the rates of chromosome aberration and micronuclei (p < 0.01) in bone marrows of mice. In addition, NTHSP could markedly inhibit the expressions of Bax protein and promote the expressions of Bcl-2 protein, accordingly inhibit the releases of cytochrome c and expressions of activated Caspase-3, and therefore block the mitochondrial apoptotic pathway of splenocytes in mice induced by (60)Co-gamma radiation. These results suggested that NTHSP might be a natural radioprotective agent against the injuries induced by radiation. PMID- 25703010 TI - The European Federation of Organisations for Medical Physics Policy Statement no. 15: recommended guidelines on the role of the Medical Physicist within the hospital governance board. AB - This EFOMP Policy Statement presents an outline on hospital governance and encourages the participation of the Medical Physicist in the hospital governance. It also emphasises how essential it is for Medical Physicists to engage in their hospital's governing board's committees for the overall good of the patient. PMID- 25703011 TI - Application of Gafchromic EBT2 film for intraoperative radiation therapy quality assurance. AB - PURPOSE: Intraoperative radiation therapy (IORT) using electron beam is commonly done by mobile dedicated linacs that have a variable range of electron energies. This paper focuses on the evaluation of the EBT2 film response in the green and red colour channels for IORT quality assurance (QA). METHODS: The calibration of the EBT2 films was done in two ranges; 0-8 Gy for machine QA by red channel and 8 24 Gy for patient-specific QA by green channel analysis. Irradiation of calibration films and relative dosimetries were performed in a water phantom. To evaluate the accuracy of the film response in relative dosimetry, gamma analysis was used to compare the results of the Monte Carlo simulation and ionometric dosimetry. Ten patients with early stage breast cancer were selected for in-vivo dosimetry using the green channel of the EBT2 film. RESULTS: The calibration curves were obtained by linear fitting of the green channel and a third-order polynomial function in the red channel (R2=0.99). The total dose uncertainty was up to 4.2% and 4.7% for the red and green channels, respectively. There was a good agreement between the relative dosimetries of films by the red channel, Monte Carlo simulations and ionometric values. The mean dose difference of the in vivo dosimetry by green channel of this film and the expected values was about 1.98% +/- 0.75. CONCLUSION: The results of this study showed that EBT2 film can be considered as an appropriate tool for machine and patient-specific QA in IORT. PMID- 25703012 TI - Development and validation of a risk calculator to differentiate flares from infections in systemic lupus erythematosus patients with fever. AB - OBJECTIVE: To develop and validate a predictive risk calculator algorithm that assesses the probability of flare versus infection in febrile patients with systemic lupus erythematosus (SLE). METHODS: We evaluated SLE patients admitted because of fever in the Department of Autoimmune Diseases of our Hospital between January 2000 and February 2013. Included patients were those with final diagnosis of infection, SLE flare or both. Data on clinical manifestations, treatment and laboratory results were collected. Variables considered clinically relevant were used to build up all possible logistic regression models to differentiate flares from infections. Best predictive variables for SLE relapses based on their higher area under the receiver operating characteristic (ROC) curve (AUC) were selected to be included in the calculator. The algorithm was developed in a random sample of 60% the cohort and validated in the remaining 40%. RESULTS: One hundred and thirty SLE patients presented 210 episodes of fever. Fever was attributed to SLE activity and to infection in 45% and 48% of the cases, respectively. Three independent variables for prediction of flares were consistently selected by multivariate analysis: days of fever, anti-dsDNA antibody titres and C-reactive protein levels. Combination of these variables resulted in an algorithm with calculated AUC of 0.92 (95% CI: 0.87 to 0.97). The AUC for the validation cohort was of 0.79 (95% CI: 0.68 to 0.91). CONCLUSION: The proposed flare risk predictive calculator could be a useful diagnostic tool for differentiation between flares and infections in febrile SLE patients. PMID- 25703013 TI - Metabolism of the designer drug alpha-pyrrolidinobutiophenone (alpha-PBP) in humans: identification and quantification of the phase I metabolites in urine. AB - Urinary phase I metabolites of alpha-pyrrolidinobutiophenone (alpha-PBP) in humans were investigated by analyzing urine specimens obtained from drug abusers. Unequivocal identification and accurate quantification of major metabolites were realized using gas chromatography-mass spectrometry and liquid chromatography tandem mass spectrometry with newly synthesized authentic standards. Two major phase I metabolic pathways were revealed: (1) reduction of the ketone group to 1 phenyl-2-(pyrrolidin-1-yl)butan-1-ol (OH-alpha-PBP, diastereomers) partly followed by conjugation to its glucuronide and (2) oxidation at the 2"-position of the pyrrolidine ring to alpha-(2"-oxo-pyrrolidino)butiophenone (2"-oxo-alpha PBP) via the putative intermediate alpha-(2"-hydroxypyrrolidino)butiophenone (2" OH-alpha-PBP). Of the phase I metabolites retaining the structural characteristics of the parent drug, OH-alpha-PBP was the most abundant in all specimens examined. Comparison of the phase I metabolism of alpha-PBP and alpha pyrrolidinovalerophenone (alpha-PVP) suggested a relationship between the aliphatic side chain length and the metabolic pathways in alpha pyrrolidinophenones: the shorter aliphatic side chain (1) led to more extensive metabolism via reduction of the ketone group than via the oxidation at the 2" position of the pyrrolidine ring and (2) influenced the isomeric ratio of a pair of diastereomers. PMID- 25703014 TI - Rapid discrimination of maggots utilising ATR-FTIR spectroscopy. AB - Entomological evidence is used in forensic investigations to indicate time since death. The species and age of maggots or flies that are present at the scene can be used when estimating how much time has passed since death. Current methods that are used to identify species and developmental stage of larvae and fly samples are highly subjective, costly and often time consuming processes and require the expertise of an entomologist or species identification via DNA analysis. The use of vibrational spectroscopy, as an alternative identification method, would allow for a quicker, cheaper and less subjective technique and would allow entomological evidence to be used more commonly in the forensic process. This proof of principle study shows the potential for using attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR) as a rapid tool for differentiating between various species of larvae, such as those commonly found at crime scenes. The proposed regime would provide a rapid and valuable tool resulting in reduced time for both species identification and life cycle determination, particularly in forensic situations. PMID- 25703015 TI - A pilot trial targeting the ICOS-ICOS-L pathway in nonhuman primate kidney transplantation. AB - Costimulation blockade with the B7-CD28 pathway-specific agent belatacept is now used in clinical kidney transplantation, but its efficacy remains imperfect. Numerous alternate costimulatory pathways have been proposed as targets to synergize with belatacept, one of which being the inducible costimulator (ICOS) ICOS ligand (ICOS-L) pathway. Combined ICOS-ICOS-L and CD28-B7 blockade has been shown to prevent rejection in mice, but has not been studied in primates. We therefore tested a novel ICOS-Ig human Fc-fusion protein in a nonhuman primate (NHP) kidney transplant model alone and in combination with belatacept. ICOS-Ig did not prolong rejection-free survival as a monotherapy or in combination with belatacept. In ICOS-Ig alone treated animals, most graft-infiltrating CD4(+) and CD8(+) T cells expressed ICOS, and ICOS(+) T cells were present in peripheral blood to a lesser degree. Adding belatacept reduced the proportion of graft infiltrating ICOS(+) T cells and virtually eliminated their presence in peripheral blood. Graft-infiltrating T cells in belatacept-resistant rejection were primarily CD8(+) CD28(-) , but importantly, very few CD8(+) CD28(-) T cells expressed ICOS. We conclude that ICOS-Ig, alone or combined with belatacept, does not prolong renal allograft survival in NHPs. This may relate to selective loss of ICOS with CD28 loss. PMID- 25703016 TI - Reversible crystal deformation of a single-crystal host of copper(II) 1 naphthoate-pyrazine through crystal phase transition induced by methanol vapor sorption. AB - A novel microporous single crystal of [Cu(II)2(1-NA)4(pyz)]n (1-NA: 1-naphthoate, pyz: pyrazine) exhibited bending and straightening action on a macroscopic scale during the first-order crystal phase transition induced by methanol vapor sorption. PMID- 25703017 TI - Altered microRNA expression in bovine skeletal muscle with age. AB - Age-dependent decline in skeletal muscle function leads to several inherited and acquired muscular disorders in elderly individuals. The levels of microRNAs (miRNAs) could be altered during muscle maintenance and repair. We therefore performed a comprehensive investigation for miRNAs from five different periods of bovine skeletal muscle development using next-generation small RNA sequencing. In total, 511 miRNAs, including one putatively novel miRNA, were identified. Thirty six miRNAs were differentially expressed between prenatal and postnatal stages of muscle development including several myomiRs (miR-1, miR-206 and let-7 families). Compared with miRNA expression between different muscle tissues, 14 miRNAs were up-regulated and 22 miRNAs were down-regulated in the muscle of postnatal stage. In addition, a novel miRNA was predicted and submitted to the miRBase database as bta-mir-10020. A dual luciferase reporter assay was used to demonstrate that bta mir-10020 directly targeted the 3'-UTR of the bovine ANGPT1 gene. The overexpression of bta-mir-10020 significantly decreased the DsRed fluorescence in the wild-type expression cassette compared to the mutant type. Using three computational approaches - miranda, pita and rnahybrid - these differentially expressed miRNAs were also predicted to target 3609 bovine genes. Disease and biological function analyses and the KEGG pathway analysis revealed that these targets were statistically enriched in functionality for muscle growth and disease. Our miRNA expression analysis findings from different states of muscle development and aging significantly expand the repertoire of bovine miRNAs now shown to be expressed in muscle and could contribute to further studies on growth and developmental disorders in this tissue type. PMID- 25703018 TI - The spectrum of Malassezia species isolated from students with pityriasis vesicolor in Nigeria. AB - Pityriasis versicolor (PV) is a common superficial fungal infection of the skin caused by Malassezia. Initially M. furfur was suggested as its main aetiological agent; however, more recent studies suggest M. globosa as the dominant species. The possibility of a variance in predominant species based on geographical basis has not been fully evaluated. The objective of this study was to identify the Malassezia species on affected and non-affected skin of students with PV who reside in a tropical environment (Abuja, Nigeria) and correlate them to clinical characteristics. In this study, the literature on prevalence of Malassezia genus in PV was also reviewed. Samples were taken from 304 PV lesions and 110 normal appearing skin. Microscopy, culture and identification of Malassezia species utilising polymerase chain reaction-restriction fragment length polymorphism analysis were performed. Three Malassezia species were detected in PV with the major species being M. furfur. On normal appearing skin, M. furfur (77.6%) and M. restricta (10.4%) were both detected. No case of M. globosa was identified in this study. There was no significant difference between species identified and clinical features of PV. M. furfur is probably still the most predominant species causing PV in the tropical environment. PMID- 25703019 TI - Two guard cell mitogen-activated protein kinases, MPK9 and MPK12, function in methyl jasmonate-induced stomatal closure in Arabidopsis thaliana. AB - Methyl jasmonate (MeJA) and abscisic acid (ABA) signalling cascades share several signalling components in guard cells. We previously showed that two guard cell preferential mitogen-activated protein kinases (MAPKs), MPK9 and MPK12, positively regulate ABA signalling in Arabidopsis thaliana. In this study, we examined whether these two MAP kinases function in MeJA signalling using genetic mutants for MPK9 and MPK12 combined with a pharmacological approach. MeJA induced stomatal closure in mpk9-1 and mpk12-1 single mutants as well as wild-type plants, but not in mpk9-1 mpk12-1 double mutants. Consistently, the MAPKK inhibitor PD98059 inhibited the MeJA-induced stomatal closure in wild-type plants. MeJA elicited reactive oxygen species (ROS) production and cytosolic alkalisation in guard cells of the mpk9-1, mpk12-1 and mpk9-1 mpk12-1 mutants, as well in wild-type plants. Furthermore, MeJA triggered elevation of cytosolic Ca(2+) concentration ([Ca(2+)]cyt ) in the mpk9-1 mpk12-1 double mutant as well as wild-type plants. Activation of S-type anion channels by MeJA was impaired in mpk9-1 mpk12-1. Together, these results indicate that MPK9 and MPK12 function upstream of S-type anion channel activation and downstream of ROS production, cytosolic alkalisation and [Ca(2+)]cyt elevation in guard cell MeJA signalling, suggesting that MPK9 and MPK12 are key regulators mediating both ABA and MeJA signalling in guard cells. PMID- 25703020 TI - Encapsulation of functional organic compounds in nanoglass for optically anisotropic coatings. AB - A novel approach is presented for the encapsulation of organic functional molecules between two sheets of 1 nm thin silicate layers, which like glass are transparent and chemically stable. An ordered heterostructure with organic interlayers strictly alternating with osmotically swelling sodium interlayers can be spontaneously delaminated into double stacks with the organic interlayers sandwiched between two silicate layers. The double stacks show high aspect ratios of >1000 (typical lateral extension 5000 nm, thickness 4.5 nm). This newly developed technique can be used to mask hydrophobic functional molecules and render them completely dispersible in water. The combination of the structural anisotropy of the silicate layers and a preferred orientation of molecules confined in the interlayer space allows polymer nanocomposite films to be cast with a well-defined orientation of the encapsulated molecules, thus rendering the optical properties of the nanocoatings anisotropic. PMID- 25703021 TI - Melanocytic naevi clustered on normal background skin. AB - Several types of maculopapular melanocytic naevi can occur in a multiple form, and be arranged in a nonrandom fashion on the skin. The most frequently reported segmentally grouped naevi are lentigines. Two types of segmentally arranged lentigines probably exist. The first is associated with neurofibromatosis (NF)1 or NF1 signs, features scattered light-brown lesions and can be considered a type of mosaic NF1. By contrast, non-NF1 associated lesions are characterized by densely packed, dark lesions, and can be defined as 'non-NF1 checkerboard arranged lentigines'. Blue naevi, Spitz naevi and common acquired melanocytic naevi can occur, clustered in an agminated (or cannonball) shape. However, if large enough, they always follow a checkerboard pattern. Hence, such mosaic conditions should be termed 'checkerboard-arranged blue naevi', 'checkerboard arranged Spitz naevi' and 'checkerboard-arranged common acquired melanocytic naevi'. Segmentally arranged dysplastic melanocytic naevi probably represent a mosaic form of dysplastic naevus syndrome. Dysplastic melanocytic naevi confined to a cutaneous segment could be defined as 'isolated segmental dysplastic naevus syndrome', while segmentally arranged dysplastic melanocytic naevi co-occurring with widespread, nonsegmental dysplastic melanocytic naevi might configure a 'superimposed segmental dysplastic naevus syndrome'. Small congenital melanocytic naevi are always grouped along Blaschko lines. The only other instances following Blaschko lines are the so-called 'linear lentiginous naevus' and a unique case of multiple deep penetrating naevi. PMID- 25703022 TI - Muscle ultrasound from diagnostic tool to outcome measure--Quantification is the challenge. PMID- 25703024 TI - Erratum for: Different Ways to On-Line Hyphenate Centrifugal Partition Chromatography and Mass Spectrometry: Application to Prenylated Xanthones from Garcinia mangostana. PMID- 25703023 TI - Brain changes associated with thromboxane receptor antagonist SQ 29,548 treatment in a mouse model. AB - The purpose of this study was to characterize behavioral and physiological effects of a selective thromboxane (TP) receptor antagonist, SQ 29,548, in the C57Bl/6 mouse model. At 6 months of age, male mice were given either sham or drug i.p. injections for 3 days at a dose of 2 mg/kg each day. On the day after the final injection, mice were subjected to behavioral testing before brain collection. Left hemisphere hippocampi were collected from all mice for protein analysis via Western blot. Right brain hemispheres were fixed and embedded in gelatin and then serially sectioned. The sections were immunostained with anti-c Fos antibodies. Prostaglandin analysis was performed from remaining homogenized brain samples, minus the hippocampi. Injection of SQ 29,548 decreased selective brain prostaglandin levels compared with sham controls. This correlated with robust increases in limbic-region c-Fos immunoreactivity in the SQ 29,548 injected mice. However, drug-treated mice demonstrated no significant changes in relevant hippocampal protein levels compared with sham treatments, as determined from Western blots. Surprisingly, injection of SQ 29,548 caused mixed changes in parameters of depression and anxiety-like behavior in the mice. In conclusion, the results indicate that administration of peripheral TP receptor antagonists alters brain levels of prostanoids and influences neuronal activity, with only minimal alterations of behavior. Whether the drug affects neurons directly or through a secondary pathway involving endothelium or other tissues remains unclear. PMID- 25703025 TI - Activation of beta2-adrenergic receptor by (R,R')-4'-methoxy-1-naphthylfenoterol inhibits proliferation and motility of melanoma cells. AB - (R,R')-4'-methoxy-1-naphthylfenoterol [(R,R')-MNF] is a highly-selective beta2 adrenergic receptor (beta2-AR) agonist. Incubation of a panel of human-derived melanoma cell lines with (R,R')-MNF resulted in a dose- and time-dependent inhibition of motility as assessed by in vitro wound healing and xCELLigence migration and invasion assays. Activity of (R,R')-MNF positively correlated with the beta2-AR expression levels across tested cell lines. The anti-motility activity of (R,R')-MNF was inhibited by the beta2-AR antagonist ICI-118,551 and the protein kinase A inhibitor H-89. The adenylyl cyclase activator forskolin and the phosphodiesterase 4 inhibitor Ro 20-1724 mimicked the ability of (R,R')-MNF to inhibit migration of melanoma cell lines in culture, highlighting the importance of cAMP for this phenomenon. (R,R')-MNF caused significant inhibition of cell growth in beta2-AR-expressing cells as monitored by radiolabeled thymidine incorporation and xCELLigence system. The MEK/ERK cascade functions in cellular proliferation, and constitutive phosphorylation of MEK and ERK at their active sites was significantly reduced upon beta2-AR activation with (R,R')-MNF. Protein synthesis was inhibited concomitantly both with increased eEF2 phosphorylation and lower expression of tumor cell regulators, EGF receptors, cyclin A and MMP-9. Taken together, these results identified beta2-AR as a novel potential target for melanoma management, and (R,R')-MNF as an efficient trigger of anti-tumorigenic cAMP/PKA-dependent signaling in beta2-AR-expressing lesions. PMID- 25703026 TI - The role of miR-100-mediated Notch pathway in apoptosis of gastric tumor cells. AB - MicroRNAs (miRNAs) are small non-coding regulatory molecules that influence many biological functions, including apoptosis, but their role in the regulation of apoptosis in gastric tumor cells has not been intensively investigated. Here, we showed that miR-100 was specifically upregulated in human epithelium-derived gastric cancer cells and that silencing miR-100 expression in human gastric epithelial cancer cells initiated a robust apoptotic response in vitro. Our in vivo assays indicated that the development of gastric cancer was inhibited by the miR-100 antagonism via initiating apoptosis of tumor. The results presented that antagonism of miR-100 increased the expression level of HS3ST2, the target gene of miR-100, and further resulted in the activation of the Notch-apoptosis pathway in tumor cells. The data also revealed that silencing of miR-100 expression sensitized gastric cancer cells to chemotherapy. Therefore our study presented a novel miR-100 mediated Notch pathway in apoptosis of tumor cells. PMID- 25703027 TI - Variations of ITSS-Morphology and their Relationship to Location and Tumor Volume in Patients with Glioblastoma. AB - BACKGROUND: Susceptibility weighted imaging and assessment of intratumoral susceptibility signal (ITSS) morphology is used to identify high-grade glioma (HGG) in patients with suspected brain neoplasm. PURPOSE: The aim of this study was to outline variations in ITSS-morphology and their relationship to location as well as volume of the lesion in patients with glioblastoma (GB). MATERIALS AND METHODS: Contrast-enhanced SWI (CE-SWI) images of 40 patients with histologically confirmed GB were analyzed retrospectively with particular attention to ITSS morphology dividing all lesions into two groups. Considering the location of the lesion within brain parenchyma, lesions with and without involvement of the subventricular zone (SVZ+/SVZ-) were discerned. Additionally, the contrast enhancing tumor volume was evaluated. Statistical analysis was based on a classification analysis resulting in a classification rule (tree) as well as Mann Whitney-U test. RESULTS: The distribution of ITSS-scores showed differences between the SVZ+ and SVZ- groups. While SVZ-GB showed only fine-linear or dot like ITSS, in SVZ+ GB the ITSS-morphology changed with the tumor volume, that is, in larger tumors dense and conglomerated ITSS were the predominant finding. CONCLUSION: Our findings indicate that ITSS-morphology is not a random phenomenon. Location of GB, as well as tumor volume, appear to be factors contributing to ITSS morphology. PMID- 25703028 TI - Effects of water availability on free amino acids, sugars, and acrylamide-forming potential in potato. AB - Irrigation is used frequently in potato cultivation to maximize yield, but water availability may also affect the composition of the crop, with implications for processing properties and food safety. Five varieties of potatoes, including drought-tolerant and -sensitive types, which had been grown with and without irrigation, were analyzed to show the effect of water supply on concentrations of free asparagine, other free amino acids, and sugars and on the acrylamide-forming potential of the tubers. Two varieties were also analyzed under more severe drought stress in a glasshouse. Water availability had profound effects on tuber free amino acid and sugar concentrations, and it was concluded that potato farmers should irrigate only if necessary to maintain the health and yield of the crop, because irrigation may increase the acrylamide-forming potential of potatoes. Even mild drought stress caused significant changes in composition, but these differed from those caused by more extreme drought stress. Free proline concentration, for example, increased in the field-grown potatoes of one variety from 7.02 mmol/kg with irrigation to 104.58 mmol/kg without irrigation, whereas free asparagine concentration was not affected significantly in the field but almost doubled from 132.03 to 242.26 mmol/kg in response to more severe drought stress in the glasshouse. Furthermore, the different genotypes were affected in dissimilar fashion by the same treatment, indicating that there is no single, unifying potato tuber drought stress response. PMID- 25703029 TI - Comparison of biorelevant simulated media mimicking the intestinal environment to assess the solubility profiles of poorly soluble drugs. AB - During the discovery stage in lead identification/optimization, compounds are characterized for their solubilities in biorelevant media and these data are often used to model the in vivo behavior of the compounds and predict the fraction absorbed. These media are selected to closely approximate the composition of human intestinal fluid. Owing to the complexity and variability in human intestinal fluid composition, it is essential that the chosen simulated media mimic the in vivo condition as closely as possible. Several recipes have been developed and are routinely used in assessing the solubilities of compounds. It is necessary to revisit these recipes and modify them as the understanding of the human GI tract increases. In the present work, we have evaluated the solubilities of six model compounds in several media and have proposed slight modifications to the currently used recipes based on our own data and that reported in the literature. PMID- 25703030 TI - Diary Reports of Concerns in Mothers of Infant Siblings of Children with Autism Across the First Year of Life. AB - We examined the home-based concerns reported by mothers of infant siblings of children with autism across the first year of life. At all three ages measured, mothers of high-risk infants were significantly more likely than mothers of low risk infants to report language, social communication, and restricted and repetitive behavior concerns but were not more likely to report general, medically based concerns. At 6 and 9 months of age, maternal concerns were poorly related to infant or family variables. At 12 months of age, there were moderate correlations between maternal concerns and infant behavior, and concerns were associated with the proband's autism symptoms and mothers' concurrent depressive symptoms. These findings highlight the need to examine high-risk infants' development in the family context. PMID- 25703031 TI - Diagnostic Yield of Chromosomal Microarray Analysis in a Cohort of Patients with Autism Spectrum Disorders from a Highly Consanguineous Population. AB - Autism Spectrum Disorders are a complicated group of disorders characterized with heterogeneous genetic etiologies. The genetic investigations for this group of disorders have expanded considerably over the past decade. In our study we designed a tired approach and studied the diagnostic yield of chromosomal microarray analysis on patients referred to the Genetic and Developmental Medicine clinic in Sultan Qaboos University in Oman for autism spectrum disorders in a highly consanguineous population. Copy number variants were seen in 27% of our studied cohort of patients and it was strongly associated with dysmorphic features and congenital anomalies. PMID- 25703032 TI - Brief Report: Infants Developing with ASD Show a Unique Developmental Pattern of Facial Feature Scanning. AB - Infants are interested in eyes, but look preferentially at mouths toward the end of the first year, when word learning begins. Language delays are characteristic of children developing with autism spectrum disorder (ASD). We measured how infants at risk for ASD, control infants, and infants who later reached ASD criterion scanned facial features. Development differed across groups. The preference for the eyes region decreased with age in infants who were at risk of ASD. For the control group the change in feature preference was marginally significant for a quadratic model, reflecting a decrease in the preference for eyes at 9 months followed by a recovery. The infants who later reached ASD criterion did not show a significant change across time. PMID- 25703033 TI - Evaluation of a visualization assay for blood on forensic evidence. AB - In forensics, bloodstains on dark fabrics might be invisible for the naked eye. Although several visualization, presumptive, and confirmatory blood tests have been developed, all have one or more disadvantages, especially on DNA analysis. We report here the use of a visualization assay that can visually detect blood drops up to 1/20 dilution. In this assay, the fabric is placed between two wet filter papers and covered by glass surfaces on both sides. Pressure is applied on the glass surfaces in which bloodstains transfer onto the filter papers through capillary forces. Detected stains can be tested with other more sensitive presumptive blood tests performed on the filter paper. Even more, DNA analysis can be performed on the transferred bloodstains. The presented visualization assay is easy to perform, extremely cheap, requires little hands on time, and does not affect bloodstain pattern analysis. PMID- 25703034 TI - Women's opinions on the legalisation of abortion in Chile 2009-2013. AB - Chile is one of only four countries in the world where there is no explicit legal exception to prohibitions on abortion, and where the criminalisation of abortion endangers women's health and may be misaligned with public opinion. In this study we explored attitudes towards the legalisation of abortion and differences in levels of support across time. Among Chilean women in 2009 and 2013, we examined: (1) an additive index indicating support for legalisation of abortion in several situations and (2) support for each situation separately. We investigated the demographic characteristics associated with support for legalisation using multivariate regression. Over 70% of women supported the legalisation of abortion in cases of risk to the woman's life, rape and foetal malformation, and support was higher in 2013 compared to 2009 (beta = 0.28; 95% CI: 0.12, 0.44). Women with increasing education and those attending church services less frequently were more likely to support the legalisation of abortion (beta = 0.27; 95% CI: 0.11, 0.43), while those affiliated to a religion other than Catholicism (beta = - 0.32; 95% CI: - 0.48, - 0.16) were less likely to do so. Our study is the first to examine public opinions on abortion in Chile and differences in levels of support across time periods. Results indicate that current policies may not reflect trends in public opinion. PMID- 25703035 TI - Influence of multi-leaf collimator leaf width in radiosurgery via volumetric modulated arc therapy and 3D dynamic conformal arc therapy. AB - PURPOSE: To study the influence of Multileaf Collimator (MLC) leaf width in radiosurgery treatment planning for Volumetric Modulated Arc Therapy (VMAT) and 3D Dynamic Conformal Arc Therapy (3D-DCA). MATERIAL AND METHODS: 16 patients with solitary brain metastases treated with radiosurgery via the non-coplanar VMAT were replanned for the 3D-DCA. For each planning technique two MLC leaf width sizes were utilized, i.e. 5 mm and 2.5 mm. These treatment plans were compared using dosimetric indices (conformity, gradient and mean dose for brain tissue) and the normal tissue complication probability (NTCP). RESULTS: An improvement in planning quality for VMAT was observed versus 3D-DCA for any MLC leaf width, mainly with regards to dose conformity and to a lesser extent regards dose gradient. No significant difference was observed for any of both techniques using smaller leaf width. However, dose gradient was improved in favor of the 2.5 mm MLC for either of both techniques (15% VMAT and 10% 3D-DCA); being noticeable for lesions smaller than 10cm(3). Nonetheless, the NTCP index was not significantly affected by variations in the dose gradient index. CONCLUSIONS: This, our present study, suggests that the use of an MLC leaf width of 2.5 mm via the noncoplanar VMAT and 3D-DCA techniques provides improvement in terms of dose gradient for small volumes, over those results obtained with an MLC leaf width of 5 mm. The 3D DCA does also benefit from MLC leaf widths of a smaller size, mainly in terms of conformity. PMID- 25703036 TI - Pioglitazone blocks ethanol induction of microglial activation and immune responses in the hippocampus, cerebellum, and cerebral cortex in a mouse model of fetal alcohol spectrum disorders. AB - BACKGROUND: Fetal alcohol spectrum disorders (FASD) result from fetal exposure to alcohol and are the leading cause of mental retardation in the United States. There is currently no effective treatment that targets the causes of these disorders. Thus, novel therapies are critically needed to limit the neurodevelopmental and neurodegenerative pathologies associated with FASD. METHODS: A neonatal mouse FASD model was used to examine the role of the neuroimmune system in ethanol (EtOH)-induced neuropathology. Neonatal C57BL/6 mice were treated with EtOH, with or without pioglitazone, on postnatal days 4 through 9, and tissue was harvested 1 day post treatment. Pioglitazone is a peroxisome proliferator-activated receptor (PPAR)-gamma agonist that exhibits anti-inflammatory activity and is neuroprotective. We compared the effects of EtOH with or without pioglitazone on cytokine and chemokine expression and microglial morphology in the hippocampus, cerebellum, and cerebral cortex. RESULTS: In EtOH-treated animals compared with controls, cytokines interleukin 1beta and tumor necrosis factor-alpha mRNA levels were increased significantly in the hippocampus, cerebellum, and cerebral cortex. Chemokine CCL2 mRNA was increased significantly in the hippocampus and cerebellum. Pioglitazone effectively blocked the EtOH-induced increase in the cytokines and chemokine in all tissues to the level expressed in handled-only and vehicle-treated control animals. EtOH also produced a change in microglial morphology in all brain regions that was indicative of microglial activation, and pioglitazone blocked this EtOH-induced morphological change. CONCLUSIONS: These studies indicate that EtOH activates microglia to a pro-inflammatory stage and also increases the expression of neuroinflammatory cytokines and chemokines in diverse regions of the developing brain. Further, the anti-inflammatory and neuroprotective PPAR gamma agonist pioglitazone blocked these effects. It is proposed that microglial activation and inflammatory molecules expressed as a result of EtOH treatment during brain development contribute to the sequelae associated with FASD. Thus, pioglitazone and anti-inflammatory pharmaceuticals more broadly have potential as novel therapeutics for FASD. PMID- 25703037 TI - Divergence of craniofacial developmental trajectories among avian embryos. AB - BACKGROUND: Morphological divergence among related species involves changes to developmental processes. When such variation arises in development has garnered considerable theoretical interest relating to the broader issue of how development may constrain evolutionary change. The hourglass model holds that while early developmental events may be highly evolvable, there is a phylotypic stage when key developmental events are conserved. Thus, evolutionary divergence among related species should tend to arise after such a stage of reduced evolvability and, consequently, reduced variation among species. We test this prediction by comparing developmental trajectories among three avian species of varying relatedness (chick, quail, and duck) to locate their putative point of divergence. Three-dimensional geometric morphometrics and trajectory analyses were used to measure the significance of the facial shape variation observed among these species. RESULTS: Duck embryos, being more distantly related, differed from the more closely-related chick and quail embryos in the enlargement of their frontonasal prominences. Phenotypic trajectory analyses demonstrated divergence of the three species, most notably, duck. CONCLUSIONS: The results demonstrate that the two more closely related species share similar facial morphologies for a longer time during development, while ducks diverge. This suggests a surprising lability of craniofacial development during early face formation. Developmental Dynamics 244:1158-1167, 2015. (c) 2015 Wiley Periodicals, Inc. PMID- 25703038 TI - An extended CCR5 ECL2 peptide forms a helix that binds HIV-1 gp120 through non specific hydrophobic interactions. AB - C-C chemokine receptor 5 (CCR5) serves as a co-receptor for HIV-1. The CCR5 N terminal segment, the second extracellular loop (ECL2) and the transmembrane helices have been implicated in binding the envelope glycoprotein gp120. Peptides corresponding to the sequence of the putative ECL2 as well as peptides containing extracellular loops 1 and 3 (ECL1 and ECL3) were found to inhibit HIV-1 infection. The aromatic residues in the C-terminal half of an ECL2 peptide were shown to interact with gp120. In the present study, we found that, in aqueous buffer, the segment Q188-Q194 in an elongated ECL2 peptide (R168-K197) forms an amphiphilic helix, which corresponds to the beginning of the fifth transmembrane helix in the crystal structure of CCR5. Two-dimensional saturation transfer difference NMR spectroscopy and dynamic filtering studies revealed involvement of Y187, F189, W190 and F193 of the helical segment in the interaction with gp120. The crystal structure of CCR5 shows that the aromatic side chains of F189, W190 and F193 point away from the binding pocket and interact with the membrane or with an adjacent CCR5 molecule, and therefore could not interact with gp120 in the intact CCR5 receptor. We conclude that these three aromatic residues of ECL2 peptides interact with gp120 through hydrophobic interactions that are not representative of the interactions of the intact CCR5 receptor. The HIV-1 inhibition by ECL2 peptides, as well as by ECL1 and ECL3 peptides and peptides corresponding to ECL2 of CXCR4, which serves as an alternative HIV-1 co-receptor, suggests that there is a hydrophobic surface in the envelope spike that could be a target for HIV-1 entry inhibitors. DATABASE: The structures and NMR data of ECL2S (Q186-T195) were deposited under Protein Data Bank ID 2mzx and BioMagResBank ID 25505. PMID- 25703039 TI - A cross sectional study of prevalence and correlates of current and past risks in schizophrenia. AB - BACKGROUND: The growing burden of chronic often untreated mental illness has increased the importance of risk assessment in people suffering from major mental disorders. AIMS: The present study was undertaken to obtain prevalence of various risks and predictive factors for self-harm, violence and various other risks among randomly recruited schizophrenia subjects (N=270) on the basis of past history of their disorder. METHOD: Using a rigorous translation, back translation and acceptability process, a specially constructed semi-structured assessment interview, based on a prior NHS Trust risk assessment interview along with the Diagnostic Interview for Genetic Studies (DIGS), detailed information was obtained for various risks. RESULTS: Risk of violence (historical) was reported among 65.55%, and risk of self-neglect among 53.33%, risk to others (47.41%), risk of coming to harm (24.07%), self-harm (22.59%), risk from others (11.85%), fire risk (2.96%). Risk of violence (historical) and risk to others was related to 'ever' having emotions related to harm and self-harm, 'current' emotions related to violence and poor compliance to treatment. CONCLUSION: Regular risk assessment is essential to assess emotions related to violence and non-adherence to treatment. Assessment of risk helps clinicians predict the risks involved in management and in timely intervention. PMID- 25703040 TI - Impact of a stress management program on stress perception of nurses working with psychiatric patients. AB - Nurses caring for psychiatric patients may have to face violent emotions and unpredictable behaviour which can be quite stressful. A stress management program may equip nurses with skills to cope effectively with the stress. A one group pre test and post-test design was adopted to test this hypothesis. Both gender nurses caring for psychiatric patients were invited to undergo 10 consecutive, one hour sessions of a stress management program. The DCL Stress scale (The De Villiers, Carson & Leary Stress Scale; Carson et al., 1997a,b,c) was used to collect data immediately after intervention and four weeks later. RM ANOVA with spss 16 showed that pre-intervention mean stress reduced significantly (p=0.000) from 57.45+/ 16.42 to 41.06+/-16.51 immediately following the intervention and 26.43+/-12.82 (p=0.000) four weeks after the intervention. The stress management strategies positively impacted on nurses' stress levels. PMID- 25703041 TI - Does psychological resilience mediate the impact of social support on geriatric depression? An exploratory study among Chinese older adults in Singapore. AB - Social support and resilience were considered to be two significant influential factors for depression in late life. The study aims to present a mediation model for understanding the interrelations among social support, resilience, and geriatric depression. A cross-sectional survey study was conducted among 162 community-dwelling Chinese older adults in Singapore. Findings indicated a significant indirect effect of social support on geriatric depression through the mediation of resilience, by controlling demographic variables. Further, an identical influencing pattern between problem-solving resilience and emotion regulation resilience were found in the two individual models, suggesting a similar mediation role in linking social support and geriatric depression. These results extended and integrated earlier findings on the relationship of psychosocial factors and geriatric depression, and pointed out practical implications for future work on depression interventions. PMID- 25703042 TI - Fipronil promotes motor and behavioral changes in honey bees (Apis mellifera) and affects the development of colonies exposed to sublethal doses. AB - Bees play a crucial role in pollination and generate honey and other hive products; therefore, their worldwide decline is cause for concern. New broad spectrum systemic insecticides such as fipronil can harm bees and their use has been discussed as a potential threat to bees' survival. In the present study, the authors evaluate the in vitro toxicity of fipronil and note behavioral and motor activity changes in Africanized adult Apis mellifera that ingest or come into contact with lethal or sublethal doses of fipronil. The effects of sublethal doses on brood viability, population growth, behavior, and the expression of the defensin 1 gene in adult bees were studied in colonies fed with contaminated sugar syrup (8 ug fipronil L(-1) ). Fipronil is highly toxic to bees triggering agitation, seizures, tremors, and paralysis. Bees that are exposed to a lethal or sublethal doses showed reduced motor activity. The number of eggs that hatched, the area occupied by worker eggs, and the number of larvae and pupae that developed were reduced, adult bees showed lethargy, and colonies were abandoned when they were exposed to sublethal doses of fipronil. No change was seen in the bees' expression of defensin 1. The authors conclude that fipronil is highly toxic to honey bees and even sublethal doses may negatively affect the development and maintenance of colonies. PMID- 25703043 TI - Family caregivers' mental health is associated with postoperative recovery of elderly patients with hip fracture: a sample in Taiwan. AB - OBJECTIVE: This study investigated the relationship between family caregivers' mental health and postoperative recovery for elderly patients with hip fracture in Taiwan. METHODS: This study is a secondary analysis of data from a randomized controlled trial with 12-month follow-up on 276 family caregiver-patient dyads. Categories of caregiver mental-health trajectory groups were identified by latent class finite-mixture modeling. Differences in these groups were explored using the generalized estimating equation approach for effects on patients' postoperative recovery, including pain intensity, range of motion, maximum muscle strength, recovery of self-care ability, mobility, re-hospitalization, and health related quality of life. RESULTS: The patterns of family caregivers' mental health best fit a three-group trajectory model (poor, moderate, and good). Compared to patients with caregivers in the "poor" mental health group, patients with caregivers in the "good" group had better trajectories in physical functional recovery, including mobility, muscle strength, hip flexion and extension, and ankle extension. These patients were also less likely to be hospitalized, experienced less pain, and had better physical and mental health. Patients with caregivers in the "moderate" group likewise performed better than those in the "poor" group. CONCLUSION: During the first year following discharge, postoperative recovery of patients after hip fracture was associated with their family caregivers' mental health. When a family caregiver's mental health was "poor," the patient recovering after hip-fracture surgery was more likely to recover poorly. These results suggest that health care providers could consider family caregivers' mental well-being while estimating recovery times and health outcomes of patients following hip fracture. PMID- 25703044 TI - Reply: To PMID 24893954. PMID- 25703045 TI - MEMS: Enabled Drug Delivery Systems. AB - Drug delivery systems play a crucial role in the treatment and management of medical conditions. Microelectromechanical systems (MEMS) technologies have allowed the development of advanced miniaturized devices for medical and biological applications. This Review presents the use of MEMS technologies to produce drug delivery devices detailing the delivery mechanisms, device formats employed, and various biomedical applications. The integration of dosing control systems, examples of commercially available microtechnology-enabled drug delivery devices, remaining challenges, and future outlook are also discussed. PMID- 25703047 TI - 'MetaTaal': enhancing complex syntax in children with specific language impairment--a metalinguistic and multimodal approach. AB - BACKGROUND: Currently, most research on the effective treatment of morphosyntax in children with specific language impairment (SLI) pertains to younger children. In the last two decades, several studies have provided evidence that intervention for older school-age children with SLI can be effective. These metalinguistic intervention approaches teach grammatical rules explicitly and use shapes and colours as two-dimensional visual support. Reading or writing activities form a substantial part of these interventions. However, some children with SLI are poor readers and might benefit more from an approach that is less dependent on literacy skills. AIMS: To examine the effectiveness of a combined metalinguistic and multimodal approach in older school-age children with SLI. The intervention was adapted to suit poor readers and targeted the improvement of relative clause production, because relative clauses still pose difficulties for older children with SLI. METHODS & PROCEDURES: Participants were 12 monolingual Dutch children with SLI (mean age 11;2). All children visited a special school for children with speech and language disorders in the Netherlands. A quasi-experimental multiple baseline design was chosen to evaluate the effectiveness of the intervention. A set of tasks was constructed to test relative clause production and comprehension. Two balanced versions were alternated in order to suppress a possible learning effect from multiple presentations of the tasks. After 3 monthly baseline measurements, the children received individual treatment with a protocolled intervention programme twice a week during 5 weeks. The tests were repeated directly post-therapy and at a retention measurement 3 months later. During the intervention programme, the speech therapist delivering the treatment remained blind to the test results. OUTCOMES & RESULTS: No significant changes were found during the baseline measurements. However, measurement directly post therapy showed that 5 h of intervention produced significant improvement on the relative clause production tasks, but not on the relative clause comprehension task. The gains were also maintained 3 months later. CONCLUSIONS & IMPLICATIONS: The motor and tactile/kinesthetic dimensions of the 'MetaTaal' metalinguistic intervention approach are a valuable addition to the existing metalinguistic approaches. This study supports the evidence that grammatical skills in older school-age children with SLI can be remediated with direct intervention using a metalinguistic approach. The current tendency to diminish direct intervention for older children with SLI should be reconsidered. PMID- 25703048 TI - Quantitative Determination of Luminal and Abluminal Membrane Distributions of Transporters in Porcine Brain Capillaries by Plasma Membrane Fractionation and Quantitative Targeted Proteomics. AB - Abluminal or luminal localization of transporter in plasma membranes at the blood brain barrier (BBB) is critical for their physiological and pharmacological roles. Therefore, the purpose of this study was to develop a new method to investigate membrane localization of transporters, through quantitative measurement of protein expression levels in fractionated plasma membrane prepared from porcine brain capillaries. Luminal-abluminal distribution ratios were calculated from the results of quantitative targeted absolute proteomics of fractionated membranes, after correction for cross-contamination based on measurements of luminal and abluminal membrane markers. BCRP expression was greater at the luminal membrane than at the abluminal membrane, supporting the usefulness of the distribution ratio as a quantitative indicator of localization. The distribution ratios suggested luminal-dominant localizations of GLUT1 and OATP3A1, and abluminal-dominant localizations of ABCA1 and FATP1. For OATP3A1, ABCA1 and FATP1, these results require reconsideration of their functions at the BBB. Species differences were examined using expression levels normalized to Na(+) /K(+) -ATPase. BCRP expression is dominant over multidrug resistance 1 expression in porcine BBB, as in other primates including humans. This methodology for quantitative measurement of protein localization is expected to improve our understanding of the roles of transporters at the BBB, and should be applicable to other polarized cells. PMID- 25703049 TI - Body condition score of Nellore beef cows: a heritable measure to improve the selection of reproductive and maternal traits. AB - Despite the economic importance of beef cattle production in Brazil, female reproductive performance, which is strongly associated with production efficiency, is not included in the selection index of most breeding programmes due to low heritability and difficulty in measure. The body condition score (BCS) could be used as an indicator of these traits. However, so far little is known about the feasibility of using BCS as a selection tool for reproductive performance in beef cattle. In this study, we investigated the sources of variation in the BCS of Nellore beef cows, quantified its association with reproductive and maternal traits and estimated its heritability. BCS was analysed using a logistic model that included the following effects: contemporary group at weaning, cow weight and hip height, calving order, reconception together with the weight and scores of conformation and early finishing assigned to calves at weaning. In the genetic analysis, variance components of BCS were estimated through Bayesian inference by fitting an animal model that also included the aforementioned effects. The results showed that BCS was significantly associated with all of the reproductive and maternal variables analysed. The estimated posterior mean of heritability of BCS was 0.24 (highest posterior density interval at 95%: 0.093 to 0.385), indicating an involvement of additive gene action in its determination. The present findings show that BCS can be used as a selection criterion for Nellore females. PMID- 25703050 TI - Links between teacher assessment and child self-assessment of mental health and behavior among children affected by HIV/AIDS. AB - Teachers are considered to be one of the most important influences in the lives of students. Teachers' assessments of students may be a primary source of information on children's mental and behavioral health; however, this topic has received little attention in research. We examined this issue through linking teachers' ratings of students and mental and behavioral outcomes of children affected by HIV. The hypothesis is that teacher ratings will be predictive of specific child mental and behavioral health outcomes. A quantitative cross sectional design with self-administered paper-and-pencil instruments was used. The sample included 1221 children (aged 6-18, grades 1-11) affected by HIV including 755 orphans who lost one or both parents to AIDS and 466 vulnerable children living with HIV-infected parents in a central province of China. The corresponding teacher sample included 185 participants. Each child completed an assessment inventory of demographic information and mental and behavioral health measures. Teachers completed a questionnaire about children's school performance. SEM analyses revealed a good model fit according to all fit indices: comparative fit index = 0.93, root mean square error of approximation = 0.07, and standardized root mean square residual = 0.04. Structural equation modeling revealed that problem ratings by teachers were positively associated with child loneliness and behavioral problems, social competence ratings by teachers were negatively related to child depression, and personal growth and social interaction ratings by teachers were negatively related to child loneliness, depression, and trauma. The current study represents a unique contribution to the field in that it recognizes that teachers can be a valuable source of information on children's psychological health. Results from this study have implications for health prevention and intervention for children and families suffering from HIV/AIDS. PMID- 25703051 TI - Bridging topological and functional information in protein interaction networks by short loops profiling. AB - Protein-protein interaction networks (PPINs) have been employed to identify potential novel interconnections between proteins as well as crucial cellular functions. In this study we identify fundamental principles of PPIN topologies by analysing network motifs of short loops, which are small cyclic interactions of between 3 and 6 proteins. We compared 30 PPINs with corresponding randomised null models and examined the occurrence of common biological functions in loops extracted from a cross-validated high-confidence dataset of 622 human protein complexes. We demonstrate that loops are an intrinsic feature of PPINs and that specific cell functions are predominantly performed by loops of different lengths. Topologically, we find that loops are strongly related to the accuracy of PPINs and define a core of interactions with high resilience. The identification of this core and the analysis of loop composition are promising tools to assess PPIN quality and to uncover possible biases from experimental detection methods. More than 96% of loops share at least one biological function, with enrichment of cellular functions related to mRNA metabolic processing and the cell cycle. Our analyses suggest that these motifs can be used in the design of targeted experiments for functional phenotype detection. PMID- 25703052 TI - Comparison of the purification of biologically active IL-7 cytokine expressed in Escherichia coli and Pichia pastoris. AB - The large scale screening of cytokine mutants is a component of binding and activity mapping and requires an efficient method of cytokine protein expression. Here, we compared recombinant IL-7 expression with and purification from Escherichia coli and Pichia pastoris. The IL-7 cytokine contains three disulfide bonds that are essential for its biological activity, and which are formed upon secretion through P. pastoris, but not in the reducing cytoplasm of E. coli. In contrast to a previous report we found that P. pastoris secretes active but N linked hyperglycosylated IL-7. Enzymatic deglycosylation was incompatible with activity measurements in a cell based assay. E. coli expressed IL-7 was refolded from solubilized inclusion bodies. A chromatographic purification step between inclusion body solubilization and refolding increased the yield of biologically active monomeric IL-7, and decreased the amount of inactive soluble aggregates. Cation exchange chromatography of untagged IL-7, and IMAC of His-tagged IL-7 improved refolding yields to a similar extend, indicating that the removal of contaminating components in the solubilized inclusion bodies improves refolding efficiency. We conclude that a chromatographic purification step of IL-7 solubilized from E. coli inclusion bodies increases refolding yield, and may be a suitable general rescue strategy for obtaining folded and biologically active proteins from inclusion bodies. PMID- 25703053 TI - Secretagogin, a hexa EF-hand calcium-binding protein: high level bacterial overexpression, one-step purification and properties. AB - Secretagogin (SCGN), a hexa EF-hand calcium-binding protein, is highly expressed in the endocrine cells (especially in pancreatic islets) and in restricted neuronal sub-populations, albeit at comparatively low level. Since SCGN is predicted to be a potential neuroendocrine marker in carcinoid tumors of lung and gastrointestinal tract, it is of paramount importance to understand the features of this protein in different environment for assigning its crucial functions in different tissues and under pathophysiological conditions. To score out the limitation of protein for in vitro studies, we report a one-step, high purity and high level bacterial purification of secretagogin by refolding from the inclusion bodies yielding about 40mg protein per litre of bacterial culture. We also report previously undocumented Ca(2+)/Mg(2+) binding and hydrodynamic properties of secretagogin. PMID- 25703054 TI - Recombinant production of biologically active giant grouper (Epinephelus lanceolatus) growth hormone from inclusion bodies of Escherichia coli by fed batch culture. AB - Growth hormone (GH) performs important roles in regulating somatic growth, reproduction, osmoregulation, metabolism and immunity in teleosts, and thus, it has attracted substantial attention in the field of aquaculture application. Herein, giant grouper GH (ggGH) cDNA was cloned into the pET28a vector and expressed in Shuffle(r) T7 Competent Escherichia coli. Recombinant N-terminal 6* His-tagged ggGH was produced mainly in insoluble inclusion bodies; the recombinant ggGH content reached 20% of total protein. For large-scale ggGH production, high-cell density E. coli culture was achieved via fed-batch culture with pH-stat. After 30h of cultivation, a cell concentration of 41.1g/l dry cell weight with over 95% plasmid stability was reached. Maximal ggGH production (4.0g/l; 22% total protein) was achieved via mid-log phase induction. Various centrifugal forces, buffer pHs and urea concentrations were optimized for isolation and solubilization of ggGH from inclusion bodies. Hydrophobic interactions and ionic interactions were the major forces in ggGH inclusion body formation. Complete ggGH inclusion body solubilization was obtained in PBS buffer at pH 12 containing 3M urea. Through a simple purification process including Ni NTA affinity chromatography and refolding, 5.7mg of ggGH was obtained from 10ml of fed-batch culture (45% recovery). The sequence and secondary structure of the purified ggGH were confirmed by LC-MS/MS mass spectrometry and circular dichroism analysis. The cell proliferation-promoting activity was confirmed in HepG2, ZFL and GF-1 cells with the WST-1 colorimetric bioassay. PMID- 25703055 TI - Heterotrimetallic coordination polymers: {Cu(II)Ln(III)Fe(III)} chains and {Ni(II)Ln(III)Fe(III)} layers: synthesis, crystal structures, and magnetic properties. AB - The use of the [Fe(III) (AA)(CN)4](-) complex anion as metalloligand towards the preformed [Cu(II) (valpn)Ln(III)](3+) or [Ni(II) (valpn)Ln(III) ](3+) heterometallic complex cations (AA=2,2'-bipyridine (bipy) and 1,10-phenathroline (phen); H2 valpn=1,3-propanediyl-bis(2-iminomethylene-6-methoxyphenol)) allowed the preparation of two families of heterotrimetallic complexes: three isostructural 1D coordination polymers of general formula {[Cu(II) (valpn)Ln(III) (H2O)3 (MU-NC)2 Fe(III) (phen)(CN)2 {(MU-NC)Fe(III) (phen)(CN)3}]NO3 ?7 H2O}n (Ln=Gd (1), Tb (2), and Dy (3)) and the trinuclear complex [Cu(II) (valpn)La(III) (OH2 )3 (O2 NO)(MU-NC)Fe(III) (phen)(CN)3 ]?NO3 ?H2O?CH3 CN (4) were obtained with the [Cu(II) (valpn)Ln(III)](3+) assembling unit, whereas three isostructural heterotrimetallic 2D networks, {[Ni(II) (valpn)Ln(III) (ONO2 )2 (H2 O)(MU-NC)3 Fe(III) (bipy)(CN)]?2 H2 O?2 CH3 CN}n (Ln=Gd (5), Tb (6), and Dy (7)) resulted with the related [Ni(II) (valpn)Ln(III) ](3+) precursor. The crystal structure of compound 4 consists of discrete heterotrimetallic complex cations, [Cu(II) (valpn)La(III) (OH2)3 (O2 NO)(MU-NC)Fe(III) (phen)(CN)3 ](+), nitrate counterions, and non-coordinate water and acetonitrile molecules. The heteroleptic {Fe(III) (bipy)(CN)4} moiety in 5-7 acts as a tris-monodentate ligand towards three {Ni(II) (valpn)Ln(III)} binuclear nodes leading to heterotrimetallic 2D networks. The ferromagnetic interaction through the diphenoxo bridge in the Cu(II)-Ln(III) (1-3) and Ni(II)-Ln(III) (5-7) units, as well as through the single cyanide bridge between the Fe(III) and either Ni(II) (5-7) or Cu(II) (4) account for the overall ferromagnetic behavior observed in 1 7. DFT-type calculations were performed to substantiate the magnetic interactions in 1, 4, and 5. Interestingly, compound 6 exhibits slow relaxation of the magnetization with maxima of the out-of-phase ac signals below 4.0 K in the lack of a dc field, the values of the pre-exponential factor (tauo) and energy barrier (Ea ) through the Arrhenius equation being 2.0*10(-12) s and 29.1 cm(-1), respectively. In the case of 7, the ferromagnetic interactions through the double phenoxo (Ni(II)-Dy(III)) and single cyanide (Fe(III)-Ni(II)) pathways are masked by the depopulation of the Stark levels of the Dy(III) ion, this feature most likely accounting for the continuous decrease of chiMT upon cooling observed for this last compound. PMID- 25703056 TI - Rosiglitazone ameliorates senescence-like phenotypes in a cellular photoaging model. AB - BACKGROUND: Rosiglitazone (RO), a second-generation thiazolidinedione used mainly in the treatment of non-insulin-dependent diabetes mellitus, has been discovered to be a high-affinity ligand for peroxisome proliferator-activated receptor-gamma (PPAR-gamma). Several studies have revealed that PPAR-gamma is also involved in the regulation of oxidative stress and chronic inflammation associated with aging process in vivo as well as with cellular senescence in vitro. We sought to investigate whether RO pretreatment will counteract the photoaging process using a well-established cellular photoaging model. METHODS: Murine dermal fibroblasts (MDFs) were cultured in the absence or presence of RO for 48h, followed by exposure to repeated UVB irradiation. The senescent phenotypes were evaluated including cell viability, senescence-associated beta-galactosidase (SA-beta-gal) expression, cell morphology, ROS generation, cell cycle, production and degradation of extracellular matrix (ECM), and the potential mechanisms were discussed. RESULTS: Pretreatment with RO (40MUM) significantly decreased the staining intensity and the percentage of SA-beta-gal-positive cells and reserved the elongated cell shape compared with UVB group. The cells pretreated with RO also showed decreased UVB-induced degradation of type I collagen by decreasing MMPs expressions. In addition, we observed counteraction of cell-cycle arrest and repression of UVB-induced p53 and p21 in the presence of RO. We further confirmed a significant decrease in ROS accumulation accompanied by an increase in catalase in RO group. CONCLUSIONS: RO, a potent PPAR-gamma activator, counteracts senescence-like phenotypes, including long-term growth arrest, flattened morphology, degradation of ECM and SA-beta-gal-positive staining in MDFs by inhibiting the expression of MMPs and increasing the synthesis of catalase when administered to repeated UVB irradiation. The novel application of RO may lead to innovative and effective anti-photoaging therapies. PMID- 25703057 TI - The biological basis for poly-L-lactic acid-induced augmentation. AB - BACKGROUND: Granulomatous reactions to poly-L-lactic acid (PLLA)-based filler have been described previously. Neither the biological background of these partly late-onset reactions or the desired augmenting effect of PLLA has been studied to date. Histological studies have revealed foreign body reactions and foreign body giant cell formation. OBJECTIVE: The aim of this study was to increase our knowledge about the biological mechanisms behind the augmenting effect of PLLA based filler. METHODS: We characterised the cell infiltrate and collagen type of PLLA-treated tissue by immunofluorescence staining. The expression of genes related to collagen metabolism was determined. RESULTS: CD68(+) macrophages were found next to PLLA. CD90(+) fibroblasts were found alongside. alphaSMA-positive structures indicated myofibroblasts and neovascularisation. Substantial collagen type III deposition was detected next to PLLA particles and collagen type I was found at the periphery of PLLA encapsulations. mRNA expression for collagen type I and III transcripts, as well as for TGFbeta1 and TIMP1, was upregulated significantly. CONCLUSION: PLLA-induced augmentation is most likely based on capsule formation orchestrating macrophages, (myo-)fibroblasts, and collagen type I and III fibres. We observed considerably slower degradation of PLLA particles than described previously. Thus PLLA particles were still retrievable 28 months after subcutaneous application. PMID- 25703058 TI - Impact of daily cooling treatment on skin inflammation in patients with chronic venous disease. AB - People with chronic venous disease are at high risk for developing venous leg ulcers. Inflammation is posited as a pathological factor for this chronic condition as evidenced by persistently elevated skin temperature. As part of a larger trial to test the effects of a cooling regimen on leg ulcer prevention, the objective of this preliminary study was to evaluate the first 30 days of intense daily cooling. Compared to a placebo control cuff, a gel cuff applied to the most severely affected lower leg skin for 30 min daily showed no statistically significant differences between temperatures taken in the home at baseline compared to those measured at the 1 month follow up visit. There were also no differences in temperatures noted between the two groups, although the temperatures in the treatment group were lower 30 min after treatment, an indication of adherence. There was no discernable decrease or increase in temperature at a given time point during the 30 day treatment period compared to the control group. It may be better to have patients monitor skin temperature on a daily basis and then apply the cuff as necessary, rather than requiring daily cooling based on baseline measurement. This "prn" approach may provide a sufficient cooling milieu to prevent escalation of inflammation and thwart ulcer occurrence or recurrence. Clinical trials registration #NCT01509599. PMID- 25703059 TI - Plasma IL-33 in atopic patients correlates with pro-inflammatory cytokines and changes cholesterol transport protein expression: a surprising neutral overall impact on atherogenicity. AB - OBJECTIVE: Interleukin (IL)-33 has been associated with atopic and inflammatory conditions. IL-33 may be atheroprotective inducing a Th1-to-Th2 immunologic switch. However, the role of IL-33 in cardiovascular disease remains unclear. This study examines the effect of physiological and elevated IL-33 levels in plasma from atopic patients (AP) on cholesterol metabolism in human macrophages as compared to plasma from healthy controls (HC). METHODS: Twenty-five AP and 25 HC were enrolled in this study. Plasma samples were analysed for levels of IL-33, IFN-gamma, TNF-alpha, IL-17alpha, IL-5 and soluble ST2. THP-1 differentiated macrophages were exposed to HC and AP plasma. Expression of proteins involved in reverse cholesterol transport (ABCA1, ABCG1 and 27-hydroxylase) and scavenger receptors, responsible for uptake of modified lipids (CD36, ScR-A1, CXCL16 and LOX-1), was measured using QRT-PCR and immunoblotting techniques. RESULTS: IL-33 was significantly higher in AP plasma: 106.7 +/- 95 pg/mL versus HC plasma (53.4 +/- 23 pg/mL). IL-33 concentration strongly correlated with levels of IFN-gamma (r = 0.85), TNFalpha (r = 0.9) and IL-17alpha (r = 0.94). No significant difference was found in soluble ST2 levels. An important contrast was observed for 27-hydroxylase: normal IL-33 in AP plasma amplified 27-hydroxylase while increased IL-33 suppressed it. Expression of CD36 and SR-A1 was greater in macrophages exposed to plasma with high IL-33, while CXCL16 was higher in cells grown in the presence of plasma with normal IL-33. CONCLUSIONS: Here, we demonstrate that high levels of IL-33 and a high IL-33/soluble ST2 ratio correlates with elevated levels of IFN-gamma, TNF-alpha and IL-17alpha as well as IL-5, demonstrating that IL-33 has pleiotropic effects. However, elevated IL-33 did not significantly impact lipid accumulation in macrophages overall. Given the wide variety of cellular responses regulated by IL-33, further investigation with a larger sample size will allow us to clarify the threshold concentration of IL 33 that leads to optimal cholesterol balance. PMID- 25703060 TI - Characterization of disulfide bonds by planned digestion and tandem mass spectrometry. AB - The identification of disulfide bonds provides critical information regarding the structure and function of a protein and is a key aspect in understanding signaling cascades in biological systems. Recent proteomic approaches using digestion enzymes have facilitated the characterization of disulfide-bonds and/or oxidized products from cysteine residues, although these methods have limitations in the application of MS/MS. For example, protein digestion to obtain the native form of disulfide bonds results in short lengths of amino acids, which can cause ambiguous MS/MS analysis due to false positive identifications. In this study we propose a new approach, termed planned digestion, to obtain sufficient amino acid lengths after cleavage for proteomic approaches. Application of the DBond software to planned digestion of specific proteins accurately identified disulfide-linked peptides. RNase A was used as a model protein in this study because the disulfide bonds of this protein have been well characterized. Application of this approach to peptides digested with Asp-N/C (chemical digestion) and trypsin under acid hydrolysis conditions identified the four native disulfide bonds of RNase A. Missed cleavages introduced by trypsin treatment for only 3 hours generated sufficient lengths of amino acids for identification of the disulfide bonds. Analysis using MS/MS successfully showed additional fragmentation patterns that are cleavage products of S-S and C-S bonds of disulfide-linkage peptides. These fragmentation patterns generate thioaldehydes, persulfide, and dehydroalanine. This approach of planned digestion with missed cleavages using the DBond algorithm could be applied to other proteins to determine their disulfide linkage and the oxidation patterns of cysteine residues. PMID- 25703061 TI - Genetic reconstructions of invasion history. AB - A diverse array of molecular markers and constantly evolving analytical approaches have been employed to reconstruct the invasion histories of the most notorious invasions. Detailed information on the source(s) of introduction, invasion route, type of vectors, number of independent introductions and pathways of secondary spread has been corroborated for a large number of biological invasions. In this review, I present the promises and limitations of current techniques while discussing future directions. Broad phylogeographic surveys of native and introduced populations have traced back invasion routes with surprising precision. These approaches often further clarify species boundaries and reveal complex patterns of genetic relationships with noninvasive relatives. Moreover, fine-scale analyses of population genetics or genomics allow deep inferences on the colonization dynamics across invaded ranges and can reveal the extent of gene flow among populations across various geographical scales, major demographic events such as genetic bottlenecks as well as other important evolutionary events such as hybridization with native taxa, inbreeding and selective sweeps. Genetic data have been often corroborated successfully with historical, geographical and ecological data to enable a comprehensive reconstruction of the invasion process. The advent of next-generation sequencing, along with the availability of extensive databases of repository sequences generated by barcoding projects opens the opportunity to broadly monitor biodiversity, to identify early invasions and to quantify failed invasions that would otherwise remain inconspicuous to the human eye. PMID- 25703062 TI - Resistance to hepatitis C virus: potential genetic and immunological determinants. AB - Studies of individuals who were highly exposed but seronegative (HESN) for HIV infection led to the discovery that homozygosity for the Delta32 deletion mutation in the CCR5 gene prevents viral entry into target cells, and is associated with resistance to infection. Additionally, evidence for protective immunity has been noted in some HESN groups, such as sex workers in The Gambia. Population studies of individuals at high risk for hepatitis C virus infection suggest that an HESN phenotype exists. The body of evidence, which suggests that protective immunity allows clearance of hepatitis C virus without seroconversion is growing. Furthermore, proof-of-principle evidence from in-vitro studies shows that genetic polymorphisms can confer resistance to establishment of infection. This Review discusses the possibility that genetic mutations confer resistance against hepatitis C virus, and also explores evidence for protective immunity, including via genetically programmed variations in host responses. The data generally strengthens the notion that investigations of naturally arising polymorphisms within the hepatitis C virus interactome, and genetic association studies of well characterised HESN individuals, could identify potential targets for vaccine design and inform novel therapies. PMID- 25703063 TI - Successful use of hepatitis B surface antigen-positive liver grafts - an effective source for donor organs in endemic areas: a single-center experience. AB - BACKGROUND: Due to high prevalence of hepatitis B virus (HBV) infection in Taiwan, liver grafts from donors positive for hepatitis B surface antigen (HBsAg) without progressive disease can be effective alternative source of donor organs. This study aims to prove the safety of living donor liver transplantation (LDLT) using HBsAg-positive liver grafts and its long-term outcome. MATERIAL AND METHODS: We studied 14 consecutive LDLT recipients that received HBsAg-positive grafts from November 2009 to December 2013 for various indications. All donors were chronic HBsAg carriers with normal liver function tests. Median follow-up was 46 months (range, 35-59). RESULTS: All the donors and recipients recovered well post-transplant with no reactivation of HBV to date. Two of the recipients died due to extra-hepatic recurrence of HCC. At median follow-up of 46 months, 4 year cumulative survival of recipients was 77.38%. CONCLUSIONS: In endemic areas, HBsAg-positive donor organs can clearly be used effectively under viral immunoprophylaxis. HBV disease reactivation does not appear to be a threat even with hepatitis B immunoglobulin (HBIG)-free antiviral monoprophylaxis regimen. This study thus proves the safety and feasibility of the option of using HBsAg positive grafts in high-prevalence areas. PMID- 25703064 TI - A prospective analysis of clinical efficacy and safety in chronic myeloid leukemia-chronic phase patients with imatinib resistance or intolerance as evaluated using European LeukemiaNet 2013 criteria. AB - BACKGROUND: We conducted a phase II study to evaluate the efficacy and safety of dasatinib in Japanese patients with imatinib-resistant or imatinib-intolerant chronic myeloid leukemia (CML). METHODS: From 2009 to 2011, 54 CML-chronic phase (CP) patients with resistance (n = 40) or intolerance (n = 25) to imatinib were registered to undergo dasatinib treatment. Eleven patients showed both resistance and intolerance to imatinib. Coincidentally, the resistance criteria in this study were the same as a non-optimal response to tyrosine kinase inhibitors (TKIs) as defined in the European LeukemiaNet (ELN) 2013 recommendations. RESULTS: The overall incidence rate of major molecular response (MMR) at 12 months was 62.3% (n = 47). Forty patients with resistance to imatinib who were 'warning' and 'failure' patients based on the ELN 2013 recommendations were assessed; cumulative MMR and MR(4.5) rates were 62.5% (n = 39) and 21.0% (n = 40), respectively, at 12 months. Twelve patients who showed a BCR-ABL transcript level >1% on the international scale did not achieve a MMR or discontinued dasatinib treatment because of insufficient effects. With regard to safety issues, grade 3/4 non-hematologic adverse events (AEs) were infrequent. CONCLUSIONS: Patients with non-optimal responses (who meet ELN 2013 warning and failure criteria) to imatinib should be switched quickly to dasatinib, which is less toxic in CML-CP patients, to improve their prognoses. A BCR-ABL1 IS of <1% at 3 months of dasatinib administration is a landmark for good therapeutic outcome. PMID- 25703065 TI - The Cognistat (neurobehavioural cognitive status exam): Administering the full test in stroke patients for optimal results. AB - BACKGROUND: One of the most commonly administered tools occupational therapists use for stroke patients is the Cognistat, which was designed as a brief screening tool of cognitive functioning. Evaluations in samples of patients have identified a high false-negative rate if the Cognistat is administered using the 'screen metric' approach. Assessing the Cognistat based on its intended design can ensure consistency and accuracy among occupational therapists for this commonly administered tool. Thus, this study examined the accuracy of administering the entire Cognistat in comparison to the screen-metric approach and the factor analytic structure within stroke patients. METHODS: The full Cognistat was administered to stroke patients receiving inpatient rehabilitation. RESULTS: Seventy-five patients who experienced a recent stroke met inclusion criteria. An inconsistency between the screen and metric items was found for five of 10 subscales. Additionally, a principal component analysis (PCA) found the Cognistat to be a two factor structure with six of the subscales loading on Factor 1, while the remaining subscales loaded on Factor 2. CONCLUSIONS: Our findings confirm that occupational therapists should administer the full Cognistat to stroke patients rather than the original screen-metric approach. A two-factor structure was also supported in our results, suggesting that occupational therapists' scoring practices should reflect this finding and use the differentiated score out of 10 rather than a global sum. However, additional research is necessary to consider the clinical and theoretical significance of the Cognistats' subscale clustering. PMID- 25703066 TI - Endoscopic transcanal corridors to the lateral skull base: Initial experiences. AB - OBJECTIVES/HYPOTHESIS: Surgical approaches to the lateral skull base, internal auditory canal (IAC), and petrous bone are widely known and have been extensively recorded. Despite the benign nature and limited dimensions of lesions located in this anatomical region, extirpative surgical approaches are often required to reach and remove the disease. The aim of present report was to describe our initial experiences with minimally invasive endoscopic approaches to the lateral skull base. STUDY DESIGN: Retrospective review of patients' charts and video recordings from surgery. METHODS: Twelve patients were included in the study. Three main corridors to the lateral skull base were identified: the transcanal suprageniculate corridor, the transcanal transpromontorial corridor, and the transcanal infracochlear corridor. Landmarks, tips, and pitfalls of the approaches have been reviewed and highlighted. RESULTS: These corridors provide a direct approach to pathology involving the fundus, IAC, cochlea, petrous apex and geniculate ganglion region, without any external incision. The pathology was successfully removed in most cases with no important postoperative complications and reasonable facial nerve outcomes. CONCLUSIONS: The transcanal endoscopic approaches to the lateral skull base proved to be successful for pathology removal involving the fundus, IAC, cochlea, petrous apex, and geniculate ganglion region. Future widespread application of this kind of approach in lateral skull base surgery will depend on the development of technology, and surgical and anatomical refinements. LEVEL OF EVIDENCE: 4. PMID- 25703067 TI - Injury-induced acquired dermal melanocytosis arising on an operation scar. PMID- 25703068 TI - Long-term in vivo clearance of gadolinium-based AGuIX nanoparticles and their biocompatibility after systemic injection. AB - We previously reported the synthesis of gadolinium-based nanoparticles (NPs) denoted AGuIX (activation and guiding of irradiation by X-ray) NPs and demonstrated their potential as an MRI contrast agent and their efficacy as radiosensitizing particles during X-ray cancer treatment. Here we focus on the elimination kinetics of AGuIX NPs from the subcellular to whole-organ scale using original and complementary methods such as laser-induced breakdown spectroscopy (LIBS), intravital two-photon microscopy, inductively coupled plasma optical emission spectrometry (ICP-OES), transmission electron microscopy (TEM), and electrospray ionization mass spectrometry (ESI-MS). This combination of techniques allows the exact mechanism of AGuIX NPs elimination to be elucidated, including their retention in proximal tubules and their excretion as degraded or native NPs. Finally, we demonstrated that systemic AGuIX NP administration induced moderate and transient effects on renal function. These results provide useful and promising preclinical information concerning the safety of theranostic AGuIX NPs. PMID- 25703069 TI - What do we know about phytotherapy of benign prostatic hyperplasia? AB - Benign prostatic hyperplasia (BPH) is one of the most common urological diseases in aging men. Because of its long latency, BPH is a good target for prevention. The aim of the study has been to review the various options of treatment, currently available, in the field of phytotherapy. Watchful waiting, pharmacological therapy, and surgery are also helpful, depending on the severity of the disease. Although drug therapy (alpha1-blockers, 5alpha-reductase inhibitors) and surgery (prostatectomy, transurethral resection, etc.) seem to be most effective for patients with moderate-severe BPH, herbal medicines (i.e., Serenoa repens, Pygeum africanum, Urtica dioica) are also commonly used in patients with mild-moderate symptoms. On the basis of preclinical studies several mechanisms of action have been postulated, including 5alpha-reductase inhibition, alpha-adrenergic antagonism, dihydrotestosterone and estrogen receptor inhibition. Randomized clinical trials indicate significant efficacy in improving urinary symptoms and mild adverse effects for some phytotherapeutic agents, while further clinical evidence is needed for others (e.g., Epilobium spp., Secale cereale, Roystonea regia). Healthcare professionals should be constantly informed about BPH phytotherapy, taking into account the risk/benefit profile of the use of medicinal plants in the management of BPH. PMID- 25703070 TI - Concentrated green tea supplement: biological activity and molecular mechanisms. AB - AIM: This study was undertaken to determine the biological activity of a green tea supplement with respect to cells and erythrocyte membranes and the molecular mechanism of that activity. MAIN METHODS: The extract's activity was evaluated on the basis of its hemolytic, antioxidant and antiinflammatory actions. In addition, the extract's effect on the physical properties of the erythrocyte membrane was examined. We also conducted a detailed analysis of supplement ingredients using high-yield liquid chromatography, supplemented with standard tests of total content of polyphenols and flavonoids in the supplement. KEY FINDINGS: The study showed that green tea extract has a high antioxidant and anti inflammatory capacity with no deleterious effect on red blood cells. The extract modifies the physical properties of the erythrocyte membrane, apparently by binding to its hydrophilic region, with consequent rigidity of the hydrophobic region, increased hydration and a moderate increase in its resistance to changes in tonicity of the medium. Because the extract's components anchor in the polar region of membrane lipids, they are able to effectively scavenge free radicals in the immediate vicinity of the membrane and hinder their diffusion into its interior. SIGNIFICANCE: Green tea supplement at concentrations markedly exceeding the blood plasma physiological polyphenol concentrations has no destructive effect on the erythrocyte membrane. Due to the high content of flavan-3-ols, the supplement exhibits high biological activity, which makes it an alternative source of those substances to the commonly used infusion of green tea leaves. PMID- 25703071 TI - Endoscopic management of non-iatrogenic gastrointestinal perforations--A case series. PMID- 25703072 TI - Cognitive functioning throughout the treatment history of clinical late-life depression. AB - OBJECTIVE: Previous investigations into the relationship between late-life depressive symptoms and cognitive functioning have resulted in mixed findings concerning whether or not depressive symptoms and cognitive functioning are related. The mixed reports may be due in part to differences in clinical and nonclinical samples and to inadequate consideration of the dynamic nature (i.e., fluctuating course) of depressive symptoms and cognitive functioning in older adults. The current study examined the chronic, acute, and longitudinal relationships between depressive symptoms and cognitive functioning in older adults in an ongoing treatment study of major depressive disorder (MDD). METHODS: The neurocognitive outcomes of depression in the elderly study operates in a naturalistic treatment milieu using a pharmacological treatment algorithm and regular psychiatric assessment. Four hundred and fifty-three older adults [mean age 70 years, standard deviation (SD) = 7.2] meeting criteria for MDD at study enrollment received annual neuropsychological testing and depressive symptom monitoring for an average of 8.5 years (SD = 4.5). RESULTS: Hierarchical linear modeling revealed that higher age, lower education, and higher average/chronic levels of depressive symptoms were related to lower cognitive functioning. Additionally, results revealed that when an individual's depressive symptoms are higher than is typical for a specific individual, general cognitive function was worse than average. There was no evidence of lagged/longitudinal relationships between depressive symptoms and cognitive functioning in older adults in treatment for MDD. CONCLUSIONS: Cognitive functioning and depressive symptoms are concurrently associated in older adults with MDD, highlighting the potential importance for stabilizing mood symptoms as a means to manage cognitive deficits in late-life depression. PMID- 25703073 TI - Cytotoxicity of elastomeric power chains in artificial saliva: an in vitro study. AB - INTRODUCTION: The main aim of this paper is to investigate the cytotoxicity of elastomeric power chains after stretching and immersion in a solution of artificial saliva. MATERIALS AND METHOD: Two brands of grey polyurethane power chains available from two different firms (GAC, G&H) were selected for cytotoxicity assay. Each segment was stretched up to an initial force of approximately 200 g. Then each segment was kept stretched using appropriate equipment. The samples were tested in artificial saliva at two pH levels, pH7 and pH4. Following incubation, the saliva was removed, filtered and placed in contact with cell culture media using the RD line. RESULTS AND DISCUSSION: At this supernatant dilution, no statistically significant difference was observed between the different groups of power chains studied in terms of cell viability. The GAC and G&H power chains, whether stretched or not and immerged in either pH7 or pH4 saliva, showed no toxic effect on RD cells (human cell line). PMID- 25703076 TI - Symphyseal distraction in the context of orthodontic treatment: a series of 35 cases. AB - INTRODUCTION: Use of symphyseal distraction osteogenesis to treat a mandibular bone deficit with tooth-jaw discrepancy due to lack of space makes it possible to avoid the risks associated with the techniques usually envisaged (stripping, labioversion of incisors, extractions). PATIENTS AND METHOD: This retrospective study presents the symphyseal distraction technique used in the maxillofacial surgery department of Lille University Hospital between January 1998 and March 2013. Treatment efficacy, complications and the stability of results were all evaluated. RESULTS: Thirty-five patients were included in the study. The gain of inter-mental-foramen space was on average 7 mm (3-12, standard deviation 1.8 mm). A good occlusal result with dental Class I and no labioversion of the lower incisors was obtained in 27 of the 35 patients (77%). CONCLUSION: Mandibular distraction by symphyseal osteotomy seems to be a quick, safe treatment for an anterior transversal mandibular deficit giving results that are stable over time. Its success depends on good collaboration between the orthodontist and the surgeon, and on strict patient selection. PMID- 25703077 TI - Surgery improves survival in elderly with breast cancer. A study of 465 patients in a single institution. AB - INTRODUCTION: Breast cancer treatment in elderly patients is controversial. This single-centre study was conducted to review the treatment and outcomes for octogenarian women treated for breast cancer. METHODS: Data from all patients aged 80 years or more with primary breast cancer treated at our institution between 1995 and 2012 were included. Patients with carcinoma in-situ (stage 0) and advanced breast cancer (stage IV) were excluded. RESULTS: The study population consisted of 369 patients (median age 84 years). A total of 277 (75%) patients underwent surgical treatment (PST) and 92 (25%) received primary endocrine treatment (PET). Prognostic factors (HER-2, tumour grade, lymphovascular invasion and subsequent adjuvant therapy) were homogeneously distributed in both groups. PST and PET were stratified according to stage: 273 (66%) patients with early stage disease (I, IIA, IIB) and 96 (34%) with locally advanced disease (IIIA, IIIB, IIIC). Patients were followed-up for a median of 63 months. In patients with early stage disease, the mean breast cancer-specific survival (BCSS) was 109 months (95% CI = 101-115) in PST patients, and 50 months (95% CI = 40-60) in PET patients (P < 0.01). Conversely, for patients with locally advanced breast cancer, there was no significant difference in BCSS between the surgical and non-surgical groups. In the PST group, BCSS and disease free survival were significantly better among patients who underwent standard surgical treatment than among those who received suboptimal treatment. There were no differences in the Charlson comorbidity index scores between the PST and PET groups. CONCLUSION: In women >=80 years with early-stage breast cancer, standard surgical treatment was associated with a better BCSS when compared with PET. PMID- 25703078 TI - Liver resection rate following downsizing chemotherapy with cetuximab in metastatic colorectal cancer: UK retrospective observational study. AB - AIMS: The high objective response rate to cetuximab along with chemotherapy in patients with colorectal liver metastases makes it an effective downsizing protocol to facilitate surgery in those with initially unresectable disease. Adoption of this strategy has been variable in the UK. A retrospective observational study was conducted in 7 UK specialist liver surgical centres to describe the liver resection rate following a downsizing protocol of cetuximab and chemotherapy and to evaluate the quality and efficiency of processes by which the treatment was provided. METHODS: Data were collected in 2012 by reviewing medical records of patients with colorectal metastases confined to the liver, defined as unresectable without downsizing therapy at first review by a specialist Multi Disciplinary Team (MDT). RESULTS: Sixty patients were included; 29 (48%) underwent liver resection following cetuximab and chemotherapy. Of the 29, 17 (59% or 28% of all patients) achieved R0 resection and 7 (24% or 12% of all patients) R1 resection. All treated patients were KRAS wild-type. CONCLUSION: In specialist liver surgical centres, where patients are evaluated for liver resection, optimal management by MDT using KRAS testing, cetuximab and chemotherapy results in a 28% R0 resection rate in patients with initially unresectable colorectal cancer liver metastases. PMID- 25703079 TI - Development of imidazoline-2-thiones based two-photon fluorescence probes for imaging hypochlorite generation in a co-culture system. AB - We designed and prepared the imidazoline-2-thione containing OCl(-) probes, PIS and NIS, which operate through specific reactions with OCl(-) that yield corresponding fluorescent imidazolium ions. Importantly, we demonstrated that PIS can be employed to image OCl(-) generation in macrophages in a co-culture system. We have also employed two-photon microscopy and PIS to image OCl(-) in live cells and tissues, indicating that this probe could have wide biological applications. PMID- 25703080 TI - Erratum: Interstitial modification of palladium nanoparticles with boron atoms as a green catalyst for selective hydrogenation. PMID- 25703081 TI - Poor contrast enhanced ultrasonography! There is no limit to its decline in the diagnosis of hepatocellular carcinoma on cirrhosis! PMID- 25703082 TI - Reply to: ''Poor contrast enhanced ultrasonography! There is no limit to its decline in the diagnosis of hepatocellular carcinoma on cirrhosis!''. PMID- 25703083 TI - Is it worthy of switching to PegIFN alfa-2a in patients achieving virological suppression with entecavir? PMID- 25703084 TI - Improvement of liver injury and survival by JNK2 and iNOS deficiency in liver transplants from cardiac death mice. AB - BACKGROUND & AIMS: Inclusion of liver grafts from cardiac death donors (CDD) would increase the availability of donor livers but is hampered by a higher risk of primary non-function. Here, we seek to determine mechanisms that contribute to primary non-function of liver grafts from CDD with the goal to develop strategies for improved function and outcome, focusing on c-Jun-N-terminal kinase (JNK) activation and mitochondrial depolarization, two known mediators of graft failure. METHODS: Livers explanted from wild-type, inducible nitric oxide synthase knockout (iNOS(-/-)), JNK1(-/-) or JNK2(-/-) mice after 45-min aorta clamping were implanted into wild-type recipients. Mitochondrial depolarization was detected by intravital confocal microscopy in living recipients. RESULTS: After transplantation of wild-type CDD livers, graft iNOS expression and 3 nitrotyrosine adducts increased, but hepatic endothelial NOS expression was unchanged. Graft injury and dysfunction were substantially higher in CDD grafts than in non-CDD grafts. iNOS deficiency and inhibition attenuated injury and improved function and survival of CDD grafts. JNK1/2 and apoptosis signal regulating kinase-1 activation increased markedly in wild-type CDD grafts, which was blunted by iNOS deficiency. JNK inhibition and JNK2 deficiency, but not JNK1 deficiency, decreased injury and improved function and survival of CDD grafts. Mitochondrial depolarization and binding of phospho-JNK2 to Sab, a mitochondrial protein linked to the mitochondrial permeability transition, were higher in CDD than in non-CDD grafts. iNOS deficiency, JNK inhibition and JNK2 deficiency all decreased mitochondrial depolarization and blunted ATP depletion in CDD grafts. JNK inhibition and deficiency did not decrease 3-nitrotyrosine adducts in CDD grafts. CONCLUSION: The iNOS-JNK2-Sab pathway promotes CDD graft failure via increased mitochondrial depolarization, and is an attractive target to improve liver function and survival in CDD liver transplantation recipients. PMID- 25703085 TI - PPARalpha gene expression correlates with severity and histological treatment response in patients with non-alcoholic steatohepatitis. AB - BACKGROUND & AIMS: Peroxisome proliferator-activated receptors (PPARs) have been implicated in non-alcoholic steatohepatitis (NASH) pathogenesis, mainly based on animal data. Gene expression data in NASH patients are scarce. We studied liver PPARalpha, beta/delta, and gamma expression in a large cohort of obese patients assessed for presence of NAFLD at baseline and 1 year follow-up. METHODS: Patients presented to the obesity clinic underwent a hepatic work-up. If NAFLD was suspected, liver biopsy was performed. Gene expression was studied by mRNA quantification. Patients were reassessed after 1 year. RESULTS: 125 patients were consecutively included in the study, of which 85 patients had paired liver biopsy taken at 1 year of follow-up. Liver PPARalpha expression negatively correlated with the presence of NASH (p=0.001) and with severity of steatosis (p=0.003), ballooning (p=0.001), NASH activity score (p=0.008) and fibrosis (p=0.003). PPARalpha expression was positively correlated to adiponectin (R(2)=0.345, p=0.010) and inversely correlated to visceral fat (R(2)=-0.343, p<0.001), HOMA IR (R(2)=-0.411, p<0.001) and CK18 (R(2)=-0.233, p=0.012). Liver PPARbeta/delta and PPARgamma expression did not correlate with any histological feature nor with glucose metabolism or serum lipids. At 1 year, correlation of PPARalpha expression with liver histology was confirmed. In longitudinal analysis, an increase in expression of PPARalpha and its target genes was significantly associated with histological improvement (p=0.008). CONCLUSION: Human liver PPARalpha gene expression negatively correlates with NASH severity, visceral adiposity and insulin resistance and positively with adiponectin. Histological improvement is associated with an increase in expression of PPARalpha and its target genes. These data might suggest that PPARalpha is a potential therapeutic target in NASH. PMID- 25703086 TI - Daclatasvir and asunaprevir plus peginterferon alfa and ribavirin in HCV genotype 1 or 4 non-responders. AB - BACKGROUND & AIMS: Improved therapies for peginterferon/ribavirin null or partial responders are needed. This study evaluated daclatasvir (NS5A inhibitor) and asunaprevir (NS3 protease inhibitor) plus peginterferon alfa-2a and ribavirin in this patient population. METHODS: This open-label, phase 3 study (HALLMARK-QUAD; NCT01573351) treated patients with chronic hepatitis C virus (HCV) genotype 1 (n=354) or 4 (n=44) infection who had a prior null or partial response to peginterferon/ribavirin. Patients received daclatasvir 60 mg once-daily plus asunaprevir 100mg twice-daily, with weekly peginterferon alfa-2a and weight-based ribavirin for 24 weeks. The primary endpoint was sustained virological response at post-treatment week 12 (SVR12) among genotype 1-infected patients. RESULTS: Daclatasvir plus asunaprevir and peginterferon/ribavirin demonstrated SVR12 rates of 93% (95% CI 90-96) in prior non-responders infected with HCV genotype 1. SVR12 rates among genotype 4-infected patients were 98% (95% CI 93-100); one patient had a missing post-treatment week-12 HCV-RNA measurement, but achieved an SVR at post-treatment week 24, yielding a 100% SVR rate in genotype 4 patients. Prior peginterferon/ribavirin response, sex, age, IL28B genotype, or cirrhosis status did not influence SVR12 rates. Serious adverse events occurred in 6% of patients; 5% discontinued treatment due to an adverse event. Grade 3/4 laboratory abnormalities included neutropenia (22%), lymphopenia (16%), anemia (6%), thrombocytopenia (4%), and ALT/AST elevations (3% each). CONCLUSIONS: Daclatasvir plus asunaprevir and peginterferon/ribavirin demonstrated high rates of SVR12 in genotype 1- or 4-infected prior null or partial responders. The combination was well tolerated and no additional safety and tolerability concerns were observed compared with peginterferon/ribavirin regimens. PMID- 25703088 TI - Tractography of the optic radiation: a repeatability and reproducibility study. AB - Our main objective was to evaluate the repeatability and reproducibility of optic radiation (OR) reconstruction from diffusion MRI (dMRI) data. 14 adults were scanned twice with the same 60-direction dMRI sequence. Peaks in the diffusion profile were estimated with the single tensor (ST), Q-ball (QSH) and persistent angular structure (PAS) methods. Segmentation of the OR was performed by two experimenters with probabilistic tractography based on a manually drawn region-of interest (ROI) protocol typically employed for OR segmentation, with both standard and extended sets of ROIs. The repeatability and reproducibility were assessed by calculating the intra-class correlation coefficient (ICC) of intra- and inter-rater experiments, respectively. ICCs were calculated for commonly used dMRI metrics (FA, MD, AD, RD) and anatomical dimensions of the optic radiation (distance from Meyer's loop to the temporal pole, ML-TP), as well as the Dice similarity coefficient (DSC) between the raters' OR segmentation. Bland-Altman plots were also calculated to investigate bias and variability in the reproducibility measurements. The OR was successfully reconstructed in all subjects by both raters. The ICC was found to be in the good to excellent range for both repeatability and reproducibility of the dMRI metrics, DSC and ML-TP distance. The Bland-Altman plots did not show any apparent systematic bias for any quantities. Overall, higher ICC values were found for the multi-fiber methods, QSH and PAS, and for the standard set of ROIs. Considering the good to excellent repeatability and reproducibility of all the quantities investigated, these findings support the use of multi-fiber OR reconstruction with a limited number of manually drawn ROIs in clinical applications utilizing either OR microstructure characterization or OR dimensions, as is the case in neurosurgical planning for temporal lobectomy. PMID- 25703089 TI - Do Parents Foster Self-Esteem? Testing the Prospective Impact of Parent Closeness on Adolescent Self-Esteem. AB - Close parent-child relationships are viewed as important for the development of global self-esteem. Cross-sectional research supports this hypothesis, but longitudinal studies provide inconsistent prospective effects. The current study uses data from Germany (N = 982) and the United States (N = 451) to test longitudinal relations between parent-child closeness and adolescent self-esteem. The authors used self-, parent-, and observer-reported parent-child closeness and self-reported self-esteem from ages 12 to 16. Results replicated concurrent correlations found in the literature, but six longitudinal models failed to show prospective relations. Thus, the longitudinal effect of parent-child closeness and self-esteem is difficult to detect with adolescent samples. These findings suggest the need for additional theorizing about influences on adolescent self esteem development and longitudinal research with younger samples. PMID- 25703090 TI - Affinity screening using competitive binding with fluorine-19 hyperpolarized ligands. AB - Fluorine-19 NMR and hyperpolarization form a powerful combination for drug screening. Under a competitive equilibrium with a selected fluorinated reporter ligand, the dissociation constant (K(D)) of other ligands of interest is measurable using a single-scan Carr-Purcell-Meiboom-Gill (CPMG) experiment, without the need for a titration. This method is demonstrated by characterizing the binding of three ligands with different affinities for the serine protease trypsin. Monte Carlo simulations show that the highest accuracy is obtained when about one-half of the bound reporter ligand is displaced in the binding competition. Such conditions can be achieved over a wide range of affinities, allowing for rapid screening of non-fluorinated compounds when a single fluorinated ligand for the binding pocket of interest is known. PMID- 25703091 TI - Meralgia paresthetica after subcutaneous injection of glatiramer acetate. PMID- 25703092 TI - [Tropicaltelemedicine.org: A new tool for medical cooperation projects]. PMID- 25703093 TI - Light-dependent transcriptional events during resting egg hatching of the rotifer Brachionus manjavacas. AB - Rotifer resting eggs often have to endure harsh environmental conditions during the diapause phase. They are stimulated by light to hatch. In order to study the hatching mechanism, we observed resting eggs and measured their transcriptional expression under different light exposure periods (total darkness, and after 30 min, and 4h light). By using differential-display reverse transcription PCR (DDRT PCR), we isolated 80 genes that displayed different expression patterns in response to the three light treatments: 20 genes were expressed in total darkness, 40 different genes were differentially expressed under 30 min light, and 20 further genes were expressed after 4h of light. The resting eggs showed no phenotypic differences in embryonic development during the 4h illumination period. In general, the expression patterns of the analyzed genes in resting eggs were differentially modulated by light exposure time. In total darkness, resting eggs mainly expressed genes encoding cell defense and homeostasis functions. In the 30 min illumination group, we found enriched expression of genes encoding fatty acid metabolism-related components, including Acyl-CoA dehydrogenase (ACAD). Genes encoding cellular and embryonic developmental functions were highly observed in the 30 min-illuminated group but were not observed in the 4h illuminated group. Real-time RT-PCR revealed that several transcripts such as encoding V-type H(+)-translocating pyrophosphatase (V-PPase) and Meckelin had prolonged expression levels when exposed to light for 4h. In the 4h illuminated group, the RecQ protein-like 5 (RECQL5) gene was enriched. This RECQL5 gene may be expressed to protect the developing embryo from continuous light exposure. The data presented in this study indicate that DDRT-PCR-aided gene screening can be helpful to isolate candidate genes involved in the hatching process. PMID- 25703094 TI - Therapeutic options in Charcot-Marie-Tooth diseases. AB - Charcot-Marie-Tooth (CMT) diseases represent a heterogeneous genetic disorder (more than 80 genes are implicated in these inherited neuropathies), but sharing a similar phenotype. In recent years, advances in molecular genetics and molecular biology, and also the development of various animal models of CMT, have led to a better understanding. Taken together, this knowledge represents a prerequisite for the development of future therapies in CMT, and in peripheral nervous system disorders in general. The efficacy of various substances has been shown in vitro and also in vivo (in animal models); but, no significant positive effect has yet been confirmed in humans. However, some of these trials are still in development, and we may expect positive results in the future. Although CMT is still an incurable disease, symptomatic treatments (physiotherapy, surgery, analgesic, etc.) are crucial to improve the quality of life of CMT patients. PMID- 25703095 TI - Ribosome excursions during mRNA translocation mediate broad branching of frameshift pathways. AB - Programmed ribosomal frameshifting produces alternative proteins from a single transcript. -1 frameshifting occurs on Escherichia coli's dnaX mRNA containing a slippery sequence AAAAAAG and peripheral mRNA structural barriers. Here, we reveal hidden aspects of the frameshifting process, including its exact location on the mRNA and its timing within the translation cycle. Mass spectrometry of translated products shows that ribosomes enter the -1 frame from not one specific codon but various codons along the slippery sequence and slip by not just -1 but also -4 or +2 nucleotides. Single-ribosome translation trajectories detect distinctive codon-scale fluctuations in ribosome-mRNA displacement across the slippery sequence, representing multiple ribosomal translocation attempts during frameshifting. Flanking mRNA structural barriers mechanically stimulate the ribosome to undergo back-and-forth translocation excursions, broadly exploring reading frames. Both experiments reveal aborted translation around mutant slippery sequences, indicating that subsequent fidelity checks on newly adopted codon position base pairings lead to either resumed translation or early termination. PMID- 25703096 TI - Sensory detection of food rapidly modulates arcuate feeding circuits. AB - Hunger is controlled by specialized neural circuits that translate homeostatic needs into motivated behaviors. These circuits are under chronic control by circulating signals of nutritional state, but their rapid dynamics on the timescale of behavior remain unknown. Here, we report optical recording of the natural activity of two key cell types that control food intake, AgRP and POMC neurons, in awake behaving mice. We find unexpectedly that the sensory detection of food is sufficient to rapidly reverse the activation state of these neurons induced by energy deficit. This rapid regulation is cell-type specific, modulated by food palatability and nutritional state, and occurs before any food is consumed. These data reveal that AgRP and POMC neurons receive real-time information about the availability of food in the external world, suggesting a primary role for these neurons in controlling appetitive behaviors such as foraging that promote the discovery of food. PMID- 25703097 TI - Parents' Evaluations of Their Children's Dysphonia: The Mamas and the Papas. AB - OBJECTIVES: This study aimed to evaluate the validity and reliability of a Hebrew translation of the Pediatric Voice Handicap Index (pVHI). It also examined differences between mothers and fathers in evaluating their child's dysphonia. STUDY DESIGN: Observational design. METHODS: The pVHI was first translated and adapted to Hebrew. The translated version was, then, administered to a group of 141 parents of children aged younger than 14 years. Fifty-eight parents had a dysphonic child, and 83 had a nondysphonic child. Based on the parents' responses to the pVHI, statistical analyses were performed, evaluating validity and reliability, as well as group differences. Following, a subset of the participants, in which only cases where the responses of both parents were available, was examined for evaluating differences between the responses of mothers (n = 46) and fathers (n = 46). RESULTS: Statistical analyses revealed high reliability of the Hebrew version of the pVHI (Cronbach alpha = .97). Parents of the dysphonic children rated their children significantly higher than parents of the nondysphonic group (P < 0.001). Mothers of the dysphonic children rated their children significantly higher than the fathers, on all subscales of the questionnaire (>=0.001 P < 0.047). In contrast, no significant differences were found between mothers and fathers of the nondysphonic children (P > 0.05). CONCLUSIONS: The Hebrew version of the pVHI is a reliable tool for quantifying parents' perception of their child's voice handicap. Mothers of dysphonic children evaluate their children's voice handicap more severely than fathers, whereas both parents of nondysphonic children perform this evaluation similarly. PMID- 25703098 TI - Label-Free Tracking of Single Organelle Transportation in Cells with Nanometer Precision Using a Plasmonic Imaging Technique. AB - Imaging and tracking of nano- and micrometer-sized organelles in cells with nanometer precision is crucial for understanding cellular behaviors at the molecular scale. Because of the fast intracellular dynamic processes, the imaging and tracking method must also be fast. In addition, to ensure that the observed dynamics is relevant to the native functions, it is critical to keep the cells under their native states. Here, a plasmonics-based imaging technique is demonstrated for studying the dynamics of organelles in 3D with high localization precision (5 nm) and temporal (10 ms) resolution. The technique is label-free and can track subcellular structures in the native state of the cells. Using the technique, nanometer steps of organelle (e.g., mitochondria) transportation are observed along neurite microtubules in primary neurons, and the 3D structure of neurite microtubule bundles is reconstructed at the nanometer scale from the tracks of the moving organelles. PMID- 25703099 TI - miR Profiling Identifies Cyclin-Dependent Kinase 6 Downregulation as a Potential Mechanism of Acquired Cisplatin Resistance in Non-Small-Cell Lung Carcinoma. AB - To identify the mechanisms of cisplatin resistance, global microRNA (miR) expression was tested. The expression of miR-145 was consistently higher in resistant cells. The expression of cyclin-dependent kinase 6 (CDK6), a potential target of miR-145, was lower in resistant cells, and inhibition of CDK4/6 protected cells from cisplatin. Cell cycle inhibition, currently being tested in clinical trials, might be antagonistic to cisplatin and other cytotoxic drugs. BACKGROUND: Non-small-cell lung cancer (NSCLC) is the leading cause of cancer related death. Platinum-based chemotherapeutic drugs are the most active agents in treating advanced disease. Resistance to these drugs is common and multifactorial; insight into the molecular mechanisms involved will likely enhance efficacy. MATERIALS AND METHODS: A set of NSCLC platinum-resistant sublines was created from the Calu6 cell line. Cell viability was quantified using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Differentially expressed microRNAs (miRs) in these lines were identified using Affymetrix miR arrays. The potential genes targeted by these miRs were searched using the TargetScan algorithm. The expression levels of miRs and mRNA were tested using real-time polymerase chain reaction. RESULTS: miR-145 was reproducibly elevated in all the resistant sublines tested; however, modulation of miR-145 levels alone in these cells did not affect their response to cisplatin. A potential target of miR-145 is cyclin-dependent kinase 6 (CDK6), an important regulator of cell proliferation. The mRNA and protein levels of CDK6 were both downregulated in the resistant sublines. An inhibitor of CDK4/6 (PD0332991) protected parental NSCLC cells from cisplatin cytotoxicity. CONCLUSION: In the present study, we identified miRs differentially expressed in cisplatin-resistant cell lines, including miR-145. A predicted target of miR-145 is CDK6, and its expression was found to be downregulated in the resistant sublines, although not directly by miR-145. Inhibition of CDK6 antagonizes cisplatin-induced NSCLC cell cytotoxicity, suggesting that agents that inhibit CDK6 should be avoided during cisplatin therapy. PMID- 25703101 TI - 'Men don't need to know everything': a field trial of a discreet, female initiated, contraceptive barrier method (FemCapTM) among Haitian-American women. AB - Worldwide, women report the need for safe, non-hormonal, woman-initiated methods of family planning. Cervical barriers provide such technology but are under researched and under-promoted. In the USA, there are few studies of cervical barriers among women at high unmet need for contraception. A feasibility study of the FemCapTM was conducted among US women of Haitian origin. Participants were heterosexual and seeking to avoid pregnancy. At first visit, participants completed baseline assessments, underwent group counselling and were fitted with FemCapTM. Women were asked to insert or use the cap at home. The second visit (2 3 weeks) included an interviewer-administered questionnaire and a focus-group discussion. Participants (n = 20) were Haitian-born (70%), married (55%) and parous (85%). Their mean age was 32.6 years. Seventy percent reported recent unprotected sex. All women inserted the device at home and 9 women used it during intercourse, including 5 without prior partner negotiation. Of 20 women, 11 liked FemCapTM very much or somewhat; 7 considered it 'OK'; 2 disliked it. Best-liked attributes were comfort, discreet wear and reusability. Difficulties with removal abated over time. Qualitative data revealed a high value placed on lack of systemic side effects. Use of FemCapTM was feasible and acceptable, supporting expansion of research, particularly among relevant populations with unmet need. PMID- 25703100 TI - A Pilot Trial of Cisplatin/Etoposide/Radiotherapy Followed by Consolidation Docetaxel and the Combination of Bevacizumab (NSC-704865) in Patients With Inoperable Locally Advanced Stage III Non-Small-Cell Lung Cancer: SWOG S0533. AB - BACKGROUND: The aim of this trial was to determine feasibility of incorporating bevacizumab (B) into concurrent chemoradiotherapy (CRT) for locally advanced non small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with unresectable stage III NSCLC, performance status of 0 to 1, and adequate organ function were accrued in 2 strata, low- and high-risk (squamous histology, hemoptysis, tumor with cavitation and/or adjacent to a major vessel). Cohort 1 patients received cisplatin 50 mg/m(2) days (d) 1 and 8, etoposide 50 mg/m(2) (d 1-5) for 2 cycles concurrent with radiotherapy (64.8 Gy) followed by docetaxel (D) 75 mg/m(2) and B 15 mg/kg for 3 cycles. If safety was established, then accrual would continue to cohort 2 (B, d 15, 36, 57) and then subsequently to cohort 3 (B, d 1, 22, 43). RESULTS: Twenty-nine patients (17 low- and 12 high-risk) registered to cohort 1. Twenty-six patients (including 4 squamous, 1 adenosquamous) were assessable. Twenty-five completed CRT. Grade 3/4 toxicities during CRT included acceptable rates of hematologic toxicity, esophagitis, and pneumonitis. Of 21 assessable for safety with D/B consolidation, major adverse events were pneumonitis (2 Grade 3) and 2 episodes of fatal hemoptysis in the high-risk group, resulting in closure of this stratum. The low-risk stratum subsequently closed because of slow accrual. Median overall survival was 46 months for low-risk and 17 months for high-risk strata. CONCLUSION: Bevacizumab was not safely integrated into CRT for stage III NSCLC in patients considered at high risk for hemoptysis. In lower risk patients, data are insufficient to determine safety or efficacy. PMID- 25703102 TI - Preventing central line-associated bloodstream infections: a qualitative study of management practices. AB - OBJECTIVE: To identify factors that may explain hospital-level differences in outcomes of programs to prevent central line-associated bloodstream infections. DESIGN: Extensive qualitative case study comparing higher- and lower-performing hospitals on the basis of reduction in the rate of central line-associated bloodstream infections. In-depth interviews were transcribed verbatim and analyzed to determine whether emergent themes differentiated higher- from lower performing hospitals. SETTING: Eight US hospitals that had participated in the federally funded On the CUSP-Stop BSI initiative. PARTICIPANTS: One hundred ninety-four interviewees including administrative leaders, clinical leaders, professional staff, and frontline physicians and nurses. RESULTS: A main theme that differentiated higher- from lower-performing hospitals was a distinctive framing of the goal of "getting to zero" infections. Although all sites reported this goal, at the higher-performing sites the goal was explicitly stated, widely embraced, and aggressively pursued; in contrast, at the lower-performing hospitals the goal was more of an aspiration and not embraced as part of the strategy to prevent infections. Five additional management practices were nearly exclusively present in the higher-performing hospitals: (1) top-level commitment, (2) physician-nurse alignment, (3) systematic education, (4) meaningful use of data, and (5) rewards and recognition. We present these strategies for prevention of healthcare-associated infection as a management "bundle" with corresponding suggestions for implementation. CONCLUSIONS: Some of the variance associated with CLABSI prevention program outcomes may relate to specific management practices. Adding a management practice bundle may provide critical guidance to physicians, clinical managers, and hospital leaders as they work to prevent healthcare associated infections. PMID- 25703103 TI - Advanced human T-cell leukemia virus type 1 carriers and early-stage indolent adult T-cell leukemia-lymphoma are indistinguishable based on CADM1 positivity in flow cytometry. AB - We previously reported that the cell adhesion molecule 1 (CADM1) versus CD7 plot in flow cytometry reflects disease progression in human T-cell leukemia virus type 1 (HTLV-1) infection. In CD4(+) cells from peripheral blood, CADM1(-) CD7(+) (P), CADM1(+) CD7(dim) (D) and CADM1(+) CD7(-) (N) subpopulations are observed. The D and N subpopulations increase as asymptomatic HTLV-1 carriers (AC) progress to indolent adult T-cell leukemia-lymphoma (ATL) and the N subpopulation then expands in aggressive ATL. In the present study we examined whether the analysis can estimate the risk of developing ATL in advanced AC. Peripheral blood samples from AC (N = 41) and indolent ATL patients (N = 19) were analyzed by flow cytometry using the CADM1 versus CD7 plot for CD4(+) cells and inverse long PCR (clonality analysis) of FACS-sorted subpopulations. Almost all AC with a high HTLV-1 proviral load (>4 copies/100 cells) had a CADM1(+) (D + N) frequency of >10%. AC with 25% < CADM1(+) <= 50% contained expanded clones similar to smoldering-type ATL. In many patients in the 25% < CADM1(+) <= 50% group, the proportion of abnormal lymphocytes was distributed around the 5% line, which divides AC and smoldering-type ATL in Shimoyama's classification. In conclusion, the CADM1 versus CD7 plot is useful for selection of putative high-risk AC. The characteristics of some AC and smoldering ATL are said to be similar; however, long-term follow up is required and the clinical outcome (e.g. rate of transformation) of these cases should be used to determine whether to include them in the same clinical category. PMID- 25703104 TI - Ultrasonic activation and chemical modification of photosensitizers enhances the effects of photodynamic therapy against Enterococcus faecalis root-canal isolates. AB - BACKGROUND: The aim of this study was to evaluate the effect of photodynamic therapy (PDT) on Enterococcus faecalis biofilms in artificially infected root canals using modified photosensitizers and passive ultrasonic activation. METHODS: Two hundred and seventy extracted human teeth with one root canal were instrumented utilizing ProTaper files, autoclaved, infected with E. faecalis T9 for 72 h and divided into different groups: irrigation with 3% sodium hypochlorite (NaOCl), 20% ethylenediaminetetraacetic acid (EDTA), or 20% citric acid, PDT without irrigation, PDT accompanied by irrigation with NaOCl, EDTA, or citric acid, PDT using an EDTA-based photosensitizer or a citric-acid-based photosensitizer and PDT with ultrasonic activation of the photosensitizer. A 15 mg/ml toluidine blue served as the photosensitizer, activated by a 100 mW LED light source. Sterile paper points were used for sampling the root canals and dentin chips were collected to assess the remaining contamination after treatment. Samples were cultured on blood agar plates and colony forming units were quantified. RESULTS: PDT alone achieved a reduction in E. faecalis counts by 92.7%, NaOCl irrigation alone and combined with PDT by 99.9%. The antibacterial effects increased by the combination of irrigation using EDTA or citric acid and PDT compared to irrigation alone. More than 99% of E. faecalis were killed using PDT with the modified photosensitizers and ultrasonic activation. CONCLUSIONS: NaOCl based disinfection achieved the highest antimicrobial effect. Using PDT with an EDTA-based or citric-acid-based phozosensitizer or activating the photosensitizer with ultrasound resulted in a significantly higher reduction in E. faecalis counts compared to conventional PDT. PMID- 25703105 TI - A wheat lipid transfer protein (TdLTP4) promotes tolerance to abiotic and biotic stress in Arabidopsis thaliana. AB - Lipid transfer proteins (LTPs) are members of the family of pathogenesis-related proteins (PR-14) that are believed to be involved in plant defense responses. In this study, we report the isolation and characterization of a novel gene TdLTP4 encoding an LTP protein from durum wheat [Triticum turgidum L. subsp. Durum Desf.]. Molecular Phylogeny analyses of wheat TdLTP4 gene showed a high identity to other plant LTPs. Predicted three-dimensional structural model revealed the presence of six helices and nine loop turns. Expression analysis in two local durum wheat varieties with marked differences in salt and drought tolerance, revealed a higher transcript accumulation of TdLTP4 under different stress conditions in the tolerant variety, compared to the sensitive one. The overexpression of TdLTP4 in Arabidopsis resulted in a promoted plant growth under various stress conditions including NaCl, ABA, JA and H2O2 treatments. Moreover, the LTP-overexpressing lines exhibit less sensitivity to jasmonate than wild-type plants. Furthermore, detached leaves from transgenic Arabidopsis expressing TdLTP4 gene showed enhanced fungal resistance against Alternaria solani and Botrytis cinerea. Together, these data provide the evidence for the involvement of TdLTP4 gene in the tolerance to both abiotic and biotic stresses in crop plants. PMID- 25703106 TI - Molecular analysis of a mammary analog secretory carcinoma in the upper lip: Novel search for genetic and epigenetic abnormalities in MASC. AB - INTRODUCTION: Mammary analog secretory carcinoma (MASC) is a newly described rare malignancy of the salivary glands characterized by an ETS variant 6 (ETV6) neurotrophic tyrosine kinase receptor type 3 (NTRK3) fusion gene (EN fusion gene). PRESENTATION OF CASE: We present a case of MASC derived from the left upper lip in a 61-year-old woman. ETV6 rearrangement was detected by fluorescence in situ hybridization (FISH). The presence of EN fusion transcripts was verified by reverse-transcriptase polymerase chain reaction (RT-PCR) and sequencing of the PCR products. Accordingly, this tumor was diagnosed as MASC. Moreover, we performed mutation analysis of the 50 known cancer-related genes using next generation sequencing. No mutation of cancer-related genes was identified here. Subsequently, the methylation status in promoter region of tumor-suppressor genes, RASSF1A and RARB2, was examined. Both genes have been reported to be methylated in malignant salivary gland tumors, but they were found to be unmethylated. DISCUSSION: Recent studies have demonstrated that distinct types of malignant salivary gland carcinomas are driven by specific, highly recurrent genetic alterations. Detection of molecular abnormalities could be powerful diagnostic tools in the field of salivary gland tumors in near future. CONCLUSION: We experienced a rare malignant salivary gland carcinoma, MASC. We diagnosed this tumor by molecular approach and subsequently tried to identify novel molecular abnormalities. Although no novel molecular alteration except for EN fusion gene was identified, this result might represent the favorable prognosis of patients with MASC. PMID- 25703107 TI - Strategic science with policy impact. PMID- 25703108 TI - Strengthening of accountability systems to create healthy food environments and reduce global obesity. AB - To achieve WHO's target to halt the rise in obesity and diabetes, dramatic actions are needed to improve the healthiness of food environments. Substantial debate surrounds who is responsible for delivering effective actions and what, specifically, these actions should entail. Arguments are often reduced to a debate between individual and collective responsibilities, and between hard regulatory or fiscal interventions and soft voluntary, education-based approaches. Genuine progress lies beyond the impasse of these entrenched dichotomies. We argue for a strengthening of accountability systems across all actors to substantially improve performance on obesity reduction. In view of the industry opposition and government reluctance to regulate for healthier food environments, quasiregulatory approaches might achieve progress. A four step accountability framework (take the account, share the account, hold to account, and respond to the account) is proposed. The framework identifies multiple levers for change, including quasiregulatory and other approaches that involve government-specified and government-monitored progress of private sector performance, government procurement mechanisms, improved transparency, monitoring of actions, and management of conflicts of interest. Strengthened accountability systems would support government leadership and stewardship, constrain the influence of private sector actors with major conflicts of interest on public policy development, and reinforce the engagement of civil society in creating demand for healthy food environments and in monitoring progress towards obesity action objectives. PMID- 25703109 TI - Smart food policies for obesity prevention. AB - Prevention of obesity requires policies that work. In this Series paper, we propose a new way to understand how food policies could be made to work more effectively for obesity prevention. Our approach draws on evidence from a range of disciplines (psychology, economics, and public health nutrition) to develop a theory of change to understand how food policies work. We focus on one of the key determinants of obesity: diet. The evidence we review suggests that the interaction between human food preferences and the environment in which those preferences are learned, expressed, and reassessed has a central role. We identify four mechanisms through which food policies can affect diet: providing an enabling environment for learning of healthy preferences, overcoming barriers to the expression of healthy preferences, encouraging people to reassess existing unhealthy preferences at the point-of-purchase, and stimulating a food-systems response. We explore how actions in three specific policy areas (school settings, economic instruments, and nutrition labelling) work through these mechanisms, and draw implications for more effective policy design. We find that effective food policy actions are those that lead to positive changes to food, social, and information environments and the systems that underpin them. Effective food policy actions are tailored to the preference, behavioural, socioeconomic, and demographic characteristics of the people they seek to support, are designed to work through the mechanisms through which they have greatest effect, and are implemented as part of a combination of mutually reinforcing actions. Moving forward, priorities should include comprehensive policy actions that create an enabling environment for infants and children to learn healthy food preferences and targeted actions that enable disadvantaged populations to overcome barriers to meeting healthy preferences. Policy assessments should be carefully designed on the basis of a theory of change, using indicators of progress along the various pathways towards the long-term goal of reducing obesity rates. PMID- 25703110 TI - Christina Roberto: taking a broad view on combating obesity. PMID- 25703111 TI - Patchy progress on obesity prevention: emerging examples, entrenched barriers, and new thinking. AB - Despite isolated areas of improvement, no country to date has reversed its obesity epidemic. Governments, together with a broad range of stakeholders, need to act urgently to decrease the prevalence of obesity. In this Series paper, we review several regulatory and non-regulatory actions taken around the world to address obesity and discuss some of the reasons for the scarce and fitful progress. Additionally, we preview the papers in this Lancet Series, which each identify high-priority actions on key obesity issues and challenge some of the entrenched dichotomies that dominate the thinking about obesity and its solutions. Although obesity is acknowledged as a complex issue, many debates about its causes and solutions are centred around overly simple dichotomies that present seemingly competing perspectives. Examples of such dichotomies explored in this Series include personal versus collective responsibilities for actions, supply versus demand-type explanations for consumption of unhealthy food, government regulation versus industry self-regulation, top-down versus bottom-up drivers for change, treatment versus prevention priorities, and a focus on undernutrition versus overnutrition. We also explore the dichotomy of individual versus environmental drivers of obesity and conclude that people bear some personal responsibility for their health, but environmental factors can readily support or undermine the ability of people to act in their own self-interest. We propose a reframing of obesity that emphasises the reciprocal nature of the interaction between the environment and the individual. Today's food environments exploit people's biological, psychological, social, and economic vulnerabilities, making it easier for them to eat unhealthy foods. This reinforces preferences and demands for foods of poor nutritional quality, furthering the unhealthy food environments. Regulatory actions from governments and increased efforts from industry and civil society will be necessary to break these vicious cycles. PMID- 25703112 TI - Management of obesity: improvement of health-care training and systems for prevention and care. AB - Although the caloric deficits achieved by increased awareness, policy, and environmental approaches have begun to achieve reductions in the prevalence of obesity in some countries, these approaches are insufficient to achieve weight loss in patients with severe obesity. Because the prevalence of obesity poses an enormous clinical burden, innovative treatment and care-delivery strategies are needed. Nonetheless, health professionals are poorly prepared to address obesity. In addition to biases and unfounded assumptions about patients with obesity, absence of training in behaviour-change strategies and scarce experience working within interprofessional teams impairs care of patients with obesity. Modalities available for the treatment of adult obesity include clinical counselling focused on diet, physical activity, and behaviour change, pharmacotherapy, and bariatric surgery. Few options, few published reports of treatment, and no large randomised trials are available for paediatric patients. Improved care for patients with obesity will need alignment of the intensity of therapy with the severity of disease and integration of therapy with environmental changes that reinforce clinical strategies. New treatment strategies, such as the use of technology and innovative means of health-care delivery that rely on health professionals other than physicians, represent promising options, particularly for patients with overweight and patients with mild to moderate obesity. The co-occurrence of undernutrition and obesity in low-income and middle-income countries poses unique challenges that might not be amenable to the same strategies as those that can be used in high-income countries. PMID- 25703113 TI - Mobilisation of public support for policy actions to prevent obesity. AB - Public mobilisation is needed to enact obesity-prevention policies and to mitigate reaction against their implementation. However, approaches in public health focus mainly on dialogue between public health professionals and political leaders. Strategies to increase popular demand for obesity-prevention policies include refinement and streamlining of public information, identification of effective obesity frames for each population, strengthening of media advocacy, building of citizen protest and engagement, and development of a receptive political environment with change agents embedded across organisations and sectors. Long-term support and investment in collaboration between diverse stakeholders to create shared value is also important. Each actor in an expanded coalition for obesity prevention can make specific contributions to engaging, mobilising, and coalescing the public. The shift from a top-down to a combined and integrated bottom-up and top-down approach would need an overhaul of current strategies and reprioritisation of resources. PMID- 25703115 TI - Rethinking and reframing obesity. PMID- 25703114 TI - Child and adolescent obesity: part of a bigger picture. AB - The prevalence of childhood overweight and obesity has risen substantially worldwide in less than one generation. In the USA, the average weight of a child has risen by more than 5 kg within three decades, to a point where a third of the country's children are overweight or obese. Some low-income and middle-income countries have reported similar or more rapid rises in child obesity, despite continuing high levels of undernutrition. Nutrition policies to tackle child obesity need to promote healthy growth and household nutrition security and protect children from inducements to be inactive or to overconsume foods of poor nutritional quality. The promotion of energy-rich and nutrient-poor products will encourage rapid weight gain in early childhood and exacerbate risk factors for chronic disease in all children, especially those showing poor linear growth. Whereas much public health effort has been expended to restrict the adverse marketing of breastmilk substitutes, similar effort now needs to be expanded and strengthened to protect older children from increasingly sophisticated marketing of sedentary activities and energy-dense, nutrient-poor foods and beverages. To meet this challenge, the governance of food supply and food markets should be improved and commercial activities subordinated to protect and promote children's health. PMID- 25703116 TI - gamma-(S)-Trifluoromethyl proline: evaluation as a structural substitute of proline for solid state (19)F-NMR peptide studies. AB - gamma-(4S)-Trifluoromethyl proline was synthesised according to a modified literature protocol with improved yield on a multigram scale. Conformational properties of the amide bond formed by the amino acid were characterised using N acetyl methyl ester model. The amide populations (s-trans vs. s-cis) and thermodynamic parameters of the isomerization were found to be similar to the corresponding values for intact proline. Therefore, the gamma-trifluoromethyl proline was suggested as a structurally low-disturbing proline substitution in peptides for their structural studies by (19)F-NMR. Indeed, the exchange of native proline for gamma-trifluoromethyl proline in the peptide antibiotic gramicidin S was shown to preserve the overall amphipathic peptide structure. The utility of the amino acid as a selective (19)F-NMR label was demonstrated by observing the re-alignment of the labelled gramicidin S in oriented lipid bilayers. PMID- 25703117 TI - Drug delivery and release systems for targeted tumor therapy. AB - Most toxic agents currently used for chemotherapy show a narrow therapeutic window, because of their inability to distinguish between healthy and cancer cells. Targeted drug delivery offers the possibility to overcome this issue by selectively addressing structures on the surface of cancer cells, therefore reducing undesired side effects. In this broad field, peptide-drug conjugates linked by intracellular cleavable structures have evolved as highly promising agents. They can specifically deliver toxophores to tumor cells by targeting distinct receptors overexpressed in cancer. In this review, we focus on these compounds and describe important factors to develop a highly efficient peptide drug conjugate. The necessary properties of tumor-targeting peptides are described, and the different options for cleavable linkers used to connect toxic agents and peptides are discussed, and synthetic considerations for the introduction of these structures are reported. Furthermore, recent examples and current developments of peptide-drug conjugates are critically evaluated with a special focus on the applied linker structures and their future use in cancer therapy. PMID- 25703118 TI - Insights into the slow-onset tight-binding inhibition of Escherichia coli dihydrofolate reductase: detailed mechanistic characterization of pyrrolo [3,2-f] quinazoline-1,3-diamine and its derivatives as novel tight-binding inhibitors. AB - Dihydrofolate reductase (DHFR) is a pivotal enzyme involved in the de novo pathway of purine synthesis, and hence, represents an attractive target to disrupt systems that require rapid DNA turnover. The enzyme acquires resistance to available drugs by various molecular mechanisms, which necessitates the continuous discovery of novel antifolates. Previously, we identified a set of novel molecules that showed binding to E. coli DHFR by means of a thermal shift without establishing whether they inhibited the enzyme. Here, we show that a fraction of those molecules represent potent and novel inhibitors of DHFR activity. 7-[(4-aminophenyl)methyl]-7H-pyrrolo [3,2-f] quinazoline-1,3-diamine, a molecule with no reported inhibition of DHFR, potently inhibits the enzyme with a Ki value of 7.42 +/- 0.92 nm by competitive displacement of the substrate dihydrofolic acid. It shows uncompetitive inhibition vis-a-vis NADPH, indicating that the inhibitor has markedly increased affinity for the NADPH-bound form of the enzyme. Further, we demonstrate that the mode of binding of the inhibitor to the enzyme-NADPH binary complex conforms to the slow-onset, tight-binding model. By contrast, mechanistic characterization of the parent molecule 7H-pyrrolo [3,2 f] quinazoline-1,3-diamine shows that lack of (4-aminophenyl)-methyl group at the seventh position abolishes the slow onset of inhibition. This finding provides novel insights into the role of substitutions on inhibitors of E. coli DHFR and represents the first detailed kinetic investigation of a novel diaminopyrroloquinazoline derivative on a prokaryotic DHFR. Furthermore, marked differences in the potency of inhibition for E. coli and human DHFR makes this molecule a promising candidate for development as an antibiotic. PMID- 25703119 TI - Incidence, prognostic impact, and optimal definition of contrast-induced acute kidney injury in consecutive patients with stable or unstable coronary artery disease undergoing percutaneous coronary intervention. insights from the all comer PRODIGY trial. AB - BACKGROUND: Contrast-induced acute kidney injury (CI-AKI) is associated with poor outcome. Whether this association differs in stable coronary artery disease (CAD) as compared to acute coronary syndrome (ACS) patients is unknown. Definitions and Methods: PRODIGY trial patients were defined as stable CAD or ACS according to the initial presentation. CI-AKI was defined as an increase (Delta) of serum creatinine (SCr) >=25% above baseline. Two endpoints were considered: all-cause death and the composite of death, stroke, or myocardial infarction (MI). The interaction between CI-AKI, clinical setting, and the impact of increasing DeltaSCr% cut-offs were also explored. RESULTS: Two thousand three patients were enrolled in the PRODIGY trial, 85 patients were excluded for missing SCr data, leading to a population of 1,918 patients. CI-AKI incidence was 6.7% in stable CAD and 12.2% in ACS patients. CI-AKI was associated with all-cause mortality [adjusted hazard ratio (aHR) of 2.05, 95% confidence interval (CI) 1.38-3.05, P < 0.001] and the composite of death, stroke, or MI [aHR of 1.49, 95% CI 1.13-1.97, P < 0.001]. The risk of CI-AKI for the composite endpoint was higher in stable CAD, P for interaction: 0.048. A DeltaSCr of 35% was associated with the highest aHR for all-cause mortality: 2.34 [95% CI, 1.46-3.76, P < 0.001] and the composite of death, stroke, or MI: 1.70 [95% CI, 1.20-2.40, P > 0.001]. CONCLUSIONS: In a large, contemporary, all-comers percutaneous coronary intervention population, CI-AKI was associated with an increased risk of all cause death and the composite of death, stroke, or MI. While CI-AKI is more common in ACS than in stable CAD patients, its adjusted prognostic impact on the composite endpoint appears to be more pronounced in patients with stable CAD. PMID- 25703120 TI - Helicobacter pylori second-line rescue therapy with levofloxacin- and bismuth containing quadruple therapy, after failure of standard triple or non-bismuth quadruple treatments. AB - BACKGROUND: The most commonly used second-line Helicobacter pylori eradication regimens are bismuth-containing quadruple therapy and levofloxacin-containing triple therapy, both offering suboptimal results. Combining bismuth and levofloxacin may enhance the efficacy of rescue eradication regimens. AIMS: To evaluate the efficacy and tolerability of a second-line quadruple regimen containing levofloxacin and bismuth in patients whose previous H. pylori eradication treatment failed. METHODS: This was a prospective multicenter study including patients in whom a standard triple therapy (PPI-clarithromycin amoxicillin) or a non-bismuth quadruple therapy (PPI-clarithromycin-amoxicillin metronidazole, either sequential or concomitant) had failed. Esomeprazole (40 mg b.d.), amoxicillin (1 g b.d.), levofloxacin (500 mg o.d.) and bismuth (240 mg b.d.) was prescribed for 14 days. Eradication was confirmed by (13) C-urea breath test. Compliance was determined through questioning and recovery of empty medication envelopes. Incidence of adverse effects was evaluated by questionnaires. RESULTS: 200 patients were included consecutively (mean age 47 years, 67% women, 13% ulcer). Previous failed therapy included: standard clarithromycin triple therapy (131 patients), sequential (32) and concomitant (37). A total of 96% took all medications correctly. Per-protocol and intention to-treat eradication rates were 91.1% (95%CI = 87-95%) and 90% (95%CI = 86-94%). Cure rates were similar regardless of previous (failed) treatment or country of origin. Adverse effects were reported in 46% of patients, most commonly nausea (17%) and diarrhoea (16%); 3% were intense but none was serious. CONCLUSIONS: Fourteen-day bismuth- and levofloxacin-containing quadruple therapy is an effective (>=90% cure rate), simple and safe second-line strategy in patients whose previous standard triple or non-bismuth quadruple (sequential or concomitant) therapies have failed. PMID- 25703121 TI - The effect of ring size on the optical behavior of novel photochromic push-pull dyes. AB - The photophysical behaviors of newly synthesized photochromic dyes have been investigated in different solvents of various polarities using steady-state absorption and emission techniques. It was found that, the absorption and emission spectra of these dyes depend on the ring size and the solvent polarity. The higher values of the dipole moments of the investigated dyes in the excited state than those in the ground state suggest that these dyes can serve as good candidate components of nonlinear optical materials. Additionally, the photoisomerization parameters (percentage of composition of cis isomers and quantum yields of photoisomerization) depend on the polarity and the viscosity of the used solvents as well as the ring size. The molecular motion that occurs in the isomerization process has facilitated the development of molecular devices. Finally, the halochromic behaviors of the investigated dyes promise them to act as acid-base indicators. PMID- 25703122 TI - [Updates from RoFo]. PMID- 25703123 TI - [Multimodality imaging of hepatic PEComa ]. PMID- 25703124 TI - Magnetic resonance imaging of the bowel: today and tomorrow. AB - Magnetic resonance imaging of the small bowel has been feasible for more than 15 years. This review is meant to give an overview of typical techniques, sequences and indications. Furthermore, newly evaluated promising techniques are presented, which have an impact on the advance of MR imaging of the small and large bowel. PMID- 25703127 TI - [96th German Roentgen Congress, 13 - 16 2015 in Hamburg - "Technical innovations are the spice of life for us"]. PMID- 25703129 TI - [Interview - "We will suggest modifications"]. PMID- 25703131 TI - [Correction and repeal of fee decision by the German Mandatory Health Insurance Organization - when does confidentiality help?]. PMID- 25703132 TI - Cyclophosphamide, bortezomib, and dexamethasone combination in waldenstrom macroglobulinemia. PMID- 25703133 TI - Tailoring the endovascular management of transplant renal artery stenosis. AB - In this study we analyze the different types of endovascular interventions (EVIs) in de novo transplant renal artery stenosis (TRAS) and its anatomical subtypes to examine any variation in recovery of allograft function, blood pressure control, EVI patency and allograft survival with respect to EVI type (DES: drug-eluting stent, BMS: bare-metal stent, PTA: percutaneous transluminal angioplasty). Forty five patients underwent a total of 50 primary EVIs (DES: 18, BMS: 26, PTA: 6). Patients were stratified according to medical co-morbidities, graft characteristics, biopsy results, clinical presentation and TRAS anatomic subtypes (anastomotic: 26, postanastomotic: 17, bend-kink: 2). There was significant improvement in allograft function and mean arterial blood pressure (MAP) control across all interventions (pre-EVI-creatinine [CR]: 2.8 +/- 1.4, post-EVI-Cr: 2.1 +/- 0.7, p < 0.001; pre-EVI-MAP: 117 +/- 16, post-EVI-MAP: 112 +/- 17, p = 0.03) with no significant difference among EVI types. There was no significant difference in allograft survival with respect to EVI type. Patency was significantly higher in EVIs performed with DES and BMS compared to PTA (p = 0.001). In the postanastomotic TRAS subtype, patency rates were significantly higher in DES compared to BMS (p = 0.012) in vessels of comparable reference diameter (<=5 mm). PMID- 25703134 TI - Optimization of antifungal production by an alkaliphilic and halotolerant actinomycete, Streptomyces sp. SY-BS5, using response surface methodology. AB - OBJECTIVE: Optimization of medium components and physicochemical parameters for antifungal production by an alkaliphilic and salt-tolerant actinomycete designated Streptomyces sp. SY-BS5; isolated from an arid region in south of Algeria. MATERIALS AND METHODS: The strain showed broad-spectrum activity against pathogenic and toxinogenic fungi. Identification of the actinomycete strain was realized on the basis of 16S rRNA gene sequencing. Antifungal production was optimized following one-factor-at-a-time (OFAT) and response surface methodology (RSM) approaches. The most suitable medium for growth and antifungal production was found using one-factor-at-a-time methodology. The individual and interaction effects of three nutritional variables, carbon source (glucose), nitrogen source (yeast extract) and sodium chloride (NaCl) were optimized by Box-Behnken design. Finally, culture conditions for the antifungal production, pH and temperature were studied and determined. RESULTS: Analysis of the 16S rRNA gene sequence (1454 nucleotides) assigned this strain to Streptomyces genus with 99% similarity with Streptomyces cyaneofuscatus JCM4364(T), the most closely related. The results of the optimization study show that concentrations 3.476g/L of glucose, 3.876g/L of yeast extract and 41.140g/L of NaCl are responsible for the enhancement of antifungal production by Streptomyces sp. SY-BS5. The preferable culture conditions for antifungal production were pH 10, temperature 30 degrees C for 09 days. CONCLUSION: This study proved that RSM is usual and powerful tool for the optimization of antifungal production from actinomycetes. PMID- 25703135 TI - Portrayal of alcohol intoxication on YouTube. AB - BACKGROUND: We aimed to characterize the content of leading YouTube videos related to alcohol intoxication and to examine factors associated with alcohol intoxication in videos that were assessed positively by viewers. METHODS: We systematically captured the 70 most relevant and popular videos on YouTube related to alcohol intoxication. We employed an iterative process to codebook development which resulted in 42 codes in 6 categories: video characteristics, character socio demographics, alcohol depiction, degree of alcohol use, characteristics associated with alcohol, and consequences of alcohol. RESULTS: There were a total of 333,246,875 views for all videos combined. While 89% of videos involved males, only 49% involved females. The videos had a median of 1,646 (interquartile range [IQR] 300 to 22,969) "like" designations and 33 (IQR 14 to 1,261) "dislike" designations each. Liquor was most frequently represented, followed by beer and then wine/champagne. Nearly one-half (44%) of videos contained a brand reference. Humor was juxtaposed with alcohol use in 79% of videos, and motor vehicle use was present in 24%. There were significantly more likes per dislike, indicating more positive sentiment, when there was representation of liquor (29.1 vs. 11.4, p = 0.008), brand references (32.1 vs. 19.2, p = 0.04), and/or physical attractiveness (67.5 vs. 17.8, p < 0.001). CONCLUSIONS: Internet videos depicting alcohol intoxication are heavily viewed. Nearly, half of these videos involve a brand-name reference. While these videos commonly juxtapose alcohol intoxication with characteristics such as humor and attractiveness, they infrequently depict negative clinical outcomes. The popularity of this site may provide an opportunity for public health intervention. PMID- 25703136 TI - Founder haplotype analysis of Fanconi anemia in the Korean population finds common ancestral haplotypes for a FANCG variant. AB - A common ancestral haplotype is strongly suggested in the Korean and Japanese patients with Fanconi anemia (FA), because common mutations have been frequently found: c.2546delC and c.3720_3724delAAACA of FANCA; c.307+1G>C, c.1066C>T, and c.1589_1591delATA of FANCG. Our aim in this study was to investigate the origin of these common mutations of FANCA and FANCG. We genotyped 13 FA patients consisting of five FA-A patients and eight FA-G patients from the Korean FA population. Microsatellite markers used for haplotype analysis included four CA repeat markers which are closely linked with FANCA and eight CA repeat markers which are contiguous with FANCG. As a result, Korean FA-A patients carrying c.2546delC or c.3720_3724delAAACA did not share the same haplotypes. However, three unique haplotypes carrying c.307+1G>C, c.1066C > T, or c.1589_1591delATA, that consisted of eight polymorphic loci covering a flanking region were strongly associated with Korean FA-G, consistent with founder haplotypes reported previously in the Japanese FA-G population. Our finding confirmed the common ancestral haplotypes on the origins of the East Asian FA-G patients, which will improve our understanding of the molecular population genetics of FA-G. To the best of our knowledge, this is the first report on the association between disease-linked mutations and common ancestral haplotypes in the Korean FA population. PMID- 25703137 TI - Combination of radiation therapy and firocoxib for the treatment of canine nasal carcinoma. AB - Carcinomas represent two-thirds of canine nasosinal neoplasms. Although radiation therapy (RT) is the standard of care, the incidence of local recurrence following treatment is high. Cyclooxygenase-isoform-2 (COX-2) is expressed in 71-95% of canine nasal carcinomas and has been implicated in tumor growth and angiogenesis. Accordingly, COX-2 inhibition seems rational to improve outcome. Dogs with histologically confirmed, previously untreated nasal carcinomas were randomized to receive the combination of a selective COX-2 inhibitor (firocoxib) and palliative RT (Group 1) or RT and placebo (Group 2). Patients were regularly monitored with blood tests, urinalysis, and computed tomography. Pet owners were asked to complete monthly a quality-of-life questionnaire. Twenty-four dogs were prospectively enrolled. According to Adams modified system, there were five stage 1, five stage 2, three stage 3, and 11 stage 4 tumors. Two dogs had metastases to regional lymph nodes. Median progression-free interval and overall survival were 228 and 335 days in Group 1 (n = 12) and 234 and 244 days in Group 2 (n = 12). These differences were not statistically significant. The involvement of regional lymph nodes was significantly associated with progression-free interval and overall survival (P = 0.004). Quality of life was significantly improved in Group 1 (P = 0.008). In particular, a significant difference was observed for activity and appetite. Although not providing a significant enhancement of progression free interval and overall survival, firocoxib in combination with RT is safe and improved life quality in dogs with nasal carcinomas. PMID- 25703138 TI - Effect of chronic hypoxia on RAGE and its soluble forms in lungs and plasma of mice. AB - The receptor for advanced glycation end products (RAGE) is a multi-ligand receptor. Alternative splicing and enzymatic shedding produce soluble forms that protect against damage by ligands including Advanced Glycation End products (AGEs). A link between RAGE and oxygen levels is evident from studies showing RAGE-mediated injury following hyperoxia. The effect of hypoxia on pulmonary RAGE expression and circulating sRAGE levels is however unknown. Therefore mice were exposed to chronic hypoxia for 21 d and expression of RAGE, sheddases in lungs and circulating sRAGE were determined. In addition, accumulation of AGEs in lungs and expression of the AGE detoxifying enzyme GLO1 and receptors were evaluated. In lung tissue gene expression of total RAGE, variants 1 and 3 were elevated in mice exposed to hypoxia, whereas mRAGE and sRAGE protein levels were decreased. In the hypoxic group plasma sRAGE levels were enhanced. Although the levels of pro-ADAM10 were elevated in lungs of hypoxia exposed mice, the relative amount of the active form was decreased and gelatinase activity unaffected. In the lungs, the RAGE ligand HMGB1 was decreased and of the AGEs, only LW-1 was increased by chronic hypoxia. Gene expression of AGE receptors 2 and 3 was significantly upregulated. Chronic hypoxia is associated with downregulation of pulmonary RAGE protein levels, but a relative increase in sRAGE. These alterations might be part of the adaptive and protective response mechanism to chronic hypoxia and are not associated with AGE formation except for the fluorophore LW-1 which emerges as a novel marker of tissue hypoxia. PMID- 25703139 TI - Tamoxifen induces the development of hernia in mice by activating MMP-2 and MMP 13 expression. AB - Hernia is a disease with defects in collagen synthesis/metabolism. However, the underlying mechanisms for hernia formation have not been fully defined. Tamoxifen is a selective estrogen receptor modulator and used for patients with breast cancer. Tamoxifen also has pleiotropic and side effects. Herein, we report that tamoxifen treatment resulted in an appearance of a large bulge in the low abdomen between the hind legs in male but not in female mice. The autopsy demonstrated that the low abdominal wall was broken and a large amount of intestine herniated out of the abdominal cavity. Histological analysis indicated that tamoxifen caused structural abnormalities in the low abdominal wall which were associated with decreased type II collagen content. Furthermore, we determined increased matrix metalloproteinase-2 (MMP-2) and MMP-13 expression in the tissue. In vitro, tamoxifen induced MMP-2 and MMP-13 expression in fibroblasts. The promoter activity analysis and ChIP assay demonstrate that induction of MMP-13 expression was associated with activation of JNK-AP-1 and ERK1/2 signaling pathways while induction of MMP-2 expression was related to activation of the ERK1/2 signaling pathway. Taken together, our study establishes a novel murine hernia model, defines a severe side effect of tamoxifen, and suggests a caution to male patients receiving tamoxifen treatment. PMID- 25703140 TI - CEACAM6 promotes tumor angiogenesis and vasculogenic mimicry in gastric cancer via FAK signaling. AB - CEACAM6 is a member of glycosylphosphatidylinositol-linked immunoglobulin superfamily that is implicated in a variety of human cancers. In our previous study, we reported that CEACAM6 was overexpressed in gastric cancer tissues and promoted cancer metastasis. The purpose of this study is to determine the role of CEACAM6 in tumor angiogenesis and mimicry formation. We found that overexpressed CEACAM6 promoted tubule formation dependent on HUVEC cells and vasculogenic mimicry formation of gastric cancer cells; opposing results were achieved in CEACAM6-silenced groups. Moreover, we found that mosaic vessels formed by HUVEC cells and gastric cancer cells were observed in vitro by 3D-culture assay. Overexpressed CEACAM6 in gastric cancer cells promoted tumor growth, VEGF expression and vasculogenic mimicry structures formation in vivo. In accordance with these observations, we found that phosphorylation of FAK and phosphorylation of paxillin were up-regulated in CEACAM6-overexpressing gastric cancer cells, and FAK inhibitor Y15 could reduce tubule and vasculogenic mimicry formation. These findings suggest that CEACAM6 promotes tumor angiogenesis and vasculogenic mimicry formation via FAK signaling in gastric cancer and CEACAM6 may be a new target for cancer anti-vascular treatment. PMID- 25703141 TI - A case for diagnosis. PMID- 25703142 TI - Selection-based discovery of macrocyclic peptides for the next generation therapeutics. AB - Naturally occurring macrocyclic peptides represent a unique class of compounds that exhibit various biological activities ranging from antibiotics to immunosuppressant. Although the discovery of such macrocyclic peptides had relied on their isolation from living organisms, recent advances in ribosomal peptide synthesis and in display techniques made it possible to use artificially generated macrocyclic peptide libraries for selection of ligands for biologically relevant proteins. In this review, we discuss the technologies and their applications for the discovery of peptide ligands. PMID- 25703143 TI - Critical role of YY1 in cardiac morphogenesis. AB - BACKGROUND: Yin Yang 1 (YY1), the only DNA binding polycomb group protein, was reported to regulate cardiomyocyte differentiation during early cardiac mesoderm development. However, whether it contributes to cardiac morphogenesis at later developmental stage(s) during embryogenesis is unknown. RESULTS: We excised YY1 in murine hearts during embryogenesis using two temporal-spatially controlled cre activation approaches, and revealed critical roles of YY1 in cardiac structural formation. Alpha-myosin heavy chain-cre (alpha-MHC-cre)-mediated cardiomyocyte specific ablation of YY1 (MHC-YY1) resulted in perinatal death of mutant mice, and Nkx2.5-cre-mediated YY1 null embryos (Nkx2.5-YY1) died embryonically. In the Nkx2.5-YY1 mutants, the endocardial cushions (ECs) of both atrioventricular canal (AVC) and outflow tract (OFT) were hypoplastic due to decreased proliferation and increased apoptosis. Endothelial-to-mesenchymal transition (EMT) progress was also compromised in ECs. Nkx2.5-YY1 mutant hearts had normal formation of extracellular matrix, suggesting that the impaired EMT resulted from the direct loss of YY1. We further uncovered that a number of factors that are involved in normal cardiogenesis were downstream targets of YY1. CONCLUSIONS: YY1 plays a critical role in cardiac development and occupies a high-level position within the hierarchy of the cardiac transcriptional network that governs normal cardiogenesis. PMID- 25703144 TI - State-of-the-art anterior cruciate ligament tears: A primer for primary care physicians. AB - The purpose of this article is to provide primary care physicians and other members of the medical community with an updated, general review on the subject of anterior cruciate ligament (ACL) tears. We aim to enhance awareness of these injuries and to prepare those practicing in the primary care setting to address these injuries. Because ACL injuries are quite common, it is very likely that a primary care physician will encounter these injuries and need to address them acutely. The current literature is replete with new concepts and controversies regarding ACL injuries, and this article provides a concise review for our target audience in regard to the care of a patient with an ACL injury. This article is composed of an overview with current epidemiologic data, basic anatomy and physiology, clinical presentation, physical examination findings, imaging modalities, and treatment options. After reading this short article, a medical care provider should understand ACL injuries and their appropriate management. PMID- 25703145 TI - Unusual suicide in Italy: criminological and medico-legal observations-a proposed definition of "atypical suicide" suitable for international application. AB - This work is the result of a kind of categorization of suicidal conduct based on an empirical-phenomenological approach, with integrated assessment of certain criteria, such as the dynamics, correlation of types of injury and how they were produced, evidence gathered during official inspections in loco, and case history findings about "suicide." This categorization is an attempt to provide a nosographic definition of atypical suicide, that is, cases in which the parameters of "typical" suicide are missing. Case studies are described, taken from a systematic exploration mainly of the Italian specialized literature of the 20th century, supplemented by earlier references when deemed significant. In depth analysis of atypical suicide can supply additional interpretations of the problem of differential diagnosis of suicide, homicide, and accidental death, that is, the real punctum dolens in overall medico-legal determination of the cause of death in scenarios in which death cannot be definitely traced to a deliberate act. PMID- 25703146 TI - Sonogenerated metal-hydrogen sponges for reactive hard templating. AB - We present sonogenerated magnesium-hydrogen sponges for effective reactive hard templating. Formation of differently organized nanomaterials is possible by variation of sonochemical parameters and solution composition: Fe2O3 nanorods or composite dendritic Fe2O3/Fe3O4 nanostructures. PMID- 25703147 TI - Bees, birds and yellow flowers: pollinator-dependent convergent evolution of UV patterns. AB - Colour is one of the most obvious advertisements of flowers, and occurs in a huge diversity among the angiosperms. Flower colour is responsible for attraction from a distance, whereas contrasting colour patterns within flowers aid orientation of flower visitors after approaching the flowers. Due to the striking differences in colour vision systems and neural processing across animal taxa, flower colours evoke specific behavioural responses by different flower visitors. We tested whether and how yellow flowers differ in their spectral reflectance depending on the main pollinator. We focused on bees and birds and examined whether the presence or absence of the widespread UV reflectance pattern of yellow flowers predicts the main pollinator. Most bee-pollinated flowers displayed a pattern with UV-absorbing centres and UV-reflecting peripheries, whereas the majority of bird-pollinated flowers are entirely UV- absorbing. In choice experiments we found that bees did not show consistent preferences for any colour or pattern types. However, all tested bee species made their first antennal contact preferably at the UV-absorbing area of the artificial flower, irrespective of its spatial position within the flower. The appearance of UV patterns within flowers is the main difference in spectral reflectance between yellow bee- and bird pollinated flowers, and affects the foraging behaviour of flower visitors. The results support the hypothesis that flower colours and the visual capabilities of their efficient pollinators are adapted to each other. PMID- 25703148 TI - Examining aging sexual stigma attitudes among adults by gender, age, and generational status. AB - OBJECTIVES: Stigma related to later life sexuality could produce detrimental effects for older adults, through individual concerns and limited sexual health care for older adults. Identifying groups at risk for aging sexual stigma will help to focus interventions to reduce it. Accordingly, the purpose of this study was to examine cross-sectional trends in aging sexual stigma attitudes by age group, generational status, and gender. METHOD: An online survey was administered to a national sample of adults via a crowdsourcing tool, in order to examine aging sexual stigma across age groups, generational status, and gender (N = 962; 47.0% male, 52.5% female, and .5% other; mean age = 45 years). An aging sexual stigma index was formulated from the attitudinal items of the Aging Sexual Knowledge and Attitudes Scale. RESULTS: This sample reported moderately permissive attitudes toward aging sexuality, indicating a low level of aging sexual stigma. Though descriptive data showed trends of stigma attitudes increasing with age and later generations, there were no significant differences between age groups or generations in terms of aging sexual stigma beliefs. Men, regardless of age and/or generation, were found to espouse significantly higher stigmatic beliefs than women or those reporting 'other' gender. CONCLUSIONS: Aging sexual stigma beliefs may not be prevalent among the general population as cohorts become more sexually liberal over time, though men appear more susceptible to these beliefs. However, in order to more comprehensively assess aging sexual stigma, future research may benefit from measuring explicit and implicit aging sexual stigma beliefs. PMID- 25703149 TI - Speckled lentiginous nevus syndrome associated with an abnormality of tongue. PMID- 25703150 TI - Gas chromatography-mass spectrometry method optimized using response surface modeling for the quantitation of fungal off-flavors in grapes and wine. AB - An optimized method for the quantitation of volatile compounds responsible for off-aromas, such as earthy odors, found in wine and grapes was developed. The method involved a fast and simple headspace solid-phase microextraction-gas chromatography-mass spectrometry (HS-SPME-GC-MS) for simultaneous determination of 2-isopropyl-3-methoxypyrazine, 2-isobutyl-3-methoxypyrazine, 3-octanone, fenchone, 1-octen-3-one, trans-2-octen-1-ol, fenchol, 1-octen-3-ol, 2 methylisoborneol, 2,4,6-trichloroanisole, geosmin, 2,4,6-tribromoanisole, and pentachloroanisole. The extraction of the temperature and time were optimized using response surface methodology in both wine base (WB) and grape base (GB). Low limits of detection (0.1-5 ng/L in WB and 0.05-1.6 in GB) and quantitation (0.3-17 in WB and 0.2-6.2 in GB) with good recoveries (83-131%) and repeatability [4.3-9.8% coefficient of variation (CV) in WB and 5.1-11.1% CV in GB] and reproducibility (3.6-10.2 in WB and 1.9-10.9 in GB) indicate that the method has excellent sensitivity and is suitable for the analysis of these off-flavor compounds in wine and grape juice samples. PMID- 25703151 TI - Intrinsic and extrinsic risk factors for nonunion after nonoperative treatment of midshaft clavicle fractures. AB - BACKGROUND: The optimal treatment of midshaft clavicle fractures remains controversial. Nonunion is usually considered to be an uncommon complication following a nonoperatively treated clavicle fracture. HYPOTHESIS: Not every midshaft clavicular fractures shares the same risk of developing nonunion after nonoperative treatment. The present study was performed to identify the intrinsic and extrinsic independent factors that are independently predictive of nonunion in patients with midshaft clavicular fractures after nonoperative treatment. MATERIALS AND METHODS: We performed a retrospective study of a series of 804 patients (391 men and 413 women with a median age of 51.3 years) with a radiographically confirmed midshaft clavicle fracture, which was treated nonoperatively. There were 96 patients who underwent nonunion. Putative intrinsic (patient-related) and extrinsic (injured-related) risk factors associated with nonunion were determined with the use of bivariate and multivariate statistical analyses. RESULTS: By bivariate analysis, the risk of nonunion was significantly increased by several intrinsic risk factors including age, sex, and smoking and extrinsic risk factors including displacement of the fracture and the presence of comminution (P<0.05 for all). On multivariate analysis, smoking (OR=4.16, 95% CI: 1.01-14.16), fracture displacement (OR=7.81, 95% CI: 2.27-25.38) and comminution of fracture (OR=3.86, 95% CI: 1.16-13.46) were identified as independent predictive factors. CONCLUSION: The risk factors for nonunion after nonoperative treatment of midshaft clavicle fractures are multifactorial. Smoking, fracture displacement and comminution of fracture are independent predictors for an individual likelihood of nonunion. Further studies are still required to evaluate these factors in the future. LEVEL OF EVIDENCE: Level III, case-control study. PMID- 25703152 TI - Flexor digitorum brevis tendon transfer to the flexor digitorum longus tendon according to Valtin in posttraumatic flexible claw toe deformity due to extrinsic toe flexor shortening. AB - Claw toe deformity after posterior leg compartment syndrome is rare but incapacitating. When the mechanism is flexor digitorum longus (FDL) shortening due to ischemic contracture of the muscle after posterior leg syndrome, a good treatment option is the Valtin procedure in which the flexor digitorum brevis (FDB) is transferred to the FDL after FDL tenotomy. The Valtin procedure reduces the deformity by lengthening and reactivating the FDL. Here, we report the outcomes of FDB to FDL transfer according to Valtin in 10 patients with posttraumatic claw toe deformity treated a mean of 34 months after the injury. Toe flexion was restored in all 10 patients, with no claw toe deformity even during dorsiflexion of the ankle. PMID- 25703153 TI - Quality of life after total laryngectomy: functioning, psychological well-being and self-efficacy. AB - BACKGROUND: Quality of life (QoL) is an important construct when assessing treatment outcomes. AIMS: To examine the relative contributions of functioning, psychological well-being and self-efficacy on self-perceived QoL with a sample of total laryngectomy patients in Australia who had surgery for advanced laryngeal cancer. METHODS & PROCEDURES: In a cross-sectional study, 113 members of the Laryngectomy Associations of New South Wales and of Victoria, Australia, were recruited, and each was sent a series of questionnaires for postal return. Four psychometrically validated measures were used for participants to document their QoL, functioning (speech, swallowing), psychological well-being and general self efficacy. OUTCOMES & RESULTS: Eighty-six (77%) questionnaires were returned and 83 were analysed. The cohort consists of 70 men and 13 women aged between 46 and 88 years. Overall, this sample of total laryngectomy survivors demonstrated significantly reduced physical health QoL (p < 0.001) and social relationship QoL (p = 0.011) and higher levels of depression (p = 0.008) and anxiety (p = 0.001) when compared with normative samples. This was in the context of them having higher than normal self-efficacy scores and, at worst, mild (self-rated) impairment of speech and of swallowing. Psychological well-being (sr(2) = 0.43, p < 0.001) had a stronger association than functioning (speech, swallowing, sr(2) = 0.08, p < 0.05) for their psychological QoL. Psychological well-being (sr(2) = 0.17, p < 0.001) and not functioning (sr(2) = 0.05, p > 0.05) were significantly associated with social relationship QoL. Self-efficacy scores were significantly higher than norms in this cohort, but were not associated with either their psychological QoL or social relationship QoL, after controlling for psychological well-being and functioning. CONCLUSIONS & IMPLICATIONS: For survivors of laryngeal cancer treated by total laryngectomy, it is important to be aware of the impact of psychological well-being (depression, anxiety, stress) on self perceived QoL. In addition to rehabilitating function (speech, swallowing), specific interventions to assist these individuals better manage their psychological well-being will likely improve their perceived life satisfaction/QoL. PMID- 25703154 TI - Satisfaction with economic and social rights and quality of life in a post disaster zone in China: evidence from earthquake-prone Sichuan. AB - OBJECTIVE: This study explored the influence of satisfaction with economic and social rights (ESR) on the quality of life (QOL) of people in post-disaster zones in Sichuan, China. METHODS: Data from a survey conducted in 2013 in the 5 hardest hit counties in the earthquake-prone area of Sichuan were used. QOL was measured by use of the brief version of the World Health Organization Quality of Life questionnaire (WHOQOL-BREF). Structural equation models were developed to determine the specific features of the influence of satisfaction with ESR on QOL. RESULTS: The mean values of both the WHOQOL-BREF scale and the ESR satisfaction scale were lower than the midpoint of the scales. Satisfaction with ESR had a significant effect on psychological health, social relationships, and environment, apart from physical health. Satisfaction with the right to food had the greatest effect on QOL, followed by the rights to education, work, health, social security, and housing. CONCLUSIONS: Satisfaction with ESR had a significant positive influence on the QOL of people in a post-disaster zone, particularly satisfaction with the right to food. Policies on food and education guarantees and mental health intervention are highlighted. PMID- 25703155 TI - Uptake, distribution, depletion, and in ovo transfer of isomers of hexabromocyclododecane flame retardant in diet-exposed American kestrels (Falco sparverius). AB - Hexabromocyclododecane (HBCDD) is a flame retardant and a global contaminant, yet the toxicokinetics of HBCDD diastereoisomers remains unknown in wildlife species. The present study examined in captive American kestrels (Falco sparverius) (diastereo) isomer-specific HBCDD uptake, depletion, tissue distribution, and transfer to eggs in a dietary dosing study with an HBCDD technical mixture (HBCDD TM). Adult tissue and plasma collections were from separate cohorts of unpaired individual males (n = 10) and females (n = 10) exposed for 21 d to 800 ng/g wet weight of HBCDD-TM (in safflower oil and injected into their cockerel [brain] diet), followed by a 25-d depuration period. A separate cohort of 12 males only was used for control adult tissue and plasma collections. For egg collections, separate cohorts of 11 control pairs (n = 22 birds) and 20 HBCDD-exposed pairs (n = 40 birds) were allowed to breed, and their eggs were collected (n = 19 exposed eggs and n = 10 control eggs). The sum (Sigma) HBCDD concentrations were near or below detection (<0.01-0.1 ng/g wet wt) in all control samples but quantifiable in all samples from exposed birds (no differences [p > 0.05] between males and females). Arithmetic mean SigmaHBCDD concentrations were highest in fat >> eggs > liver > plasma. The mean SigmaHBCDD depletion rate in plasma between the uptake and depuration periods was estimated to be 0.22 ng/g/d with a half-life of approximately 15 d. The gamma-HBCDD diastereoisomer was >60% of the SigmaHBCDD in plasma after the uptake period and similar to the HBCDD-TM (~80%). After the depuration period, alpha-HBCDD was >70% of the HBCDD in plasma, fat, liver, and eggs; and this alpha-HBCDD domination indicated isomer-specific accumulation as a result of selective metabolism, uptake, protein binding, and/or in ovo transport. PMID- 25703156 TI - Beta-blockers in patients with cirrhosis and infections: don't blame too soon! PMID- 25703157 TI - Segment-2 sequencing and cross-neutralization studies confirm existence of a neutralization resistant VP2 phenotypic variant of bluetongue virus serotype 1 in India. AB - Segment-2 (seg-2) of a bluetongue virus seropype-1 (BTV-1) isolate WGV104/08/Ind of Indian origin was sequenced and its neutralization behavior was studied to understand the antigenic similarity and relationship with other BTV-1 isolates. Multiple alignments of the coding region of seg-2 of WGV104/08/Ind revealed 97.6 99.0% and 97.2-98.4% similarity with other Indian BTV-1 isolates at nucleotide and deduced amino acid sequence level respectively. Several conservative and non conservative substitutions were observed on the deduced VP2 amino acid sequence of WGV104/08/Ind. Non-conservative substitution of Lys119Glu on the B-cell epitope and Arg330Gly on the neutralizing epitope of VP2 of this isolate was observed. Using isolate-specific heterologous hyperimmune serum (HIS) the phenotypic antigenic relationship (r) was determined between WGV104/08/Ind and other Indian BTV-1 isolates which ranged from 0.092 to 0.208. The relationship score ranged from 0.203 to 0.295 when neutralization behavior of other Indian BTV 1 isolates was studied with the HIS of WGV104/08/Ind. Antigenic similarity (R) between WGV104/08/Ind and other Indian BTV-1 isolates was estimated from a reciprocal cross-neutralization study and ranged from 14.70% to 24.80% indicating existence of major subtype antigenic divergence and neutralization resistant behavior of WGV104/08/Ind. PMID- 25703158 TI - Reappearance of Salmonella serovar Choleraesuis var. Kunzendorf in Danish pig herds. AB - Salmonella enterica serovar Choleraesuis is a porcine adapted serovar which may cause serious outbreaks in pigs. Here we describe outbreaks of salmonellosis due to S. Choleraesuis in four Danish pig farms in 2012-2013 by clinic, serology, and microbiology and compare the isolates to those of a previous outbreak in 1999 2000. The infection was in some herds associated with high mortality and a moderate to high sero-prevalence was found. In 2012-2013 the disease contributed to increased mortality but occurred concomitant with other disease problems in the herds, which likely delayed the diagnosis by up to several months. Nine isolates from the four farms in 2012-2013 and 14 isolates obtained from the outbreak in Denmark in 1999-2000 were subjected to typing using pulsed-field gel electrophoresis (PFGE). Seven isolates were selected for whole genome sequencing (WGS). The PFGE results of 23 isolates displayed five different profiles. The isolates from 2012 to 2013 revealed two distinct profiles, both different from the isolates recovered in 1999-2000. Two of the 2012-2013 farms shared PFGE profiles and had also transported pigs between them. The profile found in the two other 2012-2013 farms was indistinguishable but no epidemiological connection between these farms was found. Analysis of the number of single nucleotide polymorphisms (SNPs) from the WGS data indicated that the isolates from the farms in 2012-2013 were more closely related to each other than to isolates from the outbreak in 1999. It was therefore concluded that the infection was a new introduction and not a persistent infection since the outbreak in 1999. It may further be suggested that there were two or three independent rather than a single introduction. The re-introduction of S. Choleraesuis in Denmark emphasizes the importance of strict hygiene measures in the herds. Further investigations using WGS are now in progress on a larger collection of isolates to study clonality at European level and trace the origin of the infections. PMID- 25703159 TI - A ten-year review of soft tissue reactions around percutaneous titanium implants for auricular prosthesis. AB - OBJECTIVES/HYPOTHESIS: Soft tissue reactions around abutments are the most common complications of percutaneous osseointegrated implants. The main objective of this study was to review our series of osseointegrated implants, evaluate the degree of adverse skin reactions around the auricular abutments, and compare with skin reactions in the pediatric bone-anchored hearing aid (BAHA) population. The reason for comparing these two groups was the difference in abutment shape and position in skin with different characteristics. STUDY DESIGN: A retrospective case analysis of 131 patient notes. METHODS: We retrospectively studied 131 pediatric and adult patients who underwent an osseointegrated auricular prosthesis over a 10-year period (1997-2007). RESULTS: There were 95 adults and 36 children who had been implanted and fitted with an auricular prosthesis during the 10-year study period. All patients were followed up postoperatively for a 2 year minimum up to a 14-year maximum follow-up. Thirteen (13/36, 36%) children and seven adults (7/95, 7%) had a skin reaction around the ear prosthesis. CONCLUSIONS: The literature review has supported our study results and has shown that children have higher skin reactions in both BAHA and auricular prostheses than adults. Adverse skin reactions in the pediatric auricular group were significantly lower that the pediatric BAHA group. LEVEL OF EVIDENCE: 4 PMID- 25703160 TI - The economic burden of gastroschisis: costs of a birth defect. AB - BACKGROUND: Intestinal dysfunction and feeding intolerance are comorbidities associated with the abdominal wall birth defect of gastroschisis (GS). These factors contribute to prolonged hospitalization in this population of patients. The purpose of this study was to evaluate the economic burden on a state and national level. METHODS: From 2007-2011, the Healthcare Cost and Utilization Project database was queried for the following national and state of Texas data: number of discharges, length of stay (LOS), costs, and charges for all pediatric hospital stays +/- CPT code 54.71 denoting GS repair for infants aged <1 y. The effect of GS on LOS, cost, and charges was calculated by the weighted average of the differences and is represented by the combined estimated difference (CED). RESULTS: Infants <1 y represent 74% of all pediatric discharges nationally and only 0.04% of these discharges are accounted for by GS patients. Nationally, GS patients had significantly longer LOS (CED 38.5 +/- 0.9 d, P < 0.0001); increased costs (CED $79,733 +/- $2119, P < 0.0001); and charges (CED $249,999 +/- $9562, P < 0.0001). The Texas state data mirrored our findings for the national data. There was no significant difference in the LOS, costs, and charges between the national and state level. CONCLUSIONS: Our study shows that GS patients represent an extremely small minority of national and Texas pediatric discharges; however, these patients LOS and costs greatly exceed non-GS patients. Further investigation into factors influencing the development of intestinal dysfunction in these patients is needed to significantly impact the economic burden of the abdominal wall birth defect of GS. PMID- 25703161 TI - Receptor analysis of differential sensitivity change to succinylcholine induced by nerve injury in rat gastrocnemius. AB - BACKGROUND: Urgent tracheal intubation is common in intensive care units and the emergency room, and succinylcholine is a first-line neuromuscular blocker used in these situations. Paraplegic or critically ill patients may be at a high risk of receiving succinylcholine because the denervation stage changes nicotinic receptors, which affect the efficacy and safety of succinylcholine. The objective of this study was to determine the receptor subtypes associated with changes in the pharmacodynamics of succinylcholine and its time-line trend. METHODS: Denervated gastrocnemius was collected from tibial nerve transected rats. To determine the 50% effective dose of succinylcholine and rocuronium at 0 (control), 1, 3, 7, 14, and 28 d after denervation, action potential amplitude was monitored by an intracellular recording method. Subunits alpha1, alpha7, epsilon, and gamma of the acetylcholine receptor (AChR) were quantified by real time polymerase chain reaction. Receptor amount and pharmacodynamic changes were analyzed by correlation and regression analysis. RESULTS: The pharmacodynamic change in succinylcholine was a dynamic process, and at the same time alpha7, epsilon, and gamma-nicotinic AChR genes in denervated muscle were significantly changed but only alpha7 was closely correlated with the action of succinylcholine. Subunit gamma and alpha7 were related to pharmacodynamic change in the nondepolarizing neuromuscular agent, rocuronium. CONCLUSIONS: Nerve injury may alter nicotinic AChR subtypes in skeletal muscle at different stages, which probably affected the pharmacodynamics of neuromuscular blockers in different ways. Denervation time and stage and the type of neuromuscular blocker and dosage should be taken into consideration when using these drugs in patients with nerve injury. PMID- 25703162 TI - Identification of ideal resuscitation pressure with concurrent traumatic brain injury in a rat model of hemorrhagic shock. AB - BACKGROUND: Traumatic brain injury (TBI) is often associated with uncontrolled hemorrhagic shock (UHS), which contributes significantly to the mortality of severe trauma. Studies have demonstrated that permissive hypotension resuscitation improves the survival for uncontrolled hemorrhage. What the ideal target mean arterial pressure (MAP) is for TBI with UHS remains unclear. METHODS: With the rat model of TBI in combination with UHS, we investigated the effects of a series of target resuscitation pressures (MAP from 50-90 mm Hg) on animal survival, brain perfusion, and organ function before hemorrhage controlled. RESULTS: Rats in 50-, 60-, and 70-mm Hg target MAP groups had less blood loss and less fluid requirement, a better vital organ including mitochondrial function and better cerebral blood flow, and animal survival (8, 6, and 7 of 10, respectively) than 80- and 90-mm Hg groups. The 70-mm Hg group had a better cerebral blood flow and cerebral mitochondrial function than in 50- and 60-mm Hg groups. In contrast, 80- and 90-mm Hg groups resulted in an excessive hemodilution, a decreased blood flow, an increased brain water content, and more severe cerebral edema. CONCLUSIONS: A 50-mm Hg target MAP is not suitable for the resuscitation of TBI combined with UHS. A 70 mm Hg of MAP is the ideal target resuscitation pressure for this trauma, which can keep sufficient perfusion to the brain and keep good organ function including cerebral mitochondrial function. PMID- 25703163 TI - See one, do one, and teach none: resident experience as a teaching assistant. AB - BACKGROUND: Training of surgical residents depends on graduated autonomy in and out of the operating room. We sought to define trends in operative volume and number of teaching cases in graduating surgical residents over time. METHODS: We queried the Accreditation Council for Graduate Medical Education general surgery case log (1999-2012) for all case categories in which graduating chief residents performed a median of 20 or more cases during their training. Median (10th and 90th percentiles) number of cases performed as surgeon chief, surgeon junior and teaching assistant (TA) were analyzed using R(2) for all trends. RESULTS: The median number of cases performed by graduating chief residents remained stable over time (965-971; R(2) = 0.01). Surgeon junior cases increased slightly (718 725; R(2) = 0.07), whereas surgeon chief cases decreased slightly (246-235; R(2) = 0.08). The most frequently performed cases were in the categories of the large intestine (125 [85,167], biliary (109 [74,167]), and abdominal hernia (99 [67.5,139]). The median number of TA cases decreased by 79% (126-27; R(2) = 0.34), with the most significant decrease occurring early in the study period (median: 126-22; R(2) = 0.91). The number of median teaching cases decreased in every category analyzed, with the most pronounced occurring in the categories of thoracic (9-0 [100%]; R(2) = 0.37) and breast (6-0 [100%]; R(2) = 0.55). The only categories with a median number of teaching cases >1 in 2012 were the large intestine (5), biliary (4), and abdominal hernia repairs (3). CONCLUSIONS: Despite a relative stability of case volume over time, GSRs are graduating with relatively few cases recorded as TA. Improved opportunities for trainees to take on the role of TA while in residency may lead to improved confidence as surgeons on graduation. PMID- 25703164 TI - OCTET-CY: a phase II study to investigate the efficacy of post-transplant cyclophosphamide as sole graft-versus-host prophylaxis after allogeneic peripheral blood stem cell transplantation. AB - OBJECTIVE: Post-transplant cyclophosphamide is increasingly used as graft-versus host disease (GvHD) prophylaxis in the setting of bone marrow transplantation. No data have been published on the use of single-agent GvHD prophylaxis with post transplant cyclophosphamide in the setting of peripheral blood stem cell transplantation (PBSCT). METHODS: In a phase II trial, 11 patients with myeloma or lymphoma underwent conditioning with fludarabine and busulfan followed by T replete PBSCT and application of 50 mg/kg/d of cyclophosphamide on day+3 and +4 without other concurrent immunosuppression (IS). RESULTS: Median time to leukocyte, neutrophil, and platelet engraftment was 18, 21, and 18 d. The incidence of grade II-IV and grade III-IV GvHD was 45% and 27%, with a non relapse mortality (NRM) of 36% at one and 2 yr. After median follow-up of 927 d, overall and relapse-free survival was 64% and 34%. Three patients did not require any further systemic IS until day+100 and thereafter. Analysis of immune reconstitution demonstrated rapid T- and NK-cell recovery. B- and CD3+/CD161+NK/T cell recovery was superior in patients not receiving additional IS. CONCLUSION: Post-transplant cyclophosphamide as sole IS in PBSCT is feasible and allows rapid immune recovery. Increased rates of severe acute GvHD explain the observed NRM and may advise a temporary combination partner such as mTor-inhibitors in the PBSCT setting. PMID- 25703165 TI - The English (H6R) familial Alzheimer's disease mutation facilitates zinc-induced dimerization of the amyloid-beta metal-binding domain. AB - Interaction of Zn(2+) with the metal-binding domain of the English (H6R) amyloid beta mutant results in the formation of peptide dimers. The mutation causes the exclusion of His6 from the zinc chelation pattern observed in the intact domain and triggers the assembly of the dimers via zinc ions coordinated by (11)EVHH(14) fragments. PMID- 25703166 TI - ONO-1301, a sustained-release prostacyclin analog, ameliorates the renal alterations in a mouse type 2 diabetes model possibly through its protective effects on mesangial cells. AB - Diabetic nephropathy is the most common pathological disorder predisposing patients to end-stage renal disease. Considering the increasing prevalence of type 2 diabetes mellitus worldwide, novel therapeutic approaches are urgently needed. ONO-1301 is a novel sustained-release prostacyclin analog that inhibits thromboxane A2 synthase. Here we examined the therapeutic effects of the intermittent administration of slow-release ONO-1301 (SR-ONO) on diabetic nephropathy in obese type 2 diabetes mice, as well as its direct effects on mesangial cells. The subcutaneous injection of SR-ONO (3mg/kg) every 3 wks did not affect the obesity or hyperglycemia in the db/db obese mice used as a model of type 2 diabetes, but it significantly ameliorated their albuminuria, glomerular hypertrophy, glomerular accumulation of type IV collagen, and monocyte/macrophage infiltration, and also the increase of TGF-beta1, alpha smooth muscle actin (alpha-SMA) and MCP-1 compared to vehicle treatment. In cultured mouse mesangial cells, ONO-1301 concentration-dependently suppressed the increases in TGF-beta, type IV collagen, alpha-SMA, MCP-1 and fibronectin induced by high ambient glucose, at least partly through prostacyclin (PGI2) receptor mediated signaling. Taken together, these results suggest the potential therapeutic efficacy of the intermittent administration of SR-ONO against type 2 diabetic nephropathy, possibly through protective effects on mesangial cells. PMID- 25703167 TI - Assessment of melanoma-initiating cell markers and conventional parameters in sentinel lymph nodes of malignant melanoma. AB - Sentinel lymph node (SLN) biopsies have widely been used for the detection of occult LN metastasis of malignant melanoma (MM). In addition to conventional biomarkers, we assessed the diagnostic and prognostic significance of melanoma initiating cell (MIC) markers in SLNs of MM. We examined the expressions of gp100, MART-1 and tyrosinase mRNA for routine diagnosis and those of ABCB5, CD133, nestin, KDM5B, NGFR and RANK mRNA as MIC markers. The presence of micrometastasis was confirmed immunohistochemically using antibodies to S-100, HMB-45, MART-1, and tyrosinase. Discordance between immunohistochemical and molecular data was observed in 14 of 70 (20.0%) patients, among whom five (7.1%) were positive for only molecular markers;two of these five patients tested positive for micrometastasis by repeated immunohistochemical stainings. The quantitative expression levels of gp100, MART-1, and tyrosinase mRNA were significantly higher in the metastatic LNs;the cut-off values remain to be elucidated. ABCB5 mRNA expression was detected more frequently in the metastatic SLNs (p<0.05) and in the group of patients with recurrence. To make a definite diagnosis of metastasis, we still need a combination of immunohistochemical and molecular probes. ABCB5 might be a suitable molecular marker for the detection of melanoma-initiating cells in SLNs. PMID- 25703168 TI - MRI of rheumatoid arthritis:comparing the outcome measures in rheumatology clinical trials (OMERACT) scoring and volume of synovitis for the assessment of biologic therapy. AB - The outcome measures in rheumatology clinical trials (OMERACT) scores are the most mature quantitation system for rheumatoid arthritis (RA) on magnetic resonance imaging (MRI). Direct measuring techniques of synovial volume have been reported with good reproducibility, although few reports have demonstrated the changes of these measures in response to treatment. To assess these clinical responses, we evaluated the correlation of the changes of clinical activity score 28-joints disease activity score (DAS28-CRP) with the changes of OMERACT scores and with synovial volume measurements. Eight RA patients who were treated by biologic agents were examined with MRI of the dominant affected wrist and finger joints before and one year after the treatment. The total OMERACT score was reduced from 48.0 to 41.3, and synovial volume was reduced from 15.4 to 8.8 milliliters. Positive correlations were seen between the changes of DAS28-CRP and the changes of OMERACT synovitis score (r=0.27), OMERACT total score (r=0.43) and synovial volume (r=0.30). Limited to synovium assessment, synovial volume showed a better correlation with DAS28-CRP than the OMERACT synovitis score. On the other hand, the OMERACT total score showed a higher correlation with DAS28-CRP than synovial volume, probably because the OMERACT total score includes scores for bone erosion and bone edema as well. PMID- 25703169 TI - Magnified endoscopic features of duodenal follicular lymphoma and other whitish lesions. AB - The sensitivity and specificity of magnified endoscopic features for differentiating follicular lymphoma from other diseases with duodenal whitish lesions have never been investigated. Here we compared the magnified endoscopic features of duodenal follicular lymphoma with those of other whitish lesions. We retrospectively reviewed the cases of patients with follicular lymphoma (n=9), lymphangiectasia (n=7), adenoma (n=10), duodenitis (n=4), erosion (n=1), lymphangioma (n=1), and hyperplastic polyp (n=1). The magnified features of the nine follicular lymphomas included enlarged villi (n=8), dilated microvessels (n=5), and opaque white spots of various sizes (n=9). The lymphangiectasias showed enlarged villi, dilated microvessels, and white spots, but the sizes of the white spots were relatively homogeneous and their margin was clear. Observation of the adenoma and duodenitis revealed only whitish villi. Although the lymphangioma was indistinguishable from the follicular lymphomas by magnified features, it was easily diagnosed based on the macroscopic morphology. In conclusion, magnified endoscopic features, in combination with macroscopic features, are useful for differentiating follicular lymphomas from other duodenal diseases presenting whitish lesions. PMID- 25703170 TI - Comparison of urinary levels of 8-hydroxy-2'-deoxyguanosine between young females with and without depressive symptoms during different menstrual phases. AB - This study aimed to clarify the association between depressive symptoms and a marker of oxidative stress-induced DNA damage in young females. Since the menstrual cycle may confound or modify this association, depressive symptoms and urinary levels of 8-hydroxy-2' deoxyguanosine (8-OHdG) were evaluated during each menstrual phase. A total of 57 female fourth-year students (aged 21.6+/-0.8) from a Japanese health science university were studied. The menstrual cycle was divided into 3 phases:menstrual (days 1 to 3 after the onset of menses);proliferative (days 13 to 15);and secretory (days 24 to 26). Depressive symptoms were assessed by the self-rating depression scale (SDS). Positive depressive symptoms were defined as a score of 53 or more during 2 different menstrual phases. The association between the presence of depressive symptoms and 8-OHdG levels adjusting for the menstrual cycle was examined by two-way analysis of variance with the menstrual cycle (menstrual, proliferative, and secretory phases) as the within-individual factor. The menstrual cycle did not show a significant correlation with urinary 8-OHdG levels. On the other hand, the menstrual cycle-adjusted 8-OHdG level was significantly higher in those with depressive symptoms (7.01ng/mL) than in those without them (3.98ng/mL). The ROC curve analysis showed that urinary 8-OHdG levels had reasonably high discriminative performance throughout all the menstrual cycles (0.73-0.81;all p<0.05). These results indicated the presence of oxidative stress in subjects with depressive symptoms independent of the menstrual cycle. PMID- 25703171 TI - Trend of human papillomavirus genotypes in cervical neoplasia observed in a newly developing township in Yangon, Myanmar. AB - Persistent infection with oncogenic types of human papillomavirus (HPV) is the most important risk factor associated with cervical cancer. This study detected the oncogenic HPV genotypes in cervical neoplasia in relation to clinicopathological findings using a cross-sectional descriptive method in 2011 and 2012. Cervical swabs and colposcopy-directed cervical biopsy tissues were collected from 108 women (median age 45 years;range 20-78) showing cervical cytological changes at Sanpya General Hospital, Yangon, Myanmar. HPV DNA testing and genotyping were performed by polymerase chain reaction and restriction fragment length polymorphism. HPV was identified in women with cervical intraepithelial neoplasia (CIN) 1 (44.4%), CIN2 (63.2%), CIN3 (70.6%), and squamous cell carcinoma (SCC) (74.1%). The association between cervical neoplasia and HPV positivity was highly significant (p=0.008). Most patients infected with HPV were between 40-49 years of age, and the youngest were in the 20- to 29-year old age group. The most common genotype was HPV 16 (65.6%) with the following distribution:70% in CIN1, 41.7% in CIN2, 91.7% in CIN3, and 60% in SCC. HPV-31 was the second-most frequent (21.9%):30% in CIN1, 33.3% in CIN2, 8.3% in CIN3, and 15% in SCC. The third-most frequent-genotype was HPV-18 (7.8%):8.3% in CIN1, and 20% in SCC. Another genotype was HPV-58 (4.7%):16.7% in CIN1 and 5% in SCC. The majority of CIN/SCC cases were associated with HPV genotypes 16, 31, 18, and 58. If oncogenic HPV genotypes are positive, the possibility of cervical neoplasia can be predicted. Knowledge of the HPV genotypes distribution can predict the effectiveness of the currently used HPV vaccine. PMID- 25703172 TI - A case of incomplete atypical femoral fracture with histomorphometrical evidence of osteomalacia. AB - Roughly half of the femoral fracture patients diagnosed with AFF according to the criteria suggested by a task force of the American Society for Bone and Mineral Research (ASBMR) have not undergone bisphosphonate (BP) therapy. One suspected cause of such fractures is severe bone loss due to osteomalacia, but the pathogenesis remains unknown. We report a case of an 84-year-old woman with AFF not treated by BP therapy, in whom underlying osteomalacia was histologically diagnosed. The involvement of femoral curvature and spino-pelvic malaligment in the fracture in the present case was considered. PMID- 25703173 TI - A rare case of inflammatory myofibroblastic tumor of the diaphragmatic parietal pleura with dissemination. AB - Inflammatory myofibroblastic tumor (IMT) is a rare neoplasm that occurs at different sites in the body. Pleural IMT in particular is especially rare. IMTs infrequently tend to have malignancy. We report a rare case of advanced diaphragmatic parietal pleural IMT with dissemination. A 30-year-old woman complained of right upper abdominal pain. Computed tomography showed a large lobulated mass over the right diaphragm, but no disseminated nodules were noted. Intraoperatively, we found the primary tumor arising from the diaphragmatic parietal pleura and a dozen disseminated nodules, and we removed them completely. The histopathological and immunohistochemical diagnosis was IMT. PMID- 25703174 TI - Sleep impairment and insomnia in sickle cell disease: a retrospective chart review of clinical and psychological indicators. AB - PURPOSE: To examine clinical and psychological indicators associated with sleeplessness and insomnia in adult patients with sickle cell. DATA SOURCES: PubMed, Scopus, Cochrane Library. Data were collected from adult sickle cell participants (N = 72) in outpatient clinics at a Midwest National Cancer Institute designated comprehensive cancer center. A retrospective chart review observed for clinical and psychological indicators associated with sleeplessness and insomnia. CONCLUSIONS: Findings included that adults with sickle cell experienced insomnia (47%) and sleep impairment (15%). Significant associations existed between pain and sleep impairment (p = .00), insomnia and pain (p = .00), morning hours of sleep (p = .00), and evening hours (p = .00). Pain may contribute to insomnia or interrupt sleep; daytime sleeping was not conducive to nighttime sleep. Anxiolytics, antidepressants, and long-acting opioids were not associated with insomnia (p = .00, p = .43, and p = .10), respectively; reduction in anxiety may reduce insomnia. Long-acting opioids may provide for improved pain control sleep. IMPLICATIONS FOR PRACTICE: Healthcare providers play a pivotal role in the assessment of sleep impairment or disorders. Effective management is necessary for improved quality of life. Further investigation is warranted to understand the meaning of sleep impairment in adult patients with sickle cell with prospective controlled studies to examine the efficacy of interventions. PMID- 25703175 TI - Effects of titanium dioxide nanoparticles on lead bioconcentration and toxicity on thyroid endocrine system and neuronal development in zebrafish larvae. AB - Nanoparticles (NPs) have attracted considerable attention because of their wide range of applications. Interactions between heavy metals (e.g., Pb) and NPs in aquatic environments may modify the bioavailability and toxicity of heavy metals. Therefore, this study investigated the influence of NPs (e.g., nano-TiO2) on the bioavailability and toxicity of Pb and its effects in the thyroid endocrine and nervous systems of zebrafish (Danio rerio) larvae. Zebrafish embryos (2-h post fertilization) were exposed to five concentrations of Pb alone (0, 5, 10, 20, and 30MUg/L) or in combination with nano-TiO2 (0.1mg/L) until 6 days post fertilization. Results showed that the bioconcentration of Pb was significantly enhanced when combined with nano-TiO2 than when used alone. Zebrafish exposure to Pb alone at 30MUg/L significantly decreased the thyroid hormone levels (T4 and T3), whereas nano-TiO2 treatment alone did not produce detectable changes. The levels of T4 and T3 were further decreased when Pb was combined with nano-TiO2 than when used alone. The transcription of the thyroid hormone-related factor tg gene was remarkably down-regulated by Pb treatment alone but up-regulated when Pb was combined with nano-TiO2. The significant up-regulation of tshbeta gene and the down-regulation of TTR gene expression in the hypothalamic-pituitary-thyroid were observed in Pb with or without nano-TiO2 treatment groups. In addition, the transcription of genes involved in central nervous system (CNS) development (alpha-tubulin, mbp, gfap and shha) were significantly down-regulated by Pb and nano-TiO2 co-exposure as compared with Pb exposure alone. The locomotion activity analyzes confirmed that nano-TiO2 might enhance the toxicity of Pb to CNS development. These results suggest that nano-TiO2 increase bioconcentration of lead, which lead to the disruption of thyroid endocrine and neuronal system in zebrafish larvae. PMID- 25703176 TI - Mixture effects of levonorgestrel and ethinylestradiol: estrogenic biomarkers and hormone receptor mRNA expression during sexual programming. AB - Synthetic progesterone (progestins) and estrogens are widely used pharmaceuticals. Given that their simultaneous unintentional exposure occurs in wildlife and also in human infants, data on mixture effects of combined exposures to these hormones during development is needed. Using the Xenopus (Silurana) tropicalis test system we investigated mixture effects of levonorgestrel (LNG) and ethinylestradiol (EE2) on hormone sensitive endpoints. After larval exposure to LNG (0.1nM), or EE2 (0.1nM) singly, or in combination with LNG (0.01, 0.1, 1.0nM), the gonadal sex ratio was determined histologically and hepatic mRNA levels of genes encoding vitellogenin (vtg beta1) and the estrogen (esr1, esr2), progesterone (ipgr) and androgen (ar) receptors were quantified using quantitative PCR. All EE2-exposed groups showed female-biased sex ratios and increased vtg beta1 mRNA levels compared with the controls. Compared with the EE2 alone group (positive control) there were no significant alterations in vtg beta1 levels or in sex ratios in the co-exposure groups. Exposure to LNG-alone caused an increase in ar mRNA levels in females, but not in males, compared to the controls and the co-exposed groups, indicating that co-exposure to EE2 counteracted the LNG-induced ar levels. No treatment related impacts on the mRNA expression of esr1, esr2, and ipgr in female tadpoles were found, suggesting that these endpoints are insensitive to long-term exposure to estrogen or progestin. Due to the EE2-induced female-biased sex ratios, the mRNA expression data for the low number of males in the EE2-exposed groups were not statistically analyzed. In conclusion, our results suggest that induced vtg expression is a robust biomarker for estrogenic activity in exposure scenarios involving both estrogens and progestins. Developmental exposure to LNG caused an induction of hepatic ar mRNA expression that was antagonized by combined exposure to EE2 and LNG. To our knowledge this is the first study to report effects of combined exposures to EE2 and LNG during the period of sexual programming. PMID- 25703177 TI - Combined toxicity of two crystalline phases (anatase and rutile) of Titania nanoparticles towards freshwater microalgae: Chlorella sp. AB - In view of the increasing usage of anatase and rutile crystalline phases of titania NPs in the consumer products, their entry into the aquatic environment may pose a serious risk to the ecosystem. In the present study, the possible toxic impact of anatase and rutile nanoparticles (individually and in binary mixture) was investigated using freshwater microalgae, Chlorella sp. at low exposure concentrations (0.25, 0.5 and 1mg/L) in freshwater medium under UV irradiation. Reduction of cell viability as well as a reduction in chlorophyll content were observed due to the presence of NPs. An antagonistic effect was noted at certain concentrations of binary mixture such as (0.25, 0.25), (0.25, 0.5), and (0.5, 0.5) mg/L, and an additive effect for the other combinations, (0.25, 1), (0.5, 0.25), (0.5, 1), (1, 0.25), (1, 0.5), and (1, 1) mg/L. The hydrodynamic size analyses in the test medium revealed that rutile NPs were more stable in lake water than the anatase and binary mixtures [at 6h, the sizes of anatase (1mg/L), rutile NPs (1mg/L), and binary mixture (1, 1mg/L) were 948.83+/ 35.01nm, 555.74+/-19.93nm, and 1620.24+/-237.87nm, respectively]. The generation of oxidative stress was found to be strongly dependent on the crystallinity of the nanoparticles. The transmission electron microscopic images revealed damages in the nucleus and cell membrane of algal cells due to the interaction of anatase NPs, whereas rutile NPs were found to cause chloroplast and internal organelle damages. Mis-shaped chloroplasts, lack of nucleus, and starch-pyrenoid complex were noted in binary-treated cells. The findings from the current study may facilitate the environmental risk assessment of titania NPs in an aquatic ecosystem. PMID- 25703178 TI - Medicare's intensive behavioral therapy for obesity: an exploratory cost effectiveness analysis. AB - INTRODUCTION: Medicare coverage recently was expanded to include intensive behavioral therapy for obese individuals in primary care settings. PURPOSE: To examine the potential cost effectiveness of Medicare's intensive behavioral therapy for obesity, accounting for uncertainty in effectiveness and utilization. METHODS: A Markov simulation model of type 2 diabetes was used to estimate long term health benefits and healthcare system costs of intensive behavioral therapy for obesity in the Medicare population without diabetes relative to an alternative of usual care. Cohort statistics were based on the 2005-2008 National Health and Nutrition Examination Survey. Model parameters were derived from the literature. Analyses were conducted in 2014 and reported in 2012 U.S. dollars. RESULTS: Based on assumptions for the maximal intervention effectiveness, intensive behavioral therapy is likely to be cost saving if costs per session equal the current reimbursement rate ($25.19) and will provide a cost effectiveness ratio of $20,912 per quality-adjusted life-year if costs equal the rate for routine office visits. The intervention is less cost effective if it is less effective in primary care settings or if fewer intervention sessions are supplied by providers or used by participants. CONCLUSIONS: If the effectiveness of the intervention is similar to lifestyle interventions tested in other settings and costs per session equal the current reimbursement rate, intensive behavioral therapy for obesity offers good value. However, intervention effectiveness and the pattern of implementation and utilization strongly influence cost effectiveness. Given uncertainty regarding these factors, additional data might be collected to validate the modeling results. PMID- 25703179 TI - Metal-organic framework templated synthesis of ultrathin, well-aligned metallic nanowires. AB - With well-defined porous structures and dimensions, metal-organic frameworks (MOFs) can function as versatile templates for the growth of metallic nanostructures with precisely controlled shapes and sizes. Using MOFs as templates, metallic nanostructures can be grown without the need of bulky surfactants and thus preserve their intrinsic surface. Additionally, the high surface area of MOFs can also ensure that the surface of the template metallic nanostructures is readily accessible, which is critical for the proper function of catalysts or sensors. The hybrid metal@MOF structures have been demonstrated to exhibit useful properties not found in either component separately. Here we report the growth of ultrafine metallic nanowires inside one-dimensional MOF pores with well-controlled shape and size. Our study shows that solvent selection plays an important role in controlling precursor loading and the reduction rate inside the MOF pores for the formation of the nanowires. The growth of the well aligned, ultrathin nanowires was monitored and characterized by transmission electron microscopy, X-ray diffraction, UV-vis spectroscopy, fluorescence studies, and Brunauer-Emmet-Teller surface area analysis. PMID- 25703181 TI - Allergic disorders and socio-economic status: a study of schoolchildren in an urban area of Makassar, Indonesia. AB - BACKGROUND: In urban centres of developing countries, there is great variation in socio-economic status (SES) and lifestyle; however, little information is available on allergic disorders in groups with high- or low-SES within the same urban area. OBJECTIVE: To determine the prevalence of allergic disorders and investigate risk factors related to them among high- and low-SES schoolchildren in Makassar, the capital city of South Sulawesi, Indonesia. METHOD: This cross sectional study was performed in 623 children originating from high- (N = 349) and low-SES (N = 274) schools. Information on reported allergic symptoms and potential factors associated with allergic disorders was obtained by questionnaire. Specific IgE and skin prick test (SPT) reactivity were determined against aeroallergens [Dermatophagoides pteronyssinus (HDM) and cockroach]. Total IgE and helminth infections were also assessed. RESULT: The prevalence of SPT to any aeroallergens was significantly higher in high-SES than in low-SES school (25% vs. 8%, P < 0.001, respectively). However, specific IgE against cockroach and total IgE were significantly lower in high- than in low-SES children. Allergic symptoms were reported more often in low- compared to high-SES children. Specific IgE to aeroallergens significantly increased the risk of SPT positivity to the same aeroallergen in the high-, but not in the low-SES children. In the high- but not in low-SES, there was a significant positive association between SPT to HDM and wheeze. Similarly, cockroach skin reactivity and elevated BMI increased the risk of eczema in the high-SES children only. CONCLUSION AND CLINICAL RELEVANCE: Skin prick test is higher in high-SES, whereas IgE and allergic symptoms are higher in low-SES children. Specific IgE is a risk factor for being SPT-positive, and SPT positivity is a risk factor for allergic symptoms but only in children of high- and not low-SES school. Therefore, the socio economic status of a child might affect the diagnosis of allergic disease in a developing country. PMID- 25703182 TI - Event-related potentials to acoustic startle probes during the anticipation of predictable and unpredictable threat. AB - The startle reflex is a robust measure of defense system activation. Startle probes also elicit ERP P300 and N100 responses that capture attentional engagement. The startle probe-elicited P300 and N100 have been primarily examined during affective picture viewing paradigms, and no study has examined these measures in the context of a threat anticipation task or in relation to threat predictability. In the present study, 131 participants completed a no (N), predictable (P), and unpredictable (U) threat-of-shock task, and the startle eye blink reflex, P300, and N100 responses to the startle probe were measured. We also examined several psychometric properties of these psychophysiological measures. Results indicated probe P300 attenuation during the P and U relative to N condition. In contrast, probe N100 enhancement was present only for the U condition. The P300 and N100 decreased (i.e., habituated) at comparable rates across the different threat conditions. The startle reflex also decreased, but only startle during the U (and not P) condition continued to differ from the N condition by the end of the task. Internal consistency of the ERP measures was acceptable and comparable to the startle reflex. Finally, the startle reflex was correlated with the probe N100, but not P300, across threat conditions. This study is one of the first to use startle probe ERPs to demonstrate that a context of potential threat also elicits attentional engagement. Furthermore, this study provides novel evidence that the probe N100 may provide a measure that is uniquely sensitive to unpredictable threat. PMID- 25703183 TI - Wii Fit exer-game training improves sensory weighting and dynamic balance in healthy young adults. AB - The Nintendo Wii Fit is a balance training tool that is growing in popularity due to its ease of access and cost-effectiveness. While considerable evidence now exists demonstrating the efficacy of the Wii Fit, no study to date has determined the specific mechanism underlying Wii Fit balance improvement. This paucity of knowledge was addressed in the present study using the NeuroCom Balance Manager's Sensory Organization Test (SOT) and Limits of Stability (LOS) test. These well recognized posturography assessments, respectively, measure sensory weighting and dynamic stability mechanisms of balance. Forty healthy, young participants were recruited into two groups: Wii Fit Balance Intervention (WFBI) (n=20) and Control (CON) (n=20). Balance training consisted of seven Wii Fit exer-games played over the course of six consecutive weeks (2-4*/week, 30-45min/day). The WFBI group performed Neurocom testing before and after the intervention, while the CON group was tested along a similar timeline with no intervention. Mixed-design ANOVAs found significant interactions for testing time point and condition 5 of the SOT (p<0.02), endpoint excursion (p<0.01), movement velocity (p<0.02), and response time (p<0.01). These effects were such that greater improvements were seen for the WFBI group following Wii Fit training. These findings suggest that individuals with known issues regarding the processing of multiple sources of sensory information and/or who have limited functional bases of support may benefit most from Wii Fit balance training. PMID- 25703184 TI - Information about oral cancer on the Internet: our patients cannot understand it. AB - Although information about cancer on the Internet can be beneficial to patients and physicians, to our knowledge, comprehension by patients has not been investigated. We used 3 search engines to select websites on oral cancer then assessed their readability using the Flesch-Kinkaid Reading Grade Level, Flesch Reading Ease Score, Gunning Fog Index, Coleman-Liau Index, Automated Readability Index, and the Simple Measure of Gobbledygook Index (SMOG). The mean scores for readability were within the range of "difficult to read" (FRES=36.04 (14.87)) with high educational requirements (FKRGL=11.44 (3.27)). This could hamper comprehension and is particularly worrying given the high percentage of people who have poor levels of literacy. PMID- 25703185 TI - Impact of dietary deviation on disease progression and gut microbiome composition in lupus-prone SNF1 mice. AB - Environmental factors, including microbes and diet, play a key role in initiating autoimmunity in genetically predisposed individuals. However, the influence of gut microflora in the initiation and progression of systemic lupus erythematosus (SLE) is not well understood. In this study, we have examined the impact of drinking water pH on immune response, disease incidence and gut microbiome in a spontaneous mouse model of SLE. Our results show that (SWR * NZB) F1 (SNF1 ) mice that were given acidic pH water (AW) developed nephritis at a slower pace compared to those on neutral pH water (NW). Immunological analyses revealed that the NW-recipient mice carry relatively higher levels of circulating autoantibodies against nuclear antigen (nAg) as well as plasma cells. Importantly, 16S rRNA gene-targeted sequencing revealed that the composition of gut microbiome is significantly different between NW and AW groups of mice. In addition, analysis of cytokine and transcription factor expression revealed that immune response in the gut mucosa of NW recipient mice is dominated by T helper type 17 (Th17) and Th9-associated factors. Segmented filamentous bacteria (SFB) promote a Th17 response and autoimmunity in mouse models of arthritis and multiple sclerosis. Interestingly, however, not only was SFB colonization unaffected by the pH of drinking water, but also SFB failed to cause a profound increase in Th17 response and had no significant effect on lupus incidence. Overall, these observations show that simple dietary deviations such as the pH of drinking water can influence lupus incidence and affect the composition of gut microbiome. PMID- 25703186 TI - Transport of bromide and pesticides through an undisturbed soil column: a modeling study with global optimization analysis. AB - The fate of pesticides in tropical soils is still not understood as well as it is for soils in temperate regions. In this study, water flow and transport of bromide tracer and five pesticides (atrazine, imazaquin, sulfometuron methyl, S metolachlor, and imidacloprid) through an undisturbed soil column of tropical Oxisol were analyzed using a one-dimensional numerical model. The numerical model is based on Richards' equation for solving water flow, and the advection dispersion equation for solving solute transport. Data from a laboratory column leaching experiment were used in the uncertainty analysis using a global optimization methodology to evaluate the model's sensitivity to transport parameters. All pesticides were found to be relatively mobile (sorption distribution coefficients lower than 2 cm(3) g(-1)). Experimental data indicated significant non-conservative behavior of bromide tracer. All pesticides, with the exception of imidacloprid, were found less persistent (degradation half-lives smaller than 45 days). Three of the five pesticides (atrazine, sulfometuron methyl, and S-metolachlor) were better described by the linear kinetic sorption model, while the breakthrough curves of imazaquin and imidacloprid were more appropriately approximated using nonlinear instantaneous sorption. Sensitivity analysis suggested that the model is most sensitive to sorption distribution coefficient. The prediction limits contained most of the measured points of the experimental breakthrough curves, indicating adequate model concept and model structure for the description of transport processes in the soil column under study. Uncertainty analysis using a physically-based Monte Carlo modeling of pesticide fate and transport provides useful information for the evaluation of chemical leaching in Hawaii soils. PMID- 25703187 TI - Timing of presentation and nature of stimuli determine retroactive interference with social recognition memory in mice. AB - The present study was designed to further investigate the nature of stimuli and the timing of their presentation, which can induce retroactive interference with social recognition memory in mice. In accordance with our previous observations, confrontation with an unfamiliar conspecific juvenile 3h and 6h, but not 22 h, after the initial learning session resulted in retroactive interference. The same effect was observed with the exposure to both enantiomers of the monomolecular odour carvone, and with a novel object. Exposure to a loud tone (12 KHz, 90 dB) caused retroactive interference at 6h, but not 3h and 22 h, after sampling. Our data show that retroactive interference of social recognition memory can be induced by exposing the experimental subjects to the defined stimuli presented <22 h after learning in their home cage. The distinct interference triggered by the tone presentation at 6h after sampling may be linked to the intrinsic aversiveness of the loud tone and suggests that at this time point memory consolidation is particularly sensitive to stress. PMID- 25703188 TI - The comparison question polygraph test: a contrast of methods and scoring. AB - We conducted a mock crime experiment with 250 paid participants (126 females, Mdn age = 30 years) contrasting the validity of the probable-lie and the directed-lie variants of the comparison question test (CQT) for the detection of deception. Subjects were assigned at random to one of eight conditions in a Guilt (Guilty/Innocent) * Test Type (Probable-Lie/Directed-Lie) * Stimulation (Between Repetition Stimulation/No Stimulation) factorial design. The data were scored by an experienced polygraph examiner who was unaware of subject assignment to conditions and with a computer algorithm known as the Objective Scoring System Version 2 (OSS2). There were substantial main effects of guilt in both the OSS2 computer scores F(1, 241) = 143.82, p < .001, eta(p)(2) = 0.371, and in the human scoring, F(1, 242) = 98.92, p<.001, eta(p)(2) = .29. There were no differences between the test types in the number of spontaneous countermeasure attempts made against them. Although under the controlled conditions of an experiment the probable-lie and the directed-lie variants of the CQT produced equivocal results in terms of detection accuracy, the directed-lie variant has much to recommend it as it is inherently more standardized in its administration and construction. PMID- 25703190 TI - Acceptability and preferences for vaginal dosage forms intended for prevention of HIV or HIV and pregnancy. AB - This paper reviews key issues found to affect acceptability and preferences for vaginal products to prevent HIV infection or HIV and pregnancy. We focus on the interplay between the biological and physico-chemical aspects of formulation and the social and behavioral issues that may affect use. The need for an HIV prevention product that women can use is driven by women's increased biological and social vulnerability to HIV infection, and thus social and behavioral research on microbicide acceptability has been conducted alongside, as well as separate from, the earliest product development efforts. Some acceptability and preference issues are specific to a product's dosage form, use-requirements, and/or use indications, while others pertain to any vaginal product used for prevention of HIV or pregnancy. Although most of the work cited here was published since 2010, it draws on a much longer trajectory of research. PMID- 25703189 TI - The neonatal Fc receptor, FcRn, as a target for drug delivery and therapy. AB - Immunoglobulin G (IgG)-based drugs are arguably the most successful class of protein therapeutics due in part to their remarkably long blood circulation. This arises from IgG interaction with the neonatal Fc receptor, FcRn. FcRn is the central regulator of IgG and albumin homeostasis throughout life and is increasingly being recognized as an important player in autoimmune disease, mucosal immunity, and tumor immune surveillance. Various engineering approaches that hijack or disrupt the FcRn-mediated transport pathway have been devised to develop long-lasting and non-invasive protein therapeutics, protein subunit vaccines, and therapeutics for treatment of autoimmune and infectious disease. In this review, we highlight the diverse biological functions of FcRn, emerging therapeutic opportunities, as well as the associated challenges of targeting FcRn for drug delivery and disease therapy. PMID- 25703191 TI - Glycemic control, inflammation, and cognitive function in older patients with type 2 diabetes. AB - OBJECTIVE: Glycated hemoglobin (HbA1c) and C-reactive protein (CRP) have been associated with cognitive impairment independently. However, it is unclear if their combination exacerbates poor cognitive function. We assessed whether long term glycemic level and glycemic variability modulate the association of systemic inflammation with cognitive function, in a sample of cognitively normal older people with type 2 diabetes. METHODS: A retrospective cohort study of 777 randomly selected participants from ~11,000 patients in the Maccabi Healthcare Services Diabetes Registry, as part of the Israel Diabetes and Cognitive Decline study. Subjects averaged 18 (+/-9.4) HbA1c measures in the Maccabi Healthcare Services Registry, which were used to calculate long-term glycemic level (HbA1c mean) and glycemic variability (HbA1c-standard deviation (SD)). Linear regression models assessed the interactions of CRP, a marker of systemic inflammation, with HbA1c-mean and HbA1c-SD on subjects' performance in tests of Memory, Executive Functions, Attention, and Semantic Categorization. RESULTS: Quadratic interactions of CRP with HbA1c-SD approached significance for executive functions and overall cognition. However, after Bonferroni adjustment, none of the interactions of CRP with HbA1c were statistically significant. In partial correlations according to HbA1c-SD tertiles, CRP was weakly correlated in the middle tertile with decreased performance in the domains of semantic categorization (r = -0.166, p = 0.011), executive functions (r = -0.136, p = 0.038), and overall cognition (r = -0.157, p = 0.016). CONCLUSIONS: Glycated hemoglobin does not substantially modulate the association of CRP with cognition in a sample of cognitively normal, community dwelling older people with relatively well-managed type 2 diabetes. PMID- 25703192 TI - Cryo-focused-ion-beam applications in structural biology. AB - The ability to precisely control the preparation of biological samples for investigations by electron cryo-microscopy is becoming increasingly important for ultrastructural imaging in biology. Precision machining instruments such as the focused ion beam microscope (FIB) were originally developed for applications in materials science. However, today we witness a growing use of these tools in the life sciences mainly due to their versatility, since they can be used both as manipulation and as imaging devices, when complemented with a scanning electron microscope (SEM). The advent of cryo-preparation equipment and accessories made it possible to pursue work on frozen-hydrated biological specimens with these two beam (FIB/SEM) instruments. In structural biology, the cryo-FIB can be used to site-specifically thin vitrified specimens for transmission electron microscopy (TEM) and tomography. Having control over the specimen thickness is a decisive factor for TEM imaging, as the thickness of the object under scrutiny determines the attainable resolution. Besides its use for TEM preparation, the FIB/SEM microscope can be additionally used to obtain three-dimensional volumetric data from biological specimens. The unique combination of an imaging and precision manipulation tool allows sequentially removing material with the ion beam and imaging the milled block faces by scanning with the electron beam, an approach known as FIB/SEM tomography. This review covers both fields of cryo-FIB applications: specimen preparation for TEM cryo-tomography and volume imaging by cryo-FIB/SEM tomography. PMID- 25703194 TI - The potato carotenoid cleavage dioxygenase 4 catalyzes a single cleavage of beta ionone ring-containing carotenes and non-epoxidated xanthophylls. AB - Down-regulation of the potato carotenoid cleavage dioxygenase 4 (StCCD4) transcript level led to tubers with altered morphology and sprouting activity, which also accumulated higher levels of violaxanthin and lutein leading to elevated carotenoid amounts. This phenotype indicates a role of this enzyme in tuber development, which may be exerted by a cleavage product. In this work, we investigated the enzymatic activity of StCCD4, by expressing the corresponding cDNA in carotenoid accumulating Escherichia coli strains and by performing in vitro assays with heterologously expressed enzyme. StCCD4 catalyzed the cleavage of all-trans-beta-carotene at the C9'-C10' double bond, leading to beta-ionone and all-trans-beta-apo-10'-carotenal, both in vivo and in vitro. The enzyme also cleaved beta,beta-cryptoxanthin, zeaxanthin and lutein either at the C9'-C10' or the C9-C10 double bond in vitro. In contrast, we did not observe any conversion of violaxanthin and only traces of activity with 9-cis-beta-carotene, which led to 9-cis-beta-apo-10'-carotenal. Our data indicate that all-trans-beta-carotene is the likely substrate of StCCD4 in planta, and that this carotene may be precursor of an unknown compound involved in tuber development. PMID- 25703193 TI - Cytochrome P450 1B1: An unexpected modulator of liver fatty acid homeostasis. AB - Cytochrome P450 1b1 (Cyp1b1) expression is absent in mouse hepatocytes, but present in liver endothelia and activated stellate cells. Increased expression during adipogenesis suggests a role of Cyp1b1 metabolism in fatty acid homeostasis. Wild-type C57BL/6j (WT) and Cyp1b1-null (Cyp1b1-ko) mice were provided low or high fat diets (LFD and HFD, respectively). Cyp1b1-deletion suppressed HFD-induced obesity, improved glucose tolerance and prevented liver steatosis. Suppression of lipid droplets in sinusoidal hepatocytes, concomitant with enhanced glycogen granules, was a consistent feature of Cyp1b1-ko mice. Cyp1b1 deletion altered the in vivo expression of 560 liver genes, including suppression of PPARgamma, stearoyl CoA desaturase 1 (Scd1) and many genes stimulated by PPARalpha, each consistent with this switch in energy storage mechanism. Ligand activation of PPARalpha in Cyp1b1-ko mice by WY-14643 was, nevertheless, effective. Seventeen gene changes in Cyp1b1-ko mice correspond to mouse transgenic expression that attenuated diet-induced diabetes. The absence of Cyp1b1 in mouse hepatocytes indicates participation in energy homeostasis through extra-hepatocyte signaling. Extensive sexual dimorphism in hepatic gene expression suggests a developmental impact of estrogen metabolism by Cyp1b1. Suppression of Scd1 and increased leptin turnover support enhanced leptin participation from the hypothalamus. Cyp1b1-mediated effects on vascular cells may underlie these changes. PMID- 25703195 TI - Highly variable reproductive isolation among pairs of Catostomus species. AB - Hybridization between diverged taxa tests the strength of reproductive isolation and can therefore reveal mechanisms of reproductive isolation. However, it remains unclear how consistent reproductive isolation is across species' ranges and to what extent reproductive isolation might remain polymorphic as species diverge. To address these questions, we compared outcomes of hybridization across species pairs of Catostomus fishes in three rivers in the Upper Colorado River basin, where an introduced species, C. commersoni, hybridizes with at least two native species, C. discobolus and C. latipinnis. We observed substantial heterogeneity in outcomes of hybridization, both between species pairs and across geographically separate rivers within each species pair. We also observed hybridization of additional related species with our focal species, suggesting that reproductive isolation in this group involves interactions of multiple evolutionary and ecological factors. These findings suggest that a better understanding of the determinants of variation in reproductive isolation is needed and that studies of reproductive isolation in hybrids should consider how the dynamics and mechanisms of reproductive isolation vary over ecological space and over evolutionary time. Our results also have implications for the conservation and management of native catostomids in the Colorado River basin. Heterogeneity in outcomes of hybridization suggests that the threat posed by hybridization and genetic introgression to the persistence of native species probably varies with extent of reproductive isolation, both across rivers and across species pairs. PMID- 25703196 TI - Big and bigger data in endovascular stroke therapy. AB - More than 30 years after initial reports demonstrated the feasibility of intra arterial or endovascular therapies for the treatment of acute ischemic stroke, big data have finally established requisite evidence for the safety and efficacy of thrombectomy. Cautious enthusiasm for this breakthrough is tempered, as we await the bigger data of these trials to understand the constellation of variables that ensured success. Noninvasive imaging, including multimodal computed tomography and MRI as used in recent endovascular trials, has dramatically advanced since that time, providing snapshots or profiles of the collaterome in a given patient. Data-driven analyses will provide the most potent argument to distinguish comprehensive stroke centers from interventional-ready sites. These trials may provide insight on the future role of telestroke, for intravenous thrombolysis and remote imaging review of multimodal computed tomography or MRI to streamline patient transfer for endovascular therapy. Rather than concluding that recent trials have answered the most important question regarding endovascular therapy, even more data are needed to effectively translate such success and extend such potential benefit to the greatest number of stroke patients encountered on a daily basis. PMID- 25703197 TI - Fascinating hydrogen atom transfer chemistry of alkenes inspired by problems in total synthesis. PMID- 25703198 TI - Do pregnancy, postpartum period and lactation predispose to recurrent toxoplasmic retinochoroiditis? AB - BACKGROUND: The aim of the study was a statistical analysis of the possible effects of pregnancy, postpartum period, and lactation on increased risk for reactivation of toxoplasmic retinochoroiditis. MATERIAL AND METHODS: A retrospective study was undertaken of the clinical records of 661 patients referred with the diagnosis of acute toxoplasmic retinochoroiditis to the Department of Zoonoses and Tropical Diseases, Medical University of Warsaw and to the Department of Ophthalmology, Medical University of Warsaw in the years 1994 2014. This group of inpatients consisted of 213 women of child-bearing age (18 to 40 years). Reactivation of toxoplasmic retinochoroiditis was observed in 24 women aged 15 to 39 years who were pregnant, in the postpartum period, or lactating. To compare the rate of the relapses in pregnant/lactating patients vs. non pregnant/non-lactating patients, the Fisher exact test was used. Calculations were performed with WinPepi software (Abramson JH (2004) WINPEPI (PEPI-for Windows) for epidemiologists. Epidemiologic Perspectives & Innovations, 2005, 1: 6). RESULTS: A total of 28 reactivations of toxoplasmic retinochoroiditis were observed (16 episodes in pregnancy, 4 in the postpartum period, and 8 during lactation) in 24 women aged 15 to 39 years. In 3 women, multiple episodes were reported (in early pregnancy and the postpartum period in 2 women, and during 2 pregnancies and lactation in 1 woman). Statistical analysis showed that the risk of an episode of toxoplasmic retinochoroiditis is 7.4-fold higher in pregnancy compared to the non-pregnant/non-lactating women (p<0.0001). CONCLUSIONS: Women of childbearing age with toxoplasma ocular lesions should be informed by their doctors about possible active recurrences during pregnancy and should be followed carefully by an ophthalmologist when pregnant. PMID- 25703199 TI - Text mining of biomedical literature: doing well, but we could be doing better. PMID- 25703200 TI - Parabrachial Nucleus Contributions to Glucagon-Like Peptide-1 Receptor Agonist Induced Hypophagia. AB - Exendin-4 (Ex4), a glucagon-like peptide-1 receptor (GLP-1R) agonist approved to treat type 2 diabetes mellitus, is well known to induce hypophagia in human and animal models. We evaluated the contributions of the hindbrain parabrachial nucleus (PBN) to systemic Ex4-induced hypophagia, as the PBN receives gustatory and visceral afferent relays and descending input from several brain nuclei associated with feeding. Rats with ibotenic-acid lesions targeted to the lateral PBN (PBNx) and sham controls received Ex4 (1 MUg/kg) before 24 h home cage chow or 90 min 0.3 M sucrose access tests, and licking microstructure was analyzed to identify components of feeding behavior affected by Ex4. PBN lesion efficacy was confirmed using conditioned taste aversion (CTA) tests. As expected, sham control but not PBNx rats developed a CTA. In sham-lesioned rats, Ex4 reduced chow intake within 4 h of injection and sucrose intake within 90 min. PBNx rats did not show reduced chow or sucrose intake after Ex4 treatment, indicating that the PBN is necessary for Ex4 effects under the conditions tested. In sham-treated rats, Ex4 affected licking microstructure measures associated with hedonic taste evaluation, appetitive behavior, oromotor coordination, and inhibitory postingestive feedback. Licking microstructure responses in PBNx rats after Ex4 treatment were similar to sham-treated rats with the exception of inhibitory postingestive feedback measures. Together, the results suggest that the PBN critically contributes to the hypophagic effects of systemically delivered GLP-1R agonists by enhancing visceral feedback. PMID- 25703201 TI - Meatal stenosis: a retrospective analysis of over 4000 patients. AB - OBJECTIVE: The literature on treatment of meatal stenosis is limited to single center series. Controversy exists regarding choice of meatotomy versus meatoplasty and need for general anesthesia. Our objective was to analyze treatment efficacy, current practice patterns and utilization of anesthesia. We hypothesized that meatoplasty would be associated with a lower re-operative rate. STUDY DESIGN: We used a hospital consortium database to identify children who were diagnosed with meatal stenosis between January 1, 2009 and December 31, 2012. Both univariate and multivariate analyses were completed to evaluate correlations between patient, surgeon and hospital characteristics and type of procedure. The propensity of surgeons to operate with or without general anesthesia was analyzed. RESULTS: We identified 4373 male patients with a diagnosis of meatal stenosis treated by 123 surgeons. Fifty-percent of boys had procedural intervention during the 4-year period. Median follow-up was 25 and 22 months after meatotomy and meatoplasty, respectively. There was a re-operative rate of 3.5% and 0.2% for office meatotomy versus meatoplasty with general anesthesia. Multivariate analysis demonstrated that being White and living in the Northeast independently increased odds of intervention. Half of the surgeons treated meatal stenosis exclusively under general anesthesia. DISCUSSION: This study is limited by an inability to determine recurrence rates. Only patients having secondary surgery at the same institution within the time period captured by the database (6 months-4 years) could be identified. As such, the true recurrence of meatal stenosis is likely higher. Although the re-operative rate is not equivalent to the recurrence rate, the two are correlated. Likewise, the surgeon's propensity to operate could be biased by their propensity to diagnosis meatal stenosis and this could affect the rates cited. In addition to the cost benefit achieved with avoidance of general anesthesia (estimated to be a 10-fold cost reduction, the 2012 Consensus Statement of the International Anesthesia Research Society has highlighted that there is increasing evidence from research studies suggesting the benefits of general anesthesia should be considered in the context of its possible harmful effects. Although this study and others have highlighted that in-office procedures are a viable alternative to meatoplasty with general anesthesia, there are multiple factors in being able to perform an office meatotomy. Arguably, the two most important are the patient's ability to cooperate and his anatomy. CONCLUSIONS: The large sample size, over 4000 patients, allowed us to show that the hypothesis, that meatoplasty would be associated with a lower re-operative rate (0.2%), is true. With a low re operative rate (3.5%), office meatotomy is a reasonable choice of surgical treatment if the child can cooperate and the anatomy is appropriate. On the other hand, if general anesthesia is utilized, formal meatoplasty is associated with a lower re-operative rate. PMID- 25703202 TI - On the radical nature of iron-catalyzed cross-coupling reactions. AB - The radical nature of iron-catalyzed cross-coupling between Grignard reagents and alkyl halides has been studied by using a combination of competitive kinetic experiments and DFT calculations. In contrast to the corresponding coupling with aryl halides, which commences through a classical two-electron oxidative addition/reductive elimination sequence, the presented data suggest that alkyl halides react through an atom-transfer-initiated radical pathway. Furthermore, a general iodine-based quenching methodology was developed to enable the determination of highly accurate concentrations of Grignard reagents, a capability that facilitates and increases the information output of kinetic investigations based on these substrates. PMID- 25703203 TI - Investigations on atrial function in fetuses with signs of impaired placental function. AB - OBJECTIVE: Cardiac dysfunction has been shown in cases of placental insufficiency, but few reports exist on fetal atrial function. The aim of this study was to generate reference values for atrial strain and compare them to results in fetuses with signs of increased placental resistance and abnormal venous circulation. METHODS: Using a 2D speckle-tracking technique, velocity and strain of the fetal atrial walls were investigated in 250 healthy fetuses and in 40 fetuses with abnormal umbilical Doppler. Influences of gestational age, heart rate, and frame rate on the measurements were investigated and reference curves constructed. RESULTS: Strain and velocity were greater for the right atrial walls compared with the left, and velocity and strain rate increased with gestational age. Increased pulsatility of the ductus venosus and umbilical vein was not associated with altered right atrial function. CONCLUSIONS: 2D speckle-tracking analysis of fetal atrial wall movement seems to be feasible. Atrial function was preserved in fetuses with placental dysfunction, even in cases of increased venous pulsatility. PMID- 25703204 TI - Plumbonacrite identified by X-ray powder diffraction tomography as a missing link during degradation of red lead in a Van Gogh painting. AB - Red lead, a semiconductor pigment used by artists since antiquity, is known to undergo several discoloration phenomena. These transformations are either described as darkening of the pigment caused by the formation of either plattnerite (beta-PbO2) or galena (PbS) or as whitening by which red lead is converted into anglesite (PbSO4) or (hydro)cerussite (2 PbCO3?Pb(OH)2; PbCO3). X ray powder diffraction tomography, a powerful analytical method that allows visualization of the internal distribution of different crystalline compounds in complex samples, was used to investigate a microscopic paint sample from a Van Gogh painting. A very rare lead mineral, plumbonacrite (3 PbCO3?Pb(OH)2?PbO), was revealed to be present. This is the first reported occurrence of this compound in a painting dating from before the mid 20th century. It constitutes the missing link between on the one hand the photoinduced reduction of red lead and on the other hand (hydro)cerussite, and thus sheds new light on the whitening of red lead. PMID- 25703205 TI - Ultrasonographic identification of nerve pathology in neuralgic amyotrophy: Enlargement, constriction, fascicular entwinement, and torsion. AB - INTRODUCTION: The aim of this study was to characterize the ultrasonographic findings on nerves in neuralgic amyotrophy. METHODS: Fourteen patients with neuralgic amyotrophy were examined using high-resolution ultrasound. RESULTS: Four types of abnormalities were found: (1) focal or diffuse nerve/fascicle enlargement (57%); (2) incomplete nerve constriction (36%); (3) complete nerve constriction with torsion (50%; hourglass-like appearance); and (4) fascicular entwinement (28%). Torsions were confirmed intraoperatively and were seen on the radial nerve in 85% of patients. A significant correlation was found between no spontaneous recovery of nerve function and constriction/torsion/fascicular entwinement (P = 0.007). CONCLUSION: Ultrasonographic nerve pathology in neuralgic amyotrophy varies in order of severity from nerve enlargement to constriction to nerve torsion, with treatment ranging from conservative to surgical. We postulate that the constriction caused by inflammation is the precursor of torsion and that development of nerve torsion is facilitated by the rotational movements of limbs. PMID- 25703206 TI - Allostery mediates ligand binding to WWOX tumor suppressor via a conformational switch. AB - While being devoid of the ability to recognize ligands itself, the WW2 domain is believed to aid ligand binding to the WW1 domain in the context of a WW1-WW2 tandem module of WW domain-containing oxidoreductase (WWOX) tumor suppressor. In an effort to test the generality of this hypothesis, we have undertaken here a detailed biophysical analysis of the binding of WW domains of WWOX alone and in the context of the WW1-WW2 tandem module to an array of putative proline-proline x-tyrosine (PPXY) ligands. Our data show that while the WW1 domain of WWOX binds to all ligands in a physiologically relevant manner, the WW2 domain does not. Moreover, ligand binding to the WW1 domain in the context of the WW1-WW2 tandem module is two-to-three-fold stronger than when treated alone. We also provide evidence that the WW domains within the WW1-WW2 tandem module physically associate so as to adopt a fixed spatial orientation relative to each other. Of particular note is the observation that the physical association of the WW2 domain with WW1 blocks access to ligands. Consequently, ligand binding to the WW1 domain not only results in the displacement of the WW2 lid but also disrupts the physical association of WW domains in the liganded conformation. Taken together, our study underscores a key role of allosteric communication in the ability of the WW2 orphan domain to chaperone physiological action of the WW1 domain within the context of the WW1-WW2 tandem module of WWOX. PMID- 25703207 TI - [Child with genital injuries on returning from Ghana]. PMID- 25703208 TI - [Pneumococcal vaccination coverage in at-risk children in Catalonia]. AB - INTRODUCTION: The public health system in Catalonia only funds pneumococcal vaccination in paediatrics for children at-risk. The aim of this study was to determine pneumococcal vaccination coverage and its association with age, sociodemographic factors and other variables. MATERIAL AND METHOD: Descriptive cross-sectional study of children aged between 2 months and 15 years old assigned to primary care centres in Catalonia and with diseases that are included for pneumococcal vaccine in the official vaccination program. The information on vaccination status and study variables were obtained from data registered in the electronic medical records in the primary care centres. An analysis was made of the association between pneumococcal vaccination and demographic and medical variables using bivariate analysis and a multiple logistic regression model. The adjusted odds ratio (aOR), with a confidence interval of 95%, was used to measure the relationships. RESULTS: Pneumococcal vaccination coverage was 47.7%. Variables which predicted pneumococcal vaccination were: age (aOR: 9.2 [7.9-10.7] in children 2 months-2 years old; aOR 8.1 [7.0-9.3] in children 3-5 years; aOR: 4.6 [4.0-5.2] in children 6-10 years), Spanish nationality (aOR: 3.9 [3.5-4.3]), correct immunisation according to systematic immunisation schedule (aOR: 2.5 [2.1 3.0]), and number of risk conditions (aOR: 3.2 [2.5-4.1] in children with 2 or more conditions). CONCLUSIONS: Pneumococcal vaccination coverage in children with risk conditions is low in Catalonia. Strategies need to be implemented to increase coverage. PMID- 25703209 TI - [Monitoring respiratory syncytial virus through the Spanish influenza surveillance system, 2006-2014]. AB - INTRODUCTION: The aim of the study is to analyze the information on respiratory syncytial virus (RSV) obtained through the Spanish Influenza Surveillance System (SISS) and to study its usefulness as supplementary information for the characterization of influenza epidemics. METHODS: The temporal patterns of both RSV and influenza viruses were analyzed by patterns comparing the weekly viral detection rates from 2006 to 2014. RESULTS: In general, the RSV circulation was characterized by showing a peak between 52-1 weeks, and circulated from 2 to 8 weeks before/prior to influenza viruses. CONCLUSION: RSV information obtained from the SISS is useful for the characterization of influenza epidemics in Spain. PMID- 25703210 TI - [Pasteurella dagmatis bacteremia in a cirrhotic patient: Beware of contact with domestic pets]. PMID- 25703211 TI - Salmonella L-forms: formation in human bile in vitro and isolation culture from patients' gallbladder samples by a non-high osmotic isolation technique. AB - Bacterial L-forms have always been considered as osmotic-pressure-sensitive cell wall-deficient bacteria and isolation culture of L-forms must use media with high osmotic pressure. However, isolation culture of stable L-forms formed in humans and animals is very difficult because they have adapted to the physiological osmotic pressure condition of the host. We use a non-high osmotic isolation technique to isolate stable L-forms of Salmonella Typhi and Salmonella Paratyphi A from bile-inducer cultures in vitro and from patients' gallbladder specimens. Multiplex PCR assay for Salmonella-specific genes and nucleotide sequencing are used to identify the Salmonella L-forms in stable L-form isolates. Using this method, we confirmed that Salmonella Paratyphi A and Salmonella Typhi cannot be isolated from bile-inducer cultures cultured for 6 h or 48 h, but the L-forms can be isolated from 1 h to 45 days. In the 524 gallbladder samples, the positive rate for bacterial forms was 19.7% and the positive rate for Salmonella spp. was 0.6% by routine bacteriological methods. The positive rate for bacterial L-forms was 75.4% using non-high osmotic isolation culture. In the L-form isolates, the positive rate of Salmonella invA gene was 3.1%. In these invA-positive L-form isolates, four were positive for the invA and flic-d genes of Salmonella Typhi, and ten were positive for the invA and flic-a genes of Salmonella Paratyphi A. PMID- 25703213 TI - Literature survey of high-impact journals revealed reporting weaknesses in abstracts of diagnostic accuracy studies. AB - OBJECTIVES: Informative journal abstracts are crucial for the identification and initial appraisal of studies. We aimed to evaluate the informativeness of abstracts of diagnostic accuracy studies. STUDY DESIGN AND SETTING: PubMed was searched for reports of studies that had evaluated the diagnostic accuracy of a test against a clinical reference standard, published in 12 high-impact journals in 2012. Two reviewers independently evaluated the information contained in included abstracts using 21 items deemed important based on published guidance for adequate reporting and study quality assessment. RESULTS: We included 103 abstracts. Crucial information on study population, setting, patient sampling, and blinding as well as confidence intervals around accuracy estimates were reported in <50% of the abstracts. The mean number of reported items per abstract was 10.1 of 21 (standard deviation 2.2). The mean number of reported items was significantly lower for multiple-gate (case-control type) studies, in reports in specialty journals, and for studies with smaller sample sizes and lower abstract word counts. No significant differences were found between studies evaluating different types of tests. CONCLUSION: Many abstracts of diagnostic accuracy study reports in high-impact journals are insufficiently informative. Developing guidelines for such abstracts could help the transparency and completeness of reporting. PMID- 25703212 TI - Epidemiology and outcome of candidaemia in patients with oncological and haematological malignancies: results from a population-based surveillance in Spain. AB - A prospective, population-based surveillance on candidaemia was implemented in five metropolitan areas of Spain from May 2010 to April 2011. We aimed to describe the distribution and susceptibility pattern of Candida species, and to evaluate risk factors for mortality in patients with oncological (solid tumours) and haematological malignancies. Adults (>= 16 years) with cancer were included in the present report. Impact of therapeutic strategies on 7- and 30-day mortality were analysed by logistic regression, adjusting for propensity score by inverse weighting probability of receiving early antifungal treatment and catheter removal. We included 238 (32.6%) patients (195 oncological, 43 haematological). Compared with oncological patients, haematological patients were more likely to have received chemotherapy (53.5% versus 17.4%, p < 0.001) or corticosteroids (41.9% versus 21%, p < 0.001), and have neutropenia (44.2% versus 1.5%, p < 0.001). Overall, 14.8% of patients developed breakthrough candidaemia. Non-albicans Candida species (71.1% versus 55.6%, p 0.056) and Candida tropicalis (22.2% versus 7.6%, p 0.011) were more frequent in haematological patients. Based on EUCAST breakpoints, 27.6% of Candida isolates were non-susceptible to fluconazole. Resistance to echinocandins was negligible. Mortality at 7 and 30 days was 12.2% and 31.5%, respectively, and did not differ significantly between the patient groups. Prompt antifungal therapy together with catheter removal (<= 48 hours) was associated with lower mortality at 7 days (adjusted OR 0.05; 95% CI 0.01-0.42) and 30 days (adjusted OR 0.27; 95% CI 0.16-0.46). In conclusion, non albicans species are emerging as the predominant isolates, particularly in haematological patients. Prompt, adequate antifungal treatment plus catheter removal may lead to a reduction in mortality. PMID- 25703214 TI - Infectious complications following transrectal ultrasound-guided prostate biopsy: a Canadian tertiary cancer center experience. PMID- 25703215 TI - Cav1.2 of L-type Calcium Channel Is a Key Factor for the Differentiation of Dental Pulp Stem Cells. AB - INTRODUCTION: L-type calcium channel (LTCC) is a unique and important factor in several cell lineages, whereas its role in the differentiation of dental pulp stem cells (DPSCs) is not well-known. In this study, we examined the function of LTCC alpha1C subunit (Cav1.2) and its distal C-terminus (DCT) during the in vitro differentiation of rat DPSCs (rDPSCs). METHODS: After fluorescence-activated cell sorting, rDPSCs were differentiated toward dentin sialophosphoprotein-positive odontoblasts and neural cells expressing specific neuronal markers. The inhibition of rDPSC differentiation via LTCC blocker nimodipine and Cav1.2 knockdown through short hairpin RNA was evaluated by using quantitative real-time polymerase chain reaction, Western blot, and immunofluorescence staining. RESULTS: Nimodipine treatment and Cav1.2 knockdown generated similar results. The number of positive calcium nodules and the protein and mRNA levels of dentin sialophosphoprotein were significantly reduced during odontogenic differentiation. The levels of microtubule-associated protein-2 and beta-III tubulin were reduced in neural differentiation. The expression of DCT decreased after odontogenic differentiation but significantly increased after neural differentiation (P < .05, n = 9). CONCLUSIONS: Our data showed that LTCC blocker nimodipine inhibits the odontogenic and neural differentiation of rDPSCs, and Cav1.2 is responsible for the activity of LTCC. The expression of DCT of Cav1.2 significantly changes during both odontogenic and neural differentiation. Thus, Cav1.2 of LTCC plays an essential role in differentiation of DPSCs, which might be mediated through the regulation of DCT levels in DPSCs. PMID- 25703217 TI - Changing views on diverticular disease: impact of aging, obesity, diet, and microbiota. AB - The development of colonic diverticulosis is a common aging change in industrialized nations. While most patients have asymptomatic diverticulosis, around one in five develops symptomatic diverticular disease. This is characterized by recurrent abdominal pain and disturbed bowel habit. Some of the pain episodes are prolonged and are due to acute diverticulitis, which itself may be complicated by abscess, perforation, fistulation, or stricture formation. Risk factors favouring the development of symptomatic diverticular disease include obesity, smoking and diets low in fiber but high in red meat and animal fat. What determines the transition from asymptomatic diverticulosis to symptomatic diverticular disease is unclear but neuromuscular changes following acute diverticulitis may be responsible in some cases. The severity of symptoms generated depends on cerebral pain processing which is influenced by psychosocial factors. These are important considerations in deciding optimal patient management. Prior theories of the cause of diverticulosis suggested that constipation was an important cause, but new data challenge this and has provoked new ideas. Underlying mechanisms causing diverticulosis include weakening of the colonic wall and/or degenerative changes in the enteric nerves. Dietary induced changes in microbiota and the host inflammatory response may underlie the subsequent development of acute/chronic diverticulitis and its sequela. PMID- 25703218 TI - Genetic associations of CLU rs9331888 polymorphism with Alzheimer's disease: A meta-analysis. AB - Recent studies showed the Clusterin gene (CLU) is associated with Alzheimer's disease (AD). However, studies investigating the association of CLU single nucleotide polymorphism (SNP) rs9331888 with AD are controversial. We then performed a meta-analysis to assess the association between CLU SNP rs9331888 and AD. Computerized bibliographic searches of PUBMED and AlzGene database were conducted for the period up to July, 2014. The strength of the association between SNP rs9331888 and AD was estimated by odds ratios (ORs) and OR 95% confidence intervals (CIs). A total of 11 studies composed of 8766 AD cases and 11,366 controls were included in this study. Significant association of SNP rs9331888 with AD was found in Caucasian population among allelic model (C vs. G: OR=1.12, 95%CI=1.06-1.17, P<0.001), additive model (CC vs. GG: OR=1.25, 95%CI=1.12-1.40, P<0.001), recessive model (CC vs. CG+GG: OR=1.20, 95%CI=1.07 1.34, P=0.001), and dominant model (CC+CG vs. GG: OR=1.13, 95%CI=1.06-1.21, P<0.001). No significant association among these models was found in Asian and overall populations. Sensitivity analysis found that one study caused the distinct heterogeneity in Asian subgroup. Our analysis demonstrated that CLU SNP rs9331888 might be associated with an increased AD risk in Caucasian population, but not in Asian population. PMID- 25703219 TI - Functional neuroimaging of amphetamine-induced striatal neurotoxicity in the pleiotrophin knockout mouse model. AB - Amphetamine-induced neurotoxic effects have traditionally been studied using immunohistochemistry and other post-mortem techniques, which have proven invaluable for the definition of amphetamine-induced dopaminergic damage in the nigrostriatal pathway. However, these approaches are limited in that they require large numbers of animals and do not provide the temporal data that can be collected in longitudinal studies using functional neuroimaging techniques. Unfortunately, functional imaging studies in rodent models of drug-induced neurotoxicity are lacking. The aim of this study was to evaluate in vivo the changes in brain glucose metabolism caused by amphetamine in the pleiotrophin knockout mouse (PTN-/-), a genetic model with increased vulnerability to amphetamine-induced neurotoxic effects. We showed that administration of amphetamine causes a significantly greater loss of striatal tyrosine hydroxylase content in PTN-/- mice than in wild-type (WT) mice. In addition, [(18)F]-FDG-PET shows that amphetamine produces a significant decrease in glucose metabolism in the striatum and prefrontal cortex in the PTN-/- mice, compared to WT mice. These findings suggest that [(18)F]-FDG uptake measured by PET is useful for detecting amphetamine-induced changes in glucose metabolism in vivo in specific brain areas, including the striatum, a key feature of amphetamine-induced neurotoxicity. PMID- 25703220 TI - Advances in diagnostics and outcome measures in peripheral neuropathies. AB - Peripheral neuropathies are a group of acquired and hereditary disorders presenting with different distribution and nerve fiber class involvement. The overall prevalence is 2.4%, increasing to 8% in the elderly population. However, the frequency may vary depending on the underlying pathogenesis and association with systemic diseases. Distal symmetric polyneuropathy is the most common form, though multiple mononeuropathies, non-length dependent neuropathy and small fiber neuropathy can occur and may require specific diagnostic tools. The use of uniform outcome measures in peripheral neuropathies is important to improve the quality of randomized controlled trials, enabling comparison between studies. Recent developments in defining the optimal set of outcome measures in inflammatory neuropathies may serve as an example for other conditions. Diagnostic and outcome measure advances in peripheral neuropathies will be discussed. PMID- 25703221 TI - Contribution of persistent sodium currents to the excitability of tonic firing substantia gelatinosa neurons of the rat. AB - The roles of persistent Na(+) currents (INaP) in intrinsic membrane properties were examined in rat substantia gelatinosa (SG) neurons of the trigeminal subnucleus caudalis using a conventional whole-cell patch clamp technique. In a voltage-clamp mode, riluzole inhibited the slow voltage ramp-induced INaP but had little effect on the peak amplitude of transient Na(+) currents in SG neurons. In a current-clamp mode, most SG neurons exhibited spontaneous action potentials and tonic firing pattern. Riluzole reduced both spontaneous and elicited action potentials in a concentration-dependent manner. The present results suggest that the riluzole-sensitive INaP plays an important role in the excitability of SG neurons and are thus, likely to contribute to the modulation of nociceptive transmission from the orofacial tissues. PMID- 25703222 TI - Reduction of spinal PGE2 concentrations prevents swim stress-induced thermal hyperalgesia. AB - We evaluated the association between spinal PGE2 and thermal hyperalgesia following repeated stress. Thermal nociception was determined in male Sprague Dawley rats using the hot-plate test, before and after forced-swimming; non conditioned rats served as controls. Animals were pretreated with ketoprofen or meloxicam, preferential COX-1 and COX-2 inhibitors, respectively. After the second hot-plate test, we measured serum corticosterone (stress marker), and lumbar spinal PGE2 (neuroinflammation marker) under peripheral inflammation (1% formalin plantar injection). Stressed rats displayed response latencies 40% shorter and inflammatory spinal PGE2 levels 95% higher than controls. Pretreatment with ketoprofen or meloxicam prevented hyperalgesia and elevation of spinal PGE2, increasing the escape behavior time during forced swimming 95% respect to saline-treated rats. Corticosterone levels in stressed rats were 97% higher than controls; COX inhibitors reduced them by 84%. PGE2 could participate in stress-induced hyperalgesia, learned helplessness, and corticosterone production, supporting the use of non-steroidal anti-inflammatory drugs (NSAIDs) for persistent pain associated with chronic stress and depression. PMID- 25703223 TI - Differential alterations in the morphology and electrophysiology of layer II pyramidal cells in the primary visual cortex of a mouse model prenatally exposed to LPS. AB - Maternal inflammation is a known risk factor for schizophrenia and autism. Since the visual processing has shown abnormalities in these disorders, we explored whether neuropathologic changes can be caused in the primary visual cortex in offsprings due to the maternal inflammation induced by a single lipopolysaccharide (LPS) injection in pregnant mouse dams. The morphology and electrophysiological properties of layer II pyramidal cells (L2PC) in the primary visual cortex were investigated with whole-cell patch-clamping recording and 3D neuron reconstruction techniques. Although the composition of two L2PC types was unchanged, a reorganization of the dendritic architecture was found in both L2PC_A and L2PC_B types, predominantly in the L2PC_A type, of the mice prenatally exposed to LPS. Moreover, prenatal LPS exposure differentially altered intrinsic electrophysiological properties of the two L2PC types. L2PC_A neurons showed reduced excitability as featured by a hyperpolarization of the resting membrane potential, whereas L2PC_B neurons showed enhanced excitability as featured by a decrease in cellular input resistance at resting membrane potential. These significant changes in neuronal morphological and electrophysiological properties might contribute to the dysfunctions of pyramidal neurons after maternal inflammation. PMID- 25703224 TI - L-Carnosine's dose-dependent effects on muscle sympathetic nerves and blood flow. AB - L-Carnosine is synthesized in mammalian muscles and brain and affects autonomic neurotransmission and physiological phenomena. To clarify the role of l carnosine, the effects of intraduodenal administration of l-carnosine on muscle sympathetic nerve activity (muscle-SNA) and blood flow (BF) were examined. The changes in muscle-SNA and BF were examined using electrophysiological and Doppler flowmeter in urethane-anesthetized rats. The effect of propranolol, a beta adrenergic antagonist, on the increase in muscle BF due to l-carnosine was also examined. Low dose (1MUg/300g body weight [bw]) of l-carnosine increased both muscle-SNA and muscle BF, while high dese (100mg/300g bw) of l-carnosine decreased both muscle-SNA and muscle BF. Furthermore, propranolol eliminated the increase in muscle BF caused by a low dose of l-carnosine. These results suggest that l-carnosine has dose-dependent effects on muscle BF via changes in muscle SNA, and the beta-adrenergic receptor is implicated in the increase in muscle BF due to l-carnosine. PMID- 25703225 TI - Multitarget surgical neuromodulation: Combined C2 and auditory cortex implantation for tinnitus. AB - Tinnitus, as a phantom sound can express itself as a pure tone and as a noise like sound. It is notoriously difficult to treat, and in medically, psychologically and audiologically intractable tinnitus patients sometimes intracranial electrodes overlying the auditory cortex are implanted. In this case report, we describe a patient who had a complete resolution of the pure tone component of his tinnitus by an auditory cortex implant, without any beneficial effect on the noise-like aspect of his tinnitus, even after changing the stimulation design to burst stimulation, which is known to treat noise-like tinnitus better than tonic stimulation. After an initial successful treatment of his noise-like component with transcutaneus electrical nerve stimulation, a wire electrode is inserted subcutaneously and connected to his internal pulse generator. With the dual stimulation his pure tone tinnitus remains abolished after 5 years of stimulation and his noise-like tinnitus is improved by 50%, from 8/10 to 4/10. This case report suggests that multi-target stimulation might be better than single target implantation in selected cases. PMID- 25703226 TI - Near infrared light mitigates cerebellar pathology in transgenic mouse models of dementia. AB - We previously reported that Alzheimer-related pathology in cerebral cortex of APP/PS1 and K3 tau transgenic mouse strains is mitigated by near infrared light (NIr). Here, we extend these observations to the cerebellum. One month of NIr treatment mitigated the deposition of beta-amyloid in cerebellar cortex of APP/PS1 mice, and the formation of neurofibrillary tangles, the hyperphosphorylation of tau, the damage caused by oxidative stress and the downregulation of cytochrome oxidase expression by Purkinje cells in the cerebellar cortex of K3 mice. These findings show the ability of NIr to mitigate degeneration in many - probably all - regions of the mouse brain. PMID- 25703227 TI - Increased frequency of circulating regulatory T cells in patients with acute cerebral hemorrhage. AB - Cerebral hemorrhage (ICH) is a serious stroke subtype, currently lacking effective treatment. Recent research has shown that CD4(+)CD25(+)FOXP3(+) regulatory T cells (Tregs) play a key role in the immune response of ischemic stroke. However, Tregs in human hemorrhagic stroke are poorly investigated. In this study, a total of 90 ICH patients and 60 healthy controls were recruited. The frequency of circulating Tregs, plasma levels of TGF-beta and IL-10, and the severity of neural dysfunction in ICH patients were investigated at different time points post ICH. We found that the peripheral frequency of Tregs in ICH patients was significantly increased, accompanied by boosted activated T cells. Importantly, the elevation of circulating Tregs in patients with severe dysfunction was much higher than that in less-severe patients, suggesting that disease severity affects circulating Tregs to exert regulatory function. Furthermore, both TGF-beta and IL-10 that are related to the function of Tregs, were also increased in the peripheral blood of ICH patients. Our results demonstrate that Tregs-mediated immune imbalance might affect the development and severity of ICH, and suggest that Tregs may be used as tools and targets of cellular immunotherapy to effectively treat acute hemorrhagic stroke. PMID- 25703228 TI - Dynamic In-Situ Experimentation on Nanomaterials at the Atomic Scale. AB - With the development of in situ techniques inside transmission electron microscopes (TEMs), external fields and probes can be applied to the specimen. This development transforms the TEM specimen chamber into a nanolab, in which reactions, structures, and properties can be activated or altered at the nanoscale, and all processes can be simultaneously recorded in real time with atomic resolution. Consequently, the capabilities of TEM are extended beyond static structural characterization to the dynamic observation of the changes in specimen structures or properties in response to environmental stimuli. This extension introduces new possibilities for understanding the relationships between structures, unique properties, and functions of nanomaterials at the atomic scale. Based on the idea of setting up a nanolab inside a TEM, tactics for design of in situ experiments inside the machine, as well as corresponding examples in nanomaterial research, including in situ growth, nanofabrication with atomic precision, in situ property characterization, and nanodevice construction are presented. PMID- 25703229 TI - Web resources for pharmacogenomics. AB - Pharmacogenomics is the study of the impact of genetic variations or genotypes of individuals on their drug response or drug metabolism. Compared to traditional genomics research, pharmacogenomic research is more closely related to clinical practice. Pharmacogenomic discoveries may effectively assist clinicians and healthcare providers in determining the right drugs and proper dose for each patient, which can help avoid side effects or adverse reactions, and improve the drug therapy. Currently, pharmacogenomic approaches have proven their utility when it comes to the use of cardiovascular drugs, antineoplastic drugs, aromatase inhibitors, and agents used for infectious diseases. The rapid innovation in sequencing technology and genome-wide association studies has led to the development of numerous data resources and dramatically changed the landscape of pharmacogenomic research. Here we describe some of these web resources along with their names, web links, main contents, and our ratings. PMID- 25703230 TI - Water diffusion within hydrated model grafted polymeric membranes with bimodal side chain length distributions. AB - The effect of bimodal side chain length distributions on pore morphology and solvent diffusion within hydrated amphiphilic polymeric membranes is predicted. Seven polymeric architectures are constructed from hydrophobic backbones from which at regular intervals side chains branch off that are alternatingly short (composed of p hydrophobic A fragments or beads) and long (q A fragments, q > p). The side chains are end-linked with a hydrophilic C fragment. Pore morphologies at a water volume fraction of 0.16 are calculated by dissipative particle dynamics (DPD). Water diffusion through the water containing pores is calculated by tracer diffusion calculations through 140 selected snapshots and from the water bead motions. Diffusion constants decrease with difference in side chain lengths, q - p. Overall, the distance between pores also decreases with q - p. The results are explained by counting for every architecture the average number of bonds between an A and the nearest C fragment. These results are in line with a database that contains more than 60 architectures. Diffusion constants tend to increase linearly with |C|(-1)|A|, where |C| and |A| are the C and A bead fractions within the architecture. is therefore expected to be an interesting design parameter for obtaining low percolation thresholds for solvent and/or proton diffusion. PMID- 25703231 TI - Intrauterine transfusion combined with partial exchange transfusion for twin anemia polycythemia sequence: modeling a novel technique. AB - INTRODUCTION: Twin anemia-polycythemia sequence (TAPS) is a newly described disease in monochorionic twin pregnancies, characterized by large inter-twin hemoglobin differences. Optimal management for TAPS is not clear. One of the possible treatment modalities is intrauterine blood transfusion (IUT) in the donor with or without combination of partial exchange transfusion (PET) in the recipient. METHODS: We applied a computational model simulation to illustrate the mechanism of IUT with and without PET in TAPS occurring after laser surgery for twin-twin transfusion syndrome (TTTS). Model simulations were performed with the representative anastomotic pattern as observed during laser intervention, and after placental dye injection. RESULTS: The model was tested against different cases where IUT was combined with PET for the treatment of post-laser TAPS. Model simulations using the observed anastomotic pattern showed a significant reduction of hyperviscosity in the recipient after IUT/PET compared to IUT without PET. DISCUSSION: In this model simulation we show that the addition of PET to IUT reduces the severity of polycythemia in the recipient. PET may thus be important to prevent complications of hyperviscosity. CONCLUSION: This model simulation shows the beneficial effect of PET for the recipient in TAPS cases treated with IUT. PMID- 25703232 TI - Neonatal iron supplementation potentiates oxidative stress, energetic dysfunction and neurodegeneration in the R6/2 mouse model of Huntington's disease. AB - Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a CAG repeat expansion that encodes a polyglutamine tract in huntingtin (htt) protein. Dysregulation of brain iron homeostasis, oxidative stress and neurodegeneration are consistent features of the HD phenotype. Therefore, environmental factors that exacerbate oxidative stress and iron dysregulation may potentiate HD. Iron supplementation in the human population is common during infant and adult-life stages. In this study, iron supplementation in neonatal HD mice resulted in deterioration of spontaneous motor running activity, elevated levels of brain lactate and oxidized glutathione consistent with increased energetic dysfunction and oxidative stress, and increased striatal and motor cortical neuronal atrophy, collectively demonstrating potentiation of the disease phenotype. Oxidative stress, energetic, and anatomic markers of degeneration were not affected in wild-type littermate iron-supplemented mice. Further, there was no effect of elevated iron intake on disease outcomes in adult HD mice. We have demonstrated an interaction between the mutant huntingtin gene and iron supplementation in neonatal HD mice. Findings indicate that elevated neonatal iron intake potentiates mouse HD and promotes oxidative stress and energetic dysfunction in brain. Neonatal-infant dietary iron intake level may be an environmental modifier of human HD. PMID- 25703233 TI - Sickness absence due to back pain or depressive episode and the risk of all-cause and diagnosis-specific disability pension: A Swedish cohort study of 4,823,069 individuals. AB - BACKGROUND: The aim of this study was to investigate the associations between sickness absence due to back pain or depressive episode with future all-cause and diagnosis-specific disability pension, while adjusting for comorbidity and socio demographics, for all and stratifying for sex. METHOD: In total, 4,823,069 individuals aged 16-64 years, living in Sweden at the end of 2004, not on old-age or disability pension in 2005 and without ongoing sickness absence at the turn of 2004/2005 formed the study population. Crude and adjusted hazard ratios (HRs) for all-cause and diagnosis-specific disability pension (2006-2010) in relation to diagnosis-specific sickness absence with sickness benefits paid by the Social Insurance Agency were estimated using Cox regression. RESULTS: The HR for all cause disability pension was 7.52 (7.25-7.52) in individuals with an incident sick-leave spell due to back pain, compared to individuals without sickness absence in 2005 in the fully adjusted (socio-demographics and comorbidity) model. The fully adjusted (multivariate) HRs for diagnosis-specific disability pension were musculoskeletal diagnoses 23.87 (22.75-25.04), mental 2.49 (2.27-2.73) or all other diagnoses, 3.44 (3.17-3.75). In individuals with an incident sick-leave spell due to a depressive episode in 2005, the multivariate adjusted HR for all cause disability pension was 12.87 (12.42-13.35), while the multivariate HRs for disability pension due to musculoskeletal diagnoses were 4.39 (3.89-4.96), for mental diagnoses 25.32 (24.29-26.38) and for all other somatic diagnoses 3.44 (3.09-3.82). Men who were sickness absent due to a depressive episode had a higher HR for disability pension compared to women. CONCLUSION: Results indicate that sickness absence due to a depressive episode or back pain is a strong risk factor for a future disability pension due to mental, musculoskeletal or other somatic diagnoses. PMID- 25703234 TI - Establishing column batch repeatability according to Quality by Design (QbD) principles using modeling software. AB - Column technology needs further improvement even today. To get information of batch-to-batch repeatability, intelligent modeling software was applied. Twelve columns from the same production process, but from different batches were compared in this work. In this paper, the retention parameters of these columns with real life sample solutes were studied. The following parameters were selected for measurements: gradient time, temperature and pH. Based on calculated results, batch-to-batch repeatability of BEH columns was evaluated. Two parallel measurements on two columns from the same batch were performed to obtain information about the quality of packing. Calculating the average of individual working points at the highest critical resolution (R(s,crit)) it was found that the robustness, calculated with a newly released robustness module, had a success rate >98% among the predicted 3(6) = 729 experiments for all 12 columns. With the help of retention modeling all substances could be separated independently from the batch and/or packing, using the same conditions, having high robustness of the experiments. PMID- 25703235 TI - Identification and quantification of phenolic compounds in Vitex negundo L. var. cannabifolia (Siebold et Zucc.) Hand.-Mazz. using liquid chromatography combined with quadrupole time-of-flight and triple quadrupole mass spectrometers. AB - A high performance liquid chromatography combined with quadrupole time-of-flight mass spectrometry method was developed for the identification of phenolic compounds in Vitex negundo L. var. cannabifolia (Siebold et Zucc.) Hand.-Mazz. A total of 31 compounds (10 phenolic acids, 19 flavonoids, and 2 iridoids) were fully or partially identified. Caffeic acid, neochlorogenic acid, cryptochlorogenin acid, isochlorogenic acid B, isochlorogenic acid A, isochlorogenic acid C, schaftoside, isoschaftoside, flavosativaside, vitexin 2" rhamnoside, and kaempferol 3-(6"-malonylglucoside) were detected for the first time in this plant. In subsequent quantitative analysis, an ultra-performance liquid chromatography combined with triple quadrupole mass spectrometry method was developed for the quantitative analysis of 17 phenolic compounds. All the analytes were detected within 8 min. The limits of detection and quantification were less than 7.251 and 26.454 ng/mL, respectively. The relative standard deviations of intra-day precision, inter-day precision, repeatability, stability, and recovery were less than 2.87%, 3.87%, 4.86%, 4.70%, and 3.61%, respectively. The validated method was applied to assess the quality of different medicinal parts (leaves, seeds, and roots) of V. negundo. The results indicated that chlorogenic acid, agnuside, isochlorogenic acid A, and isochlorogenic acid C might be selected as quantitative markers for the quality control of V. negundo. The contents of the 17 investigated compounds in leaves differed from those in the other parts. Hierarchical cluster analysis suggested that chlorogenic acid, agnuside, vitexin, and schaftoside could be potential chemical markers for the discrimination of different medicinal parts of V. negundo. This qualitative and quantitative analysis of phenolic compounds of V. negundo could provide a new tool for the quality control of this plant or its related remedies. PMID- 25703236 TI - Development of a lectin binding assay to differentiate between recombinant and endogenous proteins in pharmacokinetic studies of protein-biopharmaceuticals. AB - Human glycoproteins, expressed in hamster cell lines, show similar glycosylation patterns to naturally occurring human molecules except for a minute difference in the linkage of terminal sialic acid: both cell types lack alpha2,6-galactosyl sialyltransferase, abundantly expressed in human hepatocytes and responsible for the alpha2,6-sialylation of circulating glycoproteins. This minute difference, which is currently not known to have any physiological relevance, was the basis for the selective measurement of recombinant glycoproteins in the presence of their endogenous counterparts. The assay is based on using the lectin Sambucus nigra agglutinin (SNA), selectively binding to alpha2,6-sialylated N-glycans. Using von Willebrand factor (VWF), factor IX (FIX), and factor VIIa (FVIIa), it was demonstrated that (i) the plasma-derived proteins, but not the corresponding recombinant proteins, specifically bind to SNA and (ii) this binding can be used to deplete the plasma-derived proteins. The feasibility of this approach was confirmed in spike-recovery studies for all three recombinant coagulation proteins in human plasma and for recombinant VWF (rVWF) in macaque plasma. Analysis of plasma samples from macaques after administration of recombinant and a plasma-derived VWF demonstrated the suitability and robustness of this approach. Data showed that rVWF could be selectively measured without changing the ELISAs and furthermore revealed the limitations of baseline adjustment using a single measurement of the predose concentration only. The SNA gel-based depletion procedure can easily be integrated in existing procedures as a specific sample pre-treatment step. While ELISA-based methods were used to measure the recombinant coagulation proteins in the supernatants obtained by depletion, this procedure is applicable for all biochemical analyses. PMID- 25703237 TI - Blood-brain barrier permeability mechanisms in view of quantitative structure activity relationships (QSAR). AB - The goal of the present paper was to develop a quantitative structure-activity relationship (QSAR) method using a simple statistical approach, such as multiple linear regression (MLR) for predicting the blood-brain barrier (BBB) permeability of chemical compounds. The "best" MLR models, comprised logP and either molecular mass (M) or isolated atomic energy (E(isol)), tested on a structurally diverse set of 66 compounds, is characterized the by correlation coefficients (R) around 0.8. The obtained models were validated using leave-one-out (LOO) cross validation technique and the correlation coefficient of leave-one-out- R(LOO)(2) (Q(2)) was at least 0.6. Analysis of a case from legal medicine demonstrated informative value of our QSAR model. To best authors' knowledge the present study is a first application of the developed QSAR models of BBB permeability to case from the legal medicine. Our data indicate that molecular energy-related descriptors, in combination with the well-known descriptors of lipophilicity may have a supportive value in predicting blood-brain distribution, which is of utmost importance in drug development and toxicological studies. PMID- 25703238 TI - MCPH1 maintains long-term epigenetic silencing of ANGPT2 in chronic lymphocytic leukemia. AB - The microcephalin gene (MCPH1) [also known as inhibitor of human telomerase reverse transcriptase (hTERT) expression] is a tumor suppressor gene that is functionally involved in the DNA damage response. Angiopoietin 2 (ANGPT2) is a crucial factor regulating tumor angiopoiesis. Deregulation of angiogenesis is one of the hallmarks of many cancers, including chronic lymphocytic leukemia (CLL). In CLL, ANGPT2 is a well-studied potential prognostic marker. As MCPH1 overlaps with the ANGPT2 transcription unit on the same chromosome but in the opposite orientation, we wanted to study the functional role of MCPH1 in regulation of ANGPT2 in CLL. The mRNA expression levels of MCPH1 and ANGPT2, including the MCPH1 target gene hTERT, showed significant differences between two prognostic groups, i.e. IGHV-mutated and IGHV-unmutated (P = 0.007 for MCPH1, P = 0.0002 for ANGPT2, and P = 0.00001 for hTERT), in which the expression level of MCPH1 was inversely correlated with the expression levels of hTERT and ANGPT2. Downregulation of MCPH1 resulted in upregulation of ANGPT2, accompanied by loss of its promoter methylation. Using chromatin immunoprecipitation and coimmunoprecipitation assays, we found that MCPH1 binds to the ANGPT2 promoter and recruits DNA methyltransferases, thereby silencing ANGPT2. Thus, our data suggest a novel function for MCPH1 in regulating and maintaining ANGPT2 silencing in CLL through regulation of promoter DNA methylation. PMID- 25703240 TI - Liver transplantation nearly normalizes brain spontaneous activity and cognitive function at 1 month: a resting-state functional MRI study. AB - To investigate the short-term brain activity changes in cirrhotic patients with Liver transplantation (LT) using resting-state functional MRI (fMRI) with regional homogeneity (ReHo) method. Twenty-six cirrhotic patients as transplant candidates and 26 healthy controls were included in this study. The assessment was repeated for a sub-group of 12 patients 1 month after LT. ReHo values were calculated to evaluate spontaneous brain activity and whole brain voxel-wise analysis was carried to detect differences between groups. Correlation analyses were performed to explore the relationship between the change of ReHo with the change of clinical indexes pre- and post-LT. Compared to pre-LT, ReHo values increased in the bilateral inferior frontal gyrus (IFG), right inferior parietal lobule (IPL), right supplementary motor area (SMA), right STG and left middle frontal gyrus (MFG) in patients post-LT. Compared to controls, ReHo values of post-LT patients decreased in the right precuneus, right SMA and increased in bilateral temporal pole, left caudate, left MFG, and right STG. The changes of ReHo in the right SMA, STG and IFG were correlated with change of digit symbol test (DST) scores (P < 0.05 uncorrected). This study found that, at 1 month after LT, spontaneous brain activity of most brain regions with decreased ReHo in pre LT was substantially improved and nearly normalized, while spontaneous brain activity of some brain regions with increased ReHo in pre-LT continuously increased. ReHo may provide information on the neural mechanisms of LT' effects on brain function. PMID- 25703239 TI - Testosterone deficiency, insulin-resistant obesity and cognitive function. AB - Testosterone is an androgenic steroid hormone, which plays an important role in the regulation of male reproduction and behaviors, as well as in the maintenance of insulin sensitivity. Several studies showed that testosterone exerted beneficial effects in brain function, including preventing neuronal cell death, balancing brain oxidative stress and antioxidant activity, improving synaptic plasticity and involving cognitive formation. Although previous studies showed that testosterone deficiency is positively correlated with cognitive impairment and insulin-resistant obesity, several studies demonstrated contradictory findings. Thus, this review comprehensively summarizes the current evidence from in vitro, in vivo and clinical studies of the relationship between testosterone deficiency and insulin-resistant obesity as well as the correlation between either insulin-resistant obesity or testosterone deficiency and cognitive impairment. Controversial reports and the mechanistic insights regarding the roles of testosterone in insulin-resistant obesity and cognitive function are also presented and discussed. PMID- 25703241 TI - Assessing the early changes of cerebral glucose metabolism via dynamic (18)FDG PET/CT during cardiac arrest. AB - To study the changes of cerebral glucose metabolism (CGM) during the phase of return of spontaneous circulation (ROSC) after cardiac arrest (CA), we used 18 fluorodeoxyglucose-positron emission tomography/computed tomography ((18)FDG PET/CT) to measure the CGM changes in six beagle canine models. After the baseline (18)FDG-PET/CT was recorded, ventricular fibrillation (VF) was induced for 6 min, followed by close-chest cardiopulmonary resuscitation (CPR) in conjunction with intravenous (IV) administration of epinephrine and external defibrillator shocks until ROSC was achieved, within 30 min. The (18)FDG was recorded prior to intravenous administration at 0 h (baseline), and at 4, 24, and 48 h after CA with ROSC. We evaluated the expression of two key control factors in canine CGM, hexokinase I (HXK I) and HXK II, by immunohistochemistry at the four above mentioned time points. Electrically induced VF of 6 min duration was successfully induced in the dogs. Resuscitation was then performed to maintain blood pressure stability. Serial (18)FDG-PET/CT scans found that the CGM decreased at 4 h after ROSC and remained lower than the baseline even at 48 h. The expression of HXK I and II levels were consistent with the changes in CGM. These data from our present work showed that (18)FDG-PET/CT imaging can be used to detect decreased CGM during CA and was consistent with the results of CMRgl. Furthermore, there were also concomitant changes in the expression of HXK I and HXK II. The decrease in CGM may be an early sign of hyperacute global cerebral ischemia. PMID- 25703242 TI - Thromboprophylaxis with low-molecular-weight heparins: an assessment of the methodological quality of studies. AB - Low-molecular-weight heparin (LMWH) represents the standard of care for prophylaxis of venous thromboembolism (VTE). We conducted a review of the evidence supporting the use of the different LMWHs employed in VTE prophylaxis, in different clinical settings, and analyzed its progression over time. To evaluate the standards of methodological quality of studies, we elaborated a quality assessment tool. By electronic databases, PubMed, MEDLINE, and Scopus databases, 249 articles deemed eligible for the analysis were selected. Several LMWHs did not have publications in all clinical settings. Extended duration of prophylaxis was documented only for a few LMWH. The quality score yielded statistically significant differences between the medians of the four settings (p = 0.0021) with a higher score in major orthopedic surgery (median, 16; 95% confidence interval [CI], 15-16) when compared with general surgery (median, 14; 95% CI, 13-14; p < 0.001). Median score for studies published after the year 1990 was higher than for those published earlier (p < 0.001). We conclude that the quality of the studies supporting LMWH for VTE prophylaxis in the different clinical settings is not homogeneous and inferior for studies performed before the year 1990. Clinical interchangeability of LMWHs in clinical practice remains a critical issue, and the selection of a product should be based on evidence available for each agent, and for each clinical indication derived from clinical trials. PMID- 25703243 TI - Which patients may benefit from dose adjustment of non-vitamin K antagonist oral anticoagulants? AB - The commercially available non-vitamin K antagonist oral anticoagulants (NOAC) are an emerging therapeutic class, which includes dabigatran, rivaroxaban, apixaban, and edoxaban. Dose adjustment of the NOAC currently takes into account the presence of particular patient characteristics that may alter NOAC concentrations. These characteristics include the presence of renal impairment and concomitant drugs affecting proteins involved with the transport and metabolism of the NOAC. NOAC concentrations reflect anticoagulant activity; some studies have shown some correlation with the risks of adverse events, while others have not, and the association is debated by workers in the field. However, dose adjustment based on characteristics before dosing assumes that the patient has drug oral availability and clearance at the mean of patients with these characteristics. Direct quantification of NOAC concentrations, for example, through the use of calibrated coagulation assays, is likely to add further to individualization of dosing to the particular patient. PMID- 25703244 TI - Arterial and venous thrombosis following trauma and major orthopedic surgery: molecular mechanisms and strategies for intervention. AB - A variety of harmful effects can be triggered by trauma and major orthopedic surgery. One of the key players involved in this process is thrombin. The clinical consequence of this process has, for several decades, been considered to be formation of deep vein thrombosis and pulmonary embolism. Controlling thrombin generation and activation has therefore been the goal of thromboprophylaxis regimens administered to patients suffering from trauma or undergoing major surgery. Protecting patients from venous thromboembolism has, for many years, been the main goal of preventive strategies. However, our knowledge of cell destruction and release of substances that may cause organ damage has expanded in recent years. Release of molecules such as RNA and histones from destroyed tissues may cause cell destruction and organ damage at distal sites if released in huge amounts and disseminated systemically. This new knowledge points toward an unmet need for therapies that prevent both vascular events and organ deterioration. This article briefly reviews molecular mechanisms associated with the occurrence of vascular events and cellular destruction in patients with major bone damage caused by trauma. PMID- 25703245 TI - Incidence of arterial embolism in patients on treatment with old and new anticoagulants for venous thromboembolism. AB - The separate nature of venous and arterial thrombotic disorders has recently been challenged. Patients with venous thromboembolism (VTE) have an increased risk of subsequent symptomatic arterial cardiovascular events, the risk being higher in those with unexplained episodes. Among the implications of this association, there is the potential for old and new antithrombotic drugs to impact on the development of both venous and arterial cardiovascular events. According to the results of recent studies, aspirin in low doses, when administered for the long term management of patients with unprovoked VTE, reduces by approximately 35% the risk of recurrent VTE while offering a considerable protection against the development of arterial cardiovascular events. By contrast, there is no room to expect a reduction in the risk of subsequent arterial cardiovascular events in patients treated with vitamin K antagonists (VKA) in comparison to patients in whom VKAs are discontinued. According to the results from recent randomized clinical trials, the likelihood of arterial cardiovascular events in patients on the novel direct factor Xa inhibitors is unlikely to differ from that of patients receiving conventional anticoagulation. As dabigatran has been associated with a slight increase in the risk of myocardial infarction over warfarin, its use should be discouraged in patients with coronary heart disease. The long-term use of low-dose apixaban beyond the first months in patients with unprovoked VTE may decrease the long-term risk of arterial, as well as venous, thrombotic events. PMID- 25703246 TI - Appropriate and timely antimicrobial therapy in cirrhotic patients with spontaneous bacterial peritonitis-associated septic shock: a retrospective cohort study. AB - BACKGROUND: Spontaneous bacterial peritonitis (SBP)-associated septic shock carries significant mortality in cirrhosis. AIM: To determine whether practice related aspects of antimicrobial therapy contribute to high mortality. METHODS: Retrospective cohort study of all (n = 126) cirrhotics with spontaneous bacterial peritonitis (neutrophil count >250 or positive ascitic culture)-associated septic shock (1996-2011) from an international, multicenter database. Appropriate antimicrobial therapy implied either in vitro activity against a subsequently isolated pathogen (culture positive) or empiric management consistent with broadly accepted norms (culture negative). RESULTS: Overall hospital mortality was 81.8%. Comparing survivors (n = 23) with non-survivors (n = 103), survivors had lower Acute Physiology and Chronic Health Evaluation (APACHEII) (mean +/- s.d.; 22 +/- 7 vs. 32 +/- 8) and model for end-stage liver disease (MELD) (24 +/- 9 vs. 34 +/- 11) scores and serum lactate on admission (4.9 +/- 3.1 vs. 8.9 +/- 5.3), P < 0.001 for all. Survivors were less likely to receive inappropriate initial antimicrobial therapy (0% vs. 25%, P = 0.013) and received appropriate antimicrobial therapy earlier [median 1.8 (1.1-5.2) vs. 9.5 (3.9-14.3) h, P < 0.001]. After adjusting for covariates, APACHEII [OR, odds ratio 1.45 (1.04-2.02) per 1 unit increment, P = 0.03], lactate [OR 2.34 (1.04-5.29) per unit increment, P = 0.04] and time delay to appropriate antimicrobials [OR 1.86 (1.10-3.14) per hour increment, P = 0.02] were significantly associated with increased mortality. CONCLUSIONS: Cirrhotic patients with septic shock secondary to spontaneous bacterial peritonitis have high mortality (>80%). Each hour of delay in appropriate antimicrobial therapy was associated with a 1.86 times increased hospital mortality. Admission APACHEII and serum lactate also significantly impacted hospital mortality. Earlier initiation of appropriate antimicrobial therapy could substantially improve outcome. PMID- 25703247 TI - QSAR model as a random event: A case of rat toxicity. AB - Quantitative structure-property/activity relationships (QSPRs/QSARs) can be used to predict physicochemical and/or biochemical behavior of substances which were not studied experimentally. Typically predicted values for chemicals in the training set are accurate since they were used to build the model. QSPR/QSAR models must be validated before they are used in practice. Unfortunately, the majority of the suggested approaches of the validation of QSPR/QSAR models are based on consideration of geometrical features of clusters of data points in the plot of experimental versus calculated values of an endpoint. We believe these geometrical criteria can be more useful if they are analyzed for several splits into the training and test sets. In this way, one can estimate the reproducibility of the model with various splits and better evaluate model reliability. The probability of the correct prediction of an endpoint for external validation set (in the series of the above-mentioned splits) can provide an useful way to evaluate the domain of applicability of the model. PMID- 25703248 TI - Cannabidiol (CBD) and its analogs: a review of their effects on inflammation. AB - First isolated from Cannabis in 1940 by Roger Adams, the structure of CBD was not completely elucidated until 1963. Subsequent studies resulted in the pronouncement that THC was the 'active' principle of Cannabis and research then focused primarily on it to the virtual exclusion of CBD. This was no doubt due to the belief that activity meant psychoactivity that was shown by THC and not by CBD. In retrospect this must be seen as unfortunate since a number of actions of CBD with potential therapeutic benefit were downplayed for many years. In this review, attention will be focused on the effects of CBD in the broad area of inflammation where such benefits seem likely to be developed. Topics covered in this review are; the medicinal chemistry of CBD, CBD receptor binding involved in controlling Inflammation, signaling events generated by CBD, downstream events affected by CBD (gene expression and transcription), functional effects reported for CBD and combined THC plus CBD treatment. PMID- 25703249 TI - Novel 4-substituted-N,N-dimethyltetrahydronaphthalen-2-amines: synthesis, affinity, and in silico docking studies at serotonin 5-HT2-type and histamine H1 G protein-coupled receptors. AB - Syntheses were undertaken of derivatives of (2S,4R)-(-)-trans-4-phenyl-N,N dimethyl-1,2,3,4-tetrahydronaphthalen-2-amine (4-phenyl-2-dimethylaminotetralin, PAT), a stereospecific agonist at the serotonin 5-HT2C G protein-coupled receptor (GPCR), with inverse agonist activity at 5-HT2A and 5-HT2B GPCRs. Molecular changes were made at the PAT C(4)-position, while preserving N,N-dimethyl substitution at the 2-position as well as trans-stereochemistry, structural features previously shown to be optimal for 5-HT2 binding. Affinities of analogs were determined at recombinant human 5-HT2 GPCRs in comparison to the phylogenetically closely-related histamine H1 GPCR, and in silico ligand docking studies were conducted at receptor molecular models to help interpret pharmacological results and guide future ligand design. In most cases, C(4) substituted PAT analogs exhibited the same stereoselectivity ([-]-trans>[+] trans) as the parent PAT across 5-HT2 and H1 GPCRs, albeit, with variable receptor selectivity. 4-(4'-substituted)-PAT analogs, however, demonstrated reversed stereoselectivity ([2S,4R]-[+]-trans>[2S,4R]-[-]-trans), with absolute configuration confirmed by single X-ray crystallographic data for the 4-(4'-Cl) PAT analog. Pharmacological affinity results and computational results herein support further PAT drug development studies and provide a basis for predicting and interpreting translational results, including, for (+)-trans-4-(4'-Cl)-PAT and (-)-trans-4-(3'-Br)-PAT that were previously shown to be more potent and efficacious than their corresponding enantiomers in rodent models of psychoses, psychostimulant-induced behaviors, and compulsive feeding ('binge-eating'). PMID- 25703250 TI - False-negative FDG-PET in histologically proven extensive large cell bone marrow involvement in diffuse large B-cell lymphoma. PMID- 25703251 TI - Donor-derived Strongyloides stercoralis infection in solid organ transplant recipients in the United States, 2009-2013. AB - Infection with Strongyloides stercoralis is typically asymptomatic in immunocompetent hosts, despite chronic infection. In contrast, immunocompromised hosts such as solid organ transplant recipients are at risk for hyperinfection syndrome and/or disseminated disease, frequently resulting in fatal outcomes. Infection in these recipients may result from reactivation of latent infection or infection through transmission from an infected donor. We describe the Centers for Disease Control and Prevention's experience with seven clusters of donor derived infection from 2009 to 2013. Six of the seven (86%) donors were born in Latin America; donor screening was not performed prior to organ transplantation in any of these investigations. Eleven of the 20 (55%) organ recipients were symptomatic, two of whom died from complications of strongyloidiasis. We also describe the New York Organ Donor Network (NYODN) experience with targeted donor screening from 2010 to 2013. Of the 233 consented potential donors tested, 10 tested positive for Strongyloides antibody; and 18 organs were transplanted. The majority (86%) of the donors were born in Central or South America. Fourteen recipients received prophylaxis after transplantation; no recipients developed strongyloidiasis. The NYODN experience provides evidence that when targeted donor screening is performed prior to transplantation, donor-derived infection can be averted in recipients. PMID- 25703252 TI - The adiponectin-SIRT1-AMPK pathway in alcoholic fatty liver disease in the rat. AB - BACKGROUND: Our previous work showed that binge drinking in the rat induced hepatic steatosis which correlated with reduced expression of AMP-activated protein kinase (AMPK). In this study, we used the rat model to investigate the role of adiponectin (Adip), sirtuin 1 (SIRT1), AMPK, and lipin 1 (LIP 1) signaling, a central controlling pathway of lipid metabolism in hepatic steatosis. METHODS: The serum Adip and tumor necrosis factor-alpha (TNF-alpha) as well as liver Adip receptors (AdipoR1 and AdipoR2) SIRT1, AMPK, phosphorylated AMPK (p-AMPK), sterol regulatory element-binding proteins (SREBPs), acetyl-CoA carboxylase (ACC), LIP 1, lipocalin-2 (LCN2), and serum amyloid A1 were assessed in the rat model where 16 weeks of gavaged alcohol were administered. RESULTS: In this model of ethanol (EtOH) administration, hepatic steatosis, necrosis, as well as inflammation were increased over the 16-week period. The level of TNF-alpha in the serum was increased while the Adip content decreased significantly, and there was an inverse relationship between the content of TNF-alpha and Adip. The mRNA and protein expression of AdipoR2, SIRT1, and AMPK was suppressed by EtOH in the rats' hepatic tissue. Additionally, EtOH significantly decreased p-AMPK by 90% over the 16-week period. In parallel, there was a 2.53- and 1.82-fold increase of lipogenic genes SREBP1c and ACC, and a 3.22- and 4.12-fold increase of LIP 1 and LIP 1 beta mRNA expression, respectively, in the hepatic tissue of the rats. CONCLUSIONS: Our present observations demonstrate that the impaired Adip-SIRT1 AMPK signaling pathway contributes, at least in part, to the development of alcoholic fatty liver disease in EtOH binge rats. PMID- 25703253 TI - Neuraminidase inhibitors: who, when, where? AB - Although the neuraminidase inhibitors (NIs), oseltamivir and zanamivir were first licensed in 1999, their clinical effectiveness is still hotly debated. Two rigorous systematic reviews and meta-analyses of the data from clinical trials conducted in community settings against relatively benign influenza, both suggest that reductions in symptom duration are extremely modest, under one day. Whilst one of these reviews could find no evidence of reductions in complications, the most recent review reported clinically meaningful and statistically significant reductions in the likelihood of requiring antibiotics (44%) and hospitalizations (63%) in adult patients with confirmed influenza, treated with oseltamivir. A further meta-analysis of observational data from the 2009 influenza A(H1N1) pandemic suggested that, in hospitalised patients, NIs significantly reduced mortality in adults by 25% overall, and by 62% if started within 48 hours of symptom onset, compared with no treatment. But, the effectiveness of NIs in children is far less clear. Taken together, these data suggest that NIs should be reserved for patients with influenza who are at high-risk of complications, or when clinically assessed found to be markedly unwell, or rapidly deteriorating. In such patients, treatment should be initiated empirically, as soon as possible, preferably with follow-on virological confirmation. PMID- 25703254 TI - Clinical effect of hormonal replacement therapy with estradiol associated with noretisterone or drospirenone. A prospective randomized placebo controlled study. AB - The study was performed to compare the clinical effect of a hormone replacement therapy (HRT) with two different progestins. Postmenopausal women (PMW) with climacteric symptoms (CS) randomly received for 12 months orally, either placebo (n = 20), 1 mg estradiol (E) plus 0.5 mg noretisterone acetate (NETA; n = 40), or 2 mg drospirenone (DRSP; n = 40), a testosterone- and spironolactone-derived molecule, respectively. Weight (W) declined only during E/DRSP (p < 0.04 versus placebo). Fat mass (FM) decreased, similarly, during E/NETA and E/DRSP. Intracellular water (ICW) did not change, while extracellular water (ECW) decreased during E/DRSP (p < 0.0001) (p < 0.002 versus E/NETA). During E/NETA and E/DRSP, similar decreases were observed for insulin resistance (IR) by the homeostatic model assessment for IR (HOMA-IR) (p < 0.0001 versus placebo for both), systolic (p < 0.04 versus placebo for both) and diastolic (p < 0.002) blood pressure (BP). Lipids did not change. In comparison to placebo CS, by the Kupperman Index (KI), significantly declined (p < 0.0001) during E/NETA or E/DRSP. Menopause-specific Quality of Life (MENQoL) significantly declined versus placebo (p < 0.04) during both E/NETA and E/DRSP. In conclusion, differences between the two progestins are mainly limited to body composition (BC), where the addition of DRSP decreases ECW and body W (BW). PMID- 25703255 TI - Circulating retinol-binding protein 4 levels in gestational diabetes mellitus: a meta-analysis of observational studies. AB - Retinol-binding protein 4 (RBP4) is a novel adipocyte-derived cytokine playing an important role in the regulation of energy metabolism and insulin sensitivity. Although the association between RBP4 and metabolic dysfunction is well established, studies on the relationship between circulating RBP4 levels and the risk of gestational diabetes mellitus (GDM) have yielded inconclusive results. We performed a meta-analysis to investigate whether women with GDM had higher circulating RBP4 levels than the normglycemic pregnant women. PubMed, Web of Science and EMBASE were searched up to 1 August 2014. A total of 14 studies comprised of 884 women with GDM and 1251 normglycemic pregnant women were included. The overall results suggested that maternal circulating RBP4 levels were significantly higher in GDM than their normal controls (SMD: 0.49 MUg/ml, 95% CI: 0.23-0.75 MUg/ml, p < 0.001, random effect model). However, stratified results indicated that this significant difference only existed in the second/third trimester and was limited to Asian populations. Furthermore, subgroup analysis according to matched maternal age and BMI still demonstrated that GDM had higher circulating RBP4 levels than the normal controls. Our findings suggested that Asian women with GDM had increased circulating RBP4 levels in their second/third trimester. PMID- 25703256 TI - Therapeutic effect of sunitinib on diabetes mellitus related ovarian injury: an experimental rat model study. AB - The aim of our study is to investigate the effect of sunitinib on diabetes mellitus related-ovarian injury and fibrosis in rat models. An experimental diabetes mellitus model was created in 16 rats, and eight rats with normal blood glucose levels were included in control group (Group-1). The diabetic rats were divided into two groups:diabetic control group (water given) - Group-2 and sunitinib treatment group - Group-3. After four weeks, bilateral oophorectomy was performed and ovaries were examined histologically. The groups were compared by Student's t-test, analysis of variance (ANOVA) and Mann-Whitney's U-test. There was a significant increase in no-medication (water given) diabetic rat's ovary (Group-2) in terms of follicular degeneration, stromal degeneration, stromal fibrosis and NF-kappaB immune-expression compared with control group normal rats' ovary (Group-1) (p < 0.0001). Stromal degeneration (p = 0.04), stromal fibrosis (p = 0.01), follicular degeneration (p = 0.02), NF-kappaB immune-expression (p = 0.001) significantly decreased in sunitinib-treated diabetic rat's ovary (Group 3) when compared with no-medication (water given) diabetic rat's ovary (Group-2) (p < 0.05). When we used sunitinib in the treatment of diabetic rats, ovarian injury, fibrosis and NF-kappaB immunoexpression decreased significantly. The effects of sunitinib in rat models give hope to the improved treatment of premature ovarian failure due to diabetes mellitus in humans. PMID- 25703257 TI - Hydroxymethylbilane synthase gene mutations and polymorphisms in Brazilian families with acute intermittent porphyria. AB - Acute intermittent porphyria (AIP), an autosomal dominant disorder, is caused by a deficiency of hydroxymethylbilane synthase (HMBS). In the present study, we sought to establish a correlation between HMBS activity with the presence of mutations and polymorphisms. Enzyme activity was measured in red blood cells of four Brazilian unrelated AIP families (n = 124) and in blood donors (n = 80). The HMBS mutations in AIP family members were studied by PCR-SSCP followed by direct sequencing. Six intragenic SNPs (1345 G>A, 1500 T>C, 2377 C>A, 2478 A>G, 3581 A>G, and 7064 C>A) were determined by PCR-RFLP. Abnormal SSCP patterns in exons 7, 9, 12, and 15 were observed. DNA sequencing analysis revealed one nonsense mutation, R149X, two missense mutations, G111R and L338P, and one deletion, CT 730-731. All mutation carriers had lower enzyme activity. All polymorphisms, except 2377 C>A and 7064 C>A, showed no significant differences compared with previous reports. Mutation screening allowed the detection of the missense mutation, L338P, and the 730_731delCT deletion, two as yet unreported mutations in Brazilian AIP patients. Our findings also showed a high frequency of 2478 A>G and 3581 A>G polymorphism combinations suggesting that these polymorphisms contributed to enzymatic activity reduction in our study population. PMID- 25703258 TI - Importance of defining experimental conditions in a mouse excisional wound model. AB - The murine dorsum dermal excisional wound model has been widely utilized with or without splint application. However, variations in experimental methods create challenges for direct comparison of results provided in the literature and for design of new wound healing studies. Here, we investigated the effects of wound location and size, number of wounds, type of adhesive used for splint fixation on wound healing using splinted or unsplinted dorsum excisional full thickness wound models. One or two 6- or 8-mm full thickness wounds were made with or without splinting in genetically diabetic but heterozygous mice (Dock7(m) + / + Lepr(db) ). Two different adhesives: tissue adhesive and an over the counter cyanoacrylate adhesive (OTCA) "Krazy glue" were used to fix splints. Wound contraction, wound closure, and histopathological parameters including reepithelialization, collagen deposition and inflammation were compared between groups. No significant effect of wound number (1 vs. 2), side (left vs. right and cranial vs. caudal) or size on wound healing was observed. The OTCA group had a significantly higher splint success compared to the tissue adhesive group that resulted in significantly higher reepithelialization and collagen deposition in the OTCA group. Understanding the outcomes and effects of the variables will help investigators choose appropriate experimental conditions for the study purpose and interpret data. PMID- 25703259 TI - Synthesis and characterization of rabies virus glycoprotein-tagged amphiphilic cyclodextrins for siRNA delivery in human glioblastoma cells: in vitro analysis. AB - In man brain cancer is an aggressive, malignant form of tumour, it is highly infiltrative in nature, is associated with cellular heterogeneity and affects cerebral hemispheres of the brain. Current drug therapies are inadequate and an unmet clinical need exists to develop new improved therapeutics. The ability to silence genes associated with disease progression by using short interfering RNA (siRNA) presents the potential to develop safe and effective therapies. In this work, in order to protect the siRNA from degradation, promote cell specific uptake and enhance gene silencing efficiency, a PEGylated cyclodextrin (CD)-based nanoparticle, tagged with a CNS-targeting peptide derived from the rabies virus glycoprotein (RVG) was formulated and characterized. The modified cyclodextrin derivatives were synthesized and co-formulated to form nanoparticles containing siRNA which were analysed for size, surface charge, stability, cellular uptake and gene-knockdown in brain cancer cells. The results identified an optimised co formulation prototype at a molar ratio of 1:1.5:0.5 (cationic cyclodextrin:PEGylated cyclodextrin:RVG-tagged PEGylated cyclodextrin) with a size of 281 +/- 39.72 nm, a surface charge of 26.73 +/- 3 mV, with efficient cellular uptake and a 27% gene-knockdown ability. This CD-based formulation represents a potential nanocomplex for systemic delivery of siRNA targeting brain cancer. PMID- 25703260 TI - Cocaine, a culprit in anetoderma? PMID- 25703261 TI - Progress, challenges and the future of crop genomes. AB - The availability of plant reference genomes has ushered in a new era of crop genomics. More than 100 plant genomes have been sequenced since 2000, 63% of which are crop species. These genome sequences provide insight into architecture, evolution and novel aspects of crop genomes such as the retention of key agronomic traits after whole genome duplication events. Some crops have very large, polyploid, repeat-rich genomes, which require innovative strategies for sequencing, assembly and analysis. Even low quality reference genomes have the potential to improve crop germplasm through genome-wide molecular markers, which decrease expensive phenotyping and breeding cycles. The next stage of plant genomics will require draft genome refinement, building resources for crop wild relatives, resequencing broad diversity panels, and plant ENCODE projects to better understand the complexities of these highly diverse genomes. PMID- 25703262 TI - Oncotator: cancer variant annotation tool. AB - Oncotator is a tool for annotating genomic point mutations and short nucleotide insertions/deletions (indels) with variant- and gene-centric information relevant to cancer researchers. This information is drawn from 14 different publicly available resources that have been pooled and indexed, and we provide an extensible framework to add additional data sources. Annotations linked to variants range from basic information, such as gene names and functional classification (e.g. missense), to cancer-specific data from resources such as the Catalogue of Somatic Mutations in Cancer (COSMIC), the Cancer Gene Census, and The Cancer Genome Atlas (TCGA). For local use, Oncotator is freely available as a python module hosted on Github (https://github.com/broadinstitute/oncotator). Furthermore, Oncotator is also available as a web service and web application at http://www.broadinstitute.org/oncotator/. PMID- 25703263 TI - Visible light-mediated arylalkylation of allylic alcohols through concomitant 1,2 aryl migration. AB - A photocatalytic process for selective arylalkylation of allylic alcohols with alpha-bromo diethyl malonate has been developed. The reaction provided a straightforward approach to synthesize alpha-aryl-beta-alkylated ketones via unique 1,2-aryl migration. The procedure is highlighted by its operational simplicity and mild reaction conditions. PMID- 25703264 TI - Current concepts on the use of corticosteroid injections for knee osteoarthritis. AB - Intraarticular corticosteroid injections are commonly used by the primary care providers and orthopedic surgeons to treat knee pain associated with osteoarthritis (OA). There is a spectrum of options for treating knee OA, ranging from ice therapy to partial or total knee replacement surgery. In mid-range treatment spectrum are different kinds of injections, with the most widely used being corticosteroid and hyaluronic acid. In addition, there are different types of corticosteroids used and also commonly mixed with different local anesthetics. The purpose of this paper is address current concepts on the use of corticosteroid steroid therapy for the treatment of knee OA. PMID- 25703265 TI - Facial approximation-from facial reconstruction synonym to face prediction paradigm. AB - Facial approximation was first proposed as a synonym for facial reconstruction in 1987 due to dissatisfaction with the connotations the latter label held. Since its debut, facial approximation's identity has morphed as anomalies in face prediction have accumulated. Now underpinned by differences in what problems are thought to count as legitimate, facial approximation can no longer be considered a synonym for, or subclass of, facial reconstruction. Instead, two competing paradigms of face prediction have emerged, namely: facial approximation and facial reconstruction. This paper shines a Kuhnian lens across the discipline of face prediction to comprehensively review these developments and outlines the distinguishing features between the two paradigms. PMID- 25703266 TI - Perceptions of aging among middle-aged offspring of traumatized parents: the effects of parental Holocaust-related communication and secondary traumatization. AB - OBJECTIVES: Traumatized parents may transmit anxieties of physical deterioration and demise to their offspring. These anxieties can amplify negative perceptions of the aging process when the offspring enter old age. The current study examined how middle-aged offspring of Holocaust survivors (OHS) recount trauma-related communication by their parents, and how these reports are related to offspring's perceptions of their aging process. METHOD: The study included 450 respondents at the age range of 50-67 (mean age = 57.5, SD = 4.6): 300 OHS and 150 comparisons. Participants reported parental communication of the Holocaust, completed measures of subjective successful aging, aging and death anxieties, and reported secondary traumatization assessing symptoms, developed as a result of a close and continuous relationship with a traumatized parent. RESULTS: Latent profile analysis identified two profiles of parental Holocaust-related communication: intrusive and informative. Offspring who reported intrusive parental communication about the Holocaust perceived themselves as aging less successfully and were more anxious of aging and death than comparisons. Offspring who reported informative parental communication and comparisons did not differ in perceptions of aging. Secondary traumatization mediated these group differences, meaning, intrusive parental communication was related to higher secondary traumatization, which in turn was related to less favorable perceptions of aging. CONCLUSION: These findings allude to the possibility that secondary traumatization mold negative perceptions of the aging process among middle-aged offspring of traumatized parents. Mental health practitioners may help OHS process fragmented and intrusive remnants of parental trauma, thereby diminishing secondary traumatization, and promoting more adaptive perceptions of aging. PMID- 25703267 TI - Proposal of the new name "eruptive papular collageno-elastopathy" to unify the two indistinguishable entities, eruptive collagenoma and papular elastorrhexis. PMID- 25703268 TI - Epidemiology of musculoskeletal tumors in a national referral orthopedic department. A study of 3482 cases. AB - AIM OF THE STUDY: Musculoskeletal tumors are relatively rare, and their geographic distribution varies greatly around the world. In this study, we present the incidence, age distribution and localization of musculoskeletal tumors diagnosed and/or treated at a tertiary referral orthopedic department, catering to an entire Southeastern European country. METHODS: This was a retrospective study of prospectively collected data, in which all patients diagnosed and/or treated for musculoskeletal tumors at our Department in the period of 30 years (1981-2010) were included. RESULTS: Data of a total of 3482 patients with musculoskeletal tumors were collected. Average age of patients was 33.5 years (range, 2 months-88 years), with even distribution according to sex. Malignant tumors were seen in 20.7% of patients, more often in men (56.9%). Most common malignant tumors were osteosarcoma (estimated incidence: 1.68/million/year), chondrosarcoma (0.79/million/year) and Ewing sarcoma (0.76/million/year). Benign tumors and tumor-like lesions were found in 79.3% of patients, with slight female predominance. Most common benign bone lesions were osteochondroma (5.81/million/year), simple bone cyst (2.13/million/year), and enchondroma (2.05/million/year). CONCLUSION: This report represents a first of its kind in our region, and gives representative results to be compared to other middle and south European countries. Further nationwide studies are needed to improve strategies in bone tumor diagnosis and treatment. PMID- 25703269 TI - Spoken language comprehension of phrases, simple and compound-active sentences in non-speaking children with severe cerebral palsy. AB - BACKGROUND: Children with severe cerebral palsy (CP) (i.e. 'non-speaking children with severely limited mobility') are restricted in many domains that are important to the acquisition of language. AIMS: To investigate comprehension of spoken language on sentence type level in non-speaking children with severe CP. METHODS & PROCEDURES: From an original sample of 87 non-speaking children with severe CP, 68 passed the pre-test (i.e. they matched at least five spoken words to the corresponding objects) of a specifically developed computer-based instrument for low motor language testing (C-BiLLT), admitting them to the actual C-BiLLT computer test. As a result, the present study included 68 children with severe CP (35 boys, 33 girls; mean age 6;11 years, SD 3;0 years; age range 1;9 11;11 years) who were investigated with the C-BiLLT for comprehension of different sentence types: phrases, simple active sentences (with one or two arguments) and compound sentences. The C-BiLLT provides norm data of typically developing (TD) children (1;6-6;6 years). Binomial logistic regression analyses were used to compare the percentage correct of each sentence type in children with severe CP with that in TD children (subdivided into age groups) and to compare percentage correct within the CP subtypes. OUTCOMES & RESULTS: Sentence comprehension in non-speaking children with severe CP followed the developmental trajectory of TD children, but at a much slower rate; nevertheless, they were still developing up to at least age 12 years. Delays in sentence type comprehension increased with sentence complexity and showed a large variability between individual children and between subtypes of CP. Comprehension of simple and syntactically more complex sentences were significantly better in children with dyskinetic CP than in children with spastic CP. Of the children with dyskinetic CP, 10-13% showed comprehension of simple and compound sentences within the percentage correct of TD children, as opposed to none of the children with spastic CP. CONCLUSION & IMPLICATIONS: In non-speaking children with severe CP sentence comprehension is delayed rather than deviant. Results indicate the importance of following comprehension skills across all age groups, even beyond age 12 years. Moreover, the subtype of CP should be considered when establishing an educational programme for sentence comprehension, and augmentative and alternative communication support. In addition, educational programmes for children with severe CP should take into account the linguistic hierarchy of sentence comprehension when focusing on the input and understanding of spoken language comprehension. PMID- 25703270 TI - Exploring the predictors of early readmission to psychiatric hospital. AB - BACKGROUND: Aims of this study are to explore the associations of readmission to psychiatric hospital over time, to develop a statistical model for early readmission to psychiatric hospital and to assess the feasibility of predicting early readmission. METHOD: The sample comprised 7891 general psychiatric discharges in South London, taken from a large anonymised repository of electronic patient records. We initially explored time to readmission using Cox regression - this included investigation of time-dependent effects. Subsequently, we used logistic regression to create a predictive model for 90-day readmission. We investigated the effect on readmission of a set of variables that included demographic variables, diagnosis and legal status during the index admission, previous service use, housing variables and individual item scores on the Health of the Nation Outcome Scales (HoNOS) at admission and at discharge. RESULTS: Fifteen per cent of those discharged were readmitted within 90 days. Cox regression demonstrated that the estimated baseline hazard of readmission declined steeply after discharge and that the effects of several predictors, especially diagnosis, changed over time - most notably, personality disorder was associated with increased readmission relative to schizophrenia at the time of discharge, but did not significantly differ by 1-year postdischarge. In the logistic regression, increased readmission was associated with personality disorder diagnosis; shorter length of the index admission (excepting zero length admissions); number of discharges in the preceding 2 years; and having a high score at discharge on the HoNOS overactive and aggressive behaviour item, cognitive problems item or hallucinations and delusions items. Detention under Section 3 or a forensic section of the Mental Health Act during the index admission was associated with reduced readmission. The coefficient of discrimination for the logistic regression, which is equivalent to r 2, was 0.04 and the estimated area under the receiver operating curve was 0.65. CONCLUSIONS: The association found between early readmission and personality disorder diagnosis merits further investigation, as does the possible trade-off between reduction in length of stay and increased readmission. Other novel findings such as the associations found with HoNOS item scores also merit replication. As with previous studies, we found that the rate of readmission declines steeply after hospital discharge, so that the period immediately subsequent to discharge is a period of comparatively high risk. However, prediction of early readmission within this high-risk group remains challenging - it seems most likely that many unmeasured influences operate subsequent to the time of discharge. PMID- 25703271 TI - Transcriptional profiling of the soil invertebrate Folsomia candida in pentachlorophenol-contaminated soil. AB - Pentachlorophenol (PCP), a widely used pesticide, is considered to be an endocrine disruptor. The molecular effects of chemicals with endocrine-disrupting potential on soil invertebrates are largely unknown. In the present study, the authors explored the transcriptional expression changes of collembola (Folsomia candida) in response to PCP contamination. A total of 92 genes were significantly differentially expressed at all exposure times, and the majority of them were found to be downregulated. In addition to the transcripts encoding cytochrome P450s and transferase enzymes, chitin-binding protein was also identified in the list of common differentially expressed genes. Analyses of gene ontology annotation and enrichment revealed that cell cycle-related transcripts were significantly induced by PCP, indicating that PCP can stimulate cell proliferation in springtail, as has been reported in human breast cancer cells. Enrichment of functional terms related to steroid receptors was observed, particularly in 20 significant differentially expressed genes involved in chitin metabolism in response to PCP exposure. Combined with confirmation by quantitative polymerase chain reaction, the results indicate that the adverse effects on reproduction of springtails after exposure to PCP can be attributed to a chemical-induced delay in the molting cycle and that molting-associated genes may serve as possible biomarkers for assessing toxicological effects. PMID- 25703272 TI - Association between low education and higher global cardiovascular risk. AB - This study was designed to evaluate the impact of educational status on global cardiovascular risk in a southern Italian urban population. The study population consisted of 488 consecutive outpatients aged 18 years and older. Educational status was categorized according to the number of years of formal education as follows: (1) low education group (<10 years) and (2) medium-high education group (10-15 years). In both groups, cardiometabolic comorbidities (obesity, visceral obesity, diabetes, dyslipidemia, metabolic syndrome, microalbuminuria, left ventricular hypertrophy) and global cardiovascular risk, according to international guidelines, were analyzed. Left ventricular mass index and ejection fraction by echocardiography and E/A ratio, by pulsed-wave Doppler, were calculated. The low education group was characterized by a significantly higher prevalence of patients with visceral obesity (P=.021), hypertension (P=.010), metabolic syndrome (P=.000), and microalbuminuria (P=.000) and greater global cardiovascular risk (P=.000). Significantly increased levels of microalbuminuria (P=.000) and significantly decreased values of E/A ratio (P=.000) were also detected in the low education group. Global cardiovascular risk correlated directly with waist-to-hip ratio (P=.010), microalbuminuria (P=.015), and the metabolic syndrome (P>.012) and inversely with educational status (P=.000). Education was independently (P=.000) associated with global cardiovascular risk. These data indicate a strong association between low education and cardiometabolic comorbidities suitable to influence the evolution of chronic degenerative diseases. Preventive strategies need to be more efficient and more effective in this patient population. PMID- 25703273 TI - Macro-level determinants of young people's subjective health and health inequalities: a multilevel analysis in 27 welfare states. AB - OBJECTIVES: Cross-national studies have rarely focused on young people. The aim of this study is to investigate whether macro-level determinants are associated with health and socioeconomic inequalities in young people's health. STUDY DESIGN: Data were collected from the Health Behaviour in School-aged Children (HBSC) study in 2006, which included 11- to 15-year old adolescents from 27 European and North American countries (n=134,632). This study includes national income, health expenditure, income inequality, and welfare regime dummy-variables as macro-level determinants, using hierarchical regression modelling. MAIN OUTCOME MEASURE: Psychosomatic health complaints and socioeconomic inequalities in psychosomatic health complaints. RESULTS: Adolescents in countries with higher income inequality and with liberal welfare tradition were associated with more health complaints and a stronger relationship between socioeconomic status and macro-level determinants compared to adolescents from countries with lower income inequality or the Social Democratic regime. National income and health expenditure were not related to health complaints. Countries with higher national income, public health expenditure and income inequality showed stronger associations between socioeconomic status and psychosomatic health complaints. CONCLUSION: Results showed that macro-level characteristics are relevant determinants of health and health inequalities in adolescence. PMID- 25703274 TI - Detection of ideal reservoir level after laryngectomy using endoilluminator in voice rehabilitation. AB - OBJECTIVE: To assess the diagnostic value of a novel device, the endoilluminator, in patients who can or cannot attain effective speech after application of voice prosthesis. STUDY DESIGN: Prospective clinical study. METHODS: Thirty-four patients who underwent total laryngectomy and whose insufflation test was positive were included. As a result of efforts to develop an insufflation test that includes a light apparatus, we attained a device that we call an endoilluminator. We found that the area it illuminated when a patient achieved effective speech was a predictive factor for the test result. That is, patients for whom the upper part of the tracheostomy (where the standard tracheoesophageal fistula will be opened) was illuminated were categorized as the positive test group, whereas those for whom the neck skin above this region was illuminated were categorized as the negative test group. RESULTS: In 27 of the 34 patients, appropriate localization was determined using the endoilluminator, and these patients achieved effective speech. In the remaining seven patients, localization was inappropriate and they did not achieve effective speech during the first week, first month, or third month postpuncture. In further investigations of these seven patients, a pharyngoesophageal spasm was detected in five, and a pharyngoesophageal stricture was detected in two. CONCLUSION: Endoilluminator increases the success rate of the insufflation test by accurately predicting a patient's ability to achieve effective speech after application of voice prosthesis. PMID- 25703275 TI - Where macrolide resistance is prevalent. PMID- 25703276 TI - Clinical and laboratory characteristics in patients suffering from general paresis in the modern era. AB - BACKGROUND: No gold standard currently exists for the diagnosis of general paresis (GP), thus often resulting in unnecessarily delayed therapeutic decision. METHODS: A retrospective chart review was performed for 85 inpatients with GP in Zhongshan Hospital, Medical College of Xiamen University, and the characteristics of their clinical profiles, serum and cerebrospinal fluid (CSF) examinations, neuroimaging examination, and electroencephalogram (EEG) data were analyzed. RESULTS: Among the 85 GP patients, the clinical symptoms that were frequently observed upon admission included a variety of psychiatric-behavioral symptoms and varying degrees of cognitive impairment. All of the patients had positive serum Treponema pallidum particle agglutination (TPPA) assays, 96.47% of the patients had positive CSF TPPA assays, and 41.18% of the patients had both CSF pleocytosis and elevated CSF protein levels. Focal atrophy in one cerebral region or in multiple regions was evident in neuroimages. The EEG data primarily showed slightly abnormal EEG activity. CONCLUSION: These results demonstrate the complexity of the clinical characteristics of GP and highlight the importance of early diagnosis. PMID- 25703277 TI - Clinico-radiological spectrum and outcome in idiopathic hypertrophic pachymeningitis. AB - OBJECTIVE: To elucidate the clinico-radiological features, treatment response and outcome of a large cohort of patients (n=20) with idiopathic hypertrophic pachymeningitis (IHP) and to examine if any of these features could differentiate between IHP and secondary causes of hypertrophic pachymeningitis (SHP). METHODS: 20 patients with IHP diagnosed between 1998 and 2009 formed the study cohort. We adopted a validated clinical score to quantitatively assess and document their neurological disability and to compare their pre- and post-treatment outcomes. Appropriate statistical analysis was done to look for any clinical and/or radiological features to differentiate IHP from SHP. RESULTS: Out of the twenty eight consecutive patients with pachymeningitis, 20 were having IHP and 8 were having SHP (Tuberculosis-5, Sarcoidosis-2, Wegener's granulomatosis-1). In IHP, headache and visual symptoms dominated the clinical symptomatology (80% and 75%). In MRI, the peripheral pattern of contrast enhancement was more common with IHP (p=0.03). The posterior falx and tentorium showing a hypointense center ("fibrosis") and enhancing periphery ("active inflammation") together mimicking "Eiffel-by-night" sign was found to be more commonly associated with IHP (60% vs 12.5%, p=0.03). Biopsy was done in 9 patients. At a mean follow-up of 51 months (range 24-144 months), the mean pretreatment clinical score improved from 6.55 to 1.80 in 20 patients with IHP (p<0.001). CONCLUSIONS: Our data on the largest cohort of patients with IHP would shed light into its clinico-radiological spectrum, treatment and outcome. The prognosis is satisfactory if managed appropriately. We have highlighted the role of MRI in differentiating between IHP and other causes of SHP. PMID- 25703278 TI - Hypercholesterolemia in elders is associated with slower cognitive decline: a prospective, population-based study (NEDICES). AB - BACKGROUND: Studies investigating the association between hypercholesterolemia in the elderly and cognitive decline report discrepant outcomes. We determined in a prospective population-based cohort (NEDICES) in elders whether hypercholesterolemia was associated with slower cognitive decline. METHODS: Participants were evaluated at baseline and 3 years later. Baseline demographic variables were recorded. Hypercholesterolemia was defined by total cholesterol of >200mg/dl or current use of lipid-lowering drugs. At baseline and at follow-up, a 37-item version of the Mini-Mental State Examination (37-MMSE) was administered. RESULTS: The final sample, 2015 participants (72.9 +/- 6.1 years), comprised 1166 (57.9%) hypercholesterolemic and 849 (42.1%) non-hypercholesterolemic participants (reference category). The mean follow-up was 3.4 +/- 0.5 years. During the three year follow-up period, the 37-MMSE declined by 0.7 +/- 4.3 points (median=0 point) in non-hypercholesterolemic participants vs. 0.3 +/- 3.9 points in hypercholesterolemic participants (median=0 points) (Mann-Whitney test, p=0.007). In analyses adjusted for baseline age and other potential confounders, this difference remained robust. We also assessed the cognitive decline per unit time (i.e., the rate of cognitive decline). The rate of cognitive decline was 0.2 +/- 1.3 (median=0.0) points/year for non-hypercholesterolemic participants and 0.1 +/- 1.2 (median=0.0) points/year for hypercholesterolemic participants (Mann Whitney test, p=0.028). CONCLUSIONS: In this prospective population-based cohort study, cognitive test scores among hypercholesterolemic elders declined more slowly than observed in their non-hypercholesterolemic counterparts. Additional studies are needed to confirm these results. PMID- 25703279 TI - Translating endoplasmic reticulum biology into the clinic: a role for ER-targeted natural products? AB - ER stress has been identified as a hallmark, and sometimes trigger, of several pathologies, notably cancer, inflammation and neurodegenerative diseases like Alzheimer's and Parkinson's. Among the molecules described in literature known to affect ER function, the majority are natural products, suggesting that natural molecules may constitute a significant arsenal of chemical entities for modulating this cellular target. In this review, we will start by presenting the current knowledge of ER biology and the hallmarks of ER stress, thus paving the way for presenting the natural products that have been described as being ER modulators, either stress inducers or ER protectors. The chemistry, distribution and mechanism of action of these compounds will be presented and discussed. PMID- 25703280 TI - Role of heat shock proteins in oral squamous cell carcinoma: A systematic review. AB - BACKGROUND: Environmental and patho-physiologic stresses stimulate synthesis of heat shock proteins (HSPs) which enable the cell to survive and recover from stressful conditions, by as yet incompletely understood mechanisms. Heat shock proteins show an increased expression in a wide range of human cancers and have been associated with tumor cell proliferation, differentiation, invasion, metastasis, death, and recognition by the immune system. Yet the role of heat shock proteins in oral cancer is ambiguous. The objective of this review was to systematically assess the data available on the role of HSP expression in oral cancer with special reference to its role in diagnosis, prognosis and treatment. METHODS AND RESULTS: A systematic review of studies that investigated the HSP expression in oral squamous cell carcinoma using Scopus, Medline, Embase and Google scholar databases from their inceptions to 2013, without language restrictions was conducted. We selected 24 studies from which data extraction and validations were performed. CONCLUSION: The literature search revealed differential expression of HSPs during oral tumorigenesis with implications for the specific role of HSPs in the pathogenesis of oral cancer. HSP expression has been regarded as an independent prognostic factor for oral squamous cell carcinoma patients and HSPs are being explored as potent vehicles for delivery of preventive and treatment vaccines in cancer and other diseases. PMID- 25703281 TI - Association of thioredoxin reductase 2 (TXNRD2) gene polymorphisms with myocardial infarction in Slovene patients with type 2 diabetes mellitus. AB - OBJECTIVES: The aim of our study was to investigate the relationship between genetic polymorphisms in the mitochondrial thioredoxin reductase 2 (TrxR2) and myocardial infarction (MI) in subjects with type 2 diabetes mellitus (T2DM) of Slovenian origin. METHODS: The study population consisted of 972 Caucasian subjects with T2DM of more than 10 years' duration: 161 patients with MI and 811 patients with no history of coronary artery disease. Polymorphisms in thioredoxin reductase 2 (TXNRD2) gene, rs1548357, rs4485648, and rs5748469, were studied. RESULTS: Individuals carrying CC+CT genotypes of rs1548357 TXNRD2 polymorphism had lower prevalence of MI compared with TT genotype group (41.6% vs 52.8%, OR=0.589, 95% CI=0.368-0.942, P=0.027). CONCLUSIONS: The TXNRD2 rs 1548357 polymorphism might be a genetic risk factor for MI in subjects with T2DM of Slovenian origin. PMID- 25703282 TI - A survey of interprofessional activity of acute and long-term care employed nurse practitioners. AB - PURPOSE: To describe activities of interprofessional (IP) care, a key aspect of high-quality care, performed by nurse practitioners (NPs) employed in acute and long-term care institutions. DATA SOURCES: We developed and tested a new theory driven process tool to quantify NP everyday activities of IP care. We then invited NPs in acute and long-term care to complete the IP self-assessment tool (IPSAT). CONCLUSIONS: The IPSAT is a validated tool shown to be reliable for use with NPs. Testing with other healthcare professionals is suggested. More than 50% of NPs engage in all activities of IP care. Many engage in shared decision making, professional relationship, communication, and partnership or collaboration activities on most work days. Less-common activities were interdependence and collective problem solving including efforts to create role clarity. IMPLICATIONS FOR PRACTICE: It is important to evaluate the everyday use of activities that enhance high-quality care. Awareness and enhanced knowledge of IP care activities such as promoting interdependence, collective problem solving, and ensuring role clarity will improve care quality. The tool results are valuable for practicing NPs and their educators to reflect on practice and advance knowledge to influence purposeful engagement in interprofessional care. PMID- 25703283 TI - Diagnostic accuracy of coronary ct for the quantification of the syntax score in patients with left main and/or 3-vessel coronary disease. Comparison with invasive angiography. AB - BACKGROUND: The SYNTAX score helps in the treatment decision in multivessel coronary disease. Coronary computed tomography angiography (CTA) can measure the SYNTAX score but has been used in few patients with multivessel disease. Our aim was to assess the feasibility, accuracy and reproducibility of SYNTAX score with CCTA compared with invasive coronary angiography (ICA) in de novo left main and/or 3-vessel disease. METHODS: 57 patients with new left main and/or 3-vessel disease on ICA and a CCTA performed within the previous month were included. The SYNTAX score was calculated retrospectively for both modalities. Agreement for the global score, vessel score, different components and inter-readers was evaluated with intraclass correlation coefficient (ICC). The ability to classify SYNTAX score categories (low, intermediate and high) was assessed using weighted kappa (K) coefficient. RESULTS: CCTA-based SYNTAX score showed an acceptable concordance (ICC=0.64) and good correlation (r=0.65, p<0.001) with ICA. ICC per vessel and component ranged from 0 to 0.73. There was good agreement classifying the SYNTAX score categories (K=0.53) and interobserver reproducibility (ICC=0.85). CCTA demonstrated high diagnostic accuracy (0.84) for detecting patients in the high score group. No patient with a high CCTA SYNTAX score had a low risk score by ICA that would suggest benefit from percutaneous revascularization. CONCLUSIONS: CCTA showed good correlation, acceptable concordance, and high reproducibility for the quantification of the SYNTAX score in de novo left main and/or 3-vessel coronary disease. A high CCTA SYNTAX score identified a group of patients less likely to benefit from percutaneous coronary intervention. PMID- 25703284 TI - Norwegian nurse-midwives' perspectives on the provision of antenatal diabetes care in an outpatient setting: A qualitative study. AB - BACKGROUND: There is limited research related to nurse-midwives' accounts of their provision of antenatal diabetes care in hospital outpatient settings. This study explored the perspectives and experiences of eight Norwegian nurse-midwives regarding the provision of the midwifery aspect of an antenatal consultation as part of the diabetes specialist team. METHODS: A qualitative descriptive study was used. Eight nurse-midwives aged between 37 and 58 years, representing four Norwegian hospital outpatient clinics, participated in individual interviews. Transcribed interviews were analysed in accordance with a qualitative thematic analysis. RESULTS: Three main themes were developed: "Approaching the women as persons in order to frame strengths and normalcy", "Managing different tasks judiciously" and "Balancing conflicting values". Some of the barriers were found to be related to the organisation of care, such as short timeframes with a medical focus, which overshadowed or forced the normalcy aspects of childbearing into the background. Managing risk and evidence-based knowledge were demanding tasks to fulfil in a judicious way. Some midwives experienced ambiguity while being forced to prioritise medical factors over woman-focused care while running others' errands, an act of balancing conflicting values. CONCLUSIONS: The contextual conditions related to the organisation present barriers for pregnant women to receive woman-focused care beyond the medical approach. The midwifery contribution in this care setting should be clearly recognised and defined so that women can capitalise on the different professionals and their expert competencies and contributions in this setting. PMID- 25703285 TI - Efficacy of Hip Arthroscopy for the Management of Septic Arthritis: A Systematic Review. AB - PURPOSE: This systematic review assessed the role of hip arthroscopic irrigation and debridement for eradication of infection in native joints to ascertain outcomes and complications associated with this surgical approach. METHODS: The Medline, Embase, and PubMed databases were searched on July 20, 2014, for English language studies that addressed arthroscopic treatment of native septic hip arthritis. The studies were systematically screened and data abstracted in duplicate, with qualitative findings presented. RESULTS: There were 11 eligible studies (1 case-control study, 8 case series, and 2 case reports) reporting on 65 patients (65 hips) treated by arthroscopic irrigation and debridement for septic hip arthritis. The mean length of patient follow-up was 19.1 months (range, 6 to 84 months). The indications for surgery were as follows: pyrexia, anterior groin or hip pain with limited hip range of motion and an inability to bear weight, associated leukocytosis, an elevated erythrocyte sedimentation rate or C-reactive protein level, and/or hip imaging or aspiration results consistent with infection. Specific contraindications for surgery reported across studies included tuberculous of fungal infection, coexistence of osteomyelitis, immunocompromised individuals, and pre-existing surgery on the affected hip. The initial rate of infection eradication was 100%. All studies reported significant improvements in patient pain and function. Improvements were also observed in range of motion, as well as across both the Bennett radiographic and clinical assessments and Harris Hip Score. No complications, major or minor, were reported, and only 1 of 65 hips (1.5%) required revision arthroscopy for recurrence because of a methicillin-resistant Staphylococcus aureus infection. CONCLUSIONS: Arthroscopic native hip irrigation and debridement for septic arthritis appear to comprise a safe and effective treatment option for selected patients (e.g., no deformity, no bacterial infections, and not immunocompromised). Timely diagnosis and intervention, however, remain the most critical prognostic factors for successful outcomes. LEVEL OF EVIDENCE: Level IV, systematic review of Level IV and V studies. PMID- 25703286 TI - Impact of Hamstring Graft Diameter on Tendon Strength: A Biomechanical Study. AB - PURPOSE: The purpose of this study was to compare the tensile strength of hamstring grafts of varying combined pull-through diameters within the clinically relevant range of 6 to 9 mm. METHODS: We tested 44 non-irradiated allograft hamstring grafts (11 per group). Combined looped semitendinosus and gracilis grafts were allocated to the 6-, 7-, 8-, or 9-mm group based on the smallest diameter lumen that the graft could be "pulled through" using a surgical sizing instrument. Testing was performed on an Instron materials testing machine (Instron, Norwood, MA). Samples were secured with cryoclamps, prestressed, and pulled to failure at a rate of 10% gauge length per second. RESULTS: The mean load to failure was 2,359 +/- 474 N, 3,263 +/- 677 N, 3,908 +/- 556 N, and 4,360 +/- 606 N for the 6-, 7-, 8-, and 9-mm grafts, respectively. Minimum failure loads were as low as 1,567 N, 2,288 N, 2,874 N, and 3,720 N for each group, respectively. There were statistically significant differences between the 6- and 7-mm, 6- and 8-mm, 6- and 9-mm, and 7- and 9-mm groups (P = .01). CONCLUSIONS: Statistically different increasing tensile strength was seen as graft diameter increased. Significant variability exists in the strength of multi-stranded hamstring allografts within the diameter range of 6 to 9 mm that often falls well below the commonly accepted value of 4,000 N for a hamstring graft. CLINICAL RELEVANCE: Recent evidence suggests a higher early failure rate of hamstring autografts in subsets of patients with graft diameters of 8 mm or less. This study may increase awareness that hamstring grafts may not be nearly as strong as previously appreciated and that increasing tendon diameters by 1 to 2 mm may dramatically affect graft strength. These data may be helpful in preoperative discussions regarding variable hamstring size, strength, and potential intraoperative augmentation options. PMID- 25703287 TI - Proposed Referential Index to Resect Femoroacetabular Cam-Type Impingement During Arthroscopy Using a Cadaveric Hip Model. AB - PURPOSE: To establish a reference index for the simple identification of the optimum resection point for cam-type impingement on arthroscopy. METHODS: Twelve cadaveric left hips with a 20 degrees to 40 degrees center-edge angle, without osteoarthritis, were examined (mean age, 85 +/- 10.1 years). The pelvis was fixed such that the anterior pelvic plane and femur were parallel to the table. The resection line for impingement was first defined on the femoral head surface 5 mm distal to the acetabular labrum, from the 9-o'clock (anterior) to 12-o'clock (superior) position. Next, we measured the hip flexion angle necessary for the head-neck junction to reach the resection line. After positioning the wire on the femoral head surface along the resection line from the 9- to 12-o'clock area of the femoral head, we measured the target alpha angle on radiographs at 0 degrees , 15 degrees , 30 degrees , 45 degrees , and 60 degrees of hip flexion using the frog-leg 45/45/30 view (45 degrees of flexion, 45 degrees of abduction, and 30 degrees of external rotation) and Dunn 45 view (45 degrees of flexion, 20 degrees of abduction, and neutral rotation). RESULTS: The mean hip flexion angle at which the head-neck junction reached the resection line was 31 degrees +/- 4.6 degrees . For 0 degrees , 15 degrees , 30 degrees , 45 degrees , and 60 degrees of hip flexion, the mean target alpha angle was 75.5 degrees +/- 5.5 degrees , 65.3 degrees +/- 5.6 degrees , 56.3 degrees +/- 5.8 degrees , 49.0 degrees +/- 6.6 degrees , and 42.6 degrees +/- 5.8 degrees , respectively, using the frog-leg 45/45/30 view and 75.0 degrees +/- 6.0 degrees , 65.8 degrees +/- 6.2 degrees , 57.2 degrees +/- 7.3 degrees , 50.7 degrees +/- 6.9 degrees , and 44.2 degrees +/- 5.8 degrees , respectively, using the Dunn 45 view. There were no significant differences between the 2 radiographic techniques (P = .82, P = .84, P = .76, P = .57, and P = .52, respectively). CONCLUSIONS: A description of the degree of hip flexion during cam resection can affect the final alpha angle when using the labrum as a reference for resection. CLINICAL RELEVANCE: The described index allows systematic navigation of cam lesions during arthroscopy for femoroacetabular impingement patients using the hip flexion angle. PMID- 25703288 TI - Widespread Implementation of Medial Patellofemoral Ligament Reconstruction for Recurrent Patellar Instability Maintains Functional Outcomes at Midterm to Long Term Follow-up While Decreasing Complication Rates: A Systematic Review. AB - PURPOSE: Our primary purpose was to evaluate whether complications have increased or functional outcomes have changed as medial patellofemoral ligament (MPFL) reconstruction has been adopted by more surgeons at more institutions over recent years. Our secondary purpose was to further define the complication profile of MPFL reconstruction. METHODS: A systematic review of the literature was performed on January 12, 2014, using the keywords "medial patellofemoral ligament reconstruction," "patellar instability reconstruction," "patellofemoral ligament reconstruction," and "MPFL." Articles meeting our inclusion criteria were reviewed. Outcome measures, functional failures, complications, graft choice, and surgical technique were recorded and analyzed. RESULTS: Thirty-four articles met our exclusion and inclusion criteria and were reviewed. Nineteen articles were "new" additions to the literature, whereas 15 had previously been reported on in prior analyses ("old"). The 19 new articles reported a statistically significant decrease in functional failure rates, from 9.55% in older studies to 4.77% in more recent studies (P < .001). The major complication rate dropped from 2.01% to 0.46% in the newer studies (P = .005), and the minor complication rate decreased from 6.53% to 4.00% (P = .06). Postoperative Kujala scores did not show a statistically significant change between newer and older publications (89.0 [SD, 3.7] and 89.4 [SD, 4.9], respectively; P = .55). Comparing results by fixation type, as well as by graft choice, showed no statistically significant differences in terms of outcomes or complication profile. CONCLUSIONS: With nearly twice the number of medical centers performing reconstruction of the MPFL and outcomes reported on nearly double the number of patients in recent years, functional outcomes remain favorable as complication and failure profiles are improving. Furthermore, despite a wide array of fixation techniques, as well as multiple options for graft constructs, there are no statistically or clinically significant differences in functional outcomes over time. This finding highlights the efficacy and adoptability of MPFL reconstruction for the treatment of recurrent patellar instability. LEVEL OF EVIDENCE: Level IV, systematic review of mixed-level studies. PMID- 25703289 TI - Revision Hip Arthroscopy: A Systematic Review of Diagnoses, Operative Findings, and Outcomes. AB - PURPOSE: To determine indications for, operative findings of, and outcomes of revision hip arthroscopy. METHODS: A systematic review was registered with PROSPERO and performed based on PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Therapeutic clinical outcome studies reporting the indications for, operative findings of, and outcomes of revision hip arthroscopy were eligible for inclusion. All study-, patient-, and hip specific data were extracted and analyzed. The Modified Coleman Methodology Score was used to assess study quality. RESULTS: Five studies were included (348 revision hip arthroscopies; 333 patients; mean age, 31.4 +/- 4.2 years; 60% female patients). All 5 studies were either Level III or IV evidence. The surgeon performing revision hip arthroscopy was the same as the primary hip surgeon in only 25% of cases. The mean time between primary and revision hip arthroscopy was 27.8 +/- 7.0 months (range, 2 to 193 months). Residual femoroacetabular impingement was the most common indication for and operative finding of revision hip arthroscopy (81% of cases). The most commonly reported revision procedures were femoral osteochondroplasty (24%) and acetabuloplasty (18%). The modified Harris Hip Score was used in all 5 analyzed studies, with significant (P < .05) improvements observed in all 5 studies (weighted mean, 56.8 +/- 3.6 preoperatively v 72.0 +/- 8.3 at final follow-up [22.4 +/- 9.8 months]; P = .01). Other patient-reported outcomes (Non-Arthritic Hip Score, Hip Outcome Score, 33 item International Hip Outcome Tool, Short Form 12) showed significant improvements but were not used in all 5 analyzed studies. After revision hip arthroscopy, subsequent reported operations were hip arthroplasty in 11 patients and re-revision hip arthroscopy in 8 patients (5% total reoperation rate). CONCLUSIONS: Revision hip arthroscopy is most commonly performed for residual femoroacetabular impingement, with statistically significant and clinically relevant improvements shown in multiple patient-reported clinical outcome scores at short-term follow-up. The reoperation rate after revision hip arthroscopy is 5% within 2 years, including further arthroscopy or conversion to hip arthroplasty. LEVEL OF EVIDENCE: Level IV, systematic review of Level III and IV studies. PMID- 25703290 TI - Review: Role of genetics and the environment in the pathogenesis of canine atopic dermatitis. AB - BACKGROUND: Multiple levels of evidence support the role of genetics and the environment in the pathogenesis of canine atopic dermatitis (AD). OBJECTIVES: This review summarizes the current evidence in genetics and the effect of environmental factors on the development and perpetuation of canine AD. METHODS: Citation databases, abstracts and proceedings from international meetings published between 2001 and 2013 were reviewed in this update. Where necessary, older articles were included for background information. RESULTS: Canine AD is a heritable disease, in which interaction with environmental factors influences disease risk and phenotype. A study of British guide dogs indicated that nearly 50% of the risk of developing AD was determined by an individual's genotype. Genomic studies performed so far in canine AD have uncovered numerous gene candidates likely to be involved in pathogenesis through their role in immunity, skin barrier formation, apoptosis and inflammation. In addition to genetics, there is evidence to suggest that exposure to certain environmental factors influences the prevalence and course of canine AD. For example, living in rural areas or feeding noncommercial diets was negatively associated with the development of AD in dogs, while exposure to high levels of smoke was associated with increased prevalence of allergic skin disease. CONCLUSIONS: It is becoming clear that canine AD is genotypically complex and influenced by a variety of environmental factors. Well-designed studies with sufficient statistical power will be critical to identify the complex genetic and environmental factors involved in disease development and progression. Recognition of such factors may help to identify new targets for therapy and enable better disease prevention and management. PMID- 25703291 TI - Multicolor 3D super-resolution imaging by quantum dot stochastic optical reconstruction microscopy. AB - We demonstrate multicolor three-dimensional super-resolution imaging with quantum dots (QSTORM). By combining quantum dot asynchronous spectral blueing with stochastic optical reconstruction microscopy and adaptive optics, we achieve three-dimensional imaging with 24 nm lateral and 37 nm axial resolution. By pairing two short-pass filters with two appropriate quantum dots, we are able to image single blueing quantum dots on two channels simultaneously, enabling multicolor imaging with high photon counts. PMID- 25703292 TI - The reverse transcriptase-RNase H: from viruses to antiviral defense. AB - Ubiquitous, reverse transcriptase may have contributed to the transition from the RNA to the DNA world, a transition that also involved RNase H-like activities. Both enzymes shaped various genomes and antiviral defense systems as endogenous retroviruses (ERVs) and transposable elements (TEs). A close relationship between a dozen components of retroviruses and the small interfering RNA (siRNA) antiviral-defense machinery has been characterized. Most antiviral-defense systems involve RNase H-like enzymes destroying invading nucleic acids, RNA, or DNA. Such enzymes include RNases H, Argonaute, Dicer, Cas9, transposases, integrases, and enzymes for immunoglobulin rearrangement and splicing. Even in mammalian cells, where protein-based defense dominates, the siRNA machinery remains active, demonstrated by increased virus production and apoptosis after Dicer knockdown. We have noticed a surprising homology between the siRNA silencing system and the interferon response, as well as to siDNA and the CRISPR system. Further, ERVs serve in defense, in addition to having roles in gene regulation and cancer. PMID- 25703293 TI - Markedly raised levels of C-reactive protein are associated with culture-proven sepsis or necrotising enterocolitis in extremely preterm neonates. AB - AIM: A serious inflammatory process is suspected when C-reactive protein (CRP) is very high, and we established the causes and outcomes when CRP was >100 mg/L in neonates. METHODS: We retrospectively reviewed all 277 episodes where CRP exceeded 100 mg/L between January 2007 and December 2011 at a tertiary neonatal unit. RESULTS: Of the 6025 neonates admitted during the study period, 258 had CRP >100 mg/L at least once. The overall mortality rate was 44/258 (17%); 36 died within 7 days of CRP >100 mg/L, and 34 were extremely preterm infants. CRP exceeded 100 mg/L in 106 infants within the first 3 days of life - 74 term, 25 preterm and seven extremely preterm - with no infection identified in 81%. In contrast, infections were found in 87% of the 171 episodes from day four of life 129 extremely preterm, 23 preterm and 19 term - predominantly coagulase-negative staphylococcus sepsis and necrotising enterocolitis. CONCLUSION: Markedly elevated CRP in the first 3 days of life was most likely to affect term neonates (74/106) with no infectious cause (81%). However, CRP >100 mg/L from the fourth day of life was most likely to affect extremely preterm neonates (129/171) and have an infectious cause (87%). PMID- 25703294 TI - Utility of next-generation sequencing technologies for the efficient genetic resolution of haematological disorders. AB - Next-generation sequencing (NGS) has now evolved to be a relatively affordable and efficient means of detecting genetic mutations. Whole genome sequencing (WGS) or whole exome sequencing (WES) offers the opportunity for rapid diagnosis in many paediatric haematological conditions, where phenotypes are variable and either a large number of genes are involved, or the genes are large making sanger sequencing expensive and labour-intensive. NGS offers the potential for gene discovery in patients who do not have mutations in currently known genes. This report shows how WES was used in the diagnosis of six paediatric haematology cases. In four cases (Diamond-Blackfan anaemia, congenital neutropenia (n = 2), and Fanconi anaemia), the diagnosis was suspected based on classical phenotype, and NGS confirmed those suspicions. Mutations in RPS19, ELANE and FANCD2 were found. The final two cases (MYH9 associated macrothrombocytopenia associated with multiple congenital anomalies; atypical juvenile myelomonocytic leukaemia associated with a KRAS mutation) highlight the utility of NGS where the diagnosis is less certain, or where there is an unusual phenotype. We discuss the advantages and limitations of NGS in the setting of these cases, and in haematological conditions more broadly, and discuss where NGS is most efficiently used. PMID- 25703295 TI - Synthesis and evaluation of new alpha-methylene-gamma-lactone carbamates with NO production inhibitory effects in lipopolysaccharide-induced RAW 264.7 macrophages. AB - A series of new alpha-methylene-gamma-lactone carbamates were synthesized by an asymmetric synthetic route. The activities on inhibiting nitric oxide (NO) release of these compounds were evaluated in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages. The results indicated that most of the compounds except one exhibited potent NO inhibitory effect with IC50 value more than 2 MUMU. The cytotoxicities of these compounds were estimated via MTT assays. The results suggested that six compounds were accompanied by low cytotoxicity. The structure activity relationships were also discussed. The S configuration of C3 on lactones ring would be more helpful to NO inhibitory effect. PMID- 25703296 TI - Novel 1-(2-aryl-2-adamantyl)piperazine derivatives with antiproliferative activity. AB - Novel 1-(2-aryl-2-adamantyl)piperazine derivatives have been synthesized and evaluated in vitro for their antitumor properties against HeLa cervical carcinoma, MDA MB 231 breast cancer, MIA PaCa2 pancreatic cancer, and NCI H1975 non-small cell lung cancer. The parent piperazine 6 was found to exhibit a reasonable activity toward the HeLa and MDA MB 231 tumor cell lines (IC50= 9.2 and 8.4 MUMU, respectively). Concurrent benzene ring C4-fluorination and piperidine acetylation of the piperazino NH of compound 6 resulted in the most active compound 13 of the series in both of the above cell lines (IC50=8.4 and 6.8 MUMU, respectively). Noticeably, compounds 6 and 13 exhibited a significantly low cytotoxicity level over the normal human cells HUVEC (Human Umbilical Vein Endothelial Cells) and NHDF (Normal Human Dermal Fibroblasts). PMID- 25703297 TI - Synthesis, biological evaluation and 3D-QSAR studies of novel 5-phenyl-1H-pyrazol cinnamamide derivatives as novel antitubulin agents. AB - A series of novel 5-phenyl-1H-pyrazol derivatives (5a-5x) containing cinnamamide moiety were synthesized and their biological activities as potential tubulin polymerization inhibitors were evaluated. Among them, compound 5j exhibited the most potent inhibitory activity with an IC50 value of 1.02 MUM for tubulin, which was superior to that of Colchicine (IC50 = 1.34 MUM). Docking simulation was performed to insert compound 5j into the crystal structure of tubulin at colchicine binding site to determine the probable binding model. 3D-QSAR model was also built to provide more pharmacophore understanding that could be used to design new agents with more potent tubulin inhibitory activity. PMID- 25703298 TI - Synthesis, in vitro and in vivo antitumor activity of scopoletin-cinnamic acid hybrids. AB - A series of hybrids of scopoletin and substituted cinnamic acid were designed, synthesized and evaluated in vitro and in vivo against five human tumor cell lines [MCF-7, MDA-MB-231, A549, HCT-116, and HeLa] with doxorubicin as the positive control. Compounds 17a, 17b, 17c and 17g exhibited potent cytotoxic activity. Especially, compound 17b displayed broad spectrum activity with IC50 values ranging from 0.249 MUM to 0.684 MUM. Moreover, in a preliminary pharmacological study, 17b not only remarkably induced cellular apoptosis, but also clearly induced A549 cells cycle arrest at S phase. In vivo study showed that 17b significantly suppressed tumor growth in a dose-dependent manner without causing the loss of the mean body weight of mice, which was superior to doxorubicin. These preliminary results indicate that 17b is an optimal anti cancer leading compound and merit further structural modification. PMID- 25703299 TI - Estimation of the variance effective population size in age structured populations. AB - The variance effective population size for age structured populations is generally hard to estimate and the temporal method often gives biased estimates. Here, we give an explicit expression for a correction factor which, combined with estimates from the temporal method, yield approximately unbiased estimates. The calculation of the correction factor requires knowledge of the age specific offspring distribution and survival probabilities as well as possible correlation between survival and reproductive success. In order to relax these requirements, we show that only first order moments of these distributions need to be known if the time between samples is large, or individuals from all age classes which reproduce are sampled. A very explicit approximate expression for the asymptotic coefficient of standard deviation of the estimator is derived, and it can be used to construct confidence intervals and optimal ways of weighting information from different markers. The asymptotic coefficient of standard deviation can also be used to design studies and we show that in order to maximize the precision for a given sample size, individuals from older age classes should be sampled since their expected variance of allele frequency change is higher and easier to estimate. However, for populations with fluctuating age class sizes, the accuracy of the method is reduced when samples are taken from older age classes with high demographic variation. We also present a method for simultaneous estimation of the variance effective and census population size. PMID- 25703300 TI - The existence and abundance of ghost ancestors in biparental populations. AB - In a randomly-mating biparental population of size N there are, with high probability, individuals who are genealogical ancestors of every extant individual within approximately log2(N) generations into the past. We use this result of J. Chang to prove a curious corollary under standard models of recombination: there exist, with high probability, individuals within a constant multiple of log2(N) generations into the past who are simultaneously (i) genealogical ancestors of each of the individuals at the present, and (ii) genetic ancestors to none of the individuals at the present. Such ancestral individuals-ancestors of everyone today that left no genetic trace-represent 'ghost' ancestors in a strong sense. In this short note, we use simple analytical argument and simulations to estimate how many such individuals exist in finite Wright-Fisher populations. PMID- 25703301 TI - Diversity of A-conotoxins of three worm-hunting cone snails (Conus brunneus, Conus nux, and Conus princeps) from the Mexican Pacific coast. AB - Conus marine snails (~500 species) are tropical predators that use venoms mainly to capture prey and defend themselves from predators. The principal components of these venoms are peptides that are known as "conotoxins" and generally comprise 7 40 amino acid residues, including 0-5 disulfide bridges and distinct posttranslational modifications. The most common molecular targets of conotoxins are voltage- and ligand-gated ion channels, G protein-coupled receptors, and neurotransmitter transporters, to which they bind, typically, with high affinity and specificity. Due to these properties, several conotoxins have become molecular probes, medicines, and leads for drug design. Conotoxins have been classified into genetic superfamilies based on the signal sequence of their precursors, and into pharmacological families according to their molecular targets. The objective of this work was to identify and analyze partial cDNAs encoding conotoxin precursors belonging to the A superfamily from Conus brunneus, Conus nux, and Conus princeps. These are vermivorous species of the Mexican Pacific coast from which only one A-conotoxin, and few O- and I2-conotoxins have been reported. Employing RT-PCR, we identified 30 distinct precursors that contain 13 different predicted mature toxins. With the exception of two groups of four highly similar peptides, these toxins are diverse at both the sequence and the physicochemical levels, and they belong to the 4/3, 4/4, 4/5, 4/6, and 4/7 structural subfamilies. These toxins are predicted to target diverse nicotinic acetylcholine receptor (nAChR) subtypes: nx1d, muscle; pi1a-pi1d, alpha3beta2, alpha7, and/or alpha9alpha10; br1a, muscle, alpha3beta4, and/or alpha4beta2; and nx1a-nx1c/pi1g and pi1h, alpha3beta2, alpha3beta4, alpha9beta10, and/or alpha7. PMID- 25703302 TI - Regulation of hemolymph trehalose level by an insulin-like peptide through diel feeding rhythm of the beet armyworm, Spodoptera exigua. AB - Like vertebrate insulins, some insect insulin-like peptides (ILPs) play crucial roles in controlling immature growth, adult lifespan, and hemolymph sugar level. An ILP gene (SeILP1) was predicted from a transcriptome database of Spodoptera exigua. SeILP1 encodes 95 amino acid sequence and shares sequence homologies (33 83%) with other insect ILPs, in which six conserved cysteine residues are found in the predicted B-A chains. SeILP1 was expressed in all developmental stages of S. exigua. However, SeILP1 expression was tissue-specific because the transcript was detected in fat body and epidermis, but not in hemocytes and gut. Its expression increased with feeding activity. Hemolymph trehalose levels of the fifth instar larvae maintained a relatively constant level at 2.31+/-0.62mM. However, starvation induced a significant increase of the hemolymph trehalose level by more than twofold in 48h, at which few SeILP1 was transcribed. RNA interference of SeILP1 using its specific double-stranded RNA induced a significant increase of hemolymph trehalose level. Interestingly, a bovine insulin decreased hemolymph trehalose level in a dose-dependent manner. These results indicate that SeILP1 plays a role in suppressing hemolymph trehalose level in S. exigua. PMID- 25703303 TI - Change in expression of vesicular protein synapsin II by chronic treatment with D2 allosteric modulator PAOPA. AB - The hallmark symptoms of schizophrenia include profound disturbances in thought, perception, cognition etc., which negatively impacts an individual's quality of life. Current antipsychotic drugs are not effective in treating all symptoms of this disorder, and often cause severe movement and metabolic side effects. Consequently, there remains a strong impetus to develop safer and more efficacious therapeutics for patients, as well as elucidating the etiology of schizophrenia. Previous work in our lab has introduced a novel candidate for the treatment of this disease: the dopamine D2 receptor (D2R) allosteric modulator, 3(R)-[(2(S)-pyrrolidinylcarbonyl)amino]-2-oxo-1-pyrrolidineacetamide (PAOPA). We have previously shown that PAOPA, by selectively modulating D2R, can ameliorate schizophrenia-like symptoms in animal models, although the precise mechanism is presently not understood. Synapsin II is a presynaptic vesicular protein which has been strongly implicated in schizophrenia, as it is reduced in the prefrontal cortex of patients, and knockdown of this protein elicits schizophrenia-like phenotypes in animal models. Given the therapeutic effects of PAOPA and the role of synapsin II in schizophrenia, the objective of this study was to investigate the effect of chronic administration of PAOPA (45 days) on neuronal synapsin II protein expression in rodents. Immunoblot results revealed that the synapsin IIa, but not the IIb isoform, was increased in the dopaminergic regions of the striatum, nucleus accumbens, and medial prefrontal cortex. The results of this study implicate a role for modulation of synapsin II as a possible therapeutic mechanism of action for potential antipsychotic drug PAOPA. PMID- 25703304 TI - Predictors of incidence of clinically significant depressive symptoms in the elderly: 10-year follow-up study of the Bambui cohort study of aging. AB - OBJECTIVE: We aim to evaluate the incidence rate and predictors of clinically significant depressive symptoms (CSDS) over 10 years of follow-up from a population-based cohort study (the Bambui Cohort Study of Aging). METHODS: We calculated the predictors of incidence of CSDS over 10 years of follow-up by the Cox proportional regression analysis. Depressive symptoms were evaluated by GHQ 12 and scores of five or higher indicated CSDS. RESULTS: The annualized incidence rate of clinically significant depressive symptoms was 46 per 1000 person-year. In the multivariate analysis, the main predictors of CSDS were cognitive impairment (HR = 1,69 CI95% [1,20 - 2.37], p = 0.002), diabetes (HR = 1.59 CI95% [1.14 - 2.20], p = 0.006), use of 2 to 4 (HR = 1,95 CI95% [1.21 - 3.15], p = 0.006) and of 5 or more medications in the last 90 days (HR = 2.19 CI95% [1.31 - 3.66], p = 0.003) and higher baseline depressive symptoms (HR = 2.12 CI95% [1.61 2.78], p < 0.001). CONCLUSION: These results highlight the importance of higher depressive symptoms, cognitive impairment and endocrine-metabolic disorders to the development of depressive symptoms in older adults. These findings provide a framework for the development of interventions to prevent the emergence of clinically significant depressive symptoms in the elderly. PMID- 25703305 TI - Synthesis of the O-linked hexasaccharide containing beta-D-Galp-(1->2)-D-Galf in Trypanosoma cruzi mucins. Differences on sialylation by trans-sialidase of the two constituent hexasaccharides. AB - The hexasaccharide beta-D-Galp-(1->2)-[beta-D-Galp-(1->3)]-beta-D-Galp-(1->6) [beta-D-Galp(1->2)-beta-D-Galf(1->4)]-D-GlcNAc (10) and its beta-D-Galf-(1->2) beta-D-Galf containing isomer (7) are the largest carbohydrates in mucins of some strains of Trypanosoma cruzi. The terminal beta-D-Galp units are sites of sialylation by the parasite trans-sialidase. Hexasaccharide 10 was chemically synthesized for the first time by a [3+3] nitrilium based convergent approach, using the trichloroacetimidate method of glycosylation. The (1)H NMR spectrum of its alditol was identical to the spectrum of the product released by beta elimination from the parasite mucin. The trans-sialylation reaction studied on the benzyl glycoside of 10 showed two monosialylated products whose relative abundance changed with time. On the other hand, only one product was produced by sialylation of the benzyl glycoside of 7. A preparative synthesis of the latter and spectroscopic analysis of the product unequivocally established the sialylation site at the less hindered (1->3)-linked galactopyranose. PMID- 25703306 TI - Design, synthesis, and biological evaluation of a series of bifunctional ligands of opioids/SSRIs. AB - A series of opioid and serotonin re-uptake inhibitors (SSRIs) bifunctional ligands have been designed, synthesized, and tested for their activities and efficacies at MU-, delta- and kappa opioid receptors and SSRIs receptors. Most of the compounds showed high affinities for MU- and delta-opioid receptors and lower affinities for SSRIs and kappa opioid receptors. A docking study on the MU-opioid receptor binding pocket has been carried out for ligands 3-11. The ligands 7 and 11 have displayed the highest binding profiles for the MU-opioid receptor binding site with DeltaGbind (-12.14kcal/mol) and Ki value (1.0nM), and DeltaGbind ( 12.41kcal/mol) and Ki value (0.4nM), respectively. Ligand 3 was shown to have the potential of dual acting serotonin/norepinephrine re-uptake inhibitor (SNRI) antidepressant activity in addition to opioid activities, and thus could be used for the design of multifunctional ligands in the area of a novel approach for the treatment of pain and depression. PMID- 25703307 TI - Synthesis and biological evaluation of 3-aminoisoquinolin-1(2H)-one based inhibitors of the dual-specificity phosphatase Cdc25B. AB - The cell division cycle 25B dual specificity phosphatase (Cdc25B) regulates the normal progression of the mammalian cell cycle by dephosphorylating and activating cyclin-dependent kinase (Cdk) complexes, particularly in response to DNA damage. Elevated Cdc25B levels enable a bypass of normal cell cycle checkpoints, and the overexpression of Cdc25B has been linked to a variety of human cancers. Thus, Cdc25B is an attractive target for the development of anticancer therapeutics. Herein we describe the synthesis and biological evaluation of a series of non-quinoid inhibitors of Cdc25B containing the 3 aminoisoquinolin-1(2H)-one pharmacophore. In addition to several strategies that address specific substitution patterns on isoquinolines, we have applied a regioselective Pd-catalyzed cross-coupling methodology to synthesize a new lead structure, 6-(3-aminophenyl)-3-(phenylamino)isoquinolin-1(2H)-one (13), which proved to be a reversible, competitive Cdc25B inhibitor with a Ki of 1.9MUM. Compound 13 prevented human cancer cell growth and blocked Cdc25B-mediated mitotic checkpoint bypass. Molecular docking studies support binding near the catalytic site. PMID- 25703308 TI - Synthesis of hexahydropyrrolo[2,1-a]isoquinoline compound libraries through a Pictet-Spengler cyclization/metal-catalyzed cross coupling/amidation sequence. AB - Molecular libraries of natural product-like and structurally diverse compounds are attractive in early drug discovery campaigns. In here, we present synthetic methodology for library production of hexahydropyrrolo[2,1-a]isoquinoline (HPIQ) compounds. Two advanced HPIQ intermediates, both incorporating two handles for diversification, were synthesized through an oxidative cleavage/Pictet-Spengler reaction sequence in high overall yields. A subsequent metal-catalyzed cross coupling/amidation protocol was developed and its utility in library synthesis was validated by construction of a 20-membered natural product-like molecular library in good overall yields. PMID- 25703309 TI - Association between obstructive sleep apnea severity and glucose control in patients with untreated versus treated diabetes. AB - The purpose of this study was to determine whether the association between obstructive sleep apnea severity and glucose control differs between patients with newly diagnosed and untreated type 2 diabetes, and patients with known and treated type 2 diabetes. This multicentre cross-sectional study included 762 patients investigated by sleep recording for suspected obstructive sleep apnea, 497 of whom were previously diagnosed and treated for type 2 diabetes (treated diabetic patients), while 265 had no medical history of diabetes but had fasting blood glucose >=126 mg dL(-1) and/or glycated haemoglobin (HbA1c ) >=6.5% consistent with newly diagnosed type 2 diabetes (untreated diabetic patients). Multivariate regression analyses were performed to evaluate the independent association between HbA1c and obstructive sleep apnea severity in treated and untreated patients with diabetes. In untreated diabetic patients, HbA1c was positively associated with apnea-hypopnea index (P = 0.0007) and 3% oxygen desaturation index (P = 0.0016) after adjustment for age, gender, body mass index, alcohol habits, metabolic dyslipidaemia, hypertension, statin use and study site. The adjusted mean value of HbA1c increased from 6.68% in the lowest quartile of the apnea-hypopnea index (<17) to 7.20% in the highest quartile of the apnea-hypopnea index (>61; P = 0.033 for linear trend). In treated patients with diabetes, HbA1c was associated with non-sleep variables, including age, metabolic dyslipidaemia and insulin use, but not with obstructive sleep apnea severity. Obstructive sleep apnea may adversely affect glucose control in patients with newly diagnosed and untreated type 2 diabetes, but may have a limited impact in patients with overt type 2 diabetes receiving anti-diabetic medications. PMID- 25703310 TI - Natural history of high-grade cervical intraepithelial neoplasia: a review of prognostic biomarkers. AB - The natural history of high-grade cervical intraepithelial neoplasia (CIN) is largely unpredictable and current histopathological examination is unable to differentiate between lesions that will regress and those that will not. Therefore, most high-grade lesions are currently treated by surgical excision, leading to overtreatment and unnecessary complications. Prognostic biomarkers may differentiate between lesions that will regress and those that will not, making individualized treatment of high-grade CIN possible. This review identifies several promising prognostic biomarkers. These biomarkers include viral genotype and viral DNA methylation (viral factors), human leukocyte antigen-subtypes, markers of lymphoproliferative response, telomerase amplification and human papillomavirus-induced epigenetic effects (host factors) and Ki-67, p53 and pRb (cellular factors). All identified biomarkers were evaluated according to their role in the natural history of high-grade CIN and according to established criteria for evaluation of biomarkers (prospective-specimen-collection, retrospective-blinded-evaluation [PROBE] criteria). None of the biomarkers meets the PROBE criteria for clinical applicability and more research on prognostic biomarkers in high-grade CIN is necessary. PMID- 25703311 TI - Pentamycin shows high efficacy against Trichomonas vaginalis. AB - Trichomonas vaginalis is the causative agent of the venereal disease trichomoniasis, which is the most frequent non-viral sexually transmitted disease worldwide. Since the 1960s, metronidazole has been the standard treatment, however an increasing number of cases with metronidazole-resistant strains is being reported. In this study, pentamycin, a polyene antibiotic, was tested for its in vitro efficacy against T. vaginalis using four strains with different metronidazole susceptibilities. It was shown that pentamycin is highly active against T. vaginalis and that the effect is prompt and independent of underlying metronidazole resistance. The effective concentrations (EC values) after 1 h of treatment were in the range 1.74-2.62 MUg/mL (EC50) and 4.91-6.51 MUg/mL (EC90). Total eradication of trichomonads (EC100) was achieved in all strains by treatment with 15 MUg/mL (22 MUM) for 1 h or with >=1 MUg/mL (>=1.5 MUM) for 24 h. Long-term cultivation (12 months) under permanent drug pressure did not induce stable resistance against pentamycin in any of the strains tested. Pentamycin has been approved for intravaginal use and is a promising candidate for the topical treatment of trichomoniasis. PMID- 25703312 TI - Pharmacokinetic/pharmacodynamic analysis of an intensified regimen containing rifampicin and moxifloxacin for tuberculous meningitis. AB - Recent data suggest that intensified antimicrobial treatment may improve the outcome of tuberculous meningitis (TBM). Considering that drug exposure is the intermediate link between dose and effect, we examined the concentration-response relationship for rifampicin and moxifloxacin in TBM patients. In an open-label, phase 2 clinical trial performed in Indonesia (ClinicalTrials.gov NCT01158755), 60 TBM patients were randomised to receive standard-dose (450mg oral) or high dose rifampicin (600mg intravenous) plus either oral moxifloxacin (400mg or 800mg) or ethambutol (750mg). After 14 days, all patients continued with standard tuberculosis treatment. Pharmacokinetic sampling was performed once in every patient during the first three critical days. Differences in exposure between patients who died or survived were tested with independent samples t-tests. The relationship between drug exposure and mortality was examined using Cox regression. Compared with patients who died during the 2 weeks of intensified treatment, surviving patients had significantly higher rifampicin plasma AUC0-6h, plasma Cmax and CSF Chighest. Additionally, patients had a 32-43% lower relative likelihood of dying with an interquartile range increase in rifampicin exposure. Moxifloxacin exposure did not show a clear relationship with survival. From exposure-response curves, a rifampicin plasma AUC0-6h of ~70mg.h/L (AUC0-24h of ~116mgh/L) and a Cmax of ~22mg/L were deduced as minimum target values for treatment. A strong concentration-effect relationship was found, with higher rifampicin exposure leading to better TBM survival. The current treatment dose of rifampicin is suboptimal; higher doses of rifampicin should be evaluated. PMID- 25703315 TI - Parent ratings of child cognition and language compared with Bayley-III in preterm 3-year-olds. AB - BACKGROUND: Parent ratings on questionnaires may provide valid and cost-effective tools for screening cognitive development of children at risk of developmental delay. AIMS: In this study, we examined the convergent validity of combining parent-based reports of non-verbal cognitive abilities (PARCA3) and verbal abilities (CDI-III) in relation to the Bayley-III cognitive scale in 3-year-olds born late pre-term. METHODS: Mothers of 185 late-preterm children were asked to complete the PARCA3 and the CDI-III shortly before children reached age three; children were then assessed using the Bayley-III close to their third birthday. RESULTS: The two maternal questionnaires were significantly and moderately correlated with the Bayley-III cognitive scores. Together the maternal ratings accounted for 15% of the variance in the Bayley-III cognitive scores, after controlling for other covariates in regression analysis. In particular, the PARCA3 contributed significantly to explain variance in the Bayley-III cognitive scores when controlling for the CDI-III. However, the CDI-III was also independently associated with the Bayley-III cognitive scores. CONCLUSIONS: Parent ratings of child cognition and language together may provide cost effective screening of development in "at risk" preschoolers. PMID- 25703316 TI - Parental and professional assessment of early child development: the ASQ-3 and the Bayley-III-NL. AB - BACKGROUND: The Ages and Stages Questionnaire (ASQ-3) is frequently used for screening developmental delay in problem solving, communication, fine- and gross motor skills and personal-social behavior of infants, toddlers and preschool aged children. The adequacy of the ASQ-3 is evaluated for Dutch children by comparing results of the ASQ-3, completed by parents, to results of a standardized, professionally administered developmental assessment of cognition, fine- and gross motor skills and receptive and expressive communication for infants and toddlers: the Bayley-III-NL. METHODS: The ASQ-3 and Bayley-III-NL were administered to 1244 children aged 1 to 43months old. Two age cohorts were used: 1) the 2-16month age-versions; and 2) the 18-42month age-versions. Cutoff points for all ASQ-3 age-versions were calculated in three ways. Sensitivity and specificity of the ASQ-3 were evaluated with four methods, using different cutoff point combinations of 1 SD or 2 SD below the mean. RESULTS: Overall, sensitivity was between 7% and 77% and specificity between 53% and 99%. Sensitivity and specificity values were higher for the older age-cohort than for the younger age cohort. For the older age-cohort, the best sensitivity (69%) and specificity (92%) was found, using 1 SD for the total ASQ-3 score and 2 SD for the Bayley-III NL subtests as cutoff points. CONCLUSIONS: For the oldest age-cohort, the ASQ-3 for now has the best potential as a screener for Dutch children. The ASQ-3 identifies most children without a developmental delay according to the Bayley III-NL, but sensitivity needs improvement. PMID- 25703317 TI - Making time for mental health: computerized previsit screening in primary care. PMID- 25703318 TI - Day-to-day inconsistency in parent knowledge: links with youth health and parents' stress. AB - PURPOSE: Considerable evidence documents the linkages between higher levels of parental knowledge about youth activities and positive youth outcomes. This study investigated how day-to-day inconsistency in parental knowledge of youth activities was linked to youth behavioral, psychological, and physical health and parents' stress. METHODS: Participants were employees in the Information Technology Division of a Fortune 500 company and their children (N = 129, mean age of youth = 13.39 years, 55% female). Data were collected from parents and youth via separate workplace and in-home surveys as well as telephone diary surveys on eight consecutive evenings. We assessed day-to-day inconsistency in parental knowledge across these eight calls. RESULTS: Parents differed in their knowledge from day to day almost as much as their average knowledge scores differed from those of other parents. Controlling for mean levels of knowledge, youth whose parents exhibited more knowledge inconsistency reported more physical health symptoms (e.g., colds and flu). Knowledge inconsistency was also associated with more risky behavior for girls but greater psychological well being for older adolescents. Parents who reported more stressors also had higher knowledge inconsistency. CONCLUSIONS: Assessing only average levels of parental knowledge does not fully capture how this parenting dimension is associated with youth health. Consistent knowledge may promote youth physical health and less risky behavior for girls. Yet knowledge inconsistency also may reflect normative increases in autonomy as it was positively associated with psychological well being for older adolescents. Given the linkages between parental stress and knowledge inconsistency, parent interventions should include stress management components. PMID- 25703319 TI - Stress moderates the relationship between problematic Internet use by parents and problematic Internet use by adolescents. AB - PURPOSE: Based on the theoretical framework of Problem Behavior and Stress Reduction theories for problematic Internet use (PIU), this study aimed to investigate the relationship between parental PIU and the PIU among adolescents taking into consideration the stress levels of young people. METHODS: This was a population-based parent and adolescent dyad health survey utilizing a random sampling technique. PIU for both parents and adolescents was measured by the Internet addiction test designed by Young. The stress level of adolescents was assessed using the stress subscale of the Depression Anxiety Stress Scale (DASS). Data were analyzed using logistic regression modeling techniques with adjustment for potential confounding factors with analysis on the modification effect of stress levels on the relationship between parent and adolescent PIU. RESULTS: Of the total 1,098 parent and adolescent dyads with usable information, 263 adolescents (24.0%) and 62 parents (5.7%) could be classified as moderate and severe problematic users of the Internet. About 14% (n = 157) of adolescents could be classified with moderate-to-severe stress. Regression analysis results suggested a significant interaction between parental PIU and adolescents' stress levels on adolescent PIU. Stratified regression analyses by stress level resulted in a significant parent and adolescent PIU relationship in the low stress group (odds ratio, 3.18; 95% confidence interval 1.65-6.14). However, the association between parent and adolescent PIU in the high stress group became insignificant. CONCLUSIONS: There was a significant parent and adolescent PIU relationship; however, this relationship is differentially affected by the stress status of the adolescent. The direct implication of the results is that parental Internet use should also be assessed and included as part of the treatment regime for adolescents. PMID- 25703320 TI - Prevention of illicit drug use through a school-based program: results of a longitudinal, cluster-randomized controlled trial. AB - PURPOSE: To evaluate the long-term effects of an illicit drug use prevention program for adolescents that integrates life skills into the theory of planned behavior. METHODS: We conducted a cluster-randomized trial in which 24 participating schools were randomized to either an intervention group (12 schools, n = 1,176 students) or a control group (12 schools, n = 915 students). Participants were grade 7 students. The intervention comprised a main intervention of 10 sessions and two booster interventions. Booster 1 (four sessions) and booster 2 (two sessions) were performed at 6 months and 12 months, respectively, after completion of the main intervention. Assessments were made at baseline, after the main intervention, and after each booster session using specific questionnaires for measuring participants' attitudes, subjective norms, perceived behavioral control, and life skills. RESULTS: Retention rates were 71.9% (845/1,176) in the intervention group and 90.7% (830/915) in the control group after the 12-month follow-up. A significantly lower proportion of intervention group participants reported illicit drug use after the first and second booster sessions compared with control group participants (.1% vs. 1.7% and .2% vs. 1.7%, respectively; both p < .05). Attitudes, subjective norms, perceived behavioral control, life skills, and behavioral intention scores of the intervention group were significantly higher than those of control group after the first and second booster sessions (all p < .001), suggesting that intervention group students tended to avoid drug use. CONCLUSIONS: A drug use prevention program integrating life skills into the theory of planned behavior may be effective for reducing illicit drug use and improving planned behavior related constructs in adolescents. PMID- 25703321 TI - Reproductive health impact of a school health center. AB - PURPOSE: Although school health centers (SHCs) may improve access to reproductive health care services and contraception, published data on SHC service use and reproductive health impact are limited. METHODS: Reproductive health indicators among students at four urban high schools in a single building with an SHC in 2009 were compared with students in a school without an SHC, using a quasi experimental research design (N = 2,076 students, 1,365 from SHC and 711 from comparison school). The SHC provided comprehensive reproductive health education and services, including on-site provision of hormonal contraception. RESULTS: Students in the SHC were more likely to report receipt of health care provider counseling and classroom education about reproductive health and a willingness to use an SHC for reproductive health services. Use of hormonal contraception measured at various time points (first sex, last sex, and ever used) was greater among students in the SHC. Most 10th-12th graders using contraception in the SHC reported receiving contraception through the SHC. Comparing students in the nonintervention school to SHC nonusers to SHC users, we found stepwise increases in receipt of education and provider counseling, willingness to use the SHC, and contraceptive use. CONCLUSIONS: Students with access to comprehensive reproductive health services via an SHC reported greater exposure to reproductive health education and counseling and greater use of hormonal contraception. SHCs can be an important access point to reproductive health care and a key strategy for preventing teen pregnancy. PMID- 25703322 TI - Aging and loss to follow-up among youth living with human immunodeficiency virus in the HIV Research Network. AB - PURPOSE: In the United States, 21 years is a critical age of legal and social transition, with changes in social programs such as public insurance coverage. Human immunodeficiency virus (HIV)-infected youth have lower adherence to care and medications and may be at risk of loss to follow-up (LTFU) at this benchmark age. We evaluated LTFU after the 22nd birthday for HIV-infected youth engaged in care. LTFU was defined as having no primary HIV visits in the year after the 22nd birthday. METHODS: All HIV-infected 21-year-olds engaged in care (2002-2011) at the HIV Research Network clinics were included. We assessed the proportion LTFU and used multivariable logistic regression to evaluate demographic and clinical characteristics associated with LTFU after the 22nd birthday. We compared LTFU at other age transitions during the adolescent/young adult years. RESULTS: Six hundred forty-seven 21-year-olds were engaged in care; 91 (19.8%) were LTFU in the year after turning 22 years. Receiving care at an adult versus pediatric HIV clinic (adjusted odds ratio [AOR], 2.91; 95% confidence interval [CI], 1.42 5.93), having fewer than four primary HIV visits/year (AOR, 2.72; 95% CI, 1.67 4.42), and antiretroviral therapy prescription (AOR, .50; 95% CI, .41-.60) were independently associated with LTFU. LTFU was prevalent at each age transition, with factors associated with LTFU similar to that identified for 21-year-olds. CONCLUSIONS: Although 19.8% of 21-year-olds at the HIV Research Network sites were LTFU after their 22nd birthday, significant proportions of youth of all ages were LTFU. Fewer than four primary HIV care visits/year, receiving care at adult clinics and not prescribed antiretroviral therapy, were associated with LTFU and may inform targeted interventions to reduce LTFU for these vulnerable patients. PMID- 25703323 TI - Usual intake of added sugars and lipid profiles among the U.S. adolescents: National Health and Nutrition Examination Survey, 2005-2010. AB - PURPOSE: Although studies suggest that higher consumption of added sugars is associated with cardiovascular risk factors in adolescents, none have adjusted for measurement errors or examined its association with the risk of dyslipidemia. METHODS: We analyzed data of 4,047 adolescents aged 12-19 years from the 2005 2010 National Health and Nutrition Examination Survey, a nationally representative, cross-sectional survey. We estimated the usual percentage of calories (%kcal) from added sugars using up to two 24-hour dietary recalls and the National Cancer Institute method to account for measurement error. RESULTS: The average usual %kcal from added sugars was 16.0%. Most adolescents (88.0%) had usual intake of >=10% of total energy, and 5.5% had usual intake of >=25% of total energy. After adjustment for potential confounders, usual %kcal from added sugars was inversely associated with high-density lipoprotein (HDL) and positively associated with triglycerides (TGs), TG-to-HDL ratio, and total cholesterol (TC) to HDL ratio. Comparing the lowest and highest quintiles of intake, HDLs were 49.5 (95% confidence interval [CI], 47.4-51.6) and 46.4 mg/dL (95% CI, 45.2-47.6; p = .009), TGs were 85.6 (95% CI, 75.5-95.6) and 101.2 mg/dL (95% CI, 88.7-113.8; p = .037), TG to HDL ratios were 2.28 (95% CI, 1.84-2.70) and 2.73 (95% CI, 2.11-3.32; p = .017), and TC to HDL ratios were 3.41 (95% CI, 3.03-3.79) and 3.70 (95% CI, 3.24-4.15; p = .028), respectively. Comparing the highest and lowest quintiles of intake, adjusted odds ratio of dyslipidemia was 1.41 (95% CI, 1.01-1.95). The patterns were consistent across sex, race/ethnicity, and body mass index subgroups. No association was found for TC, low-density lipoprotein, and non-HDL cholesterol. CONCLUSIONS: Most U.S. adolescents consumed more added sugars than recommended for heart health. Usual intake of added sugars was significantly associated with several measures of lipid profiles. PMID- 25703324 TI - Do not close the gate on gatekeeper training at universities and colleges. PMID- 25703325 TI - The authors reply. PMID- 25703326 TI - Regulatory circuit of PKM2/NF-kappaB/miR-148a/152-modulated tumor angiogenesis and cancer progression. AB - Upregulation of the embryonic M2 isoform of pyruvate kinase (PKM2) emerges as a critical player in the cancer development and metabolism, yet the underlying mechanism of PKM2 overexpression remains to be elucidated. Here we demonstrate that IGF-1/IGF-IR regulates PKM2 expression by enhancing HIF-1alpha-p65 complex binding to PKM2 promoter. PKM2 expression is regulated by miR-148a/152 suppression. PKM2 directly interacts with NF-kappaB p65 subunit to promote EGR1 expression for regulating miR-148a/152 feedback circuit in normal cells, but not in cancer cells because of the DNA hypermethylation of miR-148a and miR-152 gene promoters. The silencing of miR-148a/152 contributes to the overexpression of PKM2, NF-kappaB or/and IGF-IR in some cancer cells. We show that disruption of PKM2/NF-kappaB/miR-148a/152 feedback loop can regulate cancer cell growth and angiogenesis, and is also associated with triple-negative breast cancer (TNBC) phenotype, which may have clinical implication for providing novel biomarker(s) of TNBC and potential therapeutic target(s) in the future. PMID- 25703327 TI - MDMX exerts its oncogenic activity via suppression of retinoblastoma protein. AB - Inactivation of the retinoblastoma protein (RB) has a major role in the development of human malignancies. We have previously shown that MDM2, an ubiquitin E3 ligase and major negative regulator of p53, binds to and promotes proteasome-mediated degradation of RB. MDMX, a homolog of MDM2, also binds to and inhibits p53 transactivation activity, yet it does not possess intrinsic ubiquitin ligase activity. Here, we show that MDMX binds to and promotes RB degradation in an MDM2-dependent manner. Specifically, the MDMX C-terminal ring domain binds to the RB C-pocket and enhances MDM2-RB interaction. Silencing MDMX induces RB accumulation, cell cycle arrest and senescence-like phenotypes, which are reverted by simultaneous RB knockdown. Furthermore, MDMX ablation leads to significant retardation of xenograft tumor growth, concomitant with RB accumulation. These results demonstrate that MDMX exerts oncogenic activity via suppression of RB, and suggest that both MDM2 and MDMX could be chemotherapeutic targets. PMID- 25703328 TI - Cigarette smoke mediates epigenetic repression of miR-217 during esophageal adenocarcinogenesis. AB - Although microRNAs (miRs) have been implicated in the pathogenesis of various human malignancies, limited information is available regarding mechanisms by which these noncoding RNAs contribute to initiation and progression of tobacco induced esophageal cancers. In this study, array and quantitative reverse transcriptase-PCR techniques were used to examine miR expression in immortalized esophageal epithelia (IEE) and esophageal adenocarcinoma (EAC) cells cultured in normal media with or without cigarette smoke condensate (CSC). Under relevant exposure conditions, CSC significantly decreased miR-217 expression in these cells. Endogenous levels of miR-217 expression in cultured EAC cells (EACC)/primary EACs were significantly lower than those observed in IEE/ paired normal esophageal tissues. RNA crosslink immunoprecipitation, quantitative reverse transcriptase-PCR (qRT-PCR) and immunoblot experiments demonstrated direct interaction of miR-217 with kallikrein 7 (KLK7), encoding a putative oncogene not previously implicated in EAC. Repression of miR-217 correlated with increased levels of KLK7 in primary EACs, particularly those from smokers. Chromatin and methylated DNA immunoprecipitation experiments demonstrated that CSC-mediated repression of miR-217 coincided with DNMT3b-dependent hypermethylation and decreased occupancy of nuclear factor 1 within the miR-217 genomic locus. Deoxyazacytidine induced miR-217 expression and downregulated KLK7 in EACC; deoxyazacytidine also attenuated CSC-mediated miR-217 repression and upregulation of KLK7 in IEE and EACC. Overexpression of miR-217 significantly decreased, whereas overexpression of KLK7 increased proliferation, invasion and tumorigenicity of EACC. Collectively, these data demonstrate that epigenetic repression of miR-217 contributes to the pathogenesis of EAC via upregulation of KLK7 and suggest that restoration of miR-217 expression may be a novel treatment strategy for these malignancies. PMID- 25703329 TI - Adaptive stress signaling in targeted cancer therapy resistance. AB - The identification of specific genetic alterations that drive the initiation and progression of cancer and the development of targeted drugs that act against these driver alterations has revolutionized the treatment of many human cancers. Although substantial progress has been achieved with the use of such targeted cancer therapies, resistance remains a major challenge that limits the overall clinical impact. Hence, despite progress, new strategies are needed to enhance response and eliminate resistance to targeted cancer therapies in order to achieve durable or curative responses in patients. To date, efforts to characterize mechanisms of resistance have primarily focused on molecular events that mediate primary or secondary resistance in patients. Less is known about the initial molecular response and adaptation that may occur in tumor cells early upon exposure to a targeted agent. Although understudied, emerging evidence indicates that the early adaptive changes by which tumor cells respond to the stress of a targeted therapy may be crucial for tumo r cell survival during treatment and the development of resistance. Here we review recent data illuminating the molecular architecture underlying adaptive stress signaling in tumor cells. We highlight how leveraging this knowledge could catalyze novel strategies to minimize or eliminate targeted therapy resistance, thereby unleashing the full potential of targeted therapies to transform many cancers from lethal to chronic or curable conditions. PMID- 25703330 TI - mTORC1 upregulation via ERK-dependent gene expression change confers intrinsic resistance to MEK inhibitors in oncogenic KRas-mutant cancer cells. AB - Cancer cells harboring oncogenic BRaf mutants, but not oncogenic KRas mutants, are sensitive to MEK inhibitors (MEKi). The mechanism underlying the intrinsic resistance to MEKi in KRas-mutant cells is under intensive investigation. Here, we pursued this mechanism by live imaging of extracellular signal-regulated kinases (ERK) and mammalian target of rapamycin complex 1 (mTORC1) activities in oncogenic KRas or BRaf-mutant cancer cells. We established eight cancer cell lines expressing Forster resonance energy transfer (FRET) biosensors for ERK activity and S6K activity, which was used as a surrogate marker for mTORC1 activity. Under increasing concentrations of MEKi, ERK activity correlated linearly with the cell growth rate in BRaf-mutant cancer cells, but not KRas mutant cancer cells. The administration of PI3K inhibitors resulted in a linear correlation between ERK activity and cell growth rate in KRas-mutant cancer cells. Intriguingly, mTORC1 activity was correlated linearly with the cell growth rate in both BRaf-mutant cancer cells and KRas-mutant cancer cells. These observations suggested that mTORC1 activity had a pivotal role in cell growth and that the mTORC1 activity was maintained primarily by the ERK pathway in BRaf mutant cancer cells and by both the ERK and PI3K pathways in KRas-mutant cancer cells. FRET imaging revealed that MEKi inhibited mTORC1 activity with slow kinetics, implying transcriptional control of mTORC1 activity by ERK. In agreement with this observation, MEKi induced the expression of negative regulators of mTORC1, including TSC1, TSC2 and Deptor, which occurred more significantly in BRaf-mutant cells than in KRas-mutant cells. These findings suggested that the suppression of mTORC1 activity and induction of negative regulators of mTORC1 in cancer cells treated for at least 1 day could be used as surrogate markers for the MEKi sensitivity of cancer cells. PMID- 25703331 TI - The origin of breast tumor heterogeneity. AB - How breast diversity is generated is a fascinating and fundamental question with important clinical implications. It is clear that the diversity of phenotypes displayed by breast cancer cells reflects the array of cell types present in the disease-free breast epithelium, including luminal, basal and stem cells. Therefore, it is hypothesized that the molecular regulators governing normal development of the breast epithelium may double as engines of breast tumor diversity. In the past few years, a deepened understanding of the mammary epithelial hierarchy has prompted the search for the cellular precursors of breast tumors. At the same time, the use of novel experimental strategies including the new technology of massively parallel sequencing has provided insight into the origin and evolution of breast tumors. Here, we review the current understanding of the basis of the intrinsic subtypes and the sources of inter-tumor heterogeneity. PMID- 25703333 TI - Placebo and nocebo responses in drug trials of epilepsy. AB - Placebo response can be defined as any therapeutic change on placebo, while the nocebo response is any ill effect during placebo exposure. Several meta-analytic approaches have investigated the extent of placebo response in randomized, placebo-controlled, clinical trials of focal epilepsies. Placebo response rates (proportion of patients with >=50% improvement of seizures versus baseline) ranging from 9.9% up to 15.2% have been reported. Interestingly, a sham response of 15.8% has been noted in trials of transcranial magnetic stimulation. Recently, nocebo response rates of 60.3% and 3.9% were noted, which were defined as the proportion of patients with adverse events (AEs) and those withdrawing because of intolerable AEs, respectively. Factors which were found to influence placebo response were as follows: the year of publication (with more recent studies showing higher rates of placebo response), some clinical characteristics of recruited patients (lower placebo response rates with a history of 7 or more prior lifetime AEDs, a high baseline seizure frequency, prior epilepsy surgery, and higher age at diagnosis), trial design and statistical analysis, and whether studies have been conducted in children or adults. Furthermore, placebo and nocebo rates were correlated with respective seizure outcome and adverse events of the experimental AED. Several mechanisms of placebo and nocebo responses are discussed. Specifically, the role of positive or negative expectations of patients and of investigators may influence the placebo and the nocebo response. Finally, recommendations are given on how to address placebo and nocebo responses in clinical practice. PMID- 25703332 TI - Disruption of CTCF/cohesin-mediated high-order chromatin structures by DNA methylation downregulates PTGS2 expression. AB - The CCCTC-binding factor (CTCF)/cohesin complex regulates gene transcription via high-order chromatin organization of the genome. De novo methylation of CpG islands in the promoter region is an epigenetic hallmark of gene silencing in cancer. Although the CTCF/cohesin complex preferentially targets hypomethylated DNA, it remains unclear whether the CTCF/cohesin-mediated high-order chromatin structure is affected by DNA methylation during tumorigenesis. We found that DNA methylation downregulates the expression of prostaglandin-endoperoxide synthase 2 (PTGS2), which is an inducible, rate-limiting enzyme for prostaglandin synthesis, by disrupting CTCF/cohesin-mediated chromatin looping. We show that the CTCF/cohesin complex is enriched near a CpG island associated with PTGS2 and that the PTGS2 locus forms chromatin loops through methylation-sensitive binding of the CTCF/cohesin complex. DNA methylation abolishes the association of the CTCF/cohesin complex with the PTGS2 CpG island. Disruption of chromatin looping by DNA methylation abrogates the enrichment of transcriptional components, such as positive elongation factor b, at the transcriptional start site of the PTGS2 locus. These alterations result in the downregulation of PTGS2. Our results provide evidence that CTCF/cohesin-mediated chromatin looping of the PTGS2 locus is dynamically influenced by the DNA methylation status. PMID- 25703334 TI - Unusual bonding and properties in main group element chemistry: rational synthesis, characterization, and experimental electron density determination of mixed-valent tetraphosphetes. AB - Five dispirocyclic lambda(3),lambda(5)-tetraphosphetes [{R2Si(NR(1))(NR(2))P2}2] (R(1) = R(2) and R(1) ? R(2)) are easily prepared in almost quantitative yields via photolysis of the respective bis(trimethylsilyl)phosphanyldiazaphosphasiletidines with intense visible light. These deep-yellow low-coordinate phosphorus compounds can be considered as the first higher congeners of the well-known cyclodiphosphazenes. The tetraphosphetes are remarkably stable in air and show unexpected molecular properties related to the unique bonding situation of the central four-pi-electron four-membered phosphorus ring. The extent of rhombic distortion of the central P4 ring is remarkable due to an unusually acute angle at the sigma(2)-phosphorus atoms. All of the P-P bonds are approximately equal in length. The distances are in the middle of the range given by phosphorus single and double bonds. The anisotropic absorption of visible light that can easily be observed in the case of the yellow/colorless dichroic crystals of [{Me2Si(NtBu)(NtBu)P2}2] and the exceptional (31)P NMR chemical shift of the sigma(2)-phosphorus atoms are the most remarkable features of the lambda(3),lambda(5)-tetraphosphetes. In the case of [{Me2Si(NtBu)(NtBu)P2}2], the Hansen-Coppens multipole model is applied to extract the electron density from high-resolution X-ray diffraction data obtained at 100 K. Static deformation density and topological analysis reveal a unique bonding situation in the central unsaturated P4 fragment characterized by polar sigma-bonding, pronounced out-of-ring non-bonding lone pair density on the sigma(2)-phosphorus atoms, and an additional non-classical three-center back bonding contribution. PMID- 25703335 TI - Preference-sensitive risk-cutoff values for prenatal-integrated screening test for Down syndrome. AB - OBJECTIVE: For a pregnant woman considering prenatal screening for early detection of Down Syndrome (DS), there are at least two major outcomes of interest: undetected DS live births and euploid procedure-related fetal losses. The risk-cutoff value of 1/270 has been commonly used for recommending a diagnostic test. The objective of this study was to assess the impact of women's preferences for different pregnancy outcomes on the optimal risk-cutoff values for integrated screening. METHOD: We built a Monte Carlo simulation model of 100,000 singleton second-trimester pregnancies to assess the probabilities of DS live births and euploid procedure-related fetal losses for various risk-cutoff values. To capture how undesirable some women may view an undetected DS live birth relative to a euploid procedure-related fetal loss, we used a ratio W1 : W2 of weights (penalties) assigned to these two adverse pregnancy outcomes. RESULTS: As the relative weight changes, the optimal risk-cutoff value changes significantly. CONCLUSION: A one-size-fits-all risk-cutoff value, such as 1/270, may not always be the best choice, depending on the preferences of women. Preference-sensitive risk-cutoff values for DS screening have the potential to improve the pregnancy outcomes and patient satisfaction. PMID- 25703336 TI - Gene expression and fiber type variations in repeated vastus lateralis biopsies. AB - INTRODUCTION: Muscle sample collection can introduce variation in any measured variable due to inter- and intramuscle variation. We investigated the variation in gene expression and fiber type composition after repeated biopsy sampling from the vastus lateralis muscle. METHODS: Six subjects donated 3 tissue samples each. One hour after baseline sampling from 1 vastus lateralis muscle, samples from both vastus lateralis muscles were obtained. RESULTS: The fiber type composition differed between biopsies taken from the same leg. There were no within-subject differences in gene expression between the 3 biopsies. Multivariate analysis supports a model in which gene expression differs significantly between individuals but is not affected by repeated muscle biopsy sampling from the same subject. CONCLUSION: One vastus lateralis muscle sample per subject is sufficient to establish a reliable baseline for comparing gene expression representing selected pathways over time within the same individual. PMID- 25703337 TI - When molecular probes meet self-assembly: an enhanced quenching effect. AB - We demonstrate that the incorporation of one or two amino acids of phenylalanine (F) or 4-fluoro phenylalanine ((f)F) will greatly lower the background fluorescence intensities of conventional quenched probes with quenchers. This enhanced quenching effect was due to the synergetic effect of the aggregation caused quenching and the presence of a quencher. Such strategy will not greatly affect the enzyme recognition properties to the probes. We also demonstrated that our self-assembled nanoprobe with the enhanced quenching effect showed a better performance in cells for the detection of cell apoptosis than the unassembled probes. Our study demonstrates that using molecular self-assembly can optimize and improve the performance of molecular probes and it provides a simple but very useful strategy to boost the signal-to-noise ratios of fluorescence probes. PMID- 25703338 TI - Computational strategies for understanding the nature of interaction in dioxin imprinted nanoporous trappers. AB - A new computational model capable of understanding the nature of interactions in signature complexes formed between the template (2,3,7,8-tetrachlorodibenzo-p dioxin (TCDD)) and the functional monomers (methacrylic acid (MAA)) using density functional theory (DFT) has been designed. The polymer precursors were optimized for geometries in polymerization media, computing the interaction energies between template molecules and functional monomers of transient pre-polymerized complexes (PPC), and structural and vibrational properties reference to theoretical infrared spectra were computed using DFT of B3LYP/6 311+G(d,p) hybrid functional method. Atom in molecule theory was used to analyze the hydrogen bonding characteristics of PPC of MAA-TCDD. Considering the theoretical titrations conducted in a virtual solvent box, it was found that the 1:4 molar ratio was required to form the most stable PPC in a given solvent system. The electron density plots indicate strong hydrogen bonding as shown by the 2pz dominant highest occupied molecular orbital (HOMO) character that could be the preferable sites of binding for target molecule, TCDD. Considering HOMO approach, the active adsorption sites in molecularly imprinted polymer was modeled to get insight on molecular recognition property for targeted molecule, TCDD. The proposed computational protocol is simple, accurate, and novel to design the polymer and is useful to predict the properties of polymer systems than the conventional theoretical analysis of template-monomer interactions. PMID- 25703339 TI - Bioactive benzofuran derivatives: An insight on lead developments, radioligands and advances of the last decade. AB - Benzofuran core is a highly versatile, presents in many important natural products and natural drugs. Many benzofuran containing synthetic drugs and clinical candidates have been derived from natural products. The present review will provide an insight on lead design-developments of the decade, clinical candidates and PET tracer radio-ligands containing benzofuran core along with brief target biology. Brief of the all approved drugs containing benzofuran core also have been enclosed. Main therapeutic areas covered are Cancer, Neurological disorders including anti-psychotic agent and diabetes. PMID- 25703340 TI - Rhythmic finger tapping reveals cerebellar dysfunction in essential tremor. AB - INTRODUCTION: Cerebellar circuits are hypothesized to play a central role in the pathogenesis of essential tremor. Rhythmic finger tapping is known to strongly engage the cerebellar motor circuitry. We characterize cerebellar and, more specifically, dentate nucleus function, and neural correlates of cerebellar output in essential tremor during rhythmic finger tapping employing functional MRI. METHODS: Thirty-one propranolol-sensitive essential tremor patients with upper limb tremor and 29 healthy controls were measured. T2*-weighted EPI sequences were acquired. The task consisted of alternating rest and finger tapping blocks. A whole-brain and region-of-interest analysis was performed, the latter focusing on the cerebellar cortex, dentate nucleus and inferior olive nucleus. Activations were also related to tremor severity. RESULTS: In patients, dentate activation correlated positively with tremor severity as measured by the tremor rating scale part A. Patients had reduced activation in widespread cerebellar cortical regions, and additionally in the inferior olive nucleus, and parietal and frontal cortex, compared to controls. CONCLUSION: The increase in dentate activation with tremor severity supports involvement of the dentate nucleus in essential tremor. Cortical and cerebellar changes during a motor timing task in essential tremor might point to widespread changes in cerebellar output in essential tremor. PMID- 25703341 TI - Interfacial fracture toughness of aged adhesive-dentin interfaces. AB - OBJECTIVE: To assess interfacial fracture toughness of different adhesive approaches and compare to a standard micro-tensile bond-strength (MUTBS) test after 6 months water storage. METHODS: Chevron-notched beam fracture toughness (CNB) was determined using a modified ISO 24370:2005 standard. Adhesive-dentin micro-specimens (1.0 mm * 1.0 mm * 8-10 mm) were stressed in tensile until failure to determine the micro-tensile bond strength (MUTBS). RESULTS: The highest mean MUTBS and interfacial fracture toughness were measured for the multi step adhesives Clearfil SE Bond (Kuraray Noritake) and OptiBond FL (Kerr). While large differences were observed in the bond strength values (from 7.4 to 27.2 MPa) of the one-step self-etch adhesives tested, interfacial fracture toughness was less different (from 0.7 to 1.0 MPam(1/2)). The adhesive with the lowest mean toughness (All-bond Universal, Bisco) had however the highest Weibull reliability, which might be a better parameter in regard to more consistent clinical performance. The self-adhesive composite Vertise Flow (Kerr) scored significantly lower at all levels. SIGNIFICANCE: Although the ranking of the adhesives tested using CNB and MUTBS corresponded well, the outcome of CNB appeared more reliable and less variable. PMID- 25703342 TI - Graphene-Based Integrated Photovoltaic Energy Harvesting/Storage Device. AB - Energy scavenging has become a fundamental part of ubiquitous sensor networks. Of all the scavenging technologies, solar has the highest power density available. However, the energy source is erratic. Integrating energy conversion and storage devices is a viable route to obtain self-powered electronic systems which have long-term maintenance-free operation. In this work, we demonstrate an integrated power-sheet, consisting of a string of series connected organic photovoltaic cells (OPCs) and graphene supercapacitors on a single substrate, using graphene as a common platform. This results in lighter and more flexible power packs. Graphene is used in different forms and qualities for different functions. Chemical vapor deposition grown high quality graphene is used as a transparent conductor, while solution exfoliated graphene pastes are used as supercapacitor electrodes. Solution-based coating techniques are used to deposit the separate components onto a single substrate, making the process compatible with roll-to roll manufacture. Eight series connected OPCs based on poly(3 hexylthiophene)(P3HT):phenyl-C61-butyric acid methyl ester (PC60 BM) bulk heterojunction cells with aluminum electrodes, resulting in a ~5 V open-circuit voltage, provide the energy harvesting capability. Supercapacitors based on graphene ink with ~2.5 mF cm(-2) capacitance provide the energy storage capability. The integrated-power-sheet with photovoltaic (PV) energy harvesting and storage functions had a mass of 0.35 g plus the substrate. PMID- 25703343 TI - The role of community in the development of elite handball and football players in Denmark. AB - The primary purpose of this study was to investigate the effect of the place of early development in a sample of Danish male elite and youth handball and football players. The sample included 366 handball and football players from the elite Danish league in the season 2011-2012 and a comparison sample of youth players under the age of 12 from 2003, including 147,221 football and 26,290 handball players. Odds ratio analysis showed that both population size and density significantly affected the proportional number of youth players per community and the odds of athletes reaching an elite level in football and handball. The odds for youth player registrations in both handball and football increased in rural in contrast to urban communities. However, elite football players primarily came from communities of high density (>1000 pop./km(2)), whereas elite handball players primarily came from less densely populated communities (100 to <250 pop./km(2)). Furthermore, there seems to be a relation between representation of elite and talent clubs in different communities and the probability of becoming an elite player in both sports. The limited number of elite players in both sports from rural communities may be due to national talent development strategies that do not incorporate development support for clubs in rural areas. Additionally, the results of the study clearly suggest the need to include the youth player population to advance research findings in birthplace effect studies. PMID- 25703345 TI - Characteristics of primary literature in the field of antimicrobial stewardship, 2000-2013. PMID- 25703346 TI - Long-term outcome of belatacept therapy in de novo kidney transplant recipients - a case-match analysis. AB - While belatacept has shown favorable short- and midterm results in kidney transplant recipients, only projections exist regarding its potential impact on long-term outcome. Therefore, we performed a retrospective case-match analysis of the 14 belatacept patients originally enrolled in the phase II multicenter trial at our center. Fifty six cyclosporine (CyA)-treated patients were matched according to age at transplantation, first/retransplant, and donor type. Ten years after kidney transplantation, kidney function remained superior in belatacept-treated patients compared with the CyA control group. Moreover, none of the belatacept-treated patients had donor-specific antibodies >=10 years post transplantation compared with 38.5% of tested CyA-treated subject (0/10 vs. 5/13; P = 0.045). Notably, however, patient and graft survival was virtually identical in both groups (71.4% vs. 71.3%; P = 0.976). In the present single-center study population, patients treated with belatacept demonstrated a patient and graft survival at 10 years post-transplant which was comparable to that of similarly selected CNI-treated patients. Larger studies with sufficient statistical power are necessary to definitively determine long-term graft survival with belatacept. PMID- 25703347 TI - Enzyme transformation to modulate the ligand-receptor interactions between small molecules. AB - Enzymatic transformation is a fundamental process to control ligand-receptor interactions among proteins for signal transduction in cells. Here we report the first example of enzymatic transformation regulated ligand-receptor interactions of small molecules, in which enzymatic reaction changes the stoichiometry of the ligand-receptor binding from 1 : 1 to 1 : 2. We also show that this unique integration of enzymatic transformation and ligand-receptor interactions of small molecules is able to affect the fate of cells. PMID- 25703348 TI - SCML2 establishes the male germline epigenome through regulation of histone H2A ubiquitination. AB - Gametogenesis is dependent on the expression of germline-specific genes. However, it remains unknown how the germline epigenome is distinctly established from that of somatic lineages. Here we show that genes commonly expressed in somatic lineages and spermatogenesis-progenitor cells undergo repression in a genome-wide manner in late stages of the male germline and identify underlying mechanisms. SCML2, a germline-specific subunit of a Polycomb repressive complex 1 (PRC1), establishes the unique epigenome of the male germline through two distinct antithetical mechanisms. SCML2 works with PRC1 and promotes RNF2-dependent ubiquitination of H2A, thereby marking somatic/progenitor genes on autosomes for repression. Paradoxically, SCML2 also prevents RNF2-dependent ubiquitination of H2A on sex chromosomes during meiosis, thereby enabling unique epigenetic programming of sex chromosomes for male reproduction. Our results reveal divergent mechanisms involving a shared regulator by which the male germline epigenome is distinguished from that of the soma and progenitor cells. PMID- 25703350 TI - Can cars and trucks coexist peacefully on highways? Analyzing the effectiveness of road safety policies in Europe. AB - We examine the impact on the traffic accident rate of the interaction between trucks and cars on Europe's roads using a panel data set that covers the period 1999-2010. We find that rising motorization rates for trucks lead to higher traffic fatalities, while rising motorization rates for cars do not. Empirically, the model we build predicts the positive impact of stricter speed limit legislation for trucks in the reduction of road fatalities. These findings lend support to European strategies and aimed at promoting alternative modes of freight transport, including rail and maritime transport. PMID- 25703349 TI - Ect2/Pbl acts via Rho and polarity proteins to direct the assembly of an isotropic actomyosin cortex upon mitotic entry. AB - Entry into mitosis is accompanied by profound changes in cortical actomyosin organization. Here, we delineate a pathway downstream of the RhoGEF Pbl/Ect2 that directs this process in a model epithelium. Our data suggest that the release of Pbl/Ect2 from the nucleus at mitotic entry drives Rho-dependent activation of Myosin-II and, in parallel, induces a switch from Arp2/3 to Diaphanous-mediated cortical actin nucleation that depends on Cdc42, aPKC, and Par6. At the same time, the mitotic relocalization of these apical protein complexes to more lateral cell surfaces enables Cdc42/aPKC/Par6 to take on a mitosis-specific function-aiding the assembly of a relatively isotropic metaphase cortex. Together, these data reveal how the repolarization and remodeling of the actomyosin cortex are coordinated upon entry into mitosis to provide cells with the isotropic and rigid form they need to undergo faithful chromosome segregation and division in a crowded tissue environment. PMID- 25703351 TI - Urban crash-related child pedestrian injury incidence and characteristics associated with injury severity. AB - OBJECTIVE: Describe age-based urban pedestrian versus auto crash characteristics and identify crash characteristics associated with injury severity. MATERIALS AND METHODS: Secondary analysis of the 2004-2010 National Highway and Traffic Safety Administration database for Illinois. All persons in Chicago crashes with age data who were listed as pedestrians (n=7175 child age <=19 yo, n=16,398 adult age >=20 yo) were included. Incidence and crash characteristics were analyzed by age groups and year. Main outcome measures were incidence, crash setting, and injury severity. Multivariate logistic regression analysis was performed to estimate injury severity by crash characteristics. RESULTS: Overall incidence was higher for child (146.6 per 100,000) versus adult (117.3 per 100,000) pedestrians but case fatality rate was lower (0.7% for children, 1.7% for adults). Child but not adult pedestrian injury incidence declined over time (trend test p<0.0001 for <5 yo, 5-9 yo, and 10-14 yo; p<0.05 for 15-19 yo, p=0.96 for >=20 yo). Most crashes for both children and adults took place during optimal driving conditions. Injuries were more frequent during warmer months for younger age groups compared to older (chi(2)p<0.001). Midblock crashes increased as age decreased (p<0.0001 for trend). Most crashes occurred at sites with sub-optimal traffic controls but varied by age (p<0.0001 for trend). Crashes were more likely to be during daylight on dry roads in clear weather conditions for younger age groups compared to older (chi(2)p<0.001). Daylight was associated with less severe injury (child OR 0.93, 95% CI 0.87-0.98; adult OR 0.90, 95% CI 0.87-0.93). CONCLUSION: The incidence of urban pedestrian crashes declined over time for child subgroups but not for adults. The setting of pedestrian crashes in Chicago today varies by age but is similar to that seen in other urban locales previously. Injuries for all age groups tend to be less severe during daylight conditions. Age-based prevention efforts may prove beneficial. PMID- 25703352 TI - Incidence of chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis in Calgary, Alberta, Canada. AB - This study provides an update on the incidence of chronic lymphocytic leukemia (CLL) and monoclonal B-cell lymphocytosis (MBL) in a major Canadian city using the 2008 World Health Organization (WHO) diagnostic criteria. Incidence calculations were performed using data from a centralized flow cytometry laboratory servicing southern Alberta, Canada. The age-standardized incidence of 4.01 cases of CLL per 100,000 person-years is nearly half the rate previously reported in Canada. Compared to previous criteria based on absolute lymphocyte count rather than absolute B-cell count, utilizing the 2008 WHO criteria resulted in a 47.6% decline in CLL incidence (8.42 cases per 100,000 using 1996 criteria). As a consequence, MBL rates are 64% higher. In contrast to 1996 criteria showing a peak CLL incidence between ages 70-74, age-specific incidence rates show a continuous increase with advancing age using the 2008 guidelines. We also report a higher male to female ratio of CLL than previous Canadian reports (1.80:1). CLL incidence in southern Alberta is lower than rates recently reported in the United States using the same criteria. This difference may be due in part to the low median age and the lower proportion of persons of Caucasian European ancestry present in our study population. PMID- 25703353 TI - Mesenchymal stromal cells from patients with acute myeloid leukemia have altered capacity to expand differentiated hematopoietic progenitors. AB - The bone marrow microenvironment may be permissive to the emergence and progression of acute myeloid leukemia (AML). Studying interactions between the microenvironment and leukemia cells should provide new insight for therapeutic advances. Mesenchymal stromal cells (MSCs) are central to the maintenance of the hematopoietic niche. Here we compared the functions and gene expression patterns of MSCs derived from bone marrow aspirates of healthy donors and patients with AML. MSCs expanded from AML patients had heterogeneous morphology and displayed a wide range of proliferation capacity compared to MSCs from healthy controls. The ability of AML-MSCs to support the expansion of committed hematopoietic progenitors from umbilical cord blood-derived CD34+ cells may be impaired while the expression of genes associated with maintaining hematopoietic quiescence appeared to be increased in AML-MSCs compared to healthy donors. These results highlight important potential differences in the biologic profile of MSCs from AML patients compared to healthy donors that may contribute to the emergence or progression of leukemia. PMID- 25703354 TI - Sensitization of enteric neurons to morphine by HIV-1 Tat protein. AB - BACKGROUND: Gastrointestinal (GI) dysfunction is a major cause of morbidity in acquired immunodeficiency syndrome (AIDS). HIV-1-induced neuropathogenesis is significantly enhanced by opiate abuse, which increases proinflammatory chemokine/cytokine release, the production of reactive species, glial reactivity, and neuronal injury in the central nervous system. Despite marked interactions in the gut, little is known about the effects of HIV-1 in combination with opiate use on the enteric nervous system. METHODS: To explore HIV-opiate interactions in myenteric neurons, the effects of Tat +/- morphine (0.03, 0.3, and 3 MUM) were examined in isolated neurons from doxycycline- (DOX-) inducible HIV-1 Tat(1-86) transgenic mice or following in vitro Tat 100 nM exposure (>6 h). KEY RESULTS: Current clamp recordings demonstrated increased neuronal excitability in neurons of inducible Tat(+) mice (Tat+/DOX) compared to control Tat-/DOX mice. In neurons from Tat+/DOX, but not from Tat-/DOX mice, 0.03 MUM morphine significantly reduced neuronal excitability, fast transient and late long-lasting sodium currents. There was a significant leftward shift in V(0.5) of inactivation following exposure to 0.03 MUM morphine, with a 50% decrease in availability of sodium channels at -100 mV. Similar effects were noted with in vitro Tat exposure in the presence of 0.3 MUM morphine. Additionally, GI motility was significantly more sensitive to morphine in Tat(+) mice than Tat(-) mice. CONCLUSIONS & INFERENCES: Overall, these data suggest that the sensitivity of enteric neurons to morphine is enhanced in the presence of Tat. Opiates and HIV-1 may uniquely interact to exacerbate the deleterious effects of HIV-1-infection and opiate exposure on GI function. PMID- 25703355 TI - Patterns and factors associated with low adherence to psychotropic medications during pregnancy--a cross-sectional, multinational web-based study. AB - BACKGROUND: No previous studies have explored how closely women follow their psychotropic drug regimens during pregnancy. This study aimed to explore patterns of and factors associated with low adherence to psychotropic medication during pregnancy. METHODS: Multinational web-based study was performed in 18 countries in Europe, North America, and Australia. Uniform data collection was ensured via an electronic questionnaire. Pregnant women were eligible to participate. Adherence was measured via the 8-item Morisky Medication Adherence Scale (MMAS 8). The Beliefs about Prescribed Medicines Questionnaire (BMQ-specific), the Edinburgh Postnatal Depression Scale (EPDS), and a numeric rating scale were utilized to measure women's beliefs, depressive symptoms, and antidepressant risk perception, respectively. Participants reporting use of psychotropic medication during pregnancy (n = 160) were included in the analysis. RESULTS: On the basis of the MMAS-8, 78 of 160 women (48.8%, 95% CI: 41.1-56.4%) demonstrated low adherence during pregnancy. The rates of low adherence were 51.3% for medication for anxiety, 47.2% for depression, and 42.9% for other psychiatric disorders. Smoking during pregnancy, elevated antidepressant risk perception (risk>=6), and depressive symptoms were associated with a significant 3.9-, 2.3-, and 2.5-fold increased likelihood of low medication adherence, respectively. Women on psychotropic polytherapy were less likely to demonstrate low adherence. The belief that the benefit of pharmacotherapy outweighed the risks positively correlated (r = .282) with higher medication adherence. CONCLUSIONS: Approximately one of two pregnant women using psychotropic medication demonstrated low adherence in pregnancy. Life-style factors, risk perception, depressive symptoms, and individual beliefs are important factors related to adherence to psychotropic medication in pregnancy. PMID- 25703356 TI - Clarithromycin highly-loaded gastro-floating fine granules prepared by high-shear melt granulation can enhance the efficacy of Helicobacter pylori eradication. AB - In an effort to develop a new gastro-retentive drug delivery system (GRDDS) without a large amount of additives, 75% clarithromycin (CAM) loaded fine granules were prepared with three different hydrophobic binders by high-shear melt granulation and their properties were evaluated. Granules containing the higher hydrophobic binder showed sustained drug release and were able to float over 24h. The synchrotron X-ray CT measurement indicated that both the high hydrophobicity of the binder and the void space inside the granules might be involved in their buoyancy. In an in vivo experiment, the floating granules more effectively eradicated Helicobacter pylori than a CAM suspension by remaining in the stomach for a longer period. In short, CAM highly-loaded gastro-floating fine granules can enhance the eradication efficiency of H. pylori compared with CAM alone. PMID- 25703357 TI - The viability of the Parenting Representations Interview for assessing and measuring change in parents of adolescents. AB - Parents' representations include parents' views of their adolescent, of their own parenting and of the parent-adolescent relationship. Two longitudinal studies of parents and their adolescent sons and daughters support the validity of scales coding mothers in the Parenting Representations Interview-Adolescence (PRI-A). The studies, conducted in Israel during the transition from home to military service, demonstrated that three dimensions derived from the PRI-A: positive representations of adolescents, negative emotionality and inadequate boundaries were associated with adolescents' AAI variables, relatedness-autonomy behaviors with mothers, and with other indicators, such as adolescents' wellbeing, romantic intimacy and individuation. Examining parenting representations could help practitioners pinpoint targets for intervention and evaluate the changes that families go through during psychotherapy, as well as the therapeutic process and its outcomes. The findings support the viability of the PRI for use in attachment based interventions for adolescents. PMID- 25703358 TI - Synthesis, spectroscopic and catalytic properties of some new boron hybrid molecule derivatives by BF2 and BPh2 chelation. AB - A new series of Schiff base ligands (L1-L3) and their corresponding fluorine/phenyl boron hybrid complexes [LnBF2] and [LnBPh2] (n=1, 2 or 3) have been synthesized and well characterized by both analytical and spectroscopic methods. The Schiff base ligands and their corresponding fluorine/phenyl boron hybrid complexes have been characterized by NMR ((1)H, (13)C and (19)F), FT-IR, UV-Vis, LC-MS, and fluorescence spectroscopy as well as melting point and elemental analysis. The fluorescence efficiencies of phenyl chelate complexes are greatly red-shifted compared to those of the fluorine chelate analogs based on the same ligands, presumably due to the large steric hindrance and hard pi->pi(*) transition of the diphenyl boron chelation, which can effectively prevent molecular aggregation. The boron hybrid complexes were applied to the transfer hydrogenation of acetophenone derivatives to 1-phenylethanol derivatives in the presence of 2-propanol as the hydrogen source. The catalytic studies showed that boron hybrid complexes are good catalytic precursors for transfer hydrogenation of aromatic ketones in 0.1M iso-PrOH solution. Also, we have found that both steric and electronic factors have a significant impact on the catalytic properties of this class of molecules. PMID- 25703359 TI - Deconvolution procedure of the UV-vis spectra. A powerful tool for the estimation of the binding of a model drug to specific solubilisation loci of bio-compatible aqueous surfactant-forming micelle. AB - UV-vis-spectra evolution of Nile Red loaded into Tween 20 micelles with pH and [Tween 20] have been analysed in a non-conventional manner by exploiting the deconvolution method. The number of buried sub-bands has been found to depend on both pH and bio-surfactant concentration, whose positions have been associated to Nile Red confined in aqueous solution and in the three micellar solubilisation sites. For the first time, by using an extended classical two-pseudo-phases model, the robust treatment of the spectrophotometric data allows the estimation of Nile Red binding constant to the available loci. Hosting capability towards Nile Red is exalted by the pH enhancement. Comparison between binding constant values classically evaluated and those estimated by the deconvolution protocol unveiled that overall binding values perfectly match with the mean values of the local binding sites. This result suggests that deconvolution procedure provides more precise and reliable values, which are more representative of drug confinement. PMID- 25703360 TI - A diagnostic study on folium and orchil dyes with non-invasive and micro destructive methods. AB - Folium and orchil are dyes of vegetal origin. Folium is obtained from Chrozophora tinctoria (L.) A. Juss., whereas orchil is obtained from Roccella and other genera of lichens. These dyes were used in the past to impart purple hue to paintings and textiles as substitutes for the more prised Tyrian purple dye, obtained from shellfish. Despite several citations in ancient technical treatises dating back at least to the Greek-Roman age, the identification of these dyes in artworks is rare. In the case of folium, an additional drawback is that its composition is presently unknown. In this work different non-invasive (FT-IR, FT Raman, fibre optic reflectance spectrophotometry, spectrofluorimetry, X-ray fluorescence spectrometry) and micro-invasive (surface enhanced Raman spectroscopy, matrix assisted laser desorption ionisation-time of flight-mass spectrometry, inductively coupled plasma-mass spectrometry) techniques were used in order to increase the diagnostic information available on these dyes. Measurements were carried out on the dyes extracted from raw materials and on painted or dyed parchments. The possibility to distinguish between folium and orchil by chemical analysis is discussed. PMID- 25703361 TI - Monomer spectroscopic analysis and dimer interaction energies on N-(4 methoxybenzoyl)-2-methylbenzenesulfonamide by experimental and theoretical approaches. AB - In this study, theoretical harmonic vibrational frequencies and geometric parameters of N-(4-methoxybenzoyl)-2-methylbenzenesulfonamide have been investigated by Hartree-Fock (HF), density functional theory (B3LYP hybrid functional) methods with 6-311++G (d,p) basis set, for the first time. Experimental FT-IR (400-4000cm(-1)) and Laser-Raman spectra (100-4000cm(-1)) of title compound in solid phase have been recorded. Interaction energies, N-H?O hydrogen bonds, C-H?O and aromatic pi?pi stacking interactions in dimer structures of the title compound have been evaluated by the calculation methods. The dimer calculations have aimed to present the efficacy and performance of M06 2X hybrid functional on the intermolecular interactions and more strongly bound systems for the corrected and interaction energy by the counterpoise correction procedure. The interaction energies by M06-2X approach give more stable results than HF and B3LYP, extremely. The more strongly bonds, especially, on N-H?O hydrogen bonds and pi?pi interaction for the both dimer structure have also supported that the M06-2X functional of density functional is more effective. PMID- 25703362 TI - The synthesis and characterization of azocalix[4]arene based chemosensors and investigation of their properties. AB - In the present study, azocalix[4]arenes were prepared by linking 4-methoxy, 4 methyl, 4-ethyl, 4-chloro, 4-bromo and 4-nitroaniline to calix[4]arene through a diazo-coupling reaction. A new family of azocalix[4]arene tetraester derivatives, (4a-f), have been prepared with the incorporation of ethyl ester units to azocalix[4]arene. Characterization of the synthesized azocalix[4]arenes was carried using elemental analyses, UV-vis, FT-IR and (1)H NMR spectroscopic techniques. The effect of varying pH levels and solvent types on the absorption ability of azocalix[n]arenes substituted with electron-donating and electron withdrawing groups was examined. Thermal decomposition of azocalix[4]arene derivatives (4a-f) was investigated by means of thermogravimetry (TG), differential thermogravimetry (DTG) and differential thermal analysis (DTA) analyses. In conclusion of the examination of the extraction we found a selectivity characteristic of these compounds toward Ag(+), Hg(+) and Hg(2+) cations. PMID- 25703363 TI - Synthesis, characterization and oscillator-vibrated near-infrared (NIR) luminescence of two pseudo-polymorphic [Yb4((OH)2-Salophen)4] complexes. AB - Through the self-assembly of the (OH)2-Salophen H4L (H4L=N,N'-bis(3 hydroxylsalicylidene)benzene-1,2-diamine) with LnCl3.6H2O or Ln(NO3)3.6H2O (Ln=La, Yb or Gd) in different solvent systems MeCN-EtOH and MeCN-DMF, the mixed (L)(4-) and (H2L)(2-) coordination modes induce the formation of anion independent while pseudo-polymorphic homoleptic linear tetranuclear complexes [Ln4(H2L)2(L)2(EtOH)2] (Ln=La, 1; Ln=Yb, 2 or Ln=Gd, 3) and [Ln4(H2L)2(L)2(DMF)2] (Ln=La, 4; Ln=Yb, 5 or Ln=Gd, 6), respectively. The result of their photophysical properties shows the characteristic NIR luminescence for both Yb(3+)-based complexes 2 and 5 with emissive lifetimes in microsecond ranges, while the difference of nearby and/or distant oscillator-based (OH and/or CH) vibrations from two coordinated EtOH or DMF molecules within the inner coordination spheres of Yb(3+) ions in the two complexes has a decisive effect on their NIR luminescent properties. PMID- 25703364 TI - Spectroscopic studies and molecular orbital calculations of charge transfer complexation between 3,5-dimethylpyrazole with DDQ in acetonitrile. AB - Charge transfer (CT) interaction between 3,5-dimethylpyrazole (DMP) with the pi acceptor 2,3-dichloro-5,6-dicyano-p-benzoquinon (DDQ) has been investigated spectrophotometrically in acetonitrile (AN). Simultaneous reddish brown color has been observed upon mixing donor with acceptor solutions attributing to CT complex formation. The electronic spectra of the formed complex exhibited multi-charge transfer bands at 429, 447, 506, 542 and 589nm, respectively. Job(')s method of continuous variations and spectrophotometric titration methods confirmed the formation of the studied complex in 1:2 ratio between DMP and DDQ. Benesi Hildebrand equation has been applied to calculate the stability constant of the formed complex where it recorded high value supporting formation of stable complex. Molecular orbital calculations using MM2 method and GAMESS (General Atomic and Molecular Electronic Structure System) interface computations as a package of ChemBio3D Ultra12 software were carried out for more analysis of the formed complex in the gas phase. The computational analysis included energy minimisation, stabilisation energy, molecular geometry, Mullikan charges, molecular electrostatic potential (MEP) surfaces of reactants and complex as well as characterization of the higher occupied molecular orbitals (HOMO) and lower unoccupied molecular orbitals (LUMO) surfaces of the complex. A good consistency between experimental and theoretical results has been recorded. PMID- 25703365 TI - New approach application of data transformation in mean centering of ratio spectra method. AB - Most of mean centering (MCR) methods are designed to be used with data sets whose values have a normal or nearly normal distribution. The errors associated with the values are also assumed to be independent and random. If the data are skewed, the results obtained may be doubtful. Most of the time, it was assumed a normal distribution and if a confidence interval includes a negative value, it was cut off at zero. However, it is possible to transform the data so that at least an approximately normal distribution is attained. Taking the logarithm of each data point is one transformation frequently used. As a result, the geometric mean is deliberated a better measure of central tendency than the arithmetic mean. The developed MCR method using the geometric mean has been successfully applied to the analysis of a ternary mixture of aspirin (ASP), atorvastatin (ATOR) and clopidogrel (CLOP) as a model. The results obtained were statistically compared with reported HPLC method. PMID- 25703366 TI - Relation of molecular structure to Franck-Condon bands in the visible-light absorption spectra of symmetric cationic cyanine dyes. AB - A Franck-Condon (FC) model is used to study the solution-phase absorbance spectra of a series of seven symmetric cyanine dyes having between 22 and 77 atoms. Electronic transition energies were obtained from routine visible-light absorbance and fluorescence emission spectra. Harmonic normal modes were computed using density functional theory (DFT) and a polarizable continuum solvent model (PCM), with frequencies corrected using measured mid-infrared spectra. The model predicts the relative energies of the two major vibronic bands to within 5% and 11%, respectively, and also reproduces structure-specific differences in vibronic band shapes. The bands themselves result from excitation of two distinct subsets of normal modes, one with frequencies between 150 and 625cm(-1), and the other between 850 and 1480cm(-1). Vibronic transitions excite symmetric in-plane bending of the polymethine chain, in-plane bends of the polymethine and aromatic C-H bonds, torsions and deformations of N-alkyl substituents, and in the case of the indocyanines, in-plane deformations of the indole rings. For two dyes, the model predicts vibronic coupling into symmetry-breaking torsions associated with trans-cis photoisomerization. PMID- 25703367 TI - The chemiluminescence determination of 2-chloroethyl ethyl sulfide using luminol AgNO3-silver nanoparticles system. AB - A highly sensitive chemiluminescence (CL) method for the determination of 2 chloroethyl ethyl sulfide (2-CEES) was presented. It was found that 2-chloroethyl ethyl sulfide (2-CEES) could inhibit the CL of the luminol-AgNO3 system in the presence of silver nanoparticles in alkaline solution, which made it applicable for determination of 2-CEES. The presented method is simple, convenient, rapid and sensitive. Under the optimized conditions, the calibration curve was linear in the range of 0.0001-1ngmL(-1), with the correlation coefficient of 0.992; while the limit of detection (LOD), based on signal-to-noise ratio (S/N) of 3, was 6*10(-6)ngmL(-1). Also, the relative standard deviation (RSD, n=5) for determination of 2-CEES (0.50ngmL(-1)) was 3.1%. The method was successfully applied for the determination of 2-CEES in environmental aqueous samples. PMID- 25703368 TI - Photoelectric characterization of fabricated dye-sensitized solar cell using dye extracted from red Siahkooti fruit as natural sensitizer. AB - Natural dye extracted from Siahkooti fruit with/without purification by solid phase extraction (SPE) technique was used in the fabrication of DSSC as natural sensitizer. The UV-Vis absorption spectroscopy and Fourier transform infrared (FTIR) were employed to indicate the presence of anthocyanins in the fruit of red Siahkooti. The photoelectrochemical performance and the efficiency of assembled DSSC using Siahkooti fruit dye extract were evaluated and efficiency enhancement was obtained by a preliminary purification of extracted dye. The efficiency and fill factor of the DSSC using purified Siahkooti fruit dye were 0.32% and 0.73%, respectively. The results successfully showed that the DSSC, using Siahkooti fruit extract as a dye sensitizer, is useful for the preparation of environmentally friendly, low-cost, renewable and clean sources of energy. PMID- 25703369 TI - Optical transitions of Ho(3+) in oxyfluoride glasses and upconversion luminescence of Ho(3+)/Yb(3+)-codoped oxyfluoride glasses. AB - Optical properties of Ho(3+)-doped SiO2-BaF2-ZnF2 glasses have been investigated on the basis of the Judd-Ofelt theory. Judd-Ofelt intensity parameters, radiative transition probabilities, fluorescence branching ratios and radiative lifetimes have been calculated for different glass compositions. Upconversion emissions were observed in Ho(3+)/Yb(3+)-codoped SiO2-BaF2-ZnF2 glasses under 980nm excitation. The effects of composition, concentration of the doping ions, and excitation pump power on the upconversion emissions were also systematically studied. PMID- 25703370 TI - Syntheses, crystal structures, luminescent and magnetic properties of two molecular solids containing naphthylmethylene triphenylphosphinium cations and tetra(isothiocyanate)cobalt(II) dianion. AB - The reaction of CoCl2 with the naphthalene methylated triphenylphosphinium bromide [n-NAPMeTPP]Br (n=1, 2) and KSCN, in a methanolic medium at ambient temperature, leads to the self-assembly formation of hybrid 2:1 organic-inorganic molecular solids, [1-NAPMeTPP]2[Co(NCS)4](1) and [2-NAPMeTPP]2[Co(NCS)4](2) ([NAPMeTPP](+)=(naphthylmethylene)(triphenyl)phosphinium), which have been characterized by elemental analyses, IR spectroscopy, UV-Vis spectra, ESI-MS, molar conductivity and single-crystal X-ray diffraction structural analyses. Compound 1 crystallizes in the orthorhombic space group Pna21, while 2 does in the monoclinic space group C2/c. The cations form a dimer through the weak intermolecular C-H?pi interactions in 1 and pi?pi interaction in 2, while the anion and cation are linked by the C-H?S hydrogen bond in 1. Two molecular solids show dual functionalities: (1) the broad fluorescence emission around 400nm in the solid state at room temperature; (2) the weak antiferromagnetic coupling behavior. PMID- 25703371 TI - TAME5OX, abiotic siderophore analogue to enterobactin involving 8 hydroxyquinoline subunits: thermodynamic and photophysical studies. AB - The synthesis, thermodynamic and photophysical properties of trivalent metal complexes of biomimetic nonadentate analogue, 5,5'-(2-(((8-hydroxyquinolin-5 yl)methylamino)methyl)-2-methylpropane-1,3 diyl)bis(azanediyl)bis(methylene)diquinolin-8-ol (TAME5OX), have been described. Combination of absorption and emission spectrophotometry, potentiometry, electrospray mass spectrometry, IR, and theoretical investigation were used to fully characterize metal (Fe(+3), Al(+3) and Cr(+3)) chelates of TAME5OX. In solution, TAME5OX forms protonated complexes [M(H3L)](3+) below pH 3.4, which consecutively deprotonates through one to three-proton processes with rise of pH. The formation constants (Logbeta11n) of neutral complexes formed at or above physiological pH, have been determined to be 30.18, 23.27 and 22.02 with pM values of 31.16, 18.07 and 18.12 for Fe(+3), Al(+3) and Cr(+3) ions, respectively, calculated at pH 7.4, indicating TAME5OX is a powerful among synthetic metal chelator. The results clearly demonstrate that the ligand in a tripodal orchestration firmly binds these ions over wide pH range and forms distorted octahedral complexes. The binding and the coordination event could be monitored from absorption and fluorescence spectroscopy. The high thermodynamic stability in water at physiological pH of ferric complex of TAME5OX indicates that these complexes are resistant to hydrolysis and therefore are well suited for the development of device for applications as probes. The ligand displays high sensitive fluorescence enhancement to Al(3+) at pH 7.4, in water. Moreover, TAME5OX can distinguish Al(3+) from Fe(3+) and Cr(3+) via two different sensing mechanisms: photoinduced electron transfer (PET) for Al(3+) and internal charge transfer (ICT) for Fe(3+) and Cr(3+). Density functional theory was employed for optimization and evaluation of vibrational modes, NBO analysis, excitation and emission properties of the different species of metal complexes observed by solution studies. PMID- 25703372 TI - Assessing the corneal power change after refractive surgery using Scheimpflug imaging. AB - PURPOSE: To investigate whether the Pentacam HR could accurately predict the surgically induced refractive change in patients operated with small-incision lenticule extraction (SMILE) for myopia or femto-second laser in situ keratomileusis (FS-LASIK) for myopia or hyperopic astigmatism. METHODS: Data from three groups consisting of (1) 410 myopic eyes of 410 patients operated with SMILE, (2) 111 myopic eyes of 111 patients operated with FS-LASIK, and (3) 40 eyes of 40 patients with hyperopic astigmatism operated with FS-LASIK were retrospectively analysed. The change in manifest refraction due to surgery was compared with the objectively measured change in corneal power by the Pentacam HR in three different ways: Sagittal Power (calculated as for placido topographers), True Net Power (calculated by a Gaussian optics formula), and Total Corneal Refractive Power (calculated by ray tracing). Multiple linear regression analysis was performed to investigate which parameters influenced the Pentacam HR's prediction of the change in subjective refraction due to surgery. RESULTS: The Total Corneal Refractive Power Apex, Zone calculation in a diameter of 4.0 mm effectively predicted the surgically induced refractive change for all three patient groups. The spherical equivalent was predicted with an error of 0.08 +/- 0.41 D for the SMILE eyes, 0.05 +/- 0.61 D for the myopic eyes operated with FS LASIK, and -0.15 +/- 0.49 D for the hyperopic astigmatic eyes treated with FS LASIK. Regression showed that preoperative refractive error had a significant impact on the prediction error of the Pentacam HR. CONCLUSIONS: Ray tracing calculations based on Scheimpflug imaging accurately assessed the change in manifest refraction due to corneal laser surgery. PMID- 25703373 TI - Forensic Age Estimation Using Thin-Slice Multidetector CT of the Clavicular Epiphyses Among Adolescent Western Chinese. AB - Reaching the age of 18 years is the most significant step for criminal proceedings in China. In this study, a population of 752 individuals was recruited to clarify how strong the chronological age relates to clavicular ossification status revealed by CT scans with 1 mm slice thickness in the West China Han population. Finally, the epiphysis was observed to commence fusion in females at 16.28 years and 16.74 years in males and be fully ossified by 25.97 years in females and 25.81 years in males. These findings suggested that ossification of medial clavicular epiphyseal cartilage can be used in age estimation for West China Han population with the age threshold of 18 years. By comparison with previous German studies, our results suggested that the pace of ossification of medial clavicular epiphyseal cartilage may be potentially affected by socioeconomic status. PMID- 25703375 TI - A conserved activation cluster is required for allosteric communication in HtrA family proteases. AB - In E. coli, outer-membrane stress causes a transcriptional response through a signaling cascade initiated by DegS cleavage of a transmembrane antisigma factor. Each subunit of DegS, an HtrA-family protease, contains a protease domain and a PDZ domain. The trimeric protease domain is autoinhibited by the unliganded PDZ domains. Allosteric activation requires binding of unassembled outer-membrane proteins (OMPs) to the PDZ domains and protein substrate binding. Here, we identify a set of DegS residues that cluster together at subunit-subunit interfaces in the trimer, link the active sites and substrate binding sites, and are crucial for stabilizing the active enzyme conformation in response to OMP signaling. These residues are conserved across the HtrA-protease family, including orthologs linked to human disease, supporting a common mechanism of allosteric activation. Indeed, mutation of residues at homologous positions in the DegP quality-control protease also eliminates allosteric activation. PMID- 25703376 TI - Nothing to sneeze at: a dynamic and integrative computational model of an influenza A virion. AB - The influenza virus is surrounded by an envelope composed of a lipid bilayer and integral membrane proteins. Understanding the structural dynamics of the membrane envelope provides biophysical insights into aspects of viral function, such as the wide-ranging survival times of the virion in different environments. We have combined experimental data from X-ray crystallography, nuclear magnetic resonance spectroscopy, cryo-electron microscopy, and lipidomics to build a model of the intact influenza A virion. This is the basis of microsecond-scale coarse-grained molecular dynamics simulations of the virion, providing simulations at different temperatures and with varying lipid compositions. The presence of the Forssman glycolipid alters a number of biophysical properties of the virion, resulting in reduced mobility of bilayer lipid and protein species. Reduced mobility in the virion membrane may confer physical robustness to changes in environmental conditions. Our simulations indicate that viral spike proteins do not aggregate and thus are competent for multivalent immunoglobulin G interactions. PMID- 25703377 TI - DNA-damage-inducible 1 protein (Ddi1) contains an uncharacteristic ubiquitin-like domain that binds ubiquitin. AB - Ddi1 belongs to a family of shuttle proteins targeting polyubiquitinated substrates for proteasomal degradation. Unlike the other proteasomal shuttles, Rad23 and Dsk2, Ddi1 remains an enigma: its function is not fully understood and structural properties are poorly characterized. We determined the structure and binding properties of the ubiquitin-like (UBL) and ubiquitin-associated (UBA) domains of Ddi1 from Saccharomyces cerevisiae. We found that while Ddi1UBA forms a characteristic UBA:ubiquitin complex, Ddi1UBL has entirely uncharacteristic binding preferences. Despite having a ubiquitin-like fold, Ddi1UBL does not interact with typical UBL receptors but unexpectedly binds ubiquitin, forming a unique interface mediated by hydrophobic contacts and by salt bridges between oppositely charged residues of Ddi1UBL and ubiquitin. In stark contrast to ubiquitin and other UBLs, the beta-sheet surface of Ddi1UBL is negatively charged and therefore is recognized in a completely different way. The dual functionality of Ddi1UBL, capable of binding both ubiquitin and proteasome, suggests an intriguing mechanism for Ddi1 as a proteasomal shuttle. PMID- 25703378 TI - The membrane- and soluble-protein helix-helix interactome: similar geometry via different interactions. AB - alpha Helices are a basic unit of protein secondary structure and therefore the interaction between helices is crucial to understanding tertiary and higher-order folds. Comparing subtle variations in the structural and sequence motifs between membrane and soluble proteins sheds light on the different constraints faced by each environment and elucidates the complex puzzle of membrane protein folding. Here, we demonstrate that membrane and water-soluble helix pairs share a small number of similar folds with various interhelical distances. The composition of the residues that pack at the interface between corresponding motifs shows that hydrophobic residues tend to be more enriched in the water-soluble class of structures and small residues in the transmembrane class. The latter group facilitates packing via sidechain- and backbone-mediated hydrogen bonds within the low-dielectric membrane milieu. The helix-helix interactome space, with its associated sequence preferences and accompanying hydrogen-bonding patterns, should be useful for engineering, prediction, and design of protein structure. PMID- 25703379 TI - Structural insights into Ca2+-calmodulin regulation of Plectin 1a-integrin beta4 interaction in hemidesmosomes. AB - The mechanical stability of epithelial cells, which protect organisms from harmful external factors, is maintained by hemidesmosomes via the interaction between plectin 1a (P1a) and integrin alpha6beta4. Binding of calcium-calmodulin (Ca(2+)-CaM) to P1a together with phosphorylation of integrin beta4 disrupts this complex, resulting in disassembly of hemidesmosomes. We present structures of the P1a actin binding domain either in complex with the N-ter lobe of Ca(2+)-CaM or with the first pair of integrin beta4 fibronectin domains. Ca(2+)-CaM binds to the N-ter isoform-specific tail of P1a in a unique manner, via its N-ter lobe in an extended conformation. Structural, cell biology, and biochemical studies suggest the following model: binding of Ca(2+)-CaM to an intrinsically disordered N-ter segment of plectin converts it to an alpha helix, which repositions calmodulin to displace integrin beta4 by steric repulsion. This model could serve as a blueprint for studies aimed at understanding how Ca(2+)-CaM or EF-hand motifs regulate F-actin-based cytoskeleton. PMID- 25703380 TI - Acidic ionic liquids as sustainable approach of cellulose and lignocellulosic biomass conversion without additional catalysts. AB - The use of ionic liquids (ILs) for biomass processing has attracted considerable attention recently as it provides distinct features for pre-treated biomass and fractionated materials in comparison to conventional processes. Process intensification through integration of dissolution, fractionation, hydrolysis and/or conversion in one pot should be accomplished to maximise economic and technological feasibility. The possibility of using alternative ILs capable not only of dissolving and deconstructing selectively biomass but also of catalysing reactions simultaneously are a potential solution of this problem. In this Review a critical overview of the state of the art and perspectives of the hydrolysis and conversion of cellulose and lignocellulosic biomass using acidic ILs using no additional catalyst are provided. The efficiency of the process is mainly considered with regard to the hydrolysis and conversion yields obtained and the selectivity of each reaction. The process conditions can be easily tuned to obtain sugars and/or platform chemicals, such as furans and organic acids. On the other hand, product recovery from the IL and its purity are the main challenges for the acceptance of this technology as a feasible alternative to conventional processes. PMID- 25703381 TI - Increasing the Sensitivity of Measures to Change. AB - Little attention is paid in prevention research to the ability of measures to accurately assess change, termed "responsiveness" or "sensitivity to change." This paper reviews definitions and measures of responsiveness, and suggests five strategies for increasing sensitivity to change, with central focus on prevention research with small samples: (a) improving understandability and cultural validity, (b) assuring that the measure covers the full range of the latent construct being measured, (c) eliminating redundant items, (d) maximizing sensitivity of the device used to collect responses; and (e) asking directly about change. Examples of the application of each strategy are provided. The discussion focuses on using the issues as a checklist for improving measures and the implications of sensitivity to change for prevention research with small samples. PMID- 25703382 TI - A pilot randomized controlled trial of a brief parenting intervention in low resource settings in Panama. AB - The aim of this study was to determine whether an intervention from the Triple P Positive Parenting Program system was effective in reducing parental reports of child behavioral difficulties in urban low-income settings in Panama City. A pilot parallel-group randomized controlled trial was carried out. A total of 108 parents of children 3 to 12 years old with some level of parent-rated behavioral difficulties were randomly assigned to a discussion group on "dealing with disobedience" or to a no intervention control. Blinded assessments were carried out prior to the intervention, 2 weeks, 3 months, and 6 months later. Results indicated that parental reports of child behavioral difficulties changed over time and decreased more steeply in the intervention than in the control group. The effects of the intervention on parental reports of behavioral difficulties were moderate at post-intervention and 3-month follow-up, and large at 6-month follow-up. Parents who participated in the discussion group reported fewer behavioral difficulties in their children after the intervention than those in the control condition. They also reported reduced parental stress and less use of dysfunctional parenting practices. There is a limited amount of evidence on the efficacy of parenting interventions in low-resource settings. This pilot trial was carried out using a small convenience sample living in low-income urban communities in Panama City, and therefore, the findings are of reduced generalizability to other settings. However, the methodology employed in this trial represents an example for future work in other low-resource settings. PMID- 25703383 TI - Case of angiosarcoma on the abdominal wall, an extremely rare variant, putatively shared the pathogenesis with Stewart-Treves syndrome. PMID- 25703384 TI - Acetaldehyde, not ethanol, impairs myelin formation and viability in primary mouse oligodendrocytes. AB - BACKGROUND: Excessive ethanol (EtOH) drinking is associated with white matter loss in the brain at all stages of life. Myelin-forming oligodendrocytes (OLs) are a major component of white matter, but their involvement in EtOH-mediated white matter loss is unclear. Myelination continues throughout the life with highest rates during fetal development and adolescence. However, little is known about the effects of EtOH and its principal metabolite acetaldehyde (ACD) on OLs at the cellular level. METHODS: We compared the responses to different concentrations of EtOH or ACD by primary OLs in culture. RESULTS: EtOH did not cause significant cell death at concentrations lower than 120 mM, even after 24 hours. In comparison, ACD was highly lethal at doses above 50 MUM. High concentrations of EtOH (120 mM) and ACD (500 MUM) for 24 hours did not reduce myelin in mature OLs. Myelin production and OL differentiation were significantly impaired by 7 days exposure to 500 or 50 MUM ACD but not 120 mM EtOH. CONCLUSIONS: This study shows that OLs are relatively resistant to EtOH, even at a concentration more than 4 times the typical blood EtOH concentrations associated with social drinking (10 to 30 mM). In contrast, OLs are much more sensitive to ACD than EtOH, particularly with long-term exposure. This suggests that part of white matter loss in response to EtOH, especially during high rates of myelin formation, may be due in part to the effects of its principal metabolite ACD. PMID- 25703385 TI - Banana leaf and glucose mineralization and soil organic matter in microhabitats of banana plantations under long-term pesticide use. AB - Soil organic matter (SOM) and microbial activity are key components of soil quality and sustainability. In the humid tropics of Costa Rica 3 pesticide regimes were studied-fungicide (low input); fungicide and herbicide (medium input); and fungicide, herbicide, and nematicide (high input)-under continuous banana cultivation for 5 yr (young) or 20 yr (old) in 3 microhabitats-nematicide ring around plants, litter pile of harvested banana, and bare area between litter pile and nematicide ring. Soil samples were incubated sequentially in the laboratory: unamended, amended with glucose, and amended with ground banana leaves. Soil organic matter varied with microhabitat, being greatest in the litter pile, where microbes had the greatest basal respiration with ground banana leaf, whereas microbes in the nematicide ring had the greatest respiration with glucose. These results suggest that soil microbes adapt to specific microhabitats. Young banana plantations had similar SOM compared with old plantations, but the former had greater basal microbial respiration in unamended and in glucose-amended soil and greater first-order mineralization rates in glucose-amended soil, thus indicating soil biological quality decline over time. High pesticide input did not decrease microbial activity or mineralization rate in surface soil. In conclusion, microbial activity in tropical volcanic soil is highly adaptable to organic and inorganic inputs. PMID- 25703386 TI - GeneYenta: a phenotype-based rare disease case matching tool based on online dating algorithms for the acceleration of exome interpretation. AB - Advances in next-generation sequencing (NGS) technologies have helped reveal causal variants for genetic diseases. In order to establish causality, it is often necessary to compare genomes of unrelated individuals with similar disease phenotypes to identify common disrupted genes. When working with cases of rare genetic disorders, finding similar individuals can be extremely difficult. We introduce a web tool, GeneYenta, which facilitates the matchmaking process, allowing clinicians to coordinate detailed comparisons for phenotypically similar cases. Importantly, the system is focused on phenotype annotation, with explicit limitations on highly confidential data that create barriers to participation. The procedure for matching of patient phenotypes, inspired by online dating services, uses an ontology-based semantic case matching algorithm with attribute weighting. We evaluate the capacity of the system using a curated reference data set and 19 clinician entered cases comparing four matching algorithms. We find that the inclusion of clinician weights can augment phenotype matching. PMID- 25703387 TI - Principle component analyses of questionnaires measuring individual differences in synaesthetic phenomenology. AB - Questionnaires have been developed for categorising grapheme-colour synaesthetes into two sub-types based on phenomenology: associators and projectors. The general approach has been to assume a priori the existence of two sub-types on a single dimension (with endpoints as projector and associator) rather than explore, in a data-driven fashion, other possible models. We collected responses from 175 grapheme-colour synaesthetes on two questionnaires, the Illustrated Synaesthetic Experience Questionnaire (Skelton, Ludwig, & Mohr, 2009) and Rouw and Scholte's (2007) Projector-Associator Questionnaire. After Principle Component Analysis both questionnaires were comprised of two factors which coincide with the projector/associator distinction. This suggests that projectors and associators are not opposites of each other, but separate dimensions of experience (e.g. some synaesthetes claim to be both, others claim to be neither). The revised questionnaires provide a useful tool for researchers and insights into the phenomenology of synaesthesia. PMID- 25703388 TI - A new risk factor for cardiovascular disease and associated risk factors: education. PMID- 25703389 TI - Neurological applications of transcranial high intensity focused ultrasound. AB - Advances in transcranial MRI-guided focused ultrasound have renewed interest in lesioning procedures in functional neurosurgery with a potential role in the treatment of neurological conditions such as chronic pain, brain tumours, movement disorders and psychiatric diseases. While the use of transcranial MRI guided focused ultrasound represents a new innovation in neurosurgery, ultrasound has been used in neurosurgery for almost 60 years. This paper reviews the major historical milestones that have led to modern transcranial focused ultrasound and discusses current and evolving applications of ultrasound in the brain. PMID- 25703390 TI - Next generation antithrombotic therapy: focus on antisense therapy against coagulation factor XI. AB - Although the current therapeutic armamentarium of venous thrombosis encompasses the use of vitamin K antagonists, heparins, and direct oral anticoagulants, these drugs have several important drawbacks. Antisense oligonucleotides are relatively short single-stranded nucleic acid sequences, which hybridize with a target messenger RNA (mRNA) and suppress protein synthesis. Coagulation factor XI is a key player in blood coagulation, and thus represents a potential target for antisense therapy. The available evidence reviewed in this article suggests that factor XI antisense oligonucleotides may be more effective than conventional anticoagulants in preventing the onset and propagation of thrombosis, do not require factor measurement since the reduction of mRNA synthesis appears dose dependently, robustly, and stably decreased for 3 to 5 weeks after the end of administration, with an incidence of major bleeding that is at least not greater than that associated with warfarin or low-molecular-weight heparin therapy. Despite conceptual simplicity, rational design, and relatively inexpensive cost, the preliminary findings in animal models and in patients undergoing knee surgery need to be validated in other prospective trials and cost-effective analyses before this attractive treatment option can be advocated as a new paradigm in prevention and treatment of venous thrombosis. PMID- 25703391 TI - Diagnosis and management of dementia in family practice. AB - BACKGROUND: Improving quality of care for people with dementia is a high priority. Considerable resources have been invested in financial incentives, guideline development, public awareness and educational programmes to promote earlier diagnosis and better management. OBJECTIVES: Evaluating family physicians' concordance with guidelines on diagnosis and management of people with dementia, from first documentation of symptoms to formal diagnosis. METHOD: Analysis of medical records of 136 people with dementia recruited by 19 family practices in NW London and surrounding counties. RESULTS: Practices invited 763 people with dementia to participate, 167 (22%) agreed. Complete records were available for 136 (18%). The majority of records included reference to recommended blood tests, informant history and caregiver concerns. Presence or absence of symptoms of depression, psychosis, other behavioural and psychological symptoms of dementia, and cognitive function tests were documented in 30%-40% of records. Documentation of discussions about signs and symptoms of dementia, treatment options, care, support, financial, legal and advocacy advice were uncommon. Comparison of these findings from a similar study in 2000-2002 suggests improvements in concordance with blood tests, recording informant history, presence or absence of depression or psychosis symptoms. There was no difference in documenting cognitive function tests. Immediate referral to specialists was more common in the recent study. CONCLUSION: Five years after UK dementia guidelines and immediately after the launch of the dementia strategy, family physicians appeared concordant with clinical guidelines for dementia diagnosis (other than cognitive function tests), and referred most patients immediately. However, records did not suggest systematic dementia management. PMID- 25703392 TI - Fluorescent probe for detection of Cu2+ using core-shell CdTe/ZnS quantum dots. AB - Core-shell CdTe/ZnS quantum dots capped with 3-mercaptopropionic acid (MPA) were successfully synthesized in aqueous medium by hydrothermal synthesis. These quantum dots have advantages compared to traditional quantum dots with limited biological applications, high toxicity and tendency to aggregate. The concentration of Cu(2+) has a significant impact on the fluorescence intensity of quantum dots (QDs), therefore, a rapid sensitive and selective fluorescence probe has been proposed for the detection of Cu(2+) in aqueous solution. Under optimal conditions, the fluorescence intensity of CdTe/ZnS QDs was linearly proportional to the concentration of Cu(2+) in the range from 2.5 * 10(-9) M to 17.5 * 10(-7) M with the limit of 1.5 * 10(-9) M and relative standard deviation of 0.23%. The quenching mechanism is static quenching with recoveries of 97.30-102.75%. PMID- 25703393 TI - Confidence intervals for intraclass correlation coefficients in a nonlinear dose response meta-analysis. AB - This work is motivated by a meta-analysis case study on antipsychotic medications. The Michaelis-Menten curve is employed to model the nonlinear relationship between the dose and D2 receptor occupancy across multiple studies. An intraclass correlation coefficient (ICC) is used to quantify the heterogeneity across studies. To interpret the size of heterogeneity, an accurate estimate of ICC and its confidence interval is required. The goal is to apply a recently proposed generic beta-approach for construction the confidence intervals on ICCs for linear mixed effects models to nonlinear mixed effects models using four estimation methods. These estimation methods are the maximum likelihood, second order generalized estimating equations and two two-step procedures. The beta approach is compared with a large sample normal approximation (delta method) and bootstrapping. The confidence intervals based on the delta method and the nonparametric percentile bootstrap with various resampling strategies failed in our settings. The beta-approach demonstrates good coverages with both two-step estimation methods and consequently, it is recommended for the computation of confidence interval for ICCs in nonlinear mixed effects models for small studies. PMID- 25703394 TI - Can one pill a day keep rejection away? PMID- 25703395 TI - Phonological and morphophonological effects on grammatical development in children with specific language impairment. AB - BACKGROUND: Five-year-olds with specific language impairment (SLI) often struggle with mastering grammatical morphemes. It has been proposed that verbal morphology is particularly problematic in this respect. Previous research has also shown that in young typically developing children grammatical markers appear later in more phonologically challenging contexts. AIMS: The main aim was to explore whether grammatical deficits in children with SLI are morphosyntactic in nature, or whether phonological factors also explain some of the variability in morpheme production. The analysis considered the effects of the same phonological factors on the production of three different morphemes: two verbal (past tense -ed; third person singular -s) and one nominal morpheme (possessive -s). METHODS & PROCEDURES: The participants were 30 children with SLI (21 boys) aged 4;6-5;11 years (mean = 5;1). The data were collected during grammar test sessions, which consisted of question/answer elicitations of target forms involving picture props. A total of 2301 items were analysed using binary logistic regression; the predictors included: (1) utterance position of the target word, (2) phonological complexity of its coda, (3) voicing of the final stem consonant, (4) syllabicity (allomorph type) and (5) participant accounting for the individual differences in the responses. OUTCOMES & RESULTS: The results showed a robust effect of syllabicity on the correct morpheme production. Specifically, syllabic allomorphs (e.g., She dresses) were significantly more challenging than the segmental ones (e.g., He runs) for all three morphemes. The effects of other factors were observed only for a single morpheme: coda complexity and voicing helped explain variability in past tense production, and utterance position significantly affected children's performance with the possessive. The participant factor also had a significant effect, indicating high within-group variability--often observed in SLI population. CONCLUSIONS & IMPLICATIONS: The systematic effect of syllabicity across both verbal and nominal morphemes suggests morphophonological influences in the grammatical development of children with SLI that cannot be fully explained by syntactic deficits. Poorer performance in producing syllabic allomorphs can be accounted for by much lower overall frequency of these forms, and by the 'tongue-twisting' effect of producing similar segments in succession, as in added [aeded], washes [walpha?ez]. Interestingly, the greater acoustic salience of the syllabic allomorphs (an extra syllable) does not enhance children's abilities to produce them. These findings suggest that the interconnections between different levels of language have a stronger effect on the grammatical development of children with SLI than might be expected. Allomorphy should, therefore, be taken into account when designing language assessments and speech therapy, ensuring that children receive sufficient practice with the entire set of allomorphic variants. PMID- 25703396 TI - Molecular detection of the index case of a subclinical Salmonella Kentucky epidemic on a dairy farm. AB - Salmonella enterica commonly colonizes the intestinal tract of cattle and is a leading cause of foodborne illness. A previously described investigation into the prevalence of S. enterica on a dairy farm revealed an 8-year-long asymptomatic S. enterica epidemic caused by serotypes Cerro and Kentucky in the lactating herd. To investigate the source of the S. Kentucky strains, the genomes of two S. Kentucky isolates were sequenced; one collected prior to the epidemic (2004) and one collected during the epidemic (2010). Comparative genomic analysis demonstrated significant polymorphisms between the two strains. PCR primers targeting unique and strain-specific regions were developed, and screening of the archived isolates identified the index case of the asymptomatic S. Kentucky epidemic as a heifer that was raised off-site and transported onto the study farm in 2005. Analysis of isolates collected from all heifers brought onto the farm demonstrated frequent re-introduction of clones of the epidemic strain suggesting transmission of pathogens between farms might occur repeatedly. PMID- 25703397 TI - Risk factors for methicillin-resistant Staphylococcus aureus skin and soft-tissue infections in outpatients in Taiwan. AB - Information on the risk factors for community-associated skin and soft-tissue infections (SSTIs) due to methicillin-resistant Staphylococcus aureus in Asian populations is scarce. To this end we performed a case-control study of patients treated at two hospital-affiliated outpatient clinics in Taiwan to determine potential risk factors for MRSA SSTIs. S. aureus was isolated from 39 of 100 eligible patients, and 74% were MRSA. Apart from resistance to clindamycin and erythromycin, most MRSA isolates were susceptible to appropriate antimicrobials. The significant risk factors identified by multivariate analysis for MRSA SSTIs were male gender (P = 0.09), nasal carriage of MRSA (P = 0.02), exposure to an individual who had surgery within a year before infection (P = 0.02), and antibiotic treatment for SSTI in the year before infection (P = 0.04). The identification of such factors may assist provision of appropriate treatment to patients with suspected S. aureus SSTIs particularly in Taiwan. PMID- 25703398 TI - The impact of ethnicity and geographical location of residence on the 2009 influenza H1N1 pandemic vaccination. AB - In Canada, vaccination policies against the 2009 influenza H1N1 pandemic (H1N1pdm09) were modified at different times during the autumn wave. We hypothesized that ethnicity and place of residence influenced the odds of vaccination. To test this hypothesis, we used vaccination databases for the entire province of Manitoba, and obtained the age distribution of vaccination for First Nations (FN) and non-First Nations (non-FN) populations. We used regression analysis to determine the effect of ethnicity and location of residence on odds of vaccination. We found that individuals with FN identity were over 2.8 times [95% confidence interval (CI) 2.79-2.87] more likely to receive vaccination compared to non-FN individuals. For the FN populations, on-reserve residency was associated with 5.15-fold (95% CI 5.00-5.30) higher odds of vaccination compared to off-reserve residency. Our study highlights the importance of demographic and geographical variables in developing strategies for vaccine prioritization. PMID- 25703399 TI - Analysis of potential changes in seriousness of influenza A and B viruses in Hong Kong from 2001 to 2011. AB - Continued monitoring of the seriousness of influenza viruses is a public health priority. We applied time-series regression models to data on cardio-respiratory mortality rates in Hong Kong from 2001 to 2011. We used surveillance data on outpatient consultations for influenza-like illness, and laboratory detections of influenza types/subtypes to construct proxy measures of influenza activity. In the model we allowed the regression coefficients for influenza to drift over time, and adjusted for temperature and humidity. The regression coefficient for influenza A(H3N2) increased significantly in 2005. The regression coefficients for influenza A(H1N1) and B were relatively stable over the period. Our model suggested an increase in seriousness of A(H3N2) in 2005, the year after the appearance of the A/Fujian/411/2002(H3N2)-like virus when the drifted A/California/7/2004(H3N2)-like virus appeared. Ongoing monitoring of mortality and influenza activity could permit identification of future changes in seriousness of influenza virus infections. PMID- 25703400 TI - Diphtheria outbreak in Maranhao, Brazil: microbiological, clinical and epidemiological aspects. AB - We describe microbiological, clinical and epidemiological aspects of a diphtheria outbreak that occurred in Maranhao, Brazil. The majority of the 27 confirmed cases occurred in partially (n = 16) or completely (n = 10) immunized children (n = 26). Clinical signs and characteristic symptoms of diphtheria such as cervical lymphadenopathy and pseudomembrane formation were absent in 48% and 7% of the cases, respectively. Complications such as paralysis of lower limbs were observed. Three cases resulted in death, two of them in completely immunized children. Microbiological analysis identified the isolates as Corynebacterium diphtheriae biovar intermedius with a predominant PFGE type. Most of them were toxigenic and some showed a decrease in penicillin G susceptibility. In conclusion, diphtheria remains endemic in Brazil. Health professionals need to be aware of the possibility of atypical cases of C. diphtheriae infection, including pharyngitis without pseudomembrane formation. PMID- 25703401 TI - Nasopharyngeal vs. adenoid cultures in children undergoing adenoidectomy: prevalence of bacterial pathogens, their interactions and risk factors. AB - Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis and Staphylococcus aureus colonization of the adenoids and nasopharynx in 103 preschool children who underwent adenoidectomy for recurrent upper respiratory tract infections was examined. Bacterial interactions and risk factors for bacterial colonization of the nasopharynx and adenoids, separately, were analysed statistically. The prevalence of simultaneous isolation from both anatomical sites was 45.6% for S. pneumoniae, 29.1% for H. influenzae, 15.5% for M. catarrhalis and 18.4% for S. aureus. Three pathogens were significantly more frequent together from adenoid samples; nasopharyngeal swabs more often yielded a single organism, but without statistical significance. M. catarrhalis and S. aureus significantly more frequently co-existed with S. pneumoniae and H. influenzae than with each other and a positive association of S. pneumoniae and H. influenzae in adenoid samples was evident. Several differences between risk factors for nasopharyngeal and adenoid colonization by the individual pathogens were observed. We conclude that the adenoids and nasopharynx appear to differ substantially in colonization by pathogenic microbes but occurrence of H. influenzae and S. pneumoniae in the nasopharynx could be predictive of upper respiratory tract infections. PMID- 25703402 TI - Spatio-temporal clustering of hand, foot and mouth disease at the county level in Sichuan province, China, 2008-2013. AB - China has recently experienced a marked increase in the incidence of hand, foot and mouth disease (HFMD). Effective spatio-temporal monitoring of HFMD incidence is important for successful implementation of control and prevention measures. This study monitored county-level HFMD reported incidence rates for Sichuan province, China by examining spatio-temporal patterns. County-level data on HFMD daily cases between January 2008 and December 2013 were obtained from the China Information System for Disease Control and Prevention. We first conducted purely temporal and purely spatial descriptive analyses to characterize the distribution patterns of HFMD. Then, the global Moran's I statistic and space-time scan statistic were used to detect the spatial autocorrelation and identify the high risk clusters in each year, respectively. A total of 212267 HFMD cases were reported in Sichuan province during the study period (annual average incidence 43.65/100000), and the incidence seasonal peak was between April and July. Relatively high incidence rates appeared in the northeastern-southwestern belt. HFMD had positive spatial autocorrelation at the county level with global Moran's I increasing from 0.27 to 0.52 (P < 0.001). Spatio-temporal cluster analysis detected six most-likely clusters and several secondary clusters from 2008 to 2013. The centres of the six most-likely clusters were all located in the provincial capital city Chengdu. Chengdu and its neighbouring cities had always been spatio-temporal clusters, which indicated the need for further intensive space-time surveillance. Allocating more resources to these areas at suitable times might help to reduce HFMD incidence more effectively. PMID- 25703403 TI - Predicting CCHF incidence and its related factors using time-series analysis in the southeast of Iran: comparison of SARIMA and Markov switching models. AB - Crimean-Congo haemorrhagic fever (CCHF) is endemic in the southeast of Iran. This study aimed to predict the incidence of CCHF and its related factors and explore the possibility of developing an empirical forecast system using time-series analysis of 13 years' data. Data from 2000 to 2012 were obtained from the Health Centre of Zahedan University of Medical Sciences, Climate Organization and the Veterinary Organization in the southeast of Iran. Seasonal autoregressive integrated moving average (SARIMA) and Markov switching models (MSM) were performed to examine the potential related factors of CCHF outbreaks. These models showed that the mean temperature ( degrees C), accumulated rainfall (mm), maximum relative humidity (%) and legal livestock importation from Pakistan (LIP) were significantly correlated with monthly incidence of CCHF in different lags (P < 0.05). The modelling fitness was checked with data from 2013. Model assessments indicated that the MSM had better predictive ability than the SARIMA model [MSM: root mean square error (RMSE) 0.625, Akaike's Information Criterion (AIC) 266.33; SARIMA: RMSE 0.725, AIC 278.8]. This study shows the potential of climate indicators and LIP as predictive factors in modelling the occurrence of CCHF. Our results suggest that MSM provides more information on outbreak detection and can be a better predictive model compared to a SARIMA model for evaluation of the relationship between explanatory variables and the incidence of CCHF. PMID- 25703405 TI - Unusual retropharyngeal mass. PMID- 25703404 TI - Increased prevalence of group A streptococcus isolates in streptococcal toxic shock syndrome cases in Japan from 2010 to 2012. AB - Streptococcal toxic shock syndrome (STSS) is a severe invasive infection characterized by the sudden onset of shock, multi-organ failure, and high mortality. In Japan, appropriate notification measures based on the Infectious Disease Control law are mandatory for cases of STSS caused by beta-haemolytic streptococcus. STSS is mainly caused by group A streptococcus (GAS). Although an average of 60-70 cases of GAS-induced STSS are reported annually, 143 cases were recorded in 2011. To determine the reason behind this marked increase, we characterized the emm genotype of 249 GAS isolates from STSS patients in Japan from 2010 to 2012 and performed antimicrobial susceptibility testing. The predominant genotype was found to be emm1, followed by emm89, emm12, emm28, emm3, and emm90. These six genotypes constituted more than 90% of the STSS isolates. The number of emm1, emm89, emm12, and emm28 isolates increased concomitantly with the increase in the total number of STSS cases. In particular, the number of mefA positive emm1 isolates has escalated since 2011. Thus, the increase in the incidence of STSS can be attributed to an increase in the number of cases associated with specific genotypes. PMID- 25703406 TI - [Emergency contraception: efficacy difference between levonorgestrel and ulipristal acetate depending on the follicular size at the time of an unprotected sexual intercourse]. AB - The most used treatment in the world for emergency contraception is the levonorgestrel (LNG) pill. However, its efficacy decreases if it is administered 3 days after unprotected sexual intercourse, whereas the ulipristal acetate (UPA) pill is effective up until 5 days afterwards. Pooled clinical data show that UPA is more effective than LNG when taken very shortly after intercourse (within 24h) or, conversely, between 72 and 120 h after intercourse. UPA is also more effective than LNG in inhibiting follicular rupture when administered near the time of ovulation. We show here why overall UPA is more effective than LNG in reducing the rate of unwanted pregnancies by demonstrating the effect of each product depending on the follicular size at the time of an unprotected sexual intercourse We also explain the difference between UPA and LNG in the maximum time to administration simply by the shift in ovulation and the fact that UPA has an effect on larger follicles than LNG does (18 mm vs. 14 mm), without postulating a hypothetical endometrial effect. We also explain why UPA and LNG remain emergency contraceptives and should not be used for daily contraception. PMID- 25703407 TI - Anatomy of the ventricular septal defect in outflow tract defects: similarities and differences. AB - OBJECTIVE: The study objective was to analyze the anatomy of the ventricular septal defect found in various phenotypes of outflow tract defects. METHODS: We reviewed 277 heart specimens with isolated outlet ventricular septal defect without subpulmonary stenosis (isolated outlet ventricular septal defect, 19); tetralogy of Fallot (71); tetralogy of Fallot with pulmonary atresia (51); common arterial trunk (54); double outlet right ventricle (65) with subaortic, doubly committed, or subpulmonary ventricular septal defect; and interrupted aortic arch type B (17). Special attention was paid to the rims of the ventricular septal defect viewed from the right ventricular side and the relationships between the tricuspid and aortic valves. RESULTS: The ventricular septal defect was always located in the outlet of the right ventricle, between the 2 limbs of the septal band. There was a fibrous continuity between the tricuspid and aortic valves in 74% of specimens with isolated outlet ventricular septal defect, 66% of specimens with tetralogy of Fallot, 39% of specimens with tetralogy of Fallot with pulmonary atresia, 4.6% of specimens with double outlet right ventricle, 1.8% of specimens with common arterial trunk, and zero of specimens with interrupted aortic arch type B (P < .005). When present, this continuity always involved the anterior tricuspid leaflet. CONCLUSIONS: The ventricular septal defect in outflow tract defects is always an outlet ventricular septal defect, cradled between the 2 limbs of the septal band. However, there are some differences regarding the posteroinferior and superior rims of the ventricular septal defect. These differences suggest an anatomic continuum from the isolated outlet ventricular septal defect to the interrupted aortic arch type B rather than distinct physiologic phenotypes, related to various degrees of abnormal rotation of the outflow tract during heart development: minimal in isolated outlet ventricular septal defect; incomplete in tetralogy of Fallot, tetralogy of Fallot with pulmonary atresia, and double outlet right ventricle; absent in common arterial trunk; and excessive in interrupted aortic arch type B. PMID- 25703408 TI - A new complication of transesophageal echocardiography: Pulmonary embolization of a right atrial myxoma. PMID- 25703409 TI - Gentamicin-collagen sponge reduces the risk of sternal wound infections after heart surgery: Meta-analysis. AB - OBJECTIVES: Sternal wound infections are serious postoperative complications that increase the length of hospital stay and healthcare costs. The benefit of implantable gentamicin-collagen sponges in reducing sternal wound infections has been questioned in a recent multicenter trial. We aimed to perform a comprehensive meta-analysis of studies assessing the efficacy of implantable gentamicin-collagen sponges in sternal wound infection prevention. METHODS: Multiple databases were screened for studies assessing the efficacy of implantable gentamicin-collagen sponges after heart surgery. The primary end point was sternal wound infection, and secondary end points were the occurrence of deep sternal wound infection, superficial sternal wound infection, mediastinitis, and mortality. Randomized controlled trials and observational studies were analyzed separately. By means of meta-regression, we examined the correlation between sternal wound infection and extent to which the bilateral internal thoracic artery was harvested. RESULTS: A total of 14 studies (N = 22,135, among them 4 randomized controlled trials [N = 4672]) were included in the analysis. Implantable gentamicin-collagen sponges significantly reduced the risk of sternal wound infection by approximately 40% when compared with control (risk ratio [RR], 0.61; 95% confidence interval [CI], 0.39-0.98; P = .04 for randomized controlled trials and RR, 0.61; 95% CI, 0.42-0.89; P = .01 for observational studies). A similar, significant benefit was demonstrated for deep sternal wound infection (RR, 0.60; 95% CI, 0.42-0.88; P = .008) and superficial sternal wound infection (RR, 0.60; 95% CI, 0.43-0.83; P = .002). The overall analysis revealed a reduced risk of mediastinitis (RR, 0.64; 95% CI, 0.45-0.91; P = .01). The risk of death was unchanged. A significant positive linear correlation (P = .05) was found between the log RR of sternal wound infection and the percentage of patients receiving bilateral internal thoracic artery grafts. CONCLUSIONS: Implantable gentamicin-collagen sponges significantly reduce the risk of sternal wound infection after cardiac surgery, with evidence consistent in randomized and observational-level data. However, the extent of this benefit might be attenuated in patients receiving bilateral internal thoracic artery grafts. PMID- 25703410 TI - Pericardial diverticula misdiagnosed as pericardial cysts. PMID- 25703411 TI - Poly-N-acetyl glucosamine nanofibers for negative-pressure wound therapies. AB - The wound healing promoting effect of negative wound pressure therapies (NPWT) takes place at the wound interface. The use of bioactive substances at this site represents a major research area for the development of future NPWT therapies. To assess wound healing kinetics in pressure ulcers treated by NPWT with or without the use of a thin interface membrane consisting of poly-N-acetyl glucosamine nanofibers (sNAG) a prospective randomized clinical trial was performed. The safety of the combination of NPWT and sNAG was also assessed in patients treated with antiplatelet drugs. In the performed study, the combination of NPWT and sNAG in 10 patients compared to NPWT alone in 10 patients promoted wound healing due to an improved contraction of the wound margins (p = 0.05) without a change in wound epithelization. In 6 patients treated with antiplatelet drugs no increased wound bleeding was observed in patients treated by NPWT and sNAG. In conclusion, the application of thin membranes of sNAG nanofibers at the wound interface using NPWT was safe and augmented the action of NPWT leading to improved wound healing due to a stimulation of wound contraction. PMID- 25703412 TI - Rare case of subcutaneous mycosis with intrathoracic extension due to Chaetomium strumarium. AB - A 47-year-old man presented with a 10-year history of multiple lumps over his left upper arm and shoulder and the adjoining left side of his chest and upper back. His medical history included diabetes mellitus type 2. The patient was a farmer and used to lift sacks of grains and fertilizers onto his shoulders as part of his work, although he did not recollect any history of specific trauma. Skin biopsy revealed granulomatous reaction with Splendore-Hoeppli phenomenon, while periodic-acid-Schiff and Grocott-Gomori stains confirmed fungal elements. Sabouraud agar grew Chaetomium species, and lactophenol blue mount confirmed the fungus as Chaetomium strumarium. Radiography and computed tomography of the chest revealed intrathoracic extension of the mycetoma. The patient responded well to treatment with oral Itraconazole. Subcutaneous mycosis due to C. strumarium is rarely reported in the literature, and the intrathoracic extension makes it an even rarer entity. PMID- 25703413 TI - Surgeon-performed ultrasound-guided FNAC with on-site cytopathology improves adequacy and accuracy. AB - OBJECTIVE: To demonstrate that surgeon-performed fine-needle aspiration cytology (FNAC) results in a high percent of satisfactory FNAC results; the number of passes to obtain a satisfactory cytological result with on-site cytopathological interpretation is reduced with ultrasound guidance (comparing FNAC with and without surgeon-performed ultrasound guidance); and immediate triage for indeterminate thyroid nodules can be performed in one setting for molecular testing, potentially improving selection for surgery. STUDY DESIGN: Retrospective cohort comparison. METHODS: A cytopathologist is present for on-site staining adequacy evaluation and molecular testing triage for indeterminate cytology. Overall cytological adequacy and number of passes required to obtain cytological adequacy for 200 consecutive patients are compared with a historical series of 100 consecutive patients from the same surgeon and cytopathologists without ultrasound guidance. RESULTS: The percent of patients with an adequate FNAC with ultrasound guidance was 100%. The mean number of passes with and without ultrasound guidance was 1.7 and 4.0 (P < 0.001). Indeterminate FNACs (9%) were triaged to molecular alteration testing and gene expression classifier testing. CONCLUSIONS: Surgeon-performed ultrasound-guided FNAC with an experienced cytopathologist present resulted in a cytologically adequate result in 100% of cases. Significantly fewer passes for a satisfactory result were achieved with ultrasound guidance. Indeterminate FNAC can be triaged for molecular testing in one patient visit, was required in only 9% of carefully selected patients, and improved patient selection for surgery. The percent of patients who went on to surgery was 24 of 200 (12%). The percent of patients who had malignancy was 18 of 24 (75%). PMID- 25703414 TI - A survey of genome-wide single nucleotide polymorphisms through genome resequencing in the Perigord black truffle (Tuber melanosporum Vittad.). AB - The Perigord black truffle (Tuber melanosporum Vittad.), considered a gastronomic delicacy worldwide, is an ectomycorrhizal filamentous fungus that is ecologically important in Mediterranean French, Italian and Spanish woodlands. In this study, we developed a novel resource of single nucleotide polymorphisms (SNPs) for T. melanosporum using Illumina high-throughput resequencing. The genome from six T. melanosporum geographical accessions was sequenced to a depth of approximately 20*. These geographical accessions were selected from different populations within the northern and southern regions of the geographical species distribution. Approximately 80% of the reads for each of the six resequenced geographical accessions mapped against the reference T. melanosporum genome assembly, estimating the core genome size of this organism to be approximately 110 Mbp. A total of 442 326 SNPs corresponding to 3540 SNPs/Mbps were identified as being included in all seven genomes. The SNPs occurred more frequently in repeated sequences (85%), although 4501 SNPs were also identified in the coding regions of 2587 genes. Using the ratio of nonsynonymous mutations per nonsynonymous site (pN) to synonymous mutations per synonymous site (pS) and Tajima's D index scanning the whole genome, we were able to identify genomic regions and genes potentially subjected to positive or purifying selection. The SNPs identified represent a valuable resource for future population genetics and genomics studies. PMID- 25703415 TI - How to get between the sheets: a review of recent works on the electrochemical exfoliation of graphene materials from bulk graphite. AB - Since the beginning of the 'graphene era' post-2004, there has been significant interest in developing a high purity, high yield, and scalable fabrication route toward graphene materials for both primary research purposes and industrial production. One suitable approach to graphene production lies in the realm of electrochemical exfoliation, in which a potential difference is applied between a graphite anode/cathode in the presence of an electrolyte-containing medium. Herein we review various works on the electrochemical fabrication of graphene materials specifically through the use of electrochemical intercalation and exfoliation of a graphite source electrode, focusing on the quality and purity of products formed. We categorise the most significant works in terms of anodic and cathodic control, highlighting the merits of the respective approaches, as well as indicating the challenges associated with both procedures. PMID- 25703416 TI - Correction. AB - [This corrects the article DOI: 10.7860/JCDR/2014/9485.5182.]. PMID- 25703417 TI - Genetic variant of IL28B rs12979860, as predictive marker of interferon-based therapy in Pakistani population. AB - Hepatitis C virus (HCV) genotypes and genetic variants of interleukin 28B (IL28B) are significantly associated with interferon plus ribavirin treatment of HCV infection. We investigated the distribution of HCV genotypes and single nucleotide polymorphisms (SNPs) of IL28B (rs12979860 and rs8099917) in Pakistani population. IL28B genotyping was performed by allele-specific PCR and restriction fragment length polymorphism PCR in 140 chronic hepatitis C patients (CHC) and 120 healthy controls. HCV genotype 3 (HCVG3) was the most prevalent genotype, 71.4% (n = 100/140) and with the highest treatment response of 90% (n = 90/100). The overall treatment response of all the HCV genotypes was 82% (n = 115/140). The distribution of IL28B rs12979860CC genotype in treatment responder and non responder groups was 40.8% (n = 47/115) and 16% (n = 4/25) respectively. IL28B rs12979860CC genotype demonstrated a significant correlation (p = 0.019) with interferon-based therapy of HCV infection. However, there was no observed association of IL28B rs8099917 polymorphism with treatment response in CHC patients (p = 0.264). In conclusion, HCV genotypes and IL28B rs12979860 are predictive markers for the efficiency of interferon plus ribavirin combinational therapy of HCV infection. We recommend the inclusion of testing for these markers in the clinical criteria for decision making for HCV therapy in Pakistani population. PMID- 25703418 TI - Retail clinics versus traditional primary care: Employee satisfaction guaranteed? AB - PURPOSE: To examine if differences exist in the levels of autonomy and job satisfaction among primary care nurse practitioners (NPs) employed in retail clinics versus traditional primary care settings. DATA SOURCES: Data were collected from 310 primary care NPs who attended the American Association of NP's 28th Annual Conference in June 2013. Participants completed a demographic form, the Misener NP Job Satisfaction Scale, and the Dempster Practice Behavior Scale. CONCLUSIONS: Overall, there were no differences in job satisfaction or autonomy among NPs by practice setting. Retail NPs felt less valued and were less satisfied with social interaction, but more satisfied with benefits compared to NPs in traditional settings. NPs working in retail clinics were less likely to have intentions to leave current position compared to NPs in traditional practice settings. IMPLICATIONS FOR PRACTICE: The results of this study enhance our current understanding of the linkages between levels of autonomy, job satisfaction, and practice setting among primary care NPs. The findings of this descriptive study offer valuable insights for stakeholders devoted to the development of the primary care workforce and identify modifiable factors that may influence retention and turnover rates among NPs. PMID- 25703419 TI - Use, efficacy and safety of prasugrel in patients with ST segment elevation myocardial infarction scheduled for primary percutaneous coronary intervention in clinical practice. Results of the prospective ATACS-registry. AB - BACKGROUND: Prasugrel compared to clopidogrel has been shown to improve outcome in patients with ST elevation myocardial infarction (STEMI) in the TRITON-TIMI 38 trial. Little is known about the use, efficacy and safety of prasugrel in patients with STEMI in clinical practice. METHODS: We conducted a prospective registry including patients with STEMI scheduled for primary percutaneous coronary intervention (PCI). Between October 2009 and February 2013 a total of 3291 patients with STEMI receiving a loading dose of either clopidogrel or prasugrel were included in this analysis. RESULTS: Prasugrel was predominantly used in patients <75 years, body weight >60 kg and those without prior stroke. In hospital mortality was numerically lower in the prasugrel group (1.7% vs. 4.4%), as well as non-fatal reinfarction (0.2% vs. 0.5%), non-fatal stroke (0.1% vs. 0.3%) and major cardiac and cerebrovascular events (MACCE) (2.1% vs. 5.2%), while there was no difference in major bleeding complications (0.8% vs. 0.9%). In the multivariate analysis the MACCE-rate tended to be lower in prasugrel treated patients (odds ratio 0.71, 95% confidence intervals 0.42-1.08) but bleeding-rates tended to be higher. CONCLUSIONS: In this real life experience in patients with STEMI scheduled for primary PCI, prasugrel was almost exclusively used in the label-recommended patient population and tended to be more effective but associated with more bleedings compared to clopidogrel. These results support the findings in the STEMI population in the randomized TRITON-TIMI 38 study. PMID- 25703420 TI - Predictors and prognostic consequence of gastrointestinal bleeding in patients with ST-segment elevation myocardial infarction. AB - BACKGROUND: Limited data are available on the predictors and implications of gastrointestinal (GI) bleeding in ST-segment elevation myocardial infarction (STEMI) patients treated with primary percutaneous coronary intervention (PPCI) and dual antiplatelet therapy. METHODS AND RESULTS: Predictors of and clinical outcome after GI bleeding were assessed in 2002 STEMI patients undergoing PPCI between 1-1-2003 and 31-07-2008. 139 patients suffered GI bleeding during a median follow-up of 4.9 years. Predictors of GI bleeding were age, history of bleeding, anemia, baseline thrombocytopenia, previous coronary artery bypass grafting, cardiogenic shock, anterior infarction and the use of GP IIb/IIIa inhibitor. By multivariable analysis, a first occurrence of GI bleeding was associated with a twofold increase in risk of subsequent GI bleeding (hazard ratio (HR) 2.19; 95% confidence interval (CI) 1.15-4.17). GI bleeding was not significantly associated with subsequent major adverse cardiac events (HR 1.33; 95% CI 0.98-1.79), cardiac (HR 1.40; 95% CI 0.97-2.02) and all-cause mortality (HR 1.34; 95% CI 0.96-1.85), recurrent MI (HR 0.97; 95% CI 0.58-1.63), stroke (HR 1.26; 95% CI 0.57-2.79) or stent thrombosis (HR 0.71; 95% CI 0.33-1.69). CONCLUSION: Among STEMI patients undergoing PPCI, the risk of GI bleeding is related to a number of risk factors, including advanced age, previous (GI) bleeding, GP IIB/IIIA inhibitors, anterior infarction and anemia. GI bleeding does not substantially increase the risk of subsequent recurrent ischemic events in STEMI patients undergoing PPCI, whereas the risk of GI bleeding after a first occurrence is more than doubled. PMID- 25703421 TI - Successful pregnancy and delivery in patients with uncorrected single ventricle: Three new cases and literature review. AB - Due to high risks of both maternal and fetal complications, pregnancy is not encouraged for women with uncorrected univentricular heart (UVH). Here, we report three cases of successful pregnancy and delivery in patients with uncorrected UVH. A literature review has been performed. It appears that maternal and neonatal risks are mainly associated with higher NYHA heart failure class, pulmonary hypertension, and history of congestive heart failure. In the absence of these risk factors, successful pregnancy still can be achieved with mild complications. Care by a multidisciplinary team during delivery is necessary to for a good prognosis. PMID- 25703422 TI - Transient carotid ischemia as a remote conditioning stimulus for myocardial protection in anesthetized rabbits: Insights into intracellular signaling. AB - BACKGROUND: We investigated the effectiveness of perconditioning (Perc) applied at different time points along with the role of RISK, SAFE, STAT5 and eNOS pathways. METHODS AND RESULTS: Anesthetized rabbits were subjected to 30-min ischemia/3-hour reperfusion. Perc, consisted of 4 cycles of 1-min ischemia/reperfusion, was applied in the carotid artery at different time points. Perc was started and ended during ischemia, started during ischemia and ended at the beginning of reperfusion, started at the end of ischemia and ended at reperfusion and started and ended during reperfusion. The PI3K inhibitor wortmannin, or the JAK-2 inhibitor AG490, was also applied and the infarct size was assessed. In another series assigned to the previous groups, the phosphorylation of Akt, PI3K, ERKs1/2, GSK3beta, STAT3, and STAT5 was evaluated. All Perc groups had smaller infarction compared to those without Perc, independently of PI3K or JAK-2 inhibition. STAT5 was the only molecule that was phosphorylated in parallel with cardioprotection. Since Src and angiotensin II mediate the STAT5 pathway, we administered the Scr inhibitor PP1 and the angiotensin II receptor antagonist valsartan. PP1 and valsartan prevented STAT5 phosphorylation, but did not abrogate the effect of Perc. Furthermore, the NOS inhibitor L-NAME was administered and abrogated the infarct size limiting effect of Perc. In parallel, the expression of cleaved caspase-3 was elevated only in the control and Perc-A-L-NAME groups. CONCLUSION: Perc reduces infarction independently of RISK, SAFE and STAT5 pathways. Src kinase and angiotensin II play a predominant role in STAT5 activation. eNOS may protect the myocardium through inhibition of apoptosis. PMID- 25703423 TI - Oxidized LDL attenuates protective autophagy and induces apoptotic cell death of endothelial cells: Role of oxidative stress and LOX-1 receptor expression. AB - BACKGROUND: Overproduction of oxidized-low density lipoproteins (oxyLDLs) has been found to contribute in endothelial cell (EC) dysfunction thereby leading to atherosclerosis development and progression. In particular, oxyLDLs lead to apoptotic cell death of EC via oxidative stress production, mostly subsequent to the overexpression of the scavenger receptor LOX-1. Here, we hypothesize that LOX 1 expression in EC represents a crucial event which attenuates protective autophagic response, thereby enhancing programmed endothelial cell death. METHODS AND RESULTS: Bovine aortic endothelial cells (BAECs) in culture were exposed to oxyLDL (1-100 MUM). After 48 h incubation, oxyLDL produced pronounced malondialdehyde (MDA) elevation and apoptotic cell death of BAEC as detected by FACS analysis, an effect counteracted by antioxidant N-acetyl-cysteine (NAC) as well as by the NO-donor SNAP. OxyLDL-induced apoptotic cell death was also accompanied by reduced VEGF-dependent phosphorylation of constitutive NO synthase (cNOS) in BAEC and consistent attenuation of autophagic response as detected by the expression of Beclin-1 and LC3, two reliable biomarkers of autophagy. Moreover, silencing LOX-1 receptor significantly restored LC3 expression in oxyLDL-treated BAEC, thus suggesting a key role of LOX-1 overproduction in oxyLDL induced endothelial dysfunction. CONCLUSIONS: OxyLDL leads to impaired NO generation and apoptotic cell death in BAECs. This effect occurs via the overexpression of LOX-1 and subsequent attenuation of protective autophagic response thereby contributing to the pathophysiology of oxyLDL-induced endothelial dysfunction which characterizes early stages of atherosclerotic process. PMID- 25703424 TI - Top ten risk factors for morbidity and mortality in patients with chronic systolic heart failure and elevated heart rate: The SHIFT Risk Model. AB - AIMS: We identified easily obtained baseline characteristics associated with outcomes in patients with chronic heart failure (HF) and elevated heart rate (HR) receiving contemporary guideline-recommended therapy in the SHIFT trial, and used them to develop a prognostic model. METHODS: We selected the 10 best predictors for each of four outcomes (cardiovascular death or HF hospitalisation; all-cause mortality; cardiovascular mortality; and HF hospitalisation). All variables with p<0.05 for association were entered into a forward stepwise Cox regression model. Our initial analysis excluded baseline therapies, though randomisation to ivabradine or placebo was forced into the model for the composite endpoint and HF hospitalisation. RESULTS: Increased resting HR, low ejection fraction, raised creatinine, New York Heart Association class III/IV, longer duration of HF, history of left bundle branch block, low systolic blood pressure and, for three models, age were strong predictors of all outcomes. Additional predictors were low body mass index, male gender, ischaemic HF, low total cholesterol, no history of hyperlipidaemia or dyslipidaemia and presence of atrial fibrillation/flutter. The c-statistics for the four outcomes ranged from 67.6% to 69.5%. There was no evidence for lack of fit of the models with the exception of all-cause mortality (p=0.017). Similar results were found including baseline therapies. CONCLUSION: The SHIFT Risk Model includes simple, readily obtainable clinical characteristics to produce important prognostic information in patients with chronic HF, systolic dysfunction, and elevated HR. This may help better calibrate management to individual patient risk. PMID- 25703425 TI - [Free medical care in the Ossau Valley (Bearn) during the 19th Century]. PMID- 25703426 TI - Do women grow out of risky drinking? A prospective study of three cohorts of Australian women. AB - INTRODUCTION AND AIMS: To examine women's drinking behaviour relative to Australian guidelines and identify associated factors over the lifespan. DESIGN AND METHODS: Data came from three prospective cohorts of the Australian Longitudinal Study on Women's Health aged 18-23 (n = 14,247), 45-50 (n = 13,715) and 70-75 years (n = 12,432) when first surveyed in 1996. The same women were re surveyed at roughly 3-year intervals until 2012. At each survey, four drinking behaviours were based on two guidelines: long-term drinking (no more than two standard drinks per day) and episodic drinking (no more than four standard drinks on an occasion): (i) no risk (within both guidelines); (ii) low episodic risk (less than once a month); high episodic risk (at least once a month); long-term risk (more than two drinks per day regardless of episodic drinking). RESULTS: No risk drinking increased with age, low episodic risk drinking remained almost constant between ages 18 and 39, and high episodic risk drinking declined rapidly. Few women drank at long-term risk. Factors associated with risky drinking varied with age; however, being a past or current smoker consistently increased the risk, and risks for smokers increased with age. Risky drinking was less likely to be practised by women providing care and needing help with daily tasks, or by pregnant women and those living with children. DISCUSSION AND CONCLUSIONS: Risky drinking behaviour should be addressed in younger women and in those who smoke. Interventions to reduce risky drinking, possibly in combination with reducing smoking, could be offered through general practice centres. PMID- 25703427 TI - Hierarchical porous nitrogen-doped carbon nanosheets derived from silk for ultrahigh-capacity battery anodes and supercapacitors. AB - Hierarchical porous nitrogen-doped carbon (HPNC) nanosheets (NS) have been prepared via simultaneous activation and graphitization of biomass-derived natural silk. The as-obtained HPNC-NS show favorable features for electrochemical energy storage such as high specific surface area (SBET: 2494 m(2)/g), high volume of hierarchical pores (2.28 cm(3)/g), nanosheet structures, rich N-doping (4.7%), and defects. With respect to the multiple synergistic effects of these features, a lithium-ion battery anode and a two-electrode-based supercapacitor have been prepared. A reversible lithium storage capacity of 1865 mA h/g has been reported, which is the highest for N-doped carbon anode materials to the best of our knowledge. The HPNC-NS supercapacitor's electrode in ionic liquid electrolytes exhibit a capacitance of 242 F/g and energy density of 102 W h/kg (48 W h/L), with high cycling life stability (9% loss after 10,000 cycles). Thus, a high-performance Li-ion battery and supercapacitors were successfully assembled for the same electrode material, which was obtained through a one-step and facile large-scale synthesis route. It is promising for next-generation hybrid energy storage and renewable delivery devices. PMID- 25703429 TI - Spontaneous postnatal growth is reduced in children with CHARGE syndrome. AB - AIM: There is a scarcity of data on postnatal growth in children with CHARGE syndrome, a genetic disorder. This study analysed spontaneous growth and weight in German children with CHARGE from birth to the age of 6 years. METHODS: This was a retrospective analysis of 19 children, nine females and 10 males, using data from child health records. Standard deviation scores (SDS) were calculated based on Swiss references. RESULTS: The median birthweight was 2950 g (-0.78 SDS), and the birth length was 49 cm (-0.5 SDS). There was a significant loss of median body length, at around 4 weeks of age from -0.5 to -2.3 SDS (p < 0.05). At 1 year, the median length was -2.6 SDS and it remained low until 5 years of age when the lowest value was found to be -2.8 SDS. There was a significant increase in median body mass index (BMI) from -1.15 SDS at 1 year to -0.15 SDS at 5 years (p < 0.01). CONCLUSION: Children with CHARGE syndrome displayed almost normal length and weight data at birth, with just one of the 19 infants having below average length for gestational age. However, postnatal growth was retarded during infancy and childhood, and the increase in BMI-SDS did not correlate with growth. PMID- 25703428 TI - Classification of prokaryotic genetic replicators: between selfishness and altruism. AB - Prokaryotes harbor a variety of genetic replicators, including plasmids, viruses, and chromosomes, each having different effects on the phenotype of the hosting cell. Here, we propose a classification for replicators of bacteria and archaea on the basis of their horizontal-transfer potential and the type of relationships (mutualistic, symbiotic, commensal, or parasitic) that they have with the host cell vehicle. Horizontal movement of replicators can be either active or passive, reflecting whether or not the replicator encodes the means to mediate its own transfer from one cell to another. Some replicators also have an infectious extracellular state, thus separating viruses from other mobile elements. From the perspective of the cell vehicle, the different types of replicators form a continuum from genuinely mutualistic to completely parasitic replicators. This classification provides a general framework for dissecting prokaryotic systems into evolutionarily meaningful components. PMID- 25703430 TI - Pre-operative ultrasound diagnosis of nodal metastasis in papillary thyroid carcinoma patients according to nodal compartment. AB - The aim of this study was to assess the accuracy of ultrasound (US) and individual US features in the diagnosis of nodal metastasis in patients with papillary thyroid carcinoma (PTC) with respect to nodal compartment. US diagnoses and individual US features of nodal metastases with respect to nodal compartment were investigated in 184 consecutive PTC patients who underwent pre-operative US. Histopathologic results were used as a reference standard. One hundred thirty-six of 368 (37.0%) central compartments contained one or more metastatic nodes, whereas 44 of 48 (91.7%) lateral compartments had one or more metastatic nodes. The malignancy rates of suspicious US diagnoses in the central and lateral compartments were 66.3% (53/80) and 93.3% (42/45), respectively. The central and lateral compartments differed significantly in nodal composition, echogenicity, calcification, shape, hilar echogenicity and vascularity. The accuracy of US in the diagnosis of nodal metastases from PTC was lower in the central compartment than in the lateral compartment. PMID- 25703431 TI - Periostin, a neurite outgrowth-promoting factor, is expressed at high levels in the primate cerebral cortex. AB - Periostin (POSTN or osteoblast specific factor) is an extracellular matrix protein originally identified as a protein highly expressed in osteoblasts. Recently, periostin has been reported to function in axon regeneration and neuroprotection. In the present study, we focused on periostin function in cortical evolution. We performed a comparative gene expression analysis of periostin between rodents (mice) and primates (marmosets and macaques). Periostin was expressed at higher levels in the primate cerebral cortex compared to the mouse cerebral cortex. Furthermore, we performed overexpression experiments of periostin in vivo and in vitro. Periostin exhibited neurite outgrowth activity in cortical neurons. These results suggested the possibility that prolonged and increased periostin expression in the primate cerebral cortex enhances the cortical plasticity of the mammalian cerebral cortex. PMID- 25703432 TI - Leaching of radionuclides from activated soil into groundwater. AB - Soil samples collected from the CERN site were irradiated by secondary radiation from the 400 GeV/c SPS proton beam at the H4IRRAD test area. Water samples were also irradiated at the same time. Detailed gamma spectrometry measurements and water scintillation analysis were performed to measure the radioactivity induced in the samples. FLUKA Monte Carlo simulations were performed to benchmark the induced radioactivity in the samples and to estimate the amount of tritium produced in the soil. Two leaching procedures were used and compared to quantify the radioactivity leached by water from the activated soil. The amount of tritium coming from both the soil moisture and the soil bulk was estimated. The present results are compared with literature data for the leaching of (3)H and (22)Na. PMID- 25703433 TI - Marine reservoir effect on the Southeastern coast of Brazil: results from the Tarioba shellmound paired samples. AB - On the Southeastern coast of Brazil the presence of many archaeological shellmounds offers a great potential for studying the radiocarbon marine reservoir effect (MRE). However, very few such studies are available for this region. These archaeological settlements, mostly dating from 5 to 2 kyr cal BP, include both terrestrial and marine remains in good stratigraphic context and secure association, enabling the comparison of different carbon reservoirs. In a previous study the chronology of the Sambaqui da Tarioba, located in Rio de Janeiro state, Brazil, was established based on marine mollusc shells and charcoal samples from hearths, from several layers in two excavated sectors. We now compare the different materials with the aim of studying the MRE in this region. Calibration was performed with Oxford software OxCal v4.2.3 using the marine curve Marine13 with an undetermined offset to account for local corrections for shell samples, and the atmospheric curve SHCal13 for charcoal samples. The distribution of results considering a phase model indicates a DeltaR value of -127 +/- 67 (14)C yr in the 1 sigma range and the multi-paired approach leads to a mean value of -110 +/- 94 (14)C yr. PMID- 25703434 TI - Sex-related differences in murine hepatic transcriptional and proteomic responses to TCDD. AB - 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is an environmental contaminant that produces myriad toxicities in most mammals. In rodents alone, there is a huge divergence in the toxicological response across species, as well as among different strains within a species. But there are also significant differences between males and females animals of a single strain. These differences are inconsistent across model systems: the severity of toxicity is greater in female rats than males, while male mice and guinea pigs are more sensitive than females. Because the specific events that underlie this difference remain unclear, we characterized the hepatic transcriptional response of adult male and female C57BL/6 mice to 500MUg/kg TCDD at multiple time-points. The transcriptional profile diverged significantly between the sexes. Female mice demonstrated a large number of altered transcripts as early as 6h following treatment, suggesting a large primary response. Conversely, male animals showed the greatest TCDD-mediated response 144h following exposure, potentially implicating significant secondary responses. Nr1i3 was statistically significantly induced at all time-points in the sensitive male animals. This mRNA encodes the constitutive androstane receptor (CAR), a transcription factor involved in the regulation of xenobiotic metabolism, lipid metabolism, cell cycle and apoptosis. Surprisingly though, changes at the protein level (aside from the positive control, CYP1A1) were modest, with only FMO3 showing clear induction, and no genes with sex differences. Thus, while male and female mice show transcriptional differences in their response to TCDD, their association with TCDD-induced toxicities remains unclear. PMID- 25703435 TI - Clinical significance of worry and physical symptoms in late-life generalized anxiety disorder. AB - OBJECTIVE: Worry is a hallmark feature of generalized anxiety disorder (GAD). However, age-related changes in symptom presentation raise questions about the clinical significance of these symptom clusters in later life. The aim of this study was to explore the relative contribution of worry and physical symptom frequency to clinical significance associated with late-life GAD. METHODS: A sample of 637 self-reported worriers (aged 65 years and older) was extracted from Wave 1 of the National Epidemiological Survey of Alcohol and Related Conditions. RESULTS: Consistent with previous findings, we observed reductions in worry frequency and increases in physical symptom frequency with increasing age of participants. Physical symptoms, but not worry symptoms, distinguished older adults with clinical and sub-threshold GAD. Whereas physical symptom count was associated with distress, occupational, and functional disability, worry count was only associated with distress. CONCLUSIONS: Among self-reported worriers, worry frequency provides limited clinical utility over and above physical symptom frequency. These findings suggest that physical symptom frequency may become an increasingly important feature of GAD in later life. PMID- 25703436 TI - Is the shape of the decline in risk following quitting smoking similar for squamous cell carcinoma and adenocarcinoma of the lung? A quantitative review using the negative exponential model. AB - One possible contributor to the reported rise in the ratio of adenocarcinoma to squamous cell carcinoma of the lung may be differences in the pattern of decline in risk following quitting for the two lung cancer types. Earlier, using data from 85 studies comparing overall lung cancer risks in current smokers, quitters (by time quit) and never smokers, we fitted the negative exponential model, deriving an estimate of 9.93years for the half-life - the time when the excess risk for quitters compared to never smokers becomes half that for continuing smokers. Here we applied the same techniques to data from 16 studies providing RRs specific for lung cancer type. From the 13 studies where the half-life was estimable for each type, we derived estimates of 11.68 (95% CI 10.22-13.34) for squamous cell carcinoma and 14.45 (11.92-17.52) for adenocarcinoma. The ratio of the half-lives was estimated as 1.32 (95% CI 1.20-1.46, p<0.001). The slower decline in quitters for adenocarcinoma, evident in subgroups by sex, age and other factors, may be one of the factors contributing to the reported rise in the ratio of adenocarcinoma to squamous cell carcinoma. Others include changes in the diagnosis and classification of lung cancer. PMID- 25703437 TI - Tele-transmission of EEG recordings. AB - EEG recordings can be sent for remote interpretation. This article aims to define the tele-EEG procedures and technical guidelines. Tele-EEG is a complete medical act that needs to be carried out with the same quality requirements as a local one in terms of indications, formulation of the medical request and medical interpretation. It adheres to the same quality requirements for its human resources and materials. It must be part of a medical organization (technical and medical network) and follow all rules and guidelines of good medical practices. The financial model of this organization must include costs related to performing the EEG recording, operating and maintenance of the tele-EEG network and medical fees of the physician interpreting the EEG recording. Implementing this organization must be detailed in a convention between all parties involved: physicians, management of the healthcare structure, and the company providing the tele-EEG service. This convention will set rules for network operation and finance, and also the continuous training of all staff members. The tele-EEG system must respect all rules for safety and confidentiality, and ensure the traceability and storing of all requests and reports. Under these conditions, tele-EEG can optimize the use of human resources and competencies in its zone of utilization and enhance the organization of care management. PMID- 25703438 TI - Invasive EEG explorations. AB - The Wada test was adapted from the procedure described by Wada in 1964. It still has a role in the prognostic evaluation of memory disorders after mesial temporal lobectomy. The test consists of injecting a short-acting anesthetic into one hemisphere, under continuous EEG monitoring and during carotid catheterization, to verify the function of contralateral structures. Intracranial EEG recordings deliver signals with few artifacts, and which are quite specific of the zone explored. Three types of electrodes are in common use: (a) foramen ovale (FO) electrodes: electrodes can be inserted directly, without any stereotactic procedure, to provide easy and comparative EEG recordings of the lower and middle portions of the temporal lobe close to the hippocampus. These allow validation of the temporal lobe origin of seizures using FO electrodes recording coupled with scalp EEG; (b): subdural strip or grip electrodes. This relatively aggressive technique carries infectious and hemorrhagic risks and does not allow the exploration of deep cortical structures. However, it permits precise functional cortical mapping via electrical stimulation because of dense and regular positioning of electrodes over the cortical convexity; (c) stereotactically implanted depth electrodes (stereo-electroencephalography [SEEG]). Electrodes are individually planned and inserted within the brain parenchyma through small burr holes. This technique is less aggressive than subdural grid exploration. However it offers relatively limited spatial sampling that may be less well adapted to precise functional evaluation. It allows recording from deep cortical structures and can be argued to be the gold standard of presurgical EEG exploration. PMID- 25703439 TI - EEG in children, in the laboratory or at the patient's bedside. AB - In pediatrics, EEG recordings are performed on patients from the neonatal period up to young adults. This means adapting techniques to many different conditions, concerning not only the patient's age, the need for asepsis and the patient's behavior, but also the environment (e.g. in the laboratory, at the patient's bedside, or in the neonatal intensive care unit [NICU]). Technical requirements depend on age, indication and the type of examination; in infancy, there should be a minimum of 12 EEG electrodes, ECG and respiration recording. In epileptology, surface EMG is also necessary to characterize the type of seizures and refine the diagnosis of epilepsy syndrome, on which physicians will base their treatment choice. The role of the EEG technician is essential because the quality of the recording, its analysis and conclusion will depend on the quality of the technical set-up and the interaction with the child. Sleep is a systematic part of the study up to the age of 5 years for several reasons: sleep EEG yields information on brain maturation; the EEG tracing during wakefulness can contain too many artefacts; and some grapho-elements, key to the diagnosis, only appear during sleep. The time of the examination must be chosen according to the child's usual nap times, possibly after sleep deprivation. Grapho-elements and spatio temporal organization of the EEG vary with age, and normal variants and unusual aspects are quite wide for any given age; this is why a physician experienced in pediatric EEG should perform the interpretation. This chapter concerns EEG performed in infants, children and adolescents, its technical aspects according to age and indications (general pediatrics, emergency, epilepsy). PMID- 25703440 TI - Opioid treatment at release from jail using extended-release naltrexone: a pilot proof-of-concept randomized effectiveness trial. AB - BACKGROUND AND AIMS: Relapse to addiction following incarceration is common. We estimated the feasibility and effectiveness of extended-release naltrexone (XR NTX) as relapse prevention among opioid-dependent male adults leaving a large urban jail. DESIGN: Eight-week, proof-of-concept, open-label, non-blinded randomized effectiveness trial. SETTING: New York City jails and Bellevue Hospital Center Adult Primary Care clinics, USA. PARTICIPANTS: From January 2010 to July 2013, 34 opioid-dependent adult males with no stated interest in agonist treatments (methadone, buprenorphine) received a counseling and referral intervention and were randomized to XR-NTX (n = 17) versus no medication (n = 17) within one week prior to jail release. INTERVENTION: XR-NTX (Vivitrol((r)) ; Alkermes Inc.), a long-acting injectable mu opioid receptor antagonist. MEASURES: The primary intent-to-treat outcome was post-release opioid relapse at week 4, defined as >=10 days of opioid misuse by self-report and urine toxicologies. Secondary outcomes were proportion of urine samples negative for opioids and rates of opioid abstinence, intravenous drug use (IVDU), cocaine use, community treatment participation, re-incarceration and overdose. FINDINGS: Acceptance of XR-NTX was high; 15 of 17 initiated treatment. Rates of the primary outcome of week 4 opioid relapse were lower among XR-NTX participants: 38 versus 88% [P<0.004; odds ratio (OR) = 0.08, 95% confidence interval (CI) = 0.01-0.48]; more XR-NTX urine samples were negative for opioids, 59 versus 29% (P<0.009; OR = 3.5, 95% CI = 1.4-8.5). There were no significant differences in the remaining secondary outcomes, including rates of IVDU, cocaine use, re-incarceration and overdose. CONCLUSION: Extended-release naltrexone is associated with significantly lower rates of opioid relapse among men in the United States following release from jail when compared with a no medication treatment-as-usual condition. PMID- 25703441 TI - Cost-effectiveness of therapies for melanoma. AB - Melanoma presents an important burden worldwide. Until recently, the prognosis for unresectable and metastatic melanoma was poor, with 10% of metastatic melanoma patients surviving for 2 years. The introduction of newer therapies including ipilimumab, vemurafenib, dabrafenib and trametinib improved progression free survival, with additional benefits anticipated from the forthcoming class of programmed cell death 1 inhibitors. Cost of therapy and resulting cost effectiveness is an important factor in determining patient access to specific treatments. The objective of this study was to review the published evidence regarding cost-effectiveness of melanoma therapies and provide an overview of the relative cost-effectiveness of available therapies by disease stage. For earlier stage disease, IFN-alpha has been found to be cost-effective, although its clinical benefits have not been well established. For unresectable and metastatic melanoma, newer therapies provide benefits over standard-of-care chemotherapy, but comprehensive analyses will need to be conducted to determine the most cost effective therapy. PMID- 25703442 TI - The angiotensin converting enzyme inhibitor, captopril, prevents the hyperactivity and impulsivity of neurokinin-1 receptor gene 'knockout' mice: sex differences and implications for the treatment of attention deficit hyperactivity disorder. AB - Mice lacking functional neurokinin-1 receptors (NK1R-/-) display behavioural abnormalities resembling attention deficit hyperactivity disorder (ADHD): locomotor hyperactivity, impulsivity and inattentiveness. The preferred ligand for NK1R, substance P, is metabolised by angiotensin converting enzyme (ACE), which forms part of the brain renin angiotensin system (BRAS). In view of evidence that the BRAS modulates locomotor activity and cognitive performance, we tested the effects of drugs that target the BRAS on these behaviours in NK1R-/- and wildtype mice. We first tested the effects of the ACE inhibitor, captopril, on locomotor activity. Because there are well-established sex differences in both ADHD and ACE activity, we compared the effects of captopril in both male and female mice. Locomotor hyperactivity was evident in male NK1R-/- mice, only, and this was abolished by treatment with captopril. By contrast, male wildtypes and females of both genotypes were unaffected by ACE inhibition. We then investigated the effects of angiotensin AT1 (losartan) and AT2 (PD 123319) receptor antagonists on the locomotor activity of male NK1R-/- and wildtype mice. Both antagonists increased the locomotor activity of NK1R-/- mice, but neither affected the wildtypes. Finally, we tested the effects of captopril on the performance of male NK1R-/- and wildtype mice in the 5-choice serial reaction time task (5-CSRTT) and found that ACE inhibition prevented the impulsivity of NK1R-/- mice. These results indicate that certain behaviours, disrupted in ADHD, are influenced by an interaction between the BRAS and NK1R, and suggest that ACE inhibitors could provide a novel treatment for this disorder. PMID- 25703443 TI - Engineering towards nitroreductase functionality in ene-reductase scaffolds. AB - Nitroreductases (NRs) and ene-reductases (ERs) both utilize flavin mononucleotide cofactors but catalyze distinct reactions. NRs reduce nitroaromatics, whereas ERs reduce unsaturated C=C double bonds, and these functionalities are known to somewhat overlap. Recent studies on the ER xenobiotic reductase A (XenA) from Pseudomonas putida demonstrated the possibility of increasing NR activity with active site modifications. Structural comparison between NRs and ERs led us to hypothesize that active site cavity size plays an important role in determining enzyme functionality. Residues of ER KYE1 from Kluyveromyces lactis were selected to increase the binding pocket size, compensate for hydrogen bonding pattern changes, and eliminate ER activity. Single variants were screened, and promising mutations were combined. Variant F296A/Y275A showed a 100-fold improvement in NR specific activity over wild-type, and variant H191A/F296A/Y375A exhibited complete conversion to a NR. PMID- 25703444 TI - Gastric cancer as a stem-cell disease: data and hypotheses. AB - The main function of gastric stem cells is to maintain the integrity of the gastrointestinal epithelium and replenish all the mature cell lineages. In order to accomplish this, gastric stem cells proliferate and self-renew, giving rise to transient amplifying cells which replace the constantly renewing epithelium, especially after injury induced by long-term inflammation. Gastric cancer (GC) remains the fourth most common cancer and the second leading cause of death for cancer in the world. The most accepted model of gastric carcinogenesis provides a multifactorial and multistep pathogenesis, involving a number of initiators and other continuator agents. Helicobacter pylori infection is recognized as a necessary but insufficient cause of GC. Recent advances in gastric stem cell biology point out to two hypotheses. In the first, it is postulated that resident stem cells may, in a chronically inflamed environment, as in the case of Helicobacter pylori-induced gastritis, accumulate over time a series of genetic and epigenetic changes that lead to the emergence of GC stem cells. Alternatively, the setting of chronic inflammatory stress may lead to loss of the indigenous gastric stem cells from their niches, followed by recruitment and engraftment of bone marrow derived stem cells (BMDCs) into the gastric epithelium. In the mouse model, increasing evidence supports the hypothesis that BMDCs are important cellular source of Helicobacter-induced GC. This review highlights data and hypotheses about GC as a model of stem-cell disease. PMID- 25703445 TI - Outcome of a one-stage tensile stress surgical technique and early postoperative rehabilitation in the treatment of neglected achilles tendon rupture. AB - The present study evaluated the effect of single-stage internal traction combined with early postoperative active rehabilitation and the yurt bone suture method, a new surgical technique, on the clinical outcomes after surgical repair of Achilles tendon. A total of 51 patients with neglected Achilles tendon rupture who underwent the yurt bone suture treatment also participated in an accelerated postoperative rehabilitation program. The clinical outcome was evaluated for 18 weeks using the Leppilahti scoring system, bilateral ultrasound examination, and computed tomography examination. The ultrasound and computed tomography examinations revealed that Achilles tendon elongation and adhesion occurred in none of the patients. All the patients could perform the single leg heel raise exercise for a mean of 30 +/- 7.6 seconds at 12 weeks postoperatively. In addition, the patients could participate in sport exercises and heavy physical activities by around 13 weeks postoperatively. The mean Leppilahti score was 85.8 +/- 3.7 at 8 weeks postoperatively, and it had increased to 96.1 +/- 3.2 and 100.0 +/- 0.0 at 12 and 18 weeks, respectively, after the operation. The 1-stage internal traction technique, combined with early postoperative active rehabilitation and the yurt bone surgical technique, resulted in good clinical outcomes for the treatment of neglected Achilles tendon rupture. PMID- 25703446 TI - Partial transmalleolar approach for lateral impingement after total ankle arthroplasty: a case report. AB - Advances in implant technology have made total ankle arthroplasty an increasingly popular alternative to arthrodesis for the management of ankle arthritis. However, a frequent complication of the procedure is nerve impingement related to either to heterotrophic bone growth or the prosthesis itself. Successful resolution of this complication presents a challenge to clinicians. We present a case of lateral impingement following total ankle arthroplasty that was successfully treated using a partial transmalleolar approach to effect a partial osteotomy of the lateral malleolus and create a fragment attached to the anterior talofibular and calcaneofibular ligaments. This approach provides a good operative field in the lateral gutter with minimal soft tissue impairment. It also facilitates curettage, and resolution of tissue impingement. The osteotomy site healed fully by 3 months postoperative, and the pain around the lateral malleolus resolved. Furthermore, the patient's score on the Japanese Society for Surgery of the Foot Ankle/Hindfoot Scale improved from 33 preoperatively to 82 at 6 months postoperative. PMID- 25703447 TI - On the origin of protein superfamilies and superfolds. AB - Distributions of protein families and folds in genomes are highly skewed, having a small number of prevalent superfamiles/superfolds and a large number of families/folds of a small size. Why are the distributions of protein families and folds skewed? Why are there only a limited number of protein families? Here, we employ an information theoretic approach to investigate the protein sequence structure relationship that leads to the skewed distributions. We consider that protein sequences and folds constitute an information theoretic channel and computed the most efficient distribution of sequences that code all protein folds. The identified distributions of sequences and folds are found to follow a power law, consistent with those observed for proteins in nature. Importantly, the skewed distributions of sequences and folds are suggested to have different origins: the skewed distribution of sequences is due to evolutionary pressure to achieve efficient coding of necessary folds, whereas that of folds is based on the thermodynamic stability of folds. The current study provides a new information theoretic framework for proteins that could be widely applied for understanding protein sequences, structures, functions, and interactions. PMID- 25703448 TI - Cost-effectiveness of a Home-Exercise Program Among Older People After Hospitalization. AB - BACKGROUND: Older people who have been recently discharged from hospital are at increased risk of falls and deterioration in physical functioning. OBJECTIVE: To investigate the cost-effectiveness of a 12-month home-exercise program for older adults after hospitalization. METHOD: An economic evaluation was conducted alongside a randomized controlled trial. The analysis was conducted from the health and community service provider perspective. A total of 340 people aged 60 years and older, with a recent hospital admission, were randomized into exercise and usual care control groups. Incremental costs per extra person showing improvement in mobility performance (using the Short Physical Performance Battery), per person indicating improvement in health (self-reported using a 3 point Likert scale) and per quality-adjusted life year (QALY) gained (utility measured using the EQ-5D) were estimated. Uncertainty was represented using cost effectiveness acceptability curves. Subgroup analyses for participants with better cognition (above the median MMSE score of 28) also were undertaken. RESULTS: The average cost of the intervention was $A751 per participant. The incremental cost-effectiveness of the program relative to usual care was $A22,958 per extra person showing an improvement in mobility, $A19,020 per extra person indicating an improvement in health, and $A77,403 per QALY. The acceptability curve demonstrates that the intervention had an 80% probability of being cost effective relative to the control at a threshold of $A48,000 per extra person achieving mobility improvement and $A36,000 indicating an improvement in self reported health. There was no threshold value at which the program can be considered as having an 80% probability of cost-effectiveness for the QALY outcome. Subgroup analyses for participants with better cognitive status indicated improved cost-effectiveness for all outcomes. CONCLUSION: The exercise intervention appeared to offer reasonable value for money for mobility outcomes and self-reported health status. Value for money for all measures was greater in the higher cognitive status subgroup. PMID- 25703449 TI - Identifying Potentially Preventable Emergency Department Visits by Nursing Home Residents in the United States. AB - OBJECTIVES: To identify and describe potentially preventable emergency department (ED) visits by nursing home (NH) residents in the United States. These visits are important because they are common, frequently lead to hospitalization, and can be associated with significant cost to the patient and the health care system. DESIGN: Retrospective analysis of the 2005-2010 National Hospital Ambulatory Care Survey (NHAMCS), comparing ED visits by nursing home residents that did not lead to hospital admission (potentially preventable) with those that led to admission (less likely preventable). SETTING: Nationally representative sample of US EDs; federal hospitals and hospitals with fewer than 6 beds were excluded. PARTICIPANTS: Older (age >=65 years) NH residents with an ED visit during this time period. MEASUREMENTS: Patient demographics, ED visit information including testing performed, interventions (both procedures and medications) provided, and diagnoses treated. RESULTS: Older NH residents accounted for 3857 of 208,956 ED visits during the time period of interest (1.8%). When weighted to be nationally representative, these represent 13.97 million ED visits, equivalent to 1.8 ED visits annually per NH resident in the United States. More than half of visits (53.5%) did not lead to hospital admission; of those discharged from the ED, 62.8% had normal vital signs on presentation and 18.9% did not have any diagnostic testing before ED discharge. Injuries were 1.78 times more likely to be discharged than admitted (44.8% versus 25.3%, respectively, P < .001), whereas infections were 2.06 times as likely to be admitted as discharged (22.9% versus 11.1%, respectively). Computed tomography (CT) scans were performed in 25.4% and 30.1% of older NH residents who were discharged from the ED and admitted to the hospital, respectively, and more than 70% of these were CTs of the head. NH residents received centrally acting, sedating medications before ED discharge in 9.4% of visits. CONCLUSION: This nationally representative sample of older NH residents suggests ED visits for injury, those that are associated with normal triage vital signs, and those that are not associated with any diagnostic testing are potentially preventable. Those discharged from the ED often undergo important testing and receive medications that may alter their physical examination on return to the nursing facility, highlighting the need for seamless communication of the ED course to NHs. PMID- 25703450 TI - Costs and Effects of an Ambulatory Geriatric Unit (the AGe-FIT Study): A Randomized Controlled Trial. AB - OBJECTIVES: To examine costs and effects of care based on comprehensive geriatric assessment (CGA) provided by an ambulatory geriatric care unit (AGU) in addition to usual care. DESIGN: Assessor-blinded, single-center randomized controlled trial. SETTING: AGU in an acute hospital in southeastern Sweden. PARTICIPANTS: Community-dwelling individuals aged 75 years or older who had received inpatient hospital care 3 or more times in the past 12 months and had 3 or more concomitant medical diagnoses were eligible for study inclusion and randomized to the intervention group (IG; n = 208) or control group (CG; n = 174). Mean age (SD) was 82.5 (4.9) years. INTERVENTION: Participants in the IG received CGA-based care at the AGU in addition to usual care. OUTCOME MEASURES: The primary outcome was number of hospitalizations. Secondary outcomes were days in hospital and nursing home, mortality, cost of public health and social care, participant' sense of security in care, and health-related quality of life (HRQoL). RESULTS: Baseline characteristics did not differ between groups. The number of hospitalizations did not differ between the IG (2.1) and CG (2.4), but the number of inpatient days was lower in the IG (11.1 vs 15.2; P = .035). The IG showed trends of reduced mortality (hazard ratio 1.51; 95% confidence interval [CI] 0.988-2.310; P = .057) and an increased sense of security in care interaction. No difference in HRQoL was observed. Costs for the IG and CG were 33,371 L (39,947 L) and 30,490 L (31,568 L; P = .432). CONCLUSIONS AND RELEVANCE: This study of CGA-based care was performed in an ambulatory care setting, in contrast to the greater part of studies of the effects of CGA, which have been conducted in hospital settings. This study confirms the superiority of this type of care to elderly people in terms of days in hospital and sense of security in care interaction and that a shift to more accessible care for older people with multimorbidity is possible without increasing costs. This study can aid the planning of future interventions for older people. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT01446757. PMID- 25703451 TI - Effect of long-term (2 years) exposure of mouse brains to global system for mobile communication (GSM) radiofrequency fields on astrocytic immunoreactivity. AB - This study was designed to determine whether long-term (2 years) brain exposure to mobile telephone radiofrequency (RF) fields produces any astrocytic activation as these glia react to a wide range of neural perturbations by astrogliosis. Using a purpose-designed exposure system at 900 MHz, mice were given a single, far-field whole body exposure at a specific absorption rate of 4 W/kg on five successive days per week for 104 weeks. Control mice were sham-exposed or freely mobile in a cage to control any stress caused by immobilization in the exposure module. Brains were perfusion-fixed with 4% paraformaldehyde and three coronal levels immunostained for glial fibrillary acidic protein (GFAP). These brain slices were then examined by light microscopy and the amount of this immunomarker quantified using a color deconvolution method. There was no change in astrocytic GFAP immunostaining in brains after long-term exposure to mobile telephony microwaves compared to control (sham-exposed or freely moving caged mice). It was concluded that long-term (2 years) exposure of murine brains to mobile telephone RF fields did not produce any astrocytic reaction (astrogliosis) detectable by GFAP immunostaining. PMID- 25703453 TI - Access to new endoperoxide derivatives by electrochemical oxidation of substituted 3-azabicyclo[4.1.0]hept-4-enes. AB - A series of substituted 3-azabicyclo[4.1.0]hept-4-ene derivatives were prepared and analysed by cyclic voltammetry. Preparative aerobic electrochemical oxidation reactions were then carried out. Three original endoperoxides were isolated, characterised and subjected to antimalarial and cytotoxicity activity assays. PMID- 25703452 TI - Prevalence and risk factors of micronutrient deficiencies pre- and post antiretroviral therapy (ART) among a diverse multicountry cohort of HIV-infected adults. AB - BACKGROUND & AIMS: HIV-infected adults have increased risk of several individual micronutrient deficiencies. However, the prevalence and risk factors of concurrent and multiple micronutrient deficiencies and whether micronutrient concentrations change after antiretroviral therapy (ART) initiation have not been well described. The objective of this study was to determine the prevalence and risk factors of individual, concurrent and multiple micronutrient deficiencies among ART-naive HIV-infected adults from nine countries and assess change in micronutrient status 48 weeks post-ART initiation. METHODS: A random sub-cohort (n = 270) stratified by country was selected from the multinational PEARLS clinical trial (n = 1571 ART-naive, HIV-infected adults). We measured serum concentrations of vitamins A, D (25-hydroxyvitamin), E, carotenoids and selenium pre-ART and 48 weeks post-ART initiation, and measured vitamins B6, B12, ferritin and soluble transferrin receptor at baseline only. Prevalence of single micronutrient deficiencies, concurrent (2 coexisting) or conditional (a deficiency in one micronutrient given a deficiency in another) and multiple (>=3) were determined using defined serum concentration cutoffs. We assessed mean changes in micronutrient concentrations from pre-ART to week 48 post-ART initiation using multivariable random effects models. RESULTS: Of 270 participants, 13.9%, 29.2%, 24.5% and 32.4% had 0, 1, 2 and multiple deficiencies, respectively. Pre-ART prevalence was the highest for single deficiencies of selenium (53.2%), vitamin D (42.4%), and B6 (37.3%) with 12.1% having concurrent deficiencies of all three micronutrients. Deficiency prevalence varied widely by country. 48 weeks post-ART initiation, mean vitamin A concentration increased (p < 0.001) corresponding to a 9% decrease in deficiency. Mean concentrations also increased for other micronutrients assessed 48 weeks post-ART (p < 0.001) but with minimal change in deficiency status. CONCLUSIONS: Single and multiple micronutrient deficiencies are common among HIV-infected adults pre-ART initiation but vary between countries. Importantly, despite increases in micronutrient concentrations, prevalence of individual deficiencies remains largely unchanged after 48 weeks on ART. Our results suggest that ART alone is not sufficient to improve micronutrient deficiency. PMID- 25703454 TI - Proprioception in musculoskeletal rehabilitation. Part 1: Basic science and principles of assessment and clinical interventions. AB - INTRODUCTION: Impaired proprioception has been reported as a feature in a number of musculoskeletal disorders of various body parts, from the cervical spine to the ankle. Proprioception deficits can occur as a result of traumatic damage, e.g., to ligaments and muscles, but can also occur in association with painful disorders of a gradual-onset nature. Muscle fatigue can also adversely affect proprioception and this has implications for both symptomatic and asymptomatic individuals. Due to the importance of proprioception for sensorimotor control, specific methods for assessment and training of proprioception have been developed for both the spine and the extremities. PURPOSE: The aim of this first part of a two part series on proprioception in musculoskeletal rehabilitation is to present a theory based overview of the role of proprioception in sensorimotor control, assessment, causes and findings of altered proprioception in musculoskeletal disorders and general principles of interventions targeting proprioception. IMPLICATIONS: An understanding of the basic science of proprioception, consequences of disturbances and theories behind assessment and interventions is vital for the clinical management of musculoskeletal disorders. Part one of this series supplies a theoretical base for part two which is more practically and clinically orientated, covering specific examples of methods for clinical assessment and interventions to improve proprioception in the spine and the extremities. PMID- 25703455 TI - Outbreaks of cholera in the time of Ebola: pre-emptive action needed. PMID- 25703456 TI - Extremely large air distension of the bowel. PMID- 25703457 TI - Morality in a time of Ebola. PMID- 25703458 TI - Brachioplasty-associated multiple mononeuropathies. PMID- 25703459 TI - Endovascular treatment of acute basilar artery occlusion: time to treatment is crucial. AB - AIM: To evaluate the safety and efficacy of multimodal endovascular treatment (EVT) of acute basilar artery occlusion (BAO), including bridging therapy [intravenous thrombolysis (IVT) with subsequent EVT], to compare particular EVT techniques and identify predictors of clinical outcome. MATERIALS AND METHODS: This retrospective, multi-centre study comprised 72 acute ischaemic stroke patients (51 males; mean age 59.1 +/- 13.3 years) with radiologically confirmed BAO. The following data were collected: baseline characteristics, risk factors, pre-event antithrombotic treatment, neurological deficit at time of treatment, localization of occlusion, time to therapy, recanalization rate, post-treatment imaging findings. Thirty- and 90-day outcomes were evaluated using the modified Rankin scale with a good clinical outcome defined as 0-3 points. RESULTS: Successful recanalization was achieved in 94.4% patients. Stepwise binary logistic regression analysis identified the presence of arterial hypertension (OR = 0.073 and OR = 0.067, respectively), National Institutes of Health Stroke Scale (NIHSS) at the time of treatment (OR = 0,829 and OR = 0.864, respectively), and time to treatment (OR = 0.556 and OR = 0.502, respectively) as significant independent predictors of 30- and 90-day clinical outcomes. CONCLUSION: Data from this multicentre study showed that multimodal EVT was an effective recanalization method in acute BAO. Bridging therapy shortens the time to treatment, which was identified as the only modifiable outcome predictor. PMID- 25703460 TI - Obesity and extent of emphysema depicted at CT. AB - AIM: To investigate the underlying relationship between obesity and the extent of emphysema depicted at CT. METHODS AND MATERIALS: A dataset of 477 CT examinations was retrospectively collected from a study of chronic obstructive pulmonary disease (COPD). The low attenuation areas (LAAs; <=950 HU) of the lungs were identified. The extent of emphysema (denoted as %LAA) was defined as the percentage of LAA divided by the lung volume. The association between log transformed %LAA and body mass index (BMI) adjusted for age, sex, the forced expiratory volume in one second as percent predicted value (FEV1% predicted), and smoking history (pack years) was assessed using multiple linear regression analysis. RESULTS: After adjusting for age, gender, smoking history, and FEV1% predicted, BMI was negatively associated with severe emphysema in patients with COPD. Specifically, one unit increase in BMI is associated with a 0.93-fold change (95% CI: 0.91-0.96, p<0.001) in %LAA; the estimated %LAA for males was 1.75 (95% CI: 1.36-2.26, p<0.001) times that of females; per 10% increase in FEV1% predicated is associated with a 0.72-fold change (95% CI: 0.69-0.76, p<0.001) in %LAA. CONCLUSION: Increasing obesity is negatively associated with severity of emphysema independent of gender, age, and smoking history. PMID- 25703461 TI - Clinical application of 100 kVp acquisition with an iterative reconstruction technique in retrospective electrocardiogram-gated thoracoabdominal aortic CT angiography. AB - AIM: To evaluate the feasibility of a 100 kVp tube voltage combined with an iterative reconstruction algorithm in retrospective electrocardiogram (ECG)-gated thoracoabdominal aortic CT angiography (CTA). MATERIALS AND METHODS: Ninety-eight patients who underwent clinically indicated thoracoabdominal aortic CTA were randomly assigned to two groups: group A (n = 50) were scanned to 120 kVp and group B (n = 48) to 100 kVp. The body mass index of all included patients was <25 kg/m(2). Group A scans were reconstructed with a standard filtered back projection (FBP) algorithm, and group B scans with FBP, iDose, and non-tagged algorithms. Data comparison between groups was performed using t-test and analysis of variance. RESULTS: Compared with group A, the iDose algorithm in group B yielded a higher contrast-to-noise ratio (CNR; 48.1 +/- 10.1, p < 0.05), a higher signal-to-noise ratio (SNR; 13.8 +/- 5.4, p < 0.05), and a lower standard deviation (SD; 30.3 +/- 6.9, p < 0.05). The subjective score of iDose reconstructions from group B was significantly lower than that of FBP reconstruction from group A (p < 0.05). In group B, the non-tagged algorithm resulted in a higher CNR and a higher SNR, but a higher SD and a higher subjective score than did the iDose algorithm. The average effective dose for group B was 35.8% lower than that for group A. CONCLUSION: A combination of a 100 kVp tube voltage and the iDose algorithm can help to improve image quality and reduce radiation dose in retrospective ECG-gated thoracoabdominal aortic CTA. PMID- 25703462 TI - A case of a migrating pleural lipoma: the beginning of a thoracolith? AB - Lipomas can be encountered almost anywhere in the body, yet they are rare in the pleural space of the thorax. However, they have been typically described as pleural-based fatty masses. We present a rare case of a pleural lipoma that changed its location on follow-up images. Migration and rotation of the lesion were investigated using chest computed tomography. A pathologic examination demonstrated extensive calcification and fat necrosis. The findings in this case support a mechanism of development of thoracolith. PMID- 25703463 TI - Selectivity of cytosolic phospholipase A2 type IV toward arachidonyl phospholipids. AB - Cytosolic phospholipase A2 (cPLA2 ) is an interesting protein involved in inflammatory processes and various diseases. Its catalytic mechanism as well as its substrate specificity for arachidonyl phospholipids is not typical for other phospolipases. Furthermore, a lid structure, which ensures a hydrophilic surface of the protein without any substrate bound and the movement of this flexible loop to make the hydrophobic active site accessible, is of high interest. Therefore, the focus of this work was to determine the binding mode of cPLA2 with various substrates, such as arachidonic acid, a synthetic inhibitor, a saturated phospholipid, and most importantly an arachidonyl phospholipid. To understand the selectivity of the protein toward the arachidonyl phospholipid and the interaction in a protein-ligand complex, molecular dynamics simulations were performed using the GROMOS suite of simulation programs. The simulations provide insight into the protein and showed that selective binding of arachidonyl phospholipids is because of the shape of the sn-2 tail. The amino acids Asn555 and Ala578 are involved in the strongest interactions observed in the protein ligand complexes. PMID- 25703464 TI - A functionalized Ag2S molecular architecture: facile assembly of the atomically precise ferrocene-decorated nanocluster [Ag74S19(dppp)6(fc(C{O}OCH2CH2S)2)18]. AB - A ferrocene-based dithiol 1,1'-[fc(C{O}OCH2CH2SH)2] has been prepared and treated with a Ag(I) salt to form the stable dithiolate compound [fc(C{O}OCH2CH2SAg)2]n (fc=[Fe(eta(5)-C5H4)2]). This is used as a reagent for the preparation of the nanocluster [Ag74S19(dppp)6(fc(C{O}OCH2CH2S)2)18] which was obtained in good yield (dppp=1,3-bis(diphenylphosphino)propane). PMID- 25703465 TI - Oscillatory Dynamics and In Vivo Photoacoustic Imaging Performance of Plasmonic Nanoparticle-Coated Microbubbles. AB - Microbubbles bearing plasmonic nanoparticles on their surface provide contrast enhancement for both photoacoustic and ultrasound imaging. In this work, the responses of microbubbles with surface-bound gold nanorods-termed AuMBs-to nanosecond pulsed laser excitation are studied using high-speed microscopy, photoacoustic imaging, and numerical modeling. In response to laser fluences below 5 mJ cm(-2) , AuMBs produce weak photoacoustic emissions and exhibit negligible microbubble wall motion. However, in reponse to fluences above 5 mJ cm(-2) , AuMBs undergo dramatically increased thermal expansion and emit nonlinear photoacoustic waves of over 10-fold greater amplitude than would be expected from freely dispersed gold nanorods. Numerical modeling suggests that AuMB photoacoustic responses to low laser fluences result from conductive heat transfer from the surface-bound nanorods to the microbubble gas core, whereas at higher fluences, explosive boiling may occur at the nanorod surface, producing vapor nanobubbles that contribute to rapid AuMB expansion. The results of this study indicate that AuMBs are capable of producing acoustic emissions of significantly higher amplitude than those produced by conventional sources of photoacoustic contrast. In vivo imaging performance of AuMBs in a murine kidney model suggests that AuMBs may be an effective alternative to existing contrast agents for noninvasive photoacoustic and ultrasound imaging applications. PMID- 25703466 TI - Nonarteritic anterior ischemic optic neuropathy (NAION): a misnomer. Rearranging pieces of a puzzle to reveal a nonischemic papillopathy caused by vitreous separation. PMID- 25703467 TI - Clinical trials: a need to better define the control group as current standard of care. PMID- 25703468 TI - Fires in the operating room: prepare and prevent. PMID- 25703469 TI - Re: Bakri et al.: Intraocular pressure in eyes receiving monthly ranibizumab in 2 pivotal age-related macular degeneration clinical trials (Ophthalmology 2014;121:1102-8). PMID- 25703470 TI - Re: Brown et al.: Cataract surgery cost utility revisited in 2012: a new economic paradigm (Ophthalmology 2013;120:2367-76). PMID- 25703471 TI - Re: Shah et al.: The state of ophthalmology medical student education in the United States and Canada, 2012 through 2013 (Ophthalmology 2014;121:1160-3). PMID- 25703472 TI - Author reply: To PMID 24393349. PMID- 25703473 TI - Re: Boyer et al.: Three-year, randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with diabetic macular edema (Ophthalmology 2014;121:1904-14). PMID- 25703474 TI - Investigation of a swimming pool-associated cryptosporidiosis outbreak in the Kimberley region of Western Australia. AB - Cryptosporidiosis is a gastroenteric disease caused by the protozoan parasite Cryptosporidium, which manifests primarily as watery diarrhoea. Transmitted via the faecal-oral route, infection with the parasite can occur through ingestion of water, food or other fomites contaminated with its infective oocyst stage. In the months of November and December 2012, there were 18 notified cases of cryptosporidiosis from Broome, Western Australia. The 5-year average for the Kimberley region for this period is <1 case. Interviews conducted by Broome local government staff on the notified cases revealed that 11/18 cases had been swimming at the Broome public swimming pool. Molecular analyses of extracted DNA performed on 8/18 microscopy-positive faecal samples from interviewed cases and three water samples from different locations at the hypervariable glycoprotein 60 (gp60) gene, identified the C. hominis IbA10G2 subtype in all human samples and one water sample. PMID- 25703475 TI - Transepithelial versus epithelium-off corneal cross-linking for the treatment of progressive keratoconus: a randomized controlled trial. AB - PURPOSE: To compare the clinical effects and safety of transepithelial corneal cross-linking (CXL) to epithelium-off (epi-off) CXL in progressive keratoconus. DESIGN: Randomized clinical trial (noninferiority). METHODS: Patients received either transepithelial CXL with Ricrolin TE (n = 35) or epi-off CXL with isotonic riboflavin (n = 26) in 1 academic treatment center, using a simple unrestricted randomization procedure. The main outcome measure was clinical stabilization of keratoconus after 1 year, defined as a maximal keratometry (Kmax) increase <1 diopter (D). RESULTS: Average Kmax was stable at all visits in the transepithelial group, while after epi-off CXL a significant flattening of 1.2 1.5 D was demonstrated from the 3-month follow-up onwards. The trend over time in Kmax flattening was significantly different between the groups (P = .022). Eight eyes (23%) in the transepithelial group showed a Kmax increase of >1 D after 1 year (range 1.3-5.4 D) vs none in the epi-off group (P = .017). There was significant different trend in corrected distance visual acuity (CDVA), with a more favorable outcome in the transepithelial group (P = .023). In the transepithelial group, no complications occurred and in the epi-off group, 4 eyes (15%) developed complications owing to healing problems (sterile infiltrate, herpes keratitis, central haze, and stromal scar). CONCLUSION: This study showed that although transepithelial CXL was a safe procedure without epithelial healing problems, 23% of cases showed a continued keratoconus progression after 1 year. Therefore, at this time, we do not recommend replacing epi-off CXL by transepithelial CXL for treatment of progressive keratoconus. PMID- 25703477 TI - The association between glaucoma and immunoglobulin E antibody response to indoor allergens. AB - PURPOSE: To evaluate the association between sensitization to indoor allergens and glaucoma in participants of the National Health and Nutrition Examination Survey (NHANES). DESIGN: Retrospective cross-sectional study. METHODS: This study examined the association between serum immunoglobulin E (IgE) levels for a panel of common indoor allergens and glaucoma for 2005-2006 NHANES participants. The exposures of interest were serum IgE levels to a panel of common indoor allergens. The outcome of interest was a clinical diagnosis of glaucoma based on the Rotterdam criteria. Logistic regression modeling was performed to assess the association between each type of IgE and glaucoma, while controlling for age, ethnicity, and steroid use. All estimates were weighted based on the multistage NHANES sampling design. RESULTS: Among a weighted total of 83 308 318 participants, the overall prevalence of glaucoma was 3.2% (95% confidence interval [CI]: 2.8%, 3.6%). The majority of patients were non-Hispanic white (n = 10 547 654; 77.1%). The American dust mite antigen had the highest proportion of participants with positive IgE values (n = 12 093 038; 14.5%). In the full model including all allergen-specific IgE subtypes as predictors, there were statistically significant associations between IgE subtypes and glaucoma for the cockroach (odds ratio [OR] = 2.78; 95% CI = 1.34, 5.76), cat (OR = 3.42; 95% CI = 1.10, 10.67), and dog (OR = 0.24; 95% CI = 0.06, 0.96) antigens. CONCLUSIONS: In NHANES, participants with glaucoma had significantly higher odds of sensitization to the cockroach and cat allergens compared to those without glaucoma. These findings indicate the need for further research to elucidate the role of chronic indoor allergen exposure in the development of glaucomatous optic neuropathy. PMID- 25703476 TI - Alteration of galectin-3 in tears of patients with dry eye disease. AB - PURPOSE: To investigate the expression, release, and proteolytic degradation of galectin-3 in patients with dry eye disease. DESIGN: Observational case series with a comparison group. METHODS: Tear washes and conjunctival impression cytology specimens were collected through standard procedures from 16 patients with dry eye and 11 age-matched healthy subjects. Galectin-3 content in tears was analyzed by quantitative Western blot, using recombinant galectin-3 protein to generate a calibration curve. The relative expression of galectin-3 and matrix metalloproteinase 9 (MMP9) was evaluated by quantitative polymerase chain reaction. The cleavage of galectin-3 was studied in vitro using activated recombinant MMP9 and protease inhibitors. RESULTS: The concentration of galectin 3 protein in tears, but not galectin-3 expression in conjunctival epithelium, was significantly higher in tears of patients with dry eye (0.38 ng/MUg total protein, range 0.04-1.36) compared to healthy subjects (0.12 ng/MUg total protein, range 0.00-0.41) (P < .01). By Western blot, an intact (~28.0 kDa) galectin-3 band was identified in tear samples from healthy subjects, whereas 50% of the dry eye samples were characterized by the additional presence of a partially degraded form (~25.4 kDa). In our experiments, elevated expression of MMP9 in dry eye subjects correlated with the ability of active MMP9 to cleave galectin-3 from recombinant origin. Interestingly, cleavage of endogenous galectin-3 in tear samples was impaired using a broad-spectrum proteinase inhibitor cocktail, but not the pan-specific MMP inhibitor GM6001, suggesting the presence of proteases other than MMPs in promoting galectin-3 degradation in dry eye. CONCLUSIONS: Our results indicate that release of cellular galectin-3 into tears is associated with epithelial dysfunction in dry eye, and that galectin-3 proteolytic cleavage may contribute to impaired ocular surface barrier function. PMID- 25703478 TI - Clinical efficacy of navigated panretinal photocoagulation in proliferative diabetic retinopathy. AB - PURPOSE: To compare the clinical efficacy of navigated pattern and conventional slit-lamp pattern panretinal photocoagulation (PRP). DESIGN: Randomized clinical trial. METHODS: Seventy-four eyes with proliferative diabetic retinopathy (PDR) in need of PRP were randomly assigned to 1 of 4 groups: PRP conventional pattern 30 ms, 100 ms, navigated pattern 30 ms, 100 ms pulse. Navigated laser is a fundus camera-based photocoagulator with retinal eye tracking. Outcome variables included stability of visual acuity, regression or development of neovascularization and need for retreatment sessions and surgical intervention, pain perception, and procedure time. RESULTS: There was no change in visual acuity between pre- and post-treatment measurements among the study groups. Short pulse groups in total required 22 procedures compared to 12 procedures in long pulse groups (P < .05). A trend toward worse outcome using 30 ms pulse duration treatments is expressed by slightly increased relative risk of 1.3 compared to 100 ms groups. Only 2 eyes required vitreoretinal surgery for nonclearing vitreous hemorrhage, 1 in each 30 ms group; insignificantly different between study groups (P = .98). The pain score was lower with navigated laser as compared to conventional laser in both 30 ms groups (P = .1) and 100 ms groups, where it reached statistical significance (P = .02). Pain experience was significant (P < .001) between navigated 100 ms pattern and conventional single-spot 100 ms treatments. CONCLUSIONS: This study demonstrates better clinical efficacy of 100 ms compared to 30 ms treatments using both conventional and navigated pattern lasers. The ability to use long-pulse-duration navigated pattern treatments broadens therapeutic options for PRP in proliferative diabetic retinopathy. PMID- 25703479 TI - Modeling parameters that characterize pacing of elite female 800-m freestyle swimmers. AB - Pacing offers a potential avenue for enhancement of endurance performance. We report here a novel method for characterizing pacing in 800-m freestyle swimming. Websites provided 50-m lap and race times for 192 swims of 20 elite female swimmers between 2000 and 2013. Pacing for each swim was characterized with five parameters derived from a linear model: linear and quadratic coefficients for effect of lap number, reductions from predicted time for first and last laps, and lap-time variability (standard error of the estimate). Race-to-race consistency of the parameters was expressed as intraclass correlation coefficients (ICCs). The average swim was a shallow negative quadratic with slowest time in the eleventh lap. First and last laps were faster by 6.4% and 3.6%, and lap-time variability was +/-0.64%. Consistency between swimmers ranged from low-moderate for the linear and quadratic parameters (ICC = 0.29 and 0.36) to high for the last-lap parameter (ICC = 0.62), while consistency for race time was very high (ICC = 0.80). Only ~15% of swimmers had enough swims (~15 or more) to provide reasonable evidence of optimum parameter values in plots of race time vs. each parameter. The modest consistency of most of the pacing parameters and lack of relationships between parameters and performance suggest that swimmers usually compensated for changes in one parameter with changes in another. In conclusion, pacing in 800-m elite female swimmers can be characterized with five parameters, but identifying an optimal pacing profile is generally impractical. PMID- 25703480 TI - Longitudinal changes in lean mass predict pQCT measures of tibial geometry and mineralisation at 6-7 years. AB - BACKGROUND: Studies in childhood suggest that both body composition and early postnatal growth are associated with bone mineral density (BMD). However, little is known of the relationships between longitudinal changes in fat (FM) and lean mass (LM) and bone development in pre-pubertal children. We therefore investigated these associations in a population-based mother-offspring cohort, the Southampton Women's Survey. METHODS: Total FM and LM were assessed at birth and 6-7 years of age by dual-energy x-ray absorptiometry (DXA). At 6-7 years, total cross-sectional area (CSA) and trabecular volumetric BMD (vBMD) at the 4% site (metaphysis) of the tibia was assessed using peripheral quantitative computed tomography [pQCT (Stratec XCT-2000)]. Total CSA, cortical CSA, cortical vBMD and strength-strain index (SSI) were measured at the 38% site (diaphysis). FM, LM and bone parameters were adjusted for age and sex and standardised to create within-cohort z-scores. Change in LM (DeltaLM) or FM (DeltaFM) was represented by change in z-score from birth to 7 years old and conditioned on the birth measurement. Linear regression was used to explore the associations between DeltaLM or DeltaFM and standardised pQCT outcomes, before and after mutual adjustment and for linear growth. The beta-coefficient represents SD change in outcome per unit SD change in predictor. RESULTS: DXA at birth, in addition to both DXA and pQCT scans at 6-7 years, were available for 200 children (48.5% male). DeltaLM adjusted for DeltaFM was positively associated with tibial total CSA at both the 4% (beta=0.57SD/SD, p<0.001) and 38% sites (beta=0.53SD/SD, p<0.001), cortical CSA (beta=0.48SD/SD, p<0.001) and trabecular vBMD (beta=0.30SD/SD, p<0.001), but not with cortical vBMD. These relationships persisted after adjustment for linear growth. In contrast, DeltaFM adjusted for DeltaLM was only associated with 38% total and cortical CSA, which became non significant after adjustment for linear growth. CONCLUSION: In this study, gain in childhood LM was positively associated with bone size and trabecular vBMD at 6 7 years of age. In contrast, no relationships between change in FM and bone were observed, suggesting that muscle growth, rather than accrual of fat mass, may be a more important determinant of childhood bone development. PMID- 25703481 TI - Monitoring human cytomegalovirus infection in pediatric hematopoietic stem cell transplant recipients: using an affordable in-house qPCR assay for management of HCMV infection under limited resources. AB - Quantitative real-time PCR (qPCR) assay is accepted as the method of choice for monitoring human cytomegalovirus (HCMV) infection in hematopoietic stem cell transplant recipients, but the high cost of commercial kits has hampered its use in many developing countries. In this study, an affordable in-house qPCR was used to manage HCMV infection in pediatric patients and the diagnostic value of this method was compared with the conventional pp65 antigenemia assay. A total number of 1179 samples from 82 recipients were used in this study, and the effect of some potential risk factors on HCMV reactivation was evaluated. The qPCR was able to detect HCMV reactivation earlier and with higher sensitivity than antigenemia assay. Forty-six episodes of reactivation were detected in 39 patients, of which all were detected by the qPCR assay, while only 21 episodes were diagnosed by antigenemia. The DNAemia level of 1284 IU/ml plasma was defined as the optimal cutoff value for starting pre-emptive therapy. It was shown that the acute GVHD severity and the relationship of donor and recipient are the most significant risk factors for HCMV reactivation. The data suggest that the antigenemia method for monitoring HCMV reactivation could be substituted by the qPCR assay. PMID- 25703482 TI - Reductive dismantling and functionalization of carbon nanohorns. AB - Reduction of carbon nanohorn (CNH) aggregates with potassium naphthalenide resulted in their dismantling and individualization. Furthermore, the reduced CNHs were functionalized via addition of electrophiles. PMID- 25703483 TI - Common childhood viral infections. AB - Infections caused by viruses are universal during childhood and adolescence. Clinicians will regularly care for children and adolescents who present with infections caused by a wide number of viral pathogens. These infections have varied presentations. Many infections may have clinical presentations that are specific to the infecting virus but present differently, based on the age and immunocompetence of the patient. Some children are directly impacted early in their lives when maternal disease results in an in utero infection (cytomegalovirus, rubella virus, or parvovirus B19). Other viruses may infect children in a predictable pattern as they grow older (rhinovirus or influenza virus). Fortunately, many viral infections frequently encountered in the past are no longer extant due to widespread immunization efforts. Recognition of these vaccine-preventable infections is important because outbreaks of some of these diseases (mumps or measles) continue to occur in the United States. Vigilance in vaccine programs against these viral agents can prevent their re-emergence. In addition, an increasing number of viral infections (herpes simplex virus, influenza virus, varicella zoster virus, or cytomegalovirus) can now be successfully treated with antiviral medications. Most viral infections in children result in self-limited illness and are treated symptomatically and infected children experience full recovery. This review will address the epidemiology, clinical presentation, diagnosis, treatment, and prevention of viral infections commonly encountered by the clinician. PMID- 25703484 TI - How are overlapping time intervals perceived? Evidence for a weighted sum of segments model. AB - This study investigated the way in which people time two overlapping intervals. Timing models already proposed in the literature predict different effects of the degree of overlap on each estimate, and empirical findings were compared to these predictions. Two unimodal experiments (in which each to-be-timed interval was a visual stimulus) and one bimodal experiment (in which one to-be-timed interval was auditory and the other visual) were conducted. The estimate of the first interval was either unaffected or decreased, and the estimate of the second interval consistently increased as the intervals were more temporally separated. The only model in the literature that could account for such result patterns is a single pacemaker single accumulator structure with an additional recency weighting (see the weighted sum of segments model). That is, participants appear to segment the two overlapping intervals into three non-overlapping and overlapping segments, time these segments separately, and then combine them to estimate each interval. Importantly, a recency weighting, determined by the time that has passed since the end of that segment, is also applied to each segment in the summation process. Further, in the bimodal experiment the order in which the stimuli of different modalities were presented affected the way in which they were timed, a finding that none of the current models can explain. This highlights that a comprehensive model of interval timing must consider not only the modalities of to-be-timed intervals but also the order in which different modalities must be timed. PMID- 25703485 TI - Trauma changes everything: examining the relationship between adverse childhood experiences and serious, violent and chronic juvenile offenders. AB - Among juvenile offenders, those who commit the greatest number and the most violent offenses are referred to as serious, violent, and chronic (SVC) offenders. However, current practices typically identify SVC offenders only after they have committed their prolific and costly offenses. While several studies have examined risk factors of SVCs, no screening tool has been developed to identify children at risk of SVC offending. This study aims to examine how effective the adverse childhood experiences index, a childhood trauma-based screening tool developed in the medical field, is at identifying children at higher risk of SVC offending. Data on the history of childhood trauma, abuse, neglect, criminal behavior, and other criminological risk factors for offending among 22,575 delinquent youth referred to the Florida Department of Juvenile Justice are analyzed, with results suggesting that each additional adverse experience a child experiences increases the risk of becoming a serious, violent, and chronic juvenile offender by 35, when controlling for other risk factors for criminal behavior. These findings suggest that the ACE score could be used by practitioners as a first-line screening tool to identify children at risk of SVC offending before significant downstream wreckage occurs. PMID- 25703486 TI - Irritable bowel syndrome: an integrated explanatory model for clinical practice. AB - BACKGROUND: Although irritable bowel syndrome (IBS) is a symptom-based diagnosis, clinicians' management of and communication about the disorder is often hampered by an unclear conceptual understanding of the nature of the problem. We aimed to elucidate an integrated explanatory model (EM) for IBS from the existing literature for pragmatic use in the clinical setting. METHODS: Systematic and exploratory literature searches were performed in PubMed to identify publications on IBS and EMs. KEY RESULTS: The searches did not identify a single, integrated EM for IBS. However, three main hypotheses were elucidated that could provide components with which to develop an IBS EM: (i) altered peripheral regulation of gut function (including sensory and secretory mechanisms); (ii) altered brain-gut signaling (including visceral hypersensitivity); and (iii) psychological distress. Genetic polymorphisms and epigenetic changes may, to some degree, underlie the etiology and pathophysiology of IBS and could increase the susceptibility to developing the disorder. The three model components also fit into one integrated explanation for abdominal symptoms and changes in stool habit. Additionally, IBS may share a common pathophysiological mechanism with other associated functional syndromes. CONCLUSIONS & INFERENCES: It was possible to elucidate an integrated, three-component EM as a basis for clinicians to conceptualize the nature of IBS, with the potential to contribute to better diagnosis and management, and dialog with sufferers. PMID- 25703487 TI - Updated meta-analysis of classical fear conditioning in the anxiety disorders. AB - The aim of the current study was twofold: (1) to systematically examine differences in fear conditioning between anxiety patients and healthy controls using meta-analytic methods, and (2) to examine the extent to which study characteristics may account for the variability in findings across studies. Forty four studies (published between 1920 and 2013) with data on 963 anxiety disordered patients and 1,222 control subjects were obtained through PubMed and PsycINFO, as well as from a previous meta-analysis on fear conditioning (Lissek et al.). Results demonstrated robustly increased fear responses to conditioned safety cues (CS-) in anxiety patients compared to controls during acquisition. This effect may represent an impaired ability to inhibit fear in the presence of safety cues (CS-) and/or may signify an increased tendency in anxiety disordered patients to generalize fear responses to safe stimuli resembling the conditioned danger cue (CS+). In contrast, during extinction, patients show stronger fear responses to the CS+ and a trend toward increased discrimination learning (differentiation between the CS+ and CS-) compared to controls, indicating delayed and/or reduced extinction of fear in anxiety patients. Finally, none of the included study characteristics, such as the type of fear measure (subjective vs. psychophysiological index of fear), could account significantly for the variance in effect sizes across studies. Further research is needed to investigate the predictive value of fear extinction on treatment outcome, as extinction processes are thought to underlie the beneficial effects of exposure treatment in anxiety disorders. PMID- 25703488 TI - Trauma and traumatic loss in pregnant adolescents: the impact of Trauma-Focused Cognitive Behavior Therapy on maternal unresolved states of mind and Posttraumatic Stress Disorder. AB - Pregnant adolescents are a group at high risk for exposure to traumatic experiences. The present study aimed to examine if Trauma-Focused Cognitive Behavior Therapy (TF-CBT) typically applied to Posttraumatic Stress Disorder (PTSD), could also be applied to unresolved states of mind in a sample of socially at-risk pregnant adolescents. Forty-three adolescents who were in their second trimester of pregnancy and who also had positive indices of unresolved states of mind or symptoms of PTSD were randomly assigned to either the treatment as usual (parenting classes) or intervention (parenting classes + TF-CBT) group. Adolescent mother-infant dyads were then re-assessed at infant ages 6 and 12 months on a broad range of measures, including those specific to attachment, as well as to PTSD, and adolescent behavioral adjustment. Twenty-six of the 43 (60%) recruited subjects completed all components of the study protocol. Although there were no significant effects of the TF-CBT intervention on maternal attachment, infant attachment, PTSD diagnosis and adolescent behavioral adjustment, several study limitations restrict our ability to draw firm conclusions about the efficacy of TF-CBT for use in pregnant adolescents with complex trauma. The discussion offers insight and guidance for clinical work and future intervention research efforts with this vulnerable population. PMID- 25703489 TI - Factors affecting urine reagent strip blood results in dogs and nonhuman primates and interpretation of urinalysis in preclinical toxicology studies: a Multi Institution Contract Research Organization and BioPharmaceutical Company Perspective. AB - BACKGROUND: Urinalysis data in preclinical toxicology studies can be influenced by preanalytic and analytic factors which have the potential to confound interpretation. There is a paucity of information regarding positive reagent strip urinary blood reactions in healthy nonhuman primates (NHP) and Beagle dogs used in preclinical toxicology studies. OBJECTIVES: The objectives were (1) to establish historical control data for reagent strip urinary blood reactions in healthy NHP and Beagle dogs, (2) to determine the incidence of positive urinary blood reactions during predose and dosing phases, and (3) to determine if collection practice was a relevant parameter. METHODS: Historical control data from 2 institutions in the biopharmaceutical industry were retrospectively analyzed for reagent strip urinary blood reactions in healthy NHP and Beagles. The incidence of positive results between the 2 institutions with different urine collection practices and between males and females was compared. RESULTS: The incidence of positive urinary blood reactions in NHP was comparable between institutions (<= 14% in males; <= 33% in females), while the incidence of positive urinary blood reactions in Beagles was more variable (<= 77% in males; <= 69% in females), and higher in females during the dosing phase. CONCLUSIONS: Positive urinary blood results that could potentially be misinterpreted as toxicologically relevant were identified in healthy NHP and Beagles during predose and dosing phases. Different incidences of positive results between the 2 institutions were likely related to collection practices. Strategies to reduce feces and food contamination of collected urine samples should help minimize false-positive urinary blood reactions. PMID- 25703490 TI - Evidence-balanced medicine: "real" evidence-based medicine in the elderly. PMID- 25703491 TI - A novel "box lesion" minimally invasive totally thoracoscopic surgical ablation for atrial fibrillation. AB - INTRODUCTION: Minimally invasive surgical ablation is an emerging alternative method to catheter ablation and the full surgical maze procedure for nonpharmacologic treatment of atrial fibrillation (AF). We present a totally thoracoscopic "box lesion" radiofrequency ablation procedure in patients with paroxysmal or persistent AF. MATERIALS AND METHODS: From June 2011 to October 2012, 14 patients with lone paroxysmal (n = 7) or persistent AF (n = 7) were enrolled in this study. Procedures were performed through 3 5-12 mm holes on each side of the chest wall. A bipolar ablation device was used to create a box lesion in the posterior wall of the left atrium that encircled the 4 pulmonary veins (achieving bilateral pulmonary vein/posterior left atrial wall isolation). Perioperative complications were recorded for all patients. Freedom from AF was assessed by 24-hour Holter monitoring every 3 months or during symptoms of arrhythmia. RESULTS: The ablation was successfully performed in all patients, with median operation time of 128 minutes (range, 45 to 180 minutes). No operative mortality or morbidity were noted during the study period. Freedom from AF was achieved in 12 patients (85.7%) during follow-up (median follow-up 9 months). One patient with persistent AF was shifted to paroxysmal AF. No atrial flutter or atrial tachycardia was noted during the follow-up. CONCLUSION: These early results show that totally thoracoscopic surgical ablation using a unique "box lesion" procedure for persistent or paroxysmal AF is a feasible and effective method with good short-term results. Further study is necessary to validate this result. PMID- 25703492 TI - Anaerobic bacteraemia revisited: species and susceptibilities. AB - INTRODUCTION: This retrospective study was performed to evaluate the frequency of anaerobic bacteraemia over a 10-year period, and to provide updated antibiotic susceptibilities for the more clinically relevant anaerobes causing blood stream infection. MATERIALS AND METHODS: Data were retrieved from the laboratory information system for the period 2003 to 2012. During this time, blood cultures were inoculated in BactecTM Plus vials (BD, USA) and continuously monitored in the BactecTM 9000 blood culture system (BD, USA). Anaerobic organisms were identified using commercial identification kits, predominantly API 20 A (bioMerieux, France) supplemented with Vitek ANC cards (bioMerieux, France) and AN-Ident discs (Oxoid, United Kingdom). A representative subset of isolates were retrieved from 2009 to 2011 and antimicrobial susceptibilities to penicillin, amoxicillin-clavulanate, clindamycin, imipenem, moxifloxacin, piperacillin tazobactam and metronidazole were determined using the Etest method. RESULTS: Anaerobes comprised 4.1% of all positive blood culture with 727 obligate anaerobes recovered over the 10-year period, representing a positivity rate of 0.35%. The only significant change in anaerobe positivity rates occurred between 2003 and 2004, with an increase of 0.2%. The Bacteroides fragilis group (45%) were the predominant anaerobic pathogens, followed by Clostridium species (12%), Propioniobacterium species (11%) and Fusobacterium species (6%). The most active in vitro antibiotics were imipenem, piperacillin-tazobactam, amoxicillin clavulanate and metronidazole, with susceptibilities of 95.0%, 93.3%, 90.8% and 90.8% respectively. Resistance was high to penicillin, clindamycin and moxifl oxacin. However, there were apparent differences for antibiotic susceptibilities between species. CONCLUSION: This study indicates that the anaerobes comprise a small but constant proportion of bloodstream isolates. Antibiotic resistance was high to some antibiotics, but metronidazole, the beta-lactam/beta-lactamase inhibitors and carbapenems retained good in vitro activity. PMID- 25703494 TI - Schizophrenia as a lifelong illness: implications for care. PMID- 25703493 TI - Safety and effectiveness of improving carbapenem use via prospective review and feedback in a multidisciplinary antimicrobial stewardship programme. AB - INTRODUCTION: Antimicrobial stewardship programmes (ASP) can reduce antibiotic use but patient safety concerns exist. We evaluated the safety of prospective carbapenem review and feedback and its impact on carbapenem use and patient outcomes. MATERIALS AND METHODS: After 3 months implementation of our ASP, we compared patients with and without acceptance of ASP recommendations on the use of carbapenems. Primary outcome was 30-day mortality. Secondary outcomes included duration of carbapenem use, length of hospitalisation, clinical response, microbiological clearance, 30-day readmission and mortality at discharge. RESULTS: Of 226 recommendations for 183 patients, 59.3% was accepted. De escalation, switching to oral antibiotics and antibiotic cessation comprised 72% of recommendations. Patients with acceptance of ASP recommendations had lower 30 day mortality and higher end-of-therapy clinical response despite shorter carbapenem duration (P <0.05). Predictors of 30-day mortality were Pitt bacteraemia score (adjusted odds ratio [aOR] 1.39, 95% confidence interval [CI], 1.11 to 1.74; P = 0.004) and non-acceptance of ASP recommendations (aOR 2.84, 95% CI, 1.21 to 6.64; P = 0.016). CONCLUSION: Our prospective carbapenem review and feedback mainly comprising of reducing carbapenem use is safe. PMID- 25703495 TI - A follow-up longitudinal survey on a cohort of undergraduate medical students' attitudes towards radiology. PMID- 25703496 TI - The root of unprofessionalism. PMID- 25703497 TI - Reply from author: missing the forest for the trees. PMID- 25703498 TI - 24th Seah Cheng Siang Lecture: Seeing better, doing better--evolution and application of gastrointestinal (GI) endoscopy. AB - Gastrointestinal (GI) endoscopy has evolved tremendously from the early days when candlelight was used to illuminate scopes to the extent that it has now become an integral part of the practice of modern gastroenterology. The first gastroscope was a rigid scope first introduced by Adolf Kussmaul in 1868. However this scope suffered from the 2 drawbacks of poor illumination and high risk of instrumental perforation. Rudolf Schindler improved on this by inventing the semiflexible gastroscope in 1932. But it was Basil Hirschowitz, using the principle of light conduction in fibreoptics, who allowed us to "see well" for the first time when he invented the flexible gastroscopy in 1958. With amazing speed and innovation, instrument companies, chiefly Japanese, had improved on the Hirschowitz gastroscope and invented a flexible colonoscope. Walter McCune introduced the technique of endoscopic retrograde cholangiopancreatography (ERCP) in 1968 which has now evolved into a sophisticated procedure. The advent of the digital age in the 1980s saw the invention of the videoendoscope. Videoendoscopes have allowed us to start seeing the gastrointestinal tract (GIT) "better" with high magnification and resolution and optical/digital enhancements. Fusing confocal and light microscopy with endoscopy has allowed us to perform an "optical biopsy" of the GI mucosa. Development of endoscopic ultrasonography has allowed us to see "beyond" the GIT lumen. Seeing better has allowed us to do better. Endoscopists have ventured into newer procedures such as the resection of mucosal and submucosal tumours and the field of therapeutic GI endoscopy sees no end in sight. PMID- 25703499 TI - Gender role orientation is associated with health-related quality of life differently among African-American, Hispanic, and White youth. AB - PURPOSE: This study examined the association between gender role orientation (GRO) and health-related quality of life (HRQOL) in youth, and how this relationship may differ between males and females as well as among African American, White, and Hispanic individuals. GRO has been reported to influence serious health outcomes including cancer, heart disease, mental illness, and mortality rates. However, few studies have examined the link between GRO and health outcomes for children, even though gender identity is formed in childhood. METHODS: Data were examined from 4824 participants in the Healthy PassagesTM project, a population-based survey of fifth-grade children in three US metropolitan areas. Children reported their own HRQOL using the PedsQL and degree of female, male, and androgynous GRO using the Children's Sex Role Inventory. RESULTS: Based on structural equations analysis, male GRO was positively associated with HRQOL for all racial/ethnic groups, regardless of sex, whereas female GRO was associated with better HRQOL for Hispanic and White females and poorer HRQOL for Hispanic males. Androgynous GRO was associated with better HRQOL among Hispanic and White females, but not males nor African-Americans of either sex. CONCLUSIONS: Racial/ethnic differences emerged for female and androgynous, but not male, GROs. Hispanic males are the only group for which GRO (female) was associated with poorer HRQOL. Future research should find ways to help youth overcome negative effects on health from gender beliefs and behavior patterns with sensitivity to racial/ethnic membership. PMID- 25703500 TI - Epifluorescence microscopy: a sensitive tool for studying the morphology and oriented growth of europium precipitates in KI single-crystal hosts. AB - The morphology and oriented growth of europium precipitates in well-annealed Eu2+ doped KI single crystals are investigated by epifluorescence microscopy using the proper doping ions as fluorochromes. To make this, electronic spatial reconstructions of some fields of precipitates and of some individual precipitates were built from epifluorescence microscope images of different optical cross-sections of these objects. The building procedures are carefully explained. Previously, the KI:Eu2+ system was characterized by fluorescence spectrophotometry and the KI-host long-range translational order was tested by single-plate X-ray diffraction. Precipitates are shaped as plates, with their broad faces being parallel to host lattice planes of either {100}- or {110}-forms (the {100}- or {110}-plates, respectively) and as rods lying along host lattice <100>-directions. The {100}-plates have rhomboidal broad faces with a side lying along a <100>-direction, an internal angle of about 45 degrees , as measured on the corresponding {100}-plane, and, consequently, another side (the {100}<110> side) lying along a <110> direction on this plane. The {110}-plates have rectangular broad faces with a side lying along a <100>-direction and with another side (the {110}<110>-side) lying along a <110>-direction on the corresponding {110}-plane. Spatial reconstructions of a typical precipitate field, a typical {100}-plate, a typical {110}-plate and a typical rod are described in detail. Precipitates were measured in their different dimensions and the measuring procedures are explained. The plate thicknesses and rod diameters are into a common narrow range of values (0.5-0.2 MUm) which contains also the inferior limits of the obtained length ranges for the {100}<110>- and {110}<110> sides (5.1-0.3 and 4.9-0.3 MUm, respectively). It is discussed that that three different europium precipitation states are responsible for the studied precipitation and that plates grew from rods during annealing. PMID- 25703501 TI - Multiple halo nevi subsequent to a short period of sunbathing. PMID- 25703502 TI - Synovial chondromatosis of the tempromandibular joint: relationship between MRI information and potential aggressive behavior. AB - PURPOSE: To evaluate the types of synovial condromatosis (SC) of tempromandibular joint (TMJ) on MRI and their potential aggressive behavior. METHODS: 144 patients with pure SC of TMJ were included in. On MRI, 3 types of the lesion included loose body, homogeneous mass, and mixture of both loose body and homogeneous mass. Bony evaluations included 4 stages of erosion: without erosion, chondral breakdown, bony absorption and bony perforation. RESULTS: 47 (32.6%) cases were categorized in the type of loose body, 71 (49.3%) cases in the type of homogeneous mass, and 26 (18.1%) cases in the type of mixture. 80% of bony perforation belonged to the type of homogeneous mass and 20% belonged to the type of mixture. 2 patients were found recurrence. CONCLUSION: The types of homogeneous mass and mixture of both on MRI were more aggressive. Homogeneous mass with bony erosion on MRI had potential recurrence. PMID- 25703503 TI - Developing a parametric ear model for auricular reconstruction: a new step towards patient-specific implants. AB - INTRODUCTION: Ear reconstruction is a tedious and demanding surgical procedure and the implant framework used is essential for the esthetic result. The outcome of a reconstructed ear, however, is not necessarily limited to the implant shape but rather to the available options of transplantable tissue for coverage. Apart from the visual aesthetics, ear reconstruction subsequently also requires implant dimensions to be adapted to the surgical possibilities. In this article, we have brought different disciplines together to develop a customizable ear model for 3D printing of ear implants. MATERIAL AND METHODS: Computed tomography (CT) scans were made of 4 human cadaver ears before and after soft tissue dissection using a Discovery 750 High Definition Freedom Edition scanner (GE, Milwaukee, WI, USA) and subsequently converted into an STL data set using Mimics Software (Materialise, Leuven, Belgium). These scans were then used to develop a fully adjustable parametric model based on the essential ear anatomy using Rhinoceros and Grasshopper software. RESULTS: To determine the quality of the developed models, directed Hausdorff distance (DHD) was applied as the basis for measuring the similarity between the parametric model and the ear cartilage scanning data. Two methods were used. The mean directed Haussdorff distance (MDHD) was calculated based on the distribution of point sets showing an average similarity of 0.8 mm (+/-0.05 mm). The mean similarity coefficient (SC) of the model and scan surfaces was 94% with a 2-mm threshold. CONCLUSION: This study shows that a parametric standard model could be used as a feasible method to generate custom implants based on existing ear images. PMID- 25703504 TI - A 22 years survival and prognostic factors analysis in a homogeneous series of 64 patients with advanced cancer of the tongue and the floor of the mouth. AB - PURPOSE: The aim of this study is to evaluate patients with advanced tongue and floor of the mouth carcinoma evaluating clinical and histopathologic parameters as prognostic factors for survival. METHODS: We studied retrospectively 64 patients with squamous cell carcinomas of the tongue and floor of the mouth in stage III and IV, treated by surgery at first and followed them for at least 22 years or until death, with a median follow-up of 67 months (range, 3-290 months). The prognosis factors evaluation included tumor, patient and treatment related factors using univariate and multivariate statistical analysis. RESULTS: The overall 5-year and 22-year survival rates were 34.4% and 6.3%, respectively; and the specific 5-year and 22 years survival rates 35.9%. Eleven patients (17.2%) had died of a second primary tumor and 8 (12.5%) of intercurrent diseases. Multivariable Cox regression analysis showed node capsular invasion, number of metastatic nodes and malignancy grading as the main factors associated with survival (p < 0.001). CONCLUSION: A very long-term follow-up allowed for the observation of the specific and the overall survival, influenced by age and comorbidities. The prognosis was strongly influenced by the ganglionar status and the histopathological characteristics of the primary tumor. PMID- 25703506 TI - Xylose isomerization with zeolites in a two-step alcohol-water process. AB - Isomerization of xylose to xylulose was efficiently catalyzed by large-pore zeolites in a two-step methanol-water process that enhanced the product yield significantly. The reaction pathway involves xylose isomerization to xylulose, which, in part, subsequently reacts with methanol to form methyl xyluloside (step 1) followed by hydrolysis after water addition to form additional xylulose (step 2). NMR spectroscopy studies performed with (13) C-labeled xylose confirmed the proposed reaction pathway. The most active catalyst examined was zeolite Y, which proved more active than zeolite beta, ZSM-5, and mordenite. The yield of xylulose obtained over H-USY (Si/Al=6) after 1 h of reaction at 100 degrees C was 39%. After water hydrolysis in the second reaction step, the yield increased to 47%. Results obtained from pyridine adsorption studies confirm that H-USY (6) is a catalyst that combines Bronsted and Lewis acid sites, and isomerizes xylose in alcohol media to form xylulose at low temperature. The applied zeolites are commercially available; do not contain any auxiliary tetravalent metals, for example, tin, titanium, or zirconium; isomerize xylose efficiently; are easy to regenerate; and are prone to recycling. PMID- 25703505 TI - The pharmacogenetics of alcohol use disorder. AB - BACKGROUND: Annually, the use and abuse of alcohol contributes to millions of deaths and billions of dollars in societal costs. To determine the impact of genetic variation on the susceptibility to the disorder and its response to treatment, studies have been conducted to assess the contribution of a variety of candidate genetic variants. These variants, which we review here, were chosen based upon their observed or hypothesized functional relevance to alcohol use disorder (AUD) risk or to the mechanism by which medications used to treat the disorder exert their effects. METHODS: This qualitative review examines studies in which candidate polymorphisms were tested as moderator variables to identify pharmacogenetic effects on either the subjective response to alcohol or the outcomes of pharmacotherapy. RESULTS: Although findings from these studies provide evidence of a number of clinically relevant pharmacogenetic effects, the literature is limited and there are conflicting findings that require resolution. CONCLUSIONS: Pharmacogenetic studies of AUD treatment that use greater methodological rigor and better statistical controls, such as corrections for multiple testing, may help to resolve inconsistent findings. These procedures could also lead to the discovery of more robust and clinically meaningful moderator effects. As the field evolves through methodological standardization and the use of larger study samples, pharmacogenetic research has the potential to inform clinical care by enhancing therapeutic effects and personalizing treatments. These efforts may also provide insights into the mechanisms by which medications reduce heavy drinking or promote abstinence in patients with an AUD. PMID- 25703507 TI - Gill morphometrics of the thresher sharks (Genus Alopias): Correlation of gill dimensions with aerobic demand and environmental oxygen. AB - Gill morphometrics of the three thresher shark species (genus Alopias) were determined to examine how metabolism and habitat correlate with respiratory specialization for increased gas exchange. Thresher sharks have large gill surface areas, short water-blood barrier distances, and thin lamellae. Their large gill areas are derived from long total filament lengths and large lamellae, a morphometric configuration documented for other active elasmobranchs (i.e., lamnid sharks, Lamnidae) that augments respiratory surface area while limiting increases in branchial resistance to ventilatory flow. The bigeye thresher, Alopias superciliosus, which can experience prolonged exposure to hypoxia during diel vertical migrations, has the largest gill surface area documented for any elasmobranch species studied to date. The pelagic thresher shark, A. pelagicus, a warm-water epi-pelagic species, has a gill surface area comparable to that of the common thresher shark, A. vulpinus, despite the latter's expected higher aerobic requirements associated with regional endothermy. In addition, A. vulpinus has a significantly longer water-blood barrier distance than A. pelagicus and A. superciliosus, which likely reflects its cold, well-oxygenated habitat relative to the two other Alopias species. In fast-swimming fishes (such as A. vulpinus and A. pelagicus) cranial streamlining may impose morphological constraints on gill size. However, such constraints may be relaxed in hypoxia-dwelling species (such as A. superciliosus) that are likely less dependent on streamlining and can therefore accommodate larger branchial chambers and gills. PMID- 25703508 TI - Reduced mobility of fomesafen through enhanced adsorption in biochar-amended soil. AB - The residual soil material resulting from biomass thermochemical transformation during carbon separation, known as biochar, has been introduced as a soil amendment because of its numerous environmental benefits, including uses for contaminated land management. Adsorption and leaching of fomesafen in soils amended with 3 different rates of rice hull biochar (0.5%, 1%, and 2% w/w) under laboratory conditions were investigated, and studies were performed following a batch equilibration adsorption-desorption procedure and a column experiment for leaching. Adsorption-desorption data fit with the Freundlich equation well. The adsorption coefficient of fomesafen sharply increased from 0.59 to 0.99 to 8.02 to 22.23 when the amount of biochar amendment in the soil increased from 0% to 2% (w/w). In addition, a strong correlation was found between the amount of adsorbed fomesafen and the rate of amended biochar (r > 0.992, p < 0.01). Furthermore, biochar amendments reduced the desorption percentage of fomesafen in the soils. The outcomes of the leaching experiment also illustrated that the lowest fomesafen concentration in the leachate (21.4%) occurred in the soil amended with 2% (w/w) biochar. Moreover, the adsorption coefficients (K(f)(ads)) of the soil were positively correlated with the total amount of adsorbed fomesafen in the corresponding soil columns (r = 0.990, p < 0.01) and negatively correlated with the leachate percentage (r = 0.987, p < 0.05). The results of the present study suggest that biochar amendments in agricultural soils likely alter the fate of herbicides by decreasing their transport through enhanced adsorption. PMID- 25703509 TI - Heterozygous mutations in natriuretic peptide receptor-B (NPR2) gene as a cause of short stature. AB - Based on the observation of reduced stature in relatives of patients with acromesomelic dysplasia, Maroteaux type (AMDM), caused by homozygous or compound heterozygous mutations in natriuretic peptide receptor-B gene (NPR2), it has been suggested that heterozygous mutations in this gene could be responsible for the growth impairment observed in some cases of idiopathic short stature (ISS). We enrolled 192 unrelated patients with short stature and 192 controls of normal height and identified seven heterozygous NPR2 missense or splice site mutations all in the short stature patients, including one de novo splice site variant. Three of the six inherited variants segregated with short stature in the family. Nine additional rare nonsynonymous NPR2 variants were found in three additional cohorts. Functional studies identified eight loss-of-function mutations in short individuals and one gain-of-function mutation in tall individuals. With these data, we were able to rigorously verify that NPR2 functional haploinsufficiency contributes to short stature. We estimate a prevalence of NPR2 haploinsufficiency of between 0 and 1/26 in people with ISS. We suggest that NPR2 gain of function may be a more common cause of tall stature than previously recognized. PMID- 25703510 TI - A new class of multi-stable neural networks: stability analysis and learning process. AB - Recently, multi-stable Neural Networks (NN) with exponential number of attractors have been presented and analyzed theoretically; however, the learning process of the parameters of these systems while considering stability conditions and specifications of real world problems has not been studied. In this paper, a new class of multi-stable NNs using sinusoidal dynamics with exponential number of attractors is introduced. The sufficient conditions for multi-stability of the proposed system are posed using Lyapunov theorem. In comparison to the other methods in this class of multi-stable NNs, the proposed method is used as a classifier by applying a learning process with respect to the topological information of data and conditions of Lyapunov multi-stability. The proposed NN is applied on both synthetic and real world datasets with an accuracy comparable to classical classifiers. PMID- 25703511 TI - Multistability of neural networks with discontinuous non-monotonic piecewise linear activation functions and time-varying delays. AB - This paper is concerned with the problem of coexistence and dynamical behaviors of multiple equilibrium points for neural networks with discontinuous non monotonic piecewise linear activation functions and time-varying delays. The fixed point theorem and other analytical tools are used to develop certain sufficient conditions that ensure that the n-dimensional discontinuous neural networks with time-varying delays can have at least 5(n) equilibrium points, 3(n) of which are locally stable and the others are unstable. The importance of the derived results is that it reveals that the discontinuous neural networks can have greater storage capacity than the continuous ones. Moreover, different from the existing results on multistability of neural networks with discontinuous activation functions, the 3(n) locally stable equilibrium points obtained in this paper are located in not only saturated regions, but also unsaturated regions, due to the non-monotonic structure of discontinuous activation functions. A numerical simulation study is conducted to illustrate and support the derived theoretical results. PMID- 25703512 TI - pth moment exponential stochastic synchronization of coupled memristor-based neural networks with mixed delays via delayed impulsive control. AB - This paper concerns the pth moment synchronization in an array of generally coupled memristor-based neural networks with time-varying discrete delays, unbounded distributed delays, as well as stochastic perturbations. Hybrid controllers are designed to cope with the uncertainties caused by the state dependent parameters: (a) state feedback controllers combined with delayed impulsive controller; (b) adaptive controller combined with delayed impulsive controller. Based on an impulsive differential inequality, the properties of random variables, the framework of Filippov solution, and Lyapunov functional method, sufficient conditions are derived to guarantee that the considered coupled memristor-based neural networks can be pth moment globally exponentially synchronized onto an isolated node under both of the two classes of hybrid impulsive controllers. Finally, numerical simulations are given to show the effectiveness of the theoretical results. PMID- 25703513 TI - Exposure characteristics of ferric oxide nanoparticles released during activities for manufacturing ferric oxide nanomaterials. AB - The exposure characteristics of Fe2O3 nanoparticles (NPs) released in a factory were investigated, as exposure data on this type of NP is absent. The nature of the particles was identified in terms of their concentrations [i.e. number concentration (NC(20-1000 nm)), mass concentration (MC(100-1000 nm)), surface area concentration (SAC(10-1000 nm))], size distribution, morphology and elemental composition. The relationships between different exposure metrics were determined through analyses of exposure ranking (ER), concentration ratios (CR), correlation coefficients and shapes of the particle concentration curves. Work activities such as powder screening, material feeding and packaging generated higher levels of NPs as compared to those of background particles (p < 0.01). The airborne Fe2O3 NPs exhibited a unimodal size distribution and a spindle-like morphology and consisted predominantly of the elements O and Fe. Periodic and activity-related characteristics were noticed in the temporal variations in NC(20 1000 nm) and SAC(10-1000 nm). The modal size of the Fe2O3 NPs remained relatively constant (ranging from 10 to 15 nm) during the working periods. The ER, CR values and the shapes of NC(20-1000 nm) and SAC(10-1000 nm) curves were similar; however, these were significantly different from those for MC(100-1000 nm). There was a high correlation between NC(20-1000 nm) and SAC(10-1000 nm), and relatively lower correlations between the two and MC(100-1000 nm). These findings suggest that the work activities during the manufacturing processes generated high levels of primary Fe2O3 NPs. The particle concentrations exhibited periodicity and were activity dependent. The number and SACs were found to be much more relevant metrics for characterizing NPs than was the mass concentration. PMID- 25703514 TI - Laboratory testing in the era of direct or non-vitamin K antagonist oral anticoagulants: a practical guide to measuring their activity and avoiding diagnostic errors. AB - A new generation of antithrombotic agents has recently emerged. These provide direct inhibition of either thrombin (factor IIa [FIIa]) or FXa, and are increasingly replacing the classical anticoagulants (heparin and coumarins such as warfarin) in clinical practice for a variety of conditions. These agents have been designated several acronyms, including NOACs, DOACs, and TSOACs, respectively, referring to new (novel; non-vitamin K antagonist) oral anticoagulants, direct oral anticoagulants, and target-specific oral anticoagulants, and currently include dabigatran (FIIa inhibitor), and rivaroxaban, apixaban, edoxaban, and betrixaban (FXa inhibitors). The pervading mantra that NOACs do not require laboratory monitoring is countered by ongoing recognition that laboratory testing for drug effects is needed in many situations. Moreover, since these agents "do not require" laboratory monitoring, some clinicians inappropriately take this to mean that they do not affect hemostasis tests. This review aims to briefly review the laboratory studies that have evaluated the NOACs against a wide range of laboratory assays to assess utility for qualitative or quantitative measurements of these drugs, as well as interferences that may cause misdiagnosis of hemostatic defects. Point of care testing, including use of alternate samples such as urine and serum, is also under development but is not covered extensively in this review. The main aims of this article are to provide practical guidance to general laboratory testing for NOACs, as well as to help avoid diagnostic errors associated with hemostasis testing performed on samples from treated patients, as these currently comprise major challenges to hemostasis laboratories in the era of the NOACs. PMID- 25703515 TI - Potency labeling of novel factor VIII and factor IX concentrates: past experience and current strategy. AB - Various strategies to produce "longer-lasting" factor VIII and factor IX concentrates through chemical and genetic modifications are currently under evaluation. It is now clear that these new molecules are amenable to testing using conventional methods for biological activity (one-stage clotting and chromogenic) and there is a preference to maintain labeling in International Units (IU) traceable to the WHO International Standard Concentrates. This is an achievable goal; however, many of the new molecules are associated with potency discrepancies both between methods and also within methods, for instance, when different activated partial thromboplastin time reagents are used. In the interests of global harmonization, it is important for licensing authorities to reach agreement on the choice of the potency labeling method. This choice should be supported by a thorough characterization of product potency, both in vitro and in vivo, to anticipate future issues and with a view to maintaining equivalence of the IU compared with existing licensed products. In cases where the product potency is defined using specific reagents, the robustness of the manufacturer's product standard will be crucial for product consistency. The sensitivity of measured potency to different methodologies will require manufacturers to provide guidance to clinical laboratories on suitable postinfusion testing approaches. PMID- 25703516 TI - The changing face of hemostasis testing in modern laboratories: consolidation, automation, and beyond. AB - The reality of laboratory diagnostics as a whole, and hemostasis testing in particular, is evolving under new paradigms of efficiency. The driving forces of health care and laboratory diagnostics in the third millennium are mainly represented by macro- and microeconomics. In a world with limited resources, shattered by an unprecedented economic crisis, laboratory diagnostics is undergoing a substantial reorganization, with emergence of new models under the imperative of terms, such as bedside testing, consolidation, and networking. The paradigms under which these changes are being developed include a variety of environment, preanalytical, technological, professional, and health-care aspects. The maintenance of continued quality is indeed the major challenge to be faced in the foreseeable future. In fact, some challenges prepotently emerge during a consolidation process, which basically involve delayed testing, centrifugation, transportation, and stability of the specimens, as well as the potential mismatch of sample matrix. This article is aimed to provide an overview of the current economic scenario of laboratory diagnostics and discuss the changing face of hemostasis testing in modern laboratories, providing a synthetic overview about potential drawbacks of actualized solutions. PMID- 25703517 TI - The effect of omega-3 polyunsaturated fatty acids on fibrin and thrombin generation in healthy subjects and subjects with cardiovascular disease. AB - Hypercoagulability plays a key role in the progression of cardiovascular disease (CVD). Although omega-3 polyunsaturated fatty acid (PUFA) intake has been inversely related to the risk of cardiovascular events, the mechanisms are not fully understood. The aim of this study was to investigate the effects of omega-3 on novel markers of global coagulation. The generation of fibrin and thrombin, measured via overall hemostasis potential (OHP) assay and calibrated automated thrombography, respectively, was determined in 40 healthy subjects and 16 patients with CVD at baseline and after 4 weeks of 640 mg/day omega-3 PUFA. In healthy subjects, fibrin generation was significantly reduced, as measured by overall coagulation potential (p = 0.013), OHP (p < 0.001), velocity of fibrin polymerization (p = 0.002), and significant increase in delay to fibrin generation (p = 0.002). The peak of generated thrombin was significantly reduced (p = 0.043). In subjects with CVD, omega-3 PUFA significantly reduced OHP and significantly increased the lag time to thrombin generation (both p < 0.001). Treatment with omega-3 PUFA had no effect on other fibrin and thrombin generation parameters in CVD patients. Four-week omega-3 PUFA supplementation reduced thrombotic potential in healthy subjects, as shown by reduced fibrin generation and peak thrombin. There was a greater effect on fibrin generation in healthy subjects compared with those with CVD. PMID- 25703518 TI - Treatment of hemophilia in the near future. AB - Advancements and debacles have characterized hemophilia treatment over the past 50 years. The 1970s saw the availability of plasma-derived concentrates making prophylaxis and home therapy possible. This optimistic perception changed extremely in the early 1980s, when most people with hemophilia were infected with HIV and hepatitis viruses. Then, also in the 1980s, the rapid progress in molecular biology led to the development of recombinant therapeutic products. This important advancement was a huge technological leap fresh off from the earlier 1980s disaster. Now in the 21st century, the newer bioengineering drugs open a new hopeful phase for the management of hemophilia. The current efforts are concentrated on producing novel coagulation factors with prolonged bioavailability, increased potency, and resistance to inactivation and potentially reduced immunogenicity; this phase of evolution is improving very quickly. 2014 is the year of marketing approval by the Food and Drug Administration of the first bioengineered FVIII and FIX long-acting drugs, using Fc-fusion strategy. This represents the first significant advance in the hemophilia therapy that dramatically transforms patient management by substantially reducing the frequency of injections, improving compliance, and simplifying prophylaxis and, in turn, refining the quality of life of hemophilia patients, offering them a nearly normal life expectancy, particularly to newborns with hemophilia B. PMID- 25703519 TI - Pros and cons of vitamin K antagonists and non-vitamin K antagonist oral anticoagulants. AB - Anticoagulant treatment can be currently instituted with two different classes of drugs: the vitamin K antagonists (VKAs) and the newer, "novel" or non-vitamin K antagonist oral anticoagulant drugs (NOACs). The NOACs have several practical advantages over VKAs, such as the rapid onset/offset of action, the lower potential for food and drug interactions, and the predictable anticoagulant response. However, the VKAs currently have a broader spectrum of indications, a standardized monitoring test, and established reversal strategies. The NOACs emerged as alternative options for the prevention and treatment of venous thromboembolism and for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Nevertheless, there remain some populations for whom the VKAs remain the most appropriate anticoagulant drug. This article discusses the advantages and disadvantages of VKAs and NOACs. PMID- 25703520 TI - Different models of inheritance in selected genes in patients with sticky platelet syndrome and fetal loss. AB - INTRODUCTION: The aim of this study was to evaluate the genetic variability of selected single nucleotide polymorphisms (SNPs) within GAS6 and PEAR1 genes and explore the association between selected SNPs and risk for fetal loss in women with sticky platelet syndrome (SPS). MATERIALS AND METHODS: We examined 23 female patients with SPS and history of spontaneous abortion, and 42 healthy women who served as controls. The diagnosis of SPS was established by light transmission aggregometry according to methods and criteria developed by Mammen et al. We also assessed four SNPs within the GAS6 gene (rs7400002, rs1803628, rs8191974, rs9550270) and two SNPs within PEAR1 gene (rs12041331, rs12566888). RESULTS: We identified two SNPs within PEAR1 gene (rs12041331, rs12566888) and one SNP within GAS6 gene (rs9550270) that have higher occurrence in SPS patients with history of abortion. An increased risk for abortion was observed in carriers of the rs7400002 within GAS6 gene. Conversely, we found that the T allele of PEAR1 c. -9 4663G > T polymorphism appears to be protective for fetal loss. CONCLUSION: Our results support the idea that genetic variability of GAS6 and PEAR1 genes may be associated with platelet hyperaggregability. The study also suggests a possible polygenic type of SPS heredity. PMID- 25703521 TI - Oral anticoagulant drugs and the risk of osteoporosis: new anticoagulants better than old? AB - Several drugs have been associated with an increased risk of osteoporosis when used chronically. Coumarins (warfarin, acenocoumarol, phenprocoumon, and fluindione) are oral anticoagulants widely used for the prevention and treatment of arterial and venous thromboembolic diseases. These drugs are vitamin K antagonists that interfere with gamma-carboxyglutamate formation, and consequently inhibit the carboxylation of glutamate residues of proteins that are synthesized in the bone. These effects on bone turnover and dietary restrictions in patients on anticoagulation are possible mechanisms inducing osteoporosis in coumarin users. However, conflicting evidence is available concerning the risk of osteoporosis and bone fractures in patients on treatment with these drugs. This risk is likely to be clinically relevant in long-term (more than 1 year) coumarin users. Novel direct oral anticoagulants, recently introduced in clinical practice, exert reduced interference on bone metabolism; however, limited in vitro and animal data are currently available, and their long-term effects will only become apparent in time. PMID- 25703522 TI - Development of recommendations to continue anticoagulation with one of the two types of oral anticoagulants based on the identification of patients' preference. AB - Patients with indication for anticoagulation may prefer treatment with a vitamin K antagonist (VKA) or non-vitamin K antagonist oral anticoagulant (NOAC). A questionnaire may help to identify the preference of patients for one of the two types of oral anticoagulants and to develop a score for the recommendation to continue or to change the anticoagulant. A score was developed using a questionnaire containing biographic data and eight statements on attitudes on anticoagulation and was derived to trigger continuation or change the type of anticoagulant by defining ranges of terms and weighting of the significant statements identified by logistic regression analysis. Participating patients received either anticoagulation with VKA (group 1, n = 690), were transferred from VKA to NOAC (group 2, n = 158), received NOAC de novo (group 3, n = 137) or were transferred from NOAC to VKA (group 4, n = 19). Four statements were significantly (p values between 0.0347 and < 0.0001) associated with recommendations to maintain or to change the type of anticoagulant for patients in groups 1, 2, or 3 with predictive values of c = 0.83 between groups 1 and 2 and c = 0.71 between groups 1 and 3. From the total number of replies to the statements a score of three grades and two strengths (A = strong, B = moderate) was derived for the recommendations. This tool supports recommendations as to continue or to change the presently used type of oral anticoagulant based on the identification of patients' preferences. PMID- 25703523 TI - 9H-purine scaffold reveals induced-fit pocket plasticity of the BRD9 bromodomain. AB - The 2-amine-9H-purine scaffold was identified as a weak bromodomain template and was developed via iterative structure based design into a potent nanomolar ligand for the bromodomain of human BRD9 with small residual micromolar affinity toward the bromodomain of BRD4. Binding of the lead compound 11 to the bromodomain of BRD9 results in an unprecedented rearrangement of residues forming the acetyllysine recognition site, affecting plasticity of the protein in an induced fit pocket. The compound does not exhibit any cytotoxic effect in HEK293 cells and displaces the BRD9 bromodomain from chromatin in bioluminescence proximity assays without affecting the BRD4/histone complex. The 2-amine-9H-purine scaffold represents a novel template that can be further modified to yield highly potent and selective tool compounds to interrogate the biological role of BRD9 in diverse cellular systems. PMID- 25703524 TI - Systematic review of preoperative, intraoperative and postoperative risk factors for colorectal anastomotic leaks. AB - BACKGROUND: Anastomotic leak (AL) represents a dreaded complication following colorectal surgery, with a prevalence of 1-19 per cent. There remains a lack of consensus regarding factors that may predispose to AL and the relative risks associated with them. The objective was to perform a systematic review of the literature, focusing on the role of preoperative, intraoperative and postoperative factors in the development of colorectal ALs. METHODS: A systematic review was performed to identify adjustable and non-adjustable preoperative, intraoperative and postoperative factors in the pathogenesis of AL. Additionally, a severity grading system was proposed to guide treatment. RESULTS: Of 1707 papers screened, 451 fulfilled the criteria for inclusion in the review. Significant preoperative risk factors were: male sex, American Society of Anesthesiologists fitness grade above II, renal disease, co-morbidity and history of radiotherapy. Tumour-related factors were: distal site, size larger than 3 cm, advanced stage, emergency surgery and metastatic disease. Adjustable risk factors were: smoking, obesity, poor nutrition, alcohol excess, immunosuppressants and bevacizumab. Intraoperative risk factors were: blood loss/transfusion and duration of surgery more than 4 h. Stomas lessen the consequences but not the prevalence of AL. In the postoperative period, CT is the most commonly used imaging tool, with or without rectal contrast, and a C-reactive protein level exceeding 150 mg/l on day 3-5 is the most sensitive biochemical marker. A five level classification system for AL severity and appropriate management is presented. CONCLUSION: Specific risk factors and their potential correction or indications for stoma were identified. An AL severity score is proposed to aid clinical decision-making. PMID- 25703525 TI - Do cognitive leisure activities really matter in the relationship between education and cognition? Evidence from the aging, demographics, and memory study (ADAMS). AB - OBJECTIVES: Increasing demand for early detection and prevention of dementia has shifted recent attention toward cognitive impairment with no dementia (CIND), which is often considered a possible risk path to dementia. Education and cognitive leisure activities are major predictors featured in dementia studies. However, the definition of cognitive leisure activities often has been inconsistent and diverse. This study explored different domains of these activities and their moderating roles on the relationship between education and cognition. METHOD: A sample of 704 participants aged 70 or older was drawn from the national Aging, Demographics, and Memory Study. Exploratory factor analysis was conducted to assess two domains from cognitive leisure activities: literacy and visuospatial activities. Multinomial logistic regression tested the main and moderating roles of each domain on cognition categorized as no impairment, CIND, and dementia. RESULTS: Individuals with greater engagement in both literacy and visuospatial activities were more likely to have no cognitive impairment than CIND. Individuals with greater engagement in literacy activities were less likely to have dementia compared to CIND. Literacy activities and education years had a significant interaction effect. Individuals with higher education seem to benefit more by engaging in literacy activities, as evidenced by decreased odds of having dementia. CONCLUSION: Engagement in cognitive leisure activities for both cognitively intact and impaired older adults is suggested, with more focus on literacy activities for cognitively impaired and highly educated older adults. PMID- 25703527 TI - Improved survival in liver transplant recipients receiving prolonged-release tacrolimus in the European Liver Transplant Registry. AB - This study was a retrospective analysis of the European Liver Transplant Registry (ELTR) performed to compare long-term outcomes with prolonged-release tacrolimus versus tacrolimus BD in liver transplantation (January 2008-December 2012). Clinical efficacy measures included univariate and multivariate analyses of risk factors influencing graft and patient survival at 3 years posttransplant. Efficacy measures were repeated using propensity score-matching for baseline demographics. Patients with <1 month of follow-up were excluded from the analyses. In total, 4367 patients (prolonged-release tacrolimus: n = 528; BD: n = 3839) from 21 European centers were included. Tacrolimus BD treatment was significantly associated with inferior graft (risk ratio: 1.81; p = 0.001) and patient survival (risk ratio: 1.72; p = 0.004) in multivariate analyses. Similar analyses performed on the propensity score-matched patients confirmed the significant survival advantages observed in the prolonged-release tacrolimus- versus tacrolimus BD-treated group. This large retrospective analysis from the ELTR identified significant improvements in long-term graft and patient survival in patients treated with prolonged-release tacrolimus versus tacrolimus BD in primary liver transplant recipients over 3 years of treatment. However, as with any retrospective registry evaluation, there are a number of limitations that should be considered when interpreting these data. PMID- 25703528 TI - A Taiwanese Mandarin Main Concept Analysis (TM-MCA) for quantification of aphasic oral discourse. AB - BACKGROUND: Various quantitative systems have been proposed to examine aphasic oral narratives in English. A clinical tool for assessing discourse produced by Cantonese-speaking persons with aphasia (PWA), namely Main Concept Analysis (MCA), was developed recently for quantifying the presence, accuracy and completeness of a narrative. Similar tools for Mandarin speakers are currently absent. AIMS: The first aim is to develop and establish the validity of the Taiwanese Mandarin Main Concept Analysis (TM-MCA) for the Mandarin-speaking population in Taiwan, given the paucity of related investigations. Another aim is to establish the influence of age and education level on Taiwanese Mandarin speakers' oral narrative abilities. The third purpose is to examine how well the TM-MCA could distinguish between native speakers with and without aphasia in Taiwan. The final aim is to examine the reliability and validity of the TM-MCA. METHODS & PROCEDURES: Eight speech-language pathologists (SLPs) and eight neurologically intact participants were involved to establish the TM-MCA main concepts. Another 36 neurologically intact participants and 10 PWA participated to validate the TM-MCA by contrasting their performance. OUTCOMES & RESULTS: Both age and educational level affected the oral discourse performance among the neurologically intact adults. Significant differences on the TM-MCA measures were noted between the control group and the group with aphasia. Moreover, the degree of aphasia significantly affected the oral discourse of PWA. CONCLUSIONS & IMPLICATIONS: The TM-MCA is a culturally appropriate quantitative system for the Taiwanese Mandarin population. It can be used to supplement standardized aphasia tests to help SLPs make more informative decisions not only on clinical diagnosis but also on treatment planning. PMID- 25703529 TI - Prostate high-dose-rate brachytherapy: Transrectal ultrasound based planning, a technical note. PMID- 25703530 TI - Clinical decision tool for optimal delivery of liver stereotactic body radiation therapy: Photons versus protons. AB - PURPOSE: Stereotactic body radiation therapy (SBRT) for treatment of liver tumors is often limited by liver dose constraints. Protons offer potential for more liver sparing, but clinical situations in which protons may be superior to photons are not well described. We developed and validated a treatment decision model to determine whether liver tumors of certain sizes and locations are more suited for photon versus proton SBRT. METHODS AND MATERIALS: Six spherical mock tumors from 1 to 6 cm in diameter were contoured on computed tomography images of 1 patient at 4 locations: dome, caudal, left medial, and central. Photon and proton plans were generated to deliver 50 Gy in 5 fractions to each tumor and optimized to deliver equivalent target coverage and maximal liver sparing. Using these plans, we developed a hypothesis-generating model to predict the optimal modality for maximal liver sparing based on tumor size and location. We then validated this model in 10 patients with liver tumors. RESULTS: Protons spared significantly more liver than photons for dome or central tumors >=3 cm (dome: 134 +/- 21 cm(3), P = .03; central: 108 +/- 4 cm(3), P = .01). Our model correctly predicted the optimal SBRT modality for all 10 patients. For patients with dome or central tumors >=3 cm, protons significantly increased the volume of liver spared (176 +/- 21 cm(3), P = .01) and decreased the mean liver dose (8.4 vs 12.2 Gy, P = .01) while offering no significant advantage for tumors <3 cm at any location or for caudal and left medial tumors of any size. CONCLUSIONS: When feasible, protons should be considered as the radiation modality of choice for dome and central tumors >3 cm to allow maximal liver sparing and potentially reduce radiation toxicity. Protons should also be considered for any tumor >5 cm if photon plans fail to achieve adequate coverage or exceed the mean liver threshold. PMID- 25703531 TI - The dangers of incorporating reimbursement data into clinical decision making. PMID- 25703532 TI - Fecal microbiota transplantation (FMT) for Clostridium difficile infection: focus on immunocompromised patients. AB - Clostridium difficile infection (CDI) is an emerging problem worldwide associated with significant morbidity, mortality, recurrence rates and healthcare costs. Immunosuppressed patients, including HIV-seropositive individuals, solid organ transplant recipients, patients with malignancies, hematopoietic stem cell transplant recipients, and patients with inflammatory bowel disease are increasingly recognized as being at higher risk of developing CDI where it may be associated with significant complications, recurrence, and mortality. Fecal microbiota transplantation (FMT) has proven to be an effective and safe procedure for the treatment of recurrent or refractory CDI in immunocompetent patients by restoring the gut microbiota and resistance to further recurrences. During the last two years the first data on FMT in immunocompromised patients began to appear in the medical literature. Herein we summarize the use of FMT for the treatment of CDI with a focus on immunocompromised patients. PMID- 25703533 TI - Effect of medicinal plants on wound healing. AB - In the United States alone, chronic wounds affect 6.5 million patients. It is expected that the number of chronic wounds will increase worldwide due to the increase in age-related conditions and pathologies such as diabetes, obesity, and cardiovascular diseases. An estimated excess of US$25 billion is spent annually on treatment of chronic wounds, and the burden is rapidly growing due to increasing healthcare costs, an aging population, and a sharp rise in the incidence of diabetes and obesity worldwide. While current therapeutic agents have generally inadequate efficacy and number of serious adverse effects, the medicinal plants have been used in medicine since ancient times and are well known for their abilities to promote wound healing and prevent infection without grave side effects. Thus, herbal therapy may be an alternative strategy for treatment of wounds. The purpose of this review is to provide the verified data on the medicinal plants of the world flora with wound healing activity including the biologically active substances belonging to these herbal preparations and describe in detail the various cellular and molecular mechanisms of their actions. PMID- 25703534 TI - Involvement of nitric oxide in serotonin-induced scratching in mice. AB - BACKGROUND: Serotonin is a pruritogenic substance in humans and animals, but the mechanisms of action through which serotonin induces itch response are not yet understood. AIM: To examine the possible role of nitric oxide (NO) in the profile of scratching behaviour due to intradermal injection of serotonin in mice. METHODS: Intradermal injection of serotonin (14.1-235 nmol per site) into the nape of the neck was used to elicit itch in mice. Scratching behaviour was evaluated by counting the number of bouts during 60 min after injection. To determine the possible involvement of the nitrergic system in serotonin-induced scratching, L-NG-nitroarginine methyl ester [L-NAME; a nonselective nitric oxide synthase (NOS) inhibitor], aminoguanidine [a selective inducible (i)NOS inhibitor] and L-arginine (an NO precursor) were administered intraperitoneally to control and serotonin-injected animals. RESULTS: Intradermal serotonin caused scratching in mice with a bell-shaped dose-response correlation, and the peak effective dose was 141 nmol per site. The majority of scratching bouts in animals occurred 5-10 min after injection. Ineffective doses of L-NAME (3 mg/kg IP) and aminoguanidine (100 mg/kg IP) decreased the scratching induced by intradermal serotonin injection in animals (P < 0.001 and P < 0.001), while an subeffective dose of L-arginine (100 mg/kg IP) augmented the scratching effect of serotonin (P < 0.001). CONCLUSIONS: We show for the first time that the scratching induced by intradermal serotonin is mediated by NOS, especially iNOS, activation. We conclude that NO may play a role in mediating itch responses. NO and NOS could be new targets for antipruritic agents. PMID- 25703535 TI - Less is more: extreme genome complexity reduction with ddRAD using Ion Torrent semiconductor technology. AB - Massively parallel sequencing a small proportion of the whole genome at high coverage enables answering a wide range of questions from molecular evolution and evolutionary biology to animal and plant breeding and forensics. In this study, we describe the development of restriction-site associated DNA (RAD) sequencing approach for Ion Torrent PGM platform. Our protocol results in extreme genome complexity reduction using two rare-cutting restriction enzymes and strict size selection of the library allowing sequencing of a relatively small number of genomic fragments with high sequencing depth. We applied this approach to a common freshwater fish species, the Eurasian perch (Perca fluviatilis L.), and generated over 2.2 MB of novel sequence data consisting of ~17,000 contigs, identified 1259 single nucleotide polymorphisms (SNPs). We also estimated genetic differentiation between the DNA pools from freshwater (Lake Peipus) and brackish water (the Baltic Sea) populations and identified SNPs with the strongest signal of differentiation that could be used for robust individual assignment in the future. This work represents an important step towards developing genomic resources and genetic tools for the Eurasian perch. We expect that our ddRAD sequencing protocol for semiconductor sequencing technology will be useful alternative for currently available RAD protocols. PMID- 25703536 TI - Mannitol induces selective astroglial death in the CA1 region of the rat hippocampus following status epilepticus. AB - In the present study, we addressed the question of whether treatment with mannitol, an osmotic diuretic, affects astrogliovascular responses to status epilepticus (SE). In saline-treated animals, astrocytes exhibited reactive astrogliosis in the CA1-3 regions 2-4 days after SE. In the mannitol-treated animals, a large astroglial empty zone was observed in the CA1 region 2 days after SE. This astroglial loss was unrelated to vasogenic edema formation. There was no difference in SE-induced neuronal loss between saline- and mannitol treated animals. Furthermore, mannitol treatment did not affect astroglial loss and vasogenic edema formation in the dentate gyrus and the piriform cortex. These findings suggest that mannitol treatment induces selective astroglial loss in the CA1 region independent of vasogenic edema formation following SE. These findings support the hypothesis that the susceptibility of astrocytes to SE is most likely due to the distinctive heterogeneity of astrocytes independent of hemodynamics. PMID- 25703537 TI - Function and dysfunction of leucine-rich repeat kinase 2 (LRRK2): Parkinson's disease and beyond. AB - Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinson's disease (PD). As such, functions and dysfunctions of LRRK2 in PD have been the subject of extensive investigation. In addition to PD, increasing evidence is suggesting that LRRK2 is associated with a wide range of diseases. Genome-wide association studies have implicated LRRK2 in Crohn's disease (CD) and leprosy, and the carriers with pathogenic mutations of LRRK2 show increased risk to develop particular types of cancer. LRRK2 mutations are rarely found in Alzheimer's disease (AD), but LRRK2 might play a part in tauopathies. The association of LRRK2 with the pathogenesis of apparently unrelated diseases remains enigmatic, but it might be related to the yet unknown diverse functions of LRRK2. Here, we reviewed current knowledge on the link between LRRK2 and several diseases, including PD, AD, CD, leprosy, and cancer, and discussed the possibility of targeting LRRK2 in such diseases. PMID- 25703538 TI - Chronic pulmonary aspergillosis: a frequent and potentially severe disease. AB - INTRODUCTION: Chronic pulmonary aspergillosis is a pulmonary fungal infection with various presentations that can occur on a pre-existing cavity, often a sequel of tuberculosis. The objective of our study was to report the diagnostic and therapeutic management of pulmonary aspergilloma in our structure. PATIENTS AND METHODS: We retrospectively studied 81 cases of pulmonary aspergilloma having occurred in the respiratory diseases unit of the Casablanca Ibn Rochd hospital, over 11 years. RESULTS: We included 48 male and 33 female non-immunocompromised patients, with an average age of 51 years (27-75). A history of tuberculosis was recorded in 78 cases. Hemoptysis was the revealing symptom in 73 cases. A characteristic "bell-like" image was observed in 25 cases. The serological results were positive for aspergillus in 54 cases. The treatment was surgical in 50 cases and medical in 24 cases. Five patients died. DISCUSSION: A significant number of pulmonary aspergilloma cases were recorded in our study, occurring most frequently on sequels of tuberculosis. This disease is currently common in countries highly endemic for tuberculosis; early and adequate management is required. CONCLUSION: Aspergillosis is a frequent and potentially severe disease occurring on pre-existing lesions, most often in our context sequels of tuberculosis. Surgical resection is the reference treatment but is the cause of a significant morbidity and mortality. Preventive measures are mandatory. PMID- 25703539 TI - European collaboration on relative effectiveness assessments: What is needed to be successful? AB - OBJECTIVE: The objective of this study is to identify the possible barriers and critical success factors for the implementation of European collaboration in the field of relative effectiveness assessment (REA) of drugs. METHODS: Data were gathered through semi-structured interviews with representatives from eight European health technology assessment (HTA) organisations involved in assessment of drugs for coverage decision-making (AAZ, AIFA, AHTAPol, HAS, HVB, IQWIG, NICE and ZiN). RESULTS: Potential barriers identified mainly relate to methodology, resources and challenges with implementation in the respective national processes (e.g. legal restrictions). The most critical success factors for production of cross-border assessments were the continuous cooperation of competent partners, and the quality and timely availability of the assessment. CONCLUSION: Further adaptation of the process and methods is required for optimal collaboration. In the near future it can be expected that cross-border assessments will meet in particular the needs of smaller/middle-sized European countries and also European countries with less developed HTA systems as the potential efficiency/quality gains are the highest for these countries. Therefore, national implementation of cross-border assessments is especially likely in these countries in the coming years. Once more experience is gained with cross-border assessments, and successes become more evident, efficiency/quality gains may also be likely for some larger countries with well established processes. PMID- 25703540 TI - Government interventions to aid choice: Help to self-help or paternalism? AB - A random sample of Danish respondents was asked in which aspects of every-day life they find it more difficult to adhere to behavioural patterns that they believe are best for them and their family. Individuals report high degrees of lack of self-control in specific areas of everyday life, suggesting that individuals are not consistently exhibiting utility optimising behaviour, a finding that accords with behavioural economics and the expected prevalence of irrational behaviour. We observe greater self-perceived self-control problems amongst individuals from the lower economic strata. Thus, to the extent that self control relates to environmental factors, there is justification for introducing government interventions targeting such factors to improve equity in health and to increase utility levels amongst those with lower incomes and lower levels of education. Further, the public's preferences for a range of government interventions targeting different facets of life-style were elicited. Individuals who were the target of interventions were less supportive of these interventions. Individuals in the target group whose self-perceived self-control was low tended to be more supportive, but still less so than those who were not targeted. Since support was shown to come mainly from those not targeted by the intervention, and especially from those who feel in control of their lives, our results indicate that the interventions cannot be justified on the grounds of libertarianism (help to self-help). PMID- 25703541 TI - Thiophene-based dyes for probing membranes. AB - We report the synthesis of four new cationic dipolar push-pull dyes, together with an evaluation of their photophysical and photobiological characteristics pertinent to imaging membranes by fluorescence and second harmonic generation (SHG). All four dyes consist of an N,N-diethylaniline electron-donor conjugated to a pyridinium electron-acceptor via a thiophene bridge, with either vinylene ( CH=CH-) or ethynylene (-C=C-) linking groups, and with either singly-charged or doubly-charged pyridinium terminals. The absorption and fluorescence behavior of these dyes were compared to a commercially available fluorescent membrane stain, the styryl dye FM4-64. The hyperpolarizabilities of all dyes were compared using hyper-Rayleigh scattering at 800 nm. Cellular uptake, localization, toxicity and phototoxicity were evaluated using tissue cell cultures (HeLa, SK-OV-3 and MDA 231). Replacing the central alkene bridge of FM4-64 with a thiophene does not substantially change the absorption, fluorescence or hyperpolarizability, whereas changing the vinylene-links to ethynylenes shifts the absorption and fluorescence to shorter wavelengths, and reduces the hyperpolarizability by about a factor of two. SHG and fluorescence imaging experiments in live cells showed that the doubly-charged thiophene dyes localize in plasma membranes, and exhibit lower internalization rates compared to FM4-64, resulting in less signal from the cell cytosol. At a typical imaging concentration of 1 MUM, the doubly-charged dyes showed no significant light or dark toxicity, whereas the singly-charged dyes are phototoxic even at 0.5 MUM. The doubly-charged dyes showed phototoxicity at concentrations greater than 10 MUM, although they do not generate singlet oxygen, indicating that the phototoxicity is type I rather than type II. The doubly charged thiophene dyes are more effective than FM4-64 as SHG dyes for live cells. PMID- 25703542 TI - Comparison of four molecular methods to type Salmonella Enteritidis strains. AB - This study compared the pulsed-field gel electrophoresis (PFGE), enterobacterial repetitive intergenic consensus-PCR (ERIC-PCR), multilocus variable-number of tanden-repeat analysis (MLVA), and multilocus sequence typing (MLST) methods for typing 188 Salmonella Enteritidis strains from different sources isolated over a 24-year period in Brazil. PFGE and ERIC-PCR were more efficient than MLVA for subtyping the strains. However, MLVA provided additional epidemiological information for those strains. In addition, MLST showed the Brazilian strains as belonging to the main clonal complex of S. Enteritidis, CC11, and provided the first report of two new STs in the S. enterica database but could not properly subtype the strains. Our results showed that the use of PFGE or ERIC-PCR together with MLVA is suitable to efficiently subtype S. Enteritidis strains and provide important epidemiological information. PMID- 25703543 TI - Differences in rider movement pattern between different degrees of collection at the trot in high-level dressage horses ridden on a treadmill. AB - Collection is a central term in equine dressage, defined as a shortening of the horse's stride length with retained energy and hind limb activity. How collection is induced by the rider has yet not been investigated objectively. The aim of this study was therefore to compare the movement pattern of high-level dressage riders between free trot (loose reins), passage and a range of three speeds in collected trot. Both at higher speed in collected trot and in passage, the rider's pelvis became more caudally rotated and the rider's lumbar back became more flexed. However, in passage there was also a decrease in phase-shift between horse and rider movements, suggesting that the rider used the seat more actively. In free trot, the rider's pelvis was more cranially rotated, the lumbar back was more extended, the rider's body inclined more forwards, and the phase-shift between horse and rider was increased, compared to collected trot. The observed changes were partly explainable from changes in the horse's movement pattern. However, most differences in rider body position seemed unrelated to the horse's movements, but were in accordance with instructions in equestrian texts, suggesting that those changes were voluntarily adopted by the riders. PMID- 25703544 TI - WITHDRAWN: A randomized trial to compare the Truview picture capture device, C MAC laryngoscope, and Macintosh laryngoscope in pediatric airway management. AB - AIM: To evaluate and compare the Truview picture capture device (PCD) and C-MAC laryngoscope to the standard Macintosh laryngoscope in pediatric patients. METHODS: One hundred and fifty patients with American Society of Anesthesiology status Grade I-II (ASA I-II) who were 1-6 years old (10-20 kg) were scheduled for elective surgery. They were randomized into three equal groups for laryngoscopy and intubation by either the Truview PCD (Group T), C-MAC (Group C), or Macintosh laryngoscope (Group M) under general anesthesia. The percentage of glottic opening (POGO) score, application of external laryngeal maneuver, time to intubation, number of attempts at intubation, failed intubations, episodes of desaturation, and trauma were recorded and statistically analyzed. A value of p < 0.05 was considered significant. RESULTS: The POGO scores were significantly better with the Truview PCD (94.7 +/- 12.91) than with the C-MAC and Macintosh laryngoscopes (82 +/- 24.97 and 85.1 +/- 17.07, respectively; p < 0.01). There were no failures, episodes of desaturation, or trauma in any of the patients. It took 19.24 seconds to intubate with the Truview PCD, compared to 12.32 seconds with the C-MAC laryngoscope and 10.7 seconds with the Macintosh laryngoscope (p < 0.01). An external laryngeal maneuver was required in 42% of patients in group C, compared to 38% in Group M and 16% in group T (p < 0.01). CONCLUSION: The Truview PCD offers the best laryngeal view, although it takes a longer time for intubation. The C-MAC laryngoscope provides similar laryngeal views as the Macintosh blade, and is an excellent teaching aid. PMID- 25703545 TI - Specific Radiological Findings of Traumatic Gastrointestinal Tract Injuries in Patients With Blunt Chest and Abdominal Trauma. AB - Gastrointestinal hollow viscus injury after blunt chest and abdominal trauma is uncommon and complicates 0.6%-1.2% of all cases of trauma. Early recognition of such injuries significantly decreases morbidity and mortality. Since physical examination is not accurate in detecting such injuries, contrast-enhanced computed tomography has been the mainstay for diagnosis in many emergency departments. This pictorial essay aims to review the incidence, mechanisms, and signs of gastrointestinal hollow viscus injuries in the setting of blunt chest and abdominal trauma. PMID- 25703546 TI - Molecule-like photodynamics of Au102(pMBA)44 nanocluster. AB - Photophysical properties of a water-soluble cluster Au102(pMBA)44 (pMBA = para mercaptobenzoic acid) are studied by ultrafast time-resolved mid-IR spectroscopy and density functional theory calculations in order to distinguish between molecular and metallic behavior. In the mid-IR transient absorption studies, visible or near-infrared light is used to electronically excite the sample, and the subsequent relaxation is monitored by studying the transient absorption of a vibrational mode in the ligands. Based on these studies, a complete picture of energy relaxation dynamics is obtained: (1) 0.5-1.5 ps electronic relaxation, (2) 6.8 ps vibrational cooling, (3) intersystem crossing from the lowest triplet state to the ground state with a time constant 84 ps, and (4) internal conversion to the ground state with a time constant of ~3.5 ns. A remarkable finding based on this work is that a large cluster containing 102 metal atoms behaves like a small molecule in a striking contrast to a previously studied slightly larger Au144(SC2H4Ph)60 cluster, which shows relaxation typical for metallic particles. These results therefore establish that the transition between molecular and metallic behavior occurs between Au102 and Au144 species. PMID- 25703547 TI - Video podcast: Tuberculosis. PMID- 25703548 TI - What can immunology contribute to the control of the world's leading cause of death from bacterial infection? AB - Video podcast available Go to www.immunologicalreviews.com to watch an interview with Guest Editor Carl Nathan. PMID- 25703550 TI - Release of mycobacterial antigens. AB - Mycobacterium tuberculosis has evolved from a Mycobacterium canettii-like progenitor pool into one of the most successful and widespread human pathogens. The pathogenicity of M. tuberculosis is linked to its ability to secrete/export/release selected mycobacterial proteins, and it is also established that active release of mycobacterial antigens is a prerequisite for strong immune recognition. Recent research has enabled mycobacterial secretion systems and vesicle-based release of mycobacterial antigens to be elucidated, which together with host-related specificities constitute key variables that determine the outcome of infection. Here, we discuss recently discovered, novel aspects on the nature and the regulation of antigen release of the tuberculosis agent with particular emphasis on the biological characterization of mycobacteria specific ESX/type VII secretion systems and their secreted proteins, belonging to the Esx, PE, and PPE categories. The importance of specific mycobacterial antigen release is probably best exemplified by the striking differences observed between the cellular events during infection with the ESX-1-deficient, attenuated Mycobacterium bovis BCG compared to the virulent M. tuberculosis, which are clearly important for design of more specific diagnostics and more efficient vaccines. PMID- 25703549 TI - Co-evolution of Mycobacterium tuberculosis and Homo sapiens. AB - The causative agent of human tuberculosis (TB), Mycobacterium tuberculosis, is an obligate pathogen that evolved to exclusively persist in human populations. For M. tuberculosis to transmit from person to person, it has to cause pulmonary disease. Therefore, M. tuberculosis virulence has likely been a significant determinant of the association between M. tuberculosis and humans. Indeed, the evolutionary success of some M. tuberculosis genotypes seems at least partially attributable to their increased virulence. The latter possibly evolved as a consequence of human demographic expansions. If co-evolution occurred, humans would have counteracted to minimize the deleterious effects of M. tuberculosis virulence. The fact that human resistance to infection has a strong genetic basis is a likely consequence of such a counter-response. The genetic architecture underlying human resistance to M. tuberculosis remains largely elusive. However, interactions between human genetic polymorphisms and M. tuberculosis genotypes have been reported. Such interactions are consistent with local adaptation and allow for a better understanding of protective immunity in TB. Future 'genome-to genome' studies, in which locally associated human and M. tuberculosis genotypes are interrogated in conjunction, will help identify new protective antigens for the development of better TB vaccines. PMID- 25703551 TI - The onset of adaptive immunity in the mouse model of tuberculosis and the factors that compromise its expression. AB - Mycobacterium tuberculosis (Mtb) has been evolving with its human host for over 50 000 years and is an exquisite manipulator of the human immune response. It induces both a strong inflammatory and a strong acquired immune response, and Mtb then actively regulates these responses to create an infectious lesion in the lung while maintaining a relatively ambulatory host. The CD4(+) T cell plays a critical yet contradictory role in this process by both controlling disseminated disease while promoting the development of the lesion in the lung that mediates transmission. In light of this manipulative relationship between Mtb and the human immune response, it is not surprising that our ability to vaccinate against tuberculosis (TB) has not been totally successful. To overcome the current impasse in vaccine development, we need to define the phenotype of CD4(+) T cells that mediate protection and to determine those bacterial and host factors that regulate the effective function of these cells. In this review, we describe the initiation and expression of T cells during TB as well as the fulminant inflammatory response that can compromise T-cell function and survival. PMID- 25703553 TI - T cells and adaptive immunity to Mycobacterium tuberculosis in humans. AB - The adaptive immune response mediated by T cells is critical for control of Mycobacterium tuberculosis (M. tuberculosis) infection in humans. However, the M. tuberculosis antigens and host T-cell responses that are required for an effective adaptive immune response to M. tuberculosis infection are yet to be defined. Here, we review recent findings on CD4(+) and CD8(+) T-cell responses to M. tuberculosis infection and examine the roles of distinct M. tuberculosis specific T-cell subsets in control of de novo and latent M. tuberculosis infection, and in the evolution of T-cell immunity to M. tuberculosis in response to tuberculosis treatment. In addition, we discuss recent studies that elucidate aspects of M. tuberculosis-specific adaptive immunity during human immunodeficiency virus co-infection and summarize recent findings from vaccine trials that provide insight into effective adaptive immune responses to M. tuberculosis infection. PMID- 25703552 TI - Immunology studies in non-human primate models of tuberculosis. AB - Non-human primates, primarily macaques, have been used to study tuberculosis for decades. However, in the last 15 years, this model has been refined substantially to allow careful investigations of the immune response and host-pathogen interactions in Mycobacterium tuberculosis infection. Low-dose challenge with fully virulent strains in cynomolgus macaques result in the full clinical spectrum seen in humans, including latent and active infection. Reagents from humans are usually cross-reactive with macaques, further facilitating the use of this model system to study tuberculosis. Finally, macaques develop the spectrum of granuloma types seen in humans, providing a unique opportunity to investigate bacterial and host factors at the local (lung and lymph node) level. Here, we review the past decade of immunology and pathology studies in macaque models of tuberculosis. PMID- 25703554 TI - The human immune response to tuberculosis and its treatment: a view from the blood. AB - The immune response upon infection with the pathogen Mycobacterium tuberculosis is poorly understood, hampering the discovery of new treatments and the improvements in diagnosis. In the last years, a blood transcriptional signature in tuberculosis has provided knowledge on the immune response occurring during active tuberculosis disease. This signature was absent in the majority of asymptomatic individuals who are latently infected with M. tuberculosis (referred to as latent). Using modular and pathway analyses of the complex data has shown, now in multiple studies, that the signature of active tuberculosis is dominated by overexpression of interferon-inducible genes (consisting of both type I and type II interferon signaling), myeloid genes, and inflammatory genes. There is also downregulation of genes encoding B and T-cell function. The blood signature of tuberculosis correlates with the extent of radiographic disease and is diminished upon effective treatment suggesting the possibility of new improved strategies to support diagnostic assays and methods for drug treatment monitoring. The signature suggested a previously under-appreciated role for type I interferons in development of active tuberculosis disease, and numerous mechanisms have now been uncovered to explain how type I interferon impedes the protective response to M. tuberculosis infection. PMID- 25703556 TI - Acquired immunodeficiencies and tuberculosis: focus on HIV/AIDS and diabetes mellitus. AB - The spread of human immunodeficiency virus (HIV) infection within Africa led to marked increases in numbers of cases of tuberculosis (TB), and although the epidemic peaked in 2006, there were still 1.8 million new cases in 2013, with 29.2 million prevalent cases. Half of all TB cases in Africa are in those with HIV co-infection. A brief review of the well-documented main immunological mechanisms of HIV-associated increased susceptibility to TB is presented. However, a new threat is facing TB control, which presents itself in the form of a rapid increase in the number of people living with type II diabetes mellitus (T2DM), particularly in areas that are already hardest hit by the TB epidemic. T2DM increases susceptibility to TB threefold, and the TB burden attributable to T2DM is 15%. This review addresses the much smaller body of research information available on T2DM-TB, compared to HIV-TB comorbidity. We discuss the altered clinical presentation of TB in the context of T2DM comorbidity, changes in innate and adaptive immune responses, including lymphocyte subsets and T-cell phenotypes, the effect of treatment of the different comorbidities, changes in biomarker expression and genetic predisposition to the respective morbidities, and other factors affecting the comorbidity. Although significant gains have been made in improving our understanding of the underlying mechanisms of T2DM associated increased susceptibility, knowledge gaps still exist that require urgent attention. PMID- 25703555 TI - Inherited and acquired immunodeficiencies underlying tuberculosis in childhood. AB - Tuberculosis (TB), caused by Mycobacterium tuberculosis (M.tb) and a few related mycobacteria, is a devastating disease, killing more than a million individuals per year worldwide. However, its pathogenesis remains largely elusive, as only a small proportion of infected individuals develop clinical disease either during primary infection or during reactivation from latency or secondary infection. Subacute, hematogenous, and extrapulmonary disease tends to be more frequent in infants, children, and teenagers than in adults. Life-threatening primary TB of childhood can result from known acquired or inherited immunodeficiencies, although the vast majority of cases remain unexplained. We review here the conditions conferring a predisposition to childhood clinical diseases caused by mycobacteria, including not only M.tb but also weakly virulent mycobacteria, such as BCG vaccines and environmental mycobacteria. Infections with weakly virulent mycobacteria are much rarer than TB, but the inherited and acquired immunodeficiencies underlying these infections are much better known. Their study has also provided genetic and immunological insights into childhood TB, as illustrated by the discovery of single-gene inborn errors of IFN-gamma immunity underlying severe cases of TB. Novel findings are expected from ongoing and future human genetic studies of childhood TB in countries that combine a high proportion of consanguineous marriages, a high incidence of TB, and an excellent clinical care, such as Iran, Morocco, and Turkey. PMID- 25703557 TI - CD1 and mycobacterial lipids activate human T cells. AB - For decades, proteins were thought to be the sole or at least the dominant source of antigens for T cells. Studies in the 1990s demonstrated that CD1 proteins and mycobacterial lipids form specific targets of human alphabeta T cells. The molecular basis by which T-cell receptors (TCRs) recognize CD1-lipid complexes is now well understood. Many types of mycobacterial lipids function as antigens in the CD1 system, and new studies done with CD1 tetramers identify T-cell populations in the blood of tuberculosis patients. In human populations, a fundamental difference between the CD1 and major histocompatibility complex systems is that all humans express nearly identical CD1 proteins. Correspondingly, human CD1 responsive T cells show evidence of conserved TCRs. In addition to natural killer T cells and mucosal-associated invariant T (MAIT cells), conserved TCRs define other subsets of human T cells, including germline encoded mycolyl-reactive (GEM) T cells. The simple immunogenetics of the CD1 system and new investigative tools to measure T-cell responses in humans now creates a situation in which known lipid antigens can be developed as immunodiagnostic and immunotherapeutic reagents for tuberculosis disease. PMID- 25703558 TI - MR1-restricted mucosal associated invariant T (MAIT) cells in the immune response to Mycobacterium tuberculosis. AB - The intracellular pathogen Mycobacterium tuberculosis (Mtb) and its human host have long co-evolved. Although the host cellular immune response is critical to the control of the bacterium information on the specific contribution of different immune cell subsets in humans is incomplete. Mucosal associated invariant T (MAIT) cells are a prevalent and unique T-cell population in humans with the capacity to detect intracellular infection with bacteria including Mtb. MAIT cells detect bacterially derived metabolites presented by the evolutionarily conserved major histocompatibility complex-like molecule MR1. Here, we review recent advances in our understanding of this T-cell subset and address the potential roles for MR1-restricted T cells in the control, diagnosis, and therapy of tuberculosis. PMID- 25703559 TI - B cells and antibodies in the defense against Mycobacterium tuberculosis infection. AB - Better understanding of the immunological components and their interactions necessary to prevent or control Mycobacterium tuberculosis (Mtb) infection in humans is critical for tuberculosis (TB) vaccine development strategies. Although the contributory role of humoral immunity in the protection against Mtb infection and disease is less defined than the role of T cells, it has been well established for many other intracellular pathogens. Here we update and discuss the increasing evidence and the mechanisms of B cells and antibodies in the defense against Mtb infection. We posit that B cells and antibodies have a variety of potential protective roles at each stage of Mtb infection and postulate that such roles should be considered in the development strategies for TB vaccines and other immune-based interventions. PMID- 25703560 TI - Macrophage defense mechanisms against intracellular bacteria. AB - Macrophages and neutrophils play a decisive role in host responses to intracellular bacteria including the agent of tuberculosis (TB), Mycobacterium tuberculosis as they represent the forefront of innate immune defense against bacterial invaders. At the same time, these phagocytes are also primary targets of intracellular bacteria to be abused as host cells. Their efficacy to contain and eliminate intracellular M. tuberculosis decides whether a patient initially becomes infected or not. However, when the infection becomes chronic or even latent (as in the case of TB) despite development of specific immune activation, phagocytes have also important effector functions. Macrophages have evolved a myriad of defense strategies to combat infection with intracellular bacteria such as M. tuberculosis. These include induction of toxic anti-microbial effectors such as nitric oxide and reactive oxygen intermediates, the stimulation of microbe intoxication mechanisms via acidification or metal accumulation in the phagolysosome, the restriction of the microbe's access to essential nutrients such as iron, fatty acids, or amino acids, the production of anti-microbial peptides and cytokines, along with induction of autophagy and efferocytosis to eliminate the pathogen. On the other hand, M. tuberculosis, as a prime example of a well-adapted facultative intracellular bacterium, has learned during evolution to counter-balance the host's immune defense strategies to secure survival or multiplication within this otherwise hostile environment. This review provides an overview of innate immune defense of macrophages directed against intracellular bacteria with a focus on M. tuberculosis. Gaining more insights and knowledge into this complex network of host-pathogen interaction will identify novel target sites of intervention to successfully clear infection at a time of rapidly emerging multi-resistance of M. tuberculosis against conventional antibiotics. PMID- 25703562 TI - Immunoevasion and immunosuppression of the macrophage by Mycobacterium tuberculosis. AB - By virtue of their position at the crossroads between the innate and adaptive immune response, macrophages play an essential role in the control of bacterial infections. Paradoxically, macrophages serve as the natural habitat to Mycobacterium tuberculosis (Mtb). Mtb subverts the macrophage's mechanisms of intracellular killing and antigen presentation, leading ultimately to the development of tuberculosis (TB) disease. Here, we describe mechanisms of Mtb uptake by the macrophage and address key macrophage functions that are targeted by Mtb-specific effector molecules enabling this pathogen to circumvent host immune response. The macrophage functions described in this review include fusion between phagosomes and lysosomes, production of reactive oxygen and nitrogen species, antigen presentation and major histocompatibility complex class II expression and trafficking, as well as autophagy and apoptosis. All these are Mtb targeted key cellular pathways, normally working in concert in the macrophage to recognize, respond, and activate 'proper' immune responses. We further analyze and discuss major molecular interactions between Mtb virulence factors and key macrophage proteins and provide implications for vaccine and drug development. PMID- 25703561 TI - Sensing of Mycobacterium tuberculosis and consequences to both host and bacillus. AB - Mycobacterium tuberculosis (Mtb), the primary causative agent of human tuberculosis, has killed more people than any other bacterial pathogen in human history and remains one of the most important transmissible diseases worldwide. Because of the long-standing interaction of Mtb with humans, it is no surprise that human mucosal and innate immune cells have evolved multiple mechanisms to detect Mtb during initial contact. To that end, the cell surface of human cells is decorated with numerous pattern recognition receptors for a variety of mycobacterial ligands. Furthermore, once Mtb is ingested into professional phagocytes, other host molecules are engaged to report on the presence of an intracellular pathogen. In this review, we discuss the role of specific mycobacterial products in modulating the host's ability to detect Mtb. In addition, we describe the specific host receptors that mediate the detection of mycobacterial infection and the role of individual receptors in mycobacterial pathogenesis in humans and model organisms. PMID- 25703563 TI - Trans-species communication in the Mycobacterium tuberculosis-infected macrophage. AB - Much of the infection cycle of Mycobacterium tuberculosis (Mtb) is spent within its host cell, the macrophage. As a consequence of the chronic, enduring nature of the infection, this cell-cell interaction has become highly intimate, and the bacterium has evolved to detect, react to, and manipulate the evolving, immune modulated phenotype of its host. In this review, we discuss the nature of the endosomal/lysosomal continuum, the characterization of the bacterium's transcriptional responses during the infection cycle, and the dominant environmental cues that shape this response. We also discuss how the metabolism of both cells is modulated by the infection and the impact that this has on the progression of the granuloma. Finally, we detail how these transcriptional responses can be exploited to construct reporter bacterial strains to probe the temporal and spatial environmental shifts experienced by Mtb during the course of experimental infections. These reporter strains provide new insights into the fitness of Mtb under immune- and drug-mediated pressure. PMID- 25703565 TI - Cytokine and lipid mediator networks in tuberculosis. AB - A major approach for immunologic intervention in tuberculosis involves redirecting the outcome of the host immune response from the induction of disease to pathogen control. Cytokines and lipid mediators known as eicosanoids play key roles in regulating this balance and as such represent important targets for immunologic intervention. While the evidence for cytokine/eicosanoid function derives largely from the investigation of murine and zebrafish experimental infection models, clinical studies have confirmed the existence of many of the same pathways in tuberculosis patients. Here, we summarize new data that reveal important intersections between the cytokine and eicosanoid networks in the host response to mycobacteria and discuss how targeting this crosstalk can promote resistance to lethal Mycobacterium tuberculosis infection. This approach could lead to new host-directed therapies to be used either as an adjunct for improving the efficacy of standard antibiotic treatment or for the management of drug resistant infections. PMID- 25703564 TI - Mycobacteria, metals, and the macrophage. AB - Mycobacterium tuberculosis is a facultative intracellular pathogen that thrives inside host macrophages. A key trait of M. tuberculosis is to exploit and manipulate metal cation trafficking inside infected macrophages to ensure survival and replication inside the phagosome. Here, we describe the recent fascinating discoveries that the mammalian immune system responds to infections with M. tuberculosis by overloading the phagosome with copper and zinc, two metals which are essential nutrients in small quantities but are toxic in excess. M. tuberculosis has developed multi-faceted resistance mechanisms to protect itself from metal toxicity including control of uptake, sequestration inside the cell, oxidation, and efflux. The host response to infections combines this metal poisoning strategy with nutritional immunity mechanisms that deprive M. tuberculosis from metals such as iron and manganese to prevent bacterial replication. Both immune mechanisms rely on the translocation of metal transporter proteins to the phagosomal membrane during the maturation process of the phagosome. This review summarizes these recent findings and discusses how metal-targeted approaches might complement existing TB chemotherapeutic regimens with novel anti-infective therapies. PMID- 25703566 TI - Adventures within the speckled band: heterogeneity, angiogenesis, and balanced inflammation in the tuberculous granuloma. AB - Recent work in a variety of animal models, including mice, zebrafish, and macaques, as well as in humans, has led to a reassessment of several tenets of mycobacterial infection. In this review, we describe new findings about the composition and dynamics of the tuberculous granuloma, the central host structure in mycobacterial infection, as well as inflammatory mediators that drive a successful anti-microbial response on one hand and pathological inflammation on the other. We highlight granuloma heterogeneity that emerges in the context of infection, the functional consequences of angiogenesis in tuberculous granulomas, and data that balanced inflammation in humans, with a central role for tumor necrosis factor, appears to play a key role in optimal defense against mycobacterial infection. These findings have suggested new and specific host directed therapies that await further clinical exploration. PMID- 25703567 TI - Heterogeneity in tuberculosis pathology, microenvironments and therapeutic responses. AB - Tuberculosis (TB) lesions are extremely complex and dynamic. Here, we review the multiple types and fates of pulmonary lesions that form following infection by Mycobacterium tuberculosis and the impact of this spatial and temporal heterogeneity on the bacteria they harbor. The diverse immunopathology of granulomas and cavities generates a plethora of microenvironments to which M. tuberculosis bacilli must adapt. This in turn affects the replication, metabolism, and relative density of bacterial subpopulations, and consequently their respective susceptibility to chemotherapy. We outline recent developments that support a paradigm shift in our understanding of lesion progression. The simple model according to which lesions within a single individual react similarly to the systemic immune response no longer prevails. Host-pathogen interactions within lesions are a dynamic process, driven by subtle and local differences in signaling pathways, resulting in diverging trajectories of lesions within a single host. The spectrum of TB lesions is a continuum with a large overlap in the lesion types found in latently infected and active TB patients. We hope this overview will guide TB researchers in the design, choice of read-outs, and interpretation of future studies in the search for predictive biomarkers and novel therapies. PMID- 25703568 TI - TB drug development: immunology at the table. AB - Our understanding of the host-pathogen relationship in tuberculosis (TB) can help guide drug discovery in at least two ways. First, the recognition that host immunopathology affects lesional TB drug distribution means that pharmacokinetic evaluation of drug candidates needs to move beyond measurements of drug levels in blood, whole lungs, or alveolar epithelial lining fluid to include measurements in specific types of lesions. Second, by restricting the replication of M. tuberculosis (Mtb) subpopulations in latent TB infection and in active disease, the host immune response puts Mtb into a state associated with phenotypic tolerance to TB drugs selected for their activity against replicating Mtb. This has spurred a major effort to conduct high throughput screens in vitro for compounds that can kill Mtb when it is replicating slowly if at all. Each condition used in vitro to slow Mtb's replication and thereby model the phenotypically drug-tolerant state has advantages and disadvantages. Lead candidates emerging from such in vitro studies face daunting challenges in the design of proof-of-concept studies in animal models. Moreover, some non replicating subpopulations of Mtb fail to resume replication when plated on agar, although their viability is demonstrable by other means. There is as yet no widely replicated assay in which to screen compounds for their ability to kill this 'viable but non-culturable' subpopulation. Despite these hurdles, drugs that can kill slowly replicating or non-replicating Mtb may offer our best hope for treatment-shortening combination chemotherapy of TB. PMID- 25703569 TI - Mycobacterial genes essential for the pathogen's survival in the host. AB - Mycobacterium tuberculosis (Mtb) has evolved within the human immune system as both host and reservoir. The study of genes required for its growth and persistence in vivo thus offers linked insights into its pathogenicity and host immunity. Studies of Mtb mutants have implicated metabolic adaptation (consisting of carbon, nitrogen, vitamin, and cofactor metabolism), intrabacterial pH homeostasis, and defense against reactive oxygen and reactive nitrogen species, as key determinants of its pathogenicity. However, the mechanisms of host immunity are complex and often combinatorial. Growing evidence has thus begun to reveal that the determinants of Mtb's pathogenicity may serve a broader and more complex array of functions than the isolated experimental settings in which they were initially found. Here, we review select examples, which exemplify this complexity, highlighting the distinct phases of Mtb's life cycle and the diverse microenvironments encountered therein. PMID- 25703570 TI - New insights into TB physiology suggest untapped therapeutic opportunities. AB - The current regimens used to treat tuberculosis are largely comprised of serendipitously discovered drugs that are combined based on clinical experience. Despite curing millions, these drug regimens are limited by the long course of therapy, the emergence of resistance, and the persistent tissue damage that remains after treatment. The last two decades have produced only a single new drug but have represented a renaissance in our understanding of the physiology of tuberculosis infection. The advent of mycobacterial genetics, sophisticated immunological methods, and imaging technologies have transformed our understanding of bacterial physiology as well as the contribution of the host response to disease outcome. Specific alterations in bacterial metabolism, heterogeneity in bacterial state, and drug penetration all limit the effectiveness of antimicrobial therapy. This review summarizes these new biological insights and discusses strategies to exploit them for the rational development of more effective therapeutics. Three general strategies are discussed. First, our emerging insight into bacterial physiology suggests new pathways that might be targeted to accelerate therapy. Second, we explore whether the concept of genetic synergy can be used to design effective combination therapies. Finally, we outline possible approaches to modulate the host response to accentuate antibiotic efficacy. These biology-driven strategies promise to produce more effective therapies. PMID- 25703571 TI - New tricks for old dogs: countering antibiotic resistance in tuberculosis with host-directed therapeutics. AB - Despite the availability of Mycobacterium tuberculosis (Mtb) drugs for over 50 years, tuberculosis (TB) remains at pandemic levels. New drugs are urgently needed for resistant strains, shortening duration of treatment, and targeting different stages of the disease, especially for treatment during human immunodeficiency virus co-infection. One solution to the conundrum that antibiotics kill the bacillus yet select for resistance is to target the host rather than the pathogen. Here, we discuss recent progress in so-called 'host directed therapeutics' (HDTs), focusing on two general mechanistic strategies: (i) HDTs that disrupt Mtb pathogenesis in macrophages and (ii) immunomodulatory HDTs that facilitate protective immune responses that kill Mtb or reduce deleterious responses that exacerbate disease. HDTs hold significant promise as adjunctive therapies in that they are less likely to engender resistance, will likely have efficacy against antibiotic-resistant strains, and may have activity against non-replicating Mtb. However, TB is a complex and variegated disease, and human populations exhibit significant diversity in their immune responses to it, which presents a complicated landscape for HDTs to navigate. Nevertheless, we suggest that a detailed mechanistic understanding of drug action, together with careful selection of disease stage targets and dosing strategies may overcome such limitations and allow the development of HDTs as effective adjunctive treatment options for TB. PMID- 25703573 TI - Neonates with Bartter syndrome have enormous fluid and sodium requirements. AB - AIM: Managing neonatal Bartter syndrome by achieving adequate weight gain is challenging. We assessed the correlation between weight gain in neonatal Bartter syndrome and the introduction of fluid and sodium supplementations and indomethacin during the first 4 weeks of life. METHODS: Daily fluid and electrolytes requirements were analysed using linear regression and Spearman correlation coefficients. The weight gain coefficient was calculated as daily weight gain after physiological neonatal weight loss. RESULTS: We studied seven infants. The highest weight gain coefficients occurred between weeks two and four in the five neonates who either received prompt amounts of fluid (maximum 810 mL/kg/day) and sodium (maximum 70 mmol/kg/day) or were treated with indomethacin. For the two patients with the highest weight gain coefficient, water and sodium supplementations were decreased in weeks two to four leading to a significant negative Spearman correlation between weight gain and fluid supplements (r = 0.55 and -0.68) and weight gain and sodium supplementations (r = -0.96 and 0.72). The two patients with the lowest weight gain coefficient had positive Spearman correlation coefficients between weight gain and fluid and sodium supplementations. CONCLUSION: Infants with neonatal Bartter syndrome required rapid and enormous fluid and sodium supplementations or the early introduction of indomethacin treatment to achieve adequate weight gain during the early postnatal period. PMID- 25703572 TI - Tuberculosis vaccines: barriers and prospects on the quest for a transformative tool. AB - The road to a more efficacious vaccine that could be a truly transformative tool for decreasing tuberculosis morbidity and mortality, along with Mycobacterium tuberculosis transmission, is quite daunting. Despite this, there are reasons for optimism. Abetted by better conceptual clarity, clear acknowledgment of the degree of our current immunobiological ignorance, the availability of powerful new tools for dissecting the immunopathogenesis of human tuberculosis, the generation of more creative diversity in tuberculosis vaccine concepts, the development of better fit-for-purpose animal models, and the potential of more pragmatic approaches to the clinical testing of vaccine candidates, the field has promise for delivering novel tools for dealing with this worldwide scourge of poverty. PMID- 25703574 TI - Re: Ian A. Donaldson, Roberto Alonzi, Dean Barratt, et al. Focal Therapy: Patients, Interventions, and Outcomes-A Report from a Consensus Meeting. Eur Urol 2015;67:771-7. PMID- 25703575 TI - Renal Ischemia and Function After Partial Nephrectomy: A Collaborative Review of the Literature. AB - CONTEXT: Partial nephrectomy (PN) is the current gold standard treatment for small localized renal tumors.; however, the impact of duration and type of intraoperative ischemia on renal function (RF) after PN is a subject of significant debate. OBJECTIVE: To review the current evidence on the relationship of intraoperative ischemia and RF after PN. EVIDENCE ACQUISITION: A review of English-language publications on renal ischemia and RF after PN was performed from 2005 to 2014 using the Medline, Embase, and Web of Science databases. Ninety one articles were selected with the consensus of all authors and analyzed according to the Preferred Reporting Items for Systematic Reviews and Meta Analyses criteria. EVIDENCE SYNTHESIS: The vast majority of reviewed studies were retrospective, nonrandomized observations. Based on the current literature, RF recovery after PN is strongly associated with preoperative RF and the amount of healthy kidney parenchyma preserved. Warm ischemia time (WIT) is modifiable and prolonged warm ischemia is significantly associated with adverse postoperative RF. Available data suggest a benefit of keeping WIT <25min, although the level of evidence to support this threshold is limited. Cold ischemia safely facilitates longer durations of ischemia. Surgical techniques that minimize or avoid global ischemia may be associated with improved RF outcomes. CONCLUSIONS: Although RF recovery after PN is strongly associated with quality and quantity of preserved kidney, efforts should be made to limit prolonged WIT. Cold ischemia should be preferred when longer ischemia is expected, especially in presence of imperative indications for PN. Additional research with higher levels of evidence is needed to clarify the optimal use of renal ischemia during PN. PATIENT SUMMARY: In this review of the literature, we looked at predictors of renal function after surgical resection of renal tumors. There is a strong association between the quality and quantity of renal tissue that is preserved after surgery and long term renal function. The time of interruption of renal blood flow during surgery is an important, modifiable predictor of postoperative renal function. PMID- 25703576 TI - Adherence to therapy for lower urinary tract symptoms: don't mistake association with causation! PMID- 25703577 TI - Size control during organogenesis: Development of the lateral line organs in zebrafish. AB - Many genes that play essential roles in organ growth have been identified across a range of organisms. However, the mechanisms by which growing organs can sense their sizes and stop growing when they reach their proper sizes remain poorly understood. The mechanosensory organs of the fish lateral line system (neuromasts) provide an ideal system to address this question for the following reasons. First, each superficial neuromast is composed of a small number of cells situated on the body surface, making it relatively easy to quantify organ size throughout development. Second, while the sensory cells of superficial neuromasts are continuously renewed, overall organ size is homeostatically maintained. Third, there is another type of neuromast showing an opposite mode of growth: that is, canal neuromasts increase in size in proportion to organism body size. Here, we review recent findings regarding the mechanisms that control organ size in the zebrafish lateral line. PMID- 25703578 TI - Modelling the dispersion and transport of reactive pollutants in a deep urban street canyon: using large-eddy simulation. AB - This study investigates the dispersion and transport of reactive pollutants in a deep urban street canyon with an aspect ratio of 2 under neutral meteorological conditions using large-eddy simulation. The spatial variation of pollutants is significant due to the existence of two unsteady vortices. The deviation of species abundance from chemical equilibrium for the upper vortex is greater than that for the lower vortex. The interplay of dynamics and chemistry is investigated using two metrics: the photostationary state defect, and the inferred ozone production rate. The latter is found to be negative at all locations within the canyon, pointing to a systematic negative offset to ozone production rates inferred by analogous approaches in environments with incomplete mixing of emissions. This study demonstrates an approach to quantify parameters for a simplified two-box model, which could support traffic management and urban planning strategies and personal exposure assessment. PMID- 25703579 TI - Heavy metal and nitrogen concentrations in mosses are declining across Europe whilst some "hotspots" remain in 2010. AB - In recent decades, naturally growing mosses have been used successfully as biomonitors of atmospheric deposition of heavy metals and nitrogen. Since 1990, the European moss survey has been repeated at five-yearly intervals. In 2010, the lowest concentrations of metals and nitrogen in mosses were generally found in northern Europe, whereas the highest concentrations were observed in (south )eastern Europe for metals and the central belt for nitrogen. Averaged across Europe, since 1990, the median concentration in mosses has declined the most for lead (77%), followed by vanadium (55%), cadmium (51%), chromium (43%), zinc (34%), nickel (33%), iron (27%), arsenic (21%, since 1995), mercury (14%, since 1995) and copper (11%). Between 2005 and 2010, the decline ranged from 6% for copper to 36% for lead; for nitrogen the decline was 5%. Despite the Europe-wide decline, no changes or increases have been observed between 2005 and 2010 in some (regions of) countries. PMID- 25703580 TI - Research and demonstration to improve air quality for the U.S. animal feeding operations in the 21st century - a critical review. AB - There was an increasing interest in reducing production and emission of air pollutants to improve air quality for animal feeding operations (AFOs) in the U.S. in the 21st century. Research was focused on identification, quantification, characterization, and modeling of air pollutions; effects of emissions; and methodologies and technologies for scientific research and pollution control. Mitigation effects were on pre-excretion, pre-release, pre-emission, and post emission. More emphasis was given on reducing pollutant emissions than improving indoor air quality. Research and demonstrations were generally continuation and improvement of previous efforts. Most demonstrated technologies were still in a limited scale of application. Future efforts are needed in many fundamental and applied research areas. Advancement in instrumentation, computer technology, and biological sciences and genetic engineering is critical to bring major changes in this area. Development in research and demonstration will depend on the actual political, economic, and environmental situations. PMID- 25703581 TI - Prevalence, associated factors, mood and cognitive outcomes of traumatic brain injury in later life: the health in men study (HIMS). AB - BACKGROUND: The incidence of traumatic brain injury (TBI) is rising, as are its neuropsychiatric complications. This study aims to determine (1) the prevalence of TBI, (2) the association between history of past TBI and sociodemographic, lifestyle and clinical factors, and (3) the risk of depression and cognitive impairment in later life associated with exposure to TBI. METHODS: Cross sectional study of a community-derived sample of 5486 Australian men aged 70-89 years. Information on TBI was retrieved from the Western Australian Data Linkage System (WADLS) and via self-report. We used the WADLS and self-report to ascertain history of past depression, and the Geriatric Depression Scale 15-items to assess current clinically significant symptoms of depression, defined by score >=7. We defined cognitive impairment by a mini-mental state examination score <24 or a WADLS diagnosis of dementia. RESULTS: Nine hundred fifty-three men had history of TBI (17.4%). Factors associated with TBI included coronary heart disease, stroke, poor self-perceived physical health and falls. TBI increased the odds ratio of past (odds ratio (OR) = 1.55, 95% confidence interval (CI) = 1.21, 1.99) and current depression (OR = 1.77, 95% CI = 1.36, 2.32), as well as of cognitive impairment (OR = 1.23, 95% CI = 1.00, 1.51). The population fractions of depression and cognitive impairment attributable to TBI were 6.9% (95% CI = 3.3%, 10.3%) and 3.4% (95% CI = 0.0%, 6.9%). CONCLUSIONS: History of TBI is common in older men, and is associated with increased risk of depression and cognitive impairment. If this association is truly causal, then the effective reduction of events leading to TBI (e.g., motor vehicle accidents and falls) may also decrease the prevalence of depression and cognitive impairment in later life. PMID- 25703582 TI - NMDA receptor activation regulates sociability by its effect on mTOR signaling activity. AB - Tuberous Sclerosis Complex is one example of a syndromic form of autism spectrum disorder associated with disinhibited activity of mTORC1 in neurons (e.g., cerebellar Purkinje cells). mTORC1 is a complex protein possessing serine/threonine kinase activity and a key downstream molecule in a signaling cascade beginning at the cell surface with the transduction of neurotransmitters (e.g., glutamate and acetylcholine) and nerve growth factors (e.g., Brain-Derived Neurotrophic Factor). Interestingly, the severity of the intellectual disability in Tuberous Sclerosis Complex may relate more to this metabolic disturbance (i.e., overactivity of mTOR signaling) than the density of cortical tubers. Several recent reports showed that rapamycin, an inhibitor of mTORC1, improved sociability and other symptoms in mouse models of Tuberous Sclerosis Complex and autism spectrum disorder, consistent with mTORC1 overactivity playing an important pathogenic role. NMDA receptor activation may also dampen mTORC1 activity by at least two possible mechanisms: regulating intraneuronal accumulation of arginine and the phosphorylation status of a specific extracellular signal regulating kinase (i.e., ERK1/2), both of which are "drivers" of mTORC1 activity. Conceivably, the prosocial effects of targeting the NMDA receptor with agonists in mouse models of autism spectrum disorders result from their ability to dampen mTORC1 activity in neurons. Strategies for dampening mTORC1 overactivity by NMDA receptor activation may be preferred to its direct inhibition in chronic neurodevelopmental disorders, such as autism spectrum disorders. PMID- 25703583 TI - Bevacizumab: A dose review. AB - Angiogenesis is a key process in cancer development and has been described has a hallmark of cancer. Two dose-intensities were approved for cancer treatment by the Food and Drug Administration and European Medicines Agency: 2.5mg/kg/week dose equivalent and 5mg/kg/week dose equivalent. While bevacizumab has shown its effectiveness in clinical trials, pharmacodynamics is not fully understood and a dose-effect relationship has not been proven in vivo. Direct trials comparing high or low doses are rare with potential dose-effect toxicity. Discordant data have been reported on the efficacy of doses. This review discusses the dose of bevacizumab via the analysis of studies that led to the approval of bevacizumab in clinical practice. Optimization of doses schemes could reduce potential dose effect toxicities, potentiate synergetic effects with chemotherapy and permit the prescription to a larger population with a better cost-effectiveness ratio. PMID- 25703584 TI - The influence of empowerment, authentic leadership, and professional practice environments on nurses' perceived interprofessional collaboration. AB - AIM: The aim of this study was to examine the influence of structural empowerment, authentic leadership and professional nursing practice environments on experienced nurses' perceptions of interprofessional collaboration. BACKGROUND: Enhanced interprofessional collaboration (IPC) is seen as one means of transforming the health-care system and addressing concerns about shortages of health-care workers. Organizational supports and resources are suggested as key to promoting IPC. METHODS: A predictive non-experimental design was used to test the effects of structural empowerment, authentic leadership and professional nursing practice environments on perceived interprofessional collaboration. A random sample of experienced registered nurses (n = 220) in Ontario, Canada completed a mailed questionnaire. Hierarchical multiple regression analysis was used. RESULTS: Higher perceived structural empowerment, authentic leadership, and professional practice environments explained 45% of the variance in perceived IPC (Adj. R2 = 0.452, F = 59.40, P < 0.001). CONCLUSIONS: Results suggest that structural empowerment, authentic leadership and a professional nursing practice environment may enhance IPC. IMPLICATIONS FOR NURSING MANAGEMENT: Nurse leaders who ensure access to resources such as knowledge of IPC, embody authenticity and build trust among nurses, and support the presence of a professional nursing practice environment can contribute to enhanced IPC. PMID- 25703585 TI - Methods to control the pharmaceutical cost impact of chronic conditions in the elderly. AB - Multimorbidity is the main cause of polypharmacy in elderly people, with the consequent increment in cost and use of inappropriate medication. To control cost, specific strategies have been implemented in healthcare services to reduce potentially inappropriate prescription. Many interventions are applied online during the prescription process using computerized decision support systems, for example, therapeutic algorithms and alerts. Other interventions can be categorized as offline due to their application before or after the prescription process, the main strategies being financial incentives, medication reviews and organizational change. All these strategies are complementary and multifaceted. There is evidence that some of these interventions are effective, but further research should be directed in this field, including investigation of patient cost and outcomes. PMID- 25703586 TI - Novel approaches in selective tryptophan isotope labeling by using Escherichia coli overexpression media. AB - NMR-based investigations of large protein complexes require optimized isotopic labeling schemes. We report new methods to introduce stable isotopes into tryptophan residues; these are fine-tuned to the requirements of the particular protein NMR experiment. Selective backbone labeling was performed by using a new alpha-ketoacid precursor as an additive in cell-based overexpression media. Additionally, we developed synthetic routes to certain isotopologues of indole with (13)C-(1)H spin systems surrounded by (12)C and (2)H. The corresponding proteins, overexpressed in the presence of these precursor compounds, can be effectively analyzed for conformational changes in tryptophan residues in response to external stimuli, such as interaction with other proteins or small molecules. PMID- 25703587 TI - Pathological glycogenesis through glycogen synthase 1 and suppression of excessive AMP kinase activity in myeloid leukemia cells. AB - The rapid proliferation of myeloid leukemia cells is highly dependent on increased glucose metabolism. Through an unbiased metabolomics analysis of leukemia cells, we found that the glycogenic precursor UDP-D-glucose is pervasively upregulated, despite low glycogen levels. Targeting the rate-limiting glycogen synthase 1 (GYS1) not only decreased glycolytic flux but also increased activation of the glycogen-responsive AMP kinase (AMPK), leading to significant growth suppression. Further, genetic and pharmacological hyper-activation of AMPK was sufficient to induce the changes observed with GYS1 targeting. Cancer genomics data also indicate that elevated levels of the glycogenic enzymes GYS1/2 or GBE1 (glycogen branching enzyme 1) are associated with poor survival in AML. These results suggest a novel mechanism whereby leukemic cells sustain aberrant proliferation by suppressing excess AMPK activity through elevated glycogenic flux and provide a therapeutic entry point for targeting leukemia cell metabolism. PMID- 25703588 TI - Imprinted genes in myeloid lineage commitment in normal and malignant hematopoiesis. AB - Genomic imprinting is characterized by the parent-of-origin monoallelic expression of several diploid genes because of epigenetic regulation. Imprinted genes (IGs) are key factors in development, supporting the ability of a genotype to produce phenotypes in response to environmental stimuli. IGs are highly expressed during prenatal stages but are downregulated after birth. They also affect aspects of life other than growth such as cognition, behavior, adaption to novel environments, social dominance and memory consolidation. Deregulated genomic imprinting leads to developmental disorders and is associated with solid and blood cancer as well. Several data have been published highlighting the involvement of IGs in as early as the very small embryonic-like stem cells stage and further during myeloid lineage commitment in normal and malignant hematopoiesis. Therefore, we have assembled the current knowledge on the topic, based mainly on recent findings, trying not to focus on a particular cluster but rather to have a global view of several different IGs in hematopoiesis. PMID- 25703590 TI - From Toy Story to CT Scans: Lessons From Pixar for Radiology. PMID- 25703589 TI - Comparison of dementia risk between end stage renal disease patients with hemodialysis and peritoneal dialysis--a population based study. AB - A higher risk of dementia was reported in patients undergoing maintenance hemodialysis (HD) compared to those undergoing peritoneal dialysis (PD). Selection bias and competing risk of death were not considered in previous studies. The aim of this study was to investigate dementia risk in patients undergoing HD and PD by using the Taiwan Longitudinal Health Insurance Database. We enrolled 52,332 incident HD patients and 3292 incident PD patients who were older than 40 years between January 1, 1998 and December 31, 2007. During the study period, 3775 patients were diagnosed with dementia in the HD group (177.5 per 10,000 person-years incidence rate) and 181 patients in the PD group (145.9 per 10,000 person-years incidence rate). The results revealed that the higher hazard ratio of HD compared with PD for dementia disappeared after controlling for demographic characteristics, propensity score, and competing death risk (subdistribution hazard ratio was 1.086; 95% confidence interval, 0.940-1.255). In conclusion, HD did not increase the risk of dementia in dialysis-dependent patients compared to PD. PMID- 25703591 TI - Gold-catalyzed tandem hydroamination/formal aza-Diels-Alder reaction of homopropargyl amino esters: a combined computational and experimental mechanistic study. AB - A tandem gold-catalyzed hydroamination/formal aza-Diels-Alder reaction is described. This process, which employs quaternary homopropargyl amino ester substrates, leads to the formation of an intrincate tetracyclic framework and involves the generation of four bonds and five stereocenters in a highly diastereoselective manner. Theoretical calculations have allowed us to propose a suitable mechanistic rationalization for the tandem protocol. Additionally, by studying the influence of the ligands on the rate of the gold-catalyzed reactions, it was possible to establish optimum conditions in which to perform the process with a variety of substituents on the amino ester substrates. Notably, the asymmetric version of the tandem reaction was also evaluated. PMID- 25703592 TI - IFPA meeting 2014 workshop report: Animal models to study pregnancy pathologies; new approaches to study human placental exposure to xenobiotics; biomarkers of pregnancy pathologies; placental genetics and epigenetics; the placenta and stillbirth and fetal growth restriction. AB - Workshops are an important part of the IFPA annual meeting as they allow for discussion of specialized topics. At IFPA meeting 2014 there were six themed workshops, five of which are summarized in this report. These workshops related to various aspects of placental biology but collectively covered areas of animal models, xenobiotics, pathological biomarkers, genetics and epigenetics, and stillbirth and fetal growth restriction. PMID- 25703593 TI - Distinct promoter methylation and isoform-specific expression of RASFF1A in placental biopsies from complicated pregnancies. AB - INTRODUCTION: Epigenetic changes in the placenta have been postulated to act as mediators between environmental influences and poor fetal growth. We assessed if genes with a plausible influence on growth could be aberrantly methylated in placental samples from pregnancies complicated by intrauterine growth restriction (IUGR). METHODS: A candidate gene approach was undertaken using a custom Illumina Goldengate(r) array on a collection of placental samples from growth restricted pregnancies and normally grown controls with confirmation using bisulphite pyrosequencing. RESULTS: The custom array analysis revealed that the promoter of RASSF1A was the only region with significant methylation differences between IUGR placentas and those from pregnancies with appropriate growth for gestational age (AGA). The RASSF1A promoter had increased levels of DNA methylation in IUGR samples compared to controls. Interestingly, the methylation difference was also observed in preeclamptic samples. Higher methylation was associated with a concomitant decrease in expression of the RASSF1 transcript A, but not other isoforms that originate from an alternative, nearby promoter interval. DISCUSSION: Our results do not support the hypothesis that altered DNA methylation in the placenta is a mechanism generally involved in fetal growth restriction. A specific region corresponding to the promoter of RASSF1A does display methylation changes in placenta that could be used to identify at-risk pregnancies. PMID- 25703594 TI - Fibromyalgia-like symptoms associated with irritable bowel syndrome: A challenging diagnosis of late-onset Pompe disease. AB - INTRODUCTION: Late-onset Pompe disease (LOPD) is a rare autosomal recessive disorder which usually presents as a limb-girdle myopathy with early respiratory involvement. METHODS: We report 2 sisters with an uncommon presentation of LOPD characterized by fibromyalgia-like pain associated with irritable bowel syndrome. RESULTS: In both sisters, clinical examination was normal and had remained stable for 10 years. The serum creatine kinase level was mildly elevated. Several muscle biopsies showed slight nonspecific myopathic abnormalities. A dried blood spot test indicated acid maltase deficiency. The diagnosis of LOPD was confirmed genetically. Both sisters subsequently developed proximal muscle weakness after pregnancy and started enzyme replacement therapy. Under treatment, gastrointestinal symptoms improved, but pain persisted. CONCLUSIONS: Clinicians should be aware of this atypical presentation of LOPD to enable earlier diagnosis and treatment. PMID- 25703595 TI - Intraosseous haemangioma: semantic and medical confusion. AB - The literature is rich in case reports of intraosseous haemangioma, although most of these are actually cases of venous or capillary malformations. To illustrate this confusion in terminology, we present three cases of slow-flow vascular malformations misnamed as intraosseous haemangioma. A retrospective study of children diagnosed with intraosseous haemangioma was conducted. Clinical and radiological data were evaluated. Histopathological examinations and immunohistochemical studies were redone by three independent pathologists to classify the lesions according to the International Society for the Study of Vascular Anomalies (ISSVA) and World Health Organization (WHO) classifications. Three children who had presented with jaw haemangiomas were identified. Computed tomography scan patterns were not specific. All tumours were GLUT-1-negative and D2-40-negative. The lesions were classified as central haemangiomas according to the WHO, and as slow-flow malformations according to the ISSVA. The classification of vascular anomalies is based on clinical, radiological, and histological differences between vascular tumours and malformations. Based on this classification, the evolution of the lesion can be predicted and adequate treatment applied. The binary ISSVA classification is widely accepted and should be applied for all vascular lesions. PMID- 25703596 TI - Cephalometric analysis and long-term outcomes of orthognathic surgical treatment for obstructive sleep apnoea. AB - The aim of this study was to describe skeletal and posterior airway changes after orthodontic treatment and surgical jaw advancement, and to evaluate whether there is a correlation between increasing advancement and a long-term reduction in obstructive sleep apnoea (OSA). Lateral cephalograms and polysomnography (apnoea hypopnoea index, AHI) were collected from patients treated with bilateral sagittal split osteotomy (BSSO) or maxillomandibular advancement (MMA) in combination with orthodontics. Patients completed a questionnaire and the Epworth Sleepiness Scale (ESS) to assess long-term outcomes. Descriptive statistics for cephalometric measurements and linear regression were performed to find estimates of the final OSA (AHI and ESS) as a function of mandibular advancement. Forty three patients with surgical advancement of the maxilla (5.2mm) and mandible (8.3mm) had a 4-mm increase in posterior airway. Thirty-three patients completed the long-term survey (6.3+/-2.6 years after treatment); 91% reported a reduction of OSA and were pleased with their facial appearance. The maxillomandibular and posterior airway increased. There was no evidence of a linear relationship between greater amounts of mandibular advancement and improvement of OSA. Patients with less than 10mm advancement had successful objective short-term and subjective long-term OSA reduction. PMID- 25703597 TI - Mental disorder, imprisonment and reduced life expectancy--A nationwide psychiatric inpatient cohort study. AB - BACKGROUND: There is a strong correlation between severe mental illness and criminality, but little is known about how these two problem areas together may affect health outcomes. AIM: The objective of this paper is to compare survival rates of male psychiatric inpatients over a 25-year period who have and have not been subject to imprisonment, allowing for nature of psychiatric morbidity. METHODS: A nationwide cohort of men who had ever been psychiatric inpatients was identified from Icelandic data-registers, and their diagnoses after first discharge, cumulative incidence of imprisonment, and mortality established from records. Using a nested case-control design, survival differences were determined between those ever imprisoned and those never imprisoned. RESULTS: Between January 1983 and March 2008, 7665 men were admitted to psychiatric wards in Iceland, of whom 812 (10.6%) had served a prison sentence during that time. Cumulative incidence of imprisonment was highest in the youngest age group (21%). Substance use and personality disorders were more common amongst those imprisoned. All-cause mortality, adjusted for diagnosis, age, and year of admission, was twice as high amongst those imprisoned as those not imprisoned (Hazard ratio = 2.0, 95% CI 1.5-2.6, p < 0.001). CLINICAL IMPLICATIONS: Our findings indicate that psychiatric inpatients with criminal records should receive special attention with respect to all aspects of their health, not only within psychiatric services but also through more collaboration between the healthcare and judicial systems. PMID- 25703598 TI - Ion-specific oil repellency of polyelectrolyte multilayers in water: molecular insights into the hydrophilicity of charged surfaces. AB - Surface wetting on polyelectrolyte multilayers (PEMs), prepared by alternating deposition of polydiallyldimethylammonium chloride (PDDA) and poly(styrene sulfonate) (PSS), was investigated mainly in water-solid-oil systems. The surface wetting behavior of as-prepared PEMs was well correlated to the molecular structures of the uncompensated ionic groups on the PEMs as revealed by sum frequency generation vibrational and X-ray photoelectron spectroscopies. The orientation change of the benzenesulfonate groups on the PSS-capped surfaces causes poor water wetting in oil or air and negligible oil wetting in water, while the orientation change of the quaternized pyrrolidine rings on the PDDA capped surfaces hardly affects their wetting behavior. The underwater oil repellency of PSS-capped PEMs was successfully harnessed to manufacture highly efficient filters for oil-water separation at high flux. PMID- 25703599 TI - Fabrication of Ultrathin Bi2 S3 Nanosheets for High-Performance, Flexible, Visible-NIR Photodetectors. AB - Ultrathin Bi2 S3 nanosheets with thicknesses down to 2.2 nm are fabricated. The resultant ultrathin Bi2 S3 -based photoconductor shows high sensitivity to visible-near infrared light from 405 to 780 nm with a high external photoresponsivity up to 4.4 A W(-1) , high detectivity of ~10(11) Jones, relatively fast response time of ~10 MUs, and high flexibility and durability. PMID- 25703600 TI - 'One Health' investigation: outbreak of human Salmonella Braenderup infections traced to a mail-order hatchery - United States, 2012-2013. AB - Human salmonellosis linked to contact with live poultry is an increasing public health concern. In 2012, eight unrelated outbreaks of human salmonellosis linked to live poultry contact resulted in 517 illnesses. In July 2012, PulseNet, a national molecular surveillance network, reported a multistate cluster of a rare strain of Salmonella Braenderup infections which we investigated. We defined a case as infection with the outbreak strain, determined by pulsed-field gel electrophoresis, with illness onset from 25 July 2012-27 February 2013. Ill persons and mail-order hatchery (MOH) owners were interviewed using standardized questionnaires. Traceback and environmental investigations were conducted. We identified 48 cases in 24 states. Twenty-six (81%) of 32 ill persons reported live poultry contact in the week before illness; case-patients named 12 different MOHs from eight states. The investigation identified hatchery D as the ultimate poultry source. Sampling at hatchery D yielded the outbreak strain. Hatchery D improved sanitation procedures and pest control; subsequent sampling failed to yield Salmonella. This outbreak highlights the interconnectedness of humans, animals, and the environment and the importance of industry knowledge and involvement in solving complex outbreaks. Preventing these infections requires a 'One Health' approach that leverages expertise in human, animal, and environmental health. PMID- 25703601 TI - Erratum: evaluation of the impact of automated specimen inoculation, using Previ Isola, on the quality of and technical time for stool cultures. PMID- 25703602 TI - A fluorescence resonance energy transfer-based method for histone methyltransferases. AB - A simple dye-quencher fluorescence resonance energy transfer (FRET)-based assay for methyltransferases was developed and used to determine kinetic parameters and inhibitory activity at EHMT1 and EHMT2. Peptides mimicking the truncated histone H3 tail were functionalized in each end with a dye and a quencher, respectively. When lysine-9 residues in the peptides were methylated, they were protected from cleavage by endoproteinase-EndoLysC, whereas unmethylated peptides were cleaved, resulting in an increase in fluorescent intensity. PMID- 25703603 TI - Faster may be better for anastomosis time, but does it really affect survival? PMID- 25703604 TI - Recognition of saccharides in the NIR region with a novel fluorogenic boronolectin: in vitro and live cell labeling. AB - This work describes a novel mono-boronic acid derivative of a tricarbocyanine. The probe is a genuine near-infrared fluorescence emitter with improved properties such as a large Stokes shift, excellent water solubility and sensitive fluorogenicity upon binding to carbohydrates under physiological conditions. PMID- 25703605 TI - Two pathways to causal control: use and availability of information in the environment in people with and without signs of depression. AB - Perceiving one's causal control is important for adaptive behavior. Studying depression and other individual differences has provided insight into typical as well as pathological causal processing. We set out to study factors that have been shown to distinguish those with and without signs of depression and affect perceptions of causal control: levels of behavior, the availability of outcomes and learning about the environment or context. Two experiments were carried out in which participants, scoring low and high on the Beck Depression Inventory using established cutoffs, completed a causal control task, in which outcomes occurred with a low (.25) or high probability (.75). Behavior levels were either constrained (N1=73) or unconstrained (N2=74). Overall, findings showed that levels of behavior influenced people's experiences of the context in which events occurred. For all participants, very high behavior levels eliminated sensitivity to levels of outcomes occurring in the environment and lead to judgments that were consistent with conditional probabilities as opposed to the experimenter programmed contingency. Thus increased behavior increased perceived control via influence on context experience. This effect was also evident for those scoring high on the BDI. Overall conclusions are that behavior and context provide two important interlinked psychological pathways to perceived control. However, situations that constrain people's ability to respond freely can prevent people with signs of depression from taking control of a situation that would otherwise be uncontrollable. PMID- 25703606 TI - Task choice and semantic interference in picture naming. AB - Evidence from dual-task performance indicates that speakers prefer not to select simultaneous responses in picture naming and another unrelated task, suggesting a response selection bottleneck in naming. In particular, when participants respond to tones with a manual response and name pictures with superimposed semantically related or unrelated distractor words, semantic interference in naming tends to be constant across stimulus onset asynchronies (SOAs) between the tone stimulus and the picture-word stimulus. In the present study, we examine whether semantic interference in picture naming depends on SOA in case of a task choice (naming the picture vs reading the word of a picture-word stimulus) based on tones. This situation requires concurrent processing of the tone stimulus and the picture word stimulus, but not a manual response to the tones. On each trial, participants either named a picture or read aloud a word depending on the pitch of a tone, which was presented simultaneously with picture-word onset or 350 ms or 1000 ms before picture-word onset. Semantic interference was present with tone pre-exposure, but absent when tone and picture-word stimulus were presented simultaneously. Against the background of the available studies, these results support an account according to which speakers tend to avoid concurrent response selection, but can engage in other types of concurrent processing, such as task choices. PMID- 25703607 TI - Perceptual effects of linguistic category priming: the Stapel and Semin (2007) paradigm revisited in twelve experiments. AB - Linguistic category priming is a novel paradigm to examine automatic influences of language on cognition (Semin, 2008). An initial article reported that priming abstract linguistic categories (adjectives) led to more global perceptual processing, whereas priming concrete linguistic categories (verbs) led to more local perceptual processing (Stapel & Semin, 2007). However, this report was compromised by data fabrication by the first author, so that it remains unclear whether or not linguistic category priming influences perceptual processing. To fill this gap in the literature, the present article reports 12 studies among Dutch and US samples examining the perceptual effects of linguistic category priming. The results yielded no evidence of linguistic category priming effects. These findings are discussed in relation to other research showing cultural variations in linguistic category priming effects (IJzerman, Saddlemyer, & Koole, 2014). The authors conclude by highlighting the importance of conducting and publishing replication research for achieving scientific progress. PMID- 25703608 TI - Coalition for a Healthier Community: Lessons learned and implications for future work. AB - The Coalition for a Healthier Community (CHC) initiative was implemented to improve the health and well-being of women and girls. Underpinning CHC is a gender-based focus that uses a network of community partners working collaboratively to generate relevant behavior change and improved health outcomes. Ten programs are trying to determine whether gender-focused system approaches are cost-effective ways to address health disparities in women and girls. Programs implemented through coalitions made up of academic institutions, public health departments, community-based organizations, and local, regional, and national organizations, are addressing health issues such as domestic violence, cardiovascular disease prevention, physical activity, and healthy eating. Although these programs are ongoing, they have made significant progress. Key factors contributing to their early success include a comprehensive needs assessment, robust coalitions, the diversity of populations targeted, programs based on findings of the needs assessments, evaluations taking into consideration the effect of gender, and strong academic-community partnerships. A noteworthy impact of these programs has been their ability to shape and impact public, social, and health policies at the state and local levels. However, there have been challenges associated with the implementation of such a complex program. Lessons learned are discussed in this paper. PMID- 25703609 TI - Effect of experimental stress on the small bowel and colon in healthy humans. AB - BACKGROUND: Symptoms of irritable bowel syndrome (IBS) are frequently reported to be exacerbated by stress. Animal studies suggest that corticotrophin releasing hormone (CRH) mediates the effect of stress on the bowel. We have shown that stressed IBS patients with diarrhea have constricted small bowels. We hypothesized that we could mimic this effect by applying experimental stress in the form of either hand immersion in ice water or CRH injection in healthy volunteers (HV). METHODS: The postprandial effect of the cold pressor test (repeated hand immersion in ice cold water) and injection of CRH, were assessed vs control in two groups of 18 HVs. KEY RESULTS: CRH produced a significant rise from baseline salivary cortisol levels (p = 0.004) not seen with the cold pressor test. Small bowel water content (SBWC) fell postprandially on all four treatments. SBWC was significantly reduced by both stressors but CRH caused a greater effect (anova, p < 0.003 vs p = 0.02). Ascending colon (AC) volume was greater after CRH injection compared with saline (p = 0.002) but no differences were seen with the cold pressor test vs warm water. Postprandial increase in colon volume was also reduced by CRH which also increased the sensations of distension and bloating. CONCLUSIONS & INFERENCES: Two experimental stressors were shown to constrict the small bowel, mimicking the effect previously seen in IBS-D patients. CRH increased the volume of the AC. We speculate that stress accelerates transfer of water from the small bowel to the AC. PMID- 25703610 TI - Post-Injection Delirium/Sedation Syndrome after Olanzapine Long-Acting Intramuscular Injection - Who is at Risk? AB - The post-injection olanzapine delirium/sedation syndrome (PDSS) was observed in a 60-year-old Caucasian, schizophrenic, non-smoker and underweight [body mass index (BMI), 18.2 kg/m(2) ] women after the fourth intramuscular injection of 405 mg olanzapine pamoate. Clinical symptoms of PDSS were similar to those of acute oral olanzapine intoxication. The patient received supportive treatment and recovered fully. High olanzapine concentrations in serum, with maximum level of 698 ng/mL, were confirmed by liquid chromatography with tandem mass spectrometry (LC-MS/MS). The authors wonder whether a low BMI and advanced age may predispose patients to PDSS occurrence. PMID- 25703612 TI - Effectiveness during ball screens in elite basketball games. AB - Ball screens are one of the most frequently used tactical behaviour in elite basketball games. The aim of the present study was to identify their predictors of success related to time, space, players, and tasks performed. The sample was composed of 818 ball screens corresponding to 20 close games (mean differences in score of 3.1 +/- 0.8 points) randomly selected from the playoff games of the Spanish Basketball League (2008-2011). Classification tree analysis (CHAID) was used to analyse which variable or combination of variables, better predicts effectiveness during ball screens. The main results allowed identifying interactions with dribbler actions after the screen and the orientation of the screen on the ball. The results showed no interaction with game quarter and quarter minute temporal-related variables in both analyses. The present findings allow improving coaches' strategic plans that involve selecting the most appropriate offensive approach when performing ball screens. PMID- 25703611 TI - An investigation of outcome expectancies as a predictor of treatment response for combat veterans with PTSD: comparison of clinician, self-report, and biological measures. AB - BACKGROUND: Outcome expectancy, or the degree to which a client believes that therapy will result in improvement, is related to improved treatment outcomes for multiple disorders. There is a paucity of research investigating this relation in regards to posttraumatic stress disorder (PTSD). Additionally, the bulk of the research on outcome expectancy and treatment outcomes has relied mostly on self report outcome measures. METHODS: The relation between outcome expectancy on self report measures, clinician-rated measures, and two biological indices (fear potentiated startle and cortisol reactivity) of PTSD symptoms was explored. The sample included combat veterans (N = 116) treated with virtual reality exposure therapy for PTSD. RESULTS: Results supported a negative association between outcome expectancy and both self-report and clinician-rated symptoms at the conclusion of treatment, but outcome expectancy was related to the magnitude of change during treatment for self-report measures only. Outcome expectancy was unrelated to biological measures of treatment response. CONCLUSIONS: These findings suggest that outcome expectancy may be related to patient and clinician perceptions of outcomes, but not biological indices of outcome for PTSD. PMID- 25703613 TI - Augmentation of diaphyseal fractures of the radius and ulna in toy breed dogs using a free autogenous omental graft and bone plating. AB - OBJECTIVES: Evaluation of the short-term outcome, duration of bone healing, and complications following bone plate fixation in dogs weighing <=6 kg, with and without the use of a free autogenous greater omental graft (OG). MATERIALS AND METHODS: A retrospective clinical study reviewed the medical records of 25 dogs of body weight <6 kg with mid to distal diaphyseal fractures of the radius and ulna (29 fractures) treated with open reduction bone plate fixation. Thirteen out of 29 fractures were implanted with an additional 2-3 cm3 OG lateral, cranial, and medial to the fracture site, adjacent to the bone plate. RESULTS: Median time to radiographic healing in OG fractures (n = 11) was 70 days (range 28-98) compared to 106 days (range: 56-144) in non-OG grafted fractures (n = 14). The OG dogs had no major complications; minor complications included oedema, erythema, and mild osteopenia. Six of the eight non-OG dogs for which follow-up could be obtained developed osteopenia necessitating implant removal, four of which re fractured the radius one to five months after implant removal, with one dog re fracturing the limb a second time and resulting in amputation. Telephone follow up of owners of OG dogs (n = 11) three to 15 months (median 10) post-surgery did not identify any signs of lameness or other complications. Owners of the non-OG dogs (n = 8) reported that there were not any signs of lameness six to 48 months (median 36) post-surgery. CLINICAL RELEVANCE: Free autogenous omental grafting of diaphyseal fractures of the radius and ulna was associated with radial and ulnar healing with minimal complications in dogs weighing less than 6 kg. PMID- 25703614 TI - Analysis of genetic and epigenetic effects of maize seeds in response to heavy metal (Zn) stress. AB - Conditions of environmental stress are known to lead genetic and epigenetic variability in plants. DNA methylation is one of the important epigenetic mechanisms and plays a critical role in epigenetic control of gene expression. Thus, the aim of the study was to investigate the alteration of genome methylation induced by zinc stress by using coupled restriction enzyme digestion random amplification (CRED-RA) technique in maize (Zea mays L.) seedlings. In addition, to determine the effect of zinc on mitotic activity and phytohormone level, high-pressure liquid chromatography (HPLC) and mitotic index analysis were utilized. According to the results, mitotic index decreased in all concentrations of zinc except for 5 mM dose and chromosome aberrations such as c-mitosis, stickiness, and anaphase bridges were determined. It was also observed that increasing concentrations of zinc caused an increase in methylation patterns and decrease in gibberellic acid (GA), zeatin (ZA), and indole acetic acid (IAA) levels in contrast to abscisic acid (ABA) level. Especially increasing of ABA levels under zinc stress may be a part of the defense system against heavy metal accumulation in plants. PMID- 25703615 TI - Phosphorus adsorption and sedimentation by suspended sediments from Zhushan Bay, Taihu Lake. AB - The process of phosphorus (P) transformation in particulate matter during sediment resuspension and sedimentation was studied. The P-binding forms in resuspended particles (RP) and settled particles (SP) were analyzed by sequential fractionation (modified Psenner method) and an extended extraction with ammonium oxalate. Water quality data and P fractions were used to estimate P release and uptake by the resuspended and settling sediment particles. Results of 8-h resuspension experiments showed increases of dissolved oxygen, pH, total phosphorus, and particulate phosphorus in overlying water, but no change in soluble reactive phosphorus (SRP). P fractions extracted with common sequential fractionation showed that the increase of total P in RP was mainly due to increases of redox-sensitive bound P BD (BD-SRP) and P bound to Al and Fe oxides (NaOH-SRP) (36-52 % and 30-36 % of total increased P, respectively). Comparisons between two sequential fractionations indicated that inorganic P extracted with ammonium oxalate consisted of P bound to amorphous Fe/Al oxy-hydroxides and partially of carbonate-bound P (HCl-SRP) and that increased P in RP was mainly caused by increases in P bound to amorphous oxides. It is concluded that the formation of amorphous oxides and subsequent adsorption of P lead to the increase of P in RP. However, P adsorbed by amorphous oxy-hydroxides in RP is unstable and may be released under sedimentation conditions. Meanwhile, increases in HCl-SRP, refractory P, and crystalline Fe-P were found in SP compared with RP. NaOH-SRP in SP increased gradually under sedimentation conditions. It is suggested that, during sedimentation, mobile P can be transformed to non-mobile P forms that provide long-term P retention. The findings contribute to the understanding of P cycling in particulate matter during sediment resuspension and sedimentation. PMID- 25703616 TI - On the use of Arion ater to biomonitor environmental pollution by Cd, Cu, Fe, Mn and Zn, with a special insight into the population variability. AB - The suitability of Arion ater as a biomonitor of Cd, Cu, Fe, Mn and Zn was assessed. Individual specimens were collected from 22 sampling sites. Slugs from 3 of the sites were analysed individually, whereas the slugs from the other sites were pooled to make a composite sample for each site. The tissue burdens did not differ between individuals from contaminated and uncontaminated sites, and there was no gradient of bioaccumulation of any of the elements in the surroundings of the smelter. Analysis of the individual specimens from the 3 sites revealed very high coefficients of variation for the metal concentrations. As a result of the high level of variation, large numbers of slugs are required to produce a low error in characterizing the mean concentration at each site. Furthermore, as a consequence of the similar mean concentrations and high variability, large numbers of samples are needed to detect significant differences between pairs of sites. PMID- 25703617 TI - Inactivation of Escherichia coli in fresh water with advanced oxidation processes based on the combination of O3, H2O2, and TiO2. Kinetic modeling. AB - The purpose of this work was to study the efficiency of different treatments, based on the combination of O3, H2O2, and TiO2, on fresh surface water samples fortified with wild strains of Escherichia coli. Moreover, an exhaustive assessment of the influence of the different agents involved in the treatment has been carried out by kinetic modeling of E. coli inactivation results. The treatments studied were (i) ozonation (O3), (ii) the peroxone system (O3/0.04 mM H2O2), (iii) catalytic ozonation (O3/1 g/L TiO2), and (iv) a combined treatment of O3/1 g/L TiO2/0.04 mM H2O2. It was observed that the peroxone system achieved the highest levels of inactivation of E. coli, around 6.80 log after 10 min of contact time. Catalytic ozonation also obtained high levels of inactivation in a short period of time, reaching 6.22 log in 10 min. Both treatments, the peroxone system (O3/H2O2) and catalytic ozonation (O3/TiO2), produced a higher inactivation rate of E. coli than ozonation (4.97 log after 10 min). While the combination of ozone with hydrogen peroxide or titanium dioxide thus produces an increase in the inactivation yield of E. coli regarding ozonation, the O3/TiO2/H2O2 combination did not enhance the inactivation results. The fitting of experimental values to the corresponding equations through non-linear regression techniques was carried out with Microsoft(r) Excel GInaFiT software. The inactivation results of E. coli did not respond to linear functions, and it was necessary to use mathematical models able to describe certain deviations in the bacterial inactivation processes. In this case, the inactivation results fit with mathematical models based on the hypothesis that the bacteria population is divided into two different subgroups with different degrees of resistance to treatments, for instance biphasic and biphasic with shoulder models. Graphical abstract ?. PMID- 25703618 TI - Ecophysiological and foliar nitrogen concentration responses of understorey Acacia spp. and Eucalyptus sp. to prescribed burning. AB - Eucalyptus spp. is a dominant tree genus in Australia and most Eucalyptus spp. are canopy dominant species. In Australian natural forests, Eucalyptus spp. commonly are associated with understorey legumes which play a crucial role for ecological restoration owing to their nitrogen (N) fixing ability for replenishing the soil N lost after frequent prescribed burning. This study aimed to explore to what extent physiological responses of these species differ 7 and 12 years after last fire. Two most common understorey Acacia spp., Acacia leiocalyx and A. disparrima, as well as one non-leguminous Eucalyptus resinifera, were studied due to their dominance in the forest. Both A. leiocalyx and A. disparrima showed higher carbon (C) assimilation capacity, maximum photosynthetic capacity, and moderate foliar C/N ratio compared with E. resinifera. A. leiocalyx showed various advantages compared to A. disparrima such as higher photosynthetic capacity, adaptation to wider light range and higher foliar total N (TNmass). A. leiocalyx also relied on N2-fixing ability for longer time compared to A. disparrima. The results suggested that the two Acacia spp. were more beneficial to C and N cycles for the post burning ecosystem than the non-N2-fixing species E. resinifera. A. leiocalyx had greater contribution to complementing soil N cycle long after burning compared to A. disparrima. PMID- 25703619 TI - Depth, soil type, water table, and site effects on microbial community composition in sediments of pesticide-contaminated aquifer. AB - Microbial community compositions in pesticide-contaminated aquifers have not been studied, although such information is important for remediation and maintaining freshwater sources clean under changing climate. Therefore, phospholipid (PLFAs), glycolipid (GLFAs), and neutral lipid (NLFAs) fatty acids were determined from sand and clay sediments at depths of 0.3-24.8 m, all contaminated with triazines and dichlobenil/2,6-dichlorobenzamide. The portion of fungi and Gram-negative bacteria at 0.3 m was greater than at 0.8 m, where the percentage of Gram positive bacteria, actinobacteria, and sulfate-reducing bacteria (SRB) increased. In deeper sediments, microbial biomass, activity, and diversity decreased. Clay sediments seemed to serve as a reservoir for slow pesticide elution to groundwater, and their biomarker portion for all bacteria except actinobacteria was greater than in sand sediments. The slow pesticide dissipation seemed to occur in the main groundwater flow zone, resulting in nitrogen release simultaneously with organic matter elution from gardening and bank filtration. As a result, microbial biomass, activity, and diversity were increased. This shift in conditions towards that in surface soil may be appropriate for enhanced natural attenuation of pesticides in groundwater sources. PMID- 25703620 TI - The relationship between neuropsychological functioning and FDG-PET hypometabolism in intractable mesial temporal lobe epilepsy. AB - We examined the relationship between baseline neuropsychological functioning and 18-fluorodeoxyglucose positron emission tomography (FDG-PET) in intractable mesial temporal lobe epilepsy (MTLE). We hypothesized relationships between dominant temporal lobe hypometabolism and verbal memory and between nondominant temporal lobe hypometabolism and nonverbal memory in line with the lateralized material-specific model of memory deficits in MTLE. We also hypothesized an association between performance on frontal lobe neuropsychological tests and prefrontal hypometabolism. Thirty-two patients who had undergone temporal lobectomy for treatment of MTLE and who completed both presurgical FDG-PET and comprehensive neuropsychological investigations with widely used standardized measures were included. Age-adjusted composite measures were calculated for verbal memory, nonverbal memory, relative material-specific memory, IQ, executive function, attention/working memory, and psychomotor speed. Fluorodeoxyglucose positron emission tomography was analyzed with statistical parametric mapping (SPM) to identify hypometabolism relative to healthy controls. Pearson's correlation was used to determine the relationship between regions of hypometabolism and neuropsychological functioning. Dominant temporal lobe hypometabolism was associated with relatively inferior verbal memory, while nondominant temporal lobe hypometabolism was associated with inferior nonverbal memory. No relationship was found between performance on any frontal lobe measures and prefrontal hypometabolism. Statistical parametric mapping-quantified lateralized temporal lobe hypometabolism correlates with material-specific episodic memory impairment in MTLE. In contrast, prefrontal hypometabolism is not associated with performance on frontal lobe measures. We suggest that this is because frontal lobe neuropsychology tests may not be good measures of isolated frontal lobe functioning. PMID- 25703621 TI - G protein-coupled estrogen receptor-mediated effects on cytosolic calcium and nanomechanics in brain microvascular endothelial cells. AB - G protein-coupled estrogen receptor (GPER) is a relatively recently identified non-nuclear estrogen receptor, expressed in several tissues, including brain and blood vessels. The mechanisms elicited by GPER activation in brain microvascular endothelial cells are incompletely understood. The purpose of this work was to assess the effects of GPER activation on cytosolic Ca(2+) concentration, [Ca(2+)](i), nitric oxide production, membrane potential and cell nanomechanics in rat brain microvascular endothelial cells (RBMVEC). Extracellular but not intracellular administration of G-1, a selective GPER agonist, or extracellular administration of 17-beta-estradiol and tamoxifen, increased [Ca(2+)](i) in RBMVEC. The effect of G-1 on [Ca(2+)](i) was abolished in Ca(2+) -free saline or in the presence of a L-type Ca(2+) channel blocker. G-1 increased nitric oxide production in RBMVEC; the effect was prevented by NG-nitro-l-arginine methyl ester. G-1 elicited membrane hyperpolarization that was abolished by the antagonists of small and intermediate-conductance Ca(2+) -activated K(+) channels, apamin, and charibdotoxin. GPER-mediated responses were sensitive to G 36, a GPER antagonist. In addition, atomic force microscopy studies revealed that G-1 increased the modulus of elasticity, indicative of cytoskeletal changes and increase in RBMVEC stiffness. Our results unravel the mechanisms underlying GPER mediated effects in RBMVEC with implications for the effect of estrogen on cerebral microvasculature. Activation of the G protein-coupled estrogen receptor (GPER) in rat brain microvascular endothelial cells (RBMVEC) increases [Ca(2+)](i) by promoting Ca(2+) influx. The increase in [Ca(2+)](i) leads to membrane hyperpolarization, nitric oxide (NO) production, and to cytoskeletal changes and increased cell stiffness. Our results unravel the mechanisms underlying GPER-mediated effects in RBMVEC with implications for the effect of estrogen on cerebral microvasculature. PMID- 25703622 TI - Bronchogenic cyst in the chin region. PMID- 25703623 TI - Binge drinking and eating problems in Russian adolescents. AB - BACKGROUND: Binge drinking may be linked to problematic eating behavior, although as yet, little research has been conducted on this association. The objective of this study was to examine the relationship between binge drinking and eating problems in Russian adolescents. METHODS: Data were drawn from the Social and Health Assessment, a cross-sectional school-based survey of 6th to 10th grade students (aged 12 to 17 years old) carried out in Arkhangelsk, Russia. Information was collected on various eating problems (worries about weight, feeling fat, excessive eating, fasting and excessive exercise, and purging behaviors) and binge drinking (5 or more drinks in a row). Logistic regression analysis was used to examine the relationship between binge drinking and eating problems. RESULTS: Among the 2,488 adolescents included in the statistical analysis, nearly 50% of girls expressed worries about their weight, while 35.0 and 41.5% of adolescent boys and girls reported excessive eating, respectively. The prevalence of purging behaviors (vomiting/using laxatives) was, however, much lower among both sexes (females-2.6%; males-3.3%). In a regression model adjusted for demographic factors and depressive symptoms, among girls, binge drinking was associated with 5 of the 6 eating problems with odds ratios (ORs) ranging from 1.21 (upset about weight gain) to 1.68 (excessive eating). For boys, binge drinking was linked to feeling overweight (OR: 1.47, confidence interval [CI]: 1.20 to 1.81) and vomiting/used laxatives (OR: 4.13, CI: 1.58 to 10.80). CONCLUSIONS: Many adolescents in Russia report problematic eating attitudes and behaviors, and eating problems are associated with binge drinking. More research is now needed in this setting to better understand adolescent eating problems and their association with alcohol misuse, so that contextually suitable interventions can be implemented to reduce these behaviors and mitigate their potentially detrimental effects. PMID- 25703624 TI - Electrifying white biotechnology: engineering and economic potential of electricity-driven bio-production. AB - Invited for the cover of this issue are the groups of Falk Harnisch at the Helmholtz Centre for Environmental Research (Germany) and his collaboration partners at The University of Queensland (Australia). The image depicts their vision of the world, if "electrification" of white biotechnology comes true. The Concept itself is available at 10.1002/cssc.201402736. PMID- 25703625 TI - Correlative 3D-imaging of Pipistrellus penis micromorphology: Validating quantitative microCT images with undecalcified serial ground section histomorphology. AB - Detailed knowledge of histomorphology is a prerequisite for the understanding of function, variation, and development. In bats, as in other mammals, penis and baculum morphology are important in species discrimination and phylogenetic studies. In this study, nondestructive 3D-microtomographic (microCT, uCT) images of bacula and iodine-stained penes of Pipistrellus pipistrellus were correlated with light microscopic images from undecalcified surface-stained ground sections of three of these penes of P. pipistrellus (1 juvenile). The results were then compared with uCT-images of bacula of P. pygmaeus, P. hanaki, and P. nathusii. The Y-shaped baculum in all studied Pipistrellus species has a proximal base with two club-shaped branches, a long slender shaft, and a forked distal tip. The branches contain a medullary cavity of variable size, which tapers into a central canal of variable length in the proximal baculum shaft. Both are surrounded by a lamellar and a woven bone layer and contain fatty marrow and blood vessels. The distal shaft consists of woven bone only, without a vascular canal. The proximal ends of the branches are connected with the tunica albuginea of the corpora cavernosa via entheses. In the penis shaft, the corpus spongiosum-surrounded urethra lies in a ventral grove of the corpora cavernosa, and continues in the glans under the baculum. The glans penis predominantly comprises an enlarged corpus spongiosum, which surrounds urethra and baculum. In the 12 studied juvenile and subadult P. pipistrellus specimens the proximal branches of the baculum were shorter and without marrow cavity, while shaft and distal tip appeared already fully developed. The present combination with light microscopic images from one species enabled a more reliable interpretation of histomorphological structures in the uCT-images from all four Pipistrellus species. PMID- 25703626 TI - Effects of benthos, temperature, and dose on the fate of hexabromocyclododecane in experimental coastal ecosystems. AB - The authors studied the fate of the brominated flame retardant hexabromocyclododecane (HBCDD) added in a particulate suspension to experimental ecosystems assembled from brackish (Baltic Sea) coastal bays. Two experiments examined how benthic macrofauna (over 21 d) and increased temperature (14 d) affected HBCDD concentrations and fractionation of alpha, beta, and gamma diastereomers in the water, sediment, and biota. A third experiment run over 3 seasons (231 d), studied the effect of HBCDD dose on the same endpoints. In all treatments of the 3 experiments, HBCDD partitioned mainly to the sediment, and this proportion increased with time. Presence of macrofauna tended to increase the HBCDD concentration in the sediment and decreased its concentration in the water. Increased temperature (+ 5 degrees C) decreased the amount of HBCDD in sediment and water but not in the filter- and deposit-feeding infaunal bivalves (Macoma balthica). The partitioning between water, sediment, and biota was not concentration dependent. In all treatments, sediment became enriched in gamma HBCDD, M. balthica in alpha-HBCDD, and water in alpha- and beta-HBCDD. Bioaccumulation of HBCDD in M. balthica was high in all experiments (log biota sediment accumulation factor [BSAF] > 1.25), the alpha diastereomer contributing the most (log BSAF 2.1-5.2). There is a risk of trophic transfer of HBCDD from benthic to pelagic food webs, as well as secondary poisoning of marine consumers. PMID- 25703627 TI - Genetic heterogeneity and clinical variability in musculocontractural Ehlers Danlos syndrome caused by impaired dermatan sulfate biosynthesis. AB - Bi-allelic variants in CHST14, encoding dermatan 4-O-sulfotransferase-1 (D4ST1), cause musculocontractural Ehlers-Danlos syndrome (MC-EDS), a recessive disorder characterized by connective tissue fragility, craniofacial abnormalities, congenital contractures, and developmental anomalies. Recently, the identification of bi-allelic variants in DSE, encoding dermatan sulfate epimerase 1 (DS-epi1), in a child with MC-EDS features, suggested locus heterogeneity for this condition. DS-epi1 and D4ST1 are crucial for biosynthesis of dermatan sulfate (DS) moieties in the hybrid chondroitin sulfate (CS)/DS glycosaminoglycans (GAGs). Here, we report four novel families with severe MC-EDS caused by unique homozygous CHST14 variants and the second family with a homozygous DSE missense variant, presenting a somewhat milder MC-EDS phenotype. The glycanation of the dermal DS proteoglycan decorin is impaired in fibroblasts from D4ST1- as well as DS-epi1-deficient patients. However, in D4ST1-deficiency, the decorin GAG is completely replaced by CS, whereas in DS-epi1-deficiency, still some DS moieties are present. The multisystemic abnormalities observed in our patients support a tight spatiotemporal control of the balance between CS and DS, which is crucial for multiple processes including cell differentiation, organ development, cell migration, coagulation, and connective tissue integrity. PMID- 25703628 TI - Mitochondrial division and fusion in metabolism. AB - Mitochondria govern many metabolic processes. In addition, mitochondria sense the status of metabolism and change their functions to regulate energy production, cell death, and thermogenesis. Recent studies have revealed that mitochondrial structural remodeling through division and fusion is critical to the organelle's function. It has also become clear that abnormalities in mitochondrial division and fusion are linked to the pathophysiology of metabolic diseases such as diabetes and obesity. Here, we discuss the current understanding of the mechanisms of mitochondrial dynamics and their role in cellular and organismal metabolism. PMID- 25703629 TI - The life cycle of lipid droplets. AB - Proteomic studies have revealed many potential functions of cytoplasmic lipid droplets, and recent activity has confirmed that these bona fide organelles are central not only for lipid storage and metabolism, but for development, immunity, and pathogenesis by several microbes. There has been a burst of recent activity on the assembly, maintenance and turnover of lipid droplets that reveals fresh insights. This review summarizes several novel findings in initiation of lipid droplet assembly, protein targeting, droplet fusion, and turnover of droplets through lipophagy. PMID- 25703631 TI - Role of probiotics in prevention of Candida colonization and invasive candidiasis. PMID- 25703630 TI - Acetyl-CoA and the regulation of metabolism: mechanisms and consequences. AB - Acetyl-CoA represents a key node in metabolism due to its intersection with many metabolic pathways and transformations. Emerging evidence reveals that cells monitor the levels of acetyl-CoA as a key indicator of their metabolic state, through distinctive protein acetylation modifications dependent on this metabolite. We offer the following conceptual model for understanding the role of this sentinel metabolite in metabolic regulation. High nucleocytosolic acetyl-CoA amounts are a signature of a 'growth' or 'fed' state and promote its utilization for lipid synthesis and histone acetylation. In contrast, under 'survival' or 'fasted' states, acetyl-CoA is preferentially directed into the mitochondria to promote mitochondrial-dependent activities such as the synthesis of ATP and ketone bodies. Fluctuations in acetyl-CoA within these subcellular compartments enable the substrate-level regulation of acetylation modifications, but also necessitate the function of sirtuin deacetylases to catalyze removal of spontaneous modifications that might be unintended. Thus, understanding the sources, fates, and consequences of acetyl-CoA as a carrier of two-carbon units has started to reveal its underappreciated but profound influence on the regulation of numerous life processes. PMID- 25703632 TI - When the spleen meets the fetus. AB - Patient's first pregnancy was complicated by mild thrombocytopenia caused by a 13 cm splenic cyst, who delivered vaginally without complication. Risks and management of maternal splenic cysts in pregnancy and delivery are reviewed here. PMID- 25703633 TI - Assessing vitamin D status in infants with very low birth weight. PMID- 25703634 TI - Radiation Exposure and Contrast Volume Differ between Transapical and Transfemoral Aortic Valve Implantation with the Edwards SAPIEN Aortic Valve. AB - BACKGROUND: To date, little is known about the radiation exposure and the amount of contrast medium given during the transcatheter aortic valve implantation (TAVI) procedure. This study compares our data between the transfemoral (TF) approach and the transapical (TA) approach. PATIENTS AND METHODS: A total of 216 TA and 180 TF implantations of the Edwards SAPIEN (Edwards Lifesciences, Irvine, California, United States) valve were consecutively performed by our heart team, consisting of cardiac surgeons and cardiologists. Fluoroscopy time, dose area product, and contrast volume were compared between both the approaches. RESULTS: TF-TAVI showed higher values of fluoroscopy time (13.1 +/- 5.9 vs. 7.0 +/- 5.7 minutes, p < 0.001), dose area product (5.0 +/- 3.9 vs. 2.7 +/- 1.9 mGy.m(2), p < 0.001), and contrast volume (196.7 +/- 72.7 vs. 109.2 +/- 33.8 mL, p < 0.001). All physicians performing the TF approach exceeded the mean values of the surgeons performing the TA approach. Some physicians showed a trend toward lower values with growing experience. Vascular complications and postdilatation had only a minor impact on the study parameters. CONCLUSION: TA-TAVI showed an advantage over TF-TAVI in terms of lower fluoroscopy time, dose area product, and contrast use. This was hardly reflected in the past and should be considered when comparing invasiveness of both methods. However, human factors also play a role as most physicians showed a learning curve toward lower values over time. PMID- 25703635 TI - Hematologic Effects of Heart Valve Prostheses and Vascular Grafts after Aortic Root Replacement. AB - BACKGROUND: Heart valve prosthesis as well as vascular grafts cause changes in blood parameters. This may correlate with valve-related complications, less frequently observed after repair surgery. We thus studied changes in rheology after Bentall, Ross, or Tirone David (TD) procedure. METHODS: Seventeen patients underwent a TD, 17 patients underwent a Ross, and 16 patients underwent a Bentall procedure. Venous blood samples were collected 4 +/- 3 (TD), 4 +/- 3 (Ross), and 6 +/- 3 years mean (Bentall) postoperatively. Concentrations of fibrinogen, leucocytes, platelets, haptoglobin, hemoglobin, lactate dehydrogenase (LDH), bilirubin, hematocrit, and beta-thromboglobulin were determined. Platelet function and activity were analyzed. Results were compared with those of healthy control subjects. RESULTS: Level of fibrinogen was higher in the Bentall than in the other two groups (338 +/- 63 vs. 298 +/- 43 Ross and 308 +/- 48 mg/dL TD, p > 0.05). LDH was also elevated in the Bentall group (311 +/- 45 vs. 205 +/- 30 Ross, p < 0.01 and 203 +/- 34 U/l TD, p < 0.01). Platelet count and haptoglobin levels were significantly reduced in the Bentall (190 +/- 43/nL, 2.4 +/- 1 mg/dL) and TD groups (183 +/- 52/nL, 89 +/- 57 mg/dL) in comparison to the control group (250 +/- 86/nL, 140 +/- 53 mg/dL) with p < 0.05, whereas there were no significant differences in the Ross group (214 +/- 47/nL and 129 +/- 54 mg/dL) in comparison to the control group. Leucocyte count and platelet function showed no significant differences between the groups. CONCLUSION: Polyester ascending aortic prostheses and more pronounced when combined with a prosthetic aortic valve cause hematologic changes compared with minimal deviations in Ross patients. We observed mild hemolysis, a decreased platelet count, and an increase in fibrinogen level in patients after conduit root replacement compared with procedures retaining an autologous aortic valve at midterm follow-up. PMID- 25703636 TI - Video-assisted thoracoscopic thymectomy surgery: Tor Vergata experience. AB - The therapeutic effect of thymectomy on myasthenia gravis is not completely understood. Several types of thymectomy varying in approach and extent have been performed. None of these disclosed a neat superiority over others. Patients desire thymectomy through small, painless, and cosmetically favorable operations. Video-assisted thoracoscopic surgery (VATS) thymectomy fits all these requests as well as that of the surgeon. Indeed, this approach allows for ample operative space, easy maneuverability, and extended thymectomy. No mortality, low morbidity, faster recovery, short hospital stay, and small economical costs are undoubtedly advantages of VATS over transsternal and transcervical thymectomy. In the near future, the introduction of robotic devices will lead to a new era in the surgery of the thymus. Herein we analyzed our comprehensive experience. PMID- 25703637 TI - Recurrence rate after absorbable tack fixation of mesh in laparoscopic incisional hernia repair. AB - BACKGROUND: The mesh fixation technique in laparoscopic incisional hernia repair may influence the rates of hernia recurrence and chronic pain. This study investigated the long-term risk of recurrence and chronic pain in patients undergoing laparoscopic incisional hernia repair with either absorbable or non absorbable tacks for mesh fixation. METHODS: This was a nationwide consecutive cohort study based on data collected prospectively concerning perioperative information and clinical follow-up. Patients undergoing primary, elective, laparoscopic incisional hernia repair with absorbable or non-absorbable tack fixation during a 4-year interval were included. Follow-up was by a structured questionnaire regarding recurrence and chronic pain, supplemented by clinical examination, and CT when indicated. Recurrence was defined as either reoperation for recurrence or clinical/radiological recurrence. RESULTS: Of 1037 eligible patients, 84.9 per cent responded to the questionnaire, and 816 were included for analysis. The median observation time for the cohort was 40 (range 0-72) months. The cumulative recurrence-free survival rate was 71.5 and 82.0 per cent after absorbable and non-absorbable tack fixation respectively (P = 0.007). In multivariable analysis, the use of absorbable tacks was an independent risk factor for recurrence (hazard ratio 1.53, 95 per cent c.i. 1.11 to 2.09; P = 0.008). The rate of moderate or severe chronic pain was 15.3 and 16.1 per cent after absorbable and non-absorbable tack fixation respectively (P = 0.765). CONCLUSION: Absorbable tack fixation of the mesh was associated with a higher risk of recurrence than non-absorbable tacks for laparoscopic mesh repair of incisional hernia, but did not influence chronic pain. PMID- 25703638 TI - Sunscreen use in patients with cutaneous lupus erythematosus. PMID- 25703639 TI - Analysis of signs and pathology of H5N1-infected ducks from the 2010-2011 Korean highly pathogenic avian influenza outbreak suggests the influence of age and management practices on severity of disease. AB - We compared the clinical signs, histopathological lesions and distribution of viral antigens among infected young (meat-type) and older (breeder) ducks that were naturally infected with the highly pathogenic avian influenza (HPAI) virus during the 2010-2011 Korean outbreak. The meat-type ducks had a high mortality rate (30%) and showed severe neurological signs such as head tremors and paresis. In contrast, HPAI-infected breeder ducks had minimal clinical signs but a decreased egg production rate. The histopathological characteristics of infected meat-type ducks included necrotic lesions of heart and brain, which may have primarily contributed to the high mortality rate. In contrast, the breeder ducks only presented necrotic splenitis, and viral antigens were only detected in the trachea, lungs and spleen. Younger ducks had a high viral titre in the organs, high levels of viral shedding and a high mortality rate after experimental HPAI virus infection. Compared to the breeder ducks, the meat-type ducks were raised in smaller farms that had poor quarantine and breeding facilities. It is therefore possible that better biosecurity in the breeder farms could have reduced the infection dose and subsequently the severity of the disease. Thus, age and management may be the influencing factors for HPAI susceptibility in ducks. PMID- 25703640 TI - Retroperitoneal hematoma after using the extreme lateral interbody fusion (XLIF) approach: Presentation of a case and a review of the literature. AB - The transpsoas approach, also known as extreme lateral interbody fusion (XLIF), to the lumbar spine is a novel minimally invasive technique with positive clinical outcomes and a low complication rate. There is a low risk of bleeding, due to this approach causing less soft tissue disruption than traditional spine surgery, but segmental arteries and great vessels can be damaged. Retroperitoneal haematoma is a major complication, with few cases reported. This is the first case reported in a Stand-alone XLIF and also the first case reported with haemorrhagic shock. Non-specific symptoms such tachycardia, hypotension, and anaemia are the most prevalent in this complication. With this case, our aim is to describe serious complications related to XLIF. PMID- 25703641 TI - Effect of operational conditions on sonoluminescence and kinetics of H2O2 formation during the sonolysis of water in the presence of Ar/O2 gas mixture. AB - Ultrasonic frequency is a key parameter determining multibubble sonoluminescence (MBSL) spectra of water saturated with Ar/O2 gas mixtures. At 20 kHz, the MBSL is quenched by oxygen. By contrast, at high-frequency ultrasound the maximal MBSL intensity is observed in the presence of Ar/20%O2 gas mixture. Nevertheless, oxygen has no influence on the shape of MBSL spectra. The effect of oxygen on MBSL is explained by oxygen dissociation inside the collapsing bubble which is much more effective at high ultrasonic frequency compared to 20 kHz ultrasound. In contrast to MBSL, a higher yield of H2O2 is observed in Ar/20%O2 gas mixture whatever the ultrasonic frequency. At 20 degrees C and 20% of oxygen the maximal yield of H2O2 is observed at 204-362 kHz. The maximal yield of H2O2 is shifted to 613kHz when the bulk temperature is raised up to 40 degrees C. Coupling of high frequency ultrasound with mechanical stirring and intensive Ar/O2 bubbling improves H2O2 production. Comparison of MBSL and sonochemistry allowed to conclude that H2O2 is formed from non-excited OH (X(2)Pi) and HO2 radicals. Finally, it was shown that at the studied conditions the efficiency of ultrasonic degassing is hardly influenced by frequency. PMID- 25703642 TI - Vemurafenib-induced hyperkeratosis of the areola treated with topical adapelene. AB - We present a rare condition, hyperkeratosis of the areola, induced by vemurafenib. Only a few papers have described an association of BRAF inhibitors with hyperkeratosis of the areola and/or nipple. Vemurafenib is a selective BRAF inhibitor used in patients with unresectable or metastatic melanoma who are positive for the V600 mutation. This drug has been associated with numerous cutaneous side effects, both benign and malignant. We report a male patient with vemurafenib-induced hyperkeratosis of the areola managed successfully with a topical retinoid, and describe for the first time a treatment for this side effect. PMID- 25703643 TI - Adjunctive treatment with melatonin receptor agonists for older delirious patients with the sundowning phenomenon. PMID- 25703644 TI - Can the neurodevelopmental theory account for sex differences in schizophrenia across the life span? PMID- 25703645 TI - Disadvantageous decision-making on a rodent gambling task is associated with increased motor impulsivity in a population of male rats. AB - BACKGROUND: Impulsivity is understood as a range of behaviours, but the association between these behaviours is not well understood. Although high motor impulsivity is a key symptom of disorders like pathological gambling and addiction, in which decision-making on laboratory tasks is compromised, there have been no clear demonstrations that choice and motor impulsivity are associated in the general population. We examined this association in a large population of rodents. METHODS: We performed a meta-analysis on behavioural data from 211 manipulation-naive male animals that performed a rodent gambling task in our laboratory between 2008 and 2012. The task measures an aspect of both impulsive decision-making and impulsive action, making it possible to evaluate whether these 2 forms of maladaptive behaviour are related. RESULTS: Our meta analysis revealed that motor impulsivity was positively correlated with poor decision-making under risk. Highly motor impulsive rats were slower to adopt an advantageous choice strategy and quicker to make a choice on individual trials. LIMITATIONS: The data analyzed were limited to that produced by our laboratory and did not include data of other researchers who have used the task. CONCLUSION: This work may represent the first demonstration of a clear association between choice and motor impulsivity in a nonclinical population. This lends support to the common practice of studying impulsivity in nonclinical populations to gain insight into impulse control disorders and suggests that differences in impulsive behaviours between clinical and nonclinical populations may be ones of magnitude rather than ones of quality. PMID- 25703646 TI - Sad mood induction has an opposite effect on amygdala response to emotional stimuli in euthymic patients with bipolar disorder and healthy controls. AB - BACKGROUND: Aberrant amygdala reactivity to affective stimuli represents a candidate factor predisposing patients with bipolar disorder (BD) to relapse, but it is unclear to what extent amygdala reactivity is state-dependent. We evaluated the modulatory influence of mood on amygdala reactivity and functional connectivity in patients with remitted BD and healthy controls. METHODS: Amygdala response to sad versus neutral faces was investigated using fMRI during periods of normal and sad mood induced by autobiographical scripts. We assessed the functional connectivity of the amygdala to characterize the influence of mood state on the network responsible for the amygdala response. RESULTS: We included 20 patients with remitted BD and 20 controls in our study. The sad and normal mood exerted opposite effects on the amygdala response to emotional faces in patients compared with controls (F1,38 = 5.85, p = 0.020). Sad mood amplified the amygdala response to sad facial stimuli in controls but attenuated the amygdala response in patients. The groups differed in functional connectivity between the amygdala and the inferior prefrontal gyrus (p <= 0.05, family-wise error corrected) of ventrolateral prefrontal cortex (vlPFC) corresponding to Brodmann area 47. The sad mood challenge increased connectivity during the period of processing sad faces in patients but decreased connectivity in controls. LIMITATIONS: Limitations to our study included long-term medication use in the patient group and the fact that we mapped only depressive (not manic) reactivity. CONCLUSION: Our results support the role of the amygdala-vlPFC as the system of dysfunctional contextual affective processing in patients with BD. Opposite amygdala reactivity unmasked by the mood challenge paradigm could represent a trait marker of altered mood regulation in patients with BD. PMID- 25703647 TI - Topical administration of a connexin43-based peptide augments healing of chronic neuropathic diabetic foot ulcers: A multicenter, randomized trial. AB - Nonhealing neuropathic foot ulcers remain a significant problem in individuals with diabetes. The gap-junctional protein connexin43 (Cx43) has roles in dermal wound healing and targeting Cx43 signalling accelerates wound reepithelialization. In a prospective, randomized, multicenter clinical trial we evaluated the efficacy and safety of a peptide mimetic of the C-terminus of Cx43, alpha connexin carboxy-terminal (ACT1), in accelerating the healing of chronic diabetic foot ulcers (DFUs) when incorporated into standard of care (SOC) protocols. Adults with DFUs of at least four weeks duration were randomized to receive SOC with or without topical application of ACT1. Primary outcome was mean percent ulcer reepithelialization and safety variables included incidence of treatment related adverse events (AEs) and detection of ACT1 immunogenicity. ACT1 treatment was associated with a significantly greater reduction in mean percent ulcer area from baseline to 12 weeks (72.1% vs. 57.1%; p = 0.03). Analysis of incidence and median time-to-complete-ulcer closure revealed that ACT1 treatment was associated with a greater percentage of participants that reached 100% ulcer reepitheliazation and a reduced median time-to-complete-ulcer closure. No AEs reported were treatment related, and ACT1 was not immunogenic. Treatment protocols that incorporate ACT1 may present a therapeutic strategy that safely augments the reepithelialization of chronic DFUs. PMID- 25703648 TI - Early risk stratification in pediatric type 1 diabetes. AB - In the late 1980s all Danish children with type 1 diabetes were invited for a nationwide evaluation of glycemic control. Approximately 75% (n = 720) participated and have later been referred to as The Danish Cohort of Pediatric Diabetes 1987 (DCPD1987). The results were surprisingly poor glycemic control among these young patients which lead to a great emphasis on glycemic control in the Danish Pediatric Departments. In 1995 the participants were invited for yet another evaluation but this time with main focus on early signs of microvascular complications - 339 participated. The mean HbA1c had remained at high levels (9.6%) and 60% of the participants had some level of Diabetic Retinopathy (DR). However, as the patients with DR mostly had the very milder forms it was believed that stricter glycemic control would reverse or at least stop progression of the disease in accordance with results from the large intervention study DCCT. This was investigated further at follow-up in 2011. The first study in the present thesis aimed to describe the 16-year incidence, progression and regression of DR in 185 participants from the DCPD1987 cohort. The 16-year incidence of proliferative retinopathy (PDR), 2-step progression and regression of DR was 31.0, 64.4, and 0.0%, respectively. As expected, the participants with PDR at follow-up had significantly higher HbA1c-values at both baseline and follow-up than those without PDR. However; a significantly larger decrease in HbA1c was also observed in the group with PDR over the study period, which in accordance with DCCT should have prevented the development of PDR to some extent. A surprisingly high incidence of proliferative retinopathy amongst young patients with type 1 diabetes in Denmark was found despite improvements in HbA1c over time. The improvement in HbA1c was either too small or happened too late. This study highlights that sight-threatening diabetic retinopathy remain a major concern in type 1 diabetes and the importance of early glycemic control. Identifying high-risk patients at a very early stage is not only desired for prevention of diabetic retinopathy - neuropathy and nephropathy similarly remain frequent in type 1 diabetes. Early risk stratification will allow for timely implementation of effective interventions and for individualized screening and diabetes care. The second and third studies of this thesis provide the longest prospective studies to date on both retinal vessel calibers and retinal fractal dimensions and their predictive value on diabetic microvascular complications. Semi-automated computer software has been developed to measure smaller changes in the retinal vessels on retinal photographs. Two of the first parameters to be reliably estimated by these programs were retinal vessel calibers and retinal vascular fractal dimensions (a quantitative measure on vascular complexity). There is very limited knowledge on their predictive value on diabetic complications thus far. In the second and third study, a consistent relation between narrower retinal arteriolar calibers, wider retinal venular calibers, lower fractal dimensions and the 16-year incidences of diabetic neuropathy, nephropathy and proliferative retinopathy was found. This has never been shown before. The results on vessel analyzes provides indications of a common pathogenic pathway for diabetic microvascular complications and therefore a possibility of universal risk estimation for development of neuropathy, nephropathy and retinopathy in type 1 diabetes. PMID- 25703649 TI - Progress in unraveling the genetic etiology of Parkinson disease in a genomic era. AB - Parkinson disease (PD) and Parkinson-plus syndromes are genetically heterogeneous neurological diseases. Initial studies into the genetic causes of PD relied on classical molecular genetic approaches in well-documented case families. More recently, these approaches have been combined with exome sequencing and together have identified 15 causal genes. Additionally, genome-wide association studies (GWASs) have discovered over 25 genetic risk factors. Elucidation of the genetic architecture of sporadic and familial parkinsonism, however, has lagged behind that of simple Mendelian conditions, suggesting the existence of features confounding genetic data interpretation. Here we discuss the successes and potential pitfalls of gene discovery in PD and related disorders in the post genomic era. With an estimated 30% of trait variance currently unexplained, tackling current limitations will further expedite gene discovery and lead to increased application of these genetic insights in molecular diagnostics using gene panel and exome sequencing strategies. PMID- 25703650 TI - Is magnetic resonance imaging of hepatic hemangioma any different in liver fibrosis and cirrhosis compared to normal liver? AB - PURPOSE: To compare qualitative and quantitative magnetic resonance (MR) imaging characteristics of hepatic hemangiomas in patients with normal, fibrotic and cirrhotic livers. MATERIALS AND METHODS: Retrospective, institutional review board approved study (waiver of informed consent). Eighty-nine consecutive patients with 231 hepatic hemangiomas who underwent liver MR imaging for lesion characterization were included. Lesions were classified into three groups according to the patients' liver condition: no underlying liver disease (group 1), fibrosis (group 2) and cirrhosis (group 3). Qualitative and quantitative characteristics (number, size, signal intensities on T1-, T2-, and DW MR images, T2 shine-through effect, enhancement patterns (classical, rapidly filling, delayed filling), and ADC values) were compared. RESULTS: There were 160 (69%), 45 (20%), and 26 (11%) hemangiomas in groups 1, 2 and 3, respectively. Lesions were larger in patients with normal liver (group 1 vs. groups 2 and 3; P=.009). No difference was found between the groups on T2-weighted images (fat-suppressed fast spin-echo (P=.82) and single-shot (P=.25)) and in enhancement patterns (P=.56). Mean ADC values of hemangiomas were similar between groups 1, 2 and 3 (2.11+/-.52*10(-3) mm(2)/s, 2.1+/-.53*10(-3) mm(2)/s and 2.14+/-.44*10(-3) mm(2)/s, P=87, respectively). T2 shine-through effect was less frequently observed in cirrhosis (P=.02). CONCLUSION: MR imaging characteristics of hepatic hemangioma were similar in patients with normal compared to fibrotic and cirrhotic livers. Smaller lesion size was observed with liver disease and less T2 shine-through effect was seen in hemangiomas developed on cirrhosis, the latter being an important finding to highlight in these patients at risk of developing hepatocellular carcinoma. PMID- 25703651 TI - Extraction of force-chain network architecture in granular materials using community detection. AB - Force chains form heterogeneous physical structures that can constrain the mechanical stability and acoustic transmission of granular media. However, despite their relevance for predicting bulk properties of materials, there is no agreement on a quantitative description of force chains. Consequently, it is difficult to compare the force-chain structures in different materials or experimental conditions. To address this challenge, we treat granular materials as spatially-embedded networks in which the nodes (particles) are connected by weighted edges that represent contact forces. We use techniques from community detection, which is a type of clustering, to find sets of closely connected particles. By using a geographical null model that is constrained by the particles' contact network, we extract chain-like structures that are reminiscent of force chains. We propose three diagnostics to measure these chain-like structures, and we demonstrate the utility of these diagnostics for identifying and characterizing classes of force-chain network architectures in various materials. To illustrate our methods, we describe how force-chain architecture depends on pressure for two very different types of packings: (1) ones derived from laboratory experiments and (2) ones derived from idealized, numerically generated frictionless packings. By resolving individual force chains, we quantify statistical properties of force-chain shape and strength, which are potentially crucial diagnostics of bulk properties (including material stability). These methods facilitate quantitative comparisons between different particulate systems, regardless of whether they are measured experimentally or numerically. PMID- 25703652 TI - Multiple mechanical complications in ST-segment elevation myocardial infarction with angiographically normal coronary arteries. AB - This case report discusses an unusual presentation of ST-segment elevation myocardial infarction (STEMI) with normal coronary arteries and severe mechanical complications successfully treated with surgery. An 82-year-old man presented STEMI with angiographically normal coronary arteries and no major echocardiographic alterations at discharge. At the first month follow-up, he complained of fatigue and dyspnea, and contrast echocardiography complemented by cardiac magnetic resonance imaging revealed a large left ventricular apical aneurysm with a thrombus communicating by two jets of a turbulent flow to an aneurysmatic formation of the right ventricular apex. The patient underwent a Dor procedure, which was successful. Ventricular septal defects and ventricular aneurysms are rare but devastating complications of STEMI, with almost all patients presenting multivessel coronary artery disease. Interestingly in this case, the angiographic pattern was normal. PMID- 25703653 TI - Elective percutaneous coronary intervention complicated by coronary rupture. PMID- 25703654 TI - Consumer perspectives on the concept of recovery in schizophrenia: A systematic review. AB - Subjective descriptions of recovery from schizophrenia may be different from clinical recovery measures. The aim of the review was to identify the consumer perspectives of recovery from schizophrenia. Twenty-five studies within the period of 2000-2013, including qualitative and quantitative studies were reviewed by using different search strategies. An integrated method was used and the findings were coded and related themes were identified under five areas, namely, process orientation, self orientation, family orientation, social orientation, and illness orientation. Recovery was considered as both process and outcome. Patient or client-based definitions of recovery mainly involved factors related to personal wellbeing and social inclusion, that were seemingly distant from the clinical recovery measures. Incorporating consumer descriptions of recovery in recovery oriented services can increase the outcome of the services. PMID- 25703655 TI - Protease-mediated release of chemotherapeutics from mesoporous silica nanoparticles to ex vivo human and mouse lung tumors. AB - Nanoparticles allow for controlled and targeted drug delivery to diseased tissues and therefore bypass systemic side effects. Spatiotemporal control of drug release can be achieved by nanocarriers that respond to elevated levels of disease-specific enzymes. For example, matrix metalloproteinase 9 (MMP9) is overexpressed in tumors, is known to enhance the metastatic potency of malignant cells, and has been associated with poor prognosis of lung cancer. Here, we report the synthesis of mesoporous silica nanoparticles (MSNs) tightly capped by avidin molecules via MMP9 sequence-specific linkers to allow for site-selective drug delivery in high-expressing MMP9 tumor areas. We provide proof-of-concept evidence for successful MMP9-triggered drug release from MSNs in human tumor cells and in mouse and human lung tumors using the novel technology of ex vivo 3D lung tissue cultures. This technique allows for translational testing of drug delivery strategies in diseased mouse and human tissue. Using this method we show MMP9-mediated release of cisplatin, which induced apoptotic cell death only in lung tumor regions of Kras mutant mice, without causing toxicity in tumor-free areas or in healthy mice. The MMP9-responsive nanoparticles also allowed for effective combinatorial drug delivery of cisplatin and proteasome inhibitor bortezomib, which had a synergistic effect on the (therapeutic) efficiency. Importantly, we demonstrate the feasibility of MMP9-controlled drug release in human lung tumors. PMID- 25703656 TI - Factors that predict in-hospital mortality in eosinophilic granulomatosis with polyangiitis. AB - BACKGROUND: Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare systemic small-vessel vasculitis associated with asthma, eosinophilia, and necrotizing vasculitis. EGPA is potentially life-threatening and often involves peripheral neuropathies, peptic ulcers, cerebral vessel disease, and cardiovascular disease. However, there is limited understanding of the prognostics factors for patients with EGPA. We investigated the clinical features and factors affecting patients' in-hospital mortality, using a national inpatient database in Japan. METHODS: We retrospectively collected data of EGPA patients who required hospitalization between July 2010 and March 2013, using the Diagnosis Procedure Combination database. We evaluated EGPA patients' characteristics and performed multivariate logistic regression analyses to assess the factors associated with in-hospital mortality. RESULTS: A total of 2195 EGPA patients were identified. The mean age was 61.9 years, 42.1% (924/2195) were male, and 41.6% (914/2195) had emergent admission. In-hospital deaths occurred in 97/2195 patients (4.4%). Higher in-hospital mortality was associated with age older than 65 years, disturbance of consciousness on admission, unscheduled admission, respiratory disease, cardio-cerebrovascular disease, renal disease, sepsis, and malignant disease on admission. Lower mortality was associated with female gender and peripheral neuropathies. CONCLUSIONS: Our study revealed the clinical features of EGPA patients who required hospitalization and the factors associated with their mortality. These results may be useful for physicians when assessing disease severity or treatments for hospitalized EGPA patients. PMID- 25703657 TI - Back to the future - a case for home visits for managing severe paediatric obesity. PMID- 25703658 TI - Photocatalytic degradation of methamphetamine by UV/TiO2 - kinetics, intermediates, and products. AB - Methamphetamine (MAT) is a prescription drug and often a substance of abuse. It is found in WWTP influents and effluents as well as surface waters in many regions, elevating concerns about their potential impact. MAT is not effectively removed by conventional processes of domestic wastewater treatment plants (WWTPs). To contemplate advanced treatment, this study evaluates the feasibility of eliminating MAT by UV-illuminated TiO2, a potential retrofit to existing UV disinfection units. The degradation kinetics and mechanism of MAT by TiO2 under low-wattage UV illumination (9 W with maximum output at 365 nm) were investigated. Experimental parameters were varied including the TiO2 loading, MAT concentration, and pH. During treatment, MAT and its intermediates were tracked by HPLC-MS/MS, along with TOC and IC measurements to determine the mineralization extent. In contact with 0.1 g/L of TiO2 under illumination at pH 7, an entire spike amount of 100 MUg/L of MAT was removed from deionized water after 3 min and 76 MUg/L of MAT was removed from the secondary wastewater effluent after 30 min. The degradation of MAT followed an apparent first-order kinetics. Near complete mineralization of MAT from 10 mg/L was achieved in 180 min with 0.1 g/L of TiO2 at pH 5, by which the organic nitrogen was converted to NH4(+) and NO3(-). Based on identified intermediates, two degradation pathways were deduced that involved cleavage of the side chain as well as hydroxylation of the MAT compound. The photocatalytic UV/TiO2 process shows promise in arresting the release of MAT and its intermediate derivatives into the water environment. PMID- 25703659 TI - Alkalinity and pH effects on nitrification in a membrane aerated bioreactor: an experimental and model analysis. AB - A nitrifying biofilm was grown in a laboratory-scale membrane aerated bioreactor (MABR) to calibrate and test a one-dimensional biofilm model incorporating chemical equilibria to calculate local pH values. A previously developed model (Shanahan and Semmens, 2004) based upon AQUASIM was modified to incorporate the impact of local pH changes within the biofilm on the kinetics of nitrification. Shielded microelectrodes were used to measure the concentration profiles of dissolved oxygen, ammonium, nitrate, and pH within the biofilm and the overlying boundary layer under actual operating conditions. Operating conditions were varied to assess the impact of bicarbonate loading (alkalinity), ammonium loading, and intra-membrane oxygen partial pressure on biofilm performance. Nitrification performance improved with increased ammonium and bicarbonate loadings over the range of operating conditions tested, but declined when the intra-membrane oxygen partial pressure was increased. Minor discrepancies between the measured and predicted concentration profiles within the biofilm were attributed to changes in biofilm density and vertical heterogeneities in biofilm structure not accounted for by the model. Nevertheless, predicted concentration profiles within the biofilm agreed well with experimental results over the range of conditions studied and highlight the fact that pH changes in the biofilm are significant especially in low alkalinity waters. The influent pH and buffer capacity of a wastewater may therefore have a significant impact on the performance of a membrane-aerated bioreactor with respect to nitrification, and nitrogen removal. PMID- 25703660 TI - Interpretation of the DermaLab Combo(r) pigmentation and vascularity measurements in burn scar assessment: an exploratory analysis. AB - BACKGROUND: The DermaLab Combo(r) measures pigmentation and vascularity of a burn scar more reliably than the modified Vancouver Scar Scale (mVSS). This study aims to examine how the DermaLab Combo(r) continuous measurements of pigmentation and vascularity of burns scars relate to the mVSS, a standard clinical scar assessment method; and secondly, to obtain evidence to support the concurrent validity of DermaLab Combo(r) measurements for pigmentation and vascularity. METHOD: Scar assessments were performed on an index burn scar of 100 subjects using two methods: the mVSS (two raters) and the DermaLab Combo(r) device (one rater). Using the DermaLab Combo(r), measurements of pigmentation and vascularity for the index scar and an adjacent normal skin site were obtained. Indices were generated to represent the scar pigmentation (melanin index, MI%) and scar vascularity (erythema index, EI%) relative to the patient's matched normal skin. Exploratory univariate and bivariate analyses were conducted and the concordance of classification by mVSS score using DermaLab(r) cut-off values was assessed. RESULTS: For pigmentation, the results suggest a 80% classification concordance for the DermaLab Combo(r) MI% values into mVSS pigmentation categories (hypopigmentation, normal pigmentation and hyperpigmentation) using two predictors (MI% and EI%) and visually fitted discriminant axis cut-offs. Due to the high degree of overlap of EI% values between the vascularity categories, meaningful classification of EI% values using the mVSS was not possible. CONCLUSION: Quantifying percentage changes in melanin and erythema relative to matched normal skin improved understanding of the DermaLab Combo(r) pigmentation and vascularity measurements. The DermaLab Combo(r) pigmentation MI% values were able to be classified into pigmentation categories of the mVSS, and pigmentation classification concordance was further improved with consideration of the scar's DermaLab Combo(r) vascularity EI% values. The DermaLab Combo(r) is an objective tool; however, while the measurement provides continuous numerical data that may be useful for identifying change over time in clinical scar monitoring of pigmentation and vascularity, further work will be useful to understand the DermaLab Combo(r) measurements to optimise the interpretation of these data. PMID- 25703661 TI - Paediatric burns patients: Reasons for admission at a tertiary centre. AB - AIM AND METHOD: The aim of this study was to determine the reasons why children with burns are admitted upon primary presentation to a tertiary burns centre. The study was a retrospective chart review of all children admitted to the Stuart Pegg Paediatric Burns Centre with a burns injury over an 18 month period. RESULTS: A total of 159 children with an overall median age of 25 months were included in the study. The reason for admission was able to be determined in all but two of these patients, and categorised into either severity, region of body burnt, social reasons, timing of presentation, geographical reasons, age and other. The majority of children (45%) were admitted for severity, followed by region of body burnt (24%) and social reasons (11%). One third of children were admitted because of reasons other than the biology of the burn itself (severity or body region). CONCLUSION: The findings of this study demonstrate that it is not just children with severe burns who are admitted. One third of children are admitted because of the impact of the burn injury on the family, not because of a need for immediate management of the burns injury itself. The full impact of paediatric burns on our healthcare system is not solely determined by the physical characteristics of the burn itself. PMID- 25703662 TI - Mitral valve repair via right thoracotomy for multidrug resistant pseudomonal endocarditis in a burn patient: case report and review of the literature. AB - Diagnosis and management of infectious endocarditis are particularly challenging in patients with severe burns. Cases requiring operative intervention are likely to have higher complication rates as a result of poor wound healing, recurrent bacteremia secondary to burn wound manipulation, and sequelae of anticoagulation in patients who require repeated reconstructive and cosmetic procedures. Few case reports exist describing mitral valve replacement for infectious endocarditis in burn patients. In this article, we review the literature to describe and address these challenges, and present what we believe to be the first case of mitral valve repair for infectious endocarditis in a thermally injured patient. PMID- 25703663 TI - Interrater and intrarater reliability of the Semmes Weinstein aesthesiometer to assess touch pressure threshold in burn scars. AB - Burn scars are frequently accompanied with sensory deficits often remaining present months or even years after injury. Clinimetric properties of assessment tools remain understudied within burn literature. Tactile sense of touch can be examined with the touch pressure threshold (TPT) method using the Semmes Weinstein monofilament test (SWMT). There is in recent research no consensus on the exact measurement procedure when using the SWMT. The aim of this paper was to determine the interrater and intrarater reliability of TPT within burn scars and healthy controls using the 'ascending descending' measurement procedure. We used the newly developed guidelines for reporting reliability and agreement studies (GRRAS) as a basis to report this reliability study. In total 36 individuals were tested; a healthy control group and a scar group. The interrater reliability was excellent in the scar group (ICC=0.908/SEM=0.21) and fair to good in the control group (ICC=0.731/SEM=0.12). In the scar group intrarater ICC value was excellent (ICC=0.822/SEM=0.33). Within the control group also an excellent intrarater reliability (ICC=0.807/SEM=0.27) was found. In conclusion this study shows that the SWMT with the 'ascending descending' measurement procedure is a feasible and reliable objective measure to evaluate TPT in (older) upper extremities burn scars as well as in healthy skin. PMID- 25703664 TI - Patient confidentiality and new technologies in burn care. PMID- 25703665 TI - Patient confidentiality and new technologies in burn care. PMID- 25703666 TI - Study of the use of recombinant human granulocyte-macrophage colony-stimulating factor hydrogel externally to treat residual wounds of extensive deep partial thickness burn. AB - OBJECTIVE: The objective of this study was to observe the clinical effects of recombinant human granulocyte-macrophage colony stimulating factor (rhGM-CSF) hydrogel in the treatment of residual wounds of extensive deep partial-thickness burn. METHODS: In this study, 21 subjects who sustained deep partial-thickness burns, which did not heal over 8 weeks, were observed. These were randomly assigned to two paired groups: the experimental group (using rhGM-CSF, n = 21) and the control group (using mupirocin ointment, n = 21). The wound dressings were changed once daily. Wound secretion, inflammation, granulation tissues, local and general side effects of the drug, wound healing time, and healing rate at different times were observed and compared between the two groups. The differences in the pathology of new vessels and fibroblasts between the two groups were observed, and their number in immunohistochemistry was detected. RESULTS: The wound healing time was 17.28 +/- 6.70 days in the experimental group. It was significantly shorter than that of the control group (22.14 +/- 7.38 days). The healing rates at 10 and 14 days in the experimental group were 54 +/- 27% and 60 +/- 36%, respectively. These healing rates were remarkably higher than those of the control group (43 +/- 27% and 48 +/- 30%). On the 3rd, 7th, 10th, and 14th day, the experimental group was obviously superior to the control group in wound inflammation, secretion, and granulation tissues. Furthermore, on the 7th, 10th, 14th, 21st, and 28th day, the bacterial clearance rates of the experimental group (42.85%, 52.38%, 90.47%, 95.24%, and 95.24%) were higher than those of the control group (4.76%, 4.76%, 38.10%, 76.19%, and 80.95%). On the 14th day, the average optical density of the vascular endothelial factor (VEGF) of the experimental group (0.21 +/- 0.01) is bigger than that of the control group (0.18 +/- 0.02) (P < 0.05), and the average optical density of the fibroblast growth factor (FGF) of the experimental group (0.25 +/- 0.01) is also larger than that of the control group (0.18 +/- 0.02) (P < 0.05). CONCLUSION: rhGM-CSF hydrogel effectively promotes the healing process of residual wounds of extensive deep partial-thickness burns. The hydrogel removed most of the bacteria or inhibited growth, and the local and general side reactions of the drug were mild during the study. PMID- 25703667 TI - Roles of Hoxb5 in the development of vagal and trunk neural crest cells. AB - Neural crest cells (NC) are a group of multipotent stem cells uniquely present in vertebrates. They are destined to form various organs according to their anterior posterior (A-P) levels of origin in the neural tube (NT). They develop into a wide spectrum of cell lineages under the influence of signaling cascades, neural plate border genes and NC specifier genes. Although this complex gene regulatory network (GRN) specifies the fate of NC and the combinatory action of Hox genes executed at the time of NC induction governs the patterning of NC for the formation of specific structures along the A-P axis, not much information on how GRN and Hox genes directly interact and orchestrate is available. This review summarizes recent findings on the multiple roles of Hoxb5 on the survival and cell lineage differentiation of vagal and trunk NC cells during early development, by direct transcriptional regulation of NC specifier genes (Sox9 and Foxd3) of the GRN. We will also review findings on the transcriptional regulation of Ret by Hoxb5 in the population of the vagal NC that are committed to the enteric neuron and glia lineages. Functional redundancy between Hox proteins (Hoxa5 and Hoxc5) from the same paralogue group as Hoxb5, and the cooperative effects of Hox cofactors, collaborators and transcription factors in the Hoxb5 transcriptional regulation of target genes will also be discussed. PMID- 25703668 TI - A tale of two cities: stigma and health outcomes among people with HIV who inject drugs in St. Petersburg, Russia and Kohtla-Jarve, Estonia. AB - Experiences of stigma are often associated with negative mental and physical health outcomes. The present work tested the associations between stigma and health-related outcomes among people with HIV who inject drugs in Kohtla-Jarve, Estonia and St. Petersburg, Russia. These two cities share some of the highest rates of HIV outside of sub-Saharan Africa, largely driven by injection drug use, but Estonia has implemented harm reduction services more comprehensively. People who inject drugs were recruited using respondent-driven sampling; those who indicated being HIV-positive were included in the present sample (n = 381 in St. Petersburg; n = 288 in Kohtla-Jarve). Participants reported their health information and completed measures of internalized HIV stigma, anticipated HIV stigma, internalized drug stigma, and anticipated drug stigma. Participants in both locations indicated similarly high levels of all four forms of stigma. However, stigma variables were more strongly associated with health outcomes in Russia than in Estonia. The St. Petersburg results were consistent with prior work linking stigma and health. Lower barriers to care in Kohtla-Jarve may help explain why social stigma was not closely tied to negative health outcomes there. Implications for interventions and health policy are discussed. PMID- 25703669 TI - The impact of recent chemotherapy innovation on the longevity of myeloma patients: US and international evidence. AB - The longevity of multiple myeloma patients increased sharply since the late 1990s. This increase coincided with the introduction of several important innovations in chemotherapy for myeloma. In this study, we aim to quantify the impact of recent chemotherapy innovation on the longevity of myeloma patients using both time-series US data and longitudinal data on 38 countries. We estimate that almost two-thirds (0.99 years) of the 1997-2005 increase in the life expectancy of American myeloma patients was due to an increase in the number of chemotherapy regimens now preferred by specialists. Based on a back-of-the envelope calculation, this means that the cost per US life-year gained from post 1997 chemotherapy innovation is unlikely to have exceeded $46,000. We also investigate the impact of chemotherapy innovation on the myeloma mortality rate using longitudinal country-level data on 38 countries during the period 2002 2012. Countries that had larger increases in the number of chemotherapy regimens now preferred by specialists had larger subsequent declines in myeloma mortality rates, controlling for myeloma incidence. The (marginal) effect on the mortality rate of one additional preferred chemotherapy regimen is similar in other countries to its effect in the US. Non-US prices of two of the three new drugs were lower than US prices, so recent myeloma chemotherapy innovation may have been more cost-effective in other countries than it was in the US. Recent chemotherapy innovation has had a significant positive impact on the longevity of myeloma patients in the countries in which the drugs have been available. PMID- 25703670 TI - The impact of neighborhood quality, perceived stress, and social support on depressive symptoms during pregnancy in African American women. AB - Living in a lower-quality neighborhood is associated with higher levels of depressive symptoms in the general population as well as among pregnant and postpartum women. However, little is known of the important pathways by which this association occurs. We proposed a model in which perceived stress and social support mediated the effects of neighborhood quality on depressive symptoms during pregnancy (measured by the 20-item Center for Epidemiologic Studies Depression, CES-D, scale) in a sample of 1383 African American women from the Detroit metropolitan area interviewed during their delivery hospitalization. Using structural equation modeling (SEM), we built a latent variable of neighborhood quality using 4 measures (neighborhood disorder, neighborhood safety/danger, walking environment, overall rating). We then tested two SEM mediation models. We found that lower neighborhood quality was associated with higher prevalence of depressive symptoms during pregnancy (standardized total effect = .16, p = .011). We found that perceived stress partially mediated the neighborhood quality association with depressive symptoms. Although the association of social support with depressive symptoms was negligible, social support mediated associations of neighborhood quality with perceived stress [standardized path coefficient = .38 (.02), p = .009]. Our results point to the need for public health, health care, as well as non-health related interventions (e.g. crime prevention programs) to decrease overall exposure to stressors, as well as stress levels of women living in poor quality neighborhoods. Interventions that increase the levels of social support of women during pregnancy are also needed for their potential to decrease stress and ultimately improve mental health at this important time in the life course. PMID- 25703671 TI - An exploratory discrete-time multilevel analysis of the effect of social support on the survival of elderly people in China. AB - This study undertakes a survival analysis of elderly persons in China using Chinese Longitudinal Healthy Longevity Survey 2002-2008. Employing discrete-time multilevel models, we explored the effect of social support on the survival of elderly people in China. This study focuses on objective (living arrangements and received support) and subjective activities (perceived support) of social support, finding that the effect of different activities of social support on the survival of elderly people varies according to the availability of different support resources. Specifically, living with a spouse, financial independence, perceiving care support from any resource is associated with higher survival rates for elderly people. Separate analysis focusing on urban elderly and rural elderly revealed broadly similar results. There is a larger difference between those perceiving care support from family or social service and not perceiving care support in urban areas comparing to those in rural areas. Those who cannot pay medical expenses are the least likely to survive. The higher level of economic development in province has no significant effect on the survival of elderly people for the whole sample model and the elderly people in urban areas; however, there is a negative influence on the survival of the rural elderly people. PMID- 25703672 TI - Usefulness of vaginal cytology tests in women with previous hysterectomy for benign diseases: assessment of 53,891 tests. AB - OBJECTIVE: To assess the value of vaginal screening cytology after hysterectomy for benign disease. METHODS: This cross-sectional study used cytology audit data from 2,512,039 screening tests in the metropolitan region of Campinas from 2000 to 2012; the object was to compare the prevalence of abnormal tests in women who had undergone a hysterectomy for benign diseases (n=53,891) to that of women who had had no hysterectomy. Prevalence ratios (95% confidence intervals, 95% CI) were determined, and chi-square analysis, modified by the Cochrane-Armitage test for trend, was used to investigate the effects of age. RESULTS: The prevalence of atypical squamous cells (ASC), low-grade squamous intraepithelial lesion (LSIL), and high-grade squamous intraepithelial lesion or squamous-cell carcinoma (HSIL/SCC) was 0.13%, 0.04% and 0.03%, respectively, in women who had undergone hysterectomy, and 0.93%, 0.51% and 0.26% in women who had not undergone hysterectomy. The prevalence ratios for ASC, LSIL and HSIL/SCC were 0.14 (0.11 0.17), 0.08 (0.06-0.13) and 0.13 (0.08-0.20), respectively, in women with a hysterectomy versus those without. For HSIL/SCC, the prevalence ratios were 0.09 and 0.29, respectively, for women <50 or >=50 years. The prevalence rates in women with a previous hysterectomy showed no significant variation with age. CONCLUSION: The prevalence rates of ASC, LSIL and HSIL/SCC were significantly lower in women with a previous hysterectomy for benign disease compared with those observed in women with an intact uterine cervix. This study reinforces the view that there is no evidence that cytological screening is beneficial for women who have had a hysterectomy for benign disease. PMID- 25703673 TI - Sentinel lymph node biopsy in vulvar cancer: Systematic review, meta-analysis and guideline recommendations. AB - OBJECTIVES: Traditionally, treatment for early stage vulvar cancer has included removal of the primary tumor and inguinofemoral lymph node dissection (IFLD). Sentinel lymph node biopsy (SLNB) has been proposed as an alternative to IFLD for early stage vulvar cancer patients. The aim of this project was to systematically review and assess the potential for harms and benefits with the SLNB procedure in order to make recommendations regarding the adoption of the procedure, selection of patients and appropriate technique and procedures. METHODS: A working group with expertise in gynecologic oncology and health research methodology was formed to lead the systematic review and process of guideline development. MEDLINE, Embase and The Cochrane Database of Systematic Reviews were searched for relevant articles published up to September 2014. Outcomes of interest included detection, false negative, complication and recurrence rates and indicators related to pathology. Meta-analyses were conducted where appropriate. RESULTS: The evidence base of a previously published health technology assessment was adopted. An additional search to update the HTA's evidence base located three systematic reviews, and eleven individual studies that met the inclusion criteria. According to a meta-analysis, per groin detection rate for SLNB using radiocolloid tracer and blue dye was 87% [82-92]. The false negative rate with SLNB was 6.4% [4.4 8.8], and the recurrence rates with SLNB and IFLD were 2.8% [1.5-4.4] and 1.4% [0.5-2.6], respectively. An internal and external review process elicited concerns about the necessity of performing this procedure in an appropriate organizational context. CONCLUSION: SLNB is recommended for women with unifocal tumors<4 cm and clinically non-suspicious nodes in the groin, provided that specific infrastructure and human resource needs are met. Some recommendations for appropriate techniques and procedures are also provided. PMID- 25703674 TI - Use and duration of chemotherapy and its impact on survival in early-stage ovarian cancer. AB - OBJECTIVE: Although 5-year survival for early-stage ovarian cancer is favorable, prognosis at recurrence is poor, necessitating appropriate initial management. We examined the patterns of care and the impact of the duration of chemotherapy on survival for women with early-stage ovarian cancer. METHODS: We used the SEER Medicare database to identify women >= 65 years of age with stage I ovarian cancer diagnosed from 1992 to 2009. Patients were categorized as low-risk (non clear cell histology, stage IA or IB, grade 1 or 2) or high-risk (clear cell histology, grade 3, or stage IC). We used multivariable logistic regression models to determine predictors of chemotherapy use and duration and Cox proportional hazards models to evaluate the effect of chemotherapy use and duration on survival. RESULTS: We identified 1394 patients. Among low-risk patients, 32.9% received adjuvant chemotherapy and the use of chemotherapy increased with time. Among high-risk patients, 71.9% received adjuvant chemotherapy; 44.2% had <= 3 months of treatment, and 55.8% had > 3 months of treatment. Older patients were less likely to receive chemotherapy, while those with higher stage and grade were more likely to receive chemotherapy (P<0.05 for all). Among high-risk patients, the duration of chemotherapy did not impact overall (HR=0.93, 95% CI, 0.67-1.27) or cancer specific (HR=0.93; 95% CI, 0.61 1.42) survival. CONCLUSIONS: Among early-stage ovarian cancer patients, practice patterns are widely divergent. Extended duration chemotherapy does not appear to impact survival for women with high-risk disease. PMID- 25703675 TI - Adiponectin mediates antiproliferative and apoptotic responses in endometrial carcinoma by the AdipoRs/AMPK pathway. AB - OBJECTIVE: Determine the serum adiponectin levels in endometrial carcinoma (EC) cases and controls and explore the correlation between them. We assessed the functions of AdipoR1 and AdipoR2 in endometrial cancer cells to determine whether the AMPK/ERK and Akt pathways mediate the effects of adiponectin-induced apoptosis and anti-proliferation. MATERIAL AND METHODS: The serum adiponectin levels were measured via enzyme-linked immunosorbent assay (ELISA). The proliferation and apoptosis rates were determined with MTT and annexin V/PI assays. To evaluate the activation of AMPK, ERK, and Akt and the expression of Bcl-2 and Cyclin D1, western blot analysis was performed in Ishikawa 3-H-12 cells. We down-regulated AdipoRs by si-RNA to assess their functions. RESULTS: The serum adiponectin levels were significantly decreased in patients with EC compared to controls. The adiponectin-induced apoptosis and anti-proliferation effects in EC cells were blocked by Compound C. Ishikawa 3-H-12 cells exhibited time- and dose-dependent increases in the p-AMPK levels after treatment with adiponectin. Adiponectin treatment reduced the levels of ERK and Akt phosphorylations and cyclin D1 and Bcl-2 mRNA and protein expression. Compound C blocked the effects on ERK, Akt, cyclin D1, and Bcl-2. AdipoR1 and AdipoR2 were involved in adiponectin-induced growth inhibition and ERK activation inhibition. We speculated that AdipoR1 has a greater role than adipoR2 in apoptosis and Akt activation inhibition after adiponectin treatment. CONCLUSION: Adiponectin was an apoptotic and anti-proliferation agent for EC cells, and these effects were dependent on the AMPK/ERK and Akt pathways. AdipoR1 and AdipoR2 may play different roles in this process. PMID- 25703677 TI - Insulin resistance and impaired adipogenesis. AB - The adipose tissue is crucial in regulating insulin sensitivity and risk for diabetes through its lipid storage capacity and thermogenic and endocrine functions. Subcutaneous adipose tissue (SAT) stores excess lipids through expansion of adipocytes (hypertrophic obesity) and/or recruitment of new precursor cells (hyperplastic obesity). Hypertrophic obesity in humans, a characteristic of genetic predisposition for diabetes, is associated with abdominal obesity, ectopic fat accumulation, and the metabolic syndrome (MS), while the ability to recruit new adipocytes prevents this. We review the regulation of adipogenesis, its relation to SAT expandability and the risks of ectopic fat accumulation, and insulin resistance. The actions of GLUT4 in SAT, including a novel family of lipids enhancing insulin sensitivity/secretion, and the function of bone morphogenetic proteins (BMPs) in white and beige/brown adipogenesis in humans are highlighted. PMID- 25703676 TI - Sex-specific differences in hyperoxic lung injury in mice: role of cytochrome P450 (CYP)1A. AB - Sex-specific differences in pulmonary morbidity in adults and preterm infants are well documented. Hyperoxia contributes to lung injury in experimental animals and humans. Cytochrome P450 (CYP) 1A enzymes have been shown to play a mechanistic role in hyperoxic lung injury (HLI) in animal models. Whether CYP1A enzymes contribute to gender-specific differences in relation to HLI is unknown. In this investigation, we tested the hypothesis that mice will display gender-specific differences in HLI, and that this phenomenon will be altered in mice lacking the genes for Cyp1a1 or 1a2. Eight week-old male and female wild type (WT) (C57BL/6J) mice, Cyp1a1-/-, and Cyp1a2-/- mice were exposed to 72h of hyperoxia (FiO2>0.95). Lung injury and inflammation were assessed and pulmonary and hepatic CYP1A1 and CYP1A2 levels were quantified at the enzyme activity, protein and mRNA level. Upon exposure to hyperoxia, liver and lung microsomal proteins showed higher pulmonary CYP1A1 (apoprotein level and activity) in WT females compared to WT males and a greater induction in hepatic CYP1A2 mRNA levels and activity in WT females after hyperoxia exposure. The gender based female advantage was lost or reversed in Cyp1a1-/- and Cyp1a2-/- mice. These findings suggest an important role for CYP1A enzymes in the gender-specific modulation of hyperoxic lung injury. PMID- 25703678 TI - The cost-effectiveness of irbesartan for hypertension. AB - High blood pressure is a very common problem in the adult and elderly population, both in developed and developing countries. A relatively large number of drug classes are available to treat this condition and prevent its complications, which are not only more frequent in the aforementioned patients but also those affected by metabolic syndrome and/or Type 2 diabetes. Irbesartan is an angiotensin-receptor blocker class drug with good antihypertensive efficacy and specific pharmacological characteristics, whose efficacy has been more deeply evaluated in metabolically complex hypertensive patients. In this review, the authors will analyze its effectiveness in preventing or delaying organ damage in hypertensive patients, with a closer look at the economic implications of treating hypertension with irbesartan in the context of available antihypertensive drugs. PMID- 25703680 TI - Rational design of a beta-glycosidase with high regiospecificity for triterpenoid tailoring. AB - Triterpenoids with desired glycosylation patterns have attracted considerable attention as potential therapeutics for inflammatory diseases and various types of cancer. Sugar-hydrolyzing enzymes with high substrate specificity would be far more efficient than other methods for the synthesis of such specialty triterpenoids, but they are yet to be developed. Here we present a strategy to rationally design a beta-glycosidase with high regiospecificity for triterpenoids. A beta-glycosidase with broad substrate specificity was isolated, and its crystal structure was determined at 2.0 A resolution. Based on the product profiles and substrate docking simulations, we modeled the substrate binding modes of the enzyme. From the model, the substrate binding cleft of the enzyme was redesigned in a manner that preferentially hydrolyzes glycans at specific glycosylation sites of triterpenoids. The designed mutants were shown to produce a variety of specialty triterpenoids with high purity. PMID- 25703679 TI - Methamphetamine-sensitized rats show augmented dopamine release to methylphenidate stimulation: a positron emission tomography using [18F]fallypride. AB - Previous studies demonstrated that patients with schizophrenia show greater sensitivity to psychostimulants than healthy subjects. Sensitization to psychostimulants and resultant alteration of dopaminergic neurotransmission in rodents have been suggested as a useful model of schizophrenia. This study was aimed to examine the use of methylphenidate as a psychostimulant to induce dopamine release and that of [18F]fallypride as a radioligand to estimate the release in a rat model of schizophrenia. Six rats were scanned by positron emission tomography (PET) twice before and after methylphenidate challenge to evaluate dopamine release. After the scans, these rats were sensitized by using repeated methamphetamine (MAP) administration. Then, they were re-scanned twice again before and after methylphenidate challenge to evaluate whether MAP sensitized rats show greater sensitivity to methylphenidate. We revealed a main effect of MAP-pretreatment and that of metylphenidate challenge. We found that % change of distribution volume ratio after repeated administration of MAP was greater than that before sensitization. These results suggest that methylphenidate-induced striatal dopamine release increased after sensitization to MAP. PET scan using [18F]fallypride at methylphenidate-challenge may provide a biological marker for schizophrenia and be useful to diagnose schizophrenia. PMID- 25703681 TI - Visualization and thermodynamic encoding of single-molecule partition function projections. AB - Ensemble averaging of molecular states is fundamental for the experimental determination of thermodynamic quantities. A special case occurs for single molecule investigations under equilibrium conditions, for which free energy, entropy and enthalpy at finite temperatures are challenging to determine with ensemble averaging alone. Here we report a method to directly record time averaged equilibrium probability distributions by confining an individual molecule to a nanoscopic pore of a two-dimensional metal-organic nanomesh, using temperature-controlled scanning tunnelling microscopy. We associate these distributions with partition function projections to assess real-space-projected thermodynamic quantities, aided by computational modelling. The presented molecular dynamics-based analysis is able to reproduce experimentally observed projected microstates with high accuracy. By an in silico customized energy landscape, we demonstrate that distinct probability distributions can be encrypted at different temperatures. Such modulation provides means to encode and decode information into position-temperature space. PMID- 25703682 TI - Molecular characterization of leukocyte adhesion deficiency-I in Indian patients: identification of 9 novel mutations. AB - PURPOSE: Leukocyte adhesion deficiency type-I (LAD-I) is caused by mutations in the ITGB2 gene, encoding the beta2-subunit of beta2-integrin (CD18) which leads to markedly reduced expression of CD18 on leukocytes resulting into recurrent life threatening infections. Here we aim to identify the molecular defects underlying LAD-I in Indian patients and correlate with the clinical presentation. METHODS: Blood was collected from 30 patients and their parents for absolute neutrophil count, expression of CD18 and CD11 by flow cytometry and DNA extraction. PCR and DNA sequencing of the ITGB2 gene was done for mutation characterization. RESULTS: Phenotypically, 22 patients were LAD-I(0), 1 was LAD I(-) and 7 were LAD-I(+) showing no expression and reduced expression of CD18 respectively. Nine novel mutations in 15 patients and 11 known mutations in 16 patients were detected. Prenatal diagnosis was performed for 5 families. CONCLUSION: In this study 30 patients were phenotypically and genotypically evaluated for a less known disease LAD-I. Unavailability of curative options to majority of the patients and high cost of supportive care emphasize the need to increase awareness about a suspicious case so that timely management can be given to the patient and prenatal diagnosis can be offered to their families. PMID- 25703684 TI - Protein thermodynamics and the cognitive ecology of biomedicine. AB - Assessments of scientific contributions critically influence decisions about grant funding and academic promotion. Unfortunately, there is a tendency for more junior and less assertive individuals to receive less credit than deserved. Acknowledgement of the complexity of relationships among researchers and the different modes of contributing to scientific progress could improve this situation. The thermodynamics of ligand binding is arguably among the most quantitative and empirically validated theoretical frameworks that permit precise apportionment of "credit" to multiple interacting entities that collectively account for a biologically relevant outcome, in this case, receptor-ligand complex formation. The process for assigning credit for research advances to individual researchers might benefit from emulating this thermodynamic thought process by recognizing that contributions of equal quantitative significance can be of different types and can originate through indirect effects. If the hypothesis that some categories of research contribution are frequently under valued is correct, then calling attention to this state of affairs and providing an alternative way to conceptualize the task of credit attribution has the potential to begin altering the status quo. A beginning step to improving our credit attribution process would be the empirical investigation of accounts of contributions to particular scientific advances from all research team members. PMID- 25703683 TI - BCL11A enhancer haplotypes and fetal hemoglobin in sickle cell anemia. AB - BACKGROUND: Fetal hemoglobin (HbF) levels in sickle cell anemia patients vary. We genotyped polymorphisms in the erythroid-specific enhancer of BCL11A to see if they might account for the very high HbF associated with the Arab-Indian (AI) haplotype and Benin haplotype of sickle cell anemia. METHODS AND RESULTS: Six BCL112A enhancer SNPs and their haplotypes were studied in Saudi Arabs from the Eastern Province and Indian patients with AI haplotype (HbF ~20%), African Americans (HbF ~7%), and Saudi Arabs from the Southwestern Province (HbF ~12%). Four SNPs (rs1427407, rs6706648, rs6738440, and rs7606173) and their haplotypes were consistently associated with HbF levels. The distributions of haplotypes differ in the 3 cohorts but not their genetic effects: the haplotype TCAG was associated with the lowest HbF level and the haplotype GTAC was associated with the highest HbF level and differences in HbF levels between carriers of these haplotypes in all cohorts were approximately 6%. CONCLUSIONS: Common HbF BCL11A enhancer haplotypes in patients with African origin and AI sickle cell anemia have similar effects on HbF but they do not explain their differences in HbF. PMID- 25703685 TI - Activation of non-canonical TGF-beta1 signaling indicates an autoimmune mechanism for bone marrow fibrosis in primary myelofibrosis. AB - Primary myelofibrosis (PMF) is characterized by megakaryocyte hyperplasia, dysplasia and death with progressive reticulin/collagen fibrosis in marrow and hematopoiesis in extramedullary sites. The mechanism of fibrosis was investigated by comparing TGF-beta1 signaling of marrow and spleen of patients with PMF and of non-diseased individuals. Expression of 39 (23 up-regulated and 16 down regulated) and 38 (8 up-regulated and 30 down-regulated) TGF-beta1 signaling genes was altered in the marrow and spleen of PMF patients, respectively. Abnormalities included genes of TGF-beta1 signaling, cell cycling and abnormal in chronic myeloid leukemia (EVI1 and p21(CIP)) (both marrow and spleen) and Hedgehog (marrow only) and p53 (spleen only) signaling. Pathway analyses of these alterations predict an increased osteoblast differentiation, ineffective hematopoiesis and fibrosis driven by non-canonical TGF-beta1 signaling in marrow and increased proliferation and defective DNA repair in spleen. Since activation of non-canonical TGF-beta1 signaling is associated with fibrosis in autoimmune diseases, the hypothesis that fibrosis in PMF results from an autoimmune process triggered by dead megakaryocytes was tested by determining that PMF patients expressed plasma levels of mitochondrial DNA and anti-mitochondrial antibodies greater than normal controls. These data identify autoimmunity as a possible cause of marrow fibrosis in PMF. PMID- 25703687 TI - Finite element analysis of a condylar support prosthesis to replace the temporomandibular joint. AB - This paper presents a finite element study of a temporomandibular joint (TMJ) prosthesis in which the mandibular component sits on the condyle after removal of only the diseased articular surface and minimal amount of condylar bone. The condylar support prosthesis (CSP) is customised to fit the patient and allows a large part of the joint force to be transmitted through the condyle to the ramus, rather than relying only on transfer of the load by the screws that fix the prosthesis to the ramus. The 3-dimensional structural finite element analysis compared a design of CSP with a standard commercial prosthesis and one that was modified to fit the ramus, to relate the findings to the different designs and geometrical features. The models simulated an incisal bite under high loading. In the CSP and in its fixation screws, the stresses were much lower than those in the other 2 prostheses and the bone strains were at physiological levels. The CSP gives a more physiological form of load transfer than is possible without the condylar contact, and considerably reduces the amount of strain on the bone around the screws. PMID- 25703686 TI - Diversity in gut bacterial community of school-age children in Asia. AB - Asia differs substantially among and within its regions populated by diverse ethnic groups, which maintain their own respective cultures and dietary habits. To address the diversity in their gut microbiota, we characterized the bacterial community in fecal samples obtained from 303 school-age children living in urban or rural regions in five countries spanning temperate and tropical areas of Asia. The microbiota profiled for the 303 subjects were classified into two enterotype like clusters, each driven by Prevotella (P-type) or Bifidobacterium/Bacteroides (BB-type), respectively. Majority in China, Japan and Taiwan harbored BB-type, whereas those from Indonesia and Khon Kaen in Thailand mainly harbored P-type. The P-type microbiota was characterized by a more conserved bacterial community sharing a greater number of type-specific phylotypes. Predictive metagenomics suggests higher and lower activity of carbohydrate digestion and bile acid biosynthesis, respectively, in P-type subjects, reflecting their high intake of diets rich in resistant starch. Random-forest analysis classified their fecal species community as mirroring location of resident country, suggesting eco geographical factors shaping gut microbiota. In particular, children living in Japan harbored a less diversified microbiota with high abundance of Bifidobacterium and less number of potentially pathogenic bacteria, which may reflect their living environment and unique diet. PMID- 25703688 TI - Hypoxia-induced proliferation in mesenchymal stem cells and angiotensin II mediated PI3K/AKT pathway. AB - Hypoxia could stimulate proliferation of mesenchymal stem cells (MSCs) under certain conditions. This study determined angiotensin II mechanisms and PI3K/AKT pathway in hypoxia-induced proliferation of MSCs. Hypoxia (3% oxygen) induced cellular proliferation in mouse MSCs and upregulated endogenous angiotensin II and angiotensin-converting enzyme in the cell culture and expression of AT1 receptors. The expressions of Sox2, not Oct4 and Rex1, were significantly increased by the hypoxia. The blockade of AT1 receptors, not AT2 receptors, depressed hypoxia induced the proliferative effects. Both hypoxia and exogenous angiotensin II activated p-AKT. Moreover, AT1 receptor inhibitor blocked the effects of hypoxia-mediated p-AKT upregulation. The data demonstrated that the hypoxia at 3% oxygen level could induce mouse MSC proliferation, probably as a result of the activation of PI3K signalling pathways via AT1 receptors. PMID- 25703689 TI - The unsolved problems of neuroscience. AB - Some problems in neuroscience are nearly solved. For others, solutions are decades away. The current pace of advances in methods forces us to take stock, to ask where we are going, and what we should research next. PMID- 25703690 TI - Resolution of mixed site DNA complexes with dimer-forming minor-groove binders by using electrospray ionization mass spectrometry: compound structure and DNA sequence effects. AB - Small-molecule targeting of the DNA minor groove is a promising approach to modulate genomic processes necessary for normal cellular function. For instance, dicationic diamindines, a well-known class of minor groove binding compounds, have been shown to inhibit interactions of transcription factors binding to genomic DNA. The applications of these compounds could be significantly expanded if we understand sequence-specific recognition of DNA better and could use the information to design more sequence-specific compounds. Aside from polyamides, minor groove binders typically recognize DNA at A-tract or alternating AT base pair sites. Targeting sites with GC base pairs, referred to here as mixed base pair sequences, is much more difficult than those rich in AT base pairs. Compound 1 is the first dicationic diamidine reported to recognize a mixed base pair site. It binds in the minor groove of ATGA sequences as a dimer with positive cooperativity. Due to the well-characterized behavior of 1 with ATGA and AT rich sequences, it provides a paradigm for understanding the elements that are key for recognition of mixed sequence sites. Electrospray ionization mass spectrometry (ESI-MS) is a powerful method to screen DNA complexes formed by analogues of 1 for specific recognition. We also report a novel approach to determine patterns of recognition by 1 for cognate ATGA and ATGA-mutant sequences. We found that functional group modifications and mutating the DNA target site significantly affect binding and stacking, respectively. Both compound conformation and DNA sequence directionality are crucial for recognition. PMID- 25703691 TI - Dynamic visualization of calcium-dependent signaling in cellular microdomains. AB - Cells rely on the coordinated action of diverse signaling molecules to sense, interpret, and respond to their highly dynamic external environment. To ensure the specific and robust flow of information, signaling molecules are often spatially organized to form distinct signaling compartments, and our understanding of the molecular mechanisms that guide intracellular signaling hinges on the ability to directly probe signaling events within these cellular microdomains. Ca(2+) signaling in particular owes much of its functional versatility to this type of exquisite spatial regulation. As discussed below, a number of methods have been developed to investigate the mechanistic and functional implications of microdomains of Ca(2+) signaling, ranging from the application of Ca(2+) buffers to the direct and targeted visualization of Ca(2+) signaling microdomains using genetically encoded fluorescent reporters. PMID- 25703692 TI - Amelioration of ischemia-reperfusion-induced muscle injury by the recombinant human MG53 protein. AB - INTRODUCTION: Ischemia-reperfusion injury (I-R) in skeletal muscle requires timely treatment. METHODS: Rodent models of I-R injury were used to test the efficacy of recombinant human MG53 (rhMG53) protein for protecting skeletal muscle. RESULTS: In a mouse I-R injury model, we found that mg53,-/- mice are more susceptible to I-R injury. rhMG53 applied intravenously to the wild-type mice protected I-R injured muscle, as demonstrated by reduced CK release and Evans blue staining. Histochemical studies confirmed beneficial effects of rhMG53. Of interest, rhMG53 did not protect against I-R injury in rat skeletal muscle. This was likely due to the fact that the plasma level of endogenous MG53 protein is high in rats. CONCLUSIONS: Our data suggest that rhMG53 may be a potential therapy for protection against muscle trauma. A mouse model appears to be a better choice than a rat model for evaluating potential treatments for protecting skeletal muscle. PMID- 25703693 TI - Significance of worsening renal function and nuclear cardiology for predicting cardiac death in patients with known or suspected coronary artery disease. AB - BACKGROUND: Estimated glomerular filtration rates (eGFRs) at baseline are useful to determine the severity of renal function and to predict cardiac events. However, no studies aimed to demonstrate significance of eGFRs measured during follow-up and usefulness of combination with nuclear cardiology for prediction of cardiac death in patients with coronary artery disease (CAD). METHODS: We retrospectively investigated 1739 patients with known/suspected CAD who underwent myocardial perfusion single photon emission computed tomography (SPECT), who had eGFRs measured at baseline and after one year and who underwent a three-year follow-up. The SPECT images were analyzed with the visual scoring model to estimate summed defect scores. Reduction in eGFRs (DeltaeGFR) was defined as the difference between eGFRs measured after one year and at baseline. The endpoint of the follow-up was cardiac deaths within three years after the SPECT, which were identified with medical records or responses to posted questionnaires. RESULTS: Cardiac death was observed in 54 of 1739 patients during the follow-up period (45.6+/-9.1 months). The multivariate Cox regression analysis showed baseline eGFRs, DeltaeGFR, and summed stress scores to be significant independent variables for prediction of cardiac death. The area under receiver operating characteristic curves for detection of cardiac death was 0.677 for the baseline eGFR and 0.802 for the follow-up eGFR. Sensitivity of detection of cardiac death was significantly higher in the follow-up eGFR than in the baseline eGFR (p=0.0002). Combination of the best cut-off values, i.e. 9 for the summed stress scores and 10 for the DeltaeGFR, which were suggested by receiver operating characteristic analysis, was useful for risk stratification of cardiac death both in patients with and without chronic kidney disease. CONCLUSION: Baseline and follow-up eGFRs as well as nuclear variables are useful to predict cardiac death in patients with known/suspected CAD. PMID- 25703694 TI - Facet-Dependent Optical Properties Revealed through Investigation of Polyhedral Au-Cu2O and Bimetallic Core-Shell Nanocrystals. AB - The ability to prepare Au-Cu2O core-shell nanocrystals with precise control over particle size and shape has led to the discovery of facet-dependent optical properties in cuprous oxide crystals. The use of Au cores not only allows the successful formation of Au-Cu2O core-shell nanocrystals with tunable sizes, but also enables the observation of facet-dependent optical properties in these crystals through the Au localized surface plasmon resonance (LSPR) absorption band. By tuning the Cu2O shell morphology from rhombic dodecahedral to octahedral and cubic structures, and thus the exposed facets, the Au LSPR band position can be widely tuned. Such facet-dependent optical effects are not observed in bimetallic Au-Ag and Au-Pd core-shell nanocrystals with the same precisely tuned particle sizes and shapes. It is believed that similar facet-dependent optical properties could be observed in other ionic solids and other metal-metal oxide systems. The unusually large degree of plasmonic band tuning covering from the visible to the near-infrared region in this type of nanostructure should be quite useful for a range of plasmonic applications. PMID- 25703695 TI - Operation Pied Piper: a geographical reappraisal of the impact of wartime evacuation on scarlet fever and diphtheria rates in England and Wales, 1939-1945. AB - This paper examines the geographical impact of the British Government's wartime evacuation scheme on notified rates of two common acute childhood diseases (scarlet fever and diphtheria) in the 1470 local government districts of England and Wales, 1939-1945. Drawing on the notifications of communicable diseases collated by the General Register Office (GRO), we establish pre-war (baseline) disease rates for the 1470 districts. For the war years, techniques of binary logistic regression analysis are used to assess the associations between (a) above-baseline ('raised') disease rates in evacuation, neutral and reception districts and (b) the major phases of the evacuation scheme. The analysis demonstrates that the evacuation was temporally associated with distinct national and regional effects on notified levels of disease activity. These effects were most pronounced in the early years of the dispersal (1939-1941) and corresponded with initial levels of evacuation-related population change at the regional and district scales. PMID- 25703696 TI - Cobalt(III)-catalyzed directed C-H coupling with diazo compounds: straightforward access towards extended pi-systems. AB - The first highly efficient and scalable cobalt-catalyzed directed C-H functionalization with carbene precursors is presented. This methodology provides a modular route towards a new class of conjugated polycyclic hydrocarbons with tunable emission wavelengths both in solution and in the solid state. PMID- 25703697 TI - Comparative Expression Analysis of Gametogenesis-Associated Genes in Foetal and Adult Bubaline (Bubalus bubalis) Ovaries and Testes. AB - This study was conducted to identify and analyse the expression of gametogenesis associated genes and proteins in foetal and adult buffalo gonads of both the sexes. Relative quantification of the genes was determined by qPCR and Western blotting. Immunohistochemistry was also performed for various gametogenesis associated proteins in foetal and adult gonads of both the sexes. We observed significantly (p < 0.05) increased expression of primordial germ cell-specific, meiotic as well as genes associated with oocyte maturation and development in foetal ovaries as compared to the adult ones. However, significantly (p < 0.05) increased expression of proteins associated with oocyte maturation like GDF9 and ZP4 was found in adult ovaries, indicating temporal regulation of mRNA translation during oogenesis. Meiotic genes showed significantly (p < 0.05) increased expression in adult testes as compared to foetal testes and ovaries, indicating onset of meiosis at a later stage in spermatogenesis. In general, the expression of primordial germ cell-associated as well as meiotic genes was higher in adult testes, indicating the increased biological activity in the organ. Immunohistochemistry revealed localized expression of gametogenesis-associated proteins in ovarian follicles and seminiferous tubules of testes, while the surrounding somatic tissues were devoid of these proteins. The study gives an understanding of the sequential and temporal events of gene expression as well as mRNA translation during male and female gametogenesis. It could also be concluded that follicles and seminiferous tubules are the functional units of the female and male gonads, respectively, and their function could be enhanced by appropriate chemical and genetic intervention of the somatic tissue immediately surrounding them. This assumes importance in the context that buffalo attains sexual maturity at an older age of 2-3 years and have smaller ovaries with lesser number of primordial follicles in comparison with cattle, which is suggested to be the main reason of their poor breeding performance. PMID- 25703698 TI - C-H functionalization of terminal alkynes towards stereospecific synthesis of (E) or (Z) 2-methylthio-1,4-ene-diones. AB - An efficient metal free self-sorting tandem protocol for stereospecific synthesis of 2-thio-1,4-enediones involving C-C double bond formation via direct coupling of terminal alkynes has been developed. The method was also extended to the first synthesis of beta-thio-gamma-keto-alpha,beta-unsaturated esters via a cross coupling reaction with ethyl glyoxylate. The reaction relies on a first of its kind use of Bronsted and Lewis acids to switch selectivity for the synthesis of an E or a Z-isomer respectively. PMID- 25703699 TI - Interventional radiology delivers high-value health care and is an Imaging 3.0 vanguard. AB - Given the changing climate of health care and the imperative to add value, radiologists must join forces with the rest of medicine to deliver better patient care in a more cost-effective, evidence-based manner. For several decades, interventional radiology has added value to the health care system through innovation and the provision of alternative and effective minimally invasive treatments, which have decreased morbidity, mortality, and overall cost. The clinical practice of interventional radiology embodies many of the features of Imaging 3.0, the program recently launched by the ACR. We provide a review of some of the major contributions made by interventional radiology and offer general principles from that experience, which are applicable to all radiologists. PMID- 25703700 TI - Low back pain in the emergency department-are the ACR Appropriateness Criteria being followed? AB - PURPOSE: To assess the prevalence of appropriate imaging among emergency department (ED) patients with low back pain. METHODS: Our level-1 ED records were retrospectively searched for patients with a chief compliant of "low back pain" from January to April 2013. Of 624 patients, 100 were randomly selected and analyzed for their demographics, presentation, imaging, treatment, and outcomes. The study indication for imaging was compared with the ACR Appropriateness Criteria, and the indication was deemed appropriate if it received a rating of >=5. RESULTS: The mean age of the study population was 48 years (50% women, 50% men). The majority presented with acute or acute on chronic low back pain (94 patients), and half had a precipitating event (50 patients). A total of 28 (28%) patients underwent imaging in the ED; 24 (24%) had outpatient imaging; 54 (54%) had neither ED nor outpatient imaging. In all, 96% (27 of 28) of patients imaged in the ED, and 96% (23 of 24) imaged as outpatients, were appropriately imaged. Of patients who did not undergo imaging, 96% (52 of 54) were appropriately not imaged. A total of 76 patients (76%) had follow-up after discharge: of these, 42 (55%) had resolution or return of pain to baseline with conservative management; 18 (24%) had improvement with intervention (epidural steroid injection or kyphoplasty); 8 (10%) improved with surgery; and 8 had persistent pain (11%). CONCLUSIONS: The majority of patients presenting to the ED with low back pain did not undergo imaging. The vast majority of those who underwent imaging were appropriately imaged, based on the ACR Appropriateness Criteria. PMID- 25703701 TI - Identification of ADAM10 and ADAM17 with potential roles in the spermatogenesis of the Chinese mitten crab, Eriocheir sinensis. AB - The ADAM (a disintegrin and metalloprotease) family plays an important role in sperm and egg fusion, development, inflammation, adhesion and migration. ADAM10 and ADAM17 are involved in the spermatogenesis. To better understand the role of ADAM10 and ADAM17 in the Chinese mitten crab, Eriocheir sinensis, the full-length cDNAs of ADAM10 and ADAM17 were cloned, and named Es-ADAM10 and Es-ADAM17, respectively. Sequence and structural analysis showed that Es-ADAM10 and Es ADAM17 have the typical structure of the ADAM family. Quantitative real-time reverse transcription polymerase chain reaction analysis showed that Es-ADAM10 and Es-ADAM17 mRNAs were distributed in the heart, hepatopancreas, intestines, brain, muscle, thoracic ganglia, hemolymph, stomach, testis, ovary, gill and accessory gland. Both mRNAs were highly expressed in the muscles, and relatively high in the testis, ovary and accessory gland. In addition, the Es-ADAM17 mRNA level was detected in every stage of testis development, being relatively high from July to September, the lowest during October and November, increasing from December to January, and reached a peak in January. By contrast, the expression of Es-ADAM10 mRNA was constant during testis development. Immunofluorescence further showed that Es-ADAM10 and Es-ADAM17 proteins were present in the cytoplasm and cytomembrane of spermatocytes, and both detected in the sperm. Furthermore, etoposide induced upregulation of Es-ADAM17 and Es-ADAM10 at both the mRNA and protein levels. This study first showed that Es-ADAM10 and Es-ADAM17 were also involved in the spermatogenesis and mainly participated in the later germ cell apoptosis in E. sinensis. PMID- 25703702 TI - The spectrum of MEFV gene mutations and genotypes in Van province, the eastern region of Turkey, and report of a novel mutation (R361T). AB - Familial Mediterranean fever (FMF) is the most common hereditary inflammatory periodic disease, characterized by recurrent episodes of fever and abdominal pain, synovitis, and pleuritis. The aim of this study was to determine the frequency and distribution of Mediterranean fever (MEFV) gene mutations in Van province of Eastern Anatolia and to compare them with the other studies from various regions of Turkey. Therefore, we retrospectively evaluated MEFV gene mutations in 1058 pediatric patients with suspected FMF. The MEFV gene mutations were investigated using Sanger sequencing and the multiplex minisequencing technique. We identified 37 different genotypes and 16 different mutations. The four most common mutations and allelic frequencies were M694V (36.50%), E148Q (32.77%), V726A (14.09%), and M694I (4.41%). M694V was the most common mutation, and the M694I frequency was found to be higher compared to studies from other regions of Turkey. In addition, we identified a novel missense mutation (R361T, c.1082G>C) in exon 3 of the MEFV gene in a 12-year-old boy, who had a typical FMF phenotype. In conclusion, this study evaluated the distribution of MEFV gene mutations in children with FMF as the first study conducted in Van province, Eastern Anatolia. PMID- 25703703 TI - Professor Yrjo Tapio Konttinen. PMID- 25703704 TI - Discovery of a novel and conserved Plasmodium falciparum exported protein that is important for adhesion of PfEMP1 at the surface of infected erythrocytes. AB - Plasmodium falciparum virulence is linked to its ability to sequester in post capillary venules in the human host. Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) is the main variant surface antigen implicated in this process. Complete loss of parasite adhesion is linked to a large subtelomeric deletion on chromosome 9 in a number of laboratory strains such as D10 and T9-96. Similar to the cytoadherent reference line FCR3, D10 strain expresses PfEMP1 on the surface of parasitized erythrocytes, however without any detectable cytoadhesion. To investigate which of the deleted subtelomeric genes may be implicated in parasite adhesion, we selected 12 genes for D10 complementation studies that are predicted to code for proteins exported to the red blood cell. We identified a novel single copy gene (PF3D7_0936500) restricted to P. falciparum that restores adhesion to CD36, termed here virulence-associated protein 1 (Pfvap1). Protein knockdown and gene knockout experiments confirmed a role of PfVAP1 in the adhesion process in FCR3 parasites. PfVAP1 is co-exported with PfEMP1 into the host cell via vesicle-like structures called Maurer's clefts. This study identifies a novel highly conserved parasite molecule that contributes to parasite virulence possibly by assisting PfEMP1 to establish functional adhesion at the host cell surface. PMID- 25703705 TI - Protective effect of sitagliptin against renal ischemia reperfusion injury in rats. AB - This study was designed to investigate the protective effects of sitagliptin on renal damage induced by renal ischemia reperfusion (I/R) in rats. For this, rats were randomly divided into four groups (n = 8): (1) sham group, in which the rats only underwent right nephrectomy; (2) right nephrectomy and left kidney ischemia (1 h) and reperfusion (24 h) group (I/R); (3) 5 mg/kg sitagliptin administrated group, per-oral once a day for two weeks; (4) 5 mg/kg sitagliptin administrated group, per-oral once a day for two weeks before left kidney I/R (n = 8). Sitagliptin-treated rats that underwent renal I/R demonstrated significant decrease in the serum urea nitrogen and creatinine and also, lipid peroxidation, total oxidant status and malondialdehyde level in the renal tissue when compared to the renal I/R group. Additionally, reduced glutathione, glutathione peroxidase, superoxide dismutase, catalase and total antioxidative capacity were significantly increased after renal I/R in sitagliptin-treated rats. Our histopathological findings were in accordance with these biochemical results. In sum, in the current study all of our results indicated that sitagliptin treatment ameliorated renal damage induced by renal I/R in rats. PMID- 25703706 TI - Arsenic-mediated nephrotoxicity. AB - Chronic kidney disease (CKD) is an important global health problem that affects 8 15% of the population according to epidemiological studies done in different countries. Essential to prevention is the knowledge of the environmental factors associated with this disease, and heavy metals such as lead and cadmium are clearly associated with kidney injury and CKD progression. Arsenic is one of the most abundant contaminants in water and soil, and many epidemiological studies have found an association between arsenic and type 2 diabetes mellitus, hypertension and cancer; however, there is a scarcity of epidemiological studies about its association with kidney disease, and the evidence linking urinary arsenic excretion with CKD, higher urinary excretion of low molecular proteins, albuminuria or other markers of renal in injury is still limited, and more studies are necessary to characterize the role of arsenic on renal injury and CKD progression. Global efforts to reduce arsenic exposure remain important and research is also needed to determine whether specific therapies are beneficial in susceptible populations. PMID- 25703707 TI - Periprocedural effects of statins on the incidence of contrast-induced acute kidney injury: a systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: The reports on the efficacy of statins for the prevention of contrast induced acute kidney injury (CIAKI) remain controversial. The objective of this meta-analysis was to assess the effect of statins for the prevention of CIAKI. METHODS: Comprehensive literature searches for randomized controlled trials (RCTs) of periprocedural statin treatment for prevention of CIAKI were performed using MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials Systematic Reviews and clinicaltrials.gov from inception until May 2014. The primary outcome was the incidence of CIAKI. RESULTS: Thirteen prospective RCTs were included in our analysis. Of 5803 patients with contrast exposures, 304 patients (5.2%) had CIAKI. Patients in the statin group had an overall lower incidence of CIAKI (3.6%) compared to the control group (6.9%). Intravenous (IV) fluid hydration was used in both groups of all included studies for prevention of CIAKI. There was a significant protective effect of periprocedural statins on the incidence of CIAKI when compared to the control group [risk ratios (RRs): 0.49; 95% CI: 0.37-0.66, I(2) of 25%]. CONCLUSIONS: Our study demonstrates a statistically significant protective effect of statin treatment during procedures with contrast exposures. This finding suggests the use of statins in addition to standard IV crystalloid hydration may be beneficial in the prevention of CIAKI. PMID- 25703708 TI - Sonographic findings of prescrotal superficial angiomyxoma. AB - Sonographic findings of a prescrotal superficial angiomyxoma have never been reported in the English literature. Here, we describe a case of left prescrotal superficial angiomyxoma, which was depicted on ultrasonography as a well circumscribed, heterogeneously, and mildly echogenic, unilocular complex, posterior acoustic-enhanced, and dermally attached subcutaneous mass without increased vascular flow. PMID- 25703709 TI - Mechanical performance in axial compression of a titanium polyaxial locking plate system in a fracture gap model. AB - OBJECTIVE: To evaluate the bending strength of the VetLOX(r) polyaxial locking plate system. MATERIALS AND METHODS: Thirty-five 3.5 mm 12-hole titanium VetLOX(r) plates were used to stabilize seven different construct designs in a 1 cm fracture gap simulation model. Each construct was subjected to axial compression. Mean bending stiffness (BS) and yield load (YL) of each construct design were analysed using a one-way ANOVA and Tukey post-hoc analysis. Screw angulation was measured on reconstructed computed tomography (CT) images. RESULTS: Reducing plate working length for fixed-angle constructs significantly increased BS (p <0.01) and YL (p <0.01). For a constant plate working length, increasing screw number did not significantly affect BS (p = 1.0) or YL (p = 0.86). Screw angulation measurement technique was validated by intra-class correlation coefficients (ICC) (ICC >0.9 for inter- and intra-observer measurements). An average screw angle of 13.2 degrees did not significantly affect mechanical performance although incomplete screw head-plate engagement was noted on some reconstructed CT images when angulation exceeded 10 degrees . Prefabricated screw-head inserts did not significantly increase mechanical performance. A 4 mm bone-plate stand-off distance significantly reduced BS and YL by 63% and 69% respectively. CLINICAL RELEVANCE: The VetLOX(r) system allows the benefits of polyaxial screw insertion whilst maintaining comparable bending properties to fixed angle insertion. The authors recommend accurate plate contouring to reduce the risk of plate bending. PMID- 25703710 TI - Enhancement of secondary metabolites from Bacillus Licheniformis XY-52 on immune response and expression of some immune-related genes in common carp, Cyprinus carpio. AB - This study was undertaken to isolate active secondary metabolites from immunostimulatory Bacillus Licheniformis XY-52 and evaluate their activities at 0%, 0.5%, 1.0%, and 2.0% doses supplementation with feed on immune response in common carp at weeks 1, 2, and 3. By applying chromatography techniques and successive recrystallization, two purified metabolites were obtained and identified by spectral data (mass spectrometry and nuclear magnetic resonance) as: Cyclo-(Phe-Tyr) and Cyclo-(Phe-Gly). The results revealed that humoral innate immune parameters (lysozyme activity, phagocytic activity and bactericidal activity) were significantly (P < 0.05) increased after feeding on the two active compounds-supplemented diet. Furthermore, administration of the two active compounds significantly (P < 0.05) up regulated IL-1beta, Type 1 IFN, IFN g2b, IL10 and TNF-alpha gene expression. Heat shock protein 70 (HSP70) gene expression was significantly (P < 0.05) lower as compared to control group at the end of trial. Common carp fed with the two compounds had higher survival rates (69.3%) compared to the controls (32.0%) after challenged with the pathogen, Aeromonas hydrophila. The present study indicates that the two isolated active compounds could positively influence immune response and enhance disease resistance of common carp against A. hydrophila infection. PMID- 25703711 TI - Dietary supplementation of Avicennia marina extract on immune protection and disease resistance in Amphiprion sebae against Vibrio alginolyticus. AB - The effect of Avicennia marina aqueous leaf extract on innate immune mechanisms such as total white blood cell counts (WBC), serum lysozyme activity, respiratory burst assay, alternative complement (ACH50) assay, phagocytic activity assay, disease resistance, gut bacteria, and survival rate of clownfish (Amphiprion sebae) against Vibrio alginolyticus is reported. Healthy fish challenged with V. alginolyticus (1 * 10(7) cells ml(-1)) were fed with diets supplemented (0, 1, 2, and 4%) with A. marina extract. The survival rate was 85% and 80% in infected fish fed with 4% and 8% supplementation diet; with 1% diet it was 70% while in the infected untreated group it was only 10%. The total gut bacteria flora was high in 8% and 4% supplementation diet groups with 2.8 * 10(5) and 4.7 * 10(4) cfu/g while it was 8.9 * 10(3) cfu/g in 1% diet group. The immunological parameters significantly increased on weeks 6 and 8 when infected fish were fed with 1% or 4% supplementation diet. This study reports that in clownfish challenged with V. alginolyticus, dietary administration of the 1% or 4% of A. marina extract improved the immune status and survival rate. PMID- 25703712 TI - LvDJ-1 plays an important role in resistance against Vibrio alginolyticus in Litopenaeus vannamei. AB - DJ-1 was first identified as an oncogene that transformed mouse NIH3T3 cells in cooperation with activated Ras. It has since exhibited a variety of functions in a range of organisms. In this study, the DJ-1 gene in Litopenaeus vannamei (LvDJ 1) was identified and characterized. A recombinant protein LvDJ-1 was produced in Pichia pastoris. LvDJ-1 expression in vivo was knocked down by dsRNA-mediated RNA interference (RNAi), which led to significantly decreased levels of LvDJ-1 mRNA and protein. When the L. vannamei were challenged with RNAi and Vibrio alginolyticus, the transcription and expression of copper zinc superoxide dismutase (LvCZSOD) in the hepatopancreas were dramatically lower in shrimp with knocked down LvDJ-1 than in controls. Transcription and expression of P53 (LvP53) were significantly higher in shrimp lacking LvDJ-1 than in controls. Hepatopancreas samples were analyzed using real time polymerase chain reaction and Western blot. Moreover, blood samples from the shrimp, assessed with flow cytometry, showed significant increases in respiratory burst and apoptosis in those lacking LvDJ-1 compared to the controls. Cumulative mortality in the shrimp lacking LvDJ-1 was significantly different from that in the control group after challenge with V. alginolyticus. Altogether, the results prove that LvDJ-1 regulates apoptosis and antioxidant activity, and that these functions play an important role in L. vannamei resistance against V. alginolyticus. PMID- 25703713 TI - Prospects of host-associated microorganisms in fish and penaeids as probiotics with immunomodulatory functions. AB - Aquatic animals harbor a great number of microorganisms with interesting biological and biochemical diversity. Besides serving as the natural defense system of the host, the utilization potential of this microbial association has been identified particularly as reservoirs of candidate probiotics. Host-derived probiotics have gained popularity in recent years as they offer an alternative source of beneficial microbes to the industry that is customarily dependent on the use of terrestrial microorganisms. At present, there is an overwhelming number of candidate probiotics in aquaculture but their large-scale application is restricted by bio-technological concerns and fragmentary documented probiotic actions. This paper presents the current understanding on the use of probiotics as a sustainable alternative that promotes health and welfare in fish and penaeids. In particular, this paper discusses the relevance of host microbiota and its potential as a source of candidate probiotics. It also revisits the interaction between probiotics and host immunity to provide the foundation of the immunomodulatory functions of host-derived probiotics. Several studies demonstrating the immunomodulatory capabilities of host-derived candidate probiotics are given to establish the current knowledge and provide avenues for future research and development in this thematic area of probiotics research in aquaculture. PMID- 25703714 TI - Aloe vera bathing improved physical and humoral protection in breeding stock after induced spawning in matrinxa (Brycon amazonicus). AB - In this study, we show that induced spawning causes stress, an intense loss of epithelia and immunosuppression, decreasing physical and humoral protection in fish, effects that were prevented or improved in fish bathed with Aloe vera. A. vera has several medicinal properties, including wound healing and immunostimulatory effects, which we observed in this study. Fish bathed with A. vera had a higher number of epidermal goblet cells and, in general, an improved wound healing rate compared with the control after induced spawning. These effects might be related to (1) the stimulation of leukocyte activity, represented here by the increased leukocyte respiratory activity triggered by A. vera (leukocytes are recognized as playing an important role in wound repair); (2) the antimicrobial properties of A. vera, which decrease wound infection and accelerate the healing process; and (3) several mechanisms that explain the healing effect of A. vera (increased collagen synthesis, rate of epithelialization, and anti-inflammatory and moisturizing effects). Our results also suggest that caution is necessary during the induced spawning process, especially during stripping, and A. vera bathing is recommended after intensive aquaculture operations. PMID- 25703715 TI - Neurological signs and pre- and post-traction low-field MRI findings in Dobermanns with disc-associated cervical spondylomyelopathy. AB - OBJECTIVE: To investigate whether the presence of neurological signs and magnetic resonance imaging findings could predict the presence of a traction-responsive lesion in Dobermanns affected by disc-associated cervical spondylomyelopathy. METHODS: Retrospective review of neurological signs and low-field pre- and post traction magnetic resonance imaging abnormalities of the cervical spine (abnormal vertebral body shape and vertebral tipping, intervertebral disc degeneration, protrusion and ligamentum flavum hypertrophy) in Dobermanns with disc-associated cervical spondylomyelopathy. The main outcome of interest was response to linear traction (dynamic versus static) at C6-C7 intervertebral disc space. The association between investigated variables and response to linear traction was assessed. RESULTS: The study included 25 dogs. No association was identified between neurological status grading and the presence of a static or traction responsive lesion. Of the investigated magnetic resonance findings, C7-T1 intervertebral disc degeneration was significantly (P = 0 . 03) associated with the presence of a traction-responsive lesion at C6-C7 intervertebral disc space. CLINICAL SIGNIFICANCE: The presence of C7-T1 intervertebral disc degeneration might help in predicting the presence of traction-responsive C6-C7 intervertebral disc lesions. PMID- 25703716 TI - Impact of the processes of testicular regression and recrudescence in the prostatic complex of the bat Myotis nigricans (Chiroptera: Vespertilionidae). AB - Myotis nigricans is a species of vespertilionid bat, whose males show two periods of total testicular regression during the annual reproductive cycle in the northwest Sao Paulo State, Brazil. Thus, the aim of this study was to investigate the impact of total testicular regression on the prostatic morphophisyology and its regulation. The prostatic complex (PC) of animals from the four periods of the reproductive cycle (active, regressing, regressed, and recrudescence) was analyzed by different histological, morphometric, and immunohistochemical procedures to characterize its variations, analyze its hormonal regulation and evaluate whether the prostate is affected by the processes of testicular regression and recrudescence. The results indicated a decrease in the prostatic parameters from the active to regressed periods, which are related to decreases in the testicular production of testosterone and in the prostatic expression of androgen receptor (AR), estrogen receptor alpha (ERalpha) and aromatase. However, in regressed-recrudescence periods, the prostatic expression of AR, ERalpha and aromatase increased, indicating the reactivation of the PC. Despite this, the PC appears to have a slower reactivation and seems not to follow the testicular recrudescence in morphological and morphometric terms. With these data, we demonstrate that the prostatic physiology is directly affected by total testicular regression and conclude that it is regulated by testosterone and estrogen, via the production of testosterone by the testes, its conversion to dihydrotestosterone by 5alpha-redutase and to estrogen by aromatase, and the activation/deactivation of AR and ERalpha in epithelial cells, which regulate cell expression and proliferation. PMID- 25703718 TI - A robust bioassay to assess the toxicity of metals to the Antarctic marine microalga Phaeocystis antarctica. AB - Despite evidence of contamination in Antarctic coastal marine environments, no water-quality guidelines have been established for the region because of a paucity of biological effects data for local Antarctic species. Currently, there is limited information on the sensitivity of Antarctic microalgae to metal contamination, which is exacerbated by the lack of standard toxicity testing protocols for local marine species. In the present study, a routine and robust toxicity test protocol was developed using the Antarctic marine microalga Phaeocystis antarctica, and its sensitivity was investigated following 10-d exposures to dissolved copper, cadmium, lead, zinc, and nickel. In comparisons of 10% inhibition of population growth rate (IC10) values, P. antarctica was most sensitive to copper (3.3 MUg/L), followed by cadmium (135 MUg/L), lead (260 MUg/L), and zinc (450 MUg/L). Although an IC10 value for nickel could not be accurately estimated, the no-observed-effect concentration value for nickel was 1070 MUg/L. Exposure to copper and cadmium caused changes in internal cell granularity and increased chlorophyll a fluorescence. Lead, zinc, and nickel had no effect on any of the cellular parameters measured. The present study provides valuable metal-ecotoxicity data for an Antarctic marine microalga, with P. antarctica representing one of the most sensitive microalgal species to dissolved copper ever reported when compared with temperate and tropical species. PMID- 25703719 TI - Alcohol alters the activation of ERK1/2, a functional regulator of binge alcohol drinking in adult C57BL/6J mice. AB - BACKGROUND: Binge alcohol drinking is a particularly risky pattern of alcohol consumption that often precedes alcohol dependence and addiction. The transition from binge alcohol drinking to alcohol addiction likely involves mechanisms of synaptic plasticity and learning in the brain. The mitogen-activated protein kinase (MAPK) signaling cascades have been shown to be involved in learning and memory, as well as the response to drugs of abuse, but their role in binge alcohol drinking remains unclear. The present experiments were designed to determine the effects of acute alcohol on extracellular signaling-related kinases (ERK1/2) expression and activity and to determine whether ERK1/2 activity functionally regulates binge-like alcohol drinking. METHODS: Adult male C57BL/6J mice were injected with ethanol (EtOH) (3.0 mg/kg, intraperitoneally) 10, 30, or 90 minutes prior to brain tissue collection. Next, mice that were brought to freely consume unsweetened EtOH in a binge-like access procedure were pretreated with the MEK1/2 inhibitor SL327 or the p38 MAPK inhibitor SB239063. RESULTS: Acute EtOH increased pERK1/2 immunoreactivity relative to vehicle in brain regions known to be involved in drug reward and addiction, including the central amygdala and prefrontal cortex. However, EtOH decreased pERK1/2 immunoreactivity relative to vehicle in the nucleus accumbens core. SB239063 pretreatment significantly decreased EtOH consumption only at doses that also produced nonspecific locomotor effects. SL327 pretreatment significantly increased EtOH, but not sucrose, consumption without inducing generalized locomotor effects. CONCLUSIONS: These findings indicate that ERK1/2 MAPK signaling regulates binge like alcohol drinking. As alcohol increased pERK1/2 immunoreactivity relative to vehicle in brain regions known to regulate drug self-administration, SL327 may have blocked this direct pharmacological effect of alcohol and thereby inhibited the termination of binge-like drinking. PMID- 25703720 TI - Emerging concepts of heart failure in tetralogy of Fallot. PMID- 25703721 TI - Differential dimerization of variants linked to enhanced S-cone sensitivity syndrome (ESCS) located in the NR2E3 ligand-binding domain. AB - NR2E3 encodes the photoreceptor-specific nuclear hormone receptor that acts as a repressor of cone-specific gene expression in rod photoreceptors, and as an activator of several rod-specific genes. Recessive variants located in the ligand binding domain (LBD) of NR2E3 cause enhanced short wavelength sensitive- (S-) cone syndrome (ESCS), a retinal degeneration characterized by an excess of S cones and non-functional rods. We analyzed the dimerization properties of NR2E3 and the effect of disease-causing LBD missense variants by bioluminescence resonance energy transfer (BRET(2) ) protein interaction assays. Homodimerization was not affected in presence of p.A256V, p.R039G, p.R311Q, and p.R334G variants, but abolished in presence of p.L263P, p.L336P, p.L353V, p.R385P, and p.M407K variants. Homology modeling predicted structural changes induced by NR2E3 LBD variants. NR2E3 LBD variants did not affect interaction with CRX, but with NRL and rev-erbalpha/NR1D1. CRX and NRL heterodimerized more efficiently together, than did either with NR2E3. NR2E3 did not heterodimerize with TLX/NR2E1 and RXRalpha/NR2C1. The identification of a new compound heterozygous patient with detectable rod function, who expressed solely the p.A256V variant protein, suggests a correlation between LBD variants able to form functional NR2E3 dimers and atypical mild forms of ESCS with residual rod function. PMID- 25703722 TI - Photocurrent generation from thylakoid membranes on osmium-redox-polymer-modified electrodes. AB - Thylakoid membranes (TMs) are uniquely suited for photosynthesis owing to their distinctive structure and composition. Substantial efforts have been directed towards use of isolated photosynthetic reaction centers (PRCs) for solar energy harvesting, however, few studies investigate the communication between whole TMs and electrode surfaces, due to their complex structure. Here we report on a promising approach to generate photosynthesis-derived bioelectricity upon illumination of TMs wired with an osmium-redox-polymer modified graphite electrode, and generate a photocurrent density of 42.4 MUA cm(-2). PMID- 25703723 TI - Label-free in-situ monitoring of protein tyrosine nitration in blood by surface enhanced Raman spectroscopy. AB - A novel label-free method for the in-situ monitoring of protein tyrosine nitration (PTN) was explored based on surface-enhanced Raman spectroscopy (SERS). Benefiting from the relative weak binding ability of sulfate to silver surface, the Raman signals of nitrated peptides were boosted well with sulfate-aggregated silver nanoparticles (Ag NPs). The distinction of the SERS spectra between non nitrated peptides and nitrated peptides was obtained by directly comparing SERS bands at 330-400cm(-1), allowing the rapid identification of PTN. Furthermore, without any pretreatments, the established method was successfully applied in the rapid in-situ dynamic monitoring of the mimic hemin-catalyzed PTN process in synthetic peptide, bovine serum albumin (BSA), and original human blood serum samples. The results indicated that the proposed approach could be a promising in situ label-free tool for observing PTN process, which may be quite helpful to deeply understand the mechanism of post-translation modification. PMID- 25703724 TI - Microscale microbial fuel cells: Advances and challenges. AB - The next generation of sustainable energy could come from microorganisms; evidence that it can be seen with the given rise of Electromicrobiology, the study of microorganisms' electrical properties. Many recent advances in electromicrobiology stem from studying microbial fuel cells (MFCs), which are gaining acceptance as a future alternative "green" energy technology and energy efficient wastewater treatment method. MFCs are powered by living microorganisms with clean and sustainable features; they efficiently catalyse the degradation of a broad range of organic substrates under natural conditions. There is also increasing interest in photosynthetic MFCs designed to harness Earth's most abundant and promising energy source (solar irradiation). Despite their vast potential and promise, however, MFCs and photosynthetic MFCs have not yet successfully translated into commercial applications because they demonstrate persistent performance limitations and bottlenecks associated with scaling up. Instead, microscale MFCs have received increasing attention as a unique platform for various applications such as powering small portable electronic elements in remote locations, performing fundamental studies of microorganisms, screening bacterial strains, and toxicity detection in water. Furthermore, the stacking of miniaturized MFCs has been demonstrated to offer larger power densities than a single macroscale MFC in terms of scaling up. In this overview, we discuss recent achievements in microscale MFCs as well as their potential applications. Further scientific and technological challenges are also reviewed. PMID- 25703725 TI - Determining the fate of fluorescent quantum dots on surface of engineered budding S. cerevisiae cell molecular landscape. AB - In this study, we surface engineered living S. cerevisiae cells by decorating quantum dots (QDs) and traced the fate of QDs on molecular landscape of single mother cell through several generation times (progeny cells). The fate of QDs on cell-surface was tracked through the cellular division events using confocal microscopy and fluorescence emission profiles. The extent of cell-surface QDs distribution among the offspring was determined as the mother cell divides into daughter cells. Fluorescence emission from QDs on progeny cells was persistent through the second-generation time (~240min) until all of the progeny cells lost their cell-bound QDs during the third generation time (~360min). The surface engineered yeast cells were unaffected by the QDs present on their molecular landscapes and retained their normal cellular growth, architecture and metabolic activities as confirmed by their viability, scanning electron microscopy (SEM) examinations and cytotoxicity tests, respectively. Our results demonstrated that QDs on mother cell landscape tend to distribute among its progeny cells that accompanied with concomitant reduction in QDs' fluorescence, which can be quantified. We suggest that surface engineered cells with QDs will enable investigating the cellular behavior and monitoring cell growth patterns as nanobiosensors for screening of drugs/chemicals at single cell level with fewer side effects. PMID- 25703727 TI - RETRACTED: Monolayers of pigment-protein complexes on a bare gold electrode: Orientation controlled deposition and comparison of electron transfer rate for two configurations. AB - This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the Editor-in-Chief and the Corresponding Author, Muhammad Kamran. This paper has been withdrawn as the authors did not fully consult with their project collaborators prior to publication and failed to include them as co-authors of the article. This is acknowledged by the corresponding author. The authors and the Publisher would like to apologise for any inconvenience caused. PMID- 25703726 TI - Affinity sensor based on immobilized molecular imprinted synthetic recognition elements. AB - An affinity sensor based on capacitive transduction was developed to detect a model compound, metergoline, in a continuous flow system. This system simulates the monitoring of low-molecular weight organic compounds in natural flowing waters, i.e. rivers and streams. During operation in such scenarios, control of the experimental parameters is not possible, which poses a true analytical challenge. A two-step approach was used to produce a sensor for metergoline. Submicron spherical molecularly imprinted polymers, used as recognition elements, were obtained through emulsion polymerization and subsequently coupled to the sensor surface by electropolymerization. This way, a robust and reusable sensor was obtained that regenerated spontaneously under the natural conditions in a river. Small organic compounds could be analyzed in water without manipulating the binding or regeneration conditions, thereby offering a viable tool for on site application. PMID- 25703728 TI - Fluorescein-5-isothiocyanate-conjugated protein-directed synthesis of gold nanoclusters for fluorescent ratiometric sensing of an enzyme-substrate system. AB - This study describes the synthesis of a dual emission probe for the fluorescent ratiometric sensing of hydrogen peroxide (H2O2), enzyme activity, and environmental pH change. Green-emitting fluorescein-5-isothiocyanate (FITC) was conjugated to the amino groups of bovine serum albumin (BSA). This FITC conjugated BSA acted as a template for the synthesis of red-emitting gold nanoclusters (AuNCs) under alkaline conditions. Under single wavelength excitation, FITC/BSA-stabilized AuNCs (FITC/BSA-AuNCs) emitted fluorescence at 525 and 670nm, which are sensitive to changes in solution pH and H2O2 concentration, respectively. The effective fluorescence quenching of AuNCs by H2O2 enabled FITC/BSA-AuNCs to ratiometrically detect the H2O2 product-related enzyme system and its inhibition, including glucose oxidase-catalyzed oxidation of glucose, acetylcholinesterase/choline oxidase-mediated hydrolysis and oxidation of acetylcholine, and paraoxon-induced inhibition of acetylcholinesterase activity. When pH-insensitive AuNCs were used as an internal standard, FITC/BSA-AuNCs offered a sensitive and reversible ratiometric sensing of a 0.1-pH unit change in the pH range 5.0-8.5. The pH-induced change in FITC fluorescence enabled FITC/BSA-AuNCs to detect an ammonia product-related enzyme system. This was exemplified with the determination of urea in plasma by urease mediated hydrolysis of urea. PMID- 25703729 TI - Composite materials for polymer electrolyte membrane microbial fuel cells. AB - Recently, the feasibility of using composite metal-carbon, metal-polymer, polymer carbon, polymer-polymer and carbon-carbon materials in microbial fuel cells (MFCs) has been investigated. These materials have been tested as MFC anode catalyst (microorganism) supports, cathode catalysts and membranes. These hybrid materials, possessing the properties of each component, or even with a synergistic effect, would present improved characteristics with respect to the bare components. In this paper we present an overview of the use of these composite materials in microbial fuel cells. The characteristics of the composite materials as well as their effect on MFC performance were compared with those of the individual component and/or the conventionally used materials. PMID- 25703730 TI - Approach for determination of ATP:ADP molar ratio in mixed solution by surface enhanced Raman scattering. AB - The ATP:ADP molar ratio is an important physiological factor. However, in previous literatures, ATP and ADP could not be distinguished by Raman spectroscopy due to the high similarity of molecular structure. To challenge this problem, also considering that the gamma phosphate group may interact with adenine group and cause a different variation of the Raman spectrum than that of ADP, a highly sensitive, low-cost, environment protecting, flexible and super hydrophobic Au nanoparticles/cicada wing (Au/CW) substrate with three-dimension structure was fabricated and employed as an active surface-enhanced Raman scattering (SERS) substrate to detect the ATP:ADP molar ratios. The concentration as low as 10(-8)M for ATP and ADP was analyzed to determine the limit of detection. This SERS study on various ATP:ADP molar ratios demonstrates that ATP:ADP could be distinguished and the quantitative determination of ATP content was achieved. Moreover, a principle was speculated based on the molecular structures of ATP and ADP of the Raman peaks centered at ~685 and ~731cm(-1) to explain the linear relationship between the area ratio and the molar ratio. A new method has been developed for quantitative determination of ATP:ADP molar ratio based on Au/CW substrate by the SERS method. PMID- 25703731 TI - A label-free method for detecting biothiols based on poly(thymine)-templated copper nanoparticles. AB - A novel label-free nanosensor has been developed for detecting biothiols including cysteine, glutathione and homocysteine based on poly(thymine)-templated fluorescent copper nanoparticles (CuNPs), which were controlled through thymine Hg(II)-thymine coordination. This assay provides a simple, cost-effective, and sensitive platform for the detection of biothiols. By employing this turn-on sensor, biological thiols, such as cysteine, glutathione and homocysteine, are successfully detected at concentrations as low as 12.5nM for cysteine, 15nM for glutathione, and 20nM for homocysteine. The sensing system also exhibits high selectivity against other amino acids, and the application of the sensor for biological fluids shows that the proposed method works well for real samples. PMID- 25703732 TI - Novel Coating of Surgical Suture Confers Antimicrobial Activity Against Porphyromonas gingivalis and Enterococcus faecalis. AB - BACKGROUND: The oral cavity is colonized by >10(9) bacteria, many of which can increase heart disease risk when seeded into the bloodstream. Most dentoalveolar surgeries require the use of surgical sutures. Suture placement and removal can increase the risk of postoperative infection and bacteremia. The aim of this study is to evaluate the antimicrobial activity of a novel quaternary ammonium compound, K21, when coated on different suture materials. METHODS: The periodontal pathogen Porphyromonas gingivalis and the endodontic species Enterococcus faecalis were grown to early log phase and inoculated on enriched Brucella blood agar, on which were placed identical lengths of surgical suture (chromic gut, polyester suture, silk, and nylon suture) and control unwaxed dental floss impregnated with K21 at 5%, 10%, 20%, and 25% volume/volume in ethanol vehicle. Controls included the following: 1) sutures treated with vehicle; 2) untreated sutures; and 3) unwaxed floss. Zones of inhibition in millimeters were measured at five randomized sites per suture/floss for each concentration and material used. Mean +/- SD of zones of inhibition were calculated, and analysis of variance (P <0.05) was used to determine whether differences were statistically significant. RESULTS: The results indicate that K21-coated suture at concentrations ranging from 5% to 25%, depending on the type of suture, have antimicrobial activity for P. gingivalis and E. faecalis. Nylon suture coated with K21 at 5%, 10%, 20%, and 25% resulted in zones ranging from 3 to 11 mm. Polyester suture was more effective at lower K21 concentrations with 5% (P = 0.0031), 10% (P = 0.0011), and 20% (P = 0.0002), yielding 7.5, 8.3, and 10.5 mm zones of inhibition. K21-coated silk suture yielded significant zones of inhibition at 25% (P <0.0001), whereas chromic gut was effective at K21 concentrations of 5% (P = 0.0081) and 25% (P <0.0001). CONCLUSION: It is concluded that K21-coated surgical sutures have antimicrobial activity for bacterial species of direct relevance to postoperative infection and bacteremia. PMID- 25703733 TI - Evaluation of salivary procalcitonin levels in different periodontal diseases. AB - BACKGROUND: The present study aims to investigate the levels of salivary procalcitonin (ProCT) in patients with different periodontal diseases. METHODS: Seventy-two non-smokers are included in this study: 21 individuals with chronic periodontitis (CP), 14 individuals with generalized aggressive periodontitis (GAgP), 18 individuals with gingivitis (G), and 19 periodontally healthy (H) participants. Clinical periodontal parameters, including probing depth (PD), clinical attachment level (CAL), plaque index, and gingival index (GI), were assessed in all participants. Saliva samples were collected and examined for evaluating ProCT levels. RESULTS: It was found that the median (interquartile range) salivary ProCT level was lowest in the H group: 0.00 (0.09) ng/mL; followed by the G group: 0.09 (0.11) ng/mL; the CP group: 0.15 (0.29) ng/mL; and highest in the GAgP group 0.28 (0.68) ng/mL. These differences were statistically significant between the H group and the other groups (P <0.05). There were positive correlations between the mean salivary ProCT level and GI, CAL, and PD. CONCLUSION: According to the present results, ProCT might play a role during periodontal inflammation, and an elevated salivary ProCT level is suggested as a potential biomarker for periodontal diseases. PMID- 25703734 TI - Degree of Carotid Artery Stenosis in Neurologically Asymptomatic Cardiac Surgical Patients Suffering from Perioperative Stroke: Results of an Observational Study. AB - Background Postoperative stroke in cardiac surgical patients remains a serious adverse outcome. Methods A total of 2,784 consecutively operated cardiac surgical patients without preoperative neurologic impairment were analyzed retrospectively with regard to impact of preoperative carotid stenosis on the incidence of postprocedural new onset of stroke. Therefore, all analyzed patients were assigned to four groups depending on preoperative degree of carotid artery stenosis detected by carotid duplex sonography (group I: < 50%, group II: 50-75%, group III: 76-89%, and group IV: > 90%). Results All pre-, intra-, and postoperative risk factors for neurological disorders were comparable throughout the cohort. Of the 2,784 patients, 65 (2.3%) met the inclusion criteria (preoperatively neurologically asymptomatic status, preoperatively carotid duplex ultrasonography study not older than 6 months, heart surgery with extracorporeal circulation, stroke until 48 hours after operation). Of the 65 patients who met the inclusion criteria, 43 (66.2%) were in group I, 11 (16.9%) in group II, 5 (7.7%) in group III, and 6 (9.2%) in group IV (p = 0.175). The overall incidence of an ipsilateral stroke relating to the carotid stenosis was 38 (1.4%) patients. Of these, 27 (71.1%) patients were in group I, 6 (15.8%) patients in group II, 2 (5.3%) patients in group III, and 3 (7.9%) patients in group IV (p = 0.568). Conclusion This observational study demonstrates that the degree of carotid stenosis in neurologically asymptomatic cardiac surgical patients is not able to predict the probability of perioperative stroke. Until further results from prospective randomized trials with neurologically asymptomatic cardiac surgical patients are presented, a cautious attitude for concomitant carotid endarterectomy is still justified. PMID- 25703735 TI - Association of hospital structures with mortality from ruptured abdominal aortic aneurysm. AB - BACKGROUND: There is significant variation in the mortality rates of patients with a ruptured abdominal aortic aneurysm (rAAA) admitted to hospital in England. This study sought to investigate whether modifiable differences in hospital structures and processes were associated with differences in patient outcome. METHODS: Patients diagnosed with rAAA between 2005 and 2010 were extracted from the Hospital Episode Statistics database. After risk adjustment, hospitals were grouped into low-mortality outlier, expected mortality and high-mortality outlier categories. Hospital Trust-level structure and process variables were compared between categories, and tested for an association with risk-adjusted 90-day mortality and non-corrective treatment (palliation) rate using binary logistic regression models. RESULTS: There were 9877 patients admitted to 153 English NHS Trusts with an rAAA during the study. The overall combined (operative and non operative) mortality rate was 67.5 per cent (palliation rate 41.6 per cent). Seven hospital Trusts (4.6 per cent) were high-mortality and 15 (9.8 per cent) were low-mortality outliers. Low-mortality outliers used significantly greater mean resources per bed (doctors: 0.922 versus 0.513, P < 0.001; consultant doctors: 0.316 versus 0.168, P < 0.001; nurses: 2.341 versus 1.770, P < 0.001; critical care beds: 0.045 versus 0.019, P < 0.001; operating theatres: 0.027 versus 0.019, P = 0.002) and performed more fluoroscopies (mean 12.6 versus 9.2 per bed; P = 0.046) than high-mortality outlier hospital Trusts. On multivariable analysis, greater numbers of consultants, nurses and fluoroscopies, teaching status, weekday admission and rAAA volume were independent predictors of lower mortality and, excluding rAAA volume, a lower rate of palliation. CONCLUSION: The variability in rAAA outcome in English National Health Service hospital Trusts is associated with modifiable hospital resources. Such information should be used to inform any proposed quality improvement programme surrounding rAAA. PMID- 25703736 TI - Characterization of patients with dystrophic epidermolysis bullosa for collagen VII therapy. PMID- 25703737 TI - Randomized trial to assess the effect of supervised and unsupervised video feedback on teaching practical skills. AB - BACKGROUND: Feedback is a vital component of the learning process; however, great variation exists in the quality, quantity, and method of delivery. Video feedback is not commonly used in the teaching of surgical skills. The aim of this trial was to evaluate the benefit of 2 types of video feedback-individualized video feedback (IVF), with the student reviewing their performance with an expert tutor, and unsupervised video-enhanced feedback (UVF), where the student reviews their own performance together with an expert teaching video-to determine if these improve performance when compared with a standard lecture feedback. METHODS: A prospective blinded randomized control trial comparing lecture feedback with IVF and UVF was carried out. Students were scored by 2 experts directly observing the performance and 2 blinded experts using a validated pro forma. Participants were recorded on video when performing a suturing task. They then received their feedback via any of the 3 methods before being invited to repeat the task. RESULTS: A total of 32 students were recruited between the 3 groups. There was no significant difference in suturing skill performance scores given by those directly observing the students and those blinded to the participant. There was no statistically significant difference between the 2 video feedback groups (p = 1.000), but there was significant improvement between standard lecture feedback and UVF (p = 0.047) and IVF (p = 0.001). CONCLUSION: Video feedback can facilitate greater learning of clinical skills. Students can attain a similar level of surgical skills improvement with UVF as with teacher intensive IVF. PMID- 25703738 TI - Every surgical resident should know how to perform a cricothyrotomy: an inexpensive cricothyrotomy task trainer for teaching and assessing surgical trainees. AB - OBJECTIVE: Emergency cricothyrotomy is a rare but potentially lifesaving procedure. Training opportunities for surgical residents to learn this skill are limited, and many graduating residents have never performed one during their training. We aimed to develop and validate a novel and inexpensive cricothyrotomy task trainer that can be constructed from household items. DESIGN: A model was constructed using a toilet paper roll (trachea and larynx), Styrofoam (soft tissue), cardboard (thyroid cartilage), zip tie (cricoid), and fabric (skin). Participants were asked to complete a simulated cricothyrotomy procedure using the model. They were then evaluated using a 10-point checklist (5 points total) devised by 6 general surgeons. Participants were also asked to complete an anonymous survey rating the educational value and the degree of enjoyment regarding the model. SETTING: A tertiary care teaching hospital. PARTICIPANTS: A total of 54 students and general surgery residents (11 medical students, 32 interns, and 11 postgraduate year 3 residents). RESULTS: All 54 participants completed the training and assessment. The scores ranged from 0 to 5. The mean (range) scores were 1.8 (1-4) for medical students, 3.5 (1-5) for junior residents, and 4.9 (4-5) for senior-level residents. Medical students were significantly outperformed by junior- and senior-level residents (p < 0.001). Trainees felt that the model was educational (4.5) and enjoyable (4.0). CONCLUSIONS: A low-fidelity, low-cost cricothyrotomy simulator distinguished the performance of emergency cricothyrotomy between medical students and junior- and senior-level general surgery residents. This task trainer may be ideally suited to providing basic skills to all physicians in training, especially in settings with limited resources and clinical opportunities. PMID- 25703739 TI - Widespread occurrence of both metabolic and target-site herbicide resistance mechanisms in Lolium rigidum populations. AB - BACKGROUND: Lolium rigidum populations in Australia and globally have demonstrated rapid and widespread evolution of resistance to acetyl coenzyme A carboxylase (ACCase)-inhibiting and acetolactate synthase (ALS)-inhibiting herbicides. Thirty-three resistant L. rigidum populations, randomly collected from crop fields in a most recent resistance survey, were analysed for non-target site diclofop metabolism and all known target-site ACCase gene resistance endowing mutations. RESULTS: The HPLC profile of [(14) C]-diclofop-methyl in vivo metabolism revealed that 79% of these resistant L. rigidum populations showed enhanced capacity for diclofop acid metabolism (metabolic resistance). ACCase gene sequencing identified that 91% of the populations contain plants with ACCase resistance mutation(s). Importantly, 70% of the populations exhibit both non target-site metabolic resistance and target-site ACCase mutations. CONCLUSIONS: This work demonstrates that metabolic herbicide resistance is commonly occurring in L. rigidum, and coevolution of both metabolic resistance and target-site resistance is an evolutionary reality. Metabolic herbicide resistance can potentially endow resistance to many herbicides and poses a threat to herbicide sustainability and thus crop production, calling for major research and management efforts. PMID- 25703740 TI - Human-directed social behaviour in dogs shows significant heritability. AB - Through domestication and co-evolution with humans, dogs have developed abilities to attract human attention, e.g. in a manner of seeking assistance when faced with a problem solving task. The aims of this study were to investigate within breed variation in human-directed contact seeking in dogs and to estimate its genetic basis. To do this, 498 research beagles, bred and kept under standardized conditions, were tested in an unsolvable problem task. Contact seeking behaviours recorded included both eye contact and physical interactions. Behavioural data was summarized through a principal component analysis, resulting in four components: test interactions, social interactions, eye contact and physical contact. Females scored significantly higher on social interactions and physical contact and age had an effect on eye contact scores. Narrow sense heritabilities (h(2) ) of the two largest components were estimated at 0.32 and 0.23 but were not significant for the last two components. These results show that within the studied dog population, behavioural variation in human-directed social behaviours was sex dependent and that the utilization of eye contact seeking increased with age and experience. Hence, heritability estimates indicate a significant genetic contribution to the variation found in human-directed social interactions, suggesting that social skills in dogs have a genetic basis, but can also be shaped and enhanced through individual experiences. This research gives the opportunity to further investigate the genetics behind dogs' social skills, which could also play a significant part into research on human social disorders such as autism. PMID- 25703741 TI - Exploring access and attitudes to regular sexually transmitted infection screening: the views of young, multi-ethnic, inner-city, female students. AB - BACKGROUND: Low uptake of sexually transmitted infection (STI) testing by young people is a major public health problem worldwide. The aims of this qualitative, community-based study were to explore access and attitudes to STI screening in high risk, young, ethnically diverse female students. METHODS: Qualitative semi structured interviews were conducted at an inner-London further education college with 17 women aged 16-25 years. RESULTS: The women wanted convenient, regular STI testing and perceived this as responsible behaviour. However, they doubted the maturity of their peers who were unlikely to view themselves as candidates for testing, and feared the perceived stigma associated with testing. This was reflected in their preference for confidential testing. Despite attending their general practice for non-sexual health matters, most did not consider this option for STI testing. However, the long wait in specialist clinics was an important barrier. Many younger participants would not want postal STI sample kits sent to their homes. We found dissatisfaction with sexual health education. CONCLUSIONS: STI screening for underserved groups such as young sexually active ethnically diverse female college students needs to be confidential, convenient, easily accessed and offered in ways that allow them to consider themselves as candidates for such screening without fear of social stigma. Family doctors should be aware that young women often do not perceive primary care to be an option for accessing STI screening, and could consider ways of advertising these services. Policymakers and commissioners should be aware that clinic waiting times and lack of education remain barriers to testing. PMID- 25703742 TI - 3D surface imaging of the human female torso in upright to supine positions. AB - Three-dimensional (3D) surface imaging of breasts is usually done with the patient in an upright position, which does not permit comparison of changes in breast morphology with changes in position of the torso. In theory, these limitations may be eliminated if the 3D camera system could remain fixed relative to the woman's torso as she is tilted from 0 to 90 degrees . We mounted a 3dMDtorso imaging system onto a bariatric tilt table to image breasts at different tilt angles. The images were validated using a rigid plastic mannequin and the metrics compared to breast metrics obtained from five subjects with diverse morphology. The differences between distances between the same fiducial marks differed between the supine and upright positions by less than 1% for the mannequin, whereas the differences for distances between the same fiducial marks on the breasts of the five subjects differed significantly and could be correlated with body mass index and brassiere cup size for each position change. We show that a tilt table-3D imaging system can be used to determine quantitative changes in the morphology of ptotic breasts when the subject is tilted to various angles. PMID- 25703743 TI - Posterior stabilized versus cruciate retaining total knee arthroplasty designs: conformity affects the performance reliability of the design over the patient population. AB - Commercially available fixed bearing knee prostheses are mainly divided into two groups: posterior stabilized (PS) versus cruciate retaining (CR). Despite the widespread comparative studies, the debate continues regarding the superiority of one type over the other. This study used a combined finite element (FE) simulation and principal component analysis (PCA) to evaluate "reliability" and "sensitivity" of two PS designs versus two CR designs over a patient population. Four fixed bearing implants were chosen: PFC (DePuy), PFC Sigma (DePuy), NexGen (Zimmer) and Genesis II (Smith & Nephew). Using PCA, a large probabilistic knee joint motion and loading database was generated based on the available experimental data from literature. The probabilistic knee joint data were applied to each implant in a FE simulation to calculate the potential envelopes of kinematics (i.e. anterior-posterior [AP] displacement and internal-external [IE] rotation) and contact mechanics. The performance envelopes were considered as an indicator of performance reliability. For each implant, PCA was used to highlight how much the implant performance was influenced by changes in each input parameter (sensitivity). Results showed that (1) conformity directly affected the reliability of the knee implant over a patient population such that lesser conformity designs (PS or CR), had higher kinematic variability and were more influenced by AP force and IE torque, (2) contact reliability did not differ noticeably among different designs and (3) CR or PS designs affected the relative rank of critical factors that influenced the reliability of each design. Such investigations enlighten the underlying biomechanics of various implant designs and can be utilized to estimate the potential performance of an implant design over a patient population. PMID- 25703744 TI - Mutational spectrum of the TYR and SLC45A2 genes in Pakistani families with oculocutaneous albinism, and potential founder effect of missense substitution (p.Arg77Gln) of tyrosinase. AB - BACKGROUND: Oculocutaneous albinism (OCA) is an autosomal recessive disorder of abnormal melanin formation, which results in hypopigmentation of skin, hair and eyes. OCA is classified into four types based on clinical and genetic findings. OCA1 is the most severe form of albinism, and is caused by mutations in the tyrosinase (TYR) gene, while OCA4 is caused due to mutations in SLC45A2. METHODS: In total, 13 families with >= 3 members with OCA were enrolled. Family history was ascertained and pedigrees were drawn up. Blood samples were collected and processed for DNA extraction. Linkage analysis was performed by typing three short tandem repeat markers in candidate regions of TYR and SLC45A2. Sequence analysis was performed of all the coding exons and adjacent intronic sequences of both genes. RESULTS: Eight families showed linkage to OCA1 and one family showed linkage to OCA4. Four missense substitutions (p.Arg239Trp, p.Ser192Tyr, p.Ser44Arg and p.Arg77Gln) were identified in TYR in the families with OCA1 linkage, and another missense substitution (p.Gln272Lys) was identified in the family with OCA4 linkage. One of the identified missense substitution (p.Arg77Gln) in TYR was found in five different families, which had a common haplotype. CONCLUSIONS: We identified four missense substitutions in TYR and a single missense substitution in SLC45A2. One missense substitution (p.Arg77Gln) in TYR was found in five different families that originated from the same geographical area and displayed a common haplotype, suggesting a single origin that then spread to different geographical areas of Azad Kashmir, Pakistan. PMID- 25703745 TI - Spatial variation, environmental risk and biological hazard assessment of heavy metals in surface sediments of the Yangtze River estuary. AB - 30 samples of eight heavy metals were collected in February 2011 within Yangtze River estuary (YRE). The mean concentrations met the primary standard criteria based on Marine Sediments Quality of China. The spatial distribution showed that a gradient concentration decreased gradually from inner-estuary to river mouth. Anthropogenic inputs might be the main contributor, and fine grained sediments might also aggravate the heavy metal contamination. The assessment results indicated that the YRE was in low risk of contamination caused by every single heavy metal. However, it was in considerable degree of contamination considering combination of all the heavy metals. The toxicities of heavy metals might be elevated when heavy metals were in combination. Arsenic should be of primary concern due to its higher assessment values and the potential of adverse biological effects. And the concentration of As in the YRE had a trend to increase because of anthropogenic activities nearby. PMID- 25703746 TI - Adherent scars: Do they really exist? PMID- 25703747 TI - Key steps for managing changes in the curriculum. PMID- 25703748 TI - Association between changes in the angle of mandible and reduced bone mineral density. AB - OBJECTIVE: To establish an association between the angle of mandible on an orthopantomogram (OPG) with reduced bone mineral density of femoral neck and spine on Dual Energy X-ray Absorptiometry (DXA) scan. STUDY DESIGN: Cross sectional study. PLACE AND DURATION OF STUDY: Institute of Basic Medical Sciences (IBMS), Dow University of Health Sciences (DUHS), Karachi, from December 2011 to July 2012. METHODOLOGY: Female subjects between 25 and 85 years of age were divided into premenopausal (Group-I) and postmenopausal (Group II) groups. Dual Energy X-ray Absorptiometry (DXA) scan was done to divide Group-I and Group-II into normal (pre A, post A), osteopenic (pre B, post B) and osteoporotic (pre C, post C) groups. Changes seen in angle of mandible on orthopantomogram (OPG) in subgroups of Group-I were compared with each other and with subgroups of Group II. SPSS version 16 was used to carry out the statistical analysis. Intragroup significance was evaluated through One Way Analysis Of Variance (ANOVA). For intergroup significance independent samples t-test was applied. RESULTS: The angle of mandible (A) was significantly decreased in Intragroup comparison of Group-II (0.035) between Post normal (Post A) vs. Post osteopenic (Post B) groups. Intergroup comparison between Group-I and Group-II (0.005) showed a significant decrease in angle of mandible between Pre osteopenic (Pre B) vs. Post osteopenic (Post B). CONCLUSION: As decrease in angle of mandible was observed at stage of osteopenia, it can be conveniently used for early detection of osteoporosis. PMID- 25703749 TI - Variation in admission rates of acute coronary syndrome patients in coronary care unit according to different seasons. AB - OBJECTIVE: Environmental stresses, especially extreme cold and hot weathers, have tendency to have more admissions for acute coronary syndromes. Due to scarcity of local data, we studied the variation in patient admission rates with acute coronary syndrome according to different seasons. STUDY DESIGN: Descriptive study. PLACE AND DURATION OF STUDY: Coronary Care Unit, Civil Hospital and Pakistan Steel Hospital, Karachi, from January 2011 to December 2011. METHODOLOGY: The study group comprised consecutive patients with acute coronary syndrome (unstable angina, Non ST-Elevation Myocardial Infarction (NSTEMI), ST Elevation Myocardial Infarction (STEMI) admitted to the coronary care unit. Patients with stable angina and valvular heart disease were excluded. Data was analyzed for admission according to different seasons, (winter, spring, summer and autumn). RESULTS: The mean age of the 428 cases was 48.5 +/- 10.4 years (range 27 to 73 years). Among the study group, 261 (61%) and 167 (39%) cases were male and female respectively. ST-elevation myocardial infarction, non ST elevation myocardial infarction and unstable angina were present in 206 (48%), 128 (30%) and 94 (22%) respectively. Among the 428 patients, 184 (43%) cases had hypertension, 133 (31%) cases were smokers, 103 (24%) cases had dyslipidemia and diabetes mellitus and 08 (2%) cases had history of premature coronary artery disease. The number of patients admissions with acute coronary syndrome tended to change with sudden change in season. It increased in Winter 158 (36.9%) and Summer 130 (30.3%) in comparison to Spring 80 (18.69%) and Autumn 60 (14.02%) season. CONCLUSION: It was found variation in admission rates of acute coronary syndrome patients according to different seasons. The number of admissions not only increased in the cold season (winter) but also in hot season (summer) with sudden changes in temperature. PMID- 25703750 TI - Clinical, laboratory and bacterial profile of Spontaneous Bacterial Peritonitis in Chronic Liver Disease patients. AB - OBJECTIVE: To determine the clinical and laboratory features, bacterial profile and antibiotic sensitivity pattern of Spontaneous Bacterial Peritonitis (SBP) in Chronic Liver Disease (CLD) patients presenting at a tertiary care hospital of Karachi. STUDY DESIGN: Cross-sectional study. PLACE AND DURATION OF STUDY: PMRC Centre for Gastroenterology and Hepatology and Jinnah Postgraduate Medical Centre, Karachi, from April 2010 to March 2012. METHODOLOGY: CLD patients with ascites were recruited from PMRC Centre for Gastroenterology and Hepatology and Jinnah Postgraduate Medical Centre, Karachi. Basic demographics, symptoms and clinical signs of patients were recorded. Patients with the history of antibiotic use within last 3 days or any intra-abdominal source of infection were excluded. Diagnostic paracentesis was done for ascitic fluid detailed report (D/R) and culture. Blood sample was collected for total leukocyte count, serum proteins and billirubin levels. RESULTS: Out of a total 152 CLD patients, 38 (25%) were diagnosed with SBP. Eight (24.2%) patients presented with classical SBP, 20 (52.6%) had culture negative neutrocytic ascites and 10 (26%) had bacterascites. Fever, abdominal tenderness and constipation were common in SBP patients. Ascitic fluid culture was positive in 19 (50%) patients. E. coli (65%) was the predominant pathogen followed by Enterococcus species (15%). Resistance was high against cephalosporins (78%) and fluoroquinolones (69.6%) and least against amikacin (13%) and meropenem (12%). CONCLUSION: Ascitic fluid D/R and culture together can lead to the accurate diagnosis of SBP and can guide for the right antibiotic choice as resistance to commonly prescribed antibiotic is common in such patients. PMID- 25703751 TI - Receiver operator characteristic curve analysis of the Lintula score for reduction of negative appendectomies in adults. AB - OBJECTIVE: To evaluate the Lintula score in reducing negative appendectomies in the adult population. STUDY DESIGN: Descriptive analytical study. PLACE AND DURATION OF STUDY: Surgical Department, Khyber Teaching Hospital, Peshawar, Pakistan, from August 2012 to April 2014. METHODOLOGY: A total of 408 emergency patients with a clinical diagnosis of acute appendicitis were included in the study. True or negative appendectomy status was determined per-operatively. Lintula score was calculated afterwards and evaluated for various cut-off points. RESULTS: Among the study population, 72 (17.6%) had a normal appendix by operative assessment and 336 (82.4%) had an acutely inflammed appendix. The receiver operating characteristic curve showed that the optimal cut-off point was <= 21 with 100% sensitivity, 88.4% specificity and positive and negative predictive values of 97.3% and 100%, respectively. Area under the curve was 0.963 with 90.4% overall accuracy. CONCLUSION: Utilizing the Lintula cut-off point of <= 21, negative appendectomies, unnecessary admissions and healthcare cost can all be reduced. PMID- 25703752 TI - End-of-Treatment-Response in patients treated for hepatitis C virus with standard interferon and ribavirin based on viral load. AB - OBJECTIVE: To determine the End-of-Treatment-Response (ETR) to standard interferon and ribavirin based regimen in patients of chronic hepatitis C and to compare the ETR response in low and high viral load groups. STUDY DESIGN: Descriptive study. PLACE AND DURATION OF STUDY: Virology Department, Armed Forces Institute of Pathology (AFIP), Rawalpindi, from March 2012 to May 2013. METHODOLOGY: Patients with chronic hepatitis C virus infection were included in the study. Pre-treatment viral load was determined by RoboGene Quantification kit. Based on viral load, the 400 patients were divided into two equal groups of low viral load (< 800,000 IU/ml) and high viral load (> 800,000 IU/ml). The patients were treated with standard interferon alpha (3 million units subcutaneously thrice weekly) and ribavirin (10.6 mg/kg body weight) for 6 months. ETR was measured using Sacace Biotechnologies Qualitative kit. Chi-square test was used to compare the ETR in the two viral load groups. P-value < 0.05 was considered as significant. RESULTS: Out of 400 patients, 206 (51.5%) were males and 194 (48.5%) were females. Two hundred seventy (67.5%) patients achieved ETR and 130 (35.5%) failed to do so. In low viral load group, 145 (72.5%) patients achieved and 55 (27.5%) patients did not achieve ETR. In high viral load group, 123 (61.5%) patients achieved and 77 (38.5%) did not achieve ETR. The difference in ETR between low and high viral load groups was statistically significant (p=0.019). CONCLUSION: End-of-treatment-response in patients treated for hepatitis C virus with standard interferon and ribavirin was greater in patients with low viral load as compared to patients with high viral load. PMID- 25703753 TI - Comparison of urine dipstick test with conventional urine culture in diagnosis of urinary tract infection. AB - OBJECTIVE: To determine the sensitivity, specificity, Positive Predictive Value (PPV) and Negative Predictive Value (NPV) of Urine Nitrite (NIT) and Leukocyte Esterase (LE) test compared with urine culture for diagnosis of UTI. STUDY DESIGN: Validation study. PLACE AND DURATION OF STUDY: Department of Microbiology, Army Medical College, Rawalpindi, from January 2013 to December 2013. METHODOLOGY: Three hundred fresh uncentrifuged urine samples with suspicion of UTI, were collected and tested for LE and NIT by using (COMBI-10SL, UK) strip. Nitrite was considered as positive if there was a change in color of dipstick from colorless towards pink within 60 seconds. Leukocyte esterase was considered as positive if there was a change in color from off-white towards purple within 2 minutes. Quantitative urine culture was performed by using the strips calibrated to deliver 0.02 ul of urine on Cystine Lactose Electrolyte Deficient (CLED) medium agar. All plates were incubated at 37 degrees C and read after 24 and 48 hours. Culture was considered as gold standard to evaluate the performance of dipstick test. RESULTS: Out of 300 samples, 136 were culture positive and 164 were culture negative. Out of 136 positive culture results, 103 were dipstick positive and 33 were negative. Sensitivity, specificity, positive predictive value and negative predictive value of both nitrite and leukocyte esterase were 75.74%, 68.90%, 66.66% and 77.40% respectively considering culture as gold standard. CONCLUSION: Dipstick test for the detection of leukocyte esterase and nitrite in urine are sensitive and specific and can be used reliably for the detection of UTI in resource limited setup. PMID- 25703754 TI - Correlation of CRP levels in third trimester with fetal birth weight in preeclamptic and normotensive pregnant women. AB - OBJECTIVE: To evaluate the levels of C-reactive protein, an inflammatory marker in preeclamptic and normotensive pregnant women and to determine its correlation with fetal birth weight. STUDY DESIGN: Cross-sectional analytical study. PLACE AND DURATION OF STUDY: Unit of Obstetrics and Gynaecology, Shaikh Zayed Hospital and Gynaecological Unit II of Jinnah Hospital, Lahore, from December 2011 to May 2012. METHODOLOGY: The participants included 60 cases with preeclampsia and 60 normotensive pregnant women, all in their third trimester. All the participants were in the age group of 20 - 40 years and had a BMI range of 18 - 25. High sensitive C-reactive protein (hsCRP) levels were measured by Enzyme Link Immunosorbent Assay. Statistical analysis was done using SPSS (version 15). The values were considered significant at 0.05 level of significance. RESULTS: C reactive protein levels were significantly high (p < 0.001) in the preeclamptic group with a median value of 8.8 (0.3 - 25.5) as compared to 5.4 (0.24 - 9.8) mg/l in the normotensive women. The birth weight of babies was also significantly low in the preeclamptic group. The high CRP levels were negatively correlated with fetal birth weight in preeclamptic group. CONCLUSION: Elevated C-reactive protein levels in the preeclamptic pregnant women is a part of an exaggerated maternal systemic inflammatory response, and correlates with low fetal birth weight. PMID- 25703755 TI - Diagnostic yield of Bronchoalveolar Lavage gene Xpert in smear-negative and sputum-scarce pulmonary tuberculosis. AB - OBJECTIVE: To measure the diagnostic yield of Bronchoalveolar Lavage (BAL) gene Xpert (Xpert MTB/RIF assay), to detect Mycobacterium tuberculosis (MTB) and rifampicin resistance and compare it with that of mycobacterial cultures in a suspected case of pulmonary tuberculosis. STUDY DESIGN: An analytical study. PLACE AND DURATION OF STUDY: Department of Pulmonology, Fauji Foundation Hospital (FFH), Rawalpindi, from December 2012 to August 2013. METHODOLOGY: BAL specimens of 93 patients with suspected pulmonary tuberculosis with smear-negative or sputumscarce disease, who presented to the Department of Pulmonology, FFH, Rawalpindi were inducted. A smear-negative case was one in whom three consecutive early morning sputum samples did not reveal acid fast bacilli when examined by microscopy with Zeihl Nelson (ZN) stain. Patients who had sputum amount less than 1 ml were defined to have sputumscarce disease. The same was evaluated with ZN stain, gene Xpert and mycobacterial cultures. Sensitivity analysis was carried out using culture as the gold standard. RESULTS: The frequency of positive mycobacterial cultures was 85 (91.4%). The sensitivity, specificity, positive predictive value and negative predictive values of BAL gene Xpert to detect Mycobacterium tuberculosis were 91.86%, 71.42%, 97.53% and 41.66% respectively. Xpert MTB/RIF assay had a sensitivity and specificity of 83.33% and 100% to detect rifampicin resistance. CONCLUSION: Bronchoalveolar lavage gene Xpert had a superior diagnostic yield in patients with either smear-negative or sputum-scarce pulmonary tuberculosis. Hence a positive Xpert MTB/RIF assay may be a useful adjunct to diagnosis and detection of MDR-TB in bronchoalveolar lavage specimens. PMID- 25703756 TI - Hematological manifestation in HIV infected children. AB - OBJECTIVE: To determine the common hematological abnormalities in HIV infected children and any association of these abnormalities with HIV disease severity. STUDY DESIGN: Cross-sectional study. PLACE AND DURATION OF STUDY: Regional Pediatric ART centre, Medical College and Hospital, Kolkata, West Bengal, India, from November 2011 to November 2012. METHODOLOGY: Children up to 12 years with confirmed diagnosis of HIV infection were clinically examined and tested for complete hemogram and CD4 count. Bone marrow study was done in selected patient depending on hemogram report. Children were divided in different stages according to WHO clinical staging. Each of the hematological parameters was assessed for any association with progression of disease. Fisher's Exact Test was used for determining the association between WHO clinical staging and abnormal blood parameters. P-value < 0.05 was taken as significant. RESULTS: Sixty nine percent of the study population was anemic; 47.37% (18/38), 66.67% (8/12), 71.43% (15/21) and 93.10% (27/29) of stage 1, 2, 3 and 4 respectively were anemic in the study population (p=0.001). Leucopenia was present in 34% (34/100) children. Neutropenia and lymphopenia was present in 19% (19/100) and 22% (22/100) children. Lymphopenia was present in 7.89% (3/38), 16.67% (2/12), 19.05% (4/21) and 44.83% (13/29) of patient with stage 1, 2, 3 and 4 respectively (p=0.020). Eosinophilia was present in 17% (17/100) and thrombocytopenia in 11% (11/100) children. 2 patients with stage 4 disease were with hypoplastic bone marrow. CONCLUSION: Anemia was the most common hematological abnormality in HIV infected children. Anemia and lymphopenia had a significant association with the stage of the disease. PMID- 25703757 TI - Precocious puberty in children. AB - OBJECTIVE: To determine the etiology of precocious puberty in children and to compare the clinical and laboratory parameters of central and peripheral precocious puberty. STUDY DESIGN: Cross-sectional study. PLACE AND DURATION OF STUDY: Endocrine Clinic at National Institute of Child Health, Karachi, from January 2009 to December 2011. METHODOLOGY: Children presenting with precocious puberty were included. The age of onset of puberty was documented. Clinical evaluation, Tanner staging, height, height SDS, weight, weight SDS, body mass index, bone age, pelvic USG, plasma estradiol level and GnRH stimulation were done. Ultrasound of adrenal glands, serum level of 17 hydroxyprogesterone, ACTH, Renin, aldosterone and testosterone were performed in children with peripheral precocious puberty. MRI of adrenal glands and gonads was done in patients with suspected tumor of that organ and MRI of brain was done in patients with central precocious puberty. Skeletal survey was done in patients with Mc Cune-Albright syndrome. RESULTS: CAH (81.8%) indentified as a main cause in peripheral percocious puberty and idiopathic (67.74%) in central precocious puberty. Eighty five patients were registered during this period. The conditions causing precocious puberty were central precocious puberty (36.47%), peripheral precocious puberty (38.82%), premature pubarche (10.58%) and premature thelarche (14.11%). There was a difference in the age of onset of puberty in case of central precocious puberty (mean=3, 2-6 years) versus peripheral precocious puberty (mean=5.25; 3.62 - 7.0 years). Children with central precocious puberty showed higher height SDS, weight SDS, FSH, LH than those with peripheral precocious puberty. CONCLUSION: Etiology in majority of cases with peripheral precocious puberty was congenital adrenal hyperplasia and idiopathic in central precocious puberty. Central precocious puberty children showed higher height SDS, weight SDS, FSH, LH than peripheral precocious puberty. PMID- 25703758 TI - Treat-to-target approach in daily clinical practice in Pakistani patients with early Rheumatoid Arthritis. AB - OBJECTIVE: To determine the frequency of patients with early Rheumatoid Arthritis (RA) achieving disease remission and/or low disease activity after 6 months of treatment with conventional Disease Modifying Anti-Rheumatic Drugs (DMARDs) by using treat-to-target approach in routine clinical practice. STUDY DESIGN: Descriptive study. PLACE AND DURATION OF STUDY: Division of Rheumatology, Fatima Memorial Hospital (FMH), College of Medicine and Dentistry, Lahore, from March 2011 to February 2012. METHODOLOGY: Patients with early RA defined as disease duration 2 1 year were enrolled by purposive sampling, diagnosed as per American College of Rheumatology (ACR) 1987 criteria. Treat-to-target approach was defined as per European League Against Rheumatism (EULAR) 2010 guidelines for treatment of RA with conventional DMARDs. Outcome measures of remission and low disease activity were defined as per DAS 28 score criteria. Patient response to treatment was also determined by EULAR response criteria. RESULTS: Out of 67 patients, 50 patients completed the 6 months study period, rest were lost to follow-up. All patients were started on Methotrexate and mean weekly dose at 6 months was 18.9 +/- 3.8 mg. Remission was achieved in 17 (34%) and target of low disease activity was achieved in 29 (58%) of patients. EULAR good response was seen in 28 (56%), moderate response in 21 (42%) and no response to treatment in 1 (2%). CONCLUSION: By applying treat-to-target approach in early RA, achievement of clinical remission or low disease activity with conventional DMARDs is a realistic goal in routine practice. PMID- 25703759 TI - Infective Endocarditis during pregnancy. AB - Infective Endocarditis (IE) during pregnancy is a rare but grave condition. The diagnosis and management can be challenging, especially when the pregnant patient warrants a cardiac operation under cardiopulmonary bypass. The present article describes IE during pregnancy based on a series of published case reports in the literature. IE during pregnancy often causes embolic events and mycotic aneurysms. Two-thirds of IE in the pregnant patients requires timely or urgent cardiac surgery to alleviate patients' deterioration. At least a 3-week antibiotic therapy is mandatory before cardiac surgery aiming at improving the patients' conditions. During cardiac surgery, fetal heart rates may temporarily be slowed down but may gradually recover to normal after the operation. The fetal and maternal mortalities were 16.7% and 3.3%, respectively. The fetal deaths were apparently associated with a cardiac surgery during early pregnancy. Cardiopulmonary bypass, hypothermia and rewarming can adversely affect both the mother and the fetus by triggering placental deficits, fetal hypoxia and uterine contraction. Avoidance of cardiac operations before 24th gestation week and preferably deferred until after 28th gestation week have been a plausible argument as per the possible fetal deaths related to immaturity. PMID- 25703760 TI - Peer teaching experience of the first year medical students from Turkey. AB - OBJECTIVE: To document peer teaching activity performed by first-year medical students and their views on the teaching activity. STUDY DESIGN: Survey. PLACE AND DURATION OF STUDY: Medical Education Department, Ataturk University, Erzurum, Turkey, in the 2012 - 2013 academic year. METHODOLOGY: Volunteer students were selected for peer teaching model by an academician from the Medical Education Department. Students were taught subjects selected from classes such as biochemistry and microbiology in the same way as the academicians do. Following each class activity, the teaching student was assessed by the other students on a 5-point rating scale. Written and verbal feedback was also obtained from both teaching students and participated students. Verbal feedbacks were noted by a faculty member and similar opinions were categorized. Data were analyzed by SPSS version 20 statistical program. RESULTS: Eleven students took part in the program. Feedback was received from students 171 times. The mean number of students participated was 24.4 +/- 14.3 in each program. Statistical analysis revealed that mean value for teaching materials, peer instructors and teaching environment were 4.62 +/- 0.49, 4.63 +/- 0.47 and 3.88 +/- 1. 27 respectively. CONCLUSION: Peer teaching method is a pretty good way of teaching for medical students. It is a practicable technique that can be used in medical training. Taking part in this program as a lecturer, student increased students' self confidence in the learning and teaching activities. Quite positive feedbacks were received. PMID- 25703761 TI - Anaesthetic management of caesarean section in a patient with large mediastinal mass. AB - Pregnancy is associated with both anatomical and physiological changes in the body, especially in cardiovascular and respiratory systems. Patients with anterior and middle mediastinal masses are recognized to be at risk for cardiorespiratory compromise. Likewise, pregnancy has a widely known constellation of potential complications that confront the anaesthesiologist. The combination of both (pregnancy and mediastinal mass) in a single patient presents an unusual anaesthetic challenge. Caesarean sections are usually the mode of delivery, therefore, the cardio-respiratory stability is very important. The following is the report of a 31 weeks pregnant patient with a large, symptomatic anterior and middle mediastinal mass, who required anaesthesia for emergency caesarean section. The anaesthetic management entailed Combined Spinal and Epidural (CSE) technique with safe feto-maternal outcome. PMID- 25703762 TI - Lofgren's syndrome: an acute variant of sarcoidosis diagnosed by mediastinoscopy. AB - Lofgren's syndrome is an acute clinical form of sarcoidosis that is first described by Sven Lofgren as bilateral hilar lymphadenopathy together with Erythema Nodosum (EN) and accompanying arthritis/arthralgia. This syndrome has some differences in terms of treatment, prognosis and recurrence compared to sarcoidosis. In this report, we describe a 70 years old lady who admitted with multiple erythematous lesions and arthralgia of both lower extremities and she was diagnosed as Lofgren's syndrome via mediastinoscopy. PMID- 25703763 TI - The diagnostic dilemma of progressive muscular atrophy. AB - Progressive muscle atrophy is a rare subtype of motor neuron disease that affects only the lower motor neurons and presents as asymmetrical rapidly progressive muscle weakness, atrophy and normal sensations. The diagnostic electrophysiological findings are denervation potentials in three out of four body segments (bulbar, cervical, thoracic and lumbosacral). The disease is fatal and the management is supportive. We present the report of a 45-year-old female patient who presented with unilateral foot drop and rapidly progressed to profound weakness in muscles of all limbs, neck and back along with dysarthria and dysphagia. She had been operated twice for suspected cervical and lumbosacral intervertebral disc herniations and ultimately guided in right direction after muscle biopsy, nerve conduction studies and electromyography. PMID- 25703764 TI - Level of maternal education is a significant determinant of neonatal survival: a PEARL study analysis. AB - The study analyzed the demographic and socio-economic determinants of neonatal mortality. The variables included one fetal variable (gender), three maternal variables (level of education, occupation, age), three paternal variables (level of education, occupation, age), and seven household (family) variables (nationality, consanguinity, family income, house ownership, type of housing, family type, domestic help). One calendar year data (January to December 2011) was extracted from Qatar's National Perinatal Registry and analyzed using a univariate regression model. Qatar had a total of 20,583 live births and 102 neonatal deaths during 2011 (NMR 4.95/1000). Less than secondary school maternal education level, as compared to secondary school or above maternal education level, was the only variable significantly associated with neonatal mortality (OR 2.08, 95% CI 1.23 - 3.53, p=0.009). The association between the remaining thirteen variables and neonatal mortality was non-significant. Priority investment to raise female literacy above secondary school level may significantly improve neonatal survival. PMID- 25703765 TI - Lipoma of the quadrigeminal plate cistern. PMID- 25703766 TI - Hepatic abscess originating from renal suppurative collection. PMID- 25703767 TI - The artificial divide between biomedical sciences and clinical medicine in undergraduate medical education. PMID- 25703768 TI - Authors' reply. PMID- 25703769 TI - Design and validation of pictograms in a pediatric anaphylaxis action plan. AB - BACKGROUND: Current anaphylaxis action plans (AAPs) are based on written instructions without inclusion of pictograms. OBJECTIVES: To develop an AAP with pictorial aids and to prospectively validate the pictogram components of this plan. METHODS: Participants recruited from the emergency department and allergy clinic participated in a questionnaire to validate pictograms depicting key counseling points of an anaphylactic reaction. Children >= 10 years of age and caregivers of children < 10 years with acute anaphylaxis or who carried epinephrine auto-injector for confirmed allergy were eligible. Guessability, translucency, and recall were assessed for 11 pictogram designs. Pictograms identified as correct or partially correct by at least 85% of participants were considered valid. Three independent reviewers assessed these outcome measures. RESULTS: Of the 115 total participants, 73 (63%) were female, 76 (66%) were parents/guardians, and 39 (34%) were children aged 10-17. Overall, 10 pictograms (91%) reached >= 85% for correct guessability, translucency, and recall. Four pictograms were redesigned to reach the preset validation target. One pictogram depicting symptom management (5-min wait time after first epinephrine treatment) reached 82% translucency after redesign. However, it reached 98% and 100% of correct guessability and recall, respectively. CONCLUSIONS: We prospectively designed and validated a set of pictograms to be included in an AAP. The incorporation of validated pictograms into an AAP may potentially increase comprehension of the triggers, signs and symptoms, and management of an anaphylactic reaction. PMID- 25703770 TI - Temperature dependent coordinating self-assembly. AB - Self-assemblies dominated by coordination interaction are hardly responsive to thermal stimuli. We show that in case the coordinating mode changes with temperature, the resultant assemblies also exhibit temperature dependence. The self-assemblies are constructed with perylene tetracarboxylate and metal ions. Compounds containing a perylene skeleton often self-assemble into micro-belts, which is also true for the combination of perylene tetracarboxylate and metal ions. However, a unique pinecone structure was observed upon increasing the temperature of the coordinating system. The structural transition is triggered by the change of coordinating mode between the carboxylate group and the metal ion. At low temperature, intermolecular coordination occurs which favours the growth of the coordinating self-assembly along the long axis of the perylene. However, upon the elevation of temperature, the coordination is overwhelmed by intra molecular mode. This is against the extension of the coordinating assembly due to the loss of connection between neighbouring perylenes. As a result, the pinecone structure is observed. We expect that the cases introduced in this work may inspire the design of structurally controllable temperature-dependent soft materials based on coordinating self-assembly. PMID- 25703771 TI - Multipotent Adult Progenitor Cells from Bone Marrow Differentiate into Chondrocyte-Like Cells. AB - Cartilage tissue engineering has great potential for treating chondral and osteochondral injuries. Efficient seed cells are the key to cartilage tissue engineering. Multipotent adult progenitor cells (MAPCs) have greater differentiation ability than other bone-marrow stem cells, and thus may be candidate seed cells. We attempted to differentiate MAPCs into chondrocyte-like cells to evaluate their suitability as seed cells for cartilage tissue engineering. Toluidine blue and Alcian blue staining suggested that glycosaminoglycan was expressed in differentiated cells. Immunofluorostaining indicated that differentiated human MAPCs (hMAPCs) expressed collagen II. Based on these results, we concluded that bone-marrow-derived hMAPCs could differentiate into chondrocyte-like cells in vitro. PMID- 25703772 TI - Molecular characterization of fruit-specific class III peroxidase genes in tomato (Solanum lycopersicum). AB - In this study, expression of four peroxidase genes, LePrx09, LePrx17, LePrx35 and LePrxA, was identified in immature tomato fruits, and the function in the regulation of fruit growth was characterized. Analysis of amino acid sequences revealed that these genes code for class III peroxidases, containing B, D and F conserved domains, which bind heme groups, and a buried salt bridge motif. LePrx35 and LePrxA were identified as novel peroxidase genes in Solanum lycopersicum (L.). The temporal expression patterns at various fruit growth stages revealed that LePrx35 and LePrxA were expressed only in immature green (IMG) fruits, whereas LePrx17 and LePrx09 were expressed in both immature and mature green fruits. Tissue-specific expression profiles indicated that only LePrx09 was expressed in the mesocarp but not the inner tissue of immature fruits. The effects of hormone treatments and stresses on the four genes were examined; only the expression levels of LePrx17 and LePrx09 were altered. Transcription of LePrx17 was up-regulated by jasmonic acid (JA) and pathogen infection and expression of LePrx09 was induced by ethephon, salicylic acid (SA) and JA, in particular, as well as wounding, pathogen infection and H2O2 stress. Tomato plants over-expressing LePrx09 displayed enhanced resistance to H2O2 stress, suggesting that LePrx09 may participate in the H2O2 signaling pathway to regulate fruit growth and disease resistance in tomato fruits. PMID- 25703773 TI - Short-term physiological changes in roots and leaves of sugarcane varieties exposed to H2O2 in root medium. AB - The aim of this study was to evaluate the differential sensitivity of sugarcane genotypes to H2O2 in root medium. As a hypothesis, the drought tolerant genotype would be able to minimize the oxidative damage and maintain the water transport from roots to shoots, reducing the negative effects on photosynthesis. The sugarcane genotypes IACSP94-2094 (drought tolerant) and IACSP94-2101 (drought sensitive) were grown in a growth chamber and exposed to three levels of H2O2 in nutrient solution: control; 3 mmol L(-1) and 80 mmol L(-1). Leaf gas exchange, photochemical activity, root hydraulic conductance (Lr) and antioxidant metabolism in both roots and leaves were evaluated after 15 min of treatment with H2O2. Although, root hydraulic conductance, stomatal aperture, apparent electron transport rate and instantaneous carboxylation efficiency have been reduced by H2O2 in both genotypes, IACSP94-2094 presented higher values of those variables as compared to IACSP94-2101. There was a significant genotypic variation in relation to the physiological responses of sugarcane to increasing H2O2 in root tissues, being root changes associated with modifications in plant shoots. IACSP94-2094 presented a root antioxidant system more effective against H2O2 in root medium, regardless H2O2 concentration. Under low H2O2 concentration, water transport and leaf gas exchange of IACSP94-2094 were less affected as compared to IACSP94-2101. Under high H2O2 concentration, the lower sensitivity of IACSP94 2094 was associated with increases in superoxide dismutase activity in roots and leaves and increases in catalase activity in roots. In conclusion, we propose a general model of sugarcane reaction to H2O2, linking root and shoot physiological responses. PMID- 25703774 TI - Comments on: "Update on the surgical management of Pott's disease" by S. Varatharajah, Y.-P. Charles, X. Buy, A. Walter, J.-P. Steib published in Orthop Traumatol Surg Res 2014;100:233-9. PMID- 25703775 TI - Short-segment posterior instrumentation combined with calcium sulfate cement vertebroplasty for thoracolumbar compression fractures: radiographic outcomes including nonunion and other complications. AB - OBJECTIVE: To evaluate the radiographic outcomes of short-segment posterior instrumentation plus vertebroplasty using injectable calcium sulfate cement (CSC) for thoracolumbar compression fractures. MATERIALS AND METHODS: Twenty-eight patients with a single-level thoracolumbar compression fracture, who underwent short-segment pedicle screw fixation and CSC vertebroplasty, were included in the study. The anterior vertebral body height ratio, local kyphosis angle, and the height of the intervertebral disc adjacent to the fractured vertebra were used to evaluate the radiographic results. Complications including bone nonunion, instrument failure, cement leakage, and disc vacuum formation were also assessed. RESULTS: The patients were followed up for an average of 24.20+/-5.40 months. The relative preoperative anterior body height was 55.71+/-15.29%, which improved to 94.93+/-5.39% immediately after surgery (P<0.001), and at final follow-up showed a 6.50+/-3.89% loss of height correction (P<0.001). The mean preoperative local kyphosis angle was 22.23+/-5.65 degrees , which corrected to 2.67+/-4.43 degrees immediately after surgery (P<0.001), but reverted to 6.71+/-4.95 degrees at final follow-up, showing a 4.04+/-1.91 degrees loss of correction (P<0.001). The mean height of the intervertebral disc proximal to the fractured vertebra was 9.87+/-0.91 mm before surgery, 12.53+/-0.98 mm after operation (P<0.001), and the loss of correction at final follow-up was 2.35+/-1.15 mm with a significant difference compared to immediate postoperative values (P<0.001). Bone nonunion occurred in 7 patients, 2 patients had hardware failure, 9 patients had cement leakage, and 10 patients had disc vacuum phenomenon adjacent to the fractured vertebra. CONCLUSIONS: The patients who underwent this procedure had a loss of correction of vertebral height and local kyphosis. Complications such as bone nonunion, instrument failure, cement leakage, and disc vacuum may occur. Rapid CSC resorption accounts for these radiographic outcomes and complications. LEVEL OF EVIDENCE: Level IV, retrospective study. PMID- 25703776 TI - Asthma phenotypes and lung function up to 16 years of age-the BAMSE cohort. AB - BACKGROUND: Asthma is a disease affecting many locations throughout the airway. Most studies have used spirometry as the primary assessment of airway obstruction, a method that may be less sensitive in regard to peripheral airway obstruction. The aim of this study was to elucidate the associations between asthma phenotypes based on age of onset and duration of symptoms, and (i) spirometry and (ii) small airway involvement measured by impulse oscillometry (IOS) in adolescence. METHODS: Children and adolescents taking part in BAMSE, a prospective birth cohort study, performed spirometry at 8 and 16 years and IOS at 16 years of age. Based on data collected in questionnaires, children were categorized into the following groups: 'never asthma', 'early transient asthma', 'early persistent asthma', and 'late onset asthma'. RESULTS: Compared with the never asthma group, all asthma groups were associated with lower FEV1 at 16 years of age (early transient-119 ml, 95% confidence interval -204 to -34; early persistent-410 ml, 95%CI -533; -287; and late onset-148 ml, 95%CI -237; -58). Between 8 and 16 years, significantly less increase in FEV1 was observed in the early persistent and late onset groups. The small airway index 'R5-20 ' was significantly associated with active asthma at 16 years, but not transient asthma. CONCLUSIONS: All asthma phenotypes studied were negatively associated with FEV1 in adolescence. IOS measurements indicated that active asthma could be associated with small airway impairments. These results provide new insights into the physiology underlying wheezing phenotypes based on age of onset and duration of disease. PMID- 25703777 TI - Relationships between activities of daily living, upper limb function, and visual perception in children and adolescents with unilateral cerebral palsy. AB - AIM: This study examined relationships between activities of daily living (ADL) motor and process skills, unimanual capacity, bimanual performance, and visual perception in children with unilateral cerebral palsy (CP). METHOD: Participants were 101 children with unilateral CP (51 males, 50 females; mean age 11y 9mo [SD 2y 5mo; range 8-17y]; Manual Ability Classification System [MACS] level I=24; level II=76; level III=1). Measures were (1) Assessment of Motor and Process Skills (AMPS), (2) Jebsen-Taylor Test of Hand Function (JTTHF), (3) Assisting Hand Assessment (AHA), and (4) Test of Visual Perceptual Skills, 3rd edition (TVPS-3). Regression models were constructed with the AMPS motor scale and AMPS process as the dependent variables. RESULTS: The AHA and JTTHF dominant upper limb score together explained 57% of the variance in AMPS motor scale scores. TVPS-3 Visual Sequential Memory, TVPS-3 Visual Closure, and JTTHF dominant upper limb score together explained 35% of the variance in AMPS process scale scores. INTERPRETATION: Bimanual performance and unimanual capacity of the dominant upper limb are significantly associated with ADL motor skills in children with unilateral CP. Process skills of ADL are related to visual perceptual ability and dominant upper limb unimanual capacity, which may reflect motor planning required to perform daily tasks. PMID- 25703778 TI - A baseline study of metals in herring (Clupea harengus) from the Norwegian Sea, with focus on mercury, cadmium, arsenic and lead. AB - The Norwegian spring spawning (NSS) herring is an ecologically and economically important fish population in the Norwegian Sea. It was the first of several Norwegian fish stocks subject to a baseline study designed to give a comprehensive account of the levels of contaminants in a fish species from most of its area of distribution and during different seasons. During 2006 and 2007, 800 individual herring were sampled in their feeding areas in the Norwegian Sea in spring and autumn and at their spawning grounds off the coast of Norway during late winter. Metals including Hg, Cd, As and Pb were determined in muscle samples of individual herring, and mean concentrations+/-sd (mg kg(-1) ww) were: Hg: 0.04+/-0.03, Cd: 0.010+/-0.006, As: 2.2+/-0.6 and Pb: <0.01-0.10. Apart from one sample, no individual herring exceeded the EU's maximum level for any of these elements, as has been seen also in previous monitoring. Hg and Cd concentration increased with increasing fish age and As concentration varied seasonally, possibly due to uptake during feeding (summer), elimination during starvation (winter) and up-concentration during spawning (spring). PMID- 25703779 TI - QSAR models for bioconcentration: is the increase in the complexity justified by more accurate predictions? AB - This study compares nine QSAR models for the prediction of BCF on fish: four KOW based models (Veith, Mackay, Bintein and TGD equations) and five complex models (EPI Suite BCFBAF, VEGA CAESAR, VEGA Meylan, VEGA Read-across and VEGA consensus). The aim is to test if increasing complexity leads to predictions that are more accurate than those based only on KOW are. To this end, experimental BCF data for 1056 compounds, along with experimental and predicted KOW values, were collected and used for the comparison. A particular focus has been placed on compounds for which metabolism, elimination and specific interactions with tissues can be hypothesized. VEGA Read-across improved global predictions with respect to the KOW based models and resulted to be a good approach to take into account metabolism and interactions with tissues. For the other complex models, several drawbacks were highlighted. Finally, for different classes of compounds (i.e. Perfluorinated Compounds, Organophosphorous Compounds, Synthetic Pyrethroids and Polychlorinated Biphenyls) results confirmed the mechanistic interpretation of the processes involved in their bioconcentration. PMID- 25703780 TI - Perfluoroalkyl acids (PFAAs) with isomer analysis in the commercial PFOS and PFOA products in China. AB - Perfluoroalkyl acids (PFAAs) have been widely used in consumer and industrial products for decades and are widely detected in the environment and humans all over the world. The information on the isomeric profiles of commercial products is important to identify the manufacturing origins of PFAAs in the environment. For the first time, the PFAA compositions and isomeric profiles of perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) were reported in three PFOS and five PFOA commercial products manufactured in China. The purity of the three PFOS products was 76.7-80.6%. The major impurity in the PFOS products is PFOA, which contributes more than 10%. Other impurities include perfluorohexanesulfonate (PFHxS), perfluorohexanoate (PFHxA) and perfluoroheptanoate acids (PFHpA). The percentage of linear PFOS (n-PFOS) in the three products was 66.2-71.9%, similar to that in the product manufactured by 3M (70.3%). The purity of the five PFOA products was relatively high (94.0-95.8%), and the major impurity was PFOS (2.06-3.09%). The percentage of n-PFOA in the five PFOA products was 76.4-77.9%, which was similar to that in the 3M PFOA (78%). Although it is widely accepted that telomerization is currently the predominant manufacturing method for PFOA, yielding an isomerically pure and linear product, the results in the present study suggest that electrochemical fluorination is still used by some manufacturers in China. PMID- 25703781 TI - Aberrant cell retro-programming: a possible mechanism for neurodegeneration. PMID- 25703782 TI - Did human hairlessness allow natural photobiomodulation 2 million years ago and enable photobiomodulation therapy today? This can explain the rapid expansion of our genus's brain. AB - Present hypotheses to explain human hairlessness appear to be inadequate because hairlessness is not accompanied by any immediate benefit. A new, testable, hypothesis is advanced to explain our hairlessness based on photobiomodulation research, also known as low-level light therapy. This shows that red and near infrared radiation has a very beneficial effect on superficial tissues, including the brain. Random mutation/s resulting in complete hairlessness allowed early humans to receive daily doses of red and near infrared radiation at sunset. Photobiomodulation research shows this has a twofold effect: it results in increased mitochondrial respiratory chain activity with consequent ATP 'extrasynthesis' in all superficial tissues, including the brain. It also advantageously affects the expression of over 100 genes through the activation of transcription factor NFkB which results in cerebral metabolic and haemodynamic enhancement. It is also possible that melanin can supply electrons to the respiratory chain resulting in ATP extrasynthesis. These effects would start automatically as soon as hairlessness occurred resulting in a selective sweep of the mutation/s involved. This was followed by the very rapid brain evolution of the last 2 my which, it is suggested, was due to intelligence-led evolution based initially on the increased energy and adeptness of the newly hairless individuals. PMID- 25703783 TI - Genes determining the severity of cerebral palsy: the role of single nucleotide polymorphisms on the amount and structure of apolipoprotein E. AB - AIM: Apolipoprotein E (apoE) influences repair and other processes in the brain, and the apoE4 variant is a risk factor for Alzheimer's disease and for prolonged recovery following traumatic brain injury. We previously reported that specific single nucleotide polymorphisms in the APOE or TOMM40 genes affecting the structure and production of apoE were associated with epilepsy, more impaired hand function and gastrostomy tube feeding in children with cerebral palsy (CP). This study explored how various combinations of the same polymorphisms may affect these clinical manifestations. METHODS: Successful DNA analyses of APOE and TOMM40 were carried out on 227 children. The CP Register of Norway provided details of gross and fine motor function, epilepsy and gastrostomy tube feeding. Possible associations between these clinical manifestations and various combinations of the APOEepsilon2, epsilon3 or epsilon4 alleles and of the rs59007384 polymorphism in the TOMM40 gene were explored. RESULTS: Epilepsy, impaired fine motor function and gastrostomy tube feeding were less common in children carrying the combination of rs59007384 GG and APOEepsilon2 or epsilon3 than in children with other combinations. CONCLUSION: Our findings suggest that specific combinations of genes influence the structure and production of apoE differently and affect the clinical manifestations of CP. PMID- 25703784 TI - Factors affecting response to national early warning score (NEWS). AB - INTRODUCTION: The NEWS is a physiological score, which prescribes an appropriate response for the deteriorating patient in need of urgent medical care. However, it has been suggested that compliance with early warning scoring systems for identifying patient deterioration may vary out of hours. We aimed to (1) assess the scoring accuracy and the adequacy of the prescribed clinical responses to NEWS and (2) assess whether responses were affected by time of day, day of week and score severity. METHODS: We performed a prospective observational study of 370 adult patients admitted to an acute medical ward in a London District General Hospital. Patient characteristics, NEW score, time of day, day of week and clinical response data were collected for the first 24h of admission. Patients with less than a 12h hospital stay were excluded. We analysed data with univariate and multivariate logistic regression. RESULTS: In 70 patients (18.9%) the NEW score was calculated incorrectly. There was a worsening of the clinical response with increasing NEW score. An appropriate clinical response to the NEWS was observed in 274 patients (74.1%). Patients admitted on the weekend were more likely to receive an inadequate response, compared to patients admitted during the week (p<0.0001). After adjusting for confounders, increasing NEWS score remained significantly associated with an inadequate clinical response. Furthermore, our results demonstrate a small increase in inadequate NEWS responses at night, however this was not clinically or statistically significant. CONCLUSION: The high rate of incorrectly calculated NEW scores has implications for the prescribed actions. Clinical response to NEWS score triggers is significantly worse at weekends, highlighting an important patient safety concern. PMID- 25703785 TI - Patterns of multiorgan dysfunction after pediatric drowning. AB - AIMS: To evaluate patterns of multiorgan dysfunction and neurologic outcome in children with respiratory and cardiac arrest after drowning. METHODS: Single center retrospective chart review of children aged 0-21 years admitted between January 2001 and January 2012 to the pediatric intensive care unit at Children's Hospital of Pittsburgh with a diagnosis of drowning/submersion/immersion. Organ dysfunction scores were calculated for first 24h of admission as defined by the Pediatric Logistic Organ Dysfunction Score-1 (PELOD-1) and Pediatric Multiple Organ Dysfunction Score (P-MODS). Neurologic outcome at hospital discharge was assigned Pediatric Cerebral and Overall Performance Category Scale scores. RESULTS: We identified 60 cases of pediatric drowning in which 21 children experienced cardiorespiratory arrest (CA) and 39 had respiratory arrest (RA). All children with CA had multiorgan failure and 81% had a poor neurologic outcome at hospital discharge while 49% of children with RA had multiorgan failure and none had an unfavorable neurological outcome (p<0.001). The most common organ failures in both CA and RA groups within the first 24h of admission were respiratory, followed by neurologic, cardiovascular, gastrointestinal, hematological, and least commonly, renal. CONCLUSION: Patterns of organ failure differ in children with CA and RA due to drowning. The contribution of multiorgan failure to poor outcome and evaluation of the impact of augmenting cerebral resuscitation with MOF-targeting therapies after drowning deserves to be explored. PMID- 25703787 TI - Emerging role of IL-16 in cytokine-mediated regulation of multiple sclerosis. AB - Cytokines are pleiotropic soluble mediators of cellular functions. Cytokines are critical in immune pathogenesis of human diseases, including autoimmune CD4(+) T cell mediated chronic inflammatory, demyelinating and neurodegenerative diseases of the central nervous system (CNS), multiple sclerosis (MS). In MS and its experimental model, experimental autoimmune encephalomyelitis (EAE), chronic persistence and/or reoccurrence of inflammation in the CNS causes chronic progressive or relapsing disease, accompanied with demyelination and damage to axons and oligodendrocytes, which ultimately leads to paralysis and disability. As opposed to other cytokines, whose effects are not limited to the CD4(+) T cell subset, IL-16 exerts its biological properties by exclusive binding and signaling through CD4 receptor. IL-16 selectively regulates migration of all CD4 expressing T cells regardless of their activation state, which is of critical importance for immune modulation and potential therapy of MS. Other major biological properties of IL-16 essential for the function of CD4(+) T cells include regulation of: T cell activation, CD25 expression, MHC class II expression, dendritic cell (DC)-T cell cooperation, B cell-T cell and T cell-T cell cooperation, inflammatory cytokine production and modulation of chemokine regulated T cell chemo attraction. In this article we outline immune pathogenesis of the disease necessary to understand significance of cytokines and IL-16 in MS regulation. We revisit cytokine regulation with emphasis on involvement of IL-16 mechanisms, implicated in MS progression and important for development of new therapies. We emphasize the significance of similar IL-16 mechanisms for other chronic inflammatory CNS diseases. PMID- 25703786 TI - Non-traditional cytokines: How catecholamines and adipokines influence macrophages in immunity, metabolism and the central nervous system. AB - Catecholamines and adipokines function as hormones; catecholamines as neurotransmitters in the sympathetic nervous system, and adipokines as mediators of metabolic processes. It has become increasingly clear, however, that both also function as immunomodulators of innate and adaptive immune cells, including macrophages. Macrophages can respond to, as well as produce their own catecholamines. Dopamine, noradrenaline, and adrenaline are the most abundant catecholamines in the body, and can induce both pro-inflammatory and anti inflammatory immune responses in macrophages, as well as non-immune processes such as thermogenesis. Though they are responsive to adipokines, particularly lipoproteins, leptin, and adiponectin, macrophages generally do not synthesize their own adipokines, with the exception being resistin-like molecules. Adipokines contribute to adverse metabolic and immune responses by stimulating lipid accumulation, foam cell formation and pro-inflammatory cytokine production in macrophages. Adipokines can also promote balance or resolution during metabolic and immune processes by promoting reverse lipid transport and expression of Th2 cytokines. This review will explore the mechanisms by which catecholamines and adipokines influence macrophage function in neural pathways, immunity and metabolism. PMID- 25703788 TI - Tuning electronic states of a CdSe/ZnS quantum dot by only one functional dye molecule. AB - Self-assembly of only one functionalized porphyrin dye molecule with one CdSe/ZnS quantum dot (QD) not only modifies the photoluminescence (PL) intensity but also creates a few energetically clearly distinguishable electronic states, opening additional effective relaxation pathways. The related energy modifications are in the range of 10-30 meV and show a pronounced sensitivity to the specific nature of the respective dye. We assign the emerging energies to surface states. Time resolved PL spectroscopy in combination with spectral deconvolution reveals that surface properties of QDs are a complex interplay of the nature of the dye molecule and the topography of the ligand layer across a temperature range from 77 to 290 K. This includes a kind of phase transition of trioctylphosphine oxide ligands, switching the nature of surface states observed below and above the phase transition temperature. Most importantly, our findings can be closely related to recent calculations of ligand-induced modifications of surface states of QDs. The identification of the optical properties emerged from a combination of spectroscopy on single QDs and QDs in an ensemble. PMID- 25703789 TI - Structural plasticity of the circadian timing system. An overview from flies to mammals. AB - The circadian timing system orchestrates daily variations in physiology and behavior through coordination of multioscillatory cell networks that are highly plastic in responding to environmental changes. Over the last decade, it has become clear that this plasticity involves structural changes and that the changes may be observed not only in central brain regions where the master clock cells reside but also in clock-controlled structures. This review considers experimental data in invertebrate and vertebrate model systems, mainly flies and mammals, illustrating various forms of structural circadian plasticity from cellular to circuit-based levels. It highlights the importance of these plastic events in the functional adaptation of the clock to the changing environment. PMID- 25703790 TI - The enteric glia: identity and functions. AB - Enteric glial cells were first described at the end of the 19th century, but they attracted more interest from researchers only in the last decades of the 20th. Although, they have a different embryological origin, the enteric GLIA share many characteristics with astrocytes, the main glial cell type of the central nervous system (CNS), such as in their expression of the same markers and in their functions. Here we review the construction of the enteric nervous system (ENS), with a focus on enteric glia, and also the main studies that have revealed the action of enteric glia in different aspects of gastrointestinal tract homeostasis, such as in the intestinal barrier, in communications with neurons, and in their action as progenitor cells. We also discuss recent discoveries about the roles of enteric glia in different disorders that affect the ENS, such as degenerative pathologies including Parkinson's and prion diseases, and in cases of intestinal diseases and injury. PMID- 25703791 TI - Effective dentin restorative material based on phosphate-terminated dendrimer as artificial protein. AB - In clinic, it calls for effective and simple materials to repair etched dentin. Bioinspired by the natural mineralization process guided by noncollagenous proteins (NCPs), in this work, we synthesized the fourth generation phosphate terminated polyamidoamine dendrimer (G4-PO3H2) by one-step modification. We used FT-IR and 1H NMR to characterize the structure of G4-PO3H2, and MTT assay to prove its biocompatibility. It was applied as the analog of dentin phosphophoryn (DPP: a type of NCPs) to repair dentin, due to its similar dimensional scale, topological architecture and peripheral functionalities to that of DPP. By the characterization of SEM and XRD, the effective regeneration of human dentin induced by G4-PO3H2 is characterized and illustrated both in vitro (artificial saliva) and in vivo (oral cavity of rats). It is noted that the thickness of the regenerated mineral layers are more than 10 MUm both in vitro and in vivo. The design strategy of G4-PO3H2 may be valuable for researchers in the fields of material science, stomatology and medicine to prepare various promising restorative nano-materials for biomineralized hard tissues such as bone and teeth. PMID- 25703792 TI - Neisseria meningitidis serogroup B bivalent factor H binding protein vaccine. AB - With the successful development of meningococcal vaccines against other serogroups, disease caused by Neisseria meningitidis serogroup B now accounts for a disproportionate frequency compared with other serogroups, particularly in the US and Europe. Infants and adolescents bear the highest incidence of disease, which typically manifests as meningitis and septicemia. This vaccine profile article examines a bivalent factor H binding protein (fHbp; also known as LP2086) vaccine that has now been approved by the US FDA for use in 10- to 25-year olds. The manufacturer has shelved plans for further investigation of its use in infants because of high rates of fever in Phase I and II trials in that age group. PMID- 25703793 TI - Metabolic cross-feeding via intercellular nanotubes among bacteria. AB - Bacteria frequently exchange metabolites by diffusion through the extracellular environment, yet it remains generally unclear whether bacteria can also use cell cell connections to directly exchange nutrients. Here we address this question by engineering cross-feeding interactions within and between Acinetobacter baylyi and Escherichia coli, in which two distant bacterial species reciprocally exchange essential amino acids. We establish that in a well-mixed environment E. coli, but likely not A. baylyi, can connect to other bacterial cells via membrane derived nanotubes and use these to exchange cytoplasmic constituents. Intercellular connections are induced by auxotrophy-causing mutations and cease to establish when amino acids are externally supplied. Electron and fluorescence microscopy reveal a network of nanotubular structures that connects bacterial cells and enables an intercellular transfer of cytoplasmic materials. Together, our results demonstrate that bacteria can use nanotubes to exchange nutrients among connected cells and thus help to distribute metabolic functions within microbial communities. PMID- 25703794 TI - The unexpected mechanism underlying the high-valent mono-oxo-rhenium(V) hydride catalyzed hydrosilylation of C=N functionalities: insights from a DFT study. AB - In this study, we theoretically investigated the mechanism underlying the high valent mono-oxo-rhenium(V) hydride Re(O)HCl2(PPh3)2 (1) catalyzed hydrosilylation of C=N functionalities. Our results suggest that an ionic S(N)2-Si outer-sphere pathway involving the heterolytic cleavage of the Si-H bond competes with the hydride pathway involving the C=N bond inserted into the Re-H bond for the rhenium hydride (1) catalyzed hydrosilylation of the less steric C=N functionalities (phenylmethanimine, PhCH=NH, and N-phenylbenzylideneimine, PhCH=NPh). The rate-determining free-energy barriers for the ionic outer-sphere pathway are calculated to be ~28.1 and 27.6 kcal mol(-1), respectively. These values are slightly more favorable than those obtained for the hydride pathway (by ~1-3 kcal mol(-1)), whereas for the large steric C=N functionality of N,1,1 tri(phenyl)methanimine (PhCPh=NPh), the ionic outer-sphere pathway (33.1 kcal mol(-1)) is more favorable than the hydride pathway by as much as 11.5 kcal mol( 1). Along the ionic outer-sphere pathway, neither the multiply bonded oxo ligand nor the inherent hydride moiety participate in the activation of the Si-H bond. PMID- 25703796 TI - Cell signaling, division, and organization mediated by intrinsically disordered proteins. PMID- 25703795 TI - Fgk3 glycogen synthase kinase is important for development, pathogenesis, and stress responses in Fusarium graminearum. AB - Wheat scab caused by Fusarium graminearum is an important disease. In a previous study, the FGK3 glycogen synthase kinase gene orthologous to mammalian GSK3 was identified as an important virulence factor. Although GSK3 orthologs are well conserved, none of them have been functionally characterized in fungal pathogens. In this study, we further characterized the roles of FGK3 gene. The Deltafgk3 mutant had pleiotropic defects in growth rate, conidium morphology, germination, and perithecium formation. It was non-pathogenic in infection assays and blocked in DON production. Glycogen accumulation was increased in the Deltafgk3 mutant, confirming the inhibitory role of Fgk3 on glycogen synthase. In FGK3-GFP transformants, GFP signals mainly localized to the cytoplasm in conidia but to the cytoplasm and nucleus in hyphae. Moreover, the expression level of FGK3 increased in response to cold, H2O2, and SDS stresses. In the Deltafgk3 mutant, cold, heat, and salt stresses failed to induce the expression of the stress response-related genes FgGRE2, FgGPD1, FgCTT1, and FgMSN2. In the presence of 80 mM LiCl, a GSK3 kinase inhibitor, the wild type displayed similar defects to the Deltafgk3 mutant. Overall, our results indicate that FGK3 is important for growth, conidiogenesis, DON production, pathogenicity, and stress responses in F. graminearum. PMID- 25703797 TI - Protein tyrosine phosphatases. PMID- 25703798 TI - Mouth opening in patients irradiated for head and neck cancer: a prospective repeated measures study. AB - OBJECTIVES: Aims of this prospective cohort study were (1) to analyze the course of mouth opening up to 48months post-radiotherapy (RT), (2) to assess risk factors predicting decrease in mouth opening, and (3) to develop a multivariable prediction model for change in mouth opening in a large sample of patients irradiated for head and neck cancer. MATERIALS AND METHODS: Mouth opening was measured prior to RT (baseline) and at 6, 12, 18, 24, 36, and 48months post-RT. The primary outcome variable was mouth opening. Potential risk factors were entered into a linear mixed model analysis (manual backward-stepwise elimination) to create a multivariable prediction model. The interaction terms between time and risk factors that were significantly related to mouth opening were explored. RESULTS: The study population consisted of 641 patients: 70.4% male, mean age at baseline 62.3years (sd 12.5). Primary tumors were predominantly located in the oro- and nasopharynx (25.3%) and oral cavity (20.6%). Mean mouth opening at baseline was 38.7mm (sd 10.8). Six months post-RT, mean mouth opening was smallest, 36.7mm (sd 10.0). In the linear mixed model analysis, mouth opening was statistically predicted by the location of the tumor, natural logarithm of time post-RT in months (Ln (months)), gender, baseline mouth opening, and baseline age. All main effects interacted with Ln (months). CONCLUSION: The mean mouth opening decreased slightly over time. Mouth opening was predicted by tumor location, time, gender, baseline mouth opening, and age. The model can be used to predict mouth opening. PMID- 25703799 TI - Assessment and measurement of head and neck lymphedema: state-of-the-science and future directions. AB - Currently, assessment and measurement of lymphedema in head and neck cancer patients is difficult. The aims of this report are to examine the current state of science regarding available measurement of head and neck lymphedema, to identify gaps in clinical evaluation of head and neck lymphedema, and to propose future research directions for advancing the assessment of head and neck lymphedema. The authors conducted a comprehensive literature review based on PubMed, CINAHL, Cochrane database, EMBASE, and PsycINFO from 1989 to 2014. Primary search terms included head and/or neck cancer, head and/or neck and/or face, lymphedema, edema, swelling, fibrosis, measurement, assessment, and evaluation. The authors also reviewed information from the Oncology Nursing Society, National Lymphedema Network, National Cancer Institute, American Cancer Society, and other related healthcare professional association web sites. Based on the nature/characteristics of measurement reported in the literature, methods for assessment of head and neck lymphedema can be categorized into: (1) patient reported outcome (PRO) measures (e.g., symptom tool), (2) clinician-reported outcome (CRO) measures based on clinical grading criteria via a clinical exam (external lymphedema evaluation by physical examination and internal edema examination via endoscopy), and (3) technical capacity/measurement techniques (e.g., imaging techniques). Although a number of measures have been reported in the literature, clinically useful PRO and CRO measures, and reliable and sensitive measurement techniques need to be validated to address gaps in assessment of head and neck lymphedema, and to be easily used in early identification of lymphedema and assessment of treatment/interventional effects. PMID- 25703800 TI - How far systems biology methods can contribute to understand social systems?: comment on "On the interplay between mathematics and biology, hallmarks toward a new systems biology" by N. Bellomo et al. PMID- 25703801 TI - High excimer-state emission of perylene bisimides and recognition of latent fingerprints. AB - High excimer-state emission in the H-type aggregate of a novel asymmetric perylene bisimide derivative, 6, with triethyleneglycol chains and lactose functionalization was achieved in water. Furthermore, its application for enhancing the visualization of transfer latent fingerprints from glass slides to the poly(vinylidene fluoride) (PVDF) membrane was explored, which showed clear images of the latent fingerprint in daylight and under 365 nm ultraviolet illumination. PMID- 25703802 TI - The effects of e-simulation interview training on teachers' use of open-ended questions. AB - Teachers in many parts of the world are mandated reporters of child abuse and maltreatment but very little is known concerning how they question children in suspicious circumstances. Teachers (n=36), who had previously participated in a mock interview scenario designed to characterize their baseline use of various question-types when attempting to elicit sensitive information from children, were given online training in choosing effective questions. They engaged in simulated interviews with a virtual avatar several times in one week and then participated in a mock interview scenario. The amount and proportion of open ended questions they used increased dramatically after training. The overall number of questions, and amount and proportions of specific and leading questions decreased. In particular, large decreases were observed in more risky yes-no and other forced-choice questions. Given that most teachers may feel the need to ask a child about an ambiguous situation at some point during their careers it is worthwhile to incorporate practice asking effective questions into their training, and the present research suggests that an e-learning format is effective. Additionally, effective questions encourage the development of narrative competence, and we discuss how teachers might include open-ended questions during regular classroom learning. PMID- 25703803 TI - Knockdown of CkrL by shRNA deteriorates hypoxia/reoxygenation-induced H9C2 cardiomyocyte apoptosis and survival inhibition Via Bax and downregulation of P Erk1/2. AB - Integrin beta1 subunit and its downstream molecule integrin-linked kinase and focal adhesion kinase have been confirmed to be essential to cell survival and inhibition of apoptosis and hypoxia/reoxygenation (H/R)-induced injuries in cardiomyocytes. However, it is still unclear whether CrkL [v-crk avian sarcoma virus CT-10 oncogene homolog (Crk)-like], which acts also as a component of the integrin pathway, could also affect H/R-induced injuries in the cardiomyocytes. The rat-derived H9C2 cardiomyocytes were infected with a CrkL small hairpin RNA interference recombinant lentivirus, which knockdowns the endogenous CrkL expression in the cardiomyocytes. Apoptosis, cell proliferation and survival were examined in the H9C2 cardiomyocytes treated with either H/R or not. Results showed that knockdown of CrkL could significantly increase apoptosis and inhibition of the cell proliferation and survival and deteriorate the previously mentioned injuries induced by H/R. In contrast, overexpression of human CrkL could relieve the exacerbation of the previously mentioned injuries induced by CrkL knockdown in the H9C2 cardiomyocytes via regulation of Bax and extracellular signal-regulated kinase1/2 (p-ERK1/2). In conclusion, these results confirmed that knockdown of CrkL could deteriorate H/R-induced apoptosis and cell survival inhibition in rat-derived H9C2 cardiomyocytes via Bax and downregulation of p ERK1/2. It implies that CrkL could mitigate H/R-induced injuries in the cardiomyocytes. PMID- 25703804 TI - Bugs and stress 'on top of genetics': can the way we are born affect our health? PMID- 25703805 TI - Electromyographic findings in 37 patients with adult-onset acid maltase deficiency. AB - INTRODUCTION: In acid maltase deficiency (AMD), electrical myotonia (EM) may be restricted to paraspinal muscles. A comprehensive description of the electromyographic (EMG) findings in AMD is lacking. The purpose of this study is to describe the EMG features in adult-onset AMD, focusing on the distribution of EM. METHODS: A retrospective chart review of AMD patients diagnosed at Mayo Clinic over age 18 years. RESULTS: Thirty-seven patients were included. Twenty eight (76%) had EM in at least 1 muscle, and EM was more common in paraspinal and proximal limb muscles. The tensor fasciae latae (TFL) was equally sensitive to the paraspinals for EM. Three of 4 patients had EM identified in the diaphragm. CONCLUSIONS: Approximately three-quarters of adult-onset AMD patients display EM on EMG. The paraspinal muscles and TFL are the most likely to demonstrate EM, and EM can be detected in the diaphragm of adult onset AMD patients. PMID- 25703806 TI - The necropolis of Bolgare (Lombardy, Italy): Anthropological and paleopathological features of a Lombard population. AB - The mediaeval necropolis of Bolgare - St. Chierico is an important site in northern Italy, located in the Bergamo Province (about 40 km East of Milan). In order to reconstruct aspects of the demographic and health status of this Lombard population, macroscopic (morphological, metric and radiographic) and microscopic analyses were performed on over 400 skeletons for the assessments of sex (cranial and pelvic morphology, metrics), age (subadults: dental and bone development; adults: mainly pubic symphysis, auricular surface of the ilium, 4th rib) and stature, for the determination of ancestry and the identification of pathologies. Results proved the sample to be heterogeneous with males, females, adults and subadults. The sample seemed to be composed of several groups, including individuals with northern or eastern (Uralic) European features and, on the other hand, individuals with central European or Mediterranean characteristics. The first may be indicative of migrations of Lombards (suggested by tall stature estimates); the second could be considered autochthonous, bearing features more typical of northern Italian populations. Among palaeopathological finds, the study showed the presence of tuberculosis, gout, DISH and degenerative pathologies particularly on the pelvis and spinal column. The population of Bolgare constitutes one of the main sources of anthropological data on Lombards in Italy. PMID- 25703807 TI - Functional mapping of dynamic happy and fearful facial expressions in young adults with familial risk for psychosis - Oulu Brain and Mind Study. AB - BACKGROUND: Social interaction requires mirroring to other people's mental state. Psychotic disorders have been connected to social interaction and emotion recognition impairment. We compared the brain activity between young adults with familial risk for psychosis (FR) and matched controls during visual exposure to emotional facial expression. We also investigated the role of the amygdala, the key region for social interaction and emotion recognition. METHODS: 51 FR and 52 control subjects were drawn from the Northern Finland 1986 Birth Cohort (Oulu Brain and Mind Study). None of the included participants had developed psychosis. The FR group was defined as having a parent with psychotic disorder according to the Finnish Hospital Discharge Register. Participants underwent functional MRI (fMRI) using visual presentation of dynamic happy and fearful facial expressions. FMRI data were processed to produce maps of activation for happy and fearful facial expression, which were then compared between groups. Two spherical regions of interest (ROIs) in the amygdala were set to extract BOLD responses during happy and fearful facial expression. BOLD responses were then compared with subjects' emotion recognition, which was assessed after fMRI. Psychophysiological interaction (PPI) for the left and right amygdala during happy and fearful facial expression was conducted using the amygdala as seed regions. RESULTS: FR subjects had increased activity in the left premotor cortex and reduced deactivation of medial prefrontal cortex structures during happy facial expression. There were no between-group differences during fearful facial expression. The FR group also showed a statistically significant linear correlation between mean amygdala BOLD response and facial expression recognition. PPI showed that there was a significant negative interaction between the amygdala and the dorsolateral prefrontal cortex (dlPFC) and superior temporal gyrus in FR subjects. CONCLUSIONS: Increased activations by positive valence in FR were in brain regions crucial to emotion recognition and social interaction. Increased activation of the premotor cortex may serve as a compensatory mechanism as FR subjects may have to exert more effort on processing the stimuli, as has been found earlier in schizophrenia. Failure to deactivate PFC structures may imply error in the default mode network. Abnormal PFC function in FR was also suggested by PPI, as the dlPFC showed decreased functional connectivity with the amygdala in the FR group. This may indicate that in FR subjects the amygdala have to take a greater role in emotion recognition and social functioning. This inference was supported by our discovery of statistically significant correlations between the amygdala BOLD response and emotion recognition in the FR group but not in controls. PMID- 25703808 TI - Ultrahigh Responsivity in Graphene-ZnO Nanorod Hybrid UV Photodetector. AB - Ultraviolet (UV) photodetectors based on ZnO nanostructure/graphene (Gr) hybrid channel field-effect transistors (FETs) are investigated under illumination at various incident photon intensities and wavelengths. The time-dependent behaviors of hybrid-channel FETs reveal a high sensitivity and selectivity toward the near UV region at the wavelength of 365 nm. The devices can operate at low voltage and show excellent selectivity, high responsivity (RI ), and high photoconductive gain (G). The change in the transfer characteristics of hybrid-channel FETs under UV light illumination allows to detect both photovoltage and photocurrent. The shift of the Dirac point (V Dirac ) observed during UV exposure leads to a clearer explanation of the response mechanism and carrier transport properties of Gr, and this phenomenon permits the calculation of electron concentration per UV power density transferred from ZnO nanorods and ZnO nanoparticles to Gr, which is 9 * 10(10) and 4 * 10(10) per mW, respectively. The maximum values of RI and G infer from the fitted curves of RI and G versus UV intensity are 3 * 10(5) A W( 1) and 10(6) , respectively. Therefore, the hybrid-channel FETs studied herein can be used as UV sensing devices with high performance and low power consumption, opening up new opportunities for future optoelectronic devices. PMID- 25703809 TI - Root Cause Analysis of Quality Defects Using HPLC-MS Fingerprint Knowledgebase for Batch-to-batch Quality Control of Herbal Drugs. AB - INTRODUCTION: The batch-to-batch quality consistency of herbal drugs has always been an important issue. OBJECTIVES: To propose a methodology for batch-to-batch quality control based on HPLC-MS fingerprints and process knowledgebase. METHODS: The extraction process of Compound E-jiao Oral Liquid was taken as a case study. After establishing the HPLC-MS fingerprint analysis method, the fingerprints of the extract solutions produced under normal and abnormal operation conditions were obtained. Multivariate statistical models were built for fault detection and a discriminant analysis model was built using the probabilistic discriminant partial-least-squares method for fault diagnosis. RESULTS: Based on multivariate statistical analysis, process knowledge was acquired and the cause-effect relationship between process deviations and quality defects was revealed. The quality defects were detected successfully by multivariate statistical control charts and the type of process deviations were diagnosed correctly by discriminant analysis. CONCLUSION: This work has demonstrated the benefits of combining HPLC-MS fingerprints, process knowledge and multivariate analysis for the quality control of herbal drugs. PMID- 25703810 TI - Asian genotypes of dengue virus 4 in Brazil. AB - Dengue virus, commonly transmitted by mosquitoes, causes a human disease of significant social impact and presents a serious public health problem in Brazil. This report describes the unusual emergence of DENV-4 in northern Brazil after a nearly 30-year-long absence. DENV-4 genotype I is of Asian origin and was identified in the serum of patients receiving treatment at a hospital serving the Salvador area (Brazilian state of Bahia). The identification of dengue virus serotypes through molecular and phylogenetic analysis is essential for predicting disease severity or fatal illness, principally in endemic countries such as Brazil. PMID- 25703811 TI - Tetracyanido(difluorido)phosphates M(+) [PF2 (CN)4 ](.). AB - The systematic study of the reaction of M[PF6 ] salts and Me3 SiCN led to a synthetic method for the synthesis and isolation of a series of salts containing the unprecedented [PF2 (CN)4 ](-) ion in good yields. The reaction temperature, pressure, and stoichiometry were optimized. The crystal structures of M[PF2 (CN)4 ] (M=[nBu4 N](+) , Ag(+) , K(+) , Li(+) , H5 O2 (+) ) were determined. X-ray crystallography showed the exclusive formation of the cis isomer in accord with (31) P and (19) F solution NMR spectroscopy data. Starting with the K[PF2 (CN)4 ] the room temperature ionic liquid EMIm[PF2 (CN)4 ] was prepared exhibiting a rather low viscosity. PMID- 25703812 TI - Stem cells from foetal adnexa and fluid in domestic animals: an update on their features and clinical application. AB - Over the past decade, stem cell research has emerged as an area of major interest for its potential in regenerative medicine applications. This is in constant need of new cell sources to conceive regenerative medicine approaches for diseases that are still without therapy. Scientists drew the attention towards alternative sources such as foetal adnexa and fluid, as these sources possess many advantages: first of all, cells can be extracted from discarded foetal material and it is non-invasive and inexpensive for the patient; secondly, abundant stem cells can be obtained; and finally, these stem cell sources are free from ethical considerations. Cells derived from foetal adnexa and fluid preserve some of the characteristics of the primitive embryonic layers from which they originate. Many studies have demonstrated the differentiation potential in vitro and in vivo towards mesenchymal and non-mesenchymal cell types; in addition, the immune modulatory properties make these cells a good candidate for allo- and xenotransplantation. Naturally occurring diseases in domestic animals can be more ideal as disease model of human genetic and acquired diseases and could help to define the potential therapeutic use efficiency and safety of stem cells therapies. This review offers an update on the state of the art of characterization of domestic animals' MSCs derived from foetal adnexa and fluid and on the latest findings in pre-clinical or clinical setting of the stem cell populations isolated from these sources. PMID- 25703813 TI - DNA methylation of channel-related genes in cancers. AB - DNA methylation at CpG sites is an epigenetic mechanism that regulates cellular gene expression. In cancer cells, aberrant methylation is correlated with the abnormalities in expression of genes that are known to be involved in the particular characteristics of cancer cells such as proliferation, apoptosis, migration or invasion. During the past 30 years, accumulating data have definitely convinced the scientific community that ion channels are involved in cancerogenesis and cancer properties. As they are situated at the cell surface, they might be prime targets in the development of new therapeutic strategies besides their potential use as prognostic factors. Despite the progress in our understanding of the remodeling of ion channels in cancer cells, the molecular mechanisms underlying their over- or down-expression remained enigmatic. In this review, we aimed to summarize the available data on gene promoter methylation of ion channels and to investigate their clinical significance as novel biomarkers in cancer. This article is part of a Special Issue entitled: Membrane channels and transporters in cancers. PMID- 25703814 TI - Investigation of the effects of distance from sources on apoptosis, oxidative stress and cytosolic calcium accumulation via TRPV1 channels induced by mobile phones and Wi-Fi in breast cancer cells. AB - TRPV1 is a Ca2+ permeable channel and gated by noxious heat, oxidative stress and capsaicin (CAP). Some reports have indicated that non-ionized electromagnetic radiation (EMR)-induces heat and oxidative stress effects. We aimed to investigate the effects of distance from sources on calcium signaling, cytosolic ROS production, cell viability, apoptosis, plus caspase-3 and -9 values induced by mobile phones and Wi-Fi in breast cancer cells MCF-7 human breast cancer cell lines were divided into A, B, C and D groups as control, 900, 1800 and 2450 MHz groups, respectively. Cells in Group A were used as control and were kept in cell culture conditions without EMR exposure. Groups B, C and D were exposed to the EMR frequencies at different distances (0 cm, 1 cm, 5 cm, 10 cm, 20 cm and 25 cm) for 1h before CAP stimulation. The cytosolic ROS production, Ca2+ concentrations, apoptosis, caspase-3 and caspase-9 values were higher in groups B, C and D than in A group at 0 cm, 1 cm and 5 cm distances although cell viability (MTT) values were increased by the distances. There was no statistically significant difference in the values between control, 20 and 25 cm. Wi-Fi and mobile phone EMR placed within 10 cm of the cells induced excessive oxidative responses and apoptosis via TRPV1-induced cytosolic Ca2+ accumulation in the cancer cells. Using cell phones and Wi-Fi sources which are farther away than 10 cm may provide useful protection against oxidative stress, apoptosis and overload of intracellular Ca2+. This article is part of a Special Issue entitled: Membrane channels and transporters in cancers. PMID- 25703815 TI - The template-assisted synthesis of polypyrrole hollow microspheres with a double shelled structure. AB - Double-shelled polypyrrole hollow microspheres were synthesized via a novel template-assisted concept, using iron oxide hollow microspheres as both the sacrificial template and initiator in acidic solution. PMID- 25703816 TI - Secretory proteins without a transport signal are retained in secretory granules during maturation in rat parotid acinar cells. AB - OBJECTIVE: The acinar cells of the parotid gland are filled with numerous secretory granules (SGs), which accumulate the digestion enzyme amylase. SGs mature accompanied with membrane remodelling such as fusion and budding of small vesicles. However, little is understood about the mechanism of the condensation of SG contents during maturation. In this study, we examined whether secretory proteins need a specific signal to be retained in SGs. DESIGN: To induce internalization of the luminal membrane after exocytosis, we injected the beta adrenergic agonist isoproterenol into rats. Acinar cells were then incubated with Lucifer Yellow (LY) dye as a tracer for 3h for uptake into immature secretory granules (ISGs). To observe whether LY was retained in SGs after maturation, we continued incubating the cultured acinar cells for 2 days. RESULTS: The localization of LY into ISGs was confirmed by the following four methods: (1) co localization of the fluorescence of LY and amylase by confocal laser microscopy, (2) detection of the fluorescence from purified ISGs, (3) secretion of the fluorescence together with amylase upon stimulation, and (4) observation of the intracellular localization of LY by electron microscopy. Moreover, we observed co localization of some of the SGs with the fluorescence of LY after cell culture. CONCLUSIONS: Although the fusion and budding of small vesicles may contribute to the process of granule maturation, LY remained in the SGs even after maturation. These results suggest that secretory proteins that have no transport signal are not excluded from SGs, and they are retained in SGs during granule maturation in exocrine parotid glands. PMID- 25703817 TI - Effect of asymmetric force on the condylar cartilage, subchondral bone and collagens in the temporomandibular joints. AB - This study aimed to define the effects of asymmetric force on rat temporomandibular joints (TMJs). A total of 232 10-week-old rats were used in the experiment. Their left TMJs were kept forward and upward with 40g or 120g. The histological and osteogenic changes, as well as the expression of type I, II and III collagens were observed. Our results showed that the curve of the cartilage thickness changes in the anterior part of the treated side in the heavy force group (HS) decreased first and increased later during the strength and the recovery periods, while the reverse changes were shown in the middle and posterior parts. The cartilage thickness change on the other side in the heavy force group (HO) was the opposite. Additionally, the cartilage thickness change on the treated side and the other side of the light force group (LS and LO) were similar to but not as significantly changed as HS and HO. There were significant differences among the experimental groups. The subchondral bone trabecula also decreased after the pressure loading and removing, then recovered, without significant differences among these groups. Furthermore, more pathological changes such as fractures, bone cysts, the degradation of type II collagen and the increased expression of type III collagen were observed on the treated sides following the application of heavy force. In contrast, more osteogenesis and more active changes were found in the light force group. In conclusion, our study demonstrated that asymmetric force exerted different effects on the cartilage, subchondral bone and collagens of TMJs. Greater changes occurred in the heavy force group, and light force provided more benefits for TMJs remodelling. PMID- 25703818 TI - A comparison of treatment adherence in individuals with a first episode of psychosis and inpatients with psychosis. AB - In predicting treatment compliance in individuals with severe mental illness, research has focused on variables such as substance abuse, personality, history of child abuse, and symptomatology, although these relationships have not been investigated in great detail in individuals at the onset of mental illness. To better understand these correlates of treatment compliance, two samples were examined: a sample of 117 individuals presenting with a first episode of psychosis and a more chronic forensic sample of 65 participants recruited from a psychiatric hospital. These samples were investigated for service engagement in terms of violence history, substance abuse, symptom severity, psychopathic traits and history of childhood abuse. Linear regressions performed for the first episode sample revealed that childhood physical abuse was the strongest predictor of poor service engagement, followed by problems with alcohol, a history of physical violence, any history of violence and higher psychopathic traits. Linear regression revealed for the forensic group that a lower level of service engagement was most strongly predicted by a history of childhood abuse and a higher score on the Brief Psychiatric Rating Scale (BPRS). Results are presented in light of the existing literature and clinical implications are discussed. PMID- 25703819 TI - Inter-disciplinary teaching strategies for mental health law. AB - The use of an inter-disciplinary teaching strategy in the context of mental health law is explored here as a means of balancing concerns for the patient's best interests and maximizing their autonomy. One law professor and one psychiatrist participated in joint teaching sessions in the Queen's University School of Medicine, and share their strategies for overcoming perceived conflicts between patient's legal rights and the practice of psychiatry. PMID- 25703820 TI - The impact of defendant ethnicity on the psycholegal opinions of forensic mental health evaluators. AB - The impact of ethnicity on clinicians' decision making has received a great deal of attention and research. Several studies have documented that client ethnicity significantly influences diagnoses, testing and assessment protocols, recommendations for treatment, and expected outcomes. However, there is limited research examining the impact of a criminal defendant's ethnicity upon forensic mental health experts. To examine this issue, the authors reviewed 816 forensic reports on competency to stand trial submitted to the Hawaii judiciary between 2007 and 2008 and compared recommendation rates across categories of defendant ethnicity. Significant differences between ethnic groups were found in recommendations of competency to stand trial. Specifically, Asian misdemeanant populations were found to be incompetent to stand trial at higher rates than other ethnic groups. These findings highlight the potential impact that ethnicity may have on clinicians' decision making in certain forensic settings. PMID- 25703821 TI - The C-terminal tail of tetraspanin proteins regulates their intracellular distribution in the parasite Trichomonas vaginalis. AB - The parasite Trichomonas vaginalis is the causative agent of trichomoniasis, a prevalent sexually transmitted infection. Here, we report the cellular analysis of T.vaginalis tetraspanin family (TvTSPs). This family of membrane proteins has been implicated in cell adhesion, migration and proliferation in vertebrates. We found that the expression of several members of the family is up-regulated upon contact with vaginal ectocervical cells. We demonstrate that most TvTSPs are localized on the surface and intracellular vesicles and that the C-terminal intracellular tails of surface TvTSPs are necessary for proper localization. Analyses of full-length TvTSP8 and a mutant that lacks the C-terminal tail indicates that surface-localized TvTSP8 is involved in parasite aggregation, suggesting a role for this protein in parasite : parasite interaction. PMID- 25703822 TI - Methamphetamine promotes alpha-tubulin deacetylation in endothelial cells: the protective role of acetyl-l-carnitine. AB - Methamphetamine (METH) is a powerful psychostimulant drug used worldwide for its reinforcing properties. In addition to the classic long-lasting monoaminergic disrupting effects extensively described in the literature, METH has been consistently reported to increase blood brain barrier (BBB) permeability, both in vivo and in vitro, as a result of tight junction and cytoskeleton disarrangement. Microtubules play a critical role in cell stability, which relies on post translational modifications such as alpha-tubulin acetylation. As there is evidence that psychostimulants drugs modulate the expression of histone deacetylases (HDACs), we hypothesized that in endothelial cells METH-mediation of cytoplasmatic HDAC6 activity could affect tubulin acetylation and further contribute to BBB dysfunction. To validate our hypothesis, we exposed the bEnd.3 endothelial cells to increasing doses of METH and verified that it leads to an extensive alpha-tubulin deacetylation mediated by HDACs activation. Furthermore, since we recently reported that acetyl-l-carnitine (ALC), a natural occurring compound, prevents BBB structural loss in a context of METH exposure, we reasoned that ALC could also preserve the acetylation of microtubules under METH action. The present results confirm that ALC is able to prevent METH-induced deacetylation providing effective protection on microtubule acetylation. Although further investigation is still needed, HDACs regulation may become a new therapeutic target for ALC. PMID- 25703823 TI - Mutagenic potential of the isoflavone irilone in cultured V79 cells. AB - After consumption of red clover-based dietary supplements, plasma concentrations of the isoflavone irilone (IRI) equal that of the well-investigated daidzein. Since some isoflavones are genotoxic, the potential of IRI to induce mutations was investigated. Gene mutations were determined by hypoxanthine-guanine phosphoribosyltransferase (HPRT) assay and sequencing of mutant cDNA, chromosome and genome mutations by micronucleus assay complemented by immunochemical staining of centromere proteins and microtubules in cultured V79 cells. Cell proliferation was monitored by electronic cell counting, flow cytometry and fluorescence microscopy. IRI did not affect the mutant frequency in the Hprt locus but altered the mutation spectrum by increasing the proportion of deletions and decreasing that of base pair substitutions. Induction of chromosome mutations was supported by a slight but significant increase in the number of micronucleated cells containing chromosomal fragments despite activation of three cell cycle checkpoints possibly interfering with micronuclei formation. Moreover, IRI exhibited a strong aneugenic potential characterized by disrupted mitotic spindles, mitotic arrest, and asymmetrical cell divisions leading to chromosome loss, nuclear fragmentation as well as mitotic catastrophe. Thus, IRI might be another isoflavone to be taken into account in safety assessment of dietary supplements. PMID- 25703824 TI - Indoxyl sulfate induces oxidative stress and hypertrophy in cardiomyocytes by inhibiting the AMPK/UCP2 signaling pathway. AB - As a typical protein-bound uremic toxin, indoxyl sulfate is considered to be able to induce cardiomyocytes hypertrophy by promoting oxidative stress in chronic kidney disease (CKD). Uncoupling protein 2 (UCP2), a member of the uncoupling protein family, may protect cardiomyocytes from oxidative stress by suppressing mitochondrial reactive oxygen species (ROS). In the present study, we aimed to determine whether UCP2 was involved in indoxyl sulfate-induced cardiomyocytes hypertrophy. We demonstrated that indoxyl sulfate could increase the ROS levels in a time and dose-dependent manner in cultured neonatal rat cardiomyocytes. Significant increases in [(3)H]-leucine incorporation, cell volume, and the mRNA expression levels of atrial natriuretic factor (ANF), brain natriuretic peptide (BNP), and beta myosin heavy chain (beta-MHC) were detected in cardiomyocytes after treatement with indoxyl sulfate at the concentration of 500MUM for 48h, accompanied by a decreased expression of UCP2. In contrast, cardiomyocytes transfected with the lentiviral vector carrying UCP2 gene were resistant to indoxyl sulfate-induced ROS production and cell hypertrophy. Additionally, indoxyl sulfate-induced UCP2 reduction was correlated with the inhibition of AMP activated protein kinase (AMPK) activity, while pretreatment with AICAR, an AMPK activator, effectively attenuated indoxyl sulfate-induced UCP2 down-regulation and hypertrophy in cardiomyocytes. Taken together, these results suggest that indoxyl sulfate-induced cardiomyocytes hypertrophy was partly due to the inhibition of AMPK/UCP2 signaling and the enhancement of oxidative stress. PMID- 25703825 TI - The differential expression of mgl mRNA by Porphyromonas gingivalis affects the production of methyl mercaptan. AB - OBJECTIVE: A large number of individuals have halitosis. The total amount of volatile sulfur compounds, which are the main cause of halitosis, has been correlated with periodontitis following bacterial infection. In this study, Porphyromonas gingivalis (Pg), a major periodontopathogenic bacterium, was isolated from patients with halitosis by the amplification of 16S rRNA, and the ability of isolated Pg to produce methyl mercaptan (CH3 SH) was determined to clarify the relationship between halitosis and Pg infection. MATERIALS AND METHODS: CH3 SH concentrations were measured in patients using Oral Chroma. The production of CH3 SH by Pg standard and clinical strains was also measured in vitro. Real-time PCR was performed to compare the expression of mgl mRNA (which encoded l-methionine-a-deamino-g-mercaptomethane-lyase) among the Pg strains. The production of CH3 SH and the expression of mgl mRNA were also determined to assess the effects of oriental medicine. RESULTS: The production of CH3 SH and the expression of mgl mRNA strongly correlated with each other in the presence of l-methionine. The expression of mgl mRNA by Pg W83 was strongly inhibited by magnoliaceae. CONCLUSION: The production of CH3 SH was correlated with the expression of mgl. Furthermore, the oriental medicine, magnoliaceae, may represent a potential treatment for halitosis. PMID- 25703826 TI - Formation of the Scandinavian Obesity Surgery Registry, SOReg. AB - BACKGROUND: Obesity surgery is expanding, the quality of care is ever more important, and learning curve assessment should be established. A large registry cohort can show long-term effects on obesity and its comorbidities, complications, and long-term side effects of surgery, as well as changes in health-related quality of life (QoL). Sweden is ideally suited to the task of data collection and audit, with universal use of personal identification numbers, nation-wide registries permitting cross-matching to analyze causes of death, in hospital care, and health-related absenteeism. METHOD: In 2004, the Scandinavian Obesity Surgery Registry (SOReg) was initiated and government financing secured. A project group created a national database covering all public as well as private hospitals. Data entry was to be made online, operative definitions of comorbidity were formed, and complication severity scored. Several forms of audit were devised. RESULTS: After pilot studies, the system has been running in its present form since 2007. Since 15 January 2013, SOReg covers all bariatric surgery centers in Sweden. The number of operations in the database exceeded 40,000 (March 2014), with a median follow-up of 2.94 years. Audit shows that >98% of data are correct. All results are publicized annually on the Internet. COMMENTS: Using this systematic approach, it has been possible to cover >99% of all bariatric surgery, cross-matching our data with nation-wide registries for in hospital care, cause of death, and permitting regular nation-wide audit. Several scientific studies have used, or are using, what seems to be the most comprehensive database in obesity surgery. PMID- 25703827 TI - Modelling the influence of predicted future climate change on the risk of wind damage within New Zealand's planted forests. AB - Wind is the major abiotic disturbance in New Zealand's planted forests, but little is known about how the risk of wind damage may be affected by future climate change. We linked a mechanistic wind damage model (ForestGALES) to an empirical growth model for radiata pine (Pinus radiata D. Don) and a process based growth model (cenw) to predict the risk of wind damage under different future emissions scenarios and assumptions about the future wind climate. The cenw model was used to estimate site productivity for constant CO2 concentration at 1990 values and for assumed increases in CO2 concentration from current values to those expected during 2040 and 2090 under the B1 (low), A1B (mid-range) and A2 (high) emission scenarios. Stand development was modelled for different levels of site productivity, contrasting silvicultural regimes and sites across New Zealand. The risk of wind damage was predicted for each regime and emission scenario combination using the ForestGALES model. The sensitivity to changes in the intensity of the future wind climate was also examined. Results showed that increased tree growth rates under the different emissions scenarios had the greatest impact on the risk of wind damage. The increase in risk was greatest for stands growing at high stand density under the A2 emissions scenario with increased CO2 concentration. The increased productivity under this scenario resulted in increased tree height, without a corresponding increase in diameter, leading to more slender trees that were predicted to be at greater risk from wind damage. The risk of wind damage was further increased by the modest increases in the extreme wind climate that are predicted to occur. These results have implications for the development of silvicultural regimes that are resilient to climate change and also indicate that future productivity gains may be offset by greater losses from disturbances. PMID- 25703828 TI - Functional and time-course changes in single word production from childhood to adulthood. AB - Picture naming tasks are widely used both in children and adults to investigate language production for research and for assessment purposes. The main theoretical models of single word production based on the investigation of picture naming in adults provide a detailed account of the principal mental operations involved in the transformation of an abstract concept into articulated speech and their temporal dynamics. These models and in particular their time course do not apply directly to children who display much longer production latencies than adults. Here we investigate the functional processes and the temporal dynamics of word encoding in school-age children and adults. ERPs were analysed from picture onset to the onset of articulation in 32 children and 32 adults performing the same overt picture naming task. Waveform analyses were not informative since differences appeared throughout the entire period, due to an early shift of waveform morphology and to larger amplitudes in children. However, when the sequences of periods of topographic stability were considered, different patterns of electric fields at scalp only appeared in approximately the first third of the analysed period, corresponding to the P1-N1 complex. From about 200 ms in adults and from 300 ms in children to articulation onset similar patterns of global topography were observed across groups but with a different time distribution. These results indicate qualitative changes in an early time-window, likely corresponding to pre-linguistic processes, and only quantitative changes in later time-windows, suggesting similar mental operations underlying lexical processes between age-school children and adults, with temporal dynamic changes during development. PMID- 25703829 TI - The interplay of composition and concept specificity in the left anterior temporal lobe: an MEG study. AB - A fundamental function of natural language is to focus the interlocutor's attention to specific entities and circumstances from the vast set of possibilities in the environment. In other words, as an utterance progresses, the narrower its reference typically becomes. Intriguingly, there is substantial convergence in the neural localization of conceptual specificity effects at the single word level and combinatory effects at the phrasal level, both systematically affecting the left anterior temporal lobe (LATL). However, the relationship between these two types of effects is not well understood. The current study used MEG to characterize the temporal progression of both types of effects in minimal two-word phrases (e.g., tomato soup), where single word specificity was varied in both first and second position (e.g., tomato vs. vegetable; soup vs. dish). These combinatory phrases were further compared to non combinatory single nouns of high and low specificity. Our most robust result was an effect of the specificity of the first word while processing the second word: responses to the second word were the largest when it was being composed with a more specific as opposed to a more general modifier. In the modifier position, specificity had no reliable effects, while non-combinatory single nouns did show a subtle LATL increase when specific. In all, our findings show that when non semantic factors such as frequency are controlled for, conceptual specificity weakly modulates LATL activity in non-combinatory situations (i.e., at a single noun), but robustly affects the size of the LATL composition effect. Thus LATL activity appears to be most strongly driven by the composition of concepts as opposed to access to single concepts. PMID- 25703830 TI - Layer-specific response properties of the human lateral geniculate nucleus and superior colliculus. AB - The human LGN and SC consist of distinct layers, but their layer-specific response properties remain poorly understood. In this fMRI study, we characterized visual response properties of the magnocellular (M) and parvocellular (P) layers of the human LGN, as well as at different depths in the SC. Results show that fMRI is capable of resolving layer-specific signals from the LGN and SC. Compared to the P layers of the LGN, the M layers preferred higher temporal frequency, lower spatial frequency stimuli, and their responses saturated at lower contrast. Furthermore, the M layers are colorblind while the P layers showed robust response to both chromatic and achromatic stimuli. Visual responses in the SC were strongest in the superficial voxels, which showed similar spatiotemporal and contrast response properties as the M layers of the LGN, but were sensitive to color and responded strongly to isoluminant color stimulus. Thus, the non-invasive fMRI measures show that the M and P layers of human LGN have similar response properties as that observed in non-human primates and the superficial layers of the human SC prefer transient inputs but are not colorblind. PMID- 25703831 TI - Functional subdivision of the human periaqueductal grey in respiratory control using 7 tesla fMRI. AB - The periaqueductal grey (PAG) is a nucleus within the midbrain, and evidence from animal models has identified its role in many homeostatic systems including respiration. Animal models have also demonstrated a columnar structure that subdivides the PAG into four columns on each side, and these subdivisions have different functions with regard to respiration. In this study we used ultra-high field functional MRI (7 T) to image the brainstem and superior cortical areas at high resolution (1mm(3)voxels), aiming to identify activation within the columns of the PAG associated with respiratory control. Our results showed deactivation in the lateral and dorsomedial columns of the PAG corresponding with short (~10s) breath holds, along with cortical activations consistent with previous respiratory imaging studies. These results demonstrate the involvement of the lateral and dorsomedial PAG in the network of conscious respiratory control for the first time in humans. This study also reveals the opportunities of 7 T functional MRI for non-invasively investigating human brainstem nuclei at high resolutions. PMID- 25703832 TI - Short-term wound complications and predictive variables for complication after limb amputation in dogs and cats. AB - OBJECTIVES: To identify short-term wound complications and associated predictive factors following amputation in dogs and cats. MATERIALS AND METHODS: Retrospective review of case records of dogs and cats undergoing thoracic or pelvic limb amputation. Preoperative data on signalment, body weight, limb amputated, reason for amputation and laboratory parameters were collected. Details regarding surgical procedures and use of anaesthesia such as total surgical and anaesthesia times, incidences of intraoperative hypotension or hypothermia, method of muscle excision and type of skin closure utilized were recorded. Postoperative data on duration of hospital stay, use of postoperative antibiotics, use of a wound soaker catheter, wound complications noted both during hospitalization and at recheck and treatments if applicable were collected. RESULTS: In total, 67 records were identified including 39 dogs and 28 cats. Wound infection/inflammation complications occurred in 20.9% of cases and wound infection complications in 9%; 12.8% in dogs and 3.6% in cats. One (1.5%) complication was classified as major, which occurred immediately postoperatively. Nine (13.4%) minor complications occurred immediately after surgery and four (6.0%) were identified at recheck. Age was the only significant predictor of postoperative infection/inflammation following pelvic or thoracic limb amputation. CLINICAL SIGNIFICANCE: Short-term wound complications following pelvic or thoracic limb amputation in cats and dogs were typically minor and resolved after treatment. PMID- 25703833 TI - Setup of a bone aging experimental model in the rabbit comparing changes in cortical and trabecular bone: Morphological and morphometric study in the femur. AB - Bone aging was studied in an experimental model (rabbit femur) in three populations aged 0.5, 1.5, and 7.5 years. Cortical bone histology was compared with a data set from a 1.5-month-old population of an earlier published paper. From 0.5-year-old onward, the mean femur length did not increase further. Thereafter, the mean marrow area increased and the cortical area decreased significantly with aging. This was associated with a structural pattern transformation from plexiform to laminar and then Haversian-like type. The distal meta-epiphysis bone trabecular density of the oldest populations also was significantly lower in specific regions of interest (ROI). Percentage sealed primary vascular canals in laminar bone significantly increased with aging without variation of percentage sealed secondary osteons. Remodeling rate reflected by the density of cutting cones did not significantly change among the age populations. These data suggest that laminar bone vascular pattern is more functional in the fast diaphyseal expansion but not much streamlined with the renewal of blood flow during secondary remodeling. Bone aging was characterized by: 1) secondary remodeling subendosteally; 2) increment of sealed primary vascular canals number; 3) increased calcium content of the cortex; 4) cortical and trabecular bone mass loss in specific ROIs. Taken together, the present data may give a morphological and morphometric basis to perform comparative studies on experimental models of osteoporosis in the rabbit. PMID- 25703834 TI - The bacterial alkyltransferase-like (eATL) protein protects mammalian cells against methylating agent-induced toxicity. AB - In both pro- and eukaryotes, the mutagenic and toxic DNA adduct O(6) methylguanine (O(6)MeG) is subject to repair by alkyltransferase proteins via methyl group transfer. In addition, in prokaryotes, there are proteins with sequence homology to alkyltransferases, collectively designated as alkyltransferase-like (ATL) proteins, which bind to O(6)-alkylguanine adducts and mediate resistance to alkylating agents. Whether such proteins might enable similar protection in higher eukaryotes is unknown. Here we expressed the ATL protein of Escherichia coli (eATL) in mammalian cells and addressed the question whether it is able to protect them against the cytotoxic effects of alkylating agents. The Chinese hamster cell line CHO-9, the nucleotide excision repair (NER) deficient derivative 43-3B and the DNA mismatch repair (MMR) impaired derivative Tk22-C1 were transfected with eATL cloned in an expression plasmid and the sensitivity to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) was determined in reproductive survival, DNA double-strand break (DSB) and apoptosis assays. The results indicate that eATL expression is tolerated in mammalian cells and conferes protection against killing by MNNG in both wild-type and 43-3B cells, but not in the MMR-impaired cell line. The protection effect was dependent on the expression level of eATL and was completely ablated in cells co-expressing the human O(6)-methylguanine-DNA methyltransferase (MGMT). eATL did not protect against cytotoxicity induced by the chloroethylating agent lomustine, suggesting that O(6)-chloroethylguanine adducts are not target of eATL. To investigate the mechanism of protection, we determined O(6)MeG levels in DNA after MNNG treatment and found that eATL did not cause removal of the adduct. However, eATL expression resulted in a significantly lower level of DSBs in MNNG-treated cells, and this was concomitant with attenuation of G2 blockage and a lower level of apoptosis. The results suggest that eATL confers protection against methylating agents by masking O(6)MeG/thymine mispaired adducts, preventing them from becoming a substrate for mismatch repair-mediated DSB formation and cell death. PMID- 25703835 TI - Genetic variants in the DNA repair gene NEIL3 and the risk of myocardial infarction in a nested case-control study. The HUNT Study. AB - BACKGROUND: Enhanced generation of reactive oxygen species and increased oxidative-induced DNA damage have been identified as possible contributors to atherosclerosis. The base excision repair (BER) pathway is the principal mechanism by which mammalian cells repair oxidative DNA damage. BER deficiency can potentially accelerate atherogenesis. METHODS: We evaluated the association of Single Nucleotide Polymorphisms (SNPs) in genes encoding four different BER proteins (NEIL3, OGG1, APEX1 and XRCC1) with the incidence of myocardial infarction in a nested case-control study among participants of the second survey of the HUNT Study. The study population included 1624 cases and 4087 age- and sex matched controls. RESULTS: For the NEIL3 SNP rs12645561, the TT genotype was associated with increased risk of MI (OR 1.47, 95% CI 1.02-2.12, p uncorrected for multiple comparisons = 0.04) both in the genotypic test (compared to the CC genotype) and in the recessive genetic model (compared to the CC and CT genotypes combined). For the other two NEIL3 SNPs (rs10013040 and rs1395479) and for the SNPs of OGG1 (rs1052133), APEX1 (rs1878703) and XRCC1 (rs25489) we observed no association with risk of myocardial infarction. CONCLUSION: We found that the NEIL3 rs12645561 SNP TT genotype was associated with increased risk of myocardial infarction. If confirmed in other studies, this association may suggest a possible role of attenuated DNA repair, and NEIL3 in particular, in atherogenesis. PMID- 25703836 TI - Sensitivity of shovelnose sturgeon (Scaphirhynchus platorynchus) and pallid sturgeon (S. albus) early life stages to 3,3',4,4',5-pentachlorobiphenyl and 2,3,7,8-tetrachlorodibenzo-P-dioxin exposure. AB - Concern exists that polychlorinated biphenyls (PCBs) may be contributing to the current decline of shovelnose sturgeon (Scaphirhynchus platorynchus) and the US federally endangered pallid sturgeon (Scaphirhynchus albus). Waterborne exposures with newly fertilized eggs were used to assess developmental and morphological effects of 2 of the most potent aryl hydrocarbon receptor (AhR) agonists, 3,3',4,4',5-pentachlorobiphenyl (PCB-126) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), on early life stage shovelnose and pallid sturgeon. No dose-related effects of PCB-126 were observed on percent development or hatch in either species at concentrations as high as 1711 ng/g egg. Effects of TCDD on percent development were not assessed in shovelnose sturgeon. However, percent development was not affected by TCDD in pallid sturgeon, and percent hatch was unaffected by TCDD doses as high as 60 ng/g egg to 81 ng/g egg in either species. Morphological pathologies such as yolk sac edema and craniofacial deformities were typical of AhR agonist exposure and were similar in both species. Calculated PCB-126 50% lethal dose (LD50, 95% fiducial limits) values were 196 ng/g egg (188 203 ng/g) for shovelnose and 159 ng/g egg (122-199 ng/g) for pallid sturgeon. Likewise, calculated TCDD LD50 values were 13 ng/g egg (11-15 ng/g) for shovelnose and 12 ng/g egg (10-14 ng/g) for pallid sturgeon. These LD50 values are among the highest recorded in early life stage fish, suggesting that early life stage Scaphirhynchus sturgeon may be comparatively insensitive to AhR agonists. PMID- 25703837 TI - Visceral white adipose tissue is susceptible to alcohol-induced lipodystrophy in rats: role of acetaldehyde. AB - BACKGROUND: Chronic alcohol exposure causes lipid dyshomeostasis at the adipose liver axis, reducing lipid storage in white fat and increasing lipid deposit in the liver. Previous studies have shown that visceral fat, rather than subcutaneous fat, is a risk factor for metabolic diseases. This study was conducted to determine whether chronic alcohol exposure differentially affects lipid metabolism in visceral (epididymal) and subcutaneous fat, and the mechanisms underlying the alcohol effects. METHODS: Male Wistar rats were pair fed the Lieber-DeCarli control or alcohol liquid diet for 12 weeks to determine the effects of alcohol on the white fat. Tissue explants culture and 3T3-L1 culture were conducted to define the role of acetaldehyde in alcohol-induced adipose tissue dysfunction. RESULTS: Chronic alcohol feeding significantly reduced visceral fat mass and down-regulated peroxisome proliferator activator receptor-gamma and CCAAT/enhancer binding protein-alpha, 2 important transcription factors in regulation of lipogenesis. The protein levels of lipogenic enzymes including phospho-ATP-citrate lyase, acetyl-CoA carboxylase, fatty acid synthase, lipin1, and diacylglycerol acyltransferase 2 in the visceral fat were reduced. In contrast, chronic alcohol exposure did not affect subcutaneous fat mass and had less effect on the protein levels of lipogenic enzymes and regulators. Accordingly, the visceral fat showed a lower protein level of aldehyde detoxification enzymes compared to the subcutaneous fat. Acetaldehyde treatment to either visceral fat explants or 3T3-L1 adipocytes produced similar effects on lipogenic enzymes and regulators as observed in animal model. CONCLUSIONS: These results demonstrated that visceral fat is more susceptible to alcohol toxicity compared to subcutaneous fat, and disruption of adipose lipogenesis contributes to the pathogenesis of alcoholic lipodystrophy. PMID- 25703838 TI - Current technologies, economics, and perspectives for 2,5-dimethylfuran production from biomass-derived intermediates. AB - Since the U.S. Department of Energy (DOE) published a perspective article that described the potential of the top ten biomass-derived platform chemicals as petroleum replacements for high-value commodity and specialty chemicals, researchers around the world have been motivated to develop technologies for the conversion of biomass and biomass-derived intermediates into chemicals and fuels. Among several biorefinery processes, the conversion of biomass carbohydrates into 2,5-dimethylfuran (DMF) has received significant attention because of its low oxygen content, high energy content, and high octane value. DMF can further serve as a petroleum-replacement, biorenewable feedstock for the production of p-xylene (pX). In this review, we aim specifically to present a concise and up-to-date analysis of DMF production technologies with a critical discussion on catalytic systems, mechanistic insight, and process economics, which includes sensitivity analysis, so that more effective catalysts can be designed. Special emphasis has been given to bifunctional catalysts that improve DMF yields and selectivity and the synergistic effect of the bifunctional sites. Process economics for the current processes and the scope for further improvement are discussed. It is anticipated that the chemistry detailed in this review will guide researchers to develop more practical catalytic processes to enable the economic production of bio-based DMF. Processes for the upgrade of DMF to pX are also described. PMID- 25703839 TI - Meta-analysis of drug-eluting balloon angioplasty and drug-eluting stent placement for infrainguinal peripheral arterial disease. AB - PURPOSE: To perform a meta-analysis of randomized controlled trials (RCTs) of drug-eluting balloon (DEB) angioplasty and drug-eluting stents (DESs) for infrainguinal peripheral arterial disease. MATERIALS AND METHODS: Systematic searches were performed for all relevant RCTs. RESULTS: Eight RCTs for DEB angioplasty and 12 RCTs for a DES in peripheral arterial disease were identified. Meta-analysis demonstrated statistically significant superiority of DEB over plain balloon angioplasty of femoral-popliteal disease for late lumen loss, restenosis, and target lesion revascularization, with no benefit in major amputation or mortality. Statistically significant superiority of DEB over percutaneous transluminal angioplasty (PTA) was demonstrated for infrapopliteal disease for restenosis and target lesion revascularization. Drug-eluting stents showed statistically significant superiority over bare metal stents (BMSs) of femoral-popliteal disease for late lumen loss and restenosis, with no benefit in mortality or amputation. Drug-eluting stents showed statistically significant superiority over BMSs of infrapopliteal disease restenosis and target lesion revascularization, with no benefit in amputation or mortality. CONCLUSIONS: Drug eluting balloon angioplasty and DESs demonstrated superior outcomes compared to PTA and BMS, with no difference in amputation or mortality. PMID- 25703840 TI - High-valent metal-oxo intermediates in energy demanding processes: from dioxygen reduction to water splitting. AB - Four-electron reduction of dioxygen to water and splitting of water to dioxygen are extremely important processes in the context of attaining clean renewable energy sources. High-valent metal-oxo cores are proposed as reactive intermediates in these vital processes, although they have only been isolated in extremely rare cases in the biological systems thereby making the mechanism ambiguous. Recent biomimetic studies have, however, aided in our understanding of the fundamental reactivity of the high-valent metal-oxo species in various reactions relevant to energy conversion. All these studies are summarized in the present review. PMID- 25703841 TI - Anti-factor XIII A subunit (FXIII-A) autoantibodies block FXIII-A2 B2 assembly and steal FXIII-A from native FXIII-A2 B2. AB - BACKGROUND: Autoimmune hemophilia-like disease (hemorrha-philia or hemorrhagic disorder) caused by anti-factor XIII antibodies (termed AH13) or 'autoimmune FXIII deficiency' is a life-threatening bleeding disorder. AH13 was thought to be rare worldwide. OBJECTIVES: Because the number of diagnosed AH13 cases has recently been increasing, at least in Japan, we conducted a nationwide survey supported by the Japanese Ministry of Health, Labor, and Welfare, and explored the pathologic mechanism(s) of AH13. METHODS: We diagnosed AH13 cases during the last 11 years according to the presence of anti-FXIII autoantibodies confirmed by a dot blot assay and ELISA, and characterized 33 of these both immunologically and biochemically. RESULTS: The AH13 cases were immunologically classified into three types, Aa, Ab, and B. Type Aa autoantibodies, observed in 27 cases, were directed against the native FXIII A subunit (FXIII-A), and blocked FXIII activation. The autoantibodies not only prevented assembly of new FXIII-A2 B2 heterotetramers, but also removed FXIII-A from native FXIII-A2 B2 heterotetramers by forming an FXIII-A-IgG complex. Type Ab autoantibodies, detected in three cases, preferentially bound to activated FXIII-A and inhibited its activity. Type Aa and Ab autoantibodies were 'neutralizing' FXIII antibodies (or FXIII inhibitors), and thus could be screened with functional assays. Type B antibodies, detected in two cases, were non-neutralizing anti-FXIII B subunit (FXIII-B) autoantibodies that possibly accelerated the clearance of FXIII, and thus could be diagnosed exclusively with immunologic methods. CONCLUSION: There are three major types of anti-FXIII autoantibody, with distinct targets and mechanisms that cause AH13. PMID- 25703842 TI - Organizing stem cell units in the Drosophila ovary. AB - Organogenesis utilizes processes fundamental to development: cell proliferation, cell differentiation and morphogenesis. Each of these processes is complex in itself; the challenge of studying organogenesis is to determine how all of them integrate to shape organs with recurring precision. This review focuses on the emerging understanding of how synchronized proliferation and differentiation of both somatic and germ cell lineages form 16-20 germ line stem cell (GSC) units in the ovary of Drosophila melanogaster. Recent work demonstrates that the Insulin, ecdysone, Epidermal Growth Factor, Decapentaplegic and Activin signaling pathways are used reiteratively for proliferation and differentiation in both somatic and germ cell lineages. This linkage underlies ovarian coordinated development and provides opportunity for correction mechanisms for stem cell unit numbers. PMID- 25703843 TI - On the organ trail: insights into organ regeneration in the planarian. AB - Advances in stem cell biology have led to the derivation of diverse cell types, yet challenges remain in creating complex tissues and functional organs. Unlike humans, some animals regenerate all missing tissues and organs successfully after dramatic injuries. Studies of organisms with exceptional regenerative capacity, like planarians, could complement in vitro studies and reveal mechanistic themes underlying regeneration on the scale of whole organs and tissues. In this review, we outline progress in understanding planarian organ regeneration, with focus on recent studies of the nervous, digestive, and excretory systems. We further examine molecular mechanisms underlying establishment of diverse cell fates from the planarian stem cell pool. Finally, we explore conceptual directions for future studies of organ regeneration in planarians. PMID- 25703844 TI - Complete mitochondrial genome of Military Macaw (Ara militaris): its comparison with mitogenomes of two other Ara species. AB - The Military Macaw is one of the eight species of the genus Ara. The genus is one of six genera, which form morphologically diverse group termed as Macaws. Parrots of this group differ in body size on demand of the genus and species. Six of Ara species are classified as large Macaws. Based on morphological similarities and differences, these species can be segregated into three pairs according to their plumage coloration. Representative mitochondrial genomes were sequenced only for A. glaucogularis (blue and yellow coloration) and A. macao (predominantly red/scarlet). Ara militaris is one of two predominantly green species and full mitochondrial genome of considered species was sequenced in this study. It's comparison with A. glaucogularis and A. macao mitogenomes revealed higher degree of identity between militaris and macao sequences than between militaris and glaucogularis mtDNAs. Ara militaris mitogenome will be indispensable to refine the phylogenetic relationships within Macaw group. PMID- 25703845 TI - Complete mitochondrial genome of the Loligo opalescence. AB - In this study, we determined the complete mitochondrial genome of the Loligo opalescence. The genome was 17,370 bp in length and contained 13 protein-coding genes, 22 transfer RNA genes, 2 ribosomal RNA genes and 3 main non-coding regions. The composition and order of genes, were similar to most other invertebrates. The overall base composition of L. opalescence is A 38.62%, C 19.40%, T 32.37% and G 9.61%, with a highly A + T bias of 70.99%. All of the three control regions (CR) contain termination-associated sequences and conserved sequence blocks. This mitogenome sequence data would play an important role in the investigation of phylogenetic relationship, taxonomic resolution and phylogeography of the Loliginidae. PMID- 25703846 TI - Characterization of the complete mitochondrial genome of Formica selysi (Insecta: Hymenoptera: Formicidae: Formicinae). AB - The complete mitochondrial genome of Formica selysi has been assembled from Illumina sequencing data with an average coverage of 2733X. The circular genome was 16,752 bp in length, and consists of 13 protein-coding genes (PCGs), 22 transfer RNAs (tRNAs), two ribosomal RNAs (rRNAs) and one D-loop region. All PCGs initiated with ATN codons and terminated with the TAA codon. The nucleotide composition was highly asymmetric (40.33% A, 11.07% C, 5.66% G and 42.94% T) with an overall GC content of 16.73%. Unlike those of most other insects, the mitochondrial genome of F. selysi was characterized by an obviously high proportion of intergenic spacers. These data would contribute to the evolutionary studies of this and related ant taxa. PMID- 25703847 TI - The role of mitochondrial tRNA variants in female breast cancer. AB - Mitochondrial tRNA (Mt-tRNA) variants have been found to be involved in the carcinogenesis of breast cancer. These tRNAs, which played critical roles in mitochondrial protein synthesis, were important regulators in tumorigenesis. Distinguishing the polymorphisms or mutations in mt-tRNA genes was still puzzling for the clinicians and geneticists when confronted with the breast cancer. In this study, we performed a detailed analysis of recently reported mutations in mt tRNA genes and further discussed the relationship between these variants and breast cancer. PMID- 25703848 TI - Complete mitochondrial genome of Mitred Conure (Psittacara mitratus): its comparison with mitogenome of Socorro Conure (Psittacara brevipes). AB - The Mitred Conure (Psittacara mitratus) is a species native to the forests and woodlands in the Andes in central Peru, south through west-central Bolivia, to northwestern Argentina. The genus Psittacara have recently been distinguished on the basis of molecular revision of the Aratinga species. In consequence, it became one of the nine genera, which form morphologically diverse group termed as Conures. Although, the number of species/subspecies belonging to Psittacara remains controversial, it is now believed that the genus is represented by 11 species. Taxonomic position of Mitred Conure was determined by molecular research and makes the species crucial for examination of evolutionary diversification of the genus. Therefore, we sequenced complete mitochondrial genome of P. mitratus mitogenome to gain a source of comprehensive molecular data. It will be indispensable to refine the phylogenetic relationships within "Psittacara group" as well as within the tribe Arini. PMID- 25703849 TI - Complete mitochondrial genome of Red-throated Conure (Psittacara rubritorquis): its comparison with mitogenome of Socorro Conure (Psittacara brevipes). AB - According to some taxonomists the Red-throated Conure (Psittacara rubritorquis) is considered a subspecies of Green Conure (Psittacara holochlora). Some other classifications treat rubritorquis as a separate species based on relatively minor morphological differences between both species/subspecies. So far, taxonomic position of P. rubritorquis was determined by molecular researches using only ND2 gene sequence or incomplete combined mitochondrial ND2, COI and CYTB gene sequences. Obtained outcomes found that P. rubritorquis should be treated as a subspecies of P. holochlora. However, the lack of P. h. brewsterii and P. h. strenua samples as well as incompleteness of combined mitochondrial sequence do not exclude opposite scenario. Therefore, we sequenced P. rubritorquis mitogenome to gain a source of molecular data appropriate for future examination of evolutionary diversification of the P. holochlora group. PMID- 25703850 TI - Complete mitochondrial genome sequence of Melipona scutellaris, a Brazilian stingless bee. AB - Melipona scutellaris is a Brazilian stingless bee species and a highly important native pollinator besides its use in rational rearing for honey production. In this study, we present the whole mitochondrial DNA sequence of M. scutellaris from a haploid male. The mitogenome has a size of 14,862 bp and harbors 13 protein-coding genes (PCGs), 2 rRNA genes and 21 tRNA genes. PMID- 25703851 TI - DNA barcoding of marine ornamental fishes from India. AB - India has rich marine ornamental fish diversity with 400 fish species distributed in Gulf of Munnar/Palk Bay, Gulf of Kutch, and in reefs around Andaman & Nicobar and Lakshadweep Islands. Marine ornamental fish identification at the field level is very difficult because of their high diversity and profound changes in appearance during their developmental stages and camouflage. To facilitate ornamental fish trading with ease and in compliance with the biodiversity act, DNA barcoding technique could be used to accurately identify species. In this study, DNA barcodes were generated for 31 species of commercially important marine ornamental fishes from India. The average genetic distance (K2P model) within species, genus, and family was 0.446, 13.08, and 20.09%, respectively. Intraspecific variation has increased several folds (15-20 times) after including conspecific sequences from different geographical locations. The presence of allopatric lineages/cryptic species was observed in the Indo-pacific region. The NJ tree constructed based on K2P values showed distinct clusters shared by congeneric species specific to populations. PMID- 25703852 TI - A new polymorphic positions discovered in mitochondrial DNA hypervariable region HVIII from central and north-central of Iraq. AB - The aim of this research is to study the mitochondria non-coding region by using Sanger sequencing technique and establish the degree of variation characteristic of a fragment. FTA(r) Technology (FTATM paper DNA extraction) is utilized to extract DNA. A portion of a non-coding region encompassing positions 438 to 574 for HVIII amplified in accordance with the Anderson reference sequence. PCR products purified by EZ-10 spin column were then sequenced and detected by using the ABI 3730xL DNA analyzer. The new polymorphic positions 469 and 482 that are described in this study may in future be suitable sources for identification purpose. The data obtained can be used to identify variable nucleotide positions characterized by frequent occurrence, most promising for identification variants. PMID- 25703853 TI - Complete mitochondrial genome of a parthenogenetic subterranean termite, Reticulitermes aculabialis Tsai et Hwang (Isoptera: Rhinotermitidae). AB - The complete mitochondrial genome of a parthenogenetic termite Reticulitermes aculabialis was assembled and analyzed. The mitogenome is 16,475 bp long and contains the same gene repertoire and gene order as other Reticulitermes species (13 protein-coding genes, 22 tRNA genes, 2 rRNA genes and control region). Coding genes (PCGs, tRNAs and rRNAs) are 14,688 bp in length, occupying 89.15% of the total genomic size. The A + T content of the mitogenome is 65.78%. PMID- 25703854 TI - Mitochondrial genome of the Neophocaena asiaeorientalis asiaeorientalis (Phocaenidae: Neophocaena). AB - Yangtze finless porpoise, Neophocaena asiaeorientalis asiaeorientalis, is a cetacea animal which has been reclassified as a Critically Endangered species by IUCN in 2013. In this study, we determined the complete mitochondrial genome of N. a. asiaeorientalis for use in future phylogenetic analyses. The complete mitochondrial genome of N. a. asiaeorientalis (16,385 bp in length) contained 37 genes (13 protein-coding genes, 2 rRNA genes, and 22 tRNA genes) and a non-coding region (D-loop). Additionally, a rep-origin (35 bp) exists which is located between tRNA(Asn) and tRNA(Cys). PMID- 25703855 TI - Sri Lankan-born women who have given birth in Victoria: a survey of their primary postpartum health-care needs. AB - Women who migrate are vulnerable after giving birth. Normal postpartum adaptive challenges are heightened by separation from family and lack of familiarity with local services. The aim was to investigate primary care needs among Sri Lankan born women with at least one Victorian-born child aged under 2 years. Health care, information and support needs and unmet needs were assessed in a structured Sinhala or English survey offered in print, online or by telephone. Fifty women provided data. Most (80%) had at least one relative from Sri Lanka to stay for postpartum support. Despite this, many had difficulties settling (62%), feeding (58%) and soothing (42%) their babies. They used significantly fewer health services on average (2.3) than mothers in the general community (2.8) (P<0.004). Only 32% of primiparous women attended at least one First-Time Parents' group session. Of women experiencing infant care difficulties, only two-thirds accessed care from a Maternal and Child Health Nurse and only one-third from a General Practitioner. Sri Lankan-born mothers have significant unmet needs for primary care, which are not reduced by informal support. A two-pronged approach is indicated in which women are informed about primary care availability, and the cultural competence and client friendliness of services is strengthened. PMID- 25703856 TI - Deciding on adjuvant chemotherapy for elderly patients with stage III colon cancer: a qualitative insight into the perspectives of surgeons and medical oncologists. AB - OBJECTIVE: The aim of this study is to identify doctor-related factors determining the decision-making for adjuvant chemotherapy for patients with stage III colon cancer aged >=75years. MATERIALS AND METHODS: 21 surgeons and 15 medical oncologists from 10 community hospitals were asked to complete a short questionnaire including tick-box questions regarding motives for non-referral/non treatment, consultation of geriatricians, chemotherapy schemes prescribed and an open question regarding tolerability of chemotherapy. RESULTS: 29 medical specialists returned a completed questionnaire (response 81%). The motives for non-referral/non-treatment reported most often were comorbidity/bad general health condition of the patient; surgical complications; and treatment offered but refused by patient/family. 39% of the surgeons and 55% of the medical oncologists reported consultation of a geriatrician in 2-30% of their decisions. CAPOX and capecitabine were reported by medical oncologists as the most frequently prescribed regimens. Factors that influenced the decision for monotherapy or combination therapy were comorbidity; general health condition of the patient; and toxicity profile of the chemotherapeutics. In general, medical oncologists defined grade <=2 toxicities as tolerable, with the exception of neuropathy, for which grade <=1 toxicity was accepted. CONCLUSIONS: In case medical oncologists prescribe adjuvant chemotherapy to elderly patients with stage III colon cancer, the chemotherapy schemes used are in line with clinical guidelines and they agree on acceptable levels of toxicity. However, the variation among surgeons and medical oncologists in motives for non-referral, non treatment and consultation of geriatricians when deciding on adjuvant chemotherapy for elderly patients with stage III colon cancer, shows the complexity and need for specific knowledge. PMID- 25703857 TI - Providing parents with individualised support in a neonatal intensive care unit reduced stress, anxiety and depression. AB - AIM: This study assessed the effectiveness of an individualised intervention to reduce parental stress, anxiety and depression in a neonatal intensive care unit (NICU). METHODS: Parents of infants admitted to the NICU for a minimum of 4 weeks underwent a five-step individualised intervention programme delivered by a psychologist. RESULTS: The study population comprised 40 mothers and 25 fathers in the intervention group and 40 mothers and 29 fathers in the control group who received the standard support. Similar stress levels were observed in both groups before the intervention. However, after 15 days, the group that received the individualised intervention showed a statistically significant lower level of anxiety, with none of the mothers and fathers in the intervention group reporting anxiety, compared with 2.5% of mothers and 10.3% of fathers in the control group. At discharge, 50% of mothers and 80% of fathers in the intervention group reported no level of depression, compared to all the mothers and fathers in the control group. CONCLUSION: An intervention programme individualised to the needs of mothers and fathers with infants admitted to a NICU for at least 4 weeks was effective in reducing anxiety and depression compared to the standard care. PMID- 25703858 TI - Death with dignity: young patient with brain tumor puts a face on the right-to die movement. PMID- 25703859 TI - Breastfeeding may help prevent aggressive breast cancer in African American women. PMID- 25703861 TI - Reproducibility of Cutaneous Vascular Conductance Responses to Slow Local Heating Assessed Using seven-Laser Array Probes. AB - OBJECTIVE: Gradual local heating of the skin induces a largely NO-mediated vasodilatation. However, use of this assessment of microvascular health is limited because little is known about its reproducibility. METHODS: Healthy volunteers (n = 9) reported twice to the laboratory. CVC, derived from laser Doppler flux and mean arterial pressure, was examined in response to a standardized local heating protocol (0.5 degrees C per 150 second from 33 degrees C to 42 degrees C, followed by 20 minutes at 44 degrees C). Skin responses were examined at two locations on the forearm (between-site). Heating was repeated after a break of 24-72 hours (between-day). Reproducibility of skin responses at 33-42 degrees C is presented for absolute CVC and relative CVC responses corrected for maximal CVC at 44 degrees C (%CVCmax ). RESULTS: Between-day reproducibility of baseline CVC and %CVCmax for both sites was relatively poor (22-30%). At 42 degrees C, CVC and %CVCmax responses showed less variation (9 19%), whilst absolute CVC responses at 44 degrees C were 14-17%. Between-day variation for %CVCmax increased when using data from site 1 on day 1, but site 2 on the subsequent day (25%). CONCLUSION: Day-to-day reproducibility of baseline laser Doppler-derived skin perfusion responses is poor, but acceptable when absolute and relative skin perfusion to a local gradual heating protocol is utilized and site-to-site variation is minimized. PMID- 25703862 TI - A reddish, pedunculated, granulomatous nodule on the nasal dorsum. PMID- 25703863 TI - Preliminary results of contrast-enhanced sonography in the evaluation of the response of uveal melanoma to gamma-knife radiosurgery. AB - PURPOSE: Our aim was to prospectively analyze the use of contrast-enhanced ultrasound (CEUS) in the quantitative assessment of the response of uveal melanoma (UM) to gamma-knife radiosurgery (GKR), investigating whether changes in tumor vascularization precede thickness reduction, which on average occurs at 12 months after GKR. METHODS: Ten patients with UM treated with GKR underwent sonography (US) and CEUS at baseline and at 3, 6, and 12 months after GKR. The transverse diameter, thickness, and quantitative parameters of the UM (ie, area under the curve in the wash-in phase, wash-in perfusion index, peak enhancement, and wash-in rate) were calculated by using dedicated software and compared by using Wilcoxon's signed-rank test. RESULTS: The mean tumor thickness on US was significantly less at both 6 (6.6 mm) and 12 months after GKR (5.8 mm) than it was at baseline (8.3 mm; p < 0.05, both comparisons). Compared with baseline data, the median flow quantitative parameters on CEUS were significantly changed as follows: the peak enhancement (in arbitrary units [au]) at baseline was 5 * 10(6) ; 6 months after GKR, it was 2 * 10(1) (p < 0.05), and 12 months after GKR, it was 4 * 10(1) (p < 0.05). The wash-in rate (in au) at baseline was 1 * 10(6) ; 6 months after GKR, it was 2.1 (p < 0.05), and 12 months after GKR, it was 9.3 (p < 0.05). The wash-in perfusion index (in au) at baseline was 2 * 10(7) ; 6 months after GKR, it was 7 * 10(1) (p < 0.05), and 12 months after GKR, it was 1 * 10(2) (p < 0.05). The area under the curve during the wash-in phase (in au) at baseline was 1 * 10(8) ; 12 months after GKR, it was reduced to 6 * 10(2) (p < 0.05). CONCLUSIONS: At 6 months after GKR, a reduction of tumor thickness, as detected on US, occurred in 6 of the 10 patients, whereas a reduction in all the quantitative parameters measured on CEUS occurred in all 10 patients. However, a larger population is needed to investigate whether CEUS could become the first choice technique for monitoring the response of UM to GKR. PMID- 25703864 TI - In Vivo length changes of the proximal interphalangeal joint proper and accessory collateral ligaments during flexion. AB - PURPOSE: To investigate the length changes in proper collateral ligament (PCL) and accessory collateral ligament (ACL) during flexion of the proximal interphalangeal (PIP) joint in vivo and how portions of the PCL and ACL stabilize the PIP joint. METHODS: We obtained computed tomography scans of the index, middle, and ring fingers of one hand from 6 volunteers at 0 degrees , 30 degrees , 60 degrees , 90 degrees , and full flexion of the PIP joint. Radial and ulnar PCL and ACL were measured and analyzed with computer modeling. RESULTS: The data showed that during flexion the average length of the dorsal portion of the radial and ulnar PCL increased significantly and reached a maximum at 90 degrees . The volar portion of the radial and ulnar PCL and the distal portion of the radial and ulnar ACL shortened continuously from extension to full flexion. CONCLUSIONS: The proximal and middle portions of each ACL are nearly isometric, the dorsal portion of each PCL becomes taut only in flexion, and the volar portion of PCL and the distal portion of ACL become taut only in extension. The current findings indicate that the dorsal portion of PCL is the most stabilizing structure during flexion of the PIP joint, and that the volar portion of PCL and the distal portion of ACL provide the crucial lateral stability to the joint at extension. CLINICAL RELEVANCE: The results may provide information relevant to the ligaments of PIP joint reconstruction and rehabilitation. PMID- 25703865 TI - Anatomy and biomechanics of the forearm interosseous membrane. AB - PURPOSE: To examine the anatomy and function of the forearm interosseous membrane by exploring the anatomical insertions of the central band (CB) on the radius and the ulna and by quantifying the length of the intact ligament and replacement grafts located at the original CB attachment sites and alternative locations. METHODS: Eight fresh cadaver forearms were supinated and pronated and the wrist was extended and flexed while the motion between the distal radius and ulna were recorded. The length of the CB was computed for the intact CB as well for several alternative graft orientations and positions. RESULTS: The maximum length of the CB did not significantly change among different wrist motions. However, with the wrist in a static neutral position, the CB length was significantly shorter in forearm supination than in neutral. During active forearm rotation when CB replacement grafts were positioned distal or proximal to the original CB site, yet still parallel to it, each had a similar trend to be longer in neutral than in supination. If a graft was more transversely oriented, the computed CB length would be 1.6 mm shorter in supination than in neutral. CONCLUSIONS: These results support tensioning a CB graft with the forearm in supination if the goal is to maximize graft tension and to maintain the native 22 degrees angle for a CB graft between the radius and ulna. The results also suggest that the CB graft can probably be located slightly distal or slightly proximal to its original attachment sites. CLINICAL RELEVANCE: Reconstruction of the interosseous membrane has been hampered by a lack of understanding of its length changes with forearm or wrist motion. These results provide a starting point in helping clinicians understand how to more precisely reconstruct this ligament in an anatomical manner. PMID- 25703866 TI - Breast feeding a sick child; can social media influence practice? AB - Breast milk represents optimum infant nutrition. The World Health Organization's recommendation that babies should be exclusively breastfed for a minimum of 6 months (Kramer & Kakuma, 2001) remains unchanged in its second decade (Kramer & Kakuma, 2014), which is acknowledged in industrialized countries by successive policies and guidelines for the promotion and care of breastfeeding in children's wards and departments. The known protective influence of breast milk in preventing the onset of disease in later life is of particular import for any sick infant, but the user voice as represented by Helen Calvert's Twitter campaign @heartmummy#hospitalbreastfeeding has united service user and professional voices to call for improved breastfeeding support in pediatric care. Although breastfeeding rates in industrialized countries drop markedly in the first 6 weeks, breastfed babies with cardiac conditions benefit from better oxygen saturations, faster weight gain, and shorter hospital stays. Unwell babies are most in need of the benefits of breast milk. However, families and staff overcome physical barriers to the initiation and maintenance of breastfeeding, including lack of space, privacy, and separation of the maternal-infant dyad. Many women are motivated to breastfeed or express milk but are reluctant to approach health professionals for help and advice. Despite robust evidence and sound guidelines and policies, breastfeeding knowledge and experience amongst Child Health professionals is often inadequate and leaves them unable to support families. While @heartmummy#hospitalbreastfeeding highlights the issue, Child Health strategy needs investment in young people's long term health by increasing staff skills and focusing on breastfeeding as a core therapeutic intervention. Lactation Consultants could offer training, disseminate good practice, and address the needs of breastfeeding families. PMID- 25703867 TI - Relationship between donor sperm parameters and pregnancy outcome after intrauterine insemination: analysis of 2821 cycles in 1355 couples. AB - The aim of this study was to investigate whether sperm parameters can affect the pregnancy outcome of artificial intrauterine insemination with cryopreserved donor spermatozoon (AID). A total of 1355 couples received 2821 AID treatment cycles in the Reproductive Medicine Center of the Tongji Medical College between January 2010 and December 2013, and the data were collected and retrospectively analysed. The relationship between pre-freezing, post-thawing as well as optimised sperm parameters and AID pregnancy outcome was investigated. Clinical pregnancy rate and cumulated pregnancy rate were also calculated. A total of 728 cycles from 2821 treatment cycles achieved pregnancies, and cumulated pregnancy rate was 25.81%. Pre-freezing progressive sperm motility in pregnant cycles was higher than that in nonpregnant cycles (P = 0.001); logistic regression analysis also indicated that pre-freezing progressive sperm motility was the only parameter affecting pregnancy outcome (P = 0.0001). Our study also showed that the cumulated pregnancy rate increased progressively and reached a plateau after the fifth cycle. In conclusion, pre-freezing progressive sperm motility should be a valuable predictor for AID pregnancy outcome. Female fertility factors should be considered, or IVF/ICSI should be recommended when couples received more than 5 AID cycles without pregnancy. PMID- 25703868 TI - Increasing Pap smear rates at an urban Aboriginal Community Controlled Health Service through translational research and continuous quality improvement. AB - This article describes translational research (TR) and continuous quality improvement (CQI) processes used to identify and address barriers and facilitators to Pap smear screening within an urban Aboriginal Community Controlled Health Service (ACCHS). Rapid Plan-Do-Study-Act (PDSA) cycles were conducted, informed by client surveys, a data collection tool, focus groups and internal research. There was a statistically significant increase in Pap smear numbers during PDSA cycles, continuing at 10 months follow up. The use of TR with CQI appears to be an effective and acceptable way to affect Pap smear screening. Community and service collaboration should be at the core of research in Aboriginal and Torres Strait Islander health settings. This model is transferrable to other settings and other health issues. PMID- 25703869 TI - Real dilemmas regarding blood transfusion. PMID- 25703870 TI - New-onset coronary aneurism and late-acquired incomplete scaffold apposition after full polymer jacket of a chronic total occlusion with bioresorbable scaffolds. PMID- 25703871 TI - Extravasation from an accessory renal artery: a critical complication associated with percutaneous coronary intervention. PMID- 25703872 TI - Transatrial intrapericardial tricuspid annuloplasty. AB - OBJECTIVES: This study sought to demonstrate transcatheter deployment of a circumferential device within the pericardial space to modify tricuspid annular dimensions interactively and to reduce functional tricuspid regurgitation (TR) in swine. BACKGROUND: Functional TR is common and is associated with increased morbidity and mortality. There are no reported transcatheter tricuspid valve repairs. We describe a transcatheter extracardiac tricuspid annuloplasty device positioned in the pericardial space and delivered by puncture through the right atrial appendage. We demonstrate acute and chronic feasibility in swine. METHODS: Transatrial intrapericardial tricuspid annuloplasty (TRAIPTA) was performed in 16 Yorkshire swine, including 4 with functional TR. Invasive hemodynamics and cardiac magnetic resonance imaging (MRI) were performed at baseline, immediately after annuloplasty and at follow-up. RESULTS: Pericardial access via a right atrial appendage puncture was uncomplicated. In 9 naive animals, tricuspid septal lateral and anteroposterior dimensions, the annular area and perimeter, were reduced by 49%, 31%, 59%, and 24% (p < 0.001), respectively. Tricuspid leaflet coaptation length was increased by 53% (p < 0.001). Tricuspid geometric changes were maintained after 9.7 days (range, 7 to 14 days). Small effusions (mean, 46 ml) were observed immediately post-procedure but resolved completely at follow up. In 4 animals with functional TR, severity of regurgitation by intracardiac echocardiography was reduced. CONCLUSIONS: Transatrial intrapericardial tricuspid annuloplasty is a transcatheter extracardiac tricuspid valve repair performed by exiting the heart from within via a transatrial puncture. The geometry of the tricuspid annulus can interactively be modified to reduce severity of functional TR in an animal model. PMID- 25703873 TI - Outcomes of spot stenting versus long stenting after intentional subintimal approach for long chronic total occlusions of the femoropopliteal artery. AB - OBJECTIVES: This study sought to compare the outcomes of spot stenting versus long stenting after intentional subintimal approach for long femoropopliteal chronic total occlusions (CTO). BACKGROUND: The optimal stenting strategy following the subintimal recanalization of long femoropopliteal chronic total occlusions has not been investigated. METHODS: A total of 196 limbs in 163 patients, implanted with bare nitinol stents after subintimal approach in long femoropopliteal occlusions (lesion length 25 +/- 8 cm), were retrospectively analyzed. The primary patency was compared between spot stenting (n = 129) and long stenting (n = 67). RESULTS: Baseline characteristics and immediate procedural results were similar between groups. Adjusted-primary patency (47% vs. 77%, p < 0.001) and adjusted-freedom from target lesion revascularization (52% vs. 84%, p < 0.001) at 2 years were significantly lower in the long stenting group than in the spot stenting group. The incidence of stent fracture, fracture type, and restenosis pattern did not differ between groups. Long stenting was an independent predictor of restenosis (hazard ratio [HR]: 2.0) along with other risk factors such as nonuse of clopidogrel (HR: 3.3) or cilostazol (HR: 2.2), small stent diameter (HR: 0.6), poor run-off (HR: 1.9), and post-procedural ankle brachial index (HR: 0.1). Compared with spot stenting after adjustment using inverse probability of treatment weighting, long stenting, especially involving the P2 or P3 segment of the popliteal artery, was independently associated with 7.5-fold increases in restenosis risk (p < 0.001). CONCLUSIONS: The primary patency was significantly higher with spot stenting than with long stenting following subintimal approach for long femoropopliteal chronic total occlusions. The risk of restenosis was especially higher when long stenting was extended to the distal popliteal artery. PMID- 25703874 TI - Embolization of cardiac arteriovenous malformation with onyx. PMID- 25703875 TI - Percutaneous closure of a large ascending aorta pseudoaneurysm due to mediastinitis using an amplatzer occluder device. PMID- 25703876 TI - Functional tricuspid regurgitation: percutaneous therapies needed. PMID- 25703877 TI - Do we know the best treatment for in-stent restenosis via network meta-analysis (NMA)?: simple methods any interventionalist can use to assess NMA quality and a call for better NMA presentation. PMID- 25703878 TI - Novel approaches for preventing or limiting events (Naples) III trial: randomized comparison of bivalirudin versus unfractionated heparin in patients at increased risk of bleeding undergoing transfemoral elective coronary stenting. AB - OBJECTIVES: This study sought to assess the safety and the efficacy of bivalirudin compared with unfractionated heparin (UFH) alone in the subset of patients at increased risk of bleeding undergoing transfemoral elective percutaneous coronary intervention (PCI). BACKGROUND: Bivalirudin, a synthetic direct thrombin inhibitor, determines a significant decrease of in-hospital bleeding following PCI. METHODS: This is a single-center, investigator-initiated, randomized, double-blind, controlled trial. Consecutive biomarker-negative patients at increased bleeding risk undergoing PCI through the femoral approach were randomized to UFH (UFH group; n = 419) or bivalirudin (bivalirudin group; n = 418). The primary endpoint was the rate of in-hospital major bleeding. RESULTS: The primary endpoint occurred in 11 patients (2.6%) in the UFH group versus 14 patients (3.3%) in the bivalirudin group (odds ratio: 0.78; 95% confidence interval: 0.35 to 1.72; p = 0.54). Distribution of access-site and non-access site bleeding was 18% and 82% in the UFH group versus 50% and 50% in the bivalirudin group (p = 0.10). CONCLUSIONS: The results of this randomized study, carried out at a single institution, suggest that there is no difference in major bleeding rate between bivalirudin and UFH in increased-risk patients undergoing transfemoral PCI. (Novel Approaches in Preventing and Limiting Events III Trial: Bivalirudin in High-Risk Bleeding Patients [NAPLES III]; NCT01465503). PMID- 25703879 TI - Persistence of iatrogenic atrial septal defect after interventional mitral valve repair with the MitraClip system: a note of caution. AB - OBJECTIVES: The purpose of this study was to investigate the persistence rates of iatrogenic atrial septal defect (iASD) after interventional edge-to-edge repair with serial transesophageal echocardiography examinations and close clinical follow-up (FU). BACKGROUND: Transcatheter mitral valve repair (TMVR) with the MitraClip system (Abbott Vascular, Abbott Park, Illinois) is a therapeutic alternative to surgery in selected high-risk patients. Clip placement requires interatrial transseptal puncture and meticulous manipulation of the steerable sheath. The persistence of iASD after MitraClip procedures and its clinical relevance is unknown. METHODS: A total of 66 patients (76.7% male, mean age 77.1 +/- 7.9 years) with symptomatic mitral regurgitation (MR) at prohibitive surgical risk (EuroSCORE II 10.1 +/- 6.1%) underwent MitraClip procedures and completed 6 months of FU. RESULTS: Transesophageal echocardiography after FU showed persistent iASD in 50% of cases. Patients with iASD did not significantly differ from patients without ASD concerning baseline characteristics, New York Heart Association functional class, severity of MR, and acute procedural success rates (p > 0.05). When comparing procedural details and hemodynamic measures between groups, MitraClip procedures took longer in patients without iASD (82.4 +/- 39.7 min vs. 68.9 +/- 45.5 min; p = 0.05), and echocardiography after FU showed less decrease of systolic pulmonary artery pressures in the iASD group (-1.6 +/- 14.1 mm Hg vs. 9.3 +/- 17.4 mm Hg; p = 0.02). Clinically, patients with iASD presented more often with New York Heart Association functional classes >II after FU (57% vs. 30%; p = 0.04), showed higher levels of N-terminal pro-brain natriuretic peptide (6,667.3 +/- 7,363.9 ng/dl vs. 4,835.9 +/- 6,681.7 ng/dl; p = 0.05), and had less improvement in 6-min walking distances (20.8 +/- 107.4 m vs. 114.6 +/- 116.4 m; p = 0.001). Patients with iASD showed higher death rates during 6 months (16.6% vs. 3.3%; p = 0.05). Cox regression analysis found that only persistence of iASD (p = 0.04) was associated with 6-month survival. CONCLUSIONS: The persistence rate of 50% iASD after MitraClip procedures is considerably high. Persistent interatrial shunting was associated with worse clinical outcomes and increased mortality. Further studies are warranted to investigate if persistent interatrial shunting is the mediator or marker of advanced disease in these patients. PMID- 25703880 TI - Focal stenting versus "metal jacket" for long subintimal recanalization of the femoropopliteal artery. PMID- 25703881 TI - Noncompliance and cessation of dual antiplatelet therapy after coronary stenting: looking at the speck rather than noticing the log? PMID- 25703882 TI - Longitudinal elongation, axial compression, and effects on strut geometry of bioresorbable vascular scaffolds: insights from 2- and 3-dimensional optical coherence tomography imaging. PMID- 25703883 TI - Blood transfusion after percutaneous coronary intervention and risk of subsequent adverse outcomes: a systematic review and meta-analysis. AB - OBJECTIVES: This study sought to define the prevalence and prognostic impact of blood transfusions in contemporary percutaneous coronary intervention (PCI) practice. BACKGROUND: Although the presence of anemia is associated with adverse outcomes in patients undergoing PCI, the optimal use of blood products in patients undergoing PCI remains controversial. METHODS: A search of EMBASE and MEDLINE was conducted to identify PCI studies that evaluated blood transfusions and their association with major adverse cardiac events (MACE) and mortality. Two independent reviewers screened the studies for inclusion, and data were extracted from relevant studies. Random effects meta-analysis was used to estimate the risk of adverse outcomes with blood transfusions. Statistical heterogeneity was assessed by considering the I(2) statistic. RESULTS: Nineteen studies that included 2,258,711 patients with more than 54,000 transfusion events were identified (prevalence of blood transfusion 2.3%). Crude mortality rate was 6,435 of 50,979 (12.6%, 8 studies) in patients who received a blood transfusion and 27,061 of 2,266,111 (1.2%, 8 studies) in the remaining patients. Crude MACE rates were 17.4% (8,439 of 48,518) in patients who had a blood transfusion and 3.1% (68,062 of 2,212,730) in the remaining cohort. Meta-analysis demonstrated that blood transfusion was independently associated with an increase in mortality (odds ratio: 3.02, 95% confidence interval: 2.16 to 4.21, I(2) = 91%) and MACE (odds ratio: 3.15, 95% confidence interval: 2.59 to 3.82, I(2) = 81%). Similar observations were recorded in studies that adjusted for baseline hematocrit, anemia, and bleeding. CONCLUSIONS: Blood transfusion is independently associated with increased risk of mortality and MACE events. Clinicians should minimize the risk for periprocedural transfusion by using available bleeding-avoidance strategies and avoiding liberal transfusion practices. PMID- 25703884 TI - The transseptal conundrum. PMID- 25703885 TI - Thrombotic complications associated with early and late nonadherence to dual antiplatelet therapy. AB - OBJECTIVES: This study sought to assess the frequency and clinical impact of dual antiplatelet therapy (DAPT) nonadherence. BACKGROUND: There are limited data on the impact of DAPT nonadherence during the first year after a second-generation drug-eluting stent placement. METHODS: After successful Endeavor zotarolimus eluting stent implantation, 2,265 patients were enrolled in a registry with limited exclusions and monitored during 12 months of prescribed DAPT. Predictors of any nonadherence (ANA) at 6 months were analyzed by multivariable analysis, and the association between ANA at 6 or 12 months with the endpoints of death, myocardial infarction, and stent thrombosis was assessed. RESULTS: The study population included 30% female patients, 34% with diabetes and 36% with acute coronary syndromes. ANA occurred in 208 patients (9.6%) before 6 months and 378 patients (18.5%) before 1 year. Major bleeding (odds ratio [OR]: 12.83, 95% confidence interval [CI]: 7.55 to 21.80, p < 0.001) was the only predictor of ANA at 6 months. In time-dependent analyses, ANA before 6 months was associated with an increased risk of death or myocardial infarction (7.6% vs. 3.0%, p < 0.001) and a numerical increase in stent thrombosis (2.0% vs. 0.9%, p = 0.12). After adjustment for baseline differences, ANA within 6 months remained associated with death or MI (OR: 1.95, 95% CI: 1.02 to 3.75). ANA occurring after 6 months did not increase the risk of subsequent ischemic events. CONCLUSIONS: DAPT ANA occurs frequently and is associated with increased risk for thrombotic complications if it occurs within the first 6 months. Major bleeding was a significant correlate of DAPT ANA within 6 months. (EDUCATE: The MEDTRONIC Endeavor Drug Eluting Stenting: Understanding Care, Antiplatelet Agents and Thrombotic Events; NCT01069003). PMID- 25703886 TI - Comparison among drug-eluting balloon, drug-eluting stent, and plain balloon angioplasty for the treatment of in-stent restenosis: a network meta-analysis of 11 randomized, controlled trials. AB - OBJECTIVES: A Bayesian network meta-analysis was performed comparing the efficacy and safety of drug-eluting balloons (DEB), drug-eluting stents (DES), or plain old balloon angioplasty (POBA) for treatment of in-stent restenosis (ISR). BACKGROUND: Optimal treatment options for ISR have not been well established. METHODS: Randomized, controlled trials comparing DEB, DES, and POBA for the treatment of ISR after percutaneous coronary intervention with bare metal stent or DES were included. The primary outcome was target lesion revascularization (TLR). The pairwise posterior median odds ratio (OR) with 95% credible interval (CrI) was the effect measure. RESULTS: This analysis included 2,059 patients from 11 RCTs. The risk of TLR was markedly lower in patients treated with DEB (OR: 0.22, 95% CrI: 0.10 to 0.42) or DES (OR: 0.24, 95% CrI: 0.11 to 0.47) than in those treated with POBA in a random-effects model. In a comparison of DEB and DES, the risk of TLR (OR: 0.92, 95% CrI: 0.43 to 1.90) was similar. The risk of MI or all-cause mortality was lowest in the DEB group compared with the DES and POBA groups, which did not meet statistical significance. The risk of major adverse cardiac events, which was mainly driven by TLR, was also significantly lower in the DEB or and DES group (OR: 0.28, 95% CrI: 0.14 to 0.53) than in the POBA group, but it was similar between the DEB and DES groups (OR: 0.84, 95% CrI: 0.45 to 1.50). The probability of being ranked as the best treatment was 59.9% (DEB), 40.1% (DES), and 0.1% (POBA) in terms of TLR, whereas it was 63.0% (DEB), 35.3% (POBA), and 1.7% (DES) in terms of MI. CONCLUSIONS: Local drug delivery by DEB or DES for ISR lesions was markedly better than POBA in preventing TLR, but not for MI or mortality. Among the 2 different strategies of drug delivery for ISR lesions, treatment with DEB showed a trend of less development of MI than did treatment with DES. PMID- 25703887 TI - Outcomes with cangrelor versus clopidogrel on a background of bivalirudin: insights from the CHAMPION PHOENIX (A Clinical Trial Comparing Cangrelor to Clopidogrel Standard Therapy in Subjects Who Require Percutaneous Coronary Intervention [PCI]). AB - OBJECTIVES: The aim of this study was to examine the efficacy and bleeding outcomes of cangrelor in patients in the CHAMPION PHOENIX (A Clinical Trial Comparing Cangrelor to Clopidogrel Standard Therapy in Subjects Who Require Percutaneous Coronary Intervention [PCI]) who underwent percutaneous coronary intervention with bivalirudin. BACKGROUND: Cangrelor is a potent intravenous P2Y12 inhibitor with rapid onset and offset. In the CHAMPION PHOENIX, cangrelor compared with clopidogrel significantly reduced 48-h ischemic events including stent thrombosis, without increasing major bleeding. Bivalirudin has demonstrated ischemic outcomes similar to those with heparin plus glycoprotein IIb/IIIa inhibition, with reduced bleeding but increased early stent thrombosis. METHODS: In the modified intent-to-treat population, 2,059 patients (18.8%) received bivalirudin, with 1,014 patients in the cangrelor treatment arm and 1,045 in the clopidogrel treatment arm. RESULTS: At 48 h, the primary endpoint of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis was lower with cangrelor versus clopidogrel (48 [4.7%] vs. 70 [6.7%]; odds ratio [OR]: 0.68, p = 0.047). Death was similar in both arms (2 [0.2%] vs. 2 [0.2%]). Myocardial infarction was reduced by cangrelor (37 [3.6%] vs. 59 [5.6%]; OR: 0.63, p = 0.03), as was death/myocardial infarction (39 [3.8%] vs. 61 [5.8%]; OR: 0.65, p = 0.04). Cangrelor was associated with a nonsignificant trend toward less stent thrombosis (7 [0.7%] vs. 15 [1.4%]; OR: 0.48, p = 0.10), which was evident within 2 h after percutaneous coronary intervention (p = 0.057). GUSTO (Global Use of Strategies to Open Occluded Arteries) severe bleeding was similar in both arms (2 of 1,021 [0.2%] vs. 2 of 1,055 [0.2%]) as were other bleeding definitions and transfusions. Efficacy and safety results were consistent in patients with stable angina, non-ST-segment elevation acute coronary syndrome, and ST-segment elevation myocardial infarction (p for interaction: 0.62 and 0.29). CONCLUSIONS: Cangrelor may offer an attractive benefit risk profile when used in combination with bivalirudin. PMID- 25703888 TI - Insights from the early experience of the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry. AB - The current system for postmarket surveillance of medical devices in the United States is limited. To help change this paradigm for transcatheter valve therapies (TVTs), starting with transcatheter aortic valve replacement, the Society of Thoracic Surgeons and the American College of Cardiology partnered to form the TVT Registry program in close collaboration with the U.S. Food and Drug Administration and the Center for Medicare and Medicaid Services. The goal of the TVT Registry is to measure and improve quality of care and patient outcomes in clinical practice and to have a pivotal role in the scientific evidence and surveillance for medical devices. Challenges were faced in the early experience of the registry included developing multistakeholder partnerships, data collection requirements, and the use of the registry for pre- and post-market device evaluations. In addressing these challenges, the TVT Registry demonstrates that it is feasible for professional societies to assume a pivotal role in pre- and/or post-market studies, leveraging a clinical registry infrastructure. Sharing the TVT Registry experience may help other professional societies and stakeholders better anticipate and plan for these challenges. PMID- 25703889 TI - Novel radiation reduction protocol. PMID- 25703890 TI - A potential procedural complication 2 years after percutaneous coronary intervention to treat left anterior descending artery lesions with the T-stenting and the small protrusion technique. PMID- 25703891 TI - The arranged marriage of cangrelor and bivalirudin. PMID- 25703892 TI - Referral patterns for mediastinal staging with EBUS across a UK Lung Cancer Network: A report from the Manchester Cancer EBUS sub-group. PMID- 25703893 TI - Clinical outcomes in patients with small cell lung cancer in a single institute: Comparative analysis of radiographic screening with symptom-prompted patients. AB - OBJECTIVES: The present study was performed to evaluate the differences in clinical characteristics and survival outcomes of patients with small cell lung cancer (SCLC) according to methods used for detecting the disease: radiographic screening or symptomatically prompted. MATERIALS AND METHODS: The clinical findings and actual treatment outcomes were estimated according to three means of detection of SCLC: computed tomography (CT), radiographic test, and symptom prompted cases. RESULTS: We identified 147 patients (male/female ratio: 127/20; mean age: 68.1 years old) between 2000 and 2011. The patients were divided into three categories according to method of detection: chest CT (CT; n=24), radiographic screening (CXR; n=37), and symptom-prompted cases (symptom; n=86). There was no significant shift to early TNM stage distribution in the CT or CXR group compared with the symptom group. However, the rates of limited disease (LD) SCLC were significantly higher in the CT and CXR groups than the symptom group. Median survival times were 17.0 months (95% confidence interval (CI): 11.6-22.4) in the CT group, 19.0 months (95%CI: 11.7-126.3) in the CXR group, and 12.0 months (95%CI: 9.6-14.4) in the symptom group. There were statistically significant differences in overall survival between CT and symptom groups (P<0.05) and between CXR and symptom groups (P<0.001). However, there was no significant difference in survival between CT and CXR groups. CONCLUSIONS: Radiographic (CT plus CXR) testing contributes to better clinical outcome in patients with SCLC. PMID- 25703894 TI - Comparison of the in vitro activity of echinocandins against Candida albicans, Candida dubliniensis, and Candida africana by time-kill curves. AB - Candida albicans remains the most common fungal pathogen. This species is closely related to 2 phenotypically similar cryptic species, Candida dubliniensis and Candida africana. This study aims to compare the antifungal activities of echinocandins against 7 C. albicans, 5 C. dubliniensis, and 2 C. africana strains by time-kill methodology. MIC values were similar for the 3 species; however, differences in killing activity were observed among species, isolates, and echinocandins. Echinocandins produced weak killing activity against the 3 species. In all drugs, the fungicidal endpoint (99.9% mortality) was reached at <=31 h with >=0.5 MUg/mL for anidulafungin in 4 C. albicans and 1 C. dubliniensis, for caspofungin in 1 C. albicans and 2 C. dubliniensis, and for micafungin in 4 C. albicans and 1 C. dubliniensis. None of echinocandins showed lethality against C. africana. Identification of these new cryptic species and time-kill studies would be recommendable when echinocandin treatment fails. PMID- 25703895 TI - Microbiological and clinical aspects of respiratory infections associated with Bordetella bronchiseptica. AB - Bordetella bronchiseptica is a well-known veterinary pathogen, but its implication in human disease is probably not fully recognized. The purpose of this study was to determine the clinical significance of 36 B. bronchiseptica isolates from respiratory samples of 22 patients. Therefore, we describe microbiological characteristics, including phenotypic and genotypic identification as well as antimicrobial susceptibilities of the isolates. Clonal relatedness was evaluated using pulsed-field gel electrophoresis (PFGE). Most of the patients had some underlying immunosuppressive condition. Eighteen out of 22 (82%) patients had respiratory symptoms, and the death of 2 patients was associated with respiratory infection.All strains were correctly identified at species level by the simultaneous use of phenotypic methods and were confirmed by specific amplification of the upstream region of the fla gene. Tigecycline, minocycline, doxycycline, colistin, and meropenem were the most active agents tested. PFGE analysis revealed that repeated infections involving each patient had been caused by the same strain. PMID- 25703896 TI - Legal cognitive requirements impact on pharmacy practice and patient outcomes. PMID- 25703898 TI - How to CHAIR an academic session. PMID- 25703897 TI - Patient-reported outcomes in heart failure: existing measures and future uses. AB - Patient-reported outcomes (PROs) are any report obtained directly from a patient about how they feel or function in relation to their health condition and its therapies. Strong support for PROs exists at multiple levels of the health-care community from regulatory boards to clinical researchers. PROs are particularly important in heart failure because it is a common chronic illness marked with acute exacerbations, often requiring hospitalization, and significant symptom burden. Use of PROs to understand patient perspectives will help providers deliver more patient-centered care, and thus improve the quality of care. This review provides a contemporary overview of the current state of PROs in heart failure and suggests future directions and opportunities to advance PRO use to provide more comprehensive care. Advancing PRO measurement along with incorporating longitudinal measures in national databases and local electronic health records will serve to improve patient-centered care for patients with heart failure. PMID- 25703899 TI - Levels of rare earth elements, heavy metals and uranium in a population living in Baiyun Obo, Inner Mongolia, China: a pilot study. AB - The Baiyun Obo deposit is the world's largest rare earth elements (REE) deposit. We aimed to investigate levels of REE, heavy metals (HMs) and uranium (U) based on morning urine samples in a population in Baiyun Obo and to assess the possible influence of rare earth mining processes on human exposure. In the mining area, elevated levels were found for the sum of the concentrations of light REE (LREE) and heavy REE (HREE) with mean values at 3.453 and 1.151 MUg g(-1) creatinine, which were significantly higher than those in the control area. Concentrations of HMs and U in the population increased concomitantly with increasing REE levels. The results revealed that besides REE, HMs and U were produced with REE exploitation. Gender, age, educational level, alcohol and smoking habit were major factors contributing to inter-individual variation. Males were more exposed to these metals than females. Concentrations in people in the senior age group and those with only primary education were low. Drinking and smoking were associated with the levels of LREE, Cr, Cu, Cd and Pb in morning urine. Hence this study provides basic and useful information when addressing public and environmental health challenges in the areas where REE are mined and processed. PMID- 25703900 TI - Lead in the soil-mulberry (Morus alba L.)-silkworm (Bombyx mori) food chain: translocation and detoxification. AB - The translocation of lead (Pb) in the soil-mulberry-silkworm food chain and the process of Pb detoxification in the mulberry-silkworm chain were investigated. The amount of Pb in mulberry, silkworm, feces and silk increased in a dose responsive manner to the Pb contents in the soils. Mulberry roots sequestered most of the Pb, ranging from 230.78 to 1209.25 mg kg(-1). Over 92% of the Pb in the mulberry leaves was deposited in the cell wall, and 95.29-95.57% of the Pb in the mulberry leaves was integrated with oxalic acid, pectates and protein, and it had low bioavailability. The Pb concentrations in the silkworm feces were 4.50 4.64 times higher than those in the leaves. The synthesis of metallothioneins in three tissues of the silkworms was induced to achieve Pb homeostasis under Pb stress. These results indicated the mechanism involved in Pb transfer along the food chain was controlled by the detoxification of Pb in different trophic levels. Planting mulberry and rearing silkworm could be a promising approach for the remediation of Pb-polluted soils due to the Pb tolerance of mulberry and silkworm. PMID- 25703901 TI - Hormetic effect of ionic liquid 1-ethyl-3-methylimidazolium acetate on bacteria. AB - The biological effect of ionic liquids (ILs) is one of the highly debated topics as they are being contemplated for various industrial applications. 1-ethyl-3 methylimidazolium acetate ([EMIM][Ac]) showed remarkable hormesis on anaerobic Clostridium sp. and aerobic Pseudomonas putida. Bacterial growth was stimulated at up to 2.5 g L(-1) and inhibited at >2.5 g L(-1) of [EMIM][Ac]. The growth of Clostridium sp. and P. putida were higher by 0.4 and 4-fold respectively, in the presence of 0.5 g L(-1) [EMIM][Ac]. Assessment of the effect of [EMIM][Ac] under different growth conditions showed that the hormesis of [EMIM][Ac] was mediated via regulation of medium pH. Hormetic effect of [EMIM][Ac] was evident only in medium with poor buffering capacity and in the presence of a fermentable substrate as the carbon source. The hormetic effect of [EMIM][Ac] on bacterial growth is most likely associated with the buffering capacity of acetate anion. These observations have implications in ILs toxicity studies and ecological risk assessment. PMID- 25703902 TI - Ecotoxicological effects of graphene oxide on the protozoan Euglena gracilis. AB - Potential environmental risks posed by nanomaterials increase with their extensive production and application. As a newly emerging carbon material, graphene oxide (GO) exhibits excellent electrochemical properties and has promising applications in many areas. However, the ecotoxicity of GO to organisms, especially aquatic organisms, remains poorly understood. Accordingly, this study examined the toxicity of GO with protozoa Euglena gracilis as test organism. Growth inhibition test was initially performed to investigate acute toxic effects. Protozoa were subsequently exposed to GO ranging from 0.5 mg L(-1) to 5 mg L(-1) for 10 d. The growth, photosynthetic pigment content, activities of antioxidant enzymes, ultrastructure of the protozoa, as well as the shading effect of GO, were analyzed to determine the mechanism of the toxicity effect. Results showed that the 96 h EC50 value of GO in E. gracilis was 3.76+/-0.74 mg L(-1). GO at a concentration of 2.5 mg L(-1) exerted significant (P<0.01) adverse effects on the organism. These effects were evidenced by the inhibition of growth and the enhancement of malondialdehyde content and antioxidant enzyme activities. Shading effect and oxidative stress may be responsible for GO toxicity. PMID- 25703903 TI - Biodegradable drug-eluting pellets provide steady and sustainable cisplatin release in the intrapleural cavity: in vivo and in vitro studies. AB - The purpose of this study is to develop biodegradable drug-eluting pellets to provide a sustainable delivery of cisplatin intrapleurally. Poly(d,l)-lactide-co glycolide (PLGA) (LA:GA=50:50) copolymer and cisplatin were mixed, compressed, and sintered to construct biodegradable pellets and placed in phosphate-buffered saline to test the characteristics of in vitro release. In vivo, equal amounts of cisplatin (10mg/kg) were introduced into rabbit pleural cavities either by free form (Gr1) or pellets form (Gr2). Cisplatin concentrations in the collected pleural effusion and blood were measured and compared by repeated measurement ANOVA. In vitro, approximately 5% of the cisplatin was released in the first day while the rest was gradually released in the following 50 days. In vivo, the cisplatin level in the pleural fluid was equally high during the first 2 days but dropped quickly in Gr1 while remaining high in Gr2 for 18 days, the difference was statistically significant (P<0.001) In contrast, the plasma cisplatin level was 10 times significantly higher in Gr1 than in Gr2 (P<0.001), which resulted in two early deaths of rabbits. Thus we concluded that our biodegradable pellets could achieve high and steady cisplatin release in the pleural cavity. This novel drug delivery system may have the potential to serve as an adjuvant treatment for malignant pleural lesion. PMID- 25703904 TI - Resonance enhanced AFM-IR: a new powerful way to characterize blooming on polymers used in medical devices. AB - In this paper we demonstrated the application of resonance enhanced AFM-IR to the study of the medical device surfaces. Surface state is one of the most important parameter on the biocompatibility of an implantable medical device. By using this new technique, it was possible to obtain with high resolution topographic and chemical maps and to identify the chemical nature of very thin deposit observed on the surface. This was illustrated with the case of lubricant exudation on polyurethane used in the making of implantable catheters. PMID- 25703905 TI - Reduced muscarinic parotid secretion is underlain by impaired NO signaling in diabetic rabbits. AB - OBJECTIVES: The influence of experimental diabetes (alloxan, 100 mg kg(-1) ) was studied on rabbit parotid gland function. MATERIAL AND METHODS: Carbachol-induced parotid secretion in vivo, and in vitro quantification of inducible nitric oxide synthase (iNOS) mRNA expression, by real-time RT-PCR, and activity of superoxide dismutase (SOD) and total antioxidant capacity (TAC) in commercial colorimetric assays were measured in parotid glands of non-diabetic and diabetic rabbits. RESULTS: Carbachol-induced dose-dependent increase in parotid secretion significantly reduced in diabetic rabbits. Functional studies in the presence of muscarinic receptor and nitric oxide synthase (NOS) antagonists revealed that in M3 receptor-mediated carbachol secretion, nitric oxide, deriving mainly from neuronal NOS (nNOS) in control, and iNOS in diabetic rabbits, was involved. Also, upregulation of iNOS mRNA expression and enhanced SOD activity and TAC were detected in diabetic glands. CONCLUSIONS: Our data suggest that decreased M3 receptor-mediated parotid secretion in diabetic rabbits appears to be due to alterations in NO signaling, mainly due to iNOS induction, accompanied by elevated antioxidant response. PMID- 25703906 TI - Causes and risk factors of urinary incontinence: Avicenna's point of view vs. contemporary findings. AB - PURPOSE: To extract the causes and risk factors of urinary incontinence from an old medical text by Avicenna entitled "Canon of Medicine" and comparing it with contemporary studies. MATERIALS AND METHODS: In this study, etiology and risk factors of urinary incontinence were extracted from Avicenna's "Canon of Medicine". Commentaries written on this book and other old reliable medical texts about bladder and its diseases were also studied. Then the achieved information was compared with contemporary findings of published articles. RESULTS: Urinary incontinence results from bladder dysfunction in reservoir phase. Bladder's involuntary muscles and voluntary external sphincter are two main components which are involved in this process. Urinary incontinence can exist without obvious structural and neuronal etiologies. According to Avicenna, distemperment of muscular tissue of bladder and external sphincter is the cause for urinary incontinence in such cases. Distemperment is the result of bothering qualities in tissue, i.e.: "wet" and "cold". They are the two bothering qualities which are caused by extracorporeal and intracorporeal factors. Interestingly, the positive associations of some of these factors with urinary incontinence have been shown in recent researches. CONCLUSION: "Cold" and "wet" distemperment of bladder and external sphincter can be independent etiologies of urinary incontinence which should be investigated. PMID- 25703907 TI - Prolapsed vaginal ureterocele as a cause of urinary incontinence in a child. PMID- 25703908 TI - A comparison of the effects of morphine and sublingual desmopressin combination therapy with morphine alone in treatment of renal colic: a controlled clinical trial. AB - PURPOSE: To compare the therapeutic efficacy of combined desmopressin and morphine with morphine and placebo on acute renal colic. MATERIALS AND METHODS: In a single blind case-control clinical trial 81 consecutive patients, 54 males and 27 females with the mean age of 30.12 +/- 9.88 years, presenting with acute renal colic to the urology emergency unit were studied. The patients were randomly assigned into two groups. The 40 cases were treated with 0.1 mg/kg IM morphine and 60 MUg of sublingual desmopressin melt; whereas the 41 controls received the same dose of morphine beside a placebo. RESULTS: There were no significant statistical differences regarding the mean age, gender, stone size, location and affected side between the two groups. Our results showed a significantly higher acuity of pain in the study group in comparison to the controls at 10, 20 and 30 minutes of receiving the medication (P = .06, .017 and P = .008, respectively). CONCLUSION: No superiority was found in adding desmopressin to morphine compared to the traditional treatments (opioids only) in relieving the pain of acute renal colic cases. PMID- 25703909 TI - The effectiveness of flexible ureterorenoscopy for opaque and non-opaque renal stones. AB - PURPOSE: To evaluate the treatment success rate of flexible ureterorenoscopy (URS) for opaque and non-opaque renal stones. MATERIALS AND METHODS: Ninety-four patients, who underwent flexible URS for renal stones between October 2012 and January 2014, were included. The patients were divided into two groups according to stone radiolucency. The patients were evaluated with preoperative and postoperative (at the weeks 4) computed tomography. Success of the treatment was defined as stone-free status and residual fragments < 4 mm. RESULTS: Success of the treatment was observed in 79 (84%) patients. Sex, stone size, and stone location were factors affecting treatment success. Seventy-five (79.8%) patients had opaque stones, and 19 (20.2%) had non-opaque stones. The treatment success rates for opaque and non-opaque stones were 86.6% and 73.6%, respectively (P = .167). Flexible URS was a successful modality with acceptable morbidity to treat renal stones. CONCLUSION: These results show that radiolucent and opaque stones can be effectively treated by flexible URS. PMID- 25703910 TI - Association between tissue miR-141, miR-200c and miR-30b and bladder cancer: a matched case-control study. AB - PURPOSE: To evaluate the expression of microRNAs in tissue samples from patients with bladder cancer and to compare it with healthy adjacent tissue samples as controls. MATERIALS AND METHODS: Thirty five tissue samples from patients with newly diagnosed untreated bladder transitional cell carcinoma and 35 adjacent normal urothelium were collected during 2013 to 2014. TRIzol reagent was used to isolate total RNA including microRNAs. RNA concentration and purity were determined using a nanodrop spectrophotometer. Also 1% agarose gel electrophoresis was used to assess integrity of RNA. Real-Time Quantitative Reverse Transcription PCR (qRT-PCR) method was performed using the PARSGENOME microRNA RT-PCR system. Data was analyzed by STATA 11. RESULTS: A couple of patients were female the remainder were male. Mean age of patients were 71.06 +/- 11.43 years. The expression level of miR-30b, miR-141 and miR-200c in case group were significantly higher than that of control normal tissue samples. miR-141 had higher expression rate in malignant tissue than two other miRNAs (P < .001). CONCLUSION: There was a more expression rate of miR-200c, miR-141 and miR-30b in bladder cancer tissues than healthy adjacent control tissues. Further studies are needed to draw final conclusion. PMID- 25703911 TI - Novel approach for pain control in patients undergoing prostate biopsy: iliohypogastric nerve block with or without topical application of prilocaine lidocaine: a randomized controlled trial. AB - PURPOSE: To investigate the efficacy of a novel anesthetic technique called iliohypogastric nerve block (INB) for pain control in patients undergoing prostate biopsy. MATERIALS AND METHODS: A total of 59 consecutive patients who underwent transrectal ultrasound guided prostates biopsies were included in the study. Patients were randomized into four groups: (1) control, no method of anesthesia was administered, (2) intrarectal prilocaine-lidocaine cream application, (3) INB and (4) INB + intrarectal prilocaine-lidocaine cream application (combined group). Patients were asked to use a scale of 0-10 in a Visual Analogue Scale (VAS) questionnaire about pain during probe insertion (VAS 1) and prostate biopsy (VAS 2). RESULTS: The mean VAS 1 and VAS 2 scores were 0.7 and 4.9 for controls, 0.5 and 1.8 for INB, 0.5 and 2.6 for the intrarectal cream group, and 0.4 and 1.8 for the combined group. The mean VAS 1 scores were not different between groups. However, the mean VAS 2 scores were significantly lower in INB, prilocaine-lidocaine cream and combined groups compared to the control group (P < .001). In addition, the INB group had significantly lower VAS 2 scores compared to the cream application group (P = .03). On the other hand, there was no difference between the INB and combined groups (P = .8). CONCLUSION: Any form of anesthesia was superior to none. However, INB alone seemed to be superior to prilocaine-lidocaine cream application in patients undergoing prostate biopsy. Addition of prilocaine-lidocaine cream application to INB may not provide better analgesia. PMID- 25703912 TI - Predictors of urinary continence recovery after modified radical prostatectomy for clinically high-risk prostate cancer. AB - PURPOSE: To retrospectively determine predictors of urinary continence (UC) recovery in clinically high-risk prostate cancer (PCa) patients treated with modified radical prostatectomy (RP). MATERIALS AND METHODS: A total of 184 patients with clinically high-risk PCa who underwent modified RP in a single Chinese center were retrospectively reviewed. Pelvic floor muscle training with biofeedback was routinely performed after catheter removal. UC was defined as wearing 0 or 1 protective pad daily. Univariate and multivariate Cox regression analyses were performed to determine the predictors of UC recovery. RESULTS: The median age at surgery was 69.5 years (range 48-82), and the median follow-up duration was 40 months (range 12-111). Only 40 patients (21.7%) received a nerve sparing procedure. For patients with restored UC, the median time to continence was 1 month (range 1-24). UC recovery at 1 month, 6 months, 12 months and the most recent follow-up was observed in 99 (53.8%), 158 (85.9%), 171 (92.9%) and 174 (94.6%) patients, respectively. Multivariate Cox regression analysis showed that patient age < 70 years (hazard ratio 1.684, P = .003) and smaller prostate volume (hazard ratio 0.989, P = .036), but not the surgical approach or treatment with a nerve-sparing procedure, independently predicted UC recovery. CONCLUSION: Age < 70 years and smaller prostate volume were independent predictors of UC recovery in clinically high-risk PCa patients. The adverse factors of high-risk disease were not significantly associated with UC recovery. These results may help surgeons preoperatively counsel patients regarding expected UC outcomes following RP. PMID- 25703913 TI - Does the histopathologic pattern of the ureteropelvic junction affect the outcome of pyeloplasty. AB - PURPOSE: To investigate the effects of the histopathologic pattern of obstructed ureteropelvic junction (UPJ) specimens, including collagen type 3, elastin, fibrosis and Cajal cells, on the outcome of pyeloplasty. MATERIALS AND METHODS: Histopathological specimens obtained following Anderson-Hynes pyeloplasty from 52 patients with intrinsic ureteropelvic junction obstruction (UPJO) between January 2005 and January 2008 were evaluated histopathologically. Patients with extrinsic or secondary UPJO were excluded. Preoperative and postoperative radiographic evaluations were performed either via diuretic renography or intravenous pyelography, or both. Six months post-surgery the patients were divided into 2 groups, as successful surgery (group 1) and unsuccessful surgery (group 2). Histopathological findings (collagen type 3, elastin, fibrosis and Cajal cells) in each group were statistically compared. RESULTS: The study included 52 patients (21 female and 31 male). Mean age of the entire study population was 39.42 +/- 14.5 years, versus 39.63 +/- 14.9 years in group 1 (n = 47) and 37.4 +/ 10.0 years in group 2 (n = 5). Median follow-up was 18 months. There weren't any significant differences in collagen type 3, elastin, fibrosis, or Cajal cells between the 2 groups (P > .05). CONCLUSION: The histopathologic pattern of UPJ was not a factor associated with the success of pyeloplasty. Based on the present findings, we conclude that surgical technique is more important than the histopathologic pattern of UPJ for the successful treatment of UPJO. PMID- 25703914 TI - Changing concepts in microsurgical pediatric varicocelectomy: is retroperitoneal approach better than subinguinal one? AB - PURPOSE: To compare and to assess two different microsurgical "lymphatic-sparing" techniques (subinguinal/inguinal vs. retroperitoneal) used for the treatment of a pediatric and adolescent varicocele in terms of success rate, complications and mean operative time. MATERIALS AND METHODS: A retrospective study included 54 consecutive patients affected by a varicocele and treated with a microsurgical (loupes--operating microscope) magnification. Thirty-four out of 54 (group 1) underwent subinguinal ligation with the help of loupes magnification (* 3); 20 out of 54 (group 2) underwent retroperitoneal (Palomo like) ligation with preservation of lymphatics and with the help of an operating microscope (* 6 to 10). The two groups were homogeneous in terms of mean age, clinical and color Doppler ultrasound grade of disease. Pre- and post-operative testicular volume was measured in all cases. All the procedures were performed under general anesthesia and in an outpatient basis. RESULTS: Mean post-operative follow-up time was 23.6 months. In group 1 we observed 3 (8.8%) early complications (wound's infection, transient hydrocele), 2 (5.8%) recurrences and 1 (2.9%) major complication (atrophy of the testis). Mean operative time was 45 +/- 6 min. In group 2 we did not observe complications and/or varicocele recurrence and mean operative time was 38 +/- 7 min. Comparison of mean operative time between the two groups resulted statistically significant differences (P < .05) such as the difference in testicular "catch-up" growth volume between pre- and post-operative evaluations. CONCLUSION: Retroperitoneal microsurgical "lymphatic-sparing" varicocelectomy is safe and effective method. In our experience, it is preferable, in the pediatric and adolescent patient, to the subinguinal/inguinal approach in terms of success rate, complications and operative time duration. PMID- 25703915 TI - Adrenocortical carcinoma with renal vein tumor thrombus extension. PMID- 25703916 TI - Syndrome of Spigelian hernia and cryptorchidism: new evidence pertinent to pathogenic hypothesis. PMID- 25703917 TI - A childhood case of solitary intrascrotal and extratesticular neurofibroma. PMID- 25703918 TI - Renal artery thrombosis secondary to blunt abdominal trauma with accessory renal artery supplying the kidney segment: a rare case report. PMID- 25703919 TI - Determining a membrane's shear modulus, independent of its area-dilatation modulus, via capsule flow in a converging micro-capillary. AB - Determination of the elastic properties of the membrane of artificial capsules is essential for the better design of the various devices that are utilized in their engineering and biomedical applications. However this task is complicated owing to the combined effects of the shear and area-dilatation moduli on the capsule deformation. Based on computational investigation, we propose a new methodology to determine a membrane's shear modulus, independent of its area-dilatation modulus, by flowing strain-hardening capsules in a converging micro-capillary of comparable size under Stokes flow conditions, and comparing the experimental measurements of the capsule elongation overshooting with computational data. The capsule prestress, if any, can also be determined with the same methodology. The elongation overshooting is practically independent of the viscosity ratio for low and moderate viscosity ratios, and thus a wide range of capsule fluids can be employed. Our proposed experimental device can be readily produced via glass fabrication while owing to the continuous flow in the micro-capillary, the characterization of a large number of artificial capsules is possible. PMID- 25703921 TI - Controlled formation of mixed nanoscale domains of high capacity Fe2O3-FeF3 conversion compounds by direct fluorination. AB - We report a direct fluorination method under fluorine gas atmosphere using a fluidized bed reactor for converting nanophase iron oxide (n-Fe2O3) to an electrochemically stable and higher energy density iron oxyfluoride/fluoride phase. Interestingly, no noticeable bulk iron oxyfluoride phase (FeOF) phase was observed even at fluorination temperature close to 300 degrees C. Instead, at fluorination temperatures below 250 degrees C, scanning transmission electron microscopy coupled with electron energy loss spectroscopy (STEM-EELS) and X-ray photoelectron spectroscopy (XPS) analysis showed surface fluorination with nominal composition, Fe2O3-xF2x (x < 1). At fluorination temperatures of 275 degrees C, STEM-EELS results showed porous interconnected nanodomains of FeF3 and Fe2O3 coexisting within the same particle, and overall the particles become less dense after fluorination. We performed potentiometric intermittent titration and electrochemical impedance spectroscopy studies to understand the lithium diffusion (or apparent diffusion) in both the oxyfluoride and mixed phase FeF3 + Fe2O3 composition, and correlate the results to their electrochemical performance. Further, we analyze from a thermodynamical perspective, the observed formation of the majority fluoride phase (77% FeF3) and the absence of the expected oxyfluoride phase based on the relative formation energies of oxide, fluoride, and oxyfluorides. PMID- 25703922 TI - A formal medication reconciliation programme in a haemodialysis unit can identify medication discrepancies and potentially prevent adverse drug events. AB - BACKGROUND: Patients on haemodialysis have been identified as high-risk for medication discrepancies and adverse drug events. Medication reconciliation is an important patient safety initiative to prevent adverse drug events. The primary objective of our study was to determine the number and types of medication discrepancies and drug therapy problems (DTPs) identified in patients on haemodialysis. Our second objective was to assess the potential clinical impact and severity of all unintentional medication discrepancies identified. METHODS: Patients in an academic haemodialysis unit were interviewed to obtain a best possible medication history (BPMH) between May and August 2010. The BPMH was documented and discrepancies were identified, classified and resolved with the interprofessional team. An interprofessional panel conducted a discrepancy clinical impact assessment for potential adverse drug events. RESULTS: Two hundred and twenty-eight patients on haemodialysis were interviewed and 512 discrepancies were identified for 151 patients (3.4 discrepancies per patient). Of these, 174 (34%) were undocumented intentional discrepancies and 338 (66%) were unintentional discrepancies. The unintentional discrepancies were classified as 21% omissions, 36% commissions and 43% incorrect dose/frequency. Most drug therapy problems were related to patient taking a medication that was not indicated (25%), medication required but patient not taking (25%), patient not willing to take the medication as prescribed (28%) or incorrect dosing of a drug (20%). Overall, 6% of discrepancies were classified as clinically significant potential adverse drug events. CONCLUSION: Medication discrepancies appear to be common in patients on haemodialysis. Formal interprofessional medication reconciliation practice models are essential to identify discrepancies and prevent patients from experiencing adverse drug events. PMID- 25703923 TI - Oxidation-state analysis of ceria by X-ray photoelectron spectroscopy. AB - Three different methods to determine the oxide-phase concentration in mixed cerium oxide by hard X-ray photoelectron spectroscopy are applied and quantitatively compared. Synchrotron-based characterization of the O 1s region was used as a benchmark to introduce a method based on the weighted superposition of the Ce 3d spectra of the pure Ce(3+) and Ce(4+) phases, which was shown to lead to reliable and highly accurate determination of the mean oxidation state in mixed cerium oxides. The results obtained reveal a linear relation between the third distinct final state (u''') satellite peak intensity of the Ce(4+) phase and the Ce(4+) concentration by proper inclusion of Ce(3+)-related plasmon satellite peaks, which contradicts previous claims of nonlinear behavior. In contrast, quantitative conventional peak-fitting procedures were shown to be well suited for the Ce 2p region due to its relatively simple structure. Additional satellite features observed in the Ce 3d spectrum of CeO2 were proposed to originate from plasmon contributions. PMID- 25703924 TI - Fatty acid ethyl esters disrupt neonatal alveolar macrophage mitochondria and derange cellular functioning. AB - BACKGROUND: Chronic alcohol exposure alters the function of alveolar macrophages (AM), impairing immune defenses in both adult and neonatal lungs. Fatty acid ethyl esters (FAEEs) are biological markers of prenatal alcohol exposure in newborns. FAEEs contribute to alcohol-induced mitochondrial (MT) damage in multiple organs. We hypothesized that in utero ethanol exposure would increase FAEEs in the neonatal lung and that direct exposure of neonatal AM to FAEEs would contribute to MT injury and cellular dysfunction. METHODS: FAEEs were measured in neonatal guinea pig lungs after +/- in utero ethanol exposure via gas chromatography/mass spectrometry. The NR8383 cell line and freshly isolated neonatal guinea pig AM were exposed to ethyl oleate (EO) in vitro. MT membrane potential, MT reactive oxygen species generation (mROS), phagocytosis, and apoptosis were evaluated after exposure to EO +/- the MT-specific antioxidant mito-TEMPO (mitoT) or +/- the pan-caspase inhibitor Z-VAD-FMK. Whole lung FAEEs were compared using the Mann-Whitney U-test. Cellular results were analyzed using 1-way analysis of variance, followed by the Student-Newman-Keuls Method for post hoc comparisons. RESULTS: In utero ethanol significantly increased ethyl linoleate and the combinations of ethyl oleate + linoleate + linolenate (OLL), and OLL + stearate in the neonatal lung. In vitro EO caused significant MT dysfunction in both NR8383 and primary neonatal AM, as indicated by increased mROS and loss of MT membrane potential. Impaired phagocytosis and apoptosis were significantly increased in both the cell line and primary AM after EO exposure. MitoT conferred significant but only partial protection against EO-induced MT injury, as did caspase inhibition with Z-VAD-FMK. CONCLUSIONS: In utero ethanol exposure increased FAEEs in the neonatal guinea pig lung. Direct exposure to the FAEE EO significantly contributed to AM dysfunction, in part via oxidant injury to the MT and in part via secondary apoptosis. PMID- 25703925 TI - Development and validation of the geriatric depression inventory in Chinese culture. AB - BACKGROUND: Depression among older adults is under-recognized either in the community or in general hospitals in Chinese culture. This study aimed to develop a culturally appropriate screening instrument for late-life depression in the non psychiatric settings and to test its reliability and validity for a diagnosis of depression. METHODS: Using a Delphi method, we developed a geriatric depression inventory (GDI), consisting of 12 core symptoms of depressive disorder in old age. We investigated its reliability and validity on 89 patients with late-life depression and 249 non-depression controls. Both self-report (GDI-SR) and physician-interview (GDI-RI) versions were assessed. RESULTS: Cronbach's alpha coefficient was 0.843 for GDI-SR and 0.880 for GDI-RI. Both GDI-SR and GDI-RI showed good concurrent validity with the 15-item Geriatric Depression Scale (GDS 15) (GDI-SR: r = 0.750, p < 0.001; GDI-RI: r = 0.733, p < 0.001). The area under the curve of the receiver operating characteristic (ROC) was 0.938 for GDI-SR and 0.961 for GDI-RI, suggesting good to excellent discrimination of depression versus non-depression. Using a cut-off of three items endorsed, sensitivity and specificity were 92.1% and 81.9% for GDI-SR, and 93.3% and 87.1% for GDI-RI. CONCLUSIONS: The GDI, either based on self-report or rater interview, is a reliable and valid instrument for the detection of depression among older adults in non-psychiatric medical settings in Chinese culture. PMID- 25703926 TI - Effects of the phosphodiesterase 5 inhibitor Tadalafil on bladder function in a rat model of partial bladder outlet obstruction. AB - AIMS: To investigate the effect of the phosphodiesterase 5 (PDE5) inhibitor Tadalafil on bladder blood flow and bladder function in a rat model of partial bladder outlet obstruction (BOO). METHODS: Female 14-15-week-old Sprague-Dawley rats were divided into three groups. BOO was surgically induced in rats by placing a rubber ring around the urethra. BOO rats were administered daily oral Tadalafil (BOO-Tadalafil) or vehicle (BOO-Vehicle), while sham-operated animals were treated with vehicle (Sham). On the 14th day after surgery, micturition behavior was recorded for 24 hr by using a metabolic cage. On the 15th day after surgery, bladder blood flow and bladder weight were measured. The expression of PDE5 mRNA in the vesical and iliac arteries of intact rats was measured by reverse transcriptase-polymerase chain reaction. RESULTS: BOO led to a significant decrease in bladder blood flow and a significant increase in bladder weight. These changes were partially suppressed by Tadalafil treatment. The number of micturitions in the BOO group was significantly increased and the average micturition volume was significantly decreased, without affecting the total micturition volume. Repeated Tadalafil treatment markedly inhibited the increase in micturition frequency and the decrease in average micturition volume. PDE5 mRNA was expressed in the vesical and iliac arteries. CONCLUSION: Tadalafil suppressed the reduction in bladder blood flow caused by BOO in rats and improved urinary function. This action of Tadalafil may contribute to its amelioration of bladder function. Neurourol. Urodynam. 35:444-449, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 25703927 TI - Serum periostin levels correlate with airway hyper-responsiveness to methacholine and mannitol in children with asthma. AB - BACKGROUND: Periostin is a matricellular protein, and its synthesis in airway epithelial cells and lung fibroblasts is induced by interleukin (IL)-4 and IL-13. The significance of periostin as a biomarker of TH 2-induced airway inflammation, and (importantly) as a measure of the response to TH 2-targeted therapy, has recently been emphasized. We explored the relationship between periostin and airway hyperresponsiveness (AHR) in asthmatic children. METHODS: The study included 83 children aged 6-15 years in an asthmatic group (n = 54) and healthy controls (n = 29). We measured the periostin levels in serum and performed methacholine and mannitol provocation challenges. The responses to mannitol were expressed as the provocative dose causing a 15% fall in the FEV1 (the PD15 dose). RESULTS: Of the 54 subjects with asthma, all had positive methacholine bronchial provocation test (BPT) results and 38 had positive mannitol BPT results. Children with asthma had significantly higher periostin levels than controls [76.0 (65.0 91.8) vs 71.0 (57.5-80.0) ng/mL; P = 0.017]. Periostin levels were significantly correlated with both the methacholine PC20 and mannitol PD15 values. CONCLUSION: Serum levels of periostin, a new biomarker induced by IL-13, were higher in asthmatic children, and were associated with AHR to methacholine and mannitol. PMID- 25703928 TI - Epoxide based inhibitors of the hepatitis C virus non-structural 2 autoprotease. AB - Hepatitis C virus (HCV) non-structural 2 (NS2) encodes an essential protease activity responsible for processing at the NS2-NS3 junction which represents an attractive antiviral target. Attempts to inhibit the NS2 autoprotease with mechanism-based protease inhibitors and substrate peptides have had limited success. We report a series of epoxide-containing small molecules capable of blocking NS2-NS3 proteolysis in vitro and demonstrate the potential for selectivity towards the NS2 autoprotease. A compound within this series was able to perturb HCV genome replication in a subgenomic replicon system only when polyprotein processing was dependent on NS2 autoprotease activity, in addition it inhibited replication of full length HCV. These findings suggest blocking HCV polyprotein processing through inhibition of the NS2 autoprotease represents a viable route to exert an antiviral effect. PMID- 25703929 TI - Knockdown of Myosin VI Inhibits Proliferation of Hepatocellular Carcinoma Cells In Vitro. AB - Hepatocellular carcinoma is the primary malignancy of the liver and is the third leading cause of cancer-related death worldwide. Despite its severity, the treatment methods for hepatocellular carcinoma are limited due to poor prognosis. This study identified the short hairpin RNA-mediated silencing of myosin VI as a potential approach for the treatment of hepatocellular carcinoma. Firstly, the expression of myosin VI was analyzed in 57 hepatocellular carcinoma samples and 10 non-neoplastic samples by immunohistochemistry. The results demonstrated that myosin VI expression was much stronger in hepatocellular carcinoma tissues than in adjacent normal tissues. Myosin VI short hairpin RNA was then transduced into HepG2 and SMMC-7721 hepatocellular carcinoma cell lines, respectively, using a lentivirus delivery system. Knockdown of myosin VI led to a significant reduction in cell proliferation and colony-forming capacity, as well as a blockade of cell cycle progression. Moreover, an obvious decrease in PRAS40 phosphorylation and a concomitant increase in p38 phosphorylation were observed in myosin VI knockdown cells, which suggest that myosin VI silencing inhibits hepatocellular carcinoma cell growth in vitro probably via inactivation of PRAS40 and activation of p38 mitogen-activated protein kinase-dependent signaling pathway. This study highlights the potential of myosin VI to be developed as a target for hepatocellular carcinoma therapy. PMID- 25703930 TI - Sex hormones predict the sensory strength and vividness of mental imagery. AB - Mystery surrounds the cause of large individual differences in mental imagery vividness and strength, and how these might map onto mental disorders. Here, we report the concentration of sex hormones predicts the strength and vividness of visual mental imagery. We employed an objective measure of imagery utilizing binocular rivalry and a subjective questionnaire to assess imagery. The strength and vividness of imagery was greater for females in the mid luteal phase than both females in the late follicular phase and males. Further, imagery strength and vividness were significantly correlated with salivary progesterone concentration. For the same participants, performance on visual and verbal working memory tasks was not predicted by progesterone concentration. These results suggest sex hormones might influence visual imagery, but not general working memory. As hormone concentration changes over time, this implies a partial dynamic basis for individual differences in visual mental imagery, any dependent cognition and mental disorders. PMID- 25703931 TI - 113Cd NMR experiments reveal an unusual metal cluster in the solution structure of the yeast splicing protein Bud31p. AB - Establishing the binding topology of structural zinc ions in proteins is an essential part of their structure determination by NMR spectroscopy. Using (113)Cd NMR experiments with (113)Cd-substituted samples is a useful approach but has previously been limited mainly to very small protein domains. Here we used (113)Cd NMR spectroscopy during structure determination of Bud31p, a 157-residue yeast protein containing an unusual Zn3Cys9 cluster, demonstrating that recent hardware developments make this approach feasible for significantly larger systems. PMID- 25703932 TI - Hericium erinaceus polysaccharide-protein HEG-5 inhibits SGC-7901 cell growth via cell cycle arrest and apoptosis. AB - HEG-5 is a novel polysaccharide-protein purified from the fermented mycelia of Hericium erinaceus CZ-2. The present study aims to investigate the effects of HEG 5 on proliferation, cell cycle and apoptosis of human gastric cancer cells SGC 7901. Here, we first uncover that HEG-5 significantly inhibited the proliferation and colony formation of SGC-7901 cells by promoting apoptosis and cell cycle arrest at S phase. RT-PCR and Western blot analysis suggested that HEG-5 could decrease the expressions of Bcl2, PI3K and AKT1, while increase the expressions of Caspase-8, Caspase-3, p53, CDK4, Bax and Bad. These findings indicated that the Caspase-8/-3-dependent, p53-dependent mitochondrial-mediated and PI3k/Akt signaling pathways involved in the molecular events of HEG-5 induced apoptosis and cell cycle arrest. Thus, our study provides in vitro evidence that HEG-5 may be taken as a potential candidate for treating gastric cancer. PMID- 25703933 TI - Intraoperative radiotherapy of the breast for early-stage breast cancer: ready for primetime. AB - The findings of the TARGIT A and ELIOT prospective, randomized controlled trials provide compelling data regarding the efficacy and safety of single fraction intraoperative radiotherapy as an alternative to standard postoperative radiotherapy in the management of early-stage breast cancer. This editorial summarizes the findings of both studies and discusses the importance of patient selection in identifying potential candidates for intraoperative radiotherapy. PMID- 25703934 TI - Association of Fusobacterium nucleatum with clinical and molecular features in colorectal serrated pathway. AB - Human gut microbiota is being increasingly recognized as a player in colorectal cancers (CRCs). Evidence suggests that Fusobacterium nucleatum (F. nucleatum) may contribute to disease progression and is associated with CpG island methylator phenotype (CIMP) and microsatellite instability (MSI) in CRCs; however, to date, there are no reports about the relationship between F. nucleatum and molecular features in the early stage of colorectal tumorigenesis. Therefore, we investigated the presence of F. nucleatum in premalignant colorectal lesions. In total, 465 premalignant lesions (343 serrated lesions and 122 non-serrated adenomas) and 511 CRCs were studied. We determined the presence of F. nucleatum and analyzed its association with molecular features including CIMP, MSI and microRNA-31 status. F. nucleatum was detected in 24% of hyperplastic polyps, 35% of sessile serrated adenomas (SSAs), 30% of traditional serrated adenomas (TSAs) and 33% of non-serrated adenomas. F. nucleatum was more frequently detected in CIMP-high premalignant lesions than in CIMP-low/zero lesions (p = 0.0023). In SSAs, F. nucleatum positivity increased gradually from sigmoid colon to cecum (p = 0.042). F. nucleatum positivity was significantly higher in CRCs (56%) than in premalignant lesions of any histological type (p < 0.0001). In conclusion, F. nucleatum was identified in premalignant colorectal lesions regardless of histopathology but was more frequently associated with CIMP-high lesions. Moreover, F. nucleatum positivity increased according to histological grade, suggesting that it may contribute to the progression of colorectal neoplasia. Our data also indicate that F. nucleatum positivity in SSAs may support the "colorectal continuum" concept. PMID- 25703935 TI - Caleosin from Chlorella vulgaris TISTR 8580 is salt-induced and heme-containing protein. AB - Physiological and functional properties of lipid droplet-associated proteins in algae remain scarce. We report here the caleosin gene from Chlorella vulgaris encodes a protein of 279 amino acid residues. Amino acid sequence alignment showed high similarity to the putative caleosins from fungi, but less to plant caleosins. When the C. vulgaris TISTR 8580 cells were treated with salt stress (0.3 M NaCl), the level of triacylglycerol increased significantly. The mRNA contents for caleosin in Chlorella cells significantly increased under salt stress condition. Caleosin gene was expressed in E. coli. Crude extract of E. coli cells exhibited the cumene hydroperoxide-dependent oxidation of aniline. Absorption spectroscopy showed a peak around 415 nm which was decreased upon addition of cumene hydroperoxide. Native polyacrylamide gel electrophoresis suggests caleosin existed as the oligomer. These data indicate that a fresh water C. vulgaris TISTR 8580 contains a salt-induced heme-protein caleosin. PMID- 25703937 TI - Feasibility of a screening program for at-risk children following accidental injury. AB - Screening is recommended as a simple method for identifying those who should be monitored for risk following trauma. Effective methods for implementing large scale screening programs are yet to be established. This study tested the feasibility and utility of a screening program with hospitalized youth exposed to injury in 3 Australian hospitals. Eligible families (N = 1,134) were contacted and 546 children (48.0%) screened for risk of posttraumatic stress disorder (PTSD) at 1-2 weeks postinjury. There were 95 (17.4%) children whose screen result was at risk. A rescreening phase was introduced during the study, with 68 children completing the rescreen at 4-6 weeks postinjury, and 26 (38.2% of those rescreened) still at risk. Of those initially screened, 29 (5.3%) completed diagnostic assessments, 21 (3.8%) were diagnosed with partial or full PTSD, and 17 (3.1%) commenced treatment. Screening was successful at identifying and reaching children with PTSD, but the response rate was lower than expected, which limited the utility of the program. The addition of a rescreening phase demonstrated that not all at-risk children required intervention. These findings replicate previous studies that have shown natural remission in PTSD symptoms and highlight the potential for rescreening as part of a watchful waiting approach. PMID- 25703936 TI - Deployment-related psychiatric and behavioral conditions and their association with functional disability in OEF/OIF/OND veterans. AB - Understanding the factors that influence veterans' functional outcome after deployment is critical to provide appropriately targeted care. Mild traumatic brain injury (mTBI) and posttraumatic stress disorder (PTSD) have been related to disability, but other psychiatric and behavioral conditions are not as well examined. We investigated the impact of deployment-related psychiatric and behavioral conditions on disability among 255 OEF/OIF/OND service members and veterans. Structured clinical interviews assessed TBI and the psychiatric conditions of depression, PTSD, anxiety, and substance use. Self-report questionnaires assessed disability and the behavioral conditions of sleep disturbance and pain. Over 90% of participants had a psychiatric and/or behavioral condition, with approximately half presenting with >= 3 conditions. Exploratory factor analysis revealed 4 clinically relevant psychiatric and behavioral factors which accounted for 76.9% of the variance: (a) depression, PTSD, and military mTBI (deployment trauma factor); (b) pain and sleep (somatic factor); (c) anxiety disorders, other than PTSD (anxiety factor); and (d) substance abuse or dependence (substance use factor). Individuals with the conditions comprising the deployment trauma factor were more likely to be substantially disabled than individuals with depression and PTSD, but no military mTBI, OR = 3.52; 95% CI [1.09, 11.37]. Depression, PTSD, and a history of military mTBI may comprise an especially harmful combination associated with high risk for substantial disability. PMID- 25703938 TI - School-based psychological screening in the aftermath of a disaster: are parents satisfied and do their children access treatment? AB - This study investigated parents' satisfaction with postdisaster school-based screening and whether satisfaction was related to follow-through with screening recommendations. From among 1,268 there were 224 children, ages 7-18 years (M = 10.97, SD = 2.44 years) screened for emotional distress 4 months after a flood and 130 parents who completed the screening evaluation. Of the 44 children who showed severe emotional distress, less than 50% of their parents reported concerns and only 29.5% had sought assistance. Following screening, 86.7% of these children completed treatment. Overall satisfaction ratings by parents were high, with 99.2% very or mostly satisfied. PMID- 25703939 TI - The evidence is finally here: Ocular vestibular evoked myogenic potentials are mainly dependent on utricular pathway function. PMID- 25703940 TI - P300-based brain-computer interface (BCI) event-related potentials (ERPs): People with amyotrophic lateral sclerosis (ALS) vs. age-matched controls. AB - OBJECTIVE: Brain-computer interfaces (BCIs) aimed at restoring communication to people with severe neuromuscular disabilities often use event-related potentials (ERPs) in scalp-recorded EEG activity. Up to the present, most research and development in this area has been done in the laboratory with young healthy control subjects. In order to facilitate the development of BCI most useful to people with disabilities, the present study set out to: (1) determine whether people with amyotrophic lateral sclerosis (ALS) and healthy, age-matched volunteers (HVs) differ in the speed and accuracy of their ERP-based BCI use; (2) compare the ERP characteristics of these two groups; and (3) identify ERP-related factors that might enable improvement in BCI performance for people with disabilities. METHODS: Sixteen EEG channels were recorded while people with ALS or healthy age-matched volunteers (HVs) used a P300-based BCI. The subjects with ALS had little or no remaining useful motor control (mean ALS Functional Rating Scale-Revised 9.4 (+/-9.5SD) (range 0-25)). Each subject attended to a target item as the items in a 6*6 visual matrix flashed. The BCI used a stepwise linear discriminant function (SWLDA) to determine the item the user wished to select (i.e., the target item). Offline analyses assessed the latencies, amplitudes, and locations of ERPs to the target and non-target items for people with ALS and age matched control subjects. RESULTS: BCI accuracy and communication rate did not differ significantly between ALS users and HVs. Although ERP morphology was similar for the two groups, their target ERPs differed significantly in the location and amplitude of the late positivity (P300), the amplitude of the early negativity (N200), and the latency of the late negativity (LN). CONCLUSIONS: The differences in target ERP components between people with ALS and age-matched HVs are consistent with the growing recognition that ALS may affect cortical function. The development of BCIs for use by this population may begin with studies in HVs but also needs to include studies in people with ALS. Their differences in ERP components may affect the selection of electrode montages, and might also affect the selection of presentation parameters (e.g., matrix design, stimulation rate). SIGNIFICANCE: P300-based BCI performance in people severely disabled by ALS is similar to that of age-matched control subjects. At the same time, their ERP components differ to some degree from those of controls. Attention to these differences could contribute to the development of BCIs useful to those with ALS and possibly to others with severe neuromuscular disabilities. PMID- 25703941 TI - The P300 component wave reveals differences in subclinical anxious-depressive states during bimodal oddball tasks: An effect of stimulus congruence. AB - OBJECTIVE: We previously found that using a bimodal oddball design with synchronized pairs of audio-visual stimuli increased the sensitivity of the P300 wave to subclinical differences in depression. We wondered: (1) whether these P300 modulations were due to facilitated discrimination of deviant vs. frequent stimuli and (2) whether congruency of the stimuli was necessary to produce this effect. METHOD: Two groups of participants (students displaying anxious depressive tendencies as the subclinical group and healthy students as the control group) had to detect deviant stimuli among frequent stimuli in oddball tasks. Experiment 1 involved either single faces (Single condition) or two similar faces presented side-by-side (Double condition). Experiment 2 involved audio (A), visual (V), bimodal congruent (AVC), and bimodal incongruent (AVI) oddball tasks. RESULTS: While the easiest Double condition produced the fastest reaction times and shortest P300 latencies, there were no significant differences in P300 modulation between the groups in Experiment 1. In Experiment 2, P300 amplitudes of the control group were higher in response to AVC tasks than in response to unimodal (A or V) or AVI tasks. CONCLUSIONS: The increased sensitivity of the P300 wave to subclinical differences that we observed here is not related to an enhanced discrimination effect. However, during bimodal tasks, stimulus congruency is necessary for the appearance of the increased P300 sensitivity. SIGNIFICANCE: The impaired "bimodal congruence effect" in patients with subclinical depression/anxiety suggests these patients have altered integrative processes, which has potential implications for cognitive therapy. PMID- 25703942 TI - Cognitive enhancement of healthy young adults with hyperbaric oxygen: A preliminary resting-state fMRI study. AB - OBJECTIVE: To date, no study has examined the effect of hyperbaric oxygen (HBO) on the cognitive performance and spontaneous brain activity in healthy adults using resting-state functional magnetic resonance imaging (rsfMRI). Our aim was to reveal the neural mechanism underlying the change in cognitive performance caused by increased oxygen. METHODS: In this study, we acquired fMRI data from 20 healthy young adults and used placebo-controlled (PBO) rsfMRI to identify the effect of HBO on the cognitive measures and the regional homogeneity (ReHo) in healthy adults. RESULTS: Compared to the PBO group, the HBO group showed the following: (1) the scores of the spatial working memory and memory quotient were significantly increased after HBO administration; (2) the ReHo value was significantly increased in three clusters, the left hippocampus, right inferior frontal, and lingual gyri, and for these three clusters, their functional connectivity with the subcortical brain system was significantly increased after HBO administration; and (3) the changes of ReHo values in these clusters generated by HBO administration were correlated with several aspects of cognitive performance, clarifying the cognitive locus of the effect. CONCLUSION: Our results suggested that the increased availability of oxygen can, to some extent, improve memory performance. SIGNIFICANT: Our findings may improve our understanding of the role of HBO in clinical and practical applications. PMID- 25703943 TI - Epidemiology of vestibular evoked myogenic potentials: Data from the Baltimore Longitudinal Study of Aging. AB - OBJECTIVE: To evaluate whether age-related changes in vestibular evoked myogenic potentials (VEMPs) differ by demographic and cardiovascular risk groups. METHODS: Participants in the Baltimore Longitudinal Study of Aging underwent cervical and ocular VEMP testing. VEMP latency, amplitude, asymmetry ratios, and prevalence of absent responses were compared across demographic and cardiovascular risk groups. RESULTS: In 257 participants (mean age 72.9, 57% female), ocular VEMP (oVEMP) n10 latency increased by 0.12ms/decade while amplitude decreased by 2.9MUV/decade. Black participants had better oVEMP function (shorter latency, increased amplitude, and decreased odds of absent responses) relative to white participants. In 250 participants (mean age 72.6, 54% female), EMG-corrected cervical VEMP (cVEMP) amplitude decreased by 0.14MUV/decade and p13 latency was 0.38ms longer in males. The odds of absent responses were significantly higher in individuals age ?80 for oVEMPs, and age ?70 for cVEMPs. Cardiovascular risk factors had no association with VEMP parameters. CONCLUSIONS: We confirmed age related declines in otolith function, and observed a protective effect of black race on oVEMP latency and amplitude. SIGNIFICANCE: These results illustrate how measures of otolith function change with age in community-dwelling adults. Further investigations are needed to ascertain whether better otolith function in blacks might contribute to a lower risk of mobility disability and falls. PMID- 25703944 TI - Systematic review and meta-analysis of ustekinumab for moderate to severe psoriasis: comment. PMID- 25703945 TI - Recovery and purification of recombinant 503 antigen of Leishmania infantum chagasi using expanded bed adsorption chromatography. AB - Visceral leishmaniasis, a disease caused by Leishmania infantum chagasi, represents a major public health problem in many areas of the world. However, there is currently no vaccine for human use. The aim of this work was to purify the 503 antigen of Leishmania i. chagasi directly from unclarified Escherichia coli feedstock through expanded bed adsorption (EBA) chromatography. Batch experiments were performed to optimize the adsorption and elution conditions of the antigen onto a STREAMLINE Chelating resin using two central composite rotatable designs (CCRD). The results showed that the optimal binding conditions of the 503 antigen were pH 8.0 in the presence of 2.4 M NaCl. For the elution of the target protein, the optimized conditions included the presence of 600.0 mM imidazole. The adsorption isothermal data of the 503 antigen were fitted to the Langmuir adsorption isotherm. The EBA experiment successfully recovered 59.2% of the 503 antigen from the unclarified E. coli homogenate with a purification factor of 6.0. PMID- 25703946 TI - gamma-Hydroxybutyrate analysis in human serum with liquid chromatography-tandem mass spectrometry on the basis of MS3 mass transition. AB - An LC-MS/MS/MS GHB quantification method in human serum supported by the adduct formation process with the components of the mobile phase was developed and validated. The continuous infusion of GHB made the identification of a GHB MS3 mass transition possible (185/103/85). A Luna 5 MUm C18 (2) 100A, 150 mm * 2 mm analytical column and the elution with a programmed flow of the mobile phase consisting of 10% A (H2O/methanol=95/5, v/v) and 90% B (H2O/methanol=3/97, v/v), both with 10 mM ammonium acetate and 0.1% acetic acid (pH=3.2) were used. The analytical sample preparation consisted of protein precipitation with 1 mL of the mobile phase B. The calculated limit of detection/quantification was 0.28/0.96 MUg/mL, respectively. The study presented demonstrated that the process of analyte adduct formation with the components of the mobile phase can be used successfully to generate MS3 transitions in the case of very small molecules which cannot be detected in this way by the application of conventional analytical strategies. PMID- 25703947 TI - A validated liquid chromatography-tandem mass spectrometry method for the determination of methyl gallate and pentagalloyl glucopyranose: application to pharmacokinetic studies. AB - Methyl gallate (MG) and pentagalloyl glucopyranose (PGG) are bioactive phenolic compounds that are widely distributed in herbs and plant foods. Their potential activities include anti-oxidant, anti-inflammatory, anti-cancer, anti-bacterial and anti-viral activities. However, knowledge concerning the pharmacokinetic characteristics of MG and PGG is limited. The purpose of this study was to develop a sensitive and reproducible ultra-performance liquid chromatography tandem mass spectrometric (UPLC-MS/MS) method to simultaneously quantify MG and PGG in rat blood samples. The linear response ranges for MG and PGG were 0.0195 20 and 0.0390-20 MUM, respectively. The lower limit of quantification was 0.0195 MUM for MG and 0.0390 MUM for PGG. The intra- and inter-day variances were less than 15%, and accuracy was within 80-120%. This assay was successfully applied to pharmacokinetic studies in Sprague-Dawley rats after intraperitoneal administration of MG and PGG (20 mg/kg). The values of areas under the blood concentration time curves (AUC0-24 h) for MG and PGG were 109.9 +/- 73.40 and 38.78 +/- 24.53 h*MUM, respectively. The maximum blood concentrations (Cmax) of MG and PGG were 34.72 +/- 17.32 and 6.39 +/- 4.25 MUM, respectively. The time required to reach the maximum concentration (Tmax) was 0.85 +/- 0.70 h for both MG and PGG. The values of the elimination rate constant (Ke), elimination half life (t1/2), volume of distribution (Vd), clearance (Cl) and mean resident time (MRTlast) were 0.056 +/- 0.032 h(-1), 17.50 +/- 12.25 h, 530.95 +/- 247.54 L/kg, 159.91+/-76.05L/h/kg, 8.71 +/- 2.53 h for MG and 0.023 +/- 0.012 h(-1), 38.66 +/- 22.89 h, 7838.89 +/- 3474.72 L/kg, 30.98 +/- 21.73 L/h/kg, 12.47 +/- 2.77 h for PGG, respectively. In conclusion, a UPLC-MS/MS method was fully validated over a wide linear range and used to quantify the levels of MG and PGG in pharmacokinetic studies of MG and PGG in rats. The main advantages of this method are the use of small blood volumes (10 MUL), rapid analysis (5 min) and excellent recoveries. PMID- 25703948 TI - Determination of acacetin in rat plasma by UPLC-MS/MS and its application to a pharmacokinetic study. AB - A rapid, sensitive and selective ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) was developed and validated for the determination and pharmacokinetic investigation of acacetin in rat plasma. Sample preparation was accomplished through a simple one-step deproteinization procedure with 0.2 mL of acetonitrile to a 0.1 mL plasma sample. Plasma samples were separated by UPLC on an Acquity UPLC BEH C18 column using a mobile phase consisting of acetonitrile 0.1% formic acid in water with gradient elution. The total run time was 2.0 min and the elution of acacetin was at 0.83 min. The detection was performed on a triple quadrupole tandem mass spectrometer equipped with positive-ion electrospray ionization (ESI) by multiple reaction monitoring (MRM) of the transitions at m/z 285.3->242.2 for acacetin and m/z 237.2->194.3 for carbamazepine (internal standard). The calibration curve was linear over the range of 1-1600 ng/mL with a lower limit of quantitation (LLOQ) of 1.0 ng/mL. Mean recovery of acacetin in plasma was in the range of 78.4-85.2%. Intra-day and inter-day precision were both <10.5%. This method was successfully applied in pharmacokinetic study after intravenous administration of 5.0mg/kg acacetin in rats. PMID- 25703949 TI - Gender-related pharmacokinetics and bioavailability of a novel anticancer chalcone, cardamonin, in rats determined by liquid chromatography tandem mass spectrometry. AB - A reversed phase liquid chromatography tandem mass spectrometry method was developed and validated for quantification of cardamonin, a potential anticancer chalcone, in rat serum. Curcumin was used as an internal standard. Following liquid-liquid extraction using n-hexane and ethyl acetate (60:40, v/v), the processed samples were chromatographed on a C18 column using acetonitrile and ammonium acetate buffer (0.01 M, pH 4.5) (85:15, v/v) as mobile phase at a flow rate of 0.6 mL min(-1). Mass spectrometric detection was performed in the negative electrospray ionization mode by multiple reaction monitoring (m/z 269 >122 and 367->217 for cardamonin and curcumin, respectively). The method was validated in terms of selectivity, accuracy, precision, sensitivity, reproducibility, dilution integrity and stability. The linearity was established in the range of 1-200 ng mL(-1) (r>=0.999). The recovery of cardamonin from spiked serum was always >90%. The intra- and inter-day precision (%RSD) and accuracy (%bias) were well within the acceptable limits. The method was applied for single oral and intravenous dose pharmacokinetics in male and female Sprague Dawley rats. Following oral dose, cardamonin showed peak serum concentration that occurred at ~2 h with very low bioavailability in both male (0.6%) and female (4.8%) rats. Cardamonin exhibited a significant gender influence on pharmacokinetics and bioavailability in rats. PMID- 25703950 TI - Determination of kurarinone in rat plasma by UPLC-MS/MS. AB - A sensitive and rapid ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method was developed to determine kurarinone in rat plasma using chlorzoxazone as the internal standard (IS). Sample preparation was accomplished through a liquid-liquid extraction procedure with ethyl acetate to 0.2 mL plasma sample. The analyte and IS were separated on an Acquity UPLC BEH C18 column (2.1 mm * 50 mm, 1.7 MUm) with the mobile phase of acetonitrile and 1% formic acid in water with gradient elution at a flow rate of 0.40 mL/min. The detection was performed on a triple quadrupole tandem mass spectrometer equipped with electrospray ionization (ESI) by multiple reactions monitoring (MRM) of the transitions at m/z 437.0->301.2 for kurarinone and m/z 168.1->132.1 for IS. The linearity of this method was found to be within the concentration range of 20 2000 ng/mL with a lower limit of quantification of 20 ng/mL. Only 3.0 min was needed for an analytical run. The matrix effect was 94.7-107.2% for kurarinone. The intra- and inter-day precision (RSD%) were less than 8.2% and accuracy (RE%) was within +/-9.0%. The recovery ranged from 77.3% to 85.6%. Kurarinone was sufficiently stable under all relevant analytical conditions. The method was also successfully applied to the pharmacokinetic study of kurarinone in rats. PMID- 25703951 TI - Evaluation and comparison of three different separation techniques for analysis of retroamide enantiomers and their biological evaluation against h-P2X7 receptor. AB - The P2X receptors are seven-transmembrane domain G protein-coupled receptors and the 7 subtypes of P2X receptors identified in humans, and named P2X1 to P2X7, are channel receptors whose endogenous ligand is ATP. New antagonists of the P2X7 receptor were developed, since this purinergic receptor was highlighted to be involved in many diseases such as different types of pain, cancer, ischemia, neurodegenerative diseases (including Parkinson's and Alzheimer's diseases) characterized by inflammatory processes. With the aim of evaluate the impact of chirality on the pharmacological activity of a new P2X7R antagonist, a semi preparative method was developed in supercritical fluid chromatography (SFC). Among four polysaccharide based chiral stationary phases: Chiralcel OD-H and OJ-H and Chiralpak AS-H and AD-H, the last one namely amylose tris (3,5 dimethylphenylcarbamate) with a mobile phase consisted of carbon dioxide-ethanol (80:20, v/v), led to the successful separation of the enantiomers in short run time and with good resolution. Limits of detection and quantification were calculated and were found equal for compound 1, to 1.37 MUM and 4.57 MUM respectively, for peak 1 and were equal to 1.60 MUM and 5.30 MUM respectively, for peak 2 at lambda=210 nm. Before carrying out the pharmacological evaluation of each enantiomer, two complementary methodologies, e.g. liquid chromatography and capillary electrophoresis were performed in parallel to improve the limits of detection and quantification to assess the enantiomeric purity. HPLC using a Chiralpak AD stationary phase led to four times lower limits of detection and quantification with regard to SFC. In the same time, capillary electrophoresis involving dual cyclodextrins system constituted of a SBE-beta-CD and a MM-beta-CD mixture enhanced the signal-to-noise ratio and led to similar limits of detection and quantification with regard to SFC. No trace of the other enantiomer was found in the isolated one. Biological activities of individual enantiomers were then evaluated and revealed no cytotoxicity against cell lines and a significant difference in terms of their IC50 values with respect to the investigated racemate (6.43 MUM): 3.49 MUM for the (R)-enantiomer and >10(-4)MUM for the (S) enantiomer, for compound 1, showing that, this antagonist activity is stereospecific. PMID- 25703952 TI - Ultrahigh Photogain Nanoscale Hybrid Photodetectors. AB - A class of ultrasensitive nanoscale hybrid photodetectors formed from carbon electrode-molecule junctions using P3HT:PCBM as photoresponsive semiconductors are demonstrated. The unique device architecture, tunability of nanoscale channel lengths and the optimized contact nature of semiconductor/electrode interfaces led to ultrahigh photogains of 1000 with graphene nanoelectrodes and 1 000 000 with single-walled carbon nanotube nanoelectrodes. PMID- 25703953 TI - What lessons can be learned about asthma phenotypes in children from cohort studies? AB - 'Phenotyping' asthma by multivariate analyses and more recently by unsupervised analysis has been performed in children cohorts. We describe the key findings that have emerged from these cohorts. It would appear that there are three wheeze phenotypes in children of preschool age: the mild episodic viral wheeze phenotype; the multitrigger atopic wheeze; and, less often encountered, the severe non-atopic wheeze. Early onset of allergy in asthma (more prevalent in boys) is associated with poor prognosis unlike the severe non-atopic wheeze phenotype which has a female predominance. The prognosis of the severe non-atopic wheeze depends on time of onset (early or late) of allergic expression. At school age, the risk of severe asthmatic exacerbations is associated with eosinophil predominant inflammation frequently related to allergic asthma, whereas neutrophil inflammation is associated with moderate-to-severe asthma with poorer lung function. Nevertheless, allergic asthma is also a heterogeneous disease with a severe allergic phenotype strongly associated with atopic dermatitis and very high eosinophil-driven inflammatory markers. Further studies are required to find non-invasive biological markers in very young children to better define wheezing phenotypes associated with an elevated risk of developing severe asthma with a view to personalizing treatment. PMID- 25703954 TI - Nanoparticles for controlled delivery and sustained release of chlorhexidine in the oral environment. AB - OBJECTIVES: Chlorhexidine (CHX) is in widespread use as a topical antimicrobial agent. Within the field of oral medicine, it is used in the prevention of ventilator-associated pneumonia as well as in the treatment of oral candidosis and microbial-associated lichenoid reactions. The objective of this study was to develop a strategy for controlled, sustained topical delivery of CHX using nanoparticle technology. METHODS: Chlorhexidine was applied to hydroxyapatite, selected as a tooth analogue, as conventional CHX digluconate solutions and as aqueous suspensions of CHX hexametaphosphate nanoparticles with total CHX concentrations of 1, 2.2 and 5 mM. Soluble CHX release from the treated hydroxyapatite was monitored over a period of 7 days. RESULTS: A repeated measures ANOVA with post hoc LSD test indicated that CHX release was 2-3* greater, and sustained for longer, when CHX was delivered as CHX hexametaphosphate nanoparticles than in aqueous solution with 2.2 and 5 mM CHX (P = 0.020 and 0.013, respectively), but there was no statistically significant difference at 1 mM CHX (P = 0.172). CONCLUSIONS: Chlorhexidine hexametaphosphate nanoparticles increased both the local dose and duration of soluble CHX delivery when applied to hydroxyapatite surfaces. This may provide a means to deliver a sustained dose of CHX with less frequent interventions. PMID- 25703955 TI - Revisiting Lewis dot structure weightings: a pair density perspective. AB - A method based on a real space partitioning to measure the importance of Lewis structures is proposed in this work. A matrix containing diverse QTAIM atomic and diatomic properties endowed with significance within a Lewis structure framework is expanded in terms of what we call Lewis-structure matrices. Each of these matrices flawlessly describes an individual resonance structure and its associated linear expansion coefficient (Q-ALE coefficient) indicates the importance or convenience of the given Lewis structure. These coefficients were inspected looking at their evolution in a series of usual chemical issues. Among all the results, we find of interest that sigma resonance structures in systems with pi electrons are more important than normally expected, which justifies why the qualitative predictions arising from the application of the resonance model and the quantitative results based on QTAIM properties are sometimes discrepant. Likewise, we observe that the variation of the dielectric constant of the medium affects the pi resonance to a greater extent than it does the sigma one. Other interesting results in this manuscript are connected to homolytic dissociation of diatomic molecules, periodic trends in hydrogen compounds, and polarization of aromatic systems as a consequence of their interaction with electric fields and with diverse ions. PMID- 25703956 TI - The prevalance of and factors associated with intra-abdominal hypertension on admission day in critically ill pediatric patients: A multicenter study. AB - PURPOSE: To investigate admission prevalence of intraabdominal hypertension (IAH) and to determine clinical and laboratory characteristics on admission day associated with IAH in critically ill pediatric patients. MATERIALS AND METHODS: One hundred thirty newly admitted critically ill pediatric patients were included. Intra-abdominal pressure (IAP) was measured 4 times (every 6 hours) with the bladder pressure method. Data included the demographics, diagnostic category, pediatric logistic organ dysfunction score and pediatric risk of mortality score II, clinical concomitant factors, and conditions potentially associated with increased intra-abdominal pressure. RESULTS: Seventy patients (56.1%) had a normal IAP (<=10 mmHg, mean IAP [mmHg] 7.18 +/- 1.85), while 60 patients (43.9%) had IAP >10 mmHg (mean IAP [mmHg] 15.46 +/- 5.21). Hypothermia frequency, lactate levels, number of patients with oligo-anuria, and mechanical ventilation requirement were higher among patients with IAH compared to patients without IAH (both, P< .05). Hypothermia (OR, 3.899; 95% CI, 1.305-11.655; P< .03) and lactate levels (OR, 1.283 for each mmol/L increase; 95% CI, 1.138-1.447; P< .001) were only significantly associated with IAH. CONCLUSIONS: Intra-abdominal hypertension seems to affect nearly half of newly admitted critically ill pediatric patients. Lactate level and the presence of hypothermia seem to be the independent predictors of the presence of IAH. PMID- 25703957 TI - Exercise-based rehabilitation after hospital discharge for survivors of critical illness with intensive care unit-acquired weakness: A pilot feasibility trial. AB - PURPOSE: The aim of this study was to investigate feasibility of exercise-based rehabilitation delivered after hospital discharge in patients with intensive care unit-acquired weakness (ICU-AW). MATERIALS AND METHODS: Twenty adult patients, mechanically ventilated for more than 48 hours, with ICU-AW diagnosis at ICU discharge were included in a pilot feasibility randomized controlled trial receiving a 16-session exercise-based rehabilitation program. Twenty-one patients without ICU-AW participated in a nested observational cohort study. Feasibility, clinical, and patient-centered outcomes were measured at hospital discharge and at 3 months. RESULTS: Intervention feasibility was demonstrated by high adherence and patient acceptability, and absence of adverse events, but this must be offset by the low proportion of enrolment for those screened. The study was underpowered to detect effectiveness of the intervention. The use of manual muscle testing for the diagnosis of ICU-AW lacked robustness as an eligibility criterion and lacked discrimination for identifying rehabilitation requirements. Process evaluation of the trial identified methodological factors, categorized by "population," "intervention," "control group," and "outcome." CONCLUSIONS: Important data detailing the design, conduct, and implementation of a multicenter randomized controlled trial of exercise-based rehabilitation for survivors of critical illness after hospital discharge have been reported. REGISTRATION: Clinical Trials Identifier NCT00976807. PMID- 25703958 TI - Involving patients in health technology funding decisions: stakeholder perspectives on processes used in Australia. AB - BACKGROUND: Governments use a variety of processes to incorporate public perspectives into policymaking, but few studies have evaluated these processes from participants' point of view. OBJECTIVE: The objective of this study was twofold: to understand the perspectives of selected stakeholders with regard to involvement processes used by Australian Advisory Committees to engage the public and patients; and to identify barriers and facilitators to participation. DESIGN: Twelve semi-structured interviews were conducted with representatives of different stakeholder groups involved in health technology funding decisions in Australia. Data were collected and analysed using a theoretical framework created by Rowe and Frewer, but adapted to more fully acknowledge issues of power and influence. RESULTS: Stakeholder groups disagreed as to what constitutes effective and inclusive patient involvement. Barriers reported by interviewees included poor communication, a lack of transparency, unworkable deadlines, and inadequate representativeness. Also described were problems associated with defining the task for patients and their advocates and with the timing of patient input in the decision-making process. Interviewees suggested that patient participation could be improved by increasing the number of patient organizations engaged in processes and including those organizations at different stages of decision making, especially earlier. CONCLUSIONS: The different evaluations made by stakeholder groups appear to be underpinned by contrasting conceptions of public involvement and its value, in line with Graham Martin's work which distinguishes between 'technocratic' and 'democratic' public involvement. Understanding stakeholders' perspectives and the contrasting conceptions of public involvement could foster future agreement on which processes should be used to involve the public in decision making. PMID- 25703959 TI - Normal values of Hertel exophthalmometry in a Chinese Han population from Shenyang, Northeast China. AB - Aims of this study were to determine the normal range of absolute and relative Hertel exophthalmometric values (EVs) in a Chinese Han population. This population-based cross-sectional study consisted of 2010 healthy Han Chinese (1051 females and 959 males) aged between 8-87 years living in Shenyang, Northeast China, including 515 children (aged 8-14 years), 517 teenagers (aged 15 19 years), 582 adults (aged 20-69 years) and 396 elderly (aged 70-87 years). A Hertel exophthalmometer was used by the same physician for the measurement of EV and inter-orbital distance (IOD). For the entire study population, the Hertel EVs ranged from 10 mm to 22 mm; the mean EVs for the left eye (OS) and right eye (OD) were 15.0 +/- 1.9 mm and 15.0 +/- 2.0 mm, respectively; the upper normal limits of the EVs (mean + 2 SD) for OS and OD were 18.8 mm and 19.0 mm, respectively; the mean relative EV was 0.20 +/- 0.43 mm. Age, but not sex, had a significant effect on the EV. We concluded that our study provides normative ophthalmic data in a Chinese Han population. The normal EVs, asymmetry and IOD values have been established for clinical reference. PMID- 25703960 TI - Ventricular assist device thrombosis: A wide spectrum of clinical presentation. PMID- 25703961 TI - Use of clinically relevant responder threshold criteria to evaluate the response to treatment in the phase III PATENT-1 study. AB - BACKGROUND: In PATENT-1, riociguat significantly improved 6-minute walking distance (6MWD) and a range of secondary end-points in patients with pulmonary arterial hypertension (PAH). We investigated whether riociguat increased the proportion of patients achieving clinically relevant responder thresholds compared with placebo during PATENT-1. METHODS: In PATENT-1, a randomized, double blind study, treatment-naive patients or patients on background PAH-targeted therapy with symptomatic PAH received 12 weeks of treatment with placebo, riociguat up to 2.5 mg 3 times daily, or riociguat up to 1.5 mg 3 times daily. Increases in 6MWD >=40 m, 6MWD >=380 m, cardiac index >=2.5 liter/min/m(2), mixed venous oxygen saturation >=65%, World Health Organization functional class I/II, N-terminal pro-brain natriuretic peptide <1,800 pg/ml, and right atrial pressure <8 mm Hg were chosen as threshold criteria of a positive response. RESULTS: Riociguat increased the proportion of treatment-naive patients and patients on background PAH-targeted therapy with 6MWD >=380 m at Week 12 (+21% and +15%, respectively), whereas there was a small reduction in 6MWD in placebo-treated patients for both sub-groups. Riociguat also increased the proportion of treatment-naive patients and patients on background PAH-targeted therapy achieving World Health Organization functional class I/II (+12% and +19%, respectively) and cardiac index >=2.5 liter/min/m(2) (+30% and +33%, respectively) at Week 12, whereas there was little change in the respective placebo groups. CONCLUSIONS: Compared with placebo, riociguat increased the proportion of treatment-naive patients and patients on background PAH-targeted therapy who fulfilled criteria defining a positive response to therapy. PMID- 25703962 TI - Effect of chronic left ventricular unloading on myocardial remodeling: Multimodal assessment of two heterotopic heart transplantation techniques. AB - BACKGROUND: Cardiac recovery is possible by means of mechanical unloading yet remains rare. Excessive unloading-associated myocardial atrophy and fibrosis may adversely affect the process of reverse remodeling. In this study, we sought to evaluate the effect of different intensities of chronic left ventricular (LV) unloading on myocardial remodeling. METHODS: Twenty-five isogenic Lewis rats underwent complete LV unloading (CU, n = 15) induced by heterotopic heart transplantation or partial LV unloading (PU, n = 10) by heterotopic heart-lung transplantation. Information obtained from serial echocardiography, 2-deoxy 2[(18)F]fluoro-d-glucose ((18)F-FDG)-positron emission tomography, and an LV pressure-volume catheter were used to evaluate the morphology, glucose metabolism, and hemodynamic performance of the orthotopic hearts and heterotopic transplants over 4 weeks. Cell size, collagen content, tissue cytokines (interleukin [IL]-1alpha, IL-2, IL-6, IL-10, tumor necrosis factor-alpha, and vascular endothelial growth factor), and matrix metalloproteinase-2 and -9 were also determined. The recorded parameters included LV end-systolic dimension, LV end-diastolic dimension, posterior wall thickness, diastolic interventricular septum thickness, LV fractional shortening, and LV ejection fraction. RESULTS: We demonstrated an LV load-dependent relationship using echo-based structural (left posterior wall thickness, diastolic interventricular septum thickness, and left ventricular end-diastolic dimension) and functional (LV fractional shortening and LV ejection fraction) parameters, as well as an (18)F-FDG uptake (all p < 0.05). This load-dependent relationship was also evidenced in measurements from the pressure-volume conductance catheter (stroke volume, stroke work, cardiac output, dP/dTmax, and -dP/dTmin; all p < 0.05). Significant myocardial atrophy and fibrosis were observed in unloaded hearts, whereas concentrations of cytokines and matrix metalloproteinases were comparable in both unloading conditions. CONCLUSIONS: Partial and complete unloading affected the remodeling of non failing hearts in a rodent model to different extents on myocardial atrophy, fibrosis, glucose metabolism, and mechanical work. Cardiac atrophy is the prominent change after mechanical unloading, which exaggerates the proportion of total collagen that is responsible for diastolic dysfunction. PMID- 25703963 TI - Women's Experiences of Fetal Movements before the Confirmation of Fetal Death- Contractions Misinterpreted as Fetal Movement. AB - BACKGROUND: Decreased fetal movement often precedes a stillbirth. The objective of this study was to describe women's experiences of fetal movement before the confirmation of fetal death. METHODS: Data were collected through a Web-based questionnaire. Women with stillbirths after 28 gestational weeks were self recruited. Content analysis was used to analyze the answers to one open question. The statements from mothers of a stillborn, born during gestational weeks 28 to 36 were compared with those of a stillborn at term. RESULTS: The women's 215 answers were divided into three categories: decreased, weak, and no fetal movement at all; 154 (72%) of the descriptions were divided into three subcategories: decreased and weak movement (106; 49%), no movement at all (35; 16%), and contraction interpreted as movement (13; 6%). The category fetal movement as normal includes 39 (18%) of the descriptions. The third category, extremely vigorous fetal activity followed by no movement at all, includes 22 (10%) of the descriptions. Eight (15%) of the women with stillbirths in gestational weeks 28 to 36 interpreted contractions as fetal movement as compared to 5 (5%) of the women with stillbirths at term. DISCUSSION: Uterine contractions can be interpreted as fetal movement. A single episode of extremely vigorous fetal activity can precede fetal death. The majority of the women experienced decreased, weaker, or no fetal movement at all 2 days before fetal death was diagnosed. Mothers should be educated to promptly report changes in fetal movement to their health care providers. Using fetal movement information to evaluate possible fetal distress may lead to reductions in stillbirths. PMID- 25703964 TI - Relationship between hip abductor strength and external hip and knee adduction moments in medial knee osteoarthritis. AB - BACKGROUND: Alterations in hip abductor strength and hip and knee adduction moments during gait are associated with knee osteoarthritis. This study examines the relationship between hip abductor strength and hip and knee adduction moments during gait in individuals with symptomatic medial knee osteoarthritis. METHODS: Ninety-nine participants underwent maximal isometric hip abductor strength testing and 3D gait analysis. Pearson correlations examined relationships between non-normalized maximal hip abductor strength (Nm), peak external hip and knee adduction moments (Nm) and knee adduction moment impulse (Nm?s). Linear regressions examined these relationships while controlling for body size (height and mass) and walking speed. FINDINGS: Positive relationships existed between non normalized hip abductor strength and hip and knee adduction moments (r=0.28 and 0.37, respectively, p<0.01) as well as the knee adduction moment impulse (r=0.47, p<0.01). However, after controlling for body size and walking speed, hip abductor strength was not a significant predictor of hip or knee adduction moments (B= 0.08, and 0.04, respectively, p>0.05) but was a significant predictor of knee adduction moment impulse (B=0.05, p=0.005), explaining 6% of the variance. INTERPRETATION: While a significant relationship between hip abductor strength and knee adduction moment impulse was noted, hip abductor strength only explained a small amount of variance in the impulse. Our findings support previous research of healthy individuals and those with mild to moderate knee osteoarthritis and suggests hip abductor strength has little influence on hip and knee adduction moments during gait. PMID- 25703965 TI - The proteins (12 and 15 kDa) isolated from heat-killed Lactobacillus plantarum L67 induces apoptosis in HT-29 cells. AB - A number of scientific studies have revealed that Lactobacillus strains have beneficial bioactivities in the gastrointestinal tract. In this study, the production of intracellular reactive oxygen species (ROS) and the amounts of intracellular calcium, protein kinase C activity, cytochrome c, Bid, Bcl-2, Bax and the apoptosis-mediated proteins [caspase-8, caspase-3 and poly ADP ribose polymerase (PARP)] were evaluated to understand the induction of programmed cell death in HT-29 cells by Lactobacillus plantarum L67. The results obtained from this study indicated that the relative intensities of the apoptotic-related factors (intracellular ROS and intracellular calcium) and of apoptotic signals (Bax and t-Bid) increased with increasing concentrations of the membrane proteins isolated from heat-killed L. plantarum L67, whereas the relative intensities of cytochrome c, Bcl-2, caspase-8, caspase-3 and PARP decreased. This study determines whether proteins (12 and 15 kDa) isolated from heat-killed L. plantarum L67 induce programmed cell death in HT-29 cells. Proteins isolated from L. plantarum L67 can stimulate the apoptotic signals and then consequently induce programmed cell death in HT-29 cells. The results in this study suggest that the proteins isolated from L. plantarum L67 could be used as an antitumoural agent in probiotics and as a component of supplements or health foods. PMID- 25703966 TI - [Ophthalmology in the paintings by Hieronymus Bosch (II). The temptation of saint Anthony. Prado Museum (Madrid)]. PMID- 25703967 TI - [Saint Benedict's vision of the globe and the three angels. Alonso Cano. Prado Museum (Madrid)]. PMID- 25703968 TI - Ocular pathology in the paintings of El Greco (I). Saint John the Evangelist. Prado Museum (Madrid). PMID- 25703969 TI - [Ocular pathology in the paintings of Vicente Lopez Portana (I). The painter Francisco de Goya. Prado Museum (Madrid)]. PMID- 25703970 TI - [Ocular pathology in Lady and girl (II). Adriaen van Cronenburch. Prado Museum (Madrid)]. PMID- 25703971 TI - [Glasses and Saint Jerome in the Prado Museum (III). Jan Massys]. PMID- 25703972 TI - Ocular pathology in the paintings of Rafael Tejeo Diaz. Pedro Benitez and his daughter Mary of the Cross. Prado Museum (Madrid). PMID- 25703973 TI - [Ophthalmology in the paintings by Hieronymus Bosch (VIII). The creation. Prado Museum (Madrid)]. PMID- 25703974 TI - [Angels with multiple wings and eyes and thurifers. The hermitage of the Vera Cruz of Maderuelo (Segovia). Prado Museum (Madrid)]. PMID- 25703975 TI - [Ocular pathology in the paintings of Vicente Lopez Portana (II). Felix Antonio Maximo Lopez, first organist of the Royal Chapel. Prado Museum (Madrid)]. PMID- 25703976 TI - [Ophthalmology in the paintings by Hieronymus Bosch (VI). The garden of earthly delights. Prado Museum (Madrid)]. PMID- 25703977 TI - [Glasses and saint Jerome in the Prado Museum (II). Saint Jerome meditating. Joss van Cleve workshop]. PMID- 25703978 TI - [The surgeon. Jan Sanders van Hemessen. Prado Museum (Madrid)]. PMID- 25703979 TI - [Ophthalmology in the paintings by Hieronymus Bosch (V). Haywain. Prado Museum (Madrid)]. PMID- 25703980 TI - Glasses in The Contemporary Poets. A Reading of Zorilla at the Painter's Studio by Antonio Maria Esquivel y Suarez de Urbina. Prado Museum (Madrid). PMID- 25703981 TI - [Ophthalmology in the paintings by Hieronymus Bosch (IV). The temptation of saint Anthony (attributed to Bosch). Prado Museum (Madrid)]. PMID- 25703982 TI - [Ocular pathology in the paintings of Goya (I). The duke and duchess of Osuna and their children. Prado Museum (Madrid)]. PMID- 25703983 TI - [Ophthalmology in the paintings by Hieronymus Bosch (VII). A crossbowman. Prado Museum (Madrid)]. PMID- 25703984 TI - [Glasses and Saint Jerome in the Prado Museum (I). Marinus van Reymerswaele]. PMID- 25703985 TI - [Ophthalmology in the paintings by Hieronymus Bosch (III). The temptation of saint Anthony (copy). El Prado museum (Madrid)]. PMID- 25703986 TI - Ocular pathology in the paintings of Diego Velazquez (III). Las Meninas or The Family of Philip IV. Prado museum (Madrid). PMID- 25703987 TI - [Ophthalmology in the paintings by Hieronymus Bosch (I). Table of the mortal sins. Prado Museum (Madrid)]. PMID- 25703988 TI - [Ocular pathology in Lady and girl (I). Adriaen van Cronenburch. Prado Museum (Madrid)]. PMID- 25703989 TI - [Ocular pathology in the paintings of Goya (II). The painter Francisco Bayeu. Prado Museum (Madrid)]. PMID- 25703990 TI - Motion sensor strategies for automated optimization of deep brain stimulation in Parkinson's disease. AB - BACKGROUND: Deep brain stimulation (DBS) is a well-established treatment for Parkinson's disease (PD). Optimization of DBS settings can be a challenge due to the number of variables that must be considered, including presence of multiple motor signs, side effects, and battery life. METHODS: Nine PD subjects visited the clinic for programming at approximately 1, 2, and 4 months post-surgery. During each session, various stimulation settings were assessed and subjects performed motor tasks while wearing a motion sensor to quantify tremor and bradykinesia. At the end of each session, a clinician determined final stimulation settings using standard practices. Sensor-based ratings of motor symptom severities collected during programming were then used to develop two automated programming algorithms--one to optimize symptom benefit and another to optimize battery life. Therapeutic benefit was compared between the final clinician-determined DBS settings and those calculated by the automated algorithm. RESULTS: Settings determined using the symptom optimization algorithm would have reduced motor symptoms by an additional 13 percentage points when compared to clinician settings, typically at the expense of increased stimulation amplitude. By adding a battery life constraint, the algorithm would have been able to decrease stimulation amplitude by an average of 50% while maintaining the level of therapeutic benefit observed using clinician settings for a subset of programming sessions. CONCLUSIONS: Objective assessment in DBS programming can identify settings that improve symptoms or obtain similar benefit as clinicians with improvement in battery life. Both options have the potential to improve post operative patient outcomes. PMID- 25703992 TI - Gender differences in stroke, mortality, and hospitalization among patients with atrial fibrillation: A systematic review. AB - OBJECTIVE: To conduct a systematic review of gender differences in stroke, mortality, and hospitalization for patients with atrial fibrillation and/or flutter (AF/Afl). METHODS: Full texts, published, peer-reviewed, English language articles from 1999 through July 2014 were examined. Articles with populations of patients with AF/Afl were included if they conducted longitudinal analysis of any of three outcomes: stroke, mortality, and hospitalization, and reported or compared at least one of the outcomes according to gender. RESULTS: Seventeen articles were included: sixteen on stroke, nine on mortality, and one on hospitalization. In nine articles women had more strokes (RRs 0.89-1.9). Findings about gender differences in mortality (RRs 0.69-2.8) and hospitalizations were equivocal. CONCLUSIONS: Few articles examine differences in outcomes between men and women with AF/Afl. Given the prevalence of AF/Afl and health care costs it is vital to determine gender differences to evaluate appropriate therapies to decrease stroke, mortality, and hospitalizations. PMID- 25703993 TI - Genetic polymorphisms in DNA repair and oxidative stress pathways may modify the association between body size and postmenopausal breast cancer. AB - PURPOSE: Obesity is associated with increased bioavailability of estrogen, hyperinsulinemia, and chronic inflammation, all of which may promote tumor growth. Given DNA repair and oxidative stress pathways may work together with these mechanisms to influence carcinogenesis, we hypothesized that genetic variation in these pathways may modify the obesity-postmenopausal breast cancer (BC) association. METHODS: Resources from a population-based case-control study (990 cases and 970 controls) were used to construct logistic regression models. Body mass index (BMI, weight [kilogram]/height [square meter]) was assessed 1 year before reference date. We characterized interactions between BMI and 29 genetic polymorphisms in oxidative stress and DNA repair pathways. RESULTS: Age adjusted odds ratios (95% confidence intervals) for postmenopausal BC were 1.24 (1.00-1.52) and 1.35 (1.09-1.71) for 25 >= BMI < 30 and BMI >= 30 kg/m(2), respectively. We observed multiplicative interactions (P <= .05) for eight gene polymorphisms in DNA repair and oxidative stress pathways. For example, among MPO variant allele carriers, obesity was associated with a twofold increased risk of postmenopausal BC (2.13 [1.35-3.36]); however, in wild-type homozygotes, the relationship was less pronounced (1.33 [0.93-1.89]). Our findings were no longer significant after Bonferroni correction. CONCLUSIONS: Obesity may be particularly deleterious for postmenopausal BC development in the presence of biologically plausible DNA repair or oxidative stress genotypes. PMID- 25703994 TI - Volatile signalling by sesquiterpenes from ectomycorrhizal fungi reprogrammes root architecture. AB - The mutualistic association of roots with ectomycorrhizal fungi promotes plant health and is a hallmark of boreal and temperate forests worldwide. In the pre colonization phase, before direct contact, lateral root (LR) production is massively stimulated, yet little is known about the signals exchanged during this step. Here, we identify sesquiterpenes (SQTs) as biologically active agents emitted by Laccaria bicolor while interacting with Populus or Arabidopsis. We show that inhibition of fungal SQT production by lovastatin strongly reduces LR proliferation and that (-)-thujopsene, a low-abundance SQT, is sufficient to stimulate LR formation in the absence of the fungus. Further, we show that the ectomycorrhizal ascomycote, Cenococcum geophilum, which cannot synthesize SQTs, does not promote LRs. We propose that the LR-promoting SQT signal creates a win win situation by enhancing the root surface area for plant nutrient uptake and by improving fungal access to plant-derived carbon via root exudates. PMID- 25703995 TI - Spontaneaous linear gastric tears in a cat. AB - An 11-year-old female cat presented for chronic vomiting. Endoscopy revealed an altered gastric mucosa and spontaneous formation of linear gastric tears during normal organ insufflations. The histopathological diagnosis was atrophic gastritis with Helicobacter pylori infection. Medical treatment permitted a complete resolution of clinical signs. The linear tears observed resembled gastric lesions rarely reported in humans, called "Mallory-Weiss syndrome". To the authors' knowledge this is the first report of spontaneous linear gastric tears in animals. PMID- 25703996 TI - Essence of education in dermatology. PMID- 25703997 TI - Genetic polymorphisms of lipid metabolism gene SAR1 homolog B and the risk of Alzheimer's disease and vascular dementia. AB - BACKGROUND/PURPOSE: Lipid metabolism is involved in beta amyloid generation, which has been related with the progression of Alzheimer's disease (AD). No study has explored the association between polymorphisms of SAR1 homolog B (SAR1B) and the risk of dementia previously. METHODS: This is a case-control study. A total of 279 AD and 117 vascular dementia (VaD) patients were recruited from neurology clinics at three teaching hospitals in Taiwan from 2007 to 2010. Controls (n = 466) were recruited from the elderly health checkup program and volunteers in the hospital during the same time interval. Three common (frequency >= 5%) haplotype tagging single nucleotide polymorphisms were selected from the lipid metabolism gene SAR1B to assess its association with AD and VaD. RESULTS: Homozygous variants of rs11948613 were associated with a decreased AD risk (CC vs. TT: adjusted odds ratio = 0.39, 95% confidence interval = 0.15-0.98) with a population attributable risk of 26.7%. This association decreased further in apolipoprotein E epsilon4 (ApoE epsilon4) noncarriers (adjusted odds ratio = 0.28, 95% confidence interval = 0.09-0.91). No association was found for VaD. Two common haplotypes (with a cumulative frequency of 95.7% in controls) were identified for SAR1B, and no association was found for AD or VaD. Simultaneous screening using rs11948613 and ApoE epsilon4 significantly improved the sensitivity of ApoE epsilon4 alone (from 0.40 to 0.75). CONCLUSION: SAR1B polymorphisms were associated with AD risk; results were not significant after correction for multiple tests. Simultaneous screening using SAR1B rs11948613 and ApoE epsilon4 status offered a better sensitivity for AD screening. PMID- 25703998 TI - The correlation of electrochemical measurements and molecular junction conductance simulations in beta-strand peptides. AB - Understanding the electronic properties of single peptides is not only of fundamental importance, but it is also paramount to the realization of peptide based molecular electronic components. Electrochemical and theoretical studies are reported on two beta-strand-based peptides, one with its backbone constrained with a triazole-containing tether introduced by Huisgen cycloaddition (peptide 1) and the other a direct linear analogue (peptide 2). Density functional theory (DFT) and non-equilibrium Green's function were used to investigate conductance in molecular junctions containing peptides 3 and 4 (analogues of 1 and 2). Although the peptides share a common beta-strand conformation, they display vastly different electronic transport properties due to the presence (or absence) of the side-bridge constraint and the associated effect on backbone rigidity. These studies reveal that the electron transfer rate constants of 1 and 2, and the conductance calculated for 3 and 4, differ by approximately one order of magnitude, thus providing two distinctly different conductance states and what is essentially a molecular switch. A definitive correlation of electrochemical measurements and molecular junction conductance simulations is demonstrated using two different charge transfer techniques. This study furthers our understanding of the electronic properties of peptides at the molecular level, which provides an opportunity to fine-tune their molecular orbital energies through suitable structural manipulation. PMID- 25703999 TI - Response to 'The 3Rs: A student perspective'. PMID- 25704000 TI - Creation of mHealth content aimed at medical students. PMID- 25704001 TI - Adapt surgical training to the European Working Time Directive. PMID- 25704002 TI - The 3Rs: A student perspective. PMID- 25704003 TI - Response to 'Creation of mHealth content aimed at medical students'. PMID- 25704004 TI - Response to 'An uninformed methodology'. PMID- 25704005 TI - Peculiar salivary glands in a silk-producing mite Bakericheyla chanayi (Cheyletidae). AB - This is the first ultrastructural investigation of salivary glands in the family Cheyletidae. In both sexes of Bakericheyla chanayi, paired acinous salivary glands and tubular coxal glands were shown to be united into the common podocephalic system. The secretory portion of the salivary gland includes medial and lateral lobes composed of the five and two cells, respectively, with clearly distinct ultrastructure. The cytoplasm of the cells is occupied by the secretory granules containing fine fibrous material. The fine structure of both cell types suggest a proteinaceous nature of their secretions. A single central process extending from the apical face of each secretory cell passes through the common acinar cavity to enter the conducting duct. A pair of intercalary cells at the base of the conducting duct links it with the secretory portion of the gland. Extending towards the acinar cavity, protrusions of intercalary cells alternate the apical regions of the secretory cells and form with them highly-specialized contacts characterized by the apical network of microtubules and microfilaments. Two possible ways of secretion are suggested: 1) exocytosis into the acinar cavity and 2) direct passage via the central processes. The detection of axon profiles in the gland body suggests a neural control for the glandular cell function. In tritonymphs, neither secretion nor large lateral lobe cells were observed up to the pharate stage when the lateral lobe undergoes rapid differentiation. The arrangement of the acinous gland is compared to that of other arthropods. Its composition appears to be close to the class three of insect glands. The involvement of the lateral lobe cells in silk production is discussed. PMID- 25704006 TI - Neurogenic changes in the upper airway of obstructive sleep apnoea. AB - Obstructive sleep apnoea (OSA) is linked to local neural injury that evokes airway muscle remodelling. The upper airway muscles of patients with OSA are exposed to intermittent hypoxia as well as vibration induced by snoring. A range of electrophysiological and other studies have established altered motor and sensory function of the airway in OSA. The extent to which these changes impair upper airway muscle function and their relationship to the progression of OSA remains undefined. This review will collate the evidence for upper airway remodelling in OSA, particularly the electromyographic changes in upper airway muscles of patients with OSA. PMID- 25704007 TI - Inpatient management of migraine. AB - Migraine is a frequently disabling disorder which may require inpatient treatment. Admission criteria for migraine include intractable migraine, nausea and/or vomiting, severe disability, and dependence on opioids or barbiturates. The inpatient treatment of migraine is based on observational studies and expert opinion rather than placebo-controlled trials. Well-established inpatient treatments for migraine include dihydroergotamine, neuroleptics/antiemetics, lidocaine, intravenous aspirin, and non-pharmacologic treatment such as cognitive behavioral therapy. Short-acting treatments possibly associated with medication overuse, such as triptans, opioids, or barbiturate-containing compounds, are generally avoided. While the majority of persons with migraine are admitted on an emergency basis for only a few days, outcome studies and infusion protocols during elective admissions at tertiary headache centers suggest a longer length of stay may be needed for persons with intractable migraine. PMID- 25704008 TI - Influenza virus adaptation PB2-627K modulates nucleocapsid inhibition by the pathogen sensor RIG-I. AB - The cytoplasmic RNA helicase RIG-I mediates innate sensing of RNA viruses. The genomes of influenza A virus (FLUAV) are encapsidated by the nucleoprotein and associated with RNA polymerase, posing potential barriers to RIG-I sensing. We show that RIG-I recognizes the 5'-triphosphorylated dsRNA on FLUAV nucleocapsids but that polymorphisms at position 627 of the viral polymerase subunit PB2 modulate RIG-I sensing. Compared to mammalian-adapted PB2-627K, avian FLUAV nucleocapsids possessing PB2-627E are prone to increased RIG-I recognition, and RIG-I-deficiency partially restores PB2-627E virus infection of mammalian cells. Heightened RIG-I sensing of PB2-627E nucleocapsids correlates with previously established lower affinity of 627E-containing PB2 for nucleoprotein and is increased by further nucleocapsid instability. The effect of RIG-I on PB2-627E nucleocapsids is independent of antiviral signaling, suggesting that RIG-I nucleocapsid binding alone can inhibit infection. These results indicate that RIG I is a direct avian FLUAV restriction factor and highlight nucleocapsid disruption as an antiviral strategy. PMID- 25704010 TI - A perspective on sigma-1 receptor research: past and future. PMID- 25704009 TI - Concerted activation of the AIM2 and NLRP3 inflammasomes orchestrates host protection against Aspergillus infection. AB - Invasive pulmonary aspergillosis is a leading cause of infection-associated mortality in immunocompromised individuals. Aspergillus fumigatus infection produces ligands that could activate inflammasomes, but the contribution of these host defenses remains unclear. We show that two inflammasome receptors, AIM2 and NLRP3, recognize intracellular A. fumigatus and collectively induce protective immune responses. Mice lacking both AIM2 and NLRP3 fail to confine Aspergillus hyphae to inflammatory foci, leading to widespread hyphal dissemination to lung blood vessels. These mice succumb to infection more rapidly than WT mice or mice lacking a single inflammasome receptor. AIM2 and NLRP3 activation initiates assembly of a single cytoplasmic inflammasome platform, composed of the adaptor protein ASC along with caspase-1 and caspase-8. Combined actions of caspase-1 and caspase-8 lead to processing of pro-inflammatory cytokines IL-1beta and IL-18 that critically control the infection. Thus, AIM2 and NLRP3 form a dual cytoplasmic surveillance system that orchestrates responses against A. fumigatus infection. PMID- 25704011 TI - Sigma-1 receptor: the novel intracellular target of neuropsychotherapeutic drugs. AB - Sigma-1 receptor ligands have been long expected to serve as drugs for treatment of human diseases such as neurodegenerative disorders, depression, idiopathic pain, drug abuse, and cancer. Recent research exploring the molecular function of the sigma-1 receptor started unveiling underlying mechanisms of the therapeutic activity of those ligands. Via the molecular chaperone activity, the sigma-1 receptor regulates protein folding/degradation, ER/oxidative stress, and cell survival. The chaperone activity is activated or inhibited by synthetic sigma-1 receptor ligands in an agonist-antagonist manner. Sigma-1 receptors are localized at the endoplasmic reticulum (ER) membranes that are physically associated with the mitochondria (MAM: mitochondria-associated ER membrane). In specific types of neurons (e.g., those at the spinal cord), sigma-1 receptors are also clustered at ER membranes that juxtapose postsynaptic plasma membranes. Recent studies indicate that sigma-1 receptors, partly in sake of its unique subcellular localization, regulate the mitochondria function that involves bioenergetics and free radical generation. The sigma-1 receptor may thus provide an intracellular drug target that enables controlling ER stress and free radical generation under pathological conditions. PMID- 25704012 TI - Activation of sigma-1 receptor chaperone in the treatment of neuropsychiatric diseases and its clinical implication. AB - Endoplasmic reticulum (ER) protein sigma-1 receptor represents unique chaperone activity in the central nervous system, and it exerts a potent influence on a number of neurotransmitter systems. Several lines of evidence suggest that activation of sigma-1 receptor plays a role in the pathophysiology of neuropsychiatric diseases, as well as in the mechanisms of some therapeutic drugs and neurosteroids. Preclinical studies showed that some selective serotonin reuptake inhibitors (SSRIs; fluvoxamine, fluoxetine, excitalopram), donepezil, and ifenprodil act as sigma-1 receptor agonists. Furthermore, sigma-1 receptor agonists could improve the N-methyl-D-aspartate (NMDA) antagonist phencyclidine (PCP)-induced cognitive deficits in mice. A study using positron emission tomography have demonstrated that an oral administration of fluvoxamine or donepezil could bind to sigma-1 receptor in the healthy human brain, suggesting that sigma-1 receptor might be involved in the therapeutic mechanisms of these drugs. Moreover, case reports suggest that sigma-1 receptor agonists, including fluvoxamine, and ifenprodil, may be effective in the treatment of cognitive impairment in schizophrenia, delirium in elderly people, and flashbacks in post traumatic stress disorder. In this review article, the author would like to discuss the clinical implication of sigma-1 receptor agonists, including endogenous neurosteroids, in the neuropsychiatric diseases. PMID- 25704013 TI - Role of the Sigma-1 receptor in Amyotrophic Lateral Sclerosis (ALS). AB - Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease affecting spinal cord motoneurons (MN) with an associative connection to Frontotemporal Lobar Dementia (FTLD). The endoplasmic reticulum (ER) bound Sigma-1 Receptor (S1R) chaperone protein localizes to specialized ER cisternae within 10 nm of the plasma membrane in spinal cord ventral horn cholinergic post synaptic C terminals. Removal of the S1R gene in the Superoxide Dismutase-1 (SOD-1) mouse model of ALS exacerbated the neurodegenerative condition and resulted in a significantly reduced longevity when compared to the SOD-1/S1R wild type (WT) mouse. The proposed amelioration of the ALS phenotype by the S1R is likely due to a "brake" on excitation of the MN as evidenced by a reduction in action potential generation in the MN of the WT when compared to the S1R KO mouse MN. Although the precise signal transduction pathway(s) regulated by the S1R in the MN has/have not been elucidated at present, it is likely that direct or indirect functional interactions occur between the S1R in the ER cisternae with voltage gated potassium channels and/or with muscarinic M2 receptor signaling in the post synaptic plasma membrane. Possible mechanisms for regulation of MN excitability by S1R are discussed. PMID- 25704014 TI - Role of sigma-1 receptors in neurodegenerative diseases. AB - Neurodegenerative diseases with distinct genetic etiologies and pathological phenotypes appear to share common mechanisms of neuronal cellular dysfunction, including excitotoxicity, calcium dysregulation, oxidative damage, ER stress and mitochondrial dysfunction. Glial cells, including microglia and astrocytes, play an increasingly recognized role in both the promotion and prevention of neurodegeneration. Sigma receptors, particularly the sigma-1 receptor subtype, which are expressed in both neurons and glia of multiple regions within the central nervous system, are a unique class of intracellular proteins that can modulate many biological mechanisms associated with neurodegeneration. These receptors therefore represent compelling putative targets for pharmacologically treating neurodegenerative disorders. In this review, we provide an overview of the biological mechanisms frequently associated with neurodegeneration, and discuss how sigma-1 receptors may alter these mechanisms to preserve or restore neuronal function. In addition, we speculate on their therapeutic potential in the treatment of various neurodegenerative disorders. PMID- 25704015 TI - The involvement of the sigma-1 receptor in neurodegeneration and neurorestoration. AB - The sigma-1 receptor (Sig-1R) is a single 25 kD polypeptide and a chaperone protein immersed in lipid rafts of the endoplasmic reticulum (ER) where it interacts with mitochondria at the mitochondria-associated ER membrane domain (MAM). Upon activation, the Sig-1R binds to the inositol trisphosphate receptor (IP3R), and modulates cellular calcium (Ca(2+)) homeostasis. Also, the activated Sig-1R modulates plasma membrane receptor and ion channel functions, and may regulate cellular excitability. Further, the Sig-1R promotes trafficking of lipids and proteins essential for neurotransmission, cell growth and motility. Activation of the Sig-1R provides neuroprotection and is neurorestorative in cellular and animal models of neurodegenerative diseases and brain ischaemia. Neuroprotection appears to be due to inhibition of cellular Ca(2+) toxicity and/or inflammation, and neurorestoration may include balancing abberant neurotransmission or stimulation of synaptogenesis, thus remodelling brain connectivity. Single nucleotide polymorphisms and mutations of the SIGMAR1 gene worsen outcome in Alzheimer's disease and myotrophic lateral sclerosis supporting a role of Sig-1R in neurodegenerative disease. The combined neuroprotective and neurorestorative actions of the Sig-1R, provide a broad therapeutic time window of Sig-1R agonists. The Sig-1R is therefore a strong therapeutic target for the development of new treatments for neurodegenerative diseases and stroke. PMID- 25704016 TI - The role of SIGMAR1 gene mutation and mitochondrial dysfunction in amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) patients exhibit diverse pathologies such as endoplasmic reticulum (ER) stress and mitochondrial dysfunction in motor neurons. Five to ten percent of patients have familial ALS, a form of the disease caused by mutations in ALS-related genes, while sporadic forms of the disease occur in 90-95% of patients. Recently, it was reported that familial ALS patients exhibit a missense mutation in SIGMAR1 (c.304G > C), which encodes sigma-1 receptor (Sig 1R), substituting glutamine for glutamic acid at amino acid residue 102 (p.E102Q). Expression of that mutant Sig-1R(E102Q) protein reduces mitochondrial ATP production, inhibits proteasome activity and causes mitochondrial injury, aggravating ER stress-induced neuronal death in neuro2A cells. In this issue, we discuss mechanisms underlying mitochondrial impairment seen in ALS motor neurons and propose that therapies that protect mitochondria might improve the quality of life (QOL) of ALS patients and should be considered for clinical trials. PMID- 25704017 TI - Significance of nitric oxide synthases: Lessons from triple nitric oxide synthases null mice. AB - Nitric oxide (NO) is synthesized by three distinct NO synthases (neuronal, inducible, and endothelial NOSs), all of which are expressed in almost all tissues and organs in humans. The regulatory roles of NOSs in vivo have been investigated in pharmacological studies with non-selective NOS inhibitors. However, the specificity of the inhibitors continues to be an issue of debate, and the authentic significance of NOSs is still poorly understood. To address this issue, we generated mice in which all three NOS genes are completely disrupted. The triple NOSs null mice exhibited cardiovascular abnormalities, including hypertension, arteriosclerosis, myocardial infarction, cardiac hypertrophy, diastolic heart failure, and reduced EDHF responses, with a shorter survival. The triple NOSs null mice also displayed metabolic abnormalities, including metabolic syndrome and high-fat diet-induced severe dyslipidemia. Furthermore, the triple NOSs null mice showed renal abnormalities (nephrogenic diabetes insipidus and pathological renal remodeling), lung abnormalities (accelerated pulmonary fibrosis), and bone abnormalities (increased bone mineral density and bone turnover). These results provide evidence that NOSs play pivotal roles in the pathogenesis of a wide variety of disorders. This review summarizes the latest knowledge on the significance of NOSs in vivo, based on lessons learned from experiments with our triple mutant model. PMID- 25704018 TI - Anticancer and antimetastatic effects of cordycepin, an active component of Cordyceps sinensis. AB - Cordyceps sinensis, a fungus that parasitizes on the larva of Lepidoptera, has been used as a valued traditional Chinese medicine. We investigated the effects of water extracts of Cordyceps sinensis (WECS), and particularly focused on its anticancer and antimetastatic actions. Based on in vitro studies, we report that WECS showed an anticancer action, and this action was antagonized by an adenosine A3 receptor antagonist. Moreover, this anticancer action of WECS was promoted by an adenosine deaminase inhibitor. These results suggest that one of the components of WECS with an anticancer action might be an adenosine or its derivatives. Therefore, we focused on cordycepin (3'-deoxyadenosine) as one of the active ingredients of WECS. According to our experiments, cordycepin showed an anticancer effect through the stimulation of adenosine A3 receptor, followed by glycogen synthase kinase (GSK)-3beta activation and cyclin D1 suppression. Cordycepin also showed an antimetastatic action through inhibiting platelet aggregation induced by cancer cells and suppressing the invasiveness of cancer cells via inhibiting the activity of matrix metalloproteinase (MMP)-2 and MMP-9, and accelerating the secretion of tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 from cancer cells. In conclusion, cordycepin, an active component of WECS, might be a candidate anticancer and antimetastatic agent. PMID- 25704019 TI - Involvement of serotonergic system in the effect of a metabotropic glutamate 5 receptor antagonist in the novelty-suppressed feeding test. AB - The blockade of metabotropic glutamate 5 (mGlu5) receptor has been reported to exert antidepressant effects in several animal models. We previously reported that both ketamine and an mGlu5 receptor antagonist exerted an effect in a novelty-suppressed feeding (NSF) test, and that the effect of ketamine may be mediated through an alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor-dependent increase in serotonergic transmission. However, the involvement of the serotonergic system in the effect of mGlu5 receptor antagonists in the NSF test is not well understood. Therefore, we examined the roles of the serotonergic system in the effect of an mGlu5 receptor antagonist, 6 methyl-2-(phenylethynyl)pyridine hydrochloride (MPEP), in the NSF test in mice. The administration of MPEP significantly shortened the latency to feed, which was not attenuated by the AMPA receptor antagonist, 2,3-dioxo-6-nitro-1,2,3,4 tetrahydrobenzo[f]quinoxaline-7-sulfonamide (NBQX). The effect of MPEP was abolished by the tryptophan hydroxylase inhibitor, para-chlorophenylalanine (PCPA). Moreover, the effect of MPEP was blocked by a serotonin (5-HT)2A/2C receptor antagonist, ritanserin, but not by a 5-HT1A receptor antagonist, N-{2-[4 (2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridynyl) cyclohexane-carboxamide (WAY100635). These results suggest that the effect of an mGlu5 receptor antagonist may be mediated by the serotonergic system, including the stimulation of the 5-HT2A/2C receptor, in an AMPA receptor-independent manner in the NSF test. PMID- 25704020 TI - Different chronotherapeutic effects of valsartan and olmesartan in non-dipper hypertensive patients during valsartan treatment at morning. AB - This study was undertaken to evaluate the differences in chronotherapeutic effects of angiotensin-II receptor blockers, valsartan and olmesartan in hypertensive patients with non-dipper blood pressure (BP) pattern during valsartan at morning. Ninety four patients were enrolled, and 40 patients were judged to be non-dippers. In these patients, same dose of valsartan was changed to evening (Val-E, n = 12), or olmesartan (equivalent dose of valsartan) was given at morning (Olm-M, n = 13) or evening (Olm-E, n = 15) for 4 months. BP decreased during sleep and increased during waking hours in Val-E group. In Olm-M and Olm-E groups, BP decreased during sleep and waking hours. Percent reduction in BP at night-time compared to BP at waking hours significantly increased after changing the dose regimen in each group. Serum creatinine decreased and estimated glomerular filtration rate (eGFR) elevated in Olm-M and Olm-E, but not Val-E groups. Positive correlation between systolic BP (SBP) during sleep and serum creatinine, and negative correlation between SBP during sleep and eGFR were detected. These data suggest that dipper BP pattern could be obtained by chronotherapeutic approach using valsartan and olmesartan in non-dipper patients with valsartan at morning. Morning and evening olmesartan, but not evening valsartan improved renal function in these patients. PMID- 25704021 TI - Olmesartan inhibits cultured rat aortic smooth muscle cell death induced by cyclic mechanical stretch through the inhibition of the c-Jun N-terminal kinase and p38 signaling pathways. AB - Acute aortic dissection (AAD) is a life-threating disease; however, there is almost no effective pharmacotherapy for it. An increase in c-Jun N-terminal kinase (JNK) phosphorylation and smooth muscle cell (SMC) apoptosis is observed tissues in patients with AAD. Therefore, we hypothesized that an acute rise in blood pressure leads to SMC death through phosphorylation of JNK or p38, which may cause AAD. We investigated the influence of cyclic mechanical stretch, which mimics an acute increase in blood pressure, on cultured rat aortic SMCs (RASMCs) and examined the changes in JNK and p38 phosphorylation. Further, we investigated the effect of olmesartan, an angiotensin II receptor blocker, on stretch-induced RASMC death. We found that mechanical stretch-induced RASMC death in a time dependent manner, which correlated with the phosphorylation of JNK and p38. Olmesartan inhibited RASMC death and the phosphorylation of JNK and p38. JNK and p38 inhibitors reversed stretch-induced RASMC death. These results suggest that acute mechanical stretch causes JNK and p38 phosphorylation, which may result in SMC death leading to aortic dissection. Olmesartan may be used for pharmacotherapy to prevent aortic dissection, independent of its blood pressure lowering effect, through its inhibition of JNK and p38 phosphorylation. PMID- 25704022 TI - 3,3'-Diindolylmethane increases bone mass by suppressing osteoclastic bone resorption in mice. AB - 3,3'-Diindolylmethane (DIM), a major acid-condensation product or metabolite of indole-3-carbinol which is found in cruciferous vegetables, has been shown to have anticancer, anti-inflammatory, and multiple immune stimulating effects. However, its function in bone metabolism is poorly understood. This study evaluated the effect of DIM on bone mass in mice under physiological and pathological conditions. Eight-week-old female mice received injections of a vehicle or 0.1mg/g of DIM, twice a week for four weeks. We found that DIM treatment significantly increased bone mass as assessed by dual-energy X-ray absorptiometry (DEXA) and micro-computed tomography (MUCT). Further, Bone histomorphometric analyses showed that this treatment significantly reduced bone resorption parameters, but did not increase bone formation parameters. Furthermore, we use ovariectomized (OVX)-induced osteoporotic mouse model, and explore function of DIM in skeletal pathological processes. Bone phenotype analyses revealed that the administration of DIM in this study effectively prevented OVX-induced bone loss resulting from increased bone resorption. Our results demonstrated that DIM increased bone mass by suppressing osteoclastic bone resorption in bone metabolism under both physiological and pathological conditions. Accordingly, DIM may be of value in the treatment and the possible prevention of bone diseases characterized by bone loss, such as postmenopausal osteoporosis. PMID- 25704023 TI - TRAIL pathway is associated with inhibition of colon cancer by protopanaxadiol. AB - Among important components of American ginseng, protopanaxadiol (PPD) showed more active anticancer potential than other triterpenoid saponins. In this study, we determined the in vivo effects of PPD in a mouse cancer model first. Then, using human colorectal cancer cell lines, we observed significant cancer cell growth inhibition by promoting G1 cell cycle redistribution and apoptosis. Subsequently, we characterized the downstream genes targeted by PPD in HCT-116 cancer cells. Using Affymetrix high density GeneChips, we obtained the gene expression profile of the cells. Microarray data indicated that the expression levels of 76 genes were changed over two-fold after PPD, of which 52 were upregulated while the remaining 24 were downregulated. Ingenuity pathway analysis of top functions affected was carried out. Data suggested that by regulating the interactions between p53 and DR4/DR5, the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) pathway played a key role in the action of PPD, a promising colon cancer inhibitory compound. PMID- 25704024 TI - Blockade of voltage-gated K+ currents in rat mesenteric arterial smooth muscle cells by MK801. AB - MK801 (dizocilpine), a phencyclidine (PCP) derivative, is a potent noncompetitive antagonist of the N-Methyl-D-aspartate receptor (NMDAr). Another PCP derivative, ketamine, was reported to block voltage-gated K(+) (Kv) channels, which was independent of NMDAr function. Kv currents are major regulators of the membrane potential (Em) and excitability of muscles and neurons. Here, we investigated the effect of MK801 on the Kv channels and Em in rat mesenteric arterial smooth muscle cells (RMASMCs). We used the whole-cell patch clamp technique to analyze the effect of MK801 enantiomers on Kv channels and Em. (+)MK801 inhibited Kv channels in a concentration-dependent manner (IC50 of 89.1 +/- 13.1 MUM, Hill coefficient of 1.05 +/- 0.08). The inhibition was voltage- and state- independent. (+)MK801 didn't influence steady-state activation and inactivation of Kv channels. (+)MK801 treatment depolarized Em in a concentration-dependent manner and concomitantly decreased membrane conductance. (-)MK801 also similarly inhibited the Kv channels (IC50 of 134.0 +/- 17.5 MUM, Hill coefficient of 0.87 +/- 0.09). These results indicate that MK801 directly inhibits the Kv channel in a state-independent manner in RMASMCs. This MK801-mediated inhibition of Kv channels should be considered when assessing the various pharmacological effects produced by MK801, such as schizophrenia, neuroprotection, and hypertension. PMID- 25704025 TI - Mechanism of action of hypoglycemic effects of an intestine-specific inhibitor of microsomal triglyceride transfer protein (MTP) in obese rats. AB - Diminished insulin sensitivity in the peripheral tissues and failure of pancreatic beta cells to secrete insulin are known major determinants of type 2 diabetes mellitus. JTT-130, an intestine-specific microsomal transfer protein inhibitor, has been shown to suppress high fat-induced obesity and ameliorate impaired glucose tolerance while enhancing glucagon-like peptide-1 (GLP-1) secretion. We investigated the effects of JTT-130 on glucose metabolism and elucidated the mechanism of action, direct effects on insulin sensitivity and glucose-stimulated insulin secretion in a high fat diet-induced obesity rat model. Male Sprague Dawley rats fed a high-fat diet were treated with a single administration of JTT-130. Glucose tolerance, hyperglycemic clamp and hyperinsulinemic-euglycemic testing were performed to assess effects on insulin sensitivity and glucose-stimulated insulin secretion, respectively. Plasma GLP-1 and tissue triglyceride content were also determined under the same conditions. A single administration of JTT-130 suppressed plasma glucose elevations after oral glucose loading and increased the disposition index while elevating GLP-1. JTT 130 also enhanced glucose-stimulated insulin secretion in hyperglycemic clamp tests, whereas increased insulin sensitivity was observed in hyperinsulinemic euglycemic clamp tests. Single-dose administration of JTT-130 decreased lipid content in the liver and skeletal muscle. JTT-130 demonstrated acute and direct hypoglycemic effects by enhancing insulin secretion and/or insulin sensitivity. PMID- 25704026 TI - The effects of AP521, a novel anxiolytic drug, in three anxiety models and on serotonergic neural transmission in rats. AB - We investigated the anxiolytic effects and mechanism of action of a new anxiolytic drug, (R)-piperonyl-1,2,3,4-tetrahydro[1]benzothieno[2,3-c]pyridine-3- carboxamide hydrochloride (AP521). AP521 showed equal or more potent anxiolytic like effects compared with diazepam, a benzodiazepine receptor agonist, or tandospirone, a partial 5-hydroxytryptamine (5-HT)1A receptor agonist, in three rat anxiety models; the Vogel-type conflict test, elevated plus maze test, and conditioned fear stress test. Although AP521 did not bind to the benzodiazepine receptor, it did bind to 5-HT1A, 5-HT1B, 5-HT1D, 5-HT5A and 5-HT7 receptors, and showed agonist activity for the human 5-HT1A receptor expressed in HEK293 cells. Tandospirone, which can stimulate the presynaptic 5-HT1A receptors in the raphe, tended to decrease extracellular 5-HT concentration in the medial prefrontal cortex (mPFC) in rats. In contrast, AP521 increased extracellular 5-HT concentration. In addition, AP521 enhanced the anti-freezing effect of citalopram, a selective serotonin reuptake inhibitor, in the fear conditioning model in rats and enhanced the citalopram-caused increase of the extracellular 5 HT concentration in the mPFC. These results suggest that AP521 exhibits potent anxiolytic effects by acting as a postsynaptic 5-HT1A receptor agonist and by enhancing serotonergic neural transmission in the mPFC by a novel mechanism of action. PMID- 25704027 TI - Glutamine protects against cisplatin-induced nephrotoxicity by decreasing cisplatin accumulation. AB - Cisplatin is a chemotherapeutic drug but induces acute kidney injury (AKI). Cisplatin-induced AKI depends on several signaling pathways leading to apoptosis in tubular epithelial cells. Glutamine is a substrate for the synthesis of glutathione, the most abundant intracellular thiol and antioxidant, and plays an important role in protecting cells from apoptosis induced by different stimuli. In the present study, we investigated the protective effect of glutamine on cisplatin-induced AKI. Rats were divided into control, glutamine, cisplatin, and cisplatin plus glutamine groups. Glutamine ameliorated renal dysfunction, tissue injury, and cisplatin-induced apoptosis. Cisplatin increased cell death, caspase 3 cleavage, activation of MAPKs and p53, oxidative stress, and mRNA expression of TNF-alpha and TNFR1 in HK-2 cells. Glutamine treatment reduced cisplatin-induced these changes in HK-2 cells. Notably, glutamine reduced the cisplatin-induced expression of organic cation transporter 2 (OCT2) and cisplatin accumulation. Our results suggest that the protective effect of glutamine on cisplatin is specific for proximal tubular cells and the initial effects may be related to attenuation of cisplatin uptake. Thus, glutamine administration might represent a new strategy for the treatment of cisplatin-induced AKI. PMID- 25704028 TI - Phosphatidylinositol4-phosphate 5-kinase prevents the decrease in the HERG potassium current induced by Gq protein-coupled receptor stimulation. AB - The human ether-a-go-go-related gene (HERG) potassium current (IHERG) has been shown to decrease in amplitude following stimulation with Gq protein-coupled receptors (GqRs), such as alpha1-adrenergic and M1-muscarinic receptors (alpha1R and M1R, respectively), at least partly via the reduction of membrane phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2). The present study was designed to investigate the modulation of HERG channels by PI(4,5)P2 and phosphatidylinositol4-phosphate 5-kinase (PI(4)P5-K), a synthetic enzyme of PI(4,5)P2. Whole-cell patch-clamp recordings were used to examine the activity of HERG channels expressed heterologously in Chinese Hamster Ovary cells. The stimulation of alpha1R with phenylephrine or M1R with acetylcholine decreased the amplitude of IHERG accompanied by a significant acceleration of deactivation kinetics and the effects on IHERG were significantly attenuated in cells expressing PI(4)P5-K. The density of IHERG in cells expressing GqRs alone was significantly increased by the coexpression of PI(4)P5-K without significant differences in the voltage dependence of activation and deactivation kinetics. The kinase-deficient substitution mutant, PI(4)P5-K-K138A did not have these counteracting effects on the change in IHERG by M1R stimulation. These results suggest that the current density of IHERG is closely dependent on the membrane PI(4,5)P2 level, which is regulated by PI(4)P5-K and GqRs and that replenishing PI(4,5)P2 by PI(4)P5-K recovers IHERG. PMID- 25704029 TI - BCL2 promotor methylation and miR-15a/16-1 upregulation is associated with sanguinarine-induced apoptotic death in rat HSC-T6 cells. AB - Previous studies show that several pathways are involved in sanguinarine-induced apoptotic cell death, including AKT downregulation, inhibition of NF-kB activation, mediation of ROS production, downregulation of anti-apoptosis proteins XIAP and cIAP-1, upregulation of BAX, and downregulation of BCL2. In this study, we found out that the quenching of ROS generation by N-acetyl-l cysteine (NAC), a scavenger of ROS, reversed sanguinarine-induced apoptosis effects, also we found out that sanguinarine-induced rat hepatic stellate T6 cells (HSC-T6 cells) apoptosis was correlated with the generation of increased ROS, which was followed by the activation of caspase-8 (-3, -6, and -9), and the decreasing in the miltochondrial membrane potential (MMP) and the down-regulation of anti-apoptotic protein Bcl-2. It is not clear whether BCL2's downregulation relates to its promoter methylation and miR-15a/16-1 expression which can bind to BCL2 3'-UTR (un-translation reagon). We showed that sanguinarine-induced down regulation of BCL2 was associated with the increased methylation rate of BCL2 promotor district and the increased expression of miR-15a/16-1. HSC-T6 cells treatment with 5-Aza-2'-deoxycytidine (5'-Aza-CdR) impeded sanguinarine-induced BCL2 promotor district methylation and recovered BCL2's expression. Over expression of BCL2 using pEGFP-N1 vector decreased sanguinarine-induced HSC-T6 cells apoptotic death significantly but not completely. These observations clearly showed that BCL2 down regulation was associated with its promoter methylation and miR-15a/16-1 upregulation in sanguinarine-induced Rat HSC-T6 cells. PMID- 25704030 TI - Paroxetine prevented the down-regulation of astrocytic L-Glu transporters in neuroinflammation. AB - The extracellular L-glutamate (L-Glu) concentration is elevated in neuroinflammation, thereby causing excitotoxicity. One of the mechanisms is down regulation of astrocyte L-Glu transporters. Some antidepressants have anti inflammatory effects. We therefore investigated effects of various antidepressants on the down-regulation of astrocyte L-Glu transporters in the in vitro neuroinflammation model. Among these antidepressants, only paroxetine was effective. We previously demonstrated that the down-regulation of astrocyte L-Glu transporters was caused by L-Glu released from activated microglia. We here clarified that only paroxetine inhibited L-Glu release from microglia. This is the novel action of paroxetine, which may bring advantages on the therapy of neuroinflammation. PMID- 25704031 TI - Muscarinic cholinoceptor-mediated activation of JNK negatively regulates intestinal secretion in mice. AB - Regulation of intestinal secretion is important for body fluid homeostasis. We investigated the role of three MAP kinases (MAPKs) as negative regulators in muscarinic cholinoceptor (mAChR)-mediated intestinal secretion in mice. Electrophysiological analyses revealed that mAChR stimulation enhanced intestinal chloride secretion, which was further augmented by the inhibition of JNK but not by that of ERK or p38 with specific inhibitors SP600125, U0126 or SB203580, respectively. Immunoblot analyses in colonic mucosa showed that mAChR stimulation increased MAPKs phosphorylation that was suppressed by the specific inhibitor for each MAPK. This suggests that JNK is a major negative regulator in mAChR-induced intestinal secretion. PMID- 25704032 TI - White matter microstructure in bipolar disorder is influenced by the serotonin transporter gene polymorphism 5-HTTLPR. AB - Bipolar disorder (BD) is associated with signs of widespread disruption of white matter (WM) integrity. A polymorphism in the promoter of the serotonin transporter (5-HTTLPR) influenced functional cortico-limbic connectivity in healthy subjects and course of illness in BD, with the short (s) allele being associated with lower functional connectivity, and with earlier onset of illness and poor response to treatment. We tested the effects of 5-HTTLPR on diffusion tensor imaging (DTI) measures of WM microstructure in 140 inpatients, affected by a major depressive episode in course of BD, of Italian descent. We used whole brain tract-based spatial statistics in the WM skeleton with threshold-free cluster enhancement of DTI measures of WM microstructure: axial, radial and mean diffusivity and fractional anisotropy. Compared with l/l homozygotes, 5-HTTLPR*s carriers showed significantly increased radial and mean diffusivity in several brain WM tracts, including corpus callosum, cingulum bundle, uncinate fasciculus, corona radiata, thalamic radiation, inferior and superior longitudinal fasciculus and inferior fronto-occipital fasciculus. An increase of mean and radial diffusivity, perpendicular to the main axis of the WM tract, is thought to signify increased space between fibers, thus suggesting demyelination or dysmyelination, or loss of bundle coherence. The effects of 5-HTTLPR on the anomalous emotional processing in BD might be mediated by changes of WM microstructure in key WM tracts contributing to the functional integrity of the brain. PMID- 25704033 TI - Muscle pathology grade for facioscapulohumeral muscular dystrophy biopsies. AB - INTRODUCTION: As we move toward planning for clinical trials in facioscapulohumeral muscular dystrophy (FSHD), a better understanding of the clinical relationship with morphological changes in FSHD muscle biopsies will be important for stratifying patients and understanding post-therapeutic changes in muscle. METHODS: We performed a prospective cross-sectional study of quadriceps muscle biopsies in 74 genetically confirmed FSHD participants (64 with FSHD type 1 and 10 with FSHD type 2). We compared a 12-point muscle pathology grade to genetic mutation, disease severity score, and quantitative myometry. RESULTS: Pathology grade had moderate correlations with genetic mutation (rho = -0.45, P < 0.001), clinical severity score (rho = 0.53, P < 0.001), disease duration (rho = 0.31, P = 0.03), and quantitative myometry (rho = -0.47, P < 0.001). We found no difference in the frequency of inflammation between FSHD types 1 and 2. CONCLUSIONS: The pathology grade of quadriceps muscle may be a useful marker of disease activity in FSHD, and it may have a role in stratification for future clinical trials. PMID- 25704034 TI - Carbon-supported base metal nanoparticles: cellulose at work. AB - Pyrolysis of base metal salt loaded microcrystalline cellulose spheres gives a facile access to carbon-supported base metal nanoparticles, which have been characterized with temperature-dependent XRD, SEM, TEM, ICP-MS and elemental analysis. The role of cellulose is multifaceted: 1) it facilitates a homogeneous impregnation of the aqueous base metal salt solutions, 2) it acts as an efficacious (carbonaceous) support material for the uniformly dispersed base metal salts, their oxides and the metal nanoparticles derived therefrom, and 3) it contributes as a reducing agent via carbothermal reduction for the conversion of the metal oxide nanoparticles into the metal nanoparticles. Finally, the base metal nanoparticles capable of forming metastable metal carbides catalytically convert the carbonaceous support into a mesoporous graphitic carbon material. PMID- 25704035 TI - Protective effects of caffeic acid phenethyl ester against acute radiation induced hepatic injury in rats. AB - Caffeic acid phenyl ester (CAPE) is a potent anti-inflammatory agent and it can eliminate the free radicals. The current study was intended to evaluate the protective effect of CAPE against the acute radiation-induced liver damage in rats. Male Sprague-Dawley rats were intraperitoneally administered with CAPE (30 mg/kg) for 3 consecutive days before exposing them to a single dose of 30 Gy of beta-ray irradiation to upper abdomen. We found that pretreatment with CAPE significantly decreased the serum levels of alanine aminotransferase and aspartate aminotransferase and increased the activity of superoxide dismutase and glutathione. Histological evaluation further confirmed the protection of CAPE against radiation-induced hepatotoxicity. TUNEL assay showed that CAPE pretreatment inhibited hepatocyte apoptosis. Moreover, CAPE inhibited the nuclear transport of NF-kappaB p65 subunit, decreased the level of tumor necrosis factor alpha, nitric oxide and inducible nitric oxide synthase. Taken together, these results suggest that pretreatment with CAPE offers protection against radiation induced hepatic injury. PMID- 25704036 TI - BAY 11-7082 ameliorates diabetic nephropathy by attenuating hyperglycemia mediated oxidative stress and renal inflammation via NF-kappaB pathway. AB - Diabetic nephropathy is a serious microvascular complication for patients associated with diabetes mellitus. Recent studies have suggested that NF-kappaB is the main transcription factor for the inflammatory response mediated progression of diabetic nephropathy. Hence, the present study is hypothesized to explore the renoprotective nature of BAY 11-7082 an IkappaB phosphorylation inhibitor on Streptozotocin (STZ) induced diabetic nephropathy in Sprague-Dawley (SD) rats. Male SD rats were divided into five groups, group I sham control, group II drug control, group III diabetic control (STZ 50mg/kg), group IV and V are test drug groups to which a single dose of STZ 50mg/kg was injected initially and later received BAY 11-7082 1mg/kg and 3mg/kg, respectively from 5th to 8th week. Eight weeks after STZ injection, diabetic rats exhibited significant renal dysfunction, as evidenced by reduced creatinine clearance, increased blood glucose, urea nitrogen and creatinine, which were reversed to near normal by BAY 11-7082. BAY 11-7082 treated rats showed significant improvement in the decreased enzymatic antioxidant SOD, non-enzymatic antioxidant GSH levels, and elevated lipid peroxidation and nitric oxide levels as observed in the diabetic rats. BAY 11-7082 treatment was found to significantly recover kidney histological architecture in the diabetic rats. Altered levels of inflammatory cytokines like TNF-alpha, IL-1beta, IL-6 and nuclear transcriptional factor subunit NF-kappaB p65 were reverted to the normal level upon treatment with BAY 11-7082. Our results suggest that by limiting the activation of NF-kappaB, thereby reducing the expression of inflammatory cytokines and by inhibiting the oxidative damage BAY 11-7082 protect the rats against diabetic nephropathy. PMID- 25704037 TI - Neisseria meningitidis factor H-binding protein fHbp: a key virulence factor and vaccine antigen. AB - Neisseria meningitidis is a leading cause of meningitis and sepsis worldwide. The first broad-spectrum multicomponent vaccine against serogroup B meningococcus (MenB), 4CMenB (Bexsero((r))), was approved by the EMA in 2013, for prevention of MenB disease in all age groups, and by the US FDA in January 2015 for use in adolescents. A second protein-based MenB vaccine has also been approved in the USA for adolescents (rLP2086, Trumenba((r))). Both vaccines contain the lipoprotein factor H-binding protein (fHbp). Preclinical studies demonstrated that fHbp elicits a robust bactericidal antibody response that correlates with the amount of fHbp expressed on the bacterial surface. fHbp is able to selectively bind human factor H, the key regulator of the alternative complement pathway, and this has important implications both for meningococcal pathogenesis and for vaccine design. Here, we review the functional and structural properties of fHbp, the strategies that led to the design of the two fHbp-based vaccines and the data generated during clinical studies. PMID- 25704038 TI - Rapid single-molecule imaging in cyclic olefin copolymer channels. AB - Rapid preparation of high quality capture surfaces is a major challenge for surface-based single-molecule protein binding assays. Here we introduce a simple method to activate microfluidic chambers made from cyclic olefin copolymer for single-molecule imaging with total internal reflection fluorescence microscopy. We describe a surface coating protocol and demonstrate single-molecule imaging in off-the-shelf microfluidic parts that can be activated for binding assays within a few minutes. As the first example, biotinylated protein directly captured on the neutravidin-coated surface was detected using fluorescently labeled antibody. We then showed detection of a fusion construct containing green fluorescence protein and verified its single fluorophore behavior by observing stepwise photobleaching events. Finally, a target protein was identified in the crude cell lysate using antibody-sandwich complex formation. In all experiments, controls were completed to ensure that nonspecific binding to the surface was minimal. Based on our results, we conclude that the simple surface preparation described in this paper enables single-molecule imaging assays without time-consuming coating procedures. PMID- 25704039 TI - World Kidney Day 2015: CKD in disadvantaged populations. PMID- 25704040 TI - Childhood CKD affects the entire family. PMID- 25704041 TI - Use of the Kidney Failure Risk Equation to reduce uncertainty in predicting time to ESRD. PMID- 25704042 TI - Better informing older patients with kidney failure in an era of patient-centered care. PMID- 25704043 TI - NephMadness 2015: nephrology as a cornerstone of medicine. PMID- 25704044 TI - In reply to 'Intravenous iron, inflammation, and ventricular dysfunction during hemodialysis'. PMID- 25704045 TI - Intravenous iron, inflammation, and ventricular dysfunction during hemodialysis. PMID- 25704046 TI - More evidence needed before lower dialysate sodium concentrations can be recommended. PMID- 25704047 TI - In reply to 'More evidence needed before lower dialysate sodium concentrations can be recommended'. PMID- 25704048 TI - Quiz page March 2015: unexplained kidney failure in a patient with bladder cancer. AKI secondary to metastatic infiltration of the kidneys by poorly differentiated urothelial cancer. PMID- 25704049 TI - Randomized study of teaching ultrasound-guided vascular cannulation using a phantom and the freehand versus needle guide-assisted puncture techniques. AB - PURPOSE: The task of ultrasound-guided vessel cannulation can be technically difficult. Needle guides have been designed to facilitate vessel puncture. We aimed to identify and compare the learning curves of participants performing vessel puncture with conventional freehand (FH) and needle guide-assisted (NG) techniques. METHODS: Thirty-six participants were randomly allocated to either the FH or the NG group. They were asked to consecutively perform as many as 30 vessel punctures on a simulated phantom model. Quantitative metrics (time taken and number of skin and posterior-wall punctures) were recorded and compared between the two groups. The cumulative sum and moving F-test statistical methods were used to delineate the learning curves. RESULTS: There was a significantly lower rate of posterior-wall punctures in the NG group than in the FH group (15% versus 26%; p < 0.0001). Participants in the NG group also performed significantly fewer skin punctures than did those in the FH group (mean, 405 versus 515; p < 0.0001). Cumulative sum statistical method analysis showed that participants in the NG group surmounted the learning curve earlier (13 attempts; interquartile range, 10.3-17.0) than did those in the FH group (19 attempts; interquartile range, 15.0-27.5). The number of attempts to surmount the learning curve was significantly less for the FH group (7.2 versus 16 attempts; p = 0.007) when using the moving F-test. CONCLUSIONS: The NG puncture allows a greater number of trainees to cross the learning threshold and offers the advantages of fewer posterior-wall punctures and skin punctures. The use of NG puncture may result in a shorter path to proficiency, allowing trainees to attempt needle puncture earlier and with a greater degree of safety. PMID- 25704050 TI - Comparison of a modified mid-coronal sectioning technique and Wilson's technique when conducting eye and brain examinations in rabbit teratology studies. AB - BACKGROUND: There are two methods used when examining fetal rabbit eyes and brain in teratology studies. One method employs prior fixation before serial sectioning (Wilson's technique) and the other uses fresh tissue (mid-coronal sectioning). METHODS: We modified the mid-coronal sectioning technique to include removal of eyes and brain for closer examination and to increase the number of structures that can be evaluated and compared it to the Wilson's technique. We found that external examination of the head, in conjunction with either sectioning method, is equally sensitive in identifying developmental defects. We evaluated 40,401 New Zealand White (NZW) and Dutch-Belted (DB) rabbit fetuses for external head alterations, of which 28,538 fetuses were further examined for eye and brain alterations using the modified mid-coronal sectioning method (16,675 fetuses) or Wilson's technique (11,863 fetuses). The fetuses were from vehicle control or drug-treated pregnant rabbits in embryo-fetal development studies conducted to meet international regulatory requirements for the development of new drugs. RESULTS: Both methods detected the more common alterations (microphthalmia and dilated lateral cerebral ventricles) and other less common findings (changes in size and/or shape of eye and brain structures). CONCLUSIONS: While both methods are equally sensitive at detecting common and rare developmental defects, the modified mid-coronal sectioning technique eliminates the use of chemicals and concomitant fixation artifacts that occur with the Wilson's technique and allows for examination of 100% intact fetuses thereby increasing potential for detecting eye and brain alterations as these findings occur infrequently in rabbits. PMID- 25704051 TI - The fate of Amazonian ecosystems over the coming century arising from changes in climate, atmospheric CO2, and land use. AB - There is considerable interest in understanding the fate of the Amazon over the coming century in the face of climate change, rising atmospheric CO2 levels, ongoing land transformation, and changing fire regimes within the region. In this analysis, we explore the fate of Amazonian ecosystems under the combined impact of these four environmental forcings using three terrestrial biosphere models (ED2, IBIS, and JULES) forced by three bias-corrected IPCC AR4 climate projections (PCM1, CCSM3, and HadCM3) under two land-use change scenarios. We assess the relative roles of climate change, CO2 fertilization, land-use change, and fire in driving the projected changes in Amazonian biomass and forest extent. Our results indicate that the impacts of climate change are primarily determined by the direction and severity of projected changes in regional precipitation: under the driest climate projection, climate change alone is predicted to reduce Amazonian forest cover by an average of 14%. However, the models predict that CO2 fertilization will enhance vegetation productivity and alleviate climate-induced increases in plant water stress, and, as a result, sustain high biomass forests, even under the driest climate scenario. Land-use change and climate-driven changes in fire frequency are predicted to cause additional aboveground biomass loss and reductions in forest extent. The relative impact of land use and fire dynamics compared to climate and CO2 impacts varies considerably, depending on both the climate and land-use scenario, and on the terrestrial biosphere model used, highlighting the importance of improved quantitative understanding of all four factors - climate change, CO2 fertilization effects, fire, and land use - to the fate of the Amazon over the coming century. PMID- 25704052 TI - Family history of alcoholism and brain activation: commentary on "Increased forebrain activations in youths with family histories of alcohol and other substance use disorders performing a Go/No-Go task". PMID- 25704053 TI - Acute GVHD after allogeneic hematopoietic transplantation affects early marrow reconstitution and speed of engraftment. AB - Our aim was to study the influence of acute graft-versus-host disease (a-GVHD) on primary engraftment times after allogeneic transplantation. Primary engraftment and frequency of marrow granulocyte-macrophage colony-forming units and erythroid burst-forming units, at day +18, were studied in 126 allogeneic transplants. Patients were grouped according to the time when a-GVHD treatment with corticosteroids was started. The no-a-GVHD group are those who, during the first 3 months, had no need for a-GVHD treatment; the early-a-GVHD group are those who needed a-GVHD treatment within 19 days; and the postengraftment-a-GVHD group are those who were not on corticosteroid treatment at the time of engraftment but needed it after day +19. The no-a-GVHD group reached a neutrophil count (N) > 0.5 * 10(9)/L in a median of 17.8 days. The postengraftment-a-GVHD group reached N > 0.5 * 10(9)/L in a median of 21.4 days (p = 0.0003). The early-a-GVHD group had N > 0.5 * 10(9)/L in a median of +17.0 days (p = 0.23). When factors important for engraftment were studied in a multivariate analysis, postengraftment a-GVHD was a significant factor in delayed neutrophil and platelet engraftment. Both the early a-GVHD and postengraftment-a-GVHD groups showed a significant reduction in frequency of granulocyte-macrophage colony-forming units and erythroid burst forming units found in marrow at day +18. In conclusion, a-GVHD may influence early marrow reconstitution and is a relevant factor for primary myeloid and platelet engraftment. PMID- 25704054 TI - Comparison of the cytotoxicity of cladribine and clofarabine when combined with fludarabine and busulfan in AML cells: Enhancement of cytotoxicity with epigenetic modulators. AB - Clofarabine (Clo), fludarabine (Flu), and busulfan (Bu) combinations are efficacious in hematopoietic stem cell transplantation for myeloid leukemia. We sought to determine whether the more affordable drug cladribine (Clad) can provide a viable alternative to Clo, with or without panobinostat (Pano) and 5 aza-2'-deoxycytidine (DAC). Both Clad+Flu+Bu and Clo+Flu+Bu combinations showed synergistic cytotoxicity in KBM3/Bu250(6), HL60, and OCI-AML3 cell lines. Cell exposure to these drug combinations resulted in 60%-80% inhibition of proliferation; activation of the ATM pathway; increase in histone modifications; decrease in HDAC3, HDAC4, HDAC5 and SirT7 proteins; decrease in mitochondrial membrane potential; activation of apoptosis and stress signaling pathways; and downregulation of the AKT pathway. These drug combinations activated DNA-damage response and apoptosis in primary cell samples from AML patients. At lower concentrations of Clad/Clo, Flu, and Bu, inclusion of Pano and DAC enhanced cell killing, increased histone modifications and DNA demethylation, and increased the levels of P16/INK4a, P15/INK4b and P21/Waf1/Cip1 proteins. The observed DNA demethylating activity of Clad and Clo may complement DAC activity; increase demethylation of the gene promoters for SFRP1, DKK3, and WIF1; and cause degradation of beta-catenin in cells exposed to Clad/Clo+Flu+Bu+DAC+Pano. The overlapping activities of Clad/Clo+Flu+Bu, Pano, and DAC in DNA-damage formation and repair, histone modifications, DNA demethylation, and apoptosis may underlie their synergism. Our results provide a basis for supplanting Clo with Clad and for including epigenetic modifiers in the pre-hematopoietic stem cell transplantation conditioning regimen for myeloid leukemia patients. PMID- 25704055 TI - Prognostic utility of ischemic response in functional imaging tests (SPECT or stress echocardiography) in low-risk unstable angina patients. AB - BACKGROUND: The aim of this study is to determine the ability of ischemic response in imaging stress tests (single-photon emission computed tomography [SPECT] or stress echocardiography [SE]) to predict events in low-risk unstable angina patients. METHODS: Three hundred and fifty-nine patients with unstable angina (< 24 h), asymptomatic at admission, without ST-segment elevation or depression, normal troponins, and undergoing SPECT (n = 188) or SE (n = 171) during hospitalization (median = 1 day) were included. A positive imaging test (IMAGING+) was defined as the presence of reversible perfusion defects or wall motion abnormalities in at least 2 contiguous segments. Multivariate models were constructed using these results and clinical variables to predict events at 6 months. RESULTS: Ninety-nine (27%) patients had IMAGING+, 72/188 (38%) in SPECT and 27/17 (16%) in SE (p < 0.0001). Events occurred in 84 (23%) patients: 4 had myocardial infarction, 47 new hospitalizations due to angina and 33 coronary artery revascularizations. Independent predictors of coronary artery disease were: IMAGING+ (OR: 6.4, 95% CI: 3.4-11.8, p < 0.0001), history of coronary artery disease (OR: 2.5, 95% CI: 1.2-5.2, p < 0.02) and TIMI risk (OR: 1.5, 95% CI: 1.1-2.2, p < 0.03). CONCLUSIONS: In low-risk unstable angina patients, an ischemic response in functional stress tests (SPECT or SE) was associated with adverse events and severe coronary artery disease. PMID- 25704056 TI - Comparative study of reference currents and DC bus voltage control for Three Phase Four-Wire Four-Leg SAPF to compensate harmonics and reactive power with 3D SVM. AB - In this paper the performances of three reference currents and DC bus voltage control techniques for Three-Phase Four-Wire Four-Leg SAPF are compared for balanced and unbalanced load conditions. The main goals are to minimize the harmonics, reduce the magnitude of neutral current, eliminate the zero-sequence current components caused by single-phase nonlinear loads and compensate the reactive power, and on the other hand improve performances such as robustness, stabilization, trajectory pursuit, and reduce time response. The three techniques are analyzed mathematically and simulation results are compared. The techniques considered for comparative study are the PI Control, Sliding Mode Control and the Backstepping Control. Synchronous reference frame theory (SRF) in the dqo-axes is used to generate the reference currents, of the inverter. PMID- 25704057 TI - Model-free optimal controller design for continuous-time nonlinear systems by adaptive dynamic programming based on a precompensator. AB - In this paper, we consider the problem of developing a controller for continuous time nonlinear systems where the equations governing the system are unknown. Using the measurements, two new online schemes are presented for synthesizing a controller without building or assuming a model for the system, by two new implementation schemes based on adaptive dynamic programming (ADP). To circumvent the requirement of the prior knowledge for systems, a precompensator is introduced to construct an augmented system. The corresponding Hamilton-Jacobi Bellman (HJB) equation is solved by adaptive dynamic programming, which consists of the least-squared technique, neural network approximator and policy iteration (PI) algorithm. The main idea of our method is to sample the information of state, state derivative and input to update the weighs of neural network by least squared technique. The update process is implemented in the framework of PI. In this paper, two new implementation schemes are presented. Finally, several examples are given to illustrate the effectiveness of our schemes. PMID- 25704058 TI - Evidence-based practice beliefs and implementation before and after an initiative to promote evidence-based nursing in an ambulatory oncology setting. AB - BACKGROUND: The purpose of evidence-based practice (EBP) in nursing is to improve patient outcomes, providing the best and most up-to-date care practices. In 2011, a nurse-led committee convened to develop an institute-wide initiative to promote EBP with oncology nurses at the Dana-Farber Cancer Institute. AIMS: Compare and describe oncology nurse beliefs and perceived implementation of EBP and explore beliefs and implementation before and after implementing an institutional EBP initiative. METHODS: Based on the Advancing Research and Clinical practice through close Collaboration (ARCC) Model, the Evidence-Based Practice Beliefs (EBP-B) and Implementation (EBP-I) scales were distributed to all Dana-Farber Cancer Institute registered and advanced practice nurses through an online survey in 2011 (T1) and again in 2013 (T2) after the implementation of an institute-wide nursing EBP initiative (orientation, poster presentations, education). Descriptive and correlation statistics were completed on total scores and demographics. Differences in beliefs and implementation scores based on demographics were analyzed with Mann-Whitney U tests. Open-ended item responses at each time point (T) were summarized for EBP barriers and promoters. FINDINGS: Thirty-two percent (n = 112 at T1; n = 113 at T2) of 350 nurses began the survey. A history of formal EBP education and nurse role were associated with higher EBP B and EBP-I scores (p < .05). Highest level of education was significantly correlated with both EBP-B (r = .25; p = .03) and EBP-I (r = .32; p = .01). Narrative responses to open-ended questions described perceived personal and environmental barriers to engaging in EBP. LINKING EVIDENCE TO ACTION: Although no significant differences were noted in beliefs and implementation after the EBP initiative, nurses reported valuing EBP. Respondents acknowledged a lack of full preparation in the EBP process to engage in and implement EBP consistently. Nurse role, formal EBP education, and highest level of education were associated with perceptions of EBP beliefs and implementation. Nurses should be provided the mentorship and support to obtain continuing education about how to engage in EBP and about implementing EBP change. PMID- 25704059 TI - DLVO and XDLVO calculations for bacteriophage MS2 adhesion to iron oxide particles. AB - In this study, batch experiments were performed to examine the adhesion of bacteriophage MS2 to three iron oxide particles (IOP1, IOP2 and IOP3) with different particle properties. The characteristics of MS2 and iron oxides were analyzed using various techniques to construct the classical DLVO and XDLVO potential energy profiles between MS2 and iron oxides. X-ray diffractometry peaks indicated that IOP1 was mainly composed of maghemite (gamma-Fe2O3), but also contained some goethite (alpha-FeOOH). IOP2 was composed of hematite (alpha Fe2O3) and IOP3 was composed of iron (Fe), magnetite (Fe3O4) and iron oxide (FeO). Transmission electron microscope images showed that the primary particle size of IOP1 (gamma-Fe2O3) was 12.3+/-4.1nm. IOP2 and IOP3 had primary particle sizes of 167+/-35nm and 484+/-192nm, respectively. A surface angle analyzer demonstrated that water contact angles of IOP1, IOP2, IOP3 and MS2 were 44.83, 64.00, 34.33 and 33.00 degrees , respectively. A vibrating sample magnetometer showed that the magnetic saturations of IOP1, IOP2 and IOP3 were 176.87, 17.02 and 946.85kA/m, respectively. Surface potentials measured in artificial ground water (AGW; 0.075mM CaCl2, 0.082mM MgCl2, 0.051mM KCl, and 1.5mM NaHCO3; pH7.6) indicated that iron oxides and MS2 were negatively charged in AGW (IOP1=-0.0185V; IOP2=-0.0194V; IOP3=-0.0301V; MS2=-0.0245V). Batch experiments demonstrated that MS2 adhesion to iron oxides was favorable in the order of IOP1>IOP2>IOP3. This tendency was well predicted by the classical DLVO model. In the DLVO calculations, both the sphere-plate and sphere-sphere geometries predicted the same trend of MS2 adhesion to iron oxides. Additionally, noticeable differences were not found between the DLVO and XDLVO interaction energy profiles, indicating that hydrophobic interactions did not play a major role; electrostatic interactions, however, did influence MS2 adhesion to iron oxides. Furthermore, the aggregation of iron oxides was investigated with a modified XDLVO model. This model included magnetic interactions between the particles in order to predict the aggregation of iron oxides. Even though iron oxide particle aggregation could occur under experimental conditions, the DLVO model results using primary particle size were more suitable for the interactions between MS2 and the iron oxides because of fast sorption of MS2 onto the surfaces of iron oxides. PMID- 25704060 TI - Exophytic lymphoepithelial cyst of the pancreas. PMID- 25704061 TI - Surpassingly competitive electromagnetic field enhancement at the silica/silver interface for selective intracellular surface enhanced Raman scattering detection. AB - A thin plasmonic nanofilm is formed by preformed silver nanoparticles (30 nm) in the matrix of poly(vinyl alcohol) adsorbed on silica microparticles (1.5 MUm) (SiO2@Ag-PVA). By applying finite element method (FEM) analysis the surface enhanced Raman spectroscopy (SERS) enhancement factors (EFs) can reach 10(5) with higher values from 10(9) to 10(11) in the silver layer of 5 nm thickness. Nanoparticles in the SiO2@Ag-PVA nanofilm need at least 15 nm radius to exhibit SERS EFs greater than 10(7). High values of this enhancement at the silver/silica interface of spherical geometry can be reached faster by using a 532 nm compared to 785 nm excitation wavelength. By this approach different SERS spectral features can be distinguished between live fibroblasts with spread ("healthy" state) or round ("unhealthy" state) shapes. Characteristic features of secondary protein structures, detection of different acidic conditions and cholesterol with at least a 3-fold higher sensitivity are examined. Moreover, a greater amount of glucose (glucogen) and also tyrosine can be monitored in real time. This is important in identification of higher risk of diabetes as well as in several genetic metabolic disorders (e.g., phenylketonuria, tyrosinaemia type II and tyrosinosis). PMID- 25704062 TI - Role of the GP liaison nurse in a community health program to improve integration and coordination of services for the chronically ill. AB - This paper explores the role of the General Practitioner Liaison Nurse (GPLN) in improving integration and coordination of services within Primary Health Care. This position can play a major role in care coordination and cultural change. The GPLN within HealthOne Mt Druitt (HOMD) identifies patients' needs and facilitates communication, case conferencing and care coordination between health and other providers. The priority areas of children and their families at risk or with significant unmet needs, and chronic aged and complex care, were identified as target areas. This paper focuses on the GPLN within the chronic aged and complex care service model. The GPLN within HOMD was able to improve coordination and integration of services for patients of the facility. Activities included organising multidisciplinary services and addressing psychosocial issues. Patients and community health staff identified the importance of the role for improving coordination and integration of services. Decision and policy makers saw the position as vital to the implementation, operation and sustainability of HOMD. PMID- 25704063 TI - The new tuberculosis drug Perchlozone(r) shows cross-resistance with thiacetazone. AB - Perchlozone((r)) (PCZ), a new thiosemicarbazone developed by JSC Pharmasyntez (Moscow, Russia) for the treatment of tuberculosis (TB), was approved for use against multidrug-resistant disease in Russia in 2012. The mechanism of action of the drug is unknown. A well-studied thiosemicarbazone is the old TB drug thiacetazone (TAC). It has a narrow spectrum and inhibits the FASII dehydratase complex HadABC, which is involved in cell wall biosynthesis in Mycobacterium tuberculosis. TAC is a prodrug, requiring activation by the monooxygenase EthA. In this study, a comparative in vitro analysis of both drugs was performed. The two compounds had an identical spectrum of activity, spontaneous resistant mutants showed cross-resistance, and resistance was mapped to HadABC and EthA. These results suggest that PCZ, like TAC, is a prodrug and that both drugs share EthA as an activating enzyme and HadABC as their principal target. PMID- 25704064 TI - Experimental evolution in fluctuating environments: tolerance measurements at constant temperatures incorrectly predict the ability to tolerate fluctuating temperatures. AB - The ability to predict the consequences of fluctuating environments on species distribution and extinction often relies on determining the tolerances of species or genotypes in different constant environments (i.e. determining tolerance curves). However, very little is known about the suitability of measurements made in constant environments to predict the level of adaptation to rapidly fluctuating environments. To explore this question, we used bacterial clones adapted to constant or fluctuating temperatures and found that measurements across a range of constant temperatures did not indicate any adaptation to fluctuating temperatures. However, adaptation to fluctuating temperatures was only apparent if growth was measured during thermal fluctuation. Thus, tolerance curves based on measurements in constant environments can be misleading in predicting the ability to tolerate fast environmental fluctuations. Such complications could lead to false estimates of the genetic merits of genotypes and extinction risks of species due to climate change-induced thermal fluctuations. PMID- 25704065 TI - Prato and Bingel-Hirsch cycloaddition to heptagon-containing LaSc2N@C(s)(hept) C80: importance of pentalene units. AB - Possible cycloaddition sites in the heptagon-containing fullerene LaSc2N@Cs(hept) C80 are studied computationally. Thermodynamically controlled Prato addition is predicted to proceed regioselectively across the pentagon/pentagon (p/p) edges, whereas in the kinetically-controlled Bingel-Hirsch reaction the most reactive are carbons next to the p/p edge. PMID- 25704066 TI - Prediction of care burden of patients undergoing haemodialysis: development of a measuring tool. AB - BACKGROUND: The ageing of the population and new options for therapy have led to an increase in the number of patients undergoing dialysis. Rising costs in health care and new financial structures impose funding constraints on dialysis departments and force the departments to deploy nurses more efficiently. Therefore, predicting the nursing time spent on the care of patients is important. OBJECTIVE: Development of a classification tool to predict the burden of nursing care of patients undergoing dialysis. DESIGN: Observational study. PARTICIPANTS: 242 patients on dialysis in 12 centres. MEASUREMENTS: The time spent on nursing care within predefined areas, including patient independence, vascular access, psychosocial support, dialysis complexity, communication and specific nursing actions, was measured by observers. Average times and their standard deviations (SD) were calculated. Variation of patient characteristics was analysed. RESULTS: The average care time required for the four routine investigated domains, namely independence, vascular access, psychosocial support and dialysis complexity, was 59.23 (SD = 24.30) minutes per treatment per patient. CONCLUSION: Our study shows that it is possible to predict the burden of nursing care of patients undergoing dialysis by means of a classification model. PMID- 25704067 TI - Cost-effectiveness of "full spectrum endoscopy" colonoscopy for colorectal cancer screening. AB - BACKGROUND: Compared to standard forward viewing colonoscopy, we aimed to assess the cost-effectiveness of full spectrum endoscopy colonoscopy in a population based colorectal cancer screening and surveillance program. METHODS: A Markov model was constructed to simulate the occurrence of colorectal neoplasia in a cohort of 100,000 subjects aged 50-100 years. The cost-effectiveness of full spectrum endoscopy was compared with that of standard forwarding viewing colonoscopy. Sensitivity for adenomatous and hyperplastic polyps <5mm, 6-9mm, and high-risk polyps were derived from the recent randomized tandem Fuse colonoscopy study. RESULTS: The significantly higher sensitivity of full spectrum endoscopy in detecting additional adenomas resulted in an increase in cancer prevention from 58% to 74%, corresponding to a gain of 9 days per person. This 14% increase led to an absolute reduction in the cost of cancer care from $90 million to $57 million. This cost savings was only minimally impacted by the higher cost of more frequent post-polypectomy colonoscopy surveillance rates, leading to full spectrum endoscopy being associated with a savings of $145 per person. Thus, standard colonoscopy appeared to be "dominated" by the full spectrum endoscopy. CONCLUSIONS: Compared to standard colonoscopy, full spectrum endoscopy appears to be more cost-effective for colon cancer screening and surveillance. PMID- 25704068 TI - Natural history of pancreatic involvement in paediatric inflammatory bowel disease. AB - BACKGROUND: Few case reports describe the clinical features of pancreatic involvement in inflammatory bowel disease. AIM: To investigate prevalence and disease course of inflammatory bowel disease children with pancreatitis and with exclusive hyperamylasemia and hyperlipasemia. METHODS: We used a web-registry to retrospectively identify paediatric inflammatory bowel disease patients with hyperamylasemia and hyperlipasemia. Participants were re-evaluated at 6 months and 1 year. RESULTS: From a total of 649 paediatric patients, we found 27 with hyperamylasemia and hyperlipasemia (4.1%). Eleven patients (1.6%) fulfilled diagnostic criteria for acute pancreatitis. Female gender was significantly associated with acute pancreatitis (p=0.04). Twenty-five children (92.5%) had colonic disease. At 6 months 1/11 children with acute pancreatitis (9%) showed acute recurrent pancreatitis, while 1 patient (9%) had persistent hyperamylasemia and hyperlipasemia. At 12 months, 1 patient showed chronic pancreatitis (9.1%). Of the 16 children with exclusive hyperamylasemia and hyperlipasemia, 4 developed acute pancreatitis (25%), while 1 patient (6.2%) still presented exclusive hyperamylasemia and hyperlipasemia at 6 months. At 12 months, 11/16 patients (68.7%) reached a remission of pancreatic involvement, whereas 5 remaining patients (32.3%) had persistent hyperamylasemia and hyperlipasemia. CONCLUSIONS: In inflammatory bowel disease children, acute pancreatitis is more common in colonic disease and in female gender. Pancreatic function should be monitored, considering that pancreatic damage may evolve. PMID- 25704069 TI - Pyoderma gangrenosum in association with microscopic colitis, idiopathic hypereosinophilic syndrome, selective IgE deficiency and diabetes mellitus. AB - Pyoderma gangrenosum (PG) is a neutrophilic dermatosis of unknown aetiology. We report a 27-year-old male patient with diabetes, who presented with a nonhealing ulcer on the left leg, pruritic hyperpigmented papules distributed over the trunk and limbs, and chronic diarrhoea. He had eosinophilia, low haemoglobin and serum IgE levels, and raised erythrocyte sedimentation rate. Histopathology of the leg ulcer was consistent with the diagnosis of PG, while the histology of the hyperpigmented papule revealed tissue eosinophilia. Subsequent evaluation was conclusive of the diagnosis of PG, idiopathic hypereosinophilic syndrome (IHES) and selective IgE deficiency. Dexamethasone pulse therapy achieved resolution of the ulcer and reduction in the eosinophilia. Further evaluation for the persistent diarrhoea led to a diagnosis of lymphocytic colitis (LC), which responded to budesonide. To our knowledge, the association of PG with IHES, selective IgE deficiency or LC has not been previously reported. PMID- 25704070 TI - Current outcomes of the bi-directional cavopulmonary anastomosis in single ventricle patients: analysis of risk factors for morbidity and mortality, and suitability for Fontan completion. AB - OBJECTIVES: The bi-directional cavopulmonary anastomosis forms an essential staging procedure for univentricular hearts. This review aims to identify risk factors for morbidity, mortality, and suitability for Fontan completion. METHODS: A total of 114 patients undergoing cavopulmonary anastomosis between 1992 and 2012 were reviewed to assess primary - mortality and survival to Fontan completion - and secondary outcome endpoints - re-intubation, new drain, and ICU stay. Median age and weight were 8 months and 6.9 kg, respectively. In 83% of patients, 1-3 interventions had preceded. Norwood-type procedures became more prevalent over time. RESULTS: Extubation occurred after a median of 4 hours, median ICU stay was 2 days; 10 patients (8.8%) needed re-intubation and 18 received a new drain. Higher central venous pressure and transpulmonary gradient were risk factors for new drain insertion (p<0.01). Higher pre-operative pulmonary pressure correlated with increased inotropic support and prolonged intubation (p=0.01). Need for re-intubation was significantly affected by younger age at operation (p=0.01). Hospital and pre-Fontan mortality were 11.4 and 5.3%, respectively. Operative mortality was independently affected by younger age (p=0.013), lower weight (p=0.02), longer bypass time (p=0.04), and re-intubation (p=0.004). Interstage mortality was mainly influenced by moderate ventricular function (p=0.03); 82% of survivors underwent or are candidates for Fontan completion. CONCLUSION: The cavopulmonary anastomosis remains associated with adverse outcomes. Age at operation decreases with rising prevalence of complex univentricular hearts. Considering the important impact of re-intubation on hospital mortality, peri-operative management should focus on optimising cardio respiratory status. Once this selection step is taken, successful Fontan completion can be expected, provided that ventricular function is maintained. PMID- 25704071 TI - Commentary on "Caged Phosphate and the Slips and Misses in Determination of Quantum Yields for Ultraviolet-A-Induced Photouncaging" by G. Gasser and Co Workers. PMID- 25704072 TI - Determinants of efficacy and safety in epicutaneous allergen immunotherapy: summary of three clinical trials. AB - The results of our third trial on epicutaneous allergen-specific immunotherapy (EPIT) will be presented and discussed in the context of our previous trials. This monocentric, placebo-controlled, double-blind phase I/IIa trial included 98 patients with grass pollen rhinoconjunctivitis. Prior to the pollen season 2009, patients received six patches (allergen extract: n = 48; placebo: n = 50) with weekly intervals, administered onto tape-stripped skin. Allergen EPIT produced a median symptom improvement of 48% in 2009 and 40% in the treatment-free follow-up year 2010 as compared to 10% and 15% improvement after placebo EPIT (P = 0.003). After allergen EPIT but not placebo EPIT, conjunctival allergen reactivity was significantly decreased and allergen-specific IgG4 responses were significantly elevated (P < 0.001). In conclusion, our three EPIT trials found that allergen EPIT can ameliorate hay fever symptoms. Overall, treatment efficacy appears to be determined by the allergen dose. Local side-effects are determined by the duration of patch administration, while risk of systemic allergic side-effects is related to the degree of stratum corneum disruption. PMID- 25704073 TI - Neural bases of prospective memory: a meta-analysis and the "Attention to Delayed Intention" (AtoDI) model. AB - Remembering to realize delayed intentions is a multi-phase process, labelled as prospective memory (PM), and involves a plurality of neural networks. The present study utilized the activation likelihood estimation method of meta-analysis to provide a complete overview of the brain regions that are consistently activated in each PM phase. We formulated the 'Attention to Delayed Intention' (AtoDI) model to explain the neural dissociation found between intention maintenance and retrieval phases. The dorsal frontoparietal network is involved mainly in the maintenance phase and seems to mediate the strategic monitoring processes, such as the allocation of top-down attention both towards external stimuli, to monitor for the occurrence of the PM cues, and to internal memory contents, to maintain the intention active in memory. The ventral frontoparietal network is recruited in the retrieval phase and might subserve the bottom-up attention captured externally by the PM cues and, internally, by the intention stored in memory. Together with other brain regions (i.e., insula and posterior cingulate cortex), the ventral frontoparietal network would support the spontaneous retrieval processes. The functional contribution of the anterior prefrontal cortex is discussed extensively for each PM phase. PMID- 25704074 TI - Convergent evidence for mGluR5 in synaptic and neuroinflammatory pathways implicated in ASD. AB - The pathogenesis of Autism Spectrum Disorder (ASD), a serious neurodevelopmental disorder, is poorly understood. We review evidence for alterations in glutamatergic signalling in the aetiology of ASD, with a focus on the metabotropic glutamate receptor-5 (mGluR5). mGluR5 signalling is important for synapse formation, neuroplasticity and long term potentiation as well as neuroprotection and has been shown to have a regulatory role in neuroinflammation. Evidence for neuroinflammation in ASD is supported by increase in pro-inflammatory cytokines in the blood and cerebrospinal fluid (CSF) and increased number and activation of microglia in postmortem dorsolateral prefrontal cortex (DLPFC). mGlur5 signalling has also been shown to downregulate microglial activation. Therefore, we focus on mGluR5 as a potential unifying explanation for synapse alteration and neuroinflammation seen in ASD. Data from mGluR5 knockout mouse models, and syndromic and non syndromic forms of ASD are discussed in relation to how alterations in mGluR5 are associated with ASD symptoms. This review supports altered mGluR5 functioning as a convergent point in ASD pathogenesis and indicates more research is warranted into mGluR5 as a potential therapeutic target. PMID- 25704075 TI - Force control in chronic stroke. AB - Force control deficits are common dysfunctions after a stroke. This review concentrates on various force control variables associated with motor impairments and suggests new approaches to quantifying force control production and modulation. Moreover, related neurophysiological mechanisms were addressed to determine variables that affect force control capabilities. Typically, post stroke force control impairments include: (a) decreased force magnitude and asymmetrical forces between hands, (b) higher task error, (c) greater force variability, (d) increased force regularity, and (e) greater time-lag between muscular forces. Recent advances in force control analyses post stroke indicated less bimanual motor synergies and impaired low-force frequency structure. Brain imaging studies demonstrate possible neurophysiological mechanisms underlying force control impairments: (a) decreased activation in motor areas of the ipsilesional hemisphere, (b) increased activation in secondary motor areas between hemispheres, (c) cerebellum involvement, and (d) relatively greater interhemispheric inhibition from the contralesional hemisphere. Consistent with identifying neurophysiological mechanisms, analyzing bimanual motor synergies as well as low-force frequency structure will advance our understanding of post stroke force control. PMID- 25704076 TI - Organoaluminum-mediated direct cross-coupling reactions. AB - We present a direct cross-coupling reaction between arylaluminum compounds (ArAlMe2 ?LiCl) and organic halides RX (R=aryl, alkenyl, alkynyl; X=I, Br, and Cl) without any external catalyst. The reaction takes place smoothly, simply upon heating, thereby enabling the efficient and chemo-/stereoselective formation of biaryl, alkene, and alkyne coupling products with broad functional group compatibility. PMID- 25704077 TI - Activating transcription factor 5 is required for mouse olfactory bulb development via interneuron. AB - Activating transcription factor 5 (ATF5) is a stress response transcription factor of the cAMP-responsive element-binding/ATF family. Earlier, we reported that ATF5 expression is up-regulated in response to stress, such as amino acid limitation or arsenite exposure. Although ATF5 is widely expressed in the brain and the olfactory epithelium, the role of ATF5 is not fully understood. Here, the olfactory bulbs (OBs) of ATF5-deficient mice are smaller than those of wild-type mice. Histological analysis reveals the disturbed laminar structure of the OB, showing the thinner olfactory nerve layer, and a reduced number of interneurons. This is mainly due to the reduced number of bromodeoxyuridine-positive proliferating cells in the subventricular zone, where the interneuron progenitors are formed and migrate to the OBs. Moreover, the olfaction-related aggressive behavior of ATF5-deficient mice is reduced compared to wild-type mice. Our data suggest that ATF5 plays a crucial role in mouse OB development via interneuron. PMID- 25704078 TI - Immunohistochemical Expressions of MUC2, MUC5AC, and MUC6 in Normal, Helicobacter pylori Infected and Metaplastic Gastric Mucosa of Children and Adolescents. AB - OBJECTIVES: The aim of this study was to investigate expression of gastric mucins in children and adolescents and to assess their relations with age and Helicobacter pylori (H. pylori) infection. METHODS: Gastric biopsies were collected from 259 pediatric and adulthood patients with gastrointestinal symptoms among all of patients undergone gastroduodenoscopy from 1990 to 2004 at Gyeongsang National University hospital and assorted based on H. pylori infection, age, and intestinal metaplasia as follows; H. pylori infection before 5 years of age or not, H. pylori infection between 5 and 9 years of age or not, H. pylori infection between 10 and 14 years of age or not, H. pylori infection between 20 and 29 years of age or not and intestinal metaplasia between 21 and 35 years of age. Total 810 tissue slides from the subjects were examined regarding expressions of Mucin2 (MUC2), Mucin5AC (MUC5AC), and Mucin6 (MUC6) in nine groups using immunohistochemical stains. A semiquantitative approach was used to score the staining extent of tissue slide. RESULTS: Increased expressions of MUC2, MUC5AC, and MUC6 were noted in intestinal metaplasia compared with subjects infected with H. pylori between 20 and 29 years. Gastric expressions of MUC5AC were decreased in older than 5 years with H. pylori compared with in older than 5 years without H. pylori (p < .001). Expressions of MUC2 and MUC6 did not change significantly by H. pylori status. Some nuclear expressions of MUC2 and MUC6 were noted in children without intestinal metaplasia. CONCLUSIONS: MUC5AC might be affected by chronic H. pylori infection. In addition to biomarkers for intestinal metaplasia or prognostic factors for gastric cancer in adults, MUC2 and MUC6 in children might have an another role, based on ectopic gastric nuclear expressions of MUC2 and MUC6 in children without intestinal metaplasia. PMID- 25704079 TI - Epstein-Barr virus infection induces miR-21 in terminally differentiated malignant B cells. AB - The association of Epstein-Barr virus (EBV) with plasmacytoid malignancies is now well established but how the virus influences microRNA expression in such cells is not known. We have used multiple myeloma (MM) cell lines to address this issue and find that an oncomiR, miR-21 is induced after in vitro EBV infection. The PU.1 binding site in miR-21 promoter was essential for its activation by the virus. In accordance with its noted oncogenic functions, miR-21 induction in EBV infected MM cells caused downregulation of p21 and an increase in cyclin D3 expression. EBV infected MM cells were highly tumorigenic in SCID mice. Given the importance of miR-21 in plasmacytoid malignancies, our findings that EBV could further exacerbate the disease by inducing miR-21 has interesting implications both in terms of diagnosis and future miR based therapeutical approaches for the virus associated plasmacytoid tumors. PMID- 25704080 TI - Enhancement of immobilized lipase activity by design of polymer brushes on a hollow fiber membrane. AB - A polymer brush possessing aminoethanol (AE) functional groups for lipase immobilization was grafted onto a hollow fiber membrane by radiation-induced graft polymerization. Almost the AE groups-grafted polymer brushes unfold through positive charge repulsion between the AE groups, enabling multi-layer immobilization of lipase. The hydroxyl groups in AE can also retain water molecules around hydrophilic part of the lipase. In this study, we controlled the length and density of the polymer brushes consisting of the glycidyl methacrylate (GMA) by changing the concentration of GMA monomer during radiation-induced graft polymerization. Immobilized lipase showed the highest activity on the grafted membrane when 5 wt% of glycidyl methacrylate as monomer for the radiation-induced graft polymerization was used. Consequently high efficiency esterification (approximately 1600 mmol/h/g-membrane) was achieved in five-layer lipase on AE polymer brush than that in monolayer lipase on the polymer brush possessing only hydroxyl groups. Moreover, the polymer brush possessing AE functional groups for lipase immobilization maintained high activity on the reuse for several times. PMID- 25704081 TI - Sibling differences in low birth weight, dopaminergic polymorphisms, and ADHD symptomatology: evidence of GxE. AB - Low birth weight has been found to increase the risk of attention-deficit hyperactivity disorder (ADHD) in children. However, few studies adequately control for shared environmental influences (e.g., concentrated disadvantage, family structure) or examine whether interactions between birth weight and genetic factors predict ADHD. The present study addresses these limitations in prior research by examining a) whether sibling differences in low birth weight status are significantly predictive of sibling differences in behaviors symptomatic of ADHD and b) whether sibling differences in dopaminergic genes interact with sibling differences in low birth weight status to predict sibling differences in ADHD symptomatology. The results suggest that low birth weight siblings are at significantly greater risk of exhibiting symptoms of ADHD during childhood relative to their normal birth weight siblings. Moreover, possessing greater genetic risk on three dopaminergic genes (DAT1, DRD2, and DRD4) relative to a sibling appears to exacerbate the link between sibling differences in birth weight and sibling differences in ADHD symptomatology. Limitations and directions for future research are discussed. PMID- 25704082 TI - Ezetimibe stimulates intestinal glucagon-like peptide 1 secretion via the MEK/ERK pathway rather than dipeptidyl peptidase 4 inhibition. AB - OBJECTIVE: Ezetimibe is known as a Niemann-Pick C1-Like 1 (NPC1L1) inhibitor and has been used as an agent for hypercholesterolemia. In our previous study, ezetimibe administration improved glycemic control and increased glucagon like peptide-1 (GLP-1), an incretin hormone with anti-diabetic properties. However, the mechanisms by which ezetimibe stimulates GLP-1 secretion are not fully understood. Thus, the specific aim of this study was to investigate the mechanism(s) by which ezetimibe stimulates GLP-1 secretion. MATERIALS/METHODS: Male KK/H1J mice were divided into following groups: AIN-93G (NC), NC with ezetimibe (10 mg/kg/day), 45% high fat (HF) diet, and HF diet with ezetimibe. To investigate the role of ezetimibe in glucose homeostasis and GLP-1 secretion, an insulin tolerance test was performed and serum and intestinal GLP-1 levels and intestinal mRNA expression involved in GLP-1 synthesis were measured after 6 weeks of ezetimibe treatment. In vivo and in vitro dipeptidyl peptidase-4 (DPP-4) inhibition assays were employed to demonstrate the association between ezetimibe induced GLP-1 change and DPP-4. The molecular mechanism by which ezetimibe affects GLP-1 secretion was evaluated by using human enteroendocrine NCI-H716 cells. RESULTS: Ezetimibe supplementation significantly ameliorated HF-increased glucose and insulin resistance in the type 2 diabetic KK/H1J mouse model. Serum and intestinal active GLP-1 levels were significantly increased by ezetimibe in HF-fed animals. However, mRNA expression of genes involved in intestinal GLP-1 synthesis was not altered. Furthermore, ezetimibe did not inhibit the activity of either in vivo or in vitro dipeptidyl peptidase-4 (DPP-4). The direct effects of ezetimibe on GLP-1 secretion and L cell secretory mechanisms were examined in human NCI-H716 intestinal cells. Ezetimibe significantly stimulated active GLP-1 secretion, which was accompanied by the activation of mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK)/extracellular signal regulated kinase (ERK). Ezetimibe-increased GLP-1 secretion was abrogated by inhibiting the MEK/ERK pathway with PD98059. CONCLUSION: These findings suggest a possible novel biological role of ezetimibe in glycemic control to stimulate intestinal GLP-1 secretion via the MEK/ERK signaling pathway. PMID- 25704083 TI - Non-adherence in children with asthma reviewed: The need for improvement of asthma care and medical education. AB - Adherence to daily inhaled corticosteroid therapy is a key determinant of asthma control. Therefore, improving adherence to inhaled corticosteroids is the most effective method through which healthcare providers can help children with uncontrolled asthma. However, identifying non-adherent patients is difficult, and electronic monitoring is the only reliable method to assess adherence. (Non )adherence is a complex behavioural process influenced by many interacting factors. Intentional barriers to adherence are common; driven by illness perceptions and medication beliefs, patients and parents deliberately choose not to follow the doctor's recommendations. Common non-intentional barriers are related to family routines, child-raising issues, and to social issues such as poverty. Effective interventions improving adherence are complex, because they take intentional and non-intentional barriers to adherence into account. There is evidence that comprehensive, guideline-based asthma self-management programmes can be successful, with excellent adherence and good asthma control. Patient centred care focused on healthcare provider-patient/parent collaboration is the key factor determining the success of guided self-management programmes. Such care should focus on shared decision-making as this has been shown to improve adherence and healthcare outcomes. Current asthma care falls short because many physicians fail to adhere to asthma guidelines in their diagnostic approach and therapeutic prescriptions, and because of the lack of application of patient centred health care. Increased awareness of the importance of patient-centred communication and increased training in patient-centred communication skills of undergraduates and experienced attending physicians are needed to improve adherence to daily controller therapy and asthma control in children with asthma. PMID- 25704084 TI - Effects of ovariohysterectomy on oxidative stress markers in female dogs. AB - Numerous studies reported an increase of oxidative stress increases in both women and female laboratory animals after ovariectomy. However, there is little information about the evaluation of antioxidative/oxidative status in ovariectomized dogs. The purpose of this study was to examine the changes in oxidative stress markers after ovariohysterectomy (OHE) in female dogs. The study included eighteen healthy mongrel female dogs. Blood samples were collected immediately before surgery and 14 and 30 days after surgery. Following parameters of oxidative stress intensity were determined: the erythrocyte activity of glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) as well as the plasma concentrations of thiobarbituric acid reactive substances (TBARS), radical cations of N,N, diethylpara-phenylene diamine (RC-DEPPD), sulfhydryl groups (SH groups), bityrosine and formylkynurenine. The activity of GSH-Px increased markedly, although not significantly, 14 days after OHE and then significantly decreased at 30 days after OHE. A significant increase in plasma TBARS, bityrosine and formylkynurenine concentrations and a decrease in SH group content were concurrently noted at 30 days after surgery. Acquired results suggested that a loss of control over ROS production occurred in female dogs after OHE, which could lead to oxidative stress in the late post-operative period. In conclusion, our findings indicated that OHE is related with the risk of oxidative stress in the late period after operations. Given that oxidative stress contributes to the pathogenesis of various diseases, this may suggest an increased risk of disorders in ovariectomized female dogs; however, further studies are necessary to confirm this hypothesis. PMID- 25704085 TI - Age-related alteration of expression and function of TLRs and NK activity in oral candidiasis. AB - OBJECTIVE: Roles of aging or immune responses mediated by Toll-like receptors and natural killer cell in the onset or progression of human candidiasis remain unclear. This study was designed to elucidate the roles using peripheral blood mononuclear cells from healthy donors and patients with oral candidiasis. SUBJECTS AND METHODS: Subjects tested were healthy volunteers and patients who visited Dental Clinical Division of Hokkaido University Hospital. The patients with oral candidiasis included 39 individuals (25-89 years of age) with major complaints on pain in oral mucosa and/or dysgeusia. Healthy volunteers include students (25-35 years of age) and teaching staffs (50-65 years of age) of Hokkaido University Graduate School of Dental Medicine. RESULTS: Functions of Toll-like receptors 2 and 4 were downregulated significantly and the natural killer activity was slightly, but not significantly downregulated in aged healthy volunteers compared with healthy young volunteers. Functions of Toll-like receptors 2 and 4 and the natural killer activity were significantly downregulated in patients with oral candidiasis compared with healthy volunteers. CONCLUSION: Downregulation of functions of Toll-like receptors 2 and 4 as well as natural killer activity is suggested to be associated with the onset or progression of oral candidiasis in human. PMID- 25704086 TI - Identification and characterization of human xylosyltransferase II promoter single nucleotide variants. AB - The human isoenzymes xylosyltransferase-I and -II (XT-I, XT-II) catalyze the rate limiting step in proteoglycan biosynthesis. Therefore, serum XT activity, mainly representing XT-II activity, displays a powerful biomarker to quantify the actual proteoglycan synthesis rate. Serum XT activity is increased up to 44% in disorders which are characterized by an altered proteoglycan metabolism, whereby underlying regulatory mechanisms remain unclear. The aim of this study was to investigate new regulatory pathways by identifying and characterizing naturally occurring XYLT2 promoter sequence variants as well as their potential influence on promoter activity and serum XT activity. XYLT2 promoter single nucleotide variants (SNVs) were identified and genotyped in the genomic DNA of 100 healthy blood donors by promoter amplification and sequencing or restriction fragment length polymorphism analysis. The SNVs were characterized by an in silico analysis considering genetic linkage and transcription factor binding sites (TBSs). The influence of SNVs on promoter activity and serum XT activity was determined by dual luciferase reporter assay and HPLC-ESI mass spectrometry. Allele frequencies of seven XYLT2 promoter sequence variants identified were investigated. In silico analyses revealed a strong genetic linkage of SNVs c. 80delG and c.-188G > A, c.-80delG and c.-1443G > A, as well as c.-188G > A and c. 1443G > A. However, despite the generation of several SNV-associated changes in TBSs in silico, XYLT2 promoter SNVs did not significantly affect promoter activity. Serum XT activities of SNV carriers deviated up to 8% from the wild type, whereby the differences were also not statistically significant. This is the first study which identifies, genotypes and characterizes XYLT2 promoter SNVs. Our results reveal a weak genetic heterogeneity and a strong conservation of the human XYLT2 promoter region. Since the SNVs detected could be excluded as causatives for strong interindividual variabilities in serum XT activity, our data provide increasing evidence that XT-II activity is obviously regulated by hitherto unknown complex genetic pathways, such as cis- or trans-acting enhancers, silencers or miRNAs. PMID- 25704087 TI - Metabolism and cytotoxic effects of phosphatidylcholine hydroperoxide in human hepatoma HepG2 cells. AB - In this study, we investigated cellular uptake and metabolism of phosphatidylcholine hydroperoxide (PCOOH) in human hepatoma HepG2 cells by high performance liquid chromatography-tandem mass spectrometry, and then evaluated whether PCOOH or its metabolites cause pathophysiological effects such as cytotoxicity and apoptosis. Although we found that most PCOOH was reduced to PC hydroxide in HepG2 cells, the remaining PCOOH caused cytotoxic effects that may be mediated through an unusual apoptosis pathway. These results will enhance our fundamental understanding of how PCOOH, which is present in oxidized low density lipoproteins, is involved in the development of atherosclerosis. PMID- 25704088 TI - Rhamnazin, a novel inhibitor of VEGFR2 signaling with potent antiangiogenic activity and antitumor efficacy. AB - Anti-angiogenesis targeting vascular endothelial growth factor receptor 2 (VEGFR2) has emerged as an important tool for cancer therapy. The identification of new drugs from natural products has a long and successful history. In this study, we described a novel VEGFR2 inhibitor, rhamnazin, which inhibits tumor angiogenesis and growth. Rhamnazin significantly inhibited proliferation, migration and tube formation of human umbilical vascular endothelial cells (HUVECs) in vitro as well as inhibited sprouts formation of rat aorta ring. In addition, it inhibited vascular endothelial growth factor (VEGF)-induced phosphorylation of VEGFR2 and its downstream signaling regulator in HUVECs. Moreover, rhamnazin could directly inhibit proliferation of breast cancer cells MDA-MB-231 in vitro and in vivo. Oral administration of rhamnazin at a dose of 200 mg/kg/day could markedly inhibited human tumor xenograft growth and decreased microvessel densities (MVD) in tumor sections. Taken together, these preclinical evaluations suggest that rhamnazin inhibits angiogenesis and may be a promising anticancer drug candidate. PMID- 25704089 TI - The JAK2 inhibitor AZD1480 inhibits hepatitis A virus replication in Huh7 cells. AB - The JAK2 inhibitor AZD1480 has been reported to inhibit La protein expression. We previously demonstrated that the inhibition of La expression could inhibit hepatitis A virus (HAV) internal ribosomal entry-site (IRES)-mediated translation and HAV replication in vitro. In this study, we analyzed the effects of AZD1480 on HAV IRES-mediated translation and replication. HAV IRES-mediated translation in COS7-HAV-IRES cells was inhibited by 0.1-1 MUM AZD1480, a dosage that did not affect cell viability. Results showed a significant reduction in intracellular HAV HA11-1299 genotype IIIA RNA levels in Huh7 cells treated with AZD1480. Furthermore, AZD1480 inhibited the expression of phosphorylated-(Tyr-705)-signal transducer and activator of transcription 3 (STAT3) and La in Huh7 cells. Therefore, we propose that AZD1480 can inhibit HAV IRES activity and HAV replication through the inhibition of the La protein. PMID- 25704090 TI - HIV-1 Vpr suppresses the cytomegalovirus promoter in a CRL4(DCAF1) E3 ligase independent manner. AB - Although the Vpr protein of human immunodeficiency virus type 1 (HIV-1) has been shown to act as a transcriptional activator of the HIV-1 LTR and certain host genes, the current study demonstrates that it can also function as a potent inhibitor of the cytomegalovirus (CMV) promoter. Previous studies have shown that the cell cycle arrest and apoptotic functions of Vpr required recruitment of the CRL4(DCAF1) E3 ligase, but this complex is shown not to be required for inhibition of the CMV promoter. We identified conserved sites (A30/V31) from diverse Vpr from HIV/SIV that were critical for blocking the CMV promoter activity. Interestingly, the Vpr mutant A30S/V31S protein also impaired the ability of Vpr to down-regulate transcription of the host UNG2 gene. Our findings shed light on the dual functions of Vpr on the transcription of HIV-1, other viruses and host genes which may contribute to viral replication and disease progression in vivo. PMID- 25704091 TI - Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist inhibits collagen synthesis in human hypertrophic scar fibroblasts by targeting Smad3 via miR-145. AB - The transcription factor peroxisome proliferator-activated receptor-gamma (PPAR gamma) functions to regulate cell differentiation and lipid metabolism. Recently, its agonist has been documented to regulate extracellular matrix production in human dermal fibroblasts. This study explored the underlying molecular mechanisms and gene interactions in hypertrophic scar fibroblasts (HSFBs) in vitro. HSFBs were cultured and treated with or without PPAR-gamma agonist or antagonist for gene expression. Bioinformatical analysis predicted that miR-145 could target Smad3 expression. Luciferase assay was used to confirm such an interaction. The data showed that PPAR-gamma agonist troglitazone suppressed expression of Smad3 and Col1 in HSFBs. PPAR-gamma agonist induced miR-145 at the gene transcriptional level, which in turn inhibited Smad3 expression and Col1 level in HSFBs. Furthermore, ELISA data showed that Col1 level in HSFBs was controlled by a feedback regulation mechanism involved in PPAR-gamma agonist and antagonist regulated expression of miR-145 and Smad3 in HSFBs. These findings indicate that PPAR-gamma-miR-145-Smad3 axis plays a role in regulation of collagen synthesis in HSFBs. PMID- 25704092 TI - RuO2-ReO3 composite nanofibers for efficient electrocatalytic responses. AB - We present a facile synthetic route to ruthenium dioxide (RuO2)-rhenium oxide (ReO3) electrospun composite nanofibers and their electrocatalytic responses for capacitance and H2O2 sensing. The contents of rhenium oxide of electrospun ruthenium dioxide (RuO2) were carefully controlled by an electrospinning process with the preparation of the precursor solutions followed by the thermal annealing process in air. The electrochemical applications of RuO2-ReO3 electrospun composite nanofibers were then investigated by modifying these materials on the surface of glassy carbon (GC) electrodes, RuO2-ReO3(n)/GC (n = 0.0, 0.07, 0.11, and 0.13), where n denotes the relative atomic ratio of Re to the sum of Ru and Re. Specific capacitance and H2O2 reduction sensitivity were remarkably enhanced depending on the amount of ReO3 increased. Among the four compositions of RuO2 ReO3(n), RuO2-ReO3(0.11)/GC showed the highest performances, i.e., a 20.9-fold higher specific capacitance (205 F g(-1) at a potential scan rate (v) of 10 mV s( 1); a capacity loss of 19% from v = 10 to 2000 mV s(-1)) and a 7.6-fold higher H2O2 reduction sensitivity (668 MUA mM(-1) cm(-2), normalized by GC disk area), respectively, compared to only RuO2/GC. PMID- 25704093 TI - In Situ Electrochemical Synthesis and Deposition of Discotic Hexa-peri hexabenzocoronene Molecules on Electrodes: Self-Assembled Structure, Redox Properties, and Application for Supercapacitor. AB - Discotic hexa-peri-hexabenzocoronene (HBC) molecules are synthesized by electrochemical cyclodehydrogenation reaction and in situ self-assembled to pi electronic, discrete nanofibular objects with an average diameter about 70 nm, which are deposited directly onto the electrode. The nanofibers consist of columnar arrays of the pi-stacked HBC molecules and the intercolumnar distance is determined to be 1.19 nm by X-ray diffraction, which corresponds well to the distance of 1.1 nm observed by high-resolution transmitting electron microscopy. The diameter of the molecular columns matches the size of the discotic HBC molecule indicating face-to-face pi-stacking of HBC units in the column. The HBC nanofibers on electrode are redox active, and the nanosized columnar structures provide a huge surface area, which is a great benefit for the charging/discharging process, delivering excellent capacitance of 155 F g(-1) . The described electrochemical deposition method shows great advantage for self assembling the family of insoluble and structurally designable graphene-like nano materials, which constitutes an important step toward molecular electronics. PMID- 25704095 TI - Algal biofuels from urban wastewaters: maximizing biomass yield using nutrients recycled from hydrothermal processing of biomass. AB - Recent studies have proposed algal cultivation in urban wastewaters for the dual purpose of waste treatment and bioenergy production from the resulting biomass. This study proposes an enhancement to this approach that integrates cultivation of an acidophilic strain, Galdieria sulphuraria 5587.1, in a closed photobioreactor (PBR); hydrothermal liquefaction (HTL) of the wet algal biomass; and recirculation of the nutrient-rich aqueous product (AP) of HTL to the PBR to achieve higher biomass productivity than that could be achieved with raw wastewater. The premise is that recycling nutrients in the AP can maintain optimal C, N and P levels in the PBR to maximize biomass growth to increase energy returns. Growth studies on the test species validated growth on AP derived from HTL at temperatures from 180 to 300 degrees C. Doubling N and P concentrations over normal levels in wastewater resulted in biomass productivity gains of 20-25% while N and P removal rates also doubled. PMID- 25704094 TI - Higher-level phylogeny of paraneopteran insects inferred from mitochondrial genome sequences. AB - Mitochondrial (mt) genome data have been proven to be informative for animal phylogenetic studies but may also suffer from systematic errors, due to the effects of accelerated substitution rate and compositional heterogeneity. We analyzed the mt genomes of 25 insect species from the four paraneopteran orders, aiming to better understand how accelerated substitution rate and compositional heterogeneity affect the inferences of the higher-level phylogeny of this diverse group of hemimetabolous insects. We found substantial heterogeneity in base composition and contrasting rates in nucleotide substitution among these paraneopteran insects, which complicate the inference of higher-level phylogeny. The phylogenies inferred with concatenated sequences of mt genes using maximum likelihood and Bayesian methods and homogeneous models failed to recover Psocodea and Hemiptera as monophyletic groups but grouped, instead, the taxa that had accelerated substitution rates together, including Sternorrhyncha (a suborder of Hemiptera), Thysanoptera, Phthiraptera and Liposcelididae (a family of Psocoptera). Bayesian inference with nucleotide sequences and heterogeneous models (CAT and CAT + GTR), however, recovered Psocodea, Thysanoptera and Hemiptera each as a monophyletic group. Within Psocodea, Liposcelididae is more closely related to Phthiraptera than to other species of Psocoptera. Furthermore, Thysanoptera was recovered as the sister group to Hemiptera. PMID- 25704096 TI - Multi-phased anaerobic baffled reactor treating food waste. AB - This study was conducted to identify the performance of a multi-phased anaerobic baffled reactor (MP-ABR) with food waste (FW) as the substrate for biogas production and thereby to promote an efficient energy recovery and treatment method for the wastes with high organic solid content through phase separation. A four-chambered ABR was operated at an HRT of 30 days with an OLR of 0.5-1.0 g VS/Ld for a period of 175 days at 35 +/- 1 degrees C. Consistent overall removal efficiencies of 85.3% (CODt), 94.5% (CODs), 89.6% (VFA) and 86.4% (VS) were observed throughout the experiment displaying a great potential to treat FW. Biogas generated was 215.57 mL/g-VS removed d. Phase separation was observed and supported by the COD and VFA trends, and an efficient recovery of bioenergy from FW was achieved. PMID- 25704097 TI - Chemical characteristics and enzymatic saccharification of lignocellulosic biomass treated using high-temperature saturated steam: comparison of softwood and hardwood. AB - This study investigated the effect of high-temperature saturated steam treatments on the chemical characteristics and enzymatic saccharification of softwood and hardwood. The weight loss and chemical modification of cedar and beech wood pieces treated at 25, 35, and 45 atm for 5 min were determined. Fourier transform infrared and X-ray diffraction analyses indicated that solubilization and removal of hemicellulose and lignin occurred by the steam treatment. The milling treatment of steam-treated wood enhanced its enzymatic saccharification. Maximum enzymatic saccharification (i.e., 94% saccharification rate of cellulose) was obtained using steam-treated beech at 35 atm for 5 min followed by milling treatment for 1 min. However, the necessity of the milling treatment for efficient enzymatic saccharification is dependent on the wood species. PMID- 25704098 TI - High-titer lactic acid production from NaOH-pretreated corn stover by Bacillus coagulans LA204 using fed-batch simultaneous saccharification and fermentation under non-sterile condition. AB - Lactic acid (LA) is an important chemical with various industrial applications. Non-food feedstock is commercially attractive for use in LA production; however, efficient LA fermentation from lignocellulosic biomass resulting in both high yield and titer faces technical obstacles. In this study, the thermophilic bacterium Bacillus coagulans LA204 demonstrated considerable ability to ferment glucose, xylose, and cellobiose to LA. Importantly, LA204 produces LA from several NaOH-pretreated agro stovers, with remarkably high yields through simultaneous saccharification and fermentation (SSF). A fed-batch SSF process conducted at 50 degrees C and pH 6.0, using a cellulase concentration of 30 FPU (filter paper unit)/g stover and 10 g/L yeast extract in a 5-L bioreactor, was developed to produce LA from 14.4% (w/w) NaOH-pretreated non-sterile corn stover. LA titer, yield, and average productivity reached 97.59 g/L, 0.68 g/g stover, and 1.63 g/L/h, respectively. This study presents a feasible process for lignocellulosic LA production from abundant agro stovers. PMID- 25704099 TI - A lignocellulosic ethanol strategy via nonenzymatic sugar production: process synthesis and analysis. AB - The work develops a strategy for the production of ethanol from lignocellulosic biomass. In this strategy, the cellulose and hemicellulose fractions are simultaneously converted to sugars using a gamma-valerolactone (GVL) solvent containing a dilute acid catalyst. To effectively recover GVL for reuse as solvent and biomass-derived lignin for heat and power generation, separation subsystems, including a novel CO2-based extraction for the separation of sugars from GVL, lignin and humins have been designed. The sugars are co-fermented by yeast to produce ethanol. Furthermore, heat integration to reduce utility requirements is performed. It is shown that this strategy leads to high ethanol yields and the total energy requirements could be satisfied by burning the lignin. The integrated strategy using corn stover feedstock leads to a minimum selling price of $5 per gallon of gasoline equivalent, which suggests that it is a promising alternative to current biofuels production approaches. PMID- 25704100 TI - Enhancing methane production from waste activated sludge using a novel indigenous iron activated peroxidation pre-treatment process. AB - Methane production from anaerobic digestion of waste activated sludge (WAS) is limited by the slow hydrolysis rate and/or poor methane potential of WAS. This study presents a novel pre-treatment strategy based on indigenous iron (in WAS) activated peroxidation to enhance methane production from WAS. Pre-treatment of WAS for 30 min at 50mg H2O2/g total solids (dry weight) and pH 2.0 (iron concentration in WAS was 7 mg/g TS) substantially enhanced WAS solubilization. Biochemical methane potential tests demonstrated that methane production was improved by 10% at a digestion time of 16d after incorporating the indigenous iron activated peroxidation pre-treatment. Model-based analysis indicated that indigenous iron activated peroxidation pre-treatment improved the methane potential by 13%, whereas the hydrolysis rate was not significantly affected. The economic analysis showed that the proposed pre-treatment method can save the cost by $112,000 per year in a treatment plant with a population equivalent of 300,000. PMID- 25704101 TI - Combustion of an oil palm residue with elevated potassium content in a fluidized bed combustor using alternative bed materials for preventing bed agglomeration. AB - Palm kernel shell (PKS) was burned at 45 kg/s and excess air of 20-80% in a fluidized-bed combustor using alumina, dolomite, and limestone as the bed material. Temperature and gas concentrations were recorded along the reactor centerline as well as at stack. A SEM-EDS analysis was performed to investigate morphology and elemental composition of bed particles. An X-ray fluorescence method was used to determine the composition of used/reused bed materials and PM emitted from the combustor at different operating times. Excess air of 40% seems to be most appropriate for burning PKS in this combustor with an alumina bed, whereas 60% excess air is more suitable when using dolomite and limestone, as ensuring high (98.6-98.9%) combustion efficiency and acceptable CO and NO emissions. By using the selected bed materials, bed agglomeration can be prevented in this combustor. However, the bed materials exhibit substantial time domain changes in physical and chemical properties. PMID- 25704102 TI - Kinetic studies on the pyrolysis of pinewood. AB - The kinetic study for pyrolysis of pine wood has been studied by a thermogravimetric analyzer in an inert atmosphere. Non isothermal model free kinetic methods were used to evaluate kinetics at six different heating rates of 5-40 degrees C/min. Three zones can be detected from the iso-conversional plot of pine with average activation energy values of 134.32 kJ/mol, 146.89 kJ/mol and 155.76 kJ/mol in the conversion range of 1-22%, 24-84% and 85-90%, respectively. The activation energy values were used to determine the reaction mechanism using master plots and compensation parameters. The results show that the pyrolysis process of pine wood can be described by two dimensional diffusion reaction mechanism in a wide range of conversion up to 0.7, followed by close to one and half order reaction mechanism. The kinetic results were validated by making isothermal predictions from non-isothermal data. PMID- 25704103 TI - Expression of adenosine receptor subclasses in malignant and adjacent normal human prostate tissues. AB - BACKGROUND: Adenosine, a purine nucleoside plays important roles in the pathogenesis of cancer initiation and promotion via interaction with four adenosine receptors. In the present study we examined the differential expression pattern of adenosine receptors in the malignant and adjacent normal human prostate tissues. METHODS: Prostate cancer tissue samples and adjacent normal tissues were obtained from 20 patients undergoing radical prostatectomy and histopathological diagnosis was confirmed for each sample. Total RNA was extracted and reverse transcribed into cDNA and the mRNA expression levels of adenosine receptors were investigated by Taq-man real-time RT-PCR experiment. Quantitative protein analysis was done by Western blotting experiment. Moreover, the mRNA and protein expression levels of adenosine receptors were measured after androgen treatment. RESULT: Taq-man real-time RT-PCR measurements show different expression levels of adenosine receptor transcripts. A2B adenosine receptor was predominantly expressed in tumor tissues (2.4-fold) followed by significantly expression of A3 (1.6-fold) and A2A adenosine receptors (1.5-fold) compared to adjacent normal tissues. The presence of adenosine receptors at protein levels in prostate cancer tissues compared with normal tissues was shown the following rank order: A2B > A3 > A2A > A1 . Androgen receptor regulates adenosine receptors mRNA and protein expression in AR-positive LNCaP cells, which was not seen in AR negative PC-3 cells. CONCLUSION: These results indicated for the first time, the differential mRNA expression profile and protein levels of adenosine receptors in the human prostate cancer. Interestingly, the A2B adenosine receptor followed by A3 is highly expressed in prostate tumor samples in comparison with the adjacent normal tissues. The findings support the possible key role of A2B adenosine receptor in promoting cancer cell growth and suggest that A2B may be a novel target for prostate cancer treatment. PMID- 25704104 TI - Prevalence and prognostic role of right ventricular involvement in stress-induced cardiomyopathy. AB - BACKGROUND: Stress-induced cardiomyopathy (SCM) is a reversible cardiomyopathy observed in patients without significant coronary disease. The aim of this study was to assess the incidence and clinical significance of right ventricular (RV) involvement in SCM. METHODS AND RESULTS: We retrospectively analyzed echocardiograms from 40 consecutive patients who presented with SCM at Stanford University Medical Center from September 2000 to November 2010. The primary end point was overall mortality. RV involvement was observed in 20 patients (50%; global RV hypokinesia in 15 patients and focal RV apical akinesia in 5 patients). The independent correlates of RV involvement were older age (odds ratio [OR] 1.09, 95% confidence interval [CI] 1.02-1.7two, P = .01) and LVEF (per 10% decrease: OR 3.60, CI 1.77-7.32; P = .02). At a mean follow-up of 44 +/- 32 months, 12 patients (30%) died (in-hospital death in 3 patients). At multivariate analysis, the presence of an RV fractional area change <35% emerged as an independent predictor of death (OR 3.6, CI 1.06-12.41; P = .04). CONCLUSIONS: RV involvement is a common finding in SCM, and may present as either global or focal RV apical involvement. Both older age and lower LVEF are associated with a higher risk of RV involvement, which appears to be a major predictor of death. PMID- 25704105 TI - Melatonin administration alters nicotine preference consumption via signaling through high-affinity melatonin receptors. AB - RATIONALE: While it is known that tobacco use varies across the 24-h day, the time-of-day effects are poorly understood. Findings from several previous studies indicate a potential role for melatonin in these time-of-day effects; however, the specific underlying mechanisms have not been well characterized. Understanding of these mechanisms may lead to potential novel smoking cessation treatments. OBJECTIVE: The objective of this study is examine the role of melatonin and melatonin receptors in nicotine free-choice consumption METHODS: A two-bottle oral nicotine choice paradigm was utilized with melatonin supplementation in melatonin-deficient mice (C57BL/6J) or without melatonin supplementation in mice proficient at melatonin synthesis (C3H/Ibg) compared to melatonin-proficient mice lacking both or one of the high-affinity melatonin receptors (MT1 and MT2; double-null mutant DM, or MT1 or MT2). Preference for bitter and sweet tastants also was assessed in wild-type and MT1 and MT2 DM mice. Finally, home cage locomotor monitoring was performed to determine the effect of melatonin administration on activity patterns. RESULTS: Supplemental melatonin in drinking water significantly reduced free-choice nicotine consumption in C57BL/6J mice, which do not produce endogenous melatonin, while not altering activity patterns. Independently, genetic deletion of both MT1 and MT2 receptors in a melatonin-proficient mouse strain (C3H) resulted in significantly more nicotine consumption than controls. However, single genetic deletion of either the MT1 or MT2 receptor alone did not result in increased nicotine consumption. Deletion of MT1 and MT2 did not impact taste preference. CONCLUSIONS: This study demonstrates that nicotine consumption can be affected by exogenous or endogenous melatonin and requires at least one of the high-affinity melatonin receptors. The fact that expression of either the MT1 or MT2 melatonin receptor is sufficient to maintain lower nicotine consumption suggests functional overlap and potential mechanistic explanations. PMID- 25704106 TI - Association of tumor necrosis factor (TNF) promoter polymorphisms with plasma TNF alpha levels and susceptibility to diabetic nephropathy in North Indian population. AB - AIM: The concept of diabetic nephropathy (DN) as a metabolic disease is now being replaced by chronic low-grade inflammatory disease. Tumor necrosis factor-alpha (TNF-alpha) is a proinflammatory cytokine which plays an important role in the pathogenesis and clinical outcome of DN. Therefore, this work was planned to evaluate the association of -863C/A (rs1800630) and -1031T/C (rs1799964) polymorphisms in TNF gene with plasma TNF-alpha levels and DN among subjects with type 2 diabetes (T2DM) in a population from North India. METHODS: Age and sex matched 100 healthy controls (HC), 100 T2DM subjects without nephropathy (DM) and 100 subjects with DN were screened for above polymorphisms using the PCR-RFLP methods. Plasma TNF-alpha levels were measured by ELISA. Analysis of variance and logistic regression were used to associate individual polymorphisms with plasma TNF-alpha levels and DN. RESULTS: The allelic frequencies of -863C/A were 0.86/0.14 in HC, 0.72/0.23 in DM and 0.84/0.16 in DN, and that of -1031T/C were 0.89/0.11 in HC, 0.95/0.05 in DM and 0.80/0.20 in DN. The carriers of -863A allele had significantly lower plasma TNF-alpha levels (p<0.05). The -863C/A (OR=0.439, 95% CI=0.244-0.789, p=0.006) and -1031T/C (OR=3.0, 95% CI=1.355-6.642, p=0.007) were strongly associated with risk of development of DN. CONCLUSIONS: 863C/A was associated with low whereas -1031T/C with high TNF-alpha levels. The, results suggest that -863C/A polymorphism might be protective whereas -1031T/C may be associated with increased risk for DN in subjects with T2DM from North India. PMID- 25704107 TI - Potential cost savings from chemotherapy-induced febrile neutropenia with biosimilar filgrastim and expanded access to targeted antineoplastic treatment across the European Union G5 countries: a simulation study. AB - PURPOSE: The objectives of this study were to simulate for the European Union G5 countries the potential cost savings of converting patients from originator granulocyte colony-stimulating factor (G-CSF) filgrastim and pegfilgrastim to a biosimilar filgrastim, to evaluate how reallocating these savings could increase patient access to antineoplastic therapy, and to estimate the number of patients needed to convert to provide antineoplastic treatment to one patient. METHODS: Three models were built: (1) to estimate the costs of using originator G-CSFs and the savings generated from switching to a biosimilar G-CSF, (2) to estimate the incremental number of patients who could be provided antineoplastic therapy rituximab or trastuzumab-in a hypothetical panel of 10,000 patients with cancer, and (3) to calculate the number of patients needed to convert to provide access to anticancer therapy. Scenarios were developed in which the rate of conversion was varied to estimate the effect on total cost savings. This study took the perspective of the payer in the European Union. FINDINGS: The savings associated with the biosimilar filgrastim over the originator filgrastim ranged from ?785 (day 4) to ?2747 (day 14) and increased with longer duration of therapy. By contrast, the savings associated with the biosimilar filgrastim over pegfilgrastim decreased over time, ranging from ?6199 (day 4) to ?471 (day 14). In a hypothetical panel of 10,000 patients with cancer, the savings associated with the biosimilar filgrastim over the originator filgrastim and the expanded access to antineoplastic therapy improved over time, irrespective of conversion rates. Conversely, in the same hypothetical panel, the savings associated with the biosimilar filgrastim over pegfilgrastim reduced over time, irrespective of conversion rates, along with the expanded access to antineoplastic treatment. Under conversion of the originator filgrastim to the biosimilar filgrastim, the number needed to convert to expand access to rituximab ranged from 4 to 14 patients, and the number needed to convert to expand access to trastuzumab ranged from 11 to 38 patients. Under conversion of pegfilgrastim to the biosimilar filgrastim, the number needed to convert to expand access to rituximab ranged from 2 to 24 patients, and the number needed to convert to expand access to trastuzumab ranged from 5 to 63 patients. IMPLICATIONS: Use of biosimilar G-CSFs for supportive cancer care could yield potential cost savings and improve patient access to antineoplastic therapy in a budget neutral way-a financial effect with an ethical perspective. PMID- 25704108 TI - The epigenetic memory of monocytes and macrophages as a novel drug target in atherosclerosis. AB - PURPOSE: Atherosclerosis is characterized by a persistent inflammation of the arterial wall. Monocyte-derived macrophages are the most abundant immune cells in atherosclerotic plaques. After stimulation, monocytes can adopt a long-term proinflammatory phenotype. This nonspecific memory of innate immune cells is mediated by epigenetic reprogramming and has recently been termed "trained innate immunity." The goal of this study was to describe the potential role of trained immunity in the development of atherosclerosis and to discuss the potential clinical implications of this concept. METHODS: We performed a comprehensive literature search (PubMed) on the role of epigenetic programming of histones, and of trained immunity in particular, in atherogenesis. FINDINGS: In vitro studies demonstrate that modified LDL particles can induce a long-term proinflammatory phenotype in monocytes/macrophages by epigenetic reprogramming at the level of histone methylation. This scenario is associated with increased production of proatherogenic cytokines and chemokines and increased formation of foam cells. IMPLICATIONS: Preclinical evidence suggests that trained innate immunity may contribute to vascular wall inflammation in patients with risk factors for atherosclerosis. Epigenetic reprogramming is regulated by enzymes that are amenable to pharmacologic modulation. Therefore, this mechanism could be used to develop novel pharmacologic targets for the prevention or treatment of atherosclerotic vascular disease. PMID- 25704109 TI - Self-management in chronic disease: clear benefits for blood pressure control in CKD. PMID- 25704110 TI - Reliability and minimal detectable change of the weight-bearing lunge test: A systematic review. AB - Ankle dorsiflexion range of motion (DROM) is often a point of emphasis during the rehabilitation of lower extremity pathologies. With the growing popularity of weight-bearing DROM assessments, several versions of the weight-bearing lunge (WBLT) test have been developed and numerous reliability studies have been conducted. The purpose of this systematic review was to critically appraise and synthesize the studies which examined the reliability and responsiveness of the WBLT to assess DROM. A systematic search of PubMed and EBSCO Host databases from inception to September 2014 was conducted to identify studies whose primary aim was assessing the reliability of the WBLT. The Quality Appraisal of Reliability Studies assessment tool was utilized to determine the quality of included studies. Relative reliability was examined through intraclass correlation coefficients (ICC) and responsiveness was evaluated through minimal detectable change (MDC). A total of 12 studies met the eligibility criteria and were included. Nine included studies assessed inter-clinician reliability and 12 included studies assessed intra-clinician reliability. There was strong evidence that inter-clinician reliability (ICC = 0.80-0.99) as well as intra-clinician reliability (ICC = 0.65-0.99) of the WBLT is good. Additionally, average MDC scores of 4.6 degrees or 1.6 cm for inter-clinician and 4.7 degrees or 1.9 cm for intra-clinician were found, indicating the minimal change in DROM needed to be outside the error of the WBLT. This systematic review determined that the WBLT, regardless of method, can be used clinically to assess DROM as it provides consistent results between one or more clinicians and demonstrates reasonable responsiveness. PMID- 25704111 TI - Improved cosine similarity measures of simplified neutrosophic sets for medical diagnoses. AB - OBJECTIVE: In pattern recognition and medical diagnosis, similarity measure is an important mathematical tool. To overcome some disadvantages of existing cosine similarity measures of simplified neutrosophic sets (SNSs) in vector space, this paper proposed improved cosine similarity measures of SNSs based on cosine function, including single valued neutrosophic cosine similarity measures and interval neutrosophic cosine similarity measures. Then, weighted cosine similarity measures of SNSs were introduced by taking into account the importance of each element. Further, a medical diagnosis method using the improved cosine similarity measures was proposed to solve medical diagnosis problems with simplified neutrosophic information. MATERIALS AND METHODS: The improved cosine similarity measures between SNSs were introduced based on cosine function. Then, we compared the improved cosine similarity measures of SNSs with existing cosine similarity measures of SNSs by numerical examples to demonstrate their effectiveness and rationality for overcoming some shortcomings of existing cosine similarity measures of SNSs in some cases. In the medical diagnosis method, we can find a proper diagnosis by the cosine similarity measures between the symptoms and considered diseases which are represented by SNSs. Then, the medical diagnosis method based on the improved cosine similarity measures was applied to two medical diagnosis problems to show the applications and effectiveness of the proposed method. RESULTS: Two numerical examples all demonstrated that the improved cosine similarity measures of SNSs based on the cosine function can overcome the shortcomings of the existing cosine similarity measures between two vectors in some cases. By two medical diagnoses problems, the medical diagnoses using various similarity measures of SNSs indicated the identical diagnosis results and demonstrated the effectiveness and rationality of the diagnosis method proposed in this paper. CONCLUSIONS: The improved cosine measures of SNSs based on cosine function can overcome some drawbacks of existing cosine similarity measures of SNSs in vector space, and then their diagnosis method is very suitable for handling the medical diagnosis problems with simplified neutrosophic information and demonstrates the effectiveness and rationality of medical diagnoses. PMID- 25704112 TI - Predicting the risk of exacerbation in patients with chronic obstructive pulmonary disease using home telehealth measurement data. AB - BACKGROUND: The use of telehealth technologies to remotely monitor patients suffering chronic diseases may enable preemptive treatment of worsening health conditions before a significant deterioration in the subject's health status occurs, requiring hospital admission. OBJECTIVE: The objective of this study was to develop and validate a classification algorithm for the early identification of patients, with a background of chronic obstructive pulmonary disease (COPD), who appear to be at high risk of an imminent exacerbation event. The algorithm attempts to predict the patient's condition one day in advance, based on a comparison of their current physiological measurements against the distribution of their measurements over the previous month. METHOD: The proposed algorithm, which uses a classification and regression tree (CART), has been validated using telehealth measurement data recorded from patients with moderate/severe COPD living at home. The data were collected from February 2007 to January 2008, using a telehealth home monitoring unit. RESULTS: The CART algorithm can classify home telehealth measurement data into either a 'low risk' or 'high risk' category with 71.8% accuracy, 80.4% specificity and 61.1% sensitivity. The algorithm was able to detect a 'high risk' condition one day prior to patients actually being observed as having a worsening in their COPD condition, as defined by symptom and medication records. CONCLUSION: The CART analyses have shown that features extracted from three types of physiological measurements; forced expiratory volume in 1s (FEV1), arterial oxygen saturation (SPO2) and weight have the most predictive power in stratifying the patients condition. This CART algorithm for early detection could trigger the initiation of timely treatment, thereby potentially reducing exacerbation severity and recovery time and improving the patient's health. This study highlights the potential usefulness of automated analysis of home telehealth data in the early detection of exacerbation events among COPD patients. PMID- 25704113 TI - DrugNet: network-based drug-disease prioritization by integrating heterogeneous data. AB - OBJECTIVE: Computational drug repositioning can lead to a considerable reduction in cost and time in any drug development process. Recent approaches have addressed the network-based nature of biological information for performing complex prioritization tasks. In this work, we propose a new methodology based on heterogeneous network prioritization that can aid researchers in the drug repositioning process. METHODS: We have developed DrugNet, a new methodology for drug-disease and disease-drug prioritization. Our approach is based on a network based prioritization method called ProphNet which has recently been developed by the authors. ProphNet is able to integrate data from complex networks involving a wide range of types of elements and interactions. In this work, we built a network of interconnected drugs, proteins and diseases and applied DrugNet to different types of tests for drug repositioning. RESULTS: We tested the performance of our approach on different validation tests, including cross validation and tests based on real clinical trials. DrugNet achieved a mean AUC value of 0.9552+/-0.0015 in 5-fold cross validation tests, and a mean AUC value of 0.8364 for tests based on recent clinical trials (phases 0-4) not present in our data. These results suggest that DrugNet could be very useful for discovering new drug uses. We also studied specific cases of particular interest, proving the benefits of heterogeneous data integration in this problem. CONCLUSIONS: Our methodology suggests that new drugs can be repositioned by generating ranked lists of drugs based on a given disease query or vice versa. Our study shows that the simultaneous integration of information about diseases, drugs and targets can lead to a significant improvement in drug repositioning tasks. DrugNet is available as a web tool from http://genome2.ugr.es/drugnet/ (accessed 23.09.14). Matlab source code is also available on the website. PMID- 25704114 TI - Nutritional stress induces exchange of cell material and energetic coupling between bacterial species. AB - Knowledge of the behaviour of bacterial communities is crucial for understanding biogeochemical cycles and developing environmental biotechnology. Here we demonstrate the formation of an artificial consortium between two anaerobic bacteria, Clostridium acetobutylicum (Gram-positive) and Desulfovibrio vulgaris Hildenborough (Gram-negative, sulfate-reducing) in which physical interactions between the two partners induce emergent properties. Molecular and cellular approaches show that tight cell-cell interactions are associated with an exchange of molecules, including proteins, which allows the growth of one partner (D. vulgaris) in spite of the shortage of nutrients. This physical interaction induces changes in expression of two genes encoding enzymes at the pyruvate crossroads, with concomitant changes in the distribution of metabolic fluxes, and allows a substantial increase in hydrogen production without requiring genetic engineering. The stress induced by the shortage of nutrients of D. vulgaris appears to trigger the interaction. PMID- 25704115 TI - Gold-acetonyl complexes: from side-products to valuable synthons. AB - A new synthetic strategy was devised leading to the formation of complexes, such as [Au(IPr)(CH2 COCH3)]. The approach capitalizes on the formation of a decomposition product observed in the course of the synthesis of [Au(IPr)(Cl)]. A library of gold acetonyl complexes containing the most common N-heterocyclic carbene (NHC) ligands has been synthesized. These acetonyl complexes are good synthons for the preparation of numerous organogold complexes. Moreover, they have proven to be precatalysts in common gold(I)-catalyzed reactions. PMID- 25704116 TI - Identification of the appropriate dose metric for pulmonary inflammation of silver nanoparticles in an inhalation toxicity study. AB - A number of studies have shown that induction of pulmonary toxicity by nanoparticles of the same chemical composition depends on particle size, which is likely in part due to differences in lung deposition. Particle size mostly determines whether nanoparticles reach the alveoli, and where they might induce toxicity. For the risk assessment of nanomaterials, there is need for a suitable dose metric that accounts for differences in effects between different sized nanoparticles of the same chemical composition. The aim of the present study is to determine the most suitable dose metric to describe the effects of silver nanoparticles after short-term inhalation. Rats were exposed to different concentrations (ranging from 41 to 1105 ug silver/m(3) air) of 18, 34, 60 and 160 nm silver particles for four consecutive days and sacrificed at 24 h and 7 days after exposure. We observed a concentration-dependent increase in pulmonary toxicity parameters like cell counts and pro-inflammatory cytokines in the bronchoalveolar lavage fluid. All results were analysed using the measured exposure concentrations in air, the measured internal dose in the lung and the estimated alveolar dose. In addition, we analysed the results based on mass, particle number and particle surface area. Our study indicates that using the particle surface area as a dose metric in the alveoli, the dose-response effects of the different silver particle sizes overlap for most pulmonary toxicity parameters. We conclude that the alveolar dose expressed as particle surface area is the most suitable dose metric to describe the toxicity of silver nanoparticles after inhalation. PMID- 25704117 TI - Specific nanotoxicity of graphene oxide during zebrafish embryogenesis. AB - Graphene oxide (GO) has shown great potential for biological, medical, energy and electronic applications. As a consequence of these diverse applications, GO release into the ecosystem is inevitable; however, the corresponding risks are largely unknown, particularly with respect to the critical period of embryogenesis. This study revealed that GO adhered to and enveloped the chorion of zebrafish embryos mainly via hydroxyl group interactions, blocked the pore canals of the chorionic membrane, and caused marked hypoxia and hatching delay. Furthermore, GO spontaneously penetrated the chorion, entered the embryo via endocytosis, damaged the mitochondria and primarily translocated to the eye, heart and yolk sac regions, which are involved in the circulatory system of zebrafish. In these organs, GO induced excessive generation of reactive oxygen species and increased oxidative stress, DNA damage and apoptosis. Graphene oxide also induced developmental malformation of the eye, cardiac/yolk sac edema, tail flexure and heart rate reduction. In contrast to the common dose-effect relationships of nanoparticles, the adverse effects of GO on heart rate and tail/spinal cord flexure increased and then decreased as the GO concentration increased. These findings emphasize the specific adverse effects of GO on embryogenesis and highlight the potential ecological and health risks of GO. PMID- 25704118 TI - Intellectual disability and cognitive ability in Darier disease: Swedish nation wide study. AB - BACKGROUND: Darier disease is an autosomal dominant skin disorder caused by mutations in the ATP2A2 gene. Anecdotal reports suggest a relationship between Darier disease and intellectual disabilities, but these reports are based on small clinical samples and limited by absence of control populations. OBJECTIVES: To examine the risk of intellectual disability and subclinical impairments in cognitive ability in Darier disease. METHODS: We conducted a matched cohort study based on Swedish Population-, Patient- and Conscript Registers. The risk of being diagnosed with intellectual disability was estimated in 770 individuals with Darier disease, compared with matched comparison individuals without Darier disease. Associations were examined with risk ratios from conditional logistic regressions. In addition, we analysed test-based cognitive ability data (i.e. IQ data) from the Swedish conscript examination, for a subset of patients without diagnosed intellectual disability. RESULTS: Individuals with Darier disease had a sixfold increased risk of being diagnosed with intellectual disability (risk ratio 6.2, 95% confidence interval 3.1-12.4). For conscripted individuals with Darier disease but no diagnosed intellectual disability, mean cognitive ability scores were about half a standard deviation lower than for comparison subjects. CONCLUSIONS: Darier disease is associated with intellectual disability and subclinical impairments in cognitive ability. The Darier-causing mutations merit further attention in molecular genetic research on intellectual disability and cognitive ability. PMID- 25704119 TI - Immunotherapy for canine cancer--is it time to go back to the future? AB - Over the last 50 years, the significance of the immune system in the development and control of cancer has been much debated. However, recent discoveries provide evidence for a role of immunological mechanisms in the detection and destruction of cancer cells. Forty years ago veterinary oncologists were already investigating the feasibility of treating neoplasia by enhancing anticancer immunity. Unfortunately, this research was hindered by lack of a detailed understanding of cancer immunology, this limited the specificity and success of these early approaches. The great forward strides made in our understanding of onco-immunology in recent years have provided the impetus for a resurgence of interest in anticancer immunotherapy for canine patients. In this article both these initial trials and the exciting novel immunotherapeutics currently in development are reviewed. PMID- 25704120 TI - Novel antiviral compounds against gastroenteric viral infections. AB - Viral gastroenteritis is a serious viral infection which affects a large number of individuals around the world, most of them being children. The infection may occur due to different viruses, for example, coxsackievirus, adenovirus, and rotavirus. There is no available cure for such infections, and the treatment mainly depends on hospitalization and administration of nutritional supports. A new antiviral agent against gastroenteritis viral infection will be a breakthrough in healthcare. Pyrrole and pyrrolopyrimidine derivatives are well known for their biological activity as antibacterial, antifungal, and anticancer agents. These compounds also proved to possess antiviral activity. Here, we synthesized novel pyrrole and pyrrolopyrimidine compounds and examined their antiviral activity. We synthesized several new pyrrole, pyrrolo[2,3-d]pyrimidine, and pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine derivatives. The characterization of all synthesized compounds was based on microanalysis and spectral data. Moreover, we determined the non-toxic doses of these compounds on BGM, Hep-2, and MA-104 cells. We tested all the synthesized compounds for their antiviral activities against coxsackievirus B4, adenovirus type 7, and rotavirus Wa strain. Several compounds exhibited significant activities as antiviral agents. PMID- 25704121 TI - Sick and tired: mood, fatigue, and inflammation in cancer. AB - Cancer patients commonly experience depression and fatigue before, during, and after treatment. Symptoms can be debilitating, and the risks associated with unrecognized or inadequately treated depression are substantial. Inflammation may be important in the genesis of depression and fatigue in cancer patients; potential neurobiological mechanisms of inflammation-related behavioral symptoms are reviewed. Randomized studies of pharmacologic treatments for depression in cancer populations are limited, but available data are generally encouraging. Studies of pharmacologic treatments for cancer-related fatigue have been more numerous but with mixed results. A practical approach to pharmacologic treatment of depression and fatigue in cancer patients involves weighing the potential risks and benefits of specific agents, including potential for adverse or advantageous side effects. Progress in understanding the neurobiological mechanisms underlying inflammation-related behavioral symptoms will provide opportunities for the development of novel and targeted treatments. PMID- 25704122 TI - Methyl-donor deficiency in adolescence affects memory and epigenetic status in the mouse hippocampus. AB - DNA methylation is one of the essential factors in the control of gene expression. Alteration of the DNA methylation pattern has been linked to various neurological, behavioral and neurocognitive dysfunctions. Recent studies have pointed out the importance of epigenetics in brain development and functions including learning and memory. Nutrients related to one-carbon metabolism are known to play important roles in the maintenance of genomic DNA methylation. Previous studies have shown that the long-term administration of a diet lacking essential one-carbon nutrients such as methionine, choline and folic acid (methyl donors) caused global DNA hypermethylation in the brain. Therefore, the long-term feeding of a methyl-donor-deficient diet may cause abnormal brain development including learning and memory. To confirm this hypothesis, 3-week-old mice were maintained on a folate-, methionine- and choline-deficient (FMCD) or control (CON) diet for 3 weeks. We found that the methyl-donor deficiency impaired both novel object recognition and fear extinction after 3 weeks of treatment. The FMCD group showed spontaneous recovery of fear that differed from that in CON. In addition, we found decreased Gria1 gene expression and specific CpG hypermethylation of the Gria1 promoter region in the FMCD hippocampus. Our data suggest that a chronic dietary lack of methyl donors in the developmental period affects learning, memory and gene expressions in the hippocampus. PMID- 25704123 TI - Protozoa and metazoa relations to technological conditions of non-woven textile filters for wastewater treatment. AB - The objective of this study was a preliminary identification of basic groups of micro-organisms in the cross-sectional profile of geotextile filters for septic tank effluent (STE) treatment and their relations to technological conditions. Reactors with textile filters treating wastewater were investigated on a semi technical scale. Filters were vertically situated and STE was filtered through them under hydrostatic pressure at a wastewater surface height of 7-20 cm. Filters were made of four layers of non-woven TS 20 geotextile of 0.9 mm thickness. Various groups of organisms were observed; the most abundant group comprised free-swimming and crawling ciliates, less abundant were stalked ciliates and the least numerous were nematodes. The individual counts of all groups of micro-organisms investigated during the study were variable according to time and space. The high abundance of Opercularia, a commonly observed genus of stalked ciliates, was related to the high efficiency of wastewater treatment and dissolved oxygen concentration of about 1.0 g/m3. Numbers of free-swimming and crawling ciliates had a tendency to decrease in relation to the depth of filter cross-sectional profile. The variability in counts of particular groups of organisms could be related to the local stress conditions. No correlation between identified organism count and total mass concentration in the cross-sectional filter profile was found. PMID- 25704124 TI - Governing chemistry of cellulose hydrolysis in supercritical water. AB - At extremely low reaction times (0.02 s), cellulose was hydrolyzed in supercritical water (T=400 degrees C and P=25 MPa) to obtain a sugar yield higher than 95 wt%, whereas the 5-hydroxymethylfurfural (5-HMF) yield was lower than 0.01 wt %. If the reaction time was increased to 1 s, the main product was glycolaldehyde (60 wt%). Independently of the reaction time, the yield of 5-HMF was always lower than 0.01 wt%. To evaluate the reaction mechanism of biomass hydrolysis in pressurized water, several parameters (temperature, pressure, reaction time, and reaction medium) were studied for different biomasses (cellulose, glucose, fructose, and wheat bran). It was found that the H(+) and OH(-) ion concentration in the reaction medium as a result of water dissociation is the determining factor in the selectivity. The reaction of glucose isomerization to fructose and the further dehydration to 5-HMF are highly dependent on the ion concentration. By an increase in the pOH/pH value, these reactions were minimized to allow control of 5-HMF production. Under these conditions, the retroaldol condensation pathway was enhanced, instead of the isomerization/dehydration pathway. PMID- 25704125 TI - Dehydration is difficult to detect and prevent in nursing homes. PMID- 25704126 TI - An international definition for "nursing home". AB - There is much ambiguity regarding the term "nursing home" in the international literature. The definition of a nursing home and the type of assistance provided in a nursing home is quite varied by country. The International Association of Gerontology and Geriatrics and AMDA foundation developed a survey to assist with an international consensus on the definition of "nursing home." PMID- 25704127 TI - Facilitators of and barriers to hip protector acceptance and adherence in long term care facilities: a systematic review. AB - BACKGROUND: Hip protectors represent an attractive strategy for reducing hip fractures among high-risk fallers in long-term care facilities. However, clinical studies yield conflicting results regarding their clinical value. This is mainly due to poor acceptance and adherence among users in wearing these devices. As a result, there is an urgent need to identify potential barriers and facilitators to initial acceptance and continued adherence with hip protector use. PURPOSE: The objective of this systematic review is to synthesize available research evidence to identify factors that influence acceptance and adherence among older adults living in long-term care facilities. METHODS: A key word search was conducted for studies published in English between 2000 and 2013 that employed quantitative, qualitative, or mixed-methods research designs. Two independent reviewers evaluated each article for inclusion, with a third reviewer when needed to resolve discrepancies. RESULTS: Twenty-eight articles met our inclusion criteria, and facilitators and barriers were clustered into 4 socio-ecological levels: system (eg, facility commitment, staff shortages), caregiver (eg, belief in the efficacy of protectors, negative perceptions), resident (eg, clinical risk factors for falls and related fractures, acute illness), and product (eg, soft shell, discomfort). DISCUSSION: The outcomes provide decision makers, health professionals, and caregivers with a greater awareness of strategies to improve compliance with the use of hip protectors. Furthermore, researchers can use this information to design clinical trials that yield high acceptance and adherence. PMID- 25704128 TI - Choosing chemical markers for quality assurance of complex herbal medicines: Development and application of the herb MaRS criteria. AB - With increasing use of herbal medicines for chronic or serious illness, relevant quality assurance methods are essential for making claims of therapeutic benefit. Adequate demonstration of safety and efficacy based on chemical composition and ensuring consistency between manufactured batches is critical. To date, there has been no uniform standard approach or detailed framework provided to industry for selecting relevant chemical markers used to standardize herbal products. We developed the Herbal Marker Ranking System (Herb MaRS) providing guidance on prioritizing the selection of chemical markers for quality control of complex multi-herb mixtures, while also taking into account the bioactivity in relation to the symptoms of the disease and its concentration in the formula. We apply the Herb MaRS evaluation criteria to a seven-herb formulation for the treatment of irritable bowel syndrome with constipation. Our ranking scale accommodates the clinical and pharmacological use of the formulation and its claimed indications. PMID- 25704129 TI - Measuring Subtypes of Emotion Regulation: From Broad Behavioural Skills to Idiosyncratic Meaning-making. AB - The current paper introduces the notion of clinically relevant subtypes of emotion regulation behaviours. A new measure of emotion regulation, the Complexity of Emotional Regulation Scale (CERS), was established as psychometrically sound. It was positively correlated with a measure of emotional awareness (r = 0.28, p < 0.001) and negatively correlated with measures of self criticism (r = -0.28, p < 0.001) and depression (r = -0.35, p = 0.025), among others. Participants were drawn from two samples: clients from a university counselling centre and a non-clinical student sample. Comparisons were conducted between non-clinical and clinical samples to determine the effects of depression and other symptoms of psychopathology on participant's generation of strategies for emotion regulation. Participants in the clinical sample more often identified an intention to soothe but did not follow through as compared with the non clinical group, F(1, 198) = 4.662, p < 0.04. Furthermore, individuals in the non clinical sample were more likely to engage in specific, meaning-making strategies when compared with the clinical group, F(1, 198) = 5.875, p < 0.02. Implications from the current studies suggest the possible applicability of the CERS to clinical settings using an interview rather than questionnaire format. Copyright (c) 2015 John Wiley & Sons, Ltd. KEY PRACTITIONER MESSAGE: Emotion regulation should be thought of as being on a continuum of complexity, where strategies range from general ('one size fits all') action to specific ('personal and idiosyncratic') meaning. The best emotion regulation strategy depends on a client's presenting difficulty and level of distress. PMID- 25704130 TI - Experimental and theoretical studies of (E)-2-(2-hydroxystyryl)-6-(4 methoxybenzoyl)-5-(4-methoxyphenyl)-1,2,4-triazin-3(2H)-one. AB - Crystal structure of the title compound, C26H21N3O5, has been synthesized and characterized by FT-IR, (1)H NMR, (13)C NMR and X-ray single crystal determination. The molecular geometry was also calculated by using Gaussian 03 software and structure was optimized by using HF and DFT/B3LYP method with the 6 31G(d) basis sets in ground state. The comparison of the theoretical and experimental geometries of the title compound indicated that the X-ray parameters agree with the theoretically obtained values. It was seen that R(2) value changes from 0.015 to 0.021 A for bond length and angle. The calculated vibrational frequencies are also in good agreement with the experimental results. The (1)H and (13)C NMR chemical shifts values of (E)-2-(2-hydroxystyryl)-6-(4 methoxybenzoyl)-5-(4-methoxyphenyl)-1,2,4-triazin-3(2H)-one molecule have been calculated by the GIAO method. Besides, molecular electrostatic potential maps (MEP), Mulliken charges and Nonlinear Optical effects (NLO) analysis of the compound have been calculated by the HF and B3LYP/6-31G(d) methods. PMID- 25704131 TI - Chronic obstructive pulmonary disease in African- and European-American women: morbidity, mortality and healthcare utilization in the USA. AB - The impact of chronic obstructive pulmonary disease (COPD) is increasing in US women. In 2008-2010, an estimated 7.9 million US women were living with COPD. Chronic lower respiratory disease was the third leading cause of mortality in 2010 and was a major cause of morbidity. Its economic and social burden is both substantial and increasing in the USA. The annual number of COPD deaths is now higher in women than in men. In 2011, 72,584 women and 65,920 men aged 25 years and over died of COPD. The death rate in African-American women was only half compared with European-American women. Further, rates of COPD prevalence, emergency room visits and hospitalization were greater among women than men. This review reports the latest patterns and trends in several measures of COPD in US women. PMID- 25704132 TI - Extralevator abdominoperineal excision for low rectal cancer: a systematic review and meta-analysis of the short-term outcome. AB - AIM: The superiority of extralevator abdominoperineal excision (ELAPE) over conventional abdominoperineal excision (APE) remains controversial, despite the publication of many studies on this issue. The aim of this meta-analysis was to provide a clear, evidence-based comparison of the two procedures. METHOD: A systematic review and meta-analysis was conducted through a comprehensive search of the PubMed, EMBASE/Medline and Cochrane Central Library databases for all studies comparing ELAPE with conventional APE for low rectal cancer. Pooled data on circumferential resection margin (CRM) positivity, intra-operative bowel perforation, perineal wound complications and local recurrence were analysed. RESULTS: Seven studies, involving a total of 2672 patients, were included. Analysis of the pooled data did not reveal a significant difference between the two operations regarding CRM positivity [risk ratio (RR) = 0.79, 95% CI: 0.40 1.57; P = 0.50, I(2) = 86%] and perineal wound complications (RR = 0.91, 95% CI: 0.71-1.16; P = 0.44, I(2) = 49%), and showed a borderline reduced risk of intra operative bowel perforation for ELAPE, but still did not reveal a significant difference between the two groups (RR = 0.61, 95% CI: 0.37-1.00; P = 0.05, I(2) = 58%). CONCLUSION: The current evidence does not indicate a statistically significant superiority of ELAPE over conventional APE in terms of CRM positivity and intra-operative bowel perforation. PMID- 25704133 TI - Frequency of recommendations for additional imaging in diagnostic ultrasound examinations: Evaluation of radiologist, technologist, and other examination related factors. AB - OBJECTIVE: Our aim in this study was to evaluate the effect of the radiologist, technologist, and other examination-related factors on the frequency of recommendations for additional imaging (RAI) during sonographic (US) interpretation. METHODS: We retrospectively reviewed 719 US reports from a single academic medical center for the presence of RAI. All studies had been interpreted by one of three abdominal radiologists. Examinations were performed at an outpatient radiology facility with no onsite radiologist (n = 299) or at an inpatient emergency department or hospital-based outpatient setting that had an onsite radiologist (n = 420). Possible associations between the frequency of RAI and the presence of an onsite radiologist, location of the examination, body part or region imaged, patient age, technologist performing the exam, and radiologist reading the exam were evaluated. RESULTS: There were significant differences between each pair of radiologists in terms of overall frequency of RAI (p < 0.001) (radiologist 1: 12.0% [22/184]; radiologist 2: 21.6% [78/361]; and radiologist 3: 45.5% [79/174]). In addition, there were statistically significant differences in the frequency of RAI among studies scanned by the 10 different US technologists (13.6%-40.0%, p = 0.03). However, other factors such as patient age, patient sex, US unit, patient location, and radiologist location were not associated with the frequency of RAI (p = 0.15-0.93). CONCLUSIONS: The individual radiologist and technologist influenced the frequency of RAI for US examinations, whereas other examination-related factors did not. The observed substantial variability in RAI between radiologists and technologists warrants further study, with consideration of strategies to optimize RAI within US reports. PMID- 25704134 TI - The indirect effect of the therapeutic alliance and alcohol abstinence self efficacy on alcohol use and alcohol-related problems in Project MATCH. AB - BACKGROUND: Empirical literature indicates that the therapeutic alliance explains a modest but reliable proportion of variance in predicting alcohol-related outcomes among individuals in treatment for alcohol use disorders (AUDs). Hartzler and colleagues (2011) showed in the COMBINE data set that alcohol abstinence self-efficacy is a potentially important statistical mediator of the relationship between the alliance and client outcomes. METHODS: The purpose of this study was to replicate this finding in the Project MATCH data set. We used total alliance ratings on the Working Alliance Inventory and tested both client and therapist ratings in mediation analyses. RESULTS: We found that posttreatment self-efficacy accounted for the effect of therapist and client ratings of alliance (measured at session 2) on posttreatment drinking outcomes (drinks per drinking day and alcohol-related problems). In addition, we found a moderation effect of treatment, such that the association between the client's rating of the alliance and self-efficacy changes was positive for individuals in the cognitive behavioral treatment group but negative for those receiving motivation enhancement or Twelve-Step Facilitation. CONCLUSIONS: This study reaffirms the importance of the therapeutic alliance and self-efficacy in predicting AUD outcomes. Future research should examine changes in the therapeutic alliance throughout treatment and how these changes are related to self-efficacy and AUD treatment outcomes over time. PMID- 25704135 TI - Phase II/III trial of a pre-transplant farnesyl transferase inhibitor in juvenile myelomonocytic leukemia: a report from the Children's Oncology Group. AB - BACKGROUND: Juvenile myelomonocytic leukemia (JMML) is not durably responsive to chemotherapy, and approximately 50% of patients relapse after hematopoietic stem cell transplant (HSCT). Here we report the activity and acute toxicity of the farnesyl transferase inhibitor tipifarnib, the response rate to 13-cis retinoic acid (CRA) in combination with cytoreductive chemotherapy, and survival following HSCT in children with JMML. PROCEDURE: Eighty-five patients with newly diagnosed JMML were enrolled on AAML0122 between 2001 and 2006. Forty-seven consented to receive tipifarnib in a phase II window before proceeding to a phase III trial of CRA in combination with fludarabine and cytarabine followed by HSCT and maintenance CRA. Thirty-eight patients enrolled only in the phase III trial. RESULTS: Overall response rate was 51% after tipifarnib and 68% after fludarabine/cytarabine/CRA. Tipifarnib did not increase pre-transplant toxicities. Forty-six percent of the 44 patients who received protocol compliant HSCT relapsed. Five-year overall survival was 55 +/- 11% and event-free survival was 41 +/- 11%, with no significant difference between patients who did or did not receive tipifarnib. CONCLUSIONS: Administration of tipifarnib in the window setting followed by HSCT in patients with newly diagnosed JMML was safe and yielded a 51% initial response rate as a single agent, but failed to reduce relapse rates or improve long-term overall survival. PMID- 25704137 TI - Balance and Gait in People with Multiple Sclerosis: A Comparison with Healthy Controls and the Immediate Change after an Intervention based on the Bobath Concept. AB - BACKGROUND AND PURPOSE: The objective of this study is to compare the balance and gait of 11 people with multiple sclerosis (MS) to 11 healthy controls and to investigate the immediate change after a single intervention based on the Bobath concept on these activities in the MS group. METHODS: Balance was assessed by ground reaction forces (GRF) and centre of pressure movements during single limb standing (SLS), the Lateral Reach Test (LRT) and the Four Square Step Test (FSST). Gait was evaluated by GRF, ankle kinematics and spatiotemporal measures. RESULTS: Baseline measures in the MS group showed significantly greater vertical GRF variability (p = 0.008) during SLS reached less distance on the LRT (p = 0.001) and were slower completing the FSST (p < 0.001). During gait, the MS group walked slower (p = 0.005) and had less ankle plantarflexion (PF) (p = 0.001) than the control group. Less peak vertical GRF (p < 0.001) and peak propulsive GRF (p = 0.004) at terminal stance and increased vertical GRF in midstance (p = 0.005) were observed. The measures of balance and gait were re-assessed in the MS group immediately after a 20-min intervention based on the Bobath concept delivered to the most impaired foot and ankle. After the intervention, the MS group had significant changes towards the control group values with reduced mediolateral (p = 0.002) and vertical (p = 0.016) GRF variability in the SLS task, faster FSST time (p = 0.006) and increased ankle PF during gait (p = 0.002). DISCUSSION: This study provides further evidence of balance and gait limitations in people with MS and indicates that a single treatment based on principles of the Bobath concept to the foot and ankle can result in immediate improvements in balance and ankle PF during gait in people with MS. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 25704138 TI - Long-term outcomes of mitral valve repair with the Duran flexible ring. AB - BACKGROUND: Mitral annuloplasty is a reliable mitral valve repair technique. There are two types of annuloplasy rings: the rigid ring and the flexible ring. This study sought to examine the long-term results of mitral valve repair using a Duran flexible ring. METHODS: We retrospectively reviewed 226 patients who underwent primary mitral valve repair using the Duran flexible ring for mitral regurgitation between September 1994 and March 2003. Patients' mean age was 56.7 years, and 39% were female. The mean follow-up was 10.6 years (0.04 ~ 18.3), and echocardiographic follow-up was 83.3% complete. RESULTS: There were three early and 25 late deaths. Survival was 89.3 +/- 2.2 for 10 years, and 83.5 +/- 3.2% for 15 years. The 10- and 15-year freedom from reoperation on the mitral valve were 96.4 +/- 1.4 and 95.3 +/- 1.7%, respectively. The 10- and 15-year freedom from moderate or severe mitral regurgitation were 92.5 +/- 2.2 and 73.7 +/- 7.1%, respectively. Cox regression analysis revealed that age, male gender, and isolated anterior leaflet prolapse were predictive of recurrent moderate or severe mitral regurgitation. CONCLUSIONS: Mitral valve repair for mitral regurgitation using a flexible Duran ring is safe and durable for more than 10 years. PMID- 25704139 TI - Short-term complications in hip fracture surgery using spinal versus general anaesthesia. AB - BACKGROUND: Spinal anaesthesia when compared to general anaesthesia has been shown to decrease postoperative morbidity in orthopaedic surgery. The aim of the present study was to assess the differences in thirty-day morbidity and mortality for patients undergoing hip fracture surgery with spinal versus general anaesthesia. METHODS: The American College of Surgeons National Surgical Quality and Improvement Program (NSQIP) database was used to identify patients who underwent hip fracture surgery with general or spinal anaesthesia between 2010 and 2012 using CPT codes 27245 and 27244. Patient characteristics, complications, and mortality rates were compared. Univariate analysis and multivariate logistic regression were used to identify predictors of thirty-day complications. Stratified propensity scores were employed to adjust for potential selection bias between cohorts. RESULTS: 6133 patients underwent hip fracture surgery with spinal or general anaesthesia; 4318 (72.6%) patients underwent fracture repair with general anaesthesia and 1815 (27.4%) underwent fracture repair with spinal anaesthesia. The spinal anaesthesia group had a lower unadjusted frequency of blood transfusions (39.34% versus 45.49%; p<0.0001), deep vein thrombosis (0.72% versus 1.64%; p=0.004), urinary tract infection (8.87% versus 5.76%; p<0.0001), and overall complications (45.75% versus 48.97%; p=0.001). The length of surgery was shorter in the spinal anaesthesia group (55.81 versus 65.36 min; p<0.0001). After multivariate logistic regression was used to adjust for confounders, general anaesthesia (odds ratio, 1.29; 95% confidence interval, 1.14-1.47; p=0.0002) was significantly associated with increased risk for complication after hip fracture surgery. Age, female sex, body mass index, hypertension, transfusion, emergency procedure, operation time, and ASA score were risk factors for complications after hip fracture repair (all p<0.05). CONCLUSIONS: Patients who underwent hip fracture surgery with general anaesthesia had a higher risk of thirty-day complications as compared to patients who underwent hip fracture repair with spinal anaesthesia. Surgeons should consider using spinal anaesthesia for hip fracture surgery. PMID- 25704140 TI - Outcomes of 807 Thompson hip hemiarthroplasty procedures and the effect of surgical approach on dislocation rates. AB - The majority of displaced intracapsular fractures in our unit are managed with a Thompson hip hemiarthroplasty. Recent UK guidance from the National Institute for Health and Care Excellence has, however, advised against the continued used of the Thompson implant in patients with hip fracture. The aim of this study was to review the outcomes and complications after Thompson hip hemiarthroplasty, including the impact of modern surgical approaches and cementing, whilst controlling for confounding factors. We reviewed the outcomes following Thompson hip hemiarthroplasty from a series of 807 cases performed between April 2008 and November 2013. Of these, 721 (89.3%) were cemented and 86 (10.7%) uncemented. A total of 575 (71.3%) procedures were performed in female patients. The anterolateral approach was performed in 753 (93.3%) and the posterior approach with enhanced soft tissue repair in 54 (6.7%). Overall, there were 23 dislocations (2.9%). Dislocation following the posterior approach occurred in 13.0% (seven of 54) in comparison to 2.1% (16 of 753) with the anterolateral approach (odds ratio (OR) 8.5 (95% confidence interval (CI) 2.8-26.3), p < 0.001). Patients were discharged home in 459 cases (56.9%), to a care home or other hospital in 273 cases (33.8%). Of the total number of patients, 75 died during their admission (9.3%), and 51.8% (338 of 653) returned home within 30 days. The 30-day mortality was 7.1% (57 cases) and the 1-year mortality was 16.6% (116 of 699). We recommend against the continued use of the posterior approach in hip hemiarthroplasty, as enhanced soft tissue repair did not reduce the dislocation rates to an acceptable level in this series utilising the Thompson implant. Our findings, however, demonstrate satisfactory results for patients treated with the Thompson hip hemiarthroplasty performed through an anterolateral approach. We suggest that the continued use of this implant in a carefully selected patient cohort is justifiable. PMID- 25704141 TI - Basal haemoglobin levels as prognostic factor for early death in elderly patients with a hip fracture--A twenty year observation study. AB - INTRODUCTION: Hip fractures are a significant cause of mortality and morbidity in the elderly. This study investigated the relationship between initial haemoglobin (Hb) levels and a prognostic parameter for outcome in those patients. PATIENTS AND METHODS: A total of 3595 consecutive patients with diagnosed hip fractures were included in our study (72.2% females). Anaemia was defined according to WHO criteria, with according subgroups mild, moderate and severe anaemia. Data collection was performed prospectively and statistical evaluation was performed retrospectively. RESULTS: Mean follow up in our study group was 11.2 +/- 0.3 months. The mean age of our study group was 78.5 years (SEM +/- 0.2 years). To facilitate analysis, patients were divided in two groups: <= 84 years (60.1%) and >= 85 years (39.9%). Mortality <12 months was 12.2% (n = 439). In our study population lower Hb levels ad admission were associated with a markedly elevated short-term mortality. In a multivariate logistic regression model adjusted for age and sex, mild anaemia at admission caused a 1.5 (CI: 1.1-1.9), moderate anaemia a 2.6 (95 CI: 2.0-3.4), and severe anaemia a 3.6 (CI: 1.8-6.9) fold increase in three months mortality compared to patients without anaemia. Total lymphocyte count (1.2 +/- 0) did not show any differences between the subgroups. CONCLUSION: Those findings in our study population with 3595 patients over a period of twenty years have proven that initial Hb levels are a useful and cost effective parameter to predict mortality in elderly patients with a hip fracture. This prognostic factor may help to increase the outcome of elderly patients with a hip fracture. PMID- 25704142 TI - Improving secondary prevention screening in clinical encounters using mhealth among prelicensure master's entry clinical nursing students. AB - AIMS: To determine the feasibility and acceptability of a mHealth application among nursing students for health promotion and secondary prevention health recommendations for hospitalized adult patients. METHODS: A pretest-posttest design with a convenience sample of 169 prelicensure master's entry clinical nursing students in a large urban public university. Survey questions assessed intention to use, perceived usefulness, perceived ease of use, subjective norm, voluntariness, clinical area relevance, output quality, and result demonstrability of the United States Preventive Services Task Force (USPSTF) evidence-based practice guidelines via the mHealth application. RESULTS: Descriptive statistics and frequencies were used to explore sociodemographics; paired t-tests were used to evaluate pre- and posttest differences. Pre- and posttest significant differences (p < .01) were found between intention to use, perceived usefulness, subjective norm, voluntariness, image, clinical relevance, result demonstrability, and output quality (p < .02). Ease use of a mHealth application was not significantly different. LINKING EVIDENCE TO ACTION: These findings highlight the need to integrate evidence-based practice tools using mHealth technology among prelicensure master's entry clinical nursing students in order to engage and foster translational learning and improve dissemination of secondary prevention screening guidelines among hospitalized patients. PMID- 25704143 TI - Cep68 can be regulated by Nek2 and SCF complex. AB - Centrosome cohesion maintains centrosomes in close proximity until mitosis, when cell cycle-dependent regulatory signaling events dissolve cohesion and promote centrosome separation in preparation for bipolar spindle assembly at mitosis. Cohesion is regulated by the antagonistic activities of the mitotic NIMA-related kinase 2 (Nek2), protein phosphatase 1, the cohesion fiber components rootletin, centrosomal Nek2-associated protein 1 (C-Nap1) and Cep68. The centrosomal protein Cep68 is essential for centrosome cohesion and dissociates from centrosomes at the onset of mitosis. Here, our cell line studies show the C-terminal 300-400 amino acids of Cep68 are necessary to localize Cep68 to interphase centrosomes while C-terminal 400-500 amino acids might regulate Cep68 dissociation from centrosomes at mitotic onset. In addition, Nek2 was demonstrated to phosphorylate Cep68 in vivo and this phosphorylation appears to promote Cep68 degradation in mitosis. We further show that the SCF complex destroys Cep68 at mitosis through recognition by the beta-Trcp F box component of SCF. Together, the findings provide a new insight into the control of centrosome separation by Cep68 during mitosis. PMID- 25704144 TI - An in-depth analysis of ethics teaching in Canadian physiotherapy and occupational therapy programs. AB - PURPOSE: The purpose of this study was to examine current approaches and challenges to teaching ethics in entry-level Canadian physiotherapy (PT) and occupational therapy (OT) programs. METHODS: Educators responsible for teaching ethics in the 28 Canadian PT and OT programs (n = 55) completed an online survey. RESULTS: The quantity of ethics teaching is highly variable, ranging from 5 to 65 h. Diverse obstacles to ethics teaching were reported, relating to the organization and structure of academic programs, student issues and the topic of ethics itself. Specific challenges included time constraints, large class sizes, a lack of pedagogical tools adapted to teaching this complex subject, a perceived lack of student interest for the subject and a preference for topics related to clinical skills. Of note, 65% of ethics educators who participated in the survey did not have any specialized training in ethics. CONCLUSION: Significant cross program variation in the number of hours dedicated to ethics and the diversity of pedagogical methods used suggests that there is little consensus about how best to teach ethics. Further research on ethics pedagogy in PT and OT programs (i.e. teaching and evaluation approaches and effectiveness of current ethics teaching) would support the implementation of more evidence-based ethics education. Implications for Rehabilitation Ethics educators in Canadian PT and OT programs are experimenting with diverse educational approaches to teach ethical reasoning and decision-making to students, including lectures, problem-based learning, directed readings, videos, conceptual maps and clinical elective debriefing, but no particular method has been shown to be more effective for developing ethical decision-making/reasoning. Thus, research on the effectiveness of current methods is needed to support ethics educators and programs to implement evidence-based ethics education training. In our survey, 65% of ethics educators did not have any specialized training in ethics. Ensuring that educators are well equipped to support the development of necessary theoretical and applied competencies can be promoted by initiatives including the creation of tailored ethics teaching and evaluation tools, and by establishing communities of practice among ethics educators. This survey identified heterogeneity in ethics teaching content, format and duration, and location within the curriculum. In order to be able to assess more precisely the place accorded to ethics teaching in PT and OT programs, careful mapping of ethics content inside and across rehabilitation programs is needed - both in Canada and internationally. These initiatives would help advance understanding of ethics teaching practices in rehabilitation. PMID- 25704145 TI - Hemorrhage due to radiation-induced sarcoma of the mandible: treatment with percutaneous cryotherapy. PMID- 25704146 TI - Ethylene vinyl alcohol copolymer (Onyx(r)) in peripheral interventional radiology: indications, advantages and limitations. AB - Onyx((r)) is a remarkable liquid embolizing agent that may allow a well-trained operator to undertake challenging embolization procedures. In multiple interventional radiology indications, the physico-chemical properties of Onyx((r)) allow safe embolization. The purpose of this article is to review the advantages and disadvantages of Onyx((r)) and identify its main indications. PMID- 25704147 TI - Diffusion-weighted MR imaging in musculoskeletal diseases: current concepts. AB - MR imaging is currently regarded as a pivotal technique for the assessment of a variety of musculoskeletal conditions. Diffusion-weighted MR imaging (DWI) is a relatively recent sequence that provides information on the degree of cellularity of lesions. Apparent diffusion coefficient (ADC) value provides information on the movement of water molecules outside the cells. The literature contains many studies that have evaluated the role of DWI in musculoskeletal diseases. However, to date they yielded conflicting results on the use and the diagnostic capabilities of DWI in the area of musculoskeletal diseases. However, many of them have showed that DWI is a useful technique for the evaluation of the extent of the disease in a subset of musculoskeletal cancers. In terms of tissue characterization, DWI may be an adjunct to the more conventional MR imaging techniques but should be interpreted along with the signal of the lesion as observed on conventional sequences, especially in musculoskeletal cancers. Regarding the monitoring of response to therapy in cancer or inflammatory disease, the use of ADC value may represent a more reliable additional tool but must be compared to the initial ADC value of the lesions along with the knowledge of the actual therapy. PMID- 25704148 TI - Pyogenic spondylodiscitis due to pleurovertebral fistula complicating radiofrequency ablation of pulmonary carcinoma. PMID- 25704149 TI - Management of thyroid nodules on US with benign or atypical cytological features. PMID- 25704150 TI - Necrotizing pseudotumoral hepatic brucelloma: Imaging-pathologic correlation. PMID- 25704151 TI - Health assessments for Indigenous Australians at Orange Aboriginal Medical Service: health problems identified and subsequent follow up. AB - This study aimed to document the types, management and follow up of health issues identified by all Aboriginal Health Assessments (AHA) performed at Orange Aboriginal Medical Service from 1 January 2011 to 31 December 2012. This was done with a retrospective audit of clinical records. In total, 1169 AHAs were performed: 41% child, 53% adult and 6% older person AHAs. Newly identified health issues were documented in 85% (984). Being overweight (41%; 476) and smoking (26%; 301) were the common risk factors identified. As a result of the AHA, most children who were not up-to-date with their vaccinations received catch-up immunisations; 11% (36) of adult women (n=314) received a Pap smear, although Pap smear status was unknown or not up-to-date for 61% (192); 27% (311) of cases were prescribed new medication; and 1239 referrals were made but only 40% were attended. At 6 months following the AHA, 26% (240) of cases with newly identified health issues were completely managed and followed up, whereas 25% (226) received no follow up. The AHAs are useful for identifying new health issues; however, follow up of the identified health issues should be improved. If AHAs are to improve health outcomes, appropriate management and follow up of the identified health issues are essential. PMID- 25704152 TI - Layer number dependence of MoS2 photoconductivity using photocurrent spectral atomic force microscopic imaging. AB - Atomically thin MoS2 is of great interest for electronic and optoelectronic applications because of its unique two-dimensional (2D) quantum confinement; however, the scaling of optoelectronic properties of MoS2 and its junctions with metals as a function of layer number as well the spatial variation of these properties remain unaddressed. In this work, we use photocurrent spectral atomic force microscopy (PCS-AFM) to image the current (in the dark) and photocurrent (under illumination) generated between a biased PtIr tip and MoS2 nanosheets with thickness ranging between n = 1 to 20 layers. Dark current measurements in both forward and reverse bias reveal characteristic diode behavior well-described by Fowler-Nordheim tunneling with a monolayer barrier energy of 0.61 eV and an effective barrier scaling linearly with layer number. Under illumination at 600 nm, the photocurrent response shows a marked decrease for layers up to n = 4 but increasing thereafter, which we describe using a model that accounts for the linear barrier increase at low n, but increased light absorption at larger n creating a minimum at n = 4. Comparative 2D Fourier analysis of physical height and photocurrent images shows high spatial frequency spatial variations in substrate/MoS2 contact that exceed the frequencies imposed by the underlying substrates. These results should aid in the design and understanding of optoelectronic devices based on quantum confined atomically thin MoS2. PMID- 25704153 TI - Spatially varying selection shapes life history clines among populations of Drosophila melanogaster from sub-Saharan Africa. AB - Clines in life history traits, presumably driven by spatially varying selection, are widespread. Major latitudinal clines have been observed, for example, in Drosophila melanogaster, an ancestrally tropical insect from Africa that has colonized temperate habitats on multiple continents. Yet, how geographic factors other than latitude, such as altitude or longitude, affect life history in this species remains poorly understood. Moreover, most previous work has been performed on derived European, American and Australian populations, but whether life history also varies predictably with geography in the ancestral Afro tropical range has not been investigated systematically. Here, we have examined life history variation among populations of D. melanogaster from sub-Saharan Africa. Viability and reproductive diapause did not vary with geography, but body size increased with altitude, latitude and longitude. Early fecundity covaried positively with altitude and latitude, whereas lifespan showed the opposite trend. Examination of genetic variance-covariance matrices revealed geographic differentiation also in trade-off structure, and QST -FST analysis showed that life history differentiation among populations is likely shaped by selection. Together, our results suggest that geographic and/or climatic factors drive adaptive phenotypic differentiation among ancestral African populations and confirm the widely held notion that latitude and altitude represent parallel gradients. PMID- 25704155 TI - Peroxone mineralization of chemical oxygen demand for direct potable water reuse: Kinetics and process control. AB - Mineralization of organics in secondary effluent by the peroxone process was studied at a direct potable water reuse research treatment system serving an occupied four-bedroom, four bath university residence hall apartment. Organic concentrations were measured as chemical oxygen demand (COD) and kinetic runs were monitored at varying O3/H2O2 dosages and ratios. COD degradation could be accurately described as the parallel pseudo-1st order decay of rapidly and slowly oxidizable fractions, and effluent COD was reduced to below the detection limit (<0.7 mg/L). At dosages >=4.6 mg L(-1) h(-1), an O3/H2O2 mass ratio of 3.4-3.8, and initial COD <20 mg/L, a simple first order decay was indicated for both single-passed treated wastewater and recycled mineral water, and a relationship is proposed and demonstrated to estimate the pseudo-first order rate constant for design purposes. At this O3/H2O2 mass ratio, ORP and dissolved ozone were found to be useful process control indicators for monitoring COD mineralization in secondary effluent. Moreover, an average second order rate constant for OH oxidation of secondary effluent organics (measured as MCOD) was found to be 1.24 * 10(7) +/- 0.64 * 10(7) M(-1) S(-1). The electric energy demand of the peroxone process is estimated at 1.73-2.49 kW h electric energy for removal of one log COD in 1 m(3) secondary effluent, comparable to the energy required for desalination of medium strength seawater. Advantages/disadvantages of the two processes for municipal wastewater reuse are discussed. PMID- 25704154 TI - Root-flipped multiband refocusing pulses. AB - PURPOSE: To design low peak power multiband refocusing radiofrequency pulses, with application to simultaneous multislice spin echo MRI. THEORY AND METHODS: Multiband Shinnar-Le Roux beta polynomials were designed using convex optimization. A Monte Carlo algorithm was used to determine patterns of beta polynomial root flips that minimized the peak power of the resulting refocusing pulses. Phase-matched multiband excitation pulses were also designed to obtain linear-phase spin echoes. Simulations compared the performance of the root flipped pulses with time-shifted and phase-optimized pulses. Phantom and in vivo experiments at 7T validated the function of the root-flipped pulses and compared them to time-shifted spin echo signal profiles. RESULTS: Averaged across number of slices, time-bandwidth product, and slice separation, the root-flipped pulses have 46% shorter durations than time-shifted pulses with the same peak radiofrequency amplitude. Unlike time-shifted and phase-optimized pulses, the root-flipped pulses' excitation errors do not increase with decreasing band separation. Experiments showed that the root-flipped pulses excited the desired slices at the target locations, and that for equivalent slice characteristics, the shorter root-flipped pulses allowed shorter echo times, resulting in higher signal than time-shifted pulses. CONCLUSION: The proposed root-flipped multiband radiofrequency pulse design method produces low peak power pulses for simultaneous multislice spin echo MRI. PMID- 25704156 TI - Modelling the fate of nitrite in an urbanized river using experimentally obtained nitrifier growth parameters. AB - Maintaining low nitrite concentrations in aquatic systems is a major issue for stakeholders due to nitrite's high toxicity for living species. This study reports on a cost-effective and realistic approach to study nitrite dynamics and improve its modelling in human-impacted river systems. The implementation of different nitrifying biomasses to model riverine communities and waste water treatment plant (WWTP)-related communities enabled us to assess the impact of a major WWTP effluent on in-river nitrification dynamics. The optimal kinetic parameters and biomasses of the different nitrifying communities were determined and validated by coupling laboratory experiments and modelling. This approach was carried out in the Seine River, as an example of a large human-impacted river with high nitrite concentrations. The simulation of nitrite fate was performed at a high spatial and temporal resolution (Deltat = 10 min, dx- = 500 m) including water and sediment layers along a 220 km stretch of the Seine River for a 6-year period (2007-2012). The model outputs were in good agreement with the peak of nitrite downstream the WWTP as well as its slow decrease towards the estuary. Nitrite persistence between the WWTP and the estuary was mostly explained by similar production and consumption rates of nitrite in both water and sediment layers. The sediment layer constituted a significant source of nitrite, especially during high river discharges (0.1-0.4 mgN h(-1) m(-2)). This points out how essential it is to represent the benthic layer in river water quality models, since it can constitute a source of nitrite to the water-column. As a consequence of anthropogenic emissions and in-river processes, nitrite fluxes to the estuary were significant and varied from 4.1 to 5.5 TN d(-1) in low and high water discharge conditions, respectively, over the 2007-2012 period. This study provides a methodology that can be applied to any anthropized river to realistically parametrize autochthonous and WWTP-related nitrifier communities and simulate nitrite dynamics. Based on simulation analysis, it is shown that high spatio-temporal resolution hydro-ecological models are efficient to 1) estimate water quality criteria and 2) forecast the effect of future management strategies. Process-based simulations constitute essential tools to complete our understanding of nutrient cycling, and to decrease monitoring costs in the context of water quality and eutrophication management in river ecosystems. PMID- 25704157 TI - Sex-related differences in patients with ST-elevation myocardial infarction undergoing primary PCI: A long-term mortality study. AB - OBJECTIVES: To assess sex differences in clinical presentation, in-hospital and long-term outcome in ST-elevated myocardial infarction (STEMI) patients undergoing primary PCI (PPCI). BACKGROUND: Several studies have shown higher rates of mortality in women. These differences are not always confirmed after adjusting for confounding variables. METHODS: From January 2007 to December 2011, 325 consecutive patients (23.1% females and 76.9% males) were prospectively treated and retrospectively analyzed. Primary outcome was in-hospital and long term mortality. RESULTS: Women were older (71.8+/-11.7 vs. 62.5+/-12.6years; p<0.0001), presented more renal failure (45.3% vs. 20.8%; p<0.0001) and severe haemodynamic impairment (9.3% vs. 3.6%; p=0.04). In-hospital overall mortality (14.7% vs. 4.8%; p=0.003) and cardiac death (12% vs. 2%; p=0.002) were significantly higher in women. The multivariate analysis identified age (OR 1.07; 95% CI: 1.01-1.13), resuscitated cardiac arrest (CCA) and cardiogenic shock (CS) (OR 15.31; 95% CI: 4.30-61.75), renal failure (OR 0.20; 95% CI: 0.06-0.68), but not sex (OR 1.49; 95% CI: 0.53-4.22) as independent prognostic factors of in hospital mortality. During a median follow-up of 46.5months (IQR range 32.7 63.1months), long-term overall mortality (24.2% vs. 11.0%; p=0.007) and cardiac death (4.8% vs. 1.7%; p=0.02) were significantly higher in women. The multivariate analysis identified age (HR 1.06; 95% CI: 1.02-1.11), previous AMI (HR 3.9; 95% CI: 1.63-9.35), renal failure (HR 5.21; 95% CI: 2.12-12.85), technical success (HR 0.35; 95% CI: 0.14-0.84) but not sex (HR 0.90; 95% CI: 0.42 1.94) as independent prognostic factors of long-term mortality. CONCLUSIONS: Worse clinical presentation rather than sex may explain the excess of mortality in women with STEMI undergoing PPCI. PMID- 25704158 TI - Administration of erythropoietin in patients with myocardial infarction: does it make sense? An updated and comprehensive meta-analysis and systematic review. AB - This systematic review with meta-analysis sought to determine protective effects of erythropoietin on clinical outcomes following percutaneous coronary intervention (PCI). Medline, Embase, Elsevier and Sciences online database as well as Google scholar literature were used for selecting appropriate studies with randomized controlled design. The effect sizes measured were odds ratio (OR) for categorical variables and weighted mean difference (WMD) with 95% confidence interval for calculating differences between mean values of duration of hospitalization in intervention and control groups. Values of P<0.1 for Q test or I(2)>50% indicated significant heterogeneity between the studies. The literature searches of all major databases retrieved 973 studies. After screening, a total of 15 trials that reported outcomes were identified. Pooled analysis was performed on left ventricular ejection fraction (WMD of -0.047; 95% CI: -0.912 to 0.819; P=0.9), left ventricular end diastolic volume (WMD of -0.363; 95% CI: 3.902 to 3.175; P=0.8), left ventricular end systolic volume (WMD of 0.346; 95% CI: -2.533 to 3.226; P=0.8), infarct size (WMD of -0.446; 95% CI: -2.352 to 1.460; P=0.6), stroke (OR of 2.1; 95% CI: 0.58 to 7.54; P=0.2), re-myocardial infarction (OR of 1.06; 95% CI: 0.52 to 2.185; P=0.8), heart failure (OR of 0.53; 95% CI: 0.259 to 1.105; P=0.09), mortality (OR of 0.56; 95% CI: 0.27 to 1.19; P=0.13), thrombosis (OR of 0.774; 95% CI: 0.41 to 1.45; P=0.4), major adverse cardiovascular events (OR of 0.926; 95% CI: 0.63 to 1.35; P=0.6). Short-term administration of EPO in patients with myocardial infarction (MI) undergoing PCI does not result in improvement in cardiac function, reduction of infarct size and all-cause mortality. Low dose EPO therapy may not be the choice of treatment for the patients with MI, while higher doses might be more effective. PMID- 25704159 TI - Selective biomineralization of Co3(PO4)2-sponges triggered by His-tagged proteins: efficient heterogeneous biocatalysts for redox processes. AB - We report a selective method to make functional bio-inorganic materials by mineralizing cobalt-phosphate in the presence of His-tagged enzymes. We have demonstrated that the His-tag drives the biomineralization forming sponge-like structures where both inorganic and biological elements co-localize. The bio inorganic catalysts were re-used for several redox reaction cycles demonstrating their potential to be used in synthetic chemistry. PMID- 25704160 TI - Isolation and Identification of Brucella melitensis Biovar 3 from Vaccinated Small Ruminants: A Public Health Threat in Kosovo. AB - In 2011, a human brucellosis case with severe clinical symptoms was reported at the University Clinic for Infectious Diseases in Prishtina, Kosovo. A trace-back investigation was conducted to find the source of human infection. A total of 49 blood samples and 15 corresponding milk samples from sheep and goats raised on the patient's farm were taken for serological and molecular analysis. Serology using RBT and CFT revealed 11 positive animals. Twelve milk samples were PCR positive. A Brucella strain isolated from a goat's milk sample was classified as Brucella melitensis biovar 3, indicating the first ever isolation and report in Kosovo. The use of the Bruce-ladder PCR provided differentiation between the field strain and the vaccine strain. Hence, the accidental transmission of the vaccine strain Rev 1 that was previously used for the vaccination of the farm animals could be excluded. The findings of this study show that brucellosis is still a public health threat in Kosovo despite control measures. PMID- 25704161 TI - Cotton major latex protein 28 functions as a positive regulator of the ethylene responsive factor 6 in defense against Verticillium dahliae. AB - In this study, we identified a defense-related major latex protein (MLP) from upland cotton (designated GhMLP28) and investigated its functional mechanism. GhMLP28 transcripts were ubiquitously present in cotton plants, with higher accumulation in the root. Expression of the GhMLP28 gene was induced by Verticillium dahliae inoculation and was responsive to defense signaling molecules, including ethylene, jasmonic acid, and salicylic acid. Knockdown of GhMLP28 expression by virus-induced gene silencing resulted in increased susceptibility of cotton plants to V. dahliae infection, while ectopic overexpression of GhMLP28 in tobacco improved the disease tolerance of the transgenic plants. Further analysis revealed that GhMLP28 interacted with cotton ethylene response factor 6 (GhERF6) and facilitated the binding of GhERF6 to GCC box element. Transient expression assay demonstrated that GhMLP28 enhanced the transcription factor activity of GhERF6, which led to the augmented expression of some GCC-box genes. GhMLP28 proteins were located in both the nucleus and cytoplasm and their nuclear distribution was dependent on the presence of GhERF6. Collectively, these results demonstrate that GhMLP28 acts as a positive regulator of GhERF6, and synergetic actions of the two proteins may contribute substantially to protection against V. dahliae infection in cotton plants. PMID- 25704162 TI - Cyanobacterial flv4-2 Operon-Encoded Proteins Optimize Light Harvesting and Charge Separation in Photosystem II. AB - Photosystem II (PSII) complexes drive the water-splitting reaction necessary to transform sunlight into chemical energy. However, too much light can damage and disrupt PSII. In cyanobacteria, the flv4-2 operon encodes three proteins (Flv2, Flv4, and Sll0218), which safeguard PSII activity under air-level CO2 and in high light conditions. However, the exact mechanism of action of these proteins has not been clarified yet. We demonstrate that the PSII electron transfer properties are influenced by the flv4-2 operon-encoded proteins. Accelerated secondary charge separation kinetics was observed upon expression/overexpression of the flv4-2 operon. This is likely induced by docking of the Flv2/Flv4 heterodimer in the vicinity of the QB pocket of PSII, which, in turn, increases the QB redox potential and consequently stabilizes forward electron transfer. The alternative electron transfer route constituted by Flv2/Flv4 sequesters electrons from QB(-) guaranteeing the dissipation of excess excitation energy in PSII under stressful conditions. In addition, we demonstrate that in the absence of the flv4-2 operon encoded proteins, about 20% of the phycobilisome antenna becomes detached from the reaction centers, thus decreasing light harvesting. Phycobilisome detachment is a consequence of a decreased relative content of PSII dimers, a feature observed in the absence of the Sll0218 protein. PMID- 25704163 TI - Arabidopsis DET1 represses photomorphogenesis in part by negatively regulating DELLA protein abundance in darkness. AB - Arabidopsis De-etiolated 1 (DET1) is one of the key repressors that maintain the etiolated state of seedlings in darkness. The plant hormone gibberellic acid (GA) also participates in this process, and plants deficient in GA synthesis or signaling show a partially de-etiolated phenotype in darkness. However, how DET1 and the GA pathway work in concert in repressing photomorphogenesis remains largely unknown. In this study, we found that the abundance of DELLA proteins in det1-1 was increased in comparison with that in the wild-type plants. Mutation in DET1 changed the sensitivity of hypocotyl elongation of mutant seedlings to GA and paclobutrazol (PAC), an inhibitor of GA synthesis. However, we did not find obvious differences between det1-1 and wild-type plants with regard to the bioactive GA content or the GA signaling upstream of DELLAs. Genetic data showed that removal of several DELLA proteins suppressed the det1-1 mutant phenotype more obviously than GA treatment, indicating that DET1 can regulate DELLA proteins via some other mechanisms. In addition, a large-scale transcriptomic analysis revealed that DET1 and DELLAs play antagonistic roles in regulating expression of photosynthetic and cell elongation-related genes in etiolated seedlings. Taken together, our results show that DET1 represses photomorphogenesis in darkness in part by reducing the abundance of DELLA proteins. PMID- 25704164 TI - Crystal structure analysis of extrinsic PsbP protein of photosystem II reveals a manganese-induced conformational change. PMID- 25704165 TI - Microrheological insights into the dynamics of amyloplasts in root gravity sensing cells. PMID- 25704166 TI - Characteristics of keratinocytes in facial solar lentigo with flattened rete ridges: comparison with melasma. AB - BACKGROUND: Flattened rete ridges occurring on the face are not uncommon in solar lentigo (SL). AIM: To investigate the morphological changes of keratinocytes in facial SL with flattened rete ridges and melasma. METHODS: In total, 25 patients with facial SL showing flattened rete ridges and 20 patients with melasma, in which rete ridge flattening is also a common feature, were included in the study. Skin biopsies were performed on lesional skin and perilesional normal skin. RESULTS: The histological findings showed that the epidermis was significantly thicker in SL skin with flattened rete ridges compared with perilesional normal skin. Comparative quantitative analysis of epidermal morphology revealed that the individual keratinocytes were larger in size in lesional skin, without a significant change in the number of cells. Anti-p16 antibody staining was more intense in lesional epidermis, suggesting senescence of keratinocytes in the thickened epidermis. By contrast, melasma samples showed no significant difference in epidermal thickness or keratinocyte morphology in terms of number or size compared with normal skin. CONCLUSIONS: These findings suggest that senescent changes in keratinocytes are important in the development of SL, even in the absence of rete ridge elongation, and the removal of keratinocytes harbouring melanin could be a possible strategy for SL treatment. PMID- 25704167 TI - Exercise-induced ventricular re-polarisation changes in moderate congenital aortic valve stenosis. AB - Introduction Pressure overload increases in patients with moderate aortic valvular stenosis during exercise. In the absence of symptoms, it remains difficult, however, to discriminate patients for surgery based only on pressure overload. Other parameters, such as the dispersion of ventricular re-polarisation (d-QT), which reportedly increases with the transvalvular pressure gradient, have not been fully studied in this condition. OBJECTIVE: To determine the pattern of QT and d-QT response to exercise testing in children with moderate aortic valve stenosis in order to evaluate the impact of pressure overload from an electrophysiological perspective. Materials and methods In all, 15 patients were compared with 15 controls paired for age (14.8+/-2.5 versus 14.2+/-1.5 years old) and gender (66.7% male). All the patients underwent exercise stress testing with 12-lead electrocardiograph recording. QT was measured from the onset of QRS to the apex (QTa) at rest, at peak exercise, and at 1 and 3 minutes upon recovery. QT was corrected using the Fridericia equation, and d-QT was calculated. RESULTS: Resting QTc was similar among the study groups, but increased significantly in study patients compared with the control group at maximal effort (p=0.004) and after 1 (p<0.001) and 3 (p<0.001) minutes of recovery. A significant association was identified between groups for d-QT (p=0.034), and post-hoc tests revealed a significant difference only at rest (p=0.001). CONCLUSIONS: Ventricular re polarisation abnormalities can be unmasked and highlighted by the assessment of electrical re-polarisation during exercise challenge in patients with asymptomatic moderate aortic valve stenosis. Using QT response to exercise could be beneficial for better optimisation of risk stratification in these patients. PMID- 25704168 TI - Photoswitching Behavior of a Cyclohexene-Bridged versus a Cyclopentene-Bridged Dithienylethene System. AB - Photoswitching is an intriguing way of incorporating functionality into molecules or their subunits. Dithienylethene switches are particularly promising, but have so far mostly been studied with five-membered ring (cyclopentenyl) backbones. We aim at comparing the switching properties of backbones with five and six carbon atoms in the ring. A major advantage is that cyclohexenyl rings offer new options for chiral functionalization. A slight change in the reaction conditions of a McMurry ring closure reaction leads to the formation of dithienyl derivatives with a cyclohexene backbone in reasonable yield. Density functional theory calculations were carried out, demonstrating the similarity of both compounds. Experimental results confirm the theoretical outcomes. PMID- 25704169 TI - Effects of pro-inflammatory cytokines on cannabinoid CB1 and CB2 receptors in immune cells. AB - AIMS: To investigate the regulation of cannabinoid receptors CB1 and CB2 on immune cells by pro-inflammatory cytokines and its potential relevance to the inflammatory neurological disease, multiple sclerosis (MS). CB1 and CB2 signalling may be anti-inflammatory and neuroprotective in neuroinflammatory diseases. Cannabinoids can suppress inflammatory cytokines but the effects of these cytokines on CB1 and CB2 expression and function are unknown. METHODS: Immune cells from peripheral blood were obtained from healthy volunteers and patients with MS. Expression of CB1 and CB2 mRNA in whole blood cells, peripheral blood mononuclear cells (PBMC) and T cells was determined by quantitative real time polymerase chain reaction (qRT-PCR). Expression of CB1 and CB2 protein was determined by flow cytometry. CB1 and CB2 signalling in PBMC was determined by Western blotting for Erk1/2. RESULTS: Pro-inflammatory cytokines IL-1beta, IL-6 and TNF-alpha (the latter likely NF-kappaB dependently) can upregulate CB1 and CB2 on human whole blood and peripheral blood mononuclear cells (PBMC). We also demonstrate upregulation of CB1 and CB2 and increased IL-1beta, IL-6 and TNF alpha mRNA in blood of patients with MS compared with controls. CONCLUSION: The levels of CB1 and CB2 can be upregulated by inflammatory cytokines, which can explain their increase in inflammatory conditions including MS. PMID- 25704170 TI - A comparison of high- and low-virulence Flavobacterium columnare strains reveals differences in iron acquisition components and responses to iron restriction. AB - Flavobacterium columnare, the causative agent of columnaris disease causes substantial mortality worldwide in numerous freshwater finfish species. Due to its global significance, an improved understanding of the factors that contribute to virulence is urgently needed. In a laboratory challenge, we found that significantly greater mortality was observed in channel catfish Ictalurus punctatus (Rafinesque) challenged with isolate LSU-066-04 (LSU) as compared to fish challenged with isolate LV-359-01 (LV). Strikingly, mortality was 100% in LSU-challenged fish, with all fish dying within the first 24 h after challenge, while mortality in the LV-challenged group was significantly lower with 26.7% of fish dying on days 1-4 post-challenge. There were no differences in initial bacterial adhesion between the isolates at 1-2 h post-challenge; however, by 4 h LSU-challenged fish had a greater bacterial load on the gill. Next, to better understand this variation in virulence, we examined transcriptional and functional attributes related to iron acquisition. The isolates were differentially sensitive to iron restriction both in vitro and in vivo and the basal expression of TonB family member genes and a ferroxidase gene differed significantly. Our findings provide new insight into iron uptake and pathogen virulence, and offer promising new targets for columnaris prevention and treatment. PMID- 25704172 TI - Synthesis of well-defined adenosine diphosphate ribose oligomers. AB - The post-translational modification of proteins that is known as adenosine diphosphate ribosylation (ADPr) regulates a wide variety of important biological processes, such as DNA-damage repair and cellular metabolism. This modification is also involved in carcinogenesis and the process of aging. Therefore, a better understanding of the function of ADP-ribosylation is crucial for the development of novel therapeutics. To facilitate the elucidation of the biology of ADPr, the availability of well-defined fragments of poly(ADP-ribose) is essential. Herein we report a solid-phase synthetic approach for the preparation of ADP-ribose oligomers of exactly defined length. The methodology is exemplified by the first reported synthesis of an ADP-ribose dimer and trimer. PMID- 25704171 TI - Prenatal exposure of guinea pigs to the organophosphorus pesticide chlorpyrifos disrupts the structural and functional integrity of the brain. AB - This study was designed to test the hypothesis that prenatal exposure of guinea pigs to the organophosphorus (OP) pesticide chlorpyrifos (CPF) disrupts the structural and functional integrity of the brain. Pregnant guinea pigs were injected with chlorpyrifos (25 mg/kg, s.c.) or vehicle (peanut oil) once per day for 10 consecutive days, starting approximately on the 50th day of gestation. Cognitive behavior of female offspring was examined starting at 40-45 post-natal days (PND) using the Morris water maze (MWM), and brain structural integrity was analyzed at PND 70 using magnetic resonance imaging (MRI) methods, including T2 weighted anatomical scans and diffusion kurtosis imaging (DKI). The offspring of exposed mothers had significantly decreased body weight and brain volume, particularly in the frontal regions of the brain including the striatum. Furthermore, the offspring demonstrated significant spatial learning deficits in MWM recall compared to the vehicle group. Diffusion measures revealed reduced white matter integrity within the striatum and amygdala that correlated with spatial learning performance. These findings reveal the lasting effect of prenatal exposure to CPF as well as the danger of mother to child transmission of CPF in the environment. PMID- 25704181 TI - A novel tribological study on DLC-coated micro-dimpled orthopedics implant interface. AB - This study investigates a tribological performance of diamond like carbon (DLC) coated micro dimpled prosthesis heads against ceramic cups in a novel pendulum hip joint simulator. The simulator enables determining friction coefficient and viscous effects of a concave shaped specimen interface (conformal contact). Two types of DLC such as hydrogenated amorphous carbon (a-C:H) and tetrahedral amorphous carbon (Ta-C) and one set of micro dimple (diameter of 300um, depth of 70um, and pitch of 900um) were fabricated on metallic prosthesis heads. The experiment results reveal a significant friction coefficient reduction to the 'dimpled a-C:H/ceramic' prosthesis compared to a 'Metal (CoCr)/ceramic' prosthesis because of their improved material and surface properties and viscous effect. The post-experiment surface analysis displays that the dimpled a-C:H yielded a minor change in the surface roughness, and generated a larger sizes of wear debris (40-200nm sized, equivalent diameter), a size which could be certainly stored in the dimple, thus likely to reducing their possible third body abrasive wear rate. Thus, dimpled a:C-H can be used as a 'metal on ceramic hip joint interface', whereas the simulator can be utilized as an advanced bio tribometer. PMID- 25704182 TI - Epigenetic dysregulation of KCa 3.1 channels induces poor prognosis in lung cancer. AB - Epigenomic changes are an important feature of malignant tumors. How tumor aggressiveness is affected by DNA methylation of specific loci is largely unexplored. In genome-wide DNA methylation analyses, we identified the KCa 3.1 channel gene (KCNN4) promoter to be hypomethylated in an aggressive non-small cell lung carcinoma (NSCLC) cell line and in patient samples. Accordingly, KCa 3.1 expression was increased in more aggressive NSCLC cells. Both findings were strong predictors for poor prognosis in lung adenocarcinoma. Increased KCa 3.1 expression was associated with aggressive features of NSCLC cells. Proliferation and migration of pro-metastatic NSCLC cells depended on KCa 3.1 activity. Mechanistically, elevated KCa 3.1 expression hyperpolarized the membrane potential, thereby augmenting the driving force for Ca(2+) influx. KCa 3.1 blockade strongly reduced the growth of xenografted NSCLC cells in mice as measured by positron emission tomography-computed tomography. Thus, loss of DNA methylation of the KCNN4 promoter and increased KCa 3.1 channel expression and function are mechanistically linked to poor survival of NSCLC patients. PMID- 25704183 TI - Helicobacter pylori Induces Serine Phosphorylation of EGFR via Novel TAK1-p38 Activation Pathway in an HB-EGF-Independent Manner. AB - BACKGROUND: The interaction of Helicobacter pylori with gastric epithelial cells can result in the activation of transcription factor NF-kappaB via TGF-beta activated kinase 1 (TAK1). In this study, we have demonstrated the role of H. pylori in the activation of EGFR via TAK1-mediated phosphorylation of p38. MATERIALS AND METHODS: Gastric epithelial AGS or MKN-45 cells were co-cultured with wild-type or cagA(-) H. pylori strains. H. pylori was added to the cells, and the activation of EGFR, p65 (NF-kappaB) subunit, p38, ERK, and TAK1 was examined by Western blotting. Infected cells were pretreated with or without ligands, chemical inhibitors, anti-HB-EGF antibody, and siRNAs to evaluate the effects on phosphorylation of various EGFR residues. Fluorescence microscopy and flow cytometry were performed to detect the internalization of EGFR. RESULTS: Incubating cells with wild-type and CagA(-) H. pylori strains resulted in the rapid and transient phosphorylation of serine residues of EGFR. RNAi experiments using siRNA against TAK1 and p38 pathways blocked the phosphorylation of serine residue. Immunofluorescence and flow cytometry revealed that EGFR was internalized in H. pylori-infected cells after EGFR phosphorylation in a p38 dependent manner. In contrast, pretreatment with gefitinib and anti-HB-EGF antibody did not block both the phosphorylation and internalization of EGFR. CONCLUSION: Helicobacter pylori induces internalization of EGFR via novel TAK1 p38-serine activation pathway which is independent of HB-EGF. The interaction between TAK1 and EGFR in H. pylori-infected cells might open new dimensions in understanding H. pylori-associated gastric carcinogenesis. PMID- 25704184 TI - Early identification of an atypical case of type A dissection by transthoracic echocardiography by the emergency physician. AB - Thoracic aortic dissection is a lethal disease, and emergency department diagnosis is limited by imperfect diagnostic testing and limited resources;however, this case report illustrates the nonspecific presentation of thoracic aortic dissection and the use of emergency physician use of transthoracic echocardiography with the addition of suprasternal notch views to help differentiate all-cause chest pain and aid in accurate diagnosis,as well as earlier surgical correction for best patient outcomes in cases of thoracic aortic dissection. PMID- 25704185 TI - Mitral valve thrombosis in pregnancy: successful restoration with thrombolysis. PMID- 25704186 TI - The utility of inferior vena cava diameter and the degree of inspiratory collapse in patients with systolic heart failure. AB - INTRODUCTION: Both inferior vena cava (IVC) diameter and the degree of inspiratory collapse are used in the estimation of right atrial pressure. AIM: The purpose of this study is to evaluate the utility of IVC diameter, using echocardiography as a marker of volume overload and the relationship between these parameters and N-terminal pro-B natriuretic peptide (NT-proBNP) in patients with systolic heart failure (HF). METHODS: We included 136 consecutive patients with systolic HF (left ventricular ejection fraction, <50%), including 80 patients with acutely decompensated HF and 56 patients with compensated HF as well as 50 subjects without a diagnosis of HF. All patients underwent transthoracic echocardiography to assess both their IVC diameters and the degree of inspiratory collapse (>=50%, <50%, and no change [absence] groups); NT-proBNP levels were measured, and these data were compared between the 2 groups. RESULTS: Inferior vena cava diameter and NT-proBNP were significantly higher among the patients with HF than among the control subjects (21.7 +/- 2.6 vs 14.5 +/- 1.6 mm, P < .001 and 4789 [330-35000] vs 171 [21-476], P < .001). The mean IVC diameter was higher among the patients with decompensated HF than among the patients with compensated HF (23.2 +/- 2.1 vs 19.7 +/- 1.9 mm, P < .001). The values of NT-proBNP were associated with different collapsibility of IVC subgroups among HF patients. The NT-proBNP levels were 2760 (330-27336), 5400 (665-27210), and 16806 (1786-35000), regarding the collapsibility of the IVC subgroups: greater than or equal to 50%, less than 50%, and absence groups, P < .001, respectively, among HF patients. There was a significant positive correlation between IVC diameter and NT-proBNP (r = 0.884, P < .001). A cut off value of an IVC diameter greater than or equal to 20.5 mm predicted a diagnosis of compensated HF with a sensitivity of 90% and a specificity of 73%. CONCLUSIONS: Inferior vena cava diameter correlated significantly with NT-proBNP in patients with HF. Inferior vena cava diameter may be a useful variable in determining a patient's volume status in the setting of HF and may also enable clinicians to distinguish patients with decompensated HF from those with compensated HF. PMID- 25704187 TI - Brain natriuretic peptide: the reason of respiratory distress is heart disease or lung disease? AB - OBJECTIVES: The aim of this study was to determine whether plasma levels of amino terminal brain natriuretic peptide (BNP) could differentiate between heart failure and lung disease among infants with acute bronchiolitis. METHODS: Sixty eight infants (age range, 1-26 months; median age, 5.9 +/- 5.0 months) who presented with respiratory distress underwent physical examination, plasma BNP measurement, and echocardiography within 24 hours after admission. Nineteen (28%) patients had congenital heart disease. The control group was consisted of 30 healthy infants. RESULTS: Although mean plasma BNP levels were 118.9 +/- 219.5 pg/mL in patients with isolated bronchiolitis (n = 49), it was 841.2 +/- 1475.8 pg/mL in patients with congenital heart disease (n = 19). Plasma BNP levels were significantly higher in infants with congenital heart disease (P = .001). CONCLUSION: It was shown that plasma BNP levels were affected much more in cardiac disease rather than lung disease. Among infants with respiratory distress, plasma BNP measurements can differentiate congenital heart disease and lung disease and can be used to monitor the effects of treatment for infants with heart failure. RESPONSE TO REVIEWERS: The comments were taken for consideration. The patient groups control BNP levels were attached to the results. As it was a clinical study and multiple factors (respiratory score, respiratory rate, treatment, etc) may effect on BNP levels, the tables could not be decreased to 1 table. PMID- 25704188 TI - Actual and perceived exposure to electromagnetic fields and non-specific physical symptoms: an epidemiological study based on self-reported data and electronic medical records. AB - BACKGROUND: There is continuing scientific debate and increasing public concern regarding the possible effects of electromagnetic fields (EMF) on general population's health. To date, no epidemiological study has investigated the possible association between actual and perceived EMF exposure and non-specific physical symptoms (NSPS) and sleep quality, using both self-reported and general practice (GP)-registered data. METHODS: A health survey of adult (>= 18) participants (n=5933) in the Netherlands was combined with the electronic medical records (EMRs) of NSPS as registered by general practitioners. Characterization of actual exposure was based on several proxies, such as prediction models of radiofrequency (RF)-EMF exposure, geo-coded distance to high-voltage overhead power lines and self-reported use/distance of/to indoor electrical appliances. Perceived exposure and the role of psychological variables were also examined. RESULTS: Perceived exposure had a poor correlation with the actual exposure estimates. No significant association was found between modeled RF-EMF exposure and the investigated outcomes. Associations with NSPS were observed for use of an electric blanket and close distance to an electric charger during sleep. Perceived exposure, perceived control and avoidance behavior were associated with the examined outcomes. The association between perceived exposure was stronger for self-reported than for GP-registered NSPS. There was some indication, but no consistent pattern for an interaction between idiopathic environmental intolerance (IEI-EMF) and the association between actual exposure and NSPS. CONCLUSIONS: In conclusion, there is no convincing evidence for an association between everyday life RF-EMF exposure and NSPS and sleep quality in the population. Better exposure characterization, in particular with respect to sources of extremely low frequency magnetic fields (ELF-MF) is needed to draw more solid conclusions. We argue that perceived exposure is an independent determinant of NSPS. PMID- 25704189 TI - Environmental carcinogens and mutational pathways in atherosclerosis. AB - Atherosclerosis is associated with DNA damage in both circulating and vessel-wall cells and DNA adducts derived from exposure to environmental mutagens are abundant in atherosclerotic vessels. Environmental chemical carcinogens identified as risk factor for atherosclerosis include polycyclic aromatic hydrocarbons (benzo(a)pyrene, dimethylbenz(a)anthracene, beta-naphthoflavone, pyrene, 3-methylcolanthrene), arsenic, cadmium, 1,3-butadiene, cigarette smoke. Accordingly, polymorphisms of genes encoding for phase I/II metabolic reaction and DNA repair are risk factor for cardiovascular diseases, although their role is negligible as compared to other risk factors. The pathogenic relevance of mutation-related molecular damage in atherosclerosis has been demonstrated in experimental animal models involving the exposure to chemical mutagens. The relevance of mutation-related events in worsening atherosclerosis prognosis has been demonstrated in human clinical studies mainly as referred to mitochondrial DNA damage. Atherosclerosis is characterized by the occurrence of high level of oxidative damage in blood vessel resulting from both endogenous and exogenous sources. Mitochondrial damage is a main endogenous source of oxidative stress whose accumulation causes activation of intrinsic apoptosis through BIRC2 inhibition and cell loss contributing to plaque development and instability. Environmental physical mutagens, including ionizing radiation, are a risk factor for atherosclerosis even at the low exposure dose occurring in case of occupational exposure or the high exposure doses occurring during radiotherapy. Conversely, the role of exciting UV radiation in atherosclerosis is still uncertain. This review summarizes the experimental and clinical evidence supporting the pathogenic role of mutation-related pathway in atherosclerosis examining the underlying molecular mechanisms. PMID- 25704190 TI - Elevated expression of Notch-1 and EGFR induced apoptosis in glioblastoma multiforme patients. AB - OBJECTIVE: The Notch signaling pathway has been well recognized as important adjuster in glioma tumorigenesis and could regulate the glioma cell proliferation through downstream factors such as epidermal growth factor receptor (EGFR). Our current study was aim to investigate the clinical association between Notch-1 gene and EGFR gene as well as cell survival rate in human glioblastoma multiforme (GBM) samples. PATIENTS AND METHODS: Samples from 90 patients with GBMs and 20 normal brain tissues were analyzed in our study. Western blot and immunohistochemistry was used to detect Notch and EGFR protein expression. RT-PCR was used to detect Notch and EGFR mRNA expression. Apoptosis was detected with flow cytometry. RESULTS: Results demonstrated that the Notch and EGFR gene mRNA and protein levels were dramatically higher in GBM tissues compared to normal brain. Further analysis found these increased mRNA levels were only associated with patient survival period, but not related to patient age, gender and tumor size. A positive correlation was observed between Notch and EGFR protein expression. The positive correlations were also exhibited between Notch-1, EGFR gene expression and apoptosis percentage. CONCLUSION: Our study verified both Notch-1 and EGFR involved in GBM tumorigenesis and may provide important information for GBM clinical treatment and prognosis. PMID- 25704191 TI - Cryptococcal meningitis in Chinese patients with systemic lupus erythematosus. AB - OBJECTIVE: Systemic lupus erythematosus (SLE) is a chronic immunologic disorder that can affect multiple organ systems and makes the patient susceptible to infection. Cryptococcal meningitis (CM) is a rare but often fatal complication of SLE. DESIGN: In this study, 6 patients with CM were identified among 631 patients with SLE. The demographic, clinical, laboratory profiles, serological features and outcomes of these 6 SLE patients with CM were retrospectively analyzed. RESULTS: The mean age of these patients was 24.1 years (range 12-42) at the time of SLE diagnosis, and 27.1 years (range 14-42) at the time of Cryptococcus neoformans infection, with mean disease duration of 37 months (range 3-72). Four patients had active SLE. All patients were receiving glucocorticoids therapy (mean prednisone dose of 20.5 (5.0-36.0) mg/day) at the onset of infection. Five patients had received other immunosuppressive drugs. The most common presentations of CM were headache and fever and 4 of the 6 patients were normal on physical examination. The cerebrospinal fluid (CSF) indices (protein and glucose) were normal in 4 cases, whereas they were mildly abnormal in the other 2 patients. White counts in the CSF ranged from 8 to 240 cells/mm. C. neoformans were isolated from CSF of 4 patients. The isolation of crytococci from extraneural sites, including blood and lungs, was found in 2 patients. Results of the head computed tomography scan were unremarkable in 5 of the patients. The infection was completely resolved in 5 patients, and it was resolved with serious sequelae in one patient. CONCLUSIONS: In conclusion, the key to a rapid diagnosis of CM in patients with SLE is to maintain a high degree of awareness which will help avoid delays in treatment. This is mainly due to the fact that the clinical presentation and laboratory results from routine hematological, biochemical and CSF analyses of CM in patients with SLE are mostly non-specific. PMID- 25704192 TI - The value of intraoperative sonography in low grade glioma surgery. AB - OBJECTIVE: There is a number of different methods to localize a glioma intraoperatively. Neuronavigation, intraoperative MRI, 5-aminolevulinic acid, as well as intraoperative sonography. Every method has its advantages and disadvantages. Low grade gliomas do not show a specific signal with 5 aminolevulinic acid and are difficult to distinguish macroscopically from normal tissue. In the present study we stress out the importance of intraoperative diagnostic ultrasound for localization of low grade gliomas. METHODS: We retrospectively evaluated the charts and MRIs of 34 patients with low grade gliomas operated in our department from 2011 until December 2014. The efficacy of ultrasound as an intraoperative navigational tool was assessed. In 15 patients ultrasound was used and in 19 not. Only histologically proven low grades gliomas (astrocytomas grade II) were evaluated. RESULTS: In none of the patients where ultrasound (combined with neuronavigation) was used (N=15) to find the tumors, the target was missed, whereas the exclusive use of neuronavigation missed the target in 5 of 19 cases of small subcortical low grade gliomas. CONCLUSIONS: Intraoperative ultrasound is an excellent tool in localizing low grade gliomas intraoperatively. It is an inexpensive, real time neuronavigational tool, which overcomes brain shift. Even when identifying the tumors with ultrasound is very reliable, the extend of resection and the decision to remove any residual tumor with the help of ultrasound is at the moment unreliable. PMID- 25704193 TI - Aquagrams of raw milk for oestrus detection in dairy cows. AB - The purpose of this research was to develop rapid and cost-effective method for oestrus detection in dairy cows by means of near infrared spectroscopy and aquaphotomics, using raw milk from individual cows. We found that aquaphotomics approach showed consistent specific water spectral pattern of milk at the oestrus periods of the investigated Holstein cows. Characteristic changes were detected especially in foremilk collected at morning milking. They were reflected in calculated aquagrams of milk spectra where distinctive spectral pattern of oestrus showed increased light absorbance of strongly hydrogen-bonded water. Results showed that monitoring of raw milk near infrared spectra provides an opportunity for analysing hormone levels indirectly, through the changes of water spectral pattern caused by complex physiological changes related to fertile periods. PMID- 25704194 TI - The GPCR heterotetramer: challenging classical pharmacology. AB - Two concepts are gaining increasing acceptance in G protein-coupled receptor (GPCR) pharmacology: (i) pre-coupling of GPCRs with their preferred signaling molecules, and (ii) GPCR oligomerization. This is begging for the introduction of new models such as GPCR oligomer-containing signaling complexes with GPCR homodimers as functional building blocks. This model favors the formation of GPCR heterotetramers - heteromers of homodimers coupled to their cognate G protein. The GPCR heterotetramer offers an optimal framework for a canonical antagonistic interaction between activated Gs and Gi proteins, which can simultaneously bind to their respective preferred receptors and to adenylyl cyclase (AC) catalytic units. This review addresses the current evidence for pre-coupling of the various specific components that provide the very elaborate signaling machinery exemplified by the Gs-Gi-AC-coupled GPCR heterotetramer. PMID- 25704195 TI - Sleep in children with atopic dermatitis. PMID- 25704196 TI - Spectroscopic and structural studies on lactose species in aqueous solution combining the HATR and Raman spectra with SCRF calculations. AB - In this work, the alpha and beta isomers, the alpha-lactose monohydrate and dihydrate and the dimeric species of lactose were studied from the spectroscopic point of view in gas and aqueous solution phases combining the infrared, Horizontal Attenuated Total Reflectance (HATR) and Raman spectra with the density functional theory (DFT) calculations. Aqueous saturated solutions of alpha lactose monohydrate and solutions at different molar concentrations of alpha lactose monohydrate in water were completely characterized by infrared, HATR and Raman spectroscopies. For all the species in solution, the solvent effects were studied using the solvation polarizable continuum (PCM) and solvation (SM) models and, then, their corresponding solvation energies were predicted. The vibrational spectra of those species in aqueous solution were completely assigned by employing the Scaled Quantum Mechanics Force Field (SQMFF) methodology and the self-consistent reaction field (SCRF) calculations. The stabilities of all those species were studied by using the natural bond orbital (NBO), and atoms in molecules (AIM) calculations. PMID- 25704197 TI - Isolation and characterization of unhydrolyzed oligosaccharides from switchgrass (Panicum virgatum, L.) xylan after exhaustive enzymatic treatment with commercial enzyme preparations. AB - Switchgrass (Panicum virgatum, L.) is a potential renewable source of carbohydrates for use in microbial conversion to biofuels. Xylan comprises approximately 30% of the switchgrass cell wall. To understand the limitations of commercial enzyme mixtures, alkali-extracted, isolated switchgrass xylan was hydrolyzed by the action of two commercial enzyme cocktails, in the presence and absence of an additional alpha-arabinofuranosidase enzyme. The two most abundant enzymatic digestion products from each commercial enzyme treatment were separated and characterized by LC-MS(n), linkage analysis, and NMR. The most abundant oligosaccharide from each commercial cocktail was susceptible to hydrolysis when supplemented with a GH62 alpha-arabinofuranosidase enzyme; further characterization confirmed the presence of (1->3)-alpha-arabinose linkages. These results demonstrate the lack of the required selectivity for arabinose-containing substrates in the commercial enzyme preparations tested. One product from each condition remained intact and was found to contain (1->2)-beta-xylose-(1->3) alpha-arabinose side chains; this linkage acts as a source of oligosaccharide recalcitrance. PMID- 25704198 TI - Room-temperature ionic liquids enhanced green synthesis of beta-glycosyl 1-ester. AB - We herein report an efficient synthesis of beta-glycosyl 1-ester in room temperature ionic liquids (RTILs) promoted via silver salt and quaternary ammonium salt (PTC) with good or excellent yields. All products were isolated exclusively as the beta-anomers. Four different RTILs, eight metal salts and four quaternary ammonium salts were screened in the glycosylation reaction. The synergistic effect of C6mim.OTf, Ag2O and tetrabutylammonium iodine gave the best results. Their promotion to the system was integral. Thorough study provided insight into the catalytic activity of ionic liquid structure, metal salts and quaternary ammonium salt to these reactions. It is worth mentioning that the yield of aliphatic compound 2,3,4,6-tetra-O-acetyl-beta-D-galactopyranosyl butyrate (3l) was highly improved when using C6mim.OTf as solvent compared with the normal volatile solvents under the same catalysts. This green approach has been proved to be practical and compatible with a wide range from aliphatic to aromatic substrates. PMID- 25704203 TI - Limits of ideomotor action-outcome acquisition. AB - Ideomotor theory proposes that goal-directed action emerges from the implicit, incidental acquisition of bi-directional associations between actions and their outcomes. In line with this idea, a simple two-stage priming paradigm has provided evidence that presentation of outcomes primes previously associated actions. In the current study we compare the standard priming paradigm with two actions and two unique outcomes (Experiment 1) with two more complex, but otherwise identical versions (Experiment 2: two vs. four actions with four outcomes). Our results show stronger evidence of action-outcome learning in the simple compared to the more complex versions. We suggest that, when using the classic two-stage paradigm, action-outcome acquisition is limited to just a few action-outcome associations that can be concurrently learned-at least if learning is not supported by discriminative stimuli and outcomes are not salient or motivationally relevant. This article is part of a Special Issue entitled SI: Prediction and Attention. PMID- 25704202 TI - Chronic cocaine disrupts mesocortical learning mechanisms. AB - The addictive power of drugs of abuse such as cocaine comes from their ability to hijack natural reward and plasticity mechanisms mediated by dopamine signaling in the brain. Reward learning involves burst firing of midbrain dopamine neurons in response to rewards and cues predictive of reward. The resulting release of dopamine in terminal regions is thought to act as a teaching signaling to areas such as the prefrontal cortex and striatum. In this review, we posit that a pool of extrasynaptic dopaminergic D1-like receptors activated in response to dopamine neuron burst firing serve to enable synaptic plasticity in the prefrontal cortex in response to rewards and their cues. We propose that disruptions in these mechanisms following chronic cocaine use contribute to addiction pathology, in part due to the unique architecture of the mesocortical pathway. By blocking dopamine reuptake in the cortex, cocaine elevates dopamine signaling at these extrasynaptic receptors, prolonging D1-receptor activation and the subsequent activation of intracellular signaling cascades, and thus inducing long-lasting maladaptive plasticity. These cellular adaptations may account for many of the changes in cortical function observed in drug addicts, including an enduring vulnerability to relapse. Therefore, understanding and targeting these neuroadaptations may provide cognitive benefits and help prevent relapse in human drug addicts. PMID- 25704205 TI - Laser therapy reduces gelatinolytic activity in the rat trigeminal ganglion during temporomandibular joint inflammation. AB - OBJECTIVES: To investigate whether low-level laser therapy (LLLT) alters the expression and activity of MMP-2 and MMP-9 in the trigeminal ganglion (TG) during different stages of temporomandibular joint (TMJ) inflammation in rats. It also evaluated whether LLLT modifies mechanical allodynia and orofacial hyperalgesia. MATERIALS AND METHODS: Wistar rats (+/-250 g) were divided into groups that received saline (SAL) or complete Freund's adjuvant (CFA, 50 MUl) in the TMJ, and that later underwent LLLT (20 J cm(-2) ) at their TMJ or not (groups SAL, SAL + LLLT, CFA, and CFA + LLLT). LLLT was applied on days 3, 5, 7, and 9 after SAL or CFA. Mechanical allodynia was evaluated on days 1, 3, 5, 7, and 10; orofacial hyperalgesia was assessed on day 10. Gelatin zymography and in situ zymography aided quantification of MMPs in the TG. RESULTS: Low-level laser therapy abolished the reduction in the mechanical orofacial threshold and the increase in orofacial rubbing during the orofacial formalin test induced by CFA. LLLT also decreased the CFA-induced rise in the levels of MMP-9 and MMP-2 as well as the gelatinolytic activity in the TG. CONCLUSION: Low-level laser therapy could constitute an adjuvant therapy to treat temporomandibular disorders and prevent inflammation-induced alterations in the levels of MMP-2 and MMP-9 and in the gelatinolytic activity in TGs. PMID- 25704206 TI - Efficacy and biological safety of lopinavir/ritonavir based anti-retroviral therapy in HIV-1-infected patients: a meta-analysis of randomized controlled trials. AB - Lopinavir/ritonavir (LPV/r) is the first ritonavir-boosted protease-inhibitor used in second-line anti-retroviral treatment (ART) in resource-limited regions. To evaluate the efficacy and safety outcomes of LPV/r in treatment-naive and experienced HIV-infected adults and pregnant women, we performed a meta-analysis of randomized controlled trials. Ten cohorts from 8 articles involving 2,584 ART naive patients, 5 cohorts from 4 articles involving 1,124 ART-experienced patients, and 8 cohorts from 7 articles involving 2,191 pregnant women were selected for the meta-analyses. For ART-naive patients, the virologic response rate (72.3%) of LPV/r combined with tenofovir (TDF) plus lamivudine/emtricitabine (3TC/FTC) arms was significantly greater than that of LPV/r plus non-TDF-FTC arms (65.5%, p = 0.047). For ART-experienced patients, the use of LPV/r revealed a 55.7% probability of virologic success. The incidence of abnormal total cholesterol (6.9%) for ART-experienced patients was significantly lower than that for ART-naive patients (13.1%, p < 0.001). The use of LPV/r in pregnant women revealed a mother-to-child transmission (MTCT) rate of 1.1%, preterm birth rate of 13.2%, and low birth weight rate of 16.2%. Our meta-analysis indicated that LPV/r was an efficacious regimen for ART-naive patients and was more tolerable for ART-experienced patients. LPV/r also displayed a significant effect in preventing MTCT. PMID- 25704204 TI - The axon-glia unit in white matter stroke: mechanisms of damage and recovery. AB - Approximately one quarter of all strokes in humans occur in white matter, and the progressive nature of white matter lesions often results in severe physical and mental disability. Unlike cortical grey matter stroke, the pathology of white matter stroke revolves around disrupted connectivity and injured axons and glial cells, rather than neuronal cell bodies. Consequently, the mechanisms behind ischemic damage to white matter elements, the regenerative responses of glial cells and their signaling pathways, all differ significantly from those in grey matter. Development of effective therapies for white matter stroke would require an enhanced understanding of the complex cellular and molecular interactions within the white matter, leading to the identification of new therapeutic targets. This review will address the unique properties of the axon-glia unit during white matter stroke, describe the challenging process of promoting effective white matter repair, and discuss recently-identified signaling pathways which may hold potential targets for repair in this disease. This article is part of a Special Issue entitled SI: Cell Interactions In Stroke. PMID- 25704207 TI - Prediction of small-for-gestational-age neonates: screening by fetal biometry at 19-24 weeks. AB - OBJECTIVE: To investigate the value of fetal biometry at 19-24 weeks' gestation in the prediction of delivery of small-for-gestational-age (SGA) neonates, in the absence of pre-eclampsia (PE), and examine the potential value of such assessment in deciding whether the third-trimester scan should be at 32 and/or 36 weeks' gestation. METHODS: This was a screening study in 88,187 singleton pregnancies, including 5003 (5.7%) that delivered SGA neonates with birth weight < 5(th) percentile (SGA < 5(th)). Multivariable logistic regression analysis was used to determine if screening by a combination of maternal characteristics and medical history and Z-scores of fetal head circumference (HC), abdominal circumference (AC) and femur length (FL) had significant contribution in predicting SGA neonates. A model was developed for selecting the gestational age for third trimester assessment, at 32 and/or 36 weeks, based on the results of screening at 19-24 weeks. RESULTS: Combined screening by maternal factors and fetal biometry at 19-24 weeks, predicted 76%, 58% and 44% of SGA < 5(th) delivering < 32, 32-36 and >= 37 weeks' gestation, respectively, at a false-positive rate (FPR) of 10%. The detection rate (DR) of SGA < 5(th) delivering at 32-36 weeks improved from 58% to 82% with screening at 32 weeks rather than at 19-24 weeks. Similarly, the DR of SGA < 5(th) delivering >= 37 weeks improved from 44% with screening at 19 24 weeks to 61% and 76% with screening at 32 and 36 weeks, respectively. In a hypothetical model, it was estimated that if the desired objective of prenatal screening is to predict about 80% of the cases of SGA < 5(th), it would be necessary to select 28% of the population at the 19-24-week assessment to be reassessed at 32 weeks and 41% to be reassessed at 36 weeks; in 59% of pregnancies there would be no need for a third-trimester scan. CONCLUSION: Prenatal prediction of a high proportion of SGA neonates necessitates the undertaking of screening in the third trimester of pregnancy, in addition to assessment in the second trimester, and the timing of such screening, either at 32 and/or 36 weeks, should be contingent on the results of the assessment at 19 24 weeks. PMID- 25704208 TI - Self-assessment of color categories and its relationship with HLA profiling in Brazilian bone marrow donors. AB - The Brazil Ministry of Health maintains a Registry of Bone Marrow Donors that corresponds to approximately 12% of the Bone Marrow Donors Worldwide registry. This registry contains information on ethnicity (by self-assessment of color) and HLA-A, -B, and -DRB1 type. The self-assessment of color tool has been extensively used for admixed population characterization. In this context, Brazil represents a highly admixed population, resulting from 5 centuries of colonization and interbreeding, mainly, but not exclusively, among Native Americans, Europeans, and Africans. Here we evaluated self-assessed skin color and HLA genetic information from 71,291 bone marrow donors of southern Brazil to verify how likely is the HLA profiling correspondence within and between self-assessed color groups. We found that HLA itself was a better ancestry indicator than was self assessed color. Therefore, self-assessment of color in highly admixed populations, such as that of Brazil, is not indicative of higher correspondence in the HLA profiles within skin color groups. PMID- 25704209 TI - Treatment of proximal humerus fractures with a CFR-PEEK plate: 2-year results of a prospective study and comparison to fixation with a conventional locking plate. AB - BACKGROUND: A radiolucent carbon fiber-reinforced polyetheretherketone (CFR-PEEK) plate was recently introduced for fixation of proximal humerus fractures. Prospective clinical and radiographic results of patients treated with a CFR-PEEK plate are compared with those of patients treated with a conventional locking plate. METHODS: Twenty-nine patients (mean age, 66 years) were treated with a CFR PEEK plate for a 3- or 4-part proximal humerus fracture. Patients were clinically and radiographically re-examined at 6 weeks, 6 months, 12 months, and 24 months with the Simple Shoulder Test, Constant-Murley score (CMS), and Oxford Shoulder Score (OSS) as well as with simple radiographs. In addition, results were compared with a matched group of patients treated with a conventional locking plate. RESULTS: At the final follow-up examination at 24 months, patients achieved a mean Simple Shoulder Test score of 58%, a mean CMS of 71.3 points (range, 44-97), and a mean OSS of 27.4 points (range, 8-45). Bone union was confirmed in all patients. Compared with patients treated with the conventional locking plate, patients treated with the CFR-PEEK plate achieved significantly better results with regard to the CMS and the OSS (P = .038 and .029, respectively). Furthermore, loss of reduction with subsequent varus deformity was less frequently observed in the CFR-PEEK plate group. CONCLUSION: Fixation of proximal humerus fractures with a CFR-PEEK plate provides satisfying clinical and radiographic results after 2 years of follow-up. The results are comparable to those achieved with conventional locking plates. PMID- 25704210 TI - Surgical anatomy of the lower trapezius tendon transfer. AB - BACKGROUND: The precise surgical anatomy of the lower trapezius tendon transfer has not been well described. A precise anatomic description of the different trapezius segments and the associated neurovascular structures is crucial for operative planning and execution. We aimed (1) to establish a reliable demarcation between the middle and lower trapezius, (2) to establish the precise relationship of the main neurovascular pedicle to the muscle belly, and (3) to evaluate the utility of the relationships established in (1) and (2) by using the results of this study to perform cadaveric lower trapezius tendon harvest. METHODS: In phase 1, a single surgeon performed all measurements using 10 cadavers. In phase 2, 10 cadaveric shoulders were used to harvest the tendon by using the relationships established in phase 1. RESULTS: We found anatomically distinct insertion sites for the lower and middle trapezius. The lower trapezius inserted at the scapular spine dorsum and the middle trapezius inserted broadly along the superior surface of the scapular spine. The distance from tip of tendon insertion to the nearest nerve at the most superior portion of the lower trapezius was 58 mm (standard deviation +/- 18). By use of these relationships, there were no cases of neurovascular injury during our cadaveric tendon harvests. CONCLUSION: The lower trapezius can be reliably and consistently identified without violating fibers of the middle trapezius. Muscle splitting can be performed safely without encountering the spinal accessory nerve (approximately 2 cm medial to the medial scapular border). PMID- 25704211 TI - Infection after primary anatomic versus primary reverse total shoulder arthroplasty. AB - BACKGROUND: Deep periprosthetic infection is a serious complication after total shoulder arthroplasty (TSA) and is associated with suboptimal clinical results. This retrospective study aimed to determine whether a difference in infection rate existed after primary anatomic TSA (aTSA) and primary reverse TSA (rTSA). METHODS: A TSA database was retrospectively reviewed to identify primary TSAs performed from 2004 to 2012 and isolate cases of confirmed deep periprosthetic infection. Data collected included age, sex, preoperative diagnosis, previous nonarthroplasty operative history, implant type, and infecting organism. RESULTS: From 814 primary TSAs performed, deep periprosthetic infections were confirmed in 16 shoulders. Infections occurred in 6 aTSAs and 10 rTSAs, with no significant difference among the prosthesis types. Pathogens included Staphylococcus spp, Propionibacterium acnes, and Escherichia coli. In the subgroup of shoulders with no previous operations, no significant difference in infection rate was found among the prosthesis types. Shoulders with previous nonarthroplasty operations undergoing primary TSA exhibited a significantly higher (P = .016) infection rate compared with shoulders with no operative history. Both aTSA and rTSA performed in previously operated-on shoulders demonstrated higher infection rates compared with shoulders with no prior operative intervention. The infection rate was significantly higher (P = .016) in the rTSA group. CONCLUSIONS: There is no difference in infection rate after primary aTSA and primary rTSA in shoulders that have not undergone previous operative interventions. Infection is more likely to develop in shoulders undergoing primary rTSA that have had one or more nonarthroplasty operative procedures. PMID- 25704212 TI - Specific kinematics and associated muscle activation in individuals with scapular dyskinesis. AB - BACKGROUND: Knowledge of the kinematics and associated muscular activity in individuals with scapular dyskinesis may provide insight into the injury mechanism and inform the planning of treatment strategies. We investigated scapular kinematics and associated muscular activation during arm movements in individuals with scapular dyskinesis. METHODS: A visual-based palpation method was used to evaluate 82 participants with unilateral shoulder pain. Scapular movements during arm raising/lowering movements were classified as abnormal single pattern (inferior angle prominence, pattern I; medial border prominence, pattern II; excessive/inadequate scapular elevation or upward rotation, pattern III), abnormal mixed patterns, or normal pattern (pattern IV). Scapular kinematics and associated muscular activation were assessed with an electromagnetic motion-capturing system and surface electromyography. RESULTS: More scapular internal rotation was found in pattern II subjects (4 degrees , P = .009) and mixed pattern I and II subjects (4 degrees , P = .023) than in control subjects during arm lowering. Scapular posterior tipping (3 degrees , P = .028) was less in pattern I subjects during arm lowering. Higher upper trapezius activity (14%, P = .01) was found in pattern II subjects during arm lowering. In addition, lower trapezius (5%, P = .025) and serratus anterior activity (10%, P = .004) were less in mixed pattern I and II subjects during arm lowering. CONCLUSIONS: Specific alterations of scapular muscular activation and kinematics were found in different patterns of scapular dyskinesis. The findings also validated the use of a comprehensive classification test to assess scapular dyskinesis, especially in the lowering phase of arm elevation. PMID- 25704213 TI - New meso-substituted corroles possessing pentafluorophenyl groups--synthesis and spectroscopic characterization. AB - The investigation presented in this paper deals with new free-base corroles substituted with different peripheral groups. These aromatic macrocycles were efficiently synthesized by a [2+1] approach from dipyrromethanes. Moreover, the basic spectroscopic studies of the dyes in chloroform were conducted, and the UV Vis absorption, fluorescence and ESR parameters were estimated. The experimental data were supported by quantum chemical calculations. The presence of monomeric dye structures is concentration independent (10(-6)-10(-4) M), as expected for dyes in a solvent of low polarity, and rules out aggregate formation of corroles dissolved in chloroform. The excitation emission and fluorescence life-time values confirm the monomeric structure of the corroles. The spectra were compared with the time-dependent density functional theory (TD-DFT) results for the HOMO LUMO states. The ESR examinations strongly show that for any type of studied fluorine corrole an unpaired electron is localized on the corrole macroring but not on the substituents both before and after light illumination. Laser illumination creates additional radicals, however with different effectiveness depending on the sample. PMID- 25704214 TI - Changes in lens stiffness due to capsular opacification in accommodative lens refilling. AB - Accommodation may be restored to presbyopic lenses by refilling the lens capsular bag with a soft polymer. After this accommodative lens refilling prevention of capsular opacification is a requirement, since capsular opacification leads to a decreased clarity of the refilled lens. It has been hypothesized that capsular fibrosis causing the capsular opacification results in increased stiffness of the lens capsular bag, therewith contributing to a decrease in accommodative amplitude of the lens. However, the change in viscoelastic properties of refilled lenses due to capsular fibrosis has never been measured directly. In this study we examined natural lenses from enucleated porcine eyes and refilled lenses directly after refilling and after three months of culturing, when capsular fibrosis had developed, and determined their viscoelastic properties with a low load compression tester. Control refilled lenses were included in which capsular opacification was prevented by treatment with actinomycin D. We related lens stiffening to the degree of capsular opacification, as derived from the microscopic images taken with a confocal laser scanning microscope. Overall, the refilled lenses directly after refilling were softer than refilled lenses after three months of culturing, and refilled lenses treated with actinomycin D were softer compared with untreated refilled lenses. The degree of capsular opacification as assessed by microscopy corresponds to an increase in lens stiffness. This indicates that the viscoelastic properties of the refilled lens are influenced by capsular fibrosis and modulated by treatment of the lens epithelium. In conclusion, this study shows that the development of capsular fibrosis negatively affects the viscoelastic properties of isolated, cultured refilled lenses. PMID- 25704215 TI - Preparation of a (219)Rn trap to measure the half-life of (211)Pb. AB - A Petri dish was filled with liquid scintillator and then used to trap (219)Rn from a (223)Ra source. The liquid scintillator was then transferred to a vial which was measured in a custom-built triple-to-double coincidence ratio (TDCR) counter. Two Cherenkov samples were prepared in a similar manner. The measurements were used to determine the (211)Pb half-life which was found to be 36.165(37)min. PMID- 25704216 TI - Benefit of cystatin C in evaluation of renal function and prediction of survival in patients with cirrhosis. AB - AIM: The assessment of renal function is of vital importance in management of patients with cirrhosis. While serum creatinine (Cr) is routinely used for this purpose, Cr-based estimated glomerular filtration rate (eGFR) does not reflect true renal function because of muscle wasting and impaired liver function. By contrast, cystatin C (CysC) is unrelated to muscle volume and liver function. In this study, we examined whether CysC-based GFR estimation is beneficial in assessment of renal function in patients with cirrhosis. METHODS: First, we assessed the performance of GFR-predicting equations based on serum Cr or CysC in 14 patients with cirrhosis, by comparison with inulin clearance as a gold standard of GFR (measured GFR [mGFR]). Next, in 49 patients with cirrhosis, we examined serum Cr and CysC at baseline, and examined which GFR-predicting equations were more suitable for predicting the outcome. RESULTS: In the first experiment, mGFR was 54.3 +/- 23.0 mL/min, and CysC-based GFR-estimating equations had better performances compared with Cr-based equations in terms of bias, precision and accuracy. Cr-based estimated GFR (eGFRcreat) was significantly different from mGFR (P < 0.05). In the follow-up study of 49 patients (observational period, 30.7 +/- 32.0 months), multivariate analysis demonstrated that CysC-based estimated GFR (eGFRcys), along with albumin, Child Pugh grade and presence of hepatocellular carcinoma, was independently associated with overall survival (odds ratio, 4.19; 95% confidence interval, 1.44-12.2, P = 0.009). CONCLUSION: These results suggest that eGFRcys could estimate renal function and predict outcome more accurately compared with Cr-based eGFR in cirrhotic patients. PMID- 25704217 TI - Safety and tolerability of TRAIL receptor agonists in cancer treatment. AB - Targeting the death receptor pathway of apoptosis represents a promising approach for the development of novel cancer therapeutics, since death receptors on the cell surface are directly linked to the apoptotic machinery. The tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) receptor/ligand system is of particular interest among the death receptor superfamily for therapeutic targeting in cancer, since TRAIL has been reported to preferentially induce apoptosis in cancer cells, while sparing non-malignant cells. Evaluation of TRAIL receptor agonists in clinical trials has revealed that they are, in principle, well-tolerated but exert limited efficacy in unselective patient populations. Currently, the challenge resides in the development of rational TRAIL-based combination therapies with potent TRAIL receptor agonists in order to exploit the potential of death receptor targeting for cancer therapy. PMID- 25704218 TI - Dynamic imaging of accommodation by swept-source anterior segment optical coherence tomography. AB - PURPOSE: To study the accommodation process in normal eyes using a commercially available clinical system based on swept-source anterior segment optical coherence tomography (AS-OCT). SETTING: Ophthalmology Department, University of Parma, Italy. DESIGN: Evaluation of diagnostic technology. METHODS: Right eyes were analyzed using swept-source AS-OCT (Casia SS-1000). The optical vergence of the internal coaxial fixation target was adjusted during imaging to obtain monocular accommodation stimuli with different amplitudes (0, 3.0, 6.0, and 9.0 diopters [D]). Overlapping of real and conjugate OCT images enabled imaging of all the anterior segment optical surfaces in a single frame. Central corneal thickness (CCT), anterior chamber depth (ACD), and lens thickness were extracted from the OCT scans acquired at different static accommodation stimulus amplitudes. The crystalline lens was analyzed dynamically during accommodation and disaccommodation by acquiring sequential OCT images of the anterior segment at a rate of 8 frames per second. The lens thickness was extracted from the temporal sequence of OCT images and plotted as a function of time. RESULTS: The study analyzed 14 eyes of 14 subjects aged 18 to 46 years. During accommodation, the decrease in the ACD was statistically significant (P < .05), as were the increase in the lens thickness (P < .001) and the slight movement forward of the lens central point (P < .01). The CCT and anterior chamber width measurements did not change statistically significantly during accommodation. The lens thickness at 0 D was positively correlated with age (P < .01). CONCLUSION: High-resolution real-time imaging and biometry of the accommodating anterior segment can be effectively performed using a commercially available swept-source AS-OCT clinical device. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 25704219 TI - Passive range of movement of the shoulder: a standardized method for measurement and assessment of intrarater reliability. AB - OBJECTIVE: The purpose of this study was to determine the intrarater reliability and reproducibility of a standardized procedure for measuring passive shoulder movement in asymptomatic individuals. METHODS: A single assessor used a digital inclinometer and standardized protocol to measure the passive range of motion of 7 shoulder movements in 168 asymptomatic shoulders. Following a warm-up maneuver, 3 measurements were taken for each movement on 2 occasions. Both shoulders were measured using a standardized order of movement. Selection of measurement beginning with left or right shoulder was randomly determined. The entire process was repeated 7 days later to assess reproducibility. Intraclass correlation coefficients (ICCs) with 95% confidence intervals and standard errors of measurement (SEMs) were calculated to assess the intrarater reliability of the methods. RESULTS: The intrarater reliability of our methods was substantial for total shoulder flexion (ICC = 0.82, SEM = 12.3 degrees ), whereas all other movements demonstrated moderate reliability (ICC range = 0.64-0.75) except external rotation in neutral abduction, for which reliability was classed as slight (ICC = 0.28, SEM = 31 degrees ). Moderate reliability was evident for all movements on follow-up at 7 days (ICC range = 0.60-0.77). CONCLUSIONS: These methods of measurement have moderate to substantial reliability for the majority of tested passive shoulder movements, with moderate reliability sustained after 1 week, in a large sample of asymptomatic individuals. PMID- 25704220 TI - Comparison of parameters characterizing lumbar lordosis in radiograph and photogrammetric examination of adults. AB - OBJECTIVE: The purpose of this study was to test validity of photogrammetry compared with radiography as a method of measuring the Cobb angle and the size of anterior-posterior spine curvatures in adults. METHODS: The study included 50 volunteers, 23 men and 27 women whose mean age was 52.6 years. The average weight of the subjects was 81.3 kg, average body height was 172.0 cm, and the average body mass index was 27.4. Based on radiologic examination, the length and depth of lumbar lordosis were determined and the size of the Cobb angle of lumbar scoliosis. After the radiologic examination, a photogrammetric test was performed for each subject with the projection moire phenomenon. RESULTS: The Pearson correlation found statistically significant associations concerning the length of lordosis (P < .001) and the Cobb angle (P < .001). Correlation of the depth of lordosis indicated a strong trend (P = .063). CONCLUSIONS: This study found that the moire method of photogrammetric measurement produced similar findings to radiographic measurements in determining size of the Cobb angle and the length of lumbar lordosis. PMID- 25704221 TI - The effect of adding forward head posture corrective exercises in the management of lumbosacral radiculopathy: a randomized controlled study. AB - OBJECTIVE: The purpose of this study was to determine the immediate and long-term effects of a multimodal program, with the addition of forward head posture correction, in patients with chronic discogenic lumbosacral radiculopathy. METHODS: This randomized clinical study included 154 adult patients (54 females) who experienced chronic discogenic lumbosacral radiculopathy and had forward head posture. One group received a functional restoration program, and the experimental group received forward head posture corrective exercises. Primary outcomes were the Oswestry Disability Index (ODI). Secondary outcomes included the anterior head translation, lumbar lordosis, thoracic kyphosis, trunk inclination, lateral deviation, trunk imbalance, surface rotation, pelvic inclination, leg and back pain scores, and H-reflex latency and amplitude. Patients were assessed at 3 intervals (pretreatment, 10-week posttreatment, and 2 year follow-up). RESULTS: A general linear model with repeated measures indicated a significant group * time effect in favor of the experimental group on the measures of ODI (F = 89.7; P < .0005), anterior head translation (F = 23.6; P < .0005), H-reflex amplitude (F = 151.4; P < .0005), H-reflex latency (F = 99.2; P < .0005), back pain (F = 140.8; P < .0005), and leg pain (F = 72; P < .0005). After 10 weeks, the results revealed an insignificant difference between the groups for ODI (P = .08), back pain (P = .29), leg pain (P = .019), H-reflex amplitude (P = .09), and H-reflex latency (P = .098). At the 2-year follow-up, there were significant differences between the groups for all variables adopted for this study (P < .05). CONCLUSIONS: The addition of forward head posture correction to a functional restoration program seemed to positively affect disability, 3-dimensional spinal posture parameters, back and leg pain, and S1 nerve root function of patients with chronic discogenic lumbosacral radiculopathy. PMID- 25704222 TI - Life and death in the family: early parental death, parental remarriage, and offspring suicide risk in adulthood. AB - Early-life parental death (PD) may increase suicide and other mortality risk in adulthood. The potential implications of subsequent remarriage of the widowed parent (RWP) for suicide have not been well examined. Data came from the Utah Population Database for birth cohorts between 1886 and 1960, yielding a sample of N = 663,729 individuals, including 4533 suicides. Cox models showed PD was associated with increased adult suicide risk before age 50, and with increased risk of cardiovascular disease deaths (CVD) for adults of all ages. For females, RWP attenuated the suicide relationship before age 50 (though not statistically significant), but significantly exacerbated it after age 50. RWP had no significant impact for males. Further, for females, PD's positive association with suicide was stronger than with CVD before age 50. These findings reinforce the importance of biological and social mechanisms in linking early-life stressors to adult mental and physical health. PMID- 25704223 TI - Evaluation of the plasmatic and parenchymal elution kinetics of two different irinotecan-loaded drug-eluting embolics in a pig model. AB - PURPOSE: To evaluate and compare irinotecan elution kinetics of two drug-eluting embolic agents in a porcine model. MATERIALS AND METHODS: Embolization of the left liver lobe was performed in 16 domestic pigs, with groups of two receiving 1 mL of DC Bead M1 (70-150 um) or Embozene TANDEM (75 um) loaded with 50 mg irinotecan. Irinotecan plasma levels were measured at 0, 10, 20, 30, 60, 120, 180, and 240 minutes after completed embolization and at the time of euthanasia (24 h, 48 h, 72 h, or 7 d). Liver tissue samples were taken to measure irinotecan tissue concentrations. RESULTS: The highest irinotecan plasma concentrations of both embolic agents were measured 10 and 20 minutes after embolization, and concentrations were significantly higher for DC Bead M1 versus Embozene TANDEM (P = .0019 and P = .0379, respectively). At 48 hours and later follow-up, no irinotecan was measurable in the plasma. For both embolic agents, the highest irinotecan tissue concentration was found after 24 hours and decreased in a time dependent manner at later follow-up intervals. Additionally, SN-38 tissue levels for both agents were therapeutic at 24 hours, with therapeutic levels of SN-38 at 48 hours in one liver embolized with TANDEM particles. Histopathologic analysis revealed ischemic, inflammatory, and fibrotic tissue reactions. CONCLUSIONS: Irinotecan is measurable in plasma and hepatic tissue after liver embolization with both types of irinotecan-eluting embolic agents. DC Bead M1 shows early burst elution kinetics, whereas Embozene TANDEM has a lower and slower release profile. The initial burst is significantly greater after embolization with DC Bead M1 than with Embozene TANDEM. PMID- 25704224 TI - Ultrasound-accelerated catheter-directed thrombolysis for acute submassive pulmonary embolism. AB - PURPOSE: To evaluate the safety and efficacy of ultrasound-accelerated catheter directed thrombolysis (USAT) in patients with submassive pulmonary embolism (PE). MATERIALS AND METHODS: This retrospective study comprised 45 consecutive patients (15 prospective, 30 retrospective) who underwent USAT for submassive PE from June 2012-May 2014. Inclusion criteria were right ventricular dysfunction (RVD) as indicated by right ventricle-to-left ventricle (RV:LV) ratio > 0.9, symptoms of < 2 weeks' duration, and absence of absolute contraindication to thrombolysis. All patients underwent pulmonary artery catheterization with a standardized protocol (24 mg recombinant tissue plasminogen activator). Hemodynamic evaluation immediately after USAT, RV:LV ratio evaluation at 48-72 hours after USAT by computed tomography angiography and echocardiography, and adverse event reporting for a minimum of 30 days were performed. Outcomes and complications are reported as per the Society of Interventional Radiology Reporting Standards for Endovascular Treatment of Pulmonary Embolism. RESULTS: USAT was technically successful in 100% (n = 45) of patients. Main pulmonary artery pressure significantly decreased from 49.8 mm Hg to 31.1 mm Hg (P < .0001). RVD significantly improved with mean RV:LV ratios decreasing from 1.59 to 0.93 (P < .0001). There were 6 complications: 4 minor bleeding episodes at access sites and 2 major bleeding complications (flank and arm hematoma). All-cause mortality at 30 days was 0%. There were no readmissions for PE at 30 days after discharge. CONCLUSIONS: Ultrasound-accelerated catheter-directed thrombolysis using a standardized low-dose protocol is a safe and efficacious method of treatment of submassive PE to reduce acute pulmonary hypertension and RVD. PMID- 25704225 TI - Cardiovascular risk factors and thoracic aortic wall thickness in a general population. AB - PURPOSE: To evaluate the association of cardiovascular risk factors with wall thickness of the ascending and descending thoracic aorta in the general population. MATERIALS AND METHODS: The study included 1,176 individuals (523 women) 21-83 years old from the Study of Health in Pomerania without history of stroke or myocardial infarction. Aortic wall thickness (AWT) was determined by cine magnetic resonance imaging. The associations of AWT with the cardiovascular risk factors male sex, age, smoking, body mass index (BMI), systolic and diastolic blood pressure, hemoglobin A1c, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides were assessed by multivariable linear regression models, and interaction effects were tested. RESULTS: Male sex (beta = .086, P < .001), age (beta = .006, P < .001), and BMI (beta = .013, P < .001) were positively associated with the AWT of the ascending aorta. Male sex (beta = .105, P < .001), age (beta = .006, P < .001), current smoker (beta = .044, P = .010), BMI (beta = .013, P < .001), and HDL-C (beta = .057, P = .008) revealed a positive association with AWT of the descending aorta. LDL-C (beta = -.024, P = .009; beta = -.018, P = .010) was inversely associated with the AWT of the ascending and descending aorta, respectively. Triglyceride levels (beta = .024, P = .027; beta = .018, P = .024) showed a positive association with the AWT of the ascending and descending aorta, respectively, in men, but not in women. CONCLUSIONS: Established cardiovascular risk factors, including male sex, older age, smoking, high BMI, and high triglyceride levels, were associated with increasing thoracic AWT of the ascending and descending aorta. High HDL-C and low LDL-C levels were correlated with AWT. PMID- 25704226 TI - Safety and efficacy of 70-150 MUm and 100-300 MUm drug-eluting bead transarterial chemoembolization for hepatocellular carcinoma. AB - PURPOSE: To compare the safety and efficacy of using 70-150 MUm drug-eluting beads (DEBs) (LC BeadM1; Biocompatibles UK Ltd, Farnham, Surrey, United Kingdom) in addition to 100-300 MUm DEBs with 100-300 MUm DEBs alone in transarterial chemoembolization for treatment of hepatocellular carcinoma (HCC). MATERIALS AND METHODS: A cohort of patients with HCC who underwent transarterial chemoembolization with two vials of 100-300 MUm DEBs (group 1, 55 procedures among 42 patients, 33 men, average Model for End-Stage Liver Disease score 10 +/- 0.6, 67% Child-Pugh A, 33% Child-Pugh B) was retrospectively compared with a cohort of patients who underwent transarterial chemoembolization with one vial of 70-150 MUm DEBs followed by one vial of 100-300 MUm DEBs (group 2, 51 procedures among 42 patients, 29 men, average Model for End-Stage Liver Disease score 9 +/- 0.6, 73% Child-Pugh A, 27% Child-Pugh B) in regard to adverse events and response on 1-month follow-up imaging using modified Response Evaluation Criteria In Solid Tumors criteria. RESULTS: There was no difference in 1-month imaging response (P = .3). Patients in group 2 were readmitted more often within 1 month for hepatobiliary adverse events (group 2, 25%; group 1, 9%; P < .0001), including ascites, gastrointestinal hemorrhage, biliary dilatation, and cholecystitis. CONCLUSIONS: Despite similar efficacy based on short-term follow-up imaging, transarterial chemoembolization with smaller DEBs (70-150 MUm) followed by larger DEBs (100-300 MUm) may cause more hepatobiliary adverse events. PMID- 25704227 TI - Genetic diversity of porcine reproductive and respiratory syndrome virus in Thailand and Southeast Asia from 2008 to 2013. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) affects the swine industry worldwide. Annual surveillances taken from 2008 to 2013 revealed a 13.86% prevalence of PRRSVs in swine populations in Thailand. The selected positive samples were genetically characterized based on global systems and phylogenetic trees that were constructed using 967 ORF5 samples from this study, the collective sequences from Thailand and Southeast Asia and reference sequences. The results showed that both types I and II have been circulating in Thai swine and that genotype II was more prevalent than genotype I. Only type II was found in other countries in Southeast Asia. Type I PRRSVs from Thailand are clustered in subtype 1, clades A, D and H. Type II PRRSVs are topologically classified in lineage 1 and sublineages 5.1, 5.2 and 8.7, of which sublineage 8.7 was predominant, especially after 2010. PRRSVs in sublineage 8.7 are divided into two groups: classical NA and HP-PRRSV. An analysis of all HP-PRRSVs in Southeast Asia revealed four separate clades--A (SX2009-like), B (09HEN1-like), JXA1-like and GXFCH08-like--reflecting four different introductions of these viruses into Thailand, Lao PDR, Cambodia and Vietnam. HP-PRRSV first appeared in Thailand and Cambodia in 2008, 2 years before the first epidemic outbreaks. Recently, the genetics of PRRSVs in Southeast Asia have become more diverse. Thus, PRRSV genetics must be continually characterized and phylogenetically analyzed using global systematic classifications to provide annual genetic information for PRRS control and vaccine selection. PMID- 25704228 TI - Species-level identification of staphylococci isolated from bovine mastitis in Brazil using partial 16S rRNA sequencing. AB - Staphylococci isolated from bovine milk and not classified as Staphylococcus aureus represent a heterogeneous group of microorganisms that are frequently associated with bovine mastitis. The identification of these microorganisms is important, although it is difficult and relatively costly. Genotypic methods add precision in the identification of Staphylococcus species. In the present study, partial 16S rRNA sequencing was used for the species identification of coagulase positive and coagulase-negative staphylococci isolated from bovine mastitis. Two hundred and two (95%) of the 213 isolates were successfully identified at the species level. The assigning of an isolate to a particular species was based on >=99% identity with 16S rRNA sequences deposited in GenBank. The identified isolates belonged to 13 different Staphylococcus species; Staphylococcus chromogenes, S. aureus and Staphylococcus epidermidis were the most frequently identified species. Eight isolates could not be assigned to a single species, as the obtained sequences showed 99% or 100% similarity to sequences from two or three different Staphylococcus species. The relatedness of these isolates with the other isolates and reference strains was visualized using a cladogram. In conclusion, 16S rRNA sequencing was an objective and accurate method for the proper identification of Staphylococcus species isolated from bovine mastitis. Additional target genes could be used in non-conclusive cases for the species level identification of these microorganisms. PMID- 25704229 TI - Direct and selective hydrogenolysis of arenols and aryl methyl ethers. AB - For valorization of biomass, the conversion of lignin to deoxygenated bulk aromatic compounds is an emerging subject of interest. Because aromatic rings are susceptible to metal-catalysed hydrogenation, the selective hydrogenolysis of carbon-oxygen bonds still remains a great challenge. Herein we report direct and selective hydrogenolysis of sp(2) C-OH bonds in substituted phenols and naphthols catalysed by hydroxycyclopentadienyl iridium complexes. The corresponding arenes were obtained in up to 99% yields, indicating the possible production of arenes from lignin-derived bio-oils. Furthermore, the same catalysts were applied to the unprecedented selective hydrogenolysis of the sp(3) C-O bonds in aryl methyl ethers. Thus, the hydrodeoxygenation of vanillylacetone, a lignin model compound, afforded alkylbenzenes as the major products via triple deoxygenation. PMID- 25704230 TI - Mechanism of phosphine borane deprotection with amines: the effects of phosphine, solvent and amine on rate and efficiency. AB - The kinetics of borane transfer from simple tertiary phosphine borane adducts to a wide range of amines have been determined. All data obtained, including second order kinetics, lack of cross-over, and negative entropies of activation for reaction of triphenylphosphine borane with quinuclidine and triethylamine, are consistent with a direct (SN 2-like) transfer process, rather than a dissociative (SN 1-like) process. The identities of the amine, phosphine, and solvent all impact substantially on the rate (k) and equilibrium (K) of the transfer, which in some cases vary by many orders of magnitude. P-to-N transfer is more efficient with cyclic amines in apolar solvents due to reduced entropic costs and ground state destabilisation. Taken as a whole, the data allow informed optimisation of the deprotection step from the stand-point of rate, or synthetic convenience. In all cases, both reactants should be present at high initial concentration to gain kinetic benefit from the bimolecularity of the process. Ultimately, the choice of amine is dictated by the identity of the phosphine borane complex. Aryl-rich phosphine boranes are sufficiently reactive to allow use of diethylamine or pyrrolidine as a volatile low polarity solvent and reactant, whereas more alkyl rich phosphines benefit from the use of more reactive amines, such as 1,4 diaza[2.2.2]bicyclooctane (DABCO), in apolar solvents at higher temperatures. PMID- 25704231 TI - The RING finger E3 ligase STRF1 is involved in membrane trafficking and modulates salt-stress response in Arabidopsis thaliana. AB - Salt stress is a detrimental factor for plant growth and development. The response to salt stress has been shown to involve components in the intracellular trafficking system, as well as components of the ubiquitin-proteasome system (UPS). In this article, we have identified in Arabidopsis thaliana a little reported ubiquitin ligase involved in salt-stress response, which we named STRF1 (Salt Tolerance RING Finger 1). STRF1 is a member of RING-H2 finger proteins and we demonstrate that it has ubiquitin ligase activity in vitro. We also show that STRF1 localizes mainly at the plasma membrane and at the intracellular endosomes. strf1-1 loss-of-function mutant seedlings exhibit accelerated endocytosis in roots, and have altered expression of several genes involved in the membrane trafficking system. Moreover, protein trafficking inhibitor, brefeldin A (BFA), treatment has increased BFA bodies in strf1-1 mutant. This mutant also showed increased tolerance to salt, ionic and osmotic stresses, reduced accumulation of reactive oxygen species during salt stress, and increased expression of AtRbohD, which encodes a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase involved in H2 O2 production. We conclude that STRF1 is a membrane trafficking related ubiquitin ligase, which helps the plant to respond to salt stress by monitoring intracellular membrane trafficking and reactive oxygen species (ROS) production. PMID- 25704232 TI - Emotion recognition in children with Fetal Alcohol Spectrum Disorders. AB - There is a limited amount of research that examines social-emotional functioning in children with Fetal Alcohol Spectrum Disorder (FASD), and the majority of it relies on parent and teacher reports of social impairments. Because these provide broad measures of social function, they fail to elucidate the underlying specific skills with which this group of children has difficulty. The current study examines emotion-recognition abilities in children with FASD, as it plays a central role in social interaction. Participants were 22 children with diagnosed FASD (ages 8-14), and age- and gender-matched typically developing controls. Tasks included measures of emotion recognition from three nonlinguistic modalities: facial expressions, emotional tone of voice, and body positioning and movement. Participant's parents completed measures of adaptive and behavioral function that were related to children's performance on aspects of emotion recognition. Overall, the results show that children with FASD have more difficulties with emotion recognition than typically developing age-matched peers, but these difficulties may not be clinically significant (e.g., smaller effect size) or may be specific to the age of the individual exhibiting the emotion (i.e., child vs. adult). These results are discussed in the context of previous studies. PMID- 25704233 TI - Efficacy of neoadjuvant cetuximab alone or with platinum salt for the treatment of unresectable advanced nonmetastatic cutaneous squamous cell carcinomas. AB - BACKGROUND: Refractory locally advanced or metastatic nonmelanoma skin cancer (NMSC) is a frequent therapeutic impasse. OBJECTIVES: To address the question of the efficacy of induction therapy with cetuximab as neoadjuvant treatment for locally advanced NMSC. METHODS: From 2008 to 2013, all patients with a diagnosis of unresectable locally advanced skin squamous cell carcinoma were treated with neoadjuvant cetuximab alone (CM) or combined with a platinum salt and 5 fluorouracil (CC). Resectability, and clinical and pathological response, as well as relapse-free and overall survival were evaluated. RESULTS: Thirty-four patients, with a median age of 74.5 years, were evaluated. Twenty-five patients received CC. After three cycles of CC, 23 of 25 patients whose tumours were initially unresectable became amenable to surgery (92%). A complete histological response was observed in 15 (65%) patients. The mean progression-free and mean overall survival in operated patients were 8.5 and 26.0 months, respectively. CONCLUSIONS: There was a good response in terms of resectability and tumour control in the majority of patients, with few relapses, despite the initially poor prognosis of these tumours in this elderly group of patients. However, this therapeutic strategy needs to be validated in a prospective, randomized study. PMID- 25704234 TI - Jasmonate-dependent depletion of soluble sugars compromises plant resistance to Manduca sexta. AB - Jasmonates regulate plant secondary metabolism and herbivore resistance. How they influence primary metabolites and how this may affect herbivore growth and performance are not well understood. We profiled sugars and starch of jasmonate biosynthesis-deficient and jasmonate-insensitive Nicotiana attenuata plants and manipulated leaf carbohydrates through genetic engineering and in vitro complementation to assess how jasmonate-dependent sugar accumulation affects the growth of Manduca sexta caterpillars. We found that jasmonates reduce the constitutive and herbivore-induced concentration of glucose and fructose in the leaves across different developmental stages. Diurnal, jasmonate-dependent inhibition of invertase activity was identified as a likely mechanism for this phenomenon. Contrary to our expectation, both in planta and in vitro approaches showed that the lower sugar concentrations led to increased M. sexta growth. As a consequence, jasmonate-dependent depletion of sugars rendered N. attenuata plants more susceptible to M. sexta attack. In conclusion, jasmonates are important regulators of leaf carbohydrate accumulation and this determines herbivore growth. Jasmonate-dependent resistance is reduced rather than enhanced through the suppression of glucose and fructose concentrations, which may contribute to the evolution of divergent resistance strategies of plants in nature. PMID- 25704235 TI - Nonivamide enhances miRNA let-7d expression and decreases adipogenesis PPARgamma expression in 3T3-L1 cells. AB - Red pepper and its major pungent principle, capsaicin (CAP), have been shown to be effective anti-obesity agents by reducing energy intake, enhancing energy metabolism, decreasing serum triacylglycerol content, and inhibiting adipogenesis via activation of the transient receptor potential cation channel subfamily V member 1 (TRPV1). However, the binding of CAP to the TRPV1 receptor is also responsible for its pungent sensation, strongly limiting its dietary intake. Here, the effects of a less pungent structural CAP-analog, nonivamide, on adipogenesis and underlying mechanisms in 3T3-L1 cells were studied. Nonivamide was found to reduce mean lipid accumulation, a marker of adipogenesis, to a similar extent as CAP, up to 10.4% (P < 0.001). Blockage of the TRPV1 receptor with the specific inhibitor trans-tert-butylcyclohexanol revealed that the anti adipogenic activity of nonivamide depends, as with CAP, on TRPV1 receptor activation. In addition, in cells treated with nonivamide during adipogenesis, protein levels of the pro-adipogenic transcription factor peroxisome-proliferator activated receptor gamma (PPARgamma) decreased. Results from miRNA microarrays and digital droplet PCR analysis demonstrated an increase in the expression of the miRNA mmu-let-7d-5p, which has been associated with decreased PPARgamma levels. PMID- 25704236 TI - A new method to evaluate the positional stability of a self-drilling miniscrew. AB - OBJECTIVES: To evaluate the positional stability of miniscrews during orthodontic treatment change in cone-beam computed tomography (CBCT). SETTING AND SAMPLE POPULATION: Twenty adult volunteers were enrolled. METHODS: In all participants, at least two maxillary first premolars were extracted because of protrusion. Each volunteer received six miniscrews in the maxilla, including two loaded miniscrews to retract anterior teeth and four unloaded miniscrews. CBCT scans were obtained at the beginning of space closure (T1) and approximately 11.8 months later (T2). Three-dimensional miniscrew models were constructed at T1 and T2, and the central axes were calculated using a principal component analysis (PCA) technique. Finally, we measured and compared the angle change of all the miniscrews from T1 to T2. RESULTS: The angle change values of the unloaded and loaded miniscrews were 1.64 +/- 1.25 degrees and 1.67 +/- 1.15 degrees , respectively. No significant differences in the angle change were observed. CONCLUSION: Cone-beam computed tomography images revealed both the unloaded and loaded miniscrews to be positionally stable during en-masse retraction in this study. PMID- 25704237 TI - Emotional attachment and emotional availability tele-intervention for adoptive families. AB - This study evaluated the new online Emotional Attachment and Emotional Availability (EA2) Intervention for use with adoptive families in enhancing parent-child EA, parental perceptions of EA, child attachment behaviors, parent child emotional attachment, and reducing parent-reported child behavioral problems and parenting-related stress. Participants in this study were adoptive parents and their adopted children ages 1.5 to 5 years old (N = 15 dyads). Participants were placed in an immediate intervention group (IG) or a delayed intervention group (DG) that would receive the 6-week EA2 Tele-Intervention after the IG. Results revealed significant differences in the IG in child behavioral problems, parent-child EA, parental perceptions of EA, and parent-child emotional attachment, improvements not seen in the DG. Analysis of effects of the DG after receiving the EA2 Tele-Intervention revealed significant differences over time also in most of these qualities. PMID- 25704238 TI - European trends in greenhouse gases emissions from integrated solid waste management. AB - The European Union (EU) has 28 member states, each with very different characteristics (e.g. surface, population density, per capita gross domestic product, per capita municipal solid waste (MSW) production, MSW composition, MSW management options). In this paper several integrated waste management scenarios representative of the European situation have been generated and analysed in order to evaluate possible trends in the net emission of greenhouse gases and in the required landfill volume. The results demonstrate that an integrated system with a high level of separate collection, efficient energy recovery in waste-to energy plants and very limited landfill disposal is the most effective according to the indices adopted. Moreover, it is evident that a fully integrated system can make MSW management a carbon sink with a potentiality of up to approximately 40 Mt CO2eq year(-1). PMID- 25704239 TI - Childhood dystonias. AB - OPINION STATEMENT: Dystonia is a movement disorder caused by diverse etiologies. Its treatment in children is particularly challenging due to the complexity of the development of the nervous system from birth to young adulthood. The treatment options of childhood dystonia include several oral pharmaceutical agents, botulinum toxin injections, and deep brain stimulation (DBS) therapy. The choice of drug therapy relies on the suspected etiology of the dystonia and the adverse effect profile of the drugs. Dystonic syndromes with known etiologies may require specific interventions, but most dystonias are treated by trying serially a handful of medications starting with those with the best risk/benefit profile. In conjunction to drug therapy, botulinum toxin injections may be used to target a problematic group dystonic muscles. The maximal botulinum toxin dose is limited by the weight of the child, therefore limiting the number of the muscles amenable to such treatment. When drugs and botulinum toxin injections fail to control the child's disabling dystonia, DBS therapy may be offered as a last remedy. Delivering optimal DBS therapy to children with dystonia requires a multidisciplinary team of experienced pediatric neurosurgeons, neurologists, and nurses to select adequate candidates, perform this delicate stereotactic procedure, and optimize DBS delivery. Even in the best hands, the response of childhood dystonia to DBS therapy varies greatly. Future therapy of childhood dystonia will parallel the advancement of knowledge of the pathophysiology of dystonic syndromes and the development of clinical and research tools for their study. PMID- 25704240 TI - CDK6 levels regulate quiescence exit in human hematopoietic stem cells. AB - Regulated blood production is achieved through the hierarchical organization of dormant hematopoietic stem cell (HSC) subsets that differ in self-renewal potential and division frequency, with long-term (LT)-HSCs dividing the least. The molecular mechanisms underlying this variability in HSC division kinetics are unknown. We report here that quiescence exit kinetics are differentially regulated within human HSC subsets through the expression level of CDK6. LT-HSCs lack CDK6 protein. Short-term (ST)-HSCs are also quiescent but contain high CDK6 protein levels that permit rapid cell cycle entry upon mitogenic stimulation. Enforced CDK6 expression in LT-HSCs shortens quiescence exit and confers competitive advantage without impacting function. Computational modeling suggests that this independent control of quiescence exit kinetics inherently limits LT HSC divisions and preserves the HSC pool to ensure lifelong hematopoiesis. Thus, differential expression of CDK6 underlies heterogeneity in stem cell quiescence states that functionally regulates this highly regenerative system. PMID- 25704241 TI - Anterior cervical discectomy and fusion surgery for cervical radiculopathy: is time of essence? AB - COMMENTARY ON: Burneikiene S, Nelson EL, Mason A, Rajpal S, Villavicencio AT. The duration of symptoms and clinical outcomes in patients undergoing anterior cervical discectomy and fusion for degenerative disc disease and radiculopathy. Spine J 2015;15:427-32 (in this issue). PMID- 25704242 TI - Central cord syndrome: is operative treatment the standard of care? AB - COMMENTARY ON: Brodell DW, Jain A, Elfar JC, Mesfin A. National trends in the management of central cord syndrome: an analysis of 16,134 patients. Spine J 2015;15:435-42 (in this issue). PMID- 25704243 TI - Carboxylesterase 1 c.428G>A single nucleotide variation increases the antiplatelet effects of clopidogrel by reducing its hydrolysis in humans. AB - Carboxylesterase 1 (CES1) hydrolyzes the prodrug clopidogrel to an inactive carboxylic acid metabolite. We studied the pharmacokinetics and pharmacodynamics of 600 mg oral clopidogrel in healthy white volunteers, including 10 carriers and 12 noncarriers of CES1 c.428G>A (p.Gly143Glu, rs71647871) single nucleotide variation (SNV). Clopidogrel carboxylic acid to clopidogrel area under the plasma concentration-time curve from 0 hours to infinity (AUC0-infinity ) ratio was 53% less in CES1 c.428G>A carriers than in noncarriers (P = 0.009), indicating impaired hydrolysis of clopidogrel. Consequently, the AUC0-infinity of clopidogrel and its active metabolite were 123% (P = 0.004) and 67% (P = 0.009) larger in the c.428G>A carriers than in noncarriers. Consistent with these findings, the average inhibition of P2Y12 -mediated platelet aggregation 0-12 hours after clopidogrel intake was 19 percentage points higher in the c.428G>A carriers than in noncarriers (P = 0.036). In conclusion, the CES1 c.428G>A SNV increases clopidogrel active metabolite concentrations and antiplatelet effects by reducing clopidogrel hydrolysis to inactive metabolites. PMID- 25704244 TI - Morphometric MRI alterations and postoperative seizure control in refractory temporal lobe epilepsy. AB - Refractory mesial temporal lobe epilepsy (mTLE) is a debilitating condition potentially amenable to resective surgery. However, between 40 and 50% patients continue to experience postoperative seizures. The development of imaging prognostic markers of postoperative seizure outcome is a crucial objective for epilepsy research. In the present study, we performed analyses of preoperative cortical thickness and subcortical surface shape on MRI in 115 of patients with mTLE and radiologically defined hippocampal sclerosis being considered for surgery, and 80 healthy controls. Patients with excellent (International League Against Epilepsy outcome (ILAE) I) and suboptimal (ILAE II-VI) postoperative outcomes had a comparable distribution of preoperative atrophy across the cortex, basal ganglia, and amygdala. Conventional volumetry of whole hippocampal and extrahippocampal subcortical structures, and of global gray and white matter, could not differentiate between patient outcome groups. However, surface shape analysis revealed localized atrophy of the thalamus bilaterally and of the posterior/lateral hippocampus contralateral to intended resection in patients with persistent postoperative seizures relative to those rendered seizure free. Data uncorrected for multiple comparisons also revealed focal atrophy of the ipsilateral hippocampus posterior to the margins of resection in patients with persistent seizures. This data indicates that persistent postoperative seizures after temporal lobe surgery are related to localized preoperative shape alterations of the thalamus bilaterally and the hippocampus contralateral to intended resection. Imaging techniques that have the potential to unlock prognostic markers of postoperative outcome in individual patients should focus assessment on a bihemispheric thalamohippocampal network in prospective patients with refractory mTLE being considered for temporal lobe surgery. PMID- 25704245 TI - The impact of a dedicated multidisciplinary team on the management of early rectal cancer. AB - AIM: Local excision of early rectal cancer (ERCa) offers comparable survival and reduced operative morbidity compared with radical surgery, yet it risks an adverse oncological outcome if performed in the wrong setting. This retrospective review considers the impact of the introduction of a specialist early rectal cancer multidisciplinary team (ERCa MDT) on the investigation and management of ERCa. METHOD: A retrospective comparative cohort study was undertaken. Patients with a final diagnosis of pT1 rectal cancer at our unit were identified for two 12-month periods before and after the introduction of the specialist ERCa MDT. Data on investigations and therapeutic interventions were compared. RESULTS: Nineteen patients from 2006 and 24 from 2011 were included. In 2006, 12 patients underwent MRI and four transrectal ultrasound (TRUS) examination, while in 2011, 18 and 20, respectively, received MRI and TRUS. In 2006 four patients underwent incidental ERCa polypectomy, with all having a positive resection margin leading to anterior resection. In 2011 only one case with a positive margin following extended endoscopic mucosal resection was identified. Definitive local excision without subsequent resection occurred in two patients in 2006 and in 16 in 2011. CONCLUSION: The study demonstrates an improvement in preoperative ERCa staging, a reduction in margin positivity and an increase in the use of local excision following the implementation of a specialist ERCa MDT. The increased detection of rectal neoplasms through screening and surveillance programmes requires further investigation and management. A specialist ERCa MDT will improve management and should be available to all practitioners involved with patients with ERCa. PMID- 25704246 TI - General practitioners' knowledge, attitude and prescribing of antibiotics for upper respiratory tract infections in Selangor, Malaysia: findings and implications. AB - BACKGROUND: Antibiotics are widely prescribed especially for upper respiratory tract infections (URTIs). Their irrational use can increase costs and resistance. AIM: Assess knowledge, attitude and prescribing of antibiotics for URTIs in Selangor, Malaysia, using a cross-sectional survey among general practitioners (GPs) working in private clinics in 2011. RESULTS: One hundred and thirty-nine physicians completed the questionnaire (response rate = 34.8%). 49.6% (n = 69) agreed antibiotics are helpful in treating URTIs, with most GPs agreeing antibiotics may reduce URTI duration and complications. The majority of GPs reported they felt patients expected antibiotics, with 36.7% (n = 51) agreeing patients would change doctors if they did not prescribe antibiotics and 21.6% (n = 30) agreeing when requested they prescribe antibiotics even if they believe them to be unnecessary. When assessed against six criteria, most GPs had a moderate level of knowledge of prescribing for URTIs. However, antibiotic prescriptions could be appreciably reduced. CONCLUSION: Further programs are needed to educate GPs and patients about antibiotics building on current initiatives. PMID- 25704247 TI - Sonographic appearances of torsion of the appendix testis and appendix epididymis in children. AB - PURPOSE: The most common cause of acute scrotum in prepubertal boys is torsion of the testicular or epididymal appendages. The purpose of this retrospective study was to characterize the features of these lesions as viewed on sonographic (US) and color Doppler US examination. METHODS: During a 220-week period, 527 male patients 0-17 years old had been referred from the pediatric emergency department for scrotal US evaluation. Torsion of the appendix testis or appendix epididymis had been diagnosed in 19 (3.6%) patients, 3-14 years old (mean, 9.4 years); those patients became our study cohort. The clinical diagnoses in 15 of those patients had been suspected testicular torsion (n = 7), trauma (n = 4), suspected epididymitis and/or orchitis (n = 3), and suspected hydrocele (n = 1). The remaining four patients had been referred owing to nonspecific pain. None of the 19 patients had had the "blue-dot sign" on physical examination. RESULTS: In the 19 patients diagnosed with torsion of the intrascrotal appendages, color Doppler US demonstrated a round or oval avascular lesion with heterogeneous echotexture (n = 18), posterior enhancement (n = 13), and hyperemia of the surrounding structures (n = 15). All lesions (appendages) were adjacent (n = 16) or in close proximity (n = 3) to the upper pole of the testis. Fifteen of the appendages were adjacent to both the testis and the epididymis, four were adjacent to the epididymis alone, and none were adjacent to the testis alone. Owing to the close proximity of the upper pole of the testis, the epididymis, and the appendage, differentiation between testicular and epididymal appendages was not possible. CONCLUSIONS: Torsion of the intrascrotal appendages has a typical appearance on color Doppler US; thus, we believe that it is the method of choice for diagnosing torsion of the scrotal appendages and safely ruling out other disorders as well as avoiding unwarranted surgical intervention or antibiotic treatment. PMID- 25704248 TI - Expression profiles of relaxin family peptides and their receptors indicate their influence on spermatogenesis in the domestic cat (Felis catus). AB - Disturbed spermatogenesis is a common problem in felines. Studying spermatogenesis in the domestic cat can improve the understanding of the biological background and help to counteract fertility problems in other feline species. Here, we analyzed 3 relaxin family peptides (relaxin, relaxin-3, and INSL3) and their receptors (RXFP1, RXFP2, and RXFP3) as potential spermatogenic factors involving their expression in the testis at different stages of its development. It may be concluded from its stage-dependent expression that relaxin, together with RXFP1, appears to be involved in the first stage of spermatogenesis, whereas relaxin-3 via binding to RXFP3 influences spermiogenesis. Furthermore, correlations were observed between relaxin, relaxin 3, RXFP1, RXFP2 and RXFP3 messenger RNA expression, and the relative numbers of haploid cells in testes. The peptide INSL3 was highly expressed at all testis development stages. Because of the low and stage-independent expression of its receptor RXFP2, an auto- and/or paracrine function of INSL3 in spermatogenesis seems unlikely. In the adult testis, messenger RNA expression of relaxin, RXFP1, and RXFP3 predominantly occurs in the tubular testis compartment, whereas INLS3 is mainly expressed in the interstitium. PMID- 25704249 TI - The IFNgamma-PKR pathway in the prefrontal cortex reactions to chronic excessive alcohol use. AB - BACKGROUND: Brain cell death is a major pathological consequence of alcohol neurotoxicity. However, the molecular cascades in alcohol-induced brain tissue injury are unclear. METHODS: Using Western blot and double immunofluorescence, we examined the expression of interferon (IFN)-induced protein kinase R (PKR), phosphorylated-PKR (p-PKR), and IFN gamma (IFNgamma) in the prefrontal cortex (PFC) of postmortem brains from subjects with alcohol use disorders (AUD). RESULTS: The protein levels of PKR, p-PKR, and IFNgamma were significantly increased in subjects with AUD compared with control subjects without AUD, and a younger age of onset of AUD was significantly correlated with higher protein levels of p-PKR. In addition, elevated PKR- and p-PKR-IR were observed in both neurons and astrocytes in the PFC of subjects with AUD compared to subjects without AUD. CONCLUSIONS: The activation of the IFNgamma-PKR pathway in PFC of humans is associated with chronic excessive ethanol use with an age of onset dependent manner, and activation of this pathway may play a pivotal role in AUD related brain tissue injury. This study provides insight into neurodegenerative key factors related to AUD and identifies potential targets for the treatment of alcohol-induced neurotoxicity. PMID- 25704250 TI - Evaluating whether nature's intrinsic value is an axiom of or anathema to conservation. AB - That at least some aspects of nature possess intrinsic value is considered by some an axiom of conservation. Others consider nature's intrinsic value superfluous or anathema. This range of views among mainstream conservation professionals potentially threatens the foundation of conservation. One challenge in resolving this disparity is that disparaging portrayals of nature's intrinsic value appear rooted in misconceptions and unfounded presumptions about what it means to acknowledge nature's intrinsic value. That acknowledgment has been characterized as vacuous, misanthropic, of little practical consequence to conservation, adequately accommodated by economic valuation, and not widely accepted in society. We reviewed the philosophical basis for nature's intrinsic value and the implications for acknowledging that value. Our analysis is rooted to the notion that when something possesses intrinsic value it deserves to be treated with respect for what it is, with concern for its welfare or in a just manner. From this basis, one can only conclude that nature's intrinsic value is not a vacuous concept or adequately accommodated by economic valuation. Acknowledging nature's intrinsic value is not misanthropic because concern for nature's welfare (aside from its influence on human welfare) does not in any way preclude also being concerned for human welfare. The practical import of acknowledging nature's intrinsic value rises from recognizing all the objects of conservation concern (e.g., many endangered species) that offer little benefit to human welfare. Sociological and cultural evidence indicates the belief that at least some elements of nature possess intrinsic value is widespread in society. Our reasoning suggests the appropriateness of rejecting the assertion that nature's intrinsic value is anathema to conservation and accepting its role as an axiom. PMID- 25704251 TI - Propagation of dysbindin-1B aggregates: exosome-mediated transmission of neurotoxic deposits. AB - Given the detection of aggregated deposits in chronic mental diseases (CMD), the disturbance of proteostasis in those diseases is receiving increasing attention. The study of aggregated proteins can contribute to our understanding of the chronic and progressive condition of such diseases. Dysbindin, encoded by the schizophrenia susceptibility gene DTNBP1, has been reported to co-aggregate with DISC1. However, there has been no evidence to date on the aggregation tendency of dysbindin. Therefore, we investigated the isoform-specific aggregation of dysbindin. We found that dysbindin-1B aggregated into cell-invasive deposits in mice. Because of the efficient propagation of dysbindin-1B, we further studied the mechanism of propagation and identified it as exosome-mediated transmission of the aggregates. In addition, aggregates of dysbindin-1B were toxic. Through exosome-mediated propagation, the deposits of dysbindin-1B exerted toxic effects on recipient neurons a long distance away from the initial aggregation site in mice brain. The rapid long distance propagation of neurotoxic deposits of dysbindin-1B in affected neuronal circuitry indicates a possible mechanism for the progressive deterioration of neurons and cognitive function in CMD. PMID- 25704252 TI - Identification of TMPRSS6 cleavage sites of hemojuvelin. AB - Hemojuvelin (HJV), the coreceptor of the BMP-SMAD pathway that up-regulates hepcidin transcription, is a repulsive guidance molecule (RGMc) which undergoes a complex intracellular processing. Following autoproteolysis, it is exported to the cell surface both as a full-length and a heterodimeric protein. In vitro membrane HJV (m-HJV) is cleaved by the transmembrane serine protease TMPRSS6 to attenuate signalling and to inhibit hepcidin expression. In this study, we investigated the number and position of HJV cleavage sites by mutagenizing arginine residues (R), potential TMPRSS6 targets, to alanine (A). We analysed translation and membrane expression of HJV R mutants and the pattern of fragments they release in the culture media in the presence of TMPRSS6. Abnormal fragments were observed for mutants at arginine 121, 176, 218, 288 and 326. Considering that all variants, except HJV(R121A) , lack autoproteolytic activity and some (HJV(R176A) and HJV(R288A) ) are expressed at reduced levels on cell surface, we identified the fragments originating from either full-length or heterodimeric proteins and defined the residues 121 and 326 as the TMPRSS6 cleavage sites in both isoforms. Using the N-terminal FLAG-tagged HJV, we showed that residue 121 is critical also in the rearrangement of the N-terminal heterodimeric HJV. Exploiting the recently reported RGMb crystallographic structure, we generated a model of HJV that was used as input structure for all-atoms molecular dynamics simulation in explicit solvent. As assessed by in silico studies, we concluded that some arginines in the von Willebrand domain appear TMPRSS6 insensitive, likely because of partial protein structure destabilization. PMID- 25704253 TI - The Robson ten-group classification system for appraising deliveries at a tertiary referral hospital in Brazil. AB - OBJECTIVE: To evaluate the distribution of women according to the Robson 10-group classification system (RTGCS) and the occurrence of severe maternal morbidity (SMM) by mode of delivery at a tertiary referral hospital. METHODS: A retrospective cross-sectional study was conducted of all women admitted to the Women's Hospital at the University of Campinas (Campinas, Brazil) for delivery between January 2009 and July 2013. Women were grouped according to RTGCS. Mode of delivery and SMM (defined as need for admission to the intensive care unit) were assessed. RESULTS: Among 12 771 women, 5957 (46.6%) delivered by cesarean. Overall, 3594 (28.1%) women were in group 1 (nulliparous, single pregnancy, cephalic, term, spontaneous labor), 2328 (18.2%) in group 5 (>=1 previous cesarean, single pregnancy, cephalic, term), and 2112 (16.5%) in group 3 (multiparous excluding previous cesarean, single pregnancy, cephalic, term, spontaneous labor). Group 5 contributed the most cesarean deliveries (1626 [27.3%]), followed by group 2 (nulliparous, single pregnancy, cephalic, term, induced labor or cesarean before labor; 1049 [17.6%]). SMM was more common among women undergoing cesarean delivery than among those delivering vaginally in groups 1-5. CONCLUSION: The RTGCS allowed the identification of groups with the highest frequency of cesarean delivery and an assessment of SMM. This should be considered in related health policies. PMID- 25704254 TI - Factors associated with poor attendance at the postpartum clinic six weeks after delivery in Cameroon. AB - OBJECTIVE: To identify reasons why women do not attend the 6-week postpartum clinic in Cameroon. METHODS: A retrospective cross-sectional cohort survey was undertaken among women who had delivered at the University Teaching Hospital in Yaounde between November 15 and December 31, 2013. Their medical files were retrieved and reviewed. Women who had not attended the 6-week postpartum clinic were contacted by telephone 2 months after delivery to establish reasons for non attendance. RESULTS: Among 120 included women, 85 (70.8%) did not attend the 6 week postpartum clinic. Compared with women who had attended the 6-week visit, more women who had not attended the visit had delivered vaginally, had no postpartum complications, and had not been counseled to attend the visit (P<0.001 for all). The main reason given for not attending this clinic was the feeling of well-being (n=36 [42.4%]). CONCLUSION: The benefits of attending the 6-week postpartum clinic should be emphasized in Cameroon, especially to women who have experienced uncomplicated vaginal delivery. PMID- 25704255 TI - A clinical study assessing the efficacy of a new variant of the levonorgestrel intrauterine system for abnormal uterine bleeding. AB - OBJECTIVE: To evaluate the efficacy and safety of a new variant of the levonorgestrel-intrauterine system (LNG-IUS)-Emily-for the treatment of abnormal uterine bleeding (AUB). METHODS: A prospective, multicenter, single-arm, phase 4 study was conducted at six centers in India between July 2012 and August 2013. Eligible women were aged 30-50years, had completed their family, had AUB, and a pictorial bleeding assessment chart (PBAC) score of at least 100. After screening (visit 1) and insertion of the device (visit 2), participants were followed up at 1week, 1month, 3months, and 6months. The primary outcomes were menstrual blood loss (assessed by PBAC) and quality of life (assessed by the EQ-5D-3L questionnaire). RESULTS: Among 63 participants, 45 (71%) completed the study. Mean PBAC score decreased from 238.0+/-128.7 at screening to 13.1+/-19.2 at 6months (P<0.001). EQ-5D-3L score increased from 79.0+/-14.1 at visit 2 to 86.3+/ 9.0 at 6months (P=0.003). No serious adverse events related to the device were reported. CONCLUSION: Among women with AUB, use of the Emily LNG-IUS significantly reduces menstrual bleeding and improves quality of life. Clinical Trials Registry of India: CTRI/2012/07/002843. PMID- 25704256 TI - Impact of sink location on hand hygiene compliance for Clostridium difficile infection. AB - Hand hygiene with soap and water after the care of a patient with Clostridium difficile infection is essential to reduce nosocomial transmission in an outbreak situation. Factors that may pose barriers to user completion of infection prevention measures, such as hand hygiene, are of interest. We undertook a quantitative study to evaluate the relationship between sink location and compliance with handwashing among health care workers and visitors in a surgical transplant unit. We found that placement of 2 more easily visible sinks in a surgical transplant unit was associated with improved adherence to handwashing. PMID- 25704257 TI - Diagnosing ventilator-associated pneumonia in pediatric intensive care. AB - The Centers for Disease Control and Prevention's criteria were applied by independent investigators for ventilator-associated pneumonia (VAP) diagnosis in critically ill children and compared with tracheal aspirate cultures (TACs). In addition, correlation between antibiotic use, VAP incidence, and epidemiology of TACs was investigated. A modest agreement (kappa = 0.41) was found on radiologic findings between 2 investigators. VAP incidence was 7.7 episodes per 1,000 ventilator days, but positive TACs were the most significant factor for driving high antimicrobial usage in the pediatric intensive care unit. PMID- 25704258 TI - Animal models for anti-emphysema drug discovery. AB - INTRODUCTION: Emphysema is characterized by an abnormal and permanent enlargement of airspaces accompanied by destruction of their walls. Up to now, there is no cure for emphysema, and animal models may be important for new drug discovery. AREAS COVERED: Herein, the authors review animal models of emphysema since the protease-antiprotease hypothesis as well as the results obtained with compounds tested in these models. Of particular importance are animal models of cigarette smoke exposure since it is the most important risk factor of emphysema. The authors also analyze two approaches to drug testing, that is, the approach aimed at preventing emphysema and the one aimed at reversing it. EXPERT OPINION: It has been suggested that early and late interventions do not have the same protective effect and that late interventions are much more likely to reveal treatments beneficial in humans. However, this is not always the case, and a compound that prevents emphysema when administered as an early intervention can also have the same protective effect when given as a late intervention. Furthermore, the fact that a compound detected by means of early intervention is now in clinical practice shows that early intervention studies can be predictive for efficacy in humans. PMID- 25704260 TI - Primary health-care responses to methamphetamine use in Australian Indigenous communities. AB - Crystal methamphetamine (commonly known as 'ice') use is currently a deeply concerning problem for some Australian Indigenous peoples and can cause serious harms to individual, families and communities. This paper is intended to support best practice responses by primary health-care staff working with Australian Indigenous people who use methamphetamine. It draws on a systematic search of relevant databases to identify literature from January 1999 to February 2014, providing an overview of prevalence, treatment, education and harm reduction, and community responses. The prevalence of methamphetamine use is higher in Indigenous than non-Indigenous communities, particularly in urban and regional settings. No evidence was identified that specifically related to effective treatment and treatment outcomes for Indigenous Australians experiencing methamphetamine dependence or problematic use. While studies involving methamphetamine users in the mainstream population suggest that psychological and residential treatments show short-term promise, longer-term outcomes are less clear. Community-driven interventions involving Indigenous populations in Australia and internationally appear to have a high level of community acceptability; however, outcomes in terms of methamphetamine use are rarely evaluated. Improved national data on prevalence of methamphetamine use among Indigenous people and levels of treatment access would support service planning. We argue for the importance of a strength-based approach to addressing methamphetamine use, to counteract the stigma and despair that frequently accompanies it. PMID- 25704259 TI - Indirect association of DAT1 genotype with executive function through white matter volume in orbitofrontal cortex. AB - The dopamine transporter (DAT1) gene has been associated with impulsivity and executive functioning. Further, DAT1 has been associated with brain structural characteristics and resting state connectivity. This study tested an indirect effect model in which DAT1 genotype (9-repeat (9R) carriers vs 10-repeat (10R) homozygotes) is linked to phenotypes representing impulsivity and executive function (planning behavior) through effects on white matter (WM) volumes in prefrontal cortex (PFC), particularly orbitofrontal cortex (OFC). Adolescents (ages 14-18, n=38) were recruited from substance use treatment (n=22) and the community (n=16) to increase phenotype variation. Results indicated that DAT1 10/10 genotype was associated with lower WM volume in the PFC, specifically the left OFC. Further, lower WM volume in the left OFC predicted more difficulties in self-reported planning behavior, but not impulsivity. Indirect effect analysis indicated that lower WM volume in the left OFC mediated the association between DAT1 10/10 genotype and difficulties in planning behavior. Results suggest a brain structural mechanism, involving lower WM volume in the left OFC, as a link in the association between DAT1 genotype and a specific aspect of executive function. Genetic effects on regional WM volume that are linked to behavioral outcomes could ultimately inform the development of tailored interventions that address an individual's unique risk factors. PMID- 25704261 TI - Use of fast HPLC multiple reaction monitoring cubed for endogenous retinoic acid quantification in complex matrices. AB - Retinoic acid (RA), an essential active metabolite of vitamin A, controls numerous physiological processes. In addition to the analytical challenges owing to its geometric isomers, low endogenous abundance, and often localized occurrence, nonspecific interferences observed during liquid chromatography (LC) multiple reaction monitoring (MRM) quantification methods have necessitated lengthy chromatography to obtain accurate quantification free of interferences. We report the development and validation of a fast high performance liquid chromatography (HPLC) multiplexing multiple reaction monitoring cubed (MRM(3)) assay for selective and sensitive quantification of endogenous RA from complex matrices. The fast HPLC separation was achieved using an embedded amide C18 column packed with 2.7 MUm fused-core particles which provided baseline resolution of endogenous RA isomers (all-trans-RA, 9-cis-RA, 13-cis-RA, and 9,13 di-cis-RA) and demonstrated significant improvements in chromatographic efficiency compared to porous particle stationary phases. Multiplexing technology further enhanced sample throughput by a factor of 2 by synchronizing parallel HPLC systems to a single mass spectrometer. The fast HPLC multiplexing MRM(3) assay demonstrated enhanced selectivity for endogenous RA quantification in complex matrices and had comparable analytical performance to robust, validated LC-MRM methodology for RA quantification. The quantification of endogenous RA using the described assay was validated on a number of mouse tissues, nonhuman primate tissues, and human plasma samples. The combined integration of fast HPLC, MRM(3), and multiplexing yields an analysis workflow for essential low-abundance endogenous metabolites that has enhanced selectivity in complex matrices and increased throughput that will be useful in efficiently interrogating the biological role of RA in larger study populations. PMID- 25704262 TI - Food shopping profiles and their association with dietary patterns: a latent class analysis. AB - BACKGROUND: Food shopping is a complex behavior that consists of multiple dimensions. Little research has explored multiple dimensions of food shopping or examined how it relates to dietary intake. OBJECTIVE: To identify patterns (or classes) of food shopping across four domains (fresh food purchasing, conscientious food shopping, food shopping locations, and food/beverage purchasing on or near campus) and explore how these patterns relate to dietary intake among college students. DESIGN: A cross-sectional online survey was administered. PARTICIPANTS/SETTING: Students attending a public 4-year university and a 2-year community college in the Twin Cities (Minnesota) metropolitan area (N=1,201) participated in this study. MAIN OUTCOME MEASURES: Fast-food and soda consumption as well as meeting fruit and vegetable, fiber, added sugar, calcium, dairy, and fat recommendations. STATISTICAL ANALYSES: Crude and adjusted latent class models and adjusted logistic regression models were fit. RESULTS: An eight class solution was identified: "traditional shopper" (14.9%), "fresh food and supermarket shopper" (14.1%), "convenience shopper" (18.8%), "conscientious convenience shopper" (13.8%), "conscientious, fresh food, convenience shopper" (11.8%), "conscientious fresh food shopper" (6.6%), "conscientious nonshopper" (10.2%), and "nonshopper" (9.8%). "Fresh food and supermarket shoppers" and "conscientious fresh food shoppers" had better dietary intake (for fast food, calcium, dairy, and added sugar), whereas "convenience shoppers" and "conscientious convenience shoppers," and "nonshoppers" had worse dietary intake (for soda, calcium, dairy, fiber, and fat) than "traditional shoppers." CONCLUSIONS: These findings highlight unique patterns in food shopping and associated dietary patterns that could inform tailoring of nutrition interventions for college students. Additional research is needed to understand modifiable contextual influences of healthy food shopping. PMID- 25704263 TI - Does osteonecrosis of the femoral head increase surgical and medical complication rates after total hip arthroplasty? A comprehensive analysis in the United States. AB - Total hip arthroplasty (THA) is a definitive option for end-stage osteonecrosis of the femoral head (ONFH). Historically, higher revision rates were observed in this population compared to THA for osteoarthritis (OA). This study provides a comprehensive evaluation of postoperative medical and surgical complications comparing THA in ONFH and OA at 90 days, 1 year, and 2 years after surgery. The PearlDiver database identified 45,002 OA and 8,429 ONFH patients who underwent THA. Mechanical complications (prosthetic loosening and osteolysis, implant failure), dislocation, renal and respiratory complications were significantly increased in the ONFH group within 2 years after THA. Pulmonary embolism rates where increased in younger ONFH patients within 2 years after THA. This data helps clinicians in the postoperative risk assessment of patients with ONFH. PMID- 25704264 TI - Common factors associated with osteonecrosis of the femoral head in young patients requiring total hip arthroplasty. AB - Osteonecrosis of the femoral head is a pathologic condition that commonly affects young patients and requires treatment with total hip arthroplasty (THA). The most common factors associated with osteonecrosis in young patients have not been previously described in the literature. A retrospective study was conducted to describe the most common factors associated with osteonecrosis in patients aged 35 or younger requiring a primary THA. This study included 235 patients and found that the most common factor associated with osteonecrosis was corticosteroid use (61%), followed by idiopathic causes (11%), trauma (9%), other causes (8%), haemoglobinopathies (7%), and alcoholism (3%). There was no significant difference in age between risk groups (p-value = 0.35), however there were significant differences in sex (p-value = 0.02) and unilateral versus bilateral surgery (p-value<0.01). Several factors are associated with the development of osteonecrosis of the femoral head in young patients, and these factors should be given consideration in determining disease aetiology and counselling patients. PMID- 25704265 TI - Effects of fire and three fire-fighting chemicals on main soil properties, plant nutrient content and vegetation growth and cover after 10 years. AB - The study addresses a knowledge-gap in the long-term ecological consequences of fire and fire-fighting chemicals. Ten years after a prescribed fire and the application of three fire-fighting chemicals, their effects on the soil-plant system were evaluated. Five treatments were established: unburnt soils (US) and burnt soils treated with water alone (BS), foaming agent (BS+Fo), Firesorb (BS+Fi) and ammonium polyphosphate (BS+Ap). Soils (0-2 cm depth) and foliar material of shrubs (Erica umbellata, Pterospartum tridentatum and Ulex micranthus) and trees (Pinus pinaster) were analysed for total N, delta(15)N, and soil-available and plant total macronutrients and trace elements. Soil pH, NH4(+) N and NO3(-)-N; pine basal diameter and height; and shrub cover and height were also measured. Compared with US plots, burnt soils had less nitrates and more Mo. Although differences were not always significant, BS+Ap had the highest levels of soil available P, Na and Al. Plants from BS+Ap plots had higher values of delta(15)N (P. pinaster and E. umbellata), P (all species), Na (P. tridentatum and U. micranthus) and Mg (E. umbellata and P. tridentatum) than other treatments; while K in plants from BS+Ap plots was the highest among treatments for P. pinaster and the lowest for the shrubs. Pines in US plots were higher and wider than in burnt treatments, except for BS+Ap, where the tallest and widest trees were found, although half of them were either dead (the second highest mortality after BS+Fi) or had a distorted trunk. BS+Ap was the treatment with strongest effects on plants, showing E. umbellata the lowest coverage and height, P. tridentatum the highest coverage, U. micranthus one of the lowest coverages and being the only treatment where Genista triacanthos was absent. Consequently, it is concluded that both fire and ammonium polyphosphate application had significant effects on the soil-plant system after 10 years. PMID- 25704266 TI - Emission and profile characteristic of volatile organic compounds emitted from coke production, iron smelt, heating station and power plant in Liaoning Province, China. AB - 107 kinds of C2-C12 volatile organic compound (VOC) mass concentrations and profiles for four types of coal-fired stationary sources in Liaoning Province were studied by a dilution sampling system and GC-MS analysis method, which are of significant importance with regard to VOC emissions in northeast of China. The results showed that there were some differences among these VOC source profiles. The total mass concentrations of analyzed 107 VOC species varied from 10,917 to 19,652 MUg m(-3). Halogenated hydrocarbons exhibited higher mass percentages for the VOC source profiles of iron smelt (48.8%) and coke production plant (37.7%). Aromatic hydrocarbons were the most abundant in heating station plant (69.1%). Ketones, alcohols and acetates held 45.0% of total VOCs in thermal power plant. For non-methane hydrocarbons (NMHCs), which are demanded for photochemical assessment in the USA, toluene and n-hexane were the most abundant species in the iron smelt, coke production and thermal power plant, with the mass percentages of 64.8%, 52.7% and 38.6%, respectively. Trimethylbenzene, n-propylbenzene and o,m ethyltoluene approximately accounted for 70.0% in heating station plant. NMHCs emitted from coke production, iron smelt, heating station and power plant listed above presented different chemical reactivities. The average OH loss rate of NMHCs from heating station, was 4 to 5.6 times higher than that of NMHCs from iron smelt, coke production and power plant, which implies that VOCs emitted from heating station in northeast of China should be controlled firstly to avoid photochemical ozone pollution and protect human health. There are significant variations in the ratios of benzene/toluene and m, p-xylene/ethylbenzene of these coal-fired source profiles. The representativeness of the coal-fired sources studied and the VOC samples collected should be more closely examined. The accuracy of VOC source profiles related to coal-fired processes is highly dependent on location and sampling method. PMID- 25704267 TI - A comparative life cycle assessment of conventional hand dryer and roll paper towel as hand drying methods. AB - A comparative life cycle assessment, under a cradle to gate scope, was carried out between two hand drying methods namely conventional hand dryer use and dispenser issued roll paper towel use. The inventory analysis for this study was aided by the deconstruction of a hand dryer and dispenser unit besides additional data provided by the Physical Resources department, from the product system manufacturers and information from literature. The LCA software SimaPro, supported by the ecoinvent and US-EI databases, was used towards establishing the environmental impacts associated with the lifecycle stages of both the compared product systems. The Impact 2002+ method was used for classification and characterization of these environmental impacts. An uncertainty analysis addressing key input data and assumptions made, a sensitivity analysis covering the use intensity of the product systems and a scenario analysis looking at a US based use phase for the hand dryer were also conducted. Per functional unit, which is to achieve a pair of dried hands, the dispenser product system has a greater life cycle impact than the dryer product system across three of four endpoint impact categories. The use group of lifecycle stages for the dispenser product system, which represents the cradle to gate lifecycle stages associated with the paper towels, constitutes the major portion of this impact. For the dryer product system, the use group of lifecycle stages, which essentially covers the electricity consumption during dryer operation, constitutes the major stake in the impact categories. It is evident from the results of this study that per dry, for a use phase supplied by Ontario's grid (2010 grid mix scenario) and a United States based manufacturing scenario, the use of a conventional hand dryer (rated at 1800 W and under a 30s use intensity) has a lesser environmental impact than with using two paper towels (100% recycled content, unbleached and weighing 4 g) issued from a roll dispenser. PMID- 25704268 TI - Interactions between natural organic matter, sulfur, arsenic and iron oxides in re-oxidation compounds within riparian wetlands: nanoSIMS and X-ray adsorption spectroscopy evidences. AB - Arsenic (As) is a toxic and ubiquitous element which can be responsible for severe health problems. Recently, Nano-scale Secondary Ions Mass Spectrometry (nanoSIMS) analysis has been used to map organomineral assemblages. Here, we present a method adapted from Belzile et al. (1989) to collect freshly precipitated compounds of the re-oxidation period in a natural wetland environment using a polytetrafluoroethylene (PTFE) sheet scavenger. This method provides information on the bulk samples and on the specific interactions between metals (i.e. As) and the natural organic matter (NOM). Our method allows producing nanoSIMS imaging on natural colloid precipitates, including (75)As(-), (56)Fe(16)O(-), sulfur ((32)S(-)) and organic matter ((12)C(14)N) and to measure X-ray adsorption of sulfur (S) K-edge. A first statistical treatment on the nanoSIMS images highlights two main colocalizations: (1) (12)C(14)N(-), (32)S(-), (56)Fe(16)O(-) and (75)As(-), and (2) (12)C(14)N(-), (32)S(-) and (75)As(-). Principal component analyses (PCAs) support the importance of sulfur in the two main colocalizations firstly evidenced. The first component explains 70% of the variance in the distribution of the elements and is highly correlated with the presence of (32)S(-). The second component explains 20% of the variance and is highly correlated with the presence of (12)C(14)N(-). The X-ray adsorption near edge spectroscopy (XANES) on sulfur speciation provides a quantification of the organic (55%) and inorganic (45%) sulfur compositions. The co-existence of reduced and oxidized S forms might be attributed to a slow NOM kinetic oxidation process. Thus, a direct interaction between As and NOM through sulfur groups might be possible. PMID- 25704269 TI - Reproductive Ratio for the Local Spread of African Swine Fever in Wild Boars in the Russian Federation. AB - African swine fever (ASF) has caused the swine industry of the Russian Federation substantial economic losses over the last 7 years, and the disease spread from there to a number of neighbouring countries. Wild boar has been involved in the spread of the disease both at local and at transboundary levels. Understanding ASF dynamics in wild boars is prerequisite to preventing the spread and to designing and applying effective surveillance and control plans. The reproductive ratio (R0 ) is an epidemiological indicator commonly used to quantify the extent of disease spread. Here, it was estimated in nine spatio-temporal clusters of ASF in wild boar cases in the Russian Federation (2007-2013). Clusters were defined by exploring the maximum distance of association of ASF cases using K Ripley analysis and spatio-temporal scan statistics. A maximum spatial association of 133 km in wild boar cases was identified which is within de the conventional radius of surveillance zone (100-150 km). The mean range value of R0 = 1.58 (1.13-3.77) was lower compared to values previously estimated for ASF transmission within farms but similar to early estimates between farm (R0 = 2 3), in domestic pigs using notification data in the Russian Federation. Results obtained provide quantitative knowledge on the epidemiology of ASF in wild boars in the Russian Federation. They identify the ASF transmission rate value in affected natural wild populations, for the first time, which could provide basis for modelling ASF transmission and suggest that current surveillance radius should be reviewed to make surveillance in wild nature more targeted and effective. PMID- 25704270 TI - New Treatment Options for Patients With Metastatic Prostate Cancer: What Is The Optimal Sequence? AB - Systemic treatment of men with metastatic prostate cancer is rapidly evolving. Androgen deprivation therapy remains the first-line treatment for advanced disease and the backbone of sequential strategies. For patients with extensive metastatic disease the addition of docetaxel markedly improves survival. In case patients develop castration-resistant prostate cancer, several new therapeutic strategies are available. Large trials have shown a survival benefit for patients treated with sipuleucel-T, docetaxel, cabazitaxel, abiraterone, enzalutamide, or radium-223. Along with these new available treatment options, the sequence of applying them has become a serious matter of debate. In this review we provide an overview of current systemic treatment options for metastatic prostate cancer and propose considerations to optimally sequence registered new therapies. In addition, we hypothesize on improvement of outcome with potential combination strategies. PMID- 25704271 TI - Sonication-assisted alcoholysis of boron nitride nanotubes for their sidewalls chemical peeling. AB - Boron nitride (BN)-based nanomaterials attract considerable attention due to their unique properties. In this study, we found that sonication treatment of multiwalled boron nitride nanotubes (BNNTs) in primary alcohols had led to chemical peeling of their sidewalls through alcoholysis, thereby producing boron nitride nanoribbons (BNNRs). PMID- 25704272 TI - [International adoption has matured]. PMID- 25704273 TI - [International adoption in Spain: Current situation]. PMID- 25704274 TI - Cardiac MRI in patients with complex CHD following primary or secondary implantation of MRI-conditional pacemaker system. AB - OBJECTIVES: In patients with CHD, cardiac MRI is often indicated for functional and anatomical assessment. With the recent introduction of MRI-conditional pacemaker systems, cardiac MRI has become accessible for patients with pacemakers. The present clinical study aims to evaluate safety, susceptibility artefacts, and image reading of cardiac MRI in patients with CHD and MRI conditional pacemaker systems. Material and methods CHD patients with MRI conditional pacemaker systems and a clinical need for cardiac MRI were examined with a 1.5-T MRI system. Lead function was tested before and after MRI. Artefacts and image readings were evaluated using a four-point grading scale. RESULTS: A total of nine patients with CHD (mean age 34.0 years, range 19.5-53.6 years) received a total of 11 cardiac MRI examinations. Owing to clinical indications, seven patients had previously been converted from conventional to MRI-conditional pacemaker systems. All MRI examinations were completed without adverse effects. Device testing immediately after MRI and at follow-up showed no alteration of pacemaker device and lead function. Clinical questions could be addressed and answered in all patients. CONCLUSION: Cardiac MRI can be performed safely with high certainty of diagnosis in CHD patients with MRI-conditional pacemaker systems. In case of clinically indicated lead and box changing, CHD patients with non-MRI-conditional pacemaker systems should be considered for complete conversion to MRI-conditional systems. PMID- 25704275 TI - Modification of the optical spectrum of Cytosine by the formation of an ordered monolayer of molecules at a au(110)/electrolyte interface. AB - An analysis of the reflection anisotropy spectrum (RAS) of an ordered monolayer of cytosine adsorbed at a Au(110)/electrolyte interface is found to contain optical contributions from both the substrate and the cytosine. The spectrum of cytosine in an aqueous environment is significantly broadened by the interaction between the molecule and the Au(110). Successful simulations of the Au(110)/cytosine interface consisting of two additional molecular transitions, which sit in the middle of previously observed molecular absorption bands, are produced by an empirical Lorentzian transition model that is consistent with previous theoretical and experimental studies. While this analysis alone cannot determine the number of pi->pi* dipole transitions, it confirms that the only cytosine transitions that contribute to the optical response of the Au(110)/cytosine interface are located in the plane of the molecule, which is vertical to the gold surface with the long axis along the [1$?bar 1$0] direction. PMID- 25704276 TI - Risks of peripheral arterial occlusive disease in patients with obstructive sleep apnoea: a population-based case-control study. AB - OBJECTIVES: This study aimed to evaluate the risk of peripheral arterial occlusive disease (PAOD) in patients with obstructive sleep apnoea (OSA) using a nationwide claim database in Taiwan. DESIGN: A population-based case-control study. SETTING: Data from the Longitudinal Health Insurance Database 2000 of the Taiwan's National Health Insurance Research Database. PARTICIPANTS: Eleven thousand eight hundred and seventeen adult patients diagnosed with PAOD between January 1, 2001 and December 31, 2010 and 35 451 controls without PAOD frequency matched by sex, 10-year age interval and year of index date. MAIN OUTCOME MEASURES: Obstructive sleep apnoea and a number of comorbidities prior to the index date were assessed and analysed with logistic regression analyses. RESULTS: Univariate logistic regression analysis showed that PAOD was significantly associated with OSA (odds ratio, OR = 1.60, P < 0.001). Multivariate logistic regression analysis, adjusted for coronary artery disease or myocardial infarction, chronic kidney disease, hyperurecaemia and obesity, also showed that PAOD was significantly associated with OSA (adjusted OR = 1.37, P = 0.014). However, the association was attenuated when it was further adjusted for hypertension, hyperlipidaemia and diabetes mellitus (DM). CONCLUSION: Findings from this nationwide population-based study indicated that PAOD was significantly associated with OSA. Further studies are warranted to determine whether OSA may contribute to the development of PAOD indirectly via increasing the risks of hypertension, hyperlipidaemia and/or DM. PMID- 25704277 TI - Arsenic levels from different land-use settings in Pakistan: Bio-accumulation and estimation of potential human health risk via dust exposure. AB - The present study aims at assessing arsenic (As) levels in outdoor dust and human exposure risks at different land use setting (i.e., rural, industrial, urban) from Punjab, Pakistan. The results showed higher As concentrations (mg/kg) in all the sample types ( i.e., dust, hair and nail) collected from industrial sites (9.78, 2.36, 2.5) followed by urban (7.59, 0.38, 0.88) and rural sites (6.95, 0.52, 1.12), respectively. In the current study, we also carried out human risk assessment via contaminated dust exposure, which suggested that dust ingestion is the major route of As contamination for the associated population, followed by the inhalation and dermal contact, at all studied land use settings. Hazard Index (HI) calculated for non-carcinogenic health risks for adults showed higher values at industrial (0.65) and urban (0.53) sites, which reflected that dust exposure is the major contributing source of human arsenic burden and may pose several adverse health effects. Carcinogenic risk values showed that at industrial areas the risk of carcinogenesis to the associated population is mainly due to As contaminated dust exposure. Hair (60%) and nail samples (70%) collected from industrial land use were found above the WHO threshold limit of 1mg/kg, suggested high risks for human health in the studied area. The results of the present study would be useful for assessing the human health risks due to arsenic contamination via dust exposure in different parts of country. PMID- 25704278 TI - Persistent organochlorines in 13 shark species from offshore and coastal waters of Korea: Species-specific accumulation and contributing factors. AB - Data on persistent organochlorines (OCs) in sharks are scarce. Concentrations of OCs such as polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs) were determined in the muscle tissue of 13 shark species (n=105) collected from offshore (Indian and Pacific Oceans) and coastal waters of Korea, to investigate species-specific accumulation of OCs and to assess the potential health risks associated with consumption of shark meat. Overall OC concentrations were highly variable not only among species but also within the same species of shark. The concentrations of PCBs, DDTs, chlordanes, hexachlorobenzene, and heptachlor in all shark species ranged from 65 years who had undergone primary TKA were enrolled. These patients were assigned to the delirium group of 11 patients (11 knees) or the non-delirium group of 276 patients (354 knees). The incidence of delirium among the patients was 3.1% (11/365). Univariate logistic regression analysis indicated that a history of dementia, older age, lower body mass index (BMI) level, and a postoperative day 3 blood urea nitrogen (BUN) level of >14.9 mg/dL were risk factors. However, multivariate logistic regression analysis indicated that a history of dementia (adjusted odds ratio [AOR]: 10.4, [1.09, 100]), older age (AOR: 1.15, [1.01, 1.31]), and a postoperative day 3 BUN level of >14.9 mg/dL (AOR: 4.76, [1.15, 19.7]) were independent risk factors. Based on our findings, we believe that the surgeons should be careful to avoid the postoperative delirium and ensure the appropriate management for patients who have these risk factors. PMID- 25704296 TI - Use of subcutaneous-C1 INH for acute therapy and prophylaxis of a child with HAE. PMID- 25704297 TI - D-lactic acidosis in haematological malignancy. PMID- 25704298 TI - Probiotics and gut health in infants: A preliminary case-control observational study about early treatment with Lactobacillus reuteri DSM 17938. AB - AIMS: We performed this case-control observational study to evaluate the effects of early administration of Lactobacillus reuteri DSM 17938 on microbial composition in infants' gastrointestinal tract. METHODS: Early fecal microbiota composition was analyzed by using selective and differential cultural methods. Genomic DNA from positive Escherichia coli and Cronobacter sakazakii colonies was extracted and DNA was processed by multiplex PCR assay. RESULTS: Fecal samples of 30 hospitalized infants who previously received probiotics and 30 not receiving probiotics were analyzed. We find that the two groups showed differences in gut microbial strains composition and richness. Infant treated with probiotics have a lower total anaerobic gram negative counts (p=0.03) and a higher total anaerobic gram-positive counts (p=0.02). Enterobacteriaceae and enterococci were significantly higher (p=0.04) in the control group. No significant differences were observed for total aerobic counts, lactobacilli and bifidobacteria. C. sakazaki was found only in one infant recruited in the control group. Infants not previously treated with probiotics showed a higher colonization by diarrheagenic E. coli (EPEC) (p=0.04). CONCLUSIONS: Our findings enhanced our understanding of the effects of probiotics on gut health in pediatric subjects. Early administration of L. reuteri in infancy could improve gut health by reducing pathogens colonization. PMID- 25704299 TI - Schizophrenia and bipolar disorder: The road from similarities and clinical heterogeneity to neurobiological types. AB - Although diagnosis is a central issue in medical care, in psychiatry its value is still controversial. The function of diagnosis is to indicate treatments and to help clinicians take better care of patients. The fundamental role of diagnosis is to predict outcome and prognosis. To date serious concern persists regarding the clinical utility and predictive validity of the diagnosis system in psychiatry, which is at the most syndromal. Schizophrenia and bipolar disorder, which nosologists consider two distinct disorders, are the most discussed psychiatric illnesses. Recent findings in different fields of psychiatric research, such as neuroimaging, neuropathology, neuroimmunology, neuropsychology and genetics, have led to other conceptualizations. Individuals with schizophrenia or bipolar disorder vary greatly with regard to symptoms, illness course, treatment response, cognitive and functional impairment and biological correlates. In fact, it is possible to find heterogeneous correlates even within the same syndrome, i.e., from one stage of the disorder to another. Thus, it is possible to identify different subsyndromes, which share some clinical and neurobiological characteristics. The main goal of modern psychiatry is to ovethrow these barriers and to obtain a better understanding of the biological profiles underlying heterogeneous clinical features and thus reduce the variance and lead to a homogeneous definition. The translational research model, which connects the basic neuroscience research field with clinical experience in psychiatry, aims to investigate different neurobiological features of syndromes and of the shared neurobiological features between two syndromes. In fact, this approach should help us to better understand the neurobiological pathways underlying clinical entities, and even to distinguish different, more homogeneous, diagnostic subtypes. PMID- 25704300 TI - Soluble urokinase plasminogen activator receptor--a valuable biomarker in systemic lupus erythematosus? AB - Systemic lupus erythematosus (SLE) is a potentially severe autoimmune condition with an unpredictable disease course, often with fluctuations in disease activity over time. Long term inflammation and drug-related side-effects may subsequently lead to permanent organ damage, a consequence which is intimately connected to decreased quality of life and mortality. New lupus biomarkers that convey information regarding inflammation and/or organ damage are thus warranted. Today, there is no clinical biomarker that indicates the risk of damage accrual. Herein we highlight the urokinase plasminogen activator receptor (uPAR) and especially its soluble form (suPAR) that besides having biological functions in e.g. proteolysis, cell migration and tissue homeostasis, recently has emerged as a promising biomarker of inflammation and prognosis of several disorders. A strong association between suPAR and organ damage in SLE was recently demonstrated, and preliminary data (presented in this review) suggests the possibility of a predictive value of suPAR blood levels. The involvement of suPAR in the pathogenesis of SLE remains obscure, but its effects in leukocyte recruitment, phagocytic uptake of dying cells (efferocytosis) and complement regulation suggests that the central parts of the SLE pathogenesis could be regulated by suPAR, and vice versa. PMID- 25704301 TI - IgG subclass distribution in patients with monoclonal gammopathy. PMID- 25704302 TI - The clinical and diagnostic utility of S100B in preterm newborns. AB - Preterm birth is still the most important cause of perinatal mortality and morbidity. Follow-up studies showed that the majority of neurological abnormalities during childhood are already present in the first week after birth. In this light, the knowledge of the timing of the insult and/or of the contributing factors is of utmost relevance in order to avoid adverse neurological outcome. Notwithstanding, the considerable advances in perinatal clinical care and monitoring, the early detection of cases at risk for brain damage is still a challenge because, when radiological pictures are still negative, brain damage may be already at a subclinical stage, with symptoms hidden by therapeutic strategies. Thus, it could be very relevant to measure quantitative parameters, such as neuroproteins, able to detect subclinical lesions at a stage when routine brain monitoring procedures are still silent. In the last decade, the assay of the brain-specific protein S100B in different biological fluids proved useful information on brain function and damage in the perinatal period. Therefore, the present study provides an overview of the most recent findings on S100B role as a reliable marker of brain development/damage in preterm high risk fetuses and newborns. PMID- 25704303 TI - PI3K/Akt signaling in osteosarcoma. AB - Osteosarcoma (OS) is the most common nonhematologic bone malignancy in children and adolescents. Despite the advances of adjuvant chemotherapy and significant improvement of survival, the prognosis remains generally poor. As such, the search for more effective anti-OS agents is urgent. The phosphatidylinositol 3 kinase (PI3K)/Akt pathway is thought to be one of the most important oncogenic pathways in human cancer. An increasing body of evidence has shown that this pathway is frequently hyperactivated in OS and contributes to disease initiation and development, including tumorigenesis, proliferation, invasion, cell cycle progression, inhibition of apoptosis, angiogenesis, metastasis and chemoresistance. Inhibition of this pathway through small molecule compounds represents an attractive potential therapeutic approach for OS. The aim of this review is to summarize the roles of the PI3K/Akt pathway in the development and progression of OS, and to highlight the therapeutic potential of targeting this signaling pathway. Knowledge obtained from the application of these compounds will help in further understanding the pathogenesis of OS and designing subsequent treatment strategies. PMID- 25704304 TI - Relationship between blood metals and inflammation in taxi drivers. AB - BACKGROUND: Cardiovascular disease is a cause of concern in public health worldwide, reinforcing the need for studies related to the identification of potential agents that contribute to the inflammation process and atherosclerosis. This study aimed to evaluate whether metals are associated with inflammatory and kidney damage and could contribute to the atherosclerosis process. METHODS: Blood metals, inflammatory markers, homocysteine, antioxidants and renal markers were measured in 42 taxi drivers and 27 controls (non-occupationally exposed). RESULTS: Taxi drivers had increased Hg, As, Pb and Cd levels, however Cu and Zn levels were decreased compared to controls (p<0.05). Hg, As and Pb levels were positively associated with pro-inflammatory cytokines, nitric oxide and negatively associated with glutathione peroxidase. Moreover, Hg, As and Pb presented positive associations with homocysteine, an independent risk factor for atherosclerosis. Regarding markers of kidney function, N-acetyl-beta-d glucosaminidase levels were increased in taxi drivers and correlated to inflammation markers. CONCLUSION: Hg levels were found above the recommended limits in taxi drivers and both Hg and As levels showed associations with inflammatory process, oxidative status and homocysteine. Thus, chemical substances as Hg and As can be considered as additional contributors to the development of cardiovascular diseases. PMID- 25704305 TI - Adverse drug reaction reports for cardiometabolic drugs from sub-Saharan Africa: a study in VigiBase. AB - OBJECTIVE: Identifying key features in individual case safety reports (ICSR) of suspected adverse drug reactions (ADRs) with cardiometabolic drugs from sub Saharan Africa (SSA) compared with reports from the rest of the world (RoW). METHODS: Reports on suspected ADRs of cardiometabolic drugs (ATC: A10[antidiabetic], B01[antithrombotics] and C[cardiovascular]) were extracted from WHO Global database, VigiBase((r)) (1992-2013). We used vigiPoint, a logarithmic odds ratios (log2 OR)-based method to study disproportional reporting between SSA and RoW. Case-defining features were considered relevant if the lower limit of the 99% CI > 0.5. RESULTS: In SSA, 3773 (9%) of reported ADRs were for cardiometabolic drugs, in RoW for 18%. Of these, 79% originated from South Africa and 81% were received after 2007. Most reports were for drugs acting on the renin angiotensin system (36% SSA & 14% RoW). Compared with RoW, reports were more often sent for patients 18-44 years old (log2 OR 0.95 [99 CI 0.80; 1.09]) or with non-fatal outcome (log2 OR 1.16 [99 CI 1.10; 1.22]). Eight ADRs (cough, angioedema, lip swelling, face oedema, swollen tongue, throat irritation, drug ineffective and blood glucose abnormal) and seven drugs (enalapril, rosuvastatin, perindopril, vildagliptin, insulin glulisine, nifedipine and insulin lispro) were disproportionally more reported in SSA than in the RoW. CONCLUSIONS: 'In recent years, the number of adverse drug reactions (ADRs) reported in Sub-Saharan Africa (SSA) has sharply increased. The data showed the well-known population-based differential ADR profile of ACE inhibitors in the SSA population.' PMID- 25704306 TI - Efficient demyristoylase activity of SIRT2 revealed by kinetic and structural studies. AB - Sirtuins are a class of enzymes originally identified as nicotinamide adenine dinucleotide (NAD)-dependent protein lysine deacetylases. Among the seven mammalian sirtuins, SIRT1-7, only SIRT1-3 possess efficient deacetylase activity in vitro, whereas SIRT4-7 possess very weak in vitro deacetylase activity. Several sirtuins that exhibit weak deacetylase activity have recently been shown to possess more efficient activity for the removal other acyl lysine modifications, such as succinyl lysine and palmitoyl lysine. Here, we demonstrate that even the well-known deacetylase SIRT2 possesses efficient activity for the removal of long-chain fatty acyl groups. The catalytic efficiency (kcat/Km) for the removal of a myristoyl group is slightly higher than that for the removal of an acetyl group. The crystal structure of SIRT2 in complex with a thiomyristoyl peptide reveals that SIRT2 possesses a large hydrophobic pocket that can accommodate the myristoyl group. Comparison of the SIRT2 acyl pocket to those of SIRT1, SIRT3, and SIRT6 reveals that the acyl pockets of SIRT1-3 are highly similar, and to a lesser degree, similar to that of SIRT6. The efficient in vitro demyristoylase activity of SIRT2 suggests that this activity may be physiologically relevant and warrants future investigative studies. PMID- 25704307 TI - Solvent vapor annealing of block copolymers in confined topographies: commensurability considerations for nanolithography. AB - The directed self-assembly of block copolymer (BCP) materials in topographically patterned substrates (i.e., graphoepitaxy) is a potential methodology for the continued scaling of nanoelectronic device technologies. In this Communication, an unusual feature size variation in BCP nanodomains under confinement with graphoepitaxially aligned cylinder-forming poly(styrene)-block-poly(4 vinylpyridine) (PS-b-P4VP) BCP is reported. Graphoepitaxy of PS-b-P4VP BCP line patterns (CII ) is accomplished via topo-graphy in hydrogen silsequioxane (HSQ) modified substrates and solvent vapor annealing (SVA). Interestingly, reduced domain sizes in features close to the HSQ guiding features are observed. The feature size reduction is evident after inclusion of alumina into the P4VP domains followed by pattern transfer to the silicon substrate. It is suggested that this nano-domain size perturbation is due to solvent swelling effects during SVA. It is proposed that using a commensurability value close to the solvent vapor annealed periodicity will alleviate this issue leading to uniform nanofins. PMID- 25704308 TI - Extracellular vesicles--Their role in the packaging and spread of misfolded proteins associated with neurodegenerative diseases. AB - Many cell types, including neurons, are known to release small membranous vesicles known as exosomes. In addition to their protein content these vesicles have recently been shown to contain messenger RNA (mRNA) and micro RNA (miRNA) species. Roles for these vesicles include cell-cell signalling, removal of unwanted proteins, and transfer of pathogens (including prion-like misfolded proteins) between cells, such as infectious prions. Prions are the infectious particles that are responsible for transmissible neurodegenerative diseases such as Creutzfeldt-Jakob disease (CJD) of humans or bovine spongiform encephalopathy (BSE) of cattle. Exosomes are also involved in processing the amyloid precursor protein (APP), which is associated with Alzheimer's disease (AD). As exosomes can be isolated from circulating fluids such as serum, urine, and cerebrospinal fluid (CSF), they provide a potential source of biomarkers for neurological conditions. Here, we review the roles these vesicles play in neurodegenerative disease and highlight their potential in diagnosing these disorders through analysis of their RNA content. PMID- 25704309 TI - Gram-negative and Gram-positive bacterial extracellular vesicles. AB - Like mammalian cells, Gram-negative and Gram-positive bacteria release nano-sized membrane vesicles into the extracellular environment either in a constitutive manner or in a regulated manner. These bacterial extracellular vesicles are spherical bilayered proteolipids enriched with bioactive proteins, lipids, nucleic acids, and virulence factors. Recent progress in this field supports the critical pathophysiological functions of these vesicles in both bacteria-bacteria and bacteria-host interactions. This review provides an overview of the current understanding on Gram-negative and Gram-positive bacterial extracellular vesicles, especially regarding the biogenesis, components, and functions in poly species communities. We hope that this review will stimulate additional research in this emerging field of bacterial extracellular vesicles and contribute to the development of extracellular vesicle-based diagnostic tools and effective vaccines against pathogenic Gram-negative and Gram-positive bacteria. PMID- 25704310 TI - EVpedia: A community web resource for prokaryotic and eukaryotic extracellular vesicles research. AB - For cell-to-cell communication, all living cells including archaea, bacteria, and eukaryotes secrete nano-sized membrane vesicles into the extracellular space. These extracellular vesicles harbor specific subsets of proteins, mRNAs, miRNAs, lipids, and metabolites that represent their cellular status. These vesicle specific cargos are considered as novel diagnostic biomarkers as well as therapeutic targets. With the advancement in high-throughput technologies on multiomics studies and improvements in bioinformatics approaches, a huge number of vesicular proteins, mRNAs, miRNAs, lipids, and metabolites have been identified, and our understanding of these complex extracellular organelles has considerably increased during these past years. In this review, we highlight EVpedia (http://evpedia.info), a community web portal for systematic analyses of prokaryotic and eukaryotic extracellular vesicles research. PMID- 25704311 TI - Incidental prostate cancer in Asian men: high prevalence of incidental prostatic adenocarcinoma in Chinese patients undergoing radical cystoprostatectomy for treatment of bladder cancer and selection of candidates for prostate-sparing cystectomy. AB - BACKGROUND: Previous studies report a low prevalence of incidental prostate cancer in Chinese patients (3-7%). We evaluated incidental prostatic adenocarcinoma (PCa) and urothelial carcinoma (UCa) involvement of the prostate in cystoprostatectomy specimens. METHODS: We analyzed 340 cystoprostatectomy specimens from patients who underwent radical cystoprostatectomy for the treatment of bladder cancer in China from 2004 to 2014. None of the patients had known prostate cancer prior to cystoprostatectomy. RESULTS: Overall, 180 (53%) patients had either PCa or UCa in the prostate. We found that 95 (28%) had PCa and 115 (34%) had UCa involvement of prostate. The rate of incidental prostate cancer was 21% and 31%, respectively, from two study periods (2004-2008 and 2009 2014). Among the 95 patients with PCa, 19 (20%) had Gleason score of >=7, nine (10%) had PCa tumor volume >0.5 cc, and eight (8.4%) had extracapsular extension. Of the 115 with prostatic UCa, 61 had prostatic urethra and/or periurethral prostatic duct involvement only, while 54 had prostatic stromal invasion. Age (odds ratio [OR] = 1.04, P = 0.001), increasing stage of bladder tumor (OR = 1.28, P = 0.005), multifocal tumors of bladder (OR = 3.22, P < 0.001), carcinoma in situ (CIS) in the bladder (OR = 5.52, P < 0.001), and bladder neck involvement (OR = 6.12, P < 0.001) were strongly associated with prostatic UCa. CONCLUSIONS: The rate of incidental PCa in cystoprostatectomy specimens in China has increased over the last decade. Patients with advanced age, elevated serum PSA level, advanced bladder tumor stage, multifocal bladder tumors, CIS in the bladder, and tumor location at the bladder neck should be excluded as candidates for prostate sparing cystectomy. PMID- 25704312 TI - Standard free energy of the equilibrium between the trans-monomer and the cyclic dimer of acetic acid in the gas phase from infrared spectroscopy. AB - Survey jet-cooled spectra of acetic acid have been recorded in the infrared region (200-4000 cm(-1)) over a wide range of expansion conditions. From the variations of the relative intensities of the signals, vibrational transitions have been assigned unambiguously to the trans-monomer and cyclic-dimer. The IR active fundamental frequencies have been determined at the instrumental accuracy of 0.5 cm(-1). This analysis of the jet-cooled spectra supported by electronic structure calculations permitted us to characterize the trans-monomer/cyclic dimer equilibrium. From static cell spectra at 298 K, variations of the molar fractions ratio as a function of the total pressure were used to estimate the equilibrium constant and the Gibbs free energy of dimerization at 298 K. The very good agreement with the literature data shows that the present method is able to produce, from a single study, a free energy value as reliable as the one obtained from a large collection of data. In addition, the semi-empirical free energy value was used to estimate the accuracy of electronic structure calculations and in turn the accuracy of the derived useful information such as the dissociation energy of the complex (i.e. the strength of the hydrogen bonds) or the relative energies within the conformational landscape. PMID- 25704313 TI - Synthesis, structural characterization and DNA interaction of zinc complex from 2,6-diacetylpyridine dihydrazone and {4-[(2E)-2-(hydroxyimino)acetyl]phenoxy} acetic acid. AB - A new water soluble zinc complex has been prepared and structurally characterized. The Zn(II) complex was synthesized by the reaction of 2,6 diacetylpyridine dihydrazone (dph) with {4-[(2E)-2-(hydroxyimino)acetyl]phenoxy} acetic acid (H2L) in the presence of zinc(II) acetate. Single crystal X-ray diffraction study revealed that the zinc ion is situated in distorted trigonal bipyramidal environment where the equatorial position is occupied by the nitrogen atom of pyridine ring and the oxygen atoms of acetate groups of two oxime ligands (H2L) whereas the axial positions of the zinc complex are occupied by the imine nitrogen atoms of dph ligand. Characterization of the complex with FTIR, (1)H and (13)C NMR, UV-vis and elemental analysis also confirmed the proposed structure. Interaction of the Zn(II) complex with calf-thymus DNA (CT-DNA) was investigated through UV-vis spectroscopy and viscosity measurements. The results suggest that the complex preferably bind to DNA through the groove binding mode. The zinc complex cleaves plasmid pBR 322 DNA in the presence and absence of an oxidative agent (H2O2), possibly through a hydrolytic pathway which is also supported by DNA cleave experiments in the presence of different radical scavengers. The nuclease activity of the zinc complex significantly depends on concentration of the complex and incubation time both in the presence and absence of H2O2. DNA cleave activity is inhibited in the presence of methyl green indicating that the zinc complex seems to bind the major groove of DNA. PMID- 25704314 TI - Low level laser therapy against radiation induced oral mucositis in elderly head and neck cancer patients-a randomized placebo controlled trial. AB - OBJECTIVES: Radiotherapy (RT) is treatment of choice for Elderly Head and Neck Cancer (HNC) patients. Oral mucositis (OM) during RT affects patient's routine oral activities and overall health. Low Level Laser Therapy (LLLT) provided some promising results against cancer therapy induced OM in children and adults. No study specifically evaluated effects of LLLT against RT induced OM in elderly HNC patients until date, hence we did this study. MATERIAL AND METHODS: This double blinded study randomized 46 elderly HNC patients scheduled for RT [Dosage=66 Gray (2 Gy/fraction), 5 fractions/week, total 33 fractions for 6.5 weeks], into laser (22) and placebo (24) groups. Laser group patients received LLLT [Helium-Neon, lambda=632.8 nm, power density=0.024 W/cm(2), dosage=3.0 J/point at six anatomical sites bilaterally i.e. 12 locations, total dose/session=36 J, beam aperture diameter=0.6 mm, beam spot size=1 cm(2), irradiated area diameter=1 cm(2), irradiation time/point=125 s, 5 sessions/week, non-contact method-distance between probe and irradiated tissues <1 cm, whereas placebo group did not receive laser. OM grades (RTOG/EORTC Scale), oral pain, weight loss, need for morphine analgesics and tube feeding, and RT break were recorded by a blinded assessor. Descriptive statistics and repeated measures ANOVA were used for analysis keeping p<0.05. RESULTS: Significant reduction in the incidence and duration of severe OM (p=0.016) and severe pain (p=0.023) and weight loss (p=0.004) was observed in laser than placebo group. No difference was found for enteral feeding use (p=0.667) between two groups. CONCLUSIONS: LLLT decreased the severity of OM and oral pain in elderly HNC patients. Also, lesser weight loss, morphine analgesic use and radiation break happened in laser group. PMID- 25704315 TI - Safe and effective treatment with daclatasvir and asunaprevir in a liver transplant recipient with severe cholestatic hepatitis C. AB - Severe cholestatic hepatitis C (SCH) is a unique variant of recurrent hepatitis C that occurs after liver transplantation. Unfortunately, the prognosis of SCH is poor, and interferon (IFN) therapy has been reported to not improve the prognosis. We herein report a case of progressive SCH with acute cellular rejection (ACR) and bacterial infection, which was successfully treated using IFN free therapy with daclatasvir and asunaprevir. A 43-year-old man was diagnosed with SCH and mild ACR at day 48 after liver transplantation, and IFN-free therapy with daclatasvir and asunaprevir was started. Although he experienced catheter related bacteremia on the first day, the IFN-free therapy was safely continued, which immediately caused his liver function to improve. His bilirubin levels decreased from 11.1 to 2.1 mg/dL and serum hepatitis C virus RNA levels became undetectable after 4 weeks of the treatment. This case indicates that IFN-free therapy for progressive SCH with acute cellular rejection and bacterial infection is safe and effective, and may improve the outcomes of hepatitis C virus positive transplant recipients. PMID- 25704316 TI - Microbial Consortium Associated with the Antarctic Marine Ciliate Euplotes focardii: An Investigation from Genomic Sequences. AB - We report the characterization of the bacterial consortium associated to Euplotes focardii, a strictly psychrophilic marine ciliate that was maintained in laboratory cultures at 4 degrees C after its first isolation from Terra Nova Bay, in Antarctica. By Illumina genome analyser, we obtained 11,179 contigs of potential prokaryotic origin and classified them according to the NCBI's prokaryotic attributes table. The majority of these sequences correspond to either Bacteroidetes (16 %) or Proteobacteria (78 %). The latter were dominated by gamma- (39 %, including sequences related to the pathogenic genus Francisella), and alpha-proteobacterial (30 %) sequences. Analysis of the Pfam domain family and Gene Ontology term variation revealed that the most frequent terms that appear unique to this consortium correspond to proteins involved in "transmembrane transporter activity" and "oxidoreductase activity". Furthermore, we identified genes that encode for enzymes involved in the catabolism of complex substance for energy reserves. We also characterized members of the transposase and integrase superfamilies, whose role in bacterial evolution is well documented, as well as putative antifreeze proteins. Antibiotic treatments of E. focardii cultures delayed the cell division of the ciliate. To conclude, our results indicate that this consortium is largely represented by bacteria derived from the original Antarctic sample and may contribute to the survival of E. focardii in laboratory condition. Furthermore, our results suggest that these bacteria may have a more general role in E. focardii survival in its natural cold and oxidative environment. PMID- 25704317 TI - Community Structure of Skin Microbiome of Gulf Killifish, Fundulus grandis, Is Driven by Seasonality and Not Exposure to Oiled Sediments in a Louisiana Salt Marsh. AB - Mucus of fish skin harbors complex bacterial communities that likely contribute to fish homeostasis. When the equilibrium between the host and its external bacterial symbionts is disrupted, bacterial diversity decreases while opportunistic pathogen prevalence increases, making the onset of pathogenic bacterial infection more likely. Because of that relationship, documenting temporal and spatial microbial community changes may be predictive of fish health status. The 2010 Deepwater Horizon oil spill was a potential stressor to the Gulf of Mexico's coastal ecosystem. Ribosomal intergenic spacer analysis (RISA) and pyrosequencing were used to analyze the bacterial communities (microbiome) associated with the skin and mucus of Gulf killifish (Fundulus grandis) that were collected from oiled and non-oiled salt marsh sites in Barataria Bay, LA. Water samples and fin clips were collected to examine microbiome structure. The microbiome of Gulf killifish was significantly different from that of the surrounding water, mainly attributable to shifts in abundances of Cyanobacteria and Proteobacteria. The Gulf killifish's microbiome was dominated by Gammaproteobacteria, specifically members of Pseudomonas. No significant difference was found between microbiomes of fish collected from oiled and non oiled sites suggesting little impact of oil contamination on fish bacterial assemblages. Conversely, seasonality significantly influenced microbiome structure. Overall, the high similarity observed between the microbiomes of individual fish observed during this study posits that skin and mucus of Gulf killifish have a resilient core microbiome. PMID- 25704318 TI - Peripheral Lesions Identified on Ultrawide Field Imaging Predict Increased Risk of Diabetic Retinopathy Progression over 4 Years. AB - OBJECTIVE: To determine whether peripheral diabetic retinopathy (DR) lesions identified on ultrawide field (UWF) imaging are associated with increased DR progression. DESIGN: Prospective, longitudinal cohort. PARTICIPANTS: Two hundred eyes of 100 participants previously enrolled in a comparative instrument validation study. METHODS: Baseline mydriatic 7-standard field Early Treatment Diabetic Retinopathy Study (ETDRS) photographs and UWF images were obtained. On UWF images, DR lesions with a greater extent outside versus inside standard ETDRS fields were defined as predominantly peripheral lesions (PPLs). Follow-up ETDRS photographs were obtained 4.2+/-0.3 years after baseline. Baseline and follow-up DR severity were graded from ETDRS photographs. MAIN OUTCOME MEASURES: Rates of 2 step or more progression and progression to proliferative DR (PDR) in eyes with PPLs compared with eyes without PPLs identified on UWF imaging at baseline. RESULTS: In eyes without PDR (n = 109) at baseline, 56 (51%) had at least 1 field with PPLs and 43 (39%) had DR progression. Compared with eyes without PPLs, eyes with PPLs had a 3.2-fold increased risk of 2-step or more DR progression (6 [11%] vs. 19 [34%]; P = 0.005) and a 4.7-fold increased risk for progression to PDR (3 [6%] vs. 14 [25%]; P = 0.005). These findings remained statistically significant after adjusting for gender, diabetes type, diabetes duration, hemoglobin A1c (HbA1c) levels, and baseline DR severity. Increasing extent of fields with PPLs increased the risk for 2-step or more DR progression (P = 0.004) and progression to PDR (P = 0.009). CONCLUSIONS: Presence and increasing extent of PPLs were associated with increased risk of DR progression over 4 years, independent of baseline DR severity and HbA1c levels. Increasing extent of PPLs substantially increased the risk of DR progression and progression to PDR, especially with less severe DR at baseline. These findings demonstrate that detailed peripheral retinal evaluation provides important information that is necessary to assess completely the risk of DR progression. PMID- 25704320 TI - Antibody Production against B19 Virus in Ocular Fluid of JIA-Associated Uveitis Patients. PMID- 25704319 TI - Association between SNPs of Metalloproteinases and Prostaglandin F2alpha Receptor Genes and Latanoprost Response in Open-Angle Glaucoma. AB - PURPOSE: To determine whether single nucleotide polymorphisms (SNPs) of genes coding for matrix metalloproteinases (MMPs) and the prostaglandin F2alpha receptor gene (PTGFR) are related to a response to latanoprost in a white Spanish population of glaucomatous patients. DESIGN: Case-control study. PARTICIPANTS: One hundred twenty-four patients with open-angle glaucoma. METHODS: Genotyping was performed in 117 patients with primary open-angle glaucoma with a minimum treatment duration of 4 weeks. Candidate genes and individual polymorphisms were selected according to the effect on the mechanism of action of latanoprost. Multi SNP haplotype analyses for associations also were tested. MAIN OUTCOME MEASURES: Diurnal intraocular pressure reduction and genotyping of the SNPs in the MMPs and PTGFR. RESULTS: The PTGFR SNPs were associated with positive (rs6686438, rs10786455) and negative (rs3753380, rs6672484, rs11578155) responses to latanoprost. Multiple testing found 2 genes, PTGFR and MMP-1, were related to refractoriness to latanoprost. CONCLUSIONS: The SNPs of the PTGFR and MMP-1 genes may determine the latanoprost response in a white European Spanish population. This study identified 5 SNPs related to the latanoprost response; 1 SNP, rs3753380, already has been associated with a poor response to latanoprost in a healthy Japanese population. Latanoprost is a commonly used antiglaucomatous drug, and increased knowledge of its mechanism of action will lead to advances in pharmacogenetics. PMID- 25704321 TI - Cataract surgery outcomes in bangladeshi children. AB - PURPOSE: To measure visual acuity (VA) outcomes, complication rates, and the social impact of cataract surgery in a cohort who underwent surgery as children in Bangladesh. DESIGN: Case series. PARTICIPANTS: A total of 471 of 850 children from 6 Bangladeshi districts who had been identified as cataract blind using key informants (KIs) between 2004 and 2009 during the Bangladesh Childhood Cataract Campaign (BCCC) together with all those children not included in the BCCC database but in the Child Sight Foundation (CSF) database who had been identified as cataract blind. METHODS: The subjects and families were contacted again by KIs and transported to local examination centers, where parents and subjects were administered a questionnaire and subjects underwent full ocular examination. Where operative data were available (15%), they were analyzed in conjunction with questionnaire and examination findings. Statistical analysis was performed using SPSS Statistics (IBM, Armonk, NY). MAIN OUTCOME MEASURES: Presenting and best corrected visual acuities (BCVAs), cause(s) of poor outcome, postoperative refraction, and school attendance. RESULTS: A total of 407 of the participants had undergone bilateral surgery as children, with a mean follow-up of 8.8 years. The mean age at examination was 16 years (range, 5-28 years; standard deviation [SD], 4.6 years); 63% of those examined were male; 22% had a binocular presenting VA of >20/60; and 53% were severely visually impaired or blind (VA <20/200). After refraction, 33% had VA >20/60 in their better eye and 33% had VA <20/200. Factors that predicted poor VA in multivariate logistic regression analysis were nystagmus (P < 0.001), longer delay in presentation (P < 0.001), and magnitude of absolute spherical equivalent refractive error (P<0.001). Some 50% had nystagmus, and 69% of those currently aged <=16 years were attending school. Better acuity was associated with school attendance (P < 0.001), whereas gender was not. CONCLUSIONS: Approximately one third of all participants had a BCVA of >=20/60 in their better eye. Amblyopia and nystagmus limited visual outcome, indicating the need for earlier detection and treatment. This is the first study to show the link between pediatric cataract outcome and access to education, a millennium development goal. PMID- 25704322 TI - An ultrasonographic technique to assess the jugular venous pulse: a proof of concept. AB - The purpose of the work described here was to investigate the feasibility of assessing the jugular venous pulse (JVP) using ultrasound (US) equipment. Three young healthy subjects underwent a B-mode US scan of the internal jugular vein (IJV) to acquire a sonogram sequence in the transverse plane. On each acquired sonogram, the IJV contour was manually traced, and both the cross-sectional area (CSA) and the perimeter were measured. The CSA data set represents the US jugular diagram (USJD). The arterial distension waveform of the subjects was compared with its USJD. The correlation between the CSA and the perimeter was assessed during the cardiac cycle to verify IJV distension. For each subject, a short sonogram sequence of a few seconds was recorded, and the USJD obtained exhibited periodic behavior. Furthermore, for all subjects, the CSA was found to be correlated with the perimeter (Pearson coefficient, R > 0.9), indicating that the IJV in supine position is distended. We compared 390 manually traced contours of the IJV cross-sectional area with corresponding values semi-automatically calculated by an algorithm developed in-house. For all subjects, the sensitivity, specificity and accuracy were around 95%, 85% and 90% respectively. We found that a diagram reflecting the JVP can be obtained by analyzing a B-mode sonogram sequence of the IJV; such a diagram can result in a new methodology to assess the IJV functionality. PMID- 25704323 TI - IGF2 signaling and regulation in cancer. AB - Upregulation of IGF2 occurs in both childhood and adult malignancies. Its overexpression is associated with resistance to chemotherapy and worse prognosis. IGF2 promoter usage is developmentally regulated; however, malignant tissues are characterized by re-activation of the fetal IGF2 promoters, especially P3. In this review, we describe the mechanisms of IGF2 signaling and regulation in normal and malignant tissues and their clinical implications. PMID- 25704324 TI - An Unexpected Cause of Hypoxemia After Left Pneumonectomy Due to Late Presentation of an Intracardiac Shunt: A Case Report and Review of the Literature. PMID- 25704325 TI - Patient understanding of the importance of statin use in the perioperative period. AB - OBJECTIVE: Perioperative hydroxy-3-methyl glutaryl coenzyme A reductase inhibitors (statins) have been shown to decrease morbidity and mortality after noncardiac surgery. The objective of this study was to assess patient understanding of the potential benefits of perioperative statins in a select population already on chronic therapy. A secondary aim was to determine the frequency with which patients recalled having a discussion with their provider regarding perioperative statins. DESIGN: Survey. SETTING: Teaching hospital. PARTICIPANTS: Patients taking daily statins presenting to a preoperative medical evaluation clinic were offered a 12-question survey that assessed their understanding of the potential benefit of taking the medication in the perioperative period. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: One hundred thirty-two patients completed the questionnaire. The mean age was 68.3 years (standard deviation, 9.0); 42% were female. The most frequent surgical referral to the clinic was orthopedics, at 36%. The most common statin prescribed was atorvastatin, in 35% of patients. Twenty-seven percent of patients (n = 36) recognized that perioperative statins are beneficial; 44% of these patients (n = 14) cited decreased cholesterol during the procedure as the reason, representing 12% of the total sampled population. Twenty-two percent (n = 8) of those recognizing the benefit of perioperative statins identified a decrease in the risk of heart attack or death as the reason. This represented only 6% of the total sample. One percent of surgeons mentioned statins in relation to the planned surgery; 2% of primary or prescribing physicians mentioned the medication in relation to surgery. CONCLUSIONS: This study suggested low patient understanding of the potential importance and reasons for perioperative statins. In addition, this study also suggested that the information regarding the importance of perioperative statins is not being relayed to the patient at the level of the surgeon or primary care physician. All physicians involved in perioperative care can offer improved patient education to promote compliance with statin therapy in hopes of a favorable impact on perioperative outcomes. PMID- 25704326 TI - Vascular function and cardiovascular risk factors in women with severe flushing. AB - Cardiovascular disease is the leading cause of death in women of postmenopausal age worldwide. It is a relatively rare occurrence before the menopause and the increase in incidence coincides with the most common symptom associated with menopausal transition, hot flushing. Interest in cardiovascular disease post menopause has largely focused on the effect of hormone therapy on risk of coronary events and stroke, with vasomotor symptoms considered merely a nuisance symptom, but recent work suggests that the presence of flushing may be a marker of underlying cardiovascular disease. PMID- 25704327 TI - A multicentre-bonded [Zn(I)]8 cluster with cubic aromaticity. AB - Polynuclear zinc clusters [Znx] (x>2) with multicentred Zn-Zn bonds and +1 oxidation state zinc (that is, zinc(I) or Zn(I)) are to our knowledge unknown in chemistry. Here we report the polyzinc compounds with an unusual cubic [Zn(I)8(HL)4(L)8](12-) (L=tetrazole dianion) cluster core, composed of zinc(I) ions and short Zn-Zn bonds (2.2713(19) A). The [Zn(I)8]-bearing compounds possess surprisingly high stability in air and solution. Quantum chemical studies reveal that the eight Zn 4s(1) electrons in the [Zn(I)8] cluster fully occupy four bonding molecular orbitals and leave four antibonding ones entirely empty, leading to an extensive electron delocalization over the cube and significant stabilization. The bonding pattern of the cube represents a class of aromatic system that we refer to as cubic aromaticity, which follows a 6n+2 electron counting rule. Our finding extends the aromaticity concept to cubic metallic systems, and enriches Zn-Zn bonding chemistry. PMID- 25704328 TI - Health care utilization of patients with multiple chronic diseases in The Netherlands: Differences and underlying factors. AB - PURPOSE: To examine health care utilization of people with multiple chronic diseases in The Netherlands compared to people with one chronic disease, and to identify different subgroups of multimorbid patients based on differences in health care utilization. METHODS: All patients diagnosed with one or more chronic diseases in 2008-2009 (N=17,443) were selected from the nationwide NIVEL Primary Care Database, and data on their GP contacts were included. Data on hospital admissions (from the Dutch Hospital Data database) and household size and income (from the Integral Household Incomes database 2010) were added. Chi-square-tests and multivariate regression analyses were performed to test for differences between multimorbid patients and patients with one chronic disease, and between subgroups of multimorbid patients derived from cluster analysis. RESULTS: Multimorbid patients (40% of the total sample) had more GP contacts, prescribed medications, and hospital admissions (all p<.0001) than patients with one chronic disease. The largest cluster of multimorbid patients (80%) was characterized by a relatively low level of health care utilization. Two smaller clusters comprised patients with a (very) high level of health care utilization - these people were mainly older, more often female, had a lower income, a smaller household size, and suffered from more chronic diseases. CONCLUSIONS: Among the vast majority of multimorbid patients health care utilization is only slightly higher compared to patients with one chronic disease. Extensive health care utilization among people with multimorbidity seems to be related to patient characteristics as well as illness characteristics. PMID- 25704329 TI - Health-related quality of life and multimorbidity in community-dwelling telecare assisted elders in the Basque Country. AB - INTRODUCTION: Multimorbidity is more common in the elderly population and negatively affects health-related quality of life (QoL). The aims of the study were to report the QoL of users of the Basque telecare public service (BTPS) and to establish its relationship with multimorbidity. METHODS: The EuroQol questionnaire was administered to 1125 users of the service. Their sociodemographic and healthcare characteristics were obtained from BTPS databases and the Basque healthcare service. Multiple regression analysis was performed on the overall questionnaire index to determine the effect of chronic diseases and sociodemographic. Moreover, the effects of the different diseases on specific dimensions of the test were explored by logistic regression. RESULTS: Of the users interviewed, 82% were women, 88% >=75 years and 66% lived alone. The average of chronic pathologies was higher among men (5.3 vs. 4.6), for the lower age range and among those not living alone (P<0.001). For QoL, men and people aged over 84 obtained better scores (0.64 and 0.61, respectively). Worse QoL was associated with being a woman, multimorbidity, and living with one or more people. The existence of multimorbidity meant impaired QoL of 2.6 points for each additional disease over the overall score (P<0.001). CONCLUSIONS: This study reveals that for the population covered by BTPS the impact of chronic pathologies, multimorbidity and their social context affects QoL very diversely. These diverse social and healthcare needs of community-dwelling elders allow the development and implementation of personalised services, such as telecare that facilitate them to remain at home. PMID- 25704330 TI - Heart rate and cardiovascular protection. AB - Recent large epidemiological studies have confirmed that an elevated resting heart rate is an independent predictor of cardiovascular and overall mortality in the general population as well as in patients with hypertension, coronary heart disease and chronic heart failure. Pathophysiological studies indicate that a higher heart rate has detrimental effects that favor myocardial ischemia, ventricular arrhythmias, as well as an increase in vascular oxidative stress, endothelial dysfunction and atherosclerosis progression. Benefits of heart rate lowering drugs, such as beta-blockers and ivabradine, in reducing overall and cardiovascular-related mortality, have been demonstrated particularly in patients with coronary heart disease and heart failure. However, despite these evidences, resting heart rate is still an overlooked cardiovascular risk factor. PMID- 25704331 TI - Regio- and chemoselective N-1 acylation of indoles: Pd-catalyzed domino cyclization to afford 1,2-fused tricyclic indole scaffolds. AB - A concise method for the synthesis of 1,2-fused tricyclic indole scaffolds by domino cyclization involving a Pd-catalyzed Sonogashira coupling, indole cyclization, regio- and chemoselective N-1 acylation, and 1,4-Michael addition is reported. This method provides straightforward access to tetrahydro[1,4]diazepino[1,2-a]indole and hexahydro[1,5]diazocino[1,2-a]indole scaffolds. PMID- 25704332 TI - The diversion of 2-C-methyl-D-erythritol-2,4-cyclodiphosphate from the 2-C-methyl D-erythritol 4-phosphate pathway to hemiterpene glycosides mediates stress responses in Arabidopsis thaliana. AB - 2-C-Methyl-D-erythritol-2,4-cyclodiphosphate (MEcDP) is an intermediate of the plastid-localized 2-C-methyl-D-erythritol-4-phosphate (MEP) pathway which supplies isoprenoid precursors for photosynthetic pigments, redox co-factor side chains, plant volatiles, and phytohormones. The Arabidopsis hds-3 mutant, defective in the 1-hydroxy-2-methyl-2-(E)-butenyl-4-diphosphate synthase step of the MEP pathway, accumulates its substrate MEcDP as well as the free tetraol 2-C methyl-D-erythritol (ME) and glucosylated ME metabolites, a metabolic diversion also occurring in wild type plants. MEcDP dephosphorylation to the free tetraol precedes glucosylation, a process which likely takes place in the cytosol. Other MEP pathway intermediates were not affected in hds-3. Isotopic labeling, dark treatment, and inhibitor studies indicate that a second pool of MEcDP metabolically isolated from the main pathway is the source of a signal which activates salicylic acid induced defense responses before its conversion to hemiterpene glycosides. The hds-3 mutant also showed enhanced resistance to the phloem-feeding aphid Brevicoryne brassicae due to its constitutively activated defense response. However, this MEcDP-mediated defense response is developmentally dependent and is repressed in emerging seedlings. MEcDP and ME exogenously applied to adult leaves mimics many of the gene induction effects seen in the hds-3 mutant. In conclusion, we have identified a metabolic shunt from the central MEP pathway that diverts MEcDP to hemiterpene glycosides via ME, a process linked to balancing plant responses to biotic stress. PMID- 25704333 TI - Sex influences the clinical course of lupus erythematosus: a retrospective cohort study. PMID- 25704334 TI - Homeostasis of the temperature sensitivity of respiration over a range of growth temperatures indicated by a modified Arrhenius model. AB - The temperature dependence of plant respiratory rate (R) changes in response to growth temperature. Here, we used a modified Arrhenius model incorporating the temperature dependence of activation energy (Eo ), and compared the temperature dependence of R between cold-sensitive and cold-tolerant species. We analyzed the temperature dependences of leaf CO2 efflux rate of plants cultivated at low (LT) or high temperature (HT). In plants grown at HT (HT plants), Eo at low measurement temperature varied among species, but Eo at growth temperature in HT plants did not vary and was comparable to that in plants grown at LT (LT plants), suggesting that the limiting process was similar at the respective growth temperatures. In LT plants, the integrated value of loge R, a measure of respiratory capacity, in cold-sensitive species was lower than that in cold tolerant species. When plants were transferred from HT to LT, the respiratory capacity changed promptly after the transfer compared with the other parameters. These results suggest that a similar process limits R at different growth temperatures, and that the lower capacity of the respiratory system in cold sensitive species may explain their low growth rate at LT. PMID- 25704335 TI - Strengthening the Role of Unmarried Fathers: Findings from the Co-Parent Court Project. AB - While the importance of fathers in unmarried coparent families is a strong area of social and political interest, a dearth of community-based interventions exists for supporting the role of fathers in at-risk families. The Co-Parent Court (CPC) was a 3-year demonstration project evaluating the effectiveness of a collaborative intervention to support unmarried coparents establishing paternity and improving their coparenting relationships and paternal involvement in their child's life. A randomized-control experimental design was employed. The paper will explore father involvement and coparent relationship outcomes. PMID- 25704336 TI - Notch4 Signaling Confers Susceptibility to TRAIL-Induced Apoptosis in Breast Cancer Cells. AB - Notch signaling has been established as a key regulator of cell fate in development, differentiation, and homeostasis. In breast cancers, increased Notch1 and Notch4 activity have been implicated in tumor progression and, accumulation of the intracellular domain of Notch4 (ICN4), reported in basal breast cancer cells. While, TNF-related apoptosis-inducing ligand (TRAIL) receptor agonists have demonstrated selectively in targeting tumor cells, the majority of primary tumors are resistant to TRAIL. This necessitates the identification of factors that might regulate TRAIL sensitivity. Here we investigate TRAIL sensitivity in tumor cells following the modulation of Notch (1 and 4) activity using siRNA-mediated depletions or ectopic expression of GFP tagged constructs of the intracellular domains of Notch1 (ICN1) or Notch4 (ICN4). Our findings suggest that Notch4, but not Notch1 signaling, sensitizes breast tumor cells to TRAIL-induced apoptosis. ICN4-induced sensitization to TRAIL is characterized by CBF1-dependence. Apoptosis was mediated via caspase-8 activation and regulated by the Bcl-2 family pro-apoptotic proteins Bak and Bid. Finally, we present evidence that endogenous Notch4 activity regulates susceptibility to TRAIL in basal-like breast cancer cells but not in cell lines of luminal origin. These experiments reveal a hitherto unexplored Notch4-TRAIL signaling axis in breast cancer cells. PMID- 25704337 TI - Birth and motherhood: childbirth experience and mothers' perceptions of themselves and their babies. AB - Childbirth is a major experience in a woman's life, but the relation between childbirth experiences and later mother-infant outcomes has been understudied. This study examined the relation between mode of delivery and subjective birth experience (e.g., perception of control, social support during labor and delivery), and mothers' descriptions of their babies and their maternal self esteem, both powerful predictors of maternal caregiving behavior. This study had three questions: (a) Do mode of delivery and subjective birth experience predict mothers' descriptions of their babies and maternal self-esteem? (b) Are the effects of mode of delivery on mothers' descriptions and maternal self-esteem mediated by subjective birth experience? (c) Does infant age moderate any of these pathways? The sample consisted of 269 mothers of full-term, healthy infants who gave birth in the year prior to the study. Mode of delivery showed a direct effect on how mothers describe their babies, but not maternal self-esteem, which was not mediated by subjective birth experience. Subjective birth experience had direct effects on both outcomes. Infant age did not moderate any of these pathways. Results point to the subjective aspects of childbirth as important components of women's experience of labor and delivery. Implications are discussed. PMID- 25704338 TI - Environmental effect of antioxidant additives on exhaust emission reduction in compression ignition engine fuelled with Annona methyl ester. AB - The aim of the present study is to analyse the effect of antioxidant l-ascorbic acid on engine performance and emissions of a diesel engine fuelled with methyl ester of Annona oil (MEAO). The antioxidant is mixed in various concentrations (100-400 mg) with MEAO. Result shows that the antioxidant additive mixture (MEAO+LA200) is effective in control of nitrogen oxides (NOx) and hydrocarbon (HC) emission of MEAO-fuelled engine without doing any engine modification. In this study by using MEAO, the NOx emission is reduced by about 23.38% at full load while compared with neat diesel fuel. Likewise there is a reduction in carbon monoxide, smoke, and HC by about 48%, 28.57% and 29.71% at full load condition compared with neat diesel fuel. PMID- 25704339 TI - Females Have Larger Ratio of Second-to-Fourth Digits Than Males in Four Species of Salamandridae, Caudata. AB - Digit ratio (2D:4D) denotes the relative length of the second and fourth digits. It is considered to be a suitable biomarker of the in utero balance of fetal sex hormones, which affect early development of individuals behavioral and morphological characteristics. In recent decades, digit ratio attracted a great attention in biology and psychology. However, for unmasking the biological basis of the phenomenon, extensive studies on non-human animals are necessary. Despite it was hypothesized that digit ratio is well conserved in all Tetrapoda, and there exist studies on mammals, birds, and reptiles, there are only two such study on anuran amphibians. Therefore, the aim of this study is to investigate the 2D:4D in the most basal salamanders, Caudata. We have studied digit ratio in four species of newts: Triturus cristatus, Mesotriton alpestris, Lissotriton montandoni, and Lissotriton vulgaris, using museum collection. We used computerized measuring of each limbs photos. We have found out that, in M. alpestris, females 2D:4D of all four limbs were significantly larger than in males. In L. montandoni and L. vulgaris, only 2D:4D of rear limbs significantly differed, in females being larger. In T. cristatus, digit ratios of males and females did not statistically differ. Thus, the results confirmed our hypothesis that at least in M. alpestris, L. montandoni, and L. vulgaris, females seem to have larger 2D:4D comparing to males, the pattern known from most mammals and opposite to birds, reptiles and anuran amphibians. PMID- 25704340 TI - Experimental subarachnoid hemorrhage: double cisterna magna injection rat model- assessment of delayed pathological effects of cerebral vasospasm. AB - Aneurysmal subarachnoid hemorrhage comprises of an early phase after the bleeding and a late phase of delayed consequences of the bleeding. The development of delayed injury mechanisms, like the reduction of cerebral blood flow (CBF) due to cerebral vasospasm (CVS), seems mainly to depend on the amount and the duration of the subarachnoid blood clot. The reduction of CBF may lead to cerebral ischemia and delayed neurological deterioration. The rat double cisterna magna injection model reproduces the time course of the delayed consequences of CVS and imitates the clinical setting more precise than other rodent subarachnoid hemorrhage models. Therefore, the rat double cisterna magna injection model seems to be predisposed to be used to mimick the delayed consequences of subarachnoid hemorrhage. We reviewed the existing literature on this animal model and propose a standard protocol including technical considerations, as well as advantages and limitations of this model. PMID- 25704341 TI - Inter-subject and Inter-session Variability of Plasticity Induction by Non invasive Brain Stimulation: Boon or Bane? PMID- 25704342 TI - Ambulatory blood pressure monitoring: mercury rising. PMID- 25704343 TI - The heterogeneity and diversity of hypertension in CKD. PMID- 25704344 TI - Epidemiology of hypertension in CKD. AB - Both hypertension (HTN) and CKD are serious interrelated global public health problems. Nearly 30% and 15% of US adults have HTN and CKD, respectively. Because HTN may cause or result from CKD, HTN prevalence is higher and control more difficult with worse kidney function. Etiology of CKD, presence and degree of albuminuria, and genetic factors all influence HTN severity and prevalence. In addition, socioeconomic and lifestyle factors influence HTN prevalence and control. There are racial and ethnic disparities in the prevalence, treatment, risks, and outcomes of HTN in patients with CKD. Control of blood pressure (BP) in Hispanic and African Americans with CKD is worse than it is whites. There are disparities in the patterns of treatment and rates of progression of CKD in patients with HTN. The presence and severity of CKD increase treatment resistance. HTN is also extremely prevalent in patients receiving hemodialysis, and optimal targets for BP control are being elucidated. Although the awareness, treatment, and control of HTN in CKD patients is improving, control of BP in patients at all stages of CKD remains suboptimal. PMID- 25704345 TI - Blood pressure targets in CKD. AB - With the release of the 2014 Guidelines for the Management of Hypertension in Adults, a significant amount of discussion has ensued around both the 9 major recommendations promulgated by the Panel and the nature of the evidence base used to formulate those recommendations. In this article, the author will review the data used to support the 2 recommendations made by the Panel that specifically addressed treatment goals (Recommendation 4) and desirable agents to use (Recommendation 8) in hypertensive patients with CKD. Most published recommendations are actually similar, and there is a general consensus that the blood pressure goal should be at least less than 140/90 mm Hg in CKD; some recommend a target of less than 130/80 mm Hg in patients with CKD who have significant proteinuria. This article represents the view of the author and should not be construed as Panel endorsement. PMID- 25704346 TI - The complex relationship between CKD and ambulatory blood pressure patterns. AB - Hypertension and CKD frequently coexist, and both are risk factors for cardiovascular events and mortality. Among people with hypertension, the loss of the normal fall in night-time BP, called nondipping, can only be diagnosed by ambulatory BP monitoring (ABPM) and is a risk factor for cardiovascular events. The pathophysiology of nondipping is complex, and CKD is an independent risk factor for nondipping. In fact, nondipping can be seen in as many as 80% of people with CKD. However, the evidence for nondipping as an independent risk factor or causal agent for adverse outcomes in CKD remains mixed. ABPM has been shown to be superior to clinical BP measurement for correlating with end-organ damage and prognosis in CKD. This review covers the evidence for the use of ABPM in CKD, the evidence linking ABPM patterns to outcome in CKD and the evidence for treatment of nondipping in CKD. PMID- 25704347 TI - Reducing salt intake for prevention of cardiovascular disease--times are changing. AB - The evidence relating blood pressure to salt intake in humans originates from population studies and randomized clinical trials of interventions on dietary salt intake. Estimates from meta-analyses of trials in normotensive subjects generally are similar to estimates derived from prospective population studies (+1.7 mm Hg increase in systolic blood pressure per 100-mmol increment in 24-hour urinary sodium). This estimate, however, does not translate into an increased risk of incident hypertension in subjects consuming a high salt diet. Prospective studies relating health outcomes to 24-hour urinary sodium excretion produced inconsistent results. Taken together, available evidence does not support the current recommendations of a generalized and indiscriminate reduction of salt intake at the population level, although the blood pressure-lowering effect of dietary sodium restriction might be of value in hypertensive patients. PMID- 25704348 TI - Management of hypertension in CKD: beyond the guidelines. AB - Hypertension (HTN) and CKD are closely associated with an intermingled cause and effect relationship. Blood pressure (BP) typically rises with declines in kidney function, and sustained elevations in BP hasten progression of kidney disease. This review addresses current management issues in HTN in patients with CKD including altered circadian rhythm of BP, timing of antihypertensive medication dosing, BP targets, diagnostic challenges in evaluating secondary forms of HTN, and the role of salt restriction in CKD. HTN in patients with CKD is often accompanied by a decrease in the kidney's ability to remove salt. Addressing this salt sensitivity is critical for the management of HTN in CKD. In addition to the well-established use of an ACEI or angiotensin receptor blocker, dietary salt restriction and appropriate diuretic therapy make up the mainstay of HTN treatment in patients with CKD. Bedtime dosing of antihypertensive medications can restore nocturnal dips in BP, and future clinical practice guidelines may recommend bedtime dosing of 1 or more antihypertensive medications in patients with CKD. PMID- 25704349 TI - Aldosterone blockade in CKD: emphasis on pharmacology. AB - Besides its epithelial effect on sodium retention and potassium excretion in the distal tubule, aldosterone promotes inflammation and fibrosis in the heart, kidneys, and blood vessels. As glomerular filtration rate falls, aldosterone is inappropriately elevated relative to extracellular fluid expansion. In addition, studies in CKD patients on angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and/or direct renin inhibitors have shown that aldosterone levels paradoxically rise in approximately 30% to 40% of patients on these renin angiotensin system-blocking drugs. Hence, there is interest in using mineralocorticoid receptor blockers that directly target the inflammatory and fibrotic effects of aldosterone in CKD patients. This interest, however, is tempered by a number of unresolved issues, including the safety of using such drugs in advanced CKD and ESRD populations, and the potential for differences in drug efficacy according to race and ethnicity of patient populations. A better understanding of mineralocorticoid receptor blocker pharmacology should help inform future research directions and clinical practice decisions as to how best to use these agents in CKD. PMID- 25704350 TI - Renal denervation for resistant hypertension and beyond. AB - Despite the availability of more than 125 approved antihypertensive medications, 36 million (48%) of 75 million people with hypertension, including 16 million treated with antihypertensive medications in the United States, do not achieve guideline blood pressure goals known to reduce cardiovascular morbidity and mortality and progression of kidney disease; 3% to 6% of these 75 million hypertensive individuals are estimated to have resistant hypertension. A major contributing factor for poor blood pressure control, besides inadequate diuretic therapy, is failure of antihypertensive agents to inhibit the sympathetic nervous system effectively. Consequently, alternative device-driven approaches have been developed. Recent technical advances targeting renal sympathetic nerves, that is, renal denervation therapy, are the focus of more invasive therapies to treat resistant hypertension. Encouraging results from the SYMPLICITY HTN-2 trial, regarding efficacy and safety of renal denervation therapy, were countered by disappointing efficacy results of SYMPLICITY HTN-3. Reasons for these divergent results and the future of the field are discussed. PMID- 25704351 TI - Hitting the mark: blood pressure targets and agents in those with prevalent cardiovascular disease and heart failure. AB - Blood pressure (BP) is one of the key modifiable risk factors for cardiovascular disease (CVD) both in primary and secondary prevention of disease. In this review, we discuss BP treatment in prevalent CVD and heart failure. Evidence for specific agents based on their neurohormonal effects and evidence for target values for systolic or diastolic BP are covered. The potential adverse effects of overtreatment of BP are also discussed. BP targets for those with CVD should generally be less than 140/90 mm Hg but require individualization of therapy for any further reduction based on the clinical setting. PMID- 25704352 TI - Hypertension in minority populations: new guidelines and emerging concepts. AB - Persistent disparities in hypertension, CKD, and associated cardiovascular disease have been noted in the United States among racial/ethnic minority groups. Overall, these disparities are largely mediated by social determinants of health. Yet, emerging data suggest additional biologic factors in racial/ethnic disparities in hypertension prevalence, complications, particularly CKD, and responses to treatment. Nevertheless, race is a social construct and not a physiologic concept, and ethnicity, federally defined as the binary "Hispanic/Latino" or "not Hispanic/Latino," is also imprecise. However, race/ethnicity categories may help interpret health-related data, including surveillance and research, and are important in ensuring that clinical trials remain generalizable to diverse populations. There is significant heterogeneity among prespecified groups and, perhaps, greater genetic differences within than between certain racial/ethnic groups. This review will explore hypertension epidemiology, pathophysiology, and management among the diverse and growing US minority groups, specifically African Americans and Hispanics because much less data are available across the wide spectrum of diverse populations. We will highlight the intersection of hypertension and increasingly prevalent CKD, particularly in African Americans. Finally, we propose multidimensional treatment approaches to hypertension among diverse populations, encompassing population, community, health system, and individual-based approaches. PMID- 25704353 TI - Hypertension, living kidney donors, and transplantation: where are we today? AB - Hypertension is a prevalent problem in kidney transplant recipients that is known to be a "traditional" risk factor for atherosclerotic cardiovascular disease leading to premature allograft failure and death. Donor, peritransplant, and recipient factors affect hypertension risk. Blood pressure control after transplantation is inversely associated with glomerular filtration rate (GFR). Calcineurin inhibitors, the most commonly used class of immunosuppressives, cause endothelial dysfunction, increase vascular tone, and sodium retention via the renin-angiotensin-aldosterone system resulting in systemic hypertension. Steroid withdrawal seems to have little impact on blood pressure control. Newer agents like belatacept appear to be associated with less hypertension. Transplant renal artery stenosis is an important, potentially treatable cause of hypertension. Dihydropyridine calcium channel blockers mitigate calcineurin inhibitor nephrotoxicity and may be associated with improved estimated GFR. Angiotensin converting enzyme inhibitors and angiotensin receptor blockers are not recommended in the first 3 to 6 months given their effects on reduced estimated GFR, anemia, and hyperkalemia. The use of beta-blockers may be associated with improved patient survival, even for patients without cardiovascular disease. Living donation may increase blood pressure by 5 mm Hg or more. Some transplant centers accept Caucasian living donors with well-controlled hypertension on a single agent if they agree to close follow-up. PMID- 25704354 TI - Blood pressure goals and treatment in pregnant patients with chronic kidney disease. AB - As the age of pregnant women and prevalence of obesity and diabetes are increasing, so is the prevalence of medical disorders during pregnancy, particularly hypertension and the associated CKD. Pregnancy can worsen kidney function in women with severe disease, and hypertension puts them at risk for pre eclampsia and the associated complications. There are no specific guidelines for hypertension management in this population, and tight control will not prevent pre-eclampsia. Women with end-stage kidney disease should be placed on intense dialysis regimens to improve obstetric outcomes, and angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are best avoided. This article will review the rationale for a management plan that includes a multidisciplinary team to discuss risks and develop a plan before conception, antepartum monitoring for maternal and fetal morbidity, individualization of medical management using medications with established records during pregnancy, and balancing the level of blood pressure control proved to protect kidney function against the potential effects that aggressive blood pressure control could have on the fetal-placental unit. PMID- 25704355 TI - Novel therapies for FSGS: preclinical and clinical studies. AB - Focal segmental glomerulosclerosis (FSGS) is a rare but important cause of end stage kidney disease in children and adults. Current therapy, consisting of corticosteroids and calcineurin inhibitors, fails to achieve a sustained remission in most patients. Therefore, there is a pressing need to develop new treatments for this glomerulopathy. Traditional approaches have focused on agents that modulate the immune system. In this review, we summarize preclinical and clinical data with newer agents that may ameliorate FSGS. We focus on drugs that inhibit immune injury or inflammation, such as abatacept, rituximab, adalimumab, and stem cells. The potential of agents that block the glomerular action of circulating permeability factors such as soluble urokinase receptor is reviewed. Finally, because fibrosis represents the final common pathway of glomerular damage in FSGS, the experience with a wide range of antifibrotic agents is presented. Despite extensive research on the podocyte dysfunction in the pathogenesis of FSGS, there are few agents that directly target podocyte structure or viability. We conclude that FSGS is a heterogeneous disorder and that intensified translational research is vital to improve our understanding of distinct subtypes that have a defined prognosis and predictable response to targeted therapeutic interventions. PMID- 25704356 TI - Development of effective connectivity in the core network for face perception. AB - This study measured effective connectivity within the core face network in young children using a paediatric magnetoencephalograph (MEG). Dynamic casual modeling (DCM) of brain responses was performed in a group of adults (N = 14) and a group of young children aged from 3 to 6 years (N = 15). Three candidate DCM models were tested, and the fits of the MEG data to the three models were compared at both individual and group levels. The results show that the connectivity structure of the core face network differs significantly between adults and children. Further, the relative strengths of face network connections were differentially modulated by experimental conditions in the two groups. These results support the interpretation that the core face network undergoes significant structural configuration and functional specialization between four years of age and adulthood. PMID- 25704357 TI - Efficacy and quality of life after transcutaneous posterior tibial neuromodulation for faecal incontinence. AB - AIM: The aim of this study was to evaluate the efficacy of transcutaneous neuromodulation of the posterior tibial nerve for faecal incontinence and to assess quality of life after the procedure. METHOD: A prospective non-randomized cohort study was conducted in a tertiary centre from September 2010 to May 2013. All patients with faecal incontinence who met the inclusion criteria were included and were treated as outpatients during a 3-month period by unilateral neuromodulation of the posterior tibial nerve. The patients were followed 3 monthly for 1 year. Severity scales, a bowel diary and quality of life scales were evaluated prospectively before and after treatment. RESULTS: Twenty-seven patients of median age 67 (interquartile range 60-69) years and a male to female ratio of 1/6 were included. Faecal incontinence was for solid stools in 48.1% of patients with urgency in 55.6%. About one-third (34.6%) had a sphincter defect on ultrasound and reduction of anal canal pressure in 85.2%. There was a significant improvement in episodes of incontinence on the Wexner score and visual analogue scale assessment and a decrease in the number of episodes of incontinence per unit time. The Fecal Incontinence Quality of Life score was improved at the end of the follow-up. No adverse effects were observed. The cost of the treatment was ?135 per patient. CONCLUSION: Transcutaneous posterior tibial nerve neuromodulation provides good treatment for faecal incontinence in terms of efficacy and quality of life. PMID- 25704358 TI - Cannabis and the maturing brain: Role in psychosis development. AB - A common viewpoint has proliferated that cannabis use is mostly harmless. Some argue that by not supporting its use, we are missing a great therapeutic opportunity. The general public view on cannabis may partially be a result of poor knowledge translation. In fact, the "war on drugs" approach has not allowed for basic education on the varied effects of cannabis on the brain, especially at highly critical phases of brain development such as adolescence. PMID- 25704359 TI - Will the Modi government succumb to US and industry pressure to modify its pro access pharmaceutical patent policy? AB - The US has persistently pressured India to adopt US-style patent protections on pharmaceuticals for many years. That pressure has intensified recently because of Indian rules that have blocked patents on medicines widely patented elsewhere and because India has issued a compulsory license. Under the leadership of its new Prime Minister (PM), Narendra Modi, India has already made several overtures to appease US pressure. The two countries have established a bilateral intellectual property (IP) Working Group that will meet regularly as part of their Trade Policy Forum. This allows the US fox in India's patent law chicken house. In addition, India has issued a Draft National IPR Policy that is highly pro-IP and that promises consensus-oriented negotiations with international partners. These signals have been reinforced by decisions to drop price controls on nonessential medicines, to appoint a pro-IP economic advisor, and to stall issuance of additional compulsory licenses. On the other hand, both PM Modi and the Draft IP Policy state the need for a balance in IP, including a balance that promotes public health and that avoids granting of secondary patents. The world will see other countries copying India's pro-access rules at the same time that India continues to be pressured by the US. PMID- 25704360 TI - The difficulty in defining binge eating in obese women: how it affects prevalence levels in presurgical bariatric patients. AB - OBJECTIVE: We aim to determine how increasing the specificity of binge eating criteria affects the prevalence of self-reported binge eating among presurgical bariatric patients. METHOD: 197 women ages 20 to 65 being assessed for bariatric surgery with a BMI greater than 30kg/m(2) were interviewed and completed the Eating and Exercise Examination. RESULTS: The prevalence of self-reported binge eating was 55% (n=109). The addition of the criterion 'more than a little loss of control/distress' reduced the rate to 23% (n=45), a minimum of six servings of food reduced the rate to 34% (n=67). The addition of a minimum frequency of twice per week for six months (DSM-VI) reduced the rate to 22% (n=43), or once per week for three months (DSM-5) reduced the rate to 53% (n=104). DISCUSSION: More precise definitions and diagnostic criteria for binge eating may result in more consistent reports of prevalence levels of BED. PMID- 25704361 TI - Pharmacokinetic modeling of tranexamic acid for patients undergoing cardiac surgery with normal renal function and model simulations for patients with renal impairment. AB - Tranexamic acid (TXA), an effective anti-fibrinolytic agent that is cleared by glomerular filtration, is used widely for cardiopulmonary bypass (CPB) surgery. However, an effective dosing regimen has not been fully developed in patients with renal impairment. The aims of this study were to characterize the inter patient variability associated with pharmacokinetic parameters and to recommend a new dosing adjustment based on the BART dosing regimen for CPB patients with chronic renal dysfunction (CRD). Recently published data on CPB patients with normal renal function (n = 15) were re-examined with a two-compartment model using the ADAPT5 and NONMEMVII to identify covariates that explain inter-patient variability and to ascertain whether sampling strategies might affect parameter estimation. A series of simulations was performed to adjust the BART dosing regimen for CPB patients with renal impairment. Based on the two-compartmental model, the number of samples obtained after discontinuation of TXA infusion was found not to be critical in parameter estimation (p > 0.05). Both body weight and creatinine clearance were identified as significant covariates (p < 0.005). Simulations showed significantly higher than normal TXA concentrations in CRD patients who received the standard dosing regimen in the BART trial. Adjustment of the maintenance infusion rate based on the percent reduction in renal clearance resulted in predicted plasma TXA concentrations that were safe and therapeutic (~100 mg.L(-1) ). Our proposed dosing regimen, with consideration of renal function, is predicted to maintain effective target plasma concentrations below those associated with toxicity for patients with renal failure for CPB. PMID- 25704362 TI - Alcohol and the brain-liver axis: a further case of mind over matter? PMID- 25704363 TI - Outcome and prognostic factors for children with supratentorial primitive neuroectodermal tumors treated with carboplatin during radiotherapy: a report from the Children's Oncology Group. AB - BACKGROUND: Supratentorial PNETs (sPNET) are uncommon embryonal malignancies of the central nervous system whose prognosis has historically been poor. We evaluated the outcome and prognostic factors of children with sPNET treated prospectively on a Children's Oncology Group trial. PROCEDURE: Following surgery, patients received craniospinal radiotherapy with concurrent carboplatin followed by six months of maintenance chemotherapy with cyclophosphamide and vincristine. RESULTS: Five-year overall survival (OS) and progression-free survival (PFS) for all patients was 58 +/- 7% and 48 +/- 7%. For patients with pineoblastoma (n = 23), five-year OS and PFS was 81 +/- 9% and 62 +/- 11%. Extent of resection but not M-stage was prognostic. Five-year OS and PFS for 37 patients with non-pineal tumors (NPsPNET) was 44 +/- 8% and 39 +/- 8%, significantly worse than for PB (P = 0.055 and 0.009 respectively). Extent of resection and major radiotherapy deviations were prognostic. Five year OS was 59 +/- 11.4% for those undergoing complete resection versus 10.4 +/- 7% for those who did not (P = 0.017). Central pathologic review called 14 (38%) "classic" sPNET, 8 (22%) "undifferentiated" and 13 (35%) "malignant gliomas." There was no significant difference between the subgroups, although survival distributions approached significance when the combined "classic" and "undifferentiated" group was compared to the "malignant gliomas." CONCLUSIONS: Carboplatin during RT followed by 6 months of non intensive chemotherapy is a feasible treatment strategy for patients with sPNET. Aggressive surgical resection should be attempted if feasible. The classification of supratentorial small cell malignancies can be difficult. PMID- 25704364 TI - Loss in body weight is an independent prognostic factor for mortality in chronic heart failure: insights from the GISSI-HF and Val-HeFT trials. AB - AIMS: Uncertainties remain on the biological and prognostic significance and therapeutic implications of loss in body weight (W-LOSS) in chronic heart failure (HF) patients. We assessed whether W-LOSS added additional prognostic value to classical clinical risk factors in two separate and large cohorts of patients with chronic HF. The factors associated with W-LOSS were studied. METHODS AND RESULTS: W-LOSS and estimated plasma volume changes were measured serially in the GISSI-HF (n = 6820) and Val-HeFT trials (n = 4892). In both studies, experiencing at least one episode of >=5% W-LOSS during the first year of follow-up was considered a sign of wasting. In GISSI-HF, self-reported unintentional W-LOSS >=2 kg between two consecutive clinical visits within 1 year was also considered a sign of wasting. W-LOSS occurred in 16.4% and 15.7% of the patients enrolled in GISSI-HF and Val-HeFT, respectively (unintentional >=2 kg W-LOSS occurred in 18.9% in GISSI-HF). In multivariable analyses adjusting for a number of baseline covariates as well as for plasma volume changes, W-LOSS was found to be independently associated with mortality and adverse cardiovascular and non cardiovascular outcomes, with a significant net reclassification improvement (cfNRI) and an increase in integrated discrimination improvement (IDI). W-LOSS was independently associated with several features representing the severity of HF, including baseline NT-proBNP and high sensitivity C-reactive protein (hsCRP) in Val-HeFT. CONCLUSIONS: W-LOSS was a frequent finding in the GISSI-HF and Val HeFT trials, associated with multiple patient features, and added additional prognostic information beyond clinical variables of HF severity, including estimated plasma volume changes. PMID- 25704365 TI - Towards a framework for assessment and management of cumulative human impacts on marine food webs. AB - Effective ecosystem-based management requires understanding ecosystem responses to multiple human threats, rather than focusing on single threats. To understand ecosystem responses to anthropogenic threats holistically, it is necessary to know how threats affect different components within ecosystems and ultimately alter ecosystem functioning. We used a case study of a Mediterranean seagrass (Posidonia oceanica) food web and expert knowledge elicitation in an application of the initial steps of a framework for assessment of cumulative human impacts on food webs. We produced a conceptual seagrass food web model, determined the main trophic relationships, identified the main threats to the food web components, and assessed the components' vulnerability to those threats. Some threats had high (e.g., coastal infrastructure) or low impacts (e.g., agricultural runoff) on all food web components, whereas others (e.g., introduced carnivores) had very different impacts on each component. Partitioning the ecosystem into its components enabled us to identify threats previously overlooked and to reevaluate the importance of threats commonly perceived as major. By incorporating this understanding of system vulnerability with data on changes in the state of each threat (e.g., decreasing domestic pollution and increasing fishing) into a food web model, managers may be better able to estimate and predict cumulative human impacts on ecosystems and to prioritize conservation actions. PMID- 25704366 TI - High antiallergic activity of 5,6,4'-trihydroxy-7,8,3'-trimethoxyflavone and 5,6 dihydroxy-7,8,3',4'-tetramethoxyflavone from eau de cologne mint (Mentha*piperita citrata). AB - The following compounds with higher antiallergic activities were isolated from eau de cologne mint leaves: 5,6,4'-trihydroxy-7,8-dimethoxyflavone (6), 5,6,4' trihydroxy-7,8,3'-trimethoxyflavone (7), 5,6-dihydroxy-7,3',4'-trimethoxyflavone (8), 5,6-dihydroxy-7,8,3',4'-tetramethoxyflavone (9), and 5,6-dihydroxy-7,8,4' trimethoxyflavone (10). The IC50 values of compounds 6-10 against RBL-2H3 cells were 6.7, 2.4, 5.6, 3.0, and 6.1MUM. Compounds 7 and 9 (IC50 2.4MUM and 3.0MUM) had the highest antiallergic activities among the flavonoids previously reported. The amounts of 7, 9, and 10 isolated were fairly high, at 177.7mg/kg, 278.0mg/kg, and 179.7mg/kg in the mint, respectively. LD5 value (index of toxicity) and LD5/IC50 ratio of 7 and 9 indicate that the safety is greater than that of luteolin, a typical antiallergic substance. The extract containing powerful antiallergic flavones, 6-10 with higher hydrophobicity could be selectively separated from the extract containing luteolin and other flavonoid glycosides by partition with dichloromethane and water. Therefore, compounds 7 and 9 in mint, and the dichloromethane extract would be the most potent and preventive resources against type I allergy. PMID- 25704367 TI - Five new diarylheptanoids from the rhizomes of Curcuma kwangsiensis and their antiproliferative activity. AB - Five new diarylheptanoids (1-5), along with nine known ones (6-14), were isolated from the rhizomes of Curcuma kwangsiensis. Their structures were established on the basis of spectroscopic analyses. Compounds 1-3 were cyclic diarylheptanoids rarely discovered from C. kwangsiensis. Of all the isolated compounds, compound 4 showed moderate antiproliferative activity on HH and HaCaT cells. PMID- 25704368 TI - New triquinane and gymnomitrane sesquiterpenes from fermentation of the basidiomycete Antrodiella albocinnamomea. AB - Five new triquinane-type sesquiterpenes, antrodins A-E (1-5) and a new gymnomitrane sesquiterpene, antrodin F (6), together with three known compounds 7 9 were isolated from fermentation of Antrodiella albocinnamomea. Their structures were elucidated through extensive spectroscopic methods including 2D NMR and HRMS analyses. The absolute configurations of 1 and 6 were determined using single crystal X-ray diffraction analyses. The isolated compounds were investigated for their cytotoxicities against five human cancer cell lines. PMID- 25704369 TI - Zingerone silences quorum sensing and attenuates virulence of Pseudomonas aeruginosa. AB - Quorum sensing in Pseudomonas aeruginosa plays an imperative role in virulence factor, biofilm formation and antimicrobial resistance. Blocking quorum sensing pathways are viewed as viable anti-virulent therapy in association with traditional antimicrobial therapy. Anti-quorum sensing dietary phytochemicals with may prove to be a safe and viable choice as anti-virulent drug candidates. Previously, our lab proved zingerone as potent anti-biofilm agent hence; further its anti-virulent and anti-quorum activities were evaluated. Zingerone, besides decreasing swimming, swarming and twitching phenotypes of P. aeruginosa PAO1, reduced biofilm forming capacity and production of virulence factors including rhamnolipid, elastase, protease, pyocyanin, cell free and cell bound hemolysin (p<0.001) indicating anti-virulent property attributing towards attenuation of virulence of P. aeruginosa. Further zingerone not only had marked effect on the production of quorum sensing signal molecules by clinical isolates of P. aeruginosa but also showed significant interference with the activation of QS reporter strains. To study the mechanism of blocking quorum sensing cascade, in silico analysis was carried out. Anti-QS activity was attributed to interference with the ligand receptor interaction of zingerone with QS receptors (TraR, LasR, RhlR and PqsR). Zingerone showed a good comparative docking score to respective autoinducer molecules which was even higher than that of vanillin, a proven anti quorum sensing phytochemical. The results of the present study revealed the anti quorum sensing activity of zingerone targeting ligand-receptor interaction, hence proposing zingerone as a suitable anti-virulent drug candidate against P. aeruginosa infections. PMID- 25704370 TI - The regulation of connective tissue growth factor expression influences the viability of human trabecular meshwork cells. AB - Connective tissue growth factor (CTGF) induces extracellular matrix (ECM) synthesis and contractility in human trabecular meshwork (HTM) cells. Both processes are involved in the pathogenesis of primary open-angle glaucoma. To date, little is known about regulation and function of CTGF expression in the trabecular meshwork (TM). Therefore, we analysed the effects of different aqueous humour proteins and stressors on CTGF expression in HTM cells. HTM cells from three different donors were treated with endothelin-1, insulin-like growth factor (IGF)-1, angiotensin-II, H2 O2 and heat shock and were analysed by immunohistochemistry, real-time RT-PCR and Western blotting. Viability after H2 O2 treatment was measured in CTGF silenced HTM-N cells and their controls. Latrunculin A reduced expression of CTGF by about 50% compared to untreated HTM cells, whereas endothelin-1, IGF-1, angiotensin-II, heat shock and oxidative stress led to a significant increase. Silencing of CTGF resulted in a delayed expression of alphaB-crystallin and in reduced cell viability in comparison to the controls after oxidative stress. Conversely, CTGF treatment led to a higher cell viability rate after H2 O2 treatment. CTGF expression is induced by factors that have been linked to glaucoma. An increased level of CTGF appears to protect TM cells against damage induced by stress. The beneficial effect of CTGF for viability of TM cells is likely associated with the effects on increased ECM synthesis and higher contractility of the TM, thereby contributing to reduced aqueous humour outflow facility causing increased intraocular pressure. PMID- 25704371 TI - The primacy of vital signs--acute care nurses' and midwives' use of physical assessment skills: a cross sectional study. AB - BACKGROUND: Registered nurses and midwives play an essential role in detecting patients at risk of deterioration through ongoing assessment and action in response to changing health status. Yet, evidence suggests that clinical deterioration frequently goes unnoticed in hospitalised patients. While much attention has been paid to early warning and rapid response systems, little research has examined factors related to physical assessment skills. OBJECTIVES: To determine a minimum data set of core skills used during nursing assessment of hospitalised patients and identify nurse and workplace predictors of the use of physical assessment to detect patient deterioration. DESIGN: The study used a single-centre, cross-sectional survey design. SETTING AND PARTICIPANTS: The study included 434 registered nurses and midwives (Grades 5-7) involved in clinical care of patients on acute care wards, including medicine, surgery, oncology, mental health and maternity service areas, at a 929-bed tertiary referral teaching hospital in Southeast Queensland, Australia. METHODS: We conducted a hospital-wide survey of registered nurses and midwives using the 133-item Physical Assessment Skills Inventory and the 58-item Barriers to Registered Nurses' Use of Physical Assessment Scale. Median frequency for each physical assessment skill was calculated to determine core skills. To explore predictors of core skill utilisation, backward stepwise general linear modelling was conducted. Means and regression coefficients are reported with 95% confidence intervals. A p value <.05 was considered significant for all analyses. RESULTS: Core skills used by most nurses every time they worked included assessment of temperature, oxygen saturation, blood pressure, breathing effort, skin, wound and mental status. Reliance on others and technology (F=35.77, p<.001), lack of confidence (F=5.52, p=.02), work area (F=3.79, p=.002), and clinical role (F=44.24, p<.001) were significant predictors of the extent of physical assessment skill use. CONCLUSIONS: The increasing acuity of the acute care patient plausibly warrants more than vital signs assessment; however, our study confirms nurses' physical assessment core skill set is mainly comprised of vital signs. The focus on these endpoints of deterioration as dictated by early warning and rapid response systems may divert attention from and devalue comprehensive nursing assessment that could detect subtle changes in health status earlier in the patient's hospitalisation. PMID- 25704372 TI - Language proficiency and nursing registration. AB - This discussion paper focuses on English proficiency standards for nursing registration in Australia, how Australia has dealt with the issue of language proficiency, and the factors which have led to the establishment of the current language standards. Also, this paper will provide a comparison of the two language tests that are currently accepted in Australia (OET and IELTS), including the appropriateness of these tests and the minimum standards used. The paper will also examine the use of educational background as an indicator of language proficiency. Finally, communication-based complaints in the post registration environment will be explored, and some discussion will be provided about why pre-registration measures might have failed to prevent such problematic situations from occurring. PMID- 25704374 TI - Ontology for assessment studies of human-computer-interaction in surgery. AB - OBJECTIVE: New technologies improve modern medicine, but may result in unwanted consequences. Some occur due to inadequate human-computer-interactions (HCI). To assess these consequences, an investigation model was developed to facilitate the planning, implementation and documentation of studies for HCI in surgery. METHODS AND MATERIAL: The investigation model was formalized in Unified Modeling Language and implemented as an ontology. Four different top-level ontologies were compared: Object-Centered High-level Reference, Basic Formal Ontology, General Formal Ontology (GFO) and Descriptive Ontology for Linguistic and Cognitive Engineering, according to the three major requirements of the investigation model: the domain-specific view, the experimental scenario and the representation of fundamental relations. Furthermore, this article emphasizes the distinction of "information model" and "model of meaning" and shows the advantages of implementing the model in an ontology rather than in a database. RESULTS: The results of the comparison show that GFO fits the defined requirements adequately: the domain-specific view and the fundamental relations can be implemented directly, only the representation of the experimental scenario requires minor extensions. The other candidates require wide-ranging extensions, concerning at least one of the major implementation requirements. Therefore, the GFO was selected to realize an appropriate implementation of the developed investigation model. The ensuing development considered the concrete implementation of further model aspects and entities: sub-domains, space and time, processes, properties, relations and functions. CONCLUSIONS: The investigation model and its ontological implementation provide a modular guideline for study planning, implementation and documentation within the area of HCI research in surgery. This guideline helps to navigate through the whole study process in the form of a kind of standard or good clinical practice, based on the involved foundational frameworks. Furthermore, it allows to acquire the structured description of the applied assessment methods within a certain surgical domain and to consider this information for own study design or to perform a comparison of different studies. The investigation model and the corresponding ontology can be used further to create new knowledge bases of HCI assessment in surgery. PMID- 25704375 TI - Submuscular Approach for Subcutaneous Implantable Cardioverter Defibrillator: A Potential Alternative Technique. PMID- 25704376 TI - Photoallergic Contact Dermatitis Due to Chlorpromazine: A Report of 2 Cases. PMID- 25704377 TI - Dermoscopic Features of Pigmented Fungiform Papillae of the Tongue. PMID- 25704378 TI - Cutaneous Plasmacytosis in a White Man. PMID- 25704379 TI - Advanced elemental characterization during Pt-In catalyst formation by wavelet transformed X-ray absorption spectroscopy. AB - Complementary to conventional X-ray absorption near edge structure (XANES) and Fourier transformed (FT) extended X-ray absorption fine structure (EXAFS) analysis, the systematic application of wavelet transformed (WT) XAS is shown to disclose the physicochemical mechanisms governing Pt-In catalyst formation. The simultaneous k- and R-space resolution of the WT XAS signal allows for the efficient allocation of the elemental nature to each R-space peak. Because of its elemental discrimination capacity, the technique delivers structural models which can subsequently serve as an input for quantitative FT EXAFS modeling. The advantages and limitations of applying WT XAS are demonstrated (1) before and (2) after calcination to 650 degrees C of a Pt(acac)2 impregnated Mg(In)(Al)Ox support and (3) after subsequent H2 reduction to 650 degrees C. Combined XANES, FT, and WT XAS analysis shows that the acac ligands of the Pt precursor decompose during calcination, leading to atomically dispersed Pt(4+) cations on the Mg(In)(Al)Ox support. H2 reduction treatment eventually results in the formation of 1.5 nm Pt-In alloyed nanoparticles. Widespread use and systematic application of wavelet-based XAS can potentially reveal in greater detail the intricate mechanisms involved in catalysis, chemistry, and related fields. PMID- 25704380 TI - Characterization of the non-sexual flocculation of fission yeast cells that results from the deletion of ribosomal protein L32. AB - We recently reported that deleting either of the two paralogous rpl32 genes resulted in non-sexual flocculation in fission yeast. This study represents the first report that these non-sexually flocculating fission yeast cells exhibit a thicker cell wall, an increased wall protein content with smeared glycosylated wall proteins, and increased cell wall polysaccharide content and adhesin-binding sugar residues (i.e. glucose, mannose and galactose). These changes reflect the wall features of flocculating cells that mediate recognition and connections between cells. Furthermore, this study demonstrates that this non-sexual flocculation is an adhesin-mediated process: (a) the transcription levels of several members of the Mam3/Map4 family of adhesins (i.e. PFL3, PFL7 and PFL6) and a Flo11-like adhesin protein are upregulated in rpl32-1Delta and rpl32-2Delta cells; (b) this non-sexual flocculation of rpl32-1Delta and rpl32-2Delta cells was eliminated by heating or enzyme digestion; (c) this non-sexual flocculation of rpl32-1Delta and rpl32-2Delta cells was enhanced by Ca(2+) and some other divalent metal ions, which stabilize the active conformation of adhesins; and (d) this non-sexual flocculation of rpl32-1Delta and rpl32-2Delta cells was competitively inhibited by glucose, galactose or mannose rather than only by galactose, as reported previously. Although different adhesin genes are selectively expressed under particular physiological or environmental conditions, the functions of these adhesins are the same and are interchangeable. PMID- 25704381 TI - Editorial: Hypoxia imaging in nuclear medicine. PMID- 25704382 TI - Hypoxia imaging. Guest editorial. PMID- 25704383 TI - Biology of hypoxia. AB - There is an important and strong, but complex influence of the tumor microenvironment on tumor cells' phenotype, aggressiveness, and treatment sensitivity. One of the most frequent and best-studied aspects of the tumor microenvironment is hypoxia. Low oxygen tension often occurs in tumor cells by several mechanisms, for example, poor angiogenesis and increased oxygen consumption. Hypoxia is a heterogeneous concept with oxygen tensions ranging from <0.01% (anoxia) to 5%, and can be chronic, acute, or cycling, all with differential effects on tumor cells. Quantification of tumor hypoxia can be performed directly or indirectly, and with exogenous or endogenous markers. Tumor cells launch different intracellular signaling pathways to survive hypoxia, such as hypoxia-inducible factor 1-mediated gene expression, the unfolded protein response, and AKT-mammalian target of rapamycin signaling. These pathways induce aggressive, metastatic, and treatment-insensitive tumors and are considered potential targets for (additive) therapy. Hypoxia leads to important, yet currently not well-understood changes in microRNA expression, epigenetics, and metabolism. Further, treatment-insensitive tumors arise through hypoxia-induced Darwinian selection of apoptosis-deficient, p53-mutated tumor cells. In conclusion, hypoxia has profound and largely still poorly understood effects on tumor cells with a major effect on the tumor's biology. PMID- 25704384 TI - The clinical significance of hypoxia in human cancers. AB - Hypoxia is present to some extent in most solid malignant human cancers because of an imbalance between the limited oxygen delivery capacity of the abnormal vasculature and the high oxygen consumption of tumor cells. This drives a complex and dynamic compensatory response to enable continued cell survival, including genomic changes leading to selection of hypoxia-adapted cells with a propensity to invade locally, metastasize, and recur following surgery or radiotherapy. There is indisputable clinical evidence from numerous observational and therapeutic studies across a range of tumor types to implicate hypoxia as a key determinant of cancer behavior and treatment outcome. Despite this, hypoxia targeted treatment has failed to influence clinical practice. This is explained, in part, by emerging findings to indicate that hypoxia is not equally important in all patients even when present to the same extent. The impact of hypoxia on patient outcome and the benefit of hypoxia-targeted treatments are greatest in situations where hypoxia is a primary biological driver of disease behavior patients with tumors having a "hypoxic driver" phenotype. The challenge for the clinical and scientific communities moving forward is to develop robust precision cancer medicine strategies for identifying these patients in the setting of other etiologic, genomic, and host-tumor factors, considering not only the state of the tumor at diagnosis but also changing patient and tumor characteristics over time. PMID- 25704385 TI - The chemistry and radiochemistry of hypoxia-specific, radiohalogenated nitroaromatic imaging probes. AB - Hypoxia is prevalent in many solid tumors. Hypoxic tumors tend to exhibit rapid growth and aberrant vasculature, which lead to oxygen (O2) depletion and impaired drug delivery. The reductive environment in hypoxic tumors alters cellular metabolism, which can trigger transcriptional responses; induce genetic alterations; promote invasion, metastasis, resistance to radiotherapy and chemotherapy, tumor progression, and recurrence; and leads to poor local control and reduced survival rates. Therefore, exploiting the reductive microenvironment in hypoxic tumors by delivering electron-affinic, O2-mimetic radioactive drugs that bioreductively activate selectively in the hypoxic microenvironment offers a logical approach to molecular imaging of focal hypoxia. Because these agents also radiosensitize hypoxic cells, they provide an innovative approach to the therapy management of such tumors. To date, nuclear imaging of hypoxic tumor has proven to be clinically effective, whereas chemical radiosensitization by these compounds has not been helpful. The current review provides an insight into the chemistry, radiochemistry, and purification strategies for selected nitroaromatics that directly exploit the bioreductive environment in hypoxic cells. Both experimental and calculated single-electron reduction potentials of electron-affinic compounds, nitroimidazoles in particular, correlate with in vitro radiosensitizing properties, making them preferred choices for use as radiopharmaceuticals for diagnostic imaging and as sensitizers to enhance the killing effects of low-energy-transfer x-rays (O2-mimetic radiosensitization). Extensive research and careful drug design have led to the development of several potentially useful hypoxia-targeting drugs, for example, [(18)F]FAZA, [(18)F]FMISO, [(18)F]EF5, and [(123)I]IAZA, that accrue selectively in hypoxic cells. These molecular probes are now globally used in clinical hypoxia imaging, including cancer. Future innovative developments must, however, consider hypoxia selective molecular processes and the physicochemical properties of the drugs that dictate their biodistribution, hypoxia-selective accumulation, pharmacokinetics, clearance, biochemical behavior, and metabolism. This will facilitate their ultimate transformation to effective molecular theranostics, leading to improved multimodal management of cancer. PMID- 25704386 TI - Hypoxia imaging in gliomas with 18F-fluoromisonidazole PET: toward clinical translation. AB - There is significant interest in the development of improved image-guided therapy for neuro-oncology applications. Glioblastomas (GBM) in particular present a considerable challenge because of their pervasive nature, propensity for recurrence, and resistance to conventional therapies. MRI is routinely used as a guide for planning treatment strategies. However, this imaging modality is not able to provide images that clearly delineate tumor boundaries and affords only indirect information about key tumor pathophysiology. With the emergence of PET imaging with new oncology radiotracers, mapping of tumor infiltration and other important molecular events such as hypoxia is now feasible within the clinical setting. In particular, the importance of imaging hypoxia levels within the tumoral microenvironment is gathering interest, as hypoxia is known to play a central role in glioma pathogenesis and resistance to treatment. One of the hypoxia radiotracers known for its clinical utility is (18)F-fluoromisodazole ((18)F-FMISO). In this review, we highlight the typical causes of treatment failure in gliomas that may be linked to hypoxia and outline current methods for the detection of hypoxia. We also provide an overview of the growing body of studies focusing on the clinical translation of (18)F-FMISO PET imaging, strengthening the argument for the use of (18)F-FMISO hypoxia imaging to help optimize and guide treatment strategies for patients with glioblastoma. PMID- 25704387 TI - F-18 fluoromisonidazole for imaging tumor hypoxia: imaging the microenvironment for personalized cancer therapy. AB - Hypoxia in solid tumors is one of the seminal mechanisms for developing aggressive trait and treatment resistance in solid tumors. This evolutionarily conserved biological mechanism along with derepression of cellular functions in cancer, although resulting in many challenges, provide us with opportunities to use these adversities to our advantage. Our ability to use molecular imaging to characterize therapeutic targets such as hypoxia and apply this information for therapeutic interventions is growing rapidly. Evaluation of hypoxia and its biological ramifications to effectively plan appropriate therapy that can overcome the cure-limiting effects of hypoxia provides an objective means for treatment selection and planning. Fluoromisonidazole (FMISO) continues to be the lead radiopharmaceutical in PET imaging for the evaluation, prognostication, and quantification of tumor hypoxia, one of the key elements of the tumor microenvironment. FMISO is less confounded by blood flow, and although the images have less contrast than FDG-PET, its uptake after 2 hours is an accurate reflection of inadequate regional oxygen partial pressure at the time of radiopharmaceutical administration. By virtue of extensive clinical utilization, FMISO remains the lead candidate for imaging and quantifying hypoxia. The past decade has seen significant technological advances in investigating hypoxia imaging in radiation treatment planning and in providing us with the ability to individualize radiation delivery and target volume coverage. The presence of widespread hypoxia in the tumor can be effectively targeted with a systemic hypoxic cell cytotoxin or other agents that are more effective with diminished oxygen partial pressure, either alone or in combination. Molecular imaging in general and hypoxia imaging in particular will likely become an important in vivo imaging biomarker of the future, complementing the traditional direct tissue sampling methods by providing a snap shot of a primary tumor and metastatic disease and in following treatment response and will serve as adjuncts to personalized therapy. PMID- 25704388 TI - Optimizing hypoxia detection and treatment strategies. AB - Clinical studies using Eppendorf needle sensors have invariably documented the resistance of hypoxic human tumors to therapy. These studies first documented the need for individual patient measurement of hypoxia, as hypoxia varied from tumor to tumor. Furthermore, hypoxia in sarcomas and cervical cancer leads to distant metastasis or local or regional spread, respectively. For various reasons, the field has moved away from direct needle sensor oxygen measurements to indirect assays (hypoxia-inducible factor-related changes and bioreductive metabolism) and the latter can be imaged noninvasively. Many of hypoxia's detrimental therapeutic effects are reversible in mice but little treatment improvement in hypoxic human tumors has been seen. The question is why? What factors cause human tumors to be refractory to antihypoxia strategies? We suggest the primary cause to be the complexity of hypoxia formation and its characteristics. Three basic types of hypoxia exist, encompassing various diffusional (distance from perfused vessel), temporal (on or off cycling), and perfusional (blood flow efficiency) limitations. Surprisingly, there is no current information on their relative prevalence in human tumors and even animal models. This is important because different hypoxia subtypes are predicted to require different diagnostic and therapeutic approaches, but the implications of this remain unknown. Even more challenging, no agreement exists for the best way to measure hypoxia. Some results even suggest that hypoxia is unlikely to be targetable therapeutically. In this review, the authors revisit various critical aspects of this field that are sometimes forgotten or misrepresented in the recent literature. As most current noninvasive imaging studies involve PET-isotope-labeled 2 nitroimidazoles, we emphasize key findings made in our studies using 2-(2-nitro 1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl)acetamide (EF5) and F-18-labeled EF5. These show the importance of differentiating hypoxia subtypes, optimizing drug pharmacology, ensuring drug and isotope stability, identifying key biochemical and physiological variables in tumors, and suggesting therapeutic strategies that are most likely to succeed. PMID- 25704389 TI - Evaluation of hypoxia with copper-labeled diacetyl-bis(N methylthiosemicarbazone). AB - Imaging of hypoxia is important in many diseases states in oncology, cardiology, and neurology. The radiopharmaceutical, copper-labeled diacetyl-bis(N methylthiosemicarbazone), has been used to assess hypoxia in many studies. In particular, copper-labeled diacetyl-bis(N-methylthiosemicarbazone) has been used in oncologic settings to investigate tumor hypoxia and the role of this parameter in response to therapy and outcome. Some groups have conducted imaging studies assessing the role of hypoxia in cardiovascular and neurologic disorders. Additionally, several groups have made significant progress into understanding the mechanism by which this compound accumulates in cells. Multiple preclinical and clinical studies have been conducted, shedding light on the importance of careful image analysis when using this tracer. This review article focuses on the recent preclinical and clinical studies with this tracer. PMID- 25704390 TI - Epidemiology of Foot and Mouth Disease in Ethiopia: a Retrospective Analysis of District Level Outbreaks, 2007-2012. AB - This study aimed at determining the incidence, distribution, risk factors, and causal serotypes of foot and mouth disease (FMD) outbreaks in Ethiopia based on 5 years of retrospective outbreak data (September 2007 until August 2012). District level outbreak data were collected from 115 randomly selected districts using a questionnaire administered to district animal health officers. The national incidence of FMD outbreaks during the study period was 1.45 outbreaks per five district years. Outbreaks were geographically widespread affecting all major regional states in the country and were more frequent in the central, southern, and southeastern parts of the country. Neither long-term nor seasonal trends were observed in the incidence of outbreaks. A mixed effects logistic regression analysis revealed that the type of production system (market oriented system versus subsistence systems), presence of a major livestock market and/or route, and adjacency to a national parks or wildlife sanctuary were found to be associated with increased risk of outbreaks in the districts. FMD virus serotypes O, A, SAT 2, and SAT 1 were identified as the causal serotypes of the outbreaks during the study period. Whereas O was the dominant serotype, SAT 2 was the serotype that showed increase in relative frequency of occurrence. The estimated incidence of outbreaks is useful in assessing the economic impacts of the disease, and the identified risk factors provide important knowledge to target a progressive FMD control policy for Ethiopia. PMID- 25704391 TI - New insights in the neuroanatomy of the human adult superior hypogastric plexus and hypogastric nerves. AB - BACKGROUND: The superior hypogastric plexus (SHP) is an autonomic plexus, located ventrally to the abdominal aorta and its bifurcation, innervating pelvic viscera. It is classically described as being composed of merely sympathetic fibres. However, post-operative complications after surgery damaging the peri-aortic retroperitoneal compartment suggest the existence of parasympathetic fibres. This immunohistochemical study describes the neuroanatomical composition of the human mature SHP. MATERIAL AND METHODS: Eight pre-determined retroperitoneal localizations including the lumbar splanchnic nerves, the SHP and the HN were studied in four human cadavers. Control tissues (white rami, grey rami, vagus nerve, splanchnic nerves, sympathetic ganglia, sympathetic chain and spinal nerve) were collected to verify the results. All tissues were stained with haematoxylin and eosin and antibodies S100, tyrosine hydroxylase (TH), vasoactive intestinal peptide (VIP) and myelin basic protein (MBP) to identify pre- and postganglionic parasympathetic and sympathetic nerve fibres. RESULTS: All tissues comprising the SHP and hypogastric nerves (HN) showed isolated expression of TH, VIP and MBP, revealing the presence of three types of fibres: postganglionic adrenergic sympathetic fibres marked by TH, unmyelinated VIP-positive fibres and myelinated preganglionic fibres marked by MBP. Analysis of control tissues confirmed that TH, VIP and MBP were well usable to interpret the neurochemical composition of the SHP and HN. CONCLUSION: The human SHP and HN contain sympathetic and most likely postganglionic parasympathetic fibres. The origin of these fibres is still to be elucidated, however surgical damage in the peri aortic retroperitoneal compartment may cause pelvic organ dysfunction related to both parasympathetic and sympathetic denervation. PMID- 25704392 TI - Carbon dot based nanopowders and their application for fingerprint recovery. AB - The incorporation of a minor amount of carbogenic nanoparticles into powder compositions imparts remarkable colour-tuneability, without compromising the flowability. In a proof-of-concept demonstration we report the use of these hybrid nanopowders for the visual enhancement of latent fingerprints where they effectively resolve issues arising from poor contrast against multi-coloured or patterned backgrounds. PMID- 25704393 TI - Separation anxiety disorder from the perspective of DSM-5: clinical investigation among subjects with panic disorder and associations with mood disorders spectrum. AB - OBJECTIVE/INTRODUCTION: High levels of comorbidity between separation anxiety disorder (SEPAD) and panic disorder (PD) have been found in clinical settings. In addition, there is some evidence for a relationship involving bipolar disorder (BD) and combined PD and SEPAD. We aim to investigate the prevalence and correlates of SEPAD among patients with PD and whether the presence of SEPAD is associated with frank diagnoses of mood disorders or with mood spectrum symptoms. METHODS: Adult outpatients (235) with PD were assessed by the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I), the Panic Disorder Severity Scale (PDSS), the Structured Clinical Interview for Separation Anxiety Symptoms (SCI SAS), and the Mood Spectrum Self-Report Instrument (MOODS-SR, lifetime version). RESULTS: Of ther 235 subjects, 125 (53.2%) were categorized as having SEPAD and 110 (46.8%) as not. Groups did not differ regarding onset of PD, lifetime prevalence of obsessive compulsive disorder (OCD), social phobia, simple phobia, BD I and II, or major depressive disorder (MDD). SEPAD subjects were more likely to be female and younger; they showed higher rates of childhood SEPAD, higher PDSS scores, and higher MOODS-SR total and manic component scores than subjects without SEPAD. Discussion SEPAD is highly prevalent among PD subjects. Patients with both PD and SEPAD show higher lifetime mood spectrum symptoms than patients with PD alone. Specifically, SEPAD is correlated with the manic/hypomanic spectrum component. CONCLUSION: Our data confirm the high prevalence of SEPAD in clinical settings. Moreover, our findings corroborate a relationship between mood disorders and SEPAD, highlighting a relationship between lifetime mood spectrum symptoms and SEPAD. PMID- 25704394 TI - Combined effects of temperature, pressure, and co-solvents on the polymerization kinetics of actin. AB - In vivo studies have shown that the cytoskeleton of cells is very sensitive to changes in temperature and pressure. In particular, actin filaments get depolymerized when pressure is increased up to several hundred bars, conditions that are easily encountered in the deep sea. We quantitatively evaluate the effects of temperature, pressure, and osmolytes on the kinetics of the polymerization reaction of actin by high-pressure stopped-flow experiments in combination with fluorescence detection and an integrative stochastic simulation of the polymerization process. We show that the compatible osmolyte trimethylamine-N-oxide is not only able to compensate for the strongly retarding effect of chaotropic agents, such as urea, on actin polymerization, it is also able to largely offset the deteriorating effect of pressure on actin polymerization, thereby allowing biological cells to better cope with extreme environmental conditions. PMID- 25704395 TI - Primary oropharyngeal herpes simplex virus infection in adults: a profile of thirty-two immunoserologically confirmed cases. PMID- 25704396 TI - Electrochemically mediated atom transfer radical polymerization from a substrate surface manipulated by bipolar electrolysis: fabrication of gradient and patterned polymer brushes. AB - We report the first ever use of electrochemically mediated atom transfer radical polymerization (eATRP) employing a bipolar electrochemical method for the fabrication of both gradient and patterned polymer brushes. A potential gradient generated on a bipolar electrode allowed the formation of a concentration gradient of a Cu(I) polymerization catalyst through the one-electron reduction of Cu(II) , resulting in the gradient growth of poly(NIPAM) brushes from an initiator-modified substrate surface set close to a bipolar electrode. These polymer brushes could be fabricated in three-dimensional gradient shapes with control over thickness, steepness, and modified area by varying the electrolytic conditions. Moreover, by site-selective application of potential during bipolar electrolysis, a polymer brush with a circular pattern was successfully formed. Polymerization was achieved using both a polar monomer (NIPAM) and a nonpolar monomer (MMA) with the eATRP system. PMID- 25704397 TI - Streptococcus agalactiae isolates from cultured fishes in Malaysia manifesting low resistance pattern towards selected antibiotics. PMID- 25704398 TI - Autotaxin, a secreted lysophospholipase D, as a promising therapeutic target in chronic inflammation and cancer. AB - Autotaxin (ATX) is a member of the nucleotide pyrophosphatase/phosphodiesterase family of ectoenzymes that hydrolyzes phosphodiester bonds of various nucleotides. It possesses lysophospholipase D activity, catalyzing the hydrolysis of lysophosphatidylcholine into lysophosphatidic acid (LPA), and it is considered the major LPA-producing enzyme in the circulation. LPA is a bioactive phospholipid with diverse functions in almost every mammalian cell type, which exerts its action through binding to specific G protein-coupled receptors and stimulates various cellular functions, including migration, proliferation and survival. As a consequence, both ATX and LPA have attracted the interest of researchers, in an effort to understand their roles in physiology and pathophysiology. The present review article aims to summarize the existing knowledge as to the implications of ATX in chronic inflammatory diseases and cancer and to highlight the low molecular weight compounds, which have been developed as leads for the discovery of novel medicines to treat inflammatory diseases and cancer. PMID- 25704399 TI - Lysophosphatidic acid receptor (LPAR) modulators: The current pharmacological toolbox. AB - Lysophosphatidic acids (LPA) are key lipid-signalling molecules that regulate a remarkably diverse set of cellular events, such as motility, chemotaxis, cell cycle progression, viability, and wound healing. The physiological and pathophysiological consequences of LPA signalling are evident and misregulation of LPA signalling can lead to pathologies like cancer, atherosclerosis, ischaemia, and fibrosis. LPA exerts its biological actions mainly through several types of G protein-coupled receptors, some of which display opposing or redundant effects. For this reason, selective LPA receptor small-molecule ligands can shine light on LPA biology and present an exciting opportunity for drug discovery endeavours. This review provides insights into the detailed chemical nature and pharmacological profile of the small-molecules thus far developed as LPA receptor modulators, as well as information on the preparation of key pharmaceuticals. This summary will facilitate future research efforts and nurture collaboration between chemists and biologists working in this emerging field. PMID- 25704400 TI - Relaxor ferroelectric-based electrocaloric polymer nanocomposites with a broad operating temperature range and high cooling energy. AB - Electrocaloric nanocomposites simultaneously derive high electrocaloric strength from inorganic inclusions and high dielectric strength from the polymer matrix to display a pronounced electrocaloric effect (ECE). By designing the inorganic filler and polymer matrix, which are both relaxor ferroelectrics with the ambient temperature phase transition and minimized hysteresis, a large ECE becomes accessible with high cooling efficiency over a broad temperature range at and near room temperature. PMID- 25704401 TI - Non-applicability of the Gibbs-Duhem relation in nonextensive thermodynamics. Case of micellar solutions. AB - This work is a discussion on the applicability of the Gibbs-Duhem relationship. We show that it does not exist in the nonextensive thermodynamic approaches. To illustrate this, we have chosen to present the properties of three surfactants (dodecyltrimethylammonium bromide (DTABr), sodium dodecyl sulfate (SDS), sodium decanoate (NaDec) in aqueous solutions at 298 K) whose behavior after the micellization threshold can be described by the rules of the nonextensive thermodynamics. We show that the Gibbs-Duhem relationship does not apply to these systems and we propose to formalize the deviation from this law. The consequences of this study are discussed for the different approaches that involve the use of Gibbs-Duhem relation in the case of micellized solutions. In particular, the applicability of the Gibbs relation which links surface tension and the chemical potentials of solutes is considered. More generally, this study warns against the blind application of the Gibbs-Duhem (or Gibbs) relation, to any system. PMID- 25704402 TI - Functional reassignment of Cellvibrio vulgaris EpiA to cellobiose 2-epimerase and an evaluation of the biochemical functions of the 4-O-beta-D-mannosyl-D-glucose phosphorylase-like protein, UnkA. AB - The aerobic soil bacterium Cellvibrio vulgaris has a beta-mannan-degradation gene cluster, including unkA, epiA, man5A, and aga27A. Among these genes, epiA has been assigned to encode an epimerase for converting D-mannose to D-glucose, even though the amino acid sequence of EpiA is similar to that of cellobiose 2 epimerases (CEs). UnkA, whose function currently remains unknown, shows a high sequence identity to 4-O-beta-D-mannosyl-D-glucose phosphorylase. In this study, we have investigated CE activity of EpiA and the general characteristics of UnkA using recombinant proteins from Escherichia coli. Recombinant EpiA catalyzed the epimerization of the 2-OH group of sugar residue at the reducing end of cellobiose, lactose, and beta-(1->4)-mannobiose in a similar manner to other CEs. Furthermore, the reaction efficiency of EpiA for beta-(1->4)-mannobiose was 5.5 * 10(4)-fold higher than it was for D-mannose. Recombinant UnkA phosphorolyzed beta D-mannosyl-(1->4)-D-glucose and specifically utilized D-glucose as an acceptor in the reverse reaction, which indicated that UnkA is a typical 4-O-beta-D-mannosyl D-glucose phosphorylase. PMID- 25704403 TI - Antitumor effect of antitissue factor antibody-MMAE conjugate in human pancreatic tumor xenografts. AB - Tissue factor (TF) triggers the extrinsic blood coagulation cascade and is highly expressed in various types of cancer. In this study, we investigated the antitumor effect of an antibody-drug conjugate (ADC) consisting of an anti-TF monoclonal antibody and monomethyl auristatin E (MMAE). MMAE was conjugated to an anti-human TF or anti-mouse TF antibody using a valine-citrulline linker that could be potentially hydrolyzed by cathepsin B in the acidic environment of the lysosome. The cytotoxic and antitumor effects of the ADCs against four pancreatic cancer cell lines were analyzed. Both the ADC with the anti-human TF antibody and that with the anti-mouse TF antibody were stable under physiological conditions. The anti-human ADC was internalized in TF-expressing human tumor cell lines, followed by effective MMAE release. The half maximal inhibitory concentration (IC50 ) of MMAE was approximately 1 nM for all of the cell lines used. Meanwhile, the IC50 of anti-human ADC was 1.15 nM in the cell lines showing high TF expression, while exceeding 100 nM in the cells showing low TF expression levels. Anti-human ADC with passive and active targeting ability exerted significant suppression of tumor growth as compared to that observed in the saline group (p < 0.01). Also significant tumor growth suppressions were seen at the anti-mouse ADC and control ADC groups compared to the saline group (p < 0.01) due to EPR effect. Because various clinical human cancers express highly amount of TF, this new anti TF ADC may deserve a clinical evaluation. PMID- 25704404 TI - A rare pathogen for subacute osteomyelitis in adolescent: Serratia marcescens. AB - INTRODUCTION: There are various pathogens reported for osteomyelitis. Osteomyelitis is bone infection which produces pain and fever, also threatens bone instability. It can lead to nonunion. The purpose of this report was to describe a case with union delay of the tibia due to serratia marcescens osteomyelitis. Serratia marcescens is an unexpected pathogen for subacute osteomyelitis in adolescence. Because of difficulty of diagnosis, treatment can be delayed or the situation can cause complications like nonunion or loss of function. PRESENTATION OF CASE: Serratia marcescens is an unexpected pathogen for subacute osteomyelitis in adolescence. Because of difficulty of diagnosis, treatment can be delayed or cause complications like nonunion or loss of function. We present a meningomyelocele female adolescent operated with distal tibia varus osteotomy for correcting ankle valgus deformity. Insufficient healing was determined at osteotomy side on radiographs. The patient's erythrocyte sedimentation rate and CRP level was slightly higher with minimal clinical inflammation. MRI examination showed abscess formation at T2 imaging. Debridement, grafting and circular external fixation was performed. Sulperazon was started for drug therapy. Union was achieved after compression and distraction osteogenesis by circular external fixator. Orthopedic surgeons should be aware of opportunistic infections like serratia and keep in mind as a probable cause of disease. DISCUSSION: Osteomyelitis is one of our main problems in orthopedics. Serratia does not come to mind as a causative factor when we learn the patient has osteomyelitis. We give treatment for the most expected pathogens like staphylococcus species firstly. This shows us the importance of bone biopsies and wound culture tests. Presented case is diagnosed as serratia osteomyelitis after culture results and given treatment with antibiotics and debridement. CONCLUSION: Orthopedic surgeons should be aware of opportunistic infections like serratia and keep in mind when diagnosing the unexpected problem. PMID- 25704405 TI - Gas induction for pyloromyotomy. AB - BACKGROUND: Infants with pyloric stenosis are considered to be at high risk of aspiration on induction of anesthesia. Traditionally, texts have recommended classic rapid sequence induction (RSI) or awake intubation (AI). AI has generally fallen out of favor, while the components of RSI have become increasingly controversial. Infants are at high risk of hypoxemia if ventilation is not maintained while waiting for neuromuscular blockade to establish. The efficacy of cricoid pressure (CP) to prevent aspiration has not been proven. It can impair visualization of the glottis and make intubation difficult. It is debatable whether any RSI technique is needed for pyloromyotomy. A recent review of 235 infants reported no aspiration events. These children were anesthetized with a variety of techniques, including RSI, gas induction, and AI. In our institution, we teach a gaseous induction. The nasogastric tube is used to empty the stomach and anesthesia is induced with sevoflurane. A nondepolarizing muscle relaxant is administered and ventilation maintained until neuromuscular blockade is established and intubating conditions are optimal. We report our experience of this technique. METHOD: A retrospective medical notes review of all patients undergoing pyloromyotomy between 2005 and 2012. RESULTS: There were 269 patients (84.4% male, mean weight 3.74 kg +/- 0.74). Two hundred and fifty-two (93.7%) received gas inductions and 17 (6.3%) intravenous (IV) inductions. Two children received an RSI. No patient-specific factors were identified to explain operator choice in those receiving IV inductions. There were no recorded aspiration events. CONCLUSION: Gas induction can be considered for children undergoing pyloromyotomy. PMID- 25704406 TI - The influence of do-not-resuscitate status on the outcomes of patients undergoing emergency vascular operations. AB - BACKGROUND: Do-not-resuscitate (DNR) orders allow patients to communicate their wishes regarding cardiopulmonary resuscitation. Although DNR status may influence physician decision making regarding resuscitation, the effect of DNR status on outcomes of patients undergoing emergency vascular operation remains unknown. The aim of this study was to analyze the effect of DNR status on the outcomes of emergency vascular surgery. METHODS: The National Surgical Quality Improvement Program database was queried to identify all patients requiring emergency vascular surgical interventions between 2005 and 2010. Demographics, clinical data, and outcomes were extracted. Patients were compared according to DNR status. The primary outcome measure was 30-day mortality. RESULTS: During the study period, 16,678 patients underwent emergency vascular operations (10.8% of the total vascular surgery population). Of those, 548 patients (3.3%) had a DNR status. The differences in rates of open or endovascular repair or of intraoperative blood requirement between the two groups were not significant. After adjusting for differences in demographics and clinical data, DNR patients were more likely to have higher rates of graft failure (8.7% vs 2.4%; adjusted P < .01) and failure to wean from mechanical ventilation (14.9 % vs 9.9%; adjusted P < .001). DNR status was associated with a 2.5-fold rise in 30-day mortality (35.0% vs 14.0%; 95% confidence interval, 1.7-2.9; adjusted P < .001). CONCLUSIONS: The presence of a DNR order was independently associated with mortality. Patient and family counseling on surgical expectations before emergency vascular operations is warranted because the risks of perioperative events are significantly elevated when a DNR order exists. PMID- 25704407 TI - Safety and efficacy of antiplatelet/anticoagulation regimens after Viabahn stent graft treatment for femoropopliteal occlusive disease. AB - OBJECTIVE: We aimed to determine the safety and efficacy of antiplatelet/anticoagulation regimens after placement of Viabahn stent graft (W. L. Gore & Associates, Flagstaff, Ariz) for the treatment of femoropopliteal occlusive disease. METHODS: Clinical, angiographic, and procedural data for patients undergoing endovascular treatment of femoropopliteal occlusive disease using Viabahn covered stent grafts at a single institution between 2006 and 2013 were retrospectively reviewed. Graft patency and freedom from thrombolysis, major adverse limb event, and reintervention were determined by Kaplan-Meier analysis. The influence of relevant variables on clinical outcome was determined through univariate and multivariate Cox proportional hazards analyses. RESULTS: Viabahn stent grafts were placed in a total of 91 limbs in 61 patients (66% men; mean age, 69 +/- 12 years) during the study period. Indication for intervention was either claudication (n = 59) or critical limb ischemia (n = 32), with the majority (70%) classified as TransAtlantic Inter-Society Consensus II C (n = 33) or D (n = 31) lesions. Mean follow-up was 38.3 months (range, 1-91 months). Postprocedural pharmacologic regimens included aspirin, clopidogrel, and warfarin (47%); indefinite aspirin and clopidogrel (46%); or aspirin and temporary clopidogrel (7%). Primary and secondary patency rates were 60%, 44%, and 36% and 95%, 82%, and 74% at 1 year, 3 years, and 5 years, respectively. Kaplan-Meier analysis demonstrated more aggressive antiplatelet/anticoagulation regimens to be associated with improved primary patency and freedom from reintervention. Cox proportional hazards analysis demonstrated TransAtlantic Inter-Society Consensus II D lesions, tobacco use, coronary artery disease, and smaller stent diameter to be independent risk factors for stent graft failure. Bleeding events were limited to those in the aspirin, clopidogrel, and warfarin group (11.6% [n = 5]; P = .052), although the majority of these events were not life-threatening, and only two cases required blood transfusion. CONCLUSIONS: Increasingly aggressive antithrombotic regimens after Viabahn stent graft placement trended toward improved overall clinical outcomes, although the marginal patency benefit observed with the addition of warfarin to dual antiplatelet therapy was tempered by an observed increased risk of bleeding complications. Longer term follow-up and multicenter studies are needed to further define optimal type and duration of antithrombotic therapy after endovascular peripheral interventions. PMID- 25704408 TI - The effect of a hospitalist comanagement service on vascular surgery inpatients. AB - OBJECTIVE: Vascular surgery patients have increased medical comorbidities that amplify the complexity of their care. We assessed the effect of a hospitalist comanagement service on inpatient vascular surgery outcomes. METHODS: We divided 1059 patients into two cohorts for comparison: 515 between January 2012 and December 2012, before the implementation of a hospitalist comanagement service, and 544 between January 2013 and October 2013, after the initiation of a hospitalist comanagement service. Nine vascular surgeons and 10 hospitalists participated in the hospitalist comanagement service. End points measured were in hospital mortality, length of stay (LOS), 30-day readmission rates, visual analog scale pain scores (0-10), inpatient adult safety assessments using the Agency for Healthcare Research and Quality (AHRQ) Patient Safety Indicators, and resident perceptions assessed by survey. RESULTS: The in-hospital mortality rate decreased from 1.75% to 0.37% after the implementation of the hospitalist comanagement service (P = .016), with a decrease in the observed-to-expected ratio from 0.89 to 0.22. The risk-adjusted in-hospital mortality decreased from 1.56% to 0.0008% (P = .003). Mean LOS was lower in the base period, at 5.1 days vs 5.5 days (P < .001), with an observed-to-expected ratio of 0.83 and 0.78, respectively. The risk-adjusted LOS increased from 4.2 days to 4.3 days (P < .001). The overall 30 day readmission rate was unchanged, at 23.1% compared with 22.8% (P = .6). The related 30-day readmission rate was also similar, at 11.5% compared with 11.4% (P = .5). Patients reporting no pain during hospitalization increased from 72.8% before the hospitalist comanagement service to 77.8% after (P = .04). Reports of moderate pain decreased from 14% to 9.6% (P = .016). Mild and severe pain scores were similar between the two groups. Adult safety measured by AHRQ demonstrated a decrease from three to zero patients in the number of deaths among surgical patients with treatable complications (P = .04). Most house staff reported that the comanagement program had a positive effect on patient care and education. CONCLUSIONS: The hospitalist comanagement service has resulted in a significant decrease in in-hospital mortality rates, patient safety, as measured by AHRQ, and improved pain scores. Resident surveys demonstrated perceived improvement in patient care and education. Continued observation will be necessary to assess the long-term effect of the hospitalist comanagement service on quality metrics. PMID- 25704409 TI - Brilliant blue FCF is a nontoxic dye for saphenous vein graft marking that abrogates response to injury. AB - BACKGROUND: Injury to saphenous vein grafts during surgical preparation may contribute to the subsequent development of intimal hyperplasia, the primary cause of graft failure. Surgical skin markers currently used for vascular marking contain gentian violet and isopropanol, which damage tissue and impair physiologic functions. Brilliant blue FCF (FCF) is a nontoxic dye alternative that may also ameliorate preparation-induced injury. METHODS: Porcine saphenous vein (PSV) was used to evaluate the effect of FCF on physiologic responses in a muscle bath. Cytotoxicity of FCF was measured using human umbilical venous smooth muscle cells. Effect of FCF on the development of intimal hyperplasia was evaluated in organ culture using PSV. Intracellular calcium fluxes and contractile responses were measured in response to agonists and inhibitors in rat aorta and human saphenous vein. RESULTS: Marking with FCF did not impair smooth muscle contractile responses and restored stretch injury-induced loss in smooth muscle contractility of PSV. Gentian violet has cytotoxic effects on human umbilical venous smooth muscle cells, whereas FCF is nontoxic. FCF inhibited intimal thickening in PSV in organ culture. Contraction induced by 2'(3')-O-(4 benzoylbenzoyl)adenosine 5'-triphosphate and intracellular calcium flux were inhibited by FCF, oxidized adenosine triphosphate, KN-62, and brilliant blue G, suggesting that FCF may inhibit the purinergic receptor P2X7. CONCLUSIONS: Our studies indicated that FCF is a nontoxic marking dye for vein grafts that ameliorates vein graft injury and prevents intimal thickening, possibly due to P2X7 receptor inhibition. FCF represents a nontoxic alternative for vein graft marking and a potentially therapeutic approach to enhance outcome in autologous transplantation of human saphenous vein into the coronary and peripheral arterial circulation. PMID- 25704410 TI - The compatibility of p-branch "off-the-shelf" fenestrated endovascular graft in Asian patients with juxtarenal aortic aneurysm. AB - OBJECTIVE: The Zenith pivot branch (p-branch) fenestrated endovascular graft (Cook Medical, Bloomington, Ind) is a new "off-the-shelf" device to treat patients with juxtarenal aortic aneurysms (JRAs). Two options are currently available, which appear to suit >70% of white patients. This study investigates the anatomic applicability of the p-branch fenestrated graft in a cohort of Asian patients with JRA. METHODS: Computed tomography images of 51 consecutive Asian patients with JRA (43 men; mean age, 76.8 years) were analyzed on an Aquarius workstation (TeraRecon, San Mateo, Calif) and matched to two current configurations of the p-branch (options A and B: single superior mesenteric artery [SMA] and two renal fenestrations, and a celiac axis scallop). With use of the SMA as reference, the anatomic positions of both renal arteries and the celiac axis were figured together with their diameters on a template generated on MATLAB (MathWorks, Natick, Mass), and then they were matched with two graft configurations. The renal artery origins were assessed for three classes of "closeness of fit" based on diameter: perfect match, marginal match, and mismatch, respectively, defined as the renal artery origins being located entirely inside, partially inside, and completely outside their corresponding fenestrations. The suitability of the p-branch graft design to the aneurysms was then evaluated. RESULTS: A total of 31 JRA patients (60.8%) were regarded as suitable candidates for one or both p-branch stent grafts (20 with option A, 22 with option B, and 11 with both options). In 35 patients (68.6%), both renal arteries could be aligned with the fenestrations. Among them, 16 patients (31.4%) were perfectly matched, whereas 19 patients (37.2%) were only marginally suitable. The major reason for exclusion was the misalignment of the renal fenestrations. In 16 patients with unsuitable renal fenestrations, 8 were attributed to the right renal origins being located too distally compared with their corresponding fenestrations. Another reason for exclusion was the position of the celiac axis scallop in four patients (7.84%), and insufficient aortic length for the graft was encountered in another four. If the right renal fenestration of option B was adjusted to 20 mm caudal to the SMA fenestration (level with the left fenestration), the match of renal fenestration could reach 78.4% (40 of 51). CONCLUSIONS: The present design of the p-branch off-the-shelf fenestrated graft is feasible for a good proportion of JRA patients in Asia. Further refinement of design may improve the anatomic match, especially a lower right renal artery origin. PMID- 25704411 TI - Outcomes of endovascular abdominal aortic aneurysm repair in high-risk patients. AB - OBJECTIVE: Although the endovascular aneurysm repair trial 2 (EVAR-2) demonstrated no benefit of EVAR in high-risk (HR) patients, EVAR is still performed widely in this patient cohort. This study compares the midterm outcomes after EVAR in HR patients with those in normal-risk (NR) patients. In turn, these data are compared with the EVAR-2 data. METHODS: A retrospective review from January 2006 to December 2013 identified 247 patients (75 HR [30.4%], 172 NR [69.6%]) who underwent elective EVAR for infrarenal aortic aneurysm in an academic tertiary institution and its affiliated Veterans Administration hospital. The same HR criteria used in the EVAR-2 trial were employed. Overall survival, graft-related complications, and reintervention rates were estimated by the Kaplan-Meier method. HR group outcomes were compared with the EVAR-2 data. RESULTS: HR patients had a larger abdominal aortic aneurysm size and had a higher prevalence of cardiac disease (P < .01), chronic obstructive pulmonary disease (P = .02), renal insufficiency (P < .01), and cancer (P < .01). Use of aspirin (63% HR vs 66% NR; P = .6), statin (83% HR vs 72% NR; P = .2), and beta-blockers (71% HR vs 60% NR; P = .2) was similar; in the EVAR-2 trial, the corresponding use of these medications was 58%, 42%, and not available, respectively. Perioperative mortality (0% HR vs 1.2% NR; P = 1.0) and early complication rates (4% HR vs 6% NR; P = .8) were similar. In contrast, perioperative mortality in the EVAR-2 trial was 9%. At a mean follow-up of 3 years, the incidence rates of delayed secondary interventions for aneurysm- or graft-related complications were 7% for HR patients and 10% for NR patients (P = .5). The 1-, 2-, and 4-year survival rates in HR patients (85%, 77%, 65%) were lower than those in NR patients (97%, 97%, 93%; P < .001), but this was more favorable compared with a 36% 4-year survival in the EVAR-2 trial. No difference was seen in long-term reintervention free survival in HR and NR patients (P = .8). Backward stepwise logistic regression analysis identified five prognostic indicators for post-EVAR death: age, chronic kidney disease stages 4 and 5, congestive heart failure, home oxygen use, and current cancer therapy. CONCLUSIONS: EVAR can be performed in patients unfit for open surgical repair with excellent early survival and long-term durability. These outcomes in the HR group compare more favorably to the EVAR-2 trial data. However, not all HR patients for open surgical repair derive the benefit from EVAR. The decision to proceed with EVAR in HR patients should be individualized, depending on the number and severity of risk factors. PMID- 25704412 TI - Role of high shear rate in thrombosis. AB - Acute arterial occlusions occur in high shear rate hemodynamic conditions. Arterial thrombi are platelet-rich when examined histologically compared with red blood cells in venous thrombi. Prior studies of platelet biology were not capable of accounting for the rapid kinetics and bond strengths necessary to produce occlusive thrombus under these conditions where the stasis condition of the Virchow triad is so noticeably absent. Recent experiments elucidate the unique pathway and kinetics of platelet aggregation that produce arterial occlusion. Large thrombi form from local release and conformational changes in von Willebrand factor under very high shear rates. The effect of high shear hemodynamics on thrombus growth has profound implications for the understanding of all acute thrombotic cardiovascular events as well as for vascular reconstructive techniques and vascular device design, testing, and clinical performance. PMID- 25704413 TI - The concentrations of inflammatory cytokines and acute-phase proteins in the peripheral blood and uterine washings in cows with pyometra. AB - The development of pyometra in cows depends largely on the state of local immunity of the uterus. The objective of the study was to evaluate the concentration of the following proinflammatory cytokines: tumour necrosis factor (TNF-alpha) and interleukin-6 (IL-6); anti-inflammatory cytokine: interleukin-10 (IL-10); and acute-phase proteins (APPs): haptoglobin (Hp) and serum amyloid A (SAA), in serum and uterine washings in cows with pyometra and healthy animals. The study was performed on 20 cows divided into two groups based on the results of cytological and ultrasonographic tests: a pyometra and a healthy group (10 cows per group). Experimental material consisted of blood serum and uterine washings. The levels of the following cytokines, TNF-alpha, IL-6, IL-10 and APPs Hp and SAA, in the study material were determined by ELISA. The results showed that the values of TNF-alpha, IL-6, IL-10 as well as SAA and Hp were significantly higher in serum of cows with pyometra compared to controls (p < 0.001). The uterine washings had significantly higher levels of IL-6, IL-10, and Hp in pyometra cows compared to the control (p < 0.001). Our results indicate that it is possible to monitor the course of pyometra in cows based on the evaluation of the concentration of cytokines and Hp in the serum and uterine washings. Simultaneous evaluation of selected indicators of antagonistic interaction can be helpful in determining the current status of local immunity of the uterus. On this basis, it could be possible to properly select an adjunctive therapy in the form of immunomodulating preparations. PMID- 25704414 TI - Reply to "Sepsis drives the cost in perforated peptic ulcer". PMID- 25704415 TI - The Charlson age comorbidity index predicts early mortality after surgery for pancreatic cancer. AB - BACKGROUND: Although operative resection represents the only hope for cure in pancreatic cancer, it is associated with significant morbidity and mortality. Furthermore, in some patients disease progression occurs very early postoperatively and no tangible benefit is seen from the operation. Identification of preoperative predictors of death within the first year of surgery could help in the counseling of patients diagnosed with pancreatic cancer. METHODS: We studied retrospectively patients who underwent resection for pancreatic adenocarcinoma from 2002 to 2012. We calculated the age-adjusted Charlson Age Comorbidity Index (CACI) and used logistic regression models to determine predictors of mortality within 1 year of surgery. Kaplan-Meier curves and Cox proportional hazards models were developed to determine hazard ratios on survival. RESULTS: Surgery with curative intent was performed in 497 patients; 136 (27%) died within the first year. A CACI score of >4 was predictive of increased duration of stay (P < .001), postoperative complications (P = .042), and mortality within 1 year of pancreatic resection (P < .001). A CACI score of >= 6 increased 3-fold the odds of death within the first year. CONCLUSION: CACI is useful to predict outcome after pancreatectomy for pancreatic cancer. Patients with a high CACI score have a <50% likelihood of being alive 1 year postoperatively. This information should be used when considering the appropriateness of pancreatic resection in patients with multiple comorbidities. PMID- 25704416 TI - Resection of the mesopancreas in pancreatic head adenocarcinoma: Is it outside of the International Study Group on Pancreatic Surgery definition and consensus statement for standard and extended pancreatectomy? PMID- 25704417 TI - A systematic review and meta-analysis of portal vein ligation versus portal vein embolization for elective liver resection. AB - INTRODUCTION: This meta-analysis aimed to review the percentage increase in future liver remnant (FLR) and perioperative outcomes after portal vein ligation (PVL) and portal vein embolization (PVE) before liver resection. METHODS: An electronic search was performed of the MEDLINE, EMBASE, and PubMed databases using both subject headings (MeSH) and truncated word searches to identify all articles published that related to this topic. Pooled risk ratios were calculated for categorical outcomes and mean differences for secondary continuous outcomes using the fixed-effects and random-effects models for meta-analysis. RESULTS: Seven studies involving 218 patients met the inclusion criteria. There was no difference in the increase in FLR between the 2 groups 39% (PVE) versus 27% (PVL; mean difference [MD] 6.04; 95% CI, -0.23, 12.32; Z = 1.89; P = .06). Similarly, there was no difference in the morbidity (risk ratio [RR], 1.08; 95% CI, 0.55, 2.09; Z = 0.21; P = .83) and mortality (RR, 0.87; 95% CI, 0.19, 3.92; Z = 0.18; P = .85) in the 2 groups after liver resection. While awaiting liver resection after PVL and PVE, no difference was noted in the number of patients developing disease progression (RR, 0.93; 95% CI, 0.52, 1.66; Z = 0.24; P = .81). In a subset analysis comparing FLR with PVE and PVL as part of the procedure called an associating liver partition with PVL for staged hepatectomy (ALPPS), there was a significant increase in FLR in favor of ALPPS (MD, -17.09; 95% CI, -32.78, -1.40; Z = 2.14; P = .03). CONCLUSION: PVL and PVE result in comparable percentage increase in FLR with similar morbidity and mortality rates. The ALPPS procedure results in an improved percentage increase in FLR compared with PVE alone. PMID- 25704418 TI - Thirty years of disclosure of conflict of interest in surgery journals. AB - BACKGROUND: A conflict of interest (COI) creates the risk that a professional judgment will be unduly influenced by a secondary interest. In practice, the leading concern is the creation of bias by industry sponsorship. Several organizations for ethics in scientific publishing exist, and standardized disclosure forms have been developed. The aim of this study was to investigate the present status of the definition, management, and disclosure of COI in journals devoted to general and abdominal surgery. METHODS: Information on publisher, definition of COI, whether COI disclosure was mandatory, publication of the disclosure statement with the article, and when publication of disclosure statements was introduced were gathered from instructions for authors and from journal editors and presented descriptively. The hypothesis that journals with a disclosure policy have greater impact factors was tested with a Wilcoxon rank-sum test. RESULTS: A sample of 64 journals was investigated. In 8 journals (13%) disclosure was deemed unnecessary. In the remaining 56 journals (88%) disclosure of COI was mandatory and in 39 of these journals (61%) the COI statement was published with the article. Journals declaring COI disclosure as mandatory had a greater impact factor (0.626 vs 1.732; P = .006). CONCLUSION: Transparency is critical to the reliability of evidence-based medicine. All efforts should be made to give the reader the maximum amount of information. We recommend that every surgeon maintain a standardized, up-to-date disclosure form. PMID- 25704419 TI - Objective structured assessment of nontechnical skills: Reliability of a global rating scale for the in-training assessment in the operating room. AB - BACKGROUND: Nontechnical skills are critical for patient safety in the operating room (OR). As a result, regulatory bodies for accreditation and certification have mandated the integration of these competencies into postgraduate education. A generally accepted approach to the in-training assessment of nontechnical skills, however, is lacking. The goal of the present study was to develop an evidence-based and reliable tool for the in-training assessment of residents' nontechnical performance in the OR. METHODS: The Objective Structured Assessment of Nontechnical Skills tool was designed as a 5-point global rating scale with descriptive anchors for each item, based on existing evidence-based frameworks of nontechnical skills, as well as resident training requirements. The tool was piloted on scripted videos and refined in an iterative process. The final version was used to rate residents' performance in recorded OR crisis simulations and during live observations in the OR. RESULTS: A total of 37 simulations and 10 live procedures were rated. Interrater agreement was good for total mean scores, both in simulation and in the real OR, with intraclass correlation coefficients >0.90 in all settings for average and single measures. Internal consistency of the scale was high (Cronbach's alpha = 0.80). CONCLUSION: The Objective Structured Assessment of Nontechnical Skills global rating scale was developed as an evidence-based tool for the in-training assessment of residents' nontechnical performance in the OR. Unique descriptive anchors allow for a criterion referenced assessment of performance. Good reliability was demonstrated in different settings, supporting applications in research and education. PMID- 25704420 TI - Right-sided bursectomy as an access plane for aesthetic resection of the posterior leaf of the lesser sac from the head of the pancreas en block with the No. 6 and 14v lymph nodes in advanced lower third gastric cancer. PMID- 25704421 TI - A laboratory marker, FIB-4 index, as a predictor for long-term outcomes of hepatocellular carcinoma patients after curative hepatic resection. AB - BACKGROUND: Liver fibrosis is associated with the prognosis of patients with hepatocellular carcinoma (HCC) after treatment. The laboratory marker for liver fibrosis, the FIB-4 index, is reportedly correlated with the degree of liver fibrosis. We evaluated the predictive value of FIB-4 index on the recurrence and survival of HCC patients who underwent curative hepatectomy. METHODS: A total of 431 consecutive patients who underwent hepatectomy for primary, nonrecurrent HCC were analyzed. The FIB-4 index was calculated from the patient's age, serum alanine aminotransferase and aspartate aminotransferase levels, and platelet count at the time of HCC diagnosis. Postoperative recurrence and survival rates were compared according to tumor characteristics, tumor markers, Child-Pugh class, and the FIB-4 index. RESULTS: The pretreatment FIB-4 index was associated with recurrence and survival rates, independent of HCC progression or tumor marker levels in a multivariate analysis. Recurrence rates after hepatectomy were higher in patients with a FIB-4 index >3.25 versus <=3.25 (5-year recurrence rates 69.6% vs 54.8%; P = .0049). Survival was also worse in patients with a FIB 4 index >3.25 than those with a FIB-4 index <=3.25 (5-year survival rates 67.1% vs 72.2%; P = .0030). CONCLUSION: The FIB-4 index is a predictive marker for long term outcomes in patients with HCC treated with curative hepatic resection. PMID- 25704422 TI - Identification of a safe and adequate division point of the left-sided bile duct with magnetic resonance cholangiography during donor left lateral sectionectomy. AB - BACKGROUND: Multiple bile duct (BD) openings on the graft can cause postoperative BD-related complications as the result of their small orifices and multiple anastomoses. This study aimed to determine a safe and adequate BD division point during donor left lateral sectionectomy. METHODS: Left BD was classified into type I: B4 enters the common trunks of B2 and B3; type II: B2 joins the common channels of B3 and B4; or type III: B2, B3, and B4 join. We assessed the chance of multiple openings with 3 BD types in 43 left lateral living donor grafts from January 2004 to January 2011. We also analyzed the potential for multiple openings and right-sided BD injury, based on BD types, during left lateral sectionectomy according to the distance from the crossing point of the right lateral border of the umbilical portion of the left portal vein at the left BD (point U) via preoperative magnetic resonance imaging from another 90 living donors who underwent several types of hepatectomy from January 2012 to December 2012. RESULTS: There was a statistically marginal relevance for multiple openings between BD type I and type II (33.3% in type II vs 7.4% in type I, P = .078), and the optimal BD division points were different by BD types (right-side 5 mm from point U in type I; 10 mm in type II; and 12 mm in type III). CONCLUSION: The safe and adequate BD division point should be determined according to the left BD types during living donor left lateral sectionectomy. PMID- 25704423 TI - Enteral nutrient deprivation in patients leads to a loss of intestinal epithelial barrier function. AB - OBJECTIVE: To investigate the effect of nutrient withdrawal on human intestinal epithelial barrier function (EBF). We hypothesized that unfed mucosa results in decreased EBF. This was tested in a series of surgical small intestinal resection specimens. DESIGN: Small bowel specifically excluding inflamed tissue, was obtained from pediatric patients (aged 2 days to 19 years) undergoing intestinal resection. EBF was assessed in Ussing chambers for transepithelial resistance (TER) and passage of fluorescein isothiocyanate (FITC)-dextran (4 kD). Tight junction and adherence junction proteins were imaged with immunofluorescence staining. Expression of Toll-like receptors (TLR) and inflammatory cytokines were measured in loop ileostomy takedowns in a second group of patients. RESULTS: Because TER increased with patient age (P < .01), results were stratified into infant versus teenage groups. Fed bowel had significantly greater TER versus unfed bowel (P < .05) in both age populations. Loss of EBF was also observed by an increase in FITC-dextran permeation in enteral nutrient-deprived segments (P < .05). Immunofluorescence staining showed marked declines in intensity of ZO-1, occludin, E-cadherin, and claudin-4 in unfed intestinal segments, as well as a loss of structural formation of tight junctions. Analysis of cytokine and TLR expression showed significant increases in tumor necrosis factor (TNF)-alpha and TLR4 in unfed segments of bowel compared with fed segments from the same individual. CONCLUSION: EBF declined in unfed segments of human small bowel. This work represents the first direct examination of EBF from small bowel derived from nutrient-deprived humans and may explain the increased incidence of infectious complications seen in patients not receiving enteral feeds. PMID- 25704424 TI - Impact of the European Working Time Directive (EWTD) on the operative experience of surgery residents. AB - BACKGROUND: In Europe and the United States, work hour restrictions are considered to be particularly burdensome for residents in surgery specialties. The aim of this study was to examine whether reduction of the work week to 48 hours resulting from the implementation of the European Working Time Directive has affected the operative experience of surgery residents. METHODS: This study was conducted in a general surgery training region in the Netherlands, consisting of 1 university hospital and 6 district training hospitals. Operating records summarizing the surgical procedures performed as "primary surgeon" in the operating theater for different grades of surgeons were retrospectively analyzed for the period 2005-2012 by the use of linear regression models. Operative procedures performed by residents were considered the main outcome measure. RESULTS: In total, 235,357 operative procedures were performed, including 47,458 (20.2%) in the university hospital and 187,899 (79.8%) in the district training hospitals (n = 5). For residents in the university hospital, the mean number of operative procedures performed per 1.0 full-time equivalent increased from 128 operations in 2005 to 204 operations in 2012 (P = .001), whereas for residents in district training hospitals, no substantial differences were found over time. The mean (+/-SD) operative caseload of 64 residents who completed the 6-year training program between 2005 and 2012 was 1,391 +/- 226 (range, 768-1856). A comparison of the operative caseload according to year of board-certification showed no difference. CONCLUSION: Implementation of the European Working Time Directive has not affected adversely the number of surgical procedures performed by residents within a general surgical training region in the Netherlands. PMID- 25704425 TI - Mid-term outcomes of self-expanding covered stent grafts for repair of popliteal artery aneurysms. AB - BACKGROUND: Enthusiasm for endovascular therapies has led to the use of stent graft repairs for popliteal artery aneurysms. In this report, we review our experience with this technique. METHODS: A retrospective review was performed of all endovascular popliteal artery aneurysm repairs (EVPARs) performed by the vascular surgery group at a tertiary care medical center. Patient demographic data, operative details, and outcomes were examined. RESULTS: We performed 33 EVPARs in 28 patients. All patients were male with a mean age of 76 years (range, 60-91). Mean aneurysm diameter was 3.2 cm (range, 1.5-6.3). All repairs were performed using a self-expanding covered stent graft. Among the patients, 18% were symptomatic at the time of repair. The median number of stents used was 2 (range, 1-4). Median duration of stay was 1 day (range, 0-12). The 1-year and 2 year patency were 87% and 81%, respectively, with a mean follow-up of 23 months. Loss of patency was associated with both poor distal runoff (P = .007) and increasing number of stents used (P = .03). Early complications were seen in 4 patients including: stent oversizing leading to in-folding, perforation of a tibial artery, access site hematoma, and access vessel dissection. CONCLUSION: As experience with EVPAR continues to grow, caution must be applied in its use. Careful patient selection, proper operative technique, and correct vessel sizing are required for good outcomes. Poor distal runoff and use of numerous stents leads to diminished patency rates. PMID- 25704426 TI - Vein resections >3 cm during pancreatectomy are associated with poor 1-year patency rates. AB - BACKGROUND: Resection of the superior mesenteric vein (SMV) and portal vein (PV) involved in pancreatic neoplasms improves the chances of complete tumor removal. No consensus exists, however, on the optimal reconstructive approach, and postoperative venous stenosis in the first 6 months to 1 year can cause patient morbidity. We investigated medium-term patency after direct, end-to-end venous anastomosis and evaluate predictive factors for stenosis or occlusion. METHODS: We analyzed retrospectively the records of 810 patients who underwent pancreatectomy at our institution from January 2000 through April 2014, and 197 patients who underwent concurrent SMV/PV resection were selected. The venous anastomosis was assessed every 4 or 6 months postoperatively by the use of portography with computed tomography. Preoperative and intraoperative variables were evaluated for their possible association with the development of severe anastomotic stenosis (>=70% occlusion). RESULTS: Among patients whose cancer did not recur during the 1-year follow-up period, 18 developed severe stenosis. Univariate analyses showed that operation time >=520 minutes and length of SMV/PV resection >=31 mm were associated with the development of severe anastomotic stenosis. Multivariate analysis showed that length of SMV/PV resection >=31 mm was among independent predictors of medium-term, severe anastomotic stenosis (hazard ratio, 5.96; 95% confidence interval 1.79-22.69; P = .003). CONCLUSION: Direct end-to-end anastomosis of the PV system is safe and offers patients with periampullary neoplasia improved chances of complete tumor excision. When tension free anastomosis cannot be guaranteed, generally in cases requiring >=31 mm of SMV/PV resection, venous autografting may decrease the likelihood of anastomotic stenosis. PMID- 25704427 TI - Reconsidering the ethics of sham interventions in an era of emerging technologies. AB - BACKGROUND: Our aim was to ethically evaluate the arguments in favor and against sham interventions, as presented in literature. Two developments underscore the need to reconsider the ethics of sham interventions. First, the number of clinical trials investigating interventions in the field of regenerative medicine are increasing, in which the choice for a placebo requires an invasive intervention. Second, the increased awareness of the lack of systematic research in surgery stresses the need to discuss the necessity and acceptability of sham controlled clinical trials. METHODS: A systematic search in Medline was performed, of which 104 articles were considered relevant. RESULTS: Arguments in favor of a sham controlled design are that it increases the scientific validity and the benefits to society while at the same time the risks and harm can be acceptable. Arguments against sham controls include that they pose unacceptable risks to participants, present difficulties with informed consent, that the use of deceptive tactics is unethical, and that the feasibility of such controls is compromised because of a lack of public support. CONCLUSION: None of the published literature fully rejects sham interventions, and many regard sham interventions acceptable provided the conditions of scientific necessity, reasonable risks, and valid informed consent are fulfilled. Further debate should no longer address whether a sham control is ethically acceptable but rather when these conditions are fulfilled. PMID- 25704428 TI - Extended liver resections for intrahepatic cholangiocarcinoma: friend or foe? AB - BACKGROUND: In patients with intrahepatic cholangiocarcinoma (ICC), extended liver resections (ELRs) increase the rate of resectability. The aims of the present study were to evaluate the morbidity and oncologic outcomes of ELR compared with other liver resections (LR) for ICC. METHODS: All LR for ICC that were performed in our center between January 1997 and September 2013 and conducted with curative intent were included in this retrospective analysis. ELRs were defined by resections of >=5 liver segments. The factors that influenced the occurrence of major complications (Clavien >= 3) and overall survival (OS) were tested with univariate and multivariate analyses. RESULTS: One hundred seven patients (82 men and 25 women) were resected, and 27 (25.3%) underwent ELRs. Compared with the LRs, the ELRs were performed in larger tumors (P = .003) and were significantly associated with more complex surgeries such as vascular (P < .001) or biliary reconstructions (P < .001). Multivariate analysis revealed that ELR was an independent risk factor for major complications (odds ratio [OR], 6.2; 95% CI, 2.11-19.62; P < .001). Compared with the other LRs, ELRs had no effects on OS or disease-free survival (P = .881 and P = .228, respectively). Perioperative blood transfusion (Hazard ratio (HR), 2.51; 95% CI, 1.49-4.23; P < .001), the presence of >1 nodule (HR, 3.17; 95% CI, 1.67-5.97; P < .001), and age >=65 years (HR, 1.72; 95% CI, 1.03-2.86; P = .036) were independent prognostic factors for OS. CONCLUSION: This study suggests that ELRs performed for large ICCs do not affect negatively oncologic outcomes, despite the increased risk of major complications. PMID- 25704429 TI - Long-term outcomes after prophylactic bursectomy in patients with resectable gastric cancer: Final analysis of a multicenter randomized controlled trial. AB - BACKGROUND: Bursectomy, a traditional operative procedure to remove the peritoneal lining covering the pancreas and the anterior plane of the transverse mesocolon, has been performed for serosa-positive gastric cancer in Japan and Eastern Asia. We conducted a multicenter, randomized, controlled trial to demonstrate the noninferiority of the omission of bursectomy. METHODS: Between July 2002 and January 2007, 210 patients with cT2-3 gastric adenocarcinoma were randomized intraoperatively to D2 gastrectomy with or without bursectomy. The primary endpoint was overall survival (OS). We provide the results of the final analysis of the complete 5-year follow-up data. RESULTS: After the median follow up of 80 months, 5-year OS was 77.5% for the bursectomy group and 71.3% for the nonbursectomy group (2-sided P = .16 for superiority; 1-sided P = .99 for noninferiority). The hazard ratio for death in the nonbursectomy group was 1.40 (95% CI, 0.87-2.25). The 5-year recurrence-free survivals were 73.7% and 66.6% in the bursectomy and nonbursectomy groups, respectively (2-sided P = .33 for superiority; 1-sided P = .99 for noninferiority). Cox multivariate analysis revealed that bursectomy was an independent prognostic factor of good OS (P = .033). Subgroup analysis showed a trend toward improved survival after bursectomy for tumors in the middle or lower third of the stomach and for pathologically serosa-positive tumors. CONCLUSION: The final analysis could not demonstrate the noninferiority of the omission of bursectomy. Bursectomy should not be abandoned as a futile procedure. PMID- 25704430 TI - Laparoscopic distal pancreatectomy employing radical en bloc procedure for adenocarcinoma: Technical details and outcomes. AB - BACKGROUND: Although laparoscopic distal pancreatectomy (LDP) has increasingly gained popularity, there are only a few reports mentioning application and outcomes of LDP for adenocarcinoma of the body and tail of the pancreas. The aim of our study is to demonstrate technical details of LDP employing radical en bloc procedure (en bloc LDP) and to evaluate the short- and long-term outcomes of en bloc LDP applied for adenocarcinoma. METHODS: We evaluated 23 consecutive patients who underwent LDP for adenocarcinoma in the body or tail of the pancreas. Our concepts of en bloc LDP for adenocarcinoma comprise 3 principles: en bloc removal of retroperitoneal structures, lymph node (LN) dissection, and preservation of the spleen. RESULTS: En bloc LDP without splenectomy was performed in 17 patients (74%) and en bloc LDP with splenectomy was in 6 patients (26%). Mean +/- standard deviation operation time was 203 +/- 54 minutes, and mean estimated blood loss was 208 +/- 264 mL. Conversion to open distal pancreatectomy was required in 1 patient (4%) owing to the severe adhesions around the pancreas. The overall morbidity rate following en bloc LDP was 47% (n = 11), and the rate of pancreatic fistula was 39% (n = 9). There were no 30-day or in-hospital mortalities. Mean tumor size was 32 +/- 12 mm, and mean number of harvested LNs was 19.8 +/- 9.3. No patient had positive margins on final histologic diagnosis. The 1-, 3-, and 5-year overall survival rates were 67%, 49%, and 33%, respectively. CONCLUSION: En bloc LDP can be applied safely by the surgeon with advanced experience in minimally invasive surgery with satisfactory short- and long-term outcomes, supporting further application of LDP for adenocarcinoma with advances in operative techniques and technological innovations. PMID- 25704431 TI - Secretome from human adipose-derived stem cells protects mouse liver from hepatic ischemia-reperfusion injury. AB - BACKGROUND: Despite widespread interest in stem cells, their clinical application is largely limited owing to safety and cost concerns. We intended to overcome these limitations by evaluating whether the secretome of human adipose tissue derived stem cells (ASCs) could be used to reverse ischemia/reperfusion (IR) injury in mice. METHODS: After establishment of hepatic IR injury in BALB/c mice, the mice were infused with saline solution (saline group), 1.0 * 106 human ASCs (ASC group), 25-fold-concentrated ASC-conditioned medium (ASC-secretome group), which was the same volume as used for the ASC infusion, or concentrated control medium (medium-only group). After reperfusion, we obtained serum and liver specimens and compared parameters reflecting the degree of injury and mechanisms between the groups. RESULTS: At 6 hours after reperfusion, serum interleukin (IL) 6 levels were decreased in both ASC and ASC-secretome groups (P < .05). At 12 and 24 hours after reperfusion, both ASC and ASC-secretome groups also demonstrated lesser histologic scores than did their controls (P < .05). In addition, the decreases in the expression of the cell adhesion markers intercellular adhesion molecule-1 and platelet-endothelial cell adhesion molecule-1 and in neutrophil infiltration into the liver were noted in the ASC-secretome group as well as in the ASC group. CONCLUSION: ASC and ASC-secretome infusions both alleviated liver damage and improved the liver microenvironment after hepatic IR injury. Our results indicate that the therapeutic potential of ASCs may result from a paracrine effect mediated by the ASC secretome; our work suggests a novel secretome-based therapeutic strategy to treat hepatic IR injury. PMID- 25704432 TI - Selective removal of erythromycin by magnetic imprinted polymers synthesized from chitosan-stabilized Pickering emulsion. AB - Magnetic imprinted polymers (MIPs) were synthesized by Pickering emulsion polymerization and used to adsorb erythromycin (ERY) from aqueous solution. The oil-in-water Pickering emulsion was stabilized by chitosan nanoparticles with hydrophobic Fe3O4 nanoparticles as magnetic carrier. The imprinting system was fabricated by radical polymerization with functional and crosslinked monomer in the oil phase. Batches of static and dynamic adsorption experiments were conducted to analyze the adsorption performance on ERY. Isotherm data of MIPs well fitted the Freundlich model (from 15 degrees C to 35 degrees C), which indicated heterogeneous adsorption for ERY. The ERY adsorption capacity of MIPs was about 52.32 MUmol/g at 15 degrees C. The adsorption kinetics was well described by the pseudo-first-order model, which suggested that physical interactions were primarily responsible for ERY adsorption. The Thomas model used in the fixed-bed adsorption design provided a better fit to the experimental data. Meanwhile, ERY exhibited higher affinity during adsorption on the MIPs compared with the adsorption capacity of azithromycin and chloramphenicol. The MIPs also exhibited excellent regeneration capacity with only about 5.04% adsorption efficiency loss in at least three repeated adsorption-desorption cycles. PMID- 25704433 TI - Enhanced removal of Zn(2+) or Cd(2+) by the flocculating Chlorella vulgaris JSC 7. AB - Microalgae are attracting attention due to their potentials in mitigating CO2 emissions and removing environmental pollutants. However, harvesting microalgal biomass from diluted cultures is one of the bottlenecks for developing economically viable processes for this purpose. Microalgal cells can be harvested by cost-effective sedimentation when flocculating strains are used. In this study, the removal of Zn(2+) and Cd(2+) by the flocculating Chlorella vulgaris JSC-7 was studied. The experimental results indicated that more than 80% Zn(2+) and 60% Cd(2+) were removed by the microalgal culture within 3 days in the presence up to 20.0mg/L Zn(2+) and 4.0mg/L Cd(2+), respectively, which were much higher than that observed with the culture of the non-flocculating C. vulgaris CNW11. Furthermore, the mechanism underlying this phenomenon was explored by investigating the effect of Zn(2+) and Cd(2+) on the growth and metabolic activities of the microalgal strains. It was found that the flocculation of the microalga improved its growth, synthesis of photosynthetic pigments and antioxidation activity under the stressful conditions, indicating a better tolerance to the heavy metal ions for a potential in removing them more efficiently from contaminated wastewaters, together with a bioremediation of other nutritional components contributed to the eutrophication of aquatic ecosystems. PMID- 25704434 TI - Effect of soil properties on the toxicity of Pb: assessment of the appropriateness of guideline values. AB - Soil contamination with lead is a worldwide problem. Pb can cause adverse effects, but its mobility and availability in the terrestrial environment are strongly controlled by soil properties. The present study investigated the influence of different soil properties on the solubility of lead in laboratory spiked soils, and its toxicity in three bioassays, including Lactuca sativa root elongation and Vibrio fischeri illumination tests applied to aqueous extracts and basal soil respiration assays. Final aim was to compare soil-dependent toxicity with guideline values. The L. sativa bioassay proved to be more sensitive to Pb toxicity than the V. fischeri and soil respiration tests. Toxicity was significantly correlated with soil properties, with soil pH, carbonate and organic carbon content being the most important factors. Therefore, these variables should be considered when defining guideline values. PMID- 25704435 TI - Preparation and characterization of an organic/inorganic hybrid sorbent (PLE) to enhance selectivity for As(V). AB - For the selective removal of arsenate (As(V)) a hybrid sorbent was prepared using a non-toxic natural organic material, chitosan, by loading a transition metal, nickel. The immobilization of nickel was achieved by coordination with a deprotonated amino group (NH2) in the chitosan polymer chain. The amount of nickel was directly correlated to the presence of the amino group and was calculated to be 62 mg/g. FTIR spectra showed a peak shift from 1656 to 1637 cm( 1) after Ni(2+) loading, indicating the complexation between the amino group and nickel, and a peak of As(V) was observed at 834 cm(-1). An increase of sulfate concentration from 100 mg/L to 200 mg/L did not significantly affect As(V) sorption, and an increase in the concentration of bicarbonate reduced the As(V) uptake by 33%. The optimal pH of the solution was determined at pH 10, which is in accordance with the fraction of HAsO4(2-) and AsO4(-3). According to a fixed column test, a break through behavior of As(V) revealed that selectivity for As(V) was over sulfate. Regeneration using 5% NaCl extended the use of sorbent to up to uses without big loss of sorption capacity. PMID- 25704436 TI - Nivolumab for advanced squamous cell lung cancer: what are the next steps? PMID- 25704437 TI - Hormone therapy increases ovarian cancer risk. PMID- 25704438 TI - Gene mutation order affects cancer behaviour. PMID- 25704439 TI - Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. AB - BACKGROUND: Patients with squamous non-small-cell lung cancer that is refractory to multiple treatments have poor outcomes. We assessed the activity of nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, for patients with advanced, refractory, squamous non-small-cell lung cancer. METHODS: We did this phase 2, single-arm trial at 27 sites (academic, hospital, and private cancer centres) in France, Germany, Italy, and USA. Patients who had received two or more previous treatments received intravenous nivolumab (3 mg/kg) every 2 weeks until progression or unacceptable toxic effects. The primary endpoint was the proportion of patients with a confirmed objective response as assessed by an independent radiology review committee. We included all treated patients in the analyses. This study is registered with ClinicalTrials.gov, number NCT01721759. FINDINGS: Between Nov 16, 2012, and July 22, 2013, we enrolled and treated 117 patients. 17 (14.5%, 95% CI 8.7-22.2) of 117 patients had an objective response as assessed by an independent radiology review committee. Median time to response was 3.3 months (IQR 2.2-4.8), and median duration of response was not reached (95% CI 8.31-not applicable); 13 (77%) of 17 of responses were ongoing at the time of analysis. 30 (26%) of 117 patients had stable disease (median duration 6.0 months, 95% CI 4.7-10.9). 20 (17%) of 117 patients reported grade 3-4 treatment-related adverse events, including: fatigue (five [4%] of 117 patients), pneumonitis (four [3%]), and diarrhoea (three [3%]). There were two treatment associated deaths caused by pneumonia and ischaemic stroke that occurred in patients with multiple comorbidities in the setting of progressive disease. INTERPRETATION: Nivolumab has clinically meaningful activity and a manageable safety profile in previously treated patients with advanced, refractory, squamous non-small cell lung cancer. These data support the assessment of nivolumab in randomised, controlled, phase 3 studies of first-line and second-line treatment. FUNDING: Bristol-Myers Squibb. PMID- 25704440 TI - Weight and body mass index among female contraceptive clients. AB - OBJECTIVES: As obesity may affect the efficacy of some contraceptives, we examined weight, body mass index (BMI) and prevalence of obesity among female contraceptive clients at 231 U.S. health centers. A secondary aim was to analyze differences in contraceptive method use by obesity status. STUDY DESIGN: Cross sectional study using de-identified electronic health record data from family planning centers. We analyzed contraceptive visits made by 147,336 females aged 15-44 years in 2013. RESULTS: A total of 46.1% of clients had BMI >=25. Mean body weight was 154.4 lb (S.D.=41.9); mean BMI was 26.1 (S.D.=6.6). A total of 40% had BMI >=26, when levonorgestrel emergency contraception may become less effective. Obese clients had higher odds of using a tier 1 or tier 3 contraceptive method and had lower odds of using a tier 2 or hormonal method than non-obese clients. CONCLUSIONS: About half of contraceptive clients would be categorized as overweight or obese. Contraceptive method choices differed by obesity status. IMPLICATIONS: About half of contraceptive clients in this study population were overweight or obese. Contraceptive method choices differed by obesity status. All women - regardless of body size - should receive unbiased, evidence-based counseling on the full range of contraceptive options so that they can make informed choices. PMID- 25704441 TI - Risk of infection and disease with Mycobacterium tuberculosis among children identified through prospective community-based contact screening in Indonesia. AB - OBJECTIVE: To identify characteristics of the child contact, index case or environment that are associated with infection or tuberculosis in child contacts in an urban community in Indonesia. METHOD: Children who were close contacts of an index case with pulmonary tuberculosis were screened for infection and disease in Yogyakarta, Indonesia from August 2010 to December 2012. Data of the index case and child were collected prospectively, and all child contacts had clinical assessment, tuberculin skin test (TST) and chest X-ray performed. Those with clinically suspected tuberculosis also had sputum examined by Xpert MTB/RIF and culture. Child contacts were managed according to national guidelines, followed for 12 months and had a final classification of either tuberculosis 'disease', latent tuberculous infection (LTBI) or 'exposed only'. RESULTS: About 269 children of 141 index cases were investigated. Final classification was tuberculosis in 25 (9%) and LTBI in 121 (45%). The risk of infection was significantly greater if the source case was female (AOR 1.7; 95% CI: 1.0-2.8), had sputum smear-positive tuberculosis (AOR 3.0; 95% CI 1.5-6.0) or slept in the same room (AOR 1.7, 95% CI 1.0-2.9). A positive TST was independently associated with a diagnosis of tuberculosis (AOR 7.3; 95% CI 2.4-22). CONCLUSION: This study highlights the high risk and the risk factors associated with tuberculosis and LTBI among child contacts in Indonesia. PMID- 25704442 TI - Proteins interacting with cloning scars: a source of false positive protein protein interactions. AB - A common approach for exploring the interactome, the network of protein-protein interactions in cells, uses a commercially available ORF library to express affinity tagged bait proteins; these can be expressed in cells and endogenous cellular proteins that copurify with the bait can be identified as putative interacting proteins using mass spectrometry. Control experiments can be used to limit false-positive results, but in many cases, there are still a surprising number of prey proteins that appear to copurify specifically with the bait. Here, we have identified one source of false-positive interactions in such studies. We have found that a combination of: 1) the variable sequence of the C-terminus of the bait with 2) a C-terminal valine "cloning scar" present in a commercially available ORF library, can in some cases create a peptide motif that results in the aberrant co-purification of endogenous cellular proteins. Control experiments may not identify false positives resulting from such artificial motifs, as aberrant binding depends on sequences that vary from one bait to another. It is possible that such cryptic protein binding might occur in other systems using affinity tagged proteins; this study highlights the importance of conducting careful follow-up studies where novel protein-protein interactions are suspected. PMID- 25704443 TI - Formation of DNA-copolymer fibrils through an amyloid-like nucleation polymerization mechanism. AB - Conjugation of a hydrophobic poly(2-oxazoline) bearing tertiary amide groups along its backbone with a short single stranded nucleotide sequence results in an amphiphilic comb/graft copolymer, which organizes in fibrils upon direct dissolution in water. Supported by circular dichroism, atomic force microscopy, transmission electron microscopy, and scattering data, fibrils are formed through inter- and intramolecular hydrogen bonding between hydrogen accepting amide groups along the polymer backbone and hydrogen donating nucleic acid grafts leading to the formation of hollow tubes. PMID- 25704444 TI - Oxygen nonstoichiometry, the defect equilibrium model and thermodynamic quantities of the Ruddlesden-Popper oxide Sr3Fe2O(7-delta). AB - Oxygen nonstoichiometry of the Ruddlesden-Popper oxide Sr3Fe2O7-delta was measured at intermediate temperatures (773-1073 K) by coulometric titration and high temperature gravimetry. The oxygen nonstoichiometric behavior was analyzed using the defect equilibrium model with localized electrons. From the defect chemical analysis, estimated oxygen vacancy concentration at the O3 sites increases and at the O1 sites decreases with the increasing temperature. This characteristic behavior is considered to be caused by the redistribution of oxygen and vacancies between the O1 and O3 sites. The obtained thermodynamic quantities of the partial molar enthalpy of oxygen, h(O) - h degrees (O), and the partial molar entropy of oxygen, s(O) - s degrees (O), calculated from the Gibbs Helmholtz equation are in good agreement with those from the statistical thermodynamic calculation based on the defect equilibrium model, indicating that the proposed defect equilibrium model is reasonable. PMID- 25704445 TI - Antibiotic resistance patterns of more than 120 000 clinical Escherichia coli isolates in Southeast Austria, 1998-2013. AB - Antibiotic resistance patterns of more than 120 000 clinical Escherichia coli isolates were retrospectively analysed. Isolates originated from both hospitalized patients and outpatients from the region of southeast Austria from 1998 to 2013. Except for amoxicillin/clavulanic acid, nitrofurantoin and piperacillin/tazobactam, all of the antibiotics analysed showed increasing proportions of resistant isolates over time, which were most prominent for ampicillin (from 25.4% in 1998 to 40% in 2013), cefotaxime (0.1% to 6.7%), ceftazidime (0.3% to 14.2%), ciprofloxacin (4.3% to 16.7%) and trimethoprim/sulfamethoxazole (14.6% to 24.8%). There was a marked increase in extended-spectrum beta-lactamase-positive isolates (0.1% to 6.3%) starting in 2005, with male patients and hospital-related patients showing a higher increase than female patients and outpatients. Proportions of resistant isolates for most antibiotics were generally higher for male patients and hospital-related patients. Amikacin, nitrofurantoin and trimethoprim/sulfamethoxazole showed a marked increase in resistance proportions among male subjects aged 10 to 19 years which were absent for female subjects, indicating a strong modulation potential of host characteristics. PMID- 25704446 TI - Predicted residual activity of rilpivirine in HIV-1 infected patients failing therapy including NNRTIs efavirenz or nevirapine. AB - Rilpivirine is a second-generation nonnucleoside reverse-transcriptase inhibitor (NNRTI) currently indicated for first-line therapy, but its clinical benefit for HIV-1 infected patients failing first-generation NNRTIs is largely undefined. This study quantified the extent of genotypic rilpivirine resistance in viral isolates from 1212 patients upon failure of efavirenz- or nevirapine-containing antiretroviral treatment, of whom more than respectively 80% and 90% showed high level genotypic resistance to the failing NNRTI. Of all study patients, 47% showed a rilpivirine resistance-associated mutation (RPV-RAM), whereas preserved residual rilpivirine activity was predicted in half of the patients by three genotypic drug resistance interpretation algorithms. An NNRTI-dependent impact on rilpivirine resistance was detected. Compared with the use of nevirapine, the use of efavirenz was associated with a 32% lower risk of having a RPV-RAM and a 50% lower risk of predicted reduced rilpivirine susceptibility. Most prevalent RPV RAMs after nevirapine experience were Y181C and H221Y, whereas L100I+K103N, Y188L and K101E occurred most in efavirenz-experienced patients. Predicted rilpivirine activity was not affected by HIV-1 subtype, although frequency of individual mutations differed across subtypes. In conclusion, this genotypic resistance analysis strongly suggests that the latest NNRTI, rilpivirine, may retain activity in a large proportion of HIV-1 patients in whom resistance failed while they were on an efavirenz- or nevirapine-containing regimen, and may present an attractive option for second-line treatment given its good safety profile and dosing convenience. However, prospective clinical studies assessing the effectiveness of rilpivirine for NNRTI-experienced patients are warranted to validate knowledge derived from genotypic and phenotypic drug resistance studies. PMID- 25704447 TI - State-wide surveillance of antibiotic resistance patterns and spa types of methicillin-resistant Staphylococcus aureus from blood cultures in North Rhine Westphalia, 2011-2013. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of bacteraemia. We aimed to obtain a complete picture of severe MRSA infections by characterizing all MRSA isolates from bloodstream infections in the largest German federal state (North Rhine-Westphalia, 18 million inhabitants) using S. aureus protein A (spa) sequence-typing and antimicrobial susceptibility testing. MRSA isolates (n = 1952) were collected prospectively (2011-2013) and spa-typed. Among 181 different spa types, t003 (n = 746 isolates; 38.2%) and t032 (n = 594; 30.4%) were predominant. Analysis of the geographical occurrence of spa clonal complexes (spa-CCs) and spa types revealed divergent distribution between federal state districts for spa-CCs 003 (p < 0.001; including t003, p < 0.001 and t264, p < 0.001), 008 (p 0.021), 011 (p 0.002), 032 (p < 0.001; including t022, p 0.014 and t032, p < 0.001) and spa type t2807 (p < 0.001). MICs of antimicrobial substances were tested using broth microdilution. Of all isolates, 96% were resistant to fluoroquinolones, 78% to erythromycin, 70% to clindamycin, 4% to gentamicin, 2% to rifampicin, 0.4% to daptomycin, 0.1% to linezolid and 0% to vancomycin, respectively. Vancomycin MICs of 2 mg/L involved 0.5% of the isolates. In conclusion, the detection of regional molecular clusters added valuable information for epidemiological case tracing and allowed conclusions to be reached on the importance of newly emerging MRSA reservoirs, such as livestock (spa-CC011), for MRSA bacteraemia in some parts of the federal state. Susceptibility testing revealed broad resistance to substances used for oral treatment, but demonstrated that those antibiotics that are mostly applied for treatment of MRSA bacteraemia and important combination partners were highly susceptible. PMID- 25704448 TI - Viruses detected by systematic multiplex polymerase chain reaction in adults with suspected community-acquired pneumonia attending emergency departments in France. AB - Infectious agents associated with community-acquired pneumonia (CAP) are under studied. This study attempted to identify viruses from the upper respiratory tract in adults visiting emergency departments for clinically suspected CAP. Adults with suspected CAP enrolled in the ESCAPED study (impact of computed tomography on CAP diagnosis) had prospective nasopharyngeal (NP) samples studied by multiplex PCR (targeting 15 viruses and four intracellular bacteria). An adjudication committee composed of infectious disease specialists, pneumologists and radiologists blinded to PCR results reviewed patient records, including computed tomography and day 28 follow up, to categorize final diagnostic probability of CAP as definite, probable, possible, or excluded. Among the 254 patients enrolled, 78 (31%) had positive PCR, which detected viruses in 72/254 (28%) and intracellular bacteria in 8 (3%) patients. PCR was positive in 44/125 (35%) patients with definite CAP and 21/83 (25%) patients with excluded CAP. The most frequent organisms were influenza A/B virus in 27 (11%), rhinovirus in 20 (8%), coronavirus in seven (3%), respiratory syncytial virus in seven (3%) and Mycoplasma pneumoniae in eight (3%) of 254 patients. Proportion of rhinovirus was higher in patients with excluded CAP compared with other diagnostic categories (p = 0.01). No such difference was observed for influenza virus. Viruses seem common in adults attending emergency departments with suspected CAP. A concomitant clinical, radiological and biological analysis of the patient's chart can contribute to either confirm their role, or suggest upper respiratory tract infection or shedding. Their imputability and impact in early management of CAP deserve further studies. CLINICAL TRIALS REGISTRATION: NCT01574066. PMID- 25704449 TI - Subtalar Joint Distraction Arthrodesis to Correct Calcaneal Valgus in Pediatric Patients with Tarsal Coalition: A Case Series. AB - Subtalar joint middle facet coalitions commonly present in children who have a painful, rigid, pes planovalgus foot type. The middle facet coalition allows rearfoot forces to be distributed medially through the coalition, and this can result in arthritis or lateral tarsal wedging. The senior author has used a wedged bone graft distraction subtalar joint arthrodesis to correct calcaneal valgus and restore the talar height in these patients. The tight, press-fit nature of the tricortical iliac crest allograft provides stability and can negate the need for internal fixation. We retrospectively reviewed 9 pediatric subtalar joint distraction arthrodesis procedures performed on 8 patients during a 6-year period. All patients began weightbearing at 6 weeks after surgery. All patients had osseous union, and no complications developed that required a second surgery. The clinical outcomes, assessed at a mean of 25.5 (range, 6.3 to 75.8) months postoperatively, were satisfactory. The mean American Orthopaedic Foot and Ankle Society score was 90.1 (range, 79 to 94), on a 94-point scale. The wedged distraction arthrodesis technique has not been previously described for correction of pediatric patients with lateral tarsal wedging, but it is an effective option and yields successful outcomes. PMID- 25704450 TI - The pertussis problem: classical epidemiology and strain characterization should go hand in hand. PMID- 25704452 TI - Analysis of miRNA expression patterns in human and mouse hepatocellular carcinoma cells. AB - AIM: Hepatocellular carcinoma (HCC), one of the most common malignancies in adults displays aberrant miRNA expression during its pathogenesis. We assessed expression of miRNA in surgically resected human HCC of an early stage and murine HCC with a high malignancy in order to find miRNA overexpressed in HCC regardless of tumor stage and underlying etiology. Further, the role of the deregulated miRNA in HCC pathogenesis was investigated. METHODS: miRNA were isolated from HCC tissues and surrounding non-tumorous tissues from HCC patients and a murine transgenic model of HCC. A quantitative reverse transcription polymerase chain reaction was performed to determine expression levels of miRNA. Human HCC cell lines stably expressing individual miRNA were generated to investigate the biological function of overexpressed miRNA. RESULTS: We found that levels of miR 221, -181b-1, -155-5p, -25 and -17-5p were significantly upregulated in both human and murine HCC regardless of tumor stage, underlying etiology or the presence of fibrosis. Using HCC cell lines stably expressing respective miRNA, we found that miR-221 increased the proliferation of hepatoma cells, while miR-17-5p induced cell migration. CONCLUSION: We identified miRNA that are consistently upregulated in HCC. The overexpressed miRNA could potentially be used as a bona fide biomarker for HCC. PMID- 25704453 TI - Multiple anatomical variations of the renal vessels associated with malrotated and unrotated kidneys: a case report. AB - Variations in the number of renal vessels represent the most common anatomical variations in renal vasculature. Here, a rare case of multiple anatomical variations of renal vessels was found in a 70-year-old female cadaveric dissection. Three renal arteries and two renal veins were observed to supply the right kidney, which was malrotated and ectopic; on the left side, the kidney was unrotated and presented two renal arteries and normal renal vein. In particular, we paid attention to the pattern of the three renal arteries that originated from the lateral side of the aorta and passed anteriorly to the inferior vena cava. A rare case of ovarian vein that drained into the right renal vein was also reported. The descriptions of these multiple anatomical variations should be considered by clinicians for performing correct surgical and radiological procedures. PMID- 25704454 TI - Psychophysical "blinding" methods reveal a functional hierarchy of unconscious visual processing. AB - Numerous non-invasive experimental "blinding" methods exist for suppressing the phenomenal awareness of visual stimuli. Not all of these suppressive methods occur at, and thus index, the same level of unconscious visual processing. This suggests that a functional hierarchy of unconscious visual processing can in principle be established. The empirical results of extant studies that have used a number of different methods and additional reasonable theoretical considerations suggest the following tentative hierarchy. At the highest levels in this hierarchy is unconscious processing indexed by object-substitution masking. The functional levels indexed by crowding, the attentional blink (and other attentional blinding methods), backward pattern masking, metacontrast masking, continuous flash suppression, sandwich masking, and single-flash interocular suppression, fall at progressively lower levels, while unconscious processing at the lowest levels is indexed by eye-based binocular-rivalry suppression. Although unconscious processing levels indexed by additional blinding methods is yet to be determined, a tentative placement at lower levels in the hierarchy is also given for unconscious processing indexed by Troxler fading and adaptation-induced blindness, and at higher levels in the hierarchy indexed by attentional blinding effects in addition to the level indexed by the attentional blink. The full mapping of levels in the functional hierarchy onto cortical activation sites and levels is yet to be determined. The existence of such a hierarchy bears importantly on the search for, and the distinctions between, neural correlates of conscious and unconscious vision. PMID- 25704455 TI - Heterotrimeric G protein mediates ethylene-induced stomatal closure via hydrogen peroxide synthesis in Arabidopsis. AB - Heterotrimeric G proteins function as key players in hydrogen peroxide (H2O2) production in plant cells, but whether G proteins mediate ethylene-induced H2O2 production and stomatal closure are not clear. Here, evidences are provided to show the Galpha subunit GPA1 as a missing link between ethylene and H2O2 in guard cell ethylene signalling. In wild-type leaves, ethylene-triggered H2O2 synthesis and stomatal closure were dependent on activation of Galpha. GPA1 mutants showed the defect of ethylene-induced H2O2 production and stomatal closure, whereas wGalpha and cGalpha overexpression lines showed faster stomatal closure and H2O2 production in response to ethylene. Ethylene-triggered H2O2 generation and stomatal closure were impaired in RAN1, ETR1, ERS1 and EIN4 mutants but not impaired in ETR2 and ERS2 mutants. Galpha activator and H2O2 rescued the defect of RAN1 and EIN4 mutants or etr1-3 in ethylene-induced H2O2 production and stomatal closure, but only rescued the defect of ERS1 mutants or etr1-1 and etr1 9 in ethylene-induced H2O2 production. Stomata of CTR1 mutants showed constitutive H2O2 production and stomatal closure, but which could be abolished by Galpha inhibitor. Stomata of EIN2, EIN3 and ARR2 mutants did not close in responses to ethylene, Galpha activator or H2O2, but do generate H2O2 following challenge of ethylene or Galpha activator. The data indicate that Galpha mediates ethylene-induced stomatal closure via H2O2 production, and acts downstream of RAN1, ETR1, ERS1, EIN4 and CTR1 and upstream of EIN2, EIN3 and ARR2. The data also show that ETR1 and ERS1 mediate both ethylene and H2O2 signalling in guard cells. PMID- 25704456 TI - Synthesis of mesoporous wall-structured TiO2 on reduced graphene oxide nanosheets with high rate performance for lithium-ion batteries. AB - Mesoporous wall-structured TiO2 on reduced graphene oxide (RGO) nanosheets were successfully fabricated through a simple hydrothermal process without any surfactants and annealed at 400 degrees C for 2 h under argon. The obtained mesoporous structured TiO2 -RGO composites had a high surface area (99 0307 m(2) g(-1)) and exhibited excellent electrochemical cycling (a reversible capacity of 260 mAh g(-1) at 1.2 C and 180 mAh g(-1) at 5 C after 400 cycles), demonstrating it to be a promising method for the development of high-performance Li-ion batteries. PMID- 25704457 TI - Cyclic stretching of soft substrates induces spreading and growth. AB - In the body, soft tissues often undergo cycles of stretching and relaxation that may affect cell behaviour without changing matrix rigidity. To determine whether transient forces can substitute for a rigid matrix, we stretched soft pillar arrays. Surprisingly, 1-5% cyclic stretching over a frequency range of 0.01-10 Hz caused spreading and stress fibre formation (optimum 0.1 Hz) that persisted after 4 h of stretching. Similarly, stretching increased cell growth rates on soft pillars comparative to rigid substrates. Of possible factors linked to fibroblast growth, MRTF-A (myocardin-related transcription factor-A) moved to the nucleus in 2 h of cyclic stretching and reversed on cessation; but YAP (Yes-associated protein) moved much later. Knockdown of either MRTF-A or YAP blocked stretch dependent growth. Thus, we suggest that the repeated pulling from a soft matrix can substitute for a stiff matrix in stimulating spreading, stress fibre formation and growth. PMID- 25704458 TI - The reliability of Cameriere's method in Turkish children: a preliminary report. AB - Dental age estimation in children is an important issue both legally and medically. Currently, however, there is a lack of contemporary dental age estimation standards for a Turkish population. This study assessed the accuracy of Cameriere's method by examining the panoramic radiographs of 573 healthy Turkish children between the ages of 8 and 15 years. Radiographs of the left permanent developing mandibular teeth, except wisdom teeth, were evaluated. All subjects were divided into 7 groups according to their chronological age. The Intra-class Correlation Coefficient was used to determine the intra- and inter observer agreement error. A comparison of the distributions of estimation errors among age groups was performed using the Nemenyi test. There were no significant differences between inter-observer (p=0.352), and intra-observer readings after 2 weeks (p=0.275 and p=0.273, respectively). The dental age was underestimated when using Cameriere's method with a mean difference of -0.35 years (-0.24 years for girls and -0.47 years for boys). The median values of the differences between dental and chronological age were -0.44 years in boys (range: -3.70, 4.06) and 0.21 years in girls (range: -2.74, 3.29). In addition, the differences between dental and chronological ages in the different age groups decreased with increasing chronological age. Results from the Nemenyi test implied that Cameriere's method is more accurate for girls than for boys in this cohort of a Turkish population. PMID- 25704459 TI - The 'too muchness' of excitement: sexuality in light of excess, attachment and affect regulation. AB - This paper brings together contemporary thinking about early attachment and affect regulation with our clinical and theoretical understanding of the problems of adult sexuality. In addition to recent theories of affect regulation and attachment, we incorporate Laplanche's idea of 'excess', which was an important transitional concept integrating real experience with fantasy in sexuality. We elaborate the idea of excess-- 'too-muchness' --to illuminate the early overwhelming of the psyche that affects the formation of sexuality. Linked to recent theoretical developments, this idea helps to grasp the relationship between sexual excitement and early affect regulation, showing how excitement becomes dangerous, thus impeding or distorting desire. The 'too-muchness' of excitement recalls the experience of being a stimulated, overwhelmed, unsoothed child and influences later inability to tolerate sexual arousal and the excitement affect. A clinical case illustrates this connection between attachment trauma, anxiety about sexuality, as well as shameful experiences of gender identity as an area of trauma. We emphasize the importance of working through the terrors and desires of the mother-baby relationship as they emerge in the transference-countertransference in order to develop the ability to hold excitement and stimulation without experiencing the too-much as the intolerable. This includes the working-through of ruptures related to overstimulation as well as the delicate balance of attention to fantasy and intersubjective work in the transference. PMID- 25704460 TI - Repeatability of in vitro power profile measurements for multifocal contact lenses. AB - PURPOSE: To evaluate the repeatability of an optical device (NIMO TR1504, Lambda X, Belgium) for measuring multifocal contact lens power profiles. METHODS: The NIMO TR1504 was used to measure power profiles 30 times for each of 10 different contact lenses from 4 major companies. All contact lenses were labelled as -3D for distance vision; half were for high addition and half for low addition. The optical zone in all measurements was set to 3-mm radius. For each lens, the median power profile and the residuals of the 30 measurements were calculated. The 95% confidence bands and two indices that summarize measurement errors were calculated: the repeatability limit and an index of repeatability heterogeneity, quantifying heterogeneity of measurement errors over the optical zone. RESULTS: The repeatability limit was good (from 0.04D to 0.12D), for all multifocal contact lenses. Variability of measurement errors of power profiles was quite homogeneous along the optical zone for all lenses, although for some lenses variability was slightly higher in the centre than peripherally. CONCLUSIONS: The repeatability of measured power profiles obtained by the NIMO TR1504 is lower than 0.12D for the multifocal contact lenses. PMID- 25704461 TI - Assessment of corneal thickness and tear meniscus during contact-lens wear. AB - PURPOSE: To assess the effect of seven different daily disposable contact lenses upon corneal thickness, as well as upon tear meniscus volume, by using optical coherence tomography (OCT). METHODS: Thirty-four young healthy subjects wore seven different types of daily disposable soft contact lenses, each for a period of 12h: Delefilcon A, Nelfilcon A, Omafilcon A, Filcon II3, Narafilcon A, Etafilcon A and Hilafilcon B. Central and mid-peripheral corneal thickness and lower tear meniscus volume (TMV) were measured using an OCT device during contact lens wear at 4-h intervals throughout a 12-h period. Measurements were also recorded without any contact lenses being worn during a day. RESULTS: In the no lens scenario a small but significant (p<0.05) thinning in the cornea was observed after the 12-h period. Overall, as for contact-lens wear, it was the Hilafilcon B lens that caused the greatest thickness increase in the central area, whereas the Etafilcon A caused it in the mid-peripheral cornea. Delefilcon A was the lens that showed the most similar behavior to the naked eye. As for TMV, it decreased with all the lenses, but it was the Delefilcon A lens the one that caused the smallest drop in TMV (p=0.007). CONCLUSIONS: OCT makes it possible to evaluate both corneal thickness variations and TMV changes as a result of contact-lens wear. The changes in corneal thickness hereafter presented are not clinically significant. On the other hand, TMV drop could indicate discomfort for contact-lens users. PMID- 25704462 TI - Sagittal height differences of frequent replacement silicone hydrogel contact lenses. AB - PURPOSE: This study aims to evaluate the sagittal height differences among a selection of commercially available monthly or two weekly replacement silicone hydrogel soft lenses. METHODS: The sagittal height (CL-SAG) of four frequent replacement silicone hydrogel lenses (lotrafilcon B, balafilcon A, comfilcon A and senofilcon A) was measured for all base curve radius manufactured in spherical (-3.00D and +3.00D) and toric (=C-0.75*180 degrees ) designs (11 spherical and 8 toric lenses in total). Two different lenses of each lens type were evaluated (the intra CL-SAG) using the SHSOphthalmic omniSpect by Optocraft. RESULTS: The intra CL-SAG difference (the difference between two identical lenses from the same batch) was 11+/-SD 2MUm. The CL-SAG of all minus lenses ranged from 3454 to 3765MUm (an inter CL-SAG difference of 311MUm), while the plus spherical lenses ranged from 3493 to 3757MUm (inter CL-SAG difference 264MUm). In the toric lens group, the range in toric minus lenses was 3495-3953MUm (inter CL-SAG difference 458MUm) and 3493-3980MUm in the plus group (inter CL-SAG difference 487MUm). The inter CL-SAG difference between the spherical and the toric lenses was statistically significant (p=0.03). CONCLUSION: Marked differences in sagittal height among different commercially available frequent replacement silicone hydrogel lenses exist. Different lenses with the same package base curve value had marked differences in CL-SAG, with potential clinical significance on eye in terms of lens behavior. The inter CL-SAG variance in the spherical lens group was smaller than in the toric lens group. PMID- 25704463 TI - Low toric soft contact lens acceptance study. AB - PURPOSE: The aim of the study was to evaluate the objective and subjective visual performance of custom toric contact lenses (TL) and their spherical off-the-shelf counterparts (SL) in subjects with low amounts of astigmatism. METHODS: Twenty three habitual soft lens wearers (40 eyes, 25-35 years) manifesting 0.50-1.00DC and <=+/-3.00DS were recruited. Air Optix Aqua (Lotrafilcon B) was fit using the spherical equivalent of the manifest refraction. Intelliwave toric in Efrofilcon A (Definitive) was fit using the manifest refraction and keratometric data. Comprehensive visual performance tests were done through manifest refraction in a trial frame; in SL; and in TL. A subjective evaluation of quality of vision was also obtained. RESULTS: ANOVA revealed that, at the morning visit (AM), high contrast logMAR distance visual acuity (HCDVA) was significantly better (p<0.01) in spectacles as compared to SL. A similar trend was noted at the afternoon visit (PM). In addition, at the PM visit, HCDVA was significantly better (p<0.01) for TL as compared to their SL. ANOVA revealed that, at the PM visit, low contrast distance visual acuity (LCDVA) was significantly better (p=0.05) in spectacles as compared to SL. None of these differences were clinically significant. In addition, no statistically significant difference (p>0.05) in subjective vision rating scores was noted between SL and TL. CONCLUSIONS: The present investigation found no clinically significant difference in visual performance between spherical and toric soft contact lenses in low astigmats. PMID- 25704464 TI - Chemical and morphological filters in a specialized floral mimicry system. AB - Many plant species attract insect pollinators through chemical mimicry of their oviposition sites, often detaining them in a trap chamber that ensures pollen transfer. These plant mimics are considered to be unspecialized at the pollinator species level, yet field observations of a mycoheterotrophic rainforest orchid (Gastrodia similis), which emits an odour reminiscent of rotting fruit, indicate that it is pollinated by a single drosophilid fly species (Scaptodrosophila bangi). We investigated the roles of floral volatiles and the dimensions of the trap chamber in enforcing this specialization, using gas chromatography-mass spectrometry analyses, bioassays and scanning electron microscopy. We showed that G. similis flowers predominantly emit three fatty-acid esters (ethyl acetate, ethyl isobutyrate and methyl isobutyrate) that were shown in experiments to attract only Scaptodrosophila flies. We additionally showed that the trap chamber, which flies enter into via a touch-sensitive 'trapdoor', closely matches the body size of the pollinator species S. bangi and plays a key role in pollen transfer. Our study demonstrates that specialization in oviposition site mimicry is due primarily to volatile chemistry and is reflected in the dimensions of the trapping apparatus. It also indicates that mycoheterotrophic plants can be specialized both on mycorrhizal fungi and insect pollinators. PMID- 25704465 TI - The risk of nail changes with taxane chemotherapy: a systematic review of the literature and meta-analysis. PMID- 25704466 TI - Spatiotemporal Expression of EAPP Modulates Neuronal Apoptosis and Reactive Astrogliosis After Spinal Cord Injury. AB - E2F-associated phosphoprotein (EAPP) is a novel E2F binding protein that interacts with the activating members of the E2F transcription factors family and involved in various biological processes. However, the expression and function of EAPP in central nervous system (CNS) are still unknown. In this study, we performed an acute spinal cord injury (SCI) model in adult rats, we found that EAPP protein levels were significantly increased and reached a peak at day 3, and then gradually returned to normal level at day 14 after spinal cord injury and we observed that the expression of EAPP is enhanced in the gray and white matter. Spatially, increased levels of EAPP were striking in neurons and astrocytes. Moreover, colocalization of EAPP/active caspase-3 was detected in neurons, and colocalization of EAPP/proliferating cell nuclear antigen (PCNA) was detected in astrocytes after spinal cord injury. These results indicated that EAPP might play an important role in neuronal apoptosis and reactive astrogliosis. Furthermore in vitro, EAPP depletion by siRNA inhibited astrocyte proliferation, migration and CDK4/cyclinD1 expression. Meanwhile, EAPP knockdown also reduce neuronal apoptosis and cell cycle related proteins. Which indicated that EAPP might integrate cell cycle progression and play a crucial role in cell proliferation and apoptosis. Taken together, we speculated that EAPP was involved in biochemical and physiological responses after SCI. PMID- 25704467 TI - Voice Assessment After Treatment of Subacute and Chronic Cough With Inhaled Steroids. AB - INTRODUCTION: Inhaled steroids are widely used for persistent cough treatment. Although the side effects of long-term inhaled steroids have been well described in the literature, their laryngeal side effects after short-term use have not yet been defined. The aim of this study was to evaluate the effect of 1 month application of inhaled steroid treatment on voice parameters in patients with subacute or chronic cough. Furthermore, the efficacy of inhaled steroids on cough was investigated, as well. MATERIAL AND METHODS: This study included 46 patients (27 females and 19 males) with a persistent cough lasting at least 3 weeks and treated with inhaled steroids. All patients were examined by a pulmonologist and lung auscultation where a posteroanterior chest X-ray and spirometry were performed. The patients were also examined by an otolaryngologist. Anterior rhinoscopy, flexible fiberoptic nasopharyngoscopy, and laryngostroboscopy were performed. Also, the patients' acoustic voice analyses were performed and recorded using a multidimensional voice program. Cough symptom index (CSI) scores were used to evaluate the response to treatment. Patients with an underlying disease that was unresponsive to inhaled steroids were excluded from study. The 46 patients were administered inhaled budesonide 400 mcg twice a day, for 1 month, and their acoustic voice analyses were performed again at the end of the treatment. In addition, CSI scores were determined after stopping medication. RESULTS: When pretreatment and posttreatment acoustic voice analysis parameters (Fo, Jita, Jitt, Shim, APQ, vAm, and NHR) were compared, statistically significant differences were detected for vAm (P = 0.001) and F0 (P0.003). After treatment with inhaled steroids, the CSI score reduced from 3 to 1 (median), and the difference was statistically significant. CONCLUSIONS: Inhaled budesonide treatment in the proper dose seems to be an effective treatment for persistent cough, in the selected patient group. In addition, short-term budesonide application did not cause any negative effects on the voice parameters in these patients. These findings may be related to the steroid formulation used, the application method, and the duration of treatment. Further studies are needed on a larger group of patients with different formulations of inhaled steroids to clarify aforementioned issues. PMID- 25704468 TI - Tuning Features of Chinese Folk Song Singing: A Case Study of Hua'er Music. AB - OBJECTIVES: The learning and teaching of different singing styles, such as operatic and Chinese folk singing, was often found to be very challenging in professional music education because of the complexity of varied musical properties and vocalizations. By studying the acoustical and musical parameters of the singing voice, this study identified distinctive tuning characteristics of a particular folk music in China-Hua'er music-to inform the ineffective folk singing practices, which were hampered by the neglect of inherent tuning issues in music. METHODS: Thirteen unaccompanied folk song examples from four folk singers were digitally audio recorded in a sound studio. Using an analyzing toolkit consisting of Praat, PeakFit, and MS Excel, the fundamental frequencies (F0) of these song examples were extracted into sets of "anchor pitches" mostly used, which were further divided into 253 F0 clusters. The interval structures of anchor pitches within each song were analyzed and then compared across 13 examples providing parameters that indicate the tuning preference of this particular singing style. RESULTS: The data analyses demonstrated that all singers used a tuning pattern consisting of five major anchor pitches suggesting a nonequal-tempered bias in singing. This partly verified the pentatonic scale proposed in previous empirical research but also argued a potential misunderstanding of the studied folk music scale that failed to take intrinsic tuning issues into consideration. CONCLUSIONS: This study suggests that, in professional music training, any tuning strategy should be considered in terms of the reference pitch and likely tuning systems. Any accompanying instruments would need to be tuned to match the underlying tuning bias. PMID- 25704469 TI - A Comparative Analysis of Pitch Detection Methods Under the Influence of Different Noise Conditions. AB - OBJECTIVES/HYPOTHESIS: Pitch is one of the most important components in various speech processing systems. The aim of this study was to evaluate different pitch detection methods in terms of various noise conditions. STUDY DESIGN: Prospective study. METHODS: For evaluation of pitch detection algorithms, time-domain, frequency-domain, and hybrid methods were considered by using Keele and CSTR speech databases. Each of them has its own advantages and disadvantages. RESULTS: Experiments have shown that BaNa method achieves the highest pitch detection accuracy. CONCLUSIONS: The development of methods for pitch detection, which are robust to additive noise at different signal-to-noise ratio, is an important field of research with many opportunities for enhancement the modern methods. PMID- 25704470 TI - The impact of tonsillectomy with or without adenoidectomy on voice: acoustic and aerodynamic assessments. AB - OBJECTIVE: To study the objective acoustic assessment and aerodynamic assessment of pediatric patients after tonsillectomy with or without adenoidectomy. STUDY DESIGN: Prospective cohort study. METHODS: Pediatric patients who had received tonsillectomy in our department since 2011 October to 2012 September were selected as study objects. The acoustic analysis was performed by the Multi Dimensional Voice Program and aerodynamic examination was performed by Phonatory Aerodynamic System. The preoperative and postoperative (1 month after surgery) data were compared. RESULTS: The postoperative acoustic index had no obvious change compared with the preoperative data. Among the aerodynamic index, postoperative maximum phonation time prolonged and postoperative subglottal pressure decreased comparing with preoperative index. CONCLUSIONS: From the aerodynamic point of view, tonsillectomy with or without adenoidectomy plays a positive role in the improvement of voice production. PMID- 25704471 TI - Effects of Electronic Nicotine Delivery System on Larynx: Experimental Study. AB - OBJECTIVE: We aimed to assess the effects of electronic nicotine delivery system (ENDS) or also termed electronic cigarette vapor on the laryngeal mucosa of rats. MATERIALS AND METHODS: Sixteen female Wistar albino rats were divided into two groups. The study group was exposed to ENDS vapor for 1 hour/day for 4 weeks. The control group was not subjected to any chemical or physical stimulus. The vocal folds of the study and control group rats were evaluated histopathologically by hematoxylin and eosin staining and immunohistochemically by Ki67 staining. Epithelial distribution, inflammation, hyperplasia, and metaplasia were evaluated. RESULTS: Epithelial distribution and inflammation did not differ between the two groups. Two cases of hyperplasia were detected in the study group but there was no hyperplasia in the control group. Four cases of metaplasia were detected in the study group and one case in the control group. Statistical analysis revealed no significant difference between the study and control groups (P = 0.131 and 0.106, respectively). CONCLUSIONS: Exposure to ENDS for 4 weeks caused hyperplasia and metaplasia of the laryngeal mucosa of rats but this was not significant statistically. These results implemented that further studies with larger cohort and longer duration are required to evaluate long-term effects. PMID- 25704472 TI - Using Hyaluronic Acid for Improving Vocal Function in a Prepubescent Boy With an Atrophied Right Vocal Fold. AB - OBJECTIVES: A single case study is reported of a child who underwent several surgical procedures as result of congenital grade III subglottic stenosis. The anterior aspect of the right vocal cord was damaged and underwent atrophy during one of these procedures. Now, an active 10-year-old, the patient has become increasingly aware of his vocal limitations on functional activities. Injection of hyaluronic acid into the vocal folds has been known to provide improved voice quality in adults although there are no known cases reported of this procedure in children. METHODS: This article reports voice outcomes after injection of hyaluronic acid into the Reinke's space in a single case study. Voice recordings were made before, after, and 1 month after injection. The voice recordings were subject to acoustic and perceptual analysis. RESULTS: Post and follow-up voice recordings demonstrate decreased jitter, shimmer, and harmonics-to-noise ratio. Perceptual evaluation indicates improved voice quality. CONCLUSION: Injection of hyaluronic acid in children who require voice augmentation is possible and may contribute to increased vocal function and improved voice outcomes. PMID- 25704473 TI - Laryngocele: Experience at a Tertiary Care Hospital of Eastern India. AB - OBJECTIVES: To study the details of clinical profile and management of laryngocele at a tertiary care teaching hospital of eastern India. STUDY DESIGN: A prospective study. Case series of six patients of laryngocele. METHODS: Six patients of laryngocele were examined at the Outpatient Department of ENT of Institute of Medical Sciences & SUM Hospital, Bhubaneswar, Odisha, India, between August 2010 and January 2014. The details of the patients, such as age, gender, occupations, clinical presentations, imaging modalities and treatment options, are discussed. RESULTS: The common clinical presentations of laryngocele are hoarseness of voice and swelling in the neck. Sometimes, laryngocele patients are asymptomatic. The patients were in the range of 45-70 years old, among them five were males and one was female. The diagnosis was made clinically and radiologically. Among the six patients, five were treated by surgical approach. CONCLUSIONS: Laryngocele is an abnormal dilatation of the laryngeal saccule. It is a very rare clinical condition. Hoarseness of voice and swelling in the neck are common clinical presentations in laryngocele. Imaging studies are essential for making diagnosis, determining the type, localization, extent of laryngocele and for treatment. Surgery is the treatment of choice in laryngocele. PMID- 25704474 TI - Diagnosis of dysphonia among municipal employees: individual and work factors. AB - OBJECTIVE: To investigate the association between occupational status and the distribution of dysphonia. METHODS: In 2009, a sample of 5646 (14%) of the population of 38,304 municipal employees of Belo Horizonte was obtained. A questionnaire was made available on an Internet Web site that could be entered only after the respondent had given consent. The response variable was drawn up with reference to the question: "Has a doctor ever told you that you have dysphonia?," for which the possible responses were yes or no. The following variables were included in the logistic regression model: sociodemographic data, work characteristics, and lifestyle habits. RESULTS: The associations relating to dysphonia were found to be different between men and women. Differing from men, occupational factors influenced the outcome among women. Among men, there were significant associations between dysphonia and sociodemographic characteristics, health-related factors, and lifestyle factors. CONCLUSION: Gender differentials should be taken into consideration in health promotion actions among this group of municipal employees. PMID- 25704475 TI - Voice Disorders in Teachers: Clinical, Videolaryngoscopical, and Vocal Aspects. AB - GOAL: Dysphonia is more prevalent in teachers than among the general population. The objective of this study was to analyze clinical, vocal, and videolaryngoscopical aspects in dysphonic teachers. METHODS: Ninety dysphonic teachers were inquired about their voice, comorbidities, and work conditions. They underwent vocal auditory-perceptual evaluation (maximum phonation time and GRBASI scale), acoustic voice analysis, and videolaryngoscopy. The results were compared with a control group consisting of 90 dysphonic nonteachers, of similar gender and ages, and with professional activities excluding teaching and singing. RESULTS: In both groups, there were 85 women and five men (age range 31-50 years). In the controls, the majority of subjects worked in domestic activities, whereas the majority of teachers worked in primary (42.8%) and secondary school (37.7%). Teachers and controls reported, respectively: vocal abuse (76.7%; 37.8%), weekly hours of work between 21 and 40 years (72.2%; 80%), under 10 years of practice (36%; 23%), absenteeism (23%; 0%), sinonasal (66%; 20%) and gastroesophageal symptoms (44%; 22%), hoarseness (82%; 78%), throat clearing (70%; 62%), and phonatory effort (72%; 52%). In both groups, there were decreased values of maximum phonation time, impairment of the G parameter in the GRBASI scale (82%), decrease of F0 and increase of the rest of acoustic parameters. Nodules and laryngopharyngeal reflux were predominant in teachers; laryngopharyngeal reflux, polyps, and sulcus vocalis predominated in the controls. CONCLUSIONS: Vocal symptoms, comorbidities, and absenteeism were predominant among teachers. The vocal analyses were similar in both groups. Nodules and laryngopharyngeal reflux were predominant among teachers, whereas polyps, laryngopharyngeal reflux, and sulcus were predominant among controls. PMID- 25704476 TI - Subjective and Objective Effects of Androgen Ablation Therapy on Voice. AB - OBJECTIVES: The aim of present study was to evaluate possible side effects of androgen deprivation therapy (ADT) on voice quality by means of objective and subjective measures. STUDY DESIGN: Cross-sectional. METHODS: Thirty-five male patients who had been diagnosed with prostate cancer and who had been using bicalutamide and goserelin acetate combination for at least 12 months were included in the study. Thirty healthy nonsmoker males of similar age and without any laryngeal pathology constituted the control group. Acoustic and aerodynamic voice analyses and voice handicap index-10 were applied to both groups. Maximum phonation time, fundamental frequency, jitter, shimmer, and noise-to-harmonic ratio were determined during acoustic and aerodynamic voice analyses. RESULTS: Maximum phonation times were 18.86 +/- 5.24 and 24.20 +/- 3.59 in ADT and control groups, respectively. It was significantly higher in the control group. Fundamental frequencies were 143.73 +/- 18.47 and 135.00 +/- 13.18 in ADT and control groups, respectively. Jitter values were 2.72 +/- 0.62 and 1.99 +/- 0.27 in ADT and control groups, respectively. Shimmer values were 11.50 +/- 1.81 and 10.48 +/- 1.36 in ADT and control groups, respectively. Fundamental frequency, jitter, and shimmer values were significantly higher in the ADT group. Noise-to harmonic ratio values did not differ between groups. Voice handicap index-10 result was significantly higher in the ADT group. CONCLUSIONS: ADT has adverse effects on the human voice. Prospective studies with long-term follow-up of a larger cohort are required for more detailed analysis. PMID- 25704477 TI - Why use a thermophilic aerobic membrane reactor for the treatment of industrial wastewater/liquid waste? AB - This paper describes the advantages of thermophilic aerobic membrane reactor (TAMR) for the treatment of high strength wastewaters. The results were obtained from the monitoring of an industrial and a pilot scale plant. The average chemical oxygen demand (COD) removal yield was equal to 78% with an organic loading rate (OLR) up to 8-10 kgCOD m(-3) d(-1) despite significant scattering of the influent wastewater composition. Total phosphorus (TP) was removed with a rate of 90%, the most important removal mechanism being chemical precipitation (as hydroxyapatite, especially), which is improved by the continuous aeration that promotes phosphorus crystallization. Moreover, surfactants were removed with efficiency between 93% and 97%. Finally, the experimental work showed that thermophilic processes (TPPs) are complementary with respect to mesophilic treatments. PMID- 25704478 TI - Effective detection and quantification of dietetically absorbed plant microRNAs in human plasma. AB - The detection of exogenous plant microRNAs in human/animal plasma/sera lies at the foundation of exploring their cross-kingdom regulatory functions. It is necessary to establish a standard operation procedure to promote study in this nascent field. In this study, 18 plant miRNAs were assessed in watermelon juice and mixed fruits by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). CT values, no-template controls and standard curves for each miRNA were used to evaluate the specificity and sensitivity of qRT-PCR and to obtain concentrations. Sixteen miRNAs were selected and measured in human plasma from volunteers after drinking juice. The CT values of 6 plant miRNAs in human plasma fell outside the linear ranges of their standard curves. The remaining 10 miRNAs were present at high basal levels, and 6 of them showed a dynamic physiological pattern in plasma (absorption rates of 0.04% to 1.31%). Northern blotting was used to confirm the qRT-PCR results. Critical issues such as RNA extraction and internal controls were also addressed. PMID- 25704479 TI - Efficacy and tolerability of anthracycline-based therapy in elderly patients with diffuse large B-cell lymphoma. AB - INTRODUCTION: Although diffuse large B-cell lymphoma (DLBCL) can be cured with rituximab and anthracycline-based therapy, within the elderly population there are additional factors to consider in selecting a treatment regimen including comorbid conditions, decreased drug metabolism, decreased hematologic reserve, reduced performance status, and regimen-related toxicity. PATIENTS AND METHODS: We performed a retrospective cohort analysis of patients with DLBCL aged >= 65 years at time of diagnosis treated with either an anthracycline-containing regimen (ACR; n = 59) or a non-ACR (n = 13) to assess factors that led to treatment selection, tolerability, and outcomes. RESULTS: The mean age was 73 years in the ACR and 77 years in the non-ACR group (P = .009), and median left ventricular ejection fraction (LVEF) at diagnosis was 60% in the ACR group and 45% in the non-ACR group (P < .001). With an ACR, elderly DLBCL patients had a median overall survival of 28 months and a 2-year progression-free survival (PFS) of 64%. After an ACR, 14 patients [24%] (out of 59 total patients) had a decrease in LVEF, 7 patients [15%] (% is based off of those who we had the data collected, so this is out of 45 with this specific data) required a dose reduction of the anthracycline, and 15 patients [33%] (% is based off of those who we had the data collected, so this is out of 45 with this specific data) could not complete the regimen as planned. Hospitalization due to toxicity occurred in 20 patients [44%] (% is based off of those who we had the data collected, so this is out of 45 with data) of patients in the ACR group and 3 patients [75%] (% is based off of those who we had the data collected, so this is out of 4 with this specific data) in the non-ACR group, and was the only predictor of overall survival. CONCLUSION: Results of this study suggest that elderly patients with DLBCL experience meaningful PFS with ACRs, but a third experience toxicity requiring therapy modification. Future studies should examine larger patient populations and define treatments with outcomes similar to ACR that also decrease toxicity and hospitalization in the elderly DLBCL population. PMID- 25704480 TI - Proliferative role of TRAF4 in breast cancer by upregulating PRMT5 nuclear expression. AB - In this study, we examined protein arginine methyltransferase 5 (PRMT5) and tumor necrosis factor receptor-associated 4 (TRAF4) expression in breast cancer to find the interaction mechanism between the two. We examined TRAF4 and PRMT5 expression by immunohistochemistry and found that their expression is positively correlated in breast cancer. Besides, PRMT5 expression was significantly associated with histological type and tumor size (p < 0.05). PRMT5 nuclear expression was significantly associated with HER2 expression (p < 0.05). PRMT5 and TRAF4 were both overexpressed in breast cancer tissues and cells, and we found that PRMT5 binds to the zinc finger structures in TRAF4 by coimmunoprecipitation and Western blotting. We also tested the potential regulatory effect between TRAF4 and PRMT5. TRAF4 upregulated PRMT5 expression, which occurred predominantly in the nucleus, on which TRAF4 promotion of cell proliferation in breast cancer is mainly dependent. PRMT5 may play an important role in activation of the NF-kappaB signaling pathway. PMID- 25704481 TI - Apoptotic Mediators are Upregulated in the Skeletal Muscle of Chronic/Progressive Mouse Model of Parkinson's Disease. AB - Apoptosis has been implicated in the pathogenesis of Parkinson disease (PD). Parkinson disease is characterized by skeletal muscle abnormalities. The aim of this study is to illustrate the impact of PD induction on the expression of apoptotic mediators. Twenty normal albino mice were randomly selected and equally divided in control and PD groups. Chronic Parkinsonism was induced in the PD group using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and probenecid (MPTP/p). After that, samples from gastrocnemius muscles were evaluated by immunohistochemistry to examine the expression of p53 and active caspase-3 in the two groups of animals. P53 and active caspase-3 expression was significantly higher in gastrocnemius skeletal muscle in PD mice compared with that in the control mice (P value <0.01). Furthermore, we show PD gastrocnemius muscle atrophy measured by significant reduction (P < 0.01) in the muscle fiber cross sectional area. Thus, our present data suggest that PD induction increased the expression of the apoptotic mediators p53 and active caspase-3 in gastrocnemius muscle, indicating the induction of apoptosis, which was correlative with gastrocnemius muscle atrophy subsequent to the induction of PD. PMID- 25704482 TI - Elevated tumour markers are normalized in most patients with pseudomyxoma peritonei 7 days after complete tumour removal. AB - AIM: Elevation of the preoperative tumour markers in pseudomyxoma peritonei (PMP) is common and is a risk factor for recurrence. There has, however, been no documentation of the effect of complete tumour removal on tumour markers levels after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). The aim of the study was to compare the tumour markers 7 days after surgery in patients with elevated preoperative levels. METHOD: This was an observational prospective study of patients with PMP of appendiceal origin treated in one of the UK National Referral Centres for this condition. Thirty patients [median age = 61 (range: 31-74) years; six men] with an elevated preoperative level of carcinoembryonic antigen (CEA), carbohydrate antigen 125 (CA-125) and/or carbohydrate antigen 19-9 (CA19-9) underwent repeated estimation, 7 days after CRS and HIPEC for PMP. RESULTS: The median preoperative CEA level of 12 MUg/l fell to 0.75 MUg/l postoperatively (P < 0.0001), CA-125 fell from 45 to 31 kU/l (P = 0.183) and CA19-9 fell from 134 to 37 kU/l (P = 0.003). The CEA was raised in 22 (73%) of 30 patients preoperatively and in two (7%) of 30 patients 7 days after surgery (P < 0.0001). The corresponding data for CA-125 were 18 (60%) and 13 (43%) (P = 0.196) and for CA19-9 they were 24 (80%) and 16 (53%) (P = 0.028). CONCLUSION: This is the first documentation of a reduction or normalization of CEA 7 days after CRS, but not for CA19-9 or CA-125. This may indicate completeness of surgical resection and could aid selection for adjuvant therapy and predict prognosis. Long-term follow-up is, however, necessary to determine the significance of this observation. PMID- 25704483 TI - Laser ablation inductively coupled plasma mass spectrometry imaging of metals in experimental and clinical Wilson's disease. AB - Wilson's disease is an autosomal recessive disorder in which the liver does not properly release copper into bile, resulting in prominent copper accumulation in various tissues. Affected patients suffer from hepatic disorders and severe neurological defects. Experimental studies in mutant mice in which the copper transporting ATPase gene (Atp7b) is disrupted revealed a drastic, time-dependent accumulation of hepatic copper that is accompanied by formation of regenerative nodes resembling cirrhosis. Therefore, these mice represent an excellent exploratory model for Wilson's disease. However, the precise time course in hepatic copper accumulation and its impact on other trace metals within the liver is yet poorly understood. We have recently established novel laser ablation inductively coupled plasma mass spectrometry protocols allowing quantitative metal imaging in human and murine liver tissue with high sensitivity, spatial resolution, specificity and quantification ability. By use of these techniques, we here aimed to comparatively analyse hepatic metal content in wild-type and Atp7b deficient mice during ageing. We demonstrate that the age-dependent accumulation of hepatic copper is strictly associated with a simultaneous increase in iron and zinc, while the intrahepatic concentration and distribution of other metals or metalloids is not affected. The same findings were obtained in well-defined human liver samples that were obtained from patients suffering from Wilson's disease. We conclude that in Wilson's disease the imbalances of hepatic copper during ageing are closely correlated with alterations in intrahepatic iron and zinc content. PMID- 25704484 TI - Drugs under early investigation for the treatment of bipolar disorder. AB - INTRODUCTION: Despite the availability of several treatment options for bipolar disorder (BD), patients suffer from chronic, subsyndromal symptoms, quite frequent polarity shifts, cognitive impairment and poor community function. Overall, the current treatment outcomes for BD highlight the need to develop targeted, more effective and safe treatments. AREAS COVERED: This review focuses on compounds currently under investigation for BD, covering compounds tested through animal studies to those in Phase II clinical trials over the past 5 years. These drugs concern all phases of BD treatment, that is, mania, depression, maintenance, and cognitive dysfunction. EXPERT OPINION: Limitations exist in applying valid preclinical bipolar models and study designs. Research emphasis is given mainly on bipolar depression, with few compounds showing some evidence of efficacy. Non-effectiveness in current studies of mania and maintenance treatment reflects the need for novel compounds. Glycogen synthase kinase 3, casein kinase 1, inositol monophosphatase inhibition, histone deacetylase inhibition pathways are known targets that should proceed from preclinical to the clinical trial level. PMID- 25704485 TI - Managing fire in the mesic deciduous forest when fire history is unknown: response to Stambaugh et al. PMID- 25704486 TI - The impact of chemotherapy shortages on COG and local clinical trials: a report from the Children's Oncology Group. AB - BACKGROUND: Oncology drug shortage is associated with increased patient adverse events and decreased enrollment on clinical trials for adult patients; however, the impact of oncology drug shortages has not been well studied in children with cancer. PROCEDURE: The Children's Oncology Group (COG) distributed a 5-item survey to 226 COG site-specific principal investigators (PI's) and 14-item survey to 161 COG pharmacists to gather data the impact of chemotherapeutic shortages on clinical trials and patient care. RESULTS: The response rate was 66.4% (150/226) for PI's and 29.8% (48/161) for pharmacists. COG PI's reported daunorubicin (73%), methotrexate (56%), asparaginase/PEG-asparaginase (42%), doxorubicin (26%), thiotepa (21%), and cytarabine (20%) were most commonly in shortage, while COG pharmacists reported daunorubicin (80%), methotrexate (66%), vincristine (21%), thiotepa (41%), asparaginase/PEG-asparaginase (34%), and cytarabine (34%) were most commonly in shortage over the past two years. Pharmacists were twice as likely to report a shortage compared with PI's (OR 2.1, 95% CI: 1.6-2.7, P < 0.0001). Fifty percent (74/147) of COG PI's reported at least one patient enrolled on a clinical trial was impacted by drug shortage, and 66% (98/148) of COG PI's reported at least one patient had clinical care impacted by drug shortage. CONCLUSIONS: Chemotherapy shortages remain widespread across institutions, hinder clinical trials, and may contribute to adverse events in children with cancer. The increased frequency of chemotherapy shortages reported by pharmacists suggests that pharmacist efforts may mitigate negative impact chemotherapy shortages. Over half of pediatric institutions are implementing recommendations to address shortages, such as cross-institutional collaboration and center-level guidelines. PMID- 25704488 TI - Expression of metallothioneins I and II in kidney of doxorubicin-treated rats. AB - Metallothioneins I/II (MT) are commonly expressed in mammalian tissues and are highly inducible in the response to stress conditions. Doxorubicin (DOX) intoxication promotes oxidative stress and subsequent apoptosis leading to kidney damage. The present study investigates a correlation between endogenous MT expression and DOX-induced apoptosis in renal tubular cells. Experiments were conducted on Buffalo rats receiving DOX (8 mg/kg b.w. for 3 weeks) versus control rats injected with saline. The histopathological alterations and apoptosis (TUNEL) were evaluated in tissue sections. MT expression and tissue localization was examined using immunohistochemical method (IHC). Western blot (WB) was used to evaluate pro-caspase-3, active caspase-3 and MT expression level in tissue homogenates. Examination of renal tissue revealed severe nephrotoxicity in DOX treated animals. Apoptosis was observed in distal convoluted tubular cells, whereas MT was detected in proximal tubular cells. A significant increase in pro caspase-3, active caspase-3 and MT expression levels (WB) were seen in DOX group. Positive correlations between histopathological lesions, apoptosis and MT expression were observed. The results obtained in this study could suggest the protective and antiapoptotic effect of MT expression in renal proximal tubular cells under DOX intoxication. PMID- 25704489 TI - Towards predicting the stability of protein-stabilized emulsions. AB - The protein concentration is known to determine the stability against coalescence during formation of emulsions. Recently, it was observed that the protein concentration also influences the stability of formed emulsions against flocculation as a result of changes in the ionic strength. In both cases, the stability was postulated to be the result of a complete (i.e. saturated) coverage of the interface. By combining the current views on emulsion stability against coalescence and flocculation with new experimental data, an empiric model is established to predict emulsion stability based on protein molecular properties such as exposed hydrophobicity and charge. It was shown that besides protein concentration, the adsorbed layer (i.e. maximum adsorbed amount and interfacial area) dominates emulsion stability against coalescence and flocculation. Surprisingly, the emulsion stability was also affected by the adsorption rate. From these observations, it was concluded that a completely covered interface indeed ensures the stability of an emulsion against coalescence and flocculation. The contribution of adsorption rate and adsorbed amount on the stability of emulsions was combined in a surface coverage model. For this model, the adsorbed amount was predicted from the protein radius, surface charge and ionic strength. Moreover, the adsorption rate, which depends on the protein charge and exposed hydrophobicity, was approximated by the relative exposed hydrophobicity (QH). The model in the current state already showed good correspondence with the experimental data, and was furthermore shown to be applicable to describe data obtained from literature. PMID- 25704490 TI - Polymerase synthesis of DNA labelled with benzylidene cyanoacetamide-based fluorescent molecular rotors: fluorescent light-up probes for DNA-binding proteins. AB - Viscosity-sensitive fluorophores, fluorescent molecular rotors based on aminobenzylidene-cyanoacetamide moiety, were tethered to 2'-deoxycytidine triphosphate via a propargylamine linker and incorporated into DNA by polymerases in primer extension, nicking enzyme amplification or PCR. DNA probes incorporating modified nucleosides show a light-up response upon binding to a protein. PMID- 25704491 TI - Reversal of opioid-induced respiratory depression by BK-channel blocker GAL021: A pharmacokinetic-pharmacodynamic modeling study in healthy volunteers. AB - Opioid-induced respiratory depression (OIRD) is a serious and potentially life threatening complication of opioid overdose, abuse, and misuse. An option to avert OIRD is to treat patients on strong opioids with respiratory stimulants that do not interact with the opioid system and consequently do not compromise opioid analgesic efficacy. The BK-channel blocker GAL021 is a respiratory stimulant acting at K(+) -channels expressed on type 1 carotid body cells. The authors performed a population pharmacokinetic-pharmacodynamic (PKPD) analysis on the ability of GAL021 to reverse alfentanil-induced respiratory depression in 12 male volunteers using an isohypercapnic experimental design. The analysis showed that (1) GAL021 interacts in a multiplicative fashion with alfentanil and GAL021, which predicts that GAL021 efficacy is reduced at low ventilation levels; (2) GAL021 has a rapid onset/offset with a blood-effect site equilibration half-life not different from zero; and (3) GAL021 displays ceiling in its efficacy to reverse OIRD. PMID- 25704492 TI - Changing patterns of rotavirus strains circulating in Ireland: re-emergence of G2P[4] and identification of novel genotypes in Ireland. AB - Worldwide, Group A Rotavirus (RVA) is recognized as the most common aetiological agent of acute diarrheal disease in children. One hundred and ninety seven positive faecal samples were obtained from patients between 2006 and 2008. Reverse transcriptase polymerase chain reaction (RT-PCR) was used to amplify the VP7 and VP4 gene segments of these samples, and G and P typing was carried out subsequently. The most common strain type was G1P[8], and the emergent global G9 type was identified in both years. RVA strain type G2P[4], previously reported in Ireland in 1999, was also detected. Genotypes G2 and G3 in combination with P[4] were detected in 2006-2007 only. There was also an emergence of strain types including G3P[4], G9P[4], G2P[4 + 8] and G2G4P[8] in this study. Molecular analysis of the VP7 genes revealed G1 strains circulating within lineage Ic as previously reported in Ireland. In addition, new sublineage within lineage I of G1 strains was also identified. Analysis of G4 strain NRVL-Hum-49 revealed similarity with other human G4 viruses in lineage Ib. G9 strain NRVL-Hum-74 clustered with a unique G9 strain, CIT-254, in lineage IIIc. This data supports the observations made that the profile of RVA strains in Ireland appears to be dynamic. This study demonstrates that the circulation of human rotavirus is changing continuously in Ireland, and continued surveillance of the circulating strains is needed to detect the appearance of new strains, or new variants which may lead to vaccine breakthrough. PMID- 25704493 TI - Functional connectivity constrains the category-related organization of human ventral occipitotemporal cortex. AB - One of the most robust and oft-replicated findings in cognitive neuroscience is that several spatially distinct, functionally dissociable ventral occipitotemporal cortex (VOTC) regions respond preferentially to different categories of concrete entities. However, the determinants of this category related organization remain to be fully determined. One recent proposal is that privileged connectivity of these VOTC regions with other regions that store and/or process category-relevant properties may be a major contributing factor. To test this hypothesis, we used a multicategory functional magnetic resonance imaging (MRI) localizer to individually define category-related brain regions of interest (ROIs) in a large group of subjects (n = 33). We then used these ROIs in resting-state functional connectivity MRI analyses to explore spontaneous functional connectivity among these regions. We demonstrate that during rest, distinct category-preferential VOTC regions show differentially stronger functional connectivity with other regions that have congruent category preference, as defined by the functional localizer. Importantly, a "tool" preferential region in the left medial fusiform gyrus showed differentially stronger functional connectivity with other left lateralized cortical regions associated with perceiving and knowing about common tools-posterior middle temporal gyrus (involved in perception of nonbiological motion), lateral parietal cortex (critical for reaching, grasping, manipulating), and ventral premotor cortex (involved in storing/executing motor programs)-relative to other category related regions in VOTC of both the right and left hemisphere. Our findings support the claim that privileged connectivity with other cortical regions that store and/or process category-relevant properties constrains the category-related organization of VOTC. PMID- 25704494 TI - The systematic development and pilot randomized evaluation of counselling for alcohol problems, a lay counselor-delivered psychological treatment for harmful drinking in primary care in India: the PREMIUM study. AB - BACKGROUND: Despite harmful drinking causing a significant burden on global health, there is a large treatment gap, especially in low- and middle-income countries. A major barrier to care is the lack of adequately skilled human resources to deliver contextually appropriate treatments. This paper describes the systematic process used to develop Counselling for Alcohol Problems (CAP), a brief psychological treatment (PT) for delivery by lay counselors in routine primary care settings to men with harmful drinking in India. METHODS: CAP was developed using a methodology involving 3 sequential steps: (i) identifying potential treatment strategies; (ii) developing a theoretical framework for the treatment; and (iii) evaluating the acceptability and feasibility of the treatment. RESULTS: CAP is a 3-phase treatment delivered over 1 to 4 sessions based on a motivational interviewing (MI) stance and involves the following strategies: assessment and personalized feedback, family engagement, drink refusal skills, skills to address drinking urges, problem-solving skills and handling difficult emotions, and relapse prevention and management. Data from a case series were used to inform several adaptations to enhance the acceptability of CAP to the recipients and feasibility of delivery by lay counselors of the treatment, for example expansion of the target group to include alcohol-dependent patients and the extension of the delivery settings to include home-based delivery. There was preliminary evidence of the effectiveness of CAP. CONCLUSIONS: CAP is an acceptable brief PT for harmful drinking delivered by lay counselors in primary care whose effectiveness is currently being tested in a randomized controlled trial based in primary care in Goa, India. PMID- 25704495 TI - Regional hippocampal damage in heart failure. AB - AIMS: Heart failure (HF) patients show cognitive and mood impairments, including short-term memory loss and depression, that have an adverse impacting on quality of life and self-care management. Brain regions, including the hippocampus, a structure significantly involved in memory and mood, show injury in HF, but the integrity of specific hippocampal subregions is unclear. METHODS AND RESULTS: To assess regional hippocampal volume loss, we evaluated 17 HF patients (mean age +/ SD, 54.4 +/- 2.0 years; 12 male, left ventricular ejection fraction 28.3 +/- 6.8%; New York Heart Association class II/III 94%/6%) and 34 healthy control subjects (52.3 +/- 1.3 years; 24 male) using high-resolution T1-weighted magnetic resonance imaging and evaluated localized surface changes with morphometric procedures. Hippocampi were manually outlined, and volumes calculated from normalized tracings. Volume differences between groups were assessed by two sample t-tests, and regional differences were assessed by surface morphometry. Patients with HF exhibited smaller hippocampal volumes than controls (right 3060 +/- 146 mm(3) vs. 3478 +/- 94 mm(3), P = 0.02; left 3021 +/- 145 mm(3) vs. 3352 +/- 98 mm(3), P = 0.06). Volume reductions were detected principally in CA1, an area integral to an array of learning and memory functions, as well as in mid to posterior CA3 and subiculum. CONCLUSION: The hippocampus shows regional volume reduction in HF, which may contribute to short-term memory loss and depression associated with the condition. PMID- 25704496 TI - Effects of dietary n-6:n-3 PUFA ratio on fatty acid composition, free amino acid profile and gene expression of transporters in finishing pigs. AB - Revealing the expression patterns of fatty acid and amino acid transporters as affected by dietary n-6:n-3 PUFA ratio would be useful for further clarifying the importance of the balance between n-6 and n-3 PUFA. A total of ninety-six finishing pigs were fed one of four diets with the ratio of 1:1, 2.5:1, 5:1 and 10:1. Pigs fed the dietary n-6:n-3 PUFA ratio of 5:1 had the highest (P< 0.05) daily weight gain, and those fed the dietary n-6:n-3 PUFA ratio of 1:1 had the largest loin muscle area (P< 0.01). The concentration of n-3 PUFA was raised as the ratio declined (P< 0.05) in the longissimus dorsi and subcutaneous adipose tissue. The contents of tryptophan, tasty amino acids and branched-chain amino acids in the longissimus dorsi were enhanced in pigs fed the dietary n-6:n-3 PUFA ratios of 1:1-5:1. The mRNA expression level of the fatty acid transporter fatty acid transport protein-1 (FATP-1) was declined (P< 0.05) in the longissimus dorsi of pigs fed the dietary n-6:n-3 PUFA ratios of 1:1-5:1, and increased (P< 0.05) in the subcutaneous adipose tissue of pigs fed the dietary n-6:n-3 PUFA ratios of 5:1 and 10:1. The expression profile of FATP-4 was similar to those of FATP-1 in the adipose tissue. The mRNA expression level of the amino acid transceptors LAT1 and SNAT2 was up-regulated (P< 0.05) in the longissimus dorsi of pigs fed the dietary n-6:n-3 PUFA ratios of 1:1 and 2.5:1. In conclusion, maintaining the dietary n-6:n-3 PUFA ratios of 1:1-5:1 would facilitate the absorption and utilisation of fatty acids and free amino acids, and result in improved muscle and adipose composition. PMID- 25704497 TI - Endogenous central suppressive mechanisms regulating cough as potential targets for novel antitussive therapies. AB - Cough and the accompanying sensation known as the urge-to-cough are complex neurobiological phenomena dependent on sensory and motor neural processing at many levels of the neuraxis. In addition to the excitatory neural circuits that provide the positive drive for inducing cough and the urge-to-cough, recent studies have highlighted the existence of likely inhibitory central neural processes that can be engaged to suppress cough sensorimotor processing. In many respects, the balance between excitatory and inhibitory central cough control may be a critical determinant of cough in health and disease which argues for the importance of understanding the biology of these putative central inhibitory processes. This brief review summarises the current knowledge of the central circuits that govern voluntary and involuntary cough suppression and posits the notion of targeting central suppressive mechanisms as a treatment for disordered cough in disease. PMID- 25704499 TI - Engineering interfacial photo-induced charge transfer based on nanobamboo array architecture for efficient solar-to-chemical energy conversion. AB - Engineering interfacial photo-induced charge transfer for highly synergistic photocatalysis is successfully realized based on nanobamboo array architecture. Programmable assemblies of various components and heterogeneous interfaces, and, in turn, engineering of the energy band structure along the charge transport pathways, play a critical role in generating excellent synergistic effects of multiple components for promoting photocatalytic efficiency. PMID- 25704500 TI - Therapeutic targets for overactive bladder other than smooth muscle. AB - INTRODUCTION: For a long time, our concepts of regulation of urinary bladder function in health and disease as well as of the target structures of therapeutics have focused on detrusor smooth muscle cells. However, other structures including urothelium, afferent nerves and bladder blood vessels may also be important in pathophysiology and its treatment. AREAS COVERED: Based on a selective review of literature, we discuss the role of urothelium, afferent nerve fibers and bladder blood vessels in bladder pathophysiology and as targets for treatment. EXPERT OPINION: There is solid evidence now that multiple anatomical structures within the urinary bladder contribute to the regulation of its function and hence may be targets for established and emerging drugs. However, most previous studies have looked at the various target structures in isolation. In contrast, we propose that they should be seen as a network sensing and responding to alterations in the cellular environment or to xenobiotics. Studies are emerging in which the interaction of two of these structures is explored. Major advances in our understanding of bladder function are expected to result from studies integrating multiple such structures but these may be technically challenging and difficult to perform and interpret. PMID- 25704498 TI - Peripheral neural circuitry in cough. AB - Cough is a reflex that serves to protect the airways. Excessive or chronic coughing is a major health issue that is poorly controlled by current therapeutics. Significant effort has been made to understand the mechanisms underlying the cough reflex. The focus of this review is the evidence supporting the role of specific airway sensory nerve (afferent) populations in the initiation and modulation of the cough reflex in health and disease. PMID- 25704501 TI - Circulating tumor cells as a longitudinal biomarker in patients with advanced chemorefractory, RAS-BRAF wild-type colorectal cancer receiving cetuximab or panitumumab. AB - A still relevant number of patients with RAS-BRAF wild-type colorectal cancer (CRC) do not respond to treatment with antiepidermal growth factor receptor (EGFR) monoclonal antibodies cetuximab and panitumumab, suggesting that additional biomarkers to guide patient selection are urgently needed. Circulating tumor cells (CTCs) may represent such a biomarker. In this prospective study, 38 patients with advanced RAS-BRAF-wild-type CRC received third-line therapy with cetuximab-irinotecan or panitumumab. Peripheral blood samples for CTC status determination were collected at baseline, during treatment at early (2-4 weeks) and at later (8-10 weeks) times. CTC enrichment was done with the AdnaTest ColonCancerSelect kit, whereas CTC detection was done with the AdnaTest ColonCancerDetect kit. CTC status positivity was defined according to the kit manufacturer's thresholds. Fifty percent of patients were defined as CTC positive at baseline and the overall RECIST response rate was 26%. CTC baseline status was not associated with treatment response, whereas early CTC status and CTC status changes during treatment were significantly associated with tumor response. Kaplan-Meier analysis showed a significantly shorter progression-free survival (median, 2.0 versus 4.0 months, p = 0.004) and overall survival (4.7 versus11.4, p = 0.039) in patients with early CTC + status compared with CTC - ones. In multivariable analysis including classical prognostic factors, the CTC status changes profile during treatment was an independent predictor of both progression free survival (p < 0.001) and overall-survival (p = 0.001). CTC status assessed early during treatment with anti-EGFR monoclonal antibodies may predict treatment failure in advance compared to imaging-based tools. PMID- 25704503 TI - Safety evaluation of the consumption of high dose milk fat globule membrane in healthy adults: a double-blind, randomized controlled trial with parallel group design. AB - Consumption of milk fat globule membrane (MFGM) in combination with habitual exercise suppresses age-associated muscle loss. The effects of high dose MFGM, however, are not known. A double-blind, randomized controlled trial with parallel group design was conducted to evaluate the safety of consuming high dose MFGM tablets. The subjects were 32 healthy adult men and women. Subjects were given 5 times the recommended daily intake of the tablets containing 6.5 g of MFGM or whole milk powder for 4 weeks. Stomach discomfort and diarrhea were observed; however, these symptoms were transitory and slight and were not related to consumption of the test tablets. In addition, there were no clinically significant changes in anthropometric measurements or blood tests. Total degree of safety assessed by the physicians of all subjects was "safe." These findings suggest that consumption of the tablets containing 6.5 g MFGM for 4 weeks is safe for healthy adults. PMID- 25704502 TI - A re-evaluation of the role of B cells in protective immunity to Chlamydia infection. AB - Chlamydia trachomatis is the etiological agent of the most commonly reported bacterial sexual transmitted infection (STI) in North America and Europe. The control of Chlamydia infection is hindered by the asymptomatic nature of initial infection but the consequence of untreated infection seriously threatens the reproductive health of young women. Unfortunately, there is no licensed vaccine for Chlamydia vaccine, in part due to our incomplete understanding of the immune response to Chlamydia urogenital infection. It has been well established that T cell-mediated immunity plays a dominant role in protective immunity against Chlamydia and thus the importance of B cells is somewhat underappreciated. Here, we summarize recent progress on understanding the role of B cells during Chlamydia genital tract infections and discuss how B cells and humoral immunity make an effective contribution to host defense against important intracellular pathogens, including Chlamydia. PMID- 25704505 TI - CA 19-9 in evaluation of adnexal mass: retrospective cohort analysis and review of the literature. AB - OBJECTIVE: The aim of this study was to estimate the diagnostic accuracy of serum marker CA 19-9 levels in the triage of adnexal masses. METHODS: This retrospective cohort study was carried out in patients referred to the Gynecology Department at Carmel Medical Center due to adnexal masses. All patients underwent preoperative measurements of serum CA 125 and CA 19-9 and surgery with histopathologically confirmed diagnosis. RESULTS: Between January 2005 and December 2012, 503 patients with adnexal masses were evaluated with serum tumor markers. Combination of CA 19-9 with CA 125, compared with CA 125 levels alone, suggested a nonsignificant effect on sensitivity (86.9% vs. 88.9%, respectively, p = 0.54) or specificity (79.5% vs. 73.5%, p = 0.1) in differentiating malignant from benign adnexal masses. CA 19-9 was not helpful in detecting mucinous histological types or borderline tumors. Mean CA 19-9 levels were higher in metastatic cases compared with primary ovarian malignancy (488.7 +/- 1,457 vs. 46.3 +/- 149.8 U/mL, respectively, p = 0.001). In mature cystic teratomas, mean CA 19-9 levels were higher and CA 125 levels were lower than in ovarian carcinoma (p = 0.049 and p = 0.0012, respectively). CONCLUSIONS: The combination of the tumor markers CA 19-9 and CA 125 did not contribute significantly to the detection of malignant adnexal masses compared with CA 125 alone. As our results suggest that higher CA 19-9 levels could be helpful in differentiating metastatic tumors from primary ovarian malignancy; this issue should be investigated in large well-designed prospective cohort trials. PMID- 25704504 TI - Urinary tract symptoms and erectile function in patients at risk of prostate cancer. AB - INTRODUCTION AND OBJECTIVE: We estimate that more tan 63000 prostate biopsies are performed in our country each year. There are no functional status data of those patients and if there is a relationship between biopsy result and functional status. In order to solve that question we have performed this study. MATERIAL AND METHOD: 1,128 prostate biopsies were included. Patients fill in the IPSS, IIEF-5 and ICIQ-SF questionnaires before the prostate biopsy was performed. A prospective data collection of clinical, pathological and questionnaires results was done. A descriptive analysis was carried out. IPSS and IIEF-5 results were categorized. Results were compared depending on the biopsy result. In the subgroup of patients with prostate cancer, questionnaires results were stratify according to the clinical risk group. RESULTS: The mean age of the sample was 65. Prostate cancer detection rate was 32,71%, 52,2% of the sample had mild lower urinary tract symptoms (LUTS) and 13,4% had severe LUTS at the time of the biopsy. Regarding the impact of LUTS on quality of life (QOL), only 12,6% showed a perfect QOL. More than 50 percent of patients suffered from some degree of erectile dysfunction at the time of the biopsy. According to ICIQ-SF, 24% of the sample experienced some kind of urinary incontinence, although it is true that most of them classified it as small amount. Patients with a positive biopsy had a lower IPSS and IIEF-5 average score. There were no differences in the prostate cancer detection rate stratified by the severity of LUTS. CONCLUSIONS: Patients undergoing prostate biopsy have, with a high probability, LUTS. Approximately 50% suffer from some degree of erectile dysfunction and 24% had some kind of urinary leakage. PMID- 25704506 TI - SOX2 expression in gastrointestinal cancers of Iranian patients. AB - PURPOSE: Gastrointestinal (GI) malignancies are among the 5 most common cancers in Iran, and their high associated mortality rates are attributable to late diagnosis and poor treatment options. SOX2, a transcription factor necessary for maintenance and induction of pluripotency and self-renewal, has been identified as a lineage-survival oncogene in several cancers. In the present study, we examined SOX2 expression in esophageal squamous cell carcinoma (ESCC), gastric adenocarcinoma and colon squamous cell carcinoma (SCC), as well as normal GI tissues, in Iranian patients. METHODS: To elucidate the role of SOX2 in GI carcinogenesis, formalin-fixed tissues were analyzed using immunohistochemistry (IHC), while frozen ESCC samples were studied by quantitative reverse transcription polymerase chain reaction (qRT-PCR). RESULTS: IHC studies indicated presence of SOX2+ cells in a subset of cancerous and normal tissues of stomach and colon, while no significant difference was observed between groups, and no correlation was found between SOX2 expression and tumors grades. Nevertheless, studying ESCC samples with IHC and qRT-PCR revealed overexpression of SOX2 in comparison with normal adjacent tissues. CONCLUSIONS: The present results are in line with other studies and indicate SOX2 up-regulation in ESCC; however, due to our small sample size and contradictory reports, more research is needed to determine the importance of SOX2 in GI cancers. PMID- 25704507 TI - Moving from discovery to validation in circulating microRNA research. AB - BACKGROUND: MicroRNAs (miRNAs), small noncoding RNAs, are involved in tumorigenesis and in the development of various cancers. Quantitative real-time polymerase chain reaction (qPCR) is the most commonly used tool to investigate miRNA expression, and qPCR low-density arrays are increasingly being used as an experimental technique for both the identification of potentially relevant miRNAs and their subsequent validation. Due to the reduced number of microRNAs to be validated, this phase is generally performed on ad hoc customized cards for which a technical robustness is assumed similar to that of the high-throughput cards used during the identification phase. METHODS: With the aim of investigating the degree of reproducibility between the 2 types of cards, we analyzed plasma circulating miRNAs evaluated in 60 subjects enrolled in a colorectal cancer screening program. RESULTS: Our results showed a reproducibility between the 2 methods that was not fully satisfactory, with a concordance correlation coefficient equal to 0.69 (95% confidence interval, 0.12-0.92). CONCLUSIONS: This report highlights the need to add a technical validation step to the high throughput-based miRNA identification workflow, after their discovery and before the validation step in an independent series. PMID- 25704508 TI - Physicochemical and biological characterization of 1,2-dialkoylamidopropane-based lipoplexes for gene delivery. AB - Elucidation of the molecular and formulation requirements for efficient lipofection is a prerequisite to enhance the biological activity of cationic lipid-mediated gene delivery systems. To this end, the in vitro lipofection activity of the ionizable asymmetric 1,2-dialkoylamidopropane-based derivatives bearing a single primary amine group as the cationic head group was evaluated. The electrostatic interactions of these cationic lipids with plasmid DNA in serum free medium were investigated by means of gel electrophoresis retardation and Eth Br quenching assays. The effect of the inclusion of the helper lipid DOPE in the formulation on these interactions was also considered. The physicochemical properties of these lipids in terms of bilayer fluidity and extent of ionization were investigated using fluorescence anisotropy and surface potential techniques, respectively. The results showed that only the active lipid, 1,2lmp[5], existed in a liquid crystalline state at physiological temperature. Moreover, the extent of ionization of this lipid in assemblies was significantly higher that it's saturated analogues. Inclusion of the helper lipid DOPE improved the encapsulation and association between 1,2lmp[5] and plasmid DNA, which was reflected by the significant boost of lipofection activity of the 1,2lmp[5]/DOPE formulation as compared to the lipid alone. In conclusion, membrane fluidity and sufficient protonation of ionizable cationic lipid are required for efficient association and encapsulation of plasmid DNA and elicit of improved in vitro lipofection activity. PMID- 25704509 TI - Bark beetle controls epithelial morphogenesis by septate junction maturation in Drosophila. AB - Epithelial tissues separate body compartments with different compositions. Tight junctions (TJs) in vertebrates and septate junctions (SJs) in invertebrates control the paracellular flow of molecules between these compartments. This epithelial barrier function of TJs and SJs must be stably maintained in tissue morphogenesis during cell proliferation and cell movement. Here, we show that Bark beetle (Bark), a putative transmembrane scavenger receptor-like protein, is essential for the maturation but not the establishment of SJs in Drosophila. Embryos that lack bark establish functional SJs, but due to rudimentary septae formation during subsequent embryonic development, these become non-functional. Furthermore, cell adhesion is impaired at the lateral cell membrane and the core protein complexes of SJs are mis-localised, but appear to form otherwise normally in such embryos. We propose a model in which Bark acts as a scaffold protein that mediates cell adhesion and mounting of SJ core complexes during cell rearrangement in tissue morphogenesis. PMID- 25704510 TI - The myogenic repressor gene Holes in muscles is a direct transcriptional target of Twist and Tinman in the Drosophila embryonic mesoderm. AB - Understanding the regulatory circuitry controlling myogenesis is critical to understanding developmental mechanisms and developmentally-derived diseases. We analyzed the transcriptional regulation of a Drosophila myogenic repressor gene, Holes in muscles (Him). Previously, Him was shown to inhibit Myocyte enhancer factor-2 (MEF2) activity, and is expressed in myoblasts but not differentiating myotubes. We demonstrate that different phases of Him embryonic expression arises through the actions of different enhancers, and we characterize the enhancer required for its early mesoderm expression. This Him early mesoderm enhancer contains two conserved binding sites for the basic helix-loop-helix regulator Twist, and one binding site for the NK homeodomain protein Tinman. The sites for both proteins are required for enhancer activity in early embryos. Twist and Tinman activate the enhancer in tissue culture assays, and ectopic expression of either factor is sufficient to direct ectopic expression of a Him-lacZ reporter, or of the endogenous Him gene. Moreover, sustained expression of twist in the mesoderm up-regulates mesodermal Him expression in late embryos. Our findings provide a model to define mechanistically how Twist can both promotes myogenesis through direct activation of Mef2, and can place a brake on myogenesis, through direct activation of Him. PMID- 25704513 TI - [Coronary stents: don't administer platelet aggregation inhibitors too long. ]. PMID- 25704511 TI - An oncologist's friend: How Xenopus contributes to cancer research. AB - One of the most striking features of the Xenopus system is the versatility in providing a unique range of both in vitro and in vivo models that are rapid, accessible and easily manipulated. Here we present an overview of the diverse contribution that Xenopus has made to advance our understanding of tumour biology and behaviour; a contribution that goes beyond the traditional view of Xenopus as a developmental model organism. From the utility of the egg and oocyte extract system to the use of whole embryos as developmental or induced tumour models, the Xenopus system has been fundamental to investigation of cell cycle mechanisms, cell metabolism, cell signalling and cell behaviour, and has allowed an increasing appreciation of the parallels between early development and the pathogenesis of tumour progression and metastasis. Although not the prototypical oncological model system, we propose that Xenopus is an adaptable and multifunctional tool in the oncologist's arsenal. PMID- 25704512 TI - BMP-dependent gene repression cascade in Drosophila eggshell patterning. AB - Bone Morphogenetic Proteins (BMPs) signal by activating Smad transcription factors to control a number of decisions during animal development. In Drosophila, signaling by the BMP ligand Decapentaplegic (Dpp) involves the activity of brinker (brk) which, in most contexts, is repressed by Dpp. Brk encodes a transcription factor which represses BMP signaling output by antagonizing Smad-dependent target gene activation. Here, we study BMP-dependent gene regulation during Drosophila oogenesis by following the signal transmission from Dpp to its target broad (br), a gene with a crucial function in eggshell patterning. We identify regulatory sequences that account for expression of both brk and br, and connect these to the transcription factors of the pathway. We show that Dpp directly regulates brk transcription through Smad- and Schnurri (Shn)-dependent repression. Brk is epistatic to Dpp in br expression and activates br indirectly, through removal of a repressor, which is yet to be identified. Our work provides first cis-regulatory insights into transcriptional interpretation of BMP signaling in eggshell morphogenesis and defines a transcriptional cascade that connects Dpp to target gene regulation. PMID- 25704514 TI - [Type 2 diabetes: Metformin: first choice at the start of therapy]. PMID- 25704515 TI - [ECG in diabetics: prolonged p wave predicts fatal strokes]. PMID- 25704518 TI - [Acute renal failure: a disease picture with many names]. PMID- 25704519 TI - [Diagnosis and pathophysiology of acute renal failure - is prevention possible?]. AB - Acute kidney injury (AKI) in critically ill patients is on a dramatic rise. The same holds true for community acquired AKI. Two main mechanisms are responsible for this increase: the rising prevalence of chronic kidney disease and the progress in diagnostic and therapeutic procedures pushing the limits of impossible. Several new biomarkers have not only helped to identify patients at risk for AKI and diagnosing AKI within hours after the insult, they also helped improve our pathophysiological understanding of AKI. The increase in AKI and new diagnostic markers of it is currently not matched by an increase in prophylactic or therapeutic interventions. It is quite the opposite. For decades we have seen spectacular effects of new drugs and interventions in the preclinical setting, always followed by a miserable failure at the bedside. It seems that one non pharmacological intervention, i. e. the human resource of being educated in nephrology might be of importance not only for those suffering from AKI in the intensive care unit but also for those surviving it. This comes to no surprise if one considers acute and chronic kidney diseases not as separate entities but rather as closely interconnected. PMID- 25704520 TI - [Is acute renal failure in elderly patients crucial for all-cause mortality?]. AB - Acute kidney injury (AKI) in the elderly is associated with high risks of chronic kidney disease (CKD), hospital- and all-cause mortality. Based on the decreased renal function in older age groups and age-specific co-morbidity as hypertension, cardiovascular complications, and diabetes mellitus, the risk for AKI is increased. In outpatients inadequate pharmacotherapy and self-medication contribute to increased risk of AKI while in hospital settings severe infection, cardiovascular interventions with contrast media and major surgery may result in higher rates of AKI. Every fourth case is on risk for recurrent AKI followed by advanced CKD and renal replacement therapy. In the oldest old with high co morbidity condition indication of renal replacement in AKI should be processed by shared-decision making. In many cases palliative care in this setting may be appropriate. PMID- 25704521 TI - [Acute renal failure and vasculitis - when to consider it and what to do about it?]. AB - Renal involvement in systemic autoimmune diseases such as ANCA-vasculitis is common. Acute kidney injury (AKI) limits the prognosis of the patient and needs to be detected early. However, AKI is in early phases clinically inapparent and at first contact with the patient, extra-renal symptoms may dominate the clinical presentation. Serum-Creatinine and urinary analysis provide useful information on the extent of renal involvement. A renal biopsy should confirm the diagnosis. Treatment needs to be adapted to the extent of ANCA-vasculitis and in cases with severe organ failure plasmapheresis should be performed. Maintenance immunosuppressive is necessary to prevent relapses and the patients should be monitored closely to detect renal flares early. PMID- 25704522 TI - [Lung involvement in patients with primary biliary cirrhosis]. AB - HISTORY AND CLINICAL FINDINGS: For several months a 29 years old woman suffered from dry cough, dyspnea, and weakness. The clinical examination was without any abnormal findings. INVESTIGATIONS: Liver function tests and erythrocyte sedimentation rate were raised. High resolution CT chest scan showed multiple patchy alveolar and interstitial infiltrates. Transbronchial and surgical lung biopsy confirmed a moderate alveolitis with granulomas. DIAGNOSIS: primary biliary cirrhosis (pbc) complicated by lung disease could be diagnosed through increased titer of antimitochondrial antibodies and the laparoscopy. TREATMENT AND COURSE: Under treatment of pbc with either corticosteroids or Ursodeoxycholic acid, liver enzymes decreased and pulmonary symptoms disappeared. CONCLUSION: To detect lung involvement in patients with pbc early, lung function tests and diffusion capacity should be monitored regularly. An otherwise unexpected rise in liver function tests, particularly in patients with underlying interstitial lung disease or sarcoid granulomatosis should promptly be investigated further. PMID- 25704523 TI - [Fibroscan of the liver]. PMID- 25704524 TI - [Pharmacokinetics of antibiotics in obese and critical care patients]. AB - Against the background of reduced susceptibility of many pathogens to available antibacterial agents an optimized dosing of antibiotics is of increasing importance to avoid therapeutic failures and / or microbial resistance. Consideration of the individual body weight, as well as kidney and liver function of a patient and the pharmacodynamics and pharmacokinetic properties of the antibiotic should enable an individualized dosing. An optimized approach could increase efficacy and safety of an antimicrobial therapy significantly. Aimed studies in overweight patients during the clinical development of a new antibiotic are necessary as a substantial prerequisite for a pharmacokinetically based optimized dosing. Intensive care patients also exhibit major changes in pharmacokinetics of antibiotics due to pathophysiological changes. An increased volume of distribution, an increased clearance and reduced protein binding require treatment with increased doses. On the other hand, in patients with acute renal failure often doses have to be reduced and / or the dosing interval has to be prolonged. Renal function should be assessed on the basis of the creatinine clearance. An estimation with the often applied plasma creatinine-based equations can lead to wrong results in critically ill patients, a directly measured urinary creatinine clearance is a more reasonable procedure. However, so far only few prospective studies which investigated the effect of alternative dosing strategies on the therapeutic outcome have been published. Certainly, further comprehensive studies are necessary. PMID- 25704525 TI - [What is new in treating Helicobacter pylori infection?]. AB - Helicobacter pylori (HP) infection is the commonest chronic bacterial infection of man. Most gastroduodenal ulcers are due to HP infection. In addition, HP infection is considered to be the main aetiological factor of gastric carcinogenesis. For more than 30 years antibiotic therapy has been very effective in eradicating HP. Both antibiotic resistance and insufficient adherence to treatment threaten the efficacy of eradication therapy. Secondary antimicrobial resistance rates of H. pylori as published by the German National Reference Centre show the drastic increase of antibiotic resistance. If the initial standard triple therapy fails, the secondary resistances rise up to about 62 % for metronidazole, 66 % for clarithromycin and 21 % for quinolones. Therefore we should aim at a highly effective first-line treatment strategy that takes into account any risk of antibiotic resistance in an individual patient. Adherence to therapy and eradication efficacy will have to be monitored even more carefully in the future. PMID- 25704526 TI - [When patients bring their own medical devices into hospital - position paper of the German Society for Sleep Research and Sleep Medicine, Section 8 of the German Society of Pneumology and the Association of Pneumological hospitals]. PMID- 25704527 TI - [Communication with hypertensive patients]. PMID- 25704528 TI - [Trend of quality of hospital care in German hospitals between 2008 and 2011: a study from national quality assurance data]. AB - BACKGROUND AND OBJECTIVES: According to S 137 social code book (SGB) V, data from the national quality assurance are published annually. Objective of this study was to analyse the long-term development of the quality of hospital care. METHODS: On the basis of national data and results of another study covering the years 2004-2008, quality indicators with comparable results of at least 3 subsequent years were included. 292 quality indicators of 26 service groups and 14 medical fields were included. We identified a trend with linear regression and continuous change. RESULTS: 95 % of the performance measures showed either an improvement of quality (105 measures, 36 %) or a stable condition (173 measures, 59 %). Five percent of the quality indicators (14 measures) showed a deterioration. Eleven of the 14 measures assessed quality in coronary angiography and percutaneous coronary intervention. CONCLUSION: Evaluated with performance measures from the national quality assurance, the quality of hospital care improved from 2008-2011, as already from 2004-2008. The deterioration of quality in 5 % of measures shows the need for action in particular situations of care. PMID- 25704529 TI - Feasibility of an experiential community garden and nutrition programme for youth living in public housing. AB - OBJECTIVE: Few published community garden studies have focused on low socio economic youth living in public housing or used a community-based participatory research approach in conjunction with youth-focused community garden programmes. The objective of the present study was to evaluate the feasibility (i.e. demand, acceptability, implementation and limited-effectiveness testing) of a 10-week experiential theory-based gardening and nutrition education programme targeting youth living in public housing. DESIGN: In this mixed-methods feasibility study, demand and acceptability were measured using a combination of pre- and post programme surveys and interviews. Implementation was measured via field notes and attendance. Limited-effectiveness was measured quantitatively using a pre-post design and repeated-measures ANOVA tests. SETTING: Two public housing sites in the Dan River Region of south central Virginia, USA. SUBJECTS: Forty-three youth (primarily African American), twenty-five parents and two site leaders. RESULTS: The positive demand and acceptability findings indicate the high potential of the programme to be used and be suitable for the youth, parents and site leaders. Field notes revealed numerous implementation facilitators and barriers. Youth weekly attendance averaged 4.6 of 10 sessions. Significant improvements (P<0.05) were found for some (e.g. fruit and vegetable asking self-efficacy, overall gardening knowledge, knowledge of MyPlate recommendations), but not all limited effectiveness measures (e.g. willingness to try fruits and vegetables, fruit and vegetable eating self-efficacy). CONCLUSIONS: This community-based participatory research study demonstrates numerous factors that supported and threatened the feasibility of a gardening and nutrition programme targeting youth in public housing. Lessons learned are being used to adapt and strengthen the programme for future efforts targeting fruit and vegetable behaviours. PMID- 25704530 TI - beta-Tricalcium phosphate for bone replacement: stability and integration in sheep. AB - Implants of microporous beta-tricalcium phosphate (beta-TCP) were developed for primarily stable supply of bone defects. A consistent stability over the healing period should be retained in sheep. beta-TCP cylindrical shaped implants, with 7 mm diameter, 25 mm length, medium pore diameter 5 MUm and 40% porosity were developed. Fresh bone defects of 21 sheep in the medial femur condyle were filled with the implants. At time zero, after 6, 12 and 24 weeks the knees of each 7 animals were studied. Specimens were investigated radiologically, followed by biomechanical and histological analysis. Radiological analysis showed progressive resorption. 6 weeks after surgery results of the indentation test were slightly lower, after 12 and 24 weeks higher than on the healthy opposite knee. At 6 weeks a phagocyte reaction overbalanced. After 12 weeks bone regeneration around the implant was seen. After 24 weeks a highly advanced resorption of TCP implant was realized. The trabecular structure of the new bone increased after 24 weeks. Using microporous beta-TCP implants continuous stable filling of bone defects can be reached in sheep. Microporous beta-TCP implants are resorbed and replaced by bone. PMID- 25704531 TI - Validation of a method to accurately correct anterior superior iliac spine marker occlusion. AB - Anterior superior iliac spine (ASIS) marker occlusion commonly occurs during three-dimensional (3-D) motion capture of dynamic tasks with deep hip flexion. The purpose of this study was to validate a universal technique to correct ASIS occlusion. 420 ms of bilateral ASIS marker occlusion was simulated in fourteen drop vertical jump (DVJ) trials (n=14). Kinematic and kinetic hip data calculated for pelvic segments based on iliac crest (IC) marker and virtual ASIS (produced by our algorithm and a commercial virtual join) trajectories were compared to true ASIS marker tracking data. Root mean squared errors (RMSEs; mean+/-standard deviation) and intra-class correlations (ICCs) between pelvic tracking based on virtual ASIS trajectories filled by our algorithm and true ASIS position were 2.3+/-0.9 degrees (ICC=0.982) flexion/extension, 0.8+/-0.2 degrees (ICC=0.954) abduction/adduction for hip angles, and 0.40+/-0.17 N m (ICC=1.000) and 1.05+/ 0.36 N m (ICC=0.998) for sagittal and frontal plane moments. RMSEs for IC pelvic tracking were 6.9+/-1.8 degrees (ICC=0.888) flexion/extension, 0.8+/-0.3 degrees (ICC=0.949) abduction/adduction for hip angles, and 0.31+/-0.13 N m (ICC=1.00) and 1.48+/-0.69 N m (ICC=0.996) for sagittal and frontal plane moments. Finally, the commercially-available virtual join demonstrated RMSEs of 4.4+/-1.5 degrees (ICC=0.945) flexion/extension, 0.7+/-0.2 degrees (ICC=0.972) abduction/adduction for hip angles, and 0.97+/-0.62 N m (ICC=1.000) and 1.49+/-0.67 N m (ICC=0.996) for sagittal and frontal plane moments. The presented algorithm exceeded the a priori ICC cutoff of 0.95 for excellent validity and is an acceptable tracking alternative. While ICCs for the commercially available virtual join did not exhibit excellent correlation, good validity was observed for all kinematics and kinetics. IC marker pelvic tracking is not a valid alternative. PMID- 25704532 TI - Stiffening effects of riboflavin/UVA corneal collagen cross-linking is hydration dependent. AB - The collagen cross-linking is a relatively new treatment option for strengthening the cornea, delaying, and in some cases stopping the progression of keratoconus. The uniaxial tensile experiments are among the most commonly used techniques to assess the effectiveness of this therapeutic option in enhancing tensile properties. In the present study, we investigated the possible effects of hydration on stiffening effects of corneal collagen cross-linking procedure, as measured by the uniaxial tensile testing method. For this purpose, after cross linking bovine corneas, we let the strips to dehydrate in air or swell in a solution until their thickness reached an average thickness of 0.5, 0.7, 0.9, 1.1, and 1.5 mm. Using thickness as a representative of hydration, we divided corneal strips into five different groups and measured their stress-strain behavior by conducting uniaxial tensile experiments in mineral oil. It was observed that the collagen cross-linking treatment and hydration together affect the tensile behavior of the bovine cornea. While corneal collagen cross-linking resulted in a significant increase in the tensile stress-strain response of each thickness group (P<0.01), less hydrated collagen cross-linked samples showed a significantly stiffer response (P<0.01). A master curve was found for representing the tensile behavior of the collagen cross-linked bovine cornea at different levels of hydration. The results of the present research confirmed that the amount of mechanical stiffening of the corneal collagen cross-linking, as measured by uniaxial tensile testing, strongly depends on the hydration. Therefore, it is concluded that uniaxial tensile experiments could only be used to assess stiffening effects of the collagen cross-linking treatment if the hydration of specimens is fully controlled. PMID- 25704533 TI - Toward ion-free polyelectrolyte multilayers: cyclic salt annealing. AB - Polyelectrolyte multilayers (PEMUs) are made from various combinations of polyanions and polycations. It is now understood that these ultrathin films of polyelectrolyte complex may also incorporate counterions derived from the solutions from which the PEMU was deposited or exchanged into the film postassembly. If these ions are required to compensate nonstoichiometric ratios of polycation and polyanion they cannot leave the film and exert considerable influence on film properties, such as modulus and permeability. These "extrinsic" charges also complicate fundamental studies on PEMUs. We report a method to remove almost all ionic content from a PEMU made of poly(diallyldimethylammonium chloride), PDADMAC, and poly(styrenesulfonate), PSS. In this method, a high salt concentration plasticizes the multilayer past its glass transition, dispersing all the buried excess PDADMA throughout the film. Exposure to a solution of PSS in a lower salt concentration consumes excess PDADMA near the surface without overcompensating with PSS. The process is repeated in a cyclic fashion, removing >95% of the ions charge present in the as-made PEMU. PMID- 25704534 TI - Comparative analysis of active retrotransposons in the transcriptomes of three species of heteromyid rodents. AB - Virtually every eukaryotic genome is replete with transposable elements (TEs). TE activity, or lack thereof, is of considerable evolutionary interest as TE insertions actively drive genome evolution by altering gene expression and/or function through different mechanisms. Herein, we take a comparative approach to better understand the variation in TE transcriptional activity. Our goals were to identify transcriptionally active TEs and to evaluate their relative expression levels in an effort to identify key determinants of TE activity. We do so in three related non-model rodent species (Dipodomys spectabilis, Chaetodipus baileyi, and Heteromys desmarestianus). We used these species (a) because rodents have long been productive models for the study of TEs; (b) because the known and dated relationships among these species permit strong phylogenetic inference (e.g., ancestral character states); and (c) because we have previously characterized key genes that underlie evolutionary adaptations in these species (e.g., osmoregulation). We used RNA-seq to characterize the transcriptomes of two different tissues--kidney and spleen--in each of these three species. Our data revealed a diversity of retrotransposons that were actively transcribed in these rodents (including LINEs, retroviruses/ERVs, and SINEs). We also identified tissue-specific differences in retrotransposon-activity in about half of the retrotransposons detected. We interpret these differences in TE activity in light of overall gene expression, with the transcribed SINEs enriched in differentially expressed sequences in all three species. These transcribed TEs may simply represent transpositionally active TEs. Alternatively, they may be TEs that have been co-opted to represent functionally important components of the host transcriptome (i.e., exaptations). Overall, our results contribute to a growing appreciation for the evolutionary interplay between TEs and their hosts. PMID- 25704535 TI - Transcriptional profiles underpin microsatellite status and associated features in colon cancer. AB - INTRODUCTION: While microsatellite instability is associated with prognosis and distinct clinical phenotypes in colon cancer, the basis for this remains incompletely defined. Novel bioinformatic techniques enable a detailed interrogation of the relationship between gene expression profiles and tumor characteristics. AIM: We aimed to determine if microsatellite instability high (MSI-H) and microsatellite stable (MSS) tumors could be differentiated by gene expression profiles. We investigated the basis of this using a system and network based algorithmic approach. METHODS: Microsatellite status was established using a polymerase chain reaction (PCR) panel and fragment length analysis. Gene expression was determined using Illumina(c) microarrays comprising 48,701 transcripts, and scaling normalization was conducted using Limma in R. Following filtration for non-significant changes a meta-gene was established and subjected to unsupervised hierarchical clustering using Chipster(c). A supervised learning algorithm (PAM) was used to generate a gene-expression based clinical-outcome predictor that was further tested using an independent validation group. A network based linkage analysis was conducted using Ingenuity(c) focusing on canonical, functional pathways, and associated therapeutic modalities. RESULTS: MSI-H and MSS tumors clustered separately following an unsupervised hierarchical clustering analysis. A transcriptomic classifier (with 19 component genes) was generated that reliably and reproducibly predicted microsatellite status. MSI-H associated canonical pathways were predominantly immune or inflammation related converging on increased IL-1B and thymidylate synthase expression. The network linkage analysis identified canakinumab, IL-trap and MDX-1100 as the strongest therapeutic candidates that remain to be assessed in the colon cancer setting. CONCLUSIONS: Microsatellite status is underpinned by transcriptional events and can be accurately and reliably defined by differential gene expression. A specific transcriptomic profile is pathognomonic and provides insight into the differences in biology between MSS and MSI-H colon cancers. PMID- 25704536 TI - Towards better patient safety in otolaryngology: characteristics of patient injuries and their relationship with items on the WHO Surgical Safety Checklist. AB - OBJECTIVES: Increasing knowledge of factors contributing to medical adverse events has influenced the development of preventive policies and protocols, the WHO Surgical Safety Checklist being the most widely known. Despite growing evidence of the checklist's effectiveness in surgery, its role in preventing adverse events in otolaryngology is unclear. We assessed patient injury contributing factors in otolaryngology and their relationship with WHO checklist items. STUDY DESIGN: A retrospective claim record study of national patient insurance charts in Finland. SETTING AND PARTICIPANTS: The records of all accepted patient injury claims in otolaryngology between 2001 and 2011 were searched and reviewed by two otolaryngologists. Operation-related injuries were evaluated in detail. Factors contributing to injury were identified, classified and compared with items on the WHO checklist. We also estimated whether the injury might have been prevented with a properly used checklist. RESULTS: In the 10-year study period, 188 (84.3%) of the 223 patient injuries were associated with operative care. Of these, 142 (75.5%) occurred in the operation theatre, and in 121 cases (64.4%), technical error in performing surgery was the primary cause of injury. In 18 injuries (9.6%), the error corresponded to a checklist item. Nine injuries (4.8%) could have been prevented with a properly used checklist. CONCLUSIONS: Patient injuries in otolaryngology are strongly related to operative care. The WHO checklist is one suitable tool for error prevention. PMID- 25704537 TI - Optical mechanotransduction with carbazole-based luminescent liquid single crystal elastomers. AB - Carbazole-based liquid single-crystal elastomers (LSCEs) are valuable fluorescent flexible materials to perform optical mechanotransduction under ambient conditions. Indeed, the covalent incorporation of carbazole derivatives into nematic LSCEs allows to tune their luminescence on demand under mechanical control in a quick and reversible fashion. Specifically, the fluorescence intensity for these materials can be switched back and forth in less than a second. Moreover, such a process can be performed several times without detecting any sign of fatigue in the system. In addition, these materials show excellent resistance to aging; 2 years after their preparation they exhibit the very same mechanofluorescent behavior as when freshly prepared. In fact, the here reported fluorescent systems are highly sensitive; the application of a force of 70 mN decreases the fluorescence in the elastomeric material by 7%. Thus, mechanical forces are attractive external stimuli to modulate the fluorescence of nematic elastomers rapidly and reversibly enabling thereby mechanotransduction. PMID- 25704538 TI - Loading of Hip Measured by Hip Contact Forces at Different Speeds of Walking and Running. AB - Exercise plays a pivotal role in maximizing peak bone mass in adulthood and maintaining it through aging, by imposing mechanical loading on the bone that can trigger bone mineralization and growth. The optimal type and intensity of exercise that best enhances bone strength remains, however, poorly characterized, partly because the exact peak loading of the bone produced by the diverse types of exercises is not known. By means of integrated motion capture as an input to dynamic simulations, contact forces acting on the hip of 20 young healthy adults were calculated during walking and running at different speeds. During walking, hip contact forces (HCFs) have a two-peak profile whereby the first peak increases from 4.22 body weight (BW) to 5.41 BW and the second from 4.37 BW to 5.74 BW, by increasing speed from 3 to 6 km/h. During running, there is only one peak HCF that increases from 7.49 BW to 10.01 BW, by increasing speed from 6 to 12 km/h. Speed related profiles of peak HCFs and ground reaction forces (GRFs) reveal a different progression of the two peaks during walking. Speed has a stronger impact on peak HCFs rather than on peak GRFs during walking and running, suggesting an increasing influence of muscle activity on peak HCF with increased speed. Moreover, results show that the first peak of HCF during walking can be predicted best by hip adduction moment, and the second peak of HCF by hip extension moment. During running, peak HCF can be best predicted by hip adduction moment. The present study contributes hereby to a better understanding of musculoskeletal loading during walking and running in a wide range of speeds, offering valuable information to clinicians and scientists exploring bone loading as a possible nonpharmacological osteogenic stimulus. (c) 2015 American Society for Bone and Mineral Research. PMID- 25704539 TI - Refractory dissolved organic nitrogen accumulation in high-elevation lakes. AB - The role of dissolved organic matter (DOM) as either a sink for inorganic nutrients or an additional nutrient source is an often-neglected component of nutrient budgets in aquatic environments. Here, we examined the role of DOM in reactive nitrogen (N) storage in Sierra Nevada (California, USA) lakes where atmospheric deposition of N has shifted the lakes toward seasonal phosphorus (P) limitation. Nuclear magnetic resonance (NMR) spectroscopy and isotope analyses performed on DOM isolated from Lake Tahoe reveal the accumulation of refractory proteinaceous material with a 100-200-year residence time. In contrast, smaller lakes in the same watershed contain DOM with typical terrestrial characteristics, indicating that proteins in Lake Tahoe are autochthonously produced. These data support the role of DOM as a possible sink for reactive N in these lake ecosystems and identify a potential role for DOM in affecting the inorganic nutrient stoichiometry of these environments. PMID- 25704540 TI - The magnetic anal sphincter: a seductive promise still not kept. PMID- 25704541 TI - BRAF V600E mutational status in bile duct adenomas and hamartomas. AB - AIMS: Bile duct adenomas (BDA) and bile duct hamartomas (BDH) are benign bile duct lesions considered neoplastic or secondary to ductal plate malformation, respectively. We have reported previously a high prevalence of BRAF V600E mutations detected by allele-specific polymerase chain reaction assay in BDA, and suggested that BDA may be precursors to a subset of intrahepatic cholangiocarcinomas harbouring V600E mutations. The aim of the present study was to assess the existence of BRAF V600E mutations, using immunohistochemical methods, in additional BDA as well as in BDH. METHODS AND RESULTS: Fifteen BDA and 35 BDH were retrieved from the archives of the pathology departments of two French university hospitals. All cases were reviewed by two pathologists specialized in liver diseases. BRAF V600E mutational status was investigated by immunohistochemistry. Mutated BRAF mutant protein was detected in 53% of the BDA and in none of the cases of BDH. CONCLUSION: Our findings suggest that BDA and BDH are different processes, and that BDA represent true benign neoplasms. They also support the hypothesis that mutated BDA might precede the development of the subset of intrahepatic cholangiocarcinomas harbouring BRAF V600E mutations. PMID- 25704542 TI - What's in this issue? PMID- 25704543 TI - Sex-dependent disparities in critical illness: methodological implications for critical care research. PMID- 25704546 TI - EfCCNa Exchange Programme-experience critical care in Europe. PMID- 25704547 TI - Critical care nurse recruitment: a BACCN forum. PMID- 25704548 TI - Stability determination of the formulations containing hyaluronic acid. AB - OBJECTIVES: The aim of this work was to investigate the long-term stability of four emulsions (creams and ointments) developed for carrying hyaluronic acid (HA) for dermal penetration. METHODS: The stability of obtained formulations was analysed by multiple light scattering and laser diffraction methods. RESULTS: The experimental results showed that the moisturizing creams were more stable than the ointments containing HA. The migration phenomenon of particles was observed in soft ointment with HA and the flocculation phenomenon was detected in ointment based on lanolin. The larger the water content, the more stable formulation can be, due to hygroscopic properties of HA. CONCLUSIONS: The identification of instability phenomena was shortened dramatically using optical method such as multiple light scattering. Even small changes in the stability of emulsion were determined very early. We suggest that the moisturizing creams may be more suitable than ointments to carry HA for dermal absorption. These studies are a significant first step towards further exploration into what form of HA would assure maximum effect, give consumers satisfaction and guarantee safety during application. PMID- 25704549 TI - Enhanced quantum yield of nitrogen fixation for hydrogen storage with in situ formed carbonaceous radicals. AB - NH3 is a potential hydrogen energy carrier. Here we use alcohols as hole scavengers to investigate the nitrogen photofixation mechanisms including direct and indirect electron transfer processes. The t-butanol system exhibited the highest quantum yield of 36.1%, ascribing to the in situ-formed indirect electronic transmitter CO2(-). PMID- 25704550 TI - A novel toolkit to improve percutaneous subxiphoid needle access to the healthy pericardial sac. AB - INTRODUCTION: The current practice of percutaneous subxiphoid needle access to the "healthy" pericardial sac has significant limitations. We sought to examine the feasibility of a novel toolkit designed to improve this procedure. METHODS AND RESULTS: The toolkit included a pericardial access needle and a virtual imaging platform. The needle had a 0.036 inch outer diameter, abbreviated 25 degrees bevel, and was electrically insulated except for two small surfaces recessed from the tip. Radiofrequency energy was delivered via these surfaces to facilitate pericardial perforation. The virtual imaging system demonstrated the needle in real time and in its entirety within the thoracic anatomy of the individual animal, which was reconstructed from computed tomographic images obtained preoperatively and registered to the operative field. In five large (40 60 kg) healthy pigs, percutaneous subxiphoid access to the sac using both anterior and posterior approaches was performed. Spatial inaccuracy was measured as the distance between the pericardial puncture site and the anterior or posterior descending coronary artery, the pericardium contiguous to which had been targeted by the needle. In each animal, pericardial access was gained at 4 discrete sites (2 anterior, 2 posterior). Inaccuracy was 4.2 +/- 2.2 millimeters (range 0-8 millimeters) and did not differ significantly between anterior and posterior approaches. No damage to the epicardium or coronary arteries was observed. CONCLUSIONS: Percutaneous subxiphoid access to the pericardial sac utilizing this toolkit was feasible, including safety and reasonable accuracy. PMID- 25704551 TI - A comparison of six different ballast water treatment systems based on UV radiation, electrochlorination and chlorine dioxide. AB - The spread of aquatic invasive species through ballast water is a major ecological and economical threat. Because of this, the International Maritime Organization (IMO) set limits to the concentrations of organisms allowed in ballast water. To meet these limits, ballast water treatment systems (BWTSs) were developed. The main techniques used for ballast water treatment are ultraviolet (UV) radiation and electrochlorination (EC). In this study, phytoplankton regrowth after treatment was followed for six BWTSs. Natural plankton communities were treated and incubated for 20 days. Growth, photosystem II efficiency and species composition were followed. The three UV systems all showed similar patterns of decrease in phytoplankton concentrations followed by regrowth. The two EC and the chlorine dioxide systems showed comparable results. However, UV- and chlorine-based treatment systems showed significantly different responses. Overall, all BWTSs reduced phytoplankton concentrations to below the IMO limits, which represents a reduced risk of aquatic invasions through ballast water. PMID- 25704552 TI - Cross-modal, bidirectional priming in grapheme-color synesthesia. AB - Grapheme-color synesthetes perceive achromatic graphemes to be inherently colored. In this study grapheme-color synesthetes and non-synesthetes discriminated (1) the color of visual targets presented along with aurally presented digit primes, and (2) the identity of aurally presented digit targets presented with visual color primes. Reaction times to visual color targets were longer when the color of the target was incongruent with the synesthetic percept reported for the prime. Likewise, discriminating aurally presented digit targets took longer when the color of the prime was incongruent with the synesthetic percept for the target. These priming effects were absent in non-synesthetes. We conclude that binding between digits and colors in grapheme-color synesthetes can occur bidirectionally across senses. The results are in line with the idea that synesthesia is the result of linking inducing stimuli (e.g. digits) to synesthetic percepts (colors) at an abstract - supra-modal - conceptual level of processing. PMID- 25704553 TI - Echocardiographic Predictors of Progression to Persistent or Permanent Atrial Fibrillation in Patients with Paroxysmal Atrial Fibrillation (E6P Study). AB - BACKGROUNDS: Paroxysmal atrial fibrillation (AF) frequently, but not always, progresses to persistent/permanent AF. The aim of this study was to evaluate the echocardiographic predictors of AF progression in patients with paroxysmal AF. METHODS: A multicenter, prospective, observational study was conducted that included 313 patients with paroxysmal AF who underwent two-dimensional speckle tracking echocardiography. The diameter, volume, and mechanical function of the left atrium, including global strain (epsilon) and epsilon rate, were measured. RESULTS: Progression to persistent or permanent AF occurred in 52 patients (16.6%) during a median follow-up period of 26 months. Echocardiographic measure of left atrial (LA) diameter, volume, and function (E velocity, E/A and E/e' ratio, LA expansion index, active emptying fraction, global longitudinal epsilon and epsilon rate) were associated with AF progression. LA epsilon <= 30.9% was the strongest predictor of AF progression, which was associated with a more than fourfold hazard increase for AF progression (hazard ratio, 4.224; P = .001). LA diameter > 39 mm and maximal LA volume index > 34.2 mL/m(2) were associated with about a twofold hazard increase for AF progression (hazard ratios, 1.994 and 2.649; P = .016 and P = .001, respectively). When adjusted for a model combining maximal LA volume index, E velocity, LA expansion index, and active emptying fraction, LA epsilon <= 30.9% maintained a more than threefold hazard increase for AF progression (adjusted hazard ratio, 3.970; P = .003). CONCLUSIONS: Echocardiographic measures of LA diameter, volume, and mechanical function, including LA epsilon, were associated with AF progression. LA epsilon was the strongest independent predictor of AF progression and is expected to serve as a valuable predictor of AF progression. PMID- 25704554 TI - Introgression browser: high-throughput whole-genome SNP visualization. AB - Breeding by introgressive hybridization is a pivotal strategy to broaden the genetic basis of crops. Usually, the desired traits are monitored in consecutive crossing generations by marker-assisted selection, but their analyses fail in chromosome regions where crossover recombinants are rare or not viable. Here, we present the Introgression Browser (iBrowser), a bioinformatics tool aimed at visualizing introgressions at nucleotide or SNP (Single Nucleotide Polymorphisms) accuracy. The software selects homozygous SNPs from Variant Call Format (VCF) information and filters out heterozygous SNPs, multi-nucleotide polymorphisms (MNPs) and insertion-deletions (InDels). For data analysis iBrowser makes use of sliding windows, but if needed it can generate any desired fragmentation pattern through General Feature Format (GFF) information. In an example of tomato (Solanum lycopersicum) accessions we visualize SNP patterns and elucidate both position and boundaries of the introgressions. We also show that our tool is capable of identifying alien DNA in a panel of the closely related S. pimpinellifolium by examining phylogenetic relationships of the introgressed segments in tomato. In a third example, we demonstrate the power of the iBrowser in a panel of 597 Arabidopsis accessions, detecting the boundaries of a SNP-free region around a polymorphic 1.17 Mbp inverted segment on the short arm of chromosome 4. The architecture and functionality of iBrowser makes the software appropriate for a broad set of analyses including SNP mining, genome structure analysis, and pedigree analysis. Its functionality, together with the capability to process large data sets and efficient visualization of sequence variation, makes iBrowser a valuable breeding tool. PMID- 25704555 TI - Is axillary reverse mapping feasible in breast cancer patients? AB - In the surgical treatment of breast cancer, axillary lymph node dissection (ALND) can be avoided not only in sentinel lymph node (SLN)-negative patients but also in SLN-positive patients who undergo breast-conserving surgery with whole-breast irradiation and systemic therapy. However, it should be performed not only in clinically node-positive patients but also in other SLN-positive patients who do not meet the Z-0011 criteria. The axillary reverse mapping (ARM) technique has been developing for identifying and preserving lymphatic drainage from the arm during ALND, thereby expected to minimize arm lymphedema. Nevertheless, ARM nodes could be involved not only in clinically node-positive patients but also in clinically node-negative patients. Previously, it was considered that preservation of the ARM lymphatics or lymph nodes is not oncologically safe in patients with axillary lymph node metastases. However, recent studies have demonstrated that the ARM procedure is oncologically feasible in clinically node negative, SLN-positive patients when ARM nodes do not coincide with SLNs. When ARM nodes do not coincide with SLNs, they are not involved even in SLN-positive patients. On the other hand, ARM lymphatics/nodes within the boundaries of a standard ALND should be resected in SLN-positive patients, when ARM nodes are SLN ARM nodes. Therefore, surgical treatment of the axilla can be individualized on the basis of the axillary nodal status. PMID- 25704556 TI - Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS): short-term outcome, functional changes in the future liver remnant, and tumor growth activity. AB - BACKGROUND: We compared clinical outcomes of associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) against those of classical 2 stage hepatectomy in treating metastatic liver disease. METHODS: Short-term outcomes, serial changes in volume of the future liver remnant (FLR), functional FLR volume, and tumor growth activity during the treatment period, were compared between our first 11 consecutive patients treated with ALPPS and 54 patients treated with classical 2-stage hepatectomy. RESULTS: Mortality in the ALPPS group (9%) tended to be higher than in the classical 2-stage group (2%, P = 0.341). The FLR hypertrophy ratio (FLR volume after vs. before the procedure) 1 week after the first operation in the ALPPS group (1.54 +/- 0.18) exceeded that in the classical 2-stage group (1.19 +/- 0.29, P = 0.005), being similar to the ratio at 3 weeks after the first procedure in the classical 2-stage group (1.40 +/- 0.43). However, functional volume of the FLR in the ALPPS group 1 week after the first procedure (52.1%) tended to be smaller than that in the classical group 3 weeks after the first procedure (59.2%). CONCLUSIONS: ALPPS should be used with extreme caution, giving special attention to postoperative complications and grade of functional liver regeneration. PMID- 25704557 TI - Successful endoscopic management of gastric perforation caused by ingesting a sharp chicken bone. AB - INTRODUCTION: Gastrointestinal perforation related to foreign body ingestion is uncommon. Surgical interventions aiming at removal of the offending agent and restoration of bowel continuity are sought when perforations occur. Presentation of case A 68 year old male presented with epigastric abdominal pain and anorexia for 2 days. On examination, he was febrile and had localized epigastric tenderness. Laboratory investigations revealed marked leucocytosis with no other abnormalities. Computed tomography revealed the presence of a foreign body penetrating through the full thickness of the gastric wall with its tip lying adjacent to the pancreatic head. Endoscopic trial to extract the foreign body was successfully carried out. The gastric defect was sealed by applying an endoscopic metallic clip. DISCUSSION: Gastric perforations secondary to foreign body ingestion usually follow an elusive clinical course and are rarely diagnosed early in its course. Early diagnosis allows for the utilization of minimally invasive management. Unfortunately, Most reported cases were diagnosed after intra-abdominal processes, such as abscesses, have ensued. CONCLUSION: This case illustrates the importance of early diagnosis of foreign body related gastrointestinal perforations and emphasizes the role of therapeutic endoscopy. PMID- 25704558 TI - Actinomyces-induced inflammatory myofibroblastic tumor of the colon: A rare cause of an abdominal mass: Akbulut et al. inflammatory myofibroblastictumor due to actinomyces spp. AB - INTRODUCTION: Inflammatory myofibroblastic tumors (IMFTs) are neoplastic lesions that are either benign or have low-grade malignancy potential. Although the etiopathogenesis is not entirely clear, many factors play a role in their development, including trauma, autoimmune disorders, and infectious and inflammatory processes. However, IMFTs caused by Actinomyces spp. infection are rare, with a limited number of cases reported in the literature. PRESENTATION OF CASE: A 30-year-old woman was admitted to our clinic with abdominal pain and a palpable abdominal mass. Contrast-enhanced computed tomography revealed a tumoral lesion (11*10*7cm) in the right colon. A right hemicolectomy and ileocolic anastomosis were performed, during which almost complete obstruction of the lumen by the 7.5*7.0*5.0cm tumor was observed. Histopathology and immunohistochemical findings revealed that the tumor was consistent with an IMFT that developed from an Actinomyces infection. The patient was then placed on amoxicillin and doxycycline therapy. CONCLUSION: This case demonstrates that the development of IMFT secondary to actinomycosis is difficult to predict in the preoperative period. Once an exact diagnosis is confirmed by histopathologic examination, affected patients should receive prolonged antibiotherapy. PMID- 25704560 TI - Lung ILC2s link innate and adaptive responses in allergic inflammation. AB - How allergens trigger the T helper 2 (Th2) response that characterizes allergic lung inflammation is not well understood. Epithelium-derived alarmins released after an allergen encounter activate the innate immune system, including group 2 innate lymphoid cells (ILC2s) which produce the type 2 interleukins IL-5 and IL 13. It has been recently shown that ILC2-derived cytokines are responsible not only for the innate responses underlying allergic inflammation but also for the initiation of the adaptive Th2 response. We review the role of lung ILC2s in the development of allergic inflammation and, in the context of recent findings, propose a common pathway wherein ILC2s, activated by the epithelium-derived cytokine IL-33, link the innate and the adaptive responses after allergen encounter in the lung. PMID- 25704561 TI - Surface Trapping and STM Observation of Conformational Isomers of a Bis(Terpyridine) Ligand from Metallosupramolecular Grids. AB - Tetranuclear Co-grid complexes incorporating bis-tridentate ligands, namely 4,6 bis(2,2'-bipyrid-6-yl)-2-phenylpyrimidine, were electrosprayed onto a Au(111) substrate under an ultrahigh vacuum. Fragmentation occurs leaving the ligands in four different conformations. Most ligands are found to form H-bonded dimers. The most abundant conformer of the ligand on the Au surface is an asymmetric form, which has not been observed before. The present results indicate that the fragmentation of coordination compounds during the deposition process, in principle, allows for surface trapping, identification, and investigation of high energy, out-of-equilibrium conformations of the ligand molecules at low temperatures, which otherwise would not be observable. PMID- 25704559 TI - Interferons and viruses: an evolutionary arms race of molecular interactions. AB - Over half a century has passed since interferons (IFNs) were discovered and shown to inhibit virus infection in cultured cells. Since then, researchers have steadily brought to light the molecular details of IFN signaling, catalogued their pleiotropic effects on cells, and harnessed their therapeutic potential for a variety of maladies. While advances have been plentiful, several fundamental questions have yet to be answered and much complexity remains to be unraveled. We explore the current knowledge surrounding four main questions: are type I IFN subtypes differentially produced in response to distinct pathogens? How are IFN subtypes distinguished by cells? What are the mechanisms and consequences of viral antagonism? Lastly, how can the IFN response be harnessed to improve vaccine efficacy? PMID- 25704562 TI - Validation studies of the Edinburgh Postnatal Depression Scale for the antenatal period. AB - BACKGROUND: Relatively few studies have focused on the validation of psychometric scales measuring depression during pregnancy. The aim of this review was to critically appraise and review antenatal validation studies of the Edinburgh Postnatal Depression Scale (EPDS). METHODS: A systematic search was performed in MEDLINE, EMBASE, ISI, CINAHL, SCIELO and PsyCINFO for the period 1987-2013. RESULTS: Eleven validation studies met the inclusion criteria. The study design varied between studies. Sensitivity and specificity estimates also varied between 64-100% and 73-100%, respectively. The confidence interval estimates also showed a high degree of variability. Our estimates suggest lower positive predictive values in the general population than those reported in the validation study samples. The sensitivity values in validation studies of the EPDS show fairly large variability, ranging from good to acceptable. LIMITATIONS: Future studies should have larger sample sizes and include both representative and clinical samples and look at the psychometric performance of the EPDS in each trimester. CONCLUSIONS: Due to differences in study design and variation in the cultural/linguistic adaptation, uncertainty remains regarding the comparability of the sensitivity and specificity estimates of different EPDS versions. Future studies should have larger sample sizes, include both representative and clinical samples, and look at the psychometric performance of the EPDS in each trimester. Reporting quality, especially as regards checks to ensure content validity, should be improved. PMID- 25704563 TI - The benefit of combined acupuncture and antidepressant medication for depression: A systematic review and meta-analysis. AB - Acupuncture, one of the most popular complementary therapies, is best known for its ability to provide pain relief. Accumulating evidence suggests that acupuncture may also be beneficial in depression, although its effectiveness remains uncertain in this condition. We conducted a meta-analysis of randomized trials in which the effects of acupuncture combined with antidepressant medications were compared with those of antidepressant medications alone in adults with a diagnosed depressive disorder. Thirteen randomized controlled trials involving 1046 subjects were included in the meta-analysis. Our results confirmed that the pooled standardized mean difference of the 'endpoint scores of the 17-item Hamilton rating scale for depression' was -3.74 (95% CI, -4.77 to 2.70, p<0.001) in week 1 and -2.52 (95% CI, -4.12 to -0.92; p<0.01) in week 6, indicating a significant difference in favor of acupuncture combined with selective serotonin reuptake inhibitors (SSRIs). Moreover, therapeutic response rates were statistically significantly different between the two groups (risk ratio [RR], 1.23; 95% CI, 1.10 to 1.39; p<0.001; I(2)=68%) in favor of the combined treatment group. This systematic review and meta-analysis suggest that acupuncture combined with antidepressant medication is effective, has an early onset of action, safe and well-tolerated over the first 6-week treatment period. Moreover, this treatment combination appears to result in greater therapeutic efficacy than SSRI therapy alone. More high-quality randomized clinical trials are needed to evaluate the clinical benefit and long-term effectiveness of acupuncture in the treatment of depression. PMID- 25704564 TI - Further evidence of a dissociation between decision-making under ambiguity and decision-making under risk in obsessive-compulsive disorder. AB - BACKGROUND: Deficits in decision-making have been suggested as a key concept in understanding the symptoms of obsessive-compulsive disorder (OCD). However, evidence in the extant literature remains inconclusive on whether patients with OCD show inferior performance on laboratory decision-making tasks. The aims of the present study were therefore to (1) assess decision-making under ambiguity and under risk in patients with OCD and (2) study the influence of neuropsychological and clinical variables on decision-making in OCD. METHODS: The sample consisted of 65 patients with OCD and 58 controls. The Iowa gambling task (IGT) and the game of dice task (GDT) were used to examine decision-making under ambiguity and decision-making under risk, respectively. In addition, reversal learning and executive function were assessed in terms of their relationship with decision-making tasks. RESULTS: Patients with OCD showed impairment in the IGT, but not in the GDT. Reversal learning was neither impaired nor correlated with IGT performance. Among the clinical variables, illness severity and depression were associated with IGT scores. Executive function was impaired, but no significant relationship was found between executive function and GDT performance in OCD patients. LIMITATIONS: Almost all OCD patients were on medication when they performed decision-making tasks. CONCLUSIONS: Patients with OCD are impaired in decision-making under ambiguity, but not under risk. These findings demonstrate that decision-making processes are dissociated in OCD. PMID- 25704565 TI - What factors influence long-term antidepressant use in primary care? Findings from the Australian diamond cohort study. AB - BACKGROUND: Antidepressants are one of the most commonly prescribed drugs in primary care. The rise in use is mostly due to an increasing number of long-term users of antidepressants (LTU AD). Little is known about the factors driving increased long-term use. We examined the socio-demographic, clinical factors and health service use characteristics associated with LTU AD to extend our understanding of the factors that may be driving the increase in antidepressant use. METHODS: Cross-sectional analysis of 789 participants with probable depression (CES-D>=16) recruited from 30 randomly selected Australian general practices to take part in a ten-year cohort study about depression were surveyed about their antidepressant use. RESULTS: 165 (21.0%) participants reported <2 years of antidepressant use and 145 (18.4%) reported >=2 years of antidepressant use. After adjusting for depression severity, LTU AD was associated with: single (OR 1.56, 95%CI 1.05-2.32) or recurrent episode of depression (3.44, 2.06-5.74); using SSRIs (3.85, 2.03-7.33), sedatives (2.04, 1.29-3.22), or antipsychotics (4.51, 1.67-12.17); functional limitations due to long-term illness (2.81, 1.55 5.08), poor/fair self-rated health (1.57, 1.14-2.15), inability to work (2.49, 1.37-4.53), benefits as main source of income (2.15, 1.33-3.49), GP visits longer than 20min (1.79, 1.17-2.73); rating GP visits as moderately to extremely helpful (2.71, 1.79-4.11), and more self-help practices (1.16, 1.09-1.23). LIMITATIONS: All measures were self-report. Sample may not be representative of culturally different or adolescent populations. Cross-sectional design raises possibility of "confounding by indication". CONCLUSIONS: Long-term antidepressant use is relatively common in primary care. It occurs within the context of complex mental, physical and social morbidities. Whilst most long-term use is associated with a history of recurrent depression there remains a significant opportunity for treatment re-evaluation and timely discontinuation. PMID- 25704566 TI - Enhanced surface-and-interface coupling in Pd-nanoparticle-coated LaAlO3/SrTiO3 heterostructures: strong gas- and photo-induced conductance modulation. AB - Pd nanoparticle (NP) coated LaAlO3/SrTiO3 (LAO/STO) heterointerface exhibits more notable conductance (G) change while varying the ambient gas (N2, H2/N2, and O2) and illuminating with UV light (wavelength: 365 nm) than a sample without the NPs. Simultaneous Kelvin probe force microscopy and transport measurements reveal close relationships between the surface work function (W) and G of the samples. Quantitative analyses suggest that a surface adsorption/desorption-mediated reaction and redox, resulting in a band-alignment modification and charge transfer, could explain the gas- and photo-induced conductance modulation at the LAO/STO interface. Such surface-and-interface coupling enhanced by catalytic Pd NPs is a unique feature, quite distinct from conventional semiconductor hetero junctions, which enables the significant conductance tunability at ultrathin oxide heterointerfaces by external stimuli. PMID- 25704567 TI - Small bowel volvulus after transabdominal preperitoneal hernia repair due to improper use of V-LocTM barbed absorbable wire - do we always "read the instructions first"? AB - INTRODUCTION: Transabdominal preperitoneal endoscopic hernia repair (TAPP) is part of primary surgical health care. While both, the reported recurrence rate and procedure specific morbidity are consistently low, rare serious complications occur. PRESENTIATION OF CASE: A 36-year-old male patient developed bowel obstruction three days after both-sided TAPP for inguinal hernia repair. A computer tomography scan of the abdomen revealed a small bowel volvulus in the right lower quadrant of the abdomen requiring urgent revisional surgery. Intraoperatively, the small bowel and its mesenterial vessels were found to be twisted around a 5cm long V-LocTM barbed absorbable suturing wire. After successful laparoscopic adhesiolysis, removal of the wire and detorquing of the bowel conglomerate, resection of small intestine was not necessary. The patient's further postoperative recovery was uneventful. DISCUSSION: Due to the barbed configuration of the V-LocTM wire, a gapless continuous suturing of the peritoneum without laparoscopic knotting is easily and fast to accomplish. In this case the recommendation of the manufacturer to shorten the wire was not strictly followed and neither had the suture stump been extraperitonealized in order to avoid such rare complications. CONCLUSION: Surgeons need to be aware of relevant "tricks and traps" of routinely performed procedures and have to know all tools and material they use very well. This case may therefore increase our attention when it comes to little things which actually do matter. PMID- 25704568 TI - EPR study of Cu(2+) ion doped orotato(nicotinamid)cobalt(II) single crystal. AB - We have studied the Cu(2+) ion doped orotato(nicotinamid)cobalt(II) complex by using EPR spectroscopy and X-ray diffraction. The single crystal is triclinic with the space group P1?. The unit cell dimensions of the crystal are a=7.2785(4)A, b=10.2349(5)A, c=12.7372(6)A, alpha=69.297(4) degrees , beta=74.791(4) degrees and gamma=76.995(4) degrees , with Z=2. We analyzed the EPR spectra of both single crystal and powder of the complex at room temperature. EPR analysis indicates the presence of only one Cu(2+) site. We obtained the spin Hamiltonian parameters from the single crystal data for the complex. The spin Hamiltonian parameters are gx=2.032, gy=2.116, gz=2.319, Ax=28G, Ay=66G, Az=126G. These data indicate that the symmetry of paramagnetic center is rhombic. We constructed the ground state wave function of the Cu(2+) ion. PMID- 25704569 TI - Antimicrobial susceptibility of uropathogens isolated from Cambodian children. AB - BACKGROUND: Bacterial resistance to commonly used antimicrobials is an increasing problem in Asia but information concerning the antimicrobial susceptibility of bacteria causing urinary tract infections (UTIs) in children is limited. METHODS: This was a 5-year retrospective study of children with suspected UTI attending a paediatric hospital in north-west Cambodia. Urines with a positive culture containing a single organism with a count of >10(5) colony-forming units (CFU)/ml were considered diagnostic of infection. The organism was identified and the resistance pattern (using CLSI guidelines) and presence of an extended-spectrum beta-lactamase (ESBL) phenotype was determined. RESULTS: In total, there were 217 episodes of infection, 210 (97%) with Gram-negative bacteria. Escherichia coli was the most common infecting isolate with high levels of resistance to most oral antibiotics, except nitrofurantoin. Nearly half of the E. coli (44%) were extended-spectrum cephalosporin (ESC)-resistant with the proportion increasing significantly over the 5-year period. ESC-resistant E. coli were more likely to be multi-drug-resistant and 91% demonstrated an ESBL phenotype. CONCLUSION: The data highlight the importance of microbiological surveillance of UTIs in children, particularly in areas where there are known to be multiply resistant organisms. PMID- 25704570 TI - Novel serum biomarkers for detection of excessive alcohol use. AB - BACKGROUND: Construct interview that correctly identifies those with alcohol use disorder have limitation, especially when the subjects are motivated to minimize the magnitude of drinking behavior. Current laboratory tests to detect excessive alcohol consumption are limited by marginal sensitivity/specificity. Excessive drinking has been shown to affect several organ systems, which may be reflected in changes in quantity of plasma proteins. Our aim was to employ novel proteomic analyses to identify potential markers for excessive alcohol use. METHODS: A prospective case-control study included 49 controls and 54 excessive drinkers (discovery cohort). The serum proteomic analyses in these subjects were performed, and the results were tested in the verification cohort (40 controls and 40 excessive drinkers). RESULTS: Using the appropriate cutoff and confirmation with ELISA, we identified 4 proteins which were significantly elevated in the serum of excessive drinkers: AT-rich interactive domain containing protein 4B (ARID4B), phosphatidylcholine-sterol acyltransferase (LCAT), hepatocyte growth factor-like protein (MST1), and ADP-ribosylation factor 6 (ARL6). The performance of the conventional markers (aspartate aminotransferase [AST], alanine aminotransferase [ALT], gamma-glutamyl transpeptidase [GGT], percentage of carbohydrate-deficient transferrin [%CDT], and mean corpuscular volume [MCV]) discriminating between excessive alcohol use and controls had an area under the curve (AUC) ranging from 0.21 (ALT) to 0.67 (MCV). The AUC of these novel proteins showed the improvement in the detection of excessive drinkers compared to conventional laboratory tests, ranging from 0.73 (for ARID4B) to 0.86 (for ARL6). CONCLUSIONS: We have identified 4 novel proteins that can discern subjects with excessive alcohol use. Further studies are needed to determine the clinical implications of these markers to detect excessive alcohol use and confirm abstinence. PMID- 25704572 TI - Addition of MCP-1 and MIP-3beta to the IL-8 appraisal in peritoneal fluid enhances the probability of identifying women with endometriosis. AB - Chemokines have been associated with endometriosis. Our study was aimed at evaluating the levels of six chemokines--CXCL8 (IL-8), CXCL12 (SDF-1), CCL2 (MCP 1), CCL5 (RANTES), CCL19 (MIP-3beta), and CCL21 (6-Ckine)--in the peritoneal fluid (PF) of patients with and controls without endometriosis by multiplexed cytokine assay. In this retrospective case-control study conducted at the Charite University Hospital, patients (n = 36) and controls (n = 27) were enrolled. The patients were separated into groups according to stage of the disease: I-II (n = 21), III-IV (n = 1 5), and according to clinical findings: peritoneal endometriosis (PE; n = 7), deep-infiltrating endometriosis (DIE) affecting the retrocervical area (n = 13) or the bowel/rectovaginal site (n = 14). The subjects were also separated according to the cycle phase: follicular (n = 14) or luteal (n = 8) and the previous use (n = 25) or not (n = 38) of hormones. PF was collected from all subjects (n = 63) consecutively during laparoscopy. The concentration of chemokines in the PF was assessed using Luminex((r)) x-MAP((r)) technology. Sensitivity and specificity were calculated. A model of multiple logistic regressions estimated the odds of endometriosis for each combination of the chemokines detected. We observed significantly higher concentrations of IL-8 (p < 0.001), MCP-1 (p = 0.014), and MIP-3beta (p = 0.022) in the PF of women with endometriosis than in the controls. A joint evaluation revealed that elevated levels of the three chemokines had a positive endometriosis prediction value of 89.1%. The combined assessment of MCP-1, MIP-3beta, and IL-8 concentration in PF improved the likelihood of identifying patients with endometriosis. Future studies should investigate this panel in peripheral blood samples. PMID- 25704573 TI - The neurons, the brain: flow cytometry for black holes. PMID- 25704578 TI - Prospect evaluation as a function of numeracy and probability denominator. AB - This study examines how numeracy and probability denominator (a direct-ratio probability, a relative frequency with denominator 100, a relative frequency with denominator 10,000) affect the evaluation of prospects in an expected-value based pricing task. We expected that numeracy would affect the results due to differences in the linearity of number perception and the susceptibility to denominator neglect with different probability formats. An analysis with functional measurement verified that participants integrated value and probability into an expected value. However, a significant interaction between numeracy and probability format and subsequent analyses of the parameters of cumulative prospect theory showed that the manipulation of probability denominator changed participants' psychophysical response to probability and value. Standard methods in decision research may thus confound people's genuine risk attitude with their numerical capacities and the probability format used. PMID- 25704579 TI - Toddlers encode similarities among novel words from meaningful sentences. AB - Toddlers can learn about the meanings of individual words from the structure and semantics of the sentences in which they are embedded. However, it remains unknown whether toddlers encode similarities among novel words based on their positions within sentences. In three experiments, two-year-olds listened to novel words embedded in familiar sentence frames. Some novel words consistently occurred in the subject position across sentences, and others in the object position across sentences. An auditory semantic task was used to test whether toddlers encoded similarities based on sentential position, for (a) pairs of novel words that occurred within the same sentence, and (b) pairs of novel words that occurred in the same position across sentences. The results suggest that while toddlers readily encoded similarity based on within-sentence occurrences, only toddlers with more advanced grammatical knowledge encoded the positional similarities of novel words across sentences. Moreover, the encoding of these cross-sentential relationships only occurred if the exposure sentences included a familiar verb. These studies suggest that the types of lexical relationships that toddlers learn depend on the child's current level of language development, as well as the structure and meaning of the sentences surrounding the novel words. PMID- 25704580 TI - From self to social cognition: Theory of Mind mechanisms and their relation to Executive Functioning. AB - 'Theory of Mind' refers to the ability to attribute mental states to oneself and other people (Premack & Woodruff, 1978). This study examined the extent to which 'Self' and 'Other' belief-attribution processes within the Theory of Mind (ToM) mechanism could be distinguished behaviourally, and whether these separable components differentially related to Executive Functioning (EF) abilities. A computerized false-belief task, utilizing a matched-design to allow direct comparison of self-oriented vs. other-oriented belief-attribution, was used to assess ToM, and a face-image Stroop task was employed to assess EF, within a population of typically-developed adults. Results revealed significantly longer reaction times when attributing beliefs to other people as opposed to recognizing and attributing beliefs to oneself. Intriguingly, results revealed that 'perspective-shift' requirements (i.e. changing from adoption of the 'self' perspective to the perspective of the 'other', or vice versa) across false-belief trials influenced reaction times. Reaction times were significantly longer when the perspective shift was from self-to-other than from other-to-self. It is suggested that the 'self' forms the stem of understanding the 'other', and is therefore processed regardless of ultimate task demands; in contrast, the 'other' perspective is only processed when explicitly required. We conclude that adopting another person's perspective, even when their belief state is matched to one's own, requires more cognitive effort than recalling and reflecting on self oriented belief-states. PMID- 25704581 TI - Verbal framing of statistical evidence drives children's preference inferences. AB - Although research has shown that statistical information can support children's inferences about specific psychological causes of others' behavior, previous work leaves open the question of how children interpret statistical information in more ambiguous situations. The current studies investigated the effect of specific verbal framing information on children's ability to infer mental states from statistical regularities in behavior. We found that preschool children inferred others' preferences from their statistically non-random choices only when they were provided with verbal information placing the person's behavior in a specifically preference-related context, not when the behavior was presented in a non-mentalistic action context or an intentional choice context. Furthermore, verbal framing information showed some evidence of supporting children's mental state inferences even from more ambiguous statistical data. These results highlight the role that specific, relevant framing information can play in supporting children's ability to derive novel insights from statistical information. PMID- 25704582 TI - The influence of visual feedback from the recent past on the programming of grip aperture is grasp-specific, shared between hands, and mediated by sensorimotor memory not task set. AB - Goal-directed movements, such as reaching out to grasp an object, are necessarily constrained by the spatial properties of the target such as its size, shape, and position. For example, during a reach-to-grasp movement, the peak width of the aperture formed by the thumb and fingers in flight (peak grip aperture, PGA) is linearly related to the target's size. Suppressing vision throughout the movement (visual open loop) has a small though significant effect on this relationship. Visual open loop conditions also produce a large increase in the PGA compared to when vision is available throughout the movement (visual closed loop). Curiously, this differential effect of the availability of visual feedback is influenced by the presentation order: the difference in PGA between closed- and open-loop trials is smaller when these trials are intermixed (an effect we have called 'homogenization'). Thus, grasping movements are affected not only by the availability of visual feedback (closed loop or open loop) but also by what happened on the previous trial. It is not clear, however, whether this carry-over effect is mediated through motor (or sensorimotor) memory or through the interference of different task sets for closed-loop and open-loop feedback that determine when the movements are fully specified. We reasoned that sensorimotor memory, but not a task set for closed and open loop feedback, would be specific to the type of response. We tested this prediction in a condition in which pointing to targets was alternated with grasping those same targets. Critically, in this condition, when pointing was performed in open loop, grasping was always performed in closed loop (and vice versa). Despite the fact that closed- and open loop trials were alternating in this condition, we found no evidence for homogenization of the PGA. Homogenization did occur, however, in a follow-up experiment in which grasping movements and visual feedback were alternated between the left and the right hand, indicating that sensorimotor (or motor) memory can operate both within and between hands when the response type is kept the same. In a final experiment, we ruled out the possibility that simply alternating the hand used to perform the grasp interferes with motor or sensorimotor memory. We did this by showing that when the hand was alternated within a block of exclusively closed- or open-loop trials, homogenization of the PGA did not occur. Taken together, the results suggest that (1) interference from simply switching between task sets for closed or open-loop feedback or from switching between the hands cannot account homogenization in the PGA and that (2) the programming and execution of grasps can borrow not only from grasping movements executed in the past by the same hand, but also from grasping movements executed with the other hand. PMID- 25704583 TI - The developing cognitive substrate of sequential action control in 9- to 12-month olds: evidence for concurrent activation models. AB - Nine-month-olds start to perform sequential actions. Yet, it remains largely unknown how they acquire and control such actions. We studied infants' sequential action control by employing a novel gaze-contingent eye tracking paradigm. Infants experienced occulo-motor action sequences comprising two elementary actions. To contrast chaining, concurrent and integrated models of sequential action control, we then selectively activated secondary actions to assess interactions with the primary actions. Behavioral and pupillometric results suggest 12-month-olds acquire sequential action without elaborate strategy through exploration. Furthermore, the inhibitory mechanisms ensuring ordered performance develop between 9 and 12 months of age, and are best captured by concurrent models. PMID- 25704584 TI - Factors prognostic of eligibility for allogeneic HCT among older patients with AML-CR1 and adverse- or intermediate-risk cytogenetics. AB - The introduction of reduced-intensity conditioning (RIC) regimens has made possible allogeneic hematopoietic cell transplantation (allo-HCT) in older patients with acute myeloid leukemia (AML). However, the optimal timing of allo HCT in these patients and its relative risks and benefits when compared with chemotherapies have not been determined. This retrospective study by the Fukuoka Blood and Marrow Transplant Group compared RIC allo-HSCT with non-transplant therapies, the choice based on donor availability, in AML patients in their first complete remission (CR1). The prognostic value of various patient characteristics and disease-specific variables were investigated in 299 patients aged >=60 years with AML in CR1. Among the 107 patients aged 60-65 years, 54 of whom received allo-HCT and 53 of whom continued chemotherapies; allo-HCT, adverse-risk group, and hematopoietic cell transplantation-comorbidity index were significant predictors of survival outcomes. Among 192 patients aged >=66 years deemed ineligible for allo-HCT, relapse and Karnofsky performance status after induction therapy were significant predictors of survival outcomes. Findings from this study may facilitate a new standard of care for older AML patients in CR1 who are considered candidates for allo-HCT. PMID- 25704585 TI - Investigational therapies targeting quorum-sensing for the treatment of Staphylococcus aureus infections. AB - INTRODUCTION: Antibiotic resistance is a serious global health concern for developed and developing nations. MRSA represents a particularly severe public health threat that is associated with high morbidity and mortality. The lack of novel antibiotics has led scientists to explore therapies targeting bacterial virulence mechanisms and virulence regulators, including those controlling cell cell communication. AREAS COVERED: The authors discuss the role of quorum-sensing in Staphylococcus aureus infections and components of the system that are being targeted using novel investigational drugs. In particular, the authors examine the role of the accessory gene regulator (Agr) system in virulence regulation of S. aureus pathogenesis. Finally, the authors present and compare natural and synthetic compounds that have been found to interfere with Agr functionality. EXPERT OPINION: There is a great need to develop new therapeutic methods to combat S. aureus infections. These include anti-virulence therapies that target key global regulators involved with the establishment and propagation of infection. Several molecules have been found to interfere with S. aureus virulence regulation, especially those targeting the Agr quorum-sensing signaling molecule. These preliminary findings warrant further investigation and validation, with the goal of refining a compound that has broad-spectrum inhibitory effects on most S. aureus strains and Agr subtypes. PMID- 25704586 TI - Polymeric photocatalysts based on graphitic carbon nitride. AB - Semiconductor-based photocatalysis is considered to be an attractive way for solving the worldwide energy shortage and environmental pollution issues. Since the pioneering work in 2009 on graphitic carbon nitride (g-C3N4) for visible light photocatalytic water splitting, g-C3N4 -based photocatalysis has become a very hot research topic. This review summarizes the recent progress regarding the design and preparation of g-C3N4 -based photocatalysts, including the fabrication and nanostructure design of pristine g-C3N4 , bandgap engineering through atomic level doping and molecular-level modification, and the preparation of g-C3N4 based semiconductor composites. Also, the photo-catalytic applications of g-C3N4 based photocatalysts in the fields of water splitting, CO2 reduction, pollutant degradation, organic syntheses, and bacterial disinfection are reviewed, with emphasis on photocatalysis promoted by carbon materials, non-noble-metal cocatalysts, and Z-scheme heterojunctions. Finally, the concluding remarks are presented and some perspectives regarding the future development of g-C3N4 -based photocatalysts are highlighted. PMID- 25704587 TI - Clarifying the role of fire in the deciduous forests of eastern North America: reply to Matlack. PMID- 25704588 TI - Volumetric and two-dimensional image interpretation show different cognitive processes in learners. AB - RATIONALE AND OBJECTIVES: In current practice, radiologists interpret digital images, including a substantial amount of volumetric images. We hypothesized that interpretation of a stack of a volumetric data set demands different skills than interpretation of two-dimensional (2D) cross-sectional images. This study aimed to investigate and compare knowledge and skills used for interpretation of volumetric versus 2D images. MATERIALS AND METHODS: Twenty radiology clerks were asked to think out loud while reading four or five volumetric computed tomography (CT) images in stack mode and four or five 2D CT images. Cases were presented in a digital testing program allowing stack viewing of volumetric data sets and changing views and window settings. Thoughts verbalized by the participants were registered and coded by a framework of knowledge and skills concerning three components: perception, analysis, and synthesis. The components were subdivided into 16 discrete knowledge and skill elements. A within-subject analysis was performed to compare cognitive processes during volumetric image readings versus 2D cross-sectional image readings. RESULTS: Most utterances contained knowledge and skills concerning perception (46%). A smaller part involved synthesis (31%) and analysis (23%). More utterances regarded perception in volumetric image interpretation than in 2D image interpretation (Median 48% vs 35%; z = -3.9; P < .001). Synthesis was less prominent in volumetric than in 2D image interpretation (Median 28% vs 42%; z = -3.9; P < .001). No differences were found in analysis utterances. CONCLUSIONS: Cognitive processes in volumetric and 2D cross-sectional image interpretation differ substantially. Volumetric image interpretation draws predominantly on perceptual processes, whereas 2D image interpretation is mainly characterized by synthesis. The results encourage the use of volumetric images for teaching and testing perceptual skills. PMID- 25704589 TI - Nonvascular Interventional Procedures in an Urban General Hospital: Analysis of 2001-2010 with Comparison to the Previous Decade. AB - RATIONALE AND OBJECTIVES: To determine trends in nonvascular image-guided procedures at an urban general hospital over a 10-year period and to compare utilization of nonvascular interventional radiology (IR) over the decade 2001 2010 to a previously reported analysis for 1991-2000. METHODS: With institutional review board approval, a 20-year quality assurance database verified against the radiology information system was queried for procedure location (eg, pleura, liver, bowel, and abdomen) and type (eg, biopsy, catheter insertion, and transient drainage), demographics, and change over time. Yearly admissions and new hospital numbers assigned each year served to normalize for overall hospital activity. RESULTS: A total of 50,195 IR procedures were performed in 24,309 distinct patients (male:female, 12,625:11,684; average age, 60 years), 940 procedures performed in age <20 years, and 571 procedures performed in patients aged >=90 years. A total of 15345, 4377, and 1754 patients had one, two, or three procedures, respectively; 470 had >=10 procedures. Twenty-seven supervising radiologists and 277 individuals participated as operators, double the previous decade. Biopsy (4.8% average yearly increase), abdominal drainage (7.3%), paracentesis (12.9%), tube manipulation (13.0%), suprapubic bladder tube insertion (21.0%), and gastrostomy (44.6%) all increased strongly (P < .001) over 120 months but not biliary drainage, nephrostomy, or chest tubes. Procedures increased faster than either admissions or new hospital numbers (P < .001). For each 1000 new hospital numbers, IR service performed 48 procedures versus 31 the previous decade (P < .0005). CONCLUSIONS: Referrals for nonvascular IR procedures have doubled over 2 decades, outpacing growth in new hospital patients and requiring increased resource allocation. PMID- 25704590 TI - Restriction of molecular twisting on a gold nanoparticle surface. AB - To understand the photophysical properties of intramolecular charge transfer (ICT) and twisted intramolecular charge transfer (TICT) states on a gold nanoparticle (Au NP) surface, we have designed and synthesized a new coumarin molecule (C3) that exists both as ICT and TICT states in its excited state in a polar environment. On a Au NP surface, an excited C3 molecule only exists as an ICT state owing to restricted molecular rotation of a diethylamino group; as a result, no conversion from the ICT to TICT state was observed. Selection of the preferential state of a molecule with dual emitting states can be helpful for selected biological applications. PMID- 25704591 TI - Psoriasis Area and Severity Index 75 rate of classical inpatient dithranol therapy under daily life conditions. PMID- 25704592 TI - Sympathetic nervous system activation and beta-adrenoceptor blockade in right heart failure. AB - Right heart failure may develop from pulmonary arterial hypertension or various forms of congenital heart disease. Right ventricular adaptation to the increased afterload is the most important prognostic factor in pulmonary hypertension and congenital heart disease, which share important pathophysiological mechanisms, despite having different aetiologies. There is substantial evidence of increased sympathetic nervous system activation in right heart failure related to both pulmonary hypertension and congenital heart disease. It is unknown to which degree this activation is an adaptive response, a maladaptive response, or if it mainly reflects disease progression. Several experimental studies and clinical trials have been conducted to answer these questions. Here, we review the existing knowledge on sympathetic nervous system activation and the effects of beta-adrenoceptor blockade in experimental and clinical right heart failure. This review identifies important gaps in our understanding of the right ventricle and discusses the potential of beta-blockers in the treatment of right heart failure. PMID- 25704593 TI - Catalytic upgrading of biomass-derived methyl ketones to liquid transportation fuel precursors by an organocatalytic approach. AB - A highly efficient water-tolerant, solid-base catalyst for the self-condensation of biomass-derived methyl ketones to jet-diesel fuel precursors was developed by grafting site-isolated secondary amines on silica-alumina supports. It is shown that apart from the nature and density of amine groups and the spatial separation of the acidic and basic sites, the acidity of the support material plays a critical role in defining the catalytic activity. It is also found that a combination of weakly acidic silanol/aluminol with secondary amine groups can mimic proline catalysts and are more effective in catalyzing the selective dimerization reaction than the combination of amines with organic acids. In situ FTIR measurements demonstrate that acidic groups activate methyl ketones through their carbonyl groups leading to a favorable C?C bond formation step involving an enamine intermediate. DFT analysis of the reaction pathway confirms that C?C bond formation is the rate-limiting step. PMID- 25704594 TI - An alternative interpretation of the ultracold methylhydroxycarbene rearrangement mechanism: cooperative effects. AB - Recent studies have reported surprising results related to the rearrangement of carbenes under ultracold conditions, making use of sophisticated models of quantum tunnelling to explain the observed phenomena. Here, we demonstrate that a methylhydroxycarbene (H3C-C-OH) rearrangement is possible by making changes in molecularity (i.e., through cooperative effects), owing to intermolecular hydrogen bond/H-transfer. The model used for accomplishing these changes in molecularity suggests the occurrence of two chemical species during the rearrangement and preferential formation of acetaldehyde. We propose an alternative interpretation for the methylhydroxycarbene rearrangement, as well as for a bimolecular isomerization mechanism for acetaldehyde formation with an activation barrier, Ea, of +0.25 kcal mol(-1), relative to 1a' (-8.06 kcal mol( 1) relative to 1a); this barrier is lower than that required by H-tunnelling as proposed by Schreiner et al. We also note that the mechanism for obtaining vinyl alcohol leads to the simultaneous formation of acetaldehyde through an Ea of +13.53 kcal mol(-1), relative to 1a (+0.93 kcal mol(-1) relative to 1b), again confirming the predominant presence of acetaldehyde. PMID- 25704595 TI - Transmission of haemorrhagic fever with renal syndrome in china and the role of climate factors: a review. AB - Haemorrhagic fever with renal syndrome (HFRS) is a rodent-borne disease that poses a serious public health threat in China. HFRS is caused by hantaviruses, mainly Seoul virus in urban areas and Hantaan virus in agricultural areas. Although preventive measures including vaccination programs and rodent control measures have resulted in a decline in cases in recent years, there has been an increase in incidence in some areas and new endemic areas have emerged. This review summarises the recent literature relating to the effects of climatic factors on the incidence of HFRS in China and discusses future research directions. Temperature, precipitation and humidity affect crop yields, rodent breeding patterns and disease transmission, and these can be influenced by a changing climate. Detailed surveillance of infections caused by Hantaan and Seoul viruses and further research on the viral agents will aid in interpretation of spatiotemporal patterns and a better understanding of the environmental and ecological drivers of HFRS amid China's rapidly urbanising landscape and changing climate. PMID- 25704596 TI - Development of a coxsackievirus A16 neutralization test based on the enzyme linked immunospot assay. AB - Coxsackievirus A16 (CA16) is one of the major pathogens responsible for hand, foot and mouth disease (HFMD). The assessment of the humoral immunity response is indispensable in the development of vaccines against enteroviruses. The neutralization test based on the inhibition of cytopathic effects (Nt-CPE) is a common method for measuring neutralizing antibodies against CA16. However, an efficient neutralization test needs to be developed for seroepidemiological surveys and clinical trials of CA16 vaccines because Nt-CPE is time-consuming and labor-intensive. In this study, a high-throughput neutralization test for CA16 based on the enzyme-linked immunospot assay (Nt-ELISPOT) was developed. The monoclonal antibody 7D10, which reacted with the viral protein VP1, was used to detect the cells infected with CA16. The neutralizing titers of sera were proven to be unchanged over an infectious dose range from 10 to 10,000TCID50 per well. The Nt-ELISPOT results correlated well with the Nt-CPE results (R(2) = 0.9250), and the detection period was shortened from five days to approximately 30h. Overall, the Nt-ELISPOT is a reliable and efficient method for measuring neutralizing antibodies against CA16. PMID- 25704597 TI - Evaluation of the swab sampling method to recover viruses from fomites. AB - The monitoring of virus contamination on fomites, especially at hospitals has been used for a more effective evaluation of the microbiological quality of surfaces. Swab sampling is the method used currently, although the use of an internal control process (ICP) has not yet been assessed. The aim of this study is to determine the recovery rate of murine norovirus 1 (MNV-1) and bacteriophage PP7 on different surfaces in order to assess their potential use as an ICP. For this purpose both viruses were spiked experimentally both on porous and non porous formic as well as on rubberized surfaces. Quantitative PCR (qPCR) showed a variable efficiency with a percentage recovery ranging from 0.6 to 77% according to viruses and surfaces. A global analysis suggested that MNV-1 could be used as a potential ICP for the swab sampling method. PMID- 25704598 TI - A generic assay for whole-genome amplification and deep sequencing of enterovirus A71. AB - Enterovirus A71 (EV-A71) has emerged as the most important cause of large outbreaks of severe and sometimes fatal hand, foot and mouth disease (HFMD) across the Asia-Pacific region. EV-A71 outbreaks have been associated with (sub)genogroup switches, sometimes accompanied by recombination events. Understanding EV-A71 population dynamics is therefore essential for understanding this emerging infection, and may provide pivotal information for vaccine development. Despite the public health burden of EV-A71, relatively few EV-A71 complete-genome sequences are available for analysis and from limited geographical localities. The availability of an efficient procedure for whole genome sequencing would stimulate effort to generate more viral sequence data. Herein, we report for the first time the development of a next-generation sequencing based protocol for whole-genome sequencing of EV-A71 directly from clinical specimens. We were able to sequence viruses of subgenogroup C4 and B5, while RNA from culture materials of diverse EV-A71 subgenogroups belonging to both genogroup B and C was successfully amplified. The nature of intra-host genetic diversity was explored in 22 clinical samples, revealing 107 positions carrying minor variants (ranging from 0 to 15 variants per sample). Our analysis of EV-A71 strains sampled in 2013 showed that they all belonged to subgenogroup B5, representing the first report of this subgenogroup in Vietnam. In conclusion, we have successfully developed a high-throughput next-generation sequencing-based assay for whole-genome sequencing of EV-A71 from clinical samples. PMID- 25704599 TI - Aurantiamide acetate suppresses the growth of malignant gliomas in vitro and in vivo by inhibiting autophagic flux. AB - We aim to investigate the effect of aurantiamide acetate isolated from the aerial parts of Clematis terniflora DC against gliomas. Human malignant glioma U87 and U251 cells were incubated with different concentrations (0-100 MUM) of aurantiamide acetate. Aurantiamide acetate greatly decreased the cell viability in a dose- and time-dependent manner. It induced moderate mitochondrial fragmentation and the loss of mitochondrial membrane potential. No significant difference was found in the alternation of other intracellular organelles, although F-actin structure was slightly disturbed. Apparent ultrastructure alternation with increased autophagosome and autolysosome accumulation was observed in aurantiamide acetate-treated cells. The expression of LC3-II was greatly up-regulated in cells exposed to aurantiamide acetate (P < 0.05 compared with control). The cytoplasmic accumulation of autophagosomes and autolysosomes induced by aurantiamide acetate treatment was confirmed by fluorescent reporter protein labelling. Administration of chloroquine (CQ), which inhibits the fusion step of autophagosomes, further increased the accumulation of autophagosomes in the cytoplasm of U87 cells. Autophagy inhibition by 3-methyladenine, Bafilomycin A1 or CQ had no influence on aurantiamide acetate-induced cytotoxicity, whereas autophagy stimulator rapamycin significantly suppressed aurantiamide acetate induced cell death. The anti-tumour effects of aurantiamide acetate were further evaluated in tumour-bearing nude mice. Intratumoural injection of aurantiamide acetate obviously suppressed tumour growth, and increased number of autophagic vacuoles was observed in tumour tissues of animals receiving aurantiamide acetate. Our findings suggest that aurantiamide acetate may suppress the growth of malignant gliomas by blocking autophagic flux. PMID- 25704600 TI - Race/ethnicity moderates the relationship between chronic life stress and quality of life in type 2 diabetes. AB - AIMS: To determine whether chronic life stress is differentially associated with quality of life (QoL) for Blacks vs. Hispanics with type 2 diabetes. METHODS: We assessed self-reported chronic stress and QoL in 125 patients with type 2 diabetes who self-identified as either non-Hispanic Black or Hispanic. Separate cross-sectional two-way interaction models (stress * race/ethnicity) with physical and mental health as outcomes were examined. RESULTS: The two-way interaction predicted mental (b=3.12, P=.04) but not physical health. Simple slopes analyses indicated that under conditions of high stress, Blacks (b=-4.4, P<.001), but not Hispanics, experienced significantly lower levels of mental health. In exploratory analyses, we examined a three-way interaction (stress * race/ethnicity * social support) with physical and mental health as outcomes. Results indicated the three-way interaction predicted mental (b=.62, P=.01) but not physical health. Simple slopes analyses indicated that under conditions of high stress, high levels of social support improved mental health for Hispanics (b=1.2, P<.001), but not for Blacks. CONCLUSIONS: Black patients with type 2 diabetes may be particularly vulnerable to the deleterious effects of high chronic stress. Social support buffers effects of stress on mental health in Hispanics but not Blacks, which suggests differences in the use and/or quality of social support between Hispanics and Blacks. Longitudinal investigations that examine race/ethnicity, stress, social support, and QoL should help clarify the processes that underlie these observed relations. PMID- 25704601 TI - Effect of pantoprazole on insulin secretion in drug-naive patients with type 2 diabetes. AB - To evaluate the effect of pantoprazole during 45 days on insulin secretion in drug-naive patients with type 2 diabetes, a randomized, double blind, placebo control clinical trial was performed in 14 drug-naive volunteers. Significant increases in late insulin phase and total insulin secretion, and decreases in HbA1c levels were found. PMID- 25704604 TI - Waste generated in high-rise buildings construction: a quantification model based on statistical multiple regression. AB - Reducing construction waste is becoming a key environmental issue in the construction industry. The quantification of waste generation rates in the construction sector is an invaluable management tool in supporting mitigation actions. However, the quantification of waste can be a difficult process because of the specific characteristics and the wide range of materials used in different construction projects. Large variations are observed in the methods used to predict the amount of waste generated because of the range of variables involved in construction processes and the different contexts in which these methods are employed. This paper proposes a statistical model to determine the amount of waste generated in the construction of high-rise buildings by assessing the influence of design process and production system, often mentioned as the major culprits behind the generation of waste in construction. Multiple regression was used to conduct a case study based on multiple sources of data of eighteen residential buildings. The resulting statistical model produced dependent (i.e. amount of waste generated) and independent variables associated with the design and the production system used. The best regression model obtained from the sample data resulted in an adjusted R(2) value of 0.694, which means that it predicts approximately 69% of the factors involved in the generation of waste in similar constructions. Most independent variables showed a low determination coefficient when assessed in isolation, which emphasizes the importance of assessing their joint influence on the response (dependent) variable. PMID- 25704602 TI - Identification of functional variants for cleft lip with or without cleft palate in or near PAX7, FGFR2, and NOG by targeted sequencing of GWAS loci. AB - Although genome-wide association studies (GWASs) for nonsyndromic orofacial clefts have identified multiple strongly associated regions, the causal variants are unknown. To address this, we selected 13 regions from GWASs and other studies, performed targeted sequencing in 1,409 Asian and European trios, and carried out a series of statistical and functional analyses. Within a cluster of strongly associated common variants near NOG, we found that one, rs227727, disrupts enhancer activity. We furthermore identified significant clusters of non coding rare variants near NTN1 and NOG and found several rare coding variants likely to affect protein function, including four nonsense variants in ARHGAP29. We confirmed 48 de novo mutations and, based on best biological evidence available, chose two of these for functional assays. One mutation in PAX7 disrupted the DNA binding of the encoded transcription factor in an in vitro assay. The second, a non-coding mutation, disrupted the activity of a neural crest enhancer downstream of FGFR2 both in vitro and in vivo. This targeted sequencing study provides strong functional evidence implicating several specific variants as primary contributory risk alleles for nonsyndromic clefting in humans. PMID- 25704603 TI - Homozygous SLC6A17 mutations cause autosomal-recessive intellectual disability with progressive tremor, speech impairment, and behavioral problems. AB - We report on Dutch and Iranian families with affected individuals who present with moderate to severe intellectual disability and additional phenotypes including progressive tremor, speech impairment, and behavioral problems in certain individuals. A combination of exome sequencing and homozygosity mapping revealed homozygous mutations c.484G>A (p.Gly162Arg) and c.1898C>G (p.Pro633Arg) in SLC6A17. SLC6A17 is predominantly expressed in the brain, encodes a synaptic vesicular transporter of neutral amino acids and glutamate, and plays an important role in the regulation of glutamatergic synapses. Prediction programs and 3D modeling suggest that the identified mutations are deleterious to protein function. To directly test the functional consequences, we investigated the neuronal subcellular localization of overexpressed wild-type and mutant variants in mouse primary hippocampal neuronal cells. Wild-type protein was present in soma, axons, dendrites, and dendritic spines. p.Pro633Arg altered SLC6A17 was found in soma and proximal dendrites but did not reach spines. p.Gly162Arg altered SLC6A17 showed a normal subcellular distribution but was associated with an abnormal neuronal morphology mainly characterized by the loss of dendritic spines. In summary, our genetic findings implicate homozygous SLC6A17 mutations in autosomal-recessive intellectual disability, and their pathogenic role is strengthened by genetic evidence and in silico and in vitro functional analyses. PMID- 25704605 TI - Principles of pulse oximetry and its clinical application in neonatal medicine. AB - Pulse oximetry is one of the most commonly used monitoring devices in clinical medicine. It was first introduced to neonatal medicine in the mid-1980s to monitor oxygenation and guide therapy, and it is now used widely in the delivery room during resuscitation. More recently, it is utilized to screen for congenital heart disease. Pulse oximetry is based on the variation in the ratio of the light absorbances of tissues during systole and diastole. It has become the mainstay of non-invasive continuous oxygen monitoring but with a wide variation in clinical practices and without good research evidence. This article provides a brief historical overview of pulse oximetry development, its principles, advantages and limitations, and the clinical applications in neonatal medicine. PMID- 25704606 TI - Inhibition of wild-type p53-induced phosphatase 1 promotes liver regeneration in mice by direct activation of mammalian target of rapamycin. AB - The liver possesses extraordinary regenerative capacity in response to injury. However, liver regeneration (LR) is often impaired in disease conditions. Wild type p53-induced phosphatase 1 (Wip1) is known as a tumor promoter and enhances cell proliferation, mainly by deactivating antioncogenes. However, in this work, we identified an unexpected role of Wip1 in LR. In contrast to its known role in promoting cell proliferation in extrahepatic tissue, we found that Wip1 suppressed hepatocyte proliferation after partial hepatectomy (PHx). Deletion of Wip1 increased the rate of LR after PHx. Enhanced LR in Wip1-deficient mice was a result of the activation of the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) pathway. Furthermore, we showed that Wip1 physically interacted with and dephosphorylated mTOR. Interestingly, inhibition of Wip1 also activated the p53 pathway during LR. Disruption of the p53 pathway further enhanced LR in Wip1 deficient mice. Therefore, inhibition of Wip1 has a dual role in LR, i.e., promoting hepatocyte proliferation through activation of the mTORC1 pathway, meanwhile suppressing LR through activation of the p53 pathway. However, the proregenerative role of mTORC1 overwhelms the antiproliferative role of p53. Furthermore, CCT007093, a Wip1 inhibitor, enhanced LR and increased the survival rate of mice after major hepatectomy. CONCLUSION: mTOR is a new direct target of Wip1. Wip1 inhibition can activate the mTORC1 pathway and enhance hepatocyte proliferation after hepatectomy. These findings have clinical applications in cases where LR is critical, including acute liver failure, cirrhosis, or small for-size liver transplantations. PMID- 25704607 TI - A new algorithm for design, operation and cost assessment of struvite (MgNH4PO4) precipitation processes. AB - Deliberate struvite (MgNH4PO4) precipitation from wastewater streams has been the topic of extensive research in the last two decades and is expected to gather worldwide momentum in the near future as a P-reuse technique. A wide range of operational alternatives has been reported for struvite precipitation, including the application of various Mg(II) sources, two pH elevation techniques and several Mg:P ratios and pH values. The choice of each operational parameter within the struvite precipitation process affects process efficiency, the overall cost and also the choice of other operational parameters. Thus, a comprehensive simulation program that takes all these parameters into account is essential for process design. This paper introduces a systematic decision-supporting tool which accepts a wide range of possible operational parameters, including unconventional Mg(II) sources (i.e. seawater and seawater nanofiltration brines). The study is supplied with a free-of-charge computerized tool (http://tx.technion.ac.il/~agrengn/agr/Struvite_Program.zip) which links two computer platforms (Python and PHREEQC) for executing thermodynamic calculations according to predefined kinetic considerations. The model can be (inter alia) used for optimizing the struvite-fluidized bed reactor process operation with respect to P removal efficiency, struvite purity and economic feasibility of the chosen alternative. The paper describes the algorithm and its underlying assumptions, and shows results (i.e. effluent water quality, cost breakdown and P removal efficiency) of several case studies consisting of typical wastewaters treated at various operational conditions. PMID- 25704608 TI - Emerging drugs for the treatment of wound healing. AB - INTRODUCTION: Wound healing can be characterized as underhealing, as in the setting of chronic wounds, or overhealing, occurring with hypertrophic scar formation after burn injury. Topical therapies targeting specific biochemical and molecular pathways represent a promising avenue for improving and, in some cases normalizing, the healing process. AREAS COVERED: A brief overview of both normal and pathological wound healing has been provided, along with a review of the current clinical guidelines and treatment modalities for chronic wounds, burn wounds and scar formation. Next, the major avenues for wound healing drugs, along with drugs currently in development, are discussed. Finally, potential challenges to further drug development, and future research directions are discussed. EXPERT OPINION: The large body of research concerning wound healing pathophysiology has provided multiple targets for topical therapies. Growth factor therapies with the ability to be targeted for localized release in the wound microenvironment are most promising, particularly when they modulate processes in the proliferative phase of wound healing. PMID- 25704609 TI - Clicking on professionalism? Thoughts on teaching students about social media and its impact on dental professionalism. PMID- 25704610 TI - Stability of cosmetic emulsion containing different amount of hemp oil. AB - OBJECTIVE: The aim of the study was to determine the optimal conditions, that is the content of hemp oil and time of homogenization to obtain stable dispersion systems. METHODS: For this purpose, six emulsions were prepared, their stability was examined empirically and the most correctly formulated emulsion composition was determined using a computer simulation. Variable parameters (oil content and homogenization time) were indicated by the optimization software based on Kleeman's method. Physical properties of the synthesized emulsions were studied by numerous techniques involving particle size analysis, optical microscopy, Turbiscan test and viscosity of emulsions. RESULTS: The emulsion containing 50 g of oil and being homogenized for 6 min had the highest stability. Empirically determined parameters proved to be consistent with the results obtained using the computer software. The computer simulation showed that the most stable emulsion should contain from 30 to 50 g of oil and should be homogenized for 2.5-6 min. CONCLUSIONS: The computer software based on Kleeman's method proved to be useful for quick optimization of the composition and production parameters of stable emulsion systems. Moreover, obtaining an emulsion system with proper stability justifies further research extended with sensory analysis, which will allow the application of such systems (containing hemp oil, beneficial for skin) in the cosmetic industry. PMID- 25704611 TI - Isobavachalcone attenuates lipopolysaccharide-induced ICAM-1 expression in brain endothelial cells through blockade of toll-like receptor 4 signaling pathways. AB - Inflammation has been implicated in the pathogenesis of various cerebral diseases. Thus, control of brain inflammation is regarded as one of the important therapeutic strategies for the treatment of neurodegenerative diseases such as Alzheimer's disease and stroke. Isobavachalcone, a flavonoid from Psoralea corylifolia, is known to possess a wide spectrum of biological activities and is expected to be useful in preventing or treating neurodegenerative diseases. However, very little is known regarding its effects on cerebral inflammation. In this study, we examined the effect of isobavachalcone on leukocyte adhesion and intercellular adhesion molecule-1 (ICAM-1) expression in brain endothelial cells activated with lipopolysaccharide (LPS) and explored the possible mechanisms involved. Isobavachalcone significantly down-regulated LPS-induced ICAM-1 expression and leukocyte-endothelial cell adhesion and suppressed NF-kappaB activity which is implicated in the expression of ICAM-1. It attenuated ICAM-1 expression as well as NF-kappaB transcriptional activity induced by macrophage activating lipopeptide 2-kDa (MALP-2) or polyriboinosinic polyribocytidylic acid (poly[I:C]). Isobavachalcone also down-regulated LPS or poly[I:C]-induced expression of IFN-beta, which can indirectly activate NF-kappaB. These data imply that isobavachalcone can modulate both MyD88-dependent and TRIF-dependent signaling of toll-like receptor 4 (TLR4). Taken together, our data suggest that isobavachalcone inhibits LPS-induced ICAM-1 expression and leukocyte adhesion to brain endothelial cell by blocking TLR4 signaling and thus, has the potential to ameliorate neuronal injury in brain diseases associated with inflammation. PMID- 25704612 TI - Effects of novel hybrids of caffeic acid phenethyl ester and NSAIDs on experimental ocular inflammation. AB - In this study, we report the design and synthesis of novel hybrids of caffeic acid phenetyl ester (CAPE) and non-steroidal anti-inflammatory drugs (NSAIDs). We assessed their effects on an experimental ocular inflammation in New Zealand rabbits. The formulations of CAPE-aspirin and CAPE-indomethacin hybrids were topical instilled in the rabbit's eye. Afterwards, the anti-inflammatory activity was evaluated by grading the clinical signs and by assessing the inflammatory cell count, protein, PGE2 and TNFalpha levels in the aqueous humor. Furthermore, ocular tolerability of hybrids formulations was evaluated in a separate set of animals by using a modified Draize test. The ocular inflammation in the control group was significantly higher than in both the hybrid-treated groups, as indicated by clinical grading and biomarkers assessment. However, only the CAPE aspirin hybrid reduced, in a significant dose-dependent manner, the ocular inflammation elicited by paracentesis. CAPE-indomethacin hybrid was able to significantly attenuate the clinical grading and the PGE2 aqueous levels only at the highest dose (0.1%). CAPE-aspirin significantly reduced PGE2 and TNFalpha levels in the aqueous humor as well as proteins and PMNs. Finally, all formulations showed no ocular irritation compared with vehicle-treated group. In conclusion, CAPE-aspirin shows full anti-inflammatory efficacy in experimental model of ocular inflammation demonstrating an optimal pharmacological and safety profile. Taken together these data indicate that CAPE-aspirin hybrid represents a valid and safe new chemical entity potentially useful for the treatment of ocular inflammation. PMID- 25704613 TI - Anti-allergic and anti-inflammatory properties of a potent histamine H1 receptor antagonist, desloratadine citrate disodium injection, and its anti-inflammatory mechanism on EA.hy926 endothelial cells. AB - The present study, demonstrates that, desloratadine citrate disodium injection (DLC) possesses antihistaminic, anti-allergic and anti-inflammatory properties and elucidates its molecular mechanisms of anti-inflammatory properties. In vitro antihistamine activity of DLC was determined in guinea pig isolated tissues. In vivo antihistamine effects were evaluated after following intravenous administration of DLC in mice with histamine- induced paw edema and in rats with increased capillary permeability. Anti-allergic effects were assessed through passive cutaneous anaphylactic (PCA) reactions in sensitized rodents and ovalbumin-induced allergic rhinitis in rats. Anti-inflammatory properties and molecular mechanisms of DLC were determined on histamine- and lipopolysaccharide (LPS)-induced EA.hy926 endothelial cells. DLC exhibited significant and reversible inhibition of histamine-induced contractions of isolated guinea pig ileum with pA2 value of 8.88. Histamine-induced paw edema and increased capillary permeability were notably inhibited by DLC intravenous administration. In the model of PCA reactions, DLC showed significant activity in a dose-dependent nd potently inhibited both the early-phase and late-phase allergic reaction of ovalbumin-induced allergic rhinitis in rats. DLC alleviated the rhinitis symptoms and inhibited inflammatory cell infiltration, IL-4 and protein leakage in nasal lavage fluid (NLF). In EA.hy926 cells, DLC significantly inhibited the histamine- and LPS- induced IL-6 and IL-8 production and P-selectin and intercellular cell adhesion molecule-1 (ICAM-1) expression. Moreover, DLC reduced translocation of nuclear factor-kappaB (NF-kappaB) to the nucleus in activated EA.hy926 cells. These results provide evidence that DLC possesses potent antihistaminic, anti allergic and, anti-inflammatory properties via suppressing IL-6, IL-8, P-selectin and ICAM-1 expression. PMID- 25704614 TI - Pharmacological evidence that histamine H3 receptors inhibit the vasodepressor responses by selective stimulation of the rat perivascular sensory CGRPergic outflow. AB - This study has investigated whether pharmacological activation of Gi/o coupled histamine H3/H4 receptors inhibits the rat vasodepressor sensory outflow. For this purpose, 100 male Wistar rats were pithed, artificially ventilated and pretreated (i.v.) with: 25mg/kg gallamine, 2mg/kg/min hexamethonium and 20MUg/kg/min methoxamine, followed by i.v. continuous infusions of physiological saline (0.02ml/min) or immepip (3.1, 10 or 31MUg/kg/min; a histamine H3/H4 receptor agonist). Under these conditions, electrical stimulation (0.56-5.6Hz; 50V and 2ms) of the spinal cord (T9-T12) resulted in frequency-dependent vasodepressor responses, which were: (i) unchanged during the infusions of saline or immepip (3.1MUg/kg/min); and (ii) significantly but, surprisingly, not dose dependently inhibited by 10 and 31MUg/kg/min immepip. Moreover, the sensory inhibition by 10MUg/kg/min immepip (which failed to inhibit the vasodepressor responses by i.v. bolus injections of alpha-CGRP; 0.1-1ug/kg) was: (i) essentially unaltered after i.v. administration of saline (1ml/kg) or blocking doses of the antagonists ketotifen (100MUg/kg; H1), ranitidine (1000MUg/kg; H2) or JNJ7777120 (310MUg/kg; H4); and (ii) abolished after i.v. thioperamide (310ug/kg; H3). In conclusion, our results suggest that immepip-induced inhibition of the vasodepressor sensory outflow is mainly mediated by prejunctional activation of histamine H3 receptors. PMID- 25704615 TI - Correspondences between the binding characteristics of a non-natural peptide, Lei Dab7, and the distribution of SK subunits in the rat central nervous system. AB - Small-conductance calcium-activated potassium channels (SK1-SK3 channels) are responsible for long-lasting hyperpolarization following action potential and contribute to the neuronal firing and integration signal. Two peptide toxins: apamin and Leiurotoxin 1, block this SK channels with high affinities. We generated a modified Leiurotoxin 1 (Lei-Dab7) that inhibits SK2 channels with a high selectivity. Competitive binding of radio-iodinated apamin to different rat brain structures, in the presence of native apamin and Lei-Dab7, has shown that dissociation constants differ by a factor of 1000 and thus demonstrated that ligand affinity is as important as ligand selectivity for a specific receptor. However, the lack of ligands discriminating between SK channel subunits is impeding the understanding of the role of each heteromeric SK channel type in different tissues. Our study aims to better understand the molecular combinations of SK channels and their association with specific functional implications. On this purpose, a clustering technique allows us to identify five groups of brain structures reflecting singular profiles of affinity and selectivity of Lei-Dab7 in comparison with apamin. The analysis of correspondences between Lei-Dab7 binding and distribution of SK subunits in these groups of brain structures suggests that functional heteromeric SK channels are involved in specific information processes. PMID- 25704616 TI - Acute and subchronic antinociceptive effects of nociceptin/orphanin FQ receptor agonists infused by intrathecal route in rats. AB - Severe pain occurs in the context of many diseases and conditions and is a leading cause of disability. Nociceptin/orphanin FQ (N/OFQ) is the endogenous ligand of the N/OFQ peptide (NOP) receptor. This peptidergic system controls pain transmission and in particular spinally administered N/OFQ has robust antinociceptive properties. The aim of this study was to investigate the spinal antinociceptive properties of NOP peptide agonists after acute and subchronic treatment in rats. Doses unable to alter motor coordination were selected. UFP 112 (full NOP agonist) and UFP-113 (partial NOP agonist) were administered intrathecally (i.t.) by spinal catheterization. Acute injection of UFP-112 induced antinociceptive response at lower dosages (0.03-1nmol i.t.) compared to morphine and similar to N/OFQ. UFP-113 was effective in a 0.001-1nmol i.t. dose range. The antinociceptive effects of NOP ligands were no longer evident in rats knockout for the NOP gene, while those of morphine were maintained. The continuous spinal infusion (by osmotic pumps) of 0.1nmol/h UFP-112 and UFP-113 showed antinociceptive action comparable to 1-3nmol/h morphine or N/OFQ. The antinociceptive effect of morphine progressively decreased and was no longer significant after 6 days of treatment. Similar results were obtained with N/OFQ, UFP-112, and UFP-113. The acute i.t. injection of morphine in animals tolerant to N/OFQ and UFP-112 evoked analgesic effects. Neither morphine nor N/OFQ induced antinociceptive effects in morphine- and UFP-113-tolerant rats. In conclusion this study highlights the analgesic efficacy and potency of UFP-112 and UFP-113 underlining the relevance of NOP system in analgesia. PMID- 25704617 TI - Leukotriene C4 induces bronchoconstriction and airway vascular hyperpermeability via the cysteinyl leukotriene receptor 2 in S-hexyl glutathione-treated guinea pigs. AB - Cysteinyl leukotrienes act through G-protein-coupled receptors termed cysteinyl leukotriene 1 (CysLT1) and cysteinyl leukotriene 2 (CysLT2) receptors. However, little is known about the pathophysiological role of CysLT2 receptors in asthma. To elucidate the possible involvement of CysLT2 receptors in bronchoconstriction and airway vascular hyperpermeability, we have established a novel guinea pig model of asthma. In vitro study confirmed that CHO-K1 cells, expressing guinea pig CysLT2 and CysLT1 receptors are selectively stimulated by LTC4 and LTD4, respectively. However, when LTC4 was intravenously injected to guinea pigs, the resulting bronchoconstriction was fully abrogated by montelukast, a CysLT1 receptor antagonist, indicating rapid metabolism of LTC4 to LTD4 in the lung. We found that treatment with S-hexyl glutathione (S-hexyl GSH), an inhibitor of gamma-glutamyl transpeptidase, significantly increased LTC4 content and LTC4/(LTD4 plus LTE4) ratio in the lung. Under these circumstances, LTC4-induced bronchoconstriction became resistant to montelukast, but sensitive to Compound A, a CysLT2 receptor antagonist, depending on the dose of S-hexyl GSH. Combination with montelukast and Compound A completely abrogated this spasmogenic response. Additionally, we confirmed that LTC4 elicits airway vascular hyperpermeability via CysLT2 receptors in the presence of high dose of S-hexyl GSH as evidenced by complete inhibition of LTC4-induced hyperpermeability by Compound A, but not montelukast. These results suggest that CysLT2 receptors mediate bronchoconstriction and airway vascular hyperpermeability in guinea pigs and that the animal model used in this study may be useful to elucidate the functional role of CysLT2 receptors in various diseases, including asthma. PMID- 25704618 TI - KAG-308, a newly-identified EP4-selective agonist shows efficacy for treating ulcerative colitis and can bring about lower risk of colorectal carcinogenesis by oral administration. AB - Agonists for EP4 receptor, a prostaglandin E2 receptor subtype, appear to be a promising therapeutic strategy for ulcerative colitis (UC) due to their anti inflammatory and epithelial regeneration activities. However, the clinical development of orally-available EP4 agonists for mild to moderate UC has not yet been reported. Furthermore, the possibility of an increased risk of colitis associated cancer (CAC) through direct proliferative effects on epithelial cells via EP4 signaling has not been ruled out. Recently, we identified KAG-308 as an orally-available EP4-selective agonist. Here, we investigated the pharmacological and pharmacokinetic profiles of KAG-308. Then, we compared KAG-308 and sulfasalazine (SASP) for their abilities to prevent colitis and promote mucosal healing in a mouse model of dextran sulfate sodium (DSS)-induced colitis. Finally, the effect of KAG-308 treatment on CAC was evaluated in an azoxymethane (AOM)/DSS-induced CAC mouse model. KAG-308 selectively activated EP4 and potently inhibited tumor necrosis factor-alpha production in peripheral whole blood and T cells. Oral administration of KAG-308, which showed relatively high bioavailability, suppressed the onset of DSS-induced colitis and promoted histological mucosal healing, while SASP did not. KAG-308 also prevented colorectal carcinogenesis by inhibiting colitis development and consequently decreasing mortality in a CAC model, whereas SASP had marginal effects. In contrast, MF-482, an EP4 antagonist, increased mortality. These results indicated that orally-administered KAG-308 suppressed colitis development and promoted mucosal healing. Moreover, it exhibited preventive effects on colorectal carcinogenesis, and thus may be a new therapeutic strategy for the management of UC that confers a reduced risk of colorectal carcinogenesis. PMID- 25704619 TI - IgE and IgA produced by OX40-OX40L or CD40-CD40L interaction in B cells-mast cells re-activate FcepsilonRI or FcalphaRI on mast cells in mouse allergic asthma. AB - Mast cells are major effector cells of allergic diseases related to IgE. This study was undertaken to determine whether IgE or IgA, produced by CD40-CD40L or OX40-OX40L interactions between B cells and mast cells, re-activate FcepsilonRI or FcalphaRI on mast cell surface. C57BL mice were sensitized and subjected to OVA challenge to induce asthma. Bone marrow-derived mast cells (BMMCs) and primary B cells were co-cultured. Mast cell recruitment into airways was stained by May-Grunwald Giemsa, the expression of markers or signaling molecules were determined by immunohistochemistry or Western blotting, and co-localization of B cells and mast cells by immunofluorescence. Anti-CD40 plus anti-OX40L Abs synergistically reduced IgE and IgA production, and mediators (histamine, LTs and cytokines) released in mast cells, and additively reduced other responses, such as, numbers of mast cells, the expression of markers (tryptase, mMCP5, B220 and CD19), surface molecules (CD40, CD40L, OX40 and OX40L), FcepsilonRI or FcalphaRI and the co-localization of BMMCs and B cells, and IgE- or IgA-producing cells, as compared with individual blocking Ab treatment which reducedresponses in BAL cells or lung tissues of OVA-challenged mice or in co-culture of B and mast cells. The data suggest that IgE and IgA, produced by OX40-OX40L or CD40-CD40L interaction between B cells and mast cells, may re-activate receptors of FCepsilonRI and FcalphaRI on mast cell surfaces, followed by more mediator release, and furthermore, that treatment with anti-CD40 plus anti-OX40L Abs offers a potential treatment for allergic asthma. PMID- 25704620 TI - Prevalence of airflow obstruction and reduced forced vital capacity in an Aboriginal Australian population: The cross-sectional BOLD study. AB - BACKGROUND AND OBJECTIVE: Mortality and hospital separation data suggest a higher burden of chronic obstructive pulmonary disease (COPD) in indigenous than non indigenous subpopulations of high-income countries. This study sought to accurately measure the true prevalence of post-bronchodilator airflow obstruction and forced vital capacity reduction in representative samples of Indigenous and non-Indigenous Australians. METHODS: This study applies cross-sectional population-based survey of Aboriginal and non-Indigenous residents of the Kimberley region of Western Australia aged 40 years or older, following the international Burden Of Lung Disease (BOLD) protocol. Quality-controlled spirometry was conducted before and after bronchodilator. COPD was defined as Global initiative for chronic Obstructive Lung Disease (GOLD) Stage 2 and above (post-bronchodilator forced expiratory volume in 1 s/forced vital capacity (FEV1 /FVC) ratio <0.7 and FEV1 < 80% predicted). RESULTS: Complete data were available for 704 participants. The prevalence of COPD, adjusted for age, gender and body weight in Aboriginal participants (7.2%, 95% confidence interval (CI) 3.9 to 10.4) was similar to that seen in non-Indigenous Kimberley participants (8.2%, 95% CI 5.7 to 10.7) and non-Indigenous residents of the remainder of Australia (7.1%, 95% CI 6.1 to 8.0). The prevalence of low FVC (<80% predicted) was substantially higher in Aboriginal compared with non-Indigenous participants (74.0%, 95% CI 69.1 to 78.8, vs 9.7%, 95% CI 7.1 to 12.4). CONCLUSIONS: Low FVC, rather than airflow obstruction, characterizes the impact of chronic lung disease previously attributed to COPD in this population subject to significant social and economic disadvantage. Environmental risk factors other than smoking as well as developmental factors must be considered. These findings require further investigation and have implications for future prevention of chronic lung disease in similar populations. PMID- 25704621 TI - Single- or multiple-session viscosupplementation protocols for temporomandibular joint degenerative disorders: a randomized clinical trial. AB - The aim of the study was to compare the effectiveness of two single-session protocols, either adopting high- (protocol A) or medium-molecular weight hyaluronic acid (protocol B), with the reference five-session protocol of temporomandibular joint (TMJ) lavage plus viscosupplementation (protocol C) in the management of chronic TMJ degenerative disorders. A randomized clinical trial (RCT) with ten participants per treatment group was designed, with multiple observation points, ending at 6 months after treatment. Pain levels on a 10-point VAS scale were selected as the primary outcome variable to rate treatment effectiveness, along with a number of secondary outcome parameters. Findings showed that Group C patients had the highest decrease in pain levels. Nonparametric permutation analyses revealed that the global effect of treatment was significantly different between the three protocols (P = 0.024). Pairwise comparisons showed that the differences of treatment effect between the two single-session interventions were negligible (global P-value = 0.93). On the contrary, the five-session protocol was significantly superior to both single session protocols (global P-values ranging from 0.003 to 0.012). In conclusion, in a population of age-, sex-, and psychosocial aspects-matched study groups, the standard of reference five-session protocol proved to be superior at 6 months as far as the decrease in pain levels was concerned, whilst there were no differences between the two single-session interventions. The absence of differences in treatment effect as for some other secondary clinical outcome variables may suggest that there is further space for future investigations attempting to reduce the number of multiple interventions for TMJ viscosupplementation. PMID- 25704622 TI - The Effect of Simvastatin on Infection-Induced Inflammatory Response of Human Fetal Membranes. AB - PROBLEM: Inflammatory cytokines and matrix metalloproteinases (MMPs) contribute to preterm labor pathophysiology. The objective of this study was to test anti inflammatory properties of simvastatin in human fetal membranes exposed to lipopolysaccharide (LPS). METHOD OF STUDY: Normal term human fetal membrane explants (n = 11) were allocated to one of the six study groups: control, LPS only (100 ng/mL), simvastatin only (125 ng/mL), simvastatin given 6 hrs prior to LPS (S-L), simvastatin given 6 hrs post-LPS (L-S), and simvastatin and LPS given simultaneously (L+S). Explants were incubated for 24 hrs. Multiplex ELISA for cytokines: IL-1beta, IL-6, IL-10, and TNF-alpha; soluble cytokine receptors: sIL 1R2, sIL-6R, sTNFR1, and R2; MMPs (1, 2, 7, 9, and 10); and tissue inhibitor of metalloproteinase-2 (TIMP-2) was performed on tissue culture supernatants. Pairwise comparison between different groups was conducted by least square mean estimates. RESULTS: Compared with controls, LPS stimulation increased cytokine production and their tissue bioavailability (measured as the molar ratio of cytokine to its soluble receptor), thus confirming membrane immune reactivity (P < 0.01). Pre-treatment with simvastatin (S-L) reduced IL-6 (P = 0.02), TNF-alpha (P = 0.02), and MMP-9 (P = 0.01); post-treatment (L-S) reduced IL-1beta (P = 0.02) and TNF-alpha (P = 0.04), while simultaneous treatment (L+S) did not reduce any of the cytokines tested. Simvastatin reduced the molar ratio of TNF alpha/sTNFR1 or R2 and IL-1beta/sIL-1R2 (P = 0.01 and 0.04 in S-L group; P = 0.01 and 0.004 in L-S group, respectively). S-L additionally reduced MMP-9/TIMP-2 molar ratio (P = 0.0007). CONCLUSIONS: Simvastatin downregulates LPS-induced inflammatory response and restores homeostasis between pro- and anti-inflammatory processes. Simvastatin may reduce fetal inflammatory response associated with infection-induced preterm birth. PMID- 25704623 TI - Correlation of 15-prostagladin dehydrogenase expression with clinicopathological factors and survival rate in gastric adenocarcinoma. AB - INTRODUCTION: The prostaglandin (PG) E2 level, which is associated with oncogenesis, progression and metastasis in various types of cancer, is determined by reciprocal regulation of 15-prostaglandin dehydrogenase (15-PGDH) and cyclooxygenase-2. This study investigated 15-PGDH expression in gastric adenocarcinoma, the associations between 15-PGDH expression and clinicopathological factors, and the correlation between 15-PGDH expression and the 5-year gastric-cancer-specific survival rate (5-year GCSS). METHODS: From 175 patients who underwent gastrectomy, we obtained biopsies of gastric adenocarcinoma tissues and adjacent normal tissues for preparation as formalin fixed, paraffin-embedded specimens and conducted an immunohistochemical analysis. RESULTS: 15-PGDH expression was low in 65.1% of cases. 15-PGDH expression showed no relationship with age or gender, but was significantly correlated with the pathologic type, T stage, N stage, TNM stage, positive lymph node metastasis, metastasis to a larger quantity of lymph nodes, positive lymphatic invasion, positive vascular invasion, positive perineural invasion, and palliative gastrectomy. The 5-year GCSS of the low-expression group was 77.19% and a lower level of 15-PGDH expression correlated to a lower 5-year GCSS. 15-PGDH expression significantly influenced the 5-year GCSS on univariate but not multivariate analysis. CONCLUSION: Our findings indicate that 15-PGDH expression was low in gastric adenocarcinoma and was correlated with the clinicopathological factors associated with prognosis and a more advanced stage of gastric adenocarcinoma. Also, 15-PGDH expression was significantly associated with the 5-year GCSS, but was not an independent prognostic factor thereof. PMID- 25704624 TI - Impact of aging on frontostriatal reward processing. AB - Healthy aging is associated with a progressive decline across a range of cognitive functions. An important factor underlying this decline may be the age related impairment in stimulus-reward processing. Several studies have investigated age-related effects, but compared young versus old subjects. This is the first study to investigate the effect of aging on brain activation during reward processing within a continuous segment of the adult life span. We scanned 49 healthy adults aged 40-70 years, using functional MRI. We adopted a simple reward task, which allowed separate evaluation of neural responses to reward anticipation and receipt. The effect of reward on performance accuracy and speed was not related to age, indicating that all subjects could perform the task correctly. We identified a whole-brain significant age-related decline of ventral striatum activation during reward anticipation as compared to neutral anticipation. Importantly, the specificity of this finding was underscored by the observation that there was no general decline in activation during anticipation. Activation in the ventral striatum increased with age during reward receipt as compared to receiving neutral outcome. Finally, activation in the ventromedial prefrontal cortex during outcome was not affected by age. Our data demonstrate that the typical shift in striatal activation from reward receipt to reward anticipation in young adults disappears with healthy aging. These changes are consistent the well-ocumented age-related decline of striatal dopamine availability, and may provide a stepping stone for further research of age related neurodegenerative diseases. PMID- 25704626 TI - Anion transport across varying lipid membranes--the effect of lipophilicity. AB - The anion transport properties of a range of alkyl-substituted phenylthioureas were tested in vesicles of different lipid composition. Although changes in the bilayer affected the rate of transport for all compounds in the series, the 'ideal' log P for peak activity did not change depending on the composition of the bilayers tested. PMID- 25704627 TI - Profilin-1 expression is associated with high grade and stage and decreased disease-free survival in renal cell carcinoma. AB - Clear cell renal cell carcinoma (ccRCC) is associated with high mortality, although individual outcomes are highly variable. Identification of patients with increased risk of disease progression can guide customizing management plan according to disease severity. Profilin-1 (Pfn1) has been recently identified as overexpressed in metastatic ccRCC compared with primary tumors. We examined Pfn1 expression in a tissue microarray of 384 cases of histologically confirmed primary ccRCC with detailed clinical follow-up. Profilin-1 expression showed both cytoplasmic and nuclear staining patterns. The immunoexpression of Pfn1 was scored in a semiquantitative fashion. There was no significant difference in Pfn1 expression between normal kidney and kidney ccRCC. Our results show that strong cytoplasmic Pfn1 expression is associated with high-grade (P < .001) and high stage (III-IV) (P = .018) disease. Univariate analysis of the data set showed that higher Pfn1 expression is associated with significantly shorter disease-free survival (hazard ratio 7.36, P = .047) and also lower overall survival. Kaplan Meier analysis showed that high cytoplasmic expression of Pfn1 was also associated with a statistically significant lower disease-free survival (P = .018). It was also associated with lower overall survival, although this was not statistically significant. Profilin-1 lost its prognostic significance in the multivariate analysis when controlling for grade and stage. Profilin-1 expression was not associated with significant prognostic deference in the subgroup of patients with stage 1 disease. Our results suggest that the evaluation of Pfn1 by immunohistochemistry may help to identify patients with an increased risk of disease progression. We validated our results at the messenger RNA level on an independent patient cohort. Higher messenger RNA expression of Pfn1 is associated with significantly lower survival. PMID- 25704628 TI - Cutaneous basal cell carcinosarcomas: evidence of clonality and recurrent chromosomal losses. AB - Cutaneous carcinosarcomas are heterogeneous group of tumors composed of malignant epithelial and mesenchymal components. Although mutation analyses have identified clonal changes between these morphologically disparate components in some subtypes of cutaneous carcinosarcoma, few cases have been analyzed thus far. To our knowledge, copy number variations (CNVs) and copy-neutral loss of heterozygosity (CN-LOH) have not been investigated in cutaneous carcinosarcomas. We analyzed 4 carcinosarcomas with basal cell carcinoma and osteosarcomatous components for CNVs/CN-LOH by comparative genomic hybridization/single-nucleotide polymorphism array, TP53 hot spot mutations by polymerase chain reaction and Sanger sequencing, and TP53 genomic rearrangements by fluorescence in situ hybridization. All tumors displayed multiple CNV/CN-LOH events (median, 7.5 per tumor). Three of 4 tumors displayed similar CNV/CN-LOH patterns between the epithelial and mesenchymal components within each tumor, supporting a common clonal origin. Recurrent changes included allelic loss at 9p21 (CDKN2A), 9q (PTCH1), and 17p (TP53). Allelic losses of chromosome 16 including CDH1 (E cadherin) were present in 2 tumors and were restricted to the sarcomatous component. TP53 mutation analysis revealed an R248L mutation in both epithelial and mesenchymal components of 1 tumor. No TP53 rearrangements were identified. Our findings indicate that basal cell carcinosarcomas harbor CNV/CN-LOH changes similar to conventional basal cell carcinoma, with additional changes including recurrent 9p21 losses and a relatively high burden of copy number changes. In addition, most cutaneous carcinosarcomas show evidence of clonality between epithelial and mesenchymal components. PMID- 25704629 TI - Epstein-Barr virus-positive diffuse large B-cell lymphoma in children: a disease reminiscent of Epstein-Barr virus-positive diffuse large B-cell lymphoma of the elderly. AB - Pediatric Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (EBV+ DLBCL) is a rare disease in nonimmunocompromised hosts. In a review of 231 cases of malignant lymphoma (87 Hodgkin lymphoma and 144 non-Hodgkin lymphoma) occurring in Iraqi children, 7 cases (5% of NHLs) were classified as EBV+ DLBCL. Six children presented with nodal disease, and 1 presented with extranodal localization (bone). In all cases, the disease was at an advanced clinical stage (III/IV). Evidence of immunodeficiency (Evans syndrome and selective IgA deficiency) was observed in a single case. Two cases were "monomorphic" with immunoblastic histology, and 5 cases were "polymorphic" with histologic aspects reminiscent of nodular lymphocyte-predominant Hodgkin lymphoma (2 cases) and of CD30+ classical Hodgkin lymphoma (3 cases). In all cases, tumor cells were EBV infected (EBER+/LMP-1+), were medium-large B-cells (CD20+/CD79a+/PAX-5+/BOB 1+/OCT-2+) of non-germinal center (non-GC) origin (CD10-/MUM-1+), and had high proliferative activity (50%-70%). Chromosomal translocations involving BCL2, MYC, and IGH genes were not observed. IGH monoclonality could be demonstrated in 3 of 3 investigated cases. Six cases of EBV-negative DLBCL (4% of NHL) were present in the same series. All had monomorphic histology with centroblastic/immunoblastic morphology; 3 cases were of GC type and 3 of non-GC type. Our findings indicate that in Iraq, DLBCLs are 9% of NHLs. Moreover, 2 different types of the disease do exist; the EBV-positive cases, with strong histologic and immunohistochemical resemblance with EBV+ DLBCL of the elderly, and the EBV-negative cases, which are similar to the pediatric DLBCL usually observed in Western populations. PMID- 25704630 TI - Developmental exposure to cuprizone reduces intermediate-stage progenitor cells and cholinergic signals in the hippocampal neurogenesis in rat offspring. AB - The exposure to cuprizone (CPZ) leads to demyelination in the central nervous system in rodents. To examine the developmental effects of CPZ exposure on hippocampal neurogenesis, pregnant rats were treated with 0, 0.1 or 0.4% CPZ in the diet from gestational day 6 to day 21 after delivery. On postnatal day 21, male offspring had a decreased density of new glue2(+) oligodendrocyte progenitor cells in the dentate hilus and in the area of the cerebellar medulla in the presence of 0.4% CPZ. With regard to neurogenesis-related parameters, offspring had decreased T box brain 2(+) progenitor cells and increased apoptotic cells, as detected by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling, which was accompanied by the up-regulation of Casp12 and Bcl2l11 in the subgranular zone, and increased reelin(+) interneurons in the dentate hilus. In addition, the density of phosphorylated TrkB(+) interneurons decreased in the dentate hilus, which was accompanied by transcript down-regulation of Bdnf and Chrna7 in the dentate gyrus. Moreover, granule cells expressing gene products of immediate-early genes, i.e., Arc and Fos, decreased. These results suggest that maternal exposure to 0.4% CPZ decreases proliferative type-2 progenitor cells via endoplasmic reticulum stress-mediated apoptosis and inhibition of cholinergic signals to intermediate-stage progenitor cells following reduced oligodendrocyte production and suppression of the brain-derived neurotrophic factor signaling cascade. Increases in reelin-expressing interneurons may compensate for impaired granule cell migration and/or correct positioning due to decreased immediate early gene-mediated neuronal plasticity. However, all observed fluctuations disappeared at the adult stage, suggesting that CPZ-induced developmental neurotoxicity was reversible. PMID- 25704631 TI - Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. AB - Acetaminophen (APAP) overdosage results in hepatotoxicity, but the underlying molecular mechanisms are still not completely understood. In the current study, we focused on mitochondrial-specific oxidative liver injury induced by APAP exposure. Owning to genetic polymorphisms in the CYP2E1 gene or varying inducibility by xenobiotics, the CYP2E1 mRNA level and protein activity vary extensively among individuals. As CYP2E1 is a known ROS generating enzyme, we chose HepG2 to minimize CYP2E1-induced ROS formation, which will help us better understand the APAP induced mitochondrial-specific hepatotoxicity in a subpopulation with low CYP2E1 activity. HepG2 cells were exposed to a low and toxic dose (0.5 and 10mM) of APAP and analyzed at four time points for genome wide gene expression. Mitochondria were isolated and electron spin resonance spectroscopy was performed to measure the formation of mitochondrial ROS. The yield of ATP was measured to confirm the impact of the toxic dose of APAP on cellular energy production. Our results indicate that 10mM APAP significantly influences the expression of mitochondrial protein-encoding genes in association with an increase in mitochondrial ROS formation. Additionally, 10mM APAP affects the expression of genes encoding the subunits of electron transport chain (ETC) complexes, which may alter normal mitochondrial functions by disrupting the assembly, stability, and structural integrity of ETC complexes, leading to a measurable depletion of ATP, and cell death. The expression of mitochondrium specific antioxidant enzyme, SOD2, is reduced which may limit the ROS scavenging ability and cause imbalance of the mitochondrial ROS homeostasis. Overall, transcriptome analysis reveals the molecular processes involved in the observed APAP-induced increase of mitochondrial ROS formation and the associated APAP induced oxidative stress. PMID- 25704632 TI - Effect of voluntary physical activity initiated at age 7 months on skeletal hindlimb and cardiac muscle function in mdx mice of both genders. AB - INTRODUCTION: The effects of voluntary activity initiated in adult mdx (C57BL/10ScSc-DMD(mdx) /J) mice on skeletal and cardiac muscle function have not been studied extensively. METHODS: We studied the effects of 3 months of voluntary wheel running initiated at age 7 months on hindlimb muscle weakness, increased susceptibility to muscle contraction-induced injury, and left ventricular function in mdx mice. RESULTS: We found that voluntary wheel running did not worsen the deficit in force-generating capacity and the force drop after lengthening contractions in either mdx mouse gender. It increased the absolute maximal force of skeletal muscle in female mdx mice. Moreover, it did not affect left ventricular function, structural heart dimensions, cardiac gene expression of inflammation, fibrosis, or remodeling markers. CONCLUSION: These results indicate that voluntary activity initiated at age 7 months had no detrimental effects on skeletal or cardiac muscles in either mdx mouse gender. PMID- 25704633 TI - Diabetes and Other Risk Factors for Multi-drug Resistant Tuberculosis in a Mexican Population with Pulmonary Tuberculosis: Case Control Study. AB - BACKGROUND AND AIMS: Multidrug resistant tuberculosis (MDR-TB) poses problems in treatment, costs and treatment outcomes. It is not known if classically described risk factors for MDR-TB in other countries are the same in Mexico and the frequency of the association between diabetes mellitus (DM) and MDR-TB in our country is not clear. We undertook this study to analyze risk factors associated with the development of MDR-TB, with emphasis on DM. METHODS: A case-control study in the state of San Luis Potosi (SLP), Mexico was carried out. All pulmonary MDR-TB patients diagnosed in the state of SLP between 1998 and 2013 (36 cases) evaluated at a state pharmacoresistant tuberculosis (TB) clinic and committee; 139 controls were randomly selected from all pulmonary non-multidrug resistant tuberculosis (non-MDR-TB) cases identified between 2003 and 2008. Cases and controls were diagnosed and treated under programmatic conditions. RESULTS: Age, gender, malnutrition, being a health-care worker, HIV/AIDS status, and drug abuse were not significantly different between MDR-TB and non-MDR-TB patients. Significant differences between MDR-TB and non-MDR-TB patients were DM (47.2 vs. 28.1%; p = 0.028); previous anti-TB treatments (3 vs. 0, respectively; p <0.001), and duration of first anti-TB treatment (8 vs. 6 months, respectively; p <0.001). CONCLUSIONS: MDR-TB and DM are associated in 47.2% of MDR TB cases (17/36) in this study. Other recognized factors were not found to be significantly different in MDR-TB compared to non-MDR-TB in this study. Cost-feasible strategies must be implemented in the treatment of DM-TB in order to prevent the selection of MDR TB. PMID- 25704634 TI - Genetic and Clinical Analysis in a Cohort of Patients with Wilson's Disease in Southwestern China. AB - BACKGROUND AND AIMS: Wilson's disease (WD), characterized by a disorder of copper metabolism, is an inherited autosomal recessive disease caused by mutations in the ATP7B gene. METHODS: To explore genotype-phenotype correlations in Chinese WD patients and to evaluate the frequency of the ATP7B mutations, we described 77 clinically and biochemically confirmed WD patients and detected mutations in ten WD families from southwestern China. Clinical features were presented and all the exons of the ATP7B gene were screened. RESULTS: The appearance of Kayser Fleischer (K-F) rings was closely related to onset age, particularly before 10 years old. For those patients with predominantly neurological symptoms, MRI was the most sensitive and preferred examination. Eight mutations of the ATP7B gene were detected including seven reported mutations (c.2302dup, c.2304delC, c.2333 G>T, c.2621 C>T, c.2755 C>G, c.2975 C>T and c.1366 G>C) and four novel mutations (c.3446 G>A, c.3767insCA, c.3406 G>A and c.3700delG). c.2333 G>T was detected in 6/20 alleles (30%), accounting for the largest proportion, which could be regarded as a mutation hotspot in this region. CONCLUSIONS: Our study extends the mutation spectrum of ATP7B and analyzes the relationship between mutations in the ATP7B gene and clinical findings of WD. PMID- 25704635 TI - [Hypovolemic shock in a patients with cirrhosis secondary to hematoma of the psoas]. PMID- 25704636 TI - Association of marital status and colorectal cancer screening participation in the USA. AB - AIM: In the USA, for both men and women, colorectal cancer (CRC) ranks third in incidence and second in mortality. Despite evidence that it decreases mortality, CRC screening in the USA remains under-utilized. Some European studies have suggested that marital status affects participation in CRC screening, but the effect of marital status on CRC screening participation in the USA is unknown. In this study, the aim was to compare CRC screening participation rates among married and unmarried couples, separated, widowed, never married and divorced adults living in the USA. METHOD: This was a retrospective data analysis of the 2010 Behavioural Risk Factor Surveillance System survey. The population studied included 239,300 participants, aged 50-75 years, who completed the 2010 survey. Logistic regression analysis was conducted to assess the association between adherence with CRC screening guidelines and marital status while accounting for survey stratum/weight and covariates. RESULTS: Individuals who were divorced or separated, never married or widowed had decreased odds of adherence with CRC screening guidelines compared with individuals who were married and unmarried couples. CONCLUSION: In this study, individuals living in the USA who were married and unmarried couples had increased odds of undergoing CRC screening compared to individuals in other marital status groups. Public health interventions are needed to promote CRC screening participation in these other groups. PMID- 25704637 TI - Chamber bioaerosol study: human emissions of size-resolved fluorescent biological aerosol particles. AB - Humans are a prominent source of airborne biological particles in occupied indoor spaces, but few studies have quantified human bioaerosol emissions. The chamber investigation reported here employs a fluorescence-based technique to evaluate bioaerosols with high temporal and particle size resolution. In a 75-m(3) chamber, occupant emission rates of coarse (2.5-10 MUm) fluorescent biological aerosol particles (FBAPs) under seated, simulated office-work conditions averaged 0.9 +/- 0.3 million particles per person-h. Walking was associated with a 5-6* increase in the emission rate. During both walking and sitting, 60-70% or more of emissions originated from the floor. The increase in emissions during walking (vs. while sitting) was mainly attributable to release of particles from the floor; the associated increased vigor of upper body movements also contributed. Clothing, or its frictional interaction with human skin, was demonstrated to be a source of coarse particles, and especially of the highly fluorescent fraction. Emission rates of FBAPs previously reported for lecture classes were well bounded by the experimental results obtained in this chamber study. In both settings, the size distribution of occupant FBAP emissions had a dominant mode in the 3-5 MUm diameter range. PMID- 25704638 TI - Simple tool for prediction of parotid gland sparing in intensity-modulated radiation therapy. AB - Sparing one or both parotid glands is a key goal when planning head and neck cancer radiation treatment. If the planning target volume (PTV) overlaps one or both parotid glands substantially, it may not be possible to achieve adequate gland sparing. This finding results in physicians revising their PTV contours after an intensity-modulated radiation therapy (IMRT) plan has been run and reduces workflow efficiency. We devised a simple formula for predicting mean parotid gland dose from the overlap of the parotid gland and isotropically expanded PTV contours. We tested the tool using 44 patients from 2 institutions and found agreement between predicted and actual parotid gland doses (mean absolute error = 5.3 Gy). This simple method could increase treatment planning efficiency by improving the chance that the first plan presented to the physician will have optimal parotid gland sparing. PMID- 25704639 TI - Suppression of nuclear spin bath fluctuations in self-assembled quantum dots induced by inhomogeneous strain. AB - Interaction with nuclear spins leads to decoherence and information loss in solid state electron-spin qubits. One particular, ineradicable source of electron decoherence arises from decoherence of the nuclear spin bath, driven by nuclear nuclear dipolar interactions. Owing to its many-body nature nuclear decoherence is difficult to predict, especially for an important class of strained nanostructures where nuclear quadrupolar effects have a significant but largely unknown impact. Here, we report direct measurement of nuclear spin bath coherence in individual self-assembled InGaAs/GaAs quantum dots: spin-echo coherence times in the range 1.2-4.5 ms are found. Based on these values, we demonstrate that strain-induced quadrupolar interactions make nuclear spin fluctuations much slower compared with lattice-matched GaAs/AlGaAs structures. Our findings demonstrate that quadrupolar effects can potentially be used to engineer optically active III-V semiconductor spin-qubits with a nearly noise-free nuclear spin bath, previously achievable only in nuclear spin-0 semiconductors, where qubit network interconnection and scaling are challenging. PMID- 25704640 TI - PfRH5 as a candidate vaccine for Plasmodium falciparum malaria. AB - PfRH5 has recently emerged as a strong vaccine candidate for Plasmodium falciparum malaria. Antibodies inhibit invasion of erythrocytes by merozoites and blood-stage replication, and PfRH5 is a significant target of acquired human immunity. Recent studies have shown protective efficacy of PfRH5 vaccines in a non-human primate model of malaria. PMID- 25704641 TI - Expression of TGFbeta superfamily components and other markers of oocyte quality in oocytes selected by brilliant cresyl blue staining: relevance to early embryonic development. AB - Brilliant cresyl blue (BCB) is a super-vital stain that has been used to select competent oocytes in different species. One objective of the present study was to assess the relationship between BCB staining, which correlates with an oocyte's developmental potential, and the transcript abundance for select TGFbeta superfamily components, SMAD2/3 and SMAD1/5 phosphorylation levels, and oocyte (JY1) and cumulus-cell (CTSB, CTSK, CTSS, and CTSZ) transcript markers in bovine oocytes and/or adjacent cumulus cells. The capacity of exogenous follistatin or JY1 supplementation or cathepsin inhibitor treatment to enhance development of embryos derived from low-quality oocytes, based on BCB staining, was also determined. Cumulus-oocyte complexes (COCs) from abattoir-derived ovaries were subjected to BCB staining, and germinal-vesicle-stage oocytes and cumulus cells were harvested from control, BCB+, and BCB- (low-quality oocyte) groups for real time PCR or Western-blot analysis. Remaining COCs underwent in vitro maturation, in vitro fertilization, and embryo culture in the presence or absence of the above exogenous supplements. Levels of FST, JY1, BMP15, and SMAD1, 2, 3, and 5 transcripts were higher in BCB+ oocytes whereas CTSB, CTSK, CTSS, and CTSZ mRNA abundance was higher in cumulus cells surrounding BCB- oocytes. Western-blot analysis revealed higher SMAD1/5 and SMAD2/3 phosphorylation in BCB+ than BCB- oocytes. Embryo-culture studies demonstrated that follistatin and cathepsin inhibitor treatment, but not JY-1 treatment, improve the developmental competence of BCB- oocytes. These results contribute to a better understanding of molecular indices of oocyte competence. PMID- 25704642 TI - Etiology and management of esophageal food impaction: a population based study. AB - OBJECTIVE: Esophageal food impaction (FI) is a common clinical problem with limited information on incidence. Previous population based studies are lacking. The incidence, main etiological factors, recurrence and outcome of FI was determined in the present study in a population based setting. MATERIAL AND METHODS: This was a study of consecutive adult patients who presented with FI from 2008 to 2013 at the National University Hospital of Iceland. The mean crude incidence rate of FI was calculated. Retrospective analysis was undertaken on relevant clinical data such as type of bolus, management, complications, recurrence rate, risk factors for recurrence, and outcome. RESULTS: Overall 308 patients had endoscopically confirmed FI, males 199/308 (65%), median age 62 years. The mean crude incidence was 25 per 100,000 inhabitants per year. The types of FI was meat (68%), fish (12%), vegetable (4%) and other food/objects (16%). Causes for the FI included: esophageal strictures (45%), hiatal hernia (22%), eosinophilic esophagitis (EoE) (16%) and esophageal carcinoma (2%). Recurrence appeared in 21%, in which 24/48 (50%) had EoE vs. 40/260 (15%) in others (p = 0.0001). The removal of the foreign body was successful in 98% of the cases during the first endoscopy. Endoscopic associated complications included four (1.3%) aspirations, one (0.3%) esophageal perforation and one Boerhaave syndrome at presentation (both had EoE). CONCLUSIONS: The incidence of FI is the highest reported to date. EoE was strongly associated with recurrence of FI. In a population based setting endoscopy is a safe and effective procedure for removing FI. PMID- 25704643 TI - Impact of casein and egg white proteins on the structure of wheat gluten-based protein-rich food. AB - BACKGROUND: There is a growing interest in texturally and nutritionally satisfying vegetable alternatives to meat. Wheat gluten proteins have unique functional properties but a poor nutritional value in comparison to animal proteins. This study investigated the potential of egg white and bovine milk casein with well-balanced amino acid composition to increase the quality of wheat gluten-based protein-rich foods. RESULTS: Heating a wheat gluten (51.4 g)-water (100.0 mL) blend for 120 min at 100 degrees C increased its firmness less than heating a wheat gluten (33.0 g)-freeze-dried egg white (16.8 g)-water (100.0 mL) blend. In contrast, the addition of casein to the gluten-water blend negatively impacted firmness after heating. Firmness was correlated with loss of protein extractability in sodium dodecyl sulfate containing medium during heating, which was higher with egg white than with casein. Even more, heat-induced polymerization of the gluten-water blend with egg white but not with casein was greater than expected from the losses in extractability of gluten and egg white on their own. CONCLUSION: Structure formation was favored by mixing gluten with egg white but not with casein. These observations were linked to the intrinsic polymerization behavior of egg white and casein, but also to their interaction with gluten. Thus not all nutritionally suitable proteins can be used for enrichment of gluten-based protein-rich foods. PMID- 25704644 TI - Occurrence of pathogenic Acanthamoeba genotypes in nasal swabs of cancer patients in Iran. AB - Incidences of Acanthamoeba granulomatous encephalitis (AGE) have been increased due to a rise in the number of high-risk people, such as immunodeficient patients. Indeed, immunosuppress situation can render the patient in acquiring opportunistic Acanthamoeba infections. In this study, analysis was carried out to verify the presence of free-living amoebae of Acanthamoeba genus in nasal swabs of cancer patients in hospitals of Tehran, Iran. Detection of isolates was based on morphotyping and PCR sequencing of the Diagnostic Fragment 3 (DF3) to identify strains at the genotype level. In addition, the pathogenic potential of the isolates was assayed using temperature and osmotolerance assays. The obtained results revealed that nine isolated strains belonging to T4 genotype-exhibited pathogenic potential. After sequencing, genotype T4 was found to be the most common one in the samples included in this study. Genotype T3 and T5 were also identified. To the best of our knowledge, this is the first study on the typing of Acanthamoeba strains at the genotype level in cancer patients in Iran and worldwide. PMID- 25704645 TI - Changes in the levels of Cryspovirus during in vitro development of Cryptosporidium parvum. AB - The purpose of this study was to develop and utilize semi-quantitative RT-PCR and PCR assays for measuring the level of Cryspovirus, the viral symbiont of Cryptosporidium parvum, during in vitro development of the protozoan. Cultures of human carcinoma cells (HCT-8) were inoculated with excysting C. parvum sporozoites, followed by harvest of cells and culture medium at 2-, 24-, 48-, and 72-h post-infection. Changes in viral RNA levels were detected by RT-PCR using primers specific for RNA encoding the 40-kDa capsid protein (CP) or RNA-dependent RNA polymerase (RdRp). Parasite or host DNA was quantified by PCR specific for C. parvum or human glyceraldehyde-3-phosphate dehydrogenase (HuGAPDH). An internal standard (competitor) was incorporated into all assays as a control for PCR inhibition. Intracellular levels of C. parvum DNA increased between 2- and 48-h post-infection, and then decreased at 72 h. Culture medium overlying these C. parvum-infected cells displayed a similar increase in CP and RdRp signal, reaching peak levels at 48 h. However, the CP and RdRp levels in cellular RNA displayed only a modest increase between 2 and 48 h, and exhibited no change (CP) or decreased (RdRp) at 72 h. These data suggest that during the first 48 h of C. parvum in vitro development, Cryspovirus is released into the media overlying cells but remains at fairly constant levels within infected cells. PMID- 25704646 TI - Dietary freshwater clam (Corbicula fluminea) extract suppresses accumulation of hepatic lipids and increases in serum cholesterol and aminotransferase activities induced by dietary chloretone in rats. AB - We investigated the ameliorative effect of freshwater clam extract (FCE) on fatty liver, hypercholesterolemia, and liver injury in rats exposed to chloretone. Furthermore, we examined the effects of major FCE components (fat and protein fractions) to determine the active components in FCE. Chloretone increased serum aminotransferase activities and led to hepatic lipid accumulation. Serum aminotransferase activities and hepatic lipid content were lower in rats fed total FCE or fat/protein fractions of FCE. Expression of fatty acid synthase and fatty acid desaturase genes was upregulated by chloretone. Total FCE and fat/protein fractions of FCE suppressed the increase in gene expression involved in fatty acid synthesis. Serum cholesterol levels increased twofold upon chloretone exposure. Total FCE or fat/protein fractions of FCE showed hypocholesterolemic effects in rats with hypercholesterolemia induced by chloretone. These suggest that FCE contains at least two active components against fatty liver, hypercholesterolemia, and liver injury in rats exposed to chloretone. PMID- 25704647 TI - The role of primary transoral laser microsurgery in laryngeal cancer: a retrospective study. AB - OBJECTIVE: To investigate the oncologic and survival outcomes of primary transoral laser microsurgery in laryngeal cancer. DESIGN: Retrospective analysis of a database of all patients undergoing primary transoral laser microsurgery with or without adjunctive therapy from June 2000 to October 2013. The median follow-up time was 33 months. SETTING: A teaching hospital. PARTICIPANTS: Two hundred and three patients underwent primary transoral laser microsurgery. Of these, 166 had glottic and 37 had supraglottic squamous cell carcinoma. MAIN OUTCOME MEASURES: Overall survival, disease-specific survival, local control and rate of salvage laryngectomy. RESULTS: Primary transoral laser microsurgery was performed exclusively in 149 (73%) patients, 16 (8%) had transoral laser microsurgery followed by postoperative (chemo)radiotherapy, 6 (3%) had transoral laser microsurgery with neck dissection, and 32 (16%) had transoral laser microsurgery in combination with neck dissection and postoperative (chemo)radiotherapy. In glottic cancer, the 5-year local control was 86%, 86% and 76% in carcinoma in situ (Tis), early-stage (T1, T2) and late-stage (T3, T4) disease, respectively. The 5-year disease-specific survival was 93% in Tis, 96% in early-stage and 65% at late-stage disease. In supraglottic cancer, the 5-year local control was 66% in early-stage and 88% in late-stage disease. The 5-year disease-specific survival was 80% and 75%, respectively. The rate of salvage laryngectomy was 9.9%. CONCLUSION: In carefully selected patients with laryngeal cancer, primary transoral laser microsurgery with or without adjunctive therapy can be organ preserving. It can provide a valid treatment option for patients. PMID- 25704648 TI - Records review of musculoskeletal injuries in aeromedical evacuation personnel. AB - BACKGROUND: Aeromedical evacuation providers care for patients during air transport. By applying standard medical practices, oftentimes developed for ground care, these practitioners perform their mission duties under additional physical stress in this unique medical environment. Awkward postures and excessive forces are common occurrences among personnel operating in this domain. Additionally, anecdotal reports highlight the risk of developing musculoskeletal injuries for these providers. Currently, there is limited research focusing on musculoskeletal injuries in aeromedical evacuation providers. PURPOSE: To determine the prevalence of musculoskeletal injuries and associated symptoms in aeromedical evacuation providers to understand the risk and burden of these injuries to military personnel. METHODS: This study utilized a retrospective review of military medical records containing ICD-9 codes to investigate the incidence of musculoskeletal injuries within flight nurses and medical technicians compared to their non-flying counterparts from 2006 through 2011. Data were analyzed from 2013 through 2014. RESULTS: Although musculoskeletal injuries were identified within the test populations, results showed fewer injuries for aeromedical evacuation populations compared to non-aeromedical evacuation counterparts. CONCLUSIONS: One contributing factor may be a potential under-reporting of musculoskeletal injuries resulting from the fear of being placed on limited flying status. As flyers, aeromedical evacuation personnel must undergo yearly medical examinations and complete training courses that emphasize proper lifting techniques and physical requirements necessary for the safe and efficient transport of patients on various platforms. These additional requirements may create a healthy worker effect, likely contributing to lower musculoskeletal injuries. PMID- 25704649 TI - Hemispheric lateralization in top-down attention during spatial relation processing: a Granger causal model approach. AB - Magnetoencephalography was recorded during a matching-to-sample plus cueing paradigm, in which participants judged the occurrence of changes in either categorical (CAT) or coordinate (COO) spatial relations. Previously, parietal and frontal lobes were identified as key areas in processing spatial relations and it was shown that each hemisphere was differently involved and modulated by the scope of the attention window (e.g. a large and small cue). In this study, Granger analysis highlighted the patterns of causality among involved brain areas -the direction of information transfer ran from the frontal to the visual cortex in the right hemisphere, whereas it ran in the opposite direction in the left side. Thus, the right frontal area seems to exert top-down influence, supporting the idea that, in this task, top-down signals are selectively related to the right side. Additionally, for CAT change preceded by a small cue, the right frontal gyrus was not involved in the information transfer, indicating a selective specialization of the left hemisphere for this condition. The present findings strengthen the conclusion of the presence of a remarkable hemispheric specialization for spatial relation processing and illustrate the complex interactions between the lateralized parts of the neural network. Moreover, they illustrate how focusing attention over large or small regions of the visual field engages these lateralized networks differently, particularly in the frontal regions of each hemisphere, consistent with the theory that spatial relation judgements require a fronto-parietal network in the left hemisphere for categorical relations and on the right hemisphere for coordinate spatial processing. PMID- 25704650 TI - Scrub typhus in rural Rajasthan and a review of other Indian studies. AB - BACKGROUND: Scrub typhus is an acute febrile illness which has been reported from various parts of India with Rajasthan recently joining the list of affected states. AIM: To report a series of paediatric scrub typhus cases from rural Rajasthan. STUDY DESIGN: Retrospective review of children with scrub typhus admitted to the wards and paediatric intensive care unit (PICU) of a tertiary care hospital. METHODS: The study was undertaken over an 8-month period from May to December 2013. All patients with a clinical presentation and/or serological confirmation of scrub typhus who tested negative for malaria, enteric fever, dengue, leptospirosis and urinary tract infection (UTI) were included. A range of investigations were undertaken including IgM-ELISA for scrub typhus, followed by appropriate medical management. RESULTS: Thirty patients satisfied the inclusion criteria. The mean (SD, range) age of the patients was 8.56 (3.43, 3-16) years. The most common clinical features were fever (n = 30, 100%), headache (n = 20, 66%), myalgia (n = 15, 50%), hepatosplenomegaly (n = 18, 60%) and pallor (n = 5, 16%). Typical features such as eschar and rash were observed in only one (3.3%) and three (10%) patients, respectively; none had generalised lymphadenopathy or conjunctival congestion. IgM-ELISA for scrub typhus was positive in 28 patients (93.3%) and 27 responded to doxycycline within 24-72 hours. One of the three patients who required PICU support responded to intravenous chloramphenicol and, of the other two (6.6%), one died of acute respiratory distress syndrome and the other owing to acute renal failure. CONCLUSION: A high index of suspicion is essential for early diagnosis and prevention of complications in scrub typhus together with prompt referral from rural areas to a higher centre. Awareness of the disease manifestations may further help to prevent excessive investigations in patients presenting with non-specific febrile illness and reduce the economic burden to the family and society in resource-constrained settings. PMID- 25704651 TI - Comparison of stigmatizing experiences between Canadian and Korean patients with depression and bipolar disorders. AB - INTRODUCTION: Stigma is one of the key barriers to mental health services, and there have been growing efforts to develop antistigma programs. However, little research has been done on quantifying experiences of stigma and their psychosocial impacts in the perspectives of those who suffer from mental illnesses. It is essential to develop an instrument that quantifies the extent and impact of stigma. Therefore, we conducted a study to conduct a field test on The Inventory of Stigmatizing Experiences and measure the difference in perceived stigma and its psychosocial impacts on Korean and Canadian patients with depression and bipolar disorders. METHODS: A cross-sectional comparison study was conducted. Data collection took place at a tertiary care hospital located in Seoul, South Korea. Data for the Canadian patient group were retrieved from a previous study conducted by Lazowski et al. RESULTS: In total, 214 Canadian and 51 Korean individuals with depression and bipolar disorder participated. Canadian participants reported significantly higher experience with stigma (P<0.05) and its impact (P<0.05) compared with Korean participants. Both subscales of the inventory (the Stigma Experiences Scale and the Stigma Impact Scale) were highly reliable, with reliability coefficients of 0.81 and 0.93, respectively. DISCUSSION: In conclusion, there seems to be higher level of stigma and impact in the Canadian population compared with the Korean population. These differences in stigma experience and their impact in different populations suggest the need to develop more tailored antistigma programs. The Inventory of Stigmatizing Experiences is a highly reliable instrument. PMID- 25704652 TI - Effect of ketotifen in obese patients with type 2 diabetes mellitus. AB - AIM: Mast cells are found to be an important contributor in obesity induced insulin resistance. We evaluate the effect of ketotifen in obese patient with type 2 diabetes (T2DM) treated with glimepiride. METHOD: In a randomized controlled study we recruited forty-eight obese patients with T2DM from Internal Medicine Department at Tanta University Hospital, Egypt. They were classified into three groups: group 1, those who received glimepiride (GL) 3mg/d alone; group 2, those who received GL 3mg/d+ketotifen 1mg once daily; and group 3, those who received GL 3mg/d+ketotifen 1mg twice daily. Fasting blood samples were obtained before and 12weeks after treatment for biochemical analysis of glycemic and inflammatory biomarkers. Data were statistically analyzed by paired Student's t-test and one way analysis of variance; p<0.05 was considered statistically significant. RESULTS: The obtained data suggested that the addition of ketotifen in twice daily dose has a beneficial effect on all measured parameters except adiponectin. However, glimepiride plus ketotifen once daily only affected the level of inflammatory biomarkers without any significant effect on other parameters. CONCLUSIONS: The co-administration of ketotifen twice daily plus glimepiride improves glycemic and inflammatory process in obese patients with T2DM. PMID- 25704653 TI - High-level expression of Hsp90beta is associated with poor survival in resectable non-small-cell lung cancer patients. AB - AIMS: The aim of this study was to investigate the expression of Hsp90beta and GRP94, and elucidate the clinical significance of their expression, in patients with resectable non-small-cell lung cancer (NSCLC). METHODS AND RESULTS: Surgical tissue specimens were obtained from 208 patients with NSCLC who underwent surgical resection. The expression levels of Hsp90beta and GRP94 were assessed with tissue microarrays and immunohistochemistry. No correlations were observed between Hsp90beta or GRP94 expression and several clinicopathological factors. The high-Hsp90beta group [median overall survival (OS) 20.4 months; 95% confidence interval (CI) 0.000-40.864] showed a significant decrease in OS as compared with the low-Hsp90beta group (median OS not reached; P = 0.003). In contrast to the Hsp90beta analysis, the GRP94 analysis did not show a difference in OS. Moreover, in subgroup analyses of patients with squamous cell carcinoma histology, OS (P = 0.012) and relapse-free survival (P = 0.044) were significantly worse in the high-Hsp90beta group than in the low-Hsp90beta group. Multivariate analysis suggested that old age [hazard ratio (HR) 1.568; 95% CI 1.019-2.412; P = 0.041], advanced disease (HR 2.066; 95% CI 1.218-3.502; P = 0.007) and high Hsp90beta expression (HR 1.802; 95% CI 1.061-3.060; P = 0.029) were independent poor prognostic factors for OS. CONCLUSIONS: Hsp90beta expression might be a useful marker of poor OS, although further large prospective studies are warranted to validate our findings. PMID- 25704654 TI - An efficient machine learning approach for diagnosis of paraquat-poisoned patients. AB - Numerous people die of paraquat (PQ) poisoning because they were not diagnosed and treated promptly at an early stage. Till now, determination of PQ levels in blood or urine is still the only way to confirm the PQ poisoning. In order to develop a new diagnostic method, the potential of machine learning technique was explored in this study. A newly developed classification technique, extreme learning machine (ELM), was taken to discriminate the PQ-poisoned patients from the healthy controls. 15 PQ-poisoned patients recruited from The First Affiliated Hospital of Wenzhou Medical University who had a history of direct contact with PQ and 16 healthy volunteers were involved in the study. The ELM method is examined based on the metabolites of blood samples determined by gas chromatography coupled with mass spectrometry in terms of classification accuracy, sensitivity, specificity and AUC (area under the receiver operating characteristic (ROC) curve) criterion, respectively. Additionally, the feature selection was also investigated to further boost the performance of ELM and the most influential feature was detected. The experimental results demonstrate that the proposed approach can be regarded as a success with the excellent classification accuracy, AUC, sensitivity and specificity of 91.64%, 0.9156%, 91.33% and 91.78%, respectively. Promisingly, the proposed method might serve as a new candidate of powerful tools for diagnosis of PQ-poisoned patients with excellent performance. PMID- 25704655 TI - Multilocus genotyping of potentially zoonotic Giardia duodenalis in pet chinchillas (Chinchilla lanigera) in China. AB - Giardia duodenalis is a common protozoan that colonizes and reproduces in the small intestine, causing giardiasis. This parasite infects a wide range of vertebrate hosts, including humans, domestic animals and wildlife. It has been suggested that chinchillas (Chinchilla lanigera) kept as domestic pets are potential reservoirs for the zoonotic transmission of G. duodenalis. In this study, 140 chinchilla samples from four cities in China were examined to determine the prevalence of G. duodenalis. Thirty-eight (27.1%) chinchillas were found to be positive for G. duodenalis. The prevalence of infection was analyzed in relation to collection site, age and sex. Molecular characterization was also carried out on the 38 chinchilla samples to determine common genotypes. G. duodenalis assemblages A and B were identified in the chinchilla samples by analysis of the small subunit ribosomal RNA (ssur RNA) gene. Genotyping at the subtype level using multiple genes (glutamate dehydrogenase (gdh), triose phosphate isomerase (tpi) and beta-giardin (bg) genes) determined that the majority of assemblage A isolate sequences were identical to subtype AI. Assemblage B isolates showed variability among the nucleotide sequences belonging to subtype BIV. This is the first report of G. duodenalis in chinchillas from China. As subtype AI and BIV are associated with human infection, G. duodenalis in chinchillas should be regarded as zoonotic. PMID- 25704656 TI - Impact of freezing on the emergence of Culicoides chiopterus and Culicoides dewulfi from bovine dung. AB - The emergence of Culicoides chiopterus (Meigen), 1830 and C. dewulfi Goetghebuer, 1936 (Diptera: Ceratopogonidae) from cowpats in northwestern Germany was investigated. In order to investigate the survival of both species at low temperatures, cowpat subsamples were frozen for 48h at -18 and -21 degrees C. Emergence from frozen and non-frozen samples was compared. The number of emerging adults of C. chiopterus from samples frozen at -18 degrees C was greatly reduced and no emergence was observed from samples frozen at -21 degrees C. No adult C. dewulfi emerged from frozen samples, suggesting this species is less resistant to these temperatures, compared to C. chiopterus. PMID- 25704658 TI - Nanoparticle-based autoimmune disease therapy. AB - The goal of immunotherapy against autoimmunity is to block pathogenic inflammation without impairing immunity against infections and tumours. Regulatory T-cells (Tregs) play a central role in maintaining immune homeostasis, and autoimmune inflammation is frequently associated with decreased numbers and/or function of these T-cells. Therapies harnessing Tregs to treat autoimmune inflammation remain under-developed with caveats ranging from the lack of antigenic and disease specificity to the potential phenotypic and functional instability of in vitro-expanded Treg cells in vivo. Here, we review nanotechnology-based approaches designed to promote immune tolerance through various mechanisms, ranging from systemic or local suppression of antigen presenting cells and deletion of antigen-specific T-cells, to the systemic expansion of antigen- and disease-specific Treg cells in vivo. PMID- 25704659 TI - Contributions of the specialised DNA polymerases to replication of structured DNA. AB - It is becoming increasingly clear that processive DNA replication is threatened not only by DNA damage but also by secondary structures that can form in the DNA template. Failure to resolve these structures promptly leads to both genetic instability, for instance DNA breaks and rearrangements, and to epigenetic instability, in which inaccurate propagation of the parental chromatin state leads to unscheduled changes in gene expression. Multiple overlapping mechanisms are needed to deal with the wide range of potential DNA structural challenges to replication. This review focuses on the emerging mechanisms by which specialised DNA polymerases, best known for their role in the replication of damaged DNA, contribute to the replication of undamaged but structured DNA, particularly G quadruplexes. PMID- 25704661 TI - A rational computational study of surface defect-mediated stabilization of low dimensional Pt nanostructures on TiN(100). AB - Platinum is known as a catalyst with exceptional reactivity for many important reactions, e.g. the oxygen reduction reaction. To reduce the high cost of pure platinum catalysts, platinum on a carbon support is widely used in industrial fuel cell applications. However, these Pt/C systems suffer from poor stability. As a cost-efficient and more durable alternative, Pt single-atom catalysts on a TiN support have recently been suggested, and it has been shown that the single atom catalysts are stable when anchored at a nitrogen vacancy site on the TiN surface in a nitrogen-lean environment. To further explore the perspective of Pt/TiN catalytic systems, we provide insights into the stability and morphology of Pt nanostructures at the TiN(100) surface, using a density-functional theory approach in combination with ab initio atomistic thermodynamics. Our results show that the formation of two-dimensional Pt nano-layers is preferred over the formation of three-dimensional Pt nano-clusters on the TiN substrate. Similar to the single-atom catalysts, nano-layers of Pt can be stabilized on the TiN(100) surface by surface nitrogen vacancies under nitrogen-lean conditions. By analyzing the electronic metal-support interaction (EMSI) between the Pt nano layer and the TiN surface with surface defects, we demonstrate that a strong EMSI between the surrounding Ti and Pt atoms is important for stabilizing the catalyst nano-layer at the TiN surface, and that N vacancies lead to stronger Pt-Ti interaction. This work provides a rational computational platform for the design of new generation high-performance Pt-based fuel cells. PMID- 25704660 TI - A proposal: Evolution of PCNA's role as a marker of newly replicated DNA. AB - Processivity clamps that hold DNA polymerases to DNA for processivity were the first proteins known to encircle the DNA duplex. At the time, polymerase processivity was thought to be the only function of ring shaped processivity clamps. But studies from many laboratories have identified numerous proteins that bind and function with sliding clamps. Among these processes are mismatch repair and nucleosome assembly. Interestingly, there exist polymerases that are highly processive and do not require clamps. Hence, DNA polymerase processivity does not intrinsically require that sliding clamps evolved for this purpose. We propose that polymerases evolved to require clamps as a way of ensuring that clamps are deposited on newly replicated DNA. These clamps are then used on the newly replicated daughter strands, for processes important to genomic integrity, such as mismatch repair and the assembly of nucleosomes to maintain epigenetic states of replicating cells during development. PMID- 25704662 TI - Comparison of adenoma detection and miss rates between a novel balloon colonoscope and standard colonoscopy: a randomized tandem study. AB - BACKGROUND AND STUDY AIMS: Although colonoscopy is the "gold standard" for colorectal cancer screening, a significant number of adenomas are still missed during standard colonoscopy, often because they are hidden behind colonic folds and flexures. The aim of this study was to assess the ability of a novel balloon colonoscope (G-EYE endoscope; Smart Medical Systems, Ra'anana, Israel) to increase adenoma detection and reduce the miss rate compared with standard colonoscopy. PATIENTS AND METHODS: This was a multicenter, randomized, prospective, controlled study in patients (age >= 40 years) undergoing colonoscopy for screening or diagnostic work-up (including surveillance). Patients underwent same-day, back-to-back tandem colonoscopy. Patients in Group A underwent standard colonoscopy followed by balloon colonoscopy, and patients in Group B underwent balloon colonoscopy followed by the standard technique. The adenoma detection and miss rates were compared between the two colonoscopy procedures. RESULTS: A total of 126 patients were enrolled and randomized into Group A (n = 60) or Group B (n = 66). The adenoma miss rate of balloon colonoscopy was significantly lower than that of standard colonoscopy (7.5 % vs. 44.7 %; P = 0.0002). The detection of additional adenomas by balloon colonoscopy was significant (81.0 %; P = 0.0002), in particular, the relative amount of adenomas detected in the ascending colon by balloon colonoscopy was 41 % versus 14 % for standard colonoscopy. CONCLUSIONS: A novel balloon colonoscopy technique detected significantly more adenomas than standard colonoscopy, and missed fewer adenomas. Balloon colonoscopy has the potential to increase the effectiveness of colorectal cancer screening and surveillance colonoscopy. PMID- 25704663 TI - The effect of long term under- and over-feeding on the expression of genes related to glucose metabolism in mammary tissue of sheep. AB - Glucose utilisation for lactose synthesis in the mammary gland involves expression of a large number of genes whose nutritional regulation remains poorly defined. In this study, the effect of long term under- and over-feeding on the expression of genes [glucose transporter 1: GLUT1, glucose transporter 3: GLUT3, Sodium glucose contransporter 1: SGLT1, two isoforms of beta- (1,4) galactosyltransferase: beta- (1,4) GAT1, beta- (1,4) GAT3 and alpha-lactalbumin: LALBA] related to glucose metabolism in sheep mammary tissue (MT) was examined. Twenty-four lactating dairy sheep were divided into three homogenous sub-groups and fed the same ration in quantities which met 70% (underfeeding), 100% (control) and 130% (overfeeding) of their energy and crude protein requirements. The results showed a significant reduction on mRNA of GLUT1 and LALBA gene in the MT of underfed sheep, compared with the respective controls and overfed and a significant reduction on mRNA level of SGLT1 and beta- (1,4) GAT1 in the MT of underfed sheep, compared with the overfed ones. A significant increase in the GLUT3 mRNA accumulation in the MT of both under- and over- fed sheep was found. Additionally, a trend of reduction on beta- (1,4) GAT3 mRNA level in the MT of the underfed sheep, compared with the overfed, was observed. A close positive relationship was obtained between the mRNA transcripts accumulation of GLUT1, SGLT1, beta- (1,4) GAT1 and LALBA gene with the milk lactose content and milk lactose yield respectively. In conclusion, feeding level and consequently nutrient availability, may affect glucose uptake and utilisation in sheep MT by altering the GLUT1, GLUT3, SGLT1, beta- (1,4) GAT1 and LALBA gene expression involved in their metabolic pathways. PMID- 25704664 TI - ER Stress During the Pubertal Growth Spurt Results in Impaired Long-Bone Growth in Chondrocyte-Specific ERp57 Knockout Mice. AB - Long-bone growth by endochondral ossification is cooperatively accomplished by chondrocyte proliferation, hypertrophic differentiation, and appropriate secretion of collagens, glycoproteins, and proteoglycans into the extracellular matrix (ECM). Before folding and entering the secretory pathway, ECM macromolecules in general are subject to extensive posttranslational modification, orchestrated by chaperone complexes in the endoplasmic reticulum (ER). ERp57 is a member of the protein disulfide isomerase (PDI) family and facilitates correct folding of newly synthesized glycoproteins by rearrangement of native disulfide bonds. Here, we show that ERp57-dependent PDI activity is essential for postnatal skeletal growth, especially during the pubertal growth spurt characterized by intensive matrix deposition. Loss of ERp57 in growth plates of cartilage-specific ERp57 knockout mice (ERp57 KO) results in ER stress, unfolded protein response (UPR), reduced proliferation, and accelerated apoptotic cell death of chondrocytes. Together this results in a delay of long-bone growth with the following characteristics: (1) enlarged growth plates; (2) expanded hypertrophic zones; (3) retarded osteoclast recruitment; (4) delayed remodeling of the proteoglycan-rich matrix; and (5) reduced numbers of bone trabeculae. All the growth plate and bone abnormalities, however, become attenuated after the pubertal growth spurt, when protein synthesis is decelerated and, hence, ERp57 function is less essential. PMID- 25704665 TI - Molecular techniques to interrogate and edit the Chlamydomonas nuclear genome. AB - The success of the green alga Chlamydomonas reinhardtii as a model organism is to a large extent due to the wide range of molecular techniques that are available for its characterization. Here, we review some of the techniques currently used to modify and interrogate the C. reinhardtii nuclear genome and explore several technologies under development. Nuclear mutants can be generated with ultraviolet (UV) light and chemical mutagens, or by insertional mutagenesis. Nuclear transformation methods include biolistic delivery, agitation with glass beads, and electroporation. Transforming DNA integrates into the genome at random sites, and multiple strategies exist for mapping insertion sites. A limited number of studies have demonstrated targeted modification of the nuclear genome by approaches such as zinc-finger nucleases and homologous recombination. RNA interference is widely used to knock down expression levels of nuclear genes. A wide assortment of transgenes has been successfully expressed in the Chlamydomonas nuclear genome, including transformation markers, fluorescent proteins, reporter genes, epitope tagged proteins, and even therapeutic proteins. Optimized expression constructs and strains help transgene expression. Emerging technologies such as the CRISPR/Cas9 system, high-throughput mutant identification, and a whole-genome knockout library are being developed for this organism. We discuss how these advances will propel future investigations. PMID- 25704666 TI - Interaction between anthelmintic treatment and vaccine responses in ponies naturally infected with cyathostomins. AB - Anthelmintics and vaccines are commonly given concurrently in routine equine management, but it is unknown to what extent an interaction between the two exists. Cyathostomins can modulate the local immune response by stimulating a type 2 helper T cell (Th2) response. In addition, anti-inflammatory effects of ivermectin have been found in rodent models. It is unknown whether these anti inflammatory effects affect the acute phase response elicited by commonly used vaccines. This study evaluated how the acute phase inflammatory response, leukocyte expression of pro-inflammatory cytokines, and vaccine-specific titers induced by simultaneous injection of three vaccines (West Nile Virus, Equine Herpes Rhinopneumonitis, and Keyhole Limpet Hemocyanin) were modulated by concurrent administration of ivermectin or pyrantel pamoate in ponies naturally infected with cyathostomins. Mixed-breed yearling ponies were blocked by gender and fecal strongyle egg count, then randomly assigned to three treatment groups: ivermectin (n=8), pyrantel pamoate (n=8), and control (n=7). All ponies received vaccinations intramuscularly on days 0 and 29, and anthelmintics were administered on the same days. Whole blood, serum and plasma samples were collected one, three and 14 days after each vaccination. Samples were analyzed for concentrations of acute phase reactants (haptoglobin, serum amyloid A, fibrinogen and iron), mRNA expression levels of cytokines (interleukin (IL) 1beta, IL-4, IL-10, tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma) in leukocytes, and vaccine-specific antibody titers. A marked acute-phase response was noted following both vaccinations. In contrast, the pattern of change in cytokine expression was less pronounced and more variable. Statistical differences were observed between groups for haptoglobin, fibrinogen, IL-1beta, IL-4, and IL-10, but differences were generally small and none of the vaccine titers were different between the groups. Taken together, the study found some signs of modulation of immunologic or inflammatory responses to the administered vaccines, when anthelmintics were administered concurrently, but these are unlikely to have practical implications for vaccination routines. PMID- 25704667 TI - High pressure Raman spectroscopy of H2O-CH3OH mixtures. AB - Complex intra-molecular interactions and the hydrogen-bonding network in H2O volatile mixtures play critical roles in many dynamics processes in physical chemistry, biology, and Earth and planetary sciences. We used high pressure Raman spectroscopy to study the pressure evolution of vibrational frequencies and bonding behavior in H2O-CH3OH mixtures. We found that the presence of low CH3OH content in H2O increases the transition pressure where water crystallizes to ice VI, but does not significantly change the pressure where ice VI transforms to ice VII. Furthermore, the stiffening rates of C-H stretching frequencies domega/dP in CH3OH significantly decrease upon the crystallization of water, and the softening rates of the O-H stretching frequencies of ice VII are suppressed over a narrow pressure range, after which the frequencies of these modes shift with pressure in ways similar to pure CH3OH and ice VII, respectively. Such complex pressure evolution of Raman frequencies along with pronounced variations in Raman intensities of CH3OH within the sample, and the hysteresis of the water-ice VI phase transition suggest pressure-induced segregation of low content CH3OH from ice VII. These findings indicate the significant influence of volatiles on the crystallization of sub-surface ocean and thermal evolution within large icy planets and satellites. PMID- 25704668 TI - Cycloelimination of imidazolidin-2-ylidene N-heterocyclic carbenes: mechanism and insights into the synthesis of stable "NHC-CDI" amidinates. AB - We report the discovery that 1,3-bis(aryl)imidazolidin-2-ylidenes, one of the most widely studied classes of N-heterocyclic carbenes (NHCs), undergo quantitative conversion to zwitterionic "NHC-CDI" amidinates upon heating to ~100 degrees C in solution. The mechanism of this novel NHC decomposition process is studied in detail. These studies enabled the rational synthesis of a new class of bench stable amidinates from a panel of NHCs and carbodiimides. We expect these constructs to find utility in a variety of applications. PMID- 25704669 TI - bZIP17 and bZIP60 Regulate the Expression of BiP3 and Other Salt Stress Responsive Genes in an UPR-Independent Manner in Arabidopsis thaliana. AB - Plants can be severely affected by salt stress. Since these are sessile organisms, they have developed different cellular responses to cope with this problem. Recently, it has been described that bZIP17 and bZIP60, two ER-located transcription factors, are involved in the cellular response to salt stress. On the other hand, bZIP60 is also involved in the unfolded protein response (UPR), a signaling pathway that up-regulates the expression of ER-chaperones. Coincidentally, salt stress produces the up-regulation of BiP, one of the main chaperones located in this organelle. Then, it has been proposed that UPR is associated to salt stress. Here, by using insertional mutant plants on bZIP17 and bZIP60, we show that bZIP17 regulate the accumulation of the transcript for the chaperone BiP3 under salt stress conditions, but does not lead to the accumulation of UPR-responding genes such as the chaperones Calnexin, Calreticulin, and PDIL under salt treatments. In contrast, DTT, a known inducer of UPR, leads to the up-regulation of all these chaperones. On the other hand, we found that bZIP60 regulates the expression of some bZIP17 target genes under conditions were splicing of bZIP60 does not occur, suggesting that the spliced and unspliced forms of bZIP60 play different roles in the physiological response of the plant. Our results indicate that the ER-located transcription factors bZIP17 and bZIP60 play a role in salt stress but this response goes through a signaling pathway that is different to that triggered by the unfolded protein response. PMID- 25704670 TI - What is the true nitrogenase reaction? A guided approach. AB - Only diazotrophic bacteria, called Rizhobia, living as symbionts in the root nodules of leguminous plants and certain free-living prokaryotic cells can fix atmospheric N2 . In these microorganisms, nitrogen fixation is carried out by the nitrogenase protein complex. However, the reduction of nitrogen to ammonia has an extremely high activation energy due to the stable (unreactive) N=N triple bond. The structural and functional features of the nitrogenase protein complex, based on the stepwise transfer of eight electrons from reduced ferredoxin to the nitrogenase, coupled to the hydrolysis of 16 ATP molecules, to fix one N2 molecule into two NH3 molecules, is well understood. Yet, a number of different nitrogenase-catalyzed reactions are present in biochemistry textbooks, which might cause misinterpretation. In this article, we show that when trying to balance the reaction catalyzed by the nitrogenase protein complex, it is important to show explicitly the 16 H(+) released by the hydrolysis of the 16 ATP molecules needed to fix the atmospheric N2. PMID- 25704671 TI - Sulindac has strong antifibrotic effects by suppressing STAT3-related miR-21. AB - Pulmonary fibrosis (PF) is a disease with an unknown cause and a poor prognosis. In this study, we aimed to explore the pathogenesis of PF and the mechanism of sulindac in attenuating bleomycin (BLM)-induced PF. The rat PF model was induced by BLM and verified through histological studies and hydroxyproline assay. The severity of BLM-induced PF in rats and other effects, such as the extent of the wet lung to bw ratios, thickening of alveolar interval or collagen deposition, was obviously ameliorated in sulindac-treated rat lungs compared with BLM-induced lungs. Sulindac also reversed the epithelial mesenchymal transition (EMT) and inhibited the PF process by restoring the levels of E-cadherin and alpha-smooth muscle actin (SMA) in A549 cells. Our results further demonstrated that the above effects of sulindac might be related to regulating of interferon gamma (IFN gamma) expression, which further affects signal transducers and activators of transcription 3 (STAT3) and phosphorylated STAT3 (p-STAT3) levels. Moreover, higher miR-21 levels with the decreased E-cadherin and increased alpha-SMA expressions were found in transforming growth factor-beta1-treated A549 cells, which can be reversed by sulindac. Collectively, our results demonstrate that by decreasing IFN-gamma-induced STAT3/p-STAT3 expression to down-regulate miR-21, sulindac could significantly reverse EMT in A549 cells and prevent BLM-induced PF. PMID- 25704672 TI - Mapping the development of facial expression recognition. AB - Reading the non-verbal cues from faces to infer the emotional states of others is central to our daily social interactions from very early in life. Despite the relatively well-documented ontogeny of facial expression recognition in infancy, our understanding of the development of this critical social skill throughout childhood into adulthood remains limited. To this end, using a psychophysical approach we implemented the QUEST threshold-seeking algorithm to parametrically manipulate the quantity of signals available in faces normalized for contrast and luminance displaying the six emotional expressions, plus neutral. We thus determined observers' perceptual thresholds for effective discrimination of each emotional expression from 5 years of age up to adulthood. Consistent with previous studies, happiness was most easily recognized with minimum signals (35% on average), whereas fear required the maximum signals (97% on average) across groups. Overall, recognition improved with age for all expressions except happiness and fear, for which all age groups including the youngest remained within the adult range. Uniquely, our findings characterize the recognition trajectories of the six basic emotions into three distinct groupings: expressions that show a steep improvement with age - disgust, neutral, and anger; expressions that show a more gradual improvement with age - sadness, surprise; and those that remain stable from early childhood - happiness and fear, indicating that the coding for these expressions is already mature by 5 years of age. Altogether, our data provide for the first time a fine-grained mapping of the development of facial expression recognition. This approach significantly increases our understanding of the decoding of emotions across development and offers a novel tool to measure impairments for specific facial expressions in developmental clinical populations. PMID- 25704673 TI - The perioperative surgical home: an innovative clinical care delivery model. PMID- 25704674 TI - Assessing the quality of ophthalmic anesthesia. AB - STUDY OBJECTIVE: The study objective is to evaluate a scoring system to assess the quality of anesthesia used in ophthalmic surgery. DESIGN: This is an observational prospective study. SETTING: The setting is at an operating theater. PATIENTS: Patients are all patients undergoing ophthalmic surgery, October 2012. INTERVENTIONS: Quality of ophthalmic anesthesia was measured using an interval scale by the operating surgeon. Parameters were graded depending on the type and route of anesthetic: central eye position, anesthesia, akinesia of the eye and or body, soft tissue or orbital hemorrhage, and absence of vitreous bulge. MEASUREMENTS: The measurements are quality score and proportion of optimal and suboptimal cases of anesthesia and number of surgical complications. MAIN RESULTS: Data were collected on 349 consecutive cases including cataract (55%), retinal (14%), corneal transplant (6%), and strabismus surgery (6%). Sub-Tenon was the most commonly performed (31%) followed by peribulbar (PB) (26%), general anesthesia (GA) (20%), topical (17%), and retrobulbar (RB) (6%) anesthesia. There were 11 surgical complications: posterior capsule rupture (7), dislocated lens (2), and orbital hemorrhage (2). Sub-Tenon had lower quality scores than PB (P = .006), RB (P = .028), and GA (P <.001); and PB and RB had lower scores than GA (P < .01). There was a significant association between suboptimal anesthesia and surgical complications (P < .001), odds ratio = 3.94 (95% confidence interval, 1.03-15.12; P = .046). CONCLUSIONS: The quality of ophthalmic anesthesia is an important component of the surgical procedure and should be considered in any risk stratification. Suboptimal anesthesia is associated with an increased rate of surgical complications. PMID- 25704675 TI - Microfluidic synthesis of rigid nanovesicles for hydrophilic reagents delivery. AB - We present a hollow-structured rigid nanovesicle (RNV) fabricated by a multi stage microfluidic chip in one step, to effectively entrap various hydrophilic reagents inside, without complicated synthesis, extensive use of emulsifiers and stabilizers, and laborious purification procedures. The RNV contains a hollow water core, a rigid poly (lactic-co-glycolic acid) (PLGA) shell, and an outermost lipid layer. The formation mechanism of the RNV is investigated by dissipative particle dynamics (DPD) simulations. The entrapment efficiency of hydrophilic reagents such as calcein, rhodamine B and siRNA inside the hollow water core of RNV is ~90 %. In comparison with the combination of free Dox and siRNA, RNV that co-encapsulate siRNA and doxorubicin (Dox) reveals a significantly enhanced anti tumor effect for a multi-drug resistant tumor model. PMID- 25704676 TI - Oxidative stability of structured lipid-based infant formula emulsion: effect of antioxidants. AB - The effect of permitted antioxidants, including alpha-tocopherol, beta-carotene, ascorbyl palmitate, ascorbic acid, citric acid, and their combinations, on the lipid oxidation of structured lipid (SL)-based infant formula (IF) was evaluated. The 3.5% oil-in-water IF emulsion was formulated with a human milk fat analogue enriched with docosahexaenoic acid and stearidonic acid, and the antioxidants were added at 0.005% and 0.02% of the oil. The peroxide value, anisidine value, and hexanal concentration of emulsion samples were measured over a 28-day period. The results showed that whether a compound exhibited antioxidant behavior depended on its mechanism of action, polarity, concentration, and environmental conditions. The most effective antioxidant was ascorbyl palmitate at 0.005%, and a synergistic antioxidant effect was found between alpha-tocopherol and beta carotene. A high correlation was observed between anisidine value and hexanal content. Our findings have important implications for the successful incorporation of SL into IF products for infant nutrition and health. PMID- 25704677 TI - Optimization of a Solid-Phase Microextraction method for the Gas Chromatography Mass Spectrometry analysis of blackberry (Rubus ulmifolius Schott) fruit volatiles. AB - A Solid-Phase Microextraction method for the Gas Chromatography-Mass Spectrometry analysis of blackberry (Rubus sp.) volatiles has been fully optimized by means of a Box-Behnken experimental design. The optimized operating conditions (Carboxen/Polydimethylsiloxane fiber coating, 66 degrees C, 20 min equilibrium time and 16 min extraction time) have been applied to the characterization for the first time of the volatile composition of Rubus ulmifolius Schott blackberries collected in Italy and Spain. A total of 74 volatiles of different functionality were identified; esters and aliphatic alcohols were the predominant classes in both sample types. Methylbutanal (2.02-25.70%), ethanol (9.84-68.21%), 2,3-butanedione (2.31-14.71%), trans-2-hexenal (0.49-17.49%), 3-hydroxy-2 butanone (0.08-7.39%), 1-hexanol (0.56-16.39%), 1-octanol (0.49-10.86%) and methylbutanoic acid (0.53-21.48%) were the major compounds in most blackberries analyzed. Stepwise multiple regression analysis of semiquantitative data showed that only two variables (ethyl decanoate and ethyl acetate) were necessary for a successful differentiation of blackberries according to their harvest location. PMID- 25704678 TI - Novel molecular imprinted polymers over magnetic mesoporous silica microspheres for selective and efficient determination of protocatechuic acid in Syzygium aromaticum. AB - Improving sites accessibility can increase the binding efficiency of molecular imprinted polymers (MIPs). In this work, we firstly synthesized MIPs over magnetic mesoporous silica microspheres (Fe3O4@mSiO2@MIPs) for the selective recognition of protocatechuic acid (PCA). The resulting Fe3O4@mSiO2@MIPs were characterized by transmission electron microscopy (TEM), Fourier transform infrared spectrometer (FT-IR), thermo-gravimetric analysis (TGA), Brunauer-Emmett Teller (BET), and vibration sample magnetometer (VSM), and evaluated by adsorption isotherms/kinetics and competitive adsorption. The maximum adsorption capacity of PCA on Fe3O4@mSiO2@MIPs was 17.2mg/g (2.3 times that on Fe3O4@SiO2@MIPs). In addition, Fe3O4@mSiO2@MIPs showed a short equilibrium time (140min), rapid magnetic separation (5s) and high stability (retained 94.4% after six cycles). Subsequently, Fe3O4@mSiO2@MIPs were successfully applied for the selective and efficient determination of PCA (29.3MUg/g) from Syzygium aromaticum. Conclusively, we combined three advantages into Fe3O4@mSiO2@MIPs, namely, Fe3O4 core for quick separation, mSiO2 layer for enough accessible sites, and surface imprinting MIPs for fast binding and excellent selectivity, to extract PCA from complex systems. PMID- 25704679 TI - Differentiation of geographical origin of cream products in Poland according to their fatty acid profile. AB - Fatty acid (FA) composition of bovine milk fat from cream samples, originating from three regions of Poland (one mountainous and two lowland ones) and collected within 2 years, was analysed aiming at identifying the region of production by applying principal component analysis (PCA). From the 44 FAs identified by gas chromatography, two groups were discerned: seasonally variable (n=17) and non seasonal (n=7). The biplots showed that different FAs could serve as markers of geographical origin of cream samples. The CLA, vaccenic acid, C18:39c12c15c, total C18:1 trans and C18:39c12c15c n-6 (GLA) were found indicative of mountainous regions, and the short-chain saturated FAs (SCFA; C4:0-C11:0) - of the lowland ones. The Opole province was characterised by a high content of linoleic acid. It was concluded that the origin of a cream sample could be fairly well identified by gas chromatography combined with chemometric analysis of milk fat FAs. PMID- 25704680 TI - Distribution of sulfamonomethoxine and trimethoprim in egg yolk and white. AB - The distribution of sulfamonomethoxine (SMM) and trimethoprim (TMP) in egg yolk and white was measured during and after administration of a SMM/TMP combination in laying hens in doses of 8 g l(-)(1) and 12 g l(-)(1) in drinking water for 7 days. The SMM concentration reached maximal levels on day 2 of the post-treatment period for both doses (MUg kg(-)(1)): 5920 and 9453 in yolk; 4831 and 6050 in white, in doses 1 and 2, respectively. Significant differences in the SMM and TMP concentrations between yolk and white in post treatment period were found. SMM dropped below the LOD (1.9 MUg kg(-1)) in yolk after day 16 and 19 for doses 1 and 2. TMP reached maximal levels on day 3 after drug administration for doses 1 and 2 (MUg kg(-)(1)): 6521 and 7329 in yolk, 1370 and 1539 in white. TMP residues were measured above LOD (0.3 MUg kg(-)(1)) in yolk for both doses on day 37 post treatment. PMID- 25704681 TI - Grape seed and apple tannins: emulsifying and antioxidant properties. AB - Tannins are natural antioxidants found in plant-based foods and beverages, whose amphiphilic nature could be useful to both stabilize emulsions and protect unsaturated lipids from oxidation. In this paper, the use of tannins as antioxidant emulsifiers was studied. The main parameters influencing the stability of emulsions (i.e. tannins structure and concentration, aqueous phase pH, and ionic strength) were identified and optimized. Oil in water emulsions stabilized with tannins were compared with those stabilized with two commercial emulsifying agents, poly(vinyl alcohol) (PVA) and polyoxyethylene hydrogenated castor oil. In optimized conditions, the condensed tannins allowed to obtain a stability equivalent to that of PVA. Tannins presented good antioxidant activity in oil in water emulsion, as measured by the conjugated autoxidizable triene (CAT) assay. PMID- 25704682 TI - Sensory and physicochemical analyses of roasted marama beans [Tylosema esculentum (Burchell) A. Schreiber] with specific focus on compounds that may contribute to bitterness. AB - The role of phenolics and saponins in contributing to bitterness in marama beans, an underutilized legume, especially when roasted, was investigated. Marama beans were roasted at 150 degrees C for 20, 25 or 30 min, then dehulled to separate cotyledons, and pastes were prepared from these. Water extracts were prepared from full fat and defatted flours from roasted and unroasted marama cotyledons. A sensory panel evaluated the sensory attributes of marama pastes and water extracts. Marama water extracts were analysed for total phenolic content, phenolic composition and saponin content. Roasting of marama beans for more than 20 min resulted in negative properties, such as bitterness. The major extractable phenolic acids present in marama water extracts were gallic and protocatechuic acids which increased as a function of roasting time. Saponin content of the water extracts was in the range of 55-63 mg/l. The identified phenolic acids, saponins and other as yet unidentified compounds may contribute to the perceived bitterness. PMID- 25704683 TI - Preparation and characterization of clove essential oil-loaded liposomes. AB - In this study, suitable formulations of natural soybean phospholipid vesicles were developed to improve the stability of clove essential oil and its main component, eugenol. Using an ethanol injection method, saturated (Phospholipon 80H, Phospholipon 90H) and unsaturated soybean (Lipoid S100) phospholipids, in combination with cholesterol, were used to prepare liposomes at various eugenol and clove essential oil concentrations. Liposomal batches were characterized and compared for their size, polydispersity index, Zeta potential, loading rate, encapsulation efficiency and morphology. The liposomes were tested for their stability after storing them for 2 months at 4 degrees C by monitoring changes in their mean size, polydispersity index and encapsulation efficiency (EE) values. It was found that liposomes exhibited nanometric oligolamellar and spherical shaped vesicles and protected eugenol from degradation induced by UV exposure; they also maintained the DPPH-scavenging activity of free eugenol. Liposomes constitute a suitable system for encapsulation of volatile unstable essential oil constituents. PMID- 25704684 TI - Multiresidue method for the determination of pharmacologically active substances in egg and honey using a continuous solid-phase extraction system and gas chromatography-mass spectrometry. AB - A sensitive, selective, efficient gas chromatography-mass spectrometry method for the simultaneous determination of 22 pharmacologically active substances (antibacterials, nonsteroidal antiinflammatories, antiseptics, antiepileptics, lipid regulators, beta-blockers and hormones) in eggs and honey was developed. The sample pretreatment includes precipitation of proteins and lipids with acetonitrile:water (3:2, v/v), centrifugation and continuous solid-phase extraction for cleanup and preconcentration. The proposed method was validated with quite good analytical results including limits of detection of 0.4-3.3 ng/kg for 2g of sample and good linearity (r(2)>0.995) throughout the studied concentration ranges. The recoveries of analytes from real honey and egg samples spiked at concentrations of 15-2,000 ng/kg fell in the range 87-102%, with relative standard deviations from 2.6% to 7.0%. The method was successfully used to determine the target compounds in various types of eggs (hen, quail and duck) and honey samples (flower, forest, acacia, sunflower, clover and pine tree). Two samples of hen eggs bought at supermarkets and one of quail eggs were found to contain florfenicol, pyrimethamine, estrone and 17beta-estradiol at levels from 0.095 to 2.7 MUg/kg. PMID- 25704685 TI - Antioxidant capacity index based on gold nanoparticles formation. Application to extra virgin olive oil samples. AB - A simple gold nanoparticles (AuNPs) based colorimetric assay for the antioxidant activity determination has been developed. The AuNP formation is mediated by extra virgin olive oil (EVOO's) endogenous polyphenols; the reaction is described by a sigmoidal curve. The ratio KAuNPs/Xc(50) (slope of the linear part of the sigmoid/concentration at half value of the absorbance) was found to be the optimal parameter to report the antioxidant capacity with respect to the single KAuNPs or Xc(50) values. The obtained data demonstrated that the compounds with ortho-diphenols functionality are most active in reducing gold (III) to gold (0). Thus, intermediate activity was found for gallic acid, while tyrosol (mono phenols) had a significant lower activity than the others antioxidant compounds (at least one order of magnitude). In the analysis of olive oil samples, a significant correlation among classical methods used to determine antioxidant activity and the proposed parameter was found with R values in the 0.96-0.97 range. PMID- 25704686 TI - Citral exerts its antifungal activity against Penicillium digitatum by affecting the mitochondrial morphology and function. AB - This work investigated the effect of citral on the mitochondrial morphology and function of Penicillium digitatum. Citral at concentrations of 2.0 or 4.0 MUL/mL strongly damaged mitochondria of test pathogen by causing the loss of matrix and increase of irregular mitochondria. The deformation extent of the mitochondria of P. digitatum enhanced with increasing concentrations of citral, as evidenced by a decrease in intracellular ATP content and an increase in extracellular ATP content of P. digitatum cells. Oxygen consumption showed that citral resulted in an inhibition in the tricarboxylic acid cycle (TCA) pathway of P. digitatum cells, induced a decrease in activities of citrate synthetase, isocitrate dehydrogenase, alpha-ketoglutarate dehydrogenase, succinodehydrogenase and the content of citric acid, while enhancing the activity of malic dehydrogenase in P. digitatum cells. Our present results indicated that citral could damage the mitochondrial membrane permeability and disrupt the TCA pathway of P. digitatum. PMID- 25704687 TI - Mechanistic insights into solubilization of rice protein isolates by freeze milling combined with alkali pretreatment. AB - The solubilization of rice protein isolates (RPIs) has been regarded as one of the critical and challenging processes affecting commercial availability. Simultaneous treatment with freezing and milling (freeze-milling) combined with alkali pretreatment can remarkably increase the maximum achievable amounts of soluble RPIs by up to 42 times. This study investigates the mechanism of solubilization of RPIs by freeze-milling (RPI(fm)). Structural analyses reveal that milling causes proteins to unfold with ice crystals formed inside protein bodies. Fluorescent and Fourier transform infrared spectra show that RPI(fm) possesses disrupted hydrophobic surface and exposed hydrophilic inner groups. Size exclusion chromatography results reveal that RPI(fm) exhibits disaggregation and strong water-protein interactions. These results indicate that freeze-milling may be a promising manufacturing technique in food industry. PMID- 25704688 TI - Determination of arsenic species in rice samples using CPE and ETAAS. AB - A highly sensitive and selective procedure for the determination of arsenate and total arsenic in food by electrothermal atomic absorption spectrometry after cloud point extraction (ETAAS/CPE) was developed. The procedure is based on the formation of a complex of As(V) ions with molybdate in the presence of 50.0 mmol L(-1) sulfuric acid. The complex was extracted into the surfactant-rich phase of 0.06% (w/v) Triton X-114. The variables affecting the complex formation, extraction and phase separation were optimized using factorial designs. Under the optimal conditions, the calibration graph was linear in the range of 0.05-10.0 MUg L(-1). The detection and quantification limits were 10 and 33 ng L(-1), respectively and the corresponding value for the relative standard deviation for 10 replicates was below 5%. Recovery values of between 90.8% and 113.1% were obtained for spiked samples. The accuracy of the method was evaluated by comparison with the results obtained for the analysis of a rice flour sample (certified material IRMM-804) and no significant difference at the 95% confidence level was observed. The method was successfully applied to the determination of As(V) and total arsenic in rice samples. PMID- 25704689 TI - The effect of deamidation on the structural, functional, and rheological properties of glutelin prepared from Akebia trifoliata var. australis seed. AB - The characteristics of glutelin samples from Akebia trifoliata var. australis seeds (AG) that had been deamidated by malic acid (MDAG) and by citric acid (CDAG) were investigated. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis showed high-molecular-weight subunits that were degraded into smaller fragments, and FTIR indicated a decrease in the number of beta-sheet groups and an increase in the amount of beta-turns in the deamidated samples. These results could be caused by the cleaving of partial disulfide bonds to form new sulfhydryl groups during deamidation. Citric acid was found to be more effective at deamidation and hydrolysis, resulting in a higher solubility and emulsifying activity for CDAG, and MDAG also exhibited some improvement in terms of surface hydrophobicity and emulsion ability. Rheology showed that the gelation point for deamidated samples was increased, and the gel network was strengthened. The amounts of essential amino acids that were well-preserved and the improved solubility, emulsification, and rheology properties of AG after acid-heating deamidation show that this technique can be useful for treating other plant-based food ingredients in the future. PMID- 25704690 TI - Ultrasound-assisted heating extraction of pectin from grapefruit peel: optimization and comparison with the conventional method. AB - The extraction of pectin from grapefruit peel by ultrasound-assisted heating extraction (UAHE) was investigated using response surface methodology and compared with the conventional heating extraction (CHE). The optimized conditions were power intensity of 12.56 W/cm(2), extraction temperature of 66.71 degrees C, and sonication time of 27.95 min. The experimental optimized yield was 27.34%, which was well matched with the predicted value (27.46%). Compared with CHE, UAHE provided higher yield increased by 16.34% at the temperature lowered by 13.3 degrees C and the time shortened by 37.78%. Image studies showed that pectin extracted by UAHE showed better color and more loosen microstructure compared to that extracted by CHE, although Fourier Transform Infrared Analysis indicated insignificant difference in their chemical structures. Furthermore, UAHE pectin possessed lower viscosity, molecular weight and degree of esterification, but higher degree of branching and purity than CHE pectin, indicating that the former was preliminarily modified during the extraction process. PMID- 25704691 TI - Antioxidant activity and bioaccessibility of size-different nanoemulsions for lycopene-enriched tomato extract. AB - Lycopene nanoemulsions were prepared to protect the antioxidant activity and improve the bioaccessibility of lycopene-enriched tomato extract (containing 6% of lycopene) by an emulsification-evaporation method. Lycopene nanoemulsions, with droplet sizes between 100 and 200 nm, exhibited higher anti-radical efficiency and antioxidant activity, than did those smaller than 100 nm. Strong protectability of lycopene in droplets smaller than 100 nm was associated with relatively slower rates of DPPH and ABTS reactions. In vitro bioaccessibility values of lycopene-enriched tomato extract, lycopene nanoemulsions with droplets larger than 100 nm (approximately 150 nm on average), and lycopene nanoemulsions with droplets smaller than 100 nm (69 nm on average) were 0.01, 0.53, and 0.77, respectively. Interestingly, nanoemulsions with droplets smaller than 100 nm showed the highest in vitro bioaccessibility, which could be interpreted as evidence of nanoemulsification enhancing the in vitro bioaccessibility of lycopene. PMID- 25704692 TI - Judgment of pure fermented soy sauce by fluorescence resonance energy transfer of OPA-tryptophan adduct. AB - Tryptophan was detected with a flow-injection manifold after reacting with mM order of fluorogenic o-phthalaldehyde (OPA)/thiol reagent (pH 10.0) in the carrier stream (0.63 mL/min). Based on the intra-molecular fluorescence resonance energy transfer of OPA-tryptophan adduct, the difference in fluorescence intensity obtained at 280 and 300 nm excitation was used to detect tryptophan content with satisfactory precision (CV<6.5% for concentration higher than 0.5 MUM), linearity (0.1-10 MUM, R(2)=0.9893) and sensitivity (~10 nM). Since tryptophan will decompose during manufacturing non-fermented soy sauce by acid hydrolysis procedure, the method was used to discriminate pure fermented soy sauces, adulterated soy sauces and chemical soy sauces in less than 5 min. The ratio of tryptophan to total amino acid content served as the index for the judgment, and the results were validated by capillary electrophoresis. PMID- 25704693 TI - Detection of virgin coconut oil adulteration with animal fats using quantitative cholesterol by GC * GC-TOF/MS analysis. AB - A new method based on the cholesterol level was developed to detect the presence of animal fats in virgin coconut oil (VCO). In this study, the sterols in VCO and animal fats was separated using conventional one-dimensional gas chromatography (1D GC) and comprehensive two-dimensional gas chromatography (GC*GC). Compared with 1D GC, the GC*GC system could obtain a complete baseline separation of the sterol trimethylsilyl ethers derived from cholesterol and cholestanol, so that the cholesterol content in pure VCO and false VCO adulterated with animal fats could be accurately determined. Cholesterol, a main sterol found in animal fats, represented less than 5mg/kg of VCO. The study demonstrated that the determination of the cholesterol level in VCO could be used for reliable detection of the presence of lard, chicken fat, mutton tallow, beef tallow, or their mixture in VCO at a level as little as 0.25%. PMID- 25704694 TI - Characterization and screening of pyrrolizidine alkaloids and N-oxides from botanicals and dietary supplements using UHPLC-high resolution mass spectrometry. AB - The UHPLC-QToF-MS analysis of pyrrolizidine alkaloids (PAs) from various parts of 37 botanicals and 7 products was performed. A separation by LC was achieved using a reversed-phase column and a gradient of water/acetonitrile each containing formic acid as the mobile phase. MS-MS detection was used because of its high selectivity, and ability to provide structural information. Free base and N oxides were observed by this method. PAs were analyzed and detected in plants from three different families, viz., Asteraceae, Boraginaceae and Fabaceae. The Asteraceae family was found to contain senecionine and lycopsamine type PAs. The Boraginaceae family contained lycopsamine and heliotrine type PAs and the Fabaceae family contained senecionine and monocrotaline type PAs. These PAs may serve as important markers for the detection of these plant materials in food and dietary supplements. PAs were identified in 44 samples by comparing their retention times, accurate mass and mass fragmentation patterns with those of 25 reference standards. PMID- 25704695 TI - Occurrence of Fusarium mycotoxins and their dietary intake through beer consumption by the European population. AB - Since cereals are raw materials for production of beer and beer-based drinks, the occurrence mycotoxins in 154 beer samples was topic of investigation in this study. The analyses were conducted using QuEChERS extraction and gas chromatography-tandem mass spectrometry determination. The analytical method showed recoveries for vast majority of analytes ranged from 70% to 110%, relative standard deviations lower than 15% and limits of detection from 0.05 to 8 MUg/L. A significant incidence of HT-2 toxin and deoxynivalenol (DON) were found in 9.1% and 59.7% of total samples, respectively. The exposure of European population to mycotoxins through beer consumption was assessed. No toxicological concern was associated to mycotoxins exposure for average beer consumers. Despite that, for heavy beer drinkers, the contribution of this commodity to the daily intake is not negligible, approaching or even exceeding the safety levels. PMID- 25704696 TI - Rapid immunochemical analysis of the sulfonamide-sugar conjugated fraction of antibiotic contaminated honey samples. AB - A rapid high-throughput immunochemical screening (HtiS) procedure for the analysis of the sulfonamide (SA)-sugar conjugated fraction of antibiotic contaminated honey samples has been developed. Studies performed with this matrix have indicated that sulfonamide antibiotics are conjugated to sugars rapidly and quantitatively, providing samples with very low SA immunoreactivity. Therefore, sulfonamides must be first released before the analysis, and for this purpose, a simple and fast sample preparation procedure has been established consisting of hydrolyzing the sample for 5 min, adjusting the pH and buffering the sample prior to the immunochemical analysis. Under these conditions, honey samples could be directly analyzed without any additional sample treatment, other than dilution. Recovery values of the whole analytical procedure were greater than 85%. The analysis of the same samples without the hydrolysis provided recovery values below 5%. Selectivity studies performed in hydrolyzed honey samples revealed that nine relevant sulfonamide antibiotics can be detected with limit of detection (LOD) values below the action limits established by some EU countries (Belgium, 20 MUg kg(-1), United Kingdom or Switzerland, 50 MUg kg(-1)). PMID- 25704697 TI - Evolution of phenolic compounds and metal content of wine during alcoholic fermentation and storage. AB - Changes in the principal phenolic compounds and metal content during the vinification process and storage under modified atmosphere (50% N2, 50% CO2) of Merlot and Syrah wines, from grapes cultivated in Greece, have been investigated. Comparing the variation of metals at maceration process, with the variation of monomeric anthocyanins and flavonols, an inverse relationship was noticed, that can be attributed to complexing reactions of polyphenols with particular trace elements. Cu decreased rapidly, whereas a similar behavior that could be expected for Fe and Mn was not confirmed. Differences in the profile of anthocyanins and flavonols in the fresh Merlot and Syrah wines are reported. During 1 year of storage monomeric anthocyanins declined almost tenfold, probably due to polymerization reactions and copigmentation. Also, a decrease in flavonol glycosides and increase in the respective aglycones was observed, attributed to enzymatic hydrolysis. The concentration of total phenols and all metals remained practically constant. PMID- 25704698 TI - Characterization of polyphenols and evaluation of antioxidant capacity in grape pomace of the cv. Malbec. AB - Low molecular weight polyphenols (LMW-PPs) and anthocyanins, along with the antioxidant capacity, were assessed in grape pomace extract (GPE) of red grape (Vitis vinifera L.) cv. Malbec. Twenty-six phenolics (13 LMW-PPs and 13 anthocyanins) were characterized and quantified by HPLC-MWD and UPLC-ESI-MS. The maximum concentrations of LMW-PPs corresponded to the flavanols (+)-catechin and (-)-epicatechin, whereas malvidin-3-glucoside was the most abundant anthocyanin. Piceatannol, a stilbene analogue to resveratrol with higher antioxidant activity, was firstly identified and quantified in GPE of the cv. Malbec. The antioxidant activity for Malbec GPE determined by oxygen radical absorbance capacity (ORAC) assay was 2,756 MUmol TEg(-1) GPE. Therefore, the data reported sustain the use of winemaking by-products as a cheap source of phenolic compounds suitable for biotechnological applications, as a strategy for sustainable oenology. PMID- 25704699 TI - Enantioseparation of the fungicide imazalil in orange juice by chiral HPLC. Study on degradation rates and extractive/enrichment techniques. AB - Imazalil ([1-(beta-allyloxy-2,4-dichlorophenethyl)imidazole]) is a systemic chiral fungicide used in postharvest protection of citruses against fungi development for during storage and transportation. The chemical structure of imazalil shows an asymmetric carbon in the C7 position. These enantiomers may have different toxicity. A method for both chiral enantiomers extraction and determination in orange juice is developed in order to provide their concentration and to study the degradation rates in orange juice. Spiked imazalil was extracted from orange juice by dispersive liquid-liquid micro extraction and solid phase extraction. Recovery assays of imazalil enantiomers from spiked orange juice samples showed that solid phase extraction is a better choice in order to obtain higher recovery values. Obtained chromatographic data show that within 24h the (-)-imazalil enantiomer decreases from 0.548 to 0.471 (expressed as enantiomer fraction). PMID- 25704700 TI - Effect of extrusion on phytochemical profiles in milled fractions of black rice. AB - The phytochemical profile and antioxidant activities of unprocessed and extruded milled fractions of black rice were investigated. Extrusion increased the free phenolics, anthocyanins and oxygen radical absorbance capacity (ORAC) and decreased the bound forms. The total phenolics, anthocyanins and ORAC increased by 12.6%, 5.4% and 19.7%, respectively, in bran. Extrusion decreased both free and bound phenolics and anthocyanins while ORAC values decreased by 46.5%, 88.4% and 33.1%, respectively, in polished rice and by 71.2%, 87.9% and 14.7%, respectively, in brown rice. A total of seven phenolics, gallic, chlorogenic, vanillic, caffeic, syringic, p-coumaric and ferulic acids, were detected in both forms. Cyanidin 3-glucoside (Cy-3-G), cyanidin 3-rutinoside and peonidin 3 glucoside were also detected with Cy-3-G found in the highest amounts in unprocessed and extruded rice bran. These results provide the basis for the development of different milled fractions of extruded black rice with balanced nutritional characteristics for today's functional food markets. PMID- 25704701 TI - Analysis of plasticiser migration to meat roasted in plastic bags by SPME-GC/MS. AB - Plasticisers are compounds used in the polymer industry to increase the flexibility of plastics. Some of these compounds cause endocrine dysfunction in humans and animals by interfering with the production, release, transport, metabolism, binding or elimination of natural hormones in the body and are therefore recognised as endocrine disruptors. This paper describes cold-fibre solid-phase microextraction as a sampling technique to analyse eight plasticisers in spices and roasted chicken meat stored in plastic bags by gas chromatography mass spectrometry. Limits of detection for this method ranged from 0.01 to 0.18 MUg kg(-)(1). Diisobutyl phthalate and dibutyl phthalate were found in the samples of spices and roasted chicken meat. The highest concentrations of plasticisers were found in the spices used to cook the chicken meat. PMID- 25704702 TI - Effect of immobilized Lactobacillus casei on volatile compounds of heat treated probiotic dry-fermented sausages. AB - The effect of the amount of immobilized Lactobacillus casei ATCC 393 on wheat grains on the generation of volatile compounds during the production of heat treated probiotic dry-fermented sausages was investigated. For comparison reasons, sausages containing free L. casei cells or no starter culture as well as a similar commercial product were also included in the study. Samples ripened for 8 days and heat treated to 70-72 degrees C for 8-10 min were subjected to Solid Phase Microextraction (SPME) Gas Chromatography/Mass Spectrometry (GC/MS) analysis. The starter culture affected significantly the production of volatile compounds. The highest content of esters and alcohols was observed in the sample containing 30 g of immobilized cells/kg of stuffing mixture, while the highest concentration of organic acids was observed in the sausages with no starter culture. In contrast, the commercial product contained the lowest concentration of volatiles. Principal component analysis of the semi-quantitative data revealed that the volatile composition was affected primarily by the nature and concentration of the starter culture. PMID- 25704703 TI - Reduction of biogenic amines production by eliminating the PEP4 gene in Saccharomyces cerevisiae during fermentation of Chinese rice wine. AB - Biogenic amines in Chinese rice wine have a potential threat of toxicity to human health. In this study, PEP4 gene in Saccharomyces cerevisiae was knocked out in order to evaluate its effect on biogenic amines production; the enzyme encodes proteinase A (PrA), an enzyme that is responsible for the production of free amino acids. It was found that compared to the wild type strain, the PrA activity and amino acid concentration decreased significantly, and the production of biogenic amines in this knockout strain decreased by 25.5%, from 180.1mg/L to 134.2mg/L. Especially, tyramine, cadaverine and histamine concentrations were also decreased by 57.5%, 24.6% and 54.3%, respectively. The main reason for the decrease of biogenic amines may be due to the low concentration of free amino acids. Our results provide a new strategy to minimize the biogenic amine production during fermentation of Chinese rice wine. PMID- 25704704 TI - New UHPLC-QqQ-MS/MS method for quantitative and qualitative determination of free phytoprostanes in foodstuffs of commercial olive and sunflower oils. AB - In this work, we propose a new quick and accurate analytical method by UHPLC-QqQ MS/MS which is able to identify free phytoprostanes in olive and refined sunflower oils. The recovery provided high extraction efficiencies ranging from 102.90% to 140.64% using Strata-XAW cartridge. The intra-day and inter-day variations for all target compounds ranged from 2.24% to 13.64% and 0.01% to 13.69%, respectively, and the accuracies for these parameters varied from 80.33% to 119.64% and from 80.34% to 119.90%, respectively. Results obtained reflect that refined sunflower presented more series of phytoprostanes and a 20 and 8 fold higher quantity than two types of olive oil: Extra virgin olive oil and olive oil, (containing half virgin extra olive oil and half refined olive oil). The manufacture process could be the key for the different phytoprostane production since most of the plant oils are subjected to a refining treatment. PMID- 25704705 TI - Impact of gluconic fermentation of strawberry using acetic acid bacteria on amino acids and biogenic amines profile. AB - This paper studies the amino acid profile of beverages obtained through the fermentation of strawberry puree by a surface culture using three strains belonging to different acetic acid bacteria species (one of Gluconobacter japonicus, one of Gluconobacter oxydans and one of Acetobacter malorum). An HPLC UV method involving diethyl ethoxymethylenemalonate (DEEMM) was adapted and validated. From the entire set of 21 amino acids, multiple linear regressions showed that glutamine, alanine, arginine, tryptophan, GABA and proline were significantly related to the fermentation process. Furthermore, linear discriminant analysis classified 100% of the samples correctly in accordance with the microorganism involved. G. japonicus consumed glucose most quickly and achieved the greatest decrease in amino acid concentration. None of the 8 biogenic amines were detected in the final products, which could serve as a safety guarantee for these strawberry gluconic fermentation beverages, in this regard. PMID- 25704706 TI - Bioactive amines in Mozzarella cheese from milk with varying somatic cell counts. AB - The influence of somatic cells counts (SCC) in milk on bioactive amines in Mozzarella cheese was investigated. High SCC milk had lower lactose and higher pH compared to low and medium SCC. Low spermine levels were found in milk irrespective of SCC. The cheeses had similar characteristics, but the extension and depth of proteolysis increased with SCC. Cheese from all SCC categories contained spermine; whereas tyramine and tryptamine were only detected in cheese from high SCC milk. During 60-days refrigerated storage, significant positive effects were observed between SCC and proteolysis, storage time and pH and storage time and proteolysis. There was a significant positive effect of storage time on spermine and serotonin levels. Only cheese from high SCC milk showed significantly higher serotonin levels. Tyramine and tryptamine were found in cheese from high SCC milk. PMID- 25704707 TI - Acetylation of barnyardgrass starch with acetic anhydride under iodine catalysis. AB - Barnyardgrass (Echinochloa crus-galli) is an invasive plant that is difficult to control and is found in abundance as part of the waste of the paddy industry. In this study, barnyardgrass starch was extracted and studied to obtain a novel starch with potential food and non-food applications. We report some of the physicochemical, functional and morphological properties as well as the effect of modifying this starch with acetic anhydride by catalysis with 1, 5 or 10mM of iodine. The extent of the introduction of acetyl groups increased with increasing iodine levels as catalyst. The shape of the granules remained unaltered, but there were low levels of surface corrosion and the overall relative crystallinity decreased. The pasting temperature, enthalpy and other gelatinisation temperatures were reduced by the modification. There was an increase in the viscosity of the pastes, except for the peak viscosity, which was strongly reduced in 10mM iodine. PMID- 25704708 TI - Functional, thermal and rheological properties of oat beta-glucan modified by acetylation. AB - Fibers of beta-glucan have been added to foods for their thickening properties, their ability to form gel at low concentrations, but mainly for their appeal in health promotion. Current analysis evaluates the influence of acetylation (4% and 6% acetic anhydride for 10 and 20 min) on the functional, thermal, morphological and rheological properties of the concentrate containing 31% of oat beta-glucan. The degree of substitution of the acetylated beta-glucans ranged from 0.03 to 0.12, suitable for use in foods. Acetylation increased the heterogeneity of molecule degradation and promoted a more compacted hole-less microstructure. Functional properties such as the swelling power and bile acid binding capacity were increased by acetylation. The beta-glucan gel showed a reduction in hardness and adhesiveness, which was confirmed by its rheological behavior similar to liquid. The above information is relevant to establish the industrial application of acetylated beta-glucan. PMID- 25704709 TI - Spray dried double emulsions containing procyanidin-rich extracts produced by premix membrane emulsification: effect of interfacial composition. AB - Spray drying of procyanidin-loaded W1/O/W2 emulsions produced by premix membrane emulsification (ME) enabled to produce microcapsules containing procyanidins. The interface of the emulsion droplets prior to spray drying was stabilized with several hydrophilic emulsifiers (whey protein (WPI), WPI-carboxylmethyl cellulose, WPI-gum Arabic, and WPI-chitosan). Their effect on procyanidin encapsulation efficiency, water activity, moisture and oil content, and microcapsule size distribution was investigated. Furthermore, the microstructure and droplet size distribution of redispersed microcapsules were analyzed. Although premix ME produced W1/O/W2 emulsions with a narrow droplet size distribution regardless the hydrophilic emulsifier (main peak of droplet size distribution around 9 MUm), microcapsules after spray drying and double emulsions after redispersion showed profound differences in sizes depending on the interfacial composition. WPI-CMC stabilized microcapsules not only showed the highest procyanidin content (5.3 g kg(-1)) but also gave the narrowest particle size distribution with the lowest particle size for both microcapsules and the corresponding emulsions after rehydration (7.7 and 9.9 MUm respectively). PMID- 25704710 TI - Rapid determination of trans-resveratrol in vegetable oils using magnetic hydrophilic multi-walled carbon nanotubes as adsorbents followed by liquid chromatography-tandem mass spectrometry. AB - In the present work, a rapid and simple procedure was developed and validated for the analysis of trans-resveratrol in vegetable oils based on magnetic hydrophilic multi-walled carbon nanotubes (h-MWCNT-MNPs) combined with liquid chromatography tandem mass spectrometry (LC-MS/MS). h-MWCNT-MNPs were simply obtained by wrapping amine-functionalized Fe3O4 magnetic nanoparticles into previously oxidized hydrophilic multi-walled carbon nanotubes. The major parameters affecting extraction efficiency were investigated, including the type and volume of desorption solvents, extraction and desorption time, washing solution, and sorbent amount. The limit of detection (LOD) and the limit of quantification (LOQ) were calculated as 0.6 and 2.0 MUg/kg, respectively. The recoveries of trans-resveratrol in oil samples were in the range of 90.0-110.0% with RSDs of less than 17.5%. The results showed that only peanut oil contained trans resveratrol, ranging from 8 +/- 1 to 103 +/- 12 MUg/kg. The proposed method is reliable and robust, having an excellent potential for the analysis of trans resveratrol in edible oils. PMID- 25704711 TI - Myo-inositol hexakisphosphate degradation by Bifidobacterium pseudocatenulatum ATCC 27919 improves mineral availability of high fibre rye-wheat sour bread. AB - The goal of this investigation was to develop baking products using Bifidobacterium pseudocatenulatum ATCC27919, a phytase producer, as a starter in sourdough for the production of whole rye-wheat mixed bread. This Bifidobacterium strain contributed to myo-inositol hexakisphosphate (phytate) hydrolysis, resulting in breads with higher mineral availability as was predicted by the phytate/mineral molar ratios, which remained below the inhibitory threshold values for Ca and Zn intestinal absorption. The products with sourdough showed similar technological quality as their homologous without sourdough, with levels of acetic and d/l lactic acids in dough and bread baking significantly higher with the use of sourdough. The overall acceptability scores showed that breads with 25% of whole rye flour were highly accepted regardless of the inclusion of sourdough. This work emphasises that the in situ production of phytase during fermentation by GRAS/QPS microorganisms constitutes a strategy which is particularly appropriate for reducing the phytate contents in products for human consumption. PMID- 25704712 TI - Thermal stability and kinetics of degradation of deoxynivalenol, deoxynivalenol conjugates and ochratoxin A during baking of wheat bakery products. AB - The stability of deoxynivalenol (DON), deoxynivalenol-3-glucoside (DON-3 glucoside), 3-acetyldeoxynivalenol (3-ADON), 15-acetyldeoxynivalenol (15-ADON), de-epoxy-deoxynivalenol (DOM-1) and ochratoxin A (OTA) during thermal processing has been studied. Baking temperature, time and initial mycotoxin concentration in the raw materials were assayed as factors. An improved UPLC-MS/MS method to detect DON, DON-3-glucoside, 3-ADON, 15-ADON and DOM-1 in wheat baked products was developed in the present assay. The results highlighted the importance of temperature and time in mycotoxin stability in heat treatments. OTA is more stable than DON in a baking treatment. Interestingly, the DON-3-glucoside concentrations increased (>300%) under mild baking conditions. On the other hand, it was rapidly reduced under harsh conditions. The 3-ADON decreased during the heat treatment; while DOM-1 increased after the heating process. Finally, the data followed first order kinetics for analysed mycotoxins and thermal constant rates (k) were calculated. This parameter can be a useful tool for prediction of mycotoxin levels. PMID- 25704713 TI - Homogeneity study of a corn flour laboratory reference material candidate for inorganic analysis. AB - In this work, a homogeneity study of a corn flour reference material candidate for inorganic analysis is presented. Seven kilograms of corn flour were used to prepare the material, which was distributed among 100 bottles. The elements Ca, K, Mg, P, Zn, Cu, Fe, Mn and Mo were quantified by inductively coupled plasma optical emission spectrometry (ICP OES) after acid digestion procedure. The method accuracy was confirmed by analyzing the rice flour certified reference material, NIST 1568a. All results were evaluated by analysis of variance (ANOVA) and principal component analysis (PCA). In the study, a sample mass of 400mg was established as the minimum mass required for analysis, according to the PCA. The between-bottle test was performed by analyzing 9 bottles of the material. Subsamples of a single bottle were analyzed for the within-bottle test. No significant differences were observed for the results obtained through the application of both statistical methods. This fact demonstrates that the material is homogeneous for use as a laboratory reference material. PMID- 25704714 TI - Light influence in the nutritional composition of Brassica oleracea sprouts. AB - Brassica sprouts are considered a healthy food product, whose nutritional quality can be influenced by several factors. The aim of this work was to monitor the nutritional composition changes promoted by different sprouting conditions of four varieties of Brassica oleracea (red cabbage, broccoli, Galega kale and Penca cabbage). Sprouts were grown under light/darkness cycles and complete darkness. Standard AOAC methods were applied for nutritional value evaluation, while chromatographic methods with UV-VIS and FID detection were used to determine the free amino acids and fatty acids, respectively. Mineral content was analyzed by atomic absorption spectrometry. Sprouts composition revealed them as an excellent source of protein and dietary fiber. Selenium content was one of the most distinctive feature of sprouts, being the sprouting conditions determinant for the free amino acid and fatty acids profile. The use of complete darkness was beneficial to the overall nutritional quality of the brassica sprouts studied. PMID- 25704715 TI - Discrimination of producing area of Chinese Tongshan kaoliang spirit using electronic nose sensing characteristics combined with the chemometrics methods. AB - In the ancient history of the Yue Nation, the Chinese Tongshan kaoliang spirit (CTKS) has been one of the most popular liquor in the last 2,500 years. The most common fraudulent practice for the commercialization of CTKS is to produce and sell adulterated spirit from different geographical origins. In this study, the use of GC-flash electronic nose (EN) technique combined with chemometrics analysis has proven to provide a rapid tool for the discrimination of CTKS from different geographical origins. The discriminant models were developed by using principal component analysis (PCA), and discriminant factor analysis (DFA). In addition, the volatile organic matters of CTKS were also investigated to find out the difference between samples from varied origins and adulterated liquor. The results demonstrated that the EN technique combined with chemometrics methods could be used to fingerprinting techniques to protect the fame of the prestigious CTKS and to enable its authentication. PMID- 25704716 TI - (1S,3R,4S,5R)5-O-Caffeoylquinic acid: isolation, stereo-structure characterization and biological activity. AB - Sorbus domestica fruits (sorbs) are commonly harvested and consumed for their nutritious qualities and have long been used as natural remedy against diabetes in the popular medicine. Recently, sorbs have been described as sources of antioxidant compounds including polyphenols. Chemical analyses carried out on sorbs collected in Southern Italy have led to the isolation of a chlorogenic acid isomer as the main antioxidant compound contained in the fruit butanol extract. NMR studies have identified the isolated compound as (1S,3R,4S,5R)5-O Caffeoylquinic acid. In comparison to chlorogenic acid, the isolated isomer features an inverted configuration at C4. Such configurational inversion causes the chlorogenic acid stereoisomer acid to assume a preferential conformation remarkably different from that of chlorogenic acid. This seems to account for the enhanced potency of (1S,3R,4S,5R)5-O-Caffeoylquinic acid to reduce both the glucose and cholesterol uptakes by the cell line HepG2 when compared to chlorogenic acid. PMID- 25704717 TI - Structural characterization and antioxidant activities of kappa-carrageenan oligosaccharides degraded by different methods. AB - In the present study, four kinds of kappa-carrageenan oligosaccharides were obtained by the degradation of parent kappa-carrageenan using free radical depolymerization, mild acid hydrolysis, kappa-carrageenase digestion and partial reductive hydrolysis, respectively. Their structure types were accurately and comparatively elucidated by ESI-MS and CID MS/MS. The antioxidant activities of different degraded products were investigated by four different antioxidant assays, including superoxide radical scavenging activity, hydroxyl radical scavenging activity, reducing power and DPPH radical scavenging activity. The methods of depolymerization had an influence on the antioxidant activities of kappa-carrageenan oligosaccharides obtained from kappa-carrageenan. These results indicated that the antioxidant activities of kappa-carrageenan oligosaccharides could be related to the degree of polymerization, the content of reducing sugar and sulfate groups, and the structure of reducing terminus. PMID- 25704718 TI - Development and validation of a TaqMan real-time PCR assay for the identification and quantification of roe deer (Capreolus capreolus) in food to detect food adulteration. AB - In order to protect the consumer from meat adulteration it is necessary to identify and quantify the meat content in foodstuffs. Game meat is particularly susceptible for fraudulent labeling since it is more valuable than meat from domestic animals. The paper presents a TaqMan real-time PCR assay for the quantitative determination of roe deer in meat products. The assay developed does not show cross-reactivity with 23 animal and 43 plant species tested and is therefore specific for roe deer. The amplification efficiency determined by analyzing serially diluted roe deer DNA extracts was found to be 93.9%. For quantifying the roe deer content in % (w/w), a reference system based on the myostatin gene was used. The quantification strategy was validated by determining the roe deer content in model meat mixtures and a model sausage. In addition, the real-time PCR assay was applied to the analysis of commercially available meat products. PMID- 25704719 TI - Effect of milk type and processing on iodine concentration of organic and conventional winter milk at retail: implications for nutrition. AB - Milk is the largest source of iodine in UK diets and an earlier study showed that organic summer milk had significantly lower iodine concentration than conventional milk. There are no comparable studies with winter milk or the effect of milk fat class or heat processing method. Two retail studies with winter milk are reported. Study 1 showed no effect of fat class but organic milk was 32.2% lower in iodine than conventional milk (404 vs. 595 MUg/L; P<0.001). Study 2 found no difference between conventional and Channel Island milk but organic milk contained 35.5% less iodine than conventional milk (474 vs. 306 MUg/L; P<0.001). UHT and branded organic milk also had lower iodine concentrations than conventional milk (331 MUg/L; P<0.001 and 268 MUg/L: P<0.0001 respectively). The results indicate that replacement of conventional milk by organic or UHT milk will increase the risk of sub-optimal iodine status especially for pregnant/lactating women. PMID- 25704720 TI - Relationship between the chemical components of taro rhizome mucilage and its emulsifying property. AB - The objective of this study was to determine the chemical composition of taro mucilage (TM) and explain its emulsification properties using different commercial emulsifiers and gums as benchmarks. The following analyses were performed: moisture, ether extract, protein, fiber, ash, sugar fraction, starch content, infrared spectroscopy and determination of monosaccharides and amino acids using HPLC. The analyses showed that TM has a high carbohydrate content and small protein fraction, similar to commercial gums. Commercial emulsifiers have a high content of lipids compared to TM. Therefore, it can be concluded that the emulsifying power of the studied mucilage is primarily caused by the protein content along with weakly polar amino acids, which occur in gums. The methyl group (CH3), which was observed in the infrared spectrum, and the lipid content may also contribute to the emulsifying activity by providing a hydrophobic moiety. PMID- 25704721 TI - Quantitative determination of total pigments in red meats using hyperspectral imaging and multivariate analysis. AB - This study investigated the potential of hyperspectral imaging (HSI) for quantitative determination of total pigments in red meats, including beef, goose, and duck. Partial least squares regression (PLSR) was applied to correlate the spectral data with the reference values of total pigments measured by a traditional method. In order to simplify the PLSR model based on the full spectra, eleven optimal wavelengths were selected using successive projections algorithm (SPA). The new SPA-PLSR model yielded good results with the coefficient of determination (R(2)p) of 0.953, root mean square error (RMSEP) of 9.896, and ratio of prediction to deviation (RPD) of 4.628. Finally, distribution maps of total pigments in red meats were developed using an image processing algorithm. The overall results from this study indicated HSI had the capability for predicting total pigments in red meats. PMID- 25704722 TI - Influence of peptides-phenolics interaction on the antioxidant profile of protein hydrolysates from Brassica napus. AB - The role of the peptides-phenolic compounds (PC) interaction on the antioxidant capacity profile (ACP) of protein hydrolysates from rapeseed (Brassica napus) was studied in 36 hydrolysates obtained from a PC-rich and PC-reduced protein substrate. The latent profile analysis (LPA), with data of seven in vitro methods and one assay for cellular antioxidant activity (CAA), allowed identifying five distinctive groups of hydrolysates, each one with distinctive ACP. The interaction of peptides with naturally present PC diminished in vitro antioxidant activity in comparison with their PC-reduced counterparts. However, CAA increased when peptides-PC interaction occurred. The profile with the highest average CAA (62.41 +/- 1.48%), shown by hydrolysates obtained by using alcalase, shared typical values of Cu(2+)-catalysed beta-carotene oxidation (62.41 +/- 0.43%), beta-carotene bleaching inhibition (91.75 +/- 0.22%) and Cu(2+)-chelating activity (74.53 +/- 0.58%). The possibilities for a sample to exhibit ACP with higher CAA increased with each unit of positively charged amino acids, according to multinomial logistic regression analysis. PMID- 25704724 TI - The number of subjects per variable required in linear regression analyses. AB - OBJECTIVES: To determine the number of independent variables that can be included in a linear regression model. STUDY DESIGN AND SETTING: We used a series of Monte Carlo simulations to examine the impact of the number of subjects per variable (SPV) on the accuracy of estimated regression coefficients and standard errors, on the empirical coverage of estimated confidence intervals, and on the accuracy of the estimated R(2) of the fitted model. RESULTS: A minimum of approximately two SPV tended to result in estimation of regression coefficients with relative bias of less than 10%. Furthermore, with this minimum number of SPV, the standard errors of the regression coefficients were accurately estimated and estimated confidence intervals had approximately the advertised coverage rates. A much higher number of SPV were necessary to minimize bias in estimating the model R(2), although adjusted R(2) estimates behaved well. The bias in estimating the model R(2) statistic was inversely proportional to the magnitude of the proportion of variation explained by the population regression model. CONCLUSION: Linear regression models require only two SPV for adequate estimation of regression coefficients, standard errors, and confidence intervals. PMID- 25704725 TI - Lottery ticket was more effective than a prize draw in increasing questionnaire response among cancer survivors. AB - OBJECTIVES: Compare the effect of financial incentives on response to a cancer survivors' postal questionnaire. STUDY DESIGN AND SETTING: Prostate cancer survivors in Ireland, 1.5-18 years after diagnosis, were randomized to the (1) "lottery" arm [a ? 1 lottery scratch card sent with the questionnaire (n = 2,413)] or (2) "prize" arm [entry into a draw on return of a completed questionnaire (n = 2,407)]. Impact of interventions on response overall and by survival period ("short term": < 5 years after diagnosis; "long term": >= 5 years after diagnosis) was compared as was cost-effectiveness. RESULTS: Adjusted response rate was 54.4%. Response was higher among younger men (P < 0.001) and those with earlier stage disease (P = 0.002). A modest 2.6% higher response rate was observed in the lottery compared with the prize arm [multivariate relative risk (RR) = 1.06; 95% confidence interval (CI): 1.00, 1.11]. When stratified by survival period, higher response in the lottery arm was only observed among long term survivors (multivariate RR = 1.10; 95% CI: 1.02, 1.19; short-term survivors: RR = 1.01; 95% CI: 0.94, 1.09). Costs per completed questionnaire were ? 4.54 and ? 3.57 for the lottery and prize arms, respectively. Compared with the prize arm, cost per additional questionnaire returned in the lottery arm was ? 25.65. CONCLUSION: Although more expensive, to optimize response to postal questionnaires among cancer survivors, researchers might consider inclusion of a lottery scratch card. PMID- 25704723 TI - Microparticle analysis in disorders of hemostasis and thrombosis. AB - Microparticles (MPs) are submicron vesicles released from the plasma membrane of eukaryotic cells in response to activation or apoptosis. MPs are known to be involved in numerous biologic processes, including inflammation, the immune response, cancer metastasis, and angiogenesis. Their earliest recognized and most widely accepted role, however, is the ability to promote and support the process of blood coagulation. Consequently, there is ongoing interest in studying MPs in disorders of hemostasis and thrombosis. Both phosphatidylserine (PS) exposure and the presence of tissue factor (TF) in the MP membrane may account for their procoagulant properties, and elevated numbers of MPs in plasma have been reported in numerous prothrombotic conditions. To date, however, there are few data on true causality linking MPs to the genesis of thrombosis. A variety of methodologies have been employed to characterize and quantify MPs, although detection is challenging due to their submicron size. Flow cytometry (FCM) remains the most frequently utilized strategy for MP detection; however, it is associated with significant technological limitations. Additionally, preanalytical and analytical variables can influence the detection of MPs by FCM, rendering data interpretation difficult. Lack of methodologic standardization in MP analysis by FCM confounds the issue further, although efforts are currently underway to address this limitation. Moving forward, it will be important to address these technical challenges as a scientific community if we are to better understand the role that MPs play in disorders of hemostasis and thrombosis. PMID- 25704726 TI - Investigation on formaldehyde release from preservatives in cosmetics. AB - OBJECTIVE: To understand formaldehyde residue in cosmetics, an investigation on formaldehyde release from eight preservatives (methenamine - MA, paraformaldehyde - PF, poly(p-toluenesulfonamide-co-formaldehyde) -PTSAF, quaternium-15 - QU, imidazolidinyl urea - IU, diazolidinyl urea - DU, dimethyloldimethyl hydantoin - DMDM and bronopol - BP) under various conditions was performed. METHODS: The concentration of released formaldehyde was determined by high-performance liquid chromatography with photodiode array detection after derivatization with 2,4 dinitrophenylhydrazine. RESULTS: The amounts of formaldehyde release were in the order of PF > DU > DMDM ~ QU ~ IU > MA > BP > PTSAF. The releasing amounts of formaldehyde were the highest in the presence of aqueous matrices for the releasers except QU and IU, and the releasing effect was also relative to pH. More formaldehyde was released with longer storage time and higher temperature. Furthermore, all preservatives in cosmetic matrices released fewer amounts of formaldehyde than in pure aqueous or organic matrices, and the formaldehyde releasing amounts were also cosmetic specific. CONCLUSION: Formaldehyde release was dependent on the matrix, pH, time and mainly temperature, and the releasing effect was also cosmetic specific. PMID- 25704727 TI - [Validation during exercise of a new device for cardiac output measurement using pulse wave transit time (comparison EsCCO((r)) vs. Physioflow((r)))]. AB - OBJECTIVES: EsCCO is a novel non-invasive continuous cardiac output monitoring system based on pulse wave transit time already validated at rest. The aim of our study was to compare cardiac output measurements obtained simultaneously by EsCCO((r)) (QcOP) and impedance cardiography (Physioflow((r)) ; QcIMP), in healthy subjects. PATIENTS AND METHODS: Eight healthy subjects (age: 31+/-9 years, weight: 76+/-10kg, height: 179+/-5cm) realized two exercise tests: an incremental ergocycle test performed until exertion (Pmax=269+/-48W) and a constant load exercise (P=163+/-27W). Comparison between measurements (QcOP versus QcIMP) obtained during the first test allowed to evaluate the accuracy of the device. Reliability was determined on three repeated measures during the second test, realized at ventilatory threshold. RESULTS: Correlation coefficient between both methods is 0.88 (P<0.01). Mean difference is 0.04+/-1.49L/min (95 % limits of agreement: +2.94 to -3.00L/min) and only 3/74 measures are not included between the limits of agreement. At high intensity and for cardiac output over than 15 L/min, QcOP signal is lost in almost half the time. Concerning reliability, reproducibility coefficient is 0.87 (P<0.05), only 1.8 % of this variability is due to the method. CONCLUSION: EsCCO((r)) measurements are accurate, reliable and allow a good estimation of cardiac output on healthy subjects. The signal lost observed for high cardiac output levels (>15L/min) can limit its utilization during very high intensity exercise. PMID- 25704728 TI - [A tamponade complicating an acute eosinophilic pericarditis due to a myeloproliferative/myelodysplastic syndrome]. AB - Cardiac involvement in eosinophilia is potentially fatal and requires early diagnosis and prompt treatment. We report here the case of a 71-year-old female patient with eosinophilia>10,000/mm(3) for 2 months due to a myeloproliferative/myelodysplastic syndrome, with a rapidly progressive exertional dyspnea explained by an important circumferential eosinophilic pericarditis. Due to a rapid evolution to a tamponade, an emergent surgical drainage was performed. Subsequent medical treatment combined high-dose corticosteroids (1mg/kg/day) with hydroxyurea and imatinib. The outcome was favourable with regression of the effusion, of the volume overload symptoms and decrease in eosinophilia. PMID- 25704729 TI - Experience-sensitive epigenetic mechanisms, developmental plasticity, and the biological embedding of chronic disease risk. AB - A wide range of developmental, nutritional, environmental, and social factors affect the biological activities of epigenetic mechanisms. These factors change spatiotemporal patterns of gene expression in a variety of different ways and bring significant impacts to bear on development, physiology, and disease risk throughout the life course. Abundant evidence demonstrates that behavioral stressors and adverse nutritional conditions are particularly potent inducers of epigenetic changes and enhancers of chronic disease risks. Recent insights from both human clinical studies and research with model organisms further indicate that such experience-dependent changes to the epigenome can be transmitted through the germline across multiple generations, with important consequences for the heritability of both adaptive and maladaptive phenotypes. Epigenetics research thus offers many possibilities for developing informative biomarkers of acquired chronic disease risk and determining the effectiveness of preventive and therapeutic interventions. Moreover, the experience-sensitive nature of these disease risks raises important questions about societal and individual responsibilities for the prevention of ill-health and the promotion of well-being during development, across the life course and between generations. Better understanding of how epigenetic mechanisms regulate developmental plasticity and mediate the biological embedding of chronic disease risks is therefore likely to shed important new light on the nature of the pathophysiological mechanisms linking social and health inequalities, and will help to inform public policy initiatives in this area. CONFLICT OF INTEREST: The author has declared no conflicts of interest for this article. PMID- 25704730 TI - Propeller facial artery perforator flap as first reconstructive option for nasolabial and perinasal complex defects. AB - Facial cutaneous oncological pathology often involves more than one esthetic unit due to their close boundaries. The reconstruction of both the nasolabial and perinasal regions may be especially complex and challenging for the surgeon. Traditionally, these defects have been reconstructed with local random flaps based on the vascularization provided by the superficial musculoaponeurotic system. In this article, we present our experience in the reconstruction of the aforementioned defects using the propeller facial artery perforator (FAP) flap. PATIENTS AND METHODS: A propeller FAP flap was performed for reconstruction in 12 patients with nasolabial or perinasal complex defects after tumoral resection between the years 2011 and 2013. The flap was designed parallel to the nasolabial fold in all cases for achieving direct closure and an aesthetically pleasing outcome. In one of the cases, a paramedian forehead flap was performed simultaneously. RESULTS: Nine patients healed uneventfully, with good functional and esthetic outcomes. One of the flaps developed partial necrosis of the distal end, and another developed temporary postoperative venous congestion, lymphedema, and, finally, trapdoor deformity. The latter complication also occurred in one more flap. CONCLUSION: The propeller FAP flap is reliable and versatile, with few complications, and it is especially useful when reconstructing complex defects that involve the nasolabial and perinasal regions; therefore, it should be considered as one of the first reconstructive options for the described defects. PMID- 25704731 TI - A salvage maneuver for the caudal part of the pectoralis major muscle in the reconstruction of superior thoracic wall defects: The pectoralis kite flap. AB - The pectoralis major muscle flap is the most commonly used option for chest wall reconstruction. However, its utilization should be avoided in chest wall tumors infiltrating the muscle. This article presents the utilization of the caudal part of the pectoralis major muscle as a pedicled flap in cases requiring the resection of the cranial part of the muscle due to tumor infiltration. Fourteen patients with a mean age of 60.3 years were operated for malignant thoracic wall tumors between 2011 and 2014. All tumors were located on the upper thoracic area with a mean defect size of 16.6 * 12 cm. During tumor resection, the thoracoacromial vessels and pectoral branch were preserved and dissected until reaching the pectoralis muscle. After the resection of the cranial part of the muscle, the caudal part is prepared as a pedicled island flap and used for the coverage of the resultant defect. The mean postoperative follow-up period was 10.9 months. All flaps survived without any partial or total flap loss. A case of local recurrence, two cases of hematoma requiring drainage, and two cases of local wound-healing problems were the encountered complications. The pectoral kite flap is a versatile and reliable option for the coverage of small to medium upper chest wall defects with minimal morbidity, and it gives the reconstructive surgeon the opportunity to use the non-infiltrated caudal part of the pectoralis muscle instead of an unnecessary resection of the whole muscle. PMID- 25704732 TI - I. Sleep and development: introduction to the monograph. AB - Literature on sleep and child development is growing rapidly in exciting new directions across several disciplines and with this comes a need for guiding conceptual principles and methodological tools. In this introductory chapter, the importance of sleep for child development across multiple domains is highlighted. The aims of this monograph are presented and pertain to the need to consider and integrate theory and research across multiple disciplines and use state-of-the art methodologies. A developmental ecological systems perspective adapted to sleep illustrates the multiple levels of influence and their importance in the study of child sleep and development. A focal aim is to provide examples of longitudinal studies linking sleep with child development, which are presented in seven chapters of this volume. PMID- 25704733 TI - Ii. Moving sleep and child development research forward: priorities and recommendations from the srcd-sponsored forum on sleep and child development. AB - Prevalent in typically developing children, insufficient or poor-quality sleep are matters of public health concern. Programmatic studies of the predictors and sequelae of sleep are increasing rapidly and yielding novel research paradigms that explicate connections between sleep, family processes, and child development within the sociocultural milieu. In an SRCD-sponsored Forum, established researchers and junior scholars from disparate areas of inquiry (e.g., Pediatrics; Public Health; Psychology; Anthropology) convened. An overarching goal of the Forum was to promote dialogue and collaborations, identify pivotal areas in the study of typically developing children's sleep, and integrate knowledge of sleep and child development across disciplines toward making conceptual advances about the ways that sleep and waking behaviors are intertwined. In addition to conceptual advances, a second goal focused on the need for methodological advances, including contemporary approaches and tools in the measures and analyses of sleep to help accelerate the pace and enhance the quality of research in this interdisciplinary field. PMID- 25704734 TI - Iii. Sleep assessment methods. AB - Sleep is a complex phenomenon that could be understood and assessed at many levels. Sleep could be described at the behavioral level (relative lack of movements and awareness and responsiveness) and at the brain level (based on EEG activity). Sleep could be characterized by its duration, by its distribution during the 24-hr day period, and by its quality (e.g., consolidated versus fragmented). Different methods have been developed to assess various aspects of sleep. This chapter covers the most established and common methods used to assess sleep in infants and children. These methods include polysomnography, videosomnography, actigraphy, direct observations, sleep diaries, and questionnaires. The advantages and disadvantages of each method are highlighted. PMID- 25704735 TI - Reactivity and sleep in infants: a longitudinal objective assessment. AB - Sleep patterns and temperament in the first year of life are closely related. However, research utilizing objective, rather than subjective measurements of sleep and temperament is scarce and results are inconsistent. In addition, a relative lack of longitudinal data prevents inference of causality between the two constructs. In this study, infant sleep was objectively assessed among 95 infants at 3, 6, and 12 months-of-age with an actigraph in the home setting. Reactivity to sound, light, and touch, a specific aspect of temperament, was behaviorally assessed at 3 and 6 months, both during sleep (at home) and during waking (at the laboratory). Expected maturational trends were recorded in sleep, with a temporal increase in sleep efficiency and percent of motionless sleep. Quadratic (i.e., inverse U shape) relations were found, especially among girls, when predicting change in sleep by reactivity thresholds, suggesting that both hyposensitive and hypersensitive infants are at risk for poor sleep quality. These are the first research findings suggesting that low reactivity in infancy might be associated with compromised sleep quality. The observed nonlinear effects may account for null or inconsistent results in previous studies that explored only linear associations between temperament and sleep. Future studies should address both extremes of the temperament continuum when exploring relations with sleep patterns. PMID- 25704736 TI - Sleep as a mirror of developmental transitions in infancy: the case of crawling. AB - The associations between the onset of crawling and changes in sleep were examined in 28 infants who were followed from 5 to 11 months-of-age. Motor development and sleep (actigraphy) were assessed at 2- to 3-week intervals. Along with the overall improvement in sleep consolidation, periods of increased long wake episodes were also manifested; the rise in sleep disruption was temporally linked to crawling onset. The results of the study highlight the dynamic interrelations between domains of development, indicate that emerging motor skills may involve periods of disrupted sleep, and point to the moderating effect of age. Clarifying the factors involved in the interplay between developmental milestones and sleep remains a challenge for future research. PMID- 25704737 TI - Vi. Marital conflict, vagal regulation, and children's sleep: a longitudinal investigation. AB - We examined longitudinal relations between adult interpartner conflict (referred to as marital conflict) and children's subsequent sleep minutes and quality assessed objectively via actigraphy, and tested parasympathetic nervous system (PNS) activity indexed through respiratory sinus arrhythmia reactivity (RSA-R) and initial sleep as moderators of predictive associations. At Wave 1 (W1), children (85 boys, 75 girls) with a mean age of 9.43 years (SD=.69) reported on marital conflict, and their sleep was assessed with actigraphs for seven nights. Sleep minutes, sleep efficiency, sleep activity, and number of long wake episodes were derived. RSA-R was measured in response to a lab challenge. Sleep parameters were assessed again 1 year later at Wave 2 (W2; mean age=10.39; SD=.64). Analyses consistently revealed 3-way interactions among W1 marital conflict, sleep, and RSA-R as predictors of W2 sleep parameters. Sleep was stable among children with more sleep minutes and better sleep quality at W1 or low exposure to marital conflict at W1. Illustrating conditional risk, marital conflict predicted increased sleep problems (reduced sleep minutes, worse sleep quality) at W2 among children with poorer sleep at W1 in conjunction with less apt physiological regulation (i.e., lower levels of RSA-R or less vagal withdrawal) at W1. Findings build on the scant literature and underscore the importance of simultaneous consideration of bioregulatory systems (PNS and initial sleep in this study) in conjunction with family processes in the prediction of children's later sleep parameters. PMID- 25704738 TI - Infant sleep development from 3 to 6 months postpartum: links with maternal sleep and paternal involvement. AB - The aims of this longitudinal study were to examine (a) development of infant sleep and maternal sleep from 3 to 6 months postpartum; (b) concomitant and prospective links between maternal sleep and infant sleep; and (c) triadic links between paternal involvement in infant caregiving and maternal and infant sleep. The study included 57 families that were recruited during pregnancy. Maternal and infant sleep was assessed using actigraphy and sleep diaries for 5 nights. Both fathers and mothers completed a questionnaire assessing the involvement of fathers relative to mothers in infant caregiving. The results demonstrated moderate improvement in infant and maternal sleep percent between 3 and 6 months. Maternal sleep percent at 3 months significantly predicted infant sleep percent at 6 months. Greater paternal involvement in infant daytime and nighttime caregiving at 3 months significantly predicted more consolidated maternal and infant sleep at 6 months. These findings suggest that maternal sleep is an important predictor of infant sleep and that increased involvement of fathers in infant caregiving responsibilities may contribute to improvements in both maternal and infant sleep during the first 6 months postpartum. PMID- 25704739 TI - Viii. Attachment and sleep among toddlers: disentangling attachment security and dependency. AB - Many scholars have proposed that parent-child attachment security should favor child sleep. Research has yet, however, to provide convincing support for this hypothesis. The current study used objective measures of sleep and attachment to assess the longitudinal links between mother-child attachment security and subsequent sleep, controlling for child dependency. Sixty-two middle-class families (30 girls) were met twice, when children were 15 months (Wave 1; W1) and 2 years of age (Wave 2; W2). At W1, mother-child attachment was assessed with the observer version of the Attachment Q-Sort. At W2, children wore an actigraph monitor for 72 hr. Results indicated that children more securely attached to their mothers subsequently slept more at night and had higher sleep efficiency, and these predictions were not confounded by child dependency. These findings suggest a unique role for secure attachment relationships in the development of young children's sleep regulation, while addressing methodological issues that have long precluded consensus in this literature. PMID- 25704740 TI - Bedtime routines in early childhood: prevalence, consistency, and associations with nighttime sleep. AB - The ability to transition from wakefulness to sleep is one of the most important tasks in the development of sleep during early childhood. Although establishing regular bedtime routines for children with sleep problems can be clinically effective in reducing the number of signaled night awakenings and increasing amount of sleep, it is unclear whether a regular bedtime routine would be associated with either the frequency of signaled night awakenings or nightly sleep minutes in a nonclinical sample of children. This study examined the role of a regular bedtime routine on the development of sleep regulation and consolidation in a community sample of young children. Adherence to a bedtime routine was concurrently associated with a greater amount of nightly sleep at 36 and 42 months. In addition, adherence to a bedtime routine predicted an increase in nightly sleep minutes over a 6-month period. Finally, this study demonstrated that adherence to a bedtime routine was particularly supportive of developmental gains for children of mothers who used consistent parenting practices during the day. PMID- 25704741 TI - Marital and emotional adjustment in mothers and infant sleep arrangements during the first six months. AB - Although parents' structuring of infant sleep is complexly determined, little attention has been given to parents' marital and personal adjustment in shaping sleep arrangement choices. Linkages were examined between infant sleep arrangements at 1 and 6 months and mothers' marital adjustment, co-parenting quality, and depressive symptoms. The final study sample was composed of 149 families (53% girl infants, 86% European American). Bed sharing mothers had lower co-parenting quality, and, at 6 months, more depressive symptoms than mothers of infants in solitary sleep. One-month co-parenting quality was associated with predictable shifts in sleep arrangements from 1 to 6 months, but 1-month sleep arrangements did not predict changes in personal or co-parenting quality. Findings emphasize the need for greater attention to marital and emotional health in influencing family-level decisions about infant sleep arrangements. PMID- 25704742 TI - Xi. Sleep and development: conclusions and future directions. AB - Literature on sleep and child development is growing in novel directions across several disciplines necessitating guiding conceptual principles and methodological tools. First, this volume presents a summary of discussions from an SRCD-sponsored multidisciplinary forum on sleep and development, which includes presentation of key issues and guiding recommendations for research priorities in this fast developing field. Second, enhancing accessibility to child development researchers, state of the science sleep assessment methodologies are presented with a discussion of their advantages and disadvantages. Third, seven empirical studies conducted with "typically" developing infants and children provide examples of relations between sleep and some of the many individual and familial factors that influence and are influenced by sleep. In the presentation of empirical findings, a developmental ecological systems perspective adapted to sleep was espoused to illustrate some of the multiple levels of influence in the study of child sleep and development. Collectively, studies in this volume build significantly on the literature through: (a) illustrating linkages between various sleep parameters (e.g., quality, sleeping arrangements) and other key developmental domains (e.g., attachment, parenting); (b) demonstration of longitudinal relations connecting sleep with development, which is scarce in this field; and (c) utilization of actigraphy-based assessments of sleep duration and quality, which are underutilized in the literature yet important for a more nuanced understanding of sleep and development. PMID- 25704743 TI - On sleep and development: recent advances and future directions. AB - The authors of the monograph discuss conceptual and methodological issues in the study of sleep-behavior associations, report on the advantages and disadvantages of various techniques for assessing sleep in infants and children, and suggest the importance of examining sleep-behavior relations across multiple disciplines of influence. The primary focus of this commentary is to highlight how these new perspectives contribute to our emerging understanding of sleep-behavior relations in infancy and childhood, as well as to propose further challenges and avenues for future research. PMID- 25704746 TI - Inhibitory effect on the uptake and diffusion of Cd(2+) onto soybean hull sorbent in Cd-Pb binary sorption systems. AB - The uptake of Cd(2+) and Pb(2+) ions by a soybean hull (SH) biosorbent in single and binary systems has been investigated. Sorption tests regarding SH in natura and chemically treated were carried out testing a suitable value range of solution pH, sorption temperature and shaking velocity. Sorption capacity is improved at pH 4, 30 degrees C temperature and 100 rpm. When a strong base is applied, a related-to-untreated SH increasing of 20% in the sorption capacity of Pb(2+) ions was observed, but with poor results for Cd(2+) uptake. Additionally, a relatively strong decreasing in both sorption capacities of Pb(2+) and Cd(2+) ions was evidenced for all acidic treatments. Regarding untreated SH, kinetic sorption data of both metals were well-interpreted by a pseudo second-order model and a rate-limiting step on the basis of an intra-particle diffusion model was suggested to occur. An inhibitory effect of Pb(2+) diffusion over Cd(2+) one was observed, limiting to reach the obtained maximum sorption capacity in single system. Maximum adsorption capacities of 0.49 and 0.67mequivg(-1) for Cd(2+) and Pb(2+), respectively, were predicted by the Langmuir isotherm model that reproduced well the equilibrium sorption data for single systems. The inhibitory effect of one metal over the other one was verified in equilibrium sorption data for binary systems interpreted on the basis of a modified extended Langmuir isotherm model, predicting changes in metal affinity onto the SH surface. Finally, SH is an alternative biosorbent with a great potential for the wastewater treatment containing cadmium and lead ions. PMID- 25704747 TI - The effect of sampling strategies on assessment of water quality criteria attainment. AB - Sample locations for large river studies affect the representativeness of data, and thus can alter decisions made regarding river conditions and the need for interventions to improve water quality. The present study evaluated three water quality sampling programs for Total Dissolved Solid (TDS) assessment in the Monongahela River from 2008 to 2012. The sampling plans cover the same 145 km of river but differ in frequency, sample location and type (e.g., river water sample vs drinking water plant intake sample). Differences resulting from temporal and spatial variability in sampling lead to different conclusions regarding water quality in the river (including regulatory listing decisions), especially when low flow leads to concentrations at or near the water quality criteria (500mg/L TDS). Drinking water samples exceeded the criteria 82 out of 650 samples (12.6%), while river water samples exceeded the criteria 47 out of 464 samples (10.1%). Different water sample types could provide different pictures of water quality in the river and lead to different regulatory listing decisions. PMID- 25704748 TI - Impacts of rainfall variability and expected rainfall changes on cost-effective adaptation of water systems to climate change. AB - Stormwater drainage and other water systems are vulnerable to changes in rainfall and runoff and need to be adapted to climate change. This paper studies impacts of rainfall variability and changing return periods of rainfall extremes on cost effective adaptation of water systems to climate change given a predefined system performance target, for example a flood risk standard. Rainfall variability causes system performance estimates to be volatile. These estimates may be used to recurrently evaluate system performance. This paper presents a model for this setting, and develops a solution method to identify cost-effective investments in stormwater drainage adaptations. Runoff and water levels are simulated with rainfall from stationary rainfall distributions, and time series of annual rainfall maxima are simulated for a climate scenario. Cost-effective investment strategies are determined by dynamic programming. The method is applied to study the choice of volume for a storage basin in a Dutch polder. We find that 'white noise', i.e. trend-free variability of rainfall, might cause earlier re investment than expected under projected changes in rainfall. The risk of early re-investment may be reduced by increasing initial investment. This can be cost effective if the investment involves fixed costs. Increasing initial investments, therefore, not only increases water system robustness to structural changes in rainfall, but could also offer insurance against additional costs that would occur if system performance is underestimated and re-investment becomes inevitable. PMID- 25704749 TI - Experimental study designs to improve the evaluation of road mitigation measures for wildlife. AB - An experimental approach to road mitigation that maximizes inferential power is essential to ensure that mitigation is both ecologically-effective and cost effective. Here, we set out the need for and standards of using an experimental approach to road mitigation, in order to improve knowledge of the influence of mitigation measures on wildlife populations. We point out two key areas that need to be considered when conducting mitigation experiments. First, researchers need to get involved at the earliest stage of the road or mitigation project to ensure the necessary planning and funds are available for conducting a high quality experiment. Second, experimentation will generate new knowledge about the parameters that influence mitigation effectiveness, which ultimately allows better prediction for future road mitigation projects. We identify seven key questions about mitigation structures (i.e., wildlife crossing structures and fencing) that remain largely or entirely unanswered at the population-level: (1) Does a given crossing structure work? What type and size of crossing structures should we use? (2) How many crossing structures should we build? (3) Is it more effective to install a small number of large-sized crossing structures or a large number of small-sized crossing structures? (4) How much barrier fencing is needed for a given length of road? (5) Do we need funnel fencing to lead animals to crossing structures, and how long does such fencing have to be? (6) How should we manage/manipulate the environment in the area around the crossing structures and fencing? (7) Where should we place crossing structures and barrier fencing? We provide experimental approaches to answering each of them using example Before After-Control-Impact (BACI) study designs for two stages in the road/mitigation project where researchers may become involved: (1) at the beginning of a road/mitigation project, and (2) after the mitigation has been constructed; highlighting real case studies when available. PMID- 25704750 TI - A phase 2a randomized, double-blind, placebo-controlled, sequential dose escalation study to evaluate the efficacy and safety of ASP015K, a novel Janus kinase inhibitor, in patients with moderate-to-severe psoriasis. AB - BACKGROUND: Many immune-mediated disorders, including psoriasis, involve cytokine signalling via Janus kinase (JAK) enzymes. ASP015K (also designated JNJ 54781532), a novel oral JAK inhibitor, has shown moderate selectivity for JAK3 over JAK1 and JAK2 in enzyme assays. OBJECTIVES: The objective of this study was to evaluate the efficacy and safety of escalating, sequentially grouped, doses of ASP015K vs. placebo in patients with moderate-to-severe psoriasis. METHODS: This phase 2a multicentre, double-blind, randomized, placebo-controlled study (NCT01096862) enrolled 124 patients with moderate-to-severe plaque psoriasis. Five sequential ASP015K cohorts were enrolled, consisting of four twice-daily dosing groups (10, 25, 60, 100 mg) and one once-daily dosing group (50 mg) for 6 weeks. RESULTS: The primary efficacy end point [mean change in Psoriasis Area and Severity Index score from baseline to end of treatment (EOT; day 42)] significantly favoured ASP015K (overall treatment effect; P < 0.001) vs. placebo, with greater improvements at higher doses. By EOT, the secondary end points [Physician Static Global Assessment (PSGA) score, percentage of patients achieving PSGA success, and change in percentage, body surface area (BSA)] also improved with ASP015K vs. placebo (P < 0.001 for PSGA score and BSA; P < 0.01 for PSGA success). Epidermal thickness and proliferation decreased from baseline with ASP015K vs. placebo. ASP015K was generally well tolerated, with no serious adverse events (AEs) reported. CONCLUSIONS: In patients with moderate-to-severe psoriasis, ASP015K demonstrated dose-dependent improvements in clinical and histological measures of severity over 6 weeks of treatment. At all doses, ASP015K was well tolerated, with no reported serious AEs. PMID- 25704751 TI - Fatigue and traumatic brain injury. PMID- 25704752 TI - Enhanced neural responsiveness to reward associated with obesity in the absence of food-related stimuli. AB - BACKGROUND: Obesity has been characterized by alterations in brain structure and function associated with emotion processing and regulation. Particularly, aberrations in food-related reward processing have been frequently demonstrated in obese subjects. However, it remains unclear whether reward-associated functional aberrations in obesity are specific for food-related stimuli or represent a general deficit in reward processing, extending to other stimulus domains. Given the crucial role of rewarding effects in the development of obesity and the ongoing discussion on overlapping neurobiological traits of obesity and psychiatric disorders such as depression and substance-related disorders, this study aimed to investigate the possibility of altered reward processing in obese subjects to occur in the absence of food-related stimuli during a monetary reward condition. METHODS: Twenty-nine healthy obese subjects (body mass index >30) and 29 healthy, age-, and sex-matched control subjects of normal weight underwent functional MRI during a frequently used card guessing paradigm. A Group * Condition (win vs. loss) ANOVA was conducted to investigate differences between obese and normal-weight subjects. RESULTS: We found significant Group * Condition interaction effects in brain areas involved in emotion regulation and reward processing including the insula, the striatum, and the orbitofrontal cortex (OFC). This interaction was predominantly driven by a significant increase in blood oxygenation level dependent (BOLD) response in obese individuals while experiencing reward. CONCLUSIONS: Enhanced neural activation in obesity during reward processing seems to be apparent even in the absence of food-related stimuli and, thus, might point to generalized dysfunctions in reward-related brain circuits in obese individuals. PMID- 25704753 TI - Relationships between diffusing capacity for carbon monoxide (DLCO), and quantitative computed tomography measurements and visual assessment for chronic obstructive pulmonary disease. AB - PURPOSE: To evaluate the relationships between DLCO, and Quantitative CT (QCT) measurements and visual assessment of pulmonary emphysema and to test the relative roles of visual and quantitative assessment of emphysema. MATERIALS AND METHODS: The subjects included 199 current and former cigarette smokers from the COPDGene cohort who underwent inspiratory and expiratory CT and also had diffusing capacity for carbon monoxide corrected for alveolar volume (DLCO/VA). Quantitative CT measurements included % low attenuation areas (%LAA-950ins=voxels <=-950 Hounsfield unit (HU), %LAA-910ins, and %LAA-856ins), mean CT attenuation and 15th percentile HU value on inspiratory CT, and %LAA-856exp (voxels <=-856 HU on expiratory CT). The extent of emphysema was visually assessed using a 5-point grading system. Univariate and multiple variable linear regression analyses were employed to evaluate the correlations between DLCO/VA and QCT parameters and visual extent of emphysema. RESULTS: The DLCO/VA correlated most strongly with 15th percentile HU (R(2)=0.440, p<0.001) closely followed by %LAA-950ins (R(2)=0.417, p<0.001) and visual extent of emphysema (R(2)=0.411, p<0.001). Multiple variable analysis showed that visual extent of emphysema and 15th percentile HU were independent significant predictors of DLCO/VA at an R(2) of 0.599. CONCLUSIONS: 15th percentile HU seems the best parameter to represent the respiratory condition of COPD. Visual and Quantitative CT assessment of emphysema provide complementary information to QCT analysis. PMID- 25704754 TI - An integrated computer-based procedure for teamwork in digital nuclear power plants. AB - Computer-based procedures (CBPs) are expected to improve operator performance in nuclear power plants (NPPs), but they may reduce the openness of interaction between team members and harm teamwork consequently. To support teamwork in the main control room of an NPP, this study proposed a team-level integrated CBP that presents team members' operation status and execution histories to one another. Through a laboratory experiment, we compared the new integrated design and the existing individual CBP design. Sixty participants, randomly divided into twenty teams of three people each, were assigned to the two conditions to perform simulated emergency operating procedures. The results showed that compared with the existing CBP design, the integrated CBP reduced the effort of team communication and improved team transparency. The results suggest that this novel design is effective to optim team process, but its impact on the behavioural outcomes may be moderated by more factors, such as task duration. PRACTITIONER SUMMARY: The study proposed and evaluated a team-level integrated computer-based procedure, which present team members' operation status and execution history to one another. The experimental results show that compared with the traditional procedure design, the integrated design reduces the effort of team communication and improves team transparency. PMID- 25704755 TI - Population size-structure-dependent fitness and ecosystem consequences in Trinidadian guppies. AB - Decades of theory and recent empirical results have shown that evolutionary, population, community and ecosystem properties are the result of feedbacks between ecological and evolutionary processes. The vast majority of theory and empirical research on these eco-evolutionary feedbacks has focused on interactions among population size and mean traits of populations. However, numbers and mean traits represent only a fraction of the possible feedback dimensions. Populations of many organisms consist of different size classes that differ in their impact on the environment and each other. Moreover, rarely do we know the map of ecological pathways through which changes in numbers or size structure cause evolutionary change. The goal of this study was to test the role of size structure in eco-evolutionary feedbacks of Trinidadian guppies and to begin to build an eco-evolutionary map along this unexplored dimension. We used a factorial experiment in mesocosms wherein we crossed high- and low-predation guppy phenotypes with population size structure. We tested the ability of changes in size structure to generate selection on the demographic rates of guppies using an integral projection model (IPM). To understand how fitness differences among high- and low-predation phenotypes may be generated, we measured the response of the biomass of lower trophic levels and nutrient cycling to the different phenotype and size structure treatments. We found a significant interaction between guppy phenotype and the size structure treatments for absolute fitness. Size structure had a very large effect on invertebrate biomass in the mesocosms, but there was little or no effect of the phenotype. The effect of size structure on algal biomass depended on guppy phenotype, with no difference in algal biomass in populations with more, smaller guppies, but a large decrease in algal biomass in mesocosms with phenotypes adapted to low-predation risk. These results indicate an important role for size structure partially driving eco-evolutionary feedbacks in guppies. The changes in the ecosystem suggest that the absence of a steep decline in guppy fitness of the low-predation risk populations is likely due to higher consumption of algae when invertebrates are comparatively rare. Overall, these results demonstrate size structure as a possible dimension through which eco-evolutionary feedbacks may occur in natural populations. PMID- 25704756 TI - The sGC activator inhibits the proliferation and migration, promotes the apoptosis of human pulmonary arterial smooth muscle cells via the up regulation of plasminogen activator inhibitor-2. AB - BACKGROUND: Different types of pulmonary hypertension (PH) share the same process of pulmonary vascular remodeling, the molecular mechanism of which is not entirely clarified by far. The abnormal biological behaviors of pulmonary arterial smooth muscle cells (PASMCs) play an important role in this process. OBJECTIVES: We investigated the regulation of plasminogen activator inhibitor-2 (PAI-2) by the sGC activator, and explored the effect of PAI-2 on PASMCs proliferation, apoptosis and migration. METHODS: After the transfection with PAI 2 overexpression vector and specific siRNAs or treatment with BAY 41-2272 (an activator of sGC), the mRNA and protein levels of PAI-2 in cultured human PASMCs were detected, and the proliferation, apoptosis and migration of PASMCs were investigated. RESULTS: BAY 41-2272 up regulated the endogenous PAI-2 in PASMCs, on the mRNA and protein level. In PAI-2 overexpression group, the proliferation and migration of PASMCs were inhibited significantly, and the apoptosis of PASMCs was increased. In contrast, PAI-2 knockdown with siRNA increased PASMCs proliferation and migration, inhibited the apoptosis. CONCLUSIONS: PAI-2 overexpression inhibits the proliferation and migration and promotes the apoptosis of human PASMCs. Therefore, sGC activator might alleviate or reverse vascular remodeling in PH through the up-regulation of PAI-2. PMID- 25704757 TI - Regulation of high glucose-mediated mucin expression by matrix metalloproteinase 9 in human airway epithelial cells. AB - Mucus hypersecretion is the key manifestation in patients with chronic inflammatory airway diseases and mucin 5AC (MUC5AC) is a major component of airway mucus. Matrix metalloproteinases (MMP)-9, have been found to be involved in the pathogenesis of inflammatory airway diseases. Hyperglycemia has been shown to be an independent risk factor for respiratory infections. We hypothesize that high glucose (HG)-regulates MMP-9 production and MMP-9 activity through nicotinamide adenine dinucleotide phosphate (NADPH)/reactive oxygen species (ROS) cascades pathways, leading to mucin production in human airway epithelial cells (16HBE). We show that HG increases MMP-9 production, MMP-9 activity and MUC5AC expression. These effects are prevented by small interfering RNA (siRNA) for MMP 9, indicating that HG-induced mucin production is MMP-9-dependent. HG activates MMP-9 production, MMP-9 activity and MUC5AC overproduction, which is inhibited by nPG, DMSO and DPI (inhibitors of ROS and NADPH), suggesting that HG-activated mucin synthesis is mediated by NADPH/ROS in 16HBE cells. These observations demonstrate an important role for MMP-9 activated by NADPH/ROS signaling pathways in regulating HG-induced MUC5AC expression. These findings may bring new insights into the molecular pathogenesis of the infections related to diabetes mellitus and lead to novel therapeutic intervention for mucin overproduction in chronic inflammatory airway diseases. PMID- 25704758 TI - Two members of the TRiC chaperonin complex, CCT2 and TCP1 are essential for survival of breast cancer cells and are linked to driving oncogenes. AB - Gene amplification is a common mechanism of oncogene activation in cancer. Several large-scale efforts aimed at identifying the comprehensive set of genomic regions that are recurrently amplified in cancer have been completed. In breast cancer, these studies have identified recurrently amplified regions containing known drivers such as HER2 and CCND1 as well as regions where the driver oncogene is unknown. In this study, we integrated RNAi-based functional genetic data with copy number and expression data to identify genes that are recurrently amplified, overexpressed and also necessary for the growth/survival of breast cancer cells. Further analysis using clinical data from The Cancer Genome Atlas specifically identified candidate genes that play a role in determining patient outcomes. Using this approach, we identified two genes, TCP1 and CCT2, as being recurrently altered in breast cancer, necessary for growth/survival of breast cancer cells in vitro, and determinants of overall survival in breast cancer patients. We also show that expression of TCP1 is regulated by driver oncogene activation of PI3K signaling in breast cancer. Interestingly, the TCP1 and CCT2 genes both encode for components of a multi-protein chaperone complex in the cell known as the TCP1 Containing Ring Complex (TRiC). Our results demonstrate a role for the TRiC subunits TCP1 and CCT2, and potentially the entire TRiC complex, in breast cancer and provide rationale for TRiC as a novel therapeutic target in breast cancer. PMID- 25704759 TI - Assessing the osteoblast transcriptome in a model of enhanced bone formation due to constitutive Gs-G protein signaling in osteoblasts. AB - G protein-coupled receptor (GPCR) signaling in osteoblasts (OBs) is an important regulator of bone formation. We previously described a mouse model expressing Rs1, an engineered constitutively active Gs-coupled GPCR, under the control of the 2.3 kb Col I promoter. These mice showed a dramatic age-dependent increase in trabecular bone of femurs. Here, we further evaluated the effects of enhanced Gs signaling in OBs on intramembranous bone formation by examining calvariae of 1- and 9-week-old Col1(2.3)/Rs1 mice and characterized the in vivo gene expression specifically occurring in osteoblasts with activated Gs G protein-coupled receptor signaling, at the cellular level rather than in a whole bone. Rs1 calvariae displayed a dramatic increase in bone volume with partial loss of cortical structure. By immunohistochemistry, Osterix was detected in cells throughout the inter-trabecular space while Osteocalcin was expressed predominantly in cells along bone surfaces, suggesting the role of paracrine mediators secreted from OBs driven by 2.3 kb Col I promoter could influence early OB commitment, differentiation, and/or proliferation. Gene expression analysis of calvarial OBs revealed that genes affected by Rs1 signaling include those encoding proteins important for cell differentiation, cytokines and growth factors, angiogenesis, coagulation, and energy metabolism. The set of Gs-GPCRs and other GPCRs that may contribute to the observed skeletal phenotype and candidate paracrine mediators of the effect of Gs signaling in OBs were also determined. Our results identify novel detailed in vivo cellular changes of the anabolic response of the skeleton to Gs signaling in mature OBs. PMID- 25704760 TI - Identification of the GTPase-activating protein DEP domain containing 1B (DEPDC1B) as a transcriptional target of Pitx2. AB - Pitx2 is a bicoid-related homeobox transcription factor implicated in regulating left-right patterning and organogenesis. However, only a limited number of Pitx2 downstream target genes have been identified and characterized. Here we demonstrate that Pitx2 is a transcriptional repressor of DEP domain containing 1B (DEPDC1B). The first intron of the human and mouse DEP domain containing 1B genes contains multiple consensus DNA-binding sites for Pitx2. Chromatin immunoprecipitation assays revealed that Pitx2, along with histone deacetylase 1, was recruited to the first intron of Depdc1b. In contrast, RNAi-mediated depletion of Pitx2 not only enhanced the acetylation of histone H4 in the first intron of Depdc1b, but also increased the protein level of Depdc1b. Luciferase reporter assays also showed that Pitx2 could repress the transcriptional activity mediated by the first intron of human DEPDC1B. The GAP domain of DEPDC1B interacted with nucleotide-bound forms of RAC1 in vitro. In addition, exogenous expression of DEPDC1B suppressed RAC1 activation and interfered with actin polymerization induced by the guanine nucleotide exchange factor TRIO. Moreover, DEPDC1B interacted with various signaling molecules such as U2af2, Erh, and Salm. We propose that Pitx2-mediated repression of Depdc1b expression contributes to the regulation of multiple molecular pathways, such as Rho GTPase signaling. PMID- 25704761 TI - Exploring patients' health information communication practices with social network members as a foundation for consumer health IT design. AB - BACKGROUND: There is a need to ensure that the growing number of consumer health information technologies designed to support patient engagement account for the larger social context in which health is managed. Basic research on how patients engage this larger social context is needed as a precursor to the development of patient-centered consumer health information technology (IT) solutions. PURPOSE: The purpose of this study was to inform the broader design of consumer health IT by characterizing patients' existing health information communication practices with their social network members. METHODS: This qualitative study took place between 2010 and 2012 in a Midwestern city. Eighteen patients with chronic conditions participated in a semi-structured interview that was analyzed using qualitative content analysis and descriptive statistics. Emphasis was placed on recruiting a sample representing diverse cultural groups and including participants of low socioeconomic status. RESULTS: Participants' social networks included a wide range of individuals, spanning biological relatives, divinities, and second-degree relationships. Participants' rationales for health information communication reflected seven themes: (1) characteristics and circumstances of the person, (2) characteristics and circumstances of the relationship, (3) structure and composition of the social network, (4) content of the message, (5) orientation of the goal, (6) dimensions of the context, and (7) adaptive practices. CONCLUSIONS: This study demonstrates that patients' health information communication practices are multidimensional, engaging individuals beyond formal and informal caregivers and driven by characteristics of their personal lives and larger social contexts in addition to their health problem. New models of consumer health IT must be created to better align with the realities of patients' communication routines. PMID- 25704762 TI - Evaluating clinical decision support tools for medication administration safety in a simulated environment. AB - OBJECTIVES: The specific aims of this study were to develop a methodology and tools for the design of clinical decision support systems to decrease the incidence of medication administration errors. METHODS: A mixed-methods design was utilized in this study. First, observations of medication administration practice were used to inform the design of a simulated information system with a variety of decision support tools. Then, nurses were observed administering medications in a simulated environment using the simulated system. Finally, the nurses participated in focus groups to provide input into system tools design. Observations of nurses' use of the decision support tools as well as semi structured focus groups were used to evaluate nurses' use and perceptions of the utility of the system decision support tools. RESULTS: Nurses' evaluation of the medication administration decision support tools as well as their actual performance revealed a tendency to underestimate their need for support. Their preferences were for decision support that was short, color coded, and easily accessed. Observations of medication administration showed that nurses exhibit a variety of work processes to prepare and administer medications to patients and access system decision support tools at a variety of points in this process. System design should allow flexibility of multiple points and types of information delivery to accommodate variations in workflow to minimize the tendency for system workarounds. CONCLUSIONS: This study was performed in one hospital and results may not generalize beyond this setting. However, this method used to design and test decision support could be transferred to other settings. Using simulation in this study provided a method for testing new information system design, related to a potentially dangerous procedure, in a manner that eliminated the hazards of potential unintended consequences for patients. PMID- 25704763 TI - A natural HIV p17 protein variant up-regulates the LMP-1 EBV oncoprotein and promotes the growth of EBV-infected B-lymphocytes: implications for EBV-driven lymphomagenesis in the HIV setting. AB - Human immunodeficiency virus p17 matrix protein is released by infected cells and may accumulate within lymphoid tissues where it may deregulate the biological activities of different cell populations by binding to CXCR1 and CXCR2 cellular receptors. S75X, a natural p17 variant, was recently shown to enhance the malignant properties of lymphoma cells. We investigated a reference p17 protein and the S75X variant for their ability to bind to Epstein-Barr virus (EBV) infected primary and fully transformed B-lymphocytes and trigger downstream effects of potential pathogenic relevance. We demonstrate that EBV infection of primary B-lymphocytes or the ectopic expression of the latent membrane protein-1 viral oncoprotein in EBV-negative B-cells up-regulates CXCR2, but not CXCR1. Multispectral imaging flow cytometry showed that EBV-infected primary B-cells more efficiently bind and internalize p17 proteins as compared with activated B lymphocytes. The S75X variant bound more efficiently to EBV-infected primary and fully transformed B-lymphocytes compared with reference p17, because of a higher affinity to CXCR2, and enhanced the proliferation of these cells, an effect associated with cyclin D2 and D3 up-regulation and increased interleukin-6 production. Notably, the S75X variant markedly up-regulated latent membrane protein-1 expression at both mRNA and protein levels and enhanced the activation of Akt, ERK1/2 and STAT3 signaling, thereby contributing to EBV(+) B-cell growth promotion. These results indicate that EBV infection sensitizes B-lymphocytes to CXCR2-mediated effects of p17 proteins and provide evidence supporting a possible contribution of natural p17 variants to EBV-driven lymphomagenesis in the human immunodeficiency virus setting. PMID- 25704764 TI - Sox12, a direct target of FoxQ1, promotes hepatocellular carcinoma metastasis through up-regulating Twist1 and FGFBP1. AB - Metastasis is the main reason for high recurrence and poor survival of hepatocellular carcinoma (HCC) after curative resection. However, the molecular mechanism underlying HCC metastasis remains unclear. Here, we report on a novel function of SRY (sex determining region Y)-box 12 (Sox12), a member of the SYR related high mobility group box family proteins, in promoting HCC metastasis. Overexpression of Sox12 was significantly correlated with loss of tumor encapsulation, microvascular invasion, and a higher tumor-nodule-metastasis (TNM) stage and indicated poor prognosis in human HCC patients. Sox12 expression was an independent and significant risk factor for recurrence and reduced survival after curative resection. Overexpression of Sox12 induced epithelial-mesenchymal transition by transactivating Twist1 expression. Down-regulation of Twist1 decreased Sox12-enhanced HCC migration, invasion, and metastasis, whereas up regulation of Twist1 rescued the decreased migration, invasion, and metastasis induced by Sox12 knockdown. Additionally, serial deletion, site-directed mutagenesis, and chromatin immunoprecipitation assays showed that fibroblast growth factor binding protein 1 (FGFBP1) was a direct transcriptional target of Sox12. Knockdown of FGFBP1 decreased Sox12-mediated HCC invasion and metastasis, whereas overexpression of FGFBP1 rescued the decreased invasion and metastasis induced by Sox12 knockdown. Furthermore, forkhead box Q1 (FoxQ1) directly bound to the Sox12 promoter and transactivated its expression, which contributed to Sox12 overexpression in human HCC. Knockdown of Sox12 dramatically decreased FoxQ1-mediated HCC metastasis. In two independent cohorts of human HCC tissues, Sox12 expression was positively correlated with Twist1, FGFBP1, and FoxQ1 expression, and patients with positive coexpression of Sox12/Twist1, Sox12/FGFBP1, or FoxQ1/Sox12 were associated with poorer prognosis. CONCLUSION: Up-regulated Sox12 induced by FoxQ1 promotes HCC invasion and metastasis by transactivating Twist1 and FGFBP1 expression. Thus, our study implicates Sox12 as a potential prognostic biomarker and a novel therapeutic target for HCC. PMID- 25704765 TI - Deconstructing covalent organocatalysis. AB - Modern organocatalysis has rapidly evolved into an essential component of contemporary organic synthesis. One of the most distinctive aspects of organocatalytic processes is the biomimetic nature in which the catalyst engages the substrate, often forming covalently bound intermediates in a manner reminiscent of enzyme catalysis. Indeed, the process of intramolecularization is often accompanied by a conformational change of the catalyst scaffold, further accentuating this analogy with biological systems. The isolation and study of these catalytic intermediates facilitate the rapid generation of conformation and reactivity profiles to assist in organocatalytic reaction development and/or clarify reaction outcomes. Emulating the formative advances that have derived from studying reaction intermediates in mechanistic organometallic and enzymatic catalysis, the deconstruction of covalently bound organocatalysis intermediates is gaining momentum as a design strategy. PMID- 25704766 TI - The Molecular Mechanisms of Neural Flow Coupling: A New Concept. AB - The phenomenon known as neural flow coupling (NFC) occurs at the capillary level where there are no known pressure controlling structures. Recent developments in advanced magnetic resonance imaging technologies have made possible in vivo direct investigations of water physiology that have shed new insight on the water dynamics of the cortical pericapillary space and their complex functionality in relation to NFC. Neural activities initiate a chain of events that ultimately affect NFC. First, neural activities generate extracellular acidification. Extracellular acidosis in turn produces inhibition of aquaporin-4 (AQP-4) located at the end feet of pericapillary astrocytes, the water channel which regulates water influx into the pericapillary space and, hence, interstitial flow. Reduction of pericapillary water pressure results in a negative balance between pericapillary and intraluminal capillary pressure, allowing for capillary caliber expansion. Proton permeability through the tight junctions of the blood brain barrier is significantly high owing to the Grotthuss proton "tunneling" mechanism and, therefore, carbonic anhydrase (CA) type IV (CA-IV) anchored to the luminal surface of brain capillaries functions as scavenger of extracellular protons. CA IV inhibition by acetazolamide or carbon dioxide results in the accumulation of extracellular protons, causing AQP-4 inhibition and a secondary increase in rCBF. PMID- 25704767 TI - Venous in-stent thrombosis treated by ultrasound accelerated catheter directed thrombolysis. AB - OBJECTIVE/BACKGROUND: Stent placement in the venous system is an increasingly used treatment modality in chronic venous obstruction and as additional treatment after thrombolytic therapy in ilio-femoral deep vein thrombosis (DVT). Experience in treating in-stent thrombosis with ultrasound accelerated catheter directed thrombolysis (UACDT) is reported. METHODS: A retrospective analysis of patients treated for venous stent occlusion, after percutaneous transluminal angioplasty (PTA) and stent placement for either chronic venous occlusive disease or persistent vein compression in patients with acute DVT was performed. Duration of occlusion and suspected clot age were assessed using patient complaints and typical findings on duplex ultrasonography (DUS). DUS and venography were used to assess patency and to determine the cause of re-occlusion. Acute treatment of occlusion was by UACDT. Additional procedures included PTA, stent placement, and creation of an arteriovenous (AV) fistula. RESULTS: Eighteen patients (median age 43 years; 67% male), treated for occluded stent tracts with UACDT between January 2009 and July 2014, were identified. Indications for initial stenting were treatment of chronic venous obstructive disease (12 patients) and treatment of underlying obstruction after initial thrombolysis in acute DVT (six patients). Technical success was achieved in 11/18 (61%) patients. Primary patency in 8/11 patients was 73% at last follow up (median follow up 14 months [range 0-41 months]). Additional treatments after successful lysis were re-stenting (seven patients) and creation of an AV fistula (six patients). CONCLUSION: Treatment with UACDT of recently occluded stent tracts is feasible and effective. Recanalization of the stent tract can be achieved in most cases. Additional interventions were frequently used after successful UACDT treatment. Suboptimal stent positioning caused the majority of the stent occlusions. PMID- 25704768 TI - Comparison of cryogenic and differential flow (forward and reverse fill/flush) modulators and applications to the analysis of heavy petroleum cuts by high temperature comprehensive gas chromatography. AB - The development of new efficient conversion processes to transform heavy petroleum fractions into valuable products, such as diesel, requires improved chemical knowledge of the latter. High-temperature comprehensive gas chromatography (HT-GC * GC) has proven to be a powerful technique for characterizing such complex samples. This paper reports on an evaluation of the performances of four different differential flow modulators, including two original ones that have not been previously described in the literature, in terms of dispersion, peak intensity, peak capacity and overloading. These modulators, all of which are based on Agilent capillary flow technology (CFT), are forward fill/flush (FFF) differential flow modulators with an integrated collection channel or an adjustable channel (new) and reverse fill/flush (RFF) differential flow modulators with an integrated collection channel (new) or an adjustable channel. First, the optimization of the collection channel dimensions is described. Second, an RFF and an FFF differential flow modulator possessing the same collection channel were compared. The reverse differential flow modulation significantly reduced band broadening compared to forward differential flow modulation, and the peak intensity doubled for every modulated peak when an RFF differential flow modulator was used. Then, an RFF differential flow modulator and CO2 dual-jet modulator were compared. Whereas the percentages of separation space used were similar (61% with the HT-GC * GC method using a cryogenic modulator and 59% with the method using an RFF differential flow modulator), the peak capacities were at least three times more important with differential flow modulation due to the greater length of the column used in the second dimension. The results demonstrate that the RFF differential flow modulator is an excellent tool for studying heavy petroleum cuts. It demonstrates the best performances and it is the most versatile modulator. In its two-plate version, it gives more flexibility regarding the set of columns, the flow rates and the modulation periods that can be used compared with the others. PMID- 25704769 TI - On-line comprehensive two-dimensional normal-phase liquid chromatography * reversed-phase liquid chromatography for preparative isolation of Peucedanum praeruptorum. AB - A new on-line comprehensive preparative two-dimensional normal-phase liquid chromatography * reversed-phase liquid chromatography (2D NPLC * RPLC) system was developed for the separation of complicated natural products. It was based on the use of a silica gel packed medium-pressure column as the first dimension and an ODS preparative HPLC column as the second dimension. The two dimensions were connected with normal-phase (NP) and reversed-phase (RP) enrichment units, involving a newly developed airflow assisted adsorption (AAA) technique. The instrument operation and the performance of this NPLC * RPLC separation method were illustrated by gram-scale isolation of ethanol extract from the roots of Peucedanum praeruptorum. In total, 19 compounds with high purity were obtained via automated multi-step preparative separation in a short period of time using this system, and their structures were comprehensively characterized by ESI-MS, (1)H NMR, and (13)C NMR. Including two new compounds, five isomers in two groups with identical HPLC and TLC retention values were also obtained and identified by 1D NMR and 2D NMR. This is the first report of an NPLC * RPLC system successfully applied in an on-line preparative process. This system not only solved the interfacing problem of mobile-phase immiscibility caused by NP and RP separation, it also exhibited apparent advantages in separation efficiency and sample treatment capacity compared with conventional methods. PMID- 25704770 TI - Evaluation of comprehensive two-dimensional gas chromatography with accurate mass time-of-flight mass spectrometry for the metabolic profiling of plant-fungus interaction in Aquilaria malaccensis. AB - To explore the possible obligate interactions between the phytopathogenic fungus and Aquilaria malaccensis which result in generation of a complex array of secondary metabolites, we describe a comprehensive two-dimensional gas chromatography (GC * GC) method, coupled to accurate mass time-of-flight mass spectrometry (TOFMS) for the untargeted and comprehensive metabolic profiling of essential oils from naturally infected A. malaccensis trees. A polar/non-polar column configuration was employed, offering an improved separation pattern of components when compared to other column sets. Four different grades of the oils displayed quite different metabolic patterns, suggesting the evolution of a signalling relationship between the host tree (emergence of various phytoalexins) and fungi (activation of biotransformation). In total, ca. 550 peaks/metabolites were detected, of which tentative identification of 155 of these compounds was reported, representing between 20.1% and 53.0% of the total ion count. These are distributed over the chemical families of monoterpenic and sesquiterpenic hydrocarbons, oxygenated monoterpenes and sesquiterpenes (comprised of ketone, aldehyde, oxide, alcohol, lactone, keto-alcohol and diol), norterpenoids, diterpenoids, short chain glycols, carboxylic acids and others. The large number of metabolites detected, combined with the ease with which they are located in the 2D separation space, emphasises the importance of a comprehensive analytical approach for the phytochemical analysis of plant metabolomes. Furthermore, the potential of this methodology in grading agarwood oils by comparing the obtained metabolic profiles (pattern recognition for unique metabolite chemical families) is discussed. The phytocomplexity of the agarwood oils signified the production of a multitude of plant-fungus mediated secondary metabolites as chemical signals for natural ecological communication. To the best of our knowledge, this is the most complete information available so far about essential oils of A. malaccensis, which represents a valuable extension to available data for advanced studies on microbial-mediated biotransformation of terpenes, and offers promise for potential discovery of unanticipated phytochemicals, and biotechnological exploitation. PMID- 25704771 TI - Simultaneous determination of eperisone hydrochloride and paracetamol in mouse plasma by high performance liquid chromatography-photodiode array detector. AB - This paper reports the validation of a quantitative high performance liquid chromatography-photodiode array (HPLC-PDA) method for the simultaneous analysis, in mouse plasma, of eperisone hydrochloride and paracetamol by protein precipitation using zinc sulphate-methanol-acetonitrile. The analytes were resolved on a Gemini C18 column (4.6 mm * 250 mm; 5 MUm particle size) using a gradient elution mode with a run time of 15 min, comprising re-equilibration, at 60 degrees C (+/- 1 degrees C). The method was validated over the concentration range from 0.5 to 25 MUg/mL for eperisone hydrochloride and paracetamol, in mouse plasma. Ciprofloxacin was used as Internal Standard. Results from assay validations show that the method is selective, sensitive and robust. The limit of quantification of the method was 0.5 MUg/mL for eperisone hydrochloride and paracetamol, and matrix-matched standard curves showed a good linearity, up to 25 MUg/mL with correlation coefficients (r(2))>= 0.9891. In the entire analytical range the intra and inter-day precision (RSD%) values were <= 1.15% and <= 1.46% for eperisone hydrochloride, and <= 0.35% and <= 1.65% for paracetamol. For both analytes the intra and inter-day trueness (bias%) values ranged, respectively, from -5.33% to 4.00% and from -11.4% to -4.00%. The method was successfully tested in pharmacokinetic studies after oral administration in mouse. Furthermore, the application of this method results in a significant reduction in terms of animal number, dosage, and improvement in speed, rate of analysis, and quality of pharmacokinetic parameters related to serial blood sampling. PMID- 25704772 TI - Development of a sensitive and selective liquid chromatography-mass spectrometry method for high throughput analysis of paralytic shellfish toxins using graphitised carbon solid phase extraction. AB - Routine regulatory monitoring of paralytic shellfish toxins (PST) commonly employs oxidative derivitisation and complex liquid chromatography fluorescence detection methods (LC-FL). The pre-column oxidation LC-FL method is currently implemented in New Zealand and the United Kingdom. When using this method positive samples are fractionated and two different oxidations are required to confirm the identity and quantity of each PST analogue present. There is a need for alternative methods that are simpler, provide faster turnaround times and have improved detection limits. Hydrophilic interaction liquid chromatography (HILIC) HPLC-MS/MS analysis of PST has been used for research purposes, but high detection limits and substantial sample matrix issues have prevented it from becoming a viable alternative for routine monitoring purposes. We have developed a HILIC UPLC-MS/MS method for paralytic shellfish toxins with an optimised desalting clean-up procedure on inexpensive carbon solid phase extraction cartridges for reduction of matrix interferences. This represents a major technical breakthrough and allows sensitive, selective and rapid analysis of paralytic shellfish toxins from a variety of sample types, including many commercially produced bivalve molluscan shellfish species. Additionally, this analytical approach avoids the need for complex calculations to determine sample toxicity, as unlike other methods each PST analogue is able to be quantified as a single resolved peak. This article presents the method development and optimisation information. A thorough single laboratory validation study has subsequently been performed and this data will be presented elsewhere. PMID- 25704773 TI - Multicriteria decision analysis in ranking of analytical procedures for aldrin determination in water. AB - The study presents the possibility of multi-criteria decision analysis (MCDA) application when choosing analytical procedures with low environmental impact. A type of MCDA, Preference Ranking Organization Method for Enrichment Evaluations (PROMETHEE), was chosen as versatile tool that meets all the analytical chemists- decision makers requirements. Twenty five analytical procedures for aldrin determination in water samples (as an example) were selected as input alternatives to MCDA analysis. Nine different criteria describing the alternatives were chosen from different groups--metrological, economical and the most importantly--environmental impact. The weights for each criterion were obtained from questionnaires that were sent to experts, giving three different scenarios for MCDA results. The results of analysis show that PROMETHEE is very promising tool to choose the analytical procedure with respect to its greenness. The rankings for all three scenarios placed solid phase microextraction and liquid phase microextraction--based procedures high, while liquid-liquid extraction, solid phase extraction and stir bar sorptive extraction--based procedures were placed low in the ranking. The results show that although some of the experts do not intentionally choose green analytical chemistry procedures, their MCDA choice is in accordance with green chemistry principles. The PROMETHEE ranking results were compared with more widely accepted green analytical chemistry tools--NEMI and Eco-Scale. As PROMETHEE involved more different factors than NEMI, the assessment results were only weakly correlated. Oppositely, the results of Eco-Scale assessment were well-correlated as both methodologies involved similar criteria of assessment. PMID- 25704774 TI - Preparation of the high purity gingerols from ginger by dummy molecularly imprinted polymers. AB - In this work, a dummy molecularly imprinted polymers (MIPs) were developed as the selective sorbents for preparation of the high purity gingerols from ginger for the first time. The dummy template molecule with similar structural skeleton to gingerols, N-vanillylnonanamide, has been designed and synthesized. The performance of the MIPs and non-imprinted polymers (NIPs) were evaluated including selective recognition capacity, adsorption isotherm, and adsorption kinetics. Optimization of various parameters affecting dummy molecular imprinted solid phase extraction (MISPE), such as the type and flow rate of the loading solvent, the composition and volume of the eluting solvent, and the composition and volume of the washing solvent were investigated. Gingerols with the percent recovery of 80 and the percent purity of 99.1 were obtained from the extracts of ginger by MISPE. Besides, gingerols obtained by MISPE had more powerful activity of eliminating free radical compared with extracts before extraction with the MISPE column. Application of MIPs with a high affinity toward three gingerols provides a novel method for obtaining a group of compounds which have likely active groups from natural products. PMID- 25704775 TI - Determination of aromatic sulphur compounds in heavy gas oil by using (low-)flow modulated comprehensive two-dimensional gas chromatography-triple quadrupole mass spectrometry. AB - The present research is focused on the development of a flow-modulated comprehensive two-dimensional gas chromatography-triple quadrupole mass spectrometry (FM GC * GC-MS/MS) method for the determination of classes of aromatic organic sulphur compounds (benzothiophenes, dibenzothiophenes, and benzonaphthothiophene) in heavy gas oil (HGO). The MS/MS instrument was used to provide both full-scan and multiple-reaction-monitoring (MRM) data. Linear retention index (LRI) ranges were used to define the MRM windows for each chemical class. Calibration solutions (internal standard: 1-fluoronaphthalene) were prepared by using an HGO sample, depleted of S compounds. Calibration information was also derived for the thiophene class (along with MRM and LRI data), even though such constituents were not present in the HGO. Linearity was satisfactory over the analyzed concentration range (1-100 mg/L); intra-day precision for the lowest calibration point was always below 17%. Accuracy was also satisfactory, with a maximum percentage error of 3.5% (absolute value) found among the S classes subjected to (semi-)quantification. The highest limit of quantification was calculated to be 299 MUg/L (for the C1-benzothiophene class), while the lowest was 21 MUg/L (for the C4-benzothiophene class). PMID- 25704776 TI - Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF) directly from positive blood culture flasks allows rapid identification of bloodstream infections in immunosuppressed hosts. AB - INTRODUCTION: In immunosuppressed hosts, rapid identification of microorganisms of bloodstream infections is crucial to ensuring effective antimicrobial therapy. Conventional culture requires up to 72 h from sample collection to pathogen identification. METHODS: We used the SepsiTyper Kit and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF; Microflex, Bruker) directly from positive blood culture (BacT/ALERT 3D, FN/FA vials; bioMerieux) in comparison to standard culture methodology (VITEK 2; bioMerieux) for species identification. RESULTS: A total of 62 consecutive positive blood cultures from immunosuppressed patients (solid organ or hematopoietic transplant recipients, or with febrile neutropenia) were analyzed. Culture yielded gram negative bacteria (GNB) in 27/62 (43.5%) and gram-positive (GPB) in 35/62 (56.5%) vials. For GNB, the predominant species identified by MALDI-TOF and confirmed by VITEK were Escherichia coli (16/16 correctly identified) and Enterobacter cloacae (4/4), with a sensitivity and specificity of 92.6% and 100%, respectively. For GPB, predominant species were Staphylococcus aureus (3/3), coagulase-negative staphylococci (12/24), and Enterococcus faecium (6/6) with a sensitivity of 100%, 60%, and 100%, respectively. The median time from blood collection to species identification was 27.4 h with MALDI-TOF identification and 46.6 h with conventional methodology. CONCLUSION: Using MALDI-TOF directly from positive blood cultures allowed a shorter time to identification with high sensitivity and specificity in immunosuppressed patients. PMID- 25704777 TI - [Laparoscopic surgery of benign liver tumours]. AB - 273 patients underwent elective surgical treatment for benign liver lesions at the 1st Surgical Department of Semmelweis University, Budapest, Hungary between 2004 and 2014. Laparoscopic (LAP) interventions were performed in 83 cases. Cyst fenestration in 52, and hepatic resection in 31 cases. LAP liver resections were set against to open surgery of paired group of patients with comparable demographic and clinical parameters. Data revealed that the operative time in LAP group (113.7 min) was significantly longer than that in the open surgery group (89.5 min). The average postoperative length of hospital stay was shorter after LAP surgery (5.8 vs 9.1 days). There was no postoperative complication in the LAP group, two wound infections and one biliary collection were treated by ultrasonic drainage in the open group. Three patients were given blood transfusion in the LAP, four in the open group. Operative mortality was zero, and no reoperation required. The surgical technique which is described in detail in the text enables safe resection of segments 7-8 which are difficult to approach. Our data support the safety and feasibility of laparoscopic liver resection after adequate preoperative investigations. PMID- 25704778 TI - [Nutcracker syndrome - treated by surgery]. AB - The nutcracker syndrome is caused by tight compression of the left renal vein between the superior mesenteric artery and the abdominal aorta. The consequences may vary between symptomfree conditions through moderate proteinuria and hypertension to severe hematuria. All imaging modalities have been used during diagnostic workup. Wide varieties of surgical and endovascular solutions are reported aiming to achieve decompression of the renal vein like venous or arterial transposition, bypass, renal autotransplantation, stenting, nephrectomy, etc. In our case a 21-year-old man the nutcracker syndrome was successfully solved by transposition of the superior mesenteric artery into the infrarenal aorta. PMID- 25704779 TI - [Dilemmas of the reconstruction of the major pelvic artery due to infectious aortic graft complication]. AB - INTRODUCTION: In the pelvic region thrombendarterectomy and bypass procedures are the most commonly performed procedures to treat peripheral artery occlusive diseases with chronic, severe circulation failure caused by atherosclerosis. Biologic and synthetic grafts can also be used in bypass surgeries. Application of synthetic grafts can acutely increase the development of the infectious graft complication and its mortality is still between 70 and 75% in pelvic processes. We describe the difficulties and dilemmas of an infectious aortobifemoral graft. CASE PRESENTATION: 58-year-old female patient with right lower limb trophic ulcer underwent a DSA examination showing a bilateral iliac occlusion and aortobifemoral bypass surgery with Dacron graft implantation was performed. Re occlusion and infection of the graft led to an in situ silver Dacron graft replacement. Due to the one-sided re-occlusion, a femoro-femoral crossover bypass surgery applying silver graft was performed. Despite the previously described procedures the infectious process got worse and autologous deep vein reconstruction was required beside the removal of the infectious synthetic grafts at the same time. DISCUSSION: There are local and extraanatomical solutions to reduce infectious graft complication. In pelvic infections bypass surgeries using autologous deep vein can show the best results. This procedure is the trustworthiest but also the most straining technique due to the extension of surgical time and increased blood loss. The proper surgical strategy should be selected on individual bases including cardiopulmonary load ability, patient age and technical/infrastructural possibilities. PMID- 25704780 TI - [In Process Citation]. PMID- 25704781 TI - [News of the society]. PMID- 25704782 TI - [In Process Citation]. PMID- 25704783 TI - [In Process Citation]. PMID- 25704784 TI - Sustenance and sustainability: maximizing the impact of school gardens on health outcomes. AB - OBJECTIVE: School garden programmes have become popular action-oriented learning environments in many countries, often driven by converging priorities of environmental sustainability and healthful diets. Many of these programmes have assessed the impact on dietary intake, specifically fruit and vegetable intake, and related dietary behaviours, such as knowledge, preference, motivation, intention and self-efficacy to eat and prepare fruit and vegetables. The objective of the present study was twofold: (i) to review published garden-based programmes conducted in schools targeting dietary intake and/or determinants of dietary behaviour in children; and (ii) to identify similar strategies and components employed by these garden-based programmes. DESIGN: The review included thirteen studies that have examined the impact of garden-based programmes conducted in school, either during school hours or in after-school settings, on dietary behaviours in children (kindergarten through 8th grade students). RESULTS: Three of the reviewed studies did not have a comparison or control group and simply evaluated within-group changes after a garden intervention. None of the reviewed studies were randomized, but were assigned based on school's interest and timing of new school gardens being built. Out of the eleven programmes that examined dietary intake, six found that the programme resulted in increased vegetable intake, whereas four showed no effect. Seven of the eight studies that measured preference found that the programmes resulted in increased preference for vegetables. Gardening programmes also resulted in improved attitudes towards, willingness to taste, identification of and self-efficacy to prepare/cook fruit and vegetables. Similar strategies/components employed by the majority of the programmes included: 'hands on' curriculum, incorporation of a cooking component, providing the instructors, parental and stakeholder support, food provision and using the garden as the focal point for media promotion. CONCLUSIONS: Some of the garden programmes resulted in increased vegetable intake, which has positive implications for both environment sustainability and health-related outcomes. Further, the majority resulted in some improvement in behaviour determinants more generally. However, more research is warranted to understand how to achieve long-term improvements in dietary behaviours and how to sustain the garden-based programmes in schools. PMID- 25704785 TI - Musculoskeletal simulation can help explain selective muscle degeneration in Duchenne muscular dystrophy. AB - Duchenne muscular dystrophy (DMD) is a genetic disease that occurs due to the deficiency of the dystrophin protein. Although dystrophin is deficient in all muscles, it is unclear why degeneration progresses differently across muscles in DMD. We hypothesized that each muscle undergoes a different degree of eccentric contraction during gait, which could contribute to the selective degeneration in lower limb muscle, as indicated by various amounts of fatty infiltration. By comparing eccentric contractions quantified from a previous multibody dynamic musculoskeletal gait simulation and fat fractions quantified in a recent imaging study, our preliminary analyses show a strong correlation between eccentric contractions during gait and lower limb muscle fat fractions, supporting our hypothesis. This knowledge is critical for developing safe exercise regimens for the DMD population. This study also provides supportive evidence for using multiscale modeling and simulation of the musculoskeletal system in future DMD research. PMID- 25704787 TI - DNA-ligand interactions gained and lost: light-induced ligand redistribution in a supramolecular cascade. AB - A supramolecular five-component cascade is presented that enables light controlled transport of an in situ modified ligand between three host systems based on the different complexation preferences of cyclodextrin, cucurbituril, and double-stranded DNA. The results point out novel approaches for the control of drug-DNA interactions in DNA-targeting therapy. PMID- 25704788 TI - [Differences in morbidity of neobladder versus ileal conduit: a matched pair analysis on 134 patients]. AB - OBJECTIVE: The objective of this study is to evaluate whether performing an ileal conduit (IC) versus a neobladder(NB) during radical cystectomy (RC) can play a role on the morbidity of the surgical procedure. MATERIALS AND METHODS: At our institution since 2001, a database collecting the data of more than 450 patients who have undergone RC is perspectively maintained.The records of 246 patients submitted to RC and IC and 120 to RC and NB have been reviewed for the present study. By a binary logistic regression model, a propensity score was generated joining these factors: gender,age, smoking habit, Charlson' comorbidity score, platelet antiaggregants or oral anticoagulant therapy, ASA(American Society of Anesthesiologists) score, hydronephrosis, pathologic T stage, and lymphadenectomy. A group of patients submitted to IC and another to NB having the closer propensity score were created with a matching ratio of 1:1. The following features were compared between the two groups: operative time, blood loss,intraoperative complication rate, and postoperative complications rate (overall, clavien 1-2, clavien >=, related toRC, relate to urinary reconstruction).Results: One hundred thirty-four patients were selected, 67 submitted to NB, 67 to IC, well matched according to the desired features. No differences were noted for all the compared features.Conclusion: The morbidity of RC does not seem to be dependent on the choice to perform IC versus NB. PMID- 25704789 TI - The role of renal surgery in the era of targeted therapy: the urologist's perspective. AB - Renal cell carcinoma (RCC) is increasingly diagnosed at an early stage in many countries, which has likely contributed to the recent leveling of RCC mortality. Nevertheless, despite these advances in diagnosis, up to 30% of patients have metastatic RCC at the time of diagnosis, and around 20-30% of subjects undergoing surgery will suffer recurrence. Following the recent approval and introduction in clinical practice of targeted therapies, the role and timing of surgery is being debated. In particular, targeted therapy agents have shown more favorable response rates than immunotherapy in subjects with advanced disease, and this increased efficacy raises the question whether cytoreductive nephrectomy is still beneficial in this subset of patients. On the basis of the current clinical studies, renal surgery seems to play a fundamental role also in the modern targeted therapy era. The optimal timing of surgery and the role of neoadjuvant treatment in advanced cases are still unclear. Furthermore modern urologists must acquire clinical skills in administering neoadjuvant and adjuvant therapy with noncytotoxic therapies, according to a multidisciplinary model of care for the management of patients with advanced RCC. PMID- 25704790 TI - Surgery following neoadjuvant chemotherapy for HER2-positive locally advanced breast cancer. Time to reconsider the standard attitude. AB - BACKGROUND: While the addition of targeted therapy to neoadjuvant chemotherapy (NACT) dramatically increases the rate of pathological complete response in HER2 positive breast cancer, no reduction in the rate of mastectomy has been observed in randomised studies. METHODS: A retrospective single centre analysis of all patients treated with anti HER2-based NACT for T2-4 breast cancer, focusing on patients treated with mastectomy. RESULTS: Among 165 patients treated between June 2005 and July 2012, surgery was performed immediately post-NACT in 152 cases (92%). Breast-conserving surgery could be performed for 108 of the patients (71%), with a 4-year local relapse-free survival of 97%. A mastectomy was performed in two cases following patients' wishes and in 37 cases based on pre NACT findings (n = 18) or post-NACT outcomes (n = 19). For 21 out of the 37 cases, a good pathological response was observed, and multidisciplinary reanalysis suggests that breast-conserving surgery outright may have been sufficient for 12 patients. Finally, a salvage mastectomy based on post lumpectomy pathological results was decided in five cases (11%). The 4-year metastasis-free survival was 84% for all patients operated on after NACT (n = 152). CONCLUSIONS: Given the good efficacy of anti HER2-based NACT, breast conserving surgery should be standard practice for most patients. Total mastectomy on the other hand should be restricted to a few patients, mainly those with positive margins on the lumpectomy specimen. PMID- 25704791 TI - Recellularizing of human acellular dermal matrices imaged by high-definition optical coherence tomography. AB - High-definition optical coherence tomography (HD-OCT) permits real-time 3D imaging of the impact of selected agents on human skin allografts. The real-time 3D HD-OCT assessment of (i) the impact on morphological and cellular characteristics of the processing of human acellular dermal matrices (HADMs) and (ii) repopulation of HADMs in vitro by human fibroblasts and remodelling of the extracellular matrix by these cells. Four different skin decellularization methods, Dispase II/Triton X-100, Dispase II/SDS (sodium dodecyl sulphate), NaCl/Triton X-100 and NaCl/SDS, were analysed by HD-OCT. HD-OCT features of epidermal removal, dermo-epidermal junction (DEJ) integrity, cellularity and dermal architecture were correlated with reflectance confocal microscopy (RCM), histopathology and immunohistochemistry. Human adult dermal fibroblasts were in vitro seeded on the NaCl/Triton X-100 processed HADMs, cultured up to 19 days and evaluated by HD-OCT in comparison with MTT proliferation test and histology. Epidermis was effectively removed by all treatments. DEJ was best preserved after NaCl/Triton X-100 treatment. Dispase II/SDS treatment seemed to remove all cellular debris in comparison with NaCl/Triton X-100 but disturbed the DEJ severely. The dermal micro-architectural structure and vascular spaces of (sub)papillary dermis were best preserved with the NaCl/Triton X-100. The impact on the 3D structure and vascular holes was detrimental with Dispase II/SDS. Elastic fibre fragmentation was only observed after Dispase II incubation. HD-OCT showed that NaCl/Triton X-100 processed matrices permitted in vitro repopulation by human dermal fibroblasts (confirmed by MTT test and histology) and underwent remodelling upon increasing incubation time. Care must be taken in choosing the appropriate processing steps to maintain selected properties of the extracellular matrix in HADMs. Processing HADMs with NaCl/Triton X-100 permits in vitro the proliferation and remodelling activity of human dermal fibroblasts. HD-OCT provides unique real-time and non-invasive 3D imaging of tissue-engineered skin constructs and complementary morphological and cytological information. PMID- 25704792 TI - [Prevalence and factors associated with clinical counselling on drug use among internal specialists residents of Andalusia (Spain)]. AB - OBJECTIVES: To determine the frequency of offering clinical counseling against the consumption of alcohol, tobacco and illegal drugs by internal specialist residents (EIR) of Andalusia, and the factors related to such advice. DESIGN: Multicenter cross-sectional study by self-administered questionnaire sent by mail. SETTING AND PARTICIPANTS: EIR of Andalusia. MAIN MEASUREMENTS: The questionnaire collected the frequency of counseling against the use of alcohol, tobacco and illegal drugs (dependent variable). INDEPENDENT VARIABLES: age/gender, specialty, drug consumption and Fagerstrom test. RESULTS: Out of a total of 4245 participants, 66% responded, 29% did not respond, and 5% poorly completed questionnaires. The mean age was 29.1(+/-SD 5.1) years, 69% female, 89% Spanish nationality, 84% in medical training (73% hospital, 27% family medicine). The frequency of counseling against tobacco (85%) and alcohol (82%) is higher than illegal drugs (56%, p<.001, chi(2) test). Counseling against alcohol consumption is related to family medicine (OR=2.8; 95% CI [1.4-4.6]) and nursing (OR=2.5 [1.7-4.4]), and the age of first alcohol consumption (OR=1.07 [1.03 1.1]). Counseling against smoking is related to family medicine (OR=12.9;[7.6 21.9]) and nursing (OR=8.4;[4.3-16.5]), personal consumption of tobacco (OR=1.5 [1.2-2.0]), and wine (OR=1.1 [1.04-1.3]), and age of first alcohol consumption (OR=1.06 [1.01-1.1]). Counseling against illegal drugs is related to the age of first alcohol consumption (OR=1.09 [1.05-1.1]) and smoking (OR=.58 [.4-.7]). CONCLUSION: There is a high frequency of counseling against consumption of tobacco and alcohol by EIR, although remarkably smaller for illegal drugs. The influencing factors are both formative elements of their own specialty such as personal consumption of alcohol and tobacco, which should be considered for improvement of this preventive activity. PMID- 25704793 TI - [Consensus document for the detection and management of Chagas disease in primary health care in a non-endemic areas]. AB - Chagas disease is caused by the protozoan Trypanosoma cruzi. Although it is commonly transmitted by an insect vector in continental Latin-America, in recent decades, due migration, has been diagnosed in other countries such Spain, the European country with a largest immigrant population of Latin American. For a long time, the patient remains asymptomatic, but some years after this stage, the symptoms can be serious (dilated cardiomyopathy, megacolon, megaesophagus). In addition, detection in pregnant women has a high priority because of the route of vertical transmission. Several specific guidelines about Chagas disease has been developed on the Banks of blood, maternal hospitals, HIV co-infection, organ transplant. But due to the detection of lack of information to primary care professionals, we consider to will be useful this document written and agreed to by family phisicians, pediatricians and specialists in International Health. PMID- 25704794 TI - Effects of medetomidine and xylazine on intraocular pressure and pupil size in healthy Beagle dogs. AB - OBJECTIVE: To determine the effects of intramuscular (IM) administration of medetomidine and xylazine on intraocular pressure (IOP) and pupil size in normal dogs. STUDY DESIGN: Prospective, randomized, experimental, crossover trial. ANIMALS: Five healthy, purpose-bred Beagle dogs. METHODS: Each dog was administered 11 IM injections of, respectively: physiological saline; medetomidine at doses of 5, 10, 20, 40 and 80 MUg kg(-1), and xylazine at doses of 0.5, 1.0, 2.0, 4.0 and 8.0 mg kg(-1). Injections were administered at least 1 week apart. IOP and pupil size were measured at baseline (before treatment) and at 0.25, 0.50, 0.75, 1, 2, 3, 4, 5, 6, 7, 8 and 24 hours post-injection. RESULTS: A significant decrease in IOP was observed at 6 hours after 80 MUg kg(-1) medetomidine compared with values at 0.25 and 0.50 hours, although there were no significant changes in IOP from baseline. In dogs treated with 8.0 mg kg(-1) xylazine, significant reductions in IOP were observed at 4 and 5 hours compared with that at 0.25 hours after administration. In dogs treated with 5, 10, 20 and 40 MUg kg(-1) medetomidine and 0.5, 1.0 and 2.0 mg kg(-1) xylazine, there were no significant changes in IOP. Pupil size did not change significantly after any of the medetomidine or xylazine treatments compared with the baseline value. CONCLUSIONS AND CLINICAL RELEVANCE: Low or moderate doses of medetomidine or xylazine did not induce significant changes in IOP or pupil size. In contrast, high doses of medetomidine or xylazine induced significant changes up to 8 hours after treatment, but values remained within the normal canine physiological range. The results of this study suggest a lack of significant change in IOP and pupil size in healthy dogs administered low or moderate doses of xylazine or medetomidine. PMID- 25704795 TI - Developing professional attributes in critical care nurses using Team-Based Learning. AB - Australian nurses prepare for specialty practice by undertaking postgraduate theoretical and clinical education in partnership models between universities and hospitals. In our global healthcare system, nurses require advanced critical thinking and strong communication skills to provide safe, high quality patient care. Yet, few education programs focus on developing these skills. Team-Based Learning (TBL) is a specific educational strategy that encourages and rewards students to think critically and solve clinical problems individually and in teams. The aim of this study was to investigate critical care nursing students' perceptions and experiences of TBL after it was introduced into the second half of their postgraduate specialty course. Following Ethics Committee approval, thirty-two students were invited to participate in an extended response questionnaire on their perceptions of TBL as part of a larger study. Data were analyzed thematically. Postgraduate students perceived their professional growth was accelerated due to the skills and knowledge acquired through TBL. Four themes underpinned the development and accelerated acquisition of specialty nurse attributes due to TBL: Engagement, Learning Effectiveness, Critical Thinking, and Motivation to Participate. Team-Based Learning offered deep and satisfying learning experiences for students. The early acquisition of advanced critical thinking, teamwork and communication skills, and specialty practice knowledge empowered nurses to provide safe patient care with confidence. PMID- 25704796 TI - Anti-hyperglycemic and anti-hyperlipidemic effects of Vaccinium myrtillus fruit in experimentally induced diabetes (antidiabetic effect of Vaccinium myrtillus fruit). AB - BACKGROUND: Diabetes mellitus (DM) is a metabolic disorder that is associated with an increased risk of cardiovascular disease. Vaccinium myrtillus (bilberry) is a useful plant with antidiabetic properties in traditional medicine. The aim of this study was to investigate the effects of bilberry against DM. Diabetes was induced using intraperitoneal injection of alloxan (120 mg kg(-1) body weight (BW)). Bilberry powder (2 g d(-1)) and glibenclamide (positive control; 0.6 mg kg(-1) BW) were administered for 4 weeks following alloxan injection. Serum glucose, insulin, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), very-low-density lipoprotein cholesterol (VLDL-C), triglycerides (TG) and C-reactive protein (CRP) were determined at baseline and at 2nd and 4th week of the study. RESULTS: Bilberry supplementation resulted in a significant reduction of glucose compared with the diabetic control as well as glibenclamide treatment. Bilberry elevated insulin, reduced TC, LDL-C, VLDL-C and TG levels, and prevented HDL-C decline. Serum insulin, TC and LDL-C levels were not affected by glibenclamide, and CRP did not significantly change with either bilberry or glibenclamide. Histological examinations revealed a significant elevation of islet size in the bilberry and glibenclamide-treated groups. CONCLUSION: Dietary supplementation with bilberry fruits may protect against impaired glucose and lipid metabolism in DM. PMID- 25704797 TI - Comparative epidemiology and virology of fatal and nonfatal cases of hand, foot and mouth disease in mainland China from 2008 to 2014. AB - This study aimed to analyze the epidemiology and virology of fatal and nonfatal hand, foot, and mouth disease (HFMD) cases in Mainland China. A total of 10,714,237 survivors and 3046 deaths were reported from 2008 to 2014 June, with a case fatality rate of 0.03%. The morbidity of the survivors increased from 37.6/100,000 in 2008 to 139.6/100,000 in 2013 and peaked in 2012 at 166.8/100,000. However, the mortality varied around 0.03-0.04/100,000 across the time. Most of the survivors were distributed in the southern and eastern China, predominantly in the Guangxi and Hainan Province, whereas deaths were dominant in southern (Guangxi) and southwestern (Guizhou) China. The two groups showed similar seasonal fluctuations from 2008 to 2014, peaking in spring and early summer. Of the total cases, 93.97% were children less than 5 years of age, with those <= 2 years old accounting for 60.08% versus 84.02% in the survivor and death groups, respectively. Boys were at higher risk of infection than girls in both groups. Five years of virological surveillance showed that 43.73%, 22.04%, and 34.22% of HFMD cases were due to EV71, CoxA16 and other enteroviruses, respectively. EV71 was encountered in most deaths, with no substantial effect of age, gender, month, and year on incidence. Subgenotype C4a was the prevalent EV71 strain in Mainland China, with no significant difference in the VP1 gene related to virulence between the two groups. In conclusion, based on the largest population study, fatal and nonfatal HFMD cases, mainly caused by C4a of EV71, are circulating in Mainland China with a low-cause fatality rate. PMID- 25704798 TI - Changes in delta(13)C of dark respired CO2 and organic matter of different organs during early ontogeny in peanut plants. AB - Carbon isotope composition in respired CO2 and organic matter of individual organs were measured on peanut seedlings during early ontogeny in order to compare fractionation during heterotrophic growth and transition to autotrophy in a species with lipid seed reserves with earlier results obtained on beans. Despite a high lipid content in peanut seeds (48%) compared with bean seeds (1.5%), the isotope composition of leaf- and root-respired CO2 as well as its changes during ontogeny were similar to already published data on bean seedlings: leaf-respired CO2 became (13)C-enriched reaching -21.50/00, while root-respired CO2 became (13)C-depleted reaching around -310/00 at the four-leaf stage. The opposite respiratory fractionation in leaves vs. roots already reported for C3 herbs was thus confirmed for peanuts. However, contrarily to beans, the peanut cotyledon-respired CO2 was markedly (13)C-enriched, and its (13)C-depletion was noted from the two-leaf stage onwards only. Carbohydrate amounts being very low in peanut seeds, this cannot be attributed solely to their use as respiratory substrate. The potential role of isotope fractionation during glyoxylate cycle and/or gluconeogenesis on the (13)C-enriched cotyledon-respired CO2 is discussed. PMID- 25704799 TI - On archaeal homologs of the human RNase P proteins Pop5 and Rpp30 in the hyperthermophilic archaeon Thermococcus kodakarensis. AB - The ribonuclease P (RNase P) proteins TkoPop5 and TkoRpp30, homologs of human Pop5 and Rpp30, respectively, in the hyperthermophilic archaeon Thermococcus kodakarensis were prepared and characterized with respect to pre-tRNA cleavage activity using the reconstitution system of the well-studied Pyrococcus horikoshii RNase P. The reconstituted particle containing TkoPop5 in place of the P. horikoshii counterpart PhoPop5 retained pre-tRNA cleavage activity comparable to that of the reconstituted P. horikoshii RNase P, while that containing TkoRpp30 instead of its corresponding protein PhoRpp30 had slightly lower activity than the P. horikoshii RNase P. Moreover, we determined crystal structures of TkoRpp30 alone and in complex with TkoPop5. Like their P. horikoshii counterparts, whose structures were solved previously, TkoRpp30 and TkoPop5 fold into TIM barrel and RRM-like fold, respectively. This finding demonstrates that RNase P proteins in T. kodakarensis and P. horikoshii are interchangeable and that their three-dimensional structures are highly conserved. PMID- 25704800 TI - Identification of secreted proteins as novel antigenic vaccine candidates of Haemophilus parasuis serovar 5. AB - Haemophilus parasuis (H. parasuis) is a swine pathogen responsible for the Glasser's disease, which has received more attention in the past decade due to the increasing economic losses in the pig industry worldwide. As traditional inactive vaccine of H. parasuis has obvious disadvantage, to identify efficient immunoprotective antigens would undoubtedly contribute to the development of novel subunit vaccines. The putative secreted proteins of H. parasuis are potentially essential components of more potent vaccines. In the present study, six secreted proteins (PflA, Gcp, Ndk, HsdS, RnfC and HAPS_0017) were selected from the annotated H. parasuis serovar 5 genome as immunogenic protein with bioinformatic and experimental approaches. These proteins were successfully expressed in Escherichia coli and their immunogenicity was assessed in a mouse challenge model. The results showed that subcutaneous injection with the recombinant proteins resulted in the production of antibodies with high levels. Antigen-specific lymphoproliferative responses were detected in the splenocytes of the immunized animals. CD4(+) T-cell populations were higher in the vaccinated animals 3 weeks after the booster immunization than those of the control animals. A significant increase was observed in the cytokine levels of IL-2, IL-4 and IFN gamma in the culture supernatants of splenocytes. Furthermore, immunized mice conferred different levels of protection against challenge with a lethal dose of highly virulent serovar 5 strain (H46). Our results indicate that these six secreted proteins induced a good Th1 response and protection against H. parasuis infection, could be potential subunit vaccine candidates. PMID- 25704801 TI - Development and release of a national immunization app for Canada (ImmunizeCA). AB - Digital technology has created an opportunity to reenvision the traditional immunization paper record. We describe our experience developing a government endorsed mobile immunization record in Canada. The smartphone app, ImmunizeCA is designed to assist individuals in managing their own health information. It allows individuals to store their and their family's immunization records on their smartphone. The app, which is populated by data provided by the user, contains all 13 provincial and territorial schedules, immunization information and outbreak alerts on vaccine preventable diseases. Our experience suggests mobile apps can serve as a mechanism to empower users, increase participation in the process of immunization, potentially improve immunization rates and address jurisdictional obstacles. Key measures of success will include long term uptake, acceptability as an official record, enabling data flow permitting integration with immunization information systems and the ability to rapidly iterate to address changes to both immunization practice and mobile technology. PMID- 25704802 TI - Maternal Antenatal Attachment Scale (MAAS): adaptation to Spanish and proposal for a brief version of 12 items. AB - The psychometric properties of the adapted Spanish version of the Maternal Antenatal Attachment Scale were examined. The main goal was to investigate the reliability and construct validity of the conceptual structure of Condon's proposal. Five hundred twenty-five pregnant women, attending maternal education classes in Bizkaia (Spain), answered the translated and back-translated version of the Maternal Antenatal Attachment Scale. This scale comprises 19 items with five answer choices divided into two subscales: quality of attachment and intensity of attachment. Participants also answered a questionnaire about the reproductive history that was developed ad hoc for the present study. The Spanish adaptation of the Maternal Antenatal Attachment Scale final version comprises 12 items: seven items have been removed due to their inadequate psychometric properties. Internal consistency of the inventory is moderate-high (.73) and it ranges from .68 (intensity of attachment) to .75 (quality of attachment) for the dimensions. Three alternative structural models were proven using a confirmatory factor analysis. Lastly, the two-related-factor model was chosen, as it obtained suitable fit indexes (chi (2) = 102.28; p < .001; goodness-of-fit index (GFI) = .92; comparative fit index (CFI) = .95; root mean square error of approximation (RMSEA) = .042, 90 % CI [.030-.054]). Due to its adequate psychometric properties, the Spanish version of the Maternal Antenatal Attachment Scale can be proposed as a suitable instrument for the purpose of measuring antenatal attachment. The study of antenatal attachment helps to detect possible difficulties for the mother in establishing an affective relationship with the foetus. This may affect the foetus growth, delivery and the future mother-child relationship. PMID- 25704803 TI - [Promote better nutritional behaviours among shift workers with night shift]. AB - AIM: Shift work, especially including a night shift, is associated with degradation of physical, social and psychosocial health as well as poor well being. Food imbalance and low physical activity contributed to the negative effects on health. Our objective was to promote a healthier nutritional behaviour according to the French national nutrition and health program recommendations (PNNS). METHODS: A one-year nutritional intervention with personalised dietetic counselling was proposed to 235 shift workers with night shift who came for a health prevention exam in one of the centres of the Institut Inter-Regional pour la Sante between 2009 and 2011. The intervention was three dietary interviews: at baseline with definition of goal setting, at 3 months for advice and support and at one-year for the evaluation. At 6 months, a personalised reminder letter was send. Compliance with the PNNS recommendations and level of physical activity were evaluated at baseline and at one-year by a self-administered questionnaire. Changes between baseline and follow-up were compared by paired t-tests or McNemar tests. RESULTS: The rate of follow-up was 57.4%. At the end of the study, subjects improved their compliance with PNNS guidelines concerning sweetened products (P<0.001), water (P=0.02) and salt (P=0.05), increased their leisure physical activity (P=0.001) and decreased their daily energy intakes (P<0.001). CONCLUSION: A structured intervention can improve nutritional behaviours of shift workers. This intervention enabled to inform and alert on the risk related to this work schedule and promote better nutritional behaviours. PMID- 25704804 TI - [Parsonage-Turner syndrome following varicella-zoster virus infection]. PMID- 25704805 TI - Gastric-type expression signature in serrated pathway-associated colorectal tumors. AB - Accumulating evidence has indicated that serrated pathway-associated colorectal tumors may be associated with aberrant gastric-type differentiation. Here, we investigated the immunoexpression profiles of gastric-type markers and intestinal type markers in colorectal tumors, focusing on their relation to serrated pathway associated tumors. Immunohistochemistry for 7 gastric-type markers (ANXA10, VSIG1, CLDN18, CTSE, TFF2, MUC5AC, and MUC6) and 2 intestinal-type markers (CDX2 and CK20) was performed in 36 normal gastric/colorectal mucosa tissues, 163 colorectal polyps, and 175 microsatellite-unstable colorectal carcinomas (MSI-H CRCs). In normal tissues, all 7 candidate gastric-type markers showed expressional specificity for normal gastric mucosa. Among the colorectal polyps, sessile serrated adenoma/polyps demonstrated the highest positive rate of ANXA10, CLDN18, MUC5AC, and MUC6 expression (87%, 35%, 61%, and 52%, respectively). Microvesicular hyperplastic polyps showed the highest frequencies of ANXA10, VSIG1, and TFF2 positivity (87%, 87%, and 67%, respectively). ANXA10 and MUC6 expression was not detected in all conventional adenomas. In MSI-H CRCs, the expression of ANXA10, TFF2, and MUC5AC was significantly associated with sporadic tumors (P < .001, P = .01, and P < .001, respectively). Moreover, all of the 7 gastric-type markers were significantly related to preferential expression in proximal colon carcinomas among MSI-H CRCs. CDX2 and CK20 expression was retained in all colorectal polyps, whereas there were significantly high frequencies of CDX2 loss (28%) and CK20 loss (29%) in sporadic tumors among MSI-H CRCs. In conclusion, the early gain of gastric differentiation and late loss of intestinal differentiation are immunophenotypic features in the serrated pathway to colorectal carcinoma. PMID- 25704806 TI - Adenosine A2b receptors control A1 receptor-mediated inhibition of synaptic transmission in the mouse hippocampus. AB - Adenosine is a neuromodulator mostly acting through A1 (inhibitory) and A2A (excitatory) receptors in the brain. A2B receptors (A(2B)R) are G(s/q)--protein coupled receptors with low expression in the brain. As A(2B)R function is largely unknown, we have now explored their role in the mouse hippocampus. We performed electrophysiological extracellular recordings in mouse hippocampal slices, and immunological analysis of nerve terminals and glutamate release in hippocampal slices and synaptosomes. Additionally, A(2B)R-knockout (A(2B)R-KO) and C57/BL6 mice were submitted to a behavioural test battery (open field, elevated plus maze, Y-maze). The A(2B)R agonist BAY60-6583 (300 nM) decreased the paired-pulse stimulation ratio, an effect prevented by the A(2B)R antagonist MRS 1754 (200 nM) and abrogated in A(2B)R-KO mice. Accordingly, A(2B)R immunoreactivity was present in 73 +/- 5% of glutamatergic nerve terminals, i.e. those immunopositive for vesicular glutamate transporters. Furthermore, BAY 60-6583 attenuated the A(1)R control of synaptic transmission, both the A(1)R inhibition caused by 2 chloroadenosine (0.1-1 MUM) and the disinhibition caused by the A(1)R antagonist DPCPX (100 nM), both effects prevented by MRS 1754 and abrogated in A(2B)R-KO mice. BAY 60-6583 decreased glutamate release in slices and also attenuated the A(1)R inhibition (CPA 100 nM). A(2B)R-KO mice displayed a modified exploratory behaviour with an increased time in the central areas of the open field, elevated plus-maze and the Y-maze and no alteration of locomotion, anxiety or working memory. We conclude that A(2B)R are present in hippocampal glutamatergic terminals where they counteract the predominant A(1)R-mediated inhibition of synaptic transmission, impacting on exploratory behaviour. PMID- 25704807 TI - Delayed dopamine signaling of energy level builds appetitive long-term memory in Drosophila. AB - Sensory cues relevant to a food source, such as odors, can be associated with post-ingestion signals related either to food energetic value or toxicity. Despite numerous behavioral studies, a global understanding of the mechanisms underlying these long delay associations remains out of reach. Here, we demonstrate in Drosophila that the long-term association between an odor and a nutritious sugar depends on delayed post-ingestion signaling of energy level. We show at the neural circuit level that the activity of two pairs of dopaminergic neurons is necessary and sufficient to signal energy level to the olfactory memory center. Accordingly, we have identified in these dopaminergic neurons a delayed calcium trace that correlates with appetitive long-term memory formation. Altogether, these findings demonstrate that the Drosophila brain remembers food quality through a two-step mechanism that consists of the integration of olfactory and gustatory sensory information and then post-ingestion energetic value. PMID- 25704808 TI - Broadcasting of cortical activity to the olfactory bulb. AB - Odor representations are initially formed in the olfactory bulb, which contains a topographic glomerular map of odor molecular features. The bulb transmits sensory information directly to piriform cortex, where it is encoded by distributed ensembles of pyramidal cells without spatial order. Intriguingly, piriform cortex pyramidal cells project back to the bulb, but the information contained in this feedback projection is unknown. Here, we use imaging in awake mice to directly monitor activity in the presynaptic boutons of cortical feedback fibers. We show that the cortex provides the bulb with a rich array of information for any individual odor and that cortical feedback is dependent on brain state. In contrast to the stereotyped, spatial arrangement of olfactory bulb glomeruli, cortical inputs tuned to different odors commingle and indiscriminately target individual glomerular channels. Thus, the cortex modulates early odor representations by broadcasting sensory information diffusely onto spatially ordered bulbar circuits. PMID- 25704809 TI - Focal MMP-2 and MMP-9 activity at the blood-brain barrier promotes chemokine induced leukocyte migration. AB - Although chemokines are sufficient for chemotaxis of various cells, increasing evidence exists for their fine-tuning by selective proteolytic processing. Using a model of immune cell chemotaxis into the CNS (experimental autoimmune encephalomyelitis [EAE]) that permits precise localization of immigrating leukocytes at the blood-brain barrier, we show that, whereas chemokines are required for leukocyte migration into the CNS, additional MMP-2/9 activities specifically at the border of the CNS parenchyma strongly enhance this transmigration process. Cytokines derived from infiltrating leukocytes regulate MMP-2/9 activity at the parenchymal border, which in turn promotes astrocyte secretion of chemokines and differentially modulates the activity of different chemokines at the CNS border, thereby promoting leukocyte migration out of the cuff. Hence, cytokines, chemokines, and cytokine-induced MMP-2/9 activity specifically at the inflammatory border collectively act to accelerate leukocyte chemotaxis across the parenchymal border. PMID- 25704810 TI - Bruton's tyrosine kinase phosphorylates DDX41 and activates its binding of dsDNA and STING to initiate type 1 interferon response. AB - The innate immune system senses cytosolic dsDNA and bacterial cyclic dinucleotides and initiates signaling via the adaptor STING to induce type 1 interferon (IFN) response. We demonstrate here that BTK-deficient cells have impaired IFN-beta production and TBK1/IRF3 activation when stimulated with agonists or infected with pathogens that activate STING signaling. BTK interacts with STING and DDX41 helicase. The kinase and SH3/SH2 interaction domains of BTK bind, respectively, the DEAD-box domain of DDX41 and transmembrane region of STING. BTK phosphorylates DDX41, and its kinase activities are critical for STING mediated IFN-beta production. We show that Tyr364 and Tyr414 of DDX41 are critical for its recognition of AT-rich DNA and binding to STING, and tandem mass spectrometry identifies Tyr414 as the BTK phosphorylation site. Modeling studies further indicate that phospho-Tyr414 strengthens DDX41's interaction with STING. Hence, BTK plays a critical role in the activation of DDX41 helicase and STING signaling. PMID- 25704811 TI - Targeting vascular pericytes in hypoxic tumors increases lung metastasis via angiopoietin-2. AB - Strategies to target angiogenesis include inhibition of the vessel-stabilizing properties of vascular pericytes. Pericyte depletion in early-stage non-hypoxic tumors suppressed nascent angiogenesis, tumor growth, and lung metastasis. In contrast, pericyte depletion in advanced-stage hypoxic tumors with pre established vasculature resulted in enhanced intra-tumoral hypoxia, decreased tumor growth, and increased lung metastasis. Furthermore, depletion of pericytes in post-natal retinal blood vessels resulted in abnormal and leaky vasculature. Tumor transcriptome profiling and biological validation revealed that angiopoietin signaling is a key regulatory pathway associated with pericyte targeting. Indeed, pericyte targeting in established mouse tumors increased angiopoietin-2 (ANG2/Angpt2) expression. Depletion of pericytes, coupled with targeting of ANG2 signaling, restored vascular stability in multiple model systems and decreased tumor growth and metastasis. Importantly, ANGPT2 expression correlated with poor outcome in patients with breast cancer. These results emphasize the potential utility of therapeutic regimens that target pericytes and ANG2 signaling in metastatic breast cancer. PMID- 25704812 TI - Epigenome mapping reveals distinct modes of gene regulation and widespread enhancer reprogramming by the oncogenic fusion protein EWS-FLI1. AB - Transcription factor fusion proteins can transform cells by inducing global changes of the transcriptome, often creating a state of oncogene addiction. Here, we investigate the role of epigenetic mechanisms in this process, focusing on Ewing sarcoma cells that are dependent on the EWS-FLI1 fusion protein. We established reference epigenome maps comprising DNA methylation, seven histone marks, open chromatin states, and RNA levels, and we analyzed the epigenome dynamics upon downregulation of the driving oncogene. Reduced EWS-FLI1 expression led to widespread epigenetic changes in promoters, enhancers, and super enhancers, and we identified histone H3K27 acetylation as the most strongly affected mark. Clustering of epigenetic promoter signatures defined classes of EWS-FLI1-regulated genes that responded differently to low-dose treatment with histone deacetylase inhibitors. Furthermore, we observed strong and opposing enrichment patterns for E2F and AP-1 among EWS-FLI1-correlated and anticorrelated genes. Our data describe extensive genome-wide rewiring of epigenetic cell states driven by an oncogenic fusion protein. PMID- 25704813 TI - Analysis of p53 transactivation domain mutants reveals Acad11 as a metabolic target important for p53 pro-survival function. AB - The p53 tumor suppressor plays a key role in maintaining cellular integrity. In response to diverse stress signals, p53 can trigger apoptosis to eliminate damaged cells or cell-cycle arrest to enable cells to cope with stress and survive. However, the transcriptional networks underlying p53 pro-survival function are incompletely understood. Here, we show that in oncogenic-Ras expressing cells, p53 promotes oxidative phosphorylation (OXPHOS) and cell survival upon glucose starvation. Analysis of p53 transcriptional activation domain mutants reveals that these responses depend on p53 transactivation function. Using gene expression profiling and ChIP-seq analysis, we identify several p53-inducible fatty acid metabolism-related genes. One such gene, Acad11, encoding a protein involved in fatty acid oxidation, is required for efficient OXPHOS and cell survival upon glucose starvation. This study provides new mechanistic insight into the pro-survival function of p53 and suggests that targeting this pathway may provide a strategy for therapeutic intervention based on metabolic perturbation. PMID- 25704814 TI - A mitochondria-specific isoform of FASTK is present in mitochondrial RNA granules and regulates gene expression and function. AB - The mitochondrial genome relies heavily on post-transcriptional events for its proper expression, and misregulation of this process can cause mitochondrial genetic diseases in humans. Here, we report that a novel translational variant of Fas-activated serine/threonine kinase (FASTK) co-localizes with mitochondrial RNA granules and is required for the biogenesis of ND6 mRNA, a mitochondrial-encoded subunit of the NADH dehydrogenase complex (complex I). We show that ablating FASTK expression in cultured cells and mice results specifically in loss of ND6 mRNA and reduced complex I activity in vivo. FASTK binds at multiple sites along the ND6 mRNA and its precursors and cooperates with the mitochondrial degradosome to ensure regulated ND6 mRNA biogenesis. These data provide insights into the mechanism and control of mitochondrial RNA processing within mitochondrial RNA granules. PMID- 25704815 TI - HP1 is involved in regulating the global impact of DNA methylation on alternative splicing. AB - The global impact of DNA methylation on alternative splicing is largely unknown. Using a genome-wide approach in wild-type and methylation-deficient embryonic stem cells, we found that DNA methylation can either enhance or silence exon recognition and affects the splicing of more than 20% of alternative exons. These exons are characterized by distinct genetic and epigenetic signatures. Alternative splicing regulation of a subset of these exons can be explained by heterochromatin protein 1 (HP1), which silences or enhances exon recognition in a position-dependent manner. We constructed an experimental system using site specific targeting of a methylated/unmethylated gene and demonstrate a direct causal relationship between DNA methylation and alternative splicing. HP1 regulates this gene's alternative splicing in a methylation-dependent manner by recruiting splicing factors to its methylated form. Our results demonstrate DNA methylation's significant global influence on mRNA splicing and identify a specific mechanism of splicing regulation mediated by HP1. PMID- 25704816 TI - Muscle stem cell fate is controlled by the cell-polarity protein Scrib. AB - Satellite cells are resident skeletal muscle stem cells that supply myonuclei for homeostasis, hypertrophy, and repair in adult muscle. Scrib is one of the major cell-polarity proteins, acting as a potent tumor suppressor in epithelial cells. Here, we show that Scrib also controls satellite-cell-fate decisions in adult mice. Scrib is undetectable in quiescent cells but becomes expressed during activation. Scrib is asymmetrically distributed in dividing daughter cells, with robust accumulation in cells committed to myogenic differentiation. Low Scrib expression is associated with the proliferative state and preventing self renewal, whereas high Scrib levels reduce satellite cell proliferation. Satellite cell-specific knockout of Scrib in mice causes a drastic and insurmountable defect in muscle regeneration. Thus, Scrib is a regulator of tissue stem cells, controlling population expansion and self-renewal with Scrib expression dynamics directing satellite cell fate. PMID- 25704817 TI - Feedback inhibition of CREB signaling promotes beta cell dysfunction in insulin resistance. AB - Although persistent elevations in circulating glucose concentrations promote compensatory increases in pancreatic islet mass, unremitting insulin resistance causes deterioration in beta cell function that leads to the progression to diabetes. Here, we show that mice with a knockout of the CREB coactivator CRTC2 in beta cells have impaired oral glucose tolerance due to decreases in circulating insulin concentrations. CRTC2 was found to promote beta cell function in part by stimulating the expression of the transcription factor MafA. Chronic hyperglycemia disrupted cAMP signaling in pancreatic islets by activating the hypoxia inducible factor (HIF1)-dependent induction of the protein kinase A inhibitor beta (PKIB), a potent inhibitor of PKA catalytic activity. Indeed, disruption of the PKIB gene improved islet function in the setting of obesity. These results demonstrate how crosstalk between nutrient and hormonal pathways contributes to loss of pancreatic islet function. PMID- 25704818 TI - Vascular endothelial growth factor receptor 3 controls neural stem cell activation in mice and humans. AB - Neural stem cells (NSCs) continuously produce new neurons within the adult mammalian hippocampus. NSCs are typically quiescent but activated to self-renew or differentiate into neural progenitor cells. The molecular mechanisms of NSC activation remain poorly understood. Here, we show that adult hippocampal NSCs express vascular endothelial growth factor receptor (VEGFR) 3 and its ligand VEGF C, which activates quiescent NSCs to enter the cell cycle and generate progenitor cells. Hippocampal NSC activation and neurogenesis are impaired by conditional deletion of Vegfr3 in NSCs. Functionally, this is associated with compromised NSC activation in response to VEGF-C and physical activity. In NSCs derived from human embryonic stem cells (hESCs), VEGF-C/VEGFR3 mediates intracellular activation of AKT and ERK pathways that control cell fate and proliferation. These findings identify VEGF-C/VEGFR3 signaling as a specific regulator of NSC activation and neurogenesis in mammals. PMID- 25704819 TI - ROCK-isoform-specific polarization of macrophages associated with age-related macular degeneration. AB - Age is a major risk factor in age-related macular degeneration (AMD), but the underlying cause is unknown. We find increased Rho-associated kinase (ROCK) signaling and M2 characteristics in eyes of aged mice, revealing immune changes in aging. ROCK isoforms determine macrophage polarization into M1 and M2 subtypes. M2-like macrophages accumulated in AMD, but not in normal eyes, suggesting that these macrophages may be linked to macular degeneration. M2 macrophages injected into the mouse eye exacerbated choroidal neovascular lesions, while M1 macrophages ameliorated them, supporting a causal role for macrophage subtypes in AMD. Selective ROCK2 inhibition with a small molecule decreased M2-like macrophages and choroidal neovascularization. ROCK2 inhibition upregulated M1 markers without affecting macrophage recruitment, underlining the plasticity of these macrophages. These results reveal age-induced innate immune imbalance as underlying AMD pathogenesis. Targeting macrophage plasticity opens up new possibilities for more effective AMD treatment. PMID- 25704820 TI - Transcriptome analysis of individual stromal cell populations identifies stroma tumor crosstalk in mouse lung cancer model. AB - Emerging studies have begun to demonstrate that reprogrammed stromal cells play pivotal roles in tumor growth, metastasis, and resistance to therapy. However, the contribution of stromal cells to non-small-cell lung cancer (NSCLC) has remained underexplored. We used an orthotopic model of Kras-driven NSCLC to systematically dissect the contribution of specific hematopoietic stromal cells in lung cancer. RNA deep-sequencing analysis of individually sorted myeloid lineage and tumor epithelial cells revealed cell-type-specific differentially regulated genes, indicative of activated stroma. We developed a computational model for crosstalk signaling discovery based on ligand-receptor interactions and downstream signaling networks and identified known and novel tumor-stroma paracrine and tumor autocrine crosstalk-signaling pathways in NSCLC. We provide cellular and molecular insights into components of the lung cancer microenvironment that contribute to carcinogenesis. This study has the potential for development of therapeutic strategies that target tumor-stroma interactions and may complement conventional anti-cancer treatments. PMID- 25704821 TI - A cell-signaling network temporally resolves specific versus promiscuous phosphorylation. AB - If specific and functional kinase- or phosphatase-substrate interactions are optimized for binding compared to promiscuous interactions, then changes in phosphorylation should occur faster on functional versus promiscuous substrates. To test this hypothesis, we designed a high temporal resolution global phosphoproteomics protocol to study the high-osmolarity glycerol (HOG) response in the budding yeast Saccharomyces cerevisiae. The method provides accurate, stimulus-specific measurement of phosphoproteome changes, quantitative analysis of phosphodynamics at sub-minute temporal resolution, and detection of more phosphosites. Rates of evolution of dynamic phosphosites were comparable to those of known functional phosphosites and significantly lower than static or longer time-frame dynamic phosphosites. Kinetic profile analyses indicated that putatively functional kinase- or phosphatase-substrate interactions occur more rapidly, within 60 s, than promiscuous interactions. Finally, we report many changes in phosphorylation of proteins implicated in cytoskeletal and mitotic spindle dynamics that may underlie regulation of cell cycle and morphogenesis. PMID- 25704822 TI - Synthetic quantitative array technology identifies the Ubp3-Bre5 deubiquitinase complex as a negative regulator of mitophagy. AB - Mitophagy is crucial to ensuring mitochondrial quality control. However, the molecular mechanism and regulation of mitophagy are still not fully understood. Here, we developed a quantitative methodology termed synthetic quantitative array (SQA) technology, which allowed us to perform a genome-wide screen for modulators of rapamycin-induced mitophagy in S. cerevisiae. SQA technology can be easily employed for other enzyme-based reporter systems and widely applied in yeast research. We identified 86 positive and 10 negative regulators of mitophagy. Moreover, SQA-based analysis of non-selective autophagy revealed that 63 of these regulators are specific for mitophagy and 33 regulate autophagy in general. The Ubp3-Bre5 deubiquitination complex was found to inhibit mitophagy but, conversely, to promote other types of autophagy, including ribophagy. This complex translocates dynamically to mitochondria upon induction of mitophagy. These findings point to a role of ubiquitination in mitophagy in yeast and suggest a reciprocal regulation of distinct autophagy pathways. PMID- 25704824 TI - Genetic predisposition to hyperuricaemia in rotavirus gastro-enteritis. PMID- 25704823 TI - Genome-wide RNAi screen identifies networks involved in intestinal stem cell regulation in Drosophila. AB - The intestinal epithelium is the most rapidly self-renewing tissue in adult animals and maintained by intestinal stem cells (ISCs) in both Drosophila and mammals. To comprehensively identify genes and pathways that regulate ISC fates, we performed a genome-wide transgenic RNAi screen in adult Drosophila intestine and identified 405 genes that regulate ISC maintenance and lineage-specific differentiation. By integrating these genes into publicly available interaction databases, we further developed functional networks that regulate ISC self renewal, ISC proliferation, ISC maintenance of diploid status, ISC survival, ISC to-enterocyte (EC) lineage differentiation, and ISC-to-enteroendocrine (EE) lineage differentiation. By comparing regulators among ISCs, female germline stem cells, and neural stem cells, we found that factors related to basic stem cell cellular processes are commonly required in all stem cells, and stem-cell specific, niche-related signals are required only in the unique stem cell type. Our findings provide valuable insights into stem cell maintenance and lineage specific differentiation. PMID- 25704825 TI - Association between caregiver depression and individual behavioral and psychological symptoms of dementia in Taiwanese patients. AB - INTRODUCTION: The aim of this study was to investigate caregiver depression associated with neuropsychiatric symptoms in Taiwanese people. METHODS: A cross sectional design was used in this study. Two hundred seventy-six pairs of patients with dementia and their caregivers who visited the memory clinic of a general hospital from July 2001 to October 2008 were recruited. Caregiver depression was evaluated with the Center for Epidemiologic Studies Depression Scale (CES-D); the behavioral and psychological symptoms of dementia were evaluated using the Neuropsychiatric Inventory. Demographic data of the patients and caregivers, including cognitive functions and clinical dementia ratings, were collected. In addition to descriptive statistics, we examined the relationship between each parameter and caregiver depression using Pearson correlation, independent t-test, or analysis of variance. RESULTS: The results showed a statistically significant positive correlation between the total Neuropsychiatric Inventory score and CES-D score (r = 0.345, P < 0.001) in the bivariate analyses. For individual behavioral and psychological symptoms of dementia, agitation/aggression, anxiety, nighttime behavior disturbances, irritability/lability, and hallucinations were the five leading symptoms significantly associated with caregiver depression (CES-D). DISCUSSION: Carefully managing these symptoms is likely to reduce depression in dementia caregivers. PMID- 25704826 TI - Use of reverse total shoulder arthroplasty in the Medicare population. AB - BACKGROUND: Reverse shoulder arthroplasty (RSA) has been Food and Drug Administration approved in the United States since 2004 but did not obtain a unique code until 2010. Therefore, the use of this popular procedure has yet to be reported. The purpose of this study was to examine the use and reimbursement of RSA compared with total shoulder arthroplasty (TSA) and shoulder hemiarthroplasty (SHA). METHODS: We analyzed the 100% sample of the 2011 Medicare Part A claims data for patients aged 65 years or older. Patient demographic characteristics, diagnoses, provider information, reimbursements, and lengths of stay were extracted from the claims data. RESULTS: In 2011, a total of 31,002 shoulder arthroplasty procedures were performed; 37% were RSAs, 42% were TSAs, and 21% were SHAs. Osteoarthritis was the primary diagnosis code in 91% of TSAs, 37% of SHAs, and 45% of RSAs. A primary diagnosis of osteoarthritis with no secondary code for rotator cuff tear was found in 22% of patients undergoing RSA. The mean length of stay for RSA (2.6 days; SD, 2.1 days) was longer than that for TSA (2.1 days; SD, 1.5 days) and shorter than that for SHA (3.5 days; SD, 3.6 days) (P < .001). Lower-volume surgeons (<10 arthroplasties per year) performed most shoulder arthroplasties: 57% of RSAs, 65% of TSAs, and 97% of SHAs. Seventy percent of RSAs were implanted by surgeons who performed more RSAs than TSAs and SHAs combined. CONCLUSIONS: RSA is performed with similar frequency to TSA and almost twice as much as SHA in the Medicare population. Lower-volume surgeons perform most RSAs, and a majority of surgeons perform more RSAs than all anatomic shoulder arthroplasties combined. PMID- 25704827 TI - Inpatient surgical site infection after shoulder arthroplasty. AB - BACKGROUND: Surgical site infection (SSI) after joint arthroplasty is associated with prolonged hospitalization, reoperation, inferior outcomes, and substantial resource utilization. As the number of shoulder replacements performed in the United States continues to rise, measuring the incidence of inpatient SSI after hemiarthroplasty (HSA) and total shoulder arthroplasty (TSA), and associated risk factors for infection is worthwhile. METHODS: Using the Nationwide Inpatient Sample (NIS), we reviewed 241,193 patients undergoing TSA or reverse TSA and 159,795 undergoing HSA between 2002 and 2011 and identified patients with an associated diagnosis of SSI during the admission. Demographic characteristics, preoperative diagnoses, further surgical procedures, associated comorbidities, and in-hospital events associated with SSI were sought in multivariable logistic regression analysis. RESULTS: An in-hospital SSI developed in 0.08% of patients undergoing TSA or reverse TSA and in 0.11% of patients undergoing HSA. Independent risk factors for inpatient SSI included TSA vs HSA (odds ratio [OR], 1.83), Medicaid insurance vs private insurance (OR, 3.93), diagnosis of fracture nonunion (OR, 5.76), avascular necrosis (OR 2.71), or proximal humeral fracture (OR, 2.62) vs primary osteoarthritis, comorbidities, in-hospital events (blood transfusion, pneumonia, and acute renal failure), and increased duration of hospital stay. CONCLUSIONS: The small percentage of SSI that occurs during the initial inpatient stay after shoulder arthroplasty is related to diagnoses other than primary osteoarthritis in more infirm patients with low-income government insurance (Medicaid). Patients considering shoulder arthroplasty can use this information to help decide between the potential improvement in comfort and function of the shoulder and the potential for major adverse events such as infection. PMID- 25704828 TI - Feasibility of latissimus and teres major transfer to reconstruct irreparable subscapularis tendon tear: an anatomic study. PMID- 25704829 TI - Gene transcription patterns and energy reserves in Daphnia magna show no nanoparticle specific toxicity when exposed to ZnO and CuO nanoparticles. AB - There is still a lot of contradiction on whether metal ions are solely responsible for the observed toxicity of ZnO and CuO nanoparticles to aquatic species. While most experiments have studied nanoparticle effects at organismal levels (e.g. mortality, reproduction), effects at lower levels of biological organization may clarify the role of metal ions, nanoparticles and nanoparticle aggregates. In this study, the effect of ZnO and CuO nanoparticles was tested at two lower levels: energy reserves and gene transcription and compared with zinc and copper salts. Daphnia magna was exposed during 96h to 10% immobilization concentrations of all chemicals, after which daphnids were sampled for determination of glycogen, lipid and protein concentration and for a differential gene transcription analysis using microarray. The dissolved, nanoparticle and aggregated fraction in the medium was characterized. The results showed that ZnO nanoparticles had largely dissolved directly after addition to the test medium. The CuO nanoparticles mostly formed aggregates, while only a small fraction dissolved. The exposure to zinc (both nano and metal salt) had no effect on the available energy reserves. However, in the copper exposure, the glycogen, lipid and protein concentration in the exposed daphnids was lower than in the unexposed ones. When comparing the nanoparticle (ZnO or CuO) exposed daphnids to the metal salt (zinc or copper salt) exposed daphnids, the microarray results showed no significantly differentially transcribed gene fragments. The results indicate that under the current exposure conditions the toxicity of ZnO and CuO nanoparticles to D. magna is solely caused by toxic metal ions. PMID- 25704830 TI - Effects of carcinogenic versus non-carcinogenic AHR-active PAHs and their mixtures: lessons from ecological relevance. AB - Polycyclic aromatic hydrocarbons (PAHs) are priority environmental mutagens and carcinogens that occur in the aquatic environment as mixtures rather than the individual compounds for which guidelines are issued. The present work aimed at understanding the interaction effects between carcinogenic and non-carcinogenic PAHs in a model marine fish (Dicentrarchus labrax) in realistic scenarios. Laboratory assays under ecologically-relevant parameters were conducted for 28 days with sediments spiked with low-moderate concentrations (250-800ngg(-1)) of two model PAHs, phenanthrene (non-carcinogenic) and benzo[b]fluoranthene (carcinogenic to experimental animals). Both PAHs induced hepatic histopathological changes that indicate metabolic failure and inflammation, especially in animals exposed to mixtures. Phenanthrene elicited biochemical changes better related to oxidative stress (lipid peroxidation, glutathione and glutathione S-transferase activity) and CYP function, whereas B[b]F disrupted metabolic responses and defences to toxicological challenge. Conversely, mixed PAHs yielded lesions and responses that, altogether, are compatible with the AHR dependent pathway (the basis of PAH mutagenicity), potentially generating supra additive effects. Nonetheless, the low, ecologically-relevant, concentrations of PAHs diluted dose and time-response relations. Overall, although seemingly predicting the risk of individual PAHs, environmental guidelines may not apply to mixtures by underestimating adverse effects, which calls for a redefinition of standards when determining the true risk of toxicants under realistic circumstances. PMID- 25704831 TI - Symptom reporting after the introduction of a new high-voltage power line: a prospective field study. AB - BACKGROUND: There is public concern about the potential health effects of exposure to extremely low frequency electromagnetic fields (ELF-EMF) of high voltage power lines (HVPLs). Some residents living near HVPLs believe ELF-EMF might cause non-specific health complaints. OBJECTIVES: The present study is the first to prospectively investigate whether self-reported health complaints and causal beliefs increase after the construction of a new power line. METHODS: We used a quasi-experimental design with two pretests before and two posttests after a new HVPL was put into operation. Residents living near (0-300m, n=229; 300 500m, n=489) and farther away (500-2000m, n=536) participated in the study. Linear mixed models were fitted to test whether symptom reports and beliefs that power lines caused health complaints increased more in residents living close to the new line compared to residents living farther away. RESULTS: A significantly (p<.05) larger increase from baseline in symptom reports and causal beliefs was found in residents living within 300m from the new power line when compared to residents living farther away. While symptom reports did not differ at baseline, the belief that a power line could cause these symptoms was at baseline already stronger for residents living close compared to residents living farther away. CONCLUSIONS: We found a negative impact of a new HVPL on health perceptions of nearby residents, even before the line was put into operation. PMID- 25704832 TI - Copper sulphate reduces the metabolic activity of Gammarus fossarum in laboratory and field experiments. AB - The specialised fauna of freshwater springs is affected by contamination of the water with xenobiotics from human activities in the surrounding landscape. We assessed the effects of exposure to toxins in laboratory and field experiments by using copper sulphate as a model substance and Gammarus fossarum Koch, 1836, as the model organism. This amphipod is a common representative of the European spring fauna and copper is a widespread contaminant, mainly from agricultural practice. The experiments were conducted in test chambers placed in flow channels and directly in a spring. The gammarids were fed with conditioned beech leaf discs, which had been exposed to a 0.8 mg Cu/L solution for 96 h. The feeding activity of the amphipods was quantified on the level of the organism; and the respiratory electron transport system (ETS) assay was conducted in order to determine changes on the cellular level in the test organisms. The results show that the feeding activity, when the leaf discs were contaminated with copper, was not significantly different from the control. The ETS activity of the gammarids, which had been feeding on the copper contaminated leaf discs was however significantly reduced. The results followed the same pattern for gammarids from both the laboratory and the spring. By conducting the experiments not only in a laboratory but also directly in a spring in the field, we took a crucial step towards a more realistic approach when examining environmental pollutants on an organism. Our findings demonstrate the importance of conducting experiments out in the field, in natural conditions, as well as in the laboratory. PMID- 25704833 TI - In situ evaluation of oxidative stress and immunological parameters as ecotoxicological biomarkers in a novel sentinel species (Mimachlamys varia). AB - Although the variegated scallop Mimachlamys varia seems to be a suitable sentinel species for contaminant monitoring, no study has identified biomarkers in this species. In order to fill this gap, this study conducted an in situ biomarker approach. M. varia were collected in contaminated and uncontaminated areas and responsiveness of oxidative stress and immunological biomarkers was evaluated in the digestive gland. In parallel, 14 trace element concentrations were evaluated in the same organ. Superoxide dismutase activity and malondialdehyde content responded efficiently to in situ contamination when a certain degree of contamination was reached. Laccase-type phenoloxidase showed a high sensitivity but saturation of the response was highlighted for the highest contaminations. Additionally, correlations were found between biomarkers and trace element concentrations. Taken together, results showed that biomarker approach conducted in the digestive gland of M. varia represents a sensitive analytical tool to highlight ecotoxicological issues in coastal marine ecosystems. PMID- 25704834 TI - Effects of Pb plus Cd mixtures on toxicity, and internal electrolyte and osmotic balance in the rainbow trout (Oncorhynchus mykiss). AB - The physiological and toxicological effects of Cd and Pb have been thoroughly studied, but relatively little work has been done to determine how mixtures of these metals affect fishes in soft (<100 MUmol L(-1)Ca(2+)) slightly acidic (pH ~6) waters typical of many lakes in the Canadian Shield and other regions. Recently, it has been suggested that acute exposure to Cd plus Pb mixtures (3h) had greater than additive effects on both Ca(2+) and Na(+) influx, which could potentially exacerbate disturbances to ion balance and result in greater toxicity in rainbow trout (Oncorhynchus mykiss). The goal of the present study was to test this hypothesis by assessing the physiological and toxicological effects of Cd plus Pb mixtures over longer time periods (3-5 days), but at relatively low, more environmentally relevant concentrations of these metals. Accordingly, toxicity and measurements of blood acid-base regulation (PaO2, pHa), hematology (Ht, Hb, MCHC, and Protein), ionic composition (body ions and plasma Ca(2+), Na(+), Cl(-), osmolality), unidirectional Na(+) fluxes and branchial Na(+)/K(+)-ATPase activity were measured in rainbow trout exposed to Cd plus Pb mixtures. Experiments on rainbow trout, implanted with dorsal aortic catheters for repetitive blood sampling, demonstrated that exposure to Pb alone (26 nmol PbL(-1)) was less toxic than Cd alone (6 nmol CdL(-1)), which was much less toxic to the fish than a Cd plus Pb mixture (7 nmol CdL(-1) plus 45 nmol PbL(-1)), which led to greater than additive 80% mortality by 5d. Both Cd and Pb inhibited Na(+) influx over 3d exposure to the metals, which was partially offset by decreases in the diffusive efflux (outflux) of Na(+) across the gill. Despite an absence of detectable effects of Pb alone on plasma ion balance, Cd plus Pb mixtures exacerbated Cd induced reductions in plasma Ca(2+) concentration, and resulted in pronounced reductions in plasma Na(+), Cl(-), and osmolality. No effects on Na(+)/K(+) ATPase activity were noted following exposure to Cd, Pb or Pb plus Cd mixtures. We conclude that the greater than additive toxicity of Cd plus Pb mixtures observed in the present and previous studies is because these metals not only have common, but also independent binding sites and mechanisms of action, which could exacerbate the pathophysiological effects caused by each metal alone. PMID- 25704835 TI - Delivery and management of a preterm infant in the burn unit: a multidisciplinary approach. AB - Burns during pregnancy can have profound effects on both the mother and her fetus. While the mother can suffer cardiovascular collapse, infection, hemorrhage and inhalation injury with respiratory failure, the fetus is affected through the placenta by all of these changes as well as by the transfer of drugs administered to the mother. We report a case of severely burned female patient at 29 weeks gestation, who, due to deteriorating maternal condition, was delivered and managed at 32 weeks gestation by a multidisciplinary team. To the best of our knowledge this is the first reported case of a preterm infant delivered in a burn unit. PMID- 25704836 TI - Synesthesia in twins: incomplete concordance in monozygotes suggests extragenic factors. AB - Colored-sequence synesthesia (CSS) is a neurological condition in which sequential stimuli such as letters, numbers, or days of the week trigger simultaneous, involuntary color perception. Although the condition appears to run in families and several studies have sought a genetic link, the genetic contribution to synesthesia remains unclear. We conducted the first comparative twin study of CSS and found that CSS has a pairwise concordance of 73.9% in monozygotic twins, and a pairwise concordance of 36.4% in dizygotic twins. In line with previous studies, our results suggest a heritable element of synesthesia. However, consonant with the findings of previous single-pair case studies, our large sample size verifies that synesthesia is not completely conferred by genetics; if it were, monozygotic twins should have 100% concordance. These findings implicate a genetic mechanism of CSS that may work differently than previously thought: collectively, our data suggest that synesthesia is a heritable condition with incomplete penetrance that is substantially influenced by epigenetic and environmental factors. PMID- 25704840 TI - Comparison of machine classification algorithms for fibromyalgia: neuroimages versus self-report. AB - Recent studies have posited that machine learning (ML) techniques accurately classify individuals with and without pain solely based on neuroimaging data. These studies claim that self-report is unreliable, making "objective" neuroimaging classification methods imperative. However, the relative performance of ML on neuroimaging and self-report data have not been compared. This study used commonly reported ML algorithms to measure differences between "objective" neuroimaging data and "subjective" self-report (ie, mood and pain intensity) in their ability to discriminate between individuals with and without chronic pain. Structural magnetic resonance imaging data from 26 individuals (14 individuals with fibromyalgia and 12 healthy controls) were processed to derive volumes from 56 brain regions per person. Self-report data included visual analog scale ratings for pain intensity and mood (ie, anger, anxiety, depression, frustration, and fear). Separate models representing brain volumes, mood ratings, and pain intensity ratings were estimated across several ML algorithms. Classification accuracy of brain volumes ranged from 53 to 76%, whereas mood and pain intensity ratings ranged from 79 to 96% and 83 to 96%, respectively. Overall, models derived from self-report data outperformed neuroimaging models by an average of 22%. Although neuroimaging clearly provides useful insights for understanding neural mechanisms underlying pain processing, self-report is reliable and accurate and continues to be clinically vital. PERSPECTIVE: The present study compares neuroimaging, self-reported mood, and self-reported pain intensity data in their ability to classify individuals with and without fibromyalgia using ML algorithms. Overall, models derived from self-reported mood and pain intensity data outperformed structural neuroimaging models. PMID- 25704841 TI - Decreased sensitivity to thermal stimuli in adolescents with autism spectrum disorder: relation to symptomatology and cognitive ability. AB - Social communication deficits and repetitive behaviors are established characteristics of autism spectrum disorder (ASD) and the focus of considerable study. Alterations in pain sensitivity have been widely noted clinically but remain understudied and poorly understood. The ASD population may be at greater risk for having their pain undermanaged, especially in children with impaired cognitive ability and limited language skills, which may affect their ability to express pain. Given that sensitivity to noxious stimuli in adolescents with ASD has not been systematically assessed, here we measured warm and cool detection thresholds and heat and cold pain thresholds in 20 high-functioning adolescents with ASD and 55 typically developing adolescents using a method-of-limits quantitative sensory testing protocol. Adolescents with ASD had a loss of sensory function for thermal detection (P < .001, both warm and cool detection thresholds) but not pain threshold (P > .05, both heat and cold pain thresholds) in comparison to controls, with no evidence for significant age or sex effects (P > .05). Intelligence quotients and symptomatology were significantly correlated with a loss of some types of thermal perception in the ASD population (ie, warm detection threshold, cool detection threshold, and heat pain threshold; P < .05). Decreased thermal sensitivity in adolescents with ASD may be associated with cognitive impairments relating to attentional deficits. Our findings are consistent with previous literature indicating an association between thermal perception and cortical thickness in brain regions involved in somatosensation, cognition, and salience detection. Further brain-imaging research is needed to determine the neural mechanisms underlying thermal perceptual deficits in adolescents with ASD. PERSPECTIVE: We report quantitative evidence for altered thermal thresholds in adolescents with ASD. Reduced sensitivity to warmth, coolness, and heat pain was related to impaired cognitive ability. Caregivers and clinicians should consider cognitive ability when assessing and managing pain in adolescents with ASD. PMID- 25704842 TI - Stochastic features and strategy of computational methods: comment on "On the interplay between mathematics and biology, hallmarks toward a new systems biology" by N. Bellomo et al. PMID- 25704843 TI - [Workplace Health Promotion in Small, Medium-Sized and Large Enterprises of the Health-Care Sector - Frequency, Reasons for the Company Management to Take Action and Barriers to Implementation]. AB - PURPOSE: The aim of this study was to gain insight into worksite health promotion in small and medium-sized companies compared to large concerns in Middle Franconia. Action in worksite health promotion, obstacles and demand for networks for workplace health promotion were determined. METHOD: A standardised telephone interview served for collecting data for this cross-sectional study. The interviewee was always the manager or their proxy. 106 companies were contacted. The results of this study were analysed via qualitative and quantitative methods in SPSS((r)) 20. RESULTS: It was possible to reach and interview 80 companies, a return rate of 75.5%. More than half the companies (68.8%) implemented at least one activity for worksite health promotion, especially ergonomic measures and measures to promote physical activity. Taking the size of the company into consideration when analysing the results, previous study results are confirmed. With an increasing size of the company, the relative frequency of measures for workplace health promotion rises. The motivation for worksite health promotion ranges from keeping the employees healthy (38.2%) to worksite health promotion as part of the business culture (9.1%). 81.1% of the companies consider their activity in worksite health promotion to be successful. Furthermore, 80.0% of the firms that implemented worksite health promotion were supported by a partner like a health insurance (43.2%). Those companies that did not implement any activities for worksite health promotion, state as a prime reason that they did not think about it as yet (44.0%). Besides, 44.0% of the companies without any worksite health promotion would like to implement measures. 65.5% of the companies that already took action in worksite health promotion and 56.0% of the companies that did not would like to cooperate with other firms in a network for workplace health promotion. Mutual exchange is the most important factor for them. CONCLUSION: The results of this study show that almost half of the companies that did not implement measures for worksite health promotion as yet would like to take action in this regard. For a bigger establishment of worksite health promotion, networks are predestinated and are best accompanied and supported by external professionals like health insurances, mutual indemnity associations or universities. PMID- 25704844 TI - Monte Carlo simulation and SAFT modeling study of the solvation thermodynamics of dimethylformamide, dimethylsulfoxide, ethanol and 1-propanol in the ionic liquid trimethylbutylammonium bis(trifluoromethylsulfonyl)imide. AB - Understanding fundamental solvation phenomena and mixture thermodynamic properties for organic molecules in ionic liquids is essential to the development of ionic liquids in many application areas. In the present work, molecular simulations were used to compute a wide range of properties for the pure ionic liquid trimethylbutylammonium bis(trifluoromethylsulfonyl)imide as well as mixtures of this ionic liquid with ethanol, 1-propanol, dimethylformamide, and dimethylsulfoxide. A new force field for the ionic liquid was developed and validated by computing ionic liquid surface tension and density as a function of temperature. Force fields for ethanol and propanol were taken from the literature, while new force fields were developed for dimethylformamide and dimethylsulfoxide. These force fields were shown to yield vapor-liquid coexistence curves, vapor pressure curves and critical points in excellent agreement with experimental data. Absorption isotherms, enthalpies of mixing and mixture volumes were then computed and shown to agree well with available literature. The simulations help rationalize the observed trends in solubility and enthalpy of mixing in terms of the relative strength of hydrogen bonding between the solutes and the ionic liquid. It was found that the entropy of absorption plays a very important role in the solvation process. The PCIP-SAFT equation of state was able to fit the experimental data (or simulation results when experiments were unavailable) very accurately with only small adjustable binary interaction parameters. PMID- 25704845 TI - The Effects of Androgens on Murine Cortical Bone Do Not Require AR or ERalpha Signaling in Osteoblasts and Osteoclasts. AB - In men, androgens are critical for the acquisition and maintenance of bone mass in both the cortical and cancellous bone compartment. Male mice with targeted deletion of the androgen receptor (AR) in mature osteoblasts or osteocytes have lower cancellous bone mass, but no cortical bone phenotype. We have investigated the possibility that the effects of androgens on the cortical compartment result from AR signaling in osteoprogenitors or cells of the osteoclast lineage; or via estrogen receptor alpha (ERalpha) signaling in either or both of these two cell types upon conversion of testosterone to estradiol. To this end, we generated mice with targeted deletion of an AR or an ERalpha allele in the mesenchymal (AR(f/y);Prx1-Cre or ERalpha(f/f);Osx1-Cre) or myeloid cell lineage (AR(f/y);LysM Cre or ERalpha(f/f);LysM-Cre) and their descendants. Male AR(f/y);Prx1-Cre mice exhibited decreased bone volume and trabecular number, and increased osteoclast number in the cancellous compartment. Moreover, they did not undergo the loss of cancellous bone volume and trabecular number caused by orchidectomy (ORX) in their littermate controls. In contrast, AR(f/y);LysM-Cre, ERalpha(f/f);Osx1-Cre, or ERalpha(f/f);LysM-Cre mice had no cancellous bone phenotype at baseline and lost the same amount of cancellous bone as their controls following ORX. Most unexpectedly, adult males of all four models had no discernible cortical bone phenotype at baseline, and lost the same amount of cortical bone as their littermate controls after ORX. Recapitulation of the effects of ORX by AR deletion only in the AR(f/y);Prx1-Cre mice indicates that the effects of androgens on cancellous bone result from AR signaling in osteoblasts-not on osteoclasts or via aromatization. The effects of androgens on cortical bone mass, on the other hand, do not require AR or ERalpha signaling in any cell type across the osteoblast or osteoclast differentiation lineage. Therefore, androgens must exert their effects indirectly by actions on some other cell type(s) or tissue(s). PMID- 25704846 TI - CGR2 and CGR3 have critical overlapping roles in pectin methylesterification and plant growth in Arabidopsis thaliana. AB - Pectins are critical polysaccharides of the cell wall that are involved in key aspects of a plant's life, including cell-wall stiffness, cell-to-cell adhesion, and mechanical strength. Pectins undergo methylesterification, which affects their cellular roles. Pectin methyltransferases are believed to methylesterify pectins in the Golgi, but little is known about their identity. To date, there is only circumstantial evidence to support a role for QUASIMODO2 (QUA2)-like proteins and an unrelated plant-specific protein, cotton Golgi-related 3 (CGR3), in pectin methylesterification. To add to the knowledge of pectin biosynthesis, here we characterized a close homolog of CGR3, named CGR2, and evaluated the effect of loss-of-function mutants and over-expression lines of CGR2 and CGR3 in planta. Our results show that, similar to CGR3, CGR2 is a Golgi protein whose enzyme active site is located in the Golgi lumen where pectin methylesterification occurs. Through phenotypical analyses, we also established that simultaneous loss of CGR2 and CGR3 causes severe defects in plant growth and development, supporting critical but overlapping functional roles of these proteins. Qualitative and quantitative cell-wall analytical assays of the double knockout mutant demonstrated reduced levels of pectin methylesterification, coupled with decreased microsomal pectin methyltransferase activity. Conversely, CGR2 and CGR3 over-expression lines have markedly opposite phenotypes to the double knockout mutant, with increased cell-wall methylesterification levels and microsomal pectin methyltransferase activity. Based on these findings, we propose that CGR2 and CGR3 are critical proteins in plant growth and development that act redundantly in pectin methylesterification in the Golgi apparatus. PMID- 25704847 TI - Characteristics of traditional Chinese medicine use for children with allergic rhinitis: a nationwide population-based study. AB - OBJECTIVES: Allergic rhinitis (AR) is a common allergic disorder in children, some of whom seek complementary treatments, including acupuncture and Chinese herbs. Little, however, is known about the treatment of pediatric AR with traditional Chinese medicine (TCM). To characterize TCM use in pediatric AR, we conducted a nationwide population-based study. METHODS: We screened one million randomly sampled beneficiaries of the National Health Insurance Program in Taiwan from 2002 to 2010 to identify children <18 years of age with newly diagnosed allergic rhinitis (ICD-9 code 477.9). The subjects were categorized according to their use of TCM. RESULTS: We identified 97,401 children newly diagnosed with AR for inclusion in the study. Among these children, 63.11% (N=61,472) had used TCM. There were significantly more TCM users than non-users among school-age children and adolescents (P<0.001). Most (99.1%) pediatric TCM users received Chinese herbal remedies (99.1%); only 0.9% received acupuncture or manipulative therapies. Xin-Yi-Qing-Fei-Tang (Magnolia Flower Lung-Clearing Decoction) was the most frequently prescribed TCM formulation (23.44%), and the most commonly prescribed single herb was Chan-Tui (Periostracum cicadae; 13.78%). Regarding syndrome differentiation (ZHENG) according to TCM theory, prescriptions for the Cold Syndrome exceeded those for the Hot Syndrome throughout the year in Taiwan. CONCLUSIONS: We found that approximately two-thirds of pediatric AR patients were prescribed TCM treatments in Taiwan. Further research is warranted to examine the efficacy and safety of TCM for pediatric AR patients. PMID- 25704848 TI - Pierre Robin sequence: review of diagnostic and treatment challenges. AB - Pierre Robin sequence is not a rare condition and paediatric specialists caring for respiratory related issues are likely to encounter cases in their practice. There have been a few recent reviews on the topic, mostly focusing on the surgical interventions performed for cases with severe airway obstruction. In the present review, we will highlight the different challenges that remain today in the global evaluation of infants afflicted with this condition through a thorough review of the medical literature, giving the clinician a full scope of the disease and of the various management options. The need for an improved objective evaluation of airway obstruction and for a better classification will be emphasized. We are therefore proposing a novel classification scheme that will better account for respiratory and feeding difficulties in these infants. Finally, many knowledge gaps persist regarding this condition, underlining the necessity for further research both in the genetic field and regarding the outcome of therapy. PMID- 25704849 TI - Performance of a real-time PCR assay in routine bovine mastitis diagnostics compared with in-depth conventional culture. AB - Reliable identification of the aetiological agent is crucial in mastitis diagnostics. Real-time PCR is a fast, automated tool for detecting the most common udder pathogens directly from milk. In this study aseptically taken quarter milk samples were analysed with a real-time PCR assay (Thermo Scientific PathoProof Mastitis Complete-12 Kit, Thermo Fisher Scientific Ltd.) and by semi quantitative, in-depth bacteriological culture (BC). The aim of the study was to evaluate the diagnostic performance of the real-time PCR assay in routine use. A total of 294 quarter milk samples from routine mastitis cases were cultured in the national reference laboratory of Finland and examined with real-time PCR. With BC, 251 out of 294 (85.7%) of the milk samples had at least one colony on the plate and 38 samples were considered contaminated. In the PCR mastitis assay, DNA of target species was amplified in 244 samples out of 294 (83.0%). The most common bacterial species detected in the samples, irrespective of the diagnostic method, was the coagulase negative staphylococci (CNS) group (later referred as Staphylococcus spp.) followed by Staphylococcus aureus. Sensitivity (Se) and specificity (Sp) for the PCR assay to provide a positive Staph. aureus result was 97.0 and 95.8% compared with BC. For Staphylococcus spp., the corresponding figures were 86.7 and 75.4%. Our results imply that PCR performed well as a diagnostic tool to detect Staph. aureus but may be too nonspecific for Staphylococcus spp. in routine use with the current cut-off Ct value (37.0). Using PCR as the only microbiological method for mastitis diagnostics, clinical relevance of the results should be carefully considered before further decisions, for instance antimicrobial treatment, especially when minor pathogens with low amount of DNA have been detected. Introducing the concept of contaminated samples should also be considered. PMID- 25704850 TI - Fermi arcs vs. Fermi pockets in electron-doped perovskite iridates. AB - We report on an angle resolved photoemission (ARPES) study of bulk electron-doped perovskite iridate, (Sr(1-x)La(x))3Ir2O7. Fermi surface pockets are observed with a total electron count in keeping with that expected from La substitution. Depending on the energy and polarization of the incident photons, these pockets show up in the form of disconnected "Fermi arcs", reminiscent of those reported recently in surface electron-doped Sr2IrO4. Our observed spectral variation is consistent with the coexistence of an electronic supermodulation with structural distortion in the system. PMID- 25704851 TI - Anticancer effects of adenovirus-mediated calreticulin and melanoma-associated antigen 3 expression on non-small cell lung cancer cells. AB - Non-small cell lung cancer (NSCLC) is highly prevalent and needs novel therapies. Melanoma-associated antigen 3 (MAGE-A3) is a lung cancer antigen and calreticulin (CALR) can modulate immune responses. Our previous study has shown that up regulated MAGE-A3 and CALR expression inhibits the proliferation and invasion of glioma cells. In this study, we examined the effect of adenovirus (Ad)-mediated MAGE-A3 and/or CALR expression on the proliferation, invasion, and apoptosis of human NSCLC cells and on the vascular tube formation of human endothelial cells as well as on dendritic cell (DC) activation and induced CD8(+) cytotoxic T lymphocyte (CTL) activity in vitro. We found that low levels of CALR and MAGE-A3 were expressed by A549 cells, but only very low CALR was expressed by DC. Up regulated CALR and MAGE-A3 expression by infection with Ad-CALR/MAGE-A3 significantly inhibited the proliferation and invasion, but promoted the apoptosis of A549 cells. Up-regulated CALR and MAGE-A3 expression significantly inhibited cyclin D1 expression and the AKT, ERK1/2 and NF-kappaB expression and phosphorylation in A549 cells. Up-regulated CALR expression inhibited the tube formation in human endothelial cells. Up-regulated CALR and MAGE-A3 expression synergistically enhanced classical DC activation by enhancing IL-12, but reducing IL-10 secretion. Furthermore, CTLs induced by up-regulated CALR and MAGE-A3 expressing DCs synergistically triggered A549 cell apoptosis, which was abrogated by treatment with anti-HLA I, but not anti-HLA II antibodies. Moreover, CTLs induced by CALR and MAGE-A3-expressing DCs had a higher frequency of A549 specific IFN-gamma-secreting T cells. Our data indicated that up-regulated CALR and MAGE-A3 expression inhibited the carcinogenesis of NSCLC by modulating the AKT, ERK MAPK and NF-kappaB signaling and enhanced classical DC activation and MAGE-A3-specific CTL cytotoxicity. Therefore, our findings may provide new insights in understanding the role of CALR in modulating antigen-specific T cell immunity and may aid in the design of new therapies for NSCLC. PMID- 25704852 TI - Selective modulation of microglia polarization to M2 phenotype for stroke treatment. AB - Resident microglia are the major immune cells in the brain, acting as the first defense of the central nervous system. Following cerebral ischemia, microglia respond to this injury at first and transform from surveying microglia to active state. The activated microglia play a dual role in the ischemic injury, due to distinct microglia phenotypes, including deleterious M1 and neuroprotective M2. However, microglia show transient M2 phenotype followed by a shift to M1. The high ratio of M1 to M2 is significantly related to ischemic injury. Many signal pathways participate in the alternation of microglial phenotype, presenting potential therapeutic targets for selectively modulating M2 polarization of microglia. In this review, we discuss how the M2 phenotype mediates neuroprotective effects and summarize the alternation of signaling cascades that control microglial phenotype after ischemic stroke. PMID- 25704853 TI - Homocatenation of aluminum: alkane-like structures of Li2Al2H6 and Li3Al3H8. AB - A new class of aluminum homocatenated compounds (LinAlnH2n+2) is proposed based on quantum chemical calculations. In these compounds, Al abstracts an electron from Li, becoming valence isoelectronic with C, Si, and Ge, thus mimicking respective structural features of Group 14 hydrides. Using the Coalescence Kick search program coupled with density functional theory calculations, we investigated the potential energy surfaces of Li2Al2 H6 and Li3Al3H6 . Then single-point-energy coupled-cluster calculations were performed for the lowest energy structures found. Indeed, the global minima established for Li2 Al2 H6 and Li3 Al3 H6 contain the Al2 H6(2-) and Al3H6(3-) kernels, which are isostructural with ethane (C2H6), disilane (Si2H6), digermane (Ge2 H6) and propane (C3H8), trisilane (Si3H8), trigermane (Ge3H8) molecules, respectively. Structural, energetic, and electronic characteristics of the Li2 Al2 H6 and Li3 Al3 H8 compounds are presented and the viability of their synthesis is discussed. PMID- 25704854 TI - The Osteogenic Priming of Mesenchymal Stem Cells is Impaired in Experimental Diabetes. AB - Diabetes mellitus encompasses a group of metabolic conditions embracing the dysfunction and failure of various tissues and organs, including bone. Sustained bone alterations seem to result from anabolic, rather than catabolic processes, and suggest a decreased osteoblastic recruitment and activity. Current knowledge on the cellular and molecular mechanisms were provided by studies performed with osteogenic populations cultured in diabetic-simulated conditions, and osteogenic induced precursor populations harvested from diabetic animals, sustaining an impaired cellular behavior in terms of osteogenic responsiveness and function. However, the reasons leaning to this impairment remain essentially unknown, as the priming capability and functionality of undifferentiated precursors, developed within the diabetic environment, have not been addressed. Accordingly, this work aims to evaluate the functionality and osteogenic priming capability of bone marrow-derived mesenchymal stem cells (MSCs), harvested from animals with experimental diabetes, and grown in the absence of any given differentiation factor. MSCs developed within a diabetic microenvironment displayed an impaired behavior, with diminished cell viability and proliferation, altered cytoskeleton organization, impaired osteogenic priming, and increased adipogenic activation. Further, the osteogenic induction of diabetic MSCs resulted in an impaired osteogenic commitment. The modified cell phenotype may be related, at least in part, with altered activity of ERK WNT and p38 signaling pathways in diabetic derived cultures. Specific strategies, aiming the modulation of the verified hindrances, may be of therapeutic value to enhance the functionality of diabetic MSCs and sustain an improved outcome in the metabolism and regeneration of the bone tissue in diabetic conditions. PMID- 25704855 TI - Risk of coronary artery disease in transfusion-naive thalassemia populations: A nationwide population-based retrospective cohort study. AB - OBJECTIVE: Few studies have focused on the association between coronary artery disease (CAD) and transfusion naive thalassemia populations (this term means silent carrier, thalassemia minor or intermedia), who usually had less clinical manifestations and didn't require frequently blood transfusion. DESIGN, SETTING AND PATIENTS: This nationwide population-based cohort study involved analyzing data obtained between 1998 and 2010 from the Taiwanese National Health Insurance Research Database, with a follow-up period extending to the end of 2011. We identified patients with thalassemia and selected a comparison cohort that was frequency matched with the patients with thalassemia according to age, sex, and diagnosis year at a ratio of 1 patient with thalassemia to 4 control patients. We analyzed the risks of thalassemia and CAD by using Cox proportional hazard regression models. MEASUREMENTS AND MAIN RESULTS: In this study, 1537 patients with thalassemia and 6418 controls were included. The overall risks of developing CAD were 1.5-fold in patients with thalassemia compared with those in the comparison cohort after adjustment for age, sex, and comorbidities. Patients with thalassemia and with comorbidities, including hypertension, diabetes, hyperlipidemia, and chronic obstructive pulmonary disease, were 3.73-fold more likely to develop CAD than those without thalassemia and comorbidity (95% confidence interval=2.41-5.79). CONCLUSION: This is the first large long-term cohort study of which the results showed that that transfusion-naive thalassemia populations should be considered a crucial risk factor for CAD, even in patients with relatively mild clinical manifestations of thalassemia. PMID- 25704856 TI - New insights into the hexaphenylethane riddle: formation of an alpha,o-dimer. AB - Upon reduction of a 1H-cyclobuta[de]naphthalene-4,5-diylbis(diarylmethylium) species, a new C?C bond is formed between the Calpha and Cortho atoms of the two chromophores, which presents an unprecedented coupling pattern for the dimerization of two trityl units. By attaching an annulated cyclobutane ring at the opposite peri position of the naphthalene core, the distance between the Calpha carbon atoms was elongated beyond the limit of sigma-bond formation through "scissor effects". The suppression of Calpha ?Calpha bond formation, which would lead to hexaphenylethane-type compounds, is key to the first successful isolation of the alpha,o-adducts. The 5-diarylmethylene-6 triarylmethyl-1,3-cyclohexadiene unit in the alpha,o-adducts is stable, and isomerization of the cyclohexadiene unit into an aromatic system was not observed. The newly formed Calpha ?Cortho bond was cleaved upon two-electron oxidation to regenerate the dicationic dye. PMID- 25704857 TI - An alternative laboratory designed to address ethical concerns associated with traditional TAS2R38 student genotyping. AB - The TAS2R38 alleles that code for the PAV/AVI T2R38 proteins have long been viewed as benign taste receptor variants. However, recent studies have demonstrated an expanding and medically relevant role for TAS2R38. The AVI variant of T2R38 is associated with an increased risk of both colorectal cancer and Pseudomonas aeruginosa-associated sinus infection and T2R38 variants have been implicated in off-target drug responses. To address ethical concerns associated with continued student TAS2R38 gene testing, we developed an alternative to the traditional laboratory genotyping exercise. Instead of determining their own genotype, introductory level students isolated plasmid DNA containing a section of the human TAS2R38 gene from Escherichia coli. Following PCR-mediated amplification of a section of the TAS2R38 gene spanning the SNP at position 785, students determined their assigned genotype by restriction enzyme digestion and agarose gel electrophoresis. Using the course wide genotype and phenotype data, students found that there was an association between TAS2R38 genotype and the age of persistent P. aeruginosa acquisition in cystic fibrosis "patients." Assessment data demonstrated that students taking part in this new TAS2R38 laboratory activity made clear learning gains. PMID- 25704858 TI - Evaluating the efficiency of isotope transmission for improved panel design and a comparison of the detection sensitivities of mass cytometer instruments. AB - The recent introduction of mass cytometry, a technique coupling a cell introduction system generating a stream of single cells with mass spectrometry, has greatly increased the number of parameters that can be measured per single cell. As with all new technology there is a need for dissemination of standardization and quality control procedures. Here, we characterize variations in sensitivity observed across the mass range of a mass cytometer, using different lanthanide tags. We observed a five-fold difference in lanthanide detection over the mass range and demonstrated that each instrument has its own sensitivity pattern. Therefore, the selection of lanthanide combinations is a key step in the establishment of a staining panel for mass cytometry-based experiments, particularly for multicenter studies. We propose the sensitivity pattern as the basis for panel design, instrument standardization and future implementation of normalization algorithms. PMID- 25704859 TI - Change in aneurysmal flow pulsatility after flow diverter treatment. AB - MOTIVATION: Treatment of intracranial aneurysms with flow diverters (FDs) has recently become an attractive alternative. Although considerable effort has been devoted to understand their effects on the time-averaged or peak systolic flow field, no previous study has analyzed the variability of FD-induced flow reduction along the cardiac cycle. METHODS: Fourteen saccular aneurysms, candidates for FD treatment because of their morphology, located on the internal carotid artery were virtually treated with FDs and pre- and post-treatment blood flow was simulated with CFD techniques. Common hemodynamic variables were recorded at each time step of the cardiac cycle and differences between the untreated and treated models were assessed. RESULTS: Flow pulsatility, expressed by the pulsatility index (PI) of the velocity, significantly increased (36.0%; range: 14.6-88.3%) after FD treatment. Peak systole velocity reduction was significantly smaller (30.5%; range: 19.6-51.0%) than time-averaged velocity reduction (43.0%; range: 29.1-69.8%). No changes were observed in the aneurysmal pressure. CONCLUSIONS: FD-induced flow reduction varies considerably during the cardiac cycle. FD treatment significantly increased the flow pulsatility in the aneurysm. PMID- 25704860 TI - Controlling air leaks using free pericardial fat pads as surgical sealant in pulmonary resection. AB - BACKGROUND: This study evaluated the feasibility and efficacy of a new operative method for controlling intraoperative air leaks using free pericardial fat pads as a covering sealant in pulmonary resection. METHODS: To manage air leaks that must be controlled in pulmonary resection at the first water sealing test, collected free pericardial fat was used as a covering sealant and sewn on by the suture closing the lesion. In cases of uncontrolled air leaks at the second sealing test, fibrin glue was used to fill the residual lesion between the fat and visceral pleura. Fifty-one eligible patients were enrolled in this study to evaluate the duration of postoperative air leaks and the condition of the implanted fat on chest computed tomography (CT) 6 months later. RESULTS: The mean duration of postoperative air leaks was 1.05 +/- 1.84 days in the 39 cases that received the pericardial fat covering technique only and 2.66 +/- 3.42 days in the 12 cases that received the pericardial fat covering technique combined with fibrin glue. Prolonged alveolar air leaks occurred in 1 case and 2 cases, respectively. No cases required conversion to conventional methods, and there were no further adverse events. On follow-up chest CT approximately 62.7% of obvious engrafted fat survived. CONCLUSIONS: Using free pericardial fat pads as a sealant to control air leaks in pulmonary resection is safe and has good feasibility and potent efficacy. This new method can be an innovative technique for preventing prolonged air leaks. PMID- 25704861 TI - Visceral pleural invasion remains a size-independent prognostic factor in stage I non-small cell lung cancer. AB - BACKGROUND: The prognostic effect of visceral pleural invasion remains controversial when a tumor is less than 3 cm in stage I non-small cell lung cancer patients. We conducted this meta-analysis to evaluate the prognostic impact of visceral pleural invasion in these early patients. METHODS: We searched PubMed, EMBASE, Cochrane Library, and China National Knowledge Infrastructure and included published studies on the prognostic significance of visceral pleural invasion in stage I non-small cell lung cancer. Meta-analysis was performed and heterogeneity and publication bias were also evaluated. RESULTS: Twenty-two studies were included in the meta-analysis. In all stage I patients, visceral pleural invasion was associated with death (hazard ratio1.427; p = 0.000) and recurrence (hazard ratio1.600; p = 0.000). In subgroup analyses, visceral pleural invasions were consistently associated with death in each tumor size subgroup and recurrence in tumor less than 3 cm subgroup. Publication bias was not found. CONCLUSIONS: Visceral pleural invasion is a size-independent poor prognostic factor in stage I non-small cell lung cancer patients. We suggest adjuvant treatment should be considered in stage I patients with visceral pleural invasion. PMID- 25704862 TI - The bias against integrated thoracic surgery residency applicants during general surgery interviews. AB - BACKGROUND: New paradigms for training cardiothoracic surgeons have been introduced, including the integrated thoracic surgery residency. Currently, a limited number of these programs exist, and all candidates apply to both integrated thoracic and general surgery residencies. We sought to investigate the applicants' experiences applying for both types of positions. METHODS: An online survey was distributed to applicants to three integrated thoracic surgery programs during a 2-year period. RESULTS: The response rate was 50% (90 of 180). Most respondents were fourth-year medical students (81%; 72 of 89) and were interested in adult cardiac surgery (81%; 73 of 90). Sixty-one percent (55 of 90) had an interest in cardiothoracic surgery before clinical clerkships, and 93% (84 of 90) tailored their clinical education to this interest. Fifty-seven percent (49 of 86) scored above 230 on the USMLE Step 1 examination. Ninety-two percent (80 of 87) performed research during medical school, and 78% (62 of 80), specifically within cardiothoracic surgery; 76% (61 of 80) published their work. The number of general surgery interviews varied widely, but 46% (36 of 79) interviewed at one to five integrated thoracic surgery programs, and 39% (31 of 79) interviewed at six to ten integrated thoracic surgery programs. During general surgery interviews, 36% (24 of 66) received negative comments regarding applying to integrated thoracic residencies. Fifty-two percent (38 of 73) thought that their application to integrated thoracic programs diminished their chances to match at a general surgery program. CONCLUSIONS: The applicants to the integrated thoracic surgery residencies become interested in cardiothoracic surgery early and tailor their clinical education to this interest. Although they are academically successful, they report significant negativity regarding their applications to both general surgery and integrated thoracic residencies. PMID- 25704863 TI - Biventricular Berlin Heart EXCOR pediatric use across the united states. AB - BACKGROUND: Biventricular assist device (BiVAD) support was a strong predictor of early mortality in the Berlin Heart EXCOR Pediatric investigational device exemption (IDE) study (Assess Safety and Probable Benefit of the EXCOR Pediatric Ventricular Assist Device [VAD]). In adults, it has been identified that 5% to 10% of the VAD population is benefited by BiVAD support over left ventricular assist device (LVAD) support. An analysis of the Berlin Heart study cohort was performed to characterize patients supported with BiVAD, examine risk factors of mortality in this group, and identify subsets of patients in whom BiVAD is associated with survival. METHODS: All EXCOR Pediatric devices (Berlin Heart, Inc, The Woodlands, TX) placed in North America between May 2007 and December 2010 comprised the study cohort of 204 patients (128 [63%] LVADs and 76 [37%] BiVADs). The following patient cohorts were analyzed to determine the effect of BiVAD use on survival: Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profile 1 patients, patients with abnormal bilirubin levels, patients who received previous extracorporeal membrane oxygenation (ECMO), and patients with a 10-mL pump size. RESULTS: There were more patients with BiVADs in INTERMACS profile 1 (63% compared with 46%; p = 0.018). The incidence of major bleeding, neurologic and renal dysfunction, and infection was similar between BiVAD and LVAD groups. White race, abnormal glomerular filtration rate (GFR), sites with experience of less than 5 implantations, and use of 10-mL pumps were predictors of mortality in patients who received BiVADs. BiVADs were not associated with improved survival in any patient cohort; however, they were associated with increased mortality in patients who had undergone ECMO before receiving a VAD. CONCLUSIONS: BiVAD support was not associated with improved survival in any identified subset of patients. Although not randomized, these results (which were corrected for multiple possible risk factors) suggest that some children supported with BiVADs might have done better with LVADs alone. Further prospective studies will be needed to identify patient cohorts that will be better served with BIVAD support. PMID- 25704864 TI - Low testosterone is associated with poor health status in men with human immunodeficiency virus infection: a retrospective study. AB - Men with human immunodeficiency virus (HIV) infection are often hypogonadal and develop several HIV-associated non-acquired immunodeficiency syndrome (AIDS) (HANA) conditions that impair overall health status. No studies explored the relationship between health status and serum testosterone (T) in HIV-infected men. This study aims to investigate the association between total serum T and HANA, multimorbidity, and frailty in a large cohort of 1359 HIV-infected men and to explore the relationship between patients' overall health status and serum T. Among biochemical and hormonal measurement performed the main are serum total T, free triiodothyronine (fT3), and luteinizing hormone. Other outcome measurements include anthropometry, assessment of comorbidities and disabilities, overall health status defined as the number of HANA and by the 38-item multimorbidity frailty index, anthropometry, and bone mineral density. The cumulative relative risk of comorbidities is increased in HIV-infected men with hypogonadism (p < 0.001) and hypogonadism is associated with several comorbidities. The prevalence of hypogonadism increases progressively with the increase of the number of comorbidities. Frailty index is inversely related to serum total T (age-adjusted r = 0.298, r(2) = 0.089, p < 0.0001). Serum fT3 levels are significantly lower in hypogonadal than eugonadal men (p = 0.022). This suggests that low serum T could be considered a sensitive marker of frailty and poor health status and that the latter might induce hypogonadism. The more HIV-infected men are frail the more they are hypogonadal. This suggests that hypogonadism might be a naturally occurring condition in unhealthy HIV-infected men and raises concern about the safety of T treatment. In conclusion, low serum T is associated with multimorbidity, HANA, and frailty in HIV-infected men and this association seems to be bidirectional. Given the wide attitude to offer T treatment to HIV-infected men, caution is needed when prescribing T to HIV-infected male patients, especially if the patient is unhealthy or frail. PMID- 25704865 TI - Documenting risk: A comparison of policy and information pamphlets for using epidural or water in labour. AB - BACKGROUND: Approximately 30% of Australian women use epidural analgesia for pain relief in labour, and its use is increasing. While epidural analgesia is considered a safe option from an anaesthetic point of view, its use transfers a labouring woman out of the category of 'normal' labour and increases her risk of intervention. Judicious use of epidural may be beneficial in particular situations, but its current common use needs to be assessed more closely. This has not yet been explored in the Australian context. AIM: To examine personal, social, institutional and cultural influences on women in their decision to use epidural analgesia in labour. Examining this one event in depth illuminates other birth practices, which can also be analysed according to how they fit within prevailing cultural beliefs about birth. METHODS: Ethnography, underpinned by a critical medical anthropology methodology. RESULTS: These findings describe the influence of risk culture on labour ward practice; specifically, the policies and practices surrounding the use of epidural analgesia are contrasted with those on the use of water. Engaging with current risk theory, we identify the role of power in conceptualisations of risk, which are commonly perpetuated by authority rather than evidence. CONCLUSIONS: As we move towards a risk-driven society, it is vital to identify both the conception and the consequences of promulgations of risk. The construction of waterbirth as a 'risky' practice had the effect of limiting midwifery practice and women's choices, despite evidence that points to the epidural as the more 'dangerous' option. PMID- 25704866 TI - Successful treatment of classic Kaposi sarcoma with topical timolol: report of two cases. PMID- 25704867 TI - Cerebellar gray and white matter volume and their relation with age and manual motor performance in healthy older adults. AB - OBJECTIVES: Functional neuroimaging and voxel-based morphometry studies have confirmed the important role of the cerebellum in motor behavior. However, little is known about the relationship between cerebellar gray (GMv) and white matter (WMv) volume and manual motor performance in aging individuals. This study aims to quantify the relationship between cerebellar tissue volume and manual motor performance. EXPERIMENTAL DESIGN: To gain more insight into cerebellar function and how it relates to the role of the primary motor cortex (M1), we related cerebellar GMv, WMv, and M1v to manual motor performance in 217 healthy older individuals. Left and right cerebellar GMv and WMv, and M1v were obtained using FreeSurfer. The following motor measures were obtained: grip force, tapping speed, bimanual visuomotor coordination, and manual dexterity. PRINCIPAL OBSERVATIONS: Significant positive relationships were observed between cerebellar GMv and WMv and grip strength, right cerebellar WMv and right-hand tapping speed, right cerebellar WMv and dexterity, M1v and grip strength, and right M1v and left hand dexterity, though effect sizes were small. CONCLUSIONS: Our results show that cerebellar GMv and WMv are differently associated with manual motor performance. These associations partly overlap with the brain-behavior associations between M1 and manual motor performance. Not all observed associations were lateralized (i.e., ipsilateral cerebellar and contralateral M1v associations with motor performance), which could point to age-related neural dedifferentiation. The current study provides new insights in the role of the cerebellum in manual motor performance. In consideration of the small effect sizes replication studies are needed to validate these results. PMID- 25704868 TI - Differences in host species relationships and biogeographic influences produce contrasting patterns of prevalence, community composition and genetic structure in two genera of avian malaria parasites in southern Melanesia. AB - Host-parasite interactions have the potential to influence broadscale ecological and evolutionary processes, levels of endemism, divergence patterns and distributions in host populations. Understanding the mechanisms involved requires identification of the factors that shape parasite distribution and prevalence. A lack of comparative information on community-level host-parasite associations limits our understanding of the role of parasites in host population divergence processes. Avian malaria (haemosporidian) parasites in bird communities offer a tractable model system to examine the potential for pathogens to influence evolutionary processes in natural host populations. Using cytochrome b variation, we characterized phylogenetic diversity and prevalence of two genera of avian haemosporidian parasites, Plasmodium and Haemoproteus, and analysed biogeographic patterns of lineages across islands and avian hosts, in southern Melanesian bird communities to identify factors that explain patterns of infection. Plasmodium spp. displayed isolation-by-distance effects, a significant amount of genetic variation distributed among islands but insignificant amounts among host species and families, and strong local island effects with respect to prevalence. Haemoproteus spp. did not display isolation-by-distance patterns, showed marked structuring of genetic variation among avian host species and families, and significant host species prevalence patterns. These differences suggest that Plasmodium spp. infection patterns were shaped by geography and the abiotic environment, whereas Haemoproteus spp. infection patterns were shaped predominantly by host associations. Heterogeneity in the complement and prevalence of parasite lineages infecting local bird communities likely exposes host species to a mosaic of spatially divergent disease selection pressures across their naturally fragmented distributions in southern Melanesia. Host associations for Haemoproteus spp. indicate a capacity for the formation of locally co-adapted host-parasite relationships, a feature that may limit intraspecific gene flow or range expansions of closely related host species. PMID- 25704869 TI - Designing a robust feature extraction method based on optimum allocation and principal component analysis for epileptic EEG signal classification. AB - The aim of this study is to design a robust feature extraction method for the classification of multiclass EEG signals to determine valuable features from original epileptic EEG data and to discover an efficient classifier for the features. An optimum allocation based principal component analysis method named as OA_PCA is developed for the feature extraction from epileptic EEG data. As EEG data from different channels are correlated and huge in number, the optimum allocation (OA) scheme is used to discover the most favorable representatives with minimal variability from a large number of EEG data. The principal component analysis (PCA) is applied to construct uncorrelated components and also to reduce the dimensionality of the OA samples for an enhanced recognition. In order to choose a suitable classifier for the OA_PCA feature set, four popular classifiers: least square support vector machine (LS-SVM), naive bayes classifier (NB), k-nearest neighbor algorithm (KNN), and linear discriminant analysis (LDA) are applied and tested. Furthermore, our approaches are also compared with some recent research work. The experimental results show that the LS-SVM_1v1 approach yields 100% of the overall classification accuracy (OCA), improving up to 7.10% over the existing algorithms for the epileptic EEG data. The major finding of this research is that the LS-SVM with the 1v1 system is the best technique for the OA_PCA features in the epileptic EEG signal classification that outperforms all the recent reported existing methods in the literature. PMID- 25704870 TI - GPU-based parallel group ICA for functional magnetic resonance data. AB - The goal of our study is to develop a fast parallel implementation of group independent component analysis (ICA) for functional magnetic resonance imaging (fMRI) data using graphics processing units (GPU). Though ICA has become a standard method to identify brain functional connectivity of the fMRI data, it is computationally intensive, especially has a huge cost for the group data analysis. GPU with higher parallel computation power and lower cost are used for general purpose computing, which could contribute to fMRI data analysis significantly. In this study, a parallel group ICA (PGICA) on GPU, mainly consisting of GPU-based PCA using SVD and Infomax-ICA, is presented. In comparison to the serial group ICA, the proposed method demonstrated both significant speedup with 6-11 times and comparable accuracy of functional networks in our experiments. This proposed method is expected to perform the real time post-processing for fMRI data analysis. PMID- 25704871 TI - Vestibular evoked myogenic potentials (VEMPs) evoked by air- and bone-conducted stimuli in vestibular neuritis. AB - OBJECTIVE: To compare and characterise abnormalities for short latency vestibular evoked myogenic potentials (VEMPs) elicited by air- (AC) and two differing types of bone-conducted (BC) stimuli during vestibular neuritis (VN). METHODS: AC (500Hz short tone bursts) and two BC stimuli (500Hz at the forehead and impulses at the mastoids) were used to evoke cervical and ocular potentials (cVEMPs and oVEMPs) in VN patients (n=22) and healthy subjects. RESULTS: More abnormalities were observed for the oVEMP than the cVEMP when using either AC 500Hz or BC 500Hz. The AC stimulus showed slightly more abnormalities than the BC 500Hz stimulus. In contrast, BC impulses produced frequent abnormalities for both oVEMPs and cVEMPs. The findings were modelled, based upon presumed selective lesions of the superior nerve. CONCLUSIONS: AC 500Hz stimulation was slightly better than BC 500Hz in demonstrating abnormalities in patients with VN. BC impulses behave as expected for a predominantly utricular stimulus. The relative contributions of saccular and utricular fibres differ for stimulus type and target reflex. SIGNIFICANCE: AC 500Hz is as effective as BC 500Hz for investigating VN. BC impulses act most strongly on utricular afferents. PMID- 25704872 TI - A matter of font type: The effect of serifs on the evaluation of scientific abstracts. AB - Text-based communication is one of the substantial ways of spreading scientific information. While the content and contextual aspects of written words have been widely researched, the impact of font characteristics on text perception is an almost blank page. The following study deals with the influence of serifs on the evaluation of online-presented scientific abstracts. Yet there is only evidence for faster reading times when texts are presented in sans-serif fonts, although the opposite is stated in parts of the literature. The present work examines if the presence or absence of serifs also have an impact on the appraisal of scientific texts when all other important font characteristics do not change. For this purpose, 188 university students participated in an online experiment and rated different aspects of scientific abstracts as well as of the research outlined in the abstracts. The results show that missing serifs led to increased reading speed. However, and in contrast to the perceptual fluency hypothesis, the presence of serifs had a positive effect on all evaluation dimensions. The results of a second study with 187 participants also indicated that reading fluency counteracted the liking of texts. Implications for future studies and media production are discussed. PMID- 25704873 TI - Biomass-derived carbon quantum dot sensitizers for solid-state nanostructured solar cells. AB - New hybrid materials consisting of ZnO nanorods sensitized with three different biomass-derived carbon quantum dots (CQDs) were synthesized, characterized, and used for the first time to build solid-state nanostructured solar cells. The performance of the devices was dependent on the functional groups found on the CQDs. The highest efficiency was obtained using a layer-by-layer coating of two different types of CQDs. PMID- 25704874 TI - Female participation in collective group defense in black howler monkeys (Alouatta pigra). AB - Many group-living animals actively defend a home range against neighboring groups. In many of these societies, males are the primary participants during group defense, while female participation ranges from seldom to frequent. Among howler monkeys (Alouatta spp.), loud calls (i.e., howling) are often used in the context of intergroup spacing as a form of cooperative group defense. Males initiate and lead these howling bouts, but females occasionally participate as well. During a 28-month study, I examined social and ecological factors influencing the participation of adult females in naturally occurring howling bouts of five multimale-multifemale groups of black howler monkeys (A. pigra) at Palenque National Park, Mexico. I calculated the percentage of time each female participated during howling bouts for which the participation of all resident females could be recorded >=80% of the time (N = 287). At least one female was observed to participate in 53% of the vocal displays. Female participation was significantly greater during howling bouts that were part of visual intergroup encounters compared to spontaneous calls or calls in response to nearby calls when there was no visual contact with rival groups. Female calling behavior was not influenced by the presence of infants vulnerable to infanticide or by the proximity to food resources. Nonetheless, in four of the five study groups, one female called significantly more than the other resident female(s), suggesting that these females played a special role within the group's social dynamics, not previously recognized for this species. PMID- 25704875 TI - Application of current hemorrhage control techniques for backcountry care: part one, tourniquets and hemorrhage control adjuncts. AB - Decade-long advancements in battlefield medicine have revolutionized the treatment of traumatic hemorrhage and have led to a significant reduction in mortality. Older methods such as limb elevation and pressure points are no longer recommended. Tourniquets have had a profound effect on lives saved without the commonly feared safety issues that have made them controversial. Unique tourniquet designs for inguinal and abdominal regions are now available for areas not amenable to current fielded extremity tourniquets. This article, the first of two parts, reviews the literature for advancements in prehospital hemorrhage control for any provider in the austere setting. It emphasizes the significant evidence-based advances in tourniquet use on the extremities that have occurred in battlefield trauma medicine since 2001 and reviews the newer junctional tourniquet devices. Recommendations are made for equipment and techniques for controlling hemorrhage in the wilderness setting. PMID- 25704876 TI - In reply to shark attacks and shark diving. In reply to Dr Brunnschweiler. PMID- 25704877 TI - Application of current hemorrhage control techniques for backcountry care: part two, hemostatic dressings and other adjuncts. AB - Decade-long advances in battlefield medicine have revolutionized the treatment of traumatic hemorrhage and have led to a significant reduction in mortality. Part one of this review covered the use of tourniquets on the extremities and the newer devices for use in junctional areas. Part two focuses on the use of hemostatic agents or dressings, pelvic binders, and tranexamic acid. Field applicable hemostatic dressings are safe and effective in controlling hemorrhage not amenable to extremity tourniquet application, and newer agents with increasing efficacy continue to be developed. Most of these agents are inexpensive and lightweight, making them ideal products for use in wilderness medicine. The use of pelvic binders to stabilize suspected pelvic fractures has gained new interest as these products are developed and refined, and the prehospital use of tranexamic acid, a potent antifibrinolytic, has been found to be life saving in patients at risk of death from severe hemorrhage. Recommendations are made for equipment and techniques for controlling hemorrhage in the wilderness setting. PMID- 25704878 TI - Surfactants with colloids: adsorption or absorption? AB - HYPOTHESIS: The interaction of Aerosol OT (AOT) surfactant with systems of model colloids in nonaqueous solvents (water-in-oil microemulsions, surfactant stabilized silica organosols, and sterically-stabilized PMMA latexes) is expected to be system specific. Two limiting cases are expected: adsorption, with surfactant located at the particle surfaces, or absorption, with surfactant incorporated into the particle cores. EXPERIMENTS: Two approaches have been used to determine how AOT is distributed in the colloidal systems. The stability of the colloids in different alkanes (heptane to hexadecane, including mixtures) has been studied to determine any effects on the colloid surfaces. Contrast-variation small-angle neutron scattering (SANS) measurements of the colloid cores and of AOT-colloid mixtures in colloid-matched solvent have also been performed. Normalization to account for the different scattering intensities and different particle radii have been used to enable a system-independent comparison. FINDINGS: AOT in water-in-oil microemulsions and surfactant-stabilized silica organosols is determined to be adsorbed, whereas, surprisingly, AOT in sterically stabilized PMMA latexes is found to be absorbed. Possible origins of these differences are discussed. PMID- 25704879 TI - A case of successful renal transplantation for hydatid disease after surgical treatment of disseminated cysts. AB - Hydatid disease is a systemic disorder affecting especially the liver and lungs. Although it is not endemic in Europe, it can be seen sporadically, particularly because of travel and immigration. Severe, multiple organ involvement is quite rare. A 39-year-old Kurdish male patient presented with the previous diagnosis of hydatid disease and disseminated cysts in the liver, lung, and left kidney, leading to renal failure and the need for hemodialysis. Following multiple operations, complete eradication of infectious cysts was achieved, and kidney transplantation was performed. After 4 years of follow-up, the patient is in good condition, especially with normal renal function and no sign of recurrent hydatid disease. PMID- 25704880 TI - Two steps forward, one step back: mycophenolate mofetil treatment for myasthenia gravis in the United States. PMID- 25704881 TI - Dysregulated CXCR4 expression promotes lymphoma cell survival and independently predicts disease progression in germinal center B-cell-like diffuse large B-cell lymphoma. AB - Abnormal expression of the chemokine receptor CXCR4 plays an essential role in tumor cell dissemination and disease progression. However, the significance of CXCR4 overexpression in de novo diffuse large B cell lymphoma (DLBCL) is unknown. In 743 patients with de novo diffuse large B cell lymphoma (DLBCL) who received standard Rituximab-CHOP immunochemotherapy, we assessed the expression of CXCR4 and dissected its prognostic significance in various DLBCL subsets. Our results showed that CXCR4+ patients was associated with male, bulky tumor, high Ki-67 index, activated B-cell-like (ABC) subtype, and Myc, Bcl-2 or p53 overexpression. Moreover, CXCR4+ was an independent factor predicting poorer progression-free survival in germinal-center B-cell-like (GCB)-DLBCL, but not in ABC-DLBCL; and in patients with an IPI of <=2, but not in those with an IPI>2. The lack of prognostic significance of CXCR4 in ABC-DLBCL was likely due to the activation of p53 tumor suppressor attenuating CXCR4 signaling. Furthermore, concurrent CXCR4+ and BCL2 translocation showed dismal outcomes resembling but independent of MYC/BCL2 double-hit DLBCL. Gene expression profiling suggested that alterations in the tumor microenvironment and immune responses, increased tumor proliferation and survival, and the dissemination of CXCR4+ tumor cells to distant organs or tissues were underlying molecular mechanisms responsible for the CXCR4+ associated poor prognosis. PMID- 25704882 TI - Sumoylation of HDAC2 promotes NF-kappaB-dependent gene expression. AB - The transcription factor nuclear factor-kappaB (NF-kappaB) is crucial for the maintenance of homeostasis. It is incompletely understood how nuclear NF-kappaB and the crosstalk of NF-kappaB with other transcription factors are controlled. Here, we demonstrate that the epigenetic regulator histone deacetylase 2 (HDAC2) activates NF-kappaB in transformed and primary cells. This function depends on both, the catalytic activity and an intact HDAC2 sumoylation motif. Several mechanisms account for the induction of NF-kappaB through HDAC2. The expression of wild-type HDAC2 can increase the nuclear presence of NF-kappaB. In addition, the ribosomal S6 kinase 1 (RSK1) and the tumor suppressor p53 contribute to the regulation of NF-kappaB by HDAC2. Moreover, TP53 mRNA expression is positively regulated by wild-type HDAC2 but not by sumoylation-deficient HDAC2. Thus, sumoylation of HDAC2 integrates NF-kappaB signaling involving p53 and RSK1. Since HDAC2-dependent NF-kappaB activity protects colon cancer cells from genotoxic stress, our data also suggest that high HDAC2 levels, which are frequently found in tumors, are linked to chemoresistance. Accordingly, inhibitors of NF-kappaB and of the NF-kappaB/p53-regulated anti-apoptotic protein survivin significantly sensitize colon carcinoma cells expressing wild-type HDAC2 to apoptosis induced by the genotoxin doxorubicin. Hence, the HDAC2-dependent signaling node we describe here may offer an interesting therapeutic option. PMID- 25704883 TI - Hydrazinobenzoylcurcumin inhibits androgen receptor activity and growth of castration-resistant prostate cancer in mice. AB - There is a critical need for therapeutic agents that can target the amino terminal domain (NTD) of androgen receptor (AR) for the treatment of castration resistant prostate cancer (CRPC). Calmodulin (CaM) binds to the AR NTD and regulates AR activity. We discovered that Hydrazinobenzoylcurcumin (HBC), which binds exclusively to CaM, inhibited AR activity. HBC abrogated AR interaction with CaM, suppressed phosphorylation of AR Serine81, and blocked the binding of AR to androgen-response elements. RNA-Seq analysis identified 57 androgen regulated genes whose expression was significantly (p <= 0.002) altered in HBC treated cells as compared to controls. Oncomine analysis revealed that genes repressed by HBC are those that are usually overexpressed in prostate cancer (PCa) and genes stimulated by HBC are those that are often down-regulated in PCa, suggesting a reversing effect of HBC on androgen-regulated gene expression associated with PCa. Ingenuity Pathway Analysis revealed a role of HBC affected genes in cellular functions associated with proliferation and survival. HBC was readily absorbed into the systemic circulation and inhibited the growth of xenografted CRPC tumors in nude mice. These observations demonstrate that HBC inhibits AR activity by targeting the AR NTD and suggest potential usefulness of HBC for effective treatment of CRPC. PMID- 25704884 TI - Autophagy induction by leptin contributes to suppression of apoptosis in cancer cells and xenograft model: involvement of p53/FoxO3A axis. AB - Leptin, a hormone mainly produced from adipose tissue, has been shown to induce proliferation of cancer cells. However, the molecular mechanisms underlying leptin-induced tumor progression have not been clearly elucidated. In the present study, we investigated the role of autophagy in leptin-induced cancer cell proliferation using human hepatoma (HepG2) and breast cancer cells (MCF-7), and tumor growth in a xenograft model. Herein, we showed that leptin treatment caused autophagy induction as assessed by increase in expression of autophagy-related genes, including beclin-1, Atg5 and LC3 II, further induction of autophagosome formation and autophagic flux. Interestingly, inhibition of autophagic process by treatment with inhibitors and LC3B gene silencing blocked leptin-induced increase in cell number and suppression of apoptosis, indicating a crucial role of autophagy in leptin-induced tumor progression. Moreover, gene silencing of p53 or FoxO3A prevented leptin-induced LC3 II protein expression, suggesting an involvement of p53/FoxO3A axis in leptin-induced autophagy activation. Leptin administration also accelerated tumor growth in BALB/c nude mice, which was found to be autophagy dependent. Taken together, our results demonstrate that leptin induced tumor growth is mediated by autophagy induction and autophagic process would be a promising target to regulate development of cancer caused by leptin production. PMID- 25704885 TI - Elevated NIBP/TRAPPC9 mediates tumorigenesis of cancer cells through NFkappaB signaling. AB - Regulatory mechanisms underlying constitutive and inducible NFkappaB activation in cancer remain largely unknown. Here we investigated whether a novel NIK- and IKK2-binding protein (NIBP) is required for maintaining malignancy of cancer cells in an NFkappaB-dependent manner. Real-time polymerase chain reaction analysis of a human cancer survey tissue-scan cDNA array, immunostaining of a human frozen tumor tissue array and immunoblotting of a high-density reverse phase cancer protein lysate array showed that NIBP is extensively expressed in most tumor tissues, particularly in breast and colon cancer. Lentivirus-mediated NIBP shRNA knockdown significantly inhibited the growth/proliferation, invasion/migration, colony formation and xenograft tumorigenesis of breast (MDA MB-231) or colon (HCT116) cancer cells. NIBP overexpression in HCT116 cells promoted cell proliferation, migration and colony formation. Mechanistically, NIBP knockdown in cancer cells inhibited cytokine-induced activation of NFkappaB luciferase reporter, thus sensitizing the cells to TNFalpha-induced apoptosis. Endogenous NIBP bound specifically to the phosphorylated IKK2 in a TNFalpha dependent manner. NIBP knockdown transiently attenuated TNFalpha-stimulated phosphorylation of IKK2/p65 and degradation of IkappaBalpha. In contrast, NIBP overexpression enhanced TNFalpha-induced NFkappaB activation, thus inhibiting constitutive and TNFalpha-induced apoptosis. Collectively, our data identified important roles of NIBP in promoting tumorigenesis via NFkappaBeta signaling, spotlighting NIBP as a promising target in cancer therapeutic intervention. PMID- 25704886 TI - Nfkb1/p50 and mammalian aging. PMID- 25704887 TI - Non-mutational (epigenomic) structural variation in the transcriptome of cancer cells. PMID- 25704888 TI - Xenotransplantation from the perspective of moral theology. AB - BACKGROUND: Current medical research in the area of xenotransplantation is driven by the aim to save human lives and to improve the quality of life of those suffering from organ insufficiencies. METHODS: This study reflects the therapeutic intent of xenotransplantation from a theological-ethical perspective. Regarding statements of Christian communities, the analysis focuses mainly on catholic documents. This study takes into account the document on Prospects for Xenotransplantation by the Pontifical Academy for Life as well as a position paper on xenotransplantation released as a collaboration between the German Bishops Conference (Catholic) and the Evangelical Church in Germany (Protestant). Documents of other Christian denominations will be discussed in a separate paper. Aspects concerning the areas of medicine, social ethics and animal ethics are considered as well as biographical, psychosocial, culture-bound and ideological preconditions of acceptability. These aspects also include consequences for the construction of personal identity. RESULTS AND CONCLUSION: With regard to an anthropocentrism that is based theologically and relationally, xenotransplantation--in general--can be viewed as a permissible form of therapy, given that the principles of biomedical ethics will be observed and that animals are treated with respect. PMID- 25704889 TI - Fluorescent CD4 probe for potential HIV-1 gp120 protein detection. AB - A fluorescently modified CD4 domain 1 (mD1) protein has been designed and elaborated in an in vitro expression system. This fluorescent probe contains a Forster resonance energy transfer (FRET) pair, which uses a tryptophan residue as the fluorescence donor and an acridon-2-ylalanine (Acd) as the acceptor. When excited at 260nm, energy was transferred from tryptophan to the Acd residue of mD1, and emitted fluorescence at 420nm. This fluoresence was quenched after Evans blue (EB) inhibitor or HIV-1 gp120 protein binding, presumably as a consequence of changes in the distance and dipole orientation between the donor and acceptor; the emission intensity at 420nm decreased in a concentration-dependent fashion. This fluorescent CD4 probe could be developed into a novel tool for HIV-1 gp120 protein detection. It also could be used to screen small molecules that inhibit the gp120-CD4 interaction. PMID- 25704890 TI - Ritonavir-boosted indinavir but not lopinavir inhibits erythrocytic stage Plasmodium knowlesi malaria in rhesus macaques. AB - The inhibitive activities of the human immunodeficiency virus protease inhibitors ritonavir (RTV) boosted indinavir (IDV) and RTV boosted lopinavir (LPV) for erythrocytic stage malaria were evaluated in rhesus macaques. The IDV/RTV regimen effectively inhibits the replication of Plasmodium knowlesi with clinically relevant doses, whereas the LPV/RTV regimen did not show activity against plasmodium infection. PMID- 25704891 TI - Design and synthesis of novel 2-(indol-5-yl)thiazole derivatives as xanthine oxidase inhibitors. AB - Xanthine oxidase (XO) inhibitors have been widely used for the treatment of gout. Indole rings are frequently used as active scaffold in designing inhibitors for enzymes. Herein, we describe the structure-activity relationship for novel xanthine oxidase inhibitors based on indole scaffold. A series of novel tri substituted 2-(indol-5-yl)thiazole derivatives were synthesized, and their in vitro inhibitory activities against xanthine oxidase and in vivo efficacy lowering uric acid level in blood were measured. Among them, 2-(3-cyano-2 isopropylindol-5-yl)-4-methylthiazole-5-carboxylic acid exhibits the most potent XO inhibitory activity (IC50 value: 3.5nM) and the excellent plasma uric acid lowering activity. Study of structure activity relationship indicated that hydrophobic moiety (e.g., isopropyl) at 1-position and electron withdrawing group (e.g., CN) at 3-position of indole ring and small hydrophobic group (CH3) at 4 position of the thiazole ring enhanced the XO inhibitory activity. Hydrophobic substitution such as isopropyl at 1-position of the indole moiety without any substitution at 2-position has an essential role for enhancing bioavailability and therefore for high in vivo efficacy. PMID- 25704892 TI - 5-Hydroxymethylcytosine and 5-formylcytosine containing deoxyoligonucleotides: facile syntheses and melting temperature studies. AB - An oxidation-based synthetic approach was developed for facile preparation of 5 formyl-2'-deoxycytidine and 5-hydroxymethyl-2'-deoxycytidine phosphoramidites. Upon introducing organic solvent components and copper catalysts, C5-methyl groups of 5-methyl-2'-deoxycytidine and thymidine were readily oxidized to formyl and hydroxyl functionality, respectively. Standard solid phase DNA synthesis and conventional deprotection methods were applicable to synthesize 5-formyl- or 5 hydroxymethyl-cytosine containing DNA oligonucleotides, which were used to study the effect of epigenetic modifications on DNA thermal dynamic stability. PMID- 25704893 TI - Characterization of multidrug-resistant diabetic foot ulcer enterococci. AB - INTRODUCTION: Diabetes mellitus is a highly prevalent chronic progressive disease with complications that include diabetic-foot ulcers. METHODS: Enterococci isolated from diabetic-foot infections were identified, evaluated by macro restriction analysis, and screened for virulence traits and antimicrobial resistance. RESULTS: All isolates were considered multidrug-resistant, cytolysin and gelatinase producers, and the majority also demonstrated the ability to produce biofilms. CONCLUSIONS: These results indicate the importance of enterococci in diabetic-foot infection development and persistence, especially regarding their biofilm-forming ability and resistance to clinically relevant antibiotics. PMID- 25704895 TI - Towards real-time monitoring of artemisinin resistance. PMID- 25704894 TI - Spread of artemisinin-resistant Plasmodium falciparum in Myanmar: a cross sectional survey of the K13 molecular marker. AB - BACKGROUND: Emergence of artemisinin resistance in southeast Asia poses a serious threat to the global control of Plasmodium falciparum malaria. Discovery of the K13 marker has transformed approaches to the monitoring of artemisinin resistance, allowing introduction of molecular surveillance in remote areas through analysis of DNA. We aimed to assess the spread of artemisinin-resistant P falciparum in Myanmar by determining the relative prevalence of P falciparum parasites carrying K13-propeller mutations. METHODS: We did this cross-sectional survey at malaria treatment centres at 55 sites in ten administrative regions in Myanmar, and in relevant border regions in Thailand and Bangladesh, between January, 2013, and September, 2014. K13 sequences from P falciparum infections were obtained mainly by passive case detection. We entered data into two geostatistical models to produce predictive maps of the estimated prevalence of mutations of the K13 propeller region across Myanmar. FINDINGS: Overall, 371 (39%) of 940 samples carried a K13-propeller mutation. We recorded 26 different mutations, including nine mutations not described previously in southeast Asia. In seven (70%) of the ten administrative regions of Myanmar, the combined K13 mutation prevalence was more than 20%. Geospatial mapping showed that the overall prevalence of K13 mutations exceeded 10% in much of the east and north of the country. In Homalin, Sagaing Region, 25 km from the Indian border, 21 (47%) of 45 parasite samples carried K13-propeller mutations. INTERPRETATION: Artemisinin resistance extends across much of Myanmar. We recorded P falciparum parasites carrying K13-propeller mutations at high prevalence next to the northwestern border with India. Appropriate therapeutic regimens should be tested urgently and implemented comprehensively if spread of artemisinin resistance to other regions is to be avoided. FUNDING: Wellcome Trust-Mahidol University-Oxford Tropical Medicine Research Programme and the Bill & Melinda Gates Foundation. PMID- 25704896 TI - Incorporation of liposomes containing squid tunic ACE-inhibitory peptides into fish gelatin. AB - BACKGROUND: Hydrolysates from collagen of jumbo squid (Dosidicus gigas) tunics have shown excellent angiotensin I-converting enzyme (ACE)-inhibitory activity. However, peptides directly included in food systems may suffer a decrease in activity, which could be minimized by loading them into nanoliposomes. RESULTS: A fraction of peptides with molecular weights <1 kDa obtained from hydrolyzed squid tunics, with reasonably high ACE-inhibitory activity (half-maximal inhibitory concentration IC50 = 0.096 g L(-1)), was encapsulated in phosphatidylcholine nanoliposomes. The peptide concentration affected the encapsulation efficiency and the stability of the resulting liposomes, which remained with a high zeta potential value (-54.3 mV) for at least 1 week at the most suitable peptide concentration. The optimal peptide concentration was established as 1.75 g L(-1). Liposomes obtained with this peptide concentration showed an encapsulation efficiency of 53%, a zeta potential of -59 mV, an average diameter of 70.3 nm and proved to be stable in the pH range 3-7 at 4 degrees C. CONCLUSION: Liposomes containing ACE-inhibitory peptides were incorporated in fish gelatin without detriment to the rheological properties and thermal stability of the resulting cold-induced gel. The ACE-inhibitory activity of the peptide fraction, which was not affected by the encapsulation process, conferred the bioactive potential to the nanoliposome-containing gelatin gel. PMID- 25704897 TI - Minimization of errors in biexponential T2 measurements of the prostate. AB - PURPOSE: To determine the echo times that provide the greatest precision in measurements of prostate T2s. T2 relaxation time measurements in the prostate are complicated by the structure of prostate tissue, which consists of fluid-filled glands surrounded by epithelial and stromal cells. Since the glands are large relative to diffusion distances, there is little water exchange between the two compartments and T2s are biexponential. Because the relative size and characteristics of the two compartments change in prostate tumors, accurate measurement of the characteristics of each may provide useful information on tumor grade. MATERIALS AND METHODS: T2s were measured in a group of 25 men with biopsy-proven prostate cancer. Subjects were scanned at 3T with a 16-echo turbo spin echo T2-mapping sequence. Normal prostate T2s were measured in areas showing no disease. Optimum echo times for measurement of normal prostate T2s were found by calculating the covariance matrix, which provides estimates of parameter variance. Echo times that minimize T2 variance were then found by searching over grids of different echo times. Optima for four to eight echo acquisitions were found. Optima were tested by Monte Carlo simulation. RESULTS: Fast and slow T2s were 60 msec and 360 msec, respectively. The fast signal fraction was 0.6. Optimum echo times were between 0 and 780 msec, depending on the number of echoes acquired. CONCLUSION: Use of optimum echo times can substantially improve the precision of biexponential T2 measurements. This optimization is anticipated to improve prostate cancer characterization using T2 measurements. PMID- 25704898 TI - Seasonal variation of leaf wax n-alkane production and delta(2)H values from the evergreen oak tree, Quercus agrifolia. AB - In order to understand the timing of leaf wax synthesis in higher plants, we analysed the variability in leaf wax n-alkane concentration, composition (expressed as average chain length (ACL)), and delta(2)Hwax values as well as plant source water delta(2)H values (xylem and leaf water) in the evergreen tree Quercus agrifolia over a period of 9 months, beginning with leaf flush. We identified three distinct periods of leaf development with the first month following leaf flush being characterized by de novo synthesis and possibly removal of n-alkanes. During the following 3 months, n-alkane concentrations increased sevenfold and delta(2)Hwax and ACL values increased, suggesting this period was the major leaf wax n-alkane formation period. During the remaining 4 months of the experiment, stable values suggest cessation of leaf wax n-alkane formation. We find that n-alkane synthesis in Q. agrifolia takes place over 4 months, substantially longer than that observed for deciduous trees. PMID- 25704899 TI - Granular transport in driven granular gas. AB - We numerically and theoretically investigate the behavior of a granular gas driven by asymmetric plates. The injection of energy in the dissipative system differs from one side to the opposite one. We prove that the dynamical clustering which is expected for such a system is affected by the asymmetry. As a consequence, the cluster position can be fully controlled. This property could lead to various applications in the handling of granular materials in low-gravity environment. Moreover, the dynamical cluster is characterized by natural oscillations which are also captured by a model. These oscillations are mainly related to the cluster size, thus providing an original way to probe the clustering behavior. PMID- 25704900 TI - Analyzing critical propagation in a reaction-diffusion-advection model using unstable slow waves. AB - The effect of advection on the propagation and in particular on the critical minimal speed of traveling waves in a reaction-diffusion model is studied. Previous theoretical studies estimated this effect on the velocity of stable fast waves and predicted the existence of a critical advection strength below which propagating waves are not supported anymore. In this paper, an analytical expression for the advection-velocity relation of the unstable slow wave is derived. In addition, the critical advection strength is calculated taking into account the unstable slow wave solution. We also analyze a two-variable reaction diffusion-advection model numerically in a wide parameter range. Due to the new control parameter (advection) we can find stable wave propagation in the otherwise non-excitable parameter regime, if the advection strength exceeds a critical value. Comparing theoretical predictions to numerical results, we find that they are in good agreement. Theory provides an explanation for the observed behaviour. PMID- 25704901 TI - [Targeted therapies in non-small cell lung cancer in 2014]. AB - For several years, the identification of molecular sequencing alterations has considerably changed the perception and treatment of non-small cell lung cancer (NSCLC). These alterations have been defined as "driver mutations", such as mutations in EGFR and EML4-ALK fusion gene, and are highly sensitive to specific therapies. Other targets have also been identified recently. Personalized medicine is now a reality for patients with advanced NSCLC on the basis of routine screening for EGFR, HER2, KRAS, BRAF, PI3KCA mutations and EML4-ALK rearrangement. This article describes identified biomarkers, available targeted therapies, and the main clinical research approaches in NSCLC. PMID- 25704902 TI - Contribution of exhaled nitric oxide measurement in airway inflammation assessment in asthma. A position paper from the French Speaking Respiratory Society. AB - Nitric oxide (NO) is both a gas and a ubiquitous inter- and intracellular messenger with numerous physiological functions. As its synthesis is markedly increased during inflammatory processes, NO can be used as a surrogate marker of acute and/or chronic inflammation. It is possible to quantify fractional concentration of NO in exhaled breath (FENO) to detect airway inflammation, and thus improve the diagnosis of asthma by better characterizing asthmatic patients with eosinophilic bronchial inflammation, and eventually improve the management of targeted asthmatic patients. FENO measurement can therefore be viewed as a new, reproducible and easy to perform pulmonary function test. Measuring FENO is the only non-invasive pulmonary function test allowing (1) detecting, (2) quantifying and (3) monitoring changes in inflammatory processes during the course of various respiratory disorders, including corticosensitive asthma. PMID- 25704903 TI - Topical use of antithrombotics: review of literature. AB - While antithrombotics are usually administered intravenously, subcutaneously or orally, there are a number of publications reporting topical application of anticoagulation therapy. This paper aims to review the available literature regarding clinical conditions, the details of the topical antithrombotic treatment, as well as positive or adverse effects in an attempt to ascertain the safety and efficacy of this form of treatment. Published literature was searched to identify publications reporting the use of antithrombotic treatments administered via topical application between 1st January 1990 and 1st January 2013. There were 43 studies reported in 10 different clinical conditions. Majority of the studies were randomized controlled trials (51.2%), prospective studies (18.6%) or case reports (11.6%). The clinical conditions in which topical antithrombotics were administered included: microangiopathy, acute haemorrhoids, periodontitis, dermatitis, burns, ocular conditions and surgery, blunt force impact, scars, as well as clinical conditions associated with superficial venous thrombosis (SVT). The most commonly used topical antithrombotic was heparin (79.1% of studies). The respective dosage of different antithrombotics varied depending on specific clinical conditions. While most studies reported mean improvements or resolution of symptoms/condition in patients, the patient outcomes were variable. This review demonstrates that topical antithrombotic treatment is used according to a wide variety of protocols, with a subsequent variability in patient outcomes. Specific guidelines for the use of topical antithrombotics should be developed to standardize this form of treatment and ensure the best possible outcomes for patients. PMID- 25704904 TI - Aortic pseudoaneurysm rupture secondary to pancreatitis: An endovascular approach. PMID- 25704905 TI - Infrapopliteal arterial recanalization: A true advance for limb salvage in diabetics. AB - The world is facing an epidemic of diabetes; consequently in the next years, critical limb ischemia (CLI) due to diabetic arterial disease, characterized by multiple and long occlusions of below-the-knee (BTK) vessels, will become a major issue for vascular operators. Revascularization is a key therapy in these patients as restoring adequate blood supply to the wound is essential for healing, thus avoiding major amputations. Endoluminal therapy for BTK arteries is now a key part of the vascular specialist armamentarium. Tibial artery endovascular approaches have been shown to achieve high limb salvage rates with low morbidity and mortality and endovascular interventions one should now consider to be the first line treatment in the majority of CLI patients, especially in those with associated medical comorbidities. To do so, the vascular specialist requires detailed knowledge of the BTK endovascular techniques and devices. The first step decision in tibial endovascular therapy is access. In this context, the anterograde ipsilateral approach is generally preferred. The next critical decision is the choice of the vessel(s) to be approached in order to achieve successful limb salvage. Obtaining pulsatile flow to the correct portion of the foot is the paramount for ulcer healing. As such, a good understanding of the current angiosome model should enhance clinical results. The devices used should be carefully selected and optimal choice of guide wire is also extremely important and should be based on the characteristics of the lesion (location, length, and stenosis/occlusion) together with the characteristics of the guide wire itself (tip load, stiffness, hydrophilic/hydrophobic coating, flexibility, torque transmission, trackability, and pushability). Passing through chronic total occlusions can be quite challenging. The vascular interventional radiologist needs therefore to master the techniques that have been recently described: anterograde approaches, including the drilling technique, the penetrating technique, the subintimal technique and the parallel technique; subintimal arterial flossing with anterograde-retrograde procedures (Safari); the pedal-plantar loop technique and revascularization through collateral fibular artery vessels. PMID- 25704907 TI - Visceral leishmaniasis mimicking systemic lupus erythematosus: Case series and a systematic literature review. AB - OBJECTIVE: Systemic lupus erythematosus (SLE) is an autoimmune disease that may present manifestations that resemble other diseases. Visceral leishmaniasis (VL) is a parasitic infection whose hallmarks may mimic SLE symptoms. Here, we report a case series and evaluate the published, scientific evidence of the relationship between SLE and VL infection. METHODS: To assess original studies reporting cases of VL-infected patients presenting manifestations that are capable of leading to inappropriate suspicions of SLE or mimicking an SLE flare, we performed an extensive search in several scientific databases (MEDLINE, LILACS, SciELO, and Scopus). Two authors independently screened all citations and abstracts identified by the search strategy to identify eligible studies. Secondary references were additionally obtained from the selected articles. RESULTS: The literature search identified 53 eligible studies, but only 17 articles met our criteria. Among these, 10 lupus patients with VL mimicking an SLE flare and 18 cases of VL leading to unappropriated suspicions of SLE were described. The most common manifestations in patients infected with VL were intermittent fever, pancytopenia, visceromegaly, and increased serum level of acute phase reactants. The most frequent autoantibodies were antinuclear antibodies, rheumatoid factor, and direct Coombs' test. CONCLUSION: In endemic areas for VL, the diagnosis of SLE or its exacerbation may be a clinical dilemma. Hepatosplenomegaly or isolated splenomegaly was identified in the majority of the reported cases where VL occurred, leading to unappropriated suspicions of SLE or mimicking an SLE flare. Furthermore, the lack of response to steroids, the normal levels of complement proteins C3 and C4, and the increased level of transaminases suggest a possible infectious origin. PMID- 25704910 TI - An in-depth mixed-methods approach to Ryan White HIV/AIDS care program comprehensive needs assessment from the Northeast Georgia Public Health District: the significance of patient privacy, psychological health, and social stigma to care. AB - We apply a social-ecological interpretive framework to understanding relationships among patient privacy, psychological health, social stigma, and continuity in care in the HIV treatment cascade in the rural southeastern US. This research was conducted as part of the 2013 comprehensive needs assessment for the Northeast Georgia Ryan White Consortium using an anthropologically informed mixed-methods design, and a deductive-inductive approach to thematic analysis of qualitative data obtained in interviews and focus groups with service providers and service utilizers. Our comprehensive needs assessment yielded two key components. First, we identified salient phenomena influencing introduction to, retention among, and satisfaction of patients in the Ryan White-coordinated treatment cascade in NE-GA. Second, we formulated actionable recommendations around leverage points identified in the current district-wide system of care. Results highlight spatial, institutional, and interpersonal aspects of the system of care that intersect around issues of patient privacy, psychological health, and social stigma. These intersections constitute pathways by which persons living with HIV are exposed to stigma and other negative social signals regarding their health status without sufficient access to behavioral health services. These negative issues, in turn, can erect significant barriers to long-term continuity in care. PMID- 25704908 TI - Identifying transcriptional cis-regulatory modules in animal genomes. AB - Gene expression is regulated through the activity of transcription factors (TFs) and chromatin-modifying proteins acting on specific DNA sequences, referred to as cis-regulatory elements. These include promoters, located at the transcription initiation sites of genes, and a variety of distal cis-regulatory modules (CRMs), the most common of which are transcriptional enhancers. Because regulated gene expression is fundamental to cell differentiation and acquisition of new cell fates, identifying, characterizing, and understanding the mechanisms of action of CRMs is critical for understanding development. CRM discovery has historically been challenging, as CRMs can be located far from the genes they regulate, have few readily identifiable sequence characteristics, and for many years were not amenable to high-throughput discovery methods. However, the recent availability of complete genome sequences and the development of next-generation sequencing methods have led to an explosion of both computational and empirical methods for CRM discovery in model and nonmodel organisms alike. Experimentally, CRMs can be identified through chromatin immunoprecipitation directed against TFs or histone post-translational modifications, identification of nucleosome-depleted 'open' chromatin regions, or sequencing-based high-throughput functional screening. Computational methods include comparative genomics, clustering of known or predicted TF-binding sites, and supervised machine-learning approaches trained on known CRMs. All of these methods have proven effective for CRM discovery, but each has its own considerations and limitations, and each is subject to a greater or lesser number of false-positive identifications. Experimental confirmation of predictions is essential, although shortcomings in current methods suggest that additional means of validation need to be developed. For further resources related to this article, please visit the WIREs website. CONFLICT OF INTEREST: The authors have declared no conflicts of interest for this article. PMID- 25704911 TI - The incidental relationship between serum ferritin levels and hypertension. AB - BACKGROUND AND OBJECTIVE: Although several studies have shown an association between ferritin level and hypertension, only a few studies have investigated the longitudinal relationship between them. Thus, we evaluated the incidental risk for hypertension according to baseline ferritin level. PATIENTS AND METHODS: A total of 7104 healthy Korean men matched by a propensity score, who had participated in a medical health check-up program in 2005, were followed up from 2005 to 2010. They were divided into four groups according to baseline serum ferritin level (first quartile-fourth quartile). The incidence of hypertension was compared among the four groups, and the Cox-proportional hazard model was used to assess whether the development of hypertension was associated with higher baseline serum ferritin level. RESULTS: A total of 1252 (17.6%) cases had newly developed hypertension during the 26,339.5 person-years of follow-up between 2006 and 2010. The adjusted hazard ratios (HRs) (95% confidence intervals, CIs) for incident hypertension were 1.00 (reference), 1.09 (0.91-1.30), 1.21 (1.01-1.45) and 1.28 (1.07-1.52), respectively (P for trend=0.003) through the quartiles of serum ferritin levels, respectively, after adjusting for multiple confounders. For the log-transformed serum ferritin levels as a continuous variable, adjusted HRs and 95% CIs for HTN were 1.15 (1.02-1.29). CONCLUSIONS: Elevated serum ferritin level was independently associated with the incidental risk for hypertension in Korean men. This finding suggests the value of elevated ferritin level as an early predictor of hypertension. PMID- 25704912 TI - The role of telomeres in predicting individual radiosensitivity of patients with cancer in the era of personalized radiotherapy. AB - Radiotherapy plays a key role in cancer treatments, but tumor cell death differs from one tumor to another. The response of patients to radiotherapy varies considerably and adverse side effects are difficult to prevent. The mechanisms involved in the heterogeneity of this response are not well understood. In order to enhance the efficacy and safety of radiotherapy, it is important to identify subpopulations most at risk of developing a late adverse response to radiotherapy. Telomeres are composed of multiple repeats of a unique sequence of nucleotides forming a TTAGGG pattern. They protect chromosomes from end-to-end fusion and maintain genomic stability. Telomeres have been shown to be extremely sensitive to radiotherapy especially because of their atypical DNA damage repair response, which includes partial inhibition of the non-homologous end joining repair pathway. Ionizing Radiation (IR)-induced damage to telomere DNA could lead to chromosome instability and the initiation or progression of tumor processes. Telomeres could thus be a reliable marker of IR exposure and as such become a new parameter for predicting radiosensitivity. Furthermore, short telomeres are more sensitive to radiotherapy, which could partially explain differences in tumor cell death and in inter-individual sensitivity to radiotherapy. Telomere length could be used to identify subpopulations of patients who could benefit from higher or lower doses per fraction. Finally, pharmacological interference with tumor-cell telomere biology to reduce telomere length and/or telomere stability could also enhance the effectiveness and safety of radiotherapy. Telomeres could play a key role in radiotherapy in the era of personalized medicine. PMID- 25704913 TI - Differential associations between childhood trauma subtypes and adolescent HPA axis functioning. AB - Studies examining the association between childhood trauma exposure and neuroendocrine functioning have returned inconsistent findings. To date, few studies have accounted for the role exposure to different types of childhood trauma may have on different neuroendocrine adaptations, and no study has examined this association using multiple indices of hypothalamic-pituitary adrenal axis (HPA-axis) functioning. The purpose of this study was to characterize the unique associations between exposure to physical abuse, emotional abuse, and non-intentional trauma, and multiple indices of HPA-axis functioning. METHODS: A community sample of 138 youth (aged 9-16) completed the Socially Evaluated Cold Pressor Task (SE-CPT) while their parents completed the Early Trauma Inventory (ETI). All youth then collected 4 diurnal salivary cortisol samples at home across 2 consecutive weekdays. RESULTS: High reported exposure to non-intentional trauma was associated with intact diurnal regulation but elevated cortisol at bedtime, physical abuse was associated with faster reactivity to acute stress, and emotional abuse was associated with delayed recovery of cortisol following acute stress. Taken together, there was a heterogeneous relationship among different indices of HPA-axis functioning and trauma subtype. DISCUSSION: Different types of childhood trauma exposure are related to distinct anomalies in HPA-axis functioning. This study underscores the importance of research incorporating multiple indices of HPA-axis functioning to inform our understanding of the underlying neuroendocrine dysregulation that may later lead to stress-related psychopathology. PMID- 25704914 TI - Mechanisms regulating cell membrane localization of the chemokine receptor CXCR4 in human hepatocarcinoma cells. AB - Hepatocellular carcinoma (HCC) cells with a mesenchymal phenotype show an asymmetric subcellular distribution of the chemokine receptor CXCR4, which is required for cell migration and invasion. In this work we examine the mechanisms that regulate the intracellular trafficking of CXCR4 in HCC cells. Results indicate that HCC cells present CXCR4 at the cell surface, but most of this protein is in endomembranes colocalizing with markers of the Golgi apparatus and recycling endosomes. The presence of high protein levels of CXCR4 present at the cell surface correlates with a mesenchymal-like phenotype and a high autocrine activation of the Transforming Growth Factor-beta (TGF-beta) pathway. CXCR4 traffics along the Golgi/exocyst/plasma membrane pathway and requires EXOC4 (Sec8) component of the exocyst complex. HCC cells use distinct mechanisms for the CXCR4 internalization such as dynamin-dependent endocytosis and macropinocytosis. Regardless of the endocytic mechanisms, colocalization of CXCR4 and Rab11 is observed, which could be involved not only in receptor recycling but also in its post-Golgi transport. In summary, this work highlights membrane trafficking pathways whose pharmacological targeting could subsequently result in the inactivation of one of the main guiding mechanisms used by metastatic cells to colonize secondary organs and tissues. PMID- 25704915 TI - Protective effects of ectoine on behavioral, physiological and biochemical parameters of Daphnia magna subjected to hydrogen peroxide. AB - Ectoine (ECT) is an osmoprotectant produced by halophilic microorganisms inducing protective effects against various stressful factors. However, little is known about its influence on aquatic invertebrates subjected to hydrogen peroxide (H2O2)-a commonly used oxidative disinfectant. Therefore, the aim of our study was to determine the effects of H2O2 alone (at 5 and 10 mg/L) and in the combination with various concentrations of ECT (5, 10 and 25 mg/L) on behavioral, physiological and biochemical parameters of Daphnia magna. The following endpoints were determined: mortality, heart rate, thoracic limb movement, total glutathione (GSH)/oxidized glutathione (GSSG) ratio, catalase (CAT) activity and nitric oxide (NOx) level. The study showed that daphnids exposed to the combination of H2O2+ECT showed decreased mortality, attenuated inhibition of heart rate and thoracic limb activity, less decreased GSH/GSSG ratio, lower stimulation of CAT activity and NOx level when compared to the crustaceans exposed to H2O2 alone. The most pronounced alleviation of toxic effects was observed in the combination of 5 mg/L H2O2+25 mg/L ECT. The results suggest that protective effects of ECT in D. magna subjected to H2O2 may be related to antioxidative properties of the osmoprotectant. PMID- 25704917 TI - A theoretical study of the mechanism of the atmospherically relevant reaction of chlorine atoms with methyl nitrate, and calculation of the reaction rate coefficients at temperatures relevant to the troposphere. AB - The reaction between atomic chlorine (Cl) and methyl nitrate (CH3ONO2) is significant in the atmosphere, as Cl is a key oxidant, especially in the marine boundary layer, and alkyl nitrates are important nitrogen-containing organic compounds, which are temporary reservoirs of the reactive nitrogen oxides NO, NO2 and NO3 (NOx). Four reaction channels HCl + CH2ONO2, CH3OCl + NO2, CH3Cl + NO3 and CH3O + ClNO2 were considered. The major channel is found to be the H abstraction channel, to give the products HCl + CH2ONO2. For all channels, geometry optimization and frequency calculations were carried out at the M06-2X/6 31+G** level, while relative electronic energies were improved to the UCCSD(T*) F12/CBS level. The reaction barrier (DeltaE(?)0K) and reaction enthalpy (DeltaH(RX)298K) of the H abstraction channel were computed to be 0.61 and -2.30 kcal mol(-1), respectively, at the UCCSD(T*)-F12/CBS//M06-2X/6-31+G** level. Reaction barriers (DeltaE(?)0K) for the other channels are more positive and these pathways do not contribute to the overall reaction rate coefficient in the temperature range considered (200-400 K). Rate coefficients were calculated for the H-abstraction channel at various levels of variational transition state theory (VTST) including tunnelling. Recommended ICVT/SCT rate coefficients in the temperature range 200-400 K are presented for the first time for this reaction. The values obtained in the 200-300 K region are particularly important as they will be valuable for atmospheric modelling calculations involving reactions with methyl nitrate. The implications of the results to atmospheric chemistry are discussed. Also, the enthalpies of formation, DeltaHf,298K, of CH3ONO2 and CH2ONO2 were computed to be -29.7 and 19.3 kcal mol(-1), respectively, at the UCCSD(T*)-F12/CBS level. PMID- 25704916 TI - The Hippo transducer TAZ promotes epithelial to mesenchymal transition and cancer stem cell maintenance in oral cancer. AB - The Hippo pathway has emerged as a fundamental regulator in tissue growth, organ size and stem cell functions, and tumorigenesis when deregulated. However, its roles and associated molecular mechanisms underlying oral squamous cell carcinoma (OSCC) initiation and progression remain largely unknown. Here, we identified TAZ, the downstream effector of Hippo signaling, as a novel bona fide oncogene by promoting cell proliferation, migration/invasion and chemoresistance in OSCC. TAZ promoted epithelial-to-mesenchymal transition (EMT) and also was involved in TGF beta1-induced EMT in oral cancer cells. Furthermore, enriched TAZ sustained self renewal, maintenance, tumor-seeding potential of oral cancer stem cells (CSCs). Remarkably, enforced TAZ overexpression conferred CSCs-like properties on differentiated non-CSCs and fueled phenotypic transition from non-CSCs to CSCs like cells. Mechanistically, TAZ-TEADs binding and subsequent transcriptional activation of EMT mediators and pluripotency factors are presumably responsible for TAZ-mediated EMT and non-CSCs-to-CSCs conversion. Importantly, aberrant TAZ overexpression was found to be associated with tumor size, pathological grade and cervical lymph node metastasis, as well as unfavorable prognosis. Pharmacological repression of TAZ by simvastatin resulted in potent anti-cancer effects against OSCC. Taken together, our findings have revealed critical links between TAZ, EMT and CSCs in OSCC initiation and progression, and also established TAZ as a novel cancer biomarker and viable druggable target for OSCC therapeutics. PMID- 25704918 TI - Validation of CT-MRI fusion for intraoperative assessment of stereotactic accuracy in DBS surgery. PMID- 25704919 TI - Early and subacute inflammatory response and long-term survival after hip trauma and surgery. AB - BACKGROUND: Hip fractures represent major source of morbidity in elderly patients. There is little evidence about the impact of inflammatory changes induced by hip trauma and surgery on long term survival. METHODS: We evaluated the prognostic significance of the surgery-related dynamics of white blood cell count (WBC), neutrophil to lymphocyte ratio (NLR), C-reactive protein (CRP), interleukin-6 (IL-6) and soluble adhesion molecules (including P-selectin, E selectin and VCAM) on survival in 104 consecutive patients with traumatic hip fractures recruited within the 2 years period. RESULTS: In surviving patients, the minimum follow-up length was 48 and maximum 84 months (median 60 months). The mean age of the population was 80 +/- 9 years, 72% were women. The survival rates were 69%, 45% and 38% at one, three and five years of the follow-up, respectively. Baseline serum creatinine, older age and subdural anesthesia type were associated with worse survival. The acute inflammatory response failed to predict the long term survival. In contrast, elevated WBC and IL-6 as assessed 21 days after the surgery were associated with a significantly worse outcome. CONCLUSION: The survival of elderly patients undergoing the surgery for acute hip fracture is unfavorable. In contrast to previous reports, we did not confirm that acute inflammatory response to the surgery predicts the long-term survival. On the contrary, persistent elevation of WBC and IL-6 three weeks after the surgery indicates a poor outcome. PMID- 25704920 TI - Socioeconomic status, social relations and domestic violence (DV) against elderly people in Canada, Albania, Colombia and Brazil. AB - PURPOSE: To determine whether gender, socioeconomic conditions, and/or social relations are related to recent experiences of DV in older adult populations. MATERIALS AND METHODS: Data on socioeconomic status and social relations were collected in 2012 from 1995 community-dwelling older adults in Canada, Colombia, Brazil, and Albania. Violence experienced in the last 6 months was measured using the Hurt, Insulted, Threatened with harm, or Screamed at (HITS) scale and classified according to type (physical or psychological) and perpetrator (partner or family member). Binary logistic regression analyses were used to assess associations between experiences of violence and gender, socioeconomic conditions, and social relations. RESULTS: Physical violence (by partner or family member) was reported by 0.63-0.85% of participants; the prevalence of psychological violence (by partner or family member) ranged from 3.2% to 23.5% in men and 9% to 26% in women. After adjustment for socioeconomic status, social relations, age and site, women experienced more psychological violence perpetrated by family members than did men (odds ratio (OR): 1.8; 95% CI: 1.2 2.6). Social relations, such as multifamily living arrangements and low levels of support from partners, children, and family, were associated with psychological DV. Current working status was associated with greater odds of victimization by partners among men (OR: 2.35 95% CI: 1.34-1.41), but not among women. CONCLUSIONS: Gender and social relations are important determinants of experiencing violence in older adults. The findings of this study demonstrate the importance of a gender-based approach to the study of DV in older adults. PMID- 25704921 TI - Suppression of CYP2C9 by microRNA hsa-miR-128-3p in human liver cells and association with hepatocellular carcinoma. AB - Published studies have identified genetic variants, somatic mutations, and changes in gene expression profiles that are associated with hepatocellular carcinoma (HCC), particularly involving genes that encode drug metabolizing enzymes (DMEs). CYP2C9, one of the most abundant and important DMEs, is involved in the metabolism of many carcinogens and drugs and is down-regulated in HCC. To investigate the molecular mechanisms that control CYP2C9 expression, we applied integrative approaches including in silico, in vitro, and in vivo analyses to elucidate the role of microRNA hsa-miR-128-3p in the regulation of CYP2C9 expression and translation. RNA electrophoresis mobility shift assays demonstrated a direct interaction between hsa-miR-128-3p and its cognate target, the CYP2C9 transcript. Furthermore, the expression of a luciferase reporter gene containing the 3'-UTR of CYP2C9 and the endogenous expression of CYP2C9 were suppressed by transfection of hsa-miR-128-3p. Importantly, chemically-induced up- or down-regulation of hsa-miR-128-3p correlated inversely with the expression of CYP2C9. Finally, an association analysis revealed that the expression of hsa-miR 128-3p is inversely correlated with the expression of CYP2C9 in HCC tumor tissues. Altogether, the study helped to elucidate the mechanism of CYP2C9 regulation by hsa-miR-128-3p, and the inverse association in HCC. PMID- 25704922 TI - Site-selective and metal-free aliphatic C-H oxidation enabled synthesis of [5,24,25-D3]-(25S)-Delta(7)-dafachronic acid. AB - Steroid hormones play significant roles in both worms and mammalians. (25S) Delta(7)-Dafachronic acid (Delta(7)-DA, 1) is a member of the dafachronic acid hormonal series that regulates both development and lifespan of C. elegans. Despite its importance, effective tools for the illumination of its mode of action are lacking. Herein, we report an efficient synthesis of trideuterated Delta(7)-DA, [5,24,25-D3]-(25S)-Delta(7)-dafachronic acid ([D3]-Delta(7)-DA, 2), as a useful chemical tool for subsequent biological studies. Key steps for this bioinspired synthesis approach include site-selective aliphatic C-H oxidation mediated by methyl(trifluoromethyl)dioxirane (TFDO), and the iridium/phosphine oxazoline-catalyzed late-stage asymmetric deuterium reduction. PMID- 25704923 TI - The Protective Effect of Apocynin on Cyclosporine A-Induced Hypertension and Nephrotoxicity in Rats. AB - Cyclosporine A (CsA) is the prototype of immunosuppressant drugs that has provided new perspectives in human and veterinary medicine to prevent organ transplant rejection and to treat certain autoimmune diseases and dermatologic diseases. Unfortunately, the treatment with CSA is often limited by severe adverse effects such as hypertension and nephrotoxicity. Some data suggest that reactive oxygen species (ROS) and the oxidative stress play an important role in its pathogenesis, in particular the superoxide (O2 (-)) that is the most powerful free radical generated by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase present mainly in the kidney. The present study has been designed to investigate the role of Apocynin a selective inhibitor of NADPH oxidase activity on cyclosporine-induced adverse effect. In this study, we have evaluated the effect of CsA, used alone or in association with Apocynin on blood pressure (BP), on glomerular filtration rate (GFR), on absoluted fluid reabsorption (Jv) in proximal tubule (PT), on O2 (-) concentration, and on nitric oxide (NO) production. We have demonstrated that CsA administration increases superoxide concentration in the aorta, decreases the NO concentration, reduces GFR and the Jv in PT, and induces a significant increase in BP. Moreover, we have shown that Apocynin treatment restores these hemodynamic alterations, as well as NO and superoxide productions. In conclusion, the reported data indicate that CsA induced nephrotoxicity and hypertension are related to NADPH oxidase activity, in fact Apocynin protects the kidney function and BP from toxic effects induced by CsA through the inhibition of NADPH oxidase activity. PMID- 25704924 TI - Is bigger better? An empirical analysis of waste management in New South Wales. AB - Across the world, rising demand for municipal solid waste services has seen an ongoing increase in the costs of providing these services. Moreover, municipal waste services have typically been provided through natural or legal monopolies, where few incentives exist to reduce costs. It is thus vital to examine empirically the cost structure of these services in order to develop effective public policies which can make these services more cost efficient. Accordingly, this paper considers economies of size and economies of output density in the municipal waste collection sector in the New South Wales (NSW) local government system in an effort to identify the optimal size of utilities from the perspective of cost efficiency. Our results show that - as presently constituted NSW municipal waste services are not efficient in terms of costs, thereby demonstrating that 'bigger is not better.' The optimal size of waste utilities is estimated to fall in the range 12,000-20,000 inhabitants. However, significant economies of output density for unsorted (residual) municipal waste collection and recycling waste collection were found, which means it is advantageous to increase the amount of waste collected, but maintaining constant the number of customers and the intervention area. PMID- 25704925 TI - Forecasting of municipal solid waste quantity in a developing country using multivariate grey models. AB - In order to plan, manage and use municipal solid waste (MSW) in a sustainable way, accurate forecasting of MSW generation and composition plays a key role. It is difficult to carry out the reliable estimates using the existing models due to the limited data available in the developing countries. This study aims to forecast MSW collected in Thailand with prediction interval in long term period by using the optimized multivariate grey model which is the mathematical approach. For multivariate models, the representative factors of residential and commercial sectors affecting waste collected are identified, classified and quantified based on statistics and mathematics of grey system theory. Results show that GMC (1, 5), the grey model with convolution integral, is the most accurate with the least error of 1.16% MAPE. MSW collected would increase 1.40% per year from 43,435-44,994 tonnes per day in 2013 to 55,177-56,735 tonnes per day in 2030. This model also illustrates that population density is the most important factor affecting MSW collected, followed by urbanization, proportion employment and household size, respectively. These mean that the representative factors of commercial sector may affect more MSW collected than that of residential sector. Results can help decision makers to develop the measures and policies of waste management in long term period. PMID- 25704926 TI - Precious metal recovery from waste printed circuit boards using cyanide and non cyanide lixiviants--A review. AB - Waste generated by the electrical and electronic devices is huge concern worldwide. With decreasing life cycle of most electronic devices and unavailability of the suitable recycling technologies it is expected to have huge electronic and electrical wastes to be generated in the coming years. The environmental threats caused by the disposal and incineration of electronic waste starting from the atmosphere to the aquatic and terrestrial living system have raised high alerts and concerns on the gases produced (dioxins, furans, polybrominated organic pollutants, and polycyclic aromatic hydrocarbons) by thermal treatments and can cause serious health problems if the flue gas cleaning systems are not developed and implemented. Apart from that there can be also dissolution of heavy metals released to the ground water from the landfill sites. As all these electronic and electrical waste do posses richness in the metal values it would be worth recovering the metal content and protect the environmental from the pollution. Cyanide leaching has been a successful technology worldwide for the recovery of precious metals (especially Au and Ag) from ores/concentrates/waste materials. Nevertheless, cyanide is always preferred over others because of its potential to deliver high recovery with a cheaper cost. Cyanidation process also increases the additional work of effluent treatment prior to disposal. Several non-cyanide leaching processes have been developed considering toxic nature and handling problems of cyanide with non toxic lixiviants such as thiourea, thiosulphate, aqua regia and iodine. Therefore, several recycling technologies have been developed using cyanide or non-cyanide leaching methods to recover precious and valuable metals. PMID- 25704927 TI - Structural characterization of a hydroperoxo nickel complex and its autoxidation: mechanism of interconversion between peroxo, superoxo, and hydroperoxo species. AB - Pincer-stabilized nickel(I) complexes readily react with molecular oxygen to form dinuclear 1,2-MU-peroxo-bridged nickel(II) complexes, which are the major components of a dynamic equilibrium with the corresponding mononuclear superoxo species. The peroxo complexes further react with hydrogen peroxide to give the corresponding nickel(II) hydroperoxides. One of these hitherto elusive species was characterized by X-ray diffraction for the first time [O-O bond length: 1.492(2) A]. PMID- 25704928 TI - Proteopedia: Rossmann fold: A beta-alpha-beta fold at dinucleotide binding sites. AB - The Rossmann fold is one of the most common and widely distributed super secondary structures. It is composed of a series of alternating beta strand (beta) and alpha helical (alpha) segments wherein the beta-strands are hydrogen bonded forming a beta-sheet. The initial beta-alpha-beta (betaalphabeta) fold is the most conserved segment of Rossmann folds. As this segment is in contact with the ADP portion of dinucleotides such as FAD, NAD, and NADP it is also called as an "ADP-binding betaalphabeta fold". The Proteopedia entry on the Rossmann fold (Available at: http://proteopedia.org/w/Rossmann_fold) was generated to illustrate several structural aspects of super families of FAD and NAD(P) binding proteins: (1) The coenzymes FAD and NAD(P) share the basic adenosine diphosphate (ADP) structure. (2) The betaalphabeta fold motif that is common to both FAD and NAD(P) binding enzymes accommodates the common ADP component of these two coenzymes. (3) In both FAD and NAD(P) binding sites, the tight turn between the first beta-strand and the alpha-helix is in contact with the two phosphate groups of ADP. (4) This hairpin curve includes the first two conserved glycines (Gly-x Gly) that allow the sharp turn of the polypeptide backbone. (5) The two beta strands of the betaalphabeta fold may constitute the core of a larger beta-sheet that may include up to seven beta-strands generally in parallel orientation. (6) The structures of segments between additional strands vary greatly and may be composed of a variety of structures such as multiple short helices or coils. PMID- 25704929 TI - Improvement in the neural stem cell proliferation in rats treated with modified "Shengyu" decoction may contribute to the neurorestoration. AB - ETHNOPHARMACOLOGICAL RELEVANCE: "Shengyu" decoction, a traditional Chinese medicine, has been used to treat diseases with deficit in "qi" and "blood". The modified "Shengyu" decoction (MSD) used in the present study was designed to treat traumatic brain injury (TBI) on the basis of the "Shengyu" decoction, in which additional four herbs were added. Many ingredients in these herbs have been demonstrated to be effective for the treatment of brain injury. The present study was performed to evaluate the neurorestorative effect and the underlying mechanisms of MSD on the rat brain after a TBI. MATERIALS AND METHODS: TBI was induced in the right cerebral cortex of adult rats using Feeney's weight-drop method. Intragastrical administration of MSD (1.0 ml/200 g) was begun 6h after TBI. The neurological functions and neuronal loss in the cortex and hippocampus were determined. The levels of nerve growth-related factors GDNF, NGF, NCAM, TN C, and Nogo-A and the number of GFAP(+)/GDNF(+), BrdU(+)/nestin(+), BrdU(+)/NeuN(+) immunoreactive cells in the brain ipsilateral to TBI were also measured. Moreover, the influences of MSD on these variables were observed at the same time. RESULTS: We found that treatment with MSD in TBI rats ameliorated the neurological functions and alleviated neuronal loss. MSD treatment elevated the expression of GDNF, NGF, NCAM, and TN-C, and inhibited the expression of Nogo-A. Moreover, MSD treatment increased the number of GFAP(+)/GDNF(+), BrdU(+)/nestin(+), and BrdU(+)/NeuN(+) immunoreactive cells in the cortex and hippocampus. CONCLUSION: The present results suggest that MSD treatment in TBI rats could improve the proliferation of neural stem/progenitor cells and differentiation into neurons, which may facilitate neural regeneration and tissue repair and thus contribute to the recovery of neurological functions. These effects of modified "Shengyu" decoction may provide a foundation for the use of MSD as a prescription of medicinal herbs in the traditional medicine to treat brain injuries in order to improve the neurorestoration. PMID- 25704930 TI - Neuroprotection, learning and memory improvement of a standardized extract from Renshen Shouwu against neuronal injury and vascular dementia in rats with brain ischemia. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The Renshen Shouwu capsule (RSSW) is a patented Traditional Chinese Medicine (TCM), that has been proven to improve memory and is widely used in China to apoplexy syndrome and memory deficits. To investigate the neuroprotective and therapeutic effect of the Renshen Shouwu standardized extract (RSSW) on ischemic brain neuronal injury and impairment of learning and memory related to Vascular Dementia (VD) induced by a focal and global cerebral ischemia reperfusion injury in rats. MATERIAL AND METHODS: Using in vivo rat models of both focal ischemia/reperfusion (I/R) injuries induced by a middle cerebral artery occlusion (MCAO), and VD with transient global brain I/R neuronal injuries induced by a four-vessel occlusion (4-VO) in Sprague-Dawley (SD) rats, RSSW (50,100, and 200 mg kg(-1) body weights) and Egb761(r) (80 mg kg(-1)) were administered orally for 20 days (preventively 6 days+therapeutically 14 days) in 4-VO rats, and for 7 days (3 days preventively+4 days therapeutically) in MCAO rats. Learning and memory behavioral performance was assayed using a Morris water maze test including a place navigation trial and a spatial probe trial. Brain histochemical morphology and hippocampal neuron survival was quantified using microscope assay of a puffin brain/hippocampus slice with cresyl violet staining. RESULTS: MCAO ischemia/reperfusion caused infarct damage in rat brain tissue. 4 VO ischemia/reperfusion caused a hippocampal neuronal lesion and learning and memory deficits in rats. Administration of RSSW (50, 100, and 200mg/kg) or EGb761 significantly reduced the size of the insulted brain hemisphere lesion and improved the neurological behavior of MCAO rats. In addition, RSSW markedly reduced an increase in the brain infarct volume from an I/R-induced MCAO and reduced the cerebral water content in a dose-dependent way. Administration of RSSW also increased the pyramidal neuronal density in the hippocampus of surviving rats after transient global brain ischemia and improved the learning and memory ability of rats with 4-VO induced vascular dementia in a dose dependent manner. CONCLUSIONS: The in vivo results suggested that RSSW has significant neuroprotective effects against MCAO and 4-VO I/R injury and a therapeutic effect on cognitive disorders in VD rats. RSSW also improved the learning and memory ability of VD rats. These results convincingly demonstrated that RSSW may be useful to prevent and treat ischemia/reperfusion injury and vascular dementia disease. PMID- 25704931 TI - An anodic aromatic C,C cross-coupling reaction using parallel laminar flow mode in a flow microreactor. AB - We have successfully demonstrated an efficient anodic aromatic C,C cross-coupling reaction using parallel laminar flow mode in a two-inlet flow microreactor. The model reaction proceeded effectively even in single flow-through operations and the desired cross-coupling product was obtained in much higher current yields compared to the reaction in a conventional batch type cell. PMID- 25704932 TI - Eye and skin disorders: part 1. PMID- 25704933 TI - Joseph Plenck (1735-1807): amalgam of dermatology and ophthalmology. AB - In today's world of specialization, many of our current major contributors to the medical literature tend to work in only their specialty area. Historically, that was not the case. Great physicians were great observers and often contributed to many areas of medicine. The best example of this type of physician was Joseph Plenck who, although trained as a surgeon, had major impacts on many fields of medicine including both dermatology and ophthalmology. PMID- 25704934 TI - Human ocular anatomy. AB - We review the normal anatomy of the human globe, eyelids, and lacrimal system. This contribution explores both the form and function of numerous anatomic features of the human ocular system, which are vital to a comprehensive understanding of the pathophysiology of many oculocutaneous diseases. The review concludes with a reference glossary of selective ophthalmologic terms that are relevant to a thorough understanding of many oculocutaneous disease processes. PMID- 25704935 TI - Pigmentary disorders of the eyes and skin. AB - Oculocutaneous albinism, Menkes syndrome, tuberous sclerosis, neurofibromatosis type 1, dyskeratosis congenita, lentiginosis profusa syndrome, incontinentia pigmenti, and Waardenburg syndrome all are genodermatoses that have well established gene mutations affecting multiple biological pathways, including melanin synthesis, copper transport, cellular proliferation, telomerase function, apoptosis, and melanocyte biology. Onchocerciasis results from a systemic inflammatory response to a nematode infection. Hypomelanosis of Ito is caused by chromosomal mosaicism, which underlies its phenotypic heterogeneity. Incomplete migration of melanocytes to the epidermis and other organs is the underlying feature of nevus of Ota. Vogt-Koyangi-Harada and vitiligo have an autoimmune etiology; the former is associated with considerable multiorgan involvement, while the latter is predominantly skin-limited. PMID- 25704936 TI - Eyelid and ocular surface carcinoma: diagnosis and management. AB - Eyelid cancers account for 5% to 10% of all cutaneous malignancies. The incidence of eyelid cancer is approximately 15 cases per 100,000 individuals per year. Basal cell carcinoma is by far the most common cutaneous malignancy in the periocular area; other cutaneous malignancies that occur in this area include, in decreasing order of frequency, squamous cell carcinoma, sebaceous carcinoma, melanoma, and Merkel cell carcinoma. The most common treatment for eyelid carcinomas is surgical resection with frozen section examination for margin control, but exenteration may be needed when there is orbital invasion. Adjuvant radiotherapy may be needed in patients at high risk for local recurrence; sentinel lymph node biopsy may be considered in patients at high risk for lymph node metastasis. Primary or residual in situ disease of the conjunctiva can be treated with topical chemotherapy, such as mitomycin C, 5-fluorouracil, or interferon alpha-2 b. For patients with metastatic or locally advanced basal cell or squamous cell carcinoma not amenable to surgical excision or radiotherapy, targeted therapy against the hedgehog pathway (for basal cell carcinoma) or epidermal growth factor receptor (for squamous cell carcinoma) has been shown to be effective in preventing disease progression. Patients with eyelid and ocular surface malignancies need to be monitored with careful clinical examination for at least 5years after surgical treatment, and additional investigations may be warranted in some cases. PMID- 25704937 TI - Hemangiomas and the eye. AB - Infantile hemangiomas are a common vascular birthmark with heterogeneous presentations and unique growth characteristics with early rapid growth and eventual self-involution. Hemangiomas that develop around the eye have the potential for inducing amblyopia by several mechanisms and may eventually result in permanent visual impairment in otherwise healthy infants. Segmental periocular hemangiomas carry the additional risk of associated structural anomalies and PHACE syndrome. In recent years, the treatment of periocular hemangiomas has been revolutionized by the serendipitous discovery of the effectiveness of beta blockers (systemic and topical), with most experts viewing these as first-line therapies. The management of periocular hemangiomas should involve a close partnership between an ophthalmologist and dermatologist or other relevant specialists familiar with the unique clinical features, differential diagnosis, treatment approaches, and potential complications. PMID- 25704938 TI - Melanoma of the eye: revealing hidden secrets, one at a time. AB - Melanoma of the eye can involve the uveal tract with iris, ciliary body, or choroid involvement or it can involve the conjunctiva, eyelid, or orbit. Uveal involvement with choroidal melanoma is the most common, found in light complexion Caucasians with an age-adjusted incidence of 4.3 per million persons. Early detection of uveal melanoma is critical. The ABCDEF guide helps to differentiate iris nevus from iris melanoma. The letters represent: A, age young (<=40 years); B, blood in anterior chamber; C, clock hour of mass inferiorly; D, diffuse configuration; E, ectropion; and F, feathery margins. The mnemonic of TFSOM-UHHD (To Find Small Ocular Melanoma-Using Helpful Hints Daily) helps to differentiate choroidal nevus from small melanoma and represents: T, thickness over 2 mm; F, fluid; S, symptoms; O, orange pigment; M, margin within 3 mm of the optic disc; UH, ultrasound hollow; H, halo absent; and D, drusen absent. Patients with 3 or more of these factors are likely to have melanoma. These key clinical features help to identify small melanoma at a time when therapy could be life-saving. Conjunctival melanoma usually arises from primary acquired melanosis, a flat pigmentation that can lead to melanoma. Wide excision using no touch strategy is important to tumor control. Ocular examination is advised annually for all persons for detection of refractive error, cataract, glaucoma, and other conditions, but also for the detection of asymptomatic malignancies like melanoma. One at a time, we have uncovered the secrets of ocular melanoma and we forge ahead with the goal to solve the riddle of this challenging disease. PMID- 25704939 TI - Laser treatment of periocular skin conditions. AB - Advances in laser technology in recent decades have increased the options for the treatment of dermatologic conditions of the eye and eyelid. Benign tumors can be laser-ablated with relative ease, and vascular and melanocytic lesions can be precisely targeted with modern lasers. In this contribution, we review treatment of periocular pigmented lesions, including melanocytic nevi and nevus of Ota; vascular lesions including telangiectasias, port wine stains, and infantile hemangiomas; hair removal; eyeliner tattoo removal; laser ablation of common benign periocular tumors, such as syringomas, xanthelasma, milia, and seborrheic keratoses; and laser resurfacing. The recent advent of fractionated laser technology has resulted in dramatically decreased healing times for periocular skin resurfacing and fewer adverse effects. Fractionated laser resurfacing has now nearly supplanted traditional full-field laser resurfacing, and safe treatment of rhytides on the thin skin of the eyelids is possible. Proper eye protection is, of course, essential when using lasers near the eye. Patient preparation, safety precautions, and risks--intraocular and extraocular--are discussed herein. As laser technology continues to advance, we are sure to see improvements in current treatments, as well as development of new applications of cutaneous lasers. PMID- 25704940 TI - Minimally invasive eyelid care in dermatology: medical, laser, and cosmetic therapies. AB - There is a high demand for facial aesthetic enhancement, and the periorbital region is one of the first areas to show signs of aging. Many nonsurgical therapies exist to tackle these problems. These therapies are becoming more efficacious while reducing postprocedural recovery time. The goal is to restore the natural youthful appearance rather than to create an effect that differs from the patient's appearance earlier in life. Eyelid care, and cosmetic dermatology in general, intends to restore balance and symmetry. We discuss the initial consultation, relevant anatomy for the dermatologist, and medical, laser and cosmetic therapies. PMID- 25704941 TI - Madarosis, milphosis, eyelash trichomegaly, and dermatochalasis. AB - Eyebrows, eyelashes, and eyelids are cosmetically and functionally important periocular landmarks that offer insights into a patient's emotional state. Several pathologies exist with respect to the eyebrows, eyelashes, and eyelids. Madarosis refers to loss of the eyebrows or eyelashes; milphosis refers specifically to eyelash loss. Excess growth of eyelash hair is termed trichomegaly. Excess skin in the upper or lower eyelids is called dermatochalasis. Pathology of these important structures can be reflective of important local and systemic disease processes. PMID- 25704942 TI - Regional anesthesia of the eye, orbit, and periocular skin. AB - Advances in ophthalmic surgery, together with achieving greater patient safety, have changed the requirements of regional anaesthesia of the eye, orbit, and periocular skin. Patient comfort, safety, and low complication rates are essentials of regional anesthesia, which includes invasive procedures that generate intraoperative and postoperative analgesia, as well as akinesia. We present the currently used local anesthesia (topical and subcutaneous infiltration of local anesthetics) and regional anesthetic techniques in ophthalmic procedures, describing the techniques, advantages, disadvantages, and complications in ophthalmic regional blocks, as well as some educational measures to implement them to reduce the risk of ocular complications. Currently, there is no absolutely safe ophthalmic regional block, and the anesthetic modality should be assessed on a patient and surgeon basis. Local anesthesia is the reversible loss of sensation in certain area of the body to minimize pain and obtain patient comfort. It can be achieved through topical application or injection of anesthetic agents that block the nerve impulses to that tissue. PMID- 25704943 TI - Physical and chemical injuries to eyes and eyelids. AB - Ocular and periocular injuries are common reasons for emergency department visits. In fact, an estimated 2 million Americans suffer ocular injuries each year. Evaluation and treatment of physical and chemical injuries to the eyes and eyelids begin with a systematic examination. Visual acuity and pupillary reaction should be assessed first. Evaluation of the eye should precede examination of the periocular structures due to the potential for causing further damage to a full thickness ocular injury with manipulation of the eyelids. Physical injuries to the eyes and periocular structures include lacerations, abrasions, foreign bodies, and open globe injuries and can range from minor irritation to visual devastation. Chemical injuries can be divided into alkali and acid injuries. Alkali burns are more common, due to the prevalent use of alkali substances in industrial and home cleaning applications, and usually result in more serious injuries. Definitive care of chemical injuries ranges from topical antibiotics to full-thickness skin grafts with the goal of preventing cicatricial scarring and exposure of the ocular surface. Familiarity with the various types of ocular and periocular injuries is important for all medical professionals and is critical to providing the most appropriate management. PMID- 25704944 TI - Photosensitive disorders of the skin with ocular involvement. AB - Patients with photosensitive disorders of the skin may present with ocular manifestations that are evident at birth or may be manifested later with progression of the disorder. Dermatologists should be able to recognize these and appropriately refer patients for further management. Ocular involvement associated with immunologically mediated photodermatoses, drug- and chemical induced photosensitivity, photodermatoses associated with defective DNA repair/chromosome instability, and photoaggravated dermatoses are reviewed. Photodermatoses are commonly classified into four general groups: (1) immunologically mediated photodermatoses; (2) drug- and chemical-induced photosensitivity; (3) photodermatoses associated with defective DNA repair/chromosome instability; and (4) photoaggravated dermatoses. Photodermatoses in these groups with ocular involvement will be discussed. In addition, skin diseases associated with photophobia are also described. PMID- 25704945 TI - Phototherapy-related ophthalmologic disorders. AB - Phototherapy is an effective treatment option for a variety of dermatologic disorders, and the list of indications for its use continues to grow with advances in technology and our understanding of disease processes. Commonly used types of phototherapy include PUVA, broadband UVB, narrowband UVB, photodynamic therapy, and intense pulsed light therapy. Each therapeutic modality can have adverse acute and chronic effects on periocular and ocular structures, including the conjunctiva, cornea, crystalline lens, and retina. There are many types of protective eyewear options available, including goggles and contact lenses that can be used to prevent damage to ocular structures during phototherapy, particularly if eyelid closure is incomplete. PMID- 25704946 TI - Strategic mentoring: growth for mentor and mentee. AB - Mentoring is enriching for both the mentor and mentee, but often getting started can be a primary obstacle to this useful tool. This contribution focuses on how to embark on a mentoring relationship with a junior colleague. In addition to describing various approaches to being a mentor, it outlines unproductive traps to avoid, steps to establishing a successful mentoring relationship, including conversation starters, and professional skills one can continue to develop to improve mentoring outcomes. PMID- 25704947 TI - Reference intervals for leukocyte subsets in adults: Results from a population based study using 10-color flow cytometry. AB - BACKGROUND: Reference intervals for leukocyte subsets from peripheral blood are helpful for the understanding of disease states and therapy effects. METHODS: We performed in-depth immunophenotyping for 608 healthy German adults from the Leipzig region from 40 to 79 years by 10-color flow cytometry (FCM) to gain reference information for various leukocyte subsets including subsets of granulocytes, monocytes and lymphocytes. RESULTS: First, we derived gender- and age-specific reference intervals for males and females from 40 to 59 and from 60 to 79 years, respectively. Second, we further investigated the influence of gender and age on leukocyte counts. We found significantly higher cell counts for monocytes (P < 0.001) and NK cells (P < 0.001) in men, whereas women had higher counts for B cells (P < 0.001), Th cells (P < 0.001) and regulatory T cells (P = 0.008). Furthermore, with increasing age, a decrease in Tc cells (about 8% within 5 years) and an increase in NK cells (<4% within 5 years) were observed. CONCLUSION: In future research, it should be investigated whether these are real ageing effects that can be confirmed in longitudinal studies. Furthermore, it is important to understand if the Tc cell count drop is functionally compensated by the increase of NK cells. PMID- 25704948 TI - Spontaneous neuronal network dynamics reveal circuit's functional adaptations for behavior. AB - Spontaneous neuronal activity is spatiotemporally structured, influencing brain computations. Nevertheless, the neuronal interactions underlying these spontaneous activity patterns, and their biological relevance, remain elusive. Here, we addressed these questions using two-photon calcium imaging of intact zebrafish larvae to monitor the neuron-to-neuron spontaneous activity fine structure in the tectum, a region involved in visual spatial detection. Spontaneous activity was organized in topographically compact assemblies, grouping functionally similar neurons rather than merely neighboring ones, reflecting the tectal retinotopic map despite being independent of retinal drive. Assemblies represent all-or-none-like sub-networks shaped by competitive dynamics, mechanisms advantageous for visual detection in noisy natural environments. Notably, assemblies were tuned to the same angular sizes and spatial positions as prey-detection performance in behavioral assays, and their spontaneous activation predicted directional tail movements. Therefore, structured spontaneous activity represents "preferred" network states, tuned to behaviorally relevant features, emerging from the circuit's intrinsic non-linear dynamics, adapted for its functional role. PMID- 25704949 TI - Implementation of linear sensory signaling via multiple coordinated mechanisms at central vestibular nerve synapses. AB - Signal transfer in neural circuits is dynamically modified by the recent history of neuronal activity. Short-term plasticity endows synapses with nonlinear transmission properties, yet synapses in sensory and motor circuits are capable of signaling linearly over a wide range of presynaptic firing rates. How do such synapses achieve rate-invariant transmission despite history-dependent nonlinearities? Here, ultrastructural, biophysical, and computational analyses demonstrate that concerted molecular, anatomical, and physiological refinements are required for central vestibular nerve synapses to linearly transmit rate coded sensory signals. Vestibular synapses operate in a physiological regime of steady-state depression imposed by tonic firing. Rate-invariant transmission relies on brief presynaptic action potentials that delimit calcium influx, large pools of rapidly mobilized vesicles, multiple low-probability release sites, robust postsynaptic receptor sensitivity, and efficient transmitter clearance. Broadband linear synaptic filtering of head motion signals is thus achieved by coordinately tuned synaptic machinery that maintains physiological operation within inherent cell biological limitations. PMID- 25704950 TI - RIM-binding protein links synaptic homeostasis to the stabilization and replenishment of high release probability vesicles. AB - Here we define activities of RIM-binding protein (RBP) that are essential for baseline neurotransmission and presynaptic homeostatic plasticity. At baseline, rbp mutants have a ~10-fold decrease in the apparent Ca(2+) sensitivity of release that we attribute to (1) impaired presynaptic Ca(2+) influx, (2) looser coupling of vesicles to Ca(2+) influx, and (3) limited access to the readily releasable vesicle pool (RRP). During homeostatic plasticity, RBP is necessary for the potentiation of Ca(2+) influx and the expansion of the RRP. Remarkably, rbp mutants also reveal a rate-limiting stage required for the replenishment of high release probability (p) vesicles following vesicle depletion. This rate slows ~4-fold at baseline and nearly 7-fold during homeostatic signaling in rbp. These effects are independent of altered Ca(2+) influx and RRP size. We propose that RBP stabilizes synaptic efficacy and homeostatic plasticity through coordinated control of presynaptic Ca(2+) influx and the dynamics of a high-p vesicle pool. PMID- 25704951 TI - Pathological tau disrupts ongoing network activity. AB - Pathological tau leads to dementia and neurodegeneration in tauopathies, including Alzheimer's disease. It has been shown to disrupt cellular and synaptic functions, yet its effects on the function of the intact neocortical network remain unknown. Using in vivo intracellular and extracellular recordings, we measured ongoing activity of neocortical pyramidal cells during various arousal states in the rTg4510 mouse model of tauopathy, prior to significant cell death, when only a fraction of the neurons show pathological tau. In transgenic mice, membrane potential oscillations are slower during slow-wave sleep and under anesthesia. Intracellular recordings revealed that these changes are due to longer Down states and state transitions of membrane potentials. Firing rates of transgenic neurons are reduced, and firing patterns within Up states are altered, with longer latencies and inter-spike intervals. By changing the activity patterns of a subpopulation of affected neurons, pathological tau reduces the activity of the neocortical network. PMID- 25704952 TI - How much do children's body mass indices change over intervals of 6-12 months? Statistics from before and during the obesity epidemic. AB - BACKGROUND: Researchers need to evaluate changes in children's body mass index (BMI) over periods of 6 or 12 months, yet reference statistics are limited for change in BMI. OBJECTIVES: We aim to estimate the distribution of changes in children's BMIs over periods of 6 and 12 months. METHODS: We analyze data on two cohorts of children in the Fels Longitudinal Study: an older cohort born 1946 1970 and a recent cohort born 1971-1995. Between ages 3 and 18 years, we calculate changes in BMI over intervals of 6 and 12 months. For each age, sex and cohort, we estimate the mean, standard deviation, skewness, kurtosis and percentiles of change in BMI. RESULTS: Median BMI growth peaks around age 12-13 years for girls and 13-15 years for boys. Large BMI gains are common in adolescence, and BMI losses are not uncommon at any age. Percentiles of BMI change are quite dispersed, especially for girls and especially in adolescence. In the recent cohort, the adiposity rebound is earlier and BMI gains are larger, especially at the high percentiles. CONCLUSIONS: Researchers can use these estimates to evaluate data quality, evaluate effect sizes and calculate the sample size needed to detect an effect. PMID- 25704953 TI - Next generation sequencing and its applications in forensic genetics. AB - It has been almost a decade since the first next generation sequencing (NGS) technologies emerged and quickly changed the way genetic research is conducted. Today, full genomes are mapped and published almost weekly and with ever increasing speed and decreasing costs. NGS methods and platforms have matured during the last 10 years, and the quality of the sequences has reached a level where NGS is used in clinical diagnostics of humans. Forensic genetic laboratories have also explored NGS technologies and especially in the last year, there has been a small explosion in the number of scientific articles and presentations at conferences with forensic aspects of NGS. These contributions have demonstrated that NGS offers new possibilities for forensic genetic case work. More information may be obtained from unique samples in a single experiment by analyzing combinations of markers (STRs, SNPs, insertion/deletions, mRNA) that cannot be analyzed simultaneously with the standard PCR-CE methods used today. The true variation in core forensic STR loci has been uncovered, and previously unknown STR alleles have been discovered. The detailed sequence information may aid mixture interpretation and will increase the statistical weight of the evidence. In this review, we will give an introduction to NGS and single-molecule sequencing, and we will discuss the possible applications of NGS in forensic genetics. PMID- 25704954 TI - Vibrational spectroscopy and microspectroscopy analyzing qualitatively and quantitatively pharmaceutical hot melt extrudates. AB - Since the last decade, more and more Active Pharmaceutical Ingredient (API) candidates have poor water solubility inducing low bioavailability. These molecules belong to the Biopharmaceutical Classification System (BCS) classes II and IV. Thanks to Hot-Melt Extrusion (HME), it is possible to incorporate these candidates in pharmaceutical solid forms. Indeed, HME increases the solubility and the bioavailability of these drugs by encompassing them in a polymeric carrier and by forming solid dispersions. Moreover, in 2004, the FDA's guidance initiative promoted the usefulness of Process Analytical Technology (PAT) tools when developing a manufacturing process. Indeed, the main objective when developing a new pharmaceutical process is the product quality throughout the production chain. The trend is to follow this parameter in real-time in order to react immediately when there is a bias. Vibrational spectroscopic techniques, NIR and Raman, are useful to analyze processes in-line. Moreover, off-line Raman microspectroscopy is more and more used when developing new pharmaceutical processes or when analyzing optimized ones by combining the advantages of Raman spectroscopy and imaging. It is an interesting tool for homogeneity and spatial distribution studies. This review treats about spectroscopic techniques analyzing a HME process, as well off-line as in-line, presenting their advantages and their complementarities. PMID- 25704955 TI - Chronic nicotine exposure mediates resistance to EGFR-TKI in EGFR-mutated lung cancer via an EGFR signal. AB - BACKGROUND: Some of patients with non-small cell lung cancer (NSCLC) harboring somatic activating mutations of the epidermal growth factor receptor gene (EGFR mutations) show poor responses to EGFR-tyrosine kinase inhibitors (EGFR-TKIs) treatment. Cigarette smoking is the strongest documented risk factor for the development of lung cancer. Nicotine, while not carcinogenic by itself, has been shown to induce proliferation, angiogenesis, and the epithelial-mesenchymal transition; these effects might be associated with EGFR-TKI resistance. MATERIALS AND METHODS: PC-9 and 11_18 cell lines (EGFR-mutated NSCLC cell lines) were cultured with 1MUM nicotine for 3 months and were designated as PC-9/N and 11_18/N cell lines, respectively. The sensitivities of these cell lines to EGFR TKI were then tested in vitro. Moreover, the association between the smoking status and the progression-free survival (PFS) period was investigated in patients with EGFR-mutated NSCLC who were treated with gefitinib. RESULTS: The PC 9/N and 11_18/N cell lines were resistant to EGFR-TKI, compared with controls. The phosphorylation of EGFR in these cell lines was reduced by EGFR-TKI to a smaller extent than that observed in controls, and a higher concentration of EGFR TKI was capable of further decreasing the phosphorylation. Clinically, smoking history was an independent predictor of a poor PFS period on gefitinib treatment. CONCLUSIONS: Chronic nicotine exposure because of cigarette smoking mediates resistance to EGFR-TKI via an EGFR signal. Smoking cessation is of great importance, while resistance may be overcome through the administration of high dose EGFR-TKI. PMID- 25704956 TI - Cardiovascular comorbidities and survival of lung cancer patients: Medicare data based analysis. AB - OBJECTIVES: To evaluate the role of cardiovascular disease (CVD) comorbidity in survival of patients with non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: The impact of seven CVDs (at the time of NSCLC diagnosis and during subsequent follow-up) on overall survival was studied for NSCLC patients aged 65+ years using the Surveillance, Epidemiology, and End Results data linked to the U.S. Medicare data, cancer stage- and treatment-specific. Cox regression was applied to evaluate death hazard ratios of CVDs in univariable and multivariable analyses (controlling by age, TNM statuses, and 78 non-CVD comorbidities) and to investigate the effects of 128 different combinations of CVDs on patients' survival. RESULTS: Overall, 95,167 patients with stage I (n=29,836, 31.4%), II (n=5133, 5.4%), IIIA (n=11,884, 12.5%), IIIB (n=18,020, 18.9%), and IV (n=30,294, 31.8%) NSCLC were selected. Most CVDs increased the risk of death for stages I IIIB patients, but did not significantly impact survival of stage IV patients. The worse survival of patients was associated with comorbid heart failure, myocardial infarction, and cardiac arrhythmias that occurred during a period of follow-up: HRs up to 1.85 (p<0.001), 1.96 (p<0.05), and 1.67 (p<0.001), respectively, varying by stage and treatment. The presence of hyperlipidemia at baseline (HR down to 0.71, p<0.05) was associated with better prognosis. Having multiple co-existing CVDs significantly increased mortality for all treatments, especially for stages I and II patients treated with surgery (HRs up to 2.89, p<0.05) and stages I-IIIB patients treated with chemotherapy (HRs up to 2.59, p<0.001) and chemotherapy and radiotherapy (HRs up to 2.20, p<0.001). CONCLUSION: CVDs impact the survival of NSCLC patients, particularly when multiple co existing CVDs are present; the impacts vary by stage and treatment. This data should be considered in improving cancer treatment selection process for such potentially challenging patients as the elderly NSCLC patients with CVD comorbidities. PMID- 25704957 TI - Pooled safety analysis of EGFR-TKI treatment for EGFR mutation-positive non-small cell lung cancer. AB - OBJECTIVES: Three epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) - afatinib, erlotinib, and gefitinib - are available for the treatment of patients with EGFR mutation-positive non-small cell lung cancer (NSCLC). Given the long-term exposure of such patients to EGFR-TKIs, the toxicological properties of these agents in these individuals may differ from those observed in unselected patients. We compared the frequencies of severe adverse events (AEs) among EGFR mutation-positive NSCLC patients treated with these three EGFR-TKIs. MATERIALS AND METHODS: We performed a pooled analysis of severe AEs according to the type of EGFR-TKI administered with the use of data extracted from prospective clinical trials that evaluated the clinical efficacy of gefitinib, erlotinib, or afatinib in NSCLC patients with EGFR mutations. RESULTS: Twenty-one trials published between 2006 and 2014 and including 1468 patients were eligible for analysis. Patients in 13 trials (n=457) received gefitinib, those in 5 trials (n=513) received erlotinib, and those in 3 trials (n=498) received afatinib. Rash and diarrhea of grade >=3 were significantly more frequent with afatinib therapy than with erlotinib or gefitinib therapy. The frequency of interstitial lung disease (ILD) of grade >=3 was low (0.6-2.2%) with all three EGFR-TKIs and did not differ significantly among them. Gefitinib was associated with a significantly higher frequency of hepatotoxicity of grade >=3 compared with erlotinib or afatinib. The overall frequency of AEs leading to treatment withdrawal was 6.1% (83 of 1354 evaluable patients), with such AEs occurring significantly more often with afatinib or gefitinib than with erlotinib. The most common withdrawal AEs were skin toxicity, ILD, and hepatotoxicity. CONCLUSION: Such information on AEs should facilitate selection of the most appropriate EGFR-TKI for EGFR mutation-positive NSCLC patients with regard to mitigation of the risk for certain types of toxicity. PMID- 25704958 TI - Does lung cancer attract greater stigma than other cancer types? AB - OBJECTIVES: Cancer stigma can have widespread effects, influencing the behaviour and wellbeing of patients as well as the community and even research funding. Patients with lung cancer report feeling particularly stigmatised because of the association with a behaviour (smoking) that is perceived to be personally controllable. However, there are other dimensions of cancer stigma, that might be more severe for other cancers. The present study therefore examined differences in attitudes towards lung cancer and four other cancer types, using a multidimensional measure of cancer stigma, to extend findings beyond personal responsibility attributions. MATERIALS AND METHODS: Participants were a non patient sample (n=1205) who were randomised to complete a survey online relating to one of five cancer types (lung, colorectal, skin, breast and cervical). Stigma was assessed using the Cancer Stigma Scale (CASS). RESULTS: There were significant differences across the five cancer types on all CASS subscales: awkwardness (F(4, 1009)=5.16, p<0.001), severity (F(4, 984)=26.24, p<0.001), avoidance (F(4, 1008)=5.38, p<0.001), policy opposition (F(4, 1009)=8.38, p<0.001), personal responsibility (F(4, 995)=31.67, p<0.001) and financial discrimination (F(4, 957)=9.45, p<0.001). Lung cancer attracted higher stigma scores than breast and cervical cancer on all subscales. Lung cancer was similar to skin cancer on personal responsibility, avoidance, and policy opposition, but attracted higher stigma in the domains of awkwardness, severity and financial discrimination. Lung cancer was similar to colorectal cancer for awkwardness, but significantly higher on all other subscales. CONCLUSION: Lung cancer stigma extends beyond personal responsibility attributions to other dimensions, particularly perceived severity of the disease and tolerance of financial discrimination against patients with the disease. Future work is needed to develop and evaluate interventions designed to limit cancer stigma for patients, health professionals and the community. Health policies should acknowledge the existence of lung cancer stigma and make a commitment to minimising this. PMID- 25704959 TI - Conditional genetic deletion of PTEN after a spinal cord injury enhances regenerative growth of CST axons and motor function recovery in mice. AB - Previous studies indicate that conditional genetic deletion of phosphatase and tensin homolog (PTEN) in neonatal mice enhances the ability of axons to regenerate following spinal cord injury (SCI) in adults. Here, we assessed whether deleting PTEN in adult neurons post-SCI is also effective, and whether enhanced regenerative growth is accompanied by enhanced recovery of voluntary motor function. PTEN(loxP/loxP) mice received moderate contusion injuries at cervical level 5 (C5). One group received unilateral injections of adeno associated virus expressing CRE (AAV-CRE) into the sensorimotor cortex; controls received a vector expressing green fluorescent protein (AAV-GFP) or injuries only (no vector injections). Forelimb function was tested for 14weeks post-SCI using a grip strength meter (GSM) and a hanging task. The corticospinal tract (CST) was traced by injecting mini-ruby BDA into the sensorimotor cortex. Forelimb gripping ability was severely impaired immediately post-SCI but recovered slowly over time. The extent of recovery was significantly greater in PTEN-deleted mice in comparison to either the AAV-GFP group or the injury only group. BDA tract tracing revealed significantly higher numbers of BDA-labeled axons in caudal segments in the PTEN-deleted group compared to control groups. In addition, in the PTEN-deleted group, there were exuberant collaterals extending from the main tract rostral to the lesion and into and around the scar tissue at the injury site. These results indicate that PTEN deletion in adult mice shortly post-SCI can enhance regenerative growth of CST axons and forelimb motor function recovery. PMID- 25704961 TI - Cooperative catalysis of noncompatible catalysts through compartmentalization: wacker oxidation and enzymatic reduction in a one-pot process in aqueous media. AB - A Wacker oxidation using CuCl/PdCl2 as a catalyst system was successfully combined with an enzymatic ketone reduction to convert styrene enantioselectively into 1-phenylethanol in a one-pot process, although the two reactions conducted in aqueous media are not compatible due to enzyme deactivation by Cu ions. The one-pot feasibility was achieved via compartmentalization of the reactions. Conducting the Wacker oxidation in the interior of a polydimethylsiloxane thimble enables diffusion of only the organic substrate and product into the exterior where the biotransformation takes place. Thus, the Cu ions detrimental to the enzyme are withheld from the reaction media of the biotransformation. In this one pot process, which formally corresponds to an asymmetric hydration of alkenes, a range of 1-arylethanols were formed with high conversions and 98-99 % ee. In addition, the catalyst system of the Wacker oxidation was recycled 15 times without significant decrease in conversion. PMID- 25704960 TI - Nexavar/Stivarga and viagra interact to kill tumor cells. AB - We determined whether the multi-kinase inhibitor sorafenib or its derivative regorafenib interacted with phosphodiesterase 5 (PDE5) inhibitors such as Viagra (sildenafil) to kill tumor cells. PDE5 and PDGFRalpha/beta were over-expressed in liver tumors compared to normal liver tissue. In multiple cell types in vitro sorafenib/regorafenib and PDE5 inhibitors interacted in a greater than additive fashion to cause tumor cell death, regardless of whether cells were grown in 10 or 100% human serum. Knock down of PDE5 or of PDGFRalpha/beta recapitulated the effects of the individual drugs. The drug combination increased ROS/RNS levels that were causal in cell killing. Inhibition of CD95/FADD/caspase 8 signaling suppressed drug combination toxicity. Knock down of ULK-1, Beclin1, or ATG5 suppressed drug combination lethality. The drug combination inactivated ERK, AKT, p70 S6K, and mTOR and activated JNK. The drug combination also reduced mTOR protein expression. Activation of ERK or AKT was modestly protective whereas re expression of an activated mTOR protein or inhibition of JNK signaling almost abolished drug combination toxicity. Sildenafil and sorafenib/regorafenib interacted in vivo to suppress xenograft tumor growth using liver and colon cancer cells. From multiplex assays on tumor tissue and plasma, we discovered that increased FGF levels and ERBB1 and AKT phosphorylation were biomarkers that were directly associated with lower levels of cell killing by 'rafenib + sildenafil. Our data are now being translated into the clinic for further determination as to whether this drug combination is a useful anti-tumor therapy for solid tumor patients. PMID- 25704962 TI - Primate Kinship: Contributions from Cayo Santiago. AB - Research on Cayo Santiago and Japan deserves credit for launching the study of primate kinship and for continuing to help shape it in important ways. This review describes the origins of kinship research on Cayo Santiago, beginning with Donald Sade's pioneering work establishing the concepts of kin preferences, matrilineal dominance systems and incest avoidance. It then reviews subsequent research by later Cayo Santiago researchers and alumni, focusing primarily on maternal kinship. Together these researchers have greatly expanded our knowledge of kin preferences in rhesus in terms of (i) what age-sex classes, behaviors and types of kin show them, (ii) the ways in which kinship interfaces with rank, sex, age, and dispersal patterns, and (iii) the graded and variably limited nature of kin preferences in terms of degree of relatedness. Second, the argument for kin selection at least for some types of behavior has survived challenges posed by several alternative explanations, and has been both strengthened by recent findings of paternal kin preferences and narrowed by studies showing that unilateral altruism may extend only to very close kin. Third, work on Cayo Santiago has contributed to an appreciation that both current conditions and inherent social characteristics may influence the strength of kin preferences, and fourth, it has contributed to an understanding of the possible origins of our own species' family systems. Cayo Santiago became a leader in kinship research in large part because of management practices that produce known extended lineages. These lineages have promoted and accelerated research on kinship, prompting other researchers to investigate its importance in other groups and species, where its effects only then became clear. The extended lineages remain valuable tools for research on a species that lives in a broad range of environments in the wild, including those with key parallels to Cayo Santiago. PMID- 25704964 TI - Interleukin-25 and mucosal T cells in noneosinophilic and eosinophilic chronic rhinosinusitis. AB - BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a heterogeneous disease of uncertain pathogenesis. Memory T cells acquire additional functions during the secondary response and play important roles in chronic inflammation. OBJECTIVE: To investigate characteristics of tissue memory CD4(+) T cells obtained from patients with noneosinophilic CRSwNP (NECRS) and eosinophilic CRSwNP (ECRS) by focusing on the influence of interleukin (IL)-25. METHODS: Pro allergic cytokines in tissue homogenates were measured using enzyme-linked immunosorbent assays. NP mononuclear cells and CD4(+) T cells were isolated from NPs from patients with CRSwNP. Cytokine expression and CD4(+) T-cell subpopulations were analyzed using enzyme-linked immunosorbent assay, flow cytometry, and real-time polymerase chain reaction. RESULTS: The IL-25 level in NPs increased in patients with ECRS. IL-5 and IL-9 mRNA levels expressed by tissue CD4(+) T cells were significantly elevated in patients with ECRS. Most infiltrating CD4(+) T cells in ECRS and NECRS expressed CD45RO; however, regardless of the atopic status, high IL-17RB levels were detected in CD4(+) T cells from patients with ECRS. IL-17RB mRNA levels expressed by tissue CD4(+) T cells significantly correlated with the number of eosinophils in NPs. Elevation of IL-5 and IL-9 production was found in NP mononuclear cells from patients with ECRS, but not in those from patients with NECRS, by stimulation with IL-25 under T-cell receptor stimulation. CONCLUSION: Interleukin-25 and a subpopulation of tissue T-helper type 2 and 9 cells that express increased IL-17RB levels could contribute to infiltration of eosinophils in NPs and could have produced the pathologic difference between NECRS and ECRS. PMID- 25704963 TI - Immune profile modulation of blood and mucosal eosinophils in nasal polyposis with concomitant asthma. AB - BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is frequently associated with asthma. Mucosal eosinophil (EO) infiltrate has been found to correlate with asthma and disease severity but not necessarily in every patient. Other multifactorial immune processes are required to determine disease endotypes and response to treatment. OBJECTIVE: To evaluate EO immunomodulation for migration and survival in accordance with inflammatory protein profiles and asthmatic status in CRSwNP. METHODS: Ninety-three patients (47 with asthma) with CRSwNP were included. Each patient was staged clinically according to symptom severity and polyp size. Nasal secretions were collected to establish a cytokine profile. The EOs were purified from blood samples and nasal polyps to delineate specific immunophenotypes by flow cytometry and determine in vitro EO survival in relation to asthmatic status. RESULTS: The CRSwNP in patients with asthma was characterized by eosinophilia and a high level of interleukin (IL)-5 in nasal secretions. Although EOs exhibited activation profiles after mucosal migration, there was relative down-expression of IL-5 receptor-alpha (IL-5Ralpha) on nasal EOs in patients with asthma. The EO culture with IL-5 and IL-9 showed an antiapoptotic effect in patients with asthma through IL-5Ralpha modulation. CONCLUSION: Mucosal eosinophilia seems to be induced by EO nasal trapping through modulation of adhesion receptors. In patients with asthma, EO involvement is enhanced by the antiapoptotic synergistic action of T-helper cell type 2 cytokines on IL-5Ralpha expression. This study shows for the first time that IL-9 is involved in EO homeostasis in CRSwNP and could explain the low benefit of anti IL-5 therapy for some patients with asthma and nasal polyposis. PMID- 25704965 TI - The mamey sapote fruit (Pouteria sapota) as a novel cause of IgE-mediated allergic reaction. PMID- 25704966 TI - X-linked agammaglobulinemia in a child conceived using a donor egg: a medicolegal quandary. PMID- 25704967 TI - Effect of exposure to Neospora caninum, Salmonella, and Leptospira interrogans serovar Hardjo on the economic performance of Irish dairy herds. AB - The objective of the current study was to quantify the effects of exposure to Salmonella, Neospora caninum, and Leptospira interrogans serovar Hardjo (L. hardjo) on dairy farm profitability and to simulate the effect of vaccination for Salmonella and L. hardjo on dairy farm profitability. The production effects associated with exposure to each of these pathogens in study herds were defined under 3 categories: (1) milk production effects, (2) reproduction effects (including culling), and (3) mortality effects. The production effects associated with exposure to Salmonella, N. caninum, and L. hardjo were incorporated into the Moorepark Dairy Systems Model. In the analysis, herds negative for exposure to Salmonella, N. caninum, and L. hardjo were assumed baseline herds, with all results presented relative to this base. In simulations examining the effect of vaccination for Salmonella and L. hardjo on farm profitability, vaccinated herds (vaccination costs included) were considered as baseline herds and results were presented relative to this base. Total annual profits in unvaccinated herds were reduced by ?77.31, ?94.71, and ?112.11 per cow at milk prices of ?0.24, ?0.29, and ?0.34/L, respectively, as a result of exposure to Salmonella. In the current study, herds positive for exposure to Salmonella recorded a 316-kg reduction in milk yield, whereas no association was detected between exposure to N. caninum or L. hardjo and milk production. Exposure to both N. caninum and L. hardjo was associated with compromised reproductive performance. Herds positive for exposure to N. caninum and Salmonella had greater rates of adult cow mortality and calf mortality, respectively. Vaccination for both Salmonella and L. hardjo was associated with improved performance in study herds. Exposure to N. caninum resulted in a reduction in annual farm profits of ?11.55, ?12, and ?12.44 per cow at each milk price, whereas exposure to L. hardjo resulted in a reduction in annual farm profits of ?13.83, ?13.78, and ?13.72 per cow at each milk price. Herds that tested positive for exposure to Salmonella and L. hardjo were compared with herds vaccinated for the respective pathogens. Herds vaccinated for Salmonella generated ?67.09, ?84.48, and ?101.89 per cow more profit at each milk price compared with herds positive for exposure. Similarly, herds vaccinated for L. hardjo generated ?9.74, ?9.69, and ?9.63 per cow more profit compared with unvaccinated exposed herds. However, herds that tested negative for exposure to Salmonella and L. hardjo generated additional profits of ?10.22 and ?4.09 per cow, respectively, compared with vaccinated baseline herds. PMID- 25704968 TI - Feeding dried distillers grains with solubles affects composition but not oxidative stability of milk. AB - Feeding lactating dairy cows dried distillers grains with solubles (DDGS) increases the concentration of unsaturated fatty acids in the milk from those cows, potentially leading to increased susceptibility to development of off flavors. Feeding DDGS has been loosely implicated to be a cause of development of spontaneous oxidative off-flavor in milk. We hypothesized that increased feeding of DDGS would accelerate development of off-flavors and that fortification with vitamin E (0.06% wt/wt) or C (0.06% wt/wt) would prevent spontaneous oxidative off-flavors. The objective of this research was to determine the effects of feeding DDGS to lactating dairy cows on several parameters of milk quality as determined by both chemical and sensory evaluations. Twenty-four healthy mid lactation Holstein dairy cows were fed total mixed rations containing DDGS (0, 10, or 25% dry matter). Cows were blocked by parity and randomly assigned to 1 of 2 groups (12 cows each). Each group received all 3 treatments in a 3-period Youden square design so that each cow served as her own control. Samples of milk from individual cows for proximate analysis and pooled milk for pasteurization and sensory analysis were collected on d 14, 21, and 28 of each experimental period. Pooled milk was assayed for peroxides and free fatty acids and evaluated by a trained sensory panel for the presence of 7 off-flavors common to milk on d 1, 3, and 7. Feeding 25% DDGS caused a significant decrease in daily milk yield. Increased dietary inclusion of DDGS also caused a concomitant decrease in percentage of milk fat and an increase in percentages of both solids nonfat and protein. Milk peroxides and free fatty acids were almost all below the detection limit, and the few exceptions were not found in replicated analyses. Sensory analysis revealed off-flavors only in milk from cows fed 0% DDGS when that milk was stored for 7d and when milk from cows fed 25% DDGS was fortified with 0.06% (wt/wt) vitamin C. Those few detected off-flavor scores were less than 1.5cm on a 15-cm line scale, indicating that the differences are not practically significant. Peroxide values support the findings by the sensory panel that both feeding DDGS at 10 and 25% and vitamin E and C fortification did not practically change the oxidative stability of milk. These results, taken together, indicate that feeding DDGS under our experimental conditions modified milk composition, but did not contribute to the development of off-flavors in milk. PMID- 25704969 TI - Effects of emulsifying components in the continuous phase of cream on the stability of fat globules and the physical properties of whipped cream. AB - The emulsifying components in cream are very important in controlling the physical characteristics of whipped cream. The effects of those components on the stability of fat globules and the physical characteristics of whipped cream were investigated. A low-molecular-weight emulsifier, and protein ingredients such as sodium caseinate and a casein partial hydrolysate (casein peptides), were used as emulsifying components in this investigation. The viscosity of deaerated whipped cream (called the serum viscosity) was measured to evaluate the degree of fat globule aggregation. Furthermore, the shape-retention ability, which is the degree of reduction in the firmness of whipped cream between immediately after whipping and after 1d of refrigeration, was explored. The addition of the low molecular-weight emulsifier in the continuous phase of dairy cream, which does not contain added low-molecular-weight emulsifiers, increased the stability of the fat globules and reduced the shape-retention ability of the whipped cream. The addition of protein ingredients (sodium caseinate and casein peptides) to the continuous phase of dairy cream had little effect. However, the addition of casein peptide in the continuous phase of dairy cream together with the low molecular-weight emulsifier reduced the effect of the low-molecular-weight emulsifier on the stabilization of fat globules and the shape-retention ability of the whipped cream. The addition of casein peptide did not recover the serum viscosity; thus, other mechanisms might underlie this phenomenon. PMID- 25704970 TI - Prediction of bulk tank somatic cell count violations based on monthly individual cow somatic cell count data. AB - The regulatory limit in Canada for bulk tank somatic cell count (BTSCC) was recently lowered from 500,000 to 400,000 cells/mL. Herd indices based on changes in cow somatic cell count over 2 consecutive months (e.g., proportion of healthy or chronically infected cows, cows cured, and new intramammary infection rate) could be used as predictors for BTSCC violations. The objective of this study was to develop a predictive model for exceeding the limit of 400,000 cells/mL in the next month using these herd indices. Dairy Herd Improvement (DHI) data were used from 924 dairy herds in Quebec, Canada. Test-day BTSCC was estimated by dividing the sum of all cows' DHI test-day somatic cell count times DHI test-day milk production by the total volume of milk produced by the herd on that test-day. In total, 986 of 8,681 (11.4%) estimated BTSCC exceeded 400,000 cells/mL. The final predictive model included 6 variables: mean herd somatic cell score at the current test-month, proportion of cows >500,000 cells/mL at the current test month, proportion of healthy cows during lactation at the current test-month, proportion of chronically infected cows at the current test-month, average days in milk at the current test-month, and annual mean daily milk production. The optimized sensitivity and specificity of the model were 76 and 74%, respectively. The positive predictive value and negative predictive value were 25 and 95%, respectively. This low positive predictive value and high negative predictive value demonstrated that the model was less accurate at predicting herds that would violate the estimated BTSCC threshold but very accurate at identifying herds that would not. In addition, the area under the curve for the receiver operating characteristic curve was 0.82, suggesting that the model had excellent discrimination between test-months that did and did not exceed 400,000 cells/mL. An internal validation was completed using a bootstrapped resampling-based estimation method and confirmed that the final model provided a validated estimate of predictive accuracy. This model could be used to monitor and advise clients on impending risks of exceeding the BTSCC limit. PMID- 25704971 TI - Determination of the acute toxicities of physicochemical pretreatment and advanced oxidation processes applied to dairy effluents on activated sludge. AB - In this study, the acute toxicities of raw, physicochemical pre-treated, ozonated, and Fenton reagent applied samples of dairy wastewater toward activated sludge microorganisms, evaluated using the International Organization for Standardization's respiration inhibition test (ISO 8192), are presented. Five-day biological oxygen demand (BOD5) was measured to determine the biodegradability of physicochemical treatment, ozonation, Fenton oxidation or no treatment (raw samples) of dairy wastewater. Chemical pretreatment positively affected biodegradability, and the inhibition exhibited by activated sludge was removed to a considerable degree. Ozonation and the Fenton process exhibited good chemical oxygen demand removal (61%) and removal of toxins. Low sludge production was observed for the Fenton process applied to dairy effluents. We did not determine the inhibitory effect of the Fenton-process on the activated sludge mixture. The pollutant-removal efficiencies of the applied processes and their associated operating costs were determined. PMID- 25704972 TI - Decolorization of Cheddar cheese whey by activated carbon. AB - Colored Cheddar whey is a source for whey protein recovery and is decolorized conventionally by bleaching, which affects whey protein quality. Two activated carbons were studied in the present work as physical means of removing annatto (norbixin) in Cheddar cheese whey. The color and residual norbixin content of Cheddar whey were reduced by a higher level of activated carbon at a higher temperature between 25 and 55 degrees C and a longer time. Activated carbon applied at 40g/L for 2h at 30 degrees C was more effective than bleaching by 500mg/L of hydrogen peroxide at 68 degrees C. The lowered temperature in activated-carbon treatments had less effect on protein structure as investigated for fluorescence spectroscopy and volatile compounds, particularly oxidation products, based on gas chromatography-mass spectrometry. Activated carbon was also reusable, removing more than 50% norbixin even after 10 times of regeneration, which showed great potential for decolorizing cheese whey. PMID- 25704973 TI - Antepartal insulin-like growth factor 1 and insulin-like growth factor binding protein 2 concentrations are indicative of ketosis in dairy cows. AB - A study involving a small number of cows found that the concentrations of insulin like growth hormone 1 (IGF1) may be a useful predictor of metabolic disease. Further, IGF1 may provide also a pathophysiological link to metabolic diseases such as ketosis. The objective of the current study was to test whether the low antepartal total IGF1 or IGF1 binding protein (IGFBP) concentrations might predict ketosis under field conditions. Clinical examinations and blood sampling were performed antepartum (262-270 d after artificial insemination) on 377 pluriparous pregnant Holstein Friesian cows. The presence of postpartum diseases were recorded (ketosis, fatty liver, displacement of the abomasum, hypocalcemia, mastitis, retention of fetal membranes, and clinical metritis or endometritis), and the concentrations of IGF1, IGFBP2, IGFBP3, and nonesterified fatty acids were measured. Cows with postpartum clinical ketosis had lower IGF1 concentrations antepartum than healthy cows. The sensitivity of antepartal IGF1 as a marker for postpartum ketosis was 0.87, and the specificity was 0.43; a positive predictive value of 0.91 and a negative predictive value of 0.35 were calculated. The cows with ketosis and retained fetal membranes had lower IGFBP2 concentrations compared with the healthy cows. It can be speculated that lower IGF1 production in the liver during late pregnancy may increase growth hormone secretions and lipolysis, thereby increasing the risk of ketosis. Lower IGFBP2 concentrations may reflect the suppression of IGFBP2 levels through higher growth hormone secretion. In conclusion, compared with nonesterified fatty acids as a predictive parameter, IGF1 and IGFBP2 may represent earlier biomarkers of inadequate metabolic adaptation to the high energy demand required postpartum. PMID- 25704974 TI - The somatotropic axis during the physiological estrus cycle in dairy heifers- Effect on hepatic expression of GHR and SOCS2. AB - Pituitary growth hormone (GH) release and hepatic insulin-like growth factor-I (IGF-I) production increase after an injection of 17beta-estradiol (E2) in ovariectomized dairy cattle. However, whether endogenous sexual steroid hormones also influence the hepatic GH receptor (GHR) signaling pathway during a physiological estrus cycle remains unclear. The aim of this study was to analyze the hepatic GHR signaling pathway during the luteal phase and after a period of increased E2 concentrations (after ovulation) as well as in 7 heifers before ovulation. Ovarian ultrasounds were performed daily during repeated physiological cycles (n = 56) of 30 Holstein Friesian heifers to determine ovulation [before ovulation (n = 7, bOv) and after ovulation 24-60 h after the appearance of estrus signs (n = 49, aOv)] and luteal phase (CLP; d 12 +/- 1 after ovulation). Blood samples and liver biopsies were obtained, and blood concentrations of E2, P4, insulin-like growth factor (IGF)-I, IGF-II, and GH were measured. In the liver biopsies, we determined mRNA expression of the estrogen receptor alpha (ERalpha), GHR, Janus kinase 2 (JAK2), signal transducer and activator of transcription 5B (STAT5B), suppressor of cytokine signaling (SOCS)2 and 3, IGF-I, and IGF-II by quantitative reverse transcription-PCR. The concentration of E2 was higher bOv than aOv and CLP, as expected. The concentrations of IGF-I and GH were higher bOv and aOv compared with CLP. In contrast, concentrations of IGF-II were lower aOv compared with bOv and CLP. The mRNA expression of GHR was higher in liver biopsies obtained bOv compared with aOv and CLP. Notably, the expression of SOCS2 was higher bOv than aOv and in the CLP. Increased hepatic expression of SOCS2 during estrus was detectable when IGF-I concentrations were high; this result might indicate that SOCS2 expression attenuates the GHR signal transduction pathway during the phase of increased pituitary GH release. In conclusion, hepatic GHR and SOCS2 mRNA expression appeared to be promptly and sensitively regulated by increased E2 levels before ovulation of dairy heifers. PMID- 25704975 TI - Effect of homogenization and pasteurization on the structure and stability of whey protein in milk. AB - The effect of homogenization alone or in combination with high-temperature, short time (HTST) pasteurization or UHT processing on the whey fraction of milk was investigated using highly sensitive spectroscopic techniques. In pilot plant trials, 1-L quantities of whole milk were homogenized in a 2-stage homogenizer at 35 degrees C (6.9 MPa/10.3 MPa) and, along with skim milk, were subjected to HTST pasteurization (72 degrees C for 15 s) or UHT processing (135 degrees C for 2 s). Other whole milk samples were processed using homogenization followed by either HTST pasteurization or UHT processing. The processed skim and whole milk samples were centrifuged further to remove fat and then acidified to pH 4.6 to isolate the corresponding whey fractions, and centrifuged again. The whey fractions were then purified using dialysis and investigated using the circular dichroism, Fourier transform infrared, and Trp intrinsic fluorescence spectroscopic techniques. Results demonstrated that homogenization combined with UHT processing of milk caused not only changes in protein composition but also significant secondary structural loss, particularly in the amounts of apparent antiparallel beta-sheet and alpha-helix, as well as diminished tertiary structural contact. In both cases of homogenization alone and followed by HTST treatments, neither caused appreciable chemical changes, nor remarkable secondary structural reduction. But disruption was evident in the tertiary structural environment of the whey proteins due to homogenization of whole milk as shown by both the near UV circular dichroism and Trp intrinsic fluorescence. In-depth structural stability analyses revealed that even though processing of milk imposed little impairment on the secondary structural stability, the tertiary structural stability of whey protein was altered significantly. The following order was derived based on these studies: raw whole>HTST, homogenized, homogenized and pasteurized>skimmed and pasteurized, and skimmed UHT>homogenized UHT. The methodology demonstrated in this study can be used to gain insight into the behavior of milk proteins when processed and provides a new empirical and comparative approach for analyzing and assessing the effect of processing schemes on the nutrition and quality of milk and dairy product without the need for extended separation and purification, which can be both time-consuming and disruptive to protein structures. PMID- 25704976 TI - Prevalence of thermoduric bacteria and spores in nonfat dry milk powders of Midwest origin. AB - Samples of nonfat dry milk powder were analyzed for the presence of heat resistant bacteria. The samples were collected from Midwest manufacturing companies and were evaluated for the presence of spores, thermoduric bacteria, and the total bacterial count. Three companies were included in this study, and results showed differences between each of the companies in the heat-resistant microbial groups tested. Company 3 had the highest levels of total spores and thermoduric bacteria: 3.6+/-0.14 and 3.5+/-0.13 log cfu/g, respectively. Interestingly, this company did not have the highest total bacterial count but rather the second lowest total bacterial count for the group, perhaps because of the higher proportion of thermophiles present in the powders from this company. The average level of total bacterial counts was 2.57+/-0.07 log cfu/g. Isolates obtained from the samples were identified by mass spectrometry, and all of the companies showed Bacillus licheniformis as the most prevalent bacterial species identified. PMID- 25704977 TI - Effects of partial replacement of dietary starch from barley or corn with lactose on ruminal function, short-chain fatty acid absorption, nitrogen utilization, and production performance of dairy cows. AB - In cows fed diets based on corn-alfalfa silage, replacing starch with sugar improves milk production. Although the rate of ruminal fermentation of sugar is more rapid than that of starch, evidence has been found that feeding sugar as a partial replacement for starch does not negatively affect ruminal pH despite increasing diet fermentability. The mechanism(s) for this desirable response are unknown. Our objective was to determine the effects of replacing barley or corn starch with lactose (as dried whey permeate; DWP) on ruminal function, short chain fatty acid (SCFA) absorption, and nitrogen (N) utilization in dairy cows. Eight lactating cows were used in a replicated 4 * 4 Latin square design with 28 d periods and source of starch (barley vs. corn) and level of DWP (0 vs. 6%, DM basis) as treatment factors. Four cows in 1 Latin square were ruminally cannulated for the measurement of ruminal function, SCFA absorption, and N utilization. Dry matter intake and milk and milk component yields did not differ with diet. The dietary addition of DWP tended to increase ruminal butyrate concentration (13.6 vs. 12.2 mmol/L), and increased the Cl(-)-competitive absorption rates for acetate and propionate. There was no sugar effect on minimum ruminal pH, and the duration and area when ruminal pH was below 5.8. Minimum ruminal pH tended to be lower in cows fed barley compared with those fed corn (5.47 vs. 5.61). The duration when ruminal pH was below pH 5.8 tended to be shorter (186 vs. 235 min/d), whereas the area (pH * min/d) that pH was below 5.8 was smaller (47 vs. 111) on the corn than barley diets. Cows fed the high- compared with the low-sugar diet had lower ruminal NH3-N concentration. Feeding the high-sugar diet tended to increase apparent total-tract digestibility of dry matter and organic matters and increased apparent total-tract digestibility of fat. Apparent total-tract digestibility of N tended to be greater in cows fed barley compared with those fed corn, whereas apparent total-tract digestibility of acid-digestible fiber was greater in cows fed corn compared with those fed barley. In conclusion, partially replacing dietary corn or barley starch with sugar upregulated ruminal acetate and propionate absorption, suggesting that the mechanisms for the attenuation of ruminal acidosis when sugar is fed is partly mediated via increased SCFA absorption. PMID- 25704978 TI - Estimating organic, local, and other price premiums in the Hawaii fluid milk market. AB - With retail scanner data, we applied hedonic price modeling to explore price premiums for organic, local, and other product attributes of fluid milk in Hawaii. Within the context of revealed preference, this analysis of organic and local attributes, under a single unified framework, is significant, as research in this area is deficient in the existing literature. This paper finds both organic and local attributes delivered price premiums over imported, conventional, whole fluid milk. However, the estimated price premium for organic milk (24.6%) is significantly lower than findings in the existing literature. Likewise, the price premium for the local attribute is estimated at 17.4%, again substantially lower compared with an earlier, stated preference study in Hawaii. Beyond that, we estimated a robust price premium of 19.7% for nutritional benefits claimed. The magnitude of this estimated coefficient reinforces the notion that nutrition information on food is deemed beneficial and valuable. Finally, package size measures the influence of product weight. With each larger package size, the estimate led to a corresponding larger price discount. This result is consistent with the practice of weight discounting that retailers usually offer with fresh packaged food. Additionally, we estimated a fairly high Armington elasticity of substitution, which suggests a relatively high degree of substitution between local and imported fluid milk when their relative price changes. Overall, this study establishes price premiums for organic, local, and nutrition benefits claimed for fluid milk in Hawaii. PMID- 25704979 TI - Muscle ultrasound quantifies disease progression over time in infants and young boys with duchenne muscular dystrophy. AB - INTRODUCTION: Quantitative muscle ultrasound (QUS) in boys with Duchenne muscular dystrophy (DMD) shows increased echointensity as muscle is replaced with fat and fibrosis. Studies of quantitative ultrasound in infants/young boys with DMD over time have not been reported. METHODS: We used calibrated muscle backscatter (cMB), a reproducible measure of ultrasound echointensity, to quantify muscle pathology in 5 young boys with DMD (ages 0.5-2.8 years) over 17-29 months. We compared the results with repeated assessments of function (n = 4) and with muscle ultrasound images from a cross-section of 6 male controls (0.6-3.1 years). RESULTS: cMB in boys with DMD increased (worsened) over time (P < 0.001), whereas function improved. After age 2 years, cMB in most (4 of 5) boys with DMD was higher than in any control. CONCLUSIONS: QUS measures disease progression in young boys with DMD despite functional improvements. QUS could be employed as an outcome measure for serial assessment of young boys with DMD. PMID- 25704980 TI - Elastofibroma dorsi. Our experience with 11 lesions. AB - Elastofibroma is a rare benign lesion that typically arises on the posterior chest wall beneath the scapula. The etiopathogenesis is still unclear and the knowledge about its diagnosis and management mainly comes from small case series. We collected all the data related to 11 Elastofibroma Dorsi treated at our institution between January 2003 and July 2014. The definitive diagnosis was made by histological examination of the mass. We analyzed the characteristic of the patients, (i.e. age, sex, dominant hand, and occupation), the presenting symptoms and signs, the preoperative investigations, surgical management and complications comparing our findings with the current medical literature on the subject. We found that preoperative investigations are of limited value and when clinical presentation is typical the diagnosis could be made presumptively. Surgery should be performed under general anaesthesia since local anaesthetic infiltration and sedation are often inadequate to reduce intraoperative discomfort. PMID- 25704981 TI - 2013 ASCO/CAP updated guidelines for human epidermal growth factor receptor 2 testing: Impact on routine practice. AB - The release of the new ASCO/CAP guideline recommendations for human epidermal growth factor receptor 2 testing has led to clearer descriptive definitions for immunohistochemistry categories. As soon as we started to use them we realized that an increase in the number of ISH test was occurring. Herein we report our lab data obtained by comparing the semester after the release of the new guidelines with the same semester of the previous year. The impact on routine work practice is highlighted. PMID- 25704982 TI - Long term effects of extended adjuvant endocrine therapy on quality of life in breast cancer patients. AB - OBJECTIVES: The standard treatment for hormone-receptor positive, postmenopausal early breast cancer patients is 5 years of adjuvant endocrine therapy. Previous studies demonstrate that prolonging adjuvant endocrine therapy may improve disease-free survival. However, endocrine therapy is known for its adverse events, which may negatively affect Quality of Life (QoL). The aim of this study is to assess the impact of extended adjuvant endocrine therapy on long-term QoL outcomes. METHODS: 471 patients selected from the IDEAL trial were invited to complete a questionnaire 1-1.5 years after starting with extended therapy. The questionnaire consisted of the EORTC QLQ-C30 and QLQ-BR23 questionnaires. Mean QoL outcomes were compared with EORTC reference values for stage I and II breast cancer patients and the general population. Furthermore, QoL outcomes were compared between different treatment regimens. A difference of eight points was considered clinically relevant. RESULTS: IDEAL patients receiving extended adjuvant endocrine therapy have significantly and clinically relevant better global QoL compared with reference values for stage I and II breast cancer patients (79.6 versus 64.6; p < 0.01) and the general population (79.6 versus 71.2; p < 0.01). Similar results were found for emotional function, pain, appetite loss, diarrhea and financial problems. Between treatment regimens prior to extended adjuvant endocrine therapy, differences were only found on specific QoL domains (e.g. arm symptoms). CONCLUSION: Breast cancer patients on extended adjuvant endocrine therapy have significantly and clinically relevant better global QoL compared with other stage I-II breast cancer patients and the general population, 6-8.5 years after diagnosis. PMID- 25704983 TI - Commentary to "Refluxing ureteral reimplantation: a logical method for managing neonatal UVJ obstruction". PMID- 25704984 TI - Factors associated with poor outcome for aneurysmal subarachnoid haemorrhage in a series of 334 patients. AB - OBJECTIVE: This study evaluates care-related sociodemographic, clinical, and imaging factors and influences associated with outcome at discharge in patients with aneurismal subarachnoid haemorrhage. PATIENTS AND METHOD: Retrospective cohort study in 334 patients treated at Hospital Hermanos Ameijeiras in Havana, Cuba between October 2005 and June 2014. RESULTS: Logistic regression analysis determined that the following factors were associated with higher risk of poor outcome: age older than 65 years (OR 3.51, 95% CI 1.79-5.7, P=.031), female sex (OR 2.17, 95% CI 1.22-3.84, P=.0067), systolic hypertension (OR 4.82, 95% CI 2.27 9.8, P=.0001), and hyperglycaemia at admission (OR 3.93, 95% CI 2.10-7.53, P=.0003). Certain complications were also associated with poor prognosis, including respiratory infection (OR 2.73, 95% CI 1.27-5.85, P=.0085), electrolyte disturbances (OR 3.33, 95% CI 1.33-8.28, P=.0073), hydrocephalus (OR 2.21, 95% CI 1.05-4.63, P=.0039), rebleeding (OR 16.50, 95% CI 8.24-41.24, P=.0000), symptomatic vasospasm (OR 19.00, 95% CI 8.86-41.24, P=.0000), cerebral ischaemia (OR 3.82, 95% CI 1.87-7.80, P=.000) and multiplex rebleeding (OR 6.69, 95% CI 1.35-36.39, P=.0019). Grades of iii and iv on the World Federation of Neurological Surgeons (OR 2.09, 95% CI 1.12-3.91, P=.0021) and Fisher scales (OR 5.18, 95% CI 2.65-10.29, P=.0008) were also related to poor outcome. CONCLUSIONS: Outcome of aneurysmal subarachnoid haemorrhage was related to age, sex, clinical status at admission to the stroke unit, imaging findings according to the Fisher scale, blood pressure, glycaemia and such complications as electrolyte disturbances, hydrocephalus, rebleeding, and multiplex rebleeding. PMID- 25704985 TI - Dynamic contrast-enhanced MRI evaluates the early response of human head and neck tumor xenografts following anti-EMMPRIN therapy with cisplatin or irradiation. AB - PURPOSE: To assess the early therapeutic effects of anti-EMMPRIN (extracellular matrix metalloprotease inducer) antibody with/without cisplatin or X-ray radiation in head and neck cancer mouse models using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). MATERIALS AND METHODS: Mice bearing SCC1 (or OSC19) tumor xenografts were treated with anti-EMMPRIN antibody, radiation, cisplatin, or anti-EMMPRIN antibody plus cisplatin (or radiation) for a week (n = 4-5 per group). DCE-MRI was carried out on a 9.4T small animal MR scanner on days 0, 3, and 7, and K(trans) values were averaged in a 0.5-mm-thick peripheral tumor region. Ki67 and CD31 staining were implemented for all tumors after imaging. RESULTS: The K(trans) changes of SCC1 and OSC19 tumors treated with anti-EMMPRIN antibody for 3 days were -18 +/- 8% and 4 +/- 7%, respectively, which were significantly lower than those of control groups (39 +/- 5% and 45 +/- 7%; P = 0.0025 and 0.0220, respectively). When cisplatin was added, those were -42 +/- 9% and -44 +/- 9%, respectively, and with radiation, -45 +/- 9% and -27 +/- 10%, respectively, which were also significantly lower than those of control groups (P < 0.0001 for all four comparisons). In the eight groups untreated (served as control) or treated with anti-EMMPRIN antibody with/without cisplatin or radiation, the mean K(trans) change for 3 days was significantly correlated with the mean tumor volume change for 7 days (r = 0.74, P = 0.0346), Ki67-expressing cell density (r = 0.96, P = 0.0001), and CD31 density (r = 0.84, P = 0.0084). CONCLUSION: DCE-MRI might be utilized to assess the early therapeutic effects of anti-EMMPRIN antibody with/without chemotherapy or radiotherapy in head and neck cancer. PMID- 25704986 TI - Multi element (C, H, O) stable isotope analysis for the authentication of balsamic vinegars. AB - Balsamic vinegars are important and well-acknowledged products and have become more important all over Europe during the recent past. For their analytical control, stable isotope methods play an important role to check the authenticity of the raw materials applied. For vinegar, but not yet for balsamic vinegar analysis, stable isotope methods using hydrogen, carbon, and oxygen isotope analyses by isotope ratio mass spectrometry and (2)H-NMR have already been introduced as official methods. Nevertheless, the official procedure can be also applied for balsamic vinegars. The evaluation of the stable isotope parameters obtained for the ingredients of balsamic vinegars requires a knowledge and understanding of the natural and industrial processes on which the production of balsamic vinegars is based. Ranges and 'cut-off' values for the multi element stable isotope parameters of balsamic vinegars are described, and a suitable analytical strategy is suggested. PMID- 25704987 TI - Critique and lessons learned from using multiple methods to estimate population size of men who have sex with men in Ghana. AB - Population size estimation of key populations at risk of HIV is essential to every national response. We implemented population size estimation of men who have sex with men (MSM) in Ghana using a three-stage approach within the 2011 Ghana Men's Study: during the study's formative assessment, the larger integrated bio-behavioral surveillance (IBBS) survey; and during the stakeholder meeting. We used six methods in combination within the three-stage approach (literature review, mapping with census, unique object multiplier, service multiplier, wisdom of the crowd, and modified Delphi) to generate size estimates from 16 locations (4 IBBS survey sites and 12 other locations) and used the estimates from the 16 sites to extrapolate the total MSM population size of Ghana. We estimated the number of MSM in Ghana to be 30,579 with a plausible range of 21,645-34,470. The overall estimate suggests that the prevalence of MSM in Ghana is 0.48 % of the adult male population. Lessons learned are shared to inform and improve applications of the methods in future studies. PMID- 25704988 TI - The Feasibility and Efficacy of Healthy Weight Management Program for Low Income Chinese American Overweight and Obese Children in a Primary Care Clinic. AB - INTRODUCTION: Childhood obesity is one of the most prevalent public health concerns. METHOD: A pre and post study design was used to explore the efficacy of an obesity prevention program. Children had weight, height, blood pressure, and waist circumference measured, and completed self-reported questionnaires on food intake, knowledge, self-efficacy, and health-related quality of life. Parents completed demographic and acculturation surveys. RESULTS: Seventy children participated in the study. Results demonstrated significant reduction of BMI, systolic blood pressure, and fast food consumption and improvement of self efficacy, knowledge, and quality of life. DISCUSSION: Childhood obesity intervention is feasible and has short-term efficacy. PMID- 25704989 TI - Transition to Adult Congenital Heart Disease Care: A Review. AB - The population of adults with congenital heart disease (ACHD) has grown due to recent advances in surgical procedures. The survival rate to adulthood is now more than 95%. This review identifies current recommendations and status of ACHD management and treatment in the United States by examining comprehensive guidelines for management and transition and comparing them to the current state of the science. Successful transition from pediatric to adult care begins during the adolescent years, and prepares patients for management at an ACHD regional center utilizing multidisciplinary teams of ACHD specialists. Advocacy and research needs for the ACHD population persist. PMID- 25704990 TI - Prevalence and classification of sleep-disordered breathing. PMID- 25704991 TI - Whole genome sequencing in critically ill children. PMID- 25704992 TI - Laparoscopic vs percutaneous cryoablation for the small renal mass: 15-year experience at a single center. AB - OBJECTIVE: To analyze our 15-year experience with small renal masses ablation and present oncologic and functional outcomes of laparoscopic cryoablation (LCA) and percutaneous cryoablation (PCA). MATERIALS AND METHODS: We identified patients who underwent LCA (n = 275) or PCA (n = 137) for small renal masses between 1997 and 2012. Differences in overall survival (OS) and recurrence-free survival (RFS) were analyzed using a log-rank test. Cox proportional hazard ratios model was used to determine factors that predicted OS. Fit proportional hazard risk ratios were also calculated to determine if there were any factors that affected tumor recurrence. RESULTS: Tumor sizes were equal between the 2 groups; however, tumors in the PCA group were more complex. The overall (7.27% and 7.29%) and major complications (0.7% and 3.6%) were similar. The estimated probability of 5-year OS for LCA and PCA was 89% and 82%, respectively. The estimated probability of the 5-year RFS for LCA and PCA was 79% and 80%, respectively. Heart disease (hazard ratio, 2.15; 95% confidence interval, 1.35-3.41; P = .001) and history of disease recurrence (hazard ratio, 2.49; 95% confidence interval, 1.60-3.86; P = .001; P <.0001) were predictors of death. The median follow-up time for the LCA group (4.41 years [1.67-6.91 years]) was longer than the PCA group (3.15 years [1.37-4.08 years]; P = .0001). CONCLUSION: We found no significant difference in OS or RFS at 5 years between the 2 groups. Tumor size and anterior location affected local recurrence rates, and these factors should be taken into consideration when choosing the appropriate treatment plan. RENAL nephrometry score or type of cryoablation was not associated with tumor recurrence. PMID- 25704993 TI - Ropporin gene expression in infertile asthenozoospermic men with varicocele before and after repair. AB - OBJECTIVE: To assess Ropporin gene expression in the sperm of infertile asthenozoospermic men with varicocele (Vx) before and after repair. METHODS: This study included 24 infertile asthenozoospermic men with Vx. They were subjected to history taking, clinical examination, scrotal color Doppler, and semen analysis with sperm separation. Three months after varicocelectomy, they were subjected to postoperative color Doppler, semen analysis, and sperm semiquantitative Reverse Transcription-Polymerase Chain Reaction assay for Ropporin gene expression levels. RESULTS: Ropporin gene expression is significantly associated with different types of sperm motility, except for nonprogressive sperm motility. There was significant Ropporin gene overexpression postvaricocelectomy that was correlated with improved sperm count, sperm motility, and abnormal sperm morphology with decreased veins diameters. CONCLUSION: Ropporin gene expression is related to the sperm motility. Its abnormal expression in the sperm of asthenozoospermic men with Vx is associated with impaired sperm motility that is improved after varicocelectomy. PMID- 25704994 TI - Expression and distribution of phosphodiesterase isoenzymes in the human male urethra. AB - OBJECTIVE: To investigate the expression and distribution of phosphodiesterase (PDE) isoenzymes PDE1A, PDE2A, PDE4A, PDE4B, and PDE5A in human urethral tissue. METHODS: Specimens of penile urethra were obtained from male subjects who had undergone male-to-female sex reassignment surgery. Using immunohistochemistry (immunofluorescence), the occurrence of PDE1A, PDE2A, PDE4A, PDE4B, and PDE5A, the neuronal nitric oxide synthase, calcitonin gene-related peptide, and vasoactive intestinal polypeptide was examined in urethral sections. Cytosolic supernatants prepared from isolated human urethral tissue were subjected to Western blot analysis using specific anti-PDE antibodies. RESULTS: Immunosignals specific for PDE1A, 4A, 4B, and 5A were observed in the urethral smooth musculature. The smooth muscle bundles were seen innervated by slender nerve fibers, characterized by the expression of the neuronal nitric oxide synthase, calcitonin gene-related peptide, and vasoactive intestinal polypeptide. The expression of the PDE isoenzymes mentioned was confirmed by Western blotting. CONCLUSION: The results provide evidence for a significance of both the cyclic adenosine monophosphate and cyclic guanosine monophosphate signaling in the control of human urethral smooth muscle. The selective inhibition of PDE isoenzymes might represent a pharmacologic option to influence the function of smooth musculature in the human outflow region. PMID- 25704995 TI - Bipolar transurethral resection of the prostate: Darwinian evolution of an instrumental technique. AB - Bipolar transurethral resection of the prostate (B-TURP) represents a Darwinian evolution of an instrumental technique that has been justified by reinforcing the leading position of monopolar transurethral resection of the prostate. Notwithstanding limitations, the best available evidence recommends B-TURP as an attractive alternative. It may serve as a reliable training platform for modern residents. High-quality evidence is lacking to definitely define its position in treating special subpopulations (anticoagulation dependence, comorbidities, and large adenomas). Regarding economic issues, preliminary evidence supports B-TURP, warranting further investigation. Future perspectives include attempts toward improvements of the existing technology, combining advantages with those of other new techniques, and evolution to novel, potentially safer, or more efficient techniques to address remaining challenges. PMID- 25704996 TI - Vascular complications after percutaneous nephrolithotomy: 10 years of experience. AB - OBJECTIVE: To provide a contemporary look at vascular complications after percutaneous nephrolithotomy (PNL) with access performed solely by a urologist using fluoroscopic guidance. METHODS: A retrospective review of 2792 patients who had 3338 PNLs at Indiana University Health Methodist Hospital and Mayo Clinic Rochester was performed. Patients who experienced significant bleeding requiring diagnostic renal angiography and superselective embolization (SSE) were reviewed and compared with the overall database. RESULTS: There were 15 patients (16 renal units) requiring renal angiography and SSE (0.48%). Mean time from PNL to bleeding was 7 days (range, 1-15 days) and to SSE was 9.6 days (range, 2-18 days). Mean drop in hemoglobin was 5.3 g/dL (range, 2-9 g/dL). Transfusion was needed in 9 patients (60%). There were no differences between the vascular complications group and the uneventful PNL group in mean age (55.06 vs 52.2 years; P = .519), UTI history (40% vs 38%; P = .92), mean operative time (125.8 vs 102.47 minutes; P = .192), the need for multiple access (18.75% vs 18%; P = .939), and access location. The vascular complications group had a lower stone burden than the uneventful PNL group (stones > 2 cm; 43.7% vs 74.03%; P = .014). CONCLUSION: The incidence of vascular complications in this contemporary series is one of the lowest reported to date. At our centers, vascular bleeding complications appear to be a random and rare event after PNL as we were unable to identify any specific risk factors. Early SSE avoided the need for blood transfusion in many patients. PMID- 25704997 TI - Congenital anterior urethral diverticulum: antenatal diagnosis with subsequent neonatal endoscopic management. AB - Congenital anterior urethral diverticulum is a rare cause of urethral obstruction in boys. We report on the antenatal diagnosis of this rare phenomenon, making this the sixth prenatally diagnosed case in the English literature (to the best of our knowledge). Our initial prenatal assessment, postnatal endoscopic management, along with the eventual clinical course is outlined. The embryologic theories, differential diagnosis, literature review, imaging, and treatment modalities of this entity are discussed. PMID- 25704998 TI - In vivo targeting through click chemistry. AB - Targeting small molecules to diseased tissues as therapy or diagnosis is a significant challenge in drug delivery. Drug-eluting devices implanted during invasive surgery allow the controlled presentation of drugs at the disease site, but cannot be modified once the surgery is complete. We demonstrate that bioorthogonal click chemistry can be used to target circulating small molecules to hydrogels resident intramuscularly in diseased tissues. We also demonstrate that small molecules can be repeatedly targeted to the diseased area over the course of at least one month. Finally, two bioorthogonal reactions were used to segregate two small molecules injected as a mixture to two separate locations in a mouse disease model. These results demonstrate that click chemistry can be used for pharmacological drug delivery, and this concept is expected to have applications in refilling drug depots in cancer therapy, wound healing, and drug eluting vascular grafts and stents. PMID- 25705000 TI - Review of nanomaterial aging and transformations through the life cycle of nano enhanced products. AB - In the context of assessing potential risks of engineered nanoparticles (ENPs), life cycle thinking can represent a holistic view on the impacts of ENPs through the entire value chain of nano-enhanced products from production, through use, and finally to disposal. Exposure to ENPs in consumer or environmental settings may either be to the original, pristine ENPs, or more likely, to ENPs that have been incorporated into products, released, aged and transformed. Here, key product-use related aging and transformation processes affecting ENPs are reviewed. The focus is on processes resulting in ENP release and on the transformation(s) the released particles undergo in the use and disposal phases of its product life cycle for several nanomaterials (Ag, ZnO, TiO2, carbon nanotubes, CeO2, SiO2 etc.). These include photochemical transformations, oxidation and reduction, dissolution, precipitation, adsorption and desorption, combustion, abrasion and biotransformation, among other biogeochemical processes. To date, few studies have tried to establish what changes the ENPs undergo when they are incorporated into, and released from, products. As a result there is major uncertainty as to the state of many ENPs following their release because much of current testing on pristine ENPs may not be fully relevant for risk assessment purposes. The goal of this present review is therefore to use knowledge on the life cycle of nano-products to derive possible transformations common ENPs in nano-products may undergo based on how these products will be used by the consumer and eventually discarded. By determining specific gaps in knowledge of the ENP transformation process, this approach should prove useful in narrowing the number of physical experiments that need to be conducted and illuminate where more focused effort can be placed. PMID- 25704999 TI - Sociodemographic Correlates of Cognition in the Multi-Ethnic Study of Atherosclerosis (MESA). AB - OBJECTIVE: To describe the methodology utilized to evaluate cognitive function in the Multi-Ethnic Study of Atherosclerosis (MESA) and to present preliminary results by age, sex, and race/ethnicity. DESIGN: Cross-sectional measurements of a prospective observational cohort. SETTING: Residents of 6 U.S. communities free of cardiovascular disease at baseline (2000-02). PARTICIPANTS: 4,591 adults who completed the fifth MESA clinical examination in 2011-12; mean age 70.3 (SD: 9.5) years, 53.1% women, 40.7% non-Hispanic white, 26.4% non-Hispanic black, 21.4% Hispanic, and 11.5% Chinese. MEASUREMENTS: The cognitive battery consisted of the Cognitive Abilities Screening Instrument (version 2) to evaluate global cognition, the Digit Symbol Code for processing speed and Digit Spans Forward and Backward to assess memory. Demographic, socioeconomic, and cultural covariates were also collected for descriptive statistics and multivariate modeling. RESULTS: Associations between socioeconomic factors and cognition revealed that age, race/ethnicity, education, occupational status, household income, health insurance type, household size, place of birth, years and generation in U.S., and the presence of the ApoE4 allele were significantly associated with performance on the cognitive tests, although patterns varied by specific test, racial/ethnicity, and sociocultural factors. CONCLUSION: As many of the influencing cultural and socioeconomic factors measured here are complex, multifactorial, and may not be adequately quantified, caution has been recommended with regard to comparison and interpretation of racial/ethnic group performance differences from these cross-sectional models. These data provide a baseline for future exams and more comprehensive longitudinal analyses of the contributions of subclinical and clinical diseases to cognitive function and decline. PMID- 25705001 TI - Forme fruste or 'Incomplete' bicuspid aortic valves with very small raphes: The prevalence of bicuspid valve and its significance may be underestimated. AB - BACKGROUND: Bicuspid aortic valve (BAV) comprises a broad spectrum of phenotypes. The importance of BAV in thoracic aortic aneurysm management has been debated. A subtle phenotype of BAV has been identified recently that could impact this debate. METHODS AND RESULTS: 101 consecutive patients with intact aortic valves operated in the setting of ascending aneurysm between January 2011-January 2014 were retrospectively identified. 20 were excluded because of valve calcification. 79 of 81 remaining had aortic valve phenotype described in operative reports, including tri-leaflet, bicuspid, and difficult-to-classify valves with small degrees of non-calcific fusion (raphe) at the commissures. Photographs of some three-leaflet valves with very small raphes were obtained. 18/79 (22.8%) had obvious BAVs and 61/79 (77.2%) were initially considered tri-leaflet valves. 18/61 (29.5%) of these had distinct but very small raphes and 12/18 (66.7%) involved the right/left commissure. Moderate or greater aortic insufficiency was found in 13/43 (30%) of patients with tri-leaflet valves, 8/18 (44.4%) with obvious BAVs, and in 9/18 (50%) three-leaflet valves with very small raphes. Retrospective review of computed tomography, magnetic resonance imaging and trans esophageal (but not trans-thoracic) echocardiography sometimes identified very small raphes. CONCLUSIONS: Three-leaflet aortic valves exhibiting very small raphes occur in the setting of thoracic aneurysm and aortic insufficiency and may represent forme fruste BAVs. They are sometimes identifiable with high-resolution valve imaging. Without accounting for forme fruste BAVs, the true prevalence and impact of BAV on aortic complications may have been historically underestimated. This entity warrants further study in a prospective multi-center registry. PMID- 25705002 TI - Better understanding before implanting. PMID- 25705003 TI - Carvedilol use is associated with reduced cancer risk: A nationwide population based cohort study. AB - BACKGROUND: To investigate the effect of carvedilol on the incidence of cancer in a large population-based cohort study. METHODS: Data were obtained from the Taiwan National Health Insurance Research Database. The cohort study included 6771 patients who received long-term carvedilol treatment between 2000 and 2010 (carvedilol cohort) and 6771 matched controls (noncarvedilol cohort). A Cox proportional hazards model was used to evaluate the risk of cancer in the patients treated with carvedilol. RESULTS: With the mean follow-up period of 5.17 years and 4.93 years in the carvedilol and noncarvedilol cohorts, respectively, the patients in the carvedilol cohort had a 26% reduction of cancer risk compared with those in the noncarvedilol cohort (hazard ratio [HR]=0.74; 95% confidence interval [CI]=0.63-0.87; p<.001). The sex-specific carvedilol to noncarvedilol relative risk was lower for both women (HR=0.73; 95% CI=0.56-0.94) and men (HR=0.75; 95% CI=0.61-0.92). Moreover, stratified by cancer site, treatment with carvedilol in the carvedilol cohort resulted in significantly lower incidence of stomach and lung cancers than in the noncarvedilol cohort. CONCLUSION: This nationwide population-based cohort study demonstrated that long-term treatment with carvedilol is associated with reduced upper gastrointestinal tract and lung cancer risk, indicating that carvedilol could be a potential agent in these cancers prevention. PMID- 25705004 TI - Serum levels of pigment epithelium-derived factor (PEDF) are inversely associated with circulating levels of dipeptidyl peptidase-4 (DPP-4) in humans. AB - BACKGROUND: We have previously found that advanced glycation end products (AGEs) stimulate the proteolytic cleavage of dipeptidyl peptidase-4 (DPP-4) from plasma membranes, and circulating AGE levels are independently correlated with serum DPP 4 values. Since pigment epithelium-derived factor (PEDF), one of the adipocytokines, inhibits the AGEs-induced insulin resistance and vascular damage, it is conceivable that besides AGEs, PEDF might also regulate soluble DPP-4 levels. In this study, we addressed the issue. STUDY DESIGN AND METHODS: The study involved 188 subjects (123 males and 65 females; mean age of 61.1+/-9.2) who visited our hospital for a risk-screening test or treatment for cardiovascular disease. They underwent complete history and physical examinations, and determination of blood chemistry and anthropometric variables, including visceral and subcutaneous fat areas. Serum levels of DPP-4 and PEDF levels were examined by enzyme-linked immunosorbent assay. RESULTS: Median (interquartile range) serum levels of DPP-4 and PEDF were 466.6 (400.2-545.1) ng/mL and 14.0 (10.6-17.0) MUg/mL, respectively. Multiple stepwise regression analysis revealed that female (p<0.001), aspartate aminotransferase (p<0.001), glycated hemoglobin (p<0.001) and PEDF (inversely, p=0.020) were independently associated with DPP-4 levels (R(2)=0.267). CONCLUSION: We found here for the first time that serum PEDF levels were one of the independent correlates of circulating DPP-4 levels in humans. Since DPP-4 could impair insulin action and evoke vascular damage, our present study suggests that insulin-sensitizing and atheroprotective properties of PEDF might be ascribed partly to its inhibitory actions on DPP-4. PMID- 25705005 TI - A 2-year follow-up of a randomized multicenter study comparing a paclitaxel drug eluting balloon with a paclitaxel-eluting stent in small coronary vessels the BELLO study. AB - BACKGROUND/OBJECTIVES: A prospective, multi-center, randomized trial, BELLO (Balloon Elution and Late Loss Optimization), showed that the primary endpoint of in-stent (in-balloon) late loss was significantly less with drug-eluting balloons (DEB) as compared with paclitaxel-eluting stents (PES). At 6 months, DEB and PES were associated with similar rates of angiographic restenosis, target lesion revascularization (TLR), and major adverse cardiac events (MACE) defined as death, myocardial infarction and target vessel revascularization. The aim of this study was to report 2-year clinical outcomes after treatment of de novo small vessel disease with DEB as compared with PES. METHODS: A total of 182 patients were enrolled and randomized to treatment with DEB (n=90) in 94 lesions or PES (n=92) in 98 lesions. The study endpoint was the incidence of MACE at 2-year follow-up. RESULTS: Two-year follow-up was achieved in almost all cases (97.8% in DEB group vs. 98.9% in PES group). There was a trend towards a lower incidence of MACE in the DEB group as compared with the PES group (14.8% vs. 25.3%; p=0.08). TLR rates in the DEB group were acceptable at 6 months, 1 year and 2 years and did not differ significantly from the PES group (4.4% vs. 7.6%, p=0.37; 6.7% vs. 12.1%, p=0.23; 6.8% vs. 12.1%, p=0.25, respectively). CONCLUSIONS: Our results suggest that treatment of small vessel disease with a paclitaxel DEB is associated with a trend for improved clinical outcomes as compared with PES up to 2 years. Late catch-up phenomenon requiring repeat intervention after treatment with DEB was not evident in this study. PMID- 25705006 TI - Comparative assessment of ascending aortic aneurysms in Marfan patients using ECG gated computerized tomographic angiography versus trans-thoracic echocardiography. AB - BACKGROUND: Contrast-enhanced computed tomography (CT) is routinely used as a complementary technique to trans-thoracic echocardiography (TTE) for assessing thoracic aortic aneurysms (TAA). However different measures can be obtained on CT and there are no recommendations on which to use. The objective was to determine which CT measurements most closely match reference TTE measurements in Marfan patients with TAA. METHODS: TTE measurements were obtained using the leading edge to-leading edge technique in end-diastole on the parasternal longitudinal view. ECG-gated CT measurements were obtained, using the inner-to-inner technique in end-diastole by double oblique reconstruction: on three-cavity view (3C), left ventricle-aorta view (LVAo), and strict transverse plane passing through the maximal diameter "cusp to commissure" and "cusp to cusp" for each cusp. CT and TTE were performed within one month. RESULTS: 44 Marfan patients (39 +/- 19 years, 48% men) were included. Dilatation of the ascending aorta was maximal at the level of the sinuses (TTE diameters: mean 47.5 +/- 5.3 mm). TTE diameters were similar to 3C, LVAo (mean differences: 2.2 and -0.1 mm, p=NS) and to the three "cusp to cusp" diameters (mean differences ranging from 0 to 1.1mm, p=NS), whereas "cusp to commissure" diameters were all statistically smaller than TTE (3.6 mm, 2.9 mm and 3.7 mm, p <= 0.01). CONCLUSIONS: Inner-to-inner "cusp to cusp" diameter measured on an ECG-gated CT should be used for comparison with 2D TTE aortic diameter at the level of the sinuses of Valsalva in patients with thoracic aortic aneurysms. PMID- 25705007 TI - Cortisol levels in scalp hair of patients with structural heart disease. AB - BACKGROUND: Stress is considered a modifiable risk factor for cardiovascular disease. Scalp hair analysis is a tool to assess long-term exposure to the stress hormone cortisol. We aimed to determine the association between hair cortisol concentrations (HCC) and clinical characteristics in patients with structural heart disease. Additionally, we investigated potential predictors for longitudinal change in HCC. METHODS: The study consisted of 261 patients with structural heart disease from a randomized controlled trial of mindfulness training. One sample of scalp hair was used to determine HCC both at baseline and at 12-week follow-up. In 151 patients, HCC was available (mean age: 41.3 years, range 18-65). We investigated the association between HCC at baseline and several physiological measures (BMI, blood pressure, heart rate, respiratory rate, 6 minute walk test), as well as psychological parameters (physical and mental component summary measures (SF-36), emotional distress (HADS), and perceived stress). Additionally, we used these clinical parameters to predict HCC change over time. RESULTS: The median HCC was 22.3 pg/mg of hair (23.5 interquartile range). In multivariable linear regression analyses, an association was observed between log-transformed HCC and BMI (beta 0.171, p=0.037), respiratory rate (beta 0.194, p=0.016), and the physical summary score (beta -0.163, p=0.054). Independent predictors of log-transformed HCC change after 12 weeks were mental summary score (beta -0.200, p=0.019) and diastolic blood pressure (beta -0.171, p=0.049). CONCLUSIONS: In patients with structural heart disease a positive association exists between HCC and BMI. Mental health status may predict a change in long-term cortisol over time. PMID- 25705008 TI - Vitamin D deficiency and atrial fibrillation. AB - Vitamin D deficiency has been linked with hypertension, coronary artery disease, and stroke, but there is no consensus regarding the possible association between vitamin D deficiency and atrial fibrillation (AF). Vitamin D negatively regulates the renin-angiotensin-aldosterone-system (RAAS), mediates calcium homeostasis, binds to vitamin D receptors on cardiac myocytes, and has antioxidant properties that may reduce levels of reactive oxygen species (ROS) in the atria, which contribute to inflammation and proarrhythmic substrate formation. As vitamin D status is a readily modifiable risk factor this association has potential clinical implications. An extensive search of the literature identified six studies that specifically investigated vitamin D status and AF. Results were equivocal with three studies identifying a positive association between vitamin D deficiency and AF, whilst two studies suggested there may be no association. Additionally, one study indicated that elevated vitamin D levels are associated with AF. Whilst the weight of the evidence suggests that there may be an association between vitamin D deficiency and AF, incomparable study designs and methodological limitations hinder interpretation of the current body of evidence. Further work taking into account considerations raised within this paper is required to better understand the relationship between vitamin D status and AF. PMID- 25705009 TI - High sensitivity troponin: Does the 50% delta change alter clinical outcomes in chest pain presentations to the emergency room? AB - BACKGROUND: The National Heart Foundation (NHF) and Cardiac Society of Australia and New Zealand (CSANZ) Acute Coronary Syndrome (ACS) guidelines recommend the use of a high sensitivity troponin assay (hsTrop) in the assessment of patients presenting with ACS. A troponin delta of 50% compared with the previously recommended 20% is advocated by the guidelines to aid in the clinical diagnosis of ACS. We sought to determine the clinical impact of the updated recommendation to use 50% troponin delta for patients presenting with chest pain to the emergency department. METHOD: We retrospectively collected data for all patients >18 years presenting with chest or abdominal pain with a hsTrop test performed between January-June 2012. Patients with a STEMI, lacked serial hsTrop, were on dialysis or had trauma-related pain were excluded. RESULTS: Of the 1054 eligible patients, 422 (40%) with serial hsTrop had at least one abnormal troponin (>14 ng/ml). 73 (6.9%) fell within 20-50%. Twenty-seven had clinical or ECG evidence suggestive of ACS and were referred for further cardiac investigations. Of the remainder, five patients were medically managed for ACS, 38 patients with non cardiac chest pain had no further tests. At 1 year follow-up, of the patients that did not undergo further investigations, 6 patients represented with ACS; there was no cardiac mortality. CONCLUSION: Our data showed a number of patients that would be potentially missed with the implementation of a 50% troponin. However, this loss of sensitivity was mitigated by the use of clinical acumen. PMID- 25705010 TI - Accuracy of methods for diagnosing atrial fibrillation using 12-lead ECG: A systematic review and meta-analysis. AB - BACKGROUND: Screening for atrial fibrillation (AF) using 12-lead electrocardiograms (ECGs) has been recommended; however, the best method for interpreting ECGs to diagnose AF is not known. We compared accuracy of methods for diagnosing AF from ECGs. METHODS: We searched MEDLINE, EMBASE, CINAHL and LILACS until March 24, 2014. Two reviewers identified eligible studies, extracted data and appraised quality using the QUADAS-2 instrument. Meta-analysis, using the bivariate hierarchical random effects method, determined average operating points for sensitivities, specificities, positive and negative likelihood ratios (PLR, NLR) and enabled construction of Summary Receiver Operating Characteristic (SROC) plots. RESULTS: 10 studies investigated 16 methods for interpreting ECGs (n=55,376 participant ECGs). The sensitivity and specificity of automated software (8 studies; 9 methods) were 0.89 (95% C.I. 0.82-0.93) and 0.99 (95% C.I. 0.99-0.99), respectively; PLR 96.6 (95% C.I. 64.2-145.6); NLR 0.11 (95% C.I. 0.07 0.18). Indirect comparisons with software found healthcare professionals (5 studies; 7 methods) had similar sensitivity for diagnosing AF but lower specificity [sensitivity 0.92 (95% C.I. 0.81-0.97), specificity 0.93 (95% C.I. 0.76-0.98), PLR 13.9 (95% C.I. 3.5-55.3), NLR 0.09 (95% C.I. 0.03-0.22)]. Sub group analyses of primary care professionals found greater specificity for GPs than nurses [GPs: sensitivity 0.91 (95% C.I. 0.68-1.00); specificity 0.96 (95% C.I. 0.89-1.00). Nurses: sensitivity 0.88 (95% C.I. 0.63-1.00); specificity 0.85 (95% C.I. 0.83-0.87)]. CONCLUSIONS: Automated ECG-interpreting software most accurately excluded AF, although its ability to diagnose this was similar to all healthcare professionals. Within primary care, the specificity of AF diagnosis from ECG was greater for GPs than nurses. PMID- 25705011 TI - Total ischaemic time and 9-year outcomes in STEMI patients treated with pPCI. AB - BACKGROUND: Prolonged total ischaemic time (TIT) has been shown to independently predict poor myocardial perfusion in STEMI patients and affect in-hospital mortality. We aim to evaluate the influence of TIT on long-term follow-up (F/U) and identify the factors associated with TIT in patients with STEMI treated with pPCI at a high volume centre. METHODS: In a prospective "all-comer" registry, clinical, angiographic and procedural characteristics, TIT and 9-year mortality were determined in consecutive STEMI patients treated with pPCI. Patients were divided according to TIT into three groups: A) <3, B) 3-6 and C) >6h. RESULTS: Among 1064 patients, TIT was known in 1002 patients, 5 patients were lost to F/U. For censored observations F/U was 7.2-8.8 years. There were 350, 461, and 186 patients in groups A, B, and C, respectively. Patients in group A compared to B and C were younger, more often males and smokers, less frequently had history of CAD, and more frequently had occluded infarct related artery. However, final TIMI3 was obtained more frequently. Overall 30-day mortality was 4%, one-year mortality 7% and nine-year mortality 27%. Multivariable logistic regression models indicated that longer TIT was associated with a higher risk of 9-year mortality (A-21%, B-28%, C-37%, p<0.0005). TIT>6h was independently associated with advanced age, diabetes mellitus, history of CAD and higher rate of initial TIMI grade flow 3. CONCLUSIONS: TIT is strongly related with mortality in STEMI patients even after nine years of F/U. This finding reinforces the necessity of shortening the TIT in all STEMI patients. PMID- 25705012 TI - Stress pulls us apart: anxiety leads to differences in competitive confidence under stress. AB - Social competition is a fundamental mechanism of evolution and plays a central role in structuring individual interactions and communities. Little is known about the factors that affect individuals' competitive success, particularly in humans. Key factors might include stress, a major evolutionary pressure that can affect the establishment of social hierarchies in animals, and individuals' trait anxiety, which largely determines susceptibility to stress and constitutes an important determinant of differences in competitive outcomes. Using an economic choice experiment to assess competitive self-confidence in 229 human subjects we found that, whereas competitive self-confidence is unaffected by an individual's anxiety level in control conditions, exposure to the Trier social stress test for groups drives the behavior of individuals apart: low-anxiety individuals become overconfident, and high-anxiety individuals become underconfident. Cortisol responses to stress were found to relate to self-confidence, with the direction of the effects depending on trait anxiety. Our findings identify stress as a major regulator of individuals' competitiveness, affecting self-confidence in opposite directions in high and low anxious individuals. Therefore, our findings imply that stress may provide a new channel for generating social and economic inequality and, thus, not only be a consequence, but also a cause of inequality through its impact on competitive self-confidence and decision making in financially-relevant situations. PMID- 25705013 TI - Alcohol-induced blackouts and maternal family history of problematic alcohol use. AB - BACKGROUND: Consequences of heavy drinking include alcohol-induced blackouts, which are periods of amnesia for all or part of a drinking event. One risk factor for blackouts is family history of problematic alcohol use (FH+); however, research rarely distinguishes maternal from paternal FH+. The objective of this study was to examine whether maternal or paternal FH+ better predicts likelihood of experiencing blackouts than a general measure of overall FH+, and whether gender moderates this association. METHOD: Participants (N=1164; 65.4% are female) were first-time college freshmen (age range=17-19) who participated in a 6-year, 10-assessment, longitudinal study in the United States. Alcohol-induced blackouts, the dependent measure, were dichotomized (yes/no) based on endorsement of memory problems after drinking using a single item during Years 4-6. FH+, captured at baseline, was coded if participants self-reported that their mother, father, or any of their four grandparents were a possible or definite problem drinker. RESULTS: Overall, 773 (66.4%) participants reported experiencing blackouts during Years 4-6. Women were more likely to report blackouts than men; however, compared with women with a maternal FH+, men with a maternal FH+ were more than twice as likely to report blackouts. DISCUSSION: Men appear to be more susceptible than women to the effects of a maternal FH+. Genetic and environmental explanations for this finding are discussed. In sum, these findings are an important step toward understanding a significant yet understudied negative consequence of heavy alcohol use. PMID- 25705014 TI - Motivations, substance use and other correlates amongst property and violent offenders who regularly inject drugs. AB - OBJECTIVE: To examine the prevalence, correlates and motivations for the commission of property and violent crime amongst a sample of people who inject drugs (PWID). METHOD: Data were obtained from the 2013 Illicit Drug Reporting System (IDRS), which includes a cross-sectional sample of 887 PWID. RESULTS: Eighteen percent of PWID had committed a property offence and 3% had committed a violent offence in the month preceding interview. Opioid dependence (AOR 2.57, 95% CI 1.29-5.10) and age (AOR 0.96, 95% CI 0.93-0.99) were found to be the strongest correlates of property crime. The majority of property offenders (75%) attributed their offending to financial reasons, however those under the influence of benzodiazepines were proportionately more likely to nominate opportunistic reasons as the main motivation for their last offence. Stimulant dependence (AOR 5.34, 95% CI 1.91-14.93) was the only significant correlate of past month violent crime, and the largest proportion of violent offenders (47%) attributed their offending to opportunistic reasons. The majority of both property (71%) and violent offenders (73%) reported being under the influence of drugs the last time they committed an offence; the largest proportion of property offenders reported being under the influence of benzodiazepines (29%) and methamphetamine (24%), whilst violent offenders mostly reported being under the influence of heroin and alcohol (32% respectively). CONCLUSION: Criminal motivations, substance use and other correlates vary considerably across crime types. This suggests that crime prevention and intervention strategies need to be tailored according to individual crime types, and should take into account self reported criminal motivations, as well as specific risk factors that have been shown to increase the likelihood of offending. PMID- 25705015 TI - Are Indian yoga trials more likely to be positive than those from other countries? A systematic review of randomized controlled trials. AB - OBJECTIVE: To determine whether the conclusions of randomized controlled trials (RCTs) of yoga are more likely to be positive when they were conducted in India and/or when they are published in complementary and alternative medicine (CAM) specialty journals. METHODS: Medline/PubMed, Scopus, the Cochrane Library, IndMED, and the tables of content of yoga specialty journals not listed in medical databases were screened through February 2014 for RCTs comparing yoga interventions to non-yoga interventions. The RCTs' conclusions were classified as positive (yoga is helpful for a respective condition) or not positive; and compared between RCTs that were a) conducted in India vs. outside India, and b) published in a CAM specialty journal or another type of journal. RESULTS: A total of 306 RCTs were included; 131 from India and 175 from other countries; and 84 from CAM specialty journals and 222 from other types of journals. Positive conclusions were reached in 277 RCTs (91%); with more positive RCTs being conducted in India than elsewhere (odds ratio=24.8; 95% confidence interval=3.3, 184.5; p<0.001) while type of journal was not associated with the direction of the conclusions (odds ratio=1.2; 95% confidence interval=0.5, 2.9; p=0.828). CONCLUSIONS: RCTs on yoga that are conducted in India have about 25 times the odds of reaching positive conclusions as those conducted elsewhere. Indian trials should be dealt with carefully when evaluating the helpfulness of yoga for patients in other countries and vice versa. PMID- 25705016 TI - Fluorometric imaging methods for palladium and platinum and the use of palladium for imaging biomolecules. AB - Neither palladium nor platinum is an endogenous biological metal. Imaging palladium in biological samples, however, is becoming increasingly important because bioorthogonal organometallic chemistry involves palladium catalysis. In addition to being an imaging target, palladium has been used to fluorometrically image biomolecules. In these cases, palladium species are used as imaging enabling reagents. This review article discusses these fluorometric methods. Platinum-based drugs are widely used as anticancer drugs, yet their mechanism of action remains largely unknown. We discuss fluorometric methods for imaging or quantifying platinum in cells or biofluids. These methods include the use of chemosensors to directly detect platinum, fluorescently tagging platinum-based drugs, and utilizing post-labeling to elucidate distribution and mode of action. PMID- 25705017 TI - WITHDRAWN: Hypertrophic cardiomyopathy: Genotype-positive, phenotype-"almost" negative. Diagnostic role of exercise in provocation of left ventricular outflow tract gradient. AB - The Publisher regrets that this article is an accidental duplication of an article that has already been published, http://dx.doi.org/10.1016/j.ijcard.2014.09.137. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 25705018 TI - Comparative analysis of KRAS codon 12, 13, 18, 61, and 117 mutations using human MCF10A isogenic cell lines. AB - KRAS mutations occur in one third of human cancers and cluster in several hotspots, with codons 12 and 13 being most commonly affected. It has been suggested that the position and type of amino acid exchange influence the transforming capacity of mutant KRAS proteins. We used MCF10A human mammary epithelial cells to establish isogenic cell lines that express different cancer associated KRAS mutations (G12C, G12D, G12V, G13C, G13D, A18D, Q61H, K117N) at physiological or elevated levels, and investigated the biochemical and functional consequences of the different variants. The overall effects of low-expressing mutants were moderate compared to overexpressed variants, but allowed delineation of biological functions that were related to specific alleles rather than KRAS expression level. None of the mutations induced morphological changes, migratory abilities, or increased phosphorylation of ERK, PDK1, and AKT. KRAS-G12D, G12V, G13D, and K117N mediated EGF-independent proliferation, whereas anchorage independent growth was primarily induced by K117N and Q61H. Both codon 13 mutations were associated with increased EGFR expression. Finally, global gene expression analysis of MCF10A-G13D versus MCF10A-G12D revealed distinct transcriptional changes. Together, we describe a useful resource for investigating the function of multiple KRAS mutations and provide insights into the differential effects of these variants in MCF10A cells. PMID- 25705019 TI - Single oxygen-atom insertion into P-B bonds: on- and off-metal transformation of a borylphosphine into a borylphosphinite. AB - An oxygen atom is selectively inserted into the P-B bond of a borylphosphine (L1) by reaction with Me3 NO to afford the corresponding borylphosphinite (L2). This transformation can also be effected when L1 is coordinated to rhodium. The nu(CO) values for trans-[RhCl(CO)(L)2] reveal very different electronic properties for coordinated L1 and L2 which translate into the strikingly different performances of the complexes [RhCl(L)(cod)] (L= L1 or L2, cod=1,5-cyclooctadiene) in hydrosilylation and hydroboration catalysis. PMID- 25705020 TI - Blood pressure assessment and first-line pharmacological agents in women with eclampsia. AB - BACKGROUND: Eclampsia is a life-threatening complication of pregnancy. Timely blood pressure assessment and administration of magnesium sulphate are essential management. In this retrospective single-centre study we examined the timing and magnitude of maternal blood pressure before eclampsia, and whether magnesium sulphate was administered as the first agent for treatment. METHODS: We conducted a five-year review of eclampsia in a tertiary referral obstetric hospital. Using data from electronic birthing records and hospital coding (ICD-10AM) we identified patients with the diagnostic criteria for eclampsia and assessed patient characteristics, blood pressure and pharmacological treatment. RESULTS: There were 33812 births from July 2008 to June 2013 with 19 cases of eclampsia (1:1780). Patients were 32+/-5.9years of age, 36+/-3.9weeks of gestation, 63% were nulliparous and all had a singleton pregnancy. Antepartum eclampsia occurred in 74%. In the four hours before a fit, 47% of patients had blood pressure recorded, of whom 78% were hypertensive. Magnesium sulphate was administered as first therapy in 47% of patients but it was not given to any patient transferred to hospital by ambulance. Of the patients who fitted antenatally, 86% underwent caesarean section, of whom 25% received neuraxial anaesthesia. CONCLUSIONS: Our study highlights the need for vigilance when managing pregnant women with hypertension, especially in the third trimester as eclampsia is most likely preceded by raised blood pressure. It also highlights the need for timely commencement of magnesium sulphate in the community and during transfer to hospital for the treatment of eclampsia, and for prevention of eclampsia in hospital when thresholds for severe preeclampsia are met. PMID- 25705021 TI - Abnormalities of the uncinate fasciculus correlate with executive dysfunction in patients with left temporal lobe epilepsy. AB - OBJECTIVE: To evaluate executive deficits in patients with left temporal lobe epilepsy (TLE) and to analyze the association of executive deficits and diffusion tensor imaging (DTI) parameters of the uncinate fasciculus. METHODS: This study included 14 adult left TLE patients and 15 healthy controls. Executive function was examined using neuropsychological tests, including the Stroop color-word, digit span, digit symbol, trail-making test, and verbal fluency tests. All subjects underwent brain DTI. RESULTS: Compared with controls, TLE patients needed significantly more time (P=0.036) and had more wrong answers (P<0.001) in the Stroop test, and exhibited significantly lower scores in the digit span (P=0.017), digit symbol (P=0.009), and verbal fluency (P=0.001) tests. Additionally, TLE patients took significantly longer to accomplish the trail making test (P=0.042). Fractional anisotropy (FA) of the left uncinate fasciculus in TLE patients was significantly lower compared to controls (P<0.001). FA of the left uncinate fasciculus in TLE patients and controls positively correlated with verbal fluency (r=0.565, P=0.035; r=0.561, P=0.031) and digit span (r=0.556, P=0.039; r=0.559, P=0.030) test scores. CONCLUSIONS: Patients with left TLE exhibit wide ranges of executive deficits. Abnormal FA values in the left UF ipsilateral to the epileptogenic zone suggest that disrupted integrity in the left uncinate fasciculus is related to executive deficits in patients with left TLE. PMID- 25705022 TI - Pancreatic cancer growth using magnetic resonance and bioluminescence imaging. AB - OBJECT: Pancreatic cancer is one of the most lethal human cancer and appropriate experimental tumor models are needed for the development of innovative therapeutic approaches. This paper describes an experimental model of human pancreatic cancer and a related non invasive imaging technique suitable for monitoring tumor growth and metastatization. The aim of the work was the implementation of an experimental platform suitable for assessing the efficacy of new therapeutic agents. MATERIALS AND METHODS: Human pancreatic cancer cells (PANC-1-Luc+) were injected into the pancreas of female athymic CD1 mice. Magnetic Resonance Imaging (MRI) at 4.7T and Bioluminescence Imaging (BLI) were performed in each mouse at three time points after cell inoculation (1, 2 and 3months). Two groups of mice were studied: the first group of n=13 mice in which 5*10(6) cells were injected and the second group of n=10 mice in which 2*10(6) cells were injected. MRI examination included T2w acquisitions and (at the last time point) Dynamic-contrast-enhanced-MRI (DCE-MRI). RESULTS: Each mouse underwent three longitudinal MRI and BLI examinations. BLI was more sensitive than MRI producing higher detection rate at early time points. Moreover in one case of abdominal dissemination of pancreatic tumor cells, small tumoral masses were detected by BLI and not detected by MRI. However BLI appears more prone to experimental error most likely due to photon attenuation. In 4 mice BLI produced false negative results. DCE-MRI experiments providing information on tumor perfusion were conducted successfully in this anatomical district and demonstrated that the tumor tissues from the second experimental group are more vascularized compared to the first group. CONCLUSION: The present study performed on the experimental model of pancreatic cancer here described shows that MRI and BLI are complementary techniques and that synergistic application of both can overcome the intrinsic limitations of each. PMID- 25705023 TI - Evaluating treatment options for common bovine diseases using published data and clinical experience. AB - "In this article, the authors describe the sources used by clinicians to obtain information about the efficacy of treatments. The authors discuss how the potential for bias differs by information source and how the ability to assess bias differs by information source. The authors also discuss how the clinical setting and background are important to making decisions about treatments, but clinical impressions of efficacy can be biased. The role of cohort studies, clinical impressions, case reports, case series, pharmacokinetic studies, in vivo studies, narrative review, and opinion are also discussed." PMID- 25705024 TI - Treatment of mastitis in cattle. AB - The understanding of mastitis, its cause, and the rationale for treatment or nontreatment of mastitis under various circumstances continues to evolve. This article presents research-based evidence about the use or nonuse of drugs to treat mastitis. Nondrug factors involved in decision making about mastitis, including cow characteristics and the epidemiology of mastitis, are also briefly discussed. This article provides information that helps in the making of knowledgeable, evidence-based decisions about therapy for mastitis. Focus is primarily on the use of antimicrobial drugs. PMID- 25705025 TI - Antimicrobial decision making for enteric diseases of cattle. AB - Diarrhea in neonatal and adult cattle is common and can be caused by several etiologic agents. As diagnostic testing is not always readily available, practitioners must often decide on a course of treatment based on knowledge of the likely pathogen and their own clinical experience. Antimicrobials have long been used to treat diarrhea in adults and neonates; however, there is increased pressure to prevent unnecessary use of antibiotics in food animal species. This article reviews existing data on the use of antibiotics given to cattle with enteric diseases to decide when they are necessary and which antimicrobials should be used. PMID- 25705026 TI - Clinical evidence for individual animal therapy for papillomatous digital dermatitis (hairy heel wart) and infectious bovine pododermatitis (foot rot). AB - Data supporting individual animal therapy for papillomatous digital dermatitis (PDD) and infectious pododermatitis (IP) in cattle are available for treatment with multiple drugs in the form of randomized, prospective clinical trials conducted in naturally occurring disease with negative controls and masked subjective evaluators. In the case of PDD, these trials support the use of topical tetracycline and oxytetracycline, lincomycin, a copper-containing preparation, and a nonantimicrobial cream. In individual therapy for IP, trial evidence is available to support systemic treatment with ceftiofur, florfenicol, tulathromycin, and oxytetracycline. However, it was not available for IP standards such as penicillin G, sulfadimethoxine, and tylosin. PMID- 25705027 TI - Consideration of evidence for therapeutic interventions in bovine polioencephalomalacia. AB - Randomized, masked, prospective clinical trial evidence for therapeutic intervention in naturally occurring bovine polioencephalomalacia (polio) is nonexistent. This article evaluates the use of thiamine and anti-inflammatories in the therapy of polioencephalomalacia based on available information related to the pathophysiology of the disease, induced models, disease outcome in other species (sheep), and parallels in similar disease in humans. PMID- 25705028 TI - Using individual animal susceptibility test results in bovine practice. AB - The integration of antimicrobial susceptibility test results into food animal case management can be a challenging proposition. The use of Clinical and Laboratory Standards Institute veterinary-specific interpretive criteria can assist with the antimicrobial selection process when these criteria exist for the specific antimicrobial, pathogen, host animal, disease process, and dosing regimen being considered. When veterinary-specific interpretive criteria do not exist, clinicians can, and should, evaluate microbiological, pharmacological and clinical data to ensure responsible use of antimicrobials. PMID- 25705029 TI - Making clinical decisions in cases with and without the support of clinical trials. PMID- 25705030 TI - Towards formation of fibrous woven memory devices from all-carbon electronic fibers. AB - Fibrous all-carbon woven memory devices have been formed by using reduced acid graphene oxide as a switching material, and flexible carbon nanotube fibers as electrodes. The as prepared fibrous all-carbon woven memory devices exhibited an ultra-high ON/OFF current ratio of 10(9), a fast switching speed of 3 ms, and a long life time of at least 500 cycles that could pave the way for future e textiles. PMID- 25705031 TI - Commentary: Ohm's law as an analogy for enzyme kinetics. PMID- 25705032 TI - A comparison of the cost-effectiveness of two pedometer-based telephone coaching programs for people with cardiac disease. AB - INTRODUCTION: Following a cardiac event it is recommended that cardiac patients participate in cardiac rehabilitation (CR) programs. However, little is known about the relative cost-effectiveness of lifestyle-related interventions for cardiac patients. This study aimed to compare the cost-effectiveness of a telephone-delivered Healthy Weight intervention to a telephone-delivered Physical Activity intervention for patients referred to CR in urban and rural Australia. METHODS: A cost-utility analysis was conducted alongside a randomised controlled trial of the two interventions. Outcomes were measured as Quality Adjusted Life Years (QALYs) gained. RESULTS: The estimated cost of delivering the interventions was $201.48 per Healthy Weight participant and $138.00 per Physical Activity participant. The average total cost (cost of health care utilisation plus patient costs) was $1,260 per Healthy Weight participant and $2,112 per Physical Activity participant, a difference of $852 in favour of the Healthy Weight intervention. Healthy Weight participants gained an average of 0.007 additional QALYs than did Physical Activity participants. Thus, overall the Healthy Weight intervention dominated the Physical Activity intervention (Healthy Weight intervention was less costly and more effective than the Physical Activity intervention). Subgroup analyses showed the Healthy Weight intervention also dominated the Physical Activity intervention for rural participants and for participants who did not attend CR. CONCLUSIONS: The low-contact pedometer-based telephone coaching Healthy Weight intervention is overall both less costly and more effective compared to the Physical Activity intervention, including for rural cardiac patients and patients that do not attend CR. PMID- 25705033 TI - Why send your paper to Gastroenterology: global outreach and partnerships with sister journals, CGH and CMGH, among a menu of offerings. PMID- 25705034 TI - Mass spectrometry of extracellular vesicles. AB - The review briefly summaries main features of extracellular vesicles, a joint terminology for exosomes, microvesicles, and apoptotic vesicles. These vesicles are in the center of interest in biology and medical sciences, and form a very active field of research. Mass spectrometry (MS), with its specificity and sensitivity, has the potential to identify and characterize molecular composition of these vesicles; but as yet there are only a limited, but fast-growing, number of publications that use MS workflows in this field. MS is the major tool to assess protein composition of extracellular vesicles: qualitative and quantitative proteomics approaches are both reviewed. Beside proteins, lipid and metabolite composition of vesicles might also be best assessed by MS techniques; however there are few applications as yet in this respect. The role of alternative analytical approaches, like gel-based proteomics and antibody-based immunoassays, are also mentioned. The objective of the review is to give an overview of this fast-growing field to help orient MS-based research on extracellular vesicles. PMID- 25705035 TI - Prevalence of manual Strauss LBBB criteria in patients diagnosed with the automated Glasgow LBBB criteria. AB - INTRODUCTION: About one-third of patients undergoing cardiac resynchronization therapy because of left bundle branch block (LBBB) and heart failure do not improve. Strauss et al. have developed strict criteria to more accurately define complete LBBB in this patient group. The aim of this study was to investigate the prevalence of the manual application of the Strauss criteria for LBBB (QRS >= 140 ms in men, >= 130 ms in women, along with mid-QRS notching/slurring) in consecutive patients who have been diagnosed with LBBB by the automated Glasgow criteria (QRS >= 120 ms). METHOD: In 158 consecutive patients (78 females) diagnosed with LBBB according to the automated Glasgow criteria, the manual Strauss criteria were applied. RESULTS & CONCLUSION: A majority of patients (87%) diagnosed with LBBB using the Glasgow criteria were positive for the Strauss criteria. In 70% (13/20) of the cases of disagreement the reason for disagreement was short QRS duration. PMID- 25705036 TI - In vitro effects of nanosized diamond particles on macrophages. AB - The effects of synthetic diamond nanoparticles (4-6 nm) on mouse macrophage biotropism and biocompatibility and the modulation of the macrophage functions (expression of IL-1alpha, TNF-alpha, GM-CSF, bFGF, and TGF-beta) by nanoparticles in different concentrations were studied in vitro during exposure of different duration. Macrophage endocytosis of nanodiamonds increased with increasing the concentration of nanoparticles in culture and incubation time. Nanodiamonds exhibited high biotropism and biocompatibility towards macrophages; in doses of 10-20 MUg/ml, they induced expression of GM-CSF and TGF-beta, inhibited expression of bFGF, and did not stimulate IL-1alpha and TNF-alpha. These data indicate that nanodiamond capture by macrophages in the studied experimental model led to modulation of the functional status of macrophages that determine their capacity to stimulate reparative processes without increasing proinflammatory and profibrogenic status. PMID- 25705037 TI - Use of the phytopathogenic effect for studies of Burkholderia virulence. AB - The phytopathogenic effect of the pseudomallei group Burkholderia is demonstrated on the Peireskia aculeata model. A method for evaluation of the effect is suggested. The effect correlates with the levels of Burkholderia pseudomallei, Burkholderia mallei, and Burkholderia thailandensis virulence for laboratory animals. P. aculeata can be used as a model for preliminary studies of the virulence of the above species. PMID- 25705038 TI - Isolation and culturing of trophoblasts from human terminal placenta. AB - Trophoblast culture was derived from the islets of cell migrating from the fragments of placental microvilli. The isolated cells retained their cytotrophoblast phenotype longer (until passage 2-3) and then gained characteristics of proliferating mesenchymal cells. We conclude that changes in the morphology and co-expression of epithelial (cytokeratin 7) and mesenchymal (vimentin) markers attest to epithelial mesenchymal transition. PMID- 25705039 TI - Expression of ryanodine receptor mRNA and sarcoplasmic Ca2+-ATPase mRNA in the myocardium and intracellular reorganization of cardiomyocytes in dyslipidemia and during verapamil treatment. AB - In experiments on rats, atherogenic diet led to hypercholesterolemia, while addition of verapamil to the diet led to the development of hypertriglyceridemia in these animals. Dyslipidemia induced significant changes in the cardiomyocyte ultrastructure (lytic changes in myofibrils and sarcoplasmic matrix and aggravation of autophagocytosis) that were most pronounced after addition of mercazolyl alone to the diet. After 30-day atherogenic diet, we observed a decrease in the relative content of RyR2 mRNA (by 67-73%, p<0.01) and SERCA2a mRNA (by 75-91%, p<0.01) in the myocardium. In 64 days these parameters remained reduced: by 64-72% (p<0.05) and 54-62% (p<0.05), respectively. Verapamil treatment reduced the severity and number of lytic lesions in cardiomyocytes, induced considerable glycogen accumulation in the sarcoplasm and its sequestration, promoted normalization, and prevented pronounced decrease of the relative RyR2 mRNA and SERCA2a mRNA in rat myocardium. PMID- 25705040 TI - Role of peptide bond in the realization of biological activity of short peptides. AB - We performed a comparative analysis of biological activity of Lys-Glu peptide and its amino acid constituents. It was established that Lys-Glu stimulated proliferation of splenic cells in organotypic culture, while the mixture of glutamic acid and lysine inhibited culture growth. Using the method of molecular docking, we showed that glutamic acid, lysine, and Lys-Glu peptide can interact with different DNA sequences. The energy of interaction and the most beneficial localization of glutamic acid, lysine, and Lys-Glu peptide in DNA molecule was calculated. We demonstrated the interaction of the peptide and amino acids with DNA along the minor groove. The energy of DNA interaction with the peptide is higher than with individual amino acids. The peptide bonds increase the interaction of Lys-Glu peptide with DNA, which potentiates the biological effect on cell proliferation in organotypic culture of splenic cells. PMID- 25705041 TI - Comparison of the expression of immunomodulatory factors in cultures of mesenchymal stromal cells from human extraembryonic tissues. AB - mRNA of genes (tgfbeta, il6, il10, il1beta, and vegf165) involved in cell proliferation, inflammatory, anti-inflammatory, and angiogenic processes were detected and quantified in cultures of mesenchymal stromal cells of different passages derived from human extraembryonic tissues (amniotic sac, umbilical cord, chorionic villi and trophoblast of the placenta). The concentrations of IL-10, IL 6, IL-1beta, and TGFbeta were measured. PMID- 25705042 TI - Expression of immunomodulator gene mRNA in co-culture of mesenchymal stromal cells from the placenta and human mononuclear blood cells. AB - The expression of mRNA of cytokines and immunoregulatory molecules characterizing the interaction of mesenchymal stromal cells from chorionic villi of postpartum placenta and allogenic mononuclear blood cells was studied during 3-day co culturing of these cells. The expression of foxp3, il2ra, and il10 mRNA in floating mononuclear cells increased from day 1 to 3 in co-culture, which can refl ect the process of induction of regulatory T cells in the lymphocyte population under the action of mesenchymal stromal cells. PMID- 25705043 TI - Effect of multipotent stromal cells on the function of cell mitochondria in regenerating liver. AB - Intrasplenic allogeneic transplantation of multipotent stromal cells from the umbilical cord stimulates hepatocyte proliferation and promotes recovery of liver weight in rats after subtotal resection (80% organ weight). It can be hypothesized that this effect of multipotent stromal cells is due to more rapid recovery of the number of mitochondria and normalization of mitochondrial function of liver hepatocytes. PMID- 25705044 TI - Effect of proinflammatory activation on F-actin distribution in cultured human endothelial cells under conditions of experimental microgravity. AB - We compared the state of actin cytoskeleton, morphology, and expression of VE cadherin in endothelial cells of human umbilical cord vein under conditions of TNF-alpha-mediated activation and microgravity modeling and found that 3D clinorotation for 24 h impaired the integrity of endothelial monolayer, altered cell morphology, induced cytoskeleton reorganization, and reduced the expression of VE-cadherin. The combination of experimental microgravity and proinflammatory activation led to more pronounced clearing of the perinuclear space from microfilaments and accumulation of depolymerized actin, which confirms additive effect of the studied factors on actin cytoskeleton of endothelial cells. PMID- 25705045 TI - Modeling and integral X-ray, optical, and MRI visualization of multiorgan metastases of orthotopic 4T1 breast carcinoma in BALB/c mice. AB - A model of highly metastasizing orthotopic allogeneic breast carcinoma was reproduced and standardized in experiments on BALB/c mice. 4T1 cells characterized by high metastatic activity were transfected with red fluorescent protein (RFP) gene or firefly luciferase (Luc2) gene. Unmodified 4T1 cells and modified 4T1-RFP and 4T1-Luc2 cells were subcutaneously injected to mature female mice into the second mammary fat pads. Quantitative evaluation of the primary node and visceral metastases was performed using magnetic-resonance imaging, X ray and optical tomography. Modification of 4T1 cells with RFP gene considerably reduced their invasive and metastatic potential and led to spontaneous regression of the primary tumor in 20% cases. Modification of 4T1 cells with Luc2 gene had practically no effect on proliferative, invasive, and metastatic characteristics of the tumor and provided the possibility of quantitative analysis of the primary tumor dynamics by the luminescence intensity. The survival median in mice receiving unmodified 4T1 cells and transfected 4T1-RFP and 4T1-Luc2 cells was 32, 42, and 38 days, respectively. Neither primary node nor tumor metastases accumulated gadolinium-containing contrast agent and Alasens fluorescent tracer. After implantation of 4T1 and 4T1-Luc2 cells, multiple metastases were more often detected in the lungs, liver, spleen, spine, and regional lymph nodes and less frequently in the brain, which corresponded to metastasizing profile of human breast cancer. The developed model of orthotopic breast carcinoma 4T1 in BALB/c mice with complex detection of multiple organ metastases using X-ray microCT, optical, and MRI can be recommended for preclinical studies of new antitumor preparations. PMID- 25705046 TI - [Antifungal effect of phenolic and carotenoids extracts from chiltepin (Capsicum annum var. glabriusculum) on Alternaria alternata and Fusarium oxysporum]. AB - The effect of phenolic and carotenoid extracts from chiltepin fruits on mycelial growth and the inhibition of conidial germination of Alternaria alternata and Fusarium oxysporum were investigated in the present work. Phenolic extracts inhibited mycelial growth of A.alternata by 38.46%, and significantly reduced conidial germination on the fifth day after treatment to 92% in relation to control. No significant changes were observed in the inhibition of mycelial growth in Fusarium oxysporum; however, the number of germinated conidia was reduced, showing 85% inhibition five days after treatment in relation to control. Moreover, carotenoid extracts showed 38.5% inhibition of mycelial growth and 85.3% inhibition of conidial germination of A.alternata, five days after treatment. Carotenoid extracts showed less inhibition of mycelial growth (20.3%) in F.oxysporum, with respect to A.alternata; while there was greater inhibition of conidial germination (96%) on the fifth day after treatment. Phenolic and carotenoid extracts from chiltepin may be a promising alternative as a natural fungicide against fungi of agricultural importance. PMID- 25705047 TI - Spatial distribution of canine zoonotic enteroparasites in Bahia Blanca, Argentina. AB - The objectives of this research were: (1) to determine the occurrence of zoonotic enteroparasites in dog feces from Bahia Blanca, Argentina; (2) to characterize the spatial distribution of the parasites found in association with the quality of life index (QLI) in neighborhoods of Bahia Blanca; and (3) to determine if the presence of a particular parasite genus in a stool sample was facilitated or impeded by the presence of other parasite genera. Samples of dog stools (n=475) were collected between December 2012 and December 2013 in areas with varying QLI. The association between QLI values and the presence of parasites was analyzed using logistic regression. Overall enteroparasite occurrence was 36.6%. Parasitic forms found included nematode larvae, cysts of Blastocystis spp., Giardia spp., and oocysts of Cryptosporidium spp., and eggs of Ancylostoma caninum, Toxocara canis, cestodes and Trichuris spp. For certain enteroparasites, we detected significant associations between their occurrence and QLI. Feces collected in areas with medium and low QLI were 2.46 and 5.43 times more likely, respectively, to contain A. caninum than stools from the high-QLI area. Samples from areas with low QLI were 2.36 times more likely to contain Trichuris spp. than those from the high QLI area. Regarding protozoa, feces from areas with low QLI were 2.4 times more likely to be positive than those from areas with high QLI. We demonstrated that canine zoonotic parasites have a wide distribution in the study area, and that occurrence is higher in neighborhoods with lower QLI. PMID- 25705048 TI - Room temperature synthesis of cobalt-manganese-nickel oxalates micropolyhedrons for high-performance flexible electrochemical energy storage device. AB - Cobalt-manganese-nickel oxalates micropolyhedrons were successfully fabricated by a room temperature chemical co-precipitation method. Interestingly, the Co0.5Mn0.4Ni0.1C2O4*nH2O micropolyhedrons and graphene nanosheets have been successfully applied as the positive and negative electrode materials (a battery type Faradaic electrode and a capacitive electrode, respectively) for flexible solid-state asymmetric supercapacitors. More importantly, the as-assembled device achieved a maximum energy density of 0.46 mWh.cm(-3), a decent result among devices with similar structures. The as-assembled device showed good flexibility, functioning well under both normal and bent conditions (0 degrees -180 degrees ). The resulting device showed little performance decay even after 6000 cycles, which rendered the Co0.5Mn0.4Ni0.1C2O4*nH2O//Graphene device configuration a promising candidate for high-performance flexible solid-state asymmetric supercapacitors in the field of high-energy-density energy storage devices. PMID- 25705049 TI - Early numerical foundations of young children's mathematical development. AB - This study focused on the relative contributions of the acuity of the approximate number system (ANS) and knowledge of quantitative symbols to young children's early mathematical learning. At the beginning of preschool, 191 children (Mage=46 months) were administered tasks that assessed ANS acuity and explicit knowledge of the cardinal values represented by number words, and their mathematics achievement was assessed at the end of the school year. Children's executive functions, intelligence, and preliteracy skills and their parents' educational levels were also assessed and served as covariates. Both the ANS and cardinality tasks were significant predictors of end-of-year mathematics achievement with and without control of the covariates. As simultaneous predictors and with control of the covariates, cardinality remained significantly related to mathematics achievement, but ANS acuity did not. Mediation analyses revealed that the relation between ANS acuity and mathematics achievement was fully mediated by cardinality, suggesting that the ANS may facilitate children's explicit understanding of cardinal value and in this way may indirectly influence early mathematical learning. PMID- 25705050 TI - The relation between spatial thinking and proportional reasoning in preschoolers. AB - Previous research has indicated a close link between spatial and mathematical thinking. However, what shared processes account for this link? In this study, we focused on the spatial skill of map reading and the mathematical skill of proportional reasoning and investigated whether scaling, or the ability to relate information in different-sized representations, is a shared process. Scaling was experimentally manipulated in both tasks. In the map task, 4- and 5-year-olds (N=50) were asked to point to the same position shown on a map in a larger referent space on a touch screen. The sizes of the maps were varied systematically, such that some trials required scaling and some did not (i.e., the map had the same size as the referent space). In the proportional reasoning task, children were presented with different relative amounts of juice and water and were asked to estimate each mixture on a rating scale. Again, some trials required scaling, but others could be solved by directly mapping the proportional components onto the rating scale. Children's absolute errors in locating targets in the map task were closely related to their performance in the proportional reasoning task even after controlling for age and verbal intelligence. Crucially, this was only true for trials that required scaling, whereas performance on nonscaled trials was not related. These results shed light on the mechanisms involved in the close connection between spatial and mathematical thinking early in life. PMID- 25705051 TI - Melanic Facial Patterns and their Significance in the Multicolored Asian Lady Beetle (Harmonia axyridis). AB - The relationship between the patterns present on the pronotum and the elytron of the multicolored Asian lady beetle Harmonia axyridis was investigated. In males elytron size was a significant predictor of pronotal intensity and in females the fraction of the pronotum covered in black was related to their elytral spot brightness. Other significant sex differences included females having more of their pronota covered by melanins and the pigments deposited there being more intense than in males. The potential significance of these sex differences is discussed as well as the potential for these signals to serve in a mate choice context. PMID- 25705052 TI - Sample Size Requirements for Structural Equation Models: An Evaluation of Power, Bias, and Solution Propriety. AB - Determining sample size requirements for structural equation modeling (SEM) is a challenge often faced by investigators, peer reviewers, and grant writers. Recent years have seen a large increase in SEMs in the behavioral science literature, but consideration of sample size requirements for applied SEMs often relies on outdated rules-of-thumb. This study used Monte Carlo data simulation techniques to evaluate sample size requirements for common applied SEMs. Across a series of simulations, we systematically varied key model properties, including number of indicators and factors, magnitude of factor loadings and path coefficients, and amount of missing data. We investigated how changes in these parameters affected sample size requirements with respect to statistical power, bias in the parameter estimates, and overall solution propriety. Results revealed a range of sample size requirements (i.e., from 30 to 460 cases), meaningful patterns of association between parameters and sample size, and highlight the limitations of commonly cited rules-of-thumb. The broad "lessons learned" for determining SEM sample size requirements are discussed. PMID- 25705053 TI - Small molecule probes to target the human Mediator complex. AB - The human Mediator complex is a central integrator for transcription and represents a primary interface that allows DNA-binding transcription factors to communicate their regulatory signals to the RNA polymerase II enzyme. Because Mediator is dynamic both in terms of subunit composition and structure, it presents challenges as a target for small molecule probes. Moreover, little high resolution structural information exists for Mediator. Its global requirement for transcription, as well as its distinct, transcription factor specific interaction surfaces, however, suggest that development of probes that bind specific Mediator subunits might enable gene- and pathway-specific modulation of transcription. Here we provide a brief overview of the Mediator complex, highlighting biological and structural features that make it an attractive target for molecular probes. We then outline several chemical strategies that might be effective for targeting the complex. PMID- 25705054 TI - Viewpoint: effective stakeholder communication in agriculture: together we stand, divided we fall! AB - Substantial improvements of agricultural systems are necessary to meet the future requirements of humanity. However, current agricultural knowledge and information systems are generally not well suited to meet the necessary improvements in productivity and sustainability. For more effective application of research output, research producers and research consumers should not be considered as separate individuals in the knowledge chain but as collaborating partners creating synergy. The current paper investigates the relationships between scientists and stakeholders and identifies approaches to increase the effectiveness of their communication. On-farm research has proven to be an effective means of improving exploitation of research output at farm level because it connects all relevant partners in the process. Furthermore, pilot farms can act as an effective platform for communication and dissemination. Regional networks of pilot farms should be established and connected across regions. PMID- 25705055 TI - Spatial and temporal variation in sponge spicule patches at Station M, northeast Pacific. AB - Changes in habitat-forming organisms can have complex consequences for associated species. Sessile epibenthic glass "plate" sponges (Porifera: Hexactinellida) are conspicuous inhabitants of soft-sediment abyssal areas and their siliceous spicules create persistent spicule patches on the seafloor. Sponge spicule patch density, spatial dispersion, and percent cover were examined over a seven-year period (2006-2013) using remotely operated vehicle videos from Station M in the abyssal northeast Pacific (5000N, 12300W, ~4,000 m depth). There was an apparent large increase in newly dead plate sponges in February 2007 compared with December 2006, with this trend continuing through June 2007 (mean 0.03 % cover increasing to 0.33 %). A second increase in mean percent cover of dead plate sponges occurred from May 2011 (0.24 %) through June 2012 (0.60 %). Among the 28 megafaunal taxa occurring in association with the patches, the distributions of three taxa [two sponge taxa (Porifera) and brittle stars (Ophiuroidea)] suggested selectivity for the sponge spicule patches. The community structure of visible megafauna within sponge spicule patches was different when compared with that outside the patches suggesting that the sponges, after death, provide preferred habitat patches for certain benthic megafauna. These findings indicate that sponge spicule patches contribute to habitat heterogeneity in space and time. PMID- 25705056 TI - Bayesian hierarchical structured variable selection methods with application to MIP studies in breast cancer. AB - The analysis of alterations that may occur in nature when segments of chromosomes are copied (known as copy number alterations) has been a focus of research to identify genetic markers of cancer. One high-throughput technique recently adopted is the use of molecular inversion probes (MIPs) to measure probe copy number changes. The resulting data consist of high-dimensional copy number profiles that can be used to ascertain probe-specific copy number alterations in correlative studies with patient outcomes to guide risk stratification and future treatment. We propose a novel Bayesian variable selection method, the hierarchical structured variable selection (HSVS) method, which accounts for the natural gene and probe-within-gene architecture to identify important genes and probes associated with clinically relevant outcomes. We propose the HSVS model for grouped variable selection, where simultaneous selection of both groups and within-group variables is of interest. The HSVS model utilizes a discrete mixture prior distribution for group selection and group-specific Bayesian lasso hierarchies for variable selection within groups. We provide methods for accounting for serial correlations within groups that incorporate Bayesian fused lasso methods for within-group selection. Through simulations we establish that our method results in lower model errors than other methods when a natural grouping structure exists. We apply our method to an MIP study of breast cancer and show that it identifies genes and probes that are significantly associated with clinically relevant subtypes of breast cancer. PMID- 25705057 TI - Academic Achievement and Its Impact on Friend Dynamics. AB - Academic achievement in adolescence is a key determinant of future educational and occupational success. Friends play an important role in the educational process. They provide support and resources and can both encourage and discourage academic achievement. As a result, the friends adolescents make may help to maintain and exacerbate inequality if friends are sorted on the basis of academic achievement. These observations prompt the question: How does academic achievement affect the friendship ties made? Using data from the high schools in the Add Health saturated sample, the author models network change using a stochastic actor-based Markov model for the co-evolution of networks and behavior. This model is carried out at the school level for each of the high schools included in the saturated sample. Results show that in the most typical American schools, similarity in academic achievement is an important and consistent predictor of friendship ties in a dynamic context. High-achieving students are more likely to extend ties to other high-achieving students, net of other sociodemographic, network, and proximity characteristics, while low achieving students are more likely to extend ties to other low-achieving students. Adolescents respond to changes in academic achievement by changing their friendship ties. PMID- 25705058 TI - High School Dropouts and Sexually Transmitted Infections. AB - People who drop out of high school fare worse in many aspects of life. We analyze the relationship between dropping out of high school and the probability of contracting a sexually transmitted infection (STI). Previous studies on the relationship between dropout status and sexual outcomes have not empirically addressed unobserved heterogeneity at the individual level. Using fixed effects estimators, we find evidence supporting a positive relationship between dropping out of high school and the risk of contracting an STI for females. Furthermore, we present evidence that illustrates differences between the romantic partners of dropouts versus enrolled students. These differences suggest that female dropouts may be more susceptible to contracting STIs because they partner with significantly different types of people than non-dropouts. Our results point to a previously undocumented benefit of encouraging those at risk of dropping out to stay in school longer. PMID- 25705059 TI - Enantioselective Synthesis of Spiro[cyclohexane-1,3'-indolin]-2'-ones Containing Multiple Stereocenters via Organocatalytic Michael/Aldol Cascade Reactions. AB - Organocatalytic reactions of 3-olefinic oxindoles and pentane-1,5-dial were investigated to provide access to substituted spirocyclohexane oxindoles via Michael/Aldol cascade reactions. Of particular interest, we have examined the stereochemical outcome of electron withdrawing and electron-donating groups on the oxindole ring nitrogen. Interestingly, we have observed that the N-protecting group on the oxindole has critical effect on aldol ring closure leading to ultimate stereochemical outcome of the hydroxyl center. The overall process is quite efficient and afforded products with multiple stereocenters in high yields and excellent enantioselectivities (>99% ee). PMID- 25705060 TI - Effects of transportation stress and addition of salt to transport water on the skin mucosal homeostasis of rainbow trout (Oncorhynchus mykiss). AB - Transportation of live fish is a common practice among aquaculture facilities. Many studies have previously reported how transport elicits physiological stress responses and increases disease susceptibility in farmed fish. The aim of this work is to investigate the changes that the skin of rainbow trout (Oncorhynchus mykiss) experiences due to stress. Since NaCl is commonly added to transport water as a stress mitigator, the effects of salt addition on the skin mucosa and skin-associated bacteria were also examined. Three experimental groups (Control, post-transport no salt (PTNS) and post-transport with salt (PTS)) were analyzed in a 5-hour transport acute stress model. Results indicate that the skin mucosa and the skin-associated bacteria are affected by transport stress. Total numbers of culturable skin-associated bacteria increased by ~10-fold and ~50-fold in the PTS and PTNS groups, respectively. Compared to controls, MUC2 expression was increased by 5-fold and 2-fold in the PTNS and PTS groups, respectively. Claudin 7, 8d and 12 expression levels were higher in both PTNS and PTS groups whereas antimicrobial peptide gene expression was lower than controls. Expression of the anti-inflammatory cytokine TGF-beta but not IL-1beta, IL-6 and TNF-alpha was up regulated 2-3 fold in both the PTS and PTNS groups. The addition of salt diminished some of the physiological responses measured including the numbers of skin-associated bacteria. The responses recorded here appeared to be efficient at controlling bacterial translocation since stress did not lead to significant presence of bacteria in the liver or spleen of rainbow trout. When examining the ability of skin mucus to inhibit or promote growth of the bacterial pathogen Vibrio anguillarum, the skin mucus of PTS trout was more efficient at inhibiting V. anguillarum growth (20% inhibition) compared to control or PTNS mucus (11-12% inhibition). Our data clearly indicate the skin and skin microbiota of rainbow trout undergo important physiological responses during stress. The reduction in the magnitude of the skin responses recorded when salt was added to the transport water explains a new mechanism by which salt is an effective stress mitigator in some fish species. Aquaculture specialists will benefit from the present study by taking into consideration the importance of skin health during live transport. PMID- 25705061 TI - Mercury and Arsenic Bioaccumulation and Eutrophication in Baiyangdian Lake, China. AB - Hg and As are widespread contaminants globally and particularly in Asia. We conducted a field study in Baiyangdian Lake, the largest lake in the North China Plain, to investigate bioaccumulation and trophic transfer of potentially toxic metals (total mercury and arsenic) in sites differing in proximity from the major point sources of nutrients and metals. Hg concentrations in fish and As concentrations in water are above critical threshold levels (US Environmental Protection Agency based) considered to pose some risk to humans and wildlife. Hg concentrations in biota are within the range of concentrations in lakes in the Northeast US despite the high levels of Hg emission and deposition in China whereas As concentrations are much higher. Dissolved concentrations of both Hg and As decrease with increasing chlorophyll concentrations suggesting that there is significant uptake of metal from water by algae. These results provide evidence for algal blooms controlling dissolved metal concentrations and potentially mitigating the trophic transfer of Hg to fish. This study also underscores the need for further investigation into this contaminated ecosystem and others like it in China that are an important source of fish and drinking water for consumption by local human populations. PMID- 25705062 TI - Maternal Age-Related Depletion of Offspring Genetic Variance in Immune Response to Phytohaemagglutinin in the Blue Tit (Cyanistes caeruleus). AB - Studies examining age-specific patterns in genetic variance have focussed primarily on changes in the genetic variance within cohorts. It remains unclear whether parental age may affect the genetic variance among offspring. To date, such an effect has been reported only in a single study performed in a wild bird population. Here, we provide experimental evidence that the additive genetic variance (VA) observed among offspring may be related to parental age in a wild passerine-the blue tit (Cyanistes caeruleus). To separate genetic and environmental components of phenotypic variance in nestling body size and immune function we cross-fostered nestlings between pairs of broods born to young and old mothers and used an animal model to estimate VA. We show that the genetic variance in immune response to phytohaemagglutinin (PHA) and body weight among offspring depends on maternal age. VA in response to PHA appeared to be lower among nestlings of older mothers. Such a tendency was not observed for tarsus length. We argue that the lower VA may result either from depletion of additive genetic variation due to selection acting on parents across age classes or from environmental effects confounded with parental age. Thus, our study suggests that parental age may significantly affect estimates of quantitative genetic parameters in the offspring. PMID- 25705063 TI - "Understand My Side, My Situation, and My Story:" Insights into the Service Needs Among Substance-Abusing Homeless Mothers. AB - Substance abuse among homeless mothers has negative consequences for both the mother and her child. Few researchers have examined the needs of these mothers in order to effectively intervene in their lives. This study uses a qualitative focus group research method to examine the needs of substance abusing homeless mothers recruited from a homeless families' shelter. Twenty eight women were engaged in three focus groups to identify their needs and acceptable intervention components. Content analysis of data revealed five major categories of needs: subsistence, employment, education and information, service, and counseling and connectedness needs. Findings of this study call for a multifaceted intervention approach that targets several areas of need in a coordinated manner. PMID- 25705064 TI - Media and human capital development: Can video game playing make you smarter? AB - According to the literature, video game playing can improve such cognitive skills as problem solving, abstract reasoning, and spatial logic. I test this hypothesis using The Child Development Supplement to the Panel Study of Income Dynamics. The endogeneity of video game playing is addressed by using panel data methods and controlling for an extensive list of child and family characteristics. To address the measurement error in video game playing, I instrument children's weekday time use with their weekend time use. After taking into account the endogeneity and measurement error, video game playing is found to positively affect children's problem solving ability. The effect of video game playing on problem solving ability is comparable to the effect of educational activities. PMID- 25705065 TI - Methodology for Evaluating a Partially Controlled Longitudinal Treatment Using Principal Stratification, With Application to a Needle Exchange Program. AB - We consider studies for evaluating the short-term effect of a treatment of interest on a time-to-event outcome. The studies we consider are only partially controlled in the following sense: (1) Subjects' exposure to the treatment of interest can vary over time, but this exposure is not directly controlled by the study; (2) subjects' follow-up time is not directly controlled by the study; and (3) the study directly controls another factor that can affect subjects' exposure to the treatment of interest as well as subjects' follow-up time. When factors 1 and 2 are both present in the study, evaluating the treatment of interest using standard methods, including instrumental variables, does not generally estimate treatment effects. We develop the methodology for estimating the effect of treatment 1 in this setting of partially controlled studies under explicit assumptions using the framework for principal stratification for causal inference. We illustrate our methods by a study to evaluate the efficacy of the Baltimore Needle Exchange Program to reduce the risk of human immunodeficiency virus (HIV) transmission, using data on distance of the program's sites from the subjects. PMID- 25705066 TI - Calculations and measurements of the scintillator-to-water stopping power ratio of liquid scintillators for use in proton radiotherapy. AB - Liquid scintillators are a promising detector for high-resolution three dimensional proton therapy dosimetry. Because the scintillator comprises both the active volume of the detector and the phantom material, an ideal scintillator will exhibit water equivalence in its radiological properties. One of the most fundamental of these is the scintillator's stopping power. The objective of this study was to compare calculations and measurements of scintillator-to-water stopping power ratios to evaluate the suitability of the liquid scintillators BC 531 and OptiPhase HiSafe 3 for proton dosimetry. We also measured the relative scintillation output of the two scintillators. Both calculations and measurements show that the linear stopping power of OptiPhase is significantly closer to water than that of BC-531. BC-531 has a somewhat higher scintillation output. OptiPhase can be mixed with water at high concentrations, which further improves its scintillator-to-water stopping power ratio. However, this causes the solution to become cloudy, which has a negative impact on the scintillation output and spatial resolution of the detector. OptiPhase is preferred over BC-531 for proton dosimetry because its density and scintillator-to-water stopping power ratio are more water equivalent. PMID- 25705067 TI - Understanding dynamic changes in live cell adhesion with neutron reflectometry. AB - Neutron reflectometry (NR) was used to examine various live cells adhesion to quartz substrates under different environmental conditions, including flow stress. To the best of our knowledge, these measurements represent the first successful visualization and quantization of the interface between live cells and a substrate with sub-nanometer resolution. In our first experiments, we examined live mouse fibroblast cells as opposed to past experiments using supported lipids, proteins, or peptide layers with no associated cells. We continued the NR studies of cell adhesion by investigating endothelial monolayers and glioblastoma cells under dynamic flow conditions. We demonstrated that neutron reflectometry is a powerful tool to study the strength of cellular layer adhesion in living tissues, which is a key factor in understanding the physiology of cell interactions and conditions leading to abnormal or disease circumstances. Continuative measurements, such as investigating changes in tumor cell - surface contact of various glioblastomas, could impact advancements in tumor treatments. In principle, this can help us to identify changes that correlate with tumor invasiveness. Pursuit of these studies can have significant medical impact on the understanding of complex biological problems and their effective treatment, e.g. for the development of targeted anti-invasive therapies. PMID- 25705068 TI - Using Elicited Choice Probabilities in Hypothetical Elections to Study Decisions to Vote. AB - This paper demonstrates the feasibility and usefulness of survey research asking respondents to report voting probabilities in hypothetical election scenarios. Posing scenarios enriches the data available for studies of voting decisions, as a researcher can pose many more and varied scenarios than the elections that persons actually face. Multiple scenarios were presented to over 4,000 participants in the American Life Panel (ALP). Each described a hypothetical presidential election, giving characteristics measuring candidate preference, closeness of the election, and the time cost of voting. Persons were asked the probability that they would vote in this election and were willing and able to respond. We analyzed the data through direct study of the variation of voting probabilities with election characteristics and through estimation of a random utility model of voting. Voting time and election closeness were notable determinants of decisions to vote, but not candidate preference. Most findings were corroborated through estimation of a model fit to ALP data on respondents' actual voting behavior in the 2012 election. PMID- 25705069 TI - An In Situ Method for Sizing Insoluble Residues in Precipitation and Other Aqueous Samples. AB - Particles are frequently incorporated into clouds or precipitation, influencing climate by acting as cloud condensation or ice nuclei, taking up coatings during cloud processing, and removing species through wet deposition. Many of these particles, particularly ice nuclei, can remain suspended within cloud droplets/crystals as insoluble residues. While previous studies have measured the soluble or bulk mass of species within clouds and precipitation, no studies to date have determined the number concentration and size distribution of insoluble residues in precipitation or cloud water using in situ methods. Herein, for the first time we demonstrate that Nanoparticle Tracking Analysis (NTA) is a powerful in situ method for determining the total number concentration, number size distribution, and surface area distribution of insoluble residues in precipitation, both of rain and melted snow. The method uses 500 MUL or less of liquid sample and does not require sample modification. Number concentrations for the insoluble residues in aqueous precipitation samples ranged from 2.0-3.0(+/ 0.3)*108 particles cm-3, while surface area ranged from 1.8(+/-0.7)-3.2(+/ 1.0)*107 MUm2 cm-3. Number size distributions peaked between 133-150 nm, with both single and multi-modal character, while surface area distributions peaked between 173-270 nm. Comparison with electron microscopy of particles up to 10 MUm show that, by number, > 97% residues are <1 MUm in diameter, the upper limit of the NTA. The range of concentration and distribution properties indicates that insoluble residue properties vary with ambient aerosol concentrations, cloud microphysics, and meteorological dynamics. NTA has great potential for studying the role that insoluble residues play in critical atmospheric processes. PMID- 25705070 TI - Cutting the costs of attrition: Results from the Indonesia Family Life Survey. PMID- 25705071 TI - Expectations Regarding Acquaintance Sexual Aggression Among Sorority and Fraternity Members. AB - Among women, college is a high risk period for sexual assault by male acquaintances. Differences in expectations held by men and women may contribute to misinterpretation of social cues and subsequent sexual aggression and may impair women's ability to respond effectively. This paper presents findings from a predominantly Caucasian sample (85.9%) of college sorority (n = 66) and fraternity (n = 34) members regarding the social context within which they interact and their expectations regarding perpetration of and response to sexual aggression. Results showed differences in men's and women's expectations and responses, and in particular highlighted how men's expectations were related to women's resistance of unwanted sex. Understanding the cognitive processes that men and women draw upon in social interactions can be useful for developing sexual aggression prevention and resistance interventions. PMID- 25705072 TI - An Efficient Operator for the Change Point Estimation in Partial Spline Model. AB - In bio-informatics application, the estimation of the starting and ending points of drop-down in the longitudinal data is important. One possible approach to estimate such change times is to use the partial spline model with change points. In order to use estimate change time, the minimum operator in terms of a smoothing parameter has been widely used, but we showed that the minimum operator causes large MSE of change point estimates. In this paper, we proposed the summation operator in terms of a smoothing parameter, and our simulation study showed that the summation operator gives smaller MSE for estimated change points than the minimum one. We also applied the proposed approach to the experiment data, blood flow during photodynamic cancer therapy. PMID- 25705073 TI - THROUGH HER EYES: Factors Affecting Women's Perception of and Resestance to Acquaintance Sexual Aggression Threat. AB - A major component of a woman's ability to resist assaults by strangers versus acquaintances lies in the social and cognitive context in which she is engaged with the perpetrator and within which she must recognize potential threat before engaging in a behavioral response. This paper presents questionnaire and focus group findings of heterosexual college sorority women's social contexts, perceived risks, responses, and psychological barriers to protecting themselves from sexual aggression threat by fraternity acquaintances. Several social and cognitive factors, including alcohol consumption and psychological barriers, were related to projected responses to sexual aggression. Participants in general held a high sense of invulnerability to victimization and an optimistic belief in their ability to resist sexual aggression. Several differences between previously victimized and nonvictimized women also emerged. PMID- 25705075 TI - From micropterism to hyperpterism: recognition strategy and standardized homology driven terminology of the forewing venation patterns in planthoppers (Hemiptera: Fulgoromorpha). AB - Following recent advances in the morphological interpretations of the tegmen basal cell margins in the Paraneoptera, a standardized and homology-driven groundplan terminology for tegmina types, structures and vein patterns in Hemiptera Fulgoromorpha, including fossils, is proposed. Each term is listed with a morphological definition, compared and linked to the main systems of planthopper forewing description that have been reviewed. The importance of a standardized and homology-driven terminology is stressed to enhance the quality of data in taxonomic descriptions and to strengthen phylogenetic morphological analysis results. When the interpretation of the origin of vein branches is render difficult, a three-step strategy for pattern recognition of the vein is proposed based on two principles: (1) vein forks are more informative than topology of the vein branches: a search for homologous areas, the nodal cells in particular, must first guide the recognition rather the number of branches of a vein, and (2) minimum of ad hoc evolutionary events should be invoked in the understanding of a modified vein pattern. Examples of some conflicting interpretations of venation patterns in planthoppers are discussed within different families for both extant and extinct taxa. For the first time, the concept of brachypterism is defined in a non-relative way independently from other structures, and the new one of hyperpterism is proposed; a reporting system is proposed for each of them. PMID- 25705074 TI - Genetics of Vascular Dementia. AB - Genetic studies are transforming the way we diagnose, evaluate and treat patients. The era of genome-wide association studies promised to discover common risk variants in heterogeneous disorders where previous small-scale association studies had on the whole failed. However, as we enter the post-association era a degree of disappoint is felt regarding the lack of risk factors with large effect for a number of disorders including vascular disease. Vascular disorders are sporadic by nature, though a familial component has been observed. This review will focus on vascular dementia, the genetic risk factors for vascular disorders and highlight how new technologies may overcome the limitations of genome-wide association and nominate those genes that influence disease risk. PMID- 25705076 TI - High Dose Intraveneous Vitamin C and Chikungunya Fever: A Case Report. AB - The Chikungunya (CHIKV) fever is a viral disease produced by a single-stranded RNA Alphavirus from the Togaviridae genus. Its transmission occurs only through mosquito vectors, principally Aedes aegypti. It requires a human-mosquito-human transmission cycle. It is associated with severe arthritis/arthralgias, myalgias, high fever, headache, and maculopapular rash. Joint ache appears to be symmetrical. The virus has an incubation period of 2 to 7 days, where the high fever is typically presented. It is followed by arthralgias and myalgias, and rashes, which last for 3 to 5 days. However, the arthralgias can persist for months after the infection, which can contribute to severe arthritis. As of now, no vaccine exists for the virus and no official treatment has been developed aside from standard procedures of the use of acetaminophen (paracetamol), and non steroidal anti-inflammatory drugs. This is a case report of a 54-year old Hispanic individual that reported left shoulder pain, left knee pain and fever. The symptoms started on a Saturday in September 2014 in middle of the night. The patient was treated with high doses of intravenous vitamin C over two days. The symptoms resolved after the infusions without any side effects. Based on the positive outcome in this case, we propose that intravenous vitamin C should be studied further as a potential treatment for acute viral infections. PMID- 25705077 TI - Capitalizing on Nigeria's demographic dividend: reaping the benefits and diminishing the burdens. AB - Nigeria is the most populous country in Africa and the eighth most populous country in the world, yet there is a dearth of published research about its demography. As Nigeria enters a period of potentially rapid economic growth due to the increase in the working-age population, it is critical to understand the demographic trends in the country. This paper examines the age and sex composition of Nigeria as it relates to various population characteristics using the two most recent Demographic and Health Surveys for Nigeria (2003 and 2008), as well as some data from the 2006 Census. It also highlights Nigeria's demographic composition and trends using United Nations population projection data, and its implications for the country reaping the demographic dividend. Finally, it draws some conclusions and makes some policy recommendations based on the findings. PMID- 25705078 TI - On sheep, light, and life: a special meaning for 2015. PMID- 25705079 TI - The effect of LLLT on bone metabolism in children with severe cerebral palsy (a secondary publication). AB - BACKGROUND AND AIMS: It is said that the average frequency of bone fracture in hospitalized children with severe cerebral palsy (unable to remain seated) is 1% (0.2 to 2.0%). Cerebral palsy patients' bones are known to be vulnerable to fracture, and refractory bone atrophy may be observed. However, the effect of low level laser therapy (LLLT) on bone density or bone metabolism has not been fully investigated. In recent years, tests for bone density or bone metabolism markers have become available. MATERIAL AND METHODS: In this study, we evaluated changes in bone density and bone metabolism markers in 4 children with severe cerebral palsy who underwent LLLT for an average of 22 days. RESULTS: B-ALP, a marker of ossification, increased 1 month after the start of irradiation in 3 of the 4 subjects and returned to a level close to the pre-irradiation level 2 months after the start of irradiation. In the remaining subjects in whom B-ALP failed to increase, B-ALP had been low before irradiation. Urinary N-terminal telopeptide (NTx) levels, a marker of bone resorption, decreased in 3 of the 4 subjects after the start of irradiation and remained low even 10 months later. Serum NTx levels tended to decrease in 3 of the 4 subjects. The levels of serum NTx/Crea, Deoxy Pyridinoline (DPd) and DPd/Crea (DPd/Crea) also decreased in 3 of the 4 subjects. Transient decreases in intact parathyroid hormone (PTH) levels were observed in all 4 cases. Changes were particularly apparent in 2 cases: one with high NTx levels, which showed enhanced bone resorption, and one with high PTH levels, probably due to a vitamin D (VitD) deficiency. Although the metacarpal bone density measured by DIP was found to be lower than in normal children, there were no changes due to LLLT. CONCLUSION: These results suggest that LLLT has a positive influence on bone metabolism in that it temporarily increases bone formation and suppresses bone resorption while also tending to improve secondary hyperparathyroidism caused by VitD deficiency. Enhanced bone resorption in the case with high NTx levels was noteworthy, together with marked changes in the case with high PTH levels due to VitD deficiency. These positive influences on bone metabolism merit attention as potential new indications of LLLT. PMID- 25705080 TI - Minimally invasive treatment of dental caries in primary teeth using an Er:YAG Laser. AB - INTRODUCTION: Maintaining deciduous teeth as long as possible represents a goal in pediatric dentistry and avoids a plethora of health problems. Er:YAG carious decay treatment may help for prevention as well as during the curative processes. MATERIALS AND METHODS: An Er:YAG laser was used to ablate 30 carious lesions on primary teeth. Diagnosis being conventionally dressed, treatment was conducted in respect of the following parameters: Er:YAG laser (Lite Touch, Syneron): output power from 300 mJ (enamel) to 200 mJ (dentine), frequency 20 Hz, sapphire tip (diameter 1.3 mm), air water spray ratio 8 (39 ml/min), pulse duration 50 usec., theoretical fluence ranging from 15.08 J/cm(2) for dentin to 22.61 J/cm(2) for enamel. Then cavity depth was controlled (observation + probe). Glass-ionomer cement (GC Fuji Triage capsule) or flowable composite resin or compomer were used to fill the cavities. Children's acceptance to Er-YAG laser treatment was evaluated. According to predefined criteria, each case was followed up for one month after treatment and then with further monthly follow-ups for one year. RESULTS: Clinical cases illustrate the validity of this clinical approach. The benefit of laser dental treatment has been shown to be the greatest in children. However, the lack of studies evaluating laser ablation capability in primary teeth restrains the adoption of this technology. The interaction between the Er:YAG laser and primary enamel and dentin depends on the composition of the tissues - a higher presence of water and lower presence of minerals- comparative to the permanent enamel and dentin. Thus, photoablation of primary enamel and dentin requires lower energy. This study shows that the laser parameters used (300 mJ/20 Hz for enamel and 200 mJ/20 Hz for dentin) are efficient enough for the ablation of tissues of deciduous teeth and moreover demonstrates to be well accepted by young patients. PMID- 25705081 TI - Low-power pulsed Nd:YAG laser irradiation for pre-emptive anaesthesia: A morphological and histological study. AB - BACKGROUND AND AIMS: To determine if tooth structure or dental pulp of normal healthy human premolar teeth to be extracted for orthodontic reasons exhibit morphological or histological changes following dental anaesthesia by pulsed Nd:YAG laser and subsequent cavity preparation (CP). Materials (Subjects) and Methods: 54 bilateral paired of human, healthy premolar teeth identified for inclusion in a clinical trial of Nd:YAG-induced anaesthesia and subsequently extracted for orthodontic reasons, were randomly divided into 4 treatment groups: Group 1 - teeth (n=44) were irradiated with 150 us pulsed Nd:YAG laser-1064 nm (American Dental Laser, dLase300, Sunrise Technologies Inc., Folsom, CA, USA; Average power: 1.1 +/- 0.2 W, power density: 39+ 0.7 W/cm(2), area 0.28 cm(2), 15 Hz; energy density:0. 260+ 0.047 J/cm(2)) +Sham EMLA (cream without active component) followed by cavity preparation (CP); Group 2 - Teeth (n=44) - were treated with EMLA + Sham Laser (1 mW 632.8-nm He:Ne laser aiming beam only) with CP; Group 3 Teeth (n=10) - were irradiated with pulsed Nd:YAG laser as above but minus CP; Group 4 (n=10)- was a Control group with teeth untreated (no Laser, EMLA or CP). Clinical anaesthesia was assessed by electric pulp testing (EPT) and CP. Teeth in each of the 4 groups were processed for examination by i) scanning electron microscopy (SEM); ii) longitudinal undecalcified ground sectioning (LUGS); iii) light microscopy of pulpal tissues or iv) dye penetration. RESULTS: Both Laser and EMLA groups demonstrated no alteration to mineralized tooth structure and dentinal permeability. Mild superficial pulpal changes were found in both groups (3/18 teeth) and of no statistical difference (p>0.99, the McNemar test). Neither Laser nor the Control groups minus CP, showed pulpal changes. CONCLUSIONS: Low-power pulsed Nd:YAG laser dose, as used in the clinical trial to induce anaesthesia, does not cause morphological damage to the mineralized tooth structure. Both Laser and EMLA groups showed minor superficial pulpal change following cavity preparation which was not statistically significant. Laser and Control groups minus preparation had no pulpal changes. PMID- 25705082 TI - Bactericidal effect of visible light in the presence of erythrosine on Porphyromonas gingivalis and Fusobacterium nucleatum compared with diode laser, an in vitro study. AB - OBJECTIVES: Recently, photodynamic therapy (PDT) has been introduced as a new modality in oral bacterial decontamination. Besides, the ability of laser irradiation in the presence of photosensitizing agent to lethal effect on oral bacteria is well documented. Current research aims to evaluate the effect of photodynamic killing of visible blue light in the presence of plaque disclosing agent erythrosine as photosensitizer on Porphyromonas gingivalis associated with periodontal bone loss and Fusobacterium nucleatum associated with soft tissue inflammation, comparing with the near-infrared diode laser. MATERIALS AND METHODS: Standard suspension of P. gingivalis and F. nucleatum were exposed to Light Emitting Diode (LED) (440-480 nm) used to photopolymerize composite resine dental restoration in combination with erythrosine (22 um) up to 5 minutes. Bacterial sample were also exposed to a near-infrared diode laser (wavelength, 830 nm), using identical irradiation parameters for comparison. Bacterial samples from each treatment groups (radiation-only group, erythrosine-only group and light or laser with erythrosine group) were subcultured onto the surface of agar plates. Survival of these bacteria was determined by counting the number of colony forming units (CFU) after incubation. RESULTS: Exposure to visible blue light and diode laser in conjugation with erythrosine significantly reduced both species examined viability, whereas erythrosine-treated samples exposed to visible light suggested a statically meaningful differences comparing to diode laser. In addition, bactericidal effect of visible light or diode laser alone on P. gingivalis as black-pigmented bacteria possess endogenous porphyrins was noticeably. CONCLUSION: Our result suggested that visible blue light source in the presence of plaque disclosing agent erythrosine could can be consider as potential approach of PDT to kill the main gram-negative periodontal pathogens. From a clinical standpoint, this regimen could be established as an additional minimally invasive antibacterial treatment of plaque induced periodontal pathologies. PMID- 25705083 TI - Low Level Laser Therapy for chronic knee joint pain patients. AB - BACKGROUND AND AIMS: Chronic knee joint pain is one of the most frequent complaints which is seen in the outpatient clinic in our medical institute. In previous studies we have reported the benefits of low level laser therapy (LLLT) for chronic pain in the shoulder joints, elbow, hand, finger and the lower back. The present study is a report on the effects of LLLT for chronic knee joint pain. MATERIALS AND METHODS: Over the past 5 years, 35 subjects visited the outpatient clinic with complaints of chronic knee joint pain caused by the knee osteoarthritis-induced degenerative meniscal tear. They received low level laser therapy. A 1000 mW semi-conductor laser device was used to deliver 20.1 J/cm(2) per point in continuous wave at 830nm, and four points were irradiated per session (1 treatment) twice a week for 4 weeks. RESULTS: A visual analogue scale (VAS) was used to determine the effects of LLLT for the chronic pain and after the end of the treatment regimen a significant improvement was observed (p<0.001). After treatment, no significant differences were observed in the knee joint range of motion. Discussions with the patients revealed that it was important for them to learn how to avoid postures that would cause them knee pain in everyday life in order to have continuous benefits from the treatment. CONCLUSION: The present study demonstrated that 830 nm LLLT was an effective form of treatment for chronic knee pain caused by knee osteoarthritis. Patients were advised to undertake training involving gentle flexion and extension of the knee. PMID- 25705084 TI - Effective Management of a pregnancy tumour using a soft tissue diode laser: a case Report. AB - BACKGROUND AND AIMS: Pregnancy tumours (PTs) are a non-neoplastic, reactive, inflammatory conditional gingival enlargement which occurs in the oral cavity during pregnancy. The lesion most frequently occurs on the gingiva but may also develop on the lip, tongue, oral mucosa and palate. When a large PT develops, it can interfere with mastication, speech, maintenance of oral hygiene and can be aesthetically disfiguring. The treatment of PTs depends upon the size of the lesion; smaller lesions can regress after parturition however large lesions need to be surgically removed. Conventional surgical techniques have the disadvantage of more bleeding from the surgical site and delay in healing of the scar tissue. The diode laser is a relatively new alternative to conventional surgical technique in intra-oral areas with the added advantage of bloodless procedures and rapid healing. CASE REPORT: The purpose of the present study is to highlight the management of a PT in a 25-year-old female using a diode laser delivering a painless, bloodless procedure with rapid postoperative healing. CONCLUSIONS: Diode laser excision of a persistent pregnancy tumour in a postpartum patient was safe and effective with minimal bleeding, good coagulation, and good wound healing. Among other lasers, the diode laser can therefore be considered for excisional treatment of persistent PTs. PMID- 25705085 TI - Characterization of plasmonic hole arrays as transparent electrical contacts for organic photovoltaics using high-brightness Fourier transform methods. AB - We present a methodology for probing light-matter interactions in prototype photovoltaic devices consisting of an organic semiconductor active layer with a semitransparent metal electrical contact exhibiting surface plasmon-based enhanced optical transmission. We achieve high-spectral irradiance in a spot size of less than 100 MUm using a high-brightness laser-driven light source and appropriate coupling optics. Spatially resolved Fourier transform photocurrent spectroscopy in the visible and near-infrared spectral regions allows us to measure external quantum efficiency with high sensitivity in small-area devices (<1 mm2). This allows for rapid fabrication of variable-pitch sub-wavelength hole arrays in metal films for use as transparent electrical contacts, and evaluation of the evanescent and propagating mode coupling to resonances in the active layer. PMID- 25705086 TI - Editorial. PMID- 25705087 TI - Advanced technologies for future ground-based, laser-interferometric gravitational wave detectors. AB - We present a review of modern optical techniques being used and developed for the field of gravitational wave detection. We describe the current state-of-the-art of gravitational waves detector technologies with regard to optical layouts, suspensions and test masses. We discuss the dominant sources and noise in each of these subsystems and the developments that will help mitigate them for future generations of detectors. We very briefly summarise some of the novel astrophysics that will be possible with these upgraded detectors. PMID- 25705088 TI - New asymmetric propagation invariant beams obtained by amplitude and phase modulation in frequency space. AB - In this paper, we demonstrate, numerically and experimentally that using the mask lens setup used by Durnin to generate Bessel beams Durnin [Phys. Rev. Lett. 58, 1499 (1987)], it is possible to generate different kinds of propagation invariant beams. A modification in the amplitude or phase of the field that illuminates the annular slit is proposed that corresponds to modulation in frequency space. In particular, we characterize the new invariant beams that were obtained by modulating the amplitude of the annular mask and when the incident field was modulated with a one-dimensional quadratic or cubic phase. Experimental results using an amplitude mask are shown in order to corroborate the numerical predictions. PMID- 25705089 TI - Paraxial light distribution in the focal region of a lens: a comparison of several analytical solutions and a numerical result. AB - The distribution of the complex field in the focal region of a lens is a classical optical diffraction problem. Today, it remains of significant theoretical importance for understanding the properties of imaging systems. In the paraxial regime, it is possible to find analytical solutions in the neighborhood of the focus, when a plane wave is incident on a focusing lens whose finite extent is limited by a circular aperture. For example, in Born and Wolf's treatment of this problem, two different, but mathematically equivalent analytical solutions, are presented that describe the 3D field distribution using infinite sums of [Formula: see text] and [Formula: see text] type Lommel functions. An alternative solution expresses the distribution in terms of Zernike polynomials, and was presented by Nijboer in 1947. More recently, Cao derived an alternative analytical solution by expanding the Fresnel kernel using a Taylor series expansion. In practical calculations, however, only a finite number of terms from these infinite series expansions is actually used to calculate the distribution in the focal region. In this manuscript, we compare and contrast each of these different solutions to a numerically calculated result, paying particular attention to how quickly each solution converges for a range of different spatial locations behind the focusing lens. We also examine the time taken to calculate each of the analytical solutions. The numerical solution is calculated in a polar coordinate system and is semi-analytic. The integration over the angle is solved analytically, while the radial coordinate is sampled with a sampling interval of [Formula: see text] and then numerically integrated. This produces an infinite set of replicas in the diffraction plane, that are located in circular rings centered at the optical axis and each with radii given by [Formula: see text], where [Formula: see text] is the replica order. These circular replicas are shown to be fundamentally different from the replicas that arise in a Cartesian coordinate system. PMID- 25705090 TI - Nonlocal nonlinear refractive index of gold nanoparticles synthesized by ascorbic acid reduction: comparison of fitting models. AB - In this paper, the nonlinear refractive index of colloidal gold nanoparticles under continuous wave illumination is investigated with the z-scan technique. Gold nanoparticles were synthesized using ascorbic acid as reductant, phosphates as stabilizer and cetyltrimethylammonium chloride (CTAC) as surfactant agent. The nanoparticle size was controlled with the CTAC concentration. Experiments changing incident power and sample concentration were done. The experimental z scan results were fitted with three models: thermal lens, aberrant thermal lens and the nonlocal model. It is shown that the nonlocal model reproduces with exceptionally good agreement; the obtained experimental behaviour. PMID- 25705091 TI - Non-moving Hadamard matrix diffusers for speckle reduction in laser pico projectors. AB - Personal electronic devices such as cell phones and tablets continue to decrease in size while the number of features and add-ons keep increasing. One particular feature of great interest is an integrated projector system. Laser pico projectors have been considered, but the technology has not been developed enough to warrant integration. With new advancements in diode technology and MEMS devices, laser-based projection is currently being advanced for pico-projectors. A primary problem encountered when using a pico-projector is coherent interference known as speckle. Laser speckle can lead to eye irritation and headaches after prolonged viewing. Diffractive optical elements known as diffusers have been examined as a means to lower speckle contrast. This paper presents a binary diffuser known as a Hadamard matrix diffuser. Using two static in-line Hadamard diffusers eliminates the need for rotation or vibration of the diffuser for temporal averaging. Two Hadamard diffusers were fabricated and contrast values measured showing good agreement with theory and simulated values. PMID- 25705092 TI - A novel minimal invasive mouse model of extracorporeal circulation. AB - Extracorporeal circulation (ECC) is necessary for conventional cardiac surgery and life support, but it often triggers systemic inflammation that can significantly damage tissue. Studies of ECC have been limited to large animals because of the complexity of the surgical procedures involved, which has hampered detailed understanding of ECC-induced injury. Here we describe a minimally invasive mouse model of ECC that may allow more extensive mechanistic studies. The right carotid artery and external jugular vein of anesthetized adult male C57BL/6 mice were cannulated to allow blood flow through a 1/32-inch external tube. All animals (n = 20) survived 30 min ECC and subsequent 60 min observation. Blood analysis after ECC showed significant increases in levels of tumor necrosis factor alpha, interleukin-6, and neutrophil elastase in plasma, lung, and renal tissues, as well as increases in plasma creatinine and cystatin C and decreases in the oxygenation index. Histopathology showed that ECC induced the expected lung inflammation, which included alveolar congestion, hemorrhage, neutrophil infiltration, and alveolar wall thickening; in renal tissue, ECC induced intracytoplasmic vacuolization, acute tubular necrosis, and epithelial swelling. Our results suggest that this novel, minimally invasive mouse model can recapitulate many of the clinical features of ECC-induced systemic inflammatory response and organ injury. PMID- 25705094 TI - Are Conditional Cash Transfers Effective in Urban Areas? Evidence from Mexico. AB - Conditional cash transfer (CCT) programs have spread worldwide as a new form of social assistance for the poor. Previous evaluations of CCT programs focus mainly on rural settings, and little is known about their effects in urban areas. This paper studies the short-term (one- and two-year) effects of the Mexican Oportunidades CCT program on urban children/youth. The program provides financial incentives for children/youth to attend school and for family members to visit health clinics. To participate, families had to sign up for the program and be deemed eligible. Difference-in-difference propensity score matching estimates indicate that the program is successful in increasing school enrollment, schooling attainment and time devoted to homework for girls and boys and in decreasing working rates of boys. PMID- 25705095 TI - A global stem cell niche - need of the hour. PMID- 25705093 TI - Role of the immunogenic and tolerogenic subsets of dendritic cells in multiple sclerosis. AB - Multiple sclerosis (MS) is an immune-mediated disorder in the central nervous system (CNS) characterized by inflammation and demyelination as well as axonal and neuronal degeneration. So far effective therapies to reverse the disease are still lacking; most therapeutic drugs can only ameliorate the symptoms or reduce the frequency of relapse. Dendritic cells (DCs) are professional antigen presenting cells (APCs) that are key players in both mediating immune responses and inducing immune tolerance. Increasing evidence indicates that DCs contribute to the pathogenesis of MS and might provide an avenue for therapeutic intervention. Here, we summarize the immunogenic and tolerogenic roles of DCs in MS and review medicinal drugs that may affect functions of DCs and have been applied in clinic for MS treatment. We also describe potential therapeutic molecules that can target DCs by inducing anti-inflammatory cytokines and inhibiting proinflammatory cytokines in MS. PMID- 25705096 TI - Umbilical Cord Blood Banking for Transplantation in Morocco: Problems and opportunities. AB - Since the success of the first umbilical cord blood (UCB) transplantation in a child with Fanconi anaemia in 1989, great interests have emerged for this source of stem cells. UCB provides an unlimited source of ethnically diverse stem cells and is an alternative for bone marrow (BM) and peripheral blood (PB) haematopoietic stem cell transplantation (HSCT). Thus, UCB and manipulated stem cells are now collected and banked according to international accreditation standards for listing on registries allowing rapid search and accessibility worldwide. This work aims to identify problems limiting the creation of a Moroccan cord blood bank and to highlight opportunities and issues of a new legislation promoting additional applications of cell therapy. PMID- 25705098 TI - Proceedings of the Annual Plenary Session on Regenerative Medicine (PAPRM). PMID- 25705099 TI - Proceedings of the Inventions- Inter-Disciplinary Interactions and Solutions (IIDIAS) Session. PMID- 25705097 TI - Adipose stem cell microbeads as production sources for chondrogenic growth factors. AB - Microencapsulating stem cells in injectable microbeads can enhance delivery and localization, but their ability to act as growth factor production sources is still unknown. To address this concern, growth factor mRNA levels and production from alginate microbeads with encapsulated human adipose stem cells (ASC microbeads) cultured in both growth and chondrogenic media (GM and CM) were measured over a two week period. Human ASCs in microbeads were either commercially purchased (Lonza) or isolated from six human donors and compared to human ASCs on tissue culture polystyrene (TCPS). The effects of crosslinking and alginate compositions on growth factor mRNA levels and production were also determined. Secretion profiles of IGF-I, TGF-beta3 and VEGF-A from commercial human ASC microbeads were linear and at a significantly higher rate than TCPS cultures over two weeks. For human ASCs derived from different donors, microencapsulation increased pthlh and both IGF-I and TGF-beta3 secretion. CM decreased fgf2 and VEGF-A secretion from ASC microbeads derived from the same donor population. Crosslinking microbeads in BaCl2 instead of CaCl2 did not eliminate microencapsulation's beneficial effects, but did decrease IGF-I production. Increasing the guluronate content of the alginate microbead increased IGF-I retention. Decreasing alginate molecular weight eliminated the effects microencapsulation had on increasing IGF-I secretion. This study demonstrated that microencapsulation can enhance chondrogenic growth factor production and that chondrogenic medium treatment can decrease angiogenic growth factor production from ASCs, making these cells a potential source for paracrine factors that can stimulate cartilage regeneration. PMID- 25705100 TI - Factors influencing adverse skin responses in rats receiving repeated subcutaneous injections and potential impact on neurobehavior. AB - Repeated subcutaneous (s.c.) injection is a common route of administration in chronic studies of neuroactive compounds. However, in a pilot study we noted a significant incidence of skin abnormalities in adult male Long-Evans rats receiving daily s.c. injections of peanut oil (1.0 ml/kg) in the subscapular region for 21 d. Histopathological analyses of the lesions were consistent with a foreign body reaction. Subsequent studies were conducted to determine factors that influenced the incidence or severity of skin abnormalities, and whether these adverse skin reactions influenced a specific neurobehavioral outcome. Rats injected daily for 21 d with food grade peanut oil had an earlier onset and greater incidence of skin abnormalities relative to rats receiving an equal volume (1.0 ml/kg/d) of reagent grade peanut oil or triglyceride of coconut oil. Skin abnormalities in animals injected daily with peanut oil were increased in animals housed on corncob versus paper bedding. Comparison of animals obtained from different barrier facilities exposed to the same injection paradigm (reagent grade peanut oil, 1.0 ml/kg/d s.c.) revealed significant differences in the severity of skin abnormalities. However, animals from different barrier facilities did not perform differently in a Pavlovian fear conditioning task. Collectively, these data suggest that environmental factors influence the incidence and severity of skin abnormalities following repeated s.c. injections, but that these adverse skin responses do not significantly influence performance in at least one test of learning and memory. PMID- 25705101 TI - Preservation of relational timing in speech of persons with Parkinson's disease with and without deep brain stimulation. AB - BACKGROUND: Initial shortening of stem vowels in three-word derivational paradigms (e.g., zip, zipper, zippering) was studied in persons with Parkinson's disease (PWPD) with and without deep brain stimulation (DBS), and in normal speakers. METHOD: Seven PWPD without DBS, 7 PWPD with DBS ON (DBSN) or OFF (DBSF), and 6 healthy control (CON) persons were studied. Stimuli were 7 three word paradigms consisting of a stem word and two derived longer forms created by adding the suffixes er (+1), and er+ing (+2). RESULTS: Vowel durations decreased across word forms of increasing length (initial shortening) for DBSF, DBSN, PWPD, and CON. Vowel shortening did not interact with group. For each word form, CON vowel duration was shorter than those for PWPD, DBSN and DBSF but word duration did not differ between groups. DBS did not have a significant effect on either vowel or word duration. CONCLUSION: These results agree with previous findings for a PWPD with accelerated speech and faster rates of speech in DBS-ON. Observations that vowel duration patterns are maintained in subcortical and cerebellar but not left hemisphere damage suggest that cortical control factors play a primary role in relational timing. PMID- 25705102 TI - Severe Idiopathic Dysphagia in an Acute Hospital Setting: Assessment, Management, and Outcome. AB - This case describes the course of a patient who was admitted to an acute care hospital with pneumonia and odynophagia and found to have severe, idiopathic oropharyngeal dysphagia. The assessment, treatment, and outcome are reported alongside suggestions for best practice in the treatment of dysphagia in hospital settings. Timely instrumental assessment, interdisciplinary management, and post discharge follow-up were needed to provide optimum care and to achieve a positive outcome for this patient with life-threatening dysphagia. PMID- 25705103 TI - Cannabis Withdrawal Among Detained Adolescents: Exploring the Impact of Nicotine and Race. AB - Rates of marijuana use among detained youths are exceptionally high. Research suggests a cannabis withdrawal syndrome is valid and clinically significant; however, these studies have mostly been conducted in highly controlled laboratory settings with treatment-seeking, White adults. The present study analyzed archival data to explore the magnitude of cannabis withdrawal symptoms within a diverse sample of detained adolescents while controlling for tobacco use and investigating the impact of race on symptom reports. Adolescents recruited from a juvenile correctional facility (N=93) completed a background questionnaire and the Marijuana Withdrawal Checklist. Analyses revealed a significant main effect for level of tobacco use on severity of irritability, and for level of marijuana use on severity of craving to smoke marijuana and strange/wild dreams. Furthermore, a significant main effect for race was found with Black adolescents reporting lower withdrawal discomfort scores and experiencing less severe depressed mood, difficulty sleeping, nervousness/anxiety, and strange/wild dreams. Although exploratory, these findings may have significant clinical implications for providers in juvenile detention facilities, allowing the execution of proper medical and/or behavioral interventions to assist adolescents presenting with problematic cannabis and/or tobacco withdrawal. PMID- 25705104 TI - Battered Women's Profiles Associated with Service Help-Seeking Efforts: Illuminating Opportunities for Intervention. AB - Knowledge about where battered women present for services and the violence, biopsychosocial, and demographic factors associated with their help seeking can provide social workers with guidance in anticipating needs among this portion of their clientele. The authors examined the service contact patterns of a sample of battered women (N = 448) following an incident of partner violence that triggered legal involvement. Significant group differences, tested with t tests and chi squares, between women who sought compared with those who did not seek services were found on partner violence exposure and biopsychosocial factors. Correlations and regression analyses of relationships among partner violence and biopsychosocial and demographic factors with help-seeking indices show how battered women's needs differentially relate across a range of service types. Results show distinctive profiles of needs and resources among battered women who seek violence, legal, health, economic, substance abuse, and religious helping services. PMID- 25705105 TI - Younger and Older Users' Recognition of Virtual Agent Facial Expressions. AB - As technology advances, robots and virtual agents will be introduced into the home and healthcare settings to assist individuals, both young and old, with everyday living tasks. Understanding how users recognize an agent's social cues is therefore imperative, especially in social interactions. Facial expression, in particular, is one of the most common non-verbal cues used to display and communicate emotion in on-screen agents (Cassell, Sullivan, Prevost, & Churchill, 2000). Age is important to consider because age-related differences in emotion recognition of human facial expression have been supported (Ruffman et al., 2008), with older adults showing a deficit for recognition of negative facial expressions. Previous work has shown that younger adults can effectively recognize facial emotions displayed by agents (Bartneck & Reichenbach, 2005; Courgeon et al. 2009; 2011; Breazeal, 2003); however, little research has compared in-depth younger and older adults' ability to label a virtual agent's facial emotions, an import consideration because social agents will be required to interact with users of varying ages. If such age-related differences exist for recognition of virtual agent facial expressions, we aim to understand if those age-related differences are influenced by the intensity of the emotion, dynamic formation of emotion (i.e., a neutral expression developing into an expression of emotion through motion), or the type of virtual character differing by human likeness. Study 1 investigated the relationship between age-related differences, the implication of dynamic formation of emotion, and the role of emotion intensity in emotion recognition of the facial expressions of a virtual agent (iCat). Study 2 examined age-related differences in recognition expressed by three types of virtual characters differing by human-likeness (non-humanoid iCat, synthetic human, and human). Study 2 also investigated the role of configural and featural processing as a possible explanation for age-related differences in emotion recognition. First, our findings show age-related differences in the recognition of emotions expressed by a virtual agent, with older adults showing lower recognition for the emotions of anger, disgust, fear, happiness, sadness, and neutral. These age-related difference might be explained by older adults having difficulty discriminating similarity in configural arrangement of facial features for certain emotions; for example, older adults often mislabeled the similar emotions of fear as surprise. Second, our results did not provide evidence for the dynamic formation improving emotion recognition; but, in general, the intensity of the emotion improved recognition. Lastly, we learned that emotion recognition, for older and younger adults, differed by character type, from best to worst: human, synthetic human, and then iCat. Our findings provide guidance for design, as well as the development of a framework of age related differences in emotion recognition. PMID- 25705106 TI - The Near-Road Ambient Monitoring Network and Exposure Estimates for Health Studies. AB - The transport sector is the largest source of NOx and CO emissions, and among the largest sources of PM2.5 and VOCs. As a result of EPA's new near-road monitoring requirements, high-quality measurements of ambient NO2, CO, and PM2.5 concentrations will be available from more than 120 sites adjacent to major roads in over 100 cities nationwide in the next few years. This article discusses how data from the new network will provide opportunities to further develop, calibrate, and verify exposure assessment methods and models. PMID- 25705107 TI - Effect of Sodium Chloride on the Surface and Wetting Properties of Aqueous Solutions of Cocamidopropyl Betaine. AB - Surfactants are important ingredients of personal care products and household products. The main characteristic of these compounds is to decrease the surface tension of solvent and resulting many properties such as contact angle, foam properties etc. The coexistence of other ingredients in the product may affect the properties of surfactants. One of the main components contained in almost every personal care and household product is sodium chloride. The main aim of this work was to determine the effect of this salt on some surface and usage properties of cocamidopropyl betaine (CAPB). From our experiments it was shown that the effect of added sodium chloride in the aqueous solutions of CAPB on the properties is the opposite to the one described in the literature for cationic and anionic surfactants, i.e., CMC increases with increasing ionic strength, foam height decreases with increasing salt concentration. Our investigation showed that sodium chloride makes worse the properties of the CAPB solutions examined in this work. PMID- 25705108 TI - Biodegradation of Nonylphenol Monopropoxyethoxylates. AB - Aerobic biodegradation behavior of nonylphenol monopropoxyethoxylates was investigated in two tests with different inocula-sewage sludge and river water. Both primary biodegradation and formation of different biodegradation intermediates were studied. Primary biodegradation of nonylphenol monopropoxyethoxylates was relatively fast and complete with the sewage sludge as the inoculum. On the other hand, biodegradation with river water as the inoculum was slower and primary biodegradation in this test reached only about 60 % during almost 50 days. The biodegradation intermediates from both oxidative and non oxidative pathways were found. In the non-oxidative route monopropoxy poly(ethylene glycol)s were observed which indicate existence of the central fission biodegradation pathway. In the oxidative pathway carboxylic acids were identified. The biodegradation intermediates identified with the use of high performance liquid chromatography with mass spectrometric detection persisted for many days in both tests. PMID- 25705110 TI - ON IDENTIFIABILITY OF MIXTURES OF INDEPENDENT DISTRIBUTION LAWS, . AB - We consider representations of a joint distribution law of a family of categorical random variables (i.e., a multivariate categorical variable) as a mixture of independent distribution laws (i.e. distribution laws according to which random variables are mutually independent). For infinite families of random variables, we describe a class of mixtures with identifiable mixing measure. This class is interesting from a practical point of view as well, as its structure clarifies principles of selecting a "good" finite family of random variables to be used in applied research. For finite families of random variables, the mixing measure is never identifiable; however, it always possesses a number of identifiable invariants, which provide substantial information regarding the distribution under consideration. PMID- 25705109 TI - Coding and noncoding expression patterns associated with rare obesity-related disorders: Prader-Willi and Alstrom syndromes. AB - Obesity is accompanied by hyperphagia in several classical genetic obesity related syndromes that are rare, including Prader-Willi syndrome (PWS) and Alstrom syndrome (ALMS). We compared coding and noncoding gene expression in adult males with PWS, ALMS, and nonsyndromic obesity relative to nonobese males using readily available lymphoblastoid cells to identify disease-specific molecular patterns and disturbed mechanisms in obesity. We found 231 genes upregulated in ALMS compared with nonobese males, but no genes were found to be upregulated in obese or PWS males and 124 genes were downregulated in ALMS. The metallothionein gene (MT1X) was significantly downregulated in ALMS, in common with obese males. Only the complex SNRPN locus was disturbed (downregulated) in PWS along with several downregulated small nucleolar RNAs (snoRNAs) in the 15q11 q13 region (SNORD116, SNORD109B, SNORD109A, SNORD107). Eleven upregulated and ten downregulated snoRNAs targeting multiple genes impacting rRNA processing, developmental pathways, and associated diseases were found in ALMS. Fifty-two miRNAs associated with multiple, overlapping gene expression disturbances were upregulated in ALMS, and four were shared with obese males but not PWS males. For example, seven passenger strand microRNAs (miRNAs) (miR-93*, miR-373*, miR-29b 2*, miR-30c-1*, miR27a*, miR27b*, and miR-149*) were disturbed in association with six separate downregulated target genes (CD68, FAM102A, MXI1, MYO1D, TP53INP1, and ZRANB1). Cell cycle (eg, PPP3CA), transcription (eg, POLE2), and development may be impacted by upregulated genes in ALMS, while downregulated genes were found to be involved with metabolic processes (eg, FABP3), immune responses (eg, IL32), and cell signaling (eg, IL1B). The high number of gene and noncoding RNA disturbances in ALMS contrast with observations in PWS and males with nonsyndromic obesity and may reflect the progressing multiorgan pathology of the ALMS disease process. PMID- 25705111 TI - Trends of VOC exposures among a nationally representative sample: Analysis of the NHANES 1988 through 2004 data sets. AB - Exposures to volatile organic compounds (VOCs) are ubiquitous due to emissions from personal, commercial and industrial products, but quantitative and representative information regarding long term exposure trends is lacking. This study characterizes trends from1988 to 2004 for the 15 VOCs measured in blood in five cohorts of the National Health and Nutrition Examination Survey (NHANES), a large and representative sample of U.S. adults. Trends were evaluated at various percentiles using linear quantile regression (QR) models, which were adjusted for solvent-related occupations and cotinine levels. Most VOCs showed decreasing trends at all quantiles, e.g., median exposures declined by 2.5 (m, p-xylene) to 6.4 (tetrachloroethene) percent per year over the 15 year period. Trends varied by VOC and quantile, and were grouped into three patterns: similar decreases at all quantiles (including benzene, toluene); most rapid decreases at upper quantiles (ethylbenzene, m, p-xylene, o-xylene, styrene, chloroform, tetrachloroethene); and fastest declines at central quantiles (1,4 dichlorobenzene). These patterns reflect changes in exposure sources, e.g., upper percentile exposures may result mostly from occupational exposure, while lower percentile exposures arise from general environmental sources. Both VOC emissions aggregated at the national level and VOC concentrations measured in ambient air also have declined substantially over the study period and are supportive of the exposure trends, although the NHANES data suggest the importance of indoor sources and personal activities on VOC exposures. While piecewise QR models suggest that exposures of several VOCs decreased little or any during the 1990's, followed by more rapid decreases from 1999 to 2004, questions are raised concerning the reliability of VOC data in several of the NHANES cohorts and its applicability as an exposure indicator, as demonstrated by the modest correlation between VOC levels in blood and personal air collected in the 1999/2000 cohort. Despite some limitations, the NHANES data provides a unique, long term and direct measurement of VOC exposures and trends. PMID- 25705112 TI - Extreme value analyses of VOC exposures and risks: A comparison of RIOPA and NHANES datasets. AB - Extreme value theory, which characterizes the behavior of tails of distributions, is potentially well-suited to model exposures and risks of pollutants. In this application, it emphasizes the highest exposures, particularly those that may be high enough to present acute or chronic health risks. The present study examines extreme value distributions of exposures and risks to volatile organic compounds (VOCs). Exposures of 15 different VOCs were measured in the Relationship between Indoor, Outdoor and Personal Air (RIOPA) study, and ten of the same VOCs were measured in the nationally representative National Health and Nutrition Examination Survey (NHANES). Both studies used similar sampling methods and study periods. Using the highest 5 and 10% of measurements, generalized extreme value (GEV), Gumbel and lognormal distributions were fit to each VOC in these two large studies. Health risks were estimated for individual VOCs and three VOC mixtures. Simulated data that matched the three types of distributions were generated and compared to observations to evaluate goodness-of-fit. The tail behavior of exposures, which clearly neither fit normal nor lognormal distributions for most VOCs in RIOPA, was usually best fit by the 3-parameter GEV distribution, and often by the 2-parameter Gumbel distribution. In contrast, lognormal distributions significantly underestimated both the level and likelihood of extrema. Among the RIOPA VOCs, 1,4-dichlorobenzene (1,4-DCB) caused the greatest risks, e.g., for the top 10% extrema, all individuals had risk levels above 10-4, and 13% of them exceeded 10-2. NHANES had considerably higher concentrations of all VOCs with two exceptions, methyl tertiary-butyl ether and 1,4-DCB. Differences between these studies can be explained by sampling design, staging, sample demographics, smoking and occupation. This analysis shows that extreme value distributions can represent peak exposures of VOCs, which clearly are neither normally nor lognormally distributed. These exposures have the greatest health significance, and require accurate modeling. PMID- 25705113 TI - Predictors of medication adherence among HIV-infected youth. AB - The purpose of this study was to examine the rates of medication adherence among HIV-infected adolescents/young adults and to explore the relationship between negative affect, cognitive ability/ formal reasoning, and substance use on the medication adherence of these youth. Forty-two HIV-positive youth (25 males, 17 females; age range 16 - 24) currently taking antiretroviral medications were recruited to participate in a one-hour interview. Using the time-line follow-back calendar method, 66% of participants had missed a dose of medicine in the past week while 42% missed a dose 'yesterday'. Multiple regression analyses demonstrated that both depression and age of first marijuana use were statistically significant predictors of non-adherence (p < .01, R2 = .326). Specifically, higher rates of depressive symptoms and younger age of first marijuana use predicted higher rates of non-adherence. Developmentally, 69% of the sample had yet to begin the transition from concrete thinking to formal or abstract reasoning. The results from this project demonstrate that adherence to antiretroviral medications continues to be a problem with HIV-infected youth. These results are an important first step toward the development of interventions aimed at increasing medication adherence among adolescents and young adults living with HIV. PMID- 25705114 TI - Analysis of the intratumoral adaptive immune response in well differentiated and dedifferentiated retroperitoneal liposarcoma. AB - Treatment options are limited in well differentiated (WD) and dedifferentiated (DD) retroperitoneal liposarcoma. We sought to study the intratumoral adaptive immune response and explore the potential feasibility of immunotherapy in this disease. Tumor-infiltrating lymphocytes (TILs) were isolated from fresh surgical specimens and analyzed by flow cytometry for surface marker expression. Previously reported immune cell aggregates known as tertiary lymphoid structures (TLS) were further characterized by immunohistochemistry. In all fresh tumors, TILs were found. The majority of TILs were CD4 T cells; however cytotoxic CD8 T cells were also seen (average: 20% of CD3 T cells). Among CD8 T cells, 65% expressed the immune checkpoint molecule PD-1. Intratumoral TLS may be sites of antigen presentation as DC-LAMP positive, mature dendritic cells were found juxtaposed next to CD4 T cells. Clinicopathologic correlation, however, demonstrated that presence of TLS was associated with worse recurrence-free survival in WD disease and worse overall survival in DD disease. Our data suggest that an adaptive immune response is present in WD/DD retroperitoneal liposarcoma but may be hindered by TLS, among other possible microenvironmental factors; further investigation is needed. Immunotherapy, including immune checkpoint blockade, should be evaluated as a treatment option in this disease. PMID- 25705115 TI - RISK PERCEPTION FOR ACQUAINTANCE SEXUAL AGGRESSION: A SOCIAL-COGNITIVE PERSPECTIVE. AB - Beliefs that people hold about sources of harm and their personal susceptibility to harm have been shown to play an important role in their subsequent self protection. With respect to acquaintance sexual aggression, women generally report low levels of perceived personal risk and, thus, low level preparedness to prevent or protect against this form of threat. In order to develop effective resistance efforts, a more complete understanding is needed of factors that shape perception of risk and how these factors are likely to influence-both positively and negatively-women's risk reduction and self-protection. This article addresses this need by reviewing recent literature on risk perception and identifying relevant applications of theory and findings to women's perception of risk for acquaintance sexual aggression. PMID- 25705116 TI - Posttraumatic growth and religion in Rwanda: individual well-being vs. collective false consciousness. AB - Some scholars include changes in spirituality, such as a greater commitment to their religious beliefs or an enhanced understanding of spiritual matters, in the definition of posttraumatic growth; others conclude that questions of spirituality should be excluded from this definition. This article highlights the fundamental difference of religion to other domains of posttraumatic growth because religions are ideologies (and other domains of growth are not). As ideologies, it is argued that religions can affect different levels of identity in different ways. Based on testimonial evidence from Rwandan genocide survivors, the article demonstrates that although religious beliefs can bring existential comfort at the individual level, they can also lead to a state of false consciousness at the collective level. In Rwanda, the dominant religious ideology facilitated the spiritual and moral climate in which genocide became possible. Today, religious interpretations of the Rwandan Patriotic Front's (RPF) leadership provide spiritual backing to a government which has become increasingly authoritarian. PMID- 25705117 TI - Development and GBS-genotyping of introgression lines (ILs) using two wild species of rice, O. meridionalis and O. rufipogon, in a common recurrent parent, O. sativa cv. Curinga. AB - Two populations of interspecific introgression lines (ILs) in a common recurrent parent were developed for use in pre-breeding and QTL mapping. The ILs were derived from crosses between cv Curinga, a tropical japonica upland cultivar, and two different wild donors, Oryza meridionalis Ng. accession (W2112) and Oryza rufipogon Griff. accession (IRGC 105491). The lines were genotyped using genotyping-by-sequencing (GBS) and SSRs. The 32 Curinga/O. meridionalis ILs contain 76.73 % of the donor genome in individual introgressed segments, and each line has an average of 94.9 % recurrent parent genome. The 48 Curinga/O. rufipogon ILs collectively contain 97.6 % of the donor genome with an average of 89.9 % recurrent parent genome per line. To confirm that these populations were segregating for traits of interest, they were phenotyped for pericarp color in the greenhouse and for four agronomic traits-days to flowering, plant height, number of tillers, and number of panicles-in an upland field environment. Seeds from these IL libraries and the accompanying GBS datasets are publicly available and represent valuable genetic resources for exploring the genetics and breeding potential of rice wild relatives. PMID- 25705118 TI - Enrichments of gene replacement events by Agrobacterium-mediated recombinase mediated cassette exchange. AB - We report recombinase-mediated cassette exchange (RMCE), which can permit integration of transgenes into pre-defined chromosomal loci with no co-expressed marker gene by using Agrobacterium-mediated transformation. Transgenic tobacco plants which have a single copy of negative marker genes (codA) at target loci in heterozygous and homozygous conditions were used for gene exchange by the RMCE method. By negative selection, we were able to obtain five heterozygous and four homozygous transgenic plants in which the genes were exchanged from 64 leaf segments of heterozygous and homozygous target plants, respectively. Except for one transgenic plant with an extra copy, the other eight plants had only a single copy of marker-free transgenes, and no footprint of random integrated copies was detected in half of the eight plants. The RMCE re-transformation frequencies were calculated as 6.25 % per explant and were approximately the same as the average percentage of intact single-copy transformation events for standard tobacco Agrobacterium-mediated transformation. PMID- 25705119 TI - Anthracyclines induce double-strand DNA breaks at active gene promoters. AB - Doxorubicin is a widely used chemotherapeutic drug that intercalates between DNA base-pairs and poisons Topoisomerase II, although the mechanistic basis for cell killing remains speculative. Doxorubicin and related anthracycline compounds have been shown to increase nucleosome turnover and/or eviction around promoters, which suggests that the resulting enhanced exposure of DNA might underlie cell killing. Previously, we showed that low doses of anthracyclines increase nucleosome turnover around active gene promoters, which suggests that loss of nucleosomes might contribute to cancer cell killing. Here we apply a genome-wide method to precisely map DNA double-strand breaks (DSBs) in cancer cells. We find that spontaneous DSBs occur preferentially around promoters of active genes, and that both anthracyclines and etoposide, a Topoisomerase II poison, increase DSBs around promoters, although CpG islands are conspicuously protected from DSBs. We propose that torsion-based enhancement of nucleosome turnover by anthracyclines exposes promoter DNA, ultimately causing DSBs around promoters. PMID- 25705120 TI - THE FRAGILITY OF THE FUTURE AND THE TUG OF THE PAST: LONGEVITY IN LATIN AMERICA AND THE CARIBBEAN. AB - BACKGROUND: Cohorts that will attain age 60 after 2010 in the Latin American and Caribbean region (LAC) are beneficiaries of a massive mortality decline that began as early as 1930. The bulk of this decline is due to diffusion of low-cost medical technology that improved recovery rates from infectious diseases. This changes the composition of elderly cohorts in a distinct way: more among those who could experience the deleterious impact of adverse early conditions as adults survive to attain old ages. OBJECTIVE: To compute bounds for the size of effects on old age mortality of changes in cohorts' composition by exposure to early conditions. We calculate estimates for countries in the LAC region that span the entire range of post-1950 mortality decline. METHODS: We use counterfactual population projections to estimate bounds of changes in the composition of cohorts by exposure to early conditions. These are combined with empirical effects of adverse early conditions on adult mortality to generate estimates of foregone gains in life expectancy at age 60. RESULTS: under somewhat conservative assumptions life expectancy at age 60 will at best increase much more slowly than in the past and at worst reach a steady state or decline. Foregone gains may be as high as 20% of projected values over a period of 30 to 50 years, the time it takes for cohorts that reaped the benefits of the secular mortality decline to become extinct. CONCLUSIONS: Changing composition of cohorts by early exposures constitutes a powerful force that could drag down or halt short-run progress of life expectancy at older ages. PMID- 25705121 TI - Evaluation of attitude to, knowledge of and barriers toward research among medical science students. AB - BACKGROUND: Plans to increase the role of students in health research require data on students' knowledge and views of research. The aim of the study was to evaluate these factors toward research among medical science students. METHODS: Undergraduate and postgraduate students of three medicine, dentistry and pharmacy schools in Shiraz were enrolled in a cross-sectional descriptive study using questionnaires to provide details of the parameters of attitude to, knowledge of and barriers toward research for each individual. All data was coded for each of the parameters. Data analyses were performed by one-way ANOVA/Tukey and Student's t, Pearson's correlation and Chi-squared tests. RESULTS: A total of 384 questionnaires were returned complete. Mean student scores for attitude, knowledge and barriers were 68.97 +/- 12.56, 70.99 +/- 20.97 and 75.27 +/- 15.38, respectively. On the knowledge parameter, 77.8% of students' scores fell above the middle of the possible attainable score, but 90% of attitude scores came in at below the middle of the possible attainable score. Undergraduate students (70.27 +/- 12.00) showed a more positive attitude to research than postgraduate students (65.57 +/- 13.06) (p = 0.001). Female students (72.97 +/- 20.54) had greater knowledge than males (67.09 +/- 21.56) (p = 0.010). Many barriers were highlighted by students such as lack of funding support and lack of time for research. CONCLUSIONS: Students showed favorable knowledge of research, but their attitude to the field was inadequate. More attention must be placed on these parameters in the curriculum to improve student interest in health research. The impact of barrier factors on research demonstrates that there is a need for greater availability of information in order to solve the problems and change strategies for research. PMID- 25705122 TI - "Trade policy, not morals or health policy": the US Trade Representative, tobacco companies and market liberalization in Thailand. AB - The enforced opening of Thailand's cigarette market to imports in 1990 has become a cause celebre in debates about the social and health impacts of trade agreements. At the instigation of leading US-based cigarette manufacturers, the US Trade Representative (USTR) threatened trade sanctions against Thailand to compel the government to liberalize its domestic cigarette market. Thailand's challenge to the USTR led to referral to General Agreement on Tariffs and Trade (GATT) arbitration. While GATT ruled in favour of the USTR on market access, it also found that Thailand could subsequently enact non-discriminatory tobacco control regulation without contravening the GATT agreement. This paper contributes to existing literature via its analysis of tobacco industry documents that highlight not only USTR responsiveness to lobbying from tobacco corporations, raising concerns about the drivers of globalization and the limited protection afforded to public health concerns in trade agreements. Significantly, the documents also indicate that USTR support of the tobacco industry was not unconditional, being subject to wider pressures of global trade negotiations. Such qualification notwithstanding, however,,ongoing governmental willingness to advance the international interests of tobacco corporations remains a concern from a public health perspective, particularly given the failure of the US to ratify the World Health Organization's Framework Convention on Tobacco Control. PMID- 25705123 TI - Nurses' self-reported time estimation of anticoagulation therapy: a survey of warfarin management in long-term care. AB - BACKGROUND: A nursing shortage in the United States has resulted in increased workloads, potentially affecting the quality of care. This situation is particularly concerning in long-term care (LTC) facilities, where residents are older, frailer, and may be receiving multiple medications for comorbidities, thus requiring a greater commitment of nurse time. We conducted a survey of LTC nurses to determine how much of their time each week is spent managing newly started and stable warfarin-treated residents. METHODS: Forty LTC nurses validated the questionnaire to determine what protocols/procedures are involved in warfarin management. Twenty LTC nurses completed the survey, quantifying the time they spend on procedures related to warfarin management, and how often they performed each procedure for each resident each week. RESULTS: The nurses reported that 26% of their residents were receiving warfarin; the majority (approximately 75%) of these residents began warfarin after admission to the facility. On average, the nurses spent 4.6 hours per week for treatment procedures and monitoring patients initiating warfarin therapy and 2.35 hours per week for each resident who was stable on warfarin therapy on admission. Overall, to care for an average number of newly initiated and stable warfarin patients in a medium-size LTC facility, staff nurses are estimated to spend 68 hours per week. Study limitations include the potential for bias because of the small sample size, representativeness of the sample, and the possibility of inaccuracies in respondents' self-reported time estimation of warfarin-related procedures. CONCLUSIONS: In the context of a well-documented and expanding nursing shortage in the United States, the substantial use of time and resources necessary to initiate, monitor, and manage warfarin treatment in elderly LTC patients is of concern. Until the problem of understaffing is resolved, implementation of therapies that are simpler and require less nursing time-e.g. the use of new oral anticoagulants in the place of warfarin-may be a way to free up nursing time for other essential care tasks. PMID- 25705124 TI - Changes of T-lymphocyte subpopulation and differential expression pattern of the T-bet and GATA-3 genes in diffuse large B-cell lymphoma patients after chemotherapy. AB - BACKGROUND AND OBJECTIVE: T cell-mediated immunity plays an important role in enhancing antitumor response.This study aimed to investigate the changes in the T lymphocyte subpopulation and to characterize the differential expression pattern of corresponding regulatory genes in peripheral blood mononuclear cells (PBMCs) from diffuse large B cell lymphoma (DLBCL) patients before and after chemotherapy. METHODS: A total of 56 DLBCL patients were recruited for analysis of T-cell subset distribution in the peripheral blood using flow cytometry; serum interferon (IFN)-gamma and interleukin (IL)-4 levels using enzyme-linked immunosorbent assays; and early growth response protein 1 (EGR-1), T-bet, GATA binding protein 3 (GATA-3), and transforming growth factor (TGF)-beta mRNA levels using quantitative reverse-transcription polymerase chain reaction. Twenty-six healthy subjects served as controls. RESULTS: The percentage of CD3(+)CD4(+)T lymphocytes in peripheral blood from DLBCL patients was significantly decreased, whereas the percentages of CD3(+)CD8(+)T and CD4(+)CD25(+)T cells were significantly increased compared to those in controls (p < 0.05). Serum levels of IFN-gamma and IL-4 were also significantly lower in DLBCL patients than those in controls (p < 0.05), and the levels of EGR-1, T-bet, and GATA-3 mRNA in PBMCs were lower (2.69 +/- 1.48, 9.43 +/- 2.14, and 20.83 +/- 9.05 fold, respectively) in DLBCL patients than those in controls. Furthermore, there was a positive association between the levels of EGR-1 and T-bet mRNA (p = 0.001). However, the level of TGF-beta mRNA was significantly increased in DLBCL patients, which was inversely associated with the T-bet mRNA level (p = 0.008), but positively associated with the percentage of T regulatory cells in PBMCs (p = 0.011). After three cycles of chemotherapy, the distribution of T-lymphocyte subsets in DLBCL patients were changed, and the levels of EGR-1, T-bet, and GATA-3 mRNA were significantly increased (p < 0.05) compared to those before chemotherapy. CONCLUSIONS: These results demonstrate the changes in T-lymphocyte subpopulations and the altered expression 34 pattern of the corresponding regulatory genes in PBMCs from DLBCL patients after chemotherapy, which are associated with the response of patients to treatment. The preferential expression of the T-bet gene after chemotherapy was closely correlated with the increased expression of the EGR-1 gene and decreased expression of the TGF-beta gene. PMID- 25705125 TI - Overview on the complexity of androgen receptor-targeted therapy for prostate cancer. AB - In the past decades, the field of prostate cancer (PCa) biology has developed exponentially and paralleled with that has been the growing interest in translation of laboratory findings into clinical practice. Based on overwhelming evidence of high impact research findings which support the underlying cause of insufficient drug efficacy in patients progressing on standard androgen deprivation therapy (ADT) is due to persistent activation of the androgen receptor (AR) signaling axis. Therefore, newer agents must be discovered especially because newer ADT such as abiraterone and enzalutamide are becoming ineffective due to rapid development of resistance to these agents. High throughput technologies are generating massive and highly dimensional genetic variation data that has helped in developing a better understanding of the dynamic repertoire of AR and AR variants. Full length AR protein and its variants modulate a sophisticated regulatory system to orchestrate cellular responses. We partition this multicomponent review into subsections addressing the underlying mechanisms of resistance to recent therapeutics, positive and negative regulators of AR signaling cascade, and how SUMOylation modulates AR induced transcriptional activity. Experimentally verified findings obtained from cell culture and preclinical studies focusing on the potential of natural agents in inhibiting mRNA/protein levels of AR, nuclear accumulation and enhanced nuclear export of AR are also discussed. We also provide spotlight on molecular basis of enzalutamide resistance with an overview of the strategies opted to overcome such resistance. AR variants are comprehensively described and different mechanisms that regulate AR variant expression are also discussed. Reconceptualization of phenotype- and genotype-driven studies have convincingly revealed that drug induced resistance is a major stumbling block in standardization of therapy. Therefore, we summarize succinctly the knowledge of drug resistance especially to ADT and potential avenues to overcome such resistance for improving the treatment outcome of PCa patients. PMID- 25705126 TI - Kinetic characterization of lactate dehydrogenase in normal and malignant human breast tissues. AB - BACKGROUND: Aerobic glycolysis rate is higher in breast cancer tissues than adjacent normal tissues which providethe ATP, lactate and anabolic precursors required for tumourgenesis and metastasis. Lactate dehydrogenase (LDH) is a critical enzyme during aerobic glycolysis as it is typically responsible for the production of lactate and regeneration of NAD(+), which allows for the continued functioning of glycolysis even in the absence of oxygen. LDH has been found to be highly expressed in breast tumors. Enzyme kinetic characteristics is related to environmentinvolving the enzyme, and tumor microenvironment has distinct features relative to adjacent normal tissues, thus we hypothesized that LDH should have different kinetic characteristics in breast tumors compared to normal breast tissues. METHODS: LDH was partially purifiedfrom human breast tumors and normal tissues, which were obtained directly from operating room. TheMichaelis-Menten constant (Km), maximum velocity (Vmax), activation energy (Ea) and enzyme efficiency in breast tumors and normal tissueswere determined. RESULTS: It was found that tumor LDH affinity in forward reaction was the same as normal LDH but Vmax of cancerous LDH was higher relative to normal LDH. In reverse reaction, affinity of tumor LDH for lactate and NAD(+) was lower than normal LDH, also enzyme efficiency for lactate and NAD(+) was higher in normal samples. The Ea of reverse reaction was higher in cancerous tissues. CONCLUSIONS: It was concluded that thelow LDH affinity for lactate and NAD(+) is a valuable tool for preserving lactate by cancer cells. We also conclude that increasing of LDH affinity may be a valid molecular target to abolish lactate dependent tumor growth and kinetic characteristics of LDH could be a novel diagnostic parameter for human breast cancer. PMID- 25705127 TI - Antioxidant and anti-inflammatory activity of Ocimum labiatum extract and isolated labdane diterpenoid. AB - BACKGROUND: Plants from the genus Ocimum are used as folk medicine for treating various diseases including inflammatory and immune-related diseases. Numerous reports have suggested plant extracts and their constituents as possible anti inflammatory agents. Here, in vitro evidence of Ocimum labiatum's immune enhancing and antioxidant properties is presented for the first time. METHODS: The anti-inflammatory effect of O. labiatum ethanolic extract and an isolated diterpenoid was determined using a cytometric bead array (CBA) technique. The effect on phytohemagglutinin (PHA)-induced nitric oxide (NO) production in peripheral blood mononuclear cells (PBMCs) was also assessed. A battery of antioxidant assays were used for detecting antioxidant activity while the anti inflammatory mechanism was evaluated using an ELISA-based activator protein (AP 1) (c-Jun) assay. Cytotoxicity was determined on TZM-bl and PBMCs using a tetrazolium dye and confirmed by a novel label-free real-time assay. RESULTS: A 25 MUg/mL non-cytotoxic concentration of O. labiatum extract significantly (p < 0.05) inhibited the production of pro-inflammatory cytokines; IL-2, IL-4, IL-6 and IL-17A. Except for the dual acting pro- or anti-inflammatory cytokine, IL-6, which was upregulated, a non-cytotoxic 50 MUM concentration of the isolated labdane diterpenoid compound significantly (p < 0.05) decreased the production of all the pro-inflammatory cytokines. In the anti-inflammatory pathway studies, the compound also inhibited AP-1 significantly (p < 0.05) at 50 MUM. The extract demonstrated strong, dose dependent antioxidant activity with IC50 values ranging from 13 +/- 0.8 to 54.86 +/- 1.28 MUg/mL while the terpene had no antioxidant property. The extract and diterpenoid decreased the production of the inflammatory mediator NO, at non-cytotoxic concentrations. The CC50 of the extract in TZM-bl and PBMCs was 62.6 +/- 0.6 and 30.1 +/- 0.4 MUg/mL while that of the compound was 112.6 +/- 0.2 and 70 +/- 0.4 MUM respectively. The real time studies confirmed tetrazolium dye assessed viability and also detected a unique growth pattern for the plant materials compared to untreated cells. CONCLUSIONS: O. labiatum extract demonstrated promising anti-inflammatory and antioxidant properties while the terpenoid showed anti-inflammatory but no antioxidant activity. The anti-inflammatory mechanism of the terpene was a result of inhibition of AP-1. These data represents promising first steps towards the development of naturally derived anti-inflammation drugs. PMID- 25705128 TI - Effect of Sulforaphane on NOD2 via NF-kappaB: implications for Crohn's disease. AB - BACKGROUND: Sulforaphane has well established anti-cancer properties and more recently anti-inflammatory properties have also been determined. Sulforaphane has been shown to inhibit PRR-mediated pro-inflammatory signalling by either directly targeting the receptor or their downstream signalling molecules such as the transcription factor, NF-kappaB. These results raise the possibility that PRR mediated inflammation could be suppressed by specific dietary bioactives. We examined whether sulforaphane could suppress NF-kappaB via the NOD2 pathway. METHODS: Human embryonic kidney 293T (HEK293T) cells were stably transfected with NOD2 variants and the NF-kappaB reporter, pNifty2-SEAP. The cells were co-treated with sulforaphane and MDP and secreted alkaline phosphatase (SEAP) production was determined. RESULTS: We found that sulforaphane was able to significantly suppress the ligand-induced NF-kappaB activity at physiologically relevant concentrations, achievable via the consumption of broccoli within the diet. CONCLUSIONS: These results demonstrate that the anti-inflammatory role of sulforaphane is not restricted to LPS-induced inflammatory signalling. These data add to the growing evidence that PRR activation can be inhibited by specific phytochemicals and thus suggests that diet could be a way of controlling inflammation. This is particularly important for a disease like Crohn's disease where diet can play a key role in relieving or exacerbating symptoms. PMID- 25705129 TI - Inflammation contributes to NKX3.1 loss and augments DNA damage but does not alter the DNA damage response via increased SIRT1 expression. AB - The oxidative stress response is a cellular defense mechanism that protects cells from oxidative damage and cancer development. The exact molecular mechanism by which reactive oxygen species (ROS) contribute to DNA damage and increase genome instability in prostate cancer merits further investigation. Here, we aimed to determine the effects of NKX3.1 loss on antioxidant defense in response to acute and chronic inflammation in an in vitro model. Oxidative stress-induced DNA damage resulted in increased H2AX((S139)) phosphorylation (a hallmark of DNA damage), along with the degradation of the androgen receptor (AR), p53 and NKX3.1, upon treatment with conditioned medium (CM) obtained from activated macrophages or H2O2. Furthermore, the expression and stability of SIRT1 were increased by CM treatment but not by H2O2 treatment, although the level of ATM((S1981)) phosphorylation was not changed compared with controls. Moreover, the deregulated antioxidant response resulted in upregulation of the pro-oxidant QSCN6 and the antioxidant GPX2 and downregulation of the antioxidant GPX3 after CM treatment. Consistently, the intracellular ROS level increased after chronic treatment, leading to a dose-dependent increase in the ability of LNCaP cells to tolerate oxidative damage. These data suggest that the inflammatory microenvironment is a major factor contributing to DNA damage and the deregulation of the oxidative stress response, which may be the underlying cause of the increased genetic heterogeneity during prostate tumor progression. PMID- 25705131 TI - Examination of the skeletal proteome of the brittle star Ophiocoma wendtii reveals overall conservation of proteins but variation in spicule matrix proteins. AB - BACKGROUND: While formation of mineralized tissue is characteristic of many animal taxa, the proteins that interact with mineral are diverse and appear in many cases to be of independent origin. Extracellular matrix proteins involved in mineralization do share some common features. They tend to be disordered, secreted proteins with repetitive, low complexity. The genes encoding these proteins are often duplicated and undergo concerted evolution, further diversifying the repetitive domains. This makes it difficult to identify mineralization genes and the proteins they encode using bioinformatics techniques. Here we describe the use of proteomics to identify mineralization genes in an ophiuroid echinoderm, Ophiocoma wendtii (O. wendtii). RESULTS: We have isolated the occluded proteins within the mineralized tissue of the brittle star Ophiocoma wendtii. The proteins were analyzed both unfractionated and separated on SDS-PAGE gels. Each slice was analyzed using mass spectroscopy and the amino acid sequence of the most prevalent peptides was obtained. This was compared to both an embryonic transcriptome from the gastrula stage when skeleton is being formed and a tube foot (an adult mineralized tissue) transcriptome. Thirty eight proteins were identified which matched known proteins or protein domains in the NCBI databases. These include C-type lectins, ECM proteins, Kazal type protease inhibitors, matrix metalloproteases as well as more common cellular proteins. Many of these are similar to those found in the sea urchin Strongylocentrotus purpuratus (S. purpuratus) skeleton. We did not, however, identify clear homologs to the sea urchin spicule matrix proteins, and the number of C-type lectin containing genes was much reduced compared to sea urchins. Also notably absent was MSP-130. CONCLUSIONS: Our results show an overall conservation of the types of proteins found in the mineralized tissues of two divergent groups of echinoderms, as well as in mineralized tissues in general. However, the extensive gene duplication and concerted evolution seen in the spicule matrix proteins found in the sea urchin skeleton was not observed in the brittle star. PMID- 25705130 TI - Portrait of inflammatory response to ionizing radiation treatment. AB - Ionizing radiation (IR) activates both pro-and anti-proliferative signal pathways producing an imbalance in cell fate decision. IR is able to regulate several genes and factors involved in cell-cycle progression, survival and/or cell death, DNA repair and inflammation modulating an intracellular radiation-dependent response. Radiation therapy can modulate anti-tumour immune responses, modifying tumour and its microenvironment. In this review, we report how IR could stimulate inflammatory factors to affect cell fate via multiple pathways, describing their roles on gene expression regulation, fibrosis and invasive processes. Understanding the complex relationship between IR, inflammation and immune responses in cancer, opens up new avenues for radiation research and therapy in order to optimize and personalize radiation therapy treatment for each patient. PMID- 25705132 TI - Cognitive conflict links behavioral inhibition and social problem solving during social exclusion in childhood. AB - Behavioral inhibition (BI) is a temperament characterized by heightened negative affect and social reticence to unfamiliar peers. In a longitudinal study, 291 infants were assessed for BI at 24 and 36 months of age. At age 7, N2 amplitude was measured during a Flanker task. Also at age 7, children experienced social exclusion in the lab during an interaction with an unfamiliar peer and an experimenter. Our findings indicate that children characterized as high in BI, relative to those low in BI, had larger (i.e., more negative) N2 amplitudes. Additionally, among children with a large N2, BI was positively related to withdrawal and negatively related to assertiveness during social exclusion. These findings suggest that variations in conflict detection among behaviorally inhibited children plays a role in their social behavior during stressful social situations. PMID- 25705133 TI - College Men and Alcohol Use: Positive Alcohol Expectancies as a Mediator Between Distinct Masculine Norms and Alcohol Use. AB - College men are more likely to engage in health-compromising behaviors including risky drinking behavior, and experience more alcohol-related problems, including violence and arrest, as compared to women. The study of masculine norms or societal expectations, defined as beliefs and values about what it means to be a man, is one promising area of investigation that may help explain within-group differences and differential rates of alcohol use among men. Using the gender social learning model, we investigated the role of positive alcohol expectancies as an underlying mediator between masculine norms and alcohol use among college men. Data from 804 college adult men (Mean age = 20.43) were collected through a web-based assessment. Participants completed a self-report measure of binge drinking, frequency of drinking, quantity of drinks, conformity to masculine norms, and positive alcohol expectancies measures. Structural equation modeling was used to examine relations between masculine norms, alcohol expectancies and alcohol use. The masculine norms of "Playboy" and Risk-Taking were positively related to heavy alcohol use, while Emotional Control and Heterosexual Presentation were both negatively associated with alcohol use, after controlling for fraternity Greek status and positive expectancies. Playboy and Winning norms were positively associated with positive expectancies while Power Over Women was inversely related to positive expectancies which, in turn, were associated with heavier alcohol use. This study was a novel exploration into the multiple pathways and mediators through which positive alcohol expectancies may help explain and provide specificity to the masculinity and alcohol use relationship among college men. PMID- 25705135 TI - Embracing the Future as Stewards of the Past: Charting a Course Forward for Historical Medical Libraries and Archives. PMID- 25705134 TI - Anger and Approach Motivation in Infancy: Relations to Early Childhood Inhibitory Control and Behavior Problems. AB - The relations among infant anger reactivity, approach behavior, and frontal EEG asymmetry, and their relations to inhibitory control and behavior problems in early childhood were examined within the context of a longitudinal study of temperament. Two hundred and nine infants' anger expressions to arm restraint were observed at 4 months of age. Infants' approach behaviors during play with an unpredictable toy and baseline frontal electroencephalogram (EEG) asymmetry were assessed at 9 months of age. Inhibitory control during a Go/No-Go task and parent report of behavior problems were evaluated at 4 years of age. High anger-prone infants with left, but not right, frontal EEG asymmetry showed significantly more approach behaviors and less inhibitory control relative to less anger-prone infants. Although a link between anger proneness in infancy and behavior problems in early childhood was not found, a combination of low approach behaviors and poor inhibitory control was predictive of internalizing behaviors. PMID- 25705136 TI - A TSVD Analysis of the Impact of Polarization on Microwave Breast Imaging using an Enclosed Array of Miniaturized Patch Antennas. AB - Microwave breast imaging performance is fundamentally dependent on the quality of information contained within the scattering data. We apply a truncated singular value decomposition (TSVD) method to evaluate the information contained in a simulated scattering scenario wherein a compact, shielded array of miniaturized patch antennas surrounds an anatomically realistic numerical breast phantom. In particular, we investigate the impact of different antenna orientations (and thus polarizations), namely two array configurations with uniform antenna orientations and one mixed-orientation array configuration. The latter case is of interest because it may offer greater flexibility in antenna and array design. The results of this analysis indicate that mixed-polarization configurations do not degrade information quality compared to uniform-polarization configurations and in fact may enhance imaging performance, and thus represent viable design options for microwave breast imaging systems. PMID- 25705137 TI - Scene-Motion Thresholds During Head Yaw for Immersive Virtual Environments. AB - In order to better understand how scene motion is perceived in immersive virtual environments, we measured scene-motion thresholds under different conditions across three experiments. Thresholds were measured during quasi-sinusoidal head yaw, single left-to-right or right-to-left head yaw, different phases of head yaw, slow to fast head yaw, scene motion relative to head yaw, and two scene illumination levels. We found that across various conditions 1) thresholds are greater when the scene moves with head yaw (corresponding to gain < 1:0) than when the scene moves against head yaw (corresponding to gain > 1:0), and 2) thresholds increase as head motion increases. PMID- 25705138 TI - Health related quality of life measure in systemic pediatric rheumatic diseases and its translation to different languages: an international collaboration. AB - BACKGROUND: Rheumatic diseases in children are associated with significant morbidity and poor health-related quality of life (HRQOL). There is no health related quality of life (HRQOL) scale available specifically for children with less common rheumatic diseases. These diseases share several features with systemic lupus erythematosus (SLE) such as their chronic episodic nature, multi systemic involvement, and the need for immunosuppressive medications. HRQOL scale developed for pediatric SLE will likely be applicable to children with systemic inflammatory diseases. FINDINGS: We adapted Simple Measure of Impact of Lupus Erythematosus in Youngsters (SMILEY(c)) to Simple Measure of Impact of Illness in Youngsters (SMILY(c)-Illness) and had it reviewed by pediatric rheumatologists for its appropriateness and cultural suitability. We tested SMILY(c)-Illness in patients with inflammatory rheumatic diseases and then translated it into 28 languages. Nineteen children (79% female, n=15) and 17 parents participated. The mean age was 12+/-4 years, with median disease duration of 21 months (1-172 months). We translated SMILY(c)-Illness into the following 28 languages: Danish, Dutch, French (France), English (UK), German (Germany), German (Austria), German (Switzerland), Hebrew, Italian, Portuguese (Brazil), Slovene, Spanish (USA and Puerto Rico), Spanish (Spain), Spanish (Argentina), Spanish (Mexico), Spanish (Venezuela), Turkish, Afrikaans, Arabic (Saudi Arabia), Arabic (Egypt), Czech, Greek, Hindi, Hungarian, Japanese, Romanian, Serbian and Xhosa. CONCLUSION: SMILY(c)-Illness is a brief, easy to administer and score HRQOL scale for children with systemic rheumatic diseases. It is suitable for use across different age groups and literacy levels. SMILY(c)-Illness with its available translations may be used as useful adjuncts to clinical practice and research. PMID- 25705139 TI - Endothelial progenitor cell levels in juvenile idiopathic arthritis patients: effects of anti-inflammatory therapies. AB - BACKGROUND: Juvenile idiopathic arthritis (JIA), similarly to other arthritides, can be associated with damage of endothelial layer of which structure and function is dependent on reparative properties of endothelial progenitor cells (EPC). To date, it remained unknown whether EPC numbers are altered in young JIA patients and whether on-going anti-inflammatory therapies could exert positive effects on these progenitor cells. METHODS: We performed a quantitative analysis of EPC numbers in 25 patients diagnosed with JIA according to International League of Associations for Rheumatism (ILAR) criteria [age 11.50 (7.50-15.00) years] in a broad context of inflammatory and cardiovascular parameters as well as different types of anti-inflammatory treatments. 11 healthy children [age 13.00 (11.00-14.00) years] were recruited as a control group. RESULTS: We demonstrated that EPC numbers were similar in JIA patients and control subjects (0.02% vs. 0.05%, respectively, p = 0.37). EPC levels in JIA patients were negatively correlated with index of insulin resistance (rho = -0.458, p = 0.021), endogenous insulin (rho = -0.472, p = 0.017), triglyceride (rho = -0.438, p = 0.029) and TNF-alpha levels (rho = -0.446, p = 0.026). Notably, glucocorticoid (GC) therapy, was associated with detection of decreased EPC levels in JIA patients (p = 0.023). In contrast, methothrexate (MTX) and etanercept therapy in JIA patients did not affect EPC levels (p = 0.92 and p = 0.08, respectively). CONCLUSIONS: We found that EPC numbers are maintained at normal levels in JIA patients and are not enhanced by disease-specific anti-inflammatory treatments. PMID- 25705140 TI - Conformational sampling of oligosaccharides using Hamiltonian replica exchange with two-dimensional dihedral biasing potentials and the weighted histogram analysis method (WHAM). AB - Oligosaccharides and polysaccharides exert numerous functional roles in biology through their structural diversity and conformational properties. To investigate their conformational properties using computational methods, Hamiltonian replica exchange (H-REX) combined with two-dimensional grid-based correction maps as biasing potentials (bpCMAP) significantly improves the sampling efficiency about glycosidic linkages. In the current study, we extend the application of H-REX with bpCMAP to complex saccharides and establish systematic procedures for bpCMAP construction, determination of replica distribution, and data analysis. Our main findings are that (1) the bpCMAP for each type of glycosidic linkage can be constructed from the corresponding disaccharide using gas-phase umbrella sampling simulations, (2) the replica distribution can be conveniently determined following the exact definition of the average acceptance ratio based on the assigned distribution of biasing potentials, and (3) the extracted free energy surface (or potential of mean force (PMF)) can be improved using the weighted histogram analysis method (WHAM) allowing for the inclusion of data from the excited state replicas in the calculated probability distribution. The method is applied to a branched N-glycan found on the HIV gp120 protein, and a linear N glycan. Considering the general importance of N-glycans and the wide appreciation of the sampling problem, the present method represents an efficient procedure for the conformational sampling of complex oligo- and polysaccharides under explicit solvent conditions. More generally, the use of WHAM is anticipated to be of general utility for the calculation of PMFs from H-REX simulations in a wide range of macromolecular systems. PMID- 25705141 TI - Empowering Promotores de Salud to engage in Community-Based Participatory Research. AB - BACKGROUND: Latino immigrants are less likely to be involved in addressing health related issues affecting their own community. Community health workers have played a significant role in addressing the health of underserved communities in several countries. OBJECTIVE: The objective of this article is to describe the development, implementation and evaluation of a community-based training program that empowers promotores to identify the health needs of recent Latino immigrants. Promotores were able to develop interventions based on the needs of recent Latino immigrants. METHODS: Latino community members participated in a 30 hour training program. Training was provided in 15 two-hour sessions over 3 months. Training included field work accompanied by skills development in leadership, organization, interpersonal communication, and survey implementation. Upon completion of the training, promotores conducted household surveys designed to identify community health needs. The evaluation employed quantitative measures to track promotores' canvassing activities and assessment of health behaviors. RESULTS: Out of the 22 promotores enrolled in the training program, 15 (68.18%) completed the training program. Within 3 months, promotores administered 105 household surveys and identified poor access to health care, lack of insurance (78.6%), low daily consumption of fruits (73%) and vegetables (37.5%) and frequent exposure to tobacco smoke (31.7%). CONCLUSION: Our study demonstrated the feasibility of recruiting and engaging promotores to identify health priorities within the Latino community. This initial step will inform the development of future community-based interventions. PMID- 25705142 TI - Novel synthesis method of micronized ti-zeolite na-a and cytotoxic activity of its silver exchanged form. AB - The core-shell method is used as a novel synthetic process of micronized Ti Zeolite Na-A which involves calcination at 700 degrees C of coated Egyptian Kaolin with titanium tetrachloride in acidic medium as the first step. The produced Ti-coated metakaolinite is subjected to microwave irradiation at low temperature of 80 degrees C for 2 h. The prepared micronized Ti-containing Zeolites-A (Ti-Z-A) is characterized by FTIR, XRF, XRD, SEM, and EDS elemental analysis. Ag-exchanged form of Ti-Z-Ag is also prepared and characterized. The Wt% of silver exchanged onto the Ti-Zeolite structure was determined by atomic absorption spectra. The in vitro cytotoxic activity of Ti-Z-Ag against human hepatocellular carcinoma cell line (HePG2), colon cell line carcinoma (HCT116), lung carcinoma cell line (A549), and human Caucasian breast adenocarcinoma (MCF7) is reported. The results were promising and revealed that the exchanged Ag form of micronized Ti-Zeolite-A can be used as novel antitumor drug. PMID- 25705144 TI - DNA electrochemical biosensor for metallic drugs at physiological conditions. AB - Entrapment of dsSS-DNA into the polypyrrole-polyvinyl sulphonate (dsSS-DNA-PPy PVS) film over indium-tin-oxide (ITO) coated glass has been designed to detect titanium and platinum drugs, titanocene dichloride and cisplatin. The disposable dsSS-DNA-PPy-PVS/ITO biosensor was characterized by cyclic voltammetry, attenuated total reflectance Infrared spectroscopy and atomic force microscopy. Amperometric studies by cyclic voltammetry using, dsSS-DNA-PPy PVS/ITO biosensor, demonstrated the ability of this biosensor to detect these metallic drugs in millimolar concentration by monitoring the decrease of the guanine oxidation signal as a result of the DNA damage. The concentration range detected for titanocene dichloride is 0.25 to 1.5 mM and for cisplatin is 0.06 to 1.0 mM. PMID- 25705143 TI - Analysis of Glycosaminoglycans Using Mass Spectrometry. AB - The glycosaminoglycans (GAGs) are linear polysaccharides expressed on animal cell surfaces and in extracellular matrices. Their biosynthesis is under complex control and confers a domain structure that is essential to their ability to bind to protein partners. Key to understanding the functions of GAGs are methods to determine accurately and rapidly patterns of sulfation, acetylation and uronic acid epimerization that correlate with protein binding or other biological activities. Mass spectrometry (MS) is particularly suitable for the analysis of GAGs for biomedical purposes. Using modern ionization techniques it is possible to accurately determine molecular weights of GAG oligosaccharides and their distributions within a mixture. Methods for direct interfacing with liquid chromatography have been developed to permit online mass spectrometric analysis of GAGs. New tandem mass spectrometric methods for fine structure determination of GAGs are emerging. This review summarizes MS-based approaches for analysis of GAGs, including tissue extraction and chromatographic methods compatible with LC/MS and tandem MS. PMID- 25705145 TI - Integration of untargeted metabolomics with transcriptomics reveals active metabolic pathways. AB - While recent advances in metabolomic measurement technologies have been dramatic, extracting biological insight from complex metabolite profiles remains a challenge. We present an analytical strategy that uses data obtained from high resolution liquid chromatography-mass spectrometry and a bioinformatics toolset for detecting actively changing metabolic pathways upon external perturbation. We begin with untargeted metabolite profiling to nominate altered metabolites and identify pathway candidates, followed by validation of those pathways with transcriptomics. Using the model organisms Rhodospirillum rubrum and Bacillus subtilis, our results reveal metabolic pathways that are interconnected with methionine salvage. The rubrum-type methionine salvage pathway is interconnected with the active methyl cycle in which re-methylation, a key reaction for recycling methionine from homocysteine, is unexpectedly suppressed; instead, homocysteine is catabolized by the transsulfuration pathway. Notably, the non mevalonate pathway is repressed, whereas the rubrum-type methionine salvage pathway contributes to isoprenoid biosynthesis upon 5'-methylthioadenosine feeding. In this process, glutathione functions as a coenzyme in vivo when 1 methylthio-d-xylulose 5-phosphate (MTXu 5-P) methylsulfurylase catalyzes dethiomethylation of MTXu 5-P. These results clearly show that our analytical approach enables unexpected metabolic pathways to be uncovered. PMID- 25705146 TI - Biological and Clinical Implications of Clonal Heterogeneity and Clonal Evolution in Multiple Myeloma. AB - Clonal heterogeneity and clonal evolution have emerged as critical concepts in the field of oncology over the past four decades, largely thanks to the implementation of novel technologies such as comparative genomic hybridization, whole genome/exome sequencing and epigenetic analysis. Along with the identification of cancer stem cells in the majority of neoplasia, the recognition of intertumor and intratumor variability has provided a novel perspective to understand the mechanisms behind tumor evolution and its implication in terms of treatment failure and cancer relapse or recurrence. First hypothesized over two decades ago, clonal heterogeneity and clonal evolution have been confirmed in multiple myeloma (MM), an incurable cancer of plasma cells, almost universally preceded by a pre-malignant conditioned named monoclonal gammopathy of undetermined significance (MGUS). The genetic events and molecular mechanisms underlying such evolution have been difficult to dissect. Moreover, while a role for the bone marrow microenvironment in supporting MM cell survival, proliferation and drug-resistance has been well established, whether it is directly involved in driving evolution from MGUS to MM is at present unclear. We present in this review a historical excursus on the concepts of clonal heterogeneity and clonal evolution in MM with a special emphasis on their role in the progression from MGUS to MM; the contribution of the microenvironment; and the clinical implications in terms of resistance to treatment and disease relapse/recurrence. PMID- 25705147 TI - Characterization of microbial communities in heavy crude oil from Saudi Arabia. AB - The complete mineralization of crude oil into carbon dioxide, water, inorganic compounds and cellular constituents can be carried out as part of a bioremediation strategy. This involves the transformation of complex organic contaminants into simpler organic compounds by microbial communities, mainly bacteria. A crude oil sample and an oil sludge sample were obtained from Saudi ARAMCO Oil Company and investigated to identify the microbial communities present using PCR-based culture-independent techniques. In total, analysis of 177 clones yielded 30 distinct bacterial sequences. Clone library analysis of the oil sample was found to contain Bacillus, Clostridia and Gammaproteobacteria species while the sludge sample revealed the presence of members of the Alphaproteobacteria, Betaproteobacteria, Gammaproteobacteria, Clostridia, Spingobacteria and Flavobacteria. The dominant bacterial class identified in oil and sludge samples was found to be Bacilli and Flavobacteria, respectively. Phylogenetic analysis showed that the dominant bacterium in the oil sample has the closest sequence identity to Enterococcus aquimarinus and the dominant bacterium in the sludge sample is most closely related to the uncultured Bacteroidetes bacterium designated AH.KK. PMID- 25705148 TI - Influence of long-term fertilization on soil microbial biomass, dehydrogenase activity, and bacterial and fungal community structure in a brown soil of northeast China. AB - In this study, the effect of mineral fertilizer and organic manure were evaluated on soil microbial biomass, dehydrogenase activity, bacterial and fungal community structure in a long-term (33 years) field experiment. Except for the mineral nitrogen fertilizer (N) treatment, long-term fertilization greatly increased soil microbial biomass carbon (SMBC) and dehydrogenase activity. Organic manure had a significantly greater impact on SMBC and dehydrogenase activity, compared with mineral fertilizers. Bacterial and fungal community structure was analyzed by polymerase chain reaction (PCR)-denaturing gradient gel electrophoresis (DGGE). Long-term fertilization increased bacterial and fungal ribotype diversity. Total soil nitrogen (TN) and phosphorus (TP), soil organic carbon (SOC) and available phosphorus (AP) had a similar level of influence on bacterial ribotypes while TN, SOC and AP had a larger influence than alkali-hydrolyzable nitrogen (AHN) on fungal ribotypes. Our results suggested that long-term P-deficiency fertilization can significantly decrease soil microbial biomass, dehydrogenase activity and bacterial diversity. N-fertilizer and SOC have an important influence on bacterial and fungal communities. PMID- 25705149 TI - Editor's Introduction to This Issue. PMID- 25705150 TI - Genome architecture and its roles in human copy number variation. AB - Besides single-nucleotide variants in the human genome, large-scale genomic variants, such as copy number variations (CNVs), are being increasingly discovered as a genetic source of human diversity and the pathogenic factors of diseases. Recent experimental findings have shed light on the links between different genome architectures and CNV mutagenesis. In this review, we summarize various genomic features and discuss their contributions to CNV formation. Genomic repeats, including both low-copy and high-copy repeats, play important roles in CNV instability, which was initially known as DNA recombination events. Furthermore, it has been found that human genomic repeats can also induce DNA replication errors and consequently result in CNV mutations. Some recent studies showed that DNA replication timing, which reflects the high-order information of genomic organization, is involved in human CNV mutations. Our review highlights that genome architecture, from DNA sequence to high-order genomic organization, is an important molecular factor in CNV mutagenesis and human genomic instability. PMID- 25705151 TI - A review of three different studies on hidden markov models for epigenetic problems: a computational perspective. AB - Recent technical advances, such as chromatin immunoprecipitation combined with DNA microarrays (ChIp-chip) and chromatin immunoprecipitation-sequencing (ChIP seq), have generated large quantities of high-throughput data. Considering that epigenomic datasets are arranged over chromosomes, their analysis must account for spatial or temporal characteristics. In that sense, simple clustering or classification methodologies are inadequate for the analysis of multi-track ChIP chip or ChIP-seq data. Approaches that are based on hidden Markov models (HMMs) can integrate dependencies between directly adjacent measurements in the genome. Here, we review three HMM-based studies that have contributed to epigenetic research, from a computational perspective. We also give a brief tutorial on HMM modelling-targeted at bioinformaticians who are new to the field. PMID- 25705152 TI - Reflections on the US FDA's Warning on Direct-to-Consumer Genetic Testing. AB - In November 2013, the US Food and Drug Administration (FDA) sent a warning letter to 23andMe, Inc. and ordered the company to discontinue marketing of the 23andMe Personal Genome Service (PGS) until it receives FDA marketing authorization for the device. The FDA considers the PGS as an unclassified medical device, which requires premarket approval or de novo classification. Opponents of the FDA's action expressed their concerns, saying that the FDA is overcautious and paternalistic, which violates consumers' rights and might stifle the consumer genomics field itself, and insisted that the agency should not restrict direct-to consumer (DTC) genomic testing without empirical evidence of harm. Proponents support the agency's action as protection of consumers from potentially invalid and almost useless information. This action was also significant, since it reflected the FDA's attitude towards medical application of next-generation sequencing techniques. In this review, we followed up on the FDA-23andMe incident and evaluated the problems and prospects for DTC genetic testing. PMID- 25705153 TI - Review on molecular and chemopreventive potential of nimbolide in cancer. AB - Cancer is the most dreaded disease in human and also major health problem worldwide. Despite its high occurrence, the exact molecular mechanisms of the development and progression are not fully understood. The existing cancer therapy based on allopathic medicine is expensive, exhibits side effects; and may also alter the normal functioning of genes. Thus, a non-toxic and effective mode of treatment is needed to control cancer development and progression. Some medicinal plants offer a safe, effective and affordable remedy to control the cancer progression. Nimbolide, a limnoid derived from the neem (Azadirachta indica) leaves and flowers of neem, is widely used in traditional medical practices for treating various human diseases. Nimbolide exhibits several pharmacological effects among which its anticancer activity is the most promising. The previous studies carried out over the decades have shown that nimbolide inhibits cell proliferation and metastasis of cancer cells. This review highlights the current knowledge on the molecular targets that contribute to the observed anticancer activity of nimbolide related to induction of apoptosis and cell cycle arrest; and inhibition of signaling pathways related to cancer progression. PMID- 25705154 TI - Short reads phasing to construct haplotypes in genomic regions that are associated with body mass index in korean individuals. AB - Genome-wide association (GWA) studies have found many important genetic variants that affect various traits. Since these studies are useful to investigate untyped but causal variants using linkage disequilibrium (LD), it would be useful to explore the haplotypes of single-nucleotide polymorphisms (SNPs) within the same LD block of significant associations based on high-density variants from population references. Here, we tried to make a haplotype catalog affecting body mass index (BMI) through an integrative analysis of previously published whole genome next-generation sequencing (NGS) data of 7 representative Korean individuals and previously known Korean GWA signals. We selected 435 SNPs that were significantly associated with BMI from the GWA analysis and searched 53 LD ranges nearby those SNPs. With the NGS data, the haplotypes were phased within the LDs. A total of 44 possible haplotype blocks for Korean BMI were cataloged. Although the current result constitutes little data, this study provides new insights that may help to identify important haplotypes for traits and low variants nearby significant SNPs. Furthermore, we can build a more comprehensive catalog as a larger dataset becomes available. PMID- 25705155 TI - In silico Identification of SFRP1 as a Hypermethylated Gene in Colorectal Cancers. AB - Aberrant DNA methylation, as an epigenetic marker of cancer, influences tumor development and progression. We downloaded publicly available DNA methylation and gene expression datasets of matched cancer and normal pairs from the Cancer Genome Atlas Data Portal and performed a systematic computational analysis. This study has three aims to screen genes that show hypermethylation and downregulated patterns in colorectal cancers, to identify differentially methylated regions in one of these genes, SFRP1, and to test whether the SFRP genes affect survival or not. Our results show that 31 hypermethylated genes had a negative correlation with gene expression. Among them, SFRP1 had a differentially methylated pattern at each methylation site. We also show that SFRP1 may be a potential biomarker for colorectal cancer survival. PMID- 25705156 TI - Understanding Epistatic Interactions between Genes Targeted by Non-coding Regulatory Elements in Complex Diseases. AB - Genome-wide association studies have proven the highly polygenic architecture of complex diseases or traits; therefore, single-locus-based methods are usually unable to detect all involved loci, especially when individual loci exert small effects. Moreover, the majority of associated single-nucleotide polymorphisms resides in non-coding regions, making it difficult to understand their phenotypic contribution. In this work, we studied epistatic interactions associated with three common diseases using Korea Association Resource (KARE) data: type 2 diabetes mellitus (DM), hypertension (HT), and coronary artery disease (CAD). We showed that epistatic single-nucleotide polymorphisms (SNPs) were enriched in enhancers, as well as in DNase I footprints (the Encyclopedia of DNA Elements [ENCODE] Project Consortium 2012), which suggested that the disruption of the regulatory regions where transcription factors bind may be involved in the disease mechanism. Accordingly, to identify the genes affected by the SNPs, we employed whole-genome multiple-cell-type enhancer data which discovered using DNase I profiles and Cap Analysis Gene Expression (CAGE). Assigned genes were significantly enriched in known disease associated gene sets, which were explored based on the literature, suggesting that this approach is useful for detecting relevant affected genes. In our knowledge-based epistatic network, the three diseases share many associated genes and are also closely related with each other through many epistatic interactions. These findings elucidate the genetic basis of the close relationship between DM, HT, and CAD. PMID- 25705157 TI - Genome-wide association study of metabolic syndrome in koreans. AB - Metabolic syndrome (METS) is a disorder of energy utilization and storage and increases the risk of developing cardiovascular disease and diabetes. To identify the genetic risk factors of METS, we carried out a genome-wide association study (GWAS) for 2,657 cases and 5,917 controls in Korean populations. As a result, we could identify 2 single nucleotide polymorphisms (SNPs) with genome-wide significance level p-values (<5 * 10(-8)), 8 SNPs with genome-wide suggestive p values (5 * 10(-8) <= p < 1 * 10(-5)), and 2 SNPs of more functional variants with borderline p-values (5 * 10(-5) <= p < 1 * 10(-4)). On the other hand, the multiple correction criteria of conventional GWASs exclude false-positive loci, but simultaneously, they discard many true-positive loci. To reconsider the discarded true-positive loci, we attempted to include the functional variants (nonsynonymous SNPs [nsSNPs] and expression quantitative trait loci [eQTL]) among the top 5,000 SNPs based on the proportion of phenotypic variance explained by genotypic variance. In total, 159 eQTLs and 18 nsSNPs were presented in the top 5,000 SNPs. Although they should be replicated in other independent populations, 6 eQTLs and 2 nsSNP loci were located in the molecular pathways of LPL, APOA5, and CHRM2, which were the significant or suggestive loci in the METS GWAS. Conclusively, our approach using the conventional GWAS, reconsidering functional variants and pathway-based interpretation, suggests a useful method to understand the GWAS results of complex traits and can be expanded in other genomewide association studies. PMID- 25705158 TI - Pathway Analysis of Metabolic Syndrome Using a Genome-Wide Association Study of Korea Associated Resource (KARE) Cohorts. AB - Metabolic syndrome (MetS) is a complex disorder related to insulin resistance, obesity, and inflammation. Genetic and environmental factors also contribute to the development of MetS, and through genome-wide association studies (GWASs), important susceptibility loci have been identified. However, GWASs focus more on individual single-nucleotide polymorphisms (SNPs), explaining only a small portion of genetic heritability. To overcome this limitation, pathway analyses are being applied to GWAS datasets. The aim of this study is to elucidate the biological pathways involved in the pathogenesis of MetS through pathway analysis. Cohort data from the Korea Associated Resource (KARE) was used for analysis, which include 8,842 individuals (age, 52.2 +/- 8.9 years; body mass index, 24.6 +/- 3.2 kg/m(2)). A total of 312,121 autosomal SNPs were obtained after quality control. Pathway analysis was conducted using Meta-analysis Gene Set Enrichment of Variant Associations (MAGENTA) to discover the biological pathways associated with MetS. In the discovery phase, SNPs from chromosome 12, including rs11066280, rs2074356, and rs12229654, were associated with MetS (p < 5 * 10(-6)), and rs11066280 satisfied the Bonferroni-corrected cutoff (unadjusted p < 1.38 * 10(-7), Bonferroni-adjusted p < 0.05). Through pathway analysis, biological pathways, including electron carrier activity, signaling by platelet derived growth factor (PDGF), the mitogen-activated protein kinase kinase kinase cascade, PDGF binding, peroxisome proliferator-activated receptor (PPAR) signaling, and DNA repair, were associated with MetS. Through pathway analysis of MetS, pathways related with PDGF, mitogen-activated protein kinase, and PPAR signaling, as well as nucleic acid binding, protein secretion, and DNA repair, were identified. Further studies will be needed to clarify the genetic pathogenesis leading to MetS. PMID- 25705159 TI - Genome-wide association study of hepatitis in korean populations. AB - Hepatitis is a common and serious disease for the Korean population. It is caused by a virus, the A and B types of which are plentiful in Koreans. In this study, we tried to find genetic factors for hepatitis through genome-wide association studies. We took 368 cases and 1,500 controls from Anseong and Ansan cohort data. About 300,000 single-nucleotide polymorphisms and 20 epidemiological variables were analyzed. We did not find any meaningful significant single nucleotide polymorphisms, but we confirmed the influence of major epidemiological variables on hepatitis. PMID- 25705160 TI - Effective population size of korean populations. AB - Recently, new methods have been developed for estimating the current and recent changes in effective population sizes. Based on the methods, the effective population sizes of Korean populations were estimated using data from the Korean Association Resource (KARE) project. The overall changes in the population sizes of the total populations were similar to CHB (Han Chinese in Beijing, China) and JPT (Japanese in Tokyo, Japan) of the HapMap project. There were no differences in past changes in population sizes with a comparison between an urban area and a rural area. Age-dependent current and recent effective population sizes represent the modern history of Korean populations, including the effects of World War II, the Korean War, and urbanization. The oldest age group showed that the population growth of Koreans had already been substantial at least since the end of the 19th century. PMID- 25705161 TI - Relevance Epistasis Network of Gastritis for Intra-chromosomes in the Korea Associated Resource (KARE) Cohort Study. AB - Gastritis is a common but a serious disease with a potential risk of developing carcinoma. Helicobacter pylori infection is reported as the most common cause of gastritis, but other genetic and genomic factors exist, especially single nucleotide polymorphisms (SNPs). Association studies between SNPs and gastritis disease are important, but results on epistatic interactions from multiple SNPs are rarely found in previous genome-wide association (GWA) studies. In this study, we performed computational GWA case-control studies for gastritis in Korea Associated Resource (KARE) data. By transforming the resulting SNP epistasis network into a gene-gene epistasis network, we also identified potential gene gene interaction factors that affect the susceptibility to gastritis. PMID- 25705162 TI - Genome-wide association study identifies candidate Loci associated with platelet count in koreans. AB - Platelets are derived from the fragments that are formed from the cytoplasm of bone marrow megakaryocytes-small irregularly shaped anuclear cells. Platelets respond to vascular damage, contracts blood vessels, and attaches to the damaged region, thereby stopping bleeding, together with the action of blood coagulation factors. Platelet activation is known to affect genes associated with vascular risk factors, as well as with arteriosclerosis and myocardial infarction. Here, we performed a genome-wide association study with 352,228 single-nucleotide polymorphisms typed in 8,842 subjects of the Korea Association Resource (KARE) project and replicated the results in 7,861 subjects from an independent population. We identified genetic associations between platelet count and common variants nearby chromosome 4p16.1 (p = 1.46 * 10(-10), in the KIAA0232 gene), 6p21 (p = 1.36 * 10(-7), in the BAK1 gene), and 12q24.12 (p = 1.11 * 10(-15), in the SH2B3 gene). Our results illustrate the value of large-scale discovery and a focus for several novel research avenues. PMID- 25705163 TI - The ABCG2 Polymorphism rs2725220 Is Associated with Hyperuricemia in the Korean Population. AB - Elevated serum uric acid levels are associated with a variety of adverse health outcomes, including gout, hypertension, diabetes mellitus, metabolic syndrome, and cardiovascular diseases. Several genome-wide association studies on uric acid levels have implicated the ATP-binding cassette, subfamily G, member 2 (ABCG2) gene as being possibly causal. We investigated an association between the single nucleotide polymorphism (SNP) rs2725220 in the ABCG2 gene and uric acid levels in the Korean population. A total of 991 subjects in Seoul City were used for a replication study with ABCG2 SNP rs2725220. The rs2725220 SNP in the ABCG2 gene was associated with mean uric acid levels (effect per allele 0.25 mg/dL, p < 0.0001). Subjects with the GC/CC genotype had a 1.78-fold (range, 1.22- to 2.62 fold) higher risk of having abnormal uric acid levels (>=7.0 mg/dL) than subjects with the GG genotype. When analyzed by gender, the association with ABCG2 was stronger in men than in women. The association with ABCG2 was much stronger in male subjects with body mass index (BMI) >= 26.4 (odds ratio, 5.09; 95% confidence interval, 2.41 to 10.8) than in male subjects with BMI < 26.4. This study clearly demonstrates that genetic variations in ABCG2 influence uric acid levels in Korean adults. PMID- 25705164 TI - Replication of Interactions between Genome-Wide Genetic Variants and Body Mass Index in Fasting Glucose and Insulin Levels. AB - The genetic regulation of glucose and insulin levels might be modified by adiposity. With regard to the genetic factors that are altered by adiposity, a large meta-analysis on the interactions between genetic variants and body mass index with regard to fasting glucose and insulin levels was reported by the Meta Analyses of Glucose- and Insulin-related trait Consortium (MAGIC), based on European ancestry. Because no replication study has been performed in other ethnic groups, we first examined the link between reported single-nucleotide polymorphisms (SNPs) and fasting glucose and insulin levels in a large Korean cohort (Korean Genome and Epidemiology Study cohort [KoGES], n = 5,814). The MAGIC study reported 7 novel SNPs for fasting glucose levels and 6 novel SNPs for fasting insulin levels. In this study, we attempted to replicate the association of 5 SNPs with fasting glucose levels and 5 SNPs with fasting insulin levels. One SNP (rs2293941) in PDX1 was identified as a significant obesity-modifiable factor in Koreans. Our results indicate that the novel loci that were identified by MAGIC are poorly replicated in other ethnic groups, although we do not know why. PMID- 25705165 TI - Identification and Functional Characterization of P159L Mutation in HNF1B in a Family with Maturity-Onset Diabetes of the Young 5 (MODY5). AB - Mutation in HNF1B, the hepatocyte nuclear factor-1beta (HNF-1beta) gene, results in maturity-onset diabetes of the young (MODY) 5, which is characterized by gradual impairment of insulin secretion. However, the functional role of HNF 1beta in insulin secretion and glucose metabolism is not fully understood. We identified a family with early-onset diabetes that fulfilled the criteria of MODY. Sanger sequencing revealed that a heterozygous P159L (CCT to CTT in codon 159 in the DNA-binding domain) mutation in HNF1B was segregated according to the affected status. To investigate the functional consequences of this HNF1B mutation, we generated a P159L HNF1B construct. The wild-type and mutant HNF1B constructs were transfected into COS-7 cells in the presence of the promoter sequence of human glucose transporter type 2 (GLUT2). The luciferase reporter assay revealed that P159L HNF1B had decreased transcriptional activity compared to wild-type (p < 0.05). Electrophoretic mobility shift assay showed reduced DNA binding activity of P159L HNF1B. In the MIN6 pancreatic beta-cell line, overexpression of the P159L mutant was significantly associated with decreased mRNA levels of GLUT2 compared to wild-type (p < 0.05). However, INS expression was not different between the wild-type and mutant HNF1B constructs. These findings suggests that the impaired insulin secretion in this family with the P159L HNF1B mutation may be related to altered GLUT2 expression in beta-cells rather than decreased insulin gene expression. In conclusion, we have identified a Korean family with an HNF1B mutation and characterized its effect on the pathogenesis of diabetes. PMID- 25705166 TI - Analysis of gene expression in cyclooxygenase-2-overexpressed human osteosarcoma cell lines. AB - Osteosarcoma is the most common primary bone tumor, generally affecting young people. While the etiology of osteosarcoma has been largely unknown, recent studies have suggested that cyclooxygenase-2 (COX-2) plays a critical role in the proliferation, migration, and invasion of osteosarcoma cells. To understand the mechanism of action of COX-2 in the pathogenesis of osteosarcoma, we compared gene expression patterns between three stable COX-2-overexpressing cell lines and three control cell lines derived from U2OS human osteosarcoma cells. The data showed that 56 genes were upregulated, whereas 20 genes were downregulated, in COX-2-overexpressed cell lines, with an average fold-change > 1.5. Among the upregulated genes, COL1A1, COL5A2, FBN1, HOXD10, RUNX2, and TRAPPC2are involved in bone and skeletal system development, while DDR2, RAC2, RUNX2, and TSPAN31are involved in the positive regulation of cell proliferation. Among the downregulated genes, HIST1H1D, HIST1H2AI, HIST1H3H, and HIST1H4C are involved in nucleosome assembly and DNA packaging. These results may provide useful information to elucidate the molecular mechanism of the COX-2-mediated malignant phenotype in osteosarcoma. PMID- 25705167 TI - The Usage of an SNP-SNP Relationship Matrix for Best Linear Unbiased Prediction (BLUP) Analysis Using a Community-Based Cohort Study. AB - Best linear unbiased prediction (BLUP) has been used to estimate the fixed effects and random effects of complex traits. Traditionally, genomic relationship matrix-based (GRM) and random marker-based BLUP analyses are prevalent to estimate the genetic values of complex traits. We used three methods: GRM-based prediction (G-BLUP), random marker-based prediction using an identity matrix (so called single-nucleotide polymorphism [SNP]-BLUP), and SNP-SNP variance covariance matrix (so-called SNP-GBLUP). We used 35,675 SNPs and R package "rrBLUP" for the BLUP analysis. The SNP-SNP relationship matrix was calculated using the GRM and Sherman-Morrison-Woodbury lemma. The SNP-GBLUP result was very similar to G-BLUP in the prediction of genetic values. However, there were many discrepancies between SNP-BLUP and the other two BLUPs. SNP-GBLUP has the merit to be able to predict genetic values through SNP effects. PMID- 25705168 TI - Genome-Wide Identification and Classification of MicroRNAs Derived from Repetitive Elements. AB - MicroRNAs (miRNAs) are known for their role in mRNA silencing via interference pathways. Repetitive elements (REs) share several characteristics with endogenous precursor miRNAs. In this study, 406 previously identified and 1,494 novel RE derived miRNAs were sorted from the GENCODE v.19 database using the RepeatMasker program. They were divided into six major types, based on their genomic structure. More novel RE-derived miRNAs were confirmed than identified as RE derived miRNAs. In conclusion, many miRNAs have not yet been identified, most of which are derived from REs. PMID- 25705169 TI - Molecular Characterization of Legionellosis Drug Target Candidate Enzyme Phosphoglucosamine Mutase from Legionella pneumophila (strain Paris): An In Silico Approach. AB - The harshness of legionellosis differs from mild Pontiac fever to potentially fatal Legionnaire's disease. The increasing development of drug resistance against legionellosis has led to explore new novel drug targets. It has been found that phosphoglucosamine mutase, phosphomannomutase, and phosphoglyceromutase enzymes can be used as the most probable therapeutic drug targets through extensive data mining. Phosphoglucosamine mutase is involved in amino sugar and nucleotide sugar metabolism. The purpose of this study was to predict the potential target of that specific drug. For this, the 3D structure of phosphoglucosamine mutase of Legionella pneumophila (strain Paris) was determined by means of homology modeling through Phyre2 and refined by ModRefiner. Then, the designed model was evaluated with a structure validation program, for instance, PROCHECK, ERRAT, Verify3D, and QMEAN, for further structural analysis. Secondary structural features were determined through self-optimized prediction method with alignment (SOPMA) and interacting networks by STRING. Consequently, we performed molecular docking studies. The analytical result of PROCHECK showed that 95.0% of the residues are in the most favored region, 4.50% are in the additional allowed region and 0.50% are in the generously allowed region of the Ramachandran plot. Verify3D graph value indicates a score of 0.71 and 89.791, 1.11 for ERRAT and QMEAN respectively. Arg419, Thr414, Ser412, and Thr9 were found to dock the substrate for the most favorable binding of S-mercaptocysteine. However, these findings from this current study will pave the way for further extensive investigation of this enzyme in wet lab experiments and in that way assist drug design against legionellosis. PMID- 25705170 TI - Understanding Rifampicin Resistance in Tuberculosis through a Computational Approach. AB - The disease tuberculosis, caused by Mycobacterium tuberculosis (MTB), remains a major cause of morbidity and mortality in developing countries. The evolution of drug-resistant tuberculosis causes a foremost threat to global health. Most drug resistant MTB clinical strains are showing resistance to isoniazid and rifampicin (RIF), the frontline anti-tuberculosis drugs. Mutation in rpoB, the beta subunit of DNA-directed RNA polymerase of MTB, is reported to be a major cause of RIF resistance. Amongst mutations in the well-defined 81-base-pair central region of the rpoB gene, mutation at codon 450 (S450L) and 445 (H445Y) is mainly associated with RIF resistance. In this study, we modeled two resistant mutants of rpoB (S450L and H445Y) using Modeller9v10 and performed a docking analysis with RIF using AutoDock4.2 and compared the docking results of these mutants with the wild type rpoB. The docking results revealed that RIF more effectively inhibited the wild-type rpoB with low binding energy than rpoB mutants. The rpoB mutants interacted with RIF with positive binding energy, revealing the incapableness of RIF inhibition and thus showing resistance. Subsequently, this was verified by molecular dynamics simulations. This in silico evidence may help us understand RIF resistance in rpoB mutant strains. PMID- 25705171 TI - Elucidation of the Inhibitory Effect of Phytochemicals with Kir6.2 Wild-Type and Mutant Models Associated in Type-1 Diabetes through Molecular Docking Approach. AB - Among all serious diseases globally, diabetes (type 1 and type 2) still poses a major challenge to the world population. Several target proteins have been identified, and the etiology causing diabetes has been reasonably well studied. But, there is still a gap in deciding on the choice of a drug, especially when the target is mutated. Mutations in the KCNJ11 gene, encoding the kir6.2 channel, are reported to be associated with congenital hyperinsulinism, having a major impact in causing type 1 diabetes, and due to the lack of its 3D structure, an attempt has been made to predict the structure of kir6.2, applying fold recognition methods. The current work is intended to investigate the affinity of four phytochemicals namely, curcumin (Curcuma longa), genistein (Genista tinctoria), piperine (Piper nigrum), and pterostilbene (Vitis vinifera) in a normal as well as in a mutant kir6.2 model by adopting a molecular docking methodology. The phytochemicals were docked in both wild and mutated kir6.2 models in two rounds: blind docking followed by ATP-binding pocket-specific docking. From the binding pockets, the common interacting amino acid residues participating strongly within the binding pocket were identified and compared. From the study, we conclude that these phytochemicals have strong affinity in both the normal and mutant kir6.2 model. This work would be helpful for further study of the phytochemicals above for the treatment of type 1 diabetes by targeting the kir6.2 channel. PMID- 25705172 TI - MAP: Mutation Arranger for Defining Phenotype-Related Single-Nucleotide Variant. AB - Next-generation sequencing (NGS) is widely used to identify the causative mutations underlying diverse human diseases, including cancers, which can be useful for discovering the diagnostic and therapeutic targets. Currently, a number of single-nucleotide variant (SNV)-calling algorithms are available; however, there is no tool for visualizing the recurrent and phenotype-specific mutations for general researchers. In this study, in order to support defining the recurrent mutations or phenotype-specific mutations from NGS data of a group of cancers with diverse phenotypes, we aimed to develop a user-friendly tool, named mutation arranger for defining phenotype-related SNV (MAP). MAP is a user friendly program with multiple functions that supports the determination of recurrent or phenotype-specific mutations and provides graphic illustration images to the users. Its operation environment, the Microsoft Windows environment, enables more researchers who cannot operate Linux to define clinically meaningful mutations with NGS data from cancer cohorts. PMID- 25705173 TI - Obesidad y Esperanza de Vida en Mexico Obesity and life expectancy in Mexico. AB - The high and increasing prevalence of overweight and obesity in Latin American and the Caribbean and the increasing prevalence of some obesity-related chronic diseases could be changing the current mortality patterns and the improvements in life expectancy of this population. The main objective of this study is to measure the effect of overweight and obesity on mortality in Mexico among elderly people (60 years and older). We use the Mexican Health and Ageing Study (MHAS, 2001 and 2003) that is a panel nationally-representative study of the population 50 years and older in Mexico. Our results show that excess body weight (defined by the two highest quintiles of Body Mass Index-BMI-) increases the risk of mortality at 60 years and older in Mexico. As much as 11% of the deaths among elderly that occurred during the period 2001-2003 in Mexico would have been avoided if overweight and obese people (individuals belonging to the highest two quintiles of BMI) had had the "ideal" weight (defined by the middle quintile, or third quintile, of BMI). At individual level, we estimate that individuals 60 years old with excess body weight (fourth and fifth quintiles of BMI) survive four years less, in average, than individuals with normal body weight (third quintile of BMI). PMID- 25705174 TI - Visual-induced expectations modulate auditory cortical responses. AB - Active sensing has important consequences on multisensory processing (Schroeder et al., 2010). Here, we asked whether in the absence of saccades, the position of the eyes and the timing of transient color changes of visual stimuli could selectively affect the excitability of auditory cortex by predicting the "where" and the "when" of a sound, respectively. Human participants were recorded with magnetoencephalography (MEG) while maintaining the position of their eyes on the left, right, or center of the screen. Participants counted color changes of the fixation cross while neglecting sounds which could be presented to the left, right, or both ears. First, clear alpha power increases were observed in auditory cortices, consistent with participants' attention directed to visual inputs. Second, color changes elicited robust modulations of auditory cortex responses ("when" prediction) seen as ramping activity, early alpha phase-locked responses, and enhanced high-gamma band responses in the contralateral side of sound presentation. Third, no modulations of auditory evoked or oscillatory activity were found to be specific to eye position. Altogether, our results suggest that visual transience can automatically elicit a prediction of "when" a sound will occur by changing the excitability of auditory cortices irrespective of the attended modality, eye position or spatial congruency of auditory and visual events. To the contrary, auditory cortical responses were not significantly affected by eye position suggesting that "where" predictions may require active sensing or saccadic reset to modulate auditory cortex responses, notably in the absence of spatial orientation to sounds. PMID- 25705175 TI - Function and regulation of Rnd proteins in cortical projection neuron migration. AB - The mammalian cerebral cortex contains a high variety of neuronal subtypes that acquire precise spatial locations and form long or short-range connections to establish functional neuronal circuits. During embryonic development, cortical projection neurons are generated in the areas lining the lateral ventricles and they subsequently undergo radial migration to reach the position of their final maturation within the cortical plate. The control of the neuroblast migratory behavior and the coordination of the migration process with other neurogenic events such as cell cycle exit, differentiation and final maturation are crucial to normal brain development. Among the key regulators of cortical neuron migration, the small GTP binding proteins of the Rho family and the atypical Rnd members play important roles in integrating intracellular signaling pathways into changes in cytoskeletal dynamics and motility behavior. Here we review the role of Rnd proteins during cortical neuronal migration and we discuss both the upstream mechanisms that regulate Rnd protein activity and the downstream molecular pathways that mediate Rnd effects on cell cytoskeleton. PMID- 25705176 TI - Choroid plexus dysfunction impairs beta-amyloid clearance in a triple transgenic mouse model of Alzheimer's disease. AB - Compromised secretory function of choroid plexus (CP) and defective cerebrospinal fluid (CSF) production, along with accumulation of beta-amyloid (Abeta) peptides at the blood-CSF barrier (BCSFB), contribute to complications of Alzheimer's disease (AD). The AD triple transgenic mouse model (3xTg-AD) at 16 month-old mimics critical hallmarks of the human disease: beta-amyloid (Abeta) plaques and neurofibrillary tangles (NFT) with a temporal- and regional- specific profile. Currently, little is known about transport and metabolic responses by CP to the disrupted homeostasis of CNS Abeta in AD. This study analyzed the effects of highly-expressed AD-linked human transgenes (APP, PS1 and tau) on lateral ventricle CP function. Confocal imaging and immunohistochemistry revealed an increase only of Abeta42 isoform in epithelial cytosol and in stroma surrounding choroidal capillaries; this buildup may reflect insufficient clearance transport from CSF to blood. Still, there was increased expression, presumably compensatory, of the choroidal Abeta transporters: the low density lipoprotein receptor-related protein 1 (LRP1) and the receptor for advanced glycation end product (RAGE). A thickening of the epithelial basal membrane and greater collagen-IV deposition occurred around capillaries in CP, probably curtailing solute exchanges. Moreover, there was attenuated expression of epithelial aquaporin-1 and transthyretin (TTR) protein compared to Non-Tg mice. Collectively these findings indicate CP dysfunction hypothetically linked to increasing Abeta burden resulting in less efficient ion transport, concurrently with reduced production of CSF (less sink action on brain Abeta) and diminished secretion of TTR (less neuroprotection against cortical Abeta toxicity). The putative effects of a disabled CP-CSF system on CNS functions are discussed in the context of AD. PMID- 25705178 TI - Cellular mechanisms of mutations in Kv7.1: auditory functions in Jervell and Lange-Nielsen syndrome vs. Romano-Ward syndrome. AB - As a result of cell-specific functions of voltage-activated K(+) channels, such as Kv7.1, mutations in this channel produce profound cardiac and auditory defects. At the same time, the massive diversity of K(+) channels allows for compensatory substitution of mutant channels by other functional channels of their type to minimize defective phenotypes. Kv7.1 represents a clear example of such functional dichotomy. While several point mutations in the channel result in a cardio-auditory syndrome called Jervell and Lange-Nielsen syndrome (JLNS), about 100-fold mutations result in long QT syndrome (LQTS) denoted as Romano-Ward syndrome (RWS), which has an intact auditory phenotype. To determine whether the cellular mechanisms for the diverse phenotypic outcome of Kv7.1 mutations, are dependent on the tissue-specific function of the channel and/or specialized functions of the channel, we made series of point mutations in hKv7.1 ascribed to JLNS and RWS. For JLNS mutations, all except W248F yielded non-functional channels when expressed alone. Although W248F at the end of the S4 domain yielded a functional current, it underwent marked inactivation at positive voltages, rendering the channel non-functional. We demonstrate that by definition, none of the JLNS mutants operated in a dominant negative (DN) fashion. Instead, the JLNS mutants have impaired membrane trafficking, trapped in the endoplasmic reticulum (ER) and Cis-Golgi. The RWS mutants exhibited varied functional phenotypes. However, they can be summed up as exhibiting DN effects. Phenotypic differences between JLNS and RWS may stem from tissue-specific functional requirements of cardiac vs. inner ear non-sensory cells. PMID- 25705179 TI - Screening and personalizing nootropic drugs and cognitive modulator regimens in silico. AB - The go-to cognitive enhancers of today are those that are widely available rather than optimal for the user, including drugs typically prescribed for treatment of ADHD (e.g., methylphenidate) and sleep disturbances such as narcolepsy (modafinil). While highly effective in their intended therapeutic role, performance gains in healthy populations are modest at best and profoundly inconsistent across subgroups and individuals. We propose a method for in silico screening of possible novel cognitive enhancers followed by high-throughput in vivo and in vitro validation. The proposed method uses gene expression data to evaluate the the collection of activated or suppressed signaling pathways in tissues or neurons of the cognitively enhanced brain. An algorithm maps expression data onto signaling pathways and quantifies their individual activation strength. The collective pathways and their activation form what we term the signaling pathway cloud, a biological fingerprint of cognitive enhancement (or any other condition of interest). Drugs can then be screened and ranked based on their ability to minimize, mimic, or exaggerate pathway activation or suppression within that cloud. Using this approach, one may predict the efficacy of many drugs that may enhance various aspects of cognition before costly preclinical studies and clinical trials are undertaken. PMID- 25705177 TI - Interleukin-1 and acute brain injury. AB - Inflammation is the key host-defense response to infection and injury, yet also a major contributor to a diverse range of diseases, both peripheral and central in origin. Brain injury as a result of stroke or trauma is a leading cause of death and disability worldwide, yet there are no effective treatments, resulting in enormous social and economic costs. Increasing evidence, both preclinical and clinical, highlights inflammation as an important factor in stroke, both in determining outcome and as a contributor to risk. A number of inflammatory mediators have been proposed as key targets for intervention to reduce the burden of stroke, several reaching clinical trial, but as yet yielding no success. Many factors could explain these failures, including the lack of robust preclinical evidence and poorly designed clinical trials, in addition to the complex nature of the clinical condition. Lack of consideration in preclinical studies of associated co-morbidities prevalent in the clinical stroke population is now seen as an important omission in previous work. These co-morbidities (atherosclerosis, hypertension, diabetes, infection) have a strong inflammatory component, supporting the need for greater understanding of how inflammation contributes to acute brain injury. Interleukin (IL)-1 is the prototypical pro-inflammatory cytokine, first identified many years ago as the endogenous pyrogen. Research over the last 20 years or so reveals that IL-1 is an important mediator of neuronal injury and blocking the actions of IL-1 is beneficial in a number of experimental models of brain damage. Mechanisms underlying the actions of IL-1 in brain injury remain unclear, though increasing evidence indicates the cerebrovasculature as a key target. Recent literature supporting this and other aspects of how IL-1 and systemic inflammation in general contribute to acute brain injury are discussed in this review. PMID- 25705180 TI - Systems neuroscience in focus: from the human brain to the global brain? PMID- 25705181 TI - Greater general startle reflex is associated with greater anxiety levels: a correlational study on 111 young women. AB - Startle eyeblink reflex is a valid non-invasive tool for studying attention, emotion and psychiatric disorders. In the absence of any experimental manipulation, the general (or baseline) startle reflex shows a high inter individual variability, which is often considered task-irrelevant and therefore normalized across participants. Unlike the above view, we hypothesized that greater general startle magnitude is related to participants' higher anxiety level. 111 healthy young women, after completing the State-Trait Anxiety Inventory (STAI), were randomly administered 10 acoustic white noise probes (50 ms, 100 dBA acoustic level) while integrated EMG from left and right orbicularis oculi was recorded. Results showed that participants with greater state anxiety levels exhibited larger startle reflex magnitude from the left eye (r 109 = 0.23, p < 0.05). Furthermore, individuals who perceived the acoustic probe as more aversive reported the largest anxiety scores (r 109 = 0.28, p < 0.05) and had the largest eyeblinks, especially in the left eye (r 109 = 0.34, p < 0.001). Results suggest that general startle may represent a valid tool for studying the neural excitability underlying anxiety and emotional dysfunction in neurological and mental disorders. PMID- 25705182 TI - The effect of retrosplenial cortex lesions in rats on incidental and active spatial learning. AB - The study examined the importance of the retrosplenial cortex for the incidental learning of the spatial arrangement of distinctive features within a scene. In a modified Morris water-maze, rats spontaneously learnt the location of an escape platform prior to swimming to that location. For this, rats were repeatedly placed on a submerged platform in one corner of either a rectangular (Experiment 1) or square (Experiments 2, 3) pool with walls of different appearance. The rats were then released in the center of the pool for their first test trial. In Experiment 1, the correct corner and its diagonally opposite partner (also correct) were specified by the geometric properties of the pool. Rats with retrosplenial lesions took longer to first reach a correct corner, subsequently showing an attenuated preference for the correct corners. A reduced preference for the correct corner was also found in Experiment 2, when platform location was determined by the juxtaposition of highly salient visual cues (black vs. white walls). In Experiment 3, less salient visual cues (striped vs. white walls) led to a robust lesion impairment, as the retrosplenial lesioned rats showed no preference for the correct corner. When subsequently trained actively to swim to the correct corner over successive trials, retrosplenial lesions spared performance on all three discriminations. The findings not only reveal the importance of the retrosplenial cortex for processing various classes of visuospatial information but also highlight a broader role in the incidental learning of the features of a spatial array, consistent with the translation of scene information. PMID- 25705183 TI - High interindividual variability in dose-dependent reduction in speed of movement after exposing C. elegans to shock waves. AB - In blast-related mild traumatic brain injury (br-mTBI) little is known about the connections between initial trauma and expression of individual clinical symptoms. Partly due to limitations of current in vitro and in vivo models of br mTBI, reliable prediction of individual short- and long-term symptoms based on known blast input has not yet been possible. Here we demonstrate a dose-dependent effect of shock wave exposure on C. elegans using shock waves that share physical characteristics with those hypothesized to induce br-mTBI in humans. Increased exposure to shock waves resulted in decreased mean speed of movement while increasing the proportion of worms rendered paralyzed. Recovery of these two behavioral symptoms was observed during increasing post-traumatic waiting periods. Although effects were observed on a population-wide basis, large interindividual variability was present between organisms exposed to the same highly controlled conditions. Reduction of cavitation by exposing worms to shock waves in polyvinyl alcohol resulted in reduced effect, implicating primary blast effects as damaging components in shock wave induced trauma. Growing worms on NGM agar plates led to the same general results in initial shock wave effect in a standard medium, namely dose-dependence and high interindividual variability, as raising worms in liquid cultures. Taken together, these data indicate that reliable prediction of individual clinical symptoms based on known blast input as well as drawing conclusions on blast input from individual clinical symptoms is not feasible in br-mTBI. PMID- 25705184 TI - Between-hand difference in ipsilateral deactivation is associated with hand lateralization: fMRI mapping of 284 volunteers balanced for handedness. AB - In right-handers (RH), an increase in the pace of dominant hand movement results in increased ipsilateral deactivation of the primary motor cortex (M1). By contrast, an increase in non-dominant hand movement frequency is associated with reduced ipsilateral deactivation. This pattern suggests that inhibitory processes support right hand dominance in right-handers and raises the issues of whether this phenomenon also supports left hand preference in left-handers (LH), and/or whether it relates to asymmetry of manual ability in either group. Thanks to the BIL&GIN, a database dedicated to the investigation of hemispheric specialization (HS), we studied the variation in M1 activity during right and left finger tapping tasks (FTT) in a sample of 284 healthy participants balanced for handedness. An M1 fMRI localizer was defined for each participant as an 8 mm diameter sphere centered on the motor activation peak. RH exhibited significantly larger deactivation of the ipsilateral M1 when moving their dominant hand than their non-dominant hand. In contrast, LH exhibited comparable ipsilateral M1 deactivation during either hand movement, reflecting a bilateral cortical specialization. This pattern is likely related to left-handers' good performances with their right hand and consequent lower asymmetry in manual ability compared with RH. Finally, inter-individual analyses over the whole sample demonstrated that the larger the difference in manual skill across hands, the larger the difference in ipsilateral deactivation. Overall, we propose that difference in ipsilateral deactivation is a marker of difference in manual ability asymmetry reflecting differences in the strength of transcallosal inhibition when a given hand is moving. PMID- 25705185 TI - Brain responses to musical feature changes in adolescent cochlear implant users. AB - Cochlear implants (CIs) are primarily designed to assist deaf individuals in perception of speech, although possibilities for music fruition have also been documented. Previous studies have indicated the existence of neural correlates of residual music skills in postlingually deaf adults and children. However, little is known about the behavioral and neural correlates of music perception in the new generation of prelingually deaf adolescents who grew up with CIs. With electroencephalography (EEG), we recorded the mismatch negativity (MMN) of the auditory event-related potential to changes in musical features in adolescent CI users and in normal-hearing (NH) age mates. EEG recordings and behavioral testing were carried out before (T1) and after (T2) a 2-week music training program for the CI users and in two sessions equally separated in time for NH controls. We found significant MMNs in adolescent CI users for deviations in timbre, intensity, and rhythm, indicating residual neural prerequisites for musical feature processing. By contrast, only one of the two pitch deviants elicited an MMN in CI users. This pitch discrimination deficit was supported by behavioral measures, in which CI users scored significantly below the NH level. Overall, MMN amplitudes were significantly smaller in CI users than in NH controls, suggesting poorer music discrimination ability. Despite compliance from the CI participants, we found no effect of the music training, likely resulting from the brevity of the program. This is the first study showing significant brain responses to musical feature changes in prelingually deaf adolescent CI users and their associations with behavioral measures, implying neural predispositions for at least some aspects of music processing. Future studies should test any beneficial effects of a longer lasting music intervention in adolescent CI users. PMID- 25705186 TI - Horizontal-vertical illusion in mental imagery: quantitative evidence. AB - The present study had two main goals: (1) to investigate the difference between perception and mental imagery using a visual illusion as a stimulus; (2) to inspect gender related differences in perception and imagery. Our main hypothesis, that there would be no differences between perception and mental imagery, was motivated by previous neuroimaging data. Unlike these neuroimaging studies that demonstrate great similarity between the two processes, results obtained in behavioral studies have not always been consistent. We assumed that this inconsistency was a consequence of methodological differences. Hence, we explored the two processes with a modified behavioral procedure. The additional exploration of gender differences was motivated by the discrepancy between our findings and the existing literature. In two experiments, participants estimated the lines constituting the horizontal-vertical illusion, either in perception or imagery task. Results confirmed that there was no significant difference between perception and imagery: the illusion was equally strong in both tasks. In the second experiment, an additional factor was tested, stimulus size. The results showed that, although there was no significant difference in illusion strength, there was a gender difference in the size of mental image for medium and large stimuli. While male subjects performed equally in the two tasks, female subjects tended to underestimate size in the imagery task. This tendency intensified as the stimulus size increased. Our results not only inform us about the status of illusions in imagery but also offer some answers about the spatial nature of mental representations. We hope that such precise measurements of mental representation might provide better understanding of reasoning that uses mental images. PMID- 25705187 TI - Components of action representations evoked when identifying manipulable objects. AB - We examined the influence of holding planned hand actions in working memory on the time taken to visually identify objects with handles. Features of the hand actions and position of the object's handle were congruent or incongruent on two dimensions: alignment (left vs. right) and orientation (horizontal vs. vertical). When an object was depicted in an upright view, subjects were slower to name it when its handle was congruent with the planned hand actions on one dimension but incongruent on the other, relative to when the object handle and actions were congruent on both or neither dimension. This pattern is consistent with many other experiments demonstrating that a cost occurs when there is partial feature overlap between a planned action and a perceived target. An opposite pattern of results was obtained when the depicted object appeared in a 90 degrees rotated view (e.g., a beer mug on its side), suggesting that the functional goal associated with the object (e.g., drinking from an upright beer mug) was taken into account during object perception and that this knowledge superseded the influence of the action afforded by the depicted view of the object. These results have implications for the relationship between object perception and action representations, and for the mechanisms that support the identification of rotated objects. PMID- 25705188 TI - A framework for categorizing electrode montages in transcranial direct current stimulation. PMID- 25705189 TI - The prospects of working memory training for improving deductive reasoning. PMID- 25705190 TI - Architectural constraints are a major factor reducing path integration accuracy in the rat head direction cell system. AB - Head direction cells fire to signal the direction in which an animal's head is pointing. They are able to track head direction using only internally-derived information (path integration)In this simulation study we investigate the factors that affect path integration accuracy. Specifically, two major limiting factors are identified: rise time, the time after stimulation it takes for a neuron to start firing, and the presence of symmetric non-offset within-layer recurrent collateral connectivity. On the basis of the latter, the important prediction is made that head direction cell regions directly involved in path integration will not contain this type of connectivity; giving a theoretical explanation for architectural observations. Increased neuronal rise time is found to slow path integration, and the slowing effect for a given rise time is found to be more severe in the context of short conduction delays. Further work is suggested on the basis of our findings, which represent a valuable contribution to understanding of the head direction cell system. PMID- 25705191 TI - Do interprofessional education programs produce dissension that destroys them? PMID- 25705192 TI - OpenCOR: a modular and interoperable approach to computational biology. AB - Computational biologists have been developing standards and formats for nearly two decades, with the aim of easing the description and exchange of experimental data, mathematical models, simulation experiments, etc. One of those efforts is CellML (cellml.org), an XML-based markup language for the encoding of mathematical models. Early CellML-based environments include COR and OpenCell. However, both of those tools have limitations and were eventually replaced with OpenCOR (opencor.ws). OpenCOR is an open source modeling environment that is supported on Windows, Linux and OS X. It relies on a modular approach, which means that all of its features come in the form of plugins. Those plugins can be used to organize, edit, simulate and analyze models encoded in the CellML format. We start with an introduction to CellML and two of its early adopters, which limitations eventually led to the development of OpenCOR. We then go onto describing the general philosophy behind OpenCOR, as well as describing its openness and its development process. Next, we illustrate various aspects of OpenCOR, such as its user interface and some of the plugins that come bundled with it (e.g., its editing and simulation plugins). Finally, we discuss some of the advantages and limitations of OpenCOR before drawing some concluding remarks. PMID- 25705193 TI - Multifractal analysis for all. PMID- 25705195 TI - No evidence for a bioenergetic advantage from forced swimming in rainbow trout under a restrictive feeding regime. AB - Sustained swimming at moderate speeds is considered beneficial in terms of the productive performance of salmonids, but the causative mechanisms have yet to be unequivocally established. In the present study, the effects of moderate exercise on the bioenergetics of rainbow trout were assessed during a 15 week growth experiment, in which fish were reared at three different current speeds: 1 BL s( 1), 0.5 BL s(-1) and still water (~ 0 BL s(-1)). Randomly selected groups of 100 fish were distributed among twelve 600 L tanks and maintained on a restricted diet regime. Specific growth rate (SGR) and feed conversion ratio (FCR) were calculated from weight and length measurements every 3 weeks. Routine metabolic rate (RMR) was measured every hour as rate of oxygen consumption in the tanks, and was positively correlated with swimming speed. Total ammonia nitrogen (TAN) excretion rates showed a tendency to decrease with increasing swimming speeds, yet neither they nor the resulting nitrogen quotients (NQ) indicated that swimming significantly reduced the fraction of dietary protein used to fuel metabolism. Energetic budgets revealed a positive correlation between energy expenditure and the current speed at which fish were reared, fish that were forced to swim and were fed restrictively consequentially had poorer growth and feed utilization. The results show that for rainbow trout, water current can negatively affect growth despite promoting minor positive changes in substrate utilization. We hypothesize that this may be the result of either a limited dietary energy supply from diet restriction being insufficient for both covering the extra costs of swimming and supporting enhanced growth. PMID- 25705196 TI - The neural basis of non-verbal communication-enhanced processing of perceived give-me gestures in 9-month-old girls. AB - This study investigated the neural basis of non-verbal communication. Event related potentials were recorded while 29 nine-month-old infants were presented with a give-me gesture (experimental condition) and the same hand shape but rotated 90 degrees , resulting in a non-communicative hand configuration (control condition). We found different responses in amplitude between the two conditions, captured in the P400 ERP component. Moreover, the size of this effect was modulated by participants' sex, with girls generally demonstrating a larger relative difference between the two conditions than boys. PMID- 25705194 TI - BK channels: multiple sensors, one activation gate. AB - Ion transport across cell membranes is essential to cell communication and signaling. Passive ion transport is mediated by ion channels, membrane proteins that create ion conducting pores across cell membrane to allow ion flux down electrochemical gradient. Under physiological conditions, majority of ion channel pores are not constitutively open. Instead, structural region(s) within these pores breaks the continuity of the aqueous ion pathway, thereby serves as activation gate(s) to control ions flow in and out. To achieve spatially and temporally regulated ion flux in cells, many ion channels have evolved sensors to detect various environmental stimuli or the metabolic states of the cell and trigger global conformational changes, thereby dynamically operate the opening and closing of their activation gate. The sensors of ion channels can be broadly categorized as chemical sensors and physical sensors to respond to chemical (such as neural transmitters, nucleotides and ions) and physical (such as voltage, mechanical force and temperature) signals, respectively. With the rapidly growing structural and functional information of different types of ion channels, it is now critical to understand how ion channel sensors dynamically control their gates at molecular and atomic level. The voltage and Ca(2+) activated BK channels, a K(+) channel with an electrical sensor and multiple chemical sensors, provide a unique model system for us to understand how physical and chemical energy synergistically operate its activation gate. PMID- 25705197 TI - EEG decoding of spoken words in bilingual listeners: from words to language invariant semantic-conceptual representations. AB - Spoken word recognition and production require fast transformations between acoustic, phonological, and conceptual neural representations. Bilinguals perform these transformations in native and non-native languages, deriving unified semantic concepts from equivalent, but acoustically different words. Here we exploit this capacity of bilinguals to investigate input invariant semantic representations in the brain. We acquired EEG data while Dutch subjects, highly proficient in English listened to four monosyllabic and acoustically distinct animal words in both languages (e.g., "paard"-"horse"). Multivariate pattern analysis (MVPA) was applied to identify EEG response patterns that discriminate between individual words within one language (within-language discrimination) and generalize meaning across two languages (across-language generalization). Furthermore, employing two EEG feature selection approaches, we assessed the contribution of temporal and oscillatory EEG features to our classification results. MVPA revealed that within-language discrimination was possible in a broad time-window (~50-620 ms) after word onset probably reflecting acoustic phonetic and semantic-conceptual differences between the words. Most interestingly, significant across-language generalization was possible around 550 600 ms, suggesting the activation of common semantic-conceptual representations from the Dutch and English nouns. Both types of classification, showed a strong contribution of oscillations below 12 Hz, indicating the importance of low frequency oscillations in the neural representation of individual words and concepts. This study demonstrates the feasibility of MVPA to decode individual spoken words from EEG responses and to assess the spectro-temporal dynamics of their language invariant semantic-conceptual representations. We discuss how this method and results could be relevant to track the neural mechanisms underlying conceptual encoding in comprehension and production. PMID- 25705198 TI - Is experiential-intuitive cognitive style more inclined to err on conjunction fallacy than analytical-rational cognitive style? AB - In terms of prediction by Epstein's integrative theory of personality, cognitive experiential self-theory (CEST), those people with experiential-intuitive cognitive style are more inclined to induce errors than the other people with analytical-rational cognitive style in the conjunction fallacy (two events that can occur together are seen as more likely than at least one of the two events). We tested this prediction in a revised Linda problem. The results revealed that rational and experiential cognitive styles do not statistically influence the propensity for committing the conjunction fallacy, which is contrary to the CEST's predictions. Based on the assumption that the rational vs. experiential processing is a personality trait with comparatively stabile specialities, these findings preliminarily indicate that those people who are characterized by "rational thinking" are not more inclined to use Bayes' deduction than the other people who are labeled by "intuitive thinking" or by "poor thinking." PMID- 25705199 TI - Apes have culture but may not know that they do. AB - There is good evidence that some ape behaviors can be transmitted socially and that this can lead to group-specific traditions. However, many consider animal traditions, including those in great apes, to be fundamentally different from human cultures, largely because of lack of evidence for cumulative processes and normative conformity, but perhaps also because current research on ape culture is usually restricted to behavioral comparisons. Here, we propose to analyze ape culture not only at the surface behavioral level but also at the underlying cognitive level. To this end, we integrate empirical findings in apes with theoretical frameworks developed in developmental psychology regarding the representation of tools and the development of metarepresentational abilities, to characterize the differences between ape and human cultures at the cognitive level. Current data are consistent with the notion of apes possessing mental representations of tools that can be accessed through re-representations: apes may reorganize their knowledge of tools in the form of categories or functional schemes. However, we find no evidence for metarepresentations of cultural knowledge: apes may not understand that they or others hold beliefs about their cultures. The resulting Jourdain Hypothesis, based on Moliere's character, argues that apes express their cultures without knowing that they are cultural beings because of cognitive limitations in their ability to represent knowledge, a determining feature of modern human cultures, allowing representing and modifying the current norms of the group. Differences in metarepresentational processes may thus explain fundamental differences between human and other animals' cultures, notably limitations in cumulative behavior and normative conformity. Future empirical work should focus on how animals mentally represent their cultural knowledge to conclusively determine the ways by which humans are unique in their cultural behavior. PMID- 25705200 TI - Beyond the status-quo: research on Bayesian reasoning must develop in both theory and method. PMID- 25705201 TI - New insights into pathophysiology of vestibular migraine. AB - Vestibular migraine (VM) is a common disorder in which genetic, epigenetic, and environmental factors probably contribute to its development. The pathophysiology of VM is unknown; nevertheless in the last few years, several studies are contributing to understand the neurophysiological pathways involved in VM. The current hypotheses are mostly based on the knowledge of migraine itself. The evidence of trigeminal innervation of the labyrinth vessels and the localization of vasoactive neuropeptides in the perivascular afferent terminals of these trigeminal fibers support the involvement of the trigemino-vascular system. The neurogenic inflammation triggered by activation of the trigeminal vestibulocochlear reflex, with the subsequent inner ear plasma protein extravasation and the release of inflammatory mediators, can contribute to a sustained activation and sensitization of the trigeminal primary afferent neurons explaining VM symptoms. The reciprocal connections between brainstem vestibular nuclei and the structures that modulate trigeminal nociceptive inputs (rostral ventromedial medulla, ventrolateral periaqueductal gray, locus coeruleus, and nucleus raphe magnus) are critical to understand the pathophysiology of VM. Although cortical spreading depression can affect cortical areas involved in processing vestibular information, functional neuroimaging techniques suggest a dysmodulation in the multimodal sensory integration and processing of vestibular and nociceptive information, resulting from a vestibulo-thalamo-cortical dysfunction, as the pathogenic mechanism underlying VM. The elevated prevalence of VM suggests that multiple functional variants may confer a genetic susceptibility leading to a dysregulation of excitatory-inhibitory balance in brain structures involved in the processing of sensory information, vestibular inputs, and pain. The interactions among several functional and structural neural networks could explain the pathogenic mechanisms of VM. PMID- 25705202 TI - Arm and hand movement: current knowledge and future perspective. PMID- 25705203 TI - Vasopressin Proves Es-sense-tial: Vasopressin and the Modulation of Sensory Processing in Mammals. AB - As mammals develop, they encounter increasing social complexity in the surrounding world. In order to survive, mammals must show appropriate behaviors toward their mates, offspring, and same-sex conspecifics. Although the behavioral effects of the neuropeptide arginine vasopressin (AVP) have been studied in a variety of social contexts, the effects of this neuropeptide on multimodal sensory processing have received less attention. AVP is widely distributed through sensory regions of the brain and has been demonstrated to modulate olfactory, auditory, gustatory, and visual processing. Here, we review the evidence linking AVP to the processing of social stimuli in sensory regions of the brain and explore how sensory processing can shape behavioral responses to these stimuli. In addition, we address the interplay between hormonal and neural AVP in regulating sensory processing of social cues. Because AVP pathways show plasticity during development, early life experiences may shape life-long processing of sensory information. Furthermore, disorders of social behavior such as autism and schizophrenia that have been linked with AVP also have been linked with dysfunctions in sensory processing. Together, these studies suggest that AVP's diversity of effects on social behavior across a variety of mammalian species may result from the effects of this neuropeptide on sensory processing. PMID- 25705204 TI - Insulin, aging, and the brain: mechanisms and implications. AB - There is now an impressive body of literature implicating insulin and insulin signaling in successful aging and longevity. New information from in vivo and in vitro studies concerning insulin and insulin receptors has extended our understanding of the physiological role of insulin in the brain. However, the relevance of these to aging and longevity remains to be elucidated. Here, we review advances in our understanding of the physiological role of insulin in the brain, how insulin gets into the brain, and its relevance to aging and longevity. Furthermore, we examine possible future therapeutic applications and implications of insulin in the context of available models of delayed and accelerated aging. PMID- 25705205 TI - FurA contributes to the oxidative stress response regulation of Mycobacterium avium ssp. paratuberculosis. AB - The ferric uptake regulator A (FurA) is known to be involved in iron homeostasis and stress response in many bacteria. In mycobacteria the precise role of FurA is still unclear. In the presented study, we addressed the functional role of FurA in the ruminant pathogen Mycobacterium avium ssp. paratuberculosis (MAP) by construction of a furA deletion strain (MAPDeltafurA). RNA deep sequencing revealed that the FurA regulon consists of repressed and activated genes associated to stress response or intracellular survival. Not a single gene related to metal homeostasis was affected by furA deletion. A decisive role of FurA during intracellular survival in macrophages was shown by significantly enhanced survival of MAPDeltafurA compared to the wildtype, indicating that a principal task of mycobacterial FurA is oxidative stress response regulation in macrophages. This resistance was not associated with altered survival of mice after long term infection with MAP. Our results demonstrate for the first time, that mycobacterial FurA is not involved in the regulation of iron homeostasis. However, they provide strong evidence that FurA contributes to intracellular survival as an oxidative stress sensing regulator. PMID- 25705206 TI - Colonization of lettuce rhizosphere and roots by tagged Streptomyces. AB - Beneficial microorganisms are increasingly used in agriculture, but their efficacy often fails due to limited knowledge of their interactions with plants and other microorganisms present in rhizosphere. We studied spatio-temporal colonization dynamics of lettuce roots and rhizosphere by genetically modified Streptomyces spp. Five Streptomyces strains, strongly inhibiting in vitro the major soil-borne pathogen of horticultural crops, Sclerotinia sclerotiorum, were transformed with pIJ8641 plasmid harboring an enhanced green fluorescent protein marker and resistance to apramycin. The fitness of transformants was compared to the wild-type strains and all of them grew and sporulated at similar rates and retained the production of enzymes and selected secondary metabolites as well as in vitro inhibition of S. sclerotiorum. The tagged ZEA17I strain was selected to study the dynamics of lettuce roots and rhizosphere colonization in non-sterile growth substrate. The transformed strain was able to colonize soil, developing roots, and rhizosphere. When the strain was inoculated directly on the growth substrate, significantly more t-ZEA17I was re-isolated both from the rhizosphere and the roots when compared to the amount obtained after seed coating. The re isolation from the rhizosphere and the inner tissues of surface-sterilized lettuce roots demonstrated that t-ZEA17I is both rhizospheric and endophytic. PMID- 25705207 TI - Montanide, Poly I:C and nanoparticle based vaccines promote differential suppressor and effector cell expansion: a study of induction of CD8 T cells to a minimal Plasmodium berghei epitope. AB - The development of practical and flexible vaccines to target liver stage malaria parasites would benefit from an ability to induce high levels of CD8 T cells to minimal peptide epitopes. Herein we compare different adjuvant and carrier systems in a murine model for induction of interferon gamma (IFN-gamma) producing CD8 T cells to the minimal immuno-dominant peptide epitope from the circumsporozoite protein (CSP) of Plasmodium berghei, pb9 (SYIPSAEKI, referred to as KI). Two pro-inflammatory adjuvants, Montanide and Poly I:C, and a non classical, non-inflammatory nanoparticle based carrier (polystyrene nanoparticles, PSNPs), were compared side-by-side for their ability to induce potentially protective CD8 T cell responses after two immunizations. KI in Montanide (Montanide + KI) or covalently conjugated to PSNPs (PSNPs-KI) induced such high responses, whereas adjuvanting with Poly I:C or PSNPs without conjugation was ineffective. This result was consistent with an observed induction of an immunosuppressed environment by Poly I:C in the draining lymph node (dLN) 48 h post injection, which was reflected by increased frequencies of myeloid derived suppressor cells (MDSCs) and a proportion of inflammation reactive regulatory T cells (Treg) expressing the tumor necrosis factor receptor 2 (TNFR2), as well as decreased dendritic cell (DC) maturation. The other inflammatory adjuvant, Montanide, also promoted proportional increases in the TNFR2(+) Treg subpopulation, but not MDSCs, in the dLN. By contrast, injection with non-inflammatory PSNPs did not cause these changes. Induction of high CD8 T cell responses, using minimal peptide epitopes, can be achieved by non inflammatory carrier nanoparticles, which in contrast to some conventional inflammatory adjuvants, do not expand either MDSCs or inflammation reactive Tregs at the site of priming. PMID- 25705208 TI - Bioinformatic and mass spectrometry identification of Anaplasma phagocytophilum proteins translocated into host cell nuclei. AB - Obligate intracellular bacteria have an arsenal of proteins that alter host cells to establish and maintain a hospitable environment for replication. Anaplasma phagocytophilum secrets Ankyrin A (AnkA), via a type IV secretion system, which translocates to the nucleus of its host cell, human neutrophils. A. phagocytophilum-infected neutrophils have dramatically altered phenotypes in part explained by AnkA-induced transcriptional alterations. However, it is unlikely that AnkA is the sole effector to account for infection-induced transcriptional changes. We developed a simple method combining bioinformatics and iTRAQ protein profiling to identify potential bacterial-derived nuclear-translocated proteins that could impact transcriptional programming in host cells. This approach identified 50 A. phagocytophilum candidate genes or proteins. The encoding genes were cloned to create GFP fusion protein-expressing clones that were transfected into HEK-293T cells. We confirmed nuclear translocation of six proteins: APH_0062, RplE, Hup, APH_0382, APH_0385, and APH_0455. Of the six, APH_0455 was identified as a type IV secretion substrate and is now under investigation as a potential nucleomodulin. Additionally, application of this approach to other intracellular bacteria such as Mycobacterium tuberculosis, Chlamydia trachomatis and other intracellular bacteria identified multiple candidate genes to be investigated. PMID- 25705209 TI - Biosurfactant production by Bacillus subtilis using corn steep liquor as culture medium. AB - In this work, biosurfactant production by Bacillus subtilis #573 was evaluated using corn steep liquor (CSL) as culture medium. The best results were obtained in a culture medium consisting of 10% (v/v) of CSL, with a biosurfactant production of about 1.3 g/l. To the best of our knowledge, this is the first report describing biosurfactant production by B. subtilis using CSL as culture medium. Subsequently, the effect of different metals (iron, manganese, and magnesium) on biosurfactant production was evaluated using the medium CSL 10%. It was found that for all the metals tested, the biosurfactant production was increased (up to 4.1, 4.4, and 3.5 g/l for iron, manganese, and magnesium, respectively). When the culture medium was supplemented with the optimum concentration of the three metals simultaneously, the biosurfactant production was increased up to 4.8 g/l. Furthermore, the biosurfactant exhibited a good performance in oil recovery assays when compared with chemical surfactants, which suggests its possible application in microbial enhanced oil recovery or bioremediation. PMID- 25705210 TI - The outer membrane protease PgtE of Salmonella enterica interferes with the alternative complement pathway by cleaving factors B and H. AB - The virulence factor PgtE is an outer membrane protease (omptin) of the zoonotic pathogen Salmonella enterica that causes diseases ranging from gastroenteritis to severe enteric fever. It is surface exposed in bacteria that have a short-chain, i.e., rough LPS, as observed e.g., in bacteria residing inside macrophages or just emerging from them. We investigated whether PgtE cleaves the complement factors B (B) and H (H), key proteins controlling formation and inactivation of the complement protein C3b and thereby the activity of the complement system. S. enterica serovar Typhimurium or omptin-expressing recombinant E. coli bacteria were incubated with purified human complement proteins or recombinant H fragments. PgtE cleaved both B and H, whereas its close homolog Pla of Yersinia pestis cleaved only H. H was cleaved at both N- and C-termini, while the central region resisted proteolysis. Because of multiple effects of PgtE on complement components (cleavage of C3, C3b, B, and H) we assessed its effect on the opsonophagocytosis of Salmonella. In human serum, C3 cleavage was dependent on proteolytically active PgtE. Human neutrophils interacted less with serum opsonized FITC-stained S. enterica 14028R than with the isogenic DeltapgtE strain, as analyzed by flow cytometry. In conclusion, cleavage of B and H by PgtE, together with C3 cleavage, affects the C3-mediated recognition of S. enterica by human neutrophils, thus thwarting the immune protection against Salmonella. PMID- 25705211 TI - Computational prediction of molecular pathogen-host interactions based on dual transcriptome data. AB - Inference of inter-species gene regulatory networks based on gene expression data is an important computational method to predict pathogen-host interactions (PHIs). Both the experimental setup and the nature of PHIs exhibit certain characteristics. First, besides an environmental change, the battle between pathogen and host leads to a constantly changing environment and thus complex gene expression patterns. Second, there might be a delay until one of the organisms reacts. Third, toward later time points only one organism may survive leading to missing gene expression data of the other organism. Here, we account for PHI characteristics by extending NetGenerator, a network inference tool that predicts gene regulatory networks from gene expression time series data. We tested multiple modeling scenarios regarding the stimuli functions of the interaction network based on a benchmark example. We show that modeling perturbation of a PHI network by multiple stimuli better represents the underlying biological phenomena. Furthermore, we utilized the benchmark example to test the influence of missing data points on the inference performance. Our results suggest that PHI network inference with missing data is possible, but we recommend to provide complete time series data. Finally, we extended the NetGenerator tool to incorporate gene- and time point specific variances, because complex PHIs may lead to high variance in expression data. Sample variances are directly considered in the objective function of NetGenerator and indirectly by testing the robustness of interactions based on variance dependent disturbance of gene expression values. We evaluated the method of variance incorporation on dual RNA sequencing (RNA-Seq) data of Mus musculus dendritic cells incubated with Candida albicans and proofed our method by predicting previously verified PHIs as robust interactions. PMID- 25705212 TI - Extracellular peptidase hunting for improvement of protein production in plant cells and roots. AB - Plant-based recombinant protein production systems have gained an extensive interest over the past few years, because of their reduced cost and relative safety. Although the first products are now reaching the market, progress are still needed to improve plant hosts and strategies for biopharming. Targeting recombinant proteins toward the extracellular space offers several advantages in terms of protein folding and purification, but degradation events are observed, due to endogenous peptidases. This paper focuses on the analysis of extracellular proteolytic activities in two production systems: cell cultures and root secretion (rhizosecretion), in Arabidopsis thaliana and Nicotiana tabacum. Proteolytic activities of extracellular proteomes (secretomes) were evaluated in vitro against two substrate proteins: bovine serum albumin (BSA) and human serum immunoglobulins G (hIgGs). Both targets were found to be degraded by the secretomes, BSA being more prone to proteolysis than hIgGs. The analysis of the proteolysis pH-dependence showed that target degradation was mainly dependent upon the production system: rhizosecretomes contained more peptidase activity than extracellular medium of cell suspensions, whereas variations due to plant species were smaller. Using class-specific peptidase inhibitors, serine, and metallopeptidases were found to be responsible for degradation of both substrates. An in-depth in silico analysis of genomic and transcriptomic data from Arabidopsis was then performed and led to the identification of a limited number of serine and metallo-peptidases that are consistently expressed in both production systems. These peptidases should be prime candidates for further improvement of plant hosts by targeted silencing. PMID- 25705213 TI - Chloroplast genome of Aconitum barbatum var. puberulum (Ranunculaceae) derived from CCS reads using the PacBio RS platform. AB - The chloroplast genome (cp genome) of Aconitum barbatum var. puberulum was sequenced using the third-generation sequencing platform based on the single molecule real-time (SMRT) sequencing approach. To our knowledge, this is the first reported complete cp genome of Aconitum, and we anticipate that it will have great value for phylogenetic studies of the Ranunculaceae family. In total, 23,498 CCS reads and 20,685,462 base pairs were generated, the mean read length was 880 bp, and the longest read was 2,261 bp. Genome coverage of 100% was achieved with a mean coverage of 132* and no gaps. The accuracy of the assembled genome is 99.973%; the assembly was validated using Sanger sequencing of six selected genes from the cp genome. The complete cp genome of A. barbatum var. puberulum is 156,749 bp in length, including a large single-copy region of 87,630 bp and a small single-copy region of 16,941 bp separated by two inverted repeats of 26,089 bp. The cp genome contains 130 genes, including 84 protein-coding genes, 34 tRNA genes and eight rRNA genes. Four forward, five inverted and eight tandem repeats were identified. According to the SSR analysis, the longest poly structure is a 20-T repeat. Our results presented in this paper will facilitate the phylogenetic studies and molecular authentication on Aconitum. PMID- 25705214 TI - Using giant scarlet runner bean embryos to uncover regulatory networks controlling suspensor gene activity. AB - One of the major unsolved issues in plant development is understanding the regulatory networks that control the differential gene activity that is required for the specification and development of the two major embryonic regions, the embryo proper and suspensor. Historically, the giant embryo of scarlet runner bean (SRB), Phaseolus coccineus, has been used as a model system to investigate the physiological events that occur early in embryogenesis-focusing on the question of what role the suspensor region plays. A major feature distinguishing SRB embryos from those of other plants is a highly enlarged suspensor containing at least 200 cells that synthesize growth regulators required for subsequent embryonic development. Recent studies have exploited the giant size of the SRB embryo to micro-dissect the embryo proper and suspensor regions in order to use genomics-based approaches to identify regulatory genes that may be involved in controlling suspensor and embryo proper differentiation, as well as the cellular processes that may be unique to each embryonic region. Here we review the current genomics resources that make SRB embryos a compelling model system for studying the early events required to program embryo development. PMID- 25705215 TI - Cytosine modifications in the honey bee (Apis mellifera) worker genome. AB - Epigenetic changes enable genomes to respond to changes in the environment, such as altered nutrition, activity, or social setting. Epigenetic modifications, thereby, provide a source of phenotypic plasticity in many species. The honey bee (Apis mellifera) uses nutritionally sensitive epigenetic control mechanisms in the development of the royal caste (queens) and the workers. The workers are functionally sterile females that can take on a range of distinct physiological and/or behavioral phenotypes in response to environmental changes. Honey bees have a wide repertoire of epigenetic mechanisms which, as in mammals, include cytosine methylation, hydroxymethylated cytosines, together with the enzymatic machinery responsible for these cytosine modifications. Current data suggests that honey bees provide an excellent system for studying the "social repertoire" of the epigenome. In this review, we elucidate what is known so far about the honey bee epigenome and its mechanisms. Our discussion includes what may distinguish honey bees from other model animals, how the epigenome can influence worker behavioral task separation, and how future studies can answer central questions about the role of the epigenome in social behavior. PMID- 25705216 TI - Structural modeling of tissue-specific mitochondrial alanyl-tRNA synthetase (AARS2) defects predicts differential effects on aminoacylation. AB - The accuracy of mitochondrial protein synthesis is dependent on the coordinated action of nuclear-encoded mitochondrial aminoacyl-tRNA synthetases (mtARSs) and the mitochondrial DNA-encoded tRNAs. The recent advances in whole-exome sequencing have revealed the importance of the mtARS proteins for mitochondrial pathophysiology since nearly every nuclear gene for mtARS (out of 19) is now recognized as a disease gene for mitochondrial disease. Typically, defects in each mtARS have been identified in one tissue-specific disease, most commonly affecting the brain, or in one syndrome. However, mutations in the AARS2 gene for mitochondrial alanyl-tRNA synthetase (mtAlaRS) have been reported both in patients with infantile-onset cardiomyopathy and in patients with childhood to adulthood-onset leukoencephalopathy. We present here an investigation of the effects of the described mutations on the structure of the synthetase, in an effort to understand the tissue-specific outcomes of the different mutations. The mtAlaRS differs from the other mtARSs because in addition to the aminoacylation domain, it has a conserved editing domain for deacylating tRNAs that have been mischarged with incorrect amino acids. We show that the cardiomyopathy phenotype results from a single allele, causing an amino acid change R592W in the editing domain of AARS2, whereas the leukodystrophy mutations are located in other domains of the synthetase. Nevertheless, our structural analysis predicts that all mutations reduce the aminoacylation activity of the synthetase, because all mtAlaRS domains contribute to tRNA binding for aminoacylation. According to our model, the cardiomyopathy mutations severely compromise aminoacylation whereas partial activity is retained by the mutation combinations found in the leukodystrophy patients. These predictions provide a hypothesis for the molecular basis of the distinct tissue-specific phenotypic outcomes. PMID- 25705217 TI - Novel approaches to the analysis of family data in genetic epidemiology. PMID- 25705218 TI - Post-exposure treatment of Ebola virus using passive immunotherapy: proposal for a new strategy. AB - BACKGROUND: Better treatments are urgently needed for the management of Ebola virus epidemics in Equatorial Africa. METHODS: We conducted a systematic review of the literature on the use of passive immunotherapy for the treatment or prevention of Ebola virus disease. We placed findings from this review into the context of passive immunotherapy currently used for venom-induced disease, and recent improvements in manufacturing of polyvalent antivenom products. RESULTS: Passive immunotherapy appears to be one of the most promising specific treatments for Ebola. However, its potential has been incompletely evaluated, considering the overall experience and recent improvement of immunotherapy. Development and use of heterologous serum derivatives could protect people exposed to Ebola viruses with reasonable cost and logistics. CONCLUSION: Hyperimmune equine IgG fragments and purified polyclonal whole IgG deserve further consideration as treatment for exposure to the Ebola virus. PMID- 25705220 TI - A novel multiple instance learning method based on extreme learning machine. AB - Since real-world data sets usually contain large instances, it is meaningful to develop efficient and effective multiple instance learning (MIL) algorithm. As a learning paradigm, MIL is different from traditional supervised learning that handles the classification of bags comprising unlabeled instances. In this paper, a novel efficient method based on extreme learning machine (ELM) is proposed to address MIL problem. First, the most qualified instance is selected in each bag through a single hidden layer feedforward network (SLFN) whose input and output weights are both initialed randomly, and the single selected instance is used to represent every bag. Second, the modified ELM model is trained by using the selected instances to update the output weights. Experiments on several benchmark data sets and multiple instance regression data sets show that the ELM-MIL achieves good performance; moreover, it runs several times or even hundreds of times faster than other similar MIL algorithms. PMID- 25705219 TI - Therapeutic Effects of PPAR alpha on Neuronal Death and Microvascular Impairment. AB - Peroxisome-proliferator activated receptor-alpha (PPARalpha) is a broadly expressed nuclear hormone receptor and is a transcription factor for diverse target genes possessing a PPAR response element (PPRE) in the promoter region. The PPRE is highly conserved, and PPARs thus regulate transcription of an extensive array of target genes involved in energy metabolism, vascular function, oxidative stress, inflammation, and many other biological processes. PPARalpha has potent protective effects against neuronal cell death and microvascular impairment, which have been attributed in part to its antioxidant and anti inflammatory properties. Here we discuss PPARalpha's effects in neurodegenerative and microvascular diseases and also recent clinical findings that identified therapeutic effects of a PPARalpha agonist in diabetic microvascular complications. PMID- 25705221 TI - Submucosal injection solution for endoscopic resection in gastrointestinal tract: a traditional and network meta-analysis. AB - Objective. To explore and define the current optimal submucosal injection solution used in ESD and EMR for gastrointestinal tract neoplasms in terms of clinical outcomes and other aspects. Methods. PubMed, Cochrane Library, Embase, and clinical trials register center were searched with terms of "endoscopic resection" and "submucosal injection solution" to identify relevant randomized controlled trials (RCTs). Both direct comparison using traditional meta-analysis method and indirect comparison using network meta-analysis method were performed. Results. A total of 11 RCTs with 1152 patients were included. Meta-analysis showed that, compared with normal saline, other submucosal injection solutions induced a significant increase in terms of en bloc resection rate (I (2) = 0%, OR = 2.11, 95% CI (1.36, 3.26), and P = 0.008) and complete resection rate (I (2) = 0%, OR = 2.14, 95% CI (1.41, 3.24), and P = 0.0003); and there was no significant difference in the incidence of total complications (I (2) = 0%, OR = 0.87, 95% CI (0.59, 1.29), and P = 0.49). Conclusions. Other newly developed submucosal injection solutions significantly increased en bloc resection rate and complete resection rate and decreased bleeding rate and finical cost of endoscopic resection in gastrointestinal tract, while current evidence did not find the difference between them, which need to be explored by further studies. PMID- 25705222 TI - Clinical Relationship between Steatocholecystitis and Gallbladder Contractility Measured by Cholescintigraphy. AB - Objective. Contractility of gallbladder is known to be decreased in fatty gallbladder diseases. However, clinical estimation data about this relationship is still lacking. The aim of this study was to investigate the association between steatocholecystitis and contractility of gallbladder. Methods. Patients with cholecystitis (steatocholecystitis versus nonsteatocholecystitis) who underwent cholescintigraphy before cholecystectomy were retrospectively evaluated in a single teaching hospital of Korea. The association of steatocholecystitis with contractility of gallbladder, measured by preoperative cholescintigraphy, was assessed by univariable and multivariable analysis. Results. A total of 432 patients were finally enrolled (steatocholecystitis versus nonsteatocholecystitis; 75 versus 357, calculous versus acalculous cholecystitis; 316 versus 116). In the multivariable analysis, age (OR: 0.94, 95% CI: 0.90-0.99, P = 0.01) and total serum cholesterol (OR: 1.02, 95% CI: 1.01-1.04, P = 0.04) were related to steatocholecystitis in patients with acalculous cholecystitis. Only age (OR: 0.97, 95% CI: 0.94-0.99, P = 0.004) was significantly related to steatocholecystitis in patients with calculous cholecystitis. However, ejection fraction of gallbladder reflecting contractility measured by cholescintigraphy was not related to steatocholecystitis irrespective of presence of gallbladder stone in patients with cholecystitis. Conclusion. Ejection fraction of gallbladder measured by cholescintigraphy cannot be used for the detection or confirmation of steatocholecystitis. PMID- 25705223 TI - Effect of low-dose (single-dose) magnesium sulfate on postoperative analgesia in hysterectomy patients receiving balanced general anesthesia. AB - Background and Aim. Aparallel, randomized, double blinded, placebo-controlled trial study was designed to assess the efficacy of single low dose of intravenous magnesium sulfate on post-total abdominal hysterectomy (TAH) pain relief under balanced general anesthesia. Subject and Methods. Forty women undergoing TAH surgery were assigned to two magnesium sulfate (N = 20) and normal saline (N = 20) groups randomly. The magnesium group received magnesium sulfate 50 mg.kg(-1) in 100 mL of normal saline solution i.v as single-dose, just 15 minutes before induction of anesthesia whereas patients in control group received 100 mL of 0.9% sodium chloride solution at the same time. The same balanced general anesthesia was induced for two groups. Pethidine consumption was recorded over 24 hours precisely as postoperative analgesic. Pain score was evaluated with Numeric Rating Scale (NRS) at 0, 6, 12, and 24 hours after the surgeries. Results. Postoperative pain score was lower in magnesium group at 6, 12, and 24 hours after the operations significantly (P < 0.05). Pethidine requirement was significantly lower in magnesium group throughout 24 hours after the surgeries (P = 0.0001). Conclusion. Single dose of magnesium sulfate during balanced general anesthesia could be considered as effective and safe method to reduce postoperative pain and opioid consumption after TAH. PMID- 25705224 TI - Anaplastic Thyroid Carcinoma: A ceRNA Analysis Pointed to a Crosstalk between SOX2, TP53, and microRNA Biogenesis. AB - It has been suggested that cancer stem cells (CSC) may play a central role in oncogenesis, especially in undifferentiated tumours. Anaplastic thyroid carcinoma (ATC) has characteristics suggestive of a tumour enriched in CSC. Previous studies suggested that the stem cell factor SOX2 has a preeminent hierarchical role in determining the characteristics of stem cells in SW1736 ATC cell line. In detail, silencing SOX2 in SW1736 is able to suppress the expression of the stem markers analysed, strongly sensitizing the line to treatment with chemotherapeutic agents. Therefore, in order to further investigate the role of SOX2 in ATC, a competing endogenous RNA (ceRNA) analysis was conducted in order to isolate new functional partners of SOX2. Among the interactors, of particular interest are genes involved in the biogenesis of miRNAs (DICER1, RNASEN, and EIF2C2), in the control cell cycle (TP53, CCND1), and in mitochondrial activity (COX8A). The data suggest that stemness, microRNA biogenesis and functions, p53 regulatory network, cyclin D1, and cell cycle control, together with mitochondrial activity, might be coregulated. PMID- 25705225 TI - Synergy between HDAC and PARP Inhibitors on Proliferation of a Human Anaplastic Thyroid Cancer-Derived Cell Line. AB - Anaplastic thyroid carcinoma (ATC) is a very aggressive human malignancy, having a marked degree of invasiveness and no features of thyroid differentiation. It is known that either HDAC inhibitors or PARP inhibitors have antiproliferative effects on thyroid cancer cells. Therefore, in this study the possible synergy between the two types of compounds has been investigated. The ATC-derived cell line SW1736 has been treated with the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) and the PARP inhibitor PJ34, alone or in combination. In terms of cell viability, the combination index value was always lower than 1 at various tested dosages, indicating, therefore, synergy in a wide range of doses for both compounds. Synergy was also observed in induction of apoptosis. In terms of thyroid-specific gene expression, synergy was observed for TSHR mRNA levels but not for NIS, TTF1, TTF2, and PAX8 mRNA levels. Altogether, these data suggest that the combined use of HDAC and PARP inhibitors may be a useful strategy for treatment of ATC. PMID- 25705226 TI - Pressure flow analysis in the assessment of preswallow pharyngeal bolus presence in Dysphagia. AB - Objectives. Preswallow pharyngeal bolus presence is evident in patients with oropharyngeal dysphagia. Pressure flow analysis (PFA) using high resolution manometry with impedance (HRMI) with AIMplot software is a method for objective interpretation of pharyngeal and upper esophageal sphincter (UES) pressures and bolus flow patterns during swallowing. This study aimed to observe alterations in PFA metrics in the event of preswallow pharyngeal bolus presence as seen on videofluoroscopy (VFSS). Methods. Swallows from 40 broad dysphagia patients and 8 controls were recorded with a HRMI catheter during simultaneous VFSS. Evidence of bolus presence and level reached prior to pharyngeal swallow onset was recorded. AIMPlot software derived automated PFA functional metrics. Results. Patients with bolus movement to the pyriform sinuses had a higher SRI, indicating greater swallow dysfunction. Amongst individual metrics, TNadImp to PeakP was shorter and flow interval longer in patient groups compared to controls. A higher pharyngeal mean impedance and UES mean impedance differentiated the two patient groups. Conclusions. This pilot study identifies specific altered PFA metrics in patients demonstrating preswallow pharyngeal bolus presence to the pyriform sinuses. PFA metrics may be used to guide diagnosis and treatment of patients with oropharyngeal dysphagia and track changes in swallow function over time. PMID- 25705227 TI - Sinus venosus atrial septal defect as a cause of palpitations and dyspnea in an adult: a diagnostic imaging challenge. AB - Sinus venosus atrial septal defects (SV-ASD) have nonspecific clinical presentations and represent a diagnostic imaging challenge. Transthoracic echocardiography (TTE) remains the initial diagnostic imaging modality. However, detection rates have been as low as 12%. Transesophageal echocardiography (TEE) improves diagnostic accuracy though it may not detect commonly associated partial anomalous pulmonary venous return (PAPVR). Cardiac magnetic resonance (CMR) imaging provides a noninvasive, highly sensitive and specific imaging modality of SV-ASD. We describe a case of an adult male with exercise-induced, paroxysmal supraventricular tachycardia who presented with palpitations and dyspnea. Despite nondiagnostic imaging results on TTE, CMR proved to be instrumental in visualizing a hemodynamically significant SV-ASD with PAPVR that ultimately led to surgical correction. PMID- 25705228 TI - An unusual occurrence of hepatic granulomas and secondary sitosterolemia in turner syndrome. AB - Although abnormal liver function tests occur in 50-80% of cases with Turner syndrome, there are no previous reports of overt hepatic disease or hepatic granulomas associated with Turner's syndrome. We report three cases of Turner syndrome associated with hepatic granulomas with a wide range of liver dysfunction. Of the three patients, first patient underwent liver transplantation; second patient remained stable on immunosuppressants; and third patient died from complications of decompensated liver cirrhosis as she declined liver transplantation due to multiple comorbidities. One patient had sitosterolemia, a rare inherited autosomal recessive disorder of cholesterol metabolism, after she ingested beta-sitosterol supplement and had worsening liver function tests and lipid panel. She had remarkably abnormal lipid panel that responded to ezetimibe and by stopping the beta-sitosterol supplement. PMID- 25705229 TI - Successful and Safe Treatment of Chronic Spontaneous Urticaria with Omalizumab in a Woman during Two Consecutive Pregnancies. AB - Chronic spontaneous urticaria is an itching skin disease characterised by wheals, angioedema, or both present for more than six weeks. Omalizumab is a humanized anti-IgE monoclonal antibody recently approved for treatment of chronic urticaria. Several randomised controlled trials have investigated the safety, tolerability, and efficacy of omalizumab for chronic urticaria. The safety of omalizumab in pregnancy is not known. We describe a female patient with chronic spontaneous urticaria who was treated with omalizumab continuously through two consecutive pregnancies with convincing results and no apparent toxicity. PMID- 25705230 TI - Metastatic malignant melanoma of the inguinal lymph node with unknown primary lesion. AB - Background. Malignant melanoma could present with metastasis with unknown primary (MUP) and this happens in 2-3% according to the studies. Around 90% of melanomas have cutaneous origin, but still there are melanomas that could be found in visceral organs or lymph nodes with unknown primary site. Spontaneous regression of the primary site could be an explanation. Case Report. We report a 58-year-old Caucasian male who presented with a right sided swelling in the inguinal region. Surgery was performed and biopsy showed metastatic malignant melanoma. No cutaneous lesions were identified by history or physical examination. Work up could not detect the primary lesion and patient was started on radiotherapy and immunotherapy. Conclusion. We present a case of malignant melanoma of unknown primary presenting in an unusual place which is the inguinal lymph node. Theories try to explain the pathway of development of such tumors and one of the theories mentions that it could be a spontaneous regression of the primary cutaneous lesion. Another theory is that it could be from transformation of aberrant melanocyte within the lymph node. Prognosis is postulated to be better in this case than in melanoma with a known primary. PMID- 25705231 TI - High dose dexmedetomidine: effective as a sole agent sedation for children undergoing MRI. AB - Objective. To determine the efficacy and safety of high dose dexmedetomidine as a sole sedative agent for MRI. We report our institution's experience. Design. A retrospective institutional review of dexmedetomidine usage for pediatric MRI over 5.5 years. Protocol included a dexmedetomidine bolus of 2 MUg/kg intravenously over ten minutes followed by 1 MUg/kg/hr infusion. 544 patients received high dose dexmedetomidine for MRI. A second bolus was used in 103 (18.9%) patients. 117 (21.5%) required additional medications. Efficacy, side effects, and use of additional medicines to complete the MRI were reviewed. Data was analyzed using Student's t-test, Fisher's exact test, and Analysis of Variance (ANOVA). Main Results. Dexmedetomidine infusion was associated with bradycardia (3.9%) and hypotension (18.4%). None of the patients required any intervention. Vital signs were not significantly different among the subgroup of patients receiving one or two boluses of dexmedetomidine or additional medications. Procedure time was significantly shorter in the group receiving only one dexmedetomidine bolus and increased with second bolus or additional medications (P < 0.0001). Discharge time was longer for children experiencing bradycardia (P = 0.0012). Conclusion. High dose Dexmedetomidine was effective in 78.5% of cases; 21.5% of patients required additional medications. Side effects occurred in approximately 25% of cases, resolving spontaneously. PMID- 25705232 TI - Insights and advances in chronic urticaria: a Canadian perspective. AB - In the past few years there have been significant advances which have changed the face of chronic urticaria. In this review, we aim to update physicians about clinically relevant advances in the classification, diagnosis and management of chronic urticaria that have occurred in recent years. These include clarification of the terminology used to describe and classify urticaria. We also detail the development and validation of instruments to assess urticaria and understand the impairment on quality-of-life and the morbidity caused by this disease. Additionally, the approach to management of chronic urticaria now focuses on evidence-based use of non-impairing, non-sedating H1-antihistamines given initially in standard doses and if this is not effective, in up to 4-fold doses. For urticaria refractory to H1-antihistamines, omalizumab treatment has emerged as an effective, safe option. PMID- 25705233 TI - Ameliorating Effects of Ethanol Extract of Fructus mume on Scopolamine-Induced Memory Impairment in Mice. AB - We previously reported that Fructus mume (F. mume) extract shows protective effects on memory impairments and anti-inflammatory effects induced by chronic cerebral hypoperfusion. Neurodegeneration of basal cholinergic neurons is also observed in the brain with chronic cerebral hypoperfusion. Therefore, the present study was conducted to examine whether F. mume extracts enhance cognitive function via the action of cholinergic neuron using a scopolamine-induced animal model of memory impairments. F. mume (50, 100, or 200 mg/kg) was administered to C57BL/6 mice for 14 days (days 1-14) and memory impairment was induced by scopolamine (1 mg/kg), a muscarinic receptor antagonist for 7 days (days 8-14). Spatial memory was assessed using Morris water maze and hippocampal level of acetylcholinesterase (AChE) and choline acetyltransferase (ChAT) was examined by ELISA and immunoblotting. Mice that received scopolamine alone showed impairments in acquisition and retention in Morris water maze task and increased activity of AChE in the hippocampus. Mice that received F. mume and scopolamine showed no scopolamine-induced memory impairment and increased activity of AChE. In addition, treatments of F. mume increased ChAT expression in the hippocampus. These results indicated that F. mume might enhance cognitive function via action of cholinergic neurons. PMID- 25705234 TI - Icariin Prevents Amyloid Beta-Induced Apoptosis via the PI3K/Akt Pathway in PC-12 Cells. AB - Icariin is a prenylated flavonol glycoside derived from the Chinese herb Epimedium sagittatum that exerts a variety of pharmacological activities and shows promise in the treatment and prevention of Alzheimer's disease. In this study, we investigated the neuroprotective effects of icariin against amyloid beta protein fragment 25-35 (Abeta 25-35) induced neurotoxicity in cultured rat pheochromocytoma PC12 cells and explored potential underlying mechanisms. Our results showed that icariin dose-dependently increased cell viability and decreased Abeta 25-35-induced apoptosis, as assessed by MTT assay and Annexin V/propidium iodide staining, respectively. Results of western blot analysis revealed that the selective phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 suppressed icariin-induced Akt phosphorylation, suggesting that the protective effects of icariin are associated with activation of the PI3K/Akt signaling pathway. LY294002 also blocked the icariin-induced downregulation of proapoptotic factors Bax and caspase-3 and upregulation of antiapoptotic factor Bcl-2 in Abeta 25-35-treated PC12 cells. These findings provide further evidence for the clinical efficacy of icariin in the treatment of Alzheimer's disease. PMID- 25705235 TI - In vivo and in vitro metabolites from the main diester and monoester diterpenoid alkaloids in a traditional chinese herb, the aconitum species. AB - Diester diterpenoid alkaloids (DDAs), such as aconitine (AC), mesaconitine (MA), and hypaconitine (HA), are both pharmacologically active compounds and toxic ingredients in a traditional Chinese herb, the Aconitum species. Many DDA metabolism studies have been performed to explore mechanisms for reducing toxicity in these compounds and in Aconitum species extracts for safe clinical administration. In this review, we summarize recent progress on the metabolism of toxic AC, MA, and HA and corresponding monoester diterpenoid alkaloids (MDAs) in the gastrointestinal tract and liver in different animal species and humans in vivo and/or in vitro, where these alkaloids are primarily metabolized by cytochrome P450 enzymes, carboxylesterases, and intestinal bacteria, which produces phase I metabolites, ester hydrolysed products, and lipoalkaloids. Furthermore, we classify metabolites detected in the blood and urine, where the aforementioned metabolites are absorbed and excreted. Less toxic MDAs and nontoxic alcohol amines are the primary DDA metabolites detected in the blood. Most other DDAs metabolites produced in the intestine and liver detected in the urine have not been reported in the blood. We propose an explanation for this nonconformity. Finally, taking AC, for instance, we generalize a process of toxicity reduction in the body after oral AC administration for the first time. PMID- 25705236 TI - Animal study on primary dysmenorrhoea treatment at different administration times. AB - The new methods of different administration times for the treatment of primary dysmenorrhea are more widely used clinically; however, no obvious mechanism has been reported. Therefore, an animal model which is closer to clinical evaluation is indispensable. A novel animal experiment with different administration times, based on the mice oestrous cycle, for primary dysmenorrhoea treatment was explored in this study. Mice were randomly divided into two parts (one-cycle and three-cycle part) and each part includes five groups (12 mice per group), namely, Jingqian Zhitong Fang (JQF) 6-day group, JQF last 3-day group, Yuanhu Zhitong tablet group, model control group, and normal control group. According to the one way ANOVAs, results (writhing reaction, and PGF2alpha , PGE2, NO, and calcium ions analysis by ELISA) of the JQF cycle group were in accordance with those of JQF last 3-day group. Similarly, results of three-cycle continuous administration were consistent with those of one-cycle treatment. In conclusion, the consistency of the experimental results illustrated that the novel animal model based on mice oestrous cycle with different administration times is more reasonable and feasible and can be used to explore in-depth mechanism of drugs for the treatment of primary dysmenorrhoea in future. PMID- 25705237 TI - Reversal of Multidrug Resistance by the Chinese Medicine Yiqi Jianpi Huaji Decoction and the Mechanism of Action in Human Gastric Cancer SGC7901/VCR Cells. AB - Yiqi Jianpi Huaji Decoction (YJHD), a traditional Chinese medicinal formula composed of twelve ingredients, has recently been reported to have a good clinical curative effect. The purpose of the present study was to evaluate the effects of YJHD on SGC7901/VCR gastric cancer cells and to elucidate the possible mechanism of action. First, the effects of a low dose of YJHD in combination with chemotherapeutic agents on SGC7901/VCR cells were assessed using the CCK-8 assay and flow cytometry, and the effects of YJHD on genes and proteins involved in drug resistance (MDR1, MRP, TUBB3, STMN1, and TS) were evaluated. Furthermore, transfection of SGC7901/VCR cells with siRNAs targeting these genes inhibited their expression, and the efficacy of vincristine against the cells was dramatically improved in vitro when these genes were silenced. These results demonstrate that low-dose YJHD inhibited cell proliferation, induced apoptosis, reversed MDR, and increased sensitivity to chemotherapeutic agents in vitro by downregulating P-gp, MRP, TUBB3, and STMN1 expression. MDR can be reversed by siRNAs targeting genes involved in MDR, and this strategy for cancer treatment should be evaluated in future studies. PMID- 25705238 TI - Molecular signatures in the prevention of radiation damage by the synergistic effect of N-acetyl cysteine and qingre liyan decoction, a traditional chinese medicine, using a 3-dimensional cell culture model of oral mucositis. AB - Qingre Liyan decoction (QYD), a Traditional Chinese medicine, and N-acetyl cysteine (NAC) have been used to prevent radiation induced mucositis. This work evaluates the protective mechanisms of QYD, NAC, and their combination (NAC-QYD) at the cellular and transcriptional level. A validated organotypic model of oral mucosal consisting of a three-dimensional (3D) cell tissue-culture of primary human keratinocytes exposed to X-ray irradiation was used. Six hours after the irradiation, the tissues were evaluated by hematoxylin and eosin (H and E) and a TUNEL assay to assess histopathology and apoptosis, respectively. Total RNA was extracted and used for microarray gene expression profiling. The tissue-cultures treated with NAC-QYD preserved their integrity and showed no apoptosis. Microarray results revealed that the NAC-QYD caused the upregulation of genes encoding metallothioneins, HMOX1, and other components of the Nrf2 pathway, which protects against oxidative stress. DNA repair genes (XCP, GADD45G, RAD9, and XRCC1), protective genes (EGFR and PPARD), and genes of the NFkappaB pathway were upregulated. Finally, tissue-cultures treated prophylactically with NAC-QYD showed significant downregulation of apoptosis, cytokines and chemokines genes, and constrained damage-associated molecular patterns (DAMPs). NAC-QYD treatment involves the protective effect of Nrf2, NFkappaB, and DNA repair factors. PMID- 25705239 TI - Millimeter Wave Treatment Inhibits Apoptosis of Chondrocytes via Regulation Dynamic Equilibrium of Intracellular Free Ca (2+). AB - The molecular mechanisms of TNF-alpha-induced apoptosis of chondrocyte and the role of Ca(2+) mediating the effects of MW on TNF-alpha-induced apoptosis of chondrocytes remained unclear. In this study, we investigated the molecular mechanism underlying inhibiting TNF-alpha-induced chondrocytes apoptosis of MW. MTT assay, DAPI, and flow cytometry demonstrated that MW significantly increased cell activity and inhibited chromatin condensation accompanying the loss of plasma membrane asymmetry and the collapse of mitochondrial membrane potential. Our results also indicated that MW reduced the elevation of [Ca(2+)] i in chondrocytes by LSCM. Moreover, MW suppressed the protein levels of calpain, Bax, cytochrome c, and caspase-3, while the expressions of Bcl-2, collagen II, and aggrecan were increased. Our evidences indicated that MW treatment inhibited the apoptosis of chondrocytes through depression of [Ca(2+)] i . It also inhibited calpain activation, which mediated Bax cleavage and cytochrome c release and initiated the apoptotic execution phase. In addition, MW treatment increased the expression of collagen II and aggrecan of chondrocytes. PMID- 25705240 TI - Traditional Chinese Herb Combined with Surgery versus Surgery for Varicocele Infertility: A Systematic Review and Meta-Analysis. AB - Objective. The objective of this study was to conduct a systematic review to assess the effectiveness and safety of traditional Chinese herb combined with surgery for male varicocele infertility compared to surgery. Methods. Randomized controlled trials (RCTs) data of traditional Chinese herbs combined with surgery for male varicocele fertility versus surgery were collected by searching the Cochrane Library, Embase, PubMed, and Chinese databases. The risk of bias was assessed using Cochrane Handbook. Study outcomes were presented as risk ratios (RRs) for dichotomous data. Results. Seventeen of 72 potentially relevant trials met the inclusion criteria. The methodological qualities of the RCTs were low. Compared with the surgery group, the traditional Chinese herb combined with surgery group had superiority in pregnancy rate at 3-month (RR = 1.76, and P = 0.008), 6-month (RR = 1.58, and P = 0.0005), and 2-year (RR = 1.58, and P = 0.0005) follow-ups. No RCT was found to describe the side effects. Conclusion. On considering the low methodological quality of RCTs, there was no enough evidence on traditional Chinese herb with surgery for male varicocele infertility, and more high-quality RCTs of large sample sizes are required. PMID- 25705241 TI - Increased mortality after a first myocardial infarction in human immunodeficiency virus-infected patients; a nested cohort study. AB - AIMS: HIV infection may be associated with an increased recurrence rate of myocardial infarction. Our aim was to determine whether HIV infection is a risk factor for worse outcomes in patients with coronaray artery disease. METHODS: We compared data aggregated from two ongoing cohorts: (i) the Acute Myocardial Infarction in Switzerland (AMIS) registry, which includes patients with acute myocardial infarction (AMI), and (ii) the Swiss HIV Cohort Study (SHCS), a prospective registry of HIV-positive (HIV+) patients. We included all patients who survived an incident AMI occurring on or after 1st January 2005. Our primary outcome measure was all-cause mortality at one year; secondary outcomes included AMI recurrence and cardiovascular-related hospitalisations. Comparisons used Cox and logistic regression analyses, respectively. RESULTS: There were 133 HIV+, (SHCS) and 5,328 HIV-negative [HIV-] (AMIS) individuals with incident AMI. In the SHCS and AMIS registries, patients were predominantly male (72% and 85% male, respectively), with a median age of 51 years (interquartile range [IQR] 46-57) and 64 years (IQR 55-74), respectively. Nearly all (90%) of HIV+ individuals were on successful antiretroviral therapy. During the first year of follow-up, 5 (3.6%) HIV+ and 135 (2.5%) HIV- individuals died. At one year, HIV+ status after adjustment for age, sex, calendar year of AMI, smoking status, hypertension and diabetes was associated with a higher risk of death (HR 4.42, 95% CI 1.73-11.27). There were no significant differences in recurrent AMIs (4 [3.0%] HIV+ and 146 [3.0%] HIV- individuals, OR 1.16, 95% CI 0.41-3.27) or in hospitalization rates (OR 0.68 [95% CI 0.42-1.11]). CONCLUSIONS: HIV infection was associated with a significantly increased risk of all-cause mortality one year after incident AMI. PMID- 25705242 TI - Repeated stressors in adulthood increase the rate of biological ageing. AB - BACKGROUND: Individuals of the same age can differ substantially in the degree to which they have accumulated tissue damage, akin to bodily wear and tear, from past experiences. This accumulated tissue damage reflects the individual's biological age and may better predict physiological and behavioural performance than the individual's chronological age. However, at present it remains unclear how to reliably assess biological age in individual wild vertebrates. METHODS: We exposed hand-raised adult Eurasian blackbirds (Turdus merula) to a combination of repeated immune and disturbance stressors for over one year to determine the effects of chronic stress on potential biomarkers of biological ageing including telomere shortening, oxidative stress load, and glucocorticoid hormones. We also assessed general measures of individual condition including body mass and locomotor activity. RESULTS: By the end of the experiment, stress-exposed birds showed greater decreases in telomere lengths. Stress-exposed birds also maintained higher circulating levels of oxidative damage compared with control birds. Other potential biomarkers such as concentrations of antioxidants and glucocorticoid hormone traits showed greater resilience and did not differ significantly between treatment groups. CONCLUSIONS: The current data demonstrate that repeated exposure to experimental stressors affects the rate of biological ageing in adult Eurasian blackbirds. Both telomeres and oxidative damage were affected by repeated stress exposure and thus can serve as blood-derived biomarkers of biological ageing. PMID- 25705243 TI - PTH(1-84) replacement therapy for the treatment of hypoparathyroidism. AB - Hypoparathyroidism is a rare disease characterized by hypocalcemia and insufficient circulating levels of parathyroid hormone (PTH). Conventional therapy includes calcium and active vitamin D supplementation, often in large doses. Therapy with calcium and vitamin D, however, does not address certain problematic aspects of the disease, including abnormal bone metabolism and reduced quality of life. Hypoparathyroidism is the only classic endocrine deficiency disease for which the missing hormone, PTH, is not yet an approved treatment. PTH(1-84) may soon become a therapeutic option for patients with hypoparathyroidism. PTH (1-84) has been demonstrated to maintain serum calcium while reducing or eliminating requirements for calcium and active vitamin D supplementation. Data from bone densitometry, bone turnover markers and histomorphometry of bone biopsy specimens show positive structural and dynamic effects on the skeleton. PTH replacement therapy may also be associated with improved quality of life. PTH(1-84) replacement therapy for hypoparathyroidism is promising, although further acquisition of long-term data is needed. PMID- 25705244 TI - Language performance in postmenopausal women with and without hormone therapy and men. AB - AIMS: In the current study, we explored the potential effects of hormone therapy (HT) on language functioning in healthy, postmenopausal women and compared them with men of similar ages. MATERIALS & METHODS: Language functioning on tasks of verbal fluency and object naming was examined in 100 participants (mean age: 61.9 years; 33 HT users, 15 HT non-users and 52 men) at baseline and follow-up (mean follow-up time period: 2.6 years). RESULTS: At baseline, men had higher composite language scores than HT users. However, HT users demonstrated more improvement over time compared with men, whereas HT non-users performed similarly to men, with no improvement over time. Longer duration of HT use was not associated with improved performance on language tests. CONCLUSION: These results suggest an association between HT use and better language ability in postmenopausal women. PMID- 25705245 TI - Automated characterization of flowering dynamics in rice using field-acquired time-series RGB images. AB - BACKGROUND: Flowering (spikelet anthesis) is one of the most important phenotypic characteristics of paddy rice, and researchers expend efforts to observe flowering timing. Observing flowering is very time-consuming and labor-intensive, because it is still visually performed by humans. An image-based method that automatically detects the flowering of paddy rice is highly desirable. However, varying illumination, diversity of appearance of the flowering parts of the panicles, shape deformation, partial occlusion, and complex background make the development of such a method challenging. RESULTS: We developed a method for detecting flowering panicles of rice in RGB images using scale-invariant feature transform descriptors, bag of visual words, and a machine learning method, support vector machine. Applying the method to time-series images, we estimated the number of flowering panicles and the diurnal peak of flowering on each day. The method accurately detected the flowering parts of panicles during the flowering period and quantified the daily and diurnal flowering pattern. CONCLUSIONS: A powerful method for automatically detecting flowering panicles of paddy rice in time-series RGB images taken under natural field conditions is described. The method can automatically count flowering panicles. In application to time-series images, the proposed method can well quantify the daily amount and the diurnal changes of flowering during the flowering period and identify daily peaks of flowering. PMID- 25705246 TI - Saccadic oscillations - membrane, model, and medicine. AB - Saccadic oscillations are continuous back-to-back saccades that cause excessive image motion across fovea and threaten clear vision. Acquired processes, related to immune or metabolic mechanisms, are common culprits. Saccadic oscillations are also seen in degenerative cerebellar disease or as a part of a familial syndrome of saccadic oscillations and limb tremor. Some normal individuals have innate ability to voluntarily trigger saccadic oscillations (i.e. voluntary nystagmus). Contemporary theory for the pathogenesis for saccadic oscillations has emphasized hyperexcitable or disinhibited state of the brainstem saccadic burst neuron membrane. This review discusses etiologies and treatment of saccadic oscillations in light of novel cell membrane based theory. PMID- 25705248 TI - MoDock: A multi-objective strategy improves the accuracy for molecular docking. AB - BACKGROUND: As a main method of structure-based virtual screening, molecular docking is the most widely used in practice. However, the non-ideal efficacy of scoring functions is thought as the biggest barrier which hinders the improvement of the molecular docking method. RESULTS: A new multi-objective strategy for molecular docking, named as MoDock, is presented to further improve the docking accuracy with available scoring functions. Instead of simple combination of multiple objectives with fixed weight factors, an aggregate function is adopted to approximate the real solution of the original multi-objective and multi constraint problem, which will simultaneously smooth the energy surface of the combined scoring functions. Then, method of centers and genetic algorithm are used to find the optimal solution. Tests of MoDock against the GOLD test data set reveal the multi-objective strategy improves the docking accuracy over the individual scoring functions. Meanwhile, a 70% ratio of the good docking solutions with the RMSD value below 1.0 A outperforms other 6 commonly used docking programs, even with a flexible receptor docking program included. CONCLUSIONS: The results show MoDock is an effective strategy to overcome the deviations brought by single scoring function, and improves the prediction power of molecular docking. PMID- 25705249 TI - Fingerprint analysis of processed Rhizoma Chuanxiong by high-performance liquid chromatography coupled with diode array detection. AB - BACKGROUND: Rhizoma Chuanxiong (RC) is the dried rhizome of Ligusticum chuanxiong Hort., and various types of processed Rhizoma Chuanxiong (PRC) are widely used in China. However, quality assurance and quality control of these processed medicines remain challenging. This study aims to investigate the chemical compositions of various PRC preparations by a high-performance liquid chromatography (HPLC) coupled with diode array detection (DAD) method. METHODS: A HPLC-DAD method with validation was developed for PRC samples. Seven batches of plant samples from two processing methods, stir-frying and steaming, were analyzed by the HPLC-DAD method. Common peaks in PRC chromatograms were chosen to calculate their relative retention time (RRT) and relative peak area (RPA), and similarity analyses of the chromatographic fingerprints were conducted by Similarity Evaluation System for Chromatographic Fingerprint of Traditional Chinese Medicine software (Version 2004 A). RESULTS: In the 24-h stability test, the relative standard deviation for the RRT and RPA was less than 0.07% and 2.57%, respectively. The precision was less than 0.08% for the RRT and 2.48% for the RPA. The repeatability for the RRT and RPA was less than 0.03% and 2.64%, respectively. The similarities between the seven PRC batches were range from 0.956 to 0.990. After stir-frying or steaming, the amount of ferulic acid in PRC was much higher than that in the raw material. CONCLUSIONS: The fingerprint analysis of PRC by different processing methods was feasible by HPLC-DAD. PMID- 25705250 TI - Molecular screening for Epstein Barr virus (EBV) among Sudanese patients with nasopharyngeal carcinoma (NPC). AB - OBJECTIVE: The aim of this study was to screen for the presence of Epstein Barr Virus (EBV) among Sudanese patients with Nasopharyngeal Carcinoma (NPC). METHODS: In this study, 150 tissue samples that were previously diagnosed as having NPC were screened for the presence of EBV using Polymerase Chain Reaction (PCR). PCR was performed to amplify two viral genes; EBV nuclear antigen-4 (EBNA-4) and latent membrane protein-1 (LMP1). RESULTS: EBV genes were detected in 92/150 (61.3%) tissue samples. Of the 92 infected samples, 58/92 (63%) were found among males and 34/92 (37%) were among females. CONCLUSION: EBV is prevalent in the Sudan and responsible of the vast majority of cases of NPC. PMID- 25705251 TI - HIV-1 Tat induces DNMT over-expression through microRNA dysregulation in HIV related non Hodgkin lymphomas. AB - BACKGROUND: A close association between HIV infection and the development of cancer exists. Although the advent of highly active antiretroviral therapy has changed the epidemiology of AIDS-associated malignancies, a better understanding on how HIV can induce malignant transformation will help the development of novel therapeutic agents. METHODS: HIV has been reported to induce the expression of DNMT1 in vitro, but still no information is available about the mechanisms regulating DNMT expression in HIV-related B-cell lymphomas. In this paper, we investigated the expression of DNMT family members (DNMT1, DNMT3a/b) in primary cases of aggressive B-cell lymphomas of HIV-positive subjects. RESULTS: Our results confirmed the activation of DNMT1 by HIV in vivo, and reported for the first time a marked up-regulation of DNMT3a and DNMT3b in HIV-positive aggressive B-cell lymphomas. DNMT up-regulation in HIV-positive tumors correlated with down regulation of specific microRNAs, as the miR29 family, the miR148-152 cluster, known to regulate their expression. Literature reports the activation of DNMTs by the human polyomavirus BKV large T-antigen and adenovirus E1a, through the pRb/E2F pathway. We have previously demonstrated that the HIV Tat protein is able to bind to the pocket proteins and to inactivate their oncosuppressive properties, resulting in uncontrolled cell proliferation. Therefore, we focused on the role of Tat, due to its capability to be released from infected cells and to dysregulate uninfected ones, using an in vitro model in which Tat was ectopically expressed in B-cells. CONCLUSIONS: Our findings demonstrated that the ectopic expression of Tat was per se sufficient to determine DNMT up-regulation, based on microRNA down-regulation, and that this results in aberrant hypermethylation of target genes and microRNAs. These results point at a direct role for Tat in participating in uninfected B-cell lymphomagenesis, through dysregulation of the epigenetical control of gene expression. PMID- 25705252 TI - Cytotoxic activity of triazole-containing alkyl beta-D-glucopyranosides on a human T-cell leukemia cell line. AB - BACKGROUND: Simple glycoside surfactants represent a class of chemicals that are produced from renewable raw materials. They are considered to be environmentally safe and, therefore, are increasingly used as pharmaceuticals, detergents, and personal care products. Although they display low to moderate toxicity in cells in culture, the underlying mechanisms of surfactant-mediated cytotoxicity are poorly investigated. RESULTS: We synthesized a series of triazole-linked (fluoro)alkyl beta-glucopyranosides using the copper-catalyzed azide-alkyne reaction, one of many popular "click" reactions that enable efficient preparation of structurally diverse compounds, and investigate the toxicity of this novel class of surfactant in the Jurkat cell line. Similar to other carbohydrate surfactants, the cytotoxicity of the triazole-linked alkyl beta-glucopyranosides was low, with IC50 values decreasing from 1198 to 24 MUM as the hydrophobic tail length increased from 8 to 16 carbons. The two alkyl beta-glucopyranosides with the longest hydrophobic tails caused apoptosis by mechanisms involving mitochondrial depolarization and caspase-3 activation. CONCLUSIONS: Triazole linked, glucose-based surfactants 4a-g and other carbohydrate surfactants may cause apoptosis, and not necrosis, at low micromolar concentrations via induction of the intrinsic apoptotic cascade; however, additional studies are needed to fully explore the molecular mechanisms of their toxicity. Graphical AbstractTriazole-linked, glucose-based surfactants cause apoptosis, and not necrosis, at low micromolar concentrations via induction of the intrinsic apoptotic cascade. PMID- 25705253 TI - A high throughput gold nanoparticles chemiluminescence detection of opioid receptor antagonist naloxone hydrochloride. AB - BACKGROUND: The opioid antagonist agent naloxone hydrochloride (NLX) is a drug that has high affinity for opiate receptors but do not activate these receptors. Owing to the role of this drug to block the effects of exogenous administered opioids and endogenous released endorphians we can deduce the importance of developing sensitive analytical methods for detection of such drug. In the present study gold nanoparticles (AuNPs) was employed for enhancing the chemiluminescence (CL) signals arising from luminol-ferricyanide reaction in the presence of naloxone hydrochloride using sequential injection chemiluminescence analysis (SIA). METHOD: In the present study gold nanoparticles (AuNPs) was employed for enhancing the chemiluminescence (CL) signals arising from luminol ferricyanide reaction in the presence of naloxone hydrochloride using sequential injection chemiluminescence analysis (SIA). RESULTS: The developed method was examined under optimum experimental conditions and the obtained results revealed a linear relationship between the relative CL intensity and the investigated drug at a concentration range of 1.0*10(-9)-1.0*10(-2) mol L(-1), (r = 0.9993, n=9) with detection and quantification limits of 1.6*10(-11) and 1.0*10(-9) mol L(-1), respectively. The relative standard deviation was 0.9%. CONCLUSION: The proposed method was employed for the determination of the investigated drug in bulk powder, its pharmaceutical dosage forms and biological fluids. The interference of some metals and amino acids on the CL intensity was investigated. Also the interference of some related pharmacological action drugs was tested. The obtained results of the developed method were statistically treated and compared with those obtained from other reported methods. Graphical AbstractUtility of gold nanparticles in luminol-potassium ferricyanide chemiluminescence system for determination of naloxone hydrochloride. PMID- 25705254 TI - An improved kilogram-scale preparation of atorvastatin calcium. AB - BACKGROUND: If literature protocols are followed, conversion of an advanced ketal ester intermediate (available in kilogram quantities via a published Paal-Knorr synthesis) to cholesterol-lowering drug atorvastatin calcium is hampered by several process issues, particularly at the final stage where the hemi-calcium salt is obtained. RESULTS: We developed a high-yielding synthesis of atorvastatin calcium salt on 7 kg scale that affords >99.5% product purities by introducing the following key improvements: i. isolating the pure product of the ketal deprotection step as crystalline solid, and ii. using a convenient ethyl acetate extraction procedure to isolate the pure atorvastatin calcium at the ester hydrolysis and counter-ion exchange step. CONCLUSION: The convenient and operationally simple conversion of an advanced intermediate of atorvastatin to the clinically used hemi-calcium salt form of the drug that is superior to the methods obtainable from the literature is now available to facilitate the production of atorvastatin calcium on industrial scale. Graphical abstractStepwise ketal and tert-butyl ester group hydrolysis and a modified work up protocol lead to a more convenient preparation of API-grade atorvastatin calcium. PMID- 25705255 TI - Semi-continuous anaerobic digestion for biogas production: influence of ammonium acetate supplement and structure of the microbial community. AB - BACKGROUND: As an efficient disposal method of food waste, anaerobic digestion (AD) for biogas production is widely used. In order to understand the enhanced efficiency and stability of AD by appropriate amounts of ammonia and volatile fatty acids (NH4 (+)/VFAs), the characteristics of the corresponding microbial community with ammonium acetate supplement were investigated by denatured gradient gel electrophoresis (DGGE) and pyrosequencing analyses of samples, with or without supplement of NH4 (+)/VFAs. RESULTS: In this study, four different supplement strategies of adding ammonium acetate were investigated, including a blank group (without supplement of ammonium acetate), a low group (L group, 0.7 g/L/d), a moderate group (M group, 1.0 g/L/d) and a high group (H group, 1.3 g/L/d), respectively. The average daily gas production was 1,839 mL/d, 1,655 mL/d, 1,448 mL/d and 1,488 mL/d for L, M, H and blank groups, respectively. The results reveal that the absence or overload of NH4 (+)/VFAs leads to the inhibition or failure of the AD operation. The blank and H groups were selected for further investigation of the microbial community by DGGE and pyrosequencing analyses. A significant difference of the microbial communities at different AD stages was observed between the blank and H groups. CONCLUSIONS: Ammonium acetate, as an efficient supplement, significantly influences the characteristics of a semi-continuous AD operation. The DGGE and pyrosequencing analyses indicated that the different bacterial and archaeal communities occurred in the blank and H groups at different AD stages. Thus, an appropriate ammonium acetate supplement may maintain the balance of the microbial community and could be applied to adjust the AD operation and microbial composition towards optimal biogas production. PMID- 25705256 TI - Influence of bark on fuel ethanol production from steam-pretreated spruce. AB - BACKGROUND: Bark and bark-containing forest residues have the potential for utilization as raw material for lignocellulosic ethanol production due to their abundance and low cost. However, the different physical properties and chemical composition of bark compared to the conventionally used wood chips may influence the spruce-to-ethanol bioconversion process. This study assesses the impact of bark on the overall bioconversion in two process configurations, separate hydrolysis and fermentation (SHF) and simultaneous saccharification and fermentation (SSF), utilizing steam-pretreated spruce bark and wood mixtures. RESULTS: Mixtures of different proportions of spruce bark and wood chips were subjected to SO2-catalyzed steam pretreatment at 210 degrees C for five minutes, which has been shown to be effective for the pretreatment of spruce wood chips. The final ethanol concentration was the highest without bark and decreased significantly with increasing proportions of bark in both process configurations. However, this decrease cannot be attributed solely to the lower availability of the carbohydrates in mixtures containing bark, as the ethanol yield also decreased, from 85 to 59% in SSF and from 84 to 51% in SHF, as the mass fraction of bark was increased from 0 to 100%. CONCLUSIONS: The results show that it was significantly more difficult to hydrolyse spruce bark to monomeric sugars than wood chips. Bark had an adverse effect on the whole bioconversion process due to its lower enzymatic hydrolyzability. On the other hand, bark inclusion had no detrimental effect on the fermentability of steam-pretreated spruce wood and bark mixtures. It was also observed that lower amounts of inhibitory degradation products were formed during the steam pretreatment of spruce bark than during the steam pretreatment of wood chips. PMID- 25705257 TI - The impact of a daily pre-operative surgical huddle on interruptions, delays, and surgeon satisfaction in an orthopedic operating room: a prospective study. AB - BACKGROUND: The goal of this project was to implement a daily pre-operative huddle (briefing) for orthopedic cases and evaluate the impact of the daily huddle on surgeons' perceptions of interruptions and operative delays. METHODS: Baseline measurements on interruptions, delays, and questions were obtained. Then the daily pre-operative huddle was introduced. Surgeons completed a surgical outcomes worksheet for each day's cases. Outcomes evaluated were primarily interruptions and delays starting cases before and following introduction of the huddle. RESULTS: 19 baseline observations and 19 huddle-implemented observations of surgeon's days were assessed. Overall, surgeon satisfaction increased and fewer delays occurred after introduction of huddles. Interruptions decreased in all categories including equipment, antibiotics, planned procedure and side. Time required for a huddle was less than one minute per case. CONCLUSIONS: In this pilot study, a daily pre-operative huddle improved the flow of a surgeon's day and satisfaction and indirectly provided indications of safety benefits by decreasing the number of interruptions and delays. Further studies in other surgical specialties should be conducted due to the promising results. Data was collected from three orthopedic surgeons in this phase; however, as a next step, data should be drawn from the rest of the orthopedic surgical team and other surgical subspecialties as well. PMID- 25705258 TI - Concomitant deletion of chromosome 16p13.11 and triplication of chromosome 19p13.3 in a child with developmental disorders, intellectual disability, and epilepsy. AB - BACKGROUND: Rare copy number variations (CNVs) are today recognized as an important cause of various neurodevelopmental disorders, including mental retardation and epilepsy. In some cases, a second CNV may contribute to a more severe clinical presentation. RESULTS: Here we describe a patient with epilepsy, mental retardation, developmental disorders, and dysmorphic features, who inherited a deletion of 16p13.11 and a triplication of 19p13.3 from his father and mother, respectively. The mother presented mild mental retardation and language delay too. CONCLUSIONS: We discuss the phenotypic consequences of the two CNVs and suggest that their synergistic effect is likely responsible for the complicated clinical features observed in our patient. PMID- 25705260 TI - The three-body problem of therapy with induced pluripotent stem cells. AB - Regenerative medicine has a three-body problem: alignment of the dynamics of the genome, stem cell and patient. Focusing on the rare inherited fragile skin disorder epidermolysis bullosa, three recent innovative studies have used induced pluripotent stem cells and gene correction, revertant mosaicism or genome editing to advance the prospects of better cell-based therapeutics to restore skin structure and function for epidermolysis bullosa and potentially other inherited diseases. PMID- 25705261 TI - Prediction of the potency of mammalian cyclooxygenase inhibitors with ensemble proteochemometric modeling. AB - Cyclooxygenases (COX) are present in the body in two isoforms, namely: COX-1, constitutively expressed, and COX-2, induced in physiopathological conditions such as cancer or chronic inflammation. The inhibition of COX with non-steroideal anti-inflammatory drugs (NSAIDs) is the most widely used treatment for chronic inflammation despite the adverse effects associated to prolonged NSAIDs intake. Although selective COX-2 inhibition has been shown not to palliate all adverse effects (e.g. cardiotoxicity), there are still niche populations which can benefit from selective COX-2 inhibition. Thus, capitalizing on bioactivity data from both isoforms simultaneously would contribute to develop COX inhibitors with better safety profiles. We applied ensemble proteochemometric modeling (PCM) for the prediction of the potency of 3,228 distinct COX inhibitors on 11 mammalian cyclooxygenases. Ensemble PCM models ([Formula: see text], and RMSEtest = 0.71) outperformed models exclusively trained on compound ([Formula: see text], and RMSEtest = 1.09) or protein descriptors ([Formula: see text] and RMSEtest = 1.10) on the test set. Moreover, PCM predicted COX potency for 1,086 selective and non selective COX inhibitors with [Formula: see text] and RMSEtest = 0.76. These values are in agreement with the maximum and minimum achievable [Formula: see text] and RMSEtest values of approximately 0.68 for both metrics. Confidence intervals for individual predictions were calculated from the standard deviation of the predictions from the individual models composing the ensembles. Finally, two substructure analysis pipelines singled out chemical substructures implicated in both potency and selectivity in agreement with the literature. Graphical AbstractPrediction of uncorrelated bioactivity profiles for mammalian COX inhibitors with Ensemble Proteochemometric Modeling. PMID- 25705262 TI - When drug discovery meets web search: Learning to Rank for ligand-based virtual screening. AB - BACKGROUND: The rapid increase in the emergence of novel chemical substances presents a substantial demands for more sophisticated computational methodologies for drug discovery. In this study, the idea of Learning to Rank in web search was presented in drug virtual screening, which has the following unique capabilities of 1). Applicable of identifying compounds on novel targets when there is not enough training data available for these targets, and 2). Integration of heterogeneous data when compound affinities are measured in different platforms. RESULTS: A standard pipeline was designed to carry out Learning to Rank in virtual screening. Six Learning to Rank algorithms were investigated based on two public datasets collected from Binding Database and the newly-published Community Structure-Activity Resource benchmark dataset. The results have demonstrated that Learning to rank is an efficient computational strategy for drug virtual screening, particularly due to its novel use in cross-target virtual screening and heterogeneous data integration. CONCLUSIONS: To the best of our knowledge, we have introduced here the first application of Learning to Rank in virtual screening. The experiment workflow and algorithm assessment designed in this study will provide a standard protocol for other similar studies. All the datasets as well as the implementations of Learning to Rank algorithms are available at http://www.tongji.edu.cn/~qiliu/lor_vs.html. Graphical AbstractThe analogy between web search and ligand-based drug discovery. PMID- 25705265 TI - The Tomorrow's Personalized Medicine - The Killer of Today's Statistical Medicine. PMID- 25705263 TI - The mutual interplay of lipid metabolism and the cells of the immune system in relation to atherosclerosis. AB - Atherosclerosis is a chronic inflammation in the arterial wall involving cells of the innate and adaptive immune system that is promoted by hyperlipidemia. In addition, the immune system can influence lipids and lipoprotein levels and cellular lipid homeostasis can influence the level and function of the immune cells. We will review the effects of manipulation of adaptive immune cells and immune cell products on lipids and lipoproteins, focusing mainly on studies performed in murine models of atherosclerosis. We also review how lipoproteins and cellular lipid levels, particularly cholesterol levels, influence the function of cells of the innate and adaptive immune systems. The overriding theme is that these interactions are driven by the need to provide the energy and membrane components for cell proliferation and migration, membrane expansion and other functions that are so important in the functioning of the immune cells. PMID- 25705266 TI - Neuropsychiatric side-effects of interferon-alpha treatment: pathophysiology and therapeutic options. AB - Interferon alpha (IFN-alpha) is the approved standard of care for chronic hepatitis C and B. Unfortunately, it has neuropsychiatric side-effects that have a major impact upon the quality of life and the drug adherence. The mechanism of IFN-alpha-induced behavioral changes is complex, involving interactions between the immune system, the endocrine system, the monoaminergic systems and the opioid receptors. Recent studies support the neurodegeneration hypothesis as a possible mechanism of IFN-alpha-induced depressive behavior. Although a meta-analysis showed that antidepressant pretreatment effectively reduces the incidence and severity of depressive symptoms, irrespective of pre-existing psychiatric disorders, it is not approved for prophylactic use. The "on demand" treatment strategy is justified as the majority of patients have only mild depressive symptoms. Patients with risk factors for depression undergoing IFN-alpha therapy need to be regularly screened and followed-up by a psychiatric specialist. Further studies should be conducted to show which therapy is the most appropriate to reduce the neuropsychiatric symptoms that are related to the use of IFN-alpha and to investigate the clinical significance of IFN-alpha-induced neurodegeneration. PMID- 25705267 TI - New cardiovascular risk factors and their use for an accurate cardiovascular risk assessment in hypertensive patients. AB - OBJECTIVES: To analyze the predictive value of new cardiovascular (CV) risk factors for CV risk assessment in the adult Romanian hypertensive (HT) population. METHODS: Hypertensive adults aged between 40-65 years of age, identified in national representative SEPHAR II survey were evaluated by anthropometric, BP and arterial stiffness measurements: aortic pulse wave velocity (PWVao), aortic augmentation index (AIXao), revers time (RT) and central systolic blood pressure (SBPao), 12 lead ECGs and laboratory workup. Values above the 4th quartile of mean SBP' standard deviation (s.d.) defined increased BP variability. Log(TG/HDL-cholesterol) defined atherogenic index of plasma (AIP). Serum uric acid levels above 5.70 mg/dl for women and 7.0 mg/dl for males defined hyperuricemia (HUA). CV risk was assessed based on SCORE chart for high CV risk countries. Binary logistic regression using a stepwise likelihood ratio method (adjustments for major confounders and colliniarity analysis) was used in order to validate predictors of high and very high CV risk class. RESULTS: The mean SBP value of the study group was 148.46+/-19.61 mmHg. Over forty percent of hypertensives had a high and very high CV risk. Predictors of high/very high CV risk category validated by regression analysis were: increased visit-to-visit BP variability (OR: 2.49; 95%CI: 1.67-3.73), PWVao (OR: 1.12; 95%CI: 1.02-1.22), RT (OR: 0.95; 95% CI: 0.93-0.98), SBPao (OR: 1.01; 95%CI: 1.01-1.03) and AIP (OR: 7.08; 95%CI: 3.91-12.82). CONCLUSION: The results of our study suggests that the new CV risk factors such as increased BP variability, arterial stiffness indices and AIP are useful tools for a more accurate identification of hypertensives patients at high and very high CV risk. PMID- 25705268 TI - Epicardial adipose tissue is associated with extensive coronary artery lesions in patients undergoing coronary artery bypass grafting: an observational study. AB - OBJECTIVES: To investigate the relationship between the epicardial adipose tissue (EAT) volume measured by 256-slice dual source computed tomography (DSCT) and the complexity with the presence of significant coronary artery disease (CAD) in patients undergoing coronary artery bypass graft surgery (CABG). MATERIAL AND METHODS: Study subjects were enrolled as they were undergoing DSCT for coronary evaluation. Two subgroups were formed according to coronary artery bypass history: Group A (patients with significant CAD), Group B (patients with normal coronary arteries). In both groups, EAT volume was measured by DSCT with the same technique. The complexity of CAD was assessed by using Syntax score (SxS). Group A patients were subdivided into two groups according to these results (Group A1, A2). OUTCOMES: Ninety-three patients (53 male, 40 female) with a mean age of 55.1 years were enrolled in the study (48 in group A and 45 in Group B). The serum levels of fasting plasma glucose (FPG), total cholesterol (TC) and low-density lipoprotein (LDL) were found statistically higher in Group A. In Group A, mean EAT volume was 44.87+/-21.28 cm(3) while it was in normal range (32.37+/-17.50 cm(3)) in control group (p=0.003). Higher EAT volume was found to be related to FPG (r=0.242, p=0.015) and body surface area (BSA) (r =0.268, p=0.009) and also correlated positively with CAD. On the other hand, there was no significant difference between subgroups when considering the complexity of CAD. CONCLUSIONS: Our data shows that increased EAT volume is associated with significant CAD. EAT volume contributes to the development of coronary lesions, but it does not affect the complexity of the lesions. PMID- 25705269 TI - Epidemiological aspects of genital warts in romania - a 2012 retrospective survey. AB - OBJECTIVES: Genital infection with human papillomavirus (HPV) has become one of the most frequently viral sexually transmitted diseases. The infection may remain asymptomatic, may take the form of external genital warts and may give raise to cervical cancers. The aim of this study was to assess the frequency of the patients with genital warts addressing to five tertiary referral dermato venereological units in Romania (where patients from several counties are referred) and to compare the results with the out-patient data reported by all Romanian hospitals. MATERIAL AND METHODS: Data regarding patients with external genital warts who addressed to the hospital emergency rooms, in five tertiary referral dermato-venerological units in Romania (Bucharest, Timisoara, Craiova, Constanta, Targu-Mures) were collected for the year 2012. For comparison there have been used data collected by the National School of Public Health, Management and Professional Development, during the same year. OUTCOMES: Data reported at national level in 2012 included 952 patients (731 women and 221 men) with 26 males under 20 years of age and 251 female patients in the age group 0-20 years. In the overall population (males and females combined) the total number of genital warts cases registered at the hospital emergency rooms in the five centers, in the year 2012, was 266 patients (119 men and 147 women) with 4 girls under 14 years of age and 6 male patients in the age group 0-14 years. CONCLUSIONS: The high prevalence of the infection with HPV, the costs of treatment and the psychological impact prove that prevention of the disease is the most important step for decreasing the incidence of this disease. General measures for patients awareness regarding the disease and its complications need to be completed with the recommendation for vaccination. A closer monitoring of patients would provide information for a strategic national approach leading to a better outcome. PMID- 25705270 TI - Retrospective study on osteosarcoma and ewing sarcoma - our experience. AB - INTRODUCTION: Primary bone tumors are relatively rare types of cancer. Their relative frequency is not yet well established and still there is more information needed regarding the evolution and prognosis of those patients. OBJECTIVES: We analyzed several factors (site of lesion, tumor stage, tumor volume, disease related complications, therapy related complications) that influenced the evolution of bone tumor in a lot of patients diagnosed with osteosarcoma or Ewing sarcome. MATERIAL AND METHODS: A retrospective review was conducted on hospital-based registry from the Emergency Hospital for Children "Louis Turcanu" Timisoara. Patients with newly diagnosed osteosarcoma and Ewing sarcoma, hospitalised in our clinic during a period of 10 years (1996-2006) were included. Records were analyzed for patient demographics, site of lesion, treatment and outcomes. The study group was composed of 36 patients with bone tumors, with ages betwen 3-23 years, who came from Timis and several counties around it. RESULTS: We found Ewing Sarcoma (ES) in 52.94% of cases and osteosarcoma (OS) in 47.06% of cases analyzed. We found diseases in advanced stages in 33.3% of cases in stage III and in 27.7% in stage IV. Tumoral volume had more than 200 cm3 in 53.3% of OS patients and in 21% of cases of ES. Treatment was accomplished according to the European protocols, COSS 96 in 66.6% of OS cases, EWING 99 in 73.6% of ES cases. Disease related complications were found in 26.6% of OS cases and in 51% of ES patients. CONCLUSION: In this study, the patients survival rate at 5 years after diagnosis was lower than in other studies. A possible explaination for such a high rate of mortality could be the delayed diagnosis and the advanced stage of the neoplasia, especially for Ewing sarcoma where only 16.66% of the patients were stage I or II. For the short time survival it was found a corelation with the period of time between the simptoms appearance and the moment of diagnosis, tumor stage, metastasis and severity of the complications. PMID- 25705271 TI - High Incidence of Macrolide and Tetracycline Resistance among Streptococcus Agalactiae Strains Isolated from Clinical Samples in Tehran, Iran. AB - BACKGROUND: Streptococcus agalactiae or Group B Streptococci (GBS) is an important bacterial pathogen that causes a wide range of infections including neonatal sepsis, meningitis, pneumonia and soft tissue or urinary tract infections. MATERIAL AND METHODS: One hundred and fifteen isolates of Streptococcus agalactiae collected from urine specimens of patients attending a hospital in Tehran. All isolates were screened for their capsular types and genes encoding resistance to the macrolide and tetracycline antibiotics by PCR and multiplex PCR-based methods. RESULTS: Most of isolates belonged to capsular types III (49%), V (19%), II (16%), and Ib (6%). Twelve isolates (10%) were nontypable. All isolates were susceptible to penicillin and Quinupristin-dalfopristin, but were resistant to clindamycin (35%), chloramphenicol (45%), erythromycin (35%), linezolid (1%) and tetracycline (96%). The most prevalent antimicrobial resistance gene was tetM found in 93% of the isolates followed by ermTR, ermB, and tetK, found in 23%, 16%, and 16% of isolates, respectively. The genes, tetL, tetO, ermA, ermC and mefA were not detected in any of the S. agalactiae isolates. Of the 110 tetracycline resistant S. agalactiae, 89 isolates harbored the tetM gene alone and eighteen isolates carried the tetM gene with the tetK gene. All erythromycin-resistant isolates exhibited cMLSB resistance phenotype, 22 isolates harbored the ermTR gene alone and five isolates carried the ermTR gene with the ermB gene. The rate of coexistence of genes encoding the erythromycin and tetracycline resistance determinants was 34%. CONCLUSION: The present study demonstrated that S. agalactiae isolates obtained from urine samples showed a high rate of resistance to tetracycline, chloramphenicol and macrolide antibiotics and were commonly associated with the resistance genes temM, ermTR or ermB. PMID- 25705272 TI - Detection of highly ciprofloxacin resistance acinetobacter baumannii isolated from patients with burn wound infections in presence and absence of efflux pump inhibitor. AB - The emergence of fluoroquinolone resistance among A. baumannii isolates is now of particular concern. Phenotypic and genotypic characteristics of resistance to ciprofloxacin among 50 Acinetobacter baumannii isolated from burn wound infections of Tehran were evaluated by E-test and broth microdilution in presence and absence of efflux pump inhibitor phenylalanine- arginine beta-naphthylamide (PAbetaN) and PCR-sequencing methods. All isolates were then typed by REP-PCR fingerprinting to find the clonal relationship between resistant isolates. Our results indicated that resistance to ciprofloxacin among A. baumannii isolated from burn infections in Tehran are high with resistance rate of 100% and ciprofloxacin resistant isolates have a mutation of Serine 83 ->Leucine in the quinolone resistance determining region (QRDR) of DNA gyrase subunit A (GyrA). 38% of the isolates showed MIC ranges of 64 to >=512MUg/ml and were considered as highly resistant. We could not detect Par C mutations and plasmid-mediated quinolone resistance A (qnrA) among ciprofloxacin resistant isolates. When we used the efflux pump inhibitor PAbN, MIC of ciprofloxacin was reduced two-to four folds. REP-type A (25/50; 50%), B (20/50; 30%) and C (10/50; 20%) were the most common REP-types among A. baumannii isolates. It seems that mutation in GyrA is the main mechanism of resistant to ciprofloxacin among A. baumannii isolates from burn infections and presence of efflux pumps is just secondary target for ciprofloxacin resistant among A. baumannii in Iran. Regarding with limitation of REP-types detected in this study, we found good correlation between resistance to ciprofloxacin and REP-types A-C. PMID- 25705273 TI - Selective Nonoperative Management of Abdominal Injuries in Polytrauma Patients: a Protocol only for Experienced Trauma Centers. AB - INTRODUCTION: Nowadays we are facing a steep increase in non-operative management throughout the injured body areas, with a continuous increase in the injuries' grade. OBJECTIVE: To evaluate the safety and applicability of non-operative management in major trauma patients. METHODS: Prospective observational study, in a level I trauma center, during 30 months. INCLUSION CRITERIA: major trauma patients with abdominal visceral lesions. RESULTS: There were 207 major trauma patients whose average age was 35.8 +/- 17.2 years, male being 69.6%. The most severe abdominal injuries were in the spleen (32.9%), the liver (19.2%) and the small bowel (11.6%). For the spleen lesions, the non-operative management was successful in 57.9% cases , with a failure rate of 11.6%. Non operative management was successful in 50% of liver injuries, its rate of success being independent of the hepatic injury grade. CONCLUSIONS: Selective non operative management of abdominal visceral injuries is safe and effective in major trauma patients. Nevertheless, we should stress that this type of protocol should be applied only by highly trained surgeons, able to early convert this management to difficult surgical strategies. PMID- 25705274 TI - The effect of high tibial osteotomy on the posterior tibial slope. AB - INTRODUCTION: High tibial osteotomy remains a useful procedure for delaying total knee arthroplasty for young patients with unicompartimental medial osteoarthritis of the knee. The tibial posterior slope is essential for both ligament function and knee kinematics. Even though many articles were published in the literature, the long term influence of open wedge high tibial osteotomy on the posterior slope of the tibial plateau remains unknown. OBJECTIVE: We assessed the relationship among the degree of correction, the surgical technique, the postoperative modification of tibial slope, knee flexion and Knee score at the two years. MATERIAL AND METHODS: We used for evaluation a calibrated x-rays with correction factor. All the measures were done with Cedara I-View 6.3.2 application. All 47 patients were operated in our hospital between 2008-2011, with the same technique, open wedge high tibial osteotomy with an acrylic cement wedge. All patients postponed weight bearing for 6 weeks. RESULTS: We found that there is no statistical significance (p=0.2) between the preoperative varus and the after surgery tibial slope, but the resulting posterior inclination after surgery influences the tibial posterior slope at 2 years (p<=0.005).The degree of correction has a strong influence over the increase or decrease of tibial posterior slope(p<0.005). An increase in tibial slope increases the knee flexion by 1.45 degrees for every degree of inclination (p<0.05). Functional results are not influenced by small modifications in tibial inclination (p>0.05). CONCLUSION: From this findings we may conclude that the most important factors that changes the posterior inclination of the tibia surface are the height of the cement wedge and the surgical technique, by placing the acrylic cement wedge more anteriorly. We have found that the vast majority of our high tibial osteotomies are in fact "flexion" osteotomies. At the 2 years control we have found a slight increase in tibial slope angle (average 1.77 degrees ) and knee flexion (average 2.56 degrees ) with no functional response. This is a case series study with level of evidence IV. PMID- 25705275 TI - Treatment Options for Severe Epistaxis, the Experience of Coltea ENT Clinic. AB - OBJECTIVES: The study presents the experience of the Coltea ENT Clinic with the most common emergency in ENT pathology. RESULTS: The study group comprises 51.24% women and 48.76% men with 73.14% of patients (177) coming from urban areas and the remaining 26.86% (65) from rural areas. The total number of days of hospitalization is 1411, representing an average of 5.83 days / patient. Epistaxis was anterior in 80.17% of cases (194 patients) and antero-posterior in 19.83% (48 patients). 132 patients, representing 54.55% presented elevated blood pressure whereas liver and hematological disorders are uncommon etiologies. Therapeutic interventions are mostly non-surgical 207 (85.54%), the remaining 35 cases (14.46%), requiring surgery. CONCLUSIONS: Epistaxis associated with high blood pressure is found in 54.55% of the study group. In 38.02% of cases the etiology cannot be determined. Pluri-factorial etiology is common. The most difficult to control were the cases with epistaxis of hepatic etiology, in which cases the surgical solution was required. PMID- 25705276 TI - A comparison between clinical diagnosis of death and autopsy diagnosis. A retrospective study of 131 newborns, stillborns and aborted fetuses. AB - In recent years, the autopsy was considered necessary only in medico-legal cases, or when the clinician requires it to better understand the pathology and cause of death (with the deceased family's consent). Although it has been shown in numerous studies that the autopsy and the postmortem histopathological examination are the only ones that can diagnose correctly and completely, the autopsy rate is declining. The primary motive of the family in consenting to a perinatal necropsy, may be to determine the cause of death of their child and to be aware of possible complications of their future pregnancy. This study shows the rate of concordance between clinical diagnosis and autopsy diagnosis, and the rate of concordance between macroscopic diagnosis and microscopic findings, pointing out once again the importance and the utility of the autopsy in medical practice. PMID- 25705277 TI - Acute heart failure and a pseudo cystic image in the left ventricle. AB - The association between acute heart failure (AHF) and cardiac tumor may change the short and long term management of both conditions. A 51-year-old man presented with signs of AHF. ECG showed sinus tachycardia and left ventricular (LV) hypertrophy. Chest x-Ray found dilated heart and pulmonary congestion. There were no significant changes in blood tests. Transthoracic echocardiography revealed chambers dilation, and LV ejection fraction (LVEF) of 17%. Unexpectedly, we found an apical 2/2 cm cystic image in the LV. This had a myocardium-like membrane, seen better in 3D echocardiography, suggestive for hydatic cyst. Cerebral, thoracic, and abdomino-pelvic CT scan showed no hydatic lesions. Anti Echinococcus antibodies were negative. Initially the clinical challenge was the management of the tumor in a patient with AHF and dilated cardiomyopathy. He was treated for AHF and followed up for the cystic image. He exhibited significant improvement of the clinical status and LVEF (increased to 42 %), with important cardiac reverse remodeling. Surprisingly, the apical cystic image disappeared. However, we found a hypertrophic aberrant cordae from apex to mid-septum, in the same position as the previous image. Thus, we believe that this cordae, by important remodeling and torsion generated the cystic image. This case highlights the importance of serial 2D and 3D echo examinations in patients with severely remodeled LV, and also with tumoral images. PMID- 25705278 TI - Evolution of internal carotid artery occlusion in non-traumatic carotid dissection. AB - Cervical artery dissection is becoming a more frequently identified cause of ischemic stroke among the young and middleaged patients. The pathogenesis of non traumatic dissection has not been yet entirely elucidated, but certain risk factors have been reported. We present the case of a young patient with ischemic stroke in the middle cerebral artery territory secondary to internal carotid artery dissection and occlusion, in whom we identified two rarely incriminated risk factors: migraine and recent infection (pneumonia). PMID- 25705279 TI - Complete therapeutical approach in pulmonary arterial hypertension: from vasodilators to lung transplantation - case report. AB - We present the case of a 37 years old patient with idiopathic pulmonary arterial hypertension (PAH). After initial treatment with calcium channel blockers (CCB), based on a positive vasoreactive response at right heart catheterization, due to disease progression, major vasodilator therapies were introduced in a sequential strategy: sildenafil, bosentan and treprostinil. Finally, the patient received double-lung transplantation with eventually favourable evolution despite immediate postoperative significant complications. Markers of disease progression were monitored before the transplant, and after the intervention the patient was screened according to a specific protocol for bronchiolitis obliterans and infections. According to our knowledge, this case represents a premiere in Romanian medicine, being the first lung transplant in a PAH patient. This case represents a model of PAH with a documented evolution of 8 years. We present the progression of the disease and the effective therapeutic strategies according to the current guidelines. This case reinforces the need for upgrading the Romanian National PAH Program with the inclusion of prostanoid therapy, as an option for severe patients. PMID- 25705280 TI - Composite diffuse large B-cell lymphoma and follicular B-cell lymphoma - case report and review of literature. AB - Composite lymphoma refers to the co-occurrence of two or more morphologically and immunophenotypically separate lymphomas in the same topographic site at the time of clinical presentation. It is an infrequent type of lymphoid neoplasm, present in lymphoid tissue and may be due to the existence of two genetically related neoplasms such as transformation of a single lymphoma into another more aggressive lymphoma or be due to the presence of two clonally unrelated lymphomas. This paper is presenting a case of diffuse non-Hodgkin large B-cell lymphoma with areas of low grade and high grade follicular non-Hodgkin B-cell lymphoma in a retroperitoneal lymph node and spleen of an 62 year old woman. Histopathological examination and immunohistochemistry features proved the diagnosis of composite lymphoma. PMID- 25705281 TI - Total laryngectomy - past, present, future. AB - In a period in which therapeutic approaches for malignant laryngeal tumors are focused on the principle of "organ preservation", total laryngectomy is a well coded surgical procedure, addressed to the advanced laryngeal cancer which is not suitable for conservative techniques or in case of their failure. The main objective of this work is to summarize the important events that have marked the evolution of this surgical technique to the current formula. Also this paper aims to identify, in our own casuistry, some elements of strategy and surgical technique required, in our opinion, for a successful therapeutic intervention. The fundamental significance of the study is that we must learn from the past, perform our surgeries at contemporary standards and look to the future for new solutions and approaches of the advanced laryngeal malignancies. PMID- 25705282 TI - Ibrutinib, a novel agent in relapsed or refractory chronic lymphocytic leukemia. PMID- 25705283 TI - Gene therapy and cardiomyocyte transplant in heart failure. PMID- 25705284 TI - Left ventricular strain analysis reveals better synchrony and diastolic function for septal versus apical right ventricular permanent pacing. AB - OBJECTIVES: Left ventricular function and synchrony may be altered by right ventricular (RV) apical pacing. Septal pacing might be a better alternative. We compared effects on cardiac synchrony and function, between the 2 pacing sites, in chronically implanted patients. MATERIAL AND METHODS: 40 pacing-dependent patients (74+/-9 years, 21 men), 20 paced at the apex, were studied 11+/-4 months after implantation (baseline); 32 of them were re-examined after 1 year. Systolic function was assessed from ejection fraction (EF), cardiac index (CI), mean longitudinal systolic strain (MLSS), and strain rate (MLSR); diastolic function from E/A, E/E', and E/Vp ratios. Intraventricular dyssynchrony from standard deviation (SSD) and maximal difference (MAXS) of the 12 LV myocardial systolic timings, and sum of all times from the aortic valve closure to peak strain (SUMTAVC) for those segments with post-systolic shortening; interventricular synchrony from the aorto-pulmonary delay (APD). OUTCOMES: Four patients died, all of them from the apical group. NYHA functional class was not different. Cardiac synchrony was not significantly different between the two pacing sites at baseline, and after 1 year follow-up. Although at baseline there was a greater dyssynchrony for the septal site, this did not progress at follow-up, whereas this increased for the apical site. Meanwhile, there was a higher LV filling pressure (E/E' ratio) for the apical site at 1 year (13+/-6 vs.18+/-6; p=0.04). CONCLUSIONS: Both septal and apical pacing sites affect negatively LV mechanical activation timings and synchrony. Apical, but not septal site, affects LV synchrony at 1 year, associated with increased filling pressure. PMID- 25705285 TI - Association Between PAH Mutations and VNTR Alleles in the West Azerbaijani PKU Patients. AB - INTRODUCTION: We report the frequency of IVS10nt546, R261Q, S67P, R252W, and R408W mutations linked to PAH VNTR alleles in the west Azerbaijani PKU patients. MATERIAL AND METHODS: VNTR alleles and IVS10nt546, R261Q, S67P, R252W, R408W mutations were studied in a total of 20 PKU patients by PCR and RFLP-PCR. OUTCOMES: Our analysis showed that 95% of cases were homozygote for an allele containing eight-repeat VNTR (VNTR8); while 5% were homozygote for an allele containing three-repeat VNTR (VNTR3). The IVS10nt546, R252W, and R261Q mutations were associated with VNTR8 allele, and also, R252W and S67P mutations were associated with VNTR3 allele. VNTR8 was common among mutant alleles as were IVS10nt546-VNTR8 (50%), R252W-VNTR8 (2.5%), and R261Q-VNTR8 (22.5%). The association of VNTR3 was found as R252W-VNTR3 (2.5%) and S67P-VNTR3 (2.5%) among studied cases. The frequency of IVS10nt546-VNTR8/IVS10nt546-VNTR8, IVS10nt546 VNTR8/ND-VNTR8, IVS10nt546-VNTR8/R252W-VNTR8, R261Q-VNTR8/R261Q-VNTR8, R261Q VNTR8/ND-VNTR8, and S67P-VNTR3/ R252W-VNTR3 were 30%, 35%, 5%, 20%, 5%, and 5%, respectively. R408W mutation was not found in this study. CONCLUSIONS: The present report is the first in its own kind in the west Azerbaijani population (Iran) and implies that the most common PKU mutation in this population, IVS10nt546, is exclusively associated with VNTR8 allele, and IVS10nt546-VNTR8 alleles testing should be considered for routine carrier screening and prenatal diagnostic setting. PMID- 25705286 TI - The relationship between alanerv((r)) consumption and erythrocytes' redox status in post-acute stroke patients undergoing rehabilitation. AB - OBJECTIVES: Stroke is a pathological condition associated with a redox imbalance. Both the acute and the post-acute phases after a stroke are characterized by a pro-oxidant state, which could be corrected through antioxidant supplementation. The aim of the present study was to evaluate the effect of the ALAnerv((r)) upon the redox status of erythrocytes. MATERIAL AND METHODS: For this pilot study were enrolled 28 post-acute stroke patients. They were randomly divided into a control group [(-) ALA] and a study group [(+) ALA]. Patients were hospitalized for a period of two weeks. Blood samples were taken at the beginning and at the end of this period. Patients from (+) ALA group received the nutritional supplement ALAnerv((r)). Catalase, SOD, GPx, GRed and GT activities were assessed on erythrocytes' lysates. Also, the total antioxidant capacity as well as the concentration of total thiols were evaluated. OUTCOMES: During the study period only SOD (1393.48 +/- 69.14 U/g Hb vs. 1514.06 +/- 60.80) and GRed (4.47 +/- 0.37 U/g Hb vs. 5.06 +/- 0.24) significantly increased in (+) ALA group. Catalase (173.70 +/- 14.62 k/g Hb vs. 123.41 +/- 8.71) and GT (5.55 +/- 0.26 U/g Hb vs. 4.95 +/- 0.23) activities significantly decreased during the study period. Multiple regression indicated that only SOD, GT and GRed activities were influenced by the ALAnerv((r)) consumption. There was no significant increase if the total thiols concentration. CONCLUSIONS: ALAnerv((r)) consumption could be associated with a correction of the erythrocytes' redox status. There is a need to investigate if administration of ALAnerv((r)) over a longer time period could have a more significant influence on the erythrocytes' antioxidant system. PMID- 25705287 TI - The role of distubances of phosphate metabolism in metabolic syndrome. AB - BACKGROUND: Metabolic syndrome represents a cluster of cardiovascular risk factors that has become a public health problem of epidemic proportions. It was proposed that disturbances in phosphate metabolism may represent a key feature of metabolic syndrome, with a high contribution of cardiovascular risk factors. OBJECTIVES: The aim of the study is to investigate the relationship between phosphate levels and the presence of the characteristics of metabolic syndrome, as well as the mechanisms that may responsible for reduced phosphate levels in patients with metabolic syndrome. METHODS: One hundred fifty five subjects are enrolled in the study: 64 with metabolic syndrome and 91 without this syndrome. Biochemical parameters of the metabolic syndrome study populations were compared with healthy population study. RESULTS: Patients with metabolic syndrome showed significantly lower phosphate (46%) and magnesium levels compared with controls (22.7%) (p<0.001).Because fractional excretion of phosphate was similar in both groups, we think that hypophosphatemia in patients with metabolic syndrome can be attributed to decreased dietary intake, as well as internal redistribution of this element. Lower magnesium hyperinsulimemia-induced renal magnesium wasting also may be a contributory factor. CONCLUSIONS: Patients with metabolic syndrome show significantly lower phosphate and magnesium concentrations compared with individuals who do not fulfill criteria for diagnosis of this syndrome. This reduction is likely to be attributed to reduced dietary intake and internal redistribution of phosphate and is more pronounced as the number of components of metabolic syndrome increases. The clinical significance of these disturbances, as well as their importance as targets for preventive or therapeutic interventions, remains to be established. PMID- 25705288 TI - Clinical or postmortem? The importance of the autopsy; a retrospective study. AB - Medicine is continually evolving; the new technologies of diagnosis and treatment continue to improve the life expectancy and lead to new information concerning various pathologies. The autopsy is viewed more and more as an ultimate branch of medicine and used only in extreme cases or for forensic purposes. Nevertheless, many studies, including this one, prove the utility and indispensability of the autopsies, without which a complete and accurate diagnosis cannot be made. Finally, the autopsy followed by histopathological examination of the tissues remains the ultimate and most important step for the apprehension of the diseases and for further evolution of medicine. This study reveals the correspondence rate between the clinical and the postmortem diagnosis, as well as between macroscopic and histopathological diagnosis. PMID- 25705289 TI - Delayed rupture of gallbladder following blunt abdominal trauma. AB - A 29-year-old gentleman presented to surgery emergency with severe upper abdominal pain and vomiting. He reported to had been hit in his abdomen by a ball during a cricket match. Computerized tomogram of the abdomen revealed hematoma within the gallbladder lumen, laceration of segment six of liver, and hemoperitoneum. The patient did not agree for laparotomy advised to him, and so, managed conservatively. The patient reported back to us with high grade fever, jaundice, and painful abdominal distension after seven days of discharge from the hospital. His abdominal examination showed features of generalized peritonitis. Surgical abdominal exploration revealed a single perforation in the fundus of gallbladder with frozen calot'striangle. Subtotal cholecystectomy was done. Histopathology of excised gallbladder revealed xanthogranulomatous inflammation. The present case report highlights that early exploration and cholecystectomy should be considered in patients with gallbladder injury to obviate the risk of delayed perforation. PMID- 25705290 TI - A rare case of uterine myxoid leiomyosarcoma: a case report. AB - We present the rare case of a 61-year-old female patient who was submitted in the hospital with metrorrhagia and pelvi-abdominal pain. Echographic examination revealed an heterogeneous uterine mass measuring 190/130/110 mm. Therefore, total hysterectomy with bilateral ooforectomy was performed. Grossly, the uterus presented a tumoral mass with areas of hemorrhage, necrosis and abundant mucoid degeneration. On light microscopic examination a malignant neoplastic proliferation with features of myxoid leiomyosarcoma was noted. In this paper, we presented this rare form of leiomyosarcoma with an emphasis on its particularities that have not been mentioned in the literature. PMID- 25705291 TI - Anatomical variation of hyoid bone: a case report. AB - Hyoid bone is a solitary bone localized at the level of cervical 3 vertebrae, connected to the adjacent bone structures with muscles and tendons. Anatomical variations of hyoid bone can cause difficulties in the application of forensic medicine together with clinical and surgical problems. We present a case of a 81 year-old woman, reported to got sick, who died at home. In the autopsy, the neck dissection revealed prolonged right and left greater horns of hyoid bone measured 11 cm and 7 cm respectively. We aimed to present a case with long hyoid bone horns and discuss recent literature. PMID- 25705292 TI - Spontaneous rupture of a renal cell carcinoma associated with fatal bleeding. AB - Spontaneous rupture of the renal parenchyma is rarely reported, usually seen as a complication of an underlying disease like the benign and malignant tumors of the kidney, also except from tumors among the causes of spontaneous renal rupture associated with bleeding, there were claimed vascular anomalies affecting the parenchyma, infections and coagulation disorders. Presented case was a 79-year old male found dead at home. At the autopsy in macroscopic examination; all of the organs with signs of putrefaction, free blood at perihepatic and post hepatic retroperitoneal area, bloody coat at colon serous surface and 25x30x25 cm of hematoma at the right perirenal area were observed. In dissection, 5x2 cm of crescent shaped residual kidney structure was detected at the inferior pole adjacent to the 15x5x8 cm of pale yellow tumor mass settled in the upper pole of right kidney dissection associated with kidney, and 3x3 cm of tumor rupture and bleeding area in the upper part of tumoral pseudo capsule was inspected. Tumor sections were dirty yellow in color, bleeding and a large area of autolysis in appearance were also observed. Histopathological examination of the samples prepared from the tumoral mass taken from on the right kidney revealed renal cell carcinoma. Our aim was to present a rare case of spontaneous rupture of renal cell carcinoma detected at the autopsy. PMID- 25705293 TI - Bilateral central vein occlusion in a case of diaphragmatic eventration. AB - Central Retinal Vein Occlusion (CRVO) is a severe retinal pathology, which causes visual impairment usually after the age of 40. Mostly unilateral, less than 10% of cases are bilateral. Affected young adults (under the age of 40), usually exhibit a hidden, underlying systemic disease. Thorough testing has to be done in order to spot the pathogenic agent. We present the case of a 25 years old woman with bilateral CRVO caused by Diaphragmatic Eventration and Chronic Respiratory Failure. PMID- 25705294 TI - Left ventricular non-compaction -challenges and controversies. AB - Cardiomyopathies classification is based on morphological and functional phenotypes and subcategories of familial/genetic and non-familial/non-genetic disease. The non-compaction cardiomyopathy is a rare disorder which is considered to be an unclassified cardiomyopathy according to the ESC Working Group on Myocardial and Pericardial Diseases and the World Health Organization or a primary genetically-determined cardiomyopathy according to the American Heart Association. The diagnosis of non-compaction is challenging and its nosology is debated since this morphological trait can be shared by different cardiomyopathies and non-cardiomyopathy conditions. Myocardial structure has a spectrum from normal variants to the pathological phenotype of non-compaction cardiomyopathy, which reflects the embryonic structure of the human heart due to an arrest in the compaction process during the first trimester. However, when a definite diagnosis of non-compaction is made, the diagnostic process should orient towards a genetic disease with a relatively high probability of sarcomere mutations. Non-compaction cardiomyopathy is a diagnostically challenging entity. Nowadays there are some controversies associated with this cardiomyopathy, that it worth to be discussed. PMID- 25705295 TI - Peripheral nervous system manifestations in systemic autoimmune diseases. AB - The peripheral nervous system refers to parts of the nervous system outside the brain and spinal cord. Systemic autoimmune diseases can affect both the central and peripheral nervous systems in a myriad of ways and through a heterogeneous number of mechanisms leading to many different clinical manifestations. As a result, neurological complications of these disorders can result in significant morbidity and mortality. The most common complication of peripheral nervous system (PNS) involvement is peripheral neuropathy, with symptoms of numbness, sensory paresthesias, weakness, or gait imbalance. The neuropathy may be multifocal and asymmetric or, less frequently, distal and symmetric. PMID- 25705297 TI - House dust mite - the paradox. PMID- 25705296 TI - The role of ankle-brachial index for predicting peripheral arterial disease. AB - The presence of peripheral arterial disease (PAD) is associated with higher cardiovascular morbidity and mortality, regardless of gender or its clinical form of presentation (symptomatic or asymptomatic). PAD is considered an independent predictor for cardiovascular mortality, more important for survival than clinical history of coronary artery disease. The ankle brachial index (ABI) is a sensitive and cost-effective screening tool for PAD. ABI is valuable for screening of peripheral artery disease in patients at risk and for diagnosing the disease in patients who present with lower-extremity symptoms. Compared to other diagnostic methods, ABI is superior because it is s a simple, noninvasive test, which could be routinely determined in all patients. Normal cut-off values for ABI are between 0.9 and 1.4. An abnormal ankle-brachial index- below 0.9-is a powerful independent marker of cardiovascular risk. There is an inverse correlation between ABI values, non-fatal cardiac events (myocardial infarction, stroke and heart failure exacerbation) and mortality (cardiovascular and global), the relation being nonlinear, patients with very low ABI (<0.3) having a significantly higher additional risk. Also, ABI values over 1.3-1.4 correlate with major adverse cardiovascular events. Therefore, ABI can be considered a generalized atherosclerotic predictor, identifying patients at high risk for developing cardio- or cerebrovascular events and should be incorporated into routine clinical practice. PMID- 25705298 TI - Vitamin d deficiency in postmenopausal women - biological correlates. AB - INTRODUCTION: Low vitamin D (VD) is associated with secondary hyperparathyroidism and both contribute to deleterious consequences (reduced bone mineral density (BMD), risk of fractures and falls). OBJECTIVE: To study the VD status and biological correlates in a group of postmenopausal women. MATERIAL AND METHODS: We studied 123 postmenopausal women evaluated in the C.I.Parhon National Institute of Endocrinology, the Pituitary and Neuroendocrine Diseases department. All cases had been reffered for the evaluation of BMD by the general practitioner. The evaluation included serum measurements of total and ionised calcium, phosphorus, alkaline phosphatase (ALP), 25 hydroxi vitaminD (25OHD), parathyroid hormone (PTH), osteocalcin, betacrosslaps. Central DXA osteodensitometry was performed. RESULTS: 91.9% of cases had 25OHD serum levels below 30 ng/ml (74.8% had VD deficiency, 17.1% VD insufficiency). Only 8.1% had sufficient VD levels. A history of fragility fractures was present in 45.83% of the osteoporotic patients, 27.27% of the osteopenic ones and 15.15% of the women with normal BMD. 32 women (26%) were on VD supplementation at the time of evaluation. Among these subjects, the 25OHD level was significantly higher in those with prior fragility fractures (p=0.018) and osteoporosis (p=0.008). 25OHD concentration negatively correlated with PTH, alkaline phosphatase (ALP) and osteocalcin. The bone markers evaluated had a significant inverse correlation with the radius BMD, T and Z scores (p=0.004). 27.17% of the cases with VD deficiency had secondary hyperparathyroidism. The 25OHD concentration was significantly lower in these cases (p=0.000). CONCLUSIONS: VD insufficiency is widely prevalent but still under-recognized and under-treated, possibly leading to secondary hyperparathyroidism. The compliance to VD supplementation is lower in subjects without osteoporosis or fragility fractures. Primary prevention measures should be more actively implemented. PMID- 25705299 TI - Vancomycin-resistant enteroccus faecium and enterococcus faecalis isolated from education hospital of iran. AB - INTRODUCTION: Enterococci are opportunistic pathogens which represent one of the leading agents of nosocomial infections, especially urinary tract infections (UTI) in hospitalized patients. The aim of the present study was to determine the resistance pattern and the type of resistance genes in vancomycin-resistant Enterococcus isolated from an educational hospital in Iran. MATERIALS AND METHODS: From February 2012 till February 2013, one hundred and eighty six clinical isolates from different department of educational hospitals were collected and identified as Enterococci and specified by biochemical tests. Identification was confirmed by specific PCR. Antibiotic resistance properties of strains were examined by Kerby-bauer method. PCR was performed for ddlE, ddlF, vanA and vanB genes. RESULTS: One hundred and six (57%) isolates were identified as E. faecalis and 80 (43%) of the isolates were identified as E. faecium. 24 isolates had vanA gene and 19 isolates had vanB genes. In E. faecalis isolates, 15 isolates had vanB and 4 isolates had vanA gene. In E. faecium isolates, 20 isolates had vanA and 4 isolates had vanB gene. Prevalence of van genes between E. faecalis and E. faecium were significantly different for both vanA and vanB (p<0.01, p<0.041, respectively). VRE isolates were sensitive to Linezolid, Nitrofurantoin and Tigecyclin. DISCUSSION: The overall prevalence of VRE was 23.65%, which shows an increase in VRE isolation in our region. Also, prevalence of E. faecium dramatically increased from 9% to 43% in the present study. Also increase in Gentamicin resistant isolates observed, but VRE isolates were sensitive to Linezolid, Tigecyclin and Nitrofurantoin. Stewardships for antibiotic usage in hospitals, especially for last option antibiotics, can prevent the spread of resistant isolates and losing all treatment options in the future. PMID- 25705300 TI - Antibiotic Prophylaxis Prior to Elective ERCP Does Not Alter Cholangitis Rates or Shorten Hospital Stay: Results of an Observational Prospective Study of 138 Consecutive ERCPS. AB - OBJECTIVES: The role of prophylactic antibiotherapy prior to elective endoscopic retrograde cholangiopancreatography (ERCP) is unclear. We aimed to determine whether patients receiving systemic antibiotics prior to ERCP had lower morbidity and mortality rates as well as shorter hospitalization compared to patients who did not receive antibiotic prophylaxis. MATERIALS AND METHODS: We conducted a prospective study of all patients undergoing ERCP in our unit. Antibiotic use, postERCP cholangitis rates, 30-day mortality and hospital stay were studied. Also, bacteriological examination of bile aspirates from these patients was conducted and antibiotic susceptibility was determined for the isolated pathogens. OUTCOMES: One hundred-thirty eight consecutive ERCPs conducted in our unit in a 9 month period were included. Cholangitis developed in 3 (4.6%) cases in the antibiotics groups and 3 (4%) cases in the control group (p=0.8). Hospital stay did not differ significantly between the two study groups (p=0.58). There was only one procedure-related death which was the result of postERCP pancreatitis in a patient with severe associated illnesses. Bile aspirates showed bacterial growth in 75% of the cases where bile was obtained, with E. coli being the most frequently isolated microorganism. No differences in bacteriological profiles were noted between the two study groups. CONCLUSION: There seems to be no influence on patient-related outcome of antibiotic prophylaxis prior to elective ERCP. PMID- 25705301 TI - Particularities of coronary artery disease in hypertensive patients with left bundle branch block. AB - OBJECTIVE: We mean to investigate whether the presence of hypertension could be associated with a more severe atherosclerotic coronary artery disease in patients with left bundle branch block. MATERIAL AND METHODS: To assess the current incidence and meaning of hypertension associated with atherosclerotic coronary artery disease we performed a cross-sectional analysis that included 402 patients with left bundle branch block, admitted between January 2011 and June 2013 in the Cardiovascular Diseases Institute Iasi, Romania. Of these, 194 were hypertensive, especially grade 1 and 2; 272 patients had new or presumably new left bundle branch block on their presenting electrocardiograms. The median follow up was 7 days (hospitalization period). RESULTS: The results of our study show that hypertensive patients were more likely to have a prior history of cardiovascular events, including myocardial infarction, angina pectoris, diabetes and obesity, with statistically significant differences. On the other hand, the normotensive patients had higher rates of current and previous smoking and congestive heart failure. Conventional coronary angiography was performed in 130 (67.01%) hypertensive patients and demonstrated that almost half (41.76%) of them have coronary artery disease, one in five patients being diagnosed with acute coronary syndromes. The majority of hypertensive patients evaluated by coronary angiography had either one or two coronary lesions (28.86%); in contrast, from 110 normotensive patients evaluated by coronary angiography, 78.36% had no vessel disease (p = 0.001). When coronary artery disease was present it was frequently localized on the left descendent artery in both groups, but with statistically significant differences (16.82% in normotensives vs. 32.47% in hypertensives, p = 0.001). With regards to systolic left ventricular function, normotensive patients were more likely to have a decreased ejection fraction (EF) <50% (p <0.001), almost half of them having an EF <30%. CONCLUSIONS: We have found that hypertensive patients with left bundle branch block and a clinical context suggestive of acute coronary syndrome have an elevated risk of coronary artery disease, especially one and two coronary lesions. The association of hypertension with left bundle branch block is a high probability criterion for the diagnosis of coronary artery disease, even in asymptomatic patients. PMID- 25705302 TI - Asthma Control Assessment in Children: Correlation between Asthma Control Test and Peak Expiratory Flow. AB - OBJECTIVES: To assess the correlation between asthma control test and peak expiratory flow measurements in children and the impact of certain factors influencing asthma symptoms perception over their correlation. METHODS: A prospective study including 54 patients aged 5 to 18 years old, who have been diagnosed with asthma in "Victor Gomoiu" Children's Clinical Hospital between May 2012-November 2013, was initiated. For each patient a personalized asthma monitoring plan was designed. This presumes many evaluations assigned to assess the asthma control status. These evaluations consist in counting of asthma symptoms using ACT (Asthma Control Test) and evaluation of pulmonary function using PEF measurement (peak expiratory flow) and spirometry. In each patient factors known to have an influence on asthma symptoms perception (small age, overweighting and allergic rhinitis) were searched. Finally, the correlation between ACT value and PEF variation and how this correlation is influenced by these factors were assessed. RESULTS: From all 54 included patients a total of 113 evaluations moments were recorded. The assessment of correlation between ACT score and PEF variation for all evaluations showed a strong correlation overall (p<0.01). The correlation is stronger in the small age group (5 to 6 years: p<0.01) than in the older age group (6 to 11 years: p=0.014, >12 years: p=0.03). ACT does not correlate with PEF variation in the overweight patients subgroup (p=0.226). We found the percent of overweight equal to 8.57% in the small age subgroup (5 to 6 years), 26.78% in the 6 to 11 years old group and 31.81% in the over 12 years old patient group. ACT is correlated with PEF variation in both the allergic rhinitis and non allergic rhinitis subgroups (p<0.01). CONCLUSIONS: ACT is correlated with PEF variation overall. Their correlation is not influenced by small age and the presence of allergic rhinitis, but is influenced by overweighting. PMID- 25705303 TI - Intellectual disability and epilepsy in down syndrome. AB - Down Syndrome (DS) is the most common genetic cause of mental retardation, with a reported frequency of epilepsy between 1.4-17% (1). There is a paucity of data in the literature regarding epilepsy in Down syndrome and its relation to intellectual disability. OBJECTIVES: The purpose of this article is to analyze the association of epilepsy in children with DS - frequency and type of seizures, treatment, outcome and to compare cognitive impairment of children with DS and epilepsy and DS without epilepsy from our cohort. METHODS: A four years systematic retrospective analysis of the database of the Pediatric Neurology Clinic (January 2010 - December 2013) identified a cohort of 39 pediatric cases with DS and neurological symptoms, 9 of them (23%) associating epileptic seizures. Following data were analysed: clinical and neurological examination, type/s of seizures, electroencephalography (EEG), cerebral magnetic resonance imaging (MRI), psychological examination, psychiatric evaluation in selected cases, electrocardiography (ECG), cardiac ultrasonography, ophthalmologic examination. RESULTS: 23% (9 patients) of the children with DS of our cohort presented epilepsy. Five patients had epileptic spasms (56%), one of these further developed astatic seizures. Focal seizures were observed in three patients (33%) and absence with eyelid myoclonias in one patient (11%). Two of the nine patients with DS and epilepsy had generalized seizures, both with very good response to levetiracetam (LEV). EEG was abnormal at seizure onset, and was improved after treatment. Of the nine children with DS and epilepsy, two (22%) presented mild mental retardation and seven (78%) had moderate to severe cognitive delay. Of the 30 children with DS and without epilepsy, 21 (70%) had mild mental retardation and 9 (30%) had moderate to severe cognitive impairment. CONCLUSIONS: The most frequent epileptic syndrome associated with DS is West syndrome, with good response to specific antiepileptics. All children with DS from our cohort have intelectual disability, more severe in those with epilepsy. Slight improvement of intelectual and language capabilities were seen after seizures control. PMID- 25705304 TI - Inherited thrombophilia in pregnant women with intrauterine growth restriction. AB - BACKGROUND: Intrauterine growth restriction (IUGR) is a major cause of fetal morbidity and mortality during pregnancy. The role of mutation in the factor V gene, prothrombin gene, MTHFR gene, as risk factors for intrauterine growth restriction during pregnancy, is not very well known so far. MATERIALS AND METHODS: This is a retrospective study of 151 pregnant women with a history of complicated pregnancy: intrauterine growth restriction, preeclampsia, recurrent pregnancy loss or maternal venous thromboembolism, who were admitted in Bucharest Emergency University Hospital, during the period January 2010 to July 2014. Genetic testing was performed for all the cases to detect: factor V Leiden mutation, G20210A mutation in the prothrombin gene, C677T mutation and A1298C mutation in methylenetetrahydrofolate reductase (MTHFR) gene. Blood samples were obtained as soon as the diagnosis of intrauterine growth restriction was established with ultrasonography. RESULTS: The following gene mutations were associated with increased risk of IUGR: G20210A prothrombin gene mutation (OR 4.81, 95% CI 1.05 - 2.22, p= 0.043), G1691A factor V gene mutation (factor V Leiden) (OR 1.58, 95% CI 0.61 - 4.080, p= 0.347), C677T MTHFR gene mutation (OR 1.61, 95% CI 0.79 to 3.26, p= 0.186), compound heterozygous MTHFR C677T and A1298C (OR 1.66, 95% CI 0.81- 3.42, p= 0.169). Particularly, for G20210A prothrombin gene mutation we found statistically significant risk (p<=0.05) of IUGR. PMID- 25705305 TI - Human gait and postural control after unilateral total knee arthroplasty. AB - INTRODUCTION: This study assesses the changes in human gait in the early postoperative phase of unilateral TKA, by evaluating the variability of free moment. MATERIALS AND METHOD: The study group consisted of 10 patients from the Orthopedic Department of the 'Elias' University Hospital in Bucharest who undergone unilateral knee arthroplasty with the same type of posterior cruciate ligament substituting prosthesis. For the evaluation of free moment an AMTI AccuGait force platform was used. RESULTS: Regarding the free moment peaks, for the operated and non-operated limb, increased significantly (p <0.05) in the postoperative period. The stance time was higher post-surgery for both limbs. DISCUSSION: In the early postoperative phase of unilateral TKA, free moment is higher on both the operated and the non-operated limbs, which means that the knees are subjected to higher torques. Shortly after TKA, patients tend to walk with lower speed, with small steps and reduced cadence. Stance time differences between the operated and the non-operated limbs can lead to overuse of the latter, worsening its condition. CONCLUSIONS: It is highly important to adopt a well-managed rehabilitation program in order to increase walking stability. The cost effectiveness of this procedure could be highly dependent on the rehab program. The parameters studied in this article are useful in assessing the rehabilitation protocol. PMID- 25705306 TI - Principles of surgical treatment in the midface trauma - theory and practice. AB - INTRODUCTION: Facial trauma is a common injury in the urban setting. Many studies have been published on the epidemiology and treatment of facial fractures, but few of them conducted in emergencies hospital as ours. The purpose of this study was to present theory and practice in surgical treatment of midface trauma. MATERIALS AND METHOD: We will present a retrospective study and a cases series report with our personal experience in diagnosis and treatment of middle floor facial trauma. Craniofacial trauma in context of polytrauma involves a screening condition assessment of the patient to prioritize lesions and frequently require a multidisciplinary approach: neurosurgeon, ENT surgeon, maxillo-facial surgeon, ophthalmologist, plastic surgeon and so on. Axial and coronal CT are mandatory and three-dimensional CT reconstruction can be extremely useful. Surgical indication in middle floor facial trauma is given by functional and aesthetic deficits. RESULTS: We will present the surgical principles we use in treatment of fractured nose, in fractures of maxilla, in fractures of the zygomatic arch with or without zygoma body fractures and fractures of the floor of orbit. DISCUSSIONS: The surgical technique was imposed by coexisting lesions of neuro and viscerocranium, by the complexity of the fracture, by functional or aesthetic deficits and by our surgical experience. CONCLUSIONS: The main principles in middle face trauma are an accurate and complete lesions evaluation; mixed surgery team with maxillofacial surgeon and neurosurgeon. PMID- 25705307 TI - Current Perception of Telemedicine in an EU Country. AB - OBJECTIVES: To assess the perception and expectation of beneficiaries and providers of telemedicine services in Romania. METHODS: Interview (on-line and face-to-face) of 109 representatives of medical community, from two categories: physicians, involved directly in the patient care, and medical and information technology directors of state and private owned clinics and hospitals. A third group, formed by executives from main technology service provider companies, was added in order to expand the results with their vision as potential suppliers of telemedicine projects. OUTCOMES: We evaluated 4 important aspects of telemedicine: actual status of the services, development efforts and allocated budget, expected future services, and stoppers and enablers. On the actual status we identified in 48% of the cases the existence of core services good enough to start advanced telemedicine services. We developed a metric (SOR = Supporter/Opponents Ratio) to evaluate the suitability of telemedicine services to evolve and to deliver on expectations. The analysis shows that physicians see potential for development for EHR and PACS (both with SOR >25), but the executives start looking forward to more advanced services like remote patient monitoring. Main impact is expected in collaboration and patient quality life areas and, by far, the main stoppers are reduced budgets and organizational problems to adapt to the new data models. CONCLUSIONS: We identified a strong support from the physicians related with the introduction of new type of healthcare services accompanied with high expectations. On the executive level, the expectations are different, ranging from low optimism on the technology side, to serious support on the medical side. However, there is a clear trend, able to create the first telemedicine services during the next years. PMID- 25705308 TI - Endocarditis and stroke. AB - Endocarditis is an important, although less common, cause of cerebral embolism. All forms of endocarditis share an initial common pathophysiologic pathway, best illustrated by the non-bacterial thrombotic form, but also a final potential for embolization. Stroke associated with endocarditis has signifficant mortality and morbidity rates, especially due to the frequent concomitant multiple sites of brain embolization. In this article we aim to briefly review endocarditis with a focus on stroke as a complication, while also presenting case correlates from our department. PMID- 25705309 TI - Interdisciplinary Approach in a Complex Case of STEMI. AB - We reported the case of a young man with ST-Segment Elevation Myocardial Infarction (STEMI), with ventricular fibrillation on debut and cardiogenic shock, who needed a complex interdisciplinary approach for a favourable long term outcome. A 43-year-old man was admitted with inferior STEMI and cardiogenic shock. First coronary angiography revealed total chronic occlusion of left anterior descending artery (LAD) and tight stenosis with thrombus on right coronary artery (RCA). Thrombus aspiration and stent implantation on RCA was performed with good results. LAD couldn't be opened. Intraaortic balloon pump was implanted. Forty-eight hours later, we try again to open LAD, without success. After a lot of complications, all solved with difficulty, patient was discharged cachectic and with progressive exertion on mild exercise. Two months later an implantable cardioverter-defibrillator (ICD) was decided for persistent ventricular tachycardia and after one year he was referred to a cardiac surgery centre abroad for aneurismectomy with left ventricle (LV) reconstruction and mitral valve repair. The patient is currently asymptomatic with a normal social and professional life. In conclusion, high performance cardiac surgery, after a complete interventional treatment, can improve quality of life and long-term outcome to a patient with severe cardiovascular disease. Team work between clinical cardiologists, interventional cardiologists, electrophisyologists, intensi-vists and cardiac surgeons is the key to success. PMID- 25705310 TI - Allergic bronchopulmonary aspergillosis in patient with cystic fibrosis - a case report. AB - Asthma with allergic bronchopulmonary aspergillosis (ABPA), a hypersensitivity disease of the lungs due to an immune response to Aspergillus fumigattus (Af) antigens, is rarely seen in children, other than complicating cystic fibrosis. We present the case of a 14 - year- old female teenager with cystic fibrosis (CF), admitted in our hospital with respiratory failure and persistent cyanosis. Chest X-ray showed perihilar and upper lobes pulmonary infiltrates. Her airway cultures were positive for methicillin resistant staphilococcus aureus (MRSA) and non mucoid Pseudomonas aeruginosa. She was prescribed intravenous antibiotherapy with ceftazidime and vancomycine (to which MRSA and Pseudomonas aeruginosa were susceptible). Pulmonary function testing (PFT) revealed severe obstructive lung disease. After ten days of intravenous antibiotics and first five days of corticosteroid, the patient's FEV1 was 68% of predicted. Total serum IgE and IgE antibodies to Aspergillus fumigatus were elevated. These results raised the possibility of allergic bronchopulmonary aspergillosis (ABPA). The possibility of ABPA should be considered in all pulmonary exacerbation and in order to determine if ABPA is developing or if an exacerbation is occurring, a serial monitoring of IgE levels should be performed. PMID- 25705311 TI - Esophageal Multichannel Intraluminal Impedance and pH Monitoring in the Evaluation of Achalasia and Gastroesophageal Reflux Disease in a Child with Down Syndrome: a Case Report. AB - We report the case of a rare association between achalasia and Down syndrome in a child presenting with symptoms that suggest a gastroesophageal reflux. Evaluation of the patient with 24-hour multichannel intraluminal impedance and pH recording and upper endoscopy lead to the diagnosis of achalasia. However, the persistence of the symptoms after the concurrent surgical myomectomy and fundoplication has led to repeat pH-impedance monitoring testing and endoscopy, which identified the presence of gastroesophageal reflux disease. We emphasize in this paper the importance of multichannel intraluminal impedance and pH monitoring in detecting esophageal motility disorders. PMID- 25705312 TI - Fibrous pleural plaques detected at autopsy. AB - The reported case was a 84-year-old male, dead after a traffic accident. The death was considered to be suspicious by prosecutor and an autopsy was mandated. In macroscopic autopsy investigation left tibia, fibula and multiple rib fractures, widespread seborrheic keratoses, and hyperpigmented skin lesions were detected. In the left chest cavity blood content and white colored lesions spread on the left parietal pleura and chest surface of the thoracic diaphragm were observed. The histological examination of the pleural lesions revealed fibrotic hyalinized structures with calcified foci. Investigation of pleural plaques in forensic autopsy is important for scientific classification of this interesting entity. PMID- 25705313 TI - Death due to combined intake of ethanol and toluene: a case report. AB - Toluene is a commonly used volatile organic chemical in industry and is the most often chosen illicit substance among volatile substance abusers. Studies involving healthy volunteers suggest that ethanol consumption inhibits toluene metabolism, thus increasing its blood levels. In this study, a lethal case of combined ethanol consumption and toluene inhalation has been reported. Our case was a 30-year-old male who had used volatile substance for 15 years. The autopsy revealed no abnormal findings. Toxicological analysis revealed alcohol and toluene in the blood and the cause of death was considered as toxicity due to acute combined intake of alcohol and toluene. Lethal combined ethanol and toluene intake is rarely reported in the literature. Experimental studies indicate that toluene increases the risk of ethanol dependence and each substance increases the toxic effects of the other. PMID- 25705314 TI - Chronic migraine - new treatment options. AB - Chronic migraine (CM) is defined as headache occurring more than fifteen days/month for at least three consecutive months, with headache having the clinical features of migraine without aura for at least eight days per month. Recently, new treatment options became available in chronic migraine patients. Topiramate is effective in chronic migraine, in the presence or absence of medication overuse, and/or other migraine prophylaxis. Efficacy of onabotulinumtoxin A as a preventive treatment of chronic migraine has been shown in the PREEMPT studies. Occipital nerve stimulation (ONS) is an invasive treatment for refractory chronic headaches. ONS has encouraging results in refractory chronic migraine patients in commercially funded, multi-centre randomized trials. PMID- 25705315 TI - More indications approved and safety news for dabigatran etexilate. PMID- 25705316 TI - Dimethyl fumarat - a new player in oral treatment options for relapsing forms of multiple sclerosis. PMID- 25705317 TI - Robotic-assisted tubal anastomosis with one-stitch technique. AB - The da Vinci((r)) robotic surgical system has been used more often in recent years for tubal anastomosis (TA) and has been reported to have an increased operative time. A one-stitch technique has been used for the reanastomosis step in laparoscopic TA. To date, publications on robotically-assisted TA (RATA) describe an anastomotic step with multiple (usually four) sutures placed. This retrospective case series reports tubal patency data on patients who underwent RATA with the one-stitch technique; tubal patency was the outcome measure. Eighteen women (ages 27-39) underwent RATA with the one-stitch anastomotic technique in tertiary care medical centers between February 2009 and May 2012. Tubal patency was demonstrated in 16/17 patients (94.1 %), as evidenced by postoperative hysterosalpingogram (HSG) and/or subsequent pregnancies. We report the first case series which shows that RATA with a single stitch for the reanastomotic step is effective in achieving tubal patency as evidenced by postoperative HSG and/or pregnancies. PMID- 25705318 TI - Facial emotion recognition in agenesis of the corpus callosum. AB - BACKGROUND: Impaired social functioning is a common symptom of individuals with developmental disruptions in callosal connectivity. Among these developmental conditions, agenesis of the corpus callosum provides the most extreme and clearly identifiable example of callosal disconnection. To date, deficits in nonliteral language comprehension, humor, theory of mind, and social reasoning have been documented in agenesis of the corpus callosum. Here, we examined a basic social ability as yet not investigated in this population: recognition of facial emotion and its association with social gaze. METHODS: Nine individuals with callosal agenesis and nine matched controls completed four tasks involving emotional faces: emotion recognition from upright and inverted faces, gender recognition, and passive viewing. Eye-tracking data were collected concurrently on all four tasks and analyzed according to designated facial regions of interest. RESULTS: Individuals with callosal agenesis exhibited impairments in recognizing emotions from upright faces, in particular lower accuracy for fear and anger, and these impairments were directly associated with diminished attention to the eye region. The callosal agenesis group exhibited greater consistency in emotion recognition across conditions (upright vs. inverted), with poorest performance for fear identification in both conditions. The callosal agenesis group also had atypical facial scanning (lower fractional dwell time in the eye region) during gender naming and passive viewing of faces, but they did not differ from controls on gender naming performance. The pattern of results did not differ when taking into account full-scale intelligence quotient or presence of autism spectrum symptoms. CONCLUSIONS: Agenesis of the corpus callosum results in a pattern of atypical facial scanning characterized by diminished attention to the eyes. This pattern suggests that reduced callosal connectivity may contribute to the development and maintenance of emotion processing deficits involving reduced attention to others' eyes. PMID- 25705319 TI - Delay-dependent stability of neutral system with mixed time-varying delays and nonlinear perturbations using delay-dividing approach. AB - This paper studies delay-dependent robust stability problem for neutral system with mixed time-varying delays and nonlinear perturbations. Based on the delay dividing approach, a novel Lyapunov functional is constructed, and a novel delay dependent stability criterion is derived to guarantee the robust stability of the neutral system. Expressed in terms of linear matrix inequalities, the stability condition can be checked using the numerically efficient Matlab LMI Control Toolbox. Two numerical examples are provided to demonstrate the effectiveness and the reduced conservatism of the analysis result. PMID- 25705320 TI - Moderate wine consumption is associated with lower hemostatic and inflammatory risk factors over 8 years: The study of women's health across the nation (SWAN). AB - Moderate wine consumption has been associated with reduced cardiovascular (CV) risk, but most investigations have been conducted in Caucasian populations. To investigate the relationship of wine consumption to CV risk markers, we studied a multi-ethnic sample of middle-aged, healthy women (N = 2900; 48% white, 28% black, 7% Hispanic, 8% Chinese, 9% Japanese) participating in SWAN over 7 years with repeated assessments of CV risk factors. Consumption of wine was stable and common with 20% reporting none, 69% light (<1/day), 7% moderate ( = 1/day), and 4% heavy (>1/day). To guard against underreporting, we took the maximum reported wine consumption over 7 years as the predictor. We used mixed models with a random intercept and random time to assess the relationship between wine consumption and CV risk factors with moderate consumption as the reference. Outcome variables were log-transformed where necessary. Longitudinal models were adjusted for ethnicity, age, and time-varying menopausal status, hormone therapy use, overall alcohol consumption, high density lipoprotein (HDL), statin use, and a healthy lifestyle score based on physical activity, not smoking, and weight maintenance. Interactions of wine consumption with time were not significant. Moderate wine consumers had significantly lower levels of C-reactive protein (CRP, p < .001), fibrinogen (p < .001), factor VII (p < .01), and plasminogen activator inhibitor (PAI-1, p < .05) than women who drank no or little wine. These associations were independent of significant effects of healthy lifestyle and overall alcohol consumption and similar across ethnic groups. Moderate wine consumption may protect against CVD via inflammatory and clotting pathways. PMID- 25705321 TI - High expression of miR-214 is associated with a worse disease-specific survival of the triple-negative breast cancer patients. AB - BACKGROUND: Hereditary triple-negative breast cancer patients have better recurrence-free survival than triple-negative sporadic ones. High expression of some of the miRNAs is related to worse overall and disease-free survival of triple-negative breast cancer patients. The attempt to associate expression level of some miRNA in triple-negative hereditary and sporadic breast cancers to disease specific survival was performed in this study. MATERIAL AND METHODS: Study group was made of 18 triple-negative breast cancer patients harboring the BRCA1 gene mutations and 32 triple-negative sporadic breast cancer patients. Quantitative amount of mir-10b, mir-21, mir-29a, mir-31, and mir-214 by real-time PCR was assessed. The disease-specific survival in relation of high and low levels of some of the miRNAs was analyzed using Log-rank (Mantel-Cox) test. RESULTS: MiR-214 showed significantly higher expression level in sporadic tissues than in hereditary ones (p = 0.0005). Triple-negative breast cancer patients with high level of miR-214 showed significantly worse disease-specific survival than patients with low level (p = 0.0314). CONCLUSIONS: Our finding suggests that miR 214 possibly could be used as a potential prognostic biomarker for triple negative breast cancer patients. PMID- 25705322 TI - FIRST-YEAR COLLEGE WOMEN'S MOTIVATIONS FOR HOOKING UP: A MIXED-METHODS EXAMINATION OF NORMATIVE PEER PERCEPTIONS AND PERSONAL HOOKUP PARTICIPATION. AB - This study used content analysis techniques to explore 221 first-year college women's perceptions of female peers' reasons (i.e., normative perceptions) for hooking up. Data on personal participation in hooking up were also collected. The well-established Drinking Motives Questionnaire (Cooper, 1994) was used as a framework for coding positive (enhancement or social) and negative (coping or conformity) normative hookup motivations. Participants most commonly indicated that enhancement reasons motivated peers' hookup behaviors (69.7%). Coping (23.5%), external (21.7%), social (19.5%), and conformity (16.3%) motives were cited less frequently. Furthermore, women who had hooked up since matriculating into college (61.5%, n = 136) were significantly more likely to state that their female peers hook up for enhancement reasons (a positive motive), but they were significantly less likely to perceive that typical female peers hook up for coping or conformity reasons (negative motives) (ps < .001). Findings indicate not only that college women uphold overwhelmingly positive perceptions for peers' hooking up, but there appears to be a strong relationship between college women's own hooking up participation and the positive versus negative attributions they ascribe to hooking up among their peers. This study extends the understanding of college women's perceptions and potential influences of hooking up and provides implications for harm reduction efforts. PMID- 25705323 TI - Myocardial Inflammation-Are We There Yet? AB - Several exogenous or endogenous factors can lead to inflammatory heart disease. Beside infectious myocarditis, other systemic inflammatory disorders such as sarcoidosis, systemic lupus erythematosus (SLE), systemic sclerosis (SSc), Churg Strauss syndrome, and rheumatoid arthritis can affect the myocardium. Myocardial inflammation may have a major impact on the outcome of these patients, resulting in sudden cardiac death, severe arrhythmias, or end-stage heart failure. The current gold standard for definite confirmation of inflammatory heart disease is endomyocardial biopsy (EMB), but is invasive and suffers low sensitivity and specificity due to sampling errors. Thus, non-invasive methods for detecting the extent and changes over time of the inflammatory myocardial disease are needed. Cardiac magnetic resonance (CMR) is such a non-invasive method. We will describe and discuss different approaches for CMR assessment of inflammatory myocardial disease including early gadolinium enhancement (EGE), T2-weighted imaging, late gadolinium enhancement (LGE), the newer mapping proton relaxation techniques (T1 pre-contrast, T1 post-contrast, T2 mapping), and the hybrid PET/MRI technique. PMID- 25705324 TI - A Virtual Patient Simulator Based on Human Connectome and 7 T MRI for Deep Brain Stimulation. AB - This paper presents a virtual model of patients with Deep Brain Stimulation implants. The model is based on Human Connectome and 7 Tesla Magnetic Resonance Imaging (MRI) data. We envision that the proposed virtual patient simulator will enable radio frequency power dosimetry on patients with deep brain stimulation implants undergoing MRI. Results from the proposed virtual patient study may facilitate the use of clinical MRI instead of computed tomography scans. The virtual patient will be flexible and morphable to relate to patient-specific neurological and psychiatric conditions such as Obsessive Compulsive Disorder, which benefit from deep brain stimulation. PMID- 25705325 TI - MULTI-MODAL DATA FUSION SCHEMES FOR INTEGRATED CLASSIFICATION OF IMAGING AND NON IMAGING BIOMEDICAL DATA. AB - With a wide array of multi-modal, multi-protocol, and multi-scale biomedical data available for disease diagnosis and prognosis, there is a need for quantitative tools to combine such varied channels of information, especially imaging and non imaging data (e.g. spectroscopy, proteomics). The major problem in such quantitative data integration lies in reconciling the large spread in the range of dimensionalities and scales across the different modalities. The primary goal of quantitative data integration is to build combined meta-classifiers; however these efforts are thwarted by challenges in (1) homogeneous representation of the data channels, (2) fusing the attributes to construct an integrated feature vector, and (3) the choice of learning strategy for training the integrated classifier. In this paper, we seek to (a) define the characteristics that guide the 4 independent methods for quantitative data fusion that use the idea of a meta-space for building integrated multi-modal, multi-scale meta-classifiers, and (b) attempt to understand the key components which allowed each method to succeed. These methods include (1) Generalized Embedding Concatenation (GEC), (2) Consensus Embedding (CE), (3) Semi-Supervised Multi-Kernel Graph Embedding (SeSMiK), and (4) Boosted Embedding Combination (BEC). In order to evaluate the optimal scheme for fusing imaging and non-imaging data, we compared these 4 schemes for the problems of combining (a) multi-parametric MRI with spectroscopy for prostate cancer (CaP) diagnosis in vivo, and (b) histological image with proteomic signatures (obtained via mass spectrometry) for predicting prognosis in CaP patients. The kernel combination approach (SeSMiK) marginally outperformed the embedding combination schemes. Additionally, intelligent weighting of the data channels (based on their relative importance) appeared to outperform unweighted strategies. All 4 strategies easily outperformed a naive decision fusion approach, suggesting that data integration methods will play an important role in the rapidly emerging field of integrated diagnostics and personalized healthcare. PMID- 25705326 TI - Targeting Metal-Abeta Aggregates with Bifunctional Radioligand [11C]L2-b and a Fluorine-18 Analogue [18F]FL2-b. AB - Interest in quantifying metal-Abeta species in vivo led to the synthesis and evaluation of [11C]L2-b and [18F]FL2-b as radiopharmaceuticals for studying the metallobiology of Alzheimer's disease (AD) using positron emission tomography (PET) imaging. [11C]L2-b was synthesized in 3.6% radiochemical yield (nondecay corrected, n = 3), >95% radiochemical purity, from the corresponding desmethyl precursor. [18F]FL2-b was synthesized in 1.0% radiochemical yield (nondecay corrected, n = 3), >99% radiochemical purity, from a 6-chloro pyridine precursor. Autoradiography experiments with AD positive and healthy control brain samples were used to determine the specificity of binding for the radioligands compared to [11C]PiB, a known imaging agent for beta-amyloid (Abeta) aggregates. The Kd for [11C]L2-b and [18F]FL2-b were found to be 3.5 and 9.4 nM, respectively, from those tissue studies. Displacement studies of [11C]L2-b and [18F]FL2-b with PiB and AV-45 determined that L2-b binds to Abeta aggregates differently from known radiopharmaceuticals. Finally, brain uptake of [11C]L2-b was examined through microPET imaging in healthy rhesus macaque, which revealed a maximum uptake at 2.5 min (peak SUV = 2.0) followed by rapid egress (n = 2). PMID- 25705327 TI - Robust Unsupervised Arousal Rating: A Rule-Based Framework with Knowledge Inspired Vocal Features. AB - Studies in classifying affect from vocal cues have produced exceptional within corpus results, especially for arousal (activation or stress); yet cross-corpora affect recognition has only recently garnered attention. An essential requirement of many behavioral studies is affect scoring that generalizes across different social contexts and data conditions. We present a robust, unsupervised (rule based) method for providing a scale-continuous, bounded arousal rating operating on the vocal signal. The method incorporates just three knowledge-inspired features chosen based on empirical and theoretical evidence. It constructs a speaker's baseline model for each feature separately, and then computes single feature arousal scores. Lastly, it advantageously fuses the single-feature arousal scores into a final rating without knowledge of the true affect. The baseline data is preferably labeled as neutral, but some initial evidence is provided to suggest that no labeled data is required in certain cases. The proposed method is compared to a state-of-the-art supervised technique which employs a high-dimensional feature set. The proposed framework achieves highly competitive performance with additional benefits. The measure is interpretable, scale-continuous as opposed to discrete, and can operate without any affective labeling. An accompanying Matlab tool is made available with the paper. PMID- 25705328 TI - Effects of methylprednisolone on neuroprotective effects of delay hypothermia on spinal cord injury in rat. AB - STUDY DESIGN: A retrospective study. PURPOSE: The aim of this study was to evaluate the effects of delayed hypothermia on spinal cord injuries in rats. In addition, the effect of methylprednisolone on therapeutic window of hypothermia was evaluated. OVERVIEW OF LITERATURE: Several studies have demonstrated that early hypothermia is the most effective neuroprotective modality. However, delayed hypothermia seems to be more practical for patients with traumatic spinal cord injuries. A combination of hypothermia and other neuroprotective methods, such as using methylprednisolone, may help extend the therapeutic window of hypothermia. METHODS: One hundred and twenty male rats were categorized into six groups. The rats in five groups were subjected to spinal cord injury using the weight drop method, followed by treatment, consisting of early hypothermia, late hypothermia, late hypothermia plus methylprednisolone, or methylprednisolone only. Biochemical tests including catalase, malondialdehyde, and superoxide level were evaluated in the injured spinal cord. Behavioral functions of the hind limb were evaluated by Basso-Battle-Bresnaham locomotor rating scale and tail-flick tests. RESULTS: Functional and biochemical evaluation showed both early and late hypothermia had significant neuroprotective effects. The treated groups did not differ significantly from one another in the behavioral tests. Hypothermia had better biochemical results compared to methylprednisolone. Also, methylprednisolone was shown to extend the therapeutic window of delayed hypothermia. CONCLUSIONS: Hypothermia showed a significant neuroprotective effect, which can be improved with further studies optimizing the duration of hypothermia and the rewarming period. Moreover, the therapeutic effect of the delayed hypothermia can be extended by methylprednisolone. PMID- 25705329 TI - Expression of hyaluronidase-4 in a rat spinal cord hemisection model. AB - STUDY DESIGN: Examination of hyaluronidase-4 (Hyal-4) expression in a rat spinal cord hemisection model. PURPOSE: To determine the status of Hyal-4 expression after hemisection of the spinal cord, and the relationship between its expression and that of chondroitin sulfate proteoglycans (CSPGs). OVERVIEW OF LITERATURE: CSPGs are expressed at the site of spinal cord injury and inhibit axon regeneration. Administration of exogenous chrondroitinase ABC (ChABC), derived from bacteria, digested CSPGs and promoted axonal regrowth. Using a rat hemisection model, we have demonstrated peak CSPGs levels at by 3 weeks after injury but then decreased spontaneously. Could there be an endogenous enzyme similar to ChABC in the spinal cord? It has been suggested that Hyal-4 is involved in CSPG degradation. METHODS: A rat hemisection model was prepared and spinal cord frozen sections were prepared at 4 days and 1, 2, 3, 4, 5, and 6 weeks post-cordotomy and stained for CSPGs and Hyal-4 and subjected to Western blotting. RESULTS: CSPGs appeared at the injury site at 4 days after hemisection, reached a peak after 3 weeks, and then decreased. Hyal-4 was observed around the injury site from 4 days after cordotomy and increased until after 5-6 weeks. Double staining showed Hyal-4 around CSPGs. Western blotting identified a band corresponding to Hyal-4 from 4 days after hemisection. CONCLUSIONS: Hyal-4 was expressed in a rat hemisection model in areas surrounding CSPGs, and as its peak was delayed compared with that of CSPGs. These results suggest the involvement of Hyal-4 in the digestion of CSPGs. PMID- 25705330 TI - Repair using conventional implant for ruptured annulus fibrosus after lumbar discectomy: surgical technique and case series. AB - STUDY DESIGN: A retrospective review of annulus fibrosus repair (AR) using a novel technique with a conventional implant. PURPOSE: The purpose of this study was to present the feasibility and clinico-radiological outcomes of a novel AR technique using a conventional implant to minimize recurrence following a lumbar discectomy (LD). OVERVIEW OF LITERATURE: Conventional repair techniques to prevent recurrence following LD have several drawbacks. The AR surgical technique has received little attention as an adjunct to LD. METHODS: A total of 19 patients who underwent novel AR following LD, and who were available for follow up for at least three years, were enrolled in this study. Several variables, including the type and size of disc herniation, and the degree of disc degeneration, were evaluated preoperatively. Postoperatively, the presence of clinical and radiological recurrence of disc herniation was evaluated from pain intensity and functional statuses, as well as an enhanced L-spine magnetic resonance imaging at the final follow-up. The presence of a peripheral hollow rim and inserted anchor mobilization were also evaluated during the follow-up. RESULTS: During follow-ups, there were no recurrences of disc herniation or complications, including neurovascular complications. Pain and functional disability improved significantly after surgery, and the improvement was maintained throughout the three-year follow-up period. No mobilization or implant peripheral hollow rim was observed during the follow-up. CONCLUSIONS: This study examined the feasibility of a novel and easily available annulus implant technique following LD. These results suggest performing AR with this technique may be a valuable alternative for optimizing outcomes, if the procedure is performed in proper candidates. PMID- 25705331 TI - A comparison of computed tomography measures for diagnosing cervical spinal stenosis associated with myelopathy: a case-control study. AB - STUDY DESIGN: Retrospective comparative study. PURPOSE: To assess differences in computed tomography (CT) imaging parameters between patients with cervical myelopathy and controls. OVERVIEW OF LITERATURE: There is a lack of information regarding the best predictor of symptomatic stenosis based on osseous canal dimensions. We postulate that smaller osseous canal dimensions increase the risk of symptomatic central stenosis. METHODS: CT images and medical records of patients with cervical myelopathy (19 patients, 8 males; average age, 64.4+/-13.4 years) and controls (18 patients, 14 males; average age, 60.4+/-11.0 years) were collected. A new measure called the laminar roof pitch angle (=angle between the lamina) was conducted along with linear measures, ratios and surrogates of canal perimeter and area at each level C2-C7 (222 levels). Receiver-operator curves were used to assess the diagnostic value of each. Rater reliability was assessed for the measures. RESULTS: The medial-lateral (ML) diameter (at mid-pedicle level) and calculated canal area (=anterior-posterior.*ML diameters) were the most accurate and highly reliable. ML diameter below 23.5 mm and calculated canal area below 300 mm(2) generated 82% to 84% sensitivity and 67% to 68% sensitivity. No significant correlations were identified between age, height, weight, body mass in dex and gender for each of the CT measures. CONCLUSIONS: CT measures including ML dimensions were most predictive. This study is the first to identify an important role for the ML dimension in cases of slowly progressive compressive myelopathy. A ML reserve may be protective when the canal is progressively compromised in the anterior-posterior dimension. PMID- 25705332 TI - A Prospective Randomized Clinical Trial Comparing Bone Union Rate Following Anterior Cervical Discectomy and Fusion Using a Polyetheretherketone Cage: Hydroxyapatite/B-Tricalcium Phosphate Mixture versus Hydroxyapatite/Demineralized Bone Matrix Mixture. AB - STUDY DESIGN: Prospective randomized noninferiority trial. PURPOSE: To evaluate whether the union rate of anterior cervical discectomy and fusion (ACDF) using a polyetheretherketone (PEEK) cage filled with a mixture of hydroxyapatite (HA) and demineralized bone matrix (DBM) is inferior to that of a mixture of beta tricalcium phosphate (beta-TCP) and HA. OVERVIEW OF LITERATURE: There have been no clinical trials investigating the outcomes of a mixture of HA and DBM in a PEEK cage in ACDF. METHODS: Eighty-five eligible patients were randomly assigned to group B (n=43), in which a PEEK cage with a mixture of HA and DBM was used, or group C (n=42), in which a PEEK cage with a mixture of HA and beta-TCP was used. The primary study endpoint was the fusion rate, which was assessed with dynamic radiographs and computed tomography (CT) scans. Secondary endpoints included pain intensity using a visual analogue scale, functional outcome using a neck disability index score, laboratory tests of inflammatory profiles, and the infection rate. RESULTS: Seventy-seven patients (38 in group B and 39 in group C) were included in the final analysis. One year postoperatively, bone fusion was achieved in 87% of group B patients and 87% of group C patients on dynamic radiographs, and 87% of group B patients and 72% of group C patients on CT scans (p=1.00 and 0.16, respectively). There were also no between-groups differences with respect to the secondary endpoints. CONCLUSIONS: A HA/DBM mixture inside a PEEK cage can provide noninferior outcomes compared to a HA/TCP mixture in ACDF. PMID- 25705333 TI - Analysis of postoperative pain at the anterior iliac crest harvest site: a prospective study of the intraoperative local administration of ropivacaine. AB - STUDY DESIGN: This was a prospective randomized comparative study. PURPOSE: The aim of this study was to objectify donor site-related pain following anterior iliac crest graft harvesting, in patients who have undergone multilevel anterior cervical discectomy and fusion with plating (ACDFP); and to assess the effect of an intraoperative local single injection of ropivacaine on postoperative pain. OVERVIEW OF LITERATURE: Multilevel ACDFP can be associated with a high non-union rate. Autogenous iliac bone has been used to increase union rates, although a high incidence of donor site-related pain has been reported. METHODS: Forty consecutive patients who required 3-level or 4-level ACDFP were prospectively assessed for donor site-related pain. Pain levels were assessed daily for five days postoperative using the visual analog scale (VAS). Patients were randomly assigned to group A or B. In group A patients, 7-10 mL of ropivacaine (0.2%) was injected into the iliac crest after iliac crest graft harvesting. Morphine usage via patient controlled analgesia was calculated. At six months postoperative, patient complaints at the harvest site were documented. RESULTS: Patients were randomly assigned to group A or B. In group A, ropivacaine was locally administered at the site of the iliac crest graft harvest after fascia closure. In group B, no additional treatments were administered. The average patient age in group A was 56+/-7.6 years, whereas the average age of patients in group B was 52.6+/-10.4 years. Group A had an average of 0.6+/-0.7 previous surgeries per patient, whereas group B had an average of 0.8+/-1.0 previous surgeries per patient. The average number of levels fused in group A was 3.6+/-0.7, whereas the average number of levels fused in group B was 3.7+/-0.9 (all p>0.05). In group A, the mean ropivacaine volume administered was 8.4+/-1.5 mL. No patient complaints regarding chronic pain, were reported six months postoperatively. No complications were encountered from the harvest site, and all patients underwent successful 3-level and 4-level ACDFP. Statistical analysis showed significant differences for VAS on postoperative day 1 (p=0.004) and day 2 (p=0.005). CONCLUSIONS: VAS assessment showed overall moderate perioperative morbidity in terms of donor site-related pain, which was reduced by administering ropivacaine. PMID- 25705334 TI - Comparison of the Japanese orthopaedic association score and the Japanese orthopaedic association cervical myelopathy evaluation questionnaire scores: time dependent changes in patients with cervical spondylotic myelopathy and posterior longitudinal ligament. AB - STUDY DESIGN: Prospective cohort study. PURPOSE: To identify differences in time dependent perioperative changes between the Japanese Orthopaedic Association (JOA) score and the JOA Cervical Myelopathy Evaluation Questionnaire (JOACMEQ) score in patients with cervical spondylotic myelopathy (CSM) and posterior longitudinal ligament (OPLL) who underwent cervical laminoplasty. OVERVIEW OF LITERATURE: The JOA score does not take into consideration patient satisfaction or quality of life. Accordingly, the JOACMEQ was designed in 2007 as a patient centered assessment tool. METHODS: We studied 21 patients who underwent cervical laminoplasty. We objectively evaluated the time-dependent changes in JOACMEQ scores and JOA scores for all patients before surgery and at 2 weeks, 3 months, 6 months, and 1 year after surgery. RESULTS: The average total JOA score and the recovery rate improved significantly after surgery in both groups, with a slightly better recovery rate in the OPLL group. Cervical spine function improved significantly in the CSM group but not in the OPLL group. Upper- and lower extremity functions were more stable in the CSM group than in the OPLL group. The effectiveness rate of the JOACMEQ for measuring quality of life was quite low in both groups. In both groups, the Spearman contingency coefficients were dispersed widely except for upper- and lower-extremity function. CONCLUSIONS: Scores for upper- and lower-extremity function on the JOACMEQ correlated well with JOA scores. Because the JOACMEQ can also assess cervical spine function and quality of life, factors that cannot be assessed by the JOA score alone, the JOACMEQ is a more comprehensive evaluation tool. PMID- 25705335 TI - Foramen Magnum Meningioma: Some Anatomical and Surgical Remarks through Five Cases. AB - STUDY DESIGN: Foramen magnum meningioma foramen magnum meningioma (FMM) represents 2% all of meningiomas. The clinical symptomatology is usually insidious and consists of headache, neck pain and hypoesthesia in C2 dermatome. Because of their location, the management is challenging. PURPOSE: The purpose of this paper is to present our experience in the surgery of FMM. OVERVIEW OF LITERATURE: Since 1938, numerous series have been published but they are very heterogeneous with high variability of location and surgical approaches. METHODS: During two years, we operated 5 patients with FMM. All the patients had magnetic resonance imaging (MRI) with angio-MRI to study the relationship between tumour and vertebral artery (VA). In all the cases, we used prone position. RESULTS: In one case, considering the tumour localization (posterior and pure intradural) the tumour was removed via a midline suboccipital approach with craniotomy and C1-C2 laminectomy. In all other cases, meningiomas were posterolateral (classification of George) with extradural extension in one case. In all cases, VA was surrounded by tumor. So, we opted for a modified postero-lateral approach with inverted L incision, craniotomy and C1-C2 laminectomy without resect occipital condyle. Epidural part of VA was identified and mobilized laterally. Once VA was identified we opened dura mater and began to remove the tumour. CONCLUSIONS: In this paper, we present five cases of operated FMM, describe our approaches, the reason of each approach and propose some surgical remarks. PMID- 25705336 TI - Total disc arthroplasty for treating lumbar degenerative disc disease. AB - STUDY DESIGN: Lumber disc arthroplasty is a technological advancement that has occurred in the last decade to treat lumbar degenerative disk diseases. PURPOSE: The aim of this retrospective study was to establish the impact and outcomes of managing patients with lumbar degenerative disk disease who have been treated with lumbar total disc arthroplasty (TDA). OVERVIEW OF LITERATURE: Several studies have shown promising results following this surgery. METHODS: We reviewed the files of 104 patients at the Department of Neurosurgery in Colmar (France) who had been operated on by lumbar spine arthroplasty (Prodisc) between April 2002 and October 2008. RESULTS: Among the 104 patients, 67 were female and 37 were male with an average age of 33.1 years. We followed the cases for a mean of 20 months. The most frequent level of discopathy was L4-L5 with 62 patients (59.6%) followed by L5-S1 level with 52 patients (50%). Eighty-three patients suffered from low back pain, 21 of which were associated with radiculopathy. The status of 82 patients improved after surgery according to the Oswestry Disability Index score, and 92 patients returned to work. CONCLUSIONS: The results indicate that TDA is a good alternative treatment for lumbar spine disk disease, particularly for patients with disabling and chronic low back pain. This technique contributes to improve living conditions with correct patient selection for surgery. PMID- 25705337 TI - Surgical correction in patients with lumbar degenerative kyphosis who had low bone mineral density: an analysis of 40 patients with a minimum follow-up of two years. AB - STUDY DESIGN: Retrospective study. PURPOSE: To investigate influence of bone mineral density (BMD) on the surgical correction of lumbar degenerative kyphosis (LDK). OVERVIEW OF LITERATURE: No studies so far have reported the influence of BMD on the surgical correction of LDK. METHODS: Forty LDK patients with more than 2 years follow-up were studied. Pelvic incidence (PI), pelvic tilt, sacral slope, sagittal vertical axis (SVA), lumbar lordosis (LL), and thoracic kyphosis were measured preoperatively, immediate postoperatively and at final follow-up. Adverse outcomes: proximal adjacent fractures, sagittal decompensation, pseudoarthrosis, and cage subsidence were documented. RESULTS: There were 37 females and 3 males. Average age was 65.1+/-4.5 years and mean follow-up was 34.2+/-16.7 months. 42.5% were Takemitsu type 3 curves, 27.5% type 2, 20.0% type 4 and 10.0% type 1. 37.5% had osteopenia, 40.0% osteoporosis and 22.5% had severe osteoporosis. SVA improved from 237.0+/-96.7 mm preoperatively to 45.3+/-41.8 mm postoperatively (p=0.000). LL improved from 10.5 degrees +/-14.7 degrees to 40.6 degrees +/-10.9 degrees postoperatively (p=0.000). At final follow-up SVA deteriorated to 89.8+/-72.2 mm and LL to 34.7 degrees +/-15.8 degrees (p=0.000). The association between late sagittal decompensation, pseudoarthrosis, or proximal adjacent fractures and osteoporosis was insignificant. The difference between immediate postoperative LL and PI (PIDiff) had a significant association with sagittal decompensation and pseudoarthrosis. CONCLUSIONS: Osteoporosis did not influence the degree of correction, late sagittal decompensation, proximal adjacent fractures, and pseudoarthrosis in LDK. PIDiff had a significant association with sagittal decompensation and pseudoarthrosis. PMID- 25705338 TI - The efficacy of intramuscular calcitonin injection in the management of lumbar spinal stenosis. AB - STUDY DESIGN: A prospective, cross-sectional, non-randomized study. PURPOSE: To assess the effectiveness of intramuscular calcitonin injection in the treatment of lumbar spinal stenosis (LSS). OVERVIEW OF LITERATURE: LSS, manifesting as chronic low back pain and neurogenic claudication, is a chronic condition with an increasing incidence in the elderly population having inadequate effective conservative treatment options. METHODS: In this study, 36 patients with LSS who were diagnosed based on the clinical findings and magnetic resonance imaging were included. Patients received 100 IU of calcitonin per week for one month and were evaluated before and after treatment using the Oswestry disability index (ODI) questionnaire and visual analogue scale (VAS). Before treatment, the patients were divided into two subgroups based on their ODI results: patients with mild to moderate low back pain (disability, 0%-40%) and patients with severe or very severe low back pain (disability, 40%-100%). RESULTS: In patients with mild to moderate low back pain, there were no significant changes in the ODI and VAS after calcitonin injection. But in patients with severe or very severe low back pain, pain severity, personal functions, ability to lift and carry objects, time interval between standing and initiation of pain, social life, disability percentage, and VAS were significantly improved after treatment with calcitonin. CONCLUSIONS: It seems that an intramuscular injection of low dose of calcitonin may have some beneficial effects on the pain due to LSS, especially in patients who suffer from severe or very severe low back pain. PMID- 25705339 TI - An evaluation of the effectiveness of hyaluronidase in the selective nerve root block of radiculopathy: a double blind, controlled clinical trial. AB - STUDY DESIGN: Prospective, double-blind, randomized controlled trial. PURPOSE: To determine the ability of hyaluronidase to provide longer lasting pain relief and functional improvement in patients with lumbar radiculopathy. OVERVIEW OF LITERATURE: Selective nerve root block (SNRB) is a good treatment option in lumbar radiculopathy. We studied the effectiveness of hyaluronidase when added to the traditional SNRB regimen. METHODS: A sample size of 126 patients per group was necessary. A sample of 252 patients who underwent an injection procedure with or without hyaluronidase due to radiculopathy was included in this study. The patients were randomly divided into two groups: the control (C) group and the hyaluronidase (H) group. After SNRB due to radiculopathy, the visual analog scale (VAS) was compared at 2, 4, 6, 8, and 12 weeks between the two groups, and the Oswestry disability index (ODI) was compared at 12 weeks between the two groups. RESULTS: Both groups seemed to have general improvement in VAS, but in C group, the VAS was higher than the H group 2 and 4 weeks after the surgery, and the difference in time-group change between 2 groups was statistically significant (p <0.05). ODI improved in both groups, and the difference in time-group change between 2 groups was not statistically significant (p >0.05). CONCLUSIONS: The rebound pain (the re-occurrence of pain within 2-4 weeks after injection) that occurs within 2-4 weeks after the injection of the routine regimen can be reduced when hyaluronidase is added to the routine SNRB regimen. PMID- 25705340 TI - Clinical Outcomes of Surgical Treatments for Traumatic Spinal Injuries due to Snowboarding. AB - STUDY DESIGN: Retrospective study. PURPOSE: To assess treatment outcomes of snowboarding-related spinal and spinal cord injuries. OVERVIEW OF LITERATURE: Snowboarding-related spinal or spinal cord injury have a great impact on social and sporting activities. METHODS: A retrospective review of 19 cases of surgically treated snowboard-related injury was done. Analyzed parameters included site of injury, type of fracture, peri- and postoperative complications, pre- and postoperative neurological status, activities of daily living, and participation in sports activities at the final follow-up. RESULTS: The major site of injury was the thoracolumbar junction caused by fracture-dislocation (13/19 cases). The remaining 6 cases had cervical spine injuries. Over 60% of the patients had Frankel A and B paralysis. All patients were surgically treated by posterior fusion with instrumentation. Five underwent additional anterior fusion. Surgical outcome was restoration of ambulatory capacity in 12 patients (63.2%). Ultimately, 15 patients (78.9%) could return to work. Patients with complete paralysis upon admission showed reduced ambulatory capacity compared to those with incomplete paralysis. None of the patients again participated in any sports activities, including snowboarding. CONCLUSIONS: Snowboarding-related spinal or spinal cord injury has a great impact on social as well as sports activities. It is necessary to enhance promotion of injury prevention emphasizing the snowboarders' responsibility code. PMID- 25705341 TI - Diastematomyelia: a surgical case with long-term follow-up. AB - Few reports have described the involvement of syringomyelia associated with diastematomyelia in the etiology of neurological deficits. We reported a case with syringomyelia associated with diastematomyelia. A female patient with diastematomyelia was followed up clinically over 14 years. At the age of 8, she developed clubfoot deformity with neurological deterioration. Motor function of the right peroneus demonstrated grade 2 in manual muscle tests. Continuous intracanial bony septum and double cords with independent double dura were observed at upper thoracic spine. Magnetic resonance imaging revealed a tethering of the spinal cord and syringomyelia distal to the level of diastematomyelia. Extirpation of the osseum septum and duralplasty were performed surgically. She grew without neurological deterioration during 7 years postoperatively. A long term followed up case with syringomyelia that was possibly secondary to the tethering of the spinal cord associated with diastematomyelia, and effective treatment with extirpation of the osseum septum and duralplasty was described. PMID- 25705342 TI - Spinal stenosis presenting with scrotal and perianal claudication. AB - A 63-year-old gentleman presented with a one-year duration of progressive neurogenic claudication. However, unlike most patients who presents with leg symptoms, his pain was felt in his scrotal and perianal region. This was exacerbated with walking and standing, but he had immediate relief with sitting. An magnetic resonance imaging (MRI) was performed which showed severe central canal stenosis. An L3/4 and L4/5 surgical decompression and a transforaminal lumbar interbody fusion was performed, and the patient made good recovery with immediate resolution of symptoms. Although rare, spinal stenosis should be considered a differential when approaching a patient with perianal and scrotal claudication, even in the absence of leg claudication. An MRI is useful to confirm the diagnosis. This rare symptom may be a sign of severe cauda equina compression and we recommend decompression with predictable good results. PMID- 25705343 TI - Cervical ossification of posterior longitudinal ligament in x-linked hypophosphatemic rickets revealing homogeneously increased vertebral bone density. AB - There is no report that describes in detail the radiological and intraoperative findings of rickets with symptomatic cervical ossification of the posterior longitudinal ligament. Here, we describe a case of X-linked hypophosphatemic rickets with cervical ossification of the posterior longitudinal ligament presenting unique radiological and intraoperative findings. The patient presented progressive tetraparesis. Magnetic resonance imaging studies revealed severe cervical spinal cord compression caused by ossification of the posterior longitudinal ligament. Computed tomography scans revealed homogeneously increased vertebral bone density. An expansive laminoplasty was performed. At surgery, homogeneously hard lamina bone was burdened in drilling and opening of the laminae. The patient's neurological symptoms were improved postoperatively. Bony fusion of the hinges occurred postoperatively. Therefore, expansive laminoplasty could be performed for symptomatic cervical ossification of the posterior longitudinal ligament with X-linked hypophosphatemic rickets. However, unusual bone characters should be taken into consideration for careful operation during surgery. PMID- 25705344 TI - Brown tumor of the cervical spines: a case report with literature review. AB - To report a rare case of axis brown tumor and to review literature of cervical spine brown tumor. Brown tumor is a rare bone lesion, incidence less than 5% in primary hyperparathyroidism. It is more common in secondary hyperparathyroidism with up to 13% of cases. Brown tumor reactive lesion forms as a result of disturbed bone remodeling due to long standing increase in parathyroid hormones. Cervical spine involvement is extremely rare, can be confused with serous spine lesions. To date, only four cases of cervical spine involvement have been reported. Three were due to secondary hyperparathyroidism. Only one was reported to involve the axis and was due to secondary hyperparathyroidism. This is the first reported case of axis brown tumor due to primary hyperparathyroidism. A case report of brown tumor is presented. A literature review was conducted by a Medline search of reported cases of brown tumor, key words: brown tumor, osteoclastoma and cervical lesions. The resulting papers were reviewed and cervical spine cases were listed then classified according to the level, cause, and management. Only four previous cases involved the cervical spine. Three were caused by secondary hyperparathyroidism and one was by primary hyperparathyroidism which involved the C6. Our case was the first case of C2 involvement of primary hyperparathyroidism and it was managed conservatively. Brown tumor, a rare spinal tumor that presents with high PTH and giant cells, requires a high level of suspicion. PMID- 25705345 TI - Horner's Syndrome Secondary to Epidural Anaesthesia Following Posterior Instrumented Scoliosis Correction. AB - An 11-year-old girl underwent T4 to L1 posterior instrumented scoliosis correction for adolescent idiopathic scoliosis. Postoperative clinical examination revealed left-sided Horner's syndrome which was preceded by left sided C8 paraesthesia. The Horner's syndrome resolved after 14 hours following weaning and removal of the epidural catheter. Horner's syndrome following posterior instrumented scoliosis correction associated to epidural use is extremely rare. Surgeons must be aware of the risks of epidural placement and the need for close monitoring of associated complications. Alternative aetiology producing a Horner's syndrome must always be considered because of its devastating long term sequela if missed. PMID- 25705346 TI - Combat-related intradural gunshot wound to the thoracic spine: significant improvement and neurologic recovery following bullet removal. AB - The vast majority of combat-related penetrating spinal injuries from gunshot wounds result in severe or complete neurological deficit. Treatment is based on neurological status, the presence of cerebrospinal fluid (CSF) fistulas, and local effects of any retained fragment(s). We present a case of a 46-year-old male who sustained a spinal gunshot injury from a 7.62-mm AK-47 round that became lodged within the subarachnoid space at T9-T10. He immediately suffered complete motor and sensory loss. By 24-48 hours post-injury, he had recovered lower extremity motor function fully but continued to have severe sensory loss (posterior cord syndrome). On post-injury day 2, he was evacuated from the combat theater and underwent a T9 laminectomy, extraction of the bullet, and dural laceration repair. At surgery, the traumatic durotomy was widened and the bullet, which was laying on the dorsal surface of the spinal cord, was removed. The dura was closed in a water-tight fashion and fibrin glue was applied. Postoperatively, the patient made a significant but incomplete neurological recovery. His stocking pattern numbness and sub-umbilical searing dysthesia improved. The spinal canal was clear of the foreign body and he had no persistent CSF leak. Postoperative magnetic resonance imaging of the spine revealed contusion of the spinal cord at the T9 level. Early removal of an intra-canicular bullet in the setting of an incomplete spinal cord injury can lead to significant neurological recovery following even high-velocity and/or high-caliber gunshot wounds. However, this case does not speak to, and prior experience does not demonstrate, significant neurological benefit in the setting of a complete injury. PMID- 25705348 TI - Commentary on lumbar lordosis in chronic mechanical back pain. PMID- 25705347 TI - Treatment of thoracolumbar fracture. AB - The most common fractures of the spine are associated with the thoracolumbar junction. The goals of treatment of thoracolumbar fracture are leading to early mobilization and rehabilitation by restoring mechanical stability of fracture and inducing neurologic recovery, thereby enabling patients to return to the workplace. However, it is still debatable about the treatment methods. Neurologic injury should be identified by thorough physical examination for motor and sensory nerve system in order to determine the appropriate treatment. The mechanical stability of fracture also should be evaluated by plain radiographs and computed tomography. In some cases, magnetic resonance imaging is required to evaluate soft tissue injury involving neurologic structure or posterior ligament complex. Based on these physical examinations and imaging studies, fracture stability is evaluated and it is determined whether to use the conservative or operative treatment. The development of instruments have led to more interests on the operative treatment which saves mobile segments without fusion and on instrumentation through minimal invasive approach in recent years. It is still controversial for the use of these treatments because there have not been verified evidences yet. However, the morbidity of patients can be decreased and good clinical and radiologic outcomes can be achieved if the recent operative treatments are used carefully considering the fracture pattern and the injury severity. PMID- 25705349 TI - Pelvic incidence as a determinant for chronic low back pain: few comments. PMID- 25705350 TI - Response to Comments on "Correlation between Radiologic Sign of Lumbar Lordosis and Functional Status in Patients with Chronic Mechanical Low Back Pain". PMID- 25705351 TI - Response to: Surgery-Related Complications and Sequelae in Management of Tuberculosis of Spine. PMID- 25705352 TI - 'Single' v. 'panel' appointed forensic mental observations: Is the referral process ethically justifiable? AB - OBJECTIVE: To compare the outcome and psychiatric morbidity of the forensic mental observation referrals, in the two legally created groups of detainees awaiting trial - the 'singles', representing the minor violent and non-violent offenders evaluated by a single-state appointed psychiatrist, v. the 'panels', representing the seriously violent offenders evaluated by two or more psychiatrists. METHODS: A retrospective record review covered 200 cases, comprising all individuals admitted to the forensic unit of Sterkfontein Hospital for 30 days psychiatric observation from January to August 2010. Pearson's chi2 test for categorical data were used to determine statistical significance. RESULTS: Of 110 singles, 49 (44.55%) were found fit for trial and 40 (40.4%) were found criminally responsible. Of the 90 'panel' cases 60 (66.67%) were found ft for trial and 57 (64.77%) were found criminally responsible (p=0.002 and p=0.001, respectively). CONCLUSION: Those charged with seriously violent offences appear more likely to be found both fit and responsible, compared with those charged with less serious offences. PMID- 25705353 TI - Incidence of multidrug resistant Vibrio parahaemolyticus isolated from Ponnani, South India. AB - BACKGROUND AND OBJECTIVES: The prevalence of Vibrio parahaemolyticus has been reported from Ponnani earlier, however incidence of multidrug resistant strains have been encountered recently in clinical laboratories. The source for such strains and their presence in this major fish landing centre has been investigated. MATERIALS AND METHODS: Antibiotic sensitivity tests on isolates of V. parahaemolyticus isolated from three different substrates were conducted following disc diffusion method. RESULTS: Populations of V. parahaemolyticus (cfu/ml) were relatively high in sediment samples (7.67 +/- 2.08), compared to shrimp (5.33 +/-1.53) and water samples (3.67 +/- 1.15). V. parahaemolyticus isolated from water showed relatively higher antibiotic resistance pattern compared to other two groups. The highest incidence of antibiotic resistance was recorded against cephalothin and nitrofurantonine; the lowest was against tobramycin, piperacillin and amikacin. Maximum multiple drug resistant (MDR) strains were encountered from water samples followed by shrimps. CONCLUSION: Results emerging from the present study clearly showed that Ponnani has a fairly good population of antibiotic resistant strains of V. parahaemolyticus. The present study provides an insight on the microbial population of V. parahaemolyticus in Ponnani harbour and warrants the need to develop control measures to reduce incidences of post-harvest contamination of seafood. PMID- 25705354 TI - Recombinant toxin-coregulated pilus A (TcpA) as a candidate subunit cholera vaccine. AB - BACKGROUND AND OBJECTIVES: The toxin co-regulated pilus A (TcpA) has been described as a critical pathogenicity factor of Vibrio cholerae. TcpA is a candidate for making subunit vaccine against cholera. The aim of this study was to produce a candidate vaccine by expressing recombinant TcpA in E. coli. MATERIALS AND METHODS: In this study, the toxin co-regulated pilus A gene from EL Tor, V. cholerae subspecies, was amplified by PCR and sub-cloned into prokaryotic expression vector pGEX4T1. E. coli BL21 (DE3) was transformed with pGEX4T1- TcpA and gene expression was induced by IPTG and purified by GST resin. The integrity of the product was confirmed by Western blot analysis using a standard rabbit anti-V. cholerae antibody. Sera reactivity of infected individuals was further analyzed against the recombinant TcpA protein. RESULTS: The concentration of purified recombinant protein was calculated to be 8 mg/L of initial culture. The integrity of product was confirmed by Western blot analysis using a standard rabbit anti V. cholerae antibody. Sera reactivity of infected individual was further analyzed against the recombinant TcpA protein. The obtained data indicated that recombinant TcpA protein from V. cholerae was recognized by patient serum and animal sera. CONCLUSION: These results show that the recombinant TcpA is antigenic and could be used in a carrier host as an oral vaccine against cholera. PMID- 25705355 TI - Bacterial urinary tract infection in renal transplant recipients and their antibiotic resistance pattern: A four-year study. AB - BACKGROUND AND OBJECTIVE: Urinary tract infections (UTIs) are the most common infections in renal transplant recipients and are considered a potential cause of bacteremia, sepsis, and affects graft outcomes. The aim of the present study was to determine the incidence of UTI among renal transplant recipients and investigation of antimicrobial susceptibility pattern of causative agents. MATERIALS AND METHODS: In total, 1165 patients from March 2009 to December 2012, in transplant center of Golestan Hospital, Ahvaz, Iran, were investigated. Qualitative urine cultures were performed for all cases, causative microorganisms were identified and colony count was performed according to the standard protocol. Antibiotic susceptibility testing was then performed to determine the susceptibility pattern of recovered bacteria from confirmed UTIs. RESULTS: UTI was diagnosed in 391 patients(33.56%). Gram-negative bacteria were the most prevalent isolated microorganisms with E. coli (43.53%), followed by Enterobacter spp. (35.37%) as the major organisms. Among Gram positives, Coagulase-negative Staphylococci was isolated from 6.8% of cases. The rate of resistance to all tested antibiotics was highest in Enterobacter spp., however the most common resistance were seen against cefixime, cephalotin, and cotrimoxazole in all tested gram negatives. CONCLUSION: the rate of UTIs among renal transplant recipients was noticeable in this study with high antibiotic resistance. Multi resistant bacterial infections are potentially life-threatening emerging problem in renal transplantation. Prophylactic measures must be applied to patients at greater risk. PMID- 25705356 TI - Staphylococcus aureus nasal carriage and patterns of antibiotic resistance in bacterial isolates from patients and staff in a dialysis center of southeast Iran. AB - BACKGROUND AND OBJECTIVES: Staphylococcus aureus is an important infection in hemodialysis patients. We studied the prevalence of nasal carriage of methicillin resistant Staphylococcus aureus (MRSA) and its antibiotic resistance pattern in patients receiving hemodialysis as well as in dialysis unit staff. MATERIALS AND METHODS: From June to September 2012, we evaluated 74 cases including 61 patients on hemodialysis and 13 dialysis unit staff. Nasal swabs were taken from all cases and were cultured on a blood medium agar. We identified S. aureus based on conventional laboratory methods. For antimicrobial resistance patterns, we used disk diffusion method. Oxacillin MIC, oxacillin and cefoxcitin disk diffusion methods were used for detection of MRSA. Disk approximation test (D-test) was applied for the frequency of erythromycin induced clindamycin resistance. RESULTS: S. aureus carrier state was determined in 12 of the 61 patients on hemodialysis (19.67%) and 5 of the 13 dialysis unit staffs (38.46%). In hemodialyzed patients, MRSA and MSSA carrier of S. aureus were 6.56% and 13.11%, respectively. All nasal carriage states in studied staffs were MSSA. All isolated S. aureus were found to be sensitive to vancomycin, teicoplanin, and rifampin. However, reduced sensitivity of MRSA isolates to other antibiotics was noted. Resistance frequencies to tested antibiotic was as follows: cefteriaxone and penicillin (100%), tetracycline and doxycilin (75%), gentamicin, cloxacillin, and cefazolin (50%), ciprofloxacin, trimethoprim-sulfamethoxazol, erythromycin, and clindamycin (25%). The resistance rate of isolated MSSA against tested antibiotics was lower than isolated MRSA. Inducible clindamycin resistance was shown in 25% of identified MRSA strains. CONCLUSION: S. aureus nasal carrier state was lower than former reports from other parts of Iran. The antibiotic resistance patterns also differed, perhaps due to different pattern of administering antibiotics at our hospital. Screening of these patients should be noted as a health priority and microbial sensitivity tests should be considered in order to optimize treatment options. PMID- 25705357 TI - Invasive community-acquired Staphylococcus aureus among pediatric population of Eastern Iran. AB - BACKGROUND AND OBJECTIVE: Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) is increasingly reported worldwide. We aimed to determine the frequency of invasive CA-MRSA in children admitted to the pediatric wards of Imam Reza and Ghaem hospitals of Mashhad, Iran. MATERIALS AND METHODS: In this retrospective study, data regarding S. aureus isolates from pediatric patients' sterile body sites (i.e. blood' joint, bone and lymph node aspiration) were retrieved in a time period from March 2006 to March 2012. Disc diffusion data was analyzed to determine the resistance pattern of the isolates, and differentiation between community-acquired and nosocomial S. aureus was done according to CDC guidelines. RESULTS: Twenty three invasive community-acquired S. aureus isolates from sterile body sites were identified, of which seventeen (74%) were CA-MRSA. The CA-MRSA isolates showed high frequency of resistance to non-beta-lactam antibiotics (71% to erythromycin' 53% to co-trimoxazole, 44% to gentamicin and 36% to ciprofloxacin). CONCLUSION: In this study, the majority of invasive community-acquired S. aureus isolates were found to be CA-MRSA. Therefore, we recommend that primary treatment should be with antibiotics such as clindamycin, vancomycin, linezolid or daptomycin for any invasive infection suspected to be caused by S. aureus in these two hospitals. PMID- 25705358 TI - Prevalence of HHV-6 in cerebrospinal fluid of children younger than 2 years of age with febrile convulsion. AB - BACKGROUND AND OBJECTIVE: Febrile convulsion is a common disorder in children. Viral infections such as human herpes virus 6 (HHV-6) which results in roseola infantum may contribute to developing seizure. The objective of this study was to determine the prevalence of HHV-6 by detecting DNA in cerebrospinal fluid (CSF) of children with febrile convulsion and without any rash of roseola infantum. MATERIALS AND METHODS: In this descriptive cross-sectional study, CSF of 100 children younger than 2 years of age with febrile convulsion was evaluated for detecting HHV-6 DNA by PCR. All of them were referred to emergency ward in Pediatric Medical Center from March 2010 to March 2011. General information, clinical manifestations, laboratory tests and outcomes were collected in the questionnaires. RESULTS: One hundred children including 59 males and 41 females were evaluated. HHV-6 was detected from CSF in six patients (6%) by PCR. Mean age was 8 months old. All children were younger than 12 months old. The most common primary manifestation was fever alone. None of them had rash. Majority of cases occurred in winter. All patients recovered without any encephalitis. CONCLUSION: These findings showed that primary infection with HHV-6 is frequently associated with febrile convulsion in infants which may be at risk for subsequent development of epilepsy. PMID- 25705359 TI - Phylogenetic analysis of neuraminidase gene of H9N2 avian influenza viruses isolated from chicken in Iran during 2010-2011. AB - BACKGROUNDS AND OBJECTIVES: Classified as low pathogenic avian influenza (LPAI) viruses, the H9N2 subtype causes severe respiratory disease in poultry farms and occasional respiratory disease in humans. In this study, the neuraminidase (NA) gene of three Avian Influenza (AI) H9N2 strains isolated from poultry farms in Iran during 2010-11, as well as other reported Iranian H9N2 isolates, were genetically analyzed and their nucleotide changes were evaluated. MATERIALS AND METHODS: The NA gene of three AIVs were sequenced and evaluated for genetic characteristics and phylogenetic relationship. RESULTS: One new potential glycosylation site (PGS) at amino acid position 306 was observed in one of the studied isolates (A/Chicken/Iran/N102/2011). Antigenic sites of NA in Iranian H9N2 isolates have varied in a yearly manner. The Iranian isolates can be divided into 2 main subgroups; 11-T like subgroup viruses isolated mainly during 1998 2004 and second subgroup viruses isolated during 2004-2009. Interestingly, the three studied isolates fell into a third subgroup. The nucleotide sequences of the three studied isolates showed high identity to recent Pakistani H9N2 isolates (94.5-97%) compared to former Iranian AIV isolates (89-94%). CONCLUSION: High frequency of substitutions in the NA gene of studied isolates in recent years and effects of those substitutions on the pathogenicity of AI virus highlight the need to continue surveillance of genetic characteristics of AIV H9N2 in Iran. PMID- 25705360 TI - Onychomycosis in north-East of iran. AB - BACKGROUND AND OBJECTIVES: Onychomycosis is a common fungal infection which has been conducted in many parts of the world. The aim of this study was to evaluate the epidemiology and to identify the aetiological factors of onychomycosis in Mazandaran province, Iran. MATERIALS AND METHODS: During the period of 10 years (2003-2012) 1100 patients suspected with onychomycosis, referred to the Mycology Laboratory of the Referral Laboratory and Boali Sina Hospital of Mazanadaran University of Medical Sciences, Sari, Iran, were assessed for the presence of onychomycosis with mycological examination based on conventional techniques. RESULTS: Among 1100 subjects (398 males and 702 females, aged 1-88 years) onychomycosis was diagnosed in 625(56.8%) cases. Among cases of onychomycosis, laboratorial confirmation was reached through direct examination with positive cultures in 464 samples (74.3%), while only by positive direct exam in 114 cases (18.2 %) or just positive culture in 47 cases (7.5%). The results of fungal culture revealed Candida spp. isolated in (61.9%) of the cases as the most common agents of onychomycosis while among dermatophytes, Trichophyton mentagrophytes was found in 17.7% followed by T. rubrum (1.7%), Epidermophyton floccosum (0.7%), T. violaceum (0.2%), T. verrucosum (0.2%), T. tonsurans (0.2%) and Microsporum gypseum (0.2%). Among the non-dermatophyte moulds, Aspergillus spp. was the most prevalent species 14.2%. CONCLUSION: The results demonstrated that onychomycosis was diagnosed in 625(56.8%) cases and the most common isolates were Candida spp., followed by dermatophytes and moulds. This epidemiological data collected may be useful in the development of preventive and educational strategies. PMID- 25705361 TI - Effect of phosphatidylcholine on the level expression of plc genes of Aspergillus fumigatus by real time PCR method and investigation of these genes using bioinformatics analysis. AB - BACKGROUND AND OBJECTIVES: Phosphlipases are a group of enzymes that breakdown phosphatidylcholine (phospholipids) molecules producing second products. These produced products have a divers role in the cell like signal transduction and digestion in humans. In this research the effect of phosphatidylcholine on the expression of plc genes of A. fumigatus was studied. The plc genes of this fungus were also interrogated using bioinformatics studies. MATERIALS AND METHODS: Real time PCR was performed to study the expression of plc genes and these genes were interrogated using bioinformatics studies. RESULTS: There was more significant expression for all three plc genes when A. fumigatus was grown on the presence of phosphatidylcholine in the medium. The sequence of plc genes of A. fumigatus was also interrogated using bioinformatics analysis and their relationship with the other microorganisms was investigated. CONCLUSION: Real-time PCR revealed that afplc1, afplc2 and afplc3 were up-regulated in the presence of phosphatidylcholine. In this study we suggest either the plc's of A. fumigatus were present in an ancestral genome and have become lost in some lineages, or that they have been acquired from other organisms by horizontal gene transfer. We also found that plc's of this fungus appeared to be more closely related to the plant plc's than the bacterial plc's. PMID- 25705362 TI - Production and characterization of antimicrobial active substance from Spirulina platensis. AB - BACKGROUND AND OBJECTIVES: The present work was carried out to investigate the ability of Spirulina platensis to produce antimicrobial substance against bacteria and fungi. MATERIALS AND METHODS: The cells of the cyanobacterium were subjected to different extractions and the purified antagonistic compound proved to be effective against broad spectrum of bacteria and fungi. The antagonistic compound was purified using thin layer chromatography. RESULTS: The results indicated that the IR spectrum showed bands at 1269 cm(-1), 1414 cm(-1) (C-O-C), 1643 cm(-1) (CO of amide),1563 cm(-1) (C = C) and broad band 3441 cm(-1) (of OH and NH)., (1)HNMR showed delta 0.8 (-CH3), delta 1.2 (-CH2), delta 4.2(-OH), delta 7.2(-NH), delta 7.4 and delta 7.7 (aromatic CH)., Mass spectrum showed molecular ion beak at m/z = 341 (abundance (0.03%). Also, the elemental analysis gave molecular formula,C15H18NO8. CONCLUSION: The purified antimicrobial compound produced by S. platensis was more active against Gram positive, Gram negative bacteria and unicellular fungi, C. albicans. The highest biological activity was recorded against Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis and Aspergillus niger. The results of this investigation proved that cyanobacteria could be a good source for production of antimicrobial agents which could be effective when compared with contemporary antimicrobial compounds. PMID- 25705363 TI - Probiotic properties of Lactobacillus strains isolated from gizzard of local poultry. AB - BACKGROUND AND OBJECTIVE: The aim of our study was to characterize gizzard Lactobacillus fermentum-group strains on the basis of their phenotypic profiles regarding characteristics of lactobacilli. In addition, their in vitro potential probiotic properties were evaluated. MATERIALS AND METHODS: The lactic acid bacteria were isolated and identified from gizzard contents of Algerian local poultry using criteria of Bergey's Manual of Determinative Bacteriology and using methods and criteria of Sharpe. The strains were further characterized by tolerance to low pH and bile, coaggregation potential and adhesion to intestinal mucous. The antagonistic activity against some Enterobacteriaceae strains from poultry origin was also evaluated. RESULTS AND CONCLUSION: Among the strains identified, both physiological and biochemical characteristics differed noticeably. The strains coded LP3 and LP10 survived simulated gastrointestinal conditions and were considered to be acid and bile tolerant. The majority of the strains exhibited antagonistic activity towards Escherichia coli, Klebsiella spp., Enterobacter spp., Shigella spp., Salmonella spp and Citrobacter spp. The best co-aggregation properties were obtained with two isolates. Lb. fermentum LP3 alone showed adherence specificity to the chicken intestinal epithelium. PMID- 25705364 TI - Isolation and identification of local Bacillus isolates for xylanase biosynthesis. AB - BACKGROUND AND OBJECTIVES: Bacillus species are attractive industrial organisms due to their rapid growth rates leading to a short fermentation cycle and for their capacity to secrete important enzymes and proteins such as xylanase into the extracellular medium. Considering the industrial importance of xylanase, in this current study, Bacillus spp. were isolated from different soils and were screened for their xylanase production. MATERIALS AND METHODS: Bacillus isolates used in this study were obtained from a national screening program carried out during 2006-2007 in which soil samples that covered areas throughout the interior of Syria were collected. The prepared inoculum from each of Bacillus isolates was aliquoted onto xylan agar plates, incubated at 30 degrees C for 72 h and screened for xylanase synthesis. RESULTS: Xylanolytic isolates were selected depending on the clear zones of xylan hydrolysis. Fifteen isolates having the highest clearing zone were determined and grown in a solid state fermentation. Of the 15 isolates, three bacilli namely SY30A, SY185C and SY190E that showed maximum xylanase production, were identified using the 16S rDNA sequencing method. According to 16S rDNA gene sequence data, the closest phylogenetic neighbor for SY30A was Bacillus pumilus and for SY185C and SY190E isolates was Bacillus subtilis. Optimal pH and temperature for xylanase activity was 7.0 and 55oC for SY30A and 6.0 and 60oC for SY185C and SY190E, respectively. Under these conditions, the following activities were found to be around 1157 +/- 58, 916 +/- 46 and 794 +/- 39 (U/g) for SY30A, SY185C and SY190E, respectivly. CONCLUSIONS: Selected local Bacillus isolates were found to be a potential source of xylanase which was proven to be quite suitable for multiple biotechnological applications. These isolates might after extensive optimization steps be an alternative to commercially available strains. PMID- 25705366 TI - Catalytic enantioselective synthesis of 2-aryl-chromenes. AB - An enantioselective Pd-catalyzed 6-endo-trig reaction for the synthesis of 2-aryl chromenes has been developed. A systematic optimization of a TADDOL-derived ligand set resulted in the identification of a novel monodentate phosphoramidite palladium catalyst that accesses 2-aryl-2H-chromenes with high yield and enantioselectivity under mild conditions. The products obtained from this method can be transformed into biologically active compounds through functionalization of the chromene alkene. PMID- 25705365 TI - Antipurinergic therapy corrects the autism-like features in the Fragile X (Fmr1 knockout) mouse model. AB - BACKGROUND: This study was designed to test a new approach to drug treatment of autism spectrum disorders (ASDs) in the Fragile X (Fmr1) knockout mouse model. METHODS: We used behavioral analysis, mass spectrometry, metabolomics, electron microscopy, and western analysis to test the hypothesis that the disturbances in social behavior, novelty preference, metabolism, and synapse structure are treatable with antipurinergic therapy (APT). RESULTS: Weekly treatment with the purinergic antagonist suramin (20 mg/kg intraperitoneally), started at 9 weeks of age, restored normal social behavior, and improved metabolism, and brain synaptosomal structure. Abnormalities in synaptosomal glutamate, endocannabinoid, purinergic, and IP3 receptor expression, complement C1q, TDP43, and amyloid beta precursor protein (APP) were corrected. Comprehensive metabolomic analysis identified 20 biochemical pathways associated with symptom improvements. Seventeen pathways were shared with human ASD, and 11 were shared with the maternal immune activation (MIA) model of ASD. These metabolic pathways were previously identified as functionally related mediators of the evolutionarily conserved cell danger response (CDR). CONCLUSIONS: The data show that antipurinergic therapy improves the multisystem, ASD-like features of both the environmental MIA, and the genetic Fragile X models. These abnormalities appeared to be traceable to mitochondria and regulated by purinergic signaling. PMID- 25705367 TI - Development and Investigation of a Site Selective Palladium-Catalyzed 1,4 Difunctionalization of Isoprene using Pyridine-Oxazoline Ligands. AB - Palladium-catalyzed 1,4-difunctionalizations of isoprene that produce skipped polyenes are reported. Complex isomeric product mixtures are possible as a result of the difficult-to-control migratory insertion of isoprene into a Pd-alkenyl bond, but good site selectivity has been achieved using easily accessible Pyrox ligands. Mechanistic studies suggest that the control of insertion is the result of the unique electronic asymmetry and steric properties of the ligand. PMID- 25705368 TI - Photostick: a method for selective isolation of target cells from culture. AB - Sorting of target cells from a heterogeneous pool is technically difficult when the selection criterion is complex, e.g. a dynamic response, a morphological feature, or a combination of multiple parameters. At present, mammalian cell selections are typically performed either via static fluorescence (e.g. fluorescence activated cell sorter), via survival (e.g. antibiotic resistance), or via serial operations (flow cytometry, laser capture microdissection). Here we present a simple protocol for selecting cells based on any static or dynamic property that can be identified by video microscopy and image processing. The "photostick" technique uses a cell-impermeant photochemical crosslinker and digital micromirror array-based patterned illumination to immobilize selected cells on the culture dish. Other cells are washed away with mild protease treatment. The crosslinker also labels the selected cells with a fluorescent dye and a biotin for later identification. The photostick protocol preserves cell viability, permits genetic profiling of selected cells, and can be performed with complex functional selection criteria such as neuronal firing patterns. PMID- 25705369 TI - Cu-Catalyzed Transannulation Reaction of Pyridotriazoles with Terminal Alkynes under Aerobic Conditions: Efficient Synthesis of Indolizines. AB - The Cu(I)-catalyzed denitrogenative transannulation reaction of pyridotriazoles with terminal alkynes en route to indolizines was developed. Compared to the previously reported Rh-catalyzed transannulation reaction, this Cu-catalyzed method features aerobic conditions and much broader scope of pyridotriazoles and alkynes. PMID- 25705370 TI - Non-canonical Notch signaling represents an ancestral mechanism to regulate neural differentiation. AB - BACKGROUND: Cellular differentiation is a critical process during development of multicellular animals that must be tightly controlled in order to avoid precocious differentiation or failed generation of differentiated cell types. Research in flies, vertebrates, and nematodes has led to the identification of a conserved role for Notch signaling as a mechanism to regulate cellular differentiation regardless of tissue/cell type. Notch signaling can occur through a canonical pathway that results in the activation of hes gene expression by a complex consisting of the Notch intracellular domain, SuH, and the Mastermind co activator. Alternatively, Notch signaling can occur via a non-canonical mechanism that does not require SuH or activation of hes gene expression. Regardless of which mechanism is being used, high Notch activity generally inhibits further differentiation, while low Notch activity promotes differentiation. Flies, vertebrates, and nematodes are all bilaterians, and it is therefore unclear if Notch regulation of differentiation is a bilaterian innovation, or if it represents a more ancient mechanism in animals. RESULTS: To reconstruct the ancestral function of Notch signaling we investigate Notch function in a non bilaterian animal, the sea anemone Nematostella vectensis (Cnidaria). Morpholino or pharmacological knockdown of Nvnotch causes increased expression of the neural differentiation gene NvashA. Conversely, overactivation of Notch activity resulting from overexpression of the Nvnotch intracellular domain or by overexpression of the Notch ligand Nvdelta suppresses NvashA. We also knocked down or overactivated components of the canonical Notch signaling pathway. We disrupted NvsuH with morpholino or by overexpressing a dominant negative NvsuH construct. We saw no change in expression levels for Nvhes genes or NvashA. Overexpression of Nvhes genes did not alter NvashA expression levels. Lastly, we tested additional markers associated with neuronal differentiation and observed that non-canonical Notch signaling broadly suppresses neural differentiation in Nematostella. CONCLUSIONS: We conclude that one ancestral role for Notch in metazoans was to regulate neural differentiation. Remarkably, we found no evidence for a functional canonical Notch pathway during Nematostella embryogenesis, suggesting that the non-canonical hes-independent Notch signaling mechanism may represent an ancestral Notch signaling pathway. PMID- 25705371 TI - Two waves of anisotropic growth generate enlarged follicles in the spiny mouse. AB - BACKGROUND: Mammals exhibit a remarkable variety of phenotypes and comparative studies using novel model species are needed to uncover the evolutionary developmental mechanisms generating this diversity. Here, we undertake a developmental biology and numerical modeling approach to investigate the development of skin appendages in the spiny mouse, Acomys dimidiatus. RESULTS: We demonstrate that Acomys spines, possibly involved in display and protection, are enlarged awl hairs with a concave morphology. The Acomys spines originate from enlarged placodes that are characterized by a rapid downwards growth which results in voluminous follicles. The dermal condensation (dermal papilla) at the core of the follicle is very large and exhibits a curved geometry. Given its off centered position, the dermal papilla generates two waves of anisotropic proliferation, first of the posterior matrix, then of the anterior inner root sheath (IRS). Higher in the follicle, the posterior and anterior cortex cross section areas substantially decrease due to cortex cell elongation and accumulation of keratin intermediate filaments. Milder keratinization in the medulla gives rise to a foamy material that eventually collapses under the combined compression of the anterior IRS and elongation of the cortex cells. Simulations, using linear elasticity theory and the finite-element method, indicate that these processes are sufficient to replicate the time evolution of the Acomys spine layers and the final shape of the emerging spine shaft. CONCLUSIONS: Our analyses reveal how hair follicle morphogenesis has been altered during the evolution of the Acomys lineage, resulting in a shift from ancestral awl follicles to enlarged asymmetrical spines. This study contributes to a better understanding of the evolutionary developmental mechanisms that generated the great diversity of skin appendage phenotypes observed in mammals. PMID- 25705372 TI - Downregulation of IL-8, ECP, and total IgE in the tears of patients with atopic keratoconjunctivitis treated with rebamipide eyedrops. AB - Rebamipide eyedrops are approved in Japan for the treatment of dry eye disease. Some patients with allergic conjunctival diseases also manifest dry eye. Earlier we reported that rebamipide suppressed polyI:C-induced inflammatory cytokines in human conjunctival epithelial cells. In the current study we examined the effect of rebamipide eyedrops on the level of interleukin-8 (IL-8), eosinophil cationic protein (ECP), and total IgE on the ocular surface. We prescribed rebamipide eyedrops to patients with atopic keratoconjunctivitis (AKC) who presented with dry eye (6 eyes in 4 AKC patients) and measured the IL-8, ECP, and total IgE levels in their tears before- and 2, and 4-6 weeks after the start of rebamipide treatment. To measure the IL-8 and total IgE levels in their tears we used BDTM CBA Flex sets; ECP measurements were with ELISA. The level of IL-8, ECP, and total IgE in the tears of AKC patients was reduced significantly 4-6 weeks after the start of rebamipide treatment. We also recorded subjective symptoms associated with AKC, e.g. itching, foreign body sensation, and eye mucus discharge, by using a patient questionnaire. Their subjective symptoms associated with AKC were also significantly ameliorated at 2 and 4-6 weeks. Our observations suggest that the anti-inflammatory effects of rebamipide eyedrops help to combat human ocular surface inflammation and that they may be a new effective therapy in patients with AKC. PMID- 25705373 TI - gamma-Actin plays a key role in endothelial cell motility and neovessel maintenance. AB - BACKGROUND: Angiogenesis plays a crucial role in development, wound healing as well as tumour growth and metastasis. Although the general implication of the cytoskeleton in angiogenesis has been partially unravelled, little is known about the specific role of actin isoforms in this process. Herein, we aimed at deciphering the function of gamma-actin in angiogenesis. METHODS: Localization of beta- and gamma-actin in vascular endothelial cells was investigated by co immunofluorescence staining using monoclonal antibodies, followed by the functional analysis of gamma-actin using siRNA. The impact of gamma-actin knockdown on the random motility and morphological differentiation of endothelial cells into vascular networks was investigated by timelapse videomicroscopy while the effect on chemotaxis was assessed using modified Boyden chambers. The implication of VE-cadherin, VEGFR-2 and ROCK signalling was then examined by Western blotting and using pharmacological inhibitors. RESULTS: The two main cytoplasmic isoforms of actin strongly co-localized in vascular endothelial cells, albeit with some degree of spatial preference. While beta-actin knockdown was not achievable without major cytotoxicity, gamma-actin knockdown did not alter the viability of endothelial cells. Timelapse videomicroscopy experiments revealed that gamma-actin knockdown cells were able to initiate morphological differentiation into capillary-like tubes but were unable to maintain these structures, which rapidly regressed. This vascular regression was associated with altered regulation of VE-cadherin expression. Interestingly, knocking down gamma actin expression had no effect on endothelial cell adhesion to various substrates but significantly decreased their motility and migration. This anti-migratory effect was associated with an accumulation of thick actin stress fibres, large focal adhesions and increased phosphorylation of myosin regulatory light chain, suggesting activation of the ROCK signalling pathway. Incubation with ROCK inhibitors, H-1152 and Y-27632, completely rescued the motility phenotype induced by gamma-actin knockdown but only partially restored the angiogenic potential of endothelial cells. CONCLUSIONS: Our study thus demonstrates for the first time that beta-actin is essential for endothelial cell survival and gamma-actin plays a crucial role in angiogenesis, through both ROCK-dependent and -independent mechanisms. This provides new insights into the role of the actin cytoskeleton in angiogenesis and may open new therapeutic avenues for the treatment of angiogenesis-related disorders. PMID- 25705374 TI - Binding Interactions of Agents That Alter alpha-Synuclein Aggregation. AB - Further examination of peptides with well-folded antiparallel beta strands as inhibitors of amyloid formation from alpha-synuclein has resulted in more potent inhibitors. Several of these had multiple Tyr residues and represent a new lead for inhibitor design by small peptides that do not divert alpha-synuclein to non amyloid aggregate formation. The most potent inhibitor obtained in this study is a backbone cyclized version of a previously studied beta hairpin, designated as WW2, with a cross-strand Trp/Trp cluster. The cyclization was accomplished by adding a d-Pro-l-Pro turn locus across strand termini. At a 2:1 peptide to alpha synuclein ratio, cyclo-WW2 displays complete inhibition of beta-structure formation. Trp-bearing antiparallel beta-sheets held together by a disulphide bond are also potent inhibitors. 15N HSQC spectra of alpha-synuclein provided new mechanistic details. The time course of 15N HSQC spectral changes observed during beta-oligomer formation has revealed which segments of the structure become part of the rigid core of an oligomer at early stages of amyloidogenesis and that the C-terminus remains fully flexible throughout the process. All of the effective peptide inhibitors display binding-associated titration shifts in 15N HSQC spectra of alpha-synuclein in the C-terminal Q109-E137 segment. Cyclo-WW2, the most potent inhibitor, also displays titration shifts in the G41-T54 span of alpha-synuclein, an additional binding site. The earliest aggregation event appears to be centered about H50 which is also a binding site for our most potent inhibitor. PMID- 25705375 TI - Training on intellectual disability in health sciences: the European perspective. AB - BACKGROUND: Intellectual disability (ID) has consequences at all stages of life, requires high service provision and leads to high health and societal costs. However, ID is largely disregarded as a health issue by national and international organisations, as are training in ID and in the health aspects of ID at every level of the education system. SPECIFIC AIM: This paper aims to (1) update the current information about availability of training and education in ID and related health issues in Europe with a particular focus in mental health; and (2) to identify opportunities arising from the initial process of educational harmonization in Europe to include ID contents in health sciences curricula and professional training. METHOD: We carried out a systematic search of scientific databases and websites, as well as policy and research reports from the European Commission, European Council and WHO. Furthermore, we contacted key international organisations related to health education and/or ID in Europe, as well as other regional institutions. RESULTS: ID modules and contents are minimal in the revised health sciences curricula and publications on ID training in Europe are equally scarce. European countries report few undergraduate and graduate training modules in ID, even in key specialties such as paediatrics. Within the health sector, ID programmes focus mainly on psychiatry and psychology. CONCLUSION: The poor availability of ID training in health sciences is a matter of concern. However, the current European policy on training provides an opportunity to promote ID in the curricula of programmes at all levels. This strategy should address all professionals working in ID and it should increase the focus on ID relative to other developmental disorders at all stages of life. PMID- 25705376 TI - Aldehyde Dehydrogenase 1 making molecular inroads into the differential vulnerability of nigrostriatal dopaminergic neuron subtypes in Parkinson's disease. AB - A preferential dysfunction/loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) accounts for the main motor symptoms of Parkinson's disease (PD), the most common degenerative movement disorder. However, the neuronal loss is not stochastic, but rather displays regionally selectivity, indicating the existence of different DA subpopulations in the SNpc. To identify the underlying molecular determinants is thereby instrumental in understanding the pathophysiological mechanisms of PD-related neuron dysfunction/loss and offering new therapeutic targets. Recently, we have demonstrated that aldehyde dehydrogenase 1 (ALDH1A1) is one such molecular determinant that defines and protects an SNpc DA neuron subpopulation preferentially affected in PD. In this review, we provide further analysis and discussion on the roles of ALDH1A1 in the function and survival of SNpc DA neurons in both rodent and human brains. We also explore the feasibility of ALDH1A1 as a potential biomarker and therapeutic target for PD. PMID- 25705377 TI - Effects of dietary tryptophan and stocking density on the performance, meat quality, and metabolic status of broilers. AB - BACKGROUND: Highly automated cage-rearing systems are becoming increasingly popular in China. However, a high stocking density can cause oxidative stress and decrease broiler performance. The tryptophan (TRP) derivative 5-hydroxytryptophan (5-HT) has been shown to preserve membrane fluidity in birds suffering from oxidative stress. Therefore, this experiment was conducted to determine the effects of dietary TRP supplementation on performance, breast meat quality and oxidative stress in broilers reared in cages with a high or low stocking density. METHODS: Female Arbor Acres broilers (25-d-old, n = 144) were randomly allocated to 1 of 4 treatments. The birds were fed a diet based on corn, soybean meal, cottonseed meal and corn gluten meal containing either 0.18 or 0.27% TRP and were housed with stocking densities of 11 or 15.4 birds/m(2) in a 2 * 2 factorial experiment. Broiler performance was evaluated from d 25 to 42. Eight birds from each treatment were slaughtered on d 42 and plasma and breast muscle samples were collected to measure biochemical indices. RESULTS: A higher stocking density tended to be associated with reduced weight gain (P < 0.10), and significantly increased plasma glutamic-pyruvic transaminase (GPT) activity (P < 0.001). Increased dietary TRP significantly reduced the activities of lactic dehydrogenase and GPT while increasing total cholesterol in the plasma (P < 0.01), reducing drip loss of breast muscle (P < 0.10) and improving feed efficiency (P < 0.10). CONCLUSIONS: An increase in dietary TRP, 1.5-fold higher than the standard supplementation level, can alleviate oxidative stress as well as improve welfare and feed efficiency in broilers reared in cages with a high stocking density. PMID- 25705378 TI - The shared microbiota of humans and companion animals as evaluated from Staphylococcus carriage sites. AB - BACKGROUND: Staphylococcus aureus and other coagulase-positive staphylococci (CPS) colonize skin and mucous membrane sites and can cause skin and soft tissue infections (SSTIs) in humans and animals. Factors modulating methicillin resistant S. aureus (MRSA) colonization and infection in humans remain unclear, including the role of the greater microbial community and environmental factors such as contact with companion animals. In the context of a parent study evaluating the households of outpatients with community MRSA SSTI, the objectives of this study were 1) to characterize the microbiota that colonizes typical coagulase-positive Staphylococcus spp. carriage sites in humans and their companion pets, 2) to analyze associations between Staphylococcus infection and carriage and the composition and diversity of microbial communities, and 3) to analyze factors that influence sharing of microbiota between pets and humans. RESULTS: We enrolled 25 households containing 56 pets and 30 humans. Sampling locations were matched to anatomical sites cultured by the parent study for MRSA and other CPS. Bacterial microbiota were characterized by sequencing of 16S ribosomal RNA genes. Household membership was strongly associated with microbial communities, in both humans and pets. Pets were colonized with a greater relative abundance of Proteobacteria, whereas people were colonized with greater relative abundances of Firmicutes and Actinobacteria. We did not detect differences in microbiota associated with MRSA SSTI, or carriage of MRSA, S. aureus or CPS. Humans in households without pets were more similar to each other than humans in pet-owning households, suggesting that companion animals may play a role in microbial transfer. We examined changes in microbiota over a 3-month time period and found that pet staphylococcal carriage sites were more stable than human carriage sites. CONCLUSIONS: We characterized and identified patterns of microbiota sharing and stability between humans and companion animals. While we did not detect associations with MRSA SSTI, or carriage of MRSA, S. aureus or CPS in this small sample size, larger studies are warranted to fully explore how microbial communities may be associated with and contribute to MRSA and/or CPS colonization, infection, and recurrence. PMID- 25705380 TI - Pneumonia and influenza, and respiratory and circulatory hospital admissions in Belgium: a retrospective database study. AB - BACKGROUND: Influenza infections can lead to viral pneumonia, upper respiratory tract infection or facilitate co-infection by other pathogens. Influenza is associated with the exacerbation of chronic conditions like diabetes and cardiovascular disease and consequently, these result in acute hospitalizations. This study estimated the number, proportions and costs from a payer perspective of hospital admissions related to severe acute respiratory infections. METHODS: We analyzed retrospectively, a database of all acute inpatient stays from a non random sample of eleven hospitals using the Belgian Minimal Hospital Summary Data. Codes from the International Classification of Diseases, Ninth Revision, Clinical Modification was used to identify and diagnose cases of pneumonia and influenza (PI), respiratory and circulatory (RC), and the related complications. RESULTS: During 2002-2007, we estimated relative hospital admission rates of 1.69% (20960/1237517) and 21.79% (269634/1237517) due to primary PI and RC, respectively. The highest numbers of hospital admissions with primary diagnosis as PI were reported for the elderly patient group (n = 10184) followed by for children below five years of age (n = 3451). Of the total primary PI and RC hospital admissions, 56.14% (11768/20960) and 63.48% (171172/269634) of cases had at least one possible influenza-related complication with the highest incidence of complications reported for the elderly patient group. Overall mortality rate in patients with PI and RC were 9.25% (1938/20960) and 5.51% (14859/269634), respectively. Average lengths of hospital stay for PI was 11.6 +/- 12.3 days whereas for RC it was 9.1 +/- 12.7 days. Annual average costs were 20.2 and 274.6 million Euros for PI and RC hospitalizations. Average cost per hospitalization for PI and RC were 5779 and 6111 Euros (2007), respectively. These costs increased with the presence of complications (PI: 7159, RC: 7549 Euros). CONCLUSION: The clinical and economic burden of primary influenza hospitalizations in Belgium is substantial. The elderly patient group together with children aged <18 years were attributed with the majority of all primary PI and RC hospitalizations. TRIAL REGISTRATION: Not applicable. PMID- 25705381 TI - Limitation of the therapeutic effort: ethical and legal justification for withholding and/or withdrawing life sustaining treatments. AB - Withholding and withdrawing a treatment already established are two forms of limitation of the therapeutic effort (LTE). The question of undergoing or not undergoing lifesaving medical treatments is not restricted to a specific health care context, as it refers to a variety of treatments, and it does not concern a restricted group of diseases. LTE has become part of the options compatible with the good clinical practice, in accordance with a deep change in modern medicine's 'mission' along with the increased importance attributed to the patient's general, personal condition, and to the quality of his/her life. However, LTE remains a controversial issue, and it still has many opponents, in particular, but not exclusively, in those cases in which the question is the withdrawal of treatments, which a widespread conventional wisdom considers ethically and legally different from not initiating treatments. But is it justified to address LTE as a totally controversial issue, especially in case of withdrawal of treatments? The paper answers negatively by arguing that there are criteria both in medical ethics and in law often adequate enough to remove doubts, and to guide decisions and actions. PMID- 25705382 TI - Multiple logistic regression analysis of risk factors in elderly pneumonia patients: QTc interval prolongation as a prognostic factor. AB - BACKGROUND: Acute pneumonia is a serious problem in the elderly and various risk factors have already been reported, but the involvement of QTc interval prolongation remains uncertain. The aim of this study was to elucidate the prognostic factors for the development of pneumonia in elderly patients and to study the possible involvement of QTc interval prolongation. METHODS: The subjects were 249 hospitalized pneumonia patients more than 65 years old in Aki Ohta Hospital from January 2010 to December 2013. Community-acquired pneumonia patients and nursing care and healthcare-associated pneumonia patients were included in the study. The pneumonia severity index, vital signs, blood chemistry data and ECG findings were retrospectively compared using multiple logistic regression analysis. RESULTS: 39 patients died within 30 days from onset. The clinical features related to poor prognosis were: advanced age, past history of cerebral vascular disease and/or diabetes mellitus, decreased serum albumin level, higher CURB-65 or PORT index scores and QTc interval prolongation. Patients showing a prolonged QTc interval had a higher mortality than those with a normal QTc interval. A prolonged QTc interval was not related to serum calcium concentration and/or treatment with QTc prolongation drug, clarithromycin or azithromycin, but related to age, lower albumin concentration and past history of diabetes mellitus. CONCLUSIONS: These findings suggest potential prognostic factors for pneumonia in elderly patients, including a prolonged QTc interval (> 0.44 seconds). PMID- 25705383 TI - Apical ballooning and cardiomyopathy in a melanoma patient treated with ipilimumab: a case of takotsubo-like syndrome. AB - Although animal studies have shown that the immunomodulator ipilimumab causes inflammation of the myocardium, clinically significant myocarditis has been observed only infrequently. We report a case of suspected acute coronary syndrome without a culprit lesion on cardiac angiography and takotsubo cardiomyopathy (TC) like appearance on echocardiography in a patient with metastatic melanoma who received four standard doses of ipilimumab. Apical ballooning, hyperdynamic basal wall motion, systolic anterior motion of the mitral valve, and associated severe left ventricular outflow tract obstruction were present. Restaging with positron emission tomography-computed tomography done soon after discharge incidentally revealed increased fludeoxyglucose uptake in the apex. This case illustrates that a TC-like syndrome might be caused by autoimmune myocarditis after ipilimumab treatment although this was not biopsy-confirmed. Post-marketing surveillance should capture cardiac events occurring in patients treated with ipilimumab to better document and clarify a relationship to the drug, and biopsies should be considered. Physicians utilizing this novel agent should be aware of the potential for immune-related adverse events. PMID- 25705384 TI - H2A.Z: a molecular rheostat for transcriptional control. AB - The replacement of nucleosomal H2A with the histone variant H2A.Z is critical for regulating DNA-mediated processes across eukaryotes and for early development of multicellular organisms. How this variant performs these seemingly diverse roles has remained largely enigmatic. Here, we discuss recent mechanistic insights that have begun to reveal how H2A.Z functions as a molecular rheostat for gene control. We focus on specific examples in metazoans as a model for understanding how H2A.Z integrates information from histone post-translational modifications, other histone variants, and transcription factors (TFs) to regulate proper induction of gene expression programs in response to cellular cues. Finally, we propose a general model of how H2A.Z incorporation regulates chromatin states in diverse processes. PMID- 25705385 TI - Neural crest migration: trailblazing ahead. AB - Embryonic cell migration patterns are amazingly complex in the timing and spatial distribution of cells throughout the vertebrate landscape. However, advances in in vivo visualization, cell interrogation, and computational modeling are extracting critical features that underlie the mechanistic nature of these patterns. The focus of this review highlights recent advances in the study of the highly invasive neural crest cells and their migratory patterns during embryonic development. We discuss these advances within three major themes and include a description of computational models that have emerged to more rapidly integrate and test hypothetical mechanisms of neural crest migration. We conclude with technological advances that promise to reveal new insights and help translate results to human neural crest-related birth defects and metastatic cancer. PMID- 25705386 TI - Recent advances in the management of resistant hypertension. AB - And suddenly, following the preliminary results of renal denervation and carotid baroreceptor stimulation, a big interest in resistant hypertension rose, and all interventionists, many of them with no previous experience with hypertension, fell in love with hypertension and especially resistant hypertension. In the European Society of Hypertension/International Society of Hypertension (ESH/ISH) 2014 Joint Hypertension meeting in Athens, there were no more than four to five sessions related to resistant hypertension and renal denervation, while in the 2014 EuroPCR meeting there were more than 60 renal denervation sessions! In light of the growing scientific interest in the treatment of this patient group, an update on the treatment available and some concerns regarding the definition and treatment of resistant hypertension is presented. PMID- 25705387 TI - Spinal muscular atrophy: from tissue specificity to therapeutic strategies. AB - Spinal muscular atrophy (SMA) is the most frequent genetic cause of death in infants and toddlers. All cases of spinal muscular atrophy result from reductions in levels of the survival motor neuron (SMN) protein, and so SMN upregulation is a focus of many preclinical and clinical studies. We examine four issues that may be important in planning for therapeutic success. First, neuromuscular phenotypes in the SMNDelta7 mouse model closely match those in human patients but peripheral disease manifestations differ, suggesting that endpoints other than mouse lifespan may be more useful in predicting clinical outcome. Second, SMN plays important roles in multiple central and peripheral cell types, not just motor neurons, and it remains unclear which of these cell types need to be targeted therapeutically. Third, should SMN-restoration therapy not be effective in all patients, blocking molecular changes downstream of SMN reduction may confer significant benefit, making it important to evaluate therapeutic targets other than SMN. Lastly, for patients whose disease progression is slowed, but who retain significant motor dysfunction, additional approaches used to enhance regeneration of the neuromuscular system may be of value. PMID- 25705388 TI - Managing anxiety associated with neurodegenerative disorders. AB - Anxiety is a common symptom among patients with cognitive impairment. The presence of anxiety is correlated with poorer outcomes; despite this, there is limited research on anxiety related to neurodegenerative disorder. In this article, we discuss the prevalence of anxiety and factors involved in the etiology of anxiety in patients with diagnosed neurodegenerative disorders and related states of cognitive impairment as well as the evidence for currently available methods of evaluating and treating these symptoms. Specific treatments are highlighted in light of current evidence, followed by a discussion of the difficulties inherent in the study and treatment of anxiety in this population. PMID- 25705389 TI - Connective tissue disease-associated pulmonary arterial hypertension. AB - Although rare in its idiopathic form, pulmonary arterial hypertension (PAH) is not uncommon in association with various associated medical conditions, most notably connective tissue disease (CTD). In particular, it develops in approximately 10% of patients with systemic sclerosis and so these patients are increasingly screened to enable early detection. The response of patients with systemic sclerosis to PAH-specific therapy appears to be worse than in other forms of PAH. Survival in systemic sclerosis-associated PAH is inferior to that observed in idiopathic PAH. Potential reasons for this include differences in age, the nature of the underlying pulmonary vasculopathy and the ability of the right ventricle to cope with increased afterload between patients with systemic sclerosis-associated PAH and idiopathic PAH, while coexisting cardiac and pulmonary disease is common in systemic sclerosis-associated PAH. Other forms of connective tissue-associated PAH have been less well studied, however PAH associated with systemic lupus erythematosus (SLE) has a better prognosis than systemic sclerosis-associated PAH and likely responds to immunosuppression. PMID- 25705390 TI - Controversies in pulmonary hypertension due to left heart disease. AB - Left heart failure is currently the most prevalent cause of pulmonary hypertension (PH) worldwide and this is due mainly to the increased left ventricular and pulmonary venous pressures seen in this condition. Still, a quota of patients with left heart failure will have a pulmonary arterial disease "disproportionate" to the initial increase of left-sided pressures. Whatever the mechanism involved, the appearance of PH is a powerful marker, as it determines decreased exercise tolerance and survival. To date, all trials using therapies approved for pulmonary arterial hypertension (PAH) failed to demonstrate a benefit in the context of heart failure (HF) without or with PH. In addition, the comparison among studies is limited by relevant differences in definitions, methodology, and timing of assessment. A novel rigorous hemodynamic classification based on the diastolic pulmonary gradient has been recently proposed to better characterize this form of PH. This will promote uniformity in patient populations and end-points for future clinical trials. PMID- 25705391 TI - Pathophysiology of coronary artery disease leading to acute coronary syndromes. AB - Acute myocardial infarction (AMI) and sudden cardiac death (SCD) are among the most serious and catastrophic of acute cardiac disorders, accounting for hundreds of thousands of deaths each year worldwide. Although the incidence of AMI has been decreasing in the US according to the American Heart Association, heart disease is still the leading cause of mortality in adults. In most cases of AMI and in a majority of cases of SCD, the underlying pathology is acute intraluminal coronary thrombus formation within an epicardial coronary artery leading to total or near-total acute coronary occlusion. This article summarizes our current understanding of the pathophysiology of these acute coronary syndromes and briefly discusses new approaches currently being researched in an attempt to define and ultimately reduce their incidence. PMID- 25705392 TI - The role of mast cells in cancers. AB - Mast cells are immune cells that accumulate in the tumors and their microenvironment during disease progression. Mast cells are armed with a wide array of receptors that sense environment modifications and, upon stimulation, they are able to secrete several biologically active factors involved in the modulation of tumor growth. For example, mast cells are able to secrete pro angiogenic and growth factors but also pro- and anti-inflammatory mediators. Recent studies have allowed substantial progress in understanding the role of mast cells in tumorigenesis/disease progression but further studies are necessary to completely elucidate their impact in the pathophysiology of cancer. Here we review observations suggesting that mast cells could modulate tumor growth in humans. We also discuss the drawbacks related to observations from mast cell deficient mouse models, which could have consequences in the determination of a potential causative relationship between mast cells and cancer. We believe that the understanding of the precise role of mast cells in tumor development and progression will be of critical importance for the development of new targeted therapies in human cancers. PMID- 25705393 TI - Programming implantable cardioverter/defibrillators and outcomes. AB - Implantable cardioverter-defibrillators are complex technical devices with a multitude of programming options for the physician. In recent years, numerous randomized trials have been performed to define the optimal programming strategies and have provided valuable insights, especially in primary prevention patients. This article provides an actual overview on the existing evidence on the most important programming features for accurate detection and therapy of ventricular arrhythmias. PMID- 25705394 TI - Repeat or persistent Lyme disease: persistence, recrudescence or reinfection with Borrelia Burgdorferi? AB - Whether or not Borrelia burgdorferi can persist after conventional treatment with antimicrobials has been a very controversial issue. Two recent studies took different approaches to try to answer this question. In one, investigators showed that, in each of 22 instances in 17 patients with two consecutive episodes of culture-proved erythema migrans, the strains of B. burgdorferi were different based on their genotypes. This indicated that the repeat episodes were due to new infections rather than recrudescence of the original infection. In another study, in which persistence of B. burgdorferi was assessed by using xenodiagnosis, no viable B. burgdorferi were cultured from ticks fed on any of the patients. There continues to be no evidence that viable B. burgdorferi persist in humans after conventional treatment with antimicrobials. PMID- 25705395 TI - Gut-brain mechanisms controlling glucose homeostasis. AB - Our current understanding of glucose homeostasis is centered on glucose-induced secretion of insulin from pancreatic islets and insulin action on glucose metabolism in peripheral tissues. In addition, however, recent evidence suggests that neurocircuits located within a brain-centered glucoregulatory system work cooperatively with pancreatic islets to promote glucose homeostasis. Among key observations is evidence that, in addition to insulin-dependent mechanisms, the brain has the capacity to potently lower blood glucose levels via mechanisms that are insulin-independent, some of which are activated by signals emanating from the gastrointestinal tract. This review highlights evidence supporting a key role for a "gut-brain-liver axis" in control of glucose homeostasis by the brain centered glucoregulatory system and the implications of this regulatory system for diabetes pathogenesis and treatment. PMID- 25705396 TI - Journal of Intensive Care: a new journal for all intensive care physicians. PMID- 25705397 TI - Evaluation of semi-quantitative scoring of Gram staining or semi-quantitative culture for the diagnosis of ventilator-associated pneumonia: a retrospective comparison with quantitative culture. AB - BACKGROUND: Semi-quantitative Gram stain and culture methods are still commonly used for diagnosing ventilator-associated pneumonia (VAP), due to its convenience. Only a few studies, however, have assessed the reliability of these methods when compared with quantitative cultures, a current standard for the diagnosis of VAP. The objective of this study was to assess the utility of semi quantitative scores obtained using Gram stains and cultures of endotracheal aspirates when compared with quantitative cultures in the diagnosis of VAP. METHODS: A retrospective chart review of mechanically ventilated patients with clinically suspected VAP in a single intensive care unit was performed. Semi quantitative scores of Gram stains or culture results were compared with quantitative culture results of endotracheal aspirate for the diagnosis of VAP in 136 samples for 51 patients. RESULTS: The semi-quantitative scores of Gram stains and the semi-quantitative culture results significantly correlated with the log value of the quantitative culture results (r s = 0.64 and 0.75). When using a log count >=6 of quantitative cultures as the reference standard for the diagnosis of VAP, the sensitivity and specificity was 95% and 61% for Gram stain score of >=1+, and was 42% and 96% for Gram stain score >=3+, respectively. The sensitivity and specificity was 96% and 40% for the semi-quantitative culture score of >=2+, and was 59% and 86% for the semi-quantitative culture score of >=3+, respectively. CONCLUSIONS: Absence of bacteria in semi-quantitative Gram stain and poor growth (<=1+) in semi-quantitative culture method could be utilized to exclude the possibility of VAP, whereas detection of abundant (>=3+) bacteria in semi-quantitative Gram stain could be utilized to strongly suspect VAP. PMID- 25705398 TI - Arbekacin treatment of a patient infected with a Pseudomonas putida producing a metallo-beta-lactamase. AB - Treatment of infections caused by multidrug-resistant Pseudomonas species is difficult because few antibiotics active against such organisms are available. Arbekacin, a relatively new aminoglycoside, is effective against Pseudomonas spp. in vitro. However, no clinical report on arbekacin treatment of a human infection with a multidrug-resistant Pseudomonas has appeared to date. We encountered a case of pneumonia caused by a Pseudomonas strain producing a metallo-beta lactamase; the patient was successfully treated with arbekacin. A 69-year-old male presented to our hospital experiencing cardiac arrest after rescue from water. Spontaneous circulation had earlier resumed after brief application of cardiopulmonary resuscitation. The patient was subjected to induced hypothermia. He experienced severe acute respiratory distress syndrome. The patient regained consciousness on day 8 post-admission. Episodes of ventilator-associated pneumonia were recorded on days 5 and 12. The causative organism was a strain of Pseudomonas putida that produced a metallo-beta-lactamase. Combination therapy with arbekacin and levofloxacin successfully resolved the pneumonia. The patient was transferred to another hospital on day 37 to undergo further rehabilitation. Strains of P. putida producing metallo-beta-lactamases have become more widespread in recent years. Colistin is traditionally the drug of last resort to treat infections with multidrug-resistant Pseudomonas. However, colistin use is associated with a very high frequency of adverse effects, and the costs of such therapy are not covered by the Japanese health insurance system. Our results indicate that arbekacin is an efficient alternative to multidrug-resistant Pseudomonas. PMID- 25705399 TI - Efficacy of single-dose intravenous immunoglobulin administration for severe sepsis and septic shock. AB - BACKGROUND: Although some studies conducted outside of Japan have addressed the effectiveness of intravenous immunoglobulins (IVIG) in treating infections, the dosing regimens and amounts used in Japan are very different from those reported. Here, we investigate the effectiveness of single-dose administration of IVIG in sepsis patients in Japan. METHODS: We analyzed 79 patients admitted to the intensive care unit (ICU) of a tertiary care institution due to severe sepsis or septic shock. Patients were randomly divided into a group that was administered standard divided doses of IVIG (5 g/day for 3 days, designated the S group) or a group that was administered a standard single dose of IVIG (15 g/day for 1 day, H group); freeze-dried sulfonated human IVIG was used. The longitudinal assessment of procalcitonin (PCT) levels, C-reactive protein (CRP) levels, white blood cell count, blood lactate levels, IL-6 levels, Sequential Organ Failure Assessment (SOFA) score, and Systemic Inflammatory Response Syndrome (SIRS) was conducted. We also assessed mechanical ventilation duration (days), ICU stay (days), 28-day survival rate, and 90-day survival rate. RESULTS: The study showed no significant differences in PCT levels, CRP levels, 28-day survival rate, and 90-day survival rate between the two groups. However, patients in the H group showed improvements in the various SIRS diagnostic criteria, IL-6 levels, and blood lactate levels in the early stages after IVIG administration. In light of the non-recommendation of IVIG therapy in the Surviving Sepsis Campaign Guidelines 2012, our findings of significant early post-administration improvements are noteworthy. IVIG's anti inflammatory effects may account for the early reduction in IL-6 levels after treatment, and the accompanying improvements in microcirculation may improve blood lactate levels and reduce SOFA scores. However, the low dosages of IVIG in Japan may limit the anti-cytokine effects of this treatment. Further studies are needed to determine appropriate treatment regimens of single-dose IVIG. CONCLUSIONS: In this study, we investigated the effectiveness of single-dose IVIG treatment in patients with severe sepsis or septic shock. Although there were no significant effects on patient prognoses, patients who were administered single dose IVIG showed significantly improved IL-6 levels, blood lactate levels, and disease severity scores. PMID- 25705400 TI - Temperature of gas delivered from ventilators. AB - BACKGROUND: Although heated humidifiers (HHs) are the most efficient humidifying device for mechanical ventilation, some HHs do not provide sufficient humidification when the inlet temperature to the water chamber is high. Because portable and home-care ventilators use turbines, blowers, pistons, or compressors to inhale in ambient air, they may have higher gas temperature than ventilators with piping systems. We carried out a bench study to investigate the temperature of gas delivered from portable and home-care ventilators, including the effects of distance from ventilator outlet, fraction of inspiratory oxygen (FIO2), and minute volume (MV). METHODS: We evaluated five ventilators equipped with turbine, blower, piston, or compressor system. Ambient air temperature was adjusted to 24 degrees C +/- 0.5 degrees C, and ventilation was set at FIO2 0.21, 0.6, and 1.0, at MV 5 and 10 L/min. We analyzed gas temperature at 0, 40, 80, and 120 cm from ventilator outlet and altered ventilator settings. RESULTS: While temperature varied according to ventilators, the outlet gas temperature of ventilators became stable after, at the most, 5 h. Gas temperature was 34.3 degrees C +/- 3.9 degrees C at the ventilator outlet, 29.5 degrees C +/- 2.2 degrees C after 40 cm, 25.4 degrees C +/- 1.2 degrees C after 80 cm and 25.1 degrees C +/- 1.2 degrees C after 120 cm (P < 0.01). FIO2 and MV did not affect gas temperature. CONCLUSION: Gas delivered from portable and home-care ventilator was not too hot to induce heated humidifier malfunctioning. Gas soon declined when passing through the limb. PMID- 25705401 TI - A case of Strongyloides hyperinfection associated with tuberculosis. AB - Strongyloidiasis is a parasitic infection that occurs in tropical regions. Hyperinfection, which is an accelerated autoinfection, is often associated with an immunosuppressive state, such as HTLV-1 infection or steroid use. Immunosuppression can also lead to reactivation of tuberculosis infection. These infections may have interacted as a result of impaired cellular immunity. A 28 year-old Nepali male was referred to our hospital for slight abdominal pain and high fever. An abdominal CT scan showed ascites and intestinal swelling. He was admitted with suspected gastroenteritis. Results of stool microscopy on the third day of hospitalization revealed abundant strongylid larvae. We diagnosed a Strongyloides hyperinfection and prescribed ivermectin. Although the numbers of strongylid organisms in the patient's stool soon diminished, his temperature remained high. After receiving a second dose of ivermectin on day 17, he was transferred to a nearby hospital for observation, where he was noted to have massive pleural effusion. He returned to our hospital where his pleural effusion was found to be positive for adenosine deaminase (ADA), and he was diagnosed with a tuberculosis infection. Strongyloides hyperinfection can occur in a non-endemic region. It can be associated with tuberculosis infection possibly due to impaired cellular immunity. It is important to consider other possible infections when treating a patient with an infection associated with impaired cellular immunity. PMID- 25705402 TI - Subcutaneous emphysema and ultrasound sonography. AB - Subcutaneous emphysema is not a rare complication in intensive care unit patients. Recently, ultrasound guidance for central venous puncture is becoming popular; however, the information on imaging for subcutaneous emphysema is limited. We encountered a patient complicated with severe pneumomediastinum and subsequent subcutaneous emphysema. The catheter replacement was attempted, and we examined the visuality of cervical vessels using ultrasound sonography before the intervention. Internal jugular vein itself was observed despite of subcutaneously migrated air bubble; however, the range of ultrasound image was limited, and the relationship between the vessel and the adjacent tissue was unclear. PMID- 25705403 TI - Is wet swab superior to dry swab as an intranasal screening test? AB - Methicillin-resistant Staphylococcus aureus is still a great concern, and recognition of the carrier is essential for appropriate infection control in intensive care units. The utility of wet swab compared to dry swab as an intranasal screening test has not been well assessed yet. A comparative study of the wet and dry swab in its ability to detect the organism was performed against critically ill patients, and it was found that there were no statistically significant differences between the two different methods. The wet swab did not show increased sensitivity compared to dry one. PMID- 25705404 TI - Limitations of global end-diastolic volume index as a parameter of cardiac preload in the early phase of severe sepsis: a subgroup analysis of a multicenter, prospective observational study. AB - BACKGROUND: In patients with severe sepsis, depression of cardiac performance is common and is often associated with left ventricular (LV) dilatation to maintain stroke volume. Although it is essential to optimize cardiac preload to maintain tissue perfusion in patients with severe sepsis, the optimal preload remains unknown. This study aimed to evaluate the reliability of global end-diastolic volume index (GEDI) as a parameter of cardiac preload in the early phase of severe sepsis. METHODS: Ninety-three mechanically ventilated patients with acute lung injury/acute respiratory distress syndrome secondary to sepsis were enrolled for subgroup analysis in a multicenter, prospective, observational study. Patients were divided into two groups-with sepsis-induced myocardial dysfunction (SIMD) and without SIMD (non-SIMD)-according to a threshold LV ejection fraction (LVEF) of 50% on the day of enrollment. Both groups were further subdivided according to a threshold stroke volume variation (SVV) of 13% as a parameter of fluid responsiveness. RESULTS: On the day of enrollment, there was a positive correlation (r = 0.421, p = 0.045) between GEDI and SVV in the SIMD group, whereas this paradoxical correlation was not found in the non-SIMD group and both groups on day 2. To evaluate the relationship between attainment of cardiac preload optimization and GEDI value, GEDI with SVV <=13% and SVV >13% was compared in both the SIMD and non-SIMD groups. SVV <=13% implies the attainment of cardiac preload optimization. Among patients with SIMD, GEDI was higher in patients with SVV >13% than in patients with SVV <=13% on the day of enrollment (872 [785-996] mL/m(2) vs. 640 [597-696] mL/m(2); p < 0.001); this finding differed from the generally recognized relationship between GEDI and SVV. However, GEDI was not significantly different between patients with SVV <=13% and SVV >13% in the non-SIMD group on the day of enrollment and both groups on day 2. CONCLUSIONS: In the early phase of severe sepsis in mechanically ventilated patients, there was no constant relationship between GEDI and fluid reserve responsiveness, irrespective of the presence of SIMD. GEDI should be used as a cardiac preload parameter with awareness of its limitations. PMID- 25705405 TI - Neutrophil cell death in response to infection and its relation to coagulation. AB - Neutrophil is a major player in the pathophysiology of severe sepsis. Recent studies have revealed that the cell death mechanism of neutrophils directly relates to the development of organ dysfunction during sepsis. Here we discuss about the different types of neutrophil cell death such as necrosis, apoptosis, autophagy, and the unique cell death style dubbed NETosis. NETosis cells release neutrophil extracellular traps (NETs), which are composed of chromatin bound to granular and nucleic proteins. The primary purpose of NET release is thought to be the control of microbial infections; however, it acts as a danger signal for the host as well. The harmful substances such as DNA, histones, and high-mobility group box 1 (HMGB1) and many other danger-associated molecular patterns (DAMPs) released along with NETosis or from necrotic neutrophils also contribute to the pathogenesis of sepsis. At the same time, the coagulation system, which is closely tied to these neutrophil cell death mechanisms, is often over-activated. It is well known that individual bacterial pathogens express virulence factors that modulate cell death pathways and influence the coagulation disorder during sepsis. Moreover, extensive cross talk exists between these two phenomena, whereby inflammation leads to activation of coagulation and coagulation considerably affects inflammatory activity. A greater knowledge of cell death pathways in sepsis informs the potential for future therapies designed to ameliorate excessive immune responses during sepsis. PMID- 25705406 TI - Prevalence of vitamin D deficiency in critically ill patients and its influence on outcome: experience from a tertiary care centre in North India (an observational study). AB - BACKGROUND: Limited studies are available on prevalence and severity of vitamin D deficiency in a critically ill population. To the best of our knowledge, this the first study of its kind in an Indian intensive care set-up. METHODS: One hundred fifty-eight critically ill patients were prospectively enrolled for over 2 years. Demographic profile and clinical characteristics were noted. Blood sample for serum 25 (OH) D was collected on admission (4 ml). Serum 25 (OH) D was measured using radioimmunoassay kit. Vitamin D deficiency was labelled as insufficient (31 60 nmol/l), deficient (15-30 nmol/l) and undetectable (<15 nmol/l). Statistical tests used were t test, chi-square test and binary logistic regression. RESULTS: Vitamin D deficiency (<60 nmol/l) was present in 127 patients (80.4%). Twenty-six patients had (20.47%) undetectable vitamin D levels. The mean vitamin D level was higher amongst survivors (43.17 + 39.22) than in non-survivors (39.72 + 29.31). Vitamin D was not significantly associated with mortality in univariate analysis. Multiple logistic regression showed admission APACHE II (p = 0.008), lactate (p = 0.013) and pre-ICU hospital stay (p = 0.041) as independent predictors of mortality in critically ill patients (p < 0.05). CONCLUSIONS: Vitamin D deficiency is highly prevalent in critically ill patients. A causal association between vitamin D deficiency and mortality was not found in our study. Larger studies are needed to understand the relationship between vitamin D deficiency and ICU outcome. PMID- 25705407 TI - A comparison between dosages and plasma concentrations of dexmedetomidine in clinically ill patients: a prospective, observational, cohort study in Japan. AB - BACKGROUND: Dexmedetomidine is a highly selective central alpha2-agonist with anesthetic and analgesic properties for patients in intensive care units. There is little information about the relationship between dosage and plasma concentration during long drug infusions of dexmedetomidine in critically ill patients, especially in Asians. In addition, the administration of dexmedetomidine with a dosage of 0.2-0.7 MUg/kg/h in Japan is different from that with a dosage of 0.2-1.4 MUg/kg/h in European countries and the USA. There has been concern about obtaining an effective concentration with a small dosage and estimating the relationship between dosage and plasma concentration. We conducted a prospective, observational, cohort study measuring plasma dexmedetomidine concentrations. METHODS: Plasma dexmedetomidine concentrations of 67 samples from 34 patients in an intensive care unit for 2 months were measured by ultra performance liquid chromatography coupled with tandem mass spectrometry using single-blind method, and the correlation coefficient between dosages and plasma concentrations was estimated. Exclusion criteria included young patients (<16 years) and samples obtained from patients in which the dosage of dexmedetomidine was changed within 3 h. RESULTS: Among the patients, 20 (58.8%) of the 34 received dexmedetomidine at 0.20-0.83 MUg/kg/h, and in 40 of the 67 samples for which dexmedetomidine had been administered, this occurred for a median duration of 18.5 h (range, 3-87 h). The range of the dexmedetomidine plasma concentration was 0.22-2.50 ng/ml. By comparison with other studies, with a dosage of 0.2-0.7 MUg/kg/h, the patients in this setting could obtain an effective dexmedetomidine concentration. The plasma dexmedetomidine concentration was moderately correlated with the administered dosage (r = 0.653, P < 0.01). The approximate linear equation was y = 0.171x + 0.254. The range of Richmond Agitation-Sedation Scale was 0 to -5. CONCLUSIONS: We concluded that, with a dosage of 0.2-0.83 MUg/kg/h, the patients in this setting could obtain an effective dexmedetomidine concentration of 0.22-2.50 ng/ml. In addition, the plasma dexmedetomidine concentration was moderately correlated with the administered dosage (r = 0.653, P < 0.01). TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) UMIN000009115. PMID- 25705408 TI - Treatment of diffuse alveolar hemorrhage secondary to lupus erythematosus with recombinant activated factor VII administered with a jet nebulizer. AB - Diffuse alveolar hemorrhage (DAH) is a serious pulmonary complication in patients with autoimmune diseases who are undergoing chemotherapy or have had hematopoietic stem cell transplantation. The use of recombinant factor VIIa (rFVIIa) to treat the acute phase of DAH by endobronchial bronchoscopy has been shown to have a significant clinical impact on the survival and evolution of these patients. We report a clinical case of a patient with DAH secondary to systemic lupus erythematosus (SLE) who was treated with rFVIIa administered using a jet nebulizer, obtaining an adequate hemostatic effect with immediate control of DAH and a significant improvement in gas exchange. PMID- 25705409 TI - Concurrent treatment with a tumor necrosis factor-alpha inhibitor and veno-venous extracorporeal membrane oxygenation in a post-hematopoietic stem cell transplant patient with idiopathic pneumonia syndrome: a case report. AB - Idiopathic pneumonia syndrome (IPS) is a fatal non-infectious respiratory complication that develops after hematopoietic stem cell transplantation (HSCT). Because of the poor prognosis of post-HSCT patients with IPS requiring mechanical ventilatory support, performing extracorporeal membrane oxygenation (ECMO) has been regarded as relatively contraindicated in these patients. A tumor necrosis factor-alpha inhibitor, etanercept, has been reported to be a promising treatment option for post-HSCT patients with IPS; however, the phase III clinical trial of etanercept has recently been terminated without definitive conclusion. If post HSCT patients with IPS really benefit from etanercept, mechanical ventilation (MV)-dependent IPS patients might be worth receiving ECMO treatment in line with the protective lung strategy. We therefore performed veno-venous ECMO (VV-ECMO), which substantially acted as an extracorporeal carbon dioxide removal, on a 56 year-old post-HSCT male with severe MV-dependent IPS due to graft-versus-host disease. Although a serious bleeding complication due to post-HSCT thrombocytopenia occurred, the VV-ECMO was continued for 11 days. The patient successfully entered remission of the IPS and was finally extubated on the 12th MV day. However, the patient soon complained of dyspnea, probably due to cytomegalovirus infection and/or exacerbation of the IPS, and was reintubated after 3 days of extubation. The patient then rapidly developed irreversible type II respiratory failure despite the administration of etanercept and an anti cytomegalovirus agent and died on the eighth re-MV day. The autopsy findings of the patient revealed diffuse alveolar damage and alveolar hemorrhage, accompanied with bronchitis obliterans in his lungs, as well as whole body cytomegalovirus infection, which were compatible with the clinical diagnosis of the patient. We think that the legitimacy of this treatment strategy is dependent on the overall prognosis of IPS, which is influenced by the complications induced by immunosuppressants and ECMO, especially infections and bleeding. PMID- 25705410 TI - Oxygenation improves during the first 8 h of extended-duration prone positioning in patients with respiratory failure: a retrospective study. AB - BACKGROUND: A recent multicenter trial demonstrated decreased mortality when patients with acute respiratory distress syndrome were treated with prone positioning (PP). However, the optimal duration of this treatment has not been established. METHODS: From May 2010 to August 2013, 15 patients with respiratory failure underwent extended-duration prone positioning (more than 40 h) in the medical-surgical intensive care unit of a university hospital. The records of each patient were retrospectively investigated to evaluate the impact of prone positioning on the PaO2/FiO2 ratio (PFR) during the first 40 h of therapy. RESULTS: The mean age of the patients was 72.2 +/- 7.8 years, and the mean Acute Physiology and Chronic Health Evaluation II score was 19.0 +/- 6.0. The hospital mortality rate was 47% (7/15), and the median duration of prone positioning was 47.5 h (46.5-67). The mean PFR before prone positioning was 193.8 +/- 70.1, and it significantly improved to 274.7 +/- 70.7 (p = 0.02) at 8 h after prone positioning initiation. Although PFR further improved to 294.1 +/- 78.0 (p = 0.23) at 16 h, the change was not significant and PFR remained relatively constant at 289.0 +/- 88.1, 294.6 +/- 68.2, and 291.7 +/- 72.7 at 24, 32, and 40 h, respectively. CONCLUSIONS: Extended-duration prone positioning resulted in a progressive improvement in oxygenation until 8 to 16 h after treatment initiation, after which there was no significant improvement. Further studies are warranted to clarify the optimal duration of prone positioning and the actual effectiveness of extended-duration PP for respiratory failure. PMID- 25705411 TI - Effects of Rikkunshito (traditional Japanese medicine) on enteral feeding and the plasma ghrelin level in critically ill patients: a pilot study. AB - BACKGROUND: Rikkunshito is a traditional Japanese medicine that has been widely prescribed for patients with various gastrointestinal symptoms. Recently, the prokinetic effects of Rikkunshito in patients with a variety of diseases have attracted attention in Japan. The prokinetic effects of Rikkunshito are believed to result from an increase of active ghrelin, which is most abundant in the stomach and which has a gastrokinetic function. The aim of the present pilot study was to investigate the effects of Rikkunshito on intragastric enteral feeding and plasma ghrelin levels in critically ill patients. METHODS: The study population consisted of critically ill patients who were projected to require intragastric tube feeding for more than 7 days. The patients were prospectively assigned to one of two treatment groups and were randomized to receive either Rikkunshito (2.5 g) or metoclopramide (10 mg) every 8 h. All patients received standard enteral nutrition. Patients in both groups were begun on intragastric tube feeding according to our institution's feeding protocol. RESULTS: All patients were undergoing mechanical ventilation at the time of enrollment. The portions of enteral nutrition provided to the target amount and the quantity of gastric discharge were not statistically significantly different between the two groups. The Rikkunshito group reached 50% of the target amount of enteral feeding significantly earlier than the metoclopramide group, although the proportion of patients in whom enteral feeding was successful did not differ significantly between the two groups. Patients in the Rikkunshito group showed significantly higher plasma levels of active ghrelin compared to those in the metoclopramide group. CONCLUSIONS: The administration of Rikkunshito increased the plasma level of active ghrelin, and induced prokinetic effects that were greater than those observed following treatment with metoclopramide in critically ill patients. TRIAL REGISTRATION: UMIN00000356. PMID- 25705412 TI - Immediate screening method for predicting the necessity of massive transfusions in trauma patients: a retrospective single-center study. AB - BACKGROUND: Hemostatic resuscitation might improve the survival of severely injured trauma patients. Our objective was to establish a simplified screening system for determining the necessity of massive transfusions (MT) at an early stage in trauma cases. METHODS: We retrospectively analyzed the cases of trauma patients who had been transported to our institution between November 2011 and October 2013. Patients who were younger than 18 years of age or who were confirmed to have suffered a cardiac arrest at the scene or on arrival were excluded. MT were defined as transfusions involving the delivery of >=10 units of red blood cell concentrate within the first 24 h after arrival. RESULTS: A total of 259 trauma patients were included in this study (males: 178, 69%). Their mean age was 49 +/- 20, and their median injury severity score was 14.4. Thirty-three (13%) of the patients required MT. The presence of a shock index of >=1, a base excess of <= -3 mmol/L, or a positive focused assessment of sonography for trauma (FAST) result was found to exhibit sensitivity and specificity values of 0.97 and 0.81, respectively, for predicting the necessity of MT. Furthermore, this method displayed an area under the receiver operating characteristic curve of 0.934 (95% confidence interval, 0.891-0.978), which indicated that it was highly accurate. CONCLUSIONS: Our screening method based on the shock index, base excess, and FAST result is a simple and useful way of predicting the necessity of MT early after trauma. PMID- 25705414 TI - Applying results from clinical trials: tranexamic acid in trauma patients. AB - This paper considers how results from clinical trials should be applied in the care of patients, using the results of the Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage (CRASH-2) trial of tranexamic acid in bleeding trauma patients as a case study. We explain why an understanding of the mechanisms of action of the trial treatment, and insight into the factors that might be relevant to this mechanism, is critical in order to properly apply (generalise) trial results and why it is not necessary that the trial population is representative of the population in which the medicine will be used. We explain why cause (mechanism)-specific mortality is more generalizable than all cause mortality and why the risk ratio is the generalizable measure of the effect of the treatment. Overall, we argue that a biological insight into how the treatment works is more relevant when applying research results to patient care than the application of statistical reasoning. PMID- 25705415 TI - Thrombomodulin protects against lung damage created by high level of oxygen with large tidal volume mechanical ventilation in rats. AB - BACKGROUND: Ventilator-induced lung injury (VILI) is associated with inflammatory responses in the lung. Thrombomodulin (TM), a component of the coagulation system, has anticoagulant and anti-inflammatory effects. We hypothesized that the administration of recombinant human soluble TM (rhsTM) would block the development of lung injury. METHODS: Lung injury was induced by high tidal volume ventilation for 2 h with 100% oxygen in rats. Rats were ventilated with a tidal volume of 35 ml/kg with pretreatment via a subcutaneous injection of 3 mg/kg rhsTM (HV (high tidal volume)/TM) or saline (HV/SAL) 12 h before mechanical ventilation. Rats ventilated with a tidal volume of 6 ml/kg under 100% oxygen with rhsTM (LV (low tidal volume)/TM) or saline (LV/SAL) were used as controls. Lung protein permeability was determined by Evans blue dye (EBD) extravasation. RESULTS: Lung injury was successfully induced in the HV/SAL group compared with the LV/SAL group, as shown by the significant decrease in arterial oxygen pressure (PaO2), increased protein permeability, and increase in mean pulmonary artery pressure (mPAP) and ratio of mean pulmonary artery pressure to mean artery pressure (Pp/Ps). Treatment of rats with lung injury with rhsTM (HV/TM) significantly attenuated the decrease in PaO2 and the increase in both mPAP and Pp/Ps, which was associated with a decrease in the lung protein permeability. Lung tissue mRNA expressions of interleukin (IL)-1alpha, IL-1beta, IL-6, tumor necrosis factor-alpha, and macrophage inflammatory protein (MIP)-2 were significantly higher in HV than in LV rats. Rats with VILI treated with rhsTM (HV/TM) had significantly lower mRNA expressions of IL-1alpha, IL-1beta, IL-6, and MIP-2 than those expressions in HV/SAL rats. CONCLUSIONS: Administration of rhsTM may prevent the development of lung injury created by high level of oxygen with large tidal volume mechanical ventilation, which has concomitant decrease in proinflammatory cytokine and chemokine expression in the lung. PMID- 25705416 TI - Reliability of central venous pressure to assess left ventricular preload for fluid resuscitation in patients with septic shock. AB - BACKGROUND: Initial fluid resuscitation is an important hemodynamic therapy in patients with septic shock. The Surviving Sepsis Campaign Guidelines recommend fluid resuscitation with volume loading according to central venous pressure (CVP). However, patients with septic shock often develop a transient decrease in cardiac function; thus, it may be inappropriate to use CVP as a reliable marker for fluid management. METHODS: We evaluated 40 adult patients with septic shock secondary to intra-abdominal infection who received active treatment and were monitored using transthoracic echocardiography (TTE) and CVP for 2 days after admission to our intensive care unit (ICU). We measured left ventricular end diastolic diameter (LVEDD), left atrial diameter (LAD), and the pressure gradient of tricuspid regurgitation (TR?P). The shock status was treated with volume loading and inotrope/vasopressor administration according to the TTE findings. We assessed left ventricular fractional shortening (LVFS) as an index of left ventricular contractility and TR?P as an index of right ventricular afterload and then examined the correlation between CVP and LVEDD/LAD/TR?P. RESULTS: LVFS decreased to <=30% in 42.5% and 27.5% of patients with septic shock, and severe left ventricular dysfunction with LVFS <=20% developed in 12.5% and 15.0% of patients on the first and second ICU days, respectively, despite the use of inotropes/vasopressors. Mild pulmonary hypertension as indicated by TR?P >=30 mmHg was present in 27.5% and 30.0% of patients on their first and second ICU days, respectively. There was no significant correlation between CVP and LVEDD/LAD/TR?P. The hospital mortality rate in this study was 10.0%, although the predicted mortality based on the Acute Physiology and Chronic Health Evaluation II score was 58.7%. CONCLUSIONS: Our results suggest that CVP is not a reliable marker of left ventricular preload for fluid management during the initial phase of septic shock. Assessment of left ventricular preload, right ventricular overload, and left ventricular contractility using TTE seems to be more informative than the measurement of CVP for fluid resuscitation since some patients developed left ventricular dysfunction and/or right ventricular overload. PMID- 25705413 TI - The Japanese guidelines for the management of sepsis. AB - This is a guideline for the management of sepsis, developed by the Sepsis Registry Committee of The Japanese Society of Intensive Care Medicine (JSICM) launched in March 2007. This guideline was developed on the basis of evidence based medicine and focuses on unique treatments in Japan that have not been included in the Surviving Sepsis Campaign guidelines (SSCG), as well as treatments that are viewed differently in Japan and in Western countries. Although the methods in this guideline conform to the 2008 SSCG, the Japanese literature and the results of the Sepsis Registry Survey, which was performed twice by the Sepsis Registry Committee in intensive care units (ICUs) registered with JSICM, are also referred. This is the first and original guideline for sepsis in Japan and is expected to be properly used in daily clinical practice. This article is translated from Japanese, originally published as "The Japanese Guidelines for the Management of Sepsis" in the Journal of the Japanese Society of Intensive Care Medicine (J Jpn Soc Intensive Care Med), 2013; 20:124-73. The original work is at http://dx.doi.org/10.3918/jsicm.20.124. PMID- 25705417 TI - Role of prothrombin complex concentrate in perioperative coagulation therapy. AB - Prothrombin complex concentrate (PCC) is a term to describe pharmacological products that contain lyophilized, human plasma-derived vitamin K-dependent factors (F), FII, FVII, FIX, FX, and various amounts of proteins C and S. PCCs can be rapidly reconstituted in a small volume (20 ml for about 500 international units (IU)) at bedside and administered regardless of the patient's blood type. PCCs are categorized as 4-factor PCC if they contain therapeutic amounts of FVII, and 3-factor PCC when FVII content is low. In addition, activated PCC which contains activated FVII and FX with prothrombin is available for factor VIII bypassing therapy in hemophilia patients with inhibitors. Currently, 4-factor PCC is approved for the management of bleeding in patients taking warfarin, but there has been increasing use of various PCCs in the treatment of acquired perioperative coagulopathy unrelated to warfarin therapy and in the management of bleeding due to novel oral anticoagulants. There is also an ongoing controversy about plasma transfusion and its potential hazards including transfusion-related lung injury (TRALI). Early fixed ratio plasma transfusion has been implemented in many trauma centers in the USA, whereas fibrinogen concentrate and PCC are preferred over plasma transfusion in some European centers. In this review, the rationales for including PCCs in the perioperative hemostatic management will be discussed in conjunction with plasma transfusion. PMID- 25705418 TI - Clinical characteristics of redback spider bites. AB - BACKGROUND: Redback spiders (Latrodectus hasselti) (RBSs) are venomous spiders that have recently spread to Asia from Australia. Since the first case report in 1997 (Osaka), RBS bites have been a clinical and administrative issue in Japan; however, the clinical characteristics and effective treatment of RBS bites, particularly outside Australia remains unclear. This study aimed to elucidate the clinical characteristics of RBS bites and to clarify the effectiveness of the administration of antivenom for treatment. METHODS: We performed a retrospective questionnaire survey from January 2009 to December 2013 to determine the following: patient characteristics, effect of antivenom treatment, and outcomes. To clarify the characteristics of patients who develop systemic symptoms, we compared patients with localized symptoms and those with systemic symptoms. We also examined the efficacy and adverse effects in cases administered antivenom. RESULTS: Over the 5-year study period, 28 patients were identified from 10 hospitals. Of these, 39.3% were male and the median age was 32 years. Bites most commonly occurred on the hand, followed by the forearm. Over 80% of patients developed local pain and erythema, and 35.7% (10 patients) developed systemic symptoms. Baseline characteristics, vital signs, laboratory data, treatment related factors, and outcome were not significantly different between the localized and systemic symptoms groups. Six patients with systemic symptoms received antivenom, of whom four experienced symptom relief following antivenom administration. Premedication with an antihistamine or epinephrine to prevent the adverse effects of antivenom was administered in four patients, which resulted in no anaphylaxis. One out of two patients who did not receive premedication developed a mild allergic reaction after antivenom administration that subsided without treatment. CONCLUSIONS: Approximately one third of cases developed systemic symptoms, and antivenom was administered effectively and safely in severe cases. Further research is required to identify clinically applicable indications for antivenom use. PMID- 25705419 TI - A validation of presepsin levels in kidney dysfunction patients: four case reports. AB - Here, we measured presepsins (PSPs) in four patients with acute kidney injury (AKI) or chronic kidney disease (CKD) and discuss the relationship between PSP and kidney dysfunction. Case 1: an 83-year-old man was admitted to the ICU to manage postoperative respiratory failure with AKI. He had undergone resection for rectal cancer and ileal conduit replacement. On day 1 in the ICU, Escherichia coli (E. coli) was isolated by urine culture. PSP level (pg/ml) on day 2 was 2,745 without elevation of other conventional biomarkers. On day 6, the patient was diagnosed with severe sepsis, and E. coli was isolated by blood culture. By then, PSP had risen to 3,977, along with elevation of other conventional biomarkers. His kidney function recovered gradually after continuous administration of hemodiafiltration; however, PSP continued to rise up to 6,051, along with high systemic inflammatory response syndrome (SIRS) and Acute Physiology and Chronic Health Evaluation (APACHE) II values. The patient expired on day 13 due to multiple organ failure. Case 2: a 78-year-old woman with CKD on hemodialysis (HD) was admitted to the ICU after cardiovascular surgery. Continuous HD was administered postoperatively, and PSP ranged from 1,473-1,870 without signs of sepsis. Temporary elevation of other conventional biomarkers was observed postoperatively. Case 3: a 74-year-old woman with CKD on HD was admitted to the ICU after neurosurgery. She underwent intermittent HD postoperatively, and PSP ranged from 1,240-1,935 without sepsis symptoms. Temporary elevation of other conventional biomarkers was observed postoperatively. Case 4: a 62-year-old man with CKD was admitted to the ICU to control gastrointestinal bleeding. PSP was 606 without signs of infection or elevation of other conventional biomarkers. In cases 2, 3, and 4, bacteria were not isolated in blood cultures. Patients' clinical prognoses were good, with low or moderate SIRS and APACHE II scores. PSP in kidney dysfunction patients will be high despite non-infectious conditions. Therefore, evaluation of PSP in kidney dysfunction patients will be difficult. Further investigation is needed to clarify the relationship between PSP and kidney dysfunction. PMID- 25705420 TI - Plasma is ineffective in correcting mildly elevated PT-INR in critically ill children: a retrospective observational study. AB - BACKGROUND: Fresh frozen plasma transfusion is widely utilized in pediatric clinical practice to correct mild coagulopathy. Several studies on adult population have shown that transfusion of plasma cannot effectively correct mild coagulopathy when international normalized ratio (INR) is <=1.5. Much controversy exists about the generalization of this finding for pediatric populations, especially since pediatric dosages often exceed those in adults. The aim of this study is to determine the prevalence of plasma transfusion with mild coagulopathy (INR <= 1.5) and its effectiveness in a pediatric setting. METHODS: In our tertiary referral hospital, we retrospectively reviewed the electronic medical records of all patients who received plasma (April to October 2011) for mildly elevated prothrombin time (PT)-INR levels (<=1.5) and had post-transfusion PT-INR measurements; patients who received intraoperative, ECMO, or plasma exchange related plasma transfusions were excluded from this study. We abstracted demographic data and pre- and post coagulation test results for the patients included in our study. RESULTS: Among 468 plasma transfusions administered to 285 patients from April to June 2011, 60 plasma transfusions (12.8%) were given to patients with PT-INR <= 1.5 (range 1.3-1.5). Forty-one patients [median age 2.5 years (IQR, 0.14 to 13.75 years), median weight of 16.0 kg (IQR, 8.0 to 69.3 kg)] who received 41 single plasma transfusions [median dose 11 mL/Kg (IQR, 6-15)] had post-transfusion PT-INR measurements and were included in our study. There was no significant difference in their PT-INR values (p = 0.34) pre- and post transfusion. Of our study, only 15.4% patients showed post-transfusion normalization [median change in PT-INR 0.15 (IQR, 0.1-0.2)] and were not different from the remaining 85% in age, plasma dose, and bleeding status. CONCLUSIONS: The prevalence of plasma transfusion for correction of mildly elevated PT-INR levels in critically ill children is high (12.8%). Plasma transfusion showed no significant effect in correcting minor prolongation of PT INR in pediatric patients regardless of age, volume of plasma transfused per kilogram (dosage), or bleeding status. PMID- 25705421 TI - Complement, thrombotic microangiopathy and disseminated intravascular coagulation. AB - In the blurring boundaries between clinical practice and scientific observations, it is increasingly attractive to propose shared disease mechanisms that could explain clinical experience. With the advent of available therapeutic options for complement inhibition, there is a push for more widespread application in patients, despite a lack of clinically relevant research. Patients with disseminated intravascular coagulation (DIC) and thrombotic microangiopathies (TMA) frequently exhibit complement activation and share the clinical consequences of thrombocytopenia, microangiopathic hemolytic anemia, and microvascular thrombosis. However, they arise from very different molecular etiologies giving rise to cautious questions about inclusive treatment approaches because most clinical observations are associative and not cause-and-effect. Complement inhibition is successful in many cases of atypical hemolytic uremic syndrome, greatly reducing morbidity and mortality of patients by minimizing thrombocytopenia, microangiopathic hemolytic anemia, and microvascular thrombosis. But is this success due to targeting disease etiology or because complement is a sufficiently systemic target or both? These questions are important because complement activation and similar clinical features also are observed in many DIC patients, and there are mounting calls for systemic inhibition of complement mediators despite the enormous differences in the primary diseases complicated by DIC. We are in great need of thoughtful and standardized assessment with respect to both beneficial and potentially harmful consequences of complement activation in these patient populations. In this review, we discuss about what needs to be done in terms of establishing the strategy for complement inhibition in TMA and DIC, based on the current knowledge. PMID- 25705422 TI - Efficacy of antithrombin in preclinical and clinical applications for sepsis associated disseminated intravascular coagulation. AB - Antithrombin (AT) is known as an important physiological anticoagulant. AT inactivates thrombin and multiple other coagulation factors, thereby strongly inhibiting the over-activation of the coagulation system during disseminated vascular coagulation (DIC). AT also suppresses the pro-inflammatory reactions that are promoted through protease-activated receptor-1 during sepsis. One of the unique characteristics of AT is the conformational change it undergoes when binding to heparin-like molecules. The anticoagulant function is greatly accelerated after AT binds to externally administered heparin in the circulating blood. Meanwhile, AT also binds to syndecan-4 on the cell surface under physiological conditions, thereby contributing to local antithrombogenicity. The binding of AT and syndecan-4 upregulates prostaglandin I2 production, downregulates pro-inflammatory cytokine production, and suppresses the leukocyte endothelial interaction. Other than these activities, recent preclinical studies have reported that AT might inhibit neutrophil necrotic cell death and the ejection of neutrophil extracellular traps. Together, these effects may lead to the attenuation of inflammation by decreasing the level of damage-associated molecular patterns. Although a number of animal studies have demonstrated a survival benefit of AT, the clinical benefit has long been argued since the effect of high-dose AT was denied in 2001 in a large-scale randomized controlled trial targeting patients with severe sepsis. However, recent clinical studies examining the effects of a supplemental dose of AT in patients with sepsis associated DIC have revealed that AT is potentially effective for DIC resolution and survival improvement without increasing the risk of bleeding. Since DIC is still a major threat during sepsis, the optimal method of identifying this promising drug needs to be identified. PMID- 25705423 TI - Effect of a selective neutrophil elastase inhibitor on mortality and ventilator free days in patients with increased extravascular lung water: a post hoc analysis of the PiCCO Pulmonary Edema Study. AB - BACKGROUND: Neutrophil elastase plays an important role in the development and progression of acute respiratory distress syndrome (ARDS). Although the selective elastase inhibitor, sivelestat, is widely used in Japan for treating ARDS patients, its effectiveness remains controversial. The aim of the current study was to investigate the effects of sivelestat in ARDS patients with evidence of increased extravascular lung water by re-analyzing a large multicenter study database. METHODS: A post hoc analysis of the PiCCO Pulmonary Edema Study was conducted. This multicenter prospective cohort study included 23 institutions in Japan. Adult mechanically ventilated ARDS patients with an extravascular lung water index of >10 mL/kg were included and propensity score analyses were performed. The endpoints were 28-day mortality and ventilator-free days (VFDs). RESULTS: Patients were categorized into sivelestat (n = 87) and control (n = 77) groups, from which 329 inverse probability-weighted group patients (162 vs. 167) were generated. The overall 28-day mortality was 31.1% (51/164). There was no significant difference in 28-day mortality between the study groups (sivelestat vs. control; unmatched: 29.9% vs. 32.5%; difference, -2.6%, 95% confidence interval (CI), -16.8 to 14.2; inverse probability-weighted: 24.7% vs. 29.5%, difference, -4.8%, 95% CI, -14.4 to 9.6). Although administration of sivelestat did not alter the number of ventilator-free days (VFDs) in the unmatched (9.6 vs. 9.7 days; difference, 0.1, 95% CI, -3.0 to 3.1), the inverse probability-weighted analysis identified significantly more VFDs in the sivelestat group than in the control group (10.7 vs. 8.4 days, difference, -2.3, 95% CI, -4.4 to -0.2). CONCLUSIONS: Although sivelestat did not significantly affect 28-day mortality, this treatment may have the potential to increase VFDs in ARDS patients with increased extravascular lung water. Prospective randomized controlled studies are required to confirm the results of the current study. PMID- 25705424 TI - PAMPs and DAMPs as triggers for DIC. AB - Thrombosis is generally considered harmful because it compromises the blood supply to organs. However, recent studies have suggested that thrombosis under certain circumstances plays a major physiological role in early immune defense against invading pathogens. This defensive role of thrombosis is now referred to as immunothrombosis. Activated monocytes and neutrophils are two major inducers of immunothrombosis. Monocytes and neutrophils are activated when they detect pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Detection of PAMPs and DAMPs triggers tissue factor expression on monocytes and neutrophil extracellular trap (NET) release by neutrophils, promoting immunothrombosis. Although tissue factor-mediated and NET-mediated immunothrombosis plays a role in early host defense against bacterial dissemination, uncontrolled immunothrombosis may lead to disseminated intravascular coagulation. PMID- 25705425 TI - Current experience and limitations of extracorporeal cardiopulmonary resuscitation for cardiac arrest in children: a single-center retrospective study. AB - BACKGROUND: There are few reports detailing the importance of extracorporeal membrane oxygenation (ECMO) for pediatric cardiac arrest in Japan. We investigated the status and issues surrounding extracorporeal cardiopulmonary resuscitation (ECPR) at our institution. METHODS: Patients aged <15 years who underwent ECPR between April 1, 2003 and March 31, 2012 were eligible. The characteristics, cannulation site, durations of cardiopulmonary resuscitation (CPR), cannulation procedure, and ECMO, and neurologic outcomes were retrospectively reviewed. A favorable neurologic outcome was defined as Pediatric Cerebral Performance Categories 1 and 2. RESULTS: A total of 21 ECPR events were identified. The median CPR and cannulation durations were 60 and 25 min, respectively. Central and peripheral access sites were employed in 15 and six cases, respectively. Five of the 21 patients (24%) were successfully weaned from ECMO and three of the 21 (14%) survived. Two of the three survivors had a favorable neurologic outcome. CONCLUSIONS: The mortality of patients undergoing ECPR at our institution was low. However, about 10% of all patients had a favorable neurologic outcome, which suggests that ECPR may be effective in pediatric cardiac arrest patients. PMID- 25705426 TI - Thrombomodulin/activated protein C system in septic disseminated intravascular coagulation. AB - The thrombomodulin (TM)/activated protein C (APC) system plays an important role in maintaining the homeostasis of thrombosis and hemostasis and maintaining vascular integrity in vivo. TM expressed on vascular endothelium binds to thrombin, forming a 1:1 complex and acts as an anticoagulant. In addition, the thrombin-TM complex activates protein C to produce APC, which inactivates factors VIIIa and Va in the presence of protein S, thereby inhibiting further thrombin formation. Intriguingly, APC possesses anti-inflammatory as well as cytoprotective activities. Moreover, the extracellular domain of TM also possesses APC-independent anti-inflammatory and cytoprotective activities. Of note, the TM/APC system is compromised in disseminated intravascular coagulation (DIC) caused by sepsis due to various mechanisms, including cleavage of cell surface TM by exaggerated cytokines and proteases produced by activated inflammatory cells. Thus, it is reasonable to assume that reconstitution of the TM/APC system by recombinant proteins would alleviate sepsis and DIC. On the basis of the success of the Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial, the FDA approved the use of recombinant human APC (rhAPC) for severe sepsis patients in 2002. However, subsequent clinical trials failed to show clinical benefits for rhAPC, and an increased incidence of hemorrhage related adverse events was noted, which prompted the industry to withdraw rhAPC from the market. On the other hand, recombinant human soluble TM (rTM) has been used for treatment of individuals with DIC since 2008 in Japan, and a phase III clinical trial evaluating the efficacy of rTM in severe sepsis patients with coagulopathy is now ongoing in the USA, South America, Asia, Australia, European Union, and other countries. This review article discusses the molecular mechanisms by which the TM/APC system produces anticoagulant as well as anti inflammatory and cytoprotective activities in septic DIC patients. PMID- 25705427 TI - Clinical significance of procoagulant microparticles. AB - Microparticles (MPs) are small membrane vesicles that are released from many different cell types by exocytic budding of the plasma membrane in response to cellular activation or apoptosis. MPs may also be involved in clinical diseases because they express phospholipids, which function as procoagulants. Although flow cytometry is the most widely used method for studying MPs, some novel assays, such as tissue factor-dependent procoagulant assay or the ELISA method, have been reported. However, the use of quantification of MP as a clinical tool is still controversial. Elevated platelet-derived MP, endothelial cell-derived MP, and monocyte-derived MP concentrations are documented in almost all thrombotic diseases occurring in venous and arterial beds. However, the significance of MPs in various clinical conditions remains controversial. An example of this controversy is that it is unknown if MPs found in peripheral blood vessels cause thrombosis or whether they are the result of thrombosis. Numerous studies have shown that not only the quantity, but also the cellular origin and composition of circulating MPs, are dependent on the type of disease, the disease state, and medical treatment. Additionally, many different functions have been attributed to MPs. Therefore, the number and type of clinical disorders associated with elevated MPs are currently increasing. However, MPs were initially thought to be small particles with procoagulant activity. Taken together, our review suggests that MPs may be a useful biomarker to identify thrombosis. PMID- 25705428 TI - Colistin for lung infection: an update. AB - Increasing incidence of resistance of gram-negative bacteria against even newer antibiotic including carbapenem has generated interest in the old antibiotic colistin, which are being used as salvage therapy in the treatment of multidrug resistant infection. Colistin has excellent bactericidal activity against most gram-negative bacilli. It has shown persist level in the liver, kidney, heart, and muscle; while it is poorly distributed to the bones, cerebrospinal fluid, lung parenchyma, and pleural cavity. Being an old drug, colistin was never gone through the drug development process needed for compliance with competent regulatory authorities that resulted in very much limited understanding of pharmacokinetic (PK) and pharmacodynamic (PD) parameters, such as C max/MIC ratio, AUC/MIC and T > MIC that could predict the efficacy of colistin. In available PK/PD studies of colistin, mean maximum serum concentration (C max) of colistin were found just above the MIC breakpoint at steady states that would most probably lead to suboptimal for killing the bacteria, even at dosages of 3.0 million international units (MIU) i.e., 240 mg of colistimethate sodium (CMS) intravenously every 8 h. These finding stresses to use high loading as well as high maintenance dose of intravenous colistin. It is not only suboptimal plasma concentration of colistin but also poor lung tissue concentration, which has been demonstrated in recent studies, poses major concern in using intravenous colistin. Combination therapy mainly with carbapenems shows synergistic effect. In recent studies, inhaled colistin has been found promising in treatment of lung infection due to MDR gram-negative bacteria. New evidence shows less toxicity than previously reported. PMID- 25705429 TI - A case of bilateral adrenal haemorrhage following traumatic brain injury. AB - We report the case of a 57-year-old man who sustained an isolated severe traumatic brain injury (TBI). During his admission to the intensive care unit (ICU), he developed marked arterial hypotension of unclear cause. Eventually, the presence of renal angle tenderness on clinical examination and a low random cortisol level lead to the suspicion of primary adrenal insufficiency. A computed tomography scan of his abdomen demonstrated new bilateral adrenal haemorrhages. This diagnosis is not unlikely to be missed, as symptoms and laboratory tests are often nonspecific. PMID- 25705430 TI - Prognosis of patients with fulminant myocarditis managed by peripheral venoarterial extracorporeal membranous oxygenation support: a retrospective single-center study. AB - BACKGROUND: Peripheral venoarterial extracorporeal membranous oxygenation (ECMO) support is effective in patients with cardiogenic shock or fatal arrhythmia due to fulminant myocarditis. The clinical courses of fulminant myocarditis are still uncertain; therefore, it is difficult to determine the appropriate time for discontinuing ECMO or converting to a ventricular assist device. The purpose of this study was to investigate the prognosis of patients with fulminant myocarditis managed by ECMO. METHODS: Twenty-two consecutive patients with fulminant myocarditis managed by peripheral venoarterial ECMO between 1999 and 2013 were enrolled. RESULTS: Survival to discharge was 59% (13 patients), and in hospital mortality was 41% (9 patients). The age in the survivor group was significantly lower than that in the non-survivor group (survivor group vs. non survivor group; 36.5 +/- 4.1 vs. 60.2 +/- 5.0 years, p = 0.001). Although the ECMO support duration was similar between the groups (181 +/- 22 vs. 177 +/- 31 h), the rate of complication related to ECMO was significantly lower in the survivor group (15.3% vs. 66.6%, p = 0.02). When comparing the laboratory data during ECMO management between the groups, the serum bilirubin level on day 7 was significantly lower in the survivor group (total: 4.6 +/- 2.8 vs. 13.7 +/- 10.8 mg/dL, p = 0.014; direct: 2.2 +/- 0.5 vs. 9.8 +/- 4.5 mg/dL, p = 0.009). CONCLUSIONS: Fulminant myocarditis is associated with high mortality rates despite ECMO. An older age and complications related to ECMO are associated with poor prognosis. PMID- 25705431 TI - Risk factors associated with intracranial hemorrhage in neonates with persistent pulmonary hypertension on ECMO. AB - BACKGROUND: Up to 40% of infants with persistent pulmonary hypertension (PPHN) remains refractory to conventional therapies, and extracorporeal membrane oxygenation (ECMO) is offered as an effective support for this group. However, ECMO is a highly invasive and risky procedure with devastating complications such as intracranial hemorrhage (ICH). In this study, we aimed to determine the risk factors for ICH in infants with PPHN. METHODS: A case-control study of patients admitted to the pediatric intensive care unit (PICU) with PPHN requiring ECMO support was conducted. The study was carried out at a 25-bed PICU in large urban tertiary care children's hospital. A total number of 32 subjects were studied. Patients with and without ICH during ECMO were evaluated for activated clotting time (ACT), heparin dosing, platelet count, coagulation profile such as activated partial thromboplastin time (aPTT), prothrombin time (PT), international normalized ratio (INR), fibrinogen level, vital signs including heart rate and mean arterial pressure (MAP), transfusion history, gestational age, and severity of pre-ECMO illness as possible risk factors. RESULTS: Low fibrinogen level (115 +/- 13 mg/dl) and low platelet counts (37.4 +/- 18.3 Thousand/MUl) were associated with higher incidence of ICH (p = 0.009 and p = 0.005, respectively). Elevated MAP (69 +/- 4.34 mmHg) was also noticed in ICH patients (p = 0.006). CONCLUSIONS: Results demonstrated that low fibrinogen level and low platelet count were associated with ICH in PPHN patients on ECMO. While on ECMO support, maintaining fibrinogen and platelet counts within normal ranges seems crucial to prevent ICH in PPHN patients. This is the first report identifying low fibrinogen level among the risk factors for ICH in infants with PPHN on ECMO support. PMID- 25705432 TI - Update of antivenom supply for redback spider bites in Japan. AB - In autumn 2014, with great effort by the Ministry of Health, Labour and Welfare, the research group will obtain several vials of redback spider (RBS) antivenom for emergency use. However, these small amounts of antivenom are insufficient to cover the demands from majority of hospitals in Japan. The research group carefully discussed the domestic RBS antivenom production by themselves for this emergency. We have now entered the second stage for large-scale antivenom production. Although the domestic production of RBS antivenom has started, great caution is required as we move forward with this plan. PMID- 25705433 TI - Severe congenital neutropenia caused by the ELANE gene mutation in a Vietnamese boy with misdiagnosis of tuberculosis and autoimmune neutropenia: a case report. AB - BACKGROUND: Severe congenital neutropenia (SCN) is an immunodeficiency disease characterized low blood neutrophil counts, early bacterial infections, and risk of leukaemia development. Heterozygous mutations in the ELANE gene coding neutrophil elastase are associated with SCN. Patients with SCN suffer from recurrent bacterial infections and often succumb them. To our knowledge, this is the first report of SCN from Vietnam. CASE PRESENTATION: A 6-year-old boy was admitted due to severe bacterial infection and severe neutropenia. He had recurrent infections from 8 months of age, and was misdiagnosed with tuberculosis and and autoimmune neutropenia in infancy at 21 and 41 months of age, respectively. His medical report has showed severe neutropenia for many times. In direct DNA sequencing analysis, we found an ELANE gene mutation (R81P), which had been confirmed to cause SCN. CONCLUSION: The missed and delayed diagnosis may be attributable to insufficient awareness of this rare disease on the background of frequent infections even in the immunocompetent pediatric population in Vietnam. Our results indicate further evidence for the role of ELANE in SCN. PMID- 25705434 TI - Practical remediation of the PCB-contaminated soils. AB - A practical method for the elimination of PCBs from PCB-contaminated soil has been developed by the combination of Soxhlet extraction using a newly-developed modified Soxhlet extractor possessing an outlet valve on the extraction chamber with the chemical degradation. Various types of PCBs contaminated in soils could be completely extracted in refluxing hexane, and the subsequent hydrodechlorination could also be completed within 1 h in a hexane-MeOH (1 : 5) solution in the presence of Pd/C and Et3N under ordinary hydrogen pressure and temperature without the transfer of the extracted PCBs to other reaction container (a complete one-pot procedure). The present system is quite useful as a simple, safe, mild and reliable remediation method of PCB-contaminated soil. PMID- 25705435 TI - Crystal structure of (E)-1-(4'-meth-oxy-[1,1'-biphen-yl]-4-yl)-3-(3-nitro-phen yl)prop-2-en-1-one. AB - The title compound, C22H17NO4, crystallizes with two independent mol-ecules (A and B) in the asymmetric unit. Each mol-ecule exists as an E isomer with C-C=C-C torsion angles of -175.69 (17) and -178.41 (17) degrees in A and B, respectively. In mol-ecule A, the planes of the terminal benzene rings are twisted by an angle of 26.67 (10) degrees , while the biphenyl unit is non planar, the dihedral angle between the rings being 30.81 (10) degrees . The dihedral angle between the nitro-phenyl ring and the inner phenyl ring is 6.50 (9) degrees . The corresponding values in mol-ecule B are 60.61 (9), 31.07 (8) and 31.05 (9) degrees . In the crystal, mol-ecules are arranged in a head-to-head manner, with the 3-nitro-phenyl groups nearly parallel to one another. The A and B mol-ecules are linked to one another via C-H?O hydrogen bonds, forming chains lying parallel to (-320) and enclosing R 2 (2)(10) and R 2 (2)(12) ring motifs. The meth-oxy group in both mol-ecules is positionally disordered with a refined occupancy ratio of 0.979 (4):0.021 (4) for mol-ecule A and 0.55 (4):0.45 (4) for mol-ecule B. PMID- 25705436 TI - Structure cristalline de type alluaudite K0.4Na3.6Co(MoO4)3. AB - A new triple molybdate, potassium sodium cobalt tris-(molybdate), K0.4Na3.6Co(MoO4)3, was synthesized using solid-state reactions. The Co(2+) and one Na(+) cation are located at the same general site, each with occupancy 0.5. Another site (site symmetry 2) is occupied by Na(+) and K(+) cations, with occupancies of 0.597 (7) and 0.402 (6), respectively. The other two Na(+) cations and one of the two Mo atoms lie on special positions (site symmetries -1, 2 and 2, respectively). The structure is characterized by M 2O10 (M = Co/Na) dimers, which are linked by MoO4 tetra-hedra, forming infinite layers. The latter are connected firstly by insertion of one type of MoO4 tetra-hedra and secondly by sharing corners with the other type of MoO4 tetra-hedra. This results in an open three-dimensional framework with the cavities occupied by the Na(+) and K(+) cations. The structure is isotypic with Na3In2As3O12 and Na3In2P3O12. A comparison is made with structures such as K2Co2(MoO4)3 and beta-NaFe2(MoO4)3 and their differences are discussed. PMID- 25705437 TI - Crystal structure of (+/-)-(4RS,5RS,7SR)-4-[(1RS,2RS,3RS,6RS)-3-benzo-yloxy-2-(2 hy-droxy-ethyl)-6-meth-oxy-meth-oxy-2-methyl-cyclo-hex-yl]-8,10,10-trimethyl-2 oxo-1,3-dioxa-spiro-[4.5]dec-8-en-7-yl benzoate benzene monosolvate. AB - In the title compound, C36H44O10.C6H6, the dioxolane ring adopts an envelope conformation with the C atom bonded to the H atom as the flap, while the cyclo hexene and cyclo-hexane rings are in half-chair and chair conformations, respectively. In the crystal, a pair of O-H?O hydrogen bonds with an R 2 (2)(26) graph-set motif connect the benzoate mol-ecules into an inversion dimer. The dimers are linked by a weak C-H?O inter-action into a tape structure along [01 1]. The benzene mol-ecule links the tapes through C-H?O and C-H?pi inter-actions, forming a sheet parallel to (100). PMID- 25705438 TI - Crystal structures of 2-benzyl-amino-4-(4-bromo-phen-yl)-6,7,8,9-tetra-hydro-5H cyclo-hepta-[b]pyridine-3-carbo-nitrile and 2-benzyl-amino-4-(4-chloro-phen-yl) 6,7,8,9-tetra-hydro-5H-cyclo-hepta[b]pyridine-3-carbo-nitrile. AB - In the title compounds, C24H22BrN3, (I), and C24H22ClN3, (II), the 2-amino pyridine ring is fused with a cyclo-heptane ring, which adopts a half-chair conformation. The planes of the phenyl and benzene rings are inclined to that of the central pyridine ring [r.m.s. deviations = 0.0083 (1) and 0.0093 (1) A for (I) and (II), respectively] by 62.47 (17) and 72.51 (14) degrees , respectively, in (I), and by 71.44 (9) and 54.90 (8) degrees , respectively, in (II). The planes of the aromatic rings are inclined to one another by 53.82 (17) degrees in (I) and by 58.04 (9) degrees in (II). In the crystals of both (I) and (II), pairs of N-H?Nnitrile hydrogen bonds link the mol-ecules, forming inversion dimers with R 2 (2)(12) ring motifs. In (I), the resulting dimers are connected through C-H?Br hydrogen bonds, forming sheets parallel to (10-1), and pi-pi inter actions [inter-centroid distance = 3.7821 (16) A] involving inversion-related pyridine rings, forming a three-dimensional network. In (II), the resulting dimers are connected through pi-pi inter-actions [inter-centroid distance = 3.771 (2) A] involving inversion-related pyridine rings, forming a two-dimensional network lying parallel to (001). PMID- 25705439 TI - Crystal structure of 5-(4-benzyl-oxyphen-yl)-3-(4-meth-oxy-phen-yl)-6-methyl cyclo-hex-2-en-1-one. AB - The title compound, C27H26O3, crystallized with two independent mol-ecules (A and B) in the asymmetric unit. In mol-ecule A, the plane of the central benzene ring forms dihedral angles of 75.78 (14) and 52.75 (16) degrees with that of the terminal benzene rings, and the dihedral angle between the planes of the terminal benzene rings is 51.49 (17) degrees . The corresponding values for mol-ecule B are 75.18 (14), 58.11 (16) and 47.91 (16) degrees , respectively. The cyclo hexene ring adopts an envelope conformation in both mol-ecules, with the C atom to which is attached the central benzene ring as the flap. The crystal packing, is stabilized by C-H?pi inter-actions. PMID- 25705440 TI - Crystal structure of 5,5-bis-(4-methyl-benz-yl)pyrimidine-2,4,6(1H,3H,5H)-trione monohydrate. AB - The asymmetric unit of the title compound, C20H20N2O3.H2O, contains two independent mol-ecules (A and B), with similar conformations and two independent water mol-ecules. In the crystal, N-H?O and Owater-H?O hydrogen bonds link all moieties into two crystallographically independent kinds of sheets parallel to the ac plane. These independent sheets, each containing either A or B mol-ecules, are further alternately stacked along the b axis and inter-connected via C-H?piar yl inter-actions. PMID- 25705441 TI - Coordination of bis-(pyrazol-1-yl)amine to palladium(II): influence of the co ligands and counter-ions on the mol-ecular and crystal structures. AB - The structures of a series of complexes with general formula n[Pd(pza)X]Y.mH2O (n = 1, 2; X = Cl, Br, I, N3, NCS; Y = NO3, I, N3, [Pd(SCN)4]; m = 0, 0.5, 1) have been determined, where pza is the tridentate ligand bis-[2-(3,5-di-methyl-pyrazol 1-yl)eth-yl]amine, C14H23N5. In all complexes, {bis-[2-(3,5-di-methyl-pyrazol-1 yl-kappaN (2))eth-yl]amine-kappaN}chlorido-palladium nitrate, [Pd(pza)Cl]NO3, (1), {bis-[2-(3,5-di-methyl-pyrazol-1-yl-kappaN (2))eth-yl]amine-kappaN}bromido palladium nitrate, [Pd(pza)Br]NO3, (2), {bis-[2-(3,5-di-methyl-pyrazol-1-yl kappaN (2))eth-yl]amine-kappaN}iodido-palladium iodide hemihydrate, [Pd(pza)I]I.0.5H2O, (3), azido{bis-[2-(3,5-di-methyl-pyrazol-1-yl-kappaN (2))eth yl]amine-kappaN}palladium azide monohydrate, [Pd(pza)N3]N3.H2O, (4), and bis [{bis-[2-(3,5-di-methyl-pyrazol-1-yl-kappaN (2))eth-yl]amine-kappaN}(thio-cyanato kappaN)palladium] tetra-kis-(thio-cyanato-kappaS)palladate, [Pd(pza)NCS]2[Pd(SCN)4], (5), the [Pd(pza)X](+) complex cation displays a square planar coordination geometry, and the pza ligand is twisted, approximating twofold rotation symmetry. Although the pza ligand is found with the same conformation along the series, the dihedral angle between pyrazole rings depends on the co-ligand X. This angle span the range 79.0 (3)-88.6 (1) degrees for the studied complexes. In (3), two complex cations, two I(-) anions and one water mol ecule of crystallization are present in the asymmetric unit. In (5), the central amine group of pza is disordered over two positions [occupancy ratio 0.770 (18):0.230 (18)]. The complex [Pd(SCN)4](2-) anion of this compound exhibits inversion symmetry and shows the Pd(2+) transition metal cation likewise in a square-planar coordination environment. Compound (5) is also a rare occurrence of a non-polymeric compound in which the pseudohalide ligand NCS(-) behaves both as thio-cyanate and iso-thio-cyanate, i.e. is coordinating either through the N atom (in the cation) or the S atom (in the anion). PMID- 25705442 TI - Crystal structure of (E)-2-{[(4-anilinophen-yl)imino]-meth-yl}phenol. AB - The title compound, C19H16N2O, crystallized with two independent mol-ecules (A and B) in the asymmetric unit. There is an intra-molecular O-H?N hydrogen bond in each mol-ecule with the phenol ring being inclined to the central benzene ring by 4.93 (14) and 7.12 (14) degrees in mol-ecules A and B, respectively. The conformation of the two mol-ecules differs essentially in the orientation of the terminal amino-phenyl ring with respect to the central benzene ring; this dihedral angle is 50.51 (4) degrees in mol-ecule A and 54.61 (14) degrees in mol-ecule B. The two outer aromatic rings are inclined to one another by 51.39 (14) and 49.88 (14) degrees in mol-ecules A and B, respectively. In the crystal, mol-ecules are connected by N-H?O hydrogen bonds generating -A-B-A-B- zigzag chains extending along [010]. The chains are linked via C-H?pi inter-actions involving neighbouring A mol-ecules, forming slabs lying parallel to (100). PMID- 25705443 TI - Crystal structures of iso-quinoline-3-chloro-2-nitro-benzoic acid (1/1) and isoquinolinium 4-chloro-2-nitro-benzoate. AB - In each of the title isomeric compounds, C9H7.3N.C7H3.7ClNO4, (I), and C9H8N.C7H3ClNO4, (II), of iso-quinoline with 3-chloro-2-nitro-benzoic acid and 4 chloro-2-nitro-benzoic acid, the two components are linked by a short hydrogen bond between a base N atom and a carb-oxy O atom. In the hydrogen-bonded unit of (I), the H atom is disordered over two positions with N and O site occupancies of 0.30 (3) and 0.70 (3), respectively, while in (II), an acid-base inter-action involving H-atom transfer occurs and the H atom is located at the N site. In the crystal of (I), the acid-base units are connected through C-H?O hydrogen bonds into a tape structure along the b-axis direction. Inversion-related adjacent tapes are further linked through pi-pi inter-actions [centroid-centroid distances = 3.6389 (7)-3.7501 (7) A], forming a layer parallel to (001). In the crystal of (II), the acid-base units are connected through C-H?O hydrogen bonds into a ladder structure along the a-axis direction. The ladders are further linked by another C-H?O hydrogen bond into a layer parallel to (001). PMID- 25705444 TI - Crystal structure of (Z)-2-[(E)-2-benzyl-idene-hydrazin-1-yl-idene]-1,2-di-phenyl ethanone. AB - The title compound, C21H16N2O, has an almost planar (r.m.s. deviation = 0.0074 A) 1,2-di-benzyl-idenehydrazine backbone with an approximately orthogonal almost planar (r.m.s. deviation = 0.0368 A) phenyl-ethanone substituent on one of the imine C atoms. The dihedral angle between the two mean planes is 76.99 (4) degrees . In the crystal, mol-ecules are linked via C-H?O hydrogen bonds and C H?pi contacts, forming a three-dimensional structure with mol-ecules stacked along the a-axis direction. PMID- 25705445 TI - Crystal structure of 8-[7,8-bis-(4-chloro-benzo-yl)-7H-cyclo-penta-[a]ace naphthylen-9-yl]naphthalene-1-carb-oxy-lic acid. AB - The title compound, C40H22Cl2O4, was formed by a Michael-Aldol domino reaction sequence, which coupled acenaphthene-quinone with 4-chloro-aceto-phenone in the presence of KOH in methanol. The dihedral angles between the central cyclo-penta [a]ace-naphthyl-ene fused-ring system (r.m.s. deviation = 0.066 A) and the 4 chloro-benzoyl rings are 62.25 (10) and 70.19 (10) degrees . The dihedral angle between the central ring system and the naphthoic acid grouping is 62.46 (7) degrees . This twisting of the pendant rings facilitates the formation of an intra-molecular aromatic pi-pi stacking inter-action between the 4-chloro-benzoyl and naphthoic acid rings, with centroid-centroid distances of 3.4533 (16) and 3.5311 (16) A, and a C-H?pi inter-action between one of the H atoms of the central moiety and the 4-chloro-benzoyl ring with an H?pi distance of 2.57 A. In the crystal, carb-oxy-lic acid inversion dimers generate R 2 (2)(8) loops. The dimers are linked by weak C-H?O and C-H?Cl hydrogen bonds and C-H?pi inter actions, generating a three-dimensional architecture. PMID- 25705446 TI - Crystal structure of dioxidobis(pentane-2,4-dionato-kappa(2) O,O')[1-phenyl-3 (pyridin-4-yl)propane-kappaN]uranium(VI). AB - In the title compound, [UO2(C5H7O2)2(C14H15N)], the uran-yl(VI) unit ([O=U=O](2+)) is coordinated to two acetyl-acetonate (acac) anions and one 1 phenyl-3-(pyridin-4-yl)propane (ppp) mol-ecule. The geometry around the U atom is UNO6 penta-gonal-bipyramidal; two uran-yl(VI) O atoms are located at the axial positions, whereas four O atoms from two chelating bidentate acac ligands and one N atom of a ppp ligand form the equatorial plane. PMID- 25705447 TI - Crystal structure of cis-bis-(MU-beta-alanine-kappa(2) O:O')bis[tri-chlorido rhenium(III)](Re-Re) sesquihydrate. AB - The structure of the title compound, [Re2Cl6(C3H7NO2)2].1.5H2O, comprises a dinuclear complex cation [Re-Re = 2.2494 (3) A] involving cis-oriented double carboxyl-ate bridges, four equatorial chloride ions and two weakly bonded chloride ligands in the axial positions at the two rhenium(III) atoms. In the crystal, two complex mol-ecules and two water mol-ecules constitute hydrogen bonded dimers, while an extensive hydrogen-bonding network involving the groups of the zwitterionic ligand is important for generation of the framework. An additional partially occupied water molecule is disordered over two sets of sites about a symmetry centre with a site-occupancy ratio of 0.3:0.2. PMID- 25705448 TI - Crystal structure of gamma-methyl l-glutamate N-carb-oxy anhydride. AB - In the title compound, C7H9NO5, alternative name N-carb-oxy-l-glutamic anhydride gamma-methyl ester, the oxazolidine ring is essentially planar with a maximum deviation of 0.020 (3) A. In the crystal, mol-ecules are linked by N-H?O hydrogen bonds between the imino group and the carbonyl O atom in the methyl ester group, forming a tape structure along the a-axis direction. The tapes are linked by C H?O inter-actions into a sheet parallel to the ac plane. The tapes are also stacked along the b axis with short contacts between the oxazolidine rings [C?O contact distances = 2.808 (4)-3.060 (4) A], so that the oxazolidine rings are arranged in a layer parallel to the ab plane. This arrangement of the oxazolidine rings is very preferable for the polymerization of the title compound in the solid state. PMID- 25705449 TI - Crystal structure of zwitterionic 3-(2-hy-droxy-2-phospho-nato-2-phosphono-eth yl)imidazo[1,2-a]pyridin-1-ium monohydrate (minodronic acid monohydrate): a redetermination. AB - In a previous study, the X-ray structure of the title compound, C9H12N2O7P2.H2O, was reported [Takeuchi et al., (1998 ?). Chem. Pharm. Bull. 46, 1703-1709], but neither atomic coordinates nor details of the geometry were published. The structure has been redetermined with high precision as its detailed knowledge is essential to elucidate the presumed polymorphism of minodronic acid monohydrate at room temperature. The mol-ecule crystallizes in a zwitterionic form with cationic imidazolium[1,2a]pyridine and anionic phospho-nate groups. The dihedral angle formed by the planes of the pyridine and imidazole rings is 3.55 (9) degrees . A short intra-molecular C-H?O contact is present. In the crystal, mol ecules are linked by O-H?O, N-H?O and C-H?O hydrogen bonds and pi-pi inter actions [centroid-to-centroid distance = 3.5822 (11) A], forming a three dimensional structure. PMID- 25705450 TI - Crystal structure of magnesium copper(II) bis-[orthophosphate(V)] monohydrate. AB - Single crystals of magnesium copper(II) bis-[orthophosphate(V)] monohydrate, Mg1.65Cu1.35(PO4)2.H2O, were grown under hydro-thermal conditions. The crystal structure is formed by three types of cationic sites and by two unique (PO4)(3-) anions. One site is occupied by Cu(2+), the second site by Mg(2+)and the third site by a mixture of the two cations with an Mg(2+):Cu(2+) occupancy ratio of 0.657 (3):0.343 (3). The structure is built up from more or less distorted [MgO6] and [(Mg/Cu)O5(H2O)] octa-hedra, [CuO5] square-pyramids and regular PO4 tetra hedra, leading to a framework structure. Within this framework, two types of layers parallel to (-101) can be distinguished. The first layer is formed by [Cu2O8] dimers linked to PO4 tetra-hedra via common edges. The second, more corrugated layer results from the linkage between [(Cu/Mg)2O8(H2O)2] dimers and [MgO6] octa-hedra by common edges. The PO4 units link the two types of layers, leaving space for channels parallel [101], into which the H atoms of the water mol-ecules protrude. The latter are involved in O-H?O hydrogen-bonding inter actions (one bifurcated) with framework O atoms across the channels. PMID- 25705451 TI - Crystal structure of a new monoclinic polymorph of 2,4-di-hydroxy-benzaldehyde 4 methyl-thio-semi-carbazone. AB - The title compound, C9H11N3O2S, is a second monoclinic (P21/c) polymorph of the previously reported Cc form [Tan et al. (2008b ?). Acta Cryst. E64, o2224]. The mol-ecule is non-planar, with the dihedral angle between the N3CS residue (r.m.s. deviation = 0.0816 A) and the benzene ring being 21.36 (4) degrees . The conformation about the C=N bond [1.292 (2) A] is E, the two N-bound H atoms are anti, and the inner hy-droxy O-bound and outer amide N-bound H atoms form intra molecular hydrogen bonds to the imine N atom. Crucially, the H atom of the outer hy-droxy group is approximately syn to the H atom of the benzene C atom connecting the two C atoms bearing the hy-droxy substituents. This arrangement enables the formation of supra-molecular tubes aligned along [010] and sustained by N-H?O, O-H?S and N-H?S hydrogen bonds; the tubes pack with no specific inter actions between them. While the mol-ecular structure in the Cc form is comparable, the H atom of the outer hy-droxy group is approximately anti, rather than syn. This different orientation leads to the formation a three-dimensional architecture based on N-H?O and O-H?S hydrogen bonds. PMID- 25705452 TI - Crystal structure of N-[(2S,5R)-4-oxo-2,3-diphenyl-1,3-thia-zinan-5-yl]acetamide 0.375-hydrate. AB - The asymmetric unit of the title compound, C18H18N2O2S.0.375H2O, has two independent organic mol-ecules (A and B) and 3/4 of a water mol-ecule distributed over three sites. In mol-ecule A, the 1,3-thia-zine ring is in a boat conformation, with the C atoms at the 2- and 5-positions out of the plane. The angle between the two phenyl rings is 51.70 (12) degrees . In mol-ecule B, the thia-zine ring is in a half-chair conformation, with the S atom forming the back of the half-chair. The angle between the two phenyl rings is 84.44 (14) degrees . The A mol-ecule features an intra-molecular N-H?O hydrogen bond, which closes an S(5) ring motif. In the crystal, the corresponding N-H grouping of the B mol ecule participates in an inter-molecular hydrogen bond to the A mol-ecule. The A mol-ecule participates in a C-H?O inter-action back to the B mol-ecule, whilst the B mol-ecule features an intra-molecular C-H?O link, which generates an S(10) loop. PMID- 25705453 TI - Crystal structure of an eight-coordinate terbium(III) ion chelated by N,N'-bis-(2 hy-droxy-benz-yl)-N,N'-bis-(pyridin-2-ylmeth-yl)ethyl-enedi-amine (bbpen(2-)) and nitrate. AB - The reaction of terbium(III) nitrate penta-hydrate in aceto-nitrile with N,N'-bis (2-hy-droxy-benz-yl)-N,N'-bis-(pyridin-2-ylmeth-yl)ethyl-enedi-amine (H2bbpen), previously deprotonated with tri-ethyl-amine, produced the mononuclear compound [N,N'-bis-(2-oxidobenzyl-kappaO)-N,N'-bis-(pyridin-2-ylmethyl-kappaN)ethylenedi amine-kappa(2) N,N'](nitrato-kappa(2) O,O')terbium(III), [Tb(C28H28N4O2)(NO3)]. The mol-ecule lies on a twofold rotation axis and the Tb(III) ion is eight coordinate with a slightly distorted dodeca-hedral coordination geometry. In the symmetry-unique part of the mol-ecule, the pyridine and benzene rings are both essentially planar and form a dihedral angle of 61.42 (7) degrees . In the mol ecular structure, the N4O4 coordination environment is defined by the hexa dentate bbpen ligand and the bidentate nitrate anion. In the crystal, a weak C H?O hydrogen bond links mol-ecules into a two-dimensional network parallel to (001). PMID- 25705454 TI - Structure cristalline de type alluaudite KNa5Mn3(MoO4)6. AB - The new phase potassium penta-sodium trimanganese hexa-kis(molybdate), KNa5Mn3Mo6O24, has been synthesized using solid-state methods. The structure is composed of M 2O10 (M = Mn, Na) dimers and MoO4 tetra-hedra (point group symmetry 2) sharing corners and forming layers parallel to (100), which are linked via common corners of another type of MO4 tetra-hedra, forming a three-dimensional structure with two types of large channels along [001] in which two types of Na(+) cations (one with site symmetry 2, one with -1) and K(+) cations (site symmetry 2, half-occupation) are located. Mn(2+) and the third type of Na(+) cations are located at the same site M with occupancies of 0.75 and 0.25, respectively. A comparative structural description is provided between the structure of the title compound and those of the related phases Cu1.35Fe3(PO4)3 and NaAgFeMn2(PO4)3. PMID- 25705455 TI - Crystal structure of fac-tri-chlorido-[tris-(pyridin-2-yl-N)amine]-chromium(III). AB - In the neutral complex mol-ecule of the title compound, fac-[CrCl3(tpa)] [tpa is tris-(pyridin-2-yl)amine; C15H12N4], the Cr(III) ion is bonded to three N atoms that are constrained to a facial arrangement by the tpa ligand and by three chloride ligands, leading to a distorted octa-hedral coordination sphere. The average Cr-N and Cr-Cl bond lengths are 2.086 (5) and 2.296 (4) A, respectively. The complex mol-ecule is located on a mirror plane. In the crystal, a combination of C-H?N and C-H?Cl hydrogen-bonding inter-actions connect the mol-ecules into a three-dimensional network. PMID- 25705456 TI - Crystal structure of catena-poly[[[aqua-lithium(I)]-MU-pyrimidine-2-carboxyl-ato kappa(4) N (1),O (2):N (3),O (2')] hemihydrate]. AB - The title compound, {[Li(C5H3N2O2)(H2O)].0.5H2O} n , comprises four symmetry independent Li(C5H3N2O2)(H2O) units which form mol-ecular ribbons running along the c-axis direction. Within each ribbon, the ligand mol-ecule, acting in a MU2 mode, bridges two adjacent Li(+) cations using both of its N,O-bonding sites. The coordination environment of each of the four Li(+) cations can be described alternatively as either slightly distorted trigonal-bipyramidal or slightly distorted square-pyramidal. The ribbons are inter-connected by a network of O-H?O hydrogen bonds. PMID- 25705457 TI - Crystal structure of (1S,2R,4S)-1-[(morpholin-4-yl)meth-yl]-4-(prop-1-en-2 yl)cyclo-hexane-1,2-diol. AB - The asymmetric unit of the title compound, C14H25NO3, contains two independent mol-ecules with similar geometry. The morpholine and cyclo-hexane rings of both mol-ecules adopt a chair conformation. Intra-molecular O-H?N hydrogen bonds are observed. In the crystal, mol-ecules are linked by O-H?O hydrogen bonds into chains parallel to the [101] direction. The chains are further connected through C-H?O hydrogen bonds forming undulating layers parallel to the (-101) plane. The absolute configuration was assigned by reference to an unchanging chiral centre in the synthetic procedure. PMID- 25705458 TI - Crystal structure of lead(II) tartrate: a redetermination. AB - Single crystals of poly[MU4-tartrato-kappa(6) O (1),O (3):O (1'):O (2),O (4):O (4')-lead], [Pb(C4H4O6)] n , were grown in a gel medium. In comparison with the previous structure determination of this compound from laboratory powder X-ray diffraction data [De Ridder et al. (2002 ?). Acta Cryst. C58, m596-m598], the redetermination on the basis of single-crystal data reveals the absolute structure, all atoms with anisotropic displacement parameters and a much higher accuracy in terms of bond lengths and angles. It could be shown that a different space group or incorporation of water as reported for similarly gel-grown lead tartrate crystals is incorrect. In the structure, each Pb(2+) cation is bonded to eight O atoms of five tartrate anions, while each tartrate anion links four Pb(2+) cations. The resulting three-dimensional framework is stabilized by O-H?O hydrogen bonds between the OH groups of one tartrate anion and the carboxyl-ate O atoms of adjacent anions. PMID- 25705459 TI - Crystal structure of (E)-1-{2-[(5,5-dimethyl-1,3,2-dioxaphosphinan-2-yl) oxy]naphthalen-1-yl}-N-(4-fluoro-phen-yl)methanimine. AB - In the title compound, C22H21FNO3P, a 1,3,2-dioxaphosphinan-2-yloxy derivative, three O atoms are bonded in a trigonal-pyramidal manner to the P atom. The exocyclic P-O bond is significantly longer than the two endocyclic P-O bonds, viz. 1.6678 (12) A compared to 1.6046 (13) and 1.6096 (12) A. The six-membered ring which includes the P atom has a chair conformation. The fluoro-phenyl ring is inclined to the naphthalene ring system by 24.42 (7) degrees . In the crystal, mol-ecules are linked via C-H?pi inter-actions, forming slabs lying parallel to (10-1). PMID- 25705460 TI - The crystal structures of four N-(4-halophen-yl)-4-oxo-4H-chromene-3 carboxamides. AB - Four N-(4-halophen-yl)-4-oxo-4H-chromene-3-carboxamides (halo = F, Cl, Br and I), N-(4-fluoro-phen-yl)-4-oxo-4H-chromene-3-carboxamide, C16H10FNO3, N-(4-chloro phen-yl)-4-oxo-4H-chromene-3-carboxamide, C16H10ClNO3, N-(4-bromo-phen-yl)-4-oxo 4H-chromene-3-carboxamide, C16H10BrNO3, N-(4-iodo-phen-yl)-4-oxo-4H-chromene-3 carboxamide, C16H10INO3, have been structurally characterized. The mol-ecules are essentially planar and each exhibits an anti conformation with respect to the C-N rotamer of the amide and a cis geometry with respect to the relative positions of the Carom-Carom bond of the chromone ring and the carbonyl group of the amide. The structures each exhibit an intra-molecular hydrogen-bonding network comprising an N-H?O hydrogen bond between the amide N atom and the O atom of the carbonyl group of the pyrone ring, forming an S(6) ring, and a weak Carom-H?O inter-action with the O atom of the carbonyl group of the amide as acceptor, which forms another S(6) ring. All four compounds have the same supra-molecular structure, consisting of R 2 (2)(13) rings that are propagated along the a-axis direction by unit translation. There is pi-pi stacking involving inversion related mol-ecules in each structure. PMID- 25705461 TI - Crystal structure of (Z)-4-[1-(4-acetyl-anilino)ethyl-idene]-3-methyl-1-phenyl-1H pyrazol-5(4H)-one. AB - In the solid state, the title compound, C20H19N3O2, adopts the keto-amine tautomeric form, with the H atom attached to the N atom, which participates in an intra-molecular N-H?O hydrogen bond with an S(6) ring motif. The dihedral angles between the pyrazole ring and the phenyl and benzene rings are 3.69 (10) and 46.47 (9) degrees , respectively. In the crystal, mol-ecules are linked by weak C H?O hydrogen bonds, generating C(16) chains propagating in [301]. Weak aromatic pi-pi stacking inter-actions [centroid-centroid distances = 3.6123 (10) and 3.6665 (10) A] link the chains into a three-dimensional network. PMID- 25705462 TI - Crystal structure of 4,4'-(ethane-1,2-di-yl)bis-(2,6-di-bromo-aniline). AB - In the title compound, C14H12Br4N2, the mol-ecule lies across an inversion center and hence the benzene rings are strictly coplanar. In the crystal, mol-ecules are linked by N-H?N and weak N-H?Br hydrogen bonds, forming a two-dimensional network parallel to (101). In addition, type II Br?Br inter-actions [3.625 (4) A] complete a three-dimensional supra-molecular network. PMID- 25705463 TI - Crystal structure of bis-[trans-(ethane-1,2-di-amine-kappa(2) N,N')bis-(thio cyanato-kappaN)chromium(III)] tetra-chlorido-zincate from synchrotron data. AB - The structure of the title compound, [Cr(NCS)2(C2H8N2)2]2[ZnCl4], has been determined from synchrotron data. In the asymmetric unit, there are four independent halves of the Cr(III) complex cations, each of which lies on an inversion centre, and one tetra-chlorido-zincate anion in a general position. The Cr(III) atoms are coordinated by the four N atoms of two ethane-1,2-di-amine (en) ligands in the equatorial plane and two N-bound NCS(-) anions in a trans arrangement, displaying a slightly distorted octa-hedral geometry with crystallographic inversion symmetry. The Cr-N(en) and Cr-N(NCS) bond lengths range from 2.0653 (10) to 2.0837 (10) A and from 1.9811 (10) to 1.9890 (10) A, respectively. The five-membered metalla-rings are in stable gauche conformations. The [ZnCl4](2-) anion has a distorted tetra-hedral geometry. The crystal structure is stabilized by inter-molecular hydrogen bonds involving the en NH2 or CH2 groups as donors and chloride ligands of the anion and S atoms of NCS(-) ligands as acceptors. PMID- 25705464 TI - Crystal structure of 4-{[(cyano-imino)(methyl-sulfanyl)meth-yl]amino}-1,5 dimethyl-2-phenyl-2,3-di-hydro-1H-pyrazol-3-one. AB - In the title compound, C14H15N5OS, the tautomer present in the solid state is that in which the immediately exocyclic N atom bears the H atom. The central five membered ring is almost planar (r.m.s. deviation = 0.025 A), but both its N atoms are significantly pyramidalized. A classical hydrogen bond from the N-H group to the cyanide N atom forms inversion-symmetric dimers, which are further linked by C-H?O inter-actions. PMID- 25705465 TI - Crystal structure of (S)-4-carbamoyl-4-(1,3-dioxo-isoindolin-2-yl)butanoic acid. AB - In the title compound, C13H12N2O5, the phthalimide ring system is essentially planar, with a maximum deviation of 0.0479 (14) A. In the crystal, each mol-ecule is linked via six neighbouring mol-ecules into a three-dimensional network through N-H?O and O-H?O hydrogen bonds, which form an R 3 (2)(8) ring motif. PMID- 25705466 TI - Crystal structure of gamma-ethyl-l-glutamate N-carb-oxy anhydride. AB - In the title compound (alternative name N-carboxy-l-glutamic anhydride gamma ethyl ester), C8H11NO5, the oxazolidine ring is essentially planar, with a maximum deviation of 0.019 (2) A. In the crystal, mol-ecules are linked by N-H?O hydrogen bonds between the imino group and the carbonyl O atom in the ethyl ester group, forming a tape structure along the c-axis direction. The oxazolidine rings of adjacent tapes are arranged into a layer parallel to the ac plane. This arrangement is favourable for the polymerization of the title compound in the solid state. PMID- 25705467 TI - A cyclic carbo-isosteric penta-depsipeptide: cyclo(Phe(1)-d-Ala(2)-Gly(3)-Phe(4) APO(5)). AB - The title compound, cyclo(Phe(1)-d-Ala(2)-Gly(3)-Phe(4)-APO(5)), C26H32N4O5, is the minor diastereoisomer of a cyclic penta-peptidomimetic analogue containing a novel 2-amino-propyl lactone (APO) motif, which displays the same number of atoms as the native amino acid glycine and has a methyl group in place of the carbonyl O atom. The crystal structure presented here allows the analysis of the secondary structure of this unprecedented cyclic carbo-isosteric depsipeptide. The conformation of the central ring is stabilized by an intra-molecular N-H?O hydrogen bond between the carbonyl O atom of the first residue (Phe(1)) and the amide group H atom of the fourth residue (Phe(4)). Based on the previously reported hydrogen bond and on the values of the torsion angles phi and psi, the loop formed by the first, second, third and fourth residues (Phe(1), d-Ala(2), Gly(3) and Phe(4)) can be classified as a type II' beta-turn. The loop around the new peptidomimetic motif, on the other hand, resembles an open gamma-turn containing a weak N-H?O hydrogen bond between the carbonyl group O atom of the fourth residue (Phe(4)) and the amide unit H atom of the first residue (Phe(1)). In the crystal, the peptidomimetic mol-ecules are arranged in chains along the b axis direction. Within such a chain, the mol-ecules of the structure are linked via N-H?O hydrogen bonds between the amide group H atom of the secondary residue (d-Ala(2)) and the carb-oxy unit O atom of the fourth residue (Phe(4)) in a neighboring mol-ecule. The newly formed methyl stereocentre of the APO peptidomimetic motif (APO(5)) was obtained as the minor diastereoisomer in a ring closing reductive amination reaction and adopts an R configuration. PMID- 25705468 TI - Crystal structure of the coordination polymer [Fe(III) 2{Pt(II)(CN)4}3]. AB - The title complex, poly[dodeca-MU-cyanido-diiron(III)triplat-inum(II)], [Fe(III) 2{Pt(II)(CN)4}3], has a three-dimensional polymeric structure. It is built-up from square-planar [Pt(II)(CN)4](2-) anions (point group symmetry 2/m) bridging cationic [Fe(III)Pt(II)(CN)4](+) infinity layers extending in the bc plane. The Fe(II) atoms of the layers are located on inversion centres and exhibit an octa hedral coordination sphere defined by six N atoms of cyanide ligands, while the Pt(II) atoms are located on twofold rotation axes and are surrounded by four C atoms of the cyanide ligands in a square-planar coordination. The geometrical preferences of the two cations for octa-hedral and square-planar coordination, respectively, lead to a corrugated organisation of the layers. The distance between neighbouring [Fe(III)Pt(II)(CN)4](+) infinity layers corresponds to the length a/2 = 8.0070 (3) A, and the separation between two neighbouring Pt(II) atoms of the bridging [Pt(II)(CN)4](2-) groups corresponds to the length of the c axis [7.5720 (2) A]. The structure is porous with accessible voids of 390 A(3) per unit cell. PMID- 25705469 TI - Crystal structure of poly[(N,N-di-methyl-acetamide-kappaO)(MU4-5-methyl isophthalato-kappa(5) O:O,O':O'':O''')manganese(II)]. AB - The title compound, poly[(N,N-di-methyl-acetamide-kappaO)(MU4-5-methyl isophthalato-kappa(5) O,O':O',O'':O'')manganese(II)], [Mn(C9H6O4)(C3H7NO)] n , was obtained from a mixture containing MnCl2.4H2O and 5-methyl-isophthalic acid in N,N-di-methyl-acetamide solution. The Mn(2+) ion is coordinated by five O atoms from four bridging 5-methyl-isophthalate ligands and one O atom from one N,N-di-methyl-acetamide ligand, defining a considerably distorted coordination polyhedron with one very long Mn-O bond of 2.623 (2) A. The Mn(2+) ions are joined by carboxyl-ate groups, forming rod-shaped secondary building units along the a axis. The rods are further connected by 5-methyl-isophthalate ligands to form the pcu (primitive cubic net) structure. PMID- 25705470 TI - Crystal structure of di-chlorido-{4-[(E)-(meth-oxy-imino-kappaN)meth-yl]-1,3-thia zol-2-amine-kappaN (3)}palladium(II). AB - In the title compound, [PdCl2(C5H7N3OS)], the Pd(II) atom adopts a distorted square-planar coordination sphere defined by two N atoms of the bidentate ligand and two Cl atoms. The mean deviation from the coordination plane is 0.029 A. The methyl group is not coplanar with the plane of the metallacycle [torsion angle C O-N-C = 20.2 (4) degrees ]. Steric repulsion between the methyl group and atoms of the metallacycle is manifested by shortened intra-molecular H?C contacts of 2.27, 2.38 and 2.64 A, as compared with the sum of the van der Waals radii of 2.87 A. The amino group participates via one H atom in the formation of an intra molecular N-H?Cl hydrogen bond. In the crystal, the other H atom of the amino group links mol-ecules via bifurcated N-H?(Cl,O) hydrogen bonds into chains parallel to [001]. PMID- 25705471 TI - Crystal structure of bis-(3-bromo-pyridine-kappaN)bis-(O-ethyl di-thio-carbonato kappa(2) S,S')nickel(II). AB - In the title mol-ecular complex, [Ni(C3H5OS2)2(C5H4BrN)2], the Ni(2+) cation is located on a centre of inversion and has a distorted octa-hedral N2S4 environment defined by two chelating xanthate ligands and two monodentate pyridine ligands. The C-S bond lengths of the thio-carboxyl-ate group are indicative of a delocalized bond and the O-Csp (2) bond is considerably shorter than the O-Csp (3) bond, consistent with a significant contribution of one resonance form of the xanthate anion that features a formal C=O+ unit and a negative charge on each of the S atoms. The packing of the mol-ecules is stabilized by C-H?S and C-H?pi inter-actions. In addition, pi-pi inter-actions between the pyridine rings [centroid-to-centroid distance = 3.797 (3) A] are also present. In the crystal structure, mol-ecules are arranged in rows along [100], forming layers parallel to (010) and (001). PMID- 25705472 TI - Crystal structure of the one-dimensional metal-organic polymer catena poly[[tris(MU-2,4,6-tri-methyl-benzoato-kappa(2) O:O')dizinc]-MU-2,4,6-tri-methyl benzoato-kappa(2) O:O']. AB - The title complex, [Zn2(C10H11O2)4] n , has a one-dimensional polymeric structure. The asymmetric unit consists of two zinc atoms bridged by three 2,4,6 tri-methyl-benzoate anions and one bidentate bridging 2,4,6-trimethylbenzoate anion. The [Zn2(C9H11CO2)3] cluster units are inter-molecularly linked to form a one-dimensional polymer, which propagates in the direction of the crystallographic b axis. The Zn atoms adopt a tetra-hedral geometry. The Zn-O bond lengths in the intra-molecular bridges are slightly shorter than those in the inter-molecular bridges. PMID- 25705473 TI - Crystal structure of bis-(2,2'-bi-pyridine-kappa(2) N,N')bis-(thio-cyanato kappaN)mang-anese(II) 2,2'-bi-pyridine monosolvate. AB - In the crystal structure of the mononuclear title compound, [Mn(NCS)2(C10H8N2)2].C10H8N2, the Mn(II) cation is coordin-ated in an all-cis configuration by two N-bound thio-cyanate anions and two 2,2'-bi-pyridine ligands within a slightly distorted octa-hedral environment. The asymmetric unit consists of one Mn(II) cation, two thio-cyanate anions and two 2,2'-bi-pyridine ligands, as well as two non-coordinating 2,2'-bi-pyridine ligands that are each located on centres of inversion. In the crystal structure, the discrete [Mn(NCS)2(C10H8N2)2] complex mol-ecules are arranged in such a way that cavities are formed, in which the solvent 2,2'-bi-pyridine mol-ecules are located. Apart from van der Waals forces, there are no remarkable inter-molecular inter-actions present in the crystal structure. PMID- 25705474 TI - Crystal structure of [3-(1H-benzimidazol-2-yl)propano-ato-kappaN (3)][3-(1H benzimid-azol-2-yl)propanoic acid-kappaN (3)]copper(I). AB - In the title compound, [Cu(C10H9N2O2)(C10H10N2O2)], the Cu(I) ion is situated at a crystallographic centre of inversion and is coordinated in a linear environment by two benzimidazole N atoms from two symmetry-related 2-propanoic-1H benzimidazole ligands. The ligands are disordered in a sense that statistically one of the carb-oxy-lic acid groups in each mol-ecule is deprotonated. In the crystal, O-H?O hydrogen bonds link the mol-ecules into chains along the a-axis direction. These chains are additionally linked into infinite two-dimensional networks in the ab plane by N-H?O hydrogen bonds. PMID- 25705475 TI - Crystal structure of bis-(eta(5)-cyclo-penta-dien-yl)(2,3-di-ethyl-butane-1,4-di yl)hafnium(IV). AB - The title compound, [Hf(C5H5)2(C8H16)], proves a structural motif of hafna-cyclo pentane besides the coordination of two cyclo-penta-dienyl ligands in an eta(5) fashion. The hafna-cyclo-pentane ring has a twist conformation and is substituted by two ethyl groups in the beta,beta'-positions, which are trans orientated to each other. One cyclo-penta-dienyl ring and one ethyl group are each disordered over two positions with site-occupancy ratios of 0.679 (15):0.321 (15) and 0.702 (18):0.298 (18), respectively. PMID- 25705476 TI - Crystal structure of tris-(1,10-phenanthroline-kappa(2) N,N')iron(II) bis-[bis (tri-fluoro-methyl-sulfon-yl)imide] monohydrate. AB - The crystal structure of the title complex, [Fe(C12H8N2)3][(CF3SO2)2N]2.H2O, is constructed by one octa-hedral [Fe(phen)3](2+) (phen = 1,10-phenanthroline) cation (point group symmetry 2), two Tf2N(-) [bis-(tri-fluoromethyl-sulfon yl)imide] anions, and one water mol-ecule of crystallization (point group 2). The Fe-N bond lengths are indicative of a d (6) low-spin state for the Fe(II) ion in the complex. The dihedral angle between the phen ligands in the cation is 87.64 (6) degrees . The Tf2N(-) counter-anion is non-coordinating, with the -CF3 groups arranged in a trans fashion with respect to each other, leading to an anti,anti conformation of the -CF3 groups and -SO2N- moieties relative to the S-C bonds. The water mol-ecule of crystallization connects two O atoms of the Tf2N(-) anions through weak hydrogen bonds. C-H?O hydrogen-bonding inter-actions are also observed, consolidating the packing of the mol-ecules into a three-dimensional network structure. PMID- 25705477 TI - Crystal structure of 6,9-dimethyl-7H-[1,2,4]triazolo[4,3-b][1,2,4]triazepin-8(9H) one 0.40-hydrate. AB - In the mol-ecule of the title compound, C7H9N5O.0.40H2O, the seven-membered heterocyclic ring exhibits a boat conformation, whereas the five-membered triazole ring is almost planar (r.m.s. deviation = 0.005 A). In the crystal, centrosymmetric dimers are linked by pairs of C-H?O hydrogen bonds into dimers, which are further connected via O-H?N and C-H?N hydrogen bonds, forming a three dimensional network. The structure contains a partially occupied water mol-ecule lying on a twofold axis with an occupancy factor of 0.4. PMID- 25705478 TI - Crystal structure of 1,3-bis-(4-methyl-benz-yl)-1H-1,3-benzimidazol-3-ium bromide monohydrate. AB - In the title hydrated symetrically substituted 1,3-bis-(4-methyl-benz yl)benzimidazolium salt, C23H23N2 (+).Br(-).H2O, the dihedral angles between the benzimidazole ring system (r.m.s. deviation = 0.003 A) and the pendant benzene rings are 73.18 (16) and 77.52 (16) degrees . Both benzene rings lie to the same side of the benzimidazole ring system, giving the cation an overall U-shape. In the crystal, the cation is linked to the water mol-ecule by a short C-H?O hydrogen bond and the water mol-ecule forms O-H?Br hydrogen bonds. Together, these inter-actions lead to [010] chains. The packing is consolidated by C-H?Br hydrogen bonds and aromatic pi-pi stacking inter-actions [centroid-centroid distances = 3.5401 (17) and 3.8815 (18) A], generating a three-dimensional network. PMID- 25705479 TI - Crystal structure of 1-(4-meth-oxy-phen-yl)-4-(4-nitro-phen-yl)-3-phen-oxy azetidin-2-one. AB - In the title compound, C22H18N2O5, the central beta-lactam ring (r.m.s. deviation = 0.002 A) makes dihedral angles of 64.21 (14), 82.35 (12) and 20.66 (13) degrees with the phenyl ring and the nitro- and meth-oxy-benzene rings, respectively. The mol-ecular structure is stabilized by an intra-molecular C-H?O hydrogen bond. In the crystal, mol-ecules are linked via C-H?O hydrogen bonds, forming slabs lying parallel to (111). The slabs are linked via C-H?pi inter-actions, forming a three-dimensional network. PMID- 25705480 TI - Crystal structure of 1,7,8,9-tetra-chloro-4-(3,5-di-chloro-benz-yl)-10,10-dimeth oxy-4-aza-tri-cyclo-[5.2.1.0(2,6)]dec-8-ene-3,5-dione. AB - In the title compound, C17H11Cl6NO4, the configuration of the cyclo-alkene skeleton is endo,cis. The benzene ring is twisted by 58.94 (8) degrees from the attached pyrrolidine ring. Two carbonyl groups play a key role in the crystal packing. A short inter-molecular C?O distance of 3.017 (3) A reveals that one carbonyl group is involved in dipole-dipole inter-actions, which link two adjacent enanti-omers into an inversion dimer. Another carbonyl group provides an acceptor for the weak inter-molecular C-H?O hydrogen bonds which link these dimers into layers parallel to (011). PMID- 25705481 TI - Crystal structure of ethyl 2-[2-((1E)-{(1E)-2-[2-(2-eth-oxy-2-oxoeth-oxy)benzyl idene]hydrazin-1-yl-idene}meth-yl)phen-oxy]acetate. AB - The complete mol-ecule of the title compound, C22H24N2O6, is generated by crystallographic inversion symmetry and is approximately planar (r.m.s. deviation of the non-H atoms = 0.134 A). The packing consists of inter-digitated sheets inclined at 25.9 (4) degrees to one another and linked by short C-H?O hydrogen bonds. PMID- 25705482 TI - Crystal structure of 2-aza-niumyl-3-bromo-6-oxo-5,6-di-hydro-pyrido[1,2 a]quinoxalin-11-ium dibromide. AB - The title salt, C12H10BrN3O(2+).2Br(-), was synthesized from the reaction of N (1),N (4)-bis-(pyridin-2-yl-methyl-idene)benzene-1,4-di-amine and bromine in a methanol solution. All non-H atoms of the 2-aza-niumyl-3-bromo-6-oxo-5,6-di-hydro pyrido[1,2-a]quinoxalin-11-ium cation are nearly coplanar, the maximum deviation being 0.114 (4) A. In the crystal, the cations and anions are linked through N H?Br hydrogen bonds and weak C-H?Br inter-actions, forming a three-dimensional supra-molecular architecture. A short Br?Br contact [3.3088 (9) A] is observed in the crystal. PMID- 25705483 TI - Crystal structure of 2,2-di-chloro-1-(piperidin-1-yl)butane-1,3-dione. AB - In the title compound, C9H13Cl2NO2, the piperidine ring shows a chair conformation and the O-C-C-O torsion angle between the carbonyl groups is 183.6 (4) degrees . In the crystal, mol-ecules are linked into an infinite layer along the ab plane by a bifurcated C-H?O hydrogen bond between the carbonyl O atom adjacent to the methyl group and one of the methyl-ene groups next to nitro-gen and an additional hydrogen bond of the C-H?Cl type. These layers are connected into a three-dimensional supra-molecular arrangement by O?Cl contacts [2.8979 (12) and 3.1300 (12) A]. PMID- 25705484 TI - Crystal structure of 1-methane-sulfonyl-1,2,3,4-tetra-hydro-quinoline. AB - In the title compound, C10H13NO2S, the heterocyclic ring adopts a half-chair conformation and the bond-angle sum at the N atom is 347.9 degrees . In the crystal, inversion dimers linked by pairs of C-H?O hydrogen bonds generate R 2 (2)(8) loops. PMID- 25705485 TI - Crystal structure of (Z)-3-(4-meth-oxy-benzyl-idene)-2,3-di-hydro benzo[b][1,4]thia-zepin-4(5H)-one. AB - In the title compound, C17H15NO2S, the two C atoms linking the S and carbonyl C atoms of the seven-membered thia-zepine ring are disordered over two sites, with occupancies of 0.511 (4) and 0.489 (4); both disorder components adopt distorted twist-boat conformations. In the crystal, N-H?O and C-H?O hydrogen bonds link inverted-related mol-ecules into dimers, incorporating R 1 (2)(6) and R 2 (2)(8) ring motifs; the acceptor carbonyl O atom is bifurcated. These dimers are further linked by C-H?O hydrogen bonds, forming supra-molecular tapes running along the a axis. PMID- 25705486 TI - Crystal structure of 3-bromo-4-di-methyl-amino-1-methyl-1,2,4-triazol-5(4H)-one. AB - The title compound, C5H9BrN4O, was obtained as a minor by-product in the synthesis of 4-di-methyl-amino-1-methyl-1,2,4-triazolin-5-one. Except for the methyl groups of the 4-dimethylamino moiety, all the non-H atoms lie on a crystallographic mirror plane." In the crystal, the mol-ecules are linked by C Br?O=C inter-actions [Br?O = 2.877 (2) A, C-Br?O = 174.6 (1) degrees ] into infinite chains in the c-axis direction. PMID- 25705487 TI - Crystal structure of 3-(morpholin-4-yl)-1-phenyl-3-(pyridin-2-yl)propan-1-one. AB - In the title compound C18H20N2O2, the morpholine ring adopts a chair conformation with the exocyclic N-C bond in an equatorial orientation. The N atom of the morpholine ring and the C atom of the carbonyl group are in an anti conformation about the central C-C bond [torsion angle = -162.92 (11) degrees ] and the dihedral angle between the planes of the benzene ring and the pyridine ring is 83.30 (5) degrees . In the crystal, pairs of very weak C-H?pi inter-actions link the mol-ecules into inversion dimers. PMID- 25705488 TI - Crystal structure of 4-(di-methyl-amino)-pyridinium 4-amino-benzoate dihydrate. AB - In the title hydrated mol-ecular salt, C7H11N2 (+).C7H6NO2 (-).2H2O, the cation is protonated at the pyridine N atom and the dihedral angle between the benzene ring and the CO2 (-) group in the anion is 8.5 (2) degrees . In the crystal, the cation forms an N-H?O hydrogen bond to the anion and the anion forms two N-H?O hydrogen bonds to adjacent water mol-ecules. Both water mol-ecules form two O-H?O hydrogen bonds to carboxyl-ate O atoms. In combination, these hydrogen bonds generate a three-dimensional network and two weak C-H?pi inter-actions are also observed. PMID- 25705489 TI - Crystal structure of N'-(2,6-di-methyl-phen-yl)benzene-carboximidamide tetra hydro-furan monosolvate. AB - The asymmetric unit of the title compound, C15H16N2.C4H8O, contains two amidine mol-ecules (A and B) with slightly different conformations and two tetra-hydro furan (THF) solvent mol-ecules. In the amidine mol-ecules, the di-methyl-phenyl ring and the NH2 group lie to the same side of the N=C bond and the dihedral angles between the aromatic rings are 54.25 (7) (mol-ecule A) and 58.88 (6) degrees (mol-ecule B). In the crystal, N-H?N hydrogen bonds link the amidine mol ecules into [100] C(4) chains of alternating A and B mol-ecules. Both amidine mol ecules form an N-H?O hydrogen bond to an adjacent THF solvent mol-ecule. PMID- 25705490 TI - Crystal structure of 2-meth-oxy-2-[(4-methyl-phen-yl)sulfan-yl]-1-phenyl-ethan-1 one. AB - In the title beta-thio-carbonyl compound, C16H16O2S, the carbonyl and meth-oxy O atoms are approximately coplanar [O-C-C-O torsion angle = -18.2 (5) degrees ] and syn to each other, and the tolyl ring is orientated to lie over them. The dihedral angle between the planes of the two rings is 44.03 (16) degrees . In the crystal, supra-molecular chains are formed along the c axis mediated by C-H?O inter-actions involving methine and methyl H atoms as donors, with the carbonyl O atom accepting both bonds; these pack with no specific inter-molecular inter actions between them. PMID- 25705491 TI - Crystal structure of 3-carbamo-thio-yl-pyridinium thio-cyanate. AB - In the cation of the title salt, C6H7N2S(+).SCN(-), the C=S bond is oriented trans with respect to the C-C=N fragment in the pyridine ring. The planes of the aromatic ring and the thio-amide fragment of the cation make a dihedral angle of 38.31 (4) degrees . In the crystal, the components are linked by N-H?S and N-H?N, hydrogen bonds, forming a two-dimensional network parallel to (10-1). PMID- 25705492 TI - Crystal structure of 1,7,8,9-tetra-chloro-4-(2-fluoro-benz-yl)-10,10-dimeth-oxy-4 aza-tri-cyclo-[5.2.1.0(2,6)]dec-8-ene-3,5-dione. AB - In the title compound, C17H12Cl4FNO4, the configuration of the cyclo-alkene skeleton is endo,cis. The benzene ring is twisted by 71.01 (11) degrees from the attached pyrrolidine ring. In the crystal, one of the methine groups of the fused ring system forms a weak C-H?O hydrogen bond. The other methine groups participates in a C-H?F inter-action to the same adjacent mol-ecule. Together, these generate [010] chains. PMID- 25705493 TI - Crystal structure of (E)-2-[4-(4-hy-droxy-phen-yl)butan-2-yl-idene]hydrazine-1 carbo-thio-amide. AB - The title compound, C11H15N3OS, is a thio-semicarbazone derivative of the raspberry ketone rheosmin [systematic name: 4-(4-hy-droxy-phen-yl)butane-2-one]. The mol-ecule deviates from planarity, with the bridging C-C-C=N torsion angle equal to -101.3 (2) degrees . The maximum deviation from the mean plane of the non-H atoms of the thio-semicarbazone fragment [C=N-N-C(= S)-N] is 0.085 (5) A for the Schiff base N atom, and the dihedral angle between this mean plane and the aromatic ring is 50.31 (8) degrees . In the crystal, mol-ecules are linked by N-H?O, N-H?S and O-H?S hydrogen bonds, forming a three-dimensional structure, with the mol-ecules stacked along [011]. PMID- 25705494 TI - Crystal structure of (E)-2-[1-(benzo[d][1,3]dioxol-5-yl)ethyl-idene]-N-methyl hydrazine-1-carbo-thio-amide. AB - In the title compound, C11H13N3O2S, there is a short intra-molecular N-H?N contact. The benzo[d][1,3]dioxole ring system is approximately planar (r.m.s. deviation = 0.025 A) and makes a dihedral angle of 56.83 (6) degrees with the mean plane of the methyl-thio-semicarbazone fragment [-N-N-C(=S)-N-C; maximum deviation = 0.1111 (14) A for the imino N atom]. In the crystal, mol-ecules are linked via pairs of N-H?S hydrogen bonds, forming inversion dimers. The dimers are connected by N-H?S hydrogen bonds into layers parallel to (100). The H atoms of both methyl groups are disordered over two sets of sites and were refined with occupancy ratios of 0.5:0.5 and 0.75:0.25. PMID- 25705495 TI - Crystal structure of O-isopropyl [bis-(tri-methyl-sil-yl)amino](tert-butyl-amino) phosphino-thio-ate. AB - [Bis(tri-methyl-sil-yl)amino](tert-butyl-imino)-thio-phospho-rane reacts in benzene with isopropyl alcohol via 1,2-addition of an (i) PrO-H bond across the P=N bond, resulting in the title compound, C13H35N2OPSSi2. In the mol-ecule, the P atom possesses a distorted tetra-hedral environment involving two N atoms from (Me3Si)2N- and (t) BuNH- groups, one O atom from an (i) PrO group and one S atom, therefore the mol-ecule has a stereocenter on the P atom but crystal symmetry leads to a racemate. In the crystal, a pair of enanti-omers form a centrosymmetric dimer via a pair of N-H?S hydrogen bonds. PMID- 25705496 TI - Crystal structure of 4-chloro-N-[2-(piperidin-1-yl)eth-yl]benzamide monohydrate. AB - In the title compound, C14H19ClN2O2.H2O, the piperdine ring adopts a chair conformation. The dihedral angle between the mean plane of the piperidine ring and that of the phenyl ring is 41.64 (1) degrees . In the crystal, mol-ecules are linked by O-H?N, N-H?O and C-H?O hydrogen bonds involving the water mol-ecule, forming double-stranded chains propagating along [010]. PMID- 25705497 TI - Crystal structure of (2S,4R)-ethyl 4-nitro-methyl-1-[(S)-1-phenyl-eth-yl]-6 sulfanyl-idene-piperidine-2-carboxyl-ate. AB - In the title compound, C17H22N2O4S, a thio-piperidine derivative, the piperidine ring has an envelope conformation with the methyl-ene C atom opposite to the C=S bond as the flap. The nitro-methyl substituent is equatorial while the eth-oxy carbonyl group is axial. The mean planes of the nitro-methyl group, the carb-oxy group and phenyl ring are inclined to the mean plane through the five planar atoms of the piperidine ring [maximum deviation = 0.070 (4) A] by 56.8 (2), 83.8 (5) and 87.1 (2) degrees , respectively. There is an intra-molecular C-H?O hydrogen bond involving an H atom of the eth-oxy-carbonyl group and a nitro O atom. In the crystal, mol-ecules are linked by C-H?O hydrogen bonds, forming chains along [100]. The chains are linked by further C-H?O hydrogen bonds, forming corrugated layers lying parallel to (001). PMID- 25705498 TI - Crystal structure of (E)-4-{1-[2-(car-bamo-thio-yl)hydrazin-1-yl idene]ethyl}phenyl 4-methyl-benzoate. AB - The asymmetric unit of the title compound, C17H17N3O2S, consists of two independent mol-ecules, A and B, with different conformations: in mol-ecule A, the dihedral angles between the central benzene ring and the pendant tolyl and carbamo-thio-ylhydrazono groups are 71.12 (9) and 5.95 (8) degrees , respectively. The corresponding angles in mol-ecule B are 50.56 (12) and 26.43 (11) degrees , respectively. Both mol-ecules feature an intra-molecular N-H?N hydrogen bond, which closes an S(5) ring. In the crystal, mol-ecules are linked by N-H?O, N-H?S and C-H?O hydrogen bonds, generating a three-dimensional network. PMID- 25705499 TI - Crystal structure of N'-[(E)-(4-chloro-phen-yl)(phen-yl)methyl-idene]-4-methyl benzene-sulfono-hydrazide. AB - The title compound, C20H17ClN2O2S, was obtained by a condensation reaction between 4-chloro-benzo-phenone and tosyl hydrazide. The plane of the methyl substituted benzene ring forms dihedral angles of 20.12 (12) and 78.43 (13) degrees with those of the chlorine-substituted benzene ring and the benzene ring, respectively, with the last two rings forming a dihedral angle of 67.81 (13) degrees . The chlorine substituent was also found to be 0.868 (2):0.132 (2) disordered over these two rings. In the crystal, mol-ecules are linked through pairs of N-H?O hydrogen bonds, giving centrosymmetric cyclic dimers [graph set R 2 (2)(8)], which are linked by weak C-H?O and C-H?Cl inter-actions into a chain structure which extends along the a-axis direction. PMID- 25705500 TI - Crystal structure of 2,2-di-chloro-1-(piperidin-1-yl)ethanone. AB - In the title compound, C7H11Cl2NO, the piperidine ring shows a chair conformation and the bond-angle sum at the N atom is 359.9 degrees . The H atom of the di chloro-methyl group is in an eclipsed conformation with respect to the carbonyl group (H-C-C=O = -5 degrees ). In the crystal, inversion dimers are linked by pairs of C-H?O hydrogen bonds between the di-chloro-methyl group and the carbonyl O atom, which generate R 2 (2)(8) loops. The dimers are linked into a ladder-like structure propagating in the [100] direction by short O?Cl [3.1084 (9) A] contacts. PMID- 25705501 TI - Crystal structure of 2-{[(2-chloro-phen-yl)imino]-meth-yl}phenol. AB - In the title compound, C13H10ClNO, the dihedral angle between the planes of the aromatic rings is 51.42 (9) degrees and an intra-molecular O-H?N hydrogen bond closes an S(6) ring. The Cl atom and the N atom are syn. No directional inter actions beyond van der Waals contacts are observed in the crystal. PMID- 25705502 TI - Crystal structure of N (1),N (1)-diethyl-N (4)-[(quinolin-2-yl)methyl idene]benzene-1,4-di-amine. AB - The title compound, C20H21N3, is non-planar with a dihedral angle between the planes of the quinoline and phenyl-enedi-amine rings of 9.40 (4) degrees . In the crystal, mol-ecules are connected by C-H?pi inter-actions, generating a chain extending along the a-axis direction. Weak C-H?pi inter-actions also occur. PMID- 25705503 TI - Crystal structure of cyprodinil. AB - In the title compound, C14H15N3 (systematic name: 4-cyclo-propyl-6-methyl-N phenyl-pyrimidin-2-amine), which is the anilino-pyrimidine fungicide cyprodinil, the dihedral angles between the planes of the central pyrimidine ring and the terminal phenyl ring and the mean plane of the cyclo-propane ring system are 14.52 (11) and 88.79 (10) degrees , respectively. In the crystal, weak pi-pi inter-actions [3.8551 (11) A] connect the dimers into chains along the b-axis direction. PMID- 25705504 TI - 1,1'-{(Hexane-1,6-di-yl)bis-[(aza-niumylyl-idene)methanylyl-idene]}bis (naphthalen-2-olate). AB - The whole molecule of the title Schiff base compound, C28H28N2O2, is generated by inversion symmetry. It is formed from two units of ortho-hy-droxy-naphthaldehyde bridged with 1,6-di-amino-hexane. The N atoms are protonated and, thus, the structure is a bis-zwitterionic compound in the solid state. The zwitterion shows strong intra-molecular N-H?O hydrogen bonds between the iminium N and the naphthaleno-late O atoms. PMID- 25705505 TI - Crystal structure of [(2R,3R,4S)-3,4-bis(acet-yloxy)-5-iodo-3,4-di-hydro-2H-pyran 2-yl]methyl acetate. AB - In the title compound, C12H15IO7, the 3,4-di-hydro-2H-pyran ring is in a distorted half-boat conformation with the atom bearing the acet-yloxy group adjacent to the C atom bearing the methyl-acetate group lying 0.633 (6) A above the plane of the remaining ring atoms (r.m.s. deviation = 0.0907 A). In the crystal, mol-ecules are linked into a supra-molecular chain along the a axis through two C-H?O inter-actions to the same acceptor carbonyl O atom; these chains pack with no specific inter-molecular inter-actions between them. PMID- 25705506 TI - Crystal structure of chlorfluazuron. AB - The title compound (systematic name: 1-{3,5-di-chloro-4-[3-chloro-5-(tri-fluoro meth-yl)pyridin-2-yl-oxy]phen-yl}-3-(2,6-difluoro-benzo-yl)urea), C20H9Cl3F5N3O3, is a benzoyl-phenyl-urea insecticide. The dihedral angles between the planes of the central di-chloro-phenyl and the terminal di-fluoro-phenyl and chloro-pyridyl rings are 79.51 (6) and 78.84 6) degrees , respectively. In the crystal, pairs of N-H?O hydrogen bonds link adjacent mol-ecules, forming R 2 (2)(8) inversion dimers. In addition, the dimers are linked by short F?Cl [3.1060 (16) A] and Cl?Cl [3.2837 (7) A] contacts, as well as weak inter-molecular pi-pi inter actions [ring centroid separation = 3.6100 (11) and 3.7764 (13) A], resulting in a two-dimensional architecture parallel to (111). PMID- 25705507 TI - Crystal structure of N-(propan-2-yl-carbamo-thio-yl)benzamide. AB - In the crystal structure of the title compound, C11H14N2OS, the six atoms of the central C2N2OS residue are coplanar (r.m.s. deviation = 0.002 A), which facilitates the formation of an intra-molecular N-H?O hydrogen bond, which closes an S(6) loop. The terminal phenyl ring is inclined with respect to the central plane [dihedral angle = 42.10 (6) degrees ]. The most prominent feature of the crystal packing is the formation of {?HNCS}2 synthons resulting in centrosymmetric dimers. PMID- 25705508 TI - Crystal structure of 5-[bis-(methyl-sulfon-yl)meth-yl]-1,3-dimethyl-5-(methyl sulfon-yl)pyrimidine-2,4,6(1H,3H,5H)-trione. AB - In the title compound, C10H16N2O9S3, the pyrimidine ring of the 1,3-dimethyl barbituric acid moiety has an envelope conformation with the C atom carrying the methyl-sulfonyl and bis-(methyl-sulfon-yl)methyl substituents as the flap. The dihedral angle between mean plane of the pyrimidine ring and the S/C/S plane is 72.4 (3) degrees . In the crystal, mol-ecules are linked via C-H?O hydrogen bonds, forming a three-dimensional structure. PMID- 25705509 TI - Crystal structure of 2-(1,3-dioxoindan-2-yl)iso-quinoline-1,3,4-trione. AB - In the title iso-quinoline-1,3,4-trione derivative, C18H9NO5, the five-membered ring of the indane fragment adopts an envelope conformation with the nitro-gen substituted C atom being the flap. The planes of the indane benzene ring and the iso-quinoline-1,3,4-trione ring make a dihedral angle of 82.06 (6) degrees . In the crystal, mol-ecules are linked into chains extending along the bc plane via C H?O hydrogen-bonding inter-actions, enclosing R 2 (2)(8) and R 2 (2)(10) loops. The chains are further connected by pi-pi stacking inter-ations, with centroid-to centroid distances of 3.9050 (7) A, forming layers parallel to the b axis. PMID- 25705510 TI - Crystal structure of 1-(2,4-di-methyl-phen-yl)urea. AB - In the title urea derivative, C9H12N2O, the dihedral angle between the benzene ring and the mean plane of the urea group, N-C(=O)-N, is 86.6 (1) degrees . In the crystal, the urea O atom is involved in three N-H?O hydrogen bonds. Mol ecules are linked via pairs of N-H?O hydrogen bonds, forming inversion dimers with an R (2) 2(8) ring motif. The dimers are linked by further N-H?O hydrogen bonds, forming two-dimensional networks lying parallel to (100). PMID- 25705511 TI - Crystal structure of cyclo-hexyl-ammonium thio-cyanate. AB - In the title salt, C6H11NH3 (+).SCN(-), the cyclo-hexyl-ammonium ring adopts a slightly distorted chair conformation. The ammonium group occupies an equatorial position to minimize 1,3 and 1,5 diaxial inter-actions. In the crystal, the components are linked by N-H?N and N-H?S hydrogen-bonding inter-actions, resulting in a three-dimensional network. PMID- 25705512 TI - Crystal structure of (Z)-1-phenyl-3-styryl-undeca-2-en-4,10-diyn-1-ol. AB - The mol-ecule of the title compound, C25H24O, obtained by acid-catalysed 1,3 migration of an alcohol group, is T-shaped. The planes of the two phenyl rings are inclined to one another by 81.9 (2) degrees . In the crystal, mol-ecules are linked by O-H?O hydrogen bonds, forming chains along [001]. PMID- 25705513 TI - Crystal structure of (E)-1-(4'-methyl-[1,1'-biphen-yl]-4-yl)-3-(3-nitro-phen yl)prop-2-en-1-one. AB - In the title compound, C22H17NO3, the mol-ecule has an E conformation about the C=C bond, and the C-C=C-C torsion angle is -177.7 (3) degrees . The planes of the terminal benzene rings are twisted by 41.62 (16) degrees , while the biphenyl unit is non-planar, the dihedral angle between the planes of the rings being 38.02 (15) degrees . The dihedral angle between the nitro-phenyl ring and the inner benzene ring is 5.29 (16) degrees . In the crystal, mol-ecules are linked by two weak C-H?pi inter-actions, forming rectangular tubes propagating along the b-axis direction. PMID- 25705514 TI - Crystal structure of 3-(4-chloro-phen-oxy)-4-(2-nitro-phen-yl)azetidin-2-one with an unknown solvate. AB - In the title compound, C15H11ClN2O4, the central beta-lactam ring is approximately planar [maximum deviation = 0.044 (2) A for the N atom from the mean plane] and subtends dihedral angles of 61.17 (11) and 40.21 (12) degrees , respectively, with the nitro and chloro-benzene rings. Both substituents lie to the same side of the beta-lactam core. In the crystal, N-H?O hydrogen bonds link the mol-ecules into C(4) chains propagating in [010]. The chains are cross-linked by C-H?O and weak C-H?pi inter-actions, generating a three-dimensional network. The solvent mol-ecules were found to be highly disordered and their contribution to the scattering was removed with the SQUEEZE procedure in PLATON [Spek (2009 ?). Acta Cryst. D65, 148-155], which indicated a solvent cavity of volume 318 A(3) containing approximately 114 electrons. These solvent mol-ecules are not considered in the given chemical formula and other crystal data. PMID- 25705515 TI - Addressing the Inflammatory Response to Clinically Relevant Polymers by Manipulating the Host Response Using ITIM Domain-Containing Receptors. AB - Tissue contacting surfaces of medical devices initiate a host inflammatory response, characterized by adsorption of blood proteins and inflammatory cells triggering the release of cytokines, reactive oxygen species (ROS) and reactive nitrogen species (RNS), in an attempt to clear or isolate the foreign object from the body. This normal host response contributes to device-associated pathophysiology and addressing device biocompatibility remains an unmet need. Although widespread attempts have been made to render the device surfaces unreactive, the establishment of a completely bioinert coating has been untenable and demonstrates the need to develop strategies based upon the molecular mechanisms that define the interaction between host cells and synthetic surfaces. In this review, we discuss a family of transmembrane receptors, known as immunoreceptor tyrosine-based inhibitory motif (ITIM)-containing receptors, which show promise as potential targets to address aberrant biocompatibility. These receptors repress the immune response and ensure that the intensity of an immune response is appropriate for the stimuli. Particular emphasis will be placed on the known ITIM-containing receptor, Signal Regulatory Protein Alpha (SIRPhalpha), and its cognate ligand CD47. In addition, this review will discuss the potential of other ITIM-containing proteins as targets for addressing the aberrant biocompatibility of polymeric biomaterials. PMID- 25705516 TI - Postoperative pulmonary dysfunction and mechanical ventilation in cardiac surgery. AB - Postoperative pulmonary dysfunction (PPD) is a frequent and significant complication after cardiac surgery. It contributes to morbidity and mortality and increases hospitalization stay and its associated costs. Its pathogenesis is not clear but it seems to be related to the development of a systemic inflammatory response with a subsequent pulmonary inflammation. Many factors have been described to contribute to this inflammatory response, including surgical procedure with sternotomy incision, effects of general anesthesia, topical cooling, and extracorporeal circulation (ECC) and mechanical ventilation (VM). Protective ventilation strategies can reduce the incidence of atelectasis (which still remains one of the principal causes of PDD) and pulmonary infections in surgical patients. In this way, the open lung approach (OLA), a protective ventilation strategy, has demonstrated attenuating the inflammatory response and improving gas exchange parameters and postoperative pulmonary functions with a better residual functional capacity (FRC) when compared with a conventional ventilatory strategy. Additionally, maintaining low frequency ventilation during ECC was shown to decrease the incidence of PDD after cardiac surgery, preserving lung function. PMID- 25705517 TI - Australian Nurse Practitioner Practice: Value Adding through Clinical Reflexivity. AB - The role of the Australian Nurse Practitioner (NP) is in its infancy and at a crossroads where extensive research demonstrates effective quality care and yet the role remains underrecognised and underutilised. The translation of practice into "value" is critical for the sustainability of NP roles and requires the practitioner to adopt a systematic method of inquiry. Kim's (1999) "Critical Reflective Inquiry" (CRI) method was adapted by two Australian NPs who specialise in diabetes and chronic disease management. Kim highlights the intent of CRI as understanding the meaning of practice, delivering improvements to practice through self-reflection, and the critique of practice that can lead to practice changes and development of new models of care translated to "products" of value. Based on the thematically analysis of 3 years of CRI application, the authors formed 5 headings that represented the NP's practice as Specialised Care Access, Complications and Diagnostics Interventions, Pharmaceutical Treatment, Vulnerable Populations, and Leadership. The utility of CRI demonstrates how NP practice is integral to a continuous cycle of addressing health care services gaps, and the conversion of "products" into "value" and positions the NP to assimilate the role of the practitioner-researcher. PMID- 25705518 TI - Deletion of ovarian hormones induces a sickness behavior in rats comparable to the effect of lipopolysaccharide. AB - Neuroimmune factors have been proposed as the contributors to the pathogenesis of sickness behaviors. The effects of female gonadal hormones on both neuroinflammation and depression have also been well considered. In the present study, the capability of deletion of ovarian hormones to induce sickness-like behaviors in rats was compared with the effect lipopolysaccharide (LPS). The groups were including Sham, OVX, Sham-LPS, and OVX-LPS. The Sham-LPS and OVX-LPS groups were treated with LPS (250 MUg/kg) two hours before conducting the behavioral tests. In the forced swimming (FST), the immobility times in both OVX and Sham-LPS groups were higher than that of Sham (P < 0.001). In open-field (OP) test, the central crossing number by OVX and Sham-LPS groups were lower than Sham (P < 0.001) while there were no significant differences between OVX-LPS and OVX groups. In elevated plus maze (EPM), the percent of entries to the open arm by both OVX and Sham-LPS groups was lower than that of Sham group (P < 0.001). The results of present study showed that deletion of ovarian hormones induced sickness behaviors in rats which were comparable to the effects of LPS. Moreover, further investigations are required in order to better understand the mechanism(s) involved. PMID- 25705519 TI - Contralateral occlusion increases the risk of neurological complications associated with carotid endarterectomy. AB - Objective. To report on the incidence and factors associated with the development of perioperative neurological complications following CEA in patients affected by carotid stenosis with contralateral occlusion (CO) and to compare results between those patients and the whole group of patients submitted to CEA at our vascular division from 1997 to 2012. Methods. Our nonrandomized prospective experience including 1639 patients consecutively submitted to CEA was retrospectively reviewed. 136 patients presented a CO contralateral to the treated carotid stenosis. Outcomes considered for analysis were perioperative neurological death rates, major and minor stroke rates, and a combined endpoint of all neurological complications. Results. CO patients more frequently were male, smokers, younger, and symptomatic (P < 0.001), presented with a preoperative brain infarct and associated peripheral arterial disease (P < 0.0001), and presented with higher perioperative major stroke rate than patients without CO (4.4% versus 1.2%, resp., P = 0.009). Factors associated with the highest neurological risk in CO patients were age >74 years and preoperative brain infarct (P = 0.03). The combination of the abovementioned factors significantly increased complication rates in CO patients submitted to CEA. Conclusions. In our experience CO patients were at high risk for postoperative neurological complications particularly when presenting association of advanced age and preoperative brain infarction. PMID- 25705520 TI - Factors Affecting the Occurrence of Out-of-Hospital Sudden Cardiac Arrest. AB - Objective. This paper aims to discover the risk factors for sudden cardiac arrest (out-of-hospital sudden cardiac arrest (OHSCA)) which significantly affect the decision about prioritizing emergency interventions before dispatching medical emergency teams, risk of deterioration of the patient's condition at the scene, and emergency procedures. Methods. A retrospective study taking into account the international classification of diseases ICD-10 based on an analysis of medical records of Emergency Medical Service in Wroclaw (Poland). Results. The main risk factor of OHSCA is coexistence of external cause leading to illness or death (ICD Group V-10) as well as the occurrence of diseases from the group of endocrine disorders (group E), in particular diabetes. The increase in the risk of OHSCA incidence is affected by nervous system diseases (group G), especially epilepsy of various etiologies, respiratory diseases (group J), mainly COPD, and bronchial asthma or mental and behavioral disorders (group F), with particular emphasis on the drugs issue. The procedure for receiving calls for Emergency Notification Centre does not take into account clinical risk factors for sudden cardiac arrest (SCA). Conclusion. Having knowledge of OHSCA risk factors can increase the efficiency of rescue operations from rapid assessment and provision of appropriate medical team, through effective performance of medical emergency treatment and prevention of SCA or finally reducing the costs. PMID- 25705521 TI - Low infection rate after tumor hip arthroplasty for metastatic bone disease in a cohort treated with extended antibiotic prophylaxis. AB - Background. Compared to conventional hip arthroplasty, endoprosthetic reconstruction after tumor resection is associated with a substantially increased risk of periprosthetic joint infection (PJI), with reported rates of around 10% in a recent systematic review. The optimal duration of antibiotic prophylaxis for this patient population remains unknown. Material and Methods. To establish the infection rate associated with prolonged antibiotic prophylaxis in our department, we performed a retrospective review of all adult patients who underwent endoprosthetic reconstruction of the proximal femur after tumor resection for metastatic bone disease during a 4-year period from 2010 to 2013 (n = 105 patients). Results. Intravenous antibiotic prophylaxis was administrated for an extended duration of a mean of 7.4 days. The overall infection rate was 3.6% (4/111 implants), infection free survival was 96% at 2 years, and the risk of amputation associated with infection was 25% (1/4 patients). Discussion. Preemptive eradication of bacterial contamination may be of value in certain clinical situations, where the risk level and consequences of implant-associated infection are unacceptable. Our findings suggest that extended postoperative antibiotic prophylaxis may reduce the risk of PJI in patients undergoing tumor resection and endoprosthetic replacement for metastatic bone disease associated impending or de facto pathologic fractures of the proximal femur. PMID- 25705522 TI - Osteoid osteoma treated with radiofrequency ablation. AB - Purpose. Our aim is to evaluate the results of treatment with computed tomography (CT) guided percutaneous radiofrequency ablation for osteoid osteomas which were localized in a difficult area for operation. Materials and Methods. Glenoid, distal tibia, humerus shaft, proximal humerus, and in third finger of the hand proximal phalanx were involved in one patient. Proximal femur was involved in three patients, distal femur was involved in three patients, and proximal tibia was involved in two patients. 9 males and 4 females were aged 4 to 34 years (mean age: 18.5 years). All patients had pain and were evaluated with X-rays, CT, bone scintigraphy, and MRI. In all patients, RF ablation was performed with local anesthesia. The lesion heated to 90 degrees C for 6 minutes. Results. All of the patients achieved complete pain relief after ablation and were fully weight bearing without any support. In all patients, there was soft tissue edema after the procedure. During follow-up, all patients were free from the pain and there was no sign about the tumor. There was no other complication after the process. Conclusion. CT guided RFA is a minimally invasive, safe, and cost-effective treatment for osteoid osteoma placed in difficult area for surgery. PMID- 25705523 TI - Cerebral abscess potentially of odontogenic origin. AB - Odontogenic origins are rarely implicated in the formation of brain abscesses. The relative paucity of this kind of infection and the difficulty in matching the causative microorganisms of a brain abscess to an odontogenic source can explain the late management of patients. We herein describe a case of a 46-year-old man with a cerebellar abscess that was probably due to an odontogenic infection. The diagnosis supported by imaging and microscopic identification, mini craniectomy for abscess drainage followed by eradication of all potential dental infectious foci, and an antibiotic regimen based on cephalosporins, metronidazole, and vancomycine contributed to a successful outcome. PMID- 25705524 TI - Removal of an upper third molar from the maxillary sinus. AB - The maxillary sinus or antrum is the largest of the paranasal sinuses. It is located in the maxillary bone and has a proximity to the apexes of upper molars and premolars, which allows it to form a direct link between the sinus and the oral cavity. Dislocation of a foreign body or tooth to the interior of a paranasal sinus is a situation that can occur as a result of car accidents, firearm attacks, or iatrogenic in surgical procedures. Therefore, it is necessary to know how to treat this kind of situation. This study's objective is to report the case of a 23-year-old female patient, leucoderma, who sought treatment from the Surgical Unit at the Dental Faculty of the Federal University of Sergipe. She had a history of pain and edema in the right side of the genian region and two failed attempts at removing dental unit (DU) 18. The extraoral clinical exam revealed intense edema of the left hemiface with signs of infection, excoriation of the labial commissure, hematoma, a body temperature of 39 degrees C, and a limited ability to open her mouth. The patient was medicated and treated surgically. The tooth was removed from the maxillary sinus with caution, as should have been done initially. PMID- 25705525 TI - The importance of the lifelike esthetic appearance of all-ceramic restorations on anterior teeth. AB - The success of rehabilitation will not depend on just clinical procedures. A proper dental technique (ceramist) is required as well as the respect for some biomimetic principles to obtain the desired final result. This study has the purpose of describing a prosthetic rehabilitation with laminate veneers and all ceramic crowns of a patient unsatisfied with a previous esthetic treatment because of the negligence of some biomimetic principles. A 45-year-old female patient was admitted to the dental clinic complaining about the lifelike appearance of her all-ceramic restorations. Before the fabrication of new restorations, a mock-up was conducted to verify the patient's satisfaction. A ceramist conducted all the fabrication process so that surface characterizations could be visually verified and the lifelike appearance of natural tooth could be reproduced. After the cementation procedure, the patient reported being satisfied with the lifelike appearance of the new restorations. Based on the clinical findings of the present case report, it can be concluded that the reproduction of the lifelike esthetic appearance of natural teeth and the visualization of the final results before definitive procedures are essential to obtain the clinical success. PMID- 25705526 TI - Aesthetic and functional rehabilitation of the primary dentition affected by amelogenesis imperfecta. AB - The objective of this case report was to describe the oral rehabilitation of a five-year-old boy patient diagnosed with amelogenesis imperfecta (AI) in the primary dentition. AI is a group of hereditary disorders that affects the enamel structure. The patient was brought to the dental clinic complaining of tooth hypersensitivity during meals. The medical history and clinical examination were used to arrive at the diagnosis of AI. The treatment was oral rehabilitation of the primary molars with stainless steel crowns and resin-filled celluloid forms. The main objectives of the selected treatment were to enhance the esthetics, restore masticatory function, and eliminate the teeth sensitivity. The child was monitored in the pediatric dentistry clinic at four-month intervals until the mixed dentition stage. Treatment not only restored function and esthetic, but also showed a positive psychological impact and thereby improved perceived quality of life. The preventive, psychological, and curative measures of a young child with AI were successful. This result can encourage the clinicians to seek a cost-effective technique such as stainless steel crowns, and resin-filled celluloid forms to reestablish the oral functions and improve the child's psychosocial development. PMID- 25705527 TI - A Novel SMAD4 Mutation Causing Severe Juvenile Polyposis Syndrome with Protein Losing Enteropathy, Immunodeficiency, and Hereditary Haemorrhagic Telangiectasia. AB - Juvenile polyposis syndrome (JPS) is a rare genetic disorder characterized by juvenile polyps of the gastrointestinal tract. We present a new pathogenic mutation of the SMAD4 gene and illustrate the need for a multidisciplinary health care approach to facilitate the correct diagnosis. The patient, a 47-year-old Caucasian woman, was diagnosed with anaemia at the age of 12. During the following 30 years, she developed numerous gastrointestinal polyps. The patient underwent several operations, and suffered chronic abdominal pain, malnutrition, and multiple infections. Screening of the SMAD4 gene revealed a novel, disease causing mutation. In 2012, the patient suffered hypoalbuminemia and a large polyp in the small bowel was found. Gamma globulin was given but the patient responded with fever and influenza-like symptoms and refused more treatment. The patient underwent surgery in 2014 and made an uneventful recovery. At follow-up two months later albumin was 38 g/L and IgG was 6.9 g/L. Accurate diagnosis is essential for medical care. For patients with complex symptomatology, often with rare diseases, this is best provided by multidisciplinary teams including representatives from clinical genetics. Patients with a SMAD4 mutation should be followed up both for JPS and haemorrhagic hereditary telangiectasia and may develop protein loosing enteropathy and immunodeficiency. PMID- 25705528 TI - Littoral cell angioma in a patient with Crohn's disease. AB - Littoral cell angioma is a rare vascular tumor of the spleen. The pathogenesis is unknown but the lesion is associated with several malignancies and immunological disorders. The diagnosis requires histopathological examination. The malignant potential of this lesion is unknown, which is why splenectomy is recommend for all cases. Symptomatic cases generally suffer from hypersplenism and pyrexia. A previously healthy 20-year-old female was diagnosed with colonic Crohn's disease; as part of the work-up a magnetic resonance enterography was performed which showed multiple signal changes of the spleen. The patient reported chronic abdominal pain in the left upper quadrant, malaise, and fever. The unknown splenic lesions prompted a laparoscopic splenectomy; pathology revealed a littoral cell angioma. The abdominal pain and malaise remitted but the fever persisted one year despite adequate treatment of the patient's Crohn's disease. Littoral cell angioma is associated with immune-dysregulation including Crohn's disease with several reported cases. Signs and symptoms of hypersplenism and splenic lesions on imaging should raise suspicion of littoral cell angioma in patients with Crohn's disease. Magnetic resonance enterography to assess disease severity in Crohn's disease may provide an opportunity to study the prevalence and natural history of this rare splenic tumor. PMID- 25705529 TI - Deciphering autoimmune pancreatitis, a great mimicker: case report and review of the literature. AB - Background. Autoimmune pancreatitis (AIP) is an atypical chronic inflammatory pancreatic disease that appears to involve autoimmune mechanisms. In recent years, AIP has presented as a new clinical entity with its protean pancreaticobiliary and systemic presentations. Its unique pathology and overlap of clinical and radiological features and absence of serological markers foster the disease's unique position. We report a case of diffuse type 1 autoimmune pancreatitis with obstructive jaundice managed with biliary sphincterotomy, stent placement, and corticosteroids. A 50-year-old Caucasian woman presented to our hospital with epigastric pain, nausea, vomiting, and jaundice. Workup showed elevated liver function tests (LFT) suggestive of obstructive jaundice, MRCP done showed diffusely enlarged abnormal appearing pancreas with loss of normal lobulated contours, and IgG4 antibody level was 765 mg/dL. EUS revealed a diffusely hypoechoic and rounded pancreatic parenchyma with distal common bile duct (CBD) stricture and dilated proximal CBD and common hepatic duct (CHD). ERCP showed tight mid to distal CBD stricture that needed dilatation, sphincterotomy, and placement of stent that led to significant improvement in the symptoms and bilirubin level. Based on clinical, radiological, and immunological findings, a definitive diagnosis of AIP was made. Patient was started on prednisone 40 mg/day and she clinically responded in 4 weeks. PMID- 25705530 TI - Renal and neurological response with eculizumab in a patient with transplant associated thrombotic microangiopathy after allogeneic hematopoietic progenitor cell transplantation. AB - Transplantation-associated thrombotic microangiopathy (TA-TMA) is a challenge after allogeneic hematopoietic progenitor cell transplantation, considering the diagnostic uncertainties and lack of established treatment. We report a 43-year old male patient who was diagnosed as TA-TMA after allogeneic progenitor cell transplantation for a progressive ALK negative anaplastic large cell lymphoma and responded to eculizumab with dramatically improving neurological status and renal function. Rapid neurological and renal recovery achieved after eculizumab could support a possible relationship between complement activation and TA-TMA. Eculizumab should be a reasonable treatment approach in patients with TA-TMA after allogeneic hematopoietic progenitor cell transplantation. PMID- 25705531 TI - Late Occurrence of PML in a Patient Treated for Lymphoma with Immunomodulatory Chemotherapies, Bendamustine, Rituximab, and Ibritumomab Tiuxetan. AB - PML caused by John Cunningham (JC) virus is a rare but an increasingly recognized entity. With the advent of newer immunomodulatory therapies with monoclonal antibodies, there is an increasing incidence of PML. Initially concern was restricted to patients treated for multiple sclerosis with natalizumab but more case reports are being reported during treatment for other conditions like Crohn's disease and lymphoma with agents such as rituximab. We report the case of a 66-year-old woman who developed PML a year after completion of therapy with rituximab, ibritumomab, and bendamustine. PMID- 25705532 TI - Pregnancy after uterine artery embolization: a case report in a woman with leiomyomata. AB - Background. Several pregnancies have been reported after embolization of uterine artery. This procedure is an accepted nonsurgical treatment for symptomatic uterine fibroids but its safety in women desiring future childbearing is not well established. Case Report. We present a 40-year-old woman with leiomyomata who became pregnant after previously undergone uterine artery embolization for three times. The placenta was previa and the fetus was in transverse position. She had a cesarean delivery of an appropriately grown fetus at 37 weeks, which was followed by uterine atony requiring hysterectomy. Conclusion. Although pregnancy related outcomes remain understudied, the available reports evidence that pregnancies after uterine artery embolization may be at significantly increased risk for postpartum hemorrhage, cesarean delivery, abnormal placentation, and malpresentation. In patients who are undergoing this type of treatment and contemplating pregnancy, the possibility of adverse complications should be taken in consideration and women should be appropriately advised. PMID- 25705533 TI - A suspicious pancreatic mass in chronic pancreatitis: pancreatic actinomycosis. AB - Introduction. Pancreatic actinomycosis is a chronic infection of the pancreas caused by the suppurative Gram-positive bacterium Actinomyces. It has mostly been described in patients following repeated main pancreatic duct stenting in the context of chronic pancreatitis or following pancreatic surgery. This type of pancreatitis is often erroneously interpreted as pancreatic malignancy due to the specific invasive characteristics of Actinomyces. Case. A 64-year-old male with a history of chronic pancreatitis and repeated main pancreatic duct stenting presented with weight loss, fever, night sweats, and abdominal pain. CT imaging revealed a mass in the pancreatic tail, invading the surrounding tissue and resulting in splenic vein thrombosis. Resectable pancreatic cancer was suspected, and pancreatic tail resection was performed. Postoperative findings revealed pancreatic actinomycosis instead of neoplasia. Conclusion. Pancreatic actinomycosis is a rare type of infectious pancreatitis that should be included in the differential diagnosis when a pancreatic mass is discovered in a patient with chronic pancreatitis and prior main pancreatic duct stenting. Our case emphasizes the importance of pursuing a histomorphological confirmation. PMID- 25705534 TI - Primitive neuroectodermal tumor/ewing sarcoma presenting with pulmonary nodular lesions. AB - Primitive neuroectodermal tumors (PNETs) and Ewing sarcoma (EWS) belong to the same family of malignant, small, round cell neoplasms of soft tissue or bone origin. EWS-PNETs that arise in the lung parenchyma involvement are extremely rare in adults. A case of a 32-year-old male presenting with chest pain and diffuse pulmonary nodules on chest X-ray and diagnosed with Ewing sarcoma-PNETs will be presented here. PMID- 25705535 TI - Optic nerve vascular compression in a patient with a tuberculum sellae meningioma. AB - Background. Optic nerve vascular compression in patients with suprasellar tumor is a known entity but is rarely described in the literature. Case Description. We present a unique, well-documented case of optic nerve strangulation by the A1 segment of the anterior cerebral artery in a patient with a tuberculum sellae meningioma. The patient presented with pronounced progressive visual deterioration. Following surgery, there was immediate resolution of her visual deficit. Conclusion. Vascular strangulation of the optic nerve should be considered when facing progressive and/or severe visual field deterioration in patients with tumors proximal to the optic apparatus. PMID- 25705536 TI - Unilateral Optic Neuropathy and Acute Angle-Closure Glaucoma following Snake Envenomation. AB - Purpose. We aimed to describe a unique case in which a patient developed unilateral optic neuritis and angle-closure glaucoma as a result of snake envenomation. Case Report. Approximately 18 hours after envenomation, a 67-year old female patient described visual impairment and severe pain in her left eye (LE). The patient's best corrected visual acuity was 10/10 in the RE and hand motion in the LE. Cranial magnetic resonance imaging showed signs of neuropathy in the left optic nerve. In the LE, corneal haziness, closure of the iridocorneal angle, and mild mydriasis were observed and pupillary light reflex was absent. Intraocular pressure was 25 mmHg and 57 mmHg in the RE and LE, respectively. The patient was diagnosed with acute angle-closure glaucoma in the LE. Optic neuropathy was treated with intravenous pulse methylprednisolone. Left intraocular pressure was within normal range starting on the fourth day. One month after the incident, there was no sign of optic neuropathy; relative afferent pupillary defect and optic nerve swelling disappeared. Conclusions. Patients with severe headache and visual loss after snake envenomation must be carefully examined for possible optic neuropathy and angle-closure glaucoma. Early diagnosis and treatment of these cases are necessary to prevent permanent damage to optic nerves. PMID- 25705537 TI - Severe IgG4-Related Disease in a Young Child: A Diagnosis Challenge. AB - Immunoglobulin G4-related disease (IgG4-RD) is an increasingly recognized syndrome that can appear with multiple organ involvement, typically with tumor like swelling, lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells, and elevated serum IgG4 concentrations. We report the case of a 22-month-old female child with failure to thrive and recurrent respiratory tract infections since 8 months of age. Physical examination was normal except for pulmonary auscultation with bilateral crackles and wheezes. Laboratory tests revealed elevated erythrocyte sedimentation rate, and elevated serum IgG and IgG4 with polyclonal hypergammaglobulinemia. Thoracic CT and MRI showed multiple mediastinal lymphadenopathies and a nodular posterior mediastinal mass in right paratracheal location with bronchial compression. Initial fine needle aspiration biopsy was compatible with reactive lymphadenopathy but after clinical worsening a thoracoscopic partial resection of the mass was performed and tissue biopsy revealed lymphoplasmacytic infiltrate and increased number of IgG4-positive plasma cells and a ratio of IgG4/IgG positive cells above 40%. Glucocorticoids therapy was started with symptomatic improvement, reduction in the size of the mass, and decrease of serum IgG4 levels after 6 weeks. There are very few reports of IgG4-RD in children. Long-term follow-up is necessary to monitor relapses and additional organ involvement. PMID- 25705538 TI - Organizing Pneumonia Associated with Pegylated Interferon alpha and Ribavirin Therapy. AB - Hepatitis C virus infection is the leading cause of chronic liver disease in the United States of America. Pegylated interferon alpha and ribavirin combination is the mainstay of treatment. Severe pulmonary toxicities are rarely reported. We report here a case of severe form of organizing pneumonia secondary to pegylated interferon alpha therapy presenting as acute respiratory failure. Patient has near complete recovery with withdrawal of pegylated interferon alpha and steroid therapy. We report this case to raise the awareness of this rare but potentially life-threatening pulmonary complication of pegylated interferon alpha therapy. PMID- 25705539 TI - Carcinosarcoma of the thyroid gland. AB - Introduction. Surgeon has significant role in the management of such rare and controversial clinical entities related to thyroid gland. In this case report we have presented an elderly patient with rapid enlargement in thyroid that was related to carcinosarcoma. Case Presentation. A 60-year-old lady was presented with rapid enlargement of the thyroid gland. A fine needle aspiration of the nodule in right lobe was performed several weeks before presentation to our clinic. End diagnosis was a papillary carcinoma of the thyroid with spindle cell component. Thus the nodule was recognized to be a carcinosarcoma. Conclusion. Thyroid surgery merits a multidisciplinary approach. Indeed the surgeon should make a conclusive decision in some controversial and rare clinical entities such as carcinosarcoma. PMID- 25705540 TI - Photodocumentation of the development of type I posterior glottic stenosis after intubation injury. AB - Bilateral vocal fold immobility may result from bilateral recurrent laryngeal nerve paralysis or physiologic insults to the airway such as glottic scars. The progression of mucosal injury to granulation tissue, and then posterior glottis stenosis, is an accepted theory but has not been photodocumented. This paper presents serial images from common postintubation injury to less common posterior glottic stenosis with interarytenoid synechia. PMID- 25705541 TI - Management of Metachronous Bilateral Testis Cancer in a Patient with Pre-B Cell ALL. AB - We present a patient with a metachronous, second testicular cancer after being diagnosed with pre-B cell ALL and receiving induction chemotherapy for a bone marrow transplant. We discuss the management of bilateral testis masses in a young patient with a hematologic malignancy as well as the role of immunosuppressive chemotherapy in developing a second cancer. This case illustrates the importance of recognizing bilateral testicular cancer early, as well as the importance of follow-up care in oncology patients including routine measurements of tumor markers. A multidisciplinary approach between medical oncology and urology, including close monitoring of the contralateral testis, remains paramount to patient care. PMID- 25705542 TI - Seminoma presenting as renal mass, inferior vena caval thrombus, and regressed testicular mass. AB - Testicular cancer is the most common malignancy of men aged 15-40. Metastatic spread classically begins with involvement of the retroperitoneal lymph nodes, with metastases to the liver, lung, bone, and brain representing advancing disease. Treatment is based on pathologic analysis of the excised testicle and presence of elevated tumor markers. We report a case of a 34-year-old male presenting with back pain who was found to have a right renal mass with tumor extension into the inferior vena cava. Subsequent biopsy was consistent with seminoma. We review this rare case and discuss the literature regarding its diagnosis and management. PMID- 25705543 TI - Giant Pseudoaneurysm Associated with Arteriovenous Fistula of the Brachial and Femoral Arteries following Gunshot Wounds: Report of Two Cases. AB - Posttraumatic pseudoaneurysm associated with arteriovenous fistula of the upper or lower limb is exceptional. We are reporting herein the history of two cases in civil life that have been followed and repaired in our service. Both patients were shot more than a year before being referred to our tertiary hospital for an enlarging mass which was a pseudoaneurysm associated with an arteriovenous fistula. The aneurysm was repaired and the fistula closed. Due to the absence of well-trained professionals, vascular injuries and their complications are usually discovered late in Cameroon while these pseudoaneurysms can reach very dramatic sizes. This presentation intends to raise the attention on a careful clinical exam and search of vascular lesion in the case of penetrating wound of the limb associated with profuse bleeding. PMID- 25705544 TI - Among Ectasia Patients with Coexisting Coronary Artery Disease, TIMI Frame Count Correlates with Ectasia Size and Markis Type IV Is the Commonest. AB - Background. Coronary artery ectasia (CAE) occurs in 0.3 to 5.3% of patients undergoing coronary angiography. TIMI frame count (TFC) is an index of coronary flow that correlates with flow velocity. In ectasia patients, there is delayed coronary flow with increased TFC. Methods. We evaluated angiograms of 789 patients for presence of CAE, coronary artery disease (CAD), and Markis type of CAE. We measured ectasia size and length and their correlation with TFC in ectatic right coronary arteries (RCA) of patients with CAE and CAD. Results. 30 patients had CAE (3.8%). Of these 16.7% had isolated CAE, while 83.87% had CAE and CAD. Among CAE and CAD patients, the RCA was most involved (70.4%), and Markis type IV CAE was the commonest (64%). In isolated CAE, the RCA, LAD, and LCx were equally involved (33.3%). Patients with CAE and CAD had significantly higher TFC compared to controls, P = 0.035. There was a positive correlation of moderate strength, between ectasia size and TFC, r(17) = 0.598, P = 0.007. Ectasia length was not significantly correlated with TFC, rho (17) = 0.334, P = 0.163. Conclusion. Among patients undergoing angiography, CAE has a prevalence of 3.8% and Markis type IV is the commonest. Larger ectasias are associated with slower coronary flow. PMID- 25705545 TI - Personality changes after deep brain stimulation in Parkinson's disease. AB - Objectives. Deep brain stimulation of the subthalamic nucleus (STN-DBS) is a recognized therapy that improves motor symptoms in advanced Parkinson's disease (PD). However, little is known about its impact on personality. To address this topic, we have assessed personality traits before and after STN-DBS in PD patients. Methods. Forty patients with advanced PD were assessed with the Temperament and Character Inventory (TCI): the Urgency, Premeditation, Perseverance, Sensation Seeking impulsive behaviour scale (UPPS), and the Neuroticism and Lie subscales of the Eysenck Personality Questionnaire (EPQ-N, EPQ-L) before surgery and after three months of STN-DBS. Collateral information obtained from the UPPS was also reported. Results. Despite improvement in motor function and reduction in dopaminergic dosage patients reported lower score on the TCI Persistence and Self-Transcendence scales, after three months of STN-DBS, compared to baseline (P = 0.006; P = 0.024). Relatives reported significantly increased scores on the UPPS Lack of Premeditation scale at follow-up (P = 0.027). Conclusion. STN-DBS in PD patients is associated with personality changes in the direction of increased impulsivity. PMID- 25705546 TI - German translation and validation of the "freezing of gait questionnaire" in patients with Parkinson's disease. AB - Background. Freezing of Gait (FOG) is a disabling parkinsonian symptom. The Freezing of Gait Questionnaire (FOG-Q) reliably detects FOG in patients with Parkinson's disease (PD). Objectives. The aim of this study was to develop a German translated version of the FOG-Q and to assess its validity. Methods. The translation was accomplished using forward-backward-translation. The construct validity of the FOG-Q was examined in twenty-seven German native speaking PD patients. Convergent validity was assessed by correlating the FOG-Q with the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) II III, the Parkinson Disease Questionnaire 39 (PDQ-39), and the Timed Up and Go Test (TUG). Divergent validity was assessed by correlating the FOG-Q with the MDS UPDRS I. The internal consistency was measured using Cronbach's alpha (Calpha). Results. A good internal structure of the FOG-Q was found (Calpha = 0.83). Significant moderate correlations between the FOG-Q and the MDS-UPDRS item 2.13 (freezing) (r s = 0.568, P = 0.002) and between the FOG-Q and the PDQ-39 subscale mobility (r s = 0.516, P = 0.006) were found. The lack of correlation with the MDS-UPDRS I demonstrated good divergent validity. Conclusion. The German FOG-Q is a valid tool to assess FOG in German native speaking PD patients. PMID- 25705547 TI - Stability-Indicating RP-HPLC Method for Simultaneous Estimation of Enrofloxacin and Its Degradation Products in Tablet Dosage Forms. AB - The present work was the development of a simple, efficient, and reproducible stability-indicating reverse-phase high performance liquid chromatographic (RP HPLC) method for simultaneous determination enrofloxacin (EFX) and its degradation products including ethylenediamine impurity, desfluoro impurity, ciprofloxacin impurity, chloro impurity, fluoroquinolonic acid impurity, and decarboxylated impurity in tablet dosage forms. The separation of EFX and its degradation products in tablets was carried out on Kromasil C-18 (250 * 4.6 mm, 5 MUm) column using 0.1% (v/v) TEA in 10 mM KH2PO4 (pH 2.5) buffer and methanol by linear gradient program. Flow rate was 1.0 mL min(-1) with a column temperature of 35 degrees C and detection wavelength was carried out at 278 nm and 254 nm. The forced degradation studies were performed on EFX tablets under acidic, basic, oxidation, thermal, humidity, and photolytic conditions. The degraded products were well resolved from the main active drug and also from known impurities within 65 minutes. The method was validated in terms of specificity, linearity, LOD, LOQ, accuracy, precision, and robustness as per ICH guidelines. The results obtained from the validation experiments prove that the developed method is a stability-indicating method and suitable for routine analysis. PMID- 25705548 TI - A fluorescence-based method for rapid and direct determination of polybrominated diphenyl ethers in water. AB - A new method was developed for rapid and direct measurement of polybrominated diphenyl ethers (PBDEs) in aqueous samples using fluorescence spectroscopy. The fluorescence spectra of tri- to deca-BDE (BDE 28, 47, 99, 153, 190, and 209) commonly found in environment were measured at variable emission and excitation wavelengths. The results revealed that the PBDEs have distinct fluorescence spectral profiles and peak positions that can be exploited to identify these species and determine their concentrations in aqueous solutions. The detection limits as determined in deionized water spiked with PBDEs are 1.71-5.82 ng/L for BDE 28, BDE 47, BDE 190, and BDE 209 and 45.55-69.95 ng/L for BDE 99 and BDE 153. The effects of environmental variables including pH, humic substance, and groundwater chemical composition on PBDEs measurements were also investigated. These environmental variables affected fluorescence intensity, but their effect can be corrected through linear additivity and separation of spectral signal contribution. Compared with conventional GC-based analytical methods, the fluorescence spectroscopy method is more efficient as it only uses a small amount of samples (2-4 mL), avoids lengthy complicated concentration and extraction steps, and has a low detection limit of a few ng/L. PMID- 25705549 TI - Applied circular dichroism: a facile spectroscopic tool for configurational assignment and determination of enantiopurity. AB - In order to determine if electronic circular dichroism (ECD) is a good tool for the qualitative evaluation of absolute configuration and enantiopurity in the absence of chiral high performance liquid chromatography (HPLC), ECD studies were performed on several prescriptions and over-the-counter drugs. Cotton effects (CE) were observed for both S and R isomers between 200 and 300 nm. For the drugs examined in this study, the S isomers showed a negative CE, while the R isomers displayed a positive CE. The ECD spectra of both enantiomers were nearly mirror images, with the amplitude proportional to the enantiopurity. Plotting the differential extinction coefficient (Deltaepsilon) versus enantiopurity at the wavelength of maximum amplitude yielded linear standard curves with coefficients of determination (R (2)) greater than 97% for both isomers in all cases. As expected, Equate, Advil, and Motrin, each containing a racemic mixture of ibuprofen, yielded no chiroptical signal. ECD spectra of Suphedrine and Sudafed revealed that each of them is rich in 1S,2S-pseudoephedrine, while the analysis of Equate vapor inhaler is rich in R-methamphetamine. PMID- 25705550 TI - Synthesis of Pyrroloquinones via a CAN Mediated Oxidative Free Radical Reaction of 1,3-Dicarbonyl Compounds with Aminoquinones. AB - Pyrroloquinone ring systems are important structural units present in many biologically active molecules including a number of marine alkaloids. For example, they are found in a series of marine metabolites, such as tsitsikammamines, zyzzyanones, wakayin, and terreusinone. Several of these alkaloids have exhibited antimicrobial, antimalarial, antifungal, antitumor, and photoprotecting activities. Synthesis of pyrroloquinone unit is the key step in the synthesis of many of these important organic molecules. Here, we present a ceric (IV) ammonium nitrate (CAN) mediated oxidative free radical cyclization reaction of 1,3-dicarbonyl compounds with aminoquinones as a facile methodology for making various substituted pyrroloquinones. 1,3-dicarbonyl compounds used in this study are ethyl acetoacetate, acetylacetone, benzoyl acetone, and N,N dimethyl acetoacetamide. The aminoquinones used in this study are 2 (benzylamino)naphthalene-1,4-dione and 6-(benzylamino)-1-tosyl-1H-indole-4,7 dione. The yields of the synthesized pyrroloquinones ranged from 23-91%. PMID- 25705551 TI - Future directions for next-generation hospital information system. PMID- 25705552 TI - Big data analysis framework for healthcare and social sectors in Korea. AB - OBJECTIVES: We reviewed applications of big data analysis of healthcare and social services in developed countries, and subsequently devised a framework for such an analysis in Korea. METHODS: We reviewed the status of implementing big data analysis of health care and social services in developed countries, and strategies used by the Ministry of Health and Welfare of Korea (Government 3.0). We formulated a conceptual framework of big data in the healthcare and social service sectors at the national level. As a specific case, we designed a process and method of social big data analysis on suicide buzz. RESULTS: Developed countries (e.g., the United States, the UK, Singapore, Australia, and even OECD and EU) are emphasizing the potential of big data, and using it as a tool to solve their long-standing problems. Big data strategies for the healthcare and social service sectors were formulated based on an ICT-based policy of current government and the strategic goals of the Ministry of Health and Welfare. We suggest a framework of big data analysis in the healthcare and welfare service sectors separately and assigned them tentative names: 'health risk analysis center' and 'integrated social welfare service network'. A framework of social big data analysis is presented by applying it to the prevention and proactive detection of suicide in Korea. CONCLUSIONS: There are some concerns with the utilization of big data in the healthcare and social welfare sectors. Thus, research on these issues must be conducted so that sophisticated and practical solutions can be reached. PMID- 25705553 TI - Development of a smartphone application for clinical-guideline-based obesity management. AB - OBJECTIVES: The purpose of the study was to develop and evaluate a clinical guideline-based smartphone application ('app') for obesity management. METHODS: Obesity-related knowledge and functional requirements were extracted from clinical practice guidelines, a literature review, and consultations with experts. The extracted knowledge was used to design obesity-management algorithms, and the functions of the developed app are presented through a use case diagram and activity diagrams. The database and user interface were designed and then an app was developed. The proficiency and efficiency of the algorithm were evaluated using scenarios, while the user interface was assessed using a mobile heuristics evaluation tool, with its usability determined using the Post Study System Usability Questionnaire. RESULTS: In total, 131 obesity-related knowledge statements and 11 functions for the app were extracted, and 5 algorithms (comprising 1 main algorithm and 4 subalgorithms) were developed. The database comprised 11 tables and 41 screens. The app was developed using the Android SDK platform 4.0.3, JDK 1.7.0, and Eclipse. The overall proficiency and efficiency scores of the algorithm were 88.0 and 69.1, respectively. In heuristics tests, 57 comments were made, and the mean usability score was 3.47 out of 5. Thirteen usability problems were identified by the heuristics and usability evaluations. CONCLUSIONS: The app developed in this study might be helpful for weight management because it can provide high-quality health information and intervention without spatial or temporal constraints. However, the clinical effectiveness of this app still requires further investigation. PMID- 25705554 TI - Developing a common health information exchange platform to implement a nationwide health information network in South Korea. AB - OBJECTIVES: We aimed to develop a common health information exchange (HIE) platform that can provide integrated services for implementing the HIE infrastructure in addition to guidelines for participating in an HIE network in South Korea. METHODS: By exploiting the Health Level 7 (HL7) Clinical Document Architecture (CDA) and Integrating the Healthcare Enterprise (IHE) Cross enterprise Document Sharing-b (XDS.b) profile, we defined the architectural model, exchanging data items and their standardization, messaging standards, and privacy and security guidelines, for a secure, nationwide, interoperable HIE. We then developed a service-oriented common HIE platform to minimize the effort and difficulty of fulfilling the standard requirements for participating in the HIE network. The common platform supports open application program interfaces (APIs) for implementing a document registry, a document repository, a document consumer, and a master patient index. It could also be used for testing environments for the implementation of standard requirements. RESULTS: As the initial phase of implementing a nationwide HIE network in South Korea, we built a regional network for workers' compensation (WC) hospitals and their collaborating clinics to share referral and care record summaries to ensure the continuity of care for industrially injured workers, using the common HIE platform and verifying the feasibility of our technologies. CONCLUSIONS: We expect to expand the HIE network on a national scale with rapid support for implementing HL7 and IHE standards in South Korea. PMID- 25705555 TI - Aging Index using Photoplethysmography for a Healthcare Device: Comparison with Brachial-Ankle Pulse Wave Velocity. AB - OBJECTIVES: Recent studies have emphasized the potential information embedded in peripheral fingertip photoplethysmogram (PPG) signals for the assessment of arterial wall stiffening during aging. For the discrimination of arterial stiffness with age, the brachial-ankle pulse wave velocity (baPWV) has been widely used in clinical applications. The second derivative of the PPG (acceleration photoplethysmogram [APG]) has been reported to correlate with the presence of atherosclerotic disorders. In this study, we investigated the association among age, the baPWV, and the APG and found a new aging index reflecting arterial stiffness for a healthcare device. METHODS: The APG and the baPWV were simultaneously applied to assess the accuracy of the APG in measuring arterial stiffness in association with age. A preamplifier and motion artifact removal algorithm were newly developed to obtain a high quality PPG signal. In total, 168 subjects with a mean +/- SD age of 58.1 +/- 12.6 years were followed for two months to obtain a set of complete data using baPWV and APG analysis. RESULTS: The baPWV and the B ratio of the APG indices were correlated significantly with age (r = 0.6685, p < 0.0001 and r = -0.4025, p < 0.0001, respectively). A regression analysis revealed that the c and d peaks were independent of age (r = -0.3553, p < 0.0001 and r = -0.3191, p < 0.0001, respectively). CONCLUSIONS: We determined the B ratio, which represents an improved aging index and suggest that the APG may provide qualitatively similar information for arterial stiffness. PMID- 25705556 TI - Challenges and practical approaches with word sense disambiguation of acronyms and abbreviations in the clinical domain. AB - OBJECTIVES: Although acronyms and abbreviations in clinical text are used widely on a daily basis, relatively little research has focused upon word sense disambiguation (WSD) of acronyms and abbreviations in the healthcare domain. Since clinical notes have distinctive characteristics, it is unclear whether techniques effective for acronym and abbreviation WSD from biomedical literature are sufficient. METHODS: The authors discuss feature selection for automated techniques and challenges with WSD of acronyms and abbreviations in the clinical domain. RESULTS: There are significant challenges associated with the informal nature of clinical text, such as typographical errors and incomplete sentences; difficulty with insufficient clinical resources, such as clinical sense inventories; and obstacles with privacy and security for conducting research with clinical text. Although we anticipated that using sophisticated techniques, such as biomedical terminologies, semantic types, part-of-speech, and language modeling, would be needed for feature selection with automated machine learning approaches, we found instead that simple techniques, such as bag-of-words, were quite effective in many cases. Factors, such as majority sense prevalence and the degree of separateness between sense meanings, were also important considerations. CONCLUSIONS: The first lesson is that a comprehensive understanding of the unique characteristics of clinical text is important for automatic acronym and abbreviation WSD. The second lesson learned is that investigators may find that using simple approaches is an effective starting point for these tasks. Finally, similar to other WSD tasks, an understanding of baseline majority sense rates and separateness between senses is important. Further studies and practical solutions are needed to better address these issues. PMID- 25705557 TI - Performance evaluation of public hospital information systems by the information system success model. AB - OBJECTIVES: This study was to evaluate the performance of the newly developed information system (IS) implemented on July 1, 2014 at three public hospitals in Korea. METHODS: User satisfaction scores of twelve key performance indicators of six IS success factors based on the DeLone and McLean IS Success Model were utilized to evaluate IS performance before and after the newly developed system was introduced. RESULTS: All scores increased after system introduction except for the completeness of medical records and impact on the clinical environment. The relationships among six IS factors were also analyzed to identify the important factors influencing three IS success factors (Intention to Use, User Satisfaction, and Net Benefits). All relationships were significant except for the relationships among Service Quality, Intention to Use, and Net Benefits. CONCLUSIONS: The results suggest that hospitals should not only focus on systems and information quality; rather, they should also continuously improve service quality to improve user satisfaction and eventually reach full the potential of IS performance. PMID- 25705558 TI - Development of a Virtual Diabetes Register using Information Technology in New Zealand. AB - OBJECTIVES: The purpose of this study was to consider a Virtual Diabetes Registry System (VDR) and to investigate what it is and how it is used in New Zealand. New Zealand has specified diabetes mellitus (DM) as a national health priority. The Ministry of Health requires an accurate method for tracking the number of people with diagnosed with DM in the population. METHODS: We combined five national databases, all of which included a unique patient identifier: hospital admissions coded for DM, outpatient attendances for DM, DM retinal screening, prescriptions of specific anti-diabetic therapies, laboratory orders for HbA1c, as well as Primary Health Organisation (PHO) enrolments and national mortality. The algorithm was progressively modified to improve sensitivity and specificity, and it was validated against primary care registers. The algorithm was still being used in 2014. RESULTS: The prevalence of diagnosed diabetes in New Zealand at December 31, 2009 was 189,256 (4.4% of whole population). The VDR is now used to determine the official diagnosed diabetes prevalence in New Zealand; it is also used to determine the denominator of the health targets that the Ministry of Health should achieve for diabetes service indicators in New Zealand. CONCLUSIONS: This method appears to be superior to any other practicable national survey and to be both accurate and robust. The VDR has become an invaluable tool for monitoring prevalence and the policy making process, and for supporting clinical quality improvement. PMID- 25705559 TI - SMART Careplan System for Continuum of Care. AB - OBJECTIVES: This paper describes the integrated Careplan system, designed to manage and utilize the existing Electronic Medical Record (EMR) system; the system also defines key items for interdisciplinary communication and continuity of patient care. METHODS: We structured the Careplan system to provide effective interdisciplinary communication for healthcare services. The design of the Careplan system architecture proceeded in four steps-defining target datasets; construction of conceptual framework and architecture; screen layout and storyboard creation; screen user interface (UI) design and development, and pilot test and step-by-step deployment. This Careplan system architecture consists of two parts, a server-side and client-side area. On the server-side, it performs the roles of data retrieval and storage from target EMRs. Furthermore, it performs the role of sending push notifications to the client depending on the careplan series. Also, the Careplan system provides various convenient modules to easily enter an individual careplan. RESULTS: Currently, Severance Hospital operates the Careplan system and provides a stable service dealing with dynamic changes (e.g., domestic medical certification, the Joint Commission International guideline) of EMR. CONCLUSIONS: The Careplan system should go hand in hand with key items for strengthening interdisciplinary communication and information sharing within the EMR environment. A well-designed Careplan system can enhance user satisfaction and completed performance. PMID- 25705560 TI - Information Dynamics of Whole Genome Adaptation. AB - The human genome is a complex, dynamic information system that encodes principles of life and living systems. These principles are incorporated in the structure of human genome sequence variation and are foundational for the continuity of life and human survival. Using first principles of thermodynamics and statistical physics, we have developed analogous "genodynamic tools" for population genomic studies. Characterizing genomic information through the lens of physics has allowed us to develop energy measures for modeling genome-environment interactions. In developing biophysical parameters for genome-environment homeostasis, we found that stable genomic free energy trades off low genomic energy (genomic conservation and increased order) and high genomic entropy (genomic variation) with an environmental potential that drives the variation. In our approach, we assert that common variants are dynamic sites in the genome of a population and that the stability of whole genome adaptation is reflected in the frequencies of maintained diversity in common variants for the population in its environment. In this paper, we address the relativity of whole genome adaptation towards homeostasis. By this we mean that adaptive forces are directly reflected in the frequency distribution of alleles and/or haplotypes of the population relative to its environment, with adaptive forces driving the genome towards homeostasis. The use of genomic energy units as a biophysical metric in DNA sequence variation analyses provides new insights into the foundations of population biology and diversity. Using our biophysical tools, population differences directly reflect the adaptive influences of the environment on populations. PMID- 25705561 TI - It's Your Game-Tech: Toward Sexual Health in the Digital Age. AB - Adolescent sexually transmitted infection (STI) and birth rates indicate a need for effective middle school HIV/STI, and pregnancy prevention curricula to delay, or mitigate consequences of, early sexual activity. Individual and organizational barriers to adoption, implementation, and maintenance, however, can hamper dissemination of evidence-based sexual health curricula, adversely impacting fidelity and reach. Internet-based approaches may help mitigate these barriers. This paper describes the development and feasibility testing of It's Your Game (IYG)-Tech, a stand-alone 13-lesson Internet-based sexual health life-skills curriculum adapted from an existing effective sexual health curriculum-It's Your Game... Keep it Real (IYG). IYG-Tech development adaptation steps were to: 1) Select a suitable effective program and gather the original program materials; 2) Develop "proof of concept" lessons and test usability and impact; 3) Develop the program design document describing the core content, scope, and methods and strategies; and 4) produce the new program. Lab- and school-based tests with middle school students demonstrated high ratings on usability parameters and immediate impact on selected psychosocial factors related to sexual behavior perceptions of friends' beliefs, reasons for not having sex, condom use self efficacy, abstinence intentions, negotiating with others to protect personal rules, and improved knowledge about what constitutes healthy relationships (all p < .05). Youth rated IYG-Tech is favorably compared to other learning channels (>76.2% agreement) and rated the lessons as helpful in making healthy choices, selecting personal rules, detecting challenges to those rules, and protecting personal rules through negotiation and refusal skills (89.5% - 100%). Further efficacy testing is indicated for IYG-Tech as a potential strategy to deliver effective HIV/STI, and pregnancy prevention to middle school youth. PMID- 25705562 TI - Protein Conformational Landscapes and Catalysis. Influence of Active Site Conformations in the Reaction Catalyzed by L-Lactate Dehydrogenase. AB - In the last decade L-Lactate Dehydrogenase (LDH) has become an extremely useful marker in both clinical diagnosis and in monitoring the course of many human diseases. It has been assumed from the 80s that the full catalytic process of LDH starts with the binding of the cofactor and the substrate followed by the enclosure of the active site by a mobile loop of the protein before the reaction to take place. In this paper we show that the chemical step of the LDH catalyzed reaction can proceed within the open loop conformation, and the different reactivity of the different protein conformations would be in agreement with the broad range of rate constants measured in single molecule spectrometry studies. Starting from a recently solved X-ray diffraction structure that presented an open loop conformation in two of the four chains of the tetramer, QM/MM free energy surfaces have been obtained at different levels of theory. Depending on the level of theory used to describe the electronic structure, the free energy barrier for the transformation of pyruvate into lactate with the open conformation of the protein varies between 12.9 and 16.3 kcal/mol, after quantizing the vibrations and adding the contributions of recrossing and tunneling effects. These values are very close to the experimentally deduced one (14.2 kcal.mol-1) and ~2 kcal.mol-1 smaller than the ones obtained with the closed loop conformer. Calculation of primary KIEs and IR spectra in both protein conformations are also consistent with our hypothesis and in agreement with experimental data. Our calculations suggest that the closure of the active site is mainly required for the inverse process; the oxidation of lactate to pyruvate. According to this hypothesis H4 type LDH enzyme molecules, where it has been propose that lactate is transformed into pyruvate, should have a better ability to close the mobile loop than the M4 type LDH molecules. PMID- 25705563 TI - Association of Blood Biomarkers of Bone Turnover in HIV-1 Infected Individuals Receiving Anti-Retroviral Therapy (ART). AB - OBJECTIVE: To evaluate the association of bone turnover biomarkers with blood levels of alkaline phosphatase (ALP), bone-specific alkaline phosphatase (BAP), osteocalcin (OC), tartrate-resistant acid phosphatase (TRAP), parathyroid hormone (PTH), and other blood markers in HIV-1 infected men receiving anti-retroviral therapy (ART). Advances in the treatment of HIV-1 infection have extended the life span of HIV-1 infected individuals. However, these advances may come at the price of metabolic side effects and bone disorders, including premature osteopenia, osteoporosis and osteonecrosis. METHODS: Analyses of Ostase BAP, osteocalcin, and TRAP in blood were measured in three groups of MACS participants: 35 HIV-1 infected men on ART (A); 35 HIV-1- infected men not on ART (B); and 34 HIV-1 uninfected men (C). RESULTS: The mean and standard deviation results for groups A, B, and C were 19.7 +/- 6.56, 17.2 +/- 3.96, and 16.9 +/- 5.78 for ostase BAP; 7.9 +/- 9.53, 8.5 +/- 8.30, and 5.5 +/- 1.65 for osteocalcin; and 3.9 +/- 1.04, 3.1 +/- 0.81, and 2.5 +/- 0.59 for TRAP, respectively. Simple and multivariate analyses showed significant differences in mean TRAP and BAP concentrations between the three groups. In addition strong correlations between blood levels of Ostase BAP and TRAP (r=0.570, p=0.0004), and between blood levels of Ostase BAP and PTH (r=0.436, P=0.0098) for HIV-1 infected men on ART were observed. CONCLUSION: New strategies for measurement of blood and urine biochemical markers of bone formation and resorption during bone turnover can be useful for clinical monitoring of treatment of HIV-1 infected patients. Recently developed methods for measuring serum levels of TRAP and Ostase BAP represent superior laboratory tools for assessing the hyperactivity of osteoclasts, osteoblasts and bone loss in HIV-1 infected individuals receiving ART. Measurements of TRAP and BAP as bone turnover biomarkers are economical and are important for monitoring bone metabolism during ART and the need for osteoporosis treatment. PMID- 25705564 TI - Metabolic Control of Th17 Cell Generation and CNS Inflammation. AB - Multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system (CNS), results from uncontrolled auto reactive T cells that infiltrate the CNS and attack the myelin sheath. Th17 cells play a prominent role in the pathogenesis of MS and experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. Extensive studies have focused on understanding the roles of cytokine signaling and transcriptional network in the differentiation of Th17 cells and their pathogenicity in CNS inflammation. Aside from these events, activated T cells dynamically reprogram their metabolic pathways to fulfill the bioenergic and biosynthetic requirements for proper T cell functions. Emerging evidence indicates that modulation of these metabolic pathways impinges upon the differentiation of Th17 cells and the pathogenesis of EAE. Thus, a better understanding of the functions and mechanisms of T cell metabolism in Th17 cell biology may provide new avenues for therapeutic targeting of MS. In this review, we discuss the recent advances in our understanding of T cell metabolic pathways involved in Th17 cell differentiation and CNS inflammation. PMID- 25705565 TI - Host Genetic Factors and Dendritic Cell Responses Associated with the Outcome of Interferon/Ribavirin Treatment in HIV-1/HCV Co-Infected Individuals. AB - HIV-1/HCV co-infection is a significant health problem. Highly active antiretroviral treatment (HAART) against HIV-1 has proved to be fairly successful. On the other hand, direct acting antiviral drugs against HCV have improved cure rates but high cost and development of drug resistance are important concerns. Therefore PEGylated interferon (PEG-IFN) and ribavirin (RBV) still remain essential components of HCV treatment, and identification of host factors that predict IFN/RBV treatment response is necessary for effective clinical management of HCV infection. Impaired dendritic cell (DC) and T cell responses are associated with HCV persistence. It has been shown that IFN/RBV treatment enhances HCV-specific T cell functions and it is likely that functional restoration of DCs is the underlying cause. To test this hypothesis, we utilized an antibody cocktail (consisting of DC maturation, adhesion and other surface markers) to perform comprehensive phenotypic characterization of myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) in a cohort of HIV-1/HCV co-infected individuals undergoing IFN/RBV treatment. Our results show that pre-treatment frequencies of mDCs are lower in non-responders (NRs) compared to responders (SVRs) and healthy controls. Although, the treatment was able to restore the frequency of mDCs in NRs, it downregulated the frequency of CCR7+, CD54+ and CD62L+ mDCs. Pre-treatment frequencies of pDCs were lower in NRs and decreased further upon treatment. Compared to SVRs, NRs exhibited higher ratio of PD L1+/CD86+ pDCs prior to treatment; and this ratio remained high even after treatment. These findings demonstrate that enumeration and phenotypic assessment of DCs before/during therapy can help predict the treatment outcome. We also show that before treatment, PBMCs from SVRs secrete higher amounts of IFN-gamma compared to controls and NRs. Upon genotyping IFNL3 polymorphisms rs12979860, rs4803217 and ss469415590, we found rs12979860 to be a better predictor of treatment outcome. Collectively, our study led to identification of important correlates of IFN/RBV treatment response in HIV-1/HCV co-infected individuals. PMID- 25705566 TI - Considering a Relational Model for Depression in Women with Postpartum Depression. AB - PURPOSE: To extend testing of a relational theory that a low sense of belonging, delayed or impaired bonding, and loneliness are salient risk factors for postpartum depression (PPD) in women. METHODS: Data for this theory-testing analysis came from a larger prospective longitudinal cohort study and included women who were retained to the end of the study at the 6 week postpartum interview (n=564). Structural equation modeling was used to test the "fit" of the model and determine significance of direct and indirect paths. RESULTS: The model explained 35% of the variance in postpartum depression with impaired bonding and loneliness as the strongest indicators. Lower sense of belonging, less perceived social support from a healthcare practitioner and a partner, and lower parenting sense of competence were additional predictors. CONCLUSION: Study findings challenge current thinking about the relationship between impaired bonding and PPD as this study raises the possibility that impaired bonding is a risk for PPD as opposed to the reverse relationship. The study provided evidence of the importance of healthcare practitioners' alliance with patients. This paper contributes to advancing the science of women's mental health in relation to depression by considering additional predictors which might be amenable to intervention. PMID- 25705568 TI - Platelet Vascular Endothelial Growth Factor is a Potential Mediator of Transfusion-Related Acute Lung Injury. AB - OBJECTIVE: The occurrence of non-hemolytic transfusion reactions is highest with platelet and plasma administration. Some of these reactions are characterized by endothelial leak, especially transfusion related acute lung injury (TRALI). Elevated concentrations of inflammatory mediators secreted by contaminating leukocytes during blood product storage may contribute to such reactions, but platelet-secreted mediators may also contribute. We hypothesized that platelet storage leads to accumulation of the endothelial permeability mediator vascular endothelial growth factor (VEGF), and that intravascular administration of exogenous VEGF leads to extensive binding to its lung receptors. METHODS: Single donor, leukocyte-reduced apheresis platelet units were sampled over 5 days of storage. VEGF protein content of the centrifuged supernatant was determined by ELISA, and the potential contribution of VEGF from contaminating leukocytes was quantified. Isolated-perfused rat lungs were used to study the uptake of radiolabeled VEGF administered intravascularly, and the effect of unlabeled VEGF on lung leak. RESULTS: There was a time-dependent release of VEGF into the plasma fraction of the platelet concentrates (62 +/- 9 pg/ml on day one, 149 +/- 23 pg/ml on day 5; mean +/- SEM, p<0.01, n=8) and a contribution by contaminating leukocytes was excluded. Exogenous 125I-VEGF bound avidly and specifically to the lung vasculature, and unlabeled VEGF in the lung perfusate caused vascular leak. CONCLUSION: Rising concentrations of VEGF occur during storage of single donor platelet concentrates due to platelet secretion or disintegration, but not due to leukocyte contamination. Exogenous VEGF at these concentrations rapidly binds to its receptors in the lung vessels. At higher VEGF concentrations, VEGF causes vascular leak in uninjured lungs. These data provide further evidence that VEGF may contribute to the increased lung permeability seen in TRALI associated with platelet products. PMID- 25705569 TI - Animal Models of Pulmonary Hypertension: Matching Disease Mechanisms to Etiology of the Human Disease. AB - Recently a great deal of progress has been made in our understanding of pulmonary hypertension (PH). Research from the past 30 years has resulted in newer treatments that provide symptomatic improvements and delayed disease progression. Unfortunately, the cure for patients with this lethal syndrome remains stubbornly elusive. With the relative explosion of scientific literature regarding PH, confusion has arisen regarding animal models of the disease and their correlation to the human condition. This short review uniquely focuses on the clear and present need to better correlate mechanistic insights from existing and emerging animal models of PH to specific etiologies and histopathologies of human PH. A better understanding of the pathologic processes in various animal models and how they relate to the human disease should accelerate the development of newer and more efficacious therapies. PMID- 25705570 TI - Flaxseed Mitigates Acute Oxidative Lung Damage in a Mouse Model of Repeated Radiation and Hyperoxia Exposure Associated with Space Exploration. AB - BACKGROUND: Spaceflight missions may require crewmembers to conduct extravehicular activities (EVA). Pre-breathe protocols in preparation for an EVA entail 100% hyperoxia exposure that may last for a few hours and be repeated 2-3 times weekly. Each EVA is associated with additional challenges such as low levels of total body cosmic/galactic radiation exposure that may present a threat to crewmember health. We have developed a mouse model of total body radiation and hyperoxia exposure and identified acute damage of lung tissues. In the current study we evaluated the usefulness of dietary flaxseed (FS) as a countermeasure agent for such double-hit exposures. METHODS: We evaluated lung tissue changes 2 weeks post-initiation of exposure challenges. Mouse cohorts (n=5/group) were pre fed diets containing either 0% FS or 10% FS for 3 weeks and exposed to: a) normoxia (Untreated); b) >95% O2 (O2); c) 0.25Gy single fraction gamma radiation (IR); or d) a combination of O2 and IR (O2+IR) 3 times per week for 2 consecutive weeks, where 8-hour hyperoxia treatments were spanned by normoxic intervals. RESULTS: At 2 weeks post challenge, while control-diet fed mice developed significant lung injury and inflammation across all challenges, FS protected lung tissues by decreasing bronchoalveolar lavage fluid (BALF) neutrophils (p<0.003) and protein levels, oxidative tissue damage, as determined by levels of malondialdehyde (MDA) (p<0.008) and nitrosative stress as determined by nitrite levels. Lung hydroxyproline levels, a measure of lung fibrosis, were significantly elevated in mice fed 0% FS (p<0.01) and exposed to hyperoxia/radiation or the combination treatment, but not in FS-fed mice. FS also decreased levels of a pro-inflammatory, pro-fibrogenic cytokine (TGF-beta1) gene expression levels in lung. CONCLUSION: Flaxseed mitigated adverse effects in lung of repeat exposures to radiation/hyperoxia. This data will provide useful information in the design of countermeasures to early tissue oxidative damage associated with space exploration. PMID- 25705571 TI - Food Policy Approaches to Obesity Prevention: An International Perspective. AB - This paper provides a comprehensive overview of the recent obesity prevention related food policies initiated in countries worldwide. We searched and reviewed relevant research papers and government documents, focusing on those related to dietary guidelines, food labeling, regulation of food marketing, and policies affecting food prices. We also commented on the effects and challenges of some of the related policy options. There are large variations regarding what, when, and how policies have been implemented across countries. Clearly, developed countries are leading the effort, and developing countries are starting to develop some related policies. The encouraging message is that many countries have been adopting policies that might help prevent obesity and that the support for more related initiatives is strong and continues to grow. Communicating information about these practices will help researchers, public health professionals, and policy makers around the world to take action to fight the growing epidemic of obesity and other nutrition-related diseases. PMID- 25705572 TI - Diabetes group medical visits and outcomes of care in low-income, rural, uninsured persons. AB - PURPOSE: The purpose of this study was to test the effectiveness of Diabetes Group Medical Visits (DGMVs) verses usual care in a sample of low-income patients with diabetes receiving care at a rural free clinic. METHODS: Data were collected through chart review, using direct data entry into Microsoft Access. Participants were included if they met the inclusion criteria: 1) age >= 18 years; 2) diagnosis of diabetes; 3) uninsured and received care between May 2007 and August 2009. Fifty-three participants attended DGMVs and were compared to 58 participants who received usual care. RESULTS: The personal characteristics and biophysical measures of this population differed from previously studied Group Visit populations. The majority of patients were female (73.9%), white (95.5%), younger than 50 (53.2%), driving long distances to receive care (mean miles = 21, SD 20.4) and had a high school education or less (95.4%). Participants were severely obese (mean BMI = 37.6, SD 28.48) and had 5 co-morbid conditions other than diabetes (mean = 5.5, SD 2.1). Those attending DGMVs had higher baseline A1C, depression scores, BMIs, and more pain than usual care. There was a statistically significant decrease in systolic pressure from time one to time two in patients who attended DGMVs t(52) = 2.18, (p = 0.03). There was no significant impact on outcomes of patients who received usual care. However, it is important to note that the majority of patients attended three or fewer DGMVs visits in one year. CONCLUSION: Group visits may not be enough to improve outcomes in this population. Previous studies suggest that improvements are seen in those who attend more frequently. Hence, the lack of improvement in biophysical outcomes may be due to low attendance. The limited impact of this traditional style intervention in relation to low attendance argues the need to test alternative interventions to reach this population. PMID- 25705573 TI - Plasmid-Mediated Antibiotic Resistance and Virulence in Gram-negatives: the Klebsiella pneumoniae Paradigm. AB - Plasmids harbor genes coding for specific functions including virulence factors and antibiotic resistance that permit bacteria to survive the hostile environment found in the host and resist treatment. Together with other genetic elements such as integrons and transposons, and using a variety of mechanisms, plasmids participate in the dissemination of these traits resulting in the virtual elimination of barriers among different kinds of bacteria. In this article we review the current information about physiology and role in virulence and antibiotic resistance of plasmids from the gram-negative opportunistic pathogen Klebsiella pneumoniae. This bacterium has acquired multidrug resistance and is the causative agent of serious communityand hospital-acquired infections. It is also included in the recently defined ESKAPE group of bacteria that cause most of US hospital infections. PMID- 25705574 TI - Retroviral Integrase Structure and DNA Recombination Mechanism. AB - Due to the importance of human immunodeficiency virus type 1 (HIV-1) integrase as a drug target, the biochemistry and structural aspects of retroviral DNA integration have been the focus of intensive research during the past three decades. The retroviral integrase enzyme acts on the linear double-stranded viral DNA product of reverse transcription. Integrase cleaves specific phosphodiester bonds near the viral DNA ends during the 3' processing reaction. The enzyme then uses the resulting viral DNA 3'-OH groups during strand transfer to cut chromosomal target DNA, which simultaneously joins both viral DNA ends to target DNA 5'-phosphates. Both reactions proceed via direct transesterification of scissile phosphodiester bonds by attacking nucleophiles: a water molecule for 3' processing, and the viral DNA 3'-OH for strand transfer. X-ray crystal structures of prototype foamy virus integrase-DNA complexes revealed the architectures of the key nucleoprotein complexes that form sequentially during the integration process and explained the roles of active site metal ions in catalysis. X-ray crystallography furthermore elucidated the mechanism of action of HIV-1 integrase strand transfer inhibitors, which are currently used to treat AIDS patients, and provided valuable insights into the mechanisms of viral drug resistance. PMID- 25705576 TI - Can mHealth Improve Risk Assessment in Underserved Populations? Acceptability of a Breast Health Questionnaire App in Ethnically Diverse, Older, Low-Income Women. AB - BACKGROUND: Use of mobile health (mHealth) tools has expanded rapidly but little research has been done on its acceptability by low-income, diverse, older patient populations. OBJECTIVE: To assess the attitudes of a diverse group of underserved women on the acceptability and usability of mHealth tools in a clinical setting using a breast health questionnaire application (app) at a public hospital mammography clinic. METHODS: Semi-structured interviews were conducted in a breast-imaging center of an urban safety net institution from July-August 2012. Interviews included pre- and post-questions. Women completed the Athena breast health questionnaire app on an iPad and were asked about their experience and ways to improve the tool. RESULTS: Fifteen women age 45-79 years from diverse ethnic and educational backgrounds were interviewed. The majority of women, 11 of 15, preferred the Athena app over a paper version and all the women thought the app was easy to use. Two Spanish-speaking Latinas preferred paper; and two women, with limited mobile phone use, did not have a preference. Many women indicated that it would be necessary to have staff available for instruction and assistance if the app were to be implemented. CONCLUSIONS: mHealth tools are an acceptable, if not preferred, method of collecting health information for diverse, older, low income women. Further studies are required to evaluate the reliability and accuracy of data collection using mHealth tools in underserved populations. mHealth tools should be explored as a novel way to engage diverse populations to improve clinical care and bridge gaps in health disparities. PMID- 25705575 TI - Oxidants in Acute and Chronic Lung Disease. AB - Oxidants play an important role in homeostatic function, but excessive oxidant generation has an adverse effect on health. The manipulation of Reactive Oxygen Species (ROS) can have a beneficial effect on various lung pathologies. However indiscriminate uses of anti-oxidant strategies have not demonstrated any consistent benefit and may be harmful. Here we propose that nuanced strategies are needed to modulate the oxidant system to obtain a beneficial result in the lung diseases such as Acute Lung Injury (ALI) and Chronic Obstructive Pulmonary Disease (COPD). We identify novel areas of lung oxidant responses that may yield fruitful therapies in the future. PMID- 25705577 TI - Regulation and Relevance of Myofibroblast Responses in Idiopathic Pulmonary Fibrosis. AB - Idiopathic Pulmonary Fibrosis (IPF) is a chronic, progressive, incurable lung disease of unknown etiology with only limited treatment options. Current paradigms of disease pathogenesis feature recurrent or prolonged epithelial injury and an ensuing inflammatory response that culminates in the appearance of activated myofibroblasts. These cells are believed central to the excessive deposition of extracellular matrix that eventually obliterates the alveolar space to cause respiratory failure. Because the factors driving the accumulation of myofibroblasts remain poorly understood, effective therapies remain elusive. This review focuses on recent understanding of myofibroblasts including their seemingly uncontrolled proliferation and survival, their controversial origin in pathological IPF tissues, and the local biochemical and biomechanical matrix factors that drive their behavior. In addition, novel antifibrotics under development for the treatment of lung disease will be discussed. As our understanding of fibroblast and myofibroblast biology regulation expands, these cells may prove to be effective therapeutic targets. PMID- 25705578 TI - Melatonin, the Hormone of Darkness: From Sleep Promotion to Ebola Treatment. AB - Melatonin is a hormone secreted by the enigmatic pineal gland in response to darkness, hence the name hormone of darkness. It has generated a great deal of interest as a therapeutic modality for various diseases particularly sleep disorders. This pleiotropic molecule has anti-inflammatory, antioxidant and anticoagulopathic properties in addition to its endothelial protective effects. In this article we discuss melatonin secretion and mechanisms of action as well as therapeutic rationale. We also highlight the potential utility of melatonin in the deadly modern-day Ebola epidemic. PMID- 25705579 TI - Looking beyond Fear and Extinction Learning: Considering Novel Treatment Targets for Anxiety. AB - Fear conditioning studies provide valuable insight into how fears are learned and extinguished. Previous work focuses on fear and extinction learning to understand and treat anxiety disorders. However, a cascade of cognitive processes that extend beyond learning may also yield therapeutic targets for anxiety disorders. Throughout this review, we will discuss recent findings of fear generalization, memory consolidation, and reconsolidation. Factors related to effectiveness, efficiency and durability of extinction-based treatments will be addressed. Moreover, adolescence may be a key developmental stage when threat-related perturbations emerge; therefore, targeting interventions during adolescence when these nascent processes are more malleable may alter the trajectory of anxiety disorders. PMID- 25705581 TI - Myoclonic Twitching and Sleep-Dependent Plasticity in the Developing Sensorimotor System. AB - As bodies grow and change throughout early development and across the lifespan, animals must develop, refine, and maintain accurate sensorimotor maps. Here we review evidence that myoclonic twitches-brief and discrete contractions of the muscles, occurring exclusively during REM (or active) sleep, that result in jerks of the limbs-help animals map their ever-changing bodies by activating skeletal muscles to produce corresponding sensory feedback, or reafference. First, we highlight the spatiotemporal characteristics of twitches. Second, we review findings in infant rats regarding the multitude of brain areas that are activated by twitches during sleep. Third, we discuss evidence demonstrating that the sensorimotor processing of twitches is different from that of wake movements; this state-related difference in sensorimotor processing provides perhaps the strongest evidence yet that twitches are uniquely suited to drive certain aspects of sensorimotor development. Finally, we suggest that twitching may help inform our understanding of neurodevelopmental disorders, perhaps even providing opportunities for their early detection and treatment. PMID- 25705580 TI - Environmental Health Factors and Sexually Dimorphic Differences in Behavioral Disruptions. AB - Mounting evidence suggests that environmental factors-in particular, those that we are exposed to during perinatal life-can dramatically shape the organism's risk for later diseases, including neurobehavioral disorders. However, depending on the environmental insult, one sex may demonstrate greater vulnerability than the other sex. Herein, we focus on two well-defined extrinsic environmental factors that lead to sexually dimorphic behavioral differences in animal models and linkage in human epidemiological studies. These include maternal or psychosocial stress (such as social stress) and exposure to endocrine-disrupting compounds (such as one of the most prevalent, bisphenol A [BPA]). In general, the evidence suggests that early environmental exposures, such as BPA and stress, lead to more pronounced behavioral deficits in males than in females, whereas female neurobehavioral patterns are more vulnerable to later in life stress. These findings highlight the importance of considering sex differences and developmental timing when examining the effects of environmental factors on later neurobehavioral outcomes. PMID- 25705582 TI - The current progress and future prospects of personalized radiogenomic cancer study. AB - During the last twenty years, mounting studies have supported the hypothesis that there is a genetic component that plays an important role in clinically observed variability in individual tissue/organ toxicity after radiotherapy. We propose the term "Personalized Radiogenomics" for the translational study of individual genetic variations that may associate with or contribute to the responses of tissues to radiation therapy used in the treatment of all types of cancer. The missions of personalized radiogenomic research are 1) to reveal the related genes, proteins, and biological pathways responsible for non-tumor or tumor tissue toxicity resulting from radiotherapy that could be targeted with radio sensitizing and/or radio-protective agents, and 2) to identify specific genetic markers that can be used in risk prediction and evaluation models before and after clinical cancer surgery. For the members of the Terry Fox Cancer Research Lab in China Medical University and Hospital, the long-term goal is to develop SNP-based risk models that can be used to stratify patients to more precisely tailored radiotherapy protocols. Worldwide, the field has evolved over the last two decades in parallel with rapid advances in genetic and genomic technology, moving step by step from narrowly focused candidate gene studies to large-scale, collaborative genome-wide association studies. This article will summarize the candidate gene association studies published so far from the Terry Fox Cancer Research Lab as well as worldwide on the risk of radiation-related cancers and highlight some wholegenome association studies showing feasibility in fulfilling the dream of personalized radiogenomic cancer therapy. PMID- 25705583 TI - Sambucus williamsii induced embryonic stem cells differentiated into neurons. AB - The pluripotent stem cells, including embryonic stem cells (ESCs), are capable of self-renewal and differentiation into any cell type, thus making them the focus of many clinical application studies. However, the efficiency of ESCs differentiated into neurons needs to improve. In this study, we tried to increase efficiently to a neural fate in the presence of various transitional Chinese medicines through a three-step differentiation strategy. From extracts of 10 transitional Chinese medicine candidates, we determined that Sambucus williamsii (SW) extract triggers the up-regulation of Nestin and Tuj1 (neuron cells markers) gene expression levels. After determining the different concentrations of SW extract, the number of neurons in the 200 MUg/ml SW extract group was higher than the control, 50, 100, and 400 MUg/ml SW extract groups. In addition, the number of neurons in the 200 MUg/ml SW extract group was higher and higher after each time passage (three times). We also detected the Oct4, Sox2 (stem cells markers), Tuj1, and Nestin genes expression levels by RT-PCR. In the differentiated process, Oct4 and Sox2 genes decreased while the Tuj1 and Nestin genes expression levels increased. In summary, we demonstrated that SW could induce pluripotent stem cells differentiated into neurons. Thus, SW might become a powerful material for neurons-differentiating strategies. PMID- 25705584 TI - Irisflorentin improves alpha-synuclein accumulation and attenuates 6-OHDA-induced dopaminergic neuron degeneration, implication for Parkinson's disease therapy. AB - Parkinson's disease (PD) is a degenerative disorder of the central nervous system that is characterized by progressive loss of dopaminergic neurons in the substantia nigra pars compacta as well as motor impairment. Aggregation of alpha synuclein in neuronal cells plays a key role in this disease. At present, therapeutics for PD provides moderate symptomatic benefits, but it is not able to delay the development of the disease. Current efforts toward the treatment of PD are to identify new drugs that slow or arrest the progressive course of PD by interfering with a disease-specific pathogenetic process in PD patients. Irisflorentin derived from the roots of Belamcanda chinensis (L.) DC. is an herb which has been used for the treatment of inflammatory disorders in traditional Chinese medicine. The purpose of the present study was to assess the potential for irisflorentin to ameliorate PD in Caenorhabditis elegans models. Our data reveal that irisflorentin prevents alpha-synuclein accumulation in the transgenic Caenorhabditis elegans model and also improves dopaminergic neuron degeneration, food-sensing behavior, and life-span in a 6-hydroxydopamine-induced Caenorhabditis elegans model, thus indicating its potential as a anti parkinsonian drug candidate. Irisflorentin may exert its effects by promoting rpn 3 expression to enhance the activity of proteasomes and down-regulating egl-1 expression to block apoptosis pathways. These findings encourage further investigation on irisflorentin as a possible potent agent for PD treatment. PMID- 25705585 TI - Lipopolysaccharide-promoted proliferation of Caco-2 cells is mediated by c-Src induction and ERK activation. AB - As a major component of the cell wall of Gram-negative bacteria, lipopolysaccharide (LPS) can be released into the bloodstream to cause a spectrum of pathophysiological reactions. Despite the fact that colon epithelium cells in situ are continuously exposed to LPS, their biological responses as provoked by LPS as well as the underlying mechanisms are poorly defined. In the present study, we observed that LPS directly stimulated growth of Caco-2 cells as well as enhanced the amounts of c-Src, which could be partly attributable to increased c src transcript. Parallel to LPS-induced c-Src expression was FAK activation and ERK activation. Remarkably, activation of ERK and cellular proliferation by LPS could be inhibited by PP2, the specific Src inhibitor, implicating the essential role of c-Src in this process. To our knowledge, this is the first report indicating that LPS can increase cellular growth via upregulation of c-Src in colon epithelial cells. PMID- 25705586 TI - The bacterial interactions in the nasopharynx of children receiving adenoidectomy. AB - Staphylococcus aureus, Streptococcus pneumoniae, and Haemophilus influenzae are the common pathogens that colonize in the nasopharynx of children. Polymicrobial interactions are thought to play an important role in different sites throughout the human body. However, there are currently very few studies that investigate the interactions between S. aureus, S. pneumoniae, and H. influenzae in the nasopharynx. We retrospectively analyzed the adenoid tissue culture from 269 children who received adenoidectomy. S. aureus, S. pneumoniae, and H. influenzae constituted the major microorganisms which were cultured from these adenoidectomies, at 23.4%, 21.6%, and 18.2%, respectively. S. pneumoniae and H. influenzae were the most prevalent in the preschool-aged children (3 < age <= 6), whereas S. aureus was more prevalent in infants and toddlers (age <= 3) and school-aged children (age > 6). Bacterial interference was found between S. aureus and S. pneumoniae and between S. aureus and H. influenzae, whereas there was an association found between S. pneumoniae and H. influenzae. The synergism and antagonism among these three species are investigated in the following paper, with the possible mechanisms involved in these interactions also discussed. PMID- 25705587 TI - The Application of Multiple Reaction Monitoring to Assess Apo A-I Methionine Oxidations in Diabetes and Cardiovascular Disease. AB - The oxidative modification of apolipoprotein A-I 's methionine148(M148) is associated with defective HDL function in vitro. Multiple Reaction Monitoring (MRM) is a mass spectrometric technique that can be used to quantitate post translational modifications. In this study, we developed an MRM assay to monitor the abundance ratio of the peptide containing oxidized M148 to the native peptide in Apo A-I. Measurement of the oxidized-to-unoxidized-M148 ratio was reproducible (CV<5%). The extent of methionine M148 oxidation in the HDL of healthy controls, and type 2 diabetic participants with and without prior cardiovascular events (CVD) were then examined. The results suggest a significant increase in the relative ratio of the peptide containing oxidized M148 to the unmodified peptide in the HDL of participants with diabetes and CVD (p<0.001), compared to participants without CVD. Monitoring the abundance ratio of the peptides containing oxidized and unoxidized M148 by MRM provides a means of examining the relationship between M148 oxidation and vascular complications in CVD. PMID- 25705588 TI - Multiplex Screen of Serum Biomarkers in Facioscapulohumeral Muscular Dystrophy. AB - BACKGROUND: Recent studies have proposed a unified genetic model for Facioscapulohumeral muscular dystrophy (FSHD), identifying potential therapeutic targets for future clinical trials. Serum biomarkers related to disease activity will be important for proof of concept or early phase clinical studies. OBJECTIVE: To identify potential serum biomarkers in FSHD for possible use in future clinical trials. METHODS: We performed a prospective cross-sectional study of serum biomarkers in 22 FSHD patients (19 FSHD1, 3 FSHD2) compared to 23 age and gender-matched healthy controls using a commercial multiplex, microsphere based immune-fluorescent assay of 243 markers (Myriad, Human Discovery MAP 250, v2.0). RESULTS: 169 markers had values sufficient for analysis. Correction for multiple testing identified 7 biomarkers below a 5% false discovery rate: creatine kinase MB fraction (CKMB, 6.52 fold change, P<0.0001), tissue-type plasminogen activator (PLAT, 1.64 fold change, P<0.0001), myoglobin (2.23 fold change, P=0.0001), epidermal growth factor (EGF, 2.33 fold change, P=0.0004), chemokine (C-C motif) ligand 2 (1.48 fold change, P=0.0004), CD 40 ligand (1.89 fold change, P=0.001), and vitronectin (VTN, 1.28 fold change, P=0.001). Moderate correlations to measures of FSHD disease were seen for CKMB, PLAT, and EGF. Markers in the plasminogen pathway (PLAT, serpin peptidase inhibitor, and VTN) were correlated with each other in FSHD but not healthy controls. CONCLUSIONS: Commercial multiplex immune-fluorescent screening is a potentially powerful tool for identifying biomarkers for future FSHD therapeutic trials. Biomarkers identified in this study warrant further study in a larger prospective validation study. PMID- 25705589 TI - HDAC2 expression in parvalbumin interneurons regulates synaptic plasticity in the mouse visual cortex. AB - An experience-dependent postnatal increase in GABAergic inhibition in the visual cortex is important for the closure of a critical period of enhanced synaptic plasticity. Although maturation of the subclass of Parvalbumin (Pv)-expressing GABAergic interneurons is known to contribute to critical period closure, the role of epigenetics on cortical inhibition and synaptic plasticity has not been explored. The transcription regulator, histone deacetylase 2 (HDAC2), has been shown to modulate synaptic plasticity and learning processes in hippocampal excitatory neurons. We found that genetic deletion of HDAC2 specifically from Pv interneurons reduces inhibitory input in the visual cortex of adult mice, and coincides with enhanced long-term depression (LTD) that is more typical of young mice. These findings show that HDAC2 loss in Pv-interneurons leads to a delayed closure of the critical period in the visual cortex and supports the hypothesis that HDAC2 is a key negative regulator of synaptic plasticity in the adult brain. PMID- 25705590 TI - Enhanced vulnerability to distraction does not account for working memory capacity reduction in people with schizophrenia. AB - Although working memory impairment has been well-documented among people with schizophrenia (PSZ), the underlying mechanism of this impairment remains unknown. The present study was conducted in a large sample of PSZ and healthy control subjects (HCS) to test the hypothesis that one putative mechanism-vulnerability to distraction from task-irrelevant stimuli-(1) can account for working memory impairment among PSZ, and (2) is associated with other neurocognitive and clinical variables that are highly predictive of functional outcome in schizophrenia. Participants (127 PSZ and 124 HCS) completed a visual change detection task in which a distractor stimulus (mask) was presented on half of the trials during the delay period between sample and test array. PSZ lost proportionately more information from working memory than did HCS, but this effect was small (Cohen's d = 0.36-0.38), and large differences between groups in working memory capacity remained when differences in distractibility were factored out. Furthermore, vulnerability to distraction was not strongly associated with any clinical or cognitive variables of interest. These results suggest that, although PSZ may be somewhat more susceptible to distraction than HCS, this impairment is unlikely to be a significant factor accounting for the robust capacity deficits observed in this population. PMID- 25705591 TI - General considerations of ruptured abdominal aortic aneurysm: ruptured abdominal aortic aneurysm. AB - Although development of surgical technique and critical care, ruptured abdominal aortic aneurysm still carries a high mortality. In order to obtain good results, various efforts have been attempted. This paper reviews initial management of ruptured abdominal aortic aneurysm and discuss the key point open surgical repair and endovascular aneurysm repair. PMID- 25705592 TI - Surgical Management of Mitral Regurgitation in Patients with Marfan Syndrome during Infancy and Early Childhood. AB - BACKGROUND: Mitral regurgitation is one of the leading causes of cardiovascular morbidity in pediatric patients with Marfan syndrome. The purpose of this study was to contribute to determining the appropriate surgical strategy for these patients. METHODS: From January 1992 to May 2013, six patients with Marfan syndrome underwent surgery for mitral regurgitation in infancy or early childhood. RESULTS: The median age at the time of surgery was 47 months (range, 3 to 140 months) and the median follow-up period was 3.6 years (range, 1.3 to 15.5 years). Mitral valve repair was performed in two patients and four patients underwent mitral valve replacement with a mechanical prosthesis. There was one reoperation requiring valve replacement for aggravated mitral regurgitation two months after repair. The four patients who underwent mitral valve replacement did not experience any complications related to the prosthetic valve. One late death occurred due to progressive emphysema and tricuspid regurgitation. CONCLUSION: Although repair can be an option for some patients, it may not be durable in infantile-onset Marfan syndrome patients who require surgical management during infancy or childhood. Mitral valve replacement is a feasible treatment option for these patients. PMID- 25705593 TI - Outcome and graft patency in coronary artery bypass grafting with coronary endarterectomy. AB - BACKGROUND: Controversy persists regarding the use of coronary endarterectomy (CE) in patients with severe coronary artery disease. We compared the comorbidities and perioperative characteristics of patients undergoing coronary artery bypass grafting (CABG) with and without CE. METHODS: This study was performed in two private hospitals in Shiraz, Iran from May 2010 to December 2011 on 967 patients who underwent CABG without CE and 84 patients who underwent CABG with CE (the CE+ group). After follow-up at 9.66+/-3.65 months post-surgery, 28 patients from the CE+ group underwent angiography to evaluate the patency of grafts and native coronary vessels. RESULTS: Patients in the CE+ group had a more prevalent history of diabetes (48% vs. 36%) and number of diseased vessels (2.88+/-0.39 vs. 2.70+/-0.85). The overall hospital mortality was 1.8%, and no significant difference was observed between the two groups. In the 28 patients who underwent reangiography, 113 vessels were bypassed and 29 endarterectomies were performed, mostly on the left anterior descending artery (12 endarterectomies) and the right coronary artery (8 endarterectomies). In the endarterectomized vessels, a 66% patency rate was found in both the grafts and the native vessels. The native coronary vessels were more likely to be patent when the left internal mammary artery was used as a conduit than when a saphenous vein bypass graft was used. CONCLUSION: The lack of a significant difference in postoperative complications in patients who underwent CABG with or without CE may indicate that CE does not expose patients to a higher risk of complications. Since most of the endarterectomized vessels were shown to be patent during the follow-up period, we propose that endarterectomy is a viable option for patients with severely diseased vessels. PMID- 25705594 TI - Surgical results of third or more cardiac valve operation. AB - BACKGROUND: We evaluated operative outcomes after third or more cardiac operations for valvular heart disease, and analyzed whether pericardial coverage with artificial membrane is helpful for subsequent reoperation. METHODS: From 2000 to 2012, 149 patients (male: female=70: 79; mean age at operation, 57.0+/ 11.3 years) underwent their third to fifth operations for valvular heart disease. Early results were compared between patients who underwent their third operation (n=114) and those who underwent fourth or fifth operation (n=35). Outcomes were also compared between 71 patients who had their pericardium open during the previous operation and 27 patients who had artificial membrane coverage. RESULTS: Intraoperative adverse events occurred in 22 patients (14.8%). Right atrium (n=6) and innominate vein (n=5) were most frequently injured. In-hospital mortality rate was 9.4%. Total cardiopulmonary bypass time (225+/-77 minutes vs. 287+/-134 minutes, p=0.012) and the time required to prepare aortic cross clamp (209+/-57 minutes vs. 259+/-68 minutes, p<0.001) increased as reoperations were repeated. However, intraoperative event rate (13.2% vs. 20.0%), in-hospital mortality (9.6% vs. 8.6%) and postoperative complications were not statistically different according to the number of previous operations. Pericardial closure using artificial membrane at previous operation was not beneficial in reducing intraoperative events (25.9% vs. 18.3%) and shortening operation time preparing aortic cross clamp (248+/-64 minutes vs. 225+/-59 minutes) as compared to no closure. CONCLUSION: Clinical outcomes of the third or more operations for valvular heart disease were acceptable in terms of intraoperative adverse events and in-hospital mortality rates. There were no differences in the incidence of intraoperative adverse events, early mortality and postoperative complications between third cardiac operation and fourth or more. PMID- 25705595 TI - Sternal healing after coronary artery bypass grafting using bilateral internal thoracic arteries: assessment by computed tomography scan. AB - BACKGROUND: This study aimed to investigate sternal healing over time and the incidence of poor sternal healing in patients undergoing coronary artery bypass graft (CABG) surgery using bilateral internal thoracic arteries. METHODS: This study enrolled 197 patients who underwent isolated CABG using skeletonized bilateral internal thoracic arteries (sBITA) from 2006 through 2009. Postoperative computed tomography (CT) angiography was performed on all patients at monthly intervals for three to six months after surgery. In 108 patients, an additional CT study was performed 24 to 48 months after surgery. The axial CT images were used to score sternal fusion at the manubrium, the upper sternum, and the lower sternum. These scores were added to evaluate overall healing: a score of 0 to 1 reflected poor healing, a score of 2 to 4 was defined as fair healing, and a score of 5 to 6 indicated complete healing. Medical records were also retrospectively reviewed to identify perioperative variables associated with poor early sternal healing. RESULTS: Three to six months after surgery, the average total score of sternal healing was 2.07+/-1.52 and 68 patients (34.5%) showed poor healing. Poor healing was most frequently found in the manubrium, which was scored as zero in 72.6% of patients. In multivariate analysis, the factors associated with poor early healing were shorter post-surgery time, older age, diabetes mellitus, and postoperative renal dysfunction. In later CT images, the average sternal healing score improved to 5.88+/-0.38 and complete healing was observed in 98.2% of patients. CONCLUSION: Complete sternal healing takes more than three months after a median sternotomy for CABG using sBITA. Healing is most delayed in the manubrium. PMID- 25705596 TI - Retrospective analysis of thoracoscopic surgery for esophageal submucosal tumors. AB - BACKGROUND: Surgical enucleation is the treatment of choice for esophageal submucosal tumors (SMTs) with symptomatic, larger, or ill-defined lesions. The enucleation of SMTs has traditionally been performed via thoracotomy. However, minimally invasive approaches have recently been introduced and successfully applied. In this study, we present our experiences with the thoracotomic and thoracoscopic approaches to treating SMTs. METHODS: We retrospectively reviewed 53 patients with SMTs who underwent surgical enucleation between August 1996 and July 2013. Demographic and clinical features, tumor-related factors, the surgical approach, and outcomes were analyzed. RESULTS: There were 36 males (67.9%) and 17 females (32.1%); the mean age was 49.2+/-11.8 years (range, 16 to 79 years). Histology revealed leiomyoma in 51 patients, a gastrointestinal stromal tumor in one patient, and schwannoma in one patient. Eighteen patients (34.0%) were symptomatic. Fourteen patients underwent a planned thoracotomic enucleation. Of the 39 patients for whom a thoracoscopic approach was planned, six patients required conversion to thoracotomy because of overly small tumors or poor visualization in five patients and accidental mucosal injury in one patient. No mortality or major postoperative complications occurred. Compared to thoracotomy, the thoracoscopic approach had a slightly shorter operation time, but this difference was not statistically significant (120.0+/-45.6 minutes vs. 161.5+/ 71.1 minutes, p=0.08). A significant difference was found in the length of the hospital stay (9.0+/-3.2 days vs. 16.5+/-5.4 days, p<0.001). CONCLUSION: The thoracoscopic enucleation of submucosal esophageal tumors is safe and is associated with a shorter length of hospital stay compared to thoracotomic approaches. PMID- 25705597 TI - Surgical treatment for occlusion of graft arteriovenous fistula in patients undergoing hemodialysis. AB - BACKGROUND: Maintenance of adequate vascular access for hemodialysis is important in patients with end-stage renal disease. Once arteriovenous fistula (AVF) occlusion occurs, the patient should be treated with rescue therapy. This study was performed to evaluate the results of a rescue therapy for AVF occlusion. METHODS: From January 2008 to December 2012, 47 patients who underwent surgical rescue therapy for AVF occlusion after graft AVF formation, were enrolled in this study. The patients were divided into two groups, namely the graft repair group (group A, n=19) and the thrombectomy group (group B, n=28). Postoperative results of both groups were analyzed retrospectively. RESULTS: There were no statistically significant differences in the clinical characteristics between the two groups. In terms of the duration of AVF patency after the first rescue therapy, group A showed a longer AVF patency duration than group B (24.5+/-21.9 months versus 17.7+/-13.6 months), but there was no statistically significant difference (p=0.310). In terms of the annual frequency of AVF occlusion after the rescue therapy of group A was lower than that of group B (0.59 versus 0.71), but there was no statistically significant difference (p=0.540). The AVF patency rates at 1, 2, 3, and 5 years after the first rescue therapy in group A were 52.6%, 31.5%, 21.0%, and 15.7%, respectively, and those in group B, they were 32.1%, 25.0%, 17.8%, and 7.14%, respectively. There was no statistically significant difference (p=0.402). CONCLUSION: Graft repair revealed comparable results. Although there was no statistically significant difference, the patent duration and annual frequency of AVF occlusion of group A were better than those of group B. Therefore, graft repair is considered as a safe and useful procedure for maintaining graft AVF. PMID- 25705598 TI - Potts shunt in patients with primary pulmonary hypertension. AB - Idiopathic pulmonary arterial hypertension eventually leads to right-sided heart failure and sudden death. Its mortality rate in children is still high, despite improvements in pharmacological therapy, and therefore novel treatments are necessary. The Potts shunt, which creates an anastomosis between the left pulmonary artery and the descending aorta, has been proposed as a theoretically promising palliative surgical technique to decompress the right ventricle. We report the case of a 12-year-old girl with suprasystemic idiopathic pulmonary hypertension and right ventricular failure who underwent a Potts shunt for palliation with good short-term results. PMID- 25705599 TI - Cardiac Resynchronization Therapy in Infant with Dilated Cardiomyopathy during Extracorporeal Membrane Oxygenator. AB - Although heart transplantation is a final therapeutic option in pediatric patients with dilated cardiomyopathy (DCMP), the shortage of pediatric heart donors is a major obstacle. In adults with DCMP characterized by cardiac dyssynchrony, cardiac resynchronization therapy (CRT) is known to be an effective treatment option. However, there is a lack of evidence on the effectiveness of CRT in infants with DCMP. Several studies have reported improvement in hemodynamics and cardiac performance following CRT in infants with DCMP. Here, we report CRT in an infant with DCMP during extracorporeal membrane oxygenation with 5 months of follow-up. PMID- 25705600 TI - Management of recurrent paravalvular leakage in a very high-risk patient: a case report. AB - Interventional device closure has emerged as a less invasive alternative to surgery in the management of paravalvular leakage. However, this procedure involves various problems such as a high probability of residual leakage or hemolysis. Here, we report a case of residual paravalvular leakage despite two attempts at interventional closure in a patient with a history of four previous mitral valve replacements. The fifth operation for the primary repair of paravalvular leakage was performed successfully. Careful evaluation before the procedure and specially designed devices are essential for the interventional treatment of paravalvular leakage. Surgery can be performed adequately in the management of paravalvular leakage even in high-risk patients. PMID- 25705601 TI - Left ventricular pseudoaneurysm after valve replacement. AB - We present a case of left ventricular pseudoaneurysm, which is a very rare and fatal complication of cardiac procedures such as mitral valve replacement. A 55 year-old woman presented to the Department of Thoracic and Cardiovascular Surgery at Hanyang University Seoul Hospital with chest pain. Ten years prior, the patient had undergone double valve replacement due to aortic regurgitation and mitral steno-insufficiency. Surgical repair was successfully performed using a prosthetic pericardial patch via a left lateral thoracotomy. PMID- 25705602 TI - An unusual biatrial cardiac myxoma in a young patient. AB - This is a report of a biatrial cardiac myxoma in a young man with a 10-month history of exertional dyspnea and palpitation. The echocardiogram revealed biatrial myxoma prolapsing through the mitral and tricuspid valves during diastole. All cardiac chambers were enlarged and dysfunctional. The electrocardiogram revealed a rapid ventricular response with atrial flutter rhythm. The masses were resected and diagnosed as myxoma by a histological examination. The follow-up echocardiogram revealed significant improvement in ventricular function and reduction in the cardiac chambers' volume. There was no evidence of myxoma recurrence. The most probable cause of the patient's heart failure was considered to be tachycardia-induced cardiomyopathy. PMID- 25705603 TI - Extra-anatomic Aortic Bypass for the Management of Mid-Aortic Syndrome Caused by Takayasu arteritis. AB - Lower limb ischemia caused by multiple stenosis of the thoracoabdominal aorta is one of the rare clinical manifestations of Takayasu arteritis. The optimal management of such mid-aortic syndrome related with Takayasu arteritis has not been established to date. Here we report a case of extra-anatomic aortic bypass through minimally invasive techniques to treat lower limb ischemia caused by Takayasu arteritis. PMID- 25705604 TI - Thoracic Duct Embolization with Lipiodol for Chylothorax due to Thoracic Endovascular Aortic Repair with Debranching Procedure. AB - Chylothorax is a rare postoperative complication of a thoracic surgical procedure. Here, we report a case of chylothorax after thoracic endovascular aortic repair with debranching for the distal arch aneurysm of the aorta. First, the patient was treated by a medical method (nil per os, fat-free diet, and octreotide), but this method failed. The patient strongly refused surgical treatment. Therefore, we tried to occlude the thoracic duct by lymphangiography Lipiodol, and this line of treatment was successful. PMID- 25705605 TI - Video-assisted thoracoscopic division of vascular rings. AB - This study reports our early experience with thoracoscopic division of vascular rings. Three patients were reviewed; their ages at surgery were 25 months, 4 years, and 57 years. All patients were suffering from complete vascular rings involving combinations of the right aortic arch, left ligamentum arteriosum, Kommerell's diverticulum, and retroesophageal left subclavian artery. The median surgical time was 180.5 minutes, and the patients showed immediate recovery. Three complications, namely chylothorax, transient supraventricular tachycardia, and left vocal cord palsy, were observed. Our early experience indicates that thoracoscopic division of a vascular ring may provide early recovery and could be a promising operative choice. PMID- 25705606 TI - Diffuse Large B-cell Lymphoma Arising from Chronic Tuberculous Empyema. AB - Pyothorax-associated lymphoma is a relatively rare type of lymphoma that occurs in patients who have long histories of tuberculous pleuritis or induced pneumothorax. It is a type of non-Hodgkin's lymphoma of mainly the B-cell phenotype and is strongly associated with Epstein-Barr virus infection. A majority of these cases have been reported in Japan, although some cases have occurred in Western countries. Here, we describe a case of pyothorax-associated lymphoma in a patient with a 30-year history of chronic tuberculous empyema. The patient underwent decortication under the impression of chronic empyema with fistula. The histopathologic diagnosis was a diffuse large B-cell lymphoma associated chronic inflammation. PMID- 25705607 TI - Primary Sternal Osteomyelitis Caused by Actinomyces israelii. AB - Primary sternal osteomyelitis is a rare disease. Common infectious organisms causing primary sternal osteomyelitis include Staphylococcus aureus and Pseudomonas aeruginosa. Actinomyces species are common saprophytes of the oral cavity, but there have been few reports in the literature of primary sternal osteomyelitis caused by Actinomyces species. We describe a case of primary sternal osteomyelitis caused by Actinomyces israelii without pulmonary involvement. PMID- 25705608 TI - A successfully treated case of gorham-stout syndrome with sternal involvement. AB - Gorham-Stout Syndrome (GSS) is a rare disease characterized by localized bone resorption. Any part of the skeleton may be affected; therefore, symptoms can vary depending on the site involved. Pathological analysis reveals lymphovascular proliferation and osteolysis in the affected lesion, but the etiology of the disease is poorly understood. When GSS occurs in the chest, chylothorax or respiratory failure may occur. Thus far, a standard treatment for GSS has not been established, and the prognosis remains unknown. The following case report describes a successfully treated case of GSS in a 16-year-old boy with an affected sternum and ribs. PMID- 25705609 TI - An unusual presentation of schwannoma in the interatrial space. AB - We report the case of a 69-year-old woman who was diagnosed with intracardiac schwannoma without symptoms. Preoperative echocardiography and cardiac magnetic resonance imaging showed a mass attached to the interatrial septum. The initial diagnosis was a myxoma or a bronchogenic cyst. The tumor was successfully excised under cardiopulmonary bypass. However, the pathology of the excised tumor was consistent with schwannoma. We suggest that cardiovascular surgeons consider schwannoma to be a possible differential diagnosis for a mass close to the interatrial septum. PMID- 25705610 TI - Epigenome engineering in cancer: fairytale or a realistic path to the clinic? AB - Epigenetic modifications such as histone post-transcriptional modifications, DNA methylation, and non-protein-coding RNAs organize the DNA in the nucleus of eukaryotic cells and are critical for the spatio-temporal regulation of gene expression. These epigenetic modifications are reversible and precisely regulated by epigenetic enzymes. In addition to genetic mutations, epigenetic modifications are highly disrupted in cancer relative to normal tissues. Many epigenetic alterations (epi-mutations) are associated with aberrations in the expression and/or activity of epigenetic enzymes. Thus, epigenetic regulators have emerged as prime targets for cancer therapy. Currently, several inhibitors of epigenetic enzymes (epi-drugs) have been approved for use in the clinic to treat cancer patients with hematological malignancies. However, one potential disadvantage of epi-drugs is their lack of locus-selective specificity, which may result in the over-expression of undesirable parts of the genome. The emerging and rapidly growing field of epigenome engineering has opened new grounds for improving epigenetic therapy in view of reducing the genome-wide "off-target" effects of the treatment. In the current review, we will first describe the language of epigenetic modifications and their involvement in cancer. Next, we will overview the current strategies for engineering of artificial DNA-binding domains in order to manipulate and ultimately normalize the aberrant landscape of the cancer epigenome (epigenome engineering). Lastly, the potential clinical applications of these emerging genome-engineering approaches will be discussed. PMID- 25705611 TI - Milk- and solid-feeding practices and daycare attendance are associated with differences in bacterial diversity, predominant communities, and metabolic and immune function of the infant gut microbiome. AB - The development of the infant intestinal microbiome in response to dietary and other exposures may shape long-term metabolic and immune function. We examined differences in the community structure and function of the intestinal microbiome between four feeding groups, exclusively breastfed infants before introduction of solid foods (EBF), non-exclusively breastfed infants before introduction of solid foods (non-EBF), EBF infants after introduction of solid foods (EBF+S), and non EBF infants after introduction of solid foods (non-EBF+S), and tested whether out of-home daycare attendance was associated with differences in relative abundance of gut bacteria. Bacterial 16S rRNA amplicon sequencing was performed on 49 stool samples collected longitudinally from a cohort of 9 infants (5 male, 4 female). PICRUSt metabolic inference analysis was used to identify metabolic impacts of feeding practices on the infant gut microbiome. Sequencing data identified significant differences across groups defined by feeding and daycare attendance. Non-EBF and daycare-attending infants had higher diversity and species richness than EBF and non-daycare attending infants. The gut microbiome of EBF infants showed increased proportions of Bifidobacterium and lower abundance of Bacteroidetes and Clostridiales than non-EBF infants. PICRUSt analysis indicated that introduction of solid foods had a marginal impact on the microbiome of EBF infants (24 enzymes overrepresented in EBF+S infants). In contrast, over 200 bacterial gene categories were overrepresented in non-EBF+S compared to non-EBF infants including several bacterial methyl-accepting chemotaxis proteins (MCP) involved in signal transduction. The identified differences between EBF and non EBF infants suggest that breast milk may provide the gut microbiome with a greater plasticity (despite having a lower phylogenetic diversity) that eases the transition into solid foods. PMID- 25705612 TI - The complex amino acid diet of Francisella in infected macrophages. AB - Francisella tularensis, the agent of the zoonotic disease tularemia, is a highly infectious bacterium for a large number of animal species and can be transmitted to humans by various means. The bacterium is able to infect a variety of cell types but replicates in mammalian hosts mainly in the cytosol of infected macrophages. In order to resist the stressful and nutrient-restricted intracellular environments, it encounters during its systemic dissemination, Francisella has developed dedicated stress resistance mechanisms and adapted its metabolic and nutritional needs. Recent data form our laboratory and from several other groups have shown that Francisella simultaneously relies on multiple host amino acid sources during its intracellular life cycle. This review will summarize how intracellular Francisella use different amino acid sources, and their role in phagosomal escape and/or cytosolic multiplication and systemic dissemination. We will first summarize the data that we have obtained on two amino acid transporters involved in Francisella phagosomal escape and cytosolic multiplication i.e., the glutamate transporter GadC and the asparagine transporter AnsP, respectively. The specific contribution of glutamate and asparagine to the physiology of the bacterium will be evoked. Then, we will discuss how Francisella has adapted to obtain and utilize host amino acid resources, and notably the contribution of host transporters and autophagy process in the establishment of a nutrient-replete intracellular niche. PMID- 25705613 TI - Autogenous fresh demineralized tooth graft prepared at chairside for dental implant. AB - BACKGROUND: This study aimed to evaluate the clinical usefulness of autogenous fresh demineralized tooth (auto-FDT) graft prepared at the chairside for alveolar bone grafting during dental implant surgery. METHODS: In total, 38 patients requiring both tooth extraction (for endodontic or periodontal reasons or third molar extraction) and alveolar bone regeneration for dental implant placement were included. Within 2 h after clean extraction, the teeth were prepared at the chairside to serve as bone graft material. In the same sitting, blocks or chips of this graft material were used to reconstruct defects at the osteotomy site simultaneously with or before implant placement. Twelve months after prosthesis fabrication and placement, the clinical findings and implant success rates were evaluated. Histological studies were randomly conducted for selected cases. RESULTS: Clinical evaluation showed favorable wound healing with minimal complications and good bone support for the implants. No implant was lost after 12 months of function following prosthetic rehabilitation. Histological examination revealed new bone formation induced by the graft material. CONCLUSIONS: Chairside preparation of autogenous fresh demineralized teeth after extraction can be a useful alternative to the use of autogenous bone or other graft materials for the immediate reconstruction of alveolar bone defects to facilitate subsequent implant placement. PMID- 25705614 TI - NO Better Way to Protect the Heart during Ischemia-Reperfusion: To be in the Right Place at the Right Time. PMID- 25705615 TI - Putting public health ethics into practice: a systematic framework. AB - It is widely acknowledged that public health practice raises ethical issues that require a different approach than traditional biomedical ethics. Several frameworks for public health ethics (PHE) have been proposed; however, none of them provides a practice-oriented combination of the two necessary components: (1) a set of normative criteria based on an explicit ethical justification and (2) a structured methodological approach for applying the resulting normative criteria to concrete public health (PH) issues. Building on prior work in the field and integrating valuable elements of other approaches to PHE, we present a systematic ethical framework that shall guide professionals in planning, conducting, and evaluating PH interventions. Based on a coherentist model of ethical justification, the proposed framework contains (1) an explicit normative foundation with five substantive criteria and seven procedural conditions to guarantee a fair decision process, and (2) a six-step methodological approach for applying the criteria and conditions to the practice of PH and health policy. The framework explicitly ties together ethical analysis and empirical evidence, thus striving for evidence-based PHE. It can provide normative guidance to those who analyze the ethical implications of PH practice including academic ethicists, health policy makers, health technology assessment bodies, and PH professionals. It will enable those who implement a PH intervention and those affected by it (i.e., the target population) to critically assess whether and how the required ethical considerations have been taken into account. Thereby, the framework can contribute to assuring the quality of ethical analysis in PH. Whether the presented framework will be able to achieve its goals has to be determined by evaluating its practical application. PMID- 25705616 TI - Lean-proteome strains - next step in metabolic engineering. PMID- 25705617 TI - Nitric oxide, interorganelle communication, and energy flow: a novel route to slow aging. AB - The mitochondrial lifecycle (mitochondrial biogenesis, dynamics, and removal by mitophagy) is carefully orchestrated to ensure the efficient generation of cellular energy and to maintain reactive oxygen species (ROS) production within an optimal range for cellular health. Based on latest research, these processes largely depend on mitochondrial interactions with other cell organelles, so that the ER- and peroxisome-mitochondrial connections might intervene in the control of cellular energy flow. Damaged organelles are cleared by autophagic mechanisms to assure the quality and proper function of the intracellular organelle pool. Nitric oxide (NO) generated through the endothelial nitric oxide synthase (eNOS) acts a gas signaling mediator to promote mitochondrial biogenesis and bioenergetics, with a favorable impact in diverse chronic diseases of the elderly. Obesity, diabetes and aging share common pathophysiological mechanisms, including mitochondrial impairment and dysfunctional eNOS. Here we review the evidences that eNOS-dependent mitochondrial biogenesis and quality control, and possibly the complex interplay among cellular organelles, may be affected by metabolic diseases and the aging processes, contributing to reduce healthspan and lifespan. Drugs or nutrients able to sustain the eNOS-NO generating system might contribute to maintain organelle homeostasis and represent novel preventive and/or therapeutic approaches to chronic age-related diseases. PMID- 25705618 TI - What's New in the Toolbox for Constipation and Fecal Incontinence? AB - Constipation and fecal incontinence (FI) are common complaints predominantly affecting the elderly and women. They are associated with significant morbidity and high healthcare costs. The causes are often multi-factorial and overlapping. With the advent of new technologies, we have a better understanding of their underlying pathophysiology which may involve disruption at any levels along the gut-brain-microbiota axis. Initial approach to management should always be the exclusion of secondary causes. Mild symptoms can be approached with conservative measures that may include dietary modifications, exercise, and medications. New prokinetics (e.g., prucalopride) and secretagogues (e.g., lubiprostone and linaclotide) are effective and safe in constipation. Biofeedback is the treatment of choice for dyssynergic defecation. Refractory constipation may respond to neuromodulation therapy with colectomy as the last resort especially for slow transit constipation of neuropathic origin. Likewise, in refractory FI, less invasive approach can be tried first before progressing to more invasive surgical approach. Injectable bulking agents, sacral nerve stimulation, and SECCA procedure have modest efficacy but safe and less invasive. Surgery has equivocal efficacy but there are promising new techniques including dynamic graciloplasty, artificial bowel sphincter, and magnetic anal sphincter. Despite being challenging, there are no short of alternatives in our toolbox for the management of constipation and FI. PMID- 25705619 TI - Current and emerging therapy for celiac disease. AB - At present, strict and lifelong gluten-free diet is the only effective treatment for celiac disease. Even small amounts of gluten (50 mg/day) can be immunogenic; therefore all food and food items and drugs that contain gluten and its derivatives must be eliminated completely from the diet. While prescribing gluten free diet is easy; the key to the success is the dietary counseling by a nutrition specialist and maintenance of adherence to GFD by the patient. In recent times, a number of targets to halt the process of immunological injury have been explored to find out alternative treatment for celiac disease. These targets include exploration of ancient wheat if they are less immunogenic, intra luminal digestion of gluten using prolylendopeptidases, pretreatment of whole gluten with bacterial-derived peptidase before ingestion; prevention of passage of immunogenic peptides through the tight junctions such as zonulin antagonists, Blocking of HLA-DQ2 to prevent binding of immunogenic peptides, inhibition of transglutaminase 2, immune-modulation, and induction of tolerance to gluten using gluten tolerizing vaccines, use of gluten-sequestering polymers, use of anti inflammatory drugs (glucocorticoids, budesonides) and anti-cytokines such as anti TNF-alpha, and anti-interleukin-15. While many of these targets are still in the pre-clinical phase, some of them including zonulin antagonist and endopeptidases have already reached phase II and phase III clinical trials. Furthermore, while these targets appear very exciting; they at best are likely to be used as adjunctive therapy rather than a complete replacement for gluten-free diet. PMID- 25705620 TI - Surgical site infections following spine surgery: eliminating the controversies in the diagnosis. AB - Surgical site infection (SSI) following spine surgery is a dreaded complication with significant morbidity and economic burden. SSIs following spine surgery can be superficial, characterized by obvious wound drainage or deep-seated with a healed wound. Staphylococcus aureus remains the principal causal agent. There are certain pre-operative risk factors that increase the risk of SSI, mainly diabetes, smoking, steroids, and peri-operative transfusions. Additionally, intra operative risk factors include surgical invasiveness, type of fusion, implant use, and traditional instead of minimally invasive approach. A high level of suspicion is crucial to attaining an early definitive diagnosis and initiating appropriate management. The most common presenting symptom is back pain, usually manifesting 2-4 weeks and up to 3 months after a spinal procedure. Scheduling a follow-up visit between weeks 2 and 4 after surgery is therefore necessary for early detection. Inflammatory markers are important diagnostic tools, and comparing pre-operative with post-operative levels should be done when suspecting SSIs following spine surgery. Particularly, serum amyloid A is a novel inflammatory marker that can expedite the diagnosis of SSIs. Magnetic resonance imaging remains the diagnostic modality of choice when suspecting a SSI following spine surgery. While 18F-fluorodeoxyglucose-positron emission tomography is not widely used, it may be useful in challenging cases. Despite their low yield, blood cultures should be collected before initiating antibiotic therapy. Samples from wound drainage should be sent for Gram stain and cultures. When there is a high clinical suspicion of SSI and in the absence of superficial wound drainage, computed tomography-guided aspiration of paraspinal collections is warranted. Unless the patient is hemodynamically compromised, antibiotics should be deferred until proper specimens for culture are secured. PMID- 25705621 TI - Molecular handoffs in nitrergic neurotransmission. AB - Postsynaptic density (PSD) proteins in excitatory synapses are relatively immobile components, while there is a structured organization of mobile scaffolding proteins lying beneath the PSDs. For example, shank proteins are located further away from the membrane in the cytosolic faces of the PSDs, facing the actin cytoskeleton. The rationale of this organization may be related to important roles of these proteins as "exchange hubs" for the signaling proteins for their migration from the subcortical cytosol to the membrane. Notably, PSD95 have also been demonstrated in prejunctional nerve terminals of nitrergic neuronal varicosities traversing the gastrointestinal smooth muscles. It has been recently reported that motor proteins like myosin Va play important role in transcytosis of nNOS. In this review, the hypothesis is forwarded that nNOS delivered to subcortical cytoskeleton requires interactions with scaffolding proteins prior to docking at the membrane. This may involve significant role of "shank," named for SRC-homology (SH3) and multiple ankyrin repeat domains, in nitric oxide synthesis. Dynein light chain LC8-nNOS from acto-myosin Va is possibly exchanged with shank, which thereafter facilitates transposition of nNOS for binding with palmitoyl-PSD95 at the nerve terminal membrane. Shank knockout mice, which present with features of autism spectrum disorders, may help delineate the role of shank in enteric nitrergic neuromuscular transmission. Deletion of shank3 in humans is a monogenic cause of autism called Phelan McDermid syndrome. One fourth of these patients present with cyclical vomiting, which may be explained by junctionopathy resulting from shank deficit in enteric nitrergic nerve terminals. PMID- 25705622 TI - Beyond the Intestinal Celiac Mucosa: Diagnostic Role of Anti-TG2 Deposits, a Systematic Review. AB - AIM: To review the existing literature on the role and significance of intestinal transglutaminase 2 immunoglobulin A deposits (TG2 deposits) in patients with overt celiac disease (CD), potential celiac disease (PCD), and other autoimmune or gluten-related conditions. METHODS: We conducted a systematic review of studies published in English, evaluating presence and characteristics of TG2 deposits in subjects with overt CD, PCD, gluten-related diseases [dermatitis herpetiformis (DH), gluten-ataxia (GA)], autoimmune disorders (type-1 diabetes), and other conditions. Studies were identified through a MEDLINE search (1950 2013). RESULTS: Twenty-three studies were included in the review. Eleven studies were performed in children. Overall TG2 deposits were present in 100% of adults with overt CD, while in children prevalence ranged from 73.2 to 100%. Six studies with an established definition of PCD were considered, prevalence of deposits ranging from 64.7 to 100%. A single study followed-up PCD patients with repeated biopsies and identified presence of intestinal deposits as the best marker to reveal progression toward villous atrophy. Two studies investigated presence of deposits in DH, reporting prevalence between 63 and 79%. A single study documented TG2 deposits in 100% of patients with GA. In children with type-1 diabetes (T1D), positivity of intestinal TG2 deposits ranged from 25 to 78%. CONCLUSION: Transglutaminase 2 IgA deposits seem to be a constant feature in overt CD patients and are frequently detectable in other gluten-related conditions (DH and GA). The vast majority of PCD patients express TG2 deposits at the intestinal level, but no sufficient data are available to exactly define their prognostic role as a marker of evolution toward overt CD. The frequent finding of TG2 deposits in the intestinal mucosa of patients with T1D is an interesting observation deserving further evaluation. PMID- 25705623 TI - Geriatric medicine in an aging society: up for a challenge? PMID- 25705624 TI - A grand challenge of factors influencing lung health. PMID- 25705625 TI - Thrombosis Prevention without Anticoagulation. PMID- 25705626 TI - Intestinal tumor in a dish. AB - Predicting the response of colorectal cancer (CRC) tumors to novel chemotherapeutic agents is significantly complicated by their underlying genetic and epigenetic diversity. Large-scale clinical trials involving thousands of patients are often necessary in order to accurately determine efficacy during drug development. Recent advances in genetic sequencing has allowed us to improve the prediction of drug response through genetic stratification of patients into smaller populations, yet the complexity of the cancer genome still often confounds accuracy of drug response prediction. Ultimately, we may need to replicate patient's own tumor in a dish in order to test drug responses so that the optimal treatment can be identified. We recently developed highly efficient and tractable organoid culture system for intestinal stem cells, in which single stem cells form 3D structures recapitulating original tissue architecture. This technology has also been applied to colorectal tumors and enables us to monitor the growth and response of the patient's own tumors. In this review, we provide an overview focusing on CRC organoid culture and its perspective for clinical applications. PMID- 25705627 TI - Challenges in nuclear medicine: innovative theranostic tools for personalized medicine. PMID- 25705629 TI - Novel Idea: Virulence-Based Therapy Against Helicobacter pylori Infection (Smart Therapy). PMID- 25705628 TI - Myosin Va but Not nNOSalpha is Significantly Reduced in Jejunal Musculomotor Nerve Terminals in Diabetes Mellitus. AB - Nitric oxide (NO) mediated slow inhibitory junction potential and mechanical relaxation after electrical field stimulation (EFS) is impaired in diabetes mellitus. Externally added NO donor restore nitrergic function, indicating that this reduction result from diminution of NO synthesis within the pre-junctional nerve terminals. The present study aimed to investigate two specific aims that may potentially provide pathophysiological insights into diabetic nitrergic neuropathy. Specifically, alteration in nNOSalpha contents within jejunal nerve terminals and a local subcortical transporter myosin Va was tested 16 weeks after induction of diabetes by low dose streptozotocin (STZ) in male Wistar rats. The results show that diabetic rats, in contrast to vehicle treated animals, have: (a) nearly absent myosin Va expression in nerve terminals of axons innervating smooth muscles and (b) significant decrease of myosin Va in neuronal soma of myenteric plexus. In contrast, nNOSalpha staining in diabetic jejunum neuromuscular strips showed near intact expression in neuronal cell bodies. The space occupancy of nitrergic nerve fibers was comparable between groups. Normal concentration of nNOSalpha was visualized within a majority of nitrergic terminals in diabetes, suggesting intact axonal transport of nNOSalpha to distant nerve terminals. These results reveal the dissociation between presences of nNOSalpha in the nerve terminals but deficiency of its transporter myosin Va in the jejunum of diabetic rats. This significant observation of reduced motor protein myosin Va within jejunal nerve terminals may potentially explain impairment of pre-junctional NO synthesis during EFS of diabetic gut neuromuscular strips despite presence of the nitrergic synthetic enzyme nNOSalpha. PMID- 25705630 TI - What is the Future of the Gut Microbiota-Related Treatment? Toward Modulation of Microbiota in Preventive and Therapeutic Medicine. PMID- 25705631 TI - Similarity in Transcytosis of nNOSalpha in Enteric Nerve Terminals and Beta Cells of Pancreatic Islet. PMID- 25705632 TI - Biofilm Disrupting Technology for Orthopedic Implants: What's on the Horizon? AB - The use of orthopedic implants in joints has revolutionized the treatment of patients with many debilitating chronic musculoskeletal diseases such as osteoarthritis. However, the introduction of foreign material into the human body predisposes the body to infection. The treatment of these infections has become very complicated since the orthopedic implants serve as a surface for multiple species of bacteria to grow at a time into a resistant biofilm layer. This biofilm layer serves as a protectant for the bacterial colonies on the implant making them more resistant and difficult to eradicate when using standard antibiotic treatment. In some cases, the use of antibiotics alone has even made the bacteria more resistant to treatment. Thus, there has been surge in the creation of non-antibiotic anti-biofilm agents to help disrupt the biofilms on the orthopedic implants to help eliminate the infections. In this study, we discuss infections of orthopedic implants in the shoulder then we review the main categories of anti-biofilm agents that have been used for the treatment of infections on orthopedic implants. Then, we introduce some of the newer biofilm disrupting technology that has been studied in the past few years that may advance the treatment options for orthopedic implants in the future. PMID- 25705633 TI - A bridge between multi-omics data and the management of hepatocellular carcinoma. PMID- 25705634 TI - Multi-omics in prognosis of hepatocellular carcinoma. PMID- 25705635 TI - Comprehensive characterization of hepatitis B virus-associated multifocal hepatocellular carcinoma using a multi-omics strategy. PMID- 25705636 TI - Multifocal hepatocellular carcinoma: intrahepatic metastasis or multicentric carcinogenesis? AB - Multifocal Hepatocellular carcinoma (HCC) may be multiple HCCs of multicentric origin (MO) or intrahepatic metastases (IM) arising from a primary HCC. Numerous attempts to differentiate the two types of multifocal HCC have been made including the valuation of the clinicopathologic characteristics of MO and IM patients and the recurrence time, loss-of-heterozygosity analysis of specific DNA microsatellite loci to distinguish multiclonal MO from IM of monoclonal origin, and the research of diagnostic and progression markers through genomic and proteomic analyses. These approaches, however, have been unsatisfactory hitherto. Recently, a multi-omic analysis of HBV-related multifocal HCCs, including intergraded genomics and transcriptomics, was performed and the results, validated by a cohort of 174 HCC patients, were correlated with HCC clinicopathological data. The two multifocal HCC types were effectively discerned by multi-omics profiling that could predict HCC clonality and aggressiveness. Further, the dual-specificity protein kinase TTK was recognized as a prognostic marker for HCC. Multi-omics strategy potentially opens new perspectives for the diagnosis, prognosis and personalized treatment of multi-focal HCC. Further work aimed at extending this strategy to HCC with other etiology, simplifying the analysis, and reducing its costs is necessary for its routine clinical application. PMID- 25705637 TI - Recent advances in the development of farnesoid X receptor agonists. AB - Farnesoid X receptors (FXRs) are nuclear hormone receptors expressed in high amounts in body tissues that participate in bilirubin metabolism including the liver, intestines, and kidneys. Bile acids (BAs) are the natural ligands of the FXRs. FXRs regulate the expression of the gene encoding for cholesterol 7 alpha hydroxylase, which is the rate-limiting enzyme in BA synthesis. In addition, FXRs play a critical role in carbohydrate and lipid metabolism and regulation of insulin sensitivity. FXRs also modulate live growth and regeneration during liver injury. Preclinical studies have shown that FXR activation protects against cholestasis-induced liver injury. Moreover, FXR activation protects against fatty liver injury in animal models of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), and improved hyperlipidemia, glucose intolerance, and insulin sensitivity. Obeticholic acid (OCA), a 6alpha-ethyl derivative of the natural human BA chenodeoxycholic acid (CDCA) is the first-in class selective FXR agonist that is ~100-fold more potent than CDCA. Preliminary human clinical trials have shown that OCA is safe and effective. In a phase II clinical trial, administration of OCA was well-tolerated, increased insulin sensitivity and reduced markers of liver inflammation and fibrosis in patients with type II diabetes mellitus and NAFLD. In two clinical trials of OCA in patients with primary biliary cirrhosis (PBC), a progressive cholestatic liver disease, OCA significantly reduced serum alkaline phosphatase (ALP) levels, an important disease marker that correlates well with clinical outcomes of patients with PBC. Together, these studies suggest that FXR agonists could potentially be used as therapeutic tools in patients suffering from nonalcoholic fatty and cholestatic liver diseases. Larger and Longer-term studies are currently ongoing. PMID- 25705638 TI - Osteonecrosis of the knee: review. AB - Osteonecrosis is a devastating disease that can lead to end-stage arthritis of various joint including the knee. There are three categories of osteonecrosis that affect the knee: spontaneous osteonecrosis of the knee (SONK), secondary, and post-arthroscopic. Regardless of osteonecrosis categories, the treatment of this disease aims to halt further progression or delay the onset of end-stage arthritis of the knee. However, once substantial joint surface collapse has occurred or there are sign of degenerative arthritis, joint arthroplasty is the most appropriate treatment option. Currently, the non-operative treatment options consist of observation, non-steroidal anti-inflammatory drugs (NSAIDs), protected weight bearing, and analgesia as needed. Operative interventions include joint preserving surgery, unilateral knee arthroplasty (UKA), or total knee arthroplasty (TKA) depending on the extent and type of disease. Joint preserving procedures (i.e., arthroscopy, core decompression, osteochondral autograft, and bone grafting) are usually attempted in pre-collapse and some post-collapse lesions, when the articular cartilage is generally intact with only the underlying subchondral bone being affected. Conversely, after severe subchondral collapse has occurred, procedures that attempt to salvage the joint are rarely successful and joint arthroplasty are necessary to relieve pain. The purpose of this article is to highlight the recent evidence concerning the treatment options across the spectrum of management of osteonecrosis of the knee including lesion observation, medications, joint preserving techniques, and total joint arthroplasties. PMID- 25705639 TI - Advances and challenges in the molecular biology and treatment of glioblastoma-is there any hope for the future? AB - Malignant gliomas, such as glioblastoma multiforme (GBM), present some of the greatest challenges in the management of cancer patients worldwide. Even with aggressive surgical resections and recent advances in radiotherapy and chemotherapy, the prognosis for GBM patients remains dismal and quality of life is poor. Although new molecular pathways crucial to the biology and invasive ability of GBM are coming to light, translation of basic science achievements into clinical practice is slow. Optimal management requires a multidisciplinary approach and knowledge of potential complications arising from both disease and treatment. To help illustrate "where we are going" with GBM, we here include a detailed depiction of the molecular alterations underlying this fatal disease, as well as intensive research over the past two decades that has led to considerable advances in the understanding of basic GBM biology, pathogenesis and therapeutic approaches. PMID- 25705640 TI - Cardiovascular disease in systemic sclerosis. AB - Cardiovascular (CV) system involvement is a frequent complication of autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). It still remains unclear if a premature atherosclerosis (ATS) occurs even in systemic sclerosis (SSc). Although microvascular disease is a hallmark of SSc, in the last few years a number of studies highlighted a higher prevalence of macrovascular disease in SSc patients in comparison to healthy individuals and these data have been correlated with a poorer prognosis. The mechanisms promoting ATS in SSc are not fully understood, but it is believed to be secondary to multi system organ inflammation, endothelial wall damage and vasculopathy. Both traditional risk factors and endothelial dysfunction have been proposed to participate to the onset and progression of ATS in such patients. In particular, endothelial cell injury induced by anti-endothelial antibodies, ischemia/reperfusion damage, immune-mediated cytotoxicity represent the main causes of vascular injury together with an impaired vascular repair mechanism that determine a defective vasculogenesis. Aim of this review is to analyse both causes and clinical manifestations of macrovascular involvement and ATS in SSc. PMID- 25705641 TI - Diagnosis of Helicobacter pylori using the rapid urease test. AB - Helicobacter pylori (H. pylori) is a major human pathogen which causes progressive gastroduodenal damage. Guidelines recommend that, unless there are compelling reasons to delay, treatment is indicated for all patients in whom the infection is diagnosed. The rapid urease test (RUT) is a popular diagnostic test in that it is a rapid, cheap and simple test that detects the presence of urease in or on the gastric mucosa. The sensitivity and specificity are generally high and many versions have been approved for use in humans. Best results are obtained if biopsies are obtained from both the antrum and corpus. The tissue sample embedded in the RUT gel can also be utilized for other tests such as for molecular based tests of microbial susceptibility or for host factors. False positive results are rare if the RUT contains an antibacterial agent to prevent growth of urease-containing contaminants and the tests are discarded at 24 hours. The use of antimicrobial drugs and proton pump inhibitors as well as the presence of intestinal metaplasia may result in false-negative results. A negative test should not be used as the criteria for cure or in cases where accuracy is important for patient management such as in upper gastrointestinal bleeding. Interpretation of the test should take into account the pretest probability and the prevalence of H. pylori in the population. The test can also be used to provide an informal assessment of the accuracy of the histopathology result and discrepancies should prompt a review of the histopathology and discussions with the pathologist. PMID- 25705642 TI - Diagnosis of Helicobacter pylori by invasive test: histology. AB - The accurate detection of Helicobacter pylori (H. pylori), a major cause of gastric cancer, is essential for managing infected patients. Among various diagnostic methods, histology plays a pivotal role in detecting H. pylori and it also provided more information about the degree of inflammation and associated pathology, such as, atrophic gastritis (AG), intestinal metaplasia (IM), and gastric cancer. The diagnosis of H. pylori could be performed in hematoxylin and eosin (H&E) staining, however the specificity can be improved by special stains such as modified Giemsa, Warthin-Starry silver, Genta, and immunohistochemical (IHC) stains. Thus, at least two kinds of stain methods are recommended for diagnosis in practice; H&E staining is routine and Giemsa stain seems to have advantage over other stains because of its simplicity and consistency. IHC stain may be useful in special situations. However, histology has several limitations, including higher cost, longer turnaround time, dependence on the skills of the operator, and interobserver variability in assessment. Furthermore, the density of H. pylori can vary at different sites, possibly leading to sampling error, and the sensitivity of histology may decrease in patients taking proton pump inhibitor (PPI). The updated Sydney system recommend to take five biopsy specimens from different sites; however if this is not possible, the gastric body greater curvature could be a better site to detect current H. pylori infections, especially in the presence of peptic ulcer bleeding, AG and IM, or gastric cancer. In the presence of peptic ulcer bleeding, histology is also the most reliable test. PPIs can affect the result of histology and should be stopped 2 weeks before testing. Postbiopsy bleeding may be increased in patients with anticoagulation therapy, so careful precautions should be taken. PMID- 25705643 TI - Evaluation of methods for H. pylori detection in PPI consumption using culture, rapid urease test and smear examination. AB - BACKGROUND: Culture, rapid urease test (RUT) and smear examination have been used as reliable methods for diagnosis of H. pylori infection. Accurate performance of these tests requires good quality biopsies with considerable number of bacterial cells. However, consumption of proton pump inhibitors (PPIs) affects growth and urease activity of H. pylori, leading to false negative results. In this study the efficacy of culture, RUT and smear examination was assessed and the effect of PPI consumption was evaluated. METHODS: Two antral biopsies from 530 dyspeptic patients with and without PPI consumption were used for RUT, culture and smear examination. Statistical analysis was used to determine the association between results of culture, RUT or smear examination and PPI consumption. Sensitivity and specificity of three tests were calculated by standard methods. RESULTS: H. pylori infection was detected in 40% of patients by culture, 48.3% by RUT and 21.1% by smear examination and the overall detection rate was 54%. A strong correlation was found between PPI consumption and negative results of culture and RUT (P<0.05) but not smear examination. The sensitivity of RUT was reduced as a result of PPI consumption. This reduction was more profound in 1-hr RUT (92.2% to 74.4%) compared with 24-hr RUT (93.9% to 81.6%). CONCLUSIONS: Prevalence of H. pylori was declined, compared with previous studies. This decrement could be due to false negative results of H. pylori diagnostic tests, among which culture and RUT are mostly affected by PPI. Accordingly, PPI consumption should be stopped before performance of endoscopy. PMID- 25705644 TI - Stereotactic ablative radiotherapy: aim for a cure of cancer. PMID- 25705645 TI - Prof. Weihai Xu: 3D intracranial artery printing transforms the future of stroke. PMID- 25705646 TI - Chemical Atherogenesis: Role of Endogenous and Exogenous Poisons in Disease Development. AB - Chemical atherogenesis is an emerging field that describes how environmental pollutants and endogenous toxins perturb critical pathways that regulate lipid metabolism and inflammation, thus injuring cells found within the vessel wall. Despite growing awareness of the role of environmental pollutants in the development of cardiovascular disease, the field of chemical atherogenesis can broadly include both exogenous and endogenous poisons and the study of molecular, biochemical, and cellular pathways that become dysregulated during atherosclerosis. This integrated approach is logical because exogenous and endogenous toxins often share the same mechanism of toxicity. Chemical atherogenesis is a truly integrative discipline because it incorporates concepts from several different fields, including biochemistry, chemical biology, pharmacology, and toxicology. This review will provide an overview of this emerging research area, focusing on cellular and animal models of disease. PMID- 25705647 TI - A brief analysis of suicide methods and trends in Virginia from 2003 to 2012. AB - BACKGROUND: The objective is to analyze and compare Virginia suicide data from 2003 to 2012 to US suicide data. METHODS: Suicide trends by method, age, gender, and race were obtained from Virginia's Office of the Chief Medical Examiner's annual reports. RESULTS: Similar to US suicide rates, suicide rates in Virginia increased between 2003 and 2012 from 10.9/100,000 people to 12.9/100,000 people. The most common methods were firearm, asphyxia, and intentional drug overdose, respectively. The increase in asphyxia (r = 0.77, P <= 0.01) and decrease in CO poisoning (r = -0.89, P <= 0.01) were significant. Unlike national trends, intentional drug overdoses decreased (r = -0.55, P = 0.10). Handgun suicides increased (r = 0.61, P = 0.06) and are the most common method of firearm suicide. Hanging was the most common method of asphyxia. Helium suicides also increased (r = 0.75, P = 0.05). Middle age females and males comprise the largest percentage of suicide. Unlike national data, the increase in middle age male suicides occurred only in the 55-64-year-old age group (r = 0.79, P <= 0.01) and decreased in the 35-44-year-old age group (r = -0.60, P = 0.07) and 10-14-year-old age group (r = -0.73, P = 0.02). Suicide in all female age ranges remained stable. Caucasians represent the highest percentage of suicide. CONCLUSION: There has been a rise in suicide in Virginia and suicide rates and trends have closely resembled the national average albeit some differences. Suicide prevention needs to be enhanced. PMID- 25705648 TI - Pan-genome analysis of human gastric pathogen H. pylori: comparative genomics and pathogenomics approaches to identify regions associated with pathogenicity and prediction of potential core therapeutic targets. AB - Helicobacter pylori is a human gastric pathogen implicated as the major cause of peptic ulcer and second leading cause of gastric cancer (~70%) around the world. Conversely, an increased resistance to antibiotics and hindrances in the development of vaccines against H. pylori are observed. Pan-genome analyses of the global representative H. pylori isolates consisting of 39 complete genomes are presented in this paper. Phylogenetic analyses have revealed close relationships among geographically diverse strains of H. pylori. The conservation among these genomes was further analyzed by pan-genome approach; the predicted conserved gene families (1,193) constitute ~77% of the average H. pylori genome and 45% of the global gene repertoire of the species. Reverse vaccinology strategies have been adopted to identify and narrow down the potential core immunogenic candidates. Total of 28 nonhost homolog proteins were characterized as universal therapeutic targets against H. pylori based on their functional annotation and protein-protein interaction. Finally, pathogenomics and genome plasticity analysis revealed 3 highly conserved and 2 highly variable putative pathogenicity islands in all of the H. pylori genomes been analyzed. PMID- 25705649 TI - A potential epigenetic marker mediating serum folate and vitamin B12 levels contributes to the risk of ischemic stroke. AB - Stroke is a multifactorial disease that may be associated with aberrant DNA methylation profiles. We investigated epigenetic dysregulation for the methylenetetrahydrofolate reductase (MTHFR) gene among ischemic stroke patients. Cases and controls were recruited after obtaining signed written informed consents following a screening process against the inclusion/exclusion criteria. Serum vitamin profiles (folate, vitamin B12, and homocysteine) were determined using immunoassays. Methylation profiles for CpGs A and B in the MTHFR gene were determined using a bisulfite-pyrosequencing method. Methylation of MTHFR significantly increased the susceptibility risk for ischemic stroke. In particular, CpG A outperformed CpG B in mediating serum folate and vitamin B12 levels to increase ischemic stroke susceptibility risks by 4.73-fold. However, both CpGs A and B were not associated with serum homocysteine levels or ischemic stroke severity. CpG A is a potential epigenetic marker in mediating serum folate and vitamin B12 to contribute to ischemic stroke. PMID- 25705650 TI - New approaches, findings, and diagnostics in medical and surgical retina. PMID- 25705651 TI - Audiogram comparison of workers from five professional categories. AB - INTRODUCTION: Noise is a major cause of health disorders in workers and has unique importance in the auditory analysis of people exposed to it. The purpose of this study is to evaluate the arithmetic mean of the auditory thresholds at frequencies of 3, 4, and 6 kHz of workers from five professional categories exposed to occupational noise. METHODS: We propose a retrospective cross sectional cohort study to analyze 2.140 audiograms from seven companies having five sectors of activity: one footwear company, one beverage company, two ceramics companies, two metallurgical companies, and two transport companies. RESULTS: When we compared two categories, we noticed a significant difference only for cargo carriers in comparison to the remaining categories. In all activity sectors, the left ear presented the worst values, except for the footwear professionals (P > 0.05). We observed an association between the noise exposure time and the reduction of audiometric values for both ears. Significant differences existed for cargo carriers in relation to other groups. This evidence may be attributed to different forms of exposure. A slow and progressive deterioration appeared as the exposure time increased. PMID- 25705652 TI - Conformational B-cell epitope prediction method based on antigen preprocessing and mimotopes analysis. AB - Identification of epitopes which invokes strong humoral responses is an essential issue in the field of immunology. Various computational methods that have been developed based on the antigen structures and the mimotopes these years narrow the search for experimental validation. These methods can be divided into two categories: antigen structure-based methods and mimotope-based methods. Though new methods of the two kinds have been proposed in these years, they cannot maintain a high degree of satisfaction in various circumstances. In this paper, we proposed a new conformational B-cell epitope prediction method based on antigen preprocessing and mimotopes analysis. The method classifies the antigen surface residues into "epitopes" and "nonepitopes" by six epitope propensity scales, removing the "nonepitopes" and using the preprocessed antigen for epitope prediction based on mimotope sequences. The proposed method gives out the mean F score of 0.42 on the testing dataset. When compared with other publicly available servers by using the testing dataset, the new method yields better performance. The results demonstrate the proposed method is competent for the conformational B cell epitope prediction. PMID- 25705653 TI - Is DBM beneficial for the enhancement of bony consolidation in distraction osteogenesis? A randomized controlled trial. AB - The aim of the present study was to compare the radiographic and clinical outcomes of DBM injection and conventional treatment during tibial lengthening over an intramedullary nail in adult patients with short stature. Twenty-nine patients were randomized to receive DBM injection (n = 14) or conventional treatment without any injection (n = 15) and evaluated. The outcome was measured on the basis of the pixel value ratio (PVR) in the digital radiographs during the consolidation period; healing index; clinical assessment; and the rate of complications. In the DBM group, the mean PVR of 1 (mineral density of the callus is comparable to the adjacent bone) was reached by 40 weeks in anterior and medial cortices which was significantly different than that in the control group (P = 0.03 for anterior cortex; P = 0.04 for medial cortex). The average healing index in the DBM group was 39.8 +/- 5.3 days/cm compared to 44.3 +/- 5.8 days/cm in the control group (P = 0.05). There were no significant differences in clinical outcomes (P = 0.23) and functional status (P = 0.47) including complications (P = 0.72) between two groups. In this randomized clinical trial, injection of DBM at the time of initial operation enhanced consolidation of regenerate callus without interfering with clinical outcomes compared to that with conventional treatment. PMID- 25705654 TI - Effects of berberine on amelioration of hyperglycemia and oxidative stress in high glucose and high fat diet-induced diabetic hamsters in vivo. AB - This study investigated the effects of berberine on amelioration of hyperglycemia and hyperlipidemia and the mechanism involved in high glucose and high fat diet induced diabetic hamsters. Golden hamsters fed with high glucose and high fat diet were medicated with metformin, simvastatin, and low or high dose of berberine (50 and 100 mg.kg(-1)) for 6 weeks. The results showed that the body weights were significantly lower in berberine-treated groups than control group. Histological analyses revealed that the treatment of berberine inhibited hepatic fat accumulation. Berberine significantly reduced plasma total cholesterol, triglyceride, free fatty acid, low density lipoprotein cholesterol, malondialdehyde, thiobarbituric acid-reactive substance, and 8-isoprostane level but significantly increased plasma superoxide dismutase activity. Glucose and insulin levels were significantly reduced in metformin and berberine-treated groups. Glucose tolerance tests documented that berberine-treated mice were more glucose tolerant. Berberine treatment increased expression of skeletal muscle glucose transporter 4 mRNA and significantly decreased liver low density lipoprotein receptor mRNA expression. The study suggested that berberine was effective in lowering blood glucose and lipids levels, reducing the body weight, and alleviating the oxidative stress in diabetic hamsters, which might be beneficial in reducing the cardiovascular risk factors in diabetes. PMID- 25705655 TI - Balancing rigidity and safety of pedicle screw fixation via a novel expansion mechanism in a severely osteoporotic model. AB - Many successful attempts to increase pullout strength of pedicle screws in osteoporotic bone have been accompanied with an increased risk of catastrophic damage to the patient. To avoid this, a single-armed expansive pedicle screw was designed to increase fixation strength while controlling postfailure damage away from the nerves surrounding the pedicle. The screw was then subsequently tested in two severely osteoporotic models: one representing trabecular bone (with and without the presence of polymethylmethacrylate) and the other representing a combination of trabecular and cortical bone. Maximum pullout strength, stiffness, energy to failure, energy to removal, and size of the resulting block damage were statistically compared among conditions. While expandable pedicle screws produced maximum pullout forces less than or comparable to standard screws, they required a higher amount of energy to be fully removed from both models. Furthermore, damage to the cortical layer in the composite test blocks was smaller in all measured directions for tests involving expandable pedicle screws than those involving standard pedicle screws. This indicates that while initial fixation may not differ in the presence of cortical bone, the expandable pedicle screw offers an increased level of postfailure stability and safety to patients awaiting revision surgery. PMID- 25705656 TI - Red blood cell destruction in autoimmune hemolytic anemia: role of complement and potential new targets for therapy. AB - Autoimmune hemolytic anemia (AIHA) is a collective term for several diseases characterized by autoantibody-initiated destruction of red blood cells (RBCs). Exact subclassification is essential. We provide a review of the respective types of AIHA with emphasis on mechanisms of RBC destruction, focusing in particular on complement involvement. Complement activation plays a definitive but limited role in warm-antibody AIHA (w-AIHA), whereas primary cold agglutinin disease (CAD), secondary cold agglutinin syndrome (CAS), and paroxysmal cold hemoglobinuria (PCH) are entirely complement-dependent disorders. The details of complement involvement differ among these subtypes. The theoretical background for therapeutic complement inhibition in selected patients is very strong in CAD, CAS, and PCH but more limited in w-AIHA. The optimal target complement component for inhibition is assumed to be important and highly dependent on the type of AIHA. Complement modulation is currently not an evidence-based therapy modality in any AIHA, but a number of experimental and preclinical studies are in progress and a few clinical observations have been reported. Clinical studies of new complement inhibitors are probably not far ahead. PMID- 25705657 TI - Risk factors for reduced salivary flow rate in a Japanese population: the Hisayama Study. AB - The purpose of this study was to determine distinct risk factors causing reduced salivary flow rate in a community-dwelling population using a prospective cohort study design. This was a 5-year follow-up survey of 1,377 community-dwelling Japanese individuals aged >=40 years. The salivary flow rate was evaluated at baseline and follow-up by collecting stimulated saliva. Data on demographic characteristics, use of medication, and general and oral health status were obtained at baseline. The relationship between reduced salivary flow rate during the follow-up period and its predictors was evaluated after adjustment for confounding factors. In a multivariate logistic regression model, higher age and plaque score and lower serum albumin levels were significantly associated with greater odds of an obvious reduction in salivary flow rate (age per decade, odds ratio [OR] = 1.25, 95% confidence interval [CI] = 1.03-1.51; serum albumin levels <4 g/dL, OR = 1.60, 95% CI = 1.04-2.46; plaque score >=1, OR = 1.53, 95% CI = 1.04-2.24). In a multivariate linear regression model, age and plaque score remained independently associated with the increased rate of reduced salivary flow. These results suggest that aging and plaque score are important predictors of reduced salivary flow rate in Japanese adults. PMID- 25705658 TI - T 1 relaxation measurement of ex-vivo breast cancer tissues at ultralow magnetic fields. AB - We investigated T 1 relaxations of ex-vivo cancer tissues at low magnetic fields in order to check the possibility of achieving a T 1 contrast higher than those obtained at high fields. The T 1 relaxations of fifteen pairs (normal and cancerous) of breast tissue samples were measured at three magnetic fields, 37, 62, and 122 MUT, using our superconducting quantum interference device-based ultralow field nuclear magnetic resonance setup, optimally developed for ex-vivo tissue studies. A signal reconstruction based on Bayesian statistics for noise reduction was exploited to overcome the low signal-to-noise ratio. The ductal and lobular-type tissues did not exhibit meaningful T 1 contrast values between normal and cancerous tissues at the three different fields. On the other hand, an enhanced T 1 contrast was obtained for the mucinous cancer tissue. PMID- 25705659 TI - Irrigated tip catheters for radiofrequency ablation in ventricular tachycardia. AB - Radiofrequency (RF) ablation with irrigated tip catheters decreases the likelihood of thrombus and char formation and enables the creation of larger lesions. Due to the potential dramatic consequences, the prevention of thromboembolic events is of particular importance for left-sided procedures. Although acute success rates of ventricular tachycardia (VT) ablation are satisfactory, recurrence rate is high. Apart from the progress of the underlying disease, reconduction and the lack of effective transmural lesions play a major role for VT recurrences. This paper reviews principles of lesion formation with radiofrequency and the effect of tip irrigation as well as recent advances in new technology. Potential areas of further development of catheter technology might be the improvement of mapping by better substrate definition and resolution, the introduction of bipolar and multipolar ablation techniques into clinical routine, and the use of alternative sources of energy. PMID- 25705660 TI - Transcriptional and biochemical effects of cadmium and manganese on the defense system of Octopus vulgaris paralarvae. AB - Due to anthropogenic activities the relative concentrations of cadmium and manganese have increased in the marine environment. Cephalopods are able to accumulate such metals and, as inhabitant of coastal waters, Octopus vulgaris is continuously exposed to anthropogenic activities. Since no study is available on the effects of heavy metals at molecular level in developing octopuses, herein we exposed 1-day-old paralarvae for 24 h to 10, 100, and 1000 MUg/L of CdCl2 or MnCl2. Cd exerted a concentration-dependent inhibition of survival and a reduction in growth rate was shown while Mn exposure did not affect the survival rate even at the highest concentrations. Gene expression profiles of hsp70, sod, cat, and gst genes were analyzed by quantitative real-time PCR and defined patterns of transcription were observed. Moreover posttranscriptional analyses were also performed suggesting the impairment of metabolic functions, under strong oxidative conditions (as occurred in paralarvae exposed to Cd) or the complete detoxification events (as occurred in paralarvae exposed to Mn). PMID- 25705661 TI - The role of radiotherapy in Hodgkin's lymphoma: what has been achieved during the last 50 years? AB - Currently, Hodgkin's lymphoma (HL) has an excellent clinical outcome, with overall survival of approximately 90% in early stages of the disease. Based on young age of the majority of patients at the time of diagnosis and their long survival time, increased attention has been focused on long-term toxicity of therapy. While novel, directly targeting antitumor agents, with an excellent safety profile, have been developed for HL treatment, the role of radiotherapy is still debated. Radiotherapy may induce cardiovascular disease and impairment of thyroid or pulmonary function and, most importantly, may lead to development of secondary cancers. As a consequence, the current radiation therapy planning paradigm is mainly focused on a reduction of field size. As it was investigated in clinical trials regional therapy is as effective as extended field radiotherapy, but less toxic. Although chemotherapy is the mainstay of HL treatment, consolidative involved field radiation therapy is still considered to be the standard of care in both early and advanced stages. Recently, further field reduction has been investigated to further decrease the late radiation induced toxicity. In this paper we describe the role and safety profile of radiotherapy in the past and present and hope for the novel techniques in the future. PMID- 25705662 TI - Cholinergic synaptic transmissions were altered after single sevoflurane exposure in Drosophila pupa. AB - PURPOSE: . Sevoflurane, one of the most used general anesthetics, is widely used in clinical practice all over the world. Previous studies indicated that sevoflurane could induce neuron apoptosis and neural deficit causing query in the safety of anesthesia using sevoflurane. The present study was designed to investigate the effects of sevoflurane on electrophysiology in Drosophila pupa whose excitatory neurotransmitter is acetylcholine early after sevoflurane exposure using whole brain recording technique. METHODS: Wide types of Drosophila (canton-s flies) were allocated to control and sevoflurane groups randomly. Sevoflurane groups (1% sevoflurane; 2% sevoflurane; 3% sevoflurane) were exposed to sevoflurane and the exposure lasted 5 hours, respectively. All flies were subjected to electrophysiology experiment using patch clamp 24 hours after exposure. RESULTS: The results showed that, 24 hours after sevoflurane exposure, frequency but not the amplitude of miniature excitatory postsynaptic currents (mEPSCs) was significantly reduced (P < 0.05). Furthermore, we explored the underlying mechanism and found that calcium currents density, which partially regulated the frequency of mEPSCs, was significantly reduced after sevoflurane exposure (P < 0.05). CONCLUSIONS: All these suggested that sevoflurane could alter the mEPSCs that are related to synaptic plasticity partially through modulating calcium channel early after sevoflurane exposure. PMID- 25705663 TI - The effect of various types of motorcycle helmets on cervical spine injury in head injury patients: a multicenter study in Taiwan. AB - INTRODUCTION: The relationship between cervical spine injury (CSI) and helmet in head injury (HI) patients following motorcycle crashes is crucial. Controversy still exists; therefore we evaluated the effect of various types of helmets on CSI in HI patients following motorcycle crashes and researched the mechanism of this effect. PATIENTS AND METHODS: A total of 5225 patients of motorcycle crashes between 2000 and 2009 were extracted from the Head Injury Registry in Taiwan. These patients were divided into case and control groups according to the presence of concomitant CSI. Helmet use and types were separately compared between the two groups and the odds ratio of CSI was obtained by using multiple logistic regression analysis. RESULTS: We observed that 173 (3.3%) of the HI patients were associated with CSI. The HI patients using a helmet (odds ratio (OR) = 0.31, 95% confidence interval (CI) = 0.19-0.49), full-coverage helmet (0.19, 0.10-0.36), and partial-coverage helmet (0.35, 0.21-0.56) exhibited a significantly decreased rate of CSI compared with those without a helmet. CONCLUSION: Wearing full-coverage and partial-coverage helmets significantly reduced the risk of CSI among HI patients following motorcycle crashes. This effect may be due to the smooth surface and hard padding materials of helmet. PMID- 25705664 TI - Disturbance of oligodendrocyte function plays a key role in the pathogenesis of schizophrenia and major depressive disorder. AB - The major psychiatric disorders such as schizophrenia (SZ) and major depressive disorder (MDD) are thought to be multifactorial diseases related to both genetic and environmental factors. However, the genes responsible and the molecular mechanisms underlying the pathogenesis of SZ and MDD remain unclear. We previously reported that abnormalities of disrupted-in-Schizophrenia-1 (DISC1) and DISC1 binding zinc finger (DBZ) might cause major psychiatric disorders such as SZ. Interestingly, both DISC and DBZ have been further detected in oligodendrocytes and implicated in regulating oligodendrocyte differentiation. DISC1 negatively regulates the differentiation of oligodendrocytes, whereas DBZ plays a positive regulatory role in oligodendrocyte differentiation. We have reported that repeated stressful events, one of the major risk factors of MDD, can induce sustained upregulation of plasma corticosterone levels and serum/glucocorticoid regulated kinase 1 (Sgk1) mRNA expression in oligodendrocytes. Repeated stressful events can also activate the SGK1 cascade and cause excess arborization of oligodendrocyte processes, which is thought to be related to depressive-like symptoms. In this review, we discuss the expression of DISC1, DBZ, and SGK1 in oligodendrocytes, their roles in the regulation of oligodendrocyte function, possible interactions of DISC1 and DBZ in relation to SZ, and the activation of the SGK1 signaling cascade in relation to MDD. PMID- 25705665 TI - Engineering isoprenoid biosynthesis in Artemisia annua L. for the production of taxadiene: a key intermediate of taxol. AB - Taxadiene is the first committed precursor to paclitaxel, marketed as Taxol, arguably the most important anticancer agent against ovarian and breast cancer. In Taxus, taxadiene is directly synthesized from geranylgeranyl diphosphate (GGPP) that is the common precursor for diterpenoids and is found in most plants and microbes. In this study, Artemisia annua L., a Chinese medicinal herb that grows fast and is rich in terpenoids, was used as a genetic engineering host to produce taxadiene. The TXS (taxadiene synthase) gene, cloned from Taxus and inserted into pCAMBIA1304, was transformed into Artemisia annua L. using the Agrobacterium tumefaciens-mediated method. Thirty independent transgenic plants were obtained, and GC-MS analysis was used to confirm that taxadiene was produced and accumulated up to 129.7 MUg/g dry mass. However, the high expression of TXS did not affect plant growth or photosynthesis in transgenic Artemisia annua L. It is notable that artemisinin is produced and stored in leaves and most taxadiene accumulated in the stem of transgenic Artemisia annua L., suggesting a new way to produce two important compounds in one transgenic plant: leaves for artemisinin and stem for taxadiene. Overall, this study demonstrates that genetic engineering of the taxane biosynthetic pathway in Artemisia annua L. for the production of taxadiene is feasible. PMID- 25705666 TI - Frequency-dependent amplitude alterations of resting-state spontaneous fluctuations in late-onset depression. AB - There is limited amplitude of low-frequency fluctuation (ALFF) of resting-state functional magnetic resonance imaging (fMRI) studies in late-onset depression (LOD) but reported different results. This may be due to the impact of different frequency bands. In this study, we examined the ALFF in five different frequency bands (slow-6: 0-0.01 Hz; slow-5: 0.01-0.027 Hz; slow-4: 0.027-0.073 Hz; slow-3: 0.073-0.167 Hz, and slow-2: 0.167-0.25 Hz) within the whole brain during resting state fMRI in 16 LOD patients and 16 normal control (NC) subjects. The ALFF of primary effect of disease was widely distributed over left cerebellum anterior lobe, left cerebellum posterior lobe, left middle orbitofrontal gyrus, left superior occipital, and right superior parietal, while the interaction effect of disease and frequency was distributed over right superior frontal gyrus. Further relationship analysis findings suggest these abnormal ALFF may relate to cognitive dysfunction of LOD. Therefore, our data show that LOD patients have widespread abnormalities in intrinsic brain activity, which is dependent on the frequency band, and suggest that future studies should take the frequency bands into account when measuring intrinsic brain activity. PMID- 25705667 TI - Effects of partial substitution of fish meal by soybean meal with or without heat killed Lactobacillus plantarum (LP20) on growth performance, digestibility, and immune response of amberjack, Seriola dumerili juveniles. AB - A 56-day feeding trial was conducted to evaluate the effects of supplemented diets with heat-killed Lactobacillus plantarum (HK-LP) with graded levels of soybean meal (SBM) on growth, digestibility, blood parameters, and immune response of Seriola dumerili (initial weight, 25.05 +/- 0.1 g). Seven isonitrogenous and isolipidic practical diets were formulated to contain 0%, 15%, 30%, and 45% SBM, and each SBM level was supplemented with HK-LP at 0.0 and 0.1%. Fish fed diet which contains 30% SBM with HK-LP grew significantly faster than the other groups with notable feed intake and protein retention. Further, protein gain, whole body protein content, protease activity, protein, and lipid digestibility were significantly increased for all fish groups except for fish fed diet which contains 45% SBM with or without HK-LP. Interestingly, lysozyme activity was significantly enhanced in fish fed diets that contain 15% and 30% SBM with HK-LP. Hematocrit, peroxidase, and bactericidal activities revealed a significant increase in 30% SBM with HK-LP group. In addition, fish fed diets which contain 0% and 30% SBM with HK-LP showed higher tolerance against low salinity stress compared with other groups. In conclusion, the addition of HK-LP to amberjack diets appeared to improve SBM utilization, immune response, and stress resistance. PMID- 25705668 TI - The use of an IL-1 receptor antagonist peptide to control inflammation in the treatment of corneal limbal epithelial stem cell deficiency. AB - Corneal limbal stem cell deficiency (LSCD) may be treated using ex vivo limbal epithelial stem cells (LESCs) derived from cadaveric donor tissue. However, continuing challenges exist around tissue availability, inflammation, and transplant rejection. Lipopolysaccharide (LPS) or recombinant human IL-1beta stimulated primary human keratocyte and LESC models were used to investigate the anti-inflammatory properties of a short chain, IL-1 receptor antagonist peptide for use in LESC sheet growth to control inflammation. The peptide was characterized using mass spectroscopy and high performance liquid chromatography. Peptide cytotoxicity, patterns of cell cytokine expression in response to LPS or IL-1beta stimulation, and peptide suppression of this response were investigated by MTS/LDH assays, ELISA, and q-PCR. Cell differences in LPS stimulated toll-like receptor 4 expression were investigated using immunocytochemistry. A significant reduction in rIL-1beta stimulated inflammatory cytokine production occurred following LESC and keratocyte incubation with anti-inflammatory peptide and in LPS stimulated IL-6 and IL-8 production following keratocyte incubation with peptide (1 mg/mL) (P < 0.05). LESCs produced no cytokine response to LPS stimulation and showed no TLR4 expression. The peptide supported LESC growth when adhered to a silicone hydrogel contact lens indicating potential use in improved LESC grafting through suppression of inflammation. PMID- 25705669 TI - The shadow of silence on the sexual rights of married Iranian women. AB - There has been a recent shift in the field of sexual health, representing a move away from biomedical concerns to sexual rights frameworks. However, few studies on sexuality are based on a rights framework. The unspoken nature of sexuality in Iranian culture has led to a lack of national studies on the topic. The objective of this study was to explore the perceptions and experiences of married Iranian women on sexual rights in their sexual relationships. In this grounded theory study, 37 participants (25 married women, 5 husbands, and 7 midwives) were selected. Data were collected through in-depth interviews and analyzed through open, axial, and selective coding using MAXQDA software version 2007. The analysis revealed the core category of "sexual interaction in the shadow of silence." The interrelated categories subsumed under the core category included adopting a strategy of silence, trying to negotiate sex, seeking help, and sexual adjustment. The silence originating from women's interactions with their families and society, from girlhood to womanhood, was identified as the core concept in Iranian women's experiences of sexual rights. A focus on husbands' roles seems salient because they can direct or alter some learned feminine roles, especially silence regarding sexual matters, which then affects the realization of women's sexual rights. PMID- 25705671 TI - Salvianolic acids attenuate rat hippocampal injury after acute CO poisoning by improving blood flow properties. AB - Carbon monoxide (CO) poisoning causes the major injury and death due to poisoning worldwide. The most severe damage via CO poisoning is brain injury and mortality. Delayed encephalopathy after acute CO poisoning (DEACMP) occurs in forty percent of the survivors of acute CO exposure. But the pathological cause for DEACMP is not well understood. And the corresponding therapy is not well developed. In order to investigate the effects of salvianolic acid (SA) on brain injury caused by CO exposure from the view point of hemorheology, we employed a rat model and studied the dynamic of blood changes in the hemorheological and coagulative properties over acute CO exposure. Compared with the groups of CO and 20% mannitol + CO treatments, the severe hippocampal injury caused by acute CO exposure was prevented by SA treatment. These protective effects were associated with the retaining level of hematocrit (Hct), plasma viscosity, fibrinogen, whole blood viscosities and malondialdehyde (MDA) levels in red blood cells (RBCs). These results indicated that SA treatment could significantly improve the deformation of erythrocytes and prevent the damage caused by CO poisoning. Meanwhile, hemorheological indexes are good indicators for monitoring the pathological dynamic after acute CO poisoning. PMID- 25705670 TI - Novel insights on nutrient management of sarcopenia in elderly. AB - Sarcopenia is defined as a syndrome characterized by progressive and generalized loss of muscle mass and strength. The more rationale approach to delay the progression of sarcopenia is based on the combination of proper nutrition, possibly associated with the use of dietary supplements and a regular exercise program. We performed a narrative literature review to evaluate the till-now evidence regarding (1) the metabolic and nutritional correlates of sarcopenia; (2) the optimum diet therapy for the treatment of these abnormalities. This review included 67 eligible studies. In addition to the well recognized link between adequate intake of proteins/amino acids and sarcopenia, the recent literature underlines that in sarcopenic elderly subjects there is an unbalance in vitamin D synthesis and in omega-6/omega-3 PUFA ratio. Given the detrimental effect of these metabolic abnormalities, a change in the lifestyle must be the cornerstone in the treatment of sarcopenia. The optimum diet therapy for the sarcopenia treatment must aim at achieving specific metabolic goals, which must be reached through accession of the elderly to specific personalized dietary program aimed at achieving and/or maintaining muscle mass; increasing their intake of fish (4 times/week) or taking omega-3 PUFA supplements; taking vitamin D supplementation, if there are low serum levels. PMID- 25705672 TI - The novel quantitative technique for assessment of gait symmetry using advanced statistical learning algorithm. AB - The accurate identification of gait asymmetry is very beneficial to the assessment of at-risk gait in the clinical applications. This paper investigated the application of classification method based on statistical learning algorithm to quantify gait symmetry based on the assumption that the degree of intrinsic change in dynamical system of gait is associated with the different statistical distributions between gait variables from left-right side of lower limbs; that is, the discrimination of small difference of similarity between lower limbs is considered the reorganization of their different probability distribution. The kinetic gait data of 60 participants were recorded using a strain gauge force platform during normal walking. The classification method is designed based on advanced statistical learning algorithm such as support vector machine algorithm for binary classification and is adopted to quantitatively evaluate gait symmetry. The experiment results showed that the proposed method could capture more intrinsic dynamic information hidden in gait variables and recognize the right-left gait patterns with superior generalization performance. Moreover, our proposed techniques could identify the small significant difference between lower limbs when compared to the traditional symmetry index method for gait. The proposed algorithm would become an effective tool for early identification of the elderly gait asymmetry in the clinical diagnosis. PMID- 25705673 TI - Is there a persistent dysfunction of neurovascular coupling in migraine? AB - Changes in cerebral blood flow are one of the main features of migraine attack and have inspired the vascular theory of migraine. This traditional view has been reshaped with recent experimental data, which gave rise to the neural theory of migraine. In this review, we speculate that there might be an important link between the two theories, that is, the dysfunction of neurovascular coupling. PMID- 25705674 TI - Community structure of ammonia-oxidizing archaea and ammonia-oxidizing bacteria in soil treated with the insecticide imidacloprid. AB - The purpose of this experiment was to assess the effect of imidacloprid on the community structure of ammonia-oxidizing archaea (AOA) and ammonia-oxidizing bacteria (AOB) in soil using the denaturing gradient gel electrophoresis (DGGE) approach. Analysis showed that AOA and AOB community members were affected by the insecticide treatment. However, the calculation of the richness (S) and the Shannon-Wiener index (H) values for soil treated with the field rate (FR) dosage of imidacloprid (1 mg/kg soil) showed no changes in measured indices for the AOA and AOB community members. In turn, the 10*FR dosage of insecticide (10 mg/kg soil) negatively affected the AOA community, which was confirmed by the decrease of the S and H values in comparison with the values obtained for the control soil. In the case of AOB community, an initial decline followed by the increase of the S and H values was obtained. Imidacloprid decreased the nitrification rate while the ammonification process was stimulated by the addition of imidacloprid. Changes in the community structure of AOA and AOB could be due to an increase in the concentration of N-NH4 (+), known as the most important factor which determines the contribution of these microorganisms to soil nitrification. PMID- 25705675 TI - Status, alert system, and prediction of cyanobacterial bloom in South Korea. AB - Bloom-forming freshwater cyanobacterial genera pose a major ecological problem due to their ability to produce toxins and other bioactive compounds, which can have important implications in illnesses of humans and livestock. Cyanobacteria such as Microcystis, Anabaena, Oscillatoria, Phormidium, and Aphanizomenon species producing microcystins and anatoxin-a have been predominantly documented from most South Korean lakes and reservoirs. With the increase in frequency of such blooms, various monitoring approaches, treatment processes, and prediction models have been developed in due course. In this paper we review the field studies and current knowledge on toxin producing cyanobacterial species and ecological variables that regulate toxin production and bloom formation in major rivers (Han, Geum, Nakdong, and Yeongsan) and reservoirs in South Korea. In addition, development of new, fast, and high-throughput techniques for effective monitoring is also discussed with cyanobacterial bloom advisory practices, current management strategies, and their implications in South Korean freshwater bodies. PMID- 25705676 TI - Estimation of radiofrequency power leakage from microwave ovens for dosimetric assessment at nonionizing radiation exposure levels. AB - The electromagnetic field leakage levels of nonionizing radiation from a microwave oven have been estimated within a complex indoor scenario. By employing a hybrid simulation technique, based on coupling full wave simulation with an in house developed deterministic 3D ray launching code, estimations of the observed electric field values can be obtained for the complete indoor scenario. The microwave oven can be modeled as a time- and frequency-dependent radiating source, in which leakage, basically from the microwave oven door, is propagated along the complete indoor scenario interacting with all of the elements present in it. This method can be of aid in order to assess the impact of such devices on expected exposure levels, allowing adequate minimization strategies such as optimal location to be applied. PMID- 25705677 TI - Application of AMOR in craniofacial rabbit bone bioengineering. AB - Endogenous molecular and cellular mediators modulate tissue repair and regeneration. We have recently described antibody mediated osseous regeneration (AMOR) as a novel strategy for bioengineering bone in rat calvarial defect. This entails application of anti-BMP-2 antibodies capable of in vivo capturing of endogenous osteogenic BMPs (BMP-2, BMP-4, and BMP-7). The present study sought to investigate the feasibility of AMOR in other animal models. To that end, we examined the efficacy of a panel of anti-BMP-2 monoclonal antibodies (mAbs) and a polyclonal Ab immobilized on absorbable collagen sponge (ACS) to mediate bone regeneration within rabbit calvarial critical size defects. After 6 weeks, de novo bone formation was demonstrated by micro-CT imaging, histology, and histomorphometric analysis. Only certain anti-BMP-2 mAb clones mediated significant in vivo bone regeneration, suggesting that the epitopes with which anti-BMP-2 mAbs react are critical to AMOR. Increased localization of BMP-2 protein and expression of osteocalcin were observed within defects, suggesting accumulation of endogenous BMP-2 and/or increased de novo expression of BMP-2 protein within sites undergoing bone repair by AMOR. Considering the ultimate objective of translation of this therapeutic strategy in humans, preclinical studies will be necessary to demonstrate the feasibility of AMOR in progressively larger animal models. PMID- 25705678 TI - The involvement of microtubules and actin during the infection of Japanese encephalitis virus in neuroblastoma cell line, IMR32. AB - The role of the cytoskeleton, actin, and microtubules were examined during the process of Japanese encephalitis (JEV) infection in a human neuroblastoma cell line, IMR32. Cytochalasin D and nocodazole were used to depolymerise the cellular actin and microtubules, respectively, in order to study the effect of JEV infection in the cell. This study shows that depolymerisation of the actin cytoskeleton at early process of infection inhibits JEV infection in the cell; however infection was not inhibited when depolymerisation occurred at the later stage of infection. The microtubules, on the other hand, are required at 2 points in infection. The antigen production in the cells was inhibited when the infected cells were treated at time up to 2 hours after inoculation and there was no significant effect at later times, while the viable virus released continued to be affected until 10 hours after inoculation. In conclusion, infection of JEV in IMR32 cells required actin to facilitate early process in infection and the microtubular network is utilised as the transport system to the virus replication site and the release of mature virus. PMID- 25705679 TI - WHO multidrug therapy for leprosy: epidemiology of default in treatment in Agra district, Uttar Pradesh, India. AB - AIM: To study the magnitude of default, time of default, its causes, and final clinical outcome. METHODS: Data collected in active surveys in Agra is analyzed. Patients were given treatment after medical confirmation and were followed up. The treatment default and other clinical outcomes were recorded. RESULTS: Patients who defaulted have comparable demographic characteristics. However, among defaulters more women (62.7% in PB, 42.6% in MB) were seen than those in treatment completers (PB 52.7% and MB 35.9%). Nerve involvement was high in treatment completers: 45.7% in PB and 91.3% in MB leprosy. Overall default rate was lower (14.8%) in ROM than (28.8%) in standard MDT for PB leprosy (chi 1 (2) = 11.6, P = 0.001) and also for MB leprosy: 9.1% in ROM compared to 34.5% in MDT (chi 1 (2) = 6.0, P = 0.015). Default rate was not different (28.8% versus 34.5%, P > 0.05) in both types of leprosy given MDT. Most patients defaulted at early stage of treatment and mainly due to manageable side effects. CONCLUSION: The default in standard MDT both for PB and MB leprosy was observed to be significantly higher than in ROM treatment. Most defaults occurred at early stage of treatment and major contribution of default is due to side effects like drowsiness, weakness, vomiting, diarrhea, and so forth, related to poor general health. Although about half of the defaulters were observed to be cured 2.2% in PB-MDT and 10.9% of MB-MDT developed disability. This is an issue due to default. Attempts are needed to increase treatment compliance. The use of specially designed disease related health education along with easily administered drug regimens may help to reduce default. PMID- 25705680 TI - Environmental epidemiology of intestinal schistosomiasis in Uganda: population dynamics of biomphalaria (gastropoda: planorbidae) in Lake Albert and Lake Victoria with observations on natural infections with digenetic trematodes. AB - This study documented the population dynamics of Biomphalaria and associated natural infections with digenetic trematodes, along the shores of Lake Albert and Lake Victoria, recording local physicochemical factors. Over a two-and-a-half year study period with monthly sampling, physicochemical factors were measured at 12 survey sites and all freshwater snails were collected. Retained Biomphalaria were subsequently monitored in laboratory aquaria for shedding trematode cercariae, which were classified as either human infective (Schistosoma mansoni) or nonhuman infective. The population dynamics of Biomphalaria differed by location and by lake and had positive relationship with pH (P < 0.001) in both lakes and negative relationship with conductivity (P = 0.04) in Lake Albert. Of the Biomphalaria collected in Lake Albert (N = 6,183), 8.9% were infected with digenetic trematodes of which 15.8% were shedding S. mansoni cercariae and 84.2% with nonhuman infective cercariae. In Lake Victoria, 2.1% of collected Biomphalaria (N = 13,172) were infected with digenetic trematodes with 13.9% shedding S. mansoni cercariae, 85.7% shedding nonhuman infective cercariae, and 0.4% of infected snails shedding both types of cercariae. Upon morphological identification, species of Biomphalaria infected included B. sudanica, B. pfeifferi, and B. stanleyi in Lake Albert and B. sudanica, B. pfeifferi, and B. choanomphala in Lake Victoria. The study found the physicochemical factors that influenced Biomphalaria population and infections. The number and extent of snails shedding S. mansoni cercariae illustrate the high risk of transmission within these lake settings. For better control of this disease, greater effort should be placed on reducing environmental contamination by improvement of local water sanitation and hygiene. PMID- 25705681 TI - Detecting key genes regulated by miRNAs in dysfunctional crosstalk pathway of myasthenia gravis. AB - Myasthenia gravis (MG) is a neuromuscular autoimmune disorder resulting from autoantibodies attacking components of the neuromuscular junction. Recent studies have implicated the aberrant expression of microRNAs (miRNAs) in the pathogenesis of MG; however, the underlying mechanisms remain largely unknown. This study aimed to identify key genes regulated by miRNAs in MG. Six dysregulated pathways were identified through differentially expressed miRNAs and mRNAs in MG, and significant crosstalk was detected between five of these. Notably, crosstalk between the "synaptic long-term potentiation" pathway and four others was mediated by five genes involved in the MAPK signaling pathway. Furthermore, 14 key genes regulated by miRNAs were detected, of which six-MAPK1, RAF1, PGF, PDGFRA, EP300, and PPP1CC-mediated interactions between the dysregulated pathways. MAPK1 and RAF1 were responsible for most of this crosstalk (80%), likely reflecting their central roles in MG pathogenesis. In addition, most key genes were enriched in immune-related local areas that were strongly disordered in MG. These results provide new insight into the pathogenesis of MG and offer new potential targets for therapeutic intervention. PMID- 25705682 TI - Anemia in inflammatory bowel disease outpatients: prevalence, risk factors, and etiology. AB - Anemia is common in inflammatory bowel disease (IBD). However, epidemiological studies of nonwestern IBD populations are limited and may be confounded by demographic, socioeconomic, and disease-related influences. This study evaluated the prevalence, risk factors, and etiology of anemia in Brazilian outpatients with IBD. METHODS: In this cross-sectional study, 100 Crohn's disease (CD) patients and 100 ulcerative colitis (UC) subjects were assessed. Anemia workup included complete blood count, ferritin, transferrin saturation, serum levels of folic acid and vitamin B12, and C-reactive protein (CRP) concentration. RESULTS: The overall prevalence of anemia in IBD was 21%. There was no significant difference in the prevalence of anemia between CD subjects (24%) and UC (18%). Moderate disease activity (OR: 3.48, 95% CI, 1.95-9.64, P = 0.002) and elevated CRP levels (OR: 1.8, 95% CI, 1.04-3.11, P = 0.02) were independently associated with anemia. The most common etiologies of anemia found in both groups were iron deficiency anemia (IDA; 10% on CD and 6% on UC) followed by the anemia of chronic disease (ACD; 6% for both groups). CONCLUSIONS: In Brazilian IBD outpatients, anemia is highly concurrent condition. Disease moderate activity as well as increased CRP was strongly associated with comorbid anemia. IDA and/or ACD were the most common etiologies. PMID- 25705683 TI - Thaliporphine derivative improves acute lung injury after traumatic brain injury. AB - Acute lung injury (ALI) occurs frequently in patients with severe traumatic brain injury (TBI) and is associated with a poor clinical outcome. Aquaporins (AQPs), particularly AQP1 and AQP4, maintain water balances between the epithelial and microvascular domains of the lung. Since pulmonary edema (PE) usually occurs in the TBI-induced ALI patients, we investigated the effects of a thaliporphine derivative, TM-1, on the expression of AQPs and histological outcomes in the lung following TBI in rats. TM-1 administered (10 mg/kg, intraperitoneal injection) at 3 or 4 h after TBI significantly reduced the elevated mRNA expression and protein levels of AQP1 and AQP4 and diminished the wet/dry weight ratio, which reflects PE, in the lung at 8 and 24 h after TBI. Postinjury TM-1 administration also improved histopathological changes at 8 and 24 h after TBI. PE was accompanied with tissue pathological changes because a positive correlation between the lung injury score and the wet/dry weight ratio in the same animal was observed. Postinjury administration of TM-1 improved ALI and reduced PE at 8 and 24 h following TBI. The pulmonary-protective effect of TM-1 may be attributed to, at least in part, downregulation of AQP1 and AQP4 expression after TBI. PMID- 25705684 TI - The effect of Walterinnesia aegyptia venom proteins on TCA cycle activity and mitochondrial NAD(+)-redox state in cultured human fibroblasts. AB - Fibroblast cultures were used to study the effects of crude Walterinnesia aegyptia venom and its F1-F7 protein fractions on TCA cycle enzyme activities and mitochondrial NAD-redox state. Confluent cells were incubated with 10 MUg of venom proteins for 4 hours at 37 degrees C. The activities of all studied TCA enzymes and the non-TCA mitochondrial NADP(+)-dependent isocitrate dehydrogenase underwent significant reductions of similar magnitude (50-60% of control activity) upon incubation of cells with the crude venom and fractions F4, F5, and F7 and 60-70% for fractions F3 and F6. In addition, the crude and fractions F3-F7 venom proteins caused a drop in mitochondrial NAD(+) and NADP(+) levels equivalent to around 25% of control values. Whereas the crude and fractions F4, F5, and F7 venom proteins caused similar magnitude drops in NADH and NADPH (around 55% of control levels), fractions F3 and F6 caused a more drastic drop (60-70% of control levels) of both reduced coenzymes. Results indicate that the effects of venom proteins could be directed at the mitochondrial level and/or the rates of NAD(+) and NADP(+) biosynthesis. PMID- 25705685 TI - Latent tuberculosis infection among a large cohort of medical students at a teaching hospital in Italy. AB - The surveillance of latent tuberculosis infection (LTBI) in both healthcare workers and healthcare students is considered fundamental for tuberculosis (TB) prevention. The aim of the present study was to estimate LTBI prevalence and evaluate potential risk-factors associated with this condition in a large cohort of medical students in Italy. In a cross-sectional study, performed between March and December 2012, 1511 eligible subjects attending the Medical School of the University of Genoa, trained at the IRCCS San Martino-IST Teaching Hospital of Genoa, were actively called to undergo the tuberculin skin test (TST). All the TST positive cases were confirmed with an interferon-gamma release assay (IGRA). A standardized questionnaire was collected for multivariate risk analysis. A total of 1302 (86.2%) students underwent TST testing and completed the questionnaire. Eleven subjects (0.8%) resulted TST positive and LTBI diagnosis was confirmed in 2 (0.1%) cases. Professional exposure to active TB patients (OR 21.7, 95% CI 2.9-160.2; P value 0.003) and previous BCG immunization (OR 28.3, 95% CI 3.0-265.1; P value 0.003) are independently associated with TST positivity. Despite the low prevalence of LTBI among Italian medical students, an occupational risk of TB infection still exists in countries with low circulation of Mycobacterium tuberculosis. PMID- 25705686 TI - Infectious causes of cholesteatoma and treatment of infected ossicles prior to reimplantation by hydrostatic high-pressure inactivation. AB - Chronic inflammation, which is caused by recurrent infections, is one of the factors contributing to the pathogenesis of cholesteatoma. If reimplantation of autologous ossicles after a surgical intervention is intended, inactivation of planktonic bacteria and biofilms is desirable. High hydrostatic pressure treatment is a procedure, which has been used to inactivate cholesteatoma cells on ossicles. Here we discuss the potential inactivating effect of high hydrostatic pressure on microbial pathogens including biofilms. Recent experimental data suggest an incomplete inactivation at a pressure level, which is tolerable for the bone substance of ossicles and results at least in a considerable reduction of pathogen load. Further studies are necessary to access how far this quantitative reduction of pathogens is sufficient to prevent ongoing chronic infections, for example, due to forming of biofilms. PMID- 25705687 TI - American ginseng regulates gene expression to protect against premature ovarian failure in rats. AB - Premature ovarian failure (POF) is defined as lost ovarian functions before the age of 40. Three possible molecular markers (PLA2G4A, miR-29a, and miR-144) have been identified in our previous study by integrated analysis of mRNA and miRNA expression profiles. The present study aimed to evaluate American ginseng root's protective potential against POF by studying transcriptional and protein variations between American ginseng treatments and controls in rats. 4 Vinylcyclohexene diepoxide (VCD) was administered to rats for 14 days to induce POF. Additionally, American ginseng was administered to POF rats for one month, and PLA2G4A, miR-29a, and miR-144 expressions were measured in rat ovaries by qRT PCR. PLA2G4A protein expression was examined by Western Blot, and PGE2, LH, FSH, and E2 serum levels were detected by ELISA. PLA2G4A mRNA and protein were downregulated in American ginseng-treated rats, miR-29a and miR-144 levels increased, and PGE2 serum levels decreased, while LH, FSH, and E2 increased compared to POF induction alone. Analysis of transcriptional and protein variations suggested that American ginseng protects the ovary against POF by regulating prostaglandin biosynthesis, ovulation, and preventing ovarian aging. High hormone levels (PGE2, FSH, and LH) were reduced, and E2 secretion approached normal levels, leading to improved POF symptoms and abnormal ovulation. PMID- 25705688 TI - Influence of culture media on biofilm formation by Candida species and response of sessile cells to antifungals and oxidative stress. AB - The aims of the study were to evaluate the influence of culture media on biofilm formation by C. albicans, C. glabrata, C. krusei, and C. parapsilosis and to investigate the responses of sessile cells to antifungals and reactive oxygen species (ROS) as compared to planktonic cells. For biofilm formation, the Candida species were grown at different periods of time in YP or YNB media supplemented or not with 0.2 or 2% glucose. Sessile and planktonic cells were exposed to increasing concentrations of antifungals, H2O2, menadione or silver nanoparticles (AgNPs). Biofilms were observed by scanning electron microscopy (SEM) and quantified by the XTT assay. C. albicans formed biofilms preferentially in YPD containing 2% glucose (YPD/2%), C. glabrata in glucose-free YNB or supplemented with 0.2% glucose (YNB/0.2%), while C. krusei and C. parapsilosis preferred YP, YPD/0.2%, and YPD/2%. Interestingly, only C. albicans produced an exopolymeric matrix. This is the first report dealing with the in vitro effect of the culture medium and glucose on the formation of biofilms in four Candida species as well as the resistance of sessile cells to antifungals, AgNPs, and ROS. Our results suggest that candidiasis in vivo is a multifactorial and complex process where the nutritional conditions, the human immune system, and the adaptability of the pathogen should be considered altogether to provide an effective treatment of the patient. PMID- 25705689 TI - Guidelines for optimisation of a multiplex oligonucleotide ligation-PCR for characterisation of microbial pathogens in a microsphere suspension array. AB - With multiplex oligonucleotide ligation-PCR (MOL-PCR) different molecular markers can be simultaneously analysed in a single assay and high levels of multiplexing can be achieved in high-throughput format. As such, MOL-PCR is a convenient solution for microbial detection and identification assays where many markers should be analysed, including for routine further characterisation of an identified microbial pathogenic isolate. For an assay aimed at routine use, optimisation in terms of differentiation between positive and negative results and of cost and effort is indispensable. As MOL-PCR includes a multiplex ligation step, followed by a singleplex PCR and analysis with microspheres on a Luminex device, several parameters are accessible for optimisation. Although MOL-PCR performance may be influenced by the markers used in the assay and the targeted bacterial species, evaluation of the method of DNA isolation, the probe concentration, the amount of microspheres, and the concentration of reporter dye is advisable in the development of any MOL-PCR assay. Therefore, we here describe our observations made during the optimisation of a 20-plex MOL-PCR assay for subtyping of Salmonella Typhimurium with the aim to provide a possible workflow as guidance for the development and optimisation of a MOL-PCR assay for the characterisation of other microbial pathogens. PMID- 25705691 TI - Bioenergetics and the role of soluble cytochromes C for alkaline adaptation in gram-negative alkaliphilic Pseudomonas. AB - Very few studies have been conducted on alkaline adaptation of Gram-negative alkaliphiles. The reversed difference of H(+) concentration across the membrane will make energy production considerably difficult for Gram-negative as well as Gram-positive bacteria. Cells of the alkaliphilic Gram-negative bacterium Pseudomonas alcaliphila AL15-21(T) grown at pH 10 under low-aeration intensity have a soluble cytochrome c content that is 3.6-fold higher than that of the cells grown at pH 7 under high-aeration intensity. Cytochrome c-552 content was higher (64% in all soluble cytochromes c) than those of cytochrome c-554 and cytochrome c-551. In the cytochrome c-552-dificient mutant grown at pH 10 under low-aeration intensity showed a marked decrease in MU max? [h(-1)] (40%) and maximum cell turbidity (25%) relative to those of the wild type. Considering the high electron-retaining abilities of the three soluble cytochromes c, the deteriorations in the growth of the cytochrome c-552-deficient mutant could be caused by the soluble cytochromes c acting as electron storages in the periplasmic space of the bacterium. These electron-retaining cytochromes c may play a role as electron and H(+) condenser, which facilitate terminal oxidation at high pH under air-limited conditions, which is difficult to respire owing to less oxygen and less H(+). PMID- 25705690 TI - Angiogenesis in the placenta: the role of reactive oxygen species signaling. AB - Proper placental development and function are central to the health of both the mother and the fetus during pregnancy. A critical component of healthy placental function is the proper development of its vascular network. Poor vascularization of the placenta can lead to fetal growth restriction, preeclampsia, and in some cases fetal death. Therefore, understanding the mechanisms by which uterine stressors influence the development of the placental vasculature and contribute to placental dysfunction is of central importance to ensuring a healthy pregnancy. In this review we discuss how oxidative stress observed in maternal smoking, maternal obesity, and preeclampsia has been associated with aberrant angiogenesis and placental dysfunction resulting in adverse pregnancy outcomes. We also highlight that oxidative stress can influence the expression of a number of transcription factors important in mediating angiogenesis. Therefore, understanding how oxidative stress affects redox-sensitive transcription factors within the placenta may elucidate potential therapeutic targets for correcting abnormal placental angiogenesis and function. PMID- 25705692 TI - The potential role of polymethyl methacrylate as a new packaging material for the implantable medical device in the bladder. AB - Polydimethylsiloxane (PDMS) is used in implantable medical devices; however, PDMS is not a completely biocompatible material for electronic medical devices in the bladder. To identify novel biocompatible materials for intravesical implanted medical devices, we evaluated the biocompatibility of polymethyl methacrylate (PMMA) by analyzing changes in the levels of macrophages, macrophage migratory inhibitory factor (MIF), and inflammatory cytokines in the bladder. A ball-shaped metal coated with PMMA or PDMS was implanted into the bladders of rats, and after intravesical implantation, the inflammatory changes induced by the foreign body reaction were evaluated. In the early period after implantation, increased macrophage activity and MIF in the urothelium of the bladder were observed. However, significantly decreased macrophage activity and MIF in the bladder were observed after implantation with PMMA- or PDMS-coated metal in the later period. In addition, significantly decreased inflammatory cytokines such as IL-1beta, IL 6, and TNF-alpha were observed with time. Based on these results, we suggest that MIF plays a role in the foreign body reaction and in the biocompatible packaging with PMMA for the implanted medical devices in the bladder. PMID- 25705693 TI - The protective effect of melatonin on neural stem cell against LPS-induced inflammation. AB - Stem cell therapy for tissue regeneration has several limitations in the fact that transplanted cells could not survive for a long time. For solving these limitations, many studies have focused on the antioxidants to increase survival rate of neural stem cells (NSCs). Melatonin, an antioxidant synthesized in the pineal gland, plays multiple roles in various physiological mechanisms. Melatonin exerts neuroprotective effects in the central nervous system. To determine the effect of melatonin on NSCs which is in LPS-induced inflammatory stress state, we first investigated nitric oxide (NO) production and cytotoxicity using Griess reagent assays, LDH assay, and neurosphere counting. Also, we investigated the effect of melatonin on NSCs by measuring the mRNA levels of SOX2, TLX, and FGFR 2. In addition, western blot analyses were performed to examine the activation of PI3K/Akt/Nrf2 signaling in LPS-treated NSCs. In the present study, we suggested that melatonin inhibits NO production and protects NSCs against LPS-induced inflammatory stress. In addition, melatonin promoted the expression of SOX2 and activated the PI3K/Akt/Nrf2 signaling under LPS-induced inflammation condition. Based on our results, we conclude that melatonin may be an important factor for the survival and proliferation of NSCs in neuroinflammatory diseases. PMID- 25705694 TI - Role of NEK2A in human cancer and its therapeutic potentials. AB - Chromosome instability (CIN) has been identified as a common feature of most human cancers. A number of centrosomal kinases are thought to cause CIN in cancer cells. Part of those centrosomal kinases exhibit elevated expression in a wide variety of tumours and cancer cell lines. Additionally, critical roles in many aspects of cancer cell growth, proliferation, metastasis, and drug resistance have been assigned to some of these centrosomal kinases, such as polo-like kinase 1 (PLk1) and Aurora-A kinase. Recent studies from our group and others revealed that a centrosomal kinase, Never in Mitosis (NIMA) Related Kinase 2A (NEK2A), is frequently upregulated in multiple types of human cancers. Uncontrolled activity of NEK2A activates several oncogenic pathways and ABC transporters, thereby leading to CIN, cancer cell proliferation, metastasis, and enhanced drug resistance. In this paper, we highlight recent findings on the aberrant expression and functional significance of NEK2A in human cancers and emphasize their significance for therapeutic potentials. PMID- 25705695 TI - Strategy for the management of macular edema in retinal vein occlusion: the European VitreoRetinal Society macular edema study. AB - OBJECTIVE: To compare the efficacy of different therapies in the treatment of macular edema associated with retinal vein occlusion (RVO). DESIGN: This is a nonrandomized, multicenter collaborative study. PARTICIPANTS: 86 retina specialists from 29 countries provided clinical information, including choice of treatment and outcome, on 2,603 patients with macular edema including 738 cases of RVO. METHODS: Reported data included the type and number of treatments performed, visual acuities, and other clinical and diagnostic findings. MAIN OUTCOME MEASURES: The mean increase in visual acuity and mean number of treatments performed. RESULTS: 358 cases of central retinal vein occlusion (CRVO) and 380 cases of branch retinal vein occlusion (BRVO) were included in this investigation. Taking all RVO cases together, pars plana vitrectomy with internal limiting membrane (ILM) peeling alone resulted in an improvement in vision greater than other therapies. Those treated with intravitreal antivascular endothelial growth factor (anti-VEGF) injection alone showed the second greatest improvement in vision. Dexamethasone intravitreal implant alone and intravitreal triamcinolone alone both resulted in modest visual gains. CONCLUSIONS: In the treatment of macular edema in RVO, vitrectomy with ILM peeling may achieve visual improvement and may be a good option for certain cases. Anti-VEGF injection is the most effective of the nonsurgical treatments. PMID- 25705696 TI - Blood vessel matrix seeded with cells: a better alternative for abdominal wall reconstruction-a long-term study. AB - PURPOSE: The aim of this study was to present abdominal wall reconstruction using a porcine vascular graft seeded with MSC (mesenchymal stem cells) on rat model. MATERIAL AND METHODS: Abdominal wall defect was prepared in 21 Wistar rats. Acellular porcine-vascular grafts taken from aorta and prepared with Triton X were used. 14 aortic grafts were implanted in place, of which 7 grafts were seeded with rat MSC cells (Group I), and 7 were acellular grafts (Group II). As a control, 7 standard polypropylene meshes were used for defect augmentation (Group III). The assessment method was performed by HE and CD31 staining after 6 months. The mechanical properties have been investigated by Zwick&Roell Z0.5. RESULTS: The strongest angiogenesis and lowest inflammatory response were observed in Group I. Average capillaries density was 2.75, 0.75, and 1.53 and inflammatory effect was 0.29, 1.39, and 2.72 for Groups I, II, and III, respectively. The means of mechanical properties were 12.74 +/- 1.48, 7.27 +/- 1.56, and 14.4 +/- 3.7 N/cm in Groups I and II and control, respectively. CONCLUSIONS: Cell-seeded grafts have better mechanical properties than acellular grafts but worse than polypropylene mesh. Cells improved mechanical and physiological properties of decellularized natural scaffolds. PMID- 25705697 TI - The influence of electromagnetic radiation generated by a mobile phone on the skeletal system of rats. AB - The study was focused on the influence of electromagnetic field generated by mobile phone on the skeletal system of rats, assessed by measuring the macrometric parameters of bones, mechanical properties of long bones, calcium and phosphorus content in bones, and the concentration of osteogenesis (osteocalcin) and bone resorption (NTX, pyridinoline) markers in blood serum. The study was carried out on male rats divided into two groups: experimental group subjected to 28-day cycle of exposures in electromagnetic field of 900 MHz frequency generated by mobile phone and a control, sham-exposed one. The mobile phone-generated electromagnetic field did not influence the macrometric parameters of long bones and L4 vertebra, it altered mechanical properties of bones (stress and energy at maximum bending force, stress at fracture), it decreased the content of calcium in long bones and L4 vertebra, and it altered the concentration of osteogenesis and bone resorption markers in rats. On the basis of obtained results, it was concluded that electromagnetic field generated by 900 MHz mobile phone does not have a direct impact on macrometric parameters of bones; however, it alters the processes of bone mineralization and the intensity of bone turnover processes and thus influences the mechanical strength of bones. PMID- 25705698 TI - Novel numerical characterization of protein sequences based on individual amino acid and its application. AB - The hydrophobicity and hydrophilicity of amino acids play a very important role in protein folding and its interaction with the environment and other molecules, as well as its catalytic mechanism. Based on the two physicochemical indexes, a 2D graphical representation of protein sequences is introduced; meanwhile, a new numerical characteristic has been proposed to compute the distance of different sequences for analysis of sequence similarity/dissimilarity on the basis of this graphical representation. Furthermore, we apply the new distance in the similarities/dissimilarities of ND5 proteins of nine species and predict the four major classes based on the dataset containing 639 domains. The results show that the method is simple and effective. PMID- 25705699 TI - The gastrointestinal irritation of polygala saponins and its potential mechanism in vitro and in vivo. AB - Processing alters the pharmacological activity and reduces the gastrointestinal toxicity of the polygalae. To investigate the effect of processing, different glycosyl substituent products were tested. Hypnotic and subhypnotic doses of pentobarbital-induced sleep tests on mice were used to evaluate the sedative activity of polygala saponins with different glycosyl substituents; isolated gut motility experiment was employed to study excitatory effects of different polygala saponins; the gastrointestinal irritation effects of different polygala saponins were compared by measuring the levels of gastric PGE2 and intestinal TNF alpha on mice. When compared with control, Onjisaponin B (OJB) and tenuifolin (TEN), but not senegenin (SNG), significantly increased the number of sleeping mice and prolonged the sleeping time (P < 0.05); 80, 40, and 20 mg/L of OJB and 80 mg/L of TEN, but not SNG, obviously changed the amplitude and frequency of isolated jejunum (P < 0.05); all the three compounds significantly decreased the level of gastric PGE2 but had no obvious influences on the reduction of intestinal TNF-alpha level. For sedative and hypnotic effects, OJB > TEN > SNG; for the protection form gastrointestinal irritation and damages, OJB > TEN > SNG. Therefore, in processing Polygala, glycosyl breaking may be related to the decline of pharmacological activity and gastrointestinal toxicity of polygala saponins. PMID- 25705700 TI - Application of stochastic automata networks for creation of continuous time Markov chain models of voltage gating of gap junction channels. AB - The primary goal of this work was to study advantages of numerical methods used for the creation of continuous time Markov chain models (CTMC) of voltage gating of gap junction (GJ) channels composed of connexin protein. This task was accomplished by describing gating of GJs using the formalism of the stochastic automata networks (SANs), which allowed for very efficient building and storing of infinitesimal generator of the CTMC that allowed to produce matrices of the models containing a distinct block structure. All of that allowed us to develop efficient numerical methods for a steady-state solution of CTMC models. This allowed us to accelerate CPU time, which is necessary to solve CTMC models, ~20 times. PMID- 25705701 TI - Acute effects of alcohol on the human brain: a resting-state FMRI study. AB - The aim of this study is to assess the value of resting-state fMRI in detecting the acute effects of alcohol on healthy human brains. Thirty-two healthy volunteers were studied by conventional MR imaging and resting-state fMRI prior to and 0.5 hours after initiation of acute alcohol administration. The fMRI data, acquired during the resting state, were correlated with different breath alcohol concentrations (BrAC). We use the posterior cingulate cortex/precuneus as a seed for the default mode network (DMN) analysis. ALFF and ReHo were also used to investigate spontaneous neural activity in the resting state. Conventional MR imaging showed no abnormalities on all subjects. Compared with the prior alcohol administration, the ALFF and ReHo also indicated some specific brain regions which are affected by alcohol, including the superior frontal gyrus, cerebellum, hippocampal gyrus, left basal ganglia, and right internal capsule. Functional connectivity of the DMN was affected by alcohol. This resting-state fMRI indicates that brain regions implicated are affected by alcohol and might provide a neural basis for alcohol's effects on behavioral performance. PMID- 25705702 TI - The G allele of CaSR R990G polymorphism increases susceptibility to urolithiasis and hypercalciuria: evidences from a comprehensive meta-analysis. AB - BACKGROUND: The calcium-sensing receptor gene (CaSR) is a candidate to explain urolithiasis. A number of case-control studies were conducted to investigate associations between CaSR polymorphisms with risks of hypercalciuria and urolithiasis in humans. But the results were still inconsistent. METHODS: A meta analysis was performed to address this issue. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to estimate the strength of associations between CaSR polymorphisms and the risk of urolithiasis. The pooled standardized mean difference (SMD) with 95% CI was used for the meta-analysis of CaSR polymorphisms and urine calcium concentration. RESULTS: For urolithiasis association, the SS genotype of A986S polymorphism was a risk factor for urolithiasis in Asians and PHPT patients, but a protective factor in Caucasians. The GG genotype of R990 polymorphism was associated with an increased risk of urolithiasis, especially in Caucasians and healthy population. Regarding urine calcium concentration association, individuals with the G allele had a higher level of urine calcium than the noncarriers. CONCLUSIONS: This meta-analysis revealed that the G allele of CaSR R990G polymorphism increases susceptibility to urolithiasis and hypercalciuria. The A986S and Q1011E polymorphisms were associated with urolithiasis and hypercalciuria in specific populations. PMID- 25705703 TI - Mimicking the End Organ Architecture of Slowly Adapting Type I Afferents May Increase the Durability of Artificial Touch Sensors. AB - In effort to mimic the sensitivity and efficient information transfer of natural tactile afferents, recent work has combined force transducers and computational models of mechanosensitive afferents. Sensor durability, another feature important to sensor design, might similarly capitalize upon biological rules. In particular, gains in sensor durability might leverage insight from the compound end organ of the slowly adapting type I afferent, especially its multiple sites of spike initiation that reset each other. This work develops models of compound spiking sensors using a computational network of transduction functions and leaky integrate and fire models (together a spike encoder, the software element of a compound spiking sensor), informed by the output of an existing force transducer (hardware sensing elements of a compound spiking sensor). Individual force transducer failures are simulated with and without resetting between spike encoders to test the importance of both resetting and configuration on system durability. The results indicate that the resetting of adjacent spike encoders, upon the firing of a spike by any one, is an essential mechanism to maintain a stable overall response in the midst of transducer failure. Furthermore, results suggest that when resetting is enabled, the durability of a compound sensor is maximized when individual transducers are paired with spike encoders and multiple, paired units are employed. To explore these ideas more fully, use cases examine the design of a compound sensor to either reach a target lifetime with a set probability or determine how often to schedule maintenance to control the probability of failure. PMID- 25705704 TI - Improving Patient Care Using the Johnson-Neyman Analysis of Heterogeneity of Treatment Effects According to Individuals' Baseline Characteristics. AB - OBJECTIVE: Because each patient's baseline (pre-treatment) characteristics differ (e.g., age, sex, socioeconomic status, ethnicity/race, biomarkers), treatments do not work the same for every patient-some can even cause detrimental effects. To improve patient care, it is critical to identify such heterogeneity of treatment effects. But the standard analytic approach dichotomizes baseline characteristics (low vs. high) which often leads to a loss of critical patient-care information and power to detect heterogeneity, as the results may depend strongly on the cut points chosen. A more powerful analytic approach is to analyze baseline characteristics (i.e., covariates) measured on a continuous scale that retains all of the information available for the covariate. METHODS: In this article, we show how the Johnson-Neyman (J-N) method can be used to identify the prognostic and predictive value of baseline covariates measured on a continuous scale - findings that often cannot be determined using the traditional dichotomized approach. As an example, we used the J-N method to explore treatment effects for varying levels of the biomarker salivary mutans streptococci (MS) in a randomized clinical prevention trial comparing fluoride varnish with no fluoride varnish for 376 initially caries-free high-risk children, all of whom received oral health counseling. RESULTS: The J-N analysis showed that children with higher baseline MS values who were randomized to receive fluoride varnish had the poorest dental caries prognosis and may have benefitted most from the preventive agent. CONCLUSION: Such methods are likely to be an important tool in the field of personalized oral health care. PMID- 25705705 TI - Treg/Th17 polarization by distinct subsets of breast cancer cells is dictated by the interaction with mesenchymal stem cells. AB - Breast cancer (BC) cells (BCCs) exist within a hierarchy beginning with cancer stem cells (CSCs). Unsorted BCCs interact with mesenchymal stem cells (MSCs) to induce regulatory T cells (Tregs). This study investigated how distinct BCC subsets interacted with MSCs to polarize T-cell response, Tregs versus T helper 17 (Th17). This study tested BC initiating cells (CSCs) and the relatively more mature early and late BC progenitors. CSCs interacted with the highest avidity to MSCs. This interaction required CXCR4 and connexin 43 (Cx43)-dependant gap junctional intercellular communication (GJIC). This interaction induced Treg whereas interactions between MSCs and the progenitors induced Th17 response. The increases in Treg and Th17 depended on MSCs but not CTLA-4, which was increased in the presence of MSCs. Studies with BM stroma (fibroblasts) and MSCs from the same donors, indicated specific effects of MSCs. In total, MSC-CSC interaction required CXCR4 for GJIC. This led to increased Tregs and TGFbeta, and decreased Th17. In contrast, late and early BCCs showed reduced formation of GJIC, decreased Treg and increased Th17 and IL-17. These findings have significance to the methods by which CSCs evade the immune response. The findings could provide methods of intervention to reverse immune-mediated protection and support of BC. PMID- 25705706 TI - Differential Cerebrovascular Toxicity of Various Tobacco Products: A Regulatory Perspective. PMID- 25705707 TI - Outcomes of Hybrid Video Assisted Thoracoscopic Surgery for Pulmonary Metastasectomy. AB - BACKGROUND: Pulmonary metastasectomy is an acceptable treatment option in various metastatic lesions. The role of minimally invasive surgery for metastasectomy remains controversial. We report on a recently described hybrid video-assisted thoracoscopic surgery (hVATS) technique in the community hospital setting. METHODS: Using a retrospective study design, data on 61 patients undergoing 67 resections between April 2000 and January 2008 was collected at a single institution. Patient demographics, pathology, and clinical outcome data were recorded. Kaplan Meier estimates and multivariate Cox regression were used to assess survival and prognostic factors, respectively. RESULTS: Mean patient age was 61.7 years. The majority of lesions were solitary, unilateral, and genitourinary or gastrointestinal in origin (69%). R0 resection was achieved in 97% of cases with the most common operation being lobectomy. Mean length of stay was 4.4 days. Mean follow-up was 39.7 months and 5-year overall survival was 63.2% for the cohort; median survival was not reached. The number of lesions (univariate only) and tumor size over 4 cm influenced overall survival. CONCLUSIONS: Hybrid VATS is a safe and feasible technique in the community medical center setting and warrants additional investigation as an alternative strategy in the management of pulmonary metastases. PMID- 25705708 TI - MTA1 and MTA3 Regulate HIF1a Expression in Hypoxia-Treated Human Trophoblast Cell Line HTR8/Svneo. AB - Hypoxia plays an important role in placental trophoblast differentiation and function during early pregnancy. Hypoxia-inducible factor 1 alpha (HIF1a) is known to regulate cellular adaption to hypoxic conditions. However, our current understanding of the role of HIF1a in trophoblast physiology is far from complete. Metastasis Associated Protein 1 and 3 (MTA1 and MTA3) are components of the Nucleosome Remodeling and Deacetylase (NuRD) complex, a chromatin remodeling complex, and are highly expressed in term placental trophoblasts. However, the role of MTA1 and MTA3 in the hypoxic placental environment of early pregnancy is unknown. In the present study, we examined the association among MTA1, MTA3 and HIF1a expression under hypoxic conditions in trophoblasts both in vivo and in vitro. We first investigated the localization of MTA1 and MTA3 with HIF1a expression in the placental trophoblast of 1st trimester placenta via immunohistochemistry. Our data reveals that under physiologically hypoxic environment, MTA1 and MTA3 along with HIF1a are highly expressed by villous trophoblasts. Next, we investigated the effect of hypoxia on these genes in vitro using the first trimester-derived HTR8/SVneo cell line and observed up-regulation of MTA1 and MTA3 as well as HIF1a protein following hypoxia treatment. To investigate the direct effect of MTA1 and MTA3 upon HIF1a, we over-expressed MTA1 and MTA3 genes in HTR8/SVneo cells respectively and examined protein levels of HIF1a via Western blot as well as HIF1a target gene expression using a luciferase assay driven by a hypoxia-response element promoter (HRE-luciferase). We found that over-expressions of MTA1 and MTA3 up-regulate both HIF1a protein level and HRE-luciferase activity under hypoxic condition. In summary, both MTA1 and MTA3 are induced by hypoxia and up-regulate HIF1a expression and HIF1a target gene expression in trophoblasts. These data suggest that MTA1 and MTA3 play critical roles in trophoblast function and differentiation during early pregnancy. PMID- 25705709 TI - Anterior Mediastinal Masses in the Framingham Heart Study: Prevalence and CT Image Characteristics. AB - PURPOSE: To investigate the prevalence and CT image characteristics of anterior mediastinal masses in a population-based cohort and their association with the demographics of the participants. MATERIALS AND METHODS: Chest CT scans of 2571 Framingham Heart Study participants (mean age 58.9 years, 51% female) were evaluated by two board-certified radiologists with expertise in thoracic imaging for the presence of anterior mediastinal masses, their shape, contour, location, invasion of adjacent structures, fat content, and calcification. For participants with anterior mediastinal masses, a previous cardiac CT scan was reviewed for interval size change of the masses, when available. The demographics of the participants were studied for any association with the presence of anterior mediastinal masses. RESULTS: Of 2571, 23 participants (0.9%, 95% CI: 0.6 to 1.3) had anterior mediastinal masses on CT. The most common CT characteristics were oval shape, lobular contour, and midline location, showing soft tissue density (median 32.1 HU). Fat content was detected in a few cases (9%, 2/23). Six out of eight masses with available prior cardiac CT scans demonstrated an interval growth over a median period of 6.5 years. No risk factors for anterior mediastinal masses were detected among participants' demographics, including age, sex, BMI, and cigarette smoking. CONCLUSIONS: The prevalence of anterior mediastinal masses is 0.9% in the Framingham Heart Study. Those masses may increase in size when observed over 5-7 years. Investigation of clinical significance in incidentally found anterior mediastinal masses with a longer period of follow-up would be necessary. PMID- 25705710 TI - Neural mechanisms associated with reappraisal and attentional deployment. AB - Attentional deployment is an emotion regulation strategy that involves shifting attentional focus within an emotional scene in order to modulate emotional experience. Attentional deployment is widely used and effective at reducing negative affect, yet the supporting neural mechanisms are poorly understood. The rich literature on the neural correlates of reappraisal may help inform our understanding of attentional deployment, as reappraisal recruits common control regions associated with emotion regulation and may tap into specific mechanisms associated with directing attention. We highlight commonalities between reappraisal and attentional deployment and then focus on potentially unique aspects of attentional deployment, including the importance of parietal regions and implications for understanding the normative development of emotion regulation, as well as both well-being and psychopathology. PMID- 25705711 TI - Explicating the role of emotion dysregulation in risky behaviors: A review and synthesis of the literature with directions for future research and clinical practice. AB - Extant literature provides support for emotion dysregulation as a transdiagnostic construct with relevance to the pathogenesis and treatment of numerous psychiatric difficulties and maladaptive behaviors, including risky, self destructive, and health-compromising behaviors (e.g., substance use, risky sexual behavior). The aim of the present review is to synthesize theory and empirical research on the relationship between emotion dysregulation and risky behaviors. In addition, we highlight cutting-edge approaches for investigating the emotion dysregulation-risky behavior, including examination of the role of positive emotional experiences and inclusion of context-dependent and physiological assessments. Finally, we note the relevance of the emotion dysregulation-risky behavior relation to intervention efforts aimed at reducing risky behaviors. PMID- 25705712 TI - Comparative performance of hybrid and elite inbred rice varieties with respect to their source-sink relationship. AB - Hybrid rice varieties have higher yield potential over inbred varieties. This improvement is not always translated to the grain yield and its physiological causes are still unclear. In order to clarify it, two field experiments were conducted including two popular indica hybrids (BRRI hybrid dhan2 and Heera2) and one elite inbred (BRRI dhan45) rice varieties. Leaf area index, chlorophyll status, and photosynthetic rate of flag leaf, postheading crop growth rate, shoot reserve translocation, source-sink relation and yield, and its attributes of each variety were comprehensively analyzed. Both hybrid varieties outyielded the inbred. However, the hybrids and inbred varieties exhibited statistically identical yield in late planting. Both hybrids accumulated higher amount of biomass before heading and exhibited greater remobilization of assimilates to the grain in early plantings compared to the inbred variety. Filled grain (%) declined significantly at delayed planting in the hybrids compared to elite inbred due to increased temperature impaired-inefficient transport of assimilates. Flag leaf photosynthesis parameters were higher in the hybrid varieties than those of the inbred variety. Results suggest that greater remobilization of shoot reserves to the grain rendered higher yield of hybrid rice varieties. PMID- 25705713 TI - Workflow modelling and analysis based on the construction of task models. AB - We describe the structure of a workflow as a graph whose vertices represent tasks and the arcs are associated to workflow transitions in this paper. To each task an input/output logic operator is associated. Furthermore, we associate a Boolean term to each transition present in the workflow. We still identify the structure of workflows and describe their dynamism through the construction of new task models. This construction is very simple and intuitive since it is based on the analysis of all tasks present on the workflow that allows us to describe the dynamism of the workflow very easily. So, our approach has the advantage of being very intuitive, which is an important highlight of our work. We also introduce the concept of logical termination of workflows and provide conditions under which this property is valid. Finally, we provide a counter-example which shows that a conjecture presented in a previous article is false. PMID- 25705714 TI - Potential biosorbent derived from Calligonum polygonoides for removal of methylene blue dye from aqueous solution. AB - The ash of C. polygonoides (locally called balanza) was collected from Lakki Marwat, Khyber Pakhtunkhwa, Pakistan, and was utilized as biosorbent for methylene blue (MB) removal from aqueous solution. The ash was used as biosorbent without any physical or chemical treatment. The biosorbent was characterized by using various techniques such as Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), and scanning electron microscopy (SEM). The particle size and surface area were measured using particle size analyzer and Brunauer-Emmett-Teller equation (BET), respectively. The SEM and BET results expressed that the adsorbent has porous nature. Effects of various conditions such as initial concentration of methylene blue (MB), initial pH, contact time, dosage of biosorbent, and stirring rate were also investigated for the adsorption process. The rate of the adsorption of MB on biomass sample was fast, and equilibrium has been achieved within 1 hour. The kinetics of MB adsorption on biosorbent was studied by pseudo-first- and pseudo-second-order kinetic models and the pseudo-second-order has better mathematical fit with correlation coefficient value (R (2)) of 0.999. The study revealed that C. polygonoides ash proved to be an effective, alternative, inexpensive, and environmentally benign biosorbent for MB removal from aqueous solution. PMID- 25705715 TI - A method of calculating motion error in a linear motion bearing stage. AB - We report a method of calculating the motion error of a linear motion bearing stage. The transfer function method, which exploits reaction forces of individual bearings, is effective for estimating motion errors; however, it requires the rail-form errors. This is not suitable for a linear motion bearing stage because obtaining the rail-form errors is not straightforward. In the method described here, we use the straightness errors of a bearing block to calculate the reaction forces on the bearing block. The reaction forces were compared with those of the transfer function method. Parallelism errors between two rails were considered, and the motion errors of the linear motion bearing stage were measured and compared with the results of the calculations, revealing good agreement. PMID- 25705716 TI - A novel cost based model for energy consumption in cloud computing. AB - Cloud data centers consume enormous amounts of electrical energy. To support green cloud computing, providers also need to minimize cloud infrastructure energy consumption while conducting the QoS. In this study, for cloud environments an energy consumption model is proposed for time-shared policy in virtualization layer. The cost and energy usage of time-shared policy were modeled in the CloudSim simulator based upon the results obtained from the real system and then proposed model was evaluated by different scenarios. In the proposed model, the cache interference costs were considered. These costs were based upon the size of data. The proposed model was implemented in the CloudSim simulator and the related simulation results indicate that the energy consumption may be considerable and that it can vary with different parameters such as the quantum parameter, data size, and the number of VMs on a host. Measured results validate the model and demonstrate that there is a tradeoff between energy consumption and QoS in the cloud environment. Also, measured results validate the model and demonstrate that there is a tradeoff between energy consumption and QoS in the cloud environment. PMID- 25705717 TI - Modeling of memristive and memcapacitive behaviors in metal-oxide junctions. AB - Memristive behavior has been clearly addressed through growth and shrinkage of thin filaments in metal-oxide junctions. Capacitance change has also been observed, raising the possibility of using them as memcapacitors. Therefore, this paper proves that metal-oxide junctions can behave as a memcapacitor element by analyzing its characteristics and modeling its memristive and memcapacitive behaviors. We develop two behavioral modeling techniques: charge-dependent memcapacitor model and voltage-dependent memcapacitor model. A new physical model for metal-oxide junctions is presented based on conducting filaments variations, and its effect on device capacitance and resistance. In this model, we apply the exponential nature of growth and shrinkage of thin filaments and use Simmons' tunneling equation to calculate the tunneling current. Simulation results show how the variations of practical device parameters can change the device behavior. They clarify the basic conditions for building a memcapacitor device with negligible change in resistance. PMID- 25705718 TI - Use of selected essential oils to control aflatoxin contaminated stored cashew and detection of aflatoxin biosynthesis gene. AB - Aspergillus spp. associated with cashew from the regions of Riyadh, Dammam, and Abha were isolated and three different culture media were used to qualitatively measure aflatoxin production by Aspergillus via UV light (365 nm), which was expressed as positive or negative. The obtained data showed that six isolates of A. flavus and four isolates of A. parasiticus were positive for aflatoxin production, while all isolates of A. niger were negative. Five commercially essential oils (thyme, garlic, cinnamon, mint, and rosemary) were tested to determine their influence on growth and aflatoxin production in A. flavus and A. parasiticus by performing high-performance liquid chromatography (HPLC). The results showed that the tested essential oils caused highly significant inhibition of fungal growth and aflatoxin production in A. flavus and A. parasiticus. The extent of the inhibition of fungal growth and aflatoxin production was dependent on the type and concentration of essential oils applied. The results indicate that cinnamon and thyme oils show strong antimicrobial potential. PCR was used with four sets of primer pairs for nor-1, omt-1, ver-1, and aflR genes, enclosed in the aflatoxin biosynthetic pathway. The interpretation of the results revealed that PCR is a rapid and sensitive method. PMID- 25705719 TI - Reducing Colorectal Cancer Incidence and Disparities: Performance and Outcomes of a Screening Colonoscopy Program in South Carolina. AB - This study evaluated the efficiency, effectiveness, and racial disparities reduction potential of Screening Colonoscopies for People Everywhere in South Carolina (SCOPE SC), a state-funded program for indigent persons aged 50-64 years (45-64 years for African American (AA)) with a medical home in community health centers. Patients were referred to existing referral network providers, and the centers were compensated for patient navigation. Data on procedures and patient demographics were analyzed. Of 782 individuals recruited (71.2% AA), 85% (665) completed the procedure (71.1% AA). The adenoma detection rate was 27.8% (males 34.6% and females 25.1%), advanced neoplasm rate 7.7% (including 3 cancers), cecum intubation rate 98.9%, inadequate bowel preparation rate 7.9%, and adverse event rate 0.9%. All indicators met the national quality benchmarks. The adenoma rate of 26.0% among AAs aged 45-49 years was similar to that of older Whites and AAs. We found that patient navigation and a medical home setting resulted in a successful and high-quality screening program. The observed high adenoma rate among younger AAs calls for more research with larger cohorts to evaluate the appropriateness of the current screening guidelines for AAs, given that they suffer 47% higher colorectal cancer mortality than Whites. PMID- 25705720 TI - Inter-Rater Reliability of the Measure of Patient-Centered Communication in Health Promotion Clinic Visits with Youth. AB - Patient-centered communication during clinic visits is critical for a patient and provider to establish a relationship that explores the patient's needs and desires and tailors health care accordingly. However, there are currently limitations to measuring patient-centered communication within the clinic visit. This study will examine the inter-rater reliability of a modified version of the Measure of Patient-Centered Communication (MPCC) for use with youth in health promotion clinic visits. Transcripts from actual patient-provider interactions (n=11) with 17-23 year old participants and providers (n=6; NPs and MDs) were analyzed for inter-rater reliability of a modified version of the MPCC. The MPCC demonstrated satisfactory inter-rater reliability among the five components of patient-centered communication (kappa=0.78) and good mean inter-rater reliability among the five provider responses (percent agreement=87.5%). Measuring patient centered communication presents challenges. This study demonstrated that the MPCC could be a potential tool in this endeavor; however, adjustments are needed for it to be a reliable measure of patient-centered communication during clinic visits with youth. In order to provide patient-centered communication and care we must be able to accurately measure the communication and techniques being implemented in all patient visits. PMID- 25705721 TI - Reducing Racial Health Care Disparities: A Social Psychological Analysis. AB - Large health disparities persist between Black and White Americans. The social psychology of intergroup relations suggests some solutions to health care disparities due to racial bias. Three paths can lead from racial bias to poorer health among Black Americans. First is the already well-documented physical and psychological toll of being a target of persistent discrimination. Second, implicit bias can affect physicians' perceptions and decisions, creating racial disparities in medical treatments, although evidence is mixed. The third path describes a less direct route: Physicians' implicit racial bias negatively affects communication and the patient-provider relationship, resulting in racial disparities in the outcomes of medical interactions. Strong evidence shows that physician implicit bias negatively affects Black patients' reactions to medical interactions, and there is good circumstantial evidence that these reactions affect health outcomes of the interactions. Solutions focused on the physician, the patient, and the health care delivery system; all agree that trying to ignore patients' race or to change physicians' implicit racial attitudes will not be effective and may actually be counterproductive. Instead, solutions can minimize the impact of racial bias on medical decisions and on patient-provider relationships. PMID- 25705722 TI - Rescue of DNA damage-stalled RNA Pol II: histone H2B in action. AB - RNA Pol II elongation in eukaryotes is coupled with a series of histone modifications. Elongating RNA Pol II can be strongly stalled by lesions on the DNA template. However, it is unclear whether RNA Pol II stalling affects elongation-associated histone modifications. We have explored this important question by investigating the function of histone H2B mono-ubiquitylation (H2Bub), a well-characterized epigenetic mark associated with RNA Pol II elongation, in the cellular response to DNA lesions induced by ultraviolet (UV) radiation. We found that, in contrast to transcription elongation, RNA Pol II stalling induced by UV lesions triggers rapid and significant H2B deubiquitylation that removes ubiquitin from H2B. Interestingly, in yeast mutant cells that lack H2B deubiquitylation enzymes, rescue of the stalled RNA Pol II by transcription-coupled repair (TCR) is significantly impaired. Thus, our study has established a direct connection between RNA Pol II stalling and a histone modification response. PMID- 25705723 TI - Central and peripheral relationships between morphine and glucose on antinociception in rats. AB - Previous research from our laboratory has determined that in the absence of a gustatory response or taste hedonics, intraperitoneal (i.p.) glucose administration enhanced morphine-mediated analgesia in rats and had antinociceptive actions on its own. Two experiments examined the potential of a central mechanism for glucose's actions on morphine-mediated antinociception. Morphine (2.5 ug) was infused into the periaqueductal gray (PAG) while glucose (300 mg/kg) was injected into the peritoneal cavity, or glucose (32 nmol) was infused into the PAG while morphine (3.2 mg/kg) was injected i.p. Doses of morphine and glucose were selected based on our own prior research for being below the threshold for analgesic efficacy. Antinociception was assessed using the hot-water tail-withdrawal procedure. Tail-withdrawal latency was tested at baseline (before), and 12, 24 and 36 minutes after the i.p. injection. The results indicated that 300 mg/kg glucose, administered i.p. effectively increased the antinociceptive potency of a low dose of centrally administered morphine, while central infusion of glucose enhanced peripheral morphine-mediated antinociception. These outcomes support previous evidence of glucose's influence on the antinociception actions of opioid drugs. Furthermore, they suggest that glucose produces its enhancing actions on morphine-mediated antinociception in the brain. These results support the hypothesis that glucose does not need to go through a gustatory mechanism or taste hedonics to alter morphine's antinociceptive actions. PMID- 25705724 TI - A Dynamic Programming Algorithm for Finding the Optimal Segmentation of an RNA Sequence in Secondary Structure Predictions. AB - In this paper, we present a dynamic programming algorithm that runs in polynomial time and allows us to achieve the optimal, non-overlapping segmentation of a long RNA sequence into segments (chunks). The secondary structure of each chunk is predicted independently, then combined with the structures predicted for the other chunks, to generate a complete secondary structure prediction that is thus a combination of local energy minima. The proposed approach not only is more efficient and accurate than other traditionally used methods that are based on global energy minimizations, but it also allows scientists to overcome computing and storage constraints when trying to predict the secondary structure of long RNA sequences. PMID- 25705725 TI - MaPLE: A MapReduce Pipeline for Lattice-based Evaluation and Its Application to SNOMED CT. AB - Non-lattice fragments are often indicative of structural anomalies in ontological systems and, as such, represent possible areas of focus for subsequent quality assurance work. However, extracting the non-lattice fragments in large ontological systems is computationally expensive if not prohibitive, using a traditional sequential approach. In this paper we present a general MapReduce pipeline, called MaPLE (MapReduce Pipeline for Lattice-based Evaluation), for extracting non-lattice fragments in large partially ordered sets and demonstrate its applicability in ontology quality assurance. Using MaPLE in a 30-node Hadoop local cloud, we systematically extracted non-lattice fragments in 8 SNOMED CT versions from 2009 to 2014 (each containing over 300k concepts), with an average total computing time of less than 3 hours per version. With dramatically reduced time, MaPLE makes it feasible not only to perform exhaustive structural analysis of large ontological hierarchies, but also to systematically track structural changes between versions. Our change analysis showed that the average change rates on the non-lattice pairs are up to 38.6 times higher than the change rates of the background structure (concept nodes). This demonstrates that fragments around non-lattice pairs exhibit significantly higher rates of change in the process of ontological evolution. PMID- 25705726 TI - Empowering Personalized Medicine with Big Data and Semantic Web Technology: Promises, Challenges, and Use Cases. AB - In healthcare, big data tools and technologies have the potential to create significant value by improving outcomes while lowering costs for each individual patient. Diagnostic images, genetic test results and biometric information are increasingly generated and stored in electronic health records presenting us with challenges in data that is by nature high volume, variety and velocity, thereby necessitating novel ways to store, manage and process big data. This presents an urgent need to develop new, scalable and expandable big data infrastructure and analytical methods that can enable healthcare providers access knowledge for the individual patient, yielding better decisions and outcomes. In this paper, we briefly discuss the nature of big data and the role of semantic web and data analysis for generating "smart data" which offer actionable information that supports better decision for personalized medicine. In our view, the biggest challenge is to create a system that makes big data robust and smart for healthcare providers and patients that can lead to more effective clinical decision-making, improved health outcomes, and ultimately, managing the healthcare costs. We highlight some of the challenges in using big data and propose the need for a semantic data-driven environment to address them. We illustrate our vision with practical use cases, and discuss a path for empowering personalized medicine using big data and semantic web technology. PMID- 25705727 TI - Telehealth: the general practice perspective. AB - BACKGROUND: Three years ago the Australian Government undertook to incentivise the adoption of telehealth videoconferencing in primary care. The incentives targeted specialist consultations with patients through their general practitioner (GP), nurse, Aboriginal health worker, and aged care facility. Rural and remote patients and their GPs have benefited from improved access to specialist care in an environment where one kangaroo through your radiator can make a compelling case for remote care delivery. OBJECTIVE: To discuss some of the practical issues, challenges and opportunities related to running a GP telehealth videoconferencing ser-vice, and describe how we deliver telehealth videoconferencing in our practice. DISCUSSION: The business case has taken a back seat to the intangible savings in travel costs, lost productivity, and capacity building of local health professionals. Intuitively, delivering medical care by telehealth videoconferencing should just be an extension of day-to-day clinical practice, and an enabler of local team care and attractive to rural people. However, there remains much to be done in quantifying the scope and applicability of remote care in this context, and opportunities to deliver quality care to rural and isolated people are yet to be realised fully. PMID- 25705728 TI - Telehealth: the specialist perspective. AB - BACKGROUND: Tele-Derm National is an online consultation and educational service in dermatology designed to meet the needs of doctors working in rural and remote Australia. In existence since 2003, it is hosted on the Rural and Remote Medical Education Online site, which is run by the Australian College of Rural and Remote Medicine. OBJECTIVE: This article aims to explore the use and potential of store and-forward teledermatology in the Australian context. DISCUSSION: Doctors who use this service can manage the majority of their patients without the need for a face-to-face appointment with a specialist dermatologist and deliver similar outcomes. Using store-and-forward technology rather than videoconferencing, this site provides specialist diagnosis and management advice year round. All cases are answered within 24 hours of being submitted. There are benefits in terms of increased availability, as well as reduced time, cost and professional isolation. However, uptake remains low, potentially because of a lack of awareness, increased workload for referring practitioners and lack of financial incentives. PMID- 25705729 TI - Technology in practice - GP computer use by age. AB - Since 2005, more than 95% of general practitioners (GPs) have had access to computers in their clinical work. We have analysed the most recent 2 years of BEACH data (April 2012-March 2014) to determine whether GP age affects clinical computer use. PMID- 25705730 TI - e-Mental health for mood and anxiety disorders in general practice. AB - BACKGROUND: Australia is a world leader in the development of internet-delivered programs for the prevention and management of mood and anxiety disorders. Despite a strong evidence base of time- and cost-effectiveness, as well as clinical efficacy, the uptake of these programs in general practice remains low. OBJECTIVE: To familiarise general practitioners (GPs) with the range of online programs in Australia that have demonstrated efficacy and are currently available for use by patients with mental health problems. DISCUSSION: E-mental health programs provide an efficacious and accessible form of mental healthcare and have the potential to fill the gap for those for whom such care is inaccessible, unaffordable or unacceptable. Clinicians can also use it in a stepped-care manner to augment existing healthcare services. There are a number of online resources currently available to Australians who have mood or anxiety disorders. These resources have strong evidence to support their effectiveness. Online portals facilitate access to these programs. Recently the Australian Federal Government has funded an education program (eMHPrac) for GPs and mental health professionals, to outline what is available, indicate situations where recommending such resources is appropriate, and suggest ways in which they can be incorporated into general practice. PMID- 25705731 TI - We can manage depression better with technology. AB - BACKGROUND: Gotzsche, in Lancet Psychiatry, argued that antidepressants produce more harm than good and should be used sparingly. Ka-range et al showed that GP prescriptions of antidepressants in Australia are continuing to rise, especially in children. A rethink about the treatment of depression is indicated. OBJECTIVE: This paper provides a summary of the evidence for internet-delivered cognitive behaviour therapy, and looks at the three RACGP Handbook of Non-Drug Intervention (HANDI) recommendations for non-drug treatments for depression and arranged for the developers to comment. DISCUSSION: The systems identified by HANDI are beneficial in major depression and are supported by evidence. They have not been shown to harm or to be beneficial in depression associated with schizophrenia, bipolar disorder or substance dependence. Although little input is required from general practitioners who prescribe these courses, they may form part of a more comprehensive treatment plan. Australia is a world leader in automated internet delivered cognitive behaviour therapy. Australian clinicians should take advantage and use these courses. PMID- 25705732 TI - Digital technologies and chronic disease management. AB - BACKGROUND: Digital technologies will become a major part of our healthcare system, with particular impact in primary care. However, many healthcare professionals are not sufficiently informed of the digital technologies available today and how they and their patients can gain substantial benefit from adoption of these technologies. OBJECTIVE: To raise awareness of the potential benefits of using digital technologies for improving practice efficiencies and patient health outcomes. DISCUSSION: Implementing best practice care for patients with chronic and complex conditions is one of the greatest challenges facing general practice and other primary care providers. It has been suggested that digital technologies could assist by decreasing the administrative burden of care delivery, improving quality of care, increasing practice efficiencies and better supporting patient self-management. In this paper, we consider some areas in the management of chronic and long-term conditions where digital and mobile health solutions can make a difference today. PMID- 25705733 TI - The broadband-enabled innovation program: a working demonstration of the effective use of technology in community-based patient care. AB - BACKGROUND: Given the socioeconomic demands of the Australian society, both now and in the future, the Royal District Nursing Service (RDNS) has identified the importance of exploring suitable commercial forms of telehealth technologies to enable robust and sustainable models of care for their clients. OBJECTIVE: The aim of this article is to illustrate the practical application of technology in community-based patient care through an overview of a project that the RDNS has trialled to provide remote medicines management. DISCUSSION: The results of this project demonstrate that technology can be successfully applied in community based patient care to enhance the capacity of RDNS to deliver medications management for clients. It showed benefits in terms of increasing the efficiency of service delivery as well as staff and patient satisfaction. On the basis of this success, the program is being expanded and undergoing further evaluation to assess its impact. PMID- 25705734 TI - A rare cause of petechial rash in the 21st century. AB - Scurvy was first described by Hippocrates (460-370 BC) as a condition characterised by poor dental health, bruising, bleeding and fragile skin. Despite the widespread availability of foods rich in vitamin C in Australia, scurvy continues to afflict certain high-risk subgroups of the population. Cutaneous signs may be the only manifestation of the disease, as in the case presented below, and therefore scurvy continues to be relevant to dermatologists. PMID- 25705735 TI - Progressive rash in a migrant. PMID- 25705736 TI - New oral anticoagulants and perioperative management of anticoagulant/antiplatelet agents. AB - BACKGROUND: The strategy of whether to continue anticoagulation and antiplatelet agents during surgery depends on an evaluation of the thromboembolic risk and haemorrhagic risk of the individual patients. Procedures that carry a significant risk of bleeding may require temporary cessation of the medication. OBJECTIVE: We briefly review the use of common oral anticoagulant and antiplatelet agents, including clinical indications and limitations associated with those agents. We also discuss the risks of thromboembolism, and balancing bleeding risk in patients receiving oral anticoagulation therapy, temporary interruption of such therapy and management of such patients undergoing an elective surgical procedure. DISCUSSION: Generally, patients at high risk of thromboembolism should be considered for a more aggressive perioperative management strategy with bridging therapy. Current recommendations for dual antiplatelet treatment range from 4 weeks in patients undergoing elective stenting with bare metal stents, up to 12 months in patients with drug-eluting stents or patients undergoing coronary stenting for acute coronary syndrome. If a patient is to undergo high-bleeding risk surgery and an antiplatelet effect is not desired, clopidogrel, prasugrel and ticagrelor should be discontinued 5-7 days before the procedure. Early, effective communication between general practitioners and specialists is useful in managing high-risk patients on anticoagulation/antiplatelet agents during the perioperative periods. PMID- 25705737 TI - Unusual locations of lipoma: differential diagnosis of head and neck mass. AB - BACKGROUND: Lipomas are the most common benign neoplasm of mesenchymal origin and may arise in any location where fat is normally present. In the head and neck region, where only 13% of lipomas are seen, the posterior neck space is the most common site. OBJECTIVE: This article describes two cases of lipoma that were unusually located in the parotid gland and in the sternocleidomastoid muscle (SCM). DISCUSSION: Intraglandular lipoma of the parotid gland should be included as a rare possibility in the differential diagnosis of tumours involving the parotid gland. The extent of surgery should be determined at the time of operation with dual goals of complete mass resection, including normal tissue and facial nerve preservation. Also, intramuscuclar liopma of SCM is rare and should not be overlooked in the differential diagnosis. A thorough preoperative clinical, radiological and cytological examination should be performed to prevent recurrences due to incomplete removal of the tumour. PMID- 25705738 TI - An uncommon cause of severe chest pain. PMID- 25705739 TI - Patient use of the internet for health information. AB - BACKGROUND: The internet has become an integral part of our everyday lives, affecting the way we work and communicate. It has also changed the way patients obtain health information. This study measures the extent to which general practice patients use the internet to obtain health information, particularly in relation to the problem(s) they bring to the general practitioner (GP), and whether this differs by patient age, sex, socioeconomic status, rurality and English-speaking background status (ESB). METHODS: This research was a sub-study of the Bettering the Evaluation and Care of Health (BEACH) program (a continuous national study of general practice activity in Australia). RESULTS: Of 2944 patients, 63.4% accessed the internet in the previous month; 28.1% had sought health information online; and 17.1% had obtained information related to problems managed by the GP at that visit. Internet use and online health information seeking was inversely related to age for patients aged 15 years or older. The most socioeconomically advantaged patients were significantly more likely than the most disadvantaged to have obtained health information online. Patient sex, ESB status and rurality did not influence internet use or online health information seeking. PMID- 25705740 TI - How confident are general practitioners in teaching medical students about ethical issues on general practice placements? AB - BACKGROUND: Despite a paucity of evidence to guide teaching about medical professionalism and ethical issues, there is a widespread consensus that medical students should learn about these issues on clinical placements. Exploring the confidence of general practitioners (GPs) in teaching various topics will identify areas for further discussion, support and/or training. METHODS: A survey was developed and distributed to 65 teaching practices. Thirty-seven GPs responded by rating their confidence in teaching about 32 different ethical issues. RESULTS: Overall, GPs were confident in teaching about these issues. Confidence was lowest for doctors' social and political responsibilities; ethical lapses in colleagues; impairment in colleagues; cross-cultural issues; and moral motivation, judgement, courage and sensitivity. DISCUSSION: Further training for GP teachers may be particularly useful in the important areas of impairment and lapses in colleagues, and cross-cultural issues. Uncertainty about the scope of doctors' social and political responsibilities may limit GP confidence in teaching in these areas. PMID- 25705741 TI - Patients' use of social media: e-rating of doctors. AB - BACKGROUND: Patients are increasingly posting online reviews about their medical care, including rating their doctors. OBJECTIVE: This article discusses patients' use of social media to comment on and 'rate' their medical care, with a particular focus on what a general practitioner (GP) can do about a negative online review. DISCUSSION: The vast majority of online reviews about doctors are positive. However, the small proportion of negative online reviews can be a source of great distress to those doctors who are the subject of these reviews. GPs should seek advice before considering whether or not to respond to a negative online review. PMID- 25705742 TI - GP supervisors assessing GP registrars - theory and practice. AB - BACKGROUND: General practice supervisors are increasingly being expected to assess their registrars. OBJECTIVE: In this article we explore the issues this raises for supervisors, and discuss the literature, which suggests that global assessments are the most accurate and feasible. DISCUSSION: We suggest the following guidelines for supervisors: inform registrars at the beginning of the term about how and when they will be assessed; be clear that the aim is to decide if the registrars' practice is safe for patients and appropriate for their stage of training; ob-serve registrars at work; make an initial judgement of registrars' performance; test the initial judgement on performance applying qualitative research methods to improve trustworthiness and reduce potential biases; use the working diagnosis of registrar performance to guide the level of support and clinical oversight needed and flag registrars who require further assessment by educational organisations for remediation decisions. PMID- 25705743 TI - The biochemical changes in hippocampal formation occurring in normal and seizure experiencing rats as a result of a ketogenic diet. AB - In this study, ketogenic diet-induced biochemical changes occurring in normal and epileptic hippocampal formations were compared. Four groups of rats were analyzed, namely seizure experiencing animals and normal rats previously fed with ketogenic (KSE and K groups respectively) or standard laboratory diet (NSE and N groups respectively). Synchrotron radiation based Fourier-transform infrared microspectroscopy was used for the analysis of distributions of the main organic components (proteins, lipids, compounds containing phosphate group(s)) and their structural modifications as well as anomalies in creatine accumulation with micrometer spatial resolution. Infrared spectra recorded in the molecular layers of the dentate gyrus (DG) areas of normal rats on a ketogenic diet (K) presented increased intensity of the 1740 cm(-1) absorption band. This originates from the stretching vibrations of carbonyl groups and probably reflects increased accumulation of ketone bodies occurring in animals on a high fat diet compared to those fed with a standard laboratory diet (N). The comparison of K and N groups showed, moreover, elevated ratios of absorbance at 1634 and 1658 cm(-1) for DG internal layers and increased accumulation of creatine deposits in sector 3 of the Ammon's horn (CA3) hippocampal area of ketogenic diet fed rats. In multiform and internal layers of CA3, seizure experiencing animals on ketogenic diet (KSE) presented a lower ratio of absorbance at 1634 and 1658 cm(-1) compared to rats on standard laboratory diet (NSE). Moreover, in some of the examined cellular layers, the increased intensity of the 2924 cm(-1) lipid band as well as the massifs of 2800-3000 cm(-1) and 1360-1480 cm(-1), was found in KSE compared to NSE animals. The intensity of the 1740 cm(-1) band was diminished in DG molecular layers of KSE rats. The ketogenic diet did not modify the seizure induced anomalies in the unsaturation level of lipids or the number of creatine deposits. PMID- 25705744 TI - Simple fluorinated moiety insertion on Abeta 16-23 peptide for stain-free TEM imaging. AB - Peptide aggregation and fibre formation are one of the major underlying causes of several neurodegenerative disorders such as Alzheimer's disease. During the past decades the characterisation of these fibres has been widely studied in an attempt to further understand the nature of the related diseases and in an effort to develop treatments. Transmission electron microscopy (TEM) is one of the most commonly used techniques to identify these fibres, but requires the use of a radioactive staining agent. The procedure we report overcomes this drawback through simple addition of a fluorinated moiety to a short Amyloid beta sequence via solid phase peptide synthesis (SPPS). This method is synthetically straightforward, widely applicable to different aggregation-prone sequences and, above all, allows for stain-free TEM imaging with improved quality compared to standard imaging procedures. The presence of the fluorinated moiety does not cause major changes in the fibre structure or aggregation, but rather serves to dissipate the microscope's electron beam, thus allowing for high contrast and straightforward imaging by TEM. PMID- 25705745 TI - Direct access to macroporous chromium nitride and chromium titanium nitride with inverse opal structure. AB - We report a facile synthesis of single-phase, nanocrystalline macroporous chromium nitride and chromium titanium nitride with an inverse opal morphology. The material is characterized using XRD, SEM, HR-TEM/STEM, TGA and XPS. Interconversion of macroporous CrN to Cr2O3 and back to CrN while retaining the inverse opal morphology is also demonstrated. PMID- 25705746 TI - On-surface reductive coupling of aldehydes on Au(111). AB - On-surface synthesis of a polyphenylene vinylene oligomer via reductive coupling of a terephthalaldehyde derivative on Au(111) is reported. Scanning tunneling microscopy and photoelectron spectroscopy experiments confirmed oxygen dissociation and its desorption from the surface. Density functional theory calculations provided a reasonable reaction mechanism involving reactive sites on the substrate. PMID- 25705747 TI - Using nickel manganese oxide catalysts for efficient water oxidation. AB - Nickel-manganese oxides with variable Ni : Mn ratios, synthesised from heterobimetallic single-source precursors, turned out to be efficient water oxidation catalysts. They were subjected to oxidant-driven, photo- and electro catalytic water oxidation showing superior activity and remarkable stability. In addition, a structure-activity relation could be established. PMID- 25705748 TI - Divergence between HbA1c and fasting glucose through childhood: implications for diagnosis of impaired fasting glucose (Early Bird 52). AB - OBJECTIVE: An HbA1c threshold of >= 6.5% has recently been adopted for the diagnosis of diabetes in adults, and of >= 5.7% to identify adults at risk. Little,however, is known of HbA1c's behaviour or diagnostic value in youth. Our aim was to describe the course of HbA1c during childhood, and its association with fasting glucose. RESEARCH DESIGN AND METHODS: HbA1c and glucose were measured every year in a cohort of 326 healthy children (162 boys) from 5 to 15 years. Mixed effects modelling was used to establish the determinants of HbA1c and its development over time. ROC analysis was used to determine the diagnostic value of HbA1c in the 55 individuals who showed impaired fasting glucose(IFG - glucose >= 5.6 mmol/L). RESULTS: Glucose rose progressively from 4.3 mmol/L at 5 years to 5.1 mmol/Lat 15 years, and although there were positive associations between HbA1c and glucose, from 10 to 13 years, HbA1c fell while glucose continued to rise. IFG developed in 55 children, but HbA1c exceeded 5.7% in only 16 of them. The maximum area under the ROC curve was 0.71 at the age of 14 (p<0.001), and the sensitivity and specificity were optimal at 50 and 80% respectively,corresponding to HbA1c of 5.4%. CONCLUSIONS: Although HbA1c retains a positive association with glucose throughout childhood, it is weak, and their trends diverge from 10 years,suggesting that factors other than glycaemia systematically influence the variance of HbA1c in youth. These findings therefore limit the interpretation of HbA1c for the diagnosis of IFG during childhood. PMID- 25705749 TI - Pulse pressure in children and adolescents with type 1 diabetes mellitus in Germany and Austria. AB - BACKGROUND: Impaired blood pressure regulation contributes to the development of diabetic complications. The influence of systolic (SBP) vs.diastolic blood pressure (DBP) is still controversial. Peripheral pulse pressure(PP), the difference between SBP and DBP, is an indicator for arterial stiffness. Only little data are available for PP in children. Therefore, we studied PP regulation in type 1 diabetic children and adolescents.Methods: Blood pressure values of 46 737 patients with T1DM younger than 20 years are documented in the DPV database and were compared with the control populations of the '4th report on high blood pressure (4th report)' and the German KIGGS study. RESULTS: PP is increased in 63% (4th report) or 67% (KIGGS) of the patients,respectively. The rate of increased PP remains stable between 59 and 68%,irrespective of sex, age, and the control population. Absolute PP is elevated independently of the control population (PP T1DM 49.13+/-11.1 vs. 4th report 45.38 +/- 3 vs. KIGGS 44.58 +/- 4.6 mmHg; all p<0.0001, Wilcoxon test)and increases with age in both sexes. Age, male sex, diabetes duration, insulin dose, and body mass index (BMI) are independent factors contributing to elevated absolute PP levels and to the prevalence of wide PP. HbA1c is negligible negatively related to increased PP levels (multiple linear regression). CONCLUSIONS: In T1DM increased PP is a marker for accelerated arterial stiffness and aging and should be considered as an additional risk factor in the treatment of diabetic children. Elevated PP in children with T1DM may contribute to the high risk for early development of atherosclerosis. PMID- 25705750 TI - Adding fuel to the fire: the impact of stress on the ageing brain. AB - Both ageing and chronic stress are associated with altered brain plasticity, dysregulation of the immune system, and an increased risk of developing brain disorders; all of which have consequences for cognitive and emotional processing. Here we examine the similarities between behavioural changes during ageing and stress altered behaviours (anxiety, depressive-like behaviour, cognition, and sociability) in rodents and humans. The molecular mechanisms hypothesised to mediate age-related changes in brain function including dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis, dysregulation of neurotransmission and neurotrophic factor signalling, increased inflammatory state, genetic and epigenetic changes, oxidative stress, metabolic changes, and changes in the microbiota-gut-brain axis are discussed. Finally, we explore how the already stressed aged brain psychologically and physiologically responds to external stressors. PMID- 25705751 TI - Author response. PMID- 25705752 TI - Response. PMID- 25705753 TI - Response. PMID- 25705754 TI - [In Process Citation]. PMID- 25705755 TI - [In Process Citation]. PMID- 25705756 TI - [In Process Citation]. PMID- 25705757 TI - Validating a new methodology for optical probe design and image registration in fNIRS studies. AB - Functional near-infrared spectroscopy (fNIRS) is an imaging technique that relies on the principle of shining near-infrared light through tissue to detect changes in hemodynamic activation. An important methodological issue encountered is the creation of optimized probe geometry for fNIRS recordings. Here, across three experiments, we describe and validate a processing pipeline designed to create an optimized, yet scalable probe geometry based on selected regions of interest (ROIs) from the functional magnetic resonance imaging (fMRI) literature. In experiment 1, we created a probe geometry optimized to record changes in activation from target ROIs important for visual working memory. Positions of the sources and detectors of the probe geometry on an adult head were digitized using a motion sensor and projected onto a generic adult atlas and a segmented head obtained from the subject's MRI scan. In experiment 2, the same probe geometry was scaled down to fit a child's head and later digitized and projected onto the generic adult atlas and a segmented volume obtained from the child's MRI scan. Using visualization tools and by quantifying the amount of intersection between target ROIs and channels, we show that out of 21 ROIs, 17 and 19 ROIs intersected with fNIRS channels from the adult and child probe geometries, respectively. Further, both the adult atlas and adult subject-specific MRI approaches yielded similar results and can be used interchangeably. However, results suggest that segmented heads obtained from MRI scans be used for registering children's data. Finally, in experiment 3, we further validated our processing pipeline by creating a different probe geometry designed to record from target ROIs involved in language and motor processing. PMID- 25705758 TI - Legal and human rights achievements of Anand Grover in India and as Special Rapporteur on the Right to Health, 2008-2014. PMID- 25705759 TI - Urgent needs and participation of women must be prioritized in the Ebola response: 3 October 2014. PMID- 25705760 TI - Pubertal development in children diagnosed with diabetes mellitus type 1 before puberty. AB - STUDY OBJECTIVE: To investigate an association between pubertal development and timing of menarche with glycemic control, disease duration, and body mass index (BMI) in patients diagnosed with diabetes mellitus type 1 (DM1) before puberty. DESIGN: Retrospective study. SETTING: The study was performed at the diabetes outpatient clinic of Instituto de Puericultura e Pediatria Martagao Gesteira- IPPMG of the Federal University of Rio de Janeiro--UFRJ. PARTICIPANTS: A total of 131 children, 61 girls and 70 boys, diagnosed with DM1 before puberty participated in the study. MAIN OUTCOME MEASURES: The study investigated how age at puberty onset relates to mean glycated hemoglobin (HbA1c) before puberty, BMI percentile, and disease duration; how puberty duration relates to mean HbA1c before and during puberty and to disease duration; and how timing of menarche relates to mean HbA1c before puberty, BMI percentile, and disease duration. RESULTS: Age at puberty onset was positively correlated with mean HbA1c before puberty (r = 0.204, R(2) = 0.042; P = .019) and disease duration (r = 0.451, R(2) = 0.203; P < .0001), and negatively correlated with BMI percentile (r = -0.289, R(2) = 0.084; P = .001). Timing of menarche was negatively correlated with BMI percentile (r = -0.556, R(2) = 0.310; P < .001). CONCLUSIONS: Children with longer disease duration began puberty later than those diagnosed more recently. Girls in higher BMI percentiles reached menarche sooner. PMID- 25705761 TI - Farm assurance schemes and animal welfare. PMID- 25705763 TI - Veterinary medicines: revised proposals on record keeping. PMID- 25705762 TI - Beef on the bone ban to be lifted. PMID- 25705764 TI - Biotechnology and animal experiments. PMID- 25705765 TI - Animal welfare: concerns about global trading. PMID- 25705766 TI - Novartis acquires Vericore. PMID- 25705767 TI - Farms and the millennium bug. PMID- 25705768 TI - Careers, communication and welfare--the 1999 Lancaster seminar. PMID- 25705769 TI - Observations on the distribution of Salmonella in a pig abattoir. AB - A survey of 2211 pigs was carried out in a pig abattoir. Salmonella was isolated from 7-0 per cent of carcase swabs and from 11.6 per cent of 2205 samples of large intestinal contents. Salmonella typhimurium DT104 or DT104B was found in 3.2 per cent of the large intestinal samples (27.7 per cent of the salmonella isolates found) and in 2.7 per cent of the carcase swabs (38.7 per cent of the salmonella isolates from carcases). Within individual batches of pigs, the rate of isolation of salmonella ranged from 0 to 71.4 per cent from intestinal contents, and from 0 to 100 per cent on carcases. In a smaller subsurvey, salmonella was found in 9.1 per cent of intestinal contents, 5.8 per cent of mesenteric lymph nodes and 3.8 per cent of tonsils, but in no spleen samples. The rates of isolation of salmonella from pigs from different producer groups ranged from 0 to 21.9 per cent with 0 to 88.2 per cent of farm units within groups showing evidence of infection. S typhimurium DT104 or DT104B was isolated from large intestinal samples from 16.9 per cent of farm units. The number of salmonellae found in positive pigs ranged from 1.0 to 10(5) cfu/g intestinal contents and from 1.0 to 10(2) cfu per 0.1 m2 dressed carcase surface. Sequential sampling during the slaughter process showed that 82.9 per cent of the carcases were contaminated after bleeding, a proportion which was reduced to 5.7 per cent after scalding; after singeing none were contaminated. Estimations of surface enterobacteriaceae revealed a similar pattern of reductions and resurgences of contamination to that observed with salmonella. The rate of isolation of salmonella from pigs which had been held in lairage overnight was less than that from pigs slaughtered within two to three hours of arrival. PMID- 25705770 TI - Ultrasonographic detection of a pancreatic glucagon-secreting multihormonal islet cell tumour in a dachshund with metabolic epidermal necrosis. AB - The clinical, ultrasonographic and histopathological features of a pancreatic multihormonal islet cell tumour are described in a 12-year-old dachshund with cutaneous lesions suggestive of metabolic epidermal necrosis. This condition was suspected because of the compatible cutaneous signs, a high plasma glucagon concentration and the detection of a well defined pancreatic mass by ultrasonography. The diagnosis was confirmed postmortem and by histology. PMID- 25705771 TI - Non-invasive assessment of arterial haemoglobin oxygen saturation in cattle by pulse oximetry. AB - The aim of this study was to evaluate the practicality and accuracy of different attachment sites for the optodes of a pulse oximeter (measuring arterial haemoglobin oxygen saturation) in healthy cattle, and to assess the accuracy of pulse oximetry in diseased cattle with low haemoglobin oxygen saturation values caused by respiratory disease. The tail, the nasal septum and the genital mucosa of females provided a continuous, stable and intense signal. The smallest bias, and no significant difference between measurements of arterial haemoglobin (mSpO2) with the pulse oximeter and measurements of arterial haemoglobin oxygen saturation (SaO2) with a blood gas analyser was obtained when the probe was attached to the tail. This site was used to evaluate the accuracy of pulse oximetry in animals with respiratory disease. There was a small bias between the measurements of SaO2 and mSpO2, with a tendency for pulse oximetry to underestimate higher values and to overestimate lower values. The precision of pulse oximetry decreased substantially with the values for SaO2 < 80 per cent, which lies outside the clinically relevant range. PMID- 25705772 TI - Incidence and ocular manifestations of multifocal retinal dysplasia in the golden retriever in the UK. PMID- 25705773 TI - Targeted surveillance for bovine spongiform encephalopathy. PMID- 25705774 TI - Clinical effects of feeding low dietary phosphorus levels to high yielding dairy cows. PMID- 25705775 TI - Thoracoabdominal aortic aneurysm in two ponies. PMID- 25705776 TI - RCVS disciplinary procedures. PMID- 25705777 TI - Polyorchidism in a cat. PMID- 25705778 TI - Isolation of a pneumovirus from a Muscovy duck. PMID- 25705779 TI - "I don't like passing as a straight woman": queer negotiations of identity and social group membership. AB - For decades, sociological theory has documented how our lives are simultaneously produced through and against normative structures of sex, gender, and sexuality. These normative structures are often believed to operate along presumably "natural," biological, and essentialized binaries of male/female, man/woman, and heterosexual/ homosexual. However, as the lives and experiences of transgender people and their families become increasingly socially visible, these normative structuring binaries are called into stark question as they fail to adequately articulate and encompass these social actors' identities and social group memberships. Utilizing in-depth interviews with 50 women from the United States, Canada, and Australia, who detail 61 unique relationships with transgender men, this study considers how the experiences of these queer social actors hold the potential to rattle the very foundations upon which normative binaries rest, highlighting the increasingly blurry intersections, tensions, and overlaps between sex, gender, and sexual orientation in the 21st century. This work also considers the potential for these normative disruptions to engender opportunities for social collaboration, solidarity, and transformation. PMID- 25705780 TI - Neither ideologues nor agnostics: alternative voters' belief system in an age of partisan politics. AB - How do Americans organize their political beliefs? This article argues that party polarization and the growing prominence of moral issues in recent decades have catalyzed different responses by different groups of Americans. The article investigates systematic heterogeneity in the organization of political attitudes using relational class analysis, a graph-based method for detecting multiple patterns of opinion in survey data. Three subpopulations, each characterized by a distinctive way of organizing its political beliefs, are identified: ideologues, whose political attitudes strongly align with either liberal or conservative categories; alternatives, who are instead morally conservative but economically liberal, or vice versa; and agnostics, who exhibit weak associations between political beliefs. Individuals' sociodemographic profiles, particularly their income, education, and religiosity, lie at the core of the different ways in which they understand politics. Results show that while ideologues have gone through a process of issue alignment, alternatives have grown increasingly apart from the political agendas of both parties. The conflictual presence of conservative and liberal preferences has often been resolved by alternative voters in favor of the Republican Party. PMID- 25705781 TI - Governing inside the organization: interpreting regulation and compliance. AB - Looking inside organizations at the different positions, expertise, and autonomy of the actors, the authors use multisite ethnographic data on safety practices to develop a typology of how the regulator, as the focal actor in the regulatory process, is interpreted within organizations. The findings show that organizational actors express constructions of the regulator as an ally, threat, and obstacle that vary with organizational expertise, authority, and continuity of relationship between the organizational member and the regulator. The article makes three contributions to the current understandings of organizational governance and regulatory compliance, thereby extending both institutional and ecological accounts of organizations' behavior with respect to their environments. First, the authors document not only variation across organizations but variable compliance within an organization. Second, the variations described do not derive from alternative institutional logics, but from variations in positions, autonomy, and expertise within each organization. From their grounded theory, the authors hypothesize that these constructions carry differential normative interpretations of regulation and probabilities for compliance, and thus the third contribution, the typology, when correlated with organizational hierarchy provides the link between microlevel action and discourse and organizational performance. PMID- 25705782 TI - Blocked acculturation: cultural heterodoxy among Europe's immigrants. AB - Which immigrant groups differ most from the cultural values held by mainstream society and why? The authors explore this question using data from the European Social Survey on the values held by almost 100,000 individuals associated with 305 immigrant groups and the native majorities of 23 countries. They test whether distant linguistic or religious origins (including in Islam), value differences that immigrants "import" from their home countries, the maintenance of transnational ties and thus diasporic cultures, or legal and social disadvantage in the country of settlement shape acculturation processes. They find that only legally or socially disadvantaged groups differ from mainstream values in significant ways. For first generation immigrants, this is because the values of their countries of origin diverge more from those of natives. Among children of disadvantaged immigrants, however, value heterodoxy emerges because acculturation processes are blocked and the values of the parent generation partially maintained. From the second generation onward, therefore, cultural values are endogenous to the formation and dissolution of social boundaries, rather than shaping these as an exogenous force. PMID- 25705783 TI - Issue bricolage: explaining the configuration of the social movement sector, 1960 1995. AB - Social movements occupy a shared ideational and resource space, which is often referred to as the social movement sector. This article contributes to the understanding of the relational dynamics of the social movement sector by demonstrating how ideational linkages are formed through protest events. Using a data set of protest events occurring in the United States from 1960 to 1995, the authors model the mechanisms shaping why certain movement issues (e.g., women's and peace or environmental and gay rights) appear together at protest events. They argue that both cultural similarity and status differences between two social movement issues are the underlying mechanisms that shape joint protest and the resultant ideational linkages between issues. Finally, they show that the linking of issues at protest events results in changes in the prominence of a given issue in the social movement sector. PMID- 25705784 TI - Coevolution in management fashion: an agent-based model of consultant-driven innovation. AB - The rise of management consultancy has been accompanied by increasingly marked faddish cycles in management techniques, but the mechanisms that underlie this relationship are not well understood. The authors develop a simple agent-based framework that models innovation adoption and abandonment on both the supply and demand sides. In opposition to conceptions of consultants as rhetorical wizards who engineer waves of management fashion, firms and consultants are treated as boundedly rational actors who chase the secrets of success by mimicking their highest-performing peers. Computational experiments demonstrate that consultant driven versions of this dynamic in which the outcomes of firms are strongly conditioned by their choice of consultant are robustly faddish. The invasion of boom markets by low-quality consultants undercuts popular innovations while simultaneously restarting the fashion cycle by prompting the flight of high quality consultants into less densely occupied niches. Computational experiments also indicate conditions involving consultant mobility, aspiration levels, mimic probabilities, and client-provider matching that attenuate faddishness. PMID- 25705785 TI - Killing dental pathogens using antibacterial graphene oxide. AB - Dental caries and periodontal diseases have a close relationship with microbes such as Streptococcus mutans, Porphyromonas gingivalis and Fusobacterium nucleatum. Graphene oxide (GO), as the derivative of graphene, plays an important role in many areas including biology and medicine. In particular, it has been known as a promising antimicrobial nanomaterial. In this study, we focused on the antimicrobial property of GO against dental pathogens. With the utilization of 3 (4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) reduced test, colony forming units (CFU) counting, growth curve observation, live/dead fluorescent staining, and confocal laser scanning microscopy (CLSM), we found GO nanosheets were highly effective in inhibiting the growth of dental pathogens. Transmission electron microscopy (TEM) images revealed that the cell wall and membrane of bacteria lost their integrity and the intracellular contents leaked out after they were treated by GO. Therefore, GO nanosheets would be an effective antibacterial material against dental pathogens and the potential applications in dental care and therapy are promising. PMID- 25705786 TI - Quasi-experimental evaluation of a telephone-based peer support intervention for maternal depression. AB - AIMS: To evaluate the effect of telephone-based peer support on maternal depression and social support BACKGROUND: Postpartum depression is a global health concern and lack of treatment options mean many mothers are depressed beyond the first year after birth. Strong evidence has shown telephone-based peer support, provided by a mother recovered from depression, effectively improves depression outcomes. This model has not been tested with mothers with depression any time up to two years postpartum. DESIGN: Quasi-experimental, one group pre test, posttest. METHOD: The study population was mothers in New Brunswick, Canada with depression up to 24 months after delivery. The sample (N = 64) was recruited between May 2011-October 2013. Peer volunteers recovered from postpartum depression were trained and delivered an average of 8.84 (Range 1-13) support telephone calls. Depression and social support outcomes were assessed at intervention mid-point (average 7.43 weeks, n = 37) and end (average 13.9 weeks, n = 34). RESULTS: Mean depression significantly declined from baseline, 15.4 (N = 49), to mid-point, 8.30 and end of the study, 6.26. At mid-point 8.1% (n = 3/37) of mothers were depressed and at endpoint 11.8% (4/34) were depressed suggesting some relapse. Perceptions of social support significantly improved and higher support was significantly related with lower depression symptoms. CONCLUSION: Findings offer promise that telephone-based peer support is effective for both early postpartum depression and maternal depression up to two years after delivery. PMID- 25705787 TI - Efficacy of technology-delivered cognitive behavioural therapy for OCD versus control conditions, and in comparison with therapist-administered CBT: meta analysis of randomized controlled trials. AB - Cognitive behavioural therapy (CBT) is a well-established treatment for obsessive compulsive disorder (OCD). However, few patients receive CBT, due to factors such as geographic limitations, perceived stigmatization, and lack of CBT services. Technology-delivered cognitive behavioural therapy (T-CBT) could be an effective strategy to improve patients' access to CBT. To date, a meta-analysis on the effectiveness of T-CBT for OCD has not been conducted. This study used meta analytic techniques to summarize evidence on the efficacy of T-CBT for OCD versus control conditions and therapist-administered CBT. A meta-analysis according to Prisma guidelines was conducted on randomized controlled trials (RCTs) of T-CBT for OCD. Treatment was classified as T-CBT if evidence-based CBT active ingredients for OCD were included (psychoeducation, ERP, and cognitive restructuring), delivered through health technologies (e.g. self-help books, leaflets, and other forms of bibliotherapy) or remote communication technologies (e.g. the Internet, web-cameras, telephones, telephone-interactive voice response systems, and CD-ROMS). Studies using validated outcomes for OCD or depression were included. Eight trials were included (N = 420). Two trials were classified as at high risk of bias. T-CBT seemed to be superior to control conditions on OCD symptom outcomes at post-treatment (d = 0.82, 99% CI = 0.55-1.08, p = 0.001), but not on comorbid depression (d = 0.33, 99% CI = - 0.01-0.67, p = 0.020). Difference in the efficacy on OCD symptoms between T-CBT and therapist administered CBT was not significant, despite a trend favouring therapist administered CBT emerged (d = 0.45, 95% CI = 0.03-0.87, p = 0.033). Directions for research are discussed. Further RCTs are warranted to examine the efficacy of T-CBT for OCD. PMID- 25705788 TI - Epithelial cytokines and pulmonary allergic inflammation. AB - The triad of epithelial derived cytokines, IL-25, IL-33 and TSLP are important for the initiation and development of pulmonary immune responses to environmental stimuli. Data from experiments using mouse models provide compelling evidence for their involvement in both innate and adaptive immunity to drive type-2 responses, allergic inflammation and airway remodelling. These cytokines are known to be expressed in human lung tissue and immune cells, however their involvement in mediating allergic pulmonary responses in patients is less clear than in murine models of disease. This article focuses on evidence for the role of IL-25, IL-33 and TSLP in human allergic disease and discusses their potential as therapeutic targets for severe asthma. PMID- 25705789 TI - Photothermal therapeutic response of cancer cells to aptamer-gold nanoparticle hybridized graphene oxide under NIR illumination. AB - The objective of this study was to synthesize a nanocomposite, aptamer-gold nanoparticle-hybridized graphene oxide (Apt-AuNP-GO), to facilitate targeted treatment of tumor cells by near-infrared (NIR) light-activatable photothermal therapy. We also investigated whether Apt-AuNP-GO with NIR illumination modulates heat shock proteins (HSPs) expression leading to therapeutic response in human breast cancer cells. These findings can provide strategies for improving the photothermal therapy efficacy of cancer. The self-assembled Apt-AuNP-GO nanocomposite could selectively target MUC1-positive human breast cancer cells (MCF-7) due to the specific interaction between the MUC1-binding-aptamer and the MUC1 (type I transmembrane mucin glycoprotein) on cell membrane. In addition, Apt AuNP-GO has a high light-to-heat conversion capability for photoabsorption of NIR light, and it is able to exert therapeutic effects on MCF-7 cells at an ultralow concentration without inducing adverse effects in healthy cells. The Apt-AuNP-GO nanocomposites combine the advantages of GOs, AuNPs, and Apts, possess specific targeting capability, excellent biocompatibility, and tumor cell destruction ability, suggesting great potential for application in the photothermal therapy of breast cancer. Under NIR illumination, Apt-AuNP-GO induced transient increase in HSP70 expression, which decreased thereafter. This phenomenon may cause irreversible damage to Apt-AuNP-GO-treated MCF-7 cell under NIR illumination. We also demonstrated that the combination therapy of heat and HSP70 inhibitor could synergistically generate marked tumoricidal effects against breast cancer. These results suggest that the degree and duration of HSP70 protein expression are correlated with therapeutic effects against breast cancer for Apt-AuNP-GO assisted photothermal therapy. We believe that such a nanocomposite can be readily extended to the construction of HSP70 inhibitors-loaded Apt-AuNP-GO, which could deliver both heat and HSP70 inhibitors to tumorigenic regions for the chemo-photothermal therapy. PMID- 25705790 TI - Household chaos, sociodemographic risk, coparenting, and parent-infant relations during infants' first year. AB - Household chaos is a construct often overlooked in studies of human development, despite its theoretical links with the integrity of individual well-being, family processes, and child development. The present longitudinal study examined relations between household chaos and well-established correlates of chaos (sociodemographic risk, major life events, and personal distress) and several constructs that, to date, are theoretically linked with chaos but never before assessed as correlates (quality of coparenting and emotional availability with infants at bedtime). In addressing this aim, we introduce a new measure of household chaos (the Descriptive In-home Survey of Chaos--Observer ReporteD, or DISCORD), wholly reliant on independent observer report, which draws from household chaos theory and prior empirical work but extends the measurement of chaos to include information about families' compliance with a home visiting protocol. Household chaos was significantly associated with socioeconomic risk, negative life events, less favorable coparenting, and less emotionally available bedtime parenting, but not with personal distress. These findings emphasize the need to examine household chaos as a direct and indirect influence on child and family outcomes, as a moderator of intervention attempts to improving parenting and child development, and as a target of intervention in its own right. PMID- 25705791 TI - Heterologous replicase driven 3' end repair of Cucumber mosaic virus satellite RNA. AB - To investigate the extent of the 3' end repair in a satellite RNA of Cucumber mosaic virus (CMV) strain Q (Q(sat)) by a heterologous Tomato aspermy virus (TAV), a set of biologically active agrotransformants corresponding to the three genomic RNAs of TAV was developed. Analysis of Nicotiana benthamiana plants agroinfiltrated with TAV and either wild type or each of the six 3' deletion mutants of Q(sat) revealed that (i) heterologous replicase failed to generate Q(sat) multimers, a hallmark feature of homologous replicase dependent replication of Qsat; (ii) manifestation of severe symptom phenotypes and progeny analysis suggested that heterologous replicase was competent to repair Q(sat) deletion mutants lacking up to 3'13 nucleotides (nt) but not beyond and (iii) comparative in silico analysis indicated that the 3' secondary structural features of the repaired Q(sat) progeny from heterologous vs homologous driven replicases are remarkably very similar. The significance of these observations is discussed. PMID- 25705792 TI - miR-146a controls CXCR4 expression in a pathway that involves PLZF and can be used to inhibit HIV-1 infection of CD4(+) T lymphocytes. AB - MicroRNA miR-146a and PLZF are reported as major players in the control of hematopoiesis, immune function and cancer. PLZF is described as a miR-146a repressor, whereas CXCR4 and TRAF6 were identified as miR-146a direct targets in different cell types. CXCR4 is a co-receptor of CD4 molecule that facilitates HIV 1 entry into T lymphocytes and myeloid cells, whereas TRAF6 is involved in immune response. Thus, the role of miR-146a in HIV-1 infection is currently being thoroughly investigated. In this study, we found that PLZF mediates suppression of miR-146a to control increases of CXCR4 and TRAF6 protein levels in human primary CD4(+) T lymphocytes. We show that miR-146a upregulation by AMD3100 treatment or PLZF silencing, decreases CXCR4 protein expression and prevents HIV 1 infection of leukemic monocytic cell line and CD4(+) T lymphocytes. Our findings improve the prospects of developing new therapeutic strategies to prevent HIV-1 entry via CXCR4 by using the PLZF/miR-146a axis. PMID- 25705793 TI - The movement proteins (NSm) of distinct tospoviruses peripherally associate with cellular membranes and interact with homologous and heterologous NSm and nucleocapsid proteins. AB - Tospovirus is the only genus containing virus species which infect plants in the Bunyaviridae family. The aims of this study were to understand the in vivo membrane association of the movement protein (NSm) of the tospovirus species Bean necrotic mosaic virus, Chrysanthemum stem necrosis virus, Tomato chlorotic spot virus and Tomato spotted wilt virus and the homologous and heterologous interactions among NSm and nucleocapsid protein (N). The results obtained by bimolecular fluorescence complementation (BiFC) assay and chemical treatments after membrane fractionation revealed that the four NSm proteins are associated with the biological membranes with the N- and C-termini oriented to the cytoplasm. BiFC analysis for protein-protein interactions showed: i) dimer formation for all NSm and N proteins; ii) interaction between NSm and the cognate N and iii) heterologous interactions between the NSm and N proteins. The implications of these interactions in the life cycle of tospoviruses are discussed. PMID- 25705794 TI - Effective low-energy theory for superconducting topological insulators. AB - Candidate pairings of superconducting topological insulators support interesting surface Andreev bound states (SABSs) known as Majorana fermions. As these materials are described by a two-orbital Bernevig-Hughes-Zhang type model, a general understanding of the low-energy physics such as the possible kinds of SABSs are difficult. By virtue of an analogy between a topological insulator and a time reversal invariant topological superconductor, we propose a simple and intuitive method of constructing the low-energy effective models for superconducting topological insulators like CuxBi2Se3. Depending on the value of the chemical potential and for experimentally relevant model parameters, the low energy properties of these superconductors are shown to be determined by one copy or two copies of single-orbital effective models. If the effective pairing potential shows sign reversal upon reflection by the surface, one Kramers' pair or two Kramers' pairs of SABSs are expected to appear. Explicit analytical calculations in terms of the effective low energy model reproduce the dispersions of the numerically confirmed two pairs of SABSs for a commonly studied pairing. PMID- 25705795 TI - Holistic Facial Composite Construction and Subsequent Lineup Identification Accuracy: Comparing Adults and Children. AB - When the police have no suspect, they may ask an eyewitness to construct a facial composite of that suspect from memory. Faces are primarily processed holistically, and recently developed computerized holistic facial composite systems (e.g., EFIT-V) have been designed to match these processes. The reported research compared children aged 6-11 years with adults on their ability to construct a recognizable EFIT-V composite. Adult constructor's EFIT-Vs received significantly higher composite-suspect likeness ratings from assessors than children's, although there were some notable exceptions. In comparison to adults, the child constructors also overestimated the composite-suspect likeness of their own EFIT-Vs. In a second phase, there were no differences between adult controls and constructors in correct identification rates from video lineups. However, correct suspect identification rates by child constructors were lower than those of child controls, suggesting that a child's memory for the suspect can be adversely influenced by composite construction. Nevertheless, all child constructors coped with the demands of the EFIT-V system, and the implications for research, theory, and the criminal justice system practice are discussed. PMID- 25705796 TI - BMP/Smad signaling and embryonic cerebellum development: stem cell specification and heterogeneity of anterior rhombic lip. AB - The canonical bone morphogenetic proteins (BMPs) signaling have been shown to mediate many embryonic developmental processes. Due to its complexity, there are still many unknowns about this signal pathway including the Smad usage and requirement. Cerebellum, one of the most studied neural organs in development biology, requires canonical BMP signaling for stem cell specification. Here we review the role of canonical BMP signaling during the embryonic cerebellum development. Also, we raise several unsolved issues concerning the BMP signaling including the co-Smad independency of this signaling pathway. Besides, we also propose two models for explaining the cerebellar anterior rhombic lip (ARL) specification mechanisms. In addition, we review the heterogeneity of the ARL stem cells, which may provide new insight into understanding the neural stem cell specification process of the embryonic cerebellum. PMID- 25705797 TI - Cognitive function in patients with primary adrenal insufficiency (Addison's disease). AB - BACKGROUND: Patients with primary adrenal insufficiency (AI) need to replace glucocorticoids and mineralocorticoids that act on glucocorticoid (GR) and mineralocorticoid receptors (MR). Both receptors are highly expressed in the hippocampus and are closely associated with cognitive function, which might be impaired by insufficient or increased GR and MR stimulation. However, little is known about cognitive function in patients with AI. METHODS: It was examined whether patients with AI exhibit worse cognitive function compared to sex-, age-, and education-matched controls. Cognitive function (executive function, concentration, verbal memory, visual memory, working memory, and autobiographical memory) was assessed in 30 patients with AI (mean age 52.4 yrs. +/-14.4, n=21 women, mean duration of illness 18.2 yrs. +/-11.1) and 30 matched controls. We also measured depressive symptoms, body mass index (BMI), and blood pressure. RESULTS: Patients with AI showed more depressive symptoms, had a greater BMI and lower systolic blood pressure compared to controls. Adjusted analyses controlling for these variables revealed that patients with AI performed significantly worse in verbal learning (F=7.8, p=.007). Executive function, concentration, working memory, verbal memory, visuospatial memory, and autobiographical memory did not differ between groups. CONCLUSIONS: No clinically relevant cognitive impairment was found in patients with AI compared to matched controls. Even long-term glucocorticoid and mineralocorticoid substitution over almost two decades appears to have only subtle effects on cognition in patients with AI. PMID- 25705798 TI - Representational similarity analysis offers a preview of the noradrenergic modulation of long-term fear memory at the time of encoding. AB - Neuroimaging research on emotional memory has greatly advanced our understanding of the pathogenesis of anxiety disorders. While the behavioral expression of fear at the time of encoding does not predict whether an aversive experience will evolve into long-term fear memory, the application of multi-voxel pattern analysis (MVPA) for the analysis of BOLD-MRI data has recently provided a unique marker for memory formation. Here, we aimed to further investigate the utility of this marker by modulating the strength of fear memory with an alpha2-adrenoceptor antagonist (yohimbine HCl). Fifty-two healthy participants were randomly assigned to two conditions - either receiving 20mg yohimbine or a placebo pill (double blind) - prior to differential fear conditioning and MRI-scanning. We examined the strength of fear associations during acquisition and retention of fear (48 h later) by assessing the similarity of BOLD-MRI patterns and pupil dilation responses. Additionally, participants returned for a follow-up test outside the scanner (2-4 weeks), during which we assessed fear-potentiated startle responses. Replicating our previous findings, neural pattern similarity reflected the development of fear associations over time, and unlike average activation or pupil dilation, predicted the later expression of fear memory (pupil dilation 48 h later). While no effect of yohimbine was observed on markers of autonomic arousal, including salivary alpha-amylase (sAA), we obtained indirect evidence for the noradrenergic enhancement of fear memory consolidation: sAA levels showed a strong increase prior to fMRI scanning, irrespective of whether participants had received yohimbine, and this increase correlated with the subsequent expression of fear (48 h later). Remarkably, this noradrenergic enhancement of fear was associated with changes in neural response patterns at the time of learning. These findings provide further evidence that representational similarity analysis is a sensitive tool for studying (enhanced) memory formation. PMID- 25705799 TI - Latent trait cortisol (LTC) levels: reliability, validity, and stability. AB - The regulation of the hypothalamic pituitary adrenal (HPA) axis has received empirical attention as a mechanism contributing to individual differences in health and human development. A variety of sampling tactics and strategies index daily HPA axis functioning including the cortisol awakening response (CAR), the diurnal slope, and the area under the curve (AUGg). In an ethnically diverse sample (54% European-American, 23% Latino) of 82 adolescents (24% male, M age=18.05 years), we assessed salivary cortisol 45 times over the transition to college: 5 times per day, over 3 sequential days, across 3 waves (initially, 5, and 9 months later). Samples were collected at waking; 30 min, 3, and 8h post waking; and bedtime. Latent state-trait modeling indicated that the waking and 30 min post waking samples contributed to indices of within and across wave latent trait cortisol (LTC) levels. As such, a latent trait factor of cortisol was derived to reflect both within- and across-wave trait components of the variance in cortisol. LTC was distinct from the CAR, differentially predicted components of the diurnal profile across the day, and was highly stable across assessment waves (months). As preliminary evidence for convergent validity of LTC levels, childhood trauma was positively associated with LTC. Findings document the reliability, divergent and convergent validity, and stability of a latent trait factor of individual differences in HPA axis activity that may provide a cost efficient alternative to existing strategies and minimize participant burden. PMID- 25705800 TI - The effects of two different doses of hydrocortisone on cognition in patients with secondary adrenal insufficiency--results from a randomized controlled trial. AB - CONTEXT: A wide variety in hydrocortisone (HC) substitution dose-regimens are considered physiological for patients with secondary adrenal insufficiency (SAI). However, it is likely that cognition is negatively influenced by higher cortisol exposure to the brain. OBJECTIVE: To examine the effects of a high physiological HC dose in comparison to a low physiological HC dose on cognition. DESIGN AND SETTING: This study was a randomized double blind cross-over study at the University Medical Center Groningen. This study is registered with ClinicalTrials.gov, number NCT01546922. PATIENTS: Forty-seven patients (29 males, 18 females; mean [SD] age, 51 [14] years, range 19-73) with SAI participated. INTERVENTION(S): Patients randomly received first a low dose of HC (0.2-0.3 mg/kg body weight/day) during 10 weeks followed by a high dose (0.4-0.6 mg/kg body weight/day) for another 10 weeks, or vice versa. HC substitution was given in three divided doses with the highest dose in the morning. MAIN OUTCOME MEASURE(S): Cognitive performance (memory, attention, executive functioning and social cognition) of patients was measured at baseline and after each treatment period using a battery of 12 standardized cognitive tests. RESULTS: The higher dose of HC resulted in significantly higher systemic cortisol exposure for example measured at 1h after first dose ingestion (mean [SD], low dose: 653 [281] nmol/L; high dose: 930 [148] nmol/L; P<0.001). No differences in cognitive performance were found between the two dose regimens. CONCLUSIONS: No negative influence on memory, attention, executive functioning and social cognition was observed after 10 weeks of treatment with a higher physiological dose of HC in patients with SAI when compared to a lower dose. PMID- 25705801 TI - Pre-measurement rest time affects magnitude and reliability of toe pressure measurements. AB - OBJECTIVES: Toe pressures are used to evaluate lower extremity healing capacity and screen for peripheral arterial disease (PAD). Although toe pressures are commonly used clinically both as an independent measure and in the calculation of the toe-brachial index, the effect of pre-measurement rest duration on the magnitude and reliability of toe pressures is unknown. This study investigated the effect of pre-measurement rest duration on toe pressures. METHODS: Seventy community-based participants meeting guidelines for PAD screening were recruited. Systolic toe pressures either at the left or right hallux were manually measured using photoplethysmography following 5, 10 and 15 min of rest in a supine horizontal position. Testing was repeated 7-10 days later. RESULTS: A significant drop in toe pressure (3.86 mmHg) occurred between 5 and 10 min (p = 0.001). No significant change occurred between 10 and 15 min. Reliability after 5 min was excellent (intra-class correlation coefficient, ICC = 0.80, 95% CI 0.68-0.89), increasing slightly at 10 and 15 min (ICC = 0.86, 95% CI 0.77-0.92 and ICC = 0.82, 95% CI 0.69-0.89). CONCLUSIONS: Toe pressures stabilize after 10 min of rest in a supine horizontal position. Longer periods of pre-measurement rest did not improve reliability significantly. PMID- 25705802 TI - The Relationship Between Gait, Gross Motor Function, and Parental Perceived Outcome in Children With Clubfeet. AB - BACKGROUND: Assessment of children treated nonoperatively for idiopathic clubfoot, has primarily focused on the kinematic and kinetic results measured with gait analysis (GA). Excellent results in ankle motion and push-off power during gait have been reported at age 5; however, the assessment of gross motor function, has not been evaluated. The purpose of this study was to look at the relationship between gait measures, Peabody Developmental Motor Scales and parent perception of their child's outcome [measured with the Pediatric Outcomes Data Collection Instrument (PODCI)]. METHODS: A total of 81 children with idiopathic clubfoot were seen for both GA and Peabody testing. Children who initially underwent the Ponseti technique (n=29), the French Physical Therapy method (PT) (n=23), and a group of children initially treated nonoperatively, but who required surgical intervention before GA at 5 years of age (n=29) were enrolled. Pearson's correlation coefficient was used to establish significant relationships between gait variables, Peabody, and PODCI scores. RESULTS: Gait data showed that the Ponseti treated feet had significantly greater ankle power than feet treated surgically (P=0.0075). The Peabody results showed that the PT feet had higher stationary (P=0.0332) and overall gross motor quotient percent (GMQ%) scores (P=0.0092) than the surgical feet. No differences were found in PODCI scores. Ankle power was weakly correlated to the GMQ% (r=0.29; P=0.0102); however, the GMQ% showed a strong correlation to the parent report of Global Functioning Scale on the PODCI (r=0.48; P=0.0005). CONCLUSIONS: Minimal gait disturbances do not interfere with function or parental assessment of abilities and satisfaction at 5 year follow-up in children with idiopathic clubfeet. Nonoperative correction of clubfeet should be the goal when possible, as the Peabody scores show better function as early as 5 years of age when surgery is not required. PMID- 25705803 TI - Vitamin D Deficiency in Children Undergoing Vertical Expandable Prosthetic Titanium Rib Treatment. AB - BACKGROUND: Vitamin D deficiency is prevalent in the pediatric population and multiple risk factors have been identified. Low vitamin D levels can result in poor bone mineralization and have been associated with a significantly higher risk of forearm fracture in children. Vitamin D deficiency has also been associated with pediatric critical illness. The purpose of this study was to determine whether children undergoing vertical expandable prosthetic titanium rib (VEPTR) treatment have low vitamin D levels. METHODS: Patients undergoing VEPTR treatment at a single institution were prospectively enrolled (VEPTR). All patients either had a diagnosis of thoracic insufficiency syndrome (TIS), or were at risk of developing TIS secondary to progressive scoliosis or chest wall deformity. Exclusion criteria were patients with rickets and patients receiving vitamin D supplementation at the time of VEPTR insertion. A group of healthy children who presented with fractures during the winter season were used as controls (FX). Vitamin D status and risk factors for vitamin D deficiency were evaluated. Vitamin D deficiency was defined as serum 25-hydroxyvitamin D (25-OH D) <20 ng/mL and vitamin D insufficiency as serum 25-OH-D between 20 and 29 ng/mL. RESULTS: Twenty-eight VEPTR and 25 FX patients were compared. The average age was 8.6 years in the VEPTR group and 9.1 years in the FX group. Twenty VEPTR patients (71%) and 19 FX patients (76%) demonstrated low vitamin D levels. The average 25-OH-D level was 27.3 ng/mL in the VEPTR group and 25.4 ng/mL in the FX group. Patient characteristics and vitamin D levels were similar between the groups. No association was found between vitamin D status and sex, race, obesity, or multivitamin use. CONCLUSIONS: Low vitamin D levels are common in children undergoing VEPTR treatment. In our series, the prevalence of vitamin D deficiency in this patient population was similar to reported rates in the general pediatric population. Vitamin D status should be routinely monitored in children undergoing VEPTR treatment and supplementation should be initiated if necessary. PMID- 25705804 TI - Hemoglobin to Hematocrit Ratio: The Strongest Predictor of Femoral Head Osteonecrosis in Children With Sickle Cell Disease. AB - BACKGROUND: Femoral head osteonecrosis (ON) secondary to sickle cell disease (SCD) often progresses to femoral head collapse, requiring total hip arthroplasty. However, this treatment has a limited durability and patients with SCD have higher rates of complications, requiring multiple revision operations. Identifying risk factors linked to ON in SCD can facilitate earlier precollapse diagnosis and surgical treatment aimed at preservation of the native hip joint. METHODS: Fifty-nine children treated at our institution between January 2001 and April 2012 with SCD and ON, as diagnosed by magnetic resonance imaging or radiographic imaging, were compared with age-matched and sickle cell phenotype matched (SS, SC, Sbeta, Sbeta) controls with no evidence of ON. Two sided t-tests assuming unequal variances determined statistically risk factors and threshold values were assigned to calculate odds ratios. RESULTS: Systolic blood pressure (P=1.2*10, OR=3.68), diastolic blood pressure (P=0.0084, OR=1.41), weight in the SCD-SS population (P=0.04, OR=1.85), and hemoglobin (Hb) in the SCD-SS population (P=0.036, OR=2.56) were elevated in cases. Curiously, dividing the Hb by the hematocrit to serve as a clinical proxy for the mean corpuscular Hb concentration (MCHC) produced an excellent predictor of ON (P=2.06*10, OR=5.17), which was especially pronounced in the SCD-SS subpopulation (P=2.28*10, OR=8.65). Among children with SCD, the overall prevalence of ON was 9% (59/658) and the phenotype with the highest prevalence of ON was Sbeta thalassemia with an ON prevalence of 11.1%. There was no observed correlation between ON and height, body mass index, cholesterol, mean corpuscular volume, hematocrit, or glucocorticoid use. CONCLUSIONS: These data support a novel clinical marker, the MCHC proxy, as the strongest predictor of ON in children with SCD. High-risk children should receive hip magnetic resonance imaging to diagnose early ON and facilitate interventions focused on hip preservation, forestalling, or possibly preventing, the need for total hip arthroplasty. PMID- 25705805 TI - Aneurysmal Bone Cyst of the Cervical Spine in Children: A Review and a Focus on Available Treatment Options. AB - OBJECTIVE: To present a series of pediatric cervical spine (CS) aneurysmal bone cysts (ABC), to review the literature, and to propose a treatment algorithm. MATERIAL: We present a series of 4 cases of ABC and review the literature using PubMed, EMBASE, and Google scholar. RESULTS: Only 51 cases are documented. The mean age at diagnosis is 11.5 years, and there is a small female predominance (F:M ratio=1.6). Most of ABC occurs in the upper CS (41%), are located in the posterior component (75%), and extends in 40% of the vertebral body. A single treatment modality was used in 56.9%, whereas combination of surgery with other treatment modalities was used in the rest. Of the total number of cases, 56.8% were managed with marginal resection, and instrumentation was used in 80%. Mean follow-up was 72.5 months, with the majority of patients disease free. Pain is the most common symptom present at the latest follow-up. CONCLUSIONS: ABC of the spine is a pediatric tumor occurring rarely in the CS. Treatment options vary from simple curettage to total resection with or without instrumentation. Recurrence after surgery is highest after curettage alone. The main indications for surgery are rapid progression, despite intracystic injection, and/or the presence of neurological signs or symptoms. PMID- 25705806 TI - Ilio-Sacral (IS) Screw Fixation for Sacral and Sacroiliac Joint (SIJ) Injuries in Children. AB - BACKGROUND: Treatment of sacral fractures and sacroiliac joint (SIJ) disruption with percutaneous ilio-sacral (IS) screw fixation had become a more popular treatment option. There has been no study that specifically assessed IS fixation in children. The purpose of this study is present our results with fixation of the sacral fractures and SIJ disruption using IS screw in children 18 years old and younger. METHODS: This is a retrospective review chart for children with sacral fracture or SIJ disruption who were treated by IS fixation in the period from 2000 to 2012. The patients were assessed for the following (age, sex, type of injury, associated injuries, surgery, complications, postoperative return of function, healing of the injury, and return to function). RESULTS: In the studied period (2000 to 2012), 11 patients who had either sacral fracture (4 patients) or SIJ (7 patients) disruption were treated by IS screws. The average age of these patients was 14 years (range, 6 to 17 y). Six patients had 1 screw and 5 patients had 2 screws. Eight patients had their entire fixation in S1, and 3 patients had 1 screw in S1 and 1 screw in S2. All screws were cannulated and were inserted over a guidewire with fluoroscopy and/or navigation guidance. Five patients had added anterior fixation of the pelvis. One patient was lost for follow-up. All patients (except 1) achieved healing of their injuries with no displacement or implant failure with return of function. One patient had failure of fixation and needed revision. One patient had neurological complication related to screw insertion. CONCLUSIONS: IS screws can be safely used to treat sacral fractures and SIJ injuries in children. This was feasible in children as young as 6 years old. The complications of the procedure were minimal with good stability obtained by IS screws. PMID- 25705807 TI - The Occurrence of Occult Acetabular Dysplasia in Relatives of Individuals With Developmental Dysplasia of the Hip. AB - BACKGROUND: This study sought to determine the hip pathology of family members of patients with developmental dysplasia of the hip (DDH). The authors evaluated 120 people from 19 families known to have at least 1 member with surgically treated DDH. Each individual's functional outcome scores and pelvic radiographs were assessed for hip symptoms or pathology. METHODS: Using a genetic population database and a pediatric hospital patient population, 19 families with high rates of DDH were identified. All family members (n=120) underwent physical examination, radiographic assessment, and completion of outcome instruments [American Academy of Orthopedics (AAOS) Hip and Knee; Harris Hip Score (HHS); and Western Ontario and McMaster Universities Arthritis Index (WOMAC)]. RESULTS: The 120 subjects ranged from 1 to 84 years, 34 had orthopaedically treated DDH. Of the remaining 86 supposedly normal subjects, 23 (27%) had occult acetabular dysplasia (OAD) as defined by center edge angle (CEA) <20 and/or a Severin score of III or greater. Sixty percent of the 86 individuals were less than 30 years old, 74% of the OAD group were less than 30. Outcome scores of the treated DDH patients (AAOS, HHS, and WOMAC) were worse on the involved side regardless of age. Over age 30 individuals with OAD had statistically significant decreases in their AAOS Hip and Knee and WOMAC scores on the dysplastic side, but their HHS scores were not significantly different. CONCLUSIONS: Twenty-seven percent of first-degree and second-degree relatives of patients with DDH had unsuspected radiographic acetabular dysplasia in our study. Most of the subjects with OAD were younger than 30. After age 30, many of these patients developed symptoms. CLINICAL RELEVANCE: In families with a significant history of DDH, radiographic screening of siblings of patients with DDH to define OAD may be prudent. LEVEL OF EVIDENCE: Level I-diagnostic study. PMID- 25705808 TI - Safety and Efficacy of Apical Resection Following Growth-friendly Instrumentation in Myelomeningocele Patients With Gibbus: Growing Rod Versus Luque Trolley. AB - INTRODUCTION: Thoracolumbar/lumbar kyphosis in myelomeningocele patients is a common and severely debilitating condition, amenable only to surgical correction. Several surgical techniques have been proposed. Growth-friendly techniques should be preferred in this patient population due to an already compromised trunk height. The growing rod (GR) and Luque trolley (LT) with Galveston instrumentation are well-known growth-friendly techniques. We compared results and complications in 2 groups of patients who have undergone kyphectomy and fixation, either with the GR (group 1) or the LT with Galveston pelvic fixation (group 2). METHODS: Ten patients undergoing GR fixation and 5 patients undergoing LT with Fackler fixation following kyphectomy (vertebral column resection or multiple eggshell) were included. GRs were lengthened every 6 months. Unplanned surgery in group 1 was defined as an unscheduled operation due to complication; all subsequent operations in group 2 were considered unplanned. Thoracic and local kyphosis and T1-S1 and T1-12 heights were measured preoperatively, postoperatively, and at final follow-up. RESULTS: Mean age at initial surgery was 6 years and 6.5 years for groups 1 and 2, respectively. Mean age at the last follow-up was 12.5 years for group 1 and 13.1 years for group 2. Mean follow-up was 72.7 months for group 1 and 68.6 months for group 2. Preoperative, postoperative, and final follow-up kyphosis angles in that order for group 1 were 72.3 degrees (10 to 110 degrees), 16.9 degrees (-50 to +55 degrees), and 21.6 degrees (-41 to +97 degrees), and for group 2 106.6 degrees (81 to 132 degrees), 15.6 degrees (-37 to +50 degrees), and 19.2 degrees (-42 to +38 degrees), respectively. Postoperative and final follow-up in that order for mean T1-T12 and T1-S1 heights for group 1 were 14 (11.2 to 18.7) cm, 20.4 (19.3 to 25.7) cm and 21 (17.2 to 23.2) cm, 31.6 (23.6 to 41.5) cm. Postoperative and final follow-up in that order for mean T1-T12 and T1-S1 heights for group 2 were 15.9 (14.3 to 19.7) cm, 20.1 (15.5 to 24.6) cm and 24.4 (17.7 to 27.8) cm, 29.5 (25.3 to 31.3) cm. Growth per year was 1.05 and 0.84 cm for groups 1 and 2, respectively (P=0.297). Fourteen versus 4 unplanned surgeries were performed in groups 1 and 2, respectively, and an additional 4 implant revisions were performed in group 1 during planned lengthenings. CONCLUSIONS: Both the LT and the GR system are reasonable alternatives of fixation postkyphectomy, both of which preserve growth to differing degrees. In this patient population with an already severely stunted trunk height, the surgeon must choose whether the amount of extra growth achieved by the GR is worth the risk of an increased number of surgeries. PMID- 25705809 TI - Characteristics of Orthopaedic Malpractice Claims of Pediatric and Adult Patients in Private Practice. AB - BACKGROUND: Medical liability exposure varies based on scope of practice, patient demographics, and location of practice. There is a generally held belief that treatment of pediatric patients increases one's medicolegal risk. We examined a large national database of orthopaedic malpractice claims to determine if pediatric malpractice claims were associated with a less favorable medicolegal outcome compared with adults. METHODS: Physician Insurers Association of America is an association of medical liability insurance carriers providing liability coverage for 60% of private practice physicians in the United States. The Physician Insurers Association of America data registry of closed medical liability claims was examined, including all orthopaedic claims between 1985 and 2012 in this review. Claims were categorized based on the age of the claimant (pediatric: less than 21 y, adult: 21 y or older). These groups were compared based on percentage of claims resulting in payment, indemnity paid, and years between occurrence of incident and filing of claim. In addition, the top 10 most prevalent claims were identified and compared between groups. RESULTS: A total of 25,702 closed orthopaedic claims were included. Pediatric claims accounted for 13% of the data. The average time from incident to claim filing was 1.92 years for pediatrics and 1.59 years for adults. Pediatric claims resulted in a higher percent of payment (33% vs. 30%) and average indemnity paid ($189,732 vs. $180,171) compared with adults. Five of the top 10 conditions resulting in a claim in each group were the same. Comparing these 5 conditions, in general there were minimal differences in the average time to claim filing between the groups, but larger average indemnity paid in the pediatric group. CONCLUSIONS: There appear to be moderate differences in outcomes of orthopaedic malpractice claims between adult and pediatric patients. The longer statute of limitations associated with pediatric claims does not appear to portend a less favorable medicolegal outcome or excessively longer time to claims filing for pediatric patients. PMID- 25705810 TI - pH-regulated chemical oscillators. AB - The hydrogen ion is arguably the most ubiquitous and important species in chemistry. It also plays a key role in nearly every biological process. In this Account, we discuss systems whose behavior is governed by oscillations in the concentration of hydrogen ion. The first chemical oscillators driven by changes in pH were developed a quarter century ago. Since then, about two dozen new pH oscillators, systems in which the periodic variation in pH is not just an indicator but an essential prerequisite of the oscillatory behavior, have been discovered. Mechanistic understanding of their behavior has grown, and new ideas for their practical application have been proposed and, in some cases, tested. Here we present a catalog of the known pH oscillators, divide them into mechanistically based categories based on whether they involve a single oxidant and reductant or an oxidant and a pair of reductants, and describe general mechanisms for these two major classes of systems. We also describe in detail the chemistry of one example from each class, hydrogen peroxide-sulfide and ferricyanide-iodate-sulfite. Finally, we consider actual and potential applications. These include using pH oscillators to induce oscillation in species that would otherwise be nonoscillatory, creating novel spatial patterns, generating periodic transitions between vesicle and micelle states, stimulating switching between folded and random coil states of DNA, building molecular motors, and designing pulsating drug delivery systems. We point out the importance for future applications of finding a batch pH oscillator, one that oscillates in a closed system for an extended period of time, and comment on the progress that has been made toward that goal. PMID- 25705811 TI - Design, synthesis and biological evaluation of 1-phenanthryl tetrahydroisoquinoline derivatives as novel p21-activated kinase 4 (PAK4) inhibitors. AB - Functional versatility and elevated expression in cancers have promoted p21 activated kinase 4 (PAK4) as one of the first-in-class anti-cancer drug targets. In this study, a series of novel 1-phenanthryl-tetrahydroisoquinoline analogues have been designed and synthesized as a novel class of small-molecule PAK4 inhibitors to fit into the cavity of PAK4. All of the target compounds were evaluated for their in vitro PAK4 inhibitory activities and antiproliferative activities. Lead optimization identified all the derivatives with more potency than the lead compound, especially compound 21a. Moreover, compound 21a significantly induced the cell cycle in the G1/S phase, and inhibited migration and invasion of MCF-7 cells via the regulation of the PAK4-LIMK1-cofilin signaling pathway. A molecular modeling study showed possible novel binding modes between 21a and PAK4 and provided a structural basis for further structure-guided design of PAK4 inhibitors. PMID- 25705812 TI - Erratum. AB - The DOI for the following article was printed incorrectly. S. Merino, J. Martiinez, J. F. Masello, Y. Bedolia, and P. Quillifeldt. 2014. First Molecular Characterization of a Hepatozoon species (Apicomplexa: Hepatozoidae) Infecting Birds and Description of a New Species Infecting Storm Petrels (Aves: Hydrobatidae). Journal of Parasitology 100: 338- 343. The correct DOI is: 10.1645/13-325.1 PMID- 25705813 TI - Photorelease of incarcerated guests in aqueous solution with phenacyl esters as the trigger. AB - We report the clean, efficient photorelease of a series of carboxylic acids embedded in octa acid (OA) host and protected by a p-hydroxyphenacyl cage. A key role is played by the cage by providing hydrophobicity for entry into the OA enclosure and yet readily removable as a photoactivated protecting group for release from the host. The rapid photo-Favorskii rearrangement of the departing chromophore does not react with the host OA but diminishes hydrophobicity of the OA contents, leading to their facile release into the solvent. PMID- 25705814 TI - Teleophthalmology for first nations clients at risk of diabetic retinopathy: a mixed methods evaluation. AB - BACKGROUND: Access to health services is a particular challenge for First Nations (aboriginal Canadians) communities living in remote or underserviced areas. Teleophthalmology can provide them with the same level of retinal screening services provided to those in urban centers. This screening can lead to the identification of high-risk individuals who can then be monitored and receive treatment related to their diabetes or other health issues. OBJECTIVE: The intent was to develop, implement, and evaluate a service delivery model for teleophthalmology screening and follow-up for at-risk and diabetic First Nations clients on Vancouver Island, British Columbia, Canada. METHODS: A highly consultative, culturally appropriate, and collaborative approach was used to develop and deploy a teleophthalmology service delivery model to First Nations communities. This project was evaluated with regard to utilization and operational costs. Also, clinicians and team members involved in the teleophthalmology project provided assessments of the teleopthalmology quality, productivity, and access. Health providers in First Nations communities provided their perceptions of areas of improvement for the remote retinal screening services, areas where expansion of services could be offered, and opportunities to increase client education and health promotion. RESULTS: All 51 First Nations communities on Vancouver Island expressed interest in receiving teleopthalmology services. During the 1-year project, teleopthalmology clinics were held in 43 of 51 communities on Vancouver Island. During these clinics, 524 clients were screened and 140 of those clients were referred to a general ophthalmologist, family doctor, retinal specialist, optometrist, or other provider. Ratings of teleopthalmology system quality, information quality, service quality, and system usage were positive. Satisfaction with the teleopthalmology project was high among clinicians involved with the project. Satisfaction was also high among health providers in First Nations communities, with clinic scheduling identified as a potential area of improvement moving forward. The average cost savings per client, taking project costs into consideration, was calculated to be CAN $28.16, which was largely due to the elimination of client travel costs. CONCLUSIONS: Teleophthalmology was a welcome addition to health services by the First Nations communities on Vancouver Island, as evidenced by the 100% rate of interest from those communities. There was no evidence of dissatisfaction by clinicians involved in the teleopthalmology project or by First Nations community health providers. The now-operational teleopthalmology program is a testament to the early success of the project. PMID- 25705815 TI - Follow-up telephone calls to patients discharged after undergoing orthopaedic surgery: double-blind, randomised controlled trial of efficacy. AB - AIMS AND OBJECTIVES: To evaluate the effectiveness of a follow-up telephone call to reduce the number of issues after hospital discharge. BACKGROUND: The postdischarge period is often a time of uncertainty and risk. The decreasing length of hospital stays has increased the need for specific instructions about the postdischarge period. A telephone follow-up could be a valuable tool to fill this information gap. DESIGN: Double-blind, randomised controlled trial. METHODS: The participants included medium or low-intensity orthopaedic patients. We implemented a structured telephone follow-up call conducted by a senior orthopaedic nurse to provide educational support to the intervention group (n = 110), while the control group (n = 109) received routine care after being discharged. Data were collected between September 2011-January 2012. Statistical differences between the two groups were tested using chi-square test or Wilcoxon rank sum test, as appropriate. A linear regression model was performed to investigate factors involved into postdischarge outcomes. RESULTS: The intervention group had a statistically significant reduction in all postdischarge problems except for pain and mobilisation; the group also had a lower chance of experiencing frequent or severe problems. The educational intervention and prior poor health had a strong correlation with problems after discharge. Patients who received a telephone follow-up call believed the information provided was valuable. CONCLUSION: This nurse-led follow-up intervention significantly contributed to solving or reducing postdischarge health problems and contributed to reduce unnecessary burden on the community health system. RELEVANCE TO CLINICAL PRACTICE: A nurse-led telephone follow-up is a simple, feasible and low cost tool to improve patients' outcomes after discharge. PMID- 25705816 TI - Combined pelvic muscle exercise and yoga program for urinary incontinence in middle-aged women. AB - AIM: Urinary incontinence is a major health problem among middle-aged women. Pelvic muscle exercise is one of the primary interventions, but difficulty performing this exercise has led researchers to seek alternative or conjunctive exercise. This study aimed to examine the effect of a combined pelvic muscle exercise and yoga intervention program on urinary incontinence. METHODS: A single group pre-/post-test design was used. Subjects were recruited from a community health center in Seoul, Korea, and a questionnaire survey was conducted. Fifty five women participated in the first day of the program, 34 of whom completed the 8 week, twice weekly intervention program. Urinary incontinence was measured by five domains of urinary tract symptoms: filling factor, voiding factor, incontinence factor, sexual function, and quality of life. Also measured were attitude toward pelvic muscle exercise and pelvic muscle strength. RESULTS: Significant improvements were found in attitude toward pelvic muscle exercise, pelvic muscle strength, and incontinence factor. Daily performance of pelvic muscle exercise was positively correlated with improved incontinence factor and with quality of life related to urinary tract symptoms. CONCLUSION: A combined pelvic muscle exercise and yoga program was effective for improving overall urinary incontinence in community health center attendees in Korea. Further study is needed with a control group, different populations, and a longer intervention period. PMID- 25705817 TI - Reoperation After Holmium Laser Enucleation of the Prostate for Management of Benign Prostatic Hyperplasia: Assessment of Risk Factors with Time to Event Analysis. AB - PURPOSE: To determine risk factors of reoperation after holmium laser enucleation of the prostate (HoLEP) for management of lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH) with time to event analysis. METHODS: A prospectively maintained database was reviewed for patients undergoing HoLEP. Baseline and follow-up data were compared in terms of International Prostate Symptoms Score, quality of life, peak flow rate, residual urine, and prostate-specific antigen (PSA) at 1, 6, and 12-months and then annually. Perioperative and late adverse events were recorded. Reoperation was defined as the need for any surgical intervention to relieve bothersome LUTS after HoLEP. Multivariate logistic regression was used to determine covariates associated with reoperation and the Kaplan-Meier curve assessed the time to reoperation. RESULTS: A total of 1216 HoLEP procedures were performed between March 1998 and October 2013 with a mean prostate volume of 94.8 +/- 52.7 cc. Catheter time and hospital stay were 1.4 +/- 1.9 and 1.3 +/- 1.6 days, respectively. After a median follow up of 7.6 years (1-14 years), 52 (4.3%) patients needed reoperation for recurrent LUTS, including 13 (1.07%) for residual/recurrent adenoma, 14 (1.15%) for bladder neck contracture (BNC), and 25 (2.05%) for de novo urethral stricture. In multivariate regression, smaller prostate size (< 62 cc), PSA reduction < 50%, and history of previous prostate surgery were significantly associated with recurrence of adenoma. BNC was significantly associated with smaller glands (< 54 cc) while longer operative time and postoperative catheterization were significantly associated with urethral stricture. Kaplan-Meier curve demonstrates post-HoLEP freedom from reoperation of 96.9% at 5 years and 95.1% at 10 years. CONCLUSIONS: In a single center large series, HoLEP has 95% reoperation-free probability at 10 years. Relatively small-size prostate may have an impact on recurrence of adenoma and bladder neck contracture. PSA reduction < 50% was significantly associated with recurrence of adenoma while longer operative time and postoperative catheterization were significantly associated with postoperative urethral stricture. PMID- 25705818 TI - Natural grape extracts regulate colon cancer cells malignancy. AB - Natural dietary components are evolutionary-selected molecules able to control inflammation and cancerous transformation and progression. Because many studies assessed the beneficial properties of key molecules extracted from grapes, we aimed at investigating the properties of LiofenolTM, a natural red wine lyophilized extract, devoid of alcohol and composed by a miscellaneous of components (polyphenols, flavonoids, anthocyanins). We proved that the colon cancer cell line HCT116 responded to LiofenolTM treatment by reducing their proliferation, in association with an increase of p53 and p21 cell cycle gate keepers. LiofenolTM increased dihydroceramides, sphingolipid mediators involved in cell cycle arrest and reduced proliferation rate. We observed a strong induction of antioxidant response, with the activation of the transcriptional factor Nrf2, involved in redox homeostasis and differentiation, without altering tumor sensitivity to chemotherapy. LiofenolTM induced an important morphology change in HCT116 cells, migration inhibition, undifferentiated stem/stem-like cells markers downregulation, and E-cadherin downregulation, interested in epithelia to mesenchymal malignant transition. We conclude that lyophilized grape extract, at dose comparable to putative dietary doses, can activate molecular pathways, involving Nrf2 signaling and the modulation of structural and signaling sphingolipid mediators that cooperate in promoting differentiation and reducing proliferation of digestive tract cancer cells. PMID- 25705819 TI - General strategy to synthesize uniform mesoporous TiO2/graphene/mesoporous TiO2 sandwich-like nanosheets for highly reversible lithium storage. AB - Uniform oxide deposition on graphene to form a sandwich-like configuration is a well-known challenge mainly due to their large lattice mismatches and poor affinities. Herein, we report a general strategy to synthesize uniform mesoporous TiO2/graphene/mesoporous TiO2 sandwich-like nanosheets (denoted as G@mTiO2), which cannot be achieved by conventional one-pot synthetic methods. We show that by rational control of hydrolysis and condensation of Ti precursors in a slow way, GO sheets can be conformably coated by amorphous TiO2 shells, which then can be facilely transformed into the well-defined G@mTiO2 nanosheets by annealing. This amorphous-to-crystalline strategy conveniently allows bypassing strain fields that would inevitably arise if direct growth of mesoporous anatase shells on graphene. As distinct from the most common structures of graphene-based composites (mixed, wrapped, or anchored models), the resultant materials display a uniform sandwich-like configuration: few-layer graphene conformably encapsulated by mesoporous TiO2 shells. This new G@mTiO2 nanosheet exhibits ultrathin nature (~34 nm), small size and high crystalline nanocrystals (~6 nm), high surface areas (~252 m(2)/g) and uniform mesopores (~3.4 nm). We further show that the thickness of mesoporous TiO2 shells can be facilely adjusted as desired by controlling the ammonia content, and this facile strategy can be easily extended to design other oxide/graphene/oxide sandwich-like materials. More importantly, we showcase the benefits of the resultant G@mTiO2 nanosheets as anodes in lithium ion batteries: they deliver an extra high capacity, an excellent high-rate capability, and long cycle life. PMID- 25705820 TI - Direct conversion of bulk metals to size-tailored, monodisperse spherical non coinage-metal nanocrystals. AB - Monodisperse non-noble metal nanocrystals (NCs) that are highly uniform in shapes and particle size are much desired in various advanced applications, and are commonly prepared by either thermal decomposition or reduction, where reactive organometallic precursors or/and strong reducing agents are mandatory; however, these are usually toxic, costly, or suffer a lack of availability. Bulk Group 12 metals can now be converted into ligand-protected, highly crystalline, monodisperse spherical metal NCs with precisely controlled sizes without using any precursors and reducers. The method is based on low-power NIR-laser-induced size-selective layer-by-layer surface vaporization. The monodisperse Cd NCs show pronounced deep-UV (DUV) localized surface plasmon resonance making them highly competitive DUV-plasmonic materials. This approach will promote appreciably the emergence of a wide range of monodisperse technically important non-coinage metal NCs with compelling functionalities. PMID- 25705821 TI - Designing an online resource for people with low back pain: health-care provider perspectives. AB - People with low back pain (LBP) seek education and information from the Internet. Existing LBP websites are often of poor quality, and disparities have been identified between patient and health-care provider evaluations of LBP websites. This study aimed to identify health-care provider perspectives on desirable content for a proposed LBP website and how this information should be presented. It complements an earlier study of LBP patient (consumer) perspectives. A qualitative descriptive study, encompassing focus groups and telephone interviews, was conducted with 42 health-care professionals practising in the LBP field. Four categories of information were identified: explaining LBP; treatment and management options; myth-busting information; and communication with health care professionals. Presentation preferences included: use of visual media; interactivity; and useability and readability. Comparison with the consumer study identified differences with regard to: depth and breadth of diagnostic and treatment information; provision of lay person experiences and stories; and capacity for consumer-to-consumer interaction online. Views of both consumers and health-care providers are critical when developing an online LBP resource. Failure to address the needs of both stakeholder groups diminishes the potential of the resource to improve consumer outcomes. PMID- 25705823 TI - Preventing peanut allergy through early consumption--ready for prime time? PMID- 25705822 TI - Randomized trial of peanut consumption in infants at risk for peanut allergy. AB - BACKGROUND: The prevalence of peanut allergy among children in Western countries has doubled in the past 10 years, and peanut allergy is becoming apparent in Africa and Asia. We evaluated strategies of peanut consumption and avoidance to determine which strategy is most effective in preventing the development of peanut allergy in infants at high risk for the allergy. METHODS: We randomly assigned 640 infants with severe eczema, egg allergy, or both to consume or avoid peanuts until 60 months of age. Participants, who were at least 4 months but younger than 11 months of age at randomization, were assigned to separate study cohorts on the basis of preexisting sensitivity to peanut extract, which was determined with the use of a skin-prick test--one consisting of participants with no measurable wheal after testing and the other consisting of those with a wheal measuring 1 to 4 mm in diameter. The primary outcome, which was assessed independently in each cohort, was the proportion of participants with peanut allergy at 60 months of age. RESULTS: Among the 530 infants in the intention-to treat population who initially had negative results on the skin-prick test, the prevalence of peanut allergy at 60 months of age was 13.7% in the avoidance group and 1.9% in the consumption group (P<0.001). Among the 98 participants in the intention-to-treat population who initially had positive test results, the prevalence of peanut allergy was 35.3% in the avoidance group and 10.6% in the consumption group (P=0.004). There was no significant between-group difference in the incidence of serious adverse events. Increases in levels of peanut-specific IgG4 antibody occurred predominantly in the consumption group; a greater percentage of participants in the avoidance group had elevated titers of peanut specific IgE antibody. A larger wheal on the skin-prick test and a lower ratio of peanut-specific IgG4:IgE were associated with peanut allergy. CONCLUSIONS: The early introduction of peanuts significantly decreased the frequency of the development of peanut allergy among children at high risk for this allergy and modulated immune responses to peanuts. (Funded by the National Institute of Allergy and Infectious Diseases and others; ClinicalTrials.gov number, NCT00329784.). PMID- 25705824 TI - Association between sauna bathing and fatal cardiovascular and all-cause mortality events. AB - IMPORTANCE: Sauna bathing is a health habit associated with better hemodynamic function; however, the association of sauna bathing with cardiovascular and all cause mortality is not known. OBJECTIVE: To investigate the association of frequency and duration of sauna bathing with the risk of sudden cardiac death (SCD), fatal coronary heart disease (CHD), fatal cardiovascular disease (CVD), and all-cause mortality. DESIGN, SETTING, AND PARTICIPANTS: We performed a prospective cohort study (Finnish Kuopio Ischemic Heart Disease Risk Factor Study) of a population-based sample of 2315 middle-aged (age range, 42-60 years) men from Eastern Finland. Baseline examinations were conducted from March 1, 1984, through December 31, 1989. EXPOSURES: Frequency and duration of sauna bathing assessed at baseline. RESULTS: During a median follow-up of 20.7 years (interquartile range, 18.1-22.6 years), 190 SCDs, 281 fatal CHDs, 407 fatal CVDs, and 929 all-cause mortality events occurred. A total of 601, 1513, and 201 participants reported having a sauna bathing session 1 time per week, 2 to 3 times per week, and 4 to 7 times per week, respectively. The numbers (percentages) of SCDs were 61 (10.1%), 119 (7.8%), and 10 (5.0%) in the 3 groups of the frequency of sauna bathing. The respective numbers were 89 (14.9%), 175 (11.5%), and 17 (8.5%) for fatal CHDs; 134 (22.3%), 249 (16.4%), and 24 (12.0%) for fatal CVDs; and 295 (49.1%), 572 (37.8%), and 62 (30.8%) for all-cause mortality events. After adjustment for CVD risk factors, compared with men with 1 sauna bathing session per week, the hazard ratio of SCD was 0.78 (95% CI, 0.57 1.07) for 2 to 3 sauna bathing sessions per week and 0.37 (95% CI, 0.18-0.75) for 4 to 7 sauna bathing sessions per week (P for trend = .005). Similar associations were found with CHD, CVD, and all-cause mortality (P for trend <=.005). Compared with men having a sauna bathing session of less than 11 minutes, the adjusted hazard ratio for SCD was 0.93 (95% CI, 0.67-1.28) for sauna bathing sessions of 11 to 19 minutes and 0.48 (95% CI, 0.31-0.75) for sessions lasting more than 19 minutes (P for trend = .002); significant inverse associations were also observed for fatal CHDs and fatal CVDs (P for trend <=.03) but not for all-cause mortality events. CONCLUSIONS AND RELEVANCE: Increased frequency of sauna bathing is associated with a reduced risk of SCD, CHD, CVD, and all-cause mortality. Further studies are warranted to establish the potential mechanism that links sauna bathing and cardiovascular health. PMID- 25705825 TI - Longitudinal feasibility of MINDSET: a clinic decision aid for epilepsy self management. AB - The purpose of this paper is to report on the development and feasibility of the longitudinal version of MINDSET, a clinical tool to assist patients and health care providers in epilepsy self-management. A previous study described the feasibility of using MINDSET to identify and prioritize self-management issues during a clinic visit. This paper describes the development of the longitudinal version of MINDSET and feasibility test over multiple visits with a printed action plan for goal setting and the capacity for monitoring changes in self management. Feasibility was assessed based on 1) postvisit patient and provider interviews addressing ease of use and usefulness, patient/provider communication, and shared decision-making and 2) the capacity of the tool to monitor epilepsy characteristics and self-management over time. Results indicate MINDSET feasibility for 1) identifying and facilitating discussion of self-management issues during clinic visits, 2) providing a printable list of prioritized issues and tailored self-management goals, and 3) tracking changes in epilepsy characteristics and self-management over time. PMID- 25705826 TI - Quality care in epilepsy: Women's counseling and its association with folic acid prescription or recommendation. AB - OBJECTIVE: This study aimed to determine if annual counseling about contraception and pregnancy in the setting of treatment for epilepsy is associated with increased recommending or prescribing of folate. METHODS: This is a retrospective cohort study with medical record abstraction. We selected records from 77 women of childbearing age who had two or more visits for epilepsy at a neurology clinic. The assessment included a review of documentation from the first three visits for epilepsy within a 24-month follow-up window. We defined perfect adherence to annual counseling about the impact of epilepsy treatment on contraception or pregnancy as defect-free care for women (DFCW). A recommendation that the patient take over-the-counter folate or a prescription for folate was independently abstracted from the chart at each visit. RESULTS: The group of patients who received DFCW (N=28, 36.36%) and the group who did not receive DFCW (N=49, 63.63%) were comparable with respect to age, disease duration, baseline history of drug-resistant epilepsy (DRE), presence of concurrent psychiatric disease, epileptologist involvement, number of antiepileptic drugs (AEDs) prescribed, seizure type, and etiology. Twenty (71.4%) patients in the DFCW group and 42 (85.7%) in the non-DFCW group were not recommended or prescribed folic acid (p=0.12). CONCLUSIONS: Even with annual documentation of counseling about how epilepsy treatment may affect contraception and pregnancy, the "action" of prescribing or recommending folic acid during the ensuing 24months is frequently omitted. PMID- 25705828 TI - Don't forget health when you talk about human rights. PMID- 25705827 TI - Periictal and interictal headache including migraine in Dutch patients with epilepsy: a cross-sectional study. AB - As early as in 1898, it was noted that there was a need to find "a plausible explanation of the long recognized affinities of migraine and epilepsy". However, results of recent studies are clearly conflicting on this matter. In this cross sectional study, we aimed to define the prevalence and characteristics of both seizure-related and interictal headaches in patients with epilepsy (5-75years) seeking help in the tertiary epilepsy clinic SEIN in Zwolle. Using a questionnaire, subjects were surveyed on the existence of headaches including characteristics, duration, severity, and accompanying symptoms. Furthermore, details on epilepsy were retrieved from medical records (e.g., syndrome, seizure frequency, and use of drugs). Diagnoses of migraine, tension-type headache, or unclassifiable headache were made based on criteria of the International Classification of Headache Disorders. Between March and December 2013, 29 children and 226 adults were evaluated, 73% of whom indicated having current headaches, which is significantly more often when compared with the general population (p<0.001). Forty-nine percent indicated having solely interictal headache, while 29% had solely seizure-related headaches and 22% had both. Migraine occurs significantly more often in people with epilepsy in comparison with the general population (p<0.001), and the occurrence of tension-type headaches conforms to results in the general population. These results show that current headaches are a significantly more frequent problem amongst people with epilepsy than in people without epilepsy. When comparing migraine prevalence, this is significantly higher in the population of patients with epilepsy. PMID- 25705829 TI - A voice for people with epilepsy. PMID- 25705830 TI - Asthma diagnosis and control. PMID- 25705831 TI - FGM: the mutilation of girls and young women must stop. PMID- 25705833 TI - Liver disease in the UK. PMID- 25705834 TI - Ebola: better protection needed for Guinean health-care workers. PMID- 25705835 TI - Liver disease in the UK. PMID- 25705836 TI - Apgar score and risk of cause-specific infant mortality. PMID- 25705837 TI - Apgar score and risk of cause-specific infant mortality. PMID- 25705838 TI - Apgar score and risk of cause-specific infant mortality. PMID- 25705839 TI - Fertility preservation for age-related fertility decline. PMID- 25705840 TI - Apgar score and risk of cause-specific infant mortality - authors' reply. PMID- 25705841 TI - Fertility preservation for age-related fertility decline - authors' reply. PMID- 25705842 TI - Fertility preservation for age-related fertility decline. PMID- 25705843 TI - Contraception is as important as fertility preservation in young women with cancer. PMID- 25705844 TI - A 12-year-old child with fever, headache, shock, and coma. PMID- 25705845 TI - Design freedom in multilayer thin-film devices. AB - In fabricating inorganic thin-film devices, the relative etch rates of materials in a given etch chemistry often limit the obtainable multilayer structures. Alternatively, in fabricating multilayer organic devices by solution processing, the ability to formulate the active organic materials in orthogonal solvent systems is limiting. The pattered-by-printing method uses the combination of selective area deposition (SAD) and atomic layer deposition (ALD) to form high quality metal oxide thin-film devices. We print an inhibiting polymer ink that patterns the functional inorganic materials that are deposited via spatial ALD (SALD). The process is inherently orthogonal, as the polymer ink does not etch or swell the inorganic functional layers. Each functional layer is additively patterned as deposited, with device isolation and vias defined by the printed inhibitor. The combination of process orthogonality and additive patterning removes processing-related constraints on device design, and readily allows for any combination of bottom- and top-gate thin-film transistor architectures to be formed on the same substrate. The freedom of this approach is further demonstrated by both all-enhancement-mode circuits and enhancement-depletion-mode circuits. In addition, we present a new tool to tune circuit performance by local control of dielectric thickness. PMID- 25705846 TI - A photolithographic approach to spatially resolved cross-linked nanolayers. AB - The preparation of cross-linked nanosheets with 1-2 nm thickness and predefined shape was achieved by lithographic immobilization of trimethacryloyl thioalkanoates onto the surface of Si wafers, which were functionalized with 2 (phenacylthio)acetamido groups via a photoinduced reaction. Subsequent cross linking via free radical polymerization as well as a phototriggered Diels-Alder reaction under mild conditions on the surface led to the desired nanosheets. Electrospray ionization mass spectrometry (ESI-MS), X-ray photoelectron spectroscopy (XPS), time-of-flight secondary ion mass spectrometry (ToF-SIMS), as well as infrared reflection-absorption spectroscopy (IRRAS) confirmed the success of individual surface-modification and cross-linking reactions. The thickness and lateral size of the cross-linked structures were determined by atomic force microscopy (AFM) for samples prepared on Si wafers functionalized with a self assembled monolayer of 1H,1H,2H,2H-perfluorodecyl groups bearing circular pores obtained via a polymer blend lithographic approach, which led to the cross linking reactions occurring in circular nanoareas (diameter of 50-640 nm) yielding an average thickness of 1.2 nm (radical cross-linking), 1.8 nm (radical cross-linking in the presence of 2,2,2-trifluoroethyl methacrylate as a comonomer), and 1.1 nm (photochemical cross-linking) of the nanosheets. PMID- 25705847 TI - Genome-Wide DNA Methylation Analysis in Melanoma Reveals the Importance of CpG Methylation in MITF Regulation. AB - The microphthalmia-associated transcription factor (MITF) is a key regulator of melanocyte development and a lineage-specific oncogene in melanoma; a highly lethal cancer known for its unpredictable clinical course. MITF is regulated by multiple intracellular signaling pathways, although the exact mechanisms that determine MITF expression and activity remain incompletely understood. In this study, we obtained genome-wide DNA methylation profiles from 50 stage IV melanomas, normal melanocytes, keratinocytes, and dermal fibroblasts and utilized The Cancer Genome Atlas data for experimental validation. By integrating DNA methylation and gene expression data, we found that hypermethylation of MITF and its co-regulated differentiation pathway genes corresponded to decreased gene expression levels. In cell lines with a hypermethylated MITF-pathway, overexpression of MITF did not alter the expression level or methylation status of the MITF pathway genes. In contrast, however, demethylation treatment of these cell lines induced MITF-pathway activity, confirming that gene regulation was controlled via methylation. The discovery that the activity of the master regulator of pigmentation, MITF, and its downstream targets may be regulated by hypermethylation has significant implications for understanding the development and evolvement of melanoma. PMID- 25705848 TI - Ceramide synthase 4 regulates stem cell homeostasis and hair follicle cycling. AB - Ceramides are crucial for skin barrier function, but little is known about the regulation of epidermal appendages and whether stem cell populations that control their regeneration depend on specific ceramide species. Here we demonstrate that ceramide synthase 4 (CerS4) is highly expressed in the epidermis of adult mice where it is localized in the interfollicular epidermis and defined populations within the pilosebaceous unit. Inactivation of CerS4 in mice resulted in precocious activation of hair follicle bulge stem cells while expanding the Lrig1(+) junctional zone and sebaceous glands. This was preceded first by a decrease in bone morphogenetic protein (BMP) and a subsequent increase in Wnt signaling. This imbalance in quiescent versus activating signals likely promoted a prolonged anagen-like hair follicle state after the second catagen, which exhausted stem cells over time ultimately resulting in hair loss in aged mice. K14-Cre-mediated deletion of CerS4 revealed a similar phenotype, thus suggesting an epidermis intrinsic function of CerS4 in regulating the regeneration of the pilosebaceous unit. The data indicate that CerS4-directed epidermal ceramide composition is essential to control hair follicle stem and progenitor cell behavior potentially through its regulation of BMP and Wnt signaling. PMID- 25705849 TI - A Genome-Wide Association Study Identifies the Skin Color Genes IRF4, MC1R, ASIP, and BNC2 Influencing Facial Pigmented Spots. AB - Facial pigmented spots are a common skin aging feature, but genetic predisposition has yet to be thoroughly investigated. We conducted a genome-wide association study for pigmented spots in 2,844 Dutch Europeans from the Rotterdam Study (mean age: 66.9+/-8.0 years; 47% male). Using semi-automated image analysis of high-resolution digital facial photographs, facial pigmented spots were quantified as the percentage of affected skin area (mean women: 2.0% +/-0.9, men: 0.9% +/-0.6). We identified genome-wide significant association with pigmented spots at three genetic loci: IRF4 (rs12203592, P=1.8 * 10(-27)), MC1R (compound heterozygosity score, P=2.3 * 10(-24)), and RALY/ASIP (rs6059655, P=1.9 * 10( 9)). In addition, after adjustment for the other three top-associated loci the BNC2 locus demonstrated significant association (rs62543565, P=2.3 * 10(-8)). The association signals observed at all four loci were successfully replicated (P<0.05) in an independent Dutch cohort (Leiden Longevity Study n=599). Although the four genes have previously been associated with skin color variation and skin cancer risk, all association signals remained highly significant (P<2 * 10(-8)) when conditioning the association analyses on skin color. We conclude that genetic variations in IRF4, MC1R, RALY/ASIP, and BNC2 contribute to the acquired amount of facial pigmented spots during aging, through pathways independent of the basal melanin production. PMID- 25705850 TI - UV-Induced Wnt7a in the Human Skin Microenvironment Specifies the Fate of Neural Crest-Like Cells via Suppression of Notch. AB - Multipotent stem cells with neural crest-like properties have been identified in the dermis of human skin. These neural crest stem cell (NCSC)-like cells display self-renewal capacity and differentiate into neural crest derivatives, including epidermal pigment-producing melanocytes. NCSC-like cells share many properties with aggressive melanoma cells, such as high migratory capabilities and expression of the neural crest markers. However, little is known about which intrinsic or extrinsic signals determine the proliferation or differentiation of these neural crest-like stem cells. Here we show that, in NCSC-like cells, Notch signaling is highly activated, similar to melanoma cells. Inhibition of Notch signaling reduced the proliferation of NCSC-like cells, induced cell death, and downregulated noncanonical Wnt5a, suggesting that the Notch pathway contributes to the maintenance and motility of these stem cells. In three-dimensional skin reconstructs, canonical Wnt signaling promoted the differentiation of NCSC-like cells into melanocytes. This differentiation was triggered by the endogenous Notch inhibitor Numb, which is upregulated in the stem cells by Wnt7a derived from UV-irradiated keratinocytes. Together, these data reveal a cross talk between the two conserved developmental pathways in postnatal human skin, and highlight the role of the skin microenvironment in specifying the fate of stem cells. PMID- 25705851 TI - Papain Degrades Tight Junction Proteins of Human Keratinocytes In Vitro and Sensitizes C57BL/6 Mice via the Skin Independent of its Enzymatic Activity or TLR4 Activation. AB - Papain is commonly used in food, pharmaceutical, textile, and cosmetic industries and is known to induce occupational allergic asthma. We have previously shown that the papain-like cysteine protease Dermatophagoides pteronyssinus 1 from house dust mite exhibits percutaneous sensitization potential. We aimed here to investigate the potential of papain itself in epicutaneous sensitization. The effects of papain on tight junction (TJ) proteins were tested in vitro in human primary keratinocytes. Using C57BL/6 wild-type and Toll-like receptor 4 (TLR4) deficient mice, we analyzed the sensitization potential of papain, its effects on the skin barrier, and immune cell recruitment. Our results show that papain affects the skin barrier by increasing transepidermal water loss, degrading TJ proteins and inducing vasodilation. When topically applied, papain exhibited a high epicutaneous inflammatory potential by recruiting neutrophils, mast cells, and CD3-positive cells and by induction of a TH2-biased antibody response. However, its high potency for specific sensitization via the skin was TLR4 independent and, in spite of its capacity to degrade epidermal TJ proteins, does not rely on its enzymatic function. From our data, we conclude that papain has all features to act as a strong allergen via the skin. PMID- 25705852 TI - Positive genetic correlation between brain size and sexual traits in male guppies artificially selected for brain size. AB - Brain size is an energetically costly trait to develop and maintain. Investments into other costly aspects of an organism's biology may therefore place important constraints on brain size evolution. Sexual traits are often costly and could therefore be traded off against neural investment. However, brain size may itself be under sexual selection through mate choice on cognitive ability. Here, we use guppy (Poecilia reticulata) lines selected for large and small brain size relative to body size to investigate the relationship between brain size, a large suite of male primary and secondary sexual traits, and body condition index. We found no evidence for trade-offs between brain size and sexual traits. Instead, larger-brained males had higher expression of several primary and precopulatory sexual traits--they had longer genitalia, were more colourful and developed longer tails than smaller-brained males. Larger-brained males were also in better body condition when housed in single-sex groups. There was no difference in post copulatory sexual traits between males from the large- and small-brained lines. Our data do not support the hypothesis that investment into sexual traits is an important limiting factor to brain size evolution, but instead suggest that brain size and several sexual traits are positively genetically correlated. PMID- 25705853 TI - Cu-catalyzed asymmetric addition of sp2-hybridized zirconium nucleophiles to racemic allyl bromides. AB - Alkenylzirconium nucleophiles made in situ by the hydrozirconation of terminal alkynes undergo dynamic kinetic asymmetric allylic alkenylation with racemic allyl bromides to give enantioenriched products. PMID- 25705854 TI - How to assess species richness along single environmental gradients? Implications of potential versus realized species distributions. AB - Quantifying relationships between species richness and single environmental factors is challenging as species richness typically depends on multiple environmental factors. Recently, various methods have been proposed to tackle this challenge. Using a dataset comprising field observations of grassland vegetation and measured pH values, we compared three methods for deriving species richness response curves. One of the methods estimates species richness close to the maximum species richness observed at the sites, whereas the other two provide estimates of the potential species richness along the environmental gradient. Our response curves suggest that potential species richness of grasslands is slightly more sensitive to acidification than realized plant species richness. However, differences in corresponding environmental quality standards (EQS) for acidification were small compared to intrinsic spatial differences in natural soil pH, indicating that natural background values are more important to consider in the derivation of EQS for pH than methodological differences between the three approaches. PMID- 25705855 TI - Micronized copper wood preservatives: an efficiency and potential health risk assessment for copper-based nanoparticles. AB - Copper (Cu) is an essential biocide for wood protection, but fails to protect wood against Cu-tolerant wood-destroying fungi. Recently Cu particles (size range: 1 nm-25 MUm) were introduced to the wood preservation market. The new generation of preservatives with Cu-based nanoparticles (Cu-based NPs) is reputedly more efficient against wood-destroying fungi than conventional formulations. Therefore, it has the potential to become one of the largest end uses for wood products worldwide. However, during decomposition of treated wood Cu-based NPs and/or their derivate may accumulate in the mycelium of Cu-tolerant fungi and end up in their spores that are dispersed into the environment. Inhaled Cu-loaded spores can cause harm and could become a potential risk for human health. We collected evidence and discuss the implications of the release of Cu based NPs by wood-destroying fungi and highlight the exposure pathways and subsequent magnitude of health impact. PMID- 25705856 TI - Procedural characteristics and adverse events in diagnostic and interventional catheterisations in paediatric and adult CHD: initial report from the IMPACT Registry. AB - OBJECTIVES: To report procedural characteristics and adverse events on data collected in the registry. BACKGROUND: The IMPACT--IMproving Paediatric and Adult Congenital Treatment--Registry is a catheterisation registry of paediatric and adult patients with CHD undergoing diagnostic and interventional cardiac catheterisation. We are reporting the procedural characteristics and adverse events of patients undergoing diagnostic and interventional catheterisation procedures from January, 2011 to March, 2013. METHODS: Demographic, clinical, procedural, and institutional data elements were collected at the participating centres and entered via either a web-based platform or software provided by American College of Cardiology-certified vendors, and were collected in a secure, centralised database. Centre participation was voluntary. RESULTS: During the time frame of data collection, 19,797 procedures were entered into the IMPACT Registry. Procedures were classified as diagnostic only (35.4%); one of six specific interventions (23.8%); other or multiple interventions (40.7%); and were further broken down into four age groups. Anaesthesia was used in 84.1% of diagnostic procedures and 87.8% of interventional ones. Adverse events occurred in 10.0% of diagnostic and 11.1% of interventional procedures. CONCLUSIONS: The IMPACT Registry is gathering data to set national benchmarks for diagnostic and certain specific interventional procedures. We are seeing little differences in procedural characteristics or adverse events in diagnostic procedures compared with interventional procedures overall, but there is significant variation in adverse events amongst age categories. Risk stratification and patient acuity scores will be required for further analysis of these differences. PMID- 25705857 TI - From roaming atoms to hopping surfaces: mapping out global reaction routes in photochemistry. AB - The photodissociation of small molecules occurs upon irradiation by ultraviolet or visible light, and it is a very important chemical process in Earth's atmosphere, in the atmospheres of other planets, and in interstellar media. Photodissociation is an important method used to thoroughly investigate the fundamental issues of chemical reactivity. Photodissociation involves molecules and reaction fragments moving over ground- and excited-state potential surfaces (PESs). Molecules can move on a single PES (adiabatic pathway) or can cross over from one PES to another (nonadiabatic pathways). For a full theoretical understanding of a photodissociation mechanism, all of the important nonadiabatic and adiabatic pathways must be determined. This is not an easy task. We have developed an efficient computational method, called the global reaction route mapping (GRRM) strategy, that allows a theoretical exploration of ground- and excited-state PESs and their crossing seams in an automatic manner. In this Perspective, we summarize our approaches and present examples of their application together with newly determined chemical insights. These include the complex photodissociation mechanism of the formaldehyde molecule, the exclusive excited-state roaming dynamics of the nitrate radical, and all product channels and conformational memory in the photodissociation of the formic acid molecule. Finally, perspectives for the theoretical design of photofunctional molecules are discussed. PMID- 25705858 TI - A new modeling approach for quantifying expert opinion in the drug discovery process. AB - Expert opinion plays an important role when choosing clusters of chemical compounds for further investigation. Often, the process by which the clusters are assigned to the experts for evaluation, the so-called selection process, and the qualitative ratings given by the experts to the clusters (chosen/not chosen) need to be jointly modeled to avoid bias. This approach is referred to as the joint modeling approach. However, misspecifying the selection model may impact the estimation and inferences on parameters in the rating model, which are of most scientific interest. We propose to incorporate the selection process into the analysis by adding a new set of random effects to the rating model and, in this way, avoid the need to model it parametrically. This approach is referred to as the combined model approach. Through simulations, the performance of the combined and joint models was compared in terms of bias and confidence interval coverage. The estimates from the combined model were nearly unbiased, and the derived confidence intervals had coverage probability around 95% in all scenarios considered. In contrast, the estimates from the joint model were severely biased under some form of misspecification of the selection model, and fitting the model was often numerically challenging. The results show that the combined model may offer a safer alternative on which to base inferences when there are doubts about the validity of the selection model. Importantly, thanks to its greater numerical stability, the combined model may outperform the joint model even when the latter is correctly specified. PMID- 25705859 TI - Significance of Serum mtDNA Concentration in Lung Injury Induced by Hip Fracture. AB - Acute lung injury is the most serious and fatal complication of the elderly patients with hip fracture, but the mechanisms are unknown. Recent studies demonstrated the mitochondrial DNA (mtDNA) release was associated with lung injury after trauma. This study aimed to examine the differential release of mtDNA between younger and elderly rats suffering from hip fracture and to investigate the possible mechanism of mtDNA in the lung injury induced by hip fracture. In the first part of the study, we investigated the effects of hip fracture on the rats. The elderly and younger rats, respectively, received hip fracture operations. The degree of lung injury was evaluated, toll-like receptor 9 (TLR9) and nuclear factor kappa B (NF-kappaB) were determined using Western blot, and mtDNA were analyzed by fluorescent quantitative polymerase chain reaction. In the second part of the study, we investigated the effects of mtDNA on the rats. The elderly and younger rats directly received intravenous injections with mtDNA. After 24 h, the specimens were collected and detected as the first part. Hip fracture resulted in significant mtDNA release, TLR9 and NF kappaB p65 expression, and lung injury in the rats. Meanwhile, the mtDNA injection could indirectly induce lung injury. Compared to the younger ones, the elderly rats suffered more serious lung injury after hip fracture and mtDNA injection. These results suggest that the lung injury induced by hip fracture may be involved with the mtDNA release and its TLR9/NF-kappaB pathway. PMID- 25705860 TI - Role of Endoplasmic Reticulum Stress in Brain Damage After Cardiopulmonary Resuscitation in Rats. AB - Postcardiac arrest syndrome yields poor neurological outcomes, but the mechanisms underlying this condition remain poorly understood. This study investigated whether endoplasmic reticulum (ER) stress-mediated apoptosis is induced in injured brain after resuscitation. Sprague-Dawley rats were subjected to 6 min of cardiac arrest (CA) and then resuscitated successfully. In the first experiment, animals were sacrificed 1, 3, 6, 12, or 24 h (n = 3 per group) after successful cardiopulmonary resuscitation. Brain tissues were analyzed by real-time polymerase chain reaction and Western blotting. In the second experiment, either dimethyl sulfoxide or salubrinal (Sal; 1 mg/kg), an ER stress inhibitor, was injected 30 min before the induction of CA (n = 10 per group). Neurological deficits were evaluated 24 h after CA. Brain specimens were analyzed using electron microscopy, terminal deoxynucleotidyl transferase dUTP nick end labeling assays and immunohistochemistry. We found that the messenger RNA and protein levels of glucose-regulated protein 78, X-box binding protein 1, C/EBP homologous protein, and caspase 12 were significantly elevated after resuscitation. We also observed that rats treated with Sal exhibited an improved neurological deficit score (32.3 +/- 15.5 in the Sal group vs. 49.8 +/- 20.9 in controls, P < 0.05). In addition, morphological improvements in the hippocampal ER were observed in the Sal group compared with the dimethyl sulfoxide group 24 h after reperfusion. Furthermore, in situ immunostaining revealed that markers of ER stress were significantly inhibited by Sal pretreatment. Our findings suggested that ER stress and the associated apoptotic pathways were activated in the hippocampus after resuscitation. Administration of Sal 30 min before cardiopulmonary resuscitation ameliorated neurological dysfunction 24 h after CA, possibly through the inhibition of ER stress after postresuscitation brain injury. PMID- 25705861 TI - Evaluation of cyclosporine a as a cardio- and neuroprotective agent after cardiopulmonary resuscitation in a rat model. AB - The immunosuppressant drug cyclosporine A (CsA) is a direct inhibitor of the mitochondrial permeability transition pore, which is the common end point of many pathways of ischemic preconditioning and postconditioning. We studied the neuroprotective and cardioprotective effect of CsA after cardiac arrest (CA) in a rat model of cardiopulmonary resuscitation. After institutional approval by the Governmental Animal Care Committee, 83 rats were subjected to 6 min of CA and were randomly and investigator-blinded allocated either to placebo (n = 15) or interventional group (n = 15; 10-mg/kg body weight CsA intravenously) after restoration of spontaneous circulation (ROSC). Before CA (baseline) as well as 1 h and 3 h after ROSC, continuous measurement of stroke volume, left ventricular ejection fraction, preload adjusted maximum power, and end diastolic volume was performed using a conductance catheter. One day, 3 days, and 7 days after ROSC, neurological outcome was evaluated by a tape removal test. After 7 days of reperfusion, coronal brain sections were analyzed by counting Nissl-positive (i.e., viable) neurons and terminal deoxynucleotidyl transferase dUTP nick end labeling positive (i.e., apoptotic) cells. Animals treated with CsA had a higher stroke volume (96 [93; 107] MUL vs. 78 [73; 94] MUL; P = 0.02), higher ejection fraction (58% [51%; 63%] vs. 42% [35%; 51%]; P = 0.002), and higher preload adjusted maximum power (4.8 [3.9; 6.1] vs. 2.3 [2.0; 2.6] mW/MUL; P < 0.001). End diastolic volume remained stable in the CsA group 3 h after ROSC in comparison to baseline (160 [143; 181] MUL vs. 157 [148; 192] MUL; P = 0.56), whereas it increased in the placebo group (169 [153; 221] MUL vs. 156 [138; 166] MUL, P = 0.05). More neurons survived after administration of CsA (2.5 [1.6; 4.9] vs. 0.7 [0.4; 1.4]; P = 0.005). Compared to placebo-treated animals, the time in the tape removal test 7 days after ROSC was reduced by half in the CsA group without reaching statistical significance (26 [22; 51] vs. placebo 53 [38; 56] s; P = 0.13). Cyclosporine A treatment neither affected the number of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells nor the survival rate. Pharmacological postconditioning with CsA after successful cardiopulmonary resuscitation attenuates myocardial dysfunction and reduces neuronal damage. PMID- 25705862 TI - Grade II pilocytic astrocytoma in a 3-month-old patient with encephalocraniocutaneous lipomatosis (ECCL): case report and literature review of low grade gliomas in ECCL. AB - Encephalocraniocutaneous lipomatosis (ECCL) is a rare congenital syndrome with an unknown etiology. Since 1970, around 60 cases have been reported in English literature. ECCL is usually classified by cutaneous lesions and non-progressive intracranial or spinal lipomas; however three cases of ECCL associated with low grade glioma (LGG) have been described. We report on the fourth case of LGG in a patient with ECCL; a grade II pilocytic astrocytoma with pilomyxoid features in a 3-month-old male, the youngest in literature. PMID- 25705863 TI - Intermetallic germanides with non-centrosymmetric structures derived from the Yb3Rh4Sn13 type. AB - New germanides with composition RE3Pt4Ge13 (RE = Y, Pr, Sm, Gd, Tb, Tm) have been prepared by high-pressure, high-temperature synthesis. Their crystal structures have been refined, and the relationship of this new rhombohedral and monoclinic structure types with the primitive cubic Yb3Rh4Sn13 prototype is discussed. Band structure calculations within density functional theory confirm the distorted rhombohedral and monoclinic structural arrangements to be energetically more favorable than the simple cubic one. X-ray absorption spectroscopy and magnetic susceptibility measurements indicate that the RE-atoms are in the +3 oxidation state in all studied compounds. PMID- 25705864 TI - Solvatochromic sensor array for the identification of common organic solvents. AB - A cross-reactive colorimetric sensor array composed of solvatochromic dyes in semi-liquid matrices was used to successfully discriminate among eleven common solvents. The multidimensional array response is attributed to both chemical (i.e., analyte-dye interactions) and physical (i.e., spot blooming and refractive index alteration) changes in the sensor spot. PMID- 25705865 TI - Holography: Metasurfaces make it practical. PMID- 25705866 TI - Enhancement of near-field radiative heat transfer using polar dielectric thin films. AB - Thermal radiative emission from a hot surface to a cold surface plays an important role in many applications, including energy conversion, thermal management, lithography, data storage and thermal microscopy. Recent studies on bulk materials have confirmed long-standing theoretical predictions indicating that when the gap between the surfaces is reduced to tens of nanometres, well below the peak wavelength of the blackbody emission spectrum, the radiative heat flux increases by orders of magnitude. However, despite recent attempts, whether such enhancements can be obtained in nanoscale dielectric films thinner than the penetration depth of thermal radiation, as suggested by theory, remains experimentally unknown. Here, using an experimental platform that comprises a heat-flow calorimeter with a resolution of about 100 pW (ref. 7), we experimentally demonstrate a dramatic increase in near-field radiative heat transfer, comparable to that obtained between bulk materials, even for very thin dielectric films (50-100 nm) when the spatial separation between the hot and cold surfaces is comparable to the film thickness. We explain these results by analysing the spectral characteristics and mode shapes of surface phonon polaritons, which dominate near-field radiative heat transport in polar dielectric thin films. PMID- 25705867 TI - Domain-wall velocities of up to 750 m s(-1) driven by exchange-coupling torque in synthetic antiferromagnets. AB - The operation of racetrack memories is based on the motion of domain walls in atomically thin, perpendicularly magnetized nanowires, which are interfaced with adjacent metal layers with high spin-orbit coupling. Such domain walls have a chiral Neel structure and can be moved efficiently by electrical currents. High capacity racetrack memory requires closely packed domain walls, but their density is limited by dipolar coupling from their fringing magnetic fields. These fields can be eliminated using a synthetic antiferromagnetic structure composed of two magnetic sub-layers, exchange-coupled via an ultrathin antiferromagnetic-coupling spacer layer. Here, we show that nanosecond-long current pulses can move domain walls in synthetic antiferromagnetic racetracks that have almost zero net magnetization. The domain walls can be moved even more efficiently and at much higher speeds (up to ~750 m s(-1)) compared with similar racetracks in which the sub-layers are coupled ferromagnetically. This is due to a stabilization of the Neel domain wall structure, and an exchange coupling torque that is directly proportional to the strength of the antiferromagnetic exchange coupling between the two sub-layers. Moreover, the dependence of the wall velocity on the magnetic field applied along the nanowire is distinct from that of the single-layer racetrack due to the exchange coupling torque. The high domain wall velocities in racetracks that have no net magnetization allow for densely packed yet highly efficient domain-wall-based spintronics. PMID- 25705868 TI - Rectification of electronic heat current by a hybrid thermal diode. AB - Thermal diodes--devices that allow heat to flow preferentially in one direction- are one of the key tools for the implementation of solid-state thermal circuits. These would find application in many fields of nanoscience, including cooling, energy harvesting, thermal isolation, radiation detection and quantum information, or in emerging fields such as phononics and coherent caloritronics. However, both in terms of phononic and electronic heat conduction (the latter being the focus of this work), their experimental realization remains very challenging. A highly efficient thermal diode should provide a difference of at least one order of magnitude between the heat current transmitted in the forward temperature (T) bias configuration (Jfw) and that generated with T-bias reversal (Jrev), leading to R = Jfw/Jrev ? 1 or ? 1. So far, R ~ 1.07-1.4 has been reported in phononic devices, and R ~ 1.1 has been obtained with a quantum-dot electronic thermal rectifier at cryogenic temperatures. Here, we show that unprecedentedly high ratios of R ~ 140 can be achieved in a hybrid device combining normal metals tunnel-coupled to superconductors. Our approach provides a high-performance realization of a thermal diode for electronic heat current that could be successfully implemented in true low-temperature solid-state thermal circuits. PMID- 25705869 TI - Near-field radiative energy transfer: Nanostructures feel the heat. PMID- 25705870 TI - Metasurface holograms reaching 80% efficiency. AB - Surfaces covered by ultrathin plasmonic structures--so-called metasurfaces--have recently been shown to be capable of completely controlling the phase of light, representing a new paradigm for the design of innovative optical elements such as ultrathin flat lenses, directional couplers for surface plasmon polaritons and wave plate vortex beam generation. Among the various types of metasurfaces, geometric metasurfaces, which consist of an array of plasmonic nanorods with spatially varying orientations, have shown superior phase control due to the geometric nature of their phase profile. Metasurfaces have recently been used to make computer-generated holograms, but the hologram efficiency remained too low at visible wavelengths for practical purposes. Here, we report the design and realization of a geometric metasurface hologram reaching diffraction efficiencies of 80% at 825 nm and a broad bandwidth between 630 nm and 1,050 nm. The 16-level phase computer-generated hologram demonstrated here combines the advantages of a geometric metasurface for the superior control of the phase profile and of reflectarrays for achieving high polarization conversion efficiency. Specifically, the design of the hologram integrates a ground metal plane with a geometric metasurface that enhances the conversion efficiency between the two circular polarization states, leading to high diffraction efficiency without complicating the fabrication process. Because of these advantages, our strategy could be viable for various practical holographic applications. PMID- 25705871 TI - Mo-doped BiVO4 photoanodes synthesized by reactive sputtering. AB - We report a scalable and reproducible method for reactive co-sputtering of Mo doped BiVO4 thin films with broad compositional control. Optimal photoanode performance is achieved at a Mo concentration of 3 at. %. Incorporation of Mo promotes growth of large grains and reduces majority carrier transport limitations, resulting in maximum AM1.5G photocurrent densities of 3.5 mA cm(-2) at 1.23 V vs. RHE in pH 6.8 buffer solution containing 0.1 M Na2 SO3 as a hole scavenger. Operation as a front-illuminated water oxidation photoanode is achieved by balancing the operational stability, catalytic activity, and parasitic optical absorption of a FeOOH oxygen evolution catalyst. FeOOH/Mo:BiVO4 thin film photoanodes enable water oxidation under the front-side illumination conditions used in integrated tandem water splitting devices. PMID- 25705872 TI - Long-term nicotine replacement therapy: a randomized clinical trial. AB - IMPORTANCE: The US Food and Drug Administration adopted labeling for nicotine patches to allow use beyond the standard 8 weeks. This decision was based in part on data showing increased efficacy for 24 weeks of treatment. Few studies have examined whether the use of nicotine patches beyond 24 weeks provides additional therapeutic benefit. OBJECTIVE: To compare 8 (standard), 24 (extended), and 52 (maintenance) weeks of nicotine patch treatment for promoting tobacco abstinence. DESIGN, SETTING, AND PARTICIPANTS: We recruited 525 treatment-seeking smokers for a randomized clinical trial conducted from June 22, 2009, through April 15, 2014, through 2 universities. INTERVENTIONS: Smokers received 12 smoking cessation behavioral counseling sessions and were randomized to 8, 24, or 52 weeks of nicotine patch treatment. MAIN OUTCOMES AND MEASURES: The primary outcome was 7 day point prevalence abstinence, confirmed with breath levels of carbon monoxide at 6 and 12 months (intention to treat). RESULTS: At 24 weeks, 21.7% of participants in the standard treatment arm were abstinent, compared with 27.2% of participants in the extended and maintenance treatment arms (chi(2)(1) = 1.98; P = .17). In a multivariate model controlled for covariates, participants in the extended and maintenance treatment arms reported significantly greater abstinence rates at 24 weeks compared with participants in the standard treatment arm (odds ratio [OR], 1.70 [95% CI, 1.03-2.81]; P = .04), had a longer duration of abstinence until relapse (beta = 21.30 [95% CI, 10.30-32.25]; P < .001), reported smoking fewer cigarettes per day if not abstinent (mean [SD], 5.8 [5.3] vs 6.4 [5.1] cigarettes per day; beta = 0.43 [95% CI, 0.06-0.82]; P = .02), and reported more abstinent days (mean [SD], 80.5 [38.1] vs 68.2 [43.7] days; OR, 1.55 [95% CI, 1.06-2.26]; P = .02). At 52 weeks, participants in the maintenance treatment arm did not report significantly greater abstinence rates compared with participants in the standard and extended treatment arms (20.3% vs 23.8%; OR, 1.17 [95% CI, 0.69-1.98]; P = .57). Similarly, we found no difference in week 52 abstinence rates between participants in the extended and standard treatment arms (26.0% vs 21.7%; OR, 1.33 [95% CI, 0.72-2.45]; P = .36). Treatment duration was not associated with any adverse effects or adherence to the counseling regimen, but participants in the maintenance treatment arm reported lower adherence to the nicotine patch regimen compared with those in the standard and extended treatment arms (mean [SD], 3.94 [2.5], 4.61 [2.0], and 4.7 [2.4] patches/wk, respectively; F2,522 = 6.03; P = .003). CONCLUSIONS AND RELEVANCE: The findings support the safety of long-term use of nicotine patch treatment, although they do not support efficacy beyond 24 weeks of treatment in a broad group of smokers. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01047527. PMID- 25705873 TI - Working memory units are all in your head: Factors that influence whether features or objects are the favored units. AB - We compared two contrasting hypotheses of how multifeatured objects are stored in visual working memory (vWM); as integrated objects or as independent features. A new procedure was devised to examine vWM representations of several concurrently held objects and their features and our main measure was reaction time (RT), allowing an examination of the real-time search through features and/or objects in an array in vWM. Response speeds to probes with color, shape, or both were studied as a function of the number of memorized colored shapes. Four testing groups were created by varying the instructions and the way in which probes with both color and shape were presented. The instructions explicitly either encouraged or discouraged the use of binding information and the task-relevance of binding information was further suggested by presenting probes with both color and shapes as either integrated objects or independent features. Our results show that the unit used for retrieval from vWM depends on the testing situation. Search was fully object-based only when all factors support that basis of search, in which case retrieving 2 features took no longer than retrieving a single feature. Otherwise, retrieving 2 features took longer than retrieving a single feature. Additional analyses of change detection latency suggested that, even though different testing situations can result in a stronger emphasis on either the feature dimension or the object dimension, neither one disappears from the representation and both concurrently affect change detection performance. PMID- 25705874 TI - Requirement of cAMP signaling for Schwann cell differentiation restricts the onset of myelination. AB - Isolated Schwann cells (SCs) respond to cAMP elevation by adopting a differentiated post-mitotic state that exhibits high levels of Krox-20, a transcriptional enhancer of myelination, and mature SC markers such as the myelin lipid galactocerebroside (O1). To address how cAMP controls myelination, we performed a series of cell culture experiments which compared the differentiating responses of isolated and axon-related SCs to cAMP analogs and ascorbate, a known inducer of axon ensheathment, basal lamina formation and myelination. In axon related SCs, cAMP induced the expression of Krox-20 and O1 without a concomitant increase in the expression of myelin basic protein (MBP) and without promoting axon ensheathment, collagen synthesis or basal lamina assembly. When cAMP was provided together with ascorbate, a dramatic enhancement of MBP expression occurred, indicating that cAMP primes SCs to form myelin only under conditions supportive of basal lamina formation. Experiments using a combination of cell permeable cAMP analogs and type-selective adenylyl cyclase (AC) agonists and antagonists revealed that selective transmembrane AC (tmAC) activation with forskolin was not sufficient for full SC differentiation and that the attainment of an O1 positive state also relied on the activity of the soluble AC (sAC), a bicarbonate sensor that is insensitive to forskolin and GPCR activation. Pharmacological and immunological evidence indicated that SCs expressed sAC and that sAC activity was required for morphological differentiation and the expression of myelin markers such as O1 and protein zero. To conclude, our data indicates that cAMP did not directly drive myelination but rather the transition into an O1 positive state, which is perhaps the most critical cAMP-dependent rate limiting step for the onset of myelination. The temporally restricted role of cAMP in inducing differentiation independently of basal lamina formation provides a clear example of the uncoupling of signals controlling differentiation and myelination in SCs. PMID- 25705875 TI - Evaluation of canonical siRNA and Dicer substrate RNA for inhibition of hepatitis C virus genome replication--a comparative study. AB - Hepatitis C virus (HCV) frequently establishes persistent infections in the liver, leading to the development of chronic hepatitis and, potentially, to liver cirrhosis and hepatocellular carcinoma at later stages. The objective of this study was to test the ability of five Dicer substrate siRNAs (DsiRNA) to inhibit HCV replication and to compare these molecules to canonical 21 nt siRNA. DsiRNA molecules were designed to target five distinct regions of the HCV genome - the 5' UTR and the coding regions for NS3, NS4B, NS5A or NS5B. These molecules were transfected into Huh7.5 cells that stably harboured an HCV subgenomic replicon expressing a firefly luciferase/neoR reporter (SGR-Feo-JFH-1) and were also tested on HCVcc-infected cells. All of the DsiRNAs inhibited HCV replication in both the subgenomic system and HCVcc-infected cells. When DsiRNAs were transfected prior to infection with HCVcc, the inhibition levels reached 99.5%. When directly compared, canonical siRNA and DsiRNA exhibited similar potency of virus inhibition. Furthermore, both types of molecules exhibited similar dynamics of inhibition and frequencies of resistant mutants after 21 days of treatment. Thus, DsiRNA molecules are as potent as 21 nt siRNAs for the inhibition of HCV replication and may provide future approaches for HCV therapy if the emergence of resistant mutants can be addressed. PMID- 25705876 TI - Climate change may alter breeding ground distributions of eastern migratory monarchs (Danaus plexippus) via range expansion of Asclepias host plants. AB - Climate change can profoundly alter species' distributions due to changes in temperature, precipitation, or seasonality. Migratory monarch butterflies (Danaus plexippus) may be particularly susceptible to climate-driven changes in host plant abundance or reduced overwintering habitat. For example, climate change may significantly reduce the availability of overwintering habitat by restricting the amount of area with suitable microclimate conditions. However, potential effects of climate change on monarch northward migrations remain largely unknown, particularly with respect to their milkweed (Asclepias spp.) host plants. Given that monarchs largely depend on the genus Asclepias as larval host plants, the effects of climate change on monarch northward migrations will most likely be mediated by climate change effects on Asclepias. Here, I used MaxEnt species distribution modeling to assess potential changes in Asclepias and monarch distributions under moderate and severe climate change scenarios. First, Asclepias distributions were projected to extend northward throughout much of Canada despite considerable variability in the environmental drivers of each individual species. Second, Asclepias distributions were an important predictor of current monarch distributions, indicating that monarchs may be constrained as much by the availability of Asclepias host plants as environmental variables per se. Accordingly, modeling future distributions of monarchs, and indeed any tightly coupled plant-insect system, should incorporate the effects of climate change on host plant distributions. Finally, MaxEnt predictions of Asclepias and monarch distributions were remarkably consistent among general circulation models. Nearly all models predicted that the current monarch summer breeding range will become slightly less suitable for Asclepias and monarchs in the future. Asclepias, and consequently monarchs, should therefore undergo expanded northern range limits in summer months while encountering reduced habitat suitability throughout the northern migration. PMID- 25705877 TI - Differentiation of apical and basal dendrites in pyramidal cells and granule cells in dissociated hippocampal cultures. AB - Hippocampal pyramidal cells and dentate granule cells develop morphologically distinct dendritic arbors, yet also share some common features. Both cell types form a long apical dendrite which extends from the apex of the cell soma, while short basal dendrites are developed only in pyramidal cells. Using quantitative morphometric analyses of mouse hippocampal cultures, we evaluated the differences in dendritic arborization patterns between pyramidal and granule cells. Furthermore, we observed and described the final apical dendrite determination during dendritic polarization by time-lapse imaging. Pyramidal and granule cells in culture exhibited similar dendritic patterns with a single principal dendrite and several minor dendrites so that the cell types were not readily distinguished by appearance. While basal dendrites in granule cells are normally degraded by adulthood in vivo, cultured granule cells retained their minor dendrites. Asymmetric growth of a single principal dendrite harboring the Golgi was observed in both cell types soon after the onset of dendritic growth. Time-lapse imaging revealed that up until the second week in culture, final principal dendrite designation was not stabilized, but was frequently replaced by other minor dendrites. Before dendritic polarity was stabilized, the Golgi moved dynamically within the soma and was repeatedly repositioned at newly emerging principal dendrites. Our results suggest that polarized growth of the apical dendrite is regulated by cell intrinsic programs, while regression of basal dendrites requires cue(s) from the extracellular environment in the dentate gyrus. The apical dendrite designation is determined from among multiple growing dendrites of young developing neurons. PMID- 25705878 TI - Associations between stereotype awareness, childhood trauma and psychopathology: a study in people with psychosis, their siblings and controls. AB - INTRODUCTION: Stereotype awareness--or an individual's perception of the degree to which negative beliefs or stereotypes are held by the public--is an important factor mediating public stigma, self-stigma and their negative consequences. Research is required to assess how individuals become more sensitive to perceive stereotypes, pointing the way to therapeutic options to reduce its negative effects and increase stigma resilience. Because perception and interpretation can be guided by belief systems, and childhood trauma (CT) is reported to impact such beliefs, CT is explored in relation to stereotype awareness (SA) in persons with psychosis, their siblings and controls. METHOD: Data from the GROUP project (Genetic Risk and Outcome of Psychosis) were analyzed. SA was measured by devaluation scales which assess a respondent's perception of the degree to which stereotypes about people with mental illness and about their families are held by the public. CT was measured using the Childhood Trauma Questionnaire (short form). RESULTS: In patients, symptoms of disorganization and emotional distress were associated with SA about people with mental illness. In siblings, schizotypal features were associated with both types of SA (more schizotypy = more SA). In both patients and siblings, CT was associated with both types of SA (more CT = more SA), independent of symptoms (patients) or schizotypy (siblings). CONCLUSION: CT in people with psychosis and their siblings may sensitize to SA. Thus, CT may not only impact on risk for illness onset, it may also increase SA associated with mental illness, potentially interfering with the recovery process. CT-induced SA may indicate a heightened sensitivity to threat, which may also impact psychopathology. PMID- 25705879 TI - Predomination and new genotypes of Enterocytozoon bieneusi in captive nonhuman primates in zoos in China: high genetic diversity and zoonotic significance. AB - To appreciate the genetic diversity and zoonotic implications of Enterocytozoon bieneusi in nonhuman primates (NHPs) in zoos, we genotyped E. bieneusi in captive NHPs in seven zoos located at six major cities in China, using ribosomal internal transcribed spacer (ITS)-based PCR and sequence analyses. A total of 496 fecal specimens from 36 NHP species under nine families were analyzed and E. bieneusi was detected in 148 (29.8%) specimens of 25 NHP species from six families, including Cercopithecidae (28.7%), Cebidae (38.0%), Aotidae (75.0%), Lemuridae (26.0%), Hylobatidae (50.0%) and Hominidae (16.2%) (P = 0.0605). The infection rates were 29.0%, 15.2%, 18.2%, 37.3%, 29.2%, 37.7% and 44.8% in Shijiazhuang Zoo, Wuhan Zoo, Taiyuan Zoo, Changsha Wild Animal Zoo, Beijing Zoo, Shanghai Zoo and Shanghai Wild Animal Park, respectively (P = 0.0146). A total of 25 ITS genotypes were found: 14 known (D, O, EbpC, EbpA, Type IV, Henan-IV, BEB6, BEB4, Peru8, PigEBITS5, EbpD, CM1, CM4 and CS-1) and 11 new (CM8 to CM18). Genotype D was the most prevalent one (40/148), followed by CM4 (20/148), CM1 (15/148), O (13/148), CM16 (13/148), EbpC (11/148). Of them, genotypes D, EbpC, CM4 and O were widely distributed in NHPs (seen in 9 to 12 species) whereas genotypes CM1 and CM16 were restricted to one to three NHP species. In phylogenetic analysis, 20 genotypes (121/148, 81.8%), excluding genotypes BEB4, BEB6, CM9, CM4 and CM18, belonged to group 1 with zoonotic potential. New genotype CM9 clustered in group 2 with BEB4 and BEB6. The remaining two genotypes CM4 and CM18 formed new cluster (group 9) in between two other genotypic clusters found in primates. The findings of high diversity in E. bieneusi genotypes and their zoonotic potentiality concluded the importance of captive NHPs as reservoir hosts for human microsporidiosis. PMID- 25705880 TI - A rapid and convenient method for fluorescence analysis of in vitro cultivated metacestode vesicles from Echinococcus multilocularis. AB - We here describe a convenient method for preparation, fixation and fluorescence analysis of in vitro cultivated metacestode vesicles from E. multilocularis. Parasite materials could be prepared in one hour, did not need to be sectioned, and were subsequently utilized for further whole-mount staining assays directly. Using these preparations, in combination with conventional fluorescence staining techniques, we could detect the expression and subcellular localization of a specific protein and identify in situ proliferative or apoptotic cells in the germinal layer of metacestode vesicles. Based on this approach, future molecular and cellular analysis of Echinococcus metacestode vesicles in the in vitro system will be greatly facilitated. PMID- 25705881 TI - X-linked macrocytic dyserythropoietic anemia in females with an ALAS2 mutation. AB - Macrocytic anemia with abnormal erythropoiesis is a common feature of megaloblastic anemias, congenital dyserythropoietic anemias, and myelodysplastic syndromes. Here, we characterized a family with multiple female individuals who have macrocytic anemia. The proband was noted to have dyserythropoiesis and iron overload. After an extensive diagnostic evaluation that did not provide insight into the cause of the disease, whole-exome sequencing of multiple family members revealed the presence of a mutation in the X chromosomal gene ALAS2, which encodes 5'-aminolevulinate synthase 2, in the affected females. We determined that this mutation (Y365C) impairs binding of the essential cofactor pyridoxal 5' phosphate to ALAS2, resulting in destabilization of the enzyme and consequent loss of function. X inactivation was not highly skewed in wbc from the affected individuals. In contrast, and consistent with the severity of the ALAS2 mutation, there was a complete skewing toward expression of the WT allele in mRNA from reticulocytes that could be recapitulated in primary erythroid cultures. Together, the results of the X inactivation and mRNA studies illustrate how this X-linked dominant mutation in ALAS2 can perturb normal erythropoiesis through cell-nonautonomous effects. Moreover, our findings highlight the value of whole exome sequencing in diagnostically challenging cases for the identification of disease etiology and extension of the known phenotypic spectrum of disease. PMID- 25705882 TI - Co-clinical assessment identifies patterns of BRAF inhibitor resistance in melanoma. AB - Multiple mechanisms have been described that confer BRAF inhibitor resistance to melanomas, yet the basis of this resistance remains undefined in a sizable portion of patient samples. Here, we characterized samples from a set of patients with melanoma that included individuals at baseline diagnosis, on BRAF inhibitor treatment, and with resistant tumors at both the protein and RNA levels. Using RNA and DNA sequencing, we identified known resistance-conferring mutations in 50% (6 of 12) of the resistant samples. In parallel, targeted proteomic analysis by protein array categorized the resistant samples into 3 stable groups, 2 of which were characterized by reactivation of MAPK signaling to different levels and 1 that was MAPK independent. The molecular relevance of these classifications identified in patients was supported by both mutation data and the similarity of resistance patterns that emerged during a co-clinical trial in a genetically engineered mouse (GEM) model of melanoma that recapitulates the development of BRAF inhibitor resistance. Additionally, we defined candidate biomarkers in pre- and early-treatment patient samples that have potential for predicting clinical responses. On the basis of these observations, we suggest that BRAF inhibitor resistant melanomas can be actionably classified using protein expression patterns, even without identification of the underlying genetic alteration. PMID- 25705883 TI - Cherubism allele heterozygosity amplifies microbe-induced inflammatory responses in murine macrophages. AB - Cherubism is a rare autoinflammatory bone disorder that is associated with point mutations in the SH3-domain binding protein 2 (SH3BP2) gene, which encodes the adapter protein 3BP2. Individuals with cherubism present with symmetrical fibro osseous lesions of the jaw, which are attributed to exacerbated osteoclast activation and defective osteoblast differentiation. Although it is a dominant trait in humans, cherubism appears to be recessively transmitted in mice, suggesting the existence of additional factors in the pathogenesis of cherubism. Here, we report that macrophages from 3BP2-deficient mice exhibited dramatically reduced inflammatory responses to microbial challenge and reduced phagocytosis. 3BP2 was necessary for LPS-induced activation of signaling pathways involved in macrophage function, including SRC, VAV1, p38MAPK, IKKalpha/beta, RAC, and actin polymerization pathways. Conversely, we demonstrated that the presence of a single Sh3bp2 cherubic allele and pathogen-associated molecular pattern (PAMP) stimulation had a strong cooperative effect on macrophage activation and inflammatory responses in mice. Together, the results from our study in murine genetic models support the notion that infection may represent a driver event in the etiology of cherubism in humans and suggest limiting inflammation in affected individuals may reduce manifestation of cherubic lesions. PMID- 25705884 TI - Caspase-1-mediated pathway promotes generation of thromboinflammatory microparticles. AB - Extracellular ATP is a signal of tissue damage and induces macrophage responses that amplify inflammation and coagulation. Here we demonstrate that ATP signaling through macrophage P2X7 receptors uncouples the thioredoxin (TRX)/TRX reductase (TRXR) system and activates the inflammasome through endosome-generated ROS. TRXR and inflammasome activity promoted filopodia formation, cellular release of reduced TRX, and generation of extracellular thiol pathway-dependent, procoagulant microparticles (MPs). Additionally, inflammasome-induced activation of an intracellular caspase-1/calpain cysteine protease cascade degraded filamin, thereby severing bonds between the cytoskeleton and tissue factor (TF), the cell surface receptor responsible for coagulation activation. This cascade enabled TF trafficking from rafts to filopodia and ultimately onto phosphatidylserine positive, highly procoagulant MPs. Furthermore, caspase-1 specifically facilitated cell surface actin exposure, which was required for the final release of highly procoagulant MPs from filopodia. Together, the results of this study delineate a thromboinflammatory pathway and suggest that components of this pathway have potential as pharmacological targets to simultaneously attenuate inflammation and innate immune cell-induced thrombosis. PMID- 25705885 TI - RASA3 is a critical inhibitor of RAP1-dependent platelet activation. AB - The small GTPase RAP1 is critical for platelet activation and thrombus formation. RAP1 activity in platelets is controlled by the GEF CalDAG-GEFI and an unknown regulator that operates downstream of the adenosine diphosphate (ADP) receptor, P2Y12, a target of antithrombotic therapy. Here, we provide evidence that the GAP, RASA3, inhibits platelet activation and provides a link between P2Y12 and activation of the RAP1 signaling pathway. In mice, reduced expression of RASA3 led to premature platelet activation and markedly reduced the life span of circulating platelets. The increased platelet turnover and the resulting thrombocytopenia were reversed by concomitant deletion of the gene encoding CalDAG-GEFI. Rasa3 mutant platelets were hyperresponsive to agonist stimulation, both in vitro and in vivo. Moreover, activation of Rasa3 mutant platelets occurred independently of ADP feedback signaling and was insensitive to inhibitors of P2Y12 or PI3 kinase. Together, our results indicate that RASA3 ensures that circulating platelets remain quiescent by restraining CalDAG GEFI/RAP1 signaling and suggest that P2Y12 signaling is required to inhibit RASA3 and enable sustained RAP1-dependent platelet activation and thrombus formation at sites of vascular injury. These findings provide insight into the antithrombotic effect of P2Y12 inhibitors and may lead to improved diagnosis and treatment of platelet-related disorders. PMID- 25705886 TI - Identification of a human synaptotagmin-1 mutation that perturbs synaptic vesicle cycling. AB - Synaptotagmin-1 (SYT1) is a calcium-binding synaptic vesicle protein that is required for both exocytosis and endocytosis. Here, we describe a human condition associated with a rare variant in SYT1. The individual harboring this variant presented with an early onset dyskinetic movement disorder, severe motor delay, and profound cognitive impairment. Structural MRI was normal, but EEG showed extensive neurophysiological disturbances that included the unusual features of low-frequency oscillatory bursts and enhanced paired-pulse depression of visual evoked potentials. Trio analysis of whole-exome sequence identified a de novo SYT1 missense variant (I368T). Expression of rat SYT1 containing the equivalent human variant in WT mouse primary hippocampal cultures revealed that the mutant form of SYT1 correctly localizes to nerve terminals and is expressed at levels that are approximately equal to levels of endogenous WT protein. The presence of the mutant SYT1 slowed synaptic vesicle fusion kinetics, a finding that agrees with the previously demonstrated role for I368 in calcium-dependent membrane penetration. Expression of the I368T variant also altered the kinetics of synaptic vesicle endocytosis. Together, the clinical features, electrophysiological phenotype, and in vitro neuronal phenotype associated with this dominant negative SYT1 mutation highlight presynaptic mechanisms that mediate human motor control and cognitive development. PMID- 25705887 TI - Normalization of Naxos plakoglobin levels restores cardiac function in mice. AB - Arrhythmogenic cardiomyopathy (AC) is associated with mutations in genes encoding intercalated disc proteins and ultimately results in sudden cardiac death. A subset of patients with AC have the autosomal recessive cardiocutaneous disorder Naxos disease, which is caused by a 2-base pair deletion in the plakoglobin encoding gene JUP that results in a truncated protein with reduced expression. In mice, cardiomyocyte-specific plakoglobin deficiency recapitulates many aspects of human AC, and overexpression of the truncated Naxos-associated plakoglobin also results in an AC-like phenotype; therefore, it is unclear whether Naxos disease results from loss or gain of function consequent to the plakoglobin mutation. Here, we generated 2 knockin mouse models in which endogenous Jup was engineered to express the Naxos-associated form of plakoglobin. In one model, Naxos plakoglobin bypassed the nonsense-mediated mRNA decay pathway, resulting in normal levels of the truncated plakoglobin. Moreover, restoration of Naxos plakoglobin to WT levels resulted in normal heart function. Together, these data indicate that a gain of function in the truncated form of the protein does not underlie the clinical phenotype of patients with Naxos disease and instead suggest that insufficiency of the truncated Naxos plakoglobin accounts for disease manifestation. Moreover, these results suggest that increasing levels of truncated or WT plakoglobin has potential as a therapeutic approach to Naxos disease. PMID- 25705888 TI - Human prion protein sequence elements impede cross-species chronic wasting disease transmission. AB - Chronic wasting disease (CWD) is a fatal prion disease of North American deer and elk and poses an unclear risk for transmission to humans. Human exposure to CWD occurs through hunting activities and consumption of venison from prion-infected animals. Although the amino acid residues of the prion protein (PrP) that prevent or permit human CWD infection are unknown, NMR-based structural studies suggest that the beta2-alpha2 loop (residues 165-175) may impact species barriers. Here we sought to define PrP sequence determinants that affect CWD transmission to humans. We engineered transgenic mice that express human PrP with four amino acid substitutions that result in expression of PrP with a beta2-alpha2 loop (residues 165-175) that exactly matches that of elk PrP. Compared with transgenic mice expressing unaltered human PrP, mice expressing the human-elk chimeric PrP were highly susceptible to elk and deer CWD prions but were concurrently less susceptible to human Creutzfeldt-Jakob disease prions. A systematic in vitro survey of amino acid differences between humans and cervids identified two additional residues that impacted CWD conversion of human PrP. This work identifies amino acids that constitute a substantial structural barrier for CWD transmission to humans and helps illuminate the molecular requirements for cross species prion transmission. PMID- 25705889 TI - Effects of nasal corticosteroids on boosts of systemic allergen-specific IgE production induced by nasal allergen exposure. AB - BACKGROUND: Allergen exposure via the respiratory tract and in particular via the nasal mucosa boosts systemic allergen-specific IgE production. Intranasal corticosteroids (INCS) represent a first line treatment of allergic rhinitis but their effects on this boost of allergen-specific IgE production are unclear. AIM: Here we aimed to determine in a double-blind, placebo-controlled study whether therapeutic doses of an INCS preparation, i.e., nasal fluticasone propionate, have effects on boosts of allergen-specific IgE following nasal allergen exposure. METHODS: Subjects (n = 48) suffering from grass and birch pollen allergy were treated with daily fluticasone propionate or placebo nasal spray for four weeks. After two weeks of treatment, subjects underwent nasal provocation with either birch pollen allergen Bet v 1 or grass pollen allergen Phl p 5. Bet v 1 and Phl p 5-specific IgE, IgG1-4, IgM and IgA levels were measured in serum samples obtained at the time of provocation and one, two, four, six and eight weeks thereafter. RESULTS: Nasal allergen provocation induced a median increase to 141.1% of serum IgE levels to allergens used for provocation but not to control allergens 4 weeks after provocation. There were no significant differences regarding the boosts of allergen-specific IgE between INCS- and placebo-treated subjects. CONCLUSION: In conclusion, the application of fluticasone propionate had no significant effects on the boosts of systemic allergen-specific IgE production following nasal allergen exposure. TRIAL REGISTRATION: http://clinicaltrials.gov/NCT00755066. PMID- 25705890 TI - Molecular characterization of the peripheral airway field of cancerization in lung adenocarcinoma. AB - Field of cancerization in the airway epithelium has been increasingly examined to understand early pathogenesis of non-small cell lung cancer. However, the extent of field of cancerization throughout the lung airways is unclear. Here we sought to determine the differential gene and microRNA expressions associated with field of cancerization in the peripheral airway epithelial cells of patients with lung adenocarcinoma. We obtained peripheral airway brushings from smoker controls (n=13) and from the lung contralateral to the tumor in cancer patients (n=17). We performed gene and microRNA expression profiling on these peripheral airway epithelial cells using Affymetrix GeneChip and TaqMan Array. Integrated gene and microRNA analysis was performed to identify significant molecular pathways. We identified 26 mRNAs and 5 miRNAs that were significantly (FDR <0.1) up-regulated and 38 mRNAs and 12 miRNAs that were significantly down-regulated in the cancer patients when compared to smoker controls. Functional analysis identified differential transcriptomic expressions related to tumorigenesis. Integration of miRNA-mRNA data into interaction network analysis showed modulation of the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) pathway in the contralateral lung field of cancerization. In conclusion, patients with lung adenocarcinoma have tumor related molecules and pathways in histologically normal appearing peripheral airway epithelial cells, a substantial distance from the tumor itself. This finding can potentially provide new biomarkers for early detection of lung cancer and novel therapeutic targets. PMID- 25705891 TI - A distinct mechanism of vascular lumen formation in Xenopus requires EGFL7. AB - During vertebrate blood vessel development, lumen formation is the critical process by which cords of endothelial cells transition into functional tubular vessels. Here, we use Xenopus embryos to explore the cellular and molecular mechanisms underlying lumen formation of the dorsal aorta and the posterior cardinal veins, the primary major vessels that arise via vasculogenesis within the first 48 hours of life. We demonstrate that endothelial cells are initially found in close association with one another through the formation of tight junctions expressing ZO-1. The emergence of vascular lumens is characterized by elongation of endothelial cell shape, reorganization of junctions away from the cord center to the periphery of the vessel, and onset of Claudin-5 expression within tight junctions. Furthermore, unlike most vertebrate vessels that exhibit specialized apical and basal domains, we show that early Xenopus vessels are not polarized. Moreover, we demonstrate that in embryos depleted of the extracellular matrix factor Epidermal Growth Factor-Like Domain 7 (EGFL7), an evolutionarily conserved factor associated with vertebrate vessel development, vascular lumens fail to form. While Claudin-5 localizes to endothelial tight junctions of EGFL7 depleted embryos in a timely manner, endothelial cells of the aorta and veins fail to undergo appropriate cell shape changes or clear junctions from the cell cell contact. Taken together, we demonstrate for the first time the mechanisms by which lumens are generated within the major vessels in Xenopus and implicate EGFL7 in modulating cell shape and cell-cell junctions to drive proper lumen morphogenesis. PMID- 25705892 TI - Design of a multicomponent peptide-woven nanocomplex for delivery of siRNA. AB - We developed and tested a multicomponent peptide-woven siRNA nanocomplex (PwSN) comprising different peptides designed for efficient cellular targeting, endosomal escape, and release of siRNA. To enhance tumor-specific cellular uptake, we connected an interleukin-4 receptor-targeting peptide (I4R) to a nine arginine peptide (9r), yielding I4R-9r. To facilitate endosomal escape, we blended endosomolytic peptides into the I4R-9r to form a multicomponent nanocomplex. Lastly, we modified 9r peptides by varying the number and positions of positive charges to obtain efficient release of siRNA from the nanocomplex in the cytosol. Using this step-wise approach for overcoming the biological challenges of siRNA delivery, we obtained an optimized PwSN with significant biological activity in vitro and in vivo. Interestingly, surface plasmon resonance analyses and three-dimensional peptide models demonstrated that our designed peptide adopted a unique structure that was correlated with faster complex disassembly and a better gene-silencing effect. These studies further elucidate the siRNA nanocomplex delivery pathway and demonstrate the applicability of our stepwise strategy to the design of siRNA carriers capable of overcoming multiple challenges and achieving efficient delivery. PMID- 25705893 TI - Polymorphisms in NFKB1 and TLR4 and interaction with dietary and life style factors in relation to colorectal cancer in a Danish prospective case-cohort study. AB - Maintenance of a balance between commensal bacteria and the mucosal immune system is crucial and intestinal dysbiosis may be a key event in the pathogenesis of colorectal cancer (CRC). The toll-like receptor 4 (TLR4) is an important pattern recognition receptor that regulates inflammation and barrier function in the gut by a mechanism that involves activation of the nuclear factor-kappaB (NF-kappaB) transcription factor. Dietary and life style factors may impact these functions. We therefore used a Danish prospective case-cohort study of 1010 CRC cases and 1829 randomly selected participants from the Danish Diet, Cancer and Health cohort to investigate three polymorphisms in NFKB1 and TLR4 and their possible interactions with diet and life style factors in relation to risk of CRC. Homozygous carriage of the variant allele of the TLR4/rs5030728 polymorphism was associated with increased risk of CRC (incidence rate ratio (IRR) = 1.30; 95% confidence interval (CI): 1.05-1.60; P = 0.02 (gene-dose model); IRR = 1.24; 95%CI: 1.01-1.51; P = 0.04 (recessive model)). Del-carriers of the NFKB1/rs28362491 polymorphism had a 17% (95%CI: 1.03-1.34; P = 0.02) increased risk of CRC compared to homozygous carriers of the ins-allele. However, none of these risk estimates withstood adjustment for multiple comparisons. We found no strong gene-environment interactions between the examined polymorphism and diet and life style factors in relation to CRC risk. PMID- 25705894 TI - First discovery of acetone extract from cottonseed oil sludge as a novel antiviral agent against plant viruses. AB - A novel acetone extract from cottonseed oil sludge was firstly discovered against plant viruses including Tobacco mosaic virus (TMV), Rice stripe virus (RSV) and Southern rice black streaked dwarf virus (SRBSDV). Gossypol and beta-sitosterol separated from the acetone extract were tested for their effects on anti-TMV and analysed by nuclear magnetic resonance (NMR) assay. In vivo and field trials in different geographic distributions and different host varieties declared that this extract mixture was more efficient than the commercial agent Ningnanmycin with a broad spectrum of anti-plant-viruses activity. No phytotoxic activity was observed in the treated plants and environmental toxicology showed that this new acetone extract was environmentally friendly, indicating that this acetone extract has potential application in the control of plant virus in the future. PMID- 25705895 TI - Inequality in diabetes-related hospital admissions in England by socioeconomic deprivation and ethnicity: facility-based cross-sectional analysis. AB - OBJECTIVE: To investigate the effect of social deprivation and ethnicity on inpatient admissions due to diabetes in England. DESIGN: Facility-based cross sectional analysis. SETTING: National Health Service (NHS) trusts in England reporting inpatient admissions with better than 80% data reporting quality from 2010-2011 (355 facilities). PARTICIPANTS: Non-obstetric patients over 16 years old in all NHS facilities in England. The sample size after exclusions was 5,147,859 all-cause admissions. MAIN OUTCOME MEASURES: The relative risk of inpatient admissions and readmissions due to diabetes adjusted for confounders. RESULTS: There were 445,504 diabetes-related hospital admissions in England in 2010, giving a directly (age-sex) standardized rate of 1049.0 per 100,000 population (95% confidence interval (CI): 1046.0-1052.1). The relative risk of inpatient admission in the most deprived quintile was 2.08 times higher than that of the least deprived quintile (95% CI: 2.02-2.14), and the effect of deprivation varied across ethnicities. About 30.1% of patients admitted due to diabetes were readmitted at least once due to diabetes. South Asians showed 2.62 times (95% CI: 2.51-2.74) higher admission risk. Readmission risk increased with IMD among white British but not other ethnicities. South Asians showed slightly lower risk of readmission than white British (0.86, 95% CI: 0.80-0.94). CONCLUSIONS: More deprived areas had higher rates of inpatient admissions and readmissions due to diabetes. South Asian British showed higher admission risk and lower readmission risk than white British. However, there was almost no difference by ethnicity in readmission due to diabetes. Higher rates of admission among deprived people may not necessarily reflect higher prevalence, but higher admission rates in south Asian British may be explained by their higher prevalence because their lower readmission risk suggests no inequality in primary care to prevent readmission. Better interventions in poorer areas, are needed to reduce these inequalities. PMID- 25705896 TI - Assessing the impact of afforestation on soil organic C sequestration by means of sequential density fractionation. AB - Afforestation is a prevalent practice carried out for soil recovery and carbon sequestration. Improved understanding of the effects of afforestation on soil organic carbon (SOC) content and dynamics is necessary to identify the particular processes of soil organic matter (SOM) formation and/or decomposition that result from afforestation. To elucidate these mechanisms, we have used a sequential density fractionation technique to identify the transfer mechanisms of forest derived C to soil fractions and investigate the impact of afforestation on SOC sequestration. Surface soil samples from continuous maize crop land (C4) and forest land (C3), which had been established 5, 12 and 25 yr, respectively, on the Northeast China Plain were separated into five density fractions. SOC, nitrogen (N) concentration and delta13C data from the three forests and adjacent cropland were compared. Afforestation decreased SOC concentration in the < 2.5 g cm-3 fractions from 5 yr forest sites, but increased SOC content in the < 2.0 g cm-3 fractions from 25 yr forest sites. Afforestation did not affect soil mass distribution, SOC and N proportional weight distributions across the density fractions. The < 1.8 g cm-3 fractions from 12 and 25 yr forests showed higher C/N and lower delta13C as compared to other fractions. Incorporation of forest litter derived C occurred from low density (< 1.8 g cm-3) fractions to aggregates of higher density (1.8-2.5 g cm-3) through aggregate recombination and C transport in the pore system of the aggregates. Some forest litter-derived C could transfer from the light fractions or directly diffuse and adsorb onto mineral particles. Results from this study indicate that microaggregate protection and association between organic material and minerals provide major contribution to the SOC sequestration in the afforested soil system. PMID- 25705897 TI - Hyper-Acetylation of Histone H3K56 Limits Break-Induced Replication by Inhibiting Extensive Repair Synthesis. AB - Break-induced replication (BIR) has been implicated in restoring eroded telomeres and collapsed replication forks via single-ended invasion and extensive DNA synthesis on the recipient chromosome. Unlike other recombination subtypes, DNA synthesis in BIR likely relies heavily on mechanisms enabling efficient fork progression such as chromatin modification. Herein we report that deletion of HST3 and HST4, two redundant de-acetylases of histone H3 Lysine 56 (H3K56), inhibits BIR, sensitizes checkpoint deficient cells to deoxyribonucleotide triphosphate pool depletion, and elevates translocation-type gross chromosomal rearrangements (GCR). The basis for deficiency in BIR and gene conversion with long gap synthesis in hst3Delta hst4Delta cells can be traced to a defect in extensive DNA synthesis. Distinct from other cellular defects associated with deletion of HST3 and HST4 including thermo-sensitivity and elevated spontaneous mutagenesis, the BIR defect in hst3Delta hst4Delta cannot be offset by the deletion of RAD17 or MMS22, but rather by the loss of RTT109 or ASF1, or in combination with the H3K56R mutation, which also restores tolerance to replication stress in mrc1 mutants. Our studies suggest that acetylation of H3K56 limits extensive repair synthesis and interferes with efficient fork progression in BIR. PMID- 25705898 TI - Only the carrot, not the stick: incorporating trust into the enforcement of regulation. AB - New enforcement strategies allow agents to gain the regulator's trust and consequently face a lower audit probability. Prior research suggests that, in order to prevent lower compliance, a reduction in the audit probability (the "carrot") must be compensated with the introduction of a higher penalty for non compliance (the "stick"). However, such carrot-and-stick strategies reflect neither the concept of trust nor the strategies observed in practice. In response to this, we define trust-based regulation as a strategy that incorporates rules that allow trust to develop, and using a generic (non-cooperative) game of tax compliance, we examine whether trust-based regulation is feasible (i.e., whether, in equilibrium, a reduction in the audit probability, without ever increasing the penalty for non-compliance, does not lead to reduced compliance). The model shows that trust-based regulation is feasible when the agent sufficiently values the future. In line with the concept of trust, this strategy is feasible when the regulator is uncertain about the agent's intentions. Moreover, the model shows that (i) introducing higher penalties makes trust-based regulation less feasible, and (ii) combining trust and forgiveness can lead to a lower audit probability for both trusted and distrusted agents. Policy recommendations often point toward increasing deterrence. This model shows that the opposite can be optimal. PMID- 25705899 TI - Perioperative intravenous acetaminophen attenuates lipid peroxidation in adults undergoing cardiopulmonary bypass: a randomized clinical trial. AB - BACKGROUND: Cardiopulmonary bypass (CPB) lyses erythrocytes and induces lipid peroxidation, indicated by increasing plasma concentrations of free hemoglobin, F2-isoprostanes, and isofurans. Acetaminophen attenuates hemeprotein-mediated lipid peroxidation, reduces plasma and urine concentrations of F2-isoprostanes, and preserves kidney function in an animal model of rhabdomyolysis. Acetaminophen also attenuates plasma concentrations of isofurans in children undergoing CPB. The effect of acetaminophen on lipid peroxidation in adults has not been studied. This was a pilot study designed to test the hypothesis that acetaminophen attenuates lipid peroxidation in adults undergoing CPB and to generate data for a clinical trial aimed to reduce acute kidney injury following cardiac surgery. METHODS AND RESULTS: In a prospective double-blind placebo-controlled clinical trial, sixty adult patients were randomized to receive intravenous acetaminophen or placebo starting prior to initiation of CPB and for every 6 hours for 4 doses. Acetaminophen concentrations measured 30 min into CPB and post-CPB were 11.9 +/- 0.6 MUg/mL (78.9 +/- 3.9 MUM) and 8.7 +/- 0.3 MUg/mL (57.6 +/- 2.0 MUM), respectively. Plasma free hemoglobin increased more than 15-fold during CPB, and haptoglobin decreased 73%, indicating hemolysis. Plasma and urinary markers of lipid peroxidation also increased during CPB but returned to baseline by the first postoperative day. Acetaminophen reduced plasma isofuran concentrations over the duration of the study (P = 0.05), and the intraoperative plasma isofuran concentrations that corresponded to peak hemolysis were attenuated in those subjects randomized to acetaminophen (P = 0.03). Perioperative acetaminophen did not affect plasma concentrations of F2-isoprostanes or urinary markers of lipid peroxidation. CONCLUSIONS: Intravenous acetaminophen attenuates the increase in intraoperative plasma isofuran concentrations that occurs during CPB, while urinary markers were unaffected. TRIAL REGISTRATION: ClinicalTrials.gov NCT01366976. PMID- 25705900 TI - The alpha2,3-sialyltransferase encoded by myxoma virus is a virulence factor that contributes to immunosuppression. AB - Myxoma virus (MYXV) induces a lethal disease called Myxomatosis in European rabbits. MYXV is one of the rare viruses that encodes an alpha2,3 sialyltransferase through its M138L gene. In this study, we showed that although the absence of the enzyme was not associated with any in vitro deficit, the M138L deficient strains are highly attenuated in vivo. Indeed, while all rabbits infected with the parental and the revertant strains died within 9 days post infection from severe myxomatosis, all but one rabbit inoculated with the M138L deficient strains survived the infection. In primary lesions, this resistance to the infection was associated with an increased ability of innate immune cells, mostly neutrophils, to migrate to the site of virus replication at 4 days post infection. This was followed by the development of a better specific immune response against MYXV. Indeed, at day 9 post-infection, we observed an important proliferation of lymphocytes and an intense congestion of blood vessels in lymph nodes after M138L knockouts infection. Accordingly, in these rabbits, we observed an intense mononuclear cell infiltration throughout the dermis in primary lesions and higher titers of neutralizing antibodies. Finally, this adaptive immune response provided protection to these surviving rabbits against a challenge with the MYXV WT strain. Altogether, these results show that expression of the M138L gene contributes directly or indirectly to immune evasion by MYXV. In the future, these results could help us to better understand the pathogenesis of myxomatosis but also the importance of glycans in regulation of immune responses. PMID- 25705901 TI - Association between glaucoma and obstructive sleep apnea syndrome: a meta analysis and systematic review. AB - BACKGROUND: Obstructive sleep apnea syndrome (OSAS) is a common disease that increases the risk of diabetes, heart disease, and stroke. However, studies of an association between OSAS and glaucoma neuropathy have reported controversial findings. OBJECTIVE: The main purpose of this study was to evaluate whether a significant association exists between OSAS and glaucoma by performing a meta analysis of previous studies. METHODS: A comprehensive literature search using the PubMed and Embase databases was performed to identify cross-sectional, case control, and cohort studies related to the topic. We estimated a pooled odds ratio (OR) for the association between OSAS and glaucoma, by a fixed- or random effects model. RESULTS: In total, 16 studies with 2,278,832 participants met the inclusion criteria: one retrospective cohort study reported an adjusted hazard ratio of glaucoma of 1.67 (95% CI = 1.30-2.17). Using a fixed-effects model, the pooled OR of six case-control studies was 1.96 (95% CI = 1.37 2.80). A significant association was also identified in a meta-analysis of nine cross sectional studies using a random-effects model, which showed a pooled OR of 1.41 (95% CI = 1.11 1.79). However, the reported pooled estimates for case control studies and cross-sectional studies were based on unadjusted ORs. CONCLUSIONS: Our results suggest that OSAS is associated with the prevalence of glaucoma. However, this result was based only on unadjusted estimates. Prospective cohort studies designed to take into consideration potential confounders, or examination of data from interventional trials to determine whether a reduction in OSAS status is associated with a reduced incidence of glaucoma, are needed to clarify whether OSAS is an independent risk factor for glaucoma. PMID- 25705903 TI - Advances and challenges in the use of nanoparticles to optimize PK/PD interactions of combined anti-cancer therapies. AB - Combination chemotherapy has become the primary strategy for treating cancer; however, the clinical success of combination treatments is limited by the distinct pharmacokinetics (PK) of different drugs, which lead to nonuniform distribution and an inability to coordinate dosing regimes at the site of the tumor. In the first half of this review, we will discuss the recent development of nanoparticlebased combination strategies to overcome these limitations. Nanoparticles are able to co-encapsulate and carry multiple drugs with different hydrophobicities while maintaining precise ratiometric loading and delivery. They can also temporally sequence the release of multiple drugs and reduce undesirable PK interactions. In the second half of this review, we will touch on the key factors that affect nanoparticle stability and distribution. Nanoparticles provide a promising strategy to improve combinatorial cancer treatments by better controlling PK and metabolic differences between drugs. PMID- 25705902 TI - Tight coupling of metabolic oscillations and intracellular water dynamics in Saccharomyces cerevisiae. AB - We detected very strong coupling between the oscillating concentration of ATP and the dynamics of intracellular water during glycolysis in Saccharomyces cerevisiae. Our results indicate that: i) dipolar relaxation of intracellular water is heterogeneous within the cell and different from dilute conditions, ii) water dipolar relaxation oscillates with glycolysis and in phase with ATP concentration, iii) this phenomenon is scale-invariant from the subcellular to the ensemble of synchronized cells and, iv) the periodicity of both glycolytic oscillations and dipolar relaxation are equally affected by D2O in a dose dependent manner. These results offer a new insight into the coupling of an emergent intensive physicochemical property of the cell, i.e. cell-wide water dipolar relaxation, and a central metabolite (ATP) produced by a robustly oscillating metabolic process. PMID- 25705904 TI - CYP3A4-mediated pharmacokinetic interactions in cancer therapy. AB - Cytochromes P450 enzymes, especially CYP3A4, are responsible for metabolizing a broad range of anticancer drugs. Combination therapy is common in patients with cancer, which may cause potential drug drug interactions (DDIs) leading to increased risk of side-effects/toxicity or decreased effectiveness. The review summarizes CYP3A4-mediated DDIs, with anticancer drugs as CYP3A4 substrates or modulators, in clinical trials during cancer therapy and aims to increase clinicians' awareness to take caution to reduce the risk. PMID- 25705905 TI - Pharmacokinetic interactions between herbal medicines and prescribed drugs: focus on drug metabolic enzymes and transporters. AB - Herbal medicines have been widely used for thousands of years, and now are gaining continued popularity worldwide as a complementary or alternative treatment for a variety of diseases, rehabilitation and health care. Since herbal medicines contain more than one pharmacologically active ingredient and are commonly used with many prescribed drugs, there are potential herb-drug interactions. A variety of reported herb-drug interactions are of pharmacokinetic origin, arising from the effects of herbal medicines on metabolic enzymes and/or transporters. Such an alteration in metabolism or transport can result in changes in absorption, distribution, metabolism, and excretion (e.g., induction or inhibition of metabolic enzymes, and modulation of uptake and efflux transporters), leading to changed pharmacokinetics of the concomitantly prescribed drugs. Pharmacokinetic herb-drug interactions have more clinical significance as pharmacokinetic parameters such as the area under the plasma concentration-time curve (AUC), the maximum plasma concentration (Cmax) or the elimination half-life (t1/2) of the concomitant drug alter. This review summarizes the mechanism underlying herb-drug interactions and the approaches to identify the interactions, and discusses pharmacokinetic interactions of eight widely used herbal medicines (Ginkgo biloba, ginseng, garlic, black cohosh, Echinacea, milk thistle, kava, and St. John's wort) with conventional drugs, using various in vitro, animal in vivo, and clinical studies. The increasing understanding of pharmacokinetic herb-drug interactions will make health care professionals and patients pay more attention to the potential interactions. PMID- 25705906 TI - Are circulating metabolites important in pharmacokinetic drug-drug interactions? A retroanalysis of clinical data. AB - Pharmacokinetic (PK) drug-drug interactions (DDIs) give rise to adverse events and/or reduced efficacy. Comprehensive, systematic and mechanistic approaches have been applied in the evaluation, propagation and management of the interaction potential of a new drug during its development and clinical use. However, the role of drug metabolite(s) in DDIs was not extensively investigated. Recently, regulatory bodies have proposed that metabolites at >=25% of the parent drug's area under the time-concentration curve (AUC) and/or >10% of the total drug-related exposure should be investigated in vitro for DDI potential. This review aimed to identify the drugs and their metabolites meeting the official guidance's criteria for DDI studies, and to assess whether the eligible drugs caused significant clinical PK DDIs and furthermore whether the metabolites contributed to the observed PK DDIs. Eighty seven drugs were eligible and nearly 45% (39/87) drugs were not reported with clinical PK DDIs. About 78% (68/87) drugs demonstrated inhibitory and/or inducible effects on drug-metabolizing enzymes and/or drug transporters; while the remaining 19 (22%) parent drugs showed no such effects. For 8 drugs (~9%), their metabolites were able to inhibit and/or induce the drug-metabolizing enzymes and drug transporters. Three drugmetabolite pairs were found to be the perpetrators of the complex PK DDIs. Our retrospective analysis suggested that the PK DDI risks caused by metabolites alone might not be high, which is somewhat different from the conclusions from some other studies on this topic. However, circulating drugs often work as perpetrators of PK DDIs suggesting a need for more efforts to characterize the roles of their metabolites. Our study should be of value in stimulating discussions among the scientific community on this important topic. PMID- 25705907 TI - Quantitative evaluation of drug-drug interaction potentials by in vivo information- guided prediction approach. AB - Drug-drug interaction (DDI) is one important topic in drug discovery, drug development and clinical practice. Recently, a novel approach, in vivo information-guided prediction (IVIP), was introduced for predicting the magnitude of pharmacokinetic DDIs which are caused by changes in cytochrome P450 (CYP) activity. This approach utilizes two parameters, i.e. CR (the apparent contribution of the target metabolizing enzyme to the clearance of the substrate drug) and IX (the apparent effect of a perpetrator on the target CYP) to describe the magnitude of DDI between a perpetrator and a victim drug. The essential concept of this method assumes that at a given dose level, the IX for a given perpetrator remains constant whatever the victim drug is. Usually, this IVIP method is only based on information from clinical studies and does not need in vitro information. In this review, basic concept, application and extension, as well as pros and cons of the IVIP method were presented. How to apply this approach was also discussed. Thus far, this method displayed good performance in predicting DDIs associated with CYPs, and can be used to forecast the magnitude of a large number of possible DDIs, of which only a small portion have been investigated in clinical studies. The key concept of this static approach could even be implemented in dynamic modeling to assess risks of DDIs involving drug transporters. PMID- 25705908 TI - Editorial (thematic issue: study and prediction of pharmacokinetic drug-drug interactions). PMID- 25705909 TI - Cut-off value of total adiponectin for managing risk of developing metabolic syndrome in male Japanese workers. AB - AIM: To determine the optimal cut-off value of serum total adiponectin for managing the risk of developing metabolic syndrome (MetS) in male Japanese workers. METHODS: A total of 365 subjects without MetS aged 20-60 years were followed up prospectively for a mean of 3.1 years. The accelerated failure-time model was used to estimate time ratio (TR) and cut-off value for developing MetS. RESULTS: During follow-up, 45 subjects developed MetS. Age-adjusted TR significantly declined with decreasing total adiponectin level (<= 4.9, 5.0-6.6, 6.7-8.8 and >= 8.9 MUg/ml, P for trend = 0.003). In multivariate analyses, TR of MetS was 0.12 (95% CI 0.02-0.78; P = 0.03) in subjects with total adiponectin level of 5.0-6.6 MUg/ml, and 0.15 (95% CI 0.02-0.97; P = 0.047) in subjects with total adiponectin level <= 4.9 MUg/ml compared with those with total adiponectin level >= 8.9 MUg/ml. The accelerated failure-time model showed that the optimal cut-off value of total adiponectin for managing the risk of developing MetS was 6.2 MUg/ml. In the multivariate-adjusted model, the mean time to the development of MetS was 78% shorter for total adiponectin level <= 6.2 MUg/ml compared with > 6.2 MUg/ml (TR 0.22, 95% CI: 0.08-0.64, P = 0.005). CONCLUSION: Our findings suggest that the cut-off value for managing the risk of developing MetS is 6.2 MUg/ml in male Japanese workers. Subjects with total adiponectin level <= 6.2 MUg/ml developed MetS more rapidly than did those with total adiponectin level > 6.2 MUg/ml. PMID- 25705910 TI - Workplace surface acting and marital partner discontent: Anxiety and exhaustion spillover mechanisms. AB - Surface acting (i.e., faking and suppressing emotions at work) is repeatedly linked to employee negative moods and emotional exhaustion, but the consequences may also go beyond work boundaries. We provide a unique theoretical integration of these 2 emotional labor consequences with 2 work-to-family conflict mechanisms, mood spillover and resource drain, to explain why surface acting is likely to create marital partner discontent (i.e., partner's perceived work-to family conflict and desire for the employee to quit). A survey of 197 hotel managers and their marital partners supported that managers' surface acting was directly related to their partner wanting them to quit, and indirectly to partner's perception of work-to-family conflict via exhaustion consistent with the resource drain mechanism. Anxiety from surface acting had an indirect mediating effect on marital partner discontent through exhaustion. Importantly, controlling for dispositional negativity and job demands did not weaken these effects. Implications for theory and future research integrating work-family and emotional labor are discussed. PMID- 25705911 TI - Stressful work environment and wellbeing: What comes first? AB - The association between the psychosocial work environment, including job demands, job control, and organizational justice, and employee wellbeing has been well established. However, the exposure to adverse work environments is typically measured only using self-reported measures that are vulnerable to reporting bias, and thus any associations found may be explained by reverse causality. Using linear regression models and cross-lagged structural equation modeling (SEM), we tested the direction of the association between established job stress models (job demand control and organizational justice models) and 3 wellbeing indicators (psychological distress, sleeping problems, and job satisfaction) among 1524 physicians in a 4-year follow-up. Results from the longitudinal cross-lagged analyses showed that the direction of the association was from low justice to decreasing wellbeing rather than the reverse. Although the pattern was similar in job demands and job control, a reciprocal association was found between job control and psychological distress. PMID- 25705912 TI - Need satisfaction and employees' recovery state at work: A daily diary study. AB - The present study aimed to advance insight in the associations between employees' daily effort expenditure at work and their recovery state during the workday, and specifically focused on the role of daily work-related need satisfaction in this process. We examined (a) if high intrinsic work motivation and low self-control effort act as mediating mechanisms underlying the beneficial role of need satisfaction, and (b) to what extent need satisfaction mitigates the adverse effects of high job demands (work pressure and cognitive demands) on employee recovery. Data were collected by means of a 5-day daily diary study (2 measurements daily: in the morning before work, and at the end of the workday) among 68 participants. Multilevel analyses showed that need satisfaction at work was related to a beneficial recovery state at the end of the workday, and that this association was mediated by high intrinsic work motivation and low self control effort. Furthermore, need satisfaction attenuated the adverse effects of high work pressure on employee recovery. All in all, this study increased our understanding of employees' daily effort and recovery processes at work, and highlighted the beneficial role of need satisfaction at work. PMID- 25705913 TI - A qualitative study of stress in individuals self-employed in solo businesses. AB - This qualitative study involved 54 individuals who were self-employed in a variety of solo businesses. All participants were administered a semistructured interview that inquired into various aspects of their work experience with the data subject to reliability and validity checks. The study identified stressful incidents, coping strategies, and emotional strains arising from those stressful incidents. Uncertainty about income was a common background stressor. Recent specific stressors included dramatic slowdowns in business, reputational threat, betrayal, unreasonable customers, and medical problems. Commonly occurring strains included apprehension/anxiety, frustration, anger, and sadness/depression. The self-employed used problem-focused coping much more often than emotion-focused coping. We also identified a third kind of coping that we labeled humanitarian coping. A number of questions/hypotheses for future research emerged, including identifying (a) a tipping point bearing on when the psychological benefits of self-employment (e.g., autonomy) are overtaken by business losses outside the individual's control and (b) the coping strategies that are most useful in managing work-related stressors. PMID- 25705914 TI - A model of magneto-electric multipoles. AB - A long-known Hamiltonian of electrons with entangled spin and orbital degrees of freedom is re-examined as a model of magneto-electric multipoles (MEs). In the model, a magnetic charge and simple quantum rotator are tightly locked in action, some might say they are enslaved entities. It is shown that MEs almost perfectly accord with those inferred from an analysis of magnetic neutron diffraction data on a ceramic superconductor (YBCO) in the pseudo-gap phase. Nigh on perfection between Stone's model and inferred MEs is achieved by addition to the original model of a crystal-field potential appropriate for the magnetic space group used in the published data analysis. An impression of thermal properties of multipoles is sought from a molecular-field model. PMID- 25705915 TI - Scene text deblurring using text-specific multiscale dictionaries. AB - Texts in natural scenes carry critical semantic clues for understanding images. When capturing natural scene images, especially by handheld cameras, a common artifact, i.e., blur, frequently happens. To improve the visual quality of such images, deblurring techniques are desired, which also play an important role in character recognition and image understanding. In this paper, we study the problem of recovering the clear scene text by exploiting the text field characteristics. A series of text-specific multiscale dictionaries (TMD) and a natural scene dictionary is learned for separately modeling the priors on the text and nontext fields. The TMD-based text field reconstruction helps to deal with the different scales of strings in a blurry image effectively. Furthermore, an adaptive version of nonuniform deblurring method is proposed to efficiently solve the real-world spatially varying problem. Dictionary learning allows more flexible modeling with respect to the text field property, and the combination with the nonuniform method is more appropriate in real situations where blur kernel sizes are depth dependent. Experimental results show that the proposed method achieves the deblurring results with better visual quality than the state of-the-art methods. PMID- 25705916 TI - Low knowledge of physical health behaviours is associated with poor diet and chronic illness in adults. AB - Governments invest heavily in health promotion strategies to improve physical health behaviours. However, the dietary and physical activity practices of many Australians fail to meet minimum levels for health, leading to the unacceptably high prevalence of chronic and complex illness. Health literacy is known to impact on health behaviour, and to be related to health knowledge; however, no studies have specifically examined knowledge of physical health behaviours in an Australian context. We assessed knowledge of physical health behaviours in 1244 adults in Queensland, Australia. Almost two-thirds of respondents had a 'Good' knowledge of physical health behaviour. People with 'Good' knowledge of physical health behaviours were more likely to be female, educated beyond secondary school, be employed and have an annual household income of >$52000 (P<0.05). People with 'Low' knowledge of physical health behaviours were significantly more likely to report insufficient intake of vegetables and have at least one chronic illness (P<0.05). Binary logistic regression shows low daily intake of vegetables to have the strongest association with low knowledge of physical health behaviours. Given the association between health knowledge and health literacy, assessment of the knowledge of physical health behaviours may provide considerable insight into the effectiveness of future health promotion interventions. PMID- 25705918 TI - Photofunctional surfaces for quantitative fluorescence microscopy: monitoring the effects of photogenerated reactive oxygen species at single cell level with spatiotemporal resolution. AB - Herein, we report on the implementation of photofunctional surfaces for the investigation of cellular responses by means of quantitative fluorescence microscopy. The developed substrates are able to produce reactive oxygen species under the fluorescence microscope upon irradiation with visible light, and the behavior of cells grown on these surfaces can be consequently investigated in situ and in real time. Moreover, a suitable methodology is presented to simultaneously monitor phototriggered morphological changes and the associated molecular pathways with spatiotemporal resolution employing time-resolved fluorescence anisotropy at the single cell level. The results showed that morphological changes can be complemented with a quantitative evaluation of the associated molecular signaling cascades for the unambiguous assignment of reactive oxygen species-related photoinduced apoptosis. Indeed, similar phenotypes are associated with different cellular processes. Our methodology facilitates the in vitro design and evaluation of photosensitizers for the treatment of cancer and infectious diseases with the aid of functional fluorescence microscopy. PMID- 25705917 TI - Early hyperlipidemia promotes endothelial activation via a caspase-1-sirtuin 1 pathway. AB - OBJECTIVE: The role of receptors for endogenous metabolic danger signals associated molecular patterns has been characterized recently as bridging innate immune sensory systems for danger signals-associated molecular patterns to initiation of inflammation in bone marrow-derived cells, such as macrophages. However, it remains unknown whether endothelial cells (ECs), the cell type with the largest numbers and the first vessel cell type exposed to circulating danger signals-associated molecular patterns in the blood, can sense hyperlipidemia. This report determined whether caspase-1 plays a role in ECs in sensing hyperlipidemia and promoting EC activation. APPROACH AND RESULTS: Using biochemical, immunologic, pathological, and bone marrow transplantation methods together with the generation of new apoplipoprotein E (ApoE)(-/-)/caspase-1(-/-) double knockout mice, we made the following observations: (1) early hyperlipidemia induced caspase-1 activation in ApoE(-/-) mouse aorta; (2) caspase 1(-/-)/ApoE(-/-) mice attenuated early atherosclerosis; (3) caspase-1(-/-)/ApoE( /-) mice had decreased aortic expression of proinflammatory cytokines and attenuated aortic monocyte recruitment; and (4) caspase-1(-/-)/ApoE(-/-) mice had decreased EC activation, including reduced adhesion molecule expression and cytokine secretion. Mechanistically, oxidized lipids activated caspase-1 and promoted pyroptosis in ECs by a reactive oxygen species mechanism. Caspase-1 inhibition resulted in accumulation of sirtuin 1 in the ApoE(-/-) aorta, and sirtuin 1 inhibited caspase-1 upregulated genes via activator protein-1 pathway. CONCLUSIONS: Our results demonstrate for the first time that early hyperlipidemia promotes EC activation before monocyte recruitment via a caspase-1-sirtuin 1 activator protein-1 pathway, which provides an important insight into the development of novel therapeutics for blocking caspase-1 activation as early intervention of metabolic cardiovascular diseases and inflammations. PMID- 25705919 TI - Enhanced bioactivity of Mg-Nd-Zn-Zr alloy achieved with nanoscale MgF2 surface for vascular stent application. AB - Magnesium (Mg) alloys have revolutionized the application of temporary load bearing implants as they meet both engineering and medical requirements. However, rapid degradation of Mg alloys under physiological conditions remains the major obstacle hindering the wider use of Mg-based implants. Here we developed a simple method of preparing a nanoscale MgF2 film on Mg-Nd-Zn-Zr (denoted as JDBM) alloy, aiming to reduce the corrosion rate as well as improve the biological response. The corrosion rate of JDBM alloy exposed to artificial plasma is reduced by ~20% from 0.337 +/- 0.021 to 0.269 +/- 0.043 mm.y(-1) due to the protective effect of the MgF2 film with a uniform and dense physical structure. The in vitro cytocompatibility test of MgF2-coated JDBM using human umbilical vein endothelial cells indicates enhanced viability, growth, and proliferation as compared to the naked substrate, and the MgF2 film with a nanoscale flakelike feature of ~200-300 nm presents a much more favorable environment for endothelial cell adhesion, proliferation, and alignment. Furthermore, the animal experiment via implantation of MgF2-coated JDBM stent to rabbit abdominal aorta confirms excellent tissue compatibility of the well re-endothelialized stent with no sign of thrombogenesis and restenosis in the stented vessel. PMID- 25705920 TI - Self-assembled monolayer-assisted negative lithography. AB - Self-assembled monolayers (SAMs) have been widely employed as etching resists in wet lithography systems to form patterns in which the ordered molecular packing of the SAM regions significantly delays the etchant attack. A generally accepted recognition is that the SAMs ability to resist etching is positively correlated to the quality of the surface-assembled structures, and a more ordered molecular packing would correspond to a better etching resistance. Such a classical belief is debated in the present work by providing an alternative SAM-assisted negative lithography where ordered SAM regions are etched more quickly than their disordered counterparts. This method features a unique photoirradiation-imprinted patterning process that simply consists of two steps: (1) UV irradiation on an OH terminated SAM-modified gold surface through a photomask and (2) the subsequent immersion of the exposed substrate in an aqueous etching solution of N bromosuccinimide/pyridine to develop a wet lithographic pattern. The entire experimental process reveals a finding from previous work that the etching rate on the UV-exposed regions with disordered molecular packing could be modulated to be slower than that in the unexposed well-defined SAM regions. Longer irradiation times would also revert the patterns from negative to positive. Thus, by merely using one kind of SAM-modified surface to provide both positive and negative micropatterns on gold layers, one could obtain flexible opportunities for high resolution micro/nanofabrication resembling photolithography. PMID- 25705921 TI - Ultrafast light-induced spin-state trapping photophysics investigated in Fe(phen)2(NCS)2 spin-crossover crystal. AB - Few photoactive molecules undergo a complete transformation of physical properties (magnetism, optical absorption, etc.) when irradiated with light. Such phenomena can happen on the time scale of fundamental atomic motions leading to an entirely new state within less than 1 ps following light absorption. Spin crossover (SCO) molecules are prototype systems having the ability to switch between low spin (LS) and high spin (HS) molecular states both at thermal equilibrium and after light irradiation. In the case of Fe(II) (3d(6)) complexes in a nearly octahedral ligand field, the two possible electronic distributions among the 3d split orbitals are S = 0 for the LS diamagnetic state and S = 2 for the HS paramagnetic state. In crystals, such photoexcited states can be long lived at low temperature, as is the case for the photoinduced HS state of the [Fe(phen)2(NCS)2] SCO compound investigated here. We first show how such bistability between the diamagnetic and paramagnetic states can be characterized at thermal equilibrium or after light irradiation at low temperature. Complementary techniques provide invaluable insights into relationships between changes of electronic states and structural reorganization. But the development of such light-active materials requires the understanding of the basic mechanism following light excitation of molecules, responsible for trapping them into new electronic and structural states. We therefore discuss how we can observe a photomagnetic molecule during switching and catch on the fly electronic and structural molecular changes with ultrafast X-ray and optical absorption spectroscopies. In addition, there is a long debate regarding the mechanism behind the efficiency of such a light-induced process. Recent theoretical works suggest that such speed and efficiency are possible thanks to the instantaneous coupling with the phonons of the final state. We discuss here the first experimental proof of that statement as we observe the instantaneous activation of one key phonon mode precluding any recurrence towards the initial state. Our studies show that the structural molecular reorganization trapping the photoinduced electronic state occurs in two sequential steps: the molecule elongates first (within 170 femtosecond) and bends afterwards. This dynamics is caught via the coherent vibrational energy transfer of the two main structural modes. We discuss the transformation pathway connecting the initial photoexcited state to the final state, which involves several key reaction coordinates. These results show the need to replace the classical single coordinate picture employed so far with a more complex multidimensional energy surface. PMID- 25705922 TI - Temporalization of peak electric generation particulate matter emissions during high energy demand days. AB - Underprediction of peak ambient pollution by air quality models hinders development of effective strategies to protect health and welfare. The U.S. Environmental Protection Agency's community multiscale air quality (CMAQ) model routinely underpredicts peak ozone and fine particulate matter (PM2.5) concentrations. Temporal misallocation of electricity sector emissions contributes to this modeling deficiency. Hourly emissions are created for CMAQ by use of temporal profiles applied to annual emission totals unless a source is matched to a continuous emissions monitor (CEM) in the National Emissions Inventory (NEI). More than 53% of CEMs in the Pennsylvania-New Jersey-Maryland (PJM) electricity market and 45% nationally are unmatched in the 2008 NEI. For July 2006, a United States heat wave with high electricity demand, peak electric sector emissions, and elevated ambient PM2.5 mass, we match hourly emissions for 267 CEM/NEI pairs in PJM (approximately 49% and 12% of unmatched CEMs in PJM and nationwide) using state permits, electricity dispatch modeling and CEMs. Hourly emissions for individual facilities can differ up to 154% during the simulation when measurement data is used rather than default temporalization values. Maximum CMAQ PM2.5 mass, sulfate, and elemental carbon predictions increase up to 83%, 103%, and 310%, at the surface and 51%, 75%, and 38% aloft (800 mb), respectively. PMID- 25705923 TI - (Z)- or (E)-Selective hydrogenation of potassium (3,3,3-trifluoroprop-1-yn-1 yl)trifluoroborate: route to either isomer of beta-trifluoromethylstyrenes. AB - A Pd-catalyzed hydrogenation of potassium (3,3,3-trifluoroprop-1-yn-1 yl)trifluoroborate providing either the (Z)- or (E)-isomer of the vinylborate in >98% purity is described. The initially formed (Z)-isomer of the alkene is transformed to the (E)-isomer with time, irrespective of the catalyst used; coupling with bromo- and iodoarenes provides a variety of (Z)- or (E)-beta trifluoromethylstyrenes. Also, a safe synthesis of the alkynyltrifluoroborate from HFC-245fa and BF3.OEt2 has been described. PMID- 25705924 TI - Negative effects of internet interventions: a qualitative content analysis of patients' experiences with treatments delivered online. AB - Internet interventions are defined as the delivery of health care-related treatments via an online or a smartphone interface, and have been shown to be a viable alternative to face-to-face treatments. However, not all patients benefit from such treatments, and it is possible that some may experience negative effects. Investigations of face-to-face treatments indicate that deterioration occurs in 5-10% of all patients. The nature and scope of other negative effects of Internet interventions is, however, largely unknown. Hence, the current study explored patients' reported negative experiences while undergoing treatments delivered via the Internet. Data from four large clinical trials (total N = 558) revealed that 9.3% of patients reported some type of negative effects. Qualitative content analysis was used to explore the patients' responses to open ended questions regarding their negative experiences. Results yielded two broad categories and four subcategories of negative effects: patient-related negative effects (insight and symptom) and treatment-related negative effects (implementation and format). Results emphasize the importance of always considering negative effects in Internet-based interventions, and point to several ways of preventing such experiences, including regular assessment of negative events, increasing the flexibility of treatment schedules and therapist contact, as well as prolonging the treatment duration. PMID- 25705925 TI - Stereoselective synthesis of the diazonamide a macrocyclic core. AB - Stereoselective synthesis of the right-hand heteroaromatic macrocycle of diazonamide A features C16-C18 bond formation in the Suzuki-Miyaura cross coupling and atropodiastereoselective Dieckmann-type macrocyclization as key steps. The Suzuki-Miyaura cross-coupling gave the best yields when it was catalyzed by a palladium-dioxygen complex. PMID- 25705926 TI - Functional Connectivity Changes and Executive and Social Problems in Neurofibromatosis Type I. AB - Neurofibromatosis type 1 (NF1) has regularly been associated with cognitive, social, and behavioral problems. The fact that many different cognitive and behavioral impairments have been observed in NF1 suggests that networks of brain regions are involved rather than specific brain regions. Here, we examined whether functional connectivity was different in NF1 and, if so, whether associations were present with cognitive, social, and behavioral outcomes. Fourteen NF1 patients (8 male, age: M=12.49, SD=2.65) and 30 healthy controls (HC; 23 male, age: M=12.30, SD=2.94; p=0.835) were included. Functional connectivity was assessed using functional resting-state scanning. We analyzed brain regions that have been associated with cognitive and social functions: the bilateral ventral anterior cingulate cortex (vACC), the bilateral amygdala, the bilateral orbitofrontal cortex (OFC), and the posterior cingulate cortex (PCC). For NF1 patients, connection strengths between brain regions showing HC-NF1 differences were correlated with parent reports of cognitive, social, and behavioral functioning. Compared to HC, patients showed differences in functional connectivity between the left vACC and the frontal cortex, insula, and subcortical areas (caudate, putamen), between the left amygdala and the frontal cortex, insula, supramarginal gyrus, and PCC/precuneus, and between the left OFC and frontal and subcortical areas (caudate, pallidum). In patients, indications were found for associations between increased frontofrontal and temporofrontal functional connectivity with cognitive, social, and behavioral deficits (r range=0.536-0.851). NF1 patients showed differences in functional connectivity between areas associated with cognitive and social functioning when compared to controls. This, plus the fact that connectivity strengths in these networks were associated with worse cognitive, social, and behavioral outcomes, suggests a neuropathological basis for the widespread deficits observed in NF1. PMID- 25705927 TI - Humoral and cell-mediated immune response, and growth factor synthesis after direct intraarticular injection of rAAV2-IGF-I and rAAV5-IGF-I in the equine middle carpal joint. AB - Intraarticular (IA) administration of viral vectors expressing a therapeutic transgene is an attractive treatment modality for osteoarthritis (OA) as the joint can be treated as a contained unit. Humoral and cell-mediated immune responses in vivo can limit vector effectiveness. Transduction of articular tissues has been investigated; however, the immune response to IA vectors remains largely unknown. We hypothesized that IA rAAV2 and rAAV5 overexpressing insulin like growth factor-I (IGF-I) would result in long-term IGF-I formation but would also induce neutralizing antibodies (NAb) and anti-capsid effector T cells. Twelve healthy horses were assigned to treatment (rAAV2 or rAAV5) or control (saline) groups. Middle carpal joints were injected with 5*10(11) vector genomes/joint. Synovial fluid was analyzed for changes in composition, NAb titers, immunoglobulin isotypes, proinflammatory cytokines, and IGF-I. Serum was analyzed for antibody titers and cytokines. A T cell restimulation assay was used to assess T cell responses. Injection of rAAV2- or rAAV5-IGF-I did not induce greater inflammation compared with saline. Synovial fluid IGF-I was significantly increased in both rAAV2- and rAAV5-IGF-I joints by day 14 and remained elevated until day 56; however, rAAV5 achieved the highest concentrations. A capsid specific T cell response was not noted although all virus-treated horses had increased NAbs in serum and synovial fluid after treatment. Taken together, our data show that IA injection of rAAV2- or rAAV5-IGF-I does not incite a clinically detectable inflammatory or cell-mediated immune response and that IA gene therapy using minimally immunogenic vectors represents a clinically relevant tool for treating articular disorders including OA. PMID- 25705928 TI - Observation and quantification of nanoscale processes in lithium batteries by operando electrochemical (S)TEM. AB - An operando electrochemical stage for the transmission electron microscope has been configured to form a "Li battery" that is used to quantify the electrochemical processes that occur at the anode during charge/discharge cycling. Of particular importance for these observations is the identification of an image contrast reversal that originates from solid Li being less dense than the surrounding liquid electrolyte and electrode surface. This contrast allows Li to be identified from Li-containing compounds that make up the solid-electrolyte interphase (SEI) layer. By correlating images showing the sequence of Li electrodeposition and the evolution of the SEI layer with simultaneously acquired and calibrated cyclic voltammograms, electrodeposition, and electrolyte breakdown processes can be quantified directly on the nanoscale. This approach opens up intriguing new possibilities to rapidly visualize and test the electrochemical performance of a wide range of electrode/electrolyte combinations for next generation battery systems. PMID- 25705929 TI - Depression: a decision-theoretic analysis. AB - The manifold symptoms of depression are common and often transient features of healthy life that are likely to be adaptive in difficult circumstances. It is when these symptoms enter a seemingly self-propelling spiral that the maladaptive features of a disorder emerge. We examine this malignant transformation from the perspective of the computational neuroscience of decision making, investigating how dysfunction of the brain's mechanisms of evaluation might lie at its heart. We start by considering the behavioral implications of pessimistic evaluations of decision variables. We then provide a selective review of work suggesting how such pessimism might arise via specific failures of the mechanisms of evaluation or state estimation. Finally, we analyze ways that miscalibration between the subject and environment may be self-perpetuating. We employ the formal framework of Bayesian decision theory as a foundation for this study, showing how most of the problems arise from one of its broad algorithmic facets, namely model-based reasoning. PMID- 25705930 TI - Noncanonical secondary structure stabilizes mitochondrial tRNA(Ser(UCN)) by reducing the entropic cost of tertiary folding. AB - Mammalian mitochondrial tRNA(Ser(UCN)) (mt-tRNA(Ser)) and pyrrolysine tRNA (tRNA(Pyl)) fold to near-canonical three-dimensional structures despite having noncanonical secondary structures with shortened interhelical loops that disrupt the conserved tRNA tertiary interaction network. How these noncanonical tRNAs compensate for their loss of tertiary interactions remains unclear. Furthermore, in human mt-tRNA(Ser), lengthening the variable loop by the 7472insC mutation reduces mt-tRNA(Ser) concentration in vivo through poorly understood mechanisms and is strongly associated with diseases such as deafness and epilepsy. Using simulations of the TOPRNA coarse-grained model, we show that increased topological constraints encoded by the unique secondary structure of wild-type mt tRNA(Ser) decrease the entropic cost of folding by ~2.5 kcal/mol compared to canonical tRNA, offsetting its loss of tertiary interactions. Further simulations show that the pathogenic 7472insC mutation disrupts topological constraints and hence destabilizes the mutant mt-tRNA(Ser) by ~0.6 kcal/mol relative to wild type. UV melting experiments confirm that insertion mutations lower mt-tRNA(Ser) melting temperature by 6-9 degrees C and increase the folding free energy by 0.8 1.7 kcal/mol in a largely sequence- and salt-independent manner, in quantitative agreement with our simulation predictions. Our results show that topological constraints provide a quantitative framework for describing key aspects of RNA folding behavior and also provide the first evidence of a pathogenic mutation that is due to disruption of topological constraints. PMID- 25705931 TI - Colonisation of winter wheat grain by Fusarium spp. and mycotoxin content as dependent on a wheat variety, crop rotation, a crop management system and weather conditions. AB - Field experiments were conducted during three consecutive growing seasons (2007/08, 2008/09 and 2009/10) with four winter wheat (Triticum aestivum L.) cultivars - 'Bogatka', 'Kris', 'Satyna' and 'Tonacja' - grown on fields with a three-field crop rotation (winter triticale, spring barley, winter wheat) and in a four-field crop rotation experiment (spring wheat, spring cereals, winter rapeseed, winter wheat). After the harvest, kernels were surface disinfected with 2% NaOCl and then analysed for the internal infection by different species of Fusarium. Fusaria were isolated on Czapek-Dox iprodione dichloran agar medium and identified on the basis of macro- and micro-morphology on potato dextrose agar and synthetic nutrient agar media. The total wheat grain infection by Fusarium depended mainly on relative humidity (RH) and a rainfall during the flowering stage. Intensive rainfall and high RH in 2009 and 2010 in the period meant the proportions of infected kernels by the fungi were much higher than those in 2008 (lack of precipitation during anthesis). Weather conditions during the post anthesis period changed the species composition of Fusarium communities internally colonising winter wheat grain. The cultivars significantly varied in the proportion of infected kernels by Fusarium spp. The growing season and type of crop rotation had a distinct effect on species composition of Fusarium communities colonising the grain inside. A trend of a higher percentage of the colonised kernels by the fungi in the grain from the systems using more fertilisers and pesticides as well as the buried straw could be perceived. The most frequent species in the grain were F. avenaceum, F. tricinctum and F. poae in 2008, and F. avenaceum, F. graminearum, F. tricinctum and F. poae in 2009 and 2010. The contents of deoxynivalenol and zearalenon in the grain were correlated with the percentage of kernels colonised by F. graminearum and were the highest in 2009 in the grain from the four-field crop rotation. The content of T-2/HT-2 toxins was the highest in 2010 in grain from the three-field crop rotation and it was correlated with the isolation frequency of F. langsethiae. PMID- 25705932 TI - Pickering emulsions for food applications: background, trends, and challenges. AB - Particle-stabilized emulsions, also referred to as Pickering emulsions, have garnered exponentially increasing interest in recent years. This has also led to the first food applications, although the number of related publications is still rather low. The involved stabilization mechanisms are fundamentally different as compared to conventional emulsifiers, which can be an asset in terms of emulsion stability. Even though most of the research on Pickering emulsions has been conducted on model systems, with inorganic solid particles, recent progress has been made on the utilization of food-grade or food-compatible organic particles for this purpose. This review reports the latest advances in that respect, including technical challenges, and discusses the potential benefits and drawbacks of using Pickering emulsions for food applications, as an alternative to conventional emulsifier-based systems. PMID- 25705933 TI - The Nutraceutical Bioavailability Classification Scheme: Classifying Nutraceuticals According to Factors Limiting their Oral Bioavailability. AB - The oral bioavailability of a health-promoting dietary component (nutraceutical) may be limited by various physicochemical and physiological phenomena: liberation from food matrices, solubility in gastrointestinal fluids, interaction with gastrointestinal components, chemical degradation or metabolism, and epithelium cell permeability. Nutraceutical bioavailability can therefore be improved by designing food matrices that control their bioaccessibility (B*), absorption (A*), and transformation (T*) within the gastrointestinal tract (GIT). This article reviews the major factors influencing the gastrointestinal fate of nutraceuticals, and then uses this information to develop a new scheme to classify the major factors limiting nutraceutical bioavailability: the nutraceutical bioavailability classification scheme (NuBACS). This new scheme is analogous to the biopharmaceutical classification scheme (BCS) used by the pharmaceutical industry to classify drug bioavailability, but it contains additional factors important for understanding nutraceutical bioavailability in foods. The article also highlights potential strategies for increasing the oral bioavailability of nutraceuticals based on their NuBACS designation (B*A*T*). PMID- 25705934 TI - Comparative analysis of intestinal tract models. AB - The human gut is a complex ecosystem occupied by a diverse microbial community. Modulation of this microbiota impacts health and disease. The definitive way to investigate the impact of dietary intervention on the gut microbiota is a human trial. However, human trials are expensive and can be difficult to control; thus, initial screening is desirable. Utilization of a range of in vitro and in vivo models means that useful information can be gathered prior to the necessity for human intervention. This review discusses the benefits and limitations of these approaches. PMID- 25705935 TI - Bacillus and other spore-forming genera: variations in responses and mechanisms for survival. AB - The ubiquity of Bacilli endospores in soils facilitates their easy transfer routes to other environments, including cleanrooms and low-biomass sites required by many industries such as food production and processing. A bacterial endospore is a metabolically dormant form of life that is much more resistant to heat, desiccation, lack of nutrients, exposure to UV and gamma radiation, organic chemicals, and oxidizing agents than is a vegetative cell. For example, the heat tolerance of endospores depends on multiple factors such as sporulation temperature, core dehydration, and the presence of minerals and small, acid soluble proteins (SASPs) in the core. This review describes our current understanding of the persistence mechanisms related to sporeformers' biochemical properties and discusses in detail spores' heat, radiation, and reactive chemical resistance. In addition, it discusses the impact of contamination with spores on many areas of human activity, spore adhesive properties, and biofilm contribution to resistance. PMID- 25705936 TI - Halter traction for cervical spine injuries - initial treatment in the district hospital. PMID- 25705937 TI - Advancing care, treatment for patients with mental illness. AB - Publication of Diagnostic and Statistical Manual of Mental Disorders, Third Edition and subsequent editions vastly increased innovation of psychiatric treatment and clarified diagnosis in a wide range of practice settings. Current treatment is now more objective, consistent, and effective than in days past. Our new challenge is to reach more patients with proportionately smaller mental health resources. As we see media headlines of the tragedies of undiagnosed and untreated mental illness, this edition's articles address the pressing needs of children and adolescents, patients with chronic pain, and our military veterans. These are cause for careful consideration and risk for all physicians, not only psychiatrists. The articles in the Symposium on Mental Health will increase awareness and guide treatment and management of frequently seen conditions in primary care and general settings. The intersection of public and private treatment care settings may further complicate the sensitive and timely referral of patients as access to care necessarily adapts to available resources. PMID- 25705938 TI - Accessing the public mental health system in Texas. PMID- 25705939 TI - Behavioral Aspects of the Pre-transplant Assessment. PMID- 25705940 TI - Identification of mental disorders with potential for violence in adolescents and young adults. PMID- 25705941 TI - Identification and management of suicide risk in u.s. Military veterans. PMID- 25705942 TI - Opioid addiction screening tools for patients with chronic noncancer pain. PMID- 25705943 TI - Inadvertent stigmatization of mental disorders in a primary care setting. PMID- 25705944 TI - Pulmonary rehabilitation for chronic obstructive pulmonary disease. AB - BACKGROUND: Widespread application of pulmonary rehabilitation (also known as respiratory rehabilitation) in chronic obstructive pulmonary disease (COPD) should be preceded by demonstrable improvements in function (health-related quality of life, functional and maximal exercise capacity) attributable to the programmes. This review updates the review reported in 2006. OBJECTIVES: To compare the effects of pulmonary rehabilitation versus usual care on health related quality of life and functional and maximal exercise capacity in persons with COPD. SEARCH METHODS: We identified additional randomised controlled trials (RCTs) from the Cochrane Airways Group Specialised Register. Searches were current as of March 2014. SELECTION CRITERIA: We selected RCTs of pulmonary rehabilitation in patients with COPD in which health-related quality of life (HRQoL) and/or functional (FEC) or maximal (MEC) exercise capacity were measured. We defined 'pulmonary rehabilitation' as exercise training for at least four weeks with or without education and/or psychological support. We defined 'usual care' as conventional care in which the control group was not given education or any form of additional intervention. We considered participants in the following situations to be in receipt of usual care: only verbal advice was given without additional education; and medication was altered or optimised to what was considered best practice at the start of the trial for all participants. DATA COLLECTION AND ANALYSIS: We calculated mean differences (MDs) using a random effects model. We requested missing data from the authors of the primary study. We used standard methods as recommended by The Cochrane Collaboration. MAIN RESULTS: Along with the 31 RCTs included in the previous version (2006), we included 34 additional RCTs in this update, resulting in a total of 65 RCTs involving 3822 participants for inclusion in the meta-analysis.We noted no significant demographic differences at baseline between members of the intervention group and those who received usual care. For the pulmonary rehabilitation group, the mean forced expiratory volume at one second (FEV1) was 39.2% predicted, and for the usual care group 36.4%; mean age was 62.4 years and 62.5 years, respectively. The gender mix in both groups was around two males for each female. A total of 41 of the pulmonary rehabilitation programmes were hospital based (inpatient or outpatient), 23 were community based (at community centres or in individual homes) and one study had both a hospital component and a community component. Most programmes were of 12 weeks' or eight weeks' duration with an overall range of four weeks to 52 weeks.The nature of the intervention made it impossible for investigators to blind participants or those delivering the programme. In addition, it was unclear from most early studies whether allocation concealment was undertaken; along with the high attrition rates reported by several studies, this impacted the overall risk of bias.We found statistically significant improvement for all included outcomes. In four important domains of quality of life (QoL) (Chronic Respiratory Questionnaire (CRQ) scores for dyspnoea, fatigue, emotional function and mastery), the effect was larger than the minimal clinically important difference (MCID) of 0.5 units (dyspnoea: MD 0.79, 95% confidence interval (CI) 0.56 to 1.03; N = 1283; studies = 19; moderate-quality evidence; fatigue: MD 0.68, 95% CI 0.45 to 0.92; N = 1291; studies = 19; low-quality evidence; emotional function: MD 0.56, 95% CI 0.34 to 0.78; N = 1291; studies = 19; mastery: MD 0.71, 95% CI 0.47 to 0.95; N = 1212; studies = 19; low-quality evidence). Statistically significant improvements were noted in all domains of the St. George's Respiratory Questionnaire (SGRQ), and improvement in total score was better than 4 units (MD -6.89, 95% CI -9.26 to 4.52; N = 1146; studies = 19; low-quality evidence). Sensitivity analysis using the trials at lower risk of bias yielded a similar estimate of the treatment effect (MD -5.15, 95% CI -7.95 to -2.36; N = 572; studies = 7).Both functional exercise and maximal exercise showed statistically significant improvement. Researchers reported an increase in maximal exercise capacity (mean Wmax (W)) in participants allocated to pulmonary rehabilitation compared with usual care (MD 6.77, 95% CI 1.89 to 11.65; N = 779; studies = 16). The common effect size exceeded the MCID (4 watts) proposed by Puhan 2011(b). In relation to functional exercise capacity, the six-minute walk distance mean treatment effect was greater than the threshold of clinical significance (MD 43.93, 95% CI 32.64 to 55.21; participants = 1879; studies = 38).The subgroup analysis, which compared hospital based programmes versus community-based programmes, provided evidence of a significant difference in treatment effect between subgroups for all domains of the CRQ, with higher mean values, on average, in the hospital-based pulmonary rehabilitation group than in the community-based group. The SGRQ did not reveal this difference. Subgroup analysis performed to look at the complexity of the pulmonary rehabilitation programme provided no evidence of a significant difference in treatment effect between subgroups that received exercise only and those that received exercise combined with more complex interventions. However, both subgroup analyses could be confounded and should be interpreted with caution. AUTHORS' CONCLUSIONS: Pulmonary rehabilitation relieves dyspnoea and fatigue, improves emotional function and enhances the sense of control that individuals have over their condition. These improvements are moderately large and clinically significant. Rehabilitation serves as an important component of the management of COPD and is beneficial in improving health-related quality of life and exercise capacity. It is our opinion that additional RCTs comparing pulmonary rehabilitation and conventional care in COPD are not warranted. Future research studies should focus on identifying which components of pulmonary rehabilitation are essential, its ideal length and location, the degree of supervision and intensity of training required and how long treatment effects persist. This endeavour is important in the light of the new subgroup analysis, which showed a difference in treatment effect on the CRQ between hospital-based and community-based programmes but no difference between exercise only and more complex pulmonary rehabilitation programmes. PMID- 25705945 TI - Nailing it: promoting nail procedural training in residency and beyond. PMID- 25705946 TI - Eccrine angiomatous hamartoma: successful treatment with pulsed dual-wavelength sequential 595- and 1,064-nm laser. PMID- 25705947 TI - A prospective multicenter pilot study of the safety and efficacy of microfocused ultrasound with visualization for improving lines and wrinkles of the decollete. AB - BACKGROUND: A previous pilot study demonstrated microfocused ultrasound with visualization (MFU-V) to lift and tighten the decollete produced significant and durable aesthetic improvements. OBJECTIVE: To further evaluate the safety and effectiveness of MFU-V for improving lines and wrinkles of the decollete in a larger patient population. MATERIALS AND METHODS: Healthy women with moderate-to severe decollete skin lines and wrinkles were enrolled. After obtaining digital images, MFU-V was administered using 3 transducers emitting ultrasound at frequencies of 4 MHz and a focal depth of 4.5 mm, 7 MHz/3.0 mm, and 10 MHz/1.5 mm. During the procedure, 280 lines of discrete thermal coagulative points 25 mm long and 2 to 3 mm apart were applied to the treatment area. Additional imaging for masked assessments and live assessments were completed at 90 and 180 days. RESULTS: Among the evaluable subjects, 77 (66.4%) demonstrated aesthetic improvement at 180 days based on blinded assessments. Approximately, 75% and 65% of treated subjects demonstrated some degree of improvement at 90 and 180 days, respectively, and most were satisfied with treatment outcomes. Adverse events were generally mild. CONCLUSION: A single MFU-V treatment provided significant aesthetic improvement for moderate-to-severe decollete lines and wrinkles for at least the 180-day duration of the study. PMID- 25705948 TI - Not just nail polish: inexpensive reusable model for practicing nail procedures. PMID- 25705949 TI - A review of hand-held, home-use cosmetic laser and light devices. AB - BACKGROUND: As the market for home-use light-based and laser-based devices grows, consumers will increasingly seek advice from dermatologists regarding their safety and efficacy profiles. OBJECTIVE: To review the literature on home-use hand-held devices for various dermatologic conditions. To educate dermatologists about commercially available products their patients may be using. MATERIALS AND METHODS: A comprehensive literature search was conducted to determine the safety and efficacy of home-use laser and light devices for the treatment of the following: hair removal, acne, photoaging, scars, psoriasis, and hair regrowth. In addition, a thorough search of the Food and Drug Administration's (FDA) radiation-emitting electronic products' database was performed; by searching specific product codes, all hand-held devices that are FDA-approved for marketing in the United States were identified. RESULTS: Of the various home-use devices reviewed, intense pulsed light (IPL) for hair removal and light-emitting diode (LED) for treatment of acne have the most published data. Although the literature shows modest results for home-use IPL and LED, small sample sizes and short follow-up periods limit interpretation. CONCLUSION: There is a paucity of randomized, double-blind controlled trials to support the use of home-use laser and light devices; smaller, uncontrolled industry-sponsored single-center studies suggest that some of these devices may have modest results. PMID- 25705950 TI - Consensus statement regarding storage and reuse of previously reconstituted neuromodulators. AB - BACKGROUND: Legacy recommendations suggest that vials of botulinum toxin be used within 24 hours of reconstitution and in a single patient. Current standard of care is consistent with storage after reconstitution and use of a single vial for several patients. OBJECTIVE: To develop expert consensus regarding the effectiveness and safety of storage and reuse of botulinum toxin. MATERIALS AND METHODS: The American Society for Dermatologic Surgery authorized a task force of content experts to review the literature and provide guidance. Data extraction was followed by clinical question review, a consensus Delphi process, and validation of the results by peer review. RESULTS: After 2 rounds of Delphi process, the task force concluded by unanimous consensus and with the highest level of confidence that a vial of toxin reconstituted appropriately can, for facial muscle indications, be (1) refrigerated or refrozen for at least 4 weeks before injection without significant risk for contamination or decreased effectiveness and (2) used to treat multiple patients, assuming appropriate handling. CONCLUSION: The standard of care, which allows for use of botulinum toxin more than 24 hours after reconstitution and in more than 1 patient per vial, is appropriate and consistent with the safe and effective practice of medicine. PMID- 25705951 TI - Involuntary movements during periocular reconstruction secondary to lorazepam. PMID- 25705952 TI - A randomized controlled pilot study on ablative fractional CO2 laser for consecutive patients presenting with various scar types. AB - BACKGROUND: Although ablative fractional laser is the gold standard for acne scars, evidence is still lacking for other types of scars. OBJECTIVE: To evaluate the efficacy and safety of the ablative fractional 10,600-nm CO2 laser in the treatment of various scar types. MATERIALS AND METHODS: The authors performed an intraindividual single-blinded randomized controlled split-lesion trial. Adult patients received 3 laser treatments at 8-week intervals for scars existing at least 1 year. Primary end points were the Physician Global Assessment (PhGA) and the assessment of adverse effects. RESULTS: Twenty-five consecutive patients with atrophic (52%) or hypertrophic (48%) scars located mainly on the body (84%) were included in the study. At 6-month follow-up of 21 patients, the PhGA showed no statistically significant difference between the treated and untreated side of the scar (p = .70). Persistent erythema, postinflammatory pigmentary changes, and scarring after ulceration (n = 3) were observed as side effects. CONCLUSION: In this trial involving various types of scars, the efficacy of ablative fractional CO2 laser could not be confirmed. The authors presume that different types of scars have a different response to treatment. Future studies should aim to identify the type of scars that may benefit from ablative fractional laser therapy. PMID- 25705953 TI - A comparison of reticle size to determine follicular unit density in hair restoration. PMID- 25705954 TI - Trends in Mohs surgery from 1995 to 2010: an analysis of nationally representative data. AB - BACKGROUND: In Mohs surgery, the histologic verification of tumor removal results in a lower rate of cancer recurrence compared with simple excision. Factors associated with the increased use of Mohs surgery are not well characterized. OBJECTIVE: To investigate trends in the utilization of Mohs surgery. METHODS AND MATERIALS: The authors performed a retrospective analysis of the National Ambulatory Medical Care Survey for patient visits associated with Mohs surgery from 1995 to 2010. The authors assessed percentage of skin cancers managed with Mohs surgery, the most common locations of skin cancer managed with Mohs surgery, and patient demographics associated with Mohs surgery. RESULTS: Although there was an upward trend in the use of Mohs surgery (p = .004), a low percentage of skin cancers (average of 10.0%) were managed with this technique. When the surgical location was specified, Mohs surgery was most commonly used for the head and neck region. Demographic groups receiving Mohs surgery at higher rates included African Americans (44.2%) and patients aged 75 to 84 years (12.4%). CONCLUSION: There has been an upward trend in the use of Mohs surgery, particularly in the head and neck region where tissue preservation is essential. PMID- 25705955 TI - On the Use of the Unusual Green Pigment Brochantite (Cu4(SO4)(OH)6) in the 16th Century Portuguese-Flemish Paintings Attributed to The Master Frei Carlos Workshop. AB - This paper reports an unusual green pigment, brochantite (Cu4(SO4)(OH)6), on 16th century Portuguese-Flemish paintings, attributed to the Master Frei Carlos workshop. This green mineral is usually identified as an impurity or alteration product in the green pigments verdigris (Cu(CH3COO)2 nCu(OH)2) or malachite (CuCO3 Cu(OH)2). However, after thorough investigation with a broad range of analytical techniques, it became clear that, in this case, brochantite was applied as a pigment. The abundance, pigment granulometry, and pigment morphology suggest intentional use by this Portuguese-Flemish Master as a natural pigment rather than its accidental use as an alteration product. This seems to be a distinguishable feature to other painters (Flemish and Portuguese) working in Portugal at the beginning of the 16th century. The multi-analytical study of these easel paintings was first performed by physical imaging techniques and material characterization was carried out by optical microscopy, micro-Fourier transform infrared-spectroscopy, micro-Raman spectroscopy, scanning electron microscopy coupled with energy dispersive X-ray spectrometry, and micro-X-ray diffraction analysis (XRD). PMID- 25705956 TI - The effect of implant placement on sacroiliac joint range of motion: posterior versus transarticular. AB - STUDY DESIGN: A human cadaveric biomechanical study of 2 sacroiliac (SI) joint fusion implant placement techniques. OBJECTIVE: To evaluate and compare the biomechanical properties of 2 implant placement techniques for SI joint fusion. SUMMARY OF BACKGROUND DATA: Minimally invasive placement of SI joint fusion implants is a potential treatment of SI joint disruptions and degenerative sacroiliitis. Biomechanical studies of screw fixation within the sacrum have shown that placement and trajectory are important in the overall stability of the implant. Although clinical results have been promising, there is the possibility that a more optimal arrangement of implants may exist. METHODS: Bilateral SI joints in 7 cadaveric lumbopelvic (L4-pelvis) specimens were tested using a single leg stance model. All joints were tested intact, pubic symphysis sectioned, and treated (3 SI joint fusion implants). The implants were laterally placed using either a posterior or transarticular placement technique. The posterior technique places the implants inline in the inlet view, parallel in the outlet view, and parallel to the posterior sacral body in the lateral view. The transarticular technique places all implants across the articular portion of the SI joint. For all conditions, the range of motion was tested in flexion extension, lateral bending, and axial rotation. RESULTS: The posterior technique significantly reduced the range of motion in flexion-extension, lateral bending, and axial rotation by 27% +/- 24% (P = 0.024), 28% +/- 26% (P = 0.028), and 32% +/- 21% (P = 0.008), respectively. The transarticular technique significantly reduced the range of motion in flexion-extension, lateral bending, and axial rotation by 41% +/- 31% (P = 0.013), 36% +/- 38% (P = 0.049), and 36% +/- 28% (P = 0.015), respectively. No significant differences were detected between the posterior and transarticular placement techniques (P > 0.25). CONCLUSION: Posterior and transarticular placement of SI joint fusion implants stabilized the SI joint in flexion-extension, lateral bending, and axial rotation. LEVEL OF EVIDENCE: N/A. PMID- 25705957 TI - Good clinical outcomes and fusion rate of facet fusion with a percutaneous pedicle screw system for degenerative lumbar spondylolisthesis: minimally invasive evolution of posterolateral fusion. AB - STUDY DESIGN: A retrospective clinical and radiographical study. OBJECTIVE: To assess the clinical outcomes and fusion rate of facet fusion (FF) for degenerative lumbar spondylolisthesis (DLS). SUMMARY OF BACKGROUND DATA: On the basis of the long-term clinical and radiological follow-up studies of posterolateral fusion (PLF)-that is, intertransverse process fusion with pedicle screw instrumentation-for DLS, we recognized that FF alone would be sufficient for spinal fusion. METHODS: Eighty-eight patients who underwent FF for single level DLS were retrospectively reviewed after at least 1 year of follow-up. The control group comprised 21 patients who underwent conventional PLF. The operative technique involved a 5-cm midline skin incision, bilateral laminar fenestration, and FF with autologous bone harvested from the spinous process. Percutaneous pedicle screws were then inserted through the fascia. The fusion rate of FF was evaluated using computed tomography, and the change in the range of motion at the fused level was assessed on flexion-extension lateral radiographs. The Japanese Orthopaedic Association Back Pain Evaluation Questionnaire was used to assess the therapeutic effectiveness of FF. The results of the Roland-Morris Disability Questionnaire and the visual analogue scales of low back pain, buttock and lower limb pain, and buttock and lower limb numbness were evaluated. RESULTS: The fusion rate was 88.6% (78/88 cases). Among 10 patients with inadequate fusion, the average range of motion significantly decreased from 14.4 degrees preoperatively to 4.3 degrees postoperatively. The Japanese Orthopaedic Association Back Pain Evaluation Questionnaire category scores demonstrated therapeutic effectiveness in 93.0% of the patients for walking ability and in 73.0% of the patients for low back pain. The average preoperative scores of the Roland-Morris Disability Questionnaire and the visual analogue scales of low back pain, buttock and lower limb pain, and buttock and lower limb numbness were significantly reduced postoperatively in the FF group. CONCLUSION: FF achieved good clinical outcomes that were superior to those of conventional PLF with a comparable fusion rate. It is useful for managing DLS and is a minimally invasive evolution of PLF. LEVEL OF EVIDENCE: 3. PMID- 25705958 TI - A Randomized, Double-blind, Placebo-Controlled Crossover Trial of Oxymorphone Hydrochloride and Propoxyphene/Acetaminophen Combination for the Treatment of Neurogenic Claudication Associated With Lumbar Spinal Stenosis. AB - STUDY DESIGN: Randomized, double-blind, placebo-controlled, single-dose crossover study. OBJECTIVE: To test the analgesic efficacy of oxymorphone hydrochloride (OH) and propoxyphene/acetaminophen (PA) for patients with neurogenic claudication associated with lumbar spinal stenosis. SUMMARY OF BACKGROUND DATA: Although opioids are often prescribed for neurogenic claudication, no randomized controlled studies support their efficacy for this condition. Patients with neurogenic claudication are generally excluded from clinical trials or included with patients who have nonspecific chronic low back pain, yielding a heterogeneous study population with very different pathophysiologies and clinical presentations. METHODS: Participants received a single dose of each of the 3 treatments in random order. Treatments were separated by at least 3-day washout periods. The primary outcome variable was the time to first treadmill walking induced moderate pain (>=4 out of 10 on a Numeric Rating Scale) (Tfirst) assessed 90 minutes after treatment administration. Secondary outcome measures included patient global assessment of low back pain, Roland-Morris Disability Questionnaire, Modified Brief Pain Inventory-Short Form, Oswestry Disability Index, and Swiss Spinal Stenosis Questionnaire. RESULTS: The study was prematurely terminated because of the removal of PA from the US market. Twenty four patients were randomized; 21 completed all 3 treatment periods. There were no significant differences among the treatment groups with respect to the median Tfirst (OH-placebo: median [98.3% confidence limits]=-0.25 min [-6.54, 5.00]; PA placebo: 0.02 min [-7.65, 4.90]; OH-PA: -0.27 min [-5.56, 6.66]). CONCLUSION: This trial failed to demonstrate a benefit of OH or PA in patients experiencing neurogenic claudication. Considering the potential negative side effects of chronic opioid use, additional research is necessary to evaluate the efficacy of sustained opioid treatment specifically for neurogenic claudication. LEVEL OF EVIDENCE: 2. PMID- 25705959 TI - Adjacent segment pathology requiring reoperation after anterior cervical arthrodesis: the influence of smoking, sex, and number of operated levels. AB - STUDY DESIGN: A retrospective study. OBJECTIVE: The purpose of this study was to determine, using survivorship analysis, the rate of adjacent segment pathology (ASP) development and to identify the risk factors for reoperation. SUMMARY OF BACKGROUND DATA: The study of Hilibrand defined "adjacent segment disease" as symptomatic radiculopathy or myelopathy due to an adjacent segment documented on 2 consecutive office visits. In addition to being somewhat subjective, their criterion is not as practical as identifying the rate of adjacent pathology by the need for reoperation. METHODS: This was a retrospective analysis of 1038 consecutive patients who underwent primary anterior cervical spine arthrodesis for radiculopathy and/or myelopathy by 1 surgeon. Annual incidence and prevalence of ASP requiring surgery were calculated and survivorship was determined. We used the Cox regression for risk factor analysis. RESULTS: Secondary surgery on adjacent segments occurred at a relatively constant rate of 2.4% per year (95% confidence interval, 1.9-3.0). The Kaplan-Meier analysis predicted that 22.2% of patients would need reoperation at adjacent segments by 10 years postoperatively. Factors increasing the risk were smoking, female sex, and the number of arthrodesis segments. One or 2-segment arthrodesis had an 1.8 times greater risk than arthrodesis involving 3 or more segments. Age, neurological diagnosis, diabetes, Klippel-Feil syndrome, and noncontiguous segmental-type ossification of posterior longitudinal ligament were not significant risks. CONCLUSION: Patients treated with 1- or 2-segment anterior cervical arthrodesis are more likely to develop ASP than those treated with arthrodesis involving 3 or more segments. Smokers and women had a higher ASP reoperation rate. Our series, the largest in the literature, predicts that 22.2% of patients will require reoperation for ASP within 10 years, substantially higher than the Hilibrand study. LEVEL OF EVIDENCE: 3. PMID- 25705960 TI - Publication rate of paper presentations from the Cervical Spine Research Society annual meeting. AB - STUDY DESIGN: Observational study. OBJECTIVE: To evaluate the publication rate of podium presentations from the Cervical Spine Research Society (CSRS) annual meeting and to evaluate the publication rate of award-winning papers from the CSRS annual meeting. SUMMARY OF BACKGROUND DATA: Although various publication rates from Orthopaedic meetings have been reported, the publication rates from the CSRS annual meetings are not known. METHODS: Paper presentations and award winning papers from the 2007 to 2011 annual CSRS meeting were identified. Using PubMed, we searched for publications with a title of the paper presentations or containing the same authors. The publication rate of the award-winning papers was evaluated in the same manner. We collected the title of the journals the papers were published in and identified the most common journals. RESULTS: Of the 321 podium presentations, 211 were published (65.7%). The publication rate was highest for 2007 abstracts (77.8%), followed by 2008 and 2011 (68.5%) and lowest for 2009 (58.5%). Of the 45 award-winning papers, 35 were published (77.8%), which was significantly different compared with the non-award-winning papers (63.8%, P=0.046). Spine, The Spine Journal, and Journal of Neurosurgery: Spine were the most common publication journals for the papers. CONCLUSION: In one of the first studies evaluating the publication rate of podium presentation from the CSRS annual meetings, we found an overall publication rate of 65.8% and 77.8% for award-winning papers. This high publication rate indicates the quality of papers presented at the CSRS annual meeting. LEVEL OF EVIDENCE: 4. PMID- 25705961 TI - Novel Protamine-Based Polyelectrolyte Carrier Enhances Low-Dose rhBMP-2 in Posterolateral Spinal Fusion. AB - STUDY DESIGN: A rodent posterolateral spinal fusion model. OBJECTIVE: This study evaluated a protamine-based polyelectrolyte complex (PEC) developed to use heparin in enhancing the biological activity of low-dose recombinant human bone morphogenetic protein-2 (rhBMP-2) in spinal fusion. SUMMARY OF BACKGROUND DATA: rhBMP-2 is commonly regarded as the most potent bone-inducing molecule. However, poor pharmacokinetics and short in vivo half-life means that large amounts of the bioactive growth factor are required for consistent clinical outcomes. This has been associated with a number of adverse tissue reactions including seroma and heterotopic ossification. Glycosaminoglycans including heparin are known to stabilize rhBMP-2 bioactivity. Previous studies with poly-L-lysine (PLL) and heparin-based PEC carriers amplified the therapeutic efficacy of low-dose BMP-2. However, questions remained on the eventual clinical applicability of relatively cytotoxic PLL. In the present study, a protamine-based PEC carrier was designed to further enhance the safety and efficacy of BMP-2 by delivering lower dose within the therapeutic window. METHODS: A polyelectrolyte shell was deposited on the surface of alginate microbead templates using the polycation (protamine)/polyanion (heparin) layer-by-layer polyelectrolyte self-assembly protocol. rhBMP-2 was loaded onto the outermost layer via heparin affinity binding. Loading and release of rhBMP-2 were evaluated in vitro. The bone inductive ability of 20-fold reduction of rhBMP-2 with the different carrier vehicle was evaluated using a posterolateral spinal fusion model in rats. RESULTS: In vitro uptake and release analysis, protamine-based PEC showed higher uptake and significantly enhanced control release than PLL-based PEC (P < 0.05). In vivo implantation with protamine-based and PLL-based PEC showed better fusion performances than absorbable collagen sponge-delivered same dose of rhBMP-2, and negative control group through manual palpation, micro-computed tomography, and histological analyses. CONCLUSION: Solid posterolateral spinal fusion was achieved with 20-fold reduction of rhBMP-2 when delivered using protamine-based PEC carrier in the rat posterolateral spinal fusion model. LEVEL OF EVIDENCE: N/A. PMID- 25705962 TI - Recruitment of compensatory mechanisms in sagittal spinal malalignment is age and regional deformity dependent: a full-standing axis analysis of key radiographical parameters. AB - STUDY DESIGN: Retrospective review, full-body radiographical analysis of adult patients with sagittal spinal malalignment (SSM). OBJECTIVE: To investigate the compensatory mechanisms involved in the sagittal plane of the body after progressive spinal sagittal malalignment and to study the impact of age on compensatory mechanism recruitment. SUMMARY OF BACKGROUND DATA: Patients with SSM recruit compensatory mechanisms to maintain erect posture and horizontal gaze. Mechanisms such as pelvic retroversion, knee flexion, and pelvic shift have been proposed, but how they contribute and how age affects their recruitment are poorly understood. METHODS: Retrospective review of adult patients with SSM who underwent full-standing axis stereoradiography (EOS imaging). Radiographical measurements were performed with Surgimap. Patients were categorized on the basis of the mismatch between pelvic incidence (PI) and lumbar lordosis (PI-LL). Compensatory mechanisms were normalized to each patient's PI-LL and compared by mismatch groups. In addition, patients were subcategorized into 2 age groups (>=65 and <65 yr) and compared within the same groups of mismatch. RESULTS: A total of 161 patients with a mean age of 62.93 +/- 12.8 years. Mean sagittal vertical axis = 62.3 +/- 61.5 mm; pelvic tilt (PT) = 29.2 degrees +/- 8.4 degrees ; and PI-LL = 21.0 degrees +/- 14.9 degrees . Mismatch groups were as follows: group 1: PI-LL 0 degrees -10 degrees ; group 2: 10 degrees -20 degrees ; group 3: 20 degrees -30 degrees ; and group 4: >30 degrees . There were significant differences between all groups with regard to thoracic kyphosis (TK), PT, knee flexion angle, and pelvic shift by analysis of variance (P < 0.001). As PI-LL increased, TK and PT contribution to the compensation cascade decreased and knee flexion angle and pelvic shift contribution increased. Patients with PI-LL of more than 30 degrees who were older had significantly less PT and more TK than patients with similar PI-LL who were younger. CONCLUSION: Spinopelvic mismatch is an important driver in SSM. Pelvic retroversion and flattening of TK (reduction) become exhausted with increasing mismatch, at which point there seems to be a steady transfer of compensation toward significant participation of the lower limbs. Further analysis suggests differential recruitment of these compensatory mechanisms based upon age. LEVEL OF EVIDENCE: 3. PMID- 25705963 TI - Effects of Therapeutic Hypothermia on Apoptosis and Autophagy After Spinal Cord Injury in Rats. AB - STUDY DESIGN: Animal study. OBJECTIVE: To further investigate the effects of therapeutic hypothermia (TH), the present study compared autophagy and apoptosis after treatment with either therapeutic moderate systemic hypothermia or methylprednisolone sodium succinate (MP) in a rat model of acute spinal cord injury (SCI). SUMMARY OF BACKGROUND DATA: The neuroprotective effects of TH have recently become an important topic in the field of SCI research. METHODS: All rats were subjected to a 25-g/cm spinal cord contusion over the ninth thoracic vertebrae. After the induction of SCI, the control group did not receive any further treatment, TH group immediately received moderate systemic hypothermia for 4 hours, and MP group was administered high-dose MP. The rats were killed either 2 or 7 days after SCI, and the injured spinal cord tissues were obtained. Apoptosis and autophagy were assessed by immunohistochemical analyses and Western blot analyses. In addition, the microarchitecture of the autophagosomes was evaluated using transmission electron microscopy, and the motor activity of the rats was assessed using the Basso-Beattie-Bresnahan (BBB) locomotor rating scale. RESULTS: Compared with controls, there was a significant reduction in the expression levels of cleaved caspase-8, -9, and -3 in the TH- and MP-treated groups 2 days after SCI. Moreover, compared with the control group, the expression of LC3II and Beclin-1 exhibited a significant decrease on day 2 after treatment with TH. The numbers of transferase dUTP nicked-end labeling and LC3 positive cells were significantly lower on days 2 and 7. The Basso-Beattie Bresnahan ratings were significantly higher 6 weeks after SCI in both the TH- and MP-treated groups than in the control group. CONCLUSION: Both TH and MP have neuroprotective effects on injured spinal cord tissues via the inhibition of apoptosis and autophagy. Thus, the application of moderate systemic hypothermia may be a useful treatment modality after acute SCI. LEVEL OF EVIDENCE: N/A. PMID- 25705964 TI - Does a preoperative cognitive-behavioral intervention affect disability, pain behavior, pain, and return to work the first year after lumbar spinal fusion surgery? AB - STUDY DESIGN: A randomized clinical trial including 90 patients. OBJECTIVE: To examine the effect of a preoperative cognitive-behavioral intervention (CBT) for patients undergoing lumbar spinal fusion (LSF) surgery. SUMMARY OF BACKGROUND DATA: Few published studies have looked at the potential of rehabilitation to improve outcomes after LSF. Rehabilitation programs using CBT are recommended. Furthermore, initiating interventions preoperatively seems beneficial, but only limited data exist in the field of spine surgery. METHODS: Patients with degenerative disc disease or spondylolisthesis undergoing LSF were randomized to usual care (control group) or preoperative CBT and usual care (CBT group). Primary outcome was change in Oswestry Disability Index from baseline to 1-year follow-up. Secondary outcomes were catastrophizing, fear avoidance belief, work status, and back and leg pain. RESULTS: At 1-year follow-up, there was no statistically significant difference between the CBT group and the control group in Oswestry Disability Index score (P = 0.082). However, the CBT group had achieved a significant reduction of -15 points (-26; -4) already at 3 months (between group difference P = 0.003), and this reduction was maintained throughout the year. There were no differences between groups at 1-year follow-up with regard to any of the secondary outcomes. CONCLUSION: Participating in a preoperative CBT intervention in addition to usual care did not produce better outcomes at 1-year follow-up for patients undergoing LSF. Although the reduction in disability was achieved much faster in the CBT group, resulting in a significant difference between groups already 3 months after surgery, it did not translate into a faster return to work. Our findings support the need for further research into the use of targeted rehabilitation interventions among patients with elevated levels of catastrophizing and fear avoidance beliefs. LEVEL OF EVIDENCE: 2. PMID- 25705967 TI - Neuromuscular profile of top-level women kayakers assessed through tensiomyography. AB - The aim of this study is to assess the contractile properties and the lateral symmetry percentages of trapezius, deltoideus, and latissimus dorsi muscles of top-level female kayakers [FKs]) and to determine the gender influence and the specific training in the assessed parameters. Twenty-one volunteers participated in this study, who were stratified into 3 groups: 7 top-level FKs, 4 top-level men kayakers (MKs), and 10 physically active female non-kayakers (FNKs), and they have been assessed through tensiomyography (TMG). Reliability of the TMG assessment was tested by calculating intraclass correlation coefficient reliabilities, and all the values obtained were over 0.8. A t-test (p <= 0.05), a 1-factor analysis of variance (p <= 0.01), and Cohen's d effect sizes were implemented, and we used the algorithm of TMG-BMC tensiomyography to determine the lateral symmetry percentages. The results show that FKs and MKs differ only in the lower reaction time that FKs obtain when contracting their trapezius muscle (19.5%; p = 0.008; d = 2.13). However, FKs present >34.4% of time contraction (p = 0.003; d = 1.8) in their latissimus dorsi muscle than FNKs. Also, FKs have >123.7% of time contraction (p = 0.009; d = 1.5), >11.3% of time reaction (p = 0.01; d = 1.5), >34.8% of maximum radial displacement (p = 0.01; d = 1.35), and <20.4% of lateral symmetry (p = 0.006; d = 1.6) in their trapezius than FNKs. In conclusion, the specific training seems to have a significant influence on the FK's neuromuscular profile compared with FNKs. PMID- 25705965 TI - Inference of domestication history and differentiation between early- and late flowering varieties in pearl millet. AB - Pearl millet (Pennisetum glaucum) is a staple crop in Sahelian Africa. Farmers usually grow varieties with different cycle lengths and complementary functions in Sahelian agrosystems. Both the level of genetic differentiation of these varieties and the domestication history of pearl millet have been poorly studied. We investigated the neutral genetic diversity and population genetic structure of early- and late-flowering domesticated and wild pearl millet populations using 18 microsatellite loci and 8 nucleotide sequences. Strikingly, early- and late flowering domesticated varieties were not differentiated over their whole distribution area, despite a clear difference in their isolation-by-distance pattern. Conversely, our data brought evidence for two well-differentiated genetic pools in wild pearl millet, allowing us to test scenarios with different numbers and origins of domestication using approximate Bayesian computation (ABC). The ABC analysis showed the likely existence of asymmetric migration between wild and domesticated populations. The model choice procedure indicated that a single domestication from the eastern wild populations was the more likely scenario to explain the polymorphism patterns observed in cultivated pearl millet. PMID- 25705966 TI - Robust and fragile aspects of cortical blood flow in relation to the underlying angioarchitecture. AB - We review the organizational principles of the cortical vasculature and the underlying patterns of blood flow under normal conditions and in response to occlusion of single vessels. The cortex is sourced by a two-dimensional network of pial arterioles that feeds a three-dimensional network of subsurface microvessels in close proximity to neurons and glia. Blood flow within the surface and subsurface networks is largely insensitive to occlusion of a single vessel within either network. However, the penetrating arterioles that connect the pial network to the subsurface network are bottlenecks to flow; occlusion of even a single penetrating arteriole results in the death of a 500 MUm diameter cylinder of cortical tissue despite the potential for collateral flow through microvessels. This pattern of flow is consistent with that calculated from a full reconstruction of the angioarchitecture. Conceptually, collateral flow is insufficient to compensate for the occlusion of a penetrating arteriole because penetrating venules act as shunts of blood that flows through collaterals. Future directions that stem from the analysis of the angioarchitecture concern cellular level issues, in particular the regulation of blood flow within the subsurface microvascular network, and system-level issues, in particular the role of penetrating arteriole occlusions in human cognitive impairment. PMID- 25705968 TI - Parental education predicts change in intelligence quotient after childhood epilepsy surgery. AB - OBJECTIVE: To know whether change in the intelligence quotient (IQ) of children who undergo epilepsy surgery is associated with the educational level of their parents. METHODS: Retrospective analysis of data obtained from a cohort of children who underwent epilepsy surgery between January 1996 and September 2010. We performed simple and multiple regression analyses to identify predictors associated with IQ change after surgery. In addition to parental education, six variables previously demonstrated to be associated with IQ change after surgery were included as predictors: age at surgery, duration of epilepsy, etiology, presurgical IQ, reduction of antiepileptic drugs, and seizure freedom. We used delta IQ (IQ 2 years after surgery minus IQ shortly before surgery) as the primary outcome variable, but also performed analyses with pre- and postsurgical IQ as outcome variables to support our findings. To validate the results we performed simple regression analysis with parental education as the predictor in specific subgroups. RESULTS: The sample for regression analysis included 118 children (60 male; median age at surgery 9.73 years). Parental education was significantly associated with delta IQ in simple regression analysis (p = 0.004), and also contributed significantly to postsurgical IQ in multiple regression analysis (p = 0.008). Additional analyses demonstrated that parental education made a unique contribution to prediction of delta IQ, that is, it could not be replaced by the illness-related variables. Subgroup analyses confirmed the association of parental education with IQ change after surgery for most groups. SIGNIFICANCE: Children whose parents had higher education demonstrate on average a greater increase in IQ after surgery and a higher postsurgical--but not presurgical--IQ than children whose parents completed at most lower secondary education. Parental education--and perhaps other environmental variables--should be considered in the prognosis of cognitive function after childhood epilepsy surgery. PMID- 25705969 TI - Timing recalibration in childhood Tourette syndrome associated with persistent pimozide treatment. AB - In this study, we have tested the effects of the dopamine D2 receptor blocker pimozide on timing performance in patients with Tourette syndrome (TS). Nine children with TS were tested off-medication and following 3 months of daily treatment with pimozide. Subjects completed a time reproduction and a time production task using supra-second temporal intervals. We show that pimozide improves motor timing performance by reducing the patients' variability in reproducing the duration of visual stimuli. On the other hand, this medication has no effect on the reproduction accuracy and on both variability and accuracy of the performance on the time production task. Our results suggest that pimozide might have improved motor timing variability as a result of its beneficial side effect on endogenous dopamine levels (i.e., normalization). PMID- 25705970 TI - Training using simulation in internal medicine residencies: an educational perspective. AB - BACKGROUND: The American Board of Internal Medicine has defined through the min CEX (Clinical Examination booklet) that a resident would need to perform anywhere from 3 to 5 procedures to be competent in a given procedure. Many faculty and residents believe that this number is too low to achieve competency. METHODS: Although simulation has been required as part of medical training, we have reviewed a number of articles addressing competence and potentially fewer complications with improved patient safety. RESULTS: The Accreditation Council for Graduate Medical Education has simply stated that simulation should be part of residency training. However, this has resulted in a disorganized approach among the nearly 385 internal medicine programs in the United States. CONCLUSIONS: This article suggests a model of simulation that addresses procedures, medical codes and major medical problems that each resident achieve competence in before graduating residency. This would require minimally a doubling of the number of procedures to define competency and will do so in a far more scientific method. PMID- 25705971 TI - A time bomb in thorax: giant aortic arch aneurysm. PMID- 25705973 TI - Versatile G-quadruplex-mediated strategies in label-free biosensors and logic systems. AB - G-quadruplex (G4), as one of the significant functional nucleic acids (FNAs), has attracted researchers' wide attention, and in particular has been employed for the construction of label-free molecular sensors and logic systems based on the peroxidase-like activity of the G4-hemin complex and G4-enhanced luminescence of G4-binding organic dyes. Its cation-dependent conformation and stability provide opportunities for the recognition of metal ion inputs and application of a split G4 strategy. Moreover, coupling the G4 sequence with other FNAs, e.g. metal ion dependent DNAzymes and aptamers, has prominently broadened the range of possible targets from metal ions and DNA to diverse proteins and cells. Although there are limitations, such as a low ability of anti-interference and multiplex analysis, the excellent advantages (e.g. simplicity and low cost) endow the G4-mediated strategy with tremendous potential to be further exploited for practical bioanalysis and complicated DNA computing. PMID- 25705974 TI - High efficiency thermally activated delayed fluorescence based on 1,3,5-tris(4 (diphenylamino)phenyl)-2,4,6-tricyanobenzene. AB - A trigonal donor-acceptor molecule of 1,3,5-tris(4-(diphenylamino)phenyl)-2,4,6 tricyanobenzene (3DPA3CN) was synthesized to exhibit efficient thermally activated delayed fluorescence. By doping 3DPA3CN into a wide energy gap host, the film had a photoluminescence quantum efficiency of 100% with the reverse intersystem crossing efficiency of 100%. An OLED including the emitter exhibited a very high external quantum efficiency (eta(EQE)) of 21.4%. PMID- 25705975 TI - Monitoring reactive microencapsulation dynamics using microfluidics. AB - We use microfluidic polydimethylsiloxane (PDMS) devices to measure the kinetics of reactive encapsulations occurring at the interface of emulsion droplets. The formation of the polymeric shell is inferred from the droplet deformability measured in a series of expansion-constriction chambers along the microfluidic chip. With this tool we quantify the kinetic processes governing the encapsulation at the very early stage of shell formation with a time resolution of the order of the millisecond for overall reactions occurring in less than 0.5 s. We perform a comparison of monomer reactivities used for the encapsulation. We study the formation of polyurea microcapsules (PUMCs); the shell formation proceeds at the water-oil interface by an immediate reaction of amines dissolved in the aqueous phase and isocyanates dissolved in the oil phase. We observe that both monomers contribute differently to the encapsulation kinetics. The kinetics of the shell formation process at the oil-in-water (O/W) experiments significantly differs from the water-in-oil (W/O) systems; the component dissolved in the continuous phase has the largest impact on the kinetics. In addition, we quantified the retarding effect on the encapsulation kinetics by the interface stabilizing agent (surfactant). Our approach is valuable for quantifying in situ reactive encapsulation processes and provides guidelines to generate microcapsules with soft interfaces of tailored and controllable interfacial properties. PMID- 25705976 TI - A (3,6)-connected layer with an unprecedented adeninate nucleobase-derived heptanuclear disc. AB - A (3,6)-connected layer with an adeninate nucleobase-derived Cu(II)7 disc was reported, in which six spin-parallel Cu(II) ions in the exterior of the disc are antiferromagnetically coupled with the central one to give an S = 5/2 ground state. PMID- 25705977 TI - Personality disorder risk factors for suicide attempts over 10 years of follow up. AB - Identifying personality disorder (PD) risk factors for suicide attempts is an important consideration for research and clinical care alike. However, most prior research has focused on single PDs or categorical PD diagnoses without considering unique influences of different PDs or of severity (sum) of PD criteria on the risk for suicide-related outcomes. This has usually been done with cross-sectional or retrospective assessment methods. Rarely are dimensional models of PDs examined in longitudinal, naturalistic prospective designs. In addition, it is important to consider divergent risk factors in predicting the risk of ever making a suicide attempt versus the risk of making an increasing number of attempts within the same model. This study examined 431 participants who were followed for 10 years in the Collaborative Longitudinal Personality Disorders Study. Baseline assessments of personality disorder criteria were summed as dimensional counts of personality pathology and examined as predictors of suicide attempts reported at annual interviews throughout the 10-year follow up period. We used univariate and multivariate zero-inflated Poisson regression models to simultaneously evaluate PD risk factors for ever attempting suicide and for increasing numbers of attempts among attempters. Consistent with prior research, borderline PD was uniquely associated with ever attempting. However, only narcissistic PD was uniquely associated with an increasing number of attempts. These findings highlight the relevance of both borderline and narcissistic personality pathology as unique contributors to suicide-related outcomes. PMID- 25705978 TI - Elevated levels of callous unemotional traits are associated with reduced attentional cueing, with no specificity for fear or eyes. AB - Three theoretical explanations for the affective facet of psychopathy were tested in individuals with high levels of callous unemotional (CU) traits. Theory 1 (Blair) proposes specific difficulties in processing others' distress (particularly fear). Theory 2 (Dadds) argues for lack of attention to the eyes of faces. Theory 3 (Newman) proposes enhanced selective attention. The theories make contrasting predictions about how CU traits would affect cueing of attention from eye-gaze direction in distressed (i.e., fearful) faces; eye-gaze direction in nondistressed (i.e., happy, neutral) faces; and nonsocial stimuli (arrows). High CU adults (n = 33) showed reduced attentional cueing compared with low CU adults (n = 75) equally across all conditions (eye-gaze in distressed and nondistressed faces, arrows). The high CU group's ability to suppress following of eye-gaze emerged with practice while the low CU group showed no such reduction in gaze cueing with practice. Overall accuracy and RTs were not different for the low and high CU groups indicating equivalent task engagement. Results support an enhanced selective attention account-consistent with Newman and colleagues' Response Modulation Hypothesis--in which high CU individuals are able to suppress goal irrelevant social and nonsocial information. The current study also provides novel evidence regarding the nature of gaze-following by tracking practice effects across blocks. While supporting the common assumption that following of gaze is typically mandatory, the results also imply this can be modified by individual differences in personality. PMID- 25705979 TI - Attachment and social cognition in borderline personality disorder: Specificity in relation to antisocial and avoidant personality disorders. AB - Theory and research point to the role of attachment difficulties in borderline personality disorder (BPD). Attachment insecurity is believed to lead to chronic problems in social relationships, attributable, in part, to impairments in social cognition, which comprise maladaptive mental representations of self, others, and self in relation to others. However, few studies have attempted to identify social-cognitive mechanisms that link attachment insecurity to BPD and to assess whether such mechanisms are specific to the disorder. For the present study, empirically derived indices of mentalization, self-other boundaries, and identity diffusion were tested as mediators between attachment style and personality disorder symptoms. In a cross-sectional structural equation model, mentalization and self-other boundaries mediated the relationship between attachment anxiety and BPD. Mentalization partially mediated the relationship between attachment anxiety and antisocial personality disorder (PD) symptoms, and self-other boundaries mediated the relationship between attachment anxiety. PMID- 25705980 TI - The pain paradox: borderline personality disorder features, self-harm history, and the experience of pain. AB - Individuals with borderline personality disorder (BPD), compared to controls, report a relative absence of acute pain. In contrast, BPD is overrepresented among chronic pain patients, suggesting they experience a relative excess of chronic pain. To date, this "pain paradox" has been only partially explored; no study has examined both acute and chronic pain in the same sample. In addition, previous research has not fully examined the effect of nonsuicidal self-injury (NSSI) on either acute or chronic pain experience in BPD. Undergraduates (N = 206), oversampled for those high in BPD features, completed a Cold Pressor Task (CPT), rating their pain every 15 s over a maximum of 4 min. Following the CPT, participants completed measures of BPD features, NSSI history, past-year pain, and perceived pain tolerance. Results did not support the expected negative association between BPD features and acute pain. Multilevel modeling revealed an interaction of BPD features and NSSI history on CPT pain ratings: Among individuals in the no-NSSI group, BPD features were associated with greater acute pain. Among individuals in the NSSI group, BPD features were not significantly associated with acute pain. Results for past-year pain indicated that BPD features were associated with greater past-year pain regardless of NSSI history. This finding, coupled with the difference in the association of BPD features and acute pain between the NSSI and no-NSSI groups provides tentative evidence that the combination of BPD features and NSSI history, among nonclinical samples, is linked to a pain paradox. PMID- 25705981 TI - Elastomeric composites based on carbon nanomaterials. AB - Carbon nanomaterials including carbon black (CB), carbon nanotubes (CNTs) and graphene have attracted increasingly more interest in academia due to their fascinating properties. These nanomaterials can significantly improve the mechanical, electrical, thermal, barrier, and flame retardant properties of elastomers. The improvements are dependent on the molecular nature of the matrix, the intrinsic property, geometry and dispersion of the fillers, and the interface between the matrix and the fillers. In this article, we briefly described the fabrication processes of elastomer composites, illuminated the importance of keeping fillers at nanoscale in matrices, and critically reviewed the recent development of the elastomeric composites by incorporating CB, CNTs, and graphene and its derivatives. Attention has been paid to the mechanical properties and electrical and thermal conductivity. Challenges and further research are discussed at the end of the article. PMID- 25705982 TI - Transitioning to routine breast cancer risk assessment and management in primary care: what can we learn from cardiovascular disease? AB - To capitalise on advances in breast cancer prevention, all women would need to have their breast cancer risk formally assessed. With ~85% of Australians attending primary care clinics at least once a year, primary care is an opportune location for formal breast cancer risk assessment and management. This study assessed the current practice and needs of primary care clinicians regarding assessment and management of breast cancer risk. Two facilitated focus group discussions were held with 17 primary care clinicians (12 GPs and 5 practice nurses (PNs)) as part of a larger needs assessment. Primary care clinicians viewed assessment and management of cardiovascular risk as an intrinsic, expected part of their role, often triggered by practice software prompts and facilitated by use of an online tool. Conversely, assessment of breast cancer risk was not routine and was generally patient- (not clinician-) initiated, and risk management (apart from routine screening) was considered outside the primary care domain. Clinicians suggested that routine assessment and management of breast cancer risk might be achieved if it were widely endorsed as within the remit of primary care and supported by an online risk-assessment and decision aid tool that was integrated into primary care software. This study identified several key issues that would need to be addressed to facilitate the transition to routine assessment and management of breast cancer risk in primary care, based largely on the model used for cardiovascular disease. PMID- 25705983 TI - Ultrafine Pd nanoparticles encapsulated in microporous Co3O4 hollow nanospheres for in situ molecular detection of living cells. AB - Recent progress in the in situ molecular detection of living cells has attracted tremendous research interests due to its great significance in biochemical, physiological, and pathological investigation. Especially for the electrochemical detection of hydrogen peroxide (H2O2) released by living cells, the highly efficient and cost-effective electrocatalysts are highly desirable. In this work, we develop a novel type of microporous Co3O4 hollow nanospheres containing encapsulated Pd nanoparticles (Pd@Co3O4). Owing to the synergy effect between the permeable microporous Co3O4 shell and the ultrafine Pd nanoparticles that encapsulated in it, the resultant Pd@Co3O4 based electrode exhibits excellent electrochemical sensor performance toward H2O2, even when the content of Pd in Pd@Co3O4 hollow nanospheres is as low as 1.14 wt %, which enable it be used for real-time tracking of the secretion of H2O2 in different types of living human cells. PMID- 25705984 TI - Molecular complex composed of beta-cyclodextrin-grafted Chitosan and pH-sensitive amphipathic peptide for enhancing cellular cholesterol efflux under acidic pH. AB - Excess of cholesterol in peripheral cells is known to lead to atherosclerosis. In this study, a molecular complex composed of beta-cyclodextrin-grafted chitosan (BCC) and cellular cholesterol efflux enhancing peptide (CEEP), synthesized by modifying pH sensitive amphipathic GALA peptide, is introduced with the eventual aim of treating atherosclerosis. BCC has a markedly enhanced ability to induce cholesterol efflux from cell membranes compared to beta-cyclodextrin, and the BCC CEEP complex exhibited a 2-fold increase in cellular cholesterol efflux compared to BCC alone under weakly acidic conditions. Isothermal titration calorimetry and fluorescence spectroscopy measurements demonstrated that the random coil structure of CEEP at neutral pH converted to the alpha-helical structure at acidic pH, resulting in a three-order larger binding constant to BCC (K = 3.7 * 10(7) at pH 5.5) compared to that at pH 7.4 (K = 7.9 * 10(4)). Such high-affinity binding of CEEP to BCC at acidic pH leads to the formation of 100-nm-sized aggregate with positive surface charge, which would efficiently interact with cell membranes and induce cholesterol efflux. Since the cholesterol efflux ability of HDL is thought to be impaired under acidic environments in advanced atherosclerotic lesions, the BCC-CEEP complex might serve as a novel nanomaterial for treating atherosclerosis. PMID- 25705985 TI - Transparent nanotubular capacitors based on transplanted anodic aluminum oxide templates. AB - Transparent AlZnO/Al2O3/AlZnO nanocapacitor arrays have been fabricated by atomic layer deposition in anodic aluminum oxide templates transplanted on the AlZnO/glass substrates. A high capacitance density of 37 fF/MUm(2) is obtained, which is nearly 5.8 times bigger than that of planar capacitors. The capacitance density almost remains the same in a broad frequency range from 1 kHz to 200 kHz. Moreover, a low leakage current density of 1.7 * 10(-7) A/cm(2) at 1 V has been achieved. The nanocapacitors exhibit an average optical transmittance of more than 80% in the visible range, and thus open the door to practical applications in transparent integrated circuits. PMID- 25705986 TI - Direct observation of nanometer-scale pores of melittin in supported lipid monolayers. AB - Melittin is the most studied membrane-active peptide and archetype within a large and diverse group of pore formers. However, the molecular characteristics of melittin pores remain largely unknown. Herein, we show by atomic force microscopy (AFM) that lipid monolayers in the presence of melittin are decorated with numerous regularly shaped circular pores that can be distinguished from nonspecific monolayer defects. The specificity of these pores is reinforced through a statistical evaluation of depressions found in Langmuir-Blodgett monolayers in the presence and absence of melittin, which eventually allows characterization of the melittin-induced pores at a quantitative low-resolution level. We observed that the large majority of pores exhibit near-circular symmetry and a Gaussian distribution in size, with a mean diameter of ~8.7 nm. A distinctive feature is a ring of material found around the pores, made by, on average, three positive peaks, with a height over the level of the lipidic background of ~0.23 nm. This protruding rim is most likely due to the presence of melittin near the pore border. Although the current resolution of the AFM images in the {x, y} plane does not allow distinction of the specific organization of the peptide molecules, these results provide an unprecedented view of melittin pores formed in lipidic interfaces and open new perspectives for future structural investigations of these and other pore-forming peptides and proteins using supported monolayers. PMID- 25705987 TI - Altitude-dependent distribution of ambient gamma dose rates in a mountainous area of Japan caused by the fukushima nuclear accident. AB - Large amounts of airborne radionuclides were deposited over a wide area in eastern Japan, including mountainous regions, during the devastating Fukushima Dai-ichi nuclear power plant accident. Altitudinal distributions of ambient gamma dose rate in air were measured in a mountainous area at the northern rim of the Kanto Plain, Japan, using a portable instrument carried along the mountain trails. In the Nikko Mountain area, located 120 km north of Tokyo, the altitudinal distribution exhibited a maxima at ~900-2000 m above sea level (ASL). This area was not affected by precipitation until 2300 Japan Standard Time (JST) on March 15, 2011. By that time, a substantial amount of radionuclides had been transported from the damaged reactor, according to the numerical simulations using transport models. Meteorological sounding data indicated that the corresponding altitudes were within the cloud layer. A visual-range monitor deployed in an unmanned weather station at 1292 m ASL also recorded low visibility on the afternoon of March 15. From these findings, it was deduced that the altitude-dependent radioactive contamination was caused by the cloud/fog deposition process of the radionuclides contained in aerosols acting as cloud condensation nuclei. PMID- 25705988 TI - Copper-catalyzed hydroamination of alkynes with aliphatic amines: regioselective access to (1E,3E)-1,4-disubstituted-1,3-dienes. AB - Copper-catalyzed hydroamination of aromatic or heteroaromatic alkynes with cyclic secondary aliphatic amines undergoes generation of an enamine-type intermediate. The latter is transformed in situ via a coupling reaction with a second molecule of alkyne to afford regioselectively (1E,3E)-1,4-disubstituted-1,3-dienes with the formation of C-N, C-C, and C-H bonds. PMID- 25705989 TI - Social anxiety and the Big Five personality traits: the interactive relationship of trust and openness. AB - It is well established that social anxiety (SA) has a positive relationship with neuroticism and a negative relationship with extraversion. However, findings on the relationships between SA and agreeableness, conscientiousness, and openness to experience are mixed. In regard to facet-level personality traits, SA is negatively correlated with trust (a facet of agreeableness) and self-efficacy (a facet of conscientiousness). No research has examined interactions among the Big Five personality traits (e.g., extraversion) and facet levels of personality in relation to SA. In two studies using undergraduate samples (N = 502; N = 698), we examined the relationships between trust, self-efficacy, the Big Five, and SA. SA correlated positively with neuroticism, negatively with extraversion, and had weaker relationships with agreeableness, openness, and trust. In linear regression predicting SA, there was a significant interaction between trust and openness over and above gender. In addition to supporting previous research on SA and the Big Five, we found that openness is related to SA for individuals low in trust. Our results suggest that high openness may protect against the higher SA levels associated with low trust. PMID- 25705990 TI - Major depressive disorder and diabetes: does serotonin bridge the gap? AB - Major depressive disorder (MDD) is one of the most common psychiatric illnesses worldwide, with reported prevalence rates ranging between 10% and 19%. Pharmacotherapy is a first-line option for the management of MDD and, as a result, the use of antidepressants has increased 4 fold in the last 20 years. Serotonin is the most commonly dysregulated neurotransmitter in the etiology of MDD and this system is the primary focus of most medications used in the treatment of illness. Although antidepressant use in adults increases the risk of developing new onset type 2 diabetes, the mechanisms underlying this association are poorly defined. This review will focus on 1) the evidence from human and animal studies suggesting a link between the use of antidepressants that target serotonin signaling (i.e., SSRIs, serotonin-norepinephrine reuptake inhibitors (SNRIs), serotonin antagonist and reuptake inhibitors (SARIs), and noradrenergic and specific serotonergic antidepressants (NaSSAs)) and increased risk of diabetes, and 2) the mechanisms by which alterations in serotonin signalling by antidepressants can affect glucose homeostasis. PMID- 25705991 TI - High number of transplanted stem cells improves myocardial recovery after AMI in a porcine model. AB - OBJECTIVE: The clinical data considering the bone marrow mononuclear cell (BMMNC) therapy in treatment for acute myocardial infarction (AMI) are controversial and the mechanisms remain unknown. Our objective was to study the cardiac function and changes in cytokine levels after administration of BMMNC in experimental AMI model. DESIGN: Unlabeled or Super-Paramagnetic-Iron-Oxide-labeled BMMNCs or saline was injected into myocardium of 31 pigs after circumflex artery occlusion. Ejection fraction (EF) was measured preoperatively, postoperatively and at 21 days by echocardiography. Cardiac MRI was performed postoperatively and after 21 days in 7 BMMNC animals. Serum cytokine levels were measured at baseline, 24 h and 21 days. Cellular homing was evaluated comparing MRI and histology. RESULTS: From baseline to 21 days EF decreased less in BMMNC group (EF mean control -19 SD 12 vs. BMMNC -4 SD 15 percentage points p = 0.02). Cytokine concentrations showed high variability between the animals. MRI correlated with histology in cell detection and revealed BMMNCs in the infarction area. By MRI, EF improved 11 percentage points. The improvement in EF was associated with the number of transplanted BMMNCs detected in the myocardium. CONCLUSION: BMMNC injection after AMI improved cardiac function. Quantity of transplanted BMMNCs correlated with the improvement in cardiac function after AMI. PMID- 25705992 TI - Enantiocontrolled synthesis of a tetracyclic aminal corresponding to the core subunit of diazonamide A. AB - A chiral benzylic ether serves as an auxiliary for oxindole carboxylation (dr 5.2:1.0) that sets C10 configuration in a potential diazonamide precursor. The chiral substituent allows diastereomer separation and departs during a subsequent acid-catalyzed ring closure to form a tetracyclic aminal. With suitable N protection, crystallization affords the aminal with 98-99% ee. PMID- 25705993 TI - Hepatitis C and HIV co-infection: closing the gaps. PMID- 25705994 TI - Hospital ward antibiotic prescribing and the risks of Clostridium difficile infection. AB - IMPORTANCE: Only a portion of hospital-acquired Clostridium difficile infections can be traced back to source patients identified as having symptomatic disease. Antibiotic exposure is the main risk factor for C difficile infection for individual patients and is also associated with increased asymptomatic shedding. Contact with patients taking antibiotics within the same hospital ward may be a transmission risk factor for C difficile infection, but this hypothesis has never been tested. OBJECTIVES: To obtain a complete portrait of inpatient risk that incorporates innate patient risk factors and transmission risk factors measured at the hospital ward level and to investigate ward-level rates of antibiotic use and C difficile infection risk. DESIGN, SETTING, AND PATIENTS: A 46-month (June 1, 2010, through March 31, 2014) retrospective cohort study of inpatients 18 years or older in a large, acute care teaching hospital composed of 16 wards, including 5 intensive care units and 11 non-intensive care unit wards. EXPOSURES: Patient-level risk factors (eg, age, comorbidities, hospitalization history, antibiotic exposure) and ward-level risk factors (eg, antibiotic therapy per 100 patient-days, hand hygiene adherence, mean patient age) were identified from hospital databases. MAIN OUTCOMES AND MEASURES: Incidence of hospital-acquired C difficile infection as identified prospectively by hospital infection prevention and control staff. RESULTS: A total of 255 of 34 298 patients developed C difficile (incidence rate, 5.95 per 10,000 patient-days; 95% CI, 5.26-6.73). Ward level antibiotic exposure varied from 21.7 to 56.4 days of therapy per 100 patient-days. Each 10% increase in ward-level antibiotic exposure was associated with a 2.1 per 10,000 (P < .001) increase in C difficile incidence. The association between C difficile incidence and ward antibiotic exposure was the same among patients with and without recent antibiotic exposure, and C difficile risk persisted after multilevel, multivariate adjustment for differences in patient-risk factors among wards (relative risk, 1.34 per 10% increase in days of therapy; 95% CI, 1.16-1.57). CONCLUSIONS AND RELEVANCE: Among hospital inpatients, ward-level antibiotic prescribing is associated with a statistically significant and clinically relevant increase in C difficile risk that persists after adjustment for differences in patient-level antibiotic use and other patient- and ward-level risk factors. These data strongly support the use of antibiotic stewardship as a means of preventing C difficile infection. PMID- 25705995 TI - The bone conduction implant: Clinical results of the first six patients. AB - OBJECTIVE: To investigate audiological and quality of life outcomes for a new active transcutaneous device, called the bone conduction implant (BCI), where the transducer is implanted under intact skin. DESIGN: A clinical study with sound field audiometry and questionnaires at six-month follow-up was conducted with a bone-anchored hearing aid on a softband as reference device. STUDY SAMPLE: Six patients (age 18-67 years) with mild-to-moderate conductive or mixed hearing loss. RESULTS: The surgical procedure was found uneventful with no adverse events. The first hypothesis that BCI had a statistically significant improvement over the unaided condition was proven by a pure-tone-average improvement of 31.0 dB, a speech recognition threshold improvement in quiet (27.0 dB), and a speech recognition score improvement in noise (51.2 %). At speech levels, the signal-to noise ratio threshold for BCI was - 5.5 dB. All BCI results were better than, or similar to the reference device results, and the APHAB and GBI questionnaires scores showed statistically significant improvements versus the unaided situation, supporting the second and third hypotheses. CONCLUSIONS: The BCI provides significant hearing rehabilitation for patients with mild-to-moderate conductive or mixed hearing impairments, and can be easily and safely implanted under intact skin. PMID- 25705996 TI - Superelastic shape recovery of mechanically twinned 3,5-difluorobenzoic acid crystals. AB - Generally, superelastic behavior cannot be expected in mechanically twinned crystals because there is essentially no strain on the interface that is a driving force for spontaneous shape recovery. However, we found that single crystals of 3,5-difluorobenzoic acid are superelastic organic crystals under mechanical twinning. The unexpected shape recovery can be explained by molecular distortion on the twinning interface, which suggests a new mechanism for superelasticity in molecular materials. PMID- 25705997 TI - Highly tunable Berry phase and ambipolar field effect in topological crystalline insulator Pb(1-x)Sn(x)Se. AB - Recently, rock-salt IV-VI semiconductors, such as Pb(1-x)Sn(x)Se(Te) and SnTe, have been observed to host topological crystalline insulator (TCI) states. The nontrivial states have long been believed to exhibit ambipolar field effects and possess massive Dirac Fermions in two-dimension (2D) limit due to the surface hybridization. However, these exciting attributes of TCI remain previously inaccessible owing to the complicated control over composition and thickness. Here, we systematically investigate doping and thickness-induced topological phase transitions by electrical transport. We demonstrate the first evidence of the ambipolar properties in Pb(1-x)Sn(x)Se thin films. Surface gap opening is observed in 10 nm TCI originated from the strong finite-size effect. Importantly, magnetoconductance hosts a competition between weak antilocalization and weak localization, suggesting a strikingly tunable Berry phase evolution and strong electron-electron interaction. Our findings serve as a new probe to study electron behavior and pave the way for further exploring and manipulating this novel 2D TCI phase. PMID- 25706000 TI - Biological support media influence the bacterial biofouling community in reverse osmosis water reclamation demonstration plants. AB - The diversity of the bacterial community developed in different stages of two reverse osmosis (RO) water reclamation demonstration plants designed in a wastewater treatment plant (WWTP) in Tarragona (Spain) was characterized by applying 454-pyrosequencing of the 16S rRNA gene. The plants were fed by secondary treated effluent to a conventional pretreatment train prior to the two pass RO system. Plants differed in the material used in the filtration process, which was sand in one demonstration plant and Scandinavian schists in the second plant. The results showed the presence of a highly diverse and complex community in the biofilms, mainly composed of members of the Betaproteobacteria and Bacteroidetes in all stages, with the presence of some typical wastewater bacteria, suggesting a feed water origin. Community similarities analyses revealed that samples clustered according to filter type, highlighting the critical influence of the biological supporting medium in biofilm community structure. PMID- 25705999 TI - Expansion duroplasty improves intraspinal pressure, spinal cord perfusion pressure, and vascular pressure reactivity index in patients with traumatic spinal cord injury: injured spinal cord pressure evaluation study. AB - We recently showed that, after traumatic spinal cord injury (TSCI), laminectomy does not improve intraspinal pressure (ISP), spinal cord perfusion pressure (SCPP), or the vascular pressure reactivity index (sPRx) at the injury site sufficiently because of dural compression. This is an open label, prospective trial comparing combined bony and dural decompression versus laminectomy. Twenty one patients with acute severe TSCI had re-alignment of the fracture and surgical fixation; 11 had laminectomy alone (laminectomy group) and 10 had laminectomy and duroplasty (laminectomy+duroplasty group). Primary outcomes were magnetic resonance imaging evidence of spinal cord decompression (increase in intradural space, cerebrospinal fluid around the injured cord) and spinal cord physiology (ISP, SCPP, sPRx). The laminectomy and laminectomy+duroplasty groups were well matched. Compared with the laminectomy group, the laminectomy+duroplasty group had greater increase in intradural space at the injury site and more effective decompression of the injured cord. In the laminectomy+duroplasty group, ISP was lower, SCPP higher, and sPRx lower, (i.e., improved vascular pressure reactivity), compared with the laminectomy group. Laminectomy+duroplasty caused cerebrospinal fluid leak that settled with lumbar drain in one patient and pseudomeningocele that resolved completely in five patients. We conclude that, after TSCI, laminectomy+duroplasty improves spinal cord radiological and physiological parameters more effectively than laminectomy alone. PMID- 25706001 TI - Public health as a catalyst for interprofessional education on a health sciences campus. AB - Although interprofessional education (IPE) has existed in various formats for several decades, the need for IPE recently has taken on renewed interest and momentum. Public health has a critical role to play in furthering IPE, yet schools of public health are often underrepresented in IPE initiatives. The University of Iowa College of Public Health is serving as a catalyst for IPE activities on our health sciences campus, which includes colleges of dentistry, medicine, nursing, pharmacy, and public health. IPE-related activities have included campus visit by IPE leaders, administration of the Survey of Critical Elements for Implementing IPE, administration of the Interprofessional Learning Opportunities Inventory survey, the development of a comprehensive strategic plan, and the pilot of an IPE course for all first-year prelicensure students and Master of Health Administration students. Although more work is needed to more fully integrate IPE into the curriculum, success to date of the University of Iowa IPE initiative demonstrates that public health can play a critical role as a convener and catalyst for IPE curricular innovations on a health sciences campus. PMID- 25706002 TI - Enhancing interprofessional education: integrating public health and social work perspectives. AB - National stakeholders in health system improvement and patient safety including accreditation bodies have requested health professional educational programs to include multiple interprofessional experiences through didactic and experiential opportunities. Clinical and population health faculty at the University of South Carolina redesigned and expanded an introductory interprofessional course to include more than 500 students from public health, social work, medicine, pharmacy, and nursing. Students participated in 3 live class meetings and completed required online coursework to explore concepts related to social determinants of health and health disparities, health system improvement, patient safety, cultural competency, and ethics to address interprofessional education core competencies. Course modifications and expanded student enrollment improved understanding of key health concepts and appreciation of interprofessional collaboration. PMID- 25706003 TI - A renewed vision for higher education in public health. AB - We are transforming the educational strategy at the Harvard T. H. Chan School of Public Health guided by 5 principles: (1) development of T-shaped competencies (breadth across fields, depth in primary fields), (2) flexible and modular design accommodating different needs through the lifecycle, (3) greater experiential learning, (4) 3 levels of education (informative, formative, and transformative learning), and (5) integrated instructional design (online, in person, and in the field). We aim to create an arc of education resulting in continuous learning. We seek to bridge the research versus education dichotomy and create research teaching congruence, adapting the values of peer review and quality assessment that we routinely accept for grant and article review to education. PMID- 25706004 TI - Educating future public health leaders. PMID- 25706005 TI - Promoting innovative thinking. AB - Innovation is the engine of scientific progress, yet we do not train public health students to think creatively. I present the key concepts within an evidence-based method currently taught at the University of Texas. Habitual thought patterns involve deeply held framed expectations. Finding alternatives generates originality. Because frame breaking is difficult, a series of innovation heuristics and tools are offered including enhancing observation, using analogies, changing point of view, juggling opposites, broadening perspective, reversal, reorganization and combination, and getting the most from groups. Gaining cognitive attributes such as nonjudgment, willingness to question, mindfulness, and plasticity is also emphasized. Students completing the class demonstrate substantial increases on a standardized test of idea fluency and originality, more joyful attitudes toward science, and more pluralistic approaches. PMID- 25706006 TI - Keeping the "public" in schools of public health. AB - In this article, we compared the characteristics of public and private accredited public health training programs. We analyzed the distinct opportunities and challenges that publicly funded schools of public health face in preparing the nation's public health workforce. Using our experience in creating a new, collaborative public school of public health in the nation's largest urban public university system, we described efforts to use our public status and mission to develop new approaches to educating a workforce that meets the health needs of our region and contributes to the goal of reducing health inequalities. Finally, we considered policies that could protect and strengthen the distinct contributions that public schools of public health make to improving population health and reducing health inequalities. PMID- 25706007 TI - Preparing future faculty and professionals for public health careers. AB - Recent years have brought rapid growth in schools of public health and an increasing demand for public health practitioners. These trends highlight the need for innovative approaches to prepare doctoral graduates for academic and high-level practice positions. The University of Maryland's School of Public Health developed a "Preparing Future Faculty and Professionals" program to enrich the graduate education and professional development of its doctoral students. We describe the program's key elements, including foundational seminars to enhance students' knowledge and skills related to teaching, research, and service; activities designed to foster career exploration and increase competitiveness in the job market; and independent, faculty-mentored teaching and research experiences. We present a model for replicating the program and share student outcomes of participation. PMID- 25706008 TI - Cultural competency training for public health students: integrating self, social, and global awareness into a master of public health curriculum. AB - Cultural competency training in public health, medicine, social work, nursing, dental medicine, and other health professions has been a topic of increasing interest and significance. Despite the now burgeoning literature that describes specific knowledge, attitudes, and skills that promote cultural "competence," fully defining this complex, multidimensional term and implementing activities to enhance it remain a challenge. We describe our experiences in introducing a mandatory, full-day workshop to incoming Master of Public Health students, called "Self, Social, and Global Awareness: Personal Capacity Building for Professional Education and Practice." The purpose of the program is to provide a meaningful, structured environment to explore issues of culture, power, privilege, and social justice, emphasizing the centrality of these issues in effective public health education and practice. PMID- 25706009 TI - Mentoring for publication in the American Journal of Public Health. PMID- 25706010 TI - Developing the new Columbia core curriculum: a case study in managing radical curriculum change. AB - Curricular change is essential for maintaining vibrant, timely, and relevant educational programming. However, major renewal of a long-standing curriculum at an established university presents many challenges for leaders, faculty, staff, and students. We present a case study of a dramatic curriculum renewal of one of the nation's largest Master of Public Health degree programs: Columbia University's Mailman School of Public Health. We discuss context, motivation for change, the administrative structure established to support the process, data sources to inform our steps, the project timeline, methods for engaging the school community, and the extensive planning that was devoted to evaluation and communication efforts. We highlight key features that we believe are essential for successful curricular change. PMID- 25706011 TI - Curriculum revitalization initiative at Tulane. AB - Tulane School of Public Health and Tropical Medicine launched its curriculum revitalization initiative to examine the Master of Public Health degrees (MPH). The initiative will enhance excellence in MPH education and incorporate innovative teaching approaches. Taskforces determined the MPH core should provide the foundation for public health, integrate knowledge across public health areas, and develop skills and methods needed in practice. The MPH is being updated to provide specialized study that builds skills and practical applications based on theory and evidence-based approaches. Eleven graduate certificates were developed to provide a second area of specialization. Practica are viewed as increasingly important for students without practical experience. Teaching methods will incorporate more technology including online modules for a blended classroom approach. PMID- 25706012 TI - Our practice is our passion: development and delivery of a 21st-century doctor of public health program. AB - Twenty-first century advances have significantly altered the functions of public health professionals, resulting in a need for advanced level training in community health leadership and practice-oriented research without interruption of professional careers. We present an example of an innovative Doctor of Public Health (DrPH) program developed at the University of South Florida College of Public Health. This program incorporates 21st century public health competencies within a competency-based curricular model, delivered in a hybrid format (fall or spring online delivery and a 1-week face-to-face summer institute) in collaboration between academic and practice-based public health professionals at local and national levels. This revised competency-based program is an example of how to meet the needs of the 21st century public health practitioners while maintaining their connections to the practice world. PMID- 25706013 TI - A call to action: training public health students to be effective agents for social change. AB - In the 21st century, we face enormous public health challenges that differ fundamentally from those of the last century, because these challenges involve widespread societal change and complexity. To address these challenges, public health professionals need to be able to place their work in a larger social context, understand local and global perspectives on a deeper level, and effectively engage a wide variety of stakeholders. To confer these skills, we need to change the way we train our students. We present two examples of low-cost innovative approaches to teaching public health that promote active engagement with individuals across a wide range of backgrounds and fields and that train students to be effective agents for change. PMID- 25706014 TI - Service learning: a vehicle for building health equity and eliminating health disparities. AB - Service learning (SL) is a form of community-centered experiential education that places emerging health professionals in community-generated service projects and provides structured opportunities for reflection on the broader social, economic, and political contexts of health. We describe the elements and impact of five distinct week-long intensive SL courses focused on the context of urban, rural, border, and indigenous health contexts. Students involved in these SL courses demonstrated a commitment to community-engaged scholarship and practice in both their student and professional lives. SL is directly in line with the core public health value of social justice and serves as a venue to strengthen community campus partnerships in addressing health disparities through sustained collaboration and action in vulnerable communities. PMID- 25706015 TI - Reinventing public health education for the 21st century. PMID- 25706016 TI - Innovations in public health education: promoting professional development and a culture of health. AB - As the field of public health advances toward addressing complex, systemic problems, future public health professionals must be equipped with leadership and interprofessional skills that support collaboration and a culture of health. The University of Memphis School of Public Health has infused innovative strategies into graduate education via experiential learning opportunities to enhance leadership, collaboration, and professional development. Novel training programs such as Day One, Public Health Interdisciplinary Case Competition, and Memphis Healthy U support Association of Schools and Programs of Public Health cross cutting competencies and prepare Master of Public Health and Master of Health Administration graduates to function effectively at the outset of their careers and become catalysts for creating a culture of health. PMID- 25706017 TI - Anticipating change, sparking innovation: framing the future. AB - As the 100th anniversary of the 1915 Welch-Rose report approaches, the Association of Schools and Programs of Public Health (ASPPH) has been pursuing two initiatives to spark innovation in academic partnerships for enhancing population health: (1) Framing the Future: The Second 100 Years of Education for Public Health and (2) Reconnecting Public Health and Care Delivery to Improve the Health of Populations. We describe how ASPPH-member schools and programs accredited by the Council on Education for Public Health, along with their extraordinarily diverse array of partners, are working to improve education that better prepares health professionals to meet 21st-century population health needs. PMID- 25706018 TI - Innovating for 21st-century public health education: a case for seizing this moment. PMID- 25706019 TI - Public health 101 nanocourse: a condensed educational tool for non-public health professionals. AB - Graduate students and postdoctoral fellows-including those at the Harvard School of Public Health (HSPH)-have somewhat limited opportunities outside of traditional coursework to learn holistically about public health. Because this lack of familiarity could be a barrier to fruitful collaboration across disciplines, HSPH postdocs sought to address this challenge. In response, the Public Health 101 Nanocourse was developed to provide an overview of five core areas of public health (biostatistics, environmental health sciences, epidemiology, health policy and management, and social and behavioral sciences) in a two half-day course format. We present our experiences with developing and launching this novel approach to acquainting wider multidisciplinary audiences with the field of public health. PMID- 25706020 TI - The University of Illinois at Chicago School of Public Health Doctor of Public Health program: an innovative approach to doctoral-level practice leadership development. AB - The University of Illinois at Chicago, School of Public Health, Doctor of Public Health degree is designed to build leadership skills and an ability to contribute to the evidence base of practice. The competency-based, distance-format, doctoral level program for midcareer professionals features an action learning approach in which students apply leadership principles from the virtual classroom to real world problems at their work sites. Students demonstrate mastery of the competencies and readiness to advance to the dissertation stage through completing a portfolio by using a process of systematic reflection. The practice oriented dissertation demonstrates the ability to contribute to the evidence base of public health practice in an area of emphasis. Preliminary evaluation data indicate that the program is meeting its intended purposes. PMID- 25706021 TI - Redefining leadership education in graduate public health programs: prioritization, focus, and guiding principles. AB - Public health program graduates need leadership skills to be effective in the complex, changing public health environment. We propose a new paradigm for schools of public health in which technical and leadership skills have equal priority as core competencies for graduate students. Leadership education should focus on the foundational skills necessary to effect change independent of formal authority, with activities offered at varying levels of intensity to engage different students. Leadership development initiatives should be practice based, process focused, interdisciplinary, diversity based, adaptive, experimental, innovative, and empowering, and they should encourage authenticity. Leadership training in graduate programs will help lay the groundwork for public health professionals to have an immediate impact in the workforce and to prioritize continuous leadership development throughout their careers. PMID- 25706022 TI - Improving the use of competencies in public health education. AB - Competency-based education is the present and future of public health education. As programs have adopted competencies, many have struggled and continue to struggle with actual implementation and curricular redesign. We experienced these problems at The University of Oklahoma College of Public Health; thus, we propose an adaptable and replicable process to better implement competencies and evaluate student mastery of them throughout any public health program. We specifically recommend adopting mission-based competencies followed by a longitudinal evaluation plan like the model provided. PMID- 25706023 TI - Innovating in health care management education: development of an accelerated MBA and MPH degree program at Yale. AB - Increasingly, there is recognition of the need for individuals with expertise in both management and public health to help health care organizations deliver high quality and cost-effective care. The Yale School of Public Health and Yale School of Management began offering an accelerated Master of Business Administration (MBA) and Master of Public Health (MPH) joint degree program in the summer of 2014. This new program enables students to earn MBA and MPH degrees simultaneously from 2 fully accredited schools in 22 months. Students will graduate with the knowledge and skills needed to become innovative leaders of health care organizations. We discuss the rationale for the program, the developmental process, the curriculum, benefits of the program, and potential challenges. PMID- 25706024 TI - Solutions that stick: activating cross-disciplinary collaboration in a graduate level public health innovations course at the University of California, Berkeley. AB - Since 2011 we have taught a public health innovations course at the University of California, Berkeley. Students gain skills in systematic innovation, or human centered design, while working in small interdisciplinary teams on domestic and global health projects with client organizations. To support acquisition of meaningful problem-solving skills, we structured the course so that the majority of learning happens in scenarios that do not involve faculty. Taken by students representing 26 graduate programs (as diverse as epidemiology, city planning, and mechanical engineering), it is one of the 10 highest-rated courses offered by the School of Public Health. We present the blueprints for our course with the hope that other institutions whose students could benefit will borrow from our model. PMID- 25706025 TI - Bridging graduate education in public health and the liberal arts. AB - The University of Massachusetts Amherst is part of Five-Colleges Inc, a consortium that includes the university and four liberal arts colleges. Consortium faculty from the School of Public Health and Health Sciences at the university and from the colleges are working to bridge liberal arts with public health graduate education. We outline four key themes guiding this effort and exemplary curricular tools for innovative community-based and multidisciplinary academic and research programs. The structure of the consortium has created a novel trajectory for student learning and engagement, with important ramifications for pedagogy and professional practice in public health. We show how graduate public health education and liberal arts can, and must, work in tandem to transform public health practice in the 21st century. PMID- 25706026 TI - Public health education reform in the context of health professions education reform. PMID- 25706027 TI - Public health education at the University of Florida: synergism and educational innovation. AB - The College of Public Health and Health Professions at the University of Florida is composed of five public health departments and four clinical health professions departments, and the college is one of six that make up the university's Health Science Center. These organizational resources, along with the university's explicit emphasis on collaboration across professions, colleges, institutes, and centers and the strong leadership and full support of deans and other academic leaders, provide a strong foundation for educational innovations. Three key areas in which the college has built upon these opportunities are interprofessional education, development of One Health instructional programs, and application of cutting-edge technology to students' educational experiences. These innovations represent the types of creative approaches to preparing the 21st-century workforce that can be developed through collaboration among multiple disciplines in a major university. PMID- 25706028 TI - Innovations in graduate public health education: the Instituto Nacional de Salud Publica. AB - During the past 10 years, the Instituto Nacional de Salud Publica (National Institute of Public Health) in Mexico has meticulously revised its educational model. This analysis resulted in the transformation of its educational model by tracing a new path in the pedagogical structure and faculty development to meet current challenges and students' needs. The first stage dealt with the national and international accreditation standards that came with the 21st century. The second stage responded to evidence of cognitive research showing that students are better prepared when they are engaged, active, and responsible for their own learning. This transformation was grounded on the use of information and communication technologies and on a competency-based educational approach that has led the expansion and innovation of educational practice. PMID- 25706029 TI - A case-based, problem-based learning approach to prepare master of public health candidates for the complexities of global health. AB - Global health is a dynamic, emerging, and interdisciplinary field. To address current and emerging global health challenges, we need a public health workforce with adaptable and collaborative problem-solving skills. In the 2013-2014 academic year, the Hubert Department of Global Health at the Rollins School of Public Health-Emory University launched an innovative required core course for its first-year Master of Public Health students in the global health track. The course uses a case-based, problem-based learning approach to develop global health competencies. Small teams of students propose solutions to these problems by identifying learning issues and critically analyzing and synthesizing new information. We describe the course structure and logistics used to apply this approach in the context of a large class and share lessons learned. PMID- 25706030 TI - The integrated first year experience in the master of public health program. AB - Schools of Public Health historically introduced core curriculum courses in the first year of the Master of Public Health program as independent perspectives; these perspectives included epidemiology, biostatistics, environmental health, public health biology, health behaviors, and health policy. We performed a pilot project that integrated the core areas around diabetes as a cross-cutting public health issue to provide early exposure to the interdisciplinary nature of public health. In each core curriculum course, diabetes was explored in the curriculum and related to other core courses. Based on positive evaluations, this project will be replicated using a different health issue. Such an issue can be easily introduced as an overarching umbrella under which students are motivated to work through interdisciplinary collaboration. PMID- 25706031 TI - Methodological innovations in public health education: transdisciplinary problem solving. AB - In 2008, the faculty of the Brown School at Washington University in St. Louis designed a Master of Public Health program centered on transdisciplinary problem solving in public health. We have described the rationale for our approach, guiding principles and pedagogy for the program, and specific transdisciplinary competencies students acquire. We have explained how transdisciplinary content has been organized and delivered, how the program is being evaluated, and how we have demonstrated the feasibility of this approach for a Master of Public Health degree. PMID- 25706033 TI - High-pressure electrides: the chemical nature of interstitial quasiatoms. AB - Building on our previous chemical and physical model of high-pressure electrides (HPEs), we explore the effects of interaction of electrons confined in crystals but off the atoms, under conditions of extreme pressure. Electrons in the quantized energy levels of voids or vacancies, interstitial quasiatoms (ISQs), effectively interact with each or with other atoms, in ways that are quite chemical. With the well-characterized Na HPE as an example, we explore the ionic limit, ISQs behaving as anions. A detailed comparison with known ionic compounds points to high ISQ charge density. ISQs may also form what appear to be covalent bonds with neighboring ISQs or real atoms, similarly confined. Our study looks specifically at quasimolecular model systems (two ISQs, a Li atom and a one electron ISQ, a Mg atom and two ISQs), in a compression chamber made of He atoms. The electronic density due to the formation of bonding and antibonding molecular orbitals of the compressed entities is recognizable, and a bonding stabilization, which increases with pressure, is estimated. Finally, we use the computed Mg electride to understand metallic bonding in one class of electrides. In general, the space confined between atoms in a high pressure environment offers up quantized states to electrons. These ISQs, even as they lack centering nuclei, in their interactions with each other and neighboring atoms may show anionic, covalent, or metallic bonding, all the chemical features of an atom. PMID- 25706034 TI - Neonatal pulmonary arterial hypertension and Noonan syndrome: two fatal cases with a specific RAF1 mutation. AB - Mutations in RAF1 are associated with Noonan syndrome and hypertrophic cardiomyopathy. We present two infants with Noonan syndrome and an identical RAF1 mutation, p.Ser257Leu (c.770C>T), who developed severe pulmonary arterial hypertension (PAH) that proved to be fatal. The RAF1 gene encodes Raf-1 kinase, part of the Ras/mitogen-activated kinase (MAPK) signaling pathway, which has been linked to the development of PAH. This specific mutation has been associated with dephosphorylation of a critical serine residue and constitutive activation of the Raf-1 kinase. These two cases suggest that abnormal activation of the Ras/MAPK pathway may play a significant role in the development of pulmonary vascular disease in the subset of patients with Noonan syndrome and a specific RAF1 mutation. PMID- 25706035 TI - Ultrasound diagnosis of serous surface papillary borderline ovarian tumor: A case series with a review of the literature. AB - Serous surface papillary borderline ovarian tumors (SSPBOTs) are a rare morphologic variant of serous ovarian tumors that are typically confined to the ovarian surface, while the ovaries themselves tend to appear normal in size and shape. In this report, we describe the findings from five premenopausal women diagnosed with SSPBOTs, in whom ultrasound showed grossly normal ovaries that were partially or wholly covered with irregular solid tumors. In all five cases, histologic examination showed evidence of borderline serous tumors. These findings demonstrate that SSPBOTs can be diagnosed on a preoperative sonographic examination, which could facilitate conservative, fertility-sparing surgery in young women affected by this condition. PMID- 25706036 TI - Room temperature organocatalyzed reductive depolymerization of waste polyethers, polyesters, and polycarbonates. AB - The reductive depolymerization of a variety of polymeric materials based on polyethers, polyesters, and polycarbonates is described using hydrosilanes as reductants and metal-free catalysts. This strategy enables the selective depolymerization of waste polymers as well as bio-based polyesters to functional chemicals such as alcohols and phenols at room temperature. Commercially available B(C6 F5)3 and [Ph3 C(+),B(C6 F5)4(-)] catalysts are active hydrosilylation catalysts in this procedure and they are compatible with the use of inexpensive and air-stable polymethylhydrosiloxane and tetramethyldisiloxane as reductants. A significant advantage of this recycling method is derived from its tolerance to the additives present in waste plastics and its ability to selectively depolymerize mixtures of polymers. PMID- 25706037 TI - Crossover of positive states and experiences. PMID- 25706039 TI - Interventions to reduce waiting times for elective procedures. AB - BACKGROUND: Long waiting times for elective healthcare procedures may cause distress among patients, may have adverse health consequences and may be perceived as inappropriate delivery and planning of health care. OBJECTIVES: To assess the effectiveness of interventions aimed at reducing waiting times for elective care, both diagnostic and therapeutic. SEARCH METHODS: We searched the following electronic databases: Cochrane Effective Practice and Organisation of Care (EPOC) Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (1946-), EMBASE (1947-), the Cumulative Index to Nursing and Allied Health Literature (CINAHL), ABI Inform, the Canadian Research Index, the Science, Social Sciences and Humanities Citation Indexes, a series of databases via Proquest: Dissertations & Theses (including UK & Ireland), EconLit, PAIS (Public Affairs International), Political Science Collection, Nursing Collection, Sociological Abstracts, Social Services Abstracts and Worldwide Political Science Abstracts. We sought related reviews by searching the Cochrane Database of Systematic Reviews and the Database of Abstracts of Reviews of Effectiveness (DARE). We searched trial registries, as well as grey literature sites and reference lists of relevant articles. SELECTION CRITERIA: We considered randomised controlled trials (RCTs), controlled before-after studies (CBAs) and interrupted time series (ITS) designs that met EPOC minimum criteria and evaluated the effectiveness of any intervention aimed at reducing waiting times for any type of elective procedure. We considered studies reporting one or more of the following outcomes: number or proportion of participants whose waiting times were above or below a specific time threshold, or participants' mean or median waiting times. Comparators could include any type of active intervention or standard practice. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data from, and assessed risk of bias of, each included study, using a standardised form and the EPOC 'Risk of bias' tool. They classified interventions as follows: interventions aimed at (1) rationing and/or prioritising demand, (2) expanding capacity, or (3) restructuring the intake assessment/referral process.For RCTs when available, we reported preintervention and postintervention values of outcome for intervention and control groups, and we calculated the absolute change from baseline or the effect size with 95% confidence interval (CI). We reanalysed ITS studies that had been inappropriately analysed using segmented time-series regression, and obtained estimates for regression coefficients corresponding to two standardised effect sizes: change in level and change in slope. MAIN RESULTS: Eight studies met our inclusion criteria: three RCTs and five ITS studies involving a total of 135 general practices/primary care clinics, seven hospitals and one outpatient clinic. The studies were heterogeneous in terms of types of interventions, elective procedures and clinical conditions; this made meta-analysis unfeasible.One ITS study evaluating prioritisation of demand through a system for streamlining elective surgery services reduced the number of semi-urgent participants waiting longer than the recommended time (< 90 days) by 28 participants/mo, while no effects were found for urgent (< 30 days) versus non-urgent participants (< 365 days).Interventions aimed at restructuring the intake assessment/referral process were evaluated in seven studies. Four studies (two RCTs and two ITSs) evaluated open access, or direct booking/referral: One RCT, which showed that open access to laparoscopic sterilisation reduced waiting times, had very high attrition (87%); the other RCT showed that open access to investigative services reduced waiting times (30%) for participants with lower urinary tract syndrome (LUTS) but had no effect on waiting times for participants with microscopic haematuria. In one ITS study, same-day scheduling for paediatric health clinic appointments reduced waiting times (direct reduction of 25.2 days, and thereafter a decrease of 3.03 days per month), while another ITS study showed no effect of a direct booking system on proportions of participants receiving a colposcopy appointment within the recommended time. One RCT and one ITS showed no effect of distant consultancy (instant photography for dermatological conditions and telemedicine for ear nose throat (ENT) conditions) on waiting times; another ITS study showed no effect of a pooled waiting list on the number of participants waiting for uncomplicated spinal surgery.Overall quality of the evidence for all outcomes, assessed using the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) tool, ranged from low to very low.We found no studies evaluating interventions to increase capacity or to ration demand. AUTHORS' CONCLUSIONS: As only a handful of low-quality studies are presently available, we cannot draw any firm conclusions about the effectiveness of the evaluated interventions in reducing waiting times. However, interventions involving the provision of more accessible services (open access or direct booking/referral) show some promise. PMID- 25706040 TI - [Gender-specific Aspects of Knowledge and Gender Sensitivity in Medical Education - An Inventory]. AB - BACKGROUND: Gender competence is an essential prerequisite for individualized patient care. OBJECTIVES: The aim of this study is to survey the level of knowledge and attitudes towards gender-related aspects at 2 German medical schools. MATERIALS AND METHODS: An online questionnaire was used to collect data on gender competence in medicine including biological basics of sex differences, clinical aspects, socio-cultural factors as well as questions regarding gender role concepts. In total 1 671 students, 330 basic scientists, 413 physicians and 53 professors from the German Medical Schools Munster and Duisburg-Essen took part in the survey. RESULTS: The level of knowledge on gender-specific aspects in medicine is unsatisfactory at both medical schools. The average of correct answers on gender-related questions of all groups is less than 55%. Looking at gender sensitivity the existence and importance of gender disparities in medicine is agreed upon by the majority of participants. However, most of them regard only the patients' but not the physician's sex as relevant. CONCLUSIONS: The study reveals a lack of knowledge and the necessity for improvement: the integration of gender-specific aspects into medical routine is an important step towards a truly individualized medical care. PMID- 25706041 TI - [Is Work in Older Age Healthy? Findings from Family Run Businesses Using the Example of Bavarian Rural Economics]. AB - AIM OF STUDY: Working in second half of life is individually and socially important. The aim of this study is to multidimensionally evaluate the subjective health situation of older people, in particular those beyond the legal age of retirement who are working or assisting in family run businesses, using the example of Bavarian rural economics. METHODS: A 3 stage random sample stratified proportionally to regional population numbers was selected for a cross-sectional questionnaire survey (personal delivery, postal return n=3 176, 39.1%). Sample results can be generalised (men 59.8%, at least 65 years old 60.8%, smallest/small enterprises 61.8%). RESULTS: Life satisfaction is similar to that of the German age cohort population. In comparison to commercial and technical fields, physic and psychological complaints are lower and work pleasure is much higher. Health indicators are not dependent on enterprise structures, but on age and gender - on age partly non-linearly. CONCLUSION: Our results indicate that working in older age can be a source of subjective health. Process of family business succession may effect health. RESULTS might be applicable to other structurally similar agriculture regions and to craft sector. They promote individual confrontation with and social debate on a positive image of old age and aging. PMID- 25706042 TI - [Regional Deprivation in Germany: Nation-wide Analysis of its Association with Mortality Using the German Index of Multiple Deprivation (GIMD)]. AB - BACKGROUND: Deprivation indices are increasingly being used to assess the effects of contextual factors on health. In Germany, the recently developed 'German Index of Multiple Deprivation (GIMD)' integrates various dimensions of regional deprivation. We aim to assess the validity of the GIMD through a recalculation using more recent rural and urban district level data and by analysing its association with mortality at the national level. METHODS: We calculated a new version of the GIMD based on data from 2007 to 2010 for all 412 rural and urban districts in Germany. Mortality was quantified using indirectly standardised mortality ratios (SMRs). Correlation analyses and Poisson regression analyses were used to assess the association between the GIMD scores and total mortality, as well as premature mortality (< 65 years). RESULTS: Correlation analyses showed a positive association between the GIMD and both total mortality (p<0.001) and premature mortality (p<0.001). In the Poisson regression analyses, rural and urban districts in the quintile with the highest deprivation showed a significantly elevated risk of total mortality (RR: 1.29; 95% CI: 1.28-1.30) as well as premature mortality (RR: 1.50; 95% CI: 1.47-1.53), compared to the districts in the lowest quintile. CONCLUSION: The association between regional deprivation and mortality has already been shown for the federal state of Bavaria. Using more recent data, this relationship could be confirmed here for Germany as a whole. The GIMD has been shown to be able to effectively assess regional deprivation. Concerning public health policy, the significant, positive and stable association between regional deprivation and mortality indicates an increased need for health care provision particularly in the most deprived districts. Further studies should examine, for example, whether and how the allocation of districts to quintiles of regional deprivation changes over time, and how this affects mortality. PMID- 25706043 TI - [Access und Barriers to Recruiting Persons with Migration Background in the Field of Prehospital Emergency Care Research]. AB - OBJECTIVES: There is a lack of knowledge concerning the specific needs of migrants in the field of prehospital emergency care. One reason, amongst others, is the low participation in research of this specific group. The present study aims to elaborate the pros and cons for participation in prehospital emergency care research to ensure an adequate representation of people with migrant background. METHOD: Semi-structured interviews were conducted with 43 people with migration background who had experienced an emergency. The analysis was performed based on the statements concerning the following questions: (1) What motivated you to take part in this study? and (2) What could have prevented others from participation in this study? RESULTS: Content analysis revealed 5 categories for (1): relevance of the study, expression of appreciation, type as well as place of contact and the interviewer himself and 3 categories for (2): data protection, language barriers and personal experiences. CONCLUSION: Participation in prehospital emergency care research can be promoted by underlining the benefits of the study, in particular for other migrant emergency patients. PMID- 25706044 TI - The interaction of Saccharomyces paradoxus with its natural competitors on oak bark. AB - The natural history of the model yeast Saccharomyces cerevisiae is poorly understood and confounded by domestication. In nature, S. cerevisiae and its undomesticated relative S. paradoxus are usually found on the bark of oak trees, a habitat very different from wine or other human fermentations. It is unclear whether the oak trees are really the primary habitat for wild yeast, or whether this apparent association is due to biased sampling. We use culturing and high throughput environmental sequencing to show that S. paradoxus is a very rare member of the oak bark microbial community. We find that S. paradoxus can grow well on sterile medium made from oak bark, but that its growth is strongly suppressed when the other members of the community are present. We purified a set of twelve common fungal and bacterial species from the oak bark community and tested how each affected the growth of S. paradoxus in direct competition on oak bark medium at summer and winter temperatures, identifying both positive and negative interactions. One Pseudomonas species produces a diffusible toxin that suppresses S. paradoxus as effectively as either the whole set of twelve species together or the complete community present in nonsterilized oak medium. Conversely, one of the twelve species, Mucilaginibacter sp., had the opposite effect and promoted S. paradoxus growth at low temperatures. We conclude that, in its natural oak tree habitat, S. paradoxus is a rare species whose success depends on the much more abundant microbial species surrounding it. PMID- 25706045 TI - A retrospective comparison of ketamine dosing regimens for pediatric procedural sedation. AB - OBJECTIVE: Ketamine is a dissociative agent often used in pediatric emergency departments for procedural sedation. Institutions commonly use either 1.5 mg/kg (k1.5) or 1 mg/kg (k1.0) as intravenous dosing. We sought to determine whether patients receiving k1.0 require more administered doses during sedation than patients receiving k1.5. Furthermore, we examined whether differences existed between k1.0 and k1.5 in the total dosage, total mg/kg, and time to recovery. PATIENTS AND METHODS: A retrospective chart review examining procedural sedations from July 2010 through December 2011 was performed for sedations using k1.0 or k1.5. Cohorts were compared on the basis of the number of doses, mg/kg administered, total dosage (mg), and adverse events. RESULTS: A total of 346 patients were included, with 159 patients in k1.0 and 187 patients in k1.5. No significant differences in demographics were observed between k1.0 and k1.5. Patients in k1.5 required fewer median doses of ketamine compared with k1.0 (1.0 vs. 2.0, P=0.02). k1.0 had a higher median overall mg/kg dosage (1.71 mg/kg) than k1.5 (1.60 mg/kg) (P<0.01). k1.5 showed a decrease in the number of sedations requiring a third dose of ketamine to complete sedation as compared with k1.0 (7.57 vs. 18.47%, P=0.002). No significant difference in adverse events was found between k1.0 and k1.5. CONCLUSION: Sedations using k1.5 require fewer doses, lower mg/kg administered, but a higher total dose than k1.0. No difference was found in the rate of adverse events between the groups. Our findings suggest that ketamine sedations can be completed safely with one dose when patients are initially dosed at 1.5 mg/kg. PMID- 25706046 TI - Validation of an ELISA Synthetic Cannabinoids Urine Assay. AB - BACKGROUND: Synthetic cannabinoids are touted as legal alternatives to cannabis, at least when first released, and routine urine cannabinoid screening methods do not detect these novel psychoactive substances. Synthetic cannabinoids are widely available, are a major public health and safety problem, and a difficult challenge for drug-testing laboratories. We evaluated performance of the National Medical Services (NMS) JWH-018 direct enzyme-linked immunosorbent assay (ELISA) kit to sensitively, selectively, and rapidly screen urinary synthetic cannabinoids. METHODS: The NMS ELISA kit targeting the JWH-018 N-(5 hydroxypentyl) metabolite was used to screen 2492 urine samples with 5 and 10 mcg/L cutoffs. A fully validated liquid chromatography-tandem mass spectrometry method for 29 synthetic cannabinoids markers confirmed all presumptive positive and negative results. Performance challenges at +/-25% and +/-50% of cutoffs determined intraplate and interplate imprecision around proposed cutoffs. RESULTS: The immunoassay was linear from 1 to 500 mcg/L with intraplate and interplate imprecision of <=8.2% and <14.0%, respectively. No interferences were present from 93 common drugs of abuse, metabolites, coadministered drugs, over the-counter medications, or structurally similar compounds, and 19 of 73 individual synthetic cannabinoids (26%) exhibited moderate to high cross reactivity to JWH-018 N-(5-hydroxypentyl) metabolite. Sensitivity, specificity, and efficiency results were 83.7%, 99.4%, and 97.6%, as well as 71.6%, 99.7%, and 96.4% with the 5 and 10 mcg/L urine cutoffs, respectively. CONCLUSIONS: This high throughput immunoassay exhibited good diagnostic efficiency and documented that the NMS JWH-018 direct ELISA is a viable method for screening synthetic cannabinoids in urine targeting the JWH-018 N-(5-hydroxypentyl) and related analytes. Optimal performance was achieved with a matrix-matched 5 mcg/L urine cutoff. PMID- 25706047 TI - Poverty, inequality and mental health in low- and middle-income countries: time to expand the research and policy agendas. PMID- 25706048 TI - Novel risk score of contrast-induced nephropathy after percutaneous coronary intervention. AB - AIM: Contrast-induced nephropathy (CIN) post-percutaneous coronary intervention (PCI) is a major cause of acute kidney injury. In this study, we established a comprehensive risk score model to assess risk of CIN after PCI procedure, which could be easily used in a clinical environment. METHODS: A total of 805 PCI patients, divided into analysis cohort (70%) and validation cohort (30%), were enrolled retrospectively in this study. Risk factors for CIN were identified using univariate analysis and multivariate logistic regression in the analysis cohort. Risk score model was developed based on multiple regression coefficients. Sensitivity and specificity of the new risk score system was validated in the validation cohort. Comparisons between the new risk score model and previous reported models were applied. RESULTS: The incidence of post-PCI CIN in the analysis cohort (n = 565) was 12%. Considerably high CIN incidence (50%) was observed in patients with chronic kidney disease (CKD). Age >75, body mass index (BMI) >25, myoglobin level, cardiac function level, hypoalbuminaemia, history of chronic kidney disease (CKD), Intra-aortic balloon pump (IABP) and peripheral vascular disease (PVD) were identified as independent risk factors of post-PCI CIN. A novel risk score model was established using multivariate regression coefficients, which showed highest sensitivity and specificity (0.917, 95%CI 0.877-0.957) compared with previous models. CONCLUSION: A new post-PCI CIN risk score model was developed based on a retrospective study of 805 patients. Application of this model might be helpful to predict CIN in patients undergoing PCI procedure. PMID- 25706049 TI - Practitioner Review: Pathways to care for ADHD - a systematic review of barriers and facilitators. AB - BACKGROUND: Attention-Deficit/Hyperactivity Disorder (ADHD) is a common neurodevelopmental disorder starting in childhood that may persist into adulthood. It can be managed through carefully monitored medication and nonpharmacological interventions. Access to care for children at risk of ADHD varies both within and between countries. A systematic literature review was conducted to investigate the research evidence related to factors which influence children accessing services for ADHD. METHOD: Studies investigating access to care for children at risk of ADHD were identified through electronic searches of the international peer-reviewed and grey literature. Databases were searched from inception till 30th April 2012. This identified 23,156 articles which were subjected to three levels of screening (title, abstract and full text) by a minimum of two independent reviewers. Due to the heterogeneity in the study designs, a narrative approach was used to present the findings. RESULTS: Twenty seven papers met the inclusion criteria; these were grouped into four main themes, with some papers being included in more than one. These were wider determinants (10 papers); identification of need (9 papers); entry and continuity of care (13 papers) and interventions to improve access (4 papers). Barriers and facilitators to access were found to operate at the individual, organisational and societal level. Limited evidence of effective interventions to improve access was identified. CONCLUSION: This review explored the multilayered obstacles in the pathway to care for children at risk of ADHD and the lack of evidence-based interventions designed to address these issues, thereby indicating areas for service development and further evaluative research. PMID- 25706050 TI - Review of gastroesophageal reflux disease (GERD) in the diabetic patient. AB - This article reviews the known pathophysiological mechanisms of comorbid gastroesophageal reflux disease (GERD) in the diabetic patient, discusses therapeutic options in care, and provides an approach to its evaluation and management. We searched for review articles published in the past 10 years through a PubMed search using the filters diabetes mellitus, GERD, pathophysiology, and management. The search only yielded a handful of articles, so we independently included relevant studies from these review articles along with related citations as suggested by PubMed. We found diabetic patients are more prone to developing GERD and may present with atypical manifestations. A number of mechanisms have been proposed to elucidate the connection between these two diseases. Studies involving treatment options for comorbid disease suggest conflicting drug-drug interactions. Currently, there are no published guidelines specifically for the evaluation and management of GERD in the diabetic patient. Although there are several proposed mechanisms for the higher prevalence of GERD in the diabetic patient, this complex interrelationship requires further research. Understanding the pathophysiology will help direct diagnostic evaluation. In our review, we propose a management algorithm for GERD in the diabetic patient. PMID- 25706051 TI - Elevated diastolic, but not systolic, blood pressure measured in the emergency department predicts future development of hypertension in normotensive individuals. AB - Elevated blood pressure (BP) is reported in many individuals without hypertension presenting to the emergency department (ED). Whether this condition represents a transient state or is predictive for the development of future hypertension is unknown. This observational prospective study investigated patients admitted to an ED without a diagnosis of hypertension in whom BP values were >=140/90 mm Hg. The primary outcome was development of hypertension during follow-up. Overall, 195 patients were recruited and at the end of follow-up (average 30.14+/-15.96 months), 142 patients were diagnosed with hypertension (73%). The mean age (50+/ 12.25 vs 48.31+/-13.9, P=.419) and sex distribution (78 men/64 women vs 24 men/20 women, respectively; P=.148) were similar in both groups. There were significant differences in systolic and diastolic BP between those who developed hypertension on follow-up and those who did not (177.6 mm Hg+/-22.6/106.1 mm Hg+/-16.9 vs 168.6 mm Hg+/-18/95.2 mm Hg+/-12.2; P=.011 for systolic BP, P<.001 for diastolic BP). In multivariate analysis the only significant predictive factor for the development of hypertension was diastolic hypertension recorded in the ED (P=.03). Elevated diastolic, but not systolic, BP among patients presenting to the ED is associated with future development of hypertension in previously normotensive individuals. PMID- 25706052 TI - Extended supramolecular organization of pi-systems using yet unexplored simultaneous intra- and inter-molecular H-bonding motifs of 1,3-dihydroxy derivatives. AB - Unique H-bonding motifs of 1,3-dihydroxyl derivatives involving simultaneous intra- and inter-molecular H-bonding results in extended organization of pendant chromophores with a spatial distance suitable for pi-pi interaction. A preformed assembly with appended acceptor units exhibits host-guest interaction with specific donors by charge-transfer complex formation. PMID- 25706053 TI - Kinesio taping improves pain, range of motion, and proprioception in older patients with knee osteoarthritis: a randomized controlled trial. AB - OBJECTIVE: This study investigated the short-term effects of Kinesio taping (KT) on various types of pain, active range of motion (AROM), and proprioception in patients with knee osteoarthritis. DESIGN: Forty-six older participants (mean [SD], 57.9 [4.4] yrs) with osteoarthritis were randomly allocated to two groups: the KT group or the placebo-KT group. Taping with tension (KT application) or without tension (placebo-KT application) was applied to the quadriceps of the participants in both groups. Before and after intervention, pain intensity was measured using a visual analog scale at rest and during walking, and pressure pain thresholds (PPTs) were assessed using an algometer in the quadriceps and the tibialis anterior. In addition, pain-free AROM and proprioception were measured. RESULTS: The KT group showed attenuation of pain during walking (effect size [ES], 1.97), PPT in the quadriceps (ES, 2.58), and PPT in the tibialis anterior (ES, 2.45). This group also showed significantly improved AROM (ES, 2.01) and proprioception (ES, 1.73-1.89; P < 0.05). However, the placebo-KT group did not show significant changes in pain, AROM, or proprioception. There were significant differences between the two groups in pain during walking and PPT. In addition, pain during walking showed a significant correlation with AROM and proprioception, and a significant correlation was found between PPT and AROM. CONCLUSIONS: These results demonstrated that KT application with proper tension to the quadriceps effectively attenuates various types of pain and improves AROM and proprioception in osteoarthritis patients. Thus, KT may be a suitable intervention to improve pain, AROM, and proprioception in patients with osteoarthritis in clinics. PMID- 25706054 TI - Assessing the outcome of hand and forearm allotransplantation using the Action Research Arm Test. AB - OBJECTIVE: The aims of this study were to apply for the first time the Action Research Arm Test for functional assessment of an allotransplanted upper extremity (hand or forearm), to describe any adaptations required to this test system for the abovementioned purpose, and to use this test to record any changes in outcome over time. DESIGN: A structured approach to the Action Research Arm Test was adopted including interrater and intrarater reliability assessment at the very beginning of its use and ongoing comprehensive monitoring of patients through regular checkups. Four male patients who had undergone hand or forearm allotransplantations, in the authors' center, were examined. All 19 items in the Action Research Arm Test were reviewed, and the total score was calculated, taking into account the given time limits for each item. RESULTS: All patients showed a marked clinical improvement in their test results over time. They continued to have difficulties with performing items in the pinch subtest. The intrarater and interrater assessment achieved consistent results. CONCLUSIONS: The data of this study indicate that the Action Research Arm Test is suitable for assessing the level of upper extremity function. The test can be used to compare functional outcomes after hand and forearm allotransplantation between different centers, providing objective information concerning the quality of reconstruction. PMID- 25706055 TI - Convenient access to the tricyanoborate dianion B(CN)32- and selected reactions as a boron-centred nucleophile. AB - Alkali metal tricyanoborates M2B(CN)3 (M = Na, K) are accessible by the reaction of tricyanofluoroborates with alkali metals (i) in liquid NH3 or (ii) in THF naphthalene. The M2B(CN)3 are versatile starting materials for the synthesis of K[RB(CN)3] (R = Et, C6F5, CH2=CHCH2). PMID- 25706056 TI - Probing the exome in Alzheimer disease and other neurodegenerative disorders. PMID- 25706057 TI - One-step synthesis of gradient gadolinium ironhexacyanoferrate nanoparticles: a new particle design easily combining MRI contrast and photothermal therapy. AB - A one-step synthesis of Prussian blue nanoparticles possessing a concentration gradient of Gd3+ counterions, g-Gd-PB, has been developed, and the potential for the particles to perform as both MRI positive contrast agents and photothermal therapy agents is demonstrated. The synthesis of potassium/gadolinium ironhexacyanoferrate is performed under increasing concentration of Gd3+ ions forming particles with a higher concentration of gadolinium toward the outer layers. The proton relaxivity (r1) measured for the particles is 12.3 mM(-1) s( 1), and T1 weighted images of phantoms containing the particles show their potential as MRI contrast agents. In addition, the Prussian blue host can rapidly and efficiently convert energy from near-IR light into thermal energy, allowing g Gd-PB to be used as a photothermal therapy agent. The photothermal properties are demonstrated by measuring temperature changes of particle suspensions under irradiation and by photothermal ablation of CCRF-CEM cancer cells. PMID- 25706058 TI - Hierarchical Mn2O 3Hollow Microspheres as Anode Material of Lithium Ion Battery and Its Conversion Reaction Mechanism Investigated by XANES. AB - Hierarchical Mn2O3 hollow microspheres of diameter about 6-10 MUm were synthesized by solvent-thermal method. When serving as anode materials of LIBs, the hierarchical Mn2O3 hollow microspheres could deliver a reversible capacity of 580 mAh g(-1) at 500 mA g(-1) after 140 cycles, and a specific capacity of 422 mAh g(-1) at a current density as high as 1600 mA g(-1), demonstrating a good rate capability. Ex situ X-ray absorption near edge structure (XANES) spectrum reveals that, for the first time, the pristine Mn2O3 was reduced to metallic Mn when it discharged to 0.01 V, and oxidized to MnO as it charged to 3 V in the first cycle. Furthermore, the XANES data demonstrated also that the average valence of Mn in the sample at charged state has decreased slowly with cycling number, which signifies an incomplete lithiation process and interprets the capacity loss of the Mn2O3 during cycling. PMID- 25706059 TI - Determinants of lesbian and gay affirmative practice among heterosexual therapists. AB - The current study tested a conceptual model based on social-cognitive theory (Bandura, 1986), highlighting the influence of attitudes toward sexual minority individuals, training hours, affirmative counseling self-efficacy, and beliefs about affirmative practice on therapist engagement in lesbian and gay affirmative practice. We recruited via the Internet 443 heterosexual psychologists (n = 270), clinical social workers (n = 110), and marriage and family therapists (n = 63) residing in various parts of the United States. The majority of participants identified as female (70%) and White (88%). A path analysis indicated that beliefs and affirmative counseling self-efficacy mediated associations between attitudes and therapist engagement in affirmative practice. Furthermore, self efficacy mediated the relation between training hours and engagement in affirmative practice. Results suggest that more affirmative attitudes are linked with higher levels of affirmative counseling self-efficacy and more positive beliefs, which in turn positively influences therapist engagement in affirmative practice. Additionally, more hours of training influence affirmative counseling self-efficacy, which in turn correlates with higher levels of therapist engagement in affirmative practice. The discussion includes implications for affirmative practice training. PMID- 25706060 TI - The early formation of the working alliance from the client's perspective: A qualitative study. AB - This research used qualitative methods and archival data to examine clients' perceptions of the early formation of the working alliance. Following their first and second sessions of individual psychotherapy, 54 clients responded to structured written assignments that were rooted in Bordin's (1979) model of the alliance. Analysis yielded 884 recording units, which were organized into 4 main clusters: (a) clients' initial misgivings about psychotherapy; (b) organization and meaning-making; (c) psychotherapist supportive activities; and (d) client appreciation of techniques. Clients' perceived contributions to alliance development and their experiences of the initial interactions with their psychotherapists are explored in the context of existing theory and research. PMID- 25706061 TI - Simultaneous measurement of cholinergic tone and neuronal network dynamics in vivo in the rat brain using a novel choline oxidase based electrochemical biosensor. AB - Acetylcholine (ACh) modulates neuronal network activities implicated in cognition, including theta and gamma oscillations but the mechanisms remain poorly understood. Joint measurements of cholinergic activity and neuronal network dynamics with high spatio-temporal resolution are critical to understand ACh neuromodulation. However, current electrochemical biosensors are not optimized to measure nanomolar cholinergic signals across small regions like hippocampal sub-layers. Here, we report a novel oxidase-based electrochemical biosensor that matches these constraints. The approach is based on measurement of H2O2 generated by choline oxidase (ChOx) in the presence of choline (Ch). The microelectrode design consists of a twisted pair of 50um diameter Pt/Ir wires (sensor and sentinel), which is scalable, provides high spatial resolution and optimizes common mode rejection. Microelectrode coating with ChOx in chitosan cross-linked with benzoquinone is simple, mechanically robust and provides high sensitivity (324+/-46nAuM(-1)cm(-2)), a limit of detection of 16nM and a t50 response time of 1.4s. Local field potential (LFP)-related currents dominate high frequency component of electrochemical recordings in vivo. We significantly improved signal-to-noise-ratio compared to traditional sentinel subtraction by a novel frequency domain common mode rejection procedure that accounts for differential phase and amplitude of LFP-related currents on the two channels. We demonstrate measurements of spontaneous nanomolar Ch fluctuations, on top of which micromolar Ch increases occurred during periods of theta activity in anesthetized rats. Measurements were not affected by physiological O2 changes, in agreement with the low biosensor Km for O2 (2.6uM). Design and performance of the novel biosensor opens the way for multisite recordings of spontaneous cholinergic dynamics in behaving animals. PMID- 25706062 TI - Ultrasensitive electrochemical detection of secretoneurin based on Pb(2+) decorated reduced graphene oxide-tetraethylene pentamine as a label. AB - In this work, a novel electrochemical immunosensor for the detection of secretoneurin (SN), which uses metal ion functionalised reduced graphene oxide tetraethylene pentamine (rGO-TEPA) as a label, is reported for the first time. rGO-TEPA contains a large number of amino groups, which makes it an ideal templet for the loading of metal ions. rGO-TEPA-Pb(2+) was employed to immobilise secondary secretoneurin (SN) antibody (Ab2), and the resulting nanocomposite (Ab2 rGO-TEPA-Pb(2+)) was used as a trace tag for signal amplification. A modified electrode consisting of functionalised graphene nanosheets (Au@GS) was used as a substrate to immobilise the antibodies. Under the optimal conditions, the immunoassay exhibited high sensitivity, acceptable stability and reproducibility with a wide linear range from 0.001 to 100ngmL(-1) (R=0.996), and an ultra-low detection limit of 0.33pgmL(-1) (S/N=3). Furthermore, the immunosensor could be employed to detect SN in clinical serum samples. The proposed sensing strategy enriches the electrochemical immunoassay and exhibits potential for the point-of care diagnostic application of the clinical screening of biomarkers. PMID- 25706063 TI - "Geography of suicide in Hong Kong: spatial patterning, and socioeconomic correlates and inequalities". AB - Past urban research on Western nations tends to show high suicide rates in inner city and socioeconomically deprived areas. However, little is known about geographic variations in suicide in non-Western cities. We used Bayesian hierarchical models to estimate smoothed standardised mortality ratios (2005 2010) for suicide in people aged 10 years or above in each geographic unit in Hong Kong at two levels, i.e. large street block (n = 1639; median population = 1860) and small tertiary planning unit group (n = 204; median population = 14,850). We further analysed their associations with a range of area socioeconomic characteristics and a deprivation index. The "city centre" of Hong Kong, a generally non-deprived area, showed mostly below average suicide rates. However, there were high rates concentrating in some socioeconomically deprived, densely populated areas, including some inner city areas, across the city. Males had greater geographic variations in rates than females, except the elderly group. The use of smaller geographic units revealed finer detailed suicide distribution than the use of larger units, and showed that suicide rates were associated with indicators of socioeconomic deprivation (population with non professional jobs and low median household income), and social fragmentation (proportions of unmarried adults and divorced/separated adults), but not with Gini coefficient. Sex/age groups had different associations with suicide rates. Areas in the most deprived quintile had a suicide rate more than two times higher than the least deprived. The association between suicide and deprivation was stronger in males than females and more marked in the younger populations compared to the elderly. The spatial distribution of suicide in Hong Kong showed distinct patterning and a stronger association with income compared to findings from Western countries. Suicide prevention strategies should consider tackling the marked socioeconomic gradient in suicide and high risk in young and middle aged males living in deprived areas. PMID- 25706064 TI - Determinants of generic vs. brand drug choice: evidence from population-wide Danish data. AB - We investigate if demand for branded prescription medications in post-patent markets is patient- or doctor driven. When drugs go off-patent the brand medication often maintains non-negligible market shares. We use population-wide Danish data including all prescriptions for seven blockbuster drugs from 1998 to 2008, which amounts to 13,415,012 prescriptions. At the outset, descriptive statistics suggest large variation in drug choice over doctors. Nonetheless, using a two-way fixed effects model we find that the primary determinants of brand drug use are unobserved patient characteristics and price effects. PMID- 25706065 TI - Synthesis and mechanistic study of in situ halogen/nitrogen dual-doping in graphene tailored by stepwise pyrolysis of ionic liquids. AB - New halogen/nitrogen dual-doped graphenes (X/N-G) with thermally tunable doping levels are synthesized via the thermal reduction of graphite oxide (GO) with stepwise-pyrolyzed ionic liquids. The doping process of halogen and nitrogen into the graphene lattice proceeds via substitutional or covalent bonding through the physisorption or chemisorption of in situ pyrolyzed dopant precursors. The doping process is performed by heating to 300-400 degrees C of ionic liquid, and the chemically assisted reduction of GO is facilitated by ionic iodine, resulting in I/N-G materials possessing about three and two orders of magnitude higher conductivity (~22,200 S m(-1)) and charge carrier density (~10(21) cm(-3)), compared to those of thermally reduced GO. The thermally tunable doping levels of halogen in X/N-G significantly increase the conductivity of doped graphene to ~27,800 S m(-1). PMID- 25706066 TI - New insights into the pathophysiology of dyslipidemia in type 2 diabetes. AB - Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality for patients with type 2 diabetes, despite recent significant advances in management strategies to lessen CVD risk factors. A major cause is the atherogenic dyslipidemia, which consists of elevated plasma concentrations of both fasting and postprandial triglyceride-rich lipoproteins (TRLs), small dense low-density lipoprotein (LDL) and low high-density lipoprotein (HDL) cholesterol. The different components of diabetic dyslipidemia are not isolated abnormalities but closely linked to each other metabolically. The underlying disturbances are hepatic overproduction and delayed clearance of TRLs. Recent results have unequivocally shown that triglyceride-rich lipoproteins and their remnants are atherogenic. To develop novel strategies for the prevention and treatment of dyslipidaemia, it is essential to understand the pathophysiology of dyslipoproteinaemia in humans. Here, we review recent advances in our understanding of the pathophysiology of diabetic dyslipidemia. PMID- 25706067 TI - Integrated cognitive behavioral therapy for patients with substance use disorder and comorbid ADHD: two case presentations. AB - Two cases of integrated cognitive behavioral therapy (ICBT) for substance use disorder (SUD) and Attention Deficit Hyperactivity Disorder (ADHD) are presented illustrating that ICBT is a promising new treatment option. PMID- 25706069 TI - New and old milestones in reproductive medicine. PMID- 25706068 TI - Substance use and teen pregnancy in the United States: evidence from the NSDUH 2002-2012. AB - INTRODUCTION: Few, if any, studies have systematically examined the relationship between substance use and teen pregnancy using population-based samples. We aim to provide a comprehensive examination of substance use among pregnant adolescents in the United States. METHOD: Employing data from the National Survey on Drug Use and Health between 2002 and 2012 (n=97,850), we examine the prevalence of the past 12-month and the past 30-day substance use and substance use disorders among pregnant and non-pregnant adolescents (ages 12-17). We also examine psychosocial and pregnancy-related correlates of current substance use among the subsample of pregnant adolescents (n=810). RESULTS: Pregnant teens were significantly more likely to have experimented with a variety of substances and meet criteria for alcohol (AOR=1.65, 95% CI=1.26-2.17), cannabis (AOR=2.29, 95% CI=1.72-3.04), and other illicit drug use disorders (AOR=2.84, 95% CI=1.92-4.19). Pregnant early adolescents (ages 12-14; AOR=4.34, 95% CI=2.28-8.26) were significantly more likely and pregnant late adolescents (ages 15-17; AOR=0.71, 95% CI=0.56-0.90) significantly less likely than their non-pregnant counterparts to be current substance users. CONCLUSIONS: Study findings point not only to a relationship between pregnancy and prior substance use, but also suggest that substance use continues for many teens during pregnancy. We found that substance use is particularly problematic among early adolescents and that the prevalence of substance use attenuates dramatically as youth progress from the first to the second and third trimesters of pregnancy. PMID- 25706070 TI - 10+10: rapid decisions and fast track publication for RCTs. PMID- 25706071 TI - Prescribing safety: ensuring that new graduates are prepared. PMID- 25706073 TI - Henry Marsh: telling the stories of neurosurgery. PMID- 25706074 TI - Culture and health. PMID- 25706075 TI - Culture and health. PMID- 25706076 TI - Culture and health. PMID- 25706077 TI - Culture and health--author's reply. PMID- 25706078 TI - Favipiravir for children with Ebola. PMID- 25706079 TI - Quotations on the cover page of the journal. PMID- 25706080 TI - Teaching anthropology to medical students. PMID- 25706081 TI - Call for transparency in new generation trade deals. PMID- 25706082 TI - Violence and homicide in Mexico: a global health issue. PMID- 25706083 TI - Access to cardiac surgery in sub-Saharan Africa. PMID- 25706084 TI - Arrhythmogenic right ventricular cardiomyopathy. PMID- 25706085 TI - Delta-aminolevulinic acid dehydratase activity (ALA-D) in red mullet (Mullus barbatus) from Mediterranean waters as biomarker of lead exposure. AB - The enzyme delta-aminolevulinic acid dehydratase (ALA-D) has been investigated as biomarker of lead (Pb) exposure in red mullet (Mullus barbatus) from the Spanish continental shelf. Concentrations of Pb and Zn in muscle and organosomatic indices were also measured to explore causality. Blood ALA-D assay conditions were optimized; the optimum pH for this species has been set to 6.5. Results showed that ALA-D activity ranged from 3.2 to 16.9 nmol PBGmin(-1)mg(-1). No significant differences on ALA-D levels between genders have been detected. ALA-D Baseline level and Background Assessment Criteria (BAC) for this species have been set to 9.1 and 6.6 nmol PBGmin(-1)mg(-1), respectively. There have been detected significant differences on ALA-D activity levels among areas, though the markedly low levels of Pb measured in fish muscle seemed not to be able to produce a relevant suppression on ALA-D. In spite of this, a weak inverse relationship detected between ALA-D and Pb concentrations pointed out the potential of this biomarker in red mullet to reflect Pb bioavailability in marine environment. Nevertheless, subsequent research on ALA-D in marine fish species is recommended to be limited to areas where environmental Pb is effectively accumulated by fish. PMID- 25706086 TI - Reduction in toxicity of coking wastewater to aquatic organisms by vertical tubular biological reactor. AB - We conducted a battery of toxicity tests using photo bacterium, algae, crustacean and fish to evaluate acute toxicity profile of coking wastewater, and to evaluate the performance of a novel wastewater treatment process, vertical tubular biological reactor (VTBR), in the removal of toxicity and certain chemical pollutants. A laboratory scale VTBR system was set up to treat industrial coking wastewater, and investigated both chemicals removal efficiency and acute bio toxicity to aquatic organisms. The results showed that chemical oxygen demand (COD) and phenol reductions by VTBR were approximately 93% and 100%, respectively. VTBR also reduced the acute toxicity of coking wastewater significantly: Toxicity Unit (TU) decreased from 21.2 to 0.4 for Photobacterium phosphoreum, from 9.5 to 0.6 for Isochrysis galbana, from 31.9 to 1.3 for Daphnia magna, and from 30.0 to nearly 0 for Danio rerio. VTBR is an efficient treatment method for the removal of chemical pollutants and acute bio-toxicity from coking wastewater. PMID- 25706087 TI - Micronucleus as biomarker of genotoxicity in birds from Brazilian Cerrado. AB - Birds are considered efficient bioindicators, by their behavioral characteristics, diversified diet, and use of several vegetation layers, including in contaminated environments. The accumulation of contaminants can harm the reproductive process and survival of species, in addition to causing severe metabolic disorders. Air pollution can also affect the birds' health. Micronucleus analysis, a technique able to evaluate the organisms' sensitivity to contaminant agents, has been regarded as a practical tool for evaluating and monitoring the clastogenic and aneugenic effects caused by pollutants. The purpose of this study was to evaluate the presence of micronuclei in bird species that use forest environments and their surroundings; and to verify if the frequency and amount of micronuclei varies between species, areas and populations. Birds transiting between the Brazilian Cerrado forest and open formations were analyzed, coming from four forest fragments of Triangulo Mineiro, two close to urban areas and two more distant. Birds were captured with mist-nets for collecting blood extensions, which were used for counting micronuclei. In total, 103 individuals of 21 species were captured, and the micronucleus rate for every 5000 erythrocytes analyzed was 1.30. Only six populations had sampling sufficiency. There was no difference between the number of individuals with and without micronuclei (chi2=3.18, df=1, p=0.08). In areas closer to the urban perimeter, the micronuclei averages in birds were greater compared to the most isolated areas (H=27.534, df=3, p<0,001). In Sao Jose, the individuals of Myiothlypis flaveola presented a number of micronuclei significantly greater than the Galheiro and Agua Fria (H=9.601, df=2, p=0.008). M. flaveola clearly reflected the area quality. The micronuclei analysis in birds was effective for evaluating the area quality as well as the intensity with which the birds respond to impacts caused by the surrounding matrix. PMID- 25706088 TI - Simple preparation of carbon nanofibers with graphene layers perpendicular to the length direction and the excellent li-ion storage performance. AB - Sulfur-containing carbon nanofibers with the graphene layers approximately vertical to the fiber axis were prepared by a simple reaction between thiophene and sulfur at 550 degrees C in stainless steel autoclaves without using any templates. The formation mechanism was discussed briefly, and the potential application as anode material for lithium-ion batteries was tentatively investigated. The carbon nanofibers exhibit a stable reversible capacity of 676.8 mAh/g after cycling 50 times at 0.1 C, as well as the capacities of 623.5, 463.2, and 365.8 mAh/g at 0.1, 0.5, and 1.0 C, respectively. The excellent electrochemical performance could be attributed to the effect of sulfur. On one hand, sulfur could improve the reversible capacity of carbon materials due to its high theoretical capacity; on the other hand, sulfur could promote the formation of the unique carbon nanofibers with the graphene layers perpendicular to the axis direction, favorable to shortening the Li-ion diffusion path. PMID- 25706089 TI - Downregulation of 5-HT7 Serotonin Receptors by the Atypical Antipsychotics Clozapine and Olanzapine. Role of Motifs in the C-Terminal Domain and Interaction with GASP-1. AB - The human 5-HT7 serotonin receptor, a G-protein-coupled receptor (GPCR), activates adenylyl cyclase constitutively and upon agonist activation. Biased ligands differentially activate 5-HT7 serotonin receptor desensitization, internalization and degradation in addition to G protein activation. We have previously found that the atypical antipsychotics clozapine and olanzapine inhibited G protein activation and, surprisingly, induced both internalization and lysosomal degradation of 5-HT7 receptors. Here, we aimed to determine the mechanism of clozapine- and olanzapine-mediated degradation of 5-HT7 receptors. In the C-terminus of the 5-HT7 receptor, we identified two YXXPhi motifs, LR residues, and a palmitoylated cysteine anchor as potential sites involved in receptor trafficking to lysosomes followed by receptor degradation. Mutating either of these sites inhibited clozapine- and olanzapine-mediated degradation of 5-HT7 receptors and also interfered with G protein activation. In addition, we tested whether receptor degradation was mediated by the GPCR-associated sorting protein-1 (GASP-1). We show that GASP-1 binds the 5-HT7 receptor and regulates the clozapine-mediated degradation. Mutations of the identified motifs and residues, located in or close to Helix-VIII of the 5-HT7 receptor, modified antipsychotic-stimulated binding of proteins (such as GASP-1), possibly by altering the flexibility of Helix-VIII, and also interfered with G protein activation. Taken together, our data demonstrate that binding of clozapine or olanzapine to the 5-HT7 receptor leads to antagonist-mediated lysosomal degradation by exposing key residues in the C-terminal tail that interact with GASP-1. PMID- 25706090 TI - Exercise Augmentation of Exposure Therapy for PTSD: Rationale and Pilot Efficacy Data. AB - Brain-derived neurotrophic factor (BDNF) is associated with synaptic plasticity, which is crucial for long-term learning and memory. Some studies suggest that people suffering from anxiety disorders show reduced BDNF relative to healthy controls. Lower BDNF is associated with impaired learning, cognitive deficits, and poor exposure-based treatment outcomes. A series of studies with rats showed that exercise elevates BDNF and enhances fear extinction. However, this strategy has not been tested in humans. In this pilot study, we randomized participants (N = 9, 8 females, M(Age) = 34) with posttraumatic stress disorder (PTSD) to (a) prolonged exposure alone (PE) or (b) prolonged exposure+exercise (PE+E). Participants randomized to the PE+E condition completed a 30-minute bout of moderate-intensity treadmill exercise (70% of age-predicted HR(max)) prior to each PE session. Consistent with prediction, the PE+E group showed a greater improvement in PTSD symptoms (d = 2.65) and elevated BDNF (d = 1.08) relative to the PE only condition. This pilot study provides initial support for further investigation into exercise augmented exposure therapy. PMID- 25706091 TI - Potency of polycyclic aromatic hydrocarbons (PAHs) for induction of ethoxyresorufin-O-deethylase (EROD) activity in hepatocyte cultures from chicken, Pekin duck, and greater scaup. AB - The potency of tetrachlorodibenzo-p-dioxin (TCDD) and 18 polycyclic aromatic hydrocarbons (PAHs) for induction of ethoxyresorufin-O-deethylase (EROD) activity was assessed in primary hepatocyte cultures prepared from chicken (Gallus domesticus), Pekin duck (Anas platyrhynchos domesticus), and greater scaup (Aythya marila). TCDD and 8 of the PAHs induced EROD activity in a concentration dependent manner. Seven of these were previously shown to be acutely toxic to avian embryos, while the 10 congeners that did not produce an EROD response caused limited mortality. The rank order potency of the EROD-active congeners in all three species was as follows: TCDD>dibenz[ah]anthracene>benzo[k]fluoranthene>indeno[1,2,3 cd]pyrene>benzo[a]pyrene>chrysene~benz[a]anthracene~benz[ghi]perylene>benzo[b]nap tho[2,3-d]thiophene. Chicken hepatoctyes were more sensitive than duck hepatocytes to EROD induction by all test compounds, but the gap in species sensitivity was 100-fold for TCDD, and generally <=10-fold for PAHs. This study is the first to use in vitro methods to rank the AHR-mediated potency of PAHs in birds. These data may be useful for assessing risks associated with exposure to PAHs in the environment. PMID- 25706092 TI - Ombitasvir, paritaprevir co-dosed with ritonavir, dasabuvir, and ribavirin for hepatitis C in patients co-infected with HIV-1: a randomized trial. AB - IMPORTANCE: Patients co-infected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) are at high risk for liver disease progression. However, interferon-based treatments for HCV infection have significant toxicities, limiting treatment uptake. OBJECTIVE: To assess the all-oral 3 direct-acting antiviral (3D) regimen of ombitasvir, paritaprevir (co-dosed with ritonavir [paritaprevir/r]), dasabuvir, and ribavirin in HCV genotype 1-infected adults with HIV-1 co-infection, including patients with cirrhosis. DESIGN, SETTING, AND PARTICIPANTS: TURQUOISE-I is a randomized, open-label study. Part 1a of this pilot study was conducted at 17 sites in the United States and Puerto Rico between September 2013 and August 2014 and included 63 patients with HCV genotype 1 and HIV-1 co-infection who were HCV treatment-naive or had history of prior treatment failure with peginterferon plus ribavirin therapy. The study allowed enrollment of patients, including those with cirrhosis, with a CD4+ count of 200/mm3 or greater or CD4+ percentage of 14% or more and plasma HIV-1 RNA suppressed while taking a stable atazanavir- or raltegravir-inclusive antiretroviral regimen. INTERVENTIONS: Ombitasvir/paritaprevir/r, dasabuvir, and ribavirin for 12 or 24 weeks of treatment as randomized. MAIN OUTCOMES AND MEASURES: The primary assessment was the proportion of patients with sustained virologic response (HCV RNA <25 IU/mL) at posttreatment week 12 (SVR12). RESULTS: Among patients receiving 12 or 24 weeks of 3D and ribavirin, SVR12 was achieved by 29 of 31 (94%; 95% CI, 79%-98%) and 29 of 32 patients (91%; 95% CI, 76%-97%), respectively. Of the 5 patients who did not achieve SVR, 1 withdrew consent, 2 had confirmed virologic relapse or breakthrough, and 2 patients had clinical history and phylogenetic evidence consistent with HCV reinfection. The most common treatment-emergent adverse events were fatigue (48%), insomnia (19%), nausea (18%), and headache (16%). Adverse events were generally mild, with none reported as serious or leading to discontinuation. No patient had a confirmed HIV 1 breakthrough of 200 copies/mL or greater during treatment. CONCLUSIONS AND RELEVANCE: In this open-label, randomized uncontrolled study, treatment with the all-oral, interferon-free 3D-plus-ribavirin regimen resulted in high SVR rates among patients co-infected with HCV genotype 1 and HIV-1 whether treated for 12 or 24 weeks. Further phase 3 studies of this regimen are warranted in patients with co-infection. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01939197. PMID- 25706093 TI - Involvement of urokinase in cigarette smoke extract-induced epithelial mesenchymal transition in human small airway epithelial cells. AB - Urokinase-type plasminogen activator (uPA) augments inflammation and tissue remodeling during lung injury and repair. The uPA expression in small airway epithelium of chronic obstructive pulmonary disease (COPD) increases. Epithelial mesenchymal transition (EMT) is important in the small airway fibrosis of COPD. This study shows the uPA regulation in cigarette smoke extract (CSE)-induced EMT in human small airway epithelial cell lines (HSAEpiCs). uPA is overexpressed in the small airway epithelium of COPD patients and CSE-treated cell lines. Furthermore, uPA expression correlated with vimentin expression in the small airway epithelium of COPD patients. uPA inhibition blocks CSE-induced EMT by reversing E-cadherin and alpha-catenin expression and retarding the induction of N-cadherin and vimentin, resulting in reduction in migration. uPA overexpression in HSAEpiC cells also promotes EMT and migration. EMT is partly reversed in uPA overexpressing HSAEpiC cells through the silencing expression of uPA receptor. In conclusion, this study provides new insights into the contribution of uPA upregulation to EMT associated with small airway remodeling in COPD. PMID- 25706094 TI - Increased susceptibility of estrogen-induced bladder outlet obstruction in a novel mouse model. AB - Disorders of the prostate and lower urinary tract are common in elderly men. We investigated the role of metallothionein-1 (MT1) in prostate carcinogenesis by generating a prostate-specific, MT1-expressing mouse. Unexpectedly, genomic analyses revealed that a 12.1-kb genomic region harboring several conserved noncoding elements was unintentionally deleted, upstream of the transgene integration site in the mouse, which we named it 12.1DeltaMT1. Male 12.1DeltaMT1 mice chronically treated with testosterone (T) plus 17beta-estradiol (E2) to induce prostate cancer exhibited no evidence of precancerous or cancerous lesions. Instead, most of them exhibited a bladder outlet obstruction (BOO) phenotype not observed in treated wild-type (WT) mice. Thus, we hypothesized that 12.1DeltaMT1 is a novel model for studying the hormonal requirement for BOO induction. Adult male 12.1DeltaMT1 and WT mice were treated with T, E2, bisphenol A (BPA), T+E2, or T+BPA for up to 6 months. Histologic and immunohistochemical analysis of the prostate, bladder, and urethra were performed. No significant prostate pathologies were observed in WT or 12.1DeltaMT1 mice treated with any of the hormone regimens. As expected, prostatic regression occurred in all E2 treated animals (WT and 12.1DeltaMT1). Of great interest, despite a small prostate, 100% of E2-treated 12.1DeltaMT1 mice, but only 40% of E2-treated WT mice, developed severe BOO (P<0.01). In contrast, T+E2 treatment was less effective than E2 treatment in inducing severe BOO in 12.1DeltaMT1 mice (68%, P<0.05) and was completely ineffective in WT animals. Similarly, T, BPA, and T+BPA treatments did not induce BOO in either WT or 12.1DeltaMT1 mice. The BOO pathology includes a thinner detrusor wall, narrowing of bladder neck and urethral lumen, and basal cell hyperplasia in the bladder body and urethra. These findings indicate that 12.1DeltaMT1 mice exhibit enhanced susceptibility to E2 induced BOO that is independent of prostate enlargement but that is attenuated by the conjoint treatment with T. PMID- 25706095 TI - Centralized reminder/recall: collaboration to promote the effective use of technology. PMID- 25706097 TI - The immunology of Epstein-Barr virus-induced disease. AB - Epstein-Barr virus (EBV) is usually acquired silently early in life and carried thereafter as an asymptomatic infection of the B lymphoid system. However, many circumstances disturb the delicate EBV-host balance and cause the virus to display its pathogenic potential. Thus, primary infection in adolescence can manifest as infectious mononucleosis (IM), as a fatal illness that magnifies the immunopathology of IM in boys with the X-linked lymphoproliferative disease trait, and as a chronic active disease leading to life-threatening hemophagocytosis in rare cases of T or natural killer (NK) cell infection. Patients with primary immunodeficiencies affecting the NK and/or T cell systems, as well as immunosuppressed transplant recipients, handle EBV infections poorly, and many are at increased risk of virus-driven B-lymphoproliferative disease. By contrast, a range of other EBV-positive malignancies of lymphoid or epithelial origin arise in individuals with seemingly intact immune systems through mechanisms that remain to be understood. PMID- 25706096 TI - Molecular mechanisms in genetically defined autoinflammatory diseases: disorders of amplified danger signaling. AB - Patients with autoinflammatory diseases present with noninfectious fever flares and systemic and/or disease-specific organ inflammation. Their excessive proinflammatory cytokine and chemokine responses can be life threatening and lead to organ damage over time. Studying such patients has revealed genetic defects that have helped unravel key innate immune pathways, including excessive IL-1 signaling, constitutive NF-kappaB activation, and, more recently, chronic type I IFN signaling. Discoveries of monogenic defects that lead to activation of proinflammatory cytokines have inspired the use of anticytokine-directed treatment approaches that have been life changing for many patients and have led to the approval of IL-1-blocking agents for a number of autoinflammatory conditions. In this review, we describe the genetically characterized autoinflammatory diseases, we summarize our understanding of the molecular pathways that drive clinical phenotypes and that continue to inspire the search for novel treatment targets, and we provide a conceptual framework for classification. PMID- 25706099 TI - In silico analysis for structure, function and T-cell epitopes of a hypothetical conserved (HP-C) protein coded by PVX_092425 in Plasmodium vivax. AB - OBJECTIVE: Plasmodium spp. merozoite glycosylphosphatidylinositol-anchored proteins (GPI-APs) considered as protective immunogen in novel vaccines against malaria. To analyze the structure and function of a hypothetical conserved (HP-C) GPI-AP coded by gene PVX_092425 from Plasmodium vivax, and find its potential T cell epitopes for further vivax malaria vaccine study. METHODS: The structure, function and T-cell epitopes of the HP-C protein named Pvx_092425 were analyzed and predicted by online and offline bioinformatics software. RESULTS: The bioinformatics data showed that the Pvx_092425 is an 830 amino acid (AA) long polypeptide encoded by five exons gene PVX_092425.It contains a pectin lyase-like superfamily, an AA repeats region, a cys-rich region and a transmembrane domain (TM) in C-terminal region. The alignment analysis drew it has a unique AA repeats region among Plasmodium spp. It was located in the cytoplasm, secretory system or cellular nucleus of P. vivax merozoite. For the sequence, the fragment of I823 V829 inserts in the interior side of the membrane, and M1--A812 belongs to the cytoplasmic tail. It has seven protein-protein binding sites. The peptides with the best predicted binding affinities were human leucocyte antigen (HLA) HLA A*0203, HLA-DRB1*0101 and HLA- DRB1*0701.Among these predicted peptides, 582FLWDKALFD590 epitope interacted with HLA-DRB1*0101 allele showed best binding affinity compared to others. Structural analysis explained that the epitope fits well into the epitope-binding groove of HLA-DRB1*0101. CONCLUSIONS: It proposes that the Pvx_092425 plays a key role during erythrocyte stage and generates information that is useful for development of blood-stage vaccine to block the merozoites invasion. PMID- 25706100 TI - 2-Aryl-3-methyloctahydrophenanthrene-2,3,7-triols as potent dissociated glucocorticoid receptor agonists. AB - A significant improvement in agonist activity of the previously described 2 aryloctahydrophenanthrene-2,3,7-triol series of dissociated glucocorticoid receptor agonists (DAGRs) was achieved by modifying the substitution at C3 from (S)-3-hydroxy to (R)-3-hydroxy-3-methyl. The IC50 of the prototype 13 in the efficacy assay measuring repression of IL-1 induced MMP-13 expression was 3.5 nM, exhibiting 87% of the maximal effect of dexamethasone (DEX). It displayed a dissociated profile by exhibiting 42% of the maximal effect of DEX in a mouse mammary tumor virus (MMTV) luciferase reporter transactivation assay. Compound 13 and analogues containing heterocyclic replacements for the C2 phenyl and modified B rings showed high repression of TNFalpha production in human whole blood, with IC50 values (43-167 nM) approaching the level of DEX (21 nM). On the basis of X ray structures and force field calculations, the overall potency of this series was attributed to a favorable conformation of the C2alpha phenyl, induced by the neighboring C3alpha methyl. PMID- 25706101 TI - Interlayer-expanded molybdenum disulfide nanocomposites for electrochemical magnesium storage. AB - Mg rechargeable batteries (MgRBs) represent a safe and high-energy battery technology but suffer from the lack of suitable cathode materials due to the slow solid-state diffusion of the highly polarizing divalent Mg ion. Previous methods improve performance at the cost of incompatibility with anode/electrolyte and drastic decrease in volumetric energy density. Herein we report interlayer expansion as a general and effective atomic-level lattice engineering approach to transform inactive intercalation hosts into efficient Mg storage materials without introducing adverse side effects. As a proof-of-concept we have combined theory, synthesis, electrochemical measurement, and kinetic analysis to improve Mg diffusion behavior in MoS2, which is a poor Mg transporting material in its pristine form. First-principles simulations suggest that expanded interlayer spacing allows for fast Mg diffusion because of weakened Mg-host interactions. Experimentally, the expansion was realized by inserting a controlled amount of poly(ethylene oxide) into the lattice of MoS2 to increase the interlayer distance from 0.62 nm to up to 1.45 nm. The expansion boosts Mg diffusivity by 2 orders of magnitude, effectively enabling the otherwise barely active MoS2 to approach its theoretical storage capacity as well as to achieve one of the highest rate capabilities among Mg-intercalation materials. The interlayer expansion approach can be leveraged to a wide range of host materials for the storage of various ions, leading to novel intercalation chemistry and opening up new opportunities for the development of advanced materials for next-generation energy storage. PMID- 25706102 TI - A mixed ionic and electronic conducting dual-phase membrane with high oxygen permeability. AB - To combine good chemical stability and high oxygen permeability, a mixed ionic electronic conducting (MIEC) 75 wt% Ce(0.85)Gd(0.1)Cu(0.05)O(2-delta)-25 wt% La(0.6)Ca(0.4)FeO(3-delta)(CGCO-LCF) dual-phase membrane based on a MIEC-MIEC composite has been developed. Copper doping into Ce(0.9)Gd(0.1)O(2-delta) (CGO) oxide enhances both ionic and electronic conductivity, which then leads to a change from ionic conduction to mixed conduction at elevated temperatures. For the first time we demonstrate that an intergranular film with 2-10 nm thickness containing Ce, Ca, Gd, La, and Fe has been formed between the CGCO grains in the CGCO-LCF one-pot dual-phase membrane. A high oxygen permeation flux of 0.70 mL min(-1) cm(-2) is obtained by the CGCO-LCF one-pot dual-phase membrane with 0.5 mm thickness at 950 degrees C using pure CO2 as the sweep gas, and the membrane shows excellent stability in the presence of CO2 even at lower temperatures (800 degrees C) during long-term operation. PMID- 25706098 TI - Interleukin-22: immunobiology and pathology. AB - Interleukin-22 (IL-22) is a recently described IL-10 family cytokine that is produced by T helper (Th) 17 cells, gammadelta T cells, NKT cells, and newly described innate lymphoid cells (ILCs). Knowledge of IL-22 biology has evolved rapidly since its discovery in 2000, and a role for IL-22 has been identified in numerous tissues, including the intestines, lung, liver, kidney, thymus, pancreas, and skin. IL-22 primarily targets nonhematopoietic epithelial and stromal cells, where it can promote proliferation and play a role in tissue regeneration. In addition, IL-22 regulates host defense at barrier surfaces. However, IL-22 has also been linked to several conditions involving inflammatory tissue pathology. In this review, we assess the current understanding of this cytokine, including its physiologic and pathologic effects on epithelial cell function. PMID- 25706103 TI - W(h)ither human cardiac and body magnetic resonance at ultrahigh fields? technical advances, practical considerations, applications, and clinical opportunities. AB - The objective of this study was to document and review advances and groundbreaking progress in cardiac and body MR at ultrahigh fields (UHF, B0 >= 7.0 T) with the goal to attract talent, clinical adopters, collaborations and resources to the biomedical and diagnostic imaging communities. This review surveys traits, advantages and challenges of cardiac and body MR at 7.0 T. The considerations run the gamut from technical advances to clinical opportunities. Key concepts, emerging technologies, practical considerations, frontier applications and future directions of UHF body and cardiac MR are provided. Examples of UHF cardiac and body imaging strategies are demonstrated. Their added value over the kindred counterparts at lower fields is explored along with an outline of research promises. The achievements of cardiac and body UHF-MR are powerful motivators and enablers, since extra speed, signal and imaging capabilities may be invested to overcome the fundamental constraints that continue to hamper traditional cardiac and body MR applications. If practical obstacles, concomitant physics effects and technical impediments can be overcome in equal measure, sophisticated cardiac and body UHF-MR will help to open the door to new MRI and MRS approaches for basic research and clinical science, with the lessons learned at 7.0 T being transferred into broad clinical use including diagnostics and therapy guiding at lower fields. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 25706104 TI - Mortality following Traumatic Brain Injury Inpatient Rehabilitation. AB - The aim of this study was to examine the rate and causes of mortality following mild to severe traumatic brain injury (TBI) rehabilitation and to develop a multivariate prognostic model of mortality. We conducted a cohort study of 3341 individuals with mild to severe TBI followed-up from a post-acute inpatient rehabilitation center. Rate of death and survival between one and 26 years following injury were examined using standardized mortality ratios (SMRs) and prognostic models developed using Cox regression. A mortality rate of 9.3% was observed and an overall SMR of 1.04 (95% confidence interval [CI]=1.04-1.05). A statistically significant elevated SMR of 1.20 (95% CI=1.06-1.37) was observed for males, and both males and females had an elevated risk of death from external causes. Females also were found to have a significantly elevated SMR of 5.02 (95% CI=1.36-12.80) for intentional self-harm. Individuals ages 15-44 had a two-fold increase in mortality, compared with the general population. The multivariate Cox model indicated that increased risk of mortality was associated with older age, being male, being unemployed prior to injury, having a history of stroke, alcohol use, mental health issues, and back injury sustained in the accident. Premorbid lifestyle factors exerted a greater influence on mortality following TBI, compared with injury-related factors. This risk was especially prominent for younger individuals, who died primarily due to external causes. These findings highlight the need for interventions that address premorbid issues, such as substance abuse and mental health issues. PMID- 25706105 TI - The Vegetarian Habit in Italy: Prevalence and Characteristics of Consumers. AB - Many individuals around the world follow vegetarian diet. The aim of this study was to examine the variables associated to a vegetarian diet. Data were drawn from the national cross-sectional survey "Health and use of health care in Italy". Vegetarian habit was prevalent in 0.79% of sample, mainly females. Multivariate model has confirmed the association between vegetarianism and females, age, level of education, marital status separated/divorced/single, diabetes, bad state of perceived health. Little to no research has been conducted in this area until now. As for all types of diet, the vegetarian one should be controlled. PMID- 25706106 TI - NHLBI strategic visioning: setting an agenda together for the NHLBI of 2025. PMID- 25706108 TI - Molecular Bases of Chemoresistance in Cholangiocarcinoma. AB - The multidrug resistance (MDR) phenotype accounts for the poor response of cholangiocarcinoma to available antitumor drugs. This is an important limitation to the use of pharmacological approaches, both as adjuvant therapies and for treating advanced CCA when surgical removal is not possible. MDR is the result of a complex combination of defense mechanisms against toxic compounds already present in cholangiocytes, which play a role in the physiology of these cells by protecting the biliary epithelium from the toxins reaching the biliary tree with the blood that perfuses this tissue, or that are secreted by hepatocytes into bile, to which cholangiocytes are exposed. These mechanisms of chemoresistance (MOC) are also present, usually with enhanced efficacy, in tumors derived from cholangiolar cells. The present review article is an update of the state-of-the art regarding the MOC involved in the poor response of CCA to antitumor drugs. These MOC have been classified as: changes in the amount of drug in the cells due to decreased uptake (MOC-1a) or enhanced efflux (MOC-1b); altered proportions between prodrug, active drug and inactive metabolites (MOC-2); changes in the molecular targets of antitumor drugs (MOC-3); an enhanced ability of tumor cells to repair drug-induced DNA damage (MOC-4), and an impaired apoptosis/survival balance (MOC-5). PMID- 25706109 TI - Discovery of Novel Anti-Diabetic Drugs by Targeting Lipid Metabolism. AB - Accumulation of toxic lipids is the most common etiology of insulin resistance in type 2 diabetes and associated metabolic disorders such as obesity and non alcoholic fatty liver disease. Understanding of the underlying mechanisms has revealed various opportunities to target key regulators in lipid metabolic pathways for the treatment of metabolic diseases. Here, we review the discovery and development of potential anti-diabetic drugs with primary effects on cellular targets leading to reductions of intracellular lipids in key organs. We will particularly focus on AMPK, SIRT1, PGC-1alpha, SREBP-1c, ChREBP, ACC, PPARs and HSPs which either stimulate in fatty acid oxidation (energy expenditure) or inhibit de novo lipogenesis. PMID- 25706110 TI - Novel Antigen Targets for Immunotherapy of Acute Myeloid Leukemia. AB - Acute myeloid leukemia (AML) was the first malignancy for which immunotherapy, in the form of allogeneic hematopoietic stem cell transplantation (allo-HSCT), was integrated into the standard of care. Allo-HSCT however is an imperfect therapy associated with significant morbidity and mortality while offering only incomplete prevention of AML clinical relapse. These limitations have motivated the search for AML-related antigens that might be used as more specific and effective targets of immunotherapy. While historically such investigations have focused on protein targets expressed uniquely in AML or at significantly higher levels than in normal tissues, this article will review recent discoveries which have identified a novel selection of potential antigen targets for AML immunotherapy, such as non-protein targets including lipids and carbohydrates, neo-antigens created from genetic somatic mutations or altered splicing and post translational modification of protein targets, together with innovative ways to target overexpressed protein targets presented by cell surface peptide-MHC complexes. These novel antigens represent promising candidates for further development as targets of AML immunotherapy. PMID- 25706112 TI - Locking covalent organic frameworks with hydrogen bonds: general and remarkable effects on crystalline structure, physical properties, and photochemical activity. AB - A series of two-dimensional covalent organic frameworks (2D COFs) locked with intralayer hydrogen-bonding (H-bonding) interactions were synthesized. The H bonding interaction sites were located on the edge units of the imine-linked tetragonal porphyrin COFs, and the contents of the H-bonding sites in the COFs were synthetically tuned using a three-component condensation system. The intralayer H-bonding interactions suppress the torsion of the edge units and lock the tetragonal sheets in a planar conformation. This planarization enhances the interlayer interactions and triggers extended pi-cloud delocalization over the 2D sheets. Upon AA stacking, the resulting COFs with layered 2D sheets amplify these effects and strongly affect the physical properties of the material, including improving their crystallinity, enhancing their porosity, increasing their light harvesting capability, reducing their band gap, and enhancing their photocatalytic activity toward the generation of singlet oxygen. These remarkable effects on the structure and properties of the material were observed for both freebase and metalloporphyin COFs. These results imply that exploration of supramolecular ensembles would open a new approach to the structural and functional design of COFs. PMID- 25706111 TI - TNF superfamily protein-protein interactions: feasibility of small- molecule modulation. AB - The tumor necrosis factor (TNF) superfamily (TNFSF) contains about thirty structurally related receptors (TNFSFRs) and about twenty protein ligands that bind to one or more of these receptors. Almost all of these cell surface protein protein interactions (PPIs) represent high-value therapeutic targets for inflammatory or immune modulation in autoimmune diseases, transplant recipients, or cancers, and there are several biologics including antibodies and fusion proteins targeting them that are in various phases of clinical development. Small molecule inhibitors or activators could represent possible alternatives if the difficulties related to the targeting of protein-protein interactions by small molecules can be addressed. Compounds proving the feasibility of such approaches have been identified through different drug discovery approaches for a number of these TNFSFR-TNFSF type PPIs including CD40-CD40L, BAFFR-BAFF, TRAIL-DR5, and OX40-OX40L. Corresponding structural, signaling, and medicinal chemistry aspects are briefly reviewed here. While none of these small-molecule modulators identified so far seems promising enough to be pursued for clinical development, they provide proof-of-principle evidence that these interactions are susceptible to small-molecule modulation and can serve as starting points toward the identification of more potent and selective candidates. PMID- 25706113 TI - Meta-analysis of prognostic factors for amputation following surgical repair of lower extremity vascular trauma. AB - BACKGROUND: Lower extremity vascular trauma (LEVT) is a major cause of amputation. A clear understanding of prognostic factors for amputation is important to inform surgical decision-making, patient counselling and risk stratification. The aim was to develop an understanding of prognostic factors for amputation following surgical repair of LEVT. METHODS: A systematic review was conducted to identify potential prognostic factors. Bayesian meta-analysis was used to calculate an absolute (pooled proportion) and relative (pooled odds ratio, OR) measure of the amputation risk for each factor. RESULTS: Forty-five studies, totalling 3187 discrete LEVT repairs, were included. The overall amputation rate was 10.0 (95 per cent credible interval 7.4 to 13.1) per cent. Significant prognostic factors for secondary amputation included: associated major soft tissue injury (26 versus 8 per cent for no soft tissue injury; OR 5.80), compartment syndrome (28 versus 6 per cent; OR 5.11), multiple arterial injuries (18 versus 9 per cent; OR 4.85), duration of ischaemia exceeding 6 h (24 versus 5 per cent; OR 4.40), associated fracture (14 versus 2 per cent; OR 4.30), mechanism of injury (blast 19 per cent, blunt 16 per cent, penetrating 5 per cent), anatomical site of injury (iliac 18 per cent, popliteal 14 per cent, tibial 10 per cent, femoral 4 per cent), age over 55 years (16 versus 9 per cent; OR 3.03) and sex (men 7 per cent versus women 8 per cent; OR 0.64). Shock and nerve or venous injuries were not significant prognostic factors for secondary amputation. CONCLUSION: A significant proportion of patients who undergo lower extremity vascular trauma repair will require secondary amputation. This meta analysis describes significant prognostic factors needed to inform surgical judgement, risk assessment and patient counselling. PMID- 25706114 TI - A novel mutation in COL4A1 gene: a possible cause of early postnatal cerebrovascular events. AB - COL4A1 is located in humans on chromosome13q34 and it encodes the alpha 1 chain of type IV collagen, a component of basal membrane. It is expressed mainly in the brain, muscles, kidneys and eyes. Different COL4A1 mutations have been reported in many patients who present a very wide spectrum of clinical symptoms. They typically show a multisystemic phenotype. Here we report on the case of a patient carrying a novel de novo splicing mutation of COL4A1 associated with a distinctive clinical picture characterized by onset in infancy and an unusual evolution of the neuroradiological features. At three months of age, the child was diagnosed with a congenital cataract, while his brain MRI was normal. Over the following years, the patient developed focal epilepsy, mild diplegia, asymptomatic microhematuria, raised creatine kinase levels, MRI white matter abnormalities and brain calcification on CT. During the neuroradiological follow up the extension and intensity of the brain lesions progressively decreased. The significance of a second variant in COL4A1 carried by the child and inherited from his father remains to be clarified. In conclusion, our patient shows new aspects of this collagenopathy and possibly a COL4A1 compound heterozygosity. PMID- 25706115 TI - The population demography of Betula maximowicziana, a cool-temperate tree species in Japan, in relation to the last glacial period: its admixture-like genetic structure is the result of simple population splitting not admixing. AB - Conservation of the local genetic variation and evolutionary integrity of economically and ecologically important trees is a key aspect of studies involving forest genetics, and a population demographic history of the target species provides valuable information for this purpose. Here, the genetic structure of 48 populations of Betula maximowicziana was assessed using 12 expressed sequence tag-simple sequence repeat (EST-SSR) markers. Genetic diversity was lower in northern populations than southern ones and structure analysis revealed three groups: northern and southern clusters and an admixed group. Eleven more genomic-SSR loci were added and the demographic history of these three groups was inferred by approximate Bayesian computation (ABC). The ABC revealed that a simple split scenario was much more likely than isolation with admixture, suggesting that the admixture-like structure detected in this species was due to ancestral polymorphisms. The ABC analysis suggested that the population growth and divergence of the three groups occurred 96 800 (95% CI, 20 500-599 000) and 28 300 (95% CI, 8700-98 400) years ago, respectively. We need to be aware of several sources of uncertainty in the inference such as assumptions about the generation time, overlapping of generations, confidence intervals of the estimated parameters and the assumed model in the ABC. However, the results of the ABC together with the model-based maps of reconstructed past species distribution and palaeoecological data suggested that the modern genetic structure of B. maximowicziana originated prior to the last glacial maximum (LGM) and that some populations survived in the northern range even during the LGM. PMID- 25706116 TI - Influence of genes suppressing interferon effects in peripheral blood mononuclear cells during triple antiviral therapy for chronic hepatitis C. AB - The levels of expression of interferon-stimulated genes (ISGs) in liver are associated with response to treatment with pegylated interferon (PEG-IFN) plus ribavirin (RBV). However, associations between the responses of ISGs to IFN-based therapy and treatment efficacy or interleukin-28B (IL28B) genotype have not yet been determined. Therefore, we investigated the early responses of ISGs and interferon-lambdas (IFN-lambdas) in peripheral blood mononuclear cells (PBMCs) during PEG-IFN/RBV plus NS3/4 protease inhibitor (PI) therapy. We prospectively enrolled 50 chronic hepatitis C patients with HCV genotype 1, and collected PBMCs at baseline, 8 and 24 h after the initial administration of PEG-IFN/RBV/PI. Levels of mRNAs for selected ISGs and IFN-lambdas were evaluated by real-time PCR. All 31 patients with a favorable IL28B genotype and 13 of 19 with an unfavorable genotype achieved sustained virological responses (SVR). Levels of mRNA for A20, SOCS1, and SOCS3, known to suppress antiviral activity by interfering with the IFN signaling pathway, as well as IRF1 were significantly higher at 8 h in patients with an unfavorable IL28B genotype than in those with a favorable one (P = 0.007, 0.026, 0.0004, 0.0006, respectively), especially in the non-SVR group. Particularly, the fold-change of IRF1 at 8 h relative to baseline was significantly higher in non-SVR than in SVR cases with an unfavorable IL28B genotype (P = 0.035). In conclusion, levels of several mRNAs of genes suppressing antiviral activity in PBMCs during PEG-IFN/RBV/PI differed according to IL28B genotypes, paralleling treatment efficacy. PMID- 25706117 TI - Expression of the SNARE protein SNAP-23 is essential for cell survival. AB - Members of the SNARE-family of proteins are known to be key regulators of the membrane-membrane fusion events required for intracellular membrane traffic. The ubiquitously expressed SNARE protein SNAP-23 regulates a wide variety of exocytosis events and is essential for mouse development. Germline deletion of SNAP-23 results in early embryonic lethality in mice, and for this reason we now describe mice and cell lines in which SNAP-23 can be conditionally-deleted using Cre-lox technology. Deletion of SNAP-23 in CD19-Cre expressing mice prevents B lymphocyte development and deletion of SNAP-23 using a variety of T lymphocyte specific Cre mice prevents T lymphocyte development. Acute depletion of SNAP-23 in mouse fibroblasts leads to rapid apoptotic cell death. These data highlight the importance of SNAP-23 for cell survival and describe a mouse in which specific cell types can be eliminated by expression of tissue-specific Cre recombinase. PMID- 25706118 TI - The fucosylation inhibitor, 2-fluorofucose, inhibits vaso-occlusion, leukocyte endothelium interactions and NF-KB activation in transgenic sickle mice. AB - 2-Fluorofucose (2FF) blocks the fucosylation and the tethering of sialyl-Lewisx tetrasaccharide and structural variants on leukocytes and red blood cells to P- and E-selectins on activated endothelial cell surfaces. Because P- and E-selectin are required for vaso-occlusion in murine sickle cell disease (SCD), we investigated whether 2FF would inhibit vaso-occlusion in SCD mice. Microvascular stasis was measured in subcutaneous venules in NY1DD and HbSS-Townes SCD mice with dorsal skin-fold chambers after infusion of hemoglobin or exposure to hypoxia/reoxygenation. 2FF in drinking water or administered by gavage inhibited stasis in sickle mice in a dose-responsive manner. Significant inhibitory effects on stasis were seen 1 day post-treatment. 2FF treatment of SCD mice also significantly reduced leukocyte rolling and adhesion along the vessel walls of SCD mice and the static adhesion of neutrophils and sickle red blood cells isolated from 2FF-treated SCD mice to resting and activated endothelial cells. Total white blood cell counts increased in response to 2FF. NF-KB activation and VCAM-1 and E-selectin expression were inhibited in the livers of SCD mice consistent with an overall decrease in vascular inflammation and ischemia reperfusion physiology. Pretreatment with 2FF completely eliminated heme-induced lethality in HbSS-Townes mice, consistent with the observed anti-inflammatory and anti-adhesive properties of 2FF in SCD mice. These data suggest that 2FF may be beneficial for preventing or treating vaso-occlusive crises in SCD patients. PMID- 25706119 TI - Voluntary medical male circumcision scale-up in Nyanza, Kenya: evaluating technical efficiency and productivity of service delivery. AB - BACKGROUND: Voluntary medical male circumcision (VMMC) service delivery is complex and resource-intensive. In Kenya's context there is still paucity of information on resource use vis-a-vis outputs as programs scale up. Knowledge of technical efficiency, productivity and potential sources of constraints is desirable to improve decision-making. OBJECTIVE: To evaluate technical efficiency and productivity of VMMC service delivery in Nyanza in 2011/2012 using data envelopment analysis. DESIGN: Comparative process evaluation of facilities providing VMMC in Nyanza in 2011/2012 using output orientated data envelopment analysis. RESULTS: Twenty one facilities were evaluated. Only 1 of 7 variables considered (total elapsed operation time) significantly improved from 32.8 minutes (SD 8.8) in 2011 to 30 minutes (SD 6.6) in 2012 (95%CI = 0.0350-5.2488; p = 0.047). Mean scale technical efficiency significantly improved from 91% (SD 19.8) in 2011 to 99% (SD 4.0) in 2012 particularly among outreach compared to fixed service delivery facilities (CI -31.47959-4.698508; p = 0.005). Increase in mean VRS technical efficiency from 84% (SD 25.3) in 2011 and 89% (SD 25.1) in 2012 was not statistically significant. Benchmark facilities were #119 and #125 in 2011 and #103 in 2012. Malmquist Productivity Index (MPI) at fixed facilities declined by 2.5% but gained by 4.9% at outreach ones by 2012. Total factor productivity improved by 83% (p = 0.032) in 2012, largely due to progress in technological efficiency by 79% (p = 0.008). CONCLUSIONS: Significant improvement in scale technical efficiency among outreach facilities in 2012 was attributable to accelerated activities. However, ongoing pure technical inefficiency requires concerted attention. Technological progress was the key driver of service productivity growth in Nyanza. Incorporating service-quality dimensions and using stepwise-multiple criteria in performance evaluation enhances comprehensiveness and validity. These findings highlight site-level resource use and sources of variations in VMMC service productivity, which are important for program planning. PMID- 25706120 TI - Development and implementation of the National Cancer Institute's Food Attitudes and Behaviors Survey to assess correlates of fruit and vegetable intake in adults. AB - BACKGROUND: Low fruit and vegetable (FV) intake is a leading risk factor for chronic disease globally as well as in the United States. Much of the population does not consume the recommended servings of FV daily. This paper describes the development of psychosocial measures of FV intake for inclusion in the U.S. National Cancer Institute's 2007 Food Attitudes and Behaviors Survey. METHODS: This was a cross-sectional study among 3,397 adults from the United States. Scales included conventional constructs shown to be correlated with fruit and vegetable intake (FVI) in prior studies (e.g., self-efficacy, social support), and novel constructs that have been measured in few- to- no studies (e.g., views on vegetarianism, neophobia). FVI was assessed with an eight-item screener. Exploratory factor analysis, Cronbach's alpha, and regression analyses were conducted. RESULTS: Psychosocial scales with Cronbach's alpha >=0.68 were self efficacy, social support, perceived barriers and benefits of eating FVs, views on vegetarianism, autonomous and controlled motivation, and preference for FVs. Conventional scales that were associated (p<0.05) with FVI were self-efficacy, social support, and perceived barriers to eating FVs. Novel scales that were associated (p<0.05) with FVI were autonomous motivation, and preference for vegetables. Other single items that were associated (p<0.05) with FVI included knowledge of FV recommendations, FVI "while growing up", and daily water consumption. CONCLUSION: These findings may inform future behavioral interventions as well as further exploration of other potential factors to promote and support FVI. PMID- 25706121 TI - Loss of prolyl carboxypeptidase in two-kidney, one-clip goldblatt hypertensive mice. AB - It is well documented that angiotensin (Ang) II contributes to kidney disease progression. The protease prolyl carboxypeptidase (PRCP) is highly expressed in the kidney and may be renoprotective by degrading Ang II to Ang-(1-7). The aim of the study was to investigate whether renal PRCP protein expression and activity are altered in two-kidney, one-clip (2K1C) Goldblatt hypertensive mice. Left renal artery was constricted by using 0.12 mm silver clips. Blood pressure was measured using telemetry over the eleven weeks of study period and revealed an immediate increase in 2K1C animals during the first week of clip placement which was followed by a gradual decrease to baseline blood pressure. Similarly, urinary albumin excretion was significantly increased one week after 2K1C and returned to baseline levels during the following weeks. At 2 weeks and at the end of the study, renal pathologies were exacerbated in the 2K1C model as revealed by a significant increase in mesangial expansion and renal fibrosis. Renal PRCP expression and activity were significantly reduced in clipped kidneys. Immunofluorescence revealed the loss of renal tubular PRCP but not glomerular PRCP. In contrast, expression of prolyl endopeptidase, another enzyme capable of converting Ang II into Ang-(1-7), was not affected, while angiotensin converting enzyme was elevated in unclipped kidneys and renin was increased in clipped kidneys. Results suggest that PRCP is suppressed in 2K1C and that this downregulation may attenuate renoprotective effects via impaired Ang II degradation by PRCP. PMID- 25706122 TI - Lipidomic profiling of di- and tri-acylglycerol species in weight-controlled mice. AB - Weight control by dietary calorie restriction (DCR) or exercise has been shown to prevent cancer in various models. However, the mechanisms as to how weight control is beneficial are not well understood. While previous reports have investigated the effects of weight control on total lipid levels or lipid composition within cellular membranes, there has been little work surrounding changes to individual lipids following weight control interventions. In this study, using a model of skin carcinogenesis centered on the tumor promotion stage, CD-1 mice were randomly assigned into 4 groups: ad libitum and sedentary (control), ad libitum with exercise (AL+Exe), exercise with pair feeding of a diet isocaloric with control (PF+Exe), and sedentary with 20% DCR compared to control. After ten weeks, body weight and body fat percentages significantly decreased in the PF+Exe and DCR groups but not AL+Exe when compared with sedentary controls. Murine skin and plasma samples were obtained for analysis. Lipidomics using electrospray ionization MS/MS was employed to profile triacylglycerol (TG) and diacylglycerol (DG) species. Both plasma and tissue TG species containing fatty acid chains with length 18:1 were significantly decreased following DCR when compared to sedentary control animals. In regards to DG, the most significant changes occurred in the plasma. DG species containing fatty acids with lengths 16:1 or 18:1 were significantly decreased in PF+Exe and DCR groups when compared to sedentary controls. Due to the significant role of TG in energy storage and DG in cellular signaling, our findings of the effects of weight control on individual TG and DG species in plasma and skin tissue following exposure to a tumor promoter, may provide insight into the mechanism of weight control on cancer prevention. PMID- 25706124 TI - Using common spatial distributions of atoms to relate functionally divergent influenza virus N10 and N11 protein structures to functionally characterized neuraminidase structures, toxin cell entry domains, and non-influenza virus cell entry domains. AB - The ability to identify the functional correlates of structural and sequence variation in proteins is a critical capability. We related structures of influenza A N10 and N11 proteins that have no established function to structures of proteins with known function by identifying spatially conserved atoms. We identified atoms with common distributed spatial occupancy in PDB structures of N10 protein, N11 protein, an influenza A neuraminidase, an influenza B neuraminidase, and a bacterial neuraminidase. By superposing these spatially conserved atoms, we aligned the structures and associated molecules. We report spatially and sequence invariant residues in the aligned structures. Spatially invariant residues in the N6 and influenza B neuraminidase active sites were found in previously unidentified spatially equivalent sites in the N10 and N11 proteins. We found the corresponding secondary and tertiary structures of the aligned proteins to be largely identical despite significant sequence divergence. We found structural precedent in known non-neuraminidase structures for residues exhibiting structural and sequence divergence in the aligned structures. In N10 protein, we identified staphylococcal enterotoxin I-like domains. In N11 protein, we identified hepatitis E E2S-like domains, SARS spike protein-like domains, and toxin components shared by alpha-bungarotoxin, staphylococcal enterotoxin I, anthrax lethal factor, clostridium botulinum neurotoxin, and clostridium tetanus toxin. The presence of active site components common to the N6, influenza B, and S. pneumoniae neuraminidases in the N10 and N11 proteins, combined with the absence of apparent neuraminidase function, suggests that the role of neuraminidases in H17N10 and H18N11 emerging influenza A viruses may have changed. The presentation of E2S-like, SARS spike protein-like, or toxin-like domains by the N10 and N11 proteins in these emerging viruses may indicate that H17N10 and H18N11 sialidase-facilitated cell entry has been supplemented or replaced by sialidase-independent receptor binding to an expanded cell population that may include neurons and T-cells. PMID- 25706123 TI - Expression of recombinant human lysozyme in egg whites of transgenic hens. AB - Chicken egg lysozyme (cLY) is an enzyme with 129 amino acid (AA) residue enzyme. This enzyme is present not only in chicken egg white but also in mucosal secretions such as saliva and tears. The antibacterial properties of egg white can be attributed to the presence of lysozyme, which is used as an anti-cancer drug and for the treatment of human immunodeficiency virus (HIV) infection. In this study, we constructed a lentiviral vector containing a synthetic cLY signal peptide and a 447 bp synthetic human lysozyme (hLY) cDNA sequence driven by an oviduct-specific ovalbumin promoter, and microinjected into the subgerminal cavity of stage X chick embryos to generate transgenic chicken. The transgene inserted in the chicken chromosomes directs the synthesis and secretion of hLY which has three times higher specific activity than cLY. Three G1 transgenic chickens were identified, the only female of which expressed recombinant human lysozyme (rhLY) at 57.66 +/- 4.10 MUg/ml in the egg white and the G2 transgenic hens of the G1 transgenic cock A011 expressed rhLY at 48.72 +/- 1.54 MUg/ml. This experiment demonstrated that transgenic hens with stable oviduct-specific expression of recombinant human lysozyme proteins can be created by microinjection of lentiviral vectors. The results of this research could be contribute to the technological development using transgenic hens as a cost effective alternative to other mammalian systems, such as cow, sheep and goats, for the production of therapeutic proteins and other applications. PMID- 25706125 TI - Isovaline does not activate GABA(B) receptor-coupled potassium currents in GABA(B) expressing AtT-20 cells and cultured rat hippocampal neurons. AB - Isovaline is a non-proteinogenic amino acid that has analgesic properties. R isovaline is a proposed agonist of the gamma-aminobutyric acid type B (GABA(B)) receptor in the thalamus and peripheral tissue. Interestingly, the responses to R isovaline differ from those of the canonical GABA(B) receptor agonist R-baclofen, warranting further investigation. Using whole cell recording techniques we explored isovaline actions on GABA(B) receptors coupled to rectifying K+ channels in cells of recombinant and native receptor preparations. In AtT-20 cells transfected with GABA(B) receptor subunits, bath application of the GABA(B) receptor agonists, GABA (1 MUM) and R-baclofen (5 MUM) produced inwardly rectifying currents that reversed approximately at the calculated reversal potential for K+ R- isovaline (50 MUM to 1 mM) and S-isovaline (500 MUM) did not evoke a current. R-isovaline applied either extracellularly (250 MUM) or intracellularly (10 MUM) did not alter responses to GABA at 1 MUM. Co administration of R-isovaline (250 MUM) with a low concentration (10 nM) of GABA did not result in a response. In cultured rat hippocampal neurons that natively express GABA(B) receptors, R-baclofen (5 MUM) induced GABA(B) receptor-dependent inward currents. Under the same conditions R-isovaline (1 or 50 MUM) did not evoke a current or significantly alter R-baclofen-induced effects. Therefore, R isovaline does not interact with recombinant or native GABA(B) receptors to open K+ channels in these preparations. PMID- 25706126 TI - Soil types effect on grape and wine composition in Helan Mountain area of Ningxia. AB - Different soil types can significantly affect the composition of wine grapes and the final wine product. In this study, the effects of soil types on the composition of Cabernet Sauvignon grapes and wine produced in the Helan Mountains were evaluated. Three different representative soil types--aeolian, sierozem and irrigation silting soil were studied. The compositions of grapes and wines were measured, and in addition, the weights of 100-berry samples were determined. The grapes that grown on the aeolian and sierozem soils matured sooner than those grown on the irrigation silting soil. The highest sugar content, total soluble solids content, sugar to acid ratio and anthocyanin content were found in the grapes that grown on the aeolian soil. The wine produced from this soil had improved chroma and tone and higher-quality phenols. The grapes grown on the sierozem soil had the highest total phenol and tannin contents, which affected the wine composition. The grapes grown on the irrigation silting soil had higher acidities, but the remaining indices were lower. In addition, the grapes grown on the aeolian soil resulted in wines with better chroma and aroma. The sierozem soil was beneficial for the formation of wine tannins and phenols and significantly affected the wine composition. The quality of the grapes from the irrigation silting soil was relatively low, resulting in lower-quality wine. PMID- 25706127 TI - Subfamily Limoniinae Speiser, 1909 (Diptera, Limoniidae) from Baltic amber (Eocene): the genus Elephantomyia Osten Sacken, 1860. AB - A revision of the genus Elephantomyia Osten Sacken (Diptera: Limoniidae) from Baltic amber (Eocene) is presented. Four species--E. baltica Alexander, E. brevipalpa Loew, E. longirostris Loew, and E. pulchella Loew--are redescribed and documented with photographs and drawings. In addition, two new species of the genus are described: Elephantomyia bozenae sp. nov., and Elephantomyia irinae sp. nov. All these fossil species are placed within the subgenus Elephantomyia. A key to the extinct species of Elephantomyia is provided, and the genus' ecological pattern and evolutionary aspects are discussed. PMID- 25706128 TI - Myospheres are composed of two cell types: one that is myogenic and a second that is mesenchymal. AB - Previously, in an attempt to isolate stem cells that would be capable of regenerating injured skeletal muscle, we cultured cells derived from muscle, non adherently, in serum-free media. As a result of the culture conditions used, these cells formed spheres, and thus were referred to as myospheres. It was found that myosphere-derived cells expressed Sca-1, a marker that is not typically associated with myogenic cells, and as a result has generated some questions as to the origin of these cells. The goal of this study was to clearly determine the origin of myosphere-derived cells, and in particular to answer the question of whether myospheres contain myogenic cells. To determine if myospheres were composed of myogenic cells without altering the structure of myospheres or the culture conditions used to maintain myospheres, I isolated these cells from yellow fluorescent protein (YFP)-Myf5, YFP-MyoD, and ZsGreen-Pax7 lineage-tracing mice and monitored their growth over time. I found that myospheres do contain myogenic cells, but that these cells are gradually lost over time (within 2 months). Additionally, the use of the lineage-tracing mice gave an interesting perspective into the composition of myospheres. I found that myospheres were composed of two distinct cell types, one that is myogenic (alpha7 integrin+) and contains cells expressing Myf5, MyoD, and Pax7, and a second that is non-myogenic (alpha7 integrin-) expressing platelet-derived growth factor receptor alpha (PDGFRalpha) and Sca-1, both of which have been associated with fibro/adipocyte mesenchymal cells. PMID- 25706129 TI - Recent selective sweeps in North American Drosophila melanogaster show signatures of soft sweeps. AB - Adaptation from standing genetic variation or recurrent de novo mutation in large populations should commonly generate soft rather than hard selective sweeps. In contrast to a hard selective sweep, in which a single adaptive haplotype rises to high population frequency, in a soft selective sweep multiple adaptive haplotypes sweep through the population simultaneously, producing distinct patterns of genetic variation in the vicinity of the adaptive site. Current statistical methods were expressly designed to detect hard sweeps and most lack power to detect soft sweeps. This is particularly unfortunate for the study of adaptation in species such as Drosophila melanogaster, where all three confirmed cases of recent adaptation resulted in soft selective sweeps and where there is evidence that the effective population size relevant for recent and strong adaptation is large enough to generate soft sweeps even when adaptation requires mutation at a specific single site at a locus. Here, we develop a statistical test based on a measure of haplotype homozygosity (H12) that is capable of detecting both hard and soft sweeps with similar power. We use H12 to identify multiple genomic regions that have undergone recent and strong adaptation in a large population sample of fully sequenced Drosophila melanogaster strains from the Drosophila Genetic Reference Panel (DGRP). Visual inspection of the top 50 candidates reveals that in all cases multiple haplotypes are present at high frequencies, consistent with signatures of soft sweeps. We further develop a second haplotype homozygosity statistic (H2/H1) that, in combination with H12, is capable of differentiating hard from soft sweeps. Surprisingly, we find that the H12 and H2/H1 values for all top 50 peaks are much more easily generated by soft rather than hard sweeps. We discuss the implications of these results for the study of adaptation in Drosophila and in species with large census population sizes. PMID- 25706130 TI - MicroRNA markers for the diagnosis of pancreatic and biliary-tract cancers. AB - It is difficult to detect pancreatic cancer or biliary-tract cancer at an early stage using current diagnostic technology. Utilizing microRNA (miRNA) markers that are stably present in peripheral blood, we aimed to identify pancreatic and biliary-tract cancers in patients. With "3D-Gene", a highly sensitive microarray, we examined comprehensive miRNA expression profiles in 571 serum samples obtained from healthy patients, patients with pancreatic, biliary-tract, or other digestive cancers, and patients with non-malignant abnormalities in the pancreas or biliary tract. The samples were randomly divided into training and test cohorts, and candidate miRNA markers were independently evaluated. We found 81 miRNAs for pancreatic cancer and 66 miRNAs for biliary-tract cancer that showed statistically different expression compared with healthy controls. Among those markers, 55 miRNAs were common in both the pancreatic and biliary-tract cancer samples. The previously reported miR-125a-3p was one of the common markers; however, it was also expressed in other types of digestive-tract cancers, suggesting that it is not specific to cancer types. In order to discriminate the pancreato-biliary cancers from all other clinical conditions including the healthy controls, non-malignant abnormalities, and other types of cancers, we developed a diagnostic index using expression profiles of the 10 most significant miRNAs. A combination of eight miRNAs (miR-6075, miR-4294, miR-6880-5p, miR-6799 5p, miR-125a-3p, miR-4530, miR-6836-3p, and miR-4476) achieved a sensitivity, specificity, accuracy and AUC of 80.3%, 97.6%, 91.6% and 0.953, respectively. In contrast, CA19-9 and CEA gave sensitivities of 65.6% and 40.0%, specificities of 92.9% and 88.6%, and accuracies of 82.1% and 71.8%, respectively, in the same test cohort. This diagnostic index identified 18/21 operable pancreatic cancers and 38/48 operable biliary-tract cancers in the entire cohort. Our results suggest that the assessment of these miRNA markers is clinically valuable to identify patients with pancreato-biliary cancers who could benefit from surgical intervention. PMID- 25706131 TI - Tobacco use and mass media utilization in sub-Saharan Africa. AB - BACKGROUND: Media utilization has been identified as an important determinant of tobacco use. We examined the association between self-reported tobacco use and frequency of mass media utilization by women and men in nine low-to middle-income sub-Saharan African countries. METHODOLOGY/PRINCIPAL FINDINGS: Data for the study came from Demographic and Health Surveys conducted in Burkina Faso, Ethiopia, Liberia, Lesotho, Malawi, Swaziland, Uganda, Zambia and Zimbabwe over the period 2006-2011. Each survey population was a cross-sectional sample of women aged 15 49 years and men aged 15-59 years, with information on tobacco use and media access being obtained by face-to-face interviews. An index of media utilization was constructed based on responses to questions on the frequency of reading newspapers, frequency of watching television and frequency of listening to the radio. Demographic and socioeconomic variables were considered as potentially confounding covariates. Logistic regression models with country and cluster specific random effects were estimated for the pooled data. RESULTS: The risk of cigarette smoking increased with greater utilization to mass media. The use of smokeless tobacco and tobacco use in general declined with greater utilization to mass media. The risk of tobacco use was 5% lower in women with high media utilization compared to those with low media utilization [Adjusted Odds Ratio (AOR) = 0.95, 95% confidence interval (CI):0.82-1.00]. Men with a high media utilization were 21% less likely to use tobacco compared to those with low media utilization [AOR = 0.79, 95%CI = 0.73-0.85]. In the male sample, tobacco use also declined with the increased frequency of reading newspapers (or magazines), listening to radio and watching television. CONCLUSIONS: Mass media campaigns, conducted in the context of comprehensive tobacco control programmes, can reduce the prevalence of tobacco smoking in sub-Saharan Africa. The reach, intensity, duration and type of messages are important aspects of the campaigns but need to also address all forms of tobacco use. PMID- 25706133 TI - X-ray dose estimation from cathode ray tube monitors by Monte Carlo calculation. AB - Cathode Ray Tube (CRT) monitors are associated with the possible emission of bremsstrahlung radiation produced by electrons striking the monitor screen. Because of the low dose rate, accurate dosimetry is difficult. In this study, the dose equivalent (DE) and effective dose (ED) to an operator working in front of the monitor have been calculated using the Monte Carlo (MC) method by employing the MCNP code. The mean energy of photons reaching the operator was above 17 keV. The phantom ED was 454 MUSv y (348 nSv h), which was reduced to 16 MUSv y (12 nSv h) after adding a conventional leaded glass sheet. The ambient dose equivalent (ADE) and personal dose equivalent (PDE) for the head, neck, and thorax of the phantom were also calculated. The uncertainty of calculated ED, ADE, and PDE ranged from 3.3% to 10.7% and 4.2% to 14.6% without and with the leaded glass, respectively. PMID- 25706132 TI - Analysis of cathepsin and furin proteolytic enzymes involved in viral fusion protein activation in cells of the bat reservoir host. AB - Bats of different species play a major role in the emergence and transmission of highly pathogenic viruses including Ebola virus, SARS-like coronavirus and the henipaviruses. These viruses require proteolytic activation of surface envelope glycoproteins needed for entry, and cellular cathepsins have been shown to be involved in proteolysis of glycoproteins from these distinct virus families. Very little is currently known about the available proteases in bats. To determine whether the utilization of cathepsins by bat-borne viruses is related to the nature of proteases in their natural hosts, we examined proteolytic processing of several viral fusion proteins in cells derived from two fruit bat species, Pteropus alecto and Rousettus aegyptiacus. Our work shows that fruit bat cells have homologs of cathepsin and furin proteases capable of cleaving and activating both the cathepsin-dependent Hendra virus F and the furin-dependent parainfluenza virus 5 F proteins. Sequence analysis comparing Pteropus alecto furin and cathepsin L to proteases from other mammalian species showed a high degree of conservation; however significant amino acid variation occurs at the C-terminus of Pteropus alecto furin. Further analysis of furin-like proteases from fruit bats revealed that these proteases are catalytically active and resemble other mammalian furins in their response to a potent furin inhibitor. However, kinetic analysis suggests that differences may exist in the cellular localization of furin between different species. Collectively, these results indicate that the unusual role of cathepsin proteases in the life cycle of bat-borne viruses is not due to the lack of active furin-like proteases in these natural reservoir species; however, differences may exist between furin proteases present in fruit bats compared to furins in other mammalian species, and these differences may impact protease usage for viral glycoprotein processing. PMID- 25706134 TI - On-body calibration and measurements using a personal, distributed exposimeter for wireless fidelity. AB - This paper describes the design, calibration, and measurements with a personal, distributed exposimeter (PDE) for the on-body detection of radio frequency (RF) electromagnetic fields due to Wireless Fidelity (WiFi) networks. Numerical simulations show that using a combination of two RF nodes placed on the front and back of the body reduces the 50% prediction interval (PI50) on the incident free space electric-field strength (Equation is included in full-text article.). Median reductions of 10 dB and 9.1 dB are obtained compared to the PI50 of a single antenna placed on the body using a weighted arithmetic and geometric average, respectively. Therefore, a simple PDE topology based on two nodes, which are deployed on opposite sides of the human torso, is applied for calibration and measurements. The PDE is constructed using flexible, dual-polarized textile antennas and wearable electronics, which communicate wirelessly with a Universal Serial Bus (USB) connected receiver and can be unobtrusively integrated into a garment. The calibration of the PDE in an anechoic chamber proves that the PI50 of the measured (Equation is included in full-text article.)is reduced to 3.2 dB. To demonstrate the real-life usability of the wireless device, a subject was equipped with the PDE during a walk in the city of Ghent, Belgium. Using a sample frequency of 2 Hz, an average incident power density of 59 nW m was registered in the WiFi frequency band during this walk. PMID- 25706135 TI - Development and validation of a GEANT4 radiation transport code for CT dosimetry. AB - The authors have created a radiation transport code using the GEANT4 Monte Carlo toolkit to simulate pediatric patients undergoing CT examinations. The focus of this paper is to validate their simulation with real-world physical dosimetry measurements using two independent techniques. Exposure measurements were made with a standard 100-mm CT pencil ionization chamber, and absorbed doses were also measured using optically stimulated luminescent (OSL) dosimeters. Measurements were made in air with a standard 16-cm acrylic head phantom and with a standard 32-cm acrylic body phantom. Physical dose measurements determined from the ionization chamber in air for 100 and 120 kVp beam energies were used to derive photon-fluence calibration factors. Both ion chamber and OSL measurement results provide useful comparisons in the validation of the Monte Carlo simulations. It was found that simulated and measured CTDI values were within an overall average of 6% of each other. PMID- 25706136 TI - Winnipeg radon testing: comparison of test durations, effects of house characteristics, and efficacy of floor-drain seals. AB - A research study has investigated the correlation of radon test data for three testing periods obtained in a set of 50 homes. The homes were part of the housing stock in a long-established subdivision in Winnipeg, Manitoba, for which it was initially hypothesized that a high percentage of homes had radon levels above the Canadian guideline. Co-linear tests, all commencing on the same date, were conducted over periods of 5 d, 30 d, and 91 d under closed building conditions during the 2009-10 heating season using electret ion radon detectors, supplemented in some instances by measurements with a continuous radon monitor. Radon levels in 33 of the 50 homes exceeded the Canadian radon guideline of 200 Bq m in 91-d tests. False-positive and false-negative analyses of the 5-d tests and 30-d tests were conducted relative to the 91-d tests in the respective homes. False positive/false negative analyses indicated that the short-term and the medium-term testing results reflected the results of the 91-d tests over 85% of the time. Precision testing of the radon data was carried out in accordance with quality assurance protocols. Correlation of a building construction survey with radon data indicated that earth-floor crawl spaces were common contributors to elevated radon levels. Testing was also done to measure the efficacy of a commercial brand of floor drain seal installed to lower radon levels, which resulted in an average radon reduction of 47% in homes without earth-floor crawl spaces. PMID- 25706137 TI - Variation in the calibrated response of LiF, Al2O3, and silicon dosimeters when used for in-phantom measurements of source photons with energies between 30 KeV AND 300 KeV. AB - The MCNP5 radiation transport code was used to quantify changes in the absorbed dose conversion factor for LiF, Al2O3, and silicon-based electronic dosimeters calibrated in-air using standard techniques and summarily used to measure absorbed dose to water when placed in a water phantom. A mono-energetic photon source was modeled at energies between 30 keV and 300 keV for a point-source placed at the center of a water phantom, a point-source placed at the surface of the phantom, and for a 10-cm radial field geometry. Dosimetric calculations were obtained for water, LiF, Al2O3, and silicon at depths of 0.2 cm and 10 cm from the source. These results were achieved using the MCNP5 *FMESH photon energy fluence tally, which was coupled with the appropriate DE/DF card for each dosimetric material studied to convert energy-fluence into the absorbed dose. The dosimeter's absorbed dose conversion factor was calculated as a ratio of the absorbed dose to water to that of the dosimeter measured at a specified phantom depth. The dosimeter's calibration value also was obtained. Based on these results, the absorbed dose conversion factor for a LiF dosimeter was found to deviate from its calibration value by up to 9%, an Al2O3 dosimeter by 43%, and a silicon dosimeter by 61%. These data therefore can be used to obtain LiF, Al2O3, and silicon dosimeter correction factors for mono-energetic and poly-energetic sources at measurement depths up to 10 cm under the irradiation geometries investigated herein. PMID- 25706138 TI - Species-dependent chelation of (241)Am by DTPA Di-ethyl ester. AB - Diethylenetriaminepentaacetic acid (DTPA) is an FDA-approved chelating agent for enhancing the elimination of transuranic elements such as americium from the body. Early access to therapy minimizes deposition of these radionuclides in tissues such as the bone. Due to its poor oral bioavailability, DTPA is administered as an IV injection, delaying access. Therefore, a diethyl-ester analog of DTPA, named C2E2, was synthesized as a means to increase oral absorption. As a hexadentate ligand, it was hypothesized that C2E2 was capable of binding americium directly. Therefore, the protonation constants and americium stability constant for C2E2 were determined by potentiometric titration and a solvent extraction method, respectively. C2E2 was shown to bind americium with a log K of 19.6. The concentrations of C2E2, its metabolite C2E1, and DTPA required to achieve effective binding in rat, beagle, and human plasma were studied in vitro. Dose response curves for each ligand were established, and the 50% maximal effective concentrations were determined for each species. As expected, higher concentrations of C2E2 were required to achieve the same degree of binding as DTPA. The results indicated that chelation in beagle plasma is more representative of the human response than rats. Finally, the pharmacokinetics of C2E2 were investigated in beagles, and the data was fit to a two-compartment model with elimination from the central compartment, along with first-order absorption. Based on the in vitro data, a 100 mg kg dose of C2E2 can be expected to have an effective duration of action of 3.8 h in beagles. PMID- 25706139 TI - Derivation of a simple relationship between pulsed and steady-state dose limits due to general recombination within air-filled ionization chambers. AB - This paper discusses various calculational and measurement methods involved with general recombination losses of air-filled ionization chambers exposed to either steady-state or pulsed photon fields. Derived therefrom is a simple relationship between the pulsed and steady-state cases that allows the determination of expected pulsed-field losses from steady-state loss measurements within, for instance, typical Cs calibration fields. Several examples are provided to illustrate each calculational and measurement method, as well as the newly derived relationship. PMID- 25706140 TI - Results of a survey on the implementation of diagnostic reference levels for X rays among Dutch hospitals. AB - Diagnostic reference levels (DRLs) for medical x-ray procedures are being implemented currently in the Netherlands. By order of the Dutch Healthcare Inspectorate, a survey has been conducted among 20 Dutch hospitals to investigate the level of implementation of the Dutch DRLs in current radiological practice. It turns out that hospitals are either well underway in implementing the DRLs or have already done so. However, the DRLs have usually not yet been incorporated in the QA system of the department nor in the treatment protocols. It was shown that the amount of radiation used, as far as it was indicated by the hospitals, usually remains below the DRLs. A procedure for comparing dose levels to the DRLs has been prescribed but is not always followed in practice. This is especially difficult in the case of children, as most general hospitals receive few children. PMID- 25706141 TI - Observations on using inside air concentrations as a predictor of outside air concentrations. AB - Excavations of radiological material were performed within confined structures with known operational parameters, such as a filtered exhaust system with known filtration efficiency. Given the known efficiency, the assumption could be made that the air concentrations of radioactivity measured outside the structure would be proportional to the air concentrations measured inside the structure. To investigate this assumption, the inside concentration data was compared with the outside concentration data. The correlation of the data suggested that the inside concentrations were not a good predictor of the outside concentrations. This poor correlation was deemed to be a result of operational unknowns within the structures. PMID- 25706142 TI - The role of the health physicist in nuclear security. AB - Health physics is a recognized safety function in the holistic context of the protection of workers, members of the public, and the environment against the hazardous effects of ionizing radiation, often generically designated as radiation protection. The role of the health physicist as protector dates back to the Manhattan Project. Nuclear security is the prevention and detection of, and response to, criminal or intentional unauthorized acts involving or directed at nuclear material, other radioactive material, associated facilities, or associated activities. Its importance has become more visible and pronounced in the post 9/11 environment, and it has a shared purpose with health physics in the context of protection of workers, members of the public, and the environment. However, the duties and responsibilities of the health physicist in the nuclear security domain are neither clearly defined nor recognized, while a fundamental understanding of nuclear phenomena in general, nuclear or other radioactive material specifically, and the potential hazards related to them is required for threat assessment, protection, and risk management. Furthermore, given the unique skills and attributes of professional health physicists, it is argued that the role of the health physicist should encompass all aspects of nuclear security, ranging from input in the development to implementation and execution of an efficient and effective nuclear security regime. As such, health physicists should transcend their current typical role as consultants in nuclear security issues and become fully integrated and recognized experts in the nuclear security domain and decision making process. Issues regarding the security clearances of health physics personnel and the possibility of insider threats must be addressed in the same manner as for other trusted individuals; however, the net gain from recognizing and integrating health physics expertise in all levels of a nuclear security regime far outweighs any negative aspects. In fact, it can be argued that health physics is essential in achieving an integrated approach toward nuclear safety, security, and safeguards. PMID- 25706146 TI - Air-adapted Methanosarcina acetivorans shows high methane production and develops resistance against oxygen stress. AB - Methanosarcina acetivorans, considered a strict anaerobic archaeon, was cultured in the presence of 0.4-1% O2 (atmospheric) for at least 6 months to generate air adapted cells; further, the biochemical mechanisms developed to deal with O2 were characterized. Methane production and protein content, as indicators of cell growth, did not change in air-adapted cells respect to cells cultured under anoxia (control cells). In contrast, growth and methane production significantly decreased in control cells exposed for the first time to O2. Production of reactive oxygen species was 50 times lower in air-adapted cells versus control cells, suggesting enhanced anti-oxidant mechanisms that attenuated the O2 toxicity. In this regard, (i) the transcripts and activities of superoxide dismutase, catalase and peroxidase significantly increased; and (ii) the thiol molecules (cysteine + coenzyme M-SH + sulfide) and polyphosphate contents were respectively 2 and 5 times higher in air-adapted cells versus anaerobic-control cells. Long-term cultures (18 days) of air-adapted cells exposed to 2% O2 exhibited the ability to form biofilms. These data indicate that M. acetivorans develops multiple mechanisms to contend with O2 and the associated oxidative stress, as also suggested by genome analyses for some methanogens. PMID- 25706147 TI - Influence of owners' attachment style and personality on their dogs' (Canis familiaris) separation-related disorder. AB - Previous research has suggested that owners' attitude to their family dogs may contribute to a variety of behaviour problems in the dog, and authors assume that dogs with separation-related disorder (SRD) attach differently to the owner than typical dogs do. Our previous research suggested that these dogs may have an insecure attachment style. In the present study we have investigated whether owners' attachment style, personality traits and the personality of the dog influence the occurrence of SRD in the dog. In an internet-based survey 1508 (1185 German and 323 Hungarian) dog-owners filled in five questionnaires: Demographic questions, Separation Behaviour Questionnaire (to determine SRD), Human and Dog Big Five Inventory and Adult Attachment Scale. We found that with owners' higher score on attachment avoidance the occurrence of SRD in the dog increases. Dogs scoring higher on the neuroticism scale were more prone to develop SRD. Our results suggest that owners' attachment avoidance may facilitate the development of SRD in dogs. We assume that avoidant owners are less responsive to the dog's needs and do not provide a secure base for the dog when needed. As a result dogs form an insecure attachment and may develop SRD. However, there may be alternative explanations of our findings that we also discuss. PMID- 25706148 TI - Black holes of surgery. PMID- 25706149 TI - Single-incision open reduction and internal fixation of comminuted trapezium fractures with distal radius cancellous autograft. AB - Trapezium fractures comprise approximately 3% to 5% of all hand fractures. Although operative management of intra-articular trapezium fractures can result in good functional outcomes, there is very little literature addressing specific operative techniques. We describe a technique for open reduction and internal fixation of severely comminuted, intra-articular trapezium fractures, utilizing autogenous cancellous bone graft from the distal radius. PMID- 25706150 TI - Treatment of a fractured juxta-articular enchondroma of the middle phalanx with a Suzuki external fixator: a case report. AB - We report the case of a 47-year-old man who presented with a pathologic fracture of the middle phalanx of the fourth finger. The treatment of this juxta-articular lesion close to the proximal interphalangeal joint was performed in 2 stages. First, a biopsy was carried out combined with fixation of the fracture by a Suzuki dynamic external fixator. After 6 weeks, a curettage of the confirmed enchondroma was performed with iliac crest grafting, leaving the external fixator for another 4 weeks. With a follow-up of 48 months, a satisfying functional result has been obtained with a remarkable remodeling of the painless proximal interphalangeal joint. PMID- 25706151 TI - Evaluation of 3-dimensional superimposition techniques on various skeletal structures of the head using surface models. AB - OBJECTIVES: To test the applicability, accuracy, precision, and reproducibility of various 3D superimposition techniques for radiographic data, transformed to triangulated surface data. METHODS: Five superimposition techniques (3P: three point registration; AC: anterior cranial base; AC + F: anterior cranial base + foramen magnum; BZ: both zygomatic arches; 1Z: one zygomatic arch) were tested using eight pairs of pre-existing CT data (pre- and post-treatment). These were obtained from non-growing orthodontic patients treated with rapid maxillary expansion. All datasets were superimposed by three operators independently, who repeated the whole procedure one month later. Accuracy was assessed by the distance (D) between superimposed datasets on three form-stable anatomical areas, located on the anterior cranial base and the foramen magnum. Precision and reproducibility were assessed using the distances between models at four specific landmarks. Non parametric multivariate models and Bland-Altman difference plots were used for analyses. RESULTS: There was no difference among operators or between time points on the accuracy of each superimposition technique (p>0.05). The AC + F technique was the most accurate (D<0.17 mm), as expected, followed by AC and BZ superimpositions that presented similar level of accuracy (D<0.5 mm). 3P and 1Z were the least accurate superimpositions (0.790.05), the detected structural changes differed significantly between different techniques (p<0.05). Bland Altman difference plots showed that BZ superimposition was comparable to AC, though it presented slightly higher random error. CONCLUSIONS: Superimposition of 3D datasets using surface models created from voxel data can provide accurate, precise, and reproducible results, offering also high efficiency and increased post-processing capabilities. In the present study population, the BZ superimposition was comparable to AC, with the added advantage of being applicable to scans with a smaller field of view. PMID- 25706152 TI - Time trends of period prevalence rates of patients with inhaled long-acting beta 2-agonists-containing prescriptions: a European comparative database study. AB - BACKGROUND: Inhaled, long-acting beta-2-adrenoceptor agonists (LABA) have well established roles in asthma and/or COPD treatment. Drug utilisation patterns for LABA have been described, but few studies have directly compared LABA use in different countries. We aimed to compare the prevalence of LABA-containing prescriptions in five European countries using a standardised methodology. METHODS: A common study protocol was applied to seven European healthcare record databases (Denmark, Germany, Spain, the Netherlands (2), and the UK (2)) to calculate crude and age- and sex-standardised annual period prevalence rates (PPRs) of LABA-containing prescriptions from 2002-2009. Annual PPRs were stratified by sex, age, and indication (asthma, COPD, asthma and COPD). RESULTS: From 2002-2009, age- and sex-standardised PPRs of patients with LABA-containing medications increased in all databases (58.2%-185.1%). Highest PPRs were found in men >= 80 years old and women 70-79 years old. Regarding the three indications, the highest age- and sex-standardised PPRs in all databases were found in patients with "asthma and COPD" but with large inter-country variation. In those with asthma or COPD, lower PPRs and smaller inter-country variations were found. For all three indications, PPRs for LABA-containing prescriptions increased with age. CONCLUSIONS: Using a standardised protocol that allowed direct inter-country comparisons, we found highest rates of LABA-containing prescriptions in elderly patients and distinct differences in the increased utilisation of LABA-containing prescriptions within the study period throughout the five European countries. PMID- 25706153 TI - This special issue of The Journal of Laryngology and Otology is dedicated to Professor Shizuo Komune. Preface. PMID- 25706154 TI - Comparison of lateral microsurgical preauricular and anterior endoscopic approaches to the jugular foramen. AB - INTRODUCTION: This project compares access to the anterolateral part of the jugular foramen provided by the lateral microsurgical preauricular and the anterior endoscopic approaches, and defines the important landmarks involved in each approach. STUDY DESIGN: Cadaveric study. RESULTS: The endoscopic transnasal/transmaxillary transpterygoid corridor provides a less invasive route for selected lesions in the jugular foramen than the traditional open route through the preauricular subtemporal infratemporal fossa approach. However, the anterior endoscopic approach provides a smaller channel to the jugular foramen than the preauricular approach. CONCLUSIONS: The anterior endoscopic approach to the anterolateral part of the jugular foramen is a useful alternative to the lateral microsurgical preauricular approach in carefully selected cases. The vaginal process of the tympanic part of the temporal bone provides a valuable landmark to aid in accessing the jugular foramen in both procedures and can be drilled to open the foramen in the preauricular approach. PMID- 25706155 TI - Analysis of the passive damped oscillation of the guinea pig stapes. AB - OBJECTIVE: To investigate the characteristic physical properties of the oscillating system in the intact middle ear using a high-speed camera. DESIGN: We analysed the oscillation of the guinea pig stapes using a high-speed camera. The specimens were prepared so that the middle-ear structures were intact. Tones of various frequencies were delivered into the external auditory canal. RESULTS: We found that the stapes showed a damped oscillation after the sound stimulation had stopped. The damped oscillation after the sound stimulation showed a specimen specific frequency that was independent of the frequency of the stimulating sound. An injury to the bony labyrinth, which removed most of the mass from the oscillating system, attenuated the damped oscillation. Therefore, this damped oscillation is likely a passive motion, rather than a reverberation of the stimulating sound. CONCLUSION: Analysing the passive damped oscillation may reveal the characteristic physical properties of the oscillating system in the near-intact middle ear. Further refinement of this simple and straightforward system may enhance basic and clinical research on the middle ear in a more intuitive way. PMID- 25706156 TI - Clinical study of transcanal closure of tympanic membrane perforations using a collagen sponge. AB - MATERIALS AND METHODS: We used an artificial dermis (Terdermis), which is an atero-collagen sponge covered with a sheet of silicon. PATIENTS: Nineteen ears of 17 patients with perforation of the tympanic membrane under various conditions, including large and wet perforations, underwent operation using this collagen sponge. RESULTS: The success rate of closure after the initial surgery was 8/19. The overall success rate of closure after initial and re-operation was 14/19. The success rate of closure was 12/14 for small-sized perforations, 1/4 for middle sized perforations and 1/1 for a large-sized perforation. Middle- and large-sized perforations required multiple surgeries. The success rate of closure was 11/11 for dry perforations, 3/4 for perforations with light otorrhoea and 0/4 for perforations with extensive otorrhoea. CONCLUSION: This surgery is a low-cost and minimally invasive surgery and has a high closure rate. This surgery is effective on small-sized, dry perforations although it can also close middle- and large sized dry perforations. PMID- 25706157 TI - Efficacy of pre-operative computed tomography evaluation of the tympanic cavity for hearing improvement after stapes surgery for tympanosclerosis with stapes fixation. AB - OBJECTIVE: Our aim was to determine if stapes surgery is useful for treating inflammatory ear diseases. MATERIALS AND METHODS: Thirteen patients underwent single-stage or staged surgery for stapes fixation due to tympanosclerosis alone or with cholesteatoma. Operative criteria were: no tympanic membrane retraction, perforation or adhesion; middle-ear cavity with aeration >1 year; a fixed stapes. Computed tomography was used to analyse the relation between operative success and pre-operative pneumatisation. RESULTS: Success rate at six months was 75 per cent. Hearing results were stable with little deterioration and no complications. Patients with poor pneumatisation had good results (with improved air-bone gap) only after staged surgery. Well-aerated ears heard better even with single-stage surgery. CONCLUSIONS: Pre-operative computed tomography and intra-operative findings are necessary to determine the pneumatisation status of tympanic mastoid cavities. If criteria approved, poorly pneumatised patients underwent staged surgery. Stapedectomy achieved good hearing results for inflammatory middle-ear disease with stapes fixation. PMID- 25706158 TI - High-speed video analysis of acoustically oscillated guinea pig stapes. AB - OBJECTIVE: We investigated the ossicular movement in the near-intact middle ear in response to acoustic stimulation using a high-speed video camera and video analysis software program. DESIGN: We have designed a good visual access to the middle ear of the guinea pig by opening the ventral wall of the otic capsule, without injuring the sound-conducting structures, from the external auditory canal to the oval window. The high-speed video camera could record analysable ossicular motion up to 4000 frames per second. RESULTS: The stapes showed reciprocal movement in the same frequency as the stimulating tone, and with an amplitude proportional to the stimulating sound intensity. Injury to the tympanic membrane attenuated the stapedial motion, which was recovered to that of the control level by patch repair of the perforation. CONCLUSION: Our experimental set-up was capable of evaluating the conductive hearing, regardless of the status of the animal's sensorineural hearing or even life. Such a video analysis may provide a powerful tool to investigate the physiology of the middle ear. PMID- 25706159 TI - Cochlear implants for mumps deafness: two paediatric cases. AB - BACKGROUND: Good outcomes have been reported regarding the use of cochlear implants for mumps deafness. The mumps virus induces meningitis and/or encephalitis, which can cause central nervous system damage resulting in retrolabyrinthine hearing loss, for which a cochlear implant would be less effective. CASES: We installed a cochlear implant in two patients with bilateral mumps deafness; one achieved a good result with the cochlear implant, but the other did not. We discuss two possible reasons for the different outcomes. Case 1 was a three-year-old girl with bilateral parotid swelling, vomiting and walking disorder. One year after cochlear implant insertion, speech perception did not develop despite of good pure tone thresholds. Case 2 was an eight-year-old girl with bilateral parotid swelling. A cochlear implant enabled her to improve hearing perception. CONCLUSION: Although cochlear implants have been reported to be helpful for mumps deafness, cases that involve central nervous system damage may not achieve good results. PMID- 25706160 TI - Asymptomatic fibrous dysplasia of the temporal bone. AB - INTRODUCTION: Fibrous dysplasia is a bone disorder of unknown origin in which normal bone is replaced with fibrotic tissue and disorganised bone trabeculae. The temporal bone is rarely affected. Because of the slowly progressive course of the disease, many mild cases may never be recognised and are found incidentally. We present a patient with fibrous dysplasia of the right temporal bone, who had few complaints. OBJECTIVE: A 62-year-old man was incidentally found to have fibrous dysplasia of the temporal bone on routine computed tomography scan. METHOD: One case report. RESULTS: Computed tomography showed a thickening of the right temporal bone with a ground-glass appearance. The 62-year-old man opted for watchful waiting. CONCLUSION: We have presented an asymptomatic fibrous dysplasia of the temporal bone. Mild cases may never be recognised and are found incidentally because of their slow progression. PMID- 25706161 TI - Transnasal endoscopic surgery of post-operative maxillary cysts. AB - OBJECTIVE: The present study investigates the indications for transnasal endoscopic surgery in treating post-operative maxillary cysts. METHODS: In this retrospective study, the records of 118 patients with post-operative maxillary cysts (88 unilateral and 30 bilateral) consisting of 148 procedures were reviewed. RESULTS: A transnasal endoscopic approach was performed in 144 lesions (97.3 per cent). A combined endonasal endoscopic and canine fossa (external) approach was performed in 4 of 148 lesions, because the cysts were located distant from the nasal cavity and had a thick bony wall. A ventilation stent was placed in four patients (four cysts) to avoid post-operative meatal antrostomy stenosis. Recurrence was observed in five patients (4.2 per cent), all of whom subsequently underwent transnasal endoscopic revision surgery. CONCLUSION: Transnasal endoscopic surgery is an effective treatment for post-operative maxillary cyst with the exception of cysts located distant from the nasal cavity. PMID- 25706162 TI - Endonasal endoscopic surgery with combined middle and inferior meatal antrostomies for fungal maxillary sinusitis. AB - OBJECTIVE: The purpose of this study was to evaluate the effectiveness of the combination of inferior and middle meatal antrostomies for treatment of a maxillary sinus fungus ball by functional endoscopic sinus surgery. METHODS: A retrospective analysis including 28 patients with non-invasive fungal maxillary sinusitis was performed. Fourteen patients underwent FESS with both middle and inferior meatal antrostomies (combined group). The remaining 14 patients were treated with FESS through only the middle meatal antrostomy (control group). RESULTS: Post-operative computed tomography showed normal maxillary sinuses in all patients in the combined group. In contrast, in the control group, five patients (36 per cent) exhibited a normal maxillary sinus, seven (50 per cent) showed maxillary mucosal thickening and two (14 per cent) had persistent fungus balls in the maxillary sinus. CONCLUSION: FESS with a combination of middle and inferior meatal antrostomies proved more effective for treating fungal maxillary sinusitis. PMID- 25706163 TI - Stability of the synaptic structure in the hippocampus of BALB/c mice with allergic rhinitis. AB - OBJECTIVE: The aim of this study was to determine whether allergic rhinitis can induce structural changes in the synapse formation in the hippocampus of BALB/c mice immunocytochemically. METHODS: Allergic rhinitis was induced in mice by two intra-peritoneal injections of ovalbumin administered with a one-week interval. After two weeks, the sensitised mice were challenged with an intra-nasal injection of ovalbumin for two weeks. To analyse the hippocampal synaptic structures, sections were immunostained with antibodies against glutamic acid decarboxylase 65 and glutamic acid decarboxylase 67 (for gamma-aminobutyric acid ergic terminals), synaptophysin (for glutamatergic and gamma-aminobutyric acid ergic terminals) and spinophilin (for dendritic spines). The number of nasal rubbing movements was significantly greater in the allergic rhinitis mice than in the control mice. However, the expression patterns of the four above-mentioned synaptic markers in the hippocampus showed no detectable difference between the allergic rhinitis and control mice. RESULTS AND CONCLUSION: These data indicate that the synaptic structure in the hippocampus might remain unaltered in allergic rhinitis patients. PMID- 25706164 TI - Epidemiological study of cholesteatoma in Fukuoka City. AB - OBJECTIVE AND DESIGN: To investigate the pathogenesis of cholesteatoma, we planned to conduct a cohort study. As a first step, we conducted an epidemiological study in Fukuoka City, Japan to determine the incidence of cholesteatoma treated both with and without surgery. We also conducted a case control study to investigate the pathogenesis of cholesteatoma. RESULTS: The annual incidence of cholesteatoma, including cases treated without surgery, was 6.8-10.0 in a population of 100 000. The results of the case-control study suggested that a past history of otitis media and habitual sniffing caused by a patulous eustachian tube play a role in the pathogenesis of cholesteatoma. CONCLUSIONS: The annual incidence of cholesteatoma, including cases treated without surgery, was considered to not be high enough to perform a cohort study. The results of the case-control study suggest that otitis media and habitual sniffing due to a patulous eustachian tube, contribute to the onset of cholesteatoma. PMID- 25706165 TI - Safe and rapid contouring of fibro-osseous lesions in the orbital area using navigation with minimally invasive cranial bone registration. AB - BACKGROUND: Bone contouring is currently the best treatment for fibro-osseous lesions after bone growth arrest. Navigation systems available for this surgery allow intra-operative visualisation with improved cosmetic outcomes. However, conventional navigation systems using superficial skin registration cannot prevent subtle discrepancies. METHOD: To address this problem, we used a non invasive cranial bone registration that uses patient-specific dental templates to maintain exact registration. We created the preset goal using the mirror image of the unaffected side for unilateral lesions, and using images obtained before the onset of symptoms for bilateral lesions. This system achieved precise pre operative simulation. A sound aid in the navigation system provided information regarding proximity to critical structures and to the preset goal. RESULTS: We used this system to contour fibro-osseous lesions in three patients. All patients achieved good facial contours and improvement in symptoms. CONCLUSIONS: This method offers a safe, rapid surgical aid in treating orbital fibro-osseous lesions. PMID- 25706166 TI - Clinical outcomes of tracheoesophageal diversion for intractable aspiration. AB - OBJECTIVES: The purpose of the present study was to examine the clinical outcomes of using tracheoesophageal diversion for preventing intractable aspiration. METHOD: We retrospectively reviewed 25 patients who underwent tracheoesophageal diversion from 2003 to 2009 at our hospital (median age, 25 years; range, 0-78 years). End-to-side anastomosis was used in 16 cases and side-to-side anastomosis was used in 9. RESULTS: The average operative time was 141 minutes for end-to side anastomosis and 191 minutes for side-to-side anastomosis. Peri-operative complications were observed in only two (8 per cent) cases: one with infection and one with haematoma. No fistulas were observed. Aspiration was prevented in all cases, but the nutritional route depended on the swallowing function of the patient. Oral feeding was the main nutritional route after surgery in only four patients (16 per cent). CONCLUSION: This procedure is well suited to patients who lack speech communication and are at high risk of aspiration. PMID- 25706167 TI - New technique for laryngomicrosurgery: narrow band imaging-assisted video laryngomicrosurgery for laryngeal papillomatosis. AB - OBJECTIVE: In the present report, we describe the use of narrow band imaging during video-laryngomicrosurgery for laryngeal papillomatosis. CASE REPORT: It is difficult to peri-operatively locate all the superficial papillomatous lesions when the disease is widespread, which then results in tumor recurrence. Therefore, we have constructed a narrow band imaging video-laryngomicrosurgery system, which we have used for two cases of laryngeal papillomatosis. CONCLUSION: Our narrow band imaging-assisted video-laryngomicrosurgery system to visualise superficial laryngeal papillomatosis more clearly. PMID- 25706168 TI - Squamous cell carcinoma of the oropharynx: single-institution outcome analysis of patients treated with concurrent chemoradiotherapy. AB - PURPOSE: The object of this study was to analyse our experience with the effects of concurrent chemoradiotherapy for oropharyngeal squamous cell carcinoma, the treatment results of this therapeutic strategy and a salvage treatment for recurrent oropharyngeal squamous cell carcinoma. METHODS: Seventy-five patients with oropharyngeal squamous cell carcinoma were treated with chemoradiotherapy. The study included twenty-five of these patients who had recurrent oropharyngeal squamous cell carcinoma after chemoradiotherapy Results: The three-year actuarial survival rates for 75 patients by disease stage were as follows: stage II, 100 per cent; stage III, 71.1 per cent; stage IV, 51.7 per cent and overall, 58.2 per cent. The mean time of detection of recurrence was 6.2 months. The total salvage rates of recurrence were 21 per cent. The one and three-year tumour-free actuarial survival rates of those patients who received salvage treatment were 83 and 33 per cent. CONCLUSIONS: Surgical salvage was only feasible for early recurrent tumour. Close follow-up surveillance of early recurrence is essential after primary treatment of patients with chemoradiotherapy. PMID- 25706169 TI - Extrapulmonary small cell carcinoma in head and neck. AB - PURPOSE: The management of extrapulmonary small cell carcinoma has not been standardised to date. This study reviewed the clinical course, management and survival outcomes of patients with extrapulmonary small cell carcinoma in the head and neck region. METHODS: Nine patients with extrapulmonary small cell carcinoma in the head and neck were included in this study. RESULTS: Five patients received radical surgery followed by adjuvant chemotherapy or radiotherapy or both. Two other patients were treated with chemotherapy consisting of CPT11 plus cisplatin or CPT11 plus cisplatin plus VP-16 three times. Two other patients received chemoradiotherapy consisting of S-1 or CPT11 plus cisplatin. The median overall survival was 14.5 months, with a three-year survival rate of 23.7 per cent. CONCLUSIONS: The prognosis of extrapulmonary small cell carcinoma is generally poor. Further prospective multicentre studies are required for better understanding of disease entities and response to treatment modalities. PMID- 25706170 TI - Well-differentiated liposarcoma arising in the parapharyngeal space: a case report and review of the literature. AB - BACKGROUND: Liposarcomas rarely occur in the parapharyngeal space and only a few case reports exist. For curative therapy of liposarcoma, surgical excision remains the dominant modality. Although a wide surgical margin is important to prevent local recurrence, wide excision is often difficult in the head and neck region. CASE REPORT: We report a case of a 19-year-old female with a well differentiated liposarcoma arising in the parapharyngeal space. We removed the tumour surgically utilising a cervical-parotid approach. The histological diagnosis was well-differentiated sclerosing liposarcoma. There is no recurrence after five years and nine months of follow up. CONCLUSION: The patient's age and the tumour site made it difficult for us to make a quantitative diagnosis before the operation. Well-differentiated liposarcoma rarely develop distant metastasis, but often recur locally. The benefit of adjuvant radiotherapy for well differentiated liposarcoma is still not clear and careful and long-term follow up is necessary. PMID- 25706171 TI - Adenosquamous carcinoma of unknown primary origin: a case report and literature review. AB - BACKGROUND: Adenosquamous carcinoma is a rare variant of semicircular canal that can affect various regions, including the head and neck. Adenosquamous carcinoma is characterised pathologically by the simultaneous presence of distinct areas of semicircular canal and adenocarcinoma, and usually takes an aggressive course with local recurrences, early lymph node metastases and distant disseminations. CASE: We report a rare case of neck adenosquamous carcinoma of unknown primary origin, which was well-controlled by thorough resection without any other additional therapy. CONCLUSION: We discuss the diagnosis and treatment of adenosquamous carcinoma along with a review of pertinent literature. We also consider the potential differential diagnosis of branchiogenic carcinoma. PMID- 25706172 TI - Hyalinizing clear cell carcinoma of the nasopharynx operated by trans-oral and trans-palatal approach. AB - BACKGROUND: Hyalinizing clear cell carcinoma is a rare minor salivary gland neoplasm. The treatment of choice is surgical resection with or without post operative radiotherapy. This tumour often demonstrates a good prognosis. CASE REPORT: We report a case of hyalinizing clear cell carcinoma arising in the nasopharynx. A 27-year-old female presented with progressive hearing disturbance and tinnitus. On examination, an expansile mass was observed in her nasopharynx. Biopsy was performed and the pathology results returned as clear cell carcinoma. RESULTS AND CONCLUSION: Surgical resection was performed trans-orally accompanied by trans-palatal approach. She has no recurrence during more than two years of follow up. PMID- 25706173 TI - Is there a role of adjuvant treatment for salivary duct carcinoma? AB - OBJECTIVE: To determine the clinical effect of post-operative radiotheraphy and systemic chemotherapy for the treatment of salivary duct carcinoma. STUDY DESIGN: Retrospective review. DESIGN: The medical records of 26 patients treated by surgery with or without radiotheraphy and/or systemic chemotherapy for salivary duct carcinoma were retrospectively reviewed to investigate the role of post operative adjuvant treatment for the patients' prognosis. RESULTS: The overall three-year and five-year survival rates were 54 and 48.1 per cent, respectively. There was no correlation with the clinical stage and the patients' prognosis. The overall three-year survival of the patients with or without post-operative radiotheraphy was 64 and 33 per cent, respectively (p = 0.29). The overall three year survival of the patients with or without post-operative chemotherapy was 53 and 56 per cent, respectively (p = 0.78). CONCLUSION: Post-operative adjuvant therapy did not improve the patients' overall prognosis with salivary duct carcinoma. Developing novel treatment modalities may be necessary to improve the prognosis of this aggressive disease. PMID- 25706174 TI - [Treatment of basal joint osteoarthritis by Swanson's trapezium implant arthroplasty]. AB - BACKGROUND: Goal of the present study was the evaluation of clinical and radiological results after treatment of the first carpometacarpal joint by trapezium resection and implantation of a Swanson silicone prosthesis by means of a retrospetive study. However, up to now, only a few long-term data for this surgical technique are available. METHODS AND PATIENTS: Retrospectively the results of 100 trapezium resections in 72 patients with subsequent joint replacement by a Swanson silicone prosthesis have been followed up over 8.6 years on average. Besides the range of motion, the strengh in grip, tip pinch and key pinch were measured. The quality of pain was determined using a visual analogus pain scale from 1-10. The postoperative subjective satisfaction of patients was recorded as well as the DASH, Mayo, modified Wrist and Krimmer scores. In follow up X-ray controls, subluxations of the silicone implants as well as bony abnormalities were evaluated. RESULTS: The postoperative range of motion of the trapeziometacarpal joint in radial abduction was measured with 52 degrees and at palmar abduction with 39 degrees . The average grip strength amounted to 16.5 kg. This represented 80% of the value of the contralateral side. In tip pinch the force value was 3.3 kg, corresponding to 70% of that of the opposite side and in key pinch, it was 3.5 kg, corresponding to 71% of the healthy contralateral side. The DASH score was recorded with 22.5 points. Postoperative pain symptoms on the visual analogue pain scale were recorded at 2.4 points. The majority of the patients were satisfied or very satisfied after the surgical treatment. In X-ray controls, subluxations of the silicone implants could be detected in 54 cases (61.4%) as well as bony abnormalities in 41 cases (46.6%). However, there was no correlation between the radiological findings and patient satisfaction. CONCLUSION: Trapezium resection and joint replacement with a silicone prosthesis achieves good results. However, the high number of radiographic subluxations of the prothesis and bone abnormalities as a cause of foreign body reactions limits these results. Therefore, despite the good clinical findings, this method will not been conducted any more in our patient population. PMID- 25706175 TI - [Primary results using the mini TightRope for revision surgery for painful proximalisation of the first metacarpal after trapezectomy for CMC-1 osteoarthritis]. AB - AIM: The aim of the current study was to review the significance of the TightRope to suspend the first metacarpal in the case of a revision for patients with painful proximalisation after trapezectomy. PATIENTS AND METHOD: After an average of 25.5 months (13-60) from initial operative treatment for rhizarthrosis, revision surgery was performed on 6 female patients with a mean age of 56 years, using a Mini TightRope. Before and after revision-surgery the pain level was measured, using the visual analogue scale (1-10) as was the level of strength in the fingertips. The overall result was documented according to the evaluation scale according to Buck-Gramcko. Directly after surgery as well as at the last follow-up exam, the degree of proximalisation of the first metacarpal was radiologically measured. The follow-up period was 13.7 months on average (4-31 months). RESULTS: After revision surgery a decrease in pain level was detected, but no patient was completely pain-free. According to the visual analogue scale the pain level after surgery compared to preoperatively was: at rest at an average of 2.5 (1-4), preoperatively 3.3 (2-4); with mild load 3.5 (2-5), preoperatively 4.8 (4-6); and with high load 4.8 (3-7), preoperatively 7 (6-8). The level of strength in the fingertips was postoperatively measured at below 60% in 2 patients (preoperatively 5 patients), once between 60 and 79% (preoperatively 1 patient) and 3 times between 80 and 99%. With an average preoperative score of 11.7 (6-16) points according to Buck-Gramcko, an increase of 20.3 points could be achieved by performing the revision operation. This resulted in a score of 32 (14-44) out of 56 points. The measured distance between the distal scaphoid pole and the centre of the base of the first metacarpal was postoperatively at an average of 8.3 mm (5.6-11.4 mm). The final follow-up shows an average distance of 3.3 mm (2.8-4.3 mm). This is consistent with an average proximalisation of 5 mm. The Mini TightRope had to be removed three times. An additional operation had to be performed twice. CONCLUSION: The use of the Mini TightRope for a suspension of the first metacarpal, in cases of a painful proximalisation after trapezectomy is a procedure that can cause an improvement for a certain percentage of patients. But a further proximalisation cannot be prevented by the use of the Mini TightRope. PMID- 25706176 TI - [Application possibilities and initial experience with digital volume tomography in hand and wrist imaging]. AB - During the last decade, DVT (digital volume tomography) imaging has become a widely used standard technique in head and neck imaging. Lower radiation exposure compared to conventional computed tomography (MDCT) has been described. Recently, DVT has been developed as an extremity scanner and as such represents a new imaging technique for hand surgery. We here describe the first 24 months experience with this new imaging modality in hand and wrist imaging by presenting representative cases and by describing the technical background. Furthermore, the method's advantages and disadvantages are discussed with reference to the given literature. PMID- 25706177 TI - [Biomechanical testing of a new total wrist arthrodesis plate]. AB - PURPOSE: The aim of this study was to evaluate the biomechanical properties of the APTUS wrist fusion plate in comparison to those of the AO wrist fusion plate. MATERIAL AND METHOD: 6 APTUS wrist fusion plates (APTUS 2.5 TriLock Wrist Fusion Plate Long Bend) from Medartis (Basel, Switzerland) and 6 AO wrist fusion plates (= LCP Wrist Fusion Plate Standard Bend from Dupuy-Synthes, Bettlach, Switzerland) were installed according to the manufacturers' instructions on life sized, fibre-glass reinforced polyamide models of a healthy human hand. Then fatigue testing with increasing loads on a monoaxial material testing machine was carried out and the force-movement measurements were recorded on a PC. For up to 50,000 cycles, loading was applied in a sinus-wave frequency of 4 Hz and a force ratio (FMin/FMax) of 0.1-70 N. After 50,000 cycles and then at every 10,000 cycles the load was increased by 15% until breakage or a deformation of over 15 mm at the point of force application of the implant occurred. In addition, the tear-out resistance of 5 screws of each type of plate was examined and the system tear-out resistance calculated. The mean values and standard deviations of fatigue strength, torsional moments and fatigue limits (load cycles) were checked for normal distribution and finally the results were compared by means of non parametric and parametric statistical tests. RESULTS: Plate breakage occurred with the AO wrist fusion plate on average after 52,596 (SD+/-12,833) load cycles and with the APTUS wrist fusion plate after an average of 115,428 (SD+/-12,600) load cycles. For the AO wrist fusion plates, an average load of 6.3 (SD+/-0.8) Nm and for the APTUS plate one of 10 (SD+/-1.7) Nm led to failure. For the APTUS plate the screw tear-out resistance was calculated as 2,632 (SD+/-96) N while that for the AO plate was found to be 1,449 (SD+/-314) N. CONCLUSION: In comparison to the AO wrist fusion plate the APTUS wrist fusion plate has significantly higher fatigue resistance and tear-out strength. On the basis of 100,000 load cycles until bone healing in the case a wrist arthrodesis, use of the APTUS plate should enable bone healing to occur before the implant fails. PMID- 25706178 TI - [The Linburg-Comstock phenomenon: a review]. AB - Simultaneous flexion of thumb and fingers is described as the Linburg-Comstock phenomenon. Congenital and acquired coupling of the flexor pollicis longus (FPL) and flexor digitorum profundus (FDP) tendons is the reason for this clinical entity. Additionally, coupling of the FPL and the flexor digitorum superficialis II or III has been described. The coupling can be between the muscles, the tendon sheaths or the tendons themselves. Asymptomatic and symptomatic coupling should be differentiated. In general symptomatic congenital or acquired coupling demands surgical intervention. We report about a 35-year-old patient with a congenital asymptomatic coupling of FPL and FDP-II who suffered a distorsion of the thumb. Afterwards she complained of pain and strength loss. An accessory tendon of 3 mm in diameter and 3.5 cm length between FPL and FDP-II was identified during surgery. The patient recovered completely after resection of this coupling. PMID- 25706179 TI - [Symptomatic carpal coalition of scaphoid, trapezium and trapezoid with coexisting ipsilateral hypoplasia of the thumb]. AB - We present the case of a 54-year-old woman with symptomatic coalition of scaphoid, trapezium and trapezoid as well as a coexisting ipsilateral hypoplasia of the thumb. PMID- 25706180 TI - A genomics based discovery of secondary metabolite biosynthetic gene clusters in Aspergillus ustus. AB - Secondary metabolites (SMs) produced by Aspergillus have been extensively studied for their crucial roles in human health, medicine and industrial production. However, the resulting information is almost exclusively derived from a few model organisms, including A. nidulans and A. fumigatus, but little is known about rare pathogens. In this study, we performed a genomics based discovery of SM biosynthetic gene clusters in Aspergillus ustus, a rare human pathogen. A total of 52 gene clusters were identified in the draft genome of A. ustus 3.3904, such as the sterigmatocystin biosynthesis pathway that was commonly found in Aspergillus species. In addition, several SM biosynthetic gene clusters were firstly identified in Aspergillus that were possibly acquired by horizontal gene transfer, including the vrt cluster that is responsible for viridicatumtoxin production. Comparative genomics revealed that A. ustus shared the largest number of SM biosynthetic gene clusters with A. nidulans, but much fewer with other Aspergilli like A. niger and A. oryzae. These findings would help to understand the diversity and evolution of SM biosynthesis pathways in genus Aspergillus, and we hope they will also promote the development of fungal identification methodology in clinic. PMID- 25706181 TI - Abstracts of the Airway Vista 2015, 21-22 March, 2015, Seoul, Korea. PMID- 25706182 TI - An actigraphy study of sleep and pain in midlife women: the Study of Women's Health Across the Nation Sleep Study. AB - OBJECTIVE: We examined whether women reporting nighttime pain would have more actigraphy-measured evidence for disturbed sleep and would report feeling less rested compared with women without nighttime pain. METHODS: Up to 27 consecutive nights of actigraphy and sleep diary data from each participant were analyzed in this community-based study of 314 African-American (n = 118), white (n = 141), and Chinese (n = 55) women, aged 48 to 58 years, who were premenopausal, perimenopausal, or postmenopausal and were participating in the Study of Women's Health Across the Nation Sleep Study. Dependent variables were actigraphy measured movement and fragmentation index, total sleep time, sleep efficiency, and diary self-report of "feeling rested" after waking up. All outcomes were fitted using linear mixed-effects models to examine covariate-adjusted associations between the independent variable (nighttime pain severity) and sleep outcomes. RESULTS: Higher pain severity scores were associated with longer sleep duration but reduced sleep efficiency and less restful sleep. Women reporting nocturnal vasomotor symptoms had more sleep-related movement and sleep fragmentation, had reduced sleep efficiency, and were less likely to feel rested after wakening whether or not they reported pain. CONCLUSIONS: Midlife women who report higher nighttime pain levels have more objective evidence for less efficient sleep, consistent with self-reported less restful sleep. Nocturnal vasomotor symptoms also can contribute to restlessness and wakefulness in midlife women. PMID- 25706183 TI - Body mass index continues to accurately predict percent body fat as women age despite changes in muscle mass and height. AB - OBJECTIVE: Body mass index (BMI) is commonly used to predict obesity in clinical practice because it is suggested to closely correlate with percent body fat (%BF). With aging, women lose both lean mass and height. Because of this, many clinicians question whether BMI is an accurate predictor of obesity in aging women. In evaluating the equation for BMI (weight/height(2)), it is clear that both variables can have a dramatic effect on BMI calculation. We evaluated the relationship between BMI and %BF, as measured by dual-energy x-ray absorptiometry, in the setting of age-related changes in height loss and body composition in women. Our objective is to determine whether BMI continues to correlate with %BF as women age. METHODS: Study participants were identified using data from five osteoporosis clinical trials, where healthy participants had full-body dual-energy x-ray absorptiometry scans. Deidentified data from 274 women aged between 35 and 95 years were evaluated. %BF, weight, age, tallest height, actual height, and appendicular lean mass were collected from all participants. BMI was calculated using the actual height and the tallest height of each study participant. %BF was compared with BMI and stratified for age. RESULTS: BMI calculated using the tallest height and BMI calculated using actual height both had strong correlations with %BF. CONCLUSIONS: Surprisingly, the effects of changes in height and lean body mass balance each other out in BMI calculation. There continues to be a strong correlation between BMI and %BF in adult women as they age. PMID- 25706184 TI - Moderate to severe vasomotor and sexual symptoms remain problematic for women aged 60 to 65 years. AB - OBJECTIVE: This study aims to determine the prevalence and severity of menopausal symptoms in older postmenopausal women and, hence, the need for treatment options for women of this age. METHODS: This is a cross-sectional questionnaire-based study conducted between October 2013 and March 2014 among 2,020 women aged 40 to 65 years and living independently across Australia. The main outcome measures were the prevalence of moderate to severe vasomotor symptoms (VMS), as measured by the Menopause-Specific Quality of Life Questionnaire, and the current use of prescription therapy for menopausal symptoms. RESULTS: The prevalence of moderate to severe VMS was as follows: 2.8% in premenopausal women, 17.1% in perimenopausal women, 28.5% in postmenopausal women younger than 55 years, 15.1% in postmenopausal women aged 55 to 59 years, and 6.5% in postmenopausal women aged 60 to 65 years. Prescription therapy for menopausal symptoms was used by 135 women: 120 (5.9%) women using hormone therapy and 15 (0.7%) women using nonhormonal medication. The factors positively associated with moderate to severe VMS were smoking (odds ratio, 1.6; 95% CI, 1.1-2.3; P < 0.05) and a body mass index of 25 to 29.9 kg/m(2) (odds ratio, 1.7; 95% CI, 1.1-2.5; P < 0.05); education beyond high school was inversely associated (odds ratio, 0.7; 95% CI, 0.5-0.9; P < 0.05). CONCLUSIONS: In this large, representative, community-based sample of women, there is a high prevalence of untreated moderate to severe VMS even in women aged 60 to 65 years. The use of vaginal estrogen and nonhormonal prescription therapy with proven efficacy for treatment of menopausal symptoms is strikingly low, suggesting that menopause remains an undertreated condition. PMID- 25706185 TI - Initial nonresponse and survey response mode biases in survey research. AB - OBJECTIVE: We evaluated survey response factors (particularly initial nonresponse and survey mode) that may be associated with bias in survey research. METHODS: We examined prevention-related beliefs and outcomes for initial mail survey responders (n=209), follow-up mail survey responders (n=78), and follow-up telephone survey responders (n=74). The Pearson chi-square test and analysis of variance identified beliefs and behavioral outcomes associated with survey response mode. RESULTS: Follow-up options to the initial mail survey improved response rates (22.0-38.0 percent). Initial mail survey responders more strongly believed topical fluoride protects teeth from cavities than others (P=0.04). A significantly larger proportion of parents completing a follow-up telephone survey (30.8 percent) refused topical fluoride for their child than those completing mail surveys (10.3-10.4 percent) (P<0.0001). CONCLUSION: Multiple mode surveys with follow-up improve response rates. Initial nonresponse and survey response mode may be associated with biases in survey research. PMID- 25706186 TI - Collateral thermal damage to the pancreas by ultrasonic instruments during lymph node dissection in laparoscopic gastrectomy. AB - INTRODUCTION: Laparoscopic gastrectomy (LG) with D2 or more extended lymphadenectomy for advanced gastric cancer is technically demanding. Collateral thermal damage to the pancreas secondary to energized dissection during lymphadenectomy has been reported. We retrospectively compared the pancreatic damage between LG and open gastrectomy (OG) by measuring the amylase concentration of the drainage fluid and analyzing heat conductance to the pancreas with a porcine model. METHODS: We evaluated the data of 105 consecutive patients with gastric adenocarcinoma who underwent LG or OG with lymph node dissection. Digital thermography was used to evaluate the extent of heat conductance to the pancreas during suprapancreatic lymph node dissection by either an ultrasonically activated device or electric cautery in a porcine model. RESULTS: The incidence of clinically relevant pancreatic fistula formation was not statistically significant between the LG and OG groups (3/57 vs 0/48 cases; P = 0.306). However, the median amylase concentrations of the drainage fluid on postoperative days 1 and 3 were 1355.7 and 308.8 IU/L, respectively, in the LG group and 369.0 and 125.8 IU/L, respectively, in the OG group (P < 0.001). In the experimental model, more time was required to cool the surface of the pancreas to < 40 degrees C in the ultrasonically activated device group than in the electric cautery group (10.1 +/- 5.2 vs 5.2 +/- 3.0 s; P = 0.013). CONCLUSIONS: Unavoidable collateral thermal damage to the pancreas associated with electrosurgical devices might exist during LG. Heat conductance must be given more consideration in extended lymph node dissection. PMID- 25706187 TI - Adenosine 5'-Triphosphate Test in the Management of Patients With Syncope. AB - The response to adenosine 5'-triphosphate (ATP) identifies patients with syncope who might benefit from pacemaker therapy (ATP test). Two measures have been used to determine the outcome of the ATP test, which have lead to contrasting conclusions regarding its utility: (1) the duration of cardiac pause (CP) mainly due to AV block and (2) the longest RR interval (RRmax). We tested the hypothesis that the discrepancy regarding the utility of the ATP test is mainly because of the different way the 2 measures determine the outcome of the test. Post hoc analysis was applied to data obtained from patients with syncope (n = 33) with a positive and negative ATP test based on the CP duration and RRmax, respectively, subjected to pacemaker therapy. In 19 and 14 patients, the pacemaker was programmed to function as AAI pacing at 30 ppm (control) and as DDD pacing at 70 ppm, respectively. During the follow-up period of 17.0 +/- 8.6 months, syncope recurred in only 1 of the 14 patients with DDD pacing; in contrast, 10 of 19 patients with AAI30 pacing experienced syncope within the first 5.3 +/- 5.2 months of follow-up (P < 0.009; recurrence rate). The ATP test, the outcome of which is determined by the CP measure, is a useful diagnostic test for the identification of patients with bradycardic syncope who may benefit from pacemaker therapy; the identification of such patients would be missed when the RRmax measure is used to determine the outcome of the test. The efficacy of DDD pacing suggests that atrioventricular nodal conduction block is the primary cause of syncope in patients with a positive ATP test based on the CP measure. PMID- 25706188 TI - Theoretical investigation on the mechanism and dynamics of oxo exchange of neptunyl(VI) hydroxide in aqueous solution. AB - Four types of reaction mechanisms for the oxo ligand exchange of monomeric and dimeric neptunyl(VI) hydroxide in aqueous solution were explored computationally using density functional theory (DFT) and ab initio classical molecular dynamics. The obtained results were compared with previous studies on the oxo exchange of uranyl hydroxide, as well as with experiments. It is found that the stable T shaped [NpO3(OH)3](3-) intermediate is a key species for oxo exchange in the proton transfer in mononuclear Path I and binuclear Path IV, similar to the case of uranyl(VI) hydroxide. Path I is thought to be the preferred oxo exchange mechanism for neptunyl(VI) hydroxide in our calculations, due to the lower activation energy (22.7 and 13.1 kcal mol(-1) for DeltaG(?) and DeltaH(?), respectively) of the overall reaction. Path II via a cis-neptunyl structure assisted by a water molecule might be a competitive channel against Path I with a mononuclear mechanism, owing to a rapid dynamical process occurring in Path II. In Path IV with the binuclear mechanism, oxo exchange is accomplished via the interaction between [NpO2(OH)4](2-) and T-shaped [NpO3(OH)3](3-) with a low activation energy for the rate-determining step, however, the overall energy required to fulfill the reaction is slightly higher than that in mononuclear Path I, suggesting a possible binuclear process in the higher energy region. The chemical bonding evolution along the reaction pathways was discussed by using topological methodologies of the electron localization function (ELF). PMID- 25706189 TI - Rapidly assessing the activation conditions and porosity of metal-organic frameworks using thermogravimetric analysis. AB - A methodology utilizing a thermogravimetric analyzer to monitor propane uptake following incremental increases of the temperature is demonstrated as a means of rapidly identifying porous materials and determining the optimum activation conditions of metal-organic frameworks. PMID- 25706190 TI - Selective killing of hepatocellular carcinoma HepG2 cells by three-dimensional nanographene nanoparticles based on triptycene. AB - Carbon-based materials have been widely used in the biomedical fields including drug delivery and cancer therapies. In this paper, a recently synthesized three dimensional nanographene (NG) based on triptycene self-assembles into nanoparticles which selectively kill human hepatocellular carcinoma HepG2 cells as compared to human normal liver HL7702 cells. Obvious differences in cellular accumulation, the endocytic pathway and intracellular trafficking of NG nanoparticles are observed in HepG2 cells and HL7702 cells. Further studies reveal that NG nanoparticles significantly increase the levels of reactive oxygen species (ROS) in HepG2 cells, but not in HL7702 cells. NG nanoparticle-induced ROS result in apoptosis induction and the decrease in mitochondrial membrane potential in HepG2 cells. Moreover, IKK/nuclear factor-kappaB (NF-kappaB) signaling is found to be activated by NG nanoparticle-induced ROS and serves to antagonize NG nanoparticle-induced apoptosis in HepG2 cells. Our studies show that the distinct behaviors of cellular uptake and ROS-mediated cytotoxicity are responsible for the selective killing of HepG2 cells. This study provides a foundation for understanding the mechanism of selective induction of apoptosis in cancer cells by NG nanoparticles and designing more effective chemotherapeutical agents. PMID- 25706192 TI - Disability and assistance dog implicit association test: a novel IAT. AB - OBJECTIVE: Individuals with disabilities often face stigma and negative social interactions. Human-animal interaction literature suggests that an individual paired with an animal will be perceived differently than an individual alone. Although people with disabilities report increases in social interactions when with assistance dogs, the reasons for this remain unclear. One possibility is that attitudes toward people with disabilities are altered by the presence of assistance dogs, thus affecting the social behaviors of the perceiver. This study examines whether implicit attitudes toward individuals with disabilities differ in the presence of an assistance dog. METHOD: College students (N = 244) completed the Attitudes of Adults to Dogs scale, an item assessing dog ownership, and the Disabilities and Assistance Dog Implicit Association Test (IAT). RESULTS: A 1-sample t test demonstrated a significant IAT effect, t(240) = 3.62, p < .001, with a positive implicit bias observed toward an individual with a disability when paired with an assistance dog over the individual alone. White individuals were more likely than Black individuals to hold positive implicit attitudes toward an individual with a disability paired with a dog, F(2, 238) = 3.18, p = .04. There were no significant differences in IAT D scores based on gender or dog ownership. IMPLICATIONS: This study extends previous research regarding social interactions for individuals with disabilities who are paired with assistance dogs. Increases in positive implicit attitudes toward an individual with a disability paired with a dog may explain these changes in social interactions. Dogs may serve as a social lubricant, increasing positive social interactions for individuals with disabilities. PMID- 25706191 TI - Tracking early decline in cognitive function in older individuals at risk for Alzheimer disease dementia: the Alzheimer's Disease Cooperative Study Cognitive Function Instrument. AB - IMPORTANCE: Several large-scale Alzheimer disease (AD) secondary prevention trials have begun to target individuals at the preclinical stage. The success of these trials depends on validated outcome measures that are sensitive to early clinical progression in individuals who are initially asymptomatic. OBJECTIVE: To investigate the utility of the Cognitive Function Instrument (CFI) to track early changes in cognitive function in older individuals without clinical impairment at baseline. DESIGN, SETTING, AND PARTICIPANTS: Longitudinal study from February 2002 through February 2007 at participating Alzheimer's Disease Cooperative Study sites. Individuals were followed up annually for 48 months after the baseline visit. The study included 468 healthy older individuals (Clinical Dementia Rating scale [CDR] global scores of 0, above cutoff on the modified Mini-Mental State Examination and Free and Cued Selective Reminding Test) (mean [SD] age, 79.4 [3.6] years; age range, 75.0-93.8 years). All study participants and their study partners completed the self and partner CFIs annually. Individuals also underwent concurrent annual neuropsychological assessment and APOE genotyping. MAIN OUTCOMES AND MEASURES: The CFI scores between clinical progressors (CDR score, >=0.5) and nonprogressors (CDR score, 0) and between APOE epsilon4 carriers and noncarriers were compared. Correlations of change between the CFI scores and neuropsychological performance were assessed longitudinally. RESULTS: At 48 months, group differences between clinical progressors and non-progressors were significant for self (2.13, SE=0.45, P<.001), partner (5.08, SE=0.59, P<.001), and self plus partner (7.04, SE=0.83, P<.001) CFI total scores. At month 48, APOE epsilon4 carriers had greater progression than noncarriers on the partner (1.10, SE=0.44, P<.012) and self plus partner (1.56, SE=0.63, P<.014) CFI scores. Both self and partner CFI change were associated with longitudinal cognitive decline (self, rho=0.32, 95% CI, 0.13 to 0.46; partner, rho=0.56, 95% CI, 0.42 to 0.68), although findings suggest self-report may be more accurate early in the process, whereas accuracy of partner report improves when there is progression to cognitive impairment. CONCLUSIONS AND RELEVANCE: Demonstrating long-term clinical benefit will be critical for the success of recently launched secondary prevention trials. The CFI appears to be a brief, but informative potential outcome measure that provides insight into functional abilities at the earliest stages of disease. PMID- 25706193 TI - Depression in spinal cord injury: assessing the role of psychological resources. AB - PURPOSE: To test the spinal cord injury adjustment model (SCIAM) and to examine how psychological resources may influence depressive symptoms in persons with spinal cord injury (SCI). We expect that (a) higher general self-efficacy (GSE) and higher purpose in life (PIL) are associated with lower levels of depressive symptoms, and that (b) the effect of GSE and PIL on depressive symptoms is mediated by appraisals and coping strategies, as proposed by the SCIAM. METHOD: A nationwide cross-sectional survey (the Swiss Spinal Cord Injury Cohort Study) was conducted with individuals with SCI living in the Swiss community (N = 516). Structural equation modeling was used to test relationships between variables as specified in the SCIAM. RESULTS: Higher GSE (r = -.54) and PIL (r = -.62) were significantly associated with lower depressive symptoms. The initial model yielded poor model fit. However, the final modified model fitted well, with chi2(21) = 54.00, p < .01, RMSEA = .055 (90% CI [.038, .073]), CFI = .98, explaining 62.9% of the variance of depressive symptoms. PIL had a direct large effect and an indirect effect on depressive symptoms via appraisals and coping strategies. The influence of GSE on depressive symptoms was fully mediated by appraisals and coping strategies. CONCLUSIONS: Psychological resources of individuals with SCI can have a direct effect on depressive symptoms. The mediated pathways are present, but not exclusive in our data, yielding only partial support for the mechanism proposed by the SCIAM. PMID- 25706194 TI - Measuring disability-associated appraisals for veterans with spinal cord injury. AB - OBJECTIVE: Psychological adjustment following spinal cord injury and disorders (SCI/D) is a complex process. According to the Stress Appraisal and Coping Model, appraisals may mediate the relationship between disability and psychological adjustment. The purpose of the present study was to examine the psychometric properties and clinical utility of a short form of the Appraisals of Disability: Primary and Secondary Scale (ADAPSS-sf), a 6-item measure adapted from the original 33-item ADAPSS questionnaire. DESIGN: As part of routine clinical care at a VA Medical Center, 98 Veterans (96% male, mean age = 56) with SCI/D completed study measures as part of their annual comprehensive SCI/D evaluation. Principal-components analysis was used to examine the factor structure of the ADAPSS-sf. Multivariate linear regressions were used to examine the relationship between appraisals of disability and life satisfaction, controlling for demographics, injury characteristics and depressive symptoms. RESULTS: Demographic and SCI characteristics of the study sample are comparable to a national Veteran sample. Factor analysis revealed a 2-factor structure within the ADAPSS-sf. One factor represented appraisals signifying fear and loss, whereas the second factor represented appraisals reflecting resilience. Linear regressions showed that Veterans' disability-associated appraisals were strongly associated with life satisfaction. CONCLUSIONS: Study findings support the internal validity and a coherent 2-factor structure of the ADAPSS-sf in an outpatient Veteran population with chronic SCI/D. Additional research is warranted to test the clinical utility of the ADAPSS-sf with Veterans with SCI/D. PMID- 25706195 TI - Colloidally stable and surfactant-free protein-coated gold nanorods in biological media. AB - In this work, we investigate the ligand exchange of cetyltrimethylammonium bromide (CTAB) with bovine serum albumin for gold nanorods. We demonstrate by surface-enhanced Raman scattering measurements that CTAB, which is used as a shape-directing agent in the particle synthesis, is completely removed from solution and particle surface. Thus, the protein-coated nanorods are suitable for bioapplications, where cationic surfactants must be avoided. At the same time, the colloidal stability of the system is significantly increased, as evidenced by spectroscopic investigation of the particle longitudinal surface plasmon resonance, which is sensitive to aggregation. Particles are stable at very high concentrations (cAu 20 mg/mL) in biological media such as phosphate buffer saline or Dulbecco's Modified Eagle's Medium and over a large pH range (2-12). Particles can even be freeze-dried (lyophilized) and redispersed. The protocol was applied to gold nanoparticles with a large range of aspect ratios and sizes with main absorption frequencies covering the visible and the near-IR spectral range from 600 to 1100 nm. Thus, these colloidally stable and surfactant-free protein-coated nanoparticles are of great interest for various plasmonic and biomedical applications. PMID- 25706196 TI - The contribution of specific cell subpopulations to submandibular salivary gland branching morphogenesis. AB - Branching morphogenesis is the developmental program responsible for generating a large surface to volume ratio in many secretory and absorptive organs. To accomplish branching morphogenesis, spatiotemporal regulation of specific cell subpopulations is required. Here, we review recent studies that define the contributions of distinct cell subpopulations to specific cellular processes during branching morphogenesis in the mammalian submandibular salivary gland, including the initiation of the gland, the coordination of cleft formation, and the contribution of stem/progenitor cells to morphogenesis. In conclusion, we provide an overview of technological advances that have opened opportunities to further probe the contributions of specific cell subpopulations and to define the integration of events required for branching morphogenesis. PMID- 25706197 TI - pH-controllable synthesis of unique nanostructured tungsten oxide aerogel and its sensitive glucose biosensor. AB - This work presents a controllable synthesis of nanowire-networked tungsten oxide aerogels, which was performed by varying the pH in a polyethyleneimine (PEI) assisted hydrothermal process. An enzyme-tungsten oxide aerogel co-modified electrode shows high activity and selectivity toward glucose oxidation, thus holding great promise for applications in bioelectronics. PMID- 25706198 TI - Strontium and zoledronate hydroxyapatites graded composite coatings for bone prostheses. AB - Both strontium and zoledronate (ZOL) are known to be useful for the treatment of bone diseases associated to the loss of bone substance. In this work, we applied an innovative technique, Combinatorial Matrix-Assisted Pulsed Laser Evaporation (C-MAPLE), to deposit gradient thin films with variable compositions of Sr substituted hydroxyapatite (SrHA) and ZOL modified hydroxyapatite (ZOLHA) on Titanium substrates. Compositional gradients were obtained by simultaneous laser vaporization of the two distinct material targets. The coatings display good crystallinity and granular morphology, which do not vary with composition. Osteoblast-like MG63 cells and human osteoclasts were co-cultured on the thin films up to 21 days. The results show that Sr counteracts the negative effect of relatively high concentration of ZOL on osteoblast viability, whereas both Sr and ZOL enhance extracellular matrix deposition. In particular, ZOL promotes type I collagen production, whereas Sr increases the production of alkaline phosphatase. Moreover, ZOL exerts a greater effect than Sr on osteoprotegerin/RANKL ratio and, as a consequence, on the reduction of osteoclast proliferation and activity. The deposition method allows to modulate the composition of the thin films and hence the promotion of bone growth and the inhibition of bone resorption. PMID- 25706199 TI - Mechanical properties of a waterborne pressure-sensitive adhesive with a percolating poly(acrylic acid)-based diblock copolymer network: effect of pH. AB - Copolymerizing an acrylic acid comonomer is often beneficial for the adhesive properties of waterborne pressure-sensitive adhesives (PSAs). Here, we demonstrate a new strategy in which poly(acrylic acid) (PAA) is distributed as a percolating network within a PSA film formed from a polymer colloid. A diblock copolymer composed of PAA and poly(n-butyl acrylate) (PBA) blocks was synthesized using reversible addition-fragmentation chain transfer (RAFT) polymerization and adsorbed onto soft acrylic latex particles prior to their film formation. The thin adsorbed shells on the particles create a percolating network that raises the elastic modulus, creep resistance and tensile strength of the final film. When the film formation occurs at pH 10, ionomeric crosslinking occurs, and high tack adhesion is obtained in combination with high creep resistance. The results show that the addition of an amphiphilic PAA-b-PBA diblock copolymer (2.0 wt.%) to a soft latex provides a simple yet effective means of adjusting the mechanical and adhesive properties of the resulting composite film. PMID- 25706200 TI - Facile fabrication of highly efficient g-C3N4/BiFeO3 nanocomposites with enhanced visible light photocatalytic activities. AB - Graphitic carbon nitride/bismuth ferrite (g-C3N4/BiFeO3) nanocomposites with various g-C3N4 contents have been synthesized by a simple method. After the deposition-precipitation process, the novel BiFeO3 spindle-like nanoparticles with the size of ~100 nm were homogeneously decorated on the surfaces of the C3N4 nanosheets. A possible deposition growth mechanism is proposed on the basis of experimental results. The as-prepared g-C3N4/BiFeO3 composites exhibit high efficiency for the degradation of methyl orange (MO) under visible light irradiation, which can be mainly attributed to the synergic effect between g-C3N4 and BiFeO3. The ability to tune surface and interfacial characteristics for the optimization of photophysical properties suggests that the deposition growth process may enable formation of hybrids suitable for a range of photocatalytic applications based on g-C3N4. PMID- 25706201 TI - What's in a name? Systemic exertion intolerance disease. PMID- 25706202 TI - Rethinking personality disorder. PMID- 25706203 TI - Clinical campaigns: science-based advocacy for change. PMID- 25706204 TI - Realising an election manifesto for public health in the UK. PMID- 25706205 TI - Are the conditions right for a 21st-century medical school? PMID- 25706207 TI - Francoise Meunier: building an EORTC for the future. PMID- 25706208 TI - Medical treatment of an Ebola-infected doctor--ethics over costs? PMID- 25706209 TI - UK Defence Medical Services Ebola Treatment Facility. PMID- 25706210 TI - Assisted Dying Bill calls for stricter safeguards. PMID- 25706211 TI - Patient perspectives on telephone triage in general practice. PMID- 25706212 TI - Dalteparin for pregnant women with thrombophilia. PMID- 25706213 TI - Patient perspectives on telephone triage in general practice - authors' reply. PMID- 25706214 TI - Dalteparin for pregnant women with thrombophilia. PMID- 25706215 TI - Dalteparin for pregnant women with thrombophilia. PMID- 25706216 TI - Dalteparin for pregnant women with thrombophilia - authors' reply. PMID- 25706217 TI - Classification, assessment, prevalence, and effect of personality disorder. AB - Personality disorders are common and ubiquitous in all medical settings, so every medical practitioner will encounter them frequently. People with personality disorder have problems in interpersonal relationships but often attribute them wrongly to others. No clear threshold exists between types and degrees of personality dysfunction and its pathology is best classified by a single dimension, ranging from normal personality at one extreme through to severe personality disorder at the other. The description of personality disorders has been complicated over the years by undue adherence to overlapping and unvalidated categories that represent specific characteristics rather than the core components of personality disorder. Many people with personality disorder remain undetected in clinical practice and might be given treatments that are ineffective or harmful as a result. Comorbidity with other mental disorders is common, and the presence of personality disorder often has a negative effect on course and treatment outcome. Personality disorder is also associated with premature mortality and suicide, and needs to be identified more often in clinical practice than it is at present. PMID- 25706218 TI - Personality disorder across the life course. AB - The pervasive effect of personality disorder is often overlooked in clinical practice, both as an important moderator of mental state and physical disorders, and as a disorder that should be recognised and managed in its own right. Contemporary research has shown that maladaptive personality (when personality traits are extreme and associated with clinical distress or psychosocial impairment) is common, can be recognised early in life, evolves continuously across the lifespan, and is more plastic than previously believed. These new insights offer opportunities to intervene to support more adaptive development than before, and research shows that such intervention can be effective. Further research is needed to improve classification, assessment, and diagnosis of personality disorder across the lifespan; to understand the complex interplay between changes in personality traits and clinical presentation over time; and to promote more effective intervention at the earliest possible stage of the disorder than is done at present. Recognition of how personality disorder relates to age and developmental stage can improve care of all patients. PMID- 25706219 TI - Treatment of personality disorder. AB - The evidence base for the effective treatment of personality disorders is insufficient. Most of the existing evidence on personality disorder is for the treatment of borderline personality disorder, but even this is limited by the small sample sizes and short follow-up in clinical trials, the wide range of core outcome measures used by studies, and poor control of coexisting psychopathology. Psychological or psychosocial intervention is recommended as the primary treatment for borderline personality disorder and pharmacotherapy is only advised as an adjunctive treatment. The amount of research about the underlying, abnormal, psychological or biological processes leading to the manifestation of a disordered personality is increasing, which could lead to more effective interventions. The synergistic or antagonistic interaction of psychotherapies and drugs for treating personality disorder should be studied in conjunction with their mechanisms of change throughout the development of each. PMID- 25706220 TI - Encephalopathy and high anion gap metabolic acidosis: an unusual herald of buried bumper syndrome. PMID- 25706221 TI - Wastewater analysis to monitor use of caffeine and nicotine and evaluation of their metabolites as biomarkers for population size assessment. AB - The use of caffeine, nicotine and some major metabolites was investigated by wastewater analysis in 13 sewage treatment plants (STPs) across Italy, and their suitability was tested as qualitative and quantitative biomarkers for assessing population size and dynamics. A specific analytical method based on mass spectrometry was developed and validated in raw urban wastewater, and included two caffeine metabolites, 1-methylxanthine and 7-methylxanthine, never reported in wastewater before. All these compounds were found widely at the MUg/L level. Mass loads, calculated by multiplying concentrations by the wastewater daily flow rate and normalized to the population served by each plant, were used to compare the profiles from different cities. Some regional differences were observed in the mass loads, especially for nicotine metabolites, which were significantly higher in the south than in the center and north of Italy, reflecting smoking prevalences from population surveys. There were no significant weekly trends, although the mean mass loads of caffeine and its metabolites were slightly lower during the weekend. Most caffeine and nicotine metabolites fulfilled the requirements for an ideal biomarker for the assessment of population size, i.e. being easily detectable in wastewater, stable in sewage and during sampling, and reflecting human metabolism. Nicotine metabolites were tested as quantitative biomarkers to estimate population size and the results agreed well with census data. Caffeine and its metabolites were confirmed as good qualitative biomarkers, but additional information is needed on the caffeine metabolism in relation to the multiple sources of its main metabolites. This exploratory study opens the way to the routine use of nicotine metabolites for estimating population size and dynamics. PMID- 25706222 TI - Microbial health risks associated with exposure to stormwater in a water plaza. AB - Climate change scenarios predict an increase of intense rainfall events in summer in Western Europe. Current urban drainage systems cannot cope with such intense precipitation events. Cities are constructing stormwater storage facilities to prevent pluvial flooding. Combining storage with other functions, such as recreation, may lead to exposure to contaminants. This study assessed the microbial quality of rainwater collected in a water plaza and the health risks associated with recreational exposure. The water plaza collects street run-off, diverges first flush to the sewer system and stores the rest of the run-off in the plaza as open water. Campylobacter, Cryptosporidium and Legionella pneumophila were the pathogens investigated. Microbial source tracking tools were used to determine the origin (human, animal) of the intestinal pathogens. Cryptosporidium was not found in any sample. Campylobacter was found in all samples, with higher concentrations in samples containing human Bacteroides than in samples with zoonotic contamination (15 vs 3.7 gc (genomic copies)/100 mL). In both cases, the estimated disease risk associated with Campylobacter and recreational exposure was higher than the Dutch national incidence. This indicates that the health risk associated with recreational exposure to the water plaza is significant. L. pneumophila was found only in two out of ten pond samples. Legionnaire's disease risks were lower than the Dutch national incidence. Presence of human Bacteroides indicates possible cross-connections with the CSS that should be identified and removed. PMID- 25706223 TI - Magnetic sulfide-modified nanoscale zerovalent iron (S-nZVI) for dissolved metal ion removal. AB - Sulfide-modified nanoscale zerovalent iron (S-nZVI) is attracting a lot of attention due to its ease of production and high reactivity with organic pollutants. However, its structure is still poorly understood and its potential application in heavy metal remediation has not been explored. Herein, the structure of S-nZVI and its cadmium (Cd) removal performance under different aqueous conditions were carefully investigated. Transmission electron microscopy (TEM) with an energy-dispersive X-ray spectroscopy (EDS) analysis suggested that sulfur was incorporated into the zerovalent iron core. Scanning electron microscopy (SEM) with EDS analysis demonstrated that sulfur was also homogeneously distributed within the nanoparticles. When the concentration of Na2S2O4 was increased during synthesis, a flake-like structure (FeSx) increased significantly. S-nZVI had an optimal Cd removal capacity of 85 mg/g, which was >100% higher than for pristine nZVI. Even at pH 5, over 95% removal efficiency was observed, indicating sulfide compounds played a crucial role in metal ion removal and particle chemical stability. Oxygen impaired the structure of S-nZVI but enhanced Cd removal capacity to about 120 mg/g. Particle aging had no negative effect on removal capacity of S-nZVI, and Cd-containing mixtures remained stable in a two months experiment. S-nZVI can efficiently sequester dissolved metal ions from different contaminated water matrices. PMID- 25706224 TI - N2O production by ammonia oxidizing bacteria in an enriched nitrifying sludge linearly depends on inorganic carbon concentration. AB - The effect of inorganic carbon (IC) on nitrous oxide (N2O) production by ammonia oxidizing bacteria (AOB) was investigated over a concentration range of 0-12 mmol C/L, encompassing typical IC levels in a wastewater treatment reactors. The AOB culture was enriched along with nitrite-oxidizing bacteria (NOB) in a sequencing batch reactor (SBR) to perform complete nitrification. Batch experiments were conducted with continuous carbon dioxide (CO2) stripping or at controlled IC concentrations. The results revealed a linear relationship between N2O production rate (N2OR) and IC concentration (R(2) = 0.97) within the IC range studied, suggesting a substantial effect of IC on N2O production by AOB. Similar results were also obtained with an AOB culture treating anaerobic sludge digestion liquor. The fundamental mechanism responsible for this dependency is unclear; however, in agreement with previous studies, it was observed that the ammonia oxidation rate (AOR) was also influenced by the IC concentration, which could be well described by the Monod kinetics. These resulted in an exponential relationship between N2OR and AOR, as previously observed in experiments where AOR was altered by varying dissolved oxygen and ammonia concentrations. It is therefore possible that IC indirectly affected N2OR by causing a change in AOR. The observation in this study indicates that alkalinity (mostly contributed by IC) could be a significant factor influencing N2O production and should be taken into consideration in estimating and mitigating N2O emissions in wastewater treatment systems. PMID- 25706225 TI - Nano-TiO2 reinforced PEEK/PEI blends as biomaterials for load-bearing implant applications. AB - Biocompatible ternary nanocomposites based on poly(ether ether ketone) (PEEK)/poly(ether imide) (PEI) blends reinforced with bioactive titanium dioxide (TiO2) nanoparticles were fabricated via ultrasonication followed by melt blending. The developed biomaterials were characterized using FT-IR, SEM, XRD, DSC, TGA, and DMA. Further, their water-absorption, tensile, tribological, dielectric, and antibacterial properties were evaluated. PEI acts as a coupling agent, since it can interact both with PEEK via pi-pi stacking and polar interactions as well as with the nanoparticles through hydrogen bonding, as corroborated by the FT-IR spectra, which resulted in a homogeneous titania dispersion within the biopolymer blend without applying any particle surface treatment or polymer functionalization. A change from promotion to retardation in the crystallization rate of the matrix was found with increasing TiO2 concentration, while its crystalline structure remained unaltered. The nanoparticles stiffened, strengthened, and toughened the matrix simultaneously, and the optimal properties were achieved at 4.0 wt % TiO2. More interesting, the tensile properties were retained after steam sterilization in an autoclave or exposure to a simulated body fluid (SBF). The nanocomposites also displayed reduced water absorption though higher thermal stability, storage modulus, glass transition temperature, dielectric constant, and dielectric loss compared to the control blend. Further, remarkable enhancements in the tribological properties under both SBF and dry environments were attained. The nanoparticles conferred antibacterial action versus Gram-positive and Gram-negative bacteria in the presence and the absence of UV light, and the highest inhibition was attained at 4.0 wt % nanoparticle concentration. These nanocomposites are expected to be used in long-term load-bearing implant applications. PMID- 25706227 TI - Mechanism of the palladium-catalyzed arene C-H acetoxylation: a comparison of catalysts and ligand effects. AB - This article describes detailed mechanistic studies focused on elucidating the impact of pyridine ligands on the Pd-catalyzed C-H acetoxylation of benzene. Three different catalysts, Pd(OAc)2, Pd(OAc)2/pyridine (1:1), and Pd(OAc)2/pyridine (1:2), are compared using a combination of mechanistic tools, including rate and order studies, Hammett analysis, detailed characterization of catalyst resting states, and isotope effects. The data from these experiments implicate C-H activation as the rate-limiting step in all cases. The major difference between the three catalysts is proposed to be the resting state of Pd. Under the reaction conditions, Pd(OAc)2 rests as an acetate bridged dimer, while the Pd(OAc)2/pyridine (1:2) catalyst rests as the monomer (pyridine)2Pd(OAc)2. In contrast, a variety of experiments suggest that the highly active catalyst generated from the 1:1 combination of Pd(OAc)2 and pyridine rests as the dimeric structure [(pyridine)Pd(OAc)2]2. PMID- 25706226 TI - Top-Down Control of Serotonin Systems by the Prefrontal Cortex: A Path toward Restored Socioemotional Function in Depression. AB - Social withdrawal, increased threat perception, and exaggerated reassurance seeking behaviors are prominent interpersonal symptoms in major depressive disorder (MDD). Altered serotonin (5-HT) systems and corticolimbic dysconnectivity have long been suspected to contribute to these symptomatic facets; however, the underlying circuits and intrinsic cellular mechanisms that control 5-HT output during socioemotional interactions remain poorly understood. We review literature that implicates a direct pathway between the ventromedial prefrontal cortex (vmPFC) and dorsal raphe nucleus (DRN) in the adaptive and pathological control of social approach-avoidance behaviors. Imaging and neuromodulation during approach-avoidance tasks in humans point to the cortical control of brainstem circuits as an essential regulator of socioemotional decisions and actions. Parallel rodent studies using viral-based connectomics and optogenetics are beginning to provide a cellular blueprint of the underlying circuitry. In these studies, manipulations of vmPFC synaptic inputs to the DRN have revealed bidirectional influences on socioaffective behaviors via direct monosynaptic excitation and indirect disynaptic inhibition of 5-HT neurons. Additionally, adverse social experiences that result in permanent avoidance biases, such as social defeat, drive long-lasting plasticity in this microcircuit, potentiating the indirect inhibition of 5-HT output. Conversely, neuromodulation of the vmPFC via deep brain stimulation (DBS) attenuates avoidance biases by restoring the direct excitatory drive of 5-HT neurons and strengthening a key subset of forebrain 5-HT projections. Better understanding the cellular organization of the vmPFC-DRN pathway and identifying molecular determinants of its neuroplasticity can open fundamentally novel avenues for the treatment of affective disorders. PMID- 25706228 TI - Identification and characterization of secondary neural tube-derived embryonic neural stem cells in vitro. AB - Secondary neurulation is an embryonic progress that gives rise to the secondary neural tube, the precursor of the lower spinal cord region. The secondary neural tube is derived from aggregated Sox2-expressing neural cells at the dorsal region of the tail bud, which eventually forms rosette or tube-like structures to give rise to neural tissues in the tail bud. We addressed whether the embryonic tail contains neural stem cells (NSCs), namely secondary NSCs (sNSCs), with the potential for self-renewal in vitro. Using in vitro neurosphere assays, neurospheres readily formed at the rosette and neural-tube levels, but less frequently at the tail bud tip level. Furthermore, we identified that sNSC generated neurospheres were significantly smaller in size compared with cortical neurospheres. Interestingly, various cell cycle analyses revealed that this difference was not due to a reduction in the proliferation rate of NSCs, but rather the neuronal commitment of sNSCs, as sNSC-derived neurospheres contain more committed neuronal progenitor cells, even in the presence of epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF). These results suggest that the higher tendency for sNSCs to spontaneously differentiate into progenitor cells may explain the limited expansion of the secondary neural tube during embryonic development. PMID- 25706229 TI - Life-cycle thinking and the LEED rating system: global perspective on building energy use and environmental impacts. AB - This research investigates the relationship between energy use, geographic location, life cycle environmental impacts, and Leadership in Energy and Environmental Design (LEED). The researchers studied worldwide variations in building energy use and associated life cycle impacts in relation to the LEED rating systems. A Building Information Modeling (BIM) of a reference 43,000 ft(2) office building was developed and situated in 400 locations worldwide while making relevant changes to the energy model to meet reference codes, such as ASHRAE 90.1. Then life cycle environmental and human health impacts from the buildings' energy consumption were calculated. The results revealed considerable variations between sites in the U.S. and international locations (ranging from 394 ton CO2 equiv to 911 ton CO2 equiv, respectively). The variations indicate that location specific results, when paired with life cycle assessment, can be an effective means to achieve a better understanding of possible adverse environmental impacts as a result of building energy consumption in the context of green building rating systems. Looking at these factors in combination and using a systems approach may allow rating systems like LEED to continue to drive market transformation toward sustainable development, while taking into consideration both energy sources and building efficiency. PMID- 25706230 TI - Relationship between clinical site of isolation and ability to form biofilms in vitro in nontypeable Haemophilus influenzae. AB - Nontypeable Haemophilus influenzae (NTHi) is an opportunistic pathogen associated with a range of infections, including various lower respiratory infections, otitis media, and conjunctivitis. There is some debate as to whether or not NTHi produces biofilms and, if so, whether or not this is relevant to pathogenesis. Although many studies have examined the association between in vitro biofilm formation and isolates from a specific infection type, few have made comparisons from isolates from a broad range of isolates grouped by clinical source. In our study 50 NTHi from different clinical sources, otitis media, conjunctivitis, lower respiratory tract infections in both cystic fibrosis and non-cystic fibrosis patients, and nasopharyngeal carriage, plus 10 nasopharyngeal isolates of the commensal Haemophilus haemolyticus were tested for the ability to form biofilm by using a static microtitre plate crystal violet assay. A high degree of variation in biofilm forming ability was observed across all isolates, with no statistically significant differences observed between the groups, with the exception of the isolates from conjunctivitis. These isolates had uniformly lower biofilm forming ability compared with isolates from the other groups (p < 0.005). PMID- 25706231 TI - Side-binding proteins modulate actin filament dynamics. AB - Actin filament dynamics govern many key physiological processes from cell motility to tissue morphogenesis. A central feature of actin dynamics is the capacity of filaments to polymerize and depolymerize at their ends in response to cellular conditions. It is currently thought that filament kinetics can be described by a single rate constant for each end. In this study, using direct visualization of single actin filament elongation, we show that actin polymerization kinetics at both filament ends are strongly influenced by the binding of proteins to the lateral filament surface. We also show that the pointed-end has a non-elongating state that dominates the observed filament kinetic asymmetry. Estimates of flexibility as well as effects on fragmentation and growth suggest that the observed kinetic diversity arises from structural alteration. Tuning elongation kinetics by exploiting the malleability of the filament structure may be a ubiquitous mechanism to generate a rich variety of cellular actin dynamics. PMID- 25706232 TI - Virologic response following combined ledipasvir and sofosbuvir administration in patients with HCV genotype 1 and HIV co-infection. AB - IMPORTANCE: There is an unmet need for interferon- and ribavirin-free treatment for chronic hepatitis C virus (HCV) infection in patients co-infected with human immunodeficiency virus (HIV). OBJECTIVE: To evaluate the rates of sustained virologic response (SVR) and adverse events in previously untreated patients with HCV genotype 1 and HIV co-infection following a 12-week treatment of the fixed dose combination of ledipasvir and sofosbuvir. DESIGN, SETTING, AND PARTICIPANTS: Open-label, single-center, phase 2b pilot study of previously untreated, noncirrhotic patients with HCV genotype 1 and HIV co-infection conducted at the Clinical Research Center of the National Institutes of Health, Bethesda, Maryland, from June 2013 to September 2014. Patients included those receiving antiretroviral therapy with HIV RNA values of 50 copies/mL or fewer and a CD4 T lymphocyte count of 100 cells/mL or greater or patients with untreated HIV infection with a CD4 T-lymphocyte count of 500 cells/mL or greater. Serial measurements of safety parameters, virologic and host immune correlates, and adherence were performed. INTERVENTIONS: Fifty patients with HCV genotype 1 never before treated for HCV were prescribed a fixed-dose combination of ledipasvir (90 mg) and sofosbuvir (400 mg) once daily for 12 weeks. MAIN OUTCOMES AND MEASURES: The primary study outcome was the proportion of patients with sustained viral response (plasma HCV RNA level <12 IU/mL) 12 weeks after end of treatment. RESULTS: Forty-nine of 50 participants (98% [95% CI, 89% to 100%]) achieved SVR 12 weeks after end of treatment, whereas 1 patient experienced relapse at week 4 following treatment. In the patient with relapse, deep sequencing revealed a resistance associated mutation in the NS5A region conferring resistance to NS5A inhibitors, such as ledipasvir. The most common adverse events were nasal congestion (16% of patients) and myalgia (14%). There were no discontinuations or serious adverse events attributable to study drug. CONCLUSIONS AND RELEVANCE: In this open-label, uncontrolled, pilot study enrolling patients co-infected with HCV genotype 1 and HIV, administration of an oral combination of ledipasvir and sofosbuvir for 12 weeks was associated with high rates of SVR after treatment completion. Larger studies that also include patients with cirrhosis and lower CD4 T-cell counts are required to understand if the results of this study generalize to all patients co-infected with HCV and HIV. TRIAL REGISTRATION: clinicaltrials.gov Identifier:NCT01878799. PMID- 25706233 TI - A molecular mechanotransduction pathway regulates collective migration of epithelial cells. AB - Collective movement of epithelial cells drives essential multicellular organization during various fundamental physiological processes encompassing embryonic morphogenesis, cancer and wound healing. Yet the molecular mechanism that ensures the coordinated movement of many cells remains elusive. Here we show that a tumour suppressor protein, merlin, coordinates collective migration of tens of cells, by acting as a mechanochemical transducer. In a stationary epithelial monolayer and also in three-dimensional human skin, merlin localizes to cortical cell-cell junctions. During migration initiation, a fraction of cortical merlin relocalizes to the cytoplasm. This relocalization is triggered by the intercellular pulling force of the leading cell and depends on the actomyosin based cell contractility. Then in migrating cells, taking its cue from the intercellular pulling forces, which show long-distance ordering, merlin coordinates polarized Rac1 activation and lamellipodium formation on the multicellular length scale. Together, these results provide a distinct molecular mechanism linking intercellular forces to collective cell movements in migrating epithelia. PMID- 25706234 TI - Directional Notch trafficking in Sara endosomes during asymmetric cell division in the spinal cord. AB - Asymmetric division of neural precursor cells contributes to the generation of a variety of neuronal types. Asymmetric division is mediated by the asymmetric inheritance of fate determinants by the two daughter cells. In vertebrates, asymmetric fate determinants, such as Par3 and Mib, are only now starting to be identified. Here we show that, during mitosis of neural precursors in zebrafish, directional trafficking of Sara endosomes to one of the daughters can function as such a determinant. In asymmetric lineages, where one daughter cell becomes a neuron (n cell) whereas the other divides again to give rise to two neurons (p cell), we found that the daughter that inherits most of the Sara endosomes acquires the p fate. Sara endosomes carry an endocytosed pool of the Notch ligand DeltaD, which is thereby itself distributed asymmetrically. Sara and Notch are both essential for cell fate assignation within asymmetric lineages. Therefore, the Sara endosome system determines the fate decision between neuronal differentiation and mitosis in asymmetric lineages and thereby contributes to controlling the number of neural precursors and differentiated neurons during neurogenesis in a vertebrate. PMID- 25706235 TI - Developmental regulation of apical endocytosis controls epithelial patterning in vertebrate tubular organs. AB - Epithelial organs develop through tightly coordinated events of cell proliferation and differentiation in which endocytosis plays a major role. Despite recent advances, how endocytosis regulates the development of vertebrate organs is still unknown. Here we describe a mechanism that facilitates the apical availability of endosomal SNARE receptors for epithelial morphogenesis through the developmental upregulation of plasmolipin (pllp) in a highly endocytic segment of the zebrafish posterior midgut. The protein PLLP (Pllp in fish) recruits the clathrin adaptor EpsinR to sort the SNARE machinery of the endolysosomal pathway into the subapical compartment, which is a switch for polarized endocytosis. Furthermore, PLLP expression induces apical Crumbs internalization and the activation of the Notch signalling pathway, both crucial steps in the acquisition of cell polarity and differentiation of epithelial cells. We thus postulate that differential apical endosomal SNARE sorting is a mechanism that regulates epithelial patterning. PMID- 25706236 TI - FEAR-mediated activation of Cdc14 is the limiting step for spindle elongation and anaphase progression. AB - Cleavage of cohesins and cyclin-dependent kinase (CDK) inhibition are thought to be sufficient for triggering chromosome segregation. Here we identify an essential requirement for anaphase chromosome movement. We show that, at anaphase onset, the phosphatase Cdc14 and the polo-like kinase Cdc5 are redundantly required to drive spindle elongation. This role of Cdc14 is mediated by the FEAR network, a group of proteins that activates Cdc14 at anaphase onset, and we suggest that Cdc5 facilitates both Cdc14 activation and CDK inhibition. We further identify the kinesin-5 motor protein Cin8 as a key target of Cdc14. Indeed, Cin8 mutants lacking critical CDK phosphorylation sites suppress the requirement for Cdc14 and Cdc5 in anaphase spindle elongation. Our results indicate that cohesin dissolution and CDK inhibition per se are not sufficient to drive sister chromatid segregation but that the motor protein Cin8 must be activated to elongate the spindle. PMID- 25706237 TI - Expansion of stem cells counteracts age-related mammary regression in compound Timp1/Timp3 null mice. AB - Age is the primary risk factor for breast cancer in women. Bipotent basal stem cells actively maintain the adult mammary ductal tree, but with age tissues atrophy. We show that cell-extrinsic factors maintain the adult stem cell pool during ageing and dictate tissue stoichiometry. Mammary stem cells spontaneously expand more than 11-fold in virgin adult female mice lacking specific genes for TIMPs, the natural metalloproteinase inhibitors. Compound Timp1/Timp3 null glands exhibit Notch activation and accelerated gestational differentiation. Proteomics of mutant basal cells uncover altered cytoskeletal and extracellular protein repertoires, and we identify aberrant mitotic spindle orientation in these glands, a process that instructs asymmetric cell division and fate. We find that progenitor activity normally declines with age, but enriched stem/progenitor pools prevent tissue regression in Timp mutant mammary glands without affecting carcinogen-induced cancer susceptibility. Thus, improved stem cell content can extend mouse mammary tissue lifespan without altering cancer risk in this mouse model. PMID- 25706238 TI - Implementation science in pediatric health care: advances and opportunities. PMID- 25706239 TI - Serum 25-hydroxyvitamin D and adipose tissue vitamin D receptor gene expression: relationship with obesity and type 2 diabetes. AB - CONTEXT: The relationship between 25-hydroxyvitamin D [25(OH)D] and obesity and type 2 diabetes is not completely understood. Vitamin D receptor (VDR) expression in adipose tissue (AT) is related to obesity and might be regulated by 1,25 dihydroxyvitamin D3 [1,25(OH)2D3]. OBJECTIVE: To analyze serum 25(OH)D and VDR gene expression in AT according to body mass index (BMI) and glycemic status and the effect of 1,25(OH)2D3 on AT according to BMI. DESIGN AND PATIENTS: Two cohorts were studied: 1) 118 subjects classified according to their BMI (lean, overweight, obese, or morbidly obese [MO]) and their glycemic status (normoglycemic [NG] and prediabetic and diabetic [P&D]); and 2) 30 obese subjects (BMI > 30 kg/m(2)) classified as NG and P&D. VDR gene expression was analyzed during preadipocyte differentiation and in vitro stimulation with 1,25(OH)2D3 of AT explants from donors with different BMI values. SETTING: University Hospital. MAIN OUTCOME MEASURES: Serum 25(OH)D, parathyroid hormone (PTH), and AT VDR gene expression. RESULTS: 25(OH)D levels were lower in P&D than NG subjects, significantly so in the lean and MO groups (P < .05). 25(OH)D levels correlated negatively with homeostasis model of assessment for insulin resistance (HOMA-IR) (r = -0.200; P = .032) and glucose (r = -0.295; P = .001), but not with BMI. VDR gene expression was higher in MO than in the other BMI groups (P < .05). 1,25(OH)2D3 increased VDR gene expression in AT from obese patients (P < .05) but not from lean subjects. CONCLUSIONS: 25(OH)D levels are diminished in P&D compared to NG subjects, independently of BMI, and are closely related to glucose metabolism variables, suggesting that vitamin D deficiency is associated more with carbohydrate metabolism than with obesity. Moreover, AT has a different response to 1,25(OH)2D3 depending on the degree of obesity. PMID- 25706241 TI - Viral pathogenesis: HSV avoids the RIPper. PMID- 25706242 TI - The fallibility of memory in judicial processes: lessons from the past and their modern consequences. AB - The capability of adult and child witnesses to accurately recollect events from the past and provide reliable testimony has been hotly debated for more than 100 years. Prominent legal cases of the 1980s and 1990s sparked lengthy debates and important research questions surrounding the fallibility and general reliability of memory. But what lessons have we learned, some 35 years later, about the role of memory in the judicial system? In this review, we focus on what we now know about the consequences of the fallibility of memory for legal proceedings. We present a brief historical overview of false memories that focuses on three critical forensic areas that changed memory research: children as eyewitnesses, historic sexual abuse and eyewitness (mis)identification. We revisit some of the prominent trials of the 1980s and 1990s to not only consider the role false memories have played in judicial decisions, but also to see how this has helped us understand memory today. Finally, we consider the way in which the research on memory (true and false) has been successfully integrated into some courtroom procedures. PMID- 25706243 TI - alpha-Glucosidase Inhibitors from a Xylaria feejeensis Associated with Hintonia latiflora. AB - Two new compounds, pestalotin 4'-O-methyl-beta-mannopyranoside (1) and 3S,4R-(+) 4-hydroxymellein (2), were isolated from an organic extract of a Xylaria feejeensis, which was isolated as an endophytic fungus from Hintonia latiflora. In addition, the known compounds 3S,4S-(+)-4-hydroxymellein (3), 3S-(+)-8 methoxymellein (4), and the quinone derivatives 2-hydroxy-5-methoxy-3 methylcyclohexa-2,5-diene-1,4-dione (5), 4S,5S,6S-4-hydroxy-3-methoxy-5-methyl 5,6-epoxycyclohex-2-en-1-one (6), and 4R,5R-dihydroxy-3-methoxy-5 methylcyclohexen-2-en-1-one (7) were obtained. The structures of 1 and 2 were elucidated using a set of spectroscopic and spectrometric techniques. The absolute configuration of the stereogenic centers of 1 and 2 was determined using ECD spectroscopy combined with time-dependent density functional theory calculations. In the case of 1, comparison of the experimental and theoretical (3)J6-7 coupling constants provided further evidence for the stereochemical assignments. Compounds 2 and 3 inhibited Saccharomyces cerevisiae alpha glucosidase (alphaGHY), with IC50 values of 441 +/- 23 and 549 +/- 2.5 MUM, respectively. Their activity was comparable to that of acarbose (IC50 = 545 +/- 19 MUM), used as positive control. Molecular docking predicted that both compounds bind to alphaGHY in a site different from the catalytic domain, which could imply an allosteric type of inhibition. PMID- 25706240 TI - The effect of lifestyle intervention and metformin on preventing or delaying diabetes among women with and without gestational diabetes: the Diabetes Prevention Program outcomes study 10-year follow-up. AB - CONTEXT: Gestational diabetes (GDM) confers a high risk of type 2 diabetes. In the Diabetes Prevention Program (DPP), intensive lifestyle (ILS) and metformin prevented or delayed diabetes in women with a history of GDM. OBJECTIVE: The objective of the study was to evaluate the impact of ILS and metformin intervention over 10 years in women with and without a history of GDM in the DPP/Diabetes Prevention Program Outcomes Study. DESIGN: This was a randomized controlled clinical trial with an observational follow-up. SETTING: The study was conducted at 27 clinical centers. PARTICIPANTS: Three hundred fifty women with a history of GDM and 1416 women with previous live births but no history of GDM participated in the study. The participants had an elevated body mass index and fasting glucose and impaired glucose tolerance at study entry. INTERVENTIONS: Interventions included placebo, ILS, or metformin. OUTCOMES MEASURE: Outcomes measure was diabetes mellitus. RESULTS: Over 10 years, women with a history of GDM assigned to placebo had a 48% higher risk of developing diabetes compared with women without a history of GDM. In women with a history of GDM, ILS and metformin reduced progression to diabetes compared with placebo by 35% and 40%, respectively. Among women without a history of GDM, ILS reduced the progression to diabetes by 30%, and metformin did not reduce the progression to diabetes. CONCLUSIONS: Women with a history of GDM are at an increased risk of developing diabetes. In women with a history of GDM in the DPP/Diabetes Prevention Program Outcomes Study, both lifestyle and metformin were highly effective in reducing progression to diabetes during a 10-year follow-up period. Among women without a history of GDM, lifestyle but not metformin reduced progression to diabetes. PMID- 25706244 TI - Individual surface-engineered microorganisms as robust Pickering interfacial biocatalysts for resistance-minimized phase-transfer bioconversion. AB - A powerful strategy for long-term and diffusional-resistance-minimized whole-cell biocatalysis in biphasic systems is reported where individually encapsulated bacteria are employed as robust and recyclable Pickering interfacial biocatalysts. By individually immobilizing bacterial cells and optimizing the hydrophobic/hydrophilic balance of the encapsulating magnetic mineral shells, the encased bacteria became interfacially active and locate at the Pickering emulsion interfaces, leading to dramatically enhanced bioconversion performances by minimizing internal and external diffusional resistances. Moreover, in situ product separation and biocatalyst recovery was readily achieved using a remote magnetic field. Importantly, the mineral shell effectively protected the entire cell from long-term organic-solvent stress, as shown by the reusability of the biocatalysts for up to 30 cycles, while retaining high stereoselective catalytic activities, cell viabilities, and proliferative abilities. PMID- 25706245 TI - The galactose-binding lectin isolated from Bauhinia bauhinioides Mart seeds inhibits neutrophil rolling and adhesion via primary cytokines. AB - In this study, the amino acid sequence and anti-inflammatory effect of Bauhinia bauhinioides (BBL) lectin were evaluated. Tandem mass spectrometry revealed that BBL possesses 86 amino acid residues. BBL (1 mg/kg) intravenously injected in rats 30 min prior to inflammatory stimuli inhibited the cellular edema induced by carrageenan in only the second phase (21% - 3 h, 19% - 4 h) and did not alter the osmotic edema induced by dextran. BBL also inhibited carrageenan peritoneal neutrophil migration (51%), leukocyte rolling (58%) and adhesion (68%) and the neutrophil migration induced by TNF-alpha (64%). These effects were reversed by the association of BBL with galactose, demonstrating that the carbohydrate binding domain is essential for lectin activity. In addition, BBL reduced myeloperoxidase activity (84%) and TNF-alpha (68%) and IL1-beta (47%) levels. In conclusion, the present investigation demonstrated that BBL contains highly homologous isolectins, resulting in a total of 86 amino acid residues, and exhibits anti-inflammatory activity by inhibiting neutrophil migration by reducing TNF-alpha and IL1-beta levels via the lectin domain. PMID- 25706246 TI - Biodegradable elastomers and silicon nanomembranes/nanoribbons for stretchable, transient electronics, and biosensors. AB - Transient electronics represents an emerging class of technology that exploits materials and/or device constructs that are capable of physically disappearing or disintegrating in a controlled manner at programmed rates or times. Inorganic semiconductor nanomaterials such as silicon nanomembranes/nanoribbons provide attractive choices for active elements in transistors, diodes and other essential components of overall systems that dissolve completely by hydrolysis in biofluids or groundwater. We describe here materials, mechanics, and design layouts to achieve this type of technology in stretchable configurations with biodegradable elastomers for substrate/encapsulation layers. Experimental and theoretical results illuminate the mechanical properties under large strain deformation. Circuit characterization of complementary metal-oxide-semiconductor inverters and individual transistors under various levels of applied loads validates the design strategies. Examples of biosensors demonstrate possibilities for stretchable, transient devices in biomedical applications. PMID- 25706247 TI - Gene delivery by a cationic and thermosensitive nanogel promoted established tumor growth inhibition. AB - AIM: In vivo stability and consequent high tumor accumulation is highly desired for nonviral gene therapy. MATERIALS & METHODS: Here, a well-defined cationic nanogel system (NPS) was facilely prepared for gastric tumor therapy. RESULTS: The physical chemical properties of NPS were finely regulated and investigated. In vitro transfer efficiency of NPS was obviously promoted due to stable polyplex structure, small size, narrow size distribution and weak surface potential. Interestingly, the transfection was further enhanced by its passive targeting function. Intratumor accumulation was significantly promoted post intravenous administrated to Balb/c nude mice. Thus, the established gastric tumor (N87) growth was significantly inhibited by p53 as delivered by NPS. CONCLUSION: Such noncytotoxic cationic thermosensitive NPS can be effective for practicable gene therapy. PMID- 25706248 TI - Community supported agriculture programs: a novel venue for theory-based health behavior change interventions. AB - Local foods programs such as community supported agriculture programs (CSAs) and farmers' markets have increased greatly in popularity. However, little research has been conducted regarding the effect of involvement in local foods programs on diet-related attitudes and behaviors. A series of focus groups was conducted to identify the motives that propel individuals to join a CSA, the experiences of belonging to a CSA, and the diet-related outcomes of CSA membership. Using the Theory of Planned Behavior (TPB) as a framework to categorize findings, data suggest the potential of CSAs as a viable intervention strategy for promoting healthful diets and behaviors. PMID- 25706249 TI - Biogenic silver and gold nanoparticles synthesized using red ginseng root extract, and their applications. AB - In the present study, we report a green methodology for the synthesis of silver and gold nanoparticles, using the root extract of the herbal medicinal plant Korean red ginseng. The silver and gold nanoparticles were synthesized within 1 h and 10 min respectively. The nanoparticles generated were not aggregated, and remained stable for a long time, which suggests the nature of nanoparticles. The phytochemicals and ginsenosides present in the root extract assist in reducing and stabilizing the synthesized nanoparticles. The red ginseng root extract generated silver nanoparticles exhibit antimicrobial activity against pathogenic microorganisms including Vibrio parahaemolyticus, Staphylococcus aureus, Bacillus cereus, and Candida albicans. In addition, the silver nanoparticles exhibit biofilm degrading activity against S. aureus and Pseudomonas aeruginosa. Thus, the present study opens up a new possibility of synthesizing silver and gold nanoparticles in a green and rapid manner using Korean red ginseng root extract, and explores their biomedical applications. PMID- 25706250 TI - Synthesis of dimeric ADP-ribose and its structure with human poly(ADP-ribose) glycohydrolase. AB - Poly(ADP-ribosyl)ation is a common post-translational modification that mediates a wide variety of cellular processes including DNA damage repair, chromatin regulation, transcription, and apoptosis. The difficulty associated with accessing poly(ADP-ribose) (PAR) in a homogeneous form has been an impediment to understanding the interactions of PAR with poly(ADP-ribose) glycohydrolase (PARG) and other binding proteins. Here we describe the chemical synthesis of the ADP ribose dimer, and we use this compound to obtain the first human PARG substrate enzyme cocrystal structure. Chemical synthesis of PAR is an attractive alternative to traditional enzymatic synthesis and fractionation, allowing access to products such as dimeric ADP-ribose, which has been detected but never isolated from natural sources. Additionally, we describe the synthesis of an alkynylated dimer and demonstrate that this compound can be used to synthesize PAR probes including biotin and fluorophore-labeled compounds. The fluorescently labeled ADP-ribose dimer was then utilized in a general fluorescence polarization based PAR-protein binding assay. Finally, we use intermediates of our synthesis to access various PAR fragments, and evaluation of these compounds as substrates for PARG reveals the minimal features for substrate recognition and enzymatic cleavage. Homogeneous PAR oligomers and unnatural variants produced from chemical synthesis will allow for further detailed structural and biochemical studies on the interaction of PAR with its many protein binding partners. PMID- 25706251 TI - Beare-Stevenson syndrome: two new patients, including a novel finding of tracheal cartilaginous sleeve. AB - Beare-Stevenson syndrome (BSS) is a rare FGFR2-associated craniosynostosis syndrome with a higher rate of sudden unexplained death than related conditions such as Apert, Pfeiffer, and Crouzon syndromes. BSS presents with craniosynostosis, cutis gyrata, and significant developmental delay in most patients who survive infancy. There have only been 21 reported patients with BSS, which limits prognostication for clinicians and likely does not capture the full extent of the phenotype. Here we report on two additional patients with molecularly confirmed BSS, one each with p.Ser372Tyr and p.Tyr375Cys mutations in FGFR2. Cloverleaf skull was identified prenatally in one patient, with initial concern for Crouzon syndrome. Prenatal 3D ultrasound was performed, but cutis gyrata was only visible on retrospective examination following the clinical diagnosis of BSS after birth. Due to phenotypic overlap with Crouzon syndrome, but worse prognosis, we recommend consideration of prenatal 3D ultrasound and mutation testing for patients with suspected Crouzon to allow for prenatal diagnosis of BSS and to enable appropriate genetic counseling and postnatal care. One of our patients was noted to have a tracheal cartilaginous sleeve, which if present could explain sudden death. Of note, tracheal cartilaginous sleeves have been reported in other FGFR2-related craniosynostosis syndromes, and are associated with 90% risk of death by two years of age without tracheostomy. Tracheal cartilaginous sleeves are often only found incidentally at autopsy as they are difficult to diagnose without direct visualization of the trachea. This association and our experience suggests that BSS patients be evaluated for tracheal cartilaginous sleeve to prevent airway compromise. PMID- 25706252 TI - Targeted therapy in gastric cancer. AB - Gastric cancer is often diagnosed at an advanced stage. Although chemotherapy prolongs survival and improves quality of life, the survival of gastric cancer patients with advanced disease is short. Thanks to recent insights into the molecular pathways involved in gastric carcinogenesis, new targeted treatment options have become available for gastric cancer patients. Trastuzumab, an antibody targeted to HER-2, was shown to improve survival of advanced gastric cancer patients harboring HER-2 overexpression due to gene amplification in their tumor cells, and is currently also explored in adjuvant and neoadjuvant settings. Another agent with promising results in clinical trials is ramucirumab, an antibody targeting VEGFR-2. No clear survival benefit, however, were experienced with agents targeting EGFR (cetuximab, panitumumab), VEGF-A (bevacizumab), or mTOR (everolimus). Drugs targeting c-MET/HGF are currently under investigation in biomarker-selected cohorts, with promising results in early clinical trials. This review will summarize the current status of targeted treatment options in gastric cancer. PMID- 25706253 TI - Are extra-pair males different from cuckolded males? A case study and a meta analytic examination. AB - Traditional models for female extra-pair matings assume that females benefit indirectly from extra-pair mating behaviour. Under these so-called adaptive models, extra-pair males are hypothesized to have more compatible genotypes, larger body size, exaggerated ornaments or to be older than cuckolded males. Alternatively, ('nonadaptive') models that consider female extra-pair matings to be a by-product posit that female extra-pair mating can be maintained even if there is no benefit to females. This could happen if, for example, males gained fitness benefits from extra-pair mating, while female and male extra-pair mating behaviours were genetically correlated. Extra-pair males are also expected to be older and larger if this improves their ability to convince or coerce females to mate. We investigated whether a female's extra-pair mates differed from her cuckolded mate in both genetic and phenotypic traits by analysing data from an insular house sparrow population. We found that extra-pair males were older than cuckolded males, consistent with both models. However, in contrast to the expectations from from adaptive models, extra-pair and cuckolded males were of similar genetic relatedness, and hence expected compatibility, with the female, and had comparable body size and secondary sexual traits. We also updated previous meta-analyses examining differences between extra-pair and cuckolded males. The meta-analytic results matched results from our house sparrow case study. Although we cannot completely exclude indirect benefits for females, nonadaptive models may better explain female extra-pair matings. These neglected alternative models deserve more research attention, and this should improve our understanding of the evolution of mating systems. PMID- 25706254 TI - Docetaxel/2-Hydroxypropyl beta -Cyclodextrin Inclusion Complex Increases Docetaxel Solubility and Release from a Nanochannel Drug Delivery System. AB - Breast cancer remains the second leading cause of cancer deaths for women in the U.S. The need for new and alternative strategies to treat this cancer is imperative. Here we show the optimization of our nanochannel delivery system (nDS) for constant and sustained delivery of docetaxel (DTX) for thetreatment of triple negative breast cancer. DTX is a highly hydrophobic drug, making it difficult to reach the therapeutic levels when released in aqueous solutions from our implantable delivery system. To overcome this challenge and test the release of DTX from nDS, we prepared DTX/2-hydroxypropyl beta-cyclodextrin (DTX/HPCD) inclusion complexes in different molar ratios. The 1:10 DTX/HPCD complex achieved 5 times higher solubility than the 1:2 complex and 3 times higher in vitrorelease of DTX than with free DTX. When released in SCID/Beige mice from nanochannel system, the DTX/HPCD complex showed reduced tumor growth, comparable to the standard bolus injections of DTX, indicating that the structural stability and biological activity of DTX were retained in the complex, after its diffusion through the nanochannel system. PMID- 25706255 TI - The Impact of Combination Therapy with a-Blockers and 5ARIs on the Progression of BPH. AB - Benign prostatic hyperplasia (BPH) can be a progressive disease for some men with significant impact on their quality of life due to worsening of symptoms, risk of acute urinary retention (AUR) and surgery. Certain clinical parameters such as age, prostate volume and PSA are able to predict those patients with BPH associated LUTS that are at risk of disease progression. These patients will likely benefit most from medical therapy that provides symptom relief while at the same time may prevent disease progression. Studies have shown that a blockers, although able to rapidly alleviate symptoms, have no effect on prostate volume, risk for AUR and BPH-related surgery. On the other hand 5ARIs have proven their efficacy in reducing prostate size, the risk of AUR and prostate surgery. Therefore combination therapy with an a-blocker and a 5ARI can be the mainstay of treatment for those patients at risk of BPH progression. Patients' perspective and their needs and expectations from treatment are other crucial parameters to consider in order selecting the optimal management of BPH. Therefore physicians should take into consideration the drug properties and also the patients' preferences before deciding on the optimal pharmacological treatment for BPH associated LUTS. PMID- 25706256 TI - Targeting the multifaceted HuR protein, benefits and caveats. AB - The RNA-binding protein (RBP) HuR is one of the most widely studied regulators of the eukaryotic posttranscriptional gene expression and it plays a physiological role in mediating the cellular response to apoptotic, proliferating and survival stimuli. Following physiological or stress stimuli, HuR protein binds to Adenylate-Urydinilate rich elements (AREs) generally contained in the 3'UTR of transcripts, then it shuttles from the nucleus to the cytoplasm and regulates the half-life and/or translation of cargo mRNAs. Derangements in sub-cellular localization and expression of HuR have been associated with the pathophysiology of many diseases and this protein has been proposed as a potential drug target. Recent findings also re-evaluated HuR as a splicing and polyadenylation factor, expanding its spectrum of functional activity up to the maturation of pre-mRNAs. In this review, we generate a comprehensive picture of HuR functionality to discuss the implications of considering HuR as pharmacological target and the detrimental or positive impact that can be expected upon its modulation. Firstly, we focus on the recent findings about the mechanistic role of HuR in the nucleus and in the regulation of long non coding RNAs; then we describe the animal models and the clinical association and significance in cancer; finally, we have reviewed the pharmacological tools that influence HuR's post-transcriptional control and the efforts made to identify specific HuR inhibitors. PMID- 25706257 TI - Primary Cilia in Tumor Biology: The Primary Cilium as a Therapeutic Target in Cholangiocarcinoma. AB - Cilia are microtubule-based organelles, which are ubiquitously expressed in epithelial cells. Cholangiocytes, the epithelial cells lining the biliary tree, have primary cilia extending from their apical plasma membrane into the ductal lumen, where the cilia function as multisensory organelles transducing environmental cues into the cell interior. The decrease or loss of primary cilia has been described in several malignancies, including cholangiocarcinoma, suggesting that the loss of cilia is a common occurrence in neoplastic transformation. In this short review, we describe the expression of cilia in several cancers, explore the mechanisms and consequences of ciliary loss, and discuss the potential use of the primary cilia as therapeutic targets. PMID- 25706258 TI - Withdrawn: How to Manage Infections Caused by Antibiotic Resistant Gram-negative Bacteria - EBMT Educational Meeting from the Severe Aplastic Anaemia and Infectious Diseases Working Parties, Naples, Italy, 2014. AB - Withdrawn by the publisher. PMID- 25706259 TI - Use of gray values in CBCT and MSCT images for determination of density: influence of variation of FOV size. AB - PURPOSE: To determine the effect of field of view (FOV) size on gray values in cone beam computed tomography (CBCT) and multislice computed tomography (MSCT) images. MATERIAL AND METHODS: A phantom made up of 3 cylinders containing distilled water, plaster, and motor oil was constructed and inserted into an acrylic cylinder filled with distilled water. The phantom was scanned with a CBCT and MSCT device using 3 FOV sizes. Gray value of each material was evaluated in 40 axial slices, and the comparison between the results obtained with the same FOV size was made. RESULTS: In CBCT examinations, there was significant difference between the gray values of different FOVs for the 3 materials. In the MSCT, there was significant difference for the oil. Gray values showed significant difference between the CBCT and MSCT examinations for the 3 materials in the 3 different FOV sizes. CONCLUSIONS: Gray values determined in CBCT images are significantly influenced by the FOV size. Although the gray values obtained in MSCT have shown statistically significant differences between some acquisitions, the analysis of those differences seems to indicate low clinical relevance. PMID- 25706260 TI - Knowledge, attitudes, and perceptions of undergraduate dental students toward dental implants--an all India survey. AB - PURPOSE: This study aims to gauge the knowledge and perceptions of undergraduate dental students or residents toward dental implants. MATERIALS AND METHODS: The dental colleges in India were divided into 5 zones, and by random selection method, 7 colleges were selected from each zone. Thus, a total of 35 dental institutions were selected, which included 2800 residents. A printed questionnaire consisting of 15 questions, which assessed the level and source of information regarding implants, was prepared and distributed. RESULTS: A total of 2800 questionnaires were posted of which 2041 responses were received (response rate was 72.89%). This study shows that 81.1% of the residents believed that they were not provided sufficient information and a whopping 91.7% of them coveted more information about implants in their undergraduate curriculum. CONCLUSION: This study concludes that a revision in the undergraduate dental curriculum is required to make the students better equipped with the technicalities of implant dentistry. PMID- 25706261 TI - Periimplant bacteria associated with different transmucosal designs or smoking habits. AB - PURPOSE: This study is to compare periimplant microbiota associated with implant transmucosal designs or smoking habits. METHODS: Submucosal samples from healthy 52 implants were collected for analysis of bacteria associated with bone-level (n = 37) or tissue-level (n = 15) implants or smoking habits, using quantitative polymerase chain reaction. Profiles of periimplant bacteria of smokers (n = 5) were investigated using PhyloChip Array version G3 and compared with nonsmokers (n = 5). RESULTS: The number of bone-level implants positive for at least 1 pathogen was higher than that of tissue level; however, differences in each bacterium were insignificant. The prevalence and abundance of Treponema denticola in smokers were significantly higher than that in nonsmokers (P < 0.05). Smokers and nonsmokers exhibited similar periimplant microbiota based on the PhyloChip Array, but they could be distinguished by limiting observations to only 18 operational taxonomic units. Streptococcus macedonicus within Firmicutes and Prevotella within Bacteroidetes were more abundant in smokers compared with nonsmokers. CONCLUSION: Prevalence of putative pathogens with bone-level implants was higher than tissue-level implants in nonsmokers. Firmicutes and Bacteroidetes were significantly higher in smokers. Smoking therefore strongly influenced peri implant bacterial composition of bone-level implant. PMID- 25706262 TI - Is it safe to reuse dental implant healing abutments sterilized and serviced by dealers of dental implant manufacturers? An in vitro sterility analysis. AB - PURPOSE: This study was undertaken to investigate the sterility of used healing abutments sterilized and serviced by dealers of dental implant manufacturers. MATERIALS AND METHODS: Sixty used but sterilized healing abutments in sealed sterilization pouches were obtained from 6 manufacturers unaware of the study design and equally grouped from A to F. The sterilization pouches were examined for perforation. The driver slots and screw grooves of healing abutments were examined for calculus and scratches under a *5 LED magnifying lamp, without opening the pouches. Each abutment was immersed in brain heart infusion broth in test tubes and incubated. RESULTS: Macroscopic observation of 57 healing abutments revealed dirty screw grooves (10.5%) and partially filled driver slots (5.2%). None of the group C, E, and F samples showed turbidity. Penicillium variabile was morphologically identified in 3 abutments of group A. Enterococcus faecalis and E faecium were detected in 1 abutment each of groups B and D, respectively. CONCLUSION: Reuse of healing abutments can be cost effective in dental practice. However, used abutments sterilized and serviced by dental implant dealers might be a source of cross-infection. They should therefore be cleaned and resterilized before reuse as a precaution. PMID- 25706263 TI - Protein adsorption on a laser-modified titanium implant surface. AB - PURPOSE: The aim of this study was to investigate the earlier phase of the osseointegration of a laser-treated implant surface in terms of human protein adsorption. MATERIALS AND METHODS: Titanium surfaces were divided into machined (M), sandblasted (SB), and laser-treated (LT). The LT surfaces were created with an Nd diode-pumped laser in Q-switching, whereas the SB were treated with Al2O3. An x-ray photoelectron spectroscopy (XPS) analysis of titanium surface was performed. Titanium discs were used for albumin and fibronectin adsorption evaluation through fluorescence intensity. Fibronectin evaluation was also made with Western Blot analysis on experimental implants. RESULTS: LT discs appeared to trigger a higher albumin and fibronectin adsorption with a regular pattern. The mean count of albumin adsorption was 0.29 and 3.8 for SB and LT, respectively (P = 0.016), whereas fibronectin values were 0.67 and 4.9 for (SB) and (LT) titanium (P = 0.02). XPS analysis showed that titanium, oxygen, carbon, and nitrogen were found on all 3 surfaces. CONCLUSION: Laser-engineered porous titanium surface seems to promote, in vitro, the adsorption of albumin and fibronectin more than sandblasted (SB) or machined (M) implants. PMID- 25706264 TI - Long-term outcome of transosteotomy bone augmentation of the inferior border of the severely resorbed mandible. AB - We report a case of severe mandibular atrophy with residual crest height as short as 4.3 mm anterior to the mental foramens. The patient was reluctant to accept bone augmentation surgery and that was the motivation to perform transosteotomy bone augmentation of the inferior border of the mandible and the insertion of 4 short implants anterior to the mental foramens. The insertion torque of the 4 implants was about 65 N.cm, which allowed for the application of immediate loading protocol. Detailed follow-up during 8 years showed uneventful healing and successful prosthetic rehabilitation with screw-retained prostheses. PMID- 25706265 TI - Integrity of this journal. PMID- 25706266 TI - Evaluation of the zone of keratinized tissue using exposed acellular dermal matrix over tooth extraction sites: a randomized controlled clinical trial. AB - BACKGROUND: The presence of an adequate zone of keratinized tissue has been associated with implant health. This study evaluated the zone of keratinized tissue using exposed acellular dermal matrix (ADM) over extraction sites. MATERIAL AND METHODS: Fifteen sites received ADM, and fifteen control sites received no biomaterial. All sites were sutured with no attempt to achieve primary closure. Initial measurements of buccal and lingual keratinized tissue were taken from the mucogingival line (MGL) to the most coronal gingival margins. Final measurements were taken from the buccal MGL to the lingual MGL 90 days after surgery. Gingival biopsies were taken before implant placement. RESULTS: Test and control groups exhibited a mean value of 4.40 +/- 1.45 mm and 1.40 +/- 1.40 mm, respectively. The newly formed tissue revealed similar histological aspect of normal keratinized tissue. CONCLUSION: Exposed ADM used over tooth extraction sockets can predictably be used to increase the zone of keratinized tissue. PMID- 25706267 TI - Effects of intermittent administration of parathyroid hormone on bone augmentation in rat calvarium. AB - OBJECTIVES: This study examined the effects of parathyroid hormone (PTH) on bone augmentation beyond the skeletal envelope within a plastic cap in rat calvaria. MATERIALS AND METHODS: The calvaria of 30 rats were exposed, and 2 plastic caps were placed on each. Each of the 10 rats was treated with 35 or 105 MUg/kg (PTH 35, PTH-105) PTH 3 times per week. The control group was injected with sterile saline 3 times per week. Micro-computed tomography (CT) imaging was performed every 2 weeks for 12 weeks. Micro-CT and histological sections were used to determine the amount of bone augmentation within the plastic caps. Bone volume (BV) was calculated using BV-measuring software. RESULTS: The histomorphometric and histological analyses showed that the amount of bone augmentation was increased significantly in the PTH groups compared with the controls at 12 weeks. The PTH-105 group showed significantly more bone augmentation and osteoblasts compared with the PTH-35 group. CONCLUSIONS: These results indicate that the higher the dose of intermittent PTH administered, the greater the amount of bone formation beyond the skeletal envelop in the rat calvarium. PMID- 25706268 TI - Retrospective assessment of survival rate for short endosseous dental implants. AB - PURPOSE: The aim of this study was to determine the survival rate of short implants that were placed in a residency program. In addition, the potential influence of diabetes, smoking, sinus grafting, guided bone regeneration, and implant type on survival was analyzed. METHODS: Through a retrospective chart review, patient information and parameters for short implants being equal or less than 10 mm and regular implants being more than 10 mm were collected. The cumulative survival rate and implant and patient information from 213 consecutively placed implants from May 2002 through October 2011 were analyzed. RESULTS: The average survival time for short implants was 47.3 months, with a range of 6 to 141 months. The implant survival rate was 95.77% for short implants, which was not statistically significant from the regular implants. Smoking had a statistically significant negative effect on the survival rate of short implants. No statistical differences were found with implant survival rates for other factors. CONCLUSION: It can be concluded that short implants can be predictably placed in the mouth with a high survival rate and that smoking has a negative influence on the survival rate of the short implants. PMID- 25706269 TI - Management of a fractured, nonremovable implant: a clinical report with a 12 month follow-up. AB - Implant failures could be due to biological or mechanical factors, which also include fracture of the fixture. The present report presents a case of a single fractured implant placed in the left mandibular molar region. Since the residual portion of the fixture was perfectly osseointegrated with no signs of peri implantitis, and in direct contact with the roof of the inferior alveolar nerve canal, it was decided to treat the patient with a short implant positioned on top of the fractured, and not removing the fractured implant. Clinical and radiographical follow-up was performed for 12 months after loading. Periimplant soft tissues healing and implant osseointegration were achieved 6 months after implant placement; at the end of the follow-up a periimplant bone remodeling of 0.3 mm was observed. In conclusion, short implants could be taken into consideration as a treatment option in cases of nonremovable implants and sufficient residual bone height. PMID- 25706271 TI - Integrated annotation and analysis of in situ hybridization images using the ImAnno system: application to the ear and sensory organs of the fetal mouse. AB - An in situ hybridization (ISH) study was performed on 2000 murine genes representing around 10% of the protein-coding genes present in the mouse genome using data generated by the EURExpress consortium. This study was carried out in 25 tissues of late gestation embryos (E14.5), with a special emphasis on the developing ear and on five distinct developing sensory organs, including the cochlea, the vestibular receptors, the sensory retina, the olfactory organ, and the vibrissae follicles. The results obtained from an analysis of more than 11,000 micrographs have been integrated in a newly developed knowledgebase, called ImAnno. In addition to managing the multilevel micrograph annotations performed by human experts, ImAnno provides public access to various integrated databases and tools. Thus, it facilitates the analysis of complex ISH gene expression patterns, as well as functional annotation and interaction of gene sets. It also provides direct links to human pathways and diseases. Hierarchical clustering of expression patterns in the 25 tissues revealed three main branches corresponding to tissues with common functions and/or embryonic origins. To illustrate the integrative power of ImAnno, we explored the expression, function and disease traits of the sensory epithelia of the five presumptive sensory organs. The study identified 623 genes (out of 2000) concomitantly expressed in the five embryonic epithelia, among which many (~12%) were involved in human disorders. Finally, various multilevel interaction networks were characterized, highlighting differential functional enrichments of directly or indirectly interacting genes. These analyses exemplify an under-represention of "sensory" functions in the sensory gene set suggests that E14.5 is a pivotal stage between the developmental stage and the functional phase that will be fully reached only after birth. PMID- 25706270 TI - Osteogenic differentiation of human mesenchymal stem cells in 3-D Zr-Si organic inorganic scaffolds produced by two-photon polymerization technique. AB - Two-photon polymerization (2PP) is applied for the fabrication of 3-D Zr-Si scaffolds for bone tissue engineering. Zr-Si scaffolds with 150, 200, and 250 MUm pore sizes are seeded with human bone marrow stem cells (hBMSCs) and human adipose tissue derived stem cells (hASCs) and cultured in osteoinductive and control media for three weeks. Osteogenic differentiation of hASCs and hBMSCs and formation of bone matrix is comparatively analyzed via alkaline phosphatase activity (ALP), calcium quantification, osteocalcin staining and scanning electron microscopy (SEM). It is observed that the 150 MUm pore size Zr-Si scaffolds support the strongest matrix mineralization, as confirmed by calcium deposition. Analysis of ALP activity, osteocalcin staining and SEM observations of matrix mineralization reveal that mesenchymal stem cells cultured on 3-D scaffolds without osteogenic stimulation spontaneously differentiate towards osteogenic lineage. Nanoindentation measurements show that aging of the 2PP produced Zr-Si scaffolds in aqueous or alcohol media results in an increase in the scaffold Young's modulus and hardness. Moreover, accelerated formation of bone matrix by hASCs is noted, when cultured on the scaffolds with lower Young's moduli and hardness values (non aged scaffolds) compared to the cells cultured on scaffolds with higher Young's modulus and hardness values (aged scaffolds). Presented results support the potential application of Zr-Si scaffolds for autologous bone tissue engineering. PMID- 25706272 TI - 26Al/10Be burial dating of Xujiayao-Houjiayao site in Nihewan Basin, northern China. AB - The Xujiayao-Houjiayao site in Nihewan Basin is among the most important Paleolithic sites in China for having provided a rich collection of hominin and mammalian fossils and lithic artifacts. Based on biostratigraphical correlation and exploratory results from a variety of dating methods, the site has been widely accepted as early Upper Pleistocene in time. However, more recent paleomagnetic analyses assigned a much older age of ~500 ka (thousand years). This paper reports the application of 26Al/10Be burial dating as an independent check. Two quartz samples from a lower cultural horizon give a weighted mean age of 0.24 +/- 0.05 Ma (million years, 1sigma). The site is thus younger than 340 ka at 95% confidence, which is at variance with the previous paleomagnetic results. On the other hand, our result suggests an age of older than 140 ka for the site's lower cultural deposits, which is consistent with recent post-infrared infrared stimulated luminescence (pIR-IRSL) dating at 160-220 ka. PMID- 25706273 TI - Impact of Cytomegalovirus on Long-term Mortality and Cancer Risk After Organ Transplantation. AB - BACKGROUND: There is conflicting evidence of the effect of cytomegalovirus (CMV) infection on survival and the risk of cancer after transplantation. METHODS: All recipients of kidney, liver, heart, and lung transplants in the United Kingdom between 1987 and 2007 with known CMV immunoglobulin G status were identified from the U.K. Transplant Registry. Based on the donor-recipient CMV status, recipients were grouped into: donor (D) negative recipient (R) negative (D- R-), D-R+, D + R+ and D + R-. Cancer data were obtained from the Office for National Statistics. The impact of CMV infection on survival and cancer incidence was assessed. RESULTS: The 10-year posttransplant survival in D-R- recipients (73.6% [95%CI, 72.3, 74.9]) was significantly higher (P < 0.0001) than in other recipients (66.1% [65.3, 66.9]). Compared with the D- R- group, the risk-adjusted hazard of death within 10 years of transplantation for D+ R- group was 14% higher for kidney recipients (P = 0.0495), 13% higher for liver recipients (P = 0.16), 34% higher for heart recipients (P = 0.01), and 35% higher for lung recipients (P = 0.006). The proportion of recipients with a cardiovascular cause of death was higher (P = 0.03) among the recipients exposed to CMV (18%) as compared to the D- R- recipients (16%). The CMV status was not associated with an increased risk of cancer. CONCLUSIONS: The results from this large study demonstrate that CMV is associated with a significantly increased long-term mortality in kidney and cardiothoracic transplant recipients and an increased risk of cardiovascular death but not of posttransplant cancer. PMID- 25706274 TI - Donor-Specific Anti-HLA Antibodies and Endothelial C4d Deposition-Association With Chronic Liver Allograft Failure. AB - BACKGROUND: The significance of humoral immune response for allograft survival after liver transplantation (LT) is still a matter of debate. The aim of this cross-sectional study was to assess immunological and clinical factors associated with advanced fibrosis (F3-F4) and chronic graft failure in LT recipients. METHODS: Serum samples from 174 patients prospectively enrolled and followed up for 12 months were tested for anti-HLA antibodies and compared against donor HLA types. Immunohistochemical C4d staining was performed on formalin-fixed, paraffin embedded liver tissue. RESULTS: Mean time period from LT to enrollment was 66.9 +/- 51.9 months. Independent predictive factors for graft failure included donor positive cytomegalovirus serostatus (P = 0.02), donor-specific antibodies (DSA) against HLA class II (P = 0.03), donor age (P = 0.01), hepatitis C virus allograft reinfection (P = 0.0008), and biliary complications (P = 0.003). HLA class II DSA and HLA class I antibody positivity, hepatitis C virus reinfection, and mycophenolate mofetil-free regimens were significant risk factors for advanced fibrosis after LT. There was a significant association between C4d deposition on allograft endothelial cells and presence of class II DSA (P < 0.0001). Patients with C4d deposits had a 4.3 times higher risk of graft failure than those with negative staining and a significantly lower median time to graft failure (94.6 months [range, 3.6-158.9 months] vs 176.4 months [range, 9.4-217.8 months], P < 0.0001). CONCLUSIONS: Screening for HLA DSA might be useful for early identification of LT recipients at increased risk of graft failure who could benefit from closer surveillance and tailored immunosuppressive regimens. PMID- 25706275 TI - Posttransplantation Outcomes in Veterans With Serious Mental Illness. AB - BACKGROUND: Anticipating poor recovery due to impaired self-management and appointment-keeping, clinicians may consider serious mental illness (SMI) a significant concern in organ transplantation. However, little empirical evidence exists regarding posttransplantation outcomes for patients with SMI. METHODS: This study analyzed health services data to evaluate posttransplantation 3-year survival by SMI status in a nationwide cohort of patients in the Veterans Health Administration (VHA). RESULTS: A total of 960 recipients of solid organ or bone marrow transplants were identified from Veterans Health Administration administrative data extracts for fiscal years 2006 to 2009. Of these, 164 (17%) had an SMI diagnosis before transplantation (schizophrenia, posttraumatic stress, major depressive, and bipolar disorders); 301 (31%) had some other mental illness diagnosis (such as anxiety, adjustment reactions, or substance abuse); and 495 (52%) had no mental health diagnosis. Twenty-two patients (2%) required retransplantation and 208 patients (22%) died during follow-up. Data on whether these were primary or repeat transplantations were unavailable. Rates of attendance at postoperative outpatient visits and number of months for which immunosuppressive drugs fills were recorded were similar among mental illness groups, as were rates of diagnosed immunological rejection. Three-year mortality was equivalent among mental health groups: no mental health (19%) versus other mental illness (23%) versus SMI (27%; chi(2) = 5.11; df = 2; P = .08). In adjusted survival models, no effect of mental health status was observed. CONCLUSIONS: Serious mental illness diagnosis does not appear to be associated with adverse transplantation outcomes over the first 3 years; however, a potentially diverging survival curve may portend higher mortality at 5 years. PMID- 25706276 TI - What Should the Serum Creatinine Be After Transplantation? An Approach to Integrate Donor and Recipient Information to Assess Posttransplant Kidney Function. AB - BACKGROUND: Knowledge of an optimal expected serum creatinine (SCr) would be useful to detect early renal dysfunction after transplantation. Current measurements of posttransplant function rely on the recipient's SCr and calculations of estimated glomerular filtration rate (eGFR), based on recipient age, weight, and sex. Renal function after transplantation, however, also depends on the donor supply of functioning nephrons and adaptation in GFR of a single kidney. METHODS: We developed a formula to predict the optimal expected SCr after transplantation derived from donor and recipient Cockroft-Gault GFRs and adjusted for the single kidney adaptive response. We compared the expected SCr with the lowest observed SCr in a cohort of living (79) and deceased (67) donor allograft recipients followed up over 5 years. RESULTS: Expected SCr correlated with the observed SCr in both living and deceased donor kidney recipients, correlation was stronger among living donor kidney recipients. Recipient-to-donor body weight ratio was significantly associated with the difference between expected and observed SCr, suggesting that recipient body weight is a major predictor of posttransplant renal function. The difference between expected and observed SCr was significantly greater among deceased donor kidney recipients, suggesting poorer function in these patients, which was not detected by SCr or estimated GFR alone. CONCLUSIONS: Calculation of expected renal function for a given donor recipient combination adds relevant information to assessment of allograft function. Future studies will permit determination of a threshold difference between expected and observed SCr that should trigger investigation and potential intervention to improve allograft function. PMID- 25706277 TI - Surveillance Endomyocardial Biopsy in the Modern Era Produces Low Diagnostic Yield for Cardiac Allograft Rejection. AB - BACKGROUND: The changing epidemiology of cardiac allograft rejection has prompted many to question the yield of surveillance endomyocardial biopsy (EMB) in heart transplantation (HT) patients. We sought to determine the yield of EMB in the modern era. METHODS: We evaluated 2597 EMBs in 182 consecutive HT patients who survived to their first EMB. The EMBs were categorized as asymptomatic or clinically driven and were compared based on era of antiproliferative therapy use at our center (early azathioprine era: 1990-2000 vs modern mycophenolate era: 2000-2011). RESULTS: In the modern era, patients had a higher prevalence of risk factors for developing rejection (>= International Society of Heart and Lung Transplantation grade 2R); however, the frequency of rejection was decreased at all times (0-6 months: 60.2% vs 21.5%, P < 0.001, 6-12 months: 26.8% vs 1.8%, P < 0.001, 12-36 months: 32.3% vs 10.5%, P = 0.006). The yield of asymptomatic EMB decreased in the modern era between 0 and 6 months (10.9% vs 3.12%), 6 to 12 months (17% vs 0%), and years 2 to 3 (6.1% vs 1.5%). In the early era, the odds ratio of rejection during asymptomatic EMB compared to a clinically driven EMB was 0.47 (95% confidence interval, 0.31-0.71) and was decreased in the modern era (0.17 [0.07-0.42], P = 0.04). The probability of detecting rejection on asymptomatic EMB was significantly reduced in the modern era, even after adjustment for tacrolimus and induction therapy (1% vs 8%, P < 0.001). CONCLUSIONS: The clinical yield of surveillance EMB has decreased in the modern era. The EMB in asymptomatic patients longer than 6 months after HT warrants further scrutiny. PMID- 25706278 TI - Young Adult Kidney Transplant Recipients: Nonadherent and Happy. AB - BACKGROUND: The aim of this study was to investigate (a) the extent to which age at first renal replacement therapy, achievement of developmental milestones, satisfaction of psychological needs, and coping were related to subjective well being and medication adherence among young adult kidney transplant recipients; and (b) the relationship between subjective well-being and immunosuppressive medication adherence. METHODS: A cross-sectional, interview study was conducted among renal transplant patients aged 20 to 30 years. In addition to sociodemographic and medical characteristics, concepts measured were: subjective well-being (Positive And Negative Affect Schedule; Satisfaction With Life Scale), medication adherence (Basel Assessment of Adherence to Immunosuppressive Medication Scale), dispositional coping (Brief COPE), achievement of developmental milestones (Course of Life Questionnaire), and satisfaction of psychological needs (Basic Psychological Needs Scale). RESULTS: Sixty-two patients participated (66% men; mean age, 26 years). Sixty-five percent were classified as nonadherent in the past month. In contrast, subjective self-rated overall adherence was high. None of the variables measured were related to nonadherence. Higher feelings of competence and autonomy, and timely achievement of social and psychosexual developmental milestones were related to higher subjective well-being. Well-being and adherence did not differ according to age at diagnosis or first renal replacement therapy. CONCLUSIONS: Two thirds of participants were classified as nonadherent which conflicts with participants' own high rating of medication adherence. This emphasizes the need for continued adherence support among young adult transplant recipients; however, no targets for interventions were found in this study. Potential targets for interventions aimed at improving well-being include competence and autonomy. PMID- 25706279 TI - Long-term Clinical Relevance of De Novo Donor-Specific Antibodies After Pediatric Liver Transplantation. AB - BACKGROUND: Anti-HLA antibodies and especially donor-specific antibodies (DSA) play a significant role in graft survival after solid organ transplantation. Their impact on long-term survival in adult liver transplantation (LT) is controversial, but they may be a risk factor. The effects of DSA after pediatric LT are still unclear. METHODS: We performed a retrospective evaluation of DSA in sera from 43 children who had received transplants at our tertiary center. Twenty four patients had good long-term clinical and laboratory graft function (group 1), whereas 19 LT recipients suffered from histologically confirmed and clinically relevant chronic allograft rejection (group 2); 16 of these have already undergone retransplantation due to graft dysfunction. Inclusion criteria were availability of sera before the first LT to identify preformed antibodies in case of DSA positivity after LT and long-term follow-up at our institution. Sera were analyzed for anti-HLA antibodies using Luminex single antigen beads, where a mean fluorescence intensity value of more than 1500 was considered positive. RESULTS: The prevalence of DSA was 33% for group 1 and 68% for group 2. Antibodies were predominantly HLA class II. Values of mean fluorescence intensity were comparable in both groups. Only one of the DSA+ ve patients from group 1 exhibited preformed antibodies. In conclusion, pediatric patients with chronic rejection revealed a higher rate of de novo DSA, especially of HLA-class II DSA. Further studies are necessary to confirm these data with a larger pediatric cohort. PMID- 25706280 TI - Analysis of Post-Liver Transplant Hepatitis C Virus Recurrence Using Serial Cluster of Differentiation Antibody Microarrays. AB - BACKGROUND: Hepatitis C virus (HCV) reinfection of the liver allograft after transplantation is universal, with some individuals suffering severe disease recurrence. Predictive markers of recurrent disease severity are urgently needed. In this study, we used a cluster of differentiation (CD) microarray to predict the severity of HCV recurrence after transplantation. METHODS: The CD antibody microarray assays of live leukocytes were performed on peripheral blood taken in the first year after transplantation. The results were grouped into phases defined as; Pre-transplant (day 0), Early (day 3 to week 2), Mid (week 4 to week 10), and Late (week 12 to week 26). Hepatitis C virus severity was based on fibrosis stages in the first 2 years (F0-1 mild and F2-4 severe). RESULTS: Serial blood samples from 16 patients were taken before and after liver transplantation. A total of 98 assays were performed. Follow-up was 3 years or longer. Comparing recurrence severity, significantly greater numbers of CD antigens were differentially expressed on the pretransplant samples compared to any posttransplant timepoints. Five differentially expressed CD antigens before transplantation (CD27 PH, CD182, CD260, CD41, and CD34) were significantly expressed comparing severe to mild recurrence, whereas expression of only CD152 was significant in the late phase after transplantation. No relationship was observed between the donor or recipient interleukin-28B genotypes and HCV recurrence severity. CONCLUSIONS: This study shows that circulating leukocyte CD antigen expression has utility in assessing recurrent HCV disease severity after liver transplantation and serves as a proof of principle. Importantly, pretransplant CD antigen expression is most predictive of disease outcome. PMID- 25706281 TI - Thirty Years of Pancreas Transplantation at Leiden University Medical Center: Long-term Follow-up in a Large Eurotransplant Center. AB - BACKGROUND: An overview of 30 years of pancreas transplantation at a high volume center. Analysis of patient survival- and graft survival-associated risk factors. METHODS: All pancreas transplantations performed in our center from January 1, 1984, till December 31, 2012, were evaluated. Covariates influencing pancreas graft survival were analyzed using both univariate and multivariate analysis and Kaplan-Meier analysis. RESULTS: In the study period, 349 pancreas transplantations were performed. With the introduction of modern induction therapy in 1999, 5-year patient survival improved to 92.0% (P = 0.003). Five-year pancreas graft survival improved to 80.3% (P = 0.026). Pancreas graft survival was influenced by left or right donor kidney, transplant type, local origin of procurement team, pancreas cold ischemia time, recipient cerebrovascular disease. Pancreas donor risk index increased to 1.39 over the years and pancreas donor risk index 1.24 or higher is a risk factor for graft survival (P = 0.007). CONCLUSIONS: This study has shown excellent results in patient and pancreas graft survivals after 30 years of pancreas transplantation in a high volume center. Different donor, transplant, and recipient related risk factors influence pancreas graft survival. Even with higher risk pancreas donors, good results can be achieved. PMID- 25706282 TI - Functional proteomics screen enables enrichment of distinct cell types from human pancreatic islets. AB - The current world-wide epidemic of diabetes has prompted attempts to generate new sources of insulin-producing cells for cell replacement therapy. An inherent challenge in many of these strategies is the lack of cell-surface markers permitting isolation and characterization of specific cell types from differentiating stem cell populations. Here we introduce an iterative proteomics procedure allowing tag-free isolation of cell types based on their function. Our method detects and associates specific cell-surface markers with particular cell functionality by coupling cell capture on antibody arrays with immunofluorescent labeling. Using this approach in an iterative manner, we discovered marker combinations capable of enriching for discrete pancreatic cell subtypes from human islets of Langerhans: insulin-producing beta cells (CD9high/CD56+), glucagon-producing alpha cells (CD9-/CD56+) and trypsin-producing acinar cells (CD9-/CD56-). This strategy may assist future beta cell research and the development of diagnostic tools for diabetes. It can also be applied more generally for function-based purification of desired cell types from other limited and heterogeneous biological samples. PMID- 25706283 TI - Inverse agonistic action of 3-iodothyronamine at the human trace amine-associated receptor 5. AB - OBJECTIVE: Application of 3-iodothyronamine (3-T1AM) results in decreased body temperature and body weight in rodents. The trace amine-associated receptor (TAAR) 1, a family A G protein-coupled receptor, is a target of 3-T1AM. However, 3-T1AM effects still persist in mTaar1 knockout mice, which suggest so far unknown further receptor targets that are of physiological relevance. TAAR5 is a highly conserved TAAR subtype among mammals and we here tested TAAR5 as a potential 3-T1AM target. First, we investigated mouse Taar5 (mTaar5) expression in several brain regions of the mouse in comparison to mTaar1. Secondly, to unravel the full spectrum of signaling capacities, we examined the distinct Gs-, Gi/o-, G12/13-, Gq/11- and MAP kinase-mediated signaling pathways of mouse and human TAAR5 under ligand-independent conditions and after application of 3-T1AM. We found overlapping localization of mTaar1 and mTaar5 in the amygdala and ventromedial hypothalamus of the mouse brain. Second, the murine and human TAAR5 (hTAAR5) display significant basal activity in the Gq/11 pathway but show differences in the basal activity in Gs and MAP kinase signaling. In contrast to mTaar5, 3-T1AM application at hTAAR5 resulted in significant reduction in basal IP3 formation and MAP kinase signaling. In conclusion, our data suggest that the human TAAR5 is a target for 3-T1AM, exhibiting inhibitory effects on IP3 formation and MAP kinase signaling pathways, but does not mediate Gs signaling effects as observed for TAAR1. This study also indicates differences between TAAR5 orthologs with respect to their signaling profile. In consequence, 3-T1AM mediated effects may differ between rodents and humans. PMID- 25706284 TI - N-terminus three residues deletion mutant of human beta-defensin 3 with remarkably enhanced salt-resistance. AB - In this study, we designed and synthesized three N-terminal deletion analogs of human beta-defensin 3 (hBD-3), namely, hBD-3Delta4, hBD-3Delta7, and hBD 3Delta10, to determine the effect of N-terminal residues on the antibacterial activity and salt resistance of these peptides. The antibacterial activities and salt resistance of hBD-3 and its analogs were tested against a broad range of standard and clinically isolated strains. The deletion of nine N-terminal residues significantly reduced the antibacterial activity of hBD-3 against most of tested strains, particularly Klebsiella pneumonia. Compared with hBD-3 and other analogs, the analog with a deletion of three residues, hBD-3Delta4, exhibited significantly higher antimicrobial activity against almost all the tested strains, especially Escherichia coli and Enterococcus faecium, at high NaCl concentrations. Given its broad spectrum of antimicrobial activity and high salt resistance, hBD-3Delta4 could serve as a promising template for new therapeutic antimicrobial agents. PMID- 25706285 TI - Phylogeny and differentiation of reptilian and amphibian ranaviruses detected in Europe. AB - Ranaviruses in amphibians and fish are considered emerging pathogens and several isolates have been extensively characterized in different studies. Ranaviruses have also been detected in reptiles with increasing frequency, but the role of reptilian hosts is still unclear and only limited sequence data has been provided. In this study, we characterized a number of ranaviruses detected in wild and captive animals in Europe based on sequence data from six genomic regions (major capsid protein (MCP), DNA polymerase (DNApol), ribonucleoside diphosphate reductase alpha and beta subunit-like proteins (RNR-alpha and -beta), viral homolog of the alpha subunit of eukaryotic initiation factor 2, eIF-2alpha (vIF-2alpha) genes and microsatellite region). A total of ten different isolates from reptiles (tortoises, lizards, and a snake) and four ranaviruses from amphibians (anurans, urodeles) were included in the study. Furthermore, the complete genome sequences of three reptilian isolates were determined and a new PCR for rapid classification of the different variants of the genomic arrangement was developed. All ranaviruses showed slight variations on the partial nucleotide sequences from the different genomic regions (92.6-100%). Some very similar isolates could be distinguished by the size of the band from the microsatellite region. Three of the lizard isolates had a truncated vIF-2alpha gene; the other ranaviruses had full-length genes. In the phylogenetic analyses of concatenated sequences from different genes (3223 nt/10287 aa), the reptilian ranaviruses were often more closely related to amphibian ranaviruses than to each other, and most clustered together with previously detected ranaviruses from the same geographic region of origin. Comparative analyses show that among the closely related amphibian-like ranaviruses (ALRVs) described to date, three recently split and independently evolving distinct genetic groups can be distinguished. These findings underline the wide host range of ranaviruses and the emergence of pathogen pollution via animal trade of ectothermic vertebrates. PMID- 25706286 TI - Controlling immune rejection is a fail-safe system against potential tumorigenicity after human iPSC-derived neural stem cell transplantation. AB - Our previous work reported functional recovery after transplantation of mouse and human induced pluripotent stem cell-derived neural stem/progenitor cells (hiPSC NS/PCs) into rodent models of spinal cord injury (SCI). Although hiPSC-NS/PCs proved useful for the treatment of SCI, the tumorigenicity of the transplanted cells must be resolved before they can be used in clinical applications. The current study sought to determine the feasibility of ablation of the tumors formed after hiPSC-NS/PC transplantation through immunoregulation. Tumorigenic hiPSC-NS/PCs were transplanted into the intact spinal cords of immunocompetent BALB/cA mice with or without immunosuppressant treatment. In vivo bioluminescence imaging was used to evaluate the chronological survival and growth of the transplanted cells. The graft survival rate was 0% in the group without immunosuppressants versus 100% in the group with immunosuppressants. Most of the mice that received immunosuppressants exhibited hind-limb paralysis owing to tumor growth at 3 months after iPSC-NS/PC transplantation. Histological analysis showed that the tumors shared certain characteristics with low-grade gliomas rather than with teratomas. After confirming the progression of the tumors in immunosuppressed mice, the immunosuppressant agents were discontinued, resulting in the complete rejection of iPSC-NS/PC-derived masses within 42 days after drug cessation. In accordance with the tumor rejection, hind-limb motor function was recovered in all of the mice. Moreover, infiltration of microglia and lymphocytes was observed during the course of tumor rejection, along with apoptosis of iPSC NS/PC-generated cells. Thus, immune rejection can be used as a fail-safe system against potential tumorigenicity after transplantation of iPSC-NS/PCs to treat SCI. PMID- 25706288 TI - The female reproductive tract: congenital concerns. AB - The incidence and prevalence of conditions of the reproductive tract varies. This is related to both the complexity and spectrum of underlying and associated conditions. In some cases, only retrospective or case data are available, and likely under-reporting occurs, contributing to a lower than expected prevalence. Given the complex nature in which the reproductive tract develops in the fetus, it is important to understand the embryology, especially in situations of congenital anatomic differences. It is interesting to note not only patterns of conditions, but patterns of concurrent conditions or anomalies such as those occurring with isolated Mullerian anomalies, in conjunction with disorders of sexual differentiation or with cloacal malformations. This review will address typical presentation of these conditions, highlights of management and point to areas of research need, including clinical outcomes and genetic implications. PMID- 25706289 TI - Identification of novel miRNAs and miRNA expression profiling in wheat hybrid necrosis. AB - MicroRNAs (miRNAs) play essential roles in a vast array of biological processes, including growth and development, defense against viral infection, and responses to environmental changes in plant. Wheat hybrid necrosis is an interesting genetic phenomenon observed frequency and it is lethal or semi lethal, resulting in gradual death or loss of productivity. However, the molecular basis and mechanisms associated with hybrid necrosis in wheat are still not well understood. Here, we report the population and expression profiles of miRNAs in wheat hybrid necrosis. We identified a total of 57 conserved miRNA families as well as 182 putative novel miRNAs. Expression profiling revealed that expression of 49 known miRNAs and 165 novel miRNAs was changed in hybrid necrosis. And the expression levels of some miRNAs and their predicated targets have been confirmed by qRT-PCR. These results indicate that these miRNAs, especially miR159, miR166, miR167 and miR5072 could be involved in the extensive regulation of gene expression in response to hybrid necrosis. PMID- 25706291 TI - Clinical features and survival of lung cancer patients with pleural effusions. AB - BACKGROUND AND OBJECTIVE: The clinical relevance of pleural effusions in lung cancer has seldom been approached systematically. The aim of this study was to determine the prevalence, causes and natural history of lung cancer-associated pleural effusions, as well as their influence on survival. METHODS: Retrospective review of clinical records and imaging of 556 consecutive patients with a newly diagnosed lung cancer over a 4-year period at our institution. RESULTS: Lung cancer comprised 490 non-small cell and 66 small cell types. About 40% of patients with lung cancer developed pleural effusions at some time during the course of their disease. In half the patients, the effusions were too small to be tapped. These effusions did not progress to require a pleural intervention. Patients with minimal effusions had a worse prognosis compared to patients without pleural effusions (median survival of 7.49 vs 12.65 months, P < 0.001). Less than 20% of the 113 patients subjected to a diagnostic thoracentesis had benign causes for their effusions. Palliative pleural procedures (like therapeutic thoracenteses, pleurodesis or tunnelled pleural catheters) were conducted in 79 (84%) of the 94 malignant effusions. An effusion's size equal to or greater than half of the hemithorax was a strong predictor of the need for a palliative procedure. Overall survival of patients with malignant effusions was 5.49 months. CONCLUSIONS: Malignant pleural effusions are a poor prognostic factor in the setting of lung cancer, which includes minimal effusions not amenable to tapping. PMID- 25706290 TI - Complementary amplicon-based genomic approaches for the study of fungal communities in humans. AB - Recent studies highlight the importance of intestinal fungal microbiota in the development of human disease. Infants, in particular, are an important population in which to study intestinal microbiomes because microbial community structure and dynamics during this formative window of life have the potential to influence host immunity and metabolism. When compared to bacteria, much less is known about the early development of human fungal communities, owing partly to their lower abundance and the relative lack of established molecular and taxonomic tools for their study. Herein, we describe the development, validation, and use of complementary amplicon-based genomic strategies to characterize infant fungal communities and provide quantitative information about Candida, an important fungal genus with respect to intestinal colonization and human disease. Fungal communities were characterized from 11 infant fecal samples using primers that target the internal transcribed spacer (ITS) 2 locus, a region that provides taxonomic discrimination of medically relevant fungi. Each sample yielded an average of 27,553 fungal sequences and Candida albicans was the most abundant species identified by sequencing and quantitative PCR (qPCR). Low numbers of Candida krusei and Candida parapsilosis sequences were observed in several samples, but their presence was detected by species-specific qPCR in only one sample, highlighting a challenge inherent in the study of low-abundance organisms. Overall, the sequencing results revealed that infant fecal samples had fungal diversity comparable to that of bacterial communities in similar-aged infants, which correlated with the relative abundance of C. albicans. We conclude that targeted sequencing of fungal ITS2 amplicons in conjunction with qPCR analyses of specific fungi provides an informative picture of fungal community structure in the human intestinal tract. Our data suggests that the infant intestine harbors diverse fungal species and is consistent with prior culture based analyses showing that the predominant fungus in the infant intestine is C. albicans. PMID- 25706293 TI - Ultraviolet germicidal irradiation and its effects on elemental distributions in mouse embryonic fibroblast cells in x-ray fluorescence microanalysis. AB - Rapidly-frozen hydrated (cryopreserved) specimens combined with cryo-scanning x ray fluorescence microscopy provide an ideal approach for investigating elemental distributions in biological cells and tissues. However, because cryopreservation does not deactivate potentially infectious agents associated with Risk Group 2 biological materials, one must be concerned with contamination of expensive and complicated cryogenic x-ray microscopes when working with such materials. We employed ultraviolet germicidal irradiation to decontaminate previously cryopreserved cells under liquid nitrogen, and then investigated its effects on elemental distributions under both frozen hydrated and freeze dried states with x ray fluorescence microscopy. We show that the contents and distributions of most biologically important elements remain nearly unchanged when compared with non ultraviolet-irradiated counterparts, even after multiple cycles of ultraviolet germicidal irradiation and cryogenic x-ray imaging. This provides a potential pathway for rendering Risk Group 2 biological materials safe for handling in multiuser cryogenic x-ray microscopes without affecting the fidelity of the results. PMID- 25706292 TI - Natural indoles, indole-3-carbinol (I3C) and 3,3'-diindolylmethane (DIM), attenuate staphylococcal enterotoxin B-mediated liver injury by downregulating miR-31 expression and promoting caspase-2-mediated apoptosis. AB - Staphylococcal enterotoxin B (SEB) is a potent superantigen capable of inducing inflammation characterized by robust immune cell activation and proinflammatory cytokine release. Exposure to SEB can result in food poisoning as well as fatal conditions such as toxic shock syndrome. In the current study, we investigated the effect of natural indoles including indole-3-carbinol (I3C) and 3,3' diindolylmethane (DIM) on SEB-mediated liver injury. Injection of SEB into D galactosamine-sensitized female C57BL/6 mice resulted in liver injury as indicated by an increase in enzyme aspartate transaminase (AST) levels, induction of inflammatory cytokines, and massive infiltration of immune cells into the liver. Administration of I3C and DIM (40 mg/kg), by intraperitonal injection, attenuated SEB-induced acute liver injury, as evidenced by decrease in AST levels, inflammatory cytokines and cellular infiltration in the liver. I3C and DIM triggered apoptosis in SEB-activated T cells primarily through activation of the intrinsic mitochondrial pathway. In addition, inhibitor studies involving caspases revealed that I3C and DIM-mediated apoptosis in these activated cells was dependent on caspase-2 but independent of caspase-8, 9 and 3. In addition, I3C and DIM caused a decrease in Bcl-2 expression. Both compounds also down regulated miR-31, which directly targets caspase-2 and influences apoptosis in SEB-activated cells. Our data demonstrate for the first time that indoles can effectively suppress acute hepatic inflammation caused by SEB and that this may be mediated by decreased expression of miR-31 and consequent caspase-2-dependent apoptosis in T cells. PMID- 25706294 TI - Exploring the Adolescent Fall in Physical Activity: A 10-yr Cohort Study (EarlyBird 41). AB - INTRODUCTION: Contemporary adolescents are deemed inactive, especially girls, but whether for biological reasons associated with their maturation, changes in their behavior or because of environmental constraints, is uncertain. We examined the trends in physical activity (PA) in relation to both biological and environmental factors in an attempt to establish what drives activity patterns from childhood through adolescence. METHODS: Physical activity (7-d Actigraph accelerometry) was measured annually from 5 to 15 yr in a single cohort of some 300 UK children. Total PA (TPA; in-school and out-of-school separately and combined as whole day) and intensity-specific PA (sedentary, light, and moderate-and-vigorous [MVPA]) were analyzed. Biological age (years before/after measured peak height velocity) and pubertal stage (self-reported pubic hair development-Tanner staging) were also measured as was socioeconomic status (postcode-derived index of multiple deprivation [IMD]). RESULTS: Total PA was stable from 5 to 8 yr (trend P = 0.10) but fell progressively from 9 to 15 yr (by approximately 30% in girls and approximately 20% in boys, both P < 0.001; sex interaction, P < 0.01). Half of this fall was attributable to light intensity PA and only a quarter to MVPA. The decline in PA was related similarly to chronological and biological age, whereas pubertal stage explained the more rapid PA decline in girls (puberty-adjusted sex interaction, P = 0.51). Total PA fell to the same extent for in-school and out-of school settings (both P < 0.001), and for lower and higher IMD areas (both P < 0.001). Total PA tracked moderately to strongly from childhood into adolescence (r = 0.58; P < 0.001). CONCLUSIONS: The adolescent decline in PA is consistent across different environmental settings, attributable to falls in light intensity/habitual activity and influenced by puberty, suggesting that the inactivity of adolescence may, in part, be under biological control. PMID- 25706295 TI - How Much Do Range of Movement and Coordination Affect Paralympic Sprint Performance? AB - INTRODUCTION: Development of evidence-based methods of paralympic classification requires research quantifying the relative strength of association between ratio scaled measures of impairment and sports performance. To date, no such research has been conducted. The purpose of this study was to quantify the extent to which range of movement (ROM) and coordination affect running performance in runners with and without brain impairment. METHODS: Participants were 41 male runners, 13 with brain impairments (RBI) and 28 nondisabled (NDR). All participants completed a maximal 60-m sprint as well as a novel battery of five lower limb ROM tests and three lower limb coordination tests. RESULTS: In the coordination tests, RBI showed significantly slower mean movement times compared to NDR on all measures (e.g., 0.54 s +/- 0.12 s vs 0.34 s +/- 0.05 s). Runners with brain impairments had significantly lower range of movement on five of ten measures (e.g., 25.9 degrees +/- 5.4 degrees vs 37.0 degrees +/- 6.0 degrees ) and had significantly slower acceleration (0-15 m) (3.2 s +/- 0.3 s vs 2.8 s +/- 0.2 s) and top speed (30-60 m) (4.3 s +/- 0.6 s vs 3.8 s +/- 0.3 s). Five ROM measures significantly correlated with sprint performance in RBI and did not significantly correlate with sprint performance in NDR, satisfying convergent and divergent validity criteria. These individual tests explained 38% to 58% of the variance in sprint performance in RBI. CONCLUSION: This is the first study to quantify the extent to which eligible impairments affect performance in a paralympic sport. Five of the ROM measures significantly affected sprint performance in RBI and were deemed valid for the purposes of classifying impairments in classes T35-T38. This study is an important methodological step toward development of evidence based methods of classifying impairments in classes T35-T38 and provides practical methodological guidance to researchers in this field. PMID- 25706296 TI - Advances in exercise, fitness, and performance genomics in 2014. AB - This is the annual review of the exercise genomics literature in which we report on the highest quality papers published in 2014. We identified a number of noteworthy papers across a number of fields. In 70-89 yr olds, only 19% of angiotensin-converting enzyme (ACE) II homozygotes exhibited significant improvement in gait speed in response to a yearlong physical activity program compared to 30% of ACE D-allele carriers. New studies continue to support the notion that the genetic susceptibility to obesity, as evidenced by a genomic risk score (GRS; based on multiple single nucleotide polymorphisms), is attenuated by 40%-50% in individuals who are physically active, compared to those who are sedentary. One study reported that the polygenic risk for hypertriglyceridemia was reduced by 30%-40% in individuals with high cardiorespiratory fitness. One report showed that there was a significant interaction of a type 2 diabetes GRS with physical activity, with active individuals having the lowest risk of developing diabetes. The protective effect of physical activity was most pronounced in the low GRS tertile (hazard ratio, 0.82). The interaction observed with the diabetes GRS seemed to be dependent on a genetic susceptibility to insulin resistance and not insulin secretion. A significant interaction between PPARalpha sequence variants and physical activity levels on cardiometabolic risk was observed, with higher activity levels associated with lower risk only in carriers of specific genotypes and haplotypes. The review concludes with a discussion of the importance of replication studies when very large population or intervention discovery studies are not feasible or are cost prohibitive. PMID- 25706297 TI - Mortality in adult offspring of immigrants: a Swedish national cohort study. AB - BACKGROUND: Higher risks of psychiatric disorders and lower-than-average subjective health in adulthood have been demonstrated in offspring of immigrants in Sweden compared with offspring of native Swedes, and linked to relative socioeconomic disadvantage. The present study investigated mortality rates in relation to this inequity from a gender perspective. METHODS: We used data from national registers covering the entire Swedish population aged 18-65 years. Offspring of foreign-born parents who were either Swedish born or had received residency in Sweden before school age (<7 years) were defined as "offspring of immigrants." We used Cox regression models to examine the association between parental country of birth and mortality between 1990 and 2008, with adjustment for education, income, age and family type. RESULTS: Male offspring of immigrants from the Middle East (HR:2.00, CI:1.66-2.26), other non-European countries (HR:1.80, CI:1.36-2.36) and Finland (HR:1.56, CI:1.48-1.65) showed an age adjusted excess mortality risk from all causes of death when compared to offspring with Swedish-born parents. Income, but not education, greatly attenuated these increased mortality risks. No excess mortality rates were found among female offspring of immigrants, with the exception of external cause of death among offspring of Finnish immigrants. CONCLUSION: The study demonstrates high mortality rates in male offspring of immigrants from Finland and non European countries that are associated with economic, but not educational, disadvantage. No increased mortality rates were found among female offspring of immigrants. Future studies are needed to explain this gender differential and why income, but not education, predicts mortality in male offspring of immigrants. PMID- 25706298 TI - Acquired generalized asymptomatic livid erythema and telangiectasia. PMID- 25706299 TI - Screening diagnostic candidates for schistosomiasis from tegument proteins of adult Schistosoma japonicum using an immunoproteomic approach. AB - BACKGROUND: Schistosomiasis is one of the world's most prevalent zoonotic diseases and a serious worldwide public health problem. Since the tegument (TG) of Schistosoma japonicum is in direct contact with the host and induces a host immune response against infection, the identification of immune response target molecules in the schistosome TG is crucial for screening diagnostic antigens for this disease. METHODOLOGY/PRINCIPAL FINDINGS: In this study, an immunoproteomics approach used TG proteins as screening antigens to identify potential diagnostic molecules of S. japonicum. Ten spots corresponding to six proteins were identified that immunoreacted with sera from S. japonicum-infected rabbits but not sera from uninfected rabbits and their specific IgG antibody levels declined quickly after praziquantel treatment. Recombinant phosphoglycerate mutase (PGM) and UV excision repair protein RAD23 homolog B (RAD23) proteins were expressed and their diagnostic potential for schistosomiasis was evaluated and compared with schistosome soluble egg antigen (SEA) using ELISA. The results showed high sensitivity and specificity and low crossreactivity when rSjPGM-ELISA and rSjRAD23-ELISA were used to detect water buffalo schistosomiasis. Moreover, antibodies to rSjPGM and rSjRAD23 might be short-lived since they declined quickly after chemotherapy. CONCLUSION/SIGNIFICANCE: Therefore, the two schistosome TG proteins SjPGM and SjRAD23 were identified as potential diagnostic markers for the disease. The two recombinant proteins might have the potential to evaluate the effectiveness of drug treatments and for distinguishing between current and past infection. PMID- 25706300 TI - The effect of an oligonucleotide on the structure of cationic DODAB vesicles. AB - The effect of a small single-stranded oligonucleotide (ODN) on the structure of cationic DODAB vesicles was investigated by means of differential scanning calorimetry (DSC), small angle X-ray scattering (SAXS) and electron spin resonance (ESR) spectroscopy. ODN adsorption induced coalescence of vesicles and formation of multilamellar structures with close contact between lamellae. It also increased the phase transition temperature by 10 degrees C but decreased transition cooperativity. The ODN rigidified and stabilized the gel phase. In the fluid phase, a simultaneous decrease of ordering close to the bilayer surface and increase in bilayer core rigidity was observed in the presence of the ODN. These effects may be due not only to electrostatic shielding of DODAB head groups but also to superficial dehydration of the bilayers. The data suggest that oligonucleotides may induce the formation of a multilamellar poorly hydrated coagel-like phase below phase transition. These effects should be taken into account when planning ODN delivery employing cationic bilayer carriers. PMID- 25706301 TI - Sugarcane giant borer transcriptome analysis and identification of genes related to digestion. AB - Sugarcane is a widely cultivated plant that serves primarily as a source of sugar and ethanol. Its annual yield can be significantly reduced by the action of several insect pests including the sugarcane giant borer (Telchin licus licus), a lepidopteran that presents a long life cycle and which efforts to control it using pesticides have been inefficient. Although its economical relevance, only a few DNA sequences are available for this species in the GenBank. Pyrosequencing technology was used to investigate the transcriptome of several developmental stages of the insect. To maximize transcript diversity, a pool of total RNA was extracted from whole body insects and used to construct a normalized cDNA database. Sequencing produced over 650,000 reads, which were de novo assembled to generate a reference library of 23,824 contigs. After quality score and annotation, 43% of the contigs had at least one BLAST hit against the NCBI non redundant database, and 40% showed similarities with the lepidopteran Bombyx mori. In a further analysis, we conducted a comparison with Manduca sexta midgut sequences to identify transcripts of genes involved in digestion. Of these transcripts, many presented an expansion or depletion in gene number, compared to B. mori genome. From the sugarcane giant borer (SGB) transcriptome, a number of aminopeptidase N (APN) cDNAs were characterized based on homology to those reported as Cry toxin receptors. This is the first report that provides a large scale EST database for the species. Transcriptome analysis will certainly be useful to identify novel developmental genes, to better understand the insect's biology and to guide the development of new strategies for insect-pest control. PMID- 25706302 TI - An investigation of the endocrine-disruptive effects of bisphenol a in human and rat fetal testes. AB - Few studies have been undertaken to assess the possible effects of bisphenol A (BPA) on the reproductive hormone balance in animals or humans with often contradictory results. We investigated possible direct endocrine disruption by BPA of the fetal testes of 2 rat strains (14.5-17.5 days post-coitum) and humans (8-12 gestational weeks) and under different culture conditions. BPA concentrations of 10(-8)M and 10(-5)M for 72 h reduced testosterone production by the Sprague-Dawley fetal rat testes, while only 10-5M suppressed it in the Wistar strain. The suppressive effects at 10-5M were seen as early as 24h and 48 h in both strains. BPA at 10(-7)-10(-5)M for 72 h suppressed the levels of fetal rat Leydig cell insulin-like factor 3 (INSL3). BPA exposure at 10(-8)M, 10(-7)M, and 10(-5)M for 72 h inhibited testosterone production in fetal human testes. For the lowest doses, the effects observed occurred only when no gonadotrophin was added to the culture media and were associated with a poorly preserved testicular morphology. We concluded that (i) BPA can display anti-androgenic effects both in rat and human fetal testes; (ii) it is essential to ascertain that the divergent effects of endocrine disruptors between species in vitro do not result from the culture conditions used, and/or the rodent strain selected; (iii) the optimization of each in vitro assay for a given species should be a major objective rather than the search of an hypothetical trans-species consensual model-system, as the organization of the testis is intrinsically different between mammalian species; (iv) due to the uncertainty existing on the internal exposure of the human fetal testis to BPA, and the insufficient number of epidemiological studies on the endocrine disruptive effects of BPA, caution should be taken in the extrapolation of our present results to the human reproductive health after fetal exposure to BPA. PMID- 25706303 TI - Characterisation of the physical composition and microbial community structure of biofilms within a model full-scale drinking water distribution system. AB - Within drinking water distribution systems (DWDS), microorganisms form multi species biofilms on internal pipe surfaces. A matrix of extracellular polymeric substances (EPS) is produced by the attached community and provides structure and stability for the biofilm. If the EPS adhesive strength deteriorates or is overcome by external shear forces, biofilm is mobilised into the water potentially leading to degradation of water quality. However, little is known about the EPS within DWDS biofilms or how this is influenced by community composition or environmental parameters, because of the complications in obtaining biofilm samples and the difficulties in analysing EPS. Additionally, although biofilms may contain various microbial groups, research commonly focuses solely upon bacteria. This research applies an EPS analysis method based upon fluorescent confocal laser scanning microscopy (CLSM) in combination with digital image analysis (DIA), to concurrently characterize cells and EPS (carbohydrates and proteins) within drinking water biofilms from a full-scale DWDS experimental pipe loop facility with representative hydraulic conditions. Application of the EPS analysis method, alongside DNA fingerprinting of bacterial, archaeal and fungal communities, was demonstrated for biofilms sampled from different positions around the pipeline, after 28 days growth within the DWDS experimental facility. The volume of EPS was 4.9 times greater than that of the cells within biofilms, with carbohydrates present as the dominant component. Additionally, the greatest proportion of EPS was located above that of the cells. Fungi and archaea were established as important components of the biofilm community, although bacteria were more diverse. Moreover, biofilms from different positions were similar with respect to community structure and the quantity, composition and three-dimensional distribution of cells and EPS, indicating that active colonisation of the pipe wall is an important driver in material accumulation within the DWDS. PMID- 25706304 TI - Highly active and durable platinum-lead bimetallic alloy nanoflowers for formic acid electrooxidation. AB - The Pt84Pb16 (atomic ratio) bimetallic alloy nanoflowers (Pt84Pb16 BANFs) are synthesized by a simple one-pot hydrothermal reduction method that effectively enhance the dehydrogenation pathway of the formic acid oxidation reaction (FAOR) due to the ensemble effect and the electronic effect. As a result, the mass activity of Pt84Pb16 BANFs for the FAOR is 16.7 times higher than that of commercial Pt black at 0.3 V potential. PMID- 25706305 TI - Clinicopathological characteristics of patients with non-small-cell lung cancer who harbor EML4-ALK fusion gene: a meta-analysis. AB - BACKGROUND: A novel fusion gene of echinoderm microtubule-associated protein-like 4 (EML4) and anaplastic lymphoma kinase (ALK) has been recently identified in non small-cell lung cancers (NSCLCs). Patients with the EML4-ALK fusion gene demonstrate unique clinicopathological and physiological characteristics. Here we present a meta-analysis of large-scale studies to evaluate the clinicopathological characteristics of NSCLC patients harboring the EML4-ALK fusion gene. METHODS: Both English and Chinese databases were systematically used to search the materials of the clinicopathological characteristics of patients with NSCLC harboring the EML4-ALK fusion gene. Pooled relative risk (RR) estimates and the 95% confidence intervals (95% CI) were calculated with the fixed or random effect model. Publication bias and chi-square test were also calculated. RESULTS: 27 retrospective studies were included in our meta-analysis. These studies included a total of 6950 patients. The incidence rate of EML4-ALK fusion in NSCLC patients was found to be 6.8% (472/6950). The correlation of the EML4-ALK fusion gene and clinicopathological characteristics of NSCLC patients demonstrated a significant difference in smoking status, histological types, stage, and ethnic characteristics. The positive rate of the EML4-ALK fusion gene expression in females were slightly higher than that in males, but not significantly (P = 0.52). In addition, the EML4-ALK fusion gene was mutually exclusive of the EGFR and KRAS mutation genes (P = 0.00). CONCLUSION: Our pooled analysis revealed that the EML4-ALK fusion gene was observed predominantly in adenocarcinoma, non-smoking and NSCLC patients, especially those diagnosed in the advanced clinical stage of NSCLC. Additionally, the EML4-ALK fusion gene was exclusive of the EGFR and KRAS mutation genes. We surmise that IHC assay is a valuable tool for the prescreening of patients with ALK fusion gene in clinical practice, and FISH assay can be performed as a confirmation method. These insights might be helpful in guiding the appropriate molecular target therapy for NSCLC. PMID- 25706306 TI - A multiancestral genome-wide exome array study of Alzheimer disease, frontotemporal dementia, and progressive supranuclear palsy. AB - IMPORTANCE: Previous studies have indicated a heritable component of the etiology of neurodegenerative diseases such as Alzheimer disease (AD), frontotemporal dementia (FTD), and progressive supranuclear palsy (PSP). However, few have examined the contribution of low-frequency coding variants on a genome-wide level. OBJECTIVE: To identify low-frequency coding variants that affect susceptibility to AD, FTD, and PSP. DESIGN, SETTING, AND PARTICIPANTS: We used the Illumina HumanExome BeadChip array to genotype a large number of variants (most of which are low-frequency coding variants) in a cohort of patients with neurodegenerative disease (224 with AD, 168 with FTD, and 48 with PSP) and in 224 control individuals without dementia enrolled between 2005-2012 from multiple centers participating in the Genetic Investigation in Frontotemporal Dementia and Alzheimer's Disease (GIFT) Study. An additional multiancestral replication cohort of 240 patients with AD and 240 controls without dementia was used to validate suggestive findings. Variant-level association testing and gene-based testing were performed. MAIN OUTCOMES AND MEASURES: Statistical association of genetic variants with clinical diagnosis of AD, FTD, and PSP. RESULTS: Genetic variants typed by the exome array explained 44%, 53%, and 57% of the total phenotypic variance of AD, FTD, and PSP, respectively. An association with the known AD gene ABCA7 was replicated in several ancestries (discovery P=.0049, European P=.041, African American P=.043, and Asian P=.027), suggesting that exonic variants within this gene modify AD susceptibility. In addition, 2 suggestive candidate genes, DYSF (P=5.53*10(-5)) and PAXIP1 (P=2.26*10(-4)), were highlighted in patients with AD and differentially expressed in AD brain. Corroborating evidence from other exome array studies and gene expression data points toward potential involvement of these genes in the pathogenesis of AD. CONCLUSIONS AND RELEVANCE: Low-frequency coding variants with intermediate effect size may account for a significant fraction of the genetic susceptibility to AD and FTD. Furthermore, we found evidence that coding variants in the known susceptibility gene ABCA7, as well as candidate genes DYSF and PAXIP1, confer risk for AD. PMID- 25706307 TI - A ratiometric fluorescent nanoprobe based on terbium functionalized carbon dots for highly sensitive detection of an anthrax biomarker. AB - A ratiometric fluorescent nanoprobe based on terbium functionalized carbon dots (CDs) was designed to detect dipicolinic acid (DPA) as an anthrax biomarker with high selectivity and sensitivity. CDs were generated by one-step synthesis using an ethylenediaminetetraacetic acid precursor, and served as a scaffold for coordination with Tb(3+) and a fluorescence reference. PMID- 25706308 TI - Hierarchical microstructures formed by bidisperse colloidal suspensions within colloid-in-liquid crystal gels. AB - Past studies have reported that colloids of a single size dispersed in the isotropic phase of a mesogenic solvent can form colloid-rich networks (and gels) upon thermal quenching of the system across the isotropic-nematic phase boundary of the mesogens. Herein we report the observation and characterization of complex hierarchical microstructures that form when bidisperse colloidal suspensions of nanoparticles (NPs; iron oxide with diameters of 188 +/- 20 nm or poly(methyl methacrylate) with diameters of 150 +/- 15 nm) and microparticles (MPs; polystyrene with diameters of 2.77 +/- 0.20 MUm) are dispersed in the isotropic phase of 4-pentyl-4'-cyanobiphenyl (5CB) and thermally quenched. Specifically, we document microstructuring that results from three sequential phase separation processes that occur at distinct temperatures during stepwise cooling of the ternary mixture from its miscibility region. The first phase transition demixes the system into coexisting MP-rich and NP-rich phases; the second promotes formation of a particle network within the MP-rich phase; and the third, which coincides with the isotropic-to-nematic phase transition of 5CB, produces a second colloidal network within the NP-rich phase. We quantified the dynamics of each demixing process by using optical microscopy and Fourier transform image analysis to establish that the phase transitions occur through (i) surface directed spinodal decomposition, (ii) spinodal decomposition, and (iii) nucleation and growth, respectively. Significantly, the observed series of phase transitions leads to a hierarchical organization of cellular microstructures not observed in colloid-in-liquid crystal gels formed from monodisperse colloids. The results of this study suggest new routes to the synthesis of colloidal materials with hierarchical microstructures that combine large surface areas and organized porosity with potential applications in catalysis, separations, chemical sensing, or tissue engineering. PMID- 25706309 TI - Human papillomavirus infection correlates with inflammatory Stat3 signaling activity and IL-17 level in patients with colorectal cancer. AB - BACKGROUND: Colorectal cancer (CRC) is a major burden of public health and healthcare worldwide. Microbiota has been suggested in promoting chronic inflammation in the intestine which, in turn, promotes tumor development. This study focuses on possible correlations of human papillomavirus (HPV) infection with proinflammatory Stat3 signaling activities and the resulting levels of its downstream proinflammatory cytokine IL-17 in CRC patients. METHODS: HPV was examined using HPV Genotyping Chip technology and constitutively active Stat3 (p Stat3) and IL-17 levels were tested using immunohistochemistry (IHC) in paraffin embedded cancerous and adjacent normal tissues (ANT) from a cohort of 95 CRC patients. Correlation analyses were performed between HPV infection and clinicopathological characteristics, Stat3 activities and IL-17 levels among these CRC patients. RESULTS: Three major findings were observed: (1) HPV infection existed in a high rate of CRC cases (48.4%, 46/95), of which 45 cases (45/46, 97.8%) were high-risk HPV16-positive and only one case was HPV53 positive. (2) HPV infection correlated with poorer clinical stages (III+IV) of CRC. (3) HPV infection strongly correlated with both constitutively higher Stat3 activities (P<0.01) and higher IL-17 levels (P<0.01) only in CRC tissues but not in ANT tissues. CONCLUSIONS: HPV infection is common in CRC patients suggesting potentially preventive effectiveness of HPV vaccination among high-risk young individuals. We have for the first time revealed a tri-lateral relationship among HPV infection, constitutive Stat3 activity and IL-17 level, whose collaborative act may orchestrate a proinflammatory microenvironment in the colorectum that, in turn, may promote carcinogenesis and possibly facilitate progression of CRC. PMID- 25706310 TI - Phage-mediated dispersal of biofilm and distribution of bacterial virulence genes is induced by quorum sensing. AB - The microbiome and the phage meta-genome within the human gut are influenced by antibiotic treatments. Identifying a novel mechanism, here we demonstrate that bacteria use the universal communication molecule AI-2 to induce virulence genes and transfer them via phage release. High concentrations (i.e. 100 MUM) of AI-2 promote dispersal of bacteria from already established biofilms, and is associated with release of phages capable of infecting other bacteria. Enterococcus faecalis V583DeltaABC harbours 7 prophages in its genome, and a mutant deficient in one of these prophages (i.e. prophage 5) showed a greatly reduced dispersal of biofilm. Infection of a probiotic E. faecalis strain without lytic prophages with prophage 5 resulted in increased biofilm formation and also in biofilm dispersal upon induction with AI-2. Infection of the probiotic E. faecalis strain with phage-containing supernatants released through AI-2 from E. faecalis V583DeltaABC resulted in a strong increase in pathogenicity of this strain. The polylysogenic probiotic strain was also more virulent in a mouse sepsis model and a rat endocarditis model. Both AI-2 and ciprofloxacin lead to phage release, indicating that conditions in the gastrointestinal tract of hospitalized patients treated with antibiotics might lead to distribution of virulence genes to apathogenic enterococci and possibly also to other commensals or even to beneficial probiotic strains. PMID- 25706311 TI - In vitro evaluation of endothelial progenitor cells from adipose tissue as potential angiogenic cell sources for bladder angiogenesis. AB - Autologous endothelial progenitor cells (EPCs) might be alternative angiogenic cell sources for vascularization of tissue-engineered bladder, while isolation and culture of EPCs from peripheral blood in adult are usually time-consuming and highly inefficient. Recent evidence has shown that EPCs also exist in the adipose tissue. As adipose tissue is plentiful in the human body and can be easily harvested through a minimally invasive method, the aim of this study was to culture and characterize EPCs from adipose tissue (ADEPCs) and investigate their potential for the neovascularization of tissue-engineered bladder. Adipose stromal vascular fraction (SVF) was isolated and used for the culture of ADEPCs and adipose derived stem cells (ADSCs). After SVF was cultured for one week, ADEPCs with typical cobblestone morphology emerged and could be isolated from ADSCs according to their different responses to trypsinization. Rat bladder smooth muscle cells (RBSMCs) were isolated and cultured from rat bladder. RBSMCs exhibited typical spindle-shaped morphology. ADEPCs had higher proliferative potential than ADSCs and RBSMCs. ADEPCs stained positive for CD34, Stro-1, VEGFR 2, eNOS and CD31 but negative for alpha-SMA, CD14 and CD45. ADSCs stained positive for CD34, Stro-1 and alpha-SMA but negative for VEGFR-2, eNOS, CD31, CD14 and CD45. RBSMCs stained only positive for alpha-SMA. ADEPCs could be expanded from a single cell at an early passage to a cell cluster containing more than 10,000 cells. ADEPCs were able to uptake DiI-Ac-LDL, bind UEA-1 and form capillary-like structures in three-dimensional scaffolds (Matrigel and bladder acellular matrix). ADEPCs were also able to enhance the human umbilical vein endothelial cells' capability of capillary-like tube formation on Matrigel. Additionally, significantly higher levels of mRNA and protein of vascular endothelial growth factor were found in ADEPCs than in RBSMCs. These results suggest the potential use of ADEPCs as angiogenic cell sources for engineering bladder tissue. PMID- 25706312 TI - Optopharmacological tools for restoring visual function in degenerative retinal diseases. AB - Retinitis pigmentosa (RP) and age-related macular degeneration (AMD) are progressive retinal diseases that result from the death of rod and cone photoreceptors, ultimately leading to blindness. The only currently approved vision restoration treatment employs an implanted retinal 'chip' as a prosthetic device to electrically stimulate retinal neurons that survive after the photoreceptors are gone, thereby restoring light-driven neural signaling to the brain. Alternative strategies have been proposed, which would utilize optogenetic or optopharmacological tools to enable direct optical stimulation of surviving retinal neurons. Here, we review the latest studies evaluating the feasibility of these molecular tools as potential therapeutics for restoring visual function in human blinding disease. PMID- 25706313 TI - Simian virus Large T antigen interacts with the N-terminal domain of the 70 kD subunit of Replication Protein A in the same mode as multiple DNA damage response factors. AB - Simian virus 40 (SV40) serves as an important model organism for studying eukaryotic DNA replication. Its helicase, Large T-antigen (Tag), is a multi functional protein that interacts with multiple host proteins, including the ubiquitous ssDNA binding protein Replication Protein A (RPA). Tag recruits RPA, actively loads it onto the unwound DNA, and together they promote priming of the template. Although interactions of Tag with RPA have been mapped, no interaction between Tag and the N-terminal protein interaction domain of the RPA 70kDa subunit (RPA70N) has been reported. Here we provide evidence of direct physical interaction of Tag with RPA70N and map the binding sites using a series of pull down and mutational experiments. In addition, a monoclonal anti-Tag antibody, the epitope of which overlaps with the binding site, blocks the binding of Tag to RPA70N. We use NMR chemical shift perturbation analysis to show that Tag uses the same basic cleft in RPA70N as multiple of DNA damage response proteins. Mutations in the binding sites of both RPA70N and Tag demonstrate that specific charge reversal substitutions in either binding partner strongly diminish the interaction. These results expand the known repertoire of contacts between Tag and RPA, which mediate the many critical roles of Tag in viral replication. PMID- 25706314 TI - Silk-regulated hierarchical hollow magnetite/carbon nanocomposite spheroids for lithium-ion battery anodes. AB - Hierarchical olive-like structured carbon-Fe3O4 nanocomposite particles composed of a hollow interior and a carbon coated surface are prepared by a facile, silk protein-assisted hydrothermal method. Silk nanofibers as templates and carbon precursors first regulate the formation of hollow Fe2O3 microspheres and then they are converted into carbon by a reduction process into Fe3O4. This process significantly simplifies the fabrication and carbon coating processes to form complex hollow structures. When tested as anode materials for lithium-ion batteries, these hollow carbon-coated particles exhibit high capacity (900 mAh g( 1)), excellent cycle stability (180 cycles) and rate performance due to their unique hierarchical hollow structure and carbon coating. PMID- 25706315 TI - Increased temperature produces changes in the bioactive composition of tomato, depending on its developmental stage. AB - The present study examines the effect of an increased day temperature on vitamin C and carotenoid concentrations in tomato, depending on the developmental stage of fruits when the stress is imposed. Plants were cultivated in a growth chamber initially at 24 degrees C, and the day temperature was increased to 32 degrees C when fruits belonging to six different fruit development stages could be differentiated. Vitamin C, phytoene, phytofluene, lycopene, gamma-carotene, and violaxantin concentrations were significantly lower when a temperature of 32 degrees C was imposed during the advanced stages of fruit development compared to the levels observed in the control treatment. However, no effect or increased concentrations were observed when the temperature was increased in earlier stages, indicating the adaptation of the plant metabolism to high temperature. Finally, no effect on beta-carotene concentration was observed, regardless of the fruit developmental stage when the temperature increase was applied. PMID- 25706316 TI - Perceptual grouping does not affect multi-attribute decision making if no processing costs are involved. AB - Adaptive strategy selection implies that a decision strategy is chosen based on its fit to the task and situation. However, other aspects, such as the way information is presented, can determine information search behavior; especially when the application of certain strategies over others is facilitated. But are such display effects on multi-attribute decisions also at work when the manipulation does not entail differential costs for different decision strategies? Three Mouselab experiments with hidden information and one eye tracking experiment with an open information board revealed that decision behavior is unaffected by purely perceptual manipulations of the display based on Gestalt principles; that is, based on manipulations that induce no noteworthy processing costs for different information search patterns. We discuss our results in the context of previous findings on display effects; specifically, how the combination of these findings and our results reveal the crucial role of differential processing costs for different strategies for the emergence of display effects. This finding describes a boundary condition of the commonly acknowledged influence of information displays and is in line with the ideas of adaptive strategy selection and cost-benefit tradeoffs. PMID- 25706317 TI - Sensory processing in preterm preschoolers and its association with executive function. AB - BACKGROUND: Symptoms of abnormal sensory processing have been related to preterm birth, but have not yet been studied specifically in preterm preschoolers. The degree of association between sensory processing and other domains is important for understanding the role of sensory processing symptoms in the development of preterm children. AIMS: To test two related hypotheses: (1) preterm preschoolers have more sensory processing symptoms than full term preschoolers and (2) sensory processing is associated with both executive function and adaptive function in preterm preschoolers. STUDY DESIGN: Cross-sectional study. SUBJECTS: Preterm children (<=34weeks of gestation; n=54) and full term controls (>=37weeks of gestation; n=73) ages 3-5years. OUTCOME MEASURES: Sensory processing was assessed with the Short Sensory Profile. Executive function was assessed with (1) parent ratings on the Behavior Rating Inventory of Executive Function - Preschool version and (2) a performance-based battery of tasks. Adaptive function was assessed with the Vineland Adaptive Behavior Scales-II. RESULTS: Preterm preschoolers showed significantly more sensory symptoms than full term controls. A higher percentage of preterm than full term preschoolers had elevated numbers of sensory symptoms (37% vs. 12%). Sensory symptoms in preterm preschoolers were associated with scores on executive function measures, but were not significantly associated with adaptive function. CONCLUSIONS: Preterm preschoolers exhibited more sensory symptoms than full term controls. Preterm preschoolers with elevated numbers of sensory symptoms also showed executive function impairment. Future research should further examine whether sensory processing and executive function should be considered independent or overlapping constructs. PMID- 25706318 TI - Prematurely born infants' response to resuscitation via an endotracheal tube or a face mask. AB - BACKGROUND: Prematurely born infants may be resuscitated in the labour suite via a face mask or an endotracheal tube. AIMS: To assess prematurely born infants' initial responses to resuscitation delivered via an endotracheal tube or a face mask, to determine if the first five inflations via an endotracheal tube produced expired tidal volumes greater than 4.4ml/kg (twice the anatomical dead space) and whether the outcome of initial resuscitation via an endotracheal tube or via a face mask differed according to the first active inflation (the infant's inspiratory effort coinciding with an inflation). STUDY DESIGN: Prospective observational study. SUBJECTS: Thirty-five infants (median gestational age 25, range 23-27weeks) requiring resuscitation via an endotracheal tube (n=20) or a face mask (n=15) were studied. OUTCOME MEASURES: Inflation pressures, inflation times, expiratory tidal volumes, end tidal carbon dioxide (ETCO2) and leak were recorded. RESULTS: Before the first active inflation, only 27% of infants receiving resuscitation via an endotracheal tube had expiratory volumes greater than 4.4ml/kg. During, both endotracheal and face mask initial resuscitations, during the first active inflation the expired tidal volumes (7.7ml/kg, 5.2ml/kg) and ETCO2 levels (4.8kPa, 3.2kPa) were significantly higher than during the inflations before the first active inflation (2.8ml/kg, 1.6ml/kg; 0.36kPa, 0.2kPa respectively) (all p<0.001). CONCLUSIONS: Initial resuscitation via an endotracheal tube using currently recommended pressures, rarely produced adequate tidal volumes. Resuscitation via an endotracheal tube or a face mask was most effective when the infant's inspiratory effort coincided with an inflation. PMID- 25706319 TI - Early second trimester transvaginal ultrasound anomaly scan does not cause adverse perinatal outcome. AB - OBJECTIVE: During an early second-trimester transvaginal ultrasound anomaly scan, pressure is applied to the uterus, and the fetus is often rotated manually to allow scanning of its various organs. This study was designed to determine if performing a transvaginal ultrasound anomaly scan during the early second trimester of pregnancy is associated with adverse perinatal outcome or cord entanglement. METHODS: During the 4.5year study period we prospectively collected cases of routine ultrasound scans at 14-17weeks gestation performed as anomaly screening, together with perinatal outcome. The study population consisted of 164 women who underwent a transvaginal approach, and the control population consisted of 224 women in which a transabdominal approach was used. Data on perinatal parameters was collected from delivery charts from the four local hospitals. RESULTS: There were more operative deliveries (vaginal or Cesarean) in the transvaginal scan group (32% vs. 23%, p=0.05). However, on multiple logistic regression analysis vaginal scans were not associated with increased operative delivery rates with an adjusted odds ratio of 1.47 and a 95% confidence interval of 0.85-2.54. There were no other clinically significant differences in perinatal outcomes, or in cord entanglement. CONCLUSIONS: Transvaginal ultrasound anomaly scan conducted in the early second trimester of pregnancy is a safe procedure for the fetus. PMID- 25706320 TI - Synthesis, antioxidant and anticholinesterase activities of novel coumarylthiazole derivatives. AB - A newly series of coumarylthiazole derivatives containing aryl urea/thiourea groups were synthesized and their inhibitory effects on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) were evaluated. The result showed that all the synthesized compounds exhibited inhibitory activity to both cholinesterases. Among them, 1-(4-(8-methoxy-2-oxo-2H-chromen-3-yl)thiazol-2-yl) 3-(4-chlorophenyl)thiourea (f8, IC50 = 4.58 MUM) was found to be the most active compound against AChE, and 1-(4-fluorophenyl)-3-(4-(6-nitro-2-oxo-2H-chromen-3 yl)thiazol-2-yl)urea (e31) exhibited the strongest inhibition against BuChE with IC50 value of 4.93 MUM, which was 3.5-fold more potent than that of galantamine. The selectivity of f8 and e31 were 2.64 and 0.04, respectively. In addition, the cupric reducing antioxidant capacities (CUPRAC) and ABTS cation radical scavenging abilities of the synthesized compounds were investigated for antioxidant activity. Among them, f8, f4 and f6 (IC50=1.64, 1.82 and 2.69 MUM, respectively) showed significantly better ABTS cation radical scavenging ability than standard quercetin (IC50 = 15.49 MUM). PMID- 25706321 TI - Design, synthesis and anticancer activity of diam(m)ine platinum(II) complexes bearing a small-molecular cell apoptosis inducer dichloroacetate. AB - Four new diam(m)ine platinum complexes containing the dichloroacetate moiety in 3 dichoroacetoxylcyclobutane-1,1-dicarboxylate as the leaving group were synthesized, characterized by elemental analysis as well as by ESI(+)-MS (electrospray ionization mass spectrometry in positive mode), FT-IR, (1)H- and (13)C-NMR, and evaluated for their in vitro anticancer activity against human lung cancer cell line (A549) and ovarian cancer cell lines (SK-OV-3, SK-OV 3/DDP). Diam(m)ines used in the present study belong to the carriers of six clinically approved platinum drugs. Among the complexes synthesized, complex 2, cis-[Pt(II)(1R,2R-diaminocyclohexane).(3-dichoroacetoxylcyclobutane-1,1 dicarboxylate)] is the most promising in terms of water solubility and potential of being totally devoid of cross-drug resistance with cisplatin. Therefore, complex 2 was selected for the dichloroacetate release test. The test shows dichloroacetate can be efficiently released from complex 2 under physiological conditions via the hydrolysis of an ester bond bridging the dichloroacetate moiety and platinum pharmacophores together. Our study supports the further evaluation of this complex as a drug candidate. PMID- 25706322 TI - (Aminophosphane)gold(I) and silver(I) complexes as antibacterial agents. AB - This manuscript describes the synthesis of new Au(I) and Ag(I) complexes with aminophosphane ligands and a study of their antibacterial activity against Gram negative Salmonella enterica serovar typhimurium and Escherichia coli and Gram positive Listeria monocytogenes and Staphylococcus aureus. The bactericidal assays revealed the effectiveness of these compounds on paradigm Gram-negative and Gram-positive pathogens, showing a moderate antimicrobial activity, comparable with the antibiotics of reference, for all gold(I) complexes and the silver(I) complexes without coordinated PPh3 groups. For those complexes that were found to show inhibitory activity, serial dilutions in liquid broth method were performed for determination of MIC (minimum inhibitory concentration) and MBC (minimum bactericidal concentration). PMID- 25706323 TI - Neighborhood socioeconomic context and change in allostatic load among older Puerto Ricans: The Boston Puerto Rican health study. AB - Neighborhood context may influence health and health disparities. However, most studies have been constrained by cross-sectional designs that limit causal inference due to failing to establish temporal order of exposure and disease. We tested the impact of baseline neighborhood context (neighborhood socioeconomic status factor at the block-group level, and relative income of individuals compared to their neighbors) on allostatic load two years later. We leveraged data from the Boston Puerto Rican Health Study, a prospective cohort of aging Puerto Rican adults (aged 45-75 at baseline), with change in AL modeled between baseline and the 2nd wave of follow-up using two-level hierarchical linear regression models. Puerto Rican adults with higher income, relative to their neighbors, exhibited lower AL after two years, after adjusting for NSES, age, gender, individual-level SES, length of residence, and city. After additional control for baseline AL, this association was attenuated to marginal significance. We found no significant association of NSES with AL. Longitudinal designs are an important tool to understand how neighborhood contexts influence health and health disparities. PMID- 25706324 TI - Solvent determines nature of effective interactions between nanoparticles in polymer brushes. AB - We study the effective interaction between two parallel rod-like nanoparticles in swollen and collapsed polymer brushes as a function of penetration depth by 2D self-consistent field calculations. In vertical direction, the interaction is always attractive. In lateral direction, the behavior under good and poor solvent conditions is qualitatively different. In swollen brushes (good solvent), nanoparticles always repel each other. In collapsed brushes (poor solvent), we identify two different regimes: an immersed regime, where the nanoparticles are fully surrounded by the brush, and an interfacial regime, where they are located in the interface between brush and solvent. In the immersed regime, the lateral interactions are repulsive, in agreement with previous theoretical predictions. In the interfacial regime, they are governed by the deformations of the interface and tend to be attractive. This implies that the nature of nanoparticle interactions can be manipulated by changing the solvent condition. The influence of particle size and grafting density are also briefly discussed. PMID- 25706325 TI - Copolymerization with 2,4,6-triaminopyrimidine for the rolling-up the layer structure, tunable electronic properties, and photocatalysis of g-C3N4. AB - Copolymerization with 2,4,6-triaminopyrimidine (TAP) is developed for precise substitution of one nitrogen with carbon atom in the triazine ring of polymeric g C3N4. Direct incorporation of C4N2 ring from TAP into the network retains the structural features of g-C3N4, but induces the rolling-up of g-C3N4 sheets into tubular configuration. The band gap energy is narrowed from 2.7 to 2.4 eV by a negative shift of valence band of the g-C3N4 photocatalyst, which enhances charge carrier migration and separation, leading to higher photocatalytic activity for NO gas pollutant removal. It is attributed to the decrease of the pi-deficiency and the generation of imbalanced electron density in pi-electron conjugated units of g-C3N4 by TAP incorporation. This work provides a significant technique for precise control of heteroatom in the framework of g-C3N4 to finely adjust its intrinsic electronic properties and its photocatalytic properties. PMID- 25706327 TI - Prognostic factors in pediatric pulmonary arterial hypertension: A systematic review and meta-analysis. AB - BACKGROUND: Despite the introduction of targeted therapies in pediatric pulmonary arterial hypertension (PAH), prognosis remains poor. For the definition of treatment strategies and guidelines, there is a high need for an evidence-based recapitulation of prognostic factors. The aim of this study was to identify and evaluate prognostic factors in pediatric PAH by a systematic review of the literature and to summarize the prognostic value of currently reported prognostic factors using meta-analysis. METHODS AND RESULTS: Medline, EMBASE and Cochrane Library were searched on April 1st 2014 to identify original studies that described predictors of mortality or lung-transplantation exclusively in children with PAH. 1053 citations were identified, of which 25 were included for further analysis. Hazard ratios (HR) and 95% confidence intervals were extracted from the papers. For variables studied in at least three non-overlapping cohorts, a combined HR was calculated using random-effects meta-analysis. WHO functional class (WHO-FC, HR 2.7), (N-terminal pro-) brain natriuretic peptide ([NT-pro]BNP, HR 3.2), mean right atrial pressure (mRAP, HR 1.1), cardiac index (HR 0.7), indexed pulmonary vascular resistance (PVRi, HR 1.3) and acute vasodilator response (HR 0.3) were identified as significant prognostic factors (p <= 0.001). CONCLUSIONS: This systematic review combined with separate meta-analyses shows that WHO-FC, (NT-pro)BNP, mRAP, PVRi, cardiac index and acute vasodilator response are consistently reported prognostic factors for outcome in pediatric PAH. These variables are useful clinical tools to assess prognosis and should be incorporated in treatment strategies and guidelines for children with PAH. PMID- 25706326 TI - Identification of microRNA-mRNA dysregulations in paroxysmal atrial fibrillation. AB - BACKGROUND: The molecular mechanisms underlying the early development of atrial fibrillation (AF) remain poorly understood. Emerging evidence suggests that abnormal epigenetic modulation via microRNAs (miRNAs) might be involved in the pathogenesis of paroxysmal AF (pAF). OBJECTIVE: To identify key molecular changes associated with pAF, we conducted state-of-the-art transcriptomic studies to identify the abnormal miRNA-mRNA interactions potentially driving AF development. METHODS: High-quality total RNA including miRNA was isolated from atrial biopsies of age-matched and sex-matched pAF patients and control patients in sinus rhythm (SR; n=4 per group) and used for RNA-sequencing and miRNA microarray. Results were analyzed bioinformatically and validated using quantitative real-time (qRT) PCR and 3'UTR luciferase reporter assays. RESULTS: 113 genes and 49 miRNAs were differentially expressed (DE) in pAF versus SR patients. Gene ontology analysis revealed that most of the DE genes were involved in the "gonadotropin releasing hormone receptor pathway" and "p53 pathway". Of these DE genes, bioinformatic analyses identified 23 pairs of putative miRNA-mRNA interactions that were altered in pAF (involving 15 miRNAs and 17 mRNAs). Using qRT-PCR and 3'UTR luciferase reporter assays, the interaction between upregulation of miR-199a-5p and downregulation of FKBP5 was confirmed in samples from pAF patients. CONCLUSION: Our combined transcriptomic analysis and miRNA microarray study of atrial samples from pAF patients revealed novel pathways and miRNA-mRNA regulations that may be relevant in the development of pAF. Future studies are required to investigate the potential involvement of the gonadotropin releasing hormone receptor and p53 pathways in AF pathogenesis. PMID- 25706328 TI - Generating information-rich high-throughput experimental materials genomes using functional clustering via multitree genetic programming and information theory. AB - High-throughput experimental methodologies are capable of synthesizing, screening and characterizing vast arrays of combinatorial material libraries at a very rapid rate. These methodologies strategically employ tiered screening wherein the number of compositions screened decreases as the complexity, and very often the scientific information obtained from a screening experiment, increases. The algorithm used for down-selection of samples from higher throughput screening experiment to a lower throughput screening experiment is vital in achieving information-rich experimental materials genomes. The fundamental science of material discovery lies in the establishment of composition-structure-property relationships, motivating the development of advanced down-selection algorithms which consider the information value of the selected compositions, as opposed to simply selecting the best performing compositions from a high throughput experiment. Identification of property fields (composition regions with distinct composition-property relationships) in high throughput data enables down selection algorithms to employ advanced selection strategies, such as the selection of representative compositions from each field or selection of compositions that span the composition space of the highest performing field. Such strategies would greatly enhance the generation of data-driven discoveries. We introduce an informatics-based clustering of composition-property functional relationships using a combination of information theory and multitree genetic programming concepts for identification of property fields in a composition library. We demonstrate our approach using a complex synthetic composition property map for a 5 at. % step ternary library consisting of four distinct property fields and finally explore the application of this methodology for capturing relationships between composition and catalytic activity for the oxygen evolution reaction for 5429 catalyst compositions in a (Ni-Fe-Co-Ce)Ox library. PMID- 25706329 TI - Giant photoluminescence blinking of perovskite nanocrystals reveals single-trap control of luminescence. AB - Fluorescence super-resolution microscopy showed correlated fluctuations of photoluminescence intensity and spatial localization of individual perovskite (CH3NH3PbI3) nanocrystals of size ~200 * 30 * 30 nm(3). The photoluminescence blinking amplitude caused by a single quencher was a hundred thousand times larger than that of a typical dye molecule at the same excitation power density. The quencher is proposed to be a chemical or structural defect that traps free charges leading to nonradiative recombination. These trapping sites can be activated and deactivated by light. PMID- 25706330 TI - Therapeutic Prospect of Adipose-Derived Stromal Cells for the Treatment of Abdominal Aortic Aneurysm. AB - Aneurysm refers to the dilation of the vessel wall for more than 50%. Abdominal aortic aneurysm (AAA) refers to the dilation and weakening of all three layers of the abdominal aorta, which mostly occur infrarenally. The population aged above 50 years is at risk of AAA development, while a familiar history doubles the risk. Progression of AAA can cause immanent rupture of the vascular wall and has a high mortality and morbidity risk. They are additional risk factors for AAA development such as gender, smoking, and dyslipidemia. In general, pathological features of AAA include inflammation, degradation of the extracellular matrix (ECM), and smooth muscle cell apoptosis. The main pathophysiology of AAA development is still unknown. Besides available treatment modalities for large AAA, which associate with a high mortality risk, effective, alternative, and safer treatments are required, preferably already at an early stage of AAA. For the last decades, tissue engineering and regenerative medicine showed promising potential therapeutic effects for various (cardiovascular) diseases, including AAA. Adipose tissue-derived stromal cells (ADSC) are a candidate source of stem cells for regenerative medicine. ADSC are isolated from adipose tissue with low risk and are easily cultured and expanded while maintaining their multipotency. In addition, due to their differentiation capacity and trophic factor production, ADSC serve an important role in tissue engineering and regenerative medicine modalities. In this review, we will highlight the main pathobiology of AAA and introduce ADSC as a new promising therapeutic source for small AAA. PMID- 25706331 TI - Charge-density distribution and electrostatic flexibility of ZIF-8 based on high resolution X-ray diffraction data and periodic calculations. AB - The electron-density distribution in a prototypical porous coordination polymer ZIF-8 has been obtained in an approach combining high-resolution X-ray diffraction data and Invariom refinement. In addition, the periodic quantum chemical calculation has been used to describe the theoretical density features of ZIF-8 in the same geometry (m1) and also in a "high-pressure" form of ZIF-8 (m2) characterized by conformational change with respect to the methylimidazolate linker. A thorough comparison of the electronic and electrostatic properties in two limiting structural forms of ZIF-8 proposes additional aspects on diffusion and adsorption processes occurring within the framework. The dimensions of the four-membered (FM) and six-membered (SM) apertures of the beta cage are reliably determined from the total electron-density distribution. The analysis shows that FM in m2 becomes competitive in size to the SM aperture and should be considered for the diffusion of small molecules and cations. Bader's topological analysis (quantum theory of atoms in molecules) shows similar properties of both ZIF-8 forms. On the other hand, analysis of their electrostatic properties reveals tremendous differences. The study suggests exceptional electrostatic flexibility of the ZIF-8 framework, where small conformational changes lead to a significantly different electrostatic potential (EP) distribution, a feature that could be important for the function and dynamics of the ZIF-8 framework. The cavity surface in m1 contains 38 distinct regions with moderately positive, negative, or neutral EP and weakly positive EP in the cavity volume. In contrast to m1, the m2 form displays only two regions of different EP, with the positive one taking the whole cavity surface and the strong negative one localized entirely in the FM apertures. The EP in the cavity volume is also more positive than that in m1. A pronounced influence of the linker reorientation on the EP of the ZIF-8 forms is related to the high symmetry of the system and to an amplification of the electrostatic properties by cooperative effects of the proximally arranged structural fragments. PMID- 25706332 TI - Adherence to Buprenorphine Treatment Guidelines in a Medicaid Program. AB - BACKGROUND: Buprenorphine is the most frequently prescribed medication for treating substance use disorders in the United States, but few studies have evaluated the structure of treatment delivered in real-world settings. The purpose of this study is to investigate adherence to current buprenorphine treatment guidelines using administrative data for Massachusetts Medicaid. METHODS: We identified buprenorphine treatment episodes beginning in 2009 through pharmacy claims. We then used service claims to identify treatment-related physician, behavioral, and laboratory services received in the induction, stabilization, and maintenance phases of these treatment episodes. Rates of service utilization were compared with those recommended in treatment guidelines. RESULTS: A total of 3674 treatment episodes met inclusion criteria, representing 3005 unique Medicaid beneficiaries. Liver enzymes were tested in 47.3% of episodes, but testing for hepatitis C (23.2%), hepatitis B (19.6%), and human immunodeficiency virus (HIV; 13.7%) was less frequent. Adherence to recommended physician visit frequency was 37.6% during induction, 39.7% during stabilization, and 51.2% during maintenance. For behavioral care, adherence rates were 40.0% during induction, 41.2% during stabilization, and 41.0% during maintenance. Rates of toxicology testing met or exceeded recommendations in just over 60% of episodes in the induction (61.1%), stabilization (62.1%), and maintenance (61.4%) phases. Although rates varied by treatment phase, substantial proportions of episodes showed no evidence of physician visits (27.2-42.8%), behavioral care (44.3-60.0%), and toxicology screening (25.3-39.0%). CONCLUSIONS: Our data suggest that there is significant variability in the structure of buprenorphine treatment provided to Massachusetts Medicaid beneficiaries, and that half or less of episodes include physician and behavioral visits at recommended frequencies. The use of administrative data for this type of analysis is limited by the potential for missing or inaccurate data. More research is needed to establish the levels of services most closely associated with positive outcomes to help guide providers in offering the highest-quality care. PMID- 25706333 TI - From headache to tumour: An examination of health anxiety, health-related Internet use and 'query escalation'. AB - The current study aimed to explore the phenomenon of disease-related 'query escalation' in high/low health anxious Internet users (N = 40). During a 15 minute health-related Internet search, participants rated their anxiety and the perceived seriousness of information on each page. Post-search interviews determined the reasons for, and effects of, escalating queries to consider serious diseases. Both groups were found to be significantly more anxious after escalating queries. The high group was significantly more likely to escalate queries. Evaluating personal relevance of material was the main reason for escalations and moderated anxiety post-escalation. We conclude that searching for online disease information can increase anxiety, particularly for people worried about their health. PMID- 25706334 TI - Health behavior predictors of medication adherence among low health literacy people living with HIV/AIDS. AB - One particularly vulnerable population for HIV treatment non-adherence is persons with poor health literacy skills. For these individuals, it is important to simplify medication taking as much as possible by integrating medication adherence into other routine health behaviors. This study aims to ascertain the relationship between medication adherence and other health behaviors. Adults living with HIV (N = 422) completed intake measures and 3 months of unannounced pill counts. Endorsement of diet and exercise behaviors at intake predicted higher medication adherence, over and above other known predictors of medication adherence such as HIV symptoms, depression, social support, and stress. These results support integrating strategies for medication management into a constellation of routine health practices. PMID- 25706335 TI - Stimulus control in intermittent and daily smokers. AB - Many adult smokers are intermittent smokers (ITS) who do not smoke daily. Prior analyses have suggested that, compared with daily smokers (DS), ITS smoking was, on average, more linked to particular situations, such as alcohol consumption. However, such particular associations assessed in common across subjects may underestimate stimulus control over smoking, which may vary across persons, due to different conditioning histories. We quantify such idiographic stimulus control using separate multivariable logistic regressions for each subject to estimate how well the subject's smoking could be predicted from a panel of situational characteristics, without requiring that other subjects respond to the same stimuli. Subjects were 212 ITS (smoking 4-27 days/month) and 194 DS (5-30 cigarettes daily). Using ecological momentary assessment, subjects monitored situational antecedents of smoking for 3 weeks, recording each cigarette in an electronic diary. Situational characteristics were assessed in a random subset of smoking occasions (n = 21,539), and contrasted with assessments of nonsmoking occasions (n = 26,930) obtained by beeping subjects at random. ITS showed significantly stronger stimulus control than DS across all context domains: mood, location, activity, social setting, consumption, smoking context, and time of day. Mood and smoking context showed the strongest influence on ITS smoking; food and alcohol consumption had the least influence. ITS smoking was under very strong stimulus control; significantly more so than DS, but DS smoking also showed considerable stimulus control. Stimulus control may be an important influence on maintaining smoking and making quitting difficult for all smokers, but especially among ITS. PMID- 25706336 TI - A novel semiautomatic technique for volumetric assessment of the alveolar bone defect using cone beam computed tomography. AB - OBJECTIVE: The aims of this study were (1) to determine the three-dimensional anatomical boundaries of the alveolar bone defect in cleft lip and palate (CLP) patients, (2) to precisely translate these anatomical boundaries into reliable cephalometric landmarks and planes that can be used for cone beam computed tomography (CBCT) analysis, (3) to standardize image acquisition and reconstruction parameters, and (4) to test the reproducibility of the proposed protocol for measuring the predefined alveolar bone defect, using a third-party software. METHODS: The alveolar bone defect volume of 10 randomly selected patients with unilateral CLP (UCLP) aged 8 years and 6 months to 11 years and 2 months was evaluated on preoperative and 1-year postoperative CBCT scans using a semiautomatic, standardized protocol. The alveolar bone graft outcome was calculated as a percentage of the bone fill using the formula (VOLpre - VOLpost)/VOLpre) * 100. Intra- and interobserver reliability was assessed. RESULTS: Intra- and interobserver reproducibility was excellent for volumes and bone fill as no statistically significant difference (P < .001) was seen between the different sets of measurements, and Pearson correlation coefficients were large (intraobserver: r > .9849, interobserver: r > .8784). The Bland-Altman plots indicated that the differences between the plots were not patterned. CONCLUSIONS: Volume determination using CBCT, third-party medical image processing software, and the presently defined image acquisition and reconstruction parameters, including anatomical boundaries, is a reproducible and practical method for assessing the volumetric outcome of secondary alveolar bone grafting in patients with UCLP. PMID- 25706337 TI - Firearm-related hospitalization and risk for subsequent violent injury, death, or crime perpetration: a cohort study. AB - BACKGROUND: Risk for violent victimization or crime perpetration after firearm related hospitalization (FRH) must be determined to inform the need for future interventions. OBJECTIVE: To compare the risk for subsequent violent injury, death, or crime perpetration among patients with an FRH, those hospitalized for noninjury reasons, and the general population. DESIGN: Retrospective cohort study. SETTING: All hospitals in Washington. PATIENTS: Patients with an FRH and a random sample of those with a non-injury-related hospitalization in 2006 to 2007 (index hospitalization). MEASUREMENTS: Primary outcomes included subsequent FRH, firearm-related death, and the combined outcome of firearm- or violence-related arrest ascertained through 2011. RESULTS: Among patients with an index FRH (n = 613), rates of subsequent FRH, firearm-related death, and firearm- or violence related arrest were 329 (95% CI, 142 to 649), 100 (CI, 21 to 293), and 4221 (CI, 3352 to 5246) per 100 000 person-years, respectively. Compared with the general population, standardized incidence ratios among patients with an index FRH were 30.1 (CI, 14.9 to 61.0) for a subsequent FRH and 7.3 (CI, 2.4 to 22.9) for firearm-related death. In survival analyses that accounted for competing risks, patients with an index FRH were at greater risk for subsequent FRH (subhazard ratio [sHR], 21.2 [CI, 7.0 to 64.0]), firearm-related death (sHR, 4.3 [CI, 1.3 to 14.1]), and firearm- or violence-related arrest (sHR, 2.7 [CI, 2.0 to 3.5]) than those with a non-injury-related index hospitalization. LIMITATION: Lack of information on whether patients continued to reside in Washington during follow up may have introduced outcome misclassification. CONCLUSION: Hospitalization for a firearm-related injury is associated with a heightened risk for subsequent violent victimization or crime perpetration. Further research at the intersection of clinical care, the criminal justice system, and public health to evaluate the effectiveness of interventions delivered to survivors of firearm-related injury is warranted. PRIMARY FUNDING SOURCE: Seattle City Council and University of Washington Royalty Research Fund. PMID- 25706338 TI - Dual agonist occupancy of AT1-R-alpha2C-AR heterodimers results in atypical Gs PKA signaling. AB - Hypersecretion of norepinephrine (NE) and angiotensin II (AngII) is a hallmark of major prevalent cardiovascular diseases that contribute to cardiac pathophysiology and morbidity. Herein, we explore whether heterodimerization of presynaptic AngII AT1 receptor (AT1-R) and NE alpha2C-adrenergic receptor (alpha2C-AR) could underlie their functional cross-talk to control NE secretion. Multiple bioluminescence resonance energy transfer and protein complementation assays allowed us to accurately probe the structures and functions of the alpha2C AR-AT1-R dimer promoted by ligand binding to individual protomers. We found that dual agonist occupancy resulted in a conformation of the heterodimer different from that induced by active individual protomers and triggered atypical Gs-cAMP PKA signaling. This specific pharmacological signaling unit was identified in vivo to promote not only NE hypersecretion in sympathetic neurons but also sympathetic hyperactivity in mice. Thus, we uncovered a new process by which GPCR heterodimerization creates an original functional pharmacological entity and that could constitute a promising new target in cardiovascular therapeutics. PMID- 25706339 TI - Mechanism of photoprotection in the cyanobacterial ancestor of plant antenna proteins. AB - Plants collect light for photosynthesis using light-harvesting complexes (LHCs) an array of chlorophyll proteins that are able to reversibly switch from harvesting to energy-dissipation mode to prevent damage of the photosynthetic apparatus. LHC antennae as well as other members of the LHC superfamily evolved from cyanobacterial ancestors called high light-inducible proteins (Hlips). Here, we characterized a purified Hlip family member HliD isolated from the cyanobacterium Synechocystis sp. PCC 6803. We found that the HliD binds chlorophyll-a (Chl-a) and beta-carotene and exhibits an energy-dissipative conformation. Using femtosecond spectroscopy, we demonstrated that the energy dissipation is achieved via direct energy transfer from a Chl-a Qy state to the beta-carotene S1 state. We did not detect any cation of beta-carotene that would accompany Chl-a quenching. These results provide proof of principle that this quenching mechanism operates in the LHC superfamily and also shed light on the photoprotective role of Hlips and the evolution of LHC antennae. PMID- 25706340 TI - Collaborative centralized reminder/recall notification to increase immunization rates among young children: a comparative effectiveness trial. AB - IMPORTANCE: Reminder/recall notifications used by primary care practices increase the rates of childhood immunizations, but fewer than 20% of primary care practitioners nationally deliver such reminders. A reminder/recall notification conducted centrally by health departments in collaboration with primary care practices may reduce practice burden, reach children without a primary care practitioner, and decrease the cost of reminders/recalls. OBJECTIVE: To assess the effectiveness and cost-effectiveness of collaborative centralized (CC) vs practice-based (PB) reminder/recall approaches using the Colorado Immunization Information System (CIIS). DESIGN, SETTING, AND PARTICIPANTS: We performed a randomized pragmatic trial from September 7, 2012, through March 17, 2013, including 18,235 children aged 19 to 35 months in 15 Colorado counties. INTERVENTIONS: In CC counties, children who needed at least 1 immunization were sent as many as 4 reminders/recalls by mail or autodialed telephone calls by the CIIS. Primary care practices in these counties were given the option of endorsing the reminder/recall notification by adding the practice name to the message. In PB counties, primary care practices were invited to web-based reminder/recall training and offered financial support for sending notifications. MAIN OUTCOMES AND MEASURES: Documentation of any new immunization within 6 months constituted the primary outcome; achieving up-to-date (UTD) immunization status was secondary. We assessed the cost and cost-effectiveness of each approach and used a generalized linear mixed-effects model to assess the effect of the intervention on outcomes. RESULTS: In PB counties, 24 of 308 primary care practices (7.8%) attended reminder/recall training and 2 primary care practices (0.6%) endorsed reminder/recall notifications. Within CC counties, 129 of 229 practices (56.3%) endorsed the reminder/recall letter. Documentation rates for at least 1 immunization were 26.9% for CC vs 21.7% for PB counties (P < .001); 12.8% vs 9.3% of patients, respectively, achieved UTD status (P < .001). The effect of CC counties on children's UTD status was greater when the reminder/recall notification was endorsed by the primary care practice (19.2% vs 9.8%; P < .001). The total cost of the CC reminder/recall was $28 620 or $11.75 per child for any new immunization and $24.72 per child achieving UTD status; the total cost to the 2 practices that conducted PB reminders/recalls was $74.00 per child for any immunization and $124.45 per child achieving UTD status. The modeling resulted in an adjusted odds ratio of 1.31 (95% CI, 1.16-1.48) for any new immunization in CC vs PB counties. CONCLUSIONS AND RELEVANCE: A CC reminder/recall notification was more effective and more cost-effective than a PB system, although the effect size was modest. Endorsement by practices may further increase the effectiveness of CC reminder/recall. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01557621. PMID- 25706341 TI - SMAD signaling and redox imbalance cooperate to induce prostate cancer cell dormancy. AB - Metastasis involves the dissemination of single or small clumps of cancer cells through blood or lymphatic vessels and their extravasation into distant organs. Despite the strong regulation of metastases development by a cell dormancy phenomenon, the dormant state of cancer cells remains poorly characterized due to the difficulty of in vivo studies. We have recently shown in vitro that clonogenicity of prostate cancer cells is regulated by a dormancy phenomenon that is strongly induced when cells are cultured both at low cell density and in a slightly hypertonic medium. Here, we characterized by RT-qPCR a genetic expression signature of this dormant state which combines the presence of both stemness and differentiation markers. We showed that both TFGbeta/BMP signaling and redox imbalance are required for the full induction of this dormancy signature and cell quiescence. Moreover, reconstruction experiments showed that TFGbeta/BMP signaling and redox imbalance are sufficient to generate a pattern of genetic expression displaying all characteristic features of the dormancy signature. Finally, we observed that low cell density was sufficient to activate TGFbeta/BMP signaling and to generate a slight redox imbalance thus priming cells for dormancy that can be attained with a co-stimulus like hypertonicity, most likely through an increased redox imbalance. The identification of a dual regulation of dormancy provides a framework for the interpretation of previous reports showing a restricted ability of BMP signaling to regulate cancer cell dormancy in vivo and draws attention on the role of oxidative stress in the metastatic process. PMID- 25706342 TI - MUTYH, an adenine DNA glycosylase, mediates p53 tumor suppression via PARP dependent cell death. PMID- 25706343 TI - Associations between skill perceptions and young children's actual fundamental movement skills. AB - Given that children with low movement skill competence engage in less physical activity, it is important to understand how children's perceptions relate to actual movement competence. This study examined relationships between (i) children's self-perception and objective assessments of their movement skills (object control and locomotor) and (ii) parents' perceptions of the children's movement skills and objective assessment. Children's skill perceptions were assessed using the Pictorial Scale of Perceived Movement Skill Competence for Young Children. Parent perceptions of their child's skills were assessed using a modified version of this instrument. The Test of Gross Motor Development-2nd edition assessed children's skills objectively. Participants were 136 Australian children (51% boys; M=6.5 yr., SD=1.1) and 133 parents. Regression analyses (by sex) examined the relationship between perceptions and children's scores for actual skilled performance. Boys' perceptions were associated with their actual object control ability. Parents accurately perceived boys' object control ability and girls' locomotor ability, but not the reverse. This suggests interventions aiming to improve children's movement skills could target parents and be designed to teach parents how to recognize good and poor skill performance in their children. PMID- 25706344 TI - The role of research-article writing motivation and self-regulatory strategies in explaining research-article abstract writing ability. AB - The purpose of the study was to investigate the effects of research-article writing motivation and use of self-regulatory writing strategies in explaining second language (L2) research-article abstract writing ability, alongside the L2 literacy effect. Four measures were administered: a L2 literacy test, a research abstract performance assessment, and inventories of writing motivation and strategy. Participants were L2 graduate students in Taiwan (N=185; M age=25.8 yr., SD=4.5, range=22-53). Results of structural equation modeling showed a direct effect of motivation on research-article writing ability, but no direct effect of strategy or indirect effect of motivation via strategy on research article writing ability, with L2 literacy controlled. The findings suggest research-article writing instruction should address writing motivation, besides L2 literacy. PMID- 25706345 TI - The role of chunking in drawing Rey complex figure. AB - The study investigated the effects of chunking and perceptual patterns that guide the drawings of Rey complex figure. Ten adult participants (M age=22.2 yr., SD=4.1) reproduced a single stimulus in four drawing modes including delayed recall, tracing, copying, and immediate recall across 10 sessions producing a total of 400 trials. It was hypothesized that the effect of chunking is most obvious in the free recall tasks than in the tracing or copying tasks. Measures such as pauses, patterns of drawings, and transitions among patterns of drawings suggested that participants used chunking to aid rapid learning of the diagram. The analysis of the participants' sequence of chunk production further revealed that they used a spatial schema to organize the chunks. Findings from this study provide additional evidence to support prior studies that claim graphical information is hierarchically organized. PMID- 25706346 TI - Probing the coordinative unsaturation and local environment of Ti3+ sites in an activated high-yield Ziegler-Natta catalyst. AB - The typical activation of a fourth generation Ziegler-Natta catalyst TiCl4/MgCl2/phthalate with triethyl aluminum generates Ti(3+) centers that are investigated by multi-frequency continuous wave and pulse EPR methods. Two families of isolated, molecule-like Ti(3+) species have been identified. A comparison of the experimentally derived g tensors and (35,37)Cl hyperfine and nuclear-quadrupole tensors with DFT-computed values suggests that the dominant EPR-active Ti(3+) species is located on MgCl2(110) surfaces (or equivalent MgCl2 terminations with tetra-coordinated Mg). O2 reactivity tests show that a fraction of these Ti sites is chemically accessible, an important result in view of the search for the true catalyst active site in olefin polymerization. PMID- 25706347 TI - Applanatumin A, a new dimeric meroterpenoid from Ganoderma applanatum that displays potent antifibrotic activity. AB - Applanatumin A (1), a novel meroterpenoid dimer, was isolated from the fungus Ganoderma applanatum. Its structure and absolute configuration were assigned on the basis of spectroscopic and computational data. Notably, 1 possesses a new hexacyclic skeleton containing a spiro[benzofuran-2,1'-cyclopentane] motif. A plausible pathway, involving a key Diels-Alder reaction, is proposed for the biosynthesis of 1. Applanatumin A exhibits potent antifibrotic activity in TGF beta1-induced human renal proximal tubular cells. PMID- 25706348 TI - Evaluating fine motor coordination in children who are not ready for handwriting: which test should we take? AB - When children are not ready to write, assessment of fine motor coordination may be indicated. The purpose of this study was to evaluate which fine motor test, the Nine-Hole Peg Test (9-HPT) or the newly developed Timed Test of In-Hand Manipulation (Timed-TIHM), correlates best with handwriting readiness as measured by the Writing Readiness Inventory Tool In Context-Task Performance (WRITIC-TP). From the 119 participating children, 43 were poor performers. Convergent validity of the 9-HPT and Timed-TIHM with WRITIC-TP was determined, and test-retest reliability of the Timed-TIHM was examined in 59 children. The results showed that correlations of the 9-HPT and Timed-TIHM with the WRITIC-TP were similar (rs = -0.40). The 9-HPT and the complex rotation subtask of the Timed-TIHM had a low correlation with the WRITIC-TP in poor performers (rs = -0.30 and -0.32 respectively). Test-retest reliability of the Timed-TIHM was significant (Intraclass Correlation Coefficient = 0.71). Neither of these two fine motor tests is appeared superior. They both relate to different aspects of fine motor performance. One of the limitations of the methodology was unequal numbers of children in subgroups. It is recommended that further research is indicated to evaluate the relation between development of fine motor coordination and handwriting proficiency, on the Timed-TIHM in different age groups. PMID- 25706349 TI - Gold nanorods and curcumin-loaded nanomicelles for efficient in vivo photothermal therapy of Barrett's esophagus. AB - AIM: Provide an enhanced local drug delivery, nanoparticle(s) to minimize systemic effects and achieve enhanced permeability and drug retention into abnormal cells and stroma. MATERIALS & METHODS: Here a simultaneous loading of lipophilic gold nanorods (GNRs) and curcumin into polymeric nanomicelles made of biocompatible PLGA-b-PEG copolymer through a double re-emulsification process has been developed. RESULTS: Initial results in vitro on Barrett's esophagus and esophageal adenocarcinoma cell lines demonstrated a significant reduction in cell viability with curcumin and GNRs exposure (p < 0.05). In vivo Barrett's associated animal model confirmed these results with successful in vivo demonstrated eradication of all high-grade dysplastic premalignant cancer cells. CONCLUSION: The synthesis of this novel nanosystem containing GNRs and curcumin is safe and effective in treating and eradicating premalignant esophageal adenocarcinoma. PMID- 25706350 TI - Characteristics of Youth Food Preparation in Low-Income, African American Homes: Associations with Healthy Eating Index Scores. AB - This study explores food preparation behaviors, including types of food prepared, methods of preparation, and frequency of preparation of low-income urban African American youth ages 9-15 in Baltimore City (n = 289) and analyzes a potential association to diet quality as measured through Healthy Eating Index 2010 (HEI) scores. Overall, the youth prepared their own food 6.7 +/- 0.33 times per week without significant differences between age groups or genders as measured through pairwise comparison of means. Cereal, noodles, and sandwiches were amongst the foods prepared most frequently. Linear regression analysis found youth food preparation frequency was not significantly associated with total HEI (p = 0.59), sodium (p = 0.58), empty calories (p = 0.96), or dairy scores (p = 0.12). Younger age was associated with higher total HEI scores (p = 0.012) and higher dairy scores (p = 0.01) and female gender was associated with higher total HEI scores (p = 0.03), higher sodium scores (p = 0.03), and lower dairy scores (p = 0.008). PMID- 25706352 TI - Who Seeks Help Online for Self-Injury? AB - The objective of this study was to identify differences between young people who seek help online for self-injury and those who self-injure but do not seek help online, in order to improve online services for young people at high risk of suicide. Young people reporting a history of self-injury (N = 679) were identified as part of larger study (N = 1,463) exploring help-seeking. One third of young people with a history of self-injury reported online help-seeking for self-injury. Online help-seekers were significantly more distressed, suicidal, and had a greater degree of self-injury compared to those who did not seek help online. The Internet provides an important form of support to the most at risk young people in this population, and may be a proximal step to face-to-face help seeking. Further research is required to investigate the forms of support currently accessed by young people online, and their effectiveness. PMID- 25706353 TI - Inclusion Complexes Between Polytetrahydrofuran-b-Amylose Block Copolymers and Polytetrahydrofuran Chains. AB - Amylose inclusion complexes are prepared by complexation of synthetic amylose having a covalently attached PTHF block (PTHF-b-amylose) with guest polytetrahydrofuran of molecular weights of 650 and 1000 g . mol(-1) (PTHF650 and PTHF1000). Differential Scanning Calorimetry (DSC) analysis of the products shows a characteristic melting peak of the complexes at 140 degrees C. Compared to PTHF650, the PTHF1000 displays lower complexing ability with PTHF-b-amylose which is indicated by visible amylose retrogradation. The possible structures of the resulting products are estimated from Thermo Gravimetric Analysis (TGA) which reveals differences between PTHF-b-amylose and the corresponding complexes. In addition, X-Ray Diffraction (XRD) analysis demonstrates that the resulting structures of the complexes consist of 6-fold V-amylose helices. The results are confirmed further with Small Angle X-Ray Scattering (SAXS) diffractions which show that formation of inclusion complexes increases the crystalline size and regularity of the complex. There is a strong indication that the covalently attached PTHF block also induces the formation of V-amylose by residing in between the amylose blocks. In this case, the resulting structure of the complex is likely affected by both the complexation between amylose block and the added PTHF and by the in situ self-assembly of the block copolymers. PMID- 25706354 TI - Expression pattern and clinicopathologic significance of NKD1 in human primary hepatocellular carcinoma. AB - It has been reported that NKD1 was an antagonist of the canonical Wnt/beta catenin pathway. While there is little information regarding NKD1 expression pattern in human hepatocellular carcinoma (HCC). The aim of this study was to investigate the clinicopathologic significance and expression pattern of NKD1 in HCC. NKD1 protein expressions in 69 paired HCC cancer/adjacent non-cancerous tissues were detected by Western blot. Immunohistochemical studies were performed on 58 cases of HCC with integrated clinical information. NKD1 protein expression was divided into normal and low expression group and correlations between NKD1 protein expression and clinicopathologic factors were then evaluated. Western blot results showed that NKD1 protein levels were significantly lower in cancerous tissues compared with corresponding normal tissue (p < 0.05). In addition, we found that the level of NKD1 protein expression in HCC was significantly associated with tumor size (p = 0.011), intra or extra-hepatic metastasis (p = 0.010) and differentiation (p = 0.003). This is to our knowledge the first report investigating NKD1 protein expression pattern in HCC. Our data show that decreased NKD1 protein expression is associated with clinicopathologic factors, and suggest that NKD1 may play an important role in the development of HCC and could serve as a novel biomarker for HCC after further investigation. PMID- 25706355 TI - Electronic structure and microscopic charge-transport properties of a new-type diketopyrrolopyrrole-based material. AB - Recently, diketopyrrolopyrrole (DPP)-based materials have attracted much interest due to their promising performance as a subunit in organic field effect transistors. Using density functional theory and charge-transport models, we investigated the electronic structure and microscopic charge transport properties of the cyanated bithiophene-functionalized DPP molecule (compound 1). First, we analyzed in detail the partition of the total relaxation (polaron) energy into the contributions from each vibrational mode and the influence of bond-parameter variations on the local electron-vibration coupling of compound 1, which well explains the effects of different functional groups on internal reorganization energy (lambda). Then, we investigated the structural and electronic properties of compound 1 in its isolated molecular state and in the solid state form, and further simulated the angular resolution anisotropic mobility for both electron- and hole-transport using two different simulation methods: (i) the mobility orientation function proposed in our previous studies (method 1); and (ii) the master equation approach (method 2). The calculated electron-transfer mobility (0.00003-0.784 cm(2) V(-1) s(-1) from method 1 and 0.02-2.26 cm(2) V(-1) s(-1) from method 2) matched reasonably with the experimentally reported value (0.07 0.55 cm(2) V(-1) s(-1) ). To the best of our knowledge, this is the first time that the transport parameters of compound 1 were calculated in the context of band model and hopping models, and both calculation results suggest that the intrinsic hole mobility is higher than the corresponding intrinsic electron mobility. Our calculation results here will be instructive to further explore the potential of other higher DPP-containing quinoidal small molecules. PMID- 25706356 TI - Mutations in PIGL in a patient with Mabry syndrome. AB - Mabry syndrome, hyperphosphatasia mental retardation syndrome (HPMRS), is an autosomal recessive disease characterized by increased serum levels of alkaline phosphatase (ALP), severe developmental delay, intellectual disability, and seizures. Recent studies have revealed mutations in PIGV, PIGW, PIGO, PGAP2, and PGAP3 (genes that encode molecules of the glycosylphosphatidylinositol (GPI) anchor biosynthesis pathway) in patients with HPMRS. We performed whole-exome sequencing of a patient with severe intellectual disability, distinctive facial appearance, fragile nails, and persistent increased serum levels of ALP. The result revealed a compound heterozygote with a 13-bp deletion in exon 1 (c.36_48del) and a two-base deletion in exon 2 (c.254_255del) in phosphatidylinositol glycan anchor, class L (PIGL) that caused frameshifts resulting in premature terminations. The 13-bp deletion was inherited from the father, and the two-base deletion was inherited from the mother. Expressing c.36_48del or c.254_255del cDNA with an HA-tag at the C- or N-terminus in PIGL deficient CHO cells only partially restored the surface expression of GPI anchored proteins (GPI-APs). Nonsynonymous changes or frameshift mutations in PIGL have been identified in patients with CHIME syndrome, a rare autosomal recessive disorder characterized by colobomas, congenital heart defects, early onset migratory ichthyosiform dermatosis, intellectual disability, and ear abnormalities. Our patient did not have colobomas, congenital heart defects, or early onset migratory ichthyosiform dermatosis and hence was diagnosed with HPMRS, and not CHIME syndrome. These results suggest that frameshift mutations that result in premature termination in PIGL cause a phenotype that is consistent with HPMRS. PMID- 25706357 TI - Maintaining the balance: New Zealand secondary school nurses' perceptions of skin infections in young people--a grounded theory. AB - The objective of this study was to explore the perceptions of New Zealand secondary school nurses regarding skin infections in young people aged 14-18 years. A constructivist grounded theory method was adopted. Ten non-structured interviews were conducted with secondary school nurses working in Auckland, New Zealand, between January and July 2013. Interviews were audiotaped, transcribed and analysed using all tenets of grounded theory that included writing memos, theoretical sampling and the constant comparative method. Analysis revealed the core category Maintaining the balance, which is presented as a grounded theory model. It represents the constant state of balancing the school nurse undergoes in trying to counter the risk to the student. The nurse attempts to tip the balance in favour of action, by reducing barriers to healthcare, providing youth friendly, affordable and accessible healthcare, and following up until resolution is achieved. The nurse is aware that failing to monitor until resolution can again tip the fulcrum back to inaction, placing the young person at risk again. It is concluded that nurses are knowledgeable about the risks present in the communities they serve and are innovative in the methods they employ to ensure satisfactory outcomes for young people experiencing skin infections. School nursing is an evolving model for delivering primary healthcare to young people in New Zealand. The grounded theory model 'Maintaining the balance' describes a model of care where nursing services are delivered where young people spend time, and the nurse is immersed in the community. This model of care may be transferable to other healthcare situations. PMID- 25706358 TI - Radiologic aspects of obstetrical imaging. PMID- 25706359 TI - Practice patterns in imaging of the abdomen and pelvis of the pregnant patient: a survey from the 2012 Radiological Society Of North America Annual Meeting controversies session. PMID- 25706360 TI - The role of multimodality imaging after cesarean delivery. AB - There has been a global increase in the rate of cesarean delivery during the last 30 years. As a result, many women of reproductive age now have uterine scars. Well-recognized obstetric and gynecologic consequences include cesarean scar pregnancy, scar dehiscence or rupture, and scar endometriosis. More recently, abnormal menstrual bleeding, pelvic pain, and secondary infertility have been reported as a consequence of cesarean delivery. This article reviews the range of normal imaging findings after cesarean delivery, as well as the imaging manifestations of complications, both acute and chronic. PMID- 25706361 TI - Estimated fetal weight and birth weight associated with isolated single umbilical artery: the University of Utah experience. AB - OBJECTIVE: The objectives this study were to assess the role of third-trimester ultrasound in detection of fetal growth restriction associated with isolated single umbilical artery (SUA) and to correlate sonographic estimated fetal weight (EFW) with birth weight. METHODS: A retrospective cohort study was performed from 2000 to 2009 at a single academic center. In fetuses with isolated SUA, EFW at follow-up, birth weight, gestational age (GA) at birth, and pregnancy outcome were compared with expected values derived from a statewide database. Categorical variables were analyzed with Fisher exact test, and t tests were used to compare distributions of birth outcomes to expected outcomes. RESULTS: Two hundred twenty five of 41,821 pregnancies had isolated SUA. One hundred ninety-one had available imaging and clinical data. Of 172 with third-trimester ultrasound, the mean EFW was 51st percentile; 4.7% were less than the 10th percentile for GA. Low birth weight (defined as <2500 g), preterm birth, and stillbirth were significantly more frequent in the cohort than in the state (17.3% vs 5.15%, 19.9% vs 8.0% and 3.5% vs 0.33%, respectively, P < 0.05). Mean birth weight in the cohort was significantly lower (2963 vs 3306 g, P < 0.001) than that in the state. Even in term births, the mean weight was significantly lower than that in the state (3169 vs 3379 g, P < 0.001). Cohort mean GA at birth was 38.1 versus 38.5 weeks in the state (P < 0.05). CONCLUSIONS: Follow-up growth scans, as performed in this retrospective cohort study, did not reliably predict birth weight. Birth weight was reduced in the cohort even in the subgroup delivered at term. PMID- 25706362 TI - Ultrasound findings in fetal congenital heart block associated with maternal anti Ro/SSA and Anti-La/SSB antibodies. AB - We present the sonographic features of a second-trimester fetus diagnosed with a bradyarrhythmia at 19 weeks' gestation. The mother carried a diagnosis of Sjogren syndrome, including the presence of SSA and SSB antibodies. Ultrasound M-mode and fetal echocardiogram revealed the etiology of the bradycardia to be a complete fetal congenital heart block, likely due to transplacental passage of autoimmune anti-Ro/SSA and anti-La/SSB antibodies. Consequential to the congenital heart block, the fetus developed hydrops fetalis at 21 weeks' gestational age. We discuss the 2 major etiologies of congenital heart block and the implications in subsequent pregnancies. PMID- 25706363 TI - ACR appropriateness Criteria(r) infertility. AB - Appropriate imaging for women undergoing infertility workup depends upon the clinician's suspicion for potential causes of infertility. Transvaginal US is the preferred modality to assess the ovaries for features of polycystic ovary syndrome (PCOS), the leading cause of anovulatory infertility. For women who have a history or clinical suspicion of endometriosis, which affects at least one third of women with infertility, both MRI and pelvic US can provide valuable information. If tubal occlusion is suspected, whether due to endometriosis, previous pelvic inflammatory disease, or other cause, hysterosalpingogram (HSG) is the preferred method of evaluation. To assess for anatomic causes of recurrent pregnancy loss (RPL) such as Mullerian anomalies, synechiae, and leiomyomas, saline infusion sonohysterography, MRI and 3-D US are most appropriate. Up to 10% of women suffering recurrent pregnancy loss have a congenital Mullerian anomaly. When assessment of the pituitary gland is indicated, MRI is the imaging exam of choice.The American College of Radiology Appropriateness Criteria are evidence based guidelines for specific clinical conditions that are reviewed every three years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. PMID- 25706364 TI - Ultrasound and Doppler features of Budd-Chiari syndrome in pediatric population. AB - Budd-Chiari syndrome (BCS) occurs as a result of hepatic venous outflow obstruction. In the pediatric population, the etiologies vary as compared with the adult population. Decompensation can occur faster in this set of patients. Ultrasound and Doppler represent important imaging modalities for diagnosing BCS in children. The imaging features differ depending upon the level of obstruction, acuteness of the condition, and secondary decompensation. Caudate lobe hypertrophy is a salient feature. Obstruction at the level of hepatic veins may be manifested by ostial narrowing, echogenic thrombus, and altered flow patterns in the form of turbulent flow, nonvisualization of the veins, or reversal of flow. Obstruction in the inferior vena cava may present as an echogenic web, membrane, or thrombus with turbulent flow to absent flow within depending upon the degree of luminal compromise. Collateral formation is an important distinctive feature of subacute and chronic BCS. Collaterals that develop may be of intrahepatic or extrahepatic type. Secondary signs of liver failure would be present in late stages. Understanding the clinical presentation and imaging features can help in achieving the correct diagnosis because an early diagnosis of the disease will impact patient management. PMID- 25706365 TI - Sonography of peritoneal lymphomatosis: some new and different findings. AB - OBJECTIVE: The purpose of this study was to assess the sonographic features of lymphoma with peritoneal, omental, and mesenteric involvement. MATERIALS AND METHODS: All records of peritoneal biopsies under the guidance of ultrasound in our institutional database were retrospectively reviewed to find out cases with peritoneal, omental, and mesenteric lymphoma involvement. Sonographic studies of these patients were evaluated for the presence of peritoneal involvement, ascites, omental mass, organomegaly, retroperitoneal lymphadenopathy, and other associated findings. RESULTS: Six cases of omental lymphoma and 3 cases of mesenteric lymphoma were included in the study. All the cases were diffuse large B-cell non-Hodgkin lymphomas. Under high-frequency insonation, the omentum became markedly irregularly thickened when involved by lymphoma, and in 4 cases, "fish scale" appearance was observed, and the fish scale was proved to be normal omental tissue by pathology. Hypoechoic mass or "sandwich" appearance of thickened mesenteric tissue could be observed in mesenteric lymphoma. The amount of ascites in omental lymphoma was much more than that in mesenteric lymphoma, and intensive echogenic particulate was found in ascites in 2 cases of omental lymphoma. Retroperitoneal lymphadenectasis was seen in only 3 cases, and the most common location was para-aortic. CONCLUSIONS: The fish scale sign in the omentum and the sandwich sign of the mesentery might indicate the possibility of peritoneal lymphoma, and ultrasound seems to be the ideal imaging modality to show the thickened omentum and mesentery mass when lymphoma involves peritoneum. PMID- 25706366 TI - Reliability analysis of acoustic radiation force impulse ultrasound imaging with virtual touch tissue quantification: ex vivo ox liver. AB - The effect of scanning angle and region of interest (ROI) depth on shear-wave velocity (SWV) was investigated in this study. Shear-wave velocity of ox liver ex vivo was measured with different approaches. Region of interest was set underneath the liver capsule at depths of 1, 2, 3, 4, and 5 cm. Three groups of measurements were performed at different scanning angles. One group of measurement was conducted with a scanning angle of 0 to 15 degrees from the midline, and the other 2 groups were performed with scanning angles of 15 to 30 degrees and 30 to 45 degrees. The data on SWV from different scan angles and ROI depths were analyzed statistically. Scanning angle and ROI depth were found to be the 2 factors that affect SWV. Interaction was observed between the scan angle and ROI depth. The data at different depths within 0- to 15-degree scanning angles exhibited no significant difference. However, the reliability of SWV decreased with the increase in ROI depth. In the groups of 15 to 30 degrees and 30 to 45 degrees, a significant difference was found between the 2 different measured depths. Scanning angle and ROI depth affected the reliability of SWV measurement. The scanning angle should be confined within 15 degrees from the midline. Therefore, SWV from shallow ROI is more reliable than that at deep ROI. PMID- 25706367 TI - Intercostal artery pseudoaneurysm after ultrasound-guided liver biopsy: a case report and review of the literature. AB - We present a 58-year-old woman with a right intercostal artery pseudoaneurysm after percutaneous ultrasound (US)-guided liver biopsy. The patient presented 6 days after liver biopsy with a painful, pulsatile right-sided chest wall mass at the site of biopsy needle insertion. Intercostal artery pseudoaneurysm was diagnosed with color Doppler US. Successful treatment with percutaneous US-guided injection of thrombin resulted in complete thrombosis and closure of the pseudoaneurysm. Only 12 previous cases of intercostal artery pseudoaneurysm have been reported in the English-language literature, and this is the first reported case resulting from percutaneous liver biopsy. Given how frequently percutaneous liver biopsies are performed, it is important to raise awareness of this potentially serious complication. PMID- 25706368 TI - Atypical thyroid cancers on sonography. AB - The management of thyroid nodules is a common clinical problem. Thyroid nodules are present in up to 50% of the adult population. However, thyroid malignancy is rare, occurring in only 5% to 15% of nodules. Although certain specific patterns on imaging are almost always indicative of benignity, there is considerable overlap between the sonographic appearances of benign and malignant nodules. Radiologists should be wary of applying pattern recognition approaches too liberally as some malignant nodules may exhibit sonographic features more commonly associated with benign nodules such as cystic change, comet-tail artifact, smooth margins, echogenic echotexture, hypoechoic halos, or peripheral calcifications. This article illustrates atypical imaging appearances of thyroid malignancies and reviews recent literature in an attempt to clarify nuances in the diagnosis of malignancy in benign-appearing nodules. PMID- 25706370 TI - A2 Adenosine Receptor-mediated Cardioprotection Against Reperfusion Injury in Rat Hearts Is Associated With Autophagy Downregulation. AB - This study was undertaken to determine and confer the cardioprotective effects of the adenosine A2 receptor (A2AR) and its impact on myocardial autophagy in the setting of reperfusion. We established a rat ischemia model by subjecting rats to 30 minutes of ischemia (I) and 120 minutes of reperfusion (R). The A2AR agonists CGS21680 (A2aAR specific) and BAY60-6583 (A2bAR specific) were administered separately and in combination 5 minutes before reperfusion (postconditioning). No visible improvements in the rats' hemodynamic changes in response to either CGS or BAY were observed compared with untreated control groups (I/R). BAY significantly reduced infarct sizes, whereas CGS did not. Electron microscopy, enzyme-linked immunosorbent assay and TUNEL apoptosis staining results demonstrated that CGS and BAY play cardioprotective roles by maintaining mitochondria structural stability, decreasing serum cardiac troponin I (cTnI) concentrations and decreasing the number of apoptotic cells. CGS21680 and BAY60 6583 slightly increased the expression (vs. I/R group) of Bcl-2 and significantly attenuated the expression of Beclin-1, LC3B, and LAMP-2, as analyzed by Western blot, compared with the I/R alone group. Notably, BAY60-6583 exerts a predominant effect on mitochondria structural stabilization, apoptotic inhibition, and attenuation of LC3B/LAMP-2 expression. No synergistic effects were observed for the 2 agonists. Our data suggest that A2AR-mediated cardioprotection is associated with Beclin-1-induced autophagy downregulation in the setting of reperfusion. A2bAR activation exerts stronger cardioprotective effects against I/R injury compared with A2aAR. PMID- 25706371 TI - Thiazolidin-4-one Derivatives as Central Nervous System Potential Agents. AB - A heterocyclic compound is one which possesses a cyclic structure with at least two different kinds of hetero atoms in the ring. Nitrogen, oxygen, and sulphur are the most common heteroatoms. derivatives are an important class of heterocyclic compounds and play a vital role due to their wide range of biological activities and industrial importance. 4-Thiazolidinones are always being an attraction point for researchers because of its efficiency towards various pharmacological usages. This review is an endeavor to highlight the progress in the central nervous system activity of the 4-thiazolidinone derivatives. PMID- 25706372 TI - Identification of a conserved B-cell epitope on duck hepatitis A type 1 virus VP1 protein. AB - BACKGROUND: The VP1 protein of duck hepatitis A virus (DHAV) is a major structural protein that induces neutralizing antibodies in ducks; however, B-cell epitopes on the VP1 protein of duck hepatitis A genotype 1 virus (DHAV-1) have not been characterized. METHODS AND RESULTS: To characterize B-cell epitopes on VP1, we used the monoclonal antibody (mAb) 2D10 against Escherichia coli expressed VP1 of DHAV-1. In vitro, mAb 2D10 neutralized DHAV-1 virus. By using an array of overlapping 12-mer peptides, we found that mAb 2D10 recognized phages displaying peptides with the consensus motif LPAPTS. Sequence alignment showed that the epitope 173LPAPTS178 is highly conserved among the DHAV-1 genotypes. Moreover, the six amino acid peptide LPAPTS was proven to be the minimal unit of the epitope with maximal binding activity to mAb 2D10. DHAV-1-positive duck serum reacted with the epitope in dot blotting assay, revealing the importance of the six amino acids of the epitope for antibody-epitope binding. Competitive inhibition assays of mAb 2D10 binding to synthetic LPAPTS peptides and truncated VP1 protein fragments, detected by Western blotting, also verify that LPAPTS was the VP1 epitope. CONCLUSIONS AND SIGNIFICANCE: We identified LPAPTS as a VP1 specific linear B-cell epitope recognized by the neutralizing mAb 2D10. Our findings have potential applications in the development of diagnostic techniques and epitope-based marker vaccines against DHAV-1. PMID- 25706373 TI - Effect of crossbreeding with Limousine, Rubia Gallega and Belgium Blue on meat quality and fatty acid profile of Holstein calves. AB - The object of this work was to study the effects of crossbreeding on meat quality and fatty acid profile of Holstein calves. Samples were taken from Longissimus thoracis (LT) muscle of 36 calves of three different groups (Holstein crossed with Rubia Gallega (HF*RG), Holstein crossed with Limousine (HF*LI) and Holstein crossed with Belgian Blue (HF*BB)). Significant differences were observed in carcass weight and killing out percentage (P < 0.001) among, groups reaching the highest values in the HF*BB group (228 kg and 59.4%, respectively), while the cross with Limousine presented the lowest values for carcass weight (191 kg) and the cross with Rubia Gallega showed the lowest killing out percentages (54.9%). Meat from HF*RG animals was redder (a* 13.31) and lightest (L* 39.55) than meat from HF*LI and HF*BB groups. With regard to fatty acid profile, the saturated fatty acids were the most abundant fatty acid, followed by monounsaturated fatty acids (MUFA) and polyunsaturated fatty acids in the three groups. Crossbreeding did not affect the proportion of fatty acid. Finally, live weight, cold carcass weight, killing out, shear force, L* from LT, b*from LT, a* from fat, b* from fat, C14:0, C15:0, C16:0, C18:0, C18:3n-6, MUFA and price-to-sales ratio were the selected variables from discriminant analysis to classify the types of crossbreeding. PMID- 25706375 TI - The art of medicine. PMID- 25706374 TI - Violation of an evolutionarily conserved immunoglobulin diversity gene sequence preference promotes production of dsDNA-specific IgG antibodies. AB - Variability in the developing antibody repertoire is focused on the third complementarity determining region of the H chain (CDR-H3), which lies at the center of the antigen binding site where it often plays a decisive role in antigen binding. The power of VDJ recombination and N nucleotide addition has led to the common conception that the sequence of CDR-H3 is unrestricted in its variability and random in its composition. Under this view, the immune response is solely controlled by somatic positive and negative clonal selection mechanisms that act on individual B cells to promote production of protective antibodies and prevent the production of self-reactive antibodies. This concept of a repertoire of random antigen binding sites is inconsistent with the observation that diversity (DH) gene segment sequence content by reading frame (RF) is evolutionarily conserved, creating biases in the prevalence and distribution of individual amino acids in CDR-H3. For example, arginine, which is often found in the CDR-H3 of dsDNA binding autoantibodies, is under-represented in the commonly used DH RFs rearranged by deletion, but is a frequent component of rarely used inverted RF1 (iRF1), which is rearranged by inversion. To determine the effect of altering this germline bias in DH gene segment sequence on autoantibody production, we generated mice that by genetic manipulation are forced to utilize an iRF1 sequence encoding two arginines. Over a one year period we collected serial serum samples from these unimmunized, specific pathogen-free mice and found that more than one-fifth of them contained elevated levels of dsDNA-binding IgG, but not IgM; whereas mice with a wild type DH sequence did not. Thus, germline bias against the use of arginine enriched DH sequence helps to reduce the likelihood of producing self-reactive antibodies. PMID- 25706378 TI - The incidence of double hypoglossal canal in Japanese: evaluation with multislice computed tomography. AB - BACKGROUND AND PURPOSE: Double hypoglossal canal, namely a hypoglossal canal bridging, is a normal variation of the hypoglossal canal. Racial differences in the prevalence of double hypoglossal canal have been reported. We evaluated the prevalence of double hypoglossal canal in a Japanese population with multidetector computed tomography (MDCT). MATERIALS AND METHODS: We reviewed five hundred and ninety consecutive patients (mean age, 61 years: range, 15-94 years: 254 men, 336 women) who underwent computed tomographic angiography (CTA) of the brain for a variety of CNS abnormalities. Two radiologists achieved consensus on the canal being single or double, and measured the sizes of single canals on CT images. Kappa statistics was used to test the reliability between the 2 investigators. A logistic regression was used to evaluate the prevalence of double hypoglossal canal and the following factors: sex, age, and laterality. Student's t-test was used to evaluate the asymmetry of single hypoglossal canal diameters. Statistical significance was accepted at P < 0.05. RESULTS: Double hypoglossal canal was identified in 16.9% of the patients, and was bilateral in 2.2%. Double hypoglossal canal was significantly more frequent on the left side than right (P = 0.004, odds ratio = 1.79) and in males than females (P = 0.011, odds ratio = 1.67). A larger left or right-sided canal was found in 31.6% and 12.2% of the patients, respectively, following the same side preference as that of double hypoglossal canal. Almost perfect agreement was achieved between the two readers (k = 0.975). CONCLUSIONS: In this Japanese population, the prevalence of a double hypoglossal canal was 16.9%, of which 2.2% were bilateral. Double hypoglossal canal was more frequent in males than females, and on the left side than right. PMID- 25706379 TI - Active site loop conformation regulates promiscuous activity in a lactonase from Geobacillus kaustophilus HTA426. AB - Enzyme promiscuity is a prerequisite for fast divergent evolution of biocatalysts. A phosphotriesterase-like lactonase (PLL) from Geobacillus kaustophilus HTA426 (GkaP) exhibits main lactonase and promiscuous phosphotriesterase activities. To understand its catalytic and evolutionary mechanisms, we investigated a "hot spot" in the active site by saturation mutagenesis as well as X-ray crystallographic analyses. We found that position 99 in the active site was involved in substrate discrimination. One mutant, Y99L, exhibited 11-fold improvement over wild-type in reactivity (kcat/Km) toward the phosphotriesterase substrate ethyl-paraoxon, but showed 15-fold decrease toward the lactonase substrate delta-decanolactone, resulting in a 157-fold inversion of the substrate specificity. Structural analysis of Y99L revealed that the mutation causes a ~6.6 A outward shift of adjacent loop 7, which may cause increased flexibility of the active site and facilitate accommodation and/or catalysis of organophosphate substrate. This study provides for the PLL family an example of how the evolutionary route from promiscuity to specificity can derive from very few mutations, which promotes alteration in the conformational adjustment of the active site loops, in turn draws the capacity of substrate binding and activity. PMID- 25706381 TI - Combined surgical treatment of a pincer nail with chemical matricectomy, median nail incision, and splinting. PMID- 25706380 TI - Monitoring the early signs of cognitive decline in elderly by computer games: an MRI study. AB - BACKGROUND: It is anticipated that current and future preventive therapies will likely be more effective in the early stages of dementia, when everyday functioning is not affected. Accordingly the early identification of people at risk is particularly important. In most cases, when subjects visit an expert and are examined using neuropsychological tests, the disease has already been developed. Contrary to this cognitive games are played by healthy, well functioning elderly people, subjects who should be monitored for early signs. Further advantages of cognitive games are their accessibility and their cost effectiveness. PURPOSE: The aim of the investigation was to show that computer games can help to identify those who are at risk. In order to validate games analysis was completed which measured the correlations between results of the 'Find the Pairs' memory game and the volumes of the temporal brain regions previously found to be good predictors of later cognitive decline. PARTICIPANTS AND METHODS: 34 healthy elderly subjects were enrolled in the study. The volume of the cerebral structures was measured by MRI. Cortical reconstruction and volumetric segmentation were performed by Freesurfer. RESULTS: There was a correlation between the number of attempts and the time required to complete the memory game and the volume of the entorhinal cortex, the temporal pole, and the hippocampus. There was also a correlation between the results of the Paired Associates Learning (PAL) test and the memory game. CONCLUSIONS: The results gathered support the initial hypothesis that healthy elderly subjects achieving lower scores in the memory game have increased level of atrophy in the temporal brain structures and showed a decreased performance in the PAL test. Based on these results it can be concluded that memory games may be useful in early screening for cognitive decline. PMID- 25706382 TI - Assessment of testicular corticosterone biosynthesis in adult male rats. AB - Corticosterone is synthesized in the adrenal glands and is circulated throughout the body to perform regulatory functions in various tissues. The testis is known to synthesize and secrete testosterone and other androgens. We developed an accurate method to measure steroid content using liquid chromatography-mass spectrometry analysis. In the present study, significant levels of the precursor compounds of testosterone and corticosterone synthesis could be detected in rat testis using this method. After adrenalectomy, corticosterone remained in the blood and testicular tissue at approximately 1% of the amount present in the control testis. When the excised testicular tissue was washed and incubated with NADH, NADPH and progesterone, not only testosterone and its precursors but also 11-deoxycorticosterone and corticosterone were produced; the levels of 11 deoxycorticosterone and corticosterone increased with incubation time. The production rate of 11-deoxycorticosterone from progesterone was estimated to be approximately 1/20 that of 17-hydroxyprogesterone, and the corticosterone level was approximately 1/10 that of testosterone. These ratios coincided with those in the testicular tissue of the adrenalectomized rats, indicating that corticosterone was synthesized in the testis and not in the blood. A primary finding of this study was that corticosterone and testosterone were synthesized in a 1/10-20 ratio in the testis. It is concluded that corticosterone, which has various functions, such as the regulation of glycolysis and mediating spermatogenesis, is produced locally in the testis and that this the local production is convenient and functional to respond to local needs. PMID- 25706383 TI - Prediction of poor prognosis in breast cancer patients based on microRNA-21 expression: a meta-analysis. AB - BACKGROUND: MicroRNA-21 (miRNA-21 or miR-21) may act as a prognostic biomarker of cancer. However, the available evidence is controversial. Therefore, the present meta-analysis summarizes this evidence and evaluates the prognostic role of this gene in breast cancer. METHODS: The meta-analysis was conducted by searching the databases of PubMed, EMBASE, Web of Science and Chinese database-China National Knowledge Infrastructure (CNKI). Data were extracted from studies that investigated the association between miR-21 expression and survival outcomes in breast cancer patients. With respect to survival outcomes, the pooled hazard ratios (HRs) of miR-21 were calculated given a 95% confidence interval (CI). RESULTS: Our meta-analysis identified a total of 10 studies involving 1,439 cases. Further investigation demonstrated that a high miR-21 expression can predict poor overall survival (OS) (HR = 2.57, 95% CI: 1.37-4.81, P = 0.003) and shortened disease-free/recurrence-free survival (DFS/RFS) (HR = 1.45, 95% CI: 1.16-1.82, P = 0.001) in breast cancer patients. Moreover, high miR-21 expression was significantly correlated with lowered OS in the Asian group (HR = 5.07, 95% CI: 2.89-8.92, P < 0.001), but not in the Caucasian cohort (HR = 1.44, 95% CI: 0.99-2.10, P = 0.058). Furthermore, odds ratios (ORs) showed that up-regulated miR-21 levels were associated with multiple clinical characteristics. CONCLUSION: Our results indicated that miR-21 can predict unfavorable prognoses in breast cancer patients, especially in Asians. PMID- 25706384 TI - Studies of a murine monoclonal antibody directed against DARC: reappraisal of its specificity. AB - Duffy Antigen Receptor for Chemokines (DARC) plays multiple roles in human health as a blood group antigen, a receptor for chemokines and the only known receptor for Plasmodium vivax merozoites. It is the target of the murine anti-Fy6 monoclonal antibody 2C3 which binds to the first extracellular domain (ECD1), but exact nature of the recognized epitope was a subject of contradictory reports. Here, using a set of complex experiments which include expression of DARC with amino acid substitutions within the Fy6 epitope in E. coli and K562 cells, ELISA, surface plasmon resonance (SPR) and flow cytometry, we have resolved discrepancies between previously published reports and show that the basic epitope recognized by 2C3 antibody is 22FEDVW26, with 22F and 26W being the most important residues. In addition, we demonstrated that 30Y plays an auxiliary role in binding, particularly when the residue is sulfated. The STD-NMR studies performed using 2C3-derived Fab and synthetic peptide corroborated most of these results, and together with the molecular modelling suggested that 25V is not involved in direct interactions with the antibody, but determines folding of the epitope backbone. PMID- 25706385 TI - Interfacial interaction and lateral association of cross-seeding assemblies between hIAPP and rIAPP oligomers. AB - Cross-sequence interactions between different amyloid peptides are important not only for the fundamental understanding of amyloid aggregation and polymorphism mechanisms, but also for probing a potential molecular link between different amyloid diseases. Here, we computationally modeled and simulated a series of hybrid hIAPP (human islet amyloid polypeptide)-rIAPP (rat islet amyloid polypeptide) assemblies and probed their structural stability, lateral association, and interfacial interactions using combined peptide-packing search, molecular dynamics (MD) simulations, and the Monte Carlo sampling method. We then identified a number of stable and highly populated hIAPP-rIAPP assemblies at the lowest energy states, in which hIAPP and rIAPP oligomers were stacked laterally on top of each other to form supramolecular beta-sheet double layers in an antiparallel fashion. These hIAPP-rIAPP assemblies adopted different interfaces formed by C-terminal beta-sheets of hIAPP and rIAPP oligomers (hCCr), N-terminal beta-sheets of hIAPP and rIAPP oligomers (hNNr), and alternative N-terminal/C terminal beta-sheets of hIAPP and rIAPP oligomers (hNCr and hCNr). Different interfaces along with distinct interfacial residue packings provided different driving interfacial forces to laterally associate two beta-sheet layers of hIAPP and rIAPP together for forming polymorphic hIAPP-rIAPP assemblies. Such lateral association between hIAPP and rIAPP not only explained the experimentally observed cross-seeding behavior of hIAPP and rIAPP, but also demonstrated the co existence of polymorphic amyloid cross-seeding species. A cross-seeding mechanism for hIAPP and rIAPP aggregation was proposed on the basis of our simulated models and experimental data. This work provides a better understanding of cross-seeding aggregation and polymorphism mechanisms of amyloidogenesis. PMID- 25706386 TI - SATB1 overexpression regulates the development and progression in bladder cancer through EMT. AB - The global gene regulator Special AT-rich sequence-binding protein-1 (SATB1) has been reported to induce EMT-like changes and be associated with poor clinical outcome in several cancers. This study aims to evaluate whether SATB1 affects the biological behaviors of bladder transitional cell carcinoma (BTCC) and further elucidate if this effect works through an epithelial-mesenchymal transition (EMT) pathway. The expression of SATB1, E-cadherin (epithelial markers), vimentin (mesenchymal markers) in BTCC tissues and adjacent noncancerous tissues, as well as in two cell lines of bladder cancer were investigated. Whether the SATB1 expression is associated with clinicopathological factors or not was statistically analyzed. Cell invasion and migration, cell cycle, cell proliferation and apoptosis were evaluated in SATB1 knockdown and overexpressed cell lines. Our results showed that the expression of SATB1 was remarkably up regulated both in BTCC tissues and in bladder cancer cell lines with high potential of metastasis. The results were also associated with EMT markers and poor prognosis of BTCC patients. Moreover, SATB1 induced EMT processes through downregulation of E-cadherin, upregulation of E-cadherin repressors (Snail, Slug and vimentin). SATB1 also promoted cell cycle progression, cell proliferation, cell invasion and cell migration, but did not alter cell survival. In conclusion, our results suggest that SATB1 plays a crucial role in the progression of bladder cancer by regulating genes controlling EMT processes. Further, it may be a novel therapeutic target for aggressive bladder cancers. PMID- 25706387 TI - Integrin-associated protein promotes neuronal differentiation of neural stem/progenitor cells. AB - Neural stem/progenitor cells (NSPCs) proliferate and differentiate depending on their intrinsic properties and local environment. During the development of the mammalian nervous system, NSPCs generate neurons and glia sequentially. However, little is known about the mechanism that determines the timing of switch from neurogenesis to gliogenesis. In this study, we established a culture system in which the neurogenic potential of NSPCs is decreased in a time-dependent manner, so that short-term-cultured NSPCs differentiate into more neurons compared with long-term-cultured NSPCs. We found that short-term-cultured NSPCs express high levels of integrin-associated protein form 2 (IAP2; so-called CD47) mRNA using differential display analysis. Moreover, IAP2 overexpression in NSPCs induced neuronal differentiation of NSPCs. These findings reveal a novel mechanism by which IAP2 induces neuronal differentiation of NSPCs. PMID- 25706388 TI - Intercropped silviculture systems, a key to achieving soil fungal community management in eucalyptus plantations. AB - Fungi are ubiquitous and important contributors to soil nutrient cycling, playing a vital role in C, N and P turnover, with many fungi having direct beneficial relationships with plants. However, the factors that modulate the soil fungal community are poorly understood. We studied the degree to which the composition of tree species affected the soil fungal community structure and diversity by pyrosequencing the 28S rRNA gene in soil DNA. We were also interested in whether intercropping (mixed plantation of two plant species) could be used to select fungal species. More than 50,000 high quality sequences were analyzed from three treatments: monoculture of Eucalyptus; monoculture of Acacia mangium; and a mixed plantation with both species sampled 2 and 3 years after planting. We found that the plant type had a major effect on the soil fungal community structure, with 75% of the sequences from the Eucalyptus soil belonging to Basidiomycota and 19% to Ascomycota, and the Acacia soil having a sequence distribution of 28% and 62%, respectively. The intercropping of Acacia mangium in a Eucalyptus plantation significantly increased the number of fungal genera and the diversity indices and introduced or increased the frequency of several genera that were not found in the monoculture cultivation samples. Our results suggest that management of soil fungi is possible by manipulating the composition of the plant community, and intercropped systems can be a means to achieve that. PMID- 25706390 TI - Is partial-ALPPS safer than ALPPS? A single-center experience. PMID- 25706389 TI - Granulocyte-macrophage colony stimulatory factor enhances the pro-inflammatory response of interferon-gamma-treated macrophages to Pseudomonas aeruginosa infection. AB - Pseudomonas aeruginosa is an opportunistic pathogen that can cause severe infections at compromised epithelial surfaces, such those found in burns, wounds, and in lungs damaged by mechanical ventilation or recurrent infections, particularly in cystic fibrosis (CF) patients. CF patients have been proposed to have a Th2 and Th17-biased immune response suggesting that the lack of Th1 and/or over exuberant Th17 responses could contribute to the establishment of chronic P. aeruginosa infection and deterioration of lung function. Accordingly, we have observed that interferon (IFN)-gamma production by peripheral blood mononuclear cells from CF patients positively correlated with lung function, particularly in patients chronically infected with P. aeruginosa. In contrast, IL-17A levels tended to correlate negatively with lung function with this trend becoming significant in patients chronically infected with P. aeruginosa. These results are in agreement with IFN-gamma and IL-17A playing protective and detrimental roles, respectively, in CF. In order to explore the protective effect of IFN gamma in CF, the effect of IFN-gamma alone or in combination with granulocyte macrophage colony-stimulating factor (GM-CSF), on the ability of human macrophages to control P. aeruginosa growth, resist the cytotoxicity induced by this bacterium or promote inflammation was investigated. Treatment of macrophages with IFN-gamma, in the presence and absence of GM-CSF, failed to alter bacterial growth or macrophage survival upon P. aeruginosa infection, but changed the inflammatory potential of macrophages. IFN-gamma caused up-regulation of monocyte chemoattractant protein-1 (MCP-1) and TNF-alpha and down-regulation of IL-10 expression by infected macrophages. GM-CSF in combination with IFN-gamma promoted IL-6 production and further reduction of IL-10 synthesis. Comparison of TNF-alpha vs. IL-10 and IL-6 vs. IL-10 ratios revealed the following hierarchy in regard to the pro-inflammatory potential of human macrophages infected with P. aeruginosa: untreated < treated with GM-CSF < treated with IFN-gamma < treated with GM-CSF and IFN-gamma. PMID- 25706391 TI - Influenza A virus infection of intestinal epithelial cells enhances the adhesion ability of Crohn's disease associated Escherichia coli strains. AB - Modifications of intestinal glycoreceptors expression, in particular CEACAM6, typically found in ileal Crohn's disease (CD), favor, among the commensal species of microbiota, the enrichment in Escherichia coli. Removal of protein glycosidic residues by neuraminidase, a sialidase typical of influenza virus, increases adhesion ability of Escherichia coli to Caco-2 intestinal cells. In this study we investigated whether influenza virus infection of human intestinal epithelial cells could influence the adhesiveness of different Escherichia coli strains isolated from CD patients by altering surface glycoreceptors. Influenza virus infection of intestinal cells increased exposure of galactose and mannose residues on the cell surface. In particular, glycoreceptors Thomsen-Friedenreich and CEACAM6 were over-expressed in influenza virus infected cells. In the same experimental conditions, a significant increase in bacterial adhesiveness was observed, independently of their own adhesive ability. The increase was reverted by treatment with anti-TF and anti-CEACAM6 antibodies. Interestingly, influenza virus was able to efficiently replicate in human primary intestinal cells leading to TF exposure. Finally, intestinal infected cells produced high levels of pro inflammatory cytokines compared to control. Overall these data suggest that influenza virus infection, could constitute an additional risk factor in CD patients. PMID- 25706392 TI - Comparison of two quantitative real time PCR assays for Rickettsia detection in patients from Tunisia. AB - BACKGROUND AND OBJECTIVES: Quantitative real time PCR (qPCR) offers rapid diagnosis of rickettsial infections. Thus, successful treatment could be initiated to avoid unfavorable outcome. Our aim was to compare two qPCR assays for Rickettsia detection and to evaluate their contribution in early diagnosis of rickettsial infection in Tunisian patients. PATIENTS AND METHODS: Included patients were hospitalized in different hospitals in Tunisia from 2007 to 2012. Serology was performed by microimmunofluorescence assay using R. conorii and R. typhi antigens. Two duplex qPCRs, previously reported, were performed on collected skin biopsies and whole blood samples. The first duplex amplified all Rickettsia species (PanRick) and Rickettsia typhi DNA (Rtt). The second duplex detected spotted fever group Rickettsiae (RC00338) and typhus group Rickettsiae DNA (Rp278). RESULTS: Diagnosis of rickettsiosis was confirmed in 82 cases (57.7%). Among 44 skin biopsies obtained from patients with confirmed diagnosis, the first duplex was positive in 24 samples (54.5%), with three patients positive by Rtt qPCR. Using the second duplex, positivity was noted in 21 samples (47.7%), with two patients positive by Rp278 qPCR. Among79 whole blood samples obtained from patients with confirmed diagnosis, panRick qPCR was positive in 5 cases (6.3%) among which two were positive by Rtt qPCR. Using the second set of qPCRs, positivity was noted in four cases (5%) with one sample positive by Rp278 qPCR. Positivity rates of the two duplex qPCRs were significantly higher among patients presenting with negative first serum than those with already detectable antibodies. CONCLUSIONS: Using qPCR offers a rapid diagnosis. The PanRick qPCR showed a higher sensitivity. Our study showed that this qPCR could offer a prompt diagnosis at the early stage of the disease. However, its implementation in routine needs cost/effectiveness evaluation. PMID- 25706393 TI - Adjuvant chemotherapy with sequential cytokine-induced killer (CIK) cells in stage IB non-small cell lung cancer. AB - For non-small cell lung cancer (NSCLC) patients at stage IB, adjuvant chemotherapy does not improve survival. Evidence suggests that dendritic cell (DC)-activated cytokine-induced killer (DC-CIK) cell therapy in addition to chemotherapy improves survival for stage I-IIIA NSCLC patients after surgery, but there are not enough data to confirm this benefit specifically for those at stage IB. Herein, we retrospectively evaluated the efficacy and safety of this therapy administered to stage IB NSCLC patients. Sixty-six patients were treated with four-cycle adjuvant chemotherapy initiated 3 weeks after surgical resection. In addition, 28 of these patients underwent DC-CIK therapy on a trimonthly basis (average 3.1 times, range 1-6) beginning 1 month after chemotherapy. The disease free survival (DFS) rates of the two groups were statistically similar, although patients who received DC-CIK therapy showed slightly higher 1- and 2-year DFS rates (100.0% and 96.4%, respectively, compared with 81.6% and 76.3%). More importantly, patients in the DC-CIK therapy group had significantly longer overall survival (p=0.018). For patients who received treatment after recurrence, the DC-CIK therapy group had longer progression-free survival compared with the chemotherapy-only group. In addition, patients given DC-CIK therapy experienced less fatigue and appetite loss. The rate of adverse side effects was similar between the two groups. In conclusion, for these stage IB NSCLC patients, DC-CIK therapy significantly improved 2-year DFS rates compared with those who received chemotherapy only. DC-CIK therapy also benefited patients' quality of life, and adverse events were acceptable. PMID- 25706394 TI - MicroRNA-181a inhibits tumor proliferation, invasiveness, and metastasis and is downregulated in gastric cancer. AB - MicroRNAs (miRNAs) play crucial roles in the development and progression of human cancers, including gastric cancer. The discovery of miRNAs may provide a new and powerful tool for studying the mechanism, diagnosis, and treatment of gastric cancer. Here we show that miR-181a levels were significantly downregulated in gastric cancer tissues compared with the adjacent normal regions in 80 paired samples. Moreover, the lower levels of miR-181a were associated with the pM or pTNM stage in clinical gastric cancer patients. In addition, the ectopic expression of miR-181a in the gastric cancer cell line HGC-27 inhibited cell proliferation, cell migration, and invasion by directly interacting with the mRNA encoding the oncogenic factor Prox1. Taken together, our results indicate that miR-181a might act as a tumor suppressor in gastric cancer, which may provide a novel diagnostic and therapeutic option for human gastric cancer in the near future. PMID- 25706395 TI - Intensive chemotherapy in patients aged 70 years or older newly diagnosed with acute myeloid leukemia. AB - Acute myeloid leukemia (AML) represents a major therapeutic challenge in the elderly. Because of the high treatment-related mortality and poor overall outcomes of remission induction therapy, many older patients are not considered candidates for intensive chemotherapy. The current study evaluated prognostic factors for achievement of complete remission (CR) in newly diagnosed elderly AML patients who were treated with initial intensive chemotherapy. The study included 62 newly diagnosed AML patients >= 70 years who were treated with intensive chemotherapy. The overall response rate (CR and CRp) was 56%. Patients with favorable or intermediate cytogenetics (p=0.0036) as well as those with primary AML (p=0.0212) had a higher response rate. The median overall survival for all patients was 6.85 months (95% CI 3.7-13.5 months). The median overall survival for patients achieving remission after intensive induction chemotherapy was significantly higher than those who did not respond to therapy (20.4 months vs. 3.5 months, p<0.001). The all-cause 4-week mortality rate was 11%, and the all cause 8-week mortality rate was 17.7%. A subgroup of elderly patients may benefit more from initial intensive induction chemotherapy, specifically those patients with performance status able to tolerate induction chemotherapy and favorable cytogenetic status. However, despite high rates of initial CR, relapse rates are still high, suggesting that alternative strategies of postremission therapy are warranted. PMID- 25706396 TI - RNA interference of Biot2 induces G1 phase arrest and apoptosis in mouse colorectal cancer cell line. AB - Biot2 is a tumor-associated antigen, and it is a novel gene (GenBank EF100607) that was first identified with the SEREX technique and named by our laboratory. It is highly expressed in cancer cells and testis, with low or no expression in normal tissues. In our previous study, RNA interference of human Biot2 can inhibit tumor cell growth, and it is associated with poor prognosis of patients in clinical study; however, the mechanism of Biot2 that effects tumor growth is not yet clear. Here, in this study, we explore further the mechanism of Biot2 by silencing Biot2 in CT26 cells. It provides some theoretical basis for Biot2 as a new target for gene therapy. In CT26 cells, the expression of Biot2 was downregulated by Biot2-shRNA. It also promoted G1 phase arrest, the expression of p16 and p21, and cell apoptosis. In the mouse model, the tumor volume and the expression of PCNA of the Biot2-shRNA group significantly decreased. These results suggest that silencing Biot2 in CT26 cells by RNA interference can inhibit cell growth in vitro and in vivo. It also induces cell cycle arrest in the G1 phase and apoptosis throughout regulation of p16 and p21. Taken together, our data demonstrate that Biot2 can be a potential target of gene therapy. PMID- 25706397 TI - Inhibition of canonical NF-kappaB nuclear localization by (-)-DHMEQ via impairment of DNA binding. AB - We previously discovered (-)-DHMEQ as a selective inhibitor of NF-kappaB, and it was shown to suppress many cancer and inflammation models in animals. (-)-DHMEQ directly binds to NF-kappaB components to inhibit DNA binding, and moreover, it often inhibits nuclear translocation of NF-kappaB. The mechanism of inhibiting nuclear translocation has been elucidated for RelB, a main noncanonical NF-kappaB component. However, it was not elucidated for p65, a main canonical NF-kappaB component. In the present research, we studied how (-)-DHMEQ inhibits nuclear localization of p65. First, (-)-DHMEQ inhibited p65 nuclear accumulation in adult T-cell leukemia MT-2 cells in which canonical p65 is constitutively activated. But there was no change in the stability and importin-alpha3 affinity of p65. Then, we prepared a p65 mutant protein with Arg35Ala and Tyr36Ala (AA) mutations having no DNA-binding ability in HeLa cells. The p65 AA mutant showed reduced nuclear localization without changing the stability and importin affinity. Taken together, the mechanism of inhibition is different between RelB and p65, and inhibition of p65 nuclear localization is likely to be due to the inhibition of DNA binding changing the equilibrium between the nuclear and cytoplasmic amounts of p65. PMID- 25706398 TI - Chondroitin sulfate proteoglycan-4 (CSPG4)-specific monoclonal antibody 225.28 in detection of acute myeloid leukemia blasts. AB - Chondroitin sulfate proteoglycan-4 (CSPG4), a membrane-bound proteoglycan known to be expressed on the surface of malignant cells, has a restricted distribution in normal tissues. CSPG4 is a potential candidate tumor marker. We investigate CSPG4 expression on blasts in newly diagnosed acute myeloid leukemia (AML) patients and its relation with cytogenetic abnormalities and molecular markers known to have prognostic significance in this disease. Using hybridoma technology, we generated a specific monoclonal antibody (mAb), mAb 225.28, reactive with CSPG4. Blast samples obtained from the peripheral blood of newly diagnosed AML patients were analyzed for CSPG4 expression using the CSPG4 specific mAb and multiparameter flow cytometry. The results were correlated with cytogenetic and molecular characteristics of AML. CSPG4 was found to be expressed on a variable fraction of leukemic blasts in all AML patients with different leukemia morphology, including monoblastic cases. Reactivity of CSPG4-specific mAb with leukemic blasts was not limited to those with the rearranged MLL gene. CSPG4 was also expressed on AML blasts with a complex karyotype, FLT3 mutation, or NPM1 mutation. The results indicate that CSPG4 is expressed and detectable by flow cytometry using the mAb 225.28 on a proportion of blasts of all subtypes of AML irrespective of cytogenetic and molecular abnormalities. mAb 225.28 could be useful in detecting AML blasts by flow cytometry. PMID- 25706399 TI - Cullin7 is required for lung cancer cell proliferation and is overexpressed in lung cancer. AB - Ubiquitin ligase Cullin7 has been identified as an oncogene in some malignant diseases such as choriocarcinoma and neuroblastoma. However, the role of Cullin7 in lung cancer carcinogenesis remains unclear. In this study, we explored the functional role of Cullin7 in lung cancer cell proliferation and tumorigenesis and determined its expression profile in lung cancer. Knocking down Cullin7 expression by small interfering RNA (siRNA) in lung cancer cells inhibited cell proliferation and elevated the expression of p53, p27, and p21 proteins. The enhanced p53 expression resulted from activation of the DNA damage response pathway. Cullin7 knockdown markedly suppressed xenograft tumor growth in vivo in mice. Moreover, Cullin7 expression was increased in primary lung cancer tissues of humans. Thus, Cullin7 is required for sustained proliferation and survival of tumor cells in vitro and in vivo, and its aberrant expression may contribute to the pathogenesis of lung cancer. Thus, our study provided evidence that Cullin7 functions as a novel oncogene in lung cancer and may be a potential therapeutic target for lung cancer management. PMID- 25706400 TI - Synthesis of 3-aminoBODIPY dyes via copper-catalyzed vicarious nucleophilic substitution of 2-halogeno derivatives. AB - 2-Halogeno BODIPYs undergo copper catalysed nucleophilic substitution with alkyl amines and anilines and an amide to give the corresponding 3-aminoBODIPY derivatives. The substrates are readily prepared by the regioselective 2 halogenation of the chemically robust, preformed BODIPYs thus providing an alternative to direct nucleophilic substitution of the corresponding 3 halogenoBODIPYs which requires regioselective 3-halogenation of the more sensitive dipyrromethane intermediate. 2-Halogenation expands the scope of vicarious substitution of BODIPYs to include weaker nitrogen nucleophiles. PMID- 25706401 TI - Health benefits of sauna bathing. PMID- 25706402 TI - Dual mode quantitative imaging of microscopic viscosity using a conjugated porphyrin dimer. AB - Microviscosity is of paramount importance in materials and bio-sciences. Fluorescence imaging using molecular rotors has emerged as a versatile tool to measure microviscosity, either using a fluorescence lifetime or a ratiometric signal of the rotor; however, only a limited number of blue-to-green-emitting fluorophores with both the lifetime and the ratiometric signal sensitivity to viscosity have been reported to date. Here we report a deep red emitting dual viscosity sensor, which allows both the ratiometric and the lifetime imaging of viscosity. We study viscosity in a range of lipid-based systems and conclude that in complex dynamic systems dual detection is preferable in order to independently verify the results of the measurements as well as perform rapid detection of changing viscosity. PMID- 25706404 TI - The time window of multisensory integration: relating reaction times and judgments of temporal order. AB - Even though visual and auditory information of 1 and the same event often do not arrive at the sensory receptors at the same time, due to different physical transmission times of the modalities, the brain maintains a unitary perception of the event, at least within a certain range of sensory arrival time differences. The properties of this "temporal window of integration" (TWIN), its recalibration due to task requirements, attention, and other variables, have recently been investigated intensively. Up to now, however, there has been no consistent definition of "temporal window" across different paradigms for measuring its width. Here we propose such a definition based on our TWIN model (Colonius & Diederich, 2004). It applies to judgments of temporal order (or simultaneity) as well as to reaction time (RT) paradigms. Reanalyzing data from Megevand, Molholm, Nayak, & Foxe (2013) by fitting the TWIN model to data from both paradigms, we confirmed the authors' hypothesis that the temporal window in an RT task tends to be wider than in a temporal-order judgment (TOJ) task. This first step toward a unified concept of TWIN should be a valuable tool in guiding investigations of the neural and cognitive bases of this so-far-somewhat elusive concept. PMID- 25706403 TI - Inhibitory control in mind and brain 2.0: blocked-input models of saccadic countermanding. AB - The interactive race model of saccadic countermanding assumes that response inhibition results from an interaction between a go unit, identified with gaze shifting neurons, and a stop unit, identified with gaze-holding neurons, in which activation of the stop unit inhibits the growth of activation in the go unit to prevent it from reaching threshold. The interactive race model accounts for behavioral data and predicts physiological data in monkeys performing the stop signal task. We propose an alternative model that assumes that response inhibition results from blocking the input to the go unit. We show that the blocked-input model accounts for behavioral data as accurately as the original interactive race model and predicts aspects of the physiological data more accurately. We extend the models to address the steady-state fixation period before the go stimulus is presented and find that the blocked-input model fits better than the interactive race model. We consider a model in which fixation activity is boosted when a stop signal occurs and find that it fits as well as the blocked input model but predicts very high steady-state fixation activity after the response is inhibited. We discuss the alternative linking propositions that connect computational models to neural mechanisms, the lessons to be learned from model mimicry, and generalization from countermanding saccades to countermanding other kinds of responses. PMID- 25706405 TI - A network biology approach to denitrification in Pseudomonas aeruginosa. AB - Pseudomonas aeruginosa is a metabolically flexible member of the Gammaproteobacteria. Under anaerobic conditions and the presence of nitrate, P. aeruginosa can perform (complete) denitrification, a respiratory process of dissimilatory nitrate reduction to nitrogen gas via nitrite (NO2), nitric oxide (NO) and nitrous oxide (N2O). This study focuses on understanding the influence of environmental conditions on bacterial denitrification performance, using a mathematical model of a metabolic network in P. aeruginosa. To our knowledge, this is the first mathematical model of denitrification for this bacterium. Analysis of the long-term behavior of the network under changing concentration levels of oxygen (O2), nitrate (NO3), and phosphate (PO4) suggests that PO4 concentration strongly affects denitrification performance. The model provides three predictions on denitrification activity of P. aeruginosa under various environmental conditions, and these predictions are either experimentally validated or supported by pertinent biological literature. One motivation for this study is to capture the effect of PO4 on a denitrification metabolic network of P. aeruginosa in order to shed light on mechanisms for greenhouse gas N2O accumulation during seasonal oxygen depletion in aquatic environments such as Lake Erie (Laurentian Great Lakes, USA). Simulating the microbial production of greenhouse gases in anaerobic aquatic systems such as Lake Erie allows a deeper understanding of the contributing environmental effects that will inform studies on, and remediation strategies for, other hypoxic sites worldwide. PMID- 25706407 TI - Establishing the natural history and growth rate of ameloblastoma with implications for management: systematic review and meta-analysis. AB - BACKGROUND: Ameloblastoma is the second most common odontogenic tumor, known to be slow-growing, persistent, and locally aggressive. Recent data suggests that ameloblastoma is best treated with wide resection and adequate margins. Following primary excision, bony reconstruction is often necessary for a functional and aesthetically satisfactory outcome, making early diagnosis paramount. Despite earlier diagnosis potentially limiting the extent of resection and reconstruction, an understanding of the growth rate and natural history of ameloblastoma has been notably lacking from the literature. METHOD: A systematic review of the literature was conducted by reviewing relevant articles from PubMed and Web of Science databases. Each article's level of evidence was formally appraised according to the Centre of Evidence Based Medicine (CEBM), with data from each utilized in a meta-analysis of growth rates for ameloblastoma. RESULTS: Literature regarding the natural history of ameloblastoma is limited since the tumor is immediately acted upon at its initial detection, unless the patient voluntarily refuses a surgical intervention. From the limited data, it is derived that the highest estimated growth rate is associated with solid, multicystic type and the lowest rate with peripheral ameloblastomas. After meta-analysis, the calculated mean specific grow rate is 87.84% per year. CONCLUSION: The growth rate of ameloblastoma has been demonstrated, offering prognostic and management information, particularly in cases where a delay in management is envisaged. PMID- 25706406 TI - Rapid synthesis, RNA binding, and antibacterial screening of a peptidic aminosugar (PA) library. AB - A 215-member mono- and diamino acid peptidic-aminosugar (PA) library, with neomycin as the model aminosugar, was systematically and rapidly synthesized via solid phase synthesis. Antibacterial activities of the PA library, on 13 bacterial strains (seven Gram-positive and six Gram-negative bacterial strains), and binding affinities of the PA library for a 27-base model of the bacterial 16S ribosomal A-site RNA were evaluated using high-throughput screening. The results of the two assays were correlated using Ribosomal Binding-Bacterial Inhibition Plot (RB-BIP) analysis to provide structure-activity relationship (SAR) information. From this work, we have identified PAs that can discriminate the E. coli A-site from the human A-site by up to a 28-fold difference in binding affinity. Aminoglycoside-modifying enzyme activity studies indicate that APH(2") Ia showed nearly complete removal of activity with a number of PAs. The synthesis of the compound library and screening can both be performed rapidly, allowing for an iterative process of aminoglycoside synthesis and screening of PA libraries for optimal binding and antibacterial activity for lead identification. PMID- 25706408 TI - Effect of variation of liquid condition on transformation of sulfur and carbon in the sediment of sanitary sewer. AB - This study aims to estimate the influence of the typical variation in liquid conditions on the biochemical reaction characteristics of sulfur and carbon in the sediment of gravity sanitary sewers. Thus, a series of experimental tests were conducted with real wastewater and sewage sediment to investigate the potential biochemical process of carbon and sulfur in sediment. Results indicated that the sulfur and carbon biochemical process in sediment with neutral pH is significant in the gravity sewage system. The changes in concentration and the ratios of wastewater component substrates are the key factors in chemical oxygen demand and sulfate reduction rates. Furthermore, the condition of dissolved oxygen in liquid significantly affected the biochemical reaction processes of sulfur and carbon. Finally, the frequent alternation of anaerobic and anoxic with low dissolved oxygen effectively inhibits sulfide accumulation and simultaneously reduces carbon loss in the sewage system. PMID- 25706409 TI - An evaluation of the social and private efficiency of adoption: anaerobic digesters and greenhouse gas mitigation. AB - Climate science has begun to recognize the important role of non-carbon dioxide greenhouse gas emissions, including methane. Given the important contribution of methane, anaerobic digesters (ADs) on dairy farms in the U.S. present an opportunity to reduce greenhouse gas (GHG) emissions. We quantify the social and private costs and benefits of ADs that have been adopted in California and find that, despite high initial costs, large reductions in GHG emissions bring significant social benefits and represent good social investments given a $36 per ton social cost of carbon. Subsidies that lower the initial private investment cost can help align socially and privately optimal adoption decisions. PMID- 25706410 TI - Development of ELISA for detection of Rh1 and Rg2 and potential method of immunoaffinity chromatography for separation of epimers. AB - In this work, hybridomas producing anti-ginsenoside-Rh1 monoclonal antibodies (MAbs) were generated. These MAbs were subsequently used to create indirect competitive enzyme-linked immunosorbent assays (icELISAs). A linear correlation was obtained for G-Rh1 concentrations in the range from 26 to 512ng/mL. The regression equation was y=1.979-0.201Log2(X) with a regression coefficient of 0.9898. Precision and accuracy of the icELISA method were evaluated by the variations between replicates from well to well (intra-assay) and plate to plate (inter-assay). The recovery rates ranged from 93.16% to 108.43%. Testing with the icELISA demonstrated that the MAbs were specific for 20(S)-Rh1 and 20(S)-Rg2 with no cross-reactivity against 20(R)-Rh1 and 20(R)-Rg2. The immunoaffinity chromatography column (IAC) was constructed by covalently coupling monoclonal antibody (MAb) against G-Rh1 to CNBr-activated Sepharose 4B. When 20(R)-type-Rg2 passed through the IAC column, it was adsorbed, but the amount adsorbed was lower than that when 20(S)-type-Rg2 ran through the column. The differences in adsorption between the 20(S) and 20(R) type ginsenosides bring a new approach or method to separate 20(S)-Rg2 and 20(R)-Rg2 by IAC. Our results indicate that the icELISA is a sensitive and efficient approach for the identification of epimers, and the application of IAC using MAbs against small molecules provides a totally new thought and potential method for resolving epimers. PMID- 25706411 TI - Local immunosuppressive microenvironment enhances migration of melanoma cells to lungs in DJ-1 knockout mice. AB - DJ-1 is an oncoprotein that promotes survival of cancer cells through anti apoptosis. However, DJ-1 also plays a role in regulating IL-1beta expression, and whether inflammatory microenvironment built by dysregulated DJ-1 affects cancer progression is still unclear. This study thus aimed to compare the metastatic abilities of melanoma cells in wild-type (WT) and DJ-1 knockout (KO) mice, and to check whether inflammatory microenvironment built in DJ-1 KO mice plays a role in migration of cancer cells to lungs. First, B16F10 melanoma cells (at 6 * 10(4)) were injected into the femoral vein of mice, and formation of lung nodules, levels of lung IL-1beta and serum cytokines, and accumulation of myeloid-derived suppressor cells (MDSCs) were compared between WT and DJ-1 KO mice. Second, the cancer-bearing mice were treated with an interleukin-1 beta (IL-1beta) neutralizing antibody to see whether IL-1beta is involved in the cancer migration. Finally, cultured RAW 264.7 macrophage and B16F10 melanoma cells were respectively treated with DJ-1 shRNA and recombinant IL-1beta to explore underlying molecular mechanisms. Our results showed that IL-1beta enhanced survival and colony formation of cultured melanoma cells, and that IL-1beta levels were elevated both in DJ-1 KO mice and in cultured macrophage cells with DJ-1 knockdown. The elevated IL-1beta correlated with higher accumulation of immunosuppressive MDSCs and formation of melanoma module in the lung of DJ-1 KO mice, and both can be decreased by treating mice with IL-1beta neutralizing antibodies. Taken together, these results indicate that immunosuppressive tissue microenvironment built in DJ-1 KO mice can enhance lung migration of cancer, and IL-1beta plays an important role in promoting the cancer migration. PMID- 25706412 TI - Lack of detectable allergenicity in genetically modified maize containing "Cry" proteins as compared to native maize based on in silico & in vitro analysis. AB - BACKGROUND: Genetically modified, (GM) crops with potential allergens must be evaluated for safety and endogenous IgE binding pattern compared to native variety, prior to market release. OBJECTIVE: To compare endogenous IgE binding proteins of three GM maize seeds containing Cry 1Ab,1Ac,1C transgenic proteins with non GM maize. METHODS: An integrated approach of in silico & in vitro methods was employed. Cry proteins were tested for presence of allergen sequence by FASTA in allergen databases. Biochemical assays for maize extracts were performed. Specific IgE (sIgE) and Immunoblot using food sensitized patients sera (n = 39) to non GM and GM maize antigens was performed. RESULTS: In silico approaches, confirmed for non sequence similarity of stated transgenic proteins in allergen databases. An insignificant (p> 0.05) variation in protein content between GM and non GM maize was observed. Simulated Gastric Fluid (SGF) revealed reduced number of stable protein fractions in GM then non GM maize which might be due to shift of constituent protein expression. Specific IgE values from patients showed insignificant difference in non GM and GM maize extracts. Five maize sensitized cases, recognized same 7 protein fractions of 88-28 kD as IgE bindng in both GM and non-GM maize, signifying absence of variation. Four of the reported IgE binding proteins were also found to be stable by SGF. CONCLUSION: Cry proteins did not indicate any significant similarity of >35% in allergen databases. Immunoassays also did not identify appreciable differences in endogenous IgE binding in GM and non GM maize. PMID- 25706413 TI - Application of an optosensing chip based on molecularly imprinted polymer coated quantum dots for the highly selective and sensitive determination of sesamol in sesame oils. AB - A novel optosensing chip was constructed by anchoring the fluorescence sensing material layer based on molecularly imprinted polymer (MIP) coated CdSe/ZnS quantum dots (QDs) on a chip for highly selective and sensitive optosensing of sesamol in sesame oil. Many factors that affected the performance of the optosensing chip based on MIP-coated QDs are discussed. Under optimized conditions, the relative fluorescence intensity of the optosensing chip decreased linearly (r(2) > 0.99) with increasing sesamol concentration in the range from 2.4 * 10(-6) to 1.2 * 10(-3) mol L(-1) with a detection limit of 7.2 * 10(-8) mol L(-1). The relative standard deviation for five replicate detections of 4.8 * 10( 4) mol L(-1) sesamol was 2.2%. Recoveries of 94.8-102.3% were achieved by direct detection when the optosensing chip was used for the selective detection of sesamol in sesame oil. Practically, the optosensing approach showed high sensitivity, good selectivity, and excellent reproducibility for the detection of sesamol in real oil samples. PMID- 25706414 TI - SrGa(0.7)Co(0.3)O(3-delta) perovskite-cobalt oxide-metal nanocomposite films: magnetic and optical properties. AB - Two-phase nanocomposite films consisting of metallic Co nanoparticles below 50 nm diameter in a perovskite matrix were grown by pulsed laser deposition onto (LaAlO3)0.3(Sr2AlTaO6)0.7 (LSAT) and silicon substrates from a target of SrGa0.73Co0.27O3. The particles made up about 6% by volume of the film and were present within the film and at the substrate interface. The saturation magnetization of the film was up to 85 emu cm(-3) at 80 nm thickness and the Faraday rotation (FR) tracked the out-of-plane hysteresis loop, reaching 3000 deg cm(-1) at 10 kOe for 1550 nm wavelength. The magneto-optical figure of merit defined as FR divided by optical absorption was 0.04-0.06 deg dB(-1) due to the high optical absorption of the Co particles. PMID- 25706415 TI - Isolation of highly active monoclonal antibodies against multiresistant gram positive bacteria. AB - Multiresistant nosocomial pathogens often cause life-threatening infections that are sometimes untreatable with currently available antibiotics. Staphylococci and enterococci are the predominant Gram-positive species associated with hospital acquired infections. These infections often lead to extended hospital stay and excess mortality. In this study, a panel of fully human monoclonal antibodies was isolated from a healthy individual by selection of B-cells producing antibodies with high opsonic killing against E. faecalis 12030. Variable domains (VH and VL) of these immunoglobulin genes were amplified by PCR and cloned into an eukaryotic expression vector containing the constant domains of a human IgG1 molecule and the human lambda constant domain. These constructs were transfected into CHO cells and culture supernatants were collected and tested by opsonophagocytic assay against E. faecalis and S. aureus strains (including MRSA). At concentrations of 600 pg/ml, opsonic killing was between 40% and 70% against all strains tested. Monoclonal antibodies were also evaluated in a mouse sepsis model (using S. aureus LAC and E. faecium), a mouse peritonitis model (using S. aureus Newman and LAC) and a rat endocarditis model (using E. faecalis 12030) and were shown to provide protection in all models at a concentration of 4 MUg/kg per animal. Here we present a method to produce fully human IgG1 monoclonal antibodies that are opsonic in vitro and protective in vivo against several multiresistant Gram-positive bacteria. The monoclonal antibodies presented in this study are significantly more effective compared to another monoclonal antibody currently in clinical trials. PMID- 25706416 TI - Correction: Merit and justice: an experimental analysis of attitude to inequality. PMID- 25706418 TI - Parasites and fungi as a threat for prenatal and postnatal human development. AB - Recent literature data reveals the most common etiological agents of congenital parasitoses to be Toxoplasma gondii, Trypanosoma cruzi, Leishmania donovani and Plasmodium falciparum. An analysis of clinical data indicates that parasitic congenital infections are often asymptomatic, whereas symptomatic newborns usually display nonspecific symptoms, which greatly hinders correct diagnosis. The long-term consequences of prenatal infections are serious clinical problems. This article presents the possible routes of vertical transmissions (mother-to child) of pathogens including prenatal, perinatal, as well as postnatal routes. It highlights the role of factors involved in protozoa transmission and development of congenital parasitic diseases, such as parasite genotypes, the relationship between the timing of maternal infection and the probability of passage of the parasite through the placental barrier, and the immunological features of pregnant women. Acquired and congenital babesioses in human and experimental animals are presented. It emphasises that the mechanisms by which parasites infect the placenta and cross from mother to fetus are still poorly understood. It also describes the cellular mechanisms of infection by T. gondii, such as tachyzoites crossing biological barriers, the expression of Toll-Like Receptors (TLR) family on trophoblasts and syncytiotrophoblasts as an immune response to intrauterine infection and cases of congenital and acquired toxoplasmosis, as well as the long-term consequences of congenital invasion with T. gondii, episodes of reactivation of latent toxoplasmosis and T. gondii reinvasions. Mycological topics include a rare case of in utero fungal infection of offspring by a mother with vaginal candidosis, and the fungal contamination of ward facilities and medical equipment as potential sources of exogenous infections of newborn children. PMID- 25706417 TI - Quantitative differences in nourishment affect caste-related physiology and development in the paper wasp Polistes metricus. AB - The distinction between worker and reproductive castes of social insects is receiving increased attention from a developmental rather than adaptive perspective. In the wasp genus Polistes, colonies are founded by one or more females, and the female offspring that emerge in that colony are either non reproducing workers or future reproductives of the following generation (gynes). A growing number of studies now indicate that workers emerge with activated reproductive physiology, whereas the future reproductive gynes do not. Low nourishment levels for larvae during the worker-rearing phase of the colony cycle and higher nourishment levels for larvae when gynes are reared are now strongly suspected of playing a major role in this difference. Here, we present the results of a laboratory rearing experiment in which Polistes metricus single foundresses were held in environmental conditions with a higher level of control than in any previously published study, and the amount of protein nourishment made available to feed larvae was the only input variable. Three experimental feeding treatments were tested: restricted, unrestricted, and hand-supplemented. Analysis of multiple response variables shows that wasps reared on restricted protein nourishment, which would be the case for wasps reared in field conditions that subsequently become workers, tend toward trait values that characterize active reproductive physiology. Wasps reared on unrestricted and hand supplemented protein, which replicates higher feeding levels for larvae in field conditions that subsequently become gynes, tend toward trait values that characterize inactive reproductive physiology. Although the experiment was not designed to test for worker behavior per se, our results further implicate activated reproductive physiology as a developmental response to low larval nourishment as a fundamental aspect of worker behavior in Polistes. PMID- 25706419 TI - Toxoplasma gondii and mast cells. AB - Mast cells, discovered by Paul Burnet over one century ago, have been long recognized only as inductors of IgE-dependent allergic diseases (allergy of type I, Th2 lymphocytes dependent). However, numerous recent studies have indicated that they play an essential role in many other immunological and non immunological processes. Infection with Toxoplasma gondii elicits the induction of a strong cell-mediated immunity characterized by a highly-polarized Th1 response, which can protect against allergy. Knowledge of the contribution of mast cells to Toxoplasma invasion is still limited, and the present article discusses aspects of the relationship between mast cells and T. gondii. PMID- 25706421 TI - Epidemiology and economic benefits of treating rabbits coccidiosis in small farms from West Pomerania province, Poland. AB - The studies were carried out on 9 farms which deals with meat race of rabbits breeding. The basic herds had from 28 to 63 rabbits (total 275 rabbits) on Choszczno and Recz district in West Pomerania province. The study was based on two flotation methods:Willis-Schlaaf for qualitative and McMaster for quantitative analysis, which helped to establish the number of oocysts in 1g of feces (OPG). Ten species of coccidian were found in which 9 were intestinal (E. exigua, E. perforans, E. media, E. magna, E. irresidua, E. coecicola, E. flavescens, E. piriformis, E. intestinalis) and one was living in liver (E. stiedai). Baycox (Bayer) was used in drinking water in a dose of 25 ppm in 1 liter of water for 2 days. In rabbits from the experimental groups higher weight gain and lower mortality compared to the control group animals were observed. The results highlight the beneficial effects of coccidiostats used in the production effects in rabbits. PMID- 25706420 TI - Immunosuppression during Leishmania donovani infection: a potential target for the development of therapy. AB - Dysfunction of T-helper 1 mediated immune responses is a hallmark of the progression of visceral leishmaniosis (VL). Several factors such as altered antigen presentation, and abnormalities in MHC/HLA, antigen processing, and T cell receptor recognition regulate the onset of immunosuppression. Recent investigations on VL patients suggest that susceptibility to visceral leishmaniosis is genetically determined and varies between populations in different geographical locations. Emerging evidence also indicates the importance of the role played by myeloid derived suppressor cells in progressive VL. This study provides a mechanistic view of means to target the signaling mechanisms of immunosuppression to determine potential therapeutic interventions. PMID- 25706422 TI - Epizootic situation of mouflon Ovis aries musimon in Lower Silesia on the basis of coproscopic examinations. AB - Coproscopic examinations of mouflons Ovis aries musimon from four forest districts of Lower Silesia performed in spring and autumn from 2012 to 2014 demonstrated the presence of pulmonary nematodes and intestinal parasites, including coccidia of the genus Eimeria. Prevalence of pulmonary nematodes (mainly Muellerius capillaris) amounted to 69.78%, intestinal nematodes--56.11% and coccidia of the genus Eimeria--44.6%. The number of oocysts, eggs of intestinal helminths and larvae of pulmonary nematodes was low. Most frequently the parasites occurred in mouflons from the Jugow forest district, which is related to contact with sheep grazed in the area. PMID- 25706423 TI - Polymorphisms of the Pfatpase 6 and Pfcrt gene and their relationship with the in vitro susceptibility to dihydroartemisinin and chloroquine of Plasmodium falciparum isolates from Abobo, Cote d'Ivoire. AB - As a result of widespread resistance to chloroquine (CQ) and sulphadoxine pyrimethamine (SP), artemisinin-based combination therapy (ACT) has been recommended as a first-line anti-malarial regimen in Cote d'Ivoire since 2005. A thorough understanding of the molecular bases of P. falciparum resistance to existing drugs is therefore needed. The aims of this study were to analyze the in vitro sensitivity of P. falciparum field isolates from Abobo to CQ, pyronaridine (PYR) and dihydroartemisinine (DHA), and to investigate the polymorphisms associated with drug resistance. The standard in vitro drug sensitivity microtechnique recommended by the WHO was used to assess the sensitivity of Plasmodium falciparum isolates collected in December 2006. The Pfcrt haplotype 76 was analysed by PCR-RFLP while Pfatpase 6 amplification products were sequenced. Associations between drug sensitivity and parasite gene polymorphisms were evaluated with Cohen's kappa test. The correlation between the IC50 values for different drugs was assessed by the coefficient of determination (r2). Significance was assumed at p<0.05. Of 128 in vitro tests performed, 112 (87.5%) were successful. Of the isolates, 56.2% were resistant for CQ and 48% for PYR. One isolate (3.6%) demonstrated reduced DHA sensitivity (IC50 higher than 10 nM). The mutant K76T pfcrt codon, present in 90% of DNA fragments analyzed, was associated with CQ-R (K=0.76). The N669Y (16.1%), D734Y (28.6%) and D734H (1.8%) isolates were found to have mutant Pfatpase6, however, these mutations were not associated with diminished DHA sensitivity (k=0.01). These high levels of antimalarial drug resistance in Abobo (Cote d'Ivoire) demand further studies of drug efficacy across the whole country. PMID- 25706424 TI - The prevalence of Ehrlichia canis, Anaplasma platys and Babesia spp. in dogs in Nueva Ecija, Philippines based on multiplex polymerase chain reaction (mPCR) assay. AB - The aim of the study was to determine the prevalence of Ehrlichia canis, Anaplasma platys and Babesia spp. in dogs. It describes the practice of veterinarians in detecting tick-borne diseases in Nueva Ecija, Philippines. Seventy blood samples were collected and were subjected to multiplex PCR for the detection of E. canis, Babesia spp. and A. platys. The prevalence of babesiosis is the highest in Cabanatuan City (2/10), while a 10% prevalence (1/10) was observed in Science City of Munoz, Talavera and Sta. Rosa. E. canis were only detected in Cabanatuan City. However, no anaplasmosis was detected in any area. The prevalence of babesiosis and ehrlichiosis in Nueva Ecija is 7.14% (5/70) and 2.85% (2/70) respectively. In addition, 70% (7/10) of the Nueva Ecija veterinary practitioners encountered cases of suspected ehrlichiosis in their practice. The diagnosis of ehrlichiosis is based primarily on presented clinical signs and complete blood counts, which include a platelet count. Of the 10 respondents, half utilized test kits while 90% interpreted blood samples. Meanwhile, only 60% of the respondents used an ELISA test kit for ehrlichiosis. For some practitioners, the main reason for not utilizing a kit is the high cost. None of the respondents had previously attended cases of suspected anaplasmosis. Only one respondent diagnosed a case of babesiosis by blood smear microscopy. PMID- 25706425 TI - New data on the prevalence of Trichodectes melis (Phthiraptera, Trichodectidae) on the European badger Meles meles (Carnivora, Mustelidae). AB - Trichodectes melis is a specific ectoparasite of the European badger Meles meles. Distribution of this chewing louse is little known, although presumably it coincides with the range of its typical host. In Poland, it has been found in only a few stands in the western part of the country. It has recently been observed in the area of the Bialowieza Primeval Forest, where 81 specimens of T. melis (48 females, 7 males and 26 nymph forms) were collected from two female European badgers, mainly from the fur of the head area. No symptoms of infestation were observed. PMID- 25706426 TI - A new occurrence of Eimeria alces (Apicomplexa: Eimeridae) in elk (Alces alces) in East Poland. AB - A total of 114 elk faecal samples from the Polesie National Park and adjacent forest districts were examined in 2013 and 2014. Three samples were positive. The positive samples were from the village of Wereszczyn, the Sobibor forest district, and the Polesie National Park and Forest district, Parczew. Morphometric examination revealed that the oocysts belong to the species Eimeria alces. This is the second identification of the parasite in elk in Poland and the fifth worldwide. PMID- 25706427 TI - Prevalence of intestinal parasites among the population of the Gaza Strip, Palestine. AB - Intestinal parasitic diseases in Gaza Strip are a significant health problem. The main aim of this study is to determine the prevalence of parasitic infection among patients in the five governorates of the Gaza Strip. A cross-sectional parasitological survey was conducted on 600 patients. Stool specimens were examined microscopically for the presence of parasite eggs or larvae/cysts per wet amount by the saline iodine and formol-ether concentration method. Of 600 subjects examined, 245 (40.8%) were infected with one or more intestinal parasites. Entamoeba histolytica/dispar and Giardia lamblia were the most prevalent parasites amongst the population (28.8%), (9.5%). Female patients demonstrated a higher prevalence of intestinal parasitic infections (42.7%) than males (39.0%). However, this difference was not significant (p>0.05). According to occupation, the rate of infection was highest among farmers (56.0%), followed by employers (44.2%) with laborers showing the lowest rate (30.17%). These differences in occupational prevalence were found to be statistically significant (p<0.05). The present study demonstrates that intestinal protozoan infections are still a public health problem in the Gaza strip, with Entamoeba and Giardia infections being most common. Therefore, it is necessary to develop effective prevention and control strategies, including health education and environmental sanitation improvement. PMID- 25706428 TI - Toxoplasma gondii and women of reproductive age: an analysis of data from the Chair of Microbiology, Jagiellonian University Medical College in Cracow. AB - The aim of the study is to determine the seroprevalence and risk factors for Toxoplasma gondii infection in women of reproductive age within the Malopolska province who were examined in the Laboratory of Microbiological Diagnostics, Chair of Microbiology in Cracow in 2013-2014. Seventy-eight questionnaires completed by women of reproductive age (mean age 29.91+/-6.56) were analysed. In total, 82% of respondents signed up for serological testing while already pregnant (33 patients in the age group 18-29 years and 30 patients in the age group 30-39 years). Twenty- seven percent had no previous contact with the parasite. A statistically significant (chi-square=7.722, p=0.005) correlation between permanent residence in the countryside and the presence of anti-T. gondii antibodies was found. A significant correlation was shown in the studied group between a lack of contact with soil and negative results of serological tests for toxoplasmosis (chi-square=4.116, p=0.042). The majority of the surveyed women had already encountered this parasite. It seems that special attention should be given to rural women. Implementation of more precise testing in the diagnosis of toxoplasmosis is also essential. PMID- 25706429 TI - Evaluation of human cystic echinococcosis before and after surgery and chemotherapy by demonstration of antibodies in serum. AB - Human cystic echinococcosis (CE), caused by Echinococcus granulosus, is one of the most important and widespread parasitic zoonoses. As one of the problems that can be encountered after treating CE patients is the risk of postsurgical relapses or treatment failure, a long-term clinical and serological follow-up is required to evaluate the success and failure of therapy. Therefore, the aim of the present study was to identify the best diagnostic and prognostic ELISA markers in patients with CE. The cohort comprised 50 patients with symptomatic CE treated with antihelminthic drugs and surgery, who were followed up clinically and radiologically for a mean of 6 years (range 4-8 years). The results clearly indicate that the hydatid specific antibodies of IgE, IgG1 and IgG4 are the most important antibodies for the serological diagnosis of cystic echinococcosis during the active stage of the disease. None of the serum samples from healthy controls gave a non-specific reaction with IgE, IgG1 or IgG4, and a considerably reduced cross-reaction was observed with these antibodies. During post-operative follow-up, the IgM, IgE, IgG1, IgG2 and IgG4 antibody response provided the best correlate of disease activity. The detection of total IgG and IgG3 subclass antibody response for the assessment of post-treatment disease activity among CE patients was insensitive. All patients responded to treatment except 2 women (32 and 36 years old), in whom multiple cysts (12 and 7 cysts) were detected in the liver and lung two years after the first operation. Hence, it can be concluded that the CE-specific antibodies of IgE, IgG1 and IgG4 are the best immunological markers for diagnosis and prognosis of CE patients. PMID- 25706430 TI - Gastrointestinal parasites of free-range chickens. AB - The aim of the study was to determine the prevalence and intensity of parasitic gastrointestinal infections in free-range chickens from the West Pomerania province. Experimental material for the study was taken from 10 farms. Breeds raised in farms participating in the study included miniature chickens called Polish Lilliputians and Green- legged Partridge. A total of 104 samples of faeces were examined. The Willis-Schlaff flotation method was used to assess the prevalence of infection, and McMaster's method to evaluate the intensity. The presence of gastrointestinal parasites was found in 9 of the 10 farms. Oocysts of the genus Eimeria and eggs of gastrointestinal nematodes Ascaridia galli, Heterakis gallinarum and Trichostrongylus tenuis were isolated from the chicken faeces. Coccidiosis was found to be dominant parasitosis. The prevalence of infections on these farms with protozoa of Eimeria spp. was on average 32.7%, while for nematode species they amounted to 9.6% for Ascaridia galli, 5.7% for Heterakis gallinarum and 12.5% for Trichostrongylus tenuis. The results indicate the need to take preventive measures, designed to eliminate/reduce the risk of parasitoses in poultry from free-range systems. Focus should be placed on the hygiene of the farming conditions. PMID- 25706431 TI - Prevalence of cysticercosis in cattle and pigs in the Lublin province in the years 2009-2012. AB - Prevalence of cysticercosis among cattle and pigs slaughtered in the Lublin province in the years 2009-2012 was evaluated. The study draws its data from annual reports of the Veterinary Inspectorate in Lublin. Cysticercus bovis was detected in 1038 animals (0.19%) out of 542,963 heads of cattle in the Lublin province, whereas Cysticercus cellulosae was found in 150 (0.0044%) out of 3,367,444 examined pigs. PMID- 25706433 TI - Professor Maria Prost DVM, PhD (1921-2014). PMID- 25706432 TI - First report of hepatic cysticercosis in a rook (Corvus frugilegus) (Passerifomes, Corvidae). AB - Cysticercosis is an infection with the larval (cysticercus) stage of Taenia spp. that it is seen as cysts in various human and animal tissues. In this study, pathologic findings of hepatic cysticercosis in a rook (Corvus frugilegus) is described. To our knowledge, there is no report on hepatic cysticercosis in rook and this study shows that rooks may play a role as intermediate hosts in the transmission of parasitic infections. PMID- 25706434 TI - Professor Alojzy Ramisz--into memory of his life and work. PMID- 25706435 TI - Temperature-dependent thermal properties of supported MoS2 monolayers. AB - Thermal properties can substantially affect the operation of various electronics and optoelectronics devices based on two-dimensional materials. In this work, we describe our investigation of temperature-dependent thermal conductivity and interfacial thermal conductance of molybdenum disulfide monolayers supported on SiO2/Si substrates, using Raman spectroscopy. We observed that the calculated thermal conductivity (kappa) and interfacial thermal conductance (g) decreased with increasing temperature from 62.2 W m(-1) K(-1) and 1.94 MW m(-2) K(-1) at 300 K to 7.45 W m(-1) K(-1) and 1.25 MW m(-2) K(-1) at 450 K, respectively. PMID- 25706436 TI - Combined toxicities of methyl tert-butyl ether and its metabolite tert-butyl alcohol on earthworms via different exposure routes. AB - Methyl tert-butyl ether (MTBE) and tert-butyl alcohol (TBA) are among the major soil contaminants that threaten the health of soil ecosystems. Many MTBE contaminated sites accumulate TBA, because TBA is the intermediate of MTBE biodegradation. To access the risk of MTBE and TBA in soil, we investigated the combined toxicities of MTBE and TBA using two earthworm species, Perionyx excavatus and Eisenia andrei, as well as the toxic effects via different exposure routes. The combined toxicity showed weak antagonistic effects (LC50mix values were slightly greater than 1.0), and sensitivity toward same pollutants differed in the two earthworm species. Moreover, the toxicity of MTBE and TBA was also affected by the exposure route; both filter paper and artificial soil tests showed that dermal-only exposure to MTBE had an even greater toxic effect than combined dermal and oral exposure. Thus, we suggest that diverse environmental factors including organic materials, the physicochemical properties of the contact media, and the exposure routes of the organism, should be taken into consideration when assessing the effects of pollutants on organisms in diverse environmental systems. PMID- 25706437 TI - The effects of progesterone on transcriptional expression profiles of genes associated with hypothalamic-pituitary-gonadal and hypothalamic-pituitary-adrenal axes during the early development of zebrafish (Danio rerio). AB - Progesterone (P4) has been reported in surface water, and it may have adverse effects on aquatic organisms. This study provided the transcriptional effects of P4 during the early development of zebrafish. Zebrafish embryos were exposed for 144 h post fertilization (hpf) to 0, 6, 45 and 90 ng L(-1) P4, and transcriptional expression profiles of the hypothalamic-pituitary-gonadal (HPG) and hypothalamic-pituitary-adrenal (HPA) axes were assessed every day. For the receptor signaling pathways, P4 significantly induced the transcript of Pgr gene above 45 ng L(-1) at 72 and 144 hpf, but inhibited its transcript above 6 ng L( 1) at 96 and 120 hpf. A significant up-regulation of Vtg1 mRNA was observed at 6 ng L(-1) P4 or higher at 24, 96 and 144 hpf. For the steroidogenic pathways, the transcriptional expression of Cyp11a1 and Hsd17b3 mRNAs was mediated by 6 ng L( 1) P4 or higher according to different exposure time points. In addition, P4 resulted in a significant induction of Cyp19a1a and Cyp11b mRNA expression while it caused a significant inhibition of Hsd11b2 mRNA expression above 6 ng L(-1). For the other target genes related to hypothalamic and pituitary hormones, P4 mainly modulated the transcripts of Gnrh2, Fshb and Lhb genes at 6 ng L(-1) or higher. The overall results from the present study indicate that P4 at environmentally relevant concentrations could cause the potential effects on zebrafish reproductive and adrenal endocrine systems by interfering with the HPG and HPA axes. PMID- 25706438 TI - A theoretical investigation into the effects of temperature on spatiotemporal dynamics of EET in the FMO complex. AB - Methodologies are presented in which population dynamics are evolved in the exciton basis and spatiotemporal movement of excitations is subsequently obtained by projection to the site basis. Fluctuations of system eigenstates are explicitly included through vibrations of the chromophores, which are parametrized by ab initio calculations. Two limiting cases of dynamics are considered, namely, the incoherent regime, where state populations correspond to ensembles of classical Landau-Zener (LZ) trajectories, and the coherent regime, where the density matrix is propagated by the quantum Liouville equation (QLE). For QLE simulations, population dynamics show that bacteriochlorophyll a1 and a2 effectively act as a single unit at 77 K but as independent chromophores at 300 K. Population beatings for the lower energy exciton states are considerably slower at physiological temperatures, thus assisting transfer to the sink. Results from LZ trajectories indicate that, within the classical picture, higher temperatures result in a lower probability of the exciton reaching the sink. A broadening of the excitonic spectrum at high temperature alters the pathways of the excitons in the LZ formalism and also increases the possibility of trapping. This study supports the view that a coherent mechanism may assist EET at physiological temperatures since the trapping of excitations in intermediate energy sites is prevented. Furthermore, delocalized vibrations (i.e., superpositions of independent oscillators) are found to assist energy transfer at short times. PMID- 25706440 TI - Deciphering and prediction of plant dynamics under field conditions. AB - Elucidation of plant dynamics under fluctuating natural environments is a challenging goal in plant physiology. Recently, using a computer statistics integrating a series of transcriptome data of field-grown rice leaves during an entire crop season and several corresponding environmental data such as solar radiation and ambient temperature, most parts of transcriptome have been modeled. This reveals the detailed contributions of developmental timing, circadian clocks and each environmental factor to transcriptome dynamics in the field and can predict transcriptome dynamics under given environments. Furthermore, some traits such as flowering time in natural environments have been shown to be predicted by mathematical models based on gene-networks parameterized with data obtained in the laboratory, and phenology models refined by knowledge of molecular genetics. New molecular physiology is beginning in plant science. PMID- 25706439 TI - Fast helix formation in the B domain of protein A revealed by site-specific infrared probes. AB - Comparison of experimental and computational protein folding studies can be difficult because of differences in structural resolution. Isotope-edited infrared spectroscopy offers a direct measure of structural changes involved in protein folding at the single-residue level. Here we demonstrate the increased resolution of site-specific infrared probes to the peptide backbone in the B domain of staphylococcal protein A (BdpA). (13)C?(18)O-labeled methionine was incorporated into each of the helices using recombinant protein expression. Laser induced temperature jumps coupled with infrared spectroscopy were used to probe changes in the peptide backbone on the submillisecond time scale. The relaxation kinetics of the buried helices, solvated helices, and labeled positions were measured independently by probing the corresponding bands assigned in the amide I region. Using these wavelength-dependent measurements, we observe a fast nanosecond phase and slower microsecond phase at each position. We find at least partial formation of helices 1-3 in the fast intermediate state that precedes the transition state. These measurements provide direct, time-resolved experimental evidence of the early formation of partial helical structure in helices 1 and 3, supporting folding models proposed by computer simulations. PMID- 25706441 TI - Layer-dependent modulation of tungsten disulfide photoluminescence by lateral electric fields. AB - Large single-crystal domains of WS2 are grown by chemical vapor deposition, and their photoluminescent properties under a lateral electric field are studied. We demonstrate that monolayer and bilayer WS2 have opposite responses to lateral electric fields, with WS2 photoluminescence (PL) substantially reduced in monolayer and increased in bilayers with increasing lateral electric field strength. Temperature-dependent PL measurements are also undertaken and show behavior distinctly different than that of the lateral electric field effects, ruling out heating as the cause of the PL changes. The PL variation in both monolayer and bilayer WS2 is attributed to the transfer of photoexcited electrons from one conduction band extremum to another, modifying the resultant recombination pathways. This effect is observed in 2D transition metal dichalcogenides due to their large exciton binding energy and small energy difference between the two conduction band extrema. PMID- 25706442 TI - Molecular rectifiers: a new design based on asymmetric anchoring moieties. AB - The quest for a molecular rectifier is among the major challenges of molecular electronics. We introduce three simple rules to design an efficient rectifying molecule and demonstrate its functioning at the theoretical level, relying on the NEGF-DFT technique. The design rules notably require both the introduction of asymmetric anchoring moieties and a decoupling bridge. They lead to a new rectification mechanism based on the compression and control of the HOMO/LUMO gap by the electrode Fermi levels, arising from a pinning effect. Significant rectification ratios up to 2 orders of magnitude are theoretically predicted as the mechanism opposes resonant to nonresonant tunneling. PMID- 25706443 TI - Reward and Cognition: Integrating Reinforcement Sensitivity Theory and Social Cognitive Theory to Predict Drinking Behavior. AB - BACKGROUND: Both Reinforcement Sensitivity Theory and Social Cognitive Theory have been applied to understanding drinking behavior. We propose that theoretical relationships between these models support an integrated approach to understanding alcohol use and misuse. OBJECTIVES: We aimed to test an integrated model in which the relationships between reward sensitivity and drinking behavior (alcohol consumption, alcohol-related problems, and symptoms of dependence) were mediated by alcohol expectancies and drinking refusal self-efficacy. METHODS: Online questionnaires assessing the constructs of interest were completed by 443 Australian adults (M age = 26.40, sd = 1.83) in 2013 and 2014. RESULTS: Path analysis revealed both direct and indirect effects and implicated two pathways to drinking behavior with differential outcomes. Drinking refusal self-efficacy both in social situations and for emotional relief was related to alcohol consumption. Sensitivity to reward was associated with alcohol-related problems, but operated through expectations of increased confidence and personal belief in the ability to limit drinking in social situations. Conversely, sensitivity to punishment operated through negative expectancies and drinking refusal self-efficacy for emotional relief to predict symptoms of dependence. CONCLUSIONS: Two pathways relating reward sensitivity, alcohol expectancies, and drinking refusal self efficacy may underlie social and dependent drinking, which has implications for development of intervention to limit harmful drinking. PMID- 25706444 TI - Quartz crystal microbalance-based evaluation of the electrochemical formation of an aggregated polypyrrole particle-based layer. AB - Electrochemical quartz crystal microbalance (EQCM) was used for the evaluation of conducting polymer polypyrrole (Ppy), which was formed by a sequence of potential pulses on a Au-plated EQCM disc. The Ppy layer was obtained from freshly prepared polymerization solution consisting of pyrrole that was dissolved in phosphate buffer. The main aim of the study was to determine some aspects of the Ppy layer formation process. The polymerization process was estimated by EQCM and chronoamperometry. The Cottrell equation was used for the integration of total charge that was passing through the electrochemical cell during the formation of the Ppy-based layer. It was found that the charge of the electrical double layer, which was estimated while applying an Anson plot, is negative. From this observation, it could be assumed that the pyrrole oxidation process could be well described by principles of heterogeneous kinetics. The negative value of the electrical double layer was the result of a charge-transfer restriction. This restriction of charge transfer could occur due to partial blocking of the electrode surface by an aggregated Ppy particle-based layer. Quartz crystal motional resistance (R) was taken into account during this research. Ppy layer formation is represented schematically on the basis of the obtained experimental results and analytical data. PMID- 25706445 TI - Alkali-metal-ion-directed self-assembly of redox-active manganese(III) supramolecular boxes. AB - The ability to organize functional molecules into higher dimensional arrays with well-defined spatial relationships between the components is one of the major goals in supramolecular chemistry. We report here a new route for the preparation of supramolecular boxes, incorporating two types of metal ions: (i) alkali-metal ions, which induce the supramolecular architecture and essentially play a structural role in the final compounds; (ii) manganese(III) ions, which are redox active systems and give functionality to the new cages. Our results evidence that the size of the cavity inside the box can be tuned depending on the alkali metal used, a characteristic that gives this new family of compounds the potential to act selectively against different substrates. These compounds behave as active catalysts for disproportionation of H2O2 or for water photolysis, but they catalyze neither catecholase reaction nor peroxidase action upon using bulky organic substrates. PMID- 25706446 TI - Allele Mining Strategies: Principles and Utilisation for Blast Resistance Genes in Rice (Oryza sativa L.). AB - Allele mining is a promising way to dissect naturally occurring allelic variants of candidate genes with essential agronomic qualities. With the identification, isolation and characterisation of blast resistance genes in rice, it is now possible to dissect the actual allelic variants of these genes within an array of rice cultivars via allele mining. Multiple alleles from the complex locus serve as a reservoir of variation to generate functional genes. The routine sequence exchange is one of the main mechanisms of R gene evolution and development. Allele mining for resistance genes can be an important method to identify additional resistance alleles and new haplotypes along with the development of allele-specific markers for use in marker-assisted selection. Allele mining can be visualised as a vital link between effective utilisation of genetic and genomic resources in genomics-driven modern plant breeding. This review studies the actual concepts and potential of mining approaches for the discovery of alleles and their utilisation for blast resistance genes in rice. The details provided here will be important to provide the rice breeder with a worthwhile introduction to allele mining and its methodology for breakthrough discovery of fresh alleles hidden in hereditary diversity, which is vital for crop improvement. PMID- 25706447 TI - A suggestion to improve a day keeps your depletion away: Examining promotive and prohibitive voice behaviors within a regulatory focus and ego depletion framework. AB - One way that employees contribute to organizational effectiveness is by expressing voice. They may offer suggestions for how to improve the organization (promotive voice behavior), or express concerns to prevent harmful events from occurring (prohibitive voice behavior). Although promotive and prohibitive voices are thought to be distinct types of behavior, very little is known about their unique antecedents and consequences. In this study we draw on regulatory focus and ego depletion theories to derive a theoretical model that outlines a dynamic process of the antecedents and consequences of voice behavior. Results from 2 multiwave field studies revealed that promotion and prevention foci have unique ties to promotive and prohibitive voice, respectively. Promotive and prohibitive voice, in turn, were associated with decreases and increases, respectively, in depletion. Consistent with the dynamic nature of self-control, depletion was associated with reductions in employees' subsequent voice behavior, regardless of the type of voice (promotive or prohibitive). Results were consistent across 2 studies and remained even after controlling for other established antecedents of voice and alternative mediating mechanisms beside depletion. PMID- 25706448 TI - Creating a more quit-friendly national workforce? Individual layoff history and voluntary turnover. AB - Although Bureau of Labor Statistics data reveal that U.S. employers laid off over 30 million employees since 1994, virtually no research has addressed the behavior of layoff victims upon reemployment. In a first step, we investigate how layoffs shape voluntary turnover behavior in subsequent jobs. Utilizing a recently developed fixed effects specification of survival analysis, we find that a layoff history is positively associated with quit behavior. This effect is partially mediated by underemployment and job satisfaction in the postlayoff job. The remaining direct effect is consistent with the notion that layoffs produce a psychological spillover to postlayoff employment, which then manifests in quit behavior. We also find that layoff effects on turnover attenuate as an individual's layoffs accumulate and vary in magnitude according to the turnover "path" followed by the leaver. PMID- 25706449 TI - Metal fume fever and polymer fume fever. AB - INTRODUCTION: Inhalational exposure to metal-containing fumes generated by welding and related processes may result in the development of the clinical syndrome known as "metal fume fever." Polymer fume fever is a separate and distinct but related disorder that has been associated with inhalational exposure to specific fluorinated polymer products, such as polytetrafluoroethylene or Teflon((r)). We undertook a review of the peer-reviewed medical literature as it relates to these two disease entities in order to describe their epidemiology, pathophysiology, clinical presentation, diagnosis, treatment, prevention, and prognosis. METHODOLOGY: We performed a search of the PubMed ( www.pubmed.com ) and Ovid MEDLINE (ovidsp.tx.ovid.com) databases for keywords "metal fume fever," "polymer fume fever," and "fume fever," covering the period 1946 to September 2014, which resulted in a total of 141 citations. Limiting the search to articles published in the English language yielded 115 citations. These 115 articles were manually reviewed for relevance. In addition, the reference lists in each article retrieved were reviewed for additional relevant references. This left 48 relevant citations. EPIDEMIOLOGY: Metal fume fever occurs most commonly as an occupational disease in individuals who perform welding and other metal-joining activities for a living. It is estimated that 1,500-2,500 cases of metal fume fever occur annually in the United States. Polymer fume fever was initially identified as an occupational disease but increased regulations have resulted in decreased incidence in the occupational setting. Overheating of Teflon((r))-coated cookware is one of the more common mechanisms for exposure. PATHOPHYSIOLOGY: While the precise pathophysiology associated with the development of metal fume fever is yet to be elucidated, suggested pathophysiologic mechanisms include pro inflammatory cytokine release, neutrophil activation, and oxygen radical formation. The pathophysiologic mechanism for polymer fume fever has not been definitively elucidated but may involve similar mechanisms to those proposed for metal fume fever. CLINICAL PRESENTATION: Metal fume fever typically presents with generally non-specific complaints including influenza-like symptoms, fever, shaking chills, arthalgias, myalgias, headache, and malaise. Onset of symptoms typically occurs 4-10 h following the exposure to metal-containing fumes. While metal fume fever is typically benign and self-limited, severe cases of the disease have been reported. In patients with ongoing metal fume exposure over the course of a workweek, tachyphylaxis occurs resulting in improvement in symptoms over the course of the workweek and maximal symptoms occurring after an exposure free period such as a weekend. The clinical presentation of polymer fume fever is indistinguishable from metal fume fever, with an exposure history being necessary to distinguish the two entities. DIAGNOSIS: Chest radiographs are typically normal in cases of metal fume fever and polymer fume fever; however, mild vascular congestion may be demonstrated and severe cases may feature diffuse patchy infiltrates. Laboratory studies are typically not necessary but may demonstrate leukocytosis with leftward shift or an elevated erythrocyte sedimentation rate. TREATMENT: The primary treatment for both metal fume fever and polymer fume fever is supportive and directed at symptom relief. Oral hydration, rest, and the use of antipyretics and anti-inflammatory medications (e.g., non-steroidal anti-inflammatory drugs and aspirin) are recommended. A careful workplace exposure assessment analysis conducted by an occupational medicine specialist or clinical toxicologist in concert with a qualified industrial hygienist should be performed. PREVENTION: A careful workplace exposure assessment including measurement of ambient zinc and other metal (e.g., chrome, nickel, copper and manganese) fume concentrations or concentrations of fluorocarbon polymer decomposition products at different locations within the workplace should be performed. PROGNOSIS: Metal fume fever is typically a benign and self-limited disease entity that resolves over 12-48 h following cessation of exposure. CONCLUSIONS: Metal and polymer fume fevers generally follow a benign course with spontaneous resolution of symptoms, though both have the potential to be serious, especially in those with significant preexisting cardiorespiratory disease. PMID- 25706450 TI - Medical toxicologists' practice patterns regarding drug-induced QT prolongation in overdose patients: a survey in the United States of America, Europe, and Asia Pacific region. AB - OBJECTIVE: To describe practice patterns of medical toxicologists in the United States of America (USA), Europe, and Asia Pacific Region regarding management of drug induced QT prolongation and torsades de pointes in overdose. METHODS: A survey was developed to assess current practice patterns and consistency with guidelines published by the American Heart Association (AHA), American College of Cardiology (ACC), and European Society of Cardiology (ESC). It was reviewed by our department research committee and the American College of Medical Toxicology (ACMT). The ACMT, European Association of Poisons Centres and Clinical Toxicologists, and Asia Pacific Association of Medical Toxicology electronically disseminated the survey to their physician members in the USA, Europe and Asia Pacific Region. RESULTS: The overall response rate was 37% (229/617) (36% USA; 32% Europe; 52% Asia Pacific Region). Twelve toxicologists from Asia Pacific Region and Europe used the QT nomogram (Australia-5, New Zealand-1, United Kingdom-1) or QT alone (France-1, Russia-1, Romania-1, Germany-1, Philippines-1), in lieu of the corrected QT (QTc) to determine risks of developing torsades de pointes. Because only those who used QTc could proceed through the remainder of the survey, only 217 could do so. Approximately half of the respondents (52%) did not calculate QTc manually and based decisions on the electrocardiogram machines automated measurement. For those who corrected the QT interval themselves, the most common formula used was Bazett's (40%). There is great variation in the QTc value considered prolonged. Most responders considered QTc greater than 450 ms in men (28%) and 460 ms in women (25%) to be prolonged. Interestingly, approximately 15% of participants did not consider the QTc prolonged until it exceeded 500 ms in both men and women. Given an overdose scenario of a male patient with a QTc of 560 ms, heart rate of 90 beats/minute, 59% would not recommend administering intravenous magnesium sulfate. Forty-five percent and 36% believed magnesium could shorten QTc and prevent torsades de pointes, respectively. In addition, almost 90% believed administering 1-2 boluses of intravenous magnesium is safe, even when serum magnesium is not available. In regards to cardiac pacing of patients with QT prolongation and torsades de pointes, only 38% of the participating toxicologists' responses agreed with AHA/ACC/ESC recommendations. Furthermore, 21% would not pace a patient who developed torsades de pointes regardless of the scenario. DISCUSSION AND CONCLUSIONS: The results indicate that medical toxicologists have considerable heterogeneity in terms of management practices for overdose patients with QT prolongation and torsades de pointes. Medical toxicologists may benefit from developing evidence-based consensus guidelines for the management of this relatively common finding in overdose of QT prolonging drugs. PMID- 25706452 TI - In reply re: "comparison of F(ab')2 versus Fab antivenom for pit viper envenomation: a prospective, blinded, multicenter, randomized clinical trial". PMID- 25706451 TI - Cardiogenic shock induced reduction in cellular O2 delivery as a hallmark of acute H2S intoxication. PMID- 25706453 TI - The second act of the Affordable Care Act. PMID- 25706454 TI - Newborn screening: spotting for more. PMID- 25706455 TI - Literature and medicine: why do we care? PMID- 25706456 TI - Beyond Ebola: a new agenda for resilient health systems. PMID- 25706458 TI - Guy Thwaites: building research coalitions in Vietnam. PMID- 25706459 TI - WHO must remain a strong global health leader post Ebola. PMID- 25706460 TI - Interventions for intimate partner violence. PMID- 25706461 TI - Interventions for intimate partner violence--authors' reply. PMID- 25706462 TI - Pathological complete response in breast cancer. PMID- 25706463 TI - Pathological complete response in breast cancer. PMID- 25706464 TI - Pathological complete response in breast cancer--authors' reply. PMID- 25706465 TI - Pathological complete response in breast cancer. PMID- 25706466 TI - Hepatitis B vaccination for people who inject drugs. PMID- 25706467 TI - Hepatitis B vaccination for people who inject drugs. PMID- 25706468 TI - Hepatitis B vaccination for people who inject drugs--authors' reply. PMID- 25706469 TI - Invasive Listeria monocytogenes infection after liver transplantation: a life threatening condition. PMID- 25706470 TI - Firearm-related injury and death in the United States: a call to action from 8 health professional organizations and the American Bar Association. AB - Deaths and injuries related to firearms constitute a major public health problem in the United States. In response to firearm violence and other firearm-related injuries and deaths, an interdisciplinary, interprofessional group of leaders of 8 national health professional organizations and the American Bar Association, representing the official policy positions of their organizations, advocate a series of measures aimed at reducing the health and public health consequences of firearms. The specific recommendations include universal background checks of gun purchasers, elimination of physician "gag laws," restricting the manufacture and sale of military-style assault weapons and large-capacity magazines for civilian use, and research to support strategies for reducing firearm-related injuries and deaths. The health professional organizations also advocate for improved access to mental health services and avoidance of stigmatization of persons with mental and substance use disorders through blanket reporting laws. The American Bar Association, acting through its Standing Committee on Gun Violence, confirms that none of these recommendations conflict with the Second Amendment or previous rulings of the U.S. Supreme Court. PMID- 25706471 TI - Frequency-specific hippocampal-prefrontal interactions during associative learning. AB - Much of our knowledge of the world depends on learning associations (for example, face-name), for which the hippocampus (HPC) and prefrontal cortex (PFC) are critical. HPC-PFC interactions have rarely been studied in monkeys, whose cognitive and mnemonic abilities are akin to those of humans. We found functional differences and frequency-specific interactions between HPC and PFC of monkeys learning object pair associations, an animal model of human explicit memory. PFC spiking activity reflected learning in parallel with behavioral performance, whereas HPC neurons reflected feedback about whether trial-and-error guesses were correct or incorrect. Theta-band HPC-PFC synchrony was stronger after errors, was driven primarily by PFC to HPC directional influences and decreased with learning. In contrast, alpha/beta-band synchrony was stronger after correct trials, was driven more by HPC and increased with learning. Rapid object associative learning may occur in PFC, whereas HPC may guide neocortical plasticity by signaling success or failure via oscillatory synchrony in different frequency bands. PMID- 25706472 TI - A subcortical inhibitory signal for behavioral arrest in the thalamus. AB - Organization of behavior requires rapid coordination of brainstem and forebrain activity. The exact mechanisms of effective communication between these regions are presently unclear. The intralaminar thalamic nuclei (IL) probably serves as a central hub in this circuit by connecting the critical brainstem and forebrain areas. We found that GABAergic and glycinergic fibers ascending from the pontine reticular formation (PRF) of the brainstem evoked fast and reliable inhibition in the IL via large, multisynaptic terminals. This inhibition was fine-tuned through heterogeneous GABAergic and glycinergic receptor ratios expressed at individual synapses. Optogenetic activation of PRF axons in the IL of freely moving mice led to behavioral arrest and transient interruption of awake cortical activity. An afferent system with comparable morphological features was also found in the human IL. These data reveal an evolutionarily conserved ascending system that gates forebrain activity through fast and powerful synaptic inhibition of the IL. PMID- 25706473 TI - The dissociable effects of punishment and reward on motor learning. AB - A common assumption regarding error-based motor learning (motor adaptation) in humans is that its underlying mechanism is automatic and insensitive to reward- or punishment-based feedback. Contrary to this hypothesis, we show in a double dissociation that the two have independent effects on the learning and retention components of motor adaptation. Negative feedback, whether graded or binary, accelerated learning. While it was not necessary for the negative feedback to be coupled to monetary loss, it had to be clearly related to the actual performance on the preceding movement. Positive feedback did not speed up learning, but it increased retention of the motor memory when performance feedback was withdrawn. These findings reinforce the view that independent mechanisms underpin learning and retention in motor adaptation, reject the assumption that motor adaptation is independent of motivational feedback, and raise new questions regarding the neural basis of negative and positive motivational feedback in motor learning. PMID- 25706474 TI - What does gamma coherence tell us about inter-regional neural communication? AB - Neural oscillations have been measured and interpreted in multitudinous ways, with a variety of hypothesized functions in physiology, information processing and cognition. Much attention has been paid in recent years to gamma-band (30-100 Hz) oscillations and synchrony, with an increasing interest in 'high gamma' (>100 Hz) signals as mesoscopic measures of inter-regional communication. The biophysical origins of the measured variables are often difficult to precisely identify, however, making their interpretation fraught with pitfalls. Here we discuss how measurements of inter-regional gamma coherence can be prone to misinterpretation and suggest strategies for deciphering the roles that synchronized oscillations across brain networks may play in neural function. PMID- 25706475 TI - Nuclear export inhibitors avert progression in preclinical models of inflammatory demyelination. AB - Axonal damage has been associated with aberrant protein trafficking. We examined a newly characterized class of compounds that target nucleo-cytoplasmic shuttling by binding to the catalytic groove of the nuclear export protein XPO1 (also known as CRM1, chromosome region maintenance protein 1). Oral administration of reversible CRM1 inhibitors in preclinical murine models of demyelination significantly attenuated disease progression, even when started after the onset of paralysis. Clinical efficacy was associated with decreased proliferation of immune cells, characterized by nuclear accumulation of cell cycle inhibitors, and preservation of cytoskeletal integrity even in demyelinated axons. Neuroprotection was not limited to models of demyelination, but was also observed in another mouse model of axonal damage (that is, kainic acid injection) and detected in cultured neurons after knockdown of Xpo1, the gene encoding CRM1. A proteomic screen for target molecules revealed that CRM1 inhibitors in neurons prevented nuclear export of molecules associated with axonal damage while retaining transcription factors modulating neuroprotection. PMID- 25706477 TI - Recommendations from the workshop on Comparative Approaches to Safety Assessment of GM Plant Materials: A road toward harmonized criteria? AB - An international meeting of genetically modified (GM) food safety assessors from the main importing and exporting countries from Asia and the Americas was held in Buenos Aires, Argentina, between June 26(th) and 28(th), 2013. Participants shared their evaluation approaches, identified similarities and challenges, and used their experience to propose areas for future work. Recommendations for improving risk assessment procedures and avenues for future collaboration were also discussed. The deliberations of the meeting were also supported by a survey of participants which canvassed risk assessment approaches across the regions from which participants came. This project was initiated by Argentine Agri-Food Health and Quality National Service (SENASA, Ministry of Agriculture, Argentina), with the support of the International Life Sciences Institute (ILSI) and other partner institutions. The importance of making all possible efforts toward more integrated and harmonized regulatory oversight for GM organisms (GMOs) was strongly emphasized. This exercise showed that such harmonization is a feasible goal that would contribute to sustain a fluid trade of commodities and ultimately enhance food security. Before this can be achieved, key issues identified in this meeting will have to be addressed in the near future to enable regulatory collaboration or joint work. The authors propose that the recommendations coming out of the meeting should be used as a basis for continuing work, follow up discussions and concrete actions. PMID- 25706476 TI - Neuronal ensembles sufficient for recovery sleep and the sedative actions of alpha2 adrenergic agonists. AB - Do sedatives engage natural sleep pathways? It is usually assumed that anesthetic induced sedation and loss of righting reflex (LORR) arise by influencing the same circuitry to lesser or greater extents. For the alpha2 adrenergic receptor agonist dexmedetomidine, we found that sedation and LORR were in fact distinct states, requiring different brain areas: the preoptic hypothalamic area and locus coeruleus (LC), respectively. Selective knockdown of alpha2A adrenergic receptors from the LC abolished dexmedetomidine-induced LORR, but not sedation. Instead, we found that dexmedetomidine-induced sedation resembled the deep recovery sleep that follows sleep deprivation. We used TetTag pharmacogenetics in mice to functionally mark neurons activated in the preoptic hypothalamus during dexmedetomidine-induced sedation or recovery sleep. The neuronal ensembles could then be selectively reactivated. In both cases, non-rapid eye movement sleep, with the accompanying drop in body temperature, was recapitulated. Thus, alpha2 adrenergic receptor-induced sedation and recovery sleep share hypothalamic circuitry sufficient for producing these behavioral states. PMID- 25706478 TI - Pediatric intensive care unit mortality among Latino children before and after a multilevel health care delivery intervention. AB - IMPORTANCE: Research on health equity has focused on documenting health care disparities or understanding factors leading to disparities, but limited efforts have focused on reducing health care disparities in children. Latino children have increased prevalence of acute and chronic conditions; they have limited access and other barriers to high-quality health care, including intensive care. OBJECTIVE: To determine whether pediatric intensive care unit mortality can be reduced by a multilevel health care delivery intervention. DESIGN, SETTING, AND PARTICIPANTS: Observational study of factors associated with pediatric intensive care unit mortality at a tertiary care metropolitan children's hospital in Memphis, Tennessee. Participants were children younger than 18 years discharged from the pediatric intensive care unit during the 3-year preintervention period of 2007 to 2009 (n = 3891) and 3-year postintervention period of 2010 to 2012 (n = 4179). INTERVENTIONS: Multilevel health care intervention to address the increased odds of mortality among Latino children. MAIN OUTCOMES AND MEASURES: The odds of mortality were analyzed over the 3-year preintervention period (2007 2009) using multivariable logistic regressions to control for age, sex, race/ethnicity, severity of illness, major diagnostic categories, diagnosed infections, and insurance status. Data from the postintervention period (2010 2012) were analyzed similarly to measure the effect of changes in health care delivery. RESULTS: Unadjusted mortality rates for white, African American, and Latino children in 2007 to 2009 were 3.3%, 3.3%, and 8.6%, respectively. After controlling for covariates, no differences in the odds of mortality were observed between white children and African American children (odds ratio [OR], 1.0; 95% CI, 0.6-1.7; P = .97), but Latino children had 3.7-fold (95% CI, 1.8-7.5; P < .001) higher odds of mortality. A multilevel and multidisciplinary intervention was launched to address these differences. In the postintervention period, unadjusted mortality rates for white, African American, and Latino children were 3.6%, 3.2%, and 4.0%, respectively, with no differences observed after adjustment for covariates (OR, 0.7; 95% CI, 0.2-2.1; P = .49). The odds of mortality decreased between the preintervention period and postintervention period for Latino children (OR, 0.24; 95% CI, 0.06-0.88; P = .03) but remained unchanged for white and African American children (OR, 1.02; 95% CI, 0.73-1.43; P = .90). CONCLUSIONS AND RELEVANCE: Latino children had higher odds of mortality, even after controlling for age, sex, severity of illness, insurance status, and other covariates. These differences disappeared after culturally and linguistically sensitive interventions at multiple levels. Local multilevel interventions can reduce the effect of health care inequities on clinical outcomes, without requiring major changes in health care policy. PMID- 25706479 TI - Challenges in assessing spiritual distress in survivors of cancer. AB - BACKGROUND: Many efforts have been made to better integrate spiritual assessment into the care of patients with cancer, with varying degrees of success in different parts of the United States. Little work has been done to describe challenges that face those who seek to implement assessment in busy ambulatory settings, particularly in the northeastern section of the United States. OBJECTIVES: This study sought to test the feasibility of a screening process describing spirituality, distress, and spiritual transformation in cancer survivors after chemotherapy for lung or gastrointestinal cancer. METHODS: This descriptive pilot study took place in a rural National Cancer Institute- designated comprehensive cancer center, referral center, and outpatient medical oncology clinic. A web-based questionnaire was completed by 29 survivors, and 22 declined participation. FINDINGS: Respondents were primarily Christian, aged 60 years or older, and an average of 18 months post-diagnosis. The mean spiritual distress score was 1.38 (SD = 2.09), and the mean psychological distress score was 3.03 (SD = 2.73). Participants reported mean spiritual well-being, positive degree of spiritual growth, and little spiritual decline. The opportunity for spiritual growth among survivors creates a need for effective assessment and intervention to promote spiritual growth and mitigate spiritual decline and spiritual distress. PMID- 25706480 TI - OH-directed alkynylation of 2-vinylphenols with ethynyl benziodoxolones: a fast access to terminal 1,3-enynes. AB - The first direct alkynylation of 2-vinylphenols was developed. The rationally optimized hypervalent iodine reagent TIPS-EBX* in combination with [(Cp*RhCl2)2] as a C-H-activating transition metal catalyst enables the construction of a variety of highly substituted 1,3-enynes in high yields of up to 98%. This novel C-H activation method shows excellent chemoselectivity and exclusive (Z) stereoselectivity, and it is also remarkably mild and tolerates a variety of functional groups. Furthermore, synthetic modifications of the resulting 1,3 enynes were demonstrated. To our knowledge, this is the first example for an OH directed C-H alkynylation with hypervalent iodine reagents. PMID- 25706481 TI - Additive-free decarboxylative coupling of cinnamic acid derivatives in water: synthesis of allyl amines. AB - The first example of an additive-free decarboxylative coupling of cinnamic acid derivatives with formaldehyde and amines to afford the corresponding allyl amines is reported. This reaction is highly environmentally friendly because it was conducted in H2O and without any additives, releasing only CO2 and H2O as byproducts. This reaction showed a broad substrate scope including cyclic and acyclic amines and high functional group tolerance. Moreover, phenyl dienoic acid participated in this type of decarboxylative coupling reaction. PMID- 25706483 TI - Anthocyanin-rich cherry juice does not improve acute cognitive performance on RAVLT. PMID- 25706484 TI - Stable hydrogen and carbon isotope ratios of methoxyl groups during plant litter degradation. AB - Stable hydrogen and carbon isotope ratios of methoxyl groups (delta(2)Hmethoxyl and delta(13)Cmethoxyl values, respectively) in plant material have been shown to possess characteristic signatures. These isotopic signatures can be used for a variety of applications such as constraining the geographical origin and authenticity of biomaterials. Recently, it has also been suggested that delta(2)Hmethoxyl values of sedimentary organic matter of geological archives might serve as a palaeoclimate/-hydrology proxy. However, deposited organic matter is subject to both biotic and abiotic degradation processes, and therefore an evaluation of their potential impact on the delta(2)Hmethoxyl and delta(13)Cmethoxyl values would allow more reliable interpretations of both isotopic signatures. Here, we investigated this potential influence by exposing foliar litter of five different tree species (Sycamore maple, Mountain ash, European beech, Norway spruce and Scots pine) to natural degradation. The foliar litter was sampled at nine intervals over a 27-month period, and the bulk methoxyl content as well as the delta(2)Hmethoxyl and delta(13)Cmethoxyl values were measured. At the end of the experiment, a loss of the bulk methoxyl in the range of ~40-70% was measured. Linear regression analysis showed no dependence of delta(2)Hmethoxyl values with methoxyl content for four out of five foliar litter samples studied (R(2) in the range of 0.03 and 0.36, p > .05). On the contrary, the delta(13)Cmethoxyl values showed significant linear correlations for the great majority of the foliar litter samples (R(2) in the range of 0.51 and 0.73, p < .05). The litter species with the greatest methoxyl loss (Mountain ash, Scots pine and Norway spruce) showed the strongest (13)C enrichment, by up to ~50/00. Since delta(2)Hmethoxyl shows no systematic overall change during the course of degradation, we propose that there is considerable potential for its use as a palaeoclimate proxy for a wide range of geological archives containing, for instance, fossil wood or sedimentary organic matter. Care would need to be taken if delta(13)Cmethoxyl values of degraded organic matter are used for palaeoclimate/-environmental investigations. PMID- 25706482 TI - Novel FUS-KLF17 and EWSR1-KLF17 fusions in myoepithelial tumors. AB - Myoepithelial (ME) tumors of soft tissue and bone display a heterogeneous histologic spectrum and in about half of the cases harbor EWSR1 gene rearrangements. Despite rare case reports, the prevalence of fused in sarcoma (FUS) gene abnormalities and its related fusion partners remains undetermined among ME tumors. Therefore, we screened 66 EWSR1-negative ME tumors for FUS abnormalities by fluorescence in situ hybridization (FISH). In an index FUS rearranged case, 3'-rapid amplification of cDNA ends (RACE) was applied to identify the fusion partner. Results were further confirmed by reverse transcription-PCR, followed by FISH screening the entire cohort of FUS-rearranged and EWSR1-positive ME lesions lacking a known fusion partner. The correlation between genotype and clinicopathological features was also investigated. As a result, six (9%) FUS-rearranged cases were identified, spanning divergent age groups, tumor locations, and morphologic features. A novel FUS-KLF17 fusion was identified by 3'-RACE in an 11-year-old girl with a foot lesion associated with locoregional metastases. Three additional cases with FUS-KLF17 fusions were identified and one KLF17 rearrangement (6.3%) was found among the 16 EWSR1 positive cases tested. The KLF17-related ME tumors affected younger patients and often exhibited trabecular growth in a myxohyaline stroma, but this genotype did not correlate with a malignant phenotype. In conclusion, a small subset of ME tumors harbor FUS rearrangements, two thirds of them being associated with KLF17 fusion. FUS FISH analysis is recommended in EWSR1-negative lesions in which a ME diagnosis is suspected. KLF17 is also a rare gene fusion partner to EWSR1 rearranged ME tumors. PMID- 25706485 TI - The complex impact of risk and protective factors on suicide mortality: a study of the Ukrainian general population. AB - This study assesses the complex impact of risk and protective factors on suicide mortality in the Ukrainian general population. Data on suicide rates and socioeconomic and medical factors were obtained from the Ukrainian State Statistical Office, WHO, and the European Social Survey. Structural equation modeling was used for data analysis. Religion and education were negatively associated with suicide. The relationship between drug addiction/alcoholism and suicide was positive. The association between urbanization and suicide mortality was negative. The relationship between gross regional product (GRP) and female suicide was slightly negative. Religiosity was the protective factor most strongly linked with suicide mortality followed by urbanization. The harmful role of drug addiction and alcoholism was confirmed. The role of education and GRP is controversial. No striking gender differences were found. PMID- 25706486 TI - A population-based observational study of intensive care unit-related outcomes. With emphasis on post-hospital outcomes. AB - RATIONALE: Many studies of critical illness outcomes have been restricted to short-term outcomes, selected diagnoses, and patients in one or a few intensive care units (ICUs). OBJECTIVES: Evaluate a range of relevant outcomes in a population-based cohort of patients admitted to ICUs. METHODS: Among all adult residents of the Canadian province of Manitoba admitted to ICUs over a 9-year period, we assessed ICU, hospital, 30-day, and 180-day mortality rates; ICU and hospital lengths-of-stay; Post-hospital use of hospital care, ICU care, outpatient physician care, medications, and home care; and Post-hospital residence location. We explored data stratified by age, sex, and separate categories of geocoded income for urban and rural residents. For Post-hospital use variables we compared ICU patients with those admitted to hospitals without the need for ICU care. MEASUREMENTS AND MAIN RESULTS: After ICU admission there was a high initial death rate, which declined between 30 and 180 days and thereafter remained at the lower value. Hospital mortality was 19.0%, with 21.7% dying within 6 months of ICU admission. Women had higher hospital mortality than men (20.8 vs. 17.8%; P = 0.0008). Among urban residents there was a steady gradient of declining hospital mortality with rising income (P < 0.0001). Mean ICU length of stay was 3.96 days, increasing 0.11 d/yr over the study period (P = 0.001); median ICU length of stay was 2.33 days and did not change over time. In the year after ICU care, 41% were rehospitalized, 10% were readmitted to an ICU, 98% had outpatient physician visits, 96% used prescription medications, and 27% used home care services. Although most of these parameters were statistically higher than for hospitalizations not requiring ICU care, differences were generally small. Among hospital survivors, 2.7% were discharged to chronic care facilities, with 2.5% living in such facilities 3 months later. CONCLUSIONS: Post hospital medical resource use among ICU survivors is substantial, although similar to that after non-ICU hospitalization. Although the fraction of survivors unable to live independently was small, a larger fraction required home care services. Identifying Post-hospital supports needed by ICU survivors can be useful for policy makers and others responsible for healthcare planning. PMID- 25706487 TI - Does marijuana pose risks for chronic airflow obstruction? PMID- 25706488 TI - Guiding the guiders. Recognizing surrogates' needs and advancing communication in the intensive care unit. PMID- 25706489 TI - Health care-associated pneumonia is mostly dead. Long live the acronym PES? PMID- 25706490 TI - Use of inhaled corticosteroids among Hispanics in the United States. PMID- 25706491 TI - Identifying and targeting intensive care unit survivors at risk for excess morbidity and premature death. PMID- 25706492 TI - Climate change at the bedside? Observations from an ATS membership survey. PMID- 25706493 TI - From closing the atmospheric ozone hole to reducing climate change. Lessons learned. AB - Global warming presents U.S. and transnational leaders with enormous political and policy challenges. World leadership addressed a similar worldwide environmental challenge in the 1980s and 1990s when scientists advised that accelerating emission of man-made chlorofluorocarbons was depleting the ozone layer of the earth's atmosphere. The process that led to global agreement on reducing depletion of the ozone layer holds valuable lessons, and some ironies, for scientists and policy makers seeking now to address global climate change. By understanding the international treaty process, how science informed that process, and how the physician community played a constructive role in the transition away from commercial use of ozone-depleting gases three decades ago, environmental activists can better understand the challenges, opportunities, and potential solutions under current consideration in affecting global climate change. PMID- 25706494 TI - Achromobacter respiratory infections. AB - Achromobacteria are ubiquitous environmental organisms that may also become opportunistic pathogens in certain conditions, such as cystic fibrosis, hematologic and solid organ malignancies, renal failure, and certain immune deficiencies. Some members of this genus, such as xylosoxidans, cause primarily nosocomially acquired infections affecting multiple organ systems, including the respiratory tract, urinary tract, and, less commonly, the cardiovascular and central nervous systems. Despite an increasing number of published case reports and literature reviews suggesting a global increase in achromobacterial disease, most clinicians remain uncertain of the organism's significance when clinically isolated. Moreover, effective treatment can be challenging due to the organism's inherent and acquired multidrug resistance patterns. We reviewed all published cases to date of non-cystic fibrosis achromobacterial lung infections to better understand the organism's pathogenic potential and drug susceptibilities. We found that the majority of these cases were community acquired, typically presenting as pneumonias (88%), and were most frequent in individuals with hematologic and solid organ malignancies. Our findings also suggest that achromobacterial lung infections are difficult to treat, but respond well to extended-spectrum penicillins and cephalosporins, such as ticarcillin, piperacillin, and cefoperazone. PMID- 25706495 TI - Asthma with brain lesions. PMID- 25706496 TI - Alterations in gas exchange due to low-tidal volume ventilation. PMID- 25706497 TI - Upper airway obstruction from gonococcal thyroglossal duct cyst infection: a case report. PMID- 25706498 TI - International study on antidepressant prescription pattern at 40 major psychiatric institutions and hospitals in Asia: A 10-year comparison study. AB - INTRODUCTION: Research in prescription pattern of antidepressants in Asia is lacking. This study aims to compare the antidepressants prescription pattern in Asia in 2003-2004 and 2013. METHODS: The Research in East Asia Psychotropic Prescription Pattern on Antidepressants (REAP-AD) had worked collaboratively in 2003-2004 (REAP-AD 2003/2004) and 2013 (REAP-AD 2013) to study the prescription pattern of antidepressants in Asia. The REAP-AD 2013 study was conducted in China, Hong Kong, India, Indonesia, Japan, Korea, Malaysia, Singapore, Taiwan, and Thailand using a unified research protocol and questionnaire. RESULTS: Forty psychiatric centers participated in REAP-AD 2013 and a total of 2,319 patients receive antidepressants were analyzed. In 2013, 39.6% of the antidepressant prescriptions were for diagnoses other thandepressive disorder compared with 38.4% in REAP-AD 2003/2004. Out of all the antidepressants listed in the Anatomical Therapeutic Chemical Classification index by the World Health Organization Collaborating Center for Drug Statistics Methodology (Oslo), only 38% antidepressants were prescribed in participating centers in 2013 compared with 46% in REAP-AD 2003/2004. The selective serotonin reuptake inhibitors were the most common antidepressant prescribed in the participating centers, which was similar to the 2003-2004 survey. Prescription of newer generation antidepressants had increased in 2013 survey; on the contrary, prescription of tricyclic antidepressants had reduced. DISCUSSION: This study has contributed significantly in relation to the changing patterns of antidepressant use in all the participating Asian centers in the last 10 years. The findings are important in shaping optimal antidepressant prescription and future policy making. PMID- 25706499 TI - Multichannel Double-Row Transmission Line Array for Human MR Imaging at Ultrahigh Fields. AB - OBJECTIVE: In microstrip transmission line (MTL) transmit/receive (transceive) arrays used for ultrahigh field MRI, the array length is often constrained by the required resonant frequency, limiting the image coverage. The purpose of this study is to increase the imaging coverage and also improve its parallel imaging capability by utilizing a double-row design. METHODS: A 16-channel double-row MTL transceive array was designed, constructed, and tested for human head imaging at 7 T. Array elements between two rows were decoupled by using the induced current elimination or magnetic wall decoupling technique. In vivo human head images were acquired, and g-factor results were calculated to evaluate the performance of this double-row array. RESULTS: Testing results showed that all coil elements were well decoupled with a better than -18 dB transmission coefficient between any two elements. The double-row array improves the imaging quality of the lower portion of the human head, and has low g-factors even at high acceleration rates. CONCLUSION: Compared with a regular single-row MTL array, the double-row array demonstrated a larger imaging coverage along the z-direction with improved parallel imaging capability. SIGNIFICANCE: The proposed technique is particularly suitable for the design of large-sized transceive arrays with large channel counts, which ultimately benefits the imaging performance in human MRI. PMID- 25706500 TI - Nonlinear Dynamic Modelling of Platelet Aggregation via Microfluidic Devices. AB - The recent application of new microfluidic technologies and methods has facilitated significant progress in the understanding of the fundamental mechanisms governing blood platelet function and how these parameters affect pathological thrombus formation. In-line with these new bioengineering approaches, the application of nonlinear dynamic systems analysis holds particular potential to extend our understanding of the complex interplay between mechanical and biochemical factors that underlie this complex biological phenomenon. In this paper we propose a simple mathematical model of the main dynamics of platelet aggregation/disaggregation observed experimentally in a novel microfluidic device that approximates a severe arterial stenosis. We apply dynamic systems theory (system identification) to explore the dynamics of the biomechanical platelet aggregation response to a range of shear stress rates, inhibiting blood-born chemical pathways of platelet activation (ADP, TXA2, and thrombin). We demonstrate that the proposed model is able to replicate experimental results with low variation, and suggest that the reduced set of model parameters has the potential to be used as a simplified way to evaluate the biomechanical dynamics of platelet aggregation. The proposed model has application to the development of automatic controllers within the context of microfluidic systems that may show great utility in the clinical assessment of platelet hyperfunction. PMID- 25706501 TI - A Switched-Mode Breast Coil for 7 T MRI Using Forced-Current Excitation. AB - In high-field magnetic resonance imaging, the radio frequency wavelength within the human body is comparable to anatomical dimensions, resulting in B1 inhomogeneity and nonuniform sensitivity patterns. Thus, this relatively short wavelength presents engineering challenges for RF coil design. In this study, a bilateral breast coil for (1)H imaging at 7 T was designed and constructed using forced-current excitation. By forcing equal current through the coil elements, we reduce the effects of coupling between the elements to simplify tuning and to ensure a uniform field across both breasts. To combine the benefits of the higher power efficiency of a unilateral coil with the bilateral coverage of a bilateral coil, a switching circuit was implemented to allow the coil to be reconfigured for imaging the left, right, or both breasts. PMID- 25706502 TI - Simultaneous Reconstruction and Segmentation of Dynamic PET via Low-Rank and Sparse Matrix Decomposition. AB - Although of great clinical value, accurate and robust reconstruction and segmentation of dynamic positron emission tomography (PET) images are great challenges due to low spatial resolution and high noise. In this paper, we propose a unified framework that exploits temporal correlations and variations within image sequences based on low-rank and sparse matrix decomposition. Thus, the two separate inverse problems, PET image reconstruction and segmentation, are accomplished in a simultaneous fashion. Considering low signal to noise ratio and piece-wise constant assumption of PET images, we also propose to regularize low rank and sparse matrices with vectorial total variation norm. The resulting optimization problem is solved by augmented Lagrangian multiplier method with variable splitting. The effectiveness of proposed approach is validated on realistic Monte Carlo simulation datasets and the real patient data. PMID- 25706503 TI - A Novel Region Reconstruction Method for Fluorescence Molecular Tomography. AB - Fluorescence molecular tomography (FMT) could exploit the distribution of fluorescent biomarkers that target tumors accurately and effectively, which enables noninvasive real-time 3-D visualization as well as quantitative analysis of small tumors in small animal studies in vivo. Due to the difficulties of reconstruction, continuous efforts are being made to find more practical and efficient approaches to accurately obtain the characteristics of fluorescent regions inside biological tissues. In this paper, we propose a region reconstruction method for FMT, which is defined as an L1-norm regularization piecewise constant level set approach. The proposed approach adopts a priori information including the sparsity of the fluorescent sources and the fluorescent contrast between the target and background. When the contrast of different fluorescent sources is low to a certain degree, our approach can simultaneously solve the detection and characterization problems for the reconstruction of FMT. To evaluate the performance of the region reconstruction method, numerical phantom experiments and in vivo bead-implanted mouse experiments were performed. The results suggested that the proposed region reconstruction method was able to reconstruct the features of the fluorescent regions accurately and effectively, and the proposed method was able to be feasibly adopted in in vivo application. PMID- 25706504 TI - Numerical Investigation of the Mechanisms of Ultrasound-Modulated Bioluminescence Tomography. AB - OBJECTIVE: A hybrid imaging technique, ultrasound-modulated luminescence tomography, that uses ultrasound to modulate diffusely propagating light has been shown to improve the spatial resolution of optical images. This paper investigates the underlying modulation mechanisms and the feasibility of applying this technique to improve spatial resolution in bioluminescence tomography. METHODS: Ultrasound-modulated bioluminescence tomography was studied numerically to identify the effects of four factors (reduced optical scattering coefficient, optical absorption coefficient, refractive index, and luciferase concentration) on the depth of light modulation. In practice, an open source finite-element method tool for simulation of diffusely propagating light, near infrared fluorescence and spectral tomography, was modified to incorporate the effects of ultrasound modulation. The signal-to-noise ratios of detected modulated bioluminescent emissions are calculated using the optical and physical properties of a mouse model. RESULTS: The modulation depth of the bioluminescent emission affected by the US induced variation of local concentration of the light emitting enzyme luciferase was at least two orders of magnitude greater than that caused by variations in the other factors. For surface radiances above approximately 10(7) photons/s/cm(2)/sr, the corresponding SNRs are detectable with the currently available detector technologies. CONCLUSION: The dominant effect in generation of ultrasound-modulated bioluminescence is ultrasound induced variation in luciferase concentration. The SNR analysis confirms the feasibility of applying ultrasound-modulated bioluminescence tomography in preclinical imaging of mice. SIGNIFICANCE: The simulation model developed suggests ultrasound modulated bioluminescence tomography is a potential technique to improve the spatial resolution of bioluminescence tomography. PMID- 25706505 TI - Conceptual Network Model From Sensory Neurons to Astrocytes of the Human Nervous System. AB - From a single-cell animal like paramecium to vertebrates like ape, the nervous system plays an important role in responding to the variations of the environment. Compared to animals, the nervous system in the human body possesses more intricate organization and utility. The nervous system anatomy has been understood progressively, yet the explanation at the cell level regarding complete information transmission is still lacking. Along the signal pathway toward the brain, an external stimulus first activates action potentials in the sensing neuron and these electric pulses transmit along the spinal nerve or cranial nerve to the neurons in the brain. Second, calcium elevation is triggered in the branch of astrocyte at the tripartite synapse. Third, the local calcium wave expands to the entire territory of the astrocyte. Finally, the calcium wave propagates to the neighboring astrocyte via gap junction channel. In our study, we integrate the existing mathematical model and biological experiments in each step of the signal transduction to establish a conceptual network model for the human nervous system. The network is composed of four layers and the communication protocols of each layer could be adapted to entities with different characterizations. We verify our simulation results against the available biological experiments and mathematical models and provide a test case of the integrated network. As the production of conscious episode in the human nervous system is still under intense research, our model serves as a useful tool to facilitate, complement and verify current and future study in human cognition. PMID- 25706506 TI - An Inflection Point Method for the Determination of Pulmonary Transit Time From Contrast Echocardiography. AB - OBJECTIVE: Indicator-dilution curves (IDCs) for the estimation of pulmonary transit times (PTTs) can be generated noninvasively using contrast echocardiography. Currently, these IDCs are analyzed by manual inspection, which is not feasible in a clinical setting, or fit to a statistical model to derive parameters of interest. However, IDCs generated from patients are frequently subject to significant low-frequency noise and recirculation artifacts that obscure the first-pass signal and render model fitting impractical or inaccurate. Thus, the objective of this paper was to develop alternative computational methods to determine PTT using noisy clinical data in which the signal decay is not adequately visible. METHODS: We report on a method that uses a model fit to the rise portion of the IDCs to determine the signal inflection point. Additionally, a signal truncation algorithm was developed that enables automated analysis of the IDCs. RESULTS: We compare PTTs derived from our inflection point method to those obtained by manual inspection in 25 patients (R(2) = 0.86) and to those obtained by mean transit time calculation following fitting to a local density random walk model (R(2) = 0.80) in a subset of this cohort. CONCLUSION: Combined with a signal truncation algorithm, the inflection point method provides robust, automated determination of PTT from noisy IDCs containing recirculation artifacts. SIGNIFICANCE: The inflection point method addresses the need for computational analysis of IDCs obtained from contrast echocardiograms that are not amenable to first-pass model fitting. PMID- 25706507 TI - A Complete Color Normalization Approach to Histopathology Images Using Color Cues Computed From Saturation-Weighted Statistics. AB - GOAL: In digital histopathology, tasks of segmentation and disease diagnosis are achieved by quantitative analysis of image content. However, color variation in image samples makes it challenging to produce reliable results. This paper introduces a complete normalization scheme to address the problem of color variation in histopathology images jointly caused by inconsistent biopsy staining and nonstandard imaging condition. Method : Different from existing normalization methods that either address partial cause of color variation or lump them together, our method identifies causes of color variation based on a microscopic imaging model and addresses inconsistency in biopsy imaging and staining by an illuminant normalization module and a spectral normalization module, respectively. In evaluation, we use two public datasets that are representative of histopathology images commonly received in clinics to examine the proposed method from the aspects of robustness to system settings, performance consistency against achromatic pixels, and normalization effectiveness in terms of histological information preservation. RESULTS: As the saturation-weighted statistics proposed in this study generates stable and reliable color cues for stain normalization, our scheme is robust to system parameters and insensitive to image content and achromatic colors. CONCLUSION: Extensive experimentation suggests that our approach outperforms state-of-the-art normalization methods as the proposed method is the only approach that succeeds to preserve histological information after normalization. SIGNIFICANCE: The proposed color normalization solution would be useful to mitigate effects of color variation in pathology images on subsequent quantitative analysis. PMID- 25706508 TI - Keratinized mucosa around implants in partially edentulous posterior mandible: 10 year results of a prospective comparative study. AB - OBJECTIVE: The aim of this research was to investigate the clinical conditions around dental implants placed in the posterior mandible of healthy or moderately periodontally compromised patients, in relation to the presence or not of keratinized mucosa (KT). MATERIALS AND METHODS: One hundred and twenty-eight patients who needed an implant in the posterior mandible were consecutively enrolled in a private specialist practice. Only one implant per patient was examined originally placed either within KT or alveolar (AM) mucosa. At 10 years, clinical and radiographic measures were recorded by a calibrated operator. The number of sites treated according to therapy modalities C and D (antibiotics and/or surgery) during the 10 years was also registered. RESULTS: Ninety-eight patients completed the 10-year study. The absence of KT was associated with higher plaque accumulation, greater soft-tissue recession (REC), and a higher number of sites that required additional surgical and/or antibiotic treatment. Patient-reported outcomes regarding maintenance procedures presented major differences between the groups. In 11 of the 35 AM cases, additional free gingival graft (FGG) was successfully employed to reduce discomfort and to facilitate optimal plaque control. CONCLUSION: Implants that are not surrounded by KT are more prone to plaque accumulation and REC, even in patients exercising sufficient oral hygiene and receiving adequate supporting periodontal therapy (SPT). In selected cases, particularly in the edentulous posterior mandible, where ridge resorption leads to reduced vestibular depth and lack of KT, additional FGG can be beneficial to facilitate proper oral hygiene procedures. PMID- 25706509 TI - How does a hydrocarbon staple affect peptide hydrophobicity? AB - Water is essential for the proper folding of proteins and the assembly of protein protein/ligand complexes. How water regulates complex formation depends on the chemical and topological details of the interface. The dynamics of water in the interdomain region between an E3 ubiquitin ligase (MDM2) and three different peptides derived from the tumor suppressor protein p53 are studied using molecular dynamics. The peptides show bimodal distributions of interdomain water densities across a range of distances. The addition of a hydrocarbon chain to rigidify the peptides (in a process known as stapling) results in an increase in average hydrophobicity of the peptide-protein interface. Additionally, the hydrophobic staple shields a network of water molecules, kinetically stabilizing a water chain hydrogen-bonded between the peptide and MDM2. These properties could result in a decrease in the energy barrier associated with dehydrating the peptide-protein interface, thereby regulating the kinetics of peptide binding. PMID- 25706510 TI - Interstitial deletion 5q14.3q21.3 associated with lethal epilepsy. AB - The 5q14.3 deletion syndrome is a heterogeneous disorder with remarkable phenotypic diversity ranging from severe to mild manifestation. In this paper, we report on a patient with 5q14.3 q21.3 deletion who exhibited the severe phenotype and died at 5.5 months. This patient can be classified as having sudden unexplained death in epilepsy (SUDEP) [Tomson et al., 2008]. The deleted region (21.02 Mb, Chr.5: 88, 047, 621-109,072,596 * 1 dn), which included MEF2C and EFNA5, was a 16.5 Mb sequence that overlapped with previously reported deletions in a patient with the mild phenotype. This study further demonstrated the complexity of clinical cytogenetic correlation of the 5q14.3 deletion. PMID- 25706511 TI - Love stories: understanding the caring journeys of aged Greek-Australian carers. AB - This article documents the findings of a short-term longitudinal study that explored the caring journeys of aged Greek carers providing in-home care for their spouse. Through a deeper understanding of carers' decisions and decision making and insights from service providers and community leaders, we aimed to inform policy makers, service managers and providers about how to develop and promote culturally appropriate support services, and negotiate them with carers and care recipients in a timely way. Initially, we conducted three focus groups and one follow-up forum with service providers and Greek community leaders. Then, over a 6-month period, we conducted two in-home interviews and two telephone interviews with 12 older Greek carers. We sought to understand factors influencing carers' decision-making regarding service uptake, and we provided information about services as required. Through our thematic analysis, we found that most carers wanted to remain as independent as possible and to avoid forced separation from the one they loved, through institutionalisation. They placed great value on their caring role which, while a struggle at times, gave them a sense of meaning, purpose and belonging. We also found that carers had great resourcefulness, strength and competence. They were all in long-term relationships, had negotiated coming to a foreign country and establishing themselves and were now in the process of negotiating old age and increasing frailty while at the same time providing care and support to family and friends. Our findings suggest that services need to be communicated in ways which support what carers value, not on outdated assumptions about cultural groups, otherwise providers will perpetuate exclusion. We propose an outreach in-home service model with an emphasis on ageing well and staying at home. This model of service provision is a model of care which emphasises relationships and community, and seeks to build social and cultural capital. PMID- 25706512 TI - Hair-growth-promoting effect of conditioned medium of high integrin alpha6 and low CD 71 (alpha6bri/CD71dim) positive keratinocyte cells. AB - Keratinocyte stem/progenitor cells (KSCs) reside in the bulge region of the hair follicles and may be involved in hair growth. Hair follicle dermal papilla cells (HFDPCs) and outer root sheath (ORS) cells were treated with conditioned medium (CM) of KSCs. Moreover, the effects of KSC-CM on hair growth were examined ex vivo and in vivo. A human growth factor chip array and RT-PCR were employed to identify enriched proteins in KSC-CM as compared with CM from keratinocytes. KSC CM significantly increased the proliferation of HFDPCs and ORS cells, and increased the S-phase of the cell cycle in HFDPCs. KSC-CM led to the phosphorylation of ATK and ERK1/2 in both cell types. After subcutaneous injection of KSC-CM in C3H/HeN mice, a significant increase in hair growth and increased proliferation of hair matrix keratinocytes ex vivo was observed. We identified six proteins enriched in KSC-CM (amphiregulin, insulin-like growth factor binding protein-2, insulin-like growth factor binding protein-5, granulocyte macrophage-colony stimulating factor, Platelet-derived growth factor AA, and vascular endothelial growth factor). A growth-factor cocktail that contains these six recombinant growth factors significantly increased the proliferation of HFDPCs and ORS cells and enhanced the hair growth of mouse models. These results collectively indicate that KSC-CM has the potential to increase hair growth via the proliferative capacity of HFDPCs and ORS cells. PMID- 25706514 TI - A meta-analysis of weight status and anxiety in children and adolescents. AB - OBJECTIVE: Although some posit that youth who are overweight/obese experience greater amounts of anxiety than their peers who are normal weight, extant literature shows that the association between weight status and anxiety in youth is equivocal. Therefore, the purpose of this study was to elucidate the association between weight status and anxiety in children and adolescents through meta-analytic methods. METHOD: Electronic databases and review articles were searched for studies including quantitative data on weight status and anxiety in youth aged <=18 years. Data were analyzed using a random effects model. Putative moderators were selected a priori. RESULTS: A total of 61 studies yielded 78 effect sizes (N = 180,136) and a small but significant overall summary effect (r = .08; 95% confidence interval, 0.06-0.11; z = 6.41; p < .001). Gender, age group, and type of weight status measure significantly moderated the association. Specifically, studies with girls, children aged 12 years and under, or norm referenced measures of weight status (e.g., body mass index [BMI] z-score) evidenced significantly higher effect sizes between weight status and anxiety than studies with boys, adolescents aged 13 years and over, or non-norm referenced measures of weight status (e.g., BMI), respectively. Sample type, publication type, anxiety type, anxiety informant, and race/ethnicity were not significant moderators. CONCLUSION: Overall, the association between weight status and anxiety is small; however, study or methodological characteristics may modestly influence the effect. Longitudinal studies are needed to determine the directionality of the association, and consequently, the intended target of intervention. PMID- 25706513 TI - Assessing the antimicrobial activity of polyisoprene based surfaces. AB - There has been an intense research effort in the last decades in the field of biofouling prevention as it concerns many aspects of everyday life and causes problems to devices, the environment, and human health. Many different antifouling and antimicrobial materials have been developed to struggle against bacteria and other micro- and macro-organism attachment to different surfaces. However the "miracle solution" has still to be found. The research presented here concerns the synthesis of bio-based polymeric materials and the biological tests that showed their antifouling and, at the same time, antibacterial activity. The raw material used for the coating synthesis was natural rubber. The polyisoprene chains were fragmented to obtain oligomers, which had reactive chemical groups at their chain ends, therefore they could be modified to insert polymerizable and biocidal groups. Films were obtained by radical photopolymerization of the natural rubber derived oligomers and their structure was altered, in order to understand the mechanism of attachment inhibition and to increase the efficiency of the anti-biofouling action. The adhesion of three species of pathogenic bacteria and six strains of marine bacteria was studied. The coatings were able to inhibit bacterial attachment by contact, as it was verified that no detectable leaching of toxic molecules occurred. PMID- 25706515 TI - [Reha Aftercare--One Size Fits All? Analyses of Rehab Patients which do not Benefit from Reha Aftercare]. AB - BACKGROUND: In an own research project fund-ed by this program rehabilitation aftercare as part of a revised rehabilitation philosophy ("new credo") was tested and evaluated in a controlled longitudinal trial. Rehabilitation patients from the intervention group reported significantly better implementation of rehabilitation contents and objectives in everyday life during 12 months after their rehabilitation stay. Better long-term effects were also detectable. Anyway, not all rehabilitation patients seemed to benefit from the intervention. The present analysis focuses on this subgroup: How do rehabilitation patients that do not benefit from the "new credo" differ from rehabilitation patients that draw advantage from it? METHOD: Data from a controlled study were used for secondary analysis. 3 clinics implemented the "new credo". Primary outcomes were: participation constraints (IMET) and functional disabilities in everyday life (FFbH-R). The intervention clinics recruited a total of 166 rehabilitation patients. Data from 163 cases could be analyzed using quantitative methods. In addition, interview data from 7 unsuccessful rehabilitation patients was analyzed qualitatively. RESULTS: 102 (63%) rehabilitation patients improved their values in FFbH-R or IMET by at least 0.3 effect sizes (successful group). Among the 61 unsuccessful rehabilitation patients, 17 (10%) started rehabilitation with initial values that high that they could not reach the fixed minimal improvement criteria ("low burdened" group). They were excluded from further analysis. The remain-ing 44 (27%) rehabilitation patients constitute the "unsuccessful" group.Both groups have comparable levels of impairment concerning somatic and psychosocial parameters.At the end of the rehabilitation stay the "unsuccessful" group reached improvements of moderate to large effect sizes concerning the recorded health parameters. One year after rehabilitation "unsuccessful" rehabilitation patients fall back to their baseline levels of impairment, while the successful maintain their achieved effects after rehabilita-tion. The 2 groups rated several aspects of the intervention differently and the "unsuccessful" group rated the preparation for the time after the rehabilitation worse.The number of perceived aftercare elements proves to be the strongest predictor of failure in multivariate evaluation; "clinic facilities" is the only other independent predictor.During the interviews, "unsuccessful" patients reported different individual barriers for implementation of physical activity in daily life. CONCLUSIONS: Rehabilitation patients, who did not benefit from the new rehabilitation and aftercare concept, did neither differ in sociodemographic nor in disease-specific characteristics from the successful rehabilitation patients. However, differences in the implementation of the new rehabilitation philosophy and its individual components in the rehabilitation clinics are significantly associated with the occurrence of success or failure. Ov-er-all, the results of our study indicate a need for more flexible design of rehabilitation and aftercare adjusted to individual needs. PMID- 25706516 TI - [Evaluation of the treatment approach AOK-proReha by comparison with a historical control group: an application of the propensity score matching method]. AB - BACKGROUND: The AOK-proReha treatment approach determines the therapeutic measures during rehabilitation that should be taken in patients who have undergone total hip and total knee replacement surgery. The aim of our study is to scientifically assess the success of AOK-proReha in the routine care. METHODOLOGY: N=619 patients were surveyed about their health status at 3 time points. A historical control group was formed by referring to data of the QS Reha((r)) program and applying the propensity score matching method. RESULTS: We observed clear effects immediately after rehabilitation that revealed their maximum strength rising in most dimensions at the follow-up time point. Comparison with the control group demonstrated similar results in many dimensions. Some results were significantly better while none were significantly worse. CONCLUSION: The results of the AOK proReha approach are promising. Under appropriate conditions, the propensity score matching method is a sensible alternative to conducting a randomized controlled trial. PMID- 25706517 TI - [How can Instructions and Motivation for a Pension Influence the Response in Questionnaires?]. AB - AIMS OF THE STUDY: The study investigates whether the motivation for obtaining a pension together with written instructions change the response bias in symptom scales as well as symptom validity test. MATERIALS AND METHOD: 80 warned and 91 unwarned claimants for disability pension due to a mental illness were recruited. Participants completed a socio-demographic questionnaire (with statements to measure motivation), the module A of the HEALTH-49 as well as the SIMS. RESULTS: ANOVAs (analysis of variance) showed that warned claimants had significantly higher scores in total assets in symptom scales of the HEALTH-49 as well as the SIMS compared to the unwarned claimants. Warned persons showed higher odds for an invalid value in the SIMS. A regression analysis revealed that the item "retirement means for me a chance to be healthy" can predict the criterion total score of the SIMS. CONCLUSION: Warnings may produce negative response bias in symptom scales. Patients made negative response bias when they hope to recover through their pension. PMID- 25706518 TI - Improvement in mortality and retention among adult HIV-infected patients in the first 12 months of antiretroviral therapy in Dodoma urban district, Tanzania. AB - OBJECTIVE: To determine mortality and retention in ART programmes in Tanzania, between 2010 and 2013. METHODS: Retrospective routinely collected data were analysed from people starting ART in the period 2010-2013. Mortality and retention over the first 12 months on ART were compared across the 4 years, and adjustment was made for individual level potential confounders. RESULTS: Data from 3844 people (70.6% female) starting ART were analysed. Mortality in the first year declined from 11.4% in 2010 to 4.9% in 2013, and retention after 12 months increased from 77.8% in 2010 to 98.1% in 2013. Mortality was inversely associated with CD4 count, lowest among those with CD4 350+ cells/MUl [adjusted odds ratio (AOR) = 0.03, 95% CI 0.01-0.03], associated with male sex (AOR = 1.79, 95% CI 1.39-2.31), but not age. Lost to follow-up (LTFU) was lowest among those with CD4 = 350+ cells/MUl AOR = 0.20, 95% CI 0.10-0.30), but not associated with age or sex, and higher in urban health facilities (AOR = 1.88, 95% CI 1.15-3.09). After adjustment for individual level characteristics, there was a statistically significant yearly improvement in mortality (AOR = 0.31, 95% CI (0.21-0.44) and LTFU (AOR = 0.06, 95% CI 0.04-0.10). CONCLUSION: Mortality and retention in the first 12 months on ART have significantly improved over the 4 years from 2010 to 2013. These improvements may indicate better services, earlier initiation on ART, and strengthened systems to provide ART in Tanzania. These results refute the worries that earlier initiation on ART might lead to lower retention in the ART programme. PMID- 25706519 TI - Hearing preservation up to 3 years after gamma knife radiosurgery for Gardner Robertson class I patients with vestibular Schwannomas. AB - BACKGROUND: Vestibular schwannoma patients with Gardner-Robertson (GR) class I hearing seek to maintain high-level hearing whenever possible. OBJECTIVE: To evaluate hearing outcomes at 2 to 3 years in GR class I patients who underwent Gamma Knife radiosurgery (GKRS). METHODS: Sixty-eight patients with GR class I hearing were identified between 2006 and 2009. Twenty-five patients had no subjective hearing loss (group A) and 43 patients reported subjective hearing loss (group B) before GKRS. The median tumor volume (1 cm) and tumor margin dose (12.5 Gy) were the same in both groups. RESULTS: Serviceable hearing retention rates (GR grade I or II) were 100% for group A compared with 81% at 1 year, 60% at 2 years, and 57% at 3 years after GKRS for group B patients. Group A patients had significantly higher rates of hearing preservation in either GR class I (P < .001) or GR class II (P < .001). Patients with a pure tone average (PTA) <15 dB before GKRS had significantly higher rates of preservation of GR class I or II hearing. CONCLUSION: At 2 to 3 years after GKRS, patients without subjective hearing loss or a PTA <15 dB had higher rates of grade I or II hearing preservation. Modification of the GR hearing classification into 2 groups of grade I hearing (group A, those with no subjective hearing loss and a PTA <15 dB; and group B, those with subjective hearing loss and a PTA >15 dB) may be useful to help predict hearing preservation rates at 2 to 3 years after GKRS. PMID- 25706520 TI - Management of cervical intramedullary ependymomas with a unilateral approach: 3 dimensional operative video. PMID- 25706522 TI - Acquired lymphangiectasia of the vulva. PMID- 25706521 TI - Examination of anxiety sensitivity and distress tolerance as transdiagnostic mechanisms linking multiple anxiety pathologies to alcohol use problems in adolescents. AB - BACKGROUND: Multiple forms of anxiety psychopathology are associated with alcohol use problems in adolescents. Yet, the mechanisms underlying this association are unclear. Anxiety sensitivity (AS) and distress tolerance (DT) represent 2 distinct, conceptually relevant transdiagnostic constructs implicated in multiple manifestations of anxiety that may also underlie alcohol use problems and thereby explain why people with anxiety are more likely to have alcohol problems. METHODS: The current cross-sectional study examined whether AS and DT accounted for (i.e., statistically mediated) the relationship between manifest indicators of the 3 common anxiety phenotypes (generalized anxiety, social anxiety, and panic disorders) and alcohol problems in a sample of 534 high school students (14 to 15 years old). RESULTS: Multiple manifestations of anxiety were associated with greater alcohol use problems. AS statistically mediated multiple anxiety alcohol associations, but DT did not. CONCLUSIONS: These findings provide preliminary evidence suggesting AS may be an important transdiagnostic target for alcohol prevention programs for those in early adolescence that experience elevated anxiety symptoms. PMID- 25706523 TI - Lyman alpha photolysis of solid nitromethane (CH3NO2) and D3-nitromethane (CD3NO2)--untangling the reaction mechanisms involved in the decomposition of model energetic materials. AB - Solid nitromethane (CH3NO2) along with its isotopically labelled counterpart D3 nitromethane (CD3NO2) ices were exposed to Lyman alpha photons to investigate the mechanism involved in the decomposition of energetic materials in the condensed phase. The chemical processes in the ices were monitored online and in situ via infrared spectroscopy complimented by temperature programmed desorption studies utilizing highly sensitive reflectron time-of-flight mass spectrometry coupled with pulsed photoionization (ReTOF-PI) at 10.49 eV. The infrared data revealed the formation of cis-methylnitrite (CH3ONO), formaldehyde (H2CO), water (H2O), carbon monoxide (CO), and carbon dioxide (CO2). Upon sublimation of the irradiated samples, three classes of higher molecular weight products, which are uniquely formed in the condensed phase, were identified via ReTOF-PI: (i) nitroso compounds [nitrosomethane (CH3NO), nitrosoethane (C2H5NO), nitrosopropane (C3H7NO)], (ii) nitrite compounds [methylnitrite (CH3ONO), ethylnitrite (C2H5ONO), propylnitrite (C3H7ONO)], and (iii) higher molecular weight molecules [CH3NONOCH3, CH3NONO2CH3, CH3OCH2NO2, ONCH2CH2NO2]. The mechanistical information obtained in the present study suggest that the decomposition of nitromethane in the condensed phase is more complex compared to the gas phase under collision free conditions opening up not only hitherto unobserved decomposition pathways of nitromethane (hydrogen atom loss, oxygen atom loss, retro carbene insertion), but also the blocking of several initial decomposition steps due to the 'matrix cage effect'. PMID- 25706524 TI - High-throughput biochemical fingerprinting of Saccharomyces cerevisiae by Fourier transform infrared spectroscopy. AB - Single-channel optical density measurements of population growth are the dominant large scale phenotyping methodology for bridging the gene-function gap in yeast. However, a substantial amount of the genetic variation induced by single allele, single gene or double gene knock-out technologies fail to manifest in detectable growth phenotypes under conditions readily testable in the laboratory. Thus, new high-throughput phenotyping technologies capable of providing information about molecular level consequences of genetic variation are sorely needed. Here we report a protocol for high-throughput Fourier transform infrared spectroscopy (FTIR) measuring biochemical fingerprints of yeast strains. It includes high throughput cultivation for FTIR spectroscopy, FTIR measurements and spectral pre treatment to increase measurement accuracy. We demonstrate its capacity to distinguish not only yeast genera, species and populations, but also strains that differ only by a single gene, its excellent signal-to-noise ratio and its relative robustness to measurement bias. Finally, we illustrated its applicability by determining the FTIR signatures of all viable Saccharomyces cerevisiae single gene knock-outs corresponding to lipid biosynthesis genes. Many of the examined knock-out strains showed distinct, highly reproducible FTIR phenotypes despite having no detectable growth phenotype. These phenotypes were confirmed by conventional lipid analysis and could be linked to specific changes in lipid composition. We conclude that the introduced protocol is robust to noise and bias, possible to apply on a very large scale, and capable of generating biologically meaningful biochemical fingerprints that are strain specific, even when strains lack detectable growth phenotypes. Thus, it has a substantial potential for application in the molecular functionalization of the yeast genome. PMID- 25706525 TI - Inheritance of diapause in crosses between the northernmost and the southernmost strains of the Asian corn borer Ostrinia furnacalis. AB - The northernmost Harbin strain (N strain) of the Asian corn borer, Ostrinia furnacalis enters facultative diapause as fully grown larvae in response to short daylengths; whereas the southernmost Ledong strain (S strain) exhibits almost no diapause under the same light conditions. In the present study, we examined the inheritance of diapause induction and termination by crossing the two strains under a range of environmental conditions. The N strain showed a typical long-day response with a critical daylength of approximately15.88 h at 22 degrees C, 15.72 h at 25 degrees C and 15.14 h at 28 degrees C, whereas the S strain showed a weak photoperiodic response at 22 degrees C. The F1 progeny also showed a long-day response at 22, 25 and 28 degrees C. However, the critical daylengths in S ? * N ? crosses were significantly longer than those in N ? * S ? crosses, indicating a sex linkage in the inheritance of diapause induction, with the male parent having more influence on the following F1 progeny. The incidence of diapause in S ? * N ? crosses was the same as in the N strain under short daylengths of 11-13 h, indicating that diapause trait is completely dominant over the non-diapause trait. The critical daylength in backcross to N was significantly longer than it was in backcross to S, showing a grandfather gene effect. Whether the inheritance of diapause fits an additive hypothesis or not was dependent on the rearing photoperiod, and the capacity for diapause was transmitted genetically in the manner of incomplete dominance. The duration of diapause for the reciprocal crosses under different diapause-terminating conditions showed different patterns of inheritance. The results in this study reveal that genetic and genetic environmental interactions are involved in diapause induction and termination in O. furnacalis. PMID- 25706526 TI - Monoclonal antibodies in allergy; updated applications and promising trials. AB - Allergic disorders, as asthma, allergic rhinitis/rhinoconjunctivitis, atopic dermatitis, food allergies and anaphylaxis have an increasing burden in the general population and a growing body of evidence has shown that an increased interest has aroused to seek for more effective treatment strategies. Conventional pharmacotherapy by antihistamines, anti-leukotrienes, corticosteroids and bronchodilators can routinely control most of the cases, in addition to allergen avoidance which saves the date. Furthermore, allergen specific immunotherapy stands as the only curative method to treat the underlying cause of allergic immune response by induction of immune tolerance. However, response to pharmacotherapies can show diversity depending on the genotype and phenotype of the allergic disorders, which are known to be under the influence of multifactorial triggers. Thus, understanding the mechanisms of development of allergic disorders, in addition to selective description of the phenotypes can provide access to development of more specific therapies in order to control the disease progression. Monoclonal antibodies can be the major actors in this targeting process. Concerns about the safety, efficacy and long-term tolerability of these molecules always stand as a question for them, in order to gain indications for the treatment of allergic disorders. This review includes most recent developments and patents on usage of monoclonal antibodies for the treatment of allergic disorders. PMID- 25706527 TI - Vaccines for Patients with COPD. AB - Chronic obstructive pulmonary disease (COPD) is a lung disease characterized by chronic obstruction of lung airflow limitation. This disease is currently the fourth higher cause of death in the world, and it is predicted to be the third by the year 2020. Patients with COPD are frequently exposed to Human Rhinovirus, Respiratory Syncytial and Influenza Virus, as well as to Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis. These infectious agents are responsible for exacerbations increasing morbidity and mortality in COPD patients. Prevention of infectious exacerbations by vaccination would improve quality of life and patient survival. A literature search: "vaccination of COPD patients" was performed using Medline, the Cochrane Library and other Non-Indexed Citations for this review. This article presents a brief overview of the different studies found, on the new patents, and the future strategies on the field. PMID- 25706528 TI - New approaches to chikungunya virus vaccine development. AB - Chikungunya virus (CHIKV) is a mosquito-borne human pathogen that affects millions of individuals each year by causing non-specific flu-like symptoms, with a characteristic rash accompanied by joint pain that may last for a long time after the resolution of the infection. Despite intense research efforts, no approved vaccine or antiviral therapy is yet available. This review is based on articles retrieved by PubMed and clinical trials since 1980 to present. Virus complexity, protective and non-protective immune responses against the virus, and the most important a new patented approaches for Chikungunya vaccine development are discussed. PMID- 25706529 TI - Pyocyanina contributory factor in haem acquisition and virulence enhancement of Porphyromonas gingivalis in the lung [corrected]. AB - Several recent studies show that the lungs infected with Pseudomonas aeruginosa are often co-colonised by oral bacteria including black-pigmenting anaerobic (BPA) Porphyromonas species. The BPAs have an absolute haem requirement and their presence in the infected lung indicates that sufficient haem, a virulence up regulator in BPAs, must be present to support growth. Haemoglobin from micro bleeds occurring during infection is the most likely source of haem in the lung. Porphyromonas gingivalis displays a novel haem acquisition paradigm whereby haemoglobin must be firstly oxidised to methaemoglobin, facilitating haem release, either by gingipain proteolysis or capture via the haem-binding haemophore HmuY. P. aeruginosa produces the blue phenazine redox compound, pyocyanin. Since phenazines can oxidise haemoglobin, it follows that pyocyanin may also facilitate haem acquisition by promoting methaemoglobin production. Here we show that pyocyanin at concentrations found in the CF lung during P. aeruginosa infections rapidly oxidises oxyhaemoglobin in a dose-dependent manner. We demonstrate that methaemoglobin formed by pyocyanin is also susceptible to proteolysis by P. gingivalis Kgp gingipain and neutrophil elastase, thus releasing haem. Importantly, co-incubation of oxyhaemoglobin with pyocyanin facilitates haem pickup from the resulting methemoglobin by the P. gingivalis HmuY haemophore. Mice intra-tracheally challenged with viable P. gingivalis cells plus pyocyanin displayed increased mortality compared to those administered P. gingivalis alone. Pyocyanin significantly elevated both methaemoglobin and total haem levels in homogenates of mouse lungs and increased the level of arginine specific gingipain activity from mice inoculated with viable P. gingivalis cells plus pyocyanin compared with mice inoculated with P. gingivalis only. These findings indicate that pyocyanin, by promoting haem availability through methaemoglobin formation and stimulating of gingipain production, may contribute to virulence of P. gingivalis and disease severity when co-infecting with P. aeruginosa in the lung. PMID- 25706530 TI - Public transportation and tuberculosis transmission in a high incidence setting. AB - BACKGROUND: Tuberculosis (TB) transmission may occur with exposure to an infectious contact often in the setting of household environments, but extra domiciliary transmission also may happen. We evaluated if using buses and/or minibuses as public transportation was associated with acquiring TB in a high incidence urban district in Lima, Peru. METHODS: Newly diagnosed TB cases with no history of previous treatment and community controls were recruited from August to December 2008 for a case-control study. Crude and adjusted odd ratios (OR) and 95% confidence intervals (CI) were calculated using logistic regression to study the association between bus/minibus use and TB risk. RESULTS: One hundred forty TB cases and 80 controls were included. The overall use of buses/minibuses was 44.9%; 53.3% (72/135) among cases and 30.4% (24/79) among controls [OR: 3.50, (95% CI: 1.60-7.64)]. In the TB group, 25.7% (36/140) of subjects reported having had a recent household TB contact, and 13% (18/139) reported having had a workplace TB contact; corresponding figures for controls were 3.8% (3/80) and 4.1% (3/73), respectively[OR: 8.88 (95% CI: 2.64-29.92), and OR: 3.89 (95% CI: 1.10-13.70)]. In multivariate analyses, age, household income, household contact and using buses/minibuses to commute to work were independently associated with TB [OR for bus/minibus use: 11.8 (95% CI: 1.45-96.07)]. CONCLUSIONS: Bus/minibus use to commute to work is associated with TB risk in this high-incidence, urban population in Lima, Peru. Measures should be implemented to prevent TB transmission through this exposure. PMID- 25706531 TI - Care seeking behaviour for children with suspected pneumonia in countries in sub Saharan Africa with high pneumonia mortality. AB - Pneumonia is the leading cause of childhood mortality in sub-Saharan Africa (SSA). Because effective antibiotic treatment exists, timely recognition of pneumonia and subsequent care seeking for treatment can prevent deaths. For six high pneumonia mortality countries in SSA we examined if children with suspected pneumonia were taken for care, and if so, from which type of care providers, using national survey data of 76530 children. We also assessed factors independently associated with care seeking from health providers, also known as 'appropriate' providers. We report important differences in care seeking patterns across these countries. In Tanzania 85% of children with suspected pneumonia were taken for care, whereas this was only 30% in Ethiopia. Most of the children living in these six countries were taken to a primary health care facility; 86, 68 and 59% in Ethiopia, Tanzania and Burkina Faso respectively. In Uganda, hospital care was sought for 60% of children. 16-18% of children were taken to a private pharmacy in Democratic Republic of Congo (DRC), Tanzania and Nigeria. In Tanzania, children from the richest households were 9.5 times (CI 2.3-39.3) more likely to be brought for care than children from the poorest households, after controlling for the child's age, sex, caregiver's education and urban-rural residence. The influence of the age of a child, when controlling for sex, urban rural residence, education and wealth, shows that the youngest children (<2 years) were more likely to be brought to a care provider in Nigeria, Ethiopia and DRC. Urban-rural residence was not significantly associated with care seeking, after controlling for the age and sex of the child, caregivers education and wealth. The study suggests that it is crucial to understand country-specific care seeking patterns for children with suspected pneumonia and related determinants using available data prior to planning programmatic responses. PMID- 25706532 TI - Mitochondrial genome sequencing and development of genetic markers for the detection of DNA of invasive bighead and silver carp (Hypophthalmichthys nobilis and H. molitrix) in environmental water samples from the United States. AB - Invasive Asian bighead and silver carp (Hypophthalmichthys nobilis and H. molitrix) pose a substantial threat to North American aquatic ecosystems. Recently, environmental DNA (eDNA), genetic material shed by organisms into their environment that can be detected by non-invasive sampling strategies and genetic assays, has gained recognition as a tool for tracking the invasion front of these species toward the Great Lakes. The goal of this study was to develop new species specific conventional PCR (cPCR) and quantitative (qPCR) markers for detection of these species in North American surface waters. We first generated complete mitochondrial genome sequences from 33 bighead and 29 silver carp individuals collected throughout their introduced range. These sequences were aligned with those from other common and closely related fish species from the Illinois River watershed to identify and design new species-specific markers for the detection of bighead and silver carp DNA in environmental water samples. We then tested these genetic markers in the laboratory for species-specificity and sensitivity. Newly developed markers performed well in field trials, did not have any false positive detections, and many markers had much higher detection rates and sensitivity compared to the markers currently used in eDNA surveillance programs. We also explored the use of multiple genetic markers to determine whether it would improve detection rates, results of which showed that using multiple highly sensitive markers should maximize detection rates in environmental samples. The new markers developed in this study greatly expand the number of species-specific genetic markers available to track the invasion front of bighead and silver carp and will improve the resolution of these assays. Additionally, the use of the qPCR markers developed in this study may reduce sample processing time and cost of eDNA monitoring for these species. PMID- 25706533 TI - Effects of varying nitrogen sources on amino acid synthesis costs in Arabidopsis thaliana under different light and carbon-source conditions. AB - Plants as sessile organisms cannot escape their environment and have to adapt to any changes in the availability of sunlight and nutrients. The quantification of synthesis costs of metabolites, in terms of consumed energy, is a prerequisite to understand trade-offs arising from energetic limitations. Here, we examine the energy consumption of amino acid synthesis in Arabidopsis thaliana. To quantify these costs in terms of the energy equivalent ATP, we introduce an improved cost measure based on flux balance analysis and apply it to three state-of-the-art metabolic reconstructions to ensure robust results. We present the first systematic in silico analysis of the effect of nitrogen supply (nitrate/ammonium) on individual amino acid synthesis costs as well as of the effect of photoautotrophic and heterotrophic growth conditions, integrating day/night specific regulation. Our results identify nitrogen supply as a key determinant of amino acid costs, in agreement with experimental evidence. In addition, the association of the determined costs with experimentally observed growth patterns suggests that metabolite synthesis costs are involved in shaping regulation of plant growth. Finally, we find that simultaneous uptake of both nitrogen sources can lead to efficient utilization of energy source, which may be the result of evolutionary optimization. PMID- 25706534 TI - Activin-A and Bmp4 levels modulate cell type specification during CHIR-induced cardiomyogenesis. AB - The use of human pluripotent cell progeny for cardiac disease modeling, drug testing and therapeutics requires the ability to efficiently induce pluripotent cells into the cardiomyogenic lineage. Although direct activation of the Activin A and/or Bmp pathways with growth factors yields context-dependent success, recent studies have shown that induction of Wnt signaling using low molecular weight molecules such as CHIR, which in turn induces the Activin-A and Bmp pathways, is widely effective. To further enhance the reproducibility of CHIR induced cardiomyogenesis, and to ultimately promote myocyte maturation, we are using exogenous growth factors to optimize cardiomyogenic signaling downstream of CHIR induction. As indicated by RNA-seq, induction with CHIR during Day 1 (Days 0 1) was followed by immediate expression of Nodal ligands and receptors, followed later by Bmp ligands and receptors. Co-induction with CHIR and high levels of the Nodal mimetic Activin-A (50-100 ng/ml) during Day 0-1 efficiently induced definitive endoderm, whereas CHIR supplemented with Activin-A at low levels (10 ng/ml) consistently improved cardiomyogenic efficiency, even when CHIR alone was ineffective. Moreover, co-induction using CHIR and low levels of Activin-A apparently increased the rate of cardiomyogenesis, as indicated by the initial appearance of rhythmically beating cells by Day 6 instead of Day 8. By contrast, co-induction with CHIR plus low levels (3-10 ng/ml) of Bmp4 during Day 0-1 consistently and strongly inhibited cardiomyogenesis. These findings, which demonstrate that cardiomyogenic efficacy is improved by optimizing levels of CHIR induced growth factors when applied in accord with their sequence of endogenous expression, are consistent with the idea that Nodal (Activin-A) levels toggle the entry of cells into the endodermal or mesodermal lineages, while Bmp levels regulate subsequent allocation into mesodermal cell types. PMID- 25706535 TI - Prescription Opioids and Treatment in Rural Australia: A Failure of Policy for Indigenous Australians. PMID- 25706536 TI - Inferring regional-scale species diversity from small-plot censuses. AB - Estimation of the number of species at spatial scales too large to census directly is a longstanding ecological challenge. A recent comprehensive census of tropical arthropods and trees in Panama provides a unique opportunity to apply an inference procedure for up-scaling species richness and thereby make progress toward that goal. Confidence in the underlying theory is first established by showing that the method accurately predicts the species abundance distribution for trees and arthropods, and in particular accurately captures the rare tail of the observed distributions. The rare tail is emphasized because the shape of the species-area relationship is especially influenced by the numbers of rare species. The inference procedure is then applied to estimate the total number of arthropod and tree species at spatial scales ranging from a 6000 ha forest reserve to all of Panama, with input data only from censuses in 0.04 ha plots. The analysis suggests that at the scale of the reserve there are roughly twice as many arthropod species as previously estimated. For the entirety of Panama, inferred tree species richness agrees with an accepted empirical estimate, while inferred arthropod species richness is significantly below a previous published estimate that has been criticized as too high. An extension of the procedure to estimate species richness at continental scale is proposed. PMID- 25706537 TI - A cell-based systems biology assessment of human blood to monitor immune responses after influenza vaccination. AB - Systems biology is an approach to comprehensively study complex interactions within a biological system. Most published systems vaccinology studies have utilized whole blood or peripheral blood mononuclear cells (PBMC) to monitor the immune response after vaccination. Because human blood is comprised of multiple hematopoietic cell types, the potential for masking responses of under represented cell populations is increased when analyzing whole blood or PBMC. To investigate the contribution of individual cell types to the immune response after vaccination, we established a rapid and efficient method to purify human T and B cells, natural killer (NK) cells, myeloid dendritic cells (mDC), monocytes, and neutrophils from fresh venous blood. Purified cells were fractionated and processed in a single day. RNA-Seq and quantitative shotgun proteomics were performed to determine expression profiles for each cell type prior to and after inactivated seasonal influenza vaccination. Our results show that transcriptomic and proteomic profiles generated from purified immune cells differ significantly from PBMC. Differential expression analysis for each immune cell type also shows unique transcriptomic and proteomic expression profiles as well as changing biological networks at early time points after vaccination. This cell type specific information provides a more comprehensive approach to monitor vaccine responses. PMID- 25706538 TI - The HIV treatment cascade--a new tool in HIV prevention. PMID- 25706539 TI - High-efficiency expression of TAT-bFGF fusion protein in Escherichia coli and the effect on hypertrophic scar tissue. AB - BACKGROUND: Basic fibroblast growth factor (bFGF) is a member of the fibroblast growth factor family that has effects on wounding healing and neuro-protection. However, it is difficult to use bFGF to treat diseases that are separated by physiological barriers, such as the dermal barrier and blood brain barrier. METHODOLOGY/PRINCIPAL FINDINGS: To improve bFGF's penetration ability, we fused the recombinant human fibroblast growth factor (rhbFGF) gene with TAT. We constructed a pET3c vector that contained the recombinant bFGF gene and successfully expressed this gene in the E. coli strain BL21 (DE3) pLsS. The fusion protein was purified using CM Sepharose FF and heparin affinity chromatography. The purity of the TAT-rhbFGF was greater than 95%, as detected by SDS-PAGE. An in vitro MTT trial revealed that the modified bFGF significantly promoted the proliferation of NIH3T3 cells. The cell penetration trial and the mouse skin penetration trial demonstrated that the fusion protein had certain penetration abilities. The animal experiments confirmed that TAT-rhbFGF was effective in the treatment of the hypertrophic scars. CONCLUSIONS/SIGNIFICANCE: We have successfully expressed and purified a TAT-rhbFGF fusion protein in this study. Our results have shown that the fusion protein had a greater ability to penetrate the dermal skin layer. TAT-rhbFGF improved the physical appearance of hypertrophic scars. TAT-rhbFGF may be a potential fusion protein in the treatment of dermal disorders, including hypertrophic scar. PMID- 25706541 TI - Tumor-generated nitric oxide as an antagonist of photodynamic therapy. AB - Nitric oxide (NO) is a multifunctional free radical molecule produced naturally by nitric oxide synthase (NOS) enzymes. Many tumors exploit NO for survival and growth signaling, and also to thwart the effects of therapeutic treatments, including PDT. The anti-PDT effects of NO were discovered using animal tumor models, but the mechanisms involved are still not fully understood. Recent in vitro studies on breast and prostate cancer cells have shown that inducible NOS (iNOS) along with NO is dramatically upregulated after an ALA-PDT-like challenge. Cells were more resistant to apoptosis after a photochallenge and survivors grew, migrated, and invaded more rapidly, iNOS/NO playing a key role in all these effects. This perspective briefly reviews what is currently known about NO's negative effects on PDT and some of the signaling mechanisms involved. It also provides insights into how these effects may be attenuated by pharmacologic use of iNOS inhibitors. PMID- 25706542 TI - Outcome predictability biases learning. AB - Much of contemporary associative learning research is focused on understanding how and when the associative history of cues affects later learning about those cues. Very little work has investigated the effects of the associative history of outcomes on human learning. Three experiments extended the "learned irrelevance" paradigm from the animal conditioning literature to examine the influence of an outcome's prior predictability on subsequent learning of relationships between cues and that outcome. All 3 experiments found evidence for the idea that learning is biased by the prior predictability of the outcome. Previously predictable outcomes were readily associated with novel predictive cues, whereas previously unpredictable outcomes were more readily associated with novel nonpredictive cues. This finding highlights the importance of considering the associative history of outcomes, as well as cues, when interpreting multistage designs. Associative and cognitive explanations of this certainty matching effect are discussed. PMID- 25706543 TI - Automaticity and cognitive control in the learned predictiveness effect. AB - In novel contexts, learning is biased toward cues previously experienced as predictive compared with cues previously experienced as nonpredictive. This is known as learned predictiveness. A recent finding has shown that instructions issued about the causal status of cues influences the expression of learned predictiveness, suggesting that controlled, volitional processes play a role in this effect. Three experiments are reported further investigating the effects of instructional manipulations on learned predictiveness. Experiment 1 confirms the influence of inferential processes, extending previous work to suggest that instructions affect associative memory as well as causal reasoning. Experiments 2 and 3 used a procedure designed to tease apart inferential and automatic contributions to the bias by presenting instructed causes that were previously predictive and previously nonpredictive. The results demonstrate that the prior predictiveness of cues influences subsequent learning over and above the effect of explicit instruction. However, it appears that the relationship between explicit instruction and predictive history is interactive rather than additive. Potential explanations for this interactivity are discussed. PMID- 25706544 TI - Monkey visual short-term memory directly compared to humans. AB - Two adult rhesus monkeys were trained to detect which item in an array of memory items had changed using the same stimuli, viewing times, and delays as used with humans. Although the monkeys were extensively trained, they were less accurate than humans with the same array sizes (2, 4, & 6 items), with both stimulus types (colored squares, clip art), and showed calculated memory capacities of about 1 item (or less). Nevertheless, the memory results from both monkeys and humans for both stimulus types were well characterized by the inverse power-law of display size. This characterization provides a simple and straightforward summary of a fundamental process of visual short-term memory (STM; how VSTM declines with memory load) that emphasizes species similarities based upon similar functional relationships. By more closely matching monkey testing parameters to those of humans, the similar functional relationships strengthen the evidence suggesting similar processes underlying monkey and human VSTM. PMID- 25706545 TI - Optimal response rates in humans and rats. AB - The analysis of response rates has been highly influential in psychology, giving rise to many prominent theories of learning. There is, however, growing interest in explaining response rates, not as a global response to associations or value, but as a decision about how to space responses in time. Recently, researchers have shown that humans and mice can time a single response optimally; that is, in a way that maximizes reward. Here, we use the well-established differential reinforcement of low rates (DRL) timing task to show that humans and rats come close to optimizing reinforcement rate, but respond systematically faster than they should. PMID- 25706546 TI - Temporal distributions of schedule-induced licks, magazine entries, and lever presses on fixed- and variable-time schedules. AB - In this article, schedule-induced drinking (SID) refers to increased drinking by hungry rats exposed to intermittent delivery of food pellets. Two major accounts of SID differ in their explanation of why such drinking tends be concentrated soon after pellet delivery. Temporal discrimination theories propose that drinking is a form of displacement activity that occurs when a pellet is least likely. Adventitious reinforcement theories propose that drinking is displaced to early in an interpellet interval (IPI) by magazine-directed behavior that occurs toward the end of an IPI. The main aim of this study was to examine the latter response-competition account by recording distributions of both licking and magazine entries as SID developed when pellets were delivered to different groups either on a fixed-time (FT 30 s) or on a variable-time schedule (VT 30 s), as in Experiment 1. Although VT 30-s schedules produced essentially flat distributions of magazine entries, licking still tended to be concentrated early in an IPI. Furthermore, there was no indication (Experiments 1 and 2) that magazine entry distributions developed ahead of licking distributions. Experiment 3 examined distributions of lever presses instead of licks: Initially high rates of lever pressing declined both with response-independent schedules (FT and VT) and when a minimal response-dependency was introduced (recycling conjunctive schedule), yet this response also tended to be most frequent soon after pellet delivery. Overall, the data were generally consistent with temporal conditioning theories. PMID- 25706547 TI - Contextual control of instrumental actions and habits. AB - After a relatively small amount of training, instrumental behavior is thought to be an action under the control of the motivational status of its goal or reinforcer. After more extended training, behavior can become habitual and insensitive to changes in reinforcer value. Recently, instrumental responding has been shown to weaken when tested outside of the training context. The present experiments compared the sensitivity of instrumental responding in rats with a context switch after training procedures that might differentially generate actions or habits. In Experiment 1, lever pressing was decremented in a new context after either short, medium, or long periods of training on either random ratio or yoked random-interval reinforcement schedules. Experiment 2 found that more minimally trained responding was also sensitive to a context switch. Moreover, Experiment 3 showed that when the goal-directed component of responding was removed by devaluing the reinforcer, the residual responding that remained was still sensitive to the change of context. Goal-directed responding, in contrast, transferred across contexts. Experiment 4 then found that after extensive training, a habit that was insensitive to reinforcer devaluation was still decremented by a context switch. Overall, the results suggest that a context switch primarily influences instrumental habit rather than action. In addition, even a response that has received relatively minimal training may have a habit component that is insensitive to reinforcer devaluation but sensitive to the effects of a context switch. PMID- 25706548 TI - Renewal after the punishment of free operant behavior. AB - Three experiments examined the role of context in punishment learning. In Experiment 1, rats were trained to lever press for food in Context A and then punished for responding in Context B (by presenting response-contingent footshock). Punishment led to complete suppression of the response. However, when responding was tested (in extinction) in Contexts A and B, a strong renewal of responding occurred in Context A. In Experiment 2, renewal also occurred when initial reinforcement occurred in Context A, punishment occurred in Context B, and testing occurred in a new context (Context C). In both experiments, behavioral suppression and renewal were not observed in groups that received noncontingent (yoked) footshocks in Context B. In Experiment 3, 2 responses (lever press and chain pull) were separately reinforced in Contexts A and B and then punished in the opposite context. Although the procedure equated the contexts on their association with reinforcement and punishment, renewal of each response was observed when it was tested in its nonpunished context. The contexts also influenced response choice. Overall, the results suggest that punishment is specific to the context in which it is learned, and establish that its context specificity does not depend on a simple association between the context and shock. Like extinction, punishment may involve learning to inhibit a specific response in a specific context. Implications for theories of punishment and for understanding the cessation of problematic operant behavior (e.g., drug abuse) are discussed. PMID- 25706549 TI - Evidence for concrete but not abstract representation of length during spatial learning in rats. AB - In 4 experiments, rats had to discriminate between the lengths of 2 objects of the same color, black or white, before a test trial with the same objects but of opposite color. The experiments took place in a pool from which rats had to escape by swimming to 1 of 2 submerged platforms. For Experiments 1 and 2, the platforms were situated near the centers of panels of 1 length, but not another, that were pasted onto the gray walls of a square arena. The acquired preference for the correct length was eliminated by changing the color of the panels. In Experiment 3, the platforms were situated near the middle of the long walls of a rectangular pool, and in Experiment 4 they were situated in 1 pair of diagonally opposite corners of the same pool. Changing the color of the walls markedly disrupted the effects of the original training in both experiments. The results indicate that rats represent the length of objects not by their abstract, geometric attributes but in a more concrete fashion such as by a mental snapshot or by the amount of color stimulation they provide. PMID- 25706551 TI - Correction: in vitro and in vivo trypanocidal activity of h2bdtc-loaded solid lipid nanoparticles. AB - [This corrects the article DOI: 10.1371/journal.pntd.0002847.]. PMID- 25706550 TI - Proteomic analysis of pure human airway gland mucus reveals a large component of protective proteins. AB - Airway submucosal glands contribute to innate immunity and protect the lungs by secreting mucus, which is required for mucociliary clearance and which also contains antimicrobial, anti-inflammatory, anti-proteolytic and anti-oxidant proteins. We stimulated glands in tracheal trimmings from three lung donors and collected droplets of uncontaminated mucus as they formed at the gland orifices under an oil layer. We analyzed the mucus using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Analysis identified 5486 peptides and 441 proteins from across the 3 samples (269-319 proteins per subject). We focused on 269 proteins common to at least 2 0f 3 subjects, of which 102 (38%) had protective or innate immunity functions. While many of these have long been known to play such roles, for many others their cellular protective functions have only recently been appreciated in addition to their well-studied biologic functions (e.g. annexins, apolipoproteins, gelsolin, hemoglobin, histones, keratins, and lumican). A minority of the identified proteins are known to be secreted via conventional exocytosis, suggesting that glandular secretion occurs via multiple mechanisms. Two of the observed protective proteins, major vault protein and prohibitin, have not been observed in fluid from human epithelial cultures or in fluid from nasal or bronchoalveolar lavage. Further proteomic analysis of pure gland mucus may help clarify how healthy airways maintain a sterile environment. PMID- 25706552 TI - The new 4-O-methylhonokiol analog GS12021 inhibits inflammation and macrophage chemotaxis: role of AMP-activated protein kinase alpha activation. AB - Preventing pathologic tissue inflammation is key to treating obesity-induced insulin resistance and type 2 diabetes. Previously, we synthesized a series of methylhonokiol analogs and reported that compounds with a carbamate structure had inhibitory function against cyclooxygenase-2 in a cell-free enzyme assay. However, whether these compounds could inhibit the expression of inflammatory genes in macrophages has not been investigated. Here, we found that a new 4-O methylhonokiol analog, 3',5-diallyl-4'-methoxy-[1,1'-biphenyl]-2-yl morpholine-4 carboxylate (GS12021) inhibited LPS- or TNFalpha-stimulated inflammation in macrophages and adipocytes, respectively. LPS-induced phosphorylation of nuclear factor-kappa B (NF-kappaB)/p65 was significantly decreased, whereas NF-kappaB luciferase activities were slightly inhibited, by GS12021 treatment in RAW 264.7 cells. Either mitogen-activated protein kinase phosphorylation or AP-1 luciferase activity was not altered by GS12021. GS12021 increased the phosphorylation of AMP activated protein kinase (AMPK) alpha and the expression of sirtuin (SIRT) 1. Inhibition of mRNA expression of inflammatory genes by GS12021 was abolished in AMPKalpha1-knockdown cells, but not in SIRT1 knockout cells, demonstrating that GS12021 exerts anti-inflammatory effects through AMPKalpha activation. The transwell migration assay results showed that GS12021 treatment of macrophages prevented the cell migration promoted by incubation with conditioned medium obtained from adipocytes. GS12021 suppression of p65 phosphorylation and macrophage chemotaxis were preserved in AMPKalpha1-knockdown cells, indicating AMPK is not required for these functions of GS12021. Identification of this novel methylhonokiol analog could enable studies of the structure-activity relationship of this class of compounds and further evaluation of its in vivo potential for the treatment of insulin-resistant states and other chronic inflammatory diseases. PMID- 25706553 TI - Feasibility and inter-rater reliability of physical performance measures in acutely admitted older medical patients. AB - OBJECTIVE: Physical performance measures can be used to predict functional decline and increased dependency in older persons. However, few studies have assessed the feasibility or reliability of such measures in hospitalized older patients. Here we assessed the feasibility and inter-rater reliability of four simple measures of physical performance in acutely admitted older medical patients. DESIGN: During the first 24 hours of hospitalization, the following were assessed twice by different raters in 52 (>= 65 years) patients admitted for acute medical illness: isometric hand grip strength, 4-meter gait speed, 30-s chair stand and Cumulated Ambulation Score. Relative reliability was expressed as weighted kappa for the Cumulated Ambulation Score or as intra-class correlation coefficient (ICC1,1) and lower limit of the 95%-confidence interval (LL95%) for grip strength, gait speed, and 30-s chair stand. Absolute reliability was expressed as the standard error of measurement and the smallest real difference as a percentage of their respective means (SEM% and SRD%). RESULTS: The primary reasons for admission of the 52 included patients were infectious disease and cardiovascular illness. The mean+/- SD age was 78+/-8.3 years, and 73.1% were women. All patients performed grip strength and Cumulated Ambulation Score testing, 81% performed the gait speed test, and 54% completed the 30-s chair stand test (46% were unable to rise without using the armrests). No systematic bias was found between first and second tests or between raters. The weighted kappa for the Cumulated Ambulation Score was 0.76 (0.60-0.92). The ICC1,1 values were as follows: grip strength, 0.95 (LL95% 0.92); gait speed, 0.92 (LL95% 0.73), and 30-s chair stand, 0.82 (LL95% 0.67). The SEM% values for grip strength, gait speed, and 30-s chair stand were 8%, 7%, and 18%, and the SRD95% values were 22%, 17%, and 49%. CONCLUSION: In acutely admitted older medical patients, grip strength, gait speed, and the Cumulated Ambulation Score measurements were feasible and showed high inter-rater reliability when administered by different raters. The feasibility and inter-rater reliability of the 30-s chair stand were moderate, complicating the use of the 30-s chair stand in acutely admitted older medical patients. However, the predefined modified version of the chair stand test was both feasible and with high inter-rater reliability in this population. PMID- 25706554 TI - Comparison of gamma-irradiation with other pretreatments followed with simultaneous saccharification and fermentation on bioconversion of microcrystalline cellulose for bioethanol production. AB - The effect of gamma-irradiation pretreatment was compared with other pretreatment methods including ionic liquids (ILs), 1% HCl, 1% H2SO4, acidic aqueous Ils (AA ILs), on the bioconversion efficiency of microcrystalline cellulose (MCC) for bioethanol production. The efficiency of MCC pretreatment followed with simultaneous saccharification and fermentation (SSF) was firstly evaluated according to the variations of the irradiation-derived compounds and structure of MCC, as well as yeast growth curve and bioethanol yield. Results showed that the appropriate irradiation dose (891 kGy used in our work) could eliminate the negative effect of toxic irradiation-derived compounds on SSF for ethanol bioconversion with the yield value of 67%. Analyses of SEM, FT-IR, reducing sugar and bioethanol yield showed that the efficiency of pretreatment on MCC was ILs ~ irradiation pretreatment > AA-ILs pretreatment > 1% HCl pretreatment > 1% H2SO4 pretreatment. PMID- 25706555 TI - Sequential dilute acid and alkali pretreatment of corn stover: sugar recovery efficiency and structural characterization. AB - The objectives of this study were to explore the feasibility of applying sequential dilute acid and alkali pretreatment into the hydrolysis of corn stover and to elucidate the effects of structural changes in the biomass on its enzymatic digestibility. H2SO4 used in the first step selectively hydrolyzed 74.6 77.3% of xylan and NaOH used in the second step removed 85.9-89.4% of lignin, from the raw corn stover. Compared to single dilute acid pretreatment, the proposed combined pretreatment minimized the generation of byproducts such as acetic acid, furfural and hydroxymethylfurfural in the hydrolysates, and enhanced the enzymatic hydrolysis of the solid residue. The changes in the structural features (porosity, morphology, and crystallinity) of the solid residue were strongly correlated with the enhancement of enzymatic digestibility. The overall glucose and xylose yields finally obtained after enzymatic hydrolysis reached 89.1-97.9% and 71.0-75.9%, respectively. PMID- 25706556 TI - Harvesting effects, recovery mechanisms, and management strategies for a long lived and structural precious coral. AB - Overexploitation is a major threat for the integrity of marine ecosystems. Understanding the ecological consequences of different extractive practices and the mechanisms underlying the recovery of populations is essential to ensure sustainable management plans. Precious corals are long-lived structural invertebrates, historically overfished, and their conservation is currently a worldwide concern. However, the processes underlying their recovery are poorly known. Here, we examined harvesting effects and recovery mechanisms of red coral Corallium rubrum by analyzing long-term photographic series taken on two populations that were harvested. We compared the relative importance of reproduction and re-growth as drivers of resilience. Harvesting heavily impacted coral populations causing large decreases in biomass and strong size-class distribution shifts towards populations dominated by small colonies. At the end of the study (after 4 and 7 years) only partial recovery was observed. The observed general pattern of low recruitment and high mortality of new recruits demonstrated limited effects of reproduction on population recovery. Adversely, low mortality of partially harvested adults and a large proportion of colonies showing new branches highlighted the importance of re-growth in the recovery process. The demographic projections obtained through stochastic models confirmed that the recovery rates of C. rubrum can be strongly modulated depending on harvesting procedures. Thus, leaving the basal section of the colonies when harvesting to avoid total mortality largely enhances the resilience of C. rubrum populations and quickens their recovery. On the other hand, the high survival of harvested colonies and the significant biomass reduction indicated that abundance may not be an adequate metric to assess the conservation status of clonal organisms because it can underestimate harvesting effects. This study highlights the unsustainability of current harvesting practices of C. rubrum and provides urgently needed data to improve management practices that are still largely based on untested assumptions. PMID- 25706557 TI - Indoor air condensate as a novel matrix for monitoring inhalable organic contaminants. AB - With the population of developed nations spending nearly 90% of their time indoors, indoor air quality (IAQ) is a critical indicator of human health risks from inhalation of airborne contaminants. We present a novel approach for qualitative monitoring of IAQ through the collection and analysis of indoor air condensate discharged from heat exchangers of heating, ventilation, and air conditioning (HVAC) systems. Condensate samples were collected from six suburban homes and one business in Maricopa County, Arizona, concentrated via solid-phase extraction, analyzed for 10 endocrine disrupting chemicals (EDCs) by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and screened for additional organic compounds by gas chromatography-mass spectrometry (GC-MS). All 10 EDCs were detected in at least one of the sampled buildings. More than 100 additional compounds were detected by GC-MS, of which 40 were tentatively identified using spectral database searches. Twelve compounds listed as designated chemicals for biomonitoring by the California Environmental Contaminant Biomonitoring Program were detected. Microfiltration of condensate samples prior to extraction had no discernable effect on contaminant concentration, suggesting that contaminants were freely dissolved or associated with inhalable, submicron particles. This study is the first to document the utility of HVAC condensate for the qualitative assessment of indoor air for pollutants. PMID- 25706559 TI - S100A9 induced inflammatory responses are mediated by distinct damage associated molecular patterns (DAMP) receptors in vitro and in vivo. AB - Release of endogenous damage associated molecular patterns (DAMPs), including members of the S100 family, are associated with infection, cellular stress, tissue damage and cancer. The extracellular functions of this family of calcium binding proteins, particularly S100A8, S100A9 and S100A12, are being delineated. They appear to mediate their functions via receptor for advanced glycation endproducts (RAGE) or TLR4, but there remains considerable uncertainty over the relative physiological roles of these DAMPs and their pattern recognition receptors. In this study, we surveyed the capacity of S100 proteins to induce proinflammatory cytokines and cell migration, and the contribution RAGE and TLR4 to mediate these responses in vitro. Using adenoviral delivery of murine S100A9, we also examined the potential for S100A9 homodimers to trigger lung inflammation in vivo. S100A8, S100A9 and S100A12, but not the S100A8/A9 heterodimer, induced modest levels of TLR4-mediated cytokine production from human PBMC. In contrast, for most S100s including S100A9, RAGE blockade inhibited S100-mediated cell migration of THP1 cells and major leukocyte populations, whereas TLR4-blockade had no effect. Intranasal administration of murine S100A9 adenovirus induced a specific, time-dependent predominately macrophage infiltration that coincided with elevated S100A9 levels and proinflammatory cytokines in the BAL fluid. Inflammatory cytokines were markedly ablated in the TLR4-defective mice, but unexpectedly the loss of TLR4 signaling or RAGE-deficiency did not appreciably impact the S100A9-mediated lung pathology or the inflammatory cell infiltrate in the alveolar space. These data demonstrate that physiological levels of S100A9 homodimers can trigger an inflammatory response in vivo, and despite the capacity of RAGE and TLR4 blockade to inhibit responses in vitro, the response is predominately independent of both these receptors. PMID- 25706560 TI - Investigating the relationship between ethnic consciousness, racial discrimination and self-rated health in New Zealand. AB - In this study, we examine race/ethnic consciousness and its associations with experiences of racial discrimination and health in New Zealand. Racism is an important determinant of health and cause of ethnic inequities. However, conceptualising the mechanisms by which racism impacts on health requires racism to be contextualised within the broader social environment. Race/ethnic consciousness (how often people think about their race or ethnicity) is understood as part of a broader assessment of the 'racial climate'. Higher race/ethnic consciousness has been demonstrated among non-dominant racial/ethnic groups and linked to adverse health outcomes in a limited number of studies. We analysed data from the 2006/07 New Zealand Health Survey, a national population based survey of New Zealand adults, to examine the distribution of ethnic consciousness by ethnicity, and its association with individual experiences of racial discrimination and self-rated health. Findings showed that European respondents were least likely to report thinking about their ethnicity, with people from non-European ethnic groupings all reporting relatively higher ethnic consciousness. Higher ethnic consciousness was associated with an increased likelihood of reporting experience of racial discrimination for all ethnic groupings and was also associated with fair/poor self-rated health after adjusting for age, sex and ethnicity. However, this difference in health was no longer evident after further adjustment for socioeconomic position and individual experience of racial discrimination. Our study suggests different experiences of racialised social environments by ethnicity in New Zealand and that, at an individual level, ethnic consciousness is related to experiences of racial discrimination. However, the relationship with health is less clear and needs further investigation with research to better understand the racialised social relations that create and maintain ethnic inequities in health in attempts to better address the impacts of racism on health. PMID- 25706561 TI - A longitudinal assessment of vocabulary retention in symbol-competent chimpanzees (Pan troglodytes). AB - A number of studies from the 1960s to 1990s assessed the symbolic competence of great apes and other animals. These studies provided varying forms of evidence that some species were capable of symbolically representing their worlds, both through productive symbol use and comprehension of symbolic stimuli. One such project at the Language Research Center involved training chimpanzees (Pan troglodytes) to use lexigram symbols (geometric visual stimuli that represented objects, actions, locations, and individuals). Those studies now are more than 40 years old, and only a few of the apes involved in those studies are still alive. Three of these chimpanzees (and a fourth, control chimpanzee) were assessed across a 10-year period from 1999 to 2008 for their continued knowledge of lexigram symbols and, in the case of one chimpanzee, the continued ability to comprehend human speech. This article describes that longitudinal assessment and outlines the degree to which symbol competence was retained by these chimpanzees across that decade-long period. All chimpanzees showed retention of lexigram vocabularies, although there were differences in the number of words that were retained across the individuals. One chimpanzee also showed continual retention of human speech perception. These retained vocabularies largely consisted of food item names, but also names of inedible objects, locations, individuals, and some actions. Many of these retained words were for things that are not common in the daily lives of the chimpanzees and for things that are rarely requested by the chimpanzees. Thus, the early experiences of these chimpanzees in symbol-rich environments have produced long-lasting memories for symbol meaning, and those competencies have benefited research in a variety of topics in comparative cognition. PMID- 25706562 TI - Pale-green phenotype of atl31atl6 double mutant leaves is caused by disruption of 5-aminolevulinic acid biosynthesis in Arabidopsis thaliana. AB - Arabidopsis ubiquitin ligases ATL31 and homologue ATL6 control the carbon/nitrogen nutrient and pathogen responses. A mutant with the loss-of function of both atl31 and atl6 developed light intensity-dependent pale-green true leaves, whereas the single knockout mutants did not. Plastid ultrastructure and Blue Native-PAGE analyses revealed that pale-green leaves contain abnormal plastid structure with highly reduced levels of thylakoid proteins. In contrast, the pale-green leaves of the atl31/atl6 mutant showed normal Fv/Fm. In the pale green leaves of the atl31/atl6, the expression of HEMA1, which encodes the key enzyme for 5-aminolevulinic acid synthesis, the rate-limiting step in chlorophyll biosynthesis, was markedly down-regulated. The expression of key transcription factor GLK1, which directly promotes HEMA1 transcription, was also significantly decreased in atl31/atl6 mutant. Finally, application of 5-aminolevulinic acid to the atl31/atl6 mutants resulted in recovery to a green phenotype. Taken together, these findings indicate that the 5-aminolevulinic acid biosynthesis step was inhibited through the down-regulation of chlorophyll biosynthesis-related genes in the pale-green leaves of atl31/atl6 mutant. PMID- 25706563 TI - Enterovirus 71 virion-associated galectin-1 facilitates viral replication and stability. AB - Enterovirus 71 (EV71) infection causes a myriad of diseases from mild hand-foot and-mouth disease or herpangina to fatal brain stem encephalitis complicated with pulmonary edema. Several severe EV71 endemics have occurred in Asia-Pacific region, including Taiwan, and have become a serious threat to children's health. EV71 infection is initiated by the attachment of the virion to the target cell surface. Although this process relies primarily upon interaction between viruses and cell surface receptors, soluble factors may also influence the binding of EV71 to host cells. Galectin-1 has been reported to participate in several virus infections, but is not addressed in EV71. In this study, we found that the serum levels of galectin-1 in EV71-infected children were higher than those in non infected people. In EV71 infected cells, galectin-1 was found to be associated with the EV71 VP1 and VP3 via carbohydrate residues and subsequently released and bound to another cell surface along with the virus. EV71 propagated from galectin 1 knockdown SK-N-SH cells exhibited lower infectivity in cultured cells and less pathogenicity in mice than the virus propagated from parental cells. In addition, this galectin-1-free EV71 virus was sensitive to high temperature and lost its viability after long-term storage, which could be restored following supplement of recombinant galectin-1. Taken together, our findings uncover a new role of galectin-1 in facilitating EV71 virus infection. PMID- 25706564 TI - Highly ductile UV-shielding polymer composites with boron nitride nanospheres as fillers. AB - Polymer composites with enhanced mechanical, thermal or optical performance usually suffer from poor ductility induced by confined mobility of polymer chains. Herein, highly ductile UV-shielding polymer composites are successfully fabricated. Boron nitride (BN) materials, with a wide band gap of around ~6.0 eV, are used as fillers to achieve the remarkably improved UV-shielding performance of a polymer matrix. In addition, it is found that spherical morphology BN as a filler can keep the excellent ductility of the composites. For a comparison, it is demonstrated that traditional fillers, including conventional BN powders can achieve the similar UV-shielding performance but dramatically decrease the composite ductility. The mechanism behind this phenomenon is believed to be lubricant effects of BN nanospheres for sliding of polymer chains, which is in consistent with the thermal analyses. This study provides a new design to fabricate UV-shielding composite films with well-preserved ductility. PMID- 25706565 TI - Ethanol production from food waste at high solids content with vacuum recovery technology. AB - Ethanol production from food wastes does not only solve environmental issues but also provides renewable biofuels. This study investigated the feasibility of producing ethanol from food wastes at high solids content (35%, w/w). A vacuum recovery system was developed and applied to remove ethanol from fermentation broth to reduce yeast ethanol inhibition. A high concentration of ethanol (144 g/L) was produced by the conventional fermentation of food waste without a vacuum recovery system. When the vacuum recovery is applied to the fermentation process, the ethanol concentration in the fermentation broth was controlled below 100 g/L, thus reducing yeast ethanol inhibition. At the end of the conventional fermentation, the residual glucose in the fermentation broth was 5.7 g/L, indicating incomplete utilization of glucose, while the vacuum fermentation allowed for complete utilization of glucose. The ethanol yield for the vacuum fermentation was found to be 358 g/kg of food waste (dry basis), higher than that for the conventional fermentation at 327 g/kg of food waste (dry basis). PMID- 25706566 TI - Tissue distribution of six major bio-active components after oral administration of Zhenqi Fuzheng capsules to rats using ultra-pressure liquid chromatography tandem mass spectrometry. AB - Radix Astragali (Huangqi in Chinese) and Fructus Ligustri Lucidi (Nvzhenzi in Chinese) (2:1, w/w) are combined in an herbal formulation called Zhenqi Fuzheng capsules (ZFCs) for use in China to improve immunity, promote the recovery of normal functions after surgical operations, and as the most important adjuvant therapy in cancer. In this study, the tissue distribution profiles of the six major bio-active constituents (calycosin-7-O-beta-D-glucoside, ononin, calycosin, formononetin, astragaloside IV and astragaloside II) were examined after oral administration of ZFCs to rats. All six constituents in each tissue were detected simultaneously using UPLC-ESI-MS, and the concentration of each constituent per gram of each tissue was determined. Quantification was performed using low-energy collision tandem mass spectrometry (CID-MS/MS) in multiple reaction monitoring (MRM) scan mode for the following precursor ion->product ion transitions at m/z 447.21->285.30 for calycosin-7-O-beta-D-glucoside, m/z 285.29->270.38 for calycosin, m/z 431->269 for ononin, m/z 269->237 for formononetin, m/z 807.40 >627.50 for astragaloside IV, m/z 849.60->669.65 for astragaloside II and m/z 633.18->331.18 for the internal standard (hesperidin). The results showed that in general the tissue concentrations for all six constituents were in the following order: spleen>stomach>thymus>lung>liver>kidney>heart>testicle. The high levels in the spleen and thymus indicated that all six compounds accumulated in organs involved in the immune response, consistent with the immunity effects of ZFC. The high levels in the stomach were consistent with the oral administration of ZFC. This study was the first to compare the tissue distribution of calycosin-7-O-beta D-glucoside with that of calycosin or of ononin with that of formononetin in rats. It was also the first study to examine the tissue distribution of astragaloside II, calycosin and formononetin following oral administration of ZFC to rats. PMID- 25706567 TI - Development and validation of an UPLC-MS/MS method for the quantification of ethoxzolamide in blood, brain tissue, and bioequivalent buffers: applications to absorption, brain distribution, and pharmacokinetic studies. AB - The purpose of this study is to develop and validate an UPLC-MS/MS method to quantify ethoxzolamide in plasma (EZ) and apply the method to absorption, brain distribution, as well as pharmacokinetic studies. A C18 column was used with 0.1% of formic acid in acetonitrile and 0.1% of formic acid in water as the mobile phases to resolve EZ. The mass analysis was performed in a triple quadrupole mass spectrometer using multiple reaction monitoring (MRM) with positive scan mode. The results show that the linear range of EZ is 4.88-10,000.00 nM. The intra-day variance is less than 12.43% and the accuracy is between 88.88 and 108.00%. The inter-day variance is less than 12.87% and accuracy is between 89.27 and 115.89%. Protein precipitation was performed using methanol to extract EZ from plasma and brain tissues. Only 40 MUL of plasma is needed for analysis due to the high sensitivity of this method, which could be completed in less than three minutes. This method was used to study the pharmacokinetics of EZ in SD rats, and the transport of EZ in Caco-2 and MDCK-MDR1 overexpressing cell culture models. Our data show that EZ is not a substrate for p-glycoprotein (P-gp) and its entry into the brain may not limited by the blood-brain barrier. PMID- 25706568 TI - Qualitative and quantitative analysis of felbinac and its major metabolites in human plasma and urine by liquid chromatography tandem mass spectrometry and its application after intravenous administration of felbinac trometamol injection. AB - We present a method for the qualitative and quantitative analysis of felbinac and its major metabolites in human plasma and urine by HPLC-MS/MS and its application. Qualitative analysis through LC-Triple-TOF-MS/MS indicated that oxidization was the main phase-I metabolic pathway of felbinac in human, conjugation with sulfate and glucuronide groups produced at least 7 phase-II metabolites. Quantitative analysis through HPLC-MS/MS in MRM mode was developed and validated for the quantification of felbinac and its major metabolite (4' hydroxyfelbinac) in human plasma and urine. Linear calibration curves were obtained for felbinac and 4'-hydroxyfelbinac in plasma and urine (r>0.996); intra and inter-day precision values (RSD%) obtained were ranged from 1.13 to 6.49%, and the accuracy were between 95.9% and 108.6% for the two analytes. The pharmacokinetics and excretion analysis showed that the t1/2 of 4' hydroxyfelbinac (8.25 +/- 4.15 h) is a litter longer than that of felbinac (6.13 +/- 2.01 h), but the mean AUC(0-t) value of felbinac was about 20 times higher than that of 4'-hydroxyfelbinac; excretion of felbinac and 4'-hydroxyfelbinac reached their peak values at about 3-6h after intravenous administration of felbinac trometamol in human. PMID- 25706570 TI - Genetic testing for hemochromatosis: diagnostic or confirmatory test for iron overload? PMID- 25706571 TI - Bouveret syndrome: when there are no options. PMID- 25706572 TI - A study investigating the association of dermatological and infusion reactions to infliximab and infliximab trough levels. AB - BACKGROUND: Although infliximab is an effective therapy for inflammatory bowel disease (IBD), it is associated with dermatological events and infusion reactions. It is not known whether a relationship between these adverse events (AEs) and infliximab trough levels (ITLs) exists. OBJECTIVES: To report the prevalence of infliximab-associated AEs in IBD patients receiving stable maintenance infliximab therapy, and to correlate ITLs with dermatological and infusion reactions to infliximab. METHODS: Adult IBD patients receiving stable maintenance infliximab therapy were recruited from the University of Alberta Infusion Clinic (Edmonton, Alberta). ITLs were measured in blood samples collected before infusion, and the patients' records were reviewed for dermatological and infusion reactions to infliximab. RESULTS: One-quarter (18 of 71 [25.4%]) of patients experienced dermatological or infusion reactions to infliximab: nine (12.7%) dermatological events and nine (12.7%) infusion reactions. The median ITL was similar among patients with and without these AEs (7.2 MUg/mL [interquartile range (IQR) 2.0 MUg/mL to 13.3 MUg/mL] versus 6.6 MUg/mL [IQR 3.2 MUg/mL to 12.7 MUg/mL]; P=0.648). The median ITL of patients who experienced infusion reactions (2.0 MUg/mL [IQR 0.1 MUg/mL to 5.7 MUg/mL]) was lower than that of patients who experienced no such AEs (6.6 MUg/mL [IQR 3.2 MUg/mL to 12.7 MUg/mL]; P=0.008]) and lower than that of patients who experienced dermatological AEs (13.3 MUg/mL [IQR 8.8 MUg/mL to 17.4 MUg/mL]; P<0.001). CONCLUSION: One-quarter of IBD outpatients receiving stable maintenance infliximab therapy experienced dermatological and infusion reactions. Low ITLs were correlated with infusion reactions, and normal or high ITLs with dermatological events. PMID- 25706573 TI - Examining the clinical use of hemochromatosis genetic testing. AB - BACKGROUND: Hereditary hemochromatosis leads to an increased lifetime risk for end-organ damage due to excess iron deposition. Guidelines recommend that genetic testing be performed in patients with clinical suspicion of iron overload accompanied by elevated serum ferritin and transferrin saturation levels. OBJECTIVE: To evaluate guideline adherence and the clinical and economic impact of HFE genetic testing. METHODS: The electronic charts of patients submitted for HFE testing in 2012 were reviewed for genetic testing results, biochemical markers of iron overload and clinical history of phlebotomy. RESULTS: A total of 664 samples were sent for testing, with clinical, biochemical and phlebotomy data available for 160 patients. A positive C282Y homozygote or C282Y/H63D compound heterozygote test result was observed in 18% of patients. Patients with an at risk HFE genotype had significantly higher iron saturation, serum iron and hemoglobin (P<0.001), without higher ferritin or liver enzyme levels. Fifty percent of patients referred for testing did not have biochemical evidence of iron overload (transferrin saturation >45% and ferritin level >300 MUg/L). Patients were four times more likely to undergo phlebotomy if they were gene test positive (RR 4.29 [95% CI 2.35 to 7.83]; P<0.00001). DISCUSSION: One-half of patients referred for testing did not exhibit biochemical evidence of iron overload. Many patients with biochemical evidence of iron overload, but with negative genetic test results, did not undergo phlebotomy. A requisition to determine clinical indication for testing may reduce the use of the HFE genetic test. Finally, improvement of current genetic test characteristics would improve rationale for the test. CONCLUSION: A significant proportion of hemochromatosis genetic testing does not adhere to current guidelines and would not alter patient management. PMID- 25706574 TI - The hepatitis C genotype 1 paradox: cost per treatment is increasing, but cost per cure is decreasing. AB - Significant attention has been focused on the perceived increase in the cost of antiviral treatment for hepatitis C genotype 1 infection since the approval of the first direct-acting antiviral agents in 2011. Using Canadian list prices, the present analysis points out a paradox: while the cost per antiviral regimen is increasing, the cost per cure is decreasing, especially with interferon-free therapy. In a publicly funded health care system, the lowest cost per cure is a more valuable measure of value for public money than the cost per regimen. PMID- 25706575 TI - Plasma leptin concentrations and esophageal hypomotility in obese patients. AB - BACKGROUND: Although esophageal hypomotility is prevalent in obese patients, its cause remains unknown. Leptin, a hormone derived from adipose tissue, may be involved in this phenomenon because it has been shown to decrease gastric and intestinal motility in animals. It has been hypothesized that elevated plasma leptin concentration is a risk factor for esophageal dysmotility in obese patients. OBJECTIVE: To determine whether plasma leptin concentrations are higher in obese patients with esophageal hypomotility than in obese patients with a normal motility profile. METHOD: Fasting plasma leptin concentration (assessed by radioimmuoassay) was measured in all patients who were included in a study protocol investigating esophageal manometry before bariatric surgery. The patients completed standardized surveys regarding epidemiological data, upper gastrointestinal symptoms, medical history and medication(s). Basal levels of leptin, as well as corrected leptin scores adjusted for sex and body mass index, were compared in patients with and without esophageal dysmotility. RESULTS: Nine patients without dysmotility and eight with dysmotility were included. Both groups were comparable with regard to age (42+/-9 versus 38+/-9 years), sex (78% versus 75% women) and body mass index (49+/-10 kg/m2 versus 42+/-7 kg/m2). There were no significant differences regarding medication(s) and comorbidities between the two groups. When compared with normal predicted values, the corrected leptin scores were 30% higher in patients with dysmotility than in the control group with normal motility (P<=0.05). CONLCUSION: Obese patients with esophageal dysmotility exhibited elevated plasma leptin concentrations, suggesting a role for leptin in promoting esophageal hypomotility. PMID- 25706576 TI - The influence of non-HFE genes and steatohepatitis on increased iron stores in patients with the H63D mutation. PMID- 25706577 TI - Absorbate-induced piezochromism in a porous molecular crystal. AB - Atmospherically stable porous frameworks and materials are interesting for heterogeneous solid-gas applications. One motivation is the direct and selective uptake of pollutant/hazardous gases, where the material produces a measurable response in the presence of the analyte. In this report, we present a combined experimental and theoretical rationalization for the piezochromic response of a robust and porous molecular crystal built from an extensively fluorinated trispyrazole. The electronic response of the material is directly determined by analyte uptake, which provokes a subtle lattice contraction and an observable bathochromic shift in the optical absorption onset. Selectivity for fluorinated absorbates is demonstrated, and toluene is also found to crystallize within the pore. Furthermore, we demonstrate the application of electronic structure calculations to predict a physicochemical response, providing the foundations for the design of electronically tunable porous solids with the chemical properties required for development of novel gas-uptake media. PMID- 25706578 TI - CSI-EPT: A Contrast Source Inversion Approach for Improved MRI-Based Electric Properties Tomography. AB - Electric properties tomography (EPT) is an imaging modality to reconstruct the electric conductivity and permittivity inside the human body based on B1(+) maps acquired by a magnetic resonance imaging (MRI) system. Current implementations of EPT are based on the local Maxwell equations and assume piecewise constant media. The accuracy of the reconstructed maps may therefore be sensitive to noise and reconstruction errors occur near tissue boundaries. In this paper, we introduce a multiplicative regularized CSI-EPT method (contrast source inversion-electric properties tomography) where the electric tissue properties are retrieved in an iterative fashion based on a contrast source inversion approach. The method takes the integral representations for the electromagnetic field as a starting point and the tissue parameters are obtained by iteratively minimizing an objective function which measures the discrepancy between measured and modeled data and the discrepancy in satisfying a consistency equation known as the object equation. Furthermore, the objective function consists of a multiplicative Total Variation factor for noise suppression during the reconstruction process. Finally, the presented implementation is able to simultaneously include more than one B1(+) data set acquired by complementary RF excitation settings. We have performed in vivo simulations using a female pelvis model to compute the B1(+) fields. Three different RF excitation settings were used to acquire complementary B1(+) fields for an improved overall reconstruction. Numerical results illustrate the improved reconstruction near tissue boundaries and the ability of CSI-EPT to reconstruct small tissue structures. PMID- 25706579 TI - Robust Low-Dose CT Perfusion Deconvolution via Tensor Total-Variation Regularization. AB - Acute brain diseases such as acute strokes and transit ischemic attacks are the leading causes of mortality and morbidity worldwide, responsible for 9% of total death every year. "Time is brain" is a widely accepted concept in acute cerebrovascular disease treatment. Efficient and accurate computational framework for hemodynamic parameters estimation can save critical time for thrombolytic therapy. Meanwhile the high level of accumulated radiation dosage due to continuous image acquisition in CT perfusion (CTP) raised concerns on patient safety and public health. However, low-radiation leads to increased noise and artifacts which require more sophisticated and time-consuming algorithms for robust estimation. In this paper, we focus on developing a robust and efficient framework to accurately estimate the perfusion parameters at low radiation dosage. Specifically, we present a tensor total-variation (TTV) technique which fuses the spatial correlation of the vascular structure and the temporal continuation of the blood signal flow. An efficient algorithm is proposed to find the solution with fast convergence and reduced computational complexity. Extensive evaluations are carried out in terms of sensitivity to noise levels, estimation accuracy, contrast preservation, and performed on digital perfusion phantom estimation, as well as in vivo clinical subjects. Our framework reduces the necessary radiation dose to only 8% of the original level and outperforms the state-of-art algorithms with peak signal-to-noise ratio improved by 32%. It reduces the oscillation in the residue functions, corrects over-estimation of cerebral blood flow (CBF) and under-estimation of mean transit time (MTT), and maintains the distinction between the deficit and normal regions. PMID- 25706580 TI - Spatio-Temporal Tensor Decomposition of a Polyaffine Motion Model for a Better Analysis of Pathological Left Ventricular Dynamics. AB - Given that heart disease can cause abnormal motion dynamics over the cardiac cycle, understanding and quantifying cardiac motion can provide insight for clinicians to aid with diagnosis, therapy planning, and determining prognosis. The goal of this paper is to extract population-specific motion patterns from 3D displacements in order to identify the mean motion in a population, and to describe pathology-specific motion patterns in terms of the spatial and temporal components. Since there are common motion patterns observed in patients with the same condition, extracting these can lead towards a better understanding of the disease. Quantifying cardiac motion at a population level is not a simple task since images can vary widely in terms of image quality, size, resolution, and pose. To overcome this, we analyze the parameters obtained from a cardiac specific Polyaffine motion-tracking algorithm, which are aligned both spatially and temporally to a common reference space. Once all parameters are aligned, different subjects can be compared and analyzed in the space of Polyaffine transformations by projecting the transformations to a reduced order subspace in which dominant motion patterns in each population can be extracted. Using tensor decomposition, the spatial and temporal aspects can be decoupled in order to study the components individually. The proposed method was validated on healthy volunteers and Tetralogy of Fallot patients according to known spatial and temporal behavior for each population. A key advantage of this method is the ability to regenerate motion sequences from the models, which can be visualized in terms of the full motion. PMID- 25706581 TI - Automatic Detection of Tuberculosis in Chest Radiographs Using a Combination of Textural, Focal, and Shape Abnormality Analysis. AB - Tuberculosis (TB) is a common disease with high mortality and morbidity rates worldwide. Automatic systems to detect TB on chest radiographs (CXRs) can improve the efficiency of diagnostic algorithms for pulmonary TB. The diverse manifestation of TB on CXRs from different populations requires a system that can be adapted to deal with different types of abnormalities. A computer aided detection (CAD) system was developed which combines several subscores of supervised subsystems detecting textural, shape, and focal abnormalities into one TB score. A general framework was developed to combine an arbitrary number of subscores: subscores were normalized, collected in a feature vector and then combined using a supervised classifier into one combined score. The method was evaluated on two databases, both consisting of 200 digital CXRs, from: (A) Western high-risk group screening, (B) TB suspect screening in Africa. The subscores and combined score were compared to (1) an external, non-radiological, reference and (2) a radiological reference determined by a human expert. Performance was measured using Receiver Operator Characteristic (ROC) analysis. Different subscores performed best in the two databases. The combined TB score performed better than the individual subscores, except for the external reference in database B. The performances of the independent observer were slightly higher than the combined TB score. Compared to the external reference, differences in performance between the combined TB score and the independent observer were not significant in both databases. Supervised combination to compute an overall TB score allows for a necessary adaptation of the CAD system to different settings or different operational requirements. PMID- 25706583 TI - Physical properties of annealed ZnO nanowire/CuSCN heterojunctions for self powered UV photodetectors. AB - The low-cost fabrication of ZnO nanowire/CuSCN heterojunctions is demonstrated by combining chemical bath deposition with impregnation techniques. The ZnO nanowire arrays are completely filled by the CuSCN layer from their bottoms to their tops. The CuSCN layer is formed of columnar grains that are strongly oriented along the [003] direction owing to the polymeric form of the beta-rhombohedral crystalline phase. Importantly, an annealing step is found essential in a fairly narrow range of low temperatures, not only for outgassing the solvent from the CuSCN layer, but also for reducing the density of interfacial defects. The resulting electrical properties of annealed ZnO nanowire/CuSCN heterojunctions are strongly improved: a maximum rectification ratio of 2644 at +/-2 V is achieved following annealing at 150 degrees C under air atmosphere, which is related to a strong decrease in the reverse current density. Interestingly, the corresponding self powered UV photodetectors exhibit a responsivity of 0.02 A/W at zero bias and at 370 nm with a UV-to-visible (370-500 nm) rejection ratio of 100 under an irradiance of 100 mW/cm(2). The UV selectivity at 370 nm can also be readily modulated by tuning the length of ZnO nanowires. Eventually, a significant photovoltaic effect is revealed for this type of heterojunctions, leading to an open circuit voltage of 37 mV and a short circuit current density of 51 MUA/cm(2), which may be useful for the self-powering of the complete device. These findings show the underlying physical mechanisms at work in ZnO nanowire/CuSCN heterojunctions and reveal their high potential as self-powered UV photodetectors. PMID- 25706582 TI - An ordered water channel in Staphylococcus aureus FabI: unraveling the mechanism of substrate recognition and reduction. AB - One third of all drugs in clinical use owe their pharmacological activity to the functional inhibition of enzymes, highlighting the importance of enzymatic targets for drug development. Because of the close relationship between inhibition and catalysis, understanding the recognition and turnover of enzymatic substrates is essential for rational drug design. Although the Staphylococcus aureus enoyl-acyl carrier protein reductase (saFabI) involved in bacterial fatty acid biosynthesis constitutes a very promising target for the development of novel, urgently needed anti-staphylococcal agents, the substrate binding mode and catalytic mechanism remained unclear for this enzyme. Using a combined crystallographic, kinetic, and computational approach, we have explored the chemical properties of the saFabI binding cavity, obtaining a consistent mechanistic model for substrate binding and turnover. We identified a water molecule network linking the active site with a water basin inside the homo tetrameric protein, which seems to be crucial for the closure of the flexible substrate binding loop as well as for an effective hydride and proton transfer during catalysis. On the basis of our results, we also derive a new model for the FabI-ACP complex that reveals how the ACP-bound acyl-substrate is injected into the FabI binding crevice. These findings support the future development of novel FabI inhibitors that target the FabI-ACP interface leading to the disruption of the interaction between these two proteins. PMID- 25706584 TI - [Editorial: Guia latinoamericana para el diagnostico y tratamiento de alergia a las proteinas de la leche de vaca (GL-APLV)]. PMID- 25706585 TI - [Guia latinoamericana para el diagnostico y tratamiento de alergia a las proteinas de la leche de vaca (GL-APLV)]. AB - Cow's milk allergy (CMA) is an immune-based disease that has become an increasing problem. The diagnosis and management of CMA varies from one clinical setting to another and represents a challenge in pediatric practice. In addition, because nonallergic food reactions can be confused with CMA symptoms, there is an overdiagnosis of the disease. In response to these situations, pediatric specialties from recognized institutions throughout Latin America decided to develop a clinical guideline for diagnosis and management of cow's milk allergy. These guidelines include definitions, epidemiology, pathophysiology overview, clinical and evidencebased recommendations for the diagnosis and treatment of CMA. They also include prevention and prognosis sections and identify gaps in the current knowledge to be addressed through future research. PMID- 25706587 TI - Reducing firearm-related harms: time for us to study and speak out. PMID- 25706586 TI - Selectivity by small-molecule inhibitors of protein interactions can be driven by protein surface fluctuations. AB - Small-molecules that inhibit interactions between specific pairs of proteins have long represented a promising avenue for therapeutic intervention in a variety of settings. Structural studies have shown that in many cases, the inhibitor-bound protein adopts a conformation that is distinct from its unbound and its protein bound conformations. This plasticity of the protein surface presents a major challenge in predicting which members of a protein family will be inhibited by a given ligand. Here, we use biased simulations of Bcl-2-family proteins to generate ensembles of low-energy conformations that contain surface pockets suitable for small molecule binding. We find that the resulting conformational ensembles include surface pockets that mimic those observed in inhibitor-bound crystal structures. Next, we find that the ensembles generated using different members of this protein family are overlapping but distinct, and that the activity of a given compound against a particular family member (ligand selectivity) can be predicted from whether the corresponding ensemble samples a complementary surface pocket. Finally, we find that each ensemble includes certain surface pockets that are not shared by any other family member: while no inhibitors have yet been identified to take advantage of these pockets, we expect that chemical scaffolds complementing these "distinct" pockets will prove highly selective for their targets. The opportunity to achieve target selectivity within a protein family by exploiting differences in surface fluctuations represents a new paradigm that may facilitate design of family-selective small-molecule inhibitors of protein-protein interactions. PMID- 25706588 TI - Children's social category-based giving and its correlates: expectations and preferences. AB - Do young children use information about gender and race to guide their prosocial gestures, and to what extent is children's selective prosociality related to other intergroup phenomena? Two studies tested 3- to 5-year-old children's allocation of resources to, social preferences for, and expectations about the behaviors of unfamiliar people who varied by gender or race. In both studies, a predominantly White sample of participants gave more resources to same-gender and White children than to other-gender and Black children, respectively. Correlational analyses showed that participants' gender-based giving was related to their social preferences for, and expectations about receiving help from, children who matched their gender. Race-based giving was only related to participants' expectations that they would be more likely to receive help from White than from Black children. The findings show that gender and race can guide children's resource distribution behavior and also provide insight into factors underlying children's allocation decisions. PMID- 25706589 TI - Experimental impacts of a teacher professional development program in Chile on preschool classroom quality and child outcomes. AB - We assessed impacts on classroom quality and on 5 child language and behavioral outcomes of a 2-year teacher professional-development program for publicly funded prekindergarten and kindergarten in Chile. This cluster-randomized trial included 64 schools (child N = 1,876). The program incorporated workshops and in-classroom coaching. We found moderate to large positive impacts on observed emotional and instructional support as well as classroom organization in prekindergarten classrooms after 1 year of the program. After 2 years of the program, moderate positive impacts were observed on emotional support and classroom organization. No significant program impacts on child outcomes were detected at posttest (1 marginal effect, an increase in a composite of self-regulation and low problem behaviors, was observed). Professional development for preschool teachers in Chile can improve classroom quality. More intensive curricular approaches are needed for these improvements to translate into effects on children. PMID- 25706590 TI - I wish I had (not) taken a gap-year? The psychological and attainment outcomes of different post-school pathways. AB - Existing gap-year research indicates a number of benefits of a gap-year at the end of school and before university enrollment. Life span theory of control, however, suggests that direct goal investment, rather than delay, at developmental transitions is associated with more adaptive outcomes. Comparing these perspectives, the authors undertook 2 studies: 1 in Finland (N = 384, waves = 3) and 1 in Australia (N = 2,259, waves = 5) both with an initial time wave in the last year of high school. The authors explored the effects of a gap-year on both psychological and attainment outcomes using an extensive propensity score matching technique. The Finnish study found no difference in growth in goal commitment, effort, expectations of attainment and strain, or in actual university enrollment in those planning to enter university directly versus those who plan to take a gap-year. The Australian study found no difference in growth in outlooks for the future and career prospects, and life satisfaction between gap-year youth and direct university entrants. However, the study did find that gap-year students were more likely to drop out of a university degree. Implication for theory and practice are discussed. PMID- 25706592 TI - Enhanced processing of vocal melodies in childhood. AB - Music cognition is typically studied with instrumental stimuli. Adults remember melodies better, however, when they are presented in a biologically significant timbre (i.e., the human voice) than in various instrumental timbres (Weiss, Trehub, & Schellenberg, 2012). We examined the impact of vocal timbre on children's processing of melodies. In Study 1, 9- to 11-year-olds listened to 16 unfamiliar folk melodies (4 each of voice, piano, banjo, or marimba). They subsequently listened to the same melodies and 16 timbre-matched foils, and judged whether each melody was old or new. Vocal melodies were recognized better than instrumental melodies, which did not differ from one another, and the vocal advantage was consistent across age. In Study 2, 5- to 6-year-olds and 7- to 8 year-olds were tested with a simplified design that included only vocal and piano melodies. Both age groups successfully differentiated old from new melodies, but memory was more accurate for the older group. The older children recognized vocal melodies better than piano melodies, whereas the younger children tended to label vocal melodies as old whether they were old or new. The results provide the first evidence of differential processing of vocal and instrumental melodies in childhood. PMID- 25706591 TI - Development of auditory selective attention: why children struggle to hear in noisy environments. AB - Children's hearing deteriorates markedly in the presence of unpredictable noise. To explore why, 187 school-age children (4-11 years) and 15 adults performed a tone-in-noise detection task, in which the masking noise varied randomly between every presentation. Selective attention was evaluated by measuring the degree to which listeners were influenced by (i.e., gave weight to) each spectral region of the stimulus. Psychometric fits were also used to estimate levels of internal noise and bias. Levels of masking were found to decrease with age, becoming adult like by 9-11 years. This change was explained by improvements in selective attention alone, with older listeners better able to ignore noise similar in frequency to the target. Consistent with this, age-related differences in masking were abolished when the noise was made more distant in frequency to the target. This work offers novel evidence that improvements in selective attention are critical for the normal development of auditory judgments. PMID- 25706593 TI - Does verbal labeling influence age differences in proactive and reactive cognitive control? AB - The main goal of this study was to examine whether different types of verbal labeling can influence age-related changes in the dynamic control of behavior by inducing either a proactive or reactive mode of control. Proactive control is characterized by a strong engagement in maintaining task-relevant information to be optimally prepared while reactive control is characterized by a reactivation of task-related information during responding. To investigate dynamic shifts between these control modes, we applied the AX-Continuous-Performance-Task in 2 experiments that differed in the complexity of stimuli and types of labeling in children (range = 7-10 years), younger (range = 19-33 years), and older adults (range = 69-83 years). We expected that labeling the cue information would promote a shift from a reactive to a proactive control mode primarily in children and older adults, while labeling the probe information would result in a shift from a proactive to a reactive control mode primarily in younger adults. Results of both experiments indicated that children, younger, and older adults were equally engaged in cue processing and performed the task in a proactive manner. While cue labeling did not further promote performing the task proactively, probe labeling induced a shift to a reactive control mode, especially in children. In the first experiment, including younger children than in the second experiment, children had more problems than adults to reactivate cue information to overcome a strong response tendency. These findings support the view that verbal labeling can influence the regulation of behavior by selectively attracting attention to relevant information in a given task. PMID- 25706594 TI - Study on the interaction between 21-(Ph-NN)-NCTPP and bovine serum albumin by spectroscopic techniques. AB - The interaction between 21-(Ph-NN)-NCTPP and bovine serum albumin (BSA) was investigated by fluorescence and ultraviolet-visible (UV-Vis) spectroscopy under imitated physiological conditions. The results showed that the intrinsic fluorescence of BSA was quenched strongly by 21-(Ph-NN)-NCTPP. The binding constants (Ka) and the binding sites (n) were obtained at three different temperatures (298, 304, and 310K). The thermodynamic parameters (DeltaH, DeltaS and DeltaG) of the interaction system were calculated, the results indicated that the binding process was spontaneous and the hydrophobic interaction played a major role in [21-(Ph-NN)-NCTPP]-BSA binding process. Based on the Forster non radiation energy transfer theory, the binding distance from 21-(Ph-NN)-NCTPP to BSA was estimated to be about 3.51nm. What's more, the synchronous fluorescence spectra indicated that the conformation of BSA has not been changed. PMID- 25706595 TI - A novel green and template free approach for the synthesis of gold nanorice and its utilization as a catalyst for the degradation of hazardous dye. AB - Herein, we describe a simple, green and template free method for the production of rice shaped gold nanostructures using an aqueous extract of the egg shells of Anas platyrhynchos. The synthesized nanoparticles were characterized by UV visible, transmission electron microscopy (TEM), selected area electron diffraction pattern (SAED) and FT-IR studies. The UV-visible spectrum of the synthesized gold nanostructures showed a transverse mode surface plasmon resonance peaks (SPR) at around 540nm and a longitudinal mode at 880nm. The TEM and SAED pattern confirmed the morphology, size and crystallographic structure of the synthesized gold nanorice. The synthesized gold nanorice was utilized for the removal of a toxic Eosin Y dye by photodegradation. It was observed that the dye was degraded completely within 1h and the percentage efficiency was found to be 96.1%. PMID- 25706596 TI - A green-emitting Cu complex for oxygen-sensing purpose: synthesis, characterization and photophysical features. AB - In the present work, a green-emitting Cu(I) complex [Cu(BT-Et)(POP)]BF4 was synthesized and fully characterized, where BT-Et=4-(1-ethyl-1H-benzo[d]imidazol-2 yl)thiazole, POP=bis(2-(diphenylphosphanyl)phenyl) ether, respectively. An ethyl group was connected onto the diamine ligand to breach pi-pi attraction within solid [Cu(BT-Et)(POP)]BF4, favoring O2 molecule attack and sensitivity improvement. Its molecular identity was confirmed by single crystal analysis and theoretical calculation. [Cu(BT-Et)(POP)]BF4 emitted long-lived green emission peaking at 521nm upon photoexcitation which was vulnerable towards O2 molecule, making itself a potential oxygen sensing material. [Cu(BT-Et)(POP)]BF4 was then doped into a silica supporting matrix MCM-41. The resulting composite samples showed sensing behavior towards O2 molecule, with short response time of 10s and sensitivity of 5.56. PMID- 25706597 TI - Effect of Co(2+) and Ni(2+)-doped zinc borate nano crystalline powders by co precipitation method. AB - A simple co-precipitation method has been used for the synthesis of Co(2+) and Ni(2+)-doped zinc borate nanopowders. X-ray diffraction (XRD), Fourier transform infrared (FT-IR), UV/Vis absorption, Scanning electron microscope (SEM) with EDS and photoluminescence (PL) spectroscopies techniques has been employed for their characterization. Powder X-ray diffraction data reveals that the crystal structure belongs to monoclinic for both as-prepared samples. SEM images showed surface morphology of the prepared samples. Optical absorption spectra showed the characteristic bands of doped ions in octahedral site symmetry. From the optical absorption data crystal field and inter-electronic repulsion parameters are evaluated. The FT-IR spectra showed the characteristic vibrational bands related to ZnO, BO3 and BO4 molecules. Photoluminescence spectra exhibited the emission bands in ultraviolet and blue regions. PMID- 25706598 TI - Synthesis and characterization of 2-substituted benzimidazoles and their evaluation as anticancer agent. AB - In this work, we report a series of benzimidazole derivatives synthesized from benzene-1,2-diamine and aryl-aldehydes at room temperature. The synthesized compounds have been characterized on the basis of elemental analysis and various spectroscopic studies viz., IR, (1)H- and (13)C-NMR, ESI-MS as well by X-ray single X-ray crystallographic study. Interaction of these compounds with CT-DNA has been examined with fluorescence experiments and showed significant binding ability. All the synthesized compounds have been screened for their antitumor activities against various human cancer cell lines viz., Human breast adenocarcinoma cell line (MCF-7), Human leukemia cell line (THP-1), Human prostate cancer cell lines (PC-3) and adenocarcinomic human alveolar basal epithelial cell lines (A-549). Interestingly, all the compounds showed significant anticancer activity. PMID- 25706599 TI - Synthesis, characterization, crystal structure and cytotoxic properties of thiosemicarbazide Ni(II) and Zn(II) complexes. AB - Synthesis of new complexes of Ni(II) (1) and Zn(II) (2) with [1-(2-hydroxy-3,5 diiodobenzylidene)-4-phenylthiosemicarbazide] have been reported. The composition of these two complexes 1 and 2 is discussed on the basis of IR, (1)H NMR and UV spectral data along with their X-ray crystallographic data. The crystal structure of these two complexes has revealed that the free ligand (L) is deprotonated twice at the oxygen and sulfur atoms and they are coordinated with the complexes through phenoxide-O, azomethine-N and thiolate-S atoms. The single-crystal X-ray structures of complex (1) exhibits a square planar structure, while complex (2) reveals trigonal bipyramidal distorted square based pyramidal structure. Anticancer activity of ligand and the complexes 1-2 are evaluated in human adenocarcinoma (MCF-7) cells. The preliminary bioassay indicates that the free ligand and the complexes 1-2 exhibit inhibitory activity against the human adenocarcinoma cancer cell lines. PMID- 25706600 TI - Characterization of compounds derived from copper-oxamate and imidazolium by X ray absorption and vibrational spectroscopies. AB - In this work, compounds derived from copper-oxamate anions (ortho, meta, and para)-phenylenebis (oxamate) and imidazolium cations (1-butyl-3 methylimidazolium) were synthesized. The compounds were characterized by Raman and FTIR spectroscopies and the band assignments were supported by DFT calculations. Strong IR bands from 1610 to 1700cm(-1) dominated the spectra of the complex and can be assigned to nuCO vibrations of the [Cu(opba)](2-) anions by the comparison with the DFT data. In opposition to the FTIR spectra, the main vibrational bands in the Raman spectra are observed in the 1350-1600cm(-1) range. All bands in this region are associated to the modified benzene vibrations of the copper-phenylenebis(oxamate) anions. X-ray absorption near edge (XANES) at different energies (NK and Cu L2,3 edges) was also used to probe the interionic interactions. XANES data show that anion-cation interaction in the Cu-oxamate imidazolium changes the electronic structure around the CuN sites in the oxamate anion. PMID- 25706601 TI - Synthesis and structural elucidation of a novel polymorph of alcaftadine. AB - In this study, we have synthesized and elucidated the structure of the H1 histamine antagonist, 2-(1-methylpiperidin-4-ylidene)-4,7 diazatricyclo[8.4.0.0((3,7))]tetradeca-1(14),3,5,10,12-pentaene-6-carbaldehyde in the solution and solid-state. We have also studied the thermal dilapidation of the compound. Solution structure analysis was achieved by employing NMR spectroscopy including 2D experiments NOESY, HSQC and HMBC, while solid state investigations were undertaken using SXRD, PXRD, TGA, DSC, and IR spectroscopy. For the first time the single crystal structure of alcaftadine has now been solved. Crystallographic data are as follows: monoclinic, Cc, a=11.5694(6)A, b=14.5864(6)A, c=10.2688(4)A, alpha=90 degrees , beta=111.793(3) degrees , gamma=90 degrees , V=1609.07(13)A(3), Z=4. The Hirshfeld surface analyses also have been performed using the crystal structure. PMID- 25706602 TI - Unusual behavior of benzoic acid at low temperature: Raman spectroscopic study. AB - The Raman spectra of benzoic acid single crystals have been measured in the temperature range of 5-300K. At T<60K the spectra show at least two anomalous features, one of which is of direct relevance to intensity changes of the lattice modes in the low-wavenumber region. The intensity of modes at ~86 and ~146cm(-1) tends to zero at T->0K. It is associated with appearance of two H-bonds of different length in the same l-tautomer, and with the loss of the inversion center in the dimer. The modes at ~86 and ~146cm(-1) are assigned to symmetric stretching intra-dimer vibrations of the OH?O hydrogen bonds of the first and second order, respectively. The assignment is based on the measurements of spectral parameters as function of temperature. The other anomaly is that the series of weak and narrow bands arises in the high-wavenumber region of 2500 3700cm(-1). The bands are assigned to combination tones of O-H hydrogen bonded stretching vibration and intramolecular modes. This effect results from a low temperature transition of a conventional two wells potential of short H-bond in the l-tautomer to asymmetrical single well potential, and is due to a strong coupling of intramolecular vibrations to O-H stretching. PMID- 25706603 TI - Infrared to infrared upconversion emission in Pr(3+)/Yb(3+) co-doped La2O3 and La(OH)3 nano-phosphors: a comparative study. AB - The Pr(3+)/Yb(3+) co-doped La2O3 and La(OH)3 nano-phosphors have been synthesized through solution combustion method. The structure and morphology of the samples have been studied using X-ray diffraction (XRD) and transmission electron microscopy (TEM). The physical and optical properties of the samples have been measured and compared. A broad intense infrared emission centered at 850nm due to (1)I6->(1)G4 transition along with sharp green emission centerd at 513nm due to (3)P0->(3)H4 transition are observed on excitation with 976nm laser. The emission intensity of Pr(3+) is optimized with concentration and it is maximum at 0.08mol%. The annealed samples are found to be more crystalline and emit larger photoluminescence due to removal of quenching centers. The power dependent study of green upconversion emission indicates the involvement of two photons. The phosphor in La(OH)3 phase is more stable though the photoluminescence emission is slightly weak. La(OH)3 is less toxic compared to La2O3 and is biocompatible. It generates more heat and can be used in biothermal treatment. PMID- 25706604 TI - Fluorescence properties of Schiff base - N,N'-bis(salicylidene) - 1,2 Phenylenediamine in presence of bile acid host. AB - Fluorescence properties of Schiff base - N,N'-bis(salicylidene) - 1,2 phenylenediamine (LH2) is used to study the micelles formed by aggregation of different important bile acids like cholic acid, deoxycholic acid, chenodeoxycholic acid and glycocholic acid by steady state and picosecond time resolved fluorescence spectroscopy. The fluorescence band intensity was found out to increase with concomitant red shift with gradual addition of different bile acids. Binding constant of the probe with different bile acids as well as critical micelle concentration was obtained from the variation of fluorescence intensity on increasing concentration of bile acids in the medium. The increase in fluorescence quantum yields, fluorescence decay times and substantial decrease in nonradiative decay rate constants in bile acids micellar environment points to the restricted motion of the fluorophore inside the micellar subdomains. PMID- 25706605 TI - Self-control behaviors during the learning of a cascade juggling task. AB - This study examined the self-control behaviors of participants learning a 3-ball cascade juggle. Participants chose when they would receive one of four types of instructional assistance: (a) instructions; (b) video demonstration; (c) knowledge of performance (KP); and (d) knowledge of results (KR). Juggling proficiency was divided into three categories based on catches per attempt during retention and transfer testing. In general, participants decreased their requests for instructions and video demonstration throughout acquisition. For the most proficient performers, requests for KR increased over practice. Post-experimental interviews revealed that participants requested KR after primarily good attempts and KP after both good and bad attempts. Participant-reported reasons for requesting feedback included the confirmation of success (KR) and identification of technique flaws (KP). Overall, the findings suggest that self-control behaviors are more complex than previously demonstrated and that participants use self-control differently depending upon the type of assistance available, individual preferences, and learning needs. PMID- 25706606 TI - (BiSe)1.23CrSe2 and (BiSe)1.22(Cr1.2Se2)2: magnetic anisotropy in the first structurally characterized Bi-Se-Cr ternary compounds. AB - Compounds containing both heavy main group elements and paramagnetic transition metals form a fertile area for the study of magnetic anisotropy. We pursued the synthesis, characterization, and magnetic measurements of Bi-Se-Cr compounds: a ternary system with no structurally characterized materials. Those efforts led to the isolation of two novel misfit layer compounds, namely, (BiSe)1.23CrSe2 (1) and (BiSe)1.22(Cr1.2Se2)2 (2). The crystal structure of 1 consists of alternating BiSe and CrSe2 layers along the c-axis, and 2 is composed of alternating BiSe and (Cr1.2Se2)2 layers along the c-axis. Lattice mismatch occurs in both compounds along the b-axis and leads to positional modulation of the atoms. Field- and temperature-dependent measurements were performed to assess the degree of magnetic anisotropy. Temperature-dependent susceptibility measurements on aligned crystals of 1 display increased bifurcation of zero-field cooled and field cooled data when crystals are oriented with H perpendicular to c than when the crystals are oriented with H parallel to c. Magnetic anisotropy is less pronounced in 2 where both crystallographic orientations exhibit bifurcation at 26 K. The complexity of the magnetic behavior in both compounds likely signifies a competition between CrSe2 intralayer ferromagnetic coupling and interlayer antiferromagnetic coupling. These results highlight the exciting magnetic properties that can arise from the exploration of new ternary phases. PMID- 25706607 TI - A qualitative investigation into the relationships between social factors and suicidal thoughts and acts experienced by people with a bipolar disorder diagnosis. AB - BACKGROUND: The prevalence rate of completed suicide in bipolar disorder is estimated to be as high as 19%. Social factors or influences, such as stigmatisation and family conflict, contribute to the development of suicidal ideation in clinical and non-clinical populations. Yet, there is a lack of studies examining suicidality from a psychosocial perspective in people who experience bipolar disorder. METHOD: Semi-structured interviews were used to collect qualitative data from 20 participants with bipolar disorder. The interview focused on the effects of social factors upon participants' experiences of suicidality (suicidal thoughts, feelings or behaviours). A thematic analysis was used to understand the data. RESULTS: Social or interpersonal factors which participants identified as protective against suicidality included, 'the impact of suicide on others' and, 'reflecting on positive social experiences'. Social factors which triggered suicidal thoughts included, 'negative social experiences' and, 'not being understood or acknowledged'. Social factors which worsened suicidal thoughts or facilitated suicidal behaviour were, 'feeling burdensome,' and 'reinforcing negative self-appraisals'. LIMITATIONS: Some participants had not experienced suicidal thoughts for many years and were recalling experiences which had taken place over ten years ago. The accuracy and reliability of these memories must therefore be taken into consideration when interpreting the results. CONCLUSIONS: The themes help to enhance current understanding of the ways in which social factors affect suicidality in people who experience bipolar disorder. These results highlight the importance of considering the social context in which suicidality is experienced and incorporating strategies to buffer against the effects of negative social experiences in psychological interventions which target suicide risk in bipolar disorder. PMID- 25706608 TI - Contemporary Trends of Inpatient Surgical Management of Stone Disease: National Analysis in an Economic Growth Scenario. AB - PURPOSE: To assess trends in urologic surgical management of upper tract urolithiasis in Brazil over the past 15 years. MATERIALS AND METHODS: The Public Health System of Brazil (SUS) provides health coverage to 47% to 74% of the population. SUS has a longitudinal hospital inpatient database (SIH/SUS). Hospital discharges between January 1,1998 and December 31, 2012 were abstracted from the SIH/SUS. All inpatient hospitalizations for patients of any age with a primary/secondary diagnosis code of N20.x (calculus of kidney or ureter) were abstracted (ICD-9/10). All urolithiasis-related procedure codes were analyzed. The absolute number of procedures/year and the proportion among all techniques were analyzed for Brazil and also separately for the five distinguished regions of the country. Prevalence trends over the studied period were quantified by the estimated annual percent change (EAPC) using the least squares linear regression methodology. Significance was set at P<0.05. RESULTS: The number of surgical interventions for stone disease increased significantly from 10080 to 24713 (+145%; EAPC=1008.1; P<0.001). The most common surgical modalities in 1998 were nephrectomy (n=2918; 29%), ureterolithotomy (n=2361; 23%), and pyelolithotomy (n=1771; 18%). In 2012, ureteroscopy (URS) was the most commonly performed procedure (n=8725; 35%), followed by ureterolithotomy (n=5822; 24%), and nephrectomy (n=3466; 14%). Between 1998 and 2012, percutaneous nephrolithotomy had the highest significant relative increase (+791.8%; EAPC=0.6%; P<0.001), followed by URS (+607%; EAPC=1.78%; P<0.001). Pyelolithotomy showed the most significant decrease (-47.5%; EAPC = -0.91%; P<0.001). All five regions presented a significant positive increase in the EAPC (P<0.001). CONCLUSION: Trends of stone disease surgical management in the public health system of Brazil follow worldwide tendencies toward less invasive treatment modalities. PMID- 25706609 TI - Exploring the structure and phase behavior of plasma membrane vesicles under extreme environmental conditions. AB - Not only drastic temperature- but also pressure-induced perturbations of membrane organization pose a serious challenge to the biological cell. Although high hydrostatic pressure significantly influences the structural properties and thus functional characteristics of cells, this has not prevented life from invading the high pressure habitats of marine depths where pressures up to the 100 MPa level are encountered. Here, the temperature- and pressure-dependent structure and phase behavior of giant plasma membrane vesicles have been explored in the absence and presence of membrane proteins using a combined spectroscopic and microscopic approach. Demixing into extended liquid-ordered and liquid-disordered domains is observed over a wide range of temperatures and pressures. Only at pressures beyond 200 MPa a physiologically unfavorable all gel-like ordered lipid phase is reached at ambient temperature. This is in fact the pressure range where the membrane-protein function has generally been observed to cease, thereby shedding new light on the possible origin of this observation. PMID- 25706611 TI - Effect of Phosphoric Acid Pre-etching on Fatigue Limits of Self-etching Adhesives. AB - The purpose of this study was to use shear bond strength (SBS) and shear fatigue limit (SFL) testing to determine the effect of phosphoric acid pre-etching of enamel and dentin prior to application of self-etch adhesives for bonding resin composite to these substrates. Three self-etch adhesives--1) G- aenial Bond (GC Corporation, Tokyo, Japan); 2) OptiBond XTR (Kerr Corp, Orange, CA, USA); and 3) Scotchbond Universal (3M ESPE Dental Products, St Paul, MN, USA)--were used to bond Z100 Restorative resin composite to enamel and dentin surfaces. A stainless steel metal ring with an inner diameter of 2.4 mm was used to bond the resin composite to flat-ground (4000 grit) tooth surfaces for determination of both SBS and SFL. Fifteen specimens each were used to determine initial SBS to human enamel/dentin, with and without pre-etching with a 35% phosphoric acid (Ultra Etch, Ultradent Products Inc, South Jordan, UT, USA) for 15 seconds prior to the application of the adhesives. A staircase method of fatigue testing (25 specimens for each test) was then used to determine the SFL of resin composite bonded to enamel/dentin using a frequency of 10 Hz for 50,000 cycles or until failure occurred. A two-way analysis of variance and Tukey post hoc test were used for analysis of SBS data, and a modified t-test with Bonferroni correction was used for the SFL data. Scanning electron microscopy was used to examine the area of the bonded restorative/tooth interface. For all three adhesive systems, phosphoric acid pre-etching of enamel demonstrated significantly higher (p<0.05) SBS and SFL with pre-etching than it did without pre-etching. The SBS and SFL of dentin bonds decreased with phosphoric acid pre-etching. The SBS and SFL of bonds using phosphoric acid prior to application of self-etching adhesives clearly demonstrated different tendencies between enamel and dentin. The effect of using phosphoric acid, prior to the application of the self-etching adhesives, on SBS and SFL was dependent on the adhesive material and tooth substrate and should be carefully considered in clinical situations. PMID- 25706610 TI - Dosage of the Abcg1-U2af1 region modifies locomotor and cognitive deficits observed in the Tc1 mouse model of Down syndrome. AB - Down syndrome (DS) results from one extra copy of human chromosome 21 and leads to several alterations including intellectual disabilities and locomotor defects. The transchromosomic Tc1 mouse model carrying an extra freely-segregating copy of human chromosome 21 was developed to better characterize the relation between genotype and phenotype in DS. The Tc1 mouse exhibits several locomotor and cognitive deficits related to DS. In this report we analyzed the contribution of the genetic dosage of 13 conserved mouse genes located between Abcg1 and U2af1, in the telomeric part of Hsa21. We used the Ms2Yah model carrying a deletion of the corresponding interval in the mouse genome to rescue gene dosage in the Tc1/Ms2Yah compound mice to determine how the different behavioral phenotypes are affected. We detected subtle changes with the Tc1/Ms2Yah mice performing better than the Tc1 individuals in the reversal paradigm of the Morris water maze. We also found that Tc1/Ms2Yah compound mutants performed better in the rotarod than the Tc1 mice. This data support the impact of genes from the Abcg1-U2af1 region as modifiers of Tc1-dependent memory and locomotor phenotypes. Our results emphasize the complex interactions between triplicated genes inducing DS features. PMID- 25706612 TI - Digital workflow for virtually designing and milling ceramic lithium disilicate veneers: a clinical report. AB - Laminate veneers have been routinely used to restore and enhance the appearance of natural dentition. The traditional pathway for fabricating veneers consisted of making conventional polyvinyl siloxane impressions, producing stone casts, and fabricating final porcelain prostheses on stone dies. Pressed ceramics have successfully been used for laminate veneer fabrication for several years. Recently, digital computer-aided design/computer-aided manufacturing scanning has become commercially available to make a digital impression that is sent electronically to a dental laboratory or a chairside milling machine. However, technology has been developed to allow digital data acquisition in conjunction with electronically transmitted data that enables virtual design of restorations and milling at a remote production center. Following the aforementioned workflow will provide the opportunity to fabricate a physical cast-free restoration. This new technique has been reported recently for all-ceramic IPS e.max full-coverage pressed-ceramic restorations. However, laminate veneers are very delicate and technique-sensitive restorations when compared with all-ceramic full-coverage ones made from the same material. Complete digital design and fabrication of multiple consecutive laminate veneers seems to be very challenging. This clinical report presents the digital workflow for the virtual design and fabrication of multiple laminate veneers in a patient for enhancing the esthetics of his maxillary anterior teeth. A step-by-step process is presented with a discussion of the advantages and disadvantages of this novel technique. Additionally, the use of lithium disilicate ceramic as the material of choice and the rationale for such a decision is discussed. PMID- 25706613 TI - Longitudinal Evaluation of Bond Strength to Enamel of Dental Adhesive Systems Associated with Nd:YAG Laser. AB - OBJECTIVES: This study evaluated the durability of bond strength to enamel using total-etch (Single Bond/SB) and self-etch (Clearfil SE Bond/CSEB) adhesives associated with neodymium:yttrium-aluminu-garnet (Nd:YAG) laser irradiation through the uncured adhesives. METHODS: Bovine incisors were worn to expose an area of enamel and were divided into four groups: group 1 (control) SB + polymerization; group 2 (control) CSEB + polymerization; group 3 (laser) - SB + Nd:YAG laser (174.16 J/cm(2)) + polymerization; and group 4 (laser) CSEB + Nd:YAG (174.16 J/cm(2)) + polymerization. Blocks of composite were fabricated and stored for 24 hours or 12 months, sectioned into beams, and submitted to microtensile tests. Results were analyzed by three-way analysis of variance (ANOVA) (adhesive, technique, and storage time) and Tukey tests. RESULTS: ANOVA revealed significant differences for adhesive * technique and technique * storage time (p<0.05). The mean values (MPa) for interaction adhesive * technique (standard deviation) were as follows: SB/control = 35.78 (6.04)a; SB/laser = 26.40 (7.25)b, CSEB/control = 26.32 (5.71)b, CSEB/laser = 23.90 (7.49)b. For interaction technique * storage time the mean values were as follows: control/24 hours = 32.58 (6.49)a; control/12 months = 29.52 (8.38)a; laser/24 hours = 29.37 (5.71)a; laser/12 months = 20.92 (6.5)b. Groups with the same letters showed no statistically significant differences. CONCLUSION: Scanning electron microscope analysis showed evident areas of micromorphological alterations in lased samples after 12 months of water storage. Nd:YAG laser irradiation of enamel through unpolymerized total etch adhesive significantly reduced bond strength compared with the control. Bond strength decreased when enamel samples irradiated with Nd:YAG laser through unpolymerized adhesives were stored in water for 12 months. PMID- 25706614 TI - Localized and generalized simulated wear of resin composites. AB - A laboratory study was conducted to examine the wear of resin composite materials using both a localized and generalized wear simulation model. Twenty specimens each of seven resin composites (Esthet*X HD [HD], Filtek Supreme Ultra [SU], Herculite Ultra [HU], SonicFill [SF], Tetric EvoCeram Bulk Fill [TB], Venus Diamond [VD], and Z100 Restorative [Z]) were subjected to a wear challenge of 400,000 cycles for both localized and generalized wear in a Leinfelder-Suzuki wear simulator (Alabama machine). The materials were placed in custom cylinder shaped stainless steel fixtures. A stainless steel ball bearing (r=2.387 mm) was used as the antagonist for localized wear, and a stainless steel, cylindrical antagonist with a flat tip was used for generalized wear. A water slurry of polymethylmethacrylate (PMMA) beads was used as the abrasive media. A noncontact profilometer (Proscan 2100) with Proscan software was used to digitize the surface contours of the pretest and posttest specimens. AnSur 3D software was used for wear assessment. For localized testing, maximum facet depth (MUm) and volume loss (mm(3)) were used to compare the materials. The mean depth of the facet surface (MUm) and volume loss (mm(3)) were used for comparison of the generalized wear specimens. A one-way analysis of variance (ANOVA) and Tukey post hoc test were used for data analysis of volume loss for both localized and generalized wear, maximum facet depth for localized wear, and mean depth of the facet for generalized wear. The results for localized wear simulation were as follows [mean (standard deviation)]: maximum facet depth (MUm)--Z, 59.5 (14.7); HU, 99.3 (16.3); SU, 102.8 (13.8); HD, 110.2 (13.3); VD, 114.0 (10.3); TB, 125.5 (12.1); SF, 195.9 (16.9); volume loss (mm(3))--Z, 0.013 (0.002); SU, 0.026 (0.006); HU, 0.043 (0.008); VD, 0.057 (0.009); HD, 0.058 (0.014); TB, 0.061 (0.010); SF, 0.135 (0.024). Generalized wear simulation results were as follows: mean depth of facet (MUm)--Z, 9.3 (3.4); SU, 12.8 (3.1); HU, 15.6 (3.2); TB, 19.2 (4.8); HD, 26.8 (6.5); VD, 29.1 (5.5); SF, 35.6 (8.4); volume loss (mm(3))--Z, 0.132 (0.049); SU, 0.0179 (0.042); HU, 0.224 (0.044); TB, 0.274 (0.065); HD, 0.386 (0.101); VD, 0.417 (0.076); SF, 0.505 (0.105). The ANOVA showed a significant difference among materials (p<0.001) for facet depth and volume loss for both localized and generalized wear. The post hoc test revealed differences (p<0.05) in localized and generalized wear values among the seven resin composites examined in this study. The findings provide valuable information regarding the relative wear characteristics of the materials in this study. PMID- 25706615 TI - Contamination of Composite Resin by Glove Powder and Saliva Contaminants: Impact on Mechanical Properties and Incremental Layer Debonding. AB - This study investigated the influence of digital manipulation of a composite resin (Z250; 3M ESPE, St Paul, MN, USA) with gloves contaminated with powder and/or human stimulated saliva on the mechanical properties and incremental layer debonding of the restorative. The six groups tested were powdered gloves with or without saliva, powder-free gloves with or without saliva, powdered gloves with saliva cleaned with 70% ethanol, and no digital manipulation or contamination (control). Diametral tensile strength, flexural strength, flexural modulus, and incremental layer shear bond strength were evaluated. Each composite increment was digitally manipulated for 10 seconds. Data from each test were separately analyzed using analysis of variance and the Student-Newman-Keuls test (alpha=0.05). No significant differences for diametral tensile strength were observed. Manipulation of the composite using powder-free gloves with saliva or using gloves cleaned with ethanol generated higher flexural strength and modulus compared to the other groups. The control group and the group manipulated using powdered gloves with saliva generally showed lower mechanical performances. Lower incremental layer bond strength was observed for the group manipulated with powdered gloves without saliva. The control group and the groups manipulated with powdered gloves with saliva or cleaned with ethanol showed higher shear bond strengths. Most of the failures were cohesive. In conclusion, digital manipulation might be important for the composite resin to achieve better mechanical performance and incremental layer bond strength, provided that the gloves are not contaminated. Cleaning the gloves with ethanol might avoid the negative effects of digital manipulation using contaminated gloves. PMID- 25706616 TI - Predictable Restorative Work Flow for Computer-Aided Design/Computer-Aided Manufacture-Fabricated Ceramic Veneers Utilizing a Virtual Smile Design Principle. AB - The purpose of this case report was to present the use of a contemporary digital photograph-assisted virtual smile design principle, an intraoral digital impression, and computer-aided design/computer-aided manufacture-fabricated lithium disilicate ceramic veneers to treat a patient with esthetic needs in the maxillary anterior region. By using the proposed digital restorative work flow, this case report demonstrated an effective communication pathway between the patient, clinician, and dental laboratory technician. Effective communication can help to achieve a more predictable and satisfactory esthetic outcome. PMID- 25706617 TI - Detailed analysis of the African green monkey model of Nipah virus disease. AB - Henipaviruses are implicated in severe and frequently fatal pneumonia and encephalitis in humans. There are no approved vaccines or treatments available for human use, and testing of candidates requires the use of well-characterized animal models that mimic human disease. We performed a comprehensive and statistically-powered evaluation of the African green monkey model to define parameters critical to disease progression and the extent to which they correlate with human disease. African green monkeys were inoculated by the intratracheal route with 2.5 * 10(4) plaque forming units of the Malaysia strain of Nipah virus. Physiological data captured using telemetry implants and assessed in conjunction with clinical pathology were consistent with shock, and histopathology confirmed widespread tissue involvement associated with systemic vasculitis in animals that succumbed to acute disease. In addition, relapse encephalitis was identified in 100% of animals that survived beyond the acute disease phase. Our data suggest that disease progression in the African green monkey is comparable to the variable outcome of Nipah virus infection in humans. PMID- 25706618 TI - Efficacy and optimization of palivizumab injection regimens against respiratory syncytial virus infection. AB - IMPORTANCE: Infection with the respiratory syncytial virus (RSV) is the leading cause of hospitalizations in children, accounting for more than 90,000 hospitalizations every year in the United States. For children who are at risk for severe RSV infections, the American Academy of Pediatrics recommends immunoprophylaxis with a series of up to 5 injections of the antibody palivizumab administered monthly, beginning on November 1 of each year. However, many practitioners initiate injections at the onset of RSV season as indicated by local surveillance. OBJECTIVES: To evaluate the effectiveness of current regimens for palivizumab injections across different cities and to design an optimized regimen. DESIGN, SETTING, AND PARTICIPANTS: We performed a mathematical modeling study of the risk for hospitalization due to RSV infection. The model accounted for the pharmacokinetics of the antibody, the timing of the injections, and seasonal patterns of RSV, including geographic and year-to-year variability. We used the model to estimate the efficacy of current regimens, including the American Academy of Pediatrics recommendation, and to design a more effective injection regimen, the optimized fixed start (OFS), which uses city-specific initiation dates. Participants were the approximately 700,000 individuals who had specimens tested for RSV by National Respiratory and Enteric Virus Surveillance System laboratories in 18 US cities from July 1, 1994, through June 30, 2011 (a total of 725,741 tests). INTERVENTIONS: Different palivizumab injection regimens. MAIN OUTCOMES AND MEASURES: The primary outcome measure was reduction in hospitalizations due to RSV infections. The secondary measures were cost (number of palivizumab doses) and duration of protection (in days). RESULTS: The American Academy of Pediatrics-recommended 5-injection regimen is expected to reduce hospitalization risk by a median of 2.7% (range, -2.2% to 6.1%) compared with the conventional regimen based on RSV surveillance. The 5-injection OFS regimen is expected to further reduce risk by a median of 6.8% (range, 4.9% to 14.8%), and the 4-injection OFS regimen is expected to achieve efficacy comparable to that of the conventional 5-injection regimen while reducing costs by 20%. CONCLUSIONS AND RELEVANCE: Modified palivizumab regimens can improve protection for children at risk for severe outcomes of RSV infection and thereby lower rates of hospitalization due to RSV. PMID- 25706619 TI - Two classes of bacterial IMPDHs according to their quaternary structures and catalytic properties. AB - Inosine-5'-monophosphate dehydrogenase (IMPDH) occupies a key position in purine nucleotide metabolism. In this study, we have performed the biochemical and physico-chemical characterization of eight bacterial IMPDHs, among which six were totally unexplored. This study led to a classification of bacterial IMPDHs according to the regulation of their catalytic properties and their quaternary structures. Class I IMPDHs are cooperative enzymes for IMP, which are activated by MgATP and are octameric in all tested conditions. On the other hand, class II IMPDHs behave as Michaelis-Menten enzymes for both substrates and are tetramers in their apo state or in the presence of IMP, which are shifted to octamers in the presence of NAD or MgATP. Our work provides new insights into the IMPDH functional regulation and a model for the quaternary structure modulation is proposed. PMID- 25706620 TI - DNA for crime investigation: European co-operation model. AB - The article presents DNA related data exchange mechanism established within the framework of the European Union for the transnational crime investigation. First of all, it provides with the comprehensive overview of legal and practical state of play, pointing out that approved legal basis seeks to ensure legality and reliability in this area by establishing information exchange purposes and competent authorities involved, setting up technical requirements for the DNA analysis and DNA data bases, laying down provisions on accreditation of forensic service providers, foreseeing at least minimum common data protection requirements. Secondly, it reveals that despite being the most exhaustive international regulation on DNA related data exchange among law enforcement and judicial authorities it misses effective data protection mechanism, does not harmonize neither backgrounds for DNA collection in criminal process in general nor storage requirements and that results the variation in categories of subjects related to the crime investigation and included in data bases of different Member States. These gaps make the use of data collected and stored in another Member State vulnerable from the perspective of different rules on evidences' legality within the criminal process. The article also reveals the model's weakness in terms of assessment of its efficiency as statistics gathered for the time being show only number of coincidences (hits) of searched DNA profiles, but not the impact on crime investigation and its results. PMID- 25706621 TI - Schizophrenia-associated Risk and Protective Variants of c-Fos Encoding Gene. AB - Defects in synaptic plasticity play a key role in pathophysiology of schizophrenia. Pathomechanisms responsible for synaptic plasticity alterations in schizophrenia are very complicated and not well defined. Transcription factor c Fos plays an important role in regulation of synaptic plasticity. In the present study we evaluated the association of rs7101 and rs1063169 single nucleotide polymorphisms (SNPs) of c-Fos encoding gene (FOS) with schizophrenia. A total of 604 DNA samples of schizophrenia-affected and healthy subjects of Armenian ancestry were genotyped using polymerase chain reaction with sequence-specific primers. Also, comparative determination of the blood levels of c-Fos protein in schizophrenia patients and controls was performed using the enzyme-linked immunosorbent assay. Potential interaction between protein level and genotypes as well as relationships between genotypes/protein level and clinical-demographic characteristics of schizophrenia patients were assessed. The results obtained demonstrated that mutant allele of FOS rs1063169 SNP is negatively associated with schizophrenia and may be nominated as a protective factor for this disorder. On the other hand, according to our results, the FOS rs7101T mutant allele is positively associated with schizophrenia and, therefore, may be considered as a risk factor for this disorder. In addition, decreased c-Fos plasma levels in schizophrenia patients compared to controls were found. In conclusion, the results of this study suggest that FOS is among the candidate genes of schizophrenia and that changes in the expression of c-Fos protein may contribute to molecular pathomechanisms of schizophrenia-related alterations in synaptic plasticity. PMID- 25706623 TI - A coarse-grained MARTINI-like force field for DNA unzipping in nanopores. AB - In nanopore force spectroscopy (NFS) a charged polymer is threaded through a channel of molecular dimensions. When an electric field is applied across the insulating membrane, the ionic current through the nanopore reports on polymer translocation, unzipping, dissociation, and so forth. We present a new model that can be applied in molecular dynamics simulations of NFS. Although simplified, it does reproduce experimental trends and all-atom simulations. The scaled conductivities in bulk solution are consistent with experimental results for NaCl for a wide range of electrolyte concentrations and temperatures. The dependence of the ionic current through a nanopore on the applied voltage is symmetric and, in the voltage range used in experiments (up to 2 V), linear and in good agreement with experimental data. The thermal stability and geometry of DNA is well represented. The model was applied to simulations of DNA hairpin unzipping in nanopores. The results are in good agreement with all-atom simulations: the scaled translocation times and unzipping sequence are similar. PMID- 25706622 TI - The feasibility of an exercise intervention in males at risk of oesophageal adenocarcinoma: a randomized controlled trial. AB - OBJECTIVE: To investigate the feasibility and safety of a 24-week exercise intervention, compared to control, in males with Barrett's oesophagus, and to estimate the effect of the intervention, compared to control, on risk factors associated with oesophageal adenocarcinoma development. METHODS: A randomized controlled trial of an exercise intervention (60 minutes moderate-intensity aerobic and resistance exercise five days/week over 24 weeks; one supervised and four unsupervised sessions) versus attention control (45 minutes stretching five days/week over 24 weeks; one supervised and four unsupervised sessions) in inactive, overweight/obese (25.0-34.9 kg/m2) males with Barrett's oesophagus, aged 18-70 years. Primary outcomes were obesity-associated hormones relevant to oesophageal adenocarcinoma risk (circulating concentrations of leptin, adiponectin, interleukin-6, tumour necrosis factor-alpha, C-reactive protein, and insulin resistance [HOMA]). Secondary outcomes included waist circumference, body composition, fitness, strength and gastro-oesophageal reflux symptoms. Outcomes were measured at baseline and 24-weeks. Intervention effects were analysed using generalised linear models, adjusting for baseline value. RESULTS: Recruitment was difficult in this population with a total of 33 participants recruited (target sample size: n = 80); 97% retention at 24-weeks. Adherence to the exercise protocol was moderate. No serious adverse events were reported. A statistically significant intervention effect (exercise minus control) was observed for waist circumference (-4.5 [95% CI -7.5, -1.4] cm; p < 0.01). Effects on primary outcomes were not statistically significant. CONCLUSION: This small, exploratory trial provides important information to inform future trial development including recruitment rates and estimates of effect sizes on outcomes related to oesophageal adenocarcinoma risk. Future trials should investigate a combined dietary and exercise intervention to achieve greater weight loss in this population and relax inclusion criteria to maximize recruitment. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12609000401257. PMID- 25706624 TI - Identification of potential small molecule allosteric modulator sites on IL-1R1 ectodomain using accelerated conformational sampling method. AB - The interleukin-1 receptor (IL-1R) is the founding member of the interleukin 1 receptor family which activates innate immune response by its binding to cytokines. Reports showed dysregulation of cytokine production leads to aberrant immune cells activation which contributes to auto-inflammatory disorders and diseases. Current therapeutic strategies focus on utilizing antibodies or chimeric cytokine biologics. The large protein-protein interaction interface between cytokine receptor and cytokine poses a challenge in identifying binding sites for small molecule inhibitor development. Based on the significant conformational change of IL-1R type 1 (IL-1R1) ectodomain upon binding to different ligands observed in crystal structures, we hypothesized that transient small molecule binding sites may exist when IL-1R1 undergoes conformational transition and thus suitable for inhibitor development. Here, we employed accelerated molecular dynamics (MD) simulation to efficiently sample conformational space of IL-1R1 ectodomain. Representative IL-1R1 ectodomain conformations determined from the hierarchy cluster analysis were analyzed by the SiteMap program which leads to identify small molecule binding sites at the protein-protein interaction interface and allosteric modulator locations. The cosolvent mapping analysis using phenol as the probe molecule further confirms the allosteric modulator site as a binding hotspot. Eight highest ranked fragment molecules identified from in silico screening at the modulator site were evaluated by MD simulations. Four of them restricted the IL-1R1 dynamical motion to inactive conformational space. The strategy from this study, subject to in vitro experimental validation, can be useful to identify small molecule compounds targeting the allosteric modulator sites of IL-1R and prevent IL-1R from binding to cytokine by trapping IL-1R in inactive conformations. PMID- 25706625 TI - Convergent losses of decay mechanisms and rapid turnover of symbiosis genes in mycorrhizal mutualists. AB - To elucidate the genetic bases of mycorrhizal lifestyle evolution, we sequenced new fungal genomes, including 13 ectomycorrhizal (ECM), orchid (ORM) and ericoid (ERM) species, and five saprotrophs, which we analyzed along with other fungal genomes. Ectomycorrhizal fungi have a reduced complement of genes encoding plant cell wall-degrading enzymes (PCWDEs), as compared to their ancestral wood decayers. Nevertheless, they have retained a unique array of PCWDEs, thus suggesting that they possess diverse abilities to decompose lignocellulose. Similar functional categories of nonorthologous genes are induced in symbiosis. Of induced genes, 7-38% are orphan genes, including genes that encode secreted effector-like proteins. Convergent evolution of the mycorrhizal habit in fungi occurred via the repeated evolution of a 'symbiosis toolkit', with reduced numbers of PCWDEs and lineage-specific suites of mycorrhiza-induced genes. PMID- 25706627 TI - Stromal contribution to the colorectal cancer transcriptome. AB - Recent studies identified a poor-prognosis stem/serrated/mesenchymal (SSM) transcriptional subtype of colorectal cancer (CRC). We noted that genes upregulated in this subtype are also prominently expressed by stromal cells, suggesting that SSM transcripts could derive from stromal rather than epithelial cancer cells. To test this hypothesis, we analyzed CRC expression data from patient-derived xenografts, where mouse stroma supports human cancer cells. Species-specific expression analysis showed that the mRNA levels of SSM genes were mostly due to stromal expression. Transcriptional signatures built to specifically report the abundance of cancer-associated fibroblasts (CAFs), leukocytes or endothelial cells all had significantly higher expression in human CRC samples of the SSM subtype. High expression of the CAF signature was associated with poor prognosis in untreated CRC, and joint high expression of the stromal signatures predicted resistance to radiotherapy in rectal cancer. These data show that the distinctive transcriptional and clinical features of the SSM subtype can be ascribed to its particularly abundant stromal component. PMID- 25706628 TI - Stromal gene expression defines poor-prognosis subtypes in colorectal cancer. AB - Recent molecular classifications of colorectal cancer (CRC) based on global gene expression profiles have defined subtypes displaying resistance to therapy and poor prognosis. Upon evaluation of these classification systems, we discovered that their predictive power arises from genes expressed by stromal cells rather than epithelial tumor cells. Bioinformatic and immunohistochemical analyses identify stromal markers that associate robustly with disease relapse across the various classifications. Functional studies indicate that cancer-associated fibroblasts (CAFs) increase the frequency of tumor-initiating cells, an effect that is dramatically enhanced by transforming growth factor (TGF)-beta signaling. Likewise, we find that all poor-prognosis CRC subtypes share a gene program induced by TGF-beta in tumor stromal cells. Using patient-derived tumor organoids and xenografts, we show that the use of TGF-beta signaling inhibitors to block the cross-talk between cancer cells and the microenvironment halts disease progression. PMID- 25706630 TI - Natural variation in stomatal responses to environmental changes among Arabidopsis thaliana ecotypes. AB - Stomata are small pores surrounded by guard cells that regulate gas exchange between plants and the atmosphere. Guard cells integrate multiple environmental signals and control the aperture width to ensure appropriate stomatal function for plant survival. Leaf temperature can be used as an indirect indicator of stomatal conductance to environmental signals. In this study, leaf thermal imaging of 374 Arabidopsis ecotypes was performed to assess their stomatal responses to changes in environmental CO2 concentrations. We identified three ecotypes, Koln (Kl-4), Gabelstein (Ga-0), and Chisdra (Chi-1), that have particularly low responsiveness to changes in CO2 concentrations. We next investigated stomatal responses to other environmental signals in these selected ecotypes, with Col-0 as the reference. The stomatal responses to light were also reduced in the three selected ecotypes when compared with Col-0. In contrast, their stomatal responses to changes in humidity were similar to those of Col-0. Of note, the responses to abscisic acid, a plant hormone involved in the adaptation of plants to reduced water availability, were not entirely consistent with the responses to humidity. This study demonstrates that the stomatal responses to CO2 and light share closely associated signaling mechanisms that are not generally correlated with humidity signaling pathways in these ecotypes. The results might reflect differences between ecotypes in intrinsic response mechanisms to environmental signals. PMID- 25706629 TI - A systematic map of systematic reviews in pediatric dentistry--what do we really know? AB - OBJECTIVES: To identify, appraise and summarize existing knowledge and knowledge gaps in practice-relevant questions in pediatric dentistry. METHODS: A systematic mapping of systematic reviews was undertaken for domains considered important in daily clinical practice. The literature search covered questions in the following domains: behavior management problems/dental anxiety; caries risk assessment and caries detection including radiographic technologies; prevention and non operative treatment of caries in primary and young permanent teeth; operative treatment of caries in primary and young permanent teeth; prevention and treatment of periodontal disease; management of tooth developmental and mineralization disturbances; prevention and treatment of oral conditions in children with chronic diseases/developmental disturbances/obesity; diagnosis, prevention and treatment of dental erosion and tooth wear; treatment of traumatic injuries in primary and young permanent teeth and cost-effectiveness of these interventions. Abstracts and full text reviews were assessed independently by two reviewers and any differences were solved by consensus. AMSTAR was used to assess the risk of bias of each included systematic review. Reviews judged as having a low or moderate risk of bias were used to formulate existing knowledge and knowledge gaps. RESULTS: Out of 81 systematic reviews meeting the inclusion criteria, 38 were judged to have a low or moderate risk of bias. Half of them concerned caries prevention. The quality of evidence was high for a caries preventive effect of daily use of fluoride toothpaste and moderate for fissure sealing with resin-based materials. For the rest the quality of evidence for the effects of interventions was low or very low. CONCLUSION: There is an urgent need for primary clinical research of good quality in most clinically-relevant domains in pediatric dentistry. PMID- 25706626 TI - A common variant mapping to CACNA1A is associated with susceptibility to exfoliation syndrome. AB - Exfoliation syndrome (XFS) is the most common recognizable cause of open-angle glaucoma worldwide. To better understand the etiology of XFS, we conducted a genome-wide association study (GWAS) of 1,484 cases and 1,188 controls from Japan and followed up the most significant findings in a further 6,901 cases and 20,727 controls from 17 countries across 6 continents. We discovered a genome-wide significant association between a new locus (CACNA1A rs4926244) and increased susceptibility to XFS (odds ratio (OR) = 1.16, P = 3.36 * 10(-11)). Although we also confirmed overwhelming association at the LOXL1 locus, the key SNP marker (LOXL1 rs4886776) demonstrated allelic reversal depending on the ancestry group (Japanese: OR(A allele) = 9.87, P = 2.13 * 10(-217); non-Japanese: OR(A allele) = 0.49, P = 2.35 * 10(-31)). Our findings represent the first genetic locus outside of LOXL1 surpassing genome-wide significance for XFS and provide insight into the biology and pathogenesis of the disease. PMID- 25706631 TI - Evolution of dengue disease and entomological monitoring in Santa Cruz, Bolivia 2002 - 2008. AB - BACKGROUND: In the context of a rapid increase of dengue cases in the Americas, a monitoring system based on systematic serological control (IgM) of patients consulting for suspected dengue was developed in Bolivia at the end of the 1990s. In the most affected city of Santa Cruz, this system was complemented by an entomological surveillance program based on periodical search for immature stages of Aedes aegypti in dwelling water-holding containers. Here, we analyze these data and describe dengue patterns over 6 years (2002-2008), highlighting the spatial distribution of patients and vectors. METHODOLOGY /PRINCIPAL FINDINGS: Data mining concerned six annual epidemic cycles (2002-2008), with continuous serological and clinical results and entomological data from 16 surveys, examined at the scales of 36 urban areas and four concentric areas covering the entire city. Annual incidence varied from 0.280/00 to 0.950/00; overall incidence was higher in women and adults, and dengue dynamics followed successive periods of high (January-June) and low (July-December) transmission. Lower numbers of cases from the city center to the periphery were observed, poorly related to the more homogeneous and permanent distribution of A. aegypti. "Plant pots" were a major vector source in the city center, and "Tires" and "Odds and ends" beyond the second ring of the city. CONCLUSIONS/SIGNIFICANCE: Over the years, the increasing trend of dengue cases has been highlighted as well as its widespread distribution over the entire city, but an underestimation of the number of cases is strongly suspected. Contrary to popular belief, the city center appears more affected than the periphery, and dengue is not particularly related to waste. Interestingly, the clinical diagnosis of dengue by physicians improved over the years, whatever the gender, age and residential area of suspected cases. PMID- 25706632 TI - Fucoidan from Macrocystis pyrifera has powerful immune-modulatory effects compared to three other fucoidans. AB - Fucoidan, a sulfated polysaccharide purified from brown algae, has a variety of immune-modulation effects, such as promoting activation of dendritic cells (DCs), natural killer (NK) cells and T cells, and enhancing anti-viral and anti-tumor responses. However, the immune-modulatory effect of fucoidan from different seaweed extracts has not been thoroughly analyzed and compared. We analyzed fucoidans obtained from Ascophyllum nodosum (A. nodosum), Macrocystis pyrifera (M. pyrifera), Undaria pinnatifida (U. pinnatifida) and Fucus vesiculosus (F. vesiculosus) for their effect on the apoptosis of human neutrophils, activation of mouse NK cells, maturation of spleen DCs, proliferation and activation of T cells, and the adjuvant effect in vivo. Fucoidans from M. pyrifera and U. pinnatifida strongly delayed human neutrophil apoptosis at low concentration, whereas fucoidans from A. nodosum and F. vesiculosus delayed human neutrophil apoptosis at higher concentration. Moreover, fucoidan from M. pyrifera promoted NK cell activation and cytotoxic activity against YAC-1 cells. In addition, M. pyrifera fucoidan induced the strongest activation of spleen DCs and T cells and ovalbumin (OVA) specific immune responses compared to other fucoidans. These data suggest that fucoidan from M. pyrifera can be potentially useful as a therapeutic agent for infectious diseases, cancer and an effective adjuvant for vaccine. PMID- 25706634 TI - Anisotropic spectral-spatial total variation model for multispectral remote sensing image destriping. AB - Multispectral remote sensing images often suffer from the common problem of stripe noise, which greatly degrades the imaging quality and limits the precision of the subsequent processing. The conventional destriping approaches usually remove stripe noise band by band, and show their limitations on different types of stripe noise. In this paper, we tentatively categorize the stripes in remote sensing images in a more comprehensive manner. We propose to treat the multispectral images as a spectral-spatial volume and pose an anisotropic spectral-spatial total variation regularization to enhance the smoothness of solution along both the spectral and spatial dimension. As a result, a more comprehensive stripes and random noise are perfectly removed, while the edges and detail information are well preserved. In addition, the split Bregman iteration method is employed to solve the resulting minimization problem, which highly reduces the computational load. We extensively validate our method under various stripe categories and show comparison with other approaches with respect to result quality, running time, and quantitative assessments. PMID- 25706635 TI - A framework of joint graph embedding and sparse regression for dimensionality reduction. AB - Over the past few decades, a large number of algorithms have been developed for dimensionality reduction. Despite the different motivations of these algorithms, they can be interpreted by a common framework known as graph embedding. In order to explore the significant features of data, some sparse regression algorithms have been proposed based on graph embedding. However, the problem is that these algorithms include two separate steps: (1) embedding learning and (2) sparse regression. Thus their performance is largely determined by the effectiveness of the constructed graph. In this paper, we present a framework by combining the objective functions of graph embedding and sparse regression so that embedding learning and sparse regression can be jointly implemented and optimized, instead of simply using the graph spectral for sparse regression. By the proposed framework, supervised, semisupervised, and unsupervised learning algorithms could be unified. Furthermore, we analyze two situations of the optimization problem for the proposed framework. By adopting an l2,1-norm regularization for the proposed framework, it can perform feature selection and subspace learning simultaneously. Experiments on seven standard databases demonstrate that joint graph embedding and sparse regression method can significantly improve the recognition performance and consistently outperform the sparse regression method. PMID- 25706633 TI - Anticancer properties of lamellarins. AB - In 1985 the first lamellarins were isolated from a small oceanic sea snail. Today, more than 50 lamellarins have been inventoried and numerous derivatives synthesized and tested as antiviral or anticancer agents. The lead compound in the family is lamellarin D, characterized as a potent inhibitor of both nuclear and mitochondrial topoisomerase I but also capable of directly interfering with mitochondria to trigger cancer cell death. The pharmacology and chemistry of lamellarins are discussed here and the mechanistic portrait of lamellarin D is detailed. Lamellarins frequently serve as a starting point in the design of anticancer compounds. Extensive efforts have been devoted to create novel structures as well as to improve synthetic methods, leading to lamellarins and related pyrrole-derived marine alkaloids. PMID- 25706636 TI - Statistical model of JPEG noises and its application in quantization step estimation. AB - In this paper, we present a statistical analysis of JPEG noises, including the quantization noise and the rounding noise during a JPEG compression cycle. The JPEG noises in the first compression cycle have been well studied; however, so far less attention has been paid on the statistical model of JPEG noises in higher compression cycles. Our analysis reveals that the noise distributions in higher compression cycles are different from those in the first compression cycle, and they are dependent on the quantization parameters used between two successive cycles. To demonstrate the benefits from the analysis, we apply the statistical model in JPEG quantization step estimation. We construct a sufficient statistic by exploiting the derived noise distributions, and justify that the statistic has several special properties to reveal the ground-truth quantization step. Experimental results demonstrate that the proposed estimator can uncover JPEG compression history with a satisfactory performance. PMID- 25706637 TI - Robust discriminative tracking via landmark-based label propagation. AB - The appearance of an object could be continuously changing during tracking, thereby being not independent identically distributed. A good discriminative tracker often needs a large number of training samples to fit the underlying data distribution, which is impractical for visual tracking. In this paper, we present a new discriminative tracker via landmark-based label propagation (LLP) that is nonparametric and makes no specific assumption about the sample distribution. With an undirected graph representation of samples, the LLP locally approximates the soft label of each sample by a linear combination of labels on its nearby landmarks. It is able to effectively propagate a limited amount of initial labels to a large amount of unlabeled samples. To this end, we introduce a local landmarks approximation method to compute the cross-similarity matrix between the whole data and landmarks. Moreover, a soft label prediction function incorporating the graph Laplacian regularizer is used to diffuse the known labels to all the unlabeled vertices in the graph, which explicitly considers the local geometrical structure of all samples. Tracking is then carried out within a Bayesian inference framework, where the soft label prediction value is used to construct the observation model. Both qualitative and quantitative evaluations on the benchmark data set containing 51 challenging image sequences demonstrate that the proposed algorithm outperforms the state-of-the-art methods. PMID- 25706638 TI - Head pose estimation from a 2D face image using 3D face morphing with depth parameters. AB - This paper presents estimation of head pose angles from a single 2D face image using a 3D face model morphed from a reference face model. A reference model refers to a 3D face of a person of the same ethnicity and gender as the query subject. The proposed scheme minimizes the disparity between the two sets of prominent facial features on the query face image and the corresponding points on the 3D face model to estimate the head pose angles. The 3D face model used is morphed from a reference model to be more specific to the query face in terms of the depth error at the feature points. The morphing process produces a 3D face model more specific to the query image when multiple 2D face images of the query subject are available for training. The proposed morphing process is computationally efficient since the depth of a 3D face model is adjusted by a scalar depth parameter at feature points. Optimal depth parameters are found by minimizing the disparity between the 2D features of the query face image and the corresponding features on the morphed 3D model projected onto 2D space. The proposed head pose estimation technique was evaluated on two benchmarking databases: 1) the USF Human-ID database for depth estimation and 2) the Pointing'04 database for head pose estimation. Experiment results demonstrate that head pose estimation errors in nodding and shaking angles are as low as 7.93 degrees and 4.65 degrees on average for a single 2D input face image. PMID- 25706639 TI - Percutaneous fibrin gel injection under C-arm fluoroscopy guidance: a new minimally invasive choice for symptomatic sacral perineural cysts. AB - BACKGROUND: Symptomatic sacral perineural cysts are a common cause of chronic pain. Surgery is one choice for symptom relief but has a high risk of cyst recurrence and complications. As a simple and safe method to manage symptomatic sacral perineural cysts, C-arm fluoroscopy-guided fibrin gel injection may represent a new minimally invasive alternative. To evaluate the efficacy of this new method, we conducted a retrospective study of 42 patients. METHODS AND FINDINGS: From June 2009 to August 2012, a total of 42 patients with symptomatic sacral perineural cysts underwent C-arm fluoroscopy-guided percutaneous fibrin gel injection therapy. Patient outcomes in terms of improvements in pain and neurologic function were evaluated during a follow-up period of 13-39 months. The preoperative and postoperative pain severity were assessed according to a 10-cm visual analog pain scale, and imaging changes were evaluated by magnetic resonance imaging. We also assessed postoperative complications. Most patients experienced benefit from the procedure: twenty-five patients (59.5%) reported excellent recovery, eleven (26.2%) reported good recovery, three (7.1%) reported fair recovery, and three (7.1%) reported poor recovery. The overall effectiveness rate (excellent and good recoveries) was 85.7%. No serious postoperative complications were observed. CONCLUSION: Percutaneous fibrin gel injection under C-arm fluoroscopy guidance could be a simple, safe and effective treatment option for symptomatic sacral perineural cysts. PMID- 25706640 TI - Camelina as a sustainable oilseed crop: contributions of plant breeding and genetic engineering. AB - Camelina is an underutilized Brassicaceae oilseed plant with a considerable agronomic potential for biofuel and vegetable oil production in temperate regions. In contrast to most Brassicaceae, camelina is resistant to alternaria black spot and other diseases and pests. Sequencing of the camelina genome revealed an undifferentiated allohexaploid genome with a comparatively large number of genes and low percentage of repetitive DNA. As there is a close relationship between camelina and the genetic model plant Arabidopsis, this review aims at exploring the potential of translating basic Arabidopsis results into a camelina oilseed crop for food and non-food applications. Recently, Arabidopsis genes for drought resistance or increased photosynthesis and overall productivity have successfully been expressed in camelina. In addition, gene constructs affecting lipid metabolism pathways have been engineered into camelina for synthesizing either long-chain polyunsaturated fatty acids, hydroxy fatty acids or high-oleic oils in particular camelina strains, which is of great interest in human food, industrial or biofuel applications, respectively. These results confirm the potential of camelina to serve as a biotechnology platform in biorefinery applications thus justifying further investment in breeding and genetic research for combining agronomic potential, unique oil quality features and biosafety into an agricultural production system. PMID- 25706641 TI - CD14 and complement crosstalk and largely mediate the transcriptional response to Escherichia coli in human whole blood as revealed by DNA microarray. AB - Systemic inflammation like in sepsis is still lacking specific diagnostic markers and effective therapeutics. The first line of defense against intruding pathogens and endogenous damage signals is pattern recognition by e.g., complement and Toll like receptors (TLR). Combined inhibition of a key complement component (C3 and C5) and TLR-co-receptor CD14 has been shown to attenuate certain systemic inflammatory responses. Using DNA microarray and gene annotation analyses, we aimed to decipher the effect of combined inhibition of C3 and CD14 on the transcriptional response to bacterial challenge in human whole blood. Importantly, combined inhibition reversed the transcriptional changes of 70% of the 2335 genes which significantly responded to heat-inactivated Escherichia coli by on average 80%. Single inhibition was less efficient (p<0.001) but revealed a suppressive effect of C3 on 21% of the responding genes which was partially counteracted by CD14. Furthermore, CD14 dependency of the Escherichia coli induced response was increased in C5-deficient compared to C5-sufficient blood. The observed crucial distinct and synergistic roles for complement and CD14 on the transcriptional level correspond to their broad impact on the inflammatory response in human blood, and their combined inhibition may become inevitable in the early treatment of acute systemic inflammation. PMID- 25706642 TI - Bony healing of unstable thoracolumbar burst fractures in the elderly using percutaneously applied titanium mesh cages and a transpedicular fixation system with expandable screws. AB - INTRODUCTION: There is a high incidence of vertebral burst fractures following low velocity trauma in the elderly. Treatment of unstable vertebral burst fractures using the same principles like in stable vertebral burst fractures may show less favourable results in terms of fracture reduction, maintenance of reduction and cement leakage. In order to address these shortcomings this study introduces cementless fixation of unstable vertebral burst fractures using internal fixators and expandable intravertebral titanium mesh cages in a one stage procedure via minimum-invasive techniques. MATERIAL AND METHODS: A total of 16 consecutive patients (median age 76 years, range 58-94) with unstable thoracolumbar burst fractures and concomitant osteoporosis were treated by an internal fixator inserted via minimum invasive technique one level above and below the fractured vertebra. Fracture reduction was achieved and maintained by transpedicular placement of two titanium mesh cages into the fractured vertebral body during the same procedure. Intra- and postoperative safety of the procedure as well as analysis of reduction quality was analysed by 3D C-arm imaging or CT, respectively. Clinical and radiographic follow-up averaged 10.4 months (range 4.5 24.5). RESULTS: Stabilization of the collapsed vertebral body was achieved in all 16 cases without any intraoperative complication. Surgical time averaged 102 +/- 6.6 minutes (71-194). The postoperative kyphotic angle (KA) and Cobb angle revealed significant improvements (KA 13.7 degrees to 7.4 degrees , p < 0.001; Cobb 9.6 degrees to 6.0 degrees , p < 0.002) with partial loss of reduction at final follow-up (KA 8.3 degrees , Cobb 8.7 degrees ). VAS (Visual Analogue Scale) improved from 7.6 to 2.6 (p < 0.001). Adjacent fractures were not observed. One minor (malposition of pedicle screw) complication was encountered. CONCLUSION: Cementless fixation of osteoporotic burst fractures revealed substantial pain relief, adequate maintenance of reduction and a low complication rate. Bony healing after unstable osteoporotic burst fractures is possible. TRIAL REGISTRATION: www.germanctr.de DRKS00005657. PMID- 25706643 TI - Scripps Genome ADVISER: Annotation and Distributed Variant Interpretation SERver. AB - Interpretation of human genomes is a major challenge. We present the Scripps Genome ADVISER (SG-ADVISER) suite, which aims to fill the gap between data generation and genome interpretation by performing holistic, in-depth, annotations and functional predictions on all variant types and effects. The SG ADVISER suite includes a de-identification tool, a variant annotation web-server, and a user interface for inheritance and annotation-based filtration. SG-ADVISER allows users with no bioinformatics expertise to manipulate large volumes of variant data with ease--without the need to download large reference databases, install software, or use a command line interface. SG-ADVISER is freely available at genomics.scripps.edu/ADVISER. PMID- 25706644 TI - Whole transcriptome analysis using next-generation sequencing of sterile-cultured Eisenia andrei for immune system research. AB - Recently, earthworms have become a useful model for research into the immune system, and it is expected that results obtained using this model will shed light on the sophisticated vertebrate immune system and the evolution of the immune response, and additionally help identify new biomolecules with therapeutic applications. However, for earthworms to be used as a genetic model of the invertebrate immune system, basic molecular and genetic resources, such as an expressed sequence tag (EST) database, must be developed for this organism. Next generation sequencing technologies have generated EST libraries by RNA-seq in many model species. In this study, we used Illumina RNA-sequence technology to perform a comprehensive transcriptome analysis using an RNA sample pooled from sterile-cultured Eisenia andrei. All clean reads were assembled de novo into 41,423 unigenes using the Trinity program. Using this transcriptome data, we performed BLAST analysis against the GenBank non-redundant (NR) database and obtained a total of 12,285 significant BLAST hits. Furthermore, gene ontology (GO) analysis assigned 78 unigenes to 24 immune class GO terms. In addition, we detected a unigene with high similarity to beta-1,3-glucuronyltransferase 1 (GlcAT-P), which mediates a glucuronyl transfer reaction during the biosynthesis of the carbohydrate epitope HNK-1 (human natural killer-1, also known as CD57), a marker of NK cells. The identified transcripts will be used to facilitate future research into the immune system using E. andrei. PMID- 25706645 TI - Keeping up with the 'omics: non-equilibrium models of gene regulation. AB - Non-equilibrium processes are vital features of biological systems. Despite this universally accepted fact, gene regulation is typically formalized into models that assume thermodynamic equilibrium. As experimental evidence expands the repertoire of non-equilibrium genome regulatory mechanisms, theoreticians are challenged to devise general approaches to accommodate and suggest functions for non-equilibrium processes. Ahsendorf et al. provide one such framework, which is discussed in the context of the growing complexity of eukaryotic gene regulation. PMID- 25706649 TI - Erratum. PMID- 25706646 TI - Trends in the prevalence of depression in hospitalized patients with type 2 diabetes in Spain: analysis of hospital discharge data from 2001 to 2011. AB - BACKGROUND: This study aims to describe trends in the prevalence of depression among hospitalized patients with type 2 diabetes in Spain, 2001-2011. METHODS: We selected patients with a discharge diagnosis of type 2 diabetes using national hospital discharge data. Discharges were grouped by depression status. Prevalence of depression globally and according to primary diagnoses based on the Charlson comorbidity index (CCI) were analyzed. We calculated length of stay (LOHS) and in hospital mortality (IHM). Multivariate analysis was adjusted by age, year and comorbidity. RESULTS: From 2001 to 2011, 4,723,338 discharges with type 2 diabetes were identified (4.93% with depression). Prevalence of depression in diabetic patients increased from 3.54% in 2001 to 5.80% in 2011 (p<0.05). The prevalence of depression was significantly higher in women than in men in each year studied and increased from 5.22% in 2001 to 9.24% in 2011 (p<0.01). The highest prevalence was observed in the youngest age group (35-59 years). The median LOHS decreased significantly over this period. Men with diabetes and depression had higher IHM than women in all the years studied (p<0.05). Older age and greater comorbidity were significantly associated with a higher risk of dying, among diabetic patients with concomitant depression. CONCLUSIONS: Prevalence of depression increased significantly among hospitalized diabetic patients from 2001 to 2011 even if the health profile and LOHS have improved over this period. Programs targeted at preventing depression among persons with diabetes should be reinforced in Spain. PMID- 25706647 TI - MicroRNA 21 is a homeostatic regulator of macrophage polarization and prevents prostaglandin E2-mediated M2 generation. AB - Macrophages dictate both initiation and resolution of inflammation. During acute inflammation classically activated macrophages (M1) predominate, and during the resolution phase alternative macrophages (M2) are dominant. The molecular mechanisms involved in macrophage polarization are understudied. MicroRNAs are differentially expressed in M1 and M2 macrophages that influence macrophage polarization. We identified a role of miR-21 in macrophage polarization, and found that cross-talk between miR-21 and the lipid mediator prostaglandin E2 (PGE2) is a determining factor in macrophage polarization. miR-21 inhibition impairs expression of M2 signature genes but not M1 genes. PGE2 and its downstream effectors PKA and Epac inhibit miR-21 expression and enhance expression of M2 genes, and this effect is more pronounced in miR-21-/- cells. Among potential targets involved in macrophage polarization, we found that STAT3 and SOCS1 were enhanced in miR-21-/- cells and further enhanced by PGE2. We found that STAT3 was a direct target of miR-21 in macrophages. Silencing the STAT3 gene abolished PGE2-mediated expression of M2 genes in miR-21-/- macrophages. These data shed light on the molecular brakes involved in homeostatic macrophage polarization and suggest new therapeutic strategies to prevent inflammatory responses. PMID- 25706650 TI - PDADMAC flocculation of Chinese hamster ovary cells: enabling a centrifuge-less harvest process for monoclonal antibodies. AB - High titer (>10 g/L) monoclonal antibody (mAb) cell culture processes are typically achieved by maintaining high viable cell densities over longer culture durations. A corresponding increase in the solids and sub-micron cellular debris particle levels are also observed. This higher burden of solids (>=15%) and sub micron particles typically exceeds the capabilities of a continuous centrifuge to effectively remove the solids without a substantial loss of product and/or the capacity of the harvest filtration train (depth filter followed by membrane filter) used to clarify the centrate. We discuss here the use of a novel and simple two-polymer flocculation method used to harvest mAb from high cell mass cell culture processes. The addition of the polycationic polymer, poly diallyldimethylammonium chloride (PDADMAC) to the cell culture broth flocculates negatively-charged cells and cellular debris via an ionic interaction mechanism. Incorporation of a non-ionic polymer such as polyethylene glycol (PEG) into the PDADMAC flocculation results in larger flocculated particles with faster settling rate compared to PDADMAC-only flocculation. PDADMAC also flocculates the negatively-charged sub-micron particles to produce a feed stream with a significantly higher harvest filter train throughput compared to a typical centrifuged harvest feed stream. Cell culture process variability such as lactate production, cellular debris and cellular densities were investigated to determine the effect on flocculation. Since PDADMAC is cytotoxic, purification process clearance and toxicity assessment were performed. PMID- 25706651 TI - Polyribosomal RNA-Seq reveals the decreased complexity and diversity of the Arabidopsis translatome. AB - Recent RNA-seq studies reveal that the transcriptomes in animals and plants are more complex than previously thought, leading to the inclusion of many more splice isoforms in annotated genomes. However, it is possible that a significant proportion of the transcripts are spurious isoforms that do not contribute to functional proteins. One of the current hypotheses is that commonly used mRNA extraction methods isolate both pre-mature (nuclear) mRNA and mature (cytoplasmic) mRNA, and these incompletely spliced pre-mature mRNAs may contribute to a large proportion of these spurious transcripts. To investigate this, we compared a traditional RNA-seq dataset (total RNA-seq) and a ribosome bound RNA-seq dataset (polyribosomal RNA-seq) from Arabidopsis thaliana. An integrative framework that combined de novo assembly and genome-guided assembly was applied to reconstruct transcriptomes for the two datasets. Up to 44.8% of the de novo assembled transcripts in total RNA-seq sample were of low abundance, whereas only 0.09% in polyribosomal RNA-seq de novo assembly were of low abundance. The final round of assembly using PASA (Program to Assemble Spliced Alignments) resulted in more transcript assemblies in the total RNA-seq than those in polyribosomal sample. Comparison of alternative splicing (AS) patterns between total and polyribosomal RNA-seq showed a significant difference (G-test, p-value<0.01) in intron retention events: 46.4% of AS events in the total sample were intron retention, whereas only 23.5% showed evidence of intron retention in the polyribosomal sample. It is likely that a large proportion of retained introns in total RNA-seq result from incompletely spliced pre-mature mRNA. Overall, this study demonstrated that polyribosomal RNA-seq technology decreased the complexity and diversity of the coding transcriptome by eliminating pre mature mRNAs, especially those of low abundance. PMID- 25706652 TI - Kericho CLinic-based ART Diagnostic Evaluation (CLADE): design, accrual, and baseline characteristics of a randomized controlled trial conducted in predominately rural, district-level, HIV clinics of Kenya. AB - BACKGROUND: Prospective clinical trial data regarding routine HIV-1 viral load (VL) monitoring of antiretroviral therapy (ART) in non-research clinics of Sub Saharan Africa are needed for policy makers. METHODS: CLinic-based ART Diagnostic Evaluation (CLADE) is a randomized, controlled trial (RCT) evaluating feasibility, superiority, and cost-effectiveness of routine VL vs. standard of care (clinical and immunological) monitoring in adults initiating dual nucleoside reverse transcriptase inhibitor (NRTI)+non-NRTI ART. Participants were randomized (1:1) at 7 predominately rural, non-research, district-level clinics of western Kenya. Descriptive statistics present accrual patterns and baseline cohort characteristics. RESULTS: Over 15 months, 820 adults enrolled at 7 sites with 86 152 enrolled per site. Monthly site enrollment ranged from 2-92 participants. Full (100%) informed consent compliance was independently documented. Half (49.9%) had HIV diagnosed through voluntary counseling and testing. Study arms were similar: mostly females (57.6%) aged 37.6 (SD = 9.0) years with low CD4 (166 [SD = 106]) cells/m3). Notable proportions had WHO Stage III or IV disease (28.7%), BMI <18.5 kg/m2 (23.1%), and a history of tuberculosis (5.6%) or were receiving tuberculosis treatment (8.2%) at ART initiation. In the routine VL arm, 407/409 (99.5%) received baseline VL (234,577 SD = 151,055 copies/ml). All participants received lamivudine; 49.8% started zidovudine followed by 38.4% stavudine and 11.8% tenofovir; and, 64.4% received nevirapine as nNRTI (35.6% efavirenz). CONCLUSIONS: A RCT can be enrolled successfully in rural, non research, resource limited, district-level clinics in western Kenya. Many adults presenting for ART have advanced HIV/AIDS, emphasizing the importance of universal HIV testing and linkage-to-care campaigns. TRIAL REGISTRATION: ClinicalTrials.gov NCT01791556. PMID- 25706653 TI - Bartonella spp. in fruit bats and blood-feeding Ectoparasites in Madagascar. AB - We captured, ectoparasite-combed, and blood-sampled cave-roosting Madagascan fruit bats (Eidolon dupreanum) and tree-roosting Madagascan flying foxes (Pteropus rufus) in four single-species roosts within a sympatric geographic foraging range for these species in central Madagascar. We describe infection with novel Bartonella spp. in sampled Eidolon dupreanum and associated bat flies (Cyclopodia dubia), which nest close to or within major known Bartonella lineages; simultaneously, we report the absence of Bartonella spp. in Thaumapsylla sp. fleas collected from these same bats. This represents the first documented finding of Bartonella infection in these species of bat and bat fly, as well as a new geographic record for Thaumapsylla sp. We further relate the absence of both Bartonella spp. and ectoparasites in sympatrically sampled Pteropus rufus, thus suggestive of a potential role for bat flies in Bartonella spp. transmission. These findings shed light on transmission ecology of bat-borne Bartonella spp., recently demonstrated as a potentially zoonotic pathogen. PMID- 25706654 TI - (89)Zr-Oxine Complex PET Cell Imaging in Monitoring Cell-based Therapies. AB - PURPOSE: To develop a clinically translatable method of cell labeling with zirconium 89 ((89)Zr) and oxine to track cells with positron emission tomography (PET) in mouse models of cell-based therapy. MATERIALS AND METHODS: This study was approved by the institutional animal care committee. (89)Zr-oxine complex was synthesized in an aqueous solution. Cell labeling conditions were optimized by using EL4 mouse lymphoma cells, and labeling efficiency was examined by using dendritic cells (DCs) (n = 4), naive (n = 3) and activated (n = 3) cytotoxic T cells (CTLs), and natural killer (NK) (n = 4), bone marrow (n = 4), and EL4 (n = 4) cells. The effect of (89)Zr labeling on cell survival, proliferation, and function were evaluated by using DCs (n = 3) and CTLs (n = 3). Labeled DCs (444 555 kBq/[5 * 10(6)] cells, n = 5) and CTLs (185 kBq/[5 * 10(6)] cells, n = 3) transferred to mice were tracked with microPET/CT. In a melanoma immunotherapy model, tumor targeting and cytotoxic function of labeled CTLs were evaluated with imaging (248.5 kBq/[7.7 * 10(6)] cells, n = 4) and by measuring the tumor size (n = 6). Two-way analysis of variance was used to compare labeling conditions, the Wilcoxon test was used to assess cell survival and proliferation, and Holm-Sidak multiple tests were used to assess tumor growth and perform biodistribution analyses. RESULTS: (89)Zr-oxine complex was synthesized at a mean yield of 97.3% +/- 2.8 (standard deviation). It readily labeled cells at room temperature or 4 degrees C in phosphate-buffered saline (labeling efficiency range, 13.0%-43.9%) and was stably retained (83.5% +/- 1.8 retention on day 5 in DCs). Labeling did not affect the viability of DCs and CTLs when compared with nonlabeled control mice (P > .05), nor did it affect functionality. (89)Zr-oxine complex enabled extended cell tracking for 7 days. Labeled tumor-specific CTLs accumulated in the tumor (4.6% on day 7) and induced tumor regression (P < .05 on day 7). CONCLUSION: We have developed a (89)Zr-oxine complex cell tracking technique for use with PET that is applicable to a broad range of cell types and could be a valuable tool with which to evaluate various cell-based therapies. PMID- 25706655 TI - Effects of a brief high-fat diet and acute exercise on the mTORC1 and IKK/NF kappaB pathways in rat skeletal muscle. AB - One exercise session can improve subsequent insulin-stimulated glucose uptake by skeletal muscle in healthy and insulin-resistant individuals. Our first aim was to determine whether a brief (2 weeks) high-fat diet (HFD) that caused muscle insulin resistance would activate the mammalian target of rapamycin complex 1 (mTORC1) and/or inhibitor of kappaB kinase/nuclear factor kappaB (IKK/NF-kappaB) pathways, which are potentially linked to induction of insulin resistance. Our second aim was to determine whether acute exercise that improved insulin stimulated glucose uptake by muscles would attenuate activation of these pathways. We compared HFD-fed rats with rats fed a low-fat diet (LFD). Some animals from each diet group were sedentary and others were studied 3 h postexercise, when insulin-stimulated glucose uptake was increased. The results did not provide evidence that brief HFD activated either the mTORC1 (including phosphorylation of mTOR(Ser2448), TSC2(Ser939), p70S6K(Thr412), and RPS6(Ser235/236)) or the IKK/NF-kappaB (including abundance of IkappaBalpha or phosphorylation of NF-kappaB(Ser536), IKKalpha/beta(Ser177/181), and IkappaB(Ser32)) pathway in insulin-resistant muscles. Exercise did not oppose the activation of either pathway, as evidenced by no attenuation of phosphorylation of key proteins in the IKK/NF-kappaB pathway (NF-kappaB(Ser536), IKKalpha/beta(Ser177/181), and IkappaB(Ser32)), unaltered IkappaBalpha abundance, and no attenuation of phosphorylation of key proteins in the mTORC1 pathway (mTOR(Ser2448), TSC2(Ser939), and RPS6(Ser235/236)). Instead, exercise induced greater phosphorylation of 2 proteins of the mTORC1 pathway (PRAS40(Thr246) and p70S6K(Thr412)) in insulin-stimulated muscles, regardless of diet. Insulin resistance induced by a brief HFD was not attributable to greater activation of the mTORC1 or the IKK/NF-kappaB pathway in muscle, and exercise-induced improvement in insulin sensitivity was not attributable to attenuated activation of these pathways in muscle. PMID- 25706656 TI - Passive Facebook usage undermines affective well-being: Experimental and longitudinal evidence. AB - Prior research indicates that Facebook usage predicts declines in subjective well being over time. How does this come about? We examined this issue in 2 studies using experimental and field methods. In Study 1, cueing people in the laboratory to use Facebook passively (rather than actively) led to declines in affective well-being over time. Study 2 replicated these findings in the field using experience-sampling techniques. It also demonstrated how passive Facebook usage leads to declines in affective well-being: by increasing envy. Critically, the relationship between passive Facebook usage and changes in affective well-being remained significant when controlling for active Facebook use, non-Facebook online social network usage, and direct social interactions, highlighting the specificity of this result. These findings demonstrate that passive Facebook usage undermines affective well-being. PMID- 25706657 TI - Radiation therapy after radical prostatectomy for prostate cancer: evaluation of complications and influence of radiation timing on outcomes in a large, population-based cohort. AB - PURPOSE: To evaluate the influence of timing of salvage and adjuvant radiation therapy on outcomes after prostatectomy for prostate cancer. METHODS: Using the Surveillance, Epidemiology, and End Results-Medicare linked database, we identified prostate cancer patients diagnosed during 1995-2007 who had one or more adverse pathological features after prostatectomy. The final cohort of 6,137 eligible patients included men who received prostatectomy alone (n = 4,509) or with adjuvant (n = 894) or salvage (n = 734) radiation therapy. Primary outcomes were genitourinary, gastrointestinal, and erectile dysfunction events and survival after treatment(s). RESULTS: Radiation therapy after prostatectomy was associated with higher rates of gastrointestinal and genitourinary events, but not erectile dysfunction. In adjusted models, earlier treatment with adjuvant radiation therapy was not associated with increased rates of genitourinary or erectile dysfunction events compared to delayed salvage radiation therapy. Early adjuvant radiation therapy was associated with lower rates of gastrointestinal events that salvage radiation therapy, with hazard ratios of 0.80 (95% CI, 0.67 0.95) for procedure-defined and 0.70 (95% CI, 0.59, 0.83) for diagnosis-defined events. There was no significant difference between ART and non-ART groups (SRT or RP alone) for overall survival (HR = 1.13 95% CI = (0.96, 1.34) p = 0.148). CONCLUSIONS: Radiation therapy after prostatectomy is associated with increased rates of gastrointestinal and genitourinary events. However, earlier radiation therapy is not associated with higher rates of gastrointestinal, genitourinary or sexual events. These findings oppose the conventional belief that delaying radiation therapy reduces the risk of radiation-related complications. PMID- 25706658 TI - A concise and scalable strategy for the total synthesis of dictyodendrin B based on sequential C-H functionalization. AB - A sequential C?H functionalization strategy for the synthesis of the marine alkaloid dictyodendrin B is reported. Our synthesis begins from commercially available 4-bromoindole and involves six direct functionalizations around the heteroarene core as part of a gram-scale strategy towards the natural product. PMID- 25706659 TI - Ivabradine on aortic stiffness in patients with heart failure. AB - AIM: The aim of this study was to evaluate the effect of ivabradine treatment on aortic stiffness by measuring aortic elastic parameters in patients with heart failure (HF) receiving ivabradine treatment. MATERIALS AND METHODS: The study included clinical patients who were diagnosed with HF (ejection fraction, <35%), had sinus rhythm and persistent symptoms despite full medical treatment. The study group consisted of patients with a heart rate greater than 70 beats per minute and the control group consisted of patients with a heart rate less than 70 beats per minute. Echocardiographic measurements were conducted and aortic strain, aortic distensibility, and aortic stiffness index were calculated. RESULTS: By the end of the twelfth month, a decrease was observed in the left ventricular end-diastolic and end-systolic volumes, whereas ejection fraction was increased (P < 0.001). When aortic elastic parameters were evaluated between the 2 groups, there was no significant difference regarding aortic strain, aortic distensibility, and aortic stiffness index at the time of enrollment and during the visit at 3 months. At the twelfth month visit, aortic strain (P < 0.001) and distensibility (P < 0.001) were significantly increased, whereas there was a significant decrease in the aortic stiffness index (P < 0.001). CONCLUSIONS: During the follow-up at 12 months, significant improvements were observed in the left ventricular functions and aortic elastic parameters along with decreased heart rate in patients with HF receiving ivabradine treatment. This outcome may indicate that ivabradine treatment may correct aortic stiffness and may reduce aortic stiffness after 1 year of follow-up. PMID- 25706660 TI - Substantia nigra hyperechogenicity in Polish patients with Parkinson's disease. AB - BACKGROUND: Hyperechogenicity of the substantia nigra (SN) measured by transcranial sonography (TCS) is a characteristic feature observed in patients with Parkinson's disease (PD). To our knowledge, no SN hyperechogenicity data are available for Polish population. Moreover most of studies come from few centres, which used the one type of ultrasound device. The main aim of the study was to investigate the association between PD and SN hyperechogenicity measured by sonographic machine, not assessed so far. MATERIALS AND METHODS: In this study cross-sectional study SN hyperechogenicity was evaluated in 102 PD patients and 95 control subjects. Midbrain was visualised by Aloka Prosound 7 ultrasound device. SN area measurement, the relation to the clinical features of PD, inter- and intra-observer reliability were evaluated. RESULTS: We confirmed that SN echogenicity is significantly increased in PD patients compared to control subjects (p < 0.001). The area under curve for PD patients vs. controls was 0.93. Receiver operating characteristic analysis indicated a cut-offs for SN echogenicity at 0.19 cm2 with accuracy equal to 90%, specificity - 86% and sensitivity - 93.7%. The SN hyperechogenicity was not related to PD clinical findings. Reliability was good if an experienced sonographer performed the SN measurements. CONCLUSIONS: This study shows that the SN abnormality observed by TCS isa specific feature, which can be helpful in the process of PD diagnosing. PMID- 25706661 TI - Validity and Reliability of the 6-Minute Step Test in Healthy Individuals: A Cross-sectional Study. AB - OBJECTIVE: To determine the 6-minute step test's (6MST) reliability and validity and to establish reference performance values of this test. DESIGN: Prospective observational cross-sectional study. SETTING: Spirometry and Respiratory Physiotherapy Laboratory, Federal University of Sao Carlos (institutional). PARTICIPANTS: Ninety-one individuals [42 men and 49 women, mean age = 39 years (SD, 17 years)] without any diagnosed diseases and with normal exercise capacity [6-minute walk test (6MWT) >75% of the predicted normal]. INDEPENDENT VARIABLES: Participants underwent two 6MST on 1 day and two 6MWT on another day in randomized order. Furthermore, age, gender, height, weight, lower limbs length, abdominal circumference, percentage of body fat, and fat-free mass were obtained. MAIN OUTCOME MEASURES: Test-retest reliability was assessed by comparing the findings of the two 6MST using the intraclass correlation coefficient (ICC) and Bland-Altman plot. Validity was assessed by comparing outcomes of the 6MST to outcomes of 6MWT using the Pearson correlation coefficient. A multiple regression analysis was conducted using the stepwise method to develop an equation to predict reference values. RESULTS: The performance (mean steps +/- SD) in the first and second test was 149 +/- 34 and 149 +/- 36 steps, respectively, which was correlated to distance (in meters) in 6MWT (r = 0.72; P < 0.05). Six-minute step test performance was reliable (ICC = 0.9; 95% confidence interval: 0.85 0.93). The equation to predict reference values for the first 6MST was significant (P < 0.001 and R = 0.48): Performance(steps) = 174 to 1.05 * Age(years) to women and Performance(steps) = 209 to 1.05 * Age(years) to men. CONCLUSIONS: Six-minute step test is a reliable and valid test. Moreover, the number of steps may be predicted by demographic and anthropometric variables with moderate strength of prediction. CLINICAL RELEVANCE: Six-minute step test is an exercise test that is easy to be conducted, more tolerable than a graded exercise test, requires fewer equipments and space, and permits better monitoring of the participants. The assessment of the reliability, validity, and reference values will provide a better interpretability for clinicians to use it, especially in primary care. PMID- 25706662 TI - Comparisons of Bone Mineral Density Between Recreational and Trained Male Road Cyclists. AB - OBJECTIVE: To compare measures of training, performance, body composition, and areal bone mineral density (aBMD) between age-matched recreational and competitively trained male road cyclists. DESIGN: Cross-sectional. SETTING: Laboratory. PARTICIPANTS: Male cyclists (N = 28) aged 21-54 years riding more than 3 hours per week. ASSESSMENT OF RISK FACTORS: Men who train at high (>=8 h/wk) and moderate volumes (3-8 h/wk). MAIN OUTCOME MEASURES: Areal bone mineral density assessments by dual energy x-ray absorptiometry of the whole body, lumbar spine (L1-L4), right and left hips, maximal oxygen uptake (V[Combining Dot Above]O2max), and training history. RESULTS: Trained cyclists had higher power to weight (5.3 +/- 0.4 vs 4.7 +/- 0.3 W/kg, P = 0.001), V[Combining Dot Above]O2max (57.2 +/- 4.5 vs 53.0 +/- 6.1 mL.kg.min, P = 0.049) and training volume (10.6 +/- 2.1 vs 6.3 +/- 0.9 h/wk, P < 0.001) than recreational cyclists. Trained cyclists had lower right (0.898 +/- 0.090 vs 0.979 +/- 0.107 g/cm, P = 0.047) and left hip aBMD (0.891 +/- 0.079 vs 0.973 +/- 0.104 g/cm, P = 0.032). Z-scores identified lumbar (L1-L4) aBMD as osteopenic (-2.5 < Z-score < -1.0) in trained cyclists ( 1.39 +/- 1.09). Lumbar scans identified 12 trained and 4 recreational cyclists as osteopenic and 3 trained cyclists as osteoporotic. CONCLUSIONS: Areal bone mineral density is lower in trained male road cyclists compared with recreational, specifically at the hips. Lumbar aBMD is low in both trained and recreational cyclists. Research is needed to determine the chronic effects of cycling on aBMD and interventions that improve aBMD in this population. CLINICAL RELEVANCE: This study suggests road cycling may compromise aBMD and potentially increase the likelihood of low-trauma fractures; health care professionals should consider this exposure when exercise prescriptions are designed for patients at risk for osteopenia/osteoporosis, for example, women and older adults. PMID- 25706664 TI - Orthostatic Intolerance and Autonomic Dysfunction in Youth With Persistent Postconcussion Symptoms: A Head-Upright Tilt Table Study. AB - OBJECTIVE: To explore head-upright tilt table (HUT) signs of autonomic dysfunction in a cohort of youth with persistent postconcussion symptoms (PCSs) that include light-headedness and to correlate repeat tilt table results with symptom improvements for those patients found to have postural tachycardia syndrome (POTS) on initial testing. DESIGN: Prospective cohort design. SETTING: Nationwide Children's Hospital, Neurology Clinic. PARTICIPANTS: Thirty-four patients (13-18 years of age) with persistent PCSs. MAIN OUTCOME MEASURES: All patients underwent at least 1 tilt table test. The PCS Interview (PCS-I) and patient ratings of light-headedness and vertigo were used to measure symptom burden. Patients found to have POTS were asked to repeat tilt table testing when PCSs improved or 3 to 6 months after the initial test if symptoms persisted. RESULTS: Twenty-four of the 34 (70.6%) patients had abnormal tilt table results with patients categorized as normal (n = 10), isolated syncope (n = 10), and POTS (n = 14). Patients with POTS had higher PCS-I scores than normal patients (P < 0.001) and higher ratings of light-headedness than both normal patients (P = 0.015) and syncope patients (P = 0.04). Twelve POTS patients underwent repeat tilt table testing, and 9 of 12 (75%) no longer met POTS diagnostic criteria. All patients with resolution of POTS had corresponding improvements in PCSs, including light-headedness and vertigo. CONCLUSIONS: Our study demonstrates a high rate of tilt table abnormalities among youth with persistent PCSs. Several patients with POTS had normalization of tilt table testing when PCSs improved. These findings warrant further research of autonomic dysfunction related to concussion. CLINICAL RELEVANCE: Our study is the first to prospectively characterize autonomic dysfunction in patients with persistent PCSs using HUT testing and to show that the tilt test abnormalities normalize in some patients as PCSs improve. PMID- 25706665 TI - Hidden caring, hidden carers? Exploring the experience of carers for people with long-term conditions. AB - Informal carers make a significant contribution to illness management in communities, but many struggle to access support and remain 'hidden carers'. We aimed to explore how carers of people with common long-term conditions (LTCs, such as coronary heart disease or kidney disease) conceptualised their caring, and whether they struggled to identify themselves with the term 'carer' or access for support. We conducted semi-structured interviews with 19 informal carers of people with LTCs recruited from local support groups. Topic guides were designed to encourage participants to provide their retrospective accounts of identifying as a carer or struggling to do so. Data were analysed using the constant comparative method. The study was designed collaboratively with a patient and public involvement (PPI) partner, and we consulted with a PPI steering group of people with lived experience of caring during the study. Results showed how participants drew on comparisons with those caring for more dependent relatives in explaining their reluctance to define themselves as a carer, and resisted adopting the label due to concerns that it would threaten the identity of the cared-for person. The data were interpreted in terms of types of 'work' undertaken to manage LTCs, and revealed that carers of patients with LTCs appear to primarily engage in biographical and emotional support, which may be more difficult to conceptualise as legitimate caring 'work'. Participants indicated that health professionals may be in a unique position to validate their role as carers and encourage support seeking. The study suggests how the greater focus on self-management of LTCs in the community must be complemented by recognition of this group as potentially 'hidden carers', who support the patient to minimise the impact the illness has on their lives and consequently may minimise their own caring role, with negative implications for support seeking. PMID- 25706663 TI - Relationship Between Cognitive Assessment and Balance Measures in Adolescents Referred for Vestibular Physical Therapy After Concussion. AB - OBJECTIVE: To examine the relationship between cognitive and balance performance in adolescents with concussion. DESIGN: Retrospective case series. SETTING: Tertiary. PATIENTS: Sixty patients. INTERVENTIONS: Correlation analyses were performed to describe the relationship between symptoms, cognitive measure, and balance measure at the time of initiation of vestibular physical therapy. MAIN OUTCOME MEASURES: Cognitive performance was assessed using the Immediate Post concussion Assessment and Cognitive Testing (ImPACT). The dizziness and balance function measures included dizziness severity rating, Activities-specific Balance Confidence scale (ABC), Dizziness Handicap Inventory (DHI), Functional Gait Assessment, gait speed, Timed "UP and GO," Five Times Sit to Stand, and Sensory Organization Test (SOT). To account for multiple comparisons, the False Discovery Rate method was used. RESULTS: Performance measures of balance were significantly correlated with cognitive measures. Greater total symptom scores were related to greater impairment in the ABC and DHI (r = 0.35-0.39, P <= 0.008) and worse performance in condition 2 of the SOT (r = -0.48, P = 0.004). Among the ImPACT composite scores, lower memory scores were correlated with impaired balance performance measures (r = 0.37-0.59, P <= 0.012). Lower visual memory was also correlated with worse ABC scores. CONCLUSIONS: The significant relationships reported between the cognitive performance scores and balance measures may reflect that similar levels of functioning exist across domains in individuals with protracted recovery who receive vestibular physical therapy. CLINICAL RELEVANCE: The weak-to-moderate relationships warrant the continuous use of multiple domains of assessment. A better understanding to the relationships between the domains of functioning after concussion may improve the overall management approach for adolescents with concussion. PMID- 25706666 TI - Microarray analysis of differentially expressed genes in ovarian and fallopian tube epithelium from risk-reducing salpingo-oophorectomies. AB - Mutations in the BRCA1 and BRCA2 genes confer an increased lifetime risk for breast and ovarian cancer. Ovarian cancer risk can be decreased by risk-reducing salpingo-oophorectomy (RRSO). Studies on RRSO material have altered the paradigm of serous ovarian cancer pathogenesis. The purpose of this study was to identify candidate genes possibly involved in the pathogenesis of serous ovarian cancer by carrying out a microarray analysis of differentially expressed genes in BRCA1/2- mutation positive ovarian and fallopian tube epithelium derived from RRSO surgery. Freshly frozen ovarian and fallopian tube samples from nine BRCA1/2 mutation carriers scheduled for RRSO were prospectively collected together with five mutation-negative control patients undergoing salpingo-oophorectomy for benign indications. Microarray analysis of genome-wide gene expression was performed on ovarian and fallopian tube samples from the BRCA1/2 and control patients. The validation of microarray data was performed by quantitative real time polymerase chain reaction (qRT-PCR) in selected cases of RRSO samples and also in high grade serous carcinoma samples collected from patients with a BRCA phenotype. From 22,733 genes, 454 transcripts were identified that were differentially expressed in BRCA1/2 mutation carriers when compared with controls, pooling all ovarian and fallopian tube samples together. Of these, 299 genes were statistically significantly downregulated and 155 genes upregulated. Differentially expressed genes in BRCA1/2 samples reported here might be involved in serous ovarian carcinogenesis and provide interesting targets for further studies. PMID- 25706667 TI - A short history of fatty acid ethyl esters. PMID- 25706668 TI - Microstructure, elastic deformation behavior and mechanical properties of biomedical beta-type titanium alloy thin-tube used for stents. AB - Cold-deformability and mechanical compatibility of the biomedical beta-type titanium alloy are the foremost considerations for their application in stents, because the lower ductility restricts the cold-forming of thin-tube and unsatisfactory mechanical performance causes a failed tissue repair. In this paper, beta-type titanium alloy (Ti-25Nb-3Zr-3Mo-2Sn, wt%) thin-tube fabricated by routine cold rolling is reported for the first time, and its elastic behavior and mechanical properties are discussed for the various microstructures. The as cold-rolled tube exhibits nonlinear elastic behavior with large recoverable strain of 2.3%. After annealing and aging, a nonlinear elasticity, considered as the intermediate stage between "double yielding" and normal linear elasticity, is attributable to a moderate precipitation of alpha phase. Quantitive relationships are established between volume fraction of alpha phase (Valpha) and elastic modulus, strength as well as maximal recoverable strain (epsilonmax-R), where the epsilonmax-R of above 2.0% corresponds to the Valpha range of 3-10%. It is considered that the "mechanical" stabilization of the (alpha+beta) microstructure is a possible elastic mechanism for explaining the nonlinear elastic behavior. PMID- 25706669 TI - Challenges in choosing wisely's international future: support, evidence, and burnout. PMID- 25706670 TI - A patient with palpitations. PMID- 25706672 TI - Technetium-99m-pertechnetate scintigraphy in children with symptomatic Meckel's diverticulum. PMID- 25706671 TI - Good clinical outcomes from a 7-year holistic programme of fistula repair in Guinea. AB - OBJECTIVES: Female genital fistula remains a public health concern in developing countries. From January 2007 to September 2013, the Fistula Care project, managed by EngenderHealth in partnership with the Ministry of Health and supported by USAID, integrated fistula repair services in the maternity wards of general hospitals in Guinea. The objective of this article was to present and discuss the clinical outcomes of 7 years of work involving 2116 women repaired in three hospitals across the country. METHODS: This was a retrospective cohort study using data abstracted from medical records for fistula repairs conducted from 2007 to 2013. The study data were reviewed during the period April to August 2014. RESULTS: The majority of the 2116 women who underwent surgical repair had vesicovaginal fistula (n = 2045, 97%) and 3% had rectovaginal fistula or a combination of both. Overall 1748 (83%) had a closed fistula and were continent of urine immediately after surgery. At discharge, 1795 women (85%) had a closed fistula and 1680 (79%) were dry, meaning they no longer leaked urine and/or faeces. One hundred and fifteen (5%) remained with residual incontinence despite fistula closure. Follow-up at 3 months was completed by 1663 (79%) women of whom 1405 (84.5%) had their fistula closed and 80% were continent. Twenty-one per cent were lost to follow-up. CONCLUSION: Routine programmatic repair for obstetric fistula in low resources settings can yield good outcomes. However, more efforts are needed to address loss to follow-up, sustain the results and prevent the occurrence and/or recurrence of fistula. PMID- 25706673 TI - Commentary to 'Correction of the slope-intercept method for the measurement of glomerular filtration rate'. PMID- 25706675 TI - Severe cutaneous necroses and hemorrhagic diathesis in a 73-year-old man. PMID- 25706676 TI - Structural stability of single-layer MoS2 under large strain. AB - Out-of-plane relaxation can introduce MoS(2) in flexible electronic/optoelectronic devices, while under larger strain it is possible to frustrate the structure of MoS(2). On the basis of first-principle calculations, the ideal tensile stress strain relations and failure mechanism of single-layer MoS(2) structure under large strain is investigated. The instability of phonon modes near the K point results in the decrease of tensile stress under large strain. The relative out-of-plane movement of Mo atoms is found to contribute to the mechanism of the soft phonon mode. PMID- 25706677 TI - Exome sequencing establishes diagnosis of Alstrom syndrome in an infant presenting with non-syndromic dilated cardiomyopathy. AB - Idiopathic dilated cardiomyopathy is a heritable, genetically heterogeneous disorder characterized by progressive heart failure. Dilated cardiomyopathy typically exhibits autosomal dominant inheritance, yet frequently remains clinically silent until adulthood. We sought to discover the molecular basis of idiopathic, non-syndromic dilated cardiomyopathy in a one-month-old male presenting with severe heart failure. Previous comprehensive testing of blood, urine, and skin biopsy specimen was negative for metabolic, mitochondrial, storage, and infectious etiologies. Ophthalmologic examination was normal. Chromosomal microarray and commercial dilated cardiomyopathy gene panel testing failed to identify a causative mutation. Parental screening echocardiograms revealed no evidence of clinically silent dilated cardiomyopathy. Whole exome sequencing was carried out on the family trio on a research basis, filtering for rare, deleterious, recessive and de novo genetic variants. Pathogenic compound heterozygous truncating mutations were identified in ALMS1, diagnostic of Alstrom syndrome and prompting disclosure of genetic findings. Alstrom syndrome is a known cause for dilated cardiomyopathy in children yet delayed and mis-diagnosis are common owing to its rarity and age-dependent emergence of multisystem clinical manifestations. At six months of age the patient ultimately developed bilateral nystagmus and hyperopia, features characteristic of the syndrome. Early diagnosis is guiding clinical monitoring of other organ systems and allowing for presymptomatic intervention. Furthermore, recognition of recessive inheritance as the mechanism for sporadic disease has informed family planning. This case highlights a limitation of standard gene testing panels for pediatric dilated cardiomyopathy and exemplifies the potential for whole exome sequencing to solve a diagnostic dilemma and enable personalized care. PMID- 25706679 TI - Design, spectral characterization, DFT and biological studies of transition metal complexes of Schiff base derived from 2-aminobenzamide, pyrrole and furan aldehyde. AB - A series of two biologically active Schiff base ligands L(1), L(2) have been synthesized in equimolar reaction of 2-aminobenzamide with pyrrol-2 carboxaldehyde and furan-2-carboxaldehyde. The synthesized Schiff bases were used for complexation with different metal ions like Co(II), Ni(II) and Cu(II) by using a molar ratio of ligand: metal as 2:1. The characterization of newly formed complexes was done by (1)H NMR, UV-Vis, TGA, IR, mass spectrophotometry, EPR and molar conductivity studies. The thermal studies suggested that the complexes are more stable as compared to ligand. In DFT studies the geometries of Schiff bases and metal complexes were fully optimized with respect to the energy using the 6 31+g(d,p) basis set. On the basis of the spectral studies an octahedral geometry has been assigned for Co(II) and Ni(II) complexes and distorted octahedral geometry for Cu(II) complexes. All the synthesized compounds, were studied for their in vitro antimicrobial activities, against four bacterial strains and two fungal strains by using serial dilution method. The data also revealed that the metal complexes showed better activity than the ligands due to chelation/coordination. PMID- 25706680 TI - The use of laser-induced fluorescence or ultraviolet detectors for sensitive and selective analysis of tobramycin or erythropoietin in complex samples. AB - Complex samples analysis is a challenge in pharmaceutical and biopharmaceutical analysis. In this work, tobramycin (TOB) analysis in human urine samples and recombinant human erythropoietin (rhEPO) analysis in the presence of similar protein were selected as representative examples of such samples analysis. Assays of TOB in urine samples are difficult because of poor detectability. Therefore laser induced fluorescence detector (LIF) was combined with a separation technique, micellar electrokinetic chromatography (MEKC), to determine TOB through derivatization with fluorescein isothiocyanate (FITC). Borate was used as background electrolyte (BGE) with negative-charged mixed micelles as additive. The method was successively applied to urine samples. The LOD and LOQ for Tobramycin in urine were 90 and 200ng/ml respectively and recovery was >98% (n=5). All urine samples were analyzed by direct injection without sample pre treatment. Another use of hyphenated analytical technique, capillary zone electrophoresis (CZE) connected to ultraviolet (UV) detector was also used for sensitive analysis of rhEPO at low levels (2000IU) in the presence of large amount of human serum albumin (HSA). Analysis of rhEPO was achieved by the use of the electrokinetic injection (EI) with discontinuous buffers. Phosphate buffer was used as BGE with metal ions as additive. The proposed method can be used for the estimation of large number of quality control rhEPO samples in a short period. PMID- 25706681 TI - Photochemical ring opening and closing of three isomers of diarylethene: spin flip time-dependent density functional study. AB - The reaction mechanism of photochemical ring opening and closing transformation was investigated for diarylethene (DAE), which works as a molecular switch and photodevice. Spin-flip time-dependent density functional theory is employed to map the potential energy surfaces and to elucidate the photochemical mechanism of three isomers (normal, inverse, and mixed types) of 1,2-dithienylethene, a model DAE. The potential energy characteristics including the minimum-energy conical intersection reveals the origin of different product preferences of the three isomers. For the normal type, the excited state from either closed or open form reaches the same conical intersection that gives preferentially the closed product. The inverse type preferentially gives the closed product. The mixed type has two pathways that are easily convertible, and both open and closed reactants give both open and closed products. PMID- 25706682 TI - Aggregation dynamics of molecular bonds between compliant materials. AB - In this paper, we develop a mechanochemical modeling framework in which the spatial-temporal evolution of receptor-ligand bonds takes place at the interface between two compliant media in the presence of an externally applied tensile load. Bond translocation, dissociation and association occur simultaneously, resulting in dynamic aggregation of molecular bonds that is regulated by mechanical factors such as material compliance and applied stress. The results show that bond aggregation is energetically favorable in the out-of-equilibrium process with convoluted time scales from bond diffusion and reaction. Material stiffness is predicted to contribute to adhesion growth and an optimal level of applied stress leads to the maximized size of bond clusters for integrin-based adhesion, consistent with related experimental observations on focal adhesions of cell-matrix interactions. The stress distribution within bond clusters is generally non-uniform and governed by the stress concentration index. PMID- 25706683 TI - Single-Stage Bilateral Versus Unilateral Retrograde Intrarenal Surgery for Management of Renal Stones: A Matched-Pair Analysis. AB - PURPOSE: This study aimed to compare the effectiveness and safety of single-stage bilateral and unilateral retrograde intrarenal surgery (RIRS) for treatment of patients with renal stones. PATIENTS AND METHODS: Patients undergoing single stage bilateral RIRS for renal stones between January 2011 and April 2014 were retrospectively reviewed and matched to patients undergoing unilateral RIRS at a 1:1 ratio by the propensity score based on age, sex, body mass index, American Society of Anesthesiologists classification, stone burden, and stone location (involvement of the lower calix or not). Main outcome measures were stone-free rate per patient and per renal unit and RIRS-associated morbidity. RESULTS: Of 60 patients treated by single-stage bilateral RIRS, 59 patients were matched with patients treated by unilateral RIRS. Stone-free rates per patient for bilateral RIRS and unilateral RIRS were 84.7% and 91.5%, respectively (P=0.255). Median operative time (100 vs 65 min, P<0.001) and postoperative hospitalization (2 vs 1 d, P=0.011) was significantly longer for bilateral RIRS than unilateral RIRS. Median changes in hematocrit (1.3% vs 1.0%, P=0.964) and serum creatinine level (3 vs 2 MUmol/L, P=0.716) were similar between bilateral and unilateral RIRS. The overall complication rate was slightly higher with bilateral RIRS (11.9% vs 8.5%, P=0.542). No serious RIRS-associated morbidities occurred in either group. CONCLUSION: Single-stage bilateral RIRS was as effective and safe as unilateral RIRS among propensity score-matched patients. PMID- 25706684 TI - High-temperature spin crossover in two solvent-free coordination polymers with unusual high thermal stability. AB - Two solvent-free two-dimensional (2D) coordination polymers, (2)infinity[Fe(ptim)2] (1) and (2)infinity[Fe(ptpy)2] (2) (Hptim = 2-(5-(4-(1H imidazol-1-yl)phenyl)-4H-1,2,4-triazol-3-yl)pyridine; Hptpy = 2-(5-(4-(pyridin-3 yl)phenyl)-4H-1,2,4-triazol-3-yl)pyridine), have been successfully prepared by solvothermal reactions. Their iron atoms are bridged by the corresponding multidentate anionic ligands into dense neutral structures. The magnetic data reveal that complexes 1 and 2 are rare examples exhibiting reversible one-step high-temperature spin crossover behaviors with spin transition temperatures of 419 and 416 K, respectively. Moreover, these structures also display remarkable thermal stability up to 714 K (for 1) and 690 K (for 2), which are confirmed by thermogravimetric and variable-temperature powder X-ray diffraction analyses. PMID- 25706685 TI - Factors associated with health-related quality of life among overweight and obese Korean women. AB - Health-related quality of life (HRQOL) tends to be lower among individuals who are overweight and obese than those of normal weight, and women may be more vulnerable to lower HRQOL associated with obesity than men. Identifying factors associated with HRQOL may be crucial for improving HRQOL for overweight/obese women. We aimed to determine the factors associated with obesity-specific HRQOL among overweight/obese Korean women. A cross-sectional study was conducted with 125 women aged 20-64 years, who comprised a baseline sample in the Community based Heart and Weight Management Trial. The data were collected from September 2010 to November 2011. The Weight Efficacy Lifestyle, Beck Depression Inventory II, Interpersonal Social Evaluation List, and Impact of Weight on Quality of Life (IWQOL)-Lite scales were used to measure self-efficacy for weight control, depressive symptoms, social support, and HRQOL, respectively. Increased body mass index, lower self-efficacy for weight control, and higher levels of depressive symptoms were significantly associated with greater impairment in total IWQOL in the regression models. However, social support was not significantly associated with IWQOL. Along with weight loss strategies, other strategies for improving self-efficacy and alleviating depressive symptoms may be essential for improving HRQOL among overweight and obese women. PMID- 25706686 TI - Actomyosin tension as a determinant of metastatic cancer mechanical tropism. AB - Despite major advances in the characterization of molecular regulators of cancer growth and metastasis, patient survival rates have largely stagnated. Recent studies have shown that mechanical cues from the extracellular matrix can drive the transition to a malignant phenotype. Moreover, it is also known that the metastatic process, which results in over 90% of cancer-related deaths, is governed by intracellular mechanical forces. To better understand these processes, we identified metastatic tumor cells originating from different locations which undergo inverse responses to altered matrix elasticity: MDA-MB 231 breast cancer cells that prefer rigid matrices and SKOV-3 ovarian cancer cells that prefer compliant matrices as characterized by parameters such as tumor cell proliferation, chemoresistance, and migration. Transcriptomic analysis revealed higher expression of genes associated with cytoskeletal tension and contractility in cells that prefer stiff environments, both when comparing MDA-MB 231 to SKOV-3 cells as well as when comparing bone-metastatic to lung-metastatic MDA-MB-231 subclones. Using small molecule inhibitors, we found that blocking the activity of these pathways mitigated rigidity-dependent behavior in both cell lines. Probing the physical forces exerted by cells on the underlying substrates revealed that though force magnitude may not directly correlate with functional outcomes, other parameters such as force polarization do correlate directly with cell motility. Finally, this biophysical analysis demonstrates that intrinsic levels of cell contractility determine the matrix rigidity for maximal cell function, possibly influencing tissue sites for metastatic cancer cell engraftment during dissemination. By increasing our understanding of the physical interactions of cancer cells with their microenvironment, these studies may help develop novel therapeutic strategies. PMID- 25706687 TI - PathVisio 3: an extendable pathway analysis toolbox. AB - PathVisio is a commonly used pathway editor, visualization and analysis software. Biological pathways have been used by biologists for many years to describe the detailed steps in biological processes. Those powerful, visual representations help researchers to better understand, share and discuss knowledge. Since the first publication of PathVisio in 2008, the original paper was cited more than 170 times and PathVisio was used in many different biological studies. As an online editor PathVisio is also integrated in the community curated pathway database WikiPathways. Here we present the third version of PathVisio with the newest additions and improvements of the application. The core features of PathVisio are pathway drawing, advanced data visualization and pathway statistics. Additionally, PathVisio 3 introduces a new powerful extension systems that allows other developers to contribute additional functionality in form of plugins without changing the core application. PathVisio can be downloaded from http://www.pathvisio.org and in 2014 PathVisio 3 has been downloaded over 5,500 times. There are already more than 15 plugins available in the central plugin repository. PathVisio is a freely available, open-source tool published under the Apache 2.0 license (http://www.apache.org/licenses/LICENSE-2.0). It is implemented in Java and thus runs on all major operating systems. The code repository is available at http://svn.bigcat.unimaas.nl/pathvisio. The support mailing list for users is available on https://groups.google.com/forum/#!forum/wikipathways-discuss and for developers on https://groups.google.com/forum/#!forum/wikipathways-devel. PMID- 25706689 TI - Rhodium-catalyzed asymmetric arylation of allyl sulfones under the conditions of isomerization into alkenyl sulfones. AB - The reaction of 3-sulfolene with arylboronic acids in the presence of a chiral diene-rhodium catalyst under highly basic conditions (10 equiv of KOH) gave high yields of 3-arylsulfolanes with high enantioselectivity, where 3-sulfolene is in equilibration with 2-sulfolene by base-catalyzed isomerization and the more reactive 2-sulfolene undergoes the rhodium-catalyzed asymmetric arylation. PMID- 25706688 TI - Optical properties of rabbit brain in the red and near-infrared: changes observed under in vivo, postmortem, frozen, and formalin-fixated conditions. AB - The outcome of light-based therapeutic approaches depends on light propagation in biological tissues, which is governed by their optical properties. The objective of this study was to quantify optical properties of brain tissue in vivo and postmortem and assess changes due to tissue handling postmortem. The study was carried out on eight female New Zealand white rabbits. The local fluence rate was measured in the VIS/NIR range in the brain in vivo, just postmortem, and after six weeks' storage of the head at -20 degrees C or in 10% formaldehyde solution. Only minimal changes in the effective attenuation coefficient MUeff were observed for two methods of sacrifice, exsanguination or injection of KCl. Under all tissue conditions, MUeff decreased with increasing wavelengths. After long-term storage for six weeks at -20 degrees C, MUeff decreased, on average, by 15 to 25% at all wavelengths, while it increased by 5 to 15% at all wavelengths after storage in formaldehyde. We demonstrated that MUeff was not very sensitive to the method of animal sacrifice, that tissue freezing significantly altered tissue optical properties, and that formalin fixation might affect the tissue's optical properties.) PMID- 25706690 TI - Three centered hydrogen bonds of the type C=O...H(N)...X-C in diphenyloxamide derivatives involving halogens and a rotating CF3 group: NMR, QTAIM, NCI and NBO studies. AB - The existence of three centered C=O...H(N)...X-C hydrogen bonds (H-bonds) involving organic fluorine and other halogens in diphenyloxamide derivatives has been explored by NMR spectroscopy and quantum theoretical studies. The three centered H-bond with the participation of a rotating CF3 group and the F...H-N intramolecular hydrogen bonds, a rare observation of its kind in organofluorine compounds, has been detected. It is also unambiguously established by a number of one and two dimensional NMR experiments, such as temperature perturbation, solvent titration, (15)N-(1)H HSQC, and (19)F-(1)H HOESY, and is also confirmed by theoretical calculations, such as quantum theory of atoms in molecules (QTAIM), natural bond orbital (NBO) and non-covalent interaction (NCI). PMID- 25706691 TI - Nanoporous gold as a neural interface coating: effects of topography, surface chemistry, and feature size. AB - Designing neural interfaces that maintain close physical coupling of neurons to an electrode surface remains a major challenge for both implantable and in vitro neural recording electrode arrays. Typically, low-impedance nanostructured electrode coatings rely on chemical cues from pharmaceuticals or surface immobilized peptides to suppress glial scar tissue formation over the electrode surface (astrogliosis), which is an obstacle to reliable neuron-electrode coupling. Nanoporous gold (np-Au), produced by an alloy corrosion process, is a promising candidate to reduce astrogliosis solely through topography by taking advantage of its tunable length scale. In the present in vitro study on np-Au's interaction with cortical neuron-glia co-cultures, we demonstrate that the nanostructure of np-Au achieves close physical coupling of neurons by maintaining a high neuron-to-astrocyte surface coverage ratio. Atomic layer deposition-based surface modification was employed to decouple the effect of morphology from surface chemistry. Additionally, length scale effects were systematically studied by controlling the characteristic feature size of np-Au through variations in the dealloying conditions. Our results show that np-Au nanotopography, not surface chemistry, reduces astrocyte surface coverage while maintaining high neuronal coverage and may enhance neuron-electrode coupling through nanostructure-mediated suppression of scar tissue formation. PMID- 25706692 TI - Absorption and desorption of SO2 in aqueous solutions of diamine-based molten salts. AB - SO2 absorption and desorption behaviors were investigated in aqueous solutions of diamine-derived molten salts with a tertiary amine group on the cation and a chloride anion, including butyl-(2-dimethylaminoethyl)-dimethylammonium chloride ([BTMEDA]Cl, pKb=8.2), 1-butyl-1,4-dimethylpiperazinium chloride ([BDMP]Cl, pKb=9.8), and 1-butyl-4-aza-1-azoniabicyclo[2,2,2]octane chloride ([BDABCO]Cl, pKb=11.1). The SO2 absorption and desorption performance of the molten salt were greatly affected by the basicity of the molten salt. Spectroscopic, X-ray crystallographic, and computational results for the interactions of SO2 with molten salts suggest that two types of SO2-containg species could be generated depending on the basicity of the unquaternized amino group: a dicationic species comprising two different anions, HSO3(-) and Cl(-), and a monocationic species bearing Cl(-) interacting with neutral H2SO3. PMID- 25706693 TI - Nanoscale imaging of fundamental li battery chemistry: solid-electrolyte interphase formation and preferential growth of lithium metal nanoclusters. AB - The performance characteristics of Li-ion batteries are intrinsically linked to evolving nanoscale interfacial electrochemical reactions. To probe the mechanisms of solid electrolyte interphase (SEI) formation and to track Li nucleation and growth mechanisms from a standard organic battery electrolyte (LiPF6 in EC:DMC), we used in situ electrochemical scanning transmission electron microscopy (ec S/TEM) to perform controlled electrochemical potential sweep measurements while simultaneously imaging site-specific structures resulting from electrochemical reactions. A combined quantitative electrochemical measurement and STEM imaging approach is used to demonstrate that chemically sensitive annular dark field STEM imaging can be used to estimate the density of the evolving SEI and to identify Li-containing phases formed in the liquid cell. We report that the SEI is approximately twice as dense as the electrolyte as determined from imaging and electron scattering theory. We also observe site-specific locations where Li nucleates and grows on the surface and edge of the glassy carbon electrode. Lastly, this report demonstrates the investigative power of quantitative nanoscale imaging combined with electrochemical measurements for studying fluid solid interfaces and their evolving chemistries. PMID- 25706694 TI - Cancer: mixed messages, common purpose. PMID- 25706695 TI - Syrian refugees seeking help. PMID- 25706696 TI - Is the world ready for an Ebola vaccine? PMID- 25706699 TI - Monica Roa: legal champion of abortion rights. PMID- 25706700 TI - Rituximab for patients with nephrotic syndrome. PMID- 25706701 TI - Rituximab for patients with nephrotic syndrome. PMID- 25706702 TI - Rituximab for patients with nephrotic syndrome. PMID- 25706703 TI - Rituximab for patients with nephrotic syndrome--authors' reply. PMID- 25706704 TI - Sorafenib for patients with differentiated thyroid cancer. PMID- 25706705 TI - Sorafenib for patients with differentiated thyroid cancer. PMID- 25706706 TI - Sorafenib for patients with differentiated thyroid cancer--authors' reply. PMID- 25706707 TI - Sorafenib for patients with differentiated thyroid cancer. PMID- 25706708 TI - ASPIRE: international recognition of excellence in medical education. PMID- 25706709 TI - Patient education is crucial for the access to essential medicine. PMID- 25706710 TI - Snowflakes in the heart: an ultrasonic marker of severe hypercoagulability. PMID- 25706711 TI - Reversible modification of structure and properties of cellulose nanofibril-based multilayered thin films induced by postassembly acid treatment. AB - A postassembly acid-treatment consisting of an immersion in 5 mM HCl solution was applied to carboxylated cellulose nanofibrils (CNF)-poly(allylamine) hydrochloride (PAH) multilayered thin films. Our results show that the treatment did not affect the overall thickness of the films without any loss of the components. However, a modification of the surface morphology was observed, as well as the swelling behavior. The process was perfectly reversible since the original structure was recovered when the thin films were rinsed by ultrapure water. Moreover, a more pronounced antireflective character was detected for the treated films. The origin of these reversible modifications was discussed. Notably, the scattering length density (SLD) profiles of the films before and after treatment support the idea of a structural reorganization of the components within the film driven by the change of their charge densities induced by the acid treatment. PMID- 25706712 TI - Shotgun weddings (dekichatta kekkon) in contemporary Japan. AB - The accelerated greying of its population along with birth rates plummeting below replacement levels synergise into one of the most acute social issues in contemporary Japan. Although singleness, childlessness, delayed marriage and late in-life-childbirth have become endemic, official records nevertheless reveal an increase in childbirth among women aged 15-19 in 2013. Furthermore, official statistics for 2010 show that 50% of Japanese women aged 25 or younger who married were expecting a baby. This paper focuses on 17 Japanese mothers who had a 'shotgun wedding' (dekichatta kekkon)--a ceremony organised due to an unplanned pregnancy. Aged between 29 and 35 years, the mothers came from Tokyo and Kanagawa and were interviewed for the purposes of exploring their experiences with and viewpoints on unplanned childbirth, contraception and marriage. Grounded in a symbolic interactionist perspective, the analysis of interviews suggested that shotgun weddings largely stem from contraception issues, the will to get pregnant in order to keep a partner and homosocial pressure to prevent the termination of the unexpected pregnancy. PMID- 25706713 TI - Carotenoids of aleurone, germ, and endosperm fractions of barley, corn and wheat differentially inhibit oxidative stress. AB - The antioxidant potential of carotenoids from aleurone, germ, and endosperm fractions of barley, corn, and wheat has been evaluated. HPLC analysis confirmed the presence of lutein and zeaxanthin carotenoids (nd-15139 MUg/kg) in extracts of cereal grain fractions. The antioxidant properties using 2,2-diphenyl-1 picrylhydrazyl, oxygen radical absorbance capacity, 2,2'-azino-bis(3 ethylbenzothiazoline-6-sulfonic acid) assays revealed significantly higher (P<0.001) antioxidant activity in the germ than in the aleurone and endosperm fractions. Using 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) assay, 2,2'azobis (2-amidinopropane)dihydrochloride (AAPH)-induced cell loss was effectively reduced by preincubating Caco-2, HT-29, and FHs 74 Int cells with carotenoid extracts. Moreover, carotenoid extracts reduced (P<0.001) AAPH induced intracellular oxidation in the cell lines, suggesting antioxidant activity. Of the 84 antioxidant pathway genes included in microarray array analysis (HT-29 cells), the expressions of 28 genes were enhanced (P<0.05). Our findings suggest that carotenoids of germ, aleurone, and endosperm fractions improved antioxidant capacity and thus have the potential to mitigate oxidative stress. PMID- 25706714 TI - Rhombic cyclobutadiene with a boryl/amino-substitution pattern: boryl group migration induced by reaction with water. AB - The synthesis of a donor-acceptor cyclobutadiene featuring a boryl/amino substitution pattern is presented together with its characteristic reactivity toward water. On the basis of the results of X-ray crystallography, theoretical studies, and spectroscopic analyses, the observed rhombic structure of the cyclobutadiene was attributed to a charge-separated electronic structure. Reaction of this boryl-substituted cyclobutadiene with water induced a characteristic migration of the boryl group, due to the Lewis acidity of the boryl-substituent. PMID- 25706716 TI - American Board of Operative Dentistry certification. PMID- 25706717 TI - A TagSNP in SIRT1 gene confers susceptibility to myocardial infarction in a Chinese Han population. AB - SIRT1 exerts protective effects against endothelial cells dysfunction, inflammation and atherosclerosis, indicating an important role on myocardial infarction (MI) pathogenesis. Nonetheless, the effects of SIRT1 variants on MI risk remain poorly understood. Here we aimed to investigate the influence of SIRT1 polymorphisms on individual susceptibility to MI. Genotyping of three tagSNPs (rs7069102, rs3818292 and rs4746720) in SIRT1 gene was performed in a Chinese Han population, consisting of 287 MI cases and 654 control subjects. In a logistic regression analysis, we found that G allele of rs7069102 had increased MI risk with odds ratio (OR) of 1.57 [95% confidence interval (CI) = 1.15-2.16, Bonferroni corrected P (Pc) = 0.015] after adjustment for conventional risk factors compared to C allele. Similarly, the combined CG/GG genotypes was associated with the increased MI risk (OR = 1.64, 95% CI = 1.14-2.35, Pc = 0.021) compared to the CC genotype. Further stratified analysis revealed a more significant association with MI risk among younger subjects (<= 55 years old). Consistent with these results, the haplotype rs7069102G-rs3818292A-rs4746720T containing the rs7069102 G allele was also associated with the increased MI risk (OR = 1.41, 95% CI = 1.09-1.84, Pc = 0.040). However, we did not detect any association of rs3818292 and rs4746720 with MI risk. Our study provides the first evidence that the tagSNP rs7069102 and haplotype rs7069102G-rs3818292A-rs4746720T in SIRT1 gene confer susceptibility to MI in the Chinese Han population. PMID- 25706718 TI - Enhanced invasion of metastatic cancer cells via extracellular matrix interface. AB - Cancer cell invasion is a major component of metastasis and is responsible for extensive cell diffusion into and major destruction of tissues. Cells exhibit complex invasion modes, including a variety of collective behaviors. This phenomenon results in the structural heterogeneity of the extracellular matrix (ECM) in tissues. Here, we systematically investigated the environmental heterogeneity facilitating tumor cell invasion via a combination of in vitro cell migration experiments and computer simulations. Specifically, we constructed an ECM microenvironment in a microfabricated biochip and successfully created a three-dimensional (3D) funnel-like matrigel interface inside. Scanning electron microscopy demonstrated that the interface was at the interior defects of the nano-scale molecular anisotropic orientation and the localized structural density variations in the matrigel. Our results, particularly the correlation of the collective migration pattern with the geometric features of the funnel-like interface, indicate that this heterogeneous in vitro ECM structure strongly guides and promotes aggressive cell invasion in the rigid matrigel space. A cellular automaton model was proposed based on our experimental observations, and the associated quantitative analysis indicated that cell invasion was initiated and controlled by several mechanisms, including microenvironment heterogeneity, long-range cell-cell homotype and gradient-driven directional cellular migration. Our work shows the feasibility of constructing a complex and heterogeneous in vitro 3D ECM microenvironment that mimics the in vivo environment. Moreover, our results indicate that ECM heterogeneity is essential in controlling collective cell invasive behaviors and therefore determining metastasis efficiency. PMID- 25706720 TI - Magnetically Inserted Neural Electrodes: Tissue Response and Functional Lifetime. AB - Neural recording and stimulation have great clinical potential. Long-term neural recording remains a challenge, however, as implantable electrodes eventually fail due to the adverse effects of the host tissue response to the indwelling implant. Astrocytes and microglia attempt to engulf the electrode, increasing the electrical impedance between the electrode and neurons, and possibly pushing neurons away from the recording site. Faster insertion speed, finer tip geometry, smaller size, and lower material stiffness all seem to decrease damage caused by insertion and reduce the intensity of the tissue response. However, electrodes that are too small result in buckling, making insertion impossible. In this paper, we assess the viability of high-speed (27.8 m/s) deployment of 25 MUm, ferromagnetic microelectrodes into rat brain. To characterize functionality of magnetically inserted electrodes, 4 Long-Evans rats were implanted for 31 days with impedance measurements and neural recordings taken daily. Performance was compared to 150 MUm diameter PlasticsOne electrodes since 25 MUm electrodes buckled during "slow speed" insertion. Platinum-iron magnetically inserted electrodes resolved single unit activity throughout the duration of the study in one rat, and saw no significant change (p=0.970) in impedance (4.54% increase) from day 0 (Z0 ~ 144 kOmega,Z31 ~ 150 kOmega). These findings provide a proof-of concept for magnetic insertion as a viable insertion method that enables nonbuckling implantation of small (25 MUm) microelectrodes, with potential for neural recording applications. PMID- 25706721 TI - A Hybrid Brain-Computer Interface Based on the Fusion of P300 and SSVEP Scores. AB - The present study proposes a hybrid brain-computer interface (BCI) with 64 selectable items based on the fusion of P300 and steady-state visually evoked potential (SSVEP) brain signals. With this approach, row/column (RC) P300 and two step SSVEP paradigms were integrated to create two hybrid paradigms, which we denote as the double RC (DRC) and 4-D spellers. In each hybrid paradigm, the target is simultaneously detected based on both P300 and SSVEP potentials as measured by the electroencephalogram. We further proposed a maximum-probability estimation (MPE) fusion approach to combine the P300 and SSVEP on a score level and compared this approach to other approaches based on linear discriminant analysis, a naive Bayes classifier, and support vector machines. The experimental results obtained from thirteen participants indicated that the 4-D hybrid paradigm outperformed the DRC paradigm and that the MPE fusion achieved higher accuracy compared with the other approaches. Importantly, 12 of the 13 participants, using the 4-D paradigm achieved an accuracy of over 90% and the average accuracy was 95.18%. These promising results suggest that the proposed hybrid BCI system could be used in the design of a high-performance BCI-based keyboard. PMID- 25706719 TI - Kuwanon V inhibits proliferation, promotes cell survival and increases neurogenesis of neural stem cells. AB - Neural stem cells (NSCs) have the ability to proliferate and differentiate into neurons and glia. Regulation of NSC fate by small molecules is important for the generation of a certain type of cell. The identification of small molecules that can induce new neurons from NSCs could facilitate regenerative medicine and drug development for neurodegenerative diseases. In this study, we screened natural compounds to identify molecules that are effective on NSC cell fate determination. We found that Kuwanon V (KWV), which was isolated from the mulberry tree (Morus bombycis) root, increased neurogenesis in rat NSCs. In addition, during NSC differentiation, KWV increased cell survival and inhibited cell proliferation as shown by 5-bromo-2-deoxyuridine pulse experiments, Ki67 immunostaining and neurosphere forming assays. Interestingly, KWV enhanced neuronal differentiation and decreased NSC proliferation even in the presence of mitogens such as epidermal growth factor and fibroblast growth factor 2. KWV treatment of NSCs reduced the phosphorylation of extracellular signal-regulated kinase 1/2, increased mRNA expression levels of the cyclin-dependent kinase inhibitor p21, down-regulated Notch/Hairy expression levels and up-regulated microRNA miR-9, miR-29a and miR-181a. Taken together, our data suggest that KWV modulates NSC fate to induce neurogenesis, and it may be considered as a new drug candidate that can regenerate or protect neurons in neurodegenerative diseases. PMID- 25706722 TI - Influence of Joint Angle on EMG-Torque Model During Constant-Posture, Torque Varying Contractions. AB - Relating the electromyogram (EMG) to joint torque is useful in various application areas, including prosthesis control, ergonomics and clinical biomechanics. Limited study has related EMG to torque across varied joint angles, particularly when subjects performed force-varying contractions or when optimized modeling methods were utilized. We related the biceps-triceps surface EMG of 22 subjects to elbow torque at six joint angles (spanning 60 degrees to 135 degrees ) during constant-posture, torque-varying contractions. Three nonlinear EMG sigma -torque models, advanced EMG amplitude (EMG sigma ) estimation processors (i.e., whitened, multiple-channel) and the duration of data used to train models were investigated. When EMG-torque models were formed separately for each of the six distinct joint angles, a minimum "gold standard" error of 4.01+/-1.2% MVC(F90) resulted (i.e., error relative to maximum voluntary contraction at 90 degrees flexion). This model structure, however, did not directly facilitate interpolation across angles. The best model which did so achieved a statistically equivalent error of 4.06+/-1.2% MVC(F90). Results demonstrated that advanced EMG sigma processors lead to improved joint torque estimation as do longer model training durations. PMID- 25706723 TI - A neighborhood analysis of the consequences of Quercus suber decline for regeneration dynamics in Mediterranean forests. AB - In forests, the vulnerable seedling stage is largely influenced by the canopy, which modifies the surrounding environment. Consequently, any alteration in the characteristics of the canopy, such as those promoted by forest dieback, might impact regeneration dynamics. Our work analyzes the interaction between canopy neighbors and seedlings in Mediterranean forests affected by the decline of their dominant species (Quercus suber). Our objective was to understand how the impacts of neighbor trees and shrubs on recruitment could affect future dynamics of these declining forests. Seeds of the three dominant tree species (Quercus suber, Olea europaea and Quercus canariensis) were sown in six sites during two consecutive years. Using a spatially-explicit, neighborhood approach we developed models that explained the observed spatial variation in seedling emergence, survival, growth and photochemical efficiency as a function of the size, identity, health, abundance and distribution of adult trees and shrubs in the neighborhood. We found strong neighborhood effects for all the performance estimators, particularly seedling emergence and survival. Tree neighbors positively affected emergence, independently of species identity or health. Alternatively, seedling survival was much lower in neighborhoods dominated by defoliated and dead Q. suber trees than in neighborhoods dominated by healthy trees. For the two oak species, these negative effects were consistent over the three years of the experimental seedlings. These results indicate that ongoing changes in species' relative abundance and canopy trees' health might alter the successional trajectories of Mediterranean oak-forests through neighbor-specific impacts on seedlings. The recruitment failure of dominant late-successional oaks in the gaps opened after Q. suber death would indirectly favor the establishment of other coexisting woody species, such as drought-tolerant shrubs. This could lead current forests to shift into open systems with lower tree cover. Adult canopy decline would therefore represent an additional factor threatening the recruitment of Quercus forests worldwide. PMID- 25706724 TI - The impact of afforestation on soil organic carbon sequestration on the Qinghai Plateau, China. AB - Afforestation, the conversion of non-forested land into forest, is widespread in China. However, the dynamics of soil organic carbon (SOC) after afforestation are not well understood, especially in plateau climate zones. For a total of 48 shrub and/or tree-dominated afforestation sites on the Qinghai Plateau, Northwestern China, post-afforestation changes in SOC, total nitrogen (TN), the carbon-to nitrogen ratio (C/N) and soil bulk density (BD) were investigated to a soil depth of 60 cm using the paired-plots method. SOC and TN accumulated at rates of 138.2 g C m(-2) yr(-1) and 4.6 g N m(-2) yr(-1), respectively, in shrub-dominated afforestation sites and at rates of 113.3 g C m(-2) yr(-1) and 6.7 g N m(-2) yr( 1), respectively, in tree-dominated afforestation sites. Soil BD was slightly reduced in all layers in the shrub-dominated afforestation plots, and significantly reduced in soil layers from 0-40cm in the tree-dominated afforestation plots. The C/N ratio was higher in afforested sites relative to the reference sites. SOC accumulation was closely related to TN accumulation following afforestation, and the inclusion of N-fixing species in tree-dominated afforestation sites additionally increased the soil accumulation capacity for SOC (p < 0.05). Multiple regression models including the age of an afforestation plot and total number of plant species explained 75% of the variation in relative SOC content change at depth of 0-20 cm, in tree-dominated afforestation sites. We conclude that afforestation on the Qinghai Plateau is associated with great capability of SOC and TN sequestration. This study improves our understanding of the mechanisms underlying SOC and TN accumulation in a plateau climate, and provides evidence on the C sequestration potentials associated with forestry projects in China. PMID- 25706725 TI - Erythrocyte concentrates recovered from under-collected whole blood: experimental and clinical results. AB - BACKGROUND: Although periodic blood shortages are widespread in major Chinese cities, approximately 1 x 10(5) U of whole blood are discarded yearly because of under-collection. To reduce the wastage of acid citrate dextrose solution B (ACD B) anticoagulated under-collected whole blood (UC-WB), this study was performed to elucidate the effect of extracellular pH and holding time on erythrocyte quality. Mannitol-adenine-phosphate (MAP) erythrocyte concentrates (UC-RBCs) were prepared with UC-WB to assess the safety and efficacy of this component. METHODS: The effect of the different extracellular pH levels and storage times on erythrocytes was assessed by fluorescent probes, SDS-PAGE electrophoresis, electron microscopy and spectroscopy. In vitro properties of 34 UC-RBCs that were prepared with UC-WB at different times after collection were analyzed and compared to normal RBCs during 35 days of storage. The results of transfusion with UC-RBCs and the incidence of adverse reactions in 49 patients were determined. RESULTS: 1) Low extracellular pH levels and long storage time induced increases in RBC fluorescence polarization and mean microviscosity, changes in membrane fluidity, band 1, 2 and 3 protein expression, and erythrocyte morphology. 2) During storage for 35 days, difference in between-subjects effects of K+, hemolysis and supernatant erythrocyte membrane protein (EMP) were statistically significant (P = 0.041, 0.007 and 0.002, respectively), while the differences between these parameters in the 4 h group and comparable controls were less significant. 3) Clinical data from 49 patients confirmed that transfusions with UC-RBCs were satisfactory with no adverse reactions. CONCLUSION: These results suggest that it is feasible to prepare RBCs with ACD-B anticoagulated UC-WB at a minimum of 66% volume of the labeled collection. It was effective and safe to transfuse the UC-RBCs prepared within 4 h after collection and stored within 7 days. The use of UC-WB would be a welcome addition to limited blood resources in China. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR-TRC-13003967. PMID- 25706726 TI - [Investigation of macrolide, lincosamide and streptogramin B resistance in Staphylococcus aureus strains isolated from clinical samples by phenotypical and genotypical methods]. AB - Staphylococcus aureus is one of the most common cause of both community and healthcare-associated infections. As staphylococci have developed resistance to various antibiotics, initially to penicillins then to methicillin and glycopeptides and have the ability to cause epidemics, they continue to be a major problem from past to present. Methicillin resistance gave rise to the use of alternative antibiotics such as macrolides, however worldwide development of macrolide resistance limited the use of these antibiotics. Macrolide resistance occurs either through target site modification (MLS(B) phenotype, encoded by erm genes), efflux pumps (MS phenotype, encoded by msrA/B genes) or decreased cell wall permeability. The aim of this study was to investigate the MLS(B) resistance of clinical S.aureus strains with phenotypic and genotypic methods. A total of 404 S.aureus strains isolated from different clinical samples (50% wound, 15% tracheal aspirate and 35% other samples) of inpatients (93.3%) and outpatients (6.7%) were included in the study. Double disc synergy test (D-test) was used for the phenotypical research and PCR was used for the genotypical research of MLS(B) resistance of isolates. One hundred fifty eight (39.1%) of the S.aureus isolates were methicillin-resistant (MRSA), and 246 (60.9%) were methicillin-susceptible (MSSA). By the use of D-test, constitutive (cMLS(B)) and inducible (iMLS(B)) clindamycin resistance were detected in 19 and 111 isolates, respectively, while five isolates were MS phenotype and 268 isolates were S phenotype (susceptible to erythromycin and clindamycin). The resistance genes of 136 isolates with MLS(B) resistance phenotype were determined genotypically and among 111 isolates showing iMLS(B) phenotype ermA gene was found in 81.9% (83 MRSA, 8 MSSA), ermC gene in 10.8% (7 MRSA, 5 MSSA), msrA gene in 10.8% (11 MRSA, 1 MSSA), msrB gene in 1.8% (2 MRSA) and ermB gene in 0.9% (1 MRSA). Among 19 strains with cMLS(B) phenotype, ermA was found in 57.9% (10 MRSA, 1 MSSA), ermC in 36.8% (6 MRSA, 1 MSSA) and ermB in 15.8% (3 MRSA). Among five strains with MS phenotype, ermA was found in 80% (2 MRSA, 2 MSSA), msrA in 75% (3 MSSA), msrB in 50% (2 MSSA) and ermC in 25% (1 MSSA) of the isolates. ErmA and ermC genes were detected together in 14 isolates, ermA, ermC and msrA genes in one isolate, ermA and msrA genes in 11 isolates, ermA, msrA and msrB genes in three isolates and ermA and ermB genes in three isolates, respectively. In this study, two MRSA isolates with MS phenotype and negative D-test had only ermA gene and among two MSSA strains, erm genes were also determined in addition to msr genes. In our study RAPD-PCR method was used to investigate the clonal similarity, however no dominance of one or a number of clonal type was observed among the isolates in which the resistance genes were identified. In conclusion, the detection of MLS(B) resistance in S.aureus isolates is likely to influence the selection of antibiotics in the treatment of the infections caused by this bacteria. PMID- 25706727 TI - [Investigation of beta-lactamase genes and clonal relationship among the extended spectrum beta-lactamase producing nosocomial Escherichia coli isolates]. AB - Extended-spectrum beta-lactamase (ESBL) producing microorganisms currently cause a major problem. Among theseCTX-M beta-lactamase producing Escherichia coli has also disseminated worldwide as an important cause of both nosocomial and community-acquired infections. The aims of this study were to determine the prevalence of the beta-lactamase genes, antibiotic susceptibilities and clonal relationships of ESBL-producing nosocomial E.coli isolates. A total of 76 ESBL producing E.coli strains isolated from urine (n= 26), blood (n= 25) and wound (n= 25) specimens of hospitalized patients identified as nosocomial infection agents according to the CDC criteria between June 2010-June 2011 were included in the study. Antibiotic susceptibilities of the isolates were detected by Kirby-Bauer disc diffusion method according to CLSI recommendations. ESBL production was tested by double disc diffusion method, and cefotaxime/cefotaxime-clavulanic acid E-test strips (AB Biodisk, Sweden) were used for indeterminate results. Presence of TEM, SHV, CTX-M, OXA-2 group, 0XA-10 group, PER, VEB and GES beta-lactamase genes were investigated by polymerase chain reaction (PCR) using specific primers. Pulsed-field gel electrophoresis (PFGE) method was used for the detection of clonal relationships among the strains. Most of the ESBL-producing E.coli strains were isolated from samples of inpatients in intensive care (35%), internal medicine (16%) and general surgery (13%) units. All of the 76 strains were found susceptible to imipenem, meropenem and amikacin; however all were resistant to cefotaxime and ceftriaxone. The susceptibility rates of the isolates to cefoxitin, ertapenem, cefoperazone/sulbactam, piperacillin-tazobactam, gentamicin, ciprofloxacin, cefepime, amoxicillin-clavulanic acid, aztreonam and ceftazidime were 96%, 83%, 63%, 61%, 50%, 41%, 25%, 21%, 20% and 18%, respectively. Among E.coli isolates, the frequency of CTX-M, TEM, OXA-2 group, PER, SHV and OXA-10 group beta-lactamase genes were found as 89.5%, 59.2%, 15.8%, 14.5%, 11.8% and 3.9%, respectively, while none of the isolates were positive for VEB and GES beta-lactamase genes. In 1 (1.3%) strain none of the investigated genes were detected. PCR analyses of the isolates revealed that 25 harbored CTX-M and TEM genes together, while 20 harbored only CTX-M and two harbored only TEM genes. Single SHV gene was not detected in any of the isolates. PFGE demonstrated no major clonal relationship between ESBL-producing isolates. This study indicated that CTX-M type enzymes were highly endemic among ESBL-producing nosocomial E.coli strains in our hospital, with the polyclonal spread of ESBL producing bacteria without any dominant epidemic clone. In conclusion, it was considered that further studies are needed to explain the relationship between epidemic clones and plasmids with the use of plasmid analysis and multilocus sequence typing methods. PMID- 25706728 TI - [The presence of OXA type carbapenemases in Pseudomonas strains: first report from Turkey]. AB - Pseudomonas spp. that are one of the important nosocomial pathogens worldwide, and carbapenem resistance is observed in an increasing rate. Major factors leading to carbapenem resistance are metallo-beta-lactamases (MBLs) and carbapenem-hydrolyzing class D oxacillinases. MBLs are frequently prevalent in Pseudomonas spp., while carbapenem-hydrolyzing class D oxacillinases has been almost exclusively found in multidrug and carbapenem-resistant Acinetobacter baumannii. The aim of this study was to investigate the presence of OXA-23, OXA 40 and OXA-58 genes that encode carbapenemases, in carbapenem-resistant Pseudomonas spp. strains. A total of 184 imipenem and/or meropenem-resistant Pseudomonas spp. strains isolated from different clinical samples (85 bronchoalveolar lavage, 31 wound, 18 tracheal aspirate, 16 urine, 14 blood, 10 sputum, 3 catheter, 3 throat, 2 drainage fluid, 1 abscess, 1 peritoneal fluid) in Medical Microbiology Laboratory of Necmettin Erbakan University Meram Faculty of Medicine, between November 2011 to October 2013, were included in the study. The isolates were identified by conventional methods and an automated system (VITEK-2 Compact, bioMerieux, France), while the antibiotic susceptibility tests were performed with Kirby-Bauer disk diffusion method and automated system according to the recommendations of CLSI. The presence of OXA-23, OXA-40 and OXA-58 genes in strains were investigated by a commercial PCR kit (Hyplex CarbOxa ID; Amplex Diagnostics GmbH, Germany). Molecular studies were carried out in three steps, namely extraction of genomic DNA; multiplex PCR amplification and hybridization. In the final step, hybridization was achieved in the ELISA-based system. In our study, 12 (6.5%) out of 184 carbapenem-resistant Pseudomonas spp. strains were positive for OXA-23, 1 (0.54%) for OXA-40 and 1 (0.54%) for OXA-58, with a total positive rate of 7.6% (n= 14). Most of the carbapenem-resistant Pseudomonas spp. strains (129/184; 70%) were isolated from the samples of patients in intensive care units, and bronchoalveolar lavage specimens were the most prevalent samples (85/184; 46.2%). This study determined the presence and frequency of OXA type carbapenemases among Pseudomonas strains for the first time in our region and Turkey. These resistance genes demonstrated in Acinetobacter spp. were also detected in this study in Pseudomonas spp. and they may cause carbapenem resistance directly or by affecting the other resistance mechanisms with a synergistic effect. This study is expected to provide a basis for further studies to elucidate resistance mechanisms. PMID- 25706729 TI - [Investigation of the presence of class 1, 2, 3 integrons and their relationships with antibiotic resistance in clinical Stenotrophomonas maltophilia isolates]. AB - Stenotrophomonas maltophilia is an opportunistic emergent pathogen causing hospital-acquired infections. It is resistant to majority of the broad spectrum antibiotics due to several mechanisms which significantly limit the treatment options. Although the relationship between integrons, mobile genetic elements which play role in transferring resistance genes, and the antibiotic resistance in different gram-negative bacteria have been investigated, the data are limited in Turkey especially for S.maltophilia. The aims of this study were to detect the presence of different classes of integrons and plasmids in clinical isolates of S.maltophilia and to investigate the antibiotic resistance profiles of those isolates. One hundred S.maltophilia strains isolated from various clinical samples (32 sputum, 25 tracheal aspirates, 9 urine and blood, 7 exudates and catheters, 4 sterile body fluids and wounds, 2 CSF, 1 conjunctiva) in our microbiology laboratory during January 2011-September 2012, were included in the study. The isolates were identified by VITEK2 Compact (BioMerieux, France) or Phoenix 100 (BD, USA) automatized systems, and the susceptibilities of the strains to levofloxacin, chloramphenicol, ceftazidime and trimethoprim/sulfamethoxazol (SXT) were evaluated via broth microdilution method according to the CLSI recommendations. Class 1 (intI-1), class 2 (intI-2), class 3 (intI-3) integron gene cassettes and integron 5'-3' conserved gene regions (intI-5'-3'CS) were investigated by polymerase chain reaction (PCR) using specific primers in all of the strains. Nucleotide sequence analysis of PCR products was performed in case of positive result, and the presence and size of plasmids were further investigated. The susceptibility rates of S.maltophilia strains to ceftazidime, chloramphenicol, SXT and levofloxacin were found as 24%, 66%, 93% and 95%, respectively, while MIC(50) and MIC(90) values were 64-128 ug/ml, 8-16 ug/ml, 1/19-2/38 ug/ml and 1-2 ug/ml, respectively. In PCR amplification with intI-1, intI-2 and intI-3 primers, 12%, 2% and 10% of the isolates yielded expectative bands, respectively. DNA sequence analysis of the amplified products revealed five isolates to harbour intI-1 gene, while intI class 2 and class 3 genes were not detected in any of the strains. Furthermore in PCR amplification with intI-5'CS and 3'CS primers, 20% of the strains yielded expected bands. Sequence analysis of these amplicons revealed the presence of quaternary ammonium compound resistance protein genes (qacL) in two, aminoglycoside adenyltransferase gene (aadA) in one and integron-associated recombination site (attI1) genes in five strains. Additionally, the presence of plasmids have been detected in 9 (9%) of the strains, however all of them was integron-negative. The sizes of plasmids were 2340, 1350, 2760, 18600, 20000, 3570-2540, 2510 and 5000-2540 base pairs, respectively. When the antibiotic susceptibility patterns of strains were compared with the presence of intI gene regions, no statistically significant relationship was observed (p> 0.05). In conclusion, the demonstration of integron class 1 genes and plasmids among clinical S.maltophilia strains is regarded as a warning data to indicate the potential for spread of those resistant strains in our hospital. PMID- 25706730 TI - [Evaluation of second-line antituberculosis drug susceptibilities of multidrug resistant Mycobacterium tuberculosis complex isolates by E-test method]. AB - Multidrug-resistant (MDR) tuberculosis (TB) constitutes a restricting factor for the effective treatment of TB worldwide. Early diagnosis and appropriate treatment of patients are the most effective strategy in the control of MDR-TB. Therefore, knowledge of drug resistance patterns of the MDR-TB clinical isolates are necessary in planning of an appropriate treatment regimen for the patient. The aims of this study were to detect the susceptibilities of MDR-TB isolates to second-line anti-TB drugs by E-test method, and to compare their results with Lowenstein-Jensen (LJ) proportion method. A total of 122 MDR (resistant to isoniazid and rifampicin) Mycobacterium tuberculosis complex (MTC) strains isolated from samples of patients with pulmonary TB were included in the study. The isolates were identified by conventional methods and first-line anti-TB drug susceptibility testing was performed by the proportion method using LJ medium. The susceptibilities of the isolates to second-line anti-TB drugs [kanamycin (KN), ofloxacin (OFL), ethionamid (ETN), linezolid (LIN)] were tested by proportion method on LJ medium and E-test method on Middlebrook 7H11 medium. For this purpose, E-test strips (bioMerieux, Fransa) of KN (0.016-256 mg/ml), OFL (0.02-32 mg/ml), ETN (0.016-256 mg/ml), and LIN (0.016-256 mg/ml) were used. The susceptibility tests were evaluated in 5., 7., and 10. days after application of the E-test strips, and proportion method on LJ medium was evaluated 28 days later. Second line-anti-TB drug susceptibility results were obtained in 5 to 10 days by E-test. Of the MDR MTC strains 98% (119/122) were susceptible to KN, OFL and LIN, while 2% (3/122) of the strains were resistant to KN and ETN. The correlation between E-test and LJ proportion method was estimated as 96% for KN and ETN, 98% for OFL, and 100% for LIN. When compared with LJ proportion method, the specificity of E-test in the detection of susceptibility to KN, OFL, ETN and LIN were 60%, 38%, 60%, and 100%, respectively, while the sensitivity was 100% for all drugs. Our results indicated that E-test method exhibited high sensitivity and specificity (100%) for LIN, so it may be used alone in susceptibility testing for this drug, however since the specificity is low (38%) for OFL it should be used together with the proportion method. In conclusion, E test method might contribute for initiation of an early and effective anti-TB drug treatment and control of infection by rapid diagnosis in MDR-TB cases. PMID- 25706731 TI - [Development of a real-time polymerase chain reaction method for the identification of Candida species]. AB - Candida species are one of the major causes of nosocomial infections and are the fourth most common agent involved in bloodstream infections. The impact of non albicans Candida species is increasing, however C.albicans is still the most common species. Since the antifungal susceptibility pattern among Candida spp. may be different, rapid diagnosis and identification of non-albicans Candida spp. are important for the determination of antifungal agents that will be used for treatment. The aim of the study was to describe a real-time polymerase chain reaction (Rt-PCR) assay that rapidly detects, identifies and quantitates Candida species from blood culture samples. A total of 50 consecutive positive blood culture bottles (BACTEC, Beckton Dickinson, USA) identified at our laboratory between June-November 2013, were included in the study. Reference strains of Candida spp. (C.albicans ATCC 10231, C.glabrata ATCC 90030, C.tropicalis ATCC 1021, C.krusei ATCC 6258, C.parapsilosis ATCC 22019 and C. dubliniensis CD36) grown on Sabouraud dextrose agar were used for quality control. BACTEC bottles that were positive for Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus were also studied to search the cross-reactivity. A commercial kit (Zymo Research, USA) was used for DNA extraction. Real-time PCR was performed on LightCycler 480 (Roche, Germany) with primers and probes specific for 18S rRNA of Candida species. Twenty microlitres of the reaction mix contained 2 MUl of extracted DNA, 2 MUl of LightCycler Fast Start DNA Master Probe (Roche Diagnostics, Germany), 2 MUl of MgCl(2) (5 mmol), 2 MUl of 10x PCR buffer (Roche Diagnostics, Germany), 0.5 MUl of each primer (0.01 nmol/MUl) and 1 MUl of each probe (0.1 MUmol/MUl) (TibMolBiol, Germany). Amplification was performed using the following conditions; 95 degrees C for 10 mins and 50 cycles of denaturation at 95 degrees C for 10 secs, annealing at 62 degrees C for 10 secs and polymerisation at 72 degrees C for 20 secs. A melting curve was created by cooling the producs at 50 degrees C for 30 secs and then heating to 80 degrees C at a rate of 0.1 degrees C/sec measuring of the fluorescence simultaneously. For the quantitation of fungal DNA according to the standard curve, serial dilutions of C.albicans ATCC 10231 DNA from 3 x 10(5) to 3 x 10(2) ng/MUl were used. All of the strains were also identified by conventional methods and sequence analysis in order to compare the results obtained by Rt-PCR. In our study, all patient and standard samples could be amplified, identified and quantitated by this developed Rt-PCR method. A total of 50 strains, of them 26 were C.parapsilosis, 15 were C.glabrata, 6 were C.albicans, and 3 were C.tropicalis have been detected and identified among patient samples. The results were completely concordant with the sequencing and conventional methods, so the sensitivity and specificity of this method were estimated as 100 percent. In conclusion, it was novel Rt-PCR developed and evaluated in this study is considered as a rapid, accurate, reproducible, sensitive and specific method for the detection, identification and quantitation of commonly observed Candida spp. strains. PMID- 25706732 TI - [Demonstration of beta-1,2 mannan structures expressed on the cell wall of Candida albicans yeast form but not on the hyphal form by using monoclonal antibodies]. AB - Candida albicans is a polymorphic fungus that may be observed as both commensal and opportunistic pathogen in humans. As one of the major components of Candida cell wall structure, mannan plays an important role in the fungus-host cell interaction and in virulence. The ability to switch from yeast to hypha form of microorganism is crutial in the development of C.albicans infections. Hyphal form has different antigenic properties compared to yeast form and structural changes occur in the yeast cell wall during transition from yeast to hypha form. Although there are several factors associated with this transition process, sufficient information is not available. The aim of this study was to investigate the change of configuration in mannan structure found in C.albicans cell wall by using monoclonal antibodies. C.albicans (NIHA 207) serotype A strains were used as test strains throughout the study, together with Salmonella choleraesuis 211 and Salmonella infantis as controls with similar cell wall structures to that of C.albicans. Cultures were maintained on YPD-agar medium by incubating at 28 degrees C for yeast forms, and on YPD-broth medium in a shaking incubator at 37 degrees C for 3-4 hours for the growth of hyphal forms. Cells were harvested in the exponential phase, and after being washed, the mannan content from C.albicans were extracted from pellet by heating in 20 mM sodium citrate buffer for 90 minutes at 125 degrees C. Hybridoma technique was used for the production of monoclonal antibodies. After immunizing the Balb/C mice with antigen, the splenocytes were harvested and fusion was performed between spleen cells and F0 myeloma cells. The clones grown in HAT medium were screened for the presence of antibody producing hybrid cells by ELISA method. The antibody isotypes were determined by using a commercial kit (Pierce Biotechnology, ABD). The culture supernatants which contained monoclonal antibodies were collected and purified according to the ammonium sulphate method. Sandwich ELISA and immunofluorescence (IF) methods have been used to detect the experimental reactions. In our study, highly specific class IgM murine monoclonal antibodies (mAb-2B7) against C.albicans yeast cell wall were obtained from clone 2B7. These antibodies cross reacted with S.choleraesuis 211 and S.infantis bacteria sharing similar cell wall structure of C.albicans. The existence of mannan beta-1,2 bonds on the surface of C.albicans yeast form was confirmed with a commercial monoclonal antibody (mAb ACMK-1; Matriks Biotek((r)), Turkey) specific for those bonds. Besides, mAb-ACMK 1 interacted with C.albicans yeast form and gave intense fluorescence (high positive reaction) in IF method, but no fluorescence (negative) was detected with hyphal form. This data, obtained for the first time with this study, indicates that the mannan beta-1,2 bonds are either found infrequently or none in the fungal hyphal wall. Although both monoclonal antibodies recognize the mannan antigen, mAb-2B7 reacted with S.choleraesuis 211, while mAb-ACMK-1 did not, due to the difference of epitope specificity. In conclusion, monoclonal antibodies may facilitate the characterization of antigenic structures of Candida, which will lead for the identification of new determinants that may increase the sensitivity and specificity of commercial tests used for mannan detection in serum. PMID- 25706733 TI - [Comparison of direct microscopy, culture and polymerase chain reaction methods for the diagnosis of cutaneous leishmaniasis]. AB - Cutaneous leishmaniasis (CL) is an endemic disease especially in Southeastern Anatolia of Turkey and recently shows a trend for spread to other regions of the country including the Aegean region. The diagnosis of CL is based on combined evaluation of epidemiological data with the clinical symptoms and laboratory findings. Direct microscopic examination and culture methods are mainly used in the routine diagnosis of CL, while molecular methods are mainly used for research. The aim of this study was to detect the presence of Leishmania spp. in samples obtained from CL-suspected patients by using direct microscopy, culture and polymerase chain reaction (PCR) methods and to compare the results. A total of 55 patients who were admitted to Parasitology Laboratory of Adnan Menderes University Hospital, Aydin (located at Aegean region in Turkey), between 2012 2014 were included in the study. Smear preparations from the skin lesions of cases were fixed and stained with Giemsa, and the presence of amastigote forms were evaluated by direct microscopy. NNN medium was used for the cultivation of samples. Total genomic DNA of Leishmania from the samples were extracted with a commercial kit (NucleoSpin Tissue((r)) Kit, Macherey-Nagel, Germany) and PCR was performed by using 13A and 13B primers to amplify the 116 base pair fragment of Leishmania spp. specific kinetoplast DNA. Amastigotes were observed in 29 (53%) of the 55 samples by direct microscopy, promastigotes were detected among 34 (62%) samples in culture, and parasite-specific amplicons were revealed in 30 (55%) samples by PCR. All assays were positive in 24 patients while in 18 patients all of the tests yielded negative results. Thirty-seven (67%) out of 55 cases were diagnosed as CL when reactivity in at least one of these three methods were considered as positive. Accordingly the positivity rates of the methods were 78.4% (29/37) for direct microscopy, 92% (34/37) for culture and 81.1% (30/37) for PCR in CL-diagnosed patients, indicating culture as the most sensitive method. Regarding the culture method as gold standard, the sensitivity and specificity of direct microscopy were calculated as 76.4% and 86%, respectively, while PCR presented with 85.3% sensitivity and 95% specificity. In conclusion, it was thought that the usage of more than one method for CL diagnosis leads to increase the sensitivity and specificity which enables the diagnosis of a wide range of patients. PMID- 25706734 TI - [Investigation of the presence of Blastocystis spp. in stool samples with microscopic, culture and molecular methods]. AB - Blastocystis species are enteric protozoa frequently detected in human and animals. Seventeen subtypes (STs) have now been identified, nine of them isolating from humans. The pleomorphic structure and genetic diversity of Blastocystis spp. and the absence of standardized diagnostic methods complicate the evaluation of current data. Microscopic methods such as native-lugol and trichrome staining are most frequently used methods in routine diagnosis, while culture and molecular methods are preferred for research purposes. The aims of this study were to investigate the presence of Blastocystis spp. in the stool samples of patients with gastrointestinal complaints by microscopic and culture methods, and to detect the subtypes of isolates by polymerase chain reaction (PCR). A total of 350 stool samples collected from patients with diarrhea (n= 157) and without diarrhea (n= 193) were included in the study. Presence of Blastocystis spp. in the samples were investigated by native-lugol examination, trichrome staining and direct fluorescent antibody (DFA) methods. Ringer's solution containing 10% horse serum and 0.05% asparagine was used for cultivation. The cultures were evaluated after 3-4 days of incubation at 37 degrees C by microscopic examination. The subtypes of Blastocystis spp. strains isolated from the cultures have been identified by PCR using sequence-tagged site primers. A total of 66 (19%) stool samples, of them 26 (16.6%) were from diarrheal and 40 (21%) from non-diarrheal cases, yielded Blastocystis sp. growth in culture. Among the evaluated samples, 12% (42/350) were found positive with native-lugol examination, 17% (58/350) with trichrome staining, and 19% (66/350) with DFA method. The agreement of culture and native-lugol method was estimated as strong (kappa= 0.752), while it was very strong between culture with trichrome staining and DFA methods (kappa= 0.922 and kappa= 1.00, respectively). When the culture was accepted as reference method, the sensitivity and specificity rates of native-lugol method were 65% and 100%, trichrome staining method were 88% and 100%, and DFA method were 100% and 100%, respectively. Forty-three (65%) of Blastocystis spp. positive samples were subtyped by PCR, while 23 isolates could not be subtyped. The most frequent detected subtype was ST3 (12/43; 28%), followed by ST1 (6/43; 13.9%), ST4 (5/43; 11.6%) and ST7 (5/43; 11.6%), ST2 (3/43; 7%) and ST6 (1/43; 2.3%). ST5 was not detected in this study and 11 (25.6%) samples have been identified to have mixed subtypes. The differences of Blastocystis spp. positivity rates and the distribution of the subtypes between the patients with or without diarrhea were not found statistically significant (p> 0.05). In our study, ST3 was the most frequently identified Blastocystis spp. subtype, similar to the previous national studies, however ST6 and ST7 have been identified for the first time. In conclusion, as the sensitivity of native-lugol examination is low, culture is time-consuming and laborious and PCR methods are costly and non-standardized, rapid, practical and high sensitive DFA is considered as the favourable method in the diagnosis of Blastocystis spp. in routine laboratories. PMID- 25706735 TI - [Subtype distribution of Blastocystis isolates and evaluation of clinical symptoms detected in Aydin province, Turkey]. AB - The pathogenic potential and genetic diversity of Blastocystis are poorly understood despite being one of the most frequent intestinal parasites in routine fecal examination all around the world as well as Turkey. There are numerous defined subtypes (ST) of Blastocystis which infect animals and nine of them were isolated from human fecal samples. Blastocystis is an anaerobic parasite and generally recognized as nonpathogenic microorganism that colonizes the colon. However recent studies have indicated that the genotypes may be related with the pathogenicity and clinical symptoms of the infection. The aims of this study were to investigate the subtypes of Blastocystis isolates obtained from stool samples submitted to the parasitology laboratory of Adnan Menderes University, Faculty of Medicine, and to evaluate the clinical symptoms of infected cases. A total of 61 cases (40 male, 21 female; age range: 5-69 years, mean age: 35 +/- 19.1 years) were included in the study. Stool samples that were positive for Blastocystis cysts in direct microscopic examination, were inoculated in Jones medium and incubated at 37 degrees C for 72 hours for the growth of parasite. Genomic DNAs were isolated from Jones medium directly or frozen samples with a commercial kit (DNAzol, Invitrogen, USA). The subtypes of Blastocystis were detected by polymerase chain reaction (PCR) using ST-specific primers and the symptoms of patients were evaluated retrospectively. Forty-four (72.1%) out of 61 isolates were subtyped by PCR, while 17 (27.9%) could not be typed. The distribution of Blastocystis subtypes were found as follows; ST3 in 17 (38.6%), ST2 in 13 (29.5%), ST1 in 9 (20.5%), ST1 + ST3 in 4 (9.1%), and ST1 + ST2 in one (2.3%) of the samples. The most common symptoms among Blastocystis infected cases were abdominal pain (n= 24, 39.4%), pruritus (n= 22, 36.1%), diarrhea (n= 4, 6.6%) and constipation (n= 2, 3.3%), respectively. This is the first study investigating the genotypes of Blastocystis in Aydin province (located at Aegean region of Turkey), and the findings were consistent with those reported from other regions. The predominant subtype was found as ST3, like other studies in our country and this data supports that ST3 is a human originated genotype of Blastocystis. Additionally, the higher rate of pruritus detected among our patients infected with Blastocystis compared with the other studies was considered remarkable. In conclusion, multicenter and large-scaled molecular and clinical studies are needed to elucidate the pathogenicity and the epidemiology of Blastocystis infections. PMID- 25706736 TI - [Prevalence of Encephalitozoon intestinalis and Enterocytozoon bieneusi in cancer patients under chemotherapy]. AB - Microsporidia species are obligate intracellular parasites and constitute one of the most important opportunistic pathogens that can cause severe infections especially in immunocompromised patients. Enterocytozoon bieneusi and Encephalitozoon intestinalis are the most common species among 14 microsporidia species identified as human pathogens. The aim of this study was to investigate the prevalence of E.intestinalis and E.bieneusi in cancer patients under chemotherapy by immunofluorescent antibody and conventional staining methods. A total of 123 stool samples obtained from 93 patients (58 male, 35 female) with cancer who were followed in oncology and hematology clinics of our hospital and 30 healthy volunteers (13 male, 17 female) were included in the study. Fifty-one (55%) of the patients had complain of diarrhea. The presence of E.intestinalis and E.bieneusi were investigated by a commercial immunofluorescence antibody test using monoclonal antibodies (IFA-MAbs; Bordier Affinity Products, Switzerland) in all of the samples, and 50 of the samples were also investigated by modified trichrome, acid-fast trichrome and calcofluor staining methods. A total of 65 (69.9%) patients were found positive with IFA-MAbs method, including 43 (46.2%) E.intestinalis, 9 (9.7%) E.bieneusi and 13 (14%) mixed infections. In the control group, 5 (16.7%) subjects were positive with IFA-MAbs method, including 2 (6.7%) E.intestinalis, 1 (3.3%) E.bieneusi and 2 (6.7%) mixed infections. The difference between the positivity rate of the patient and control groups was statistically significant (p< 0.05). Of the patients with diarrhea, 68.6% (35/51) were infected with microsporidia, and the difference between cases with and without (48.6%) diarrhea was statistically significant (p< 0.05). When 50 samples in which all of the methods could be performed were evaluated, the frequency of microsporidia were detected as follows; 66% (n= 33) with IFA-MAbs, 34% (n= 17) with modified trichrome staining, 24% (n= 12) with acid-fast trichrome staining and 42% (n= 21) with calcofluor staining methods. Our data indicated that the use of IFA-MAbs method along with the conventional staining methods in diagnosis of microsporidia will increase the sensitivity. As a conclusion, the prevalence of E.intestinalis and E.bieneusi in cancer patients under chemotherapy was detected quite high (69.9%) in our study, it would be appropriate to screen these patients regularly in terms of microsporidian pathogens. PMID- 25706737 TI - [Detection of the first QnrS gene positivity in aquatic Aeromonas spp. isolates in Turkey]. AB - Aeromonas spp. are oxidase positive, gram-negative, facultative anaerobic bacilli that are widely distributed in aquatic environments. A.hydrophila, A.sobria and A.bestiarum may cause severe infections in both human and cold-blooded animals. Environmental persistance of quinolones that are widely used in both human and veterinary medicine plays an important role in the selection of resistant mutants. Plasmid-mediated resistance is one of the main mechanisms involved in quinolone resistance, and qnr, qepA, aac(6')-Ib-cr, oqxAB genes are identified as resistance determinants. Determination of various types of qnr gene in different bacteria mainly in Enterobacteriaceae, suggests that they are widely distributed in nature. Recently, plasmid-mediated quinolone resistance was defined among Aeromonas species isolated from water. The aim of this study was to investigate the presence of qnr genes among aquatic Aeromonas spp. in Turkey. A total of 45 Aeromonas strains isolated from water and fishes collected from three different geographical regions (Aegean, Mediterranean and Blacksea) in Turkey, were included in the study. The isolates were identified at species level by the use of 16S rDNA-RFLP (Restriction fragment length polymorphism) analysis and multiplex polymerase chain reaction (M-PCR). Among the isolates, 20 were identified as A.sobria, 10 as A.hydrophila, nine as A.salmonicida, four as A.bestiarum and two as A.veronii. The plasmid-mediated quinolone resistance determinants, qnrA, qnrB, qnrC and qnrS genes, were investigated by M-PCR, and sequence analysis was performed for nine qnr-positive isolates. According to the sequence analysis of the genes, qnr genes were characterized in six A.sobria, in two A.bestiarum and in one A.hydrophila isolate (9/45; 20%). When the sequence was compared with GenBank database, this gene was found as qnrS2. All qnrS positive Aeromonas spp. isolates were ciprofloxacin-susceptible, while five of them were resistant to nalidixic acid. This study is the first research about the plasmid-mediated quinolone resistance and the presence of qnrS2 genes among Aeromonas spp. isolated from fishes and water in Turkey. In conclusion, various resistance genes of aquatic bacteria may constitute a potential risk for the transmission of those genes to other bacteria as well as clinical isolates. PMID- 25706738 TI - [Investigation of pathogenic Escherichia coli strains in patients with diarrhea]. AB - The role of certain serogroups and serotypes of Escherichia coli in the etiology of gastroenteritis is increasingly appreciated. It is important to detect the virulence factors of diarrheagenic E.coli strains that differentiate them from nonpathogenic members of normal intestinal flora for the diagnosis and treatment. The aims of this study were to determine the serotypes of E.coli isolates that cause gastroenteritis and to investigate the presence of virulence genes by polymerase chain reaction (PCR). A total of 202 watery, bloody or mucoid stool samples sent to microbiology laboratory collected from patients with diarrhea who were admitted to outpatient clinics of Trakya University Health Research and Application Hospital between February to October 2009, were included in the study. A total of 254 predominantly grown E.coli strains have been isolated and identified with conventional methods from the cultures of those 202 samples. All strains were tested by slide agglutination (SA) that includes 6 units of O serogroups polyvalent antisera of enteropathogenic E.coli (EPEC), enterotoxigenic E.coli (ETEC) and enteroinvasive E.coli (EIEC). The samples which yielded positive results with SA test and the same number of negative samples selected with mapping method as controls were studied for the presence of virulence genes belonging EPEC, ETEC and EIEC by conventional PCR. In the study, 14.3% (29/202) of the samples were serogrouped with SA, of them 13 (6.4%) were identified as EPEC, 11 (5.4%) as EIEC and five (2.4%) as ETEC. Only five isolates belonging to EPEC serogroup could be defined by monovalent antiserum and they were all in O1 serogroup. Out of 29 pathogenic E.coli serotyped, 3 (10.3%) of them harbored the virulence genes of diarrheagenic strains. One sample which was positive for eaeA gene of EPEC, did not harbor bfpA and stx genes and was defined as atypical EPEC. Out of other two samples, one was positive for estA gene of ETEC and the other one for ial gene of EIEC. One strain serotyped as EPEC detected to carry estA gene of ETEC with PCR. All of the 29 control isolates that give negative results with polyvalent antisera were also negative for the presence of virulence genes. In conclusion, since serotyping and conventional PCR methods did not reveal similar results for the identification of pathogenic E.coli, multicenter and large-scaled studies performed with standardized methods are needed. PMID- 25706739 TI - [The first case of persistent vaginitis due to Aspergillus protuberus in an immunocompetent patient]. AB - The vast majority of vaginal fungal infections are caused by Candida species. However, vaginitis cases caused by molds are extremely rare. Aspergillus protuberus is previously known as a member of Aspergillus section Versicolores which can cause opportunistic infections in immunocompromised patients, however it has recently been described as a seperate species. Although the members of Aspergillus section Versicolores have been isolated rarely in cases of pulmonary infections, eye infections, otomycosis, osteomyelitis and onycomycoses, to the best of our knowledge, there is no published case of human infection caused by A.protuberus. In this report, the first case of persistent vaginitis due to A.protuberus in an immunocompetent patient was presented. A 42-year-old female patient was admitted to our hospital with the complaints of pelvic pain, vaginal itching and discharge during one month. Her symptoms had been persistant despite of the miconazole nitrate and clotrimazole therapies for probable candidal vaginitis. Fungal structures such as branched, septate hyphae together with the conidial forms were seen in microscopic examination as in the cervical smear. Thereafter, a vaginal discharge sample was taken for microbiological evaluation and similar characteristics of fungal structures were observed in the microscopic examination as of cervical smear. Then, preliminary result was reported as Aspergillus spp. At the same time, the sample was plated on Sabouraud dextrose agar (SDA) in duplicate and incubated at room temperature and at 37 degrees C. After 5 days, white, powdery and pure-looking fungal colonies were observed in SDA which was incubated at room temperature, while the other medium remained sterile. The culture was submitted to the CBS-KNAW Fungal Biodiversity Center for further characterization. Phenotypic identification showed that the isolated strain belonged to the Aspergillus section Versicolores. The strain was grown for 7 days on malt extract agar and then ITS regions were amplified and sequenced from isolated DNA for genomic characterization. The obtained sequences were compared with the NCBI database and internal databases of the CBS-KNAW Fungal Biodiversity Centre and confirmed as Aspergillus section Versicolores. As a result of recent changes in classification of fungi, analysis of partial beta tubulin and calmodulin sequences have also been used to obtain a detailed and precise characterization. Eventually, the strain has been identified as A.protuberus which is a recently accepted species distinct from Aspergillus section Versicolores. As the patient could not be contacted after the preliminary report, detailed demographical information, probable origin and route of transmission of the agent and prognosis of infection remained obscure. In conclusion, the first case of vaginitis caused by A.protuberus was described in this report with the support of clinical, pathological, microbiological and molecular data. PMID- 25706740 TI - [A rare case of Hymenolepis diminuta infection in a small child]. AB - Unlike Hymenolepis nana that transmits directly from person to person, the transmission of Hymenolepis diminuta to human is via accidentally ingesting of arthropods carrying cysticercoid larvae as intermediate host. In places with poor hygienic conditions, this cestod may cause seldom infections especially in children. Studies carried out on various populations have reported the prevalence rate of H.diminuta between 0.001% and 5.5%. Although the reported cases are mostly children, the disease can be seen in every age group. In this report, a pediatric case of H.diminuta infection is presented. A twenty one-month-old male patient with the symptoms of vomiting 3-4 times a day along with mud-like diarrhea continuing for a week was admitted to the pediatric outpatient clinic. According to the history, it was learned that the house where he lived was above a barn and there was a history of insect swallowing. Laboratory findings revealed iron-deficiency anemia. The macroscopic appearance of the stool was in a pale clay-like form, and by direct microscopic examination with lugol solution, 70-75 MUm in diameter, thick-shelled and six central hookleted eggs that are characteristic for H.diminuta were identified. A six-day course of oral niclosamide was administered to the patient beginning with 500 mg on the first day and 250 mg on the following five days, together with the treatment for the iron deficiency anemia. After fifteen days, the oral niclosamide treatment was repeated. No H.diminuta eggs were detected in the parasitological examination performed one month after completion of the second round of treatment. This case has been presented to call attention to the importance of patient anamnesis and microscopic examination in the diagnosis of H.diminuta infection which is a rarely seen parasitosis. PMID- 25706741 TI - [Seasonal and regional distribution of tularemia cases in Amasya, Turkey]. AB - Tularemia have attracted attention due to increased number of cases since 2009 in Amasya region which is located at Central Blacksea Region of Turkey. The aims of this letter were to provide information about the disease, to emphasize the importance of early treatment due to the outbreak peak in our province between 2009-2012 and water chlorination in epidemic areas. A total of 250 tularemia suspected patients (117 female, 133 male; mean age: 42 yrs) who were admitted to our hospital with the symptoms of sore throat, fever, malaise and/or presence of neck mass, from 20 different locations within last four years were included in the study. Serum samples of 73 (29.2%) patients yielded >= 1/160 titers with F.tularensis microagglutination test which were considered as positive. All positive cases presented with the oropharyngeal form of the disease. The year with the highest number of tularemia cases was 2010. When the regional distribution was evaluated, it was detected that positive cases have precipitated especially in the southeastern (highland area) and northeastern (lowland area) parts of Amasya (34/73; 46.6%). Majority of the tularemia cases (53/73; 72.6%) were identified in colder seasons. The number of cases in rural and urban centers have decreased after 2010. In conclusion, it is considered that the emergence of new cases is likely to persist due to the geographical characteristics of Amasya and occupational properties (livestock breeding) of the population. Therefore, the clinicians should consider tularemia in differential diagnosis of the cases originated from risky rural areas. PMID- 25706742 TI - How structural and physicochemical determinants shape sequence constraints in a functional enzyme. AB - The need for interfacing structural biology and biophysics to molecular evolution is being increasingly recognized. One part of the big problem is to understand how physics and chemistry shape the sequence space available to functional proteins, while satisfying the needs of biology. Here we present a quantitative, structure-based analysis of a high-resolution map describing the tolerance to all substitutions in all positions of a functional enzyme, namely a TEM lactamase previously studied through deep sequencing of mutants growing in competition experiments with selection against ampicillin. Substitutions are rarely observed within 7 A of the active site, a stringency that is relaxed slowly and extends up to 15-20 A, with buried residues being especially sensitive. Substitution patterns in over one third of the residues can be quantitatively modeled by monotonic dependencies on amino acid descriptors and predictions of changes in folding stability. Amino acid volume and steric hindrance shape constraints on the protein core; hydrophobicity and solubility shape constraints on hydrophobic clusters underneath the surface, and on salt bridges and polar networks at the protein surface together with charge and hydrogen bonding capacity. Amino acid solubility, flexibility and conformational descriptors also provide additional constraints at many locations. These findings provide fundamental insights into the chemistry underlying protein evolution and design, by quantitating links between sequence and different protein traits, illuminating subtle and unexpected sequence-trait relationships and pinpointing what traits are sacrificed upon gain of-function mutation. PMID- 25706743 TI - Acknowledging individual responsibility while emphasizing social determinants in narratives to promote obesity-reducing public policy: a randomized experiment. AB - This study tests whether policy narratives designed to increase support for obesity-reducing public policies should explicitly acknowledge individual responsibility while emphasizing social, physical, and economic (social) determinants of obesity. We use a web-based, randomized experiment with a nationally representative sample of American adults (n = 718) to test hypotheses derived from theory and research on narrative persuasion. Respondents exposed to narratives that acknowledged individual responsibility while emphasizing obesity's social determinants were less likely to engage in counterargument and felt more empathy for the story's main character than those exposed to a message that did not acknowledge individual responsibility. Counterarguing and affective empathy fully mediated the relationship between message condition and support for policies to reduce rates of obesity. Failure to acknowledge individual responsibility in narratives emphasizing social determinants of obesity may undermine the persuasiveness of policy narratives. Omitting information about individual responsibility, a strongly-held American value, invites the public to engage in counterargument about the narratives and reduces feelings of empathy for a character that experiences the challenges and benefits of social determinants of obesity. PMID- 25706744 TI - Self-organized criticality, plasticity and sensorimotor coupling. Explorations with a neurorobotic model in a behavioural preference task. AB - During the last two decades, analysis of 1/f noise in cognitive science has led to a considerable progress in the way we understand the organization of our mental life. However, there is still a lack of specific models providing explanations of how 1/f noise is generated in coupled brain-body-environment systems, since existing models and experiments typically target either externally observable behaviour or isolated neuronal systems but do not address the interplay between neuronal mechanisms and sensorimotor dynamics. We present a conceptual model of a minimal neurorobotic agent solving a behavioural task that makes it possible to relate mechanistic (neurodynamic) and behavioural levels of description. The model consists of a simulated robot controlled by a network of Kuramoto oscillators with homeostatic plasticity and the ability to develop behavioural preferences mediated by sensorimotor patterns. With only three oscillators, this simple model displays self-organized criticality in the form of robust 1/f noise and a wide multifractal spectrum. We show that the emergence of self-organized criticality and 1/f noise in our model is the result of three simultaneous conditions: a) non-linear interaction dynamics capable of generating stable collective patterns, b) internal plastic mechanisms modulating the sensorimotor flows, and c) strong sensorimotor coupling with the environment that induces transient metastable neurodynamic regimes. We carry out a number of experiments to show that both synaptic plasticity and strong sensorimotor coupling play a necessary role, as constituents of self-organized criticality, in the generation of 1/f noise. The experiments also shown to be useful to test the robustness of 1/f scaling comparing the results of different techniques. We finally discuss the role of conceptual models as mediators between nomothetic and mechanistic models and how they can inform future experimental research where self-organized critically includes sensorimotor coupling among the essential interaction-dominant process giving rise to 1/f noise. PMID- 25706745 TI - RNA-seq analysis of the response of the halophyte, Mesembryanthemum crystallinum (ice plant) to high salinity. AB - Understanding the molecular mechanisms that convey salt tolerance in plants is a crucial issue for increasing crop yield. The ice plant (Mesembryanthemum crystallinum) is a halophyte that is capable of growing under high salt conditions. For example, the roots of ice plant seedlings continue to grow in 140 mM NaCl, a salt concentration that completely inhibits Arabidopsis thaliana root growth. Identifying the molecular mechanisms responsible for this high level of salt tolerance in a halophyte has the potential of revealing tolerance mechanisms that have been evolutionarily successful. In the present study, deep sequencing (RNAseq) was used to examine gene expression in ice plant roots treated with various concentrations of NaCl. Sequencing resulted in the identification of 53,516 contigs, 10,818 of which were orthologs of Arabidopsis genes. In addition to the expression analysis, a web-based ice plant database was constructed that allows broad public access to the data. The results obtained from an analysis of the RNAseq data were confirmed by RT-qPCR. Novel patterns of gene expression in response to high salinity within 24 hours were identified in the ice plant when the RNAseq data from the ice plant was compared to gene expression data obtained from Arabidopsis plants exposed to high salt. Although ABA responsive genes and a sodium transporter protein (HKT1), are up-regulated and down-regulated respectively in both Arabidopsis and the ice plant; peroxidase genes exhibit opposite responses. The results of this study provide an important first step towards analyzing environmental tolerance mechanisms in a non-model organism and provide a useful dataset for predicting novel gene functions. PMID- 25706746 TI - The RNA-binding protein HuR is essential for the B cell antibody response. AB - Post-transcriptional regulation of mRNA by the RNA-binding protein HuR (encoded by Elavl1) is required in B cells for the germinal center reaction and for the production of class-switched antibodies in response to thymus-independent antigens. Transcriptome-wide examination of RNA isoforms and their abundance and translation in HuR-deficient B cells, together with direct measurements of HuR RNA interactions, revealed that HuR-dependent splicing of mRNA affected hundreds of transcripts, including that encoding dihydrolipoamide S-succinyltransferase (Dlst), a subunit of the 2-oxoglutarate dehydrogenase (alpha-KGDH) complex. In the absence of HuR, defective mitochondrial metabolism resulted in large amounts of reactive oxygen species and B cell death. Our study shows how post transcriptional processes control the balance of energy metabolism required for the proliferation and differentiation of B cells. PMID- 25706747 TI - Proinflammatory microenvironments within the intestine regulate the differentiation of tissue-resident CD8+ T cells responding to infection. AB - We report that oral infection with Yersinia pseudotuberculosis results in the development of two distinct populations of pathogen-specific CD8(+) tissue resident memory T cells (TRM cells) in the lamina propria. CD103(-) T cells did not require transforming growth factor-beta (TGF-beta) signaling but were true resident memory cells. Unlike CD103(+)CD8(+) T cells, which were TGF-beta dependent and were scattered in the tissue, CD103(-)CD8(+) T cells clustered with CD4(+) T cells and CX3CR1(+) macrophages and/or dendritic cells around areas of bacterial infection. CXCR3-dependent recruitment of cells to inflamed areas was critical for development of the CD103(-) population and pathogen clearance. Our studies have identified the 'preferential' development of CD103(-) TRM cells in inflammatory microenvironments within the lamina propria and suggest that this subset has a critical role in controlling infection. PMID- 25706748 TI - Expression and mutational analysis of DinB-like protein DR0053 in Deinococcus radiodurans. AB - In order to understand the mechanism governing radiation resistance in Deinococcus radiodurans, current efforts are aimed at identifying potential candidates from a large repertoire of unique Deinococcal genes and protein families. DR0053 belongs to the DinB/YfiT protein family, which is an over represented protein family in D. radiodurans. We observed that dr0053 transcript levels were highly induced in response to gamma radiation (gamma-radiation) and mitomycin C (MMC) exposure depending on PprI, RecA and the DrtR/S two-component signal transduction system. Protein profiles demonstrated that DR0053 is a highly induced protein in cultures exposed to 10 kGy gamma-radiation. We were able to determine the transcriptional start site of dr0053, which was induced upon irradiation, and to assign the 133-bp promoter region of dr0053 as essential for radiation responsiveness through primer extension and promoter deletion analyses. A dr0053 mutant strain displayed sensitivity to gamma-radiation and MMC exposure, but not hydrogen peroxide, suggesting that DR0053 helps cells recover from DNA damage. Bioinformatic analyses revealed that DR0053 is similar to the Bacillus subtilis protein YjoA, which is a substrate of bacterial protein-tyrosine kinases. Taken together, the DNA damage-inducible (din) gene dr0053 may be regulated at the transcriptional and post-translational levels. PMID- 25706749 TI - The Orinoco megadelta as a conservation target in the face of the ongoing and future sea level rise. AB - Currently, risk assessments related to rising sea levels and the adoption of defensive or adaptive measures to counter these sea level increases are underway for densely populated deltas where economic losses might be important, especially in the developed world. However, many underpopulated deltas harbouring high biological and cultural diversity are also at risk but will most likely continue to be ignored as conservation targets. In this study, we explore the potential effects of erosion, inundation and salinisation on one of the world's comparatively underpopulated megadeltas, the Orinoco Delta. With a 1 m sea level rise expected to occur by 2100, several models predict a moderate erosion of the delta's shorelines, migration or loss of mangroves, general inundation of the delta with an accompanying submersion of wetlands, and an increase in the distance to which sea water intrudes into streams, resulting in harm to the freshwater biota and resources. The Warao people are the indigenous inhabitants of the Orinoco Delta and currently are subject to various socioeconomic stressors. Changes due to sea level rise will occur extremely rapidly and cause abrupt shifts in the Warao's traditional environments and resources, resulting in migrations and abandonment of their ancestral territories. However, evidence indicates that deltaic aggradation/accretion processes at the Orinoco delta due to allochthonous sediment input and vegetation growth could be elevating the surface of the land, keeping pace with the local sea level rise. Other underpopulated and large deltas of the world also may risk immeasurable biodiversity and cultural losses and should not be forgotten as important conservation targets. PMID- 25706750 TI - Atmospherically deposited trace metals from bulk mineral concentrate port operations. AB - Although metal exposures in the environment have declined over the last two decades, certain activities and locations still present a risk of harm to human health. This study examines environmental dust metal and metalloid hazards (arsenic, cadmium, lead and nickel) associated with bulk mineral transport, loading and unloading port operations in public locations and children's playgrounds in the inner city of Townsville, northern Queensland. The mean increase in lead on post-play hand wipes (965 MUg/m(2)/day) across all sites was more than 10-times the mean pre-play loadings (95 MUg/m(2)/day). Maximum loading values after a 10-minute play period were 3012 MUg/m(2), more than seven times the goal of 400 MUg/m(2) used by the Government of Western Australia (2011). Maximum daily nickel post-play hand loadings (404 MUg/m(2)) were more than 26 times above the German Federal Immission Control Act 2002 annual benchmark of 15 MUg/m(2)/day. Repeat sampling over the 5-day study period showed that hands and surfaces were re-contaminated daily from the deposition of metal-rich atmospheric dusts. Lead isotopic composition analysis of dust wipes ((208)Pb/(207)Pb and (206)Pb/(207)Pb) showed that surface dust lead was similar to Mount Isa type ores, which are exported through the Port of Townsville. While dust metal contaminant loadings are lower than other mining and smelting towns in Australia, they exceeded national and international benchmarks for environmental quality. The lessons from this study are clear - even where operations are considered acceptable by managing authorities, targeted assessment and monitoring can be used to evaluate whether current management practices are truly best practice. Reassessment can identify opportunities for improvement and maximum environmental and human health protection. PMID- 25706751 TI - Vitamin D3supplementation in Batswana children and adults with HIV: a pilot double blind randomized controlled trial. AB - OBJECTIVES: Since vitamin D insufficiency is common worldwide in people with HIV, we explored safety and efficacy of high dose cholecalciferol (D3) in Botswana, and evaluated potential modifiers of serum 25 hydroxy vitamin D change (Delta25D). DESIGN: Prospective randomized double-blind 12-week pilot trial of subjects ages 5.0-50.9 years. METHODS: Sixty subjects randomized within five age groups to either 4000 or 7000 IU per day of D3 and evaluated for vitamin D, parathyroid hormone, HIV, safety and growth status. Efficacy was defined as serum 25 hydroxy vitamin D (25D) >=32 ng/mL, and safety as no simultaneous elevation of serum calcium and 25D. Also assessed were HIV plasma viral RNA viral load (VL), CD4%, anti-retroviral therapy (ART) regime, and height-adjusted (HAZ), weight adjusted (WAZ) and Body Mass Index (BMIZ) Z scores. RESULTS: Subjects were 50% male, age (mean+/-SD) 19.5+/-11.8 years, CD4% 31.8+/-10.4, with baseline VL log10 range of <1.4 to 3.8 and VL detectable (>1.4) in 22%. From baseline to 12 weeks, 25D increased from 36+/-9 ng/ml to 56+/-18 ng/ml (p<0.0001) and 68% and 90% had 25D >=32 ng/ml, respectively (p = 0.02). Delta25D was similar by dose. No subjects had simultaneously increased serum calcium and 25D. WAZ and BMIZ improved by 12 weeks (p<0.04). HAZ and CD4% increased and VL decreased in the 7000 IU/d group (p<0.04). Younger (5-13y) and older (30-50y) subjects had greater Delta25D than those 14-29y (26+/-17 and 28+/-12 vs. 11+/-11 ng/ml, respectively, p<=0.001). Delta25D was higher with efavirenz or nevirapine compared to protease inhibitor based treatment (22+/-12, 27+/-17, vs. 13+/-10, respectively, p<=0.03). CONCLUSIONS: In a pilot study in Botswana, 12-week high dose D3 supplementation was safe and improved vitamin D, growth and HIV status; age and ART regimen were significant effect modifiers. TRIAL REGISTRATION: ClinicalTrials.gov NCT02189902. PMID- 25706752 TI - The 3-second rule in hereditary pure cerebellar ataxia: a synchronized tapping study. AB - The '3-second rule' has been proposed based on miscellaneous observations that a time period of around 3 seconds constitutes the fundamental unit of time related to the neuro-cognitive machinery in normal humans. The aim of paper was to investigate the temporal processing in patients with spinocerebellar ataxia type 6 (SCA6) and SCA31, pure cerebellar types of spinocerebellar degeneration, using a synchronized tapping task. Seventeen SCA patients (11 SCA6, 6 SCA31) and 17 normal age-matched volunteers participated. The task required subjects to tap a keyboard in synchrony with sequences of auditory stimuli presented at fixed interstimulus intervals (ISIs) between 200 and 4800 ms. In this task, the subjects required non-motor components to estimate the time of forthcoming tone in addition to motor components to tap. Normal subjects synchronized their taps to the presented tones at shorter ISIs, whereas as the ISI became longer, the normal subjects displayed greater latency between the tone and the tapping (transition zone). After the transition zone, normal subjects pressed the button delayed relative to the tone. On the other hand, SCA patients could not synchronize their tapping with the tone even at shorter ISIs, although they pressed the button delayed relative to the tone earlier than normal subjects did. The earliest time of delayed tapping appearance after the transition zone was 4800 ms in normal subjects but 1800 ms in SCA patients. The span of temporal integration in SCA patients is shortened compared to that in normal subjects. This could represent non-motor cerebellar dysfunction in SCA patients. PMID- 25706754 TI - Ledipasvir/sofosbuvir regimens for chronic hepatitis C infection: Insights from a work productivity economic model from the United States. AB - Patients with chronic hepatitis C (CHC) exhibit reduced work productivity owing to their disease. Historically, most regimens indicated for CHC genotype 1 (GT1) patients were administered with pegylated interferon (Peg-IFN) and/or ribavirin (RBV), which further compromised work productivity during treatment. The aim of this study was to model the impact of LDV/SOF (ledipasvir/sofosbuvir), the first Peg-IFN- and RBV-free regimen for CHC GT1 patients, on work productivity from an economic perspective, compared to receiving no treatment. The WPAI-SHP (Work Productivity and Activity Index-Specific Health Problem) questionnaire was administered to patients across the ION clinical trials (N = 1,923 U.S. patients). Before initiation of treatment, patients with CHC GT1 in the ION trials exhibited absenteeism and presenteeism impairments of 2.57% and 7.58%, respectively. Patients with cirrhosis exhibited greater work productivity impairment than patients without cirrhosis. In total, 93.21% of U.S. patients in the ION trials achieved SVR; these patients exhibited absenteeism and presenteeism impairments of 2.62% (P = 0.76, when compared to baseline) and 3.53% (P < 0.0001), respectively. Monetizing these data to the entire U.S. population, our model projects an annual societal cost of $7.1 billion owing to productivity loss in untreated GT1 CHC patients. Our model projects that, when compared to no treatment, treating all CHC GT1 patients with a regimen with very high viral eradication rates (LDV/SOF) would translate to annual productivity loss savings of $2.7 billion over a 1-year time horizon. CONCLUSIONS: Patients with untreated HCV impose a substantial societal burden owing to reduced work productivity. As a result of improvements in work productivity, treatment of CHC GT1 patients with LDV/SOF-based regimens is likely to result in significant cost savings from a societal perspective, relative to no treatment. PMID- 25706753 TI - Iterative decomposition of water and fat with echo asymmetry and least-squares estimation (IDEAL) magnetic resonance imaging as a biomarker for symptomatic multiple myeloma. AB - INTRODUCTION: To evaluate the effectiveness of iterative decomposition of water and fat with echo asymmetry and least-squares estimation (IDEAL) magnetic resonance imaging (MRI) to discriminate between symptomatic and asymptomatic myeloma in lumbar bone marrow without visible focal lesions. MATERIALS AND METHODS: The lumbar spine was examined with 3-T MRI in 11 patients with asymptomatic myeloma and 24 patients with symptomatic myeloma. The fat-signal fraction was calculated from the ratio of the signal intensity in the fat image divided by the signal intensity of the corresponding ROI in the in-phase IDEAL image. The t test was used to compare the asymptomatic and symptomatic groups. ROC curves were constructed to determine the ability of variables to discriminate between symptomatic and asymptomatic myeloma. RESULTS: Univariate analysis showed that beta2-microglobulin and bone marrow plasma cell percent (BMPC%) were significantly higher and fat-signal fraction was significantly lower with symptomatic myeloma than with asymptomatic myeloma. Areas under the curve were 0.847 for beta2;-microglobulin, 0.834 for fat-signal fraction, and 0.759 for BMPC%. CONCLUSION: The fat-signal fraction as a biomarker for multiple myeloma enables discrimination of symptomatic myeloma from asymptomatic myeloma. The fat signal fraction offers superior sensitivity and specificity to BMPC% of biopsy specimens. PMID- 25706756 TI - Glycosaminoglycans and glycomimetics in the central nervous system. AB - With recent advances in the construction of synthetic glycans, selective targeting of the extracellular matrix (ECM) as a potential treatment for a wide range of diseases has become increasingly popular. The use of compounds that mimic the structure or bioactive function of carbohydrate structures has been termed glycomimetics. These compounds are mostly synthetic glycans or glycan binding constructs which manipulate cellular interactions. Glycosaminoglycans (GAGs) are major components of the ECM and exist as a diverse array of differentially sulphated disaccharide units. In the central nervous system (CNS), they are expressed by both neurons and glia and are crucial for brain development and brain homeostasis. The inherent diversity of GAGs make them an essential biological tool for regulating a complex range of cellular processes such as plasticity, cell interactions and inflammation. They are also involved in the pathologies of various neurological disorders, such as glial scar formation and psychiatric illnesses. It is this diversity of functions and potential for selective interventions which makes GAGs a tempting target. In this review, we shall describe the molecular make-up of GAGs and their incorporation into the ECM of the CNS. We shall highlight the different glycomimetic strategies that are currently being used in the nervous system. Finally, we shall discuss some possible targets in neurological disorders that may be addressed using glycomimetics. PMID- 25706755 TI - Nanocytological field carcinogenesis detection to mitigate overdiagnosis of prostate cancer: a proof of concept study. AB - PURPOSE: To determine whether nano-architectural interrogation of prostate field carcinogenesis can be used to predict prognosis in patients with early stage (Gleason 6) prostate cancer (PCa), which is mostly indolent but frequently unnecessarily treated. MATERIALS AND METHODS: We previously developed partial wave spectroscopic microscopy (PWS) that enables quantification of the nanoscale intracellular architecture (20-200 nm length scale) with remarkable accuracy. We adapted this technique to assess prostate needle core biopsies in a case control study from men with Gleason 6 disease who either progressed (n = 20) or remained indolent (n = 18) over a ~3 year follow up. We measured the parameter disorder strength (Ld) characterizing the spatial heterogeneity of the nanoscale cellular structure and nuclear morphology from the microscopically normal mucosa ~150 histologically normal epithelial cells. RESULTS: There was a profound increase in nano-architectural disorder between progressors and non-progressors. Indeed, the Ld from future progressors was dramatically increased when compared to future non progressors (1+/-0.065 versus 1.30+/-0.0614, respectively p = 0.002). The area under the receiver operator characteristic curve (AUC) was 0.79, yielding a sensitivity of 88% and specificity of 72% for discriminating between progressors and non-progressors. This was not confounded by demographic factors (age, smoking status, race, obesity), thus supporting the robustness of the approach. CONCLUSIONS: We demonstrate, for the first time, that nano-architectural alterations occur in prostate cancer field carcinogenesis and can be exploited to predict prognosis of early stage PCa. This approach has promise in addressing the clinically vexing dilemma of management of Gleason 6 PCa and may provide a paradigm for dealing with the larger issue of cancer overdiagnosis. PMID- 25706757 TI - Anti-glycation activities of phenolic constituents from Silybum marianum (Milk Thistle) flower in vitro and on human explants. AB - Glycation is an ageing reaction of naturally occurring sugars with dermal proteins, with clinical signs appearing in vivo around age 30, and increasing steadily/regularly with age. The suppleness of the dermis is affected by the formation of bridges between proteins and sugars (Maillard's reaction). The accumulation of advanced glycation end products (AGEs) in skin plays a very important role in skin ageing. Therefore, natural compounds or extracts that possess antiglycation activities may have great anti-ageing potential. In the present study, Silybum marianum flower extract (SMFE) was demonstrated to possess antiglycation activity. We found that SMFE inhibits glycation reaction between BSA and glucose. In addition, antiglycation activity of SMFE was confirmed in a human skin explants model. SMFE reduced Nepsilon-(carboxymethyl) lysine (CML) expression, whereas SMFE stimulated fibrillin-1 expression compared to treatment with methyglyoxal. An active ingredient contributing to the observed activities was identified as silibinin. The antiglycation activity of silibinin was dose dependent. The beneficial effects of silibinin may be applied to prevention or management of AGE-mediated pathologies, targeting in a pleiotropic and complementary way the biochemical and cellular bases of skin aging. PMID- 25706758 TI - Divinyl sulfone cross-linked cyclodextrin-based polymeric materials: synthesis and applications as sorbents and encapsulating agents. AB - The aim of this study was to evaluate the crosslinking abilities of divinyl sulfone (DVS) for the preparation of novel water-insoluble cyclodextrin-based polymers (CDPs) capable of forming inclusion complexes with different guest molecules. Reaction of DVS with native alpha-cyclodextrin (alpha-CD), beta cyclodextrin (beta-CD) and/or starch generates a variety of homo- and hetero-CDPs with different degrees of crosslinking as a function of the reactants' stoichiometric ratio. The novel materials were characterized by powder X-ray diffraction, electron microscopy and for their sorption of phenol and 4 nitrophenol. They were further evaluated as sorbents with phenolic pollutants (bisphenol A and beta-naphthol) and bioactive compounds (the hormone progesterone and curcumin). Data obtained from the inclusion experiments show that the degree of cross-linking has a minor influence on the yield of inclusion complex formation and highlight the important role of the CDs, supporting a sorption process based on the formation of inclusion complexes. In general, the inclusion processes are better described by a Freundlich isotherm although an important number of them can also be fitted to the Langmuir isotherm with R2 >= 0.9, suggesting a sorption onto a monolayer of homogeneous sites. PMID- 25706760 TI - Predictors of maternal state anxiety on arrival at a Japanese hospital outpatient clinic: a cross-sectional study. AB - AIMS AND OBJECTIVES: To identify the factors that predict maternal state anxiety when mothers and their sick children visit the outpatient unit of a paediatric hospital. BACKGROUND: While previous studies have focused on predictors of anxiety in mothers with ill children, the existing literature is limited in study design, research timing, respondent characteristics, sample size and data analysis. DESIGN: A cross-sectional design with self-administered questionnaires. METHODS: Mothers were recruited from the outpatient unit of a Japanese paediatric hospital (N = 1077). Participants' state anxiety scores were collected using the Japanese version of Spielberger's State-Trait Anxiety Inventory. The independent variables were the mothers' and sick children's background information. RESULTS: Participants were 1077 mothers; 990 provided valid responses. Mothers' mean state anxiety score was 49.72. Significant predictors of maternal anxiety were mothers' childrearing anxiety, child age, the sick child having a fever, sick child having siblings, having a person providing childrearing support, the mother's first visit to the hospital, out-of-hours visit and severity of the child's illness. The overall model explained 21.6% of the variance (multiple regression analysis). CONCLUSIONS: As various factors predicted maternal anxiety, identifying methods to address these factors may reduce maternal state anxiety. RELEVANCE TO CLINICAL PRACTICE: There is potential for improved understanding of the predictors of maternal state anxiety to aid in the development of materials that would best measure anxiety. The present findings may also suggest some means of providing appropriate information and support to anxious mothers. Our findings cannot demonstrate causation, however, and teaching methods and supportive practices were not investigated; therefore, a qualitative study on the concrete content of maternal anxiety and an intervention study to create support services for anxious mothers is required. In addition, prospective or longitudinal studies are also important for investigating causation. PMID- 25706761 TI - Control of organ size: development, regeneration, and the role of theory in biology. AB - How organs grow to be the right size for the animal is one of the central mysteries of biology. In a paper in BMC Biology, Khammash et al. propose a mechanism for escaping from the deficiencies of feedback control of growth as a mechanism. PMID- 25706762 TI - Adaptive topographies and equilibrium selection in an evolutionary game. AB - It has long been known in the field of population genetics that adaptive topographies, in which population equilibria maximise mean population fitness for a trait regardless of its genetic bases, do not exist. Whether one chooses to model selection acting on a single locus or multiple loci does matter. In evolutionary game theory, analysis of a simple and general game involving distinct roles for the two players has shown that whether strategies are modelled using a single 'locus' or one 'locus' for each role, the stable population equilibria are unchanged and correspond to the fitness-maximising evolutionary stable strategies of the game. This is curious given the aforementioned population genetical results on the importance of the genetic bases of traits. Here we present a dynamical systems analysis of the game with roles detailing how, while the stable equilibria in this game are unchanged by the number of 'loci' modelled, equilibrium selection may differ under the two modelling approaches. PMID- 25706763 TI - Program science--a framework for improving global maternal, newborn, and child health. PMID- 25706764 TI - Craniocervical myology and functional morphology of the small-headed therizinosaurian theropods Falcarius utahensis and Nothronychus mckinleyi. AB - Therizinosaurs represent a highly unusual clade of herbivorous theropods from the Cretaceous of North America and Asia. Following descriptions of the basicrania of the North American therizinosaurs Falcarius utahenisis and Nothronychus mckinleyi, the craniocervical musculature in both taxa is reconstructed using Tyrannosaurus, Allosaurus, and some extant birds as models. These muscles are subdivided into functional groups as dorsiflexors, lateroflexors, and ventroflexors. Lateroflexors and dorsiflexors in Nothronychus, but not Falcarius, are reduced, from the plesiomorphic theropod condition, but are still well developed. Attachments in both genera are favorable for an increase in ventroflexion in feeding, convergent with Allosaurus fragilis. Falcarius and Nothronychus are both characterized by a flat occipital condyle, followed by centra with shallow articular facets suggesting neck function very similar to that of an ostrich Struthio camelus. Neck movement was a combined result of minimal movement between the individual cervical vertebrae. PMID- 25706759 TI - Ongoing transmission of hepatitis B virus in rural parts of the Netherlands, 2009 2013. AB - BACKGROUND: Reported acute hepatitis B incidence in the Netherlands reached its nadir in 2013. However, regional signals about increased number of hepatitis B cases raised the question how hepatitis B incidence was distributed over the country. In this study, regional differences in hepatitis B epidemiology were investigated using epidemiological and molecular data. METHODS: Acute hepatitis B virus (HBV) infections, reported between 2009-2013, were included. If serum was available, a fragment of S and C gene of the HBV was amplified and sequenced. Regional differences in incidence were studied by geographical mapping of cases and cluster analysis. Regional differences in transmission were studied by constructing regional maximum parsimony trees based on the C gene to assess genetic clustering of cases. RESULTS: Between 2009 and 2013, 881 cases were notified, of which respectively 431 and 400 cases had serum available for S and C gene sequencing. Geographical mapping of notified cases revealed that incidences in rural border areas of the Netherlands were highest. Cluster analysis identified two significant clusters (p<0.000) in the South-western and North eastern regions. Genetic cluster analysis showed that rural border areas had relatively large clusters of cases with indistinguishable sequences, while other regions showed more single introductions. CONCLUSION: This study showed that regional differences in HBV epidemiology were present in the Netherlands. Rural border regions showed higher incidences and more ongoing transmission, mainly among MSM, than the more urban inland areas. Therefore, preventive measures should be enhanced in these regions. PMID- 25706765 TI - Physiological Control of Nitric Oxide in Neuronal BACE1 Translation by Heme Regulated eIF2alpha Kinase HRI Induces Synaptogenesis. AB - AIMS: Hippocampus is the brain center for memory formation, a process that requires synaptogenesis. However, hippocampus is dramatically compromised in Alzheimer's disease due to the accumulation of amyloid beta-peptide, whose production is initiated by beta-site APP Cleaving Enzyme 1 (BACE1). It is known that pathological stressors activate BACE1 translation through the phosphorylation of the eukaryotic initiation factor-2alpha (eIF2alpha) by GCN2, PERK, or PKR kinases, leading to amyloidogenesis. However, BACE1 physiological regulation is still unclear. Since nitric oxide (NO) participates directly in hippocampal glutamatergic signaling, we investigated the neuronal role of the heme-regulated eukaryotic initiation factor eIF2alpha kinase (HRI), which can bind NO by a heme group, in BACE1 translation and its physiological consequences. RESULTS: We found that BACE1 is expressed on glutamate activation with NO being the downstream effector by triggering eIF2alpha phosphorylation, as it was obtained by Western blot and luciferase assay. It is due to the activation of HRI by NO as assayed by Western blot and immunofluorescence with an HRI inhibitor and HRI siRNA. BACE1 expression was early detected at synaptic spines, contributing to spine growth and consolidating the hippocampal memory as assayed with mice treated with HRI or neuronal NO synthase inhibitors. INNOVATION: We provide the first description that HRI and eIF2alpha are working in physiological conditions in the brain under the control of nitric oxide and glutamate signaling, and also that BACE1 has a physiological role in hippocampal function. CONCLUSION: We conclude that BACE1 translation is controlled by NO through HRI in glutamatergic hippocampal synapses, where it plays physiological functions, allowing the spine growth and memory consolidation. PMID- 25706766 TI - Spatial learning while navigating with severely degraded viewing: The role of attention and mobility monitoring. AB - The ability to navigate without getting lost is an important aspect of quality of life. In 5 studies, we evaluated how spatial learning is affected by the increased demands of keeping oneself safe while walking with degraded vision (mobility monitoring). We proposed that safe low vision mobility requires attentional resources, providing competition for those needed to learn a new environment. In Experiments 1 and 2, participants navigated along paths in a real world indoor environment with simulated degraded vision or normal vision. Memory for object locations seen along the paths was better with normal compared with degraded vision. With degraded vision, memory was better when participants were guided by an experimenter (low monitoring demands) versus unguided (high monitoring demands). In Experiments 3 and 4, participants walked while performing an auditory task. Auditory task performance was superior with normal compared with degraded vision. With degraded vision, auditory task performance was better when guided compared with unguided. In Experiment 5, participants performed both the spatial learning and auditory tasks under degraded vision. Results showed that attention mediates the relationship between mobility-monitoring demands and spatial learning. These studies suggest that more attention is required and spatial learning is impaired when navigating with degraded viewing. PMID- 25706767 TI - Escape from temporal-integration masking: the roles of visible persistence and input filtering. AB - A brief target embedded in-and coterminating with-a noise mask is identified easily when the duration of the mask is long but not when it is short (Di Lollo, 1980; inverse-duration effect). Identification has been said to be mediated by the visible persistence of the target, which outlasted that of the mask. We tested an alternative account based on input filtering triggered by the onset and offset of the target, relative to those of the mask, without recourse to visible persistence. The results of Experiment 1 could not be explained wholly in terms of visible persistence but were entirely consistent with input filtering. Identification suffered in Experiment 2 when transient responses were attenuated by "ramping." In Experiment 3, accuracy improved gradually as a function of leading-mask duration. All results were consistent with a modified version of von Holst's (1954) hypothesis that a new stimulus (e.g., the present mask) establishes an input filter within the system. Any sudden onsets or offsets then lead to the perception of a new object only when they do not match the input filter, thus becoming segregated from the temporally leading stimulus. PMID- 25706768 TI - Is pop-out visual search attentive or preattentive? Yes! AB - Is the efficiency of "pop-out" visual search impaired when attention is preempted by another task? This question has been raised in earlier experiments but has not received a satisfactory answer. To constrain the availability of attention, those experiments employed an attentional blink (AB) paradigm in which report of the second of 2 targets (T2) is impaired when it is presented shortly after the first (T1). In those experiments, T2 was a pop-out search display that remained on view until response. The main finding was that search efficiency, as indexed by the slope of the search function, was not impaired during the period of the AB. With such long displays, however, the search could be postponed until T1 had been processed, thus allowing the task to be performed with full attention. That pitfall was avoided in the present Experiment 1 by presenting the search array either until response (thus allowing a postponement strategy) or very briefly (making that strategy ineffectual). Level of performance was impaired during the period of the AB, but search efficiency was unimpaired even when the display was brief. Experiment 2 showed that visual search is indeed postponed during the period of the AB, when the array remains on view until response. These findings reveal the action of at least 2 separable mechanisms, indexed by level and efficiency of pop-out search, which are affected in different ways by the availability of attention. The Guided Search 4.0 model can account for the results in both level and efficiency. PMID- 25706770 TI - Are judgments a form of data clustering? Reexamining contrast effects with the k means algorithm. AB - A number of theories have been proposed to explain in precise mathematical terms how statistical parameters and sequential properties of stimulus distributions affect category ratings. Various contextual factors such as the mean, the midrange, and the median of the stimuli; the stimulus range; the percentile rank of each stimulus; and the order of appearance have been assumed to influence judgmental contrast. A data clustering reinterpretation of judgmental relativity is offered wherein the influence of the initial choice of centroids on judgmental contrast involves 2 combined frequency and consistency tendencies. Accounts of the k-means algorithm are provided, showing good agreement with effects observed on multiple distribution shapes and with a variety of interaction effects relating to the number of stimuli, the number of response categories, and the method of skewing. Experiment 1 demonstrates that centroid initialization accounts for contrast effects obtained with stretched distributions. Experiment 2 demonstrates that the iterative convergence inherent to the k-means algorithm accounts for the contrast reduction observed across repeated blocks of trials. The concept of within-cluster variance minimization is discussed, as is the applicability of a backward k-means calculation method for inferring, from empirical data, the values of the centroids that would serve as a representation of the judgmental context. PMID- 25706769 TI - The effect of stereotype threat on performance of a rhythmic motor skill. AB - Many studies using cognitive tasks have found that stereotype threat, or concern about confirming a negative stereotype about one's group, debilitates performance. The few studies that documented similar effects on sensorimotor performance have used only relatively coarse measures to quantify performance. This study tested the effect of stereotype threat on a rhythmic ball bouncing task, where previous analyses of the task dynamics afforded more detailed quantification of the effect of threat on motor control. In this task, novices hit the ball with positive racket acceleration, indicative of unstable performance. With practice, they learn to stabilize error by changing their ball racket impact from positive to negative acceleration. Results showed that for novices, stereotype threat potentiated hitting the ball with positive racket acceleration, leading to poorer performance of stigmatized females. However, when the threat manipulation was delivered after having acquired some skill, reflected by negative racket acceleration, the stigmatized females performed better. These findings are consistent with the mere effort account that argues that stereotype threat potentiates the most likely response on the given task. The study also demonstrates the value of identifying the control mechanisms through which stereotype threat has its effects on outcome measures. PMID- 25706771 TI - Processing of Arabic diacritical marks: phonological-syntactic disambiguation of homographic verbs and visual crowding effects. AB - Diacritics convey vowel sounds in Arabic, allowing accurate word pronunciation. Mostly, modern Arabic is printed nondiacritized. Otherwise, diacritics appear either only on homographic words when not disambiguated by surrounding text or on all words as in religious or educational texts. In an eye-tracking experiment, we examined sentence processing in the absence of diacritics and when diacritics were presented in either modes. Heterophonic homographic target verbs that have different pronunciations in active and passive (e.g., [see text]/d(a)r(a)b(a)/, hit; [see text]/d(o)r(i)b(a)/, was hit) were embedded in temporarily ambiguous sentences in which in the absence of diacritics, readers cannot be certain whether the verb was active or passive. Passive sentences were disambiguated by an extra word (e.g., [see text]/b(i)j(a)d/, by the hand of). Our results show that readers benefitted from the disambiguating diacritics when present only on the homographic verb. When disambiguating diacritics were absent, Arabic readers followed their parsing preference for active verb analysis, and garden path effects were observed. When reading fully diacritized sentences, readers incurred only a small cost, likely due to increased visual crowding, but did not extensively process the (mostly superfluous) diacritics, thus resulting in a lack of benefit from the disambiguating diacritics on the passive verb. PMID- 25706772 TI - Nigella sativa improves glycemic control and ameliorates oxidative stress in patients with type 2 diabetes mellitus: placebo controlled participant blinded clinical trial. AB - BACKGROUND AND OBJECTIVE: Oxidative stress plays an important role in pathogenesis of diabetes mellitus and its complications. Our previous study has shown glucose lowering effect produced by 3 months supplementation of Nigella sativa (NS) in combination with oral hypoglycemic drugs among type 2 diabetics. This study explored the long term glucose lowering effect (over one year) of NS in patients with type 2 diabetes mellitus on oral hypoglycemic drugs and to study its effect on redox status of such patients. METHODS: 114 type 2 diabetic patients on standard oral hypoglycemic drugs were assigned into 2 groups by convenience. The control group (n = 57) received activated charcoal as placebo and NS group (n = 57) received 2g NS, daily, for one year in addition to their standard medications. Fasting blood glucose (FBG), glycosylated hemoglobin (HbA1c), C- peptide, total antioxidant capacity (TAC), superoxide dismutase (SOD), catalase (CAT), glutathione and thiobarbituric acid reactive substances (TBARS) at the baseline, and every 3 months thereafter were determined. Insulin resistance and beta-cell activity were calculated using HOMA 2 calculator. RESULTS: Comparison between the two groups showed a significant drop in FBG (from 180 +/- 5.75 to 180 +/- 5.59 in control Vs from 195 +/- 6.57 to 172 +/- 5.83 in NS group), HbA1c (from 8.2 +/- 0.12 to 8.5 +/- 0.14 in control VS from 8.6 +/- 0.13 to 8.2 +/- 0.14 in NS group), and TBARS (from 48.3 +/- 6.89 to 52.9 +/- 5.82 in control VS from 54.1 +/- 4.64 to 41.9 +/- 3.16 in NS group), in addition to a significant elevation in TAC, SOD and glutathione in NS patients compared to controls. In NS group, insulin resistance was significantly lower, while beta cell activity was significantly higher than the baseline values during the whole treatment period. CONCLUSION: Long term supplementation with Nigella sativa improves glucose homeostasis and enhances antioxidant defense system in type 2 diabetic patients treated with oral hypoglycemic drugs. TRIAL REGISTRATION: Clinical Trials Registry-India (CTRI) CTRI/2013/06/003781. PMID- 25706773 TI - Low pretherapeutic serum albumin as a risk factor for poor outcome in esophageal squamous cell carcinomas. AB - The number of esophageal cancer patients is increasing worldwide and lots of patients suffer from malnutrition and hypoalbuminemic. Serum albumin is a widely acceptable method of assessing nutritional and inflammation status in cancer patients. But whether serum albumin has prognostic value with regard to short term and long-term outcomes in patients who undergo esophagectomy for cancer is still unclear. We therefore investigated the prognostic role of serum albumin in patients with esophageal cancer. We retrospectively reviewed 208 patients who underwent esophagectomy from September 1, 2003 to December 31, 2008. Clinico pathological characteristics and postoperative outcomes were compared between different pretherapeutic serum albumin classes: low (hypoalbuminemic), <35 g/l; middle, 35-40 g/l and high, >40 g/l. Older, female, and higher T-stages were more likely to be associated with hypoalbuminemic. Meanwhile, hypoalbuminemic patients had a higher rate of postoperative mortality and complications including sepsis, respiratory insufficiency, arrhythmia, and cardiac insufficiency. But for preoperative comorbidities, no significant difference was found between different pretherapeutic serum albumin classes. The overall 5-year survival rate was 28.6%, 43.9%, and 50.8% for patients with low, middle, and high pretherapeutic serum albumin levels, respectively. Hypoalbuminemic was associated with poor survival (P = 0.016). In a multivariate analysis, the pretherapeutic albumin level was proved to be an independent predictor of survival (hazard ratio = 0.731; 95% confidence interval: 0.544-0.982, P = 0.037). Pretherapeutic serum albumin level is a significant prognostic factor for short-term and long-term outcomes in patients who undergo esophagectomy for cancer, which therefore should be taken into consideration along with other well-defined prognostic factors for better preoperative assessment and prognostic evaluation. PMID- 25706774 TI - Effects of one-hour training course and spirometry on the ability of physicians to diagnose and treat chronic obstructive pulmonary disease. AB - BACKGROUNDS: In China, the prevalence of chronic obstructive pulmonary disease (COPD) in persons 40 years of age or older is estimated at 8.2%, but this is likely a substantial underestimate. METHODS: Eight secondary hospitals which didn't have spirometries were chosen randomly in Hunan province of central south China. Physician subjects at these hospitals underwent a one-hour training course on the Chinese COPD guidelines. Physicians answered questionnaires assessing their knowledge of the guidelines before and after the training session. The mean correct scores of questionnaires were compared before and after training. Four out of the eight hospitals were given access to spirometry. Eligible patient subjects underwent spirometry testing prior to the physician visit. After seeing the patient, physicians were asked to answer a questionnaire relating to the diagnosis and severity of COPD. Physicians were then given the results of the spirometry, and asked to answer the same questionnaire. Physicians' responses before and after receiving the spirometry results were compared. RESULTS: 225 physicians participated in the training session. 207 questionnaires were completed. Mean scores (out of 100) before and after the training were 53.1 +/- 21.7 and 93.3 +/- 9.8, respectively. 18 physicians and 307 patient subjects participated in the spirometry intervention. Based on spirometric results, the prevalence of COPD was 38.8%. Physicians correctly identified the presence of COPD without spirometric data in 85 cases (76.6%); this increased to 117 cases (97.4%) once spirometric data were available. Without spirometric data, physicians incorrectly diagnosed COPD in 38 patients; this decreased to 6 patients once spirometric data were available. Spirometric data also improved the ability of physicians to correctly grade COPD severity. CONCLUSIONS: Simple educational training can substantially improve physicians' knowledge relating to COPD. Spirometry combined with education improves the ability of physicians to diagnose COPD and to assess its severity. PMID- 25706775 TI - Addition of anti-neu antibody to local irradiation can improve tumor-bearing BALB/c mouse survival through immune-mediated mechanisms. AB - This study investigated the therapeutic effects of combined local irradiation and anti-HER2/neu antibody in a mixed tumor mouse model comprised of a nonmetastatic neu-positive tumor and a metastatic neu-negative tumor. While local irradiation alone could control the primary tumor in a dose-dependent manner, it did not improve mouse survival. Combined treatment comprised of local irradiation and anti-neu antibody of tumor-bearing BALB/c mice significantly improved mouse survival (P < 0.5), even though the tumor growth was similar to that of the irradiated-alone group. The combined treatment significantly reduced metastatic tumor masses in the lung and increased immune cell infiltration in primary tumor tissues. However, immune deficient nude mice with tumors did not exhibit prolonged survival in response to the combined treatment. Collectively, these results show that combined local irradiation and anti-neu antibody can elicit an immune-mediated abscopal effect to extend survival. Although the mechanism for abscopal effects induced by the combined treatment of radiation and anti-HER2/neu antibody was not elucidated, to our knowledge this is the first published study to describe the abscopal effect induced by the combination of local irradiation and the anti-HER2/neu antibody. PMID- 25706776 TI - Inactivation of NADPH oxidases NOX4 and NOX5 protects human primary fibroblasts from ionizing radiation-induced DNA damage. AB - Human exposure to ionizing radiation from medical procedures has increased sharply in the last three decades. Recent epidemiological studies suggest a direct relationship between exposure to ionizing radiation and health problems, including cancer incidence. Therefore, minimizing the impact of radiation exposure in patients has become a priority in the development of future clinical practices. Crucial players in radiation-induced DNA damage include reactive oxygen species (ROS), but the sources of these have remained elusive. To the best of our knowledge, we show here for the first time that two members of the ROS generating NADPH oxidase family (NOXs), NOX4 and NOX5, are involved in radiation induced DNA damage. Depleting these two NOXs in human primary fibroblasts resulted in reduced levels of DNA damage as measured by levels of radiation induced foci, a marker of DNA double-strand breaks (DSBs) and the comet assay coupled with increased cell survival. NOX involvement was substantiated with fulvene-5, a NOXs-specific inhibitor. Moreover, fulvene-5 mitigated radiation induced DNA damage in human peripheral blood mononuclear cells ex vivo. Our results provide evidence that the inactivation of NOXs protects cells from radiation-induced DNA damage and cell death. These findings suggest that NOXs inhibition may be considered as a future pharmacological target to help minimize the negative effects of radiation exposure for millions of patients each year. PMID- 25706777 TI - Association of radiation-induced genes with noncancer chronic diseases in Mayak workers occupationally exposed to prolonged radiation. AB - We examined the association of gene expression with noncancer chronic disease outcomes in Mayak nuclear weapons plant workers who were exposed to radiation due to their occupation. We conducted a cross-sectional study with selection based on radiation exposure status of Mayak plant workers living in Ozyorsk who were alive in 2011 and either exposed to: combined incorporated Plutonium-239 ((239)Pu) and external gamma-ray exposure (n = 82); external gamma-ray exposure alone (n = 18); or were unexposed (n = 50) of Ozyorsk residents who provided community-based professional support for plant personnel and who were alive in 2011. Peripheral blood was taken and RNA was isolated and then converted into cDNA and stored at 20 degrees C. In a previous analysis we screened the whole genome for radiation associated candidate genes, and validated 15 mRNAs and 15 microRNAs using qRT PCR. In the current analysis we examined the association of these genes with 15 different chronic diseases on 92 samples (47 males, 45 females). We examined the radiation-to-gene and gene-to-disease associations in statistical models stratified by gender and separately for each disease and exposure. We modeled radiation exposure as gamma or (239)Pu on both the continuous and categorical scales. Unconditional logistic regression was used to calculate odds ratios (OR), 95% confidence intervals (CI), and the concordance for genes that were significantly associated with radiation exposure and a specific disease outcome were identified. Altogether 12 mRNAs and 9 microRNAs appeared to be significantly associated with 6 diseases, including thyroid diseases (3 genes, OR: 1.2-5.1, concordance: 71-78%), atherosclerotic diseases (4 genes, OR: 2.5-10, concordance: 70-75%), kidney diseases (6 genes, OR: 1.3-8.6, concordance: 69-85%), cholelithiasis (3 genes, OR: 0.2-0.3, concordance: 74-75%), benign tumors [1 gene (AGAP4), OR: 3.7, concordance: 81%] and chronic radiation syndrome (4 genes, OR: 2.5-4.3, concordance: 70-99%). Further associations were found for systolic blood pressure (6 genes, OR: 3.7-10.6, concordance: 81-88%) and body mass index [1 gene (miR-484), OR: 3.7, concordance: 81%]. All associations were gender and exposure dependent. These findings suggest that gene expression changes observed after occupational prolonged radiation exposures may increase the risk for certain noncancer chronic diseases. PMID- 25706778 TI - Body Dysmorphic Symptoms, Functional Impairment, and Depression: The Role of Appearance-Based Teasing. AB - Body dysmorphic disorder is associated with elevated social and occupational impairment and comorbid depression, but research on risk factors for body dysmorphic symptoms and associated outcomes is limited. Appearance-based teasing may be a potential risk factor. To examine the specificity of this factor, the authors assessed self-reported appearance-based teasing, body dysmorphic, and obsessive-compulsive symptom severity, functional impairment (i.e., social, occupational, family impairment), and depression in a nonclinical sample of undergraduates. As hypothesized, appearance-based teasing was positively correlated with body dysmorphic symptoms. The correlation between teasing and body dysmorphic symptoms was stronger than that between teasing and obsessive compulsive symptom severity. Last, body dysmorphic symptom severity and appearance-based teasing interacted in predicting functional impairment and depression. Specifically, appearance-based teasing was positively associated with depression and functional impairment only in those with elevated body dysmorphic symptoms. When a similar moderation was tested with obsessive-compulsive, in place of body dysmorphic, symptom severity, the interaction was nonsignificant. Findings support theory that appearance-based teasing is a specific risk factor for body dysmorphic symptoms and associated functional impairment. PMID- 25706779 TI - Enantioselective synthesis of macrocyclic heterobiaryl derivatives of molecular asymmetry by molybdenum-catalyzed asymmetric ring-closing metathesis. AB - Winding vine-shaped molecular asymmetry is induced by enantioselective ring closing metathesis with a chiral molybdenum catalyst. The reaction proceeds under mild conditions through an E-selective ring-closing metathesis leading to macrocyclic bisazoles with enantioselectivities of up to 96% ee. PMID- 25706780 TI - Takotsubo cardiomyopathy induced by a suicide attempt. PMID- 25706781 TI - Interruption of the fourth aortic arch and a persistent fifth aortic arch with coarctation: a rare morphological finding. PMID- 25706782 TI - Effect of unilateral catheter-based renal sympathetic denervation in a patient with resistant hypertension. PMID- 25706783 TI - First transapical implantation in Poland of the aortic valve bioprosthesis registered both for aortic stenosis and insufficiency. PMID- 25706784 TI - [Cardioverter-defibrillator implantation and left cardiac sympathetic denervation in a boy post cardiac arrest]. PMID- 25706785 TI - Detection of synchronous gastric schwannoma on FDG PET/CT aided by discordant metabolic response. AB - This is a case of an unsuspected synchronous gastric schwannoma demonstrating increased F-FDG accumulation on PET/CT in a 65-year-old female patient diagnosed with non-Hodgkin lymphoma on the basis of different metabolic activity to other sites of disease at staging and discordant metabolic response to therapy. The gastric schwannoma was confirmed by histopathology and immunohistochemistry after surgical resection. This case adds to the limited literature on FDG-avid gastric schwannoma and highlights the importance of investigating differential metabolic activity and response on serial PET/CT imaging. PMID- 25706786 TI - Dual-phase 99mTc-MIBI imaging findings in sporadic primary hyperplasia of parathyroid glands. AB - Primary hyperplasia of parathyroid is uncommon and rarely documented in literatures. We report an 18-year-old female patient with hyperparathyroidism due to unifocal primary hyperplasia of parathyroid glands. Dual-phase Tc-MIBI imaging was performed for this patient. We found remarkably increased MIBI uptake in the hyperplastic lesion in early imaging and no extinction of the uptake in delayed imaging. These results suggest that the dual-phase Tc-MIBI imaging is useful in localizing the hyperfunctioning lesions of primary hyperplasia of parathyroid glands. PMID- 25706787 TI - Concurrent bisphosphonate-related bilateral atypical subtrochanteric fractures and osteonecrosis of the jaw on bone scintigraphy. AB - An 82-year-old woman presented with bilateral thigh pain. She had pain in her right thigh operated for a low-trauma fracture 2 years earlier and newly developed pain in her left thigh without trauma. A whole-body bone scan revealed increased tracer uptake in her bilateral subtrochanteric femoral shafts and in the right mandible without evidence of metastatic bone disease. She had been taking bisphosphonates for 7 years to treat osteoporosis and was soon diagnosed with atypical subtrochanteric fractures and bisphosphonate-related osteonecrosis of the jaw. The bone scan simultaneously identified 2 serious adverse effects of long-term use of bisphosphonates. PMID- 25706788 TI - Functional fecal retention visualized by (111)In-DTPA colon transit scintigraphy. AB - Constipation is an extremely common problem in children, varying from mild and short-lived to severe and chronic. Chronic constipation is a serious childhood condition and requires further investigation, including blood test, colonoscopy, radio-opaque marker study, and/or scintigraphy. We present small bowel and colon transit scintigraphy of a 14-year-old girl with history of chronic constipation, abdominal pain, weight loss, and poor response to medical treatment. After oral administration of In-DTPA in water, planar and SPECT/CT images showed normal small bowel transit time and functional fecal retention in colon transit study. PMID- 25706789 TI - An incidentally detected solitary fibrous tumor on (99m)Tc-sestamibi myocardial perfusion imaging. AB - A 55-year-old woman with a mild transient chest pain but normal laboratory examination results underwent Tc-sestamibi myocardial perfusion imaging. An abnormal nodular radioactive uptake, which appeared protruding from the anterior segments, was detected. This activity was later proved to be benign solitary fibrous tumor of pleura after histopathological examination after the surgical exploration. PMID- 25706790 TI - (18)F-FDG PET/CT in an unusual case of cardiac plexiform neurofibromatosis. AB - Cardiac involvement is rare in neurofibromatosis 1 (NF 1). Very few cases of cardiac masses in this entity have been documented in the world literature. We present the F-FDG PET/CT findings in a rare case of cardiac plexiform neurofibromatosis. PMID- 25706791 TI - Simultaneous (18)F-FDOPA PET/CT-guided biopsy and radiofrequency ablation of recurrent neuroendocrine hepatic metastasis: further step toward a theranostic approach. AB - PET/CT-guided biopsy may be useful to confirm the metabolic findings when conventional imaging fails to show morphological abnormalities. Herein, we report the results of simultaneous F-FDOPA (fluorodihydroxyphenylalanine) PET/CT-guided biopsy and RFA (radiofrequency ablation) in 1 patient with hepatic metastatic evolution of a well-differentiated ileal neuroendocrine tumor. Beyond FDG, FDOPA could be successfully recommended in patients with neuroendocrine tumor for planning PET/CT-guided diagnostic biopsy, ablative treatment, and immediate efficacy assessment in a 1-step examination. PMID- 25706792 TI - Asymmetric muscle activity on (18)F-FDG PET/CT. AB - A 51-year-old man referred to our department to undergo an F-FDG PET/CT to detect primary tumor 7 days after diagnosis of one left brain metastasis on MRI in the aftermath of acute right-sided hemiparesis. F-FDG PET/CT was performed without sufficient fasting period. It showed abnormal uptake in the left apical lung nodule, suspicious for primary tumor. Moreover, F-FDG PET/CT showed extensive skeletal muscle accumulation which was more significant as expected but concerning only the left side of the body. So, acute right-sided hemiparesis was responsible for no muscle uptake, probably explained by denervation and altered muscle energetics. PMID- 25706793 TI - Radiation-Induced Esophagitis Masquerading as Disease Progression in Case of Esophageal Carcinoma: A Diagnostic Dilemma Solved on Follow-up FDG PET/CT. AB - Radiation esophagitis is one of the commonest complications of the radiotherapy involving esophagus. It is characterized by diffuse radiotracer uptake in the esophagus on 18F-FDG PET/CT. Thus, it can be often confused with the esophageal malignancy. We present the sequential 18F-FDG PET/CT images of a 45-year-old woman with locally advanced squamous cell carcinoma of the esophagus who developed radiation esophagitis after chemoradiotherapy. It was confused with the progression of the disease, and the dilemma was resolved by the follow-up PET/CT. PMID- 25706794 TI - 18F-FDG PET/CT Findings in a Patient With a Proliferating Trichilemmal Cyst. AB - Proliferating trichilemmal cyst is considered as a rare tumor that originates in the outer root sheath of hair follicle. Metastatic potential has not been yet fully established. Moreover, histological analysis does not allow precise malignancy prediction. Proliferating trichilemmal cyst glucose metabolism behavior was never previously described. Herein, we report the case of a 62-year old patient with a left shoulder proliferating trichilemmal cyst showing an intense uptake of 18F-FDG on PET/CT examination. 18F-FDG PET/CT could be proposed to optimize diagnostic strategy of patients with proliferating trichilemmal cysts. PMID- 25706795 TI - Horseshoe Kidney Incidentally Revealed on Meckel Scintigraphy. AB - An 8-year-old male patient with history of bloody stools underwent a Meckel diverticulum scintigraphy to evaluate for ectopic gastric mucosa. The static images showed 2 abnormal foci of radiotracer accumulation in the mid-abdomen. Contrary to the renal activity, the foci appeared more prominent on the anterior view and localized anteriorly to the expected kidneys location on the left lateral view. Carefully reviewed dynamic acquisition revealed faint catenary shaped activity in this region on earlier images, gradually evolving into 2 prominent foci on later images. A horseshoe kidney was suspected, the pathology being confirmed by abdominal ultrasonography. PMID- 25706796 TI - Tubercular Meningitis on 18F-FDG PET/CT: Incidentally Detected and Masquerading as Relapse in a Patient With Ovarian Burkitt Lymphoma. AB - Tuberculosis can mimic malignancy, both clinically as well as on 18F-FDG PET/CT, leading to false-positive lesions. We present such a case of a 14-year-old female patient with ovarian Burkitt lymphoma treated with chemotherapy. On post-therapy PET/CT, 18F-FDG avid meningeal enhancement was seen which was suspicious for distant relapse versus tubercular meningitis. On cerebrospinal fluid examination, diagnosis of tubercular meningitis was confirmed. PMID- 25706797 TI - Multiple Pathologies Seen on a Single Contrast-Enhanced 18F-FDG PET/CT: Reiteration of Lessons Previously Learned. AB - We here present the staging contrast-enhanced F-FDG PET/CT images of a 53-year old woman with right breast cancer. Apart from the F-FDG avid primary breast tumor, F-FDG avid thyroiditis, F-FDG avid right paratracheal tubercular lymphadenitis, and non-F-FDG avid pancreatic neuroendocrine tumor were seen on PET/CT. All the lesions were confirmed with fine-needle aspiration cytology. This interesting case demonstrates a spectrum of true-positive, false-positive, and false-negative lesions on a single F-FDG PET/CT examination. PMID- 25706798 TI - Discrete decreased activity in the lower thoracic spine on FDG PET/CT: another respiration-related artifact. AB - PURPOSE: We observed that the diaphragmatic motion causing the well-known, so called banana artifact on PET/CT images may additionally cause decreased FDG activity involving 1 or 2 lower thoracic vertebrae. The aim of this study was (1) to formally evaluate if this observation is indeed true and, if so, (2) to assess its frequency. PATIENTS AND METHODS: One hundred fifty-four PET/CT scans (81 males and 73 females, age 61 +/- 13 years) were analyzed. On the coronal CT images, the vertebra above where the hemi-diaphragmatic surfaces abut the vertebral column was defined as the target vertebra (TV). On sagittal PET images, FDG activity in TV was visually and quantitatively assessed. Then, the severity of banana artifact on coronal PET images was graded from 0 to 2: 0 if there was no artifact, 1 if a thin photopenic stripe, and 2 if a thick banana-shaped photopenic artifact in the vicinity of diaphragm. RESULTS: Visually decreased activity in TV was present in 0% (0/93), 3% (1/34), and 59% (16/27) of scans graded as 0, 1, and 2, respectively (grade 0 and/or 1 vs. grade 2, P < 0.001). The SUV ratio of TV to reference vertebrae were 0.99 +/- 0.14, 0.99 +/- 0.15, and 0.84 +/- 0.19 in grade 0, 1, and 2 scans, respectively (P < 0.001). CONCLUSION: Error of attenuation correction from respiratory motion can lead to underestimation of FDG activity in the lower thoracic spine, and this should not be interpreted as possible marrow replacement process requiring further imaging if there is coexisting banana artifact. PMID- 25706799 TI - 99mTc-HYNIC-TOC imaging in the evaluation of pancreatic masses which are potential neuroendocrine tumors. AB - PURPOSE: The aim of this investigation was to determine the accuracy of the findings and the diagnoses of Tc-hydrazinonicotinyl-Tyr3-octreotide scan (Tc HYNIC-TOC imaging) in patients with pancreatic masses which were potential neuroendocrine tumors. METHODS: Records of total 20 patients with pancreatic masses were retrospectively reviewed. All of the patients had been revealed by abdominal contrast CT and possibility of neuroendocrine tumors could not be excluded by CT imaging before Tc-HYNIC-TOC imaging. Tc-HYNIC-TOC imaging was performed at 1 and 4 hours post-tracer injection, and SPECT/CT images of the abdomen were also acquired. The image findings were compared to final diagnoses which were made from pathological examination. RESULTS: Among all 20 pancreatic masses evaluated, there were 16 malignant lesions which included 1 ductal adenocarcinoma and 15 neuroendocrine tumors. Tc-HYNIC-TOC imaging identified 14 of 15 pancreatic neuroendocrine tumors and excluded 4 of 5 lesions which were not neuroendocrine tumors. The overall sensitivity, specificity, and accuracy was therefore 93.3% (14 of 15), 80% (4 of 5), and 90.0% (18 of 20), respectively, in our patient population. CONCLUSION: Tc-HYNIC-TOC imaging provides reasonable accuracy in the evaluation pancreatic mass suspected to be neuroendocrine tumors. PMID- 25706800 TI - Factors associated with the amount of public home care received by elderly and intellectually disabled individuals in a large Norwegian municipality. AB - This study reports an analysis of factors associated with home care use in a setting in which long-term care services are provided within a publicly financed welfare system. We considered two groups of home care recipients: elderly individuals and intellectually disabled individuals. Routinely collected data on users of public home care in the municipality of Trondheim in October 2012, including 2493 people aged 67 years or older and 270 intellectually disabled people, were used. Multivariate regression analysis was used to analyse the relationship between the time spent in direct contact with recipients by public healthcare personnel and perceived individual determinants of home care use (i.e. physical disability, cognitive impairment, diagnoses, age and gender, as well as socioeconomic characteristics). Physical disability and cognitive impairment are routinely registered for long-term care users through a standardised instrument that is used in all Norwegian municipalities. Factor analysis was used to aggregate the individual items into composite variables that were included as need variables. Both physical disability and cognitive impairment were strong predictors of the amount of received care for both elderly and intellectually disabled individuals. Furthermore, we found a negative interaction effect between physical disability and cognitive impairment for elderly home care users. For elderly individuals, we also found significant positive associations between weekly hours of home care and having comorbidity, living alone, living in a service flat and having a safety alarm. The reduction in the amount of care for elderly individuals living with a cohabitant was substantially greater for males than for females. For intellectually disabled individuals, receiving services involuntarily due to severe behavioural problems was a strong predictor of the amount of care received. Our analysis showed that routinely collected data capture important predictors of home care use and thus facilitate both short-term budgeting and long-term planning of home care services. PMID- 25706801 TI - A novel zinc finger gene, ZNF465, is inappropriately expressed in acute myeloid leukaemia cells. AB - To increase our knowledge of leukaemia-associated antigens, especially in acute myeloid leukaemia (AML) M4, we prepared a phage display cDNA library using mRNA from the bone marrow cells of a patient with AML M4 at diagnosis. We immunoscreened 10(6) pfu with autologous sera and identified an antigen which we named GKT-AML8. The cDNA showed more than 99% similarity to a sequence on 2q21.2 and 95% sequence similarity to a sequence on 19q13.3. These genes were named ZNF465 and ZNF466, respectively, following HUGO Gene Nomenclature Committee (HGNC) guidelines. Expressed sequence tag data suggests that both genes are transcriptionally active. ZNF465 and ZNF466 encode a 5' kruppel associated box domain typical of negative regulators of gene transcription. We have confirmed the translational start site in the +1 frame in a near-Kozak sequence that produces a 102 amino acid polypeptide from ZNF465. The high level of sequence similarity between ZNF465 and ZNF466 makes their transcripts almost indistinguishable by real-time polymerase chain reaction (RT-PCR). However, GKT AML8 showed most sequence similarity to ZNF465 and no transcript matching the 3' ZNF466 sequence could be detected in patient samples or healthy volunteers. ZNF465/466 expression was detectable in 12/13 AML and 10/14 chronic myeloid leukaemia patients' samples but not in normal donor peripheral blood (0/8) or 0/3 bone marrow samples which had been separated into CD34(+) and CD34(-) samples. The altered expression of ZNF465/466 in patients' samples and its absence in healthy donor haematopoietic samples indicate that ZNF465 is overexpressed in early myeloid disease and as such may represent a promising target for immunotherapy. PMID- 25706803 TI - Comparison of different methods for the recovery of DNA from spores of mycotoxin producing moulds in spiked food samples. AB - Several food samples were spiked with fungal conidia to test the efficiency of different cell disruption methods and DNA extraction kits for subsequent molecular detection. For disrupting the firm cell walls of the spores, two different pretreatment methods, namely sonication and bead beating, were tested against no pretreatment. The subsequent DNA extraction and purification was performed using three different DNA extraction methods, which are based on a diverse combination of extraction principles, such as precipitation, thermic enzymatic lysis, pH-enhancement and bonding with a silica membrane. The aim of the study was to find out the suitable pretreatment and DNA extraction method for the recovery of detectable amounts of fungal DNA from different food matrices. Significance and impact of the study: The choice of 'ready-to-use' commercial kits and methods has been of great importance regarding the recovery of extracted DNA. However, these commercially available kits are neither effective nor time efficient when extracting DNA from fungal spores embedded in complex food matrices. Different extraction principles were compared and their effectiveness tested using real-time PCR. The combination of different principles for the extraction and purification of DNA was found as the most efficient method (quantity and purity) to obtain DNA from moulds and their spores from food samples. PMID- 25706802 TI - N-myristoyltransferase is a cell wall target in Aspergillus fumigatus. AB - Treatment of filamentous fungal infections relies on a limited repertoire of antifungal agents. Compounds possessing novel modes of action are urgently required. N-myristoylation is a ubiquitous modification of eukaryotic proteins. The enzyme N-myristoyltransferase (NMT) has been considered a potential therapeutic target in protozoa and yeasts. Here, we show that the filamentous fungal pathogen Aspergillus fumigatus possesses an active NMT enzyme that is essential for survival. Surprisingly, partial repression of the gene revealed downstream effects of N-myristoylation on cell wall morphology. Screening a library of inhibitors led to the discovery of a pyrazole sulphonamide compound that inhibits the enzyme and is fungicidal under partially repressive nmt conditions. Together with a crystallographic complex showing the inhibitor binding in the peptide substrate pocket, we provide evidence of NMT being a potential drug target in A. fumigatus. PMID- 25706804 TI - Abdominal wall desmoid tumors: A proposal for US-guided resection. AB - BACKGROUND: Desmoid tumors (DTs) is a benign tumor with high tendency to infiltrative evolution and recurrence. Nowadays, in abdominal localization, the standard approach is surgery with R0 condition. The need to repair post-surgical wide wall defect requires conservative technique to decrease the incidence of incisional hernia and to obtain better quality of life (QoL). METHODS: We perform an abdominal wall desmoid resection using ultrasound guide. This technique ensures to spare a wide wall area and to obtain a multilayer reconstruction minimizing postoperative risk. This approach allows good oncological results and better managing abdominal wall post-resection defect. RESULTS: We use US guided surgery to get radical approach and wall tissue spare that allows us a multilayer reconstruction minimizing post-operative complications. No recurrences were observed in one year follow up period. CONCLUSION: Our experience represents first step to consider ultrasound mediated technique usefull to optimize wall resection surgery and to minimize following complications. PMID- 25706806 TI - Development of choosing wisely recommendations for an inpatient internal medicine service. PMID- 25706805 TI - Novel GATA6 mutations in patients with pancreatic agenesis and congenital heart malformations. AB - Patients with pancreatic agenesis are born without a pancreas, causing permanent neonatal diabetes and pancreatic enzyme insufficiency. These patients require insulin and enzyme replacement therapy to survive, grow, and maintain normal blood glucose levels. Pancreatic agenesis is an uncommon condition but high throughput sequencing methods provide a rare opportunity to identify critical genes that are necessary for human pancreas development. Here we present the clinical history, evaluation, and the genetic and molecular analysis from two patients with pancreatic agenesis. Both patients were born with intrauterine growth restriction, minor heart defects and neonatal diabetes. In both cases, pancreatic agenesis was confirmed by imaging studies. The patients are clinically stable with pancreatic enzymes and insulin therapy. In order identify the etiology for their disease, we performed whole exome sequencing on both patients. For each proband we identified a de novo heterozygous mutation in the GATA6 gene. GATA6 is a homeobox containing transcription factor involved in both early development of the pancreas and heart. In vitro functional analysis of one of the variants revealed that the mutation creates a premature stop codon in the coding sequence resulting in the production of a truncated protein with loss of activity. These results show how genetic mutations in GATA6 may lead to functional inactivity and pancreatic agenesis in humans. PMID- 25706807 TI - KRAS mutation screening by chip-based DNA hybridization--a further step towards personalized oncology. AB - The use of predictive biomarkers can help to improve therapeutic options for the individual cancer patient. For the treatment of colon cancer patients with anti EGFR-based drugs, the KRAS mutation status has to be determined to pre-select responders that will benefit from this medication. Amongst others, array-based tests have been established for profiling of the KRAS mutation status. Within this article we describe an on-chip hybridization technique to screen therapeutic relevant KRAS codon 12 mutations. The DNA chip-based platform enables the reliable discrimination of selected mutations by allele-specific hybridization. Here, silver deposits represent robust endpoint signals that allow for a simple naked eye rating. With the here presented assay concept a precise identification of heterozygous and homozygous KRAS mutations, even against a background of up to 95% wild-type DNA, was realizable. The applicability of the test was successfully proven for various cancer cell lines as well as clinical tumour samples. Thus, the chip-based DNA hybridization technique seems to be a promising tool for KRAS mutation analysis to further improve personalized cancer treatment. PMID- 25706808 TI - Do meditators have higher awareness of their intentions to act? AB - Intuitively, being aware of one's inner processes to move should be crucial for the control of voluntary movements. However, research findings suggest that we are not always aware of the processes leading to movement execution. The present study investigated induced first-person access to inner processes of movement initiation and the underlying brain activities which contribute to the emergence of voluntary movement. Moreover, we investigated differences in task performance between mindfulness meditators and non-meditators while assuming that meditators are more experienced in attending to their inner processes. Two Libet-type tasks were performed; one in which participants were asked to press a button at a moment of their own decision, and the other one in which participants' attention was directed towards their inner processes of decision making regarding the intended movement which lead them to press the button. Meditators revealed a consistent readiness potential (RP) between the two tasks with correlations between the subjective intention time to act and the slope of the early RP. However, non-meditators did not show this consistency. Instead, elicited introspection of inner processes of movement initiation changed early brain activity that is related to voluntary movement processes. Our findings suggest that compared to non-meditators, meditators are more able to access the emergence of negative deflections of slow cortical potentials (SCPs), which could have fundamental effects on initiating a voluntary movement with awareness. PMID- 25706810 TI - Laparoscopic anterior pelvic exenteration for advanced sigmoid colon cancer--a video vignette. PMID- 25706811 TI - Desmoplastic cellular neurothekeoma mimicking basal cell carcinoma. PMID- 25706812 TI - Free radical-quenched SERS probes for detecting H2O2 and glucose. AB - For developing a free radical-quenched surface-enhanced Raman scattering (SERS) probe, starch, a linear molecule, was used as a protective layer to coat gold nanoshells (GNSs) as enhancement substrates and then, methylene blue (MB) was absorbed on the starch-coated GNSs as a free radical-responsive element. By detecting the change of the SERS intensity of MB on GNSs, the free radical quenched SERS probes were used to detect H2O2, a less active reactive oxygen species (ROS), which was first converted to free radicals, a highly active ROS, to react with MB absorbed on GNSs to quench its SERS. The free radical-quenched SERS probe was also used to detect glucose in the presence of glucose oxidase which converted glucose to H2O2. The free radical-quenched SERS probe would be a versatile platform for detection of biochemical processes. The integration of optically changed molecules and optical enhancement of nanomaterials provided a way for advanced materials and analytical science. PMID- 25706813 TI - Characterization of human cytochrome P450s involved in the bioactivation of tri ortho-cresyl phosphate (ToCP). AB - Tri-ortho-cresyl phosphate (ToCP) is a multipurpose organophosphorus compound that is neurotoxic and suspected to be involved in aerotoxic syndrome in humans. It has been reported that not ToCP itself but a metabolite of ToCP, namely, 2 (ortho-cresyl)-4H-1,2,3-benzodioxaphosphoran-2-one (CBDP), may be responsible for this effect as it can irreversibly bind to human butyrylcholinesterase (BuChE) and human acetylcholinesterase (AChE). The bioactivation of ToCP into CBDP involves Cytochrome P450s (P450s). However, the individual human P450s responsible for this bioactivation have not been identified yet. In the present study, we aimed to investigate the metabolism of ToCP by different P450s and to determine the inhibitory effect of the in vitro generated ToCP-metabolites on human BuChE and AChE. Human liver microsomes, rat liver microsomes, and recombinant human P450s were used for that purpose. The recombinant P450s 2B6, 2C18, 2D6, 3A4 and 3A5 showed highest activity of ToCP-bioactivation to BuChE inhibitory metabolites. Inhibition experiments using pooled human liver microsomes indicated that P450 3A4 and 3A5 were mainly involved in human hepatic bioactivation of ToCP. In addition, these experiments indicated a minor role for P450 1A2. Formation of CBDP by in-house expressed recombinant human P450s 1A2 and 3A4 was proven by both LC-MS and GC-MS analysis. When ToCP was incubated with P450 1A2 and 3A4 in the presence of human BuChE, CBDP-BuChE-adducts were detected by LC-MS/MS which were not present in the corresponding control incubations. These results confirmed the role of human P450s 1A2 and 3A4 in ToCP metabolism and demonstrated that CBDP is the metabolite responsible for the BuChE inactivation. Interindividual differences at the level of P450 1A2 and 3A4 might play an important role in the susceptibility of humans in developing neurotoxic effects, such as aerotoxic syndrome, after exposure to ToCP. PMID- 25706814 TI - Editorial comment for Tosoian et al. PMID- 25706815 TI - Hydrogen trapping ability of the pyridine-lithium+ (1:1) complex. AB - Theoretical studies have been carried out at different levels of theory to verify the hydrogen adsorption characteristics of pyridine-lithium ion (1:1) complexes. The nature of interactions associated with the bonding between pyridine and lithium as well as that between lithium and adsorbed molecular hydrogen is studied through the calculation of electron density and electron-density-based reactivity descriptors. The pyridine-lithium ion complex has been hydrogenated systematically around the lithium site, and each lithium site is found to adsorb a maximum of four hydrogen molecules with an interaction energy of ~-4.0 kcal/mol per molecule of H2. The fate of the hydrogen adsorbed in a pyridine-lithium ion complex (corresponding to the maximum adsorption) is studied in the course of a 2 ps time evolution through ab initio molecular dynamics simulation at different temperatures. The results reveal that the complex can hold a maximum of four hydrogen molecules at a temperature of 77 K, whereas it can hold only two molecules of hydrogen at 298 K. PMID- 25706816 TI - Nature of transport gap and magnetic order in zircon and scheelite type DyCrO4 from first principles. AB - Our first principles density functional theory calculations within GGA + U approximation reveal that the nature of transport gaps in the zircon and scheelite phases of DyCrO(4) are quite different. While in the scheelite phase the origin of the gap is more like that of the Mott-Hubbard systems, in the zircon phase the origin is not strictly a Mott-Hubbard or a charge transfer type. In the framework of the Zaanen-Sawatsky-Allen phase diagram, the DyCrO(4) in its zircon phase could be placed in the intermediate regime between the charge transfer and Mott-Hubbard insulators. On the issue of ground state magnetic order in these two phases, where no consensus exists so far from experimental observations, we have performed GGA and GGA + U calculations on various possible magnetic configurations. We clearly establish from our theoretical calculations that the ferrimagnetic order, where ferromagnetic Dy and Cr sublattice are aligned antiparallel to each other, is the ground state in the zircon phase, while in the scheelite phase competing long-range antiferromagnetic orders are observed. Our estimation of various superexchange interactions indicate that competing ferro- and antiferro-magnetic interactions exist which would explain the experimental observation of metamagnetic transitions on application of a small external magnetic field in these systems. PMID- 25706817 TI - WITHDRAWN: Autologous adipose tissue-derived stromal vascular fraction cells application in patients with osteoarthritis. AB - Ahead of Print article withdrawn by publisher PMID- 25706818 TI - Hepatic Stellate Cells Improve Engraftment of Human Primary Hepatocytes: A Preclinical Transplantation Study in an Animal Model. AB - Human hepatocytes are used for liver cell therapy, but the small number of engrafting cells limits the benefit of cell transplantation. We tested whether cotransplantation of hepatocytes with hepatic stellate cells (HSCs) could improve hepatocyte engraftment in vivo. Human primary hepatocytes were transplanted into SCID mice either alone or in a mixture with HSCs (quiescent or after culture activation) or LX-2 cells (ratio 20:1). Four weeks after transplantation into mouse livers, human albumin-positive (huAlb(+)) hepatocytes were found scattered. When cotransplanted in a mixture with HSCs or LX-2 cells, huAlb(+) hepatocytes formed clusters and were more numerous occupying 2- to 5.9-fold more surface on the tissue section than in livers transplanted with hepatocytes alone. Increased huAlb mRNA expression in livers transplanted with the cell mixtures confirmed those results. The presence of HSCs increased the number of hepatocytes entrapped in the host liver at an early time point posttransplantation but not their proliferation in situ as assessed by cumulative incorporation of BrdU. Importantly, 4 weeks posttransplantation, we found no accumulation of alphaSMA(+) activated HSCs or collagen deposition. To follow the fate of transplanted HSCs, HSCs derived from GFP(+) mice were injected into GFP(-) littermates: 17 h posttransplant, GFP(+) HSCs were found in the sinusoids, without proliferating or actively producing ECM; they were undetectable at later time points. Coculture with HSCs improved the number of adherent hepatocytes, with best attachment obtained when hepatocytes were seeded in contact with activated HSCs. In vivo, cotransplantation of hepatocytes with HSCs into a healthy liver recipient does not generate fibrosis, but significantly improves the engraftment of hepatocytes, probably by ameliorating cell homing. PMID- 25706819 TI - Current proceedings of cerebral palsy. AB - Cerebral palsy (CP) is a complicated disease with varying causes and outcomes. It has created significant burden to both affected families and societies, not to mention the quality of life of the patients themselves. There is no cure for the disease; therefore, development of effective therapeutic strategies is in great demand. Recent advances in regenerative medicine suggest that the transplantation of stem cells, including embryonic stem cells, neural stem cells, bone marrow mesenchymal stem cells, induced pluripotent stem cells, umbilical cord blood cells, and human embryonic germ cells, focusing on the root of the problem, may provide the possibility of developing a complete cure in treating CP. However, safety is the first factor to be considered because some stem cells may cause tumorigenesis. Additionally, more preclinical and clinical studies are needed to determine the type of cells, route of delivery, cell dose, timing of transplantation, and combinatorial strategies to achieve an optimal outcome. PMID- 25706820 TI - Longitudinal polysomnographic findings in infantile Pompe disease. AB - Infantile Pompe disease is a rare, metabolic disorder due to deficiency of the enzyme acid alpha-glucosidase that degrades lysosomal glycogen. The deficiency leads to multisystem dysfunction. Neuromuscular weakness due to metabolic myopathy is present, which predisposes children to sleep-disordered breathing. With the advent of enzyme replacement therapy (ERT), children are living longer, and there is a new natural history that is emerging. In a prior paper on our cohort of infantile Pompe disease patients, we reported a high incidence of both hypoventilation and obstructive sleep apnea (OSA). In this retrospective study, we analyzed longitudinal nocturnal polysomnography results from 10 patients with infantile-onset Pompe disease, all of which were on enzyme replacement therapy for a mean of 34.9 months at the time of follow-up study. Patients demonstrated relative stability in sleep disordered breathing, with a trend towards improvement in both OSA and central sleep apnea. ERT may help in the treatment of sleep apnea in this cohort. PMID- 25706822 TI - Local versus global fold switching in protein evolution: insight from a three letter continuous model. AB - Recent design experiments have demonstrated that some proteins can switch their folds in response to a small number of point mutations either directly, in a single mutational step, or via intermediate bistable sequences, which populate two different folds simultaneously. Here we explore the hypothesis that bistable intermediates are more common in switches between structurally similar folds while direct switches are more common between dissimilar folds. To this end, we use a reduced model with seven atoms per amino acid and three amino acid types as a biophysical basis for protein folding and stability. We compare a set of mutational pathways, selected for optimal stability properties, that lead to switches between beta-hairpin and alpha-helix folds with 16 amino acids and between [Formula: see text] and [Formula: see text] folds with 35 amino acids, respectively. Fold switching in each case is sharp, taking only a few mutations to be completed. While the sharpness of mutationally driven protein fold switching can be traced to a shift in the energy balance of the two native states, conformational entropy contributes to determining the point at which fold switching occurs along a pathway. PMID- 25706821 TI - Intraoperative imaging during Mohs surgery with reflectance confocal microscopy: initial clinical experience. AB - Mohs surgery for the removal of nonmelanoma skin cancers (NMSCs) is performed in stages, while being guided by the examination for residual tumor with frozen pathology. However, preparation of frozen pathology at each stage is time consuming and labor intensive. Real-time intraoperative reflectance confocal microscopy(RCM), combined with video mosaicking, may enable rapid detection of residual tumor directly in the surgical wounds on patients. We report our initial experience on 25 patients, using aluminum chloride for nuclear contrast. Imaging was performed in quadrants in the wound to simulate the Mohs surgeon's examination of pathology. Images and videos of the epidermal and dermal margins were found to be of clinically acceptable quality. Bright nuclear morphology was identified at the epidermal margin and detectable in residual NMSC tumors. The presence of residual tumor and normal skin features could be detected in the peripheral and deep dermal margins. Intraoperative RCM imaging may enable detection of residual tumor directly on patients during Mohs surgery, and may serve as an adjunct for frozen pathology. Ultimately, for routine clinical utility, a stronger tumor-to-dermis contrast may be necessary, and also a smaller microscope with an automated approach for imaging in the entire wound in a rapid and controlled manner. PMID- 25706823 TI - Segment-specific adhesion as a driver of convergent extension. AB - Convergent extension, the simultaneous extension and narrowing of tissues, is a crucial event in the formation of the main body axis during embryonic development. It involves processes on multiple scales: the sub-cellular, cellular and tissue level, which interact via explicit or intrinsic feedback mechanisms. Computational modelling studies play an important role in unravelling the multiscale feedbacks underlying convergent extension. Convergent extension usually operates in tissue which has been patterned or is currently being patterned into distinct domains of gene expression. How such tissue patterns are maintained during the large scale tissue movements of convergent extension has thus far not been investigated. Intriguingly, experimental data indicate that in certain cases these tissue patterns may drive convergent extension rather than requiring safeguarding against convergent extension. Here we use a 2D Cellular Potts Model (CPM) of a tissue prepatterned into segments, to show that convergent extension tends to disrupt this pre-existing segmental pattern. However, when cells preferentially adhere to cells of the same segment type, segment integrity is maintained without any reduction in tissue extension. Strikingly, we demonstrate that this segment-specific adhesion is by itself sufficient to drive convergent extension. Convergent extension is enhanced when we endow our in silico cells with persistence of motion, which in vivo would naturally follow from cytoskeletal dynamics. Finally, we extend our model to confirm the generality of our results. We demonstrate a similar effect of differential adhesion on convergent extension in tissues that can only extend in a single direction (as often occurs due to the inertia of the head region of the embryo), and in tissues prepatterned into a sequence of domains resulting in two opposing adhesive gradients, rather than alternating segments. PMID- 25706824 TI - Sensitivity Enhanced Vital Sign Detection Based on Antenna Reflection Coefficient Variation. AB - This paper presents a vital sign detection sensor based on reflection coefficient variance from an antenna used in wireless communication devices. The near-field effect is estimated by performing 3D full-wave simulations using a dipole antenna and the magnitude variation of the reflection coefficient induced by human thorax movement due to heart and lungs is observed. The results support the possibility of vital sign detection based on the magnitude variation of the reflection coefficient from an antenna, which can be explained as a narrowband modulation scheme. In particular, a sensitivity enhancement method is proposed and analyzed, and experiments are carried out for heartbeat detection using a dipole antenna with the proposed system. Experimental results are compared between the direct detection and sensitivity enhancement detection schemes. FM signal is also applied to confirm that the proposed sensor works properly in conjunction with an existing communication system. The proposed cardiopulmonary detection sensor is implemented with off-the-shelf components at 2.4 GHz and excellent performance is obtained. PMID- 25706826 TI - Corrigendum. PMID- 25706827 TI - Interpersonal reactivity and the attribution of emotional reactions. AB - The ability to identify the cause of another person's emotional reaction is an important component associated with improved success of social relationships and survival. Although many studies have investigated the mechanisms involved in emotion recognition, very little is currently known regarding the processes involved during emotion attribution decisions. Research on complementary "emotion understanding" mechanisms, including empathy and theory of mind, has demonstrated that emotion understanding decisions are often made through relatively emotion- or cognitive-based processing streams. The current study was designed to investigate the behavioral and brain mechanisms involved in emotion attribution decisions. We predicted that dual processes, emotional and cognitive, are engaged during emotion attribution decisions. Sixteen healthy adults completed the Interpersonal Reactivity Index to characterize individual differences in tendency to make emotion- versus cognitive-based interpersonal decisions. Participants then underwent functional MRI while making emotion attribution decisions. We found neuroimaging evidence that emotion attribution decisions engage a similar brain network as other forms of emotion understanding. Further, we found evidence in support of a dual processes model involved during emotion attribution decisions. Higher scores of personal distress were associated with quicker emotion attribution decisions and increased anterior insula activity. Conversely, higher scores in perspective taking were associated with delayed emotion attribution decisions and increased prefrontal cortex and premotor activity. These findings indicate that the making of emotion attribution decisions relies on dissociable emotional and cognitive processing streams within the brain. PMID- 25706825 TI - Amine oxidative N-dealkylation via cupric hydroperoxide Cu-OOH homolytic cleavage followed by site-specific fenton chemistry. AB - Copper(II) hydroperoxide species are significant intermediates in processes such as fuel cells and (bio)chemical oxidations, all involving stepwise reduction of molecular oxygen. We previously reported a Cu(II)-OOH species that performs oxidative N-dealkylation on a dibenzylamino group that is appended to the 6 position of a pyridyl donor of a tripodal tetradentate ligand. To obtain insights into the mechanism of this process, reaction kinetics and products were determined employing ligand substrates with various para-substituent dibenzyl pairs (-H,-H; -H,-Cl; -H,-OMe, and -Cl,-OMe), or with partially or fully deuterated dibenzyl N-(CH2Ph)2 moieties. A series of ligand-copper(II) bis perchlorate complexes were synthesized, characterized, and the X-ray structures of the -H,-OMe analogue were determined. The corresponding metastable Cu(II)-OOH species were generated by addition of H2O2/base in acetone at -90 degrees C. These convert (t1/2 ~ 53 s) to oxidatively N-dealkylated products, producing para substituted benzaldehydes. Based on the experimental observations and supporting DFT calculations, a reaction mechanism involving dibenzylamine H-atom abstraction or electron-transfer oxidation by the Cu(II)-OOH entity could be ruled out. It is concluded that the chemistry proceeds by rate limiting Cu-O homolytic cleavage of the Cu(II)-(OOH) species, followed by site-specific copper Fenton chemistry. As a process of broad interest in copper as well as iron oxidative (bio)chemistries, a detailed computational analysis was performed, indicating that a Cu(I)OOH species undergoes O-O homolytic cleavage to yield a hydroxyl radical and Cu(II)OH rather than heterolytic cleavage to yield water and a Cu(II)-O(*-) species. PMID- 25706828 TI - Implications of emotion regulation strategies for empathic concern, social attitudes, and helping behavior. AB - Empathic concern-a sense of caring and compassion in response to the needs of others-is a type of emotional response to the plights and misfortunes of others that predicts positive social attitudes and altruistic interpersonal behaviors. One psychological process that has been posited to facilitate empathic concern is the ability to regulate one's own emotions. However, existing research links some emotion-regulation approaches (e.g., suppression) to social outcomes that would appear at odds with empathic concern, such as decreased interpersonal closeness. In the present research, we tested whether relying on suppression to regulate one's emotions would lead to decreases in empathic concern-and related downstream variables, such as negative social attitudes and unwillingness to engage in altruistic behavior-when learning about another person's misfortune. In Study 1, dispositional and instructionally induced suppression was negatively associated with empathic concern, which led to increased stigmatizing attitudes. By contrast, instructing participants to use another emotion-regulation strategy examined for comparison-reappraisal-did not decrease empathic concern, and dispositional reliance on reappraisal was actually positively associated with empathic concern. In Study 2, the findings of Study 1 regarding the effects of habitual use of reappraisal and suppression were replicated, and reliance on suppression was also found to be associated with reluctance to engage in helping behaviors. These findings are situated within the existing literature and employed to shed new light on the interpersonal consequences of intrapersonal emotion-regulation strategies. PMID- 25706829 TI - The role of valence focus and appraisal overlap in emotion differentiation. AB - Emotion differentiation refers to the level of specificity with which people distinguish between their emotional states and is considered to play an important role for psychological well-being. Yet, not much is known about what characterizes people high or low in emotion differentiation and what underlies these differences. In 2 studies involving experience sampling (Studies 1-2) and lab based (Study 2) methods, we investigated how emotion differentiation is related to individual differences in valence focus and the overlap in appraisal patterns between emotions. In line with expectations, results showed that high levels of both positive and negative emotion differentiation are related to lower levels of valence focus and lower levels of appraisal overlap between emotions. These findings suggest that individuals who are low in emotion differentiation mainly emphasize the valence aspect of emotions while individuals who are high in emotion differentiation make stronger distinctions between emotions in terms of their underlying appraisal profiles. PMID- 25706831 TI - Context is more powerful than we think: contextual cues override facial cues even for valence. AB - Context-the external situation-overrides facial information when judging the emotion from spontaneous facial expressions, even on valence. Observers (N = 60) judged the emotion in each of 15 facial expressions of athletes in the 2012 Olympics who had just won or lost their respective event. Observers were given either correct, incorrect, or no information about the results of the event. Context consistently overrode facial information, regardless of what the facial expression displayed. PMID- 25706830 TI - Napping and the selective consolidation of negative aspects of scenes. AB - After information is encoded into memory, it undergoes an offline period of consolidation that occurs optimally during sleep. The consolidation process not only solidifies memories, but also selectively preserves aspects of experience that are emotionally salient and relevant for future use. Here, we provide evidence that an afternoon nap is sufficient to trigger preferential memory for emotional information contained in complex scenes. Selective memory for negative emotional information was enhanced after a nap compared with wakefulness in 2 control conditions designed to carefully address interference and time-of-day confounds. Although prior evidence has connected negative emotional memory formation to REM sleep physiology, we found that non-REM delta activity and the amount of slow wave sleep (SWS) in the nap were robustly related to the selective consolidation of negative information. These findings suggest that the mechanisms underlying memory consolidation benefits associated with napping and nighttime sleep are not always the same. Finally, we provide preliminary evidence that the magnitude of the emotional memory benefit conferred by sleep is equivalent following a nap and a full night of sleep, suggesting that selective emotional remembering can be economically achieved by taking a nap. PMID- 25706832 TI - Facets of emotional awareness and associations with emotion regulation and depression. AB - Emotion theories posit that effective emotion regulation depends upon the nuanced information provided by emotional awareness; attending to and understanding one's own emotions. Additionally, the strong associations between facets of emotional awareness and various forms of psychopathology may be partially attributable to associations with emotion regulation. These logically compelling hypotheses are largely uninvestigated, including which facets compose emotional awareness and how they relate to emotion regulation strategies and psychopathology. We used exploratory structural equation modeling of individual difference measures among a large adult sample (n = 919) recruited online. Results distinguished 4 facets of emotional awareness (type clarity, source clarity, involuntary attention to emotion, and voluntary attention to emotion) that were differentially associated with expressive suppression, acceptance of emotions, and cognitive reappraisal. Facets were associated with depression both directly and indirectly via associations with emotion regulation strategies. We discuss implications for theory and research on emotional awareness, emotion regulation, and psychopathology. PMID- 25706833 TI - Mental fatigue impairs emotion regulation. AB - Because healthy physical and mental functioning depends on the ability to regulate emotions, it is important to identify moderators of such regulations. Whether mental fatigue, subsequent to the depletion of cognitive resources, impairs explicit emotion regulation to negative stimuli is currently unknown. This study explored this possibility. In a within-subject design over 2 separate sessions, healthy individuals performed easy (control session) or difficult (depletion session) cognitive tasks. Subsequently, they were presented with neutral and negative pictures, with instructions to either maintain or regulate (i.e., reduce) the emotions evoked by the pictures. Emotional reactivity was probed with the startle reflex. The negative pictures evoked a similar aversive state in the control and depletion sessions as measured by startle potentiation. However, subjects were able to down-regulate their aversive state only in the control session, not in the depletion session. These results indicate that mental fatigue following performance of cognitive tasks impairs emotion regulation without affecting emotional reactivity. These findings suggest that mental fatigue needs to be incorporated into models of emotion regulation. PMID- 25706834 TI - Dissociation between recognition and detection advantage for facial expressions: a meta-analysis. AB - Happy facial expressions are recognized faster and more accurately than other expressions in categorization tasks, whereas detection in visual search tasks is widely believed to be faster for angry than happy faces. We used meta-analytic techniques for resolving this categorization versus detection advantage discrepancy for positive versus negative facial expressions. Effect sizes were computed on the basis of the r statistic for a total of 34 recognition studies with 3,561 participants and 37 visual search studies with 2,455 participants, yielding a total of 41 effect sizes for recognition accuracy, 25 for recognition speed, and 125 for visual search speed. Random effects meta-analysis was conducted to estimate effect sizes at population level. For recognition tasks, an advantage in recognition accuracy and speed for happy expressions was found for all stimulus types. In contrast, for visual search tasks, moderator analysis revealed that a happy face detection advantage was restricted to photographic faces, whereas a clear angry face advantage was found for schematic and "smiley" faces. Robust detection advantage for nonhappy faces was observed even when stimulus emotionality was distorted by inversion or rearrangement of the facial features, suggesting that visual features primarily drive the search. We conclude that the recognition advantage for happy faces is a genuine phenomenon related to processing of facial expression category and affective valence. In contrast, detection advantages toward either happy (photographic stimuli) or nonhappy (schematic) faces is contingent on visual stimulus features rather than facial expression, and may not involve categorical or affective processing. PMID- 25706835 TI - Negotiating sexuality in home care settings: older lesbians and bisexual women's experiences. AB - There is evidence that lesbians and bisexual women often face prejudice and stigma when accessing routine primary healthcare services. However, limited research to date has examined their experiences outside of primary healthcare contexts or the perspectives of older healthcare users. This paper presents findings from a qualitative study of older lesbians and bisexual women in Ontario who accessed publicly-funded home care services. In qualitative in-depth interviews, 16 women responded to questions about their decision making around disclosure of their sexuality, home care workers' reactions to disclosure and their experiences of receiving care. The thematic analysis of participants' responses demonstrated that they experienced isolation and ongoing anxiety, as well overt and subtle examples of heterosexism and discrimination. However, there was also evidence of participants' resilience and resistance to heteronormativity and sexual minority stress. These findings have implications for our understanding of lesbians' and bisexual women's healthcare experiences and for policy recommendations. PMID- 25706836 TI - Glycans as biofunctional ligands for gold nanorods: stability and targeting in protein-rich media. AB - Poly(ethylene glycol) (PEG) has become the gold standard for stabilization of plasmonic nanoparticles (NPs) in biofluids, because it prevents aggregation while minimizing unspecific interactions with proteins. Application of Au NPs in biological environments requires the use of ligands that can target selected receptors, even in the presence of protein-rich media. We demonstrate here the stabilizing effect of low-molecular-weight glycans on both spherical and rod-like plasmonic NPs under physiological conditions, as bench-marked against the well established PEG ligands. Glycan-coated NPs are resistant to adsorption of proteins from serum-containing media and avoid phagocytosis by macrophage-like cells, but retain selectivity toward carbohydrate-binding proteins in protein rich biological media. These results open the way toward the design of efficient therapeutic/diagnostic glycan-decorated plasmonic nanotools for specific biological applications. PMID- 25706837 TI - Beyond political rhetoric to new ideas for a sustainable NHS. PMID- 25706838 TI - Health care-associated infections in the USA. PMID- 25706839 TI - What are affordable vaccines? PMID- 25706840 TI - Drug-resistance mechanisms and tuberculosis drugs. PMID- 25706842 TI - Yinghao Sun: leader of research on prostate cancer in China. PMID- 25706843 TI - Effects of long-term use of cardiovascular drugs. PMID- 25706844 TI - Dual antiplatelet treatment after stenting. PMID- 25706845 TI - Dual antiplatelet treatment after stenting. PMID- 25706847 TI - Training is key to improve child health globally. PMID- 25706846 TI - Dual antiplatelet treatment after stenting - Authors' reply. PMID- 25706848 TI - Measles vaccine still saves children's lives. PMID- 25706849 TI - Integrity and the European society of cardiology. PMID- 25706850 TI - Can India be tuberculosis-free by 2050? PMID- 25706851 TI - Preparation of at-risk west African countries for Ebola. PMID- 25706852 TI - Social science intelligence in the global Ebola response. PMID- 25706853 TI - Ovarian hyperstimulation from ectopic hypersecretion of follicle stimulating hormone. PMID- 25706854 TI - Adsorption mechanism of myelin basic protein on model substrates and its bridging interaction between the two surfaces. AB - Myelin basic protein (MBP) is an intrinsically disordered (unstructured) protein known to play an important role in the stability of myelin's multilamellar membrane structure in the central nervous system. The adsorption of MBP and its capacity to interact with and bridge solid substrates has been studied using a surface forces apparatus (SFA) and a quartz crystal microbalance with dissipation (QCM-D). Adsorption experiments show that MBP molecules adsorb to the surfaces in a swollen state before undergoing a conformational change into a more compact structure with a thickness of ~3 nm. Moreover, this compact structure is able to interact with nearby mica surfaces to form adhesive bridges. The measured adhesion force (energy) between two bridged surfaces is 1.0 +/- 0.1 mN/m, (Ead = 0.21 +/- 0.02 mJ/m(2)), which is slightly smaller than our previously reported adhesion force of 1.7 mN/m (Ead = 0.36 mJ/m(2)) for MBP adsorbed on two supported lipid bilayers (Lee et al., Proc. Natl. Acad. Sci. U.S.A. 2014, 111, E768-E775). The saturated surface concentration of compact MBP on a single SiO2 surface reaches a stable value of 310 +/- 10 ng/cm(2) regardless of the bulk MBP concentration. A kinetic three-step adsorption model was developed that accurately fits the adsorption data. The developed model is a general model, not limited to intrinsically disordered proteins, that can be extended to the adsorption of various chemical compounds that undergo chemical reactions and/or conformational changes upon adsorbing to surfaces. Taken together with our previously published data (Lee et al., Proc. Natl. Acad. Sci. U.S.A. 2014, 111, E768-E775), the present results confirm that conformational changes of MBP upon adsorption are a key for strong adhesion, and that such conformational changes are strongly dependent on the nature of the surfaces. PMID- 25706856 TI - Tunable formation of ordered wrinkles in metal films with controlled thickness gradients deposited on soft elastic substrates. AB - Controlled wrinkled surface is useful for a wide range of applications, including flexible electronics, smart adhesion, wettability, stamping, sensoring, coating, and measuring. In this work, thickness-gradient-guided spontaneous formation of ordered wrinkling patterns in metal films deposited on soft elastic substrates is revealed by atomic force microscopy, theoretic analysis, and simulation. It is observed that in the thicker film region, broad cracks form, and the film surface remains flat. In the thinner film region, the cracks attenuate along the direction of the thickness decrease, and various wrinkle patterns including branched stripes, herringbones, and labyrinths can coexist. The interplay between the residual compression and the thickness gradient leading to the formation of such wrinkling patterns is discussed based on a nonlinear wrinkling model. The simulated wrinkling patterns as well as the variation trends of the wrinkle wavelength and amplitude along the gradient direction are in good agreement with the experimental observations. The report in this work could promote better understanding and fabrication of such ordered wrinkling patterns by tunable thickness gradient. PMID- 25706855 TI - Facet-dependent electrical conductivity properties of Cu2O crystals. AB - It is interesting to examine facet-dependent electrical properties of single Cu2O crystals, because such study greatly advances our understanding of various facet effects exhibited by semiconductors. We show a Cu2O octahedron is highly conductive, a cube is moderately conductive, and a rhombic dodecahedron is nonconductive. The conductivity differences are ascribed to the presence of a thin surface layer having different degrees of band bending. When electrical connection was made on two different facets of a rhombicuboctahedron, a diode like response was obtained, demonstrating the potential of using single polyhedral nanocrystals as functional electronic components. Density of state (DOS) plots for three layers of Cu2O (111), (100), and (110) planes show respective metallic, semimetal, and semiconducting band structures. By examining DOS plots for varying number of planes, the surface layer thicknesses responsible for the facet-dependent electrical properties of Cu2O crystals have been determined to be below 1.5 nm for these facets. PMID- 25706858 TI - One-pot three-component strategy for functionalized 2-aminoimidazoles via ring opening of alpha-nitro epoxides. AB - Functionalized 2-aminoimidazole derivatives have been synthesized via a three component domino reaction of alpha-nitroepoxides and cyanamide with a series of amines under mild conditions without the need for any additives. This reaction represents a practical process for the facile conversion of alpha-nitroepoxides to 2-aminoimidazoles via ring opening of epoxides. PMID- 25706857 TI - Radiofrequency-triggered tumor-targeting delivery system for theranostics application. AB - In this study, a new type of magnetic tumor-targeting PEGylated gold nanoshell drug delivery system (DOX-TSMLs-AuNSs-PEG) based on doxorubicin-loaded thermosensitive magnetoliposomes was successfully obtained. The reverse-phase evaporation method was used to construct the magnetoliposomes, and then gold nanoshells were coated on the surface of it. The DOX-TSMLs-AuNSs-PEG delivery system was synthesized after SH-PEG2000 modification. This multifunction system was combined with a variety of functions, such as radiofrequency-triggered release, chemo-hyperthermia therapy, and dual-mode magnetic resonance/X-ray imaging. Importantly, the DOX-TSMLs-AuNSs-PEG complex was found to escape from endosomes after cellular uptake by radiofrequency-induced endosome disruption before lysosomal degradation. All results in vitro and in vivo indicated that DOX TSMLs-AuNSs-PEG is a promising effective drug delivery system for diagnosis and treatment of tumors. PMID- 25706859 TI - Validation of a method for the determination of AMG 579 in cerebrospinal fluid with a focus on sample collection procedures for clinical trials. AB - Analysis of pharmaceutical compounds in cerebrospinal fluid (CSF) may present challenges due to the combination of the low protein content in this matrix and relatively low drug concentrations, often corresponding to free drug concentrations in plasma, typically found in CSF. A 30% loss of AMG 579 was observed during preparation of quality control samples and further investigation determined that this loss was likely due to binding to collection tubes. This observation also highlighted the possibility of additional losses of AMG 579 that could occur during collection of clinical samples, such as binding to catheters used in the collection of CSF. Loss of AMG 579 in QC samples was reduced from 30% to 5% when the volume of CSF stored in 1.5 mL vials was increased from 0.06 mL to 1 mL. Modest but unavoidable losses of about 20% of AMG 579 were also found following perfusion through both silicone and polypropylene (Pharmed((r)) BPT) collection catheters. Silicone tubing was used for CSF collection based on clinical site preference. An LC-MS/MS method was validated to quantify AMG 579 in human CSF to support clinical testing. The original range of the assay was 1-1000 ng/mL but the LLOQ was subsequently lowered to 0.1 ng/mL to better meet project requirements. Interday bias (% RE) and precision (% CV) were -4.2% and 12.3% at the LLOQ, and less than +/- 0.9% and 8.3% for higher concentrations, respectively. The compound was stable in human CSF for at least 5h at room temperature, 55 days at -70 degrees C (-60 to -80 degrees C range), and through three freeze-thaw cycles. Careful selection of assay conditions and materials minimized losses of the compound during sample collection and storage. While these losses could not be entirely eliminated, practical sample collection and storage conditions were established to allow for analysis of AMG 579 in human clinical trials. PMID- 25706861 TI - Sweet/dessert foods are more appealing to adolescents after sleep restriction. AB - STUDY OBJECTIVE: Examine the effect of experimental sleep restriction (SR) on adolescents' subjective hunger and perceived appeal of sweet/dessert foods versus other foods. A secondary goal was to replicate previous findings on the effects of SR on dietary intake. DESIGN: Randomized cross-over sleep restriction extension paradigm. SETTING: Sleep was obtained and monitored at home. Outcome measures were gathered during office visits. PARTICIPANTS: 31 typically developing adolescents aged 14-17 years. INTERVENTIONS: The three-week protocol consisted of a baseline week, followed randomly by five consecutive nights of SR (6.5 hours in bed) versus healthy sleep duration (HS; 10 hours in bed), a 2-night wash-out period, and a 5-night cross-over. MEASUREMENTS: Sleep was monitored via actigraphy. The morning after each experimental condition, teens rated their hunger, underwent a 24-hour diet recall interview, and rated the appeal of a series of pictures of sweet/dessert foods (e.g., ice cream, candy) and non-sweets (meat, eggs, fruits, vegetables). RESULTS: Teens rated pictures of sweet/dessert foods to be more appealing after SR than after HS (Cohen's d = .41, t = 2.07, p = .045). The sleep manipulation did not affect self-reported hunger or the appeal of non-sweet foods (p >.10). Consistent with our prior work, intake of overall calories was 11% higher and consumption of sweet/dessert servings was 52% greater during SR than HS. CONCLUSIONS: Adolescent SR appears to increase the subjective appeal of sweet/dessert foods, indicating a potential mechanism by which SR might contribute to weight gain and the risk for obesity and chronic illness. PMID- 25706860 TI - Response of benthic foraminifera to organic matter quantity and quality and bioavailable concentrations of metals in Aveiro Lagoon (Portugal). AB - This work analyses the distribution of living benthic foraminiferal assemblages of surface sediments in different intertidal areas of Ria de Aveiro (Portugal), a polihaline and anthropized coastal lagoon. The relationships among foraminiferal assemblages in association with environmental parameters (temperature, salinity, Eh and pH), grain size, the quantity and quality of organic matter (enrichment in carbohydrates, proteins and lipids), pollution caused by metals, and mineralogical data are studied in an attempt to identify indicators of adaptability to environmental stress. In particular, concentrations of selected metals in the surficial sediment are investigated to assess environmental pollution levels that are further synthetically parameterised by the Pollution Load Index (PLI). The PLI variations allowed the identification of five main polluted areas. Concentrations of metals were also analysed in three extracted phases to evaluate their possible mobility, bioavailability and toxicity in the surficial sediment. Polluted sediment in the form of both organic matter and metals can be found in the most confined zones. Whereas enrichment in organic matter and related biopolymers causes an increase in foraminifera density, pollution by metals leads to a decline in foraminiferal abundance and diversity in those zones. The first situation may be justified by the existence of opportunistic species (with high reproduction rate) that can live in low oxic conditions. The second is explained by the sensitivity of some species to pressure caused by metals. The quality of the organic matter found in these places and the option of a different food source should also explain the tolerance of several species to pollution caused by metals, despite their low reproductive rate in the most polluted areas. In this study, species that are sensitive and tolerant to organic matter and metal enrichment are identified, as is the differential sensitivity/tolerance of some species to metals enrichment. PMID- 25706862 TI - Accurate measurement of 5-methylcytosine and 5-hydroxymethylcytosine in human cerebellum DNA by oxidative bisulfite on an array (OxBS-array). AB - The Infinium 450K Methylation array is an established tool for measuring methylation. However, the bisulfite (BS) reaction commonly used with the 450K array cannot distinguish between 5-methylcytosine (5mC) and 5 hydroxymethylcytosine (5hmC). The oxidative-bisulfite assay disambiguates 5mC and 5hmC. We describe the use of oxBS in conjunction with the 450K array (oxBS-array) to analyse 5hmC/5mC in cerebellum DNA. The "methylation" level derived by the BS reaction is the combined level of 5mC and 5hmC at a given base, while the oxBS reaction gives the level of 5mC alone. The level of 5hmC is derived by subtracting the oxBS level from the BS level. Here we present an analysis method that distinguishes genuine positive levels of 5hmC at levels as low as 3%. We performed four replicates of the same sample of cerebellum and found a high level of reproducibility (average r for BS = 98.3, and average r for oxBS = 96.8). In total, 114,734 probes showed a significant positive measurement for 5hmC. The range at which we were able to distinguish 5hmC occupancy was between 3% and 42%. In order to investigate the effects of multiple replicates on 5hmC detection we also simulated fewer replicates and found that decreasing the number of replicates to two reduced the number of positive probes identified by > 50%. We validated our results using qPCR in conjunction with glucosylation of 5hmC sites followed by MspI digestion and we found good concordance with the array estimates (r = 0.94). This experiment provides a map of 5hmC in the cerebellum and a robust dataset for use as a standard in future 5hmC analyses. We also provide a novel method for validating the presence of 5hmC at low levels, and highlight some of the pitfalls associated with measuring 5hmC and 5mC. PMID- 25706863 TI - Di-(2-ethylhexyl) phthalate metabolites in urine show age-related changes and associations with adiposity and parameters of insulin sensitivity in childhood. AB - OBJECTIVES: Phthalates might be implicated with obesity and insulin sensitivity. We evaluated the levels of primary and secondary metabolites of Di-(2-ethylhexyl) phthalate (DEHP) in urine in obese and normal-weight subjects both before and during puberty, and investigated their relationships with auxological parameters and indexes of insulin sensitivity. DESIGN AND METHODS: DEHP metabolites (MEHP, 6 OH-MEHP, 5-oxo-MEHP, 5-OH-MEHP, and 5-CX-MEHP), were measured in urine by RP-HPLC ESI-MS. Traditional statistical analysis and a data mining analysis using the Auto-CM analysis were able to offer an insight into the complex biological connections between the studied variables. RESULTS: The data showed changes in DEHP metabolites in urine related with obesity, puberty, and presence of insulin resistance. Changes in urine metabolites were related with age, height and weight, waist circumference and waist to height ratio, thus to fat distribution. In addition, clear relationships in both obese and normal-weight subjects were detected among MEHP, its products of oxidation and measurements of insulin sensitivity. CONCLUSION: It remains to be elucidated whether exposure to phthalates per se is actually the risk factor or if the ability of the body to metabolize phthalates is actually the key point. Further studies that span from conception to elderly subjects besides further understanding of DEHP metabolism are warranted to clarify these aspects. PMID- 25706864 TI - Hyperbranched polyglycerol as a colloid in cold organ preservation solutions. AB - Hydroxyethyl starch (HES) is a common colloid in organ preservation solutions, such as in University of Wisconsin (UW) solution, for preventing graft interstitial edema and cell swelling during cold preservation of donor organs. However, HES has undesirable characteristics, such as high viscosity, causing kidney injury and aggregation of erythrocytes. Hyperbranched polyglycerol (HPG) is a branched compact polymer that has low intrinsic viscosity. This study investigated HPG (MW-0.5 to 119 kDa) as a potential alternative to HES for cold organ preservation. HPG was synthesized by ring-opening multibranching polymerization of glycidol. Both rat myocardiocytes and human endothelial cells were used as an in vitro model, and heart transplantation in mice as an in vivo model. Tissue damage or cell death was determined by both biochemical and histological analysis. HPG polymers were more compact with relatively low polydispersity index than HES in UW solution. Cold preservation of mouse hearts ex vivo in HPG solutions reduced organ damage in comparison to those in HES-based UW solution. Both size and concentration of HPGs contributed to the protection of the donor organs; 1 kDa HPG at 3 wt% solution was superior to HES-based UW solution and other HPGs. Heart transplants preserved with HPG solution (1 kDa, 3%) as compared with those with UW solution had a better functional recovery, less tissue injury and neutrophil infiltration in syngeneic recipients, and survived longer in allogeneic recipients. In cultured myocardiocytes or endothelial cells, significantly more cells survived after cold preservation with the HPG solution than those with the UW solution, which was positively correlated with the maintenance of intracellular adenosine triphosphate and cell membrane fluidity. In conclusion, HPG solution significantly enhanced the protection of hearts or cells during cold storage, suggesting that HPG is a promising colloid for the cold storage of donor organs and cells in transplantation. PMID- 25706865 TI - White-matter development is different in bilingual and monolingual children: a longitudinal DTI study. AB - Although numerous people grow up speaking more than one language, the impact of bilingualism on brain developing neuroanatomy is still poorly understood. This study aimed to determine whether the changes in the mean fractional-anisotropy (MFA) of language pathways are different between bilingual and monolingual children. Simultaneous-bilinguals, sequential-bilinguals and monolingual, male and female 10-13 years old children participated in this longitudinal study over a period of two years. We used diffusion tensor tractography to obtain mean fractional-anisotropy values of four language related pathways and one control bundle: 1-left-inferior-occipitofrontal fasciculus/lIFOF, 2-left-arcuate fasciculus/lAF/lSLF, 3-bundle arising from the anterior part of corpus-callosum and projecting to orbital lobe/AC-OL, 4-fibres emerging from anterior-midbody of corpus-callosum (CC) to motor cortices/AMB-PMC, 5- right-inferior-occipitofrontal fasciculus rIFOF as the control pathway unrelated to language. These values and their rate of change were compared between 3 groups. FA-values did not change significantly over two years for lAF/lSLF and AC-OL. Sequential-bilinguals had the highest degree of change in the MFA value of lIFOF, and AMB-PMC did not present significant group differences. The comparison of MFA of lIFOF yielded a significantly higher FA-value in simultaneous bilinguals compared to monolinguals. These findings acknowledge the existing difference of the development of the semantic processing specific pathway between children with different semantic processing procedure. These also support the hypothesis that age of second language acquisition affects the maturation and myelination of some language specific white-matter pathways. PMID- 25706866 TI - Antifungal susceptibilities of bloodstream isolates of Candida species from nine hospitals in Korea: application of new antifungal breakpoints and relationship to antifungal usage. AB - We applied the new clinical breakpoints (CBPs) of the Clinical and Laboratory Standards Institute (CLSI) to a multicenter study to determine the antifungal susceptibility of bloodstream infection (BSI) isolates of Candida species in Korea, and determined the relationship between the frequency of antifungal resistant Candida BSI isolates and antifungal use at hospitals. Four hundred and fifty BSI isolates of Candida species were collected over a 1-year period in 2011 from nine hospitals. The susceptibilities of the isolates to four antifungal agents were determined using the CLSI M27 broth microdilution method. By applying the species-specific CBPs, non-susceptibility to fluconazole was found in 16.4% (70/428) of isolates, comprising 2.6% resistant and 13.8% susceptible-dose dependent isolates. However, non-susceptibility to voriconazole, caspofungin, or micafungin was found in 0% (0/370), 0% (0/437), or 0.5% (2/437) of the Candida BSI isolates, respectively. Of the 450 isolates, 72 (16.0%) showed decreased susceptibility to fluconazole [minimum inhibitory concentration (MIC) >=4 MUg/ml]. The total usage of systemic antifungals varied considerably among the hospitals, ranging from 190.0 to 7.7 defined daily dose per 1,000 patient days, and fluconazole was the most commonly prescribed agent (46.3%). By Spearman's correlation analysis, fluconazole usage did not show a significant correlation with the percentage of fluconazole resistant isolates at hospitals. However, fluconazole usage was significantly correlated with the percentage of fluconazole non-susceptible isolates (r = 0.733; P = 0.025) or the percentage of isolates with decreased susceptibility to fluconazole (MIC >=4 MUg/ml) (r = 0.700; P = 0.036) at hospitals. Our work represents the first South Korean multicenter study demonstrating an association between antifungal use and antifungal resistance among BSI isolates of Candida at hospitals using the new CBPs of the CLSI. PMID- 25706867 TI - Effects of isoflurane anesthesia on ensemble patterns of Ca2+ activity in mouse v1: reduced direction selectivity independent of increased correlations in cellular activity. AB - Anesthesia affects brain activity at the molecular, neuronal and network level, but it is not well-understood how tuning properties of sensory neurons and network connectivity change under its influence. Using in vivo two-photon calcium imaging we matched neuron identity across episodes of wakefulness and anesthesia in the same mouse and recorded spontaneous and visually evoked activity patterns of neuronal ensembles in these two states. Correlations in spontaneous patterns of calcium activity between pairs of neurons were increased under anesthesia. While orientation selectivity remained unaffected by anesthesia, this treatment reduced direction selectivity, which was attributable to an increased response to the null-direction. As compared to anesthesia, populations of V1 neurons coded more mutual information on opposite stimulus directions during wakefulness, whereas information on stimulus orientation differences was lower. Increases in correlations of calcium activity during visual stimulation were correlated with poorer population coding, which raised the hypothesis that the anesthesia-induced increase in correlations may be causal to degrading directional coding. Visual stimulation under anesthesia, however, decorrelated ongoing activity patterns to a level comparable to wakefulness. Because visual stimulation thus appears to 'break' the strength of pairwise correlations normally found in spontaneous activity under anesthesia, the changes in correlational structure cannot explain the awake-anesthesia difference in direction coding. The population-wide decrease in coding for stimulus direction thus occurs independently of anesthesia-induced increments in correlations of spontaneous activity. PMID- 25706868 TI - Factors affecting cerebral oxygenation in hemodialysis patients: cerebral oxygenation associates with pH, hemodialysis duration, serum albumin concentration, and diabetes mellitus. AB - BACKGROUND: Patients undergoing hemodialysis (HD) often develop cerebral disease complications. Furthermore, cerebral regional saturation of oxygen (rSO2) was previously reported to be significantly lower in HD patients than in healthy subjects. We aimed to identify the factors affecting the cerebral rSO2 in HD patients. METHODS: Fifty-four HD patients (38 men and 16 women; mean age, 67.7 +/ 1.2 years, HD duration, 6.5 +/- 1.9 years) were recruited. Cerebral rSO2 was monitored at the forehead before HD using an INVOS 5100C (Covidien Japan, Tokyo, Japan). RESULTS: The rSO2 levels were significantly lower in HD patients compared with healthy controls (49.5 +/- 1.7% vs. 68.9 +/- 1.6%, p <0.001). Multiple regression analysis showed that cerebral rSO2 independently associated with pH (standardized coefficient: -0.35), HD duration (standardized coefficient: -0.33), and serum albumin concentration (standardized coefficient: 0.28). Furthermore, the rSO2 was significantly lower in HD patients with diabetes mellitus (DM), compared with patients without DM (46.8 +/- 1.7% vs. 52.1 +/- 1.8%, p <0.05). CONCLUSIONS: In HD patients, cerebral rSO2 was affected by multiple factors, including pH, HD duration, and serum albumin concentration. Furthermore, this is the first report describing significantly lower levels of rSO2 in HD patients with DM than in those without DM. PMID- 25706869 TI - The effects of electronic cigarette emissions on systemic cotinine levels, weight and postnatal lung growth in neonatal mice. AB - BACKGROUND/OBJECTIVE: Electronic cigarette (E-cigarettes) emissions present a potentially new hazard to neonates through inhalation, dermal and oral contact. Exposure to nicotine containing E-cigarettes may cause significant systemic absorption in neonates due to the potential for multi-route exposure. Systemic absorption of nicotine and constituents of E-cigarette emissions may adversely impact weight and lung development in the neonate. To address these questions we exposed neonatal mice to E-cigarette emissions and measured systemic cotinine levels and alveolar lung growth. METHODS/MAIN RESULTS: Neonatal mice were exposed to E-cigarettes for the first 10 days of life. E-cigarette cartridges contained either 1.8% nicotine in propylene glycol (PG) or PG vehicle alone. Daily weights, plasma and urine cotinine levels and lung growth using the alveolar mean linear intercept (MLI) method were measured at 10 days of life and compared to room air controls. Mice exposed to 1.8% nicotine/PG had a 13.3% decrease in total body weight compared to room air controls. Plasma cotinine levels were found to be elevated in neonatal mice exposed to 1.8% nicotine/PG E-cigarettes (mean 62.34+/- 3.3 ng/ml). After adjusting for sex and weight, the nicotine exposed mice were found to have modestly impaired lung growth by MLI compared to room air control mice (p<.054 trial 1; p<.006 trial 2). These studies indicate that exposure to E cigarette emissions during the neonatal period can adversely impact weight gain. In addition exposure to nicotine containing E-cigarettes can cause detectable levels of systemic cotinine, diminished alveolar cell proliferation and a modest impairment in postnatal lung growth. PMID- 25706871 TI - The frequency-response electroretinogram distinguishes cone and abnormal rod function in rd12 mice. AB - Early studies on Rpe65 knockout mice reported that remaining visual function was attributable to cone function. However, this finding has been challenged more and more as time has passed. Electroretinograms (ERGs) showed that rd12 mice, a spontaneous animal model of RPE65 Leber's congenital amaurosis, had sizeable photopic responses. Unfortunately, the recorded ERG waveform was difficult to interpret because of a remarkably delayed peak-time, which resembles a rod response more than a cone response. Here, we compare flicker ERGs in animals with normal rod and cone function (C57BL/6J mice), pure rod function (cpfl5 mice), and pure cone function (Rho(-/-) mice) under different adaptation levels and stimulus intensities. These responses were then compared with those obtained from rd12 mice. Our results showed that normal rods respond to low frequency flicker (5 and 15 Hz) and that normal cones respond to both low and high frequency flicker (5-35 Hz). As was seen in cpfl5 mice, rd12 mice had recordable responses to low frequency flicker (5 and 15Hz), but not to high frequency flicker (25 and 35 Hz). We hypothesize that abnormal rods may be the source of residual vision in rd12 mice, which is proved correct here with double mutant rd12mice. In this study, we show, for the first time, that frequency-response ERGs can effectively distinguish cone- and rod-driven responses in the rd12 mouse. It is another simple and valid method for evaluating the respective contributions of retinal rods and cones. PMID- 25706870 TI - The roles of integrins in function of human neutrophils after their migration through endothelium into interstitial matrix. AB - We investigated the changes in neutrophil phenotype and function after transendothelial migration, and the roles played by integrin receptors in their behaviour. Neutrophils were tracked microscopically as they migrated through endothelial cells into collagen gels, and were retrieved at desired times. When endothelial cells were treated with increasing doses of tumour necrosis factor alpha, neutrophils not only migrated in greater number, but also to a greater depth in the gel. Apoptosis was barely detectable in neutrophils retrieved after 24h, and many remained viable and motile at 48h. Neutrophils retrieved after 1h had increased oxidative capacity and at 24h had similar capacity as freshly isolated neutrophils. However, by then they had impaired ability to phagocytose bacteria. Compared to fresh neutrophils, total mRNA was halved by 24h, but while beta2-integrin expression decreased, beta1- and beta3-integrin increased along with ICAM-1. Studies of integrin blockade indicated that while beta2-integrins were needed to cross the endothelial barrier, no integrins were required for migration within the gel. beta2-integrins also contributed to phagocytosis, but their binding was not required for prolonged survival. These results demonstrate a model for integrated analysis of neutrophil migration and function, and describe development of effector functions and the roles of integrins in human neutrophils for the first time. PMID- 25706872 TI - The risk of cancer in patients with congenital heart disease: a nationwide population-based cohort study in Taiwan. AB - BACKGROUND: The relationship between congenital heart disease (CHD) and malignancies has not been determined. This study aimed to explore the association of CHD with malignancies and examine the risk factors for the development of cancer after a diagnosis of CHD. PATIENTS AND METHODS: This nationwide, population-based cohort study on cancer risk evaluated 31,961 patients with newly diagnosed CHD using the Taiwan National Health Insurance Research Database (NHIRD) between 1998 and 2006. The standardized incidence ratios (SIRs) for all and specific cancer types were analyzed, while the Cox proportional hazard model was used to evaluate risk factors of cancer occurrence. RESULTS: Among patients with newly diagnosed CHD regardless of ages, 187 (0.6%) subsequently developed cancers after a diagnosis of CHD. Patients with CHD had increased risk of cancer (SIR, 1.45; 95% CI, 1.25-1.67), as well as significantly elevated risks of hematologic (SIR, 4.04; 95% CI, 2.76-5.70), central nervous system (CNS) (SIR, 3.51; 95% CI, 1.92-5.89), and head and neck (SIR, 1.81; 95% CI, 1.03-2.94) malignancies. Age (HR, 1.06; 95% CI, 1.05-1.06) and co-morbid chronic liver disease (HR, 1.91; 95% CI, 1.27-2.87) were independent risk factors for cancer occurrence among CHD patients. CONCLUSION: Patients with CHD have significantly increased cancer risk, particularly hematologic, CNS, and head and neck malignancies. Physicians who care for patients with CHD should be aware of their predisposition to malignancy after the diagnosis of CHD. Further studies are warranted to clarify the association between CHD and malignancies. PMID- 25706873 TI - DNA methyltransferase 3a regulates osteoclast differentiation by coupling to an S adenosylmethionine-producing metabolic pathway. AB - Metabolic reprogramming occurs in response to the cellular environment to mediate differentiation, but the fundamental mechanisms linking metabolic processes to differentiation programs remain to be elucidated. During osteoclast differentiation, a shift toward more oxidative metabolic processes occurs. In this study we identified the de novo DNA methyltransferase 3a (Dnmt3a) as a transcription factor that couples these metabolic changes to osteoclast differentiation. We also found that receptor activator of nuclear factor-kappaB ligand (RANKL), an essential cytokine for osteoclastogenesis, induces this metabolic shift towards oxidative metabolism, which is accompanied by an increase in S-adenosylmethionine (SAM) production. We found that SAM-mediated DNA methylation by Dnmt3a regulates osteoclastogenesis via epigenetic repression of anti-osteoclastogenic genes. The importance of Dnmt3a in bone homeostasis was underscored by the observations that Dnmt3a-deficient osteoclast precursor cells do not differentiate efficiently into osteoclasts and that mice with an osteoclast-specific deficiency in Dnmt3a have elevated bone mass due to a smaller number of osteoclasts. Furthermore, inhibition of DNA methylation by theaflavin 3,3'-digallate abrogated bone loss in models of osteoporosis. Thus, this study reveals the role of epigenetic processes in the regulation of cellular metabolism and differentiation, which may provide the molecular basis for a new therapeutic strategy for a variety of bone disorders. PMID- 25706875 TI - Modeling colorectal cancer using CRISPR-Cas9-mediated engineering of human intestinal organoids. AB - Human colorectal tumors bear recurrent mutations in genes encoding proteins operative in the WNT, MAPK, TGF-beta, TP53 and PI3K pathways. Although these pathways influence intestinal stem cell niche signaling, the extent to which mutations in these pathways contribute to human colorectal carcinogenesis remains unclear. Here we use the CRISPR-Cas9 genome-editing system to introduce multiple such mutations into organoids derived from normal human intestinal epithelium. By modulating the culture conditions to mimic that of the intestinal niche, we selected isogenic organoids harboring mutations in the tumor suppressor genes APC, SMAD4 and TP53, and in the oncogenes KRAS and/or PIK3CA. Organoids engineered to express all five mutations grew independently of niche factors in vitro, and they formed tumors after implantation under the kidney subcapsule in mice. Although they formed micrometastases containing dormant tumor-initiating cells after injection into the spleen of mice, they failed to colonize in the liver. In contrast, engineered organoids derived from chromosome-instable human adenomas formed macrometastatic colonies. These results suggest that 'driver' pathway mutations enable stem cell maintenance in the hostile tumor microenvironment, but that additional molecular lesions are required for invasive behavior. PMID- 25706876 TI - Accuracy and reproducibility of adipose tissue measurements in young infants by whole body magnetic resonance imaging. AB - PURPOSE: MR might be well suited to obtain reproducible and accurate measures of fat tissues in infants. This study evaluates MR-measurements of adipose tissue in young infants in vitro and in vivo. MATERIAL AND METHODS: MR images of ten phantoms simulating subcutaneous fat of an infant's torso were obtained using a 1.5T MR scanner with and without simulated breathing. Scans consisted of a cartesian water-suppression turbo spin echo (wsTSE) sequence, and a PROPELLER wsTSE sequence. Fat volume was quantified directly and by MR imaging using k means clustering and threshold-based segmentation procedures to calculate accuracy in vitro. Whole body MR was obtained in sleeping young infants (average age 67+/-30 days). This study was approved by the local review board. All parents gave written informed consent. To obtain reproducibility in vivo, cartesian and PROPELLER wsTSE sequences were repeated in seven and four young infants, respectively. Overall, 21 repetitions were performed for the cartesian sequence and 13 repetitions for the PROPELLER sequence. RESULTS: In vitro accuracy errors depended on the chosen segmentation procedure, ranging from 5.4% to 76%, while the sequence showed no significant influence. Artificial breathing increased the minimal accuracy error to 9.1%. In vivo reproducibility errors for total fat volume of the sleeping infants ranged from 2.6% to 3.4%. Neither segmentation nor sequence significantly influenced reproducibility. CONCLUSION: With both cartesian and PROPELLER sequences an accurate and reproducible measure of body fat was achieved. Adequate segmentation was mandatory for high accuracy. PMID- 25706874 TI - LTB4 promotes insulin resistance in obese mice by acting on macrophages, hepatocytes and myocytes. AB - Insulin resistance results from several pathophysiologic mechanisms, including chronic tissue inflammation and defective insulin signaling. We found that liver, muscle and adipose tissue exhibit higher levels of the chemotactic eicosanoid LTB4 in obese high-fat diet (HFD)-fed mice. Inhibition of the LTB4 receptor Ltb4r1, through either genetic or pharmacologic loss of function, led to an anti inflammatory phenotype with protection from insulin resistance and hepatic steatosis. In vitro treatment with LTB4 directly enhanced macrophage chemotaxis, stimulated inflammatory pathways, reduced insulin-stimulated glucose uptake in L6 myocytes, and impaired insulin-mediated suppression of hepatic glucose output in primary mouse hepatocytes. This was accompanied by lower insulin-stimulated Akt phosphorylation and higher Irs-1/2 serine phosphorylation, and all of these events were dependent on Galphai and Jnk1, two downstream mediators of Ltb4r1 signaling. These observations elucidate a novel role of the LTB4-Ltb4r1 signaling pathway in hepatocyte and myocyte insulin resistance, and they show that in vivo inhibition of Ltb4r1 leads to robust insulin-sensitizing effects. PMID- 25706878 TI - Added value of arterial enhancement fraction color maps for the characterization of small hepatic low-attenuating lesions in patients with colorectal cancer. AB - OBJECTIVE: To assess the added value of arterial enhancement fraction (AEF) color maps for the differentiation of small metastases from hepatic benign lesions. SUBJECTS AND METHODS: We retrospectively analyzed 46 patients with colorectal cancer who underwent multiphasic liver CT imaging and had low-attenuating liver lesions smaller than 3 cm (123 total lesions; metastasis: benign = 32:91). AEF color maps of the liver were created from multiphasic liver CT images using dedicated software. Two radiologists independently reviewed multiphasic CT image sets alone and in combination with image sets with AEF color maps using a five point scale. The additional diagnostic value of the color maps was assessed by means of receiver-operating characteristic (ROC) analysis. RESULTS: The area under the ROC curve (Az) increased when multiphasic CT images were combined with AEF color map analysis as compared with evaluation based only on multiphasic CT images (from 0.698 to 0.897 for reader 1, and from 0.825 to 0.945 for reader 2; P < 0.001 and 0.002, respectively). The increase Az was especially significant for lesions less than 1 cm (from 0.702 to 0.888 for reader 1, and from 0.768 to 0.958 for reader 2; P = 0.001 and P = 0.001, respectively). The mean AEF of tumor adjacent parenchyma (35.07 +/- 27.2) was significantly higher than that of tumor free liver parenchyma (27.3 +/- 20.6) (P = 0.04). CONCLUSIONS: AEF color mapping can improve the diagnostic performance for small hepatic metastases from colorectal cancer and may allow for the elimination of additional examinations. PMID- 25706877 TI - Characterization of the juvenile hormone pathway in the viviparous cockroach, Diploptera punctata. AB - Juvenile hormones (JHs) are key regulators of insect development and reproduction. The JH biosynthetic pathway is known to involve 13 discrete enzymatic steps. In the present study, we have characterized the JH biosynthetic pathway in the cockroach Diploptera punctata. The effect of exogenous JH precursors on JH biosynthesis was also determined. Based on sequence similarity, orthologs for the genes directly involved in the pathway were cloned, and their spatial and temporal transcript profiles were determined. The effect of shutting down the JH pathway in adult female cockroaches was studied by knocking down genes encoding HMG-CoA reductase (HMGR) and Juvenile hormone acid methyltransferase (JHAMT). As a result, oocyte development slowed as a consequence of reduction in JH biosynthesis. Oocyte length, fat body transcription of Vg and ovarian vitellin content significantly decreased. In addition, silencing HMGR and JHAMT resulted in a decrease in the transcript levels of other genes in the pathway. PMID- 25706879 TI - A new device for step-down inhibitory avoidance task--effects of low and high frequency in a novel device for passive inhibitory avoidance task that avoids bioimpedance variations. AB - BACKGROUND: Step-down inhibitory avoidance task has been widely used to evaluate aversive memory, but crucial parameters inherent to traditional devices that may influence the behavior analysis (as stimulus frequency, animal's bioimpedance) are frequently neglected. NEW METHOD: We developed a new device for step-down inhibitory avoidance task by modifying the shape and distribution of the stainless steel bars in the box floor where the stimuli are applied. The bars are 2 mm wide, with rectangular shape, arranged in pairs at intervals of 1cm from the next pairs. Each pair makes an electrical dipole where the polarity inverts after each pulse. This device also presents a component that acquires and records the exact current received by the animal foot and precisely controls the frequency of stimulus applied during the entire experiment. RESULT: Different from conventional devices, this new apparatus increases the contact surface with bars and animal's paws, allowing the electric current pass through the animal's paws only, drastically reducing the influence of animal's bioimpedance. The analysis of recorded data showed that the current received by the animal was practically the same as applied, independent of the animal's body composition. Importantly, the aversive memory was observed at specific stimuli intensity and frequency (0.35 or 0.5 mA at 62 and 125 Hz but not at 0.20 mA or 20 Hz). Moreover, with this device it was possible to observe the well-known step-down inhibitory avoidance task memory impairment induced by guanosine. CONCLUSION: This new device offers a substantial improvement for behavioral analysis in step-down inhibitory avoidance task and allows us to precisely compare data from different animals with distinct body composition. PMID- 25706882 TI - Ozanezumab dose selection for amyotrophic lateral sclerosis by pharmacokinetic pharmacodynamic modelling of immunohistochemistry data from patient muscle biopsies. AB - Amyotrophic Lateral Sclerosis (ALS) is a rare and fatal neurodegenerative disease with a high unmet medical need. In this context, a potential therapy should be brought to patients in the most expeditious way and early exploration of pharmacology is highly beneficial. Ozanezumab, a humanised IgG monoclonal antibody against Nogo-A protein which is an inhibitor of neurite outgrowth, is currently under development for the treatment of ALS and has been recently assessed in 76 patients in a first-in-human study. Inadequate target engagement has been recognised as a major contributing reason for drug trial failures. In this work, we describe the development of a pharmacokinetic-pharmacodynamic (PKPD) model using immunohistochemistry (IHC) data of co-localization of ozanezumab with Nogo-A in skeletal muscle as a surrogate measure of target engagement. The rich plasma concentration data and the sparse IHC data after one or two intravenous doses of ozanezumab were modelled simultaneously using a non linear mixed-effect approach. The final PKPD model was a two-compartment PK model combined with an effect compartment PD model that accounted for the delay in ozanezumab concentrations to reach the site of action which is skeletal muscle. Diagnostic plots showed a satisfactory fit of both PK and IHC data. The model was used as a simulation tool to design a dose regimen for sustained drug-target co localization in a phase II study. PMID- 25706883 TI - Challenges of correlating pH change with relief of clinical symptoms in gastro esophageal reflux disease: a phase III, randomized study of Zegerid versus Losec. AB - BACKGROUND: Zegerid (on demand immediate-release omeprazole and sodium bicarbonate combination therapy) has demonstrated earlier absorption and more rapid pH change compared with Losec (standard enteric coated omeprazole), suggesting more rapid clinical relief of heartburn. This Phase III, multicenter, double-blind, double-dummy, randomized study assessed the clinical superiority of Zegerid versus Losec for rapid relief of heartburn associated with gastro esophageal reflux disease (GERD). METHODS: Patients with a history of frequent (2 3 days/week) uncomplicated GERD, were randomized to receive Zegerid (20 mg) or Losec (20 mg) with corresponding placebo. Study medication was self-administered on the first episode of heartburn, and could be taken for up to 3 days within a 14 day study period. Heartburn severity was self assessed up to 180 minutes post dose (9 point Likert scale). Primary endpoint was median time to sustained response (>=3 point reduction in heartburn severity for >=45 minutes). RESULTS: Of patients randomized to Zegerid (N=122) or Losec (N=117), 228/239 had recorded >=1 evaluable heartburn episodes and were included in the modified intent-to treat population. No significant between-group differences were observed for median time to sustained response (60.0 vs. 52.2 minutes, Zegerid [N=117] and Losec [N=111], respectively), sustained partial response (both, 37.5 minutes) and sustained total relief (both, 105 minutes). Significantly more patients treated with Zegerid reached sustained total relief within 0-30 minutes post dose in all analysis sets (p<0.05). Both treatments were well tolerated and did not raise any safety concerns. CONCLUSIONS: Superiority of Zegerid over Losec for rapid heartburn relief was not demonstrated; both treatments were equally effective however the rapid onset of action of Losec was unexpected. Factors, including aspects of study design may have contributed to this. This study supports previously reported difficulty in correlating intra-gastric pH change with clinical effect in GERD therapy, highlighting the significance of several technical considerations for studies of this type. TRIAL REGISTRATION: ClinicalTrials.gov NCT01493089. PMID- 25706884 TI - Donor HLA-specific Abs: to BMT or not to BMT? AB - The engraftment failure associated with Abs to donor-specific HLA (DSA) limits options for sensitized BMT candidates. Fourteen of fifteen patients with no other viable donor options were desensitized and transplanted using a regimen of plasmapheresis and low-dose i.v. Ig modified to accommodate pre-BMT conditioning. DSA levels were assessed by solid-phase immunoassays and cell-based crossmatch tests. DSA levels were monitored throughout desensitization and on day -1 to determine if there was any DSA rebound that would require additional treatment. A mean reduction in DSA level of 64.4% was achieved at the end of desensitization, with a subsequent reduction of 85.5% after transplantation. DSA in 11 patients was reduced to levels considered negative post-BMT, whereas DSA in three patients remained at low levels. All 14 patients achieved donor engraftment by day +60; however, seven patients suffered disease relapses. Four patients experienced mild, grade 1 GVHD. Factors influencing the response to desensitization include initial DSA strength, number, specificity, DSA rebound and a mismatch repeated from a prior transplant. While desensitization should be reserved for patients with limited donor options, careful DSA assessment and monitoring can facilitate successful engraftment after BMT. PMID- 25706881 TI - PAQR3 modulates H3K4 trimethylation by spatial modulation of the regulatory subunits of COMPASS-like complexes in mammalian cells. AB - Histone modification plays important roles in many biological processes such as development and carcinogenesis. Methylation of histone H3 lysine 4 (H3K4) is commonly associated with transcriptional activation of genes. H3K4 methylation in mammalian cells is carried out by COMPASS (complex of proteins associated with Set1)-like complexes that are composed of catalytic subunits such as MLL1 (mixed lineage leukaemia 1) and multiple regulatory subunits in which WDR5 (WD40 repeat containing protein 5), RBBP5 (retinoblastoma-binding protein 5), ASH2 (absent, small or homoeotic discs 2) and DPY30 [constituting the WRAD sub-complex (WDR5 ASH2-RBBP5-DPY30 complex)] are the major ones shared from yeast to metazoans. We report, in the present paper, a new mode of spatial regulation of H3K4 methyltransferase complexes. PAQR3 (progestin and adipoQ receptors member 3), a tumour suppressor specifically localized in the Golgi apparatus, negatively regulates H3K4 trimethylation (H3K4me3) in mammalian cells. Consistently, HOXC8 and HOXA9 gene expression was negatively regulated by PAQR3 expression levels. Hypoxia-induced H3K4me3 was augmented by PAQR3 knockdown and suppressed by PAQR3 overexpression in AGS gastric cancer cells. PAQR3 was able to interact directly or indirectly with the four members of the WRAD sub-complex and tether them to the Golgi apparatus, accompanied by reduction in histone methyltransferase activity in the nucleus. PAQR3 also interfered with the interaction of WDR5 with the C-terminus of MLL1 (C-ter). Collectively, our study indicates that PAQR3 negatively modulates H3K4 methylation via altering the subcellular compartmentalization of the core regulatory subunits of the COMPASS-like complexes in mammalian cells. PMID- 25706885 TI - Subsequent malignant neoplasms in pediatric cancer patients treated with and without hematopoietic SCT. AB - Pediatric cancer patients are at increased risk of subsequent malignant neoplasms (SMNs). However, little is known about the contribution of hematopoietic SCT (HSCT) to the development of SMNs. The objective of this study was to compare the incidence of SMNs in a population cohort of childhood cancer survivors treated with and without HSCT. A cohort of 7986 children (age 0-14 years) diagnosed with cancer in the province of Ontario, Canada between 1985 and 2009 was identified in POGONIS (Pediatric Oncology Group of Ontario Networked Information System), a population-based active cancer registry, and linked to a clinical HSCT database. Among this cohort, 796 patients had an HSCT as part of their primary treatment. Of the 375 allogeneic HSCT patients, 14 (3.7%) developed a SMN at a median follow up of 12.3 years (range: 2.0-22.9 years). Of the 421 autologous HSCT patients, 8 (1.9%) developed a SMN at a median of 4.5 years (range: 1.3-14.3 years). Of the 7190 patients who did not receive an HSCT, 160 (2.2%) developed a SMN at a median follow-up of 6.8 years (range: 0.0-24.9 years). The 15-year cumulative incidence of SMN was 3.1% among the allogeneic HSCT group, 2.5% among the autologous group and 2.3% in the non-HSCT group. The cumulative incidence curves for the allogeneic HSCT and non-transplant groups only diverged after ~15 years from primary diagnosis. Our findings further corroborate the observation that children who undergo allogeneic HSCT are at a significantly increased risk of developing SMN compared with pediatric cancer survivors treated without HSCT. PMID- 25706886 TI - Isotope effect profiles in the N-demethylation of N,N-dimethylanilines: a key to determine the pK(a) of nonheme Fe(III)-OH complexes. AB - N-demethylation of N,N-dimethylanilines promoted by [(N4Py)Fe(IV)=O](2+) occurs by an electron transfer-proton transfer (ET-PT) mechanism with a rate determining PT step. From the bell-shaped curve of the KDIE profile it has been estimated that the pK(a) of [(N4Py)Fe(III)-OH](2+) is 9.7. PMID- 25706887 TI - Uncovering the role of antibiotics in the transmission of multidrug-resistant organisms. PMID- 25706888 TI - Hierarchical clustering of breast cancer methylomes revealed differentially methylated and expressed breast cancer genes. AB - Oncogenic transformation of normal cells often involves epigenetic alterations, including histone modification and DNA methylation. We conducted whole-genome bisulfite sequencing to determine the DNA methylomes of normal breast, fibroadenoma, invasive ductal carcinomas and MCF7. The emergence, disappearance, expansion and contraction of kilobase-sized hypomethylated regions (HMRs) and the hypomethylation of the megabase-sized partially methylated domains (PMDs) are the major forms of methylation changes observed in breast tumor samples. Hierarchical clustering of HMR revealed tumor-specific hypermethylated clusters and differential methylated enhancers specific to normal or breast cancer cell lines. Joint analysis of gene expression and DNA methylation data of normal breast and breast cancer cells identified differentially methylated and expressed genes associated with breast and/or ovarian cancers in cancer-specific HMR clusters. Furthermore, aberrant patterns of X-chromosome inactivation (XCI) was found in breast cancer cell lines as well as breast tumor samples in the TCGA BRCA (breast invasive carcinoma) dataset. They were characterized with differentially hypermethylated XIST promoter, reduced expression of XIST, and over-expression of hypomethylated X-linked genes. High expressions of these genes were significantly associated with lower survival rates in breast cancer patients. Comprehensive analysis of the normal and breast tumor methylomes suggests selective targeting of DNA methylation changes during breast cancer progression. The weak causal relationship between DNA methylation and gene expression observed in this study is evident of more complex role of DNA methylation in the regulation of gene expression in human epigenetics that deserves further investigation. PMID- 25706880 TI - Epidemiology of severe acute respiratory illness (SARI) among adults and children aged >=5 years in a high HIV-prevalence setting, 2009-2012. AB - OBJECTIVE: There are few published studies describing severe acute respiratory illness (SARI) epidemiology amongst older children and adults from high HIV prevalence settings. We aimed to describe SARI epidemiology amongst individuals aged >=5 years in South Africa. METHODS: We conducted prospective surveillance for individuals with SARI from 2009-2012. Using polymerase chain reaction, respiratory samples were tested for ten viruses, and blood for pneumococcal DNA. Cumulative annual SARI incidence was estimated at one site with population denominators. FINDINGS: We enrolled 7193 individuals, 9% (621/7067) tested positive for influenza and 9% (600/6519) for pneumococcus. HIV-prevalence was 74% (4663/6334). Among HIV-infected individuals with available data, 41% of 2629 were receiving antiretroviral therapy (ART). The annual SARI hospitalisation incidence ranged from 325-617/100,000 population. HIV-infected individuals experienced a 13 19 times greater SARI incidence than HIV-uninfected individuals (p<0.001). On multivariable analysis, compared to HIV-uninfected individuals, HIV-infected individuals were more likely to be receiving tuberculosis treatment (odds ratio (OR):1.7; 95%CI:1.1-2.7), have pneumococcal infection (OR 2.4; 95%CI:1.7-3.3) be hospitalised for >7 days rather than <2 days (OR1.7; 95%CI:1.2-2.2) and had a higher case-fatality ratio (8% vs 5%;OR1.7; 95%CI:1.2-2.3), but were less likely to be infected with influenza (OR 0.6; 95%CI:0.5-0.8). On multivariable analysis, independent risk indicators associated with death included HIV infection (OR 1.8;95%CI:1.3-2.4), increasing age-group, receiving mechanical ventilation (OR 6.5; 95%CI:1.3-32.0) and supplemental-oxygen therapy (OR 2.6; 95%CI:2.1-3.2). CONCLUSION: The burden of hospitalized SARI amongst individuals aged >=5 years is high in South Africa. HIV-infected individuals are the most important risk group for SARI hospitalization and mortality in this setting. PMID- 25706889 TI - Linear-time subspace clustering via bipartite graph modeling. AB - We present a linear-time subspace clustering approach that combines sparse representations and bipartite graph modeling. The signals are modeled as drawn from a union of low-dimensional subspaces, and each signal is represented by a sparse combination of basis elements, termed atoms, which form the columns of a dictionary matrix. The sparse representation coefficients are arranged in a sparse affinity matrix, which defines a bipartite graph of two disjoint sets: 1) atoms and 2) signals. Subspace clustering is obtained by applying low-complexity spectral bipartite graph clustering that exploits the small number of atoms for complexity reduction. The complexity of the proposed approach is linear in the number of signals, thus it can rapidly cluster very large data collections. Performance evaluation of face clustering and temporal video segmentation demonstrates comparable clustering accuracies to state-of-the-art at a significantly lower computational load. PMID- 25706890 TI - Global synchronization of complex dynamical networks through digital communication with limited data rate. AB - This paper studies the global synchronization of complex dynamical network (CDN) under digital communication with limited bandwidth. To realize the digital communication, the so-called uniform-quantizer-sets are introduced to quantize the states of nodes, which are then encoded and decoded by newly designed encoders and decoders. To meet the requirement of the bandwidth constraint, a scaling function is utilized to guarantee the quantizers having bounded inputs and thus achieving bounded real-time quantization levels. Moreover, a new type of vector norm is introduced to simplify the expression of the bandwidth limit. Through mathematical induction, a sufficient condition is derived to ensure global synchronization of the CDNs. The lower bound on the sum of the real-time quantization levels is analyzed for different cases. Optimization method is employed to relax the requirements on the network topology and to determine the minimum of such lower bound for each case, respectively. Simulation examples are also presented to illustrate the established results. PMID- 25706891 TI - MRM-Lasso: A Sparse Multiview Feature Selection Method via Low-Rank Analysis. AB - Learning about multiview data involves many applications, such as video understanding, image classification, and social media. However, when the data dimension increases dramatically, it is important but very challenging to remove redundant features in multiview feature selection. In this paper, we propose a novel feature selection algorithm, multiview rank minimization-based Lasso (MRM Lasso), which jointly utilizes Lasso for sparse feature selection and rank minimization for learning relevant patterns across views. Instead of simply integrating multiple Lasso from view level, we focus on the performance of sample level (sample significance) and introduce pattern-specific weights into MRM Lasso. The weights are utilized to measure the contribution of each sample to the labels in the current view. In addition, the latent correlation across different views is successfully captured by learning a low-rank matrix consisting of pattern-specific weights. The alternating direction method of multipliers is applied to optimize the proposed MRM-Lasso. Experiments on four real-life data sets show that features selected by MRM-Lasso have better multiview classification performance than the baselines. Moreover, pattern-specific weights are demonstrated to be significant for learning about multiview data, compared with view-specific weights. PMID- 25706894 TI - Robust Blind Learning Algorithm for Nonlinear Equalization Using Input Decision Information. AB - In this paper, we propose a new blind learning algorithm, namely, the Benveniste Goursat input-output decision (BG-IOD), to enhance the convergence performance of neural network-based equalizers for nonlinear channel equalization. In contrast to conventional blind learning algorithms, where only the output of the equalizer is employed for updating system parameters, the BG-IOD exploits a new type of extra information, the input decision information obtained from the input of the equalizer, to mitigate the influence of the nonlinear equalizer structure on parameters learning, thereby leading to improved convergence performance. We prove that, with the input decision information, a desirable convergence capability that the output symbol error rate (SER) is always less than the input SER if the input SER is below a threshold, can be achieved. Then, the BG soft switching technique is employed to combine the merits of both input and output decision information, where the former is used to guarantee SER convergence and the latter is to improve SER performance. Simulation results show that the proposed algorithm outperforms conventional blind learning algorithms, such as stochastic quadratic distance and dual mode constant modulus algorithm, in terms of both convergence performance and SER performance, for nonlinear equalization. PMID- 25706892 TI - Recurrent Neural Network for Computing the Drazin Inverse. AB - This paper presents a recurrent neural network (RNN) for computing the Drazin inverse of a real matrix in real time. This recurrent neural network (RNN) is composed of n independent parts (subnetworks), where n is the order of the input matrix. These subnetworks can operate concurrently, so parallel and distributed processing can be achieved. In this way, the computational advantages over the existing sequential algorithms can be attained in real-time applications. The RNN defined in this paper is convenient for an implementation in an electronic circuit. The number of neurons in the neural network is the same as the number of elements in the output matrix, which represents the Drazin inverse. The difference between the proposed RNN and the existing ones for the Drazin inverse computation lies in their network architecture and dynamics. The conditions that ensure the stability of the defined RNN as well as its convergence toward the Drazin inverse are considered. In addition, illustrative examples and examples of application to the practical engineering problems are discussed to show the efficacy of the proposed neural network. PMID- 25706893 TI - On Extended Dissipativity of Discrete-Time Neural Networks With Time Delay. AB - In this brief, the problem of extended dissipativity analysis for discrete-time neural networks with time-varying delay is investigated. The definition of extended dissipativity of discrete-time neural networks is proposed, which unifies several performance measures, such as the Hinfinity performance, passivity, l2 - linfinity performance, and dissipativity. By introducing a triple summable term in Lyapunov function, the reciprocally convex approach is utilized to bound the forward difference of the triple-summable term and then the extended dissipativity criterion for discrete-time neural networks with time-varying delay is established. The derived condition guarantees not only the extended dissipativity but also the stability of the neural networks. Two numerical examples are given to demonstrate the reduced conservatism and effectiveness of the obtained results. PMID- 25706896 TI - A direct self-constructing neural controller design for a class of nonlinear systems. AB - This paper is concerned with the problem of adaptive neural control for a class of uncertain or ill-defined nonaffine nonlinear systems. Using a self-organizing radial basis function neural network (RBFNN), a direct self-constructing neural controller (DSNC) is designed so that unknown nonlinearities can be approximated and the closed-loop system is stable. The key features of the proposed DSNC design scheme can be summarized as follows. First, different from the existing results in literature, a self-organizing RBFNN with adaptive threshold is constructed online for DSNC to improve the control performance. Second, the control law and adaptive law for the weights of RBFNN are established so that the closed-loop system is stable in the term of Lyapunov stability theory. Third, the tracking error is guaranteed to uniformly asymptotically converge to zero with the aid of an additional robustifying control term. An example is finally given to demonstrate the design procedure and the performance of the proposed method. Simulation results reveal the effectiveness of the proposed method. PMID- 25706895 TI - A Recurrent Probabilistic Neural Network with Dimensionality Reduction Based on Time-series Discriminant Component Analysis. AB - This paper proposes a probabilistic neural network (NN) developed on the basis of time-series discriminant component analysis (TSDCA) that can be used to classify high-dimensional time-series patterns. TSDCA involves the compression of high dimensional time series into a lower dimensional space using a set of orthogonal transformations and the calculation of posterior probabilities based on a continuous-density hidden Markov model with a Gaussian mixture model expressed in the reduced-dimensional space. The analysis can be incorporated into an NN, which is named a time-series discriminant component network (TSDCN), so that parameters of dimensionality reduction and classification can be obtained simultaneously as network coefficients according to a backpropagation through time-based learning algorithm with the Lagrange multiplier method. The TSDCN is considered to enable high-accuracy classification of high-dimensional time-series patterns and to reduce the computation time taken for network training. The validity of the TSDCN is demonstrated for high-dimensional artificial data and electroencephalogram signals in the experiments conducted during the study. PMID- 25706897 TI - Nuclear organization. AB - This article discusses three reviews on the theme of nuclear organization. PMID- 25706901 TI - Dehydroepiandrosterone, molecular chaperones and the epigenetics of primate longevity. AB - Dehydroepiandrosterone (DHEA) and dehydroepiandrosterone-sulphate (DHEAS) are the most abundant circulating adrenal steroid hormones. The plasma level of DHEAS correlates with longevity in primates and varies during human development with a maximum in early adulthood and a marked decline during aging. DHEA promotes the expression of molecular chaperones which are housekeeping stress response proteins essential for the processes of folding, translocation, maintenance and repair of proteins, RNA and DNA, as well as for homeostasis, immune response and cancer resistance. The level of chaperone expression correlates with longevity and shows a decline during aging. DHEA-induced promotion of chaperone expression could contribute to the epigenetic evolution of primate longevity. PMID- 25706902 TI - Reply: To PMID 24923719. PMID- 25706900 TI - Coffee consumption and prostate cancer risk: a meta-analysis of cohort studies. AB - This meta-analysis was conducted to assess the association between coffee consumption and prostate cancer risk. Thirteen cohort studies with 34,105 cases and 539,577 participants were included in the meta-analysis. The summary relative risks (RRs) with 95% confidence intervals (CIs) for different coffee intake levels were calculated. Dose-response relationship was assessed using generalized least square trend estimation. The pooled RR for the highest vs. lowest coffee intake was 0.90 (95% CI: 0.85-0.95), with no significant heterogeneity across studies (P = 0.267; I(2) = 17.5%). The dose-response analysis showed a lower cancer risk decreased by 2.5% (RR = 0.975; 95% CI: 0.957-0.995) for every 2 cups/day increment in coffee consumption. Stratifying by geographic region, there was a statistically significant protective influence of coffee on prostate cancer risk among European populations. In subgroup analysis of prostate cancer grade, the summary RRs were 0.89 (95% CI: 0.83-0.96) for nonadvanced, 0.82 (95% CI: 0.61 1.10) for advanced and 0.76 (95% CI: 0.55-1.06) for fatal diseases. Our findings suggest that coffee consumption may be associated with a reduced risk of prostate cancer and it also has an inverse association with nonadvanced prostate cancer. Because of the limited number of studies, more prospective studies with large sample size are needed to confirm this association. PMID- 25706903 TI - Dignity-conserving care in palliative care settings: An integrative review. AB - AIMS AND OBJECTIVES: To report an integrative review of evidence relating to dignity-conserving care in palliative care settings. It will also suggest avenues for future research. BACKGROUND: Research suggests that dignity is welcomed by those receiving palliative and end of life care. However, as dignity is a subjective term, it is not always explicit how this may be employed by nurses. Given that the preferred place of care for patients with palliative care needs is the home, the issue of dignity may be particularly important for community nurses. Therefore, synthesising evidence of dignity-conserving care for community nurses caring for people with palliative care needs provides clarity in a complex area of palliative care research. DESIGN: Integrative literature review. METHOD: The review involved key bibliographic and review databases CINAHL, MEDLINE, EMBASE, ASSIA and PsycInfo. Medical Subject Headings and free terms were undertaken for articles published from January 2009-September 2014 and retrieved papers were assessed against inclusion criteria. Final included articles were reviewed for reported dignity-conserving care actions, which were classified under nine themes of the Dignity Model. RESULTS: Thirty-one articles were included. Nine Dignity Model themes were used to classify care actions: Level of Independence; Symptom Distress; Dignity-Conserving Perspectives; Dignity Conserving Practices; Privacy Boundaries; Social Support; Care Tenor; Burden to Others; and Aftermath Concerns. Reported care actions included listening, conveying empathy, communication and involving patients in care. CONCLUSION: Care actions could be classified under most of Dignity Model themes. However, there were less reported care actions related to Level of Independence and Aftermath Concerns, which meant that these had to be formulated independently. Future research should be structured around these areas to determine appropriate care actions for nurses to give dignity-conserving care that addresses these specific themes. RELEVANCE TO CLINICAL PRACTICE: Synthesising the available evidence of dignity-conserving care identifies evidence-based care actions and provides guidance to nurses in clinical practice caring for patients with palliative care needs. Future opportunities for research are identified to guide promotion of dignity in palliative care. PMID- 25706904 TI - Coenzyme Q10 and congestive heart failure; an evolving evidence base. PMID- 25706905 TI - Intracardiac lead abrasion and the risk of infective endocarditis in the young. PMID- 25706906 TI - Reversible tricuspid valve stenosis induced by ascending aorta aneurysm: an image focus. PMID- 25706899 TI - Natural photoreceptors as a source of fluorescent proteins, biosensors, and optogenetic tools. AB - Genetically encoded optical tools have revolutionized modern biology by allowing detection and control of biological processes with exceptional spatiotemporal precision and sensitivity. Natural photoreceptors provide researchers with a vast source of molecular templates for engineering of fluorescent proteins, biosensors, and optogenetic tools. Here, we give a brief overview of natural photoreceptors and their mechanisms of action. We then discuss fluorescent proteins and biosensors developed from light-oxygen-voltage-sensing (LOV) domains and phytochromes, as well as their properties and applications. These fluorescent tools possess unique characteristics not achievable with green fluorescent protein-like probes, including near-infrared fluorescence, independence of oxygen, small size, and photosensitizer activity. We next provide an overview of available optogenetic tools of various origins, such as LOV and BLUF (blue-light utilizing flavin adenine dinucleotide) domains, cryptochromes, and phytochromes, enabling control of versatile cellular processes. We analyze the principles of their function and practical requirements for use. We focus mainly on optical tools with demonstrated use beyond bacteria, with a specific emphasis on their applications in mammalian cells. PMID- 25706907 TI - A next-generation self-expandable valve implantation in a patient with failed aortic bioprosthesis. PMID- 25706908 TI - Orthogonal translation meets electron transfer: in vivo labeling of cytochrome c for probing local electric fields. AB - Cytochrome c (cyt c), a redox protein involved in diverse fundamental biological processes, is among the most traditional model proteins for analyzing biological electron transfer and protein dynamics both in solution and at membranes. Studying the role of electric fields in energy transduction mediated by cyt c relies upon appropriate reporter groups. Up to now these had to be introduced into cyt c by in vitro chemical modification. Here, we have overcome this restriction by incorporating the noncanonical amino acid p-cyanophenylalanine (pCNF) into cyt c in vivo. UV and CD spectroscopy indicate preservation of the overall protein fold, stability, and heme coordination, whereas a small shift of the redox potential was observed by cyclic voltammetry. The C=N stretching mode of the incorporated pCNF detected in the IR spectra reveals a surprising difference, which is related to the oxidation state of the heme iron, thus indicating high sensitivity to changes in the electrostatics of cyt c. PMID- 25706898 TI - Functions of ribosomal proteins in assembly of eukaryotic ribosomes in vivo. AB - The proteome of cells is synthesized by ribosomes, complex ribonucleoproteins that in eukaryotes contain 79-80 proteins and four ribosomal RNAs (rRNAs) more than 5,400 nucleotides long. How these molecules assemble together and how their assembly is regulated in concert with the growth and proliferation of cells remain important unanswered questions. Here, we review recently emerging principles to understand how eukaryotic ribosomal proteins drive ribosome assembly in vivo. Most ribosomal proteins assemble with rRNA cotranscriptionally; their association with nascent particles is strengthened as assembly proceeds. Each subunit is assembled hierarchically by sequential stabilization of their subdomains. The active sites of both subunits are constructed last, perhaps to prevent premature engagement of immature ribosomes with active subunits. Late assembly intermediates undergo quality-control checks for proper function. Mutations in ribosomal proteins that affect mostly late steps lead to ribosomopathies, diseases that include a spectrum of cell type-specific disorders that often transition from hypoproliferative to hyperproliferative growth. PMID- 25706909 TI - Transparency When Things Go Wrong: Physician Attitudes About Reporting Medical Errors to Patients, Peers, and Institutions. AB - OBJECTIVES: Transparent communication after medical error includes disclosing the mistake to the patient, discussing the event with colleagues, and reporting to the institution. Little is known about whether attitudes about these transparency practices are related. Understanding these relationships could inform educational and organizational strategies to promote transparency. METHODS: We analyzed responses of 3038 US and Canadian physicians to a medical error communication survey. We used bivariate correlations, principal components analysis, and linear regression to determine whether and how physician attitudes about transparent communication with patients, peers, and the institution after error were related. RESULTS: Physician attitudes about disclosing errors to patients, peers, and institutions were correlated (all P's < 0.001) and represented 2 principal components analysis factors, namely, communication with patients and communication with peers/institution. Predictors of attitudes supporting transparent communication with patients and peers/institution included female sex, US (vs Canadian) doctors, academic (vs private) practice, the belief that disclosure decreased likelihood of litigation, and the belief that system changes occur after error reporting. In addition, younger physicians, surgeons, and those with previous experience disclosing a serious error were more likely to agree with disclosure to patients. In comparison, doctors who believed that disclosure would decrease patient trust were less likely to agree with error disclosure to patients. Previous disclosure education was associated with attitudes supporting greater transparency with peers/institution. CONCLUSIONS: Physician attitudes about discussing errors with patients, colleagues, and institutions are related. Several predictors of transparency affect all 3 practices and are potentially modifiable by educational and institutional strategies. PMID- 25706910 TI - An Evaluation of Shared Mental Models and Mutual Trust on General Medical Units: Implications for Collaboration, Teamwork, and Patient Safety. AB - OBJECTIVES: This study examines nurse-physician teamwork and collaboration, a critical component in the delivery of safe patient care, on general medical units. To that end, we assess shared mental models and mutual trust, 2 coordinating mechanisms that help facilitate teamwork, among nurses and physicians working on general medical units. METHODS: Data were collected from 37 nurses and 42 physicians at an urban teaching medical center in the Northeastern United States. Shared mental model questionnaire items were iteratively developed with experts' input to ensure content validity. Mutual trust items were adapted from an existing scale; items were reliable. Data were analyzed using chi and independent 2-tailed t tests. RESULTS: Physicians and nurses reported significant differences in their perceptions of the professional responsible for a variety of roles (e.g., advocating for the patient [P = 0.0007], identifying a near miss/error [P = 0.003]). Medication reconciliation is only role for which nurses perceive less responsibility than physicians perceive nurses have. Regarding mutual trust, both groups reported significantly more trust within their own professions; both groups reported similar levels of trust in physicians, with physicians reporting significantly less trust in their nursing colleagues than nurses perceive (P < 0.0001). CONCLUSIONS: Although many efforts have been directed at improving nurse-physician collaboration, more work is needed. To that end, we propose increasing knowledge about their respective roles, providing opportunities for nurse and physician collaboration through rounding or committee work and enhancing the preparedness and professionalism of interactions. PMID- 25706911 TI - "The Jackson Table Is a Pain in the...": A Qualitative Study of Providers' Perception Toward a Spinal Surgery Table. AB - OBJECTIVE: The aim of this study was to define health care providers' perceptions toward prone patient positioning for spine surgery using the Jackson Table, which has not been hitherto explored. METHODS: We analyzed open-ended questionnaire data and interviews conducted with the spine surgical team regarding the current process of spinal positioning/repositioning using the Jackson Table. Participants were asked to provide an open-ended explanation as to whether they think the current process of spinal positioning/repositioning is safe for the staff or patients. Follow-up qualitative interviews were conducted with 11 of the participants to gain an in-depth understanding of the challenges and safety issues related to prone patient positioning. RESULTS: Data analysis resulted in 6 main categories: general challenges with patient positioning, role-specific challenges, challenges with the Jackson Table and the "sandwich" mechanism, safety concerns for patients, safety concerns for the medical staff, and recommendations for best practices. CONCLUSIONS: This study is relevant to everyday practice for spinal surgical team members and advances our understanding of how surgical teams qualitatively view the current process of patient positioning for spinal surgery. Providers recommended best practices for using the Jackson Table, which can be achieved through standardized practice for transfer of patients, educational tools, and checklists for equipment before patient transfer and positioning. This research has identified several important practice opportunities for improving provider and patient safety in spine surgery.This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivitives 3.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially. http://creativecommons.org/licenses/by-nc-nd/3.0. PMID- 25706913 TI - Skin and subcutaneous infections in south-east Asia. AB - PURPOSE OF REVIEW: We reviewed current literature on four different skin and subcutaneous infections which are often touted as 'emerging diseases' of south east Asia, namely melioidosis, penicilliosis, sporotrichosis and Mycobacterium marinum infection. Lack of consensus treatment guidelines, high treatment costs and limited investigative capability in certain endemic areas are among the challenges faced by managing physicians. With the increase in borderless travelling, it is hoped that this review will facilitate better understanding and heighten the clinical suspicion of such infections for clinicians in other parts of the world. RECENT FINDINGS: An increasing number of cases of melioidosis and penicilliosis have been reported within and outside its endemic areas, but epidemiological data on sporotrichosis and M. marinum infections are still sparse. The clinical features of these infections remain historically unchanged and more disseminated infections are seen particularly amongst immunocompromised patients. Although tissue culture is still the gold standard, PCR provides more rapid and accurate diagnosis. Advances in therapeutics have improved outcome in certain diseases. SUMMARY: The described spectrum of cutaneous infection in south east Asia can be imported to other areas due to increases in worldwide travel. Clinicians from other parts of the world should be aware of the common presentations of these diseases. PMID- 25706912 TI - Critical slowing down governs the transition to neuron spiking. AB - Many complex systems have been found to exhibit critical transitions, or so called tipping points, which are sudden changes to a qualitatively different system state. These changes can profoundly impact the functioning of a system ranging from controlled state switching to a catastrophic break-down; signals that predict critical transitions are therefore highly desirable. To this end, research efforts have focused on utilizing qualitative changes in markers related to a system's tendency to recover more slowly from a perturbation the closer it gets to the transition--a phenomenon called critical slowing down. The recently studied scaling of critical slowing down offers a refined path to understand critical transitions: to identify the transition mechanism and improve transition prediction using scaling laws. Here, we outline and apply this strategy for the first time in a real-world system by studying the transition to spiking in neurons of the mammalian cortex. The dynamical system approach has identified two robust mechanisms for the transition from subthreshold activity to spiking, saddle-node and Hopf bifurcation. Although theory provides precise predictions on signatures of critical slowing down near the bifurcation to spiking, quantitative experimental evidence has been lacking. Using whole-cell patch-clamp recordings from pyramidal neurons and fast-spiking interneurons, we show that 1) the transition to spiking dynamically corresponds to a critical transition exhibiting slowing down, 2) the scaling laws suggest a saddle-node bifurcation governing slowing down, and 3) these precise scaling laws can be used to predict the bifurcation point from a limited window of observation. To our knowledge this is the first report of scaling laws of critical slowing down in an experiment. They present a missing link for a broad class of neuroscience modeling and suggest improved estimation of tipping points by incorporating scaling laws of critical slowing down as a strategy applicable to other complex systems. PMID- 25706914 TI - Viral exanthems. AB - PURPOSE OF REVIEW: Determining the viral cause of a rash presents significant diagnostic challenges. We review contemporary literature on viral exanthems and suggest a structured approach to aid diagnosis. RECENT FINDINGS: Strains responsible for, and the clinical presentation of, enteroviral infections have diverged from classic descriptions. The causative relationship between antibiotic administration and rash in Epstein-Barr virus infection has been recently questioned. Major measles virus outbreaks have recently occurred in Europe and the USA. The largest Ebola virus outbreak in West Africa has resulted in importation of the virus to other countries and secondary local transmission. Autochthonous transmission of Chikungunya virus has occurred in nonendemic areas, including Europe, the Caribbean and Americas. Zika virus has re-emerged in the Pacific with local transmission from imported cases. Climate change, global warming and spillover of zoonotic viruses are contributing to the emergence and spread of viral diseases. SUMMARY: Important clues to the diagnosis of viral exanthems include their distribution and morphology, geographic location and potential exposure to vector-borne or blood-borne viruses. Diagnosis is commonly made via serology, nucleic acid tests or, rarely, viral culture. Skin biopsy is not usually required. In general, viral exanthems are self-limiting and treatment is supportive. PMID- 25706916 TI - Examining Individual Differences in Interpersonal Influence: On the Psychometric Properties of the Generalized Opinion Leadership Scale (GOLS). AB - Opinion leadership describes an individual's tendency to informally influence others' attitudes and overt behaviors. In contrast to contemporary views of opinion leadership as a highly domain-specific trait, this paper introduces a multi-faceted personality trait, generalized opinion leadership (GOL) that characterizes exceptionally influential individuals independent of a specific subject area. Two studies report on the psychometric properties of a scale to assess GOL. Study 1 is based on three independent samples (N = 1,575, N = 1,275, and N = 231) and demonstrates the factorial structure of the instrument and its measurement invariance across sex, age, and educational levels. Study 2 (N = 310) analyzes multitrait-multiinformant data to highlight the scale's discriminant validity with regard to innovativeness and trendsetting. PMID- 25706915 TI - Laparoscopic NOSE colectomy with a camera sleeve: a technique in evolution. AB - AIM: Although natural orifice specimen extraction (NOSE) reduces abdominal access trauma, specimen retrieval with a bag can be difficult, due to the size of the specimen. This technical note aims to show feasibility of laparoscopic NOSE colectomy with a camera sleeve based on a well-documented video. METHOD: Over a 9 month period all patients who had laparoscopic NOSE colectomy were included in the study. Camera sleeve extraction was compared with specimen retrieval bag extraction. RESULTS: Eight patients (6 females, median age 63 years, median BMI 23 kg/m2) underwent NOSE with a camera sleeve versus nine patients with a specimen retrieval bag. Patient characteristics and operative details were similar in both groups. There were no conversions. Median hospital stay was 4 days in both groups. CONCLUSION: Laparoscopic NOSE colectomy with a camera sleeve is feasible, but it remains to be shown that this technical modification will lead to an increase in indications for left-sided colonic resections. PMID- 25706917 TI - Anti-cancer glycosidase inhibitors from natural products: a computational and molecular modelling perspective. AB - The implementation of computational tools in pharmaceutics has proven an effectual strategy in creating harmony between the physical and chemical aspects of proteins and potential inhibitors. This is achieved by bringing to life the three dimensional retrospect of biological systems, which takes into consideration computational approaches such as quantum mechanics and molecular dynamics to facilitate drug design and discovery. In this work, we aim to provide a summary of the computational aspects of naturally derived anti-cancer inhibitors targeting the enzyme family of glycosidases. Our study offers insight into the evolution of drug discovery, molecular modelling and molecular binding modes of natural product inhibitors associated with glycosidase enzymes. PMID- 25706918 TI - Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up. AB - OBJECTIVES: Substantial evidence associates persistent organic pollutants (POP) with metabolic disturbances related to diabetes, but longitudinal studies with repeated measures are scarce. We aimed to characterize the association between background exposures to POPs with repeated measures of glucose homeostasis over 23-years. METHODS: Within the Coronary Artery Risk Development in Young Adults study (year 0 ages: 18-30 years), we measured POPs in serum obtained in 1987-88 (follow-up year 2) in 90 non-diabetic controls and 90 cases diabetes-free at year 2 who became diabetic by year 20. We analyzed 32 POPs detectable in >=75% of participants and created summary scores for 32 POPs, 23 polychlorinated biphenyls (PCB), and 8 organochlorine pesticides (OCP). Dependent variables were measures of glucose homeostasis at years 0-25 (up to 8 examinations). We explored associations using repeated measures regression adjusted for race, sex, concurrent body mass index (BMI), examination center and period, separately for cases and controls. RESULTS: The associations between the three summary scores and measures of glucose homeostasis were present for observations at ages 40-55 years, and particularly between 48-55 years: the 23 PCB summary was associated with HbA1c (never-diabetics: slope [value per unit of summary score], beta=0.008, p=0.02; diabetics: beta=0.03, p=0.07), fasting glucose (never-diabetics: beta=0.24, p=0.003; diabetics: beta=1.10, p=0.03), and insulin sensitivity% (never-diabetics: beta=-2.82, p<0.001, diabetics: beta=-0.31, p=0.30). No associations were observed at younger ages. CONCLUSIONS: Glucose homeostasis may worsen after decades of exposure to PCBs and OCPs at background environmental levels, independent of BMI and after participants reached the 5th decade of life. PMID- 25706922 TI - CT diagnosis of appendicitis in children: comparison of orthogonal planes and assessment of contrast opacification of the appendix. AB - OBJECTIVE: The aim of this study was to determine which plane is best for identification of the appendix and to assess if opacification of the appendix impacts visualization. METHODS: Retrospective review of 218 computed tomography examinations performed for suspected appendicitis was conducted by 2 pediatric radiologists evaluating conspicuity of the appendix depending on orthogonal plane and enteric contrast. RESULTS: Of the 180 cases in which the appendix was visualized, 154 were performed with multiplanar reformations. The best plane for identification of the appendix was coronal in 96, axial in 41, and sagittal in 17. Of the 218 computed tomography examinations, 169 had enteric contrast. The appendix was identified in 180 cases and completely opacified in 62, partially opacified in 26, without opacification in 59, and air filled in 33. Of the 38 cases in which the appendix was not identified, 29 had enteric contrast administration.In 131 of the 218 cases, the appendix was normal, and 58% demonstrated partial or complete opacification of the appendix. In 35 of the 218 cases, appendicitis was found, and there was predominantly no opacification or at most partial opacification of the appendix. CONCLUSIONS: The coronal plane is best to identify the appendix. No enteric contrast is required to visualize appendicitis. PMID- 25706921 TI - Useful but not used: pediatric critical care physician views on bedside ultrasound. AB - OBJECTIVE: The purpose of this study was to assess the learning needs of pediatric critical care (PCC) physicians in bedside ultrasound (BUS) use. METHODS: This was a survey-based study conducted at an academic center with a PCC fellowship program. We surveyed PCC fellows and faculty to elicit their views on BUS and asked them about the frequency of use, their perception of the clinical utility, and their level of confidence in performing different BUS applications. RESULTS: There was no statistical difference in the self-reported use of BUS applications in the faculty and fellows, except for cardiac arrest, which 66.7% of the faculty used but none of the fellows did (P < 0.05). There were no statistically significant differences between perceived usefulness and confidence in the performance of BUS applications between the fellows and faculty. The largest gaps between perceived usefulness and confidence in performing BUS applications were for left ventricle ejection fraction (Delta = 2.72), inferior vena cava collapse (Delta = 2.67), pulmonary edema (Delta = 2.22), and pneumothorax (Delta = 2.11). CONCLUSIONS: Pediatric critical care providers report limited confidence in several applications that they perceive as useful and are therefore likely motivated to learn BUS applications. Concentrating curricula on those applications with the greatest differences between usefulness and confidence and building on the confidence of those applications the PCC providers are already using will serve to expand availability and increase use of this high-impact technology. PMID- 25706923 TI - Compliance of camps in the United States with guidelines for health and safety practices. AB - OBJECTIVE: To determine the compliance of US camps with guidelines for health and safety practices as set forth by the American Academy of Pediatrics and the US Department of Homeland Security. METHODS: An electronic questionnaire was distributed to US camps during the summer of 2012 as identified by 3 online summer camp directories. RESULTS: Analysis was performed on 433 completed questionnaires. Fourteen percent of camps were considered medically related. Ninety-three percent of camps have established relationships with community emergency medical services, 34% with local orthodontists, and 37% with local mental health professionals. Camps reported the immediate availability of the following: automated external defibrillators (75%), respiratory rescue inhalers (44%), epinephrine autoinjectors (64%), cervical spine collars (62%), and backboard with restraints (76%). Camps reported the presence of the following written health policies: dehydration (91%), asthma and anaphylaxis (88%), head injuries (90%), seizures (78%), cardiac arrest (76%), and drowning (73%). Although 93% of camps have a disaster response plan, 15% never practice the plan. Sixty-eight percent of camps are familiar with community evacuation plans, and 67% have access to vehicles for transport. Camps reported the presence of the following written disaster policies: fire (96%), tornadoes (68%), arrival of suspicious individuals (84%), hostage situations (18%). CONCLUSIONS: Areas for improvement in the compliance of US camps with specific recommendations for health and safety practices were identified, such as medically preparing campers before their attendance, developing relationships with community health providers, increasing the immediate availability of several emergency medications and equipment, and developing policies and protocols for medical and disaster emergencies. PMID- 25706920 TI - Differing evolutionary histories of the ACTN3*R577X polymorphism among the major human geographic groups. AB - It has been proposed that the functional ACTN3*R577X polymorphism might have evolved due to selection in Eurasian human populations. To test this possibility we surveyed all available population-based data for this polymorphism and performed a comprehensive evolutionary analysis of its genetic diversity, in order to assess the action of adaptive and random mechanisms on its variation across human geographical distribution. The derived 577X allele increases in frequency with distance from Africa, reaching the highest frequencies on the American continent. Positive selection, detected by an extended haplotype homozygosisty test, was consistent only with the Eurasian data, but simulations with neutral models could not fully explain the results found in the American continent. It is possible that particularities of Native American population structure could be responsible for the observed allele frequencies, which would have resulted from a complex interaction between selective and random factors. PMID- 25706924 TI - CARES: improving the care and disposition of psychiatric patients in the pediatric emergency department. AB - OBJECTIVES: Pediatric psychiatric emergencies are a nationwide crisis and have contributed to an increase in behavioral health emergency department (ED) visits. A collaborative response to this crisis was the creation of the Child & Adolescent Rapid Emergency Stabilization (CARES) program. The objective of this study is to determine how the CARES unit influenced length of stay (LOS) and costs for psychiatric patients in the pediatric ED. METHODS: A retrospective review of ED patients was conducted. Children presenting 1 year before CARES, October 13, 2006, to October 13, 2007 (pre-CARES), were compared with 1 year after, October 15, 2007, to October 15, 2008 (post-CARES). The study population includes all patients presenting to the ED with psychiatric illnesses. The primary outcome is mean LOS in hours. Supplemental analyses of total charges, payments, and costs were performed. RESULTS: There were 1719 visits before and 1867 visits after CARES, with 1190 and 1273 unique patient visits, respectively. Children in both groups had similar age, gender, and ethnicity. Pre-CARES had a mean LOS of 19.7 hours (SD, 32.6), whereas post-CARES had 10.8 hours (SD, 19.9) (P < 0.0001). Evaluating only unique visits, the difference remained highly significant. Post-CARES, compared with pre-CARES, the average charge per patient decreased by $905 (P < 0.0001), average payment decreased by $111 (P < 0.06), and average total cost decreased by $569 or 38.7% (P < 0.0001). The total cost savings the year after CARES opened was $1,019,168.55. PMID- 25706919 TI - MicroRNA-214 suppresses oncogenesis and exerts impact on prognosis by targeting PDRG1 in bladder cancer. AB - MicroRNA-214 (miR-214) has been reported to be dysregulated in human bladder cancer tissues. We aimed to investigate the clinical correlation, biological significance and molecular network of miR-214 in bladder cancer. Our results showed miR-214 was down-regulated in bladder cancer tissues and significantly associated with tumor stage, lymph node status, grade, multifocality, history of non-muscle-invasive bladder cancer (NMIBC). Moreover, miR-214 could serve as an independent factor of recurrence-free survival (RFS) and overall survival (OS) for patients with muscle-invasive bladder cancer (MIBC). Restoration of miR-214 expression in bladder cancer cell lines inhibited cell proliferation, migration, invasion and markedly promoted apoptosis. Dual-luciferase reporter assay recognized PDRG1 as direct downstream target gene of miR-214. PDRG1 was significantly increased in tumors low of miR-214 and knockdown of PDRG1 mimicked the effects of miR-214 overexpression. Our findings manifest that miR-214 could exert tumor-suppressive effects in bladder cancer by directly down-regulating oncogene PDRG1 and suggest an appealing novel indicator for prognostic and therapeutic intervention of bladder cancer. PMID- 25706925 TI - Prospective validation of Alvarado score and Pediatric Appendicitis Score for the diagnosis of acute appendicitis in children. AB - OBJECTIVES: The purpose of this study was to compare the results of the Alvarado and Pediatric Appendicitis Score (PAS) scoring systems and to establish which one is more reliable in setting the diagnosis of acute appendicitis in children. METHODS: All children operated on because of acute appendicitis from October 2011 to May 2013 were enrolled in this prospective study. Both clinical scoring systems have been compared over the same patients, and cutoff values were determined by the receiver operating characteristic curve analysis. RESULTS: A total of 311 patients were included in the study, and 265 (85.2%) of them had acute appendicitis. Mean Alvarado score for patients with appendicitis was 8.2 and 6.7 for those without (P < 0.001). Mean PAS for patients with appendicitis was of 7.8 and 6.6 for those without (P < 0.001). Based on the ROC curve analysis, a cutoff value for both scoring systems was 7. In patients with acute appendicitis and Alvarado score of 7 or higher, the correct diagnosis would have been set in 236 patients (sensitivity, 89%; specificity, 59%; positive predictive value, 93.1%), whereas in patients with acute appendicitis and a PAS of 7 or higher, the correct diagnosis would have been set in 228 patients (sensitivity, 86%; specificity, 50%; positive predictive value, 90.1%). No significant difference was found in sensitivity and specificity between the observed scoring systems. CONCLUSIONS: Both scoring systems can be of assistance in setting the diagnosis of acute appendicitis, but none has adequate predictive values in assessing acute appendicitis and none can be used as an exclusive standard in setting the diagnosis of acute appendicitis in children. The final decision still remaines on the opinion of an expert pediatric surgeon. PMID- 25706926 TI - Risk factors associated with a reduced response in the treatment of erysipelas. AB - BACKGROUND: In most cases, erysipelas may be adequately treated using first-line antibiotic therapy. However, clinicians are sometimes confronted with complicated cases, in which patients do not respond to initial antibiotic therapy. The objective of this study was to identify risk factors associated with a reduced response to antibiotic therapy and, thus, a more complicated disease course. PATIENTS AND METHODS: We retrospectively analyzed the clinical course of 98 patients with erysipelas treated with standard antibiotic therapy. Patient groups showing different therapeutic responses were compared with respect to clinical data, medical history, and laboratory parameters. RESULTS: Patients with bullous or hemorrhagic erysipelas (p = 0.0008), stasis dermatitis (p = 0.01) or chronic venous insufficiency (p = 0.0004) showed a significantly reduced response to initial therapy with cefuroxime or clindamycin, respectively. Furthermore, the response to initial therapy significantly depended on C-reactive protein (p = 0.007) and neutrophil (p = 0.02) levels. CONCLUSION: In erysipelas patients with clinical complications, abnormal laboratory parameters or preexisting local skin damage, an intensified antibiotic regimen should be considered. PMID- 25706927 TI - Direct evidence of brown adipocytes in different fat depots in children. AB - Recent studies suggested the persistence of brown adipocytes in adult humans, as opposed to being exclusively present in infancy. In this study, we investigated the presence of brown-like adipocytes in adipose tissue (AT) samples of children and adolescents aged 0 to 18 years and evaluated the association with age, location, and obesity. For this, we analysed AT samples from 131 children and 23 adults by histological, immunohistochemical and expression analyses. We detected brown-like and UCP1 positive adipocytes in 10.3% of 87 lean children (aged 0.3 to 10.7 years) and in one overweight infant, whereas we did not find brown adipocytes in obese children or adults. In our samples, the brown-like adipocytes were interspersed within white AT of perirenal, visceral and also subcutaneous depots. Samples with brown-like adipocytes showed an increased expression of UCP1 (>200fold), PRDM16 (2.8fold), PGC1alpha and CIDEA while other brown/beige selective markers, such as PAT2, P2RX5, ZIC1, LHX8, TMEM26, HOXC9 and TBX1 were not significantly different between UCP1 positive and negative samples. We identified a positive correlation between UCP1 and PRDM16 within UCP1 positive samples, but not with any other brown/beige marker. In addition, we observed significantly increased PRDM16 and PAT2 expression in subcutaneous and visceral AT samples with high UCP1 expression in adults. Our data indicate that brown-like adipocytes are present well beyond infancy in subcutaneous depots of non-obese children. The presence was not restricted to typical perirenal locations, but they were also interspersed within WAT of visceral and subcutaneous depots. PMID- 25706928 TI - Human immunodeficiency virus transmission at each step of the care continuum in the United States. AB - IMPORTANCE: Human immunodeficiency virus (HIV) transmission risk is primarily dependent on behavior (sexual and injection drug use) and HIV viral load. National goals emphasize maximizing coverage along the HIV care continuum, but the effect on HIV prevention is unknown. OBJECTIVES: To estimate the rate and number of HIV transmissions attributable to persons at each of the following 5 HIV care continuum steps: HIV infected but undiagnosed, HIV diagnosed but not retained in medical care, retained in care but not prescribed antiretroviral therapy, prescribed antiretroviral therapy but not virally suppressed, and virally suppressed. DESIGN, SETTING, AND PARTICIPANTS: A multistep, static, deterministic model that combined population denominator data from the National HIV Surveillance System with detailed clinical and behavioral data from the National HIV Behavioral Surveillance System and the Medical Monitoring Project to estimate the rate and number of transmissions along the care continuum. This analysis was conducted January 2013 to June 2014. The findings reflect the HIV infected population in the United States in 2009. MAIN OUTCOMES AND MEASURES: Estimated rate and number of HIV transmissions. RESULTS: Of the estimated 1,148,200 persons living with HIV in 2009, there were 207,600 (18.1%) who were undiagnosed, 519,414 (45.2%) were aware of their infection but not retained in care, 47,453 (4.1%) were retained in care but not prescribed ART, 82,809 (7.2%) were prescribed ART but not virally suppressed, and 290,924 (25.3%) were virally suppressed. Persons who are HIV infected but undiagnosed (18.1% of the total HIV infected population) and persons who are HIV diagnosed but not retained in medical care (45.2% of the population) were responsible for 91.5% (30.2% and 61.3%, respectively) of the estimated 45,000 HIV transmissions in 2009. Compared with persons who are HIV infected but undiagnosed (6.6 transmissions per 100 person-years), persons who were HIV diagnosed and not retained in medical care were 19.0% (5.3 transmissions per 100 person-years) less likely to transmit HIV, and persons who were virally suppressed were 94.0% (0.4 transmissions per 100 person-years) less likely to transmit HIV. Men, those who acquired HIV via male to-male sexual contact, and persons 35 to 44 years old were responsible for the most HIV transmissions by sex, HIV acquisition risk category, and age group, respectively. CONCLUSIONS AND RELEVANCE: Sequential steps along the HIV care continuum were associated with reduced HIV transmission rates. Improvements in HIV diagnosis and retention in care, as well as reductions in sexual and drug use risk behavior, primarily for persons undiagnosed and not receiving antiretroviral therapy, would have a substantial effect on HIV transmission in the United States. PMID- 25706929 TI - Diagnosis of 9q22.3 microdeletion syndrome in utero following identification of craniosynostosis, overgrowth, and skeletal anomalies. AB - 9q22.3 microdeletion syndrome is a well-described contiguous deletion syndrome with features of Gorlin syndrome and other manifestations. Commonly reported findings in addition to those of Gorlin syndrome include metopic craniosynostosis, hydrocephalus, intellectual disability, and minor facial anomalies. The critical region for this condition was found to include the PTCH1 and FANCC genes; however, other genes are often deleted in affected individuals but their role in the observed phenotype is not understood. Fewer than 50 individuals with 9q22.3 microdeletion have been reported, all diagnosed postnatally on the basis of the phenotype. A confirmed prenatal diagnosis and accompanying fetal imaging has not been reported to date. We describe a patient with prenatally diagnosed 9q22.3 microdeletion syndrome following the ultrasonographic identification of trigonocephaly, macrosomia, organomegaly, ventriculomegaly, and anomalous vertebrae. PMID- 25706931 TI - Nernst effect of the intermediate valence compound YbAl3: revisiting the thermoelectric properties. AB - The Nernst effect and thermopower of the prototypical Yb-based intermediate valence compound YbAl(3) were investigated. Different to the thermopower whose absolute values are enhanced with increasing temperature and assume a broad maximum at 175 K, the Nernst coefficient of YbAl(3) is enhanced only below T ~ 75 K. While the two quantities in the heavy-fermion compound CeCu(2)Si(2) were recently found to be related by the anomalous Hall mobility due to the local asymmetric Kondo scattering, this theorem fails when being applied to YbAl(3). Rather, the thermopower of YbAl(3) is well described by a simple narrow-band model. We discuss the reason for this in terms of the intermediate valence nature of YbAl(3) that is conceptually different from the local Kondo physics. PMID- 25706930 TI - The involvement of TLR2 and TLR4 in cytokine and nitric oxide production in visceral leishmaniasis patients before and after treatment with anti-leishmanial drugs. AB - Toll-like receptors (TLRs) have significant involvement in Leishmania infection, although little is known about the relationship between these receptors, cytokines and nitric oxide (NO) in patients with visceral leishmaniasis (VL) before or after treatment with anti-leishmanial drugs. The goal of this study was to evaluate the expression of TLR2 and TLR4 in CD3+ and CD14+ cells and the production of TNF-alpha, IFN-gamma, IL-17, IL-10, TGF-beta and NO in peripheral blood mononuclear cells (PBMCs) from VL patients pre- and post-treatment with anti-leishmanial drugs. In addition, we investigated whether these receptors were involved in the production of these cytokines and NO. In the active VL patients, increased TLR2 and TLR4 expression in lymphocytes and monocytes, increased production of TNF-alpha, IL-10 and TGF-beta and decreased production of IFN gamma, IL-17 and NO were observed. After treatment, TLR2 and TLR4 were still expressed in lymphocytes and monocytes, the TNF-alpha and IL-10 levels were lower, the production of IFN-gamma, IL-17 and NO was higher, and the TGF-beta level remained high. Before treatment, the production of TNF-alpha and NO was associated with TLR2 and TLR4 expression, while IL-10 production was only associated with TLR2 expression. After treatment, both receptors were associated with the production of TNF-alpha, IFN-gamma, IL-10 and NO, while the production of IL-17 was associated only with TLR4 expression. The results presented in this study suggest that both TLR2 and TLR4 participate in the modulation of cytokine and NO production in VL patients, contributing to the pathogenesis of VL prior to treatment and the protective immune response after treatment. PMID- 25706932 TI - CRISPR-cas subtype I-Fb in Acinetobacter baumannii: evolution and utilization for strain subtyping. AB - Clustered regularly interspaced short palindromic repeats (CRISPR) are polymorphic elements found in the genome of some or all strains of particular bacterial species, providing them with a system of acquired immunity against invading bacteriophages and plasmids. Two CRISPR-Cas systems have been identified in Acinetobacter baumannii, an opportunistic pathogen with a remarkable capacity for clonal dissemination. In this study, we investigated the mode of evolution and diversity of spacers of the CRISPR-cas subtype I-Fb locus in a global collection of 76 isolates of A. baumannii obtained from 14 countries and 4 continents. The locus has basically evolved from a common ancestor following two main lineages and several pathways of vertical descent. However, this vertical passage has been interrupted by occasional events of horizontal transfer of the whole locus between distinct isolates. The isolates were assigned into 40 CRISPR based sequence types (CST). CST1 and CST23-24 comprised 18 and 9 isolates, representing two main sub-clones of international clones CC1 and CC25, respectively. Epidemiological data showed that some of the CST1 isolates were acquired or imported from Iraq, where it has probably been endemic for more than one decade and occasionally been able to spread to USA, Canada, and Europe. CST23 24 has shown a remarkable ability to cause national outbreaks of infections in Sweden, Argentina, UAE, and USA. The three isolates of CST19 were independently imported from Thailand to Sweden and Norway, raising a concern about the prevalence of CST19 in Thailand. Our study highlights the dynamic nature of the CRISPR-cas subtype I-Fb locus in A. baumannii, and demonstrates the possibility of using a CRISPR-based approach for subtyping a significant part of the global population of A. baumannii. PMID- 25706933 TI - Barriers to social participation among lonely older adults: the influence of social fears and identity. AB - INTRODUCTION: Loneliness among older adults is a major public health problem that may be associated with processes of social participation and identity. This study therefore sought to examine the relationship between social participation and identity in a sample of lonely older adults living independently in London, England. METHOD: An inductive qualitative approach, based on semi-structured interviews and thematic analysis, was employed. RESULTS: Participants commonly spoke of barriers to social participation that have been reported elsewhere, including illness/disability, loss of contact with friends/relatives, lack of a supportive community, and lack of acceptable social opportunities. However, novel findings were also derived. In particular, participants commonly minimised the difficulties they faced alone, and described attempts to avoid social opportunities. These behaviours were linked to fears about engaging in social participation opportunities, including fears of social rejection and/or exploitation, and fears of losing valued aspects of identity. DISCUSSION: It is concluded that social participation amongst lonely older people will not improve through the removal of previously reported barriers alone; instead, older peoples' beliefs, fears and identities must be addressed. Suggestions for implementing these findings within community organisations are provided. PMID- 25706934 TI - Personality disorder traits, risk factors, and suicide ideation among older adults. AB - BACKGROUND: Personality disorder traits are relatively prevalent among older adults, and can be associated with complex and chronic difficulties, including suicide risk. However, there is a lack of research regarding personality disorders and suicide ideation in older adults. Depressive symptoms and hopelessness may be important to the relation between personality disorders and suicide risk. Additionally, variables from the interpersonal theory of suicide, perceived burdensomeness and thwarted belongingness, may be critical risk factors for suicide in this population. We hypothesized that perceived burdensomeness and thwarted belongingness, theory-based variables, would act as parallel mediators of the relation between personality disorder traits and suicide ideation, whereas depressive symptoms and hopelessness would not. METHODS: The hypothesis was tested in a sample of 143 older adults recruited from a primary care setting. Participants completed self-report questionnaires of personality traits, suicide ideation, depressive symptoms, hopelessness, perceived burdensomeness, and thwarted belongingness. RESULTS: Findings from a non-parametric bootstrapping procedure indicated that perceived burdensomeness, thwarted belongingness, and depressive symptoms mediated the relation between total personality disorder traits and suicide ideation. Hopelessness did not act as a mediator. CONCLUSIONS: These findings indicate that perceived burdensomeness, thwarted belongingness, and depressive symptoms are likely important risk factors for suicide ideation among older adults. Clinicians should be aware of these issues when assessing and treating suicide risk among older adults. PMID- 25706935 TI - Predicting asthma-related emergency department visits using big data. AB - Asthma is one of the most prevalent and costly chronic conditions in the United States, which cannot be cured. However, accurate and timely surveillance data could allow for timely and targeted interventions at the community or individual level. Current national asthma disease surveillance systems can have data availability lags of up to two weeks. Rapid progress has been made in gathering nontraditional, digital information to perform disease surveillance. We introduce a novel method of using multiple data sources for predicting the number of asthma related emergency department (ED) visits in a specific area. Twitter data, Google search interests, and environmental sensor data were collected for this purpose. Our preliminary findings show that our model can predict the number of asthma ED visits based on near-real-time environmental and social media data with approximately 70% precision. The results can be helpful for public health surveillance, ED preparedness, and targeted patient interventions. PMID- 25706936 TI - Multiobjective Simulated Annealing-Based Clustering of Tissue Samples for Cancer Diagnosis. AB - In the field of pattern recognition, the study of the gene expression profiles of different tissue samples over different experimental conditions has become feasible with the arrival of microarray-based technology. In cancer research, classification of tissue samples is necessary for cancer diagnosis, which can be done with the help of microarray technology. In this paper, we have presented a multiobjective optimization (MOO)-based clustering technique utilizing archived multiobjective simulated annealing(AMOSA) as the underlying optimization strategy for classification of tissue samples from cancer datasets. The presented clustering technique is evaluated for three open source benchmark cancer datasets [Brain tumor dataset, Adult Malignancy, and Small Round Blood Cell Tumors (SRBCT)]. In order to evaluate the quality or goodness of produced clusters, two cluster quality measures viz, adjusted rand index and classification accuracy ( % CoA) are calculated. Comparative results of the presented clustering algorithm with ten state-of-the-art existing clustering techniques are shown for three benchmark datasets. Also, we have conducted a statistical significance test called t-test to prove the superiority of our presented MOO-based clustering technique over other clustering techniques. Moreover, significant gene markers have been identified and demonstrated visually from the clustering solutions obtained. In the field of cancer subtype prediction, this study can have important impact. PMID- 25706937 TI - Coupled Hidden Markov Model-Based Method for Apnea Bradycardia Detection. AB - In this paper, we present a novel framework for the coupled hidden Markov model (CHMM), based on the forward and backward recursions and conditional probabilities, given a multidimensional observation. In the proposed framework, the interdependencies of states networks are modeled with Markovian-like transition laws that influence the evolution of hidden states in all channels. Moreover, an offline inference approach by maximum likelihood estimation is proposed for the learning procedure of model parameters. To evaluate its performance, we first apply the CHMM model to classify and detect disturbances using synthetic data generated by the FitzHugh-Nagumo model. The average sensitivity and specificity of the classification are above 93.98% and 95.38% and those of the detection reach 94.49% and 99.34%, respectively. The method is also evaluated using a clinical database composed of annotated physiological signal recordings of neonates suffering from apnea-bradycardia. Different combinations of beat-to-beat features extracted from electrocardiographic signals constitute the multidimensional observations for which the proposed CHMM model is applied, to detect each apnea bradycardia episode. The proposed approach is finally compared to other previously proposed HMM-based detection methods. Our CHMM provides the best performance on this clinical database, presenting an average sensitivity of 95.74% and specificity of 91.88% while it reduces the detection delay by -0.59 s. PMID- 25706938 TI - A population-based single nucleotide polymorphism array analysis of genomic aberrations in younger adult acute lymphoblastic leukemia patients. AB - Adult acute lymphoblastic leukemia (ALL) is characterized by a high frequency of abnormal karyotypes some of which are related to outcome. Single nucleotide polymorphism (SNP) array analysis provides a highly sensitive platform to detect large and small genomic aberrations. SNP array profiling data in adult ALL are limited and further systematic studies of this patient group are needed. We performed a population-based SNP array analysis of genomic aberrations and their influence on survival in 66 Lithuanian 18-65 year old ALL patients diagnosed between 2007 and 2013. Most aberrations were detected in chromosome arm 9p, chromosome arm 6q, chromosome arm 13q, and chromosome 17. The recurrently targeted copy number abnormalities involved several leukemia-related genes CDKN2A/B, MLL, IKZF1, PAX5, RB1, TP53, and ETV6. We identified several new recurrent aberrations with possible new target genes: SMARCA4 in 19p13.2, RNASEL in 1q25.3, ARHGEF12 in 11q23.3, and LYL1 in 19p13.2. Aberrations in chromosome 13 and the RB1 gene as well as CDKN2A/B gene status were related to the outcome. PMID- 25706941 TI - The impact of diabetes on the labour force participation, savings and retirement income of workers aged 45-64 years in Australia. AB - BACKGROUND: Diabetes is a debilitating and costly condition. The costs of reduced labour force participation due to diabetes can have severe economic impacts on individuals by reducing their living standards during working and retirement years. METHODS: A purpose-built microsimulation model of Australians aged 45-64 years in 2010, Health&WealthMOD2030, was used to estimate the lost savings at age 65 due to premature exit from the labour force because of diabetes. Regression models were used to examine the differences between the projected savings and retirement incomes of people at age 65 for those currently working full or part time with no chronic health condition, full or part time with diabetes, and people not in the labour force due to diabetes. RESULTS: All Australians aged 45 65 years who are employed full time in 2010 will have accumulated some savings at age 65; whereas only 90.5% of those who are out of the labour force due to diabetes will have done so. By the time they reach age 65, those who retire from the labour force early due to diabetes have a median projected savings of less than $35,000. This is far lower than the median value of total savings for those who remained in the labour force full time with no chronic condition, projected to have $638,000 at age 65. CONCLUSIONS: Not only does premature retirement due to diabetes limit the immediate income available to individuals with this condition, but it also reduces their long-term financial capacity by reducing their accumulated savings and the income these savings could generate in retirement. Policies designed to support the labour force participation of those with diabetes, or interventions to prevent the onset of the disease itself, should be a priority to preserve living standards comparable with others who do not suffer from this condition. PMID- 25706942 TI - Heterogeneity among Mycobacterium ulcerans from French Guiana revealed by multilocus variable number tandem repeat analysis (MLVA). AB - Buruli ulcer is an emerging and neglected tropical disease caused by Mycobacterium ulcerans. Few cases have been reported so far in the Americas. With 250 cases reported since 1969, French Guiana is the only Buruli ulcer endemic area in the continent. Thus far, no genetic diversity studies of strains of M. ulcerans from French Guiana have been reported. Our goal in the present study was to examine the genetic diversity of M. ulcerans strains in this region by using the Multilocus Variable Number Tandem Repeat Analysis (MLVA) approach. A total of 23 DNA samples were purified from ulcer biopsies or derived from pure cultures. MVLA was used in the study of six previously-described Variable Number of Tandem Repeat (VNTR) markers. A total of three allelic combinations were characterized in our study: genotype I which has been described previously, genotype III which is very similar to genotype I, and genotype II which has distinctly different characteristics in comparison with the other two genotypes. This high degree of genetic diversity appears to be uncommon for M. ulcerans. Further research based on complete genome sequencing of strains belonging to genotypes I and II is in progress and should lead soon to a better understanding of genetic specificities of M. ulcerans strains from French Guiana. PMID- 25706944 TI - Trends in the use of guideline-recommended medications and in-hospital mortality of patients with acute myocardial infarction in a Chinese population. AB - OBJECTIVE: Current practice guidelines recommend the routine use of several cardiac medications early in the course of acute myocardial infarction (AMI). Our objective was to analyze temporal trends in medication use and in-hospital mortality of AMI patients in a Chinese population. METHODS: This is a retrospective observational study using electronic medical records from the hospital information system (HIS) of 14 Chinese hospitals. We identified 5599 patients with AMI between 2005 and 2011. Factors associated with medication use and in-hospital mortality were explored by using hierarchical logistic regression. RESULTS: The use of several guideline-recommended medications all increased during the study period: statins (57.7%-90.1%), clopidogrel (61.8% 92.3%), beta-Blockers (45.4%-65.1%), ACEI/ARB (46.7%-58.7%), aspirin (81.9% 92.9%), and the combinations thereof increased from 24.9% to 42.8% (P<0.001 for all). Multivariate analyses showed statistically significant increases in all these medications. The in-hospital mortality decreased from 15.9% to 5.7% from 2005 to 2011 (P<0.001). After multivariate adjustment, admission year was still a significant factor (OR = 0.87, 95% CI 0.79-0.96, P = 0.007), the use of aspirin (OR = 0.64, 95% CI 0.46-0.87), clopidogrel (OR = 0.44, 95% CI 0.31-0.61), ACEI/ARB (OR = 0.73, 95% CI 0.56-0.94) and statins (OR = 0.54, 95% CI 0.40-0.73) were associated with a decrease in in-hospital mortality. Patients with older age, cancer and renal insufficiency had higher in-hospital mortality, while they were generally less likely to receive all these medications. CONCLUSION: Use of guideline-recommended medications early in the course of AMI increased between 2005 and 2011 in a Chinese population. During this same time, there was a decrease in in-hospital mortality. PMID- 25706943 TI - SRC drives growth of antiestrogen resistant breast cancer cell lines and is a marker for reduced benefit of tamoxifen treatment. AB - The underlying mechanisms leading to antiestrogen resistance in estrogen-receptor alpha (ER)-positive breast cancer is still poorly understood. The aim of this study was therefore to identify biomarkers and novel treatments for antiestrogen resistant breast cancer. We performed a kinase inhibitor screen on antiestrogen responsive T47D breast cancer cells and T47D-derived tamoxifen and fulvestrant resistant cell lines. We found that dasatinib, a broad-spectrum kinase inhibitor, inhibited growth of the antiestrogen resistant cells compared to parental T47D cells. Furthermore western blot analysis showed increased expression and phosphorylation of Src in the resistant cells and that dasatinib inhibited phosphorylation of Src and also signaling via Akt and Erk in all cell lines. Immunoprecipitation revealed Src: ER complexes only in the parental T47D cells. In fulvestrant resistant cells, Src formed complexes with the Human Epidermal growth factor Receptor (HER)1 and HER2. Neither HER receptors nor ER were co precipitated with Src in the tamoxifen resistant cell lines. Compared to treatment with dasatinib alone, combined treatment with dasatinib and fulvestrant had a stronger inhibitory effect on tamoxifen resistant cell growth, whereas dasatinib in combination with tamoxifen had no additive inhibitory effect on fulvestrant resistant growth. When performing immunohistochemical staining on 268 primary tumors from breast cancer patients who had received tamoxifen as first line endocrine treatment, we found that membrane expression of Src in the tumor cells was significant associated with reduced disease-free and overall survival. In conclusion, Src was identified as target for treatment of antiestrogen resistant T47D breast cancer cells. For tamoxifen resistant T47D cells, combined treatment with dasatinib and fulvestrant was superior to treatment with dasatinib alone. Src located at the membrane has potential as a new biomarker for reduced benefit of tamoxifen. PMID- 25706945 TI - Dynamic combinatorial chemistry: a tool to facilitate the identification of inhibitors for protein targets. AB - Dynamic combinatorial chemistry (DCC) has emerged as a powerful strategy to identify ligands for biological targets given that it enables the target to direct the synthesis and amplification of its strongest binder(s) from the library of interconverting compounds. Since the first report of DCC applied to the discovery of binders for a protein, this elegant tool has been employed on a range of protein targets at various stages of medicinal-chemistry projects. A series of suitable, reversible reactions that are biocompatible have been established and the portfolio of analytical techniques is growing. Despite progress, in most cases, the libraries employed remain of moderate size. We present here the most recent advances in the field of DCC applied to protein targets, paying particular attention to the experimental conditions and analytical methods chosen. PMID- 25706946 TI - PyNTTTTGT and CpG immunostimulatory oligonucleotides: effect on granulocyte/monocyte colony-stimulating factor (GM-CSF) secretion by human CD56+ (NK and NKT) cells. AB - CD56+ cells have been recognized as being involved in bridging the innate and acquired immune systems. Herein, we assessed the effect of two major classes of immunostimulatory oligonucleotides (ODNs), PyNTTTTGT and CpG, on CD56+ cells. Incubation of human peripheral blood mononuclear cells (hPBMC) with some of these ODNs led to secretion of significant amounts of interferon gamma (IFN-gamma), tumor necrosis factor alpha (TNF-alpha) and granulocyte/monocyte colony stimulating factor (GM-CSF), but only if interleukin 2 (IL2) was present. IMT504, the prototype of the PyNTTTTGT ODN class, was the most active. GM-CSF secretion was very efficient when non-CpG ODNs with high T content and PyNTTTTGT motifs lacking CpGs were used. On the other hand, CpG ODNs and IFNalpha inhibited this GM-CSF secretion. Selective cell type removal from hPBMC indicated that CD56+ cells were responsible for GM-CSF secretion and that plasmacytoid dendritic cells (PDCs) regulate this process. In addition, PyNTTTTGT ODNs inhibited the IFNalpha secretion induced by CpG ODNs in PDCs by interference with the TLR9 signaling pathway. Since IFNalpha is essential for CD56+ stimulation by CpG ODNs, there is a reciprocal interference of CpG and PyNTTTTGT ODNs when acting on this cell population. This suggests that these synthetic ODNs mimic different natural alarm signals for activation of the immune system. PMID- 25706947 TI - Endosymbiont dominated bacterial communities in a dwarf spider. AB - The microbial community of spiders is little known, with previous studies focussing primarily on the medical importance of spiders as vectors of pathogenic bacteria and on the screening of known cytoplasmic endosymbiont bacteria. These screening studies have been performed by means of specific primers that only amplify a selective set of endosymbionts, hampering the detection of unreported species in spiders. In order to have a more complete overview of the bacterial species that can be present in spiders, we applied a combination of a cloning assay, DGGE profiling and high-throughput sequencing on multiple individuals of the dwarf spider Oedothorax gibbosus. This revealed a co-infection of at least three known (Wolbachia, Rickettsia and Cardinium) and the detection of a previously unreported endosymbiont bacterium (Rhabdochlamydia) in spiders. 16S rRNA gene sequences of Rhabdochlamydia matched closely with those of Candidatus R. porcellionis, which is currently only reported as a pathogen from a woodlouse and with Candidatus R. crassificans reported from a cockroach. Remarkably, this bacterium appears to present in very high proportions in one of the two populations only, with all investigated females being infected. We also recovered Acinetobacter in high abundance in one individual. In total, more than 99% of approximately 4.5M high-throughput sequencing reads were restricted to these five bacterial species. In contrast to previously reported screening studies of terrestrial arthropods, our results suggest that the bacterial communities in this spider species are dominated by, or even restricted to endosymbiont bacteria. Given the high prevalence of endosymbiont species in spiders, this bacterial community pattern could be widespread in the Araneae order. PMID- 25706948 TI - The effectiveness of pregabalin for post-tonsillectomy pain control: a randomized controlled trial. AB - BACKGROUND: Although various analgesics have been used, postoperative pain remains one of the most troublesome aspects of tonsillectomy for patients. OBJECTIVE: The aim of the present study was to evaluate the effectiveness of premedication using pregabalin compared with placebo (diazepam) on postoperative pain control in patients undergoing tonsillectomy. METHODS: Forty-eight adult patients were randomly divided into a control group and a pregabalin group. Preoperatively, patients in the control group received 4 mg diazepam orally as placebo, whereas those in the pregabalin group received 300 mg pregabalin orally. All participants were provided with patient-controlled analgesia using fentanyl for 24 hours after surgery. Postoperative pain treatment included acetaminophen 650 mg three times daily for 8 postoperative days. The primary outcome measure was the total amount of patient-controlled fentanyl consumption after tonsillectomy. Secondary outcome measures were the number of injections of ketorolac tromethamine (each 30 mg) requested by patients, pain scores, overall satisfaction scores, drowsiness, nausea, dizziness, headache, and vomiting after the surgery. P < 0.05 was considered statistically significant. RESULTS: The total amount of fentanyl demanded decreased significantly in the pregabalin group (P < 0.001). There were no significant differences in the number of ketorolac tromethamine injections, pain scores, overall satisfaction scores, drowsiness, nausea, dizziness, headache, and vomiting between the two groups. CONCLUSION: Administration of 300 mg pregabalin prior to tonsillectomy decreases fentanyl consumption compared with that after 4 mg diazepam, without an increased incidence of adverse effects. TRIAL REGISTRATION: KCT0001215. PMID- 25706949 TI - Fruits and vegetables as a healthier snack throughout the day among families with older children: findings from a survey of parent-child dyads. AB - Most U.S. youth fail to eat the recommended amount of fruits and vegetables (FV) however many consume too many calories as added sugars and solid fats, often as snacks. The aim of this study was to assess factors associated with serving FV as snacks and with meals using parent-child dyads. A cross-sectional sample of U.S. children aged 9 to 18, and their caregiver/parent (n=1522) were part of a Consumer Panel of households for the 2008 YouthStyles mail survey. Chi-square test of independence and multivariable logistic regression were used to assess associations between serving patterns of FV as snacks with variations in serving patterns, and covariates including dietary habits. Most parents (72%) reported serving FV at meals and as snacks. Fruit was most frequently served as a snack during the day (52%) and vegetables were most frequently served as a snack during the day (22%) but rarely in the morning. Significant differences in child FV intake existed among FV as a snack serving patterns by parents. Compared to children whose parents served FV only at meals, children whose parents reported serving FV as snacks in addition to meals were significantly more likely to have consumed FV the day before (using a previous day screener), P<0.05. Contributing to the growing collection of literature describing parent-child dyad dietary behaviors, these findings suggest promoting FV access and intake throughout the day, not only at meals, by including serving as snacks, may increase FV intake among older children and adolescents. PMID- 25706950 TI - Reducing variety enhances effectiveness of family-based treatment for pediatric obesity. AB - Basic research has shown that increasing variety increases energy intake, and repeated consumption of the same food increases habituation to those foods and reduces consumption. Twenty-four families with overweight/obese 8-12 year-old children and overweight/obese parents were randomly assigned to 6months of usual family based treatment (FBT) or FBT plus reduced variety of high energy-dense foods (FBT+Variety). Intention to treat mixed model ANOVA showed between group differences in child percent overweight (FBT+Variety-15.4% vs. FBT-8.9%, p=0.017) and parent BMI (FBT+Variety-3.7kg/m(2) vs. FBT-2.3kg/m(2); p=0.017). Positive relationships were observed between child zBMI and parent BMI changes (r=0.51, p=0.018), and between reductions in food variety of high energy-dense foods and reductions in child zBMI (r=0.54, p=0.02) and parent BMI (r=0.45, p=0.08). These pilot data suggest that reducing the variety of high energy dense foods and repeating meals within the context of FBT resulted in improved child and parent weight changes at six months. This represents easy to implement changes that reduce choice and may reduce response burden on families. Reducing variety may be a complement to standard FBT that enhances weight loss. Long term studies are needed to assess maintenance of these changes. PMID- 25706951 TI - Genome-wide identification of small RNAs in Bifidobacterium animalis subsp. lactis KLDS 2.0603 and their regulation role in the adaption to gastrointestinal environment. AB - OBJECTIVE: Bifidobacteria are one of the predominant bacterial species in the human gastrointestinal tract (GIT) and play a vital role in the host's health by acting as probiotics. However, how they regulate themselves to adapt to GIT of their host remains unknown. METHODS: Eighteen bifidobacterial strains were used to analyze their adaptive capacities towards simulated GIT environment. The strain with highest survival rate and adhesion ability was selected for comparative genome as well as transcriptomic analysis. RESULTS: The Bifidobacterium animalis subsp. lactis KLDS 2.0603 strain was demonstrated to have the highest survival rate and adhesion ability in simulated GIT treatments. The comparative genome analysis revealed that the KLDS 2.0603 has most similar whole genome sequence compared with BB-12 strain. Eleven intergenic sRNAs were identified after genomes prediction and transcriptomic analysis of KLDS 2.0603. Transcriptomic analysis also showed that genes (mainly sRNAs targeted genes) and sRNAs were differentially expressed in different stress conditions, suggesting that sRNAs might play a crucial role in regulating genes involved in the stress resistance of this strain towards environmental changes. CONCLUSIONS: This study first provided deep and comprehensive insights into the regulation of KLDS 2.0603 strain at transcription and post-transcription level towards environmental. PMID- 25706952 TI - Beyond symbiosis: cleaner shrimp clean up in culture. AB - Cleaner organisms exhibit a remarkable natural behaviour where they consume ectoparasites attached to "client" organisms. While this behaviour can be utilized as a natural method of parasitic disease control (or biocontrol), it is not known whether cleaner organisms can also limit reinfection from parasite eggs and larvae within the environment. Here we show that cleaner shrimp, Lysmata amboinensis, consume eggs and larvae of a harmful monogenean parasite, Neobenedenia sp., in aquaculture. Shrimp consumed parasite eggs under diurnal (63%) and nocturnal (14%) conditions as well as infectious larvae (oncomiracidia) diurnally (26%). Furthermore, we trialled the inclusion of cleaner shrimp for preventative parasite management of ornamental fish, Pseudanthias squamipinnis, and found shrimp reduced oncomiracidia infection success of host fish by half compared to controls (held without shrimp). Fish held without cleaner shrimp exhibited pigmentation changes as a result of infection, possibly indicative of a stress response. These results provide the first empirical evidence that cleaner organisms reduce parasite loads in the environment through non-symbiotic cleaning activities. Our research findings have relevance to aquaculture and the marine ornamental trade, where cleaner shrimp could be applied for prophylaxis and control of ectoparasite infections. PMID- 25706953 TI - Differential expression of metallothionein isoforms in terrestrial snail embryos reflects early life stage adaptation to metal stress. AB - The aim of this study was to analyze the expression of three metallothionein (MT) isoform genes (CdMT, CuMT and Cd/CuMT), already known from adults, in the Early Life Stage (ELS) of Cantareus aspersus. This was accomplished by detection of the MT isoform-specific transcription adopting Polymerase Chain Reaction (PCR) amplification and quantitative Real Time (qRT)-PCR of the three MT genes. Freshly laid eggs were kept for 24 hours under control conditions or exposed to three cadmium (Cd) solutions of increasing concentration (5, 10, and 15 mg Cd/L). The transcription of the three MT isoform genes was detected via PCR in 1, 6 and 12 day-old control or Cd-exposed embryos. Moreover, the transcription of this isoform genes during development was followed by qRT-PCR in 6 and 12-day-old embryos. Our results showed that the CdMT and Cd/CuMT genes, but not the CuMT gene, are expressed in embryos at the first day of development. The transcription of the 3 MT genes in control embryos increased with development time, suggesting that the capacities of metal regulation and detoxification may have gradually increased throughout embryogenesis. However in control embryos, the most highly expressed MT gene was that of the Cd/CuMT isoform, whose transcription levels greatly exceeded those of the other two MT genes. This contrasts with the minor significance of this gene in adult snails and suggests that in embryos, this isoform may play a comparatively more important role in metal physiology compared to adult individuals. This function in adult snails appears not to be related to Cd detoxification. Instead, snail embryos responded to Cd exposure by over expression of the CdMT gene in a concentration-dependent manner, whereas the expression of the Cd/CuMT gene remained unaffected. Moreover, our study demonstrates the ability of snail embryos to respond very early to Cd exposure by up-regulation of the CdMT gene. PMID- 25706954 TI - Not early referral but planned dialysis improves quality of life and depression in newly diagnosed end stage renal disease patients: a prospective cohort study in Korea. AB - BACKGROUND: Health-related quality of life (HRQOL) has recently become an important issue. It reportedly affects morbidity and mortality in patients with end-stage renal disease (ESRD). In this study, we investigated whether early referral and planned dialysis improve the HRQOL and depression of patients with ESRD. METHODS: We prospectively enrolled newly diagnosed patients with ESRD, from 31 hospitals in Korea, who completed questionnaires at 3 months after dialysis. We also got follow-up survey at 1 year after dialysis. To measure HRQOL and depression, Kidney Disease Quality of Life Short Form 36 (KDQOL-36) and Beck's Depression Inventory (BDI) were utilized. RESULTS: A total of 643 patients were analyzed. Referral type did not affect either KDQOL-36 or BDI scores. However, the planned dialysis group showed significantly better scores in 4 of 5 KDQOL-36 domains than did the unplanned group at 3 months after dialysis and partly, the effect was sustained for 1 year after dialysis. The benefit of planned dialysis was significant after adjusting for age, sex, type of dialysis, marital status, educational attainment, occupation, modified Charlson comorbidity index, albumin, and hemoglobin levels. BDI scores were also lower which indicate less depressive mood in planned dialysis group than those in unplanned group both at 3 months and 1 year after dialysis. CONCLUSIONS: Not early referral but planned dialysis improved both the short- and long-term HRQOL and depression of patients with ESRD. Nephrologists should try to help patients to initiate dialysis in a planned manner. PMID- 25706955 TI - Injuries in runners; a systematic review on risk factors and sex differences. AB - BACKGROUND: The popularity of running continues to increase, which means that the incidence of running-related injuries will probably also continue to increase. Little is known about risk factors for running injuries and whether they are sex specific. OBJECTIVES: The aim of this study was to review information about risk factors and sex-specific differences for running-induced injuries in adults. SEARCH STRATEGY: The databases PubMed, EMBASE, CINAHL and Psych-INFO were searched for relevant articles. SELECTION CRITERIA: Longitudinal cohort studies with a minimal follow-up of 1 month that investigated the association between risk factors (personal factors, running/training factors and/or health and lifestyle factors) and the occurrence of lower limb injuries in runners were included. DATA COLLECTION AND ANALYSIS: Two reviewers' independently selected relevant articles from those identified by the systematic search and assessed the risk of bias of the included studies. The strength of the evidence was determined using a best-evidence rating system. Sex differences in risk were determined by calculating the sex ratio for risk factors (the risk factor for women divided by the risk factor for men). MAIN RESULTS: Of 400 articles retrieved, 15 longitudinal studies were included, of which 11 were considered high-quality studies and 4 moderate-quality studies. Overall, women were at lower risk than men for sustaining running-related injuries. Strong and moderate evidence was found that a history of previous injury and of having used orthotics/inserts was associated with an increased risk of running injuries. Age, previous sports activity, running on a concrete surface, participating in a marathon, weekly running distance (30-39 miles) and wearing running shoes for 4 to 6 months were associated with a greater risk of injury in women than in men. A history of previous injuries, having a running experience of 0-2 years, restarting running, weekly running distance (20-29 miles) and having a running distance of more than 40 miles per week were associated with a greater risk of running-related injury in men than in women. CONCLUSIONS: Previous injury and use of orthotic/inserts are risk factors for running injuries. There appeared to be differences in the risk profile of men and women, but as few studies presented results for men and women separately, the results should be interpreted with caution. Further research should attempt to minimize methodological bias by paying attention to recall bias for running injuries, follow-up time, and the participation rate of the identified target group. PMID- 25706956 TI - Phenotypic responses of differentiated asthmatic human airway epithelial cultures to rhinovirus. AB - OBJECTIVES: Human airway epithelial cells are the principal target of human rhinovirus (HRV), a common cold pathogen that triggers the majority of asthma exacerbations. The objectives of this study were 1) to evaluate an in vitro air liquid interface cultured human airway epithelial cell model for HRV infection, and 2) to identify gene expression patterns associated with asthma intrinsically and/or after HRV infection using this model. METHODS: Air-liquid interface (ALI) human airway epithelial cell cultures were prepared from 6 asthmatic and 6 non asthmatic donors. The effects of rhinovirus RV-A16 on ALI cultures were compared. Genome-wide gene expression changes in ALI cultures following HRV infection at 24 hours post exposure were further analyzed using RNA-seq technology. Cellular gene expression and cytokine/chemokine secretion were further evaluated by qPCR and a Luminex-based protein assay, respectively. MAIN RESULTS: ALI cultures were readily infected by HRV. RNA-seq analysis of HRV infected ALI cultures identified sets of genes associated with asthma specific viral responses. These genes are related to inflammatory pathways, epithelial structure and remodeling and cilium assembly and function, including those described previously (e.g. CCL5, CXCL10 and CX3CL1, MUC5AC, CDHR3), and novel ones that were identified for the first time in this study (e.g. CCRL1). CONCLUSIONS: ALI-cultured human airway epithelial cells challenged with HRV are a useful translational model for the study of HRV-induced responses in airway epithelial cells, given that gene expression profile using this model largely recapitulates some important patterns of gene responses in patients during clinical HRV infection. Furthermore, our data emphasize that both abnormal airway epithelial structure and inflammatory signaling are two important asthma signatures, which can be further exacerbated by HRV infection. PMID- 25706957 TI - Effect of preoperatively continued aspirin use on early and mid-term outcomes in off-pump coronary bypass surgery: a propensity score-matched study of 1418 patients. AB - BACKGROUND: To date, effect of preoperatively continued aspirin administration in off-pump coronary artery bypass grafting (CABG) is less known. We aimed to assess the effect of preoperatively continued aspirin use on early and mid-term outcomes in patients receiving off-pump CABG. METHODS: From October 2009 to September 2013 at the Fuwai Hospital, 709 preoperative aspirin users were matched with unique 709 nonaspirin users using propensity score matching to obtain risk-adjusted outcome comparisons between the two groups. Early outcomes were in-hospital death, stroke, intra- and post-operative blood loss, reoperation for bleeding and blood product transfusion. Major adverse cardiac events (death, myocardial infarction or repeat revascularization), angina recurrence and cardiogenic readmission were considered as mid-term endpoints. RESULTS: There were no significant differences among the groups in baseline characteristics after propensity score matching. The median intraoperative blood loss (600 ml versus 450 ml, P = 0.56), median postoperative blood loss (800 ml versus 790 ml, P = 0.60), blood transfusion requirements (25.1% versus 24.4%, P = 0.76) and composite outcome of in-hospital death, stroke and reoperation for bleeding (2.8% versus 1.6%, P = 0.10) were similar in aspirin and nonaspirin use group. At about 4 years follow-up, no significant difference was observed among the aspirin and nonaspirin use group in major adverse cardiac events free survival estimates (95.7% versus 91.5%, P = 0.23) and freedom from cardiogenic readmission (88.5% versus 85.3%, P = 0.77) whereas the angina recurrence free survival rates was 83.7% and 73.9% in the aspirin and nonaspirin use group respectively (P = 0.02), with odd ratio for preoperative aspirin estimated at 0.71 (95% confidence interval, 0.49-1.04, P = 0.08). CONCLUSIONS: Preoperatively continued aspirin use was not associated with increased risk of intra- and post-operative blood loss, blood transfusion requirements and composite outcome of in-hospital death, stroke and reoperation for bleeding in off-pump CABG. Preoperative aspirin use tended to decrease the hazard of mid-term angina recurrence. PMID- 25706958 TI - Understanding inequities in home health care outcomes: staff views on agency and system factors. AB - Results regarding staff perspectives on contributing factors to racial/ethnic disparities in home health care outcomes are discussed. Focus group interviews were conducted with home health care staff (N = 23) who represented various agencies from three Northeastern states. Participants identified agency and system factors that contribute to disparities, including: (a) administrative staff bias/discretion, (b) communication challenges, (c) patient/staff cultural discordance, (d) cost control, and (e) poor access to community resources. Participants reported that bias can influence staff at all levels and is expressed via poor coverage of predominantly minority service areas, resulting in reduced intensity and continuity of service for minority patients. PMID- 25706960 TI - Women's, children's, and adolescents' health: who will lead? PMID- 25706959 TI - 'I am doing fine only because I have not told anyone': the necessity of concealment in the lives of people living with HIV in India. AB - In HIV prevention and care programmes, disclosure of status by HIV-positive individuals is generally encouraged to contain the infection and provide adequate support to the person concerned. Lack of disclosure is generally framed as a barrier to preventive behaviours and accessing support. The assumption that disclosure is beneficial is also reflected in studies that aim to identify determinants of disclosure and recommend individual-level measures to promote disclosure. However, in contexts where HIV infection is stigmatised and there is fear of rejection and discrimination among those living with HIV, concealment of status becomes a way to try and regain as much as possible the life that was disrupted by the discovery of HIV infection. In this study of HIV-positive women and children in India, concealment was considered essential by individuals and families of those living with HIV to re-establish and maintain their normal lives in an environment where stigma and discrimination were prevalent. This paper describes why women and care givers of children felt the need to conceal HIV status, the various ways in which people tried to do so and the implications for treatment of people living with HIV. We found that while women were generally willing to disclose their status to their husband or partner, they were very keen to conceal their status from all others, including family members. Parents and carers with an HIV-positive child were not willing to disclose this status to the child or to others. Understanding the different rationales for concealment would help policy makers and programme managers to develop more appropriate care management strategies and train care providers to assist clients in accessing care and support without disrupting their lives. PMID- 25706961 TI - A data toolkit to improve patient care. PMID- 25706962 TI - Correcting the scientific literature: retraction and republication. PMID- 25706963 TI - Human wellbeing and security: a whole of planet approach. PMID- 25706964 TI - Retraction and republication--ST-segment elevation myocardial infarction in China from 2001 to 2011 (the China PEACE-Retrospective Acute Myocardial Infarction Study): a retrospective analysis of hospital data. PMID- 25706967 TI - Matshidiso Moeti: new Director of WHO AFRO. PMID- 25706968 TI - Neglecting preventive health threatens child rights in Australia. PMID- 25706969 TI - Health and the Indian caste system. PMID- 25706970 TI - Health and the Indian caste system. PMID- 25706971 TI - Nitrous oxide in general anaesthesia. PMID- 25706972 TI - Health and the Indian caste system. PMID- 25706973 TI - Nitrous oxide in general anaesthesia. PMID- 25706974 TI - Nitrous oxide in general anaesthesia - Authors' reply. PMID- 25706975 TI - Dementia underdiagnosis in Brazil. PMID- 25706976 TI - Cardiac, renal, and central nervous system dysfunction with eosinophilia: eosinophilic granulomatosis with polyangiitis. PMID- 25706978 TI - Palladium-catalyzed alpha-arylation of enones in the synthesis of 2 alkenylindoles and carbazoles. AB - A new unified strategy has been developed for the synthesis of substituted 2 alkenylindoles and carbazoles. The strategy uses palladium-catalyzed alpha arylation of TES-enol ethers of enones as the key step. The method is highly regioselective, provides good yields, and is expected to have wide application. PMID- 25706977 TI - Altered molecular expression of the TLR4/NF-kappaB signaling pathway in mammary tissue of Chinese Holstein cattle with mastitis. AB - Toll-like receptor 4 (TLR4) mediated activation of the nuclear transcription factor kappaB (NF-kappaB) signaling pathway by mastitis initiates expression of genes associated with inflammation and the innate immune response. In this study, the profile of mastitis-induced differential gene expression in the mammary tissue of Chinese Holstein cattle was investigated by Gene-Chip microarray and bioinformatics. The microarray results revealed that 79 genes associated with the TLR4/NF-kappaB signaling pathway were differentially expressed. Of these genes, 19 were up-regulated and 29 were down-regulated in mastitis tissue compared to normal, healthy tissue. Statistical analysis of transcript and protein level expression changes indicated that 10 genes, namely TLR4, MyD88, IL-6, and IL-10, were up-regulated, while, CD14, TNF-alpha, MD-2, IL-beta, NF-kappaB, and IL-12 were significantly down-regulated in mastitis tissue in comparison with normal tissue. Analyses using bioinformatics database resources, such as the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and the Gene Ontology Consortium (GO) for term enrichment analysis, suggested that these differently expressed genes implicate different regulatory pathways for immune function in the mammary gland. In conclusion, our study provides new evidence for better understanding the differential expression and mechanisms of the TLR4 /NF-kappaB signaling pathway in Chinese Holstein cattle with mastitis. PMID- 25706979 TI - Methods for Multiloop Identification of Visual and Neuromuscular Pilot Responses. AB - In this paper, identification methods are proposed to estimate the neuromuscular and visual responses of a multiloop pilot model. A conventional and widely used technique for simultaneous identification of the neuromuscular and visual systems makes use of cross-spectral density estimates. This paper shows that this technique requires a specific noninterference hypothesis, often implicitly assumed, that may be difficult to meet during actual experimental designs. A mathematical justification of the necessity of the noninterference hypothesis is given. Furthermore, two methods are proposed that do not have the same limitations. The first method is based on autoregressive models with exogenous inputs, whereas the second one combines cross-spectral estimators with interpolation in the frequency domain. The two identification methods are validated by offline simulations and contrasted to the classic method. The results reveal that the classic method fails when the noninterference hypothesis is not fulfilled; on the contrary, the two proposed techniques give reliable estimates. Finally, the three identification methods are applied to experimental data from a closed-loop control task with pilots. The two proposed techniques give comparable estimates, different from those obtained by the classic method. The differences match those found with the simulations. Thus, the two identification methods provide a good alternative to the classic method and make it possible to simultaneously estimate human's neuromuscular and visual responses in cases where the classic method fails. PMID- 25706980 TI - Semi-Supervised Nonnegative Matrix Factorization via Constraint Propagation. AB - As is well known, nonnegative matrix factorization (NMF) is a popular nonnegative dimensionality reduction method which has been widely used in computer vision, document clustering, and image analysis. However, traditional NMF is an unsupervised learning mode which cannot fully utilize the priori or supervised information. To this end, semi-supervised NMF methods have been proposed by incorporating the given supervised information. Nevertheless, when little supervised information is available, the improved performance will be limited. To effectively utilize the limited supervised information, this paper proposed a novel semi-supervised NMF method (CPSNMF) with pairwise constraints. The method propagates both the must-link and cannot-link constraints from the constrained samples to unconstrained samples, so that we can get the constraint information of the entire data set. Then, this information is reflected to the adjustment of data weight matrix. Finally, the weight matrix is incorporated as a regularization term to the NMF objective function. Therefore, the proposed method can fully utilize the constraint information to keep the geometry of the data distribution. Furthermore, the proposed CPSNMF is explored with two formulations and corresponding update rules are provided to solve the optimization problems. Thorough experiments on standard databases show the superior performance of the proposed method. PMID- 25706981 TI - Science vs conspiracy: collective narratives in the age of misinformation. AB - The large availability of user provided contents on online social media facilitates people aggregation around shared beliefs, interests, worldviews and narratives. In spite of the enthusiastic rhetoric about the so called collective intelligence unsubstantiated rumors and conspiracy theories-e.g., chemtrails, reptilians or the Illuminati-are pervasive in online social networks (OSN). In this work we study, on a sample of 1.2 million of individuals, how information related to very distinct narratives-i.e. main stream scientific and conspiracy news-are consumed and shape communities on Facebook. Our results show that polarized communities emerge around distinct types of contents and usual consumers of conspiracy news result to be more focused and self-contained on their specific contents. To test potential biases induced by the continued exposure to unsubstantiated rumors on users' content selection, we conclude our analysis measuring how users respond to 4,709 troll information-i.e. parodistic and sarcastic imitation of conspiracy theories. We find that 77.92% of likes and 80.86% of comments are from users usually interacting with conspiracy stories. PMID- 25706982 TI - Serum lipid profile in subjects with traumatic spinal cord injury. AB - BACKGROUND AND AIMS: Few large studies have examined the relationship between spinal cord injury (SCI) and lipid profile. We studied serum lipid concentrations in subjects with traumatic SCI in relation to the degree of neurological involvement and time since injury, and compared them with values from a reference sample for the Spanish population (DRECE study). MATERIALS AND METHODS: A retrospective cohort was built from 177 consecutive cases with traumatic SCI admitted to the SCI unit of the Miguel Servet Hospital in Aragon (Spain). Outcome measures (cholesterol, triglycerides, HDL-c and LDL-c levels) were analyzed according to the ASIA Impairment Scale (AIS), neurological level of injury (involvement of all limbs vs. only lower limbs), and time since injury. All analyses were adjusted for age and sex. RESULTS: Cases without preserved motor function (AIS A or B) had lower total and HDL cholesterol than the others (-11.4 [-21.5, -1.4] mg/dL total cholesterol and -5.1 [-8.8, -1.4] mg/dL HDL-c), and cases with all-limb involvement had lower total, HDL, and LDL cholesterol than those with only lower-limb involvement (-14.0 [-24.6, -3.4] mg/dL total cholesterol, -4.1 [-8.0, -0.2] mg/dL HDL-c, and -10.0 [-19.7, -0.3] mg/dL LDL-c) (all p<0.05). No association was found between lipid concentrations and time since injury. Concentrations of lipid subfractions and triglycerides in SCI subjects were lower than in sex- and age-stratified values from the reference sample. CONCLUSION: A high degree of neurological involvement in SCI (anatomically higher lesions and AIS A or B) is associated with lower total cholesterol and HDL-c. PMID- 25706983 TI - Neurogenic hyperadrenergic orthostatic hypotension: a newly recognized variant of orthostatic hypotension in older adults with elevated norepinephrine (noradrenaline). AB - Patients with neurogenic orthostatic hypotension (OH) typically have impaired sympathetic nervous system tone and therefore low levels of upright plasma norepinephrine (NE) (noradrenaline). We report a subset of patients who clinically have typical neurogenic OH but who paradoxically have elevated upright levels of plasma NE. We retrospectively studied 83 OH patients evaluated at the Vanderbilt Autonomic Dysfunction Center between August 2007 and May 2013. Based on standing NE, patients were dichotomized into a hyperadrenergic OH group [hyperOH: upright NE >= 3.55 nmol/l (600 pg/ml), n=19] or a non-hyperadrenergic OH group [nOH: upright NE < 3.55 nmol/l (600 pg/ml), n=64]. Medical history and data from autonomic testing, including the Valsalva manoeuvre (VM), were analysed. HyperOH patients had profound orthostatic falls in blood pressure (BP), but less severe than in nOH [change in SBP (systolic blood pressure): -53 +/- 31 mmHg compared with -68 +/- 33 mmHg, P=0.050; change in DBP (diastolic blood pressure): -18 +/- 23 mmHg compared with -30 +/- 17 mmHg, P=0.01]. The expected compensatory increase in standing heart rate (HR) was similarly blunted in both hyperOH and nOH groups [84 +/- 15 beats per minute (bpm) compared with 82 +/- 14 bpm; P=0.6]. HyperOH patients had less severe sympathetic failure as evidenced by smaller falls in DBP during phase 2 of VM and a shorter VM phase 4 BP recovery time (16.5 +/- 8.9 s compared with 31.6 +/- 16.6 s; P<0.001) than nOH patients. Neurogenic hyperOH patients have severe neurogenic OH, but have less severe adrenergic dysfunction than nOH patients. Further work is required to understand whether hyperOH patients will progress to nOH or whether this represents a different disorder. PMID- 25706984 TI - Co-evolutionary dynamics of collective action with signaling for a quorum. AB - Collective signaling for a quorum is found in a wide range of organisms that face collective action problems whose successful solution requires the participation of some quorum of the individuals present. These range from humans, to social insects, to bacteria. The mechanisms involved, the quorum required, and the size of the group may vary. Here we address the general question of the evolution of collective signaling at a high level of abstraction. We investigate the evolutionary dynamics of a population engaging in a signaling N-person game theoretic model. Parameter settings allow for loners and cheaters, and for costly or costless signals. We find a rich dynamics, showing how natural selection, operating on a population of individuals endowed with the simplest strategies, is able to evolve a costly signaling system that allows individuals to respond appropriately to different states of Nature. Signaling robustly promotes cooperative collective action, in particular when coordinated action is most needed and difficult to achieve. Two different signaling systems may emerge depending on Nature's most prevalent states. PMID- 25706985 TI - Trametinib with or without vemurafenib in BRAF mutated non-small cell lung cancer. AB - V-Raf Murine Sarcoma Viral Oncogene Homolog B (BRAF) mutated lung cancer is relatively aggressive and is resistant to currently available therapies. In a recent phase II study for patients with BRAF-V600E non-small cell lung cancer (NSCLC), BRAF V600E inhibitor demonstrated evidence of activity, but 30% of this selected group progressed while on treatment, suggesting a need for developing alternative strategies. We tested two different options to enhance the efficacy of vemurafenib (BRAF V600E inhibitor) in BRAF mutated NSCLC. The first option was the addition of erlotinib to vemurafenib to see whether the combination provided synergy. The second was to induce MEK inhibition (downstream of RAF) with trametinib (MEK inhibitor). We found that the combination of vemurafenib and erlotinib was not synergistic to the inhibition of p-ERK signaling in BRAF-V600E cells. Vemurafenib caused significant apoptosis, G1 arrest and upregulation of BIM in BRAF-V600 cells. Trametinib was effective as a single agent in BRAF mutated cells, either V600E or non-V600E. Finally, the combination of vemurafenib and trametinib caused a small but significant increase in apoptosis as well as a significant upregulation of BIM when compared to either single agent. Thus, hinting at the possibility of utilizing a combinational approach for the management of this group of patients. Importantly, trametinib alone caused upregulation of p-AKT in BRAF non-V600 mutated cells, while this effect was nullified with the combination. This finding suggests that, the combination of a MEK inhibitor with a BRAF inhibitor will be more efficacious in the clinical setting for patients with BRAF mutated NSCLC. PMID- 25706986 TI - Metabolic reprogramming in mutant IDH1 glioma cells. AB - BACKGROUND: Mutations in isocitrate dehydrogenase (IDH) 1 have been reported in over 70% of low-grade gliomas and secondary glioblastomas. IDH1 is the enzyme that catalyzes the oxidative decarboxylation of isocitrate to alpha-ketoglutarate while mutant IDH1 catalyzes the conversion of alpha-ketoglutarate into 2 hydroxyglutarate. These mutations are associated with the accumulation of 2 hydroxyglutarate within the tumor and are believed to be one of the earliest events in the development of low-grade gliomas. The goal of this work was to determine whether the IDH1 mutation leads to additional magnetic resonance spectroscopy (MRS)-detectable changes in the cellular metabolome. METHODS: Two genetically engineered cell models were investigated, a U87-based model and an E6/E7/hTERT immortalized normal human astrocyte (NHA)-based model. For both models, wild-type IDH1 cells were generated by transduction with a lentiviral vector coding for the wild-type IDH1 gene while mutant IDH1 cells were generated by transduction with a lentiviral vector coding for the R132H IDH1 mutant gene. Metabolites were extracted from the cells using the dual-phase extraction method and analyzed by 1H-MRS. Principal Component Analysis was used to analyze the MRS data. RESULTS: Principal Component Analysis clearly discriminated between wild type and mutant IDH1 cells. Analysis of the loading plots revealed significant metabolic changes associated with the IDH1 mutation. Specifically, a significant drop in the concentration of glutamate, lactate and phosphocholine as well as the expected elevation in 2-hydroxyglutarate were observed in mutant IDH1 cells when compared to their wild-type counterparts. CONCLUSION: The IDH1 mutation leads to several, potentially translatable MRS-detectable metabolic changes beyond the production of 2-hydroxyglutarate. PMID- 25706987 TI - Multi-channel microfluidic biosensor platform applied for online monitoring and screening of biofilm formation and activity. AB - Bacterial colonization of surfaces and interfaces has a major impact on various areas including biotechnology, medicine, food industries, and water technologies. In most of these areas biofilm development has a strong impact on hygiene situations, product quality, and process efficacies. In consequence, biofilm manipulation and prevention is a fundamental issue to avoid adverse impacts. For such scenario online, non-destructive biofilm monitoring systems become important in many technical and industrial applications. This study reports such a system in form of a microfluidic sensor platform based on the combination of electrical impedance spectroscopy and amperometric current measurement, which allows sensitive online measurement of biofilm formation and activity. A total number of 12 parallel fluidic channels enable real-time online screening of various biofilms formed by different Pseudomonas aeruginosa and Stenotrophomonas maltophilia strains and complex mixed population biofilms. Experiments using disinfectant and antibiofilm reagents demonstrate that the biofilm sensor is able to discriminate between inactivation/killing of bacteria and destabilization of biofilm structures. The impedance and amperometric sensor data demonstrated the high dynamics of biofilms as a consequence of distinct responses to chemical treatment strategies. Gene expression of flagellar and fimbrial genes of biofilms grown inside the microfluidic system supported the detected biofilm growth kinetics. Thus, the presented biosensor platform is a qualified tool for assessing biofilm formation in specific environments and for evaluating the effectiveness of antibiofilm treatment strategies. PMID- 25706988 TI - Large unbalanced credit scoring using Lasso-logistic regression ensemble. AB - Recently, various ensemble learning methods with different base classifiers have been proposed for credit scoring problems. However, for various reasons, there has been little research using logistic regression as the base classifier. In this paper, given large unbalanced data, we consider the plausibility of ensemble learning using regularized logistic regression as the base classifier to deal with credit scoring problems. In this research, the data is first balanced and diversified by clustering and bagging algorithms. Then we apply a Lasso-logistic regression learning ensemble to evaluate the credit risks. We show that the proposed algorithm outperforms popular credit scoring models such as decision tree, Lasso-logistic regression and random forests in terms of AUC and F-measure. We also provide two importance measures for the proposed model to identify important variables in the data. PMID- 25706989 TI - Assessment of left and right ventricular diastolic and systolic functions using two-dimensional speckle-tracking echocardiography in patients with coronary slow flow phenomenon. AB - OBJECTIVE: Coronary slow-flow phenomenon (CSFP) is an angiographic diagnosis characterised by a low rate of flow of contrast agent in the normal or near normal epicardial coronary arteries. Many of the patients with CSFP may experience recurrent acute coronary syndromes. However, current clinical practice tends to underestimate the impact of CSFP due to the yet unknown effect on the cardiac function. This study was performed to evaluate left ventricular (LV) and right ventricular (RV) diastolic and systolic functions, using two-dimensional (2D) longitudinal strain and strain rate, in patients with CSFP, and to determine the relationships between the thrombolysis in myocardial infarction (TIMI) frame count (TFC) and LV and RV diastolic and systolic functions. METHODS: Sixty-three patients with CSFP and 45 age- and sex-matched controls without CSFP were enrolled in the study. Diagnosis of CSFP was made by TFC. LV and RV diastolic and systolic functions were assessed by 2D speckle-tracking echocardiography. RESULTS: LV peak early diastolic longitudinal strain rate (LSRe) was lower in patients with CSFP than in controls (P = 0.01). LV peak systolic longitudinal strain (LS) and LV peak systolic longitudinal strain rate (LSRs) were lower in patients with CSFP than in controls (P = 0.004 and P = 0.03, respectively). There was no difference in LV ejection fraction. RV peak early diastolic longitudinal strain rate (RSRe) was lower in patients with CSFP than in controls (P = 0.03). There were no differences in RV peak systolic longitudinal strain (RS), RV peak systolic longitudinal strain rate (RSRs), or RV fractional area change among the groups. The mean TFC correlated negatively with LSRe and RSRe in patients with CSFP (r = -0.26, P = 0.04 and r = -0.32, P = 0.01, respectively). CONCLUSIONS: LV diastolic and systolic functions were impaired in patients with CSFP. CSFP also affected RV diastolic function, but not RV systolic function. PMID- 25706990 TI - Cross-sectional comparison of small animal [18F]-florbetaben amyloid-PET between transgenic AD mouse models. AB - We aimed to compare [18F]-florbetaben PET imaging in four transgenic mouse strains modelling Alzheimer's disease (AD), with the main focus on APPswe/PS2 mice and C57Bl/6 mice serving as controls (WT). A consistent PET protocol (N = 82 PET scans) was used, with cortical standardized uptake value ratio (SUVR) relative to cerebellum as the endpoint. We correlated methoxy-X04 staining of beta-amyloid with PET results, and undertook ex vivo autoradiography for further validation of a partial volume effect correction (PVEC) of PET data. The SUVR in APPswe/PS2 increased from 0.95+/-0.04 at five months (N = 5) and 1.04+/-0.03 (p<0.05) at eight months (N = 7) to 1.07+/-0.04 (p<0.005) at ten months (N = 6), 1.28+/-0.06 (p<0.001) at 16 months (N = 6) and 1.39+/-0.09 (p<0.001) at 19 months (N = 6). SUVR was 0.95+/-0.03 in WT mice of all ages (N = 22). In APPswe/PS1G384A mice, the SUVR was 0.93/0.98 at five months (N = 2) and 1.11 at 16 months (N = 1). In APPswe/PS1dE9 mice, the SUVR declined from 0.96/0.96 at 12 months (N = 2) to 0.91/0.92 at 24 months (N = 2), due to beta-amyloid plaques in cerebellum. PVEC reduced the discrepancy between SUVR-PET and autoradiography from -22% to +2% and increased the differences between young and aged transgenic animals. SUVR and plaque load correlated highly between strains for uncorrected (R = 0.94, p<0.001) and PVE-corrected (R = 0.95, p<0.001) data. We find that APPswe/PS2 mice may be optimal for longitudinal amyloid-PET monitoring in planned interventions studies. PMID- 25706991 TI - Aqueous nanosilica dispersants for carbon nanotube. AB - Nanosilicas can disperse single-wall carbon nanotube (SWCNT) in aqueous solution efficiently; SWCNTs are stably dispersed in aqueous media for more than 6 months. The SWCNT dispersing solution with nanosilica can produce highly conductive transparent films which satisfy the requirements for application to touch panels. Even multiwall carbon nanotube can be dispersed easily in aqueous solution. The highly stable dispersion of SWCNTs in the presence of nanosilica is associated with charge transfer interaction which generates effective charges on the SWCNT particles, giving rise to electrostatic repulsion between the SWCNTs in the aqueous solution. Adhesion of charged nanosilicas on SWCNTs in the aqueous solution and a marked depression of the S11 peak of optical absorption spectrum of the SWCNT with nanosilicas suggest charge transfer interaction of nanosilicas with SWCNT. Thus-formed isolated SWCNTs are fixed on the flexible three dimensional silica jelly structure in the aqueous solution, leading to the uniform and stable dispersion of SWCNTs. PMID- 25706992 TI - Researcher perspectives on publication and peer review of data. AB - Data "publication" seeks to appropriate the prestige of authorship in the peer reviewed literature to reward researchers who create useful and well-documented datasets. The scholarly communication community has embraced data publication as an incentive to document and share data. But, numerous new and ongoing experiments in implementation have not yet resolved what a data publication should be, when data should be peer-reviewed, or how data peer review should work. While researchers have been surveyed extensively regarding data management and sharing, their perceptions and expectations of data publication are largely unknown. To bring this important yet neglected perspective into the conversation, we surveyed ~ 250 researchers across the sciences and social sciences- asking what expectations"data publication" raises and what features would be useful to evaluate the trustworthiness, evaluate the impact, and enhance the prestige of a data publication. We found that researcher expectations of data publication center on availability, generally through an open database or repository. Few respondents expected published data to be peer-reviewed, but peer-reviewed data enjoyed much greater trust and prestige. The importance of adequate metadata was acknowledged, in that almost all respondents expected data peer review to include evaluation of the data's documentation. Formal citation in the reference list was affirmed by most respondents as the proper way to credit dataset creators. Citation count was viewed as the most useful measure of impact, but download count was seen as nearly as valuable. These results offer practical guidance for data publishers seeking to meet researcher expectations and enhance the value of published data. PMID- 25706993 TI - Optimization of heavy chain and light chain signal peptides for high level expression of therapeutic antibodies in CHO cells. AB - Translocation of a nascent protein from the cytosol into the ER mediated by its signal peptide is a critical step in protein secretion. The aim of this work was to develop a platform technology to optimize the signal peptides for high level production of therapeutic antibodies in CHO cells. A database of signal peptides from a large number of human immunoglobulin (Ig) heavy chain (HC) and kappa light chain (LC) was generated. Most of the HC signal peptides contain 19 amino acids which can be divided into three domains and the LC signal peptides contain 22 amino acids. The signal peptides were then clustered according to sequence similarity. Based on the clustering, 8 HC and 2 LC signal peptides were analyzed for their impacts on the production of 5-top selling antibody therapeutics, namely, Herceptin, Avastin, Remicade, Rituxan, and Humira. The best HC and LC signal peptides for producing these 5 antibodies were identified. The optimized signal peptides for Rituxan is 2-fold better compared to its native signal peptides which are available in the public database. Substitution of a single amino acid in the optimized HC signal peptide for Avastin reduced its production significantly. Mass spectrometry analyses revealed that all optimized signal peptides are accurately removed in the mature antibodies. The results presented in this report are particularly important for the production of these 5 antibodies as biosimilar drugs. They also have the potential to be the best signal peptides for the production of new antibodies in CHO cells. PMID- 25706994 TI - Brain serotonin signaling does not determine sexual preference in male mice. AB - It was reported recently that male mice lacking brain serotonin (5-HT) lose their preference for females (Liu et al., 2011, Nature, 472, 95-100), suggesting a role for 5-HT signaling in sexual preference. Regulation of sex preference by 5-HT lies outside of the well established roles in this behavior established for the vomeronasal organ (VNO) and the main olfactory epithelium (MOE). Presently, mice with a null mutation in the gene for tryptophan hydroxylase 2 (TPH2), which are depleted of brain 5-HT, were tested for sexual preference. When presented with inanimate (urine scents from male or estrous female) or animate (male or female mouse in estrus) sexual stimuli, TPH2-/- males show a clear preference for female over male stimuli. When a TPH2-/- male is offered the simultaneous choice between an estrous female and a male mouse, no sexual preference is expressed. However, when confounding behaviors that are seen among 3 mice in the same cage are controlled, TPH2-/- mice, like their TPH2+/+ counterparts, express a clear preference for female mice. Female TPH2-/- mice are preferred by males over TPH2+/+ females but this does not lead to increased pregnancy success. In fact, if one or both partners in a mating pair are TPH2-/- in genotype, pregnancy success rates are significantly decreased. Finally, expression of the VNO specific cation channel TRPC2 and of CNGA2 in the MOE of TPH2-/- mice is normal, consistent with behavioral findings that sexual preference of TPH2-/- males for females is intact. In conclusion, 5-HT signaling in brain does not determine sexual preference in male mice. The use of pharmacological agents that are non selective for the 5-HT neuronal system and that have serious adverse effects may have contributed historically to the stance that 5-HT regulates sexual behavior, including sex partner preference. PMID- 25706995 TI - Covariation of the incidence of type 1 diabetes with country characteristics available in public databases. AB - BACKGROUND: The incidence of Type 1 Diabetes (T1D) in children varies dramatically between countries. Part of the explanation must be sought in environmental factors. Increasingly, public databases provide information on country-to-country environmental differences. METHODS: Information on the incidence of T1D and country characteristics were searched for in the 194 World Health Organization (WHO) member countries. T1D incidence was extracted from a systematic literature review of all papers published between 1975 and 2014, including the 2013 update from the International Diabetes Federation. The information on country characteristics was searched in public databases. We considered all indicators with a plausible relation with T1D and those previously reported as correlated with T1D, and for which there was less than 5% missing values. This yielded 77 indicators. Four domains were explored: Climate and environment, Demography, Economy, and Health Conditions. Bonferroni correction to correct false discovery rate (FDR) was used in bivariate analyses. Stepwise multiple regressions, served to identify independent predictors of the geographical variation of T1D. FINDINGS: T1D incidence was estimated for 80 WHO countries. Forty-one significant correlations between T1D and the selected indicators were found. Stepwise Multiple Linear Regressions performed in the four explored domains indicated that the percentages of variance explained by the indicators were respectively 35% for Climate and environment, 33% for Demography, 45% for Economy, and 46% for Health conditions, and 51% in the Final model, where all variables selected by domain were considered. Significant environmental predictors of the country-to-country variation of T1D incidence included UV radiation, number of mobile cellular subscriptions in the country, health expenditure per capita, hepatitis B immunization and mean body mass index (BMI). CONCLUSIONS: The increasing availability of public databases providing information in all global environmental domains should allow new analyses to identify further geographical, behavioral, social and economic factors, or indicators that point to latent causal factors of T1D. PMID- 25706997 TI - Creating a list of low-value health care activities in Swiss primary care. PMID- 25706996 TI - Immobilization and characterization of a new regioselective and enantioselective lipase obtained from a metagenomic library. AB - In previous work, a new lipase and its cognate foldase were identified and isolated from a metagenomic library constructed from soil samples contaminated with fat. This new lipase, called LipG9, is a true lipase that shows specific activities that are comparable to those of well-known industrially-used lipases with high activity against long-chain triglycerides. In the present work, LipG9 was co-expressed and co-immobilized with its foldase, on an inert hydrophobic support (Accurel MP1000). We studied the performance of this immobilized LipG9 (Im-LipG9) in organic media, in order to evaluate its potential for use in biocatalysis. Im-LipG9 showed good stability, maintaining a residual activity of more than 70% at 50 degrees C after incubation in n-heptane (log P 4.0) for 8 h. It was also stable in polar organic solvents such as ethanol (log P -0.23) and acetone (log P -0.31), maintaining more than 80% of its original activity after 8 h incubation at 30 degrees C. The synthesis of ethyl esters was tested with fatty acids of different chain lengths in n-heptane at 30 degrees C. The best conversions (90% in 3 h) were obtained for medium and long chain saturated fatty acids (C8, C14 and C16), with the maximum specific activity, 29 U per gram of immobilized preparation, being obtained with palmitic acid (C16). Im-LipG9 was sn 1,3-specific. In the transesterification of the alcohol (R,S)-1-phenylethanol with vinyl acetate and the hydrolysis of the analogous ester, (R,S)-1-phenylethyl acetate, Im-LipG9 showed excellent enantioselectivity for the R-isomer of both substrates (E> 200), giving an enantiomeric excess (ee) of higher than 95% for the products at 49% conversion. The results obtained in this work provide the basis for the development of applications of LipG9 in biocatalysis. PMID- 25706998 TI - Changes in soil carbon and enzyme activity as a result of different long-term fertilization regimes in a greenhouse field. AB - In order to discover the advantages and disadvantages of different fertilization regimes and identify the best management practice of fertilization in greenhouse fields, soil enzyme activities involved in carbon (C) transformations, soil chemical characteristics, and crop yields were monitored after long-term (20 year) fertilization regimes, including no fertilizer (CK), 300 kg N ha-1 and 600 kg N ha-1 as urea (N1 and N2), 75 Mg ha-1 horse manure compost (M), and M with either 300 or 600 kg N ha-1 urea (MN1 and MN2). Compared with CK, fertilization increased crop yields by 31% (N2) to 69% (MN1). However, compared with CK, inorganic fertilization (especially N2) also caused soil acidification and salinization. In the N2 treatment, soil total organic carbon (TOC) decreased from 14.1+/-0.27 g kg-1 at the beginning of the long-term experiment in 1988 to 12.6+/ 0.11 g kg-1 (P<0.05). Compared to CK, N1 and N2 exhibited higher soil alpha galactosidase and beta-galactosidase activities, but lower soil alpha-glucosidase and beta-glucosidase activities (P<0.05), indicating that inorganic fertilization had different impacts on these C transformation enzymes. Compared with CK, the M, MN1 and MN2 treatments exhibited higher enzyme activities, soil TOC, total nitrogen, dissolved organic C, and microbial biomass C and N. The fertilization regime of the MN1 treatment was identified as optimal because it produced the highest yields and increased soil quality, ensuring sustainability. The results suggest that inorganic fertilizer alone, especially in high amounts, in greenhouse fields is detrimental to soil quality. PMID- 25706999 TI - Role of exopolysaccharide in Aggregatibacter actinomycetemcomitans-induced bone resorption in a rat model for periodontal disease. AB - Aggregatibacter actinomycetemcomitans a causative agent of periodontal disease in humans, forms biofilm on biotic and abiotic surfaces. A. actinomycetemcomitans biofilm is heterogeneous in nature and is composed of proteins, extracellular DNA and exopolysaccharide. To explore the role played by the exopolysaccharide in the colonization and disease progression, we employed genetic reduction approach using our rat model of A. actinomycetemcomitans-induced periodontitis. To this end, a genetically modified strain of A. actinomycetemcomitans lacking the pga operon was compared with the wild-type strain in the rat infection model. The parent and mutant strains were primarily evaluated for bone resorption and disease. Our study showed that colonization, bone resorption/disease and antibody response were all elevated in the wild-type fed rats. The bone resorption/disease caused by the pga mutant strain, lacking the exopolysaccharide, was significantly less (P < 0.05) than the bone resorption/disease caused by the wild-type strain. Further analysis of the expression levels of selected virulence genes through RT PCR showed that the decrease in colonization, bone resorption and antibody titer in the absence of the exopolysaccharide might be due to attenuated levels of colonization genes, flp-1, apiA and aae in the mutant strain. This study demonstrates that the effect exerted by the exopolysaccharide in A. actinomycetemcomitans-induced bone resorption has hitherto not been recognized and underscores the role played by the exopolysaccharide in A. actinomycetemcomitans-induced disease. PMID- 25707000 TI - The cost of leg forces in bipedal locomotion: a simple optimization study. AB - Simple optimization models show that bipedal locomotion may largely be governed by the mechanical work performed by the legs, minimization of which can automatically discover walking and running gaits. Work minimization can reproduce broad aspects of human ground reaction forces, such as a double-peaked profile for walking and a single peak for running, but the predicted peaks are unrealistically high and impulsive compared to the much smoother forces produced by humans. The smoothness might be explained better by a cost for the force rather than work produced by the legs, but it is unclear what features of force might be most relevant. We therefore tested a generalized force cost that can penalize force amplitude or its n-th time derivative, raised to the p-th power (or p-norm), across a variety of combinations for n and p. A simple model shows that this generalized force cost only produces smoother, human-like forces if it penalizes the rate rather than amplitude of force production, and only in combination with a work cost. Such a combined objective reproduces the characteristic profiles of human walking (R2 = 0.96) and running (R2 = 0.92), more so than minimization of either work or force amplitude alone (R2 = -0.79 and R2 = 0.22, respectively, for walking). Humans might find it preferable to avoid rapid force production, which may be mechanically and physiologically costly. PMID- 25707001 TI - Morphology of the jaw-closing musculature in the common wombat (Vombatus ursinus) using digital dissection and magnetic resonance imaging. AB - Wombats are unique among marsupials in having one pair of upper incisors, and hypsodont molars for processing tough, abrasive vegetation. Of the three extant species, the most abundant, the common wombat (Vombatus ursinus), has had the least attention in terms of masticatory muscle morphology, and has never been thoroughly described. Using MRI and digital dissection to compliment traditional gross dissections, the major jaw adductor muscles, the masseter, temporalis and pterygoids, were described. The masseter and medial pterygoid muscles are greatly enlarged compared to other marsupials. This, in combination with the distinctive form and function of the dentition, most likely facilitates processing a tough, abrasive diet. The broad, flat skull and large masticatory muscles are well suited to generate a very high bite force. MRI scans allow more detail of the muscle morphology to be observed and the technique of digital dissections greatly enhances the knowledge obtained from gross dissections. PMID- 25707002 TI - Asymptomatic carriers of toxigenic C. difficile in long-term care facilities: a meta-analysis of prevalence and risk factors. AB - BACKGROUND: The impact of Clostridium difficile colonization in C. difficile infection (CDI) is inadequately explored. As a result, asymptomatic carriage is not considered in the development of infection control policies and the burden of carrier state in long-term care facilities (LTCFs) is unknown. PURPOSE: To explore the epidemiology of C. difficile colonization in LTCFs, identify predisposing factors and describe its impact on healthcare management. DATA SOURCES: PubMed, Embase and Web of Science (up to June 2014) without language restriction, complemented by reference lists of eligible studies. STUDY SELECTION: All studies providing extractable data on the prevalence of toxigenic C. difficile colonization among asymptomatic residents in LTCFs. DATA EXTRACTION: Two authors extracted data independently. STATISTICAL METHODS: The pooled colonization estimates were calculated using the double arcsine methodology and reported along with their 95% random-effects confidence intervals (CIs), using DerSimonian-Laird weights. We assessed the impact of patient-level covariates on the risk of colonization and effects were reported as odds ratios (OR, 95% CI). We used the colonization estimates to simulate the effective reproduction number R through a Monte Carlo technique. RESULTS: Based on data from 9 eligible studies that met the specified criteria and included 1,371 subjects, we found that 14.8% (95%CI 7.6%-24.0%) of LTCF residents are asymptomatic carriers of toxigenic C. difficile. Colonization estimates were significantly higher in facilities with prior CDI outbreak (30.1% vs. 6.5%, p = 0.01). Patient history of CDI (OR 6.07; 95% CI 2.06-17.88; effect derived from 3 studies), prior hospitalization (OR 2.11; 95% CI 1.08-4.13; derived from 3 studies) and antimicrobial use within previous 3 months (OR 3.68; 95% CI 2.04-6.62; derived from 4 studies) were associated with colonization. The predicted colonization rate at admission was 8.9%. CONCLUSION: Asymptomatic carriage of toxigenic C. difficile represents a significant burden in LTCFs and is associated with prior CDI outbreaks in the facility, a history of CDI, prior hospitalization and antimicrobial use. These findings can impact infection control measures at LTCFs. PMID- 25707003 TI - Prevalence of E/A wave fusion and A wave truncation in DDD pacemaker patients with complete AV block under nominal AV intervals. AB - AIMS: Optimization of the AV-interval (AVI) in DDD pacemakers improves cardiac hemodynamics and reduces pacemaker syndromes. Manual optimization is typically not performed in clinical routine. In the present study we analyze the prevalence of E/A wave fusion and A wave truncation under resting conditions in 160 patients with complete AV block (AVB) under the pre-programmed AVI. We manually optimized sub-optimal AVI. METHODS: We analyzed 160 pacemaker patients with complete AVB, both in sinus rhythm (AV-sense; n = 129) and under atrial pacing (AV-pace; n = 31). Using Doppler analyses of the transmitral inflow we classified the nominal AVI as: a) normal, b) too long (E/A wave fusion) or c) too short (A wave truncation). In patients with a sub-optimal AVI, we performed manual optimization according to the recommendations of the American Society of Echocardiography. RESULTS: All AVB patients with atrial pacing exhibited a normal transmitral inflow under the nominal AV-pace intervals (100%). In contrast, 25 AVB patients in sinus rhythm showed E/A wave fusion under the pre-programmed AV-sense intervals (19.4%; 95% confidence interval (CI): 12.6-26.2%). A wave truncations were not observed in any patient. All patients with a complete E/A wave fusion achieved a normal transmitral inflow after AV-sense interval reduction (mean optimized AVI: 79.4 +/- 13.6 ms). CONCLUSIONS: Given the rate of 19.4% (CI 12.6 26.2%) of patients with a too long nominal AV-sense interval, automatic algorithms may prove useful in improving cardiac hemodynamics, especially in the subgroup of atrially triggered pacemaker patients with AV node diseases. PMID- 25707004 TI - A reduced astrocyte response to beta-amyloid plaques in the ageing brain associates with cognitive impairment. AB - AIMS: beta-amyloid (Abeta) plaques are a key feature of Alzheimer's disease pathology but correlate poorly with dementia. They are associated with astrocytes which may modulate the effect of Abeta-deposition on the neuropil. This study characterised the astrocyte response to Abeta plaque subtypes, and investigated their association with cognitive impairment. METHODS: Abeta plaque subtypes were identified in the cingulate gyrus using dual labelling immunohistochemistry to Abeta and GFAP+ astrocytes, and quantitated in two cortical areas: the area of densest plaque burden and the deep cortex near the white matter border (layer VI). Three subtypes were defined for both diffuse and compact plaques (also known as classical or core-plaques): Abeta plaque with (1) no associated astrocytes, (2) focal astrogliosis or (3) circumferential astrogliosis. RESULTS: In the area of densest burden, diffuse plaques with no astrogliosis (beta = -0.05, p = 0.001) and with focal astrogliosis (beta = -0.27, p = 0.009) significantly associated with lower MMSE scores when controlling for sex and age at death. In the deep cortex (layer VI), both diffuse and compact plaques without astrogliosis associated with lower MMSE scores (beta = -0.15, p = 0.017 and beta = -0.81, p = 0.03, respectively). Diffuse plaques with no astrogliosis in layer VI related to dementia status (OR = 1.05, p = 0.025). In the area of densest burden, diffuse plaques with no astrogliosis or with focal astrogliosis associated with increasing Braak stage (beta = 0.01, p<0.001 and beta = 0.07, p<0.001, respectively), and ApoEepsilon4 genotype (OR = 1.02, p = 0.001 and OR = 1.10, p = 0.016, respectively). In layer VI all plaque subtypes associated with Braak stage, and compact amyloid plaques with little and no associated astrogliosis associated with ApoEepsilon4 genotype (OR = 1.50, p = 0.014 and OR = 0.10, p = 0.003, respectively). CONCLUSIONS: Reactive astrocytes in close proximity to either diffuse or compact plaques may have a neuroprotective role in the ageing brain, and possession of at least one copy of the ApoEepsilon4 allele impacts the astroglial response to Abeta plaques. PMID- 25707005 TI - Pluripotency gene expression and growth control in cultures of peripheral blood monocytes during their conversion into programmable cells of monocytic origin (PCMO): evidence for a regulatory role of autocrine activin and TGF-beta. AB - Previous studies have shown that peripheral blood monocytes can be converted in vitro to a stem cell-like cell termed PCMO as evidenced by the re-expression of pluripotency-associated genes, transient proliferation, and the ability to adopt the phenotype of hepatocytes and insulin-producing cells upon tissue-specific differentiation. However, the regulatory interactions between cultured cells governing pluripotency and mitotic activity have remained elusive. Here we asked whether activin(s) and TGF-beta(s), are involved in PCMO generation. De novo proliferation of PCMO was higher under adherent vs. suspended culture conditions as revealed by the appearance of a subset of Ki67-positive monocytes and correlated with down-regulation of p21WAF1 beyond day 2 of culture. Realtime-PCR analysis showed that PCMO express ActRIIA, ALK4, TbetaRII, ALK5 as well as TGF beta1 and the betaA subunit of activin. Interestingly, expression of ActRIIA and ALK4, and activin A levels in the culture supernatants increased until day 4 of culture, while levels of total and active TGF-beta1 strongly declined. PCMO responded to both growth factors in an autocrine fashion with intracellular signaling as evidenced by a rise in the levels of phospho-Smad2 and a drop in those of phospho-Smad3. Stimulation of PCMO with recombinant activins (A, B, AB) and TGF-beta1 induced phosphorylation of Smad2 but not Smad3. Inhibition of autocrine activin signaling by either SB431542 or follistatin reduced both Smad2 activation and Oct4A/Nanog upregulation. Inhibition of autocrine TGF-beta signaling by either SB431542 or anti-TGF-beta antibody reduced Smad3 activation and strongly increased the number of Ki67-positive cells. Furthermore, anti-TGF beta antibody moderately enhanced Oct4A/Nanog expression. Our data show that during PCMO generation pluripotency marker expression is controlled positively by activin/Smad2 and negatively by TGF-beta/Smad3 signaling, while relief from growth inhibition is primarily the result of reduced TGF-beta/Smad3, and to a lesser extent, activin/Smad2 signaling. PMID- 25707006 TI - Distortion correction in EPI using an extended PSF method with a reversed phase gradient approach. AB - In echo-planar imaging (EPI), such as commonly used for functional MRI (fMRI) and diffusion-tensor imaging (DTI), compressed distortion is a more difficult challenge than local stretching as spatial information can be lost in strongly compressed areas. In addition, the effects are more severe at ultra-high field (UHF) such as 7T due to increased field inhomogeneity. To resolve this problem, two EPIs with opposite phase-encoding (PE) polarity were acquired and combined after distortion correction. For distortion correction, a point spread function (PSF) mapping method was chosen due to its high correction accuracy and extended to perform distortion correction of both EPIs with opposite PE polarity thus reducing the PSF reference scan time. Because the amount of spatial information differs between the opposite PE datasets, the method was further extended to incorporate a weighted combination of the two distortion-corrected images to maximize the spatial information content of a final corrected image. The correction accuracy of the proposed method was evaluated in distortion-corrected data using both forward and reverse phase-encoded PSF reference data and compared with the reversed gradient approaches suggested previously. Further we demonstrate that the extended PSF method with an improved weighted combination can recover local distortions and spatial information loss and be applied successfully not only to spin-echo EPI, but also to gradient-echo EPIs acquired with both PE directions to perform geometrically accurate image reconstruction. PMID- 25707008 TI - Efficient emission facilitated by multiple energy level transitions in uniform graphitic carbon nitride films deposited by thermal vapor condensation. AB - Graphitic carbon nitride (g-CN) films are important components of optoelectronic devices, but current techniques for their production, such as drop casting and spin coating, fail to deliver uniform and pinhole-free g-CN films on solid substrates. Here, versatile, cost-effective, and large-area growth of uniform and pinhole-free g-CN films is achieved by using a thermal vapor condensation method under atmospheric pressure. A comparison of the X-ray diffraction and Fourier transform infrared data with the calculated infrared spectrum confirmed the graphitic build-up of films composed of tri-s-triazine units. These g-CN films possess multiple active energy states including pi*, pi, and lone-pair states, which facilitate their efficient (6% quantum yield in the solid state) photoluminescence, as confirmed by both experimental measurements and theoretical calculations. PMID- 25707007 TI - A transcriptome derived female-specific marker from the invasive Western mosquitofish (Gambusia affinis). AB - Sex-specific markers are a prerequisite for understanding reproductive biology, genetic factors involved in sex differences, mechanisms of sex determination, and ultimately the evolution of sex chromosomes. The Western mosquitofish, Gambusia affinis, may be considered a model species for sex-chromosome evolution, as it displays female heterogamety (ZW/ZZ), and is also ecologically interesting as a worldwide invasive species. Here, de novo RNA-sequencing on the gonads of sexually mature G. affinis was used to identify contigs that were highly transcribed in females but not in males (i.e., transcripts with ovary-specific expression). Subsequently, 129 primer pairs spanning 79 contigs were tested by PCR to identify sex-specific transcripts. Of those primer pairs, one female specific DNA marker was identified, Sanger sequenced and subsequently validated in 115 fish. Sequence analyses revealed a high similarity between the identified sex-specific marker and the 3' UTR of the aminomethyl transferase (amt) gene of the closely related platyfish (Xiphophorus maculatus). This is the first time that RNA-seq has been used to successfully characterize a sex-specific marker in a fish species in the absence of a genome map. Additionally, the identified sex specific marker represents one of only a handful of such markers in fishes. PMID- 25707010 TI - Accounting for informatively missing data in logistic regression by means of reassessment sampling. AB - We explore the 'reassessment' design in a logistic regression setting, where a second wave of sampling is applied to recover a portion of the missing data on a binary exposure and/or outcome variable. We construct a joint likelihood function based on the original model of interest and a model for the missing data mechanism, with emphasis on non-ignorable missingness. The estimation is carried out by numerical maximization of the joint likelihood function with close approximation of the accompanying Hessian matrix, using sharable programs that take advantage of general optimization routines in standard software. We show how likelihood ratio tests can be used for model selection and how they facilitate direct hypothesis testing for whether missingness is at random. Examples and simulations are presented to demonstrate the performance of the proposed method. PMID- 25707011 TI - Exploring new selective 3-benzylquinoxaline-based MAO-A inhibitors: design, synthesis, biological evaluation and docking studies. AB - In this investigation, we searched for novel MAO-A inhibitors using a 3 benzylquinoxaline scaffold based on our earlier findings. Series of N'-(3 benzylquinoxalin-2-yl)acetohydrazide, 4a, N'-(3-benzylquinoxalin-2 yl)benzohydrazide derivatives 4b-f, N'-[2-(3-benzyl-2-oxoquinoxalin-1(2H) yl)acetyl]benzohydrazide derivatives 7a-d, (9H-fluoren-9-yl)methyl 1-[2-(2-(3 benzyl-2-oxoquinoxalin-1(2H)-yl)acetyl)-hydrazinyl]-2-ylcarbamate derivatives 8a c, 2-(3-benzyl-2-oxoquinoxalin-1(2H)-yl)-N'-benzylidene acetohydrazide derivatives 9a-h, and ethyl 2-(3-benzyl-2-oxoquinoxalin-1(2H)-yl)acetate derivatives 10a-e were synthesized and evaluated in vitro as inhibitors of the two monoamine oxidase isoforms, MAO-A and MAO-B. Most of the compounds showed a selective MAO-A inhibitory activity in the nanomolar or low micromolar range. Compounds 4e and 9g were the most potent derivatives with high MAO-A selectivity and their molecular docking studies were performed in order to rationalize the obtained biological result. PMID- 25707009 TI - Reversing Ribot: does regression hold in language of prodromal Alzheimer's disease? AB - We consider the regression or retrogenesis hypothesis, which argues that order of acquisition in development is reversed in neurodegeneration or pathology. Originally proposed as a regression hypothesis for the study of memory disorders, specifically retrograde amnesia, by Ribot (1881), it has been extended to the study of brain aging and pathology and to language. We investigate this hypothesis in a new study of language development, aging, and pathology. Through interuniversity collaboration using a matched experimental design and task, we compare production of complex sentences containing relative clauses by normal monolingual children during normal development, healthy young adults, healthy aging adults, and aging adults diagnosed with mild cognitive impairment, a recognized potential harbinger of Alzheimer's disease. Our results refute the regression hypothesis in this area and lead to potential syntactic markers for prodromal Alzheimer's disease and predictions for future brain imaging analyses. PMID- 25707012 TI - Discovery of novel AHLs as potent antiproliferative agents. AB - Three series of novel AHL analogs were synthesized and evaluated for their in vitro cytotoxic activity against four human cancer cell lines. The SARs investigation indicated that AHLs with a terminal phenyl group, especially those with the chalcone scaffold had remarkably enhanced cytotoxicity than those with the hydrophobic side chains. Besides, some of these compounds were much more potent than 5-Fu and natural OdDHL. Through the detailed SARs discussions, we found that compounds 10a-k and 14 with the 4-amino chalcone scaffold showed excellent inhibition against all the tested cancer cell lines and were much more potent than 5-Fu and AHLs. Such scaffold may act as a template for further lead optimization. Compound 10i with a 3, 4, 5-trimethoxy group was the most potent one against all the tested cancer cell lines. Flow cytometry analysis indicated that analog 11e induced the cellular apoptosis and cell cycle arrest of MCF-7 cells at G2/M phase in a concentration-and time-dependent manner. PMID- 25707013 TI - Fused heterocycles bearing bridgehead nitrogen as potent HIV-1 NNRTIs. Part 4: design, synthesis and biological evaluation of novel imidazo[1,2-a]pyrazines. AB - Through a structure-guided core-refining approach, a series of novel imidazo[1,2 a]pyrazine derivatives were designed, synthesized and evaluated as HIV-1 non nucleoside reverse transcriptase inhibitors (NNRTIs). Biological results of antiviral assay in MT-4 cell cultures showed that 12 target compounds displayed moderate activities against wild-type (wt) HIV-1 strain (IIIB) with EC50 values ranging from 0.26 MUM to 19 MUM. Among them, 4a and 5a were found to be the two most active analogues possessing EC50 values of 0.26 MUM and 0.32 MUM respectively, comparable to delavirdine (DLV, EC50 = 0.54 MUM) and nevirapine (NVP, EC50 = 0.31 MUM) in a cell-based assay. Additionally, 9 compounds showed RT inhibitory activity superior to that of NVP. Moreover, some predicted drug-like properties of representative compounds 4a and 5a, as well as the structure activity relationship (SAR) analysis were discussed in detail. The binding mode of compound 4a was investigated by molecular simulation studies. PMID- 25707014 TI - Computer-guided drug repurposing: identification of trypanocidal activity of clofazimine, benidipine and saquinavir. AB - In spite of remarkable advances in the knowledge on Trypanosoma cruzi biology, no medications to treat Chagas disease have been approved in the last 40 years and almost 8 million people remain infected. Since the public sector and non-profit organizations play a significant role in the research efforts on Chagas disease, it is important to implement research strategies that promote translation of basic research into the clinical practice. Recent international public-private initiatives address the potential of drug repositioning (i.e. finding second or further medical uses for known-medications) which can substantially improve the success at clinical trials and the innovation in the pharmaceutical field. In this work, we present the computer-aided identification of approved drugs clofazimine, benidipine and saquinavir as potential trypanocidal compounds and test their effects at biochemical as much as cellular level on different parasite stages. According to the obtained results, we discuss biopharmaceutical, toxicological and physiopathological criteria applied to decide to move clofazimine and benidipine into preclinical phase, in an acute model of infection. The article illustrates the potential of computer-guided drug repositioning to integrate and optimize drug discovery and preclinical development; it also proposes rational rules to select which among repositioned candidates should advance to investigational drug status and offers a new insight on clofazimine and benidipine as candidate treatments for Chagas disease. One Sentence Summary: We present the computer-guided drug repositioning of three approved drugs as potential new treatments for Chagas disease, integrating computer-aided drug screening and biochemical, cellular and preclinical tests. PMID- 25707015 TI - Synthesis and antimicrobial activity of novel structural hybrids of benzofuroxan and benzothiazole derivatives. AB - New compounds containing both benzofuroxan and benzothiazole scaffolds were synthesized through electrophile/nucleophile combination of nitrobenzofuroxan derivatives and 2-mercapto- or 2-aminobenzothiazole derivatives and their biological effect on the natural strain Vibrio genus and different bacterial lux biosensors was studied. Among all the compounds synthesized, that obtained from 2 mercaptobenzothiazole and 7-chloro-4,6-dinitrobenzofuroxan was toxic for bacterial cells, and also able to activated the 1st type Quorum Sensing system. The reaction between 7-chloro-4,6-dinitrobenzofuroxan and 2-aminobenzothiazole derivatives gave two products, one bearing the benzofuroxan moiety linked to the exocyclic amino nitrogen, and the second derived from the attack of two molecules of electrophile to both the nitrogen atoms of the benzothiazole reagent. Their relative ratio is modifiable by tuning the reagents ratio and the reaction time. PMID- 25707016 TI - Birth outcomes and background exposures to select elements, the Longitudinal Investigation of Fertility and the Environment (LIFE). AB - Evidence suggests that trace exposures to select elements may increase the risk for adverse birth outcomes. To investigate further, we used multiple regression to assess associations between preconception parental exposures to Pb, Cd, and total Hg in blood, and 21 elements in urine, with n=235 singleton birth outcomes, adjusted for confounders and partner's exposure. Earlier gestational age at delivery (GA) was associated with higher tertiles of urine maternal W (-1.22 days) and paternal U (-1.07 days), but GA was later for higher tertiles of maternal (+1.11 days) and paternal (+1.30 days) blood Hg. Additional analysis indicated shorter GA associated with higher paternal urine Ba, W, and U, and with higher maternal blood Pb for boys, but GA was longer in association with higher maternal urine Cr. Birth weight (BW) was lower for higher tertiles of paternal urine Cs (-237.85g), U (-187.34g), and Zn (-209.08g), and for higher continuous Cr (P=0.021). In contrast, BW was higher for higher tertiles of paternal urine As (+194.71g) and counterintuitively for maternal blood Cd (+178.52g). Birth length (BL) was shorter for higher tertiles of urine maternal W (-1.22cm) and paternal U (-1.10cm). Yet, higher tertiles of maternal (+1.11cm) and paternal (+1.30) blood Hg were associated with longer BL. Head circumference at delivery was lower for higher tertiles of paternal urine U (-0.83cm), and for higher continuous Mo in boys (-0.57cm). Overall, associations were most consistently indicated for GA and measures of birth size with urine W and U, and paternal exposures were more frequently associated than maternal. Though limited by several factors, ours is the largest multi-element investigation of prospective couple-level trace exposures and birth outcomes to date; the novel observations for W and U merit further investigation. PMID- 25707018 TI - Outdoor characterization of radio frequency electromagnetic fields in a Spanish birth cohort. AB - There is considerable public concern in many countries about the possible adverse effects of exposure to non-ionizing radiation electromagnetic fields, especially in vulnerable populations such as children. The aim of this study was to characterize environmental exposure profiles within the frequency range 100kHz 6GHz in the immediate surrounds of the dwellings of 123 families from the INMA Granada birth cohort in Southern Spain, using spot measurements. The arithmetic mean root mean-square electric field (ERMS) and power density (SRMS) values were, respectively, 195.79mV/m (42.3% of data were above this mean) and 799.01uW/m(2) (30% of values were above this mean); median values were 148.80mV/m and 285.94uW/m(2), respectively. Exposure levels below the quantification limit were assigned a value of 0.01V/m. Incident field strength levels varied widely among different areas or towns/villages, demonstrating spatial variability in the distribution of exposure values related to the surface area population size and also among seasons. Although recorded values were well below International Commission for Non-Ionizing Radiation Protection reference levels, there is a particular need to characterize incident field strength levels in vulnerable populations (e.g., children) because of their chronic and ever-increasing exposure. The effects of incident field strength have not been fully elucidated; however, it may be appropriate to apply the precautionary principle in order to reduce exposure in susceptible groups. PMID- 25707017 TI - Key determinants of the fungal and bacterial microbiomes in homes. AB - BACKGROUND: The microbiome of the home is of great interest because of its possible impact on health. Our goal was to identify some of the factors that determine the richness, evenness and diversity of the home's fungal and bacterial microbiomes. METHOD: Vacuumed settled dust from homes (n=35) in Cincinnati, OH, were analyzed by pyrosequencing to determine the fungal and bacterial relative sequence occurrence. The correlation coefficients between home environmental characteristics, including age of home, Environmental Relative Moldiness Index (ERMI) values, occupant number, relative humidity and temperature, as well as pets (dog and cat) were evaluated for their influence on fungal and bacterial communities. In addition, linear discriminant analysis (LDA) was used for identifying fungal and bacterial genera and species associated with those housing determinants found to be significant. RESULTS: The fungal richness was found to be positively correlated with age of home (p=0.002), ERMI value (p=0.003), and relative humidity (p=0.015) in the home. However, fungal evenness and diversity were only correlated with the age of home (p=0.001). Diversity and evenness (not richness) of the bacterial microbiome in the homes were associated with dog ownership. Linear discriminant analysis showed total of 39 putative fungal genera/species with significantly higher LDA scores in high ERMI homes and 47 genera/species with significantly higher LDA scores in homes with high relative humidity. When categorized according to the age of the home, a total of 67 fungal genera/species had LDA scores above the significance threshold. Dog ownership appeared to have the most influence on the bacterial microbiome, since a total of 130 bacterial genera/species had significantly higher LDA scores in homes with dogs. CONCLUSIONS: Some key determinants of the fungal and bacterial microbiome appear to be excess moisture, age of the home and dog ownership. PMID- 25707019 TI - Raman spectroscopy of hot hydrogen above 200 GPa. AB - It has been theorized that at high pressure the increased energy of the zero point oscillations in hydrogen would destabilize the lattice and form a ground fluid state at 0 K (ref. 1). Theory has also suggested that this fluid state, representing a new state of matter, might have unusual properties governed by quantum effects, such as superfluidity or superconductivity. Here, by combining Raman spectroscopy and in situ high-temperature, high-pressure techniques, we demonstrate that above 200 GPa a new phase transition occurs as temperature is increased, for example 480 K at 255 GPa. If the transformation is interpreted as melting, it would be the lowest melting temperature of any material at these high pressures. We also find a new triple point between phases I and IV and the new phase, and demonstrate that hydrogen retains its molecular character around this point. These data may require a significant revision of the phase diagram of hydrogen above 200 GPa. PMID- 25707021 TI - High pressure: Compressed hydrogen heats up. PMID- 25707020 TI - A photoreversible protein-patterning approach for guiding stem cell fate in three dimensional gels. AB - Although biochemically patterned hydrogels are capable of recapitulating many critical aspects of the heterogeneous cellular niche, exercising spatial and temporal control of the presentation and removal of biomolecular signalling cues in such systems has proved difficult. Here, we demonstrate a synthetic strategy that exploits two bioorthogonal photochemistries to achieve reversible immobilization of bioactive full-length proteins with good spatial and temporal control within synthetic, cell-laden biomimetic scaffolds. A photodeprotection oxime-ligation sequence permits user-defined quantities of proteins to be anchored within distinct subvolumes of a three-dimensional matrix, and an ortho nitrobenzyl ester photoscission reaction facilitates subsequent protein removal. By using this approach to pattern the presentation of the extracellular matrix protein vitronectin, we accomplished reversible differentiation of human mesenchymal stem cells to osteoblasts in a spatially defined manner. Our protein patterning approach should provide further avenues to probe and direct changes in cell physiology in response to dynamic biochemical signalling. PMID- 25707022 TI - Determinism and randomness in the evolution of introns and sine inserts in mouse and human mitochondrial solute carrier and cytokine receptor genes. AB - In the homologous genes studied, the exons and introns alternated in the same order in mouse and human. We studied, in both species: corresponding short segments of introns, whole corresponding introns and complete homologous genes. We considered the total number of nucleotides and the number and orientation of the SINE inserts. Comparisons of mouse and human data series showed that at the level of individual relatively short segments of intronic sequences the stochastic variability prevails in the local structuring, but at higher levels of organization a deterministic component emerges, conserved in mouse and human during the divergent evolution, despite the ample re-editing of the intronic sequences and the fact that processes such as SINE spread had taken place in an independent way in the two species. Intron conservation is negatively correlated with the SINE occupancy, suggesting that virus inserts interfere with the conservation of the sequences inherited from the common ancestor. PMID- 25707023 TI - Thiamine responsive megaloblastic anemia syndrome: a novel homozygous SLC19A2 gene mutation identified. AB - Thiamine responsive megaloblastic anemia syndrome (TRMAS) is a rare autosomal recessive disorder especially in countries where consanguinity is uncommon. Three main features are characteristic of the disease - megaloblastic anemia, early onset deafness, and non-type I diabetes. TRMAS is a Mendelian disorder; a gene SLC19A2 coding high affinity thiamine transporter mediating vitamin B1 uptake through cell membrane has been identified. We present the first patient with TRMAS in Lithuania - a 3-year-old boy born to a non-consanguineous family with a novel homozygous SLC19A2 gene mutation. The patient had insulin dependent diabetes (onset 11 months), respiratory illness (onset 11 months), bilateral profound hearing loss (onset at 7 months, verified at 20 months), refractory anemia (onset 2 years), and decreased vision acuity and photophobia (onset 2.5 years). The psychomotor abilities developed according to age. Phenotypic evaluation did not reveal any dysmorphic features. The clinical diagnosis of TRMAS was suspected and daily supplementation with thiamine 100 mg was started. The condition of the patient markedly improved several days after the initiation of treatment. The results of SLC19A2 gene molecular testing confirmed the clinical diagnosis - novel homozygous c.[205G>T], p.[(Val69Phe)] mutation changing conserved amino acid residue or even interfering the mRNA splicing. Clinical heterogeneity, diverse dynamics, and wide spectrum of symptoms are aggravating factors in the diagnosis. The possibility of treatment demands early recognition of disorder to facilitate the improvement of the patient's condition. PMID- 25707024 TI - Entanglement entropy and fidelity susceptibility in the one-dimensional spin-1 XXZ chains with alternating single-site anisotropy. AB - We study the fidelity susceptibility in an antiferromagnetic spin-1 XXZ chain numerically. By using the density-matrix renormalization group method, the effects of the alternating single-site anisotropy D on fidelity susceptibility are investigated. Its relation with the quantum phase transition is analyzed. It is found that the quantum phase transition from the Haldane spin liquid to periodic Neel spin solid can be well characterized by the fidelity. Finite size scaling of fidelity susceptibility shows a power-law divergence at criticality, which indicates the quantum phase transition is of second order. The results are confirmed by the second derivative of the ground-state energy. We also study the relationship between the entanglement entropy, the Schmidt gap and quantum phase transitions. Conclusions drawn from these quantum information observables agree well with each other. PMID- 25707025 TI - Visible-light-triggered molecular photoswitch based on reversible E/Z isomerization of a 1,2-dicyanoethene derivative. AB - A designed bis(dithienyl) dicyanoethene-based, strictly E/Z photoswitch (4TCE) operates through state-selective (E and Z isomer) photoactivation with visible light. The E and Z isomers of 4TCE exhibit remarkably different spectroscopic characteristics, including a large separation (70 nm) in their absorption maxima (lambda(max)) and a 2.5-fold increase in molar extinction coefficient from cis to trans. The energetically stable trans form can be completely converted to the cis form within minutes when exposed to white light, whereas the reverse isomerization occurs readily upon irradiation by blue light (lambda<480 nm) or completely by thermal conversion at elevated temperatures. These features together with excellent thermal stability and photostability of both isomers make this new E/Z photoswitch a promising building block for photoswitchable materials that operate without the need for UV light. PMID- 25707027 TI - Sociocultural and Familial Influences on the Well-Being of Mexican Older Adults' Family Caregivers. AB - The current study analyzed the influence of burden on the well-being of caregivers by exploring the mediating role of sociocultural and family factors. The study sample comprised 386 Mexican caregivers between ages 19 and 87 (mean age = 49.05; SD =12.41 years). The results from the current research showed that burden scores are negatively associated with well-being, sociocultural, and family scores. However, the effect of burden on subjective well-being is minimized by the mediation effect of sociocultural and family resources between burden and well-being. The complexities of sociocultural and family influences should be taken into account to change the prevailing individualistic approach within the current stress and family caregiver well-being paradigm. PMID- 25707026 TI - Background ionizing radiation and the risk of childhood cancer: a census-based nationwide cohort study. AB - BACKGROUND: Exposure to medium or high doses of ionizing radiation is a known risk factor for cancer in children. The extent to which low-dose radiation from natural sources contributes to the risk of childhood cancer remains unclear. OBJECTIVES: In a nationwide census-based cohort study, we investigated whether the incidence of childhood cancer was associated with background radiation from terrestrial gamma and cosmic rays. METHODS: Children < 16 years of age in the Swiss National Censuses in 1990 and 2000 were included. The follow-up period lasted until 2008, and incident cancer cases were identified from the Swiss Childhood Cancer Registry. A radiation model was used to predict dose rates from terrestrial and cosmic radiation at locations of residence. Cox regression models were used to assess associations between cancer risk and dose rates and cumulative dose since birth. RESULTS: Among 2,093,660 children included at census, 1,782 incident cases of cancer were identified including 530 with leukemia, 328 with lymphoma, and 423 with a tumor of the central nervous system (CNS). Hazard ratios for each millisievert increase in cumulative dose of external radiation were 1.03 (95% CI: 1.01, 1.05) for any cancer, 1.04 (95% CI: 1.00, 1.08) for leukemia, 1.01 (95% CI: 0.96, 1.05) for lymphoma, and 1.04 (95% CI: 1.00, 1.08) for CNS tumors. Adjustment for a range of potential confounders had little effect on the results. CONCLUSIONS: Our study suggests that background radiation may contribute to the risk of cancer in children, including leukemia and CNS tumors. PMID- 25707028 TI - Image fusion of mass spectrometry and microscopy: a multimodality paradigm for molecular tissue mapping. AB - We describe a predictive imaging modality created by 'fusing' two distinct technologies: imaging mass spectrometry (IMS) and microscopy. IMS-generated molecular maps, rich in chemical information but having coarse spatial resolution, are combined with optical microscopy maps, which have relatively low chemical specificity but high spatial information. The resulting images combine the advantages of both technologies, enabling prediction of a molecular distribution both at high spatial resolution and with high chemical specificity. Multivariate regression is used to model variables in one technology, using variables from the other technology. We demonstrate the potential of image fusion through several applications: (i) 'sharpening' of IMS images, which uses microscopy measurements to predict ion distributions at a spatial resolution that exceeds that of measured ion images by ten times or more; (ii) prediction of ion distributions in tissue areas that were not measured by IMS; and (iii) enrichment of biological signals and attenuation of instrumental artifacts, revealing insights not easily extracted from either microscopy or IMS individually. PMID- 25707029 TI - De novo protein structure determination from near-atomic-resolution cryo-EM maps. AB - We present a de novo model-building approach that combines predicted backbone conformations with side-chain fit to density to accurately assign sequence into density maps. This method yielded accurate models for six of nine experimental maps at 3.3- to 4.8-A resolution and produced a nearly complete model for an unsolved map containing a 660-residue heterodimeric protein. This method should enable rapid and reliable protein structure determination from near-atomic resolution cryo-electron microscopy (cryo-EM) maps. PMID- 25707030 TI - Atomic-accuracy models from 4.5-A cryo-electron microscopy data with density guided iterative local refinement. AB - We describe a general approach for refining protein structure models on the basis of cryo-electron microscopy maps with near-atomic resolution. The method integrates Monte Carlo sampling with local density-guided optimization, Rosetta all-atom refinement and real-space B-factor fitting. In tests on experimental maps of three different systems with 4.5-A resolution or better, the method consistently produced models with atomic-level accuracy largely independently of starting-model quality, and it outperformed the molecular dynamics-based MDFF method. Cross-validated model quality statistics correlated with model accuracy over the three test systems. PMID- 25707031 TI - Estimated exposure to arsenic in breastfed and formula-fed infants in a United States cohort. AB - BACKGROUND: Previous studies indicate that concentrations of arsenic in breast milk are relatively low even in areas with high drinking-water arsenic. However, it is uncertain whether breastfeeding leads to reduced infant exposure to arsenic in regions with lower arsenic concentrations. OBJECTIVE: We estimated the relative contributions of breast milk and formula to arsenic exposure during early infancy in a U.S. METHODS: We measured arsenic in home tap water (n = 874), urine from 6-week-old infants (n = 72), and breast milk from mothers (n = 9) enrolled in the New Hampshire Birth Cohort Study (NHBCS) using inductively coupled plasma mass spectrometry. Using data from a 3-day food diary, we compared urinary arsenic across infant feeding types and developed predictive exposure models to estimate daily arsenic intake from breast milk and formula. RESULTS: Urinary arsenic concentrations were generally low (median, 0.17 MUg/L; maximum, 2.9 MUg/L) [corrected] but 7.5 times higher for infants fed exclusively with formula than for infants fed exclusively with breast milk (beta = 2.02; 95% CI: 1.21, 2.83; p < 0.0001, adjusted for specific gravity). Similarly, the median estimated daily arsenic intake by NHBCS infants was 5.5 times higher for formula fed infants (0.22 MUg/kg/day) than for breastfed infants (0.04 MUg/kg/day). Given median arsenic concentrations measured in NHBCS tap water and previously published for formula powder, formula powder was estimated to account for ~ 70% of median exposure among formula-fed NHBCS infants. CONCLUSIONS: Our findings suggest that breastfed infants have lower arsenic exposure than formula-fed infants, and that both formula powder and drinking water can be sources of exposure for U.S. infants. PMID- 25707032 TI - Intention of nursing students to work in geriatrics. AB - The current study examined factors related to nursing students' intention to work in geriatrics upon graduation. A cross-sectional, descriptive design was used. A random sample of 200 nursing students completed a questionnaire based on the Theory of Planned Behavior and Kogan's Attitudes Toward Old People Scale. Participants expressed low intention to work in geriatrics upon graduation. Results of a multiple linear regression indicated that students' attitudes toward working in geriatrics and normative and control beliefs were found to be predictors of this intention. Additionally, male and religious students were more inclined to work in geriatrics. The current study indicated that nursing students' attitudes toward working in geriatrics were significantly predictive of their intention to work in this field upon graduation. PMID- 25707033 TI - Understanding Internet Use Among Dementia Caregivers: Results of Secondary Data Analysis Using the US Caregiver Survey Data. AB - BACKGROUND: Informal caregivers of persons with dementia experience higher levels of chronic stress in the caregiving trajectory. The Internet provides diverse types of caregiver resources that may help ameliorate their stress and relevant negative outcomes. However, there is limited information about the prevalence and factors of using Internet-based resources for health- and caregiving-related purposes in informal caregivers of persons with dementia. OBJECTIVE: Specific aims of this study were (1) to determine the prevalence and factors of caregiver's health-related Internet use and (2) to compare sociodemographic and caregiving-related characteristics between health-related Internet users and non health-related Internet users among informal caregivers of persons with dementia. METHODS: This quantitative investigation was a descriptive correlational design using a secondary data analysis. Primary data were collected via a survey conducted in 2009 by the National Alliance for Caregiving and the American Association of Retired Persons. Telephone interviews utilizing standardized questionnaires were used to collect self-reported information about sociodemographics and caregiving-related history (N=450). Descriptive statistics and a hierarchical binary logistic regression analysis were completed based on the stress process model. RESULTS: Approximately 59% (265/450) of dementia caregivers were identified as health-related Internet users. Caregivers' sociodemographics and their subjective responses of caregiving stress were the most significant factors to identify health-related Internet users followed by workload assisting in instrumental activities of daily living of persons with dementia. There were significant differences for caregiver's age, levels of education and income, hours spent caregiving, and the relationship to persons with dementia between health-related Internet users and non-health-related Internet users (P<.05 for all). After controlling for confounding effects, younger age of persons with dementia (OR 0.278, 95% CI 0.085-0.906), higher education levels of caregivers (OR 3.348, 95% CI 2.019-5.552), shorter caregiving time spent per week (OR 0.452, 95% CI 0.243-0.840), higher levels of caregiver's emotional stress (OR 1.249, 95% CI 1.004-1.555), and financial hardship (OR 4.61, 95% CI 1.416-14.978) were identified as newly emerging factors of health-related Internet use. CONCLUSIONS: Although the Internet provided useful resources for caregivers of persons with dementia, dementia caregivers reported lower levels of health-related Internet use compared to the general public. Our findings confirmed the impact of age, education levels, and/or income on Internet use reported in previous studies. However, the predictive value of subjective responses of caregiving stress for health-related Internet use was a new addition. These findings will assist health care providers, researchers, and policy makers in identifying who is the least likely to access Internet-based resources and how Internet-based strategies can best be designed, implemented, and distributed to meet the needs of this group of users. PMID- 25707034 TI - A web-based program to increase knowledge and reduce cigarette and nargila smoking among Arab university students in Israel: mixed-methods study to test acceptability. AB - BACKGROUND: Among Arab citizens in Israel, cigarette and nargila (hookah, waterpipe) smoking is a serious public health problem, particularly among the young adult population. With the dramatic increase of Internet and computer use among Arab college and university students, a Web-based program may provide an easy, accessible tool to reduce smoking rates without heavy resource demands required by traditional methods. OBJECTIVE: The purpose of this research was to examine the acceptability and feasibility of a pilot Web-based program that provides tailored feedback to increase smoking knowledge and reduce cigarette and nargila smoking behaviors among Arab college/university students in Israel. METHODS: A pilot Web-based program was developed, consisting of a self administered questionnaire and feedback system on cigarette and nargila smoking. Arab university students were recruited to participate in a mixed-methods study, using both quantitative (pre-/posttest study design) and qualitative tools. A posttest was implemented at 1 month following participation in the intervention to assess any changes in smoking knowledge and behaviors. Focus group sessions were implemented to assess acceptability and preferences related to the Web-based program. RESULTS: A total of 225 participants-response rate of 63.2% (225/356) completed the intervention at baseline and at 1-month poststudy, and were used for the comparative analysis. Statistically significant reductions in nargila smoking among participants (P=.001) were found. The intervention did not result in reductions in cigarette smoking. However, the tailored Web intervention resulted in statistically significant increases in the intention to quit smoking (P=.021). No statistically significant increases in knowledge were seen at 1 month poststudy. Participants expressed high satisfaction with the intervention and 93.8% (211/225) of those who completed the intervention at both time intervals reported that they would recommend the program to their friends, indicating excellent acceptability and feasibility of the intervention. This was further emphasized in the focus group sessions. CONCLUSIONS: A tailored Web-based program may be a promising tool to reduce nargila smoking among Arab university students in Israel. The tailored Web intervention was not successful at significantly reducing cigarette smoking or increasing knowledge. However, the intervention did increase participants' intention to quit smoking. Participants considered the Web-based tool to be an interesting, feasible, and highly acceptable strategy. TRIAL REGISTRATION: TRIAL REGISTRATION: ISRCTN registry ISRCTN59207794; http://www.isrctn.com/ISRCTN59207794 (Archived by WebCite at http://www.webcitation.org/6VkYOBNOJ). PMID- 25707035 TI - Patient and provider attitudes toward the use of patient portals for the management of chronic disease: a systematic review. AB - BACKGROUND: Patient portals provide patients with the tools to better manage and understand their health status. However, widespread adoption of patient portals faces resistance from patients and providers for a number of reasons, and there is limited evidence evaluating the characteristics of patient portals that received positive remarks from patients and providers. OBJECTIVE: The objectives of this systematic review are to identify the shared characteristics of portals that receive favorable responses from patients and providers and to identify the elements that patients and providers believe need improvement. METHODS: The authors conducted a systematic search of the CINAHL and PubMed databases to gather data about the use of patient portals in the management of chronic disease. Two reviewers analyzed the articles collected in the search process in order remove irrelevant articles. The authors selected 27 articles to use in the literature review. RESULTS: Results of this systematic review conclude that patient portals show significant improvements in patient self-management of chronic disease and improve the quality of care provided by providers. The most prevalent positive attribute was patient-provider communication, which appeared in 10 of 27 articles (37%). This was noted by both patients and providers. The most prevalent negative perceptions are security (concerns) and user friendliness, both of which occurred in 11 of 27 articles (41%). The user friendliness quality was a concern for patients and providers who are not familiar with advanced technology and therefore find it difficult to navigate the patient portal. The high cost of installation and maintenance of a portal system, not surprisingly, deters some providers from implementing such technology into their practice, but this was only mentioned in 3 of the 27 articles (11%). It is possible that the incentives for meaningful use assuage the barrier of cost. CONCLUSIONS: This systematic review revealed mixed attitudes from patients and their providers regarding the use of patient portals to manage their chronic disease. The authors suggest that a standard patient portal design providing patients with the resources to understand and manage their chronic conditions will promote the adoption of patient portals in health care organizations. PMID- 25707036 TI - The wired patient: patterns of electronic patient portal use among patients with cardiac disease or diabetes. AB - BACKGROUND: As providers develop an electronic health record-based infrastructure, patients are increasingly using Web portals to access their health information and participate electronically in the health care process. Little is known about how such portals are actually used. OBJECTIVE: In this paper, our goal was to describe the types and patterns of portal users in an integrated delivery system. METHODS: We analyzed 12 months of data from Web server log files on 2282 patients using a Web-based portal to their electronic health record (EHR). We obtained data for patients with cardiovascular disease and/or diabetes who had a Geisinger Clinic primary care provider and were registered "MyGeisinger" Web portal users. Hierarchical cluster analysis was applied to longitudinal data to profile users based on their frequency, intensity, and consistency of use. User types were characterized by basic demographic data from the EHR. RESULTS: We identified eight distinct portal user groups. The two largest groups (41.98%, 948/2258 and 24.84%, 561/2258) logged into the portal infrequently but had markedly different levels of engagement with their medical record. Other distinct groups were characterized by tracking biometric measures (10.54%, 238/2258), sending electronic messages to their provider (9.25%, 209/2258), preparing for an office visit (5.98%, 135/2258), and tracking laboratory results (4.16%, 94/2258). CONCLUSIONS: There are naturally occurring groups of EHR Web portal users within a population of adult primary care patients with chronic conditions. More than half of the patient cohort exhibited distinct patterns of portal use linked to key features. These patterns of portal access and interaction provide insight into opportunities for electronic patient engagement strategies. PMID- 25707037 TI - Development of a Twitter-based intervention for smoking cessation that encourages high-quality social media interactions via automessages. AB - BACKGROUND: The medical field seeks to use social media to deliver health interventions, for example, to provide low-cost, self-directed, online self-help groups. However, engagement in online groups is often low and the informational content may be poor. OBJECTIVE: The specific study aims were to explore if sending automessages to online self-help groups encouraged engagement and to see if overall or specific types of engagement related to abstinence. METHODS: We conducted a Stage I Early Therapy Development Trial of a novel social media intervention for smoking cessation called Tweet2Quit that was delivered online over closed, 20-person quit-smoking groups on Twitter in 100 days. Social media such as Twitter traditionally involves non-directed peer-to-peer exchanges, but our hybrid social media intervention sought to increase and direct such exchanges by sending out two types of autocommunications daily: (1) an "automessage" that encouraged group discussion on an evidence-based cessation-related or community building topic, and (2) individualized "autofeedback" to each participant on their past 24-hour tweeting. The intervention was purposefully designed without an expert group facilitator and with full automation to ensure low cost, easy implementation, and broad scalability. This purely Web-based trial examined two online quit-smoking groups with 20 members each. Participants were adult smokers who were interested in quitting and were recruited using Google AdWords. Participants' tweets were counted and content coded, distinguishing between responses to the intervention's automessages and spontaneous tweets. In addition, smoking abstinence was assessed at 7 days, 30 days, and 60 days post quit date. Statistical models assessed how tweeting related to abstinence. RESULTS: Combining the two groups, 78% (31/40) of the members sent at least one tweet; and on average, each member sent 72 tweets during the 100-day period. The automessage suggested discussion topics and participants' responses to those daily automessages were related in terms of their content (r=.75, P=.012). Responses to automessages contributed 22.78% (653/2867) of the total tweets; 77.22% (2214/2867) were spontaneous. Overall tweeting related only marginally to abstinence (OR 1.03, P=.086). However, specific tweet content related to abstinence including tweets about setting of a quit date or use of nicotine patches (OR 1.52, P=.024), countering of roadblocks to quitting (OR 1.76, P=.008) and expressions of confidence about quitting (OR 1.71, SE 0.42, P=.032). Questionable, that is, non-evidence-based, information about quitting did not relate to abstinence (OR 1.12, P=.278). CONCLUSIONS: A hybrid social media intervention that combines traditional online social support with daily automessages appears to hold promise for smoking cessation. This hybrid approach capitalizes on social media's spontaneous real-time peer-to-peer exchanges but supplements this with daily automessages that group members respond to, bolstering and sustaining the social network and directing the information content. Highly engaging, this approach should be studied further. TRIAL REGISTRATION: Clinicaltrials.gov NCT01602536; https://clinicaltrials.gov/ct2/show/NCT01602536 (Archived by WebCite at http://www.webcitation.org/6WGbt0o1K). PMID- 25707039 TI - Strategic planning ensures surgical success in cases of proliferative vitreoretinopathy. AB - For this Practical Retina column, Dr. Ross Lakhanpal from Baltimore was asked to comment on the current state of thinking and management options for proliferative vitreoretinopathy (PVR) after retinal detachment (RD) surgery.We are all aware that PVR continues to be an important cause of recurrent RD after successful repair. This feared complication has been reported to occur in up to 8% of patients after undergoing RD repair. Despite the historic progress made in managing various vitreoretinal diseases over the past decade, most retina specialists will agree that an unmet need remains in this landscape. Fortunately, advances in various surgical technologies such as instrumentation, lighting, and visualization have improved the outcomes after PVR management.Dr. Lakhanpal discusses causes of PVR, management goals, surgical techniques, and pearls to avoid complications after managing PVR. His experience working in an urban tertiary surgical retina practice enables him to offer insights that will be highly valued by our community. PMID- 25707038 TI - Twitter sentiment predicts Affordable Care Act marketplace enrollment. AB - BACKGROUND: Traditional metrics of the impact of the Affordable Care Act (ACA) and health insurance marketplaces in the United States include public opinion polls and marketplace enrollment, which are published with a lag of weeks to months. In this rapidly changing environment, a real-time barometer of public opinion with a mechanism to identify emerging issues would be valuable. OBJECTIVE: We sought to evaluate Twitter's role as a real-time barometer of public sentiment on the ACA and to determine if Twitter sentiment (the positivity or negativity of tweets) could be predictive of state-level marketplace enrollment. METHODS: We retrospectively collected 977,303 ACA-related tweets in March 2014 and then tested a correlation of Twitter sentiment with marketplace enrollment by state. RESULTS: A 0.10 increase in the sentiment score was associated with an 8.7% increase in enrollment at the state level (95% CI 1.32 16.13; P=.02), a correlation that remained significant when adjusting for state Medicaid expansion (P=.02) or use of a state-based marketplace (P=.03). CONCLUSIONS: This correlation indicates Twitter's potential as a real-time monitoring strategy for future marketplace enrollment periods; marketplaces could systematically track Twitter sentiment to more rapidly identify enrollment changes and potentially emerging issues. As a repository of free and accessible consumer-generated opinions, this study reveals a novel role for Twitter in the health policy landscape. PMID- 25707040 TI - Spectral-domain optical coherence tomography measurements of choroidal thickness and outer retinal disruption in macular telangiectasia type 2. AB - BACKGROUND AND OBJECTIVE: To evaluate subfoveal choroidal thickness (CT) and the extent of outer retinal disruption in patients with macular telangiectasia type 2 (MacTel2) compared with healthy eyes. PATIENTS AND METHODS: In this prospective, observational, cohort study, 62 patients (62 eyes) with Mac-Tel2 and 130 healthy controls (130 eyes) underwent a complete ophthalmological examination, spectral domain optical coherence tomography (SD-OCT) imaging, and axial length measurements. Patients in the study group also underwent color fundus photography, fundus autofluorescence, and fluorescein angiography. En face SD-OCT imaging was used to assess abnormalities involving the photoreceptor inner segment/outer segment/ellipsoid zone (IS/OS/EZ). RESULTS: After adjusting for age and axial length, the authors found that eyes with MacTel2 had a mean CT measurement that was greater than control eyes (P = .007). There was a negative correlation between the visual acuity and the area of IS/OS/EZ damage (P = .009), but no statistically significant correlation was seen between CT and the area of IS/OS/EZ damage. CONCLUSION: Eyes with MacTel2 were found to have thicker CT measurements than control eyes. While the extent of IS/OS/EZ disruption correlated with the loss of visual acuity, this damage did not correlate with CT measurements. PMID- 25707041 TI - Comparison of retinal thicknesses measured using swept-source and spectral-domain optical coherence tomography devices. AB - BACKGROUND AND OBJECTIVE: To compare retinal thicknesses measured using swept source optical coherence tomography (SS-OCT) and spectral-domain (SD) OCT devices. PATIENTS AND METHODS: In a cohort study of 76 healthy eyes and 21 eyes with high myopia, mean retinal thicknesses in ETDRS subfields were compared between OCT scans obtained from the Topcon DRI OCT-1 (Topcon, Tokyo, Japan), Spectralis OCT (Heidelberg Engineering, Heidelberg, Germany), and Cirrus HD-OCT (Carl Zeiss Meditec, Dublin, CA). RESULTS: Central retinal thickness measurements differed significantly among the three OCT devices (Spectralis: 271 um; Cirrus: 254 um; DRI OCT-1: 238 um; P < .001), with mean differences ranging from 15.6 um to 37 um. Intraclass correlation coefficients were at least 0.94 for any pair of machines. Similar results were observed in all nine ETDRS subfields. In all sectors, retinal thickness measurements obtained using the 3-D and radial scans of the SS-OCT were similar (mean differences: 0.7 to 3.8 um). CONCLUSION: Retinal thickness measurements obtained from DRI OCT-1 and SD-OCT are different and should be accounted for when comparing results of OCT scans from different devices. PMID- 25707042 TI - A quantitative evaluation of the posterior segment of the eye using spectral domain optical coherence tomography in carotid artery stenosis: a pilot study. AB - BACKGROUND AND OBJECTIVE: To evaluate the posterior segment of the eye using spectral-domain optical coherence tomography (SD-OCT) in patients with internal carotid artery (ICA) stenosis. PATIENTS AND METHODS: Prospective study enrolling 25 patients with ICA stenosis (study group) and 25 age- and gender-matched healthy individuals (control group). Macular choroidal thickness (CT) was measured at the fovea; other CT measurements were taken 1,000 um away from the fovea in the nasal, temporal, superior, and inferior regions by enhanced-depth imaging OCT (EDI-OCT). The thicknesses of the retinal nerve fiber layer (RNFL), macula, and ganglion cell complex (GCC) were measured with SD-OCT. Correlations between the CT values and the degree of ICA stenosis were also evaluated. RESULTS: Mean macular CT values in the study group were significantly thinner than those of the control groups for all quadrants (P < .05). There was no significant correlation between the degree of ICA stenosis and the CT values. Moreover, the mean thicknesses of the RNFL, macula, and GCC did not differ between the two groups. CONCLUSION: The results suggest that CT decreases in patients with ICA stenosis compared with age-matched healthy individuals, whereas the RNFL, macular, and GCC thicknesses are comparable. PMID- 25707043 TI - Whole eye segment imaging and measurement with dual-channel spectral-domain OCT. AB - BACKGROUND AND OBJECTIVES: To image and measure whole eye segments using dual channel spectral-domain optical coherence tomography (SD-OCT) and to compare the results with those from the IOLMaster (Carl Zeiss Meditec, Dublin, CA). PATIENTS AND METHODS: Twenty eyes of 20 volunteers were recruited. Ocular dimensions, including cornea thickness, anterior chamber depth (ACD), lens thickness, anterior lens surface curvature, and axial length (AL), were calculated. The reproducibility of SD-OCT measurements, statistical significance of inter instrument difference, correlation, and agreement were evaluated. RESULTS: No significant differences were found between independent SD-OCT measurements (P > .05). The ACD and AL measured with IOLMaster were significantly shorter than those from SD-OCT (P < .001). There were high correlations and agreements in ACD (r = 0.994; 95% limits of agreement [LOA], 0.131-0.223 mm) and AL (r = 0.998; 95% LOA, 0.678-0.853 mm) between the two methods. CONCLUSION: Dual-channel SD-OCT was demonstrated to have good repeatability in imaging and measuring whole eye segments. The results had high correlations and agreements with those from the IOLMaster. PMID- 25707044 TI - Quantitative OCT subanalysis of eyes with choroidal neovascularization switched from multiple injections of bevacizumab or ranibizumab to intravitreal aflibercept. AB - BACKGROUND AND OBJECTIVE: To assess the early therapeutic response after switching from multiple injections of bevacizumab or ranibizumab to aflibercept in eyes with neovascular age-related macular degeneration (AMD). PATIENTS AND METHODS: SD-OCT scans of patients with neovascular AMD that was suboptimally responsive to multiple injections of bevacizumab or ranibizumab who were switched to aflibercept were analyzed. After segmenting these scans, the relevant volumes were computed and compared at the various time points by Student's t test. RESULTS: After switching to aflibercept, converse to the outcome of the last injection of bevacizumab or ranibizumab, statistically significant decreases of 0.32 mm(3) in neurosensory retinal volume, 0.08 mm(3) in subretinal fluid, and 0.56 mm(3) in pigment epithelial detachment were observed (P = .01, .04, and .001, respectively). The mean ETDRS visual acuity increased from 62 to 65 letters after switching (P = .04). These favorable outcomes were sustained after three monthly injections of the new drug. CONCLUSION: Switching to aflibercept therapy in eyes with persistent fluid after multiple intravitreal injections of bevacizumab or ranibizumab was associated with an early reduction in all fluid compartments and improvement in visual acuity. PMID- 25707045 TI - Anti-VEGF intravitreal bevacizumab for radiation-associated neovascular glaucoma. AB - BACKGROUND AND OBJECTIVE: To report outcomes of intravitreal bevacizumab therapy in radiation-associated neovascular glaucoma (NVG). PATIENTS AND METHODS: In this retrospective interventional case series, 12 eyes with NVG after radiation therapy for ocular malignancy were treated with periodic intravitreal injections of 1.25 mg bevacizumab. Outcome measures included changes in iris neovascularization, intraocular pressure (IOP), visual acuity, and pain. RESULTS: One month after the first injection, iris neovascularization regressed in nine of 12 eyes (75%), and IOP decreased in eight of 12 eyes (67%) by a mean of 10.1 mm Hg. Patients were monitored for a mean of 26.5 months after their first injection. Six eyes subsequently underwent enucleation for pain control (four eyes; 66%), chronic uveitis (one eye; 17%), and tumor recurrence (one eye; 17%). All remaining patients experienced deterioration in visual acuity (range: 20/160 to no light perception), but pain control was good and IOP normalized in four patients. CONCLUSION: Intravitreal bevacizumab therapy should be considered for patients with radiation-associated NVG who wish to avoid enucleation. PMID- 25707046 TI - Early evolution of the vitreomacular interface and clinical efficacy after ocriplasmin injection for symptomatic vitreomacular adhesion. AB - BACKGROUND AND OBJECTIVE: To determine early evolution of the vitreomacular interface and clinical efficacy and safety profile after ocriplasmin treatment. PATIENTS AND METHODS: Retrospective, multicenter, observational case series. Patients with vitreomacular adhesion (VMA) confirmed on optical coherence tomography (OCT) received a single intravitreal ocriplasmin injection. Changes in the vitreomacular interface were evaluated by spectral-domain OCT. Adverse events were monitored at all visits. RESULTS: Of 22 patients treated with ocriplasmin, 14 (64%) had VMA resolution, with six (43%) achieving VMA release within the first week. Eight patients (36%) showed improvement in visual acuity (VA) of at least two Snellen lines. Rate of VMA resolution was 79% for VA less than 20/40 and 38% for VA of 20/40 or greater. Safety findings include changes in the ellipsoid layer (n = 3) and transient increases in subretinal fluid (n = 6). CONCLUSION: Ocriplasmin was effective for VMA resolution, with a rapid onset of action. Patients with worse baseline VA showed a higher VMA resolution rate. PMID- 25707047 TI - Considering photodynamic therapy as a therapeutic modality in selected cases of dome-shaped macula complicated by foveal serous retinal detachment. AB - BACKGROUND AND OBJECTIVE: To study the role of photodynamic therapy (PDT) as a therapeutic modality in myopic patients with dome-shaped macula (DSM) associated with foveal serous retinal detachment (SRD). PATIENTS AND METHODS: Retrospective interventional case series. The medical records of 10 consecutive myopic patients (10 eyes) with DSM associated with subfoveal SRD and treated with PDT were reviewed. Visual gain and loss were considered as increasing or decreasing of two or more lines of best corrected visual acuity (BCVA), respectively, and eyes with fluid resolution were deemed responsive to PDT. RESULTS: All eyes underwent several PDT treatments, with a median of three and a median follow-up time of 15.5 months. At final follow-up, six eyes (60%) showed complete resolution of the foveal SRD. The baseline hypocyanescent macular area observed during late indocyanine green angiography (ICGA) frames was significantly lower in the group of patients who responded to PDT and had an increase of at least two Snellen lines in BCVA (P = .01). CONCLUSION: Data suggest that myopic eyes associated with DSM and foveal SRD may be responsive to PDT, showing total resolution of fluid accumulation and positive BCVA changes if baseline ICGA findings show evidence of a limited hypocyanescent macular area. PMID- 25707048 TI - Sustained-release dexamethasone intravitreal implant for persistent macular edema after vitrectomy for epiretinal membrane. AB - BACKGROUND AND OBJECTIVE: Persistent macular edema (ME) after surgical removal of epiretinal membrane (ERM) may impair postoperative visual recovery. Sustained release dexamethasone intravitreal implant (DEX) was used to treat recalcitrant ME after vitrectomy for ERM. PATIENTS AND METHODS: Retrospective chart review of eyes treated with DEX for ME after ERM removal. Visual and anatomic outcomes were evaluated. RESULTS: Five eyes with refractory ME on optical coherence tomography (OCT) after ERM surgery were treated with DEX. Four of five eyes demonstrated reduction in macular thickness on OCT (mean: 106 MUm), with mean percentage reduction in central foveal thickness of 25%. Visual acuity improved by one or more Snellen lines in four of five eyes. DEX effect duration was 3 to 9 months. Two eyes with OCT and visual improvement after initial DEX received multiple DEX implants for maintenance therapy. CONCLUSION: Inflammatory factors may contribute to persistent ME after vitrectomy for ERM. DEX may be a treatment option in such cases. PMID- 25707049 TI - Neovascular age-related macular degeneration associated with no light perception. AB - BACKGROUND AND OBJECTIVE: To study eyes with no light perception (NLP) occurring secondary to neovascular age-related macular degeneration (AMD). PATIENTS AND METHODS: Records of consecutive patients with neovascular AMD seen during a 10 year period were reviewed to ascertain which patients had NLP due to neovascular AMD. RESULTS: Ten of 1,150 patients (0.9%) with neovascular AMD had NLP in one eye (study eye) from neovascular AMD. All 10 patients had bilateral neovascular AMD. Each study eye had a large macular disciform scar and 360 degrees peripapillary subretinal fibrovascular tissue. Seven of nine (78%) study eyes had optic disc pallor, versus none of eight fellow eyes (P = .04). Mean fellow eye vision was 20/231, ranging from 20/50 to NLP (P = .006 vs study eyes). No seeing fellow eye had choroidal neovascularization encircling the optic disc (P = .0004). CONCLUSION: NLP from neovascular AMD is associated with 360 degrees peripapillary subretinal fibrosis. This fibrosis may cause chronic ischemic optic neuropathy contributing to extinguished vision. PMID- 25707050 TI - Vitreomacular traction syndrome: postoperative functional and anatomic outcomes. AB - BACKGROUND AND OBJECTIVE: To analyze a variety of vitreomacular traction (VMT) morphologies to establish a major classification that better reflects the preoperative predictive factors of postoperative visual and anatomic outcomes. PATIENTS AND METHODS: Thirty-six eyes submitted to vitrectomy surgery were categorized with a VMT pattern (V- or J-shaped) and diameter (focal < 1,500 um or broad > 1,500 um) based on optical coherence tomography. RESULTS: The researchers compared different classifications of VMT. Despite similar postoperative best corrected visual acuity (BCVA) values (P = .393), cases with focal VMT had greater visual improvement (P = .027) because the preoperative BCVA was significantly lower in the focal group (P = .007). However, the BCVA improvements did not differ between the groups regarding the classic VMT morphologic patterns (P = .235). CONCLUSION: Postoperative outcomes and macular disorders are closely related to VMT size. The adhesion diameter (focal or broad VMT) and not the classic VMT morphologic pattern (V- or J-shaped) may better predict the postoperative anatomic and functional outcomes. PMID- 25707051 TI - Risk factors for respiratory depression in patients undergoing retrobulbar block for vitreoretinal surgery. AB - BACKGROUND AND OBJECTIVE: To determine the risk factors for respiratory depression during retrobulbar block administration before vitreoretinal surgery. PATIENTS AND METHODS: Prospective, observational case series of 113 patients undergoing monitored anesthesia care and retrobulbar block before vitreoretinal surgery at a tertiary medical center. RESULTS: Chin lift, jaw thrust, and bag mask ventilation were performed in eight (7.1%), nine (8%), and six (5.3%) patients, respectively. No patients required intubation. Age, sex, body mass index, history of obstructive sleep apnea, American Society of Anesthesiologists physical status level, and baseline oxygen saturation were not predictive of airway intervention. Of the four anesthetic agents utilized (midazolam, fentanyl, alfentanil, and propofol), only propofol and fentanyl were associated with an increased risk for clinically significant apnea. Use of three medications for sedation was associated with a 5.4-fold increase in the relative risk of requiring a respiratory rescue intervention. CONCLUSION: During preoperative sedation for retrobulbar block administration, the use of propofol, fentanyl, or a combination of three anesthetics is associated with a statistically significant increase in the risk for respiratory depression requiring resuscitation. PMID- 25707052 TI - Imaging areas of retinal nonperfusion in ischemic branch retinal vein occlusion with swept-source OCT microangiography. AB - The authors present the case of a patient with a history of ischemic branch vein occlusion and multimodal imaging of the retinal vasculature by fluorescein angiography (FA) and ultrahigh-speed swept-source optical coherence tomography (SS-OCT) microangiography (SS-OCT laser prototype; 1,050 nm, 100,000 A scans/second). Multiple images across the macula were acquired (3 * 3 mm cubes in clusters of four repeated B-scans). En face images of the vasculature were generated by implementing an intensity differentiation algorithm. The retinal vasculature as well areas of nonperfusion could be identified precisely at multiple retinal levels. Ultrahigh-speed SS-OCT microangiography provides noninvasive, three-dimensional, high-resolution images of the retinal vasculature including the capillaries. PMID- 25707053 TI - Spectral-domain optical coherence tomography features of bilateral chorioretinitis sclopetaria. AB - The authors report a case of bilateral chorioretinitis sclopetaria in a 31-year old man who sustained a perforating gunshot trauma. On presentation, best corrected visual acuity was light perception in the right eye and counting fingers at 5 feet in the left eye. Funduscopic examination demonstrated bilateral peripapillary fibrogliotic lesions with associated pigmentation in the posterior pole. Spectral-domain optical coherence tomography scans revealed bilateral full thickness hyperreflectivity consistent with chorioretinal disruption. The patient was closely monitored, and his vision remained stable at 6-week follow-up. PMID- 25707054 TI - New insights into Stargardt disease with multimodal imaging. AB - A 20-year-old woman with bilateral mild blurring of vision presented with a bull's eye maculopathy and was diagnosed with Stargardt disease, confirmed with genetic testing. The authors present several novel multimodal imaging findings including multicolor and multi-spectral imaging that enhanced visualization of perifoveal flecks, fundus autofluorescence that revealed both perifoveal and perimacular rings of hyperautofluorescence, adaptive optics imaging that revealed unprecedented visualization of cones at the fovea due to decreased cone density, and spectral-domain optical coherence tomography that identified thickening and increased hyperreflectivity of the external limiting membrane as a possible transient biomarker of early Stargardt disease. PMID- 25707055 TI - Bevacizumab therapy and multimodal ultrawide-field imaging in immunogammopathy maculopathy secondary to Waldenstrom's macroglobulinemia. AB - Waldenstrom's macroglobulinemia (WM) is associated with retinal findings of hyperviscosity, such as venous dilation, and findings of immunogammopathy maculopathy, such as serous macular detachment. This report describes a case of bilateral serous macular detachment with intraretinal schisis-like fluid in a patient with WM. Enhanced depth imaging optical coherence tomography revealed a thickened choroid with hyperreflective accumulations in the retinal pigment epithelium layer. Ultrawide-field fundus autofluorescence demonstrated a central area of hyperautofluorescence corresponding to the area of serous macular detachment. Ultrawide-field fluorescein angiography was characteristically silent. Intravitreal bevacizumab therapy resulted in significant reduction in intraretinal fluid but minimal change in subretinal fluid. Long-term follow-up demonstrated alterations in retinal architecture and improved serous detachments. PMID- 25707056 TI - Multimodal imaging of macular serpiginous choroidopathy from acute presentation to quiescence. AB - The authors report imaging findings in a case of macular serpiginous choroidopathy (MSC). Near-infrared reflectance (NIR), fundus autofluorescence (FAF), and spectral-domain optical coherence tomography (SD-OCT) were performed on a 25-year-old man presenting with decreased visual acuity and a blind spot in his left eye. Fundus examination revealed a yellow subretinal infiltrate inferior to the macula with active edges. On SD-OCT, areas of disease activity presented as a diffuse hyperreflective signal in the outer nuclear layer (ONL). Inactive lesions presented as localized thinning of the ONL. NIR allowed clear visualization of a hyperreflective junctional line between the active and inactive areas that subsequently became disrupted. FAF revealed a diffuse hypoautofluorescent halo surrounding an area of hyperautofluorescence in the acute phase and later better-defined lesions and hypoautofluorescent lesion edges. PMID- 25707057 TI - Incomplete release of vitreomacular attachments after intravitreal ocriplasmin. AB - Ocriplasmin is a recombinant protease approved as a nonsurgical treatment for vitreomacular traction (VMT) and small macular holes with vitreomacular adhesion (VMA). Successful ocriplasmin treatment in clinical studies has been defined as nonsurgical resolution of VMA as demonstrated on optical coherence tomography (OCT) by day 28 after intravitreal injection. This report presents three eyes with improvement in visual acuity and clinical symptoms despite only partial release of VMT over 28 days after ocriplasmin injection. PMID- 25707058 TI - Regression of drusen after combined treatment using photodynamic therapy with verteporfin and ranibizumab. AB - Drusen are the clinical hallmark of age-related macular degeneration. The regression of these deposits in patients treated with argon, krypton, or diode laser photocoagulation has been reported previously. However, previous protocols with conventional laser for drusen may result in retinal pigment epithelium (RPE) damage and unwanted scotomas. The authors report a case of complete regression of soft drusen in a 65-year-old man with central visual loss and metamorphopsia due to a drusenoid RPE detachment and soft drusen who underwent reduced-fluence photodynamic therapy (PDT) and three monthly intravitreal injections of ranibizumab. Reduced-fluence PDT combined with anti-VEGF therapy may reduce drusen without inducing RPE cell damage. PMID- 25707059 TI - Bilateral central retinal artery occlusion associated with herpes simplex virus associated acute retinal necrosis and meningitis: case report and literature review. AB - A 60-year-old woman with a history of recurrent headaches and blurred vision presented with bilateral optic disc edema. Optic neuritis was suspected, and intravenous methylprednisonlone was administered. Her vision declined to hand motions in both eyes, and subsequent evaluation revealed bilateral acute retinal necrosis with bilateral central retinal artery occlusions (CRAO). Aqueous humor polymerase chain reaction analysis was positive for herpes simplex virus (HSV), establishing a diagnosis of HSV-associated bilateral acute retinal necrosis (ARN) and meningitis. CRAO has rarely been reported in association with ARN, and a fulminant course with bilateral CRAO in association with ARN has not been previously reported. This case emphasizes the importance of careful peripheral examination in patients with presumptive optic neuritis, judicious use of systemic corticosteroid in this context, and the retinal vaso-obliterative findings that may be observed in the pathogenesis of ARN. PMID- 25707060 TI - Double optic pit maculopathy. AB - The author reports a case of a 16-year-old boy with decreased vision secondary to optic pit maculopathy. Clinical examination revealed two distinct optic pits in the optic nerve head with macular schisis and no subretinal fluid. Follow-up examination at 1 year demonstrated stable macular schisis and vision. This case illustrates visual impairment secondary to optic pit maculopathy arising from two optic pits in a single optic nerve head. PMID- 25707061 TI - Pseudoxanthoma elasticum associated with vitelliform macular lesion. AB - The authors describe an uncommon association between pseudoxanthoma elasticum with typical fundus lesions and positive testing for mutation in the ABCC6 gene and the concomitant presence of a large subfoveal vitelliform lesion. PMID- 25707062 TI - Delayed expulsive choroidal hemorrhage after penetrating keratoplasty. AB - The authors report a case of a late-onset spontaneous choroidal hemorrhage in a patient with a corneal transplant that resulted in rupture of the keratoplasty wound and expulsion of ocular contents. This case is important because it highlights the predisposing factors of a delayed-onset choroidal hemorrhage including anticoagulant therapy, advanced age, glaucoma, and hypertension. PMID- 25707063 TI - Erratum. AB - The article "Dexamethasone Intravitreal Implant for Pseudophakic Cystoid Macular Edema in Patients With Diabetes" by Khurana et al, which was published in the January 2015 issue of Ophthalmic Surgery, Lasers, Imaging Retina (volume 46, number 1, pp. 56-61), has been amended to include a factual correction. An error was identified subsequent to its original publication. A statistically significant mean increase, rather than decrease, from baseline BCVA was observed by day 60 and maintained through day 180 (p. 59). This has been corrected in the full-text PDF on the journal website. The online article and its erratum are considered the version of record. PMID- 25707064 TI - 8 questions with Dr. Puliafito. PMID- 25707065 TI - Introduction. Drosophila eye development. PMID- 25707066 TI - Retinal specification and determination in Drosophila. PMID- 25707067 TI - Regulators of the morphogenetic furrow. PMID- 25707068 TI - NOTCH and the patterning of ommatidial founder cells in the developing Drosophila eye. PMID- 25707069 TI - The epidermal growth factor receptor in Drosophila eye development. PMID- 25707070 TI - Cell fate specification in the Drosophila eye. PMID- 25707071 TI - Tissue polarity in the retina. PMID- 25707072 TI - Regulation of growth and cell proliferation during eye development. PMID- 25707073 TI - Evolution of color vision. PMID- 25707074 TI - Developmental regulation through protein stability. PMID- 25707075 TI - Programmed death in eye development. PMID- 25707076 TI - Drosophila compound eye morphogenesis: blind mechanical engineers? PMID- 25707077 TI - The establishment of retinal connectivity. PMID- 25707078 TI - Homologies between vertebrate and invertebrate eyes. PMID- 25707079 TI - Applications of the Drosophila retina to human disease modeling. PMID- 25707080 TI - The effect of nano-hydroxyapatite toothpaste on enamel surface remineralization. An in vitro study. AB - PURPOSE: To compare, in vitro, the surface remineralization effect of two fluoride dentifrices. METHODS: 90 human enamel specimens, embedded in cylindrical acrylic blocks, washed and polished, served as a study material. The specimens were randomly assigned in equal numbers to the three groups (two test and one control). Initially the microhardness of the enamel surface (SMH) was assessed by Vickers method, while a profilometer was used to evaluate the surface roughness (Ra value). The enamel specimens were subjected to the preliminary demineralization, simulating the initial carious lesion formation. Subsequently, mean SMH and Ra values were re-assessed. Upon demineralization, one half of each specimen was covered with a protective varnish. The exposed fragment underwent the 3-week cycle of pH changes, according to the protocol. The groups were as follows: NHAPF group--toothpaste containing nanohydroxyapatite (nano HAP) and 1,450 ppm F; F group--toothpaste containing 1,450 ppm; and P group (placebo)- distilled water. Upon completion of the treatment period, the enamel microhardness and roughness profile were re-measured. RESULTS: The demineralization procedure resulted in statistically significant reduction of SMH level in all the groups, and the mean post demineralization values were in the range of 49.7 VHN to 51.2 VHN. Remineralization therapies led to statistically significant increase of enamel SMH value (P < 0.0001). None of the groups reached their original baseline level of SMH following the remineralization therapy. PMID- 25707081 TI - Remineralization of early caries by chewing sugar-free gum: a clinical study using quantitative light-induced fluorescence. AB - PURPOSE: To determine whether sugar-free gum can provide remineralization and caries control of active enamel caries lesions compared to baseline (before gum chewing) and to a no-gum group, following daily chewing for 12 weeks by school children; to determine whether chewing frequency can affect the extent of remineralization. METHOD: A pragmatic cluster-randomized controlled clinical trial with schools as the unit of randomization was employed. Three schools in Chengdu, PR China comprised the clusters. The study was approved by the Internal Review Board of Sichuan University. 177 school children, 8-13 years old, with at least one visible white-spot lesion were enrolled in the study. Each of the three clusters was randomly assigned to one of three groups: (1) no gum; (2) chew 2 pieces of sugar-free gum for 20 minutes, 3x per day; (3) chew 2 pieces of sugar free gum for 12 minutes, 5x per day. White-spot lesions were examined by quantitative light-induced fluorescence (QLF) at baseline and after 4, 8, and 12 weeks of treatment. RESULTS: 155 subjects completed the study. Of them, the mean values of fluorescence loss at baseline were 9.52, 9.83 and 9.17 for no-gum group, 3x per day group and 5x per day group, respectively. For the area, the mean values at baseline were 2.52, 2.61 and 2.57 mm2 for no-gum group, 3x per day group and 5x per day group, respectively. For AQ, the mean values at baseline were -27.91, -28.29 and -29.67 for no-gum group, 3x per day group and 5x per day group, respectively. To adjust for differences in groups at baseline, ANCOVA was used. After 12-weeks, for all QLF metrics, the absolute values of 5x per day group were the lowest and the no gum group was the highest; the differences among three groups were statistically significant (P < 0.05). For AQ, which was accepted as the most useful metrics of QLF system, the adjusted mean values at 12 weeks were -26.35, -19.81 and -17.58 for no-gum group, 3x per day group and 5x per day group, respectively. There were significant differences between groups. PMID- 25707082 TI - In-office study to evaluate the effects of a stabilized stannous fluoride dentifrice and an advanced manual toothbrush regimen on gingival health and plaque accumulation in Mexican adults. AB - PURPOSE: This office-based study was conducted to investigate the influence of an oral hygiene regimen, consisting of a stabilized stannous fluoride dentifrice and an advanced manual toothbrush, on gingival health and plaque accumulation in Mexican adults after 4 weeks of use. METHODS: This was an unsupervised, open label, single-treatment, 4-week study conducted in Mexico. At Baseline, gingival health and plaque coverage were assessed for each participant by dentists using categorical scales. Participants were given 0.454% stabilized stannous fluoride dentifrice (Crest Pro-Salud Limpieza Profunda) and an advanced manual toothbrush with a CrissCross bristle design (Oral-B Pro-Salud 7 Beneficios), and were instructed to follow the manufacturer's usage instructions for the products, which state to brush after every meal, at least three times daily, or as indicated by their dentists. At the end of Week 4, plaque and gingivitis were reassessed using the same scales. RESULTS: 200 participants (age range 18 - 49 years) completed the 4-week study and were considered evaluable. The mean age of the study group was 29.9 +/- 8.8 years, with 125 females and 75 males. After 4 weeks of product use, 172 participants (86%) showed noticeable improvement in their gingival health and 93% showed noticeable improvements in their overnight plaque coverage. PMID- 25707083 TI - Penetration and cytotoxicity of a bleaching gel activated by LED/laser in restored teeth. AB - PURPOSE: To evaluate the amount of hydrogen peroxide (HP) in the pulp chamber of teeth restored with composite resin and its cytotoxic effect on fibroblast cell line 3T3/NIH. METHODS: 112 human premolars were randomized into groups according to the combination of factors: Restoration: no restoration (NR); shallow (S); deep (D) and Activation by Light: yes (A) or no (NA). With exception of the groups Control and NR, Class V cavities (3 mm x 2 mm x 1 mm [S] and 3 mm x 2 mm x 2 mm [D]) were prepared and restored with composite resin. An acetate buffer was placed in the pulp chamber. The bleaching procedure was performed with 35% HP and activated or not with a LED/laser light. The buffer was mixed with leucocrystal violet and peroxide enzyme for the spectrophotometric evaluation of the optical density of the solution. For viability cell assays, different concentrations of HP were applied to fibroblast cell line. After 24 hours, the MTT and neutral red assays were evaluated. The lethal concentration of 50% of cells (LC50) was determined. Data were submitted to ANOVA and Tukey's test (alpha = 0.05). RESULTS: All experimental groups showed HP in the pulp chamber, but a higher amount was found in the pulp chamber of teeth with deep restorations (P = 0.026), regardless of light activation. The concentrations of HP that were found in the pulp chamber did not affect cell viability. PMID- 25707084 TI - Conventional and whitening toothpastes: cytotoxicity, genotoxicity and effect on the enamel surface. AB - PURPOSE: To evaluate the cytotoxicity and genotoxicity of whitening and common toothpastes, and the surface roughness of tooth enamel submitted to brushing with both toothpastes. METHODS: Samples of whitening toothpastes [Colgate Whitening (CW) and Oral-B Whitening (OBW)] and regular (non-whitening) toothpastes (Colgate and Oral-B) were extracted in culture medium. Gingival human fibroblasts (FMM-1) were placed in contact with different dilutions of culture media that had been previously exposed to such materials, and the cytotoxicity was evaluated using the MTT assay. The genotoxicity was assessed by the micronucleus formation assay in Chinese hamster fibroblasts (V79). The cell survival rate and micronuclei number were assessed before and after exposure to the toothpaste extracts. For the surface roughness evaluation, 20 bovine tooth specimens, divided into four groups according to toothpastes, were submitted to 10,000 brushing cycles. The results were analyzed using the Mann-Whitney U and two-way ANOVA tests (P < 0.05). RESULTS: MTT assay showed that Colgate was significantly less cytotoxic than CW, Oral-B and OBW at all dilutions (P < 0.01). CW was the most cytotoxic toothpaste (P < 0.01). The whitening toothpastes showed the highest numbers of micronuclei compared to the untreated control (UC) (P < 0.01). Colgate and Oral-B toothpastes were not genotoxic compared to UC (P = 0.326). The OBW toothpaste was statistically significantly abrasive to the enamel surface (P < 0.01). The whitening toothpastes and Oral-B were cytotoxic to the cells. The whitening toothpastes were more genotoxic to cells in vitro than the common toothpastes, and genotoxicity was more pronounced in the OBW toothpaste. PMID- 25707085 TI - Eighteen-month randomized clinical trial on the performance of two etch-and-rinse adhesives in non-carious cervical lesions. AB - PURPOSE: An 18-month randomized, controlled prospective study evaluated, in an intra-individual comparison, the clinical performance of two-step etch-and-rinse adhesives in non-carious cervical lesions (NCCL). METHODS: 35 subjects, with at least two similar sized NCCL participated in this study. After sample size calculation, 70 restorations were placed, according to one of the following groups: Adper Single Bond 2 (SB) and Ambar (AM). The restorations were placed incrementally using a resin composite (Opallis). The restorations were evaluated at baseline and after 6 and 18 months according to the FDI criteria. The differences in the ratings of the two materials after 6 and 18 months were tested with Fisher's exact test (alpha = 0.05), and the performance of the each material at baseline and after 6 and 18 months was evaluated by Wilcoxon test (alpha = 0.05). RESULTS: All subjects attended the 18-month recall. No significant differences were observed between the materials for any criteria evaluated. Only four restorations (two from each material) were lost after 18 months. Thus, the retention rates of both materials at 18 months were 94.2% (95% CI 81-98%). Nine restorations (four Ambar and five Adper Single Bond 2) showed marginal discoloration which was solved with a polishing procedure. Both adhesive systems showed acceptable clinical retention rates after 18 months. PMID- 25707087 TI - In vitro comparison of bonding effectiveness of different adhesive strategies. AB - ABSTRACT: Purpose: To compare the bond strength to human dentin for a variety of adhesive materials, including self-adhesive resin composites, self-etch and etch and-rinse adhesive systems and glass-ionomer cement by means of micro shear bond strength (MUSBS) test and SEM observations. METHODS: Seventy-two human molars were sectioned to obtain a 2 mm-thick slab of mid-coronal dentin and were subsequently randomly divided into nine groups (n = 8). Nine conical frustum shaped build-ups were constructed on the occlusal surface of each dentin slab using bonding agents (Group 1: OptiBond FL; Group 2: OptiBond XTR) combined with a resin composite (Premise Flow), self-adhesive resin composites (Group 3: RelyX Unicem; Group 4: RelyX Unicem 2; Group 5: SmartCem2; Group 6: SpeedCEM; Group 7: Maxcem Elite; Group 8: Vertise Flow) and a glass-ionomer cement (Group 9: Ketac Fil). Specimens were subjected to MUSBS test and observed with SEM. Data were analyzed by a mixed model and chi-square test. RESULTS: The bond strengths measured in Groups 3-9 were significantly lower than those recorded in Groups 1 and 2. There were no significant differences in bond strengths between Groups 1 and 2 or between Groups 4 through 8. The bond strength measured in Group 9 was significantly lower than those recorded in Groups 4, 5, and 6 but was not significantly different than those recorded in Groups 3, 7, and 8. Failures were mainly adhesive in all groups. PMID- 25707086 TI - Incorporation of chlorhexidine gluconate or diacetate into a glass-ionomer cement: porosity, surface roughness, and anti-biofilm activity. AB - PURPOSE: To evaluate the porosity, surface roughness and anti-biofilm activity of a glass-ionomer cement (GIC) after incorporation of different concentrations of chlorhexidine (CHX) gluconate or diacetate. METHODS: For the porosity and surface roughness tests, 10 test specimens were fabricated of the GIC Ketac Molar EasyMix (KM) and divided into the following groups: Control, GIC and 0.5% CHX diacetate; GIC and 1.0% CHX diacetate; GIC and 2.0% CHX diacetate; GIC and 0.5% CHX gluconate; GIC and 1.0% CHX gluconate; GIC and 2.0% CHX gluconate. To evaluate porosity, the test specimens were fractured. The fragments were photographed by scanning electron microscopy (SEM), and the images analyzed with the aid of the software program Image J. The surface roughness (Ra) was obtained by the mean value of three readouts performed on the surface of each specimen, always through the center. To analyze the anti-biofilm activity, strains of S. mutans ATCC 35688 were used, and the groups control and GIC +CHX diacetate 1% were divided as follows: GIC (1 day); GIC (7 days), GIC (14 days), GIC (21 days); GIC+CHX (1 day), GIC+CHX (7 days), GIC+CHX (14 days), GIC+CHX (21 days); GIC+ CHX (1 day), GIC+ CHX (7 days), GIC+ CHX (14 days) and GIC+ CHX (21 days) using 10 test specimens per group. For biofilm growth, the specimens were placed in a vertical position in 24-well plates and incubated overnight 10 times. The culture medium was renewed every 24 hours. The suspension was diluted and seeded on BHI agar for quantification of the bacteria present. For evaluation of all the tests the two way ANOVA was used, and if necessary, the Tukey test was applied, with a level of significance of 5%. RESULTS: Regarding GIC porosity, the ANOVA showed that the presence of CHX increased the porosity (P < 0.001) proportionally to the increase in concentrations (P = 0.001), without however, presenting interaction between material and concentration (P = 0.705). Regarding the number of pores, a significant increase in pores was observed with the increase in CHX concentration (P = 0.003). The surface roughness test demonstrated no statistically significant effect as to increase or reduction in roughness at any of the CHX concentrations used (P > 0.05). Anti-biofilm activity analysis pointed out a significant effect of the factors material (P = 0.006) and time (P < 0.001), with CHX diacetate CHX presenting greater effectiveness in reducing microorganisms. PMID- 25707088 TI - Effect of time between adhesive application and photoactivation on adhesion and collagen exposure. AB - PURPOSE: To evaluate the influence of the time elapsed between the application and photoactivation of Single Bond 2 (SB) on microtensile bond strength (MUTBS) and collagen exposure at the adhesive interface produced in the presence of intrapulp pressure. METHODS: Dentin occlusal surfaces were prepared in 72 molars, and divided into eight groups (n = 9). After acid etching, SB was applied, with or without simulated intrapulp pressure, and remained undisturbed for 0, 20, 40 or 60 seconds, before photoactivation. Three teeth/group were processed for staining with Goldner trichrome and evaluation of the thickness of exposed collagen zone (CZ) at the base of the hybrid layer. Composite resin build-ups were placed on the remaining six prepared teeth prior to sectioning for microtensile testing. Data were submitted to ANOVA and Tukey tests (alpha = 0.05). RESULTS: In the absence of pressure, immediate photoactivation resulted in the lowest MUTBS, while the other groups did not differ among them. Under intrapulp pressure, the lowest values were observed after 60 seconds. There was no difference in the thickness of the exposed collagen zone among the groups without pressure. However, thicker layers were recorded in the presence of pressure after 40 and 60 seconds. Waiting 60 seconds between application and photoactivation of SB significantly reduced resin-dentin bond strength when pulpal pressure was simulated. PMID- 25707089 TI - Gene therapy in dentistry: present and future. AB - Gene therapy is one of several novel biological treatments under active study for a wide variety of clinical applications, including many relevant to dentistry. This review will provide some background on this therapeutic approach, assess the current state of its applications generally, and in the oral cavity, and suggest the implications for its use in the next 25 years. PMID- 25707090 TI - Neck circumference has possibility as a predictor for metabolic syndrome in postmenopausal women. AB - Subcutaneous fat depots play an important role in regulating metabolic profile in Japanese postmenopausal women. We investigated the possibility of neck circumference (NC) as a surrogate marker for metabolic disease risk estimates in Japanese postmenopausal women. We examined the association of NC with several markers of insulin resistance, lipid metabolism and atherosclerosis in 64 healthy postmenopausal women aged 63.6 +/- 7.1 years in community-based samples in Japan. As a result, NC was significantly associated with indices of whole body obesity and visceral fat accumulation, such as body mass index (BMI) and Waist circumference (WC). In the analysis of biomarkers for insulin resistance, NC was positively correlated to HbA1c, homeostasis model assessment ratio (HOMA-R) and leptin. In addition, an increase in triglycerides (TG) and a decrease in HDL cholesterol (HDL-C) were also associated with NC. Interestingly, NC was also associated with atherosclerosis-related indices. The measurement of NC is an easy, inexpensive and reproducible method for assessment of obesity, and a possible predictor to identify the risk for future metabolic diseases in Japanese postmenopausal women. PMID- 25707091 TI - Body mass index as a predictor of postoperative complications in loop ileostomy closure after rectal resection in Japanese patients. AB - Loop ileostomy is widely employed after low rectal anastomosis to prevent pelvic sepsis from anastomotic leakage. However, stoma closure carries a risk of morbidity and even mortality in some cases. It is important to assess complications after stoma closure for maximizing the benefit of making loop ileostomy. The aim of this study was to review and examine the possible risk factors associated with complications after closure of loop ileostomies. A retrospective analysis, which focused on risk factors for complications after surgery, was performed for 82 consecutive patients who underwent elective closure of loop ileostomy from 2005-2012 at Hiroshima University Hospital. Postoperative complications developed in 22 patients (26.8%): 12 (14.6%) had an ileus, 8 (9.8%) had a wound infection, 2 (2.4%) had an intraperitoneal abscess and 1 had pseudomembranous enterocolitis. There was no postoperative mortality. In univariate analysis, gender and higher body mass index (BMI) were identified as significant risk factors for postoperative complications. After multivariate analysis, a BMI of 24 kg/m2 was identified as the cut-off value, above which significantly higher incidences of postoperative complications were observed. Furthermore, patients who succeeded in reducing their weight (BMI < 24 kg/m2) between the first and second surgeries had less morbidity than patients who remained obese (BMI > 24 kg/m2). Our study showed that the majority of complications associated with ileostomy closure are ileus. A BMI > 24 kg/m2 is an independent risk factor for postoperative complications. Weight loss programs before stoma closure might reduce postoperative complications. PMID- 25707092 TI - A case of petrous apex cholesterol granuloma successfully treated with endoscopic endonasal surgery. AB - A transcranial approach in combination with a transpetrosal setting has been the mainstream of surgical treatment of cholesterol granulomas in the petrous apex. However, endoscopic endonasal surgery has become a choice of treatment for these lesions with recent advancements in surgical techniques and instruments. We report a successful case of cholesterol granuloma managed with endoscopic endonasal surgery. A 45-year-old woman, who had a long-standing history of otitis media, presented with left abducens nerve palsy and discomfort around the left eye. Magnetic resonance (MR) imaging showed a large cystic lesion, suggesting cholesterol granuloma, in the left middle fossa abutting the cavernous sinus and lateral wall of the sphenoid sinus. We chose an endoscopic endonasal approach to drain the contents of the cyst because the lesion protruded into the left sphenoid sinus. The sphenoid sinus was widely opened and the cyst wall was fenestrated with the assistance of an image guidance navigation system. Postoperative MR images confirmed the complete collapse of the cyst. She has been free from symptoms since the operation. PMID- 25707094 TI - Introduction: Within or beyond the paradigm shift? Teleology and mechanism in the early modern medical discourse on the functions of the living body. PMID- 25707093 TI - A Japanese pedigree of familial cerebral cavernous malformations--a case report. AB - Familial cerebral cavernous malformations (FCCM) are autosomal-dominant vascular malformations. At present, 3 cerebral cavernous malformation genes (KRIT1/CCM1, MGC4607/CCM2, and PDCD10/CCM3) have been identified. Few genetic analyses of Japanese FCCM have been reported. A Japanese pedigree of 4 patients with FCCM has been reported that includes the genetic analysis of one of the patients. All 4 patients showed multiple lesions in the brain. Surgical removal was performed at our hospital due to enlargement or hemorrhage of the intracranial lesions in a 21 year-old female (Case 1) and a 30-year-old male (Case 2). The histological diagnoses were cavernous malformations. A 62-year-old female (Case 4), the mother of Cases 1, 2, and 3, suffered from intramedullary hemorrhage at T6-7 and surgical removal was performed at another hospital. Only one patient, a 32-year old female (Case 3), did not show symptoms. The genetic analysis of Case 2 demonstrated heterozygous partial deletions of exons 12-15 of the KRIT1 gene. PMID- 25707095 TI - [Medicine, philosophy and the scientific revolution. A bibliographical survey]. AB - This article examines the place that has been reserved for medicine in the historiography of the sciences. More precisely, it focuses on the motifs that have lead historians of science to grant only a minor role to medicine within the movement commonly designated by the notion of the "scientific revolution". Among those motifs, the persistent and late application of teleological schemas in the thinking of the biological and the difficulties in "mathematizing" anatomy are often invoked. Starting with an overview of the critical literature on the topic, this bibliographical essay shows how the situation has changed over the last decades. The opposition between, on the one hand, the physical sciences founded on a model of mechanistic explanation of nature and, on the other hand, the life sciences that remained guided by a finalist mode of thinking are today much put into question. What we find today is more open reflection on the diversity of "models" for understanding the living, and on how to integrate them into more complex schemas than those that simply oppose mechanism and teleology. The essay is finally based on discussions and debates among medical doctors and philosophers in the modern period, and insists on the importance of studying this "medico-philosophical" tradition in order to avoid reconstructing a posteriori a mythical history that trends to consecrate a single model of rationality. PMID- 25707096 TI - The body of the soul. Lucretian echoes in the Renaissance theories on the psychic substance and its organic repartition. AB - In the 16th and 17th centuries, when Aristotelianism still was the leading current of natural philosophy and atomistic theories began to arise, Lucretius' De Rerum Natura stood out as an attractive and dangerous model. The present paper reassesses several relevant aspects of Lucretius' materialistic psychology by focusing on the problem of the soul's repartition through the limbs discussed in Book 3. A very successful Lucretian image serves as flu rouge throughout this survey: the description of a snake chopped up, with its pieces moving on the ground (Lucretius DRN 1969, 3.657-669). The paper's first section sets the poet's theory against the background of ancient psychology, pointing out its often neglected assimilation of Aristotelian elements. The second section highlights the influence of De Rerum Natura and its physiology of the soul on Bernardino Telesio, Agostino Doni and Francis Bacon, since all of these authors engage in an original recombination of mechanical and teleological explanations. PMID- 25707097 TI - Humans, elephants, diamonds and gold: patterns of intentional design in Girolamo Cardano's natural philosophy. AB - Distancing himself from both Aristotelian and Epicurean models of natural change, and resisting delusions of anthropocentric grandeur, Cardano advanced a theory of teleology centred on the notion of non-human selfhood. In keeping with Plato, he argued that nature was ruled by the mind, meaning by "mind" a universal paragon of intelligibility instantiated through patterns of purposive action ("noetic" teleology). This allowed Cardano to defend a theory of natural finalism in which life was regarded as a primordial attribute of being, already in evidence in the most elementary forms of nature, whose main categories were ability to feign, self-interest, self-preservation and indefinite persistence. PMID- 25707098 TI - "Meam de motu & usu cordis, & circuitu sanguinis sententiam": teleology in William Harvey's De motu cordis. AB - I describe the place of teleology in William Harvey's understanding of anatomy, drawing especially on his lecture and working notes from (roughly) the decade leading up to the publication of De motu cordis. Harvey understands the goal of anatomy to be universal, final causal knowledge of the parts of animals and their variations, articulated in terms of their actiones and usus. I then carefully trace the role of teleology in the De motu cordis, distinguishing (with Harvey) between his opinion "de motu & usu cordis" and "de circuitu sanguinis". I argue that in the De motu cordis Harvey provides teleological explanations of features of the heart and arteries and their variations in terms of the circulation of the blood, understood as the actio of the heart. In this way the De motu cordis clearly embodies Harvey's understanding of the teleological character of anatomical knowledge. PMID- 25707099 TI - The theory of the circulation of blood and (different) paths of Aristotelianism. Girolamo Franzosi's De motu cordis et sanguinis in animalibus pro Aristotele et Galeno adversus anatomicos neotericos libri duo: teleology versus mechanism? AB - Few discoveries in the history of medicine had a greater impact than William Harvey's discovery of the circulation of blood, and few intellectual milieus of the early modern period had as decisive a part in the rise of 'modern' medicine and the shaping of the western scientific mentality in general than the philosophical and scientific movement of 'Venetian Aristotelianism', which grew up around the University of Padua, where Harvey himself had studied. In this chapter, I aim to explore some aspects of the intellectual movement of 'Venetian Aristotelianism' as well as the debate that ensued upon the discovery of the circulation of blood. My focus, however, is not on any of the major protagonists, but rather on a quite marginal figure in this debate, namely Hieronymus Franzosi. PMID- 25707100 TI - Teleomechanism redux? Functional physiology and hybrid models of life in early modern natural philosophy. AB - The distinction between 'mechanical' and 'teleological' has been familiar since Kant; between a fully mechanistic, quantitative science of Nature and a teleological, qualitative approach to living beings, namely 'organisms' understood as purposive or at least functional entities. The beauty of this distinction is that it apparently makes intuitive sense and maps onto historico conceptual constellations in the life sciences, regarding the status of the body versus that of the machine. I argue that the mechanism-teleology distinction is imprecise and flawed using examples including the 'functional' features present even in Cartesian physiology, the Oxford Physiologists' work on circulation and respiration, the fact that the model of the 'body-machine' is not a mechanistic reduction of organismic properties to basic physical properties but is focused on the uniqueness of organic life; and the concept of 'animal economy' in vitalist medicine, which I present as a 'teleomechanistic' concept of organism (borrowing a term of Lenoir's which he applied to nineteenth-century embryology)--neither mechanical nor teleological. PMID- 25707101 TI - [Anatomy of the body and of the mind in Francis Glisson]. AB - In this paper I shall point out that Francis Glisson's conceptualisation of irritability must be understood by looking at the epistemological context within which it developed. The theory of irritability has to be interpreted as part of an 'analogical conception' that puts the analytical operations of mind in relation to the epistemic model provided by dissection. Establishing this relation makes it possible for Glisson to think the activity of the organs as 'empirical epistemic operations'. PMID- 25707102 TI - [The application of proteomic technologies for the analysis of muscle proteins of farm animals used in the meat industry (review)]. AB - The review briefly summarizes the data on the development of proteomic technologies that became actively used in studies of the muscular proteins of farm animals used in the meat industry in 2006-2013. It has been noted that the main research trends are connected with the detection of changes in muscle proteins during post-mortem autolysis and the search for species-specific and other protein biomarkers. Particular publications regarding the development of methods based on proteomic technologies for monitoring the state of muscle proteins are considered. According to the analyzed data, we can conclude that the field is promising for the solution of a number of pressing problems in.applied biochemistry. PMID- 25707103 TI - [Production and properties of recombinant glutenin-cleaving proteinases from Eurygaster integriceps Put]. AB - cDNAs coding for a mature form of glutenin-cleaving trypsin-like proteinase (referred to as glutenin-hydrolyzing proteinase 3 or GHP3) from the insect pest Eurygaster integriceps Put. and a zymogen of this proteinase containing a signal peptide required for protein secretion were cloned into vectors pPIC9 and pPIC3.5, respectively. The constructs were used for protein expression in cells of the methylotrophic yeast Pichia pastoris. The recombinant protein corresponding to the mature form of the proteinase was secreted into the culture medium and possessed proteolytic activity, while the zymogen acquired activity after trypsin, treatment. Both recombinant enzymes hydrolyzed high-molecular weight glutenin subunits from wheat of the variety Ege-88 and a range of other soft and durum wheat varieties. Chymotrypsin inhibitor I from potatoes and related inhibitors from seeds of plants of the subclass Asteridae, the Kunitz type trypsin inhibitor from soybeans, and bovine aprotinin had a weak inhibitory effect on the recombinant proteinases, while the Bowman-Birk trypsin and chymotrypsin inhibitor from soybeans did not interact with these enzymes: PMID- 25707104 TI - [A multienzyme bioreactor based on a chitinase complex]. AB - A heterogeneous biocatalyst containing a complex of chitinolytic enzymes isolated from the culture medium of bacteria Clostridium paraputrificum on the surface of macroporous monolithic minidisc was obtained. The complex of chitinolytic enzymes was immobilized on the polymer matrix using a multistep method involving the introduction of an intermediate macromolecular spacer. The endochitinase and N acetylglucosaminidase activity of the heterogeneous biocatalyst was studied. PMID- 25707105 TI - [Bacteria that degrade low-molecular linear epsilon-caprolactam olygomers]. AB - Five bacterial strains with the unique ability to utilize low-molecular linear caprolactam olygomers (nylon olygomers) were isolated from soil samples contaminated with industrial wastes of epsilon-caprolactam. Based on the properties studied and also on the analysis of 16S rRNA gene nucleotide sequences, the strains BS2,BS3, BS9, BS38, and BS57 were classified to the general Arthrobacter, Brevibacterium, Microbacteriun, Gulosibacter, and Achromobacter, respectively. All of the strains also utilized 6-aminohexanoic and adipic acids, which are intermidiates of the epsilon-caprolactam catabolism. This indirectly points to the fact that degradation of olygomers in these bacteria occurs via the monomer degradation pathway. The BS9 and BS57 strains utilized only olygomers of the epsilon-caprolactam, while BS2, BS3, and BS38 also degraded epsilon-caprolactam and its homologs, enantolactam and caprylolactam, which differentiates the latter from the previously known degraders of olygomers and suggests the presence in these strains of enzymes with lactam hydrolase activity, in addition to 6-aminohexanoate-dimer hydrolase. PMID- 25707106 TI - [Biosensors based on the luminous bacteria Photobaterium phosphoreum immobilized in polyvinyl alcohol cryogel for the monitoring of ecotoxicants]. AB - Immobilization of Photobacterium phosphoreum bacteria in polyvinyl alcohol cryogel was performed in order to develop biosensors used for ecotoxicant biomonitoring. The immobilization procedure, storage, and application of the immobilized cells for biomonitoring were optimized. It was shown that the immobilized cells demonstrate significantly higher stability and a longer duration of light emission than free bacteria. A discrete analysis of heavy metals and chlorophenols was conducted using the obtained biosensor samples. PMID- 25707107 TI - [Bioremediation of oil-polluted soils: using the [13C]/[12C] ratio to characterize microbial products of oil hydrocarbon biodegradation]. AB - We compared data on the extent of bioremediation in soils polluted with oil. The data were obtained using conventional methods of hydrocarbon determination: extraction gas chromatography-mass spectrometry, extraction IR spectroscopy, and extraction gravimetry. Due to differences in the relative abundances of the stable carbon isotopes (13C/12C) in oil and in soil organic matter, these ratios could be used as natural isotopic labels of either substance. Extraction gravimetry in combination with characteristics of the carbon isotope composition of organic products in the soil before and after bioremediation was shown to be the most informative approach to an evaluation of soil bioremediation. At present, it is the only method enabling quantification of the total petroleum hydrocarbons in oil-polluted soil, as well as of the amounts of hydrocarbons remaining after bioremediation and those microbially transformed into organic products and biomass. PMID- 25707108 TI - [Effect of point substitutions of Asp-714 and Asp-720 residues on the structure and function of the H+ -ATPase of the yeast plasma membrane]. AB - Membrane-spanning M5 and M6 segments, which play a role in the formation of cation transport sites in H(+)-, Ca2(+)-, K(+)-, Na(+)-, and other P2-ATPases, are connected by a short extracytoplasmic loop. In the yeast plasma membrane H(+) ATPase, which belongs to a family of P2-ATPases, the loop is connected to M5 and M6 through the Asp-714 and Asp-720 residues. In this work, the effect of point amino, acidreplacements of Asp-714 and Asp-720 by Ala, Val, Asn, and Glu residues on the function of the enzyme was studied. The Asp714Asn point mutant possessed activities similar to those of the wild-type enzyme, whereas the replacement of Asp-714 by other amino acid residues disrupted biogenesis and led to a loss of activity. All mutants with substitution of Asp-720 were expressed and possessed relatively high activity. The D720V mutant displayed significantly reduced expression levels, activity, H+ transport, and ATP hydrolyzing activity. Thus, substitutions of Asp-714, except for the D714N mutant, led to significant defects in biogenesis and/or function of the enzyme. The results indicate the important role for the Asp-714 residue in biogenesis, structure stability, and enzyme function. PMID- 25707109 TI - [The effect of 1-methylcyclopropene on the components of pro- and antioxidant systems of wheat and the development of protective reactions in fungal pathogenesis]. AB - The effect of 1-methylcyclopropene (1-MCP), which inhibits the reception of ethylene, on the following has been studied: hydrogen peroxide generation, oxalate oxidase activity, peroxidase activity, catalase activity, and lignin accumulation in infected leaves of soft spring wheat (Triticum aestivum L.) breeds that differ in their resistance to the causative agent of leaf blotch Septoria nodorum Berk. A decrease in the development of leaf blotch in wheat leaves under the influence of 1-MCP was, on one hand, followed by an inhibition of catalase activity; on the other hand, it was accompanied by an increase in oxalate oxidase and peroxidase activity, as well as an accumulation of H2O2 in tissues and lignin in the infected zone. The role of the ethylene reception system in the plants' protective response to infection with a hemibiotrophic pathogen, the causative agent of leaf blotch, is discussed. PMID- 25707110 TI - [Activity of protective proteins in wheat plants treated with chitooligosaccharides with different degrees of acetylation and infection with Bipolaris sorokiniana]. AB - The influence of chitooligosaccharides (COS) with different degrees of acetylation (DA) on the production of hydrogen peroxide (H2O2) and changes in the level of gene expression of pathogenesis-related (PR) proteins (oxalate oxidase AJ556991.1, peroxidase TC 151917, chitinase AV029935L, proteinase inhibitor EU293132.1) in the roots of the wheat Triticum aestivum L. inoculated with root rot pathogen Bipolaris sorokiniana (Sacc.) Shoenaker was investigated. Differences were detected in plant responses to infection. These differences were due to the pretreatment of COS seeds with differing DA. Our results demonstrated that COS with a DA over 65% more effectively induced accumulation of H2O2 and increased the transcriptional activity of genes of PR-proteins as compared to COS with a DA of 30%. These data suggest an important role for DA in the manifestation of eliciting properties of COS, also in the presence of H2O2. PMID- 25707111 TI - [The contribution of different alpha-amylase isoenzymes of the commodity grain spring wheat in the formation of falling number values]. AB - The participation of various isoenzymes of alpha-amylase in the formation of falling number values of the commodity grain of wheat grown in the Republic of Kazakhstan was investigated. It was found that active isoenzymes alpha-AMY1 and alpha-AMY2 of the embryonic shield were present in the grain with an index over 200. A significant decrease in the falling number depended mainly on the synthesis of alpha-AMY1 and alpha-AMY2 isoenzymes in the aleurone layer. In the grain, isoenzymes with high isoelectric points (p1 > or = 7.3) were found; these isoenzymes belong to alpha-amylase or late maturing or alpha-amylase of practically mature grains. It was discovered that the exogenous hormone (gibberellic acid) induced synthesis of alpha-amylase isoenzymes of scutellum, whole caryopses, and aleurone. It was shown that the impact of exogenous gibberellic acid on the activity and structure of alpha-amylase is reduced in grain with a low falling number. PMID- 25707112 TI - [Lipases in catalytic reactions of organic chemistry]. AB - Aspects of enzymatic catalysis in lipase-catalyzed reactions of organic synthesis are discussed in the review. The data on modern methods of protein engineering and enzyme modification allowing a broader range of used substrates are briefly summarized. The application of lipase in the preparation of pharmaceuticals and agrochemicals containing no inactive enantiomers and in the synthesis of secondary alcohol enantiomers and optically active amides is demonstrated. The subject of lipase involvement in the C-C bond formation in the Michael reaction is discussed. Data on the enzymatic synthesis of construction materials- polyesters, siloxanes, etc.--are presented. Examples demonstrating the application of lipase enzymatic catalysis in industry are given. PMID- 25707113 TI - [Compartmentation of salicylate-induced proteins]. AB - A key factor of immunity, salicylic acid (exogenous or accumulating under the action of biotrophic or semibiotrophic pathogens on plants), causes the formation of not only protective antipathogenic proteins but also many proteins, which enhance the resistance of host plant cells. Salicylate-induced proteins, which are encoded by nuclear genes and formed with cytoplasmic ribosomes, function in the cytosol or are transported into nuclei, vacuoles, plastids, mitochondria, and outside the plasmalemma. This review is focused on salicylate-induced proteins, which are not only delivered into different compartments but are also involved in their transmembrane transport. PMID- 25707114 TI - [Biological effect of extracellular peptide factor from Lateococcus japonicas subsp. casei on probiotic bacteria]. AB - The biological effect of the extracellular peptide reactivating factor (RF) from Luteococcus casei on cells of probiotic cultures was studied. The RF showed the protective and reactivating effects on the Bifidobacterium bifidum cells under the action of bile salts and an acidic stress. Also, it acted as a cryoprotector during lyophilisation and long-term culture storage. The RF and the L. casei culture liquid (CL) were shown to have bifidogenic properties. The degree of protection and reactivation of lactic-acid bacteria under the action of bile salts depended on the particular strain properties. The maximum degree of protection (more than thirteen-fold) and reactivation (close to three-fold) was found in Lactobacillus casei, while the minimum values were characteristic of Lactobacillus reuterii. The resistance of lactobacilli to bile was increased in the row of L. acidophilus, L. casei, L. plantarum, L. rhamnosus, and L. reuterii correlating with the RF protection degree. PMID- 25707115 TI - [The effects of alkylhydroxybenzenes on homoserine lactone-induced manifestations of quorum sensing in bacteria]. AB - The effects of four alkylhydroxybenzene (AHB) homologs of different hydrocarbon chain lengths on synthesis of the pigment violacein induced by C6-homoserine lactone (HSL) and biofilm formation by Chromobacterium violaceum NCTC 13274 and on Escherichia coli pAL103 bioluminescence in the presence of C6-oxo-HSL were studied. It was shown that the inhibitory effect of alkylhydroxybenzenes on the growth of C. violaceum increased in the C5-AHB --> C12-AHB series in the absence of this activity in C1-AHB. Sub-inhibitory AHB concentrations reduced violacein production and suppressed biofilm formation. These effects were presented as individual and group regression dependencies between the analyzed parameters. It was shown using the bioluminescent model that the regulatory effects of AHBs are not associated with their direct competition with HSL and that they develop as a result of changes in the sensitivity of bacterial cells to the respective quorum sensing inducer. PMID- 25707116 TI - [An effective scheme to produce recombinant uracil-DNA glycosylase of Escherichia coli for PCR diagnostics]. AB - An effective scheme has been developed to produce recombinant uracil-DNA glycosylase of Escherichia coli K12 intended to be used for PCR diagnostics, making it possible to achieve a high yield of the end product using a two-stage purification. The gene encoding this enzyme was cloned into the pCWori vector within the same reading frame with six residues of histidine in the C-erminal sequence. Using this vector and the E. coli DH5alpha, a host-vector expression system has been developed and conditions for protein synthesis have been optimized. To purify the protein, metal affinity chromatography with further dialysis was used to remove imidazole. The enzyme yield was no less than 60 mg of the end protein per 1 L of the culture medium. The concordance between amino acid sequences of the recombinant and native enzymes was proved by peptide mass fingerprinting and mass spectrometry. A rapid test to determine the activity of the enzyme preparation was suggested. It was found that the activity of 1.0 mg of the recombinant protein is no less than 3 x 10(3) units. The recombinant enzyme was most stable at pH 8.0 and an ionic strength of the solution equal to 200 mM; it lost its activity completely for 10 min at 60 degrees C. Storage during 1 h at 20 degrees C resulted in the loss of no more than 30% of activity. In the enzyme preparation, the activity of DNase was absent. The free energy of the unfolding of the protein globule of the recombinant uracil-DNA glycosylase is 23.1 +/- 0.2 kJ/mol. The data obtained indicate that the recombinant enzyme may be recommended for use in PCR diagnostics to prevent the appearance of false positive results caused by pollution of the reaction mixture by products of the preceding reactions. PMID- 25707117 TI - [The process of bacterial population splitting into dissociants and long-term batch cultivation of bacteria]. AB - The growth and composition of a population were studied during long-term (up to 50 days) batch cultivation of mono and mixed cultures of Pseudomonas aeruginosa S and M-dissociants and Rhodobacter sphaeroides R- and M-dissociants without the addition of nutrients. During the cultivation of P. aeruginosa on a glucose containing mineral medium, periodic lysis followed by polyculture growth resumption in the late stationary phase occurred on account of the M-dissociant: the change in its cell number corresponded to the change in the total cell number of the association. It was shown that the periodic occurrence of reducing sugars in the medium preceded the resumption ofpolyculture growth. PMID- 25707118 TI - [Analysis of functionalized arene degradation pathways in model water-organic media]. AB - The degradation of functionalized arenes exposed to a mixed culture of chemoorganoaeroheterotrophic microorganisms has been shown to predominantly occur through oxidative intradiol decyclization of the aromatic ring. The spatial structure of the catalytic center of intradiol dioxygenase and its complexes with catechol and protocatechuic acid has been characterized using quantum chemical modeling procedures. The dependence of the total energy of the enzyme-substrate complex on the length of the bond between the iron atom and the hydroxyl group of the substrate (Fe-4-OH and Fe-1-OH) before and after the separation of water and a tyrosine residue (Tyr) from the catalytic center has been demonstrated for the first time. PMID- 25707120 TI - [Synthesis of recombinant gamma interferons resistant to proteolysis in the yeast Pichia pastoris]. AB - Genes encoding truncated versions of bovine and chicken gamma interferon genes lacking predicted protease cleavage sites at the C-terminus were constructed and expressed in the yeast Pichia Pastoris. The recombinant proteins possessed increased stability in comparison with the corresponding wild-type gamma interferons while retaining biological activity. The recombinant strains provide a useful tool for the purification of bovine and chicken gamma interferons for their use in veterinary applications. PMID- 25707119 TI - [Hydrolysis of chitozan with an enzyme complex from Myceliophthora sp]. AB - Samples of low-molecular weight chitosan with molecular masses of 8-24 kDa, identical deacetylation degrees (85%), and polydispersity indexes soluble at pH 5 7 were obtained by enzymatic hydrolysis using an enzyme complex from the micelial fungi Myceliophthora fergusii with yields of 50-80%. The optimal conditions for hydrolysis were found (pH 5.6, 37 degrees C, an enzyme/substrate ratio 1/800, 15 60 min). The obtainment of chitosan sample sets with different characteristics will enable the selection of the most efficient ones for comparison in in vitro/in vivo experiments. PMID- 25707121 TI - [Biochemical processes at the stage of withering during black tea production]. AB - We determined the molecular weight and some properties of multiple forms of phenol oxidase from tea leaves and four other perennial plants. It was shown that multiple high- and low-molecular forms of phenol oxidase differed in substrate specificity. Low-molecular forms of the enzyme mostly demonstrated hydroxylase activity, while high-molecular forms showed catechol oxidase activity. It was revealed that the withering stage of black tea production is accompanied by the formation of only high-molecular forms of phenol oxidase, which possess catechol oxidase activity crucial for the procurement of oxidative reactions and the quality of the product. PMID- 25707122 TI - [Studies on the structure of the bioregulator purified from the rat brain]. AB - From the brain tissue of Wistar rats,we purified a bioregulator, which is active at ultralow doses. Using reversed-phase HPLC, we prepared a homogenous polypeptide with a molecular weight of 4749 +/- 2 Da, which is responsible for the biological activity of the bioregulator. Using the CD spectroscopy method, we calculated the percentage of canonical elements of the secondary polypeptide structure in a solution. Using the methods of proteomics, we revealed that the structure of the investigated polypeptide was similar to the N-terminal sequence of a fragment of guanine-nucleotide binding G0-protein subunit alpha-1. PMID- 25707123 TI - Black yeast in dental unit waterlines. II. Remediation project report. PMID- 25707124 TI - Software tools of the Computis European project to process mass spectrometry images. AB - Among the needs usually expressed by teams using mass spectrometry imaging, one that often arises is that for user-friendly software able to manage huge data volumes quickly and to provide efficient assistance for the interpretation of data. To answer this need, the Computis European project developed several complementary software tools to process mass spectrometry imaging data. Data Cube Explorer provides a simple spatial and spectral exploration for matrix-assisted laser desorption/ionisation-time of flight (MALDI-ToF) and time of flight secondary-ion mass spectrometry (ToF-SIMS) data. SpectViewer offers visualisation functions, assistance to the interpretation of data, classification functionalities, peak list extraction to interrogate biological database and image overlay, and it can process data issued from MALDI-ToF, ToF-SIMS and desorption electrospray ionisation (DESI) equipment. EasyReg2D is able to register two images, in American Standard Code for Information Interchange (ASCII) format, issued from different technologies. The collaboration between the teams was hampered by the multiplicity of equipment and data formats, so the project also developed a common data format (imzML) to facilitate the exchange of experimental data and their interpretation by the different software tools. The BioMap platform for visualisation and exploration of MALDI-ToF and DESI images was adapted to parse imzML files, enabling its access to all project partners and, more globally, to a larger community of users. Considering the huge advantages brought by the imzML standard format, a specific editor (vBrowser) for imzML files and converters from proprietary formats to imzML were developed to enable the use of the imzML format by a broad scientific community. This initiative paves the way toward the development of a large panel of software tools able to process mass spectrometry imaging datasets in the future. PMID- 25707125 TI - Electron-impact ionization cross-sections of silane. AB - We have made a study of the total ionization cross-sections of a silane (SiH4) molecule caused by electron impact for a single ionization. Electron-impact ionization cross-sections (EIICS) have been calculated from threshold ionization energy to 1400 eV. The theoretical model, developed by Jain and Khare, has been used to calculate the EIICS for silane. We observed the following product ions: SiH3(+), SiH2(+), SiH(+), Si(+), H2(+) and H(+). The predicted EIICS of silane for all six fragment ions are compared with other theoretical and experimental data. The present model shows a good agreement with the previously reported data. PMID- 25707126 TI - High repetition rate atmospheric pressure matrix-assisted laser desorption/ionization in combination with liquid matrices. AB - One major drawback of matrix-assisted laser desorption/ionization (MALDI) is still the relatively poor pulse-to-pulse reproducibility of the signal intensity. This problem, caused by insufficient homogeneity in the matrix/analyte co crystallization, is usually circumvented by averaging the detected ion intensity over several shots. However, during the consecutive laser pulses, the applied matrix gets depleted and only a number of subsequent experiments can be done on the same sample spot. In order to achieve the desired long-term stability in combination with a sufficient pulse-to-pulse reproducibility, recently liquid MALDI matrices have been introduced. This contribution demonstrates the promising combination of liquid matrices with high repetition rate lasers for atmospheric pressure MALDI (AP-MALDI). To demonstrate the robustness of the new approach, two different kinds of liquid matrices were used in combination with both a typical flashlamp pumped 15 Hz laser and a diode pumped solid state laser operated at 5 kHz. The latter showed a stable ion signal over more than 3,500,000 consecutive laser pulses. PMID- 25707127 TI - High performance liquid chromatography-tandem mass spectrometry method for ex vivo metabolic studies of a rhenium-labeled radiopharmaceutical for liver cancer. AB - The radio-isotope rhenium-labeled N-[2-(triphenylmethyl)thioethyl]-3-aza-19 ethyloxycarbonyl-3-[2-(triphenylmethyl)thioethyl] octadecanoate) ligand (188Re-MN 16ET) is a novel therapeutic agent under preclinical evaluation for hepatoma. A reversed-phase high performance liquid chromatography coupled with a tandem mass spectrometric analysis method and diode array detector (DAD) involving a T type splitter was developed to characterize this pharmaceutical in rat liver tissue solution and determine its biotransformation rate. The separation was accomplished on a C18 column (chromolith silica, 4.6 mm x 100 mm) using an acetonitrile-ammonium acetate buffer gradient as the mobile phase. The detection was achieved by DAD set at 250nm and tandem mass spectrometry using electrospray ionization in the positive ion mode. Re-MN-16ET displayed a retention time of 23.2 min and a transition ion pair corresponding to m/z677 --> 631 for multiple reaction monitoring. Its biotransformation reaction in rat liver homogenate proceeded for 90 min in a 37 degrees C water bath. The characterization was conducted using aliquots that were extracted and concentrated from the reaction mixture for various incubation times. Re-MN-16ET exhibited a biotransformation half-life (t1/2) of 8-9 min in liver tissue solution and was almost completely exhausted after 90 min. Two of its metabolites, consisting of the Re-labeled carboxylic acid derivative, predominately, and its corresponding demetallized disulfide ligand were found in the liver homogenate, providing a metabolism pathway for the radio-pharmaceutical. PMID- 25707128 TI - Tissue-specific metabolite profiling of Turmeric by using laser micro-dissection, ultra-high performance liquid chromatography-quadrupole time of fight-mass spectrometry and liquid chromatography-tandem mass spectrometry. AB - Curcuma longa L. is recognized for its therapeutic and culinary uses both in Ayurveda and traditional Chinese medicine and is considered to be a boon to mankind. It has been extensively studied for its benefits and still continues to be an important drug with continued potential for further exploration and research. We studied the tissue-specific distribution of secondary metabolites to establish the validity of the use of rhizome samples from India and China, as substitutes for each other, based upon their metabolite profiles and curcumin contents. Laser microdissection was used for the isolation of microscopic tissues, such as cork, cortex and leaf-trace vascular bundles from rhizomes. Metabolite profiling was carried out by ultra-high performance liquid chromatography-quadrupole time of fight-mass spectrometry and curcumin content was estimated by a method validated as per the Harmonized Tripartite Guidelines. The cortex and cork revealed the presence of a higher number of secondary metabolites than in the leaf-trace vascular bundles. The curcumin contents in rhizome samples from both the countries, estimated with the help of a precise and accurate validated method, were found to be comparable. Based on the results, we conclude that turmeric rhizomes grown in India and China are qualitatively and quantitatively indistinguishable and therefore can be used as substitutes. The developed method can be widely applied for microscopic identification, authentication and analysis of the distribution of phytoconstituents in other botanical species of interest or of species with a significant commercial and therapeutic value. PMID- 25707129 TI - A rapid and highly specific method to evaluate the presence of 2-(2-phenylethyl) chromones in agarwood by supercritical fluid chromatography-mass spectrometry. AB - The detection and structural characterization of the major constituents of agarwood, 2-(2-phenylethyl)chromones, are important to quality control and the establishment of the authenticity of agarwood samples. However, a highly specific and rapid method for the evaluation of 2-(2-phenylethy)chromones in agarwood has not been reported to date. In this study, we developed a method using super- critical fluid chromatography in combination with mass spectrometry (SFC-MS). Tropylium ions, the characteristic product ions of 2-(2-phenylethyl)chromones in tandem mass spectrometric experiments, were selected for the targeted detection of 2-(2-phenylethyl) chromones. This method used precursor ion scans for tropylium ions with different possible substitutions on a triple-quadrupole mass spectrometer. To evaluate the usefulness of the developed method, a diethyl ether extract from a Chinese agarwood "Qi-Nan" sample was first separated using SFC, and the elutes were later subjected to precursor ion scans, which searched for 15 common substituted tropylium ions to evaluate the 2-(2-phenylethyl)chromones. In the precursor ion scans, a total of 29 2-(2-phenylethyl)chromones were detected and investigated further using tandem mass spectrometry (MS/MS) to obtain more detailed structural information. By comparing the retention times and m/z values of the precursor ions with reference standards, nine of the detected compounds were unequivocally identified. The remaining compounds were tentatively identified by analyzing the MS/MS spectra. This method provides a rapid and efficient method for evaluating the 2-(2-phenylethyl)chromones present in a sample, which aids in quality control and the establishment of the authenticity of the agarwood sample. PMID- 25707130 TI - Determination of ionization energies of a monoterpene series by atmospheric pressure photoionization using tunable vacuum ultraviolet synchrotron radiation. AB - Monoterpenes are the main class of biogenic volatile organic compounds. They promptly react with oxygen and nitrogen species, leading to the formation of secondary aerosols. The determination of their physicochemical properties, such as their ionization energies (IEs), is crucial to understand better their reactivity. We previously introduced a modified atmospheric pressure photoionization source coupled to a tunable vacuum ultraviolet source at the SOLEIL synchrotron radiation facility. Here, this set-up is employed to determine IEs of ten monoterpenes with a good precision (+/-50 meV) and a small sample consumption limited to 10 MUg. PMID- 25707131 TI - Thermal decomposition of methyltrichlorosilane, dimethyldichlorosilane and methyldichlorosilane by flash pyrolysis vacuum ultraviolet photoionization time of-flight mass spectrometry. AB - The thermal decompositions of methyltrichlorosilane (MTS) (CH3SiCl3), dimethyldichlorosilane (Si(CH3)2Cl2), and methyldichlorosilane (SiHCH3Cl2) were studied at temperatures from -1000 K to 1500 K on a short timescale of 20 MUs to 100 MUs using flash pyrolysis vacuum ultraviolet single-photon ionization time-of flight mass spectrometry. The pyrolysis of MTS proceeds primarily via Si-C bond homolysis to form the SiCl3 and methyl radicals. At elevated temperatures, SiCl2 production from secondary decomposition of SiCl3 becomes more important, and other pyrolysis pathways of MTS, including C-H bond fission and HCl elimination make minor contributions. The pyrolysis of Si(CH3)2Cl2 occurs mainly by the sequential loss of methyl radicals, ultimately forming a significant amount of SiCl2. Si(CH3)2Cl2 also has two minor decomposition channels at higher temperatures, molecular elimination of CH4 to form SiCH2Cl2 and of CH3Cl to form SiCH3Cl. The pyrolysis of SiHCH3Cl2 mainly undergoes sequential CH3 and H loss and/or molecular elimination of CH4 to form SiCl2, while molecular elimination of HCl to form SiCH3Cl also contributes. SiCl2 is produced in significant concentrations in the pyrolysis of all three molecules, suggesting that it is an important intermediate in SiC chemical vapor deposition from chloroorganosilanes. PMID- 25707132 TI - [Adequate attention is required to the diagnosis and treatment of mild-symptom erectile dysfunction]. AB - Mild-symptom erectile dysfunction (MSED) is commonly seen in clinical practice, but receives inadequate attention from both the patients and clinicians. Increasing researches have indicated that MSED is associated with not only unhealthy living habits and psychological factors but also the early progression of endothelial, metabolic and endocrine diseases. The diagnosis and treatment of MSED should be based on the relevant guidelines, with consideration of both its specific and common features. The therapeutic principle is a combination of integrated and individual solutions aimed at the causes of the disease. Drug intervention should be initiated if psychological therapy fails. Negligence of MSED may affect the quality of life of the patients and their partners, and what's more, might delay the management of some other severe underlying diseases. Adequate attention to the early diagnosis and treatment for MSED is of great significance for a deeper insight into the etiology of ED, the prevention of potential cardiovascular and metabolic diseases, and the improvement of the overall health of males. PMID- 25707133 TI - [Human umbilical cord mesenchymal stem cells may differentiate into Leydig cells through conditioned medium induction]. AB - OBJECTIVE: To explore the feasibility of inducing human umbilical cord mesenchymal stem cells (HuMSCs) to differentiate into Leydig cells through conditioned medium derived from Leydig cells. METHODS: HuMSCs and Leydig cells were obtained by tissue blocks culture attachment and enzymatic digestion respectively. HuMSCs were induced by conditioned medium of Leydig cells as an experiment group while those before induction were cultured as a control group. The expressions of LHR, 3beta-HSD and StAR in the induced HuMSCs were determined by RT-PCR after 3, 7 and 10 days of culture; those of CYP11A1, CYP17A1 and 3beta HSD measured by immunofluorescence staining after 2 weeks; and that of 3beta-HSD detected by Western blot after 4 weeks. RESULTS: The experimental group showed positively expressed LHR, 3beta-HSD and StAR at 3, 7 and 10 days, CYP11A1, CYP17A1 and 3beta-HSD at 2 weeks, and 3beta-HSD at 4 weeks, while the control group revealed negative expressions at all the time points. CONCLUSION: Induced with conditioned culture medium derived from Leydig cells, HuMSCs are likely to differentiate into steroidogenic cells and eventually into Leydig cells. PMID- 25707134 TI - [Inhibitory effect of dutasteride on the expressions of epididymal Claudin1 and beta-catenin in male rats]. AB - OBJECTIVE: To explore the molecular mechanism of dutasteride inhibiting fertility by studying its effects on the expressions of the epididymal epithelial junction proteins Claudin1 and beta-catenin in rats. METHODS: Sixteen 3-month-old SD male rats were equally divided into an experimental and a negative control group to be treated intragastrically with dutasteride at 40 mg/kg per day and the same dose of solvent, respectively, for 14 consecutive days. Then, the sperm motility and morphology of the rats were detected by computer-assisted sperm analysis, the serum levels of testosterone (T) and dihydrotestosterone (DHT) measured by ELISA, changes in the tight junction of epididymal cells observed under the transmission electron microscope, the protein and gene expressions of Claudin1 and beta catenin determined by RT-PCR and immunohistochemistry, and the conception rate of the mated female rats calculated. RESULTS: Dutasteride significantly suppressed the serum DHT level, sperm motility, and fertility of the rats (P <0.05). Interspaces between epididymal epithelial cell tight junctions were observed, the volume of epididymal fluid obviously increased, and the expressions of Claudin1 and beta-catenin gene and protein remarkably downregulated in the experimental rats (P <0.05). CONCLUSION: Dutasteride can significantly inhibit the fertility of male rats by reducing the serum DHT level, suppressing Claudin1 and beta catenin expressions, and damaging epididymal epithelial cell junctions. PMID- 25707135 TI - [Expressions of transient receptor potential A1 and related inflammatory factors in the rat model of prostatic inflammation]. AB - OBJECTIVE: To explore the molecular mechanism of pain associated with chronic prostatitis and chronic pelvic pain syndrome (CP/CPPS) in the rat model of prostatic inflammation. METHODS: Thirty-six male SD rats were equally randomized to an experimental and a control group, the former injected with 50 MUl of 3% lambda-carrageenan into the ventral prostate to make the model of non-bacterial prostatic inflammation, while the latter with the same volume of sterile saline solution. At 1, 2 and 4 weeks after modeling, the prostate, L6-S1 dorsal root ganglion (DRG) and spinal cord were harvested for examination of the expressions of the nerve growth factor (NGF), transient receptor potential ankyrin 1 (TRPA1), and calcitonin-gene-related peptide (CGRP) by immunohistochemistry and Western blot. RESULTS: The expressions of NGF, TRPA1 and CGRP in the prostatic tissue were all significantly increased in the experimental group as compared with the control (P <0.05), with a gradual decrease with the prolonging of time (P <0.05). In the L6-S1 DRG and spinal cord, the expressions of NGF, TRPA1 and CGRP exhibited no significant differences between the experimental and control groups at 1 week after modeling (P >0.05) and kept at high levels in the experimental group at 2 and 4 weeks, though not significantly different from those at 1 week (P >0.05). Statistically significant differences were observed in the expressions of the three proteins in the experimental rats among different time points (P <0.05), but not between the two groups at any time point (P >0.05). CONCLUSION: The molecular mechanism of CP/CPPS can be evaluated in the rat model of prostatic inflammation established by injecting lambda-carrageenan into the prostate. TRPA1 may play an important role in connecting the upstream and down-stream pathways of CP/CPPS-associated pain. PMID- 25707136 TI - [Correlation of autophagy-associated gene Atg5 with tumorigenesis of prostate cancer]. AB - OBJECTIVE: To investigate the correlation of the autophagy-associated gene Atg5 with the pathogenesis of prostate cancer. METHODS: Using real-time fluorescent quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and immunohistochemistry, we detected the expression of Atg5 in 50 cases of prostate intraepithelial neoplasm (PIN), 69 cases of prostate cancer (PCa), and 30 cases of benign prostatic hyperplasia (BPH). RESULTS: The expression level of Atg5 mRNA was significantly higher in PIN (5.270 +/- 0.230) and PCa (5.131 +/- 0.252) than in the BPH tissue (1.723 +/- 0.017) (P <0.01), and so was the positive rate of the Atg5 expression in the patients of the PIN group (94%) and PCa group (88.4%) than in those of the BPH group (6.7%) (P<0.01), but with no statistically significant differences between the PIN and PCa groups (P >0.05). No significant correlation was observed between the expression of Atg5 and the Gleason score of PCa (P >0.05). CONCLUSION: The upregulated expression of Atg5 might play a role in the tumorigenesis of prostate cancer. PMID- 25707137 TI - [[Urodynamic tests contribute to the choice of therapies for type-III B prostatitis]. AB - OBJECTIVE: To analyze the parameters of urodynamic tests for patients with type III B prostatitis and evaluate the significance of the results of urodynamic tests in the choice of therapies for this disease. METHODS: Urodynamic tests were performed for 87 type-III B prostatitis patients aged 22-45 (30.7 +/- 8.5) years, who had moderate or severe lower urinary tract symptoms (LUTS) and failed to respond to routine therapy. Different treatments were administered according to the results of urodynamic tests followed by observation of the therapeutic effects. RESULTS: Urodynamic abnormalities were found in 70 of the 87 patients, bladder outlet obstruction in 28 (32.2%), detrusor overactivity in 25 (28.7%), bladder hyperesthesia in 18 (20.7%), low compliance in 10 (11.5%), detrusor external urethral sphincter dyssynergia in 1 (1.1%), and impaired detrusor contractile function in 1 (1.1%). Treatments achieved obvious effectiveness in 26 cases (29.9%), effectiveness in 51 (58.6%), and no effectiveness in 10 (11.5%). CONCLUSION: Urodynamic tests contribute significantly to the choice of therapies for type-III B prostatitis patients with moderate or severe LUTS. PMID- 25707138 TI - [Impact of autosomal dominant polycystic kidney disease on the outcomes of intracytoplasmic sperm injection in infertile males]. AB - OBJECTIVE: To summarize the features and treatment of male infertility induced by autosomal dominant polycystic kidney disease (ADPKD), and compare the outcomes of intracytoplasmic sperm injection (ICSI) for infertile men with ADPKD and those with congenital bilateral absence of vas deferens (CBAVD). METHODS: We retrospectively analyzed 21 cases of ADPKD-induced infertility, 15 treated by ICSI (group A), and another 164 cases of strictly matched CBAVD-induced infertility (group B). We compared the two groups in the couples' age, the number of ICSI oocytes, and the rates of fertilization, transferrable embryos, good embryos, embryos implanted, clinical pregnancy, biochemical pregnancy, early abortion, singleton and twins in the first cycle. RESULTS: After 28 cycles of ICSI, 10 of the 15 ADPKD-induced infertility patients achieved clinical pregnancy, including 7 cases of live birth, 1 case of spontaneous abortion, and 2 cases of pregnancy maintenance. No significant differences were observed between groups A and B in the couples' age, the wives' BMI, or the numbers of ICSI oocytes and embryos transplanted (P >0.05), nor in the rates of ICSI fertilization (72.64% vs 76.17%), transferrable embryos (51.28% vs 63.24%), quality embryos (38.46% vs 49.83%), embryo implantation (17.64% vs 38.50%), abortion (0 vs 9.23%), singleton (50% vs 81.54%) and twins (50% vs 18.46%). However, the rates of clinical pregnancy (13.33% vs 42.68%, P = 0.023 <0.05) and biochemical pregnancy (13.33% vs 39.63%, P = 0.032 <0.05) were significantly lower in group A than in B. CONCLUSION: ICSI is effective in the treatment of male infertility induced by either ADPKD or CBAVD, but the ADPKD cases have a lower success rate than the CBAVD cases in an individual cycle. The affected couples should be informed of the necessity of prenatal genetic diagnosis before embryo implantation and the inevitable vertical transmission of genetic problems to the offspring. PMID- 25707139 TI - [Analysis of the quality of cryopreserved semen from male cancer patients]. AB - OBJECTIVE: To investigate the semen quality of cancer patients and search for a better way of sperm cryopreservation for them. METHODS: We retrospectively analyzed the quality of the semen from 43 cancer patients under cryopreservation in the Sperm Bank of Zhejiang Province, and compared the semen parameters between the cancer patients and 248 normal donors as well as between the testicular cancer cases (n=22) and non-testicular cancer cases (n=21). RESULTS: The cancer patients exhibited significantly lower semen quality than the normal donors as in sperm concentration (60.90 x 10(6)/ml vs 74.27 x 10(6)/ml), progressive motility (41.07% vs 51.79%), and recovery rate (49.98% vs 57.33%) (all P <0.05). Furthermore, the progressive sperm motility and sperm recovery rate after freezing were significantly decreased in the testicular cancer cases (15.68% and 42.81%) than in the non-testicular cancer cases (28.36% and 57.53%) (both P <0.05). CONCLUSION: Semen quality declines in cancer patients, and therefore early sperm cryopreservation is essential for them. Due to the poor sperm motility and recovery rate of testicular cancer patients after freezing, further investigation is required on the improvement of sperm cryopreservation methods. PMID- 25707140 TI - [Oxidative stress and semen parameters in the serum and seminal plasma of infertile men with chronic viral hepatitis]. AB - OBJECTIVE: To investigate the malondialdehyde (MDA) level and paraoxonase-1 (PON 1) activity in the serum and seminal plasma of infertile men with chronic viral hepatitis and their influence on the semen parameters of the patients. METHODS: We collected serum and semen samples from 42 infertile men, 45 infertile males with chronic viral hepatitis, and 50 healthy fertile men as controls. We measured the MDA level in the serum and seminal plasma by spectrophotometry, detected the PON-1 activity by spectrophotometry, and determined the sperm DNA fragmentation index (DFI) by acridine orange fluorescence staining. RESULTS: The MDA level was significantly higher but the PON-1 activity remarkably lower in the serum and seminal plasma of the infertile males with chronic viral hepatitis than in the healthy controls and infertile patients (P <0.01 or P <0.05). Total sperm motility and sperm survival rate were significantly lower while the sperm DFI markedly higher in the former than in the latter two groups (P <0.01 or P <0.05). No statistically significant difference was found among the three groups in sperm concentration (P >0.05). The WBC counts in the semen of the infertile and infertile with chronic viral hepatitis groups were significantly higher than that in the health controls (P <0.05). The MDA level and PON-1 activity in the seminal plasma were positively correlated with those in the serum in the infertile males with chronic viral hepatitis (r=0.57 or 0.48, P <0.01). CONCLUSION: Virus-induced chronic active hepatitis enhances oxidative stress in the reproductive system, aggravates sperm damage, and affects sperm quality parameters. PMID- 25707141 TI - [Establishment of a scoring system for predicting the positive rate of prostatic biopsy for prostate cancer]. AB - OBJECTIVE: To identify the predictors of the positive results of transrectal ultrasound (TRUS)-guided biopsy for prostate cancer. METHODS: We performed univariate and multivariate logistic regression analyses on the relevant data on 385 male patients that underwent TRUS-guided biopsy for prostate cancer, including such potential predictors as age, body mass index (BMI), symptoms, results of digital rectal examination (DRE), tPSA, fPSA, free/total PSA ratio (f/tPSA), prostate volume (PV), and PSA density (PSAD) for identification of the risk factors related to the positive rate of biopsy. Then we constructed a scoring system as a tool for predicting prostate cancer in repeat biopsies and determined the sensitivity of the system by calculating the false positive rate using the receiver operating characteristic curve. RESULTS: Among the 385 patients, 139 (36.1%) were diagnosed with prostate cancer. On multivariate analysis, age (P < 0.01), DRE (P < 0.01), tPSA (P < 0.01), fPSA (P < 0.01), f/tPSA (P < 0.01), PV (P < 0.01), and PSAD (P < 0.01) were all significant predictors of prostate cancer. Multivariate logistic regression analysis showed age, tPSA, f/tPSA, PV, and PSAD to be independent predictors, with ORs and 95% CIs of 1.07 (1.05-1.16), 1.05 (1.02-1.15), 0.97 (0.86-0.99), 0.98 (0.87-0.96), and 1.79 (1.48-2.06), respectively. Moreover, patients with the risk score of 3-5 had a significantly higher rate of prostate cancer than those with 0-2 (64% vs 11%, P < 0.001). CONCLUSION: The scoring system on the key predictors of prostate cancer can help urologists to identify the men in need of prostatic biopsy. PMID- 25707142 TI - [Incidence of depression and its related factors in cryptorchidism patients after surgical treatment]. AB - OBJECTIVE: To investigate the incidence of depression and its etiological factors in patients with cryptorchidism 6-16 years after surgical treatment. METHODS: Using Self-Rating Depression Scale and Correlation Factor Questionnaire, we investigated the incidence of depression symptoms among 70 patients with cryptorchidism 6-16 years after surgical treatment and another 70 healthy males as controls, and analyzed the related factors of depression symptoms. RESULTS: The incidence rate of depression symptoms was 50% in the cryptorchidism patients postoperatively, extremely significantly higher than 4.3% in the control group (chi2 = 23.5, P <0.01). Multiple stepwise regression analysis showed that the main risk factors of depression symptoms were worries about natural fertility (F = 15.8992, P <0.01), dissatisfaction with scrotal appearance (F = 4.6003, P <0.05), and the status of being married (F = 4.1002, P <0.05). CONCLUSION: Symptoms of depression often occur in cryptorchidism patients after operation, and the major etiological factors are infertility, dissatisfaction with scrotal appearance, and the status of being married. PMID- 25707143 TI - [Bushen Huoxue Decoction improves erectile function of patients with coronary heart disease after percutaneous coronary intervention]. AB - OBJECTIVE: To observe the effectiveness of Bushen Huoxue Decoction in improving the erectile function of male patients with coronary heart disease (CHD) after percutaneous coronary intervention (PCI) with stent implantation. METHODS: Eighty male CHD patients after PCI with stent implantation were equally assigned to receive conventional Western medicine (control group) and combination of Western medicine with Bushen Huoxue Decoction (treatment group), both for 3 months. Then we compared the pre- and post-medication IIEF-5 scores between the two groups of patients. RESULTS: Compared with pre-medication, the total IIEF-5 score was significantly increased after 3 months both in the treatment group (8.19 +/- 2.87 vs 17.83 +/- 4.92, P <0.05) and in the control (7.98 +/- 2.96 vs 12.18 +/- 3.69, P <0.05), even higher in the former than in the latter group (P <0.05), and so were the scores on the 5 specific items (all P <0.05). The total effectiveness rate was 72.5% in the treatment group, significantly higher than 47.5% in the control (P <0.05). No obvious adverse reactions and events were observed during the treatment in either of the groups. CONCLUSION: Bushen Huoxue Decoction can obviously improve the erectile function and the quality of the sexual life of CHD patients after PCI with stent implantation. PMID- 25707144 TI - [Effect and safety of L-carnitine in the treatment of idiopathic oligoasthenozoospermia: a systemic review]. AB - OBJECTIVE: To evaluate the effect and safety of L-carnitine in the treatment of idiopathic oligoasthenozoospermia based on current clinical evidence. METHODS: We searched the Cochrane Library, PubMed, MEDLINE, EMBASE, CNKI, VIP, CBM and Wanfang Database from the establishment to April 2014 for the published literature on the treatment of idiopathic oligoasthenozoospermia with L carnitine. We conducted literature screening, data extraction, and assessment of the methodological quality of the included trials according to the inclusion and exclusion criteria, followed by statistical analysis with the RevMan 5. 2 software. RESULTS: Seven randomized controlled trials involving 751 patients with idiopathic oligoasthenozoospermia met the inclusion criteria, and 678 of them were included in the meta-analysis. L-carnitine treatment achieved a significantly increased rate of spontaneous pregnancy as compared with the control group (RR = 3.2, 95% CI 1.74 to 5.87, P = 0.0002). After 12-16 and 24-26 weeks of medication, total sperm motility (WMD = 5.21, 95% CI 2.78 to 7.64, P < 0.0001 and WMD = 9.29, 95% CI 1.28 to 17.29, P = 0.02) and the percentage of progressively motile sperm (WMD = 12.44, 95% CI 4.58 to 20.31, P = 0.002 and WMD = 9.76, 95% CI 3.56 to 15.97, P = 0.002) were remarkably higher than those in the control group, but no statistically significant differences were observed in sperm concentration between the two groups (WMD = 4.91, 95% CI -2.63 to 12.45, P = 0.2 and WMD = 0.93, 95% CI -3.48 to 5.34, P = 0.68). After 12-16 weeks of treatment, the percentage of morphologically abnormal sperm was markedly decreased in the L-carnitine group as compared with the control (WMD = -2.48, 95% CI -4.35 to -0.61, P = 0.009), but showed no significant difference from the latter group after 24-26 weeks (WMD = -4.38, 95% CI -9.66 to 0.89, P = 0.1). No statistically significant difference was found in the semen volume between the two groups after 12-16 or 24-26 weeks of medication (WMD = -0.13, 95% CI -0.43 to 0.18, P = 0.42 and WMD = 0.28, 95% CI -0.02 to 0.58, P = 0.07). No serious L carnitine-related adverse events were reported in 4 of the randomniized controlled trials. CONCLUSION: The current evidence indicates that L-carnitine can improve spontaneous pregnancy and semen parameters in the treatment of idiopathic oligoasthenozoospermia, with no serious adverse reactions. PMID- 25707145 TI - [Serum p2PSA derivative indexes in prostate cancer: an update]. AB - Serum prostate-specific antigen (PSA) is composed of the PSA precursor protein (proPSA) in the absence of the leader peptide induced by human kallikrein 2 (hK2). There are many forms of PSA in the blood, including free PSA and bound PSA. Serum proPSA, as a free PSA, has many isoforms, among which, [-2]proPSA (p2PSA) cannot be activated by hK2 and therefore exists stably in the blood. Serum p2PSA is a homologous isomer of PSA. Serum prostate health index and % p2PSA, as the derivative indexes of p2PSA and molecular markers associated with the development and progression of prostate cancer, can reduce serum PSA test induced excessive diagnosis and treatment of the malignancy and improve the accuracy of its prediction. This review summarizes recent progress in the studies of serum p2PSA and its derivative indexes in prostate cancer. PMID- 25707146 TI - [Imaging fusion in the diagnosis of prostate cancer]. AB - Ultrasonography (US) is extensively used in the diagnosis of prostate cancer; but with its disadvantages of poor sensitivity and specificity, frequently causes underdiagnosis, and over 50% of the results of transrectal ultrasound (TRUS) guided biopsy fail to accord with those of surgical pathology. In addition to contrast-enhanced ultrasound and real-time elastography, various new ultrasonic techniques have been developed nowadays, such as prostate histoscanning, brachytherapy template-guided 3-dimensional mapping biopsy (3DMB), and MRI/US fusion. Prostate histoscanning is an ultrasound-based technology that uses computer-aided analysis to identify and characterize the foci of prostate cancer. 3DMB, involving the whole gland, has an even higher accuracy. MRI/US fusion integrates the advantages of pre-interventional MRI with those of peri interventional ultrasonography, and offers high-resolution images and convenient puncturing. Constant development of ultrasonography will continue to add to its clinical application value. PMID- 25707147 TI - Fair and reasonable provider audits. PMID- 25707148 TI - Patient's page. Dental procedure antibiotic pretreatment. PMID- 25707149 TI - Blake Henry, DDS, MSD, and Kathy Henry, DDS. PMID- 25707151 TI - Six ways you can help patients move forward with treatment. PMID- 25707150 TI - Taking one day at a time. PMID- 25707152 TI - A caring approach to collections for dental practices. PMID- 25707153 TI - Early dentistry in Victoria, Australia. AB - At the time of settlement and in the years leading up to the establishment in 1884 of the Odontological Society of Victoria, dentistry was an unregulated activity practised simultaneously by those that had received the best apprenticeship training and those that had no training what-so-ever. Under the influence of dentists such as John Iliffe however, this situation was soon to change. In 1887 the first Dental Act was passed making it a legal requirement for anyone practicing dentistry to be registered. In 1890, the Melbourne Dental Hospital opened its doors to its first patients, and in 1897, the Australian College of Dentistry, later to become a school within the University of Melbourne, began teaching a dental course. Combined, these three moments in history lead to the eradication of the unscrupulous practitioner and laid the path for the development and professionalization of dentistry in the state of Victoria. PMID- 25707154 TI - Ernest Victor Davey (1888-1957) a mechanical dentist and dentists in North Bristol at the time of the First World War. AB - Ernest Davey practised dentistry in Bristol until 1924 when his lack of a dental qualification restricted him to work as a dental technician. He appears to have served in this capacity in France during the First World War before returning to Bristol in 1919 where he spent the rest of his life. PMID- 25707155 TI - Albert Edwin William (LOMA) Miles (1912-2008) extracts from personal letters on dental matters. AB - Professor Miles (1912-2008) was a key player establishing dentistry as an academic subject. In the many letters he wrote to Helen Liversidge and me, he describes his involvement as Hon. Curator of the Odontological Museum, Editor Archives of Oral Biology, Assistant scientific editor of the BDJ. He writes about his association with Robert Maxwell and the Pergamon Press and his interests and friendships. PMID- 25707156 TI - Hardev Singh Coonar, his family and the Hansali Pain Clinic. AB - Many dentists over the years have also been philanthropists. Dr Coonar comes from a family of such people, making provision at a high level. This paper describes his founding of a pain clinic for the people of Hansali in India. PMID- 25707157 TI - A colleague remembered: William Ian Rees Davies 1942-2014. PMID- 25707158 TI - Dental records of Louis XI (1423-1483), the French king, and of his wife Charlotte de Savoie (1441-1483). PMID- 25707159 TI - Don't get caught in the lurch. PMID- 25707160 TI - History and meaning of I-STOP legislation. PMID- 25707161 TI - Introduction to electronic prescribing. It may seem overwhelming, but with understanding, conversion to e-prescribing is manageable.. PMID- 25707162 TI - E-prescribing: how Does It Work? Step-by-step description to get you started also proves the process is not as hard as it seems. . PMID- 25707163 TI - Can I call in an emergency prescription, and other questions raised by E prescribing. PMID- 25707164 TI - E-prescribing solutions. NYSDA comes to the aid of its members with discounted software program. PMID- 25707165 TI - Current concepts in Sjogren's syndrome and considerations for the dental practitioner. AB - Sjogren's syndrome (SS) is a debilitating systemic disease that may have oral complications. Patients may be prone to dental caries and often have difficulty speaking and swallowing. Therefore, it is important for dental professionals to be familiar with the diagnosis and management of SS. This review outlines the new SS diagnostic criteria and provides an overview of recent findings related to disease etiology. In addition, management of SS patients with xerostomia is discussed. PMID- 25707166 TI - Treatment of a recurrent ameloblastic fibroma. AB - Ameloblastic fibroma (AF), a slow-growing, benign tumor of odontogenic origin, represents 2% of all odontogenic tumors. Jaw expansion is among the most common symptoms, with diagnosis often made through routine radiographs. AFs have a recurrence rate of 18% to 43.5% after conservative enucleation. Long-term follow up by both the surgeon and referring dentist is recommended, since recurrence may be due to regrowth of residual tumor undergoing malignant transformation. Aggressive management is recommended for local tumor recurrence. En bloc excision with bone grafting, followed by implant reconstruction, can be curative and preservative of function. Treatment of a recurrent AF is described. PMID- 25707167 TI - Extranodal large B cell lymphoma of the anterior maxilla. Case report and review of literature. AB - In the oral cavity, lymphoproliferative disorders can manifest in various ways, often as an extranodal externalization. In the case presented here, it was a B cell lymphoma originating in the periapical bone of the anterior maxilla. X-ray revealed a periapical radiolucency associated with an intact tooth with no decay, fillings or history of trauma. The tooth tested non-vital. After root canal treatment, an apicoectomy was performed with a biopsy. The most common diagnosis would be of dental etiology. The pathology report revealed a non-Hodgkin's B cell lymphoma. Most often, this disease appears as localized dental or oral pathology. Non-specific signs and symptoms present in association with lymphoproliferative disorders include lymphadenopathy, trismus, pain, swelling, sinusitis, fever, sepsis, prosthetic instability and paresthesia. Early detection results in decreased morbidity and a better prognosis for the patient. PMID- 25707168 TI - One health. PMID- 25707169 TI - Is One Health delivering results? Introduction. AB - The One Health concept is responsible for a shift towards practices, policies and partnerships that better link the health of people, animals and our shared environments. The papers in this issue of the World Organisation for Animal Health Scientific and Technical Review illustrate a myriad of ways in which a One Health approach could advance or has already advanced human and animal well being. Independently, the authors conducted their own thematic analysis of One Health activities and found strong support for the notion that One Health has inspired a renaissance in veterinary public health, increased our basic knowledge of the mechanisms and natural history of many animal diseases, promoted systems approaches to health issues and encouraged stronger cross-sectoral collaboration. Unfortunately, many collaborations often end when funding ends and many remain distinct partnerships. One Health still suffers from a lack of strong environmental stakeholders and has mostly worked on infectious disease rather than addressing many of the pressing determinants of health that will confront us in the next century. There is no shared conception of health across veterinary, medical and environment sectors, and this is an issue that must be confronted if there are to be programmes that are truly integrated across people, animals and the environment. PMID- 25707170 TI - The benefits of incorporating the One Health concept into the organisation of Veterinary Services. AB - This article analyses the potential benefits of disseminating and implementing the One Health concept at the country level. It explores the need to improve administrative structures, organise inter-agency relationships, build the capacity of the veterinary profession and mainstream the issues of environment and climate change. It also stresses the importance of demographic analysis in disease control and prevention. This article contributes to the discussion by Veterinary Services on how to mainstream the One Health concept. PMID- 25707171 TI - One Health: a perspective from the human health sector. AB - Despite emerging consensus that the One Health concept involves multiple stakeholders, the human health sector has continued to view it from a predominantly human health security perspective. It has often ignored the concerns of other sectors, e.g. concerns that relate to trade, commerce, livelihoods and sustainable development, all of which are important contributors to societal well-being. In the absence of a culture of collaboration, clear One Health goals, conceptual clarity and operating frameworks, this disconnect between human health and One Health efforts has often impeded the translation of One Health from concept to reality, other than during emergency situations. If there are to be effective and sustainable One Health partnerships we must identify clear operating principles that allow flexible approaches to intersectoral collaborations. To convince technical experts and political leaders in the human health sector of the importance of intersectoral cooperation, and to make the necessary structural adjustments, we need examples of best practice models and trans-sectoral methods for measuring the risks, burden and costs across sectors. Informal collaborations between researchers and technical experts will play a decisive role in developing these methods and models and instilling societal well-being into the human health sector's view of One Health. PMID- 25707173 TI - Current initiatives in One Health: consolidating the One Health Global Network. AB - The Global Response to Avian Influenza has led to a longer-term One Health movement, which addresses risks, including zoonoses, at the human-animal- environment interface, and requires the development of innovative partnerships at the political, institutional and technical levels. One Health is a sustainable and rational option when the cumulative effects of health hazards on food and economic security are considered, but demands long-term financial investment. Projections of growth in the demand for livestock production and consumption in Asia and Africa also call for effective One Health responses. However, an effective response also requires validated evidence of the socio-economic value that the One Health approach can provide. Implementing the One Health approach depends on forging strong links between human and animal health services, the environment and public policy. The authors present a list of some of the national and transnational partnerships established since 2006. Political support, good governance and effective policies and networks are crucial building blocks for One Health sustainability. The Global Response to Avian Influenza was initially established under the joint leadership of the European Union, the United States and the United Nations System Influenza Coordination Office. Since then it has supported numerous initiatives, including the World Health Organization (WHO)/Food and Agriculture Organization of the United Nations (FAO)/World Organisation for Animal Health (OIE) Global Early Warning System (GLEWS). Indeed, the Global Response to Avian Influenza paved the way for an unprecedented WHO/FAO/OIE tripartite partnership, which promoted the integration of foodborne, neglected zoonotic and tropical diseases within the One Health movement and led to the tripartite High-Level Technical Meeting of 2011 in Mexico. The One Health Global Network, which began as a proposition at an Expert Consultation in Winnipeg, Canada, in 2009, is now a reality. While its Global Guidance Group takes shape, the choice of soft-governance--an approach which relies more on information and advisory guidelines than on hierarchy and legislation, and which aims to steer local organisations rather than to control them--remains challenging. Nonetheless, the emergence of One Health as a professional and academic discipline, together with the growing references to a One Health culture, also offers new opportunities. PMID- 25707172 TI - A history of One Health. AB - One Health is not a new concept. It can be demonstrated that its origins and development literally run the gamut from A to Z, that is to say, from Aristotle to Zoobiquity. Indeed, the consequences of the interaction that occurs between ecosystems, animals and people have shaped, and continue to shape, the course of human events and history. A reasoned and evidence-based assessment of the history of One Health must first be founded on an agreed definition of the term, but, given the many disciplines and sciences involved, finding such a definition is no easy task. Furthermore, there is an extensive and growing list of visionary individuals who have, over the centuries, attempted to promote awareness and advance the conceptto improve the management of the risks and consequences that arise at the interface between animal, human and ecosystem health. The One Health ideas of the 21st Century constitute a re-conceptualisation of health management in response to the accelerating environmental changes of the past 100 years, changes that are associated with the parallel exponential growth and concentration of the global human population. Consequently, the concept of One Health must recognise the constantly evolving relationship between animals and humans and the planet they share. PMID- 25707174 TI - Perspectives on One Health: a survey of national Delegates to the World Organisation for Animal Health, 2012. AB - In 2012, the World Organisation for Animal Health (OIE) surveyed all 178 national Delegates to better understand the perceptions and priorities of Veterinary Services with respect to One Health efforts and to guide future work in that area. For the purposes of this survey, the concept or practice of One Health was defined as 'the intersectoral collaborative approach to preventing, detecting, and controlling diseases among animals and humans, including the collaboration among the institutions and systems that support their prevention, detection and control'. A total of 120 OlE Delegates, representing countries from all five OIE regions, responded to the survey. Delegates identified zoonoses, rabies and influenza as high-priority disease areas and disease reporting and food safety as high-priority programme areas for One Health approaches. Veterinary Services participated in joint programmes, involving these priority disease and programme areas, with national intersectoral partners. Delegates reported barriers to implementing One Health approaches, including a lack of resources, the complexity of collaboration, inadequate capacity within their Veterinary Services, and a lack of adequate legislation, policy, guidance and political will for One Health activities. Delegates supported OIE efforts to enhance One Health activities, and requested that the OIE and partners provide technical information and advice and conduct training and capacity-building seminars for One Health. Veterinary Services cannot effectively apply One Health approaches at the national level without effective partnerships across sectors. The OlE can serve as a model for countries by continuing its commitment to these intersectoral partnerships at the international level. PMID- 25707175 TI - Stakeholders in One Health. AB - The stakeholders in One Health include the ultimate beneficiaries (i.e. animals, people and the environment) and the organisations that work to protect them (i.e. research institutes, government ministries, international organisations and professional bodies). However, identifying these stakeholders who will contribute to One Health activities and develop solutions to complex health problems can be difficult, as these problems often affect all sectors of society. In addition, evolving concepts about health and its dependence on environmental resilience necessitate the inclusion of ministries, organisations and disciplines that may not have been traditionally considered to be related to health. The multilateral organisations with greatest responsibilities in the global health arena have recognised that the best way to protect health security and promote overall global well-being is to work together across disciplinary and jurisdictional boundaries. Permanent regional networks and ad hoc networks created to tackle specific issues (both of which require donor investment) are also facilitating improved disease surveillance and collaborative approaches to synchronised interventions across country borders. These networks necessarily involve the key ministries for One Health, those of health, agriculture/livestock, and natural resources/environment. Ministries play a critical role in the formulation and implementation of policies for the promotion of health and disease control. They contribute to all stages of the One Heath process, as do universities, which engage by generating knowledge and capacity through teaching, research and extension services. Similarly, non-governmental organisations have a key role in stewardship; resource mobilisation; generation of knowledge; capacity development; intervention design; and implementation. Finally, communities, including rural and indigenous peoples, particularly those that are in close proximity to natural areas, are at the heart of the One Health concept. PMID- 25707176 TI - A review of the metrics for One Health benefits. AB - One Health as a concept has been with us for many years, yet it is only recently that it is actively being discussed as a way of mitigating risks in society. Initiatives in the use of this concept require methods to monitor the benefits gained from an holistic approach to health, yet there is an absence of adequate frameworks to measure One Health benefits. This paper explores the problem with a review of the available literature and an examination of methods used. It concludes that most published work on One Health describes how this concept is valuable without trying to estimate the size of benefit or type of value. A framework for measuring the advantages of a One Health approach is needed and, through the process of an international workshop and the development of a One Health business case, the authors are working towards its development. PMID- 25707177 TI - One Health in a world with climate change. AB - The One Health movement, as defined in this paper, has progressed from a focus on emerging infectious diseases to a broader set of challenges that include food security and food safety. These interact with climate change, a so-called 'wicked problem' that has links to all human activity. Climate change acts as a threat multiplier that interacts both directly and indirectly with variables, such as disease, food production, food security, food safety and poverty. A number of these interactions are briefly described in this paper before issues of complexity and interconnectedness between these variables are discussed. A common thread underpinning this current global challenge to civilisation is that the system is now dominated by the activities of humans--and many scientists label the current epoch the 'Anthropocene'. Specifically, humans have for the first time collectively overloaded the Earth's capacity to supply, absorb, replenish and stabilise. Many scientists now observe that the ecological and environmental foundations of civilisation appear to be at risk. This paper suggests that, for the One Health movement to address such challenges, the range and number of disciplines that need to be involved must be expanded. In particular, in addition to the insights provided by technical specialists, we need to engage disciplines with the capacity to advance political, economic and social reforms. This will not be easy, but it is argued that this is what is required from the One Health movement in a world with climate change. PMID- 25707178 TI - The potential contribution of Iivestock to food and nutrition security: the application of the One Health approach in livestock policy and practice. AB - Animal products are critical to the nutrition,food security, livelihoods and resilience of hundreds of millions of people throughout the world. Livestock accounts for 40% of worldwide income from agriculture. Demand for animal products is set to continue increasing in the next three decades, as is their market price. If not carefully managed, a worldwide increase in the production of animal derived products would increase pressure on natural resources (particularly water and land), significantly raising levels of dangerous greenhouse gas emissions and increasing the risk of people contracting zoonotic diseases. These realities are informing governments as they encourage the managed intensification of livestock production. They seek to do this in ways that take account of poorer people's contributions to the growth of rural economies. They look for ways to link together work on agricultural productivity, efficient food systems; infrastructure development; access to energy, water and affordable health care; and the sustenance of environmental services (including the mitigation of any further stimuli for changes in the global climate). Managed intensification of livestock production would also require long-term application of a One Health approach with its focus on mitigating health risks at the interfaces between animals and humans in different ecosystems. It will stimulate the joint working of multiple interests in pursuit of a common goal - ending hunger and malnutrition. The authors would like to see the One Health approach being incorporated within all nations' animal, environmental and public health policies and into the educational agendas of medical and veterinary undergraduate students. It must also be incorporated into preparedness, contingency planning, desk-top exercises and on-site simulations to get ready for the next mega disaster - no matter how improbable it might seem. PMID- 25707179 TI - The integration of biodiversity into One Health. AB - A better understanding of the links between biodiversity, health and disease presents major opportunities for policy development, and can enhance our understanding of how health-focused measures affect biodiversity, and conservation measures affect health. The breadth and complexity of these relationships, and the socio-economic drivers by which they are influenced, in the context of rapidly shifting global trends, reaffirm the need for an integrative, multidisciplinary and systemic approach to the health of people, livestock and wildlife within the ecosystem context. Loss of biodiversity, habitat fragmentation and the loss of natural environments threaten the full range of life-supporting services provided by ecosystems at all levels of biodiversity, including species, genetic and ecosystem diversity. The disruption of ecosystem services has direct and indirect implications for public health, which are likely to exacerbate existing health inequities, whether through exposure to environmental hazards or through the loss of livelihoods. One Health provides a valuable framework for the development of mutually beneficial policies and interventions at the nexus between health and biodiversity, and it is critical that One Health integrates biodiversity into its strategic agenda. PMID- 25707180 TI - Eradicating rabies at source. AB - Along with zoonotic influenza and antimicrobial resistance, rabies has been identified as a key One Health issue by the World Organisation for Animal Health (OIE), World Health Organization (WHO) and Food and Agriculture Organization of the United Nations (FAO). It provides an excellent example of a disease that has an impact on public, animal and environmental health, and therefore benefits from a One Health approach to management. Regrettably, this zoonotic disease is still neglected despite the fact that, annually, it kills as many as 70,000 people worldwide (chiefly children in Asia and Africa), millions of dogs suffer and die, and the disease threatens some populations of endangered wildlife. This is particularly unfortunate, given that effective means of prevention exist. As Her Royal Highness Princess Haya of Jordan pointed out in a video to mark World Rabies Day on 28 September 2013, rabies is a serious world public health problem that is all too often underestimated and even neglected. Yet we know it can be eliminated. By combatting rabies at its source in animals and vaccinating 70% of dogs, we can eradicate it. PMID- 25707181 TI - The quest for a true One Health perspective of brucellosis. AB - One Health is an interdisciplinary collaboration that aims at mitigating risks to human health arising from microorganisms present in non-human animal species, which have the potential to be transmitted and cause disease in humans. Different degrees of scientific collaboration and sectoral integration are needed for different types of zoonotic diseases, depending on the health and associated economic gains that can be expected from a One Health approach. Indeed, mitigating zoonotic risks related to emerging diseases with pandemic potential is different from mitigating risks related to endemic zoonotic diseases like brucellosis. Likewise, management of brucellosis at the wildlife-livestock interface in wildlife conservation areas is in essence different from mitigating transmission of a given Brucella species within its preferential host species, which in turn is different from mitigating the spillover of a given Brucella species to non-preferential host species, humans included. Brucellosis economic models often oversimplify and/or wrongly assess transmission between reservoir hosts and spillover hosts. Moreover,they may not properly value non-market outcomes, such as avoidance of human disease, consumer confidence and conservation biology issues. As a result, uncertainty is such that the economic predictions of these models can be questionable. Therefore, understanding the infection biology of Brucella species is a prerequisite. This paper reviews and highlights important features of the infection biology of Brucella species and the changing epidemiology of brucellosis that need to be integrated into a true One Health perspective of brucellosis. PMID- 25707182 TI - Animal and human influenzas. AB - Influenza type A viruses affect humans and other animals and cause significant morbidity, mortality and economic impact. Influenza A viruses are well adapted to cross species barriers and evade host immunity. Viruses that cause no clinical signs in wild aquatic birds may adapt in domestic poultry to become highly pathogenic avian influenza viruses which decimate poultry flocks. Viruses that cause asymptomatic infection in poultry (e.g. the recently emerged A/H7N9 virus) may cause severe zoonotic disease and pose a major pandemic threat. Pandemic influenza arises at unpredictable intervals from animal viruses and, in its global spread, outpaces current technologies for making vaccines against such novel viruses. Confronting the threat of influenza in humans and other animals is an excellent example of a task that requires a One Health approach. Changes in travel, trade in livestock and pets, changes in animal husbandry practices, wet markets and complex marketing chains all contribute to an increased risk of the emergence of novel influenza viruses with the ability to cross species barriers, leading to epizootics or pandemics. Coordinated surveillance at the animal- human interface for pandemic preparedness, risk assessment, risk reduction and prevention at source requires coordinated action among practitioners in human and animal health and the environmental sciences. Implementation of One Health in the field can be challenging because of divergent short-term objectives. Successful implementation requires effort, mutual trust, respect and understanding to ensure that long-term goals are achieved without adverse impacts on agricultural production and food security. PMID- 25707183 TI - Applying the One Health principles: a trans-sectoral coordination framework for preventing and responding to Rift Valley fever outbreaks. AB - Rift Valley fever (RVF) is a good example of a disease for which a One Health approach can significantly improve the management of outbreaks: RVF is a vector- borne zoonotic disease, its dynamics differ between eco-epidemiological patterns and are modulated by eco-climatic factors. Therefore, collaboration between sectors, disciplines and role players, as well as an understanding of the local epidemiology of the disease, are key prerequisites for proper risk assessment and outbreak control. These principles drove the Food and Agriculture Organization of the United Nations (FAO) and the World Health Organization (WHO) to develop an inter-sectoral strategic approach, with specific actions recommended for each of the four periods in the development of the outbreak (forecasting and preparedness, alert, epidemic control, post-epidemic). Through several outbreak response missions between 2006 and 2012 in various countries, an implementation framework was developed by WHO, FAO and the national authorities of affected countries and used to build national response action plans. The framework proposes a structured attribution of duty and responsibilities to committees made up of representatives of the various institutional and operational role players, and with clear mandates and terms of reference (TOR). Such an approach, ensuring real-time sharing of information, coherence in the various aspects of the response, and ownership of the strategy, has proven its efficiency. It could also be used, with appropriate adjustments in the TOR, for other zoonotic diseases. PMID- 25707184 TI - Emerging zoonotic viral diseases. AB - Zoonotic diseases are infectious diseases that are naturally transmitted from vertebrate animals to humans and vice versa. They are caused by all types of pathogenic agents, including bacteria, parasites, fungi, viruses and prions. Although they have been recognised for many centuries, their impact on public health has increased in the last few decades due to a combination of the success in reducing the spread of human infectious diseases through vaccination and effective therapies and the emergence of novel zoonotic diseases. It is being increasingly recognised that a One Health approach at the human-animal-ecosystem interface is needed for effective investigation, prevention and control of any emerging zoonotic disease. Here, the authors will review the drivers for emergence, highlight some of the high-impact emerging zoonotic diseases of the last two decades and provide examples of novel One Health approaches for disease investigation, prevention and control. Although this review focuses on emerging zoonotic viral diseases, the authors consider that the discussions presented in this paper will be equally applicable to emerging zoonotic diseases of other pathogen types. PMID- 25707185 TI - Improving specific disease outcomes through a One Health approach--tuberculosis. AB - Early discoveries in the field of tuberculosis more than a century ago indicated that the success of disease control in human populations would depend on the success of control measures in animals, and vice versa. Recognising the zoonotic importance of a cattle-derived pathogen was the beginning of the eradication of bovine tuberculosis from most of the cattle population in Europe. It was a costly and resource-intensive process, but a successful one. The resulting near disappearance of zoonotic tuberculosis from the human population exemplifies probably one of the largest One Health successes in medical history. Since that time many advances in tuberculosis diagnosis, vaccinology, molecular epidemiology and immunopathogenetic studies have been made within the disciplinary divides of human and animal health research. More recently, the discovery of similarities in the interactions between the natural hosts and the causative agents of tuberculosis, as well as similarities in the resulting disease consequences, have led to a renewed appraisal of the benefits of collaborative approaches. It is to be hoped that, in the future, the combined body of scientific knowledge will also provide the basis for practical One Health initiatives at community level. PMID- 25707186 TI - Anthrax as an example of the One Health concept. AB - Anthrax is a peracute, acute or subacute multispecies bacterial infection that occurs on many continents. It is one of the oldest infectious diseases known; the biblical fifth and sixth plagues (Exodus chapters 7 to 9) that affected first livestock and then humans were probably anthrax. From the earliest historical records until development of an effective vaccine midway through the 20th Century, anthrax was one of the foremost causes of uncontrolled mortality in cattle, sheep, goats, horses and pigs, with 'spill over' into humans, worldwide. With the development of the Sterne spore vaccine, a sharp decline in anthrax outbreaks in livestock occurred during the 1930-1980 era. There were successful national vaccination programmes in many countries during this period, complemented by the liberal use of antibiotics and the implementation of quarantine regulations and carcass disposal. However, a resurgence of this disease in livestock has been reported recently in some regions, where complacency and a false sense of security have hindered vaccination programmes. The epidemiology of anthrax involves an environmental component, as well as livestock, wildlife and human components. This makes anthrax an ideal example for discussion in the One Health context. Many outbreaks of anthrax in wildlife are undetected or unreported, owing to surveillance inadequacies and difficulties. Human disease is generally acquired accidentally during outbreaks of anthrax in domestic livestock and wildlife. The exception is deliberate targeting of humans with anthrax in the course of biowarfare or bioterrorism. PMID- 25707187 TI - The value of increasing the role of private individuals and organisations in One Health. AB - Few non-governmental organisations (NGOs) have been involved in work with wildlife diseases and the One Health concept. However, there are several NGOs and scientific institutions, on international and national levels, that can potentially play a significant role in furthering the objectives of the One Health concept by contributing to wildlife health or wildlife disease knowledge and collaborations. This is because many NGOs have dedicated members that voluntarily become involved in the wildlife aspect of the One Health concept, in many different ways. The authors have identified six international organisations, and ten national organisations that could well be involved in this work. They recommend that the World Organisation for Animal Health (OIE) Delegates, and OIE National Focal Points for Wildlife in different countries, focus on establishing links and collaboration between the Veterinary Services (including Focal Points) and various NGOs, as well as scientific institutions both on a national level and international level. PMID- 25707188 TI - Ecology and conservation: contributions to One Health. AB - Although One Health is widely promoted as a more effective approach towards human, animal and ecosystem health, the momentum is still driven largely by health professionals, predominantly from the veterinary sector. While few can doubt the merits of interdisciplinary One Health approaches to tackle complex health problems, operating across the disciplines still presents many challenges. This paper focuses on the contributions of partners from ecology and conservation to One Health approaches, and identifies four broad areas which could act as a focus for practical engagement and bring ecological and conservation objectives more to the forefront of the One Health agenda: i) developing initiatives with shared conservation and health objectives, particularly in and around protected areas and including programmes addressing human reproductive health and mental health; ii) broadening concepts of health to extend beyond indicators of disease to include the assessment of ecological impacts; iii) the integration of ecological and epidemiological monitoring systems within protected areas to support conservation management and wildlife disease surveillance; iv) building partnerships to bring conservation, health, development and animal welfare agencies together to combat threats to global biodiversity and health from the international trade in wildlife and wildlife products. PMID- 25707189 TI - One Health in social networks and social media. AB - In the rapidly evolving world of social media, social networks, mobile applications and citizen science, online communities can develop organically and separately from larger or more established organisations. The One Health online community is experiencing expansion from both the bottom up and the top down. In this paper, the authors review social media's strengths and weaknesses, earlier work examining Internet resources for One Health, the current state of One Health in social media (e.g. Facebook, Twitter, YouTube) and online social networking sites (e.g. LinkedIn and ResearchGate), as well as social media in One Health related citizen science projects. While One Health has a fairly strong presence on websites, its social media presence is more limited and has an uneven geographic distribution. In work following the Stone Mountain Meeting,the One Health Global Network Task Force Report recommended the creation of an online community of practice. Professional social networks as well as the strategic use of social media should be employed in this effort. Finally, One Health-related research projects using volunteers (citizen science) often use social media to enhance their recruitment. Including these researchers in a community of practitioners would take full advantage of their existing social media presence. In conclusion, the interactive nature of social media, combined with increasing global Internet access, provides the One Health community with opportunities to meaningfully expand their community and promote their message. PMID- 25707190 TI - World Organisation for Animal Health: strengthening Veterinary Services for effective One Health collaboration. AB - To effectively reduce health risks at the animal-human-ecosystems interface, a One Health strategy is crucially important to create strong national and regional animal health systems that are well coordinated with strong public health systems. Animal diseases, particularly those caused by new and emerging zoonotic pathogens, must be effectively controlled at their source to reduce their potentially devastating impact upon both animal and human health. As the international organisation responsible for developing standards, guidelines and recommendations for animal health, the World Organisation for Animal Health (OIE) plays an important role in minimising animal and public health risks attributable to zoonoses and other animal diseases, which can have severe consequences for global food safety and security. National Veterinary Services, which implement OIE animal health and welfare standards and other measures, are the first line of defence against these diseases, and must have the capacity to meet the core requirements necessary for their diagnosis and control. The OIE works collaboratively with the World Health Organization and Food and Agriculture Organization of the United Nations to improve the ability of national animal and public health systems to respond to current and emerging animal health risks with public health consequences. In addition to improving and aligning national laboratory capacities in high-risk areas, the OIE collaborates on One Health oriented projects for key diseases, establishing model frameworks which can be applied to manage other existing and emerging priority diseases. This article reviews the role and activities of the OIE in strengthening the national Veterinary Services of its Member Countries for a more effective and sustainable One Health collaboration. PMID- 25707191 TI - One Health in the context of medical and veterinary education. AB - This paper discusses how best to develop the educational platforms that can foster a wider appreciation of the importance of the One Health concept in medical and veterinary education. There are many compelling examples, from genetics to infectious diseases, where significant advances have been made in medicine and veterinary medicine by applying the principles of One Health, i.e. by recognising the interconnectedness between medicine, veterinary medicine and related sciences. In the medical and veterinary curriculum the objective should be to ensure that all opportunities are taken throughout preclinical and clinical teaching to incorporate the lessons which have been learned from the success stories in One Health. This will ensure that advances continue to be made and that a more pervasive and forward-looking scientific culture sustains One Health in the future. PMID- 25707192 TI - The United Nations and One Health: the International Health Regulations (2005) and global health security. AB - The One Health approach encompasses multiple themes and can be understood from many different perspectives. This paper expresses the viewpoint of those in charge of responding to public health events of international concern and, in particular, to outbreaks of zoonotic disease. Several international organisations are involved in responding to such outbreaks, including the United Nations (UN) and its technical agencies; principally, the Food and Agriculture Organization of the UN (FAO) and the World Health Organization (WHO); UN funds and programmes, such as the United Nations Development Programme, the World Food Programme, the United Nations Environment Programme, the United Nations Children's Fund; the UN linked multilateral banking system (the World Bank and regional development banks); and partner organisations, such as the World Organisation for Animal Health (OIE). All of these organisations have benefited from the experiences gained during zoonotic disease outbreaks over the last decade, developing common approaches and mechanisms to foster good governance, promote policies that cut across different sectors, target investment more effectively and strengthen global and national capacities for dealing with emerging crises. Coordination among the various UN agencies and creating partnerships with related organisations have helped to improve disease surveillance in all countries, enabling more efficient detection of disease outbreaks and a faster response, greater transparency and stakeholder engagement and improved public health. The need to build more robust national public human and animal health systems, which are based on good governance and comply with the International Health Regulations (2005) and the international standards set by the OIE, prompted FAO, WHO and the OIE to join forces with the World Bank, to provide practical tools to help countries manage their zoonotic disease risks and develop adequate resources to prevent and control disease outbreaks, particularly at the animal source. All these efforts contribute to the One Health agenda. PMID- 25707193 TI - [Activity report on a programe of the Ministry of Health, Labour and Welfare (MHLW) "Initiative to facilitate development of innovative drugs, medical devices, and cellular and tissue-based products" in National Institute of Health Sciences]. PMID- 25707194 TI - [Regulatory science researches of nanomedicines]. AB - Recently, the development of nanomedicines is progressing. These are designed to ensure high stability and to optimize the pharmacokinetics in vivo. The polymeric micelles and lipid nanoparticles are typical such examples. Because the unique size-specific interaction with biological systems or biodistribution may have significant impacts on the efficacy and safety of nanomedicines, regulatory science researches of nanomedicines are required. In this review, the authors introduce our initiatives of the regulatory science researches of nanomedicines. PMID- 25707195 TI - [Translational/regulatory science researches of NIHS for regenerative medicine and cellular therapy products]. AB - In 2013, the Japanese Diet passed the Regenerative Medicine Promotion Act and the revisions to the Pharmaceutical Affairs Act, which was also renamed as the Therapeutic Products Act (TPA). One of the aims of the new/revised Acts is to promote the development and translation of and access to regenerative/cellular therapies. In the TPA, a product derived from processing cells is categorized as a subgroup of "regenerative medicine, cellular therapy and gene therapy products" (RCGPs), products distinct from pharmaceuticals and medical devices, allowing RCGPs to obtain a conditional and time- limited marketing authorization much earlier than that under the conventional system. To foster not only RCGPs, but also innovative pharmaceuticals and medical devices, the Ministry of Health, Labour and Welfare recently launched Translational Research Program for Innovative Pharmaceuticals, Medical Devices and RCGPs. This mini-review introduces contributions of the National Institute of Health Sciences (NIHS) to research projects on RCGPs in the Program. PMID- 25707196 TI - [Collaborative study on regulatory science for facilitating clinical development of gene therapy products for genetic diseases]. AB - Gene therapy products are expected as innovative medicinal products for intractable diseases such as life-threatening genetic diseases and cancer. Recently, clinical developments by pharmaceutical companies are accelerated in Europe and the United States, and the first gene therapy product in advanced countries was approved for marketing authorization by the European Commission in 2012. On the other hand, more than 40 clinical studies for gene therapy have been completed or ongoing in Japan, most of them are conducted as clinical researches by academic institutes, and few clinical trials have been conducted for approval of gene therapy products. In order to promote the development of gene therapy products, revision of the current guideline and/or preparation of concept paper to address the evaluation of the quality and safety of gene therapy products are necessary and desired to clearly show what data should be submitted before First in-Human clinical trials of novel gene therapy products. We started collaborative study with academia and regulatory agency to promote regulatory science toward clinical development of gene therapy products for genetic diseases based on lentivirus and adeno-associated virus vectors; National Center for Child Health and Development (NCCHD), Nippon Medical School and PMDA have been joined in the task force. At first, we are preparing pre-draft of the revision of the current gene therapy guidelines in this project. PMID- 25707197 TI - [Study toward practical use of oligonucleotide therapeutics]. AB - Over the past decade, oligonucleotide-based therapeutics such as antisense oligonucleotides and small interfering RNAs (siRNAs) have been developed extensively. For example, mipomersen (Kynamro; ISIS Pharmaceuticals), which is a second-generation antisense oligonucleotide administered by subcutaneous injection, has recently been approved by the FDA for the treatment of homozygous familial hypercholesterolemia. On the other hands, methods for the evaluation of quality, efficacy and safety of oligonucleotide therapeutics have not been fully discussed. Furthermore, the regulatory guidance specific for oligonucleotide therapeutics has not been established yet. Under these circumstances, we started to collaborate with Osaka University and PMDA to discuss regulatory science focused on oligonucleotide therapeutics. Through the collaboration, we would like to propose the possible design of quality evaluation and preclinical safety evaluation of oligonucleotide therapeutics. PMID- 25707198 TI - [Projects to accelerate the practical use of innovative medical devices to collaborate with TWIns, Center for Advanced Biomedical Sciences, Waseda University and School of Engineering, The University of Tokyo]. AB - Division of Medical Devices has been conducting the projects to accelerate the practical use of innovative medical devices to collaborate with TWIns, Center for Advanced Biomedical Sciences, Waseda University and School of Engineering, The University of Tokyo. The TWIns has been studying to aim at establishment of preclinical evaluation methods by "Engineering Based Medicine", and established Regulatory Science Institute for Medical Devices. School of Engineering, The University of Tokyo has been studying to aim at establishment of assessment methodology for innovative minimally invasive therapeutic devices, materials, and nanobio diagnostic devices. This report reviews the exchanges of personnel, the implement systems and the research progress of these projects. PMID- 25707199 TI - [Collaborative projects with academia for regulatory science studies on biomarkers]. AB - Biomarkers are useful tools to be utilized as indicators/predictors of disease severity and drug responsiveness/safety, and thus are expected to promote efficient drug development and to accelerate proper use of approved drugs. Many academic achievements have been reported, but only a small number of biomarkers are used in clinical trials and drug treatments. Regulatory sciences on biomarkers for their secure development and proper qualification are necessary to facilitate their practical application. We started to collaborate with Tohoku University and Nagoya City University for sample quality, biomarker identification, evaluation of their usage, and making guidances. In this short review, scheme and progress of these projects are introduced. PMID- 25707200 TI - [Accession to the PIC/S and pharmaceutical quality system in Japan]. AB - In March, 2012, Japan made the application for membership of the Pharmaceutical Inspection convention and Pharmaceutical Inspection Co-operation scheme (PIC/S) which is an international body of a GMP inspection. The globalization of pharmaceutical manufacturing and sales has been a driving force behind the decision to become a PIC/S member. For the application for membership, Japan's GMP inspectorate needs to fulfill PIC/S requirements, for example, the inspection organization has to have a quality system as a global standard. One of the other requirements is that the GMP inspectorate can access Official Medicines Control Laboratories (OMCL) having high analytical skills and also have a quality system based on ISO 17025. I would like to describe the process to make up a quality system in the National Institute of Health Sciences and also the circumstances around the PIC/S application in Japan. PMID- 25707201 TI - [Current situations and the future prospect of monoclonal antibody products]. AB - Monoclonal antibody products and monoclonal antibody-based biopharmaceuticals have shown considerable effectiveness in the treatment for variety of diseases; cancer, auto-immune/auto-inflammation diseases and so on. Significant advance in monoclonal antibody products for cancer treatments was made with antibody-drug conjugates (ADC), and antibodies for blockade of immune checkpoints. Already 3 ADCs and 2 anti-immune-checkpoint antibodies products have been approved, and these monoclonal antibody-related product pipelines reach over 30. On the other hand, EU approved first monoclonal-antibody biosimilar, RemsimaTM (infliximab), suggesting that other monoclonal-antibody biosmilars will follow to the market. In this paper, several new issues about monoclonal antibody products will be discussed. PMID- 25707202 TI - [Immunotoxicity and environmental substances]. AB - A well functioning immune system is essential in maintaining integrity of the organism, and malfunction may have severe health consequences. Environmental substances may pose direct toxicity to components of the immune system, often leading to immunosuppression and resulting reduced resistance to infections and tumors. Alternatively, such substances may be recognized by the immune system in a specific fashion, which may result in allergy and autoimmunity. A proper risk assessment of environmental substances in terms of immunotoxicity is necessary. In this manuscript, I reviewed recent three topics about immunotoxicity: (1) IPCS/WHO Guidance for immunotoxicity risk assessment for chemicals, (2) Intestinal immunotoxicity, and (3) Epicutaneous sensitization of food proteins. PMID- 25707203 TI - [Examination of identification test of certain aromatic amines originating from azo colorants in textile and leather products using high performance liquid chromatography]. AB - Azo colorants that generate primary aromatic amines (PAAs) have been recently deliberated as a controlled harmful substance by the "Act on the Control of Household Products Containing Harmful Substances" in Japan. Therefore, we examined an identification test for 22 kinds of PAAs originating from the azo colorants in commercial textile products and leather products using high performance liquid chromatography (HPLC). When a PAAs standard solution containing 2,4-xylidine and 2,6-xylidine was analyzed using the condition according to EN14362-1:2012 at 240 nm as a basic condition, we observed enough separation for all the PAAs to identify. However, in the some sample solutions, the peaks of several PAAs were overlapped with the interference peaks, and their identifications were difficult. In these cases, some PAAs were able to identify by alteration to suitable wavelength. Furthermore, the retention time of almost PAAs and interference peaks were changed by using acetonitrile as the organic solvent in eluent or phenyl type column. These modifications were helpful for identification of PAA which was overlapped to interference substances by the basic condition. Thus, we suggest the HPLC condition for an identification test is in accordance to that described in EN14362-1:2013. And we propose that the HPLC condition can be modified as necessary. PMID- 25707204 TI - [Development of identification method for isopropyl citrate]. AB - In Japan's Specification and Standards for Food Additive, 8th edition, two identification tests involving isopropyl citrate for detecting isopropyl alcohol and citrate are stipulated. However, these identification tests use mercury compound, which is toxic, or require a time-consuming pretreatment process. To solve these problems, an identification test method using GC-FID for detecting isopropyl alcohol was developed. In this test, a good linearity was observed in the range of 0.1-40 mg/mL of isopropyl alcohol. While investigating the pretreatment process, we found that isopropyl alcohol could be detected using GC FID in the distillation step only, without involving any reflux step. The study also showed that the citrate moiety of isopropyl citrate was identified using the solution remaining after conducting the distillation of isopropyl alcohol. The developed identification tests for isopropyl citrate are simple and use no toxic materials. PMID- 25707205 TI - [The role of alterations in the brain signaling systems regulated by insulin, IGF 1 and leptin in the transition of impaired glucose tolerance to overt type 2 diabetes mellitus]. AB - One of the crucial factors leading to the development of pre-diabetes and type 2 diabetes mellitus (DM2) are the disturbances in the brain hormonal signaling systems regulated by insulin, insulin-like growth factor-1 (IGF-1) and leptin. The causes of these disturbances are the changes in the redox balance and lipid metabolism leading to lipotoxicity and endoplasmic reticulum stress in neuronal cells, as well as the dysfunctions in neurotransmitter systems of the brain that are functionally associated with insulin, IGF-1 and leptin signaling systems. The identification of molecular disturbances in insulin, IGF-1 and leptin systems of the brain in pre-diabetes and DM2 can be used for early diagnostics of these diseases, and to develop new strategies for preventive treatment of DM2 at the pre-diabetic stage. In the review, the literature data and the results of own investigations concerning the changes in the insulin, IGF-1 and leptin systems of the brain in pre-diabetes and DM2 and their role in the etiology and pathogenesis of DM2 are analyzed, and the approaches to restore the functional activity of these systems are discussed. PMID- 25707206 TI - [Influence of human fetal mesenchymal stem cells on glioma cell proliferation. A consequence of cellular crosstalk]. AB - The effect of mesenchymal stem cells (MSCs) on the growth of various tumors is ambiguous. MSCs derived from different tissues stimulate growth of some tumor types and exert antitumor effects on the other. Several recent reports have shown that crosstalk between tumor cells and MSCs contribute to these effects. The aim of this work was to study the effects of MSCs derived from fetal tissues on the proliferative activity of glioma cells in conditions of prolonged co-cultivation. We have analyzed the proliferative activity of glioma cells exposed to conditioned medium (CM) from MSCs derived from fetal bone marrow (FetMSC) and fetal muscle (M-FetMSC) as well as to CM from co-cultivation of the fetal MSCs with U251MG glioma cells. As a comparison, the influence of CM from adult dermal fibroblasts (DFs) was examined in identical experiments. Using MTT assay, we have found that CM from both the fetal MSCs and adult DFs (without their co-culturing with glioma cells) had no effect on U251MG and A172 glioma cell proliferation. However, CM from early co-cultures (3-9 days) of U251MG cells with FetMSC or M FetMSC exerted stimulatory effect on U251MG cell proliferation up to 2.3-fold increase, while CM obtained later from the same co-cultures (15-21 days) had inhibitory effect on the proliferation up to arrest of cell division. Analogous experiments with adult DFs have revealed a persistent stimulation of U251MG cell proliferative activity for all 21 days of co-culturing. Immunofluorescence analysis revealed a reduction in the expression of cell cycle protein cyclin D1 in U251MG cells after their treatment with CM taken from 21-days co-cultures of U251MG cells with FetMSC or M-FetMSC. In contrast, CM from 21-days co-cultures of U251MG cells with DFs did not decrease the expression of cyclin D1. These results show that fetal MSCs have dual effect on glioma cell proliferation. In spite of the earlier stimulatory effect on the proliferative activity, prominent inhibition of glioma cell proliferation was observed after three week co culturing of glioma cells with fetal MSCs. This is the first report demonstrating reversion of tumor cell proliferative program during co-culturing with MSCs for a long time. These data suggest that CM obtained at different time points of cell co-culturing can be used in the modeling of prolonged cellular crosstalk. PMID- 25707207 TI - [Immunochemical study of nuclear matrix proteins localization in the structure of perinucleolar chromatin]. AB - Immunofluorescence labeling of proteins with molecular mass of 27, 38, 40, 50 and 65 kDa obtained from serum of patients with autoimmune disease demonstrated different patterns (small clusters or granules) in interphase nuclei of pig kidney cells. It was remarkable that there was no staining inside the nucleoli, but the proteins immunoreactivity was detected around them in the regions of perinucleolar chromatin. Moreover, expression of nucleolar proteins, such as fibrillarin and B23, was found only in nucleoli. After extraction of DNA, PNA and histones, the proteins with molecular mass 27 and 38 kDa were found in the periphery of residual nucleoli, and proteins with molecular mass 40, 50 and 65 kDa had similar localization and were also present in karyoplasm of cells as small clusters. According to our data, nucleolar protein, fibrillarin, was distributed regularly throughout the whole volume of residual nucleoli. At the same time, B23 protein was revealed only at their periphery, where perinucleolar chromatin had localized before treatment. Thus, it has been revealed that the proteins of nuclear matrix with molecular mass 27, 38, 40, 50 and 65 kDa, as well as nucleolar protein B23 are the parts of perinucleolar chromatin, which could be considered as special chromosomal domain associated with the functioning of the nucleolus. PMID- 25707208 TI - [Effects of local induction of ipt-gene in roots on cytokinins content in leaf cells tobacco plants]. AB - Identification of cytokinins in differentiated leaf cells has received little attention. We have carried out immunohistochemical localization of cytokinins in leaves of transgenic tobacco plants in which the level of increased due to induced in their roots the expression of ipt-gene controlling cytokinin synthesis. Immuno-labeling of cytokinins with the help of antibodies raised against zeatin riboside was characteristic of mesophyll cells. The label was localized in cytoplasm adjacent to cell walls and was absent in vacuoles. Immunohistochemical staining also revealed the presence of cytokinins in guard cells. Induction of cytokinin synthesis enhanced the immunohistochemical staining of both mesophyll cells and guard cells, which was accompanied by elevated stomatal conductance. The possibility of a direct effect of cytokinins on stomatal conductance and their indirect influence through photosynthesis in the mesophyll cells is discussed. PMID- 25707209 TI - [Contractile apparatus organization of cardiomyocytes upon their cultivation in collagen gels]. AB - Cardiomyocytes are known to change their morphology and reorganize the contractile apparatus upon their culturing in 2D culture systems. Therefore, the monolayer cardiomyocyte cultures appear to be a poor model for studying of the biologically important processes in the heart. Present study relates to the searching for the most optimal culture conditions allowing cardiomyocytes to maintein their typical morphology and the native state of contractile apparatus. In this study, we investigated organization of the contractile apparatus of cardiomyocytes when cultured in 3D collagen gels of different density. It has been shown that cardiomyocytes preserve the initial organization of their contractile apparatus during prolonged cultivation in collagen gels at a concentration of 1 mg/ml, whereas partial reorganization of their contractile apparatus is observed at a concentration of 0.5 and 1.5 mg/ml. Thus, cardiomyocytes placed in 3D collagen gels with a protein concentration of 1 mg/ml could be considered as a culture be model which approximates to the natural conditions. PMID- 25707210 TI - [Ultrastructural and X-ray spectral analysis of cells U-937 during apoptosis process induced by hypertony]. AB - The results of this work concerning ultrastructural changes of U-937 cells in a state of apoptosis are largely in consistent with the same information available in the literature. However, we have got the original data on the ultrastructural changes of cell organelles and immune localization and distribution of proteasomes. It has been demonstrated that Golgi apparatus is located close to the plasma membrane in the case of apoptosis induced by incubating the cells in a hypertonic suchrose solution (200-400 mM). The fact can be considered as an indirect indication of depolymerization of cytoskeletal elements, in particular, MTs maintaining Golgi apparatus in a cell centre. In the later stages of apoptosis, the distances between Golgi cisterna are significantly increased. It can be explained by hydrolysis of golgins binding cisterna between each other. Mitochondria are not significantly changed in these cells. They have regularly disposed crista and sufficiently dense matrix with a few vacuoles. Proteasomes as rod-shaped osmiophilic particles (12 x 30 nm) have been revealed during each apoptosis stage both in nuclei and cytopl;asm of cells studied. The particles form aggregates of different densitities and sizes unlimited by membrane. It has been proposed that the particle aggregates revealed in the work are analogous to "processing bodies" or aggresomes described in the literature. They can be detected in cells under conditions of suppressed nucleus transcriptional processes in the nucleus and participate in storing and degradation of various mRNAs, RNP and proteins. The changes of intracellular contents of Na and K in a single cell during apoptosis induced by osmotic shock have been revealed using method of X-ray microanalysis. It has been demonstrated the increase in the ratio of intracellular contents Na+/K+ in the most of apoptotic cells in comparing with control cells. PMID- 25707211 TI - [Long-term cultivation of Chinese hamster fibroblasts of line V-79 RJK under elevated temperature leads to karyotype structure destabilization]. AB - In this article we show that long-term cultivation of Chinese hamster fibroblasts of line V-79 RJK at elevated temperature resulted in the selection of variants with genetic changes at the level of karyotype. From the first steps of resistance selection to elevated temperature we identified population of cells with changes in karyotype (polyploidy cells, deletions, inversions, translocations of chromosomes, and some cells with DM-chromosomes). Further cultivation was accompanied with selection of cells with paracentrical chromosome breakages and HSR's on chromosomes. Nonspecific destabilization of the karyotype (on first steps of selection) was associated with increased expression of hsc70 and pgp. After long-term incubation at an elevated temperature, the cells with karyotypic changes had the basal level of hsc70 and pgp expression. PMID- 25707212 TI - [The influence of immunization of rats with BSA-conjugated peptide 269-280 of type 3 melanocortin receptor on the metabolic parameters and thyroid functions]. AB - One of the approaches to study the role of the brain hormonal signaling systems in the regulation of biochemical and physiological processes is their shutdown using the antibodies generated to peptides corresponding to extracellular regions of receptors. The brain type 3 melanocortin receptors (M3R) play an important role in the central regulation of the metabolism and the endocrine system. However, the influence of prolonged inhibition of M3R on energy metabolism, insulin resistance, and thyroid gland (TG) function is practically not studied. The aim of the study was to investigate the influence of prolonged repeated immunization of male rats with the BSA-conjugated peptide Ala-[Pro-Thr-Asn-Pro Tyr-Cys-Ile-Cys-Thr-Thr-Ala-His269-280]-Ala (A[269- 280]A) corresponding to the third extracellular loop of M3R on their metabolic parameters and functional activity of TG. 9 months after the first immunization, the weight of rats was reduced and after 12-13 months was significantly lower than in controls. The weight of abdominal and brown adipose tissues, on the contrary, increased. At the same timeline there was an increase in the fasting glucose and insulin levels, and increase of the HOMA-IR index (by 75%) indicating that immunized animals develop insulin resistance. The rats have increased glucose utilization due to an increase of insulin production by pancreatic beta-cells. 12 months after the first immunization, the increase of the triglycerides level (by 74%) and the ratio of LDL- and HDL-cholesterol (by 36%) were revealed. 13 months after the start of immunization, the levels of free and total thyroxine and total triiodothyronine significantly decreased. In the TG plasma membranes of immunized rats the weakening adenylyl cyclase stimulating effect of thyroid-stimulating hormone was detected. Thus, long-term decrease in the bra- in M3R activity due to repeated immunization of rats with BSA-conjugated peptide A[269-280]A induces the disturbances of the peripheral metabolism and TG function. PMID- 25707213 TI - [Dynamics of pro- and macroglycogen content in hepatocytes of normal and cirrhotic rat liver at different stages of glycogenesis]. AB - The content and structure of glycogen in hepatocytes of normal and cirrhotic rat liver has been studied at definite time intervals after the administration of glucose to starving animals. In the study, an original cytofluorimetric method for detection and quatification of proglycogen (PG) and macroglycogen (MG) content in isolated hepatocytes was applied. This method is based on using Schiff reagents with different spectral characteristics. It has been determined that the content MG content in the hepatocytes of control rats increases in 10 min after initiation of glycogenesis by 52% (P < 0.01). MG content in the cells of cirrhotic liver increased only after 20 min (43%, P < 0.05) after glucose administration to starving animals. The coefficient of correlation between MG content and the total glycogen content in the hepatocytes at different stages of glycogenesis ranged from 0.90 to 0.99 (P < 0.001) in both groups of rats. Increase in PG content in hepatocytes of control rats appeared within 10-30 and 45-70 min. In the case of cirrhosis PG content increased only 60 min after the start of glycogenesis, but after 120 min it was 1.5 times higher than the control values (P < 0.001). The correlation coefficient between the PG and the total glycogen content in rat liver cells averaged 0.86 (P < 0.001) and 0.77 (P < 0.001) in control and experimental groups, respectively. Thus, the change in total glycogen content in hepatocytes of normal and cirrhotic liver is associated mainly with the level of MG. In normal cells, contribution of PG is most significant in the early glycogenesis (10-30 min), and in the cirrhotic liver--in the later stages. PMID- 25707214 TI - [Behavioral and ERP characteristics of recognition of complex images under forward masking. The influence of categorical similarity of target and masking stimuli]. AB - In psychophysical (n = 55) and neurophysiological (n = 25) experiments subjects recognized the images from two categories--"animals" and "non-living objects" under forward masking. Subjects recognized images in two experimental conditions: the target and masking stimuli (SOA = 50 ms) belonged to same category and the stimuli belonged to different categories ("compatible" or "incompatible" pairs). It was found that an efficiency of forward masking depends on the categorical proximity the mask and the target stimuli. The probability of correct answers was lower, and reaction time and it's dispersion were higher in "compatible" situation as compared with the "incompatible" one. The worsening of behavioral response in "compatible" condition was associated with decreased amplitude of N2 and P3 components of ERPs. The observed effects appeared to be more marked in animal recognition in comparison with object recognition. The results are discussed in the context of negative priming and an influence of distractor. PMID- 25707215 TI - [Comparison of event-related potentials components characteristics obtained during stimulation of symbolical and alphabetic matrixes used in brain-computer interface paradigm]. AB - In order to create a brain-computer interface (BCI) on the basis of paradigm P300 (the so-called Farwell-Donchin paradigm, FD) with a symbolical matrix used as stimuli, there were compared characteristics of event-related potentials (ERP) obtained from stimulation both by symbolical and alphabetical matrixes. The matrixes contained 6 x 6 signs (cyrillic letters or symbols-pictograms). Nine healthy adults were examined in 18 experiments during which 28 channel EEG were recorded while matrixes of two types (containing either cyrillic letters or symbols-pictograms) were used for stimulation. The obtained ERP data, i.e. amplitudes and peak latencies of the following components of ERP: N1, P3 with sub components P3a and P3b, N4 were compared and analized for different types of the stimulation matrixes. Similar changes in amplitude or peak latency received from 7 or more out of 9 examinees were taken into consideration, matching the criteria of significance. It was discovered that for components P3a, P3b and N4 the amplitudes of ERP in response to a symbolic matrix were bigger than to a letter matrix, the opposite being true for component N1. Latent periods of ERP components were shorter for a symbolic matrix than for a letter matrix in case of components N1 and P3a, and longer in case of P3b and N4. In order to find out which zones of the brain react to stimulation the most, there was conducted a pair t-test (series of pair t-tests) to analize the topography of variety of ERP responses to different types of stimuli, and, through comparing the amplitudes of ERP components, a topographical map detailing the variety of responses to the different types of matrixes was obtained. The data about the differences were analized separately for each of 28 channels, then the (absolute magnitude t-test) were summed up algebraically for all the nine examinees. Thus, it was shown, for amplitudes of all the tested ERP components in the case of pair "significant insignificant letters", the topography of the t-test is represented by two separate areas with distinct lateralization. In the case of pair "significant insignificant symbols", the field of maximum responses streanch in croas direction. In the case of pair "significant letters-significant symbols" the topography is elaboratly orgenised. PMID- 25707216 TI - [The response of EEG activation in different neurohumoral conditions]. AB - In order to examine under what neurohumoral condition response to the usual opening of the eyes is an incentive for the activation, electroencephalographic, electrocardiographic and electromyographic characteristics of the eyes open reaction in relation to the psychometric indicators of emotional stress and cognitive performance were recorded in 59 healthy women aged 18-27 every 2-3 days for 1-2 menstrual cycles, established in accordance with the morning levels of progesterone. For excluding NOVELTY factor influence one 29 women started monitoring at menstrual phase and other 30--at luteal phase of menstrual cycle. 30 women participated in a one-time monitoring, in which the relationship of these parameters with the current level of progesterone and cortisol in saliva was studied. Two factors ANOVA showed that the depth of the power suppression and the width of the individually determined low frequency alpha EEG range on follicular is more than on the luteal phase of the menstrual cycle of women and are influenced the NOVELTY. "Berger effect" indices of the upper alpha range are not changed depending on the neurohumoral status. Depth of the amplitude decrease and width of merely low-frequency alpha band could predict the activation in the eyes open response due to unidirectional changes and relationship to vegetative and hormonal characteristics of the activation. It was firstly established that eyes opening is an incentive factor to the activaition only when neurohumoral state corresponds to the follicular phase of the women mensrual cycle. This study reviles the dependence of the neuronal and vegetative activation mechanisms of the individual alpha frequency profile EEG and neurohumoral status. PMID- 25707217 TI - [Brain structures and functional pecularities in children with mental disorders and transcranial direct current stimulation]. AB - This research represents MRI and EEG-investigation in children with mental disorders perinatal genesis during tDCS. In 70% cases brain structures damages don't found or were minimal. On the contrary, in 77% cases alpha-rhythm of EEG in parietal-occipital areas was non-regular. Functional insufficiency can as a basis of high efficiency tDCS by children. In cases with autism spectrum disorders the Subscales of Woodcock-Jonson were used for the quantitative estimation of efficiency of the course of treatment with tDCS. Positive changes after the course of tDCS were revealed in psychic state, speech comprehension, communication, practical and speech experience, fine motor skills and social integration. PMID- 25707218 TI - [Correlation of brain electrical activity and motivation in healthy people]. AB - Motivation dominates in the structure of the personality and is one of the basic notions which explains the dynamics of the behavior. The literature has little data about neurophysiology of motivation. The aim of the research was to study the correlation between the motivational sphere and electrical activity of the brain at the influence of different provocations. 24 healthy people at the age of 26-36 years were examined. The results of motivation tests turned out to be uniform (the motivation to success was of a moderate or high level, there were mean values of readiness to risk and low motivation to achievement and approval). Multiple correlations between different types of motivation and electrical activity of the brain at rest, at hyperventilation with room temperature air and at isocapnic cold air hyperventilation were revealed. PMID- 25707219 TI - [Psychophysiological and cardiohemodynamic effects of solar, geomagnetic and meteorological factors in man living in Arctic area]. AB - Complex investigation of solar, geophysical and meteorological factors as well as lunar cycle-phases effects on the indices of cardiohemodynamics, emotional state and the CNS functional state was carried out in 12 males 19-38 years old living in the Arctic region (Apatity, 67 degrees 57' N, 33 degrees 39' E). The observation period was characterized by flares of M1-M2-class as well as geomagnetic storms of G1-G3 class. Adaptive modulatory effect of environmental factors was shown on the autonomic regulatory systems, as well as a strongviolation action of geomagnetic storms and solar chromosphere flares were revealed on the human functional state. Multiple regression method allowed us to obtain the dominant environmental factors by magnitude of their action on functional parameters, and to estimate the combined effect of these factors. The coefficient of determination in the most cases did not exceed 0.5, but in a certain subjects reached 0.7-0.8 on some indicators. Data show the selective nature of the multiple effects of environmental factors on indicators of functional and emotional states at various persons. Each of examined subjects living in the high latitude extreme conditions reacts on permanent climatic geographic and cosmophysical factors variation, however both a character and magnitude of reactions were dependent on personal susceptibility to isolated and combined actions of these factors. PMID- 25707220 TI - [Interlimb interactions during cyclic in-phase and antiphased movements of arms and legs and their dependence on afferent influences]. AB - Coordinated movements of arms and legs suppose the neural interaction between the generators of the rhythmics of the upper and lower extremities. In the lying position in 10 healthy subjects activity of the muscles of the upper and lower extremities was recorded when separate and joint cyclic movements of the arms and legs with different phase relationships between the movements of the limbs were performed, and under various conditions of the motor task. Antiphased active arm movements were characterized by increased muscle activity than during in-phase mode. The activity of the arm muscles under passive movements, imposed by experimenter, was significantly less than their activity when passive movements of the arms were imposed by the other arm. When loading one arm the muscle activity in the other passively moving arm increased independently from the synergy of arm movements. During motor tasks, implementing joint antiphased movements as the upper and lower extremities, compared to motor task, implementing their joint in-phase movements, there has been a significant increase in activity in the biceps brahii muscle, the tibialis anterior muscle and biceps femoris muscle. Loading of arms in these motor tasks has been accompanied by increased activity in some of the leg muscles. Increasing of frequency of rhythmic movements resulted in a significant growth of the muscle activity of the arms and legs with their cooperative movements with greater rate of rise of flexor muscles activity for arms and legs during joint antiphased movements. Thus, the spatial organization of movements and kind of afferent influences are significant factors of interlimb interaction, which, in turn, determine the type of neural interconnections that are involved in the regulation of movements. PMID- 25707221 TI - [Effect of training on treadmill performance, aerobic capacity and body reactions to acute cold exposure]. AB - An attempt was made to test the hypothesis that regular physical activity at the anaerobic threshold is able to stimulate an increase in the amount of body fat brown or beige, which can manifest itself in increasing lactate utilization during exercise and increase the reactivity in response to acute regional cooling. The methods used are: ramp test, regional acute cold exposure, measurement of gas exchange, lactate and glucose in the blood, heart rate, and heart rate variability, blood pressure and respiration variability at rest and during standard functional tests; infrared thermal imaging, statistical methods of results analysis. Workout 10 physically active volunteers (7 males and 3 females) on a treadmill at a speed corresponding to 75-80% of the persona VO2max for 30 minutes 3 times per week at a fixed ambient temperature 21-22 degrees C for 6 weeks resulted in a significant (from 19 to 39%) increase in test work duration but VO2max on average changed little. The increase in power of anaerobic threshold was associated with a sharp slowdown in the accumulation of lactate in progress of ramp test. Lactate utilization rate during the recovery period, on the contrary, increased. In general, significantly increased work efficiency at a test load. Not revealed noticeable changes in the condition and response to a standard functional tests of autonomic systems, as judged by heart rate variability, blood pressure and respiration variability at rest and during orthostatic tests and imposed breathing rhythm. The functional response of the body to acute cold exposure (1 minute cooling of the feet in ice water) is not changed after a cycle of training--either in terms of metabolism (oxygen consumption, etc.), or the dynamics of the skin temperature in areas of most probable location of brown adipose tissue (BAT). These data do not confirm the previously expressed (2010) hypothesis about the function of BAT as a universal homeostatic instrument in the body. Probably, if under the influence of physical activity and hormone irisin produced by muscles the formation of the beige adipose tissue is stimulated, the one that is involved in lactate utilization, but is not involved in thermoregulatory responses. PMID- 25707222 TI - [Effects of anxiety on cardiorespiratory function]. AB - The present study was undertaken to investigate the effect of anxiety on pulmonary function parameters and respiratory sinus arrhythmia (RSA) in healthy people under real-life conditions. This study consisted of two interrelated parts. During the first stage, eighty healthy students were examined in the following sequence: recording of heart rate variability (HRV) and respiration parameters at rest and shortly before real life stress. In a longitudinal study (the second stage), we assessed the profile of cardiorespiratory activity over 50 days in ten healthy women. Pulmonary function parameters like breath rate, tidal volume, forced expiratory volume in ones (FEV1), peak expiratory flow (PEF), forced expired flow at 25%, 50%, 75% of FVC, forced expired flow from 25-75% of FVC (FEF25-75%) and HRV measures (SDNN, RMSSD, pNN50, LF, HF, HFnorm, LF/HF ratio) of all subjects were tested. State anxiety was measured by Spielberger state anxiety inventory. Higher levels of state anxiety were associated with higher levels of breath rate, tidal volume and reduced HRV parameters, especially indicators of the RSA (HF and HFnorm) at baseline. These changes depend on the category of state anxiety: the group of students with a qualitative increase in state anxiety before examination has increased level of FEV1, PEF, forced expired flow at 25%, 50%, 75% of FVC, FEF25-75%. Less reactive students have no difference in respiratory parameters. We found a strong negative correlation between the level of HF at rest and state anxiety scores before examination. Longitudinal study found a negative correlation between RSA parameters and PEF, positive correlation between state anxiety and PEF of the majority those surveyed, except for two women with low levels of state anxiety and RSA indicators were in a narrow range. The variations of cardiorespiratory parameters during a longitudinal study depend on the changes of state anxiety. The higher level of state anxiety was associated with significant changes in RSA and the respiratory parameters. These results lend strong support to the notion that parasympathetic function is a critical physiological component of emotional processes. PMID- 25707223 TI - [Characteristics of flow standardized inspiratory lung sounds in healthy]. AB - Objectification of respiratory sounds, recorded on chest surface, is important to assess human broncho-pulmonary system. The aim is to detail the objective characteristics of basic inspiratory sounds. The study involved 36 healthy men aged 19 to 80 years. Under flow rate 0.89 +/- 0.18 L/s medians of spectral characteristics of basic inspiratory lung sounds are in the ranges: amplitude level -63.3... -56.5 dB, -3 dB cutoff frequency 269.5-359.4 Hz, -20 dB cutoff frequency 531.3-621.1 Hz, the slope of the spectrum curve between the cut-off frequencies -0.077... -0.050 dB/Hz. The high degree of bilateral symmetry of spectral characteristics is found. Significant upward trend in the cutoff frequencies is revealed between interscapular region and apices or basal areas of the lungs. The 90% limits of intersubject variability of the cutoff frequencies of the spectrum are identified in areas of chest used for lung auscultation. PMID- 25707225 TI - [Seasonal and individual characteristics of the blood fibrinolytic system reaction to the physical load]. AB - 33 untrained test subjects (16 males and 17 females aged 18) have been studied for one year for their blood fibrinolysis reaction to a one-time 20-minute bicycle-ergometric large-capacity load (N male = 2.66 watt/kg, N female = 2.3 watt/kg). It is known that at rest the blood fibrinolytic activity (FA) has its seasonal characteristics: it is relatively high in the autumn and spring and low in the winter and summer. On the average, in the winter and in the summer physical activity stimulates the blood clot lysis whereas in the autumn and in the spring it does not. The direction and the intensity of the fibrinolysis system response to work have individual features: in the autumn and in the spring they are connected with its initial state (they increase when the blood FA is low and decrease when the blood FA is high) as well as they have large fluctuations, whereas in the winter and in the summer they are not subject to these laws. According to the parameters of the directional response to the load and its permanence there are three types of response: a) Hyperfibrinolytic, which is characterized by the FA increase when there is a physical load applied in all seasons of the year, having a low initial FA level at rest; b) Hypofibrinolytic, the representatives of which have a stable reaction of fibrinolysis oppression when there is a physical load applied, not depending on the season of the year and the initial level, having a high initial level of FA in the autumn and in the spring and low--in the winter and in the summer; c) Unstable, in which the direction of the fibrinolysis system response to the physical exercises is variable. The conclusion is that the development of thromboembolic complications as a consequence of having a physical load is most likely to be expected from those who have a hypofibrinolytic type of reaction while this is very unlikely to be expected from the representatives of the hyperfibrinolytic type. PMID- 25707224 TI - [Age features of kidney response on food and physical loads in athletes--skiers]. AB - The features of renal functions in older adolescents and young adults involved in ski racing, before and after water, food, and physical activity has been studied. Renal functions in the morning as baseline demonstrated an increase in GFR and greater maturity of osmoregulatory mechanisms (higher excretion of osmotically active substances, osmotic concentration index, the reabsorption of solute-free fluid) in adult compared with adolescents. After food intake in youths osmoregulatory mechanisms provided adequate renal response--increased excretion of ions in exchange for urea, that saved osmolality. In adolescence, there was an increase of excretion of osmotically active substances in parallel with the output of urine, higher GFR and reabsorption of solute-free liquid, that confirmed the lower maturity of osmoregulatory system. The renal homeostatic response after physical training indicated involvement of volume regulatory mechanisms that did not differ between age groups. It is concluded that the development of the definitive volume regulation became earlier than osmoregulation. PMID- 25707226 TI - [Andrological status of adolescents and its connection to anthropometric and hormonal descriptions in the students of technical college group]. AB - The purpose of this investigation was to study the interrelation of andrological status with anthropometric and hormonal descriptions for age-specific features discovery of male sexual system pathological states at technical college students. 147 adolescents aged 15-17 years old were examined. Only 41 of them were found to have no abnormalities in their genital system development; in 35 adolescents sexual development was delayed; and 97 adolescents were found to have various andrological diseases (varicocele, phimosis, gynecomastia, testicular asymmetry, etc.) or clinical signs for development of these diseases. In 26 adolescences delayed sexual development was combined with the andrological pathology. The normal andrological status was usually accompanied with the highest frequency of low values of anthropometric indicators and indices that reflect the influence of various hormonal systems on the bodily constitution, as well as expressed anthropometricheterogeneity. In adolescents with andrological pathology or clinical signs for its development, in all anthropometric parameters the higher values were seen more frequently than low values against the background of highest group anthropometric homogeneity. Summative anthropometric characteristics of the adolescents group with delayed sexual development were between those of the adolescents groups with normal andrological status and andrological pathology The number of correlational relationships of anthropometric and hormonal indicators with the levels of cortisol and dehydroepiandrosteronesulphate was the lowest in the group of adolescents with normal andrological status as compared to their peers with delayed sexual development and andrological pathology. Only in the group of adolescents with normal andrological status the correlation analysis of data showed physiological influence of sexual hormones on anthropometric indicators. Thus, lower influence of sexual system hormones during this ontogenesis stage contributes to slowing down the process of sexual maturation both with the development of andrological pathology in adolescents. PMID- 25707227 TI - [The analysis of increased physical load effect on microcirculation and acoustic properties of human limb skin]. AB - Complex study of limb skin integument has been performed in 20 male "sportsmen of high qualification (track-and-field athletes and wrestlers of Graeco-Roman style) at the age of 17-25 years, as well as in inactive subjects of the same age. The results obtained by us evidence the variability of limb integumentary tissue acoustic properties in sportsmen as manifestation of adaptive response to regular increasedphysical loads experience by them every day. Some differences in microcirculation of skin integument has been established, first of all, those associated with reserve level--higher increase of capillary blood flow in leg skin during functional ischemic test and 66.2% exceeding capillary blood flow reserve index for leg in track-and-field athletes in comparison with that value in non-sportsmen. The speed of propagation of surface acoustic wave in leg skin during testing in different angular directions reliably exceeded the acoustic parameters of femoral integumentary tissue both in the track-and-field athletes and wrestlers examined, and in the subjects of non-sportsmen control group. The speed of propagation of surface acoustic wave in integumentary tissue of limb distal segments have been established to exceed those of proximal segments. When functional test was made in sportsmen for plasticity reserve reveal, modification of the shape of sound velocity envelope curve took place for the change in spatial position of the limb, evidencing the dynamicity of its elastic properties during performing movements of vital function and the presence of certain plastic reserve. PMID- 25707228 TI - [Relaxation of liquid water states with altered stoichiometry]. AB - The integral parameter of the physical state of liquid water, its stoichiometry composition, is considered. This factor takes into account that the substance of liquid water contains oxygen and hydrogen atoms in the proportion other than the ideal 2:1 ratio characteristic of a separate water molecule. The stoichiometry index chi of water--a deviation from the ideal ratio--is shown to be an independent metastable variable that determines equilibrium concentrations of the oxygen-hydrogen molecules. The optical method for measuring chi is suggested, and a laser interferometer is described that is capable of measuring the stoichiometry index to an accuracy of 10(-5). Possible applications of the instrument in biophysics of water systems are discussed. PMID- 25707229 TI - [Electrical properties of water: a new insight]. AB - New insight into the electrical properties of liquid water, from a standpoint of the physics of electrolytes, is proposed. The dielectric spectrum of water at frequencies 10(4)-10(11) Hz is described by a simple diffusional model taking into account the electrophoretic and relaxation effects inherent in electrolytes. The static dielectric permittivity and microwave absorption are derived from diffusion of Coulomb interacting H3O+ and OH- ions instead of orientational motion of H2O molecules. The drift component of diffusion provides the proton dc conductivity. Ion concentration is found to be 7 orders of magnitude higher than commonly accepted.(- 1% of the total concentration of H2O molecules). The findings refer to the basic properties of water and therefore can be the key to solving the water-related problems. PMID- 25707231 TI - [Special features of water structure formation in biosystems according to dielkometric data]. AB - Experimental data on dielectric function and dielectric loss tangent in living and non-living water-containing systems have been discussed from the viewpoint of our earlier concept on energy transfer in living systems and the role of water in this process. Estimates have been made of a mean length of fractal quasi crystals, representing the form of biomolecules hydration in the living system; the expected lengths of these quasicrystals are of order of 1000 H2O molecules. It is concluded that the peaks at the curve of frequency dependence of dielectric loss tangent in living systems is due to water sub-system, but not biomolecular vibrations. PMID- 25707230 TI - [Influence of dissolved gases on highly diluted aqueous media]. AB - In the experiments on redox potential measurement for a series of identical samples of purified and presettled water it was found that the response to ultraviolet irradiation varies appreciably within a few days after treatment, including stepwise changes. In a few hours after exposure, leading to a higher content of reactive oxygen species as compared with the equilibrium values, long term changes including variations in redox potential and optical system parameters are recorded in water and diluted aqueous media. We propose a heuristic organization model of the water-gas system with an increased content of reactive oxygen species. PMID- 25707232 TI - [Theoretical study of hydrophobicity and hydrophilicity of uracil and its dimers]. AB - The influence of hydrophilic and hydrophobic properties of the uracil elementary nucleic acids bases on its solubility and structure in aqueous solution was studied. Complexes of uracil with water molecules (from 1 to 14) were then calculated. The geometrical parameters of the hydrogen bridge of uracil and the changes in the frequency of valence vibrations of the bonds participating directly in hydrogen bond formation were calculated. It is shown that for the hydrogen bonds O(w)...HN(1) and O(w)...HN3 the hydrogen atom can tear, it may lead to tautomeric transformation of uracil. The results obtained having calculated the structure of uracil dimers, formed with the hydrogen bonds, in an isolated state and water solution, energy, dipole moments and the hydrogen bridge parameters made it possible to explain low solubility of uracil in water at room temperature. It is shown that water molecules with increase in their number are located mainly at one side of the plane of a pyrimidine uracil ring, that leads to the formation of stacking. Of two possible variants of stacking formation, the most profitable grouping is when a dipole moment of the formed dimer is equal to zero (anti-parallel stacking). PMID- 25707233 TI - [General features of the energetics of complex formation between ligand and nucleic acids]. AB - The analysis of the energy contributions of various physical factors to the complex formation between biologically active compounds and nucleic acids in aqueous solution was performed. A comparison of the energy parameters was made for ligand-ligand, intercalator-DNA, MGB-DNA and ligand-RNA groups. It was shown that the energetics of these reactions is of compensatory nature. Physical factors exerting the most pronounced influence on the energy parameters were identified. Correlation of the energy contributions to MGB-DNA complex formation and its biological effect was found. PMID- 25707234 TI - [Energy analysis of non-covalent ligand binding to nucleic acids: present and future]. AB - Generalization of current views on energy analysis of complex formation of biologically active compounds with nucleic acids is represented and the outlook for further developments is determined. PMID- 25707235 TI - [Fluorescense enhancing of 5, 10, 15, 20-tetraphenylporphyrin in complex with human serum albumin and gold nanorods]. AB - Using absorption and fluorescence spectroscopy methods we obtained the results demonstrating alterations in spectral characteristics in supramolecular system composed of gold nanorods (AuNR) (10 x 38 nm) and complexes of human serum albumin (HSA) and 5, 10, 15, 20-tetraphenylporphyrin (TPP). TPP fluorescence (max = 636 and 658 nm) was found to enhance. The dependence of fluorescence enhancing in time was of nonlinear nature. Maximum TPP fluorescence enhancing value was as high as 16% and it was achieved in 7 min after mixing the components. Simultaneously with TPP fluorescence enhancing we observed a decrease in HAS own fluorescence (max = 340 nm) and optical density reduction in maximum of longitudinal localized plasmon band of AuNR (max = 752 nm). PMID- 25707236 TI - [Study of electrokinetic potential of drug micro-carriers prepared from resorbable polymers bioplastotan]. AB - The study investigates electrokinetic potential of microparticles prepared from biodegradable poly-3-hydroxybutyrate depending upon the method of preparation employed and taking into account the size of particles maintained in liquid media. The zeta-potential of microparticles. prepared from emulsion by solvent evaporation method was -20 mV; the zeta-potential of microparticles prepared by spray drying was reduced to -95 mV. The value of zeta-potential was influenced by drug loading into microparticles; the drug-loaded microparticles maintained in balanced phosphate buffer for 30 days had higher physical stability than those without drug loading. PMID- 25707237 TI - [Structural-functional organization of the cells of Brc-1 mutant Chlamydomonas reinhardtii, supplying protoporphyrin IX in the dark]. AB - The structural-functional characteristics of the cells of wild type CC-124 and Brc-1 mutant of the unicellular green algae Chlamydomonas reinhardtii while growing in the dark and light were studied. It has been shown that the cells of the wild type in heterotrophic and mixotrophic growth conditions had a well developed structure and high functional activity due to the ability of the cells to synthesize chlorophyll both in the light and in the dark. The cells of Brc-1 mutant lost their ability to synthesize chlorophyll in the dark and the cells' color was orange due to brc-1 mutation in the nuclear gene LTS3 that regulated the activity of Mg-chelatase enzyme. In the dark the mutant cells accumulated protoporphyrin IX and had a weakly developed structure with low functional activity. It has been ascertained that due to high content of protoporphyrin IX even a short-term exposure of the cells of Brc-1 mutant to the light was accompanied by very strong destructive changes in all the membranes in a cell: plasmalemma, chloroplast, mitochondrion, shells of the nucleus and vacuoles. The reasons of these significant damages of the membrane components and O2-gas exchange in the cells of Brc-1 mutant are discussed. PMID- 25707238 TI - [Effect of dilute solutions of biologically active substances on cell membranes]. AB - The article presents data on changes in physicochemical properties of different biological membranes (plasmatic, microsomal, synaptosomes) under the action of biologically active substances, which are different in their chemical structure and the mechanism of action (natural and synthetic antioxidants, thyrotropin- releasing hormone, phorbol esters), in the wide range of concentrations (10(-22) 10(-3)M). Dose dependences of the effect of biologically active substances on the activity of membrane-bound enzymes, lipid peroxidation, the structural state of the various regions of the lipid bilayer of membranes have been obtained and analyzed in terms of their formal generality of polymodality, number and position of the maxima, a sign change of the effect. An attempt to explain the mechanism of each of the observed peaks in these curves has been made. The maximum in the range of relatively high "physiological" concentrations (10(-3)-10(-7)M) is associated with introduction of biologically active substances into biomembranes. In this study maxima in the range of ultra-low doses (10(-11)-10(-16)M) and "apparent" concentrations -(10(-18)M), where the presence of biologically active substance molecule in a reaction volume is probabilistic in nature, are explained by physicochemical properties of diluted biologically active substances solutions. This conclusion is based on our data on the changes in IR spectra of aqueous solutions of biologically active substances and the results obtained by academician A.I. Konovalov et al. concerning the physicochemical properties of dilute solutions of biologically active substances (conductivity, surface tension, charge), due to the formation of so-called "nanoassociates" from biologically active substance molecule and numerous number of water molecules. The nanoassociates formation and biological effect disappear if the low concentration solutions are kept in a special shielded permalloy container protecting its contents from external electromagnetic field. Thus, nanoassociates are the material carriers of the unique ability of the ultra-low doses of biologically active substances to exhibit biological effects. PMID- 25707239 TI - [Aqueous and salt solutions of quinine of low concentrations: self-organization, physicochemical properties and actions on the electrical characteristics of neurons]. AB - Self-organization, the physicochemical properties of aqueous and salt solutions of quinine and the effects of salt quinine solutions in a wide range of concentrations (1 x 10(-22) - 1 x 10(-3) M) on the electrical characteristics of the edible snail's identified neurons were studied. Similar non-monotonic concentration dependencies of physicochemical properties of aqueous and salt quinine solutions at low concentrations are obtained. This allows of predicting the occurrence of biological effects at low concentrations of quinine solutions. Intrinsic (within 5% of the interval) changes in membrane potential, the amplitude and duration of the neuron action potential under the influence of quinine salt solutions at concentrations of quinine of 1 x 10(-20), 1 x 10(-18), 1 x 10(-10) M are found. For these concentrations the extreme values of specific conductivity and pH are shown. PMID- 25707240 TI - [Local synchronized activity of neurons of different classes in cat primary visual cortex]. AB - The goal of the present study was to investigate the local synchronized neuronal activity in the cat visual cortex and the role of different classes of neurons in neural synchrony. Four classes of neurons were identified on the basis of electrophysiological properties of extracellular recorded cells: RS, FS, IB and FRB. It was revealed that neurons with short spikes and FRB type of activity were first engaged in synchronization. The model study revealed that neurons with the short action potential had more stable synchronized activity. PMID- 25707241 TI - [Kinetic model of changes in genetic controlling systems in cells into a state of proliferation and differentiation]. AB - A kinetic model of changes in genetic controlling systems in cells into a state of proliferation and differentiation was built. A mathematical description of that model in a form of differential equations systems was made. Solutions of those systems were presented graphically. It was shown that at minimum values of reaction rate constants linear time changes were observed in kinetic model parameters and at maximum levels they were non-linear that was characteristic of the living systems. These results point to the fact that changes in genetic controlling systems in living cells occur when reaction rate constants are maximum. PMID- 25707242 TI - [Use of fluorescence microspectral method for studying bone marrow EGFP+ cells transplantation in 5-fluorouracil-treated mice]. AB - In this paper the experimental results of bone marrow transplantation from C57BL/6-Tg(ACTB-EGFP)1Osb/J transgenic mice into C57BL/6 mice subjected to 5 fluorouracil treatment are represented. It has been shown that EGFP+ cells engraftment in bone marrow, spleen and thymus of host mice after 5-Fu treatment significantly increased. More long-term engraftment was recorded after transplantation between closely related donors and 5-fluorouracil treatment hosts. We have also obtained data on differences in the dynamics of EGFP+ cells engraftment in host investigated organs. To assess the effect of the donor's bone marrow cells on the host immune system, functional activity of the synthetic apparatus (synthetic activity) of cells in bone marrow, spleen, thymus and blood have been investigated with fluorescence microspectral method. The results obtained allow of improving techniques for bone marrow transplantation without host irradiation in order to minimize the adverse effects. PMID- 25707243 TI - [Influence of deuterium depleted water on freeze-dried tissue isotopic composition and morphofunctional body performance in rats of different generations]. AB - The influence of deuterium depleted water on the body of different rats generations was investigated in physiological conditions. As a result of this study it was established that the most significant and rapid reduction in D/H equilibrium was observed in plasma (by 36.2%), and lyophilized kidney tissues (by 15.8%). Less pronounced deuterium decrease was characteristic of liver tissue (9.3%) and heart (8.5%). Stabilization of the isotopic exchange reaction rate was fixed in the blood and tissues of rats, starting from the second generation. At the same time when deuterium depleted water (40 ppm) was used in dietary intake, the change in morphological and functional parameters in laboratory animals associated with the processes of adaptation to the effects of substress isotopic D/H gradient was also noted. The study shows that modification of:only drinking water intake regime can't significantly change the deuterium content in tissues of metabolically active organs, because of the concurrent deuterium receipt in food substances of plant and animal origin. PMID- 25707244 TI - [Influence of deuterium depleted water on the organism of laboratory animals in various functional conditions of nonspecific protective systems]. AB - The influence of deuterium depleted water with the modified isotope composition on an organism of animals is studied in physiological conditions and development of chronic endogenous intoxication of hepatorenal genesis. The influence of this water on isotope composition of plasma and tissues (the liver and kidneys) in laboratory animals is shown. The impact of this water on biochemical indicators (AST, ALT, alkaline phosphatase, creatinine, bilirubin) and dynamics in body weight of laboratory animals within 42 days is established. As a result of studies the possibility of the preventive use of deuterium depleted water for correction of metabolic processes is shown in various conditions of the functional system of the body's detoxification. PMID- 25707245 TI - [Physico-chemistry of dinitrosyl iron complexes with thiol-containing ligands underlying their beneficial treatment of endometriosis]. AB - Exogenous dinitrosyl iron complexes (DNIC) with thiol-containing ligands as NO and NO+ donors are capable of exerting both regulatory and cytotoxic effects on diverse biological processes similarly to those characteristic of endogenous nitric oxide. Regulatory activity of DNIC (vasodilation, hypotension, trombosis suppression, red blood cell elasticity increasing, skin wound healing acceleration, penile erection inducing, etc) is determined by their capacity of NO and NO+ transfer to biological targets of the latter (hemo- and thiol containing proteins, respectively) due to higher affinity of the proteins for NO and NO+ than that of DNIC. Cytotoxic activity of DNIC is endowed with rapid DNIC decomposition under action of iron-chelating compounds resulting in appearance of NO and NO+ in cells and tissues in high amount. The latter mechanism is suggested to cause the blocking effect of DNIC as cytotoxic effectors on the development of benign endometrial tumors in rats with experimental endometriosis. It is also proposed that. a similar mechanism can operate causing at least a delay of malignant tumor proliferation under action of DNIC. PMID- 25707246 TI - [Inhibitory effect of ortho-aminoazotoluene on diethylnirtosamine hepatocarcinogenesis in suckling mice. Phenomenon and possible mechanism]. AB - The modifying effect of the one compound on carcinogenicity of the other in the combined application is attributed usually to some changes in the carcinogen metabolism, i.e. its activation or inactivation. In this paper, when used separately, diethylnitrosamine (DENA) induced 4-6 times more neoplastic lesions in the liver of suckling mice than ortho-aminoazotoluene (OAT) did. However, after combined treatment with both carcinogens the total number of hepatic lesions was significantly lower than that in mice treated with DENA only. Similar effect was observed when OAT was administered 3 days before or 3 days after DENA injection. The observed protective effect is not mediated at metabolic level, because OAT has no effect on metabolism of DENA in mouse liver. Our findings can be unequivocally explained by the competition of the carcinogens for target protein molecules, presumably transcription factors, participating in hepatocyte differentiation, which differently interact with and are diversely impaired by different compounds. PMID- 25707248 TI - [Information theory of ageing: studying the effect of bone marrow transplantation on the life span of mice]. AB - In this paper the method of life span extension of multicellular organisms (human) using the reservation of stem cells followed by autotransplantation has been proposed. As the efficiency of this method results from the information theory of ageing, it is important to verify it experimentally testing the basic concepts of the theory. Taking it into consideration, the experiment on the bone marrow transplantation to old mice from young closely-related donors of the inbred line was carried out. It has been shown, that transplanted animals exhibited a survival advantage, a mean life span increased by 34% as compared to the control. This result not only demonstrates the efficiency of the proposed method for life span extension of multicellular organisms, but also confirms the basis of the information theory of ageing. PMID- 25707247 TI - [Polyacrylates of noble metals as potential antitumor drugs]. AB - The antitumor activity of polyacrylates of the noble metals containing argentum (argacryl), aurum (auracryl) and platinum (platacryl) has been studied using experimental murine solid tumor models (Lewis lung carcinoma and Acatol adenocarcinoma). It has been found that polyacrylates of the noble metals are capable of inhibiting tumor development by 50-90% compared to control. Auracryl that inhibites the growth of Lewis lung carcinoma and Acatol adenocarcinoma by 80 and 90%, respectively, compared to control is the most efficient among the tested compounds and can be recommended for the further profound preclinical studies. PMID- 25707249 TI - ["Microbiological aging" by Mechnikov. How to interpret these ideas today?]. AB - I.I. Mechnikov's hypothesis that the key to prolongation of life lies in the introduction of useful microflora to the gut was not proved. Any microflora needs nutrition and perceives the human body only as a nutrient substrate. Destruction of the basement membranes, that delimit the contacting with aggressive microbiological environment epithelium from the deeper parts of the body, can lead to chronic inflammatory diseases and aging of the skin as a consequence of the invasion of microorganisms. At the ultrastructural level it has been shown by the example of prostatitis and skin aging changes. Coupled with the penetration of germs flow of immune cells may cause autoimmune reactions due to abrupt changes in the molecular design of the intermembrane transport. Thus, the physiological process of macroorganism aging can be viewed as a consequence of its microbiological destruction. PMID- 25707250 TI - [Photomodification of blood by laser and ultraviolet radiation: a comparative study]. AB - The efficiency of in vivo blood irradiation by a laser light source (lambda = 632.8 and 670 nm) and a mercury lamp (UV light, lambda = 254 nm) was compared. Absorption spectra, gas content, oxyhemoglobin content, hemoglobin oxygen saturation, concentrations of lactate and glucose were studied for both irradiated and control samples. Hemoglobin was assumed to be the primary photoacceptor of light radiation for the indicated wavelengths. No substantial differences have been found between the effects of laser and non-laser irradiation. We conclude that the biological impact of the procedure is related to photoinduced changes in hemoglobin oxygen saturation. PMID- 25707251 TI - [Model of control of diurnal melatonin secretion by the solar radiation]. AB - The mathematical model of the control process of diurnal melatonin secretion under the influence of solar radiation on retina photoreceptors is proposed. Invariant relations for calculating melatonin secretion rate and its concentration in blood plasma are obtained. Spectral, time and energy characteristics of solar radiation synchronizing diurnal melatonin secretion and circadian rhythms in human are defined. A possibility of using the relations obtained is shown for arbitrary combination of calendar dates, local time of any time zone and geographical coordinates of a calculated point on earth surface. The adequacy of model is confirmed by coincidence of the calculation data with the results of independent experimental studies on diurnal secretion of melatonin and circadian rhythm in human. The model proposed can be used during investigation of diurnal secretion of melatonin and circadian rhythm in human. PMID- 25707252 TI - [Principal factors influencing the probability of population death]. AB - The study of the probability of population death calculated for men and women from Guatemala, Portugal and Sweden revealed three components: death rate for natural biological reasons (geometric progression coefficient is about 1,1); death rate for social and economic reasons; periodic death rate (12 year period). PMID- 25707253 TI - [Mechanism of action of combined extremely weak magnetic field on aqueous solution of amino acid]. AB - The fundamental physical mechanisms of resonance action of an extremely weak (40 nT) alternating magnetic field at the cyclotron frequency combined with a weak (40 MUT) static magnetic field, on living systems are analyzed in the present work. The experimental effects of such sort of magnetic fields were described in different papers: the very narrow resonant peaks in electrical conductivity of the aqueous solutions in the in vitro experiments and the biomedical in vivo effects on living animals of magnetic fields with frequencies tuned to some amino acids. The existing experimental in vitro data had a good repeatability in different laboratories and countries. Unfortunately, for free ions such sort of effects are absolutely impossible because the dimensions of an ion rotation radius should be measured by meters at room temperature and at very low static magnetic fields used in all the above experiments. Even for bound ions these effects should be also absolutely impossible from the positions of classic physics because of rather high viscosity of biological liquid media (blood plasma, cerebrospinal liquid, cytoplasm). Only modern quantum electrodynamics of condensed media opens the new ways for solving these problems. The proposed article is devoted to analysis of quantum mechanisms of these effects. PMID- 25707254 TI - [The functional role of neocortical gamma activity in the process of interrelations between different areas]. AB - In the context of understanding of the mechanisms of cognitive human accounting functional role in these processes of neocortical gamma activity, the science progress of the 21st century at least three new logically related directions are outstanding to: 1) combination with intracranial recordings by functional magnetic resonance imaging (fMRI) has indicated a closely correlation between the level of power of high gamma-band (90-150 Hz) at corresponding localization and the level of blood oxygenation (responses BOLD; blood oxygenation level dependent), which provides an estimate of the dynamics of power in aspect of metabolic resources; 2) results parallel evaluation of parameters gamma activity (frequency, bandwidth, amplitude) in combination with the size of BOLD responses and the GABA concentration as measured by magnetic resonance spectroscopy, formed the basis of hypothesis about the individual peculiarities (specific features) of the subject (trait); 3) new methods of measuring the phase synchrony of gamma frequencies has created the phenomenon of cross-frequency interaction (cross frequency coupling, CFC) between phases of gamma oscillations with theta, alpha waves. This phenomenon is considered by some authors as the basis of interrelations of different separated networks, possibly providing approach to understanding of various aspects of defining the mechanisms of cognitive processes. PMID- 25707255 TI - [Stress and allostasis: problems, outlooks and relationships]. AB - Concepts of stress and allostasis are discussed in the paper in their interrelation and interpenetration. General adaptation syndrome is considered in the historical aspect of Claude Bernard's, William Cannon's and Hans Selye's contributions to the field, and from the standpoint of an interdisciplinary approach. Key challenges and contradictions of the stress concept are disclosed and discussed. First, the terminology ones, since this term might be understood as stress response, stressor, state of the organism and even the consequences of stress itself. Second, it is ambivalent and contradictory nature of the stress response. From the perception of stress as a reaction to the strong negative impact of environment, researchers became to divide stress onto two types: distress as a non-specific basis of disease, and eustress as a favorable factor that extends the adaptability of human organism. The third problem is connected to the interdisciplinary nature of the stress response, the effects of which being manifested in, at least, four areas: physiology, behavior, subjective experience, and cognitive functions. Particularily, physiologists are very often ignored of a role of cognitive factors in their stress research. The authors in terms of the allostasis theory, more complex adaptation process than homeostasis, resolve contradictories of stress conception observed. The paper proposes a model of allostatic states to describe distress and eustress phenomena. PMID- 25707256 TI - [The P300-based brain-computer interface: presentation of the complex "flash + movement" stimuli]. AB - The P300 based brain-computer interface requires the detection of P300 wave of brain event-related potentials. Most of its users learn the BCI control in several minutes and after the short classifier training they can type a text on the computer screen or assemble an image of separate fragments in simple BCI based video games. Nevertheless, insufficient attractiveness for users and conservative stimuli organization in this BCI may restrict its integration into real information processes control. At the same time initial movement of object (motion-onset stimuli) may be an independent factor that induces P300 wave. In current work we checked the hypothesis that complex "flash + movement" stimuli together with drastic and compact stimuli organization on the computer screen may be much more attractive for user while operating in P300 BCI. In 20 subjects research we showed the effectiveness of our interface. Both accuracy and P300 amplitude were higher for flashing stimuli and complex "flash + movement" stimuli compared to motion-onset stimuli. N200 amplitude was maximal for flashing stimuli, while for "flash + movement" stimuli and motion-onset stimuli it was only a half of it. Similar BCI with complex stimuli may be embedded into compact control systems requiring high level of user attention under impact of negative external effects obstructing the BCI control. PMID- 25707257 TI - [The psychophysiological features of nonepileptic paroxysmal disorders]. AB - 22 patients with panic disorder without agoraphobia, 19 patients with paroxysmal atrial fibrillation and 43 healthy control subjects with use clinic technique, psychometric, neuropsychological, neurophysiological methods (quantitative EEG and auditory event-related potentials P300) were examined. Patients with panic disorder was differed from patients with paroxysmal atrial fibrillation by higher level of anxiety and greater degree cognitive functions disturbances. In comparison with healthy control subjects at panic disorders increased of P300 peak amplitude and the spectral power of EEG beta and theta bands in the right hemisphere was observed, at paroxysmal atrial fibrillation--decreased of P300 peak amplitude and the spectral power of EEG beta band in the both hemispheres. Obtained data may indicate various origin mechanisms of paroxysmal states or neurotic condition (panic disorder) and psychosomatic (paroxysmal atrial fibrillation). PMID- 25707258 TI - [The key role of calcium in the mechanism of deprivational potentiation of population responses in hippocampal CA1 neurons]. AB - We investigated a role of calcium in the mechanisms of deprivational potentiation (DeP) of the popspikes amplitude of CA1 neurons that was induced in consequence of long (60 min) interruption of rare test stimulation (0.05 Hz) of Schaffer collaterals in rat hippocampal slices. There are two phases of deprivational potentiation that have presumably different genesis: short-term initial "peak" (about 12 min) and long-term "plateau" (more than 1 h). The presence of the membrane permeable Ca2+ chelator (BAPTA-AM) in the solution, or decrease of [Ca2+](out), or depletion of intracellular Ca2+ stores (in the presence of thapsigargin/cyclopiazonic acid) led to reduction of the short-term and to suppression of the long-term phases of DeP. Thus the key role of calcium in the DeP induction mechanisms and participation of two main sources (the extracellular environment and the intracellular Ca2+ stores) was demonstrated. PMID- 25707259 TI - [Predicting the moments of critical vigilance decline by visuomotor coordination parameters]. AB - A psychomotor test for induction of the state of monotony and visuomotor coordination analysis has been developed. The subject had to follow a small cicle slowly moving in circular orbit on a screen with a "mouse" cursor. When an additional target unexpectedly appeared, he had to catch it with a cursor and click a "mouse" button when the cursor was on it. Eye movements were recorded with an eyetracker. The experts marked the episodes of declined vigilance based on EEG and video of a subject. Analysis of parameters of visuomotor coordination demonstrated their high sensitivity to the vigilance decline. We have found the increase of variability in pursuit eye movements and "mouse" cursor movements during the episodes of lowered vigilance before the appearance of the additional target and also a growing latency of saccadic eye movements, cursor movements and "mouse" button presses when the cursor contacted the additional target. For latency of saccadic eye movements, cursor movements and mouse button presses significant increase was found 2-3 min before experts can detect vigilance decline too. The ability by visuomotor coordination parameters to predict the moments of critical vigilance decline is discussed. PMID- 25707260 TI - [Molecular and cellular mechanisms of depression. Role of glucocorticoids, cytokines, neurotransmitters, and trophic factors in genesis of depressive disorders]. AB - Here we review modern data on appearance and maintenance of depression at different levels of the body. We discuss a role of impairments of emotional and motivation mechanisms of adaptive behavior in genesis of depression. We demonstate an interaction of stress response and neuroinflammatory processes in pathogenesis of depression and analyze the effects of these molecular cascades on neurotrophic support of the central mechanisms of memory and neurogenesis. PMID- 25707261 TI - [Functional alterations of the arterial vessels in experimental models of type 1 diabetes mellitus]. AB - The review analyzws the literature on the pathological alterations of endothelium, smooth muscle and vasomotor innervation of arterial vessels in animal modes of type 1 diabetes mellitus. Particular attention is paid t the analysis of mechanisms of diabetic abnormalities in the light of modern knowledge on the functioning of the main components of the vascular wall. PMID- 25707262 TI - [Neuronal NO-synthase as the molecular guard of myofiber stability. NO-dependent signaling pathways in the active and unloaded muscle]. AB - The review is dedicated to the signaling pathways triggered by the nitric oxide II in skeletal muscle. Analysis of the current literature shows that during physical exercise of various intensity and regimen the nitric oxide is an essential trigger of the signaling pathways, leading to the alteration of the structural and metabolic myofiber profile and enhancement of its functional capacity. At the same time during the elevated muscle contractile activity (for instance, eccentric activity), NO serves as a protective and stabilizing agent, preventing from the intensification of the proteolytic processes. Data obtained from the experiments with the modulation of the NO at the background of the functional (gravitational) unloading give evidence that neuronal NO synthase activation in this experimental conditions allows to stabilize the degradation pathways and prevent from disuse atrophy development. PMID- 25707263 TI - [Molecular aspects of renal desease]. AB - The review considers molecular mechanisms of chronic renal failure and cancer kidney disease. The most important molecules inducing inflammation are cytokines (MCP-1, TNFalpha, IFN-gamma, IL-1,6,8,18), matrix metalloproteinases MMP 2,3,9,14, tissue inhibitors of metalloproteinases (TIMPs) and grow factors (VEGF PDGE FGF). This signal molecules regulate the activity of immune cells and remodeling extracellular matrix (ECM) components taken place in inflammatory reactions, proliferation, apoptosis and also in the differentiation of kidney cells. On the basis of these data nowadays developed new highly selective approaches to diagnosis, prediction, estimation of efficiency of treatment of renal disease and creating of target drugs. PMID- 25707264 TI - [Galvanic vestibular stimulation in physiological and clinical studies in recent years]. AB - Galvanic vestibular stimulation is a simple, harmless, noninvasive and low-cost research technique. In spite on a long history, it has been recently found popularity as a research tool. At present occurs of its revival as a research and diagnostic tool. Considerable effects of such stimulation for motor, visual, somatosensory, vestibular and cognitive/emotional function as well as for a range of neurological and psychiatric disorders have been reported. Obviously, any process that is able to extract an information due to head acceleration signals is a candidate on galvanic vestibular stimulation. In this review, we describe the basic physiological mechanisms of action of galvanic vestibular stimulation. We also consider a modern data of its influence on human, obtained in physiological and clinical studies. PMID- 25707265 TI - [The theory of mechanical activity of lungs--a creation history, the present and development prospects]. AB - In article the history of creation of the doctrine about respiratory movements of lungs, history of classical mechanics of breathing is stated. Supervision of the paradoxical facts which became a basis for hypothesis creation, then the theory of mechanical activity of lungs are presented. The facts proving mechanical activity of lungs on an inspiration and an expiration are given. Options of interaction of intra pulmonary and extra pulmonary sources of mechanical energy are considered. Theoretical justification for development of the new direction of studying of physiology of mechanical movements of the internal which does not have own skeleton is stated. PMID- 25707268 TI - Milk and serum concentration of ceftiofur following intramammary infusion in goats. AB - Five dairy goats were used to determine the milk and serum concentrations along with elimination characteristics of ceftiofur following intramammary administration. One udder half of each goat was infused twice with 125 mg ceftiofur with a 24-h interval between infusions. Milk samples were collected at 1, 2, 8, and 12 h after the last infusion and then every 12 h for a total of 7 days. Blood was collected from each animal at 3, 8, 12, and 24 h after infusion and then every 24 h for 6 days. Following a washout period of 1 week, the experiment was repeated using the opposite udder half. The elimination half-life of ceftiofur from the mammary gland was 4.7 h. The concentration of ceftiofur was greater than published MIC90 values for Staphylococcus spp. bacteria for 24 h. Ceftiofur was absorbed into systemic circulation from the mammary gland. The maximum concentration was 552 ng/mL at 3 h after infusion, and the serum elimination half-life was 10 h. Intramammary infusion of 125 mg ceftiofur every 24 h can be expected to maintain drug concentration in milk above published MIC90 for Staphylococcus spp. PMID- 25707266 TI - Cocaine self-administration enhances excitatory responses of pyramidal neurons in the rat medial prefrontal cortex to human immunodeficiency virus-1 Tat. AB - The medial prefrontal cortex (mPFC) plays a critical role in reward-motivated behaviors. Repeated cocaine exposure dysregulates the dorsal mPFC, and this is thought to contribute to cocaine-seeking and relapse of abstinent abusers. Neuropathology of the mPFC also occurs in human immunodeficiency virus (HIV) positive individuals, and this is exaggerated in those who also abuse cocaine. The impact of the comorbid condition on mPFC neuronal function is unknown. To fill this knowledge gap, we performed a behavioral and electrophysiological study utilising adult male rats that self-administered cocaine by pressing a lever for 14 once-daily operant sessions. Saline-yoked (SAL-yoked) rats served as controls. Cue reactivity (CR) was used to indicate drug-seeking, assessed by re-exposing the rats to cocaine-paired cues wherein non-reinforced lever pressing was quantified 1 day (CR1) and 18-21 days (CR2) after the 14th operant session. Only cocaine self-administration (COC-SA) rats showed CR. One day after CR2, brain slices were prepared for electrophysiological assessment. Whole-cell patch-clamp recordings of dorsal (prelimbic) mPFC pyramidal neurons from COC-SA rats showed a significant increase in firing evoked by depolarizing currents as compared with those from SAL-yoked control rats. Bath application of the toxic HIV-1 protein transactivator of transcription (Tat) also depolarized neuronal membranes and increased evoked firing. The Tat-induced excitation was greater in the neurons from withdrawn COC-SA rats than in controls. Tat also reduced spike amplitude, and this co-varied with cocaine-seeking during CR2. Taken together, these novel findings provide support at the neuronal level for the concept that the increased excitability of mPFC pyramidal neurons following cocaine self-administration drives drug-seeking and augments the neuropathophysiology caused by HIV-1 Tat. PMID- 25707269 TI - A very slowly progressive neurogenic 'man-in-the-barrel' syndrome. PMID- 25707267 TI - Haematopoietic and immune defects associated with GATA2 mutation. AB - Heterozygous familial or sporadic GATA2 mutations cause a multifaceted disorder, encompassing susceptibility to infection, pulmonary dysfunction, autoimmunity, lymphoedema and malignancy. Although often healthy in childhood, carriers of defective GATA2 alleles develop progressive loss of mononuclear cells (dendritic cells, monocytes, B and Natural Killer lymphocytes), elevated FLT3 ligand, and a 90% risk of clinical complications, including progression to myelodysplastic syndrome (MDS) by 60 years of age. Premature death may occur from childhood due to infection, pulmonary dysfunction, solid malignancy and MDS/acute myeloid leukaemia. GATA2 mutations include frameshifts, amino acid substitutions, insertions and deletions scattered throughout the gene but concentrated in the region encoding the two zinc finger domains. Mutations appear to cause haplo insufficiency, which is known to impair haematopoietic stem cell survival in animal models. Management includes genetic counselling, prevention of infection, cancer surveillance, haematopoietic monitoring and, ultimately, stem cell transplantation upon the development of MDS or another life-threatening complication. PMID- 25707270 TI - Measuring synchrony in the mammalian central circadian circuit. AB - Circadian clocks control daily rhythms in physiology and behavior across all phyla. These rhythms are intrinsic to individual cells that must synchronize to their environment and to each other to anticipate daily events. Recent advances in recording from large numbers of cells for many circadian cycles have enabled researchers to begin to evaluate the mechanisms and consequences of intercellular circadian synchrony. Consequently, methods have been adapted to estimate the period, phase, and amplitude of individual circadian cells and calculate synchrony between cells. Stable synchronization requires that the cells share a common period. As a result, synchronized cells maintain constant phase relationships to each (e.g., with cell 1 peaking an hour before cell 2 each cycle). This chapter reviews how circadian rhythms are recorded from single mammalian cells and details methods for measuring their period and phase synchrony. These methods have been useful, for example, in showing that specific neuropeptides are essential to maintain synchrony among circadian cells. PMID- 25707271 TI - Patch-clamp electrophysiology in Drosophila circadian pacemaker neurons. AB - Circadian clocks modulate the action potential firing frequency of pacemaker neurons. This daily variation in membrane excitability has been described in multiple species: from mollusks to fruit flies and mammals. Here, we provide an overview of the Drosophila pacemaker neural network, how circadian clocks drive neuronal activity within this network and we will present electrophysiological methods that we have applied to directly measure neuronal activity and reveal signal transduction pathways. PMID- 25707273 TI - Neurophysiological analysis of the suprachiasmatic nucleus: a challenge at multiple levels. AB - Understanding the neurophysiology of the circadian timing system requires investigation at multiple levels of organization. Neurons of the suprachiasmatic nucleus (SCN) function as autonomous single-cell oscillators, which warrant studies at the single-cell level. Combining patch-clamp recordings of ion channels with imaging techniques to measure clock gene expression and intracellular calcium has proven extremely valuable to study cellular properties. To achieve and maintain rhythmic activity, SCN neurons require sufficient stimulation (i.e., input) from surrounding cells. At the network level, SCN rhythms are robust and can be measured in vitro, for example, in brain slices that contain the SCN. These recordings revealed that the collective behavior of the SCN neuronal network is strongly determined by the phase dispersal of the neurons. This phase dispersal is plastic, with high synchronization in short photoperiod, desynchronization in long photoperiod, and antiphase oscillations in aging and/or continuous light. In vivo recordings are needed in order to study the SCN as part of a larger network (i.e., interacting with other brain centers) and to study the SCN's response to light. Interestingly, superimposed on the circadian waveform are higher frequency fluctuations that are present in vivo but not in vitro. These fluctuations are attributed to input from other brain centers and computational analyses suggest that these fluctuations are beneficial to the system. Hence, the SCN's properties arise from several organizational levels, and a combination of approaches is needed in order to fully understand the circadian system. PMID- 25707274 TI - Photic entrainment in Drosophila assessed by locomotor activity recordings. AB - Light is the most important Zeitgeber to entrain the circadian clock of the fruit fly Drosophila melanogaster to the 24-h cycle on earth. The fruit fly's circadian clock is very light sensitive, mainly because about half of the 150 clock neurons in the fly's brain express the blue-light photopigment, Cryptochrome, which provokes an immediate degradation of the clock protein Timeless upon activation by light. Consequently, Drosophila's molecular clock can reset very fast to measure the changes in environmental-lighting conditions. However, usually the responses of the molecular clock to light are not directly measured, but conclusions about entrainment of the circadian clock are drawn from recording the flies' locomotor activity rhythms. Here, we review how the flies' locomotor activity can be recorded under different light regimes and how entrainment can be analyzed and properly judged. We also summarize the influence of different recording and lighting methods on the flies' activity pattern, highlight their advantages and disadvantages, and stress general pitfalls. PMID- 25707272 TI - Glial cell regulation of rhythmic behavior. AB - Brain glial cells, in particular astrocytes and microglia, secrete signaling molecules that regulate glia-glia or glia-neuron communication and synaptic activity. While much is known about roles of glial cells in nervous system development, we are only beginning to understand the physiological functions of such cells in the adult brain. Studies in vertebrate and invertebrate models, in particular mice and Drosophila, have revealed roles of glia-neuron communication in the modulation of complex behavior. This chapter emphasizes recent evidence from studies of rodents and Drosophila that highlight the importance of glial cells and similarities or differences in the neural circuits regulating circadian rhythms and sleep in the two models. The chapter discusses cellular, molecular, and genetic approaches that have been useful in these models for understanding how glia-neuron communication contributes to the regulation of rhythmic behavior. PMID- 25707275 TI - Photic regulation of clock systems. AB - Circadian rhythms in physiology and behavior provide a selective advantage by enabling organisms to anticipate rhythmic changes in their environment. These rhythms are based upon a molecular clock generated via an intracellular transcriptional-translational feedback loop involving a number of key clock genes. However, to be of practical use, circadian rhythms need to be entrained to the external environment. In mammals, the primary signal for entrainment is light detected by the photoreceptors of the eye. Research on the mechanisms of photic entrainment has identified a novel photoreceptor system in the retina, consisting of photosensitive retinal ganglion cells expressing the photopigment melanopsin. Light input from these retinal photoreceptors reaches the master circadian pacemaker in the suprachiasmatic nuclei (SCN) via the retinohypothalamic tract, where it then interacts with the molecular clock to bring about entrainment. This chapter focuses on the retinal photoreceptors mediating entrainment, and how light information from the retina is transmitted to the SCN, before detailing recent advances in our understanding of how the molecular clock within the SCN is regulated by light input. Finally, the primary assays that have been used to measure photic entrainment are described. PMID- 25707276 TI - Response of peripheral rhythms to the timing of food intake. AB - Metabolism and physiology in animals show diurnal rhythm to adapt to the daily cycles of activity-rest and the associated rhythm in feeding and fasting. Accordingly, gene expression, protein activities, and numerous metabolites show daily rhythm in abundance. The significance of these rhythms in promoting healthy lifespan and preventing disease has recently come to light. Mice with genetic disruption of circadian rhythm, mice, and humans under shift-work paradigm, and mice fed high-fat diet ad libitum exhibit chronic disruption of feeding-fasting rhythm and dampened daily rhythms in physiology, metabolism, and gene expression. These dampened rhythms are associated with metabolic diseases. Conversely, time restricted feeding, in which mice are fed for certain number of hours every day, restores rhythms and can prevent obesity and metabolic diseases even when mice are fed high-fat diet. These observations seek mechanistic explanations, which will require careful experiments in which feeding duration, genotype, nutrient, and feeding time relative to light:dark cycle will be manipulated and molecular changes in peripheral organs and a few brain regions will be assessed. This chapter will primarily focus on the use of mouse as an experimental animal and the experimental setup so that the molecular readouts can be better interpreted. PMID- 25707277 TI - Circadian regulation of cellular physiology. AB - The circadian clock synchronizes behavioral and physiological processes on a daily basis in anticipation of the light-dark cycle. In mammals, molecular clocks are present in both the central pacemaker neurons and in nearly all peripheral tissues. Clock transcription factors in metabolic tissues coordinate metabolic fuel utilization and storage with alternating periods of feeding and fasting corresponding to the rest-activity cycle. In vitro and in vivo biochemical approaches have led to the discovery of mechanisms underlying the interplay between the molecular clock and the metabolic networks. For example, recent studies have demonstrated that the circadian clock controls rhythmic synthesis of the cofactor nicotinamide adenine dinucleotide (NAD(+)) and activity of NAD(+) dependent sirtuin deacetylase enzymes to regulate mitochondrial function across the circadian cycle. In this chapter, we review current state-of-the-art methods to analyze circadian cycles in mitochondrial bioenergetics, glycolysis, and nucleotide metabolism in both cell-based and animal models. PMID- 25707278 TI - Analysis of the redox oscillations in the circadian clockwork. AB - The evolution of tight coupling between the circadian system and redox homeostasis of the cell has been proposed to coincide roughly with the appearance of the first aerobic organisms, around 3 billion years ago. The rhythmic production of oxygen and its effect on core metabolism are thought to have exerted selective pressure for the temporal segregation of numerous metabolic pathways. Until recently, the only evidence for such coupling came from studies showing circadian cycles in the abundance of various redox metabolites, with many arguing that these oscillations are simply an output from the transcription translation feedback loop. The recent discovery that the peroxiredoxin (PRX) proteins exhibit circadian cycles in their oxidation status, even in the absence of transcription, demonstrated the existence of autonomous oscillations in the redox status of the cell. The PRXs are a family of cellular thiol peroxidases, whose abundance and high reaction rate make them the major cellular sink for cellular peroxides. Interestingly, as part of the normal catalytic cycle, PRXs become inactivated by their own substrate via overoxidation of the catalytic residue, with the inactivated form of the enzyme displaying circadian accumulation. Here, we describe the biochemical properties of the PRX system, with particular emphasis on the features important for the experimental analysis of these enzymes. We will also present a detailed protocol for measuring PRX overoxidation across circadian time in adherent cell cultures, red blood cells, and fruit flies (Drosophila melanogaster), providing practical suggestions for ensuring consistency and reproducibility of the results. PMID- 25707279 TI - Clocks and cardiovascular function. AB - Circadian clocks in central and peripheral tissues enable the temporal synchronization and organization of molecular and physiological processes of rhythmic animals, allowing optimum functioning of cells and organisms at the most appropriate time of day. Disruption of circadian rhythms, from external or internal forces, leads to widespread biological disruption and is postulated to underlie many human conditions, such as the incidence and timing of cardiovascular disease. Here, we describe in vivo and in vitro methodology relevant to studying the role of circadian rhythms in cardiovascular function and dysfunction. PMID- 25707280 TI - Measuring circadian clock function in human cells. AB - Circadian clocks are present in most cells and are essential for maintenance of daily rhythms in physiology, mood, and cognition. Thus, not only neurons of the central circadian pacemaker but also many other peripheral tissues possess the same functional and self-sustained circadian clocks. Surprisingly, however, their properties vary widely within the human population. In recent years, this clock variance has been studied extensively both in health and in disease using robust lentivirus-based reporter technologies to probe circadian function in human peripheral cells as proxies for those in neurologically and physiologically relevant but inaccessible tissues. The same procedures can be used to investigate other conserved signal transduction cascades affecting multiple aspects of human physiology, behavior, and disease. Accessing gene expression variation within human populations via these powerful in vitro cell-based technologies could provide important insights into basic phenotypic diversity or to better interpret patterns of gene expression variation in disease. PMID- 25707281 TI - Human activity and rest in situ. AB - Our lives are structured by the daily alternation of activity and rest, of wake and sleep. Despite significant advances in circadian and sleep research, we still lack answers to many of the most fundamental questions about this conspicuous behavioral pattern. We strongly believe that investigating this pattern in entrained conditions, real-life and daily contexts-in situ-will help the field to elucidate some of these central questions. Here, we present two common approaches for in situ investigation of human activity and rest: the Munich ChronoType Questionnaire (MCTQ) and actimetry. In the first half of this chapter, we provide detailed instructions on how to use and interpret the MCTQ. In addition, we give an overview of the main insights gained with this instrument over the past 10 years, including some new findings on the interaction of light and age on sleep timing. In the second half of this chapter, we introduce the reader to the method of actimetry and share our experience in basic analysis techniques, including visualization, smoothing, and cosine model fitting of in situ recorded data. Additionally, we describe our new approach to automatically detect sleep from activity recordings. Our vision is that the broad use of such easy techniques in real-life settings combined with automated analyses will lead to the creation of large databases. The resulting power of big numbers will promote our understanding of such fundamental biological phenomena as sleep. PMID- 25707282 TI - Phenotyping of neurobehavioral vulnerability to circadian phase during sleep loss. AB - The two-process model of sleep-wake regulation posits a neurobiological drive for sleep that varies homeostatically (increasing as a saturating exponential during wakefulness and decreasing in a like manner during sleep) and a circadian process that neurobiologically modulates both the homeostatic drive for sleep and waking alertness and performance. Endogenous circadian rhythms in neurobehavioral functions, including physiological alertness and cognitive performance, have been demonstrated using laboratory protocols that reveal the interaction of the biological clock with the sleep homeostatic drive. Acute total sleep deprivation and chronic sleep restriction increase homeostatic sleep drive and degrade waking neurobehavioral functions as reflected in sleepiness, attention, cognitive speed, and memory. Notably, there is a high degree of stability in neurobehavioral responses to sleep loss, suggesting that these individual differences are trait like and phenotypic and are not explained by subjects' baseline functioning or a number of other potential predictors. The Psychomotor Vigilance Test is an important tool for phenotyping as it is sensitive to acute total sleep deprivation and chronic sleep restriction, is affected by the circadian and sleep homeostatic drives, shows large intersubject variability in the response to sleep loss, and tracks recovery from sleep restriction. Careful phenotyping is critical to accurately predict human performance (and individual differences) in situations in which the circadian and sleep homeostatic systems are perturbed such as acute total sleep loss, chronic sleep restriction, intermittent sleep loss, shift work, and jet lag. PMID- 25707283 TI - Genetics of human sleep behavioral phenotypes. AB - Quality sleep is critical for daily functions of human beings and thus the timing and duration of sleep are tightly controlled. However, rare genetic variants affecting sleep regulatory mechanisms can result in sleep phenotypes of extremely deviated sleep/wake onset time or duration. Using genetic analyses in families with multiple members expressing particular sleep phenotypes, these sleep associated genetic variants can be identified. Deciphering the nature of these genetic variants using animal models or biochemical methods helps further our understanding of sleep processes. In this chapter, we describe the methods for studying genetics of human sleep behavioral phenotypes. PMID- 25707284 TI - Sleep and circadian rhythm disruption and recognition memory in schizophrenia. AB - Schizophrenia patients often show irregularities in sleep and circadian rhythms and deficits in recognition memory. Similar phenotypes are seen in schizophrenia relevant genetic mouse models, such as synaptosomal associated protein of 25 kDa (Snap-25) point mutant mice, vasoactive intestinal peptide receptor 2 (Vipr2) knockout mice, and neuregulin 1 (Nrg1)-deficient mice. Sleep and circadian abnormalities and impaired recognition memory may be causally related in both schizophrenia patients and schizophrenia-relevant mouse models, since sleep deprivation, abnormal photic input, and the manipulation of core clock genes (cryptochrome 1/2) can all disrupt object recognition memory in rodent models. The recognition deficits observed in patients and mouse models (both schizophrenia-related and -unrelated) are discussed here in terms of the dual process theory of recognition, which postulates that there are two recognition mechanisms-recollection versus familiarity-that can be selectively impaired by brain lesions, neuropsychiatric conditions, and putatively, sleep and circadian rhythm disruption. However, based on this view, the findings from patient studies and studies using genetic mouse models (Nrg1 deficiency) seem to be inconsistent with each other. Schizophrenia patients are impaired at recollection (and to a lesser extent, familiarity judgments), but Nrg1-deficient mice are impaired at familiarity-based object recognition, raising concerns regarding the validity of using these genetically modified mice to model recognition phenotypes observed in patients. This issue can be resolved in future animal studies by examining performance in different variants of the spontaneous recognition task-the standard, perirhinal cortex-dependent, object recognition task versus the hippocampus-dependent object-place recognition task-in order to see which of the two recognition mechanisms is more disrupted. PMID- 25707285 TI - Methods in Enzymology. Circadian rhythms and biological clocks, part B. Preface. PMID- 25707286 TI - CD14, TLR4 and TRAM Show Different Trafficking Dynamics During LPS Stimulation. AB - Toll-like receptor 4 (TLR4) is responsible for the immediate response to Gram negative bacteria and signals via two main pathways by recruitment of distinct pairs of adaptor proteins. Mal-MyD88 [Mal (MyD88-adaptor-like) - MYD88 (Myeloid differentiation primary response gene (88))] is recruited to the plasma membrane to initiate the signaling cascade leading to production of pro-inflammatory cytokines while TRAM-TRIF [TRAM (TRIF-related adaptor molecule)-TRIF (TIR-domain containing adapter-inducing interferon-beta)] is recruited to early endosomes to initiate the subsequent production of type I interferons. We have investigated the dynamics of TLR4 and TRAM during lipopolysaccharide (LPS) stimulation. We found that LPS induced a CD14-dependent immobile fraction of TLR4 in the plasma membrane. Total internal reflection fluorescence microscopy (TIRF) revealed that LPS stimulation induced clustering of TLR4 into small punctate structures in the plasma membrane containing CD14/LPS and clathrin, both in HEK293 cells and the macrophage model cell line U373-CD14. These results suggest that laterally immobilized TLR4 receptor complexes are being formed and prepared for endocytosis. RAB11A was found to be involved in localizing TRAM to the endocytic recycling compartment (ERC) and to early sorting endosomes. Moreover, CD14/LPS but not TRAM was immobilized on RAB11A-positive endosomes, which indicates that TRAM and CD14/LPS can independently be recruited to endosomes. PMID- 25707287 TI - [Microbiological diagnosis compatible with Anaplasma sp. in a patient suffering from febrile syndrome]. PMID- 25707288 TI - A phase 2 study of inotuzumab ozogamicin and rituximab, followed by autologous stem cell transplant in patients with relapsed/refractory diffuse large B-cell lymphoma. AB - This study evaluated the safety and efficacy of inotuzumab ozogamicin (INO), a targeted humanized anti-CD22 antibody conjugated to calicheamicin, plus rituximab (R-INO) every 3 weeks, up to six cycles, followed by high dose therapy and autologous stem cell transplant (HDT-aSCT) in patients with high-risk relapsed/refractory diffuse large B-cell lymphoma (DLBCL). The primary endpoint was overall response (OR) rate after three cycles of R-INO. Sixty-three patients were enrolled. Common grade 3/4 adverse events during R-INO treatment were thrombocytopenia, lymphopenia and neutropenia. OR rate after three cycles of R INO was 28.6% (95% confidence interval: 17.9-41.4). Eighteen patients underwent HDT-aSCT; 2-year progression-free survival (PFS) for these patients was 61.1%. Serious infections and hepatic toxicity following aSCT occurred in 33% and 22%, respectively. One- and 2-year PFS rates for all enrolled patients were 28.9% and 25.3%, respectively (median, 3.0 months). R-INO had lower than expected activity as a salvage regimen for transplant eligible patients with DLBCL. PMID- 25707289 TI - Rituximab and glucocorticoids: friends or foes? It is all about timing. PMID- 25707290 TI - Multivariate analysis of binge drinking in young adult population: Data analysis of the 2007 Survey of Lifestyle, Attitude and Nutrition in Ireland. AB - AIMS: Alcohol use is the third highest risk factor for disease and disability. This study explored the association between binge drinking and mental health, general health, and diet and nutrition of young adults. METHODS: A sub-sample of 2590 adults aged 18-29 years was selected from 10 364 participants in the survey to investigate the effect of binge drinking exposure on depression, anxiety, quality of life and nutrition. The Alcohol Use Disorder Identification Test Consumption (AUDIT-C) was used to assess hazardous drinking. A short version of the World Health Organization Composite International Diagnostic Interview was used to assess mental health. The quality of life was measured through the World Health Organization Quality of Life Survey. Multivariate regression analysis was performed. Potential confounders were age, gender, social class and AUDIT-C score. A two-tailed P-value was presented with a significance cut-off point at 0.05. RESULTS: Univariate regression analysis showed significant associations between binge drinking and depression (odds ratio [OR] = 1.8; P < 0.03), eating fried food (OR = 0.4; P < 0.001) and poor quality of life (OR = 1.5; P = 0.01). In a multivariate model adjusted for age, gender, social class and the AUDIT-C results, the association between binge drinking and depression disappeared despite the high risk indicated by the OR in the univariate analysis. A significant relation was found between binge drinking and eating fried food (OR = 0.43 and P < 0.001) and quality of life (OR = 1.09; P = 0.01) in the fully adjusted models. CONCLUSIONS: The link between alcohol drinking and mental health remains poorly understood. More research into the relation between different aspects of alcohol consumption, mental health and quality of life is required. PMID- 25707291 TI - Identification by Next Generation Sequencing of a Novel PKP2 Mutation in Arrhythmogenic Right Ventricular Dysplasia. PMID- 25707292 TI - Malignant Pleural Mesothelioma: Accuracy of CT Against Immunohistochemical Test Among the Mexican Population. AB - BACKGROUND AND AIMS: Malignant pleural mesothelioma (MPM) is associated with occupational and environmental exposure to asbestos. The incidence is expected to increase as the use of asbestos is not prohibited in many countries, such as in Mexico. We undertook this study to determine sensitivity, specificity, predictive values and likelihood ratios of computed tomography (CT) in a sample from Mexican population with suspected MPM and other pleuropulmonary diseases. METHODS: CT films of 38 patients suspected of having MPM were analyzed. A single observer was blinded to MPM diagnoses. The frequencies of ten CT findings were identified. A cut-off point of >=5 CT findings was established to determine high MPM probability. Sensitivity, specificity, predictive values and likelihood ratio of the CT against biopsy using immunohistochemical testing (IHC) for MPM were calculated. RESULTS: Of the 38 patients, 31 had MPM and seven had lung adenocarcinoma. The five key findings were mediastinal pleural thickening 96.7% (n = 30), nodular pleural thickening 93.3% (n = 29), pleural mass 83.9% (n = 26), diminished lung 70.9% (n = 22) and contracted hemithorax 70.9% (n = 22). Sensitivity 96.8% (83.2-99.4), specificity 85.7% (42.2-97.6), positive likelihood ratio 6.7 (1.1-41.6), and negative likelihood ratio of 0.04 (0.01-0.2) were reported. CONCLUSIONS: Sensitivity and specificity in this study was greater than previously reported, 96.8% and 85.7 vs. 93.2 and 65.6%, respectively. CT is an easily accessible and useful tool that should be incorporated into the medical education of general physicians to improve MPM diagnosis of suspected cases. PMID- 25707293 TI - Actual Isothermal Effects of Water-Filtered Infrared A-Irradiation. AB - In this study, the athermal effects of water-filtered infrared A (wIRA) irradiation (780-1400 nm) on human dermal fibroblasts were investigated. For this purpose, cells were exposed to wIRA-irradiation (178 mW cm(-2) for 1 h), while a sophisticated experimental setup prevented warming of the samples exceeding 0.1 degrees C. The investigated parameters were the formation of reactive oxygen species (ROS), mitochondrial membrane potential and superoxide release, protein oxidation, proliferation rate, as well as intracellular Ca(2+) -release in single cells, most of them quantified via fluorescence microscopy and fluorimetric techniques. The existence of actual athermal wIRA-effects is still intensively discussed, since their detection requires a careful experimental setup and both efficient and powerful temperature regulation of the exposed samples. Here, we can definitively show that some of the supposed athermal wIRA-effects may be rather artifacts, since wIRA did not reveal any impact on the above mentioned parameters-as long as the temperature of the exposed cells was carefully maintained. Though, we were able to identify an athermal DNA-protective wIRA effect, since the induced DNA damage (quantified via 8-Oxo-G-formation) was significantly decreased after a subsequent UVB-exposure. These results suggest that many of the supposed athermal wIRA-effects can be induced by pure warming of the samples, independent from any wIRA-irradiation. PMID- 25707294 TI - Efficient quantification of the phenolic profiles of Zanthoxylum bungeanum leaves and correlation between chromatographic fingerprint and antioxidant activity. AB - Sixteen subsequent fractions were prepared from the ethyl acetate fraction of Zanthoxylum bungeanum leaves after bio-guided chromatographic separation. The HPLC profiles and antioxidant activity of the various fractions indicated that the content of eight phenolic compounds (chlorogenic acid, epicatechin, rutin, hyperoside, trifolin, quercitrin, afzelin and quercetin) and antioxidant activity vary significantly, and high concentrations of a combination of eight phenolic compounds would result in an increase of the antioxidant activity. These results suggested that the eight compounds could be used as chemical markers for quality assessment of Z. bungeanum leaves. Correlation between chromatographic fingerprint and antioxidant activity of the fractions showed that quercitrin and hyperoside play crucial roles in the antioxidant activity, and they can be seen as the milestone for quality control. The findings also suggested that five obtained fractions (E-3-3, E-2-4, E-7, E-5 and E-4) could become useful supplements for functional food ingredients and health-related products. PMID- 25707295 TI - IRcall and IRclassifier: two methods for flexible detection of intron retention events from RNA-Seq data. AB - BACKGROUND: The emergence of next-generation RNA sequencing (RNA-Seq) provides tremendous opportunities for researchers to analyze alternative splicing on a genome-wide scale. However, accurate detection of intron retention (IR) events from RNA-Seq data has remained an unresolved challenge in next-generation sequencing (NGS) studies. RESULTS: We propose two new methods: IRcall and IRclassifier to detect IR events from RNA-Seq data. Our methods combine together gene expression information, read coverage within an intron, and read counts (within introns, within flanking exons, supporting splice junctions, and overlapping with 5' splice site/ 3' splice site), employing ranking strategy and classifiers to detect IR events. We applied our approaches to one published RNA Seq data on contrasting skip mutant and wild-type in Arabidopsis thaliana. Compared with three state-of-the-art methods, IRcall and IRclassifier could effectively filter out false positives, and predict more accurate IR events. AVAILABILITY: The data and codes of IRcall and IRclassifier are available at http://mlg.hit.edu.cn/ybai/IR/IRcallAndIRclass.html. PMID- 25707296 TI - Absorption spectroscopy and imaging from the visible through mid-infrared with 20 nm resolution. AB - Absorption spectroscopy and mapping from visible through mid-IR wavelengths has been achieved with spatial resolution exceeding the limit imposed by diffraction via the photothermal induced resonance technique. Correlated vibrational (chemical), and electronic properties are obtained simultaneously with topography with a wavelength-independent resolution of ~20 nm using a single laboratory scale instrument. This marks the highest resolution reported for PTIR, as determined by comparing height and PTIR images, and its first extension to near IR and visible wavelengths. PMID- 25707297 TI - Determinants of Loneliness among Older Adults in Canada. AB - The purpose of this study was to determine the key determinants of loneliness of older Canadians. We drew on the assumptions concerning the importance of person environment fit to test the relative importance of personal characteristics, deprived living conditions, social network/social engagement, and satisfaction in explaining loneliness. Data comprised a sample of 3,799 respondents over age 65 drawn from Statistics Canada's General Social Survey, Cycle 22. Personal characteristics, social network size and composition, and satisfaction with network contact were found to be related to loneliness, as were indicators of living in economically and socially challenging conditions. Older adults who had experienced a recent downturn in their financial situation, and who lacked the help needed to cope with a recent personal challenge, reported higher levels of loneliness. A striking feature of our findings is the relatively low scores on loneliness of older Canadians compared to older adults in other countries. PMID- 25707298 TI - Application of AJCC/UICC and WHO-2010 classifications for GEP-NEN in Chinese patients. AB - OBJECTIVE: To assess the prognostic value in Chinese patients of two new systems, the World Health Organization (WHO)-2010 and the American Joint Committee on Cancer and the Union for International Cancer Control (AJCC/UICC) systems, for the classification of gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN). METHODS: One hundred and three patients with GEP-NEN treated at the First Affiliated Hospital of Nanjing Medical University from January 2003 to December 2011 were included in the study. All patients were diagnosed pathologically and had complete follow-up data. Univariate and multivariate analyses of their clinicopathological characteristics were performed. RESULTS: The 5-year survival rates were 95%, 74%, 24% and 15% based on the AJCC/UICC stages I to IV, and 92%, 62% and 29% according to WHO-2010 grades 1 to 3, respectively, in patients with GEP-NEN. A higher mortality was observed in patients with AJCC/UICC stage III and IV tumors compared with those at stage I-II, and patients with stage II compared with those with stage I, whereas there was no difference in survival between stage IV and III patients. Based on the WHO-2010 grading classification, patients with grade 3 tumors had the lowest survival rate than those with grade 1 and 2 tumors, followed by patients with grade 2 tumors. CONCLUSION: The WHO-2010 and AJCC/UICC staging systems can effectively evaluate the prognosis of patients with GEP-NEN, although the latter might not accurately discriminate the prognosis of patients with local metastasis from those having distant metastasis. PMID- 25707299 TI - Event related desynchronisation of mu-wave over right sensorimotor cortex at baseline may predict subsequent response to antipsychotics in Schizophrenia. AB - Mirror neuron system (MNS) has been demonstrated to be defective in patients with schizophrenia. This paper report findings from a high resolution (192-channel) EEG study conducted on 15 drug free/naive consenting schizophrenia patients, in which the specific role of right hemispheric MNS has been explored over 4 weeks of antipsychotic treatment. The authors used mu wave suppression paradigm, and found that baseline right MNS mu suppression correlated negatively with and predicted relative improvement in thought disturbance cluster score of PANSS during first 4 weeks of drug treatment. PMID- 25707300 TI - Survival of Lactobacillus casei strain Shirota in the intestines of healthy Chinese adults. AB - Lactobacillus casei strain Shirota (LcS) is a widely used probiotic strain with health benefits. In this study, the survival of LcS in the intestines of healthy Chinese adults was assessed and the effects of LcS on stool consistency, stool SCFAs and intestinal microbiota evaluated. Subjects consumed 100 mL per day of a probiotic beverage containing 1.0 * 10(8) CFU/mL of LcS for 14 days. LcS were enumerated using a culture method and the colony identity confirmed by ELISA. Fourteen days after ingestion, the amount of LcS recovered from fecal samples was between 6.86 +/- 0.80 and 7.17 +/- 0.57 Log10 CFU/g of feces (mean +/- SD). The intestinal microbiotas were analyzed by denaturing gradient gel electrophoresis. Principal component analysis showed that consuming LcS significantly changed fecal microbiota profiles. According to redundancy analysis, the amounts of 25 bacterial strains were significantly correlated with LcS intake (P < 0.05), 11 of them positively and fourteen negatively. Concentrations of acetic acid and propionic acid in feces were significantly lower during the ingestion period than during the baseline period (P < 0.05). These results confirm that LcS can survive passage through the gastrointestinal tract of Chinese people; however, they were found to have little ability to persist once their consumption had ceased. Furthermore, consumption of probiotic beverages containing LcS can modulate the composition of the intestinal microbiota on a long-term basis, resulting in decreased concentrations of SCFAs in the gut. PMID- 25707301 TI - Levodopa-induced neutropenia. PMID- 25707302 TI - Increased urinary indoxyl sulfate (indican): new insights into gut dysbiosis in Parkinson's disease. AB - INTRODUCTION: Changes in the composition of gut microflora have been associated with an increase in chronic diseases. Indican urinary concentration is one of the most common and easily assessable markers of intestinal dysbiosis. Little information is available on intestinal dysbiosis in Parkinson's disease (PD). We decided to investigate indican urinary concentrations in a cohort of PD patients. METHODS: A case-control study including PD patients (N = 68) on treatment with levodopa (PD) or on no pharmacological treatment (De Novo, DPD; N=34) and an age and gender-matched healthy control group (CTR; N=50). Main confounders, such as nutritional habits and constipation diagnosed according to Rome III criteria, were also investigated. RESULTS: Indican urinary concentrations were significantly higher in PD and DPD than in CTR (P < 0.001 and P < 0.01, respectively). In PD patients the concentrations were unrelated to the presence of constipation, whereas this symptom was associated with higher concentrations in controls (P=0.043). The frequency of dairy product consumption was also positively associated with increased concentrations (P=0.008). Predictors of indican concentrations were sought by multivariate linear regression analysis. The higher indican urinary concentrations found in both DPD (P=0.045) and PD (P=0.023) patients persisted after adjustment for age, gender, BMI, constipation and consumption of dairy products. CONCLUSIONS: Gut dysbiosis seems to be an important issue in PD, independently of the presence of constipation and starting from the early stages of the disease. The role of gut dysbiosis in the pathogenesis of PD deserves further investigation. PMID- 25707303 TI - Early graft loss after kidney transplantation: risk factors and consequences. AB - Early graft loss (EGL) after kidney transplantation is a catastrophic outcome that is assumed to be more likely after the use of kidneys from suboptimal donors. We therefore examined its incidence, risk factors and consequences in our center in relation to different donor types. Of 801 recipients who received a kidney-only transplant from deceased donors, 50 (6.2%) suffered EGL within 30 days of transplantation. Significant risks factors for EGL were donation after circulatory death (DCD) (odds ratio [OR] 2.88; p = 0.006), expanded criteria donor (ECD) transplantation (OR 4.22; p = 0.010), donor age (OR 1.03; p = 0.044) and recipient past history of thrombosis (OR 4.91; p = 0.001). Recipients with EGL had 12.28 times increased risk of death within the first year, but long-term survival was worse for patients remaining on the waiting list. In comparison with patients on the waiting list but not transplanted, and with all patients on the waiting list, the risk of death after EGL decreased to baseline 4 and 23 months after transplantation, respectively. Our findings suggest that DCD and ECD transplantation are significant risk factors for EGL, which is a major risk factor for recipient death. However, long-term mortality is even greater for those remaining on the waiting list. PMID- 25707304 TI - Network inference in the presence of latent confounders: the role of instantaneous causalities. AB - BACKGROUND: Detecting causal interactions in multivariate systems, in terms of Granger-causality, is of major interest in the Neurosciences. Typically, it is almost impossible to observe all components of the system. Missing certain components can lead to the appearance of spurious interactions. The aim of this study is to demonstrate the effect of this and to demonstrate that distinction between latent confounders and volume conduction is possible in some cases. NEW METHOD: Our new method uses a combination of renormalised partial directed coherence and analysis of the (partial) covariance matrix of residual noise process to detect instantaneous, spurious interactions. Sub-network analyses are performed to infer the true network structure of the underlying system. RESULTS: We provide evidence that it is possible to distinguish between instantaneous interactions that occur as a result of a latent confounder and those that occur as a result of volume conduction. COMPARISON WITH EXISTING METHODS: Our novel approach demonstrates to what extent inference of unobserved important processes as well as the distinction between latent confounders and volume conduction is possible. We suggest a combination of measures of Granger-causality and covariance selection models to achieve this numerically. CONCLUSIONS: Sub-network analyses enable a much more precise and correct inference of the true underlying network structure in some cases. From this it is possible to distinguish between unobserved processes and volume conduction. Our approach is straightforwardly adaptable to various measures of Granger-causality emphasising its ubiquitous successful applicability. PMID- 25707305 TI - Three-dimensional stereotactic atlas of the adult human skull correlated with the brain, cranial nerves, and intracranial vasculature. AB - BACKGROUND: Although the adult human skull is a complex and multifunctional structure, its 3D, complete, realistic, and stereotactic atlas has not yet been created. This work addresses the construction of a 3D interactive atlas of the adult human skull spatially correlated with the brain, cranial nerves, and intracranial vasculature. NEW METHOD: The process of atlas construction included computed tomography (CT) high-resolution scan acquisition, skull extraction, skull parcellation, 3D disarticulated bone surface modeling, 3D model simplification, brain-skull registration, 3D surface editing, 3D surface naming and color-coding, integration of the CT-derived 3D bony models with the existing brain atlas, and validation. RESULTS: The virtual skull model created is complete with all 29 bones, including the auditory ossicles (being among the smallest bones). It contains all typical bony features and landmarks. COMPARISON WITH EXISTING METHOD(S): The created skull model is superior to the existing skull models in terms of completeness, realism, and integration with the brain along with blood vessels and cranial nerves. CONCLUSIONS: This skull atlas is valuable for medical students and residents to easily get familiarized with the skull and surrounding anatomy with a few clicks. The atlas is also useful for educators to prepare teaching materials. It may potentially serve as a reference aid in the reading and operating rooms. PMID- 25707307 TI - Characterization and identification of ubiquitin conjugation sites with E3 ligase recognition specificities. AB - BACKGROUND: In eukaryotes, ubiquitin-conjugation is an important mechanism underlying proteasome-mediated degradation of proteins, and as such, plays an essential role in the regulation of many cellular processes. In the ubiquitin proteasome pathway, E3 ligases play important roles by recognizing a specific protein substrate and catalyzing the attachment of ubiquitin to a lysine (K) residue. As more and more experimental data on ubiquitin conjugation sites become available, it becomes possible to develop prediction models that can be scaled to big data. However, no development that focuses on the investigation of ubiquitinated substrate specificities has existed. Herein, we present an approach that exploits an iteratively statistical method to identify ubiquitin conjugation sites with substrate site specificities. RESULTS: In this investigation, totally 6259 experimentally validated ubiquitinated proteins were obtained from dbPTM. After having filtered out homologous fragments with 40% sequence identity, the training data set contained 2658 ubiquitination sites (positive data) and 5532 non-ubiquitinated sites (negative data). Due to the difficulty in characterizing the substrate site specificities of E3 ligases by conventional sequence logo analysis, a recursively statistical method has been applied to obtain significant conserved motifs. The profile hidden Markov model (profile HMM) was adopted to construct the predictive models learned from the identified substrate motifs. A five-fold cross validation was then used to evaluate the predictive model, achieving sensitivity, specificity, and accuracy of 73.07%, 65.46%, and 67.93%, respectively. Additionally, an independent testing set, completely blind to the training data of the predictive model, was used to demonstrate that the proposed method could provide a promising accuracy (76.13%) and outperform other ubiquitination site prediction tool. CONCLUSION: A case study demonstrated the effectiveness of the characterized substrate motifs for identifying ubiquitination sites. The proposed method presents a practical means of preliminary analysis and greatly diminishes the total number of potential targets required for further experimental confirmation. This method may help unravel their mechanisms and roles in E3 recognition and ubiquitin-mediated protein degradation. PMID- 25707308 TI - Visuospatial and mathematical dysfunction in major depressive disorder and/or panic disorder: A study of parietal functioning. AB - The parietal cortex is critical for several different cognitive functions, including visuospatial processing and mathematical abilities. There is strong evidence indicating parietal dysfunction in depression. However, it is less clear whether anxiety is associated with parietal dysfunction and whether comorbid depression and anxiety are associated with greater impairment. The present study compared participants with major depression (MDD), panic disorder (PD), comorbid MDD/PD and controls on neuropsychological measures of visuospatial processing, Judgement of Line Orientation (JLO), and mathematical abilities, Wide Range Achievement Test (WRAT) Arithmetic. Only comorbid MDD/PD was associated with decreased performance on JLO, whereas all psychopathological groups exhibited comparably decreased performance on WRAT Arithmetic. Furthermore, the results were not accounted for by other comorbid disorders, medication use or psychopathology severity. The present study suggests comorbid depression and anxious arousal are associated with impairment in visuospatial processing and provides novel evidence indicating mathematical deficits across depression and/or anxiety. Implications for understanding parietal dysfunction in internalising psychopathology are discussed. PMID- 25707309 TI - Flipping the classroom to teach population health: Increasing the relevance. AB - In recent years, there have been multiple calls to enhance the population health and health promotion aspects of nursing programs. Further impetus has been provided by passage of the Affordable Care Act in 2010 with its focus on prevention. The need to develop students who can critically think and apply knowledge learned is crucial to the development of nurses who can integrate and apply the concepts of population-focused practice in society and a healthcare system undergoing transformation. This coupled with the ever changing needs of learners requires a different approach to content delivery and presentation. Flipped classroom courses, with an online component, offer the flexibility and technology desired by current undergraduate students. The use of a flipped classroom approach to re-design a population health course in a Midwestern nursing program resulted in stronger course evaluations from students and reflected better student understanding of the relevance of such content in a nursing curriculum. PMID- 25707310 TI - Interprofessional simulation of a retained placenta and postpartum hemorrhage. AB - To improve quality and safety in healthcare, national and international organizations have called for students to receive dedicated training in interprofessional communication and collaboration. We developed a simulation for nurse-midwifery and nurse-anesthesia students, using the Core Competencies for Interprofessional Collaborative Practice framework. The simulation, involving a postpartum women with a retained placenta and acute blood loss, allowed students to collaboratively manage a high-risk situation. We present the details of the simulation and evaluation to assist educators. PMID- 25707311 TI - Candidate genes in quantitative trait loci associated with absolute and relative kidney weight in rats with Inherited Stress Induced Arterial Hypertension. AB - BACKGROUND: The kidney mass is significantly increased in hypertensive ISIAH rats with Inherited Stress Induced Arterial Hypertension as compared with normotensive WAG rats. The QTL/microarray approach was carried out to determine the positional candidate genes in the QTL for absolute and relative kidney weight. RESULTS: Several known and predicted genes differentially expressed in ISIAH and WAG kidney were mapped to genetic loci associated with the absolute and relative kidney weight in 6-month old F2 hybrid (ISIAHxWAG) males. The knowledge-driven filtering of the list of candidates helped to suggest several positional candidate genes, which may be related to the structural and mass changes in hypertensive ISIAH kidney. CONCLUSIONS: The further experimental validation of causative genes and detection of polymorphisms will provide opportunities to advance our understanding of the underlying nature of structural and mass changes in hypertensive ISIAH kidney. PMID- 25707312 TI - Membrane interaction of antimicrobial peptides using E. coli lipid extract as model bacterial cell membranes and SFG spectroscopy. AB - Supported lipid bilayers are used as a convenient model cell membrane system to study biologically important molecule-lipid interactions in situ. However, the lipid bilayer models are often simple and the acquired results with these models may not provide all pertinent information related to a real cell membrane. In this work, we use sum frequency generation (SFG) vibrational spectroscopy to study molecular-level interactions between the antimicrobial peptides (AMPs) MSI 594, ovispirin-1 G18, magainin 2 and a simple 1,2-dipalmitoyl-d62-sn-glycero-3 phosphoglycerol (dDPPG)/1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol (POPG) bilayer. We compared such interactions to those between the AMPs and a more complex dDPPG/Escherichia coli (E. coli) polar lipid extract bilayer. We show that to fully understand more complex aspects of peptide-bilayer interaction, such as interaction kinetics, a heterogeneous lipid composition is required, such as the E. coli polar lipid extract. The discrepancy in peptide-bilayer interaction is likely due in part to the difference in bilayer charge between the two systems since highly negative charged lipids can promote more favorable electrostatic interactions between the peptide and lipid bilayer. Results presented in this paper indicate that more complex model bilayers are needed to accurately analyze peptide-cell membrane interactions and demonstrates the importance of using an appropriate lipid composition to study AMP interaction properties. PMID- 25707314 TI - Arrays of quasi-hexagonally ordered silica nanopillars with independently controlled areal density, diameter and height gradients. AB - A consecutive fabrication approach of independently tailored gradients of the topographical parameters distance, diameter and height in arrays of well-ordered nanopillars on smooth SiO2-Si-wafers is presented. For this purpose, previously reported preparation techniques are further developed and combined. First, self assembly of Au-salt loaded micelles by dip-coating with computer-controlled pulling-out velocities and subsequent hydrogen plasma treatment produce quasi hexagonally ordered, 2-dimensional arrays of Au nanoparticles (NPs) with unidirectional variations of the interparticle distances along the pulling direction between 50-120 nm. Second, the distance (or areal density) gradient profile received in this way is superimposed with a diameter-controlled gradient profile of the NPs applying a selective photochemical growth technique. For demonstration, a 1D shutter is used for locally defined UV exposure times to prepare Au NP size gradients varying between 12 and 30 nm. Third, these double gradient NP arrangements serve as etching masks in a following reactive ion etching step delivering arrays of nanopillars. For height gradient generation, the etching time is locally controlled by applying a shutter made from Si wafer piece. Due to the high flexibility of the etching process, the preparation route works on various materials such as cover slips, silicon, silicon oxide, silicon nitride and silicon carbide. PMID- 25707313 TI - Mapping area variability in social and behavioural difficulties among Glasgow pre schoolers: linkage of a survey of pre-school staff with routine monitoring data. AB - BACKGROUND: Social, emotional and behavioural development in early to middle childhood impact upon many outcomes in future life and are influenced by home, neighbourhood and school environments. We used linked data to investigate differences between areas in Glasgow City in level of difficulties in pre-school age children, after consideration of demographics, including area-level deprivation. METHODS: Pre-school education staff completed Strengths and Difficulties Questionnaires (SDQ) on all children progressing to school from a local authority or partnership (local authority-funded private) pre-school in Glasgow City between 2010 and 2012. These data were linked to individual (age, gender) and area-level (deprivation) demographics from the City Council Education Services Department. Statistical models were fitted to the SDQ scores, adjusting for age, gender, area deprivation, year of school entry, pre-school establishment attended and electoral ward of residence. Correlation between neighbouring wards was incorporated to allow for clustering of scores. RESULTS: Boys and those living in more deprived areas had higher levels of difficulties. Children aged 5.0-5.5 years had fewest difficulties, while the oldest and youngest children had similar levels of difficulties. There were no significant secular trends by year of school entry. There remained differences among areas after adjusting for these variables, with children living in some areas having fewer difficulties than would be expected based on their socio-demographic characteristics. CONCLUSIONS: There remained differences in children's levels of difficulties between areas after adjusting for age, gender, area deprivation and year of school entry. Children in some very deprived areas had fewer difficulties than might be expected, while those in relatively affluent areas had more difficulties than expected based on their deprivation level. There may be other, unmeasured, individual- and area-level reasons for children's level of difficulties, and these require further exploration. PMID- 25707315 TI - Oestrous cycle-dependent expression of Fas and Bcl2 family gene products in normal canine endometrium. AB - During the oestrous cycle canine endometrium undergoes cyclical cellular proliferation, apoptosis and differentiation. To study the regulation of endometrial apoptosis and proliferation events the expression of apoptosis related genes was analysed by real-time polymerase chain reaction and cellular expression of their proteins was identified through immunohistochemistry. Cellular apoptosis and proliferation events were detected by TdT-mediated dUTP biotin nick end labeling (TUNEL) and proliferation marker Ki67 immunostaining, respectively. The highest proliferative index was observed in the follicular phase (all endometrial cellular components) and at early dioestrus (basal glands). This was associated with a low apoptotic index and a strong expression of anti- (Bcl2) and pro-apoptotic proteins (Fas, FasL, Bax). Subsequently (Days 11-45 of dioestrus), basal glandular epithelium experienced the highest apoptotic index, coincidental with a decrease of Bcl2 expression and a low ratio of Bcl2/Bax transcription. An increase in the apoptotic index of crypts, stromal and endothelial cells was observed at late dioestrus and the beginning of anoestrus. These results indicate that pro- and anti-apoptotic proteins regulate the balance between cell proliferation and death in the canine endometrium during the oestrous cycle. High Bcl2 expression in both the follicular and early dioestrous phases stimulate glandular proliferation and prevent apoptosis but, in the non pregnant uterus, a decrease in Bcl2 expression together with an increase in pro apoptotic proteins induces apoptosis of basal glandular epithelium cells. PMID- 25707306 TI - Predictive structural dynamic network analysis. AB - BACKGROUND: Classifying individuals based on magnetic resonance data is an important task in neuroscience. Existing brain network-based methods to classify subjects analyze data from a cross-sectional study and these methods cannot classify subjects based on longitudinal data. We propose a network-based predictive modeling method to classify subjects based on longitudinal magnetic resonance data. NEW METHOD: Our method generates a dynamic Bayesian network model for each group which represents complex spatiotemporal interactions among brain regions, and then calculates a score representing that subject's deviation from expected network patterns. This network-derived score, along with other candidate predictors, are used to construct predictive models. RESULTS: We validated the proposed method based on simulated data and the Alzheimer's Disease Neuroimaging Initiative study. For the Alzheimer's Disease Neuroimaging Initiative study, we built a predictive model based on the baseline biomarker characterizing the baseline state and the network-based score which was constructed based on the state transition probability matrix. We found that this combined model achieved 0.86 accuracy, 0.85 sensitivity, and 0.87 specificity. COMPARISON WITH EXISTING METHODS: For the Alzheimer's Disease Neuroimaging Initiative study, the model based on the baseline biomarkers achieved 0.77 accuracy. The accuracy of our model is significantly better than the model based on the baseline biomarkers (p value=0.002). CONCLUSIONS: We have presented a method to classify subjects based on structural dynamic network model based scores. This method is of great importance to distinguish subjects based on structural network dynamics and the understanding of the network architecture of brain processes and disorders. PMID- 25707316 TI - Baseline hydrocarbon levels in New Zealand coastal and marine avifauna. AB - The external effects of oil on wildlife can be obvious and acute. Internal effects are more difficult to detect and can occur without any external signs. To quantify internal effects from oil ingestion by wildlife during an oil spill, baseline levels of ubiquitous hydrocarbon fractions, like polycyclic aromatic hydrocarbons (PAHs), need to be established. With these baseline values the extent of impact from exposure during a spill can be determined. This research represents the first investigation of baseline levels for 22 PAHs in New Zealand coastal and marine avian wildlife. Eighty-five liver samples were tested from 18 species. PAHs were identified in 98% of livers sampled with concentrations ranging from 0 to 1341.6 ng/g lipid wt or on wet wt basis, 0 to 29.5 ng/g. Overall, concentrations were low relative to other globally reported avian values. PAH concentration variability was linked with species foraging habitat and migratory patterns. PMID- 25707318 TI - Two new indole derivatives from a marine sponge Ircinia sp. collected at Iriomote Island. AB - Two new indole derivatives, 5-hydroxy-1H-indole-3-carboxylic acid ethyl ester (1) and 5-hydroxy-1H-indole-3-glyoxylate ethyl ester (2), and seven known indole alkaloids, dragmacidonamine B (3), gesashidine A (4), hyrtiosulawesine (5), hyrtiomanzamine (6), hyrtimomine D (7), hyrtiosine A (8), and 5-hydroxy-1H-indole 3-carbaldehyde (9), were isolated from a marine sponge Ircinia sp., Irciniidae, collected at Iriomote Island. The structures of 1 and 2 were elucidated on the basis of their spectroscopic data. Compound 1 has previously been reported as a synthetic intermediate and this is the first time that it has been obtained from a natural source. PMID- 25707317 TI - An ultrahigh-performance liquid chromatography method with electrospray ionization tandem mass spectrometry for simultaneous quantification of five phytohormones in medicinal plant Glycyrrhiza uralensis under abscisic acid stress. AB - An efficient simplified method was developed to determine multiple classes of phytohormones simultaneously in the medicinal plant Glycyrrhiza uralensis. Ultrahigh-performance liquid chromatography electrospray ionization tandem mass spectrometry (UPLC/ESI-MS/MS) with multiple reaction monitoring (MRM) in negative mode was used for quantification. The five studied phytohormones are gibberellic acid (GA3), abscisic acid (ABA), jasmonic acid (JA), indole-3-acetic acid, and salicylic acid (SA). Only 100 mg of fresh leaves was needed, with one purification step based on C18 solid-phase extraction. Cinnamic acid was chosen as the internal standard instead of isotope-labeled internal standards. Under the optimized conditions, the five phytohormones with internal standard were separated within 4 min, with good linearities and high sensitivity. The validated method was applied to monitor the spatial and temporal changes of the five phytohormones in G. uralensis under ABA stress. The levels of GA3, ABA, JA, and SA in leaves of G. uralensis were increased at different times and with different tendencies in the reported stress mode. These changes in phytohormone levels are discussed in the context of a possible feedback regulation mechanism. Understanding this mechanism will provide a good chance of revealing the mutual interplay between different biosynthetic routes, which could further help elucidate the mechanisms of effective composition accumulation in medicinal plants. PMID- 25707319 TI - Determination of concentration and activity of immobilized enzymes. AB - Methods that directly measure the concentration of surface-immobilized biomolecules are scarce. More commonly, the concentration of the soluble molecule is measured before and after immobilization, and the bound concentration is assessed by elimination, assuming that all bound molecules are active. An assay was developed for measuring the active site concentration, activity, and thereby the catalytic turnover rate (kcat) of an immobilized dihydrofolate reductase as a model system. The new method yielded a similar first-order rate constant, kcat, to that of the same enzyme in solution. The findings indicate that the activity of the immobilized enzyme, when separated from the surface by the DNA spacers, has not been altered. In addition, a new immobilization method that leads to solution-like activity of the enzyme on the surface is described. The approaches developed here for immobilization and for determining the concentration of an immobilized enzyme are general and can be extended to other enzymes, receptors, and antibodies. PMID- 25707320 TI - Engineered high-affinity nanobodies recognizing staphylococcal Protein A and suitable for native isolation of protein complexes. AB - In addition to its high affinity for antibody Fc domains, staphylococcal Protein A has been shown to bind certain Fab domains. We investigated this in order to develop a small, recombinant Protein A-binding alternative to immunoglobulin G (IgG) from nanobodies, single-domain antibodies derived from a camelid variant IgG's variable region. We engineered a nanobody with affinity solely for Protein A as well as a dimerized version of higher affinity for typical multidomain Protein A constructs. Because this recombinant nanobody can be immobilized using a cleavable crosslinker, it has proven to be suitable for the isolation and mild elution of protein complexes in native conditions. PMID- 25707321 TI - Predicting target-ligand interactions using protein ligand-binding site and ligand substructures. AB - BACKGROUND: Cell proliferation, differentiation, Gene expression, metabolism, immunization and signal transduction require the participation of ligands and targets. It is a great challenge to identify rules governing molecular recognition between chemical topological substructures of ligands and the binding sites of the targets. METHODS: We suppose that the ligand-target interactions are determined by ligand substructures as well as the physical-chemical properties of the binding sites. Therefore, we propose a fragment interaction model (FIM) to describe the interactions between ligands and targets, with the purpose of facilitating the chemical interpretation of ligand-target binding. First we extract target-ligand complexes from sc-PDB database, based on which, we get the target binding sites and the ligands. Then we represent each binding site as a fragment vector based on a target fragment dictionary that is composed of 199 clusters (denoted as fragements in this work) obtained by clustering 4200 trimers according to their physical-chemical properties. And then, we represent each ligand as a substructure vector based on a dictionary containing 747 substructures. Finally, we build the FIM by generating the interaction matrix M (representing the fragment interaction network), and the FIM can later be used for predicting unknown ligand-target interactions as well as providing the binding details of the interactions. RESULTS: The five-fold cross validation results show that the proposed model can get higher AUC score (92%) than three prevalence algorithms CS-PD (80%), BLM-NII (85%) and RF (85%), demonstrating the remarkable predictive ability of FIM. We also show that the ligand binding sites (local information) overweight the sequence similarities (global information) in ligand-target binding, and introducing too much global information would be harmful to the predictive ability. Moreover, The derived fragment interaction network can provide the chemical insights on the interactions. CONCLUSIONS: The target and ligand bindings are local events, and the local information dominate the binding ability. Though integrating of the global information can promote the predictive ability, the role is very limited. The fragment interaction network is helpful for understanding the mechanism of the ligand-target interaction. PMID- 25707322 TI - Isoindoline-1,3-dione derivatives targeting cholinesterases: design, synthesis and biological evaluation of potential anti-Alzheimer's agents. AB - Alzheimer's disease is a fatal neurodegenerative disorder with a complex etiology. Because the available therapy brings limited benefits, the effective treatment for Alzheimer's disease remains the unmet challenge. Our aim was to develop a new series of donepezil-based compounds endowed with inhibitory properties against cholinesterases and beta-amyloid aggregation. We designed the target compounds as dual binding site acetylcholinesterase inhibitors with N benzylamine moiety interacting with the catalytic site of the enzyme and an isoindoline-1,3-dione fragment interacting with the peripheral anionic site of the enzyme. The results of pharmacological evaluation lead us to identify a compound 3b as the most potent and selective human acetylcholinesterase inhibitor (hAChE IC50=0.361MUM). Kinetic studies revealed that 3b inhibited acetylcholinesterase in non-competitive mode. The result of the parallel artificial membrane permeability assay for the blood-brain barrier indicated that the compound 3b would be able to cross the blood-brain barrier and reach its biological targets in the central nervous system. The selected compound 3b represents a potential lead structure for further development of anti-Alzheimer's agents. PMID- 25707323 TI - Chronic lymphocytic lymphoma presenting with recurrent demodicidosis. PMID- 25707324 TI - Expanding the spectrum: chronic urticaria and autoimmune polyendocrinopathy candidiasis-ectodermal dystrophy. PMID- 25707325 TI - Critical appraisal of androgen use in hereditary angioedema: a systematic review. AB - OBJECTIVE: To provide an objective basis for evaluating the risk-benefit ratio of long-term androgen use in patients with hereditary angioedema (HAE). DATA SOURCES: PubMed was searched with no time limitations using the keywords hereditary angioedema or angio-oedema combined with danazol, stanozolol, and androgen. STUDY SELECTION: Qualifying articles were English-language reports of androgen use in patients with HAE, with relevant safety and/or efficacy information. Reports were categorized according to level of evidence (LOE). RESULTS: The search process identified 153 citations, 63 of which contained relevant information; 2 additional publications were identified while other citations were being reviewed. Fifteen LOE 2 studies and multiple LOE 4 reports provided efficacy data, confirming a high level of prophylactic efficacy for androgen therapy in HAE, with occasional reports of poor prophylactic response. Common adverse events include weight gain, menstrual irregularities, virilization, headaches, myalgias or cramps, mood changes, and elevations in creatine phosphokinase level, liver function test results, and serum lipid level. The risk of adverse events is often correlated with dose and/or treatment duration. Rare cases of hepatic adenomas and hepatocellular carcinoma associated with long-term androgen use often had no preceding changes in liver function test results. CONCLUSION: Androgen therapy may be effective for most patients with HAE; however, potential risks and adverse effects must be carefully considered and discussed with patients when considering options for long-term HAE prophylaxis. PMID- 25707326 TI - Epinephrine doses contained in outdated epinephrine auto-injectors collected in a Florida allergy practice. PMID- 25707327 TI - The influence of leukotrienes C4 and D4 on the contractility of an inflamed porcine uterus. AB - The effect of leukotriene (LT) C4 (LTC4) and LTD4 on the contractility of an inflamed porcine uterus was investigated. On Day 3 of the estrous cycle (Day 0 of the study), either saline or Escherichia coli suspension was injected into each uterine horn. Although acute endometritis developed in all bacteria-inoculated gilts, a severe acute endometritis was noted more often on Day 8 than on Day 16. Myometrial and endometrial/myometrial strips were incubated with LTC4 or LTD4 alone, or together with a cysteinyl-LT receptor antagonist (BAY-u9773). Leukotriene C4 increased the contraction intensity in the saline- and bacteria treated uteri on Day 8; however, its effect was lower in the myometrium of inflamed uteri. Contraction frequency was found to decrease in the saline-treated uteri as opposed to inflamed ones, in which it was elevated. On Day 16, contraction intensity increased in response to LTC4 in the saline-treated uteri but was reduced in the inflamed organs. The value of this parameter was lower in the inflamed uteri than that in the saline-treated ones. Leukotriene D4 (Days 8 and 16) augmented contractility in the saline-treated uteri, but despite increasing its intensity in the inflamed organs, it decreased contraction frequency. Leukotriene C4 or LTD4, added to BAY-u9773-pretreated saline- and bacteria-treated uteri on both days, decreased the contraction intensity. On Day 16 after treatment with BAY-u9773 and LTC4, contraction intensity in the endometrium/myometrium of the inflamed uteri was lower than that in the saline treated organs. Data show that both LTC4 and LTD4 affect the contractility of inflamed porcine uteri, though LTC4 exerts a weaker contractile effect. PMID- 25707328 TI - Histologic effect of a postnatal slow-release GnRH agonist on feline gonads. AB - In postnatal domestic cats, GnRH agonists suppressed fecal concentrations of sexual steroids and delayed puberty. The aim of this study was to describe the gross and microscopic morphometric effects of a single administration of the GnRH agonist, deslorelin acetate, on the gonads of postnatally treated cats. Twenty seven postnatal male (n = 14) and female (n = 13) kittens were randomly assigned to one of the following treatment groups within the first 24 hours of birth: deslorelin acetate (1.6 mg, subcutaneous; DA, n = 16) or control that remained untreated (CO, n = 11) and spayed or castrated immediately after the onset of puberty. After surgical removal, the gonads were gross and histologically assessed. Sertoli cells also were examined immunohistochemically. Comparisons between the treatments were carried out by the Student t test. Gross gonadal wet weight and volume as well as gonadosomatic index were significantly lower in the DA than those in the CO males; these same parameters were not different in females. Primordial (461.4 + 3.0 vs. 1074.3 + 117.5; P < 0.01), primary (59.1 + 13.5 vs. 165.4 + 24.6; P < 0.01), and secondary (17.5 + 2.6 vs. 31.17 + 8.1; P < 0.05) follicles per mm(2) were decreased in DA than in CO gonads. Epididymal sperm motility and morphology were normal in all but two DA cats that had too few sperm to be evaluated. Germinal epithelial height (MUm; 39.68 + 0.92 vs. 72.7 + 1.2; P < 0.01) and most of their cellular components as well as the Sertoli (cm(3); 0.1 + 0.02 vs. 0.24 + 0.05; P < 0.01) cells were diminished in the DA cats. Gonadotropin-releasing hormone agonist endocrine disruption during the neonatal critical reproductive time window may have a potential as a contraceptive agent in domestic felids. PMID- 25707329 TI - [Pertussis vaccine. Reemergence of the disease and new vaccination strategies]. AB - Pertussis continues to be a public health problem despite the significant decrease in its incidence due to routine vaccination. Resurgence of the disease in countries that have maintained high vaccination coverage has been observed in recent years. Although vaccination is the most effective preventive control measure, both natural and artificial immunity wane over time, and thus the protection offered by current vaccines is not long-lasting. Furthermore, acellular vaccines are less effective. The implementation of new vaccine strategies is required. Vaccination of pregnant women is the most effective strategy for preventing pertussis in young infants, who are the most vulnerable, and should be recommended together with cocooning, ie vaccination of future household and extra-domiciliary contacts who are the main transmitters of the disease. PMID- 25707330 TI - Emergence of long-term balanced polymorphism under cyclic selection of spatially variable magnitude. AB - A fundamental question in evolutionary biology is what promotes genetic variation at nonneutral loci, a major precursor to adaptation in changing environments. In particular, balanced polymorphism under realistic evolutionary models of temporally varying environments in finite natural populations remains to be demonstrated. Here, we propose a novel mechanism of balancing selection under temporally varying fitnesses. Using forward-in-time computer simulations and mathematical analysis, we show that cyclic selection that spatially varies in magnitude, such as along an environmental gradient, can lead to elevated levels of nonneutral genetic polymorphism in finite populations. Balanced polymorphism is more likely with an increase in gene flow, magnitude and period of fitness oscillations, and spatial heterogeneity. This polymorphism-promoting effect is robust to small systematic fitness differences between competing alleles or to random environmental perturbation. Furthermore, we demonstrate analytically that protected polymorphism arises as spatially heterogeneous cyclic fitness oscillations generate a type of storage effect that leads to negative frequency dependent selection. Our findings imply that spatially variable cyclic environments can promote elevated levels of nonneutral genetic variation in natural populations. PMID- 25707332 TI - Monozygotic twinning after assisted reproductive technologies: a case report of asymmetric development and incidence during 19 years in an international group of in vitro fertilization clinics. AB - OBJECTIVE: To describe a case of monozygotic twinning with asymmetric development following a single fresh embryo transfer as part of an intracytoplasmic sperm injection (ICSI) treatment. Secondarily, to report the incidence of monozygotic twinning at the IVI (Instituto Valenciano de Infertilidad) clinics. DESIGN: Case report. SETTING: Private fertility centers. PATIENT(S): A 33-year-old woman with a 2-year history of primary infertility. INTERVENTION(S): Controlled ovarian hyperstimulation and ICSI treatment with single-embryo transfer. MAIN OUTCOME MEASURE(S): Incidence of monozygotic twinning at the IVI clinics. RESULT(S): We report a twin pregnancy after a single-embryo transfer. Twins were dichorionic and diamniotic. One fetus had a 6-day delay in its growth compared with the other when observed by ultrasound. Two female infants were delivered, and despite presenting congenital diseases, they were successfully treated and evolved correctly. A subsequent DNA analysis confirmed that the infants were monozygotic. Furthermore, we estimated a monozygotic twinning rate of 1.17% at the IVI clinics, taking into account those cases in which two or more embryos with heart beats were observed by ultrasound scanning after single-embryo transfers. CONCLUSION(S): Ultrasound scans performed during pregnancy suggested a possible dizygotic origin of the twins, but DNA analysis performed after birth established that they were monozygotic. Genetic analysis is the only valid tool to confirm if like-sex dichorionic twins are monozygotic or dizygotic. PMID- 25707333 TI - Major drawbacks and additional benefits of agonist trigger--not ovarian hyperstimulation syndrome related. AB - The GnRH agonist trigger alters traditional IVF paradigms when compared with hCG only triggers. The agonist trigger induces rapid luteolysis and therefore separates the oocyte maturation aspect of LH from the luteal support previously afforded by lingering hCG. This might allow customized and more optimal luteal support. The agonist trigger option also allows continued stimulation and subsequent trigger of high responders with reasonable safety, potentially leading to retrievals of larger cohorts of mature oocytes. It may also reduce the number of retrievals needed to achieve a large family. The agonist trigger might alter other paradigms as well, such as making oocyte donation more efficient per stimulation by virtually eliminating follicular-phase cycle cancellation, coasting, and premature triggering. There are both corresponding potential benefits and drawbacks of using the agonist trigger and the shifting paradigms it allows. PMID- 25707334 TI - Prospective study of time to pregnancy and adverse birth outcomes. AB - OBJECTIVE: To investigate the association between time to pregnancy (TTP) and adverse birth outcomes. DESIGN: Prospective cohort study. SETTING: Not applicable. PATIENT(S): A total of 3,521 singletons born to women aged 18-40 years at cohort entry. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Selected birth outcomes, including preterm birth (PTB, <37 weeks' gestation), low birth weight (<2,500 g), small for gestational age, large for gestational age, and placental disorders, ascertained from the Danish Medical Birth Registry and Danish National Registry of Patients. Risk ratios (RRs) and 95% confidence intervals (CIs) were estimated using log-binomial regression, with adjustment for potential confounders and fertility treatment. RESULT(S): Multivariable RRs for PTB in relation to TTP of 3-5, 6-11, and >=12 vs. <3 cycles were 1.59 (95% CI 0.94-2.69), 0.85 (95% CI 0.48-1.50), and 1.57 (95% CI 0.93-2.65). The association was slightly stronger for spontaneous PTB (TTP >=12 vs. <3 cycles: RR 1.69, 95% CI 0.84-3.42) than for medically indicated PTB (RR 1.39, 95% CI 0.62-3.12). Longer TTPs (>=12 cycles) were associated with increased risks of low birth weight (RR 1.80, 95% CI 0.97-3.35), cesarean delivery (RR 1.64, 95% CI 1.27 2.12), placental disorders (RR 2.21, 95% CI 1.07-4.56), ischemic placental disease (RR 1.56, 95% CI 0.99-2.44), pre-eclampsia (RR 1.45, 95% CI 0.79-2.65), and postpartum hemorrhage (RR 1.58, CI 1.14-2.19), and decreased risks of macrosomia (>=4,500 g; RR 0.63, 95% CI 0.35-1.13) and large for gestational age (RR 0.76, 95% CI 0.58-1.00). Longer TTP showed little association with small for gestational age. CONCLUSION(S): In a prospective cohort study of Danish pregnancy planners, delayed conception was a marker for adverse birth outcomes, after accounting for fertility treatment. PMID- 25707331 TI - Assessment of multiple intrauterine gestations from ovarian stimulation (AMIGOS) trial: baseline characteristics. AB - OBJECTIVE: To identify baseline characteristics of women with unexplained infertility to determine whether treatment with an aromatase inhibitor will result in a lower rate of multiple gestations than current standard ovulation induction medications. DESIGN: Randomized, prospective clinical trial. SETTING: Multicenter university-based clinical practices. PATIENT(S): A total of 900 couples with unexplained infertility. INTERVENTION(S): Collection of baseline demographics, blood samples, and ultrasonographic assessments. MAIN OUTCOME MEASURE(S): Demographic, laboratory, imaging, and survey characteristics. RESULT(S): Demographic characteristics of women receiving clomiphene citrate (CC), letrozole, or gonadotropins for ovarian stimulation were very consistent. Their mean age was 32.2 +/- 4.4 years and infertility duration was 34.7 +/- 25.7 months, with 59% primary infertility. More than one-third of the women were current or past smokers. The mean body mass index (BMI) was 27 and mean antimullerian hormone level was 2.6; only 11 women (1.3%) had antral follicle counts of <5. Similar observations were identified for hormonal profiles, ultrasound characterization of the ovaries, semen parameters, and quality of life assessments in both male and female partners. CONCLUSION(S): The cause of infertility in the couples recruited to this treatment trial is elusive, as the women were regularly ovulating and had evidence of good ovarian reserve both by basal FSH, antimullerian hormone levels, and antral follicle counts; the male partners had normal semen parameters. The three treatment groups have common baseline characteristics, thereby providing comparable patient populations for testing the hypothesis that use of letrozole for ovarian stimulation can reduce the rates of multiples from that observed with gonadotropin and CC treatment. CLINICAL TRIAL REGISTRATION NUMBER: NCT 01044862. PMID- 25707335 TI - Fluorescence in situ hybridization detects increased sperm aneuploidy in men with recurrent pregnancy loss. AB - OBJECTIVE: To investigate, in men presenting with recurrent pregnancy loss (RPL), the prevalence of sperm autosome and sex chromosome aneuploidy. DESIGN: Retrospective study. SETTING: Male infertility clinic. PATIENT(S): A total of 140 men with RPL provided semen samples, and five normozoospermic controls provided 140 semen samples for comparison. Recurrent pregnancy loss, documented in the female partners, was defined as a prior miscarriage and/or recurrent IVF/intracytoplasmic sperm injection failure. INTERVENTION(S): Fluorescence in situ hybridization (FISH) was used to detect numerical abnormalities in sex chromosomes (X, Y) and autosomes (13, 18, 21) in ejaculated sperm. MAIN OUTCOME MEASURE(S): Sperm aneuploidy in men with RPL and normozoospermic controls. RESULT(S): Men with RPL had a greater percentage of sperm aneuploidy within the sex chromosomes and chromosomes 18 and 13/21 (1.04% vs. 0.38%; 0.18% vs. 0.03%; 0.26% vs. 0.08%). In total, 40% of men with normal sperm density and motility had abnormal sperm aneuploidy in all the chromosomes analyzed. Men with abnormal sperm density and motility had a higher proportion of sperm sex chromosome aneuploidy than men with normal density/motility (62% vs. 45%). Men with normal strict morphology (>4%) had lower rates of sex chromosome and sperm aneuploidy than men with abnormal strict morphology (28% vs. 57%). There was no association between sperm DNA fragmentation and sperm aneuploidy. CONCLUSION(S): Men with RPL have increased sperm aneuploidy compared with controls. A total of 40% of men with RPL and normal sperm density/motility had abnormal sperm aneuploidy. Men with oligoasthenozoospermia and abnormal strict morphology had a greater percentage of sperm aneuploidy compared with men with normal semen parameters. PMID- 25707336 TI - Assisted reproductive technology and the risk of preterm birth among primiparas. AB - OBJECTIVE: To investigate the risk of preterm birth among liveborn singletons to primiparas who conceived with assisted reproductive technology (ART) using four mutually exclusive categories of infertility (female infertility only, male infertility only, female and male infertility, and unexplained infertility) and to examine preterm birth risk along the gestational age continuum. DESIGN: Retrospective cohort study. SETTING: Not applicable. PATIENT(S): Singletons born to primiparas who conceived with or without ART. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Preterm (<37 weeks' gestation) and preterm/early term birth <39 weeks' gestation). RESULT(S): For the male infertility only, female infertility only, combined male and female infertility, and unexplained infertility groups, ART-conceived singletons were significantly more likely than non-ART singletons to be born preterm: adjusted odds ratio (aOR) 1.24 (95% CI, 1.13, 1.37), aOR 1.60 (95% CI, 1.50, 1.70), aOR 1.49 (95% CI, 1.35, 1.64), and aOR 1.26 (1.12, 1.43) respectively. Among infants whose mothers were diagnosed with infertility, the odds of preterm birth were highest between 28-30 weeks [female infertility only, aOR 1.95 (95% CI, 1.59, 2.39); male and female infertility: 2.21 (95% CI, 1.62, 3.00)] compared with infants in the general population. Within the ART population, singletons of couples with female infertility only were more likely to be born preterm than singletons born to couples with other infertility diagnoses. CONCLUSION(S): Among singleton births to primiparas, those conceived with ART had an increased risk for preterm birth, even when only the male partner had been diagnosed with infertility. The risk of preterm birth for ART-conceived infants whose mothers were diagnosed with infertility included the earliest deliveries. PMID- 25707337 TI - DNA copy number variations are important in the complex genetic architecture of mullerian disorders. AB - OBJECTIVE: To clinically and genetically investigate women with mullerian disorders, including Mayer-Rokitanksy-Kuster-Hauser (MRKH) syndrome. DESIGN: Two year prospective clinical and laboratory study. SETTING: Not applicable. PATIENT(S): Thirty-five women over 16 years of age with a mullerian disorder, including MRKH. INTERVENTION(S): Women were recruited from specialist gynecology clinics or identified from the Scottish Disorders of Sex Development Register (www.sdsd.scot.nhs.uk/index.html). Associated abnormalities were detected by clinical examination, imaging studies, and biochemical analyses. Chromosomal microduplications and microdeletions were detected by array comparative genomic hybridization (CGH) and validated by fluorescence in situ hydridization. MAIN OUTCOME MEASURE(S): Identification of associated congenital and biochemical abnormalities and identification of regions of genomic imbalance using array CGH. RESULT(S): Associated congenital anomalies were common, present in 25/35 (71%) of affected women, particularly renal and skeletal abnormalities, which were present in 15/35 (43%) and 17/35 (49%) women, respectively. Using array CGH, novel or recurrent regions of genomic imbalance were identified in 4/11 (36%) women with MRKH and in 5/24 (21%) women with other mullerian abnormalities. CONCLUSION(S): Additional congenital abnormalities and regions of genomic imbalance are common in women with mullerian disorders, including MRKH. Recurrent microdeletions and microduplications associated with MRKH implicate specific possibly causative genes. The investigation of women with mullerian disorders should be thorough, and array CGH should be considered, given the potential highly significant familial implications of a chromosomal abnormality. PMID- 25707338 TI - Unraveling the fertility knot in World Health Organization type 2 anovulatory women: another step toward a pharmacogenetic treatment choice. PMID- 25707339 TI - Does ovarian reserve predict egg quality in unstimulated therapeutic donor insemination cycles? AB - OBJECTIVE: To compare reproductive outcomes of patients with very low, low, normal, and high antral follicle counts undergoing unstimulated therapeutic donor insemination (TDI) cycles. DESIGN: Retrospective cohort study. SETTING: University-affiliated regional fertility clinic. PATIENT(S): Four hundred fifty nine patients who had 1,107 TDI treatment cycles from January 2006 to December 2013. INTERVENTION(S): Unstimulated therapeutic donor insemination. MAIN OUTCOME MEASURE(S): Clinical pregnancy rates and miscarriage rates as surrogate markers for oocyte quality. RESULT(S): The overall pregnancy rate per cycle start was 12.46% in the study population. There was no difference in per-cycle or cumulative pregnancy rates among patients with very low, low, average, or high antral follicle counts within each patient age group of <=35, 36-39, and >=40 years. The overall miscarriage rate per pregnancy was 13.61%. When stratified by patient age, there was no correlation between miscarriage rate and antral follicle count. CONCLUSION(S): AFC is not a predictor of pregnancy or miscarriage rates in patients undergoing unstimulated TDI. PMID- 25707340 TI - Changing ovarian stimulation parameters in a subsequent cycle does not increase the number of euploid embryos. AB - OBJECTIVE: To compare the euploidy outcome in patients that underwent 2 ovarian stimulation cycles with trophectoderm biopsy. DESIGN: Retrospective repeated measures cohort study. SETTING: University-based fertility center. PATIENT(S): A total of 116 patients, from 2011 through 2013, that underwent 2 ovarian stimulation cycles followed by trophectoderm biopsy with array comparative genomic hybridization. INTERVENTION(S): Days of stimulation, average diameter of the 2 lead follicles on day of trigger, dose of gonadotropins, type of cycle (gonadotropin-releasing hormone [GnRH] antagonist, GnRH-antagonist plus clomiphene citrate [CC], microdose GnRH agonist). MAIN OUTCOME MEASURE(S): Number of euploid embryos. RESULT(S): Patients were analyzed based on whether they had >=1 euploid embryos in their first cycle vs. none. There was no increase in the number of euploid embryos with more days of stimulation or increases in the dose of gonadotropins in either group. Significantly more euploid embryos were seen in patients who had no euploid embryo(s) in the first cycle (Group 0) that had CC added to a GnRH-antagonist cycle (1.11 more euploid embryos) or were triggered when follicle sizes were 2 mm larger (0.40 euploid embryos), but these increases were not significant compared with a control group. Patients with euploid embryo(s) in the first cycle (Group 1) had significantly more euploid embryos when daily dose was increased by 75-149 international units, but this relationship was not significant compared with a control group with no increase in daily dose. CONCLUSION(S): No specific intervention increased the number of euploid embryos within the same patient any more than simply repeating a similar stimulation cycle. An attempt was made to control for interpatient variability, but individual patients have considerable intercycle variability. PMID- 25707341 TI - Significant understaging is seen in clinically staged T2N0 esophageal cancer patients undergoing esophagectomy. AB - This study aimed to determine the impact of preoperative staging on the treatment of clinical T2N0 (cT2N0) esophageal cancer patients undergoing esophagectomy. We reviewed a retrospective cohort of 27 patients treated at a single institution between 1999 and 2011. Clinical staging was performed with computed tomography, positron emission tomography, and endoscopic ultrasound. Patients were separated into two groups: neoadjuvant therapy followed by surgery (NEOSURG) and surgery alone (SURG). There were 11 patients (41%) in the NEOSURG group and 16 patients (59%) in the SURG group. In the NEOSURG group, three of 11 patients (27%) had a pathological complete response and eight (73%) were partial or nonresponders after neoadjuvant therapy. In the SURG group, nine of 16 patients (56%) were understaged, 6 (38%) were overstaged, and 1 (6%) was correctly staged. In the entire cohort, despite being clinically node negative, 14 of 27 patients (52%) had node-positive disease (5/11 [45%] in the NEOSURG group, and 9/16 [56%] in the SURG group). Overall survival rate was not statistically significant between the two groups (P = 0.96). Many cT2N0 patients are clinically understaged and show no preoperative evidence of node-positive disease. Consequently, neoadjuvant therapy may have a beneficial role in treatment. PMID- 25707343 TI - Adolescent disclosure of information about peers: the mediating role of perceptions of parents' right to know. AB - Following the important insight that what parents know about their adolescent offspring depends primarily on what the child tells them, this study examines how attitudes about what parents have a right to know mediate the associations between several factors (quality of parent-child relationships, time spent with family and peers, levels of antisocial and prosocial behaviors, and gender and age) and adolescents' disclosures about peer relations. In two studies of early and middle adolescents (Ns = 231, 249; M ages = 14.5, 13.0; 62.3, 51.8 % female; 53.7, 67.5 % European American), a new measure of right-to-know attitudes is derived and then applied to four facets of adolescents' experiences with peers: details of activities with peers, issues in specific relationships, and positive and negative peer characteristics. The findings indicate that adolescents are more inclined to disclose certain aspects of their peer relations than others, but these inclinations are related to several factors-especially the quality of mother-child relationships and involvement in antisocial behavior-and mediated by adolescents' attitudes regarding what parents have a right to know about peers. The results are related to autonomy development and parental oversight of adolescent peer interactions. PMID- 25707344 TI - Parathyroid hormone, calcium, and sodium bridging between osteoporosis and hypertension in postmenopausal Korean women. AB - The coexistence of osteoporosis and hypertension, which are considered distinct diseases, has been widely reported. In addition, daily intake of calcium and sodium, as well as parathyroid hormone levels (PTH), is known to be associated with osteoporosis and hypertension. This study aimed to determine the association of low calcium intake, high sodium intake, and PTH levels with osteoporosis and hypertension in postmenopausal Korean women. Data for postmenopausal Korean women aged 50 years or older were obtained from the Korea National Health and Nutrition Examination Survey 2008-2011. Osteoporosis was diagnosed using dual energy X-ray absorptiometry, while hypertension was diagnosed using blood pressure data. The odds ratios for osteoporosis and hypertension were calculated using logistic regression analysis for quartiles of the daily calcium intake, daily sodium intake, and PTH levels. Women with hypertension had a high coexistence of osteoporosis (43.6 vs. 36.5 %; P = 0.022), and vice versa (21.1 vs. 16.6 %; P = 0.022). PTH was significantly associated with osteoporosis and hypertension, and a high intake of calcium was strongly correlated with a low incidence of osteoporosis. This is the first study to report the characteristics of postmenopausal Korean women who have high dietary sodium intake and low dietary calcium intake, in association with the incidence of osteoporosis and hypertension. Osteoporosis and hypertension were strongly associated with each other, and PTH appears to be a key mediator of both diseases, suggesting a possible pathogenic link. PMID- 25707345 TI - The use of saline solution or gelled phantoms in MRI studies during testing dental materials. PMID- 25707346 TI - Editorial: response to letter to the editor. PMID- 25707348 TI - Surface conditioning protocol for the chairside repair of polymeric denture teeth. PMID- 25707350 TI - Impact of super-extended lymphadenectomy on relapse in advanced gastric cancer. AB - BACKGROUND: In gastric cancer the incidence of loco-regional recurrences decreases when lymphadenectomy is expanded from D1 to D2. The present study aimed at evaluating whether the pattern of recurrence in advanced gastric cancer (AGC) is further modified when lymphadenectomy is expanded from D2 to D3. METHODS: 568 patients undergoing curative gastrectomy for AGC (274 D2 and 294 D3) were considered; none of them received preoperative chemotherapy. MantelHaenszel test of homogeneity was used to verify whether the relation between extension of lymphadenectomy and recurrence varied as a function of each risk factor considered. The impact of D2 and D3 on relapse was further investigated by multivariable logistic regression model. RESULTS: Cumulative incidence of recurrence did not significantly differ after D2 and after D3 in the whole series (45.3% vs 46.3%; p = 0.866). However, the association between recurrence and extension of lymphadenectomy was significantly affected by histology (Mantel Haenszel test of homogeneity: p = 0.007). The risk of recurrence was higher after D3 than after D2 (45.1% vs 35.3%) in the intestinal histotype while the pattern was reversed in the mixed/diffuse histotype (48.3% vs 61.5%). This pattern was confirmed in multivariable logistic regression: the interaction between histology and extension of lymphadenectomy was highly significant (p = 0.004). In particular, cumulative incidence of locoregional recurrences was higher in the diffuse histotype after D2, while being higher in the intestinal histotype after D3. CONCLUSIONS: D3 reverses the negative impact of diffuse histotype on relapses, especially on locoregional recurrences. Therefore D3 could be considered a valid therapeutic option in histotype-oriented tailored treatment of AGC. PMID- 25707349 TI - The use of radioactive iodine-125 seed localization in patients with non-palpable breast cancer: a comparison with the radioguided occult lesion localization with 99m technetium. AB - BACKGROUND: Radioactive Seed Localization with a radioactive iodine-125 seed (RSL) and Radioguided Occult Lesion Localization with 99mTechnetium colloid (ROLL) are both attractive alternatives to wire localization for guiding breast conserving surgery (BCS) of non-palpable breast cancer. The aim of this study was to evaluate and compare the efficacy of RSL and ROLL. METHODS: We retrospectively analyzed 387 patients with unifocal non-palpable ductal carcinoma in situ (DCIS) or invasive carcinoma treated with BCS at the Netherlands Cancer Institute. In total 403 non-palpable lesions were localized either by RSL (N = 128) or by ROLL (N = 275). Primary outcome measures were positive margins and re-excision rates; the secondary outcome measure was weight of the specimen. RESULTS: Pre-operative mammography or ultrasound showed similar sizes of DCIS and invasive tumours in both RSL and ROLL groups. In the RSL group, more lesions were DCIS (58%) than in the ROLL group, where 32% of the lesions were pure DCIS. The proportions of focally positive margins (11% vs. 10%) and more than focally positive margins (9% vs. 9%) were comparable between the RSL and the ROLL group, resulting in the same re-excision rate in both RSL and ROLL groups (9% vs. 10%). For DCIS lesions, the specimen weight was significantly lower in the RSL group than in the ROLL group after adjusting for tumour size on mammography (12 g; 95% CI 2.6-21). CONCLUSION: Margin status and re-excision rates were comparable for RSL and ROLL in patients with non-palpable breast lesions. Because of the significant lower weight of the resected specimen in DCIS, the feasibility of position verification of the I-125 seed and more convenient logistics, we favour RSL over ROLL to guide breast conserving therapy. PMID- 25707351 TI - The memory structure of navigation in honeybees. AB - The analytical approach to navigation studies aims to identify elementary sensory motor processes that guide an animal to a remote site. This approach will be used here to characterize components of navigation in a flying insect, the honeybee. However, navigation studies need to go beyond an analysis of behavioral routines to come up with a synthesis. We will defend the concept of an active memory structure guiding navigation in bees that is best described as a mental or cognitive map. In our opinion, spatial/temporal relations of landmarks are stored in a mental map in such a way that behavioral routines such as expectation and planning, as indicated by shortcutting, are possible. We view the mental map of animals including the honeybee as an "action memory of spatial relations" rather than as a sensory representation as we humans experience it by introspection. Two components characterize the mental map, the relational representation of landmarks and the meaning of locations to the animal. As yet, there is little data to suggest that bees assign meaning to the experienced locations. To explore this possibility, further studies will be needed, whereby honeybees provide a unique model to address this question. PMID- 25707353 TI - Erratum to: Diagnostic criteria for IgG4-related ophthalmic disease. PMID- 25707352 TI - Effects of antiviral medications on herpetic epithelial keratitis in mice. AB - PURPOSE: Aciclovir (ACV), valaciclovir (VACV) and famciclovir (FCV) are used for systemic infections caused by herpes virus. In Japan, only topical ACV is permitted for use against herpetic keratitis. We investigated the effectiveness of topical ACV, oral VACV and oral FCV on mouse epithelial herpetic keratitis. METHODS: C57/BL76 mice were inoculated with HSV-1 McKrae strain in the cornea. Once infection was confirmed 4 days after inoculation, topical ACV, oral VACV and FCV were started and administered for 5 days. Control groups were given either topical or oral saline. On days 2, 4, 6 and 10 after medication started, tears, eyeballs, and trigeminal ganglia were examined using viral culture and real-time PCR. RESULTS: Viral culture of tears detected no HSV in the topical ACV group on day 4 after administration start; with similar results for the oral VACV group on day 4; and the oral FCV group on day 6. Real-time PCR of the eyeballs showed significant decrease of HSV DNA copy number in the topical ACV group on days 4 and 6 compared to the topical saline group. Real-time PCR of the trigeminal ganglia showed significant decrease of HSV DNA copy number in the oral VACV group on days 4 and 6, and in the oral FCV group on day 6 compared to the oral saline group. CONCLUSION: We suggest that 5-day administration of topical ACV, oral VACV and oral FCV are effective for mouse epithelial herpetic keratitis and sufficiently decrease HSV amounts in the ocular surface and eyeballs. PMID- 25707354 TI - Elevated expression of immunity-related GTPase family M in gastric cancer. AB - Recent researches have suggested that autophagy may play critical roles in tumorigenesis. Immunity-related GTPase family M (IRGM) is a human protein highlighted for its contribution to autophagy upon inflammation and infections. Studies have shown that IRGM is involved in the development of several cancers. In the current study, we investigated expression of IRGM and gastric cancer. Levels of messenger RNA (mRNA) and protein were examined by real-time reverse transcription PCR (RT-PCR) and Western blot, respectively. Data showed that mRNA level of IRGM was significantly increased in peripheral blood mononuclear cells (PBMCs) of gastric cancer patients than in PBMCs from healthy controls (p > 0.05). Moreover, both mRNA and protein levels were significantly higher in cancer tissues compared to adjacent noncancerous stomach tissues (1.28-fold, p < 0.001; 1.19-fold, p < 0.01, respectively). However, the level of IRGM seemed not to be affected by Helicobacter pylori infection. In addition, we investigated the correlation between IRGM expression and cancer stages and identified that stage IV patients had upregulated mRNA level and protein level of IRGM in cancer tissues than those stage I patients. Our findings suggest that expression of IRGM is dysregulated in gastric cancer and that the molecule may affect progression of the disease. PMID- 25707355 TI - Rab17 inhibits the tumourigenic properties of hepatocellular carcinomas via the Erk pathway. AB - The small GTPase Rab17 is a member of the Rab family and plays a critical role in the regulation of membrane trafficking polarized eukaryotic cells. However, the role of Rab17 in hepatocellular carcinoma (HCC) is not clear. In the present study, we investigated the role of Rab17 in HCC tumourgenesis. The expressions of Rab17 in non-tumour hepatic tissues and HCCs were detected via immunohistochemistry. Rab17 was found in 31 of 48 (64.6 %) and in 23 of 62 (37.1 %) of non-tumour hepatic tissue samples and HCCs (P = 0.0068), respectively, and there were significant correlations between Rab17 reductions and unfavourable variables including tumour size (P = 0.0171), differentiation level (P = 0.0126), and lymph nodal (P = 0.0044) and distant metastases (P = 0.0047). To elucidate the role of Rab17 in HCC, we generated two Rab17-overexpressing HCC cell lines. Rab17 overexpression significantly inhibited the tumourigenic properties of HCC cells in vitro and in vivo as demonstrated by reduced cell proliferation and migration, elevated G1 arrest, and decreased tumour xenograft growth. However, the attenuated tumourigenic properties of the HCC cells that were induced by Rab17 overexpression were significantly rescued by the activator of the Erk pathway EGF, which indicates that the Erk pathway plays a critical role in the Rab17 up-regulation-induced reduced tumourigenic properties of HCC cells. Rab17 might act as a tumour suppressor gene in HCCs, and the anti-tumour effects of Rab17 might be partially mediated by the Erk pathway. PMID- 25707356 TI - Antigen administration by continuous feeding enhances oral tolerance and leads to long-lasting effects. AB - The ability to avoid inflammatory responses to dietary components and microbiota antigens in the gut mucosa is achieved by a mechanism termed oral tolerance. This phenomenon is crucial to maintain the physiological immune activity in the gut and to prevent inflammatory disorders such as food allergy and inflammatory bowel diseases. Moreover, orally administered antigens induce regulatory cells that control systemic inflammatory responses as well. Given its specific, systemic and long-lasting effects, oral tolerance represents a promising approach for immunotherapies that aim to modulate inflammatory and autoimmune diseases. However, there are different protocols of feeding for induction of oral tolerance, and they have an impact in tolerance efficiency and length. Herein, we present and discuss different experimental feeding protocols and how they influence the outcome of oral administration of antigens. PMID- 25707357 TI - Structural insight into the interaction between the Hox and HMGB1 and understanding of the HMGB1-enhancing effect of Hox-DNA binding. AB - The Hox DNA binding domain, the homeodomain, plays critical roles in genetic control of development and cell fate determination. The variable regulatory functions of Hox proteins are accomplished by binding to target DNA sequences and collaborating protein partners that includes human high mobility group B1 (HMGB1). To better understand the interaction between Hox and HMGB1 and the facilitation of Hox-DNA binding by HMGB1, we solved the solution structure of the homeodomain of Hox including the N-terminal arm region (Hoxc9DBD hereafter). In addition, the details of the interaction between these two proteins, as well as DNA binding of the Hox-HMGB1 complex, were investigated by NMR, ITC, and EMSA. The results suggest that binding of the HMGB1 A-box to Hoxc9DBD makes the loop-1 (loop preceding helix-2 of Hoxc9DBD) more access to DNA backbone, which facilitate Hox-DNA binding with enhanced affinity. PMID- 25707358 TI - Oligomeric state regulated trafficking of human platelet-activating factor acetylhydrolase type-II. AB - The intracellular enzyme platelet-activating factor acetylhydrolase type-II (PAFAH-II) hydrolyzes platelet-activating factor and oxidatively fragmented phospholipids. PAFAH-II in its resting state is mainly cytoplasmic, and it responds to oxidative stress by becoming increasingly bound to endoplasmic reticulum and Golgi membranes. Numerous studies have indicated that this enzyme is essential for protecting cells from oxidative stress induced apoptosis. However, the regulatory mechanism of the oxidative stress response by PAFAH-II has not been fully resolved. Here, changes to the oligomeric state of human PAFAH II were investigated as a potential regulatory mechanism toward enzyme trafficking. Native PAGE analysis in vitro and photon counting histogram within live cells showed that PAFAH-II is both monomeric and dimeric. A Gly-2-Ala site directed mutation of PAFAH-II demonstrated that the N-terminal myristoyl group is required for homodimerization. Additionally, the distribution of oligomeric PAFAH II is distinct within the cell; homodimers of PAFAH-II were localized to the cytoplasm while monomers were associated to the membranes of the endoplasmic reticulum and Golgi. We propose that the oligomeric state of PAFAH-II drives functional protein trafficking. PAFAH-II localization to the membrane is critical for substrate acquisition and effective oxidative stress protection. It is hypothesized that the balance between monomer and dimer serves as a regulatory mechanism of a PAFAH-II oxidative stress response. PMID- 25707360 TI - From spherical to leaf-like morphologies: tunable supramolecular assembly of alkynylgold(I) complexes through variations of the alkyl chain length. AB - A series of luminescent polynuclear alkynylgold(I) complexes with different lengths of alkyl chains attached at the N-heterocyclic carbene moieties has been synthesised and demonstrated to display intriguing self-assembly behaviours through a cooperative growth mechanism. Variation of the alkyl chain length was found to cause drastic morphological differences in the aggregates and to strongly affect the thermodynamic parameters as revealed by the nucleation elongation model. PMID- 25707359 TI - Interaction proteomics of canonical Caspr2 (CNTNAP2) reveals the presence of two Caspr2 isoforms with overlapping interactomes. AB - Autism is a human developmental brain disorder characterized by impaired social interaction and communication. Contactin-associated protein-like 2 (Caspr2, CNTNAP2) is a known genetic risk factor of autism. However, how this protein might contribute to pathology is unclear. In this study, we demonstrate that Caspr2 is abundantly present in lipid raft and in the synaptic membrane but is highly depleted in the postsynaptic density. The Caspr2 protein level in hippocampus is present at a constant level during synapse formation and myelination from P0 to P84. Interaction proteomics revealed the interactors of Caspr2, including CNTN2, KCNAs, members of the ADAM family (ADAM22, ADAM23 and ADAM11), members of LGI family and MAGUKs (DLGs and MPPs). Interestingly, a short form of Caspr2 was detected, which lacks most of the extracellular domains, however, is still associated with ADAM22 and to a lesser extent LGI1 and Kv1 channels. The comprehensive Caspr2 interactome revealed here might aid in understanding the molecular mechanisms underlying autism. This article is part of a Special Issue titled Neuroproteomics: Applications in Neuroscience and Neurology. PMID- 25707361 TI - A phase 1 study of the sachet formulation of the oral dual PI3K/mTOR inhibitor BEZ235 given twice daily (BID) in patients with advanced solid tumors. AB - Introduction The PI3 kinase (PI3K) pathway is a commonly dysregulated pathway in cancers and is an attractive target for antitumor therapy. BEZ235 is a potent, highly specific and selective dual PI3K/mTOR inhibitor. Methods Patients were enrolled in a 3 + 3 dose escalation design to determine the maximum tolerated dose (MTD), toxicities, and pharmacokinetics (PK) of BEZ235 when administered twice-daily as an oral sachet. For intrapatient PK comparison, patients were to receive a lead in of the total daily dose in a QD schedule for the first 8 days of the initial 28 day cycle. Patients continued treatment until unacceptable toxicity or disease progression occurred. Results Thirty-three patients received BEZ235. Initial dose levels of 200 and 400 mg BID had no DLTs. At the 600 mg BID dose level with 1200 mg QD lead in dose two DLTs of grade 3 mucositis occurred early in the first treatment cycle, the lead-in QD dosing was eliminated. Fatigue and mucositis limited dosing at 600 mg BID in subsequent patients. The 400 mg BID dose level was re-explored, with DLTs of grade 3 hyperglycemia, dehydration, fatigue, and grade 3 thrombocytopenia. Twelve patients were enrolled at an intermediate dose of 300 mg BID; a grade 3 mucositis DLT was reported in 1 patient, and this dose was declared the MTD. Preliminary PK data demonstrate a consistent increase in PK parameters (Cmax and AUC) with dose level compared to QD dosing. Fifteen patients experienced stable disease as their best response, including 10 (colorectal [4 patients], endometrial [3 patients], carcinoid NOS, pancreas, and melanoma) who had disease control for >=16 weeks. Conclusions The recommended dose of BEZ235 administered BID as an oral sachet formulation is 300 mg BID. Toxicities seen have been reported for other dual PI3K/mTOR inhibitors. PMID- 25707362 TI - Dynamics of suspensions of hydrodynamically structured particles: analytic theory and applications to experiments. AB - We present an easy-to-use analytic toolbox for the calculation of short-time transport properties of concentrated suspensions of spherical colloidal particles with internal hydrodynamic structure, and direct interactions described by a hard core or soft Hertz pair potential. The considered dynamic properties include self diffusion and sedimentation coefficients, the wavenumber-dependent diffusion function determined in dynamic scattering experiments, and the high-frequency shear viscosity. The toolbox is based on the hydrodynamic radius model (HRM) wherein the internal particle structure is mapped on a hydrodynamic radius parameter for unchanged direct interactions, and on an existing simulation data base for solvent-permeable and spherical annulus particles. Useful scaling relations for the diffusion function and self-diffusion coefficient, known to be valid for hard-core interaction, are shown to apply also for soft pair potentials. We further discuss extensions of the toolbox to long-time transport properties including the low-shear zero-frequency viscosity and the long-time self-diffusion coefficient. The versatility of the toolbox is demonstrated by the analysis of a previous light scattering study of suspensions of non-ionic PNiPAM microgels [Eckert et al., J. Chem. Phys., 2008, 129, 124902] in which a detailed theoretical analysis of the dynamic data was left as an open task. By the comparison with Hertz potential based calculations, we show that the experimental data are consistently and accurately described using the Verlet-Weis corrected Percus-Yevick structure factor as input, and for a solvent penetration length equal to three percent of the excluded volume radius. This small amount of solvent permeability of the microgel particles has a significant dynamic effect at larger concentrations. PMID- 25707363 TI - Recovery Audit Contractor audits and appeals at three academic medical centers. AB - BACKGROUND: Outpatient (observation) and inpatient status determinations for hospitalized Medicare beneficiaries have generated increasing concern for hospitals and patients. Recovery Audit Contractor (RAC) activity alleging improper status, however, has received little attention, and there are conflicting federal and hospital reports of RAC activity and hospital appeals success. OBJECTIVE: To detail complex Medicare Part A RAC activity. DESIGN, SETTING AND PATIENTS: Retrospective descriptive study of complex Medicare Part A audits at 3 academic hospitals from 2010 to 2013. MEASUREMENTS: Complex Part A audits, outcome of audits, and hospital workforce required to manage this process. RESULTS: Of 101,862 inpatient Medicare encounters, RACs audited 8110 (8.0%) encounters, alleged overpayment in 31.3% (2536/8110), and hospitals disputed 91.0% (2309/2536). There was a nearly 3-fold increase in RAC overpayment determinations in 2 years, although the hospitals contested and won a larger percent of cases each year. One-third (645/1935, 33.3%) of settled claims were decided in the discussion period, which are favorable decisions for the hospitals not reported in federal appeals data. Almost half (951/1935, 49.1%) of settled contested cases were withdrawn by the hospitals and rebilled under Medicare Part B to avoid the lengthy (mean 555 [SD 255] days) appeals process. These original inpatient claims are considered improper payments recovered by the RAC. The hospitals also lost appeals (0.9%) by missing a filing deadline, yet there was no reciprocal case concession when the appeals process missed a deadline. No overpayment determinations contested the need for care delivered, rather that care should have been delivered under outpatient, not inpatient, status. The institutions employed an average 5.1 full-time staff in the audits process. CONCLUSIONS: These findings suggest a need for RAC reform, including improved transparency in data reporting. PMID- 25707364 TI - Combination therapy in hypertension: an Asia-Pacific consensus viewpoint. AB - Hypertension incurs a significant healthcare burden in Asia-Pacific countries, which have suboptimal rates of blood pressure (BP) treatment and control. A consensus meeting of hypertension experts from the Asia-Pacific region convened in Hanoi, Vietnam, in April 2013. The principal objectives were to discuss the growing problem of hypertension in the Asia-Pacific region, and to develop consensus recommendations to promote standards of care across the region. A particular focus was recommendations for combination therapy, since it is known that most patients with hypertension will require two or more antihypertensive drugs to achieve BP control, and also that combinations of drugs with complementary mechanisms of action achieve BP targets more effectively than monotherapy. The expert panel reviewed guidelines for hypertension management from the USA and Europe, as well as individual Asia-Pacific countries, and devised a treatment matrix/guide, in which they propose the preferred combination therapy regimens for patients with hypertension, both with and without compelling indications. This report summarizes key recommendations from the group, including recommended antihypertensive combinations for specific patient populations. These strategies generally entail initiating therapy with free drug combinations, starting with the lowest available dosage, followed by treatment with single-pill combinations once the BP target has been achieved. A single reference for the whole Asia-Pacific region may contribute to increased consistency of treatment and greater proportions of patients achieving BP control, and hence reducing hypertension-related morbidity and mortality. PMID- 25707365 TI - Observation of tissues in open aqueous solution by atmospheric scanning electron microscopy: applicability to intraoperative cancer diagnosis. AB - In the atmospheric scanning electron microscope (ASEM), a 2- to 3-um layer of the sample resting on a silicon nitride-film window in the base of an open sample dish is imaged, in liquid, at atmospheric pressure, from below by an inverted SEM. Thus, the time-consuming pretreatments generally required for biological samples to withstand the vacuum of a standard electron microscope are avoided. In the present study, various mouse tissues (brain, spinal cord, muscle, heart, lung, liver, kidney, spleen and stomach) were fixed, stained with heavy metals, and visualized in radical scavenger D-glucose solution using the ASEM. While some stains made the nuclei of cells very prominent (platinum-blue, phosphotungstic acid), others also emphasized cell organelles and membranous structures (uranium acetate or the NCMIR method). Notably, symbiotic bacteria were sometimes observed on stomach mucosa. Furthermore, kidney tissue could be stained and successfully imaged in <30 min. Lung and spinal cord tissue from normal mice and mice metastasized with breast cancer cells was also examined. Cancer cells present in lung alveoli and in parts of the spine tissue clearly had larger nuclei than normal cells. The results indicate that the ASEM has the potential to accelerate intraoperative cancer diagnosis, the diagnosis of kidney diseases and pathogen detection. Importantly, in the course of the present study it was possible to increase the observable tissue area by using a new multi-windowed ASEM sample dish and sliding the tissue across its eight windows. PMID- 25707366 TI - The sum is greater than its parts: clinical evaluations and grade inflation in the surgery clerkship. AB - BACKGROUND: This study examines grading component distributions to determine whether alterations in clinical grade determination reduce skew and improve predictive capability of the clinical evaluation. METHODS: Rotation evaluations, examination scores, and final grades were collected for third-year medical students over a 2-year period. Conditional logistic regression and ordinary least squares regression models were run using SAS 9.3. RESULTS: Conditional logistic regression demonstrated significant association between global clinical score and final grade and between average clinical evaluation score and final grade. Inclusion of shelf score into either model demonstrated increase in overall final grade. CONCLUSIONS: Regressions using global and average clinical evaluation score indicate that average score is a better fit for a norm-based grading system. Arguably, the Shelf measures clinical knowledge more objectively than clinical evaluation, but both were significant. Clinical evaluation is prone to inflation because of its subjective nature; conceivably, inflation leads to the decreased correlation with shelf score. PMID- 25707367 TI - Ultrastructural investigation of antennae in three cutaneous myiasis flies: Melophagus ovinus, Hippobosca equina, and Hippobosca longipennis (Diptera: Hippoboscidae). AB - Melophagus ovinus (Linnaeus 1758), Hippobosca equina Linnaeus, 1758, and Hippobosca longipennis Fabricius, 1805 (Diptera: Hippoboscidae) are economically and medically important ectoparasites that can act as mechanic vectors of pathogens and cause myiasis in both human and domestic animals. As essential olfactory organs, antennae of these adult hippoboscids were examined using stereoscopic and scanning electron microscopes. General morphology of the antenna is provided in detail, combined with distribution, types, size, and ultrastructures of antennal sensilla. On the antennal funiculus, two types of sensilla are observed, including basiconic sensilla and coeloconic sensilla. Four common characters are shared among the three species: (1) the scape is either obsolete or fused with the fronto-clypeus; (2) branched antennal structures (branched pedicellar microtrichiae and branched arista with only one segment) are detected; (3) the enlarged antennal pedicel completely envelops the antennal funiculus; and (4) less types of sensilla on funiculus. Disparity and diversity of the antennal and sensory structures are analyzed from the phylogenetic and functional perspective. We suggest that hippoboscids are potential model for the study of the function of coeloconic sensilla in Calyptratae. PMID- 25707368 TI - Synthesis of functional poly(disubstituted acetylene)s through the post polymerization modification route. AB - We report the recent progress in the preparation of functional poly(disubstituted acetylene)s (PDSAs) through post-polymerization modification routes. The metathesis polymerization of disubstituted acetylene monomers activated by Mo/W Sn complex catalysts, which do not tolerate highly polar functionalities, was assumed to be a key step in the polymer synthetic procedures. We and other groups have explored several approaches to prepare PDSAs with latent reactive functionalities, which are inactive to Mo/W-Sn complex catalysts but can be used as highly reactive sites for post-polymerization modification. Click chemistry, Michael-type addition reactions, the use of activated esters and other strategies are demonstrated by recently published examples. These works indicate that post polymerization modification is an efficient route to the synthesis of various functional PDSAs. PMID- 25707369 TI - The Role of Environment and Lifestyle in Determining the Risk of Multiple Sclerosis. AB - MS is a complex disease where both genetic and environmental factors contribute to disease susceptibility. The substantially increased risk of developing MS in relatives of affected individuals gives solid evidence for a genetic base for susceptibility, whereas the modest familial risk, most strikingly demonstrated in the twin studies, is a very strong argument for an important role of lifestyle/environmental factors in determining the risk of MS, sometimes interacting with MS risk genes. Lifestyle factors and environmental exposures are harder to accurately study and quantify than genetic factors. However, it is important to identify these factors since they, as opposed to risk genes, are potentially preventable. We have reviewed the evidence for environmental factors that have been repeatedly shown to influence the risk of MS: Epstein-Barr virus (EBV) infection, ultraviolet radiation (UVR) exposure habits /vitamin D status, and smoking. We have also reviewed a number of additional environmental factors, published in the past 5 years, that have been described to influence MS risk. Independent replication, preferably by a variety of methods, may give still more firm evidence for their involvement. PMID- 25707370 TI - IRAK4 gene polymorphism and odontogenic maxillary sinusitis. AB - OBJECTIVES: This study aimed to evaluate whether a specific interleukin-1 receptor-associated kinase-4 (IRAK4) gene polymorphism had any influence on the development of changes in maxillary sinus, particularly in the presence of etiological factors of dental origin. MATERIALS AND METHODS: The study population included 153 Portuguese Caucasians that were selected from a database of 504 retrospectively analysed computed tomography (CT) scans. A genetic test was performed, and a model was created through logistic analysis and regression coefficients. The statistical methodologies included were the independent Chi test, Fisher's exact test, binary logistic regression and the receiver operating characteristic (ROC) curve. RESULTS: The estimated prevalence of IRAK4 gene polymorphism found in a Portuguese Caucasian population was 26.8 % (CI 95%) [20.1, 34.7 %]. A model to predict the inflammatory response in the maxillary sinus in the presence etiological factors of dental origin was constructed. This model had the following as variables: previously diagnosed sinusitis, sinus pressure symptoms, cortical bone loss observed on CT, positive genetic test result and radiographic examination that revealed the roots of the teeth communication with the maxillary sinus, which are interpreted as risk factors. CONCLUSIONS: The constructed model should be considered an initial clinical tool. The area under the ROC curve found, AUC = 0.91, revealed that the model correctly predicts the outcome in 91.1% of cases. CLINICAL RELEVANCE: The clinical relevance of this study lies in trying to achieve a potential tool (a model) that may assist the clinician in the implementation of suitable dental treatment plans in complex cases, with probable involvement of the maxillary sinus. PMID- 25707371 TI - Sequence type 131 fimH30 and fimH41 subclones amongst Escherichia coli isolates in Australia and New Zealand. AB - The clonal composition of Escherichia coli causing extra-intestinal infections includes ST131 and other common uropathogenic clones. Drivers for the spread of these clones and risks for their acquisition have been difficult to define. In this study, molecular epidemiology was combined with clinical data from 182 patients enrolled in a case-control study of community-onset expanded-spectrum cephalosporin-resistant E. coli (ESC-R-EC) in Australia and New Zealand. Genetic analysis included antimicrobial resistance mechanisms, clonality by DiversiLab (rep-PCR) and multilocus sequence typing (MLST), and subtyping of ST131 by identification of polymorphisms in the fimH gene. The clonal composition of expanded-spectrum cephalosporin-susceptible E. coli and ESC-R-EC isolates differed, with six MLST clusters amongst susceptible isolates (median 7 isolates/cluster) and three clusters amongst resistant isolates, including 40 (45%) ST131 isolates. Population estimates indicate that ST131 comprises 8% of all E. coli within our population; the fluoroquinolone-susceptible H41 subclone comprised 4.5% and the H30 subclone comprised 3.5%. The H30 subclone comprised 39% of all ESC-R-EC and 41% of all fluoroquinolone-resistant E. coli within our population. Patients with ST131 were also more likely than those with non-ST131 isolates to present with an upper than lower urinary tract infection (RR=1.8, 95% CI 1.01-3.1). ST131 and the H30 subclone were predominant amongst ESC-R-EC but were infrequent amongst susceptible isolates where the H41 subclone was more prevalent. Within our population, the proportional contribution of ST131 to fluoroquinolone resistance is comparable with that of other regions. In contrast, the overall burden of ST131 is low by global standards. PMID- 25707372 TI - [Antihypertensive drug therapy : Where do we stand?]. AB - Antihypertensive drug therapy is one of the most successful medical measures ever, at all levels. The treatment situation in Germany has clearly improved in recent years. Nowadays, a wide range of very effective and well-tolerated hypertensive substances is available. Combination therapy has a long and successful tradition in hypertensive treatment, especially with suitable fixed combinations. Furthermore, the administration of fixed combinations is very beneficial to therapy adherence because it is essentially dependent on the number of drugs to be taken. The value of beta blockers and the double blockade of the renin-angiotensin-aldosterone system are under discussion and the interpretation of corresponding studies must be conducted very carefully. The hypertensive effect of a substance cannot be comprehensively assessed without taking the time of day, the time point of measurement and the time point of intake into consideration. This is particularly important with respect to the effect over 24 h. Optimal antihypertensive therapy must also take into consideration the individual blood pressure rhythm with respect to the dose and dosing intervals. The importance of the central (aortic) blood pressure as target blood pressure will increase. PMID- 25707373 TI - Purification of the Campylobacter jejuni Dps protein assisted by its high melting temperature. AB - Dps proteins (DNA binding protein from starved cell) form a distinct group within the ferritin superfamily. All Dps members are composed of 12 identical subunits that assemble into a conserved spherical protein shell. Dps oxidize Fe(2+) in a conserved ferroxidase center located at the interface between monomers, the product of the reaction Fe(3+), is then stored inside the protein shell in the form of non-reactive insoluble Fe2O3. The Campylobacter jejuni Dps (CjDps) has been reported to play a plethora of functions, such as DNA binding and protection, iron storage, survival in response to hydrogen peroxide and sulfatide binding. CjDps is also important during biofilm formation and caecal colonization in poultry. In order to facilitate in vitro characterisation of CjDps, it is important to have a simple and reproducible protocol for protein purification. Here we report an observation that CjDps has an unusual high melting temperature. We exploited this property for protein purification by introducing a thermal treatment step which allowed achieving homogeneity by using only two chromatographic steps. Gel filtration chromatography, circular dichroism, mass spectrometry, DNA-binding and iron oxidation analysis confirmed that the CjDps structure and function were unaffected. PMID- 25707374 TI - Potential dual imaging nanoparticle: Gd2O3 nanoparticle. AB - Gadolinium (Gd) is a unique and powerful element in chemistry and biomedicine which can be applied simultaneously to magnetic resonance imaging (MRI), X-ray computed tomography (CT), and neutron capture therapy for cancers. This multifunctionality can be maximized using gadolinium oxide (Gd2O3) nanoparticles (GNPs) because of the large amount of Gd per GNP, making both diagnosis and therapy (i.e., theragnosis) for cancers possible using only GNPs. In this study, the T1 MRI and CT dual imaging capability of GNPs is explored by synthesizing various iodine compound (IC) coated GNPs (IC-GNPs). All the IC-GNP samples showed stronger X-ray absorption and larger longitudinal water proton relaxivities (r1 = 26-38 s(-1) mM(-1) and r2/r1 = 1.4-1.9) than the respective commercial contrast agents. In vivo T1 MR and CT images of mice were also acquired, supporting that the GNP is a potential dual imaging agent. PMID- 25707375 TI - Choosing the right imaging method in muscle hernias: musculoskeletal ultrasonography. AB - Muscle hernia (MH) is a focal protrusion of muscle into the overlying subcutaneous tissue through an acquired or congenital facial defect. Herniation in the thigh muscles is not common and there are limited reports evaluating this pathology using ultrasonography (US). A 28-year-old amateur football player presented with a palpable mass on the anterior aspect of his right thigh. Sonographic examination demonstrated a MH through a fascial defect, which is called mushroom appearance. Based on the clinical and sonographic findings, the diagnosis of a MH in the rectus femoris muscle was established. Today, there is no doubt anymore on the role of musculoskeletal US in the field of sports injuries. Therefore, with its various advantages (non-invasive, practical and convenient, inexpensive, etc.), US is the key imaging method in the diagnosis of MHs. PMID- 25707376 TI - The health system burden of chronic disease care: an estimation of provider costs of selected chronic diseases in Uganda. AB - OBJECTIVE: To explore the chronic disease services in Uganda: their level of utilisation, the total service costs and unit costs per visit. METHODS: Full financial and economic cost data were collected from 12 facilities in two districts, from the provider's perspective. A combination of ingredients-based and step-down allocation costing approaches was used. The diseases under study were diabetes, hypertension, chronic obstructive pulmonary disease (COPD), epilepsy and HIV infection. Data were collected through a review of facility records, direct observation and structured interviews with health workers. RESULTS: Provision of chronic care services was concentrated at higher-level facilities. Excluding drugs, the total costs for NCD care fell below 2% of total facility costs. Unit costs per visit varied widely, both across different levels of the health system, and between facilities of the same level. This variability was driven by differences in clinical and drug prescribing practices. CONCLUSION: Most patients reported directly to higher-level facilities, bypassing nearby peripheral facilities. NCD services in Uganda are underfunded particularly at peripheral facilities. There is a need to estimate the budget impact of improving NCD care and to standardise treatment guidelines. PMID- 25707377 TI - Calcitonin gene-related peptide-expressing sensory neurons and spinal microglial reactivity contribute to pain states in collagen-induced arthritis. AB - OBJECTIVE: To evaluate the contribution of sensory neurons in ankle joints and adjacent tissue to the development of pain in collagen-induced arthritis (CIA), and to determine the relationship between pain and the appearance of clinical signs. METHODS: Mechanical and heat hypersensitivity and hind paw swelling were assessed in Lewis rats before and until 18 days following collagen immunization. We examined the effect of intrathecal administration of a calcitonin gene-related peptide (CGRP) antagonist (CGRP(8-37) ) from day 11 to day 18 postimmunization on CIA-induced hypersensitivity. During CIA development, CGRP and p-ERK immunoreactivity was quantified in lumbar dorsal root ganglia in which sensory neurons innervating the ankle joint were identified by retrograde labeling with Fluoro-Gold. Microgliosis in the lumbar dorsal horn was assessed by immunohistochemistry, and release of CGRP evoked by activity of primary afferent fibers was measured using a preparation of isolated dorsal horn with dorsal roots attached. RESULTS: CIA was associated with mechanical hypersensitivity that was evident before hind paw swelling and that was exacerbated with the development of swelling. Heat hyperalgesia developed along with swelling. Concomitant with the development of mechanical hypersensitivity, joint innervating neurons exhibited enhanced CGRP expression and an activated phenotype (increased p-ERK expression), and significant microgliosis became evident in the dorsal horn; these peripheral and central changes were augmented further with disease progression. CGRP release evoked by dorsal root stimulation was higher in the dorsal horn on day 18 in rats with CIA compared to control rats. Prolonged intrathecal administration of CGRP(8 37) attenuated established mechanical hypersensitivity and reduced spinal microgliosis. CONCLUSION: Sensory neuron-derived CGRP sustains mechanical hypersensitivity and spinal microglial reactivity in CIA, suggesting that central mechanisms play critical roles in chronic inflammatory pain. Blockade of these central events may provide pain relief in rheumatoid arthritis patients. PMID- 25707378 TI - Pregnancy weight gain charts for obese and overweight women. AB - OBJECTIVE: Reference charts for classifying and monitoring pregnancy weight gain in severely obese women do not exist. The goal was to construct pregnancy weight gain-for-gestational-age z-score charts for overweight and obese mothers, stratified by severity of obesity. METHODS: Serial weight gain measurements were abstracted from 1047, 1202, 1267, and 730 overweight, class I, II, and III obese women, respectively, delivering uncomplicated term pregnancies at Magee-Womens Hospital in Pittsburgh, PA. Multi-level linear regression models were used to express serial weight gain measurements as a function of gestational age. RESULTS: There were a median [interquartile range] of 11 [9-12] and 11 [9-13] serial weight measurements for overweight and obese (class I, II, and III) women, respectively. The rate of weight gain was minimal until 15-20 weeks and then increased in a slow, linear manner until term. The slope of weight gain flattened as pre-pregnancy BMI increased. Charts were created describing the mean, standard deviation, and select percentiles of weight gain in class I, II, and III obese and overweight pregnancies. CONCLUSIONS: These charts are an innovative tool for studying the association between gestational weight gain and adverse pregnancy outcomes. PMID- 25707381 TI - Semi-synthesis of cyclosporins. AB - BACKGROUND: Since its isolation in 1970, and discovery of its potent inhibitory activity on T-cell proliferation, cyclosporin A (CsA) has been shown to play a significant role in diverse fields of biology. Furthermore, chemical modification of CsA has led to analogs with distinct biological activities associated with its protein receptor family, cyclophilins. SCOPE OF REVIEW: This review systematically collates the synthetic chemistry performed at each of the eleven amino acids, and provides examples of the utility of such transformations. The various modifications of CsA are traced from early, modest chemistry performed at the unique Bmt residue, through the remarkable use of a polyanion enolate that can be stereoselectively manipulated, and onto application of more recently developed olefin metathesis chemistry to prepare new CsA derivatives with unexpected biological activity. MAJOR CONCLUSIONS: The myriad biological activities of CsA and its synthetic derivatives have inspired the development of new approaches to modify the CsA ring. In turn, these new CsA derivatives have served as tools in the discovery of new roles for cyclophilins. GENERAL SIGNIFICANCE: This review provides information on the types of cyclosporin derivatives that are available to the many biologists working in this field, and should be of value to the medicinal chemist trying to discover drugs based on CsA. This article is part of a Special Issue entitled Proline-directed foldases: Cell signaling catalysts and drug targets. PMID- 25707380 TI - Energetic adaptations persist after bariatric surgery in severely obese adolescents. AB - OBJECTIVE: Energetic adaptations induced by bariatric surgery have not been studied in adolescents or for extended periods postsurgery. Energetic, metabolic, and neuroendocrine responses to Roux-en-Y gastric bypass (RYGB) surgery were investigated in extremely obese adolescents. METHODS: At baseline and at 1.5, 6, and 12 months post-baseline, 24-h room calorimetry, body composition, and fasting blood biochemistries were measured in 11 obese adolescents relative to five matched controls. RESULTS: In the RYGB group, mean weight loss was 44 +/- 19 kg at 12 months. Total energy expenditure (TEE), activity EE, basal metabolic rate (BMR), sleep EE, and walking EE significantly declined by 1.5 months (P = 0.001) and remained suppressed at 6 and 12 months. Adjusted for age, sex, fat-free mass, and fat mass, EE was still lower than baseline (P = 0.001). Decreases in serum insulin, leptin, and triiodothyronine (T3), gut hormones, and urinary norepinephrine (NE) paralleled the decline in EE. Adjusted changes in TEE, BMR, and/or sleep EE were associated with decreases in insulin, homeostatic model assessment, leptin, thyroid stimulating hormone, total T3, peptide YY3-36, glucagon-like peptide-2, and urinary NE and epinephrine (P = 0.001-0.05). CONCLUSIONS: Energetic adaptations in response to RYGB-induced weight loss are associated with changes in insulin, adipokines, thyroid hormones, gut hormones, and sympathetic nervous system activity and persists 12 months postsurgery. PMID- 25707382 TI - Alcohol odor elicits appetitive facial expressions in human neonates prenatally exposed to the drug. AB - Specific memories arise during prenatal life as a function of fetal processing of chemosensory stimuli present in the amniotic fluid. Preclinical studies indicate that fetal exposure to alcohol modifies subsequent neonatal and infantile responsiveness towards the sensory attributes of the drug. It has been previously demonstrated that 1-2day-old human neonates recognize ethanol odor as a function of moderate maternal alcohol consumption during gestation. In the present study 7 14day-old newborns were assessed in terms of behavioral responsiveness to alcohol's chemosensory attributes or to a novel odor (lemon). These newborns were representative of mothers that exhibited infrequent or frequent alcohol drinking patterns during pregnancy. Different clinical assessments indicated that all newborns did not suffer congenital or genetic diseases and that they were completely healthy when behaviorally evaluated. Testing was defined by brief presentations of ethanol or lemon odorants. Two sequences of olfactory stimulation were employed. One sequence included five initial trials defined by ethanol odor stimulation followed by one trial with lemon and five additional trials with the scent of the drug (EtOH-Lem-EtOH). The alternative sequence (Lem EtOH-Lem) was primarily defined by lemon olfactory exposure. The dependent variables under analysis were duration and frequency of overall body movements and of facial expressions categorized as aversive or appetitive. The main results of this study were as follows: a) at the end of the testing procedure and independent of the sequence of olfactory stimulation, babies born to frequent drinkers exhibited signs of distress as operationalized through higher durations of aversive facial expressions, b) despite this effect, babies born to frequent drinkers relative to newborns delivered by infrequent drinkers exhibited significantly higher frequencies of appetitive facial responses when primarily stimulated with ethanol odor (EtOH-Lem-EtOH sequence) and c) when merging both samples of babies, a positive and significant correlation was found between overall maternal absolute alcohol consumption per month and frequency of appetitive facial expressions elicited by alcohol odor. In conjunction with previous preclinical research, the present results indicate that human prenatal exposure to the drug that yields no evident teratological effects is sufficient to modify the hedonic value of alcohol's chemosensory attributes. PMID- 25707384 TI - Training for a neurology career in a rare disease: The role of cyberconsults. PMID- 25707383 TI - Prenatal alcohol exposure and adolescent stress increase sensitivity to stress and gonadal hormone influences on cognition in adult female rats. AB - Abnormal activity of stress hormone (hypothalamic-pituitary-adrenal [HPA]), and gonadal hormone (hypothalamic-pituitary-gonadal [HPG]) systems is reported following prenatal alcohol exposure (PAE). PAE increases vulnerability of brain regions involved in regulation of these systems to stressors or challenges during sensitive periods of development, such as adolescence. In addition, HPA and HPG functions are linked to higher order functions such as executive function (EF), with dysregulation of either system adversely affecting EF processes, including attention and response inhibition, that influence cognition. However, how HPA and HPG systems interact to influence cognitive performance in individuals with an FASD is not fully understood. To investigate, we used a rat model of moderate PAE. Adolescent female PAE and control offspring were exposed to 10days of chronic mild stress (CMS) and cognitive function was assessed on the radial arm maze (RAM) in adulthood. On the final test day, animals were sacrificed, with blood collected for hormone analyses, and vaginal smears taken to assess estrus stage at the time of termination. Analyses showed that adolescent CMS significantly increased levels of CORT and RAM errors during proestrus in adult PAE but not control females. Moreover, CORT levels were correlated with estradiol levels and with RAM errors, but only in PAE females, with outcome dependent on adolescent CMS condition. These results suggest that PAE increases sensitivity to the influences of stress and gonadal hormones on cognition, and thus, in turn, that HPA and HPG dysregulation may underlie some of the deficits in executive function described previously in PAE females. PMID- 25707385 TI - Staphylococcal alpha-toxin induces a functional upregulation of TLR-2 on human peripheral blood monocytes. AB - Resistance to bacterial skin infections, for example with Staphylococcus aureus (S. aureus), is based on the function of intact innate immune mechanisms. Toll like receptor (TLR)-2 recognizes components of S. aureus and is known to be expressed on monocytes. Staphylococcal exotoxins such as staphylococcal enterotoxin B (SEB) or alpha-toxin are produced by many S. aureus strains. To investigate TLR-2 regulation and function on human monocytes upon stimulation with staphylococcal exotoxins to elucidate a putative feedback loop between different staphylococcal components. Monocytes were stimulated with alpha-toxin or SEB, respectively. TLR-2 expression and regulation as well as functional effects of TLR-2 stimulation with Pam3Cys (TLR-2/TLR-1), lipoteichoic acid (LTA) (TLR-2/TLR-6) and peptidoglycan (PGN) (TLR-2 and Nod) were then investigated both at the mRNA and protein level and compared to monocytes from patients with psoriasis. alpha-toxin significantly upregulated TLR-2 expression. TLR-2 mediated IL-1beta, IL-6 and IL-8 secretion was significantly augmented after upregulation with staphylococcal exotoxins. CD36 expression was significantly more downregulated after TLR-2 upregulation with SEB and consecutive LTA stimulation and TLR-2 upregulation with alpha-toxin following LTA and PGN stimulation, respectively. PGN enhanced CD54 expression after upregulation of the receptor with alpha-toxin. Expression of HLA-DR was unaffected. However, no differences were observed in monocytes from psoriasis patients compared to healthy controls. Together, our findings provide a new link between staphylococcal alpha-toxin and TLR-2 signalling in monocytes which may have implications for skin diseases where skin colonization with S. aureus and dysregulation of TLR-2 have been described. PMID- 25707387 TI - Interventional cardiology: 6-year follow-up of TAVI patients. PMID- 25707379 TI - Changes in body composition over 8 years in a randomized trial of a lifestyle intervention: the look AHEAD study. AB - OBJECTIVE: To determine the effects of an intensive lifestyle intervention versus a comparison group on body composition in obese or overweight persons with type 2 diabetes at baseline and at 1, 4, and 8 years. METHODS: Body composition was measured by dual-energy X-ray absorptiometry in a subset of 1019 Look AHEAD study volunteers randomized to intervention or comparison groups. The intervention was designed to achieve and maintain >=7% weight loss through increased physical activity and reduced caloric intake. The comparison group received social support and diabetes education. RESULTS: At 1 year, the intervention group lost fat (5.6 +/- 0.2 kg) and lean mass (2.3 +/- 0.1 kg) but regained fat (~100%) and lost lean mass between years 1 and 8. Between baseline and year 8, weight loss was greater in intervention versus comparison groups (4.0 +/- 0.4 vs. 2.3 +/- 0.4 kg); comparison group weight loss was mostly lean mass (2.1 +/- 0.17 kg). Fat mass in the intervention group was lower than that of the comparison group at all post baseline time points. CONCLUSIONS: Reduced fat mass may place the intervention group at a lower risk of obesity-linked sequelae, a hypothesis that can be tested by future studies of this cohort. PMID- 25707386 TI - Pathophysiology and clinical management of cardiac sarcoidosis. AB - Cardiac sarcoidosis is a potentially life-threatening condition characterized by formation of granulomas in the heart, resulting in conduction disturbances, atrial and ventricular arrhythmias, and ventricular dysfunction. The presentation of cardiac sarcoidosis ranges from asymptomatic with an abnormal imaging scan, to palpitations, syncope, symptoms of congestive heart failure, and sudden cardiac death. Screening for cardiac sarcoidosis has not been standardized, but the presence of cardiac symptoms on medical history and physical examination, and an abnormal electrocardiogram (ECG), Holter monitoring, or echocardiogram has been shown to be highly sensitive for detecting cardiac sarcoidosis. A signal-averaged ECG might also have a role in screening for cardiac sarcoidosis in asymptomatic patients. Although endomyocardial biopsies are highly specific for the diagnosis of cardiac sarcoidosis, procedural yield is very low and appropriate findings on cardiac MRI or PET are, therefore, often used as diagnostic surrogates. Treatment for cardiac sarcoidosis usually involves immunosuppressive therapy, particularly corticosteroids. Additional therapy might be required, depending on the clinical presentation, including implantation of an internal defibrillator, antiarrhythmic agents, and catheter ablation. PMID- 25707388 TI - Ethics of preparticipation cardiovascular screening for athletes. AB - Preparticipation screening for unsuspected cardiovascular disease is a controversial topic in the medical and lay communities. Much attention has been directed towards young competitive athletes, particularly the proposed strategy of incorporating 12-lead electrocardiograms into the screening process, even on a national or worldwide basis. However, sudden deaths of young athletes owing to genetic or congenital heart diseases have a low incidence in the general population. Furthermore, young people not engaged in competitive sports can harbour the same conditions that cause sudden death in athletes, which has gone largely unrecognized. Notably, sudden deaths from these diseases are numerically far more common in the much larger population of nonathletes. In this Perspectives article, we propose that an ethical dilemma has emerged, raising the important public-health issue of whether young individuals should be arbitrarily excluded from potentially life-saving clinical screening evaluations because they do not engage in competitive sports programmes. PMID- 25707389 TI - Genes involved in nutrient competition by Pseudomonas putida JBC17 to suppress green mold in postharvest satsuma mandarin. AB - Understanding the mechanisms underlying biocontrol activity in biocontrol agents is indispensable to implement biological control. However, the understanding of specific mechanisms for nutrient competition in nutrient limited environments is still limited. This study was performed to control green mold of postharvest satsuma mandarin (mandarin) using Pseudomonas putida JBC17 (JBC17), and identify the genes involved in nutrient competition. Treatment with JBC17 on wounded mandarin fruits at a concentration of 10(6) and 10(7) cfu ml(-1) suppressed the incidence of green mold with efficacy of 74.1 and 91.4%, respectively, compared to the untreated control. In spite of there being no antifungal activity in a dual culture test, JBC17 significantly inhibited the conidial germination of Penicillium digitatum. The results from the nutrient competition assay revealed that the inhibition of conidial germination was exerted by nutrient starvation. From the constructed transposon (Tn) library of JBC17, exopolyphosphatase (ppx) and Xaa-Pro aminopeptidase (pepP) were recognized as potential factors responsible for the inhibition of conidial germination. In conclusion, the understanding of nutrient depletion specific to the inhibition of conidial germination by JBC17 may ultimately lead to a deeper understanding of the bacterial metabolism and conidial metabolism for germination as well as biocontrol activity. PMID- 25707390 TI - Effect of the probe frequency on sensitivity of color Doppler ultrasound to color blood flow: comment on the article by Torp-Pedersen et al. PMID- 25707391 TI - Losses of soil carbon by converting tropical forest to plantations: erosion and decomposition estimated by delta(13) C. AB - Indonesia lost more tropical forest than all of Brazil in 2012, mainly driven by the rubber, oil palm, and timber industries. Nonetheless, the effects of converting forest to oil palm and rubber plantations on soil organic carbon (SOC) stocks remain unclear. We analyzed SOC losses after lowland rainforest conversion to oil palm, intensive rubber, and extensive rubber plantations in Jambi Province on Sumatra Island. The focus was on two processes: (1) erosion and (2) decomposition of soil organic matter. Carbon contents in the Ah horizon under oil palm and rubber plantations were strongly reduced up to 70% and 62%, respectively. The decrease was lower under extensive rubber plantations (41%). On average, converting forest to plantations led to a loss of 10 Mg C ha(-1) after about 15 years of conversion. The C content in the subsoil was similar under the forest and the plantations. We therefore assumed that a shift to higher delta(13) C values in plantation subsoil corresponds to the losses from the upper soil layer by erosion. Erosion was estimated by comparing the delta(13) C profiles in the soils under forest and under plantations. The estimated erosion was the strongest in oil palm (35 +/- 8 cm) and rubber (33 +/- 10 cm) plantations. The (13) C enrichment of SOC used as a proxy of its turnover indicates a decrease of SOC decomposition rate in the Ah horizon under oil palm plantations after forest conversion. Nonetheless, based on the lack of C input from litter, we expect further losses of SOC in oil palm plantations, which are a less sustainable land use compared to rubber plantations. We conclude that delta(13) C depth profiles may be a powerful tool to disentangle soil erosion and SOC mineralization after the conversion of natural ecosystems conversion to intensive plantations when soils show gradual increase of delta(13) C values with depth. PMID- 25707392 TI - Genetic variations in the VEGF pathway as prognostic factors in metastatic colorectal cancer patients treated with oxaliplatin-based chemotherapy. AB - Angiogenesis is a significant biological mechanism in the progression and metastasis of solid tumors. Vascular endothelial growth factor (VEGF), its receptors and signaling effectors have a central role in tumor-induced angiogenesis. Genetic variation in the VEGF pathway may impact on tumor angiogenesis and, hence, on clinical cancer outcomes. This study evaluates the influence of common genetic variations within the VEGF pathway in the clinical outcomes of 172 metastatic colorectal cancer (mCRC) patients treated with first line oxaliplatin/5-fluorouracil chemotherapy. A total of 27 single-nucleotide polymorphisms (SNPs) in 16 genes in the VEGF-dependent angionenesis process were genotyped using a dynamic array on the BioMarkTM system. After assessing the KRAS mutational status, we found that four SNPs located in three genes (KISS1, KRAS and VEGFR2) were associated with progression-free survival. Five SNPs in three genes (ITGAV, KRAS and VEGFR2) correlated with overall survival. The gene-gene interactions identified in the survival tree analysis support the importance of VEGFR2 rs2071559 and KISS1 rs71745629 in modulating these outcomes. This study provides evidence that functional germline polymorphisms in the VEGF pathway may help to predict outcome in mCRC patients who undergo oxaliplatin/5-fluorouracil chemotherapy. PMID- 25707393 TI - Pharmacogenomic information in drug labels: European Medicines Agency perspective. AB - Pharmacogenomics (PGx) has a growing impact on healthcare and constitutes one of the major pillars of personalised medicine. For the purpose of improved individualised drug treatment, there is an increasing effort to develop drugs suitable for specific subpopulations and to incorporate pharmacogenomic drug labels in existing and novel medicines. Here, we review the pharmacogenomic drug labels of all 517 medicinal products centrally approved in the European Union (EU) since the establishment of the European Medicines Agency in 1995. We identified all pharmacogenomic-related information mentioned in the product labels and classified it according to its main effect and function on drug treatment, that is, metabolism, transport and pharmacodynamics, and according to the place of the respective section of the Summary of Product Characteristics (SmPC). The labels are preferentially present in drugs having antineoplastic properties. We find that the number of drugs with pharmacogenomic labels in EU increases now steadily and that it will be an important task for the future to refine the legislation on how this information should be utilised for improvement of drug therapy. PMID- 25707394 TI - Development of a genetic marker set to diagnose aspirin-exacerbated respiratory disease in a genome-wide association study. AB - We developed a genetic marker set of single nucleotide polymorphisms (SNPs) by summing risk scores of 14 SNPs showing a significant association with aspirin exacerbated respiratory disease (AERD) from our previous 660 W genome-wide association data. The summed scores were higher in the AERD than in the aspirin tolerant asthma (ATA) group (P=8.58 * 10(-37)), and were correlated with the percent decrease in forced expiratory volume in 1 s after aspirin challenge (r(2)=0.150, P=5.84 * 10(-30)). The area under the curve of the scores for AERD in the receiver operating characteristic curve was 0.821. The best cutoff value of the summed risk scores was 1.01328 (P=1.38 * 10(-32)). The sensitivity and specificity of the best scores were 64.7% and 85.0%, respectively, with 42.1% positive and 93.4% negative predictive values. The summed risk score may be used as a genetic marker with good discriminative power for distinguishing AERD from ATA. PMID- 25707395 TI - High-accuracy imputation for HLA class I and II genes based on high-resolution SNP data of population-specific references. AB - Statistical imputation of classical human leukocyte antigen (HLA) alleles is becoming an indispensable tool for fine-mappings of disease association signals from case-control genome-wide association studies. However, most currently available HLA imputation tools are based on European reference populations and are not suitable for direct application to non-European populations. Among the HLA imputation tools, The HIBAG R package is a flexible HLA imputation tool that is equipped with a wide range of population-based classifiers; moreover, HIBAG R enables individual researchers to build custom classifiers. Here, two data sets, each comprising data from healthy Japanese individuals of difference sample sizes, were used to build custom classifiers. HLA imputation accuracy in five HLA classes (HLA-A, HLA-B, HLA-DRB1, HLA-DQB1 and HLA-DPB1) increased from the 82.5 98.8% obtained with the original HIBAG references to 95.2-99.5% with our custom classifiers. A call threshold (CT) of 0.4 is recommended for our Japanese classifiers; in contrast, HIBAG references recommend a CT of 0.5. Finally, our classifiers could be used to identify the risk haplotypes for Japanese narcolepsy with cataplexy, HLA-DRB1*15:01 and HLA-DQB1*06:02, with 100% and 99.7% accuracy, respectively; therefore, these classifiers can be used to supplement the current lack of HLA genotyping data in widely available genome-wide association study data sets. PMID- 25707396 TI - Sodium Fluoride Induces Apoptosis in H9c2 Cardiomyocytes by Altering Mitochondrial Membrane Potential and Intracellular ROS Level. AB - Chronic excessive fluoride intake is known to be toxic, and effects of long-term fluorosis on different organ systems have been examined. However, there are few studies about the effects of fluorosis on cardiovascular systems. Here, we studied the fluoride-induced apoptosis in H9c2 cells and determined the underlying molecular mechanisms including the cell viability, intracellular reactive oxygen species (ROS) level, the changes of mitochondrial membrane potential (DeltaPsim), and the cell apoptosis. Sodium fluoride (NaF) at concentrations of 0, 2, 4, 8, and 16 mg/L was administered to cultured H9c2 cells for up to 48 h. After the treatment, H9c2 cells were collected and the associated parameters were measured by flow cytometry. Our study found that fluoride not only inhibited H9c2 cell proliferation but also induced cell apoptosis. With the increment of NaF concentration, the apoptotic rates and ROS generation were increased, while the DeltaPsim was decreased. In summary, these data suggested that NaF-induced H9c2 cell apoptosis is mediated by direct increased intracellular ROS and downregulated DeltaPsim. PMID- 25707397 TI - In-vivo imaging of grey and white matter neuroinflammation in Alzheimer's disease: a positron emission tomography study with a novel radioligand, [18F] FEPPA. AB - Our primary aim was to compare neuroinflammation in cognitively intact control subjects and patients with Alzheimer's disease (AD) by using positron emission tomography (PET) with translocator protein 18 kDa (TSPO)-specific radioligand [(18)F]-FEPPA. [(18)F]-FEPPA PET scans were acquired on a high-resolution research tomograph in 21 patients with AD (47- 81 years) and 21 control subjects (49-82 years). They were analyzed by using a 2-tissue compartment model with arterial plasma input function. Differences in neuroinflammation, indexed as [(18)F]-FEPPA binding were compared, adjusting for differences in binding affinity class as determined by a single polymorphism in the TSPO gene (rs6971). In grey matter areas, [(18)F]-FEPPA was significantly higher in AD compared with healthy control subjects. Large increases were seen in the hippocampus, prefrontal, temporal, parietal and occipital cortex (average Cohen's d= 0.89). Voxel-based analyses confirmed significant clusters of neuroinflammation in the frontal, temporal and parietal cortex in patients with AD. In white matter, [(18)F]-FEPPA binding was elevated in the posterior limb of the internal capsule, and the cingulum bundle. Higher neuroinflammation in the parietal cortex (r= 0.7, P= 0.005), and posterior limb of the internal capsule (r= -0.8, P=0.001) was associated with poorer visuospatial function. In addition, a higher [(18)F]-FEPPA binding in the posterior limb of the internal capsule was associated with a greater impairment in language ability (r= -0.7, P=0.004). Elevated neuroinflammation can be detected in AD patients throughout the brain grey and white matter by using [(18)F]-FEPPA PET. Our results also suggest that neuroinflammation is associated with some cognitive deficits. PMID- 25707398 TI - Disruptive de novo mutations of DYRK1A lead to a syndromic form of autism and ID. AB - Dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1 A (DYRK1A) maps to the Down syndrome critical region; copy number increase of this gene is thought to have a major role in the neurocognitive deficits associated with Trisomy 21. Truncation of DYRK1A in patients with developmental delay (DD) and autism spectrum disorder (ASD) suggests a different pathology associated with loss-of-function mutations. To understand the phenotypic spectrum associated with DYRK1A mutations, we resequenced the gene in 7162 ASD/DD patients (2446 previously reported) and 2169 unaffected siblings and performed a detailed phenotypic assessment on nine patients. Comparison of our data and published cases with 8696 controls identified a significant enrichment of DYRK1A truncating mutations (P=0.00851) and an excess of de novo mutations (P=2.53 * 10(-10)) among ASD/intellectual disability (ID) patients. Phenotypic comparison of all novel (n=5) and recontacted (n=3) cases with previous case reports, including larger CNV and translocation events (n=7), identified a syndromal disorder among the 15 patients. It was characterized by ID, ASD, microcephaly, intrauterine growth retardation, febrile seizures in infancy, impaired speech, stereotypic behavior, hypertonia and a specific facial gestalt. We conclude that mutations in DYRK1A define a syndromic form of ASD and ID with neurodevelopmental defects consistent with murine and Drosophila knockout models. PMID- 25707399 TI - Valproic acid enhances neuronal differentiation of sympathoadrenal progenitor cells. AB - The antiepileptic drug valproic acid (VPA) has been shown to influence the neural differentiation and neurite outgrowth of neural stem cells. Sympathoadrenal progenitor cells share properties with neural stem cells and are considered a potential cell source in the treatment of neurodegenerative diseases. The present study therefore aims at modulating the neural differentiation potential of these cells by treatment with the histone deacetylase inhibitor VPA. We studied the epigenetic effects of VPA in two culture conditions: suspension conditions aimed to expand adrenomedullary sympathoadrenal progenitors within free-floating chromospheres and adherent cell cultures optimized to derive neurons. Treatment of chromospheres with VPA may launch neuronal differentiation mechanisms and improve their neurogenic potential upon transplantation. However, also transplantation of differentiated functional neurons could be beneficial. Treating chromospheres for 7 days with clinically relevant concentrations of VPA (2 mm) revealed a decrease of neural progenitor markers Nestin, Notch2 and Sox10. Furthermore, VPA initiated catecholaminergic neuronal differentiation indicated by upregulation of the neuronal marker beta-III-tubulin, the dopaminergic transcription factor Pitx3 and the catecholaminergic enzymes TH and GTPCH. In adherent neural differentiation conditions, VPA treatment improved the differentiation of sympathoadrenal progenitor cells into catecholaminergic neurons with significantly elevated levels of nor- and epinephrine. In conclusion, similar to neural stem cells, VPA launches differentiation mechanisms in sympathoadrenal progenitor cells that result in increased generation of functional neurons. Thus, data from this study will be relevant to the potential use of chromaffin progenitors in transplantation therapies of neurodegenerative diseases. PMID- 25707400 TI - Awareness of cancer, satisfaction with care, emotional distress, and adjustment to illness: an Italian multicenter study. AB - OBJECTIVE: The aim of the study was to examine awareness of cancer and the relationship with distress and satisfaction with care among Italian cancer patients. METHODS: Two hundred sixty-two cancer patients consecutively admitted to the Day Hospital of four cancer centers in Italy completed the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core-30, the EORTC Inpatient Satisfaction-32, the EORTC Information Questionnaire-25, the distress thermometer, the Mini-mental Adjustment to Cancer scale, a visual analogue scale of illness awareness, and questions related to the admission and unmet needs. RESULTS: Eighty-seven percent of patients were aware of their diagnosis, but 49% of those with metastatic cancer thought they have a curable disease. About one-third felt that family members often (16%) or always (13%) were hiding information or bad news in order to protect them. In multivariate analysis, the perception of being protected from bad news by the family was associated with the perceived need to talk more with the family but was not associated with demographic or clinical (Karnofsky Performance Status and stage) variables, lower emotional distress, and greater satisfaction with care and information. Also, awareness of diagnosis and prognosis was not associated with demographic or clinical variables, emotional distress, or satisfaction with care and information CONCLUSIONS: Most cancer patients were fully informed about their diagnosis, although awareness of disease was not coincident with awareness of prognosis and disease progression. Information and knowledge were not destructive of hope and did not increase distress. Family issues are still a significant factor molding openness and sharing of information. PMID- 25707401 TI - Ultrasound-assisted emulsification microextraction coupled with high-performance liquid chromatography for the simultaneous determination of fragrance allergens in cosmetics and water. AB - A simple, inexpensive, and environmentally friendly method based on ultrasound assisted emulsification microextraction followed by solidification of floating organic drop and high-performance liquid chromatography coupled to diode array detection was developed for the simultaneous determination of 18 potentially allergenic fragrance substances. Several parameters affecting the microextraction process were investigated in detail by the "one-variable-at-a-time" approach. Optimal conditions were the following: 50 MUL of 2-dodecanol as extraction solvent, 10 mL of sample containing 150 g/L of salt, and 5 min of sonication at 35 degrees C. Under the optimized conditions, method showed good linearity in the selected ranges, with squared correlation coefficients ranging from 0.948 to 0.999. Limits of detection ranged from 0.001 to 0.154 MUg/mL and enrichment factors from 9 to 237. Precision of the method, expressed as relative standard deviation, was checked at two levels obtaining good results (3.3-14.4%). Recovery studies were made in baby bath water and in eau de cologne showing acceptable accuracy. Finally, the developed method was successfully applied to different commercial cosmetic and water samples. The most commonly found analyte was linalool followed by cinnamal and lilial. Most of the analyzed samples contained at least one of the target compounds. PMID- 25707403 TI - Cubosomes: Innovative Nanostructures for Drug Delivery. AB - BACKGROUND: Some amphiphilic lipids can self-assemble to form bicontinuous cubic liquid crystalline materials in aqueous media. These cubic structures have gained considerable attention since they impart unique properties of practical interest. Cubosomes, being dispersions of an inverted type bicontinuous cubic phase, separate two continuous aqueous regions with a lipid bilayer having the propensity to incorporate drugs of varying polar characteristics. These novel versatile materials possess the properties to form a section of the next generation of advanced biocompatible nanoparticles. METHODS: This review chiefly considers the scope and importance of cubosomes as a proficient drug delivery vehicle. In addition, it also takes into account the various methods of preparation, the drug loading and release behavior as well as different methods of characterization. Their current advances in various arenas ranging from sustained drug release, burn management, melanoma therapy, vaccine delivery, protein delivery, cosmeceutical and theranostic applications are briefly summarized in this overview. RESULTS: The drug release from cubosomal dispersions have shown enhancement in bioavailability by solubilisation of poorly water soluble drugs, decrease in adverse effects, enhancement of intracellular penetration, protection against degradation, possibility of sustained drug release and the biodegradable nature of lipids is an added advantage. CONCLUSION: Recognizing the desirable properties of cubosomes, it has been proposed as a novel carrier for drug delivery systems. Their unique solubilizing, encapsulating, transporting and protecting capabilities make them an attractive vehicle for numerous in vivo drug delivery routes. PMID- 25707402 TI - Associations of 25-Hydroxyvitamin D and 1,25-Dihydroxyvitamin D With Bone Mineral Density, Bone Mineral Density Change, and Incident Nonvertebral Fracture. AB - Relationships between 1,25-dihydroxyvitamin D (1,25(OH)2 D) and skeletal outcomes are uncertain. We examined the associations of 1,25(OH)2 D with bone mineral density (BMD), BMD change, and incident non-vertebral fractures in a cohort of older men and compared them with those of 25-hydroxyvitamin D (25OHD). The study population included 1000 men (aged 74.6 +/- 6.2 years) in the Osteoporotic Fractures in Men (MrOS) study, of which 537 men had longitudinal dual-energy X ray absorptiometry (DXA) data (4.5 years of follow-up). A case-cohort design and Cox proportional hazards models were used to test the association between vitamin D metabolite levels and incident nonvertebral and hip fractures. Linear regression models were used to estimate the association between vitamin D measures and baseline BMD and BMD change. Interactions between 25OHD and 1,25(OH)2 D were tested for each outcome. Over an average follow-up of 5.1 years, 432 men experienced incident nonvertebral fractures, including 81 hip fractures. Higher 25OHD was associated with higher baseline BMD, slower BMD loss, and lower hip fracture risk. Conversely, men with higher 1,25(OH)2 D had lower baseline BMD. 1,25(OH)2 D was not associated with BMD loss or nonvertebral fracture. Compared with higher levels of calcitriol, the risk of hip fracture was higher in men with the lowest 1,25(OH)2 D levels (8.70 to 51.60 pg/mL) after adjustment for baseline hip BMD (hazard ratio [HR] = 1.99, 95% confidence interval [CI] 1.19 3.33). Adjustment of 1,25(OH)2 D data for 25OHD (and vice versa) had little effect on the associations observed but did attenuate the hip fracture association of both vitamin D metabolites. In older men, higher 1,25(OH)2 D was associated with lower baseline BMD but was not related to the rate of bone loss or nonvertebral fracture risk. However, with BMD adjustment, a protective association for hip fracture was found with higher 1,25(OH)2 D. The associations of 25OHD with skeletal outcomes were generally stronger than those for 1,25(OH)2 D. These results do not support the hypothesis that measures of 1,25(OH)2 D improve the ability to predict adverse skeletal outcomes when 25OHD measures are available. (c) 2015 American Society for Bone and Mineral Research. PMID- 25707405 TI - Association between endometrial thickness in oocyte donation cycles and pregnancy success rates. AB - Endometrial receptivity is a primary concern for embryo implantation success in fertility treatments. The present study was a retrospective analysis of 4070 cycles with donor oocytes and hormone-replacement therapy. Endometrial thickness was assessed once with transvaginal ultrasound. Patients were allowed to continue when endometrial thickness was ?5mm and had triple line morphology. Pregnancy rates, the number of gestational sacs and miscarriage rates were analysed in relation to endometrium status. Regression models were used to analyse associations, taking the day of embryo transfer into account. All patient parameters were homogeneous. Mean endometrial thickness was 7.24+/-1.66mm, the mean number of embryos transferred was 2.04+/-0.43, the pregnancy rate was 48.06% and sacs were present in 42.3% of cycles. There were no significant differences in pregnancy rates, number of gestational sacs and miscarriage rates for different endometrial thickness measurements. The present study is, to our knowledge, the largest study evaluating the role of endometrial thickness in oocyte donation cycles. Endometrial thickness >5mm is a reasonable parameter for determining treatment success, and once it is observed in a single ultrasonographic evaluation there is no need for subsequent monitoring and embryo transfer can be scheduled over the following 1-16 days, because the results are not compromised. This may lead to a significant reduction in time and cost in fertility clinics. PMID- 25707406 TI - Size-dependent mechanical properties of axial and radial mixed AlN/GaN nanostructure. AB - In this paper, continuum multiscale models are proposed to describe the size dependent mechanical properties of two kinds of heterogeneous nanostructures: radially heterogeneous nanowires and longitudinally heterogeneous nanolaminates. In both cases, the continuum models involve additional surface/interface energies, which allow capturing size effects. Several models of imperfect interface models, like coherent and spring-layer ones, are shown to respectively capture the size effects, which are reported by first-principles calculations performed on heterogeneous nanostructures. In each case, a procedure is proposed to identify the parameters of the surface/interface model in the continuum framework, based on first-principles calculations performed on slab systems. The obtained continuum models allow avoiding full computations on atomistic models, which are not affordable for large sizes (diameters, layer thickness). An increase of the overall stiffness for both kinds of heterogeneous AlN/GaN nanostructures with the decrease of the dimensions is evidenced. The continuum models are then compared with full first-principles calculations to demonstrate their accuracy and their ability to capture size effects. PMID- 25707404 TI - Effect of chlorhexidine bathing and other infection control practices on the Benefits of Universal Glove and Gown (BUGG) trial: a subgroup analysis. AB - We report the results of a subgroup analysis of the Benefits of Universal Glove and Gown trial. In 20 intensive care units, the reduction in acquisition of methicillin-resistant Staphylococcus aureus observed in this trial was observed in units also using chlorhexidine bathing and in those that previously performed active surveillance. PMID- 25707407 TI - Complete mitochondrial genome of the penguin tetra, Thayeria boehlkei. AB - The penguin tetra (Thayeria boehlkei) is one of the most popular aquarium fish and belongs to the family of Characidae. The composition, phylogeny, and classification of this family are uncertain. Here, the complete mitogenome of T. boehlkei was reported to be 16,524 bp in length. It contains 13 protein-coding genes, 22 transfer RNA genes and 2 ribosomal RNA genes. Comparing the mitochondrial genome of T. boehlkei with its congener Astyanax mexicanus revealed high-sequence similarity. The mitochondrial genome of T. boehlkei will contribute to conservation studies and evolution analysis of Characidae family. PMID- 25707408 TI - Complete mitochondrial genome of the Antarctic dragonfish, Parachaenichthys charcoti (Notothenioidei: Bathydraconidae). AB - The complete mitochondrial genome of the Antarctic dragonfish, Parachaenichthys charcoti (Vaillant, 1906), is described, representing the first complete mitochondrial genome sequence of the family Bathydraconidae. The mitochondrial genome is 18,202 base pairs in length and encodes 13 protein-coding genes, 23 tRNAs, 2 rRNAs and 2 control regions. The overall base composition is A: 25.8%, T: 25.3%, G: 17.9% and C: 31.0%, with an A:T content of 51.1%. The complete mitochondrial genome sequence will be useful for phylogenetic, evolutionary and functional studies of Antarctic Notothenioids. PMID- 25707409 TI - The complete chloroplast genome sequence of Chloranthus japonicus. AB - The complete chloroplast genome of Chloranthus japonicus, an important traditional Chinese herbal medicine, was sequenced and characterized in this study. The genome size is 158,640 bp in length with 38.9% GC content. Two inverted repeats of 26,149 bp are separated by a large single-copy region (87,724 bp) and a small single-copy region (18,618 bp). The genome contains 131 individual genes, including 86 protein-coding genes, 37 tRNA genes and 8 rRNA genes. Eighteen genes contain one or two introns. PMID- 25707410 TI - Complete mitochondrial genome of the spiny eel Sinobdella sinensis (Perciformes, Mastacembelidae). AB - In this study, the complete mitochondrial genome of Sinobdella sinensis was reported. The circular genome is 16,540 bp in length and consists of 13 protein coding genes, 22 tRNA genes, 2 ribosomal RNA genes, and 1 control region. The overall nucleotide composition was 30.0% A, 26.5% T, 28.7% C, and 14.8% G, with an A + T bias of 56.5%. The gene composition and the structural arrangement of the S. sinensis complete mtDNA were identical to most other vertebrates. The molecular data here we presented could play a useful role to study the evolutionary relationships and population genetics of Mastacembelidae fish. PMID- 25707411 TI - The complete mitogenome of the New Zealand freshwater crayfish Paranephrops planifrons White 1842 (Crustacea: Decapoda: Parastacidae). AB - The mitogenome of Paranephrops planifrons, was obtained by next generation sequencing. This crayfish has a mitochondrial genome of 16,174 base pairs with 13 protein-coding genes, 2 ribosomal subunit genes, 22 transfer RNAs (tRNA), and a non-coding AT-rich region of 771 bp. The P. planifrons nucleotide composition is: 33.63% for T, 21.92% for C, 34.46% for A, and 9.98% for G and has a 68.09% AT bias. While the mitogenome gene order for this species is consistent with aspects of the highly distinctive parastacid crayfish mitogenome gene arrangement, it has a novel gene order involving the rearrangements of a protein coding and several tRNA genes. PMID- 25707412 TI - The complete mitogenome of the fairy shrimp Phallocryptus tserensodnomi (Crustacea: Anostraca: Thamnocephalidae). AB - The sequence of the mitochondrial genome (mitogenome) of the fairy shrimp Phallocryptus tserensodnomi Alonso & Ventura 2013 (Crustacea: Anostraca: Thamnocephalidae) has been determined. It is 16,493 bp with an AT-content of 65.4%, which encodes information of the typical 37 genes as all other metazoan mitogenomes. Both AT-content and putative control region of the genome show moderate values among all mitogenomes of the Branchiopoda sequenced to date. The mitochondrial gene order shows the same arrangement with the Artemiidae which is different from the pancrustacean ancestral pattern, due to translocation and inversion of two tRNA genes. Our results will provide important materials for not only phylogenetic but also biogeographic studies of the Anostraca. PMID- 25707413 TI - The sequence and organization of complete mitochondrial genome of the yellowfin tuna, Thunnus albacares (Bonnaterre, 1788). AB - Yellowfin tuna (Thunnus albacares) is one of the most important economic fishes around the world. In the present study, we determined the complete mitochondrial DNA sequence and organization of T. albacares. The entire mitochondrial genome is a circular-molecule of 16,528 bp in length, which encodes 37 genes in all. These genes comprise 13 protein-coding genes (ATP6 and 8, COI-III, Cytb, ND1-6 and 4 L), 22 transfer RNA genes (tRNAs), and 2 ribosomal RNA genes (12S and 16S rRNAs). The complete mitochondrial genome sequence of T. albacares can provide basic information for the studies on molecular taxonomy and conservation genetics of teleost fishes. PMID- 25707414 TI - Complete mitochondrial genome of Kashgarian loach, Triplophysayarkandensis (Day, 1877) in the Tarim river. AB - Kashgarian loach, Triplophysayarkandensis (Day, 1877), a native species in the Tarim River of Northwest China, has been dramatically declined in population size in recent years. In this article, the mitochondrial genome of Kashgarian loach was first determined. The whole mtDNA sequence was 16,574 bp in length, which is similar to other bony fishes in gene order, including 2rRNA genes, 22tRNA, 13 protein-coding and 1 putative control region. PMID- 25707415 TI - Complete mitochondrial genome of Argentine shortfin squid (Illex argentines). AB - In this study, we determined the complete mitochondrial genome of the Illex argentinus. The genome was 20,278 bp in length and contained 18 protein-coding genes, 23 transfer RNA genes, 2 ribosomal RNA genes and 3 main non-coding regions. The composition and order of genes were different to some other invertebrates. The overall base composition of I. argentinus was A 39.23%, C 17.50%, T 33.71% and G 9.56%, with a highly A + T bias of 72.94%. All of the three control regions (CR) contained termination-associated sequences and conserved sequence blocks. This mitogenome sequence data would play an important role in the taxonomic resolution and phylogeography of the Ommastrephidae. PMID- 25707416 TI - The complete mitochondrial genome of the Sara Longwing Heliconius sara (Insecta: Lepidoptera: Nymphalidae). AB - The complete mitochondrial genome of the Sara Longwing Heliconius sara has been reconstructed from the whole-genome Illumina sequencing data. The mitochondrial genome is 15,372 bp in size with the highly asymmetric overall A + T content of 80.6%. Annotation of mitochondrial genome revealed a total of 37 genes, including 13 protein-coding genes (PCGs), 22 transfer RNAs (tRNAs), 2 ribosomal RNAs (rRNAs) and 1 D-loop region. Most PCGs are initiated with the ATN codons, while COX1 and ND1 start with CGA and TTG, respectively. COX1, COX2, and ND4 harbor the incomplete stop codon T, while all the others are terminated with the TAR codons. The complete mitochondrial genome of H. Sara would contribute to our further understanding of the phylogeny and evolution of the genus Heliconius and related taxa. PMID- 25707417 TI - Review of the biological properties and toxicity of usnic acid. AB - Since its first isolation in 1844, usnic acid [2,6-diacetyl-7,9-dihydroxy-8,9b dimethyl-1,3(2H,9bH)-dibenzo-furandione] has become the most extensively studied lichen metabolite and one of the few that are commercially available. Lichens belonging to usnic acid-containing genera have been used as crude drugs throughout the world. There are indications of usnic acid being a potentially interesting candidate for such activities as anti-inflammatory, analgesic, healing, antioxidant, antimicrobial, antiprotozoal, antiviral, larvicidal and UV protection. However, some studies reported the liver toxicity and contact allergy. Thus, further studies are needed to establish the efficacy and safety of usnic acid. PMID- 25707418 TI - Metabolic disorders and cardiovascular risk in treatment-naive HIV-infected patients of sub-saharan origin starting antiretrovirals: impact of westernized lifestyle. AB - In a cohort of HIV-infected patients of sub-Saharan origin we describe the incidence of metabolic syndrome, insulin resistance, and lipodystrophy after 3 years of combined antiretroviral therapy, and model the 10-year risk of cardiovascular diseases, while taking into account environmental factors. This is a multinational, prospective cohort study conducted in HIV outpatient clinics from four tertiary care centers set in France and Cote d'Ivoire. The participants were HIV-infected, treatment-naive patients eligible to start antiretroviral treatment and were of sub-Saharan African origin. The main outcome measures were the incidence of metabolic syndrome, insulin resistance, and lipodystrophy, and the assessment of the 10-year risk of cardiovascular diseases using Framingham risk prediction, D.A.D. Cardiovascular Disease Risk, and WHO/ISH prediction charts. Of 245 patients followed for up to 3 years, the incidence of metabolic syndrome, insulin resistance, and lipodystrophy was 5.5, 8.5, and 6.8 per 100 person-years of follow-up (cumulative incidence: 14.4%, 19.2%, and 18.1%, respectively). Living in France as well as female gender and being overweight were risk factors for metabolic disorders as whole and only first generation protease inhibitors were marginally associated with metabolic syndrome. Cardiovascular risk as modeled through the three equations was high in all patients with the synergistic and deleterious effect of living in France compared to Cote d'Ivoire. This cohort study shows how the synergy between HIV, antiretroviral (ARV) exposure, and westernization of life style in a cohort of HIV-infected patients of sub-Saharan origin leads to a progressive increase in the risk of lipodystrophy, as well as metabolic syndrome and insulin resistance, all associated with increased cardiovascular risk. PMID- 25707419 TI - Threat perception after the Boston Marathon bombings: The effects of personal relevance and conceptual framing. AB - We examined how the Boston Marathon bombings affected threat perception in the Boston community. In a threat perception task, participants attempted to "shoot" armed targets and avoid shooting unarmed targets. Participants viewing images of the bombings accompanied by affectively negative music and text (e.g., "Terror Strikes Boston") made more false alarms (i.e., more errors "shooting" unarmed targets) compared to participants viewing the same images accompanied by affectively positive music and text (e.g., "Boston Strong") and participants who did not view bombing images. This difference appears to be driven by decreased sensitivity (i.e., decreased ability to distinguish guns from non-guns) as opposed to a more liberal bias (i.e., favouring the "shoot" response). Additionally, the more strongly affected the participant was by the bombings, the more their sensitivity was reduced in the negatively framed condition, suggesting that this framing was particularly detrimental to the most vulnerable individuals in the affected community. PMID- 25707420 TI - Sweet syndrome as terminal event in ruxolitinib-treated myelofibrosis. PMID- 25707421 TI - Efficacy of intrapleural instillation of fibrinolytics for treating pleural empyema and parapneumonic effusion: appropriateness of including paediatric trials in meta-analysis. PMID- 25707422 TI - Polymethylmethacrylate orbital implants with interconnecting channels. A retrospective study following enucleation in dogs and cats. AB - PURPOSE: This study describes the use of polymethylmethacrylate implants with interconnecting channels (PIIC) to fill the orbit following enucleation in 31 dogs and 11 cats. METHOD: Seven channels were drilled into the implant. A central channel, running from the PIIC pole to its flat surface, was used to pass sutures anchoring the PIIC to the orbital fascia, minimizing the likelihood of extrusion. Six more channels allowed ingrowth of fibrovascular tissue into the PIIC, which reduces the risk of extrusion. Patients were evaluated 3, 10, and 30 days postoperatively, with 15 of 42 patients followed for 6-20 months. Ultrasound examination was performed in seven patients 15-510 days postoperatively, and two implants were studied histopathologically. RESULTS: Implants were well tolerated and prevented skin concavity, leading to good cosmetic results. Blood flow was imaged in vessels growing into the channels, and histopathologically a collagenous, fibrovascular capsule was seen surrounding the PIIC and invading its channels. CONCLUSIONS: PIICs are a safe and cosmetic solution to anophthalmic orbits, allowing ingrowth of blood vessels and fibrovascular tissue. PMID- 25707423 TI - Cilostazol improves cognitive function in patients with mild cognitive impairment: a retrospective analysis. AB - BACKGROUND AND PURPOSE: Cerebral ischemia and accumulation of amyloid beta (Abeta) are major risk factors for the development of dementia, including vascular dementia and Alzheimer's disease. Cilostazol, an antiplatelet drug, has been shown to improve cerebral circulation and reduce accumulation of Abeta. In this study, the long-term effect of cilostazol on cognitive function was investigated retrospectively. METHODS: Medical records at Sumotoitsuki Hospital were surveyed to find all patients treated with cilostazol and evaluated by the Mini-Mental State Examination (MMSE) during at least two visits separated by an interval of more than 6 months. Patients receiving anti-dementia drugs were excluded. Temporal changes in MMSE scores were compared between patients treated with cilostazol (n = 70) and those who ceased administration of this drug (n = 22). The mean follow-up period was 691 days. RESULTS: Decrease in MMSE score was significantly ameliorated by administration of cilostazol. Subgroup analysis revealed that cilostazol significantly improved MMSE score in patients with mild cognitive impairment, though no significant effect was observed in patients with normal cognitive function or dementia. CONCLUSIONS: Although there are limitations to such a retrospective study, these results significantly encourage undertaking a prospective cohort study to determine the effect of cilostazol on mild cognitive impairment where no treatments currently exist. PMID- 25707424 TI - The waiting room as a relational space: young patients and their families' experience in a day hospital. AB - BACKGROUND: Waiting in hospital is a condition of high stress for patients and their families, especially in childhood. The literature has investigated the emotional experiences of patients and their families, recognizing the need for a comfortable environment, attention from the staff, information and sharing emotions with others. Waiting time in day hospitals is a topic that has not yet been investigated in the literature, but is nevertheless interesting for researchers. This exploratory study investigates the experience of waiting young patients and their families go through during treatments in day hospitals. METHOD: Fifty children and adolescents from ages 7 to 15 years, admitted to the day hospital of a paediatric haematology and oncology ward of an Italian hospital, completed the Emotional Reaction Instrument (ERI) and the Child Drawing: Hospital. Their parents or relatives completed a semi-structured interview on waiting. RESULTS: The data showed that the young patients displayed a low level of anxiety and negative emotion. In contrast, the adults' experience of waiting in the day hospital entailed boredom, anxiety and concern for the emotional state of their children. These conditions can be alleviated by relationships and sharing emotions with other adults. CONCLUSIONS: This study has shown that day hospital waiting rooms should be organized and should be experienced by adults and children as relational spaces. This could provide useful suggestions in order to improve the organization of day hospital waiting rooms. PMID- 25707425 TI - Hyperbaric oxygen in the treatment of calciphylaxis: A case series and literature review. AB - AIMS: Calcific uraemic arteriolopathy (CUA) or calciphylaxis is most commonly seen in end-stage renal disease and is associated with significant morbidity and mortality. The aim of this study was to determine whether hyperbaric oxygen therapy (HBOT) is effective in healing calciphylaxis lesions and to determine if there are any patient factors that can predict wound healing and patient survival. METHODS: We identified by retrospective review all cases of CUA referred to our institution for treatment with HBOT. We documented the clinical and biochemical parameters of this patient population, the size and distribution of the lesions as well as wound outcomes and patient survival following treatment. RESULTS: A total 46 patients were identified with CUA associated with renal failure. Of the 46 patients, only 34 received a full course of HBOT. The balance was deemed unsuitable for treatment or was unable to tolerate treatment and was palliated. Of the 34 patients that received a full course of HBOT, 58% showed improvement in their wound scores, with more than half of these patients having complete healing of their wounds. The balance did not benefit from the therapy and had a very poor prognosis. Those that benefited from HBOT survived on average for more than 3 years. The only factor significantly associated with improved wound healing and survival was diabetes. CONCLUSION: This retrospective analysis suggests a role for HBOT in the treatment of CUA with more than half of the treated patients benefiting and surviving for an average of more than 3 years. PMID- 25707427 TI - Early liver transplantation for patients with acute alcoholic hepatitis: public views and the effects on organ donation. AB - Patients with severe acute alcoholic hepatitis may not survive to fulfill the standard 6 months of abstinence and counseling prior to transplantation. A prospective study demonstrated that early liver transplantation in such patients improved 2 year survival from 23% to 71% and only 3 of 26 patients returned to drinking after 1140 days; graft function was unaffected. Nonetheless, this treatment protocol may raise public concerns and affect organ donation rates. A total of 503 participants took a survey made available at an online crowdsourcing marketplace. The survey measured attitudes on liver transplantation generally and early transplantation for this patient population, in addition to measuring responses to nine vignettes describing fictional candidates. The majority of respondents (81.5%, n = 410) was at least neutral toward early transplantation for these patients; only a minority (26.3%) indicated that transplantation in any vignette would make them hesitant to donate their organs. Middle-aged patients with good social support and financial stability were viewed most favorably (p < 0.001). Age was considered the most important selection factor and financial stability the least important factor (each p < 0.001). Results indicate early transplantation for carefully selected patients with acute alcoholic hepatitis may not be as controversial to the public as previously thought. PMID- 25707428 TI - Pharmacokinetics of cefquinome in tilapia (Oreochromis niloticus) after a single intramuscular or intraperitoneal administration. AB - The pharmacokinetics of cefquinome was studied in plasma after a single dose (10 mg/kg) of intramuscular (i.m.) or intraperitoneal (i.p.) administration to tilapia (Oreochromis niloticus) in freshwater at 30 degrees C. Ten fish per sampling point were examined after treatment. The data were fitted to two compartment open models following both routes of administration. The estimates of total body clearance (CL/F), volume of distribution (Vd/F), and absorption half life (T1/2ka ) were 0.049 and 0.037 L/h/kg, 0.41 and 0.33 L/kg, and 0.028 and 0.035 h following i.m. and i.p. administration, respectively. After i.m. injection, the elimination half-life (T1/2beta ) was calculated to be 5.81 h, the maximum plasma concentration (Cmax ) to be 49.40 MUg/mL, the time to peak plasma cefquinome concentration (Tmax ) to be 0.14 h, and the area under the plasma concentration-time curve (AUC) to be 204.6 MUg h/mL. Following i.p. administration, the corresponding estimates were 6.05 h, 44.39 MUg/mL, 0.17 h and 267.8 MUg h/mL. The minimum inhibitory concentrations of cefquinome, determined for 30 strains of Streptococcus agalactiae isolated from diseased tilapia, ranged from 0.015 to 0.12 MUg/mL. Results from these studies support that 10 mg cefquinome/kg body weight daily could be expected to control tilapia bacterial pathogens inhibited in vitro by a minimal inhibitory concentration value of <=2 MUg/mL. PMID- 25707426 TI - MicroRNA expression profiling of human blood monocyte subsets highlights functional differences. AB - Within human blood there are two subsets of monocytes that can be identified by differential expression of CD16. Although numerous phenotypic and functional differences between the subsets have been described, little is known of the mechanisms underlying the distinctive properties of the two subsets. MicroRNAs (miRNAs) are small non-coding RNAs that can regulate gene expression through promoting mRNA degradation or repressing translation, leading to alterations in cellular processes. Their potential influence on the functions of monocyte subsets has not been investigated. In this study, we employed microarray analysis to define the miRNA expression profile of human monocyte subsets. We identified 66 miRNAs that were differentially expressed (DE) between CD16(+) and CD16(-) monocytes. Gene ontology analysis revealed that the predicted targets of the DE miRNAs were predominantly associated with cell death and cellular movement. We validated the functional impacts of selected DE miRNAs in CD16(-) monocytes, over expression of miR-432 significantly increases apoptosis, and inhibiting miR-19a significantly reduces cell motility. Furthermore, we found that miR-345, another DE miRNA directly targets the transcription factor RelA in monocytes, which resulted in the differential expression of RelA in monocyte subsets. This implicates miR-345 indirect regulation of many genes downstream of RelA, including important inflammatory mediators. Together, our data show that DE miRNAs could contribute substantially to regulating the functions of human blood monocytes. PMID- 25707429 TI - Effects of unsteady conditions on propulsion generated by the hand's motion in swimming: a systematic review. AB - The understanding of swimming propulsion is a key factor in the improvement of performance in this sport. Propulsive forces have been quantified under steady conditions since the 1970s, but actual swimming involves unsteady conditions. Thus, the purpose of the present article was to review the effects of unsteady conditions on swimming propulsion based on studies that have compared steady and unsteady conditions while exploring their methods, their limitations and their results, as well as encouraging new studies based on the findings of this systematic review. A multiple database search was performed, and only those studies that met all eligibility criteria were included. Six studies that compared steady and unsteady conditions using physical experiments or numerical simulations were selected. The selected studies verified the effects of one or more factors that characterise a condition as unsteady on the propulsive forces. Consequently, much research is necessary to understand the effect of each individual variable that characterises a condition as unsteady on swimming propulsion, as well as the effects of these variables as a whole on swimming propulsion. PMID- 25707430 TI - MixClone: a mixture model for inferring tumor subclonal populations. AB - BACKGROUND: Tumor genomes are often highly heterogeneous, consisting of genomes from multiple subclonal types. Complete characterization of all subclonal types is a fundamental need in tumor genome analysis. With the advancement of next generation sequencing, computational methods have recently been developed to infer tumor subclonal populations directly from cancer genome sequencing data. Most of these methods are based on sequence information from somatic point mutations, However, the accuracy of these algorithms depends crucially on the quality of the somatic mutations returned by variant calling algorithms, and usually requires a deep coverage to achieve a reasonable level of accuracy. RESULTS: We describe a novel probabilistic mixture model, MixClone, for inferring the cellular prevalences of subclonal populations directly from whole genome sequencing of paired normal-tumor samples. MixClone integrates sequence information of somatic copy number alterations and allele frequencies within a unified probabilistic framework. We demonstrate the utility of the method using both simulated and real cancer sequencing datasets, and show that it significantly outperforms existing methods for inferring tumor subclonal populations. The MixClone package is written in Python and is publicly available at https://github.com/uci-cbcl/MixClone. CONCLUSIONS: The probabilistic mixture model proposed here provides a new framework for subclonal analysis based on cancer genome sequencing data. By applying the method to both simulated and real cancer sequencing data, we show that integrating sequence information from both somatic copy number alterations and allele frequencies can significantly improve the accuracy of inferring tumor subclonal populations. PMID- 25707431 TI - 5-Azacytidine inhibits human rhabdomyosarcoma cell growth by downregulating insulin-like growth factor 2 expression and reactivating the H19 gene product miR 675, which negatively affects insulin-like growth factors and insulin signaling. AB - Insulin-like growth factor 2 (IGF2) and 1 (IGF1) and insulin (INS) promote proliferation of rhabdomyosarcoma (RMS) cells by interacting with the insulin like growth factor 1 receptor (IGF1R) and the insulin receptor (INSR). Loss of imprinting (LOI) by DNA hypermethylation at the differentially methylated region (DMR) for the IGF2-H19 locus is commonly observed in RMS cells and results in an increase in the expression of proliferation-promoting IGF2 and downregulation of proliferation-inhibiting non-coding H19 miRNAs. One of these miRNAs, miR-675, has been reported in murine cells to be a negative regulator of IGF1R expression. To better address the role of IGF2 and 1, as well as INS signaling in the pathogenesis of RMS and the involvement of LOI at the IGF2-H19 locus, we employed the DNA demethylating agent 5-azacytidine (AzaC). We observed that AzaC-mediated demethylation of the DMR at the IGF2-H19 locus resulted in downregulation of IGF2 and an increase in the expression of H19. This epigenetic change resulted in a decrease in RMS proliferation due to downregulation of IGF2 and, IGF1R expression in an miR-675-dependent manner. Interestingly, we observed that miR-675 not only inhibited the expression of IGF1R in a similar manner in human and murine cells, but we also observed its negative effect on the expression of the INSR. These results confirm the crucial role of LOI at the IGF2-H19 DMR in the pathogenesis of RMS and are relevant to the development of new treatment strategies. PMID- 25707433 TI - Characterization of binding mode of action of a blocking anti-platelet-derived growth factor (PDGF)-B monoclonal antibody, MOR8457, reveals conformational flexibility and avidity needed for PDGF-BB to bind PDGF receptor-beta. AB - Platelet derived growth factor-BB (PDGF-BB) is an important mitogen and cell survival factor during development. PDGF-BB binds PDGF receptor-beta (PDGFRbeta) to trigger receptor dimerization and tyrosine kinase activation. We present the pharmacological and biophysical characterization of a blocking PDGF-BB monoclonal antibody, MOR8457, and contrast this to PDGFRbeta. MOR8457 binds to PDGF-BB with high affinity and selectivity, and prevents PDGF-BB induced cell proliferation competitively and with high potency. The structural characterization of the MOR8457-PDGF-BB complex indicates that MOR8457 binds with a 2:1 stoichiometry, but that binding of a single MOR8457 moiety is sufficient to prevent binding to PDGFRbeta. Comparison of the MOR8457-PDGF-BB structure with that of the PDGFRbeta PDGF-BB complex suggested the potential reason for this was a substantial bending and twisting of PDGF-BB in the MOR8457 structure, relative to the structures of PDGF-BB alone, bound to a PDGF-BB aptamer or PDGFRbeta, which makes it nonpermissive for PDGFRbeta binding. These biochemical and structural data offer insights into the permissive structure of PDGF-BB needed for agonism as well as strategies for developing specific PDGF ligand antagonists. PMID- 25707432 TI - Identifying essential proteins from active PPI networks constructed with dynamic gene expression. AB - Essential proteins are vitally important for cellular survival and development, and identifying essential proteins is very meaningful research work in the post genome era. Rapid increase of available protein-protein interaction (PPI) data has made it possible to detect protein essentiality at the network level. A series of centrality measures have been proposed to discover essential proteins based on the PPI networks. However, the PPI data obtained from large scale, high throughput experiments generally contain false positives. It is insufficient to use original PPI data to identify essential proteins. How to improve the accuracy, has become the focus of identifying essential proteins. In this paper, we proposed a framework for identifying essential proteins from active PPI networks constructed with dynamic gene expression. Firstly, we process the dynamic gene expression profiles by using time-dependent model and time independent model. Secondly, we construct an active PPI network based on co expressed genes. Lastly, we apply six classical centrality measures in the active PPI network. For the purpose of comparison, other prediction methods are also performed to identify essential proteins based on the active PPI network. The experimental results on yeast network show that identifying essential proteins based on the active PPI network can improve the performance of centrality measures considerably in terms of the number of identified essential proteins and identification accuracy. At the same time, the results also indicate that most of essential proteins are active. PMID- 25707434 TI - Integrating multiple networks for protein function prediction. AB - BACKGROUND: High throughput techniques produce multiple functional association networks. Integrating these networks can enhance the accuracy of protein function prediction. Many algorithms have been introduced to generate a composite network, which is obtained as a weighted sum of individual networks. The weight assigned to an individual network reflects its benefit towards the protein functional annotation inference. A classifier is then trained on the composite network for predicting protein functions. However, since these techniques model the optimization of the composite network and the prediction tasks as separate objectives, the resulting composite network is not necessarily optimal for the follow-up protein function prediction. RESULTS: We address this issue by modeling the optimization of the composite network and the prediction problems within a unified objective function. In particular, we use a kernel target alignment technique and the loss function of a network based classifier to jointly adjust the weights assigned to the individual networks. We show that the proposed method, called MNet, can achieve a performance that is superior (with respect to different evaluation criteria) to related techniques using the multiple networks of four example species (yeast, human, mouse, and fly) annotated with thousands (or hundreds) of GO terms. CONCLUSION: MNet can effectively integrate multiple networks for protein function prediction and is robust to the input parameters. Supplementary data is available at https://sites.google.com/site/guoxian85/home/mnet. The Matlab code of MNet is available upon request. PMID- 25707435 TI - Data-driven encoding for quantitative genetic trait prediction. AB - MOTIVATION: Given a set of biallelic molecular markers, such as SNPs, with genotype values on a collection of plant, animal or human samples, the goal of quantitative genetic trait prediction is to predict the quantitative trait values by simultaneously modeling all marker effects. Quantitative genetic trait prediction is usually represented as linear regression models which require quantitative encodings for the genotypes: the three distinct genotype values, corresponding to one heterozygous and two homozygous alleles, are usually coded as integers, and manipulated algebraically in the model. Further, epistasis between multiple markers is modeled as multiplication between the markers: it is unclear that the regression model continues to be effective under this. In this work we investigate the effects of encodings to the quantitative genetic trait prediction problem. RESULTS: We first showed that different encodings lead to different prediction accuracies, in many test cases. We then proposed a data driven encoding strategy, where we encode the genotypes according to their distribution in the phenotypes and we allow each marker to have different encodings. We show in our experiments that this encoding strategy is able to improve the performance of the genetic trait prediction method and it is more helpful for the oligogenic traits, whose values rely on a relatively small set of markers. To the best of our knowledge, this is the first paper that discusses the effects of encodings to the genetic trait prediction problem. PMID- 25707436 TI - GTP-specific fab fragment-based GTPase activity assay. AB - GTPases are central cellular signaling proteins, which cycle between a GDP-bound inactive and a GTP-bound active conformation in a controlled manner. Ras GTPases are frequently mutated in cancer and so far only few experimental inhibitors exist. The most common methods for monitoring GTP hydrolysis rely on luminescent GDP- or GTP-analogs. In this study, the first GTP-specific Fab fragment and its application are described. We selected Fab fragments using the phage display technology. Six Fab fragments were found against 2'/3'-GTP-biotin and 8-GTP biotin. Selected antibody fragments allowed specific detection of endogenous, free GTP. The most potent Fab fragment (2A4(GTP)) showed over 100-fold GTP specificity over GDP, ATP, or CTP and was used to develop a heterogeneous time resolved luminescence based assay for the monitoring of GTP concentration. The method allows studying the GEF dependent H-Ras activation (GTP binding) and GAP catalyzed H-Ras deactivation (GTP hydrolysis) at nanomolar protein concentrations. PMID- 25707437 TI - Solar-simulated ultraviolet radiation induces histone 3 methylation changes in the gene promoters of matrix metalloproteinases 1 and 3 in primary human dermal fibroblasts. AB - Molecular signalling pathways delineating the induction of matrix metalloproteinases (MMPs) by ultraviolet radiation (UVR) are currently well defined; however, the effects of UVR on epigenetic mechanisms of MMP induction are not as well understood. In this study, we examined solar-simulated UVR (ssUVR)-induced gene expression changes and alterations to histone methylation in the promoters of MMP1 and MMP3 in primary human dermal fibroblasts (HDF). Gene expression changes, including the increased expression of MMP1 and MMP3, were observed using Affymetrix GeneChip arrays and confirmed by qRT-PCR. Using ChIP PCR, we showed for the first time that in HDF irradiated with 12 J/cm(2) ssUVR, the H3K4me3 transcriptional activating mark increased and the H3K9me2 transcriptional silencing mark decreased in abundance in promoters, correlating with the observed elevation of MMP1 and MMP3 mRNA levels following ssUVR exposure. Changes in mRNA levels due to a single exposure were transient and decreased 5 days after exposure. PMID- 25707438 TI - Effects of salinity and sea salt type on egg activation, fertilization, buoyancy and early embryology of European eel, Anguilla anguilla. AB - Improper activation and swelling of in vitro produced eggs of European eel, Anguilla anguilla, has been shown to negatively affect embryonic development and hatching. We investigated this phenomenon by examining the effects of salinity and sea salt type on egg dimensions, cell cleavage patterns and egg buoyancy. Egg diameter after activation, using natural seawater adjusted to different salinities, varied among female eels, but no consistent pattern emerged. Activation salinities between 30-40 practical salinity unit (psu) produced higher quality eggs and generally larger egg diameters. Chorion diameters reached maximal values of 1642 +/- 8 MUm at 35 psu. A positive relationship was found between egg neutral buoyancy and activation salinity. Nine salt types were investigated as activation and incubation media. Five of these types induced a substantial perivitelline space (PVS), leading to large egg sizes, while the remaining four salt types resulted in smaller eggs. All salt types except NaCl treatments led to high fertilization rates and had no effect on fertilization success as well as egg neutral buoyancies at 7 h post-fertilization. The study points to the importance of considering ionic composition of the media when rearing fish eggs and further studies are encouraged. PMID- 25707439 TI - Chemotypes of essential oil of unripe galls of Pistacia atlantica Desf. from Algeria. AB - The essential oils (EOs) of unripe galls (from male and female plants) of a total number of 52 samples of Pistacia atlantica collected from different regions in Algeria were analysed by GC/MS and GC. The yields of the extraction of the EO by hydrodistillation vary from low to high values (0.08-1.89% v/w). The results of both methods of principal component analysis and hierarchical ascendant classification revealed the presence of two different chemotypes: alpha-pinene chemotype and alpha-pinene/sabinene/terpinen-4-ol chemotype. PMID- 25707440 TI - Image segmentation and classification of white blood cells with the extreme learning machine and the fast relevance vector machine. AB - White blood cells (WBCs) or leukocytes are an important part of the body's defense against infectious organisms and foreign substances. WBC segmentation is a challenging issue because of the morphological diversity of WBCs and the complex and uncertain background of blood smear images. The standard ELM classification techniques are used for WBC segmentation. The generalization performance of the ELM classifier has not achieved the maximum nearest accuracy of image segmentation. This paper gives a novel technique for WBC detection based on the fast relevance vector machine (Fast-RVM). Firstly, astonishingly sparse relevance vectors (RVs) are obtained while fitting the histogram by RVM. Next, the relevant required threshold value is directly sifted from these limited RVs. Finally, the entire connective WBC regions are segmented from the original image. The proposed method successfully works for WBC detection, and effectively reduces the effects brought about by illumination and staining. To achieve the maximum accuracy of the RVM classifier, we design a search for the best value of the parameters that tune its discriminant function, and upstream by looking for the best subset of features that feed the classifier. Therefore, this proposed RVM method effectively works for WBC detection, and effectively reduces the computational time and preserves the images. PMID- 25707441 TI - Cartilage-derived extracellular matrix extract promotes chondrocytic phenotype in three-dimensional tissue culture. AB - Cell transplantation is a promising regenerative therapy for cartilage degeneration. However, obtaining sufficient numbers of cells for this purpose is a challenge, due a lack of autologous donor tissue and the difficulty of culturing chondrocytes in vitro. Tissue engineering strategies that induce or maintain chondrocytic phenotype may solve these problems by (1) broadening the range of available donor tissue, and (2) facilitating the expansion of these cells while controlling phenotypic drift. In this study, bone marrow-derived mesenchymal stem cells (MSCs) and cartilage-derived cells (CDCs) were cultured on composite hydrogels containing agarose and homogenized cartilage extracellular matrix (ECM). MSCs cultured on agarose-ECM scaffolds did not show significant signs of chondrogenic differentiation in the absence of additional cues. However, CDCs cultured on agarose-ECM scaffolds proliferated more rapidly than their ECM free counterparts and MSCs, while retaining chondrocytic morphology. These results were corroborated via expression of cartilage marker genes: in autologous constructs, SOX 9 expression was upregulated by 12.6 +/- 5.3-fold, and COL II was upregulated by 2.0 +/- 0.3-fold. Agarose-ECM composite hydrogels are therefore useful for expanding partially differentiated CDCs for applications in regenerative medicine. PMID- 25707442 TI - Comparison, synthesis and evaluation of anticancer drug-loaded polymeric nanoparticles on breast cancer cell lines. AB - Breast cancer is a major form of cancer, with a high mortality rate in women. It is crucial to achieve more efficient and safe anticancer drugs. Recent developments in medical nanotechnology have resulted in novel advances in cancer drug delivery. Cisplatin, doxorubicin, and 5-fluorouracil are three important anti-cancer drugs which have poor water-solubility. In this study, we used cisplatin, doxorubicin, and 5-fluorouracil-loaded polycaprolactone-polyethylene glycol (PCL-PEG) nanoparticles to improve the stability and solubility of molecules in drug delivery systems. The nanoparticles were prepared by a double emulsion method and characterized with Fourier Transform Infrared (FTIR) spectroscopy and Hydrogen-1 nuclear magnetic resonance ((1)HNMR). Cells were treated with equal concentrations of cisplatin, doxorubicin and 5-fluorouracil loaded PCL-PEG nanoparticles, and free cisplatin, doxorubicin and 5-fluorouracil. The 3-[4,5-dimethylthiazol-2yl]-2,5-diphenyl tetrazolium bromide (MTT) assay confirmed that cisplatin, doxorubicin, and 5-fluorouracil-loaded PCL-PEG nanoparticles enhanced cytotoxicity and drug delivery in T47D and MCF7 breast cancer cells. However, the IC50 value of doxorubicin was lower than the IC50 values of both cisplatin and 5-fluorouracil, where the difference was statistically considered significant (p?0.05). However, the IC50 value of all drugs on T47D were lower than those on MCF7. PMID- 25707443 TI - The efficacy of methylene blue encapsulated in silica nanoparticles compared to naked methylene blue for photodynamic applications. AB - BACKGROUND/AIMS: This study analyzed the physical effects of methylene blue (MB) encapsulated within silica nanoparticles (SiNPs) in photodynamic therapy. MATERIALS AND METHODS: The optimum concentration of MB needed to destroy red blood cells (RBCs) was determined, and the efficacy of encapsulated MB-SiNPs compared to that of naked MB was verified. RESULTS: The results confirmed the applicability of MB encapsulated in SiNPs on RBCs, and established a relationship between the concentration of the SiNP-encapsulated MB and the time required to rupture 50% of the RBCs (t50). CONCLUSION: The MB encapsulated in SiNPs exhibited higher efficacy compared to that of naked MB. PMID- 25707444 TI - Nano vesicular lipid carriers of angiotensin II receptor blocker: Anti hypertensive and skin toxicity study in focus. AB - OBJECTIVE: Nanoethosomal carriers of valsartan have been previously prepared, characterized and optimized. A gel formulation of valsartan vesicular lipid carriers was composed of Carbopol((r)) (1% w/w), polyethylene glycol-400 (15% w/w) and triethanolamine (0.5% w/w). The influence of the valsartan nanoethosomal formulation developed on the blood pressure of experimental hypertensive rats, and its potential for skin irritation, are presented in this report. MATERIALS AND METHODS: The experimental rats were divided into three groups; the control group received no treatment (Group A). Group B was administered methyl prednisolone acetate (20 mg/kg/week) for two weeks (hypertensive control). Group C received methyl prednisolone acetate, followed by administration of the valsartan ethosomal formulation. The blood pressure of the rats was measured using a non-invasive rat blood pressure instrument based on the tail-cuff technique. The statistical analysis was performed using GraphPad InStat 3 software. RESULTS AND DISCUSSION: The treatment group showed a significant (P < 0.05) and constant fall in blood pressure, for up to 48 h. The valsartan ethosomal formulation was found to be effective, with a 34.11% reduction in blood pressure. The formulation's potential for skin irritation was assessed by the Draize irritation score test, which ruled out the possibility of any skin irritation caused by application of the formulation in rats. CONCLUSION: Our results suggest that nanoethosomes are efficient carriers for transdermal delivery of valsartan, for the management of hypertension. PMID- 25707445 TI - Information processing biases concurrently and prospectively predict depressive symptoms in adolescents: Evidence from a self-referent encoding task. AB - Negative information processing biases have been hypothesised to serve as precursors for the development of depression. The current study examined negative self-referent information processing and depressive symptoms in a community sample of adolescents (N = 291, Mage at baseline = 12.34 +/- 0.61, 53% female, 47.4% African-American, 49.5% Caucasian and 3.1% Biracial). Participants completed a computerised self-referent encoding task (SRET) and a measure of depressive symptoms at baseline and completed an additional measure of depressive symptoms nine months later. Several negative information processing biases on the SRET were associated with concurrent depressive symptoms and predicted increases in depressive symptoms at follow-up. Findings partially support the hypothesis that negative information processing biases are associated with depressive symptoms in a nonclinical sample of adolescents, and provide preliminary evidence that these biases prospectively predict increases in depressive symptoms. PMID- 25707446 TI - Subjective and objective assessment of sleep in adolescents with mild traumatic brain injury. AB - There is increased recognition that sleep problems may develop in children and adolescents after mild traumatic brain injury (mTBI). However, few studies have utilized both subjective and objective measures to comprehensively assess sleep problems in the pediatric population following the acute post-TBI period. The aims of this study were to compare sleep in adolescents with mTBI to healthy adolescents using subjective and objective measures, and to identify the clinical correlates associated with sleep problems. One hundred adolescents (50 adolescents with mTBI recruited from three to twelve months post-injury and 50 healthy adolescents) completed questionnaires assessing sleep quality, depression, and pain symptoms, and underwent 10 day actigraphic assessment of sleep patterns. Adolescents with mTBI reported poorer sleep quality and demonstrated significantly shorter actigraphic-measured sleep duration, poorer sleep efficiency, and more wake time after onset of sleep, compared with healthy adolescents (all, p<0.05). For both groups of adolescents, poorer self-reported sleep quality was predicted by greater depressive symptoms. Poorer actigraphic sleep efficiency was predicted by membership in the mTBI group after controlling for age, sex, depressive symptoms, and presence of pain. Our findings suggest that adolescents may experience subjective and objective sleep disturbances up to one year following mTBI. These findings require further replication in larger samples. Additionally, research is needed to identify possible mechanisms for poor sleep in youth with mTBI. PMID- 25707447 TI - CBr4-mediated cross-dehydrogenative coupling reaction of amines. AB - A novel CBr4-mediated dehydrogenative Povarov/aromatization tandem reaction of glycine derivatives with alkenes, leading to complex quinoline derivatives, and a CBr4-mediated dehydrogenative C-H functionalization of N-aryl tetrahydroisoquinolines with nucleophiles to form C-C and C-P bonds are reported. The reactions were performed under very simple and mild reaction conditions; only CBr4 was used as a promoter. A plausible mechanism involving a radical process is proposed. PMID- 25707448 TI - Evaluating mean platelet volume as a new indicator for confirming the diagnosis of necrotizing pancreatitis. AB - BACKGROUND: The aim of the present study is to discuss the possible role of mean platelet volume as a new predictor in the diagnosis of necrotizing pancreatitis. METHODS: Study subjects are arranged in three different groups: Group I; control group (n= 40), Group II; acute pancreatitis (n= 40), Group III; necrotizing pancreatitis (n= 36). Demographic data and mean platelet volume values are recorded retrospectively. RESULTS: Mean platelet volume of patients in Group II was 7.9+/-0.53, while in Group III patients it was 7.2+/-0.52 (p<0.001). When we compared the study groups with ROC analysis, results demonstrated that cut off value of necrotizing pancreatitis patients as 7,8 (area under curve: 0.857), sensitivity as 86.1% and specificity as 72.5%. CONCLUSION: The current study shows that mean platelet volume in necrotizing pancreatitis patients is significantly reduced compared to that of patients in the control and acute pancreatitis group. PMID- 25707449 TI - Cyclic adenosine 5'-diphosphoribose (cADPR) mimics used as molecular probes in cell signaling. AB - Cyclic adenosine 5'-diphosphate ribose (cADPR) is a second messenger in the Ca(2+) signaling pathway. To elucidate its molecular mechanism in calcium release, a series of cADPR analogues with modification on ribose, nucleobase, and pyrophosphate have been investigated. Among them, the analogue with the modification of the northern ribose by ether linkage substitution (cIDPRE) exhibits membrane-permeate Ca(2+) agonistic activity in intact HeLa cells, human T cells, mouse cardiac myocytes and neurosecretory PC12 cell lines; thus, cIDPRE and coumarin-caged cIDPRE are valuable probes to investigate the cADPR-mediated Ca(2+) signal pathway. PMID- 25707450 TI - Blockade of PD-1 or p38 MAP kinase signaling enhances senescent human CD8(+) T cell proliferation by distinct pathways. AB - Immune enhancement is desirable in situations where decreased immunity results in increased morbidity. We investigated whether blocking the surface inhibitory receptor PD-1 and/or p38 MAP kinase could enhance the proliferation of the effector memory CD8(+) T-cell subset that re-expresses CD45RA (EMRA) and exhibits characteristics of senescence, which include decreased proliferation and telomerase activity but increased expression of the DNA damage response related protein gammaH2AX. Blocking of both PD-1 and p38 MAPK signaling in these cells enhanced proliferation and the increase was additive when both pathways were inhibited simultaneously in both young and old human subjects. In contrast, telomerase activity in EMRA CD8(+) T cells was only enhanced by blocking the p38 but not the PD-1 signaling pathway, further indicating that nonoverlapping signaling pathways were involved. Although blocking p38 MAPK inhibits TNF-alpha secretion in the EMRA population, this decrease was counteracted by the simultaneous inhibition of PD-1 signaling in these cells. Therefore, end-stage characteristics of EMRA CD8(+) T cells are stringently controlled by distinct and reversible cell signaling events. In addition, the inhibition of PD-1 and p38 signaling pathways together may enable the enhancement of proliferation of EMRA CD8(+) T cells without compromising their capacity for cytokine secretion. PMID- 25707451 TI - Occurrence of trans monounsaturated and polyunsaturated fatty acids in Colwellia psychrerythraea strain 34H. AB - Colwellia psychrerythraea strain 34H is an obligately psychrophilic bacterium that has been used as a model cold-adapted microorganism because of its psychrophilic growth profile, significant production of cold-active enzymes, and cryoprotectant extracellular polysaccharide substances. However, its fatty acid components, particularly trans unsaturated fatty acids and long-chain polyunsaturated fatty acids (LC-PUFAs), have not been fully investigated. In this study, we biochemically identified Delta9-trans hexadecenoic acid [16:1(9t)] and LC-PUFAs such as docosahexaenoic acid. These results are comparable with the fact that the strain 34H genome sequence includes pfa and cti genes that are responsible for the biosynthesis of LC-PUFAs and trans unsaturated fatty acids, respectively. Strain 34H cells grown under static conditions at 5 degrees C had higher levels of 16:1(9t) than those grown under shaken conditions, and this change was accompanied by an antiparallel decrease in the levels of Delta9-cis hexadecenoic acid [16:1(9c)], suggesting that the cis-to-trans isomerization reaction of 16:1(9c) is activated under static (microanaerobic) culture conditions, that is, the enzyme could be activated by the decreased dissolved oxygen concentration of cultures. On the other hand, the levels of LC-PUFAs were too low (less than 3% of the total), even for cells grown at 5 degrees C, to evaluate their cold-adaptive function in this bacterium. PMID- 25707452 TI - Asymptomatic pulmonary embolism in patient with fistulizing mild Crohn's disease. PMID- 25707453 TI - Spontaneous massive bilateral peri-renal hemorrhage as a complication of ANCA negative granulomatous vasculitis. AB - Spontaneous retroperitoneal hemorrhage (SRH) is a rare, life-threatening clinical entity most commonly associated with renal cell cancers. Systemic vasculitis has also been described as a rare cause of SRH. The current report describes a patient with acute kidney failure complicated by massive SRH, which occurred in the setting of anti-neutrophil cytoplasmic antibody (ANCA)-negative systemic necrotizing angiocentric granulomatous vasculitis involving multiple organs with minimal constitutional symptoms and no respiratory tract involvement. PMID- 25707454 TI - Effects of paricalcitol on urinary calcium in patients with chronic kidney disease stages 2 - 4. AB - AIMS: Secondary hyperparathyroidism is an early complication of chronic kidney disease (CKD), with increasing severity as the glomerular filtration rate decreases. Treatment with calcitriol can occasionally result in hypercalcemia and hyperphosphatemia in renal patients, but next generation vitamin-D analogs such as paricalcitol have lower intestinal absorption of calcium and phosphorous. Our aim was to assess whether paricalcitol is more beneficial than calcitriol in pre dialysis CKD patients in clinical practice. METHOD: This observational study was carried out in a clinical setting. A total of 220 patients diagnosed with CKD stages 2 - 4, who had been previously treated with calcitriol (0.25 MUg/48 hours) for 6 months, were screened. 45 patients presenting total calcium > 9.5 mg/dL or serum phosphate > 4.5 mg/dL and who did not meet exclusion criteria werefinally selected, and their calcitriol treatment was switched to paricalcitol. Baseline blood and urine analyses were performed before switching treatment, and then repeated after 6-month treatment with paricalcitol (1 MUg/45 h). Baseline and follow-up data were compared. RESULTS: No significant changes were detected in the total serum calcium, ionized calcium, serum phosphate, tubular reabsorption of phosphate, urinary phosphate, or parathyroid hormone. There was a slight decrease in plasma calcitriol levels after switching to paricalcitol. Only urinary calcium levels showed a significant decrease: 58.1 +/- 7.4 mg/24 hours during calcitriol treatment and 48.9 +/- 6.1 mg/24 hours after 6 months with paricalcitol (p = 0.04). CONCLUSION: Compared to calcitriol, paricalcitol decreases urinary calcium excretion in pre-dialysis CKD patients, suggesting that paricalcitol treatment for secondary hyperparathyroidism might result in less systemic calcium overload. PMID- 25707455 TI - Parameters of phosphorus homeostasis at normal and reduced GFR: empiric observations. AB - AIMS: Influx (IP) determines urinary excretion of phosphorus (EP). Contributions of IP and reabsorption (TRP) to serum phosphorus ([P]s) can be depicted by normalization to creatinine clearance (EP/Ccr and TRP/Ccr) or by calculation of fractional excretion and reabsorption (FEP and FTRP). We analyzed these parameters at normal and reduced GFR. METHODS: We studied 29 patients with chronic kidney disease (CKD) and 28 controls. From [cr] and [P] in serumand urine we calculated [P]u/[cr]u, EP/Ccr, TRP/Ccr, (TRP/Ccr)/(EP/Ccr), FEP, and FTRP. We compared means between groups and examined pertinent linear regressions. RESULTS: [P]s was not different in CKD and controls. [Cr]s, EP/Ccr, and FEP were higher and TRP/Ccr, (TRP/Ccr)/(EP/Ccr), and FTRP were lower in CKD. [P]u/[cr]u, a surrogate for IP, was similar in both groups. In CKD, [P]s correlated with EP/Ccr and TRP/Ccr; EP/Ccr with [P]u/[cr]u and [cr]s; and FEP with EP/Ccr, TRP/Ccr, [P]u/[cr]u, and [cr]s. In controls, [P]s correlated with TRP/Ccr; EP/Ccr with [P]u/[cr]u; and FEP with EP/Ccr and [P]u/[cr]u. In both groups, FEP was a precise inverse function of (TRP/Ccr)/(EP/Ccr). Despite wide variation in TRP/Ccr, FEP was < 20% in 26/28 controls and > 20% in 27/29 patients with CKD. CONCLUSIONS: GFR affected determinants of [P]s, EP/Ccr, and FEP. FTRP was often dissociated from TRP/Ccr at normal or reduced GFR. PMID- 25707456 TI - A rare case of renal vein thrombosis due to urinary obstruction. AB - Renal vein thrombosis (RVT) is an uncommon condition in adults and may be caused by endothelial damage, stasis, or hypercoagulable states. RVT is commonly identified in patients with nephrotic syndrome or malignancy. We present the case of a 57-yearold man with no past medical history who presented with a 1-month history of abdominal pain, dysuria, and hematuria. Initial laboratory studies were consistent with acute kidney injury (AKI). Imaging revealed bladder distension, enlargement of the prostate, bilateral hydronephrosis, and left renal vein thrombosis extending into the inferior vena cava. His renal failure and presenting symptoms resolved with placement of a Foley catheter and ureteral stent. The patient was discharged on anticoagulation. Here, we report a rare case of RVT that appears to have occurred as a consequence of obstructive uropathy causing massive bladder distention resulting in compression of the renal vein. PMID- 25707457 TI - Evaluation of increased preoperative serum high sensitive C-reactive protein and procalcitonin levels on grade and stage of clear cell renal cell carcinoma. AB - OBJECTIVES: To evaluate the relationship between preoperative high sensitive C reactive protein (hs-CRP) and procalcitonin (PCT) levels with the two important prognostic factors, tumor stage and tumor grade, in patients with clear cell renal cell carcinoma (RCC). METHODS: We evaluated 116 clear cell RCC patients who had undergone either radical or partial nephrectomy at Ankara University, Department of Urology between November 2011 and June 2014. Comparison of hs-CRP and PCT levels between the subgroups of pathological stage and nuclear grade were evaluated. The cut off value for hs-CRP and PCT was determined by receiver- operating characteristic (ROC) analysis. RESULTS: Median levels of hs-CRP and PCT levels of the patients were 0.818 mg/L and 0.0825 ng/mL, respectively. Hs-CRP levels of pT1 stage patients was found to be lower compared to the pT3-4 group (p = 0.016). Median hs-CRP levels of the grade 1 - 2 group was found to be significantly lower compared to the grade 3 - 4 group (p = 0.0001). The difference of median PCT levels between stage pT1 vs. pT2 (p = 0.003) and stage pT1 vs. pT3-4 (p = 0.0001) were statistically significant. Regarding Fuhrman grade, median PCT levels of Fuhrman grade 1 - 2 patients were significantly lower compared to grade 3 - 4 patients (p = 0.001). To predict higher Fuhrman grade of the tumor (grade 3 - 4), ROC analysis was performed and cut off values of 0.645 mg/L and 0.087 ng/mL were detected for hs-CRP and PCT, respectively. CONCLUSION: High preoperative serum hs-CRP and PCT values may play a role in the prognostic stratification of localized clear cell RCC patients. Further prospective validation is required prior to recommendation regarding suitability as biomarkers for RCC clinical prediction. PMID- 25707458 TI - An unusual case of acute kidney injury - idiopathic granulomatous tubulointerstitial nephritis. AB - We present a case which emphasizes the importance of performing a kidney biopsy in each case of acute kidney injury (AKI) of unknown etiology. The unexpected histological diagnosis of granulomatous interstitial nephritis (GIN) is a rare cause of AKI. The main causes of GIN include drugs (NSAIDs, antibiotics), sarcoidosis, and infections (mycobacterial and fungal). In our case, a 68-year old woman was admitted with AKI, absence of symptoms and unremarkable history, apart from coronary heart disease. Renal biopsy was performed, since history as well as clinical and laboratory data could not define a cause of AKI. A more meticulous clinical and laboratory investigation followed the histological diagnosis in order to rule out sarcoidosis, vasculitis or any other known causes of GIN. Finally the diagnosis was characterized as AKI due to idiopathic GIN. The patient responded well to corticosteroids. PMID- 25707459 TI - Give that back! Recovery Audit Program activity trends. PMID- 25707460 TI - Symptomatic concurrent spinal epidural lipomatosis and spinal pathology. PMID- 25707461 TI - Corneal plaque containing levofloxacin in a dog. AB - A 13-year-old castrated male Yorkshire terrier developed a corneal ulcer 2 weeks after intracapsular lens extraction (ICLE) in the right eye. The corneal ulcer was treated with levofloxacin eye drops. A plaque with a white luster developed in the central cornea 2 weeks after treatment with levofloxacin eye drops. The corneal plaque was surgically removed under inhalant anesthesia. The corneal plaque displayed antimicrobial activity against Escherichia coli. Furthermore, levofloxacin content in the plaque was confirmed by matrix-assisted laser desorption/ionization time-of-flight/time-of-flight (MALDI-TOF/TOF) mass spectrometry (MS). The corneal ulcer completely resolved 2 weeks after the surgical removal of the corneal lesion and replacement of levofloxacin eye drops with tobramycin eye drops. Although the topical use of levofloxacin is unlikely to lead to corneal chemical deposits due to the high water solubility of the drug compared to other topical fluoroquinolones, this patient developed corneal plaque of the antibiotic drop. PMID- 25707462 TI - Dispersive solid-liquid phase microextraction based on nanomagnetic Preyssler heteropolyacid: A novel method for the preconcentration of nortriptyline. AB - In this study, a new, simple, rapid, and efficient method combined with ultraviolet visible spectrophotometry and high-performance liquid chromatography analysis was developed for the extraction and determination of nortriptyline. The tendency of the Preyssler tungsten heteropolyacid, H14 [NaP5 W30 O110 ], immobilized on the surface of mesoporous nanomagnetite to adsorb the drug from the solution has been investigated. This method involves the use of an appropriate mixture of nanosorbent that was homogenized in disperser solvent (1.0 mL, ethanol). At first, the mixture containing the nanomagnetic sorbent and disperser solvent was injected into the aqueous sample, and a cloudy solution was formed. Subsequently, separation of the two phases was carried out using a magnet. In the second stage, analyte was desorbed from the sorbent by methanol as the optimal desorption solvent using sonication method. The elution solvent containing enriched analyte was introduced to the instruments for further analysis. Optimization of experimental conditions with respect to the extraction efficiency was investigated. The method was linear in the range of 25-5000, while the detection limit (LOD = 3SB /m) was 7.9 ng/mL and the limit of quantification (LOQ = 10SB /m) was 26.4 ng/mL. The relative standard deviation was 4.66%. The method was successfully applied to human hair samples. PMID- 25707464 TI - The magic of dioxygen. AB - Oxygen has to be considered one of the most important elements on Earth. Earlier, some dispute arose as to which of the three scientists, Carl Wilhelm Scheele (Sweden), Joseph Priestley (United Kingdom) or Antoine Lavoisier (France), should get credit for the air of life.Today it is agreed that the Swede discovered it first, the fire air in 1772. The British chemist published it first, the dephlogisticated air in 1775, and the Frenchman understood it first, the oxygen in 1775-1778. Surely, there is credit enough for all three to split the "Nobel Prize" awarded by Carl Djerassi and Roald Hoffmann in their play Oxygen. Molecular oxygen means life. So-called aerobes - these include humans, animals, and plants - need O2 to conserve the energy they have to gain from their environment. Eliminate O2 and these organisms cannot support an active lifestyle. What makes dioxygen that special? It is a non-metal and oxidizing agent that readily reacts with most elements to form compounds, notably oxides. From a biological point of view, the most important compound of course is water, H2O, which provides an excellent solvent for biomolecules. It influences the climate of the Earth, and it is the source of almost all of the molecular oxygen in the atmosphere. PMID- 25707463 TI - Direct contact between dendritic cells and bronchial epithelial cells inhibits T cell recall responses towards mite and pollen allergen extracts in vitro. AB - Airway epithelial cells (AECs) form a polarized barrier along the respiratory tract. They are the first point of contact with airborne antigens and are able to instruct resident immune cells to mount appropriate immune responses by either soluble or contact-dependent mechanisms. We hypothesize that a healthy, polarized epithelial cell layer inhibits inflammatory responses towards allergens to uphold homeostasis. Using an in-vitro co-culture model of the airway epithelium, where a polarized cell layer of bronchial epithelial cells can interact with dendritic cells (DCs), we have investigated recall T cell responses in allergic patients sensitized to house dust mite, grass and birch pollen. Using allergen extract loaded DCs to stimulate autologous allergen-specific T cell lines, we show that AEC-imprinted DCs inhibit T cell proliferation significantly of Bet v 1-specific T cell lines as well as decrease interleukin (IL)-5 and IL-13 production, whereas inhibition of Phl p 5-specific T cells varied between different donors. Stimulating autologous CD4(+) T cells from allergic patients with AEC-imprinted DCs also inhibited proliferation significantly and decreased production of both T helper type 1 (Th1) and Th2 cytokines upon rechallenge. The inhibitory effects of AECs' contact with DCs were absent when allergen extract-loaded DCs had been exposed only to AECs supernatants, but present after direct contact with AECs. We conclude that direct contact between DCs and AECs inhibits T cell recall responses towards birch, grass and house dust mite allergens in vitro, suggesting that AECs-DC contact in vivo constitute a key element in mucosal homeostasis in relation to allergic sensitisation. PMID- 25707465 TI - Light-dependent production of dioxygen in photosynthesis. AB - Oxygen, that supports all aerobic life, is abundant in the atmosphere because of its constant regeneration by photosynthetic water oxidation, which is catalyzed by a Mn4CaO5 cluster in photosystem II (PS II), a multi subunit membrane protein complex. X-ray and other spectroscopy studies of the electronic and geometric structure of the Mn4CaO5 cluster as it advances through the intermediate states have been important for understanding the mechanism of water oxidation. The results and interpretations, especially from X-ray spectroscopy studies, regarding the geometric and electronic structure and the changes as the system proceeds through the catalytic cycle will be summarized in this review. This review will also include newer methodologies in time-resolved X-ray diffraction and spectroscopy that have become available since the commissioning of the X-ray free electron laser (XFEL) and are being applied to study the oxygen-evolving complex (OEC). The femtosecond X-ray pulses of the XFEL allows us to outrun X-ray damage at room temperature, and the time-evolution of the photo-induced reaction can be probed using a visible laser-pump followed by the X-ray-probe pulse. XFELs can be used to simultaneously determine the light-induced protein dynamics using crystallography and the local chemistry that occurs at the catalytic center using X-ray spectroscopy under functional conditions. Membrane inlet mass spectrometry has been important for providing direct information about the exchange of substrate water molecules, which has a direct bearing on the mechanism of water oxidation. Moreover, it has been indispensable for the time-resolved X-ray diffraction and spectroscopy studies and will be briefly reviewed in this chapter. Given the role of PS II in maintaining life in the biosphere and the future vision of a renewable energy economy, understanding the structure and mechanism of the photosynthetic water oxidation catalyst is an important goal for the future. PMID- 25707467 TI - Respiratory conservation of energy with dioxygen: cytochrome C oxidase. AB - Cytochrome c oxidase (CcO) is the terminal oxidase of cell respiration which reduces molecular oxygen (O2) to H2O coupled with the proton pump. For elucidation of the mechanism of CcO, the three-dimensional location and chemical reactivity of each atom composing the functional sites have been extensively studied by various techniques, such as crystallography, vibrational and time resolved electronic spectroscopy, since the X-ray structures (2.8 A resolution) of bovine and bacterial CcO have been published in 1995.X-ray structures of bovine CcO in different oxidation and ligand binding states showed that the O2reduction site, which is composed of Fe (heme a 3) and Cu (CuB), drives a non sequential four-electron transfer for reduction of O2to water without releasing any reactive oxygen species. These data provide the crucial structural basis to solve a long-standing problem, the mechanism of the O2reduction.Time-resolved resonance Raman and charge translocation analyses revealed the mechanism for coupling between O2reduction and the proton pump: O2is received by the O2reduction site where both metals are in the reduced state (R-intermediate), giving the O2-bound form (A-intermediate). This is spontaneously converted to the P-intermediate, with the bound O2fully reduced to 2 O2-. Hereafter the P intermediate receives four electron equivalents from the second Fe site (heme a), one at a time, to form the three intermediates, F, O, and E to regenerate the R intermediate. Each electron transfer step from heme a to the O2reduction site is coupled with the proton pump.X-ray structural and mutational analyses of bovine CcO show three possible proton transfer pathways which can transfer pump protons (H) and chemical (water-forming) protons (K and D). The structure of the H pathway of bovine CcO indicates that the driving force of the proton pump is the electrostatic repulsion between the protons on the H-pathway and positive charges of heme a, created upon oxidation to donate electrons to the O2reduction site. On the other hand, mutational and time-resolved electrometric findings for the bacterial CcO strongly suggest that the D-pathway transfers both pump and chemical protons. However, the structure for the proton-gating system in the D pathway has not been experimentally identified. The structural and functional diversities in CcO from various species suggest a basic proton pumping mechanism in which heme a pumps protons while heme a 3 reduces O2as proposed in 1978. PMID- 25707468 TI - Transition metal complexes and the activation of dioxygen. AB - In order to address how diverse metalloprotein active sites, in particular those containing iron and copper, guide O2binding and activation processes to perform diverse functions, studies of synthetic models of the active sites have been performed. These studies have led to deep, fundamental chemical insights into how O2coordinates to mono- and multinuclear Fe and Cu centers and is reduced to superoxo, peroxo, hydroperoxo, and, after O-O bond scission, oxo species relevant to proposed intermediates in catalysis. Recent advances in understanding the various factors that influence the course of O2activation by Fe and Cu complexes are surveyed, with an emphasis on evaluating the structure, bonding, and reactivity of intermediates involved. The discussion is guided by an overarching mechanistic paradigm, with differences in detail due to the involvement of disparate metal ions, nuclearities, geometries, and supporting ligands providing a rich tapestry of reaction pathways by which O2is activated at Fe and Cu sites. PMID- 25707469 TI - Methane monooxygenase: functionalizing methane at iron and copper. AB - Methane monooxygenases (MMOs) catalyze the conversion of methane to methanol as the first committed step in the assimilation of this hydrocarbon into biomass and energy by methanotrophs, thus playing a significant role in the biogeochemistry of this potent greenhouse gas. Two distinct enzymes, a copper-dependent membrane protein, particulate methane monooxygenase (pMMO), and an iron-dependent cytosolic protein, soluble methane monooxygenase (sMMO), carry out this transformation using large protein scaffolds that help to facilitate the timely transport of hydrocarbon, O2, proton, and electron substrates to buried dimetallic active sites. For both enzymes, reaction of the reduced metal centers with O2leads to intermediates that activate the relatively inert C-H bonds of hydrocarbons to yield oxidized products. Among synthetic and biological catalysts, MMOs are unique because they are the only ones known to hydroxylate methane at ambient temperatures. As a need for new industrial catalysts and green chemical transformations increases, understanding how the different MMO metal centers efficiently accomplish this challenging chemistry has become the focus of intense study. This chapter examines current understanding of the sMMO and pMMO protein structures, their methods for substrate channeling, and mechanisms for the dimetallic activation of O2and C-H bonds. PMID- 25707466 TI - Production of dioxygen in the dark: dismutases of oxyanions. AB - O2-generating reactions are exceedingly rare in biology and difficult to mimic synthetically. Perchlorate-respiring bacteria enzymatically detoxify chlorite (ClO2(-) ), the end product of the perchlorate (ClO(4)(-) ) respiratory pathway, by rapidly converting it to dioxygen (O2) and chloride (Cl(-)). This reaction is catalyzed by a heme-containing protein, called chlorite dismutase (Cld), which bears no structural or sequence relationships with known peroxidases or other heme proteins and is part of a large family of proteins with more than one biochemical function. The original assumptions from the 1990s that perchlorate is not a natural product and that perchlorate respiration might be confined to a taxonomically narrow group of species have been called into question, as have the roles of perchlorate respiration and Cld-mediated reactions in the global biogeochemical cycle of chlorine. In this chapter, the chemistry and biochemistry of Cld-mediated O2generation, as well as the biological and geochemical context of this extraordinary reaction, are described. PMID- 25707470 TI - Metal enzymes in "impossible" microorganisms catalyzing the anaerobic oxidation of ammonium and methane. AB - Ammonium and methane are inert molecules and dedicated enzymes are required to break up the N-H and C-H bonds. Until recently, only aerobic microorganisms were known to grow by the oxidation of ammonium or methane. Apart from respiration, oxygen was specifically utilized to activate the inert substrates. The presumed obligatory need for oxygen may have resisted the search for microorganisms that are capable of the anaerobic oxidation of ammonium and of methane. However extremely slowly growing, these "impossible" organisms exist and they found other means to tackle ammonium and methane. Anaerobic ammonium-oxidizing (anammox) bacteria use the oxidative power of nitric oxide (NO) by forging this molecule to ammonium, thereby making hydrazine (N2H4). Nitrite-dependent anaerobic methane oxidizers (N-DAMO) again take advantage of NO, but now apparently disproportionating the compound into dinitrogen and dioxygen gas. This intracellularly produced dioxygen enables N-DAMO bacteria to adopt an aerobic mechanism for methane oxidation.Although our understanding is only emerging how hydrazine synthase and the NO dismutase act, it seems clear that reactions fully rely on metal-based catalyses known from other enzymes. Metal-dependent conversions not only hold for these key enzymes, but for most other reactions in the central catabolic pathways, again supported by well-studied enzymes from model organisms, but adapted to own specific needs. Remarkably, those accessory catabolic enzymes are not unique for anammox bacteria and N-DAMO. Close homologs are found in protein databases where those homologs derive from (partly) known, but in most cases unknown species that together comprise an only poorly comprehended microbial world. PMID- 25707471 TI - Angiogenesis-related proteins--their role in the pathogenesis and treatment of inflammatory bowel disease. AB - The etiology of inflammatory bowel disease (IBD) is still not fully understood. Angiogenesis is one of the crucial phenomena sustaining chronic inflammation in the gastrointestinal tract. It has been also shown that the most potent anti inflammatory drugs--anti-tumor necrosis factor alpha antibodies down-regulate intestinal angiogenesis, what is believed to contribute to their therapeutic efficacy. There are many proteins engaged in gastrointestinal angiogenesis, including pro-inflammatory cytokines, vascular growth factors, and adhesion molecules. Several of them are considered to be promising molecular targets for new drugs--monoclonal antibodies or fusion proteins. Here, we review new data highlighting the key role of proteins that regulate immune-mediated angiogenesis in IBD, like vascular endothelial growth factor, hypoxia inducible factor, angiopoietins, or basic fibroblast growth factor. We present the molecular mechanisms regulating the pathological proangiogenic activity in inflammatory conditions in IBD. We also discuss how new anti-cytokine regimens affect the function of angiogenesis-related proteins. PMID- 25707472 TI - Oxidative stress and antioxidative enzyme activities in chronic kidney disease and different types of renal replacement therapy. AB - The incidence and diagnosis of chronic kidney disease (CKD) is on the rise all over the world. CKD is related to ageing of the society and high morbidity due to lifestyle diseases like diabetes, atherosclerosis, and hypertension. CKD is associated with increased oxidative stress generated by uremic toxicity, chronic inflammatory state, lack of vitamins and microelements, parenteral iron administration, and dialysis procedure itself. In terms of cellular physiology, erythrocytes and blood platelets in particular have effective enzymatic and non enzymatic antioxidative system. The most efficient enzymatic antioxidants include superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, and glucose-6-phosphate dehydrogenase. Glutathione is the leading non-enzymatic free radical scavenger. In CKD, antioxidative defense is impaired and the abnormal activity of the enzymes and glutathione concentration is described in literature. The imbalance between the formation of reactive oxygen species and antioxidative system efficiency takes part in the pathogenesis of cardiovascular complications. It contributes to increased morbidity and mortality in patients with CKD. The severity of these processes depends on the type of renal replacement therapy; haemodialysis (HD) is more predisposing to such disorders than peritoneal dialysis (PD), or even conservative treatment. This can influence the outcome and the possibility of kidney transplantation. Moreover, the early function of kidney allograft seems to be dependent on perioperative antioxidative ability of platelets, which can play a potential protective role in kidney transplantation. PMID- 25707473 TI - An overview of protein identification studies in cassava. AB - Cassava (Manihot esculenta Crantz) belongs to the Euphorbiaceae family and is originated from the Southern Amazon basin. The storage root is the most important product of cassava as food for more than 800 million people in Africa, Asia and Latin America. In this review, we present a retrospective of studies aiming the identification of cassava proteins, starting from the first investigations using SDS-PAGE and classical two-dimensional gel electrophoresis (2DE) to recent studies with advanced technologies such as high-resolution 2DE, mass spectrometry, and iTRAQ-based analysis that have contributed for characterization of cassava proteome. Several cassava proteins have been identified, including those involved in the storage root formation and post-harvest physiological deterioration processes. PMID- 25707474 TI - Crypteins--an overlooked piece of peptide systems. AB - Crypteins, the hidden bioactive sequences, play an important role in the modulation of various biological processes, such as neuronal signaling, angiogenesis, immune response, inflammatory response and cell growth. Proteolytic mechanism leading to the release of crypteins possessing novel biological activities is an important factor for increasing diversity of functional molecules and represents a potential new source of peptide drugs. In this work we would like to focus on crypteins derived from the already known precursors and their potential therapeutic value. PMID- 25707475 TI - Abiotic regulation: a common way for proteins to modulate their functions. AB - Modulation of protein intrinsic activity in cells is generally carried out via a combination of four common ways, i.e., allosteric regulation, covalent modification, proteolytic cleavage and association of other regulatory proteins. Accumulated evidence indicate that changes of certain abiotic factors (e.g., temperature, pH, light and mechanical force) within or outside the cells directly influence protein structure and thus profoundly modulate the functions of a wide range of proteins, termed as abiotic regulatory proteins (e.g., heat shock factor, small heat shock protein, hemoglobin, zymogen, integrin, rhodopsin). Such abiotic regulation apparently differs from the four classic ways in perceiving and response to the signals. Importantly, it enables cells to directly and also immediately response to extracellular stimuli, thus facilitating the ability of organisms to resist against and adapt to the abiotic stress and thereby playing crucial roles in life evolution. Altogether, abiotic regulation may be considered as a common way for proteins to modulate their functions. PMID- 25707476 TI - Acceptance of mixed scientific and clinical activities in a sub-speciality urology meeting. AB - Basic urolithiasis research into the causes for stone formation has been stagnating for a long time. Emergence of effective stone treatment modalities has shifted the public and clinicians' focus away from basic research towards symptomatic treatment solutions. This has occurred in spite of urolithiasis being a highly recurrent disease with an enormous socio-economic impact warranting a prophylactic and recurrence-preventing approach. An integrated, multidisciplinary translational platform has been developed in the form of urolithiasis meetings bringing together urologists, radiologists, nephrologists, basic scientists, dieticians and other stake holders interested in stone disease, for an exchange of knowledge, mutual education and understanding, and professional networking. Traditionally, such combined meetings are split into sessions addressing the specific interests of clinicians and scientists. At the recent Experts in Stone Disease Symposium we devised and implemented a program which mixed clinical and basic science activities throughout. We interviewed delegates between sessions regarding their acceptance of this novel concept using a standardized questionnaire. Sessions were well-attended, alleviating our initial anxiety that delegates would not appreciate a "no-choice" program. Of the 74 delegates who were interviewed, 60 (81%) were urologists, and 14 (19%) were non-urologists such as nephrologists, dieticians, and students. This is representative of the overall distribution of delegates at the conference. 71% felt that a closer co-operation and understanding between clinicians and scientists will ultimately benefit both groups, as well as patients; 95% found the mixed session approach beneficial, with half appreciating it as very good and innovative; 94% believed that they had derived useful learnings from the "other side"; 94% found that such mixed sessions are useful for their future work and understanding of the urolithiasis field as a whole; 94% agreed that mixed meetings of this type are useful in enhancing networking between the different stake holders in urolithiasis treatment and research. Finally, 85% would like to visit future mixed session meetings, and 89% would encourage their juniors to attend, too. Not only was a platform created to facilitate multidisciplinary exchange and networking, but delegates from several different backgrounds were encouraged to attend presentations in disciplines other than their own. The results of our survey confirm an overwhelmingly positive acceptance of this integrated multidisciplinary concept for stone meetings. As such, we are encouraged to continue with this concept in future conferences. PMID- 25707477 TI - Efficacy and Safety of Anti-Interleukin-20 Monoclonal Antibody in Patients With Rheumatoid Arthritis: A Randomized Phase IIa Trial. AB - OBJECTIVE: Interleukin-20 (IL-20) is implicated in the pathogenesis of rheumatoid arthritis (RA). The efficacy, safety, and tolerability of NNC0109-0012, a selective anti-IL-20 recombinant human monoclonal antibody (mAb), were assessed in patients with active RA who had an inadequate response to methotrexate therapy. METHODS: Sixty-seven patients with RA were enrolled and randomized (2:1) to receive NNC0109-0012 (3 mg/kg per week, subcutaneously) or placebo in a phase IIa, double-blind, 12-week trial with a 13-week followup. The primary end point was change in the Disease Activity Score in 28 joints based on C-reactive protein level (DAS28-CRP) from baseline to week 12. RESULTS: In patients treated with NNC0109-0012, the primary end point, improvement in the DAS28-CRP at week 12, was achieved (estimated difference -0.88; P = 0.02), with significant improvement starting at week 1. A greater response was observed in seropositive patients (estimated difference -1.66; P < 0.001), which was sustained through 13 weeks of followup, whereas no improvement was noted in patients with seronegative RA. A significant proportion of patients with seropositive RA receiving NNC0109-0012, compared to those receiving placebo, achieved treatment responses according to the American College of Rheumatology 20% (ACR20) (59% versus 21%), ACR50 (48% versus 14%), and ACR70 (35% versus 0%) levels of improvement, and showed greater improvements in the Health Assessment Questionnaire disability index (P = 0.047). The most frequent adverse events reported with NNC0109-0012 were injection site reactions and infections (e.g., herpes, nasopharyngitis, respiratory, and urinary). No serious infections or discontinuations associated with NNC0109-0012 were observed. CONCLUSION: In this phase IIa trial, treatment with NNC0109-0012 (anti-IL-20 mAb) was effective in patients with seropositive RA as early as week 1, with further improvements to week 12. No safety or tolerability concerns were identified with weekly NNC0109-0012 administration. PMID- 25707478 TI - The Rheumatoid Arthritis Risk Gene LBH Regulates Growth in Fibroblast-like Synoviocytes. AB - OBJECTIVE: Fibroblast-like synoviocytes (FLS) are key players in the synovial pathology of rheumatoid arthritis (RA). Currently, there is no treatment that specifically targets these aggressive cells. By combining 3 different "omics" data sets, i.e., 1) risk genes in RA, 2) differentially expressed genes, and 3) differential DNA methylation in RA versus osteoarthritis (OA) FLS, we identified LBH (limb bud and heart development) as a candidate gene in RA. The present study was undertaken to define the role of this gene in FLS. METHODS: Synovial tissue specimens from RA and OA patients were collected at the time of joint replacement surgery. LBH expression was silenced using small interfering RNA or overexpressed using an LBH expression vector in primary FLS. Gene expression profiles were determined by microarray and assessed using Ingenuity Pathway Analysis. Effects of modified LBH expression were investigated in functional assays. RESULTS: LBH was expressed in the synovial lining layer in patients with RA. Transforming growth factor beta1 significantly increased LBH expression in primary FLS, and platelet-derived growth factor BB decreased it. Pathway analysis of the transcriptome of LBH-deficient FLS compared to control FLS identified "cellular growth and proliferation" as the most significantly enriched pathway. In growth assays, LBH deficiency increased FLS proliferation. Conversely, LBH overexpression significantly inhibited cell growth. Cell cycle analysis demonstrated a marked increase in cells entering the cell cycle in LBH-deficient FLS compared to controls. LBH did not alter apoptosis. CONCLUSION: LBH is a candidate gene for synovial pathology in RA. It is regulated by growth factors and modulates cell growth in primary FLS. Our data suggest a novel mechanism for synovial intimal hyperplasia and joint damage in RA. PMID- 25707480 TI - Erratum to: Comparison of Treatment with Sitagliptin or Sulfonylurea in Patients with Type 2 Diabetes Mellitus and Mild Renal Impairment: A Post Hoc Analysis of Clinical Trials. PMID- 25707481 TI - Constantin von Economo (1876-1931) and his legacy to neuroscience. PMID- 25707479 TI - Hippocampal sclerosis and TDP-43 pathology in aging and Alzheimer disease. AB - OBJECTIVE: To investigate the association of hippocampal sclerosis (HS) with TAR DNA binding protein of 43kDa (TDP-43) and other common age-related pathologies, dementia, probable Alzheimer disease (AD), mild cognitive impairment (MCI), and cognitive domains in community-dwelling older subjects. METHODS: Diagnoses of dementia, probable AD, and MCI in 636 autopsied subjects from the Religious Order Study and the Rush Memory and Aging Project were based on clinical evaluation and cognitive performance tests. HS was defined as severe neuronal loss and gliosis in the hippocampal CA1 and/or subiculum. The severity and distribution of TDP-43 were assessed, and other age-related pathologies were also documented. RESULTS: HS was more common in those aged >90 years (18.0%) compared to younger subjects (9.2%). HS cases commonly coexisted with TDP-43 pathology (86%), which was more severe (p < 0.001) in HS cases. Although HS also commonly coexisted with AD and Lewy body pathology; only TDP-43 pathology increased the odds of HS (odds ratio [OR] = 2.63, 95% confidence interval [CI] = 2.07-3.34). In logistic regression models accounting for age, TDP-43, and other common age-related pathologies, HS cases had higher odds of dementia (OR = 3.71, 95% CI = 1.93-7.16), MCI, and probable AD (OR = 3.75, 95% CI = 2.01-7.02). In linear regression models, including an interaction term for HS and TDP-43 pathology, HS with coexisting TDP 43 was associated with lower function in multiple cognitive domains, whereas HS without TDP-43 did not have statistically significant associations. TDP-43 without HS was separately related to lower episodic memory. INTERPRETATION: The combined roles of HS and TDP-43 pathology are significant factors underlying global cognitive impairment and probable AD in older subjects. PMID- 25707482 TI - A historical glimpse into treating childhood hydrocephalus. PMID- 25707483 TI - Risk factors for surgical site infection following pediatric spinal deformity surgery: a systematic review and meta-analysis. AB - PURPOSE: This study was conducted to identify risk factors for postoperative infection after pediatric spinal deformity surgery. METHODS: A systematic electronic literature search from inception to November 2014 was performed in the following databases: Pubmed, Embase, and Cochrane library databases. Pooled odds ratios (ORs) or standardized mean differences (SMDs) with 95 % confidence intervals (CIs) were calculated using random or fixed effects model. Newcastle Ottawa scale was used to evaluate the methodological quality, and Stata 11.0 was used to analyze data. RESULTS: The main factors associated with infection after spinal surgery were idiopathic scoliosis (OR, 0.303; 95 % CI, 0.202-0.453), neuromuscular scoliosis (OR, 2.269; 95 % CI, 1.576-3.267), ambulatory status (OR, 0.241; 95 % CI, 0.078-0.747), previous spinal surgery (OR, 4.564; 95 % CI, 1.892 11.009), sacral vertebrae fused (OR, 2.717; 95 % CI, 1.836-4.020), and allograft (OR, 8.498; 95 % CI, 4.030-17.917). There was no sufficient evidence to reveal that male gender, age, body mass index, preoperative curve, preoperative urinary tract infection, combined anterior-posterior approach, estimated blood loss, and operating room time could lead to infection after spinal surgery. CONCLUSIONS: We identified some risk factors which could be used to prevent the onset of surgical site infection in pediatric spinal deformity surgery. However, the results of this meta-analysis should be interpreted with caution because of the heterogeneity among the studies. PMID- 25707484 TI - Anticoagulant rodenticides in urban bobcats: exposure, risk factors and potential effects based on a 16-year study. AB - Anticoagulant rodenticides (ARs) are increasingly recognized as a threat to nontarget wildlife. High exposure to ARs has been documented globally in nontarget predatory species and linked to the high prevalence of an ectoparasitic disease, notoedric mange. In southern California, mange associated with AR exposure has been the proximate cause of a bobcat (Lynx rufus) population decline. We measured AR exposure in bobcats from two areas in southern California, examining seasonal, demographic and spatial risk factors across landscapes including natural and urbanized areas. The long-term study included bobcats sampled over a 16-year period (1997-2012) and a wide geographic area. We sampled blood (N = 206) and liver (N = 172) to examine exposure ante- and post mortem. We detected high exposure prevalence (89 %, liver; 39 %, blood) and for individuals with paired liver and blood data (N = 64), 92 % were exposed. Moreover, the animals with the most complete sampling were exposed most frequently to three or more compounds. Toxicant exposure was associated with commercial, residential, and agricultural development. Bobcats of both sexes and age classes were found to be at high risk of exposure, and we documented fetal transfer of multiple ARs. We found a strong association between certain levels of exposure (ppm), and between multiple AR exposure events, and notoedric mange. AR exposure was prevalent throughout both regions sampled and throughout the 16-year time period in the long-term study. ARs pose a substantial threat to bobcats, and likely other mammalian and avian predators, living at the urban-wildland interface. PMID- 25707485 TI - Estimating sensory irritation potency of volatile organic chemicals using QSARs based on decision tree methods for regulatory purpose. AB - Volatile organic compounds (VOCs) are among the priority atmospheric pollutants that have high indoor and outdoor exposure potential. The toxicity assessment of VOCs to living ecosystems has received considerable attention in recent years. Development of computational methods for safety assessment of chemicals has been advocated by various regulatory agencies. The paper proposes robust and reliable quantitative structure-activity relationships (QSARs) for estimating the sensory irritation potency and screening of the VOCs. Here, decision tree (DT) based classification and regression QSARs models, such as single DT, decision tree forest (DTF), and decision tree boost (DTB) were developed using the sensory irritation data on VOCs in mice following the OECD principles. Structural diversity and nonlinearity in the data were evaluated through the Euclidean distance and Brock-Dechert-Scheinkman statistics. The constructed QSAR models were validated with external test data and the predictive performance of these models was established through a set of coefficients recommended in QSAR literature. The performance of all three classification and regression QSAR models was satisfactory, but DTF and DTB performed relatively better. The classification and regression QSAR models (DTF, DTB) rendered classification accuracies of 98.59 and 100 %, and yielded correlations (R(2)) of 0.950 and 0.971, respectively in complete data. The lipoaffinity index and SwHBa were identified as the most influential descriptors in proposed QSARs. The developed QSARs performed better than the previous studies. The developed models exhibited high statistical confidence and identified the structural properties of the VOCs responsible for their sensory irritation, and hence could be useful tools in screening of chemicals for regulatory purpose. PMID- 25707486 TI - Variation of ventilation practices with center volume after pediatric heart surgery. AB - BACKGROUND: This study was designed to evaluate the odds of mechanical ventilation and duration of mechanical ventilation after pediatric cardiac surgery across centers of varying center volume using the Virtual PICU Systems database. HYPOTHESIS: Children receiving cardiac surgery at high-volume centers will be associated with lower odds of mechanical ventilation and shorter duration of mechanical ventilation, compared with low-volume centers. METHODS: Patients age <18 years undergoing operations (with or without cardiopulmonary bypass) for congenital heart disease at one of the participating intensive care units in the Virtual PICU Systems database were included (2009-2013). Logistic regression models and Cox proportional hazards models were fitted for the probability of conventional mechanical ventilation and duration of mechanical ventilation, respectively, to investigate the difference in the outcomes between different center volume groups with/without adjustment for other risk factors. RESULTS: A total of 10 378 patients from 43 centers qualified for inclusion. Of these, 7648 (74%) patients received conventional mechanical ventilation after cardiac surgery. Higher center volume was significantly associated with lower odds of mechanical ventilation after cardiac surgery (odds ratio: 2.68, 95% confidence interval: 2.15-3.35). However, patients receiving mechanical ventilation in these centers were associated with longer duration of mechanical ventilation, compared with lower-volume centers (hazard ratio: 1.26, 95% confidence interval: 1.16 1.37). This association was most prominent in the lower surgical-risk categories. CONCLUSIONS: Large clinical practice variations were demonstrated for mechanical ventilation following pediatric cardiac surgery among intensive care units of varied center volumes. PMID- 25707487 TI - Renal Function in De Novo Liver Transplant Recipients Receiving Different Prolonged-Release Tacrolimus Regimens-The DIAMOND Study. AB - DIAMOND: multicenter, 24-week, randomized trial investigating the effect of different once-daily, prolonged-release tacrolimus dosing regimens on renal function after de novo liver transplantation. Arm 1: prolonged-release tacrolimus (initial dose 0.2mg/kg/day); Arm 2: prolonged-release tacrolimus (0.15 0.175mg/kg/day) plus basiliximab; Arm 3: prolonged-release tacrolimus (0.2mg/kg/day delayed until Day 5) plus basiliximab. All patients received MMF plus a bolus of corticosteroid (no maintenance steroids). PRIMARY ENDPOINT: eGFR (MDRD4) at Week 24. Secondary endpoints: composite efficacy failure, BCAR and AEs. Baseline characteristics were comparable. Tacrolimus trough levels were readily achieved posttransplant; initially lower in Arm 2 versus 1 with delayed initiation in Arm 3. eGFR (MDRD4) was higher in Arms 2 and 3 versus 1 (p = 0.001, p = 0.047). Kaplan-Meier estimates of composite efficacy failure-free survival were 72.0%, 77.6%, 73.9% in Arms 1-3. BCAR incidence was significantly lower in Arm 2 versus 1 and 3 (p = 0.016, p = 0.039). AEs were comparable. Prolonged release tacrolimus (0.15-0.175mg/kg/day) immediately posttransplant plus basiliximab and MMF (without maintenance corticosteroids) was associated with lower tacrolimus exposure, and significantly reduced renal function impairment and BCAR incidence versus prolonged-release tacrolimus (0.2mg/kg/day) administered immediately posttransplant. Delayed higher-dose prolonged-release tacrolimus initiation significantly reduced renal function impairment compared with immediate posttransplant administration, but BCAR incidence was comparable. PMID- 25707488 TI - Costs of Newborn Care Following Complications During Pregnancy and Delivery. AB - The aim of this study is examine the impact of pregnancy and delivery complications on the healthcare costs of newborns during the first 3 months of life. We conducted a retrospective cohort study of newborns born to women ages 15 49 using de-identified medical and pharmacy claims from the Truven Health MarketScan Commercial Claims and Encounters database incurred between January 1, 2007 and December 31, 2011. Total healthcare costs and resource utilization were examined and compared for the first 3 months of life between cohorts of newborns either with or without evidence of categorized maternal complications. Incremental costs were also determined using multivariable analysis for the conditions found to be the most prevalent in the study population. A total of 137,040 infants were studied, 75.4% of which were born to mothers who had experienced at least one complication during pregnancy or delivery. Fetal abnormalities (26.2%), early or threatened labor (16.6%), and hemorrhage (10.8%) were the most frequently observed complications. Diabetes (8.0%) and hypertension (7.7%) were also common, with the majority of other conditions present in 1% or less of the study population. Adjusted analyses found significant differences for seven conditions where incremental costs ranged from $987 to $10,287. Complications are common during pregnancy and delivery and some complications may lead to increased healthcare costs for newborns immediately following birth. PMID- 25707489 TI - FOXA1 Expression Significantly Predict Response to Chemotherapy in Estrogen Receptor-Positive Breast Cancer Patients. AB - PURPOSE: Most estrogen receptor (ER)-positive breast cancer responds poorly to chemotherapy and no single cost-effective biomarker capable of selecting chemosensitive ones has been found yet. We investigated FOXA1 for its role in predicting chemosensitivity of this subgroup in neoadjuvant chemotherapy settings. METHODS: We reviewed pathologic slides of 123 patients who were diagnosed with ER-positive breast cancer on core needle biopsy and underwent neoadjuvant chemotherapy at our institution between 2002 and 2012. FOXA1 expression and pathologic response were evaluated. We then statistically analyzed FOXA1 expression and its relationship with chemosensitivity. RESULTS: FOXA1 expression before NAC was correlated with poor chemoresponse in ER-positive as well as luminal A and luminal B breast cancer patients (p = 0.002, 0.001, and 0.049 respectively). Significant association between change of FOXA1 staining position after NAC and chemosensitivity also was observed (p = 0.024). Multivariate analysis identified FOXA1 expression before NAC as an independent predictor of chemosensitivity in ER-positive and luminal A breast cancer patients [p = 0.002; relative risk (RR) 0.163; 95 % confidence interval (CI) 0.053-0.500, and p = 0.002; RR 0.055; 95 % CI 0.008-0.353, respectively]. Additionally, change of FOXA1 staining position after NAC was shown to be an independent predictor of chemoresponse in luminal B subtype breast cancer patients (p = 0.012; RR 0.153; 95 % CI 0.035-0.665). CONCLUSIONS: FOXA1 expression can independently predict chemosensitivity of ER-positive breast cancer patients. PMID- 25707490 TI - Treatment of Diaphragmatic Hernia Occurring After Transhiatal Esophagectomy. AB - BACKGROUND: Postesophagectomy diaphragmatic hernia (DH) is an uncommon problem but an important one to recognize and treat because of the risk of significant complications such as incarceration and strangulation. Diaphragmatic hernia appears to occur more frequently following transhiatal esophagectomy (THE) than after transthoracic procedures, likely because of the enlargement of the diaphragmatic hiatus required to perform THE. METHODS: After 199 consecutive esophagectomies were performed at Rutgers Robert Wood Johnson University Hospital between January 2000 and June 2013, ten patients were identified with DH; all underwent diaphragmatic hernia repair (DHR). All patients who underwent esophagectomy during this time period were cataloged in a prospectively maintained database that was then retrospectively reviewed. All DH were repaired using a novel biologic plug mesh technique. RESULTS: Ten esophagectomy patients developed DH; nine post-THE and one post-McKeown esophagectomy. One patient was excluded from analysis because of atypical presentation. Demographic data were similar between esophagectomy patients who developed DH and those who did not. Administration of neoadjuvant chemoradiation correlated with development of DH, but did not reach statistical significance. Complications directly related to DHR were few and mostly infectious, including empyema and pneumonia, and were more likely to occur in those who presented with acute obstruction. One patient presented with dysphagia post repair. CONCLUSIONS: Diaphragmatic hernia development post esophagectomy is an uncommon complication, but can have devastating results when there is bowel compromise. Repair by plugging the diaphragmatic hiatus with a biologic mesh is a safe and effective method for closing the defect and results in few complications. PMID- 25707491 TI - The Clinicopathologic Features and Prognostic Impact of ALK Positivity in Patients with Resected Gastric Cancer. AB - BACKGROUND: Rearrangement of ALK is an established driver aberration in lung cancer. Accordingly, this study attempted to determine the frequency and prognostic impact of ALK alterations in patients with surgically resected gastric cancer. METHODS: The study evaluated ALK alterations in whole tumor sections of 455 curatively resected gastric cancers via immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH). Any expression of ALK protein (1+, 2+, 3+ by IHC) was considered as evidence of ALK positivity (ALK+), and the relationship between ALK positivity and clinicopathologic parameters, including survival outcome, was analyzed. RESULTS: Of the 455 tumors, 38 (8.4 %) were ALK positive, as measured by IHC. Among the ALK+ patients, two displayed break-apart signals of 5 and 11 % on FISH, respectively. The ALK+ patients were younger (57 vs. 61 years; P = 0.02) and more likely to exhibit a signet ring cell component. Moreover, as ALK intensity measured by IHC increased, so did the proportion of signet ring cells in tumors (defined as >=10 % of tumor cells; P = 0.02). In terms of survival outcome, the ALK+ patients displayed worse disease-free survival (DFS) and overall survival (OS) than the ALK- patients (P = 0.010 for DFS; P = 0.023 for OS). Multivariate analysis demonstrated that ALK+ gastric cancer patients were at an increased risk of recurrence and death after adjustment for sex, age, tumor location, stage, adjuvant chemotherapy, histology, and epidermal growth factor receptor 2 (HER2) positivity (P = 0.04 for DFS; P = 0.02 for OS). CONCLUSIONS: The findings showed ALK positivity to be an independent negative prognostic factor in surgically resected gastric cancers associated with signet ring cell histology. PMID- 25707492 TI - Three-Dimensional Breast Radiotherapy and the Elective Radiation Dose at the Sentinel Lymph Node Site in Breast Cancer. AB - BACKGROUND: Several trials are presently randomizing clinically node-negative breast cancer patients treated with breast-conserving therapy (BCT) to sentinel lymph node biopsy (SLNB) or watchful waiting. We aimed to investigate the elective radiation dose at the sentinel lymph node (SLN) site while evaluating two techniques for SLN localization, in breast cancer patients treated with lumpectomy and three-dimensional (3D) whole-breast radiotherapy. METHODS: The SLN site of consecutive Tis-2N0 breast cancer patients undergoing lumpectomy and forward intensity-modulated whole-breast radiotherapy was determined by the location of the hotspot on preoperative single-photon emission computed tomography (SPECT)/computed tomography (CT) and by a surgical clip placed at the removed SLN(s) during SLNB. The radiation dose at the SLN site was subsequently determined on the postoperative radiotherapy planning CT. An elective radiation dose to the SLN site was defined as at least 95 % of the breast dose. RESULTS: Of the 42 included patients, the mean percentage of the breast dose on the SLN site was 90 % (standard deviation 26, range 7-132, median 99), with a non-significant difference between the two techniques (surgical clip or SPECT/CT) (p = 0.608). In 32/42 patients (76 %) the SLN site received an elective radiation dose. CONCLUSIONS: A surgical clip placed at the removed SLN(s) during SLNB proved to be an adequate method of determining the radiation dose at the SLN site when compared with using SPECT/CT. With the use of 3D radiotherapy, the site of the SLN is treated with an elective radiation dose in the majority of patients who are treated with BCT. PMID- 25707493 TI - The miR-506-Induced Epithelial-Mesenchymal Transition is Involved in Poor Prognosis for Patients with Gastric Cancer. AB - BACKGROUND: MicroRNAs have roles in the regulation of the epithelial-mesenchymal transition (EMT). Findings have shown that miR-506 inhibits the expression of SNAI2 and that low expression of miR-506 is associated with poor prognoses in ovarian and breast cancers. This study investigated the role of miR-506 in survival and the EMT in patients with gastric cancer. METHODS: In this study, miR 506 and SNAI2 mRNA levels were measured in 141 cases of gastric cancer by quantitative reverse transcription polymerase chain reaction, and the protein expressions of SNAI2 and E-cadherin in 39 cases were validated by immunohistochemical analysis. Next, the associations between their expression levels and clinicopathologic factors were evaluated. In addition, cell proliferation, migration, and luciferase activity of the 3' untranslated region (UTR) of SNAI2 were analyzed using pre-miR-506 precursor in two human gastric cancer cell lines. RESULTS: Low expression of miR-506 was significantly correlated with poor overall survival in both the univariate analysis (P = 0.016) and the multivariate analysis (P < 0.05). Low miR-506 expression was significantly correlated with high SNAI2 expression (P = 0.009) and poorly differentiated type (P = 0.015). In vitro, miR-506 suppressed SNAI2 expression by binding to its 3'UTR, resulting in increased expression of E-cadherin (P < 0.05), verified by immunohistochemical analysis. Pre-miR-506 transfected cells showed significantly suppressed cell proliferation and migration (P < 0.05) compared with the control cells. CONCLUSIONS: The EMT was directly suppressed by miR-506, and its low expression was an independent prognostic factor in gastric cancer patients. The data indicated that miR-506 may act as a tumor suppressor and could be a novel therapeutic agent. PMID- 25707494 TI - Comparison of the Diagnostic Accuracy of Magnetic Resonance Imaging with Sonography in the Prediction of Breast Cancer Tumor Size: A Concordance Analysis with Histopathologically Determined Tumor Size. AB - BACKGROUND: In order to effectively treat patients with breast cancer, it is important to know the precise tumor size. We compared the rates of concordance of magnetic resonance imaging (MRI)-derived and sonography-derived breast cancer tumor size with histopathologically determined tumor size. METHODS: Accuracy of MRI and sonography in establishing tumor size was evaluated by comparing preoperative images with postoperative pathologic findings. The accuracy of MRI and sonography was graded as concordance, underestimation, or overestimation and was compared in different subgroups. RESULTS: A total of 682 patients comprised the study cohort. Mean tumor size was 3.64 +/- 1.8 cm via MRI, 2.12 +/- 1.0 cm via sonography, and 2.78 +/- 1.7 cm via pathologic examination. The difference between breast sonography and MRI to pathologic tumor field size was -0.68 +/- 1.4, and 0.85 +/- 1.25 cm, respectively (P < 0.001). Sonography had a concordance rate of 54.3 %, an overestimated rate of 9.8 %, and an underestimated rate of 35.9 %. For MRI, the concordance rate was 44.1 %, the overestimated rate was 52.5 %, and the underestimated rate was 3.4 %. In subgroup analysis, breast MRI had a higher concordance rate in patients with T3 (>5 cm) lesions. When the results of MRI and sonography were considered together, the concordance rate increased from 54.3 to 62.2 %. CONCLUSION: MRI tends to overestimate the actual tumor size, while sonography frequently underestimates it. Combined sonography and MRI increases the accuracy of tumor size prediction. PMID- 25707495 TI - Reconstruction of Large Perineal and Pelvic Wounds Using Gracilis Muscle Flaps. AB - BACKGROUND: The reconstruction of large defects after abdominoperineal resections and pelvic exenterations has traditionally been accomplished with vertical rectus myocutaneous flaps (VRAMs). For patients requiring two ostomies, robot-assisted abdominoperineal resections (APRs), and to avoid the morbidity of a VRAM harvest, the authors have used the gracilis muscle flap to reconstruct the large dead space in these patients. METHODS: A retrospective analysis of 16 consecutive APRs (10 with concomitant pelvic exenterations) reconstructed with gracilis flaps during a 2-year period was performed. Gracilis muscle flaps were used to obliterate the dead space after primary skin closure was ensured with adduction of the legs. RESULTS: All 16 patients had locally advanced cancers and had received neoadjuvant chemotherapy and radiation. Of these 16 patients, 10 had pelvic exenterations. All the patients had reconstruction with gracilis flaps (6 bilateral flaps). One major wound complication in the perineum occurred as a result of an anastomotic leak in the pelvis, but this was managed with conservative dressing changes. Three patients had skin separation in the perineum greater than 5 mm with intact subcutaneous closure. No patients required operative debridement or revision of their perineal reconstruction. No perineal hernias or gross dehiscence of the skin closure occurred. CONCLUSIONS: Large pelvic and perineal reconstructions can be safely accomplished with gracilis muscle flaps and should be considered as an alternative to abdominal-based flaps. PMID- 25707496 TI - Cyclin-Dependent Kinase Activity Correlates with the Prognosis of Patients Who Have Gastrointestinal Stromal Tumors. AB - BACKGROUND: The estimation of recurrence risk remains a critical issue in relation to gastrointestinal stromal tumors (GISTs) treated with adjuvant therapy. The accuracy of the commonly used risk stratifications is not always adequate. METHODS: For this study, data were prospectively collected from 68 patients with GISTs who underwent R0 surgery between 2004 and 2009. The results from this analysis cohort were evaluated using the data obtained from an additional 40 patients in the validation cohort. Cyclin-dependent kinase 1 (CDK1) and CDK2-specific activities were measured using a non-RI kinase assay system. RESULTS: The specific activities of CDK1 and CDK2, but not their expression, significantly correlated with recurrence. The specific activities of both CDK1 and CDK2 were independently correlated with mitosis and significantly correlated with recurrence-free survival (RFS). In the multivariate analysis, CDK2-specific activity (P = 0.0006), tumor size (P = 0.0347), and KIT deletion mutations (P = 0.0006) were significantly correlated with RFS in the analysis cohort. In the validation cohort, CDK2-specific activity (P = 0.0368) was identified as an independent prognostic factor for tumor recurrences with tumor location (P = 0.0442). CONCLUSION: The results suggest that the specific activities of CDK1 and CDK2 may reflect the proliferative activity of GISTs and that CDK2-specific activity is a good prognostic factor predicting recurrence after macroscopic complete resection of GISTs. PMID- 25707497 TI - Prediction of desmoid tumor progression using miRNA expression profiling. AB - Desmoid tumor is a rare connective tissue tumor with locoregional aggressiveness but unpredictable behavior. The miRNA profile was ascertained for 26 patients included in the Desminib phase II trial and an independent validation cohort of 15 patients. Predictive and prognostic supervised analysis on the Desminib cohort failed to identify miRNAs differentially expressed between progressive and non progressive patients under imatinib treatment or between progressive and non progressive patients after discontinuation of imatinib. However, an unsupervised hierarchical clustering of the Desminib cohort identified two groups (A and B) of 13 patients each, where only the number of previous lines of treatment before inclusion in the study differed significantly between the two groups. Time to progression after discontinuation of imatinib was longer in group B than in group A. Fifteen miRNAs were highly statistically differentially expressed between groups A and B, targeting more than 3000 genes, including AGO1, BCL2, CDK6, SMAD4, PTEN, CCND1, VEGFA, and RB1. These results were confirmed in the independent validation cohort: hierarchical clustering of these 15 miRNAs identified two groups, in which time to recurrence was statistically different (28.8 months vs 68.8 months). These results provide the first indication of the prognostic value of miRNA expression profiling with a possible direct impact on patient management. A more precise miRNA signature must now be determined to select patients who would not benefit from surgical resection of their tumor and who ought to be monitored without treatment. PMID- 25707498 TI - An Evaluation of Imitation Recognition Abilities in Typically Developing Children and Young Children with Autism Spectrum Disorder. AB - Previous work has indicated that both typically developing children and children with Autism Spectrum Disorder (ASD) display a range of imitation recognition behaviors in response to a contingent adult imitator. However, it is unknown how the two groups perform comparatively on this construct. In this study, imitation recognition behaviors for children with ASD and typically developing children were observed during periods of contingent imitation imbedded in a naturalistic imitation task. Results from this study indicate that children with ASD are impaired in their ability to recognize being imitated relative to typically developing peers as demonstrated both by behaviors representing basic social attention and more mature imitation recognition. Display of imitation recognition behaviors was independent of length of contingent imitation period in typically developing children, but rate of engagement in imitation recognition behaviors was positively correlated with length of contingent imitation period in children with ASD. Exploratory findings also suggest a link between the ability to demonstrate recognition of being imitated and ASD symptom severity, language, and object imitation for young children with ASD. PMID- 25707499 TI - Artemisinin inhibits tumour necrosis factor-alpha-induced vascular smooth muscle cell proliferation in vitro and attenuates balloon injury-induced neointima formation in rats. AB - The aim of this study was to evaluate the effect of artemisinin (ART) on rat vascular smooth muscle cell (VSMC) proliferation induced by tumour necrosis factor (TNF)-alpha, cell cycle arrest, and apoptosis, and its effect on neointima formation after balloon injury of rat carotid artery. Primary rat VSMC were identified by immunofluorescence assay. The proliferation of VSMC induced by TNF alpha was significantly inhibited by ART treatment in a dose-dependent manner. Treatment with 100-MUM ART significantly reduced the expression of proliferating cell nuclear antigen. In contrast, the same treatment arrested the cell cycle in G0/G1 phase. Western blot analysis showed that the cell cycle-related proteins cyclin D1, cyclin E, cyclin-dependent kinase 2, and cyclin-dependent kinase 4 were downregulated by ART in TNF-alpha-stimulated VSMC. For apoptosis induced by ART, cleaved caspase-3/-9 was detected, and the pro-apoptotic protein Bcl-2 associated X protein was upregulated while the anti-apoptotic protein Bcl-2 was downregulated. The results suggest that ART can effectively inhibit the proliferation of VSMC induced by TNF-alpha through the apoptotic induction pathway and cell cycle arrest. Also, balloon injury indicated that ART significantly inhibited neointima formation in the rat carotid arteries. PMID- 25707500 TI - Effects of Deletion of ERalpha in Osteoblast-Lineage Cells on Bone Mass and Adaptation to Mechanical Loading Differ in Female and Male Mice. AB - Estrogen receptor alpha (ERalpha) has been implicated in bone's response to mechanical loading in both males and females. ERalpha in osteoblast lineage cells is important for determining bone mass, but results depend on animal sex and the cellular stage at which ERalpha is deleted. We demonstrated previously that when ERalpha is deleted from mature osteoblasts and osteocytes in mixed-background female mice, bone mass and strength are decreased. However, few studies exist examining the skeletal response to loading in bone cell-specific ERalphaKO mice. Therefore, we crossed ERalpha floxed (ERalpha(fl/fl)) and osteocalcin-Cre (OC Cre) mice to generate animals lacking ERalpha in mature osteoblasts and osteocytes (pOC-ERalphaKO) and littermate controls (LC). At 10 weeks of age, the left tibia was loaded in vivo for 2 weeks. We analyzed bone mass through micro CT, bone formation rate by dynamic histomorphometry, bone strength from mechanical testing, and osteoblast and osteoclast activity by serum chemistry and immunohistochemistry. ERalpha in mature osteoblasts differentially regulated bone mass in males and females. Compared with LC, female pOC-ERalphaKO mice had decreased cortical and cancellous bone mass, whereas male pOC-ERalphaKO mice had equal or greater bone mass than LC. Bone mass results correlated with decreased compressive strength in pOC-ERalphaKO female L(5) vertebrae and with increased maximum moment in pOC-ERalphaKO male femora. Female pOC-ERalphaKO mice responded more to mechanical loading, whereas the response of pOC-ERalphaKO male animals was similar to their littermate controls. PMID- 25707501 TI - Serum Uric Acid and Impaired Glucose Tolerance: The Cardiometabolic Risk in Chinese (CRC) Study. AB - Serum uric acid (SUA) elevation has been previously related to impaired fasting glucose and type 2 diabetes. The present study was comprehensive to examine the associations between SUA and impaired glucose tolerance (IGT) in Chinese adults. For this purpose, data were collected from a community-based health examination survey conducted in Central China; 2-h glucose (OGTT) and SUA were measured in 1956 men and women. In multivariate models, SUA levels were significantly associated with an increasing trend of 2-h glucose (OGTT) (P for trend < 0.0001). The odds ratios (OR; 95 % CI) of IGT across increasing quartiles of SUA were 1.0, 1.354 (0.948-2.087), 1.337 (0.959-2.251), and 2.192 (1.407-3.416), after adjusting for age, sex, body mass index, waist circumference, fasting insulin, blood pressure, serum lipids, serum creatinine, and estimated glomerular filtration rate. (P for trend = 0.001). In addition, we found an additive pattern between SUA and triglyceride (TG; P = 0.038) or between SUA and low-density lipoprotein cholesterol (LDL-C; P = 0.041) in relation to IGT. SUA was related to IGT in the Chinese adults, independent of other conventional metabolic risk factors. TG and LDL-C might modify the associations. PMID- 25707502 TI - A case of Hemichorea-Hemiballism Induced by Acute Infarction of Bilateral Corona Radiata and Cortex. AB - Movement disorders are a recognized complication of stroke. Here we present a case of hemichorea-hemiballism (HCHB) after stroke. Basal ganglia and thalamus are typically recognized as sites responsible for HCHB. The MRI scan showed acute infarction which was unexpectedly present in both sides of corona radiate and cortex, but not in basal ganglia. This cortical HCHB could have evolved due to hypoperfusion of basal ganglia undetectable at the MRI scan or due to interruption of excitatory connections from the cerebral cortex to basal ganglia. PMID- 25707503 TI - Transarterial Onyx Embolization for Patients with Cavernous Sinus Dural Arteriovenous Fistulas Who Have Failed Transvenous Embolization. AB - Transvenous embolization is the treatment of choice for cavernous sinus dural arteriovenous fistulas (csDAVFs) despite occasional difficulty in transvenous catheterization. We reported our experience in the treatment of csDAVFs by transarterial Onyx embolization in patients who had failed transvenous catheterization. We reviewed the clinical and radiographic records of csDAVFs patients receiving transarterial Onyx embolization after failed transvenous Onyx embolization at our institution over a period of 31 months. Success was defined as complete or near complete occlusion upon angiographic examination. In seven cases, the microcatheter failed to reach the cavernous sinus; in the remaining case, the internal jugular vein was occlusive. Eight sessions of the embolization and catheterization procedures via the arterial routes were conducted. Among them, five cases via the middle meningeal artery and the other three via the accessory meningeal artery. Angiography, immediately after embolization, revealed complete occlusion in seven cases (87.5 %) and partial occlusion in the remaining case. Angiographic follow-up (range, 6-10 months) showed that all patients achieved complete embolization. In cases where transvenous embolization of the cavernous sinus is difficult, transarterial embolization of the fistulas offers a safe and effective alternative. PMID- 25707504 TI - Route of intrabacterial nanotransportation system for CagA in Helicobacter pylori. AB - Helicobacter pylori (H. pylori) possesses an intrabacterial nanotransportation system (ibNoTS) for transporting CagA and urease within the bacterial cytoplasm; this system is controlled by the extrabacterial environment. The transportation routes of the system have not yet been studied in detail. In this study, we demonstrated by immunoelectron microscopy that CagA localizes closely with the MreB filament in the bacterium, and MreB polymerization inhibitor A22 obstructs ibNoTS for CagA. These findings indicate that the route of ibNoTS for CagA is closely associated with the MreB filament. Because these phenomena were not observed in ibNoTS for urease, the route of ibNoTS for CagA is different from that of ibNoTS for urease as previously suggested. We propose that the route of ibNoTS for CagA is associated with the MreB filament in H. pylori. PMID- 25707505 TI - IIIDB: a database for isoform-isoform interactions and isoform network modules. AB - BACKGROUND: Protein-protein interactions (PPIs) are key to understanding diverse cellular processes and disease mechanisms. However, current PPI databases only provide low-resolution knowledge of PPIs, in the sense that "proteins" of currently known PPIs generally refer to "genes." It is known that alternative splicing often impacts PPI by either directly affecting protein interacting domains, or by indirectly impacting other domains, which, in turn, impacts the PPI binding. Thus, proteins translated from different isoforms of the same gene can have different interaction partners. RESULTS: Due to the limitations of current experimental capacities, little data is available for PPIs at the resolution of isoforms, although such high-resolution data is crucial to map pathways and to understand protein functions. In fact, alternative splicing can often change the internal structure of a pathway by rearranging specific PPIs. To fill the gap, we systematically predicted genome-wide isoform-isoform interactions (IIIs) using RNA-seq datasets, domain-domain interaction and PPIs. Furthermore, we constructed an III database (IIIDB) that is a resource for studying PPIs at isoform resolution. To discover functional modules in the III network, we performed III network clustering, and then obtained 1025 isoform modules. To evaluate the module functionality, we performed the GO/pathway enrichment analysis for each isoform module. CONCLUSIONS: The IIIDB provides predictions of human protein-protein interactions at the high resolution of transcript isoforms that can facilitate detailed understanding of protein functions and biological pathways. The web interface allows users to search for IIIs or III network modules. The IIIDB is freely available at http://syslab.nchu.edu.tw/IIIDB. PMID- 25707506 TI - Role of tumor-associated macrophages in hematological malignancies. AB - The tumor microenvironment consists of many non-tumor cells such as leukocytes, endothelial cells, and fibroblasts, and phenotypic changes in a tumor microenvironment are believed to be involved in tumor progression and resistance to anticancer treatments. In hematological malignancies, tumor-associated macrophages (TAMs) that have infiltrated lymphoma or leukemia tissues may be involved in tumor progression, and many researchers have studied phenotypic changes in TAMs. This review article summarizes the publications related to TAMs in hematological malignancies, with an emphasis on CD163(+) protumoral TAMs, which seem to be associated with disease progression. Cell-cell interactions between protumoral TAMs and lymphoma or leukemia cells may play an important role in lymphoma or leukemia microenvironments. Although detailed molecular mechanisms of these cell-cell interactions have not yet been clarified, phenotypic characterization of TAMs is thought to be a useful approach for evaluating clinical prognosis. In addition, targeting TAMs may be a new strategy for treating malignant hematological diseases. PMID- 25707507 TI - The role of P-cadherin in skin biology and skin pathology: lessons from the hair follicle. AB - Adherens junctions (AJs) are one of the major intercellular junctions in various epithelia including the epidermis and the follicular epithelium. AJs connect the cell surface to the actin cytoskeleton and comprise classic transmembrane cadherins, such as P-cadherin, armadillo family proteins, and actin microfilaments. Loss-of-function mutations in CDH3, which encodes P-cadherin, result in two allelic autosomal recessive disorders: hypotrichosis with juvenile macular dystrophy (HJMD) and ectodermal dysplasia, ectrodactyly, and macular dystrophy (EEM) syndromes. Both syndromes feature sparse hair heralding progressive macular dystrophy. EEM syndrome is characterized in addition by ectodermal and limb defects. Recent studies have demonstrated that, together with its involvement in cell-cell adhesion, P-cadherin plays a crucial role in regulating cell signaling, malignant transformation, and other major intercellular processes. Here, we review the roles of P-cadherin in skin and hair biology, with emphasize on human hair growth, cycling and pigmentation. PMID- 25707508 TI - Microtubule-associated protein tau (Mapt) is expressed in terminally differentiated odontoblasts and severely down-regulated in morphologically disturbed odontoblasts of Runx2 transgenic mice. AB - Runx2 is an essential transcription factor for osteoblast and odontoblast differentiation and the terminal differentiation of chondrocytes. We have previously shown that the terminal differentiation of odontoblasts is inhibited in Runx2 transgenic {Tg(Col1a1-Runx2)} mice under the control of the 2.3-kb Col1a1 promoter, which directs the transgene expression to osteoblasts and odontoblasts. Odontoblasts show severe reductions in Dspp and nestin expression and lose their characteristic polarized morphology, including a long process extending to dentin, in Tg(Col1a1-Runx2) mice. We study the molecular mechanism of odontoblast morphogenesis by comparing gene expression in the molars of wild type and Tg(Col1a1-Runx2) mice, focusing on cytoskeleton-related genes. Using microarray, we found that the gene expression of microtubule-associated protein tau (Mapt), a neuronal phosphoprotein with important roles in neuronal biology and microtubule dynamics and assembly, was high in wild-type molars but severely reduced in Tg(Col1a1-Runx2) molars. Immunohistochemical analysis revealed that Mapt was specifically expressed in terminally differentiated odontoblasts including their processes in wild-type molars but its expression was barely detectable in Tg(Col1a1-Runx2) molars. Double-staining of Mapt and Runx2 showed their reciprocal expression in odontoblasts. Mapt and tubulin co-localized in odontoblasts in wild-type molars. Immunoelectron microscopic analysis demonstrated Mapt lying around alpha-tubulin-positive filamentous structures in odontoblast processes. Thus, Mapt is a useful marker for terminally differentiated odontoblasts and might play an important role in odontoblast morphogenesis. PMID- 25707509 TI - Basophil allergen threshold sensitivity and component-resolved diagnostics improve hazelnut allergy diagnosis. AB - BACKGROUND: IgE sensitization to hazelnut is common, especially in birch endemic areas. However, its clinical significance often needs to be confirmed by a food challenge. OBJECTIVE: To evaluate the clinical significance of IgE antibodies to hazelnut components and basophil allergen threshold sensitivity (CD-sens) to hazelnut, in relation to double-blind placebo-controlled food challenge (DBPCFC) in children with a suspected hazelnut allergy. METHODS: Forty children underwent a DBPCFC. CD-sens to hazelnut as well as IgE antibodies to hazelnut and its components Cor a 1, Cor a 8, Cor a 9 and Cor a 14 were analysed. Serum tryptase was measured before, during and after DBPCFC. RESULTS: Eight children had a positive DBPCFC, and all of them had a high CD-sens value to hazelnut. Of the 32 children that passed the DBPCFC, 31 were very low or negative in CD-sens. A positive DBPCFC corresponded with significantly higher CD-sens values (median 8.9, range 3.3-281) compared to children negative in challenge (median 0.05, range 0-34.7, P < 0.0001). Children positive in challenge also had higher levels of IgE-ab to Cor a 9 and Cor a 14 (P < 0.01 and P < 0.001, respectively) compared with those with a negative challenge. In relation to the results from DBPCFC, the sensitivity of CD-sens and IgE-ab to Cor a 14 was excellent (100%) and the specificity was very high (> 97% and > 94%, respectively). Five of the eight patients positive at challenge showed an increase in tryptase > 20% compared to tryptase baseline levels. CONCLUSIONS AND CLINICAL RELEVANCE: CD-sens and component-resolved diagnostics to hazelnut, used separately or in combination, may improve the diagnostic accuracy and safety and reduce overdiagnosis of hazelnut allergy. PMID- 25707510 TI - Abstracts of the Fifteenth Annual Americas Hepato-Pancreato-Biliary Congress, 11 15 March, 2015, Miami Beach, Florida. PMID- 25707511 TI - LncRNA2Function: a comprehensive resource for functional investigation of human lncRNAs based on RNA-seq data. AB - BACKGROUND: The GENCODE project has collected over 10,000 human long non-coding RNA (lncRNA) genes. However, the vast majority of them remain to be functionally characterized. Computational investigation of potential functions of human lncRNA genes is helpful to guide further experimental studies on lncRNAs. RESULTS: In this study, based on expression correlation between lncRNAs and protein-coding genes across 19 human normal tissues, we used the hypergeometric test to functionally annotate a single lncRNA or a set of lncRNAs with significantly enriched functional terms among the protein-coding genes that are significantly co-expressed with the lncRNA(s). The functional terms include all nodes in the Gene Ontology (GO) and 4,380 human biological pathways collected from 12 pathway databases. We successfully mapped 9,625 human lncRNA genes to GO terms and biological pathways, and then developed the first ontology-driven user-friendly web interface named lncRNA2Function, which enables researchers to browse the lncRNAs associated with a specific functional term, the functional terms associated with a specific lncRNA, or to assign functional terms to a set of human lncRNA genes, such as a cluster of co-expressed lncRNAs. The lncRNA2Function is freely available at http://mlg.hit.edu.cn/lncrna2function. CONCLUSIONS: The LncRNA2Function is an important resource for further investigating the functions of a single human lncRNA, or functionally annotating a set of human lncRNAs of interest. PMID- 25707512 TI - Genome-wide association of drought-related and biomass traits with HapMap SNPs in Medicago truncatula. AB - Improving drought tolerance of crop plants is a major goal of plant breeders. In this study, we characterized biomass and drought-related traits of 220 Medicago truncatula HapMap accessions. Characterized traits included shoot biomass, maximum leaf size, specific leaf weight, stomatal density, trichome density and shoot carbon-13 isotope discrimination (delta(13) C) of well-watered M. truncatula plants, and leaf performance in vitro under dehydration stress. Genome wide association analyses were carried out using the general linear model (GLM), the standard mixed linear model (MLM) and compressed MLM (CMLM) in TASSEL, which revealed significant overestimation of P-values by CMLM. For each trait, candidate genes and chromosome regions containing SNP markers were found that are in significant association with the trait. For plant biomass, a 0.5 Mbp region on chromosome 2 harbouring a plasma membrane intrinsic protein, PIP2, was discovered that could potentially be targeted to increase dry matter yield. A protein disulfide isomerase-like protein was found to be tightly associated with both shoot biomass and leaf size. A glutamate-cysteine ligase and an aldehyde dehydrogenase family protein with Arabidopsis homologs strongly expressed in the guard cells were two of the top genes identified by stomata density genome-wide association studies analysis. PMID- 25707513 TI - Association between the RAGE gene -374T/A, -429T/C polymorphisms and diabetic nephropathy: a meta-analysis. AB - AIM: The investigations into the association between the receptor for advanced glycation end products (RAGE) gene -374T/A, -429T/C polymorphisms and diabetic nephropathy (DN) in several case-control studies have rendered conflicting results. To shed light on these inconclusive findings, a meta-analysis of all the eligible studies relating these two polymorphisms to the risk of DN was conducted. METHODS: The databases were searched for relevant articles up to July 2014. A pooled estimate of the genetic association, the heterogeneity between studies, and the publication bias were investigated. RESULTS: Eight studies with 1725 cases and 1857 controls were enrolled in -374T/A polymorphism analysis. The main analysis indicated no association for the allele contrast, the recessive model and the dominant model. Subgroup analyses in Caucasians and in type 2 diabetes also showed no association between -374T/A polymorphism and DN. Five studies with 1019 cases and 792 controls were enrolled in -429T/C polymorphism analysis. The main analysis revealed heterogeneity and no association for the allele contrast and the dominant model. However, the recessive model for -429C allele diminished the heterogeneity and showed a marginal association overall [fixed-effects OR = 2.83 (1.33-6.00) and random effects OR = 2.50 (1.00-6.24), respectively]. CONCLUSIONS: Our meta-analysis indicated that the RAGE gene -429CC genotype might be a risk factor for DN in patients with type 2 diabetes. PMID- 25707514 TI - Association between graft function and serum TNF-alpha, TNFR1 and TNFR2 levels in patients with kidney transplantation. AB - INTRODUCTION: This prospective observational study aimed to assess the relevance of serial postoperative serum TNF-alpha, TNFR1 and TNFR2 measurements for predicting graft function and acute rejection episodes (AR) after transplantation. MATERIALS AND METHODS: We studied 50 kidney transplant recipients (31 female, 19 male; mean age: 38.36 +/- 12.88). Blood samples were collected immediately before and after surgery at day 7, month 1 and month 3. Serum TNF-alpha, TNFR1 and TNFR2 levels were measured by ELISA using a commercial kit (Invitrogen ELISA). Serum cystatin-C levels were measured by particle enhanced immunonephelometric method. Glomerular filtration rate (GFR) was estimated by Chronic Kidney Disease-Epidemiology (CKD-EPI) equation. Patients were assigned to their transplant outcomes in terms of acute rejection [AR(+) and AR(-)] and slow (SGF) or immediate graft function (IGF). RESULTS: Among 50 recipients, six had AR(+) and 44 had AR(-), depending on graft function: 17 had SGF and 33 had IGF. Serum creatinine, cystatin-C, TNF-alpha, TNFR1 and TNFR2 levels demonstrated consistent significantly decreases after transplantation while GFR values had consistent increases (p = 0.001). Pretransplant levels were not statistically different between AR(+) and AR(-) groups (TNF-alpha: 30.79 +/- 5.96 vs. 27.95 +/- 2.43 pg/mL, TNFR1: 55.96 +/- 21.6 vs. 40.52 +/- 7.41 ng/mL, TNFR2: 58.31 +/- 8.06 vs. 50.9 +/- 3.34 ng/mL, respectively) (p > 0.05). Serum TNF-alpha, TNFR1 and TNFR2 levels on day 7 and month 1 were also significantly higher in AR(+) group compared to AR(-) (p = 0.012, p = 0.049 for TNF-alpha, p = 0.001, p = 0.002 for TNFR1, p = 0.001, p = 0.002 for TNFR2). CONCLUSIONS: Our preliminary findings suggest that serum TNF-alpha, TNFR1 and TNFR2 levels might be considered useful markers of evaluating graft function after renal transplantation. PMID- 25707515 TI - Comparison of serum cystatin C and creatinine levels in determining glomerular filtration rate in children with stage I to III chronic renal disease. AB - BACKGROUND: Pediatric studies are relatively scarce on the superiority of cystatin C over creatinine in estimation of glomerular filtration rate (GFR). This study measured cystatin C and serum creatinine levels, and compared GFR estimated from these two parameters in patients with chronic renal disease. METHODS: This prospective, observational, controlled study included 166 patients aged 1-18 years diagnosed with stage I to III chronic renal disease, and 29 age- and sex-matched control subjects. In all patients, GFR was estimated via creatinine clearance, Schwartz formula, Zappitelli 1 and Zappitelli 2 formula and the results were compared using Bland-Altman analysis. RESULTS: Patients and controls did not differ with regard to height, body weight, BMI, serum creatinine and serum cystatin levels, and Schwartz formula-based GFR (p > 0.05). There was a significant relationship between creatinine and cystatin C levels. However, although creatinine levels showed a significant association with age, height, and BMI, cystatin C levels showed no such association. ROC analysis showed that cystatin C performed better than creatinine in detecting low GFR. CONCLUSION: Cystatin C is a more sensitive and feasible indicator than creatinine for the diagnosis of stage I to III chronic renal disease. PMID- 25707516 TI - Frequencies of apolipoprotein E alleles in depressed patients undergoing hemodialysis--a case-control study. AB - OBJECTIVE: To explore the relation between the frequencies of apolipoprotein E (ApoE) alleles and the occurrence of depression in patients undergoing hemodialysis in a Chinese population. METHODS: We examined the ApoE alleles in a sample of 288 subjects: 72 patients with depression under hemodialysis, 74 patients without depression under hemodialysis, 75 patients with depression under nondialytic treatment and 67 patients without depression under nondialytic treatment. The depression state was assessed using the Center for Epidemiological Studies Depression (CES-D) scale. Associations between the occurrence of depression and the frequencies of ApoE alleles were examined using multinomial logistic regression models with adjustment of relevant covariates. Information about sociodemographics, clinical data, vascular risk factors and cognitive function was also collected and evaluated. RESULTS: The frequencies of ApoE-E2 were significantly different between depressed and non-depressed patients irrespective of dialysis (p < 0.05), but no significant difference was found in the frequencies of ApoE-E4 (p > 0.05). Serum ApoE levels were significantly different between depressed and non-depressed patients in the whole sample (p < 0.05). Multinomial logistic regression models showed significant association between the frequency of ApoE-E2 and the occurrence of depression in the Chinese population after control of relevant covariates, including age, sex, educational level, history of smoking and drinking, vascular risk factors and cognitive function. CONCLUSIONS: No association between the frequency of ApoE-E4 and the occurrence of depression was found in patients undergoing hemodialysis. Further research is needed to find out if ApoE-E2 acts as a protective factor in Chinese dialysis population since it might decrease the prevalence of depression and delay the onset age. PMID- 25707517 TI - Variability of mycophenolic acid elimination in the renal transplant recipients - population pharmacokinetic approach. AB - The aim of this study was to develop a population pharmacokinetic (PK) model for clearance of mycophenolic acid (MPA) in adult renal transplant recipients, to quantify the PK parameters and the influence of covariates on the MPA pharmacokinetic parameters. Parameters associated with plasma concentrations of MPA at steady-state were analyzed in 70 renal transplant recipients (mean age 42.97 years; mean total body weight 75.33 kg) using nonlinear mixed-effect modeling (NONMEM). Characteristics of patients screened for influence on the pharmacokinetic parameters were gender, age, body weight, time after transplantation, whether the patient was diagnosed as having diabetes mellitus, organ source (living or deceased donor), biochemical parameters and co-therapy (tacrolimus, cyclosporine, prednisolone, omeprazole, bisoprolol, carvedilol, nifedipine). A validation set of 25 renal transplant recipients was used to estimate the predictive performance of population pharmacokinetic model. Typical mean value of MPA oral clearance, estimated by base model (without covariates) was 0.741 L h(-1). During population modeling, the full model showed that clearance of the MPA was significantly influenced by age, total daily dose of MPA, creatinine clearance, albumin level, status and gender of a donor, and the nifedipine and tacrolimus co-therapy. In the final model, clearance of MPA was reported to be significantly influenced by age, total daily dose of MPA and thenifedipine co-therapy. The derived model describes adequately MPA clearance in terms of characteristics of our patients, offering basis for individual pharmacotherapy approach. PMID- 25707518 TI - The Puerarin improves renal function in STZ-induced diabetic rats by attenuating eNOS expression. AB - Diabetic nephropathy (DN) is a serious complication and it leads to kidney failure. The endothelial nitric oxide synthases (eNOS) seems to be involved in the development and progression of DN. The Puerarin is a well-known Chinese traditional formula, which is widely used in clinical practice for the treatment of kidney disease. The present study was designed to investigate the renal protective effects of Puerarin on streptozotocin (STZ)-induced diabetic rats. Thirty Sprague-Dawley (SD) male rats were divided into three groups at random. The diabetic group and the Puerarin-treated group were intraperitoneally injected with STZ 65 mg/kg and the Puerarin-treated rats were intraperitoneally injected Puerarin 100 mg/kg/day for 4 weeks. The results showed the Puerarin could improve body weight, blood sugar, BUN and SCr levels, and reduce ultrastructural changes of kidney in diabetic rats. It also attenuated eNOS expression in glomerular endothelial cells and tubular cells of diabetic rats with Puerarin treatment (p < 0.05). The Puerarin had significant renal-protective effects for the diabetic nephropathy, possibly through regulating eNOS expression, and it may be used as a potential therapeutic reagent. PMID- 25707519 TI - Effects of silymarin on methotrexate-induced nephrotoxicity in rats. AB - Methotrexate (MTX) is widely used in the treatment of various malignancies and nononcological diseases but its use has been limited by its nephrotoxicity. Silymarin (SLY), a natural flavonoid, has been reported to have antioxidant, anti inflammatory and anti-apoptotic effects. This study was carried out to determine whether SLY exerts a protective effect against MTX-induced nephrotoxicity. Rats were divided into six groups: Group 1 (saline, i.p., single injection), Group 2 (0.5% carboxymethyl cellulose (CMC), by gavage once daily for five consecutive days), Group 3 (SLY, 300 mg/kg per day, i.p. for five consecutive days), Group 4 (MTX, 20 mg/kg, i.p., single injection), Group 5 (MTX + CMC similarly as groups 2 and 4) and Group 6 (MTX + CMC + SLY similarly as groups 2, 3 and 4). Histopathologic alterations including apoptotic changes of the kidney were evaluated. MTX injection exhibited dilated Bowman's space, inflammatory cell infiltration, glomerular and peritubular vascular congestion and swelling of renal tubular epithelium cells. Apoptotic cell death was also markedly increased in renal tubules after MTX administration. SLY treatment resulted in statistically significant amelioration in the histological alterations and reduced the number of TUNEL-positive cells as compared with the MTX treated rats (p < 0.05). In conclusion, SLY treatment leads to a reduction on MTX-induced renal damage in rats. Since SLY is safe and acceptable for human consumption, further studies to define the exact mechanism of the protecting effect of SLY on MTX-induced nephrotoxicity and the optimum dosage of this compound would be useful. PMID- 25707520 TI - Ginsenoside-Rg1 inhibits endoplasmic reticulum stress-induced apoptosis after unilateral ureteral obstruction in rats. AB - AIM: Endoplasmic reticulum (ER) stress and unfolded protein response (UPR) are implicated in many fibrotic diseases, including renal fibrosis. Whether Ginsenoside-Rg1 (G-Rg1) could attenuate renal fibrosis via suppression of ER stress and UPR has not been reported. The aim of this study was to explore the effect of G-Rg1 on ER stress and UPR-induced apoptosis in kidneys with unilateral ureteral obstruction (UUO) rat model. METHODS: Twenty-four male Sprague-Dawley rats were randomly divided into control group, model group and G-Rg1 treatment group. G-Rg1 was administered to rats by intraperitoneal injection. Renal interstitial fibrosis in the model group was developed by UUO in rats. Renal function was estimated by the levels of serum creatinine (Scr) and blood urea nitrogen (BUN). Renal pathological damage was evaluated by hematoxylin and eosin (HE) and Masson's trichrome staining. The ER stress was assessed with glucose regulated protein (GRP) 78 expression, and the proapoptotic response was detected with CCAAT/enhancer-binding protein homologous protein (CHOP) and caspase-12 expressions by Western Blot. The number of apoptotic cells was determined by Terminal-deoxynucleotidyl Transferase Mediated Nick End Labeling (TUNEL) analysis. RESULTS: UUO for 14 days aggravated renal function, renal damage and renal interstitial fibrosis, activated ER stress response (induction of GRP78 protein), enhanced the proapoptotic response (increase in CHOP and caspase-12 proteins) and increased the number of apoptotic cells (shown by the TUNEL assay). Treatment with G-Rg1 significantly ameliorates the renal pathological lesions and decreases expressions of ER stress-associated proteins and the level of apoptotic cells in kidneys. CONCLUSION: G-Rg1 suppresses renal cell apoptotic and fibrotic process partly through inhibition of ERS- and UPR-related apoptotic pathway in the kidneys after UUO. PMID- 25707521 TI - The protective effect of nesfatin-1 against renal ischemia-reperfusion injury in rats. AB - INTRODUCTION: The pathogenetic mechanisms underlying ischemia-reperfusion (I/R) injury involve oxidative stress, inflammation and apoptosis. Nesfatin-1, a novel peptide, has been reported to possess antioxidant, anti-inflammatory and anti apoptic properties. The study was to examine the potential protective effects of nesfatin-1 on renal I/R injury. MATERIALS AND METHODS: I/R model was induced by placing a clamp across left renal artery for 45 min followed by 24 h reperfusion, along with a contralateral nephrectom. Twenty-four rats divided into three groups: sham-operated group, vehicle-treated I/R and nesfatin-1-treated I/R. Nesfatin-1 was intraperitoneally injected 30 min before renal ischemia. We harvested serum and kidneys at 24 h after reperfusion. Renal function and histological changes were assessed. Marker of oxidative stress and cells in kidney were also evaluated. RESULTS: The animals with nesfatin-1 significantly improved renal functional and histologic lesions induced by I/R injury. The malondialdehyde (MDA) level decreased, whereas superoxide dismutase (SOD) and catalase (CAT) activities were significantly increased. Moreover, nesfatin-1 treated rats had a markedly decrease in apoptotic tubular cells, as well as a decrease in caspase-3 activity and an increase in the bcl-2/Bax ratio. CONCLUSIONS: This is the first evidence that nesfatin-1 treatment ameliorates acute renal I/R injury by suppressing oxidative stress and cell apoptosis. Therefore, it is promising as a potential therapeutic agent for renal IR injury. PMID- 25707522 TI - Early postoperative effects of ureterorenoscopy on morbidity and renal functions in ureteral stone patients with nondialysis-requiring renal insufficiency. AB - In this study, we aimed to investigate the effects of ureterorenoscopy (URS) on morbidity and renal functions in patients with ureteral stones and nondialysis requiring renal insufficiency. The data of 3200 patients who had ureterorenoscopic lithotripsy and diagnostic URS were analyzed retrospectively. Age, urea and creatinine levels in the preoperative period and 4 h after surgery, the size of the stone, duration of surgery, percentage change in urea and creatinine levels [(last level-first level/first level) * 100] and postoperative complications were noted. Student's t-test was used for the intergroup analysis of continuous variables. p < 0.05 was considered as statistically significant. There were 90 patients in nondialysis-requiring renal insufficiency group (group 1) and 101 patients in the control group (group 2). Percentage changes of urea and creatinine levels in the renal insufficiency and the control groups were found as -0.3% +/- 3.3, 0.67% +/- 3.9 and 2.3% +/- 23.2, 2.5% +/- 31.6 (p = 0.24 and p = 0.56), respectively. In group 1, three (3.3%) patients had postoperative febrile urinary infection, however febrile infections were not seen in any of the patients in group 2 (p = 0.06). Our results indicated that URS might be used safely in ureteral stones of the patients with nondialysis-requiring renal insufficiency. PMID- 25707523 TI - Auxin induces cell proliferation in an experimental model of mammalian renal tubular epithelial cells. AB - Indole-3-acetic acid is the main auxin produced by plants and plays a key role in the plant growth and development. This hormone is also present in humans where it is considered as a uremic toxin deriving from tryptophan metabolism. However, beyond this peculiar aspect, the involvement of auxin in human pathophysiology has not been further investigated. Since it is a growth hormone, we evaluated its proliferative properties in an in vitro model of mammalian renal tubular epithelial cells. We employed an experimental model of renal tubular epithelial cells belonging to the LLC-PK1 cell line that is derived from the kidney of healthy male pig. Growth effects of auxin against LLC-PK1 cell lines were determined by a rapid colorimetric assay. Increasing concentrations of auxin (to give a final concentration from 1 to 1000 ng/mL) were added and microplates were incubated for 72 h. Each auxin concentration was assayed in four wells and repeated four times. Cell proliferation significantly increased, compared to control cells, 72 h after addition of auxin to cultured LLC-PK1 cells. Statistically significant values were observed when 100 ng/mL (p < 0.01) and 1000 ng/mL (p < 0.05) were used. In conclusion, auxin influences cell growth not only in plants, where its role is well documented, but also in mammalian cell lines. This observation opens new scenarios in the field of tissue regeneration and may stimulate a novel line of research aiming at investigating whether this hormone really influences human physiology and pathophysiology and in particular, kidney regeneration. PMID- 25707524 TI - A comparison of the effects of ketamine and remifentanil on renal functions in coronary artery bypass graft surgery. AB - We have investigated the effects of ketamine-based and remifentanil-based anesthetic protocol on perioperative serum cystatin-C levels, and creatinine and/or cystatin-C-based eGFR equations in terms of acute kidney injury in coronary artery bypass graft (CABG) surgery. Using a simple randomization method (coin tossing), patients were divided into the two groups and not-blinded to the anesthetist. Remifentanil-midazolam-propofol or ketamine-midazolam-propofol-based anesthetic regimen was chosen. Different eGFR formulas using creatinine (MDRD, CKD-EPI, Cockrauft Gault); cystatin-C (eGFR1, eGFR2) or a combination of creatinine and cystatin-C (eGFR 3) were used to calculate estimated glomerular filtration rates (eGFRs). High-sensitive troponin T was used to determine if ketamine use in coronary surgery contributed to myocardial cell damage. Thirty seven patients were included in the study (remifentanil group = 19, ketamine Group = 18). Urea, creatinine, cystatin-C levels were comparable between the groups in all the measurement times and also postoperative day 2 samples showed statistically higher results compared to baseline (p < 0.001). Effects of ketamine and remifentanil on renal functions were found similar. Creatinine and cystatin-C-based eGFR equations resulted similar in our study. Reversible stage 1 acute kidney injury (AKI) was observed on postoperative day 2 in seven patients from the remifentanil group and six patients from the ketamine group. Hs-troponin T was found to be higher in postoperative day 1 samples; there were no significant difference between the groups. Our results indicated that patients who have normal renal functions undergoing on-pump coronary bypass surgery, effects of ketamine and remifentanil on renal functions in terms of AKI were found to be similar. PMID- 25707525 TI - Initial experience of percutaneous nephrolithotomy combined with retroperitoneal laparoendoscopic single-site partial nephrectomy in one-stage treatment of homolateral renal diseases. AB - This study investigated the feasibility of percutaneous nephrolithotomy (PCNL) combined with retroperitoneal laparoendoscopic single-site partial nephrectomy (LESS-PN) in one-stage treatment of homolateral renal calculi and tumors. Between October 2010 and July 2014 one-stage PCNL combined LESS-PN surgery was performed in 23 patients with homolateral renal calculi and tumors. Patients included 17 male and 8 female, ranged from 31 to 66 years old with a median age of 42.7. Operative parameters and occurrence rate of complications were recorded. In all cases renal tumors were successfully removed without converting to open surgery. One-stage clearance rate for renal calculi was 21/23 (91.3%), leaving two cases for second-stage operation of flexible ureteroscope lithotomy. The operation time was 95-186 min; average 128 min. Intraoperative blood loss was 40-200 mL; average 130 mL. Median warm ischemia time was 23.8 +/- 9.5 min. There were no serious post-operative complications such as massive hemorrhage or urine leakage. Length of stay was 5-7 days, average 6 days. There was no recurrence of renal calculus, renal tumors or ureterostenosis and kidney functions were normal. In conclusion, with good practice, one-stage combined operation of PCNL and retroperitoneal LESS PN in removing homolateral renal tumors and calculi was safe, feasible and would potentially reduce the operative trauma. PMID- 25707526 TI - Meta-analysis: the efficacy and safety of combined treatment with ARB and ACEI on diabetic nephropathy. AB - OBJECTIVE: Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) reduce proteinuria in diabetic nephropathy (DN). Some studies have suggested that dual blockade of the renin-angiotensin system provides additive benefits in DN but others showed increased adverse events. We performed a meta-analysis to evaluate the efficacy and safety of combination therapy for DN. METHODS: Studies were identified by searching MEDLINE, EMBASE, PubMed, and CNKI. All trials involved ACEI + ARB (combination therapy), and ACEI or ARB alone (monotherapy) for DN. The outcomes measured were urinary total proteinuria (UTP), urinary albumin excretion rate (UAER), serum creatinine, glomerular filtration rate (GFR), end-stage renal disease (ESRD), hyperkalemia, hypotension, and acute kidney injury (AKI). RESULTS: In the 32 included trials, 2596 patients received combination therapy and 3947 received monotherapy. UTP and UAER were significantly reduced by combined treatment compared with monotherapy. It was notable that low doses of combination therapy reduced UTP more than high doses. Serum creatinine, GFR, and ESRD were not significantly different between the two groups. In severe DN, the occurrence of hyperkalemia and AKI were higher with combination therapy. However, in mild DN, the prevalence of hyperkalemia and AKI were the same in both the groups. In mild DN, the occurrence of hypotension was higher with combination therapy; however, in severe DN, it was not different between the two groups. CONCLUSION: Our meta-analysis suggests that combination therapy can be used on DN with proteinuria, but should be used with caution in those with decreased renal function, especially with severe renal failure. PMID- 25707527 TI - Organic building block based microporous network SNW-1 coating fabricated by multilayer interbridging strategy for efficient enrichment of trace volatiles. AB - Microporous organic polymers (MOPs) are an emerging class of functional porous materials for diverse potential applications. Typically, tailored microporous structures of MOPs are generated by linkages of organic polymerizable monomer building blocks, providing high permanent porosity and excellent stability. Herein, we reported the first example of the application of organic building block based MOPs (OBB-MOPs) as efficient enrichment media for sample preparation. A novel multilayer interbridging strategy was proposed to fabricate OBB-MOP coatings, and hereby SNW-1 (a kind of OBB-MOPs) was coated on silica substrate with well-controlled thickness. Strong covalent bonds throughout the network and interlayer bridging improved the durability of the coating significantly. Outstanding chemical stability was observed in diverse solvents as well as solutions with a wide range of pH or high ionic strength and even under extremely harsh conditions like boiling water. The SNW-1 coating possessed a microporous network structure constructed of conjugated and nitrogen-rich building blocks. Thus, the coating exhibited a superior enrichment performance of polycyclic aromatic hydrocarbons and volatile fatty acids (VFAs) over commercial coatings based on interactions including pi-pi affinity and acid-base interaction. For further application, this coating was combined with gas chromatography/mass spectrometry for the noninvasive analysis of VFAs from tea leaf and tobacco shred samples. The low detection limits of 0.014-0.026 MUg/L were achieved with the relative standard deviations (RSDs) between 4.3 and 9.0%. Consequently, trace original VFAs from the samples were detected. Good recoveries were obtained in the range of 90-129% and 77-118% with the corresponding RSDs (n = 3) of 2.6-9.3% and 1.9-10%, respectively. PMID- 25707528 TI - PEAT: an intelligent and efficient paired-end sequencing adapter trimming algorithm. AB - BACKGROUND: In modern paired-end sequencing protocols short DNA fragments lead to adapter-appended reads. Current paired-end adapter removal approaches trim adapter by scanning the fragment of adapter on the 3' end of the reads, which are not competent in some applications. RESULTS: Here, we propose a fast and highly accurate adapter-trimming algorithm, PEAT, designed specifically for paired-end sequencing. PEAT requires no a priori adaptor sequence, which is convenient for large-scale meta-analyses. We assessed the performance of PEAT with many adapter trimmers in both simulated and real life paired-end sequencing libraries. The importance of adapter trimming was exemplified by the influence of the downstream analyses on RNA-seq, ChIP-seq and MNase-seq. Several useful guidelines of applying adapter trimmers with aligners were suggested. CONCLUSIONS: PEAT can be easily included in the routine paired-end sequencing pipeline. The executable binaries and the standalone C++ source code package of PEAT are freely available online. PMID- 25707532 TI - Formation of manganese phosphate and manganese carbonate during long-term sorption of Mn(2+) by viable Shewanella putrefaciens: effects of contact time and temperature. AB - The influence of temperature (5, 10, 22 and 30 degrees C) on the long-term (30 days) sorption of Mn(2+) by viable Shewanella putrefaciens was studied by FTIR and EXAFS. The additional Mn-removal capacity of these bacteria was found to result from the surface precipitation of Mn-containing inorganic phases. The chemical composition of the Mn-containing precipitates is temperature and contact time dependent. Mn(ii) phosphate and Mn(ii) carbonate were the two major precipitates formed in 1000 mL batches at 10, 22 and 30 degrees C. The ratio of Mn(ii) phosphate to Mn(ii) carbonate was a function of the contact time. After 30 days, MnCO3 was the dominant phase in the precipitates at 10, 22 and 30 degrees C; however, MnCO3 did not form at 5 degrees C. Mn(ii) phosphate was the only precipitate formed at 5 degrees C over 30 days. The biosynthesis of Extracellular Polymeric Substances (EPS) was much greater at the lowest temperature (5 degrees C); however, these polymeric sugars did not contribute to the additional removal of Mn(ii) under the experimental conditions. This work is one of the first reports demonstrating the ability of microbes to bioprecipitate manganese phosphate and manganese carbonate. Because of the focus on interfacial processes, this is the first report showing a molecular-level mechanism for manganese carbonate formation (in contrast to the traditionally studied aged minerals). PMID- 25707533 TI - Silver nanoparticle gated, mesoporous silica coated gold nanorods (AuNR@MS@AgNPs): low premature release and multifunctional cancer theranostic platform. AB - Multifunctional nanoparticles integrated with an imaging module and therapeutic drugs are promising candidates for future cancer diagnosis and therapy. Mesoporous silica coated gold nanorods (AuNR@MS) have emerged as a novel multifunctional cancer theranostic platform combining the large specific surface area of mesoporous silica, which guarantees a high drug payload, and the photothermal modality of AuNRs. However, premature release and side effects of exogenous stimulus still hinder the further application of AuNR@MS. To address these issues, herein, we proposed a glutathione (GSH)-responsive multifunctional AuNR@MS nanocarrier with in situ formed silver nanoparticles (AgNPs) as the capping agent. The inner AuNR core functions as a hyperthermia agent, while the outer mesoporous silica shell exhibits the potential to allow a high drug payload, thus posing itself as an effective drug carrier. With the incorporation of targeting aptamers, the constructed nanocarriers show drug release in accordance with an intracellular GSH level with maximum drug release into tumors and minimum systemic release in the blood. Meanwhile, the photothermal effect of the AuNRs upon application to near-infrared (NIR) light led to a rapid rise in the local temperature, resulting in an enhanced cell cytotoxicity. Such a versatile theranostic system as AuNR@MS@AgNPs is expected to have a wide biomedical application and may be particularly useful for cancer therapy. PMID- 25707534 TI - The topical corticosteroid classification called into question: towards a new approach. AB - Vasoconstrictor assay described in 1962 was an interesting assessment of potency of topical corticosteroids at the beginning of these new therapies, however knowledge and technology have evolved and the classification should follow. A topical corticosteroids with a strong vasoconstrictor effect, as determined by vasoconstrictor assay, has not necessary a strong anti-inflammatory effect. Therefore a specific classification adapted to the therapeutic target is needed to be more efficient and thus reduce side effects and corticophobia. PMID- 25707535 TI - The importance of manganese in the cytoplasmic maturation of cattle oocytes: blastocyst production improvement regardless of cumulus cells presence during in vitro maturation. AB - Adequate dietary intake of manganese (Mn) is required for normal reproductive performance in cattle. This study was carried out to investigate the effect of Mn during in vitro maturation of bovine cumulus-oocyte complexes (COC) on apoptosis of cumulus cells, cumulus expansion, and superoxide dismutase (SOD) activity in the COC. The role of cumulus cells on Mn transport and subsequent embryo development was also evaluated. Early apoptosis decreased in cumulus cells matured with Mn compared with medium alone. Cumulus expansion did not show differences in COC matured with or without Mn supplementation. SOD activity was higher in COC matured with 6 ng/ml Mn than with 0 ng/ml Mn. Cleavage rates were higher in COC and denuded oocytes co-cultured with cumulus cells, either with or without Mn added to in vitro maturation (IVM) medium. Regardless of the presence of cumulus cells during IVM, the blastocyst rates were higher when 6 ng/ml Mn was supplemented into IVM medium compared with growth in medium alone. Blastocyst quality was enhanced when COC were matured in medium with Mn supplementation. The results of the present study indicated that Mn supplementation to IVM medium enhanced the 'health' of COC, and improved subsequent embryo development and embryo quality. PMID- 25707536 TI - Nerve growth factor protects retinal ganglion cells against injury induced by retinal ischemia-reperfusion in rats. AB - In this study, we investigated the protective effect of mouse nerve growth factor (NGF) on retinal ganglion cell (RGC) injury induced by retinal ischemia reperfusion (RIR) in rats and explored its possible mechanisms of action. RIR caused a significant injury to RGCs and an obvious impairment of the inner retina functions, which could be seen from flash electroretinogram and flash visual evoked potential recordings. RIR also increased the expression of the apoptotic protein Bax while decreasing the expression of Bcl-2 and the phosphorylation of protein kinase B (Akt) in RGCs. Preinjection (i.m.) of NGF for 22 d reversed the injury induced by RIR and ameliorated the inner retina functions. NGF also reduced the expression of Bax and reversed the reduction of Bcl-2 and the phosphorylated Akt induced by RIR. These results indicate that NGF produces a neuroprotective effect on RGCs against RIR injury and the protective effect of NGF is mainly mediated by the PI-3K/Akt signaling pathway. PMID- 25707537 TI - Computational cell fate modelling for discovery of rewiring in apoptotic network for enhanced cancer drug sensitivity. AB - The ongoing cancer research has shown that malignant tumour cells have highly disrupted signalling transduction pathways. In cancer cells, signalling pathways are altered to satisfy the demands of continuous proliferation and survival. The changes in signalling pathways supporting uncontrolled cell growth, termed as rewiring, can lead to dysregulation of cell fates e.g. apoptosis. Hence comparative analysis of normal and oncogenic signal transduction pathways may provide insights into mechanisms of cancer drug-resistance and facilitate the discovery of novel and effective anti-cancer therapies. Here we propose a hybrid modelling approach based on ordinary differential equation (ODE) and machine learning to map network rewiring in the apoptotic pathways that may be responsible for the increase of drug sensitivity of tumour cells in triple negative breast cancer. Our method employs Genetic Algorithm to search for the most likely network topologies by iteratively generating simulated protein phosphorylation data using ODEs and the rewired network and then fitting the simulated data with real data of cancer signalling and cell fate. Most of our predictions are consistent with experimental evidence from literature. Combining the strengths of knowledge-driven and data-driven approaches, our hybrid model can help uncover molecular mechanisms of cancer cell fate at systems level. PMID- 25707540 TI - Why analyse variances in order to compare means. PMID- 25707541 TI - The time course of location-avoidance learning in fear of spiders. AB - Two experiments were designed to study the time course of avoidance learning in spider fearfuls (SFs) under controlled experimental conditions. To achieve this, we employed an immersive virtual environment (IVE): While walking freely through a virtual art museum to search for specific paintings, the participants were exposed to virtual spiders. Unbeknown to the participants, only two of four museum rooms contained spiders, allowing for avoidance learning. Indeed, the more SF the participants were, the faster they learned to avoid the rooms that contained spiders (Experiment. 1), and within the first six trials, high fearfuls already developed a preference for starting their search task in rooms without spiders (Experiment 2). These results illustrate the time course of avoidance learning in SFs, and they speak to the usefulness of IVEs in fundamental anxiety research. PMID- 25707543 TI - Betamethasone augments the antifungal effect of menadione--towards a novel anti Candida albicans combination therapy. AB - The fluorinated glucocorticoid betamethasone stimulated both the extracellular phospholipase production and hypha formation of the opportunistic human pathogen Candida albicans and also decreased the efficiency of the polyene antimycotics amphotericin B and nystatin against C. albicans in a dose-dependent manner. Importantly, betamethasone increased synergistically the anti-Candida activity of the oxidative stress generating agent menadione, which may be exploited in future combination therapies to prevent or cure C. albicans infections, in the field of dermatology. PMID- 25707544 TI - Metastasis of the gallbladder from the breast cancer. AB - AIM: Metastatic lesions of the gallbladder are an infrequent clinical condition. The metastatic lesions of gallbladder from primary breast tumors are rarely described in literature. MATERIAL OF STUDY: We report a case of an 83-year-old woman who underwent cholecystectomy for cholelithiasis by video laparoscopy (VL), and in whom a metastatic lesion was detected at the histological examination of surgical specimen. For this reason, the patient was subjected to diagnostic instrumental investigation with the aim of detecting the primary tumor, which showed the presence of infiltrating lobular carcinoma, pleomorphic variety, in the upper outer quadrant of the right breast. DISCUSSION: Breast cancer and in particular the histological type "ductal infiltrating" is frequently associated with locoregional and distant metastases, the latter especially to bones, liver, lungs and central nervous system. An analysis of literature was conducted on secondary lesions of the gallbladder from breast cancer that has allowed us to confirm the rarity of this disease only described in 18 patients: 12 from infiltrating lobular, 1 ductal origin and 2 mixed ductal and lobular infiltrating. CONCLUSIONS: The most frequent tumor histology associated with the above-mentioned metastatic localization is the metastatic infiltrating lobular carcinoma. Clinically speaking, it is difficult to suspect a metastatic localization from primary breast cancer in the gallbladder, but it is necessary to be well aware of the possibility of metastasis and to bear this in mind during the follow-up of patients with breast cancer. Although cholecystectomy is regarded as a palliative treatment in patients with metastasis in the gallbladder from breast cancer, it is intead recommended in symptomatic cases. PMID- 25707545 TI - Copper-catalyzed skeletal rearrangements of O-propargylic oximes via cleavage of a carbon-oxygen bond. AB - In this account, we describe recent developments in copper-catalyzed skeletal 2,3 rearrangement reactions of O-propargylic oximes to form four-membered cyclic nitrones, pyridine N-oxides, and amidodienes via N-allenylnitrone intermediates. The sequence of events leading up to our encounter with O-propargylic oximes is also presented. PMID- 25707546 TI - Bcl-3 puts the brakes on contact hypersensitivity. AB - B-cell lymphoma (Bcl)-3 is a nonclassical member of the IkappaB protein family known to interact with transcriptionally inactive NF-kappaB1 and NF-kappaB2 homodimers to modulate gene expression. Besides its action as an oncoprotein, Bcl 3 has been shown to have both proinflammatory and anti-inflammatory functions depending on the cell-type affected. In this issue of the European Journal of Immunology, Tassi et al. [Eur. J. Immunol. 2015. 45: 1059-1068] report that Bcl-3 inhibits the production of the proinflammatory chemokines CXCL9 and CXCL10 in keratinocytes, thereby restricting the influx of CD8(+) effector T cells in a mouse model of allergic contact dermatitis. In addition, mice with a global deficiency of Bcl-3 show enhanced ear swelling responses in the late phase of contact hypersensitivity responses. Besides keratinocytes, other radioresistant cell types appear to also utilize Bcl-3 to dampen the inflammatory response. This Commentary will discuss the evidence supporting Bcl-3 as a critical player in limiting inflammation during the later stages of contact hypersensitivity. PMID- 25707547 TI - Emerging concepts in the pathogenesis of diabetes in fibrocalculous pancreatic diabetes. AB - Fibrocalcific pancreatic diabetes (FCPD) is a rare form of diabetes affecting people in the tropics and presenting with unique clinical and radiological features. The onset of diabetes usually follows the first few episodes of abdominal pain and develops by the second or third decade of life. Endocrine and exocrine pancreatic insufficiency, brittle glycemic control, and insulin requiring, ketosis-resistant diabetes are the novel characteristics of FCPD. The etiopathogenetic mechanisms leading to FCPD remain unknown. Although defects in insulin secretion are the major contributors, growing evidence towards a possible role for insulin resistance and body composition abnormalities have added a new dimension to the disease pathogenesis. Deciphering the key pathogenetic mechanisms may have a profound effect on therapeutic strategies in future studies on FCPD. PMID- 25707548 TI - Agronomic and environmental consequences of using liquid mineral concentrates on arable farms. AB - BACKGROUND: In regions with intensive livestock systems, the processing of manure into liquid mineral concentrates is seen as an option to increase the nutrient use efficiency of manures. The agricultural sector anticipates that these products may in future be regarded as regular mineral fertilisers. We assessed the agronomic suitability and impact on greenhouse gas (GHG) and ammonia emissions of using liquid mineral concentrates on arable farms. RESULTS: The phosphate requirements on arable farms were largely met by raw pig slurry, given its large regional availability. After the initial nutrient input by means of pig slurry, the nitrogen/phosphate ratio of the remaining nutrient crop requirements determined the additional amount of liquid mineral concentrates that can be used. For sandy soils, liquid mineral concentrates could supply 50% of the nitrogen requirement, whereas for clay soils the concentrates did not meet the required nitrogen/phosphate ratio. The total GHG emissions per kg of plant available nitrogen ranged from -65 to 33 kg CO2 -equivalents. It increased in the order digestates < mineral fertiliser < raw slurries. CONCLUSIONS: Liquid mineral concentrates had limited added value for arable farms. For an increased suitability it is necessary that liquid mineral concentrates do not contain phosphate and that the nitrogen availability is increased. In the manure processing chain, anaerobic digestion had a dominant and beneficial effect on GHG emissions. PMID- 25707549 TI - Risk factors associated with clindamycin-resistant, methicillin-resistant Staphylococcus aureus in hand abscesses. AB - PURPOSE: To identify risk factors for clindamycin resistance in acute hand abscesses caused by methicillin-resistant Staphylococcus aureus (MRSA). METHODS: We performed a retrospective review of 247 consecutive culture-positive hand abscesses from 2010 to 2012 at an urban hospital. Historical and laboratory data from patients with abscesses that grew MRSA with and without clindamycin resistance were compared in a multivariate analysis. RESULTS: Methicillin resistant Staphylococcus aureus grew on culture from 103 abscesses; 16% of those isolates were resistant to clindamycin. Multivariate analysis showed that younger age, intravenous drug use, and nosocomial acquired MRSA were significant risk factors for concurrent clindamycin resistance. Patients with a history of intravenous drug use and nosocomial acquired MRSA were, respectively, 11 and 5 times more likely to have concurrent clindamycin resistance. History of MRSA infection and human immunodeficiency virus were not identified as risk factors. CONCLUSIONS: Patients with a history of intravenous drug use or recent contact with health care facilities appear to be a potential reservoir for emerging multidrug-resistant MRSA. Selection of clindamycin as an empiric antibiotic should be especially avoided for these groups. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic III. PMID- 25707550 TI - A classification system for ulnar polydactyly and clinical series. AB - PURPOSE: To describe a modified classification that includes both complicated ulnar polydactyly and ulnar polydactyly with bifid or duplicated proximal phalanx and to apply it to a clinical series. METHODS: A total of 42 patients with ulnar polydactyly were admitted to our outpatient clinic between January 2004 and January 2014 and were included in the study. Patients' clinical and radiological data were evaluated retrospectively and organized into 5 different subgroups. RESULTS: There were 20 bilateral and 22 unilateral patients with polydactyly. These were composed of 32 supernumerary digits represented as type I, 7 as type II, 9 as type III, 12 as type IV, and 2 as type V. Nine patients had bifid or duplicated proximal phalanges (types IIIA and IIIB) and 2 were of the complicated type (type V). We identified 5 types based on morphology, level of duplication, and other complicating features. CONCLUSIONS: Complicated ulnar polydactyly and ulnar polydactyly with bifid proximal phalanx are 2 important types of ulnar polydactyly with surgical implications, both separately included in the Pritsch classification system and Rayan and Al-Qattan classification systems. None of the current classification systems include both types. We believe our modified classification system will help to better define diagnosis and treatment plans for bifid proximal phalanx and complicated type ulnar polydactyly. TYPE OF STUDY/LEVEL OF EVIDENCE: Diagnostic III. PMID- 25707551 TI - Diagnostic performance of a rapid in-clinic test for the detection of Canine Parvovirus under different storage conditions and vaccination status. AB - Canine parvovirus (CPV) is one of the most common causes of acute haemorrhagic enteritis in young dogs, while clinical diagnosis is often indecisive. The aim of our study was to evaluate the diagnostic accuracy of an in-clinic rapid test in the detection of CPV infection in dogs. To this end, we compared the Rapid Diagnostic Kit of Canine Parvovirus, Coronavirus and Rotavirus antigen (Quicking((r))) to PCR, which is considered as the most reliable diagnostic method. A total of 78 duplicated faecal samples were collected from diarrhoeic dogs. Vaccination history within a month prior to the onset of diarrhoea was reported for 12 of the sampled dogs. The rapid diagnostic test was performed in 23 of the faecal samples directly, while the rest were placed into a sterile cotton tipped swab suitable for collection and transportation of viruses (Sigma Sigma-VCM((r))) and stored at -20 degrees C. The sensitivity of the Quicking rapid diagnostic test compared to PCR in the total number of samples, in samples from non-vaccinated dogs and in samples tested directly after collection were 22.22% (95% CI: 13.27-33.57%), 26.67% (95% CI: 16.08-39.66%) and 76.47% (95% CI: 50.10-93.04%) respectively, while the specificity of the test was 100% in any case. In conclusion, negative results do not exclude parvoenteritis from the differential diagnosis, especially in dogs with early vaccination history, but a positive result almost certainly indicates CPV infection. An improved sensitivity may be expected when the test is performed immediately. PMID- 25707552 TI - BagReg: Protein inference through machine learning. AB - Protein inference from the identified peptides is of primary importance in the shotgun proteomics. The target of protein inference is to identify whether each candidate protein is truly present in the sample. To date, many computational methods have been proposed to solve this problem. However, there is still no method that can fully utilize the information hidden in the input data. In this article, we propose a learning-based method named BagReg for protein inference. The method firstly artificially extracts five features from the input data, and then chooses each feature as the class feature to separately build models to predict the presence probabilities of proteins. Finally, the weak results from five prediction models are aggregated to obtain the final result. We test our method on six public available data sets. The experimental results show that our method is superior to the state-of-the-art protein inference algorithms. PMID- 25707553 TI - Double stranded viral RNA induces inflammation and insulin resistance in skeletal muscle from pregnant women in vitro. AB - OBJECTIVE: Maternal peripheral insulin resistance and increased inflammation are two features of pregnancies complicated by pre-existing maternal obesity and gestational diabetes mellitus (GDM). There is now increasing evidence that activation of Toll-like receptor (TLR) signalling pathways by viral products may play a role in the pathophysiology of diabetes. Thus, the aim of this study was to assess the effect of the TLR3 ligand and viral dsRNA analogue polyinosinic polycytidilic acid (poly(I:C)) on inflammation and the insulin signalling pathway in skeletal muscle from pregnant women. MATERIALS/METHODS: Human skeletal muscle tissue explants were performed to determine the effect of poly(I:C) on the expression and secretion of markers of inflammation, and the insulin signalling pathway and glucose uptake. RESULTS: Poly(I:C) significantly increased the expression of a number of inflammatory markers in skeletal muscle from pregnant women. Specifically, there was an increase in the expression and/or secretion of the pro-inflammatory cytokines TNF-alpha, and IL-6 and the pro-inflammatory chemokines IL-8 and MCP-1. These effect of poly(I:C) appear to mediated via a number of signalling molecules including the pro-inflammatory transcription factor NF-kappaB, and the serine threonine kinases GSK3 and AMPKalpha. Additionally, poly(I:C) decreased insulin stimulated GLUT-4 expression and glucose uptake in skeletal muscle from pregnant women. CONCLUSIONS: The in vitro data presented in this study suggests that viral infection may contribute to the pathophysiology of pregnancies complicated by pre-existing maternal obesity and/or GDM. It should be noted that the in vitro studies cannot be directly used to infer the same outcomes in the intact subject. PMID- 25707554 TI - Human monocyte subsets exhibit divergent angiotensin I-converting activity. AB - Immune cells may take part in the renin-angiotensin-aldosterone system (RAAS), which plays a pivotal role in the regulation of vascular tone and blood pressure. The aim of the study was to analyse the expression and activity of angiotensin converting enzyme type 1 (ACE1) and ACE2 in human monocytes (MO) and their subsets. The highest relative level of ACE1-, as well as ACE2-mRNA expression, was observed in CD14(++)CD16(-) (classical) MO. Moreover, in these cells, mean level of ACE2-mRNA was almost two times higher than that of ACE1-mRNA (11.48 versus 7.073 relative units, respectively). In peripheral blood mononuclear cells (PBMC), MO and classical MO, ACE1 and ACE2 protein expression was stronger compared to other MO subpopulations. The highest level of Ang II generated from Ang I in vitro was observed in classical MO. In this setting, generation of Ang (1-9) by PBMC and classical MO was higher when compared to the whole MO population (P < 0.05). The generation rate of vasoprotective Ang-(1-7) was comparable in all analysed cell populations. However, in CD14(+)CD16(++) (non classical) MO, formation of Ang-(1-7) was significantly greater than Ang II (P < 0.001). We suggest that in physiological conditions MO (but also lymphocytes forming the rest of PBMC pool) may be involved in the regulation of vessel wall homeostasis via the RAAS-related mechanisms. Moreover, non-classical MO, which are associated preferentially with the vascular endothelium, express the vasoprotective phenotype. PMID- 25707555 TI - Ethnic, socio-demographic and socio-economic differences in surgical treatment of breast cancer in New Zealand. AB - BACKGROUND: Indigenous Maori are known to experience inferior quality cancer care compared with non-Indigenous Europeans in New Zealand. However, limited data are available on ethnic/socio-economic differences in surgical treatment of breast cancer, or reasons for such variations within the local context. We investigated ethnic/socio-economic differences in rates of mastectomy, sentinel node biopsy (SNB), post-mastectomy breast reconstruction and definitive local therapy for breast cancer in New Zealand. METHODS: A retrospective review of prospective data in the Waikato Breast Cancer Register for women diagnosed during 1999-2012 was performed. Differences in rates of mastectomy (for stage I/II, T1/T2 cancers), SNB (for stage I/II, T1/T2, cN0 cancers), post-mastectomy breast reconstruction (for non-metastatic cancers in women <70 years) and definitive local therapy (for stage I/II cancers) were analysed in univariate and multivariate regression models, adjusting for covariates. RESULTS: Significantly lower mastectomy and higher reconstruction rates were associated with younger age, private compared with public hospital care and screen compared with non-screen detection. Compared with NZ Europeans, Maori (41% versus 33%, P = 0.025) were significantly more likely to undergo mastectomy for cancers, which were potentially amenable for breast conserving surgery, but were significantly less likely to undergo post mastectomy breast reconstruction (12% versus 35%, P < 0.001). No significant ethnic or socio-economic differences were observed in rates of SNB or definitive local therapy. CONCLUSIONS: This study has demonstrated lower rates of breast conserving surgery and reconstructions in Maori compared with NZ European women, and highlight the need for future research to focus on understanding the reasons behind these findings. PMID- 25707556 TI - Gadolinium modifies the cell membrane to inhibit permeabilization by nanosecond electric pulses. AB - Lanthanide ions are the only known blockers of permeabilization by electric pulses of nanosecond duration (nsEP), but the underlying mechanisms are unknown. We employed timed applications of Gd(3+) before or after nsEP (600-ns, 20 kV/cm) to investigate the mechanism of inhibition, and measured the uptake of the membrane-impermeable YO-PRO-1 (YP) and propidium (Pr) dyes. Gd(3+) inhibited dye uptake in a concentration-dependent manner. The inhibition of Pr uptake was always about 2-fold stronger. Gd(3+) was effective when added after nsEP, as well as when it was present during nsEP exposure and removed afterward. Pores formed by nsEP in the presence of Gd(3+) remained quiescent unless Gd(3+) was promptly washed away. Such pores resealed (or shrunk) shortly after the wash despite the absence of Gd(3+). Finally, a brief (3s) Gd(3+) perfusion was equally potent at inhibiting dye uptake when performed either immediately before or after nsEP, or early before nsEP. The persistent protective effect of Gd(3+) even in its absence proves that inhibition by Gd(3+) does not result from simple pore obstruction. Instead, Gd(3+) causes lasting modification of the membrane, occurring promptly and irrespective of pore presence; it makes the membrane less prone to permeabilization and/or reduces the stability of electropores. PMID- 25707557 TI - Cellular interpretation of the long-range gradient of Four-jointed activity in the Drosophila wing. AB - To understand how long-range patterning gradients are interpreted at the cellular level, we investigate how a gradient of expression of the Four-jointed kinase specifies planar polarised distributions of the cadherins Fat and Dachsous in the Drosophila wing. We use computational modelling to test different scenarios for how Four-jointed might act and test the model predictions by employing fluorescence recovery after photobleaching as an in vivo assay to measure the influence of Four-jointed on Fat-Dachsous binding. We demonstrate that in vivo, Four-jointed acts both on Fat to promote its binding to Dachsous and on Dachsous to inhibit its binding to Fat, with a bias towards a stronger effect on Fat. Overall, we show that opposing gradients of Fat and Dachsous phosphorylation are sufficient to explain the observed pattern of Fat-Dachsous binding and planar polarisation across the wing, and thus demonstrate the mechanism by which a long range gradient is interpreted. PMID- 25707558 TI - Rapid identification of efavirenz metabolites in rats and humans by ultra high performance liquid chromatography combined with quadrupole time-of-flight tandem mass spectrometry. AB - An in vivo study of efavirenz metabolites in rats and human patients with ultra high performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry combined with MetabolitePilot(MT) software is reported for the first time. Considering the polarity differences between the metabolites, solid-phase extraction and protein precipitation were both applied as a part of the sample preparation method. The structures of the metabolites and their fragment ions were identified or tentatively characterized based on the accurate mass and MS(2) data. As a result, a total of 15 metabolites, including 11 from rat samples and 13 from human samples, were identified or tentatively characterized. Two metabolites and several new metabolism pathways are reported for the first time. This study provides a practical approach for identifying complicated metabolites through the rapid and reliable ultra high performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry technique, which could be widely used for the investigation of drug metabolites. PMID- 25707559 TI - Authors' reply. PMID- 25707560 TI - Contemporary use of imaging modalities in neck mass evaluation. AB - The effective and efficient management of a patient with a neck mass in a 1-stop clinic requires a collaborative and harmonious partnership among surgeon, radiologist, and pathologist. In this article, theoretic and practical issues are addressed to optimize patient care when prescribing, planning, performing, and interpreting imaging for neck disease. PMID- 25707561 TI - Pediatric neck masses. PMID- 25707562 TI - Neck infections. PMID- 25707563 TI - Hematopoietic neck lesions. PMID- 25707564 TI - Procedure/Technique: endocrine tumors of the neck. PMID- 25707565 TI - Diagnosis and management of salivary lesions of the neck. PMID- 25707566 TI - Vascular anomalies of the neck. PMID- 25707567 TI - Soft tissue tumors of the neck. PMID- 25707568 TI - Metastatic neck disease. PMID- 25707569 TI - Reconstruction of cervical defects. PMID- 25707570 TI - Diagnosis and management of neck masses. PMID- 25707572 TI - A reactive oxygen species-mediated loop maintains increased expression of NADPH oxidases 2 and 4 in skin fibroblasts from patients with systemic sclerosis. AB - OBJECTIVE: Reactive oxygen species (ROS) contribute to the pathogenesis of fibrosis in systemic sclerosis (SSc; scleroderma), and NADPH oxidase (NOX) is an important source of ROS. Since the role of single NOX isoforms has not been previously investigated in SSc, this study was undertaken to assess the expression of NOX in SSc fibroblasts compared to normal healthy cells and to analyze their role in cell activation. METHODS: Expression of NOX isoforms in dermal fibroblasts from patients with SSc and healthy control subjects was analyzed by real-time polymerase chain reaction, immunoblotting, and immunofluorescence. NOX isoforms were silenced using small interfering RNA. Production of ROS was measured by fluorometry and confocal microscopy. RESULTS: Scleroderma fibroblasts showed up-regulation of NOX-2 and NOX-4 protein and messenger RNA (mRNA) expression. Treatment of the cells with diphenyleneiodonium, a nonselective inhibitor of flavin-containing enzymes, and silencing of NOX2 and NOX4 decreased the production of ROS as well as the expression of type I collagen and alpha-smooth muscle actin in SSc fibroblasts. ROS generated by NOX-2 and NOX 4 were involved in DNA damage and activation of a DNA repair checkpoint. Incubation of healthy control fibroblasts with platelet-derived growth factor (PDGF) or with IgG isolated from SSc patient serum enhanced the expression of NOX2 and NOX4 mRNA, via ROS, in a time-dependent manner. Treatment with actinomycin D, a transcription inhibitor, reversed the effects of PDGF stimulation but not the effects of SSc IgG. CONCLUSION: Both NOX2 and NOX4 generate ROS in SSc fibroblasts and play a critical role in cell activation and DNA damage. Expression of NOX-2 and NOX-4 in SSc fibroblasts is maintained by a ROS-mediated loop. PMID- 25707574 TI - Melanoma on a tattoo. PMID- 25707573 TI - The Histone Deacetylase Sirtuin 1 Is Reduced in Systemic Sclerosis and Abrogates Fibrotic Responses by Targeting Transforming Growth Factor beta Signaling. AB - OBJECTIVE: Persistent fibroblast activation underlies skin fibrosis in systemic sclerosis (SSc), but the transcriptional and epigenetic mechanisms controlling this process are not well understood. In view of the potent influence of acetylation status governing tissue fibrosis, we undertook this study to investigate the expression of the antiaging deacetylase enzyme sirtuin 1 (SIRT1) in SSc and its effects on fibrotic responses in vitro and in vivo. METHODS: Tissue expression of SIRTs was interrogated from publicly available genome-wide expression data sets and by immunohistochemistry. The effects of SIRT1 on modulating fibrotic responses, as well as the underlying mechanisms, were examined in human and mouse fibroblasts in culture and in an experimental fibrosis model in the mouse. RESULTS: Analysis of transcriptome data revealed a selective reduction of SIRT1 messenger RNA (mRNA) levels in SSc skin biopsy samples as well as a negative correlation of SIRT1 mRNA with the skin score. Cellular SIRT1 levels were suppressed in normal fibroblasts exposed to hypoxia or platelet-derived growth factor and were constitutively down-regulated in SSc fibroblasts. Activation of SIRT1 attenuated fibrotic responses in skin fibroblasts and skin organ cultures, while genetic or pharmacologic inhibition of SIRT1 had profibrotic effects. The antifibrotic effects of SIRT1 were due in part to decreased expression and function of the acetyltransferase p300. In mice, experimentally induced skin fibrosis was accompanied by reduced SIRT1 expression in lesional tissue fibroblasts, and both fibrosis and loss of SIRT1 in these mice were mitigated by treatment with a SIRT1 activator. CONCLUSION: SIRT1 has antifibrotic effects, and its reduced tissue expression in patients with SSc might have a direct causal role in progression of fibrosis. Pharmacologic modulation of SIRT1 in these patients therefore might represent a potential treatment strategy. PMID- 25707575 TI - [Acquired ichthyosis revealing an Hodgkin's disease]. PMID- 25707576 TI - Video self-modeling as a post-treatment fluency recovery strategy for adults. AB - PURPOSE: This multiple-baseline across subjects study investigated the effectiveness of video self-modeling (VSM) in reducing stuttering and bringing about improvements in associated self-report measures. Participants' viewing practices and perceptions of the utility of VSM also were explored. METHODS: Three adult males who had previously completed speech restructuring treatment viewed VSM recordings twice per week for 6 weeks. Weekly speech data, treatment viewing logs, and pre- and post-treatment self-report measures were obtained. An exit interview also was conducted. RESULTS: Two participants showed a decreasing trend in stuttering frequency. All participants appeared to engage in fewer avoidance behaviors and had less expectations to stutter. All participants perceived that, in different ways, the VSM treatment had benefited them and all participants had unique viewing practices. CONCLUSION: Given the increasing availability and ease in using portable audio-visual technology, VSM appears to offer an economical and clinically useful tool for clients who are motivated to use the technology to recover fluency. EDUCATIONAL OBJECTIVES: Readers will be able to describe: (a) the tenets of video-self modeling; (b) the main components of video-self modeling as a fluency recovery treatment as used in this study; and (c) speech and self-report outcomes. PMID- 25707577 TI - Emerging cardiovascular indications of mineralocorticoid receptor antagonists. AB - Mineralocorticoid receptor (MR) antagonism is a well-established treatment modality for patients with hypertension, heart failure, and left ventricular systolic dysfunction (LVSD) post-myocardial infarction (MI). There are emerging data showing potential benefits of MR antagonists in other cardiovascular conditions. Studies have shown association between MR activation and the development of myocardial fibrosis, coronary artery disease, metabolic syndrome, and cerebrovascular diseases. This review examines the preclinical and clinical data of MR antagonists for novel indications including heart failure with preserved ejection fraction (HFPEF), pulmonary arterial hypertension (PAH), arrhythmia, sudden cardiac death, valvular heart disease, metabolic syndrome, renal disease, and stroke. MR antagonists are not licensed for these conditions yet; however, emerging data suggest that indication for MR antagonists are likely to broaden; further studies are warranted. PMID- 25707579 TI - Can reverse shoulder arthroplasty in post-traumatic revision surgery restore the ability to perform activities of daily living? AB - BACKGROUND: Failed shoulder arthroplasty and failed internal fixation in fractures of the proximal humerus can benefit from implantation of a reverse total shoulder arthroplasty (RSA). While there is some evidence that RSA can improve function regarding range of motion (ROM), pain, satisfaction, and strength, there is sparse data how this translates into activities of daily living (ADLs). A marker-based 3D video motion analysis system has recently been designed that can measure changes of ROM in dynamic movements in every plane. The hypothesis was that a gain of maximum ROM also translates into the ability to perform ADLs and into a significant increase of ROM in ADLs. MATERIALS AND METHODS: Six consecutive patients (5 women, 1 man; 2* failed arthroplasty, 4* failed open reduction and internal fixation) who received RSA were examined the day before and 1 year after shoulder replacement. A 3D motion analysis system using a novel upper extremity model measured active maximum values and ROM in four ADLs. RESULTS: Comparing the pre- to the 1-year postoperative status, RSA resulted in a significant increase in mean maximum values for active flexion (humerus to thorax) of 37 degrees (S.D. +/-23 degrees ), from 50 to 87 degrees [P=0.005], and for active abduction averaging of 17 degrees (S.D. +/-13 degrees ), from 52 to 69 degrees [P=0.027]. The extension decreased significantly by about 8 degrees (S.D. +/-16 degrees ), from a mean of 39 to 31 degrees [P=0.009]. For active adduction and internal and external rotation, there were trends for improvements, but no significant changes. Only three additional tasks of the ADL (out of 13/24 preoperatively) could be performed after revision surgery. Comparing the preoperative to the postoperative ROM in the ADLs in flexion/extension, ROM improved significantly in one ("tying an apron") of four ADLs. There were no significant changes in the abduction/adduction and internal/external rotation in any ADLs. CONCLUSION: RSA in revision cases significantly improved maximum active flexion and abduction, but decreased extension in this series. However, the patients were only able to use this greater ROM to their benefit in one of four ADLs. PMID- 25707578 TI - Defective fast inactivation recovery of Nav 1.4 in congenital myasthenic syndrome. AB - OBJECTIVE: To describe the unique phenotype and genetic findings in a 57-year-old female with a rare form of congenital myasthenic syndrome (CMS) associated with longstanding muscle fatigability, and to investigate the underlying pathophysiology. METHODS: We used whole-cell voltage clamping to compare the biophysical parameters of wild-type and Arg1457His-mutant Nav 1.4. RESULTS: Clinical and neurophysiological evaluation revealed features consistent with CMS. Sequencing of candidate genes indicated no abnormalities. However, analysis of SCN4A, the gene encoding the skeletal muscle sodium channel Nav 1.4, revealed a homozygous mutation predicting an arginine-to-histidine substitution at position 1457 (Arg1457His), which maps to the channel's voltage sensor, specifically D4/S4. Whole-cell patch clamp studies revealed that the mutant required longer hyperpolarization to recover from fast inactivation, which produced a profound use-dependent current attenuation not seen in the wild type. The mutant channel also had a marked hyperpolarizing shift in its voltage dependence of inactivation as well as slowed inactivation kinetics. INTERPRETATION: We conclude that Arg1457His compromises muscle fiber excitability. The mutant fast-inactivates with significantly less depolarization, and it recovers only after extended hyperpolarization. The resulting enhancement in its use dependence reduces channel availability, which explains the patient's muscle fatigability. Arg1457His offers molecular insight into a rare form of CMS precipitated by sodium channel inactivation defects. Given this channel's involvement in other muscle disorders such as paramyotonia congenita and hyperkalemic periodic paralysis, our study exemplifies how variations within the same gene can give rise to multiple distinct dysfunctions and phenotypes, revealing residues important in basic channel function. PMID- 25707581 TI - n-back task performance and corresponding brain-activation patterns in women with restrictive and bulimic eating-disorder variants: preliminary findings. AB - Eating disorder (ED) variants characterized by "binge-eating/purging" symptoms differ from "restricting-only" variants along diverse clinical dimensions, but few studies have compared people with these different eating-disorder phenotypes on measures of neurocognitive function and brain activation. We tested the performances of 19 women with "restricting-only" eating syndromes and 27 with "binge-eating/purging" variants on a modified n-back task, and used functional magnetic resonance imaging (fMRI) to examine task-induced brain activations in frontal regions of interest. When compared with "binge-eating/purging" participants, "restricting-only" participants showed superior performance. Furthermore, in an intermediate-demand condition, "binge-eating/purging" participants showed significantly less event-related activation than did "restricting-only" participants in a right posterior prefrontal region spanning Brodmann areas 6-8-a region that has been linked to planning of motor responses, working memory for sequential information, and management of uncertainty. Our findings suggest that working memory is poorer in eating-disordered individuals with binge-eating/purging behaviors than in those who solely restrict food intake, and that observed performance differences coincide with interpretable group-based activation differences in a frontal region thought to subserve planning and decision making. PMID- 25707580 TI - Simultaneous oral and inhalational intake of molecular hydrogen additively suppresses signaling pathways in rodents. AB - Molecular hydrogen (H2) is an agent with potential applications in oxidative stress-related and/or inflammatory disorders. H2 is usually administered by inhaling H2-containing air (HCA) or by oral intake of H2-rich water (HRW). Despite mounting evidence, the molecular mechanism underlying the therapeutic effects and the optimal method of H2 administration remain unclear. Here, we investigated whether H2 affects signaling pathways and gene expression in a dosage- or dose regimen-dependent manner. We first examined the H2 concentrations in blood and organs after its administration and found that oral intake of HRW rapidly but transiently increased H2 concentrations in the liver and atrial blood, while H2 concentrations in arterial blood and the kidney were one-tenth of those in the liver and atrial blood. In contrast, inhalation of HCA increased H2 equally in both atrial and arterial blood. We next examined whether H2 alters gene expression in normal mouse livers using DNA microarray analysis after administration of HCA and HRW. Ingenuity Pathway Analysis revealed that H2 suppressed the expression of nuclear factor-kappa B (NF-kappaB)-regulated genes. Western blot analysis showed that H2 attenuated ERK, p38 MAPK, and NF-kappaB signaling in mouse livers. Finally, we evaluated whether the changes in gene expression were influenced by the route of H2 administration and found that the combination of both HRW and HCA had the most potent effects on signaling pathways and gene expression in systemic organs, suggesting that H2 may act not only through a dose-dependent mechanism but also through a complex molecular network. PMID- 25707582 TI - Left ventricular diastolic dysfunction and E/E' ratio as the strongest echocardiographic predictors of reduced exercise capacity after acute myocardial infarction. AB - BACKGROUND: The mechanisms that determine reduced exercise capacity after acute myocardial infarction (AMI) are not fully understood, especially the relative role of left ventricular diastolic and systolic function. HYPOTHESIS: To evaluate the role of different diastolic and systolic function echocardiographic parameters as predictors of reduced functional capacity in patients after AMI. METHODS: One month after AMI, 225 patients (84% male; mean age, 55.1 +/- 10.9 years) were enrolled and underwent detailed echocardiography and cardiopulmonary exercise test on the same day. Systolic and diastolic function was evaluated by echocardiography according to the latest consensus recommendations, including tissue Doppler evaluation. Exercise capacity was evaluated with peak oxygen consumption (VO(2)). RESULTS: Peak VO(2) was significantly correlated with early diastolic tissue Doppler velocity (E') septal (r = 0.42, P < 0.001), E' lateral (r = 0.35, P < 0.001), septal E/E' ratio (r = -0.35, P = 0.001), and lateral E/E' (r = -0.27, P < 0.001). These diastolic function parameters predicted impaired exercise capacity (VO(2) <19 mL/kg/min), with an area under the receiver operating characteristic curve of 0.77 (95% confidence interval [CI]: 0.68-0.86, P < 0.001) for septal E/E'. On multivariate analysis, for each unit increase in septal E/E' ratio there was a -0.35 (95% CI: -0.54 to -0.15) mL/kg/min decrease in peak VO(2) independently of age, sex, body mass index, hypertension, and diabetes. There was a mild correlation between peak VO(2) and systolic function parameters (r = 0.17, P = 0.01 with ejection fraction; and r = 0.23, P = 0.02 with lateral systolic tissue Doppler velocity) that persisted after multivariate adjustment. CONCLUSIONS: After AMI, resting diastolic function parameters were the strongest correlates of exercise tolerance. Septal E/E' ratio was the best echocardiographic predictor of reduced functional capacity. PMID- 25707583 TI - Pediatric Liver Transplant Recipients Who Undergo Transfer to the Adult Healthcare Service Have Good Long-Term Outcomes. AB - Liver transplantation has transformed survival for children with liver disease necessitating the transfer of a growing number of patients to the adult healthcare service. The impact of transfer on outcomes remains unclear. The aim of this single-center study of 137 consecutive pediatric liver transplant recipients was to examine the effect of transfer on patient and graft survival. The median time from transplant to transfer was 10.4 years and the median age of the patients at transfer was 18.6 years. After transfer, there were 5 re transplants and 12 deaths in 14 patients. The estimated posttransfer 10-year patient and graft survival was 89.9% and 86.2%, respectively. Overall, 4 patients demonstrated graft loss as a consequence of chronic rejection. Graft loss was associated with older age at first transplant (p = 0.008). When compared to young adult patients transplanted in the adult center, the transferred patients did not have inferior graft survival from the point of transfer (HR 0.28; 95% CI 0.10 0.77, p = 0.014). This suggests that transfer did not impact significantly on graft longevity. In conclusion, pediatric liver transplant recipients who undergo transfer to the adult service have good long-term outcomes. PMID- 25707584 TI - Tissue reaction to porcine intestinal Submucosa (CorMatrix) implants in pediatric cardiac patients: a single-center experience. AB - BACKGROUND: Decellularized porcine small intestine submucosa (CorMatrix, Atlanta, GA) patches have been used in the repair of congenital heart malformations. Tissue reaction to the material may create hemodynamic dysfunction and necessitate explantation. We reviewed our series of congenital cardiac patients who had a reoperation after the implantation of CorMatrix patches. METHODS: Medical records of pediatric cardiac patient who received CorMatrix patches and those of patients who underwent reoperation were reviewed. Routine histologic sections of explanted CorMatrix specimens were examined. RESULTS: Of 25 patients who had received CorMatrix patches during cardiac operations at our institution, 6 patients had undergone reoperations. All patients had hemodynamically significant lesions at the site of the CorMatrix implantation. Explanted specimens were associated with an intense inflammatory reaction consisting of numerous eosinophils, histiocytes, and plasma cells, with accompanying granulation tissue and fibrosis. CONCLUSIONS: Reaction to implanted CorMatrix patches may cause hemodynamic dysfunction and produce an intense, predominantly eosinophilic inflammatory response with developing fibrosis. Although our report is limited to a small sample of congenital cardiac patients, one should take precautions in its use in pediatric cardiac patients, and long-term follow-up is warranted. PMID- 25707585 TI - Outcomes in pediatric lung transplant recipients receiving adult allografts. AB - BACKGROUND: Clinical practice in the United States has no restrictions in allocating lungs from adult donors to pediatric recipients. METHODS: The United Network for Organ Sharing database was queried from 1987 to 2013 for pediatric lung transplant recipients (aged less than 18 years) to assess survival using continuous donor age in years and two donor age groups, >= 18 years and > 30 years, for analysis. RESULTS: Of 930 pediatric lung transplants, basic survival analysis identified a mortality hazard when adult lung allografts were transplanted into pediatric recipients; however, multivariate Cox models demonstrated that continuous donor age (hazard ratio [HR] 1.004, 95% confidence interval [CI]: 0.992-1.015, p = 0.524) as well as both categoric age groups, donor 18 years or older (HR 0.967, 95% CI: 0.714-1.309, p = 0.827) and donor older than 30 years (HR 1.168, 95% CI: 0.815-1.673, p = 0.398), did not significantly influence the risk for death. Moreover, propensity score matching analysis confirmed a lack of association of mortality risk with donor age >= 18 years (HR 1.129, 95% CI: 0.696-1.831, p = 0.623) and donor age > 30 years (HR 1.050, 95% CI: 0.569-1.937, p = 0.876). Bronchiolitis obliterans syndrome (BOS) was found to be a significant predictor of mortality in univariate analysis (HR 2.033, 95% CI: 1.639-2.521, p < 0.001), but the hazard of BOS did not vary across donor age categories. CONCLUSIONS: Adult donor lung allografts appear not to negatively affect survival in pediatric lung transplant recipients when considering confounders, and do not influence survival through an increased hazard for the development of BOS. PMID- 25707586 TI - Similar outcome in insulin-dependent and noninsulin-dependent diabetic patients after off-pump coronary artery bypass grafting with multiple skeletonized arterial conduits. AB - BACKGROUND: We were interested in whether current multiarterial off-pump coronary artery bypass graft surgery can improve the clinical outcome for insulin dependent diabetes mellitus patients. METHODS: Between January 2002 and December 2013, 1,064 consecutive patients underwent isolated off-pump coronary artery bypass surgery at our hospital; 551 of these patients had diabetes. Of these 551 patients, 166 had insulin-dependent diabetes (IDM) and the remaining 385 had noninsulin-dependent diabetes (NIDM). The propensity score was calculated to achieve one-to-two matching sets (IDM 143 versus NIDM 286). RESULTS: Ten patients (3.5%) in the NIDM group and 2 patients (1.4%) in the IDM group died in hospital (p = 0.18). Insulin dependency was not an independent risk factor for any early death or major complications. Follow-up was complete for 96.5% of the patients, with a mean follow-up of 4.6 +/- 3.8 years. Overall survival rate at 10 years was 76.3% for the NIDM group and 73.1% for the IDM group (p = 0.79). The rate of 10 year actuarial freedom from major adverse cardiac events was 89.6% in the NIDM group and 86.3% in the IDM group (p = 0.72). Multivariate Cox proportional hazard regression analysis revealed that female sex, congestive heart failure, previous myocardial infarction, lower ejection fraction, and at least one major complication were independent risk factors for combined cardiac events. Insulin dependency did not affect any outcome in the long term. CONCLUSIONS: Early and long-term outcomes after off-pump skeletonized multiarterial coronary artery bypass graft surgery were similar among the IDM and NIDM patients. PMID- 25707587 TI - The survival benefit of simultaneous heart-kidney transplantation extends beyond dialysis-dependent patients. AB - BACKGROUND: This study evaluated the effect of simultaneous heart-kidney transplantation (SHK) on survival stratified by preoperative renal function. METHODS: Patients undergoing SHK or heart transplant alone (HTA) between 1992 and 2012 were identified in the United Network for Organ Sharing database. Patients were primarily stratified by the need for dialysis before transplantation. Nondialysis patients were further stratified by preoperative glomerular filtration rate (GFR) and likelihood of postoperative development of renal failure requiring new-onset dialysis (high risk defined as >=75th percentile according to a previously derived and validated risk score). The primary outcome was 5-year survival, evaluated by Kaplan-Meier and multivariable logistic regression analyses. RESULTS: Included were 665 (2%) SHK and 38,488 (98%) HTA patients. SHK improved 5-year survival in dialysis-dependent patients (69% vs 54%, p < 0.001), with no survival difference in patients with a preoperative GFR >=60 mL/min/1.73 m(2) (84% SHK vs 77% HTA, p = 0.34). In patients with a preoperative GFR of less than 60 mL/min/1.73 m(2), being high risk for postoperative new-onset dialysis discriminated those patients who would benefit from SHK (5-year survival low risk: 82% SHK vs 76% HTA, p = 0.27; 5-year survival high risk: 86% SHK vs 67% HTA, p < 0.001). Risk-adjusted analysis confirmed these findings. SHK comprised only 2.6% of heart transplants in patients with a preoperative GFR of less than 60 mL/min/1.73 m(2) who were at high risk for postoperative renal failure. CONCLUSIONS: SHK improves long-term survival not only in dialysis-dependent patients but also in patients with reduced preoperative GFR who are at high risk for postoperative new-onset dialysis. Expansion of SHK into this subset warrants further study, especially considering its low current utilization. PMID- 25707588 TI - Metabolomics study of Saw palmetto extracts based on 1H NMR spectroscopy. AB - Preparations containing Saw palmetto extracts are used in traditional medicine to treat benign prostatic hyperplasia. According to the European and the American Pharmacopoeias, the extract is obtained from comminuted Saw palmetto berries by a suitable extracting procedure using ethanol or supercritical carbon dioxide or a mixture of n-hexane and methylpentanes. In the present study an approach to metabolomics profiling using nuclear magnetic resonance (NMR) has been used as a finger-printing tool to assess the overall composition of the extracts. The phytochemical analysis coupled with principal component analysis (PCA) showed the same composition of the Saw palmetto extracts obtained with carbon dioxide and hexane with minor not significant differences for extracts obtained with ethanol. In fact these differences are anyhow lower than the batch-to-batch variability ascribable to the natural-occurring variability in the Saw palmetto fruits' phytochemical composition. The fingerprinting analysis combined with chemometric method, is a technique, which would provide a tool to comprehensively assess the quality control of Saw palmetto extracts. PMID- 25707589 TI - Three spirostanol saponins and a flavane-O-glucoside from the fresh rhizomes of Tupistra chinensis. AB - Four new compounds, including three new spirostanol saponins [tupistroside G-I (1 3)] and a new flavane-O-glucoside [tupichiside A (4)], together with ten known compounds, were isolated from the fresh rhizomes of Tupistra chinensis. The structures of the new compounds were elucidated by spectroscopic analysis and chemical evidence. All compounds were tested in vitro for their cytotoxic activities against the Human LoVo and BGC-823 cell lines, and six of them were found to possess potent cytotoxicity. Compounds 2, 8 and 9 showed significant cytotoxicity against the tested tumor cell lines with IC50 values ranging from 0.2 to 0.9MUM. PMID- 25707590 TI - Gas-phase intramolecular cyclization of argentinated N-allylbenzamides. AB - The fragmentations of argentinated N-allylbenzamides have been exhaustively studied through collision-induced dissociation and through deuterium labeling. The intriguing elimination of AgOH is certified as the consequence of intramolecular cyclization between terminal olefin and carbonyl carbon following proton transfer to carbonyl oxygen, rather than simple enolization of amide. Linear free energy correlations and density functional theory (DFT) calculations were performed to understand the competitive relationship between AgOH loss and AgH loss, which results from the 1,2-elimination of alpha-hydrogen (to the amido nitrogen) with the silver. PMID- 25707591 TI - Databases and web tools for cancer genomics study. AB - Publicly-accessible resources have promoted the advance of scientific discovery. The era of genomics and big data has brought the need for collaboration and data sharing in order to make effective use of this new knowledge. Here, we describe the web resources for cancer genomics research and rate them on the basis of the diversity of cancer types, sample size, omics data comprehensiveness, and user experience. The resources reviewed include data repository and analysis tools; and we hope such introduction will promote the awareness and facilitate the usage of these resources in the cancer research community. PMID- 25707592 TI - Web resources for model organism studies. AB - An ever-growing number of resources on model organisms have emerged with the continued development of sequencing technologies. In this paper, we review 13 databases of model organisms, most of which are reported by the National Institutes of Health of the United States (NIH; http://www.nih.gov/science/models/). We provide a brief description for each database, as well as detail its data source and types, functions, tools, and availability of access. In addition, we also provide a quality assessment about these databases. Significantly, the organism databases instituted in the early 1990s--such as the Mouse Genome Database (MGD), Saccharomyces Genome Database (SGD), and FlyBase--have developed into what are now comprehensive, core authority resources. Furthermore, all of the databases mentioned here update continually according to user feedback and with advancing technologies. PMID- 25707593 TI - Prorenin stimulates a pro-angiogenic and pro-inflammatory response in retinal endothelial cells and an M1 phenotype in retinal microglia. AB - Angiogenesis and inflammation are causative factors in the development of neovascular retinopathies. These processes involve the retinal endothelium and the retinal immune cells, microglia. The renin-angiotensin system contributes to retinal injury via the actions of the type 1 angiotensin receptor (AT1R). However, it has been suggested that prorenin, the initiator of the renin angiotensin system cascade, influences retinal injury independently from the AT1R. We evaluated whether prorenin induced a pro-angiogenic and pro-inflammatory response in retinal endothelial cells and a pro-inflammatory phenotype in retinal microglia. Primary cultures of retinal endothelial cells and microglia were studied. Rat recombinant prorenin (2 nmol/L) stimulated the proliferation and tubulogenesis of retinal endothelial cells; it increased the levels of pro angiogenic factors, vascular endothelial growth factor, angiopoietin-1, and tyrosine kinase with immunoglobulin and epidermal growth factor homology domains, and pro-inflammatory factors, intercellular adhesion molecule-1 and monocyte chemoattractant protein-1, relative to the controls. The messenger RNA levels of the (pro)renin receptor were also increased. These effects occurred in the presence of the AT1R blocker candesartan (10 MUmol/L) and the renin inhibitor aliskiren (10 MUmol/L). Microglia, which express the (pro)renin receptor, elicited an activated phenotype when exposed to prorenin, which was characterized by increased levels of intercellular adhesion molecule-1, monocyte chemoattractant protein-1, tumour necrosis factor-alpha, interleukin-6, and interleukin-1beta and by decreased levels of interleukin-10 and arginase-1 relative to controls. Candesartan did not influence the effects of prorenin on retinal microglia. In conclusion, prorenin has distinct pro-angiogenic and pro inflammatory effects on retinal cells that are independent of the AT1R, indicating the potential importance of prorenin in retinopathy. PMID- 25707594 TI - Clinicopathological characteristics of colorectal cancer presenting under the age of 50. AB - OBJECTIVE: Previous studies suggest that colorectal cancer (CRC) presenting at a young age tends to be advanced, proximally located and associated with a poor outcome. The aim of this study was to analyse characteristics of CRC in a cohort under the age of 50. METHOD: A single centre retrospective cohort study of consecutive patients under the age of 50 receiving potentially curative resection was performed. Clinical and pathological data was collected from a prospectively maintained cancer registry database. Of 2799 patients having CRC resections between 2002 and 2013, 103 patients (3.6%) were under 50, with full survival data available on 98 (3.5%). An additional 7 patients under 50 had inoperable disease. The proportion of patients under 50 was constant throughout the study period. A group of 98 consecutive patients over the age of 50 undergoing surgery for colorectal cancer in the same centre was used for comparison. Just 7 patients (7%) had pathologically verified FAP or Lynch syndrome, although there was a high suspicion of Lynch syndrome in further 3 patients. CONCLUSION: There was a higher proportion of rectal cancer in the under 50s (p < 0.0001), although there was no significant difference in the staging of the disease or lymph node positivity. There was a greater incidence of poor differentiation in the younger patients, but there was no effect on 5-year overall survival (71.4%) which is much higher than in the reported literature. The majority of colorectal cancers presenting under the age of 50 were sporadic, and a higher proportion of rectal cancer was observed compared with the older patients, and as compared to the published literature on younger CRC patients. This paper adds to the literature by demonstrating that despite advanced stage at presentation of colorectal cancer requiring extended surgery and multimodal treatment, this young age group experienced good overall survival. PMID- 25707595 TI - Quantification of Shear Deformations and Corresponding Stresses in the Biaxially Tested Human Myocardium. AB - One goal of cardiac research is to perform numerical simulations to describe/reproduce the mechanoelectrical function of the human myocardium in health and disease. Such simulations are based on a complex combination of mathematical models describing the passive mechanical behavior of the myocardium and its electrophysiology, i.e., the activation of cardiac muscle cells. The problem in developing adequate constitutive models is the shortage of experimental data suitable for detailed parameter estimation in specific functional forms. A combination of shear and biaxial extension tests with different loading protocols on different specimen orientations is necessary to capture adequately the direction-dependent (orthotropic) response of the myocardium. In most experimental animal studies, where planar biaxial extension tests on the myocardium have been conducted, the generated shear stresses were neither considered nor discussed. Hence, in this study a method is presented which allows the quantification of shear deformations and related stresses. It demonstrates an approach for experimenters as to how the generation of these shear stresses can be minimized during mechanical testing. Experimental results on 14 passive human myocardial specimens, obtained from nine human hearts, show the efficiency of this newly developed method. Moreover, the influence of the clamping technique of the specimen, i.e., the load transmission between the testing device and the tissue, on the stress response is determined by testing an isotropic material (Latex). We identified that the force transmission between the testing device and the specimen by means of hooks and cords does not influence the performed experiments. We further showed that in-plane shear stresses definitely exist in biaxially tested human ventricular myocardium, but can be reduced to a minimum by preparing the specimens in an appropriate manner. Moreover, we showed whether shear stresses can be neglected when performing planar biaxial extension tests on fiber-reinforced materials. The used method appears to be robust to quantify normal and shear deformations and corresponding stresses in biaxially tested human myocardium. This method can be applied for the mechanical characterization of any fiber-reinforced material using planar biaxial extension tests. PMID- 25707596 TI - Estimation of inlet flow rates for image-based aneurysm CFD models: where and how to begin? AB - Patient-specific flow rates are rarely available for image-based computational fluid dynamics models. Instead, flow rates are often assumed to scale according to the diameters of the arteries of interest. Our goal was to determine how choice of inlet location and scaling law affect such model-based estimation of inflow rates. We focused on 37 internal carotid artery (ICA) aneurysm cases from the Aneurisk cohort. An average ICA flow rate of 245 mL min(-1) was assumed from the literature, and then rescaled for each case according to its inlet diameter squared (assuming a fixed velocity) or cubed (assuming a fixed wall shear stress). Scaling was based on diameters measured at various consistent anatomical locations along the models. Choice of location introduced a modest 17% average uncertainty in model-based flow rate, but within individual cases estimated flow rates could vary by >100 mL min(-1). A square law was found to be more consistent with physiological flow rates than a cube law. Although impact of parent artery truncation on downstream flow patterns is well studied, our study highlights a more insidious and potentially equal impact of truncation site and scaling law on the uncertainty of assumed inlet flow rates and thus, potentially, downstream flow patterns. PMID- 25707597 TI - A teleostan homolog of catalase from black rockfish (Sebastes schlegelii): insights into functional roles in host antioxidant defense and expressional responses to septic conditions. AB - Antioxidative defense renders a significant protection against environmental stress in organisms and maintains the correct redox balance in cells, thereby supporting proper immune function. Catalase is an indispensable antioxidant in organisms that detoxifies hydrogen peroxides produced in cellular environments. In this study, we sought to molecularly characterize a homolog of catalase (RfCat), identified from black rockfish (Sebastes schlegelii). RfCat consists of a 1581 bp coding region for a protein of 527 amino acids, with a predicted molecular weight of 60 kD. The protein sequence of RfCat harbored similar domain architecture to known catalases, containing a proximal active site signature and proximal heme ligand signature, and further sharing prominent homology with its teleostan counterparts. As affirmed by multiple sequence alignments, most of the functionally important residues were well conserved in RfCat. Furthermore, our phylogenetic analysis indicates its common vertebrate ancestral origin and a close evolutionary relationship with teleostan catalases. Recombinantly expressed RfCat demonstrated prominent peroxidase activity that varied with different substrate and protein concentrations, and protected against DNA damage. RfCat mRNA was ubiquitously expressed among different tissues examined, as detected by qPCR. In addition, RfCat mRNA expression was modulated in response to pathogenic stress elicited by Streptococcus iniae and poly I:C in blood and spleen tissues. Collectively, our findings indicate that RfCat may play an indispensable role in host response to oxidative stress and maintain a correct redox balance after a pathogen invasion. PMID- 25707599 TI - Fatty acid composition, sarcoplasmic reticular lipid oxidation, and immunity of hard clam (Meretrix lusoria) fed different dietary microalgae. AB - Fatty acid profiles, activities of biomembrane lipid peroxidation, and immunity of a seawater clam (Meretrix lusoria) fed three species of dietary microalgae were investigated. Clams of a marketable size (25 g mean weight) were fed Tetraselmis chui, Chaetoceros muelleri, or Isochrysis galbana for 8 weeks. Fatty acids, particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), in the polar lipid fractions of clams reflected those of the dietary algae species. Clams fed with T. chui and C. muelleri contained higher proportion of non-methylene interrupted (NMI) fatty acids than those fed I. galbana. Proportion of DHA in lipids of the clams fed with I. galbana was the highest among test groups. The NADH-dependent sarcoplasmic reticular lipid peroxidation activity of clams fed I. galbana was significantly greater (p < 0.05) than that of clams fed T. chui or C. muelleri. The hemocyte adhesion capacity of clams fed C. muelleri or I. galbana was significantly higher (p < 0.05) than that of clams fed T. chui. No significant differences (p >= 0.05) in total hemocyte count, phenoloxidase activity, clearance efficiency hemocyte and phagocytosis were detected among clams fed different microalgae. PMID- 25707598 TI - An evaluation of replacing fish meal with fermented soybean meal in the diet of Macrobrachium nipponense: Growth, nonspecific immunity, and resistance to Aeromonas hydrophila. AB - Partial or complete replacement of fish meal (FM) with fermented soybean meal (FSM) was examined in Macrobrachium nipponense over an 8-week growth trial. Growth and immune characteristics were evaluated. Fermented soybean meal replaced 0 (FM, control), 25% (R25), 50% (R50), 75% (R75), or 100% of the FM (R100) in five isocaloric and isonitrogenous diets. Each diet was fed to juvenile prawns (mean weight, 0.103 +/- 0.0009 g) twice daily to apparent satiation in five replicates. Weight gain and specific growth rate of M. nipponense were significantly higher in prawns fed the R25 diet than that of prawns fed the FM diet. No significant differences were observed among the other treatments. Total hemocyte count and hemolymph phagocytic activity decreased as the proportion of FSM increased. Total antioxidant activity competence and malondialdehyde level in the hepatopancreas were highest in prawns fed the R100 diet. mRNA levels of the antioxidant genes Cu-Zn superoxide dismutase and catalase, heat shock cognate protein 70, and heat shock protein 90 were significantly differentially regulated in the prawn hepatopancreas. In addition, percent mortality increased after challenge with live Aeromonas hydrophila. Percent mortality of prawns fed the R100 diet was significantly higher than that of prawns fed the FM and R25 diets. These findings demonstrate that (1) M. nipponense growth performance was not affected by including a high proportion of FSM in the diet, and the best growth performance was obtained when 25% of the FM was replaced with FSM; (2) nonspecific immunity was impaired when all of the FM was replaced with FSM. PMID- 25707600 TI - Antimicrobial response is increased in the testis of European sea bass, but not in gilthead seabream, upon nodavirus infection. AB - Antimicrobial peptides (AMPs) have a crucial role in the fish innate immune response, being considered a fundamental component of the first line of defence against pathogens. Moreover, AMPs have not been studied in the fish gonad since this is used by some pathogens as a vehicle or a reservoir to be transmitted to the progeny, as occurs with nodavirus (VNNV), which shows vertical transmission through the gonad and/or gonadal fluids, but no study has looked into the gonad of infected fish. In this framework, we have characterized the antimicrobial response triggered by VNNV in the testis of European sea bass, a very susceptible species of the virus, and in the gilthead seabream, which acts as a reservoir, both in vivo and in vitro, and compared with that present in the serum and brain (target tissue of VNNV). First, our data show a great antiviral response in the brain of gilthead seabream and in the gonad of European sea bass. In addition, for the first time, our results demonstrate that the antimicrobial activities (complement, lysozyme and bactericidal) and the expression of AMP genes such as complement factor 3 (c3), lysozyme (lyz), hepcidin (hamp), dicentracin (dic), piscidin (pis) or beta-defensin (bdef) in the gonad of both species are very different, but generally activated in the European sea bass, probably related with the differences of susceptibility upon VNNV infection, and even differs to the brain response. Furthermore, the in vitro data suggest that some AMPs are locally regulated playing a local immune response in the gonad, while others are more dependent of the systemic immune system. Data are discussed in the light to ascertain their potential role in viral clearance by the gonad to avoid vertical transmission. PMID- 25707601 TI - Different impact of heat-inactivated and viable lactic acid bacteria of aquatic origin on turbot (Scophthalmus maximus L.) head-kidney leucocytes. AB - In aquaculture, several criteria should be considered to select an appropriate probiotic, including the aquatic origin and safety of the strain and its ability to modulate the host immune response. The properties and effects of probiotics are strain-specific and some factors such as viability, dose and duration of diet supplementation may regulate their immunomodulatory activities. In this study, we assessed the in vitro effect of eight heat-inactivated and viable lactic acid bacteria (LAB) of aquatic origin belonging to the genera Enterococcus, Lactobacillus, Lactococcus, Leuconostoc, Pediococcus and Weissella on the viability and innate immune response of turbot (Scophthalmus maximus L.) leucocytes. Head-kidney leucocytes were incubated with viable and heat inactivated LAB at different concentrations. After incubation, the viability of leucocytes was evaluated using colorimetric assays (MTT and LDH) and flow cytometry (annexin V/propidium iodide). Heat-inactivated LAB showed no cytotoxic effect while viable LAB exerted variable influence on apoptosis of turbot phagocytes and lymphocytes. Leucocyte respiratory burst activity and phagocytosis were also differentially activated, as viable LAB stimulated leucocytes more efficiently than the heat-inactivated LAB. Our results suggest diverse strain specific mechanisms of interaction between the evaluated LAB and turbot leucocytes. Furthermore, our work sets up in vitro systems to evaluate the effect of LAB as potential probiotics, which will be useful to develop efficient screening. PMID- 25707602 TI - Association and Promoter Analysis of AVPR1A in Finnish Autism Families. AB - The arginine vasopressin receptor 1A gene (AVPR1A) is known to affect social communication and has been reported to associate with autism in several studies. Given that the microsatellite RS1 and a few SNPs in the promoter region of the AVPR1A have repeatedly associated with several traits, including autism it is rather surprising that the molecular explanation for these associations has remained unknown, although it has been reported that the allele length of the AVPR1A microsatellites might affect disease risk. Here we carried out an extended association analysis of three microsatellites and 12 tag single nucleotide polymorphisms (SNPs) in and around the AVPR1A gene in 205 Finnish families followed by promoter analysis. FBAT version v2.0.3 was used for family-based genetic association analyses of AVPR1A microsatellites and SNPs. The nearby microsatellite RS1 was found to harbor the best association. Interestingly, there are two potentially relevant transcription factor (TF) binding sites at RS1: for MEF2C and PBX, predicted with the Match algorithm in the TRANSFAC database. Sequence variations changing the affinity of these TFs might partly explain the AVPR1A promoter region associations shown in autism. PMID- 25707603 TI - Use of multivariate statistical techniques for the evaluation of temporal and spatial variations in water quality of the Kaduna River, Nigeria. AB - Multivariate statistical techniques, such as cluster analysis (CA) and principal component analysis/factor analysis (PCA/FA), were used to investigate the temporal and spatial variations and to interpret large and complex water quality data sets collected from the Kaduna River. Kaduna River is the main tributary of Niger River in Nigeria and represents the common situation of most natural rivers including spatial patterns of pollutants. The water samples were collected monthly for 5 years (2008-2012) from eight sampling stations located along the river. In all samples, 17 parameters of water quality were determined: total dissolved solids (TDS), pH, Thard, dissolved oxygen (DO), 5-day biochemical oxygen demand (BOD5), chemical oxygen demand (COD), NH4-N, Cl, SO4, Ca, Mg, total coliform (TColi), turbidity, electrical conductivity (EC), HCO3 (-), NO3 (-), and temperature (T). Hierarchical CA grouped 12 months into two seasons (dry and wet seasons) and classified eight sampling stations into two groups (low- and high pollution regions) based on seasonal differences and different levels of pollution, respectively. PCA/FA for each group formed by CA helped to identify spatiotemporal dynamics of water quality in Kaduna River. CA illustrated that water quality progressively deteriorated from headwater to downstream areas. The results of PCA/FA determined that 78.7 % of the total variance in low pollution region was explained by five factor, that is, natural and organic, mineral, microbial, organic, and nutrient, and 87.6 % of total variance in high pollution region was explained by six factors, that is, microbial, organic, mineral, natural, nutrient, and organic. Varifactors obtained from FA indicated that the parameters responsible for water quality variations are resulted from agricultural runoff, natural pollution, domestic, municipal, and industrial wastewater. Mann-Whitney U test results revealed that TDS, pH, DO, T, EC, TColi, turbidity, total hardness (THard), Mg, Ca, NO3 (-), COD, and BOD were identified as significant variables affecting temporal variation in river water, and TDS, EC, and TColi were identified as significant variables affecting spatial variation. In addition, box-whisker plots facilitated and supported multivariate analysis results. This study illustrates the usefulness of multivariate statistical techniques for classification and processing of large and complex data sets of water quality parameters, identification of latent pollution factors/sources and their spatial-temporal variations, and determination of the corresponding significant parameters in river water quality. PMID- 25707604 TI - Metal concentrations in irrigation canals and the Nile River in an intensively exploited agricultural area. AB - Concentrations of major and trace elements (Al, Fe, Mn, B, Cd, Co, Cr, Cu, Mo, Ni, Pb, Sr, V, and Zn) were determined in water and sediments from irrigation canals and the Nile River in an agricultural area of 120 km(2) to evaluate the impact of agricultural practices and the spatial distribution and mobility of these elements. The enrichment factors of cadmium indicate contamination in this area. Metal pollution indices are higher at locations downstream of the irrigation canals, possibly a consequence of waste discharges and phosphate fertilizing. Comparisons with consensus-based sediment quality guidelines revealed that ~92 % (Cr), ~85 % (Cu), ~46 % (Ni), and ~23 % (Zn) of the samples exceeded the threshold effect concentrations, with 7.7 % for Cr and Ni being above the probable effect concentration. Contamination with many metals in water was found in the secondary irrigation canals. The partition coefficients of all determined metals were evaluated. The major elements Al, Fe, and Mn were found to be very mobile while V was the least mobile. PMID- 25707605 TI - Use of new technologies to notify possible contagion of sexually-transmitted infections among men. AB - BACKGROUND: Among men who have sex with men (MSM), the association between searching for sexual partners' on the Internet and increased risk of sexually transmitted infections (STIs)/HIV infection, together with current low levels of partner notification (PN), justifies a study to explore the intention to use new communication technologies for PN in Spain. METHODS: Two cross-sectional surveys were performed: the first was administered online to visitors to web pages where the survey was advertised; the second was administered on paper to patients attending an STI Unit and centres similar to Community-Based Voluntary Counselling and Testing centres. RESULTS: The study population comprised 1578 Spanish residents (median age, 34 years [range: 18 to 74]); 84% lived in urban areas, and 69% reported searching for sexual partners on the Internet. Thirty seven per cent would be willing to use a website for PN, 26% did not know if they would use one, and 37% would not want to use one. The main reasons for not intending to notify STI/HIV were "shame or fear" (stable partner) and "not knowing how to contact them" (casual partner). The preferred method of notification was face to face (73%) for both stable and casual partners, although using new technologies (Short Messaging System, e-mail, web page, phone applications) was widely accepted for notifying casual partners. CONCLUSIONS: Fighting stigma and promoting alternative methods of PN among MSM and health professionals through new technologies could increase the frequency of PN. This approach will improve early detection and reduce transmission in Spain. PMID- 25707609 TI - Association between serum ligands and the skin toxicity of anti-epidermal growth factor receptor antibody in metastatic colorectal cancer. AB - Skin toxicity is a known clinical signature used to predict the prognosis of anti epidermal growth factor receptor (EGFR) antibody treatment in metastatic colorectal cancer (mCRC). There are no biological markers to predict skin toxicity before anti-EGFR antibody treatment in mCRC patients. Between August 2008 and August 2011, pretreatment serum samples were obtained from KRAS wild type (WT) patients who received anti-EGFR antibody treatment. Serum levels of ligands were measured by ELISA. A total of 103 KRAS WT patients were enrolled in the study. Progression-free survival and overall survival of patients with a high grade (grade 2-3) of skin toxicity were significantly longer than those with a low grade (grade 0-1) of skin toxicity (median progression-free survival, 6.4 months vs 2.4 months, P < 0.001; median overall survival, 14.6 months vs 7.1 months, P = 0.006). There were significant differences in distribution of serum levels of epiregulin (EREG), amphiregulin (AREG), and hepatocyte growth factor (HGF) between groups of low/high grade of skin toxicity (P < 0.048, P < 0.012, P < 0.012, respectively). In addition, serum levels of HGF, EREG, and AREG were inversely proportional to grades of skin toxicity as determined by the Cochran Armitage test (P = 0.019, P = 0.047, P = 0.021, respectively). Our study indicated that serum levels such as HGF, EREG, and AREG may be significant markers to predict the grade of skin toxicity and the prognosis of anti-EGFR antibody treatment, which contribute to improvement of the management of skin toxicity and survival time in mCRC patients. PMID- 25707610 TI - Clinical Benefit and Health-Related Quality of Life Assessment in Patients Treated with Cisplatin/S-1 Versus Cisplatin/5-FU: Secondary End Point Results From the First-Line Advanced Gastric Cancer Study (FLAGS). AB - PURPOSE: Patient-reported outcomes (PRO) of health-related quality of life (HRQoL) and time to worsening of clinical benefit parameters were evaluated as secondary end points in the phase 3 first-line advanced gastric cancer study (FLAGS) trial of cisplatin/S-1 versus cisplatin/5-fluorouracil (5-FU) in patients with previously untreated advanced gastric cancer. METHODS: The primary PRO end point was the Trial Outcome Index of the Functional Assessment of Cancer Therapy Gastric (FACT-Ga). FACT-Ga was completed at the beginning of the first 4 cycles, cycle 6, and then every 3 cycles thereafter. The Chemotherapy Convenience and Satisfaction Questionnaire (CCSQ) was administered before the first 4 cycles; clinical benefit parameters (performance status, weight loss, and anorexia) were assessed at baseline, prior to study drug administration on day 1 of each cycle after cycle 1, and at the end of study treatment. RESULTS: Compliance to questionnaire fulfillment was more than 80 % through cycle 9. Significantly, fewer patients treated with cisplatin/S-1 reported worsened physical well-being (PWB) scores (45.1 versus 51.7 %, p = 0.044) and experienced significantly longer time to worsening in PWB scores, with a median of 4.5 months (95 % confidence interval (CI), 3.1-5.1) compared to 3.0 months (2.8-4.6) with cisplatin/5-FU (CF) (p = 0.01). Patients receiving cisplatin/S-1 also reported significantly higher best and worst score of PWB as well as CCSQ scores and a longer median time to worsening in clinical benefit parameters. CONCLUSIONS: Differences in secondary end points of PWB, CCSQ scores, and clinical benefit parameters favoring the cisplatin/S-1 arm provide further evidence for considering this combination a standard therapeutic option for first-line treatment of advanced gastric cancer. PMID- 25707612 TI - Ligand design in gold catalysis and chemistry of gold-oxonium intermediates. AB - Gold catalysis is considered one of the most important breakthroughs in organic synthesis during the last decade. Many gold-catalyzed reactions suffer from high catalyst loading, which is a serious limitation on the application of gold catalysis in larger scale synthesis. Because ligands play a major role in the tuning of reactivity of transition metal catalysts, there has been an increased effort on rationally understanding ligand effects in gold catalysis and using a rational ligand design to achieve higher efficiency. In the first part of this chapter, selected examples of ligand design in gold catalysis are discussed. In the second part, the chemistry of gold-oxonium intermediate is examined. An oxonium intermediate is generated when a oxygen nucleophile (ketone, aldehyde, or ether) attacks a cationic gold-activated multiple bond. This oxonium intermediate, being a highly energetic species, has the potential to undergo further transformations such as electron transfer/rearrangement/protodeauration to form diverse products. PMID- 25707611 TI - The Effect of Discontinuing Treatment With Blosozumab: Follow-up Results of a Phase 2 Randomized Clinical Trial in Postmenopausal Women With Low Bone Mineral Density. AB - Administration of blosozumab, a humanized monoclonal antibody that binds sclerostin, increases bone formation and bone mineral density (BMD) in postmenopausal women with low BMD. To evaluate the effect of discontinuing blosozumab, we studied women enrolled in a 1-year randomized, placebo-controlled phase 2 trial for an additional year after they completed treatment. Of the 120 women initially enrolled in the study, 106 women completed treatment and continued into follow-up; 88 women completed 1 year of follow-up. At the beginning of follow-up, groups remained balanced for age, race, and body mass index, but lumbar spine and total hip BMD were increased in prior blosozumab groups, reflecting an anabolic treatment effect. At the end of follow-up, 1 year after discontinuing treatment, lumbar spine BMD remained significantly greater than placebo in women initially treated with blosozumab 270 mg every 2 weeks (Q2W) and blosozumab 180 mg Q2W (6.9% and 3.6% above baseline, respectively). Total hip BMD also declined after discontinuation of treatment but at 1 year after treatment remained significantly greater than placebo in women initially treated with blosozumab 270 mg Q2W and blosozumab 180 mg Q2W (3.9% and 2.6% above baseline, respectively). During follow-up, median serum P1NP was not consistently different between the prior blosozumab groups and placebo. A similar pattern was apparent for median serum C-terminal telopeptide of type 1 collagen (CTx) levels, with more variability. Mean serum total sclerostin concentration increased with blosozumab, indicating target engagement, and declined to baseline after discontinuation. There were no adverse events considered related to prior treatment with blosozumab. Anti-drug antibodies generally declined in patients who had detectable levels during prior treatment. These findings support the continued study of blosozumab as an anabolic therapy for treatment of osteoporosis. PMID- 25707613 TI - Protein chemical synthesis in drug discovery. AB - The discovery of novel therapeutics to combat human disease has traditionally been among the most important goals of research chemists. After a century of innovation, state-of-the-art chemical protein synthesis is now capable of efficiently assembling proteins of up to several hundred residues in length from individual amino acids. By virtue of its unique ability to incorporate non-native structural elements, chemical protein synthesis has been seminal in the recent development of several novel drug discovery technologies. In this chapter, we review the key advances in peptide and protein chemistry which have enabled our current synthetic capabilities. We also discuss the synthesis of D-proteins and their applications in mirror image phage-display and racemic protein crystallography, the synthesis of enzymes for structure-based drug discovery, and the direct synthesis of homogenous protein pharmaceuticals. PMID- 25707614 TI - New methods for chemical protein synthesis. AB - Chemical protein synthesis is a useful tool to generate pure proteins which are otherwise difficult to obtain in sufficient amounts for structure and property analysis. Additionally, because of the precise and flexible nature of chemical synthesis, it allows for controllable variation of protein sequences, which is valuable for understanding the relationships between protein structure and function. Despite the usefulness of chemical protein synthesis, it has not been widely adopted as a tool for protein characterization, mainly because of the lack of general and efficient methods for the preparation and coupling of peptide fragments and for the folding of polypeptide chains. To address these issues, many new methods have recently been developed in the areas of solid-phase peptide synthesis, peptide fragment assembly, and protein folding. Here we review these recent technological advances and highlight the gaps needing to be addressed in future research. PMID- 25707616 TI - Sialoside Arrays: New Synthetic Strategies and Applications. AB - Sialic acid-containing carbohydrates, or sialosides, play critical roles in many biological events and in diseases, including viral and bacterial infections, the immune response, the progression of tumor cell metastasis, etc. Despite the importance, the limited access to complex sialosides had prevented extensive studies on the function and significance of sialic acid structural diversity. However, recent advances in synthetic sialoside chemistry, such as the novel chemoenzymatic or stereochemical approach, have produced homogeneous size- and structure-defined sialosides to create diverse sialosides for array application. The advantage of sialoside arrays is the multivalent display of arrayed sialosides which can serve to mimic cell surface display; thus, an array-based technique is well suited for investigations of the real sialoside-mediated interactions in nature. In brief, this chapter discusses the novel strategies for synthesizing sialosides with selected examples of applications to illustrate the potential of sialoside arrays and further forecast to the trend of using nanotechnology in sialoside arrays. PMID- 25707617 TI - Surface Hopping Dynamics with DFT Excited States. AB - Nonadiabatic dynamics simulation of electronically-excited states has been a research area of fundamental importance, providing support for spectroscopy, explaining photoinduced processes, and predicting new phenomena in a variety of specialties, from basic physical-chemistry, through molecular biology, to materials engineering. The demands in the field, however, are quickly growing, and the development of surface hopping based on density functional theory (SH/DFT) has been a major advance in the field. In this contribution, the surface hopping approach, the methods for computation of excited states based on DFT, the connection between these methodologies, and their diverse implementations are reviewed. The shortcomings of the methods are critically addressed and a number of case studies from diverse fields are surveyed. PMID- 25707618 TI - [Nation-wide questionnaire of cathether use in Germany]. AB - BACKGROUND: Despite the costs that the national health care system faces with regard to treatment of urinary incontinence and related use of urinary catheters, only limited research has been focused on the subject. In collaboration with the German Association of Urologists, we conducted an online-based survey to learn more about the use of urinary catheters and the care of patients in the outpatient setting. METHODS: A comprehensive online survey consisting of 26 questions was sent to all members of the "German Federation of Urologists" (Berufsverband der Deutschen Urologen) in an e-mail. The participation was anonymous and participants were able to complete the survey only once. Data analysis was carried out by the survey provider. RESULTS: Of the 1407 urologists to whom the survey was sent, 482 answered the survey and 406 (84%) responded to all the questions. According to the survey the replacement of urinary catheters is most commonly carried out by the urologist (59%). The replacement of a catheter is usually performed in the urologists' office (59%). In an emergency setting, patients with an obstructed or displaced catheter are most likely to be taken to the nearest hospital where qualified personnel are on duty and can assist. For long-term urinary drainage in male patients, the suprapubic catheter is the primary choice (61%). In female patients, suprapubic and transurethral catheters are more evenly distributed (36% vs. 31%). CONCLUSION: The response rate of 34% to the survey indicates that there is an interest in this topic. The results of the survey suggest that patient care involving a urinary catheter in Germany is subject to heterogeneous indications and standards of care. The management of patients with urinary catheters continues to be a responsibility of the urologist. PMID- 25707619 TI - [Researchers network kick-off GeSRU Academics]. PMID- 25707620 TI - Connecting rules from paired miRNA and mRNA expression data sets of HCV patients to detect both inverse and positive regulatory relationships. AB - BACKGROUND: Intensive research based on the inverse expression relationship has been undertaken to discover the miRNA-mRNA regulatory modules involved in the infection of Hepatitis C virus (HCV), the leading cause of chronic liver diseases. However, biological studies in other fields have found that inverse expression relationship is not the only regulatory relationship between miRNAs and their targets, and some miRNAs can positively regulate a mRNA by binding at the 5' UTR of the mRNA. RESULTS: This work focuses on the detection of both inverse and positive regulatory relationships from a paired miRNA and mRNA expression data set of HCV patients through a 'change-to-change' method which can derive connected discriminatory rules. Our study uncovered many novel miRNA-mRNA regulatory modules. In particular, it was revealed that GFRA2 is positively regulated by miR-557, miR-765 and miR-17-3p that probably bind at different locations of the 5' UTR of this mRNA. The expression relationship between GFRA2 and any of these three miRNAs has not been studied before, although separate research for this gene and these miRNAs have all drawn conclusions linked to hepatocellular carcinoma. This suggests that the binding of mRNA GFRA2 with miR 557, miR-765, or miR-17-3p, or their combinations, is worthy of further investigation by experimentation. We also report another mRNA QKI which has a strong inverse expression relationship with miR-129 and miR-493-3p which may bind at the 3' UTR of QKI with a perfect sequence match. Furthermore, the interaction between hsa-miR-129-5p (previous ID: hsa-miR-129) and QKI is supported with CLIP Seq data from starBase. Our method can be easily extended for the expression data analysis of other diseases. CONCLUSION: Our rule discovery method is useful for integrating binding information and expression profile for identifying HCV miRNA mRNA regulatory modules and can be applied to the study of the expression profiles of other complex human diseases. PMID- 25707622 TI - Melatonin-mediated inhibition of Purkinje neuron P-type Ca2+ channels in vitro induces neuronal hyperexcitability through the phosphatidylinositol 3-kinase dependent protein kinase C delta pathway. AB - Although melatonin receptors are widely expressed in the mammalian central nervous system and peripheral tissues, there are limited data regarding the functions of melatonin in cerebellar Purkinje cells. Here, we identified a novel functional role of melatonin in modulating P-type Ca(2+) channels and action potential firing in rat Purkinje neurons. Melatonin at 0.1 MUm reversibly decreased peak currents (I(Ba)) by 32.9%. This effect was melatonin receptor 1 (MT(R1)) dependent and was associated with a hyperpolarizing shift in the voltage dependence of inactivation. Pertussis toxin pretreatment, intracellular application of QEHA peptide, and a selective antibody raised against the Gbeta subunit prevented the inhibitory effects of melatonin. Pretreatment with phosphatidylinositol 3-kinase (PI3K) inhibitors abolished the melatonin-induced decrease in I(Ba). Surprisingly, melatonin responses were not regulated by Akt, a common downstream target of PI3K. Melatonin treatment significantly increased protein kinase C (PKC) activity 2.1-fold. Antagonists of PKC, but not of protein kinase A, abolished the melatonin-induced decrease in I(Ba). Melatonin application increased the membrane abundance of PKCdelta, and PKCdelta inhibition (either pharmacologically or genetically) abolished the melatonin-induced IBa response. Functionally, melatonin increased spontaneous action-potential firing by 53.0%; knockdown of MT(R1) and blockade of P-type channels abolished this effect. Thus, our results suggest that melatonin inhibits P-type channels through MT(R1) activation, which is coupled sequentially to the betagamma subunits of G(i/o)-protein and to downstream PI3K-dependent PKCdelta signaling. This likely contributes to its physiological functions, including spontaneous firing of cerebellar Purkinje neurons. PMID- 25707621 TI - The genome of Leishmania panamensis: insights into genomics of the L. (Viannia) subgenus. AB - Kinetoplastid parasites of the Leishmania genus cause several forms of leishmaniasis. Leishmania species pathogenic to human are separated into two subgenera, Leishmania (Leishmania) and L. (Viannia). Species from the Viannia subgenus cause predominantly cutaneous leishmaniasis in Central and South America, occasionally leading to more severe clinical presentations. Although the genomes of several species of Leishmania have been sequenced to date, only one belongs to this rather different subgenus. Here we explore the unique features of the Viannia subgenus by sequencing and analyzing the genome of L. (Viannia) panamensis. Against a background of conservation in gene content and synteny, we found key differences at the genomic level that may explain the occurrence of molecular processes involving nucleic acid manipulation and differential modification of surface glycoconjugates. These differences may in part explain some phenotypic characteristics of the Viannia parasites, including their increased adaptive capacity and enhanced metastatic ability. PMID- 25707623 TI - Beta-blocker therapy and prognosis of heart failure patients with new-onset diabetes mellitus. AB - BACKGROUND: The influence of beta-blocker therapy (bisoprolol or carvedilol) (bB) on the prognosis of heart failure (HF) patients with diabetes mellitus (DM) is uncertain. AIMS: To assess the effect of bB on the prognosis of HF patients with new-onset DM treated with a contemporary medical regime. METHODS: Prospective study of 5314 HF patients with previously unknown DM. Mean age was 71.8+/-7.9 years, 53.0% were women, and 50.2% had HF with preserved ejection fraction (HFpEF). During a median follow-up of 56.9+/-18.2 months, 68.9% of the patients died, 88.6% were hospitalised for HF, and 1519 (27.3%) developed DM (62.3% of them received bB, 947 patients). We propensity-matched 572 HF patients with DM on bB, with 572 HF patients with DM non-treated with bB. RESULTS: Beta-blocker therapy was associated with a decreased hazard risk (HR) of all-cause death [HR: 0.68, CI 95% (0.61-0.75)], mainly because of a reduced risk of death from cardiovascular causes [HR: 0.70 (0.64-0.77)] (p<0.001). Similarly, bB was associated with a decreased HR of hospitalisation [HR: 0.82 (0.72-0.92)] (p<0.001). Nevertheless, the 30-day re-admission rate and the number of visits were not significantly associated with bB. These relationships of bB with prognosis were maintained, independently of the gender, the type of HF (HFpEF ot HFdEF), the comorbidities and the medication used (p<0.01). CONCLUSION: Therapy with bB, bisoprolol or carvedilol, is associated with a reduced mortality and morbidity of HF patients with new-onset DM, not only in men but also in women, as well as in patients with HFpEF or HFdEF. PMID- 25707624 TI - Randomised clinical trial: safety, tolerability, pharmacokinetics and pharmacodynamics of repeated doses of TAK-438 (vonoprazan), a novel potassium competitive acid blocker, in healthy male subjects. AB - BACKGROUND: TAK-438 (vonoprazan) is a potassium-competitive acid blocker that reversibly inhibits gastric H(+) , K(+) -ATPase. AIM: To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of TAK-438 in healthy Japanese and non-Japanese men. METHODS: In two Phase I, randomised, double-blind, placebo-controlled studies, healthy men (Japan N = 60; UK N = 48) received TAK 438 10-40 mg once daily at a fixed dose level for 7 consecutive days. Assessments included safety, tolerability, pharmacokinetics and pharmacodynamics (intragastric pH). RESULTS: Plasma concentration-time profiles of TAK-438 at all dose levels showed rapid absorption (median Tmax <=2 h). Mean elimination half life was up to 9 h. Exposure was slightly greater than dose proportional, with no apparent time-dependent inhibition of metabolism. There was no important difference between the two studies in AUC0-tau on Day 7. TAK-438 caused dose dependent acid suppression. On Day 7, mean 24-h intragastric pH>4 holding time ratio (HTR) with 40 mg TAK-438 was 100% (Japan) and 93.2% (UK), and mean night time pH>4 HTR was 100% (Japan) and 90.4% (UK). TAK-438 was well tolerated. The frequency of adverse events was similar at all dose levels and there were no serious adverse events. There were no important increases in serum alanine transaminase activity. Serum gastrin and pepsinogen I and II concentrations increased with TAK-438 dose. CONCLUSIONS: TAK-438 in multiple rising oral dose levels of 10-40 mg once daily for 7 days was safe and well tolerated in healthy men and caused rapid, profound and sustained suppression of gastric acid secretion throughout each 24-h dosing interval. Clinicaltrials.gov identifiers: NCT02123953 and NCT02141711. PMID- 25707625 TI - Gynaecological cancer: New standard of care-HPV testing for cervical cancer screening. PMID- 25707626 TI - Targeted therapies: Hippo effector YAP1 inhibition-towards a new therapeutic option to overcome drug resistance. PMID- 25707627 TI - Neuroendocrine cancer: SELECT-lenvatinib in thyroid cancer. PMID- 25707631 TI - A framework for a personalized surgical approach to ovarian cancer. AB - The standard approach for the treatment of advanced-stage ovarian cancer is upfront cytoreductive surgery followed by a combination of platinum-based and taxane-based chemotherapy. The extent of residual disease following upfront cytoreductive surgery correlates with objective response to adjuvant chemotherapy, rate of pathological complete response at second-look assessment operations, and progression-free survival and overall survival. Contemporary data and meta-analyses indicate a correlation between volume of residual disease and patient outcome, with those patients undergoing complete gross resection having the best outcomes. Thus, attention has focused on surgical efforts to remove as much disease as possible with the metric of 'optimal' cytoreduction being R0 disease. Because patients with R0 resection seem to have the best overall outcomes, preoperative or intraoperative assessment to avoid unnecessary primary debulking surgery has become common. The use of serum CA-125 levels, physical examination and CT imaging have lacked accuracy in determining if disease can be optimally debulked. Therefore, an algorithm that identifies patients in whom complete gross resection at primary surgery is likely to be achieved would be expected to improve patient survival. We discuss contemporary definitions of 'optimal' residual disease, and opportunities to personalize surgical therapy and improve the quality of surgical care. PMID- 25707632 TI - Clustering PPI data by combining FA and SHC method. AB - Clustering is one of main methods to identify functional modules from protein protein interaction (PPI) data. Nevertheless traditional clustering methods may not be effective for clustering PPI data. In this paper, we proposed a novel method for clustering PPI data by combining firefly algorithm (FA) and synchronization-based hierarchical clustering (SHC) algorithm. Firstly, the PPI data are preprocessed via spectral clustering (SC) which transforms the high dimensional similarity matrix into a low dimension matrix. Then the SHC algorithm is used to perform clustering. In SHC algorithm, hierarchical clustering is achieved by enlarging the neighborhood radius of synchronized objects continuously, while the hierarchical search is very difficult to find the optimal neighborhood radius of synchronization and the efficiency is not high. So we adopt the firefly algorithm to determine the optimal threshold of the neighborhood radius of synchronization automatically. The proposed algorithm is tested on the MIPS PPI dataset. The results show that our proposed algorithm is better than the traditional algorithms in precision, recall and f-measure value. PMID- 25707633 TI - Isolation and characterization of an early colonizing Rhizobium sp. R8 from a household toilet bowl. AB - The bacterial community structure was compared between the third days', one week', and three weeks' biofilm samples from the surface of a household toilet bowl. It was found that the PCR-DGGE band pattern of 16S rRNA gene was dramatically changed after the third day and was not further changed until three weeks. This result suggests that there are early and late colonizing bacterial groups. One of the early colonizers isolated from the third days' sample was Rhizobium sp. R8, a closest relative to Rhizobium giardinii, which exhibited the highest biofilm formation activity in an artificial urine condition. R8 produced extracellular polysaccharides containing galactose, glucose, and mannose at the molar ratio of 8:1:1, which were probably responsible for the biofilm formation. Its excelled biofilm formation and urease activities together with the lack of nodulation and nitrogen fixing genes in R8 suggest that this strain has been specifically adapted to urine condition in a toilet bowl. PMID- 25707634 TI - Suicide among doctors. PMID- 25707635 TI - Forensic psychiatry after 22 July 2011. PMID- 25707636 TI - [Stigmatizing drug ad]. PMID- 25707637 TI - [Galderma replies]. PMID- 25707638 TI - [Re: Paternalism on the rise?]. PMID- 25707639 TI - [A. Syse replies]. PMID- 25707641 TI - [Re: The core journal as a work tool?]. PMID- 25707642 TI - [J. Haffner replies]. PMID- 25707643 TI - [Re: Femoral fracture and temporomandibular joint destruction following the use of bisphosphonates]. PMID- 25707644 TI - [Re: Is it obesity or weight focus that is harmful?]. PMID- 25707645 TI - [E. Meland & G.B. Samdal reply]. PMID- 25707646 TI - [Re: A woman in her nineties with acute peritonitis]. PMID- 25707647 TI - [Orion Pharma Scandinavia reply]. PMID- 25707648 TI - [Dumping syndrome following gastric surgery]. PMID- 25707649 TI - [Influenza vaccination in pregnancy]. PMID- 25707650 TI - Infrared spectroscopy is the gold standard for kidney stone analysis. PMID- 25707651 TI - [Continued sales of paracetamol in stores]. PMID- 25707652 TI - [Better drug treatment of elderly]. PMID- 25707655 TI - Assessment of causal associations between illness and criminal acts in those who are acquitted by reason of insanity. AB - BACKGROUND: The court proceedings after the terrorist attacks on 22 July 2011 reignited the debate on the justification for having a rule that regulates the insanity defence exclusively on the basis of a medical condition - the medical principle. The psychological principle represents an alternative that requires a causal relationship between the psychosis and the acts committed. In this article we investigate rulings made by the courts of appeal where the accused have been found legally insane at the time of the act, and elucidate the extent to which a causal relationship between the illness and the act appears to be in evidence. MATERIAL AND METHOD: Data have been retrieved from rulings by the courts of appeal published at lovdata.no, which include anonymised rulings. Searches were made for cases under Section 39 (verdict of special sanctions) and Section 44 (acquittal by reason of insanity) of the General Civil Penal Code. Court rulings in which a possible causal relationship could be considered were included. The included rulings were carefully assessed with regard to whether a causal relationship existed between the mental disorder of the accused at the time and the criminal act. The search returned a total of 373 rulings, of which 75 were included. RESULTS: The vast majority of the charges referred to serious crimes. Diagnoses under ICD-10 category codes F20-29 (schizophrenia, schizotypal and delusional disorders) were the most frequently occurring type. In 17 of the 75 rulings (23%), it was judged that no causal relationship between the illness and the act existed. In 25 of 26 cases that involved homicide, a causal relationship between the illness and the act was judged to be evident. INTERPRETATION: The data may indicate that the medical principle results in impunity in a considerable number of rulings where the illness of the accused apparently has had no effect on the acts committed. PMID- 25707656 TI - [Fatigue in patients following traumatic brain injury and stroke]. AB - BACKGROUND: Fatigue may be defined as an experience of long-term or recurrent tiredness and reduced capacity for mental and/or physical activity, and is common following acquired brain injury. This article provides an overview of the status of knowledge on fatigue following stroke and traumatic brain injury. MATERIAL AND METHOD: An assessment of the existing literature, including a literature search, as well as the authors' own clinical experience form the basis for the content of this article. RESULTS: Existing studies use varying definitions of fatigue and apply different survey tools. The prevalence of fatigue following stroke or traumatic brain injury is uncertain due to varying inclusion criteria and survey methods, and because different times of measurement can result in different prevalence figures. Several studies estimate the prevalence to be between 50 and 70%. Our knowledge of the pathologic mechanisms is very limited; premorbid, sociodemographic, stroke/trauma-related and comorbid factors all play a role in the experience of fatigue. Therapeutic interventions include psychoeducation, regulation of activity, physical exercise and treatment of comorbid conditions. Trials have also been conducted on drug treatment, so far without convincing results. INTERPRETATION: Fatigue occurs frequently in stroke patients and patients with traumatic brain injuries, and often significantly restricts daily functioning for these patients. Our knowledge of pathologic mechanisms and evidence with regard to therapeutic interventions is deficient, and the patient population is heterogeneous. The treatment is adapted to the individual and its objective is to enable individuals to use their limited capacity in the most appropriate way possible. PMID- 25707657 TI - [Fluctuating carotid tumor]. PMID- 25707658 TI - [A man in his 60s that unexpectedly and dramatically attempts suicide]. PMID- 25707659 TI - [A woman in her fifties with neck pain and increased sedimentation rate]. AB - BACKGROUND: Spondylitis in the upper cervical spine can have an insidious onset, with symptoms mimicking low-grade infections or common musculoskeletal disorders. Some patients have neurological symptoms, and if untreated, the outcome may be fatal. CASE PRESENTATION: A woman in her fifties had general malaise, weight loss and neck pain over 6-8 weeks. Her sedimentation rate was elevated, and she developed bulbar symptoms. Biopsy and culture samples were harvested endoscopically from the prevertebral area in the C1-C2 region, and confirmed our preliminary diagnosis of localised infection. She was treated with high-dose antibiotics and rigid collar immobilisation until stability of the cervical spine was ascertained. INTERPRETATION: It is difficult to make a differential diagnosis between spondylitis, rheumatoid inflammation and malignancy in the upper cervical spine. Adequate histologic and bacterial culture samples must if possible be obtained from the prevertebral area. This is best achieved transnasally or transorally, under endoscopic and radiological guidance. The neck must be stabilised and patients must have long-term antibiotic treatment followed by permanent neck fixation if indicated. PMID- 25707660 TI - [An unusual cause of back pain]. PMID- 25707661 TI - [When elderly take their own lives--does it matter?]. PMID- 25707666 TI - [Do physicians need more sick leave?]. PMID- 25707673 TI - IAOseq: inferring abundance of overlapping genes using RNA-seq data. AB - BACKGROUND: Overlapping transcription constitutes a common mechanism for regulating gene expression. A major limitation of the overlapping transcription assays is the lack of high throughput expression data. RESULTS: We developed a new tool (IAOseq) that is based on reads distributions along the transcribed regions to identify the expression levels of overlapping genes from standard RNA seq data. Compared with five commonly used quantification methods, IAOseq showed better performance in the estimation accuracy of overlapping transcription levels. For the same strand overlapping transcription, currently existing high throughput methods are rarely available to distinguish which strand was present in the original mRNA template. The IAOseq results showed that the commonly used methods gave an average of 1.6 fold overestimation of the expression levels of same strand overlapping genes. CONCLUSIONS: This work provides a useful tool for mining overlapping transcription levels from standard RNA-seq libraries. IAOseq could be used to help us understand the complex regulatory mechanism mediated by overlapping transcripts. IAOseq is freely available at http://lifecenter.sgst.cn/main/en/IAO_seq.jsp. PMID- 25707674 TI - Ion-pair chromatography coupled to inductively coupled plasma-mass spectrometry (IPC-ICP-MS) as a method for thiomolybdate speciation in natural waters. AB - Molybdenum precipitates preferentially under reducing conditions; therefore, its occurrence in sediment records is used as an indicator of paleoredox conditions. Although thiomolybdates (MoO4-xSx(2-) with x = 1-4) supposedly are necessary intermediates in the process of molybdenum precipitation under anoxic conditions, there is no information about their abundance in natural environments, because of a lack of element-specific methods with sufficiently low detection limits. Here, we optimized ion-pair chromatographic separation for coupling to an inductively coupled plasma-mass spectrometry detector (IPC-ICP-MS). 2-Propanol (10%-25% gradient) replaced the previously used acetonitrile (25%-75%) as the solvent, to reduce the carbon load into the plasma. In synthetic solutions, formation of thiomolybdates was found to occur spontaneously in the presence of excess sulfide and the degree of thiolation was highest at pH 7. Excess hydroxyl led to a transformation of thiomolybdates to molybdate. Under acidic to neutral conditions, precipitation of molybdenum and hydrolysis of tetrathiomolybdate were observed. Flash-freezing was found to be suitable to stabilize tetrathiomolybdate, with <4% transformation over more than two months. High ionic strengths matrices (>2 mM) negatively affected the detection of molybdate, which eluted mainly in the dead volume, but had no negative effect on higher thiolated molybdates. Detection limits were ~10 nM. With the newly developed IPC-ICP-MS method, thiomolybdates were found to form spontaneously in euxinic marine waters after adding a molybdate spike and occur naturally in sulfidic geothermal waters. PMID- 25707675 TI - When a child dies: pediatric oncologists' follow-up practices with families after the death of their child. AB - OBJECTIVES: Follow-up practices with bereaved families are considered a part of good medical care, yet little is known about pediatric oncologists' protocol with families when their patients die. The objective of this study was to examine follow-up practices employed by pediatric oncologists after patient death using an in-depth qualitative analysis. METHODS: The Grounded Theory method of data collection and analysis was used. Twenty-one pediatric oncologists at two Canadian pediatric hospitals were interviewed about their follow-up practices with bereaved families after patients died. Line-by-line coding was used to establish codes and themes, and constant comparison was used to establish relationships among emerging codes and themes. RESULTS: Pediatric oncologists actively engage in follow-up practices that include making phone calls, sending an email or condolence card, attending funerals or visitations, having long-term and short-term meetings with parents, and attending hospital or departmental memorials for the deceased child. Attending funerals or visitations was less frequent and varied widely across pediatric oncologists. Reasons for not participating in bereavement follow-up practices included logistical, emotional, and practical considerations. CONCLUSIONS: While the majority of pediatric oncologists at two Canadian centers engage in some follow-up practices with bereaved families, these practices are complex and challenging because of the emotional nature of these interactions. Medical institutions should provide both structured time for this follow-up work with families, as well as medical education and financial and emotional support to pediatric oncologists who continue caring for these families long after their child has died. PMID- 25707676 TI - Electro-assembly of a chromophore-catalyst bilayer for water oxidation and photocatalytic water splitting. AB - The use of electropolymerization to prepare electrocatalytically and photocatalytically active electrodes for water oxidation is described. Electropolymerization of the catalyst Ru(II)(bda)(4-vinylpyridine)2 (bda=2,2' bipyridine-6,6'-dicarboxylate) on planar electrodes results in films containing semirigid polymer networks. In these films there is a change in the water oxidation mechanism compared to the solution analogue from bimolecular to single site. Electro-assembly construction of a chromophore-catalyst structure on mesoporous, nanoparticle TiO2 films provides the basis for a dye-sensitized photoelectrosynthesis cell (DSPEC) for sustained water splitting in a pH 7 phosphate buffer solution. Photogenerated oxygen was measured in real-time by use of a two-electrode cell design. PMID- 25707677 TI - First report of acute lymphoblastic leukemia in an Egyptian child with beta thalassemia major. AB - beta-Thalassemia (beta-thal) is the most common hereditary anemia in humans. With improvement of treatment protocols, patients are living longer and new complications have emerged. Few articles have reported the occurrence of malignancies among patients with beta-thal in different parts of the world. We herein report the first pediatric patient with beta-thal major (beta-TM), who developed acute lymphoblastic leukemia in Egypt with analysis of the different theories of pathogenesis. PMID- 25707678 TI - Prevalence of Hb S (HHB: c.20A > T) in a Honduran population of African descent. AB - Sickle cell disease is the most common hemoglobinopathy worldwide, particularly in Africa and among people of African descent. Serious clinical consequences characterize the homozygous condition. To determine the prevalence of Hb S (HBB: c.20A > T) and anemia in a community of people of African descent from Honduras, 202 individuals were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The high prevalence found indicates that it is necessary to implement a program to prevent the consequences of this disease in vulnerable populations of Honduras. PMID- 25707679 TI - Genetic determinants of beta-thalassemia intermedia in Pakistan. AB - This study covers the molecular characterization of clinically diagnosed beta thalassemia intermedia (beta-TI) patients in Pakistan. Blood samples of beta-TI patients were collected from all four provinces of Pakistan throughout the period of 2011-2013. The study was carried out using allele-specific primers through polymerase chain reaction or sequencing to determine both alpha- and beta thalassemia (alpha- and beta-thal) mutations, and restriction enzymes for the characterization of beta-globin gene arrangements. In a total of 63 patients, the IVS-I-5 (G > C) was the most frequent mutation (33.88%). The codon 30 (G > A) and IVS-II-1 (T > C) mutations were found only in the Punjabi ethnic group, while the codon 30 (G > C) and Hb S (HBB: c.20A > T) mutations were found only in the Pashtoon and Sindhi ethnic groups, respectively. In case of alpha-globin genotypes, 44 patients were normal (alphaalpha/alphaalpha), six patients carried the alphaalpha/-alpha(3.7) genotype, 12 patients carried the -alpha(3.7)/ alpha(3.7) genotype, while one patient had the alphaalpha/alphaalphaalpha(anti 3.7) genotype. We found that haplotype I was the most frequent, mostly associated with the codons 8/9 (+G) mutation, while the Saudi haplotype was found only with Hb S. PMID- 25707680 TI - Vulvar endometriosis and Nuck canal. AB - AIM: Endometriosis is not a well-known disease and sometimes its rare onset is a pathogenetic, diagnostic and therapeutic problem. The Canal of Nuck is an embryonal rest of the parietal peritoneum that accompanies the round ligament through the inguinal canal. The perviousness of the canal of Nuck could explain the pathogenesis of vulvar endometriosis. MATERIAL OF STUDY: We reported a case of vulvar endometriosis localization, which is rather uncommon, in a patient previously operated on with cyst of Nuck. DISCUSSION: One of the most helpful instrumental exams in defining the nature of vulvar swallows is magnetic resonance, but it remains difficult to diagnose vulvar endometriosis in spite of the instrumental exam in our possession. The hypothesis of retrograde menstruation is supported by the fact that ovarian localization is the most common in this disease. Extra-pelvic localization as well as vulvar one are less common. The Canal of Nuck is an embryonal rest of the parietal peritoneum that accompanies the round ligament through the inguinal canal. CONCLUSIONS: Endometriosis could be taken into consideration in differential diagnosis of vulvar swellings, and for this reason it is necessary to carry out a histological exam in every operated vulvar neoformation. We suggest vaginalis-peritonei duct contamination as a possible pathogenesis mechanism of this disease. PMID- 25707681 TI - Bioinspired modification of h-BN for high thermal conductive composite films with aligned structure. AB - With the development of microelectronic technology, the demand of insulating electronic encapsulation materials with high thermal conductivity is ever growing and much attractive. Surface modification of chemical inert h-BN is yet a distressing issue which hinders its applications in thermal conductive composites. Here, dopamine chemistry has been used to achieve the facile surface modification of h-BN microplatelets by forming a polydopamine (PDA) shell on its surface. The successful and effective preparation of h-BN@PDA microplatelets has been confirmed by SEM, EDS, TEM, Raman spectroscopy, and TGA investigations. The PDA coating increases the dispersibility of the filler and enhances its interaction with PVA matrix as well. Based on the combination of surface modification and doctor blading, composite films with aligned h-BN@PDA are fabricated. The oriented fillers result in much higher in-plane thermal conductivities than the films with disordered structures produced by casting or using the pristine h-BN. The thermal conductivity is as high as 5.4 W m(-1) K(-1) at 10 vol % h-BN@PDA loading. The procedure is eco-friendly, easy handling, and suitable for the practical application in large scale. PMID- 25707682 TI - Science and technology roadmap for graphene, related two-dimensional crystals, and hybrid systems. AB - We present the science and technology roadmap for graphene, related two dimensional crystals, and hybrid systems, targeting an evolution in technology, that might lead to impacts and benefits reaching into most areas of society. This roadmap was developed within the framework of the European Graphene Flagship and outlines the main targets and research areas as best understood at the start of this ambitious project. We provide an overview of the key aspects of graphene and related materials (GRMs), ranging from fundamental research challenges to a variety of applications in a large number of sectors, highlighting the steps necessary to take GRMs from a state of raw potential to a point where they might revolutionize multiple industries. We also define an extensive list of acronyms in an effort to standardize the nomenclature in this emerging field. PMID- 25707683 TI - In vitro embryos production after oocytes treatment with forskolin. AB - The inhibition of nuclear maturation allows time for the oocyte to accumulate molecules that are important for embryonic development. Thus, the objective of this work was to evaluate the effect of blocking oocyte meiosis with the addition of forskolin, an efficient inhibitor of nuclear maturation, in in vitro maturation (IVM) medium. Forskolin was added to the IVM medium for 6 h at concentrations of 0.1 mM, 0.05 mM or 0.025 mM, then the oocytes were allowed to mature in drug-free medium for 18 h. The oocytes were assessed for the stage of nuclear maturation, the activity and distribution of mitochondria, oocyte ultrastructure, the number of viable cells and the apoptosis rate. After forskolin treatment, the oocytes were fertilized in vitro and cultured for 7 days. On day 7, the blastocyst rate, the ultrastructure, the number of intact cells and the apoptosis rate of the blastocysts were measured. No differences were observed for the stage of nuclear maturation of the oocyte, the mitochondrial activity and distribution, the blastocyst rate or total number of intact cells. However, a higher rate of apoptosis was observed in the blastocysts produced from oocytes blocked for 6 h with the higher concentration of forskolin (P < 0.05). We conclude that all the experimental groups reached the MII stage after the addition of forskolin and that the highest concentration of forskolin caused cellular degeneration without harming embryo production on the 7th day. PMID- 25707684 TI - Contribution of autoallergy to the pathogenesis in the NOD mice. AB - The immunoglobulin isotype IgE is commonly associated with allergy. However, its involvement in autoimmune disease in general, and Type 1 diabetes (T1D) in particular, is still not completely clarified, nonetheless IgE has been observed in patients with T1D. In this article, we aimed to elucidate the contribution of IgE in the pathogenesis of the disease in a spontaneous model for T1D, i.e. the NOD mouse. We observed increased levels of IgE in splenic, lymph node and peripheral blood B cells in the NOD mice compared to the control C57BL/6 (B6) mice. No correlation was found between the IgE levels on B cells and those in the sera of these mice, indicating a B cell intrinsic property mediating IgE capture in NOD. Functionally, the B cells from NOD were similar to B6 in rescuing the IgE mediated immune response via the low affinity receptor CD23 in a transgenic adoptive transfer system. However, the involvement of IgE in diabetes development was clearly demonstrated, as treatment with anti-IgE antibodies delayed the incidence of the diabetes in the NOD mice compared to the PBS treated group. Pancreas sections from a 13-week-old NOD revealed the presence of tertiary lymphoid structures with T cells, B cells, germinal centers and IgE suggesting the presence of autoantigen specific IgE. Our study provides an insight to the commonly overlooked immunoglobulin IgE and its potential role in autoimmunity. PMID- 25707685 TI - STAT1 single nucleotide polymorphisms and susceptibility to immune thrombocytopenia. AB - Primary immune thrombocytopenia (ITP) is an acquired autoimmune bleeding disorder. One of the key mediators of IFN-gamma signaling is the signal transducer and activator of transcription 1 protein (STAT1). We evaluated the relationship between STAT1 gene single nucleotide polymorphisms (SNPs) and the associated risk of ITP in a prospective case-control study. A total of 548 children were recruited: 328 children with ITP and 220 healthy children as sex- and age-matched normal controls. The Sequenom MassArray system (Sequenom, San Diego, CA) was used to detect three SNPs genotypes in the STAT1 gene: rs10208033, rs12693591, and rs1467199. There is a statistically significant difference in STAT1 rs1467199 allele frequencies with comparison of each of the four clinical subgroups of ITP patients to the normal controls (p = 0.0432). Also, newly diagnosed ITP patients and chronic ITP patients demonstrate significant different genotypes (chi(2 )= 8.511, p = 0.0142) and allelic frequency (p = 0.0055). Although a positive STAT1 rs1467199 genotype subgroups to the STAT1 mRNA expression level cannot be established, there is a weak correlation between STAT1 mRNA level and the activity ratio of Type 1 T helper lymphocyte and Type 2 T helper lymphocyte (Th1/Th2 ratio) (p = 0.0544); correlation with IFN-gamma alone did not reach statistical significance (p = 0.1715). The findings in our study suggest that STAT1 rs1467199 SNP plays a potential role in the IFN-gamma dependent development of autoimmunity in children with ITP. The important clinical implication of STAT1 SNPs testing as a predictor of pediatric chronic ITP will be validated in future molecular and protein functional analysis. PMID- 25707686 TI - Association of joint erosion with SLC22A4 gene polymorphisms inconsistently associated with rheumatoid arthritis susceptibility. AB - Two single-nucleotide polymorphisms (SNPs) in SLC22A4 encoding an organic cation/zwitterion transporter protein, rs2073838 (commonly called slc2F1) and rs3792876 (slc2F2), had been associated with susceptibility to rheumatoid arthritis (RA) in two Japanese and one recent Chinese studies but not in other two Japanese and six Caucasian studies. In this study, the two SNPs were genotyped for 2313 Korean participants and their associations with RA susceptibility and severity were examined. SNP association with RA susceptibility was tested among 1304 RA patients and 1009 healthy controls, and association with joint erosion among 1063 erosive and 241 non-erosive RA patients. Meta-analysis for RA susceptibility association was additionally performed using 10 previous studies and the current one. The two SNPs were almost perfectly correlated with each other (r(2 )= 0.98), and therefore only slc2F1 was tested for association. RA susceptibility association was not found in Koreans (p = 0.93), but still significant in meta-analysis of six Asian studies including this Korean study (p = 0.00036, odds ratio = 1.1) or all 11 studies additionally including five Caucasian studies (p = 0.00021, odds ratio = 1.1). In contrast, an association was found for RA severity in Koreans. The minor allele A was marginally associated with 1.5-fold increased risk of joint erosion among RA patients afflicted for <=11 years (p = 0.025) or <=7 years (p = 0.029), though not among patients with longer-standing RA. Accordingly, SLC22A4 was associated with joint erosion in not-very-longstanding RA, although RA susceptibility association was weak and its clinical significance was uncertain. PMID- 25707687 TI - Selected biologic markers of inflammation and activity of Crohn's disease. AB - The study aimed to compare the accuracy of selected biologic markers in assessing the disease activity in patients with Crohn's disease (CD). The analysis included serum IL-2, IL-6, IL-17, TNF-alpha, IFN-gamma, hsCRP, peripheral CD4 + CD25 + FOXP3 + regulatory T cells, as well as fecal calprotectin and lactoferrin. A group of 55 adults with CD was enrolled to the study. Disease activity was assessed using Crohn's Disease Endoscopic Index of Severity (CDEIS), which currently represents the gold standard for the evaluation of endoscopic activity. For clinical activity scoring, the Crohn's Disease Activity Index (CDAI) was used. Concentrations of investigated markers were estimated by means of flow cytometry and enzyme-linked immunosorbent assays, and the results were correlated with both indices. The study demonstrated that both fecal markers, i.e. calprotectin (r = 0.827, p < 0.001) and lactoferrin (r = 0.704, p < 0.001), correlate closely with CDEIS score, and might be used to evaluate the severity of CD in clinical setting. The correlation of those markers with CDAI was also significant, with r = 0.742 for calprotectin (p < 0.001) and r = 0.675 for lactoferrin (p < 0.05). As for the other investigated markers, only hsCRP (r = 0.672, p < 0.001) and IL-17 (r = 0.296, p < 0.005) correlated closely with CDEIS. The correlation of the markers with CDAI was also significant, though weaker, with r = 0.518 for hsCRP (p < 0.001) and r = 0.296 for IL-17 (p < 0.05). The study showed that IL-17, despite its vague role in the pathogenesis of CD, might be a useful marker, comparable with hsCRP, in assessing the activity of the disease. PMID- 25707688 TI - Positron emission tomography/ultrasound fusion technique in patients with malignant melanoma. AB - (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET)/CT is commonly used to assess tumour recurrence in high-risk patients with malignant melanoma (MM). However, results can be ambiguous either because of the CT's insufficient soft-tissue contrast or non-specific FDG accumulation caused by inflammation. Ultrasound (US) can provide additional morphologic information that is superior to CT. For precisely combining PET and US findings, we used a real-time fusion technique based on navigated US (PET/US fusion). Here, we describe our results from patients where PET/US fusion proved helpful in differentiating unclear PET/CT findings. This fusion technique is likely to be helpful for decision making in MM patients and biopsy guidance. PMID- 25707689 TI - Effects of maternal and lactational exposure to 2-hydroxy-4-methoxybenzone on development and reproductive organs in male and female rat offspring. AB - BACKGROUND: 2-Hydroxy-4-methoxybenzophenone (HMB) is an ultraviolet (UV) absorbing compound used in many cosmetic products as a UV-protecting agent and in plastics for preventing UV-induced photodecomposition. HMB has been detected in over 95% of randomly collected human urine samples from adults and from premature infants, and it may have estrogenic potential. METHODS: To determine the effects of maternal and lactational exposure to HMB on development and reproductive organs of offspring, time-mated female Harlan Sprague-Dawley rats were dosed with 0, 1000, 3000, 10,000, 25,000, or 50,000 ppm HMB (seven to eight per group) added to chow from gestation day 6 until weaning on postnatal day (PND) 23. RESULTS AND CONCLUSION: Exposure to HMB was associated with reduced body and organ weights in female and male offspring. No significant differences were observed in the number of implantation sites/litter, mean resorptions/litter, % litters with resorptions, number and weights of live fetuses, or sex ratios between the control and HMB dose groups. Normalized anogenital distance in male pups at PND 23 was decreased in the highest dose group. Spermatocyte development was impaired in testes of male offspring in the highest dose group. In females, follicular development was delayed in the highest dose group. However, by evaluating levels of the compound in rat serum, the doses at which adverse events occurred are much higher than usual human exposure levels. Thus, exposure to less than 10,000 ppm HMB does not appear to be associated with adverse effects on the reproductive system in rats. PMID- 25707690 TI - Transcription factor and microRNA-regulated network motifs for cancer and signal transduction networks. AB - BACKGROUND: Molecular networks are the basis of biological processes. Such networks can be decomposed into smaller modules, also known as network motifs. These motifs show interesting dynamical behaviors, in which co-operativity effects between the motif components play a critical role in human diseases. We have developed a motif-searching algorithm, which is able to identify common motif types from the cancer networks and signal transduction networks (STNs). Some of the network motifs are interconnected which can be merged together and form more complex structures, the so-called coupled motif structures (CMS). These structures exhibit mixed dynamical behavior, which may lead biological organisms to perform specific functions. RESULTS: In this study, we integrate transcription factors (TFs), microRNAs (miRNAs), miRNA targets and network motifs information to build the cancer-related TF-miRNA-motif networks (TMMN). This allows us to examine the role of network motifs in cancer formation at different levels of regulation, i.e. transcription initiation (TF -> miRNA), gene-gene interaction (CMS), and post-transcriptional regulation (miRNA -> target genes). Among the cancer networks and STNs we considered, it is found that there is a substantial amount of crosstalking through motif interconnections, in particular, the crosstalk between prostate cancer network and PI3K-Akt STN.To validate the role of network motifs in cancer formation, several examples are presented which demonstrated the effectiveness of the present approach. A web-based platform has been set up which can be accessed at: http://ppi.bioinfo.asia.edu.tw/pathway/. It is very likely that our results can supply very specific CMS missing information for certain cancer types, it is an indispensable tool for cancer biology research. PMID- 25707691 TI - Evaluation of the in vitro alpha-glucosidase inhibitory activity of green tea polyphenols and different tea types. AB - BACKGROUND: The objective of this study was to determine whether green tea, black tea and oolong tea have inhibitory potential against alpha-glucosidase which may be used to control postprandial hyperglycemia in type 2 diabetes mellitus. RESULTS: Green tea polyphenols (TPs) strongly inhibited alpha-glucosidase activity by non-competitive inhibition with an IC50 value of 2.33 ug mL(-1) and the inhibitory effect was dependent on TP concentration and incubation order. Green tea, black tea and oolong tea also had dose-dependent inhibitory potential with IC50 values of 2.82, 2.25 and 1.38 ug mL(-1) (ug polyphenol mL(-1)), respectively. The study also showed that the content of unprecipitated TPs changed during enzymatic hydrolysis, leading to the change of the antioxidant activity. The change of the antioxidant activity of tea extracts revealed a similar trend to that of green TPs during enzymatic hydrolysis. CONCLUSION: Green TPs, green tea, black tea and oolong tea are excellent alpha-glucosidase inhibitors and their inhibitory potency is mainly attributed to TPs. These findings suggest that green tea, black tea and oolong tea can potentially be used to control postprandial hyperglycemia. PMID- 25707692 TI - Vaccination status and immune response to 13-valent pneumococcal conjugate vaccine in asplenic individuals. AB - Overwhelming post-splenectomy infection (OPSI) is immediately life-threatening and vaccination against encapsulated bacteria, in particular pneumococci, decreases its incidence. First, we investigated the adherence to vaccination guidelines in a retrospective study of the hospital records of splenectomised patients. Second, patients were asked to complete a questionnaire and invited to participate in a study where 12-valent pneumococcal serotype-specific IgG concentrations were determined before and 4 to 6 weeks after vaccination with PCV13. Of 79 individuals who underwent splenectomy between 2000 and 2012: 81.0% received pneumococcal vaccine, 51.9% received vaccine against Haemophilus influenzae type B and 22.8% received meningococcal vaccine. 31 individuals were deceased. 33 individuals completed questionnaires and accepted participation in the second part of the study. The participants consisted of two groups: (1) prior PPV23 (n=24) and (2) prior PPV23+PCV13 (n=9). In group 1, pre-PCV13 GMC's>=0.35MUg/mL were observed for serotypes 1, 4, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F, and GMC's<0.35MUg/mL for serotypes 3 and 5, significant increases pre- to post-PCV13 were found for serotypes 1, 3, 4, 5, 7F, 18C, 19A, 23F (p<=0.001) and 19F (p=0.01) and all 12 serotypes-specific GMC were above 0.35MUg/mL after vaccination. Group 2 did not receive vaccine in this study, but blood tests showed all 12 serotype-specific GMC>0.35MUg/mL. Adherence to guidelines regarding primary pneumococcal vaccination was adequate but only a minority received the recommended meningococcal vaccination. High levels of pneumococcal serotype specific antibodies were observed in the previous PPV23 vaccinated group, and more pronounced in the previous PCV13 group, and our data suggests that PCV13 is immunogenic for serotypes 1, 3, 4, 5, 7F, 18C, 19A, 19F and 23F, if used as a booster dose in asplenic patients with previous PPV23 vaccination. PMID- 25707693 TI - A randomized phase I study of the safety and immunogenicity of three ascending dose levels of a 3-antigen Staphylococcus aureus vaccine (SA3Ag) in healthy adults. AB - BACKGROUND: Staphylococcus aureus is a common cause of healthcare-acquired morbidity and mortality and increased healthcare resource utilization. A prophylactic vaccine is being developed that may reduce this disease burden. METHODS: Volunteers in good general health aged 50-85 (n=312) and 18-24 (n=96) years were randomized to receive a single intramuscular dose of one of three dose levels of a non-adjuvanted, 3-antigen S. aureus vaccine (SA3Ag) or placebo. SA3Ag antigens included capsular polysaccharides 5 and 8 (CP5 and CP8), each conjugated to cross-reactive material 197 (CRM197), and recombinant clumping factor A (ClfA). Safety, tolerability, and immunogenicity were evaluated. RESULTS: At day 29 post-vaccination, robust immune responses were observed in both age cohorts at all three SA3Ag dose levels. In the primary analysis population, the 50- to 85 year age stratum, geometric mean-fold-rises in competitive Luminex((r)) immunoassay antibody titers from baseline ranged from 29.2 to 83.7 (CP5), 14.1 to 31.0 (CP8), and 37.1 to 42.9 (ClfA), all (P<0.001) exceeding the pre-defined two fold rise criteria. Similar rises in opsonophagocytic activity assay titers demonstrated functionality of the immune response. Most injection-site reactions were mild in severity and there were no substantial differences (SA3Ag vs. placebo) with regard to systemic or adverse events. CONCLUSIONS: In this study of healthy adults aged 50-85 and 18-24 years, SA3Ag elicited a rapid and robust immune response and was well tolerated, with no notable safety concerns. PMID- 25707694 TI - Immune responses following meningococcal serogroups A, C, Y and W polysaccharide vaccination in C2-deficient persons: evidence for increased levels of serum bactericidal antibodies. AB - Complement C2 deficiency (C2D) is associated with immunological diseases and increased susceptibility to invasive infections caused by encapsulated bacteria such as Neisseria menigitidis. In this study we evaluate the immunogenicity of vaccination against N. menigitidis in C2D. C2D patients (n=22) and controls (n=52) were given a tetravalent meningococcal polysaccharide vaccine. Serum bactericidal antibody (SBA) titres (serogroups A, C, Y and W) were analysed using a rabbit complement source. Levels of IgG, IgM, and IgA, factor B, and factor H, polymorphisms of MBL and Fc-gamma receptors were determined. The C2D patients responded with an increased SBA titre to all four serogroups (p<0.001). The response rates define as SBA titres >=8 were found to be between 85.7% and 92.5%. The post-vaccination titres for serogroups C, Y and W were equal to healthy controls. C2D patients with a history of invasive infection had a lower post vaccination SBA titres both compared to healthy C2D persons (p=0.03) and compared to controls (p<0.0001). We found that the G2M*n/G2M*n genotype were associated with a higher SBA titres after immunization (p=0.03). None of the other investigated immunological factors appear to be important in influencing the vaccine responses. Autoimmune diseases in C2D did not affect the vaccine response. In general, vaccination against meningococci gave rise to antibody responses in the C2D patients that equal healthy controls. The response rate was lower to serogroup A and among C2D patients with history of invasive infections. The presence of G2M*n/G2M*n genotype was associated with higher SBA titres after immunization. PMID- 25707695 TI - Effect of supercooling and cell volume on intracellular ice formation. AB - Intracellular ice formation (IIF) has been linked to death of cells cryopreserved in suspension. It has been assumed that cells can be supercooled by 2 to 10 degrees C before IIF occurs, but measurements of the degree of supercooling that cells can tolerate are often confounded by changing extracellular temperature and solutions of different osmolality (which affect the cell volume). The purpose of this study was to examine how the incidence of IIF in the absence of cryoprotectants is affected by the degree of supercooling and cell volume. Human umbilical vein endothelial cells were suspended in isotonic (300 mOsm) and hypertonic (~600 to 700 mOsm) solutions and exposed to supercooling ranging from 2 to 10 degrees C before extracellular ice was nucleated. The number of cells undergoing IIF was examined in a cryostage (based on the darkening of cells upon intracellular freezing ("flashing")) as a function of the degree of supercooling, and cell survival post-thaw was assessed using a membrane integrity assay. We found that while the incidence of IIF increased with supercooling in both isotonic and hypertonic solutions, it was higher in the isotonic solution at any given degree of supercooling. Since cells in hypertonic solution were shrunken due to water efflux, we hypothesized that the difference in IIF behavior could be attributed to the decreased volume of cells in the hypertonic solution. Our results confirm that cells with a smaller diameter before extracellular ice nucleation have a decreased probability of IIF and suggest that cell volume could play a more significant role in the incidence of IIF than the extracellular ice nucleation temperature. PMID- 25707696 TI - Effect of freezing rate on motility, adenosine triphosphate content and fertilizability in beluga sturgeon (Huso huso) spermatozoa. AB - Broodstock selection programs are currently underway for sturgeon species. To complement and further these selection programs we need to develop sperm cryopreservation procedures. In the present study, we describe the effects of freezing rate (-10 degrees C, -15 degrees C, -20 degrees C, -30 degrees C and -40 degrees C/min) on gamete quality characteristics (i.e., duration of motility (s), motility percentage (%), ATP content (nmol/10(8) cells), fertilization rate (%), and hatching rate (%)) in beluga sturgeon, Huso huso. After sampling, beluga sturgeon sperm were diluted in an extender composed of 23.4mM sucrose, 0.25 mM KCl, and 30 mM Tris-HCl, pH 8.0 containing 10% methanol and subsequently frozen in a programmable freezer. Sperm frozen at -40 degrees C/min resulted in means for duration of motility (134 s), motility percentage (69%), ATP concentration (4.8 nmol/10(8) cells), fertilization rate (72%) and hatching rate (65%) that were higher (P<0.05) than those for slower cooling rates. Based on our results, 40 degrees C/min was the best freezing rate (among those tested) for cryopreservation of beluga sturgeon sperm. PMID- 25707697 TI - Long-Term Health Service Outcomes Among Women With Traumatic Brain Injury. AB - OBJECTIVES: To (1) assess long-term health care service utilization and satisfaction with health care services among women with traumatic brain injury (W TBI); (2) examine barriers that prevent W-TBI from receiving care when needed; and (3) understand the perceived supports available for W-TBI. DESIGN: Retrospective cohort study. SETTING: Community. PARTICIPANTS: W-TBI (n=105) 5 to 12 years postinjury and women without TBI (n=105) matched on age, education, and geographic location. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Pre- and postinjury data were collected using a questionnaire administered via a semistructured interview. Questions on health services utilization, satisfaction with and quality of services, barriers to receiving care, and perceived social support were from the Canadian Community Health Survey; additional questions on perceived social support were from another large-scale study of people with moderate to severe brain injury. RESULTS: Compared with women without TBI, W-TBI reported using more family physician and community health services. W-TBI reported that they did not receive care when needed (40%), particularly for emotional/mental health problems. Significantly more W-TBI reported financial and structural barriers. There were no significant differences in reported satisfaction with services between women with and without TBI. CONCLUSIONS: Health service providers and policymakers should recognize the long-term health and social needs of W-TBI and address societal factors that result in financial and structural barriers, to ensure access to needed services. PMID- 25707698 TI - Protecting children from injury. PMID- 25707699 TI - Activation of notch signaling mediates the induction and maintenance of mechanical allodynia in a rat model of neuropathic pain. AB - Neuropathic pain is a major health problem caused by dysfunction or damage of the nerve fibers in the peripheral or central nervous system. Notch signaling is a highly conserved evolutionary pathway, which regulates the fate of cells in the developing nervous system and is important in synaptic plasticity and inflammation in the adult central nervous system. The aim of the present study was to investigate the potential roles of the notch signaling pathway in the induction and maintenance of mechanical allodynia in neuropathic pain. Neuropathic pain was induced through spared nerve injury (SNI) in rats. DAPT, a gamma-secretase inhibitor of the notch signaling pathway, was intrathecally administered at different concentrations (5, 15, 50 and 150 uM), and time-points. In addition, Jagged-1 (JAG-1) peptide, a ligand of the notch signaling pathway, was administered intrathecally to normal rats. The mechanical allodynia was assessed using a von Frey test. The results demonstrated that administering DAPT prior to the appearance of pain sensitivity significantly prevented the decrease of mechanical paw withdrawal threshold (PWT) for >4 weeks (P<0.05 vs. SNI group). Administering DAPT following the appearance of pain sensitivity significantly reversed the decrease of mechanical PWT (P<0.05 vs. SNI group). Furthermore, early and late administration of DAPT resulted in dose-dependent antinociceptive effects. In addition, administration of JAG-1 induced a dose-dependent increase in the mechanical PWT of the normal rats. In conclusion, the results of the present study demonstrated that activation of notch signaling contributed to the induction and maintenance of mechanical allodynia in neuropathic pain, suggesting a potential novel therapeutic target for the treatment of neuropathic pain. PMID- 25707700 TI - Molecular signaling mechanisms of axon-glia communication in the peripheral nervous system. AB - In this article we discuss the molecular signaling mechanisms that coordinate interactions between Schwann cells and the neurons of the peripheral nervous system. Such interactions take place perpetually during development and in adulthood, and are critical for the homeostasis of the peripheral nervous system (PNS). Neurons provide essential signals to control Schwann cell functions, whereas Schwann cells promote neuronal survival and allow efficient transduction of action potentials. Deregulation of neuron-Schwann cell interactions often results in developmental abnormalities and diseases. Recent investigations have shown that during development, neuronally provided signals, such as Neuregulin, Jagged, and Wnt interact to fine-tune the Schwann cell lineage progression. In adult, the signal exchange between neurons and Schwann cells ensures proper nerve function and regeneration. Identification of the mechanisms of neuron-Schwann cell interactions is therefore essential for our understanding of the development, function and pathology of the peripheral nervous system as a whole. PMID- 25707701 TI - Drug-drug plasma protein binding interactions of ivacaftor. AB - Ivacaftor is a novel cystic fibrosis (CF) transmembrane conductance regulator (CFTR) potentiator that improves the pulmonary function for patients with CF bearing a G551D CFTR-protein mutation. Because ivacaftor is highly bound (>97%) to plasma proteins, there is the strong possibility that co-administered CF drugs may compete for the same plasma protein binding sites and impact the free drug concentration. This, in turn, could lead to drastic changes in the in vivo efficacy of ivacaftor and therapeutic outcomes. This biochemical study compares the binding affinity of ivacaftor and co-administered CF drugs for human serum albumin (HSA) and alpha1 -acid glycoprotein (AGP) using surface plasmon resonance and fluorimetric binding assays that measure the displacement of site-selective probes. Because of their ability to strongly compete for the ivacaftor binding sites on HSA and AGP, drug-drug interactions between ivacaftor are to be expected with ducosate, montelukast, ibuprofen, dicloxacillin, omeprazole, and loratadine. The significance of these plasma protein drug-drug interactions is also interpreted in terms of molecular docking simulations. This in vitro study provides valuable insights into the plasma protein drug-drug interactions of ivacaftor with co-administered CF drugs. The data may prove useful in future clinical trials for a staggered treatment that aims to maximize the effective free drug concentration and clinical efficacy of ivacaftor. PMID- 25707702 TI - Results of central pathology review of prostatic biopsies in a contemporary series from a phase III, multicenter, randomized controlled trial (SHIP0804). AB - To investigate contemporary rates of variation in the biopsy Gleason grading in prostate cancer, between local and central pathologists, based on central review of the pathological slides from Seed and Hormone for Intermediate-risk Prostate Cancer (SHIP) 0804, a phase III, multicenter, randomized, controlled study. From April 2008 to May 2011, 18 Japanese institutions participated. All H&E slides were reviewed independently, without clinical information, and a tumor grade was assigned according to the modified Gleason grading system proposed by the International Society of Urological Pathology (ISUP). Prostate biopsy specimens of 642 cases were available for evaluation. An exact concordance rate of Gleason score (GS) between local and central pathologists was determined to be 65.3%; with the under-grading and over-grading of grades to be 14.6% and 20.1%, respectively. The central review resulted in numbers of tumor-bearing cores reassigned in 99 of 616 cases in which such information by the local pathologists was available (16.1%). Discordance in biopsy Gleason grading was still found in one third of the cases in the SHIP0804 study. This information is valuable in extrapolating the diagnostic error range in contemporary clinical studies conducted without central pathological review. PMID- 25707703 TI - Predicting use of assistance when quitting: a longitudinal study of the role of quitting beliefs. AB - BACKGROUND: A growing literature addresses the need to reduce cigarette smoking prevalence by increasing the use of assistance when quitting. A key focus is to identify strategies for enhancing adoption of effective interventions in order to increase utilization of evidence-based treatments. PURPOSE: To examine the effect of beliefs regarding ability to quit on utilization of assistance for smoking cessation. A mediation model was hypothesized whereby the relationship between smoking and use of assistance is influenced by beliefs in ability to quit. METHODS: The present study includes 474 of 1000 respondents to baseline and follow-up California Smokers Cohort surveys conducted from 2011 to 2013. Included were baseline smokers who reported a 24-h quit attempt at follow-up. Baseline variables were used to predict use of assistance when quitting. RESULTS: The hypothesized model was tested using a product of coefficients method, controlling for demographics. Greater heaviness of smoking and lower belief in ability to quit were significantly related to use of assistance. Quitting beliefs significantly mediated the relationship between nicotine dependence and use of assistance. CONCLUSIONS: The present data support a mechanism whereby the effect of smoking rate on treatment utilization is mediated by beliefs in ability to quit. Greater belief in one's ability to quit may represent an obstacle to treatment utilization by reducing the likelihood of successful cessation. The present findings suggest the value of targeted messages from health care providers that normalize the need for assistance when attempting to change an addictive behavior and emphasize the difficulty of quitting without assistance. PMID- 25707704 TI - Discriminative-stimulus effects of second generation synthetic cathinones in methamphetamine-trained rats. AB - BACKGROUND: Synthetic cathinones are beta-ketophenethylamine analogs manufactured to avoid legal restrictions placed on illicit stimulants like methamphetamine. Regulating these "emerging" designer drugs require scientific evidence of abuse potential. METHODS: The present study evaluated the discriminative-stimulus effects of three synthetic cathinones, recently identified in commercial and confiscated products, in male Sprague-Dawley rats trained to discriminate methamphetamine (1.0 mg/kg) from saline under a fixed-ratio (FR) 20 schedule of food delivery. Three synthetic cathinones, 4-methyl-N-ethylcathinone (4-MEC; 1.0 8.0 mg/kg), 4-methyl-alpha-pyrrolidinopropiophenone (4-MePPP; 4.0-16.0 mg/kg), and alpha-pyrrolidinopentiophenone (alpha-PVP; 0.25-2.0 mg/kg) were tested for their ability to substitute for methamphetamine. RESULTS: Full substitution for the training dose of methamphetamine occurred at the highest doses for both 4 MePPP and alpha-PVP, and 4-MEC did not substitute at any dose tested. CONCLUSIONS: The present findings show that two synthetic cathinones, 4-MePPP and alpha-PVP, produced subjective effects similar to those of methamphetamine. The synthetic cathinone, 4-MEC, did not produce subjective effects similar to those of methamphetamine with the parameters used in the current experiment. Based on findings here and by others, these three compounds warrant further tests of abuse potential. PMID- 25707706 TI - Sleep and use of alcohol and drug in adolescence. A large population-based study of Norwegian adolescents aged 16 to 19 years. AB - BACKGROUND: Changes in sleep patterns and increased substance involvement are common in adolescence, but our knowledge of the nature of their association remains limited. The aim of this study was to examine the association between several sleep problems and sleep behaviours, and use and misuse of alcohol and illicit drugs using data from a large population-based sample. METHODS: A large population-based study from Norway conducted in 2012, the youth@hordaland study, surveyed 9328 adolescents aged 16-19 years (54% girls). Self-reported sleep measures provided information on sleep duration, sleep deficit, weekday bedtime and bedtime difference and insomnia. The main dependent variables were frequency and amount of alcohol consumption and illicit drug use, in addition to the presence of alcohol and drug problems as measured by CRAFFT. RESULTS: The results showed that all sleep parameters were associated with substance involvement in a dose-response manner. Short sleep duration, sleep deficit, large bedtime differences and insomnia were all significantly associated with higher odds of all alcohol and drug use/misuse measures. The associations were only partly attenuated by sociodemographics factors and co-existing symptoms of depression and ADHD. CONCLUSIONS: To the best of our knowledge, this is the first population based study to examine the association between sleep, and alcohol and drug use, by employing detailed measures of sleep behaviour and problems, as well as validated measures on consumption of alcohol and illicit drug use. The findings call for increased awareness of the link between sleep problems and alcohol and drugs use/misuse as a major public health issue. PMID- 25707705 TI - Long-term effects of minimum legal drinking age laws on marijuana and other illicit drug use in adulthood. AB - BACKGROUND: Exposure to permissive minimum legal drinking age (MLDA) laws (ability to purchase alcohol <21 years) during adolescence can have long-term effects, including heavy alcohol use or alcohol use disorders as adults. We examined whether exposure to permissive MLDA laws during adolescence has long term effects on illicit drug use and disorders in adulthood. METHODS: Participants from the 2004-2012 National Survey of Drug Use and Health (NSDUH) were linked with historical state MLDA laws. Participants born in 1949-1972 (age 31-63 years at observation, n = 110,300) were analyzed because they came of legal age for alcohol purchase when changes occurred in state MLDA laws. Logistic regression was used to model drug use measures as a function of exposure to permissive MLDA during adolescence, adjusting for state and birth-year fixed effects, demographics, and salient state characteristics. RESULTS: Rates of past month use, past year use, and abuse/dependence of marijuana were 4.7%, 7.8%, and 1.2%, respectively. Rates of past month use, past year use, and abuse/dependence of illicit drugs other than marijuana were 2.9%, 6.2%, and 0.7%, respectively. Among the full sample, exposure to permissive MLDA laws was not significantly associated with drug use or abuse/dependence in adulthood. Men exposed to permissive MLDA laws were at 20% increased odds of past year illicit drug use (aOR 1.20, 95% CI 1.09-1.32). CONCLUSIONS: Restricting alcohol access during adolescence did not increase long-term drug use. Allowing the purchase of alcohol among those less than 21 years of age could increase the risk of drug use later in life. PMID- 25707707 TI - Use of moist smokeless tobacco (snus) and the risk of development of alcohol dependence: a cohort study in a middle-aged population in Sweden. AB - BACKGROUND: Convincing evidence shows that smoking is associated with alcohol dependence (AD) and a positive correlation between snus and alcohol consumption was previously shown in cross-sectional studies. We performed a longitudinal evaluation of the risk of snus users to develop AD. METHODS: A cohort study in Vasterbotten County, Sweden, linked individual data on socioeconomic situation and health survey data from 21,037 men and women (46.5% men). AD was defined by the CAGE questionnaire and evaluated at baseline 1991-1997 and again after 10 years. The risk of developing AD was assessed using logistic regression analysis and propensity score matching. RESULTS: 2370 men and 430 women used snus and were without AD at baseline. Over the 10-year period, 499 men and 257 women developed AD, among whom 191 and 26, respectively, were baseline snus users. The crude relative risks of AD for male and female snus users compared to non-users were 1.8 with 95% CI (1.5, 2.2) and 2.9 (2.0, 4.3), respectively. Adjusted logistic regression showed a positive dose-response relationship between snus use and risk of AD. Analyses involving propensity score matching revealed 33 and 17 new cases of AD in men and women, respectively, after 10 years given 1000 men and 1000 women without AD had been baseline snus users rather than non-users. Results for current, previous and never smokers were similar. CONCLUSIONS: The use of snus is prospectively associated with an increased risk of AD with a dose-response relationship that is independent of smoking status. PMID- 25707708 TI - Changes in non-opioid substitution treatment episodes for pharmaceutical opioids and heroin from 2002 to 2011. AB - BACKGROUND: There has been a well-documented increase in the non-medical use of pharmaceutical opioids (PO) worldwide. However, there has been little detailed examination of treatment demand, or the characteristics of those presenting for treatment, particularly for treatments other than opioid substitution. METHODS: Data from closed drug and alcohol treatment episodes from the Alcohol and Other Drug Treatment Services National Minimum Data Set (AODTS-NMDS, representing non opioid substitution treatment) in Australia for 2002-2003 to 2010-2011 were examined. In the four jurisdictions where detailed data were available, episodes where heroin was the principal drug of concern were compared to episodes for the four most frequently reported pharmaceutical opioids (morphine, codeine, fentanyl and oxycodone). RESULTS: In 2002-2003, most (93%) opioid treatment was related to heroin with seven percent of all opioid treatment episodes reporting a PO as the principal drug of concern. In 2010-2011, 20% of all opioid treatment episodes were attributed to POs. Distinct changes over time were observed for different opioids. There was an increase in the average age at the start of treatment for heroin and oxycodone episodes, and a reduction in the proportion of females for codeine episodes, with 67% in 2002-2003 compared with 44% in 2010-2011. Codeine and oxycodone episodes had the lowest current or past injection rates. CONCLUSIONS: Clear differences were observed over time and between different opioids. Monitoring these emerging patterns will be important to inform treatment needs, particularly in light of different patterns of poly drug use, different routes of administration and changing demographic characteristics. PMID- 25707710 TI - Cognitive dysfunction and functional disability in alcohol-dependent adults with or without a comorbid affective disorder. AB - INTRODUCTION: Little is known about the relationship between cognitive dysfunction and functional disability in alcohol dependence with comorbid affective disorders. We investigated the neuropsychology of alcohol dependence in detoxified adults with and without affective comorbidity and examined the factors associated with prolonged functional disability. METHODS: From a total of 42 participants (age range = 18-44 years), 12 out of 21 alcohol-dependent participants had a comorbid affective disorder, 12 had an affective disorder only, and 9 were healthy controls. Participants completed a semi-structured clinical interview, questionnaires and comprehensive neuropsychological assessment. RESULTS: Following detoxification (median = 35 days; M = 41.2 days, SD = 17.9), visual learning and memory functioning was worse in alcohol-dependent individuals. Comorbid affective disorders did not appear to exacerbate cognitive dysfunction. Psychiatric comorbidity and current depressive symptoms were predictive of poorer functional disability. Furthermore, learning and memory, and response inhibition, contributed significantly and independently to predicting functional disability over and above clinical and demographic factors. CONCLUSIONS: Psychiatric comorbidity does not appear to be associated with more pronounced neuropsychological dysfunction in alcohol dependence. Conversely, both comorbid affective disorders and cognitive factors were critical in determining the functional outcomes of alcohol-dependent adults recently undergoing medically supervised inpatient detoxification. PMID- 25707709 TI - Acute alcohol consumption elevates serum bilirubin: an endogenous antioxidant. AB - BACKGROUND: Moderate alcohol consumption has been associated with both negative and favorable effects on health. The mechanisms responsible for reported favorable effects remain unclear. Higher (not necessarily elevated) concentrations of serum bilirubin, an antioxidant, have also been associated with reduced risk of cardiovascular disease and all-cause mortality. This study tests the hypothesis that single dose alcohol consumption elevates bilirubin providing a potential link between these observations. METHODS: 18 healthy individuals (eight cigarette smokers) were administered alcohol, calibrated to achieve blood concentrations of 20, 80 and 120 mg/dL, in random order in three laboratory sessions separated by a week. Each session was preceded by and followed by 5-7 days of alcohol abstinence. Serum bilirubin was measured at 7:45 a.m. prior to drinking, at 2p.m., and at 7:45 the next morning. Mixed effects regression models compared baseline and 24h post-drinking bilirubin concentrations. RESULTS: Total serum bilirubin (sum of indirect and direct) concentration increased significantly after drinking from baseline to 24h in non-smokers (from M = 0.38, SD = 0.24 to M = 0.51, SD = 0.30, F(1,32.2) = 24.24, p<.0001) but not in smokers (from M = 0.25, SD = 0.12 to M = 0.26, SD = 0.15, F(1,31.1) = 0.04, p = 0.84). In nonsmokers the indirect bilirubin concentration and the ratio of indirect (unconjugated) to direct (conjugated) bilirubin also increased significantly. CONCLUSIONS: Alcohol consumption leads to increases in serum bilirubin in nonsmokers. Considering the antioxidant properties of bilirubin, our findings suggest one possible mechanism for the reported association between alcohol consumption and reduced risk of some disorders that could be tested in future longitudinal studies. PMID- 25707711 TI - Review of the current use and evaluation of cell substrates for producing biologicals in selected countries. AB - In 2010, the WHO guidance document for the evaluation of cell substrates for producing biologicals was replaced with updated recommendations and in May 2013 an implementation workshop on the new recommendations was held in Beijing, China. As part of this workshop, a survey of the use and evaluation of cell substrates for producing biologicals was undertaken and the information obtained was updated in June 2014. The purpose of survey was to capture the status of national requirements related to cell substrates in various countries with particular emphasis on whether or not the updated WHO recommendations had been, or were to be, incorporated into national requirements. This paper reports the outcome of the survey and is based on information provided by regulators in eleven countries. Since the publication of the updated WHO recommendations, several activities such as the implementation workshop and publications have been undertaken by the WHO. The aim of these activities, including the publication of this article, is to contribute to the implementation of WHO recommendations so as to reduce regulatory gaps between national requirements and globally agreed expectations. PMID- 25707712 TI - Oxytocin-augmented labor and risk for autism in males. AB - The use of synthetic oxytocin (OT) to induce and/or augment labor and delivery is on the rise. Maternal exposure to OT during birth may have adverse effects on the infant's development, including increased risk for autism. Yet, studies that test this biologically plausible association and whether it is modified by sex are limited and show inconsistent findings. To this end, we conducted an epidemiological analysis, including all singleton live births in Denmark between 2000 and 2009 (N = 557,040), with a follow-up through 2012. A total of 2110 children in this cohort were subsequently diagnosed with autistic disorder according to the ICD-10-DCR. Augmentation of labor with OT was modestly associated with an increased risk for autism in males (HR 1.13; 95% CI, 1.00 1.26; P = 0.04), but not in females (0.99; 0.77-1.27; P=0.95). Among males exposed to OT augmentation, 560 were subsequently diagnosed with autistic disorder, and among those not exposed, 1177 met criteria for autism (incidence rate 103.2 and 81.4 per 100,000 person-years, respectively). Our findings suggest a modest association between OT-augmented labor and risk for autism in males. However, given the known benefits of using synthetic OT during labor and delivery caution is warranted when interpreting the findings. Future studies should also investigate dose-dependent effect of OT on infant's development. PMID- 25707713 TI - Cannabinoids & Stress: impact of HU-210 on behavioral tests of anxiety in acutely stressed mice. AB - Anxiety disorders are one of the most prevalent classes of mental disorders affecting the general population, but current treatment strategies are restricted by their limited efficacy and side effect profiles. Although the cannabinoid system is speculated to be a key player in the modulation of stress responses and emotionality, the vast majority of current research initiatives had not incorporated stress exposure into their experimental designs. This study was the first to investigate the impact of exogenous cannabinoid administration in an acutely stressed mouse model, where CD1 mice were pre-treated with HU-210, a potent CB1R agonist, prior to acute stress exposure and subsequent behavioral testing. Exogenous cannabinoid administration induced distinct behavioral phenotypes in stressed and unstressed mice. While low doses of HU-210 were anxiolytic in unstressed subjects, this effect was abolished when mice were exposed to an acute stressor. The administration of higher HU-210 doses in combination with acute stress exposure led to severe locomotor deficits that were not previously observed at the same dose in unstressed subjects. These findings suggest that exogenous cannabinoids and acute stress act synergistically in an anxiogenic manner. This study underlies the importance of including stress exposure into future anxiety-cannabinoid research due to the differential impact of cannabinoid administration on stressed and unstressed subjects. PMID- 25707714 TI - Insight into the Modulation of Dissolved Organic Matter on Microbial Remediation of PAH-Contaminated Soils. AB - Microorganisms play a key role in degradation of polycyclic aromatic hydrocarbons (PAHs) in environments. Dissolved organic matter (DOM) can enhance microbial degradation of PAHs in soils. However, it is not clear how will the soil microbial community respond to addition of DOM during bioremediation of PAH contaminated soils. In this study, DOMs derived from various agricultural wastes were applied to remediate the aging PAH-contaminated soils in a 90-day microcosm experiment. Results showed that the addition of DOMs offered a more efficient and persistent elimination of soil PAHs compared to the control which had no DOM addition. PAH removal effects were different among treatments with various DOMs; the addition of DOMs with high proportion of hydrophobic fraction could remove PAHs more efficiently from the soil. Low-molecular-weight (LMW) PAHs were more easily eliminated than that with high-molecular-weight (HMW). Addition of DOMs significantly increased abundance of 16S ribosomal RNA (rRNA), pdo1, nah, and C12O genes and obviously changed community compositions of nah and C12O genes in different ways in the PAH-contaminated soil. Phylogenetic analyses of clone libraries exhibited that all of nah sequences and most of C12O sequences were affiliated into Gammaproteobacteria and Betaproteobacteria. These results suggested that external stimuli produced by DOMs could enhance the microbial degradation of PAHs in soils through not only solubilizing PAHs but also altering abundance and composition of indigenous microbial degraders. Our results reinforce the understanding of role of DOMs in mediating degradation of PAHs by microorganims in soils. PMID- 25707715 TI - Atypical functional brain connectivity during rest in autism spectrum disorders. AB - OBJECTIVE: Connectivity atypicalities in autism spectrum disorders (ASD) have been extensively proposed. The default mode network (DMN) is critical in this study, given the insight it provides for long-distance connectivity, and the importance of regions in this network for introspection and social emotion processing, areas affected in ASD. However, study of this network has largely been limited to adults; research earlier in development is lacking. The objective of this study was to examine DMN connectivity in children/adolescents with ASD. METHODS: A total of 115 children/adolescents, aged 6 to 17 years (71 males with ASD and 44 group age-matched TD males) were included in these analyses. We examined group differences in (1) functional connectivity between the posterior cingulate cortex and regions across the brain, (2) connectivity within the DMN as a function of age and intelligence quotient (IQ), and (3) the association between DMN connectivity and empathic accuracy. RESULTS: Individuals with ASD, relative to controls, showed either stronger or weaker connectivity between the posterior cingulate cortex (PCC) and DMN regions, depending on the region, but also showed stronger connectivity with non-DMN regions. A significant group-by-age interaction was observed in functional connectivity between the PCC and medial prefrontal cortex; connectivity increased with age in controls, but decreased in individuals with ASD. No effects of IQ were found. There was a significant group difference in the relation between DMN connectivity and empathic accuracy. INTERPRETATION: Differences in functional connectivity may suggest the presence of neural atypicalities that impact the development of typical connectivity in ASD. In addition to affecting DMN dynamics, these atypicalities may also impact social-cognitive abilities. PMID- 25707717 TI - Small-signal modelling and control of photovoltaic based water pumping system. AB - This paper studies small-signal modelling and control design for a photovoltaic (PV) based water pumping system without energy storage. First, the small-signal model is obtained and then, using this model, two proportional-integral (PI) controllers, where one controller is used to control the dc-link voltage and the other one to control the speed of induction motor, are designed to meet control goals such as settling time and peak overshoot of the closed loop responses. The loop robustness of the design is also studied. For a given set of system parameters, simulations are carried out to validate the modelling and the control design. PMID- 25707716 TI - Endothelin receptor blockade ameliorates vascular fragility in endothelial cell specific Fli-1-knockout mice by increasing Fli-1 DNA binding ability. AB - OBJECTIVE: It is generally accepted that blockade of endothelin receptors has potentially beneficial effects on vasculopathy associated with systemic sclerosis (SSc). The aim of this study was to clarify the molecular mechanism underlying these effects using endothelial cell-specific Fli-1-knockout (Fli-1 ECKO) mice, an animal model of SSc vasculopathy. METHODS: Levels of messenger RNA for target genes and the expression and phosphorylation levels of target proteins were determined in human and murine dermal microvascular endothelial cells by real time quantitative reverse transcription-polymerase chain reaction and immunoblotting, respectively. The binding of Fli-1 to the target gene promoters was evaluated using chromatin immunoprecipitation. Expression levels of Fli-1 and alpha-smooth muscle actin in murine skin were evaluated using immunohistochemistry. Vascular structure and permeability were evaluated in mice injected with fluorescein isothiocyanate-dextran and Evans blue dye, respectively. RESULTS: In human dermal microvascular endothelial cells, endothelin 1 induced phosphorylation of Fli-1 at Thr(312) through the sequential activation of c-Abl and protein kinase Cdelta, leading to a decrease in Fli-1 protein levels as well as a decrease in binding of Fli-1 to the target gene promoters, whereas bosentan treatment reversed those effects. In Fli-1 ECKO mice, 4 weeks of treatment with bosentan increased endothelial Fli-1 expression, resulting in vascular stabilization and the restoration of impaired leaky vessels. CONCLUSION: The vascular fragility of Fli-1 ECKO mice was improved by bosentan through the normalization of Fli-1 protein levels and activity in endothelial cells, which may explain, in part, the mechanism underlying the beneficial effects of endothelin receptor blockade on SSc vasculopathy. PMID- 25707718 TI - Output feedback control of a mechanical system using magnetic levitation. AB - This paper presents an application of a nonlinear magnetic levitation system to the problem of efficient active control of mass-spring-damper mechanical systems. An output feedback control scheme is proposed for reference position trajectory tracking tasks on the flexible mechanical system. The electromagnetically actuated system is shown to be a differentially flat nonlinear system. An extended state estimation approach is also proposed to obtain estimates of velocity, acceleration and disturbance signals. The differential flatness structural property of the system is then employed for the synthesis of the controller and the signal estimation approach presented in this work. Some experimental and simulation results are included to show the efficient performance of the control approach and the effective estimation of the unknown signals. PMID- 25707719 TI - Inherited platelet disorders. AB - Inherited platelet disorders may be the cause of bleeding symptoms of varying severity as platelets fail to fulfil their haemostatic role after vessel injury. Platelet disorders may be difficult to diagnose (and are likely to be misdiagnosed) and raise problems in therapy and management. This review explores the clinical and molecular genetic phenotype of several inherited disorders. Inherited platelet disorders can be classified according to their platelet defects: receptor defects (adhesion or aggregation), secretion disorder, and cytoskeleton defects. The best characterized platelet receptor defects are Glanzmann thrombasthenia (integrin alphaIIbbeta3 defect) and Bernard-Soulier syndrome (defect of GPIb/IX/V). Detailed case reports of patients suffering from Glanzmann thrombasthenia (GT) or Bernard-Soulier syndrome (BSS) showing the bleeding diathesis as well as investigation of platelet aggregation/agglutination and platelet receptor expression will complement this review. In addition, Hermansky-Pudlak syndrome (HPS) as an important defect of delta-granule secretion is extensively described together with a case report of a patient suffering from HPS type 1. PMID- 25707720 TI - Discordant intestinal malrotation in identical twins. PMID- 25707721 TI - A year in reflection. PMID- 25707722 TI - Every nurse can provide effective pain management. PMID- 25707723 TI - Multimodal pain management and the future of a personalized medicine approach to pain. AB - In the soon-to-be-released clinical practice guidelines from the American Pain Society, multimodal analgesia is recommended for pain management after all surgical procedures. Multimodal analgesia is a surgery-specific population-based approach to optimize pain relief by treating pain through multiple mechanisms along multiple sites of the nociceptive pathway. The reliance on multiple medications and therapies inherent to the multimodal approach also may address individual patient differences in analgesic pharmacogenetics (ie, the influence of allelic differences in single genes and the associated variability in specific medication responses). Perioperative nurses may see a shift from surgery-specific population-based multimodal analgesic protocols to a personalized medicine approach as knowledge of the genetic influences of analgesic metabolism and pain sensitivity is translated into clinical practice. Personalized medicine is proposed as an individualized pain management treatment plan that eventually may be based on each patient's genetic coding for metabolism of analgesics and pain sensitivity. PMID- 25707724 TI - Considerations for complementary and alternative interventions for pain. AB - Nurses play an important role in pain management. When considering strategies for effective pain management, nurses must consider and be able to provide information about complementary and alternative therapies. Awareness of alternative interventions for pain extends across herbal therapies, energy medicine, and mind-body exercises. Treatment regimens that integrate conventional therapies with alternative therapies based on the medical systems of non-Western cultures may affect outcomes positively through medical interactions. Nurses should question patients and families about complementary health practices to determine whether they may affect postsurgical recovery and also to determine the level of openness to alternative practices that have evidence of success or equivalency in managing pain. PMID- 25707725 TI - Delivering quality pain management: the challenge for nurses. AB - The delivery of high-quality pain management in the perioperative environment can be challenging and difficult to quantify. Commonly used tools in delivering care, such as pain intensity ratings, individual pain experience reporting, assessments of individual patients' expectations, and patient satisfaction scores, have limitations and are not always useful when addressing quality improvement measures. Despite clinical advances in pain management, patients continue to experience inadequate pain control and inconsistent pain management practices. In this article, we discuss the challenges in providing consistent quality pain management, the need for a coordinated plan of care with a goal of meeting desired pain outcomes, and the essential role that perianesthesia and perioperative nurses play throughout the transitions in perioperative care to promote optimal pain management interventions based on the patient's individual needs. PMID- 25707726 TI - Pathophysiology of pain: implications for perioperative nursing. AB - The pathophysiology of pain is a complex process that varies according to duration (eg, acute, chronic) or type (eg, nociceptive, neuropathic, psychogenic). Perioperative nurses should understand the pathways that lead to pain to better assist in managing patients' pain symptoms. Approaching pain from a patient-centered stance includes acknowledging that pain is defined entirely by the subjective experience of the patient, which may not be proportional with the level of tissue damage. This article provides a brief description of the pathophysiology of pain and the components of nociceptive and neuropathic pain pathways to aid the perioperative nurse in pain management. PMID- 25707727 TI - Back to basics: procedural sedation. AB - Patients undergoing surgery frequently receive procedural sedation from RNs in the perioperative setting. With appropriate training, perioperative RNs can administer procedural sedation safely and effectively, helping to eliminate the pain and anxiety often experienced by patients. Facility sedation protocols should provide guidance on training requirements, the RN's role, the credentialing process, the medications the RN may use, and when anesthesia personnel should be consulted. Creating these protocols is guided by state scope of practice laws, Centers for Medicare & Medicaid Services Interpretive Guidelines, and accreditation requirements. Training, physician guidance, and appropriate protocols give the necessary support for perioperative nurses to provide safe and effective procedural sedation. PMID- 25707728 TI - New strategies to assert the value of the perioperative nurse. PMID- 25707729 TI - Protecting the surgical team from waste anesthetic gases during medical missions. PMID- 25707730 TI - Certification and patient safety. PMID- 25707732 TI - Discontinued medications: are they really discontinued? PMID- 25707733 TI - Brief report: responses to rituximab suggest B cell-independent inflammation in cutaneous systemic lupus erythematosus. AB - OBJECTIVE: The immunopathogenesis of systemic lupus erythematosus (SLE) is heterogeneous, and responses of skin to rituximab are variable. This study was undertaken to determine the phenotype of rituximab-responsive disease. METHODS: Eighty-two patients with SLE who were receiving rituximab were prospectively studied. Of these patients, 32 had significant skin involvement before or after treatment. Disease activity was assessed using the British Isles Lupus Assessment Group (BILAG) index 2004. Cutaneous lupus subtype was classified by a dermatologist as acute cutaneous lupus erythematosus (ACLE), subacute cutaneous lupus erythematosus (SCLE), chronic cutaneous lupus erythematosus (CCLE), or other skin diseases, with supportive photographs or biopsies where necessary. RESULTS: Of 26 patients with skin disease at baseline, 9 (35%) had a beneficial mucocutaneous response to rituximab at 6 months, with good responses in ACLE (6 of 14 patients [43%]), and poor responses in CCLE (0 of 8 patients) (P = 0.034). Clinical response was associated with anti-RNP negativity (P = 0.024) and anti-Ro negativity (P = 0.031). Flares of SCLE and CCLE occurred in 12 patients who either had no skin disease or had ACLE at baseline (i.e., a switch in subtype). Concomitant antimalarials or conventional immunosuppressants were not associated with response or flare rate. Posttreatment biopsies confirmed typical active SLE histology in lesions occurring during B cell depletion. CONCLUSION: Our findings indicate that the clinical response to rituximab in cutaneous manifestations of SLE depends on subtype. None of the CCLE patients responded, and new CCLE lesions were observed during B cell depletion, suggesting that initiation and activity of these lesions is not B cell dependent. Flares of a range of skin diseases after B cell depletion may indicate a change in immune regulation following B cell targeted therapy. PMID- 25707734 TI - Sealing a ruptured non-culprit coronary plaque in a patient with acute myocardial infarction with bioresorbable vascular scaffolds. AB - A 49-year-old man was admitted to the emergency department suffering from a large anterior myocardial infarction that was treated by rescue PCI. The patient also had a moderate but complex lesion in the proximal segment of the right coronary artery. Optical coherence tomography showed striking images of a ruptured and ulcerated plaque with significant thrombus content. Although the lumen was not compromised, these unique findings prompted us to treat this non-culprit lesion. We selected a bioresorbable vascular scaffold with the aim of sealing and passivating this complicated and high-risk plaque. PMID- 25707735 TI - When inappropriate becomes beneficial. AB - We report the case of a young man who accidentally received a prolonged electric discharge from electrical wires and released the electric source with the help of an inappropriate shock from his implantable cardioverter-defibrillator (ICD), after misinterpretation of the electrical signal by the device as a ventricular tachycardia. This case illustrates the "electrical noise" phenomenon, and underscores the need for precautions for patients with an ICD and their physicians. PMID- 25707736 TI - Ultra-performance liquid chromatography of amino acids for the quality assessment of pearl powder. AB - Pearls have been widely used as a traditional medicine, in cosmetics, and as a health food supplement in China since ancient times. However, the identification and quality assessment of pearl powder have been challenging tasks because of the similar morphological features and chemical composition of its common adulterants, especially conch powders. In this study, ultra-performance liquid chromatography was combined with pre-column derivatization to rapidly quantify 14 amino acids in pearl powder and its analogues. Based upon the quantification results, a quality criterion of a total amino acid content of not less than 1.10% was proposed for pearl powder. Principal component analysis indicated that leucine and phenylalanine were the amino acids characteristic for distinguishing between pearls and nacres. The area ratio of leucine to phenylalanine was demonstrated to be an effective diagnostic marker to discriminate freshwater cultured pearls, natural seawater pearls, and nacres. The proposed method, involving both the qualitative and quantitative aspects, was subsequently applied to quality assessment of pearl powders purchased commercially in various parts of China; eight out of 18 batches were deemed authentic and unadulterated. In the future, this analytical process should play a significant role in standardizing and providing quality control to the pearl powder market. PMID- 25707737 TI - Mycological Profile and Antifungal Susceptibility of Fungal Isolates from Clinically Suspected Cases of Fungal Rhinosinusitis in a Tertiary Care Hospital in North India. AB - A prospective observational study was conducted for 18 months to analyze the mycological profile of clinically suspected cases of fungal rhinosinusitis requiring endoscopic sinus surgery and test antifungal susceptibility of the isolates according to Clinical and Laboratory Standards Institute guidelines. Per operative biopsies (n = 126) from 106 patients were processed by standard mycological procedures. Out of 126 samples, 59 (46.83 %) had fungal elements on KOH mount examination. Fungal growth was obtained in 76 (60.32 %) samples, of which single fungal organism was isolated in 68 samples and more than one fungal species in eight samples. The most common isolates belonged to the genus Aspergillus (n = 53, A. flavus being most common) followed by mucormycetes (9), Candida species (7), Penicillium species (5), Alternaria species (5), Fusarium species (1), Curvularia species (1) and black yeast (1). Two hyaline septate fungal isolates could not be identified. Aspergillus species were susceptible to amphotericin B (n = 46), itraconazole (n = 48), voriconazole (n = 52), posaconazole (n = 53), caspofungin (n = 51), anidulafungin (n = 53) and micafungin (n = 53). All mucormycetes isolates (n = 9) were susceptible to amphotericin B, posaconazole and itraconazole. Filamentous non-Aspergillus, non mucormycetes isolates (n = 15) were susceptible to amphotericin B (n = 12), itraconazole (n = 13), voriconazole (n = 15), posaconazole (n = 15) and echinocandins (n = 15). Amongst the 07 Candida species, 05 isolates of Candida tropicalis were susceptible to amphotericin B, posaconazole, echinocandins and 5 flucytosine; one isolate of Candida albicans had the same susceptibility but was resistant to 5-flucytosine also, and one strain of Candida species was susceptible to all the nine antifungal drugs. PMID- 25707738 TI - Flow cytometry detection of vitamin D receptor changes during vitamin D treatment in Crohn's disease. AB - Crohn's disease (CD) is a chronic inflammatory disease associated with a dysregulated T cell response towards intestinal microflora. Vitamin D has immune modulatory effects on T cells through the nuclear vitamin D receptor (VDR) in vitro. It is unclear how oral vitamin D treatment affects VDR expression. The aim of this study was to establish a flow cytometry protocol, including nuclear and cytoplasmic VDR expression, and to investigate the effects of vitamin D treatment on T cell VDR expression in CD patients. The flow cytometry protocol for VDR staining was developed using the human acute monocytic leukaemia cell line (THP 1). The protocol was evaluated in anti-CD3/CD28-stimulated peripheral blood mononuclear cells (PBMCs) from vitamin D3- (n = 9) and placebo-treated (n = 9) CD patients. Anti-VDR-stained PBMCs were examined by flow cytometry, and their cytokine production was determined by cytokine bead array. VDR, CYP27B1 and RXRalpha mRNA expression levels in CD4(+) T cells were measured by quantitative reverse transcriptase polymerase chain reaction. The flow cytometry protocol enabled detection of cytoplasmic and nuclear VDR expression. The results were confirmed by confocal microscopy and supported by correlation with VDR mRNA expression. VDR expression in CD4(+) T cells increased following stimulation. This VDR up-regulation was inhibited with 30% by vitamin D treatment compared to placebo in CD patients (P = 0027). VDR expression was correlated with in-vitro interferon-gamma production in stimulated PBMCs (P = 0.01). Flow cytometry is a useful method with which to measure intracellular VDR expression. Vitamin D treatment in CD patients reduces T cell receptor-mediated VDR up-regulation. PMID- 25707739 TI - Placental expression of eNOS, iNOS and the major protein components of caveolae in women with pre-eclampsia. AB - Caveolae regulate many cardiovascular functions and thus could be of interest in relation to pre-eclampsia, a pregnancy specific disorder characterised by hypertension and proteinuria. We examined placental mRNA and protein expression/localisation of the caveolae components Caveolin 1-3, Cavin 1-4 as well as eNOS/iNOS in normotensive control (n = 24) and pre-eclamptic pregnancies (n = 19). Placental mRNA expression of caveolin-1, cavin 1-3, was lower and eNOS expression was increased in pre-eclampsia (P < 0.05 for all). Additionally Caveolin-1 protein expression was also reduced in pre-eclampsia (P = 0.007); this could be an adaptive response in pre-eclampsia, possibly to attenuate the oxidative stress/inflammation. PMID- 25707740 TI - Review: hCGs: different sources of production, different glycoforms and functions. AB - Human chorionic gonadotropin (hCG) is the first hormonal message from the placenta to the mother. It is detectable in maternal blood two days after implantation and behaves like an agonist of LH stimulating progesterone secretion by the corpus luteum. hCG has also a role in quiescence of the myometrium and local immune tolerance. Specific to humans, hCG is a complex glycoprotein composed of two glycosylated subunits. The alpha-subunit is identical to the pituitary gonadotropin hormones (LH, FSH, TSH), contains two N-glycosylation sites, and is encoded by a single gene (CGA). By contrast the beta-subunits are distinct in each of the hormones and confer receptor and biological specificity. The hCG beta-subunit contains two sites of N-glycosylation and four sites of O glycosylation and is encoded by a cluster of genes (CGB). In this review, we will stress the importance of hCG glycosylation state, which varies with the stage of pregnancy, its source of production and in the pathology. It is well established that hCG is mainly secreted by the syncytiotrophoblast into maternal blood where it peaks around 8-10 weeks of gestation (WG). The invasive extravillous trophoblast also secretes hCG, and in particular like choriocarcinoma cells, hyperglycosylated forms of hCG (hCG-H). In maternal blood hCG-H is high during early first trimester. In addition to its endocrine role, hCG has autocrine and paracrine roles. It promotes formation of the syncytiotrophoblast and angiogenesis through LHCG receptor. In contrast, hCG-H stimulates trophoblast invasion and angiogenesis by interacting with the TGFbeta receptor 2. hCG is largely used in antenatal screening and hCG-H represents a serum marker of early trophoblast invasion. Other abnormally glycosylated hCG are described in aneuploidies. In conclusion, hCG is the major pregnancy glycoprotein hormone, whose maternal concentration and glycan structure change all along pregnancy. Depending on its source of production, glycoforms of hCG display different biological activities and functions that are essential for pregnancy outcome. PMID- 25707741 TI - ENaC mediates human extravillous trophblast cell line (HTR8/SVneo) invasion by regulating levels of matrix metalloproteinase 2 (MMP2). AB - INTRODUCTION: Placenta dysfunction is thought to be the major etiological factor related to preeclampsia. The epithelial sodium channel (ENaC) has been localized in the apical plasma membrane of epithelia, mediating the active reabsorption of sodium in kidney, and be involved in the regulation of blood pressure. In previous studies, we found that the reduced expression of ENaC on placenta in preeclampsia patients. The aim of this study was to determine the role of MMP2 in the ENaC-induced trophoblast cell invasion ability, which is closely related to the occurrence of preeclampsia. METHODS: Here we checked whether pregnancy related hormones human chorionic gonadotropin (HCG), prolactin and aldosterone could affect ENaC expression in the first trimester extravillous trophoblast cell line (HTR8/SVneo) by RT-PCR and Western blot. Cell invasion was studied by matrigel invasion assay. Tube formation assay was used to investigate the interaction between trophoblast cells and endothelial cells. The effects of ENaC on MMP2 were further determined by RT-PCR, western blot and gelatin zymography. RESULTS: We demonstrated that HCG, prolactin and aldosterone could up-regulate the expression of alphaENaC in protein levels. Trophoblast cell invasion ability is stimulated when alphaENaC was up-regulated by aldosterone, and inhibited when ENaC was down-regulated by amiloride and alphaENaC specific RNAi (SiENA/ENaC). The interaction between HTR8/SVneo cells and HUVEC cells was enhanced when treated with aldosterone and weakened when treated with amiloride and SiRNA/ENaC. Amiloride and SiRNA/ENaC could inhibit MMP2 expression and activity. DISSCUTION: Aldosterone induced ENaC activity is important for trophoblast cells invasion. The results also indicate that ENaC could mediate trophoblast cells invasion ability through regulating expression and activity of matrix metalloproteinase-2 (MMP2). PMID- 25707742 TI - Galectin 2 (gal-2) expression is downregulated on protein and mRNA level in placentas of preeclamptic (PE) patients. AB - INTRODUCTION: Galectin 2 (gal-2) belongs to the proto type group and consists of two homologous carbohydrate recognition domains (CRDs) resulting in multiple sugar binding sites. The expression of gal-2 has been shown to be involved in processes of angiogenesis and inflammation but was not analyzed before in preeclamptic (PE) placentas. Therefore the aim of this study was an analysis of expression and localization of gal-2 in placentas from patients suffering from PE. METHODS: Placental tissues were obtained from 14 women following a normal course of pregnancy and 13 women with PE. Expression of gal-2 was evaluated with immunohistochemistry and a semi quantitative score. Gal-2 mRNA expression was quantified in placental tissue using real time TaqMan PCR. Identification of gal 2 expressing cells in the decidua was achieved by double immunofluorescence microscopy. RESULTS: Expression of gal-2 is downregulated in the syncytiotrophoblast of preeclamptic placentas. Downregulation of gal-2 could also be identified in the decidua of PE patients. These findings on protein level could be supported by the results of TaqMan PCR. Gal-2 is downregulated in PE placentas on mRNA level. Finally, gal-2 expressing cells could be identified as extravillous trophoblast cells in both normal pregnancy and PE. DISCUSSION: Gal-2 was identified as an inhibitor of arteriogenesis in a murine model supposedly via modulation of the monocyte/macrophage population. In PE, both the formation of spiral arteries as well as influx of macrophages are dramatically changed. Therefore we might speculate that disturbed transformation of spiral arteries in PE might correlate with the downregulated gal-2 expression by the trophoblast. PMID- 25707744 TI - Solid organ transplantation from hepatitis B virus-positive donors: consensus guidelines for recipient management. AB - Use of organs from donors testing positive for hepatitis B virus (HBV) may safely expand the donor pool. The American Society of Transplantation convened a multidisciplinary expert panel that reviewed the existing literature and developed consensus recommendations for recipient management following the use of organs from HBV positive donors. Transmission risk is highest with liver donors and significantly lower with non-liver (kidney and thoracic) donors. Antiviral prophylaxis significantly reduces the rate of transmission to liver recipients from isolated HBV core antibody positive (anti-HBc+) donors. Organs from anti HBc+ donors should be considered for all adult transplant candidates after an individualized assessment of the risks and benefits and appropriate patient consent. Indefinite antiviral prophylaxis is recommended in liver recipients with no immunity or vaccine immunity but not in liver recipients with natural immunity. Antiviral prophylaxis may be considered for up to 1 year in susceptible non-liver recipients but is not recommended in immune non-liver recipients. Although no longer the treatment of choice in patients with chronic HBV, lamivudine remains the most cost-effective choice for prophylaxis in this setting. Hepatitis B immunoglobulin is not recommended. PMID- 25707745 TI - Manipulating microRNAs for improved biomass and biofuels from plant feedstocks. AB - Petroleum-based fuels are nonrenewable and unsustainable. Renewable sources of energy, such as lignocellulosic biofuels and plant metabolite-based drop-in fuels, can offset fossil fuel use and reverse environmental degradation through carbon sequestration. Despite these benefits, the lignocellulosic biofuels industry still faces many challenges, including the availability of economically viable crop plants. Cell wall recalcitrance is a major economic barrier for lignocellulosic biofuels production from biomass crops. Sustainability and biomass yield are two additional, yet interrelated, foci for biomass crop improvement. Many scientists are searching for solutions to these problems within biomass crop genomes. MicroRNAs (miRNAs) are involved in almost all biological and metabolic process in plants including plant development, cell wall biosynthesis and plant stress responses. Because of the broad functions of their targets (e.g. auxin response factors), the alteration of plant miRNA expression often results in pleiotropic effects. A specific miRNA usually regulates a biologically relevant bioenergy trait. For example, relatively low miR156 overexpression leads to a transgenic feedstock with enhanced biomass and decreased recalcitrance. miRNAs have been overexpressed in dedicated bioenergy feedstocks such as poplar and switchgrass yielding promising results for lignin reduction, increased plant biomass, the timing of flowering and response to harsh environments. In this review, we present the status of miRNA-related research in several major biofuel crops and relevant model plants. We critically assess published research and suggest next steps for miRNA manipulation in feedstocks for increased biomass and sustainability for biofuels and bioproducts. PMID- 25707747 TI - Consolidation of slow or fast but not moderately evolving genes at the level of pathways and processes. AB - Conservatism versus innovation is probably the most important dichotomy of all evolving systems. In molecular evolution the distinction between conservative (negative) selection, innovative (positive) selection and unconstrained evolution (drift) is usually ambiguous at the gene level. Only rare cases with the ratio of nonsynonymous to synonymous nucleotide substitutions above unity (dN/dS>1) are thought to be due to positive selection, whereas the lower dN/dS ratio may indicate negative selection in combination with drift. The density of the dN/dS ratio for orthologous genes forms a unimodal distribution where no particular regions can be discerned. Here it is shown that at the level of overrepresented pathways and processes the picture is strikingly different. The distribution is strongly polarized with a wide completely depressed middle part. This three-phase distribution is very robust. It is observed with various substitution models and remains at very low significance of overrepresentation (up to p<0.99). This fact suggests consolidation of either negative or positive selection but not of unconstrained evolution at the level of pathways/processes. The effect is demonstrated for different phylogenetic distances: from human to other primates, mammals and vertebrates. This approach suggests estimating the boundaries for conservative and innovative selection using the pathway/process level. Emphasizing the role of a critical mass of negatively or positively selected genes in a pathway/process, it can elucidate how the bridge between 'tinkering' at the gene level and 'design' at the higher levels is forming. PMID- 25707748 TI - Commonly consumed beverages in daily life: do they cause atrial fibrillation? AB - Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia in the United States and worldwide. Caffeine, alcohol, and, more recently, energy drinks are the most commonly consumed beverages in daily living, especially by young individuals. Several questions have been raised about the implications of caffeine, alcohol, and energy drinks in cardiovascular health, especially in triggering AF. This review focuses on the role of these commonly consumed beverages as a cause of AF, with special emphasis of potential mechanisms and studies addressing this issue. PMID- 25707746 TI - Genome-wide comparative analysis of ABC systems in the Bdellovibrio-and-like organisms. AB - Bdellovibrio-and-like organisms (BALOs) are gram-negative, predatory bacteria with wide variations in genome sizes and GC content and ecological habitats. The ATP-binding cassette (ABC) systems have been identified in several prokaryotes, fungi and plants and have a role in transport of materials in and out of cells and in cellular processes. However, knowledge of the ABC systems of BALOs remains obscure. A total of 269 putative ABC proteins were identified in BALOs. The genes encoding these ABC systems occupy nearly 1.3% of the gene content in freshwater Bdellovibrio strains and about 0.7% in their saltwater counterparts. The proteins found belong to 25 ABC system families based on their structural characteristics and functions. Among these, 16 families function as importers, 6 as exporters and 3 are involved in various cellular processes. Eight of these 25 ABC system families were deduced to be the core set of ABC systems conserved in all BALOs. All Bacteriovorax strains have 28 or less ABC systems. On the contrary, the freshwater Bdellovibrio strains have more ABC systems, typically around 51. In the genome of Bdellovibrio exovorus JSS (CP003537.1), 53 putative ABC systems were detected, representing the highest number among all the BALO genomes examined in this study. Unexpected high numbers of ABC systems involved in cellular processes were found in all BALOs. Phylogenetic analysis suggests that the majority of ABC proteins can be assigned into many separate families with high bootstrap supports (>50%). In this study, a general framework of sequence structure-function connections for the ABC systems in BALOs was revealed providing novel insights for future investigations. PMID- 25707749 TI - Comprehensive spectroscopic studies on the interaction of biomolecules with surfactant detached multi-walled carbon nanotubes. AB - This paper investigates the interaction of ten diverse biomolecules with surfactant detached Multi-Walled Carbon Nanotubes (MWCNTs) using multiple spectroscopic methods. Declining fluorescence intensity of biomolecules in combination with the hyperchromic effect in UV-Visible spectra confirmed the existence of the ground state complex formation. Quenching mechanism remains static and non-fluorescent. 3D spectral data of biomolecules suggested the possibilities of disturbances to the aromatic microenvironment of tryptophan and tyrosine residues arising out of CNTs interaction. Amide band Shifts corresponding to the secondary structure of biomolecules were observed in the of FTIR and FT-Raman spectra. In addition, there exists an increased Raman intensity of tryptophan residues of biomolecules upon interaction with CNTs. Hence, the binding of the aromatic structures of CNTs with the aromatic amino acid residues, in a particular, tryptophan was evidenced. Far UV Circular spectra have showed the loss of alpha-helical contents in biomolecules upon interaction with CNTs. Near UV CD spectra confirmed the alterations in the tryptophan positions of the peptide backbone. Hence, our results have demonstrated that the interaction of biomolecules with OH-MWCNTs would involve binding cum structural changes and alteration to their aromatic micro-environment. PMID- 25707750 TI - Novel in situ gel systems based on P123/TPGS mixed micelles and gellan gum for ophthalmic delivery of curcumin. AB - Curcumin, a natural polyphenol compound, has been widely reported for diverse pharmacological effects and already been investigated for eye diseases. However, the water-insolubility of curcumin and the inherent penetration barriers in cornea make it difficult for curcumin to enter eye. This work aimed to develop ion-sensitive curcumin-loaded Pluronic P123 (P123)/D-a-tocopheryl polyethylene glycolsuccinate (TPGS) mixed micelle in situ gels (CUR-MM-ISGs) to prolong ocular retention time and improve cornea permeability. Central composite design-response surface methodology was applied for the optimization of curcumin-loaded P123/TPGS mixed micelles (CUR-MMs). Characterization tests showed that CUR-MMs were in spherical shape with small size and low critical micelle concentration. After dispersing the micelles in gellan gum solution (0.2%, w/w) at the ratio of 3:1 and 1:1 (v/v), respectively, CUR-MM-ISGs were formed and presented transparent appearance. Sustained release profile was obtained in vitro for both CUR-MM-ISGs (3:1 or 1:1, v/v). The irritation test proved that CUR-MM-ISGs as ophthalmic formulations were gentle and biocompatible towards ocular tissues. In addition, the ex vivo corneal penetration study indicated that the cumulative drug permeation amount of CUR-MM-ISGs (3:1, v/v) was respectively 1.16-fold and 1.32 fold higher than CUR-MM-ISGs (1:1, v/v) and curcumin solution. It can be concluded from these results that the developed ion-sensitive mixed micelle in situ gel system is a potential ophthalmic delivery carrier for curcumin as a poorly soluble drug. PMID- 25707751 TI - Synthesis and characterization of Bodipy functionalized magnetic iron oxide nanoparticles for potential bioimaging applications. AB - Multifunctional magnetic nanoparticles were synthesized for potential bio-imaging applications. Uniform PEI coated magnetic Fe3O4 (PEI-Fe3O4) nanoparticles were prepared by a modified co-precipitation method and then covalently conjugated with a fluorophore molecule, Bodipy-5 by the DCC/DMAP coupling reaction. The covalent binding of Bodipy-5 to the PEI coated magnetic Fe3O4 nanoparticles were confirmed by means of FTIR and XPS measurements. The imaging ability of the Bodipy coated magnetic nanoparticles was determined on two human cancer cells, A549 (human lung adenocarcinoma epithelial) and Ishikawa (endometrial adenocarcinoma), for the first time. Cytotoxicity of BOD-MNPs was evaluated in both cancer cells and healthy human umbilical vein endothelial cell line (HUVEC) by standard MTT (3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay. In vitro activities of the nanoparticles were also investigated. PMID- 25707752 TI - Inequities in cervical cancer screening among Colombian women: a multilevel analysis of a nationwide survey. AB - OBJECTIVES: To identify factors associated with whether women in Colombia have had a Pap test, evaluate differences in risk factors between rural and urban residence, and evaluate the contextual effect of the lack of education on having ever had a Pap test. METHOD: Data used were from the 2010 Colombian National Demographic and Health Survey; 40,392 women reported whether they have had a Pap test. A multilevel mixed logistic regression model was developed with random intercepts to account for clustering by neighbourhood and municipality. The model evaluated whether having a rural/urban area of residence modified the effect of identified risk factors and if the prevalence of no education at the neighbourhood level acted as a contextual effect. RESULTS: Most women (87.3%) reported having at least one Pap test. Women from lower socioeconomic quintiles (p=0.002), who were unemployed (p<0.001), and whose final health decisions depended on others (p<0.001) were less likely to have had a Pap test. Women with children were more likely to have had the test (p<0.001), and the effects of education (p=0.03), type of health insurance (p=0.01), age (p<0.001), and region (p<0.001) varied with having a rural/urban area of residence. Women living in rural areas (specifically younger ones, with no health insurance, living in the Atlantic and Amazon-Orinoquia regions, and with no education) were less likely to have had a Pap test when compared to those living in urban areas. Furthermore, women living in a neighbourhood with a higher prevalence of no education were less likely to have ever had a Pap test (p=0.005). CONCLUSIONS: In Colombia, the probability of having had a Pap test is associated with personal attributes, area of residence, and prevalence of no education in the neighbourhood. Efforts to improve access to cervical cancer screening should focus on disadvantaged women with limited education, low socioeconomic status, and no health insurance or subsidised insurance, especially those in rural/isolated areas. PMID- 25707753 TI - Ex vivo inhibition of Clostridium botulinum neurotoxin types B, C, E, and F by small molecular weight inhibitors. AB - Two small molecular weight inhibitors, compounds CB7969312 and CB7967495, that displayed inhibition of botulinum neurotoxin serotype A in a previous study, were evaluated for inhibition of botulinum neurotoxin serotypes B, C, E, and F. The small molecular weight inhibitors were assessed by molecular modeling, UPLC-based peptide cleavage assay; and an ex vivo assay, the mouse phrenic nerve - hemidiaphragm assay (MPNHDA). While both compounds were inhibitors of botulinum neurotoxin (BoNT) serotypes B, C, and F in the MPNHDA, compound CB7969312 was effective at lower molar concentrations than compound CB7967495. However, compound CB7967495 was significantly more effective at preventing BoNTE intoxication than compound CB7969312. In the UPLC-based peptide cleavage assay, CB7969312 was also more effective against LcC. Both compounds inhibited BoNTE, but not BoNTF, LcE, or LcF in the UPLC-based peptide cleavage assay. Molecular modeling studies predicted that both compounds would be effective inhibitors of BoNTs B, C, E, and F. But CB7967495 was predicted to be a more effective inhibitor of the four serotypes (B, C, E, and F) than CB7969312. This is the first report of a small molecular weight compound that inhibits serotypes B, C, E, and F in the ex vivo assay. PMID- 25707754 TI - Acute effects of intravenous nifedipine or azelnidipine on open-loop baroreflex static characteristics in rats. AB - AIMS: To assess the acute effects of intravenous azelnidipine, a third-generation L-type calcium channel blocker, on sympathetic outflow from the central nervous system and to compare the effects of intravenous azelnidipine with those of intravenous nifedipine. MAIN METHODS: In anesthetized Wistar Kyoto rats, carotid sinus baroreceptor regions were isolated. Changes in sympathetic nerve activity (SNA) and arterial pressure (AP) in response to a stepwise baroreceptor pressure input were examined before and during intravenous nifedipine or azelnidipine (for each: 100 MUg/kg bolus followed by 300 MUg/kg/h infusion, n = 6). KEY FINDINGS: Nifedipine significantly reduced the range of the AP response from 76.8 +/- 7.4 to 45.4 +/- 7.0 mmHg (P < 0.01) but did not affect the range of the SNA response (from 84.4 +/- 5.1 to 85.9 +/- 10.2%) or the SNA maximum gain (from 2.26 +/- 0.28 to 2.35 +/- 0.55%/mmHg). Similarly, azelnidipine significantly reduced the range of the AP response from 62.4 +/- 3.9 to 31.4 +/- 4.1 mmHg (P<0.01) but did not affect the range of the SNA response (from 71.2 +/- 5.5 to 74.9 +/- 7.2%) or the SNA maximum gain (from 1.64 +/- 0.17 to 2.08 +/- 0.26%/mmHg). SIGNIFICANCE: A depressor dose of nifedipine or azelnidipine does not have an acute sympathoinhibitory effect in normotensive Wistar Kyoto rats even when the level of SNA was varied over the entire operating range of the carotid sinus baroreflex. PMID- 25707755 TI - Arabidopsis Squalene Epoxidase 3 (SQE3) Complements SQE1 and Is Important for Embryo Development and Bulk Squalene Epoxidase Activity. AB - The existence of multigenic families in the mevalonate pathway suggests divergent functional roles for pathway components involved in the biosynthesis of plant sterols. Squalene epoxidases (SQEs) are key components of this pathway, and Squalene Epoxidase 1 (SQE1) has been identified as a fundamental enzyme in this biosynthetic step. In the present work, we extended the characterization of the remaining SQE family members, phylogenetically resolving between true SQEs and a subfamily of SQE-like proteins that is exclusive to Brassicaceae. Functional characterization of true SQE family members, Squalene Epoxidase 2 (SQE2) and Squalene Epoxidase 3 (SQE3), indicates that SQE3, but not SQE2, contributes to the bulk SQE activity in Arabidopsis, with sqe3-1 mutants accumulating squalene and displaying sensitivity to terbinafine. We genetically demonstrated that SQE3 seems to play a particularly significant role in embryo development. Also, SQE1 and SQE3 both localize in the endoplasmic reticulum, and SQE3 can functionally complement SQE1. Thus, SQE1 and SQE3 seem to be two functionally unequal redundant genes in the promotion of plant SQE activity in Arabidopsis. PMID- 25707756 TI - GeneCloud Reveals Semantic Enrichment in Lists of Gene Descriptions. PMID- 25707757 TI - ECRG4 acts as a tumor suppressor and as a determinant of chemotherapy resistance in human nasopharyngeal carcinoma. AB - BACKGROUND: Human nasopharyngeal carcinoma (NPC) is a malignant type of cancer with an increasing incidence. As yet, however, molecular biomarkers with a strong diagnostic impact and a major therapeutic promise have remained elusive. Here, we identified the esophageal carcinoma related gene 4 (ECRG4) as a novel candidate tumor suppressor gene and a promising therapeutic target for NPC. METHODS: RT PCR, Western blotting, methylation-specific PCR and bisulfite sequencing were performed to assess the expression and methylation status of the ECRG4 gene in primary NPC samples, NPC-derived cell lines and patient-derived peripheral blood samples. The NPC-derived cell line CNE1 was selected for treatment with a methylation inhibitor to restore ECRG4 expression. In addition, cell proliferation, invasion and colony formation assays were performed to assess the inhibitory effects of exogenous ECRG4 expression in CNE1 cells. RESULTS: Down regulated ECRG4 expression was found to occur in 82.5% (33/40) of the primary NPC biopsies tested. This down-regulation was significantly correlated with its tumor specific promoter methylation status (72.5%, 29/40) and was also observed in the matching peripheral blood samples from the NPC patients (57.5%, 23/40). Pharmacologic demethylation through 5-aza-dC treatment led to gene reactivation in ECRG4 methylated and silenced NPC cell lines. Moreover, exogenous expression of ECRG4 in the CNE1 cell line strongly inhibited its growth and invasive capacities, as well as its enhanced chemosensitivity to cisplatin through autophagy induction. CONCLUSION: Our data suggest that methylation-mediated suppression of the ECRG4 gene occurs frequently in NPC and that restoration of its expression may have therapeutic benefits. PMID- 25707758 TI - Lysine acetyltransferases cyclic adenosine monophosphate response element-binding binding protein and acetyltransferase p300 attenuate transcriptional activity of the mineralocorticoid receptor through its acetylation. AB - Acetylation of the mineralocorticoid receptor (MR) by inhibition of lysine deacetylases attenuates MR's transcriptional activity. However, the specific lysine acetyltransferases that are responsible for acetylation of the MR remain unknown. We hypothesized that the acetyltransferases cyclic adenosine monophosphate response element-binding binding protein (CBP) and acetyltransferase p300 (p300) attenuate transcriptional activity of the MR through its acetylation. Expression of MR target genes was measured by quantitative real-time polymerase chain reaction. Recruitment of MR and RNA polymerase II (Pol II) on promoters of target genes was analysed by chromatin immunoprecipitation. Acetylation of the MR was determined by western blot with an anti-acetyl-lysine antibody after immunoprecipitation with an anti-MR antibody. In human embryonic kidney (HEK) 293 cells, overexpression of CBP or p300, but not p300/CBP-associated factor, increased MR acetylation and decreased expression of MR target genes. The downregulation of target genes coincided with a decrease in the recruitment of MR and Pol II to specific hormone response elements. These results demonstrate that overexpression of CBP or p300 attenuates the transcriptional activity of the MR through its acetylation in HEK 293 cells. Our data provide strong evidence identifying CBP and p300 as lysine acetyltransferases responsible for the regulation of MR that may provide new therapeutic targets for the treatment of hypertension. PMID- 25707759 TI - Spirituality in pre-registration nurse education and practice: A review of the literature. AB - Spirituality is known to be an integral part of holistic care, yet research shows that it is not well valued or represented in nurse education and practice. However, the nursing profession continues to make efforts to redress the balance by issuing statements and guidance for the inclusion of spirituality by nurses in their practice. A systematic literature review was undertaken and confirms that nurses are aware of their lack of knowledge, understanding and skills in the area of spirituality and spiritual care, and desire to be better informed and skilled in this area. Consequently, in order for nurses to support the spiritual dimension of their role, nurse education has a vital part to play in raising spiritual awareness and facilitating competence and confidence in this domain. The literature review also reveals that studies involving pre-registration are few, but those available do provide examples of innovation and various teaching methods to deliver this topic in nursing curricular. PMID- 25707760 TI - Bricklebush (Brickellia) phylogeny reveals dimensions of the great Asteraceae radiation in Mexico. AB - Data from molecular phylogenetics were used to assess aspects of diversity and relationships in Brickellia, a large and widespread genus of Eupatorieae. The dataset included sequence data from nuclear ribosomal ITS, ETS, and plastid psbA trnH regions. An initial question was to assess the monophyly of the genus and whether Barroetea, Phanerostylis, and Kuhnia should be recognized as separate from or included in Brickellia. The results supported the hypothesis that Brickellia is monophyletic, with the small (2-3 species) Pleurocoronis as the sister group and showed Barroetea, Phanerostylis, and Kuhnia all embedded within the genus. Results of a time calibrated phylogeny from a BEAST analysis gave an estimated origination time for Brickellia at about 9 million years ago (Ma), with the oldest split within the genus dated at about 7.5Ma. A BAMM analysis based on the time calibrated tree showed that Brickellia has one rate shift in diversification associated with its origin in the late Miocene. Some lineages within the genus have had an increase in the rate of diversification over the past 5Ma, whereas other lineages have had a decrease in net diversification during this period. The results also elucidated nine clades within Brickellia which are accepted as taxonomic sections, and that will form logical units for future detailed studies. PMID- 25707761 TI - From the ground up: Integrative research in primate locomotion. AB - Primate locomotor adaptation and evolution is a principal and thriving area of research by biological anthropologists. Research in this field generally targets hypotheses regarding locomotor kinetics and kinematics, form-function associations in both the soft and hard tissue components of the musculoskeletal system, and reconstructing locomotor behavior in fossil primates. A wide array of methodological approaches is used to address adaptive hypotheses in all of these realms. Recent advances in three-dimensional shape capture, musculoskeletal physiological measurements, and analytical processing technologies (e.g., laser and CT-scans, 3D motion analysis systems, finite element analysis) have facilitated the collection and analysis of larger and more complex locomotor datasets than previously possible. With these advances in technology, new methods of form-function analyses can be developed to produce a more thorough understanding of how form reflects an organism's mechanical requirements, how shape is influenced by external environmental factors, and how these investigations of living taxa can inform questions of primate paleobiology. The papers in this special section of the American Journal of Physical Anthropology present research that builds on that foundation, by combining new data on living primates and new methodologies and approaches to answer a range of questions on extant and extinct primates. PMID- 25707764 TI - CT-proET1 predicts pulmonary hemodynamics in Scleroderma-associated pulmonary hypertension. PMID- 25707763 TI - Sex-related predictors for thromboembolic events after catheter ablation of atrial fibrillation: The Leipzig Heart Center AF Ablation Registry. AB - BACKGROUND: Females with atrial fibrillation (AF) are at increased risk for ischemic stroke but have been under-represented in AF ablation cohorts. Whether the incidence of TE in women after catheter ablation is higher is unknown. We aimed to analyze the predictive value of thromboembolic scores and other clinical variants for thromboembolism (TE) after AF catheter ablation, separately in women and men. METHODS: TE was combined endpoint of early (within first month) and late (during long-term follow-up) stroke, transient ischemic attack, or systemic embolism. Oral anticoagulation was prescribed for 6 months after catheter ablation and discontinued if CHADS2 was <2 and no AF recurrences were documented. RESULTS: The study population (n = 2,069, 66 % male, 60 +/- 10 years; 62 % paroxysmal AF) was followed for a median of 18 months (IQR 12-29). Overall 31 TE (1.5 %) occurred with 16 events within 30 days of ablation and 15 TE during the follow-up. Fourteen females (2.0 %) and 17 males (1.2 %) suffered TE (p = 0.128). On multivariate analysis, higher CHADS2 (HR 1.65, 95 % CI 1.10-2.47, p = 0.015), CHA2DS2-VASc (HR 1.42, 95 % CI 1.03-1.96, p = 0.034), R2CHADS2 (HR 1.76, 95 % CI 1.32-2.35, p < 0.001) scores, and eGFR <60 ml/min/1.73 m(2) (HR 3.95, 95 % CI 1.23-12.7, p = 0.021) were significantly associated with TE in men. In females, LV-EF (HR 0.95, 95 % CI 0.91-0.99, p = 0.021) and CHA2DS2-VASc score (HR 1.52, 95 % CI 1.01-2.28, p = 0.044) remained significant predictors for TE. CONCLUSION: TE rates after AF catheter ablation are low in both genders. In females, LV-EF and CHA2DS2-VASc score and in males all three scores and renal dysfunction were associated with TE. PMID- 25707765 TI - Prevalence and impact on outcome of electrocardiographic early repolarization patterns among stroke patients: a prospective observational study. AB - BACKGROUND: Early repolarization pattern (ER) gained attention as a risk factor for ventricular arrhythmia and sudden cardiac death in the general population. While electrocardiographic abnormalities are frequent findings in stroke patients, data on ER pattern in this population are lacking. METHODS: We assessed the prevalence of ER pattern in consecutive acute stroke patients at a tertiary stroke center. Functional outcome after 90 days was analyzed to determine the effect of an ER pattern on mortality. Multivariate logistic regression analysis was used to identify factors associated with an ER pattern. RESULTS: Out of 1141 consecutive stroke patients 771 patients remained for analysis after application of exclusion criteria. ER was observed in 62 (8.04%) patients. ER was more prevalent among subjects with intracerebral and subarachnoidal hemorrhage (13.0%) than among patients with ischemic stroke (7.0%; p = 0.024). Multiple regression analysis revealed QRS-duration (OR 0.972 95% CI 0.950-0.994, p = 0.012), QT duration (OR 1.009, 95% CI 1.004-1.014, p = 0.001) and mechanical ventilation on admission (OR 0.320, 95% CI 0.136-0.752, p = 0.009) as independent predictors for ER. Overall ER on admission was not associated with increased mortality at 3 month follow-up (ER 11.3% vs. non-ER 9.2%; p = 0.582). CONCLUSIONS: ER is frequently found among patients with acute cerebrovascular events and is more prevalent in patients with hemorrhagic compared to ischemic events. Our study yields no evidence that ER is associated with worse outcome or mortality after stroke. PMID- 25707766 TI - Common genetic basis for canopy temperature depression under heat and drought stress associated with optimized root distribution in bread wheat. AB - KEY MESSAGE: QTL related to cooler canopy temperatures are associated with optimal root distribution whereby roots proliferate at depth under drought or near to surface under hot, irrigated conditions. Previous research using a bread wheat RIL population of the Seri/Babax cross showed that common QTL were associated with cooler canopies under both drought and heat-stressed conditions. A subset of RIL was grown under water-limited and hot-irrigated field environments to test how cooler canopies are related to root development. Eight sisters and the two parents were used in the study with genotypes grouped as COOL or HOT according to their respective QTL for canopy temperature and previous phenotypic data. Root mass production and residual available soil moisture were measured around anthesis at four depth profiles (from 0 to 120 cm depth). When considering different root profiles, there was a clear interaction of QTL with environment. Under water stress, the COOL genotypes showed a deeper root system allowing the extraction of 35% more water from the 30-90 cm soil profile. The strategy under heat was to concentrate more roots at the surface, in the 0-60 cm soil layer where water was more available from surface irrigation. Since COOL genotypes showed better agronomic performance, it can be concluded that their QTL are associated with more optimal root distribution in accordance with water availability under the respective stresses. The study demonstrates the importance of root development under both water-limited and hot-irrigated environments, and shows a common genetic basis for adaptation to both stresses that appears to be associated with sensitivity of roots to proliferate where water is available in the soil profile. PMID- 25707767 TI - Microbial dynamics in glacier forefield soils show succession is not just skin deep. AB - All over the world, glaciers are receding. One key consequence of glacier area loss is the creation of new terrestrial habitats. This presents an experimental opportunity to study both community formation and the implications of glacier loss for terrestrial ecosystems. In this issue of Molecular Ecology, Rime et al. (2015) describe how microbial communities are structured according to soil depth and development in the forefield of Damma glacier in Switzerland. The study provides insights into the contrasting structures of microbial communities at different stages of soil development. An important strength of the study is the integration of soil depth into the paradigm of primary succession, a feature which has rarely been considered by other studies. These findings underscore the importance of studying the interactions between microbial communities and glaciers at a time when Earth's glacial systems are experiencing profound change. PMID- 25707768 TI - Integrated analyses to reconstruct microRNA-mediated regulatory networks in mouse liver using high-throughput profiling. AB - BACKGROUND: MicroRNAs (miRNAs) simultaneously target many transcripts through partial complementarity binding, and have emerged as a key type of post transcriptional regulator for gene expression. How miRNA accomplishes its pleiotropic effects largely depends on its expression and its target repertoire. Previous studies discovered thousands of miRNAs and numerous miRNA target genes mainly through computation and prediction methods which produced high rates of false positive prediction. The development of Argonaute cross-linked immunoprecipitation coupled with high-throughput sequencing (CLIP-Seq) provides a system to effectively determine miRNA target genes. Likewise, the accuracy of dissecting the transcriptional regulation of miRNA genes has been greatly improved by chromatin immunoprecipitation of the transcription factors coupled with sequencing (ChIP-Seq). Elucidation of the miRNA target repertoire will provide an in-depth understanding of the functional roles of microRNA pathways. To reliably reconstruct a miRNA-mediated regulatory network, we established a computational framework using publicly available, sequence-based transcription factor-miRNA databases, including ChIPBase and TransmiR for the TF-miRNA interactions, along with miRNA-target databases, including miRTarBase, TarBase and starBase, for the miRNA-target interactions. We applied the computational framework to elucidate the miRNA-mediated regulatory network in the Mir122a-/- mouse model, which has an altered transcriptome and progressive liver disease. RESULTS: We applied our computational framework to the expression profiles of miRNA/mRNA of Mir122a-/- mutant mice and wild-type mice. The miRNA-mediated network involves 40 curated TFs contributing to the aberrant expression of 65 miRNAs and 723 curated miRNA target genes, of which 56% was found in the differentially-expressed genes of Mir122a--mice. Hence, the regulatory network disclosed previously-known and also many previously-unidentified miRNA-mediated regulations in mutant mice. Moreover, we demonstrate that loss of imprinting at the chromosome 12qF1 region is associated with miRNA overexpression in human hepatocellular carcinoma and stem cells, suggesting initiation of precancerous changes in young mice deficient in miR-122. A group of 9 miRNAs was found to share miR-122 target genes, indicating synergy between miRNAs and target genes by way of multiplicity and cooperativity. CONCLUSIONS: The study provides significant insight into miRNA-mediated regulatory networks. Based on experimentally verified data, this network is highly reliable and effective in revealing previously-undetermined disease-associated molecular mechanisms. This computational framework can be applied to explore the significant TF-miRNA-miRNA target interactions in any complex biological systems with high degrees of confidence. PMID- 25707770 TI - Utility and cost-effectiveness of screening for hepatocellular carcinoma in a resource-limited setting. PMID- 25707769 TI - GATA2 promotes glioma progression through EGFR/ERK/Elk-1 pathway. AB - Among the gliomas, glioblastoma (GBM) is the highest grade and the most malignant glioma tumor. GATA2 is a hematopoietic factor that has been intensely studied in hematopoietic malignancies. Recently, the functions of GATA2 as an oncogene in other types of human cancer have been reported. However, no role for GATA2 in the development and progression of glioma has been reported to date. In the present study, we found that the expression level of GATA2 is upregulated in GBM and is correlated with GBM outcome. Ectopic expression of GATA2 or RNAi-mediated knockdown of GATA2 significantly enhanced or inhibited proliferation, migration and invasion of glioma cells. Moreover, we found that epidermal growth factor receptor and extracellular signal-regulated kinase, as upstream components of the signaling pathway, upregulate GATA2 expression; moreover, GATA2 promotes Elk-1 expression. Therefore, a genetic approach or pharmacological intervention targeting GATA2 could potentially serve as an effective strategy for treating glioma patients. PMID- 25707771 TI - Genetic variants in the Hippo pathway predict biochemical recurrence after radical prostatectomy for localized prostate cancer. AB - While localized prostate cancer is potentially curative, many patients still show biochemical recurrence (BCR) after curative treatments such as radical prostatectomy (RP). The Hippo pathway has recently been shown to be an evolutionarily conserved regulator of tissue growth, and its perturbation can trigger tumorigenesis. We hypothesize that genetic variants of the Hippo pathway may influence clinical outcomes in localized prostate cancer patients. We genotyped 53 tagging single-nucleotide polymorphisms (SNPs) from seven core Hippo pathway genes in 246 localized prostate cancer patients treated with RP. Kaplan Meier analysis and Cox proportional hazard models were utilized to identify significant SNPs that correlated with BCR. For replication, five associated SNPs were genotyped in an independent cohort of 212 patients. After adjusting for known clinicopathologic factors, the association between STK3 rs7827435 and BCR (P = 0.018) was replicated in the second stage (P = 0.026; Pcombined = 0.001). Additional integrated in silico analysis provided evidence that rs7827435 affects STK3 expression, which in turn is significantly correlated with tumor aggressiveness and patient prognosis. In conclusion, genetic variants of the Hippo pathway contribute to the variable outcomes of prostate cancer, and the discovery of these biomarkers provides a molecular approach for prognostic risk assessment. PMID- 25707773 TI - Pro-protein convertase subtilisin/kexin 9 concentrations correlate with coronary artery disease atheroma burden in a Pakistani cohort with chronic chest pain. AB - OBJECTIVE: To determine the relationship between proprotein convertase subtilisin kexin 9 (PCSK9) levels and atheroma burden in Pakistanis presenting to an ambulatory centre with chest pain. METHODS: A prospective matched case-control study of 400 patients selected for presence/absence of angiographic disease referred between 2001 and 2003. A comprehensive cardiovascular disease risk factor profile was assessed including demographics, environmental and biochemical risk factors including insulin resistance and PCSK-9 levels. Coronary atheroma burden was quantified by Gensini score. RESULTS: In this population, PCSK-9 levels were weakly correlated (r = 0.23) with male gender (p = 0.06) and number of diabetes years (p = 0.09), and inversely with log10 of lipoprotein (a) concentration (p = 0.07) but not LDL-C. In multiple regression analysis, Gensini score was associated with age (p = 0.002), established angina (p = 0.001), duration of diabetes (p = 0.05), low HDL-C (p < 0.001), lipoprotein (a) (p = 0.01), creatinine (p < 0.001), C-Reactive Protein (p = 0.02) and PSCK-9 (p = 0.05) concentrations. PCSK9 added to the regression model. Neither total cholesterol nor LDL-C were significant risk factors in this study. CONCLUSIONS: Proprotein convertase subtilisin kexin 9 concentrations are correlated with atheroma burden in Indian Asian populations from the sub-continent, not taking statin therapy, independent of LDL-C or other CVD risk factors. PMID- 25707774 TI - The source of the truth bias: Heuristic processing? AB - People believe others are telling the truth more often than they actually are; this is called the truth bias. Surprisingly, when a speaker is judged at multiple points across their statement the truth bias declines. Previous claims argue this is evidence of a shift from (biased) heuristic processing to (reasoned) analytical processing. In four experiments we contrast the heuristic-analytic model (HAM) with alternative accounts. In Experiment 1, the decrease in truth responding was not the result of speakers appearing more deceptive, but was instead attributable to the rater's processing style. Yet contrary to HAMs, across three experiments we found the decline in bias was not related to the amount of processing time available (Experiments 1-3) or the communication channel (Experiment 2). In Experiment 4 we found support for a new account: that the bias reflects whether raters perceive the statement to be internally consistent. PMID- 25707772 TI - Intracellular signals of lung cancer cells as possible therapeutic targets. AB - In recent years, several molecularly targeted therapies have been developed as part of lung cancer treatment; they have produced dramatically good results. However, among the many oncogenes that have been identified to be involved in the development of lung cancers, a number of oncogenes are not covered by these advanced therapies. For the treatment of lung cancers, which is a group of heterogeneous diseases, persistent effort in developing individual therapies based on the respective causal genes is important. In addition, for the development of a novel therapy, identification of the lung epithelial stem cells and the origin cells of lung cancer, and understanding about candidate cancer stem cells in lung cancer tissues, their intracellular signaling pathways, and the mechanism of dysregulation of the pathways in cancer cells are extremely important. However, the development of drug resistance by cancer cells, despite the use of molecularly targeted drugs for the causal genes, thus obstructing treatment, is a well-known phenomenon. In this article, we discuss major causal genes of lung cancers and intracellular signaling pathways involving those genes, and review studies on origin and stem cells of lung cancers, as well as the possibility of developing molecularly targeted therapies based on these studies. PMID- 25707775 TI - Factors affecting scientific productivity of German oral-maxillofacial surgery training centers: a retrospective cohort study. AB - PURPOSE: To identify factors associated with scientific productivity (SP) of German oral-maxillofacial surgery (OMFS) training centers. MATERIALS AND METHODS: This retrospective cohort study was composed of a set of data from German OMFS training centers. A total of eight predictor variables were grouped into demographic, structural, and personal categories. The outcome variables were average publications in 2013 per senior staff, and percentage of OMFS trainees with >1 publications. Descriptive and univariate statistics were computed using P < 0.05. RESULTS: The sample included outputs from 62 OMFS departments (34 [54.8 %] university-based; 46 [74.2 %] in large cities). Average publications were 2.4 +/- 3 per senior staff (range, 0-27), and 160 trainees (31.7 %) published >1 papers. The number of publications and productive trainees was not linked to department name and number of female senior staffs, but publication count was significantly increased when the hospital was in a metropolis (P = 0.018) or university-based (P < 0.0001), the OMFS' chairperson and >3 staffs within the department had a postdoctoral degree (German "Habilitation") (P = 0.013 and <0.0001), and the chairperson had h-index >10 or the first/last authorship in 2013 (P < 0.0001). Female senior surgeons were less scientifically productive than the male ones (P = 0.01). CONCLUSION: SP of German OMFS training centers is greatly different across the country and influenced by city size, university base, educational backgrounds, and research activities of chairpersons and senior staffs. This helps students, trainees, and young surgeons to reach the career choice that is personally appropriate. The involved organizations may need to encourage research output of less productive surgeons/centers. Increasing postdoctoral-qualified staffs will increase SP of the department. PMID- 25707776 TI - Phenotypic response of plants to simulated climate change in a long-term rain manipulation experiment: a multi-species study. AB - Many species will need to adapt to the observed climate change in order to persist. However, research about adaptation or phenotypic plasticity in response to climate change is rare. In particular, field studies are lacking that impose artificial selection for a sufficiently long time to elicit changes in phenotypic and genotypic structure of populations. Here, we present findings for an 8-year field experiment with 16 annual plant species that tested potentially adaptive phenotypic responses to precipitation change. In both a Mediterranean and a semi arid site, annual precipitation was manipulated (+/-30%) and phenotypic response was recorded. We measured flowering time as a key trait related to climatic conditions and biomass and survival as fitness correlates. Differences in traits among treatments were compared to trait shifts between sites, according to space for-time approaches. In the drier site, phenology was accelerated, but within that site, experimental drought delayed phenology, probably as a plastic response to delayed ontogenetic development. Biomass was smaller in the dry treatments of that site, but it was also reduced in irrigated plots in both sites, indicating more intense competition. The shifts from limitation by drought to limitation by competition corresponded to patterns along the gradient. This also implies a larger negative impact of climate change in the drier site. Our results suggest that experimental selection in the field caused directional responses in most species, but these were not necessarily adaptive. Furthermore, competitive release imposed by climate change may revert direct negative effects of rainfall change in determining plant performance. PMID- 25707777 TI - Disentangling the effects of shrubs and herbivores on tree regeneration in a dry Chaco forest (Argentina). AB - Successful persistence of dry forests depends on tree regeneration, which depends on a balance of complex biotic interactions. In particular, the relative importance and interactive effects of shrubs and herbivores on tree regeneration are unclear. In a manipulative study, we investigated if thornless shrubs have a direct net effect, an indirect positive effect mediated by livestock, and/or an indirect negative effect mediated by small vertebrates on tree regeneration of two key species of Chaco forest (Argentina). In a spatial association study, we also explored the existence of net positive interactions from thorny and thornless shrubs. The number of Schinopsis lorentzii seedlings was highest under artificial shade with native herbivores and livestock excluded. Even excluding livestock, no seedlings were found with natural conditions (native herbivores present with natural shade or direct sunlight) at the end of the experiment. Surprisingly, seedling recruitment was not enhanced under thornless shrubs, because there was a complementary positive effect of shade and interference. Moreover, thornless shrubs had neither positive nor negative effects on regeneration of S. lorentzii. Regeneration of Aspidosperma quebracho-blanco was minimal in all treatments. In agreement with the experiment, spatial distributions of saplings of both tree species were independent of thornless shrubs, but positively associated with thorny shrubs. Our results suggest that in general thornless shrubs may have a negligible effect and thorny shrubs a net positive effect on tree regeneration in dry forests. These findings provide a conceptual framework for testing the impact of biotic interactions on seedling recruitment in other dry forests. PMID- 25707778 TI - Metabolism. Exercise remodels subcutaneous fat tissue and improves metabolism. PMID- 25707780 TI - Reproductive endocrinology: Iodine intake in pregnancy--even a little excess is too much. PMID- 25707781 TI - Therapy. Aptamer-lipid nanoparticle conjugates for RNAi in bone. PMID- 25707782 TI - Autoimmunity. T1DM and the gut microbiome. PMID- 25707779 TI - The endocrinology of taste receptors. AB - Levels of obesity have reached epidemic proportions on a global scale, which has led to considerable increases in health problems and increased risk of several diseases, including cardiovascular and pulmonary diseases, cancer and diabetes mellitus. People with obesity consume more food than is needed to maintain an ideal body weight, despite the discrimination that accompanies being overweight and the wealth of available information that overconsumption is detrimental to health. The relationship between energy expenditure and energy intake throughout an individual's lifetime is far more complicated than previously thought. An improved comprehension of the relationships between taste, palatability, taste receptors and hedonic responses to food might lead to increased understanding of the biological underpinnings of energy acquisition, as well as why humans sometimes eat more than is needed and more than we know is healthy. This Review discusses the role of taste receptors in the tongue, gut, pancreas and brain and their hormonal involvement in taste perception, as well as the relationship between taste perception, overeating and the development of obesity. PMID- 25707783 TI - Thyroid gland: TSHR mutations and subclinical congenital hypothyroidism. PMID- 25707784 TI - Diabetes: Controlling glucose levels in elderly people--benefits versus risks. PMID- 25707785 TI - Metabolism. Hepatic insulin resistance--missing link identified. PMID- 25707786 TI - Beyond action-specific simulation: domain-general motor contributions to perception. AB - Preoccupation with action-specific simulation theory, whereby covert imitation is thought to facilitate action interpretation, has overshadowed evidence that motor structures facilitate perception of numerous visual events extending far beyond others' actions. In light of these domain-general motor contributions to perception, the case for a special role of motor representation in human action perception may be far weaker than widely believed. PMID- 25707787 TI - Education and imaging. Gastrointestinal: a case of histologically confirmed scrub typhus gastritis. PMID- 25707788 TI - Education and imaging. Gastrointestinal: Pancreatic metastatic renal cell carcinoma diagnosed by endoscopic ultrasound-guided fine needle aspiration cytology. PMID- 25707789 TI - Education and imaging. Gastrointestinal: a rare cause of small bowel obstruction, paracecal hernia. PMID- 25707790 TI - Education and imaging. Hepatology: Complete regression of locally advanced hepatocellular carcinoma following Sorafenib monotherapy. PMID- 25707791 TI - Education and imaging. Hepatology: Chilaiditi sign after right hepatectomy for hepatocellular carcinoma. PMID- 25707792 TI - A case of accidental fatal aluminum phosphide poisoning involving humans and dogs. AB - Aluminum phosphide is one of the commonest poisons encountered in agricultural areas, and manner of death in the victims is often suicidal and rarely homicidal or accidental. This paper presents an unusual case, where two humans (owner and housemaid) and eight dogs were found dead in the morning hours inside a room of a house, used as shelter for stray dogs. There was allegation by the son of the owner that his father had been killed. Crime scene visit by forensic pathologists helped to collect vital evidence. Autopsies of both the human victims and the dogs were conducted. Toxicological analysis of viscera, vomitus, leftover food, and chemical container at the crime scene tested positive for aluminum phosphide. The cause of death in both humans and dogs was aluminum phosphide poisoning. Investigation by police and the forensic approach to the case helped in ascertaining the manner of death, which was accidental. PMID- 25707793 TI - Differential DNA mismatch repair underlies mutation rate variation across the human genome. AB - Cancer genome sequencing has revealed considerable variation in somatic mutation rates across the human genome, with mutation rates elevated in heterochromatic late replicating regions and reduced in early replicating euchromatin. Multiple mechanisms have been suggested to underlie this, but the actual cause is unknown. Here we identify variable DNA mismatch repair (MMR) as the basis of this variation. Analysing ~17 million single-nucleotide variants from the genomes of 652 tumours, we show that regional autosomal mutation rates at megabase resolution are largely stable across cancer types, with differences related to changes in replication timing and gene expression. However, mutations arising after the inactivation of MMR are no longer enriched in late replicating heterochromatin relative to early replicating euchromatin. Thus, differential DNA repair and not differential mutation supply is the primary cause of the large scale regional mutation rate variation across the human genome. PMID- 25707794 TI - NIK1-mediated translation suppression functions as a plant antiviral immunity mechanism. AB - Plants and plant pathogens are subject to continuous co-evolutionary pressure for dominance, and the outcomes of these interactions can substantially impact agriculture and food security. In virus-plant interactions, one of the major mechanisms for plant antiviral immunity relies on RNA silencing, which is often suppressed by co-evolving virus suppressors, thus enhancing viral pathogenicity in susceptible hosts. In addition, plants use the nucleotide-binding and leucine rich repeat (NB-LRR) domain-containing resistance proteins, which recognize viral effectors to activate effector-triggered immunity in a defence mechanism similar to that employed in non-viral infections. Unlike most eukaryotic organisms, plants are not known to activate mechanisms of host global translation suppression to fight viruses. Here we demonstrate in Arabidopsis that the constitutive activation of NIK1, a leucine-rich repeat receptor-like kinase (LRR RLK) identified as a virulence target of the begomovirus nuclear shuttle protein (NSP), leads to global translation suppression and translocation of the downstream component RPL10 to the nucleus, where it interacts with a newly identified MYB-like protein, L10-INTERACTING MYB DOMAIN-CONTAINING PROTEIN (LIMYB), to downregulate translational machinery genes fully. LIMYB overexpression represses ribosomal protein genes at the transcriptional level, resulting in protein synthesis inhibition, decreased viral messenger RNA association with polysome fractions and enhanced tolerance to begomovirus. By contrast, the loss of LIMYB function releases the repression of translation related genes and increases susceptibility to virus infection. Therefore, LIMYB links immune receptor LRR-RLK activation to global translation suppression as an antiviral immunity strategy in plants. PMID- 25707795 TI - Integrase-mediated spacer acquisition during CRISPR-Cas adaptive immunity. AB - Bacteria and archaea insert spacer sequences acquired from foreign DNAs into CRISPR loci to generate immunological memory. The Escherichia coli Cas1-Cas2 complex mediates spacer acquisition in vivo, but the molecular mechanism of this process is unknown. Here we show that the purified Cas1-Cas2 complex integrates oligonucleotide DNA substrates into acceptor DNA to yield products similar to those generated by retroviral integrases and transposases. Cas1 is the catalytic subunit and Cas2 substantially increases integration activity. Protospacer DNA with free 3'-OH ends and supercoiled target DNA are required, and integration occurs preferentially at the ends of CRISPR repeats and at sequences adjacent to cruciform structures abutting AT-rich regions, similar to the CRISPR leader sequence. Our results demonstrate the Cas1-Cas2 complex to be the minimal machinery that catalyses spacer DNA acquisition and explain the significance of CRISPR repeats in providing sequence and structural specificity for Cas1-Cas2 mediated adaptive immunity. PMID- 25707796 TI - Hypothalamic POMC neurons promote cannabinoid-induced feeding. AB - Hypothalamic pro-opiomelanocortin (POMC) neurons promote satiety. Cannabinoid receptor 1 (CB1R) is critical for the central regulation of food intake. Here we test whether CB1R-controlled feeding in sated mice is paralleled by decreased activity of POMC neurons. We show that chemical promotion of CB1R activity increases feeding, and notably, CB1R activation also promotes neuronal activity of POMC cells. This paradoxical increase in POMC activity was crucial for CB1R induced feeding, because designer-receptors-exclusively-activated-by-designer drugs (DREADD)-mediated inhibition of POMC neurons diminishes, whereas DREADD mediated activation of POMC neurons enhances CB1R-driven feeding. The Pomc gene encodes both the anorexigenic peptide alpha-melanocyte-stimulating hormone, and the opioid peptide beta-endorphin. CB1R activation selectively increases beta endorphin but not alpha-melanocyte-stimulating hormone release in the hypothalamus, and systemic or hypothalamic administration of the opioid receptor antagonist naloxone blocks acute CB1R-induced feeding. These processes involve mitochondrial adaptations that, when blocked, abolish CB1R-induced cellular responses and feeding. Together, these results uncover a previously unsuspected role of POMC neurons in the promotion of feeding by cannabinoids. PMID- 25707798 TI - HIV: tied down by its own receptor. PMID- 25707799 TI - Microbiology: How bacteria get spacers from invaders. PMID- 25707797 TI - AAV-expressed eCD4-Ig provides durable protection from multiple SHIV challenges. AB - Long-term in vivo expression of a broad and potent entry inhibitor could circumvent the need for a conventional vaccine for HIV-1. Adeno-associated virus (AAV) vectors can stably express HIV-1 broadly neutralizing antibodies (bNAbs). However, even the best bNAbs neutralize 10-50% of HIV-1 isolates inefficiently (80% inhibitory concentration (IC80) > 5 MUg ml(-1)), suggesting that high concentrations of these antibodies would be necessary to achieve general protection. Here we show that eCD4-Ig, a fusion of CD4-Ig with a small CCR5 mimetic sulfopeptide, binds avidly and cooperatively to the HIV-1 envelope glycoprotein (Env) and is more potent than the best bNAbs (geometric mean half maximum inhibitory concentration (IC50) < 0.05 MUg ml(-1)). Because eCD4-Ig binds only conserved regions of Env, it is also much broader than any bNAb. For example, eCD4-Ig efficiently neutralized 100% of a diverse panel of neutralization-resistant HIV-1, HIV-2 and simian immunodeficiency virus isolates, including a comprehensive set of isolates resistant to the CD4-binding site bNAbs VRC01, NIH45-46 and 3BNC117. Rhesus macaques inoculated with an AAV vector stably expressed 17-77 MUg ml(-1) of fully functional rhesus eCD4-Ig for more than 40 weeks, and these macaques were protected from several infectious challenges with SHIV-AD8. Rhesus eCD4-Ig was also markedly less immunogenic than rhesus forms of four well-characterized bNAbs. Our data suggest that AAV-delivered eCD4-Ig can function like an effective HIV-1 vaccine. PMID- 25707800 TI - Neuroscience: a cellular basis for the munchies. PMID- 25707802 TI - Structure of the E. coli ribosome-EF-Tu complex at <3 A resolution by Cs corrected cryo-EM. AB - Single particle electron cryomicroscopy (cryo-EM) has recently made significant progress in high-resolution structure determination of macromolecular complexes due to improvements in electron microscopic instrumentation and computational image analysis. However, cryo-EM structures can be highly non-uniform in local resolution and all structures available to date have been limited to resolutions above 3 A. Here we present the cryo-EM structure of the 70S ribosome from Escherichia coli in complex with elongation factor Tu, aminoacyl-tRNA and the antibiotic kirromycin at 2.65-2.9 A resolution using spherical aberration (Cs) corrected cryo-EM. Overall, the cryo-EM reconstruction at 2.9 A resolution is comparable to the best-resolved X-ray structure of the E. coli 70S ribosome (2.8 A), but provides more detailed information (2.65 A) at the functionally important ribosomal core. The cryo-EM map elucidates for the first time the structure of all 35 rRNA modifications in the bacterial ribosome, explaining their roles in fine-tuning ribosome structure and function and modulating the action of antibiotics. We also obtained atomic models for flexible parts of the ribosome such as ribosomal proteins L9 and L31. The refined cryo-EM-based model presents the currently most complete high-resolution structure of the E. coli ribosome, which demonstrates the power of cryo-EM in structure determination of large and dynamic macromolecular complexes. PMID- 25707801 TI - Crystal structure of the V(D)J recombinase RAG1-RAG2. AB - V(D)J recombination in the vertebrate immune system generates a highly diverse population of immunoglobulins and T-cell receptors by combinatorial joining of segments of coding DNA. The RAG1-RAG2 protein complex initiates this site specific recombination by cutting DNA at specific sites flanking the coding segments. Here we report the crystal structure of the mouse RAG1-RAG2 complex at 3.2 A resolution. The 230-kilodalton RAG1-RAG2 heterotetramer is 'Y-shaped', with the amino-terminal domains of the two RAG1 chains forming an intertwined stalk. Each RAG1-RAG2 heterodimer composes one arm of the 'Y', with the active site in the middle and RAG2 at its tip. The RAG1-RAG2 structure rationalizes more than 60 mutations identified in immunodeficient patients, as well as a large body of genetic and biochemical data. The architectural similarity between RAG1 and the hairpin-forming transposases Hermes and Tn5 suggests the evolutionary conservation of these DNA rearrangements. PMID- 25707803 TI - Observation of antiferromagnetic correlations in the Hubbard model with ultracold atoms. AB - Ultracold atoms in optical lattices have great potential to contribute to a better understanding of some of the most important issues in many-body physics, such as high-temperature superconductivity. The Hubbard model--a simplified representation of fermions moving on a periodic lattice--is thought to describe the essential details of copper oxide superconductivity. This model describes many of the features shared by the copper oxides, including an interaction-driven Mott insulating state and an antiferromagnetic (AFM) state. Optical lattices filled with a two-spin-component Fermi gas of ultracold atoms can faithfully realize the Hubbard model with readily tunable parameters, and thus provide a platform for the systematic exploration of its phase diagram. Realization of strongly correlated phases, however, has been hindered by the need to cool the atoms to temperatures as low as the magnetic exchange energy, and also by the lack of reliable thermometry. Here we demonstrate spin-sensitive Bragg scattering of light to measure AFM spin correlations in a realization of the three dimensional Hubbard model at temperatures down to 1.4 times that of the AFM phase transition. This temperature regime is beyond the range of validity of a simple high-temperature series expansion, which brings our experiment close to the limit of the capabilities of current numerical techniques, particularly at metallic densities. We reach these low temperatures using a compensated optical lattice technique, in which the confinement of each lattice beam is compensated by a blue detuned laser beam. The temperature of the atoms in the lattice is deduced by comparing the light scattering to determinant quantum Monte Carlo simulations and numerical linked-cluster expansion calculations. Further refinement of the compensated lattice may produce even lower temperatures which, along with light scattering thermometry, would open avenues for producing and characterizing other novel quantum states of matter, such as the pseudogap regime and correlated metallic states of the two-dimensional Hubbard model. PMID- 25707804 TI - An epigenome-wide association study of total serum immunoglobulin E concentration. AB - Immunoglobulin E (IgE) is a central mediator of allergic (atopic) inflammation. Therapies directed against IgE can alleviate hay fever and allergic asthma. Genetic association studies have not yet identified novel therapeutic targets or pathways underlying IgE regulation. We therefore surveyed epigenetic associations between serum IgE concentrations and methylation at loci concentrated in CpG islands genome wide in 95 nuclear pedigrees, using DNA from peripheral blood leukocytes. We validated positive results in additional families and in subjects from the general population. Here we show replicated associations--with a meta analysis false discovery rate less than 10(-4)--between IgE and low methylation at 36 loci. Genes annotated to these loci encode known eosinophil products, and also implicate phospholipid inflammatory mediators, specific transcription factors and mitochondrial proteins. We confirmed that methylation at these loci differed significantly in isolated eosinophils from subjects with and without asthma and high IgE levels. The top three loci accounted for 13% of IgE variation in the primary subject panel, explaining the tenfold higher variance found compared with that derived from large single-nucleotide polymorphism genome-wide association studies. This study identifies novel therapeutic targets and biomarkers for patient stratification for allergic diseases. PMID- 25707805 TI - Horizontal membrane-intrinsic alpha-helices in the stator a-subunit of an F-type ATP synthase. AB - ATP, the universal energy currency of cells, is produced by F-type ATP synthases, which are ancient, membrane-bound nanomachines. F-type ATP synthases use the energy of a transmembrane electrochemical gradient to generate ATP by rotary catalysis. Protons moving across the membrane drive a rotor ring composed of 8-15 c-subunits. A central stalk transmits the rotation of the c-ring to the catalytic F1 head, where a series of conformational changes results in ATP synthesis. A key unresolved question in this fundamental process is how protons pass through the membrane to drive ATP production. Mitochondrial ATP synthases form V-shaped homodimers in cristae membranes. Here we report the structure of a native and active mitochondrial ATP synthase dimer, determined by single-particle electron cryomicroscopy at 6.2 A resolution. Our structure shows four long, horizontal membrane-intrinsic alpha-helices in the a-subunit, arranged in two hairpins at an angle of approximately 70 degrees relative to the c-ring helices. It has been proposed that a strictly conserved membrane-embedded arginine in the a-subunit couples proton translocation to c-ring rotation. A fit of the conserved carboxy terminal a-subunit sequence places the conserved arginine next to a proton binding c-subunit glutamate. The map shows a slanting solvent-accessible channel that extends from the mitochondrial matrix to the conserved arginine. Another hydrophilic cavity on the lumenal membrane surface defines a direct route for the protons to an essential histidine-glutamate pair. Our results provide unique new insights into the structure and function of rotary ATP synthases and explain how ATP production is coupled to proton translocation. PMID- 25707806 TI - Exit from dormancy provokes DNA-damage-induced attrition in haematopoietic stem cells. AB - Haematopoietic stem cells (HSCs) are responsible for the lifelong production of blood cells. The accumulation of DNA damage in HSCs is a hallmark of ageing and is probably a major contributing factor in age-related tissue degeneration and malignant transformation. A number of accelerated ageing syndromes are associated with defective DNA repair and genomic instability, including the most common inherited bone marrow failure syndrome, Fanconi anaemia. However, the physiological source of DNA damage in HSCs from both normal and diseased individuals remains unclear. Here we show in mice that DNA damage is a direct consequence of inducing HSCs to exit their homeostatic quiescent state in response to conditions that model physiological stress, such as infection or chronic blood loss. Repeated activation of HSCs out of their dormant state provoked the attrition of normal HSCs and, in the case of mice with a non functional Fanconi anaemia DNA repair pathway, led to a complete collapse of the haematopoietic system, which phenocopied the highly penetrant bone marrow failure seen in Fanconi anaemia patients. Our findings establish a novel link between physiological stress and DNA damage in normal HSCs and provide a mechanistic explanation for the universal accumulation of DNA damage in HSCs during ageing and the accelerated failure of the haematopoietic system in Fanconi anaemia patients. PMID- 25707808 TI - Mining the bladder cancer-associated genes by an integrated strategy for the construction and analysis of differential co-expression networks. AB - BACKGROUND: Bladder cancer is the most common malignant tumor of the urinary system and it is a heterogeneous disease with both superficial and invasive growth. However, its aetiological agent is still unclear. And it is indispensable to find key genes or modules causing the bladder cancer. Based on gene expression microarray datasets, constructing differential co-expression networks (DCNs) is an important method to investigate diseases and there have been some relevant good tools such as R package 'WGCNA', 'DCGL'. RESULTS: Employing an integrated strategy, 36 up-regulated differentially expressed genes (DEGs) and 356 down regulated DEGs were selected and main functions of those DEGs are cellular physiological precess(24 up-regulated DEGs; 167 down-regulated DEGs) and cellular metabolism (19 up-regulated DEGs; 104 down-regulated DEGs). The up-regulated DEGs are mainly involved in the the pathways related to "metabolism". By comparing two DCNs between the normal and cancer states, we found some great changes in hub genes and topological structure, which suggest that the modules of two different DCNs change a lot. Especially, we screened some hub genes of a differential subnetwork between the normal and the cancer states and then do bioinformatics analysis for them. CONCLUSIONS: Through constructing and analyzing two differential co-expression networks at different states using the screened DEGs, we found some hub genes associated with the bladder cancer. The results of the bioinformatics analysis for those hub genes will support the biological experiments and the further treatment of the bladder cancer. PMID- 25707807 TI - Cas9 specifies functional viral targets during CRISPR-Cas adaptation. AB - Clustered regularly interspaced short palindromic repeat (CRISPR) loci and their associated (Cas) proteins provide adaptive immunity against viral infection in prokaryotes. Upon infection, short phage sequences known as spacers integrate between CRISPR repeats and are transcribed into small RNA molecules that guide the Cas9 nuclease to the viral targets (protospacers). Streptococcus pyogenes Cas9 cleavage of the viral genome requires the presence of a 5'-NGG-3' protospacer adjacent motif (PAM) sequence immediately downstream of the viral target. It is not known whether and how viral sequences flanked by the correct PAM are chosen as new spacers. Here we show that Cas9 selects functional spacers by recognizing their PAM during spacer acquisition. The replacement of cas9 with alleles that lack the PAM recognition motif or recognize an NGGNG PAM eliminated or changed PAM specificity during spacer acquisition, respectively. Cas9 associates with other proteins of the acquisition machinery (Cas1, Cas2 and Csn2), presumably to provide PAM-specificity to this process. These results establish a new function for Cas9 in the genesis of prokaryotic immunological memory. PMID- 25707809 TI - Molecular docking based virtual screening of natural compounds as potential BACE1 inhibitors: 3D QSAR pharmacophore mapping and molecular dynamics analysis. AB - Beta-site APP cleaving enzyme1 (BACE1) catalyzes the rate determining step in the generation of Abeta peptide and is widely considered as a potential therapeutic drug target for Alzheimer's disease (AD). Active site of BACE1 contains catalytic aspartic (Asp) dyad and flap. Asp dyad cleaves the substrate amyloid precursor protein with the help of flap. Currently, there are no marketed drugs available against BACE1 and existing inhibitors are mostly pseudopeptide or synthetic derivatives. There is a need to search for a potent inhibitor with natural scaffold interacting with flap and Asp dyad. This study screens the natural database InterBioScreen, followed by three-dimensional (3D) QSAR pharmacophore modeling, mapping, in silico ADME/T predictions to find the potential BACE1 inhibitors. Further, molecular dynamics of selected inhibitors were performed to observe the dynamic structure of protein after ligand binding. All conformations and the residues of binding region were stable but the flap adopted a closed conformation after binding with the ligand. Bond oligosaccharide interacted with the flap as well as catalytic dyad via hydrogen bond throughout the simulation. This led to stabilize the flap in closed conformation and restricted the entry of substrate. Carbohydrates have been earlier used in the treatment of AD because of their low toxicity, high efficiency, good biocompatibility, and easy permeability through the blood-brain barrier. Our finding will be helpful in identify the potential leads to design novel BACE1 inhibitors for AD therapy. PMID- 25707810 TI - Serum MicroRNA-21 as a Biomarker for Allergic Inflammatory Disease in Children. AB - MicroRNAs (miRs) have emerged as useful biomarkers for different disease states, including allergic inflammatory diseases such as asthma and eosinophilic esophagitis (EoE). Serum miRs are a possible non-invasive method for diagnosis of such diseases. We focused on microRNA-21 (miR-21) levels in serum, in order to assess the feasibility of using this gene as a non-invasive biomarker for these diseases in the clinic, as well as to better understand the expression pattern of miR-21 in allergic inflammation. We used quantitative PCR (QPCR) to assay miR-21 and other control miRs in esophageal biopsies from EoE patients and serum samples from EoE and asthma patients. Serum levels of miR-21 were significantly elevated in patients with asthma, whereas serum miR-21 levels were not associated with the presence of allergen-specific IgE (i.e. atopy). Esophageal biopsies showed a large elevation of miR-21 in EoE and an increase in miR-21 in EoE serum. Control U6 miR did not vary between asthma and control patients, however EoE serum had significantly decreased U6 microRNA compared to controls. The decreased U6 in EoE sera did not completely account for the relative increase in miR-21 in the sera of EoE patients. We report for the first time that miR-21 is elevated in the sera of both asthma and EoE patients. We find no relation between serum miR-21 levels and atopy. Our results thus suggest miR-21 is a novel biomarker for human allergic inflammatory diseases. PMID- 25707811 TI - Estimating copy numbers of alleles from population-scale high-throughput sequencing data. AB - BACKGROUND: With the recent development of microarray and high-throughput sequencing (HTS) technologies, a number of studies have revealed catalogs of copy number variants (CNVs) and their association with phenotypes and complex traits. In parallel, a number of approaches to predict CNV regions and genotypes are proposed for both microarray and HTS data. However, only a few approaches focus on haplotyping of CNV loci. RESULTS: We propose a novel approach to infer copy unit alleles and their numbers in each sample simultaneously from population scale HTS data by variational Bayesian inference on a generative probabilistic model inspired by latent Dirichlet allocation, which is a well studied model for document classification problems. In simulation studies, we evaluated concordance between inferred and true copy unit alleles for lower-, middle-, and higher-copy number dataset, in which precision and recall were >= 0.9 for data with mean coverage >= 10* per copy unit. We also applied the approach to HTS data of 1123 samples at highly variable salivary amylase gene locus and a pseudogene locus, and confirmed consistency of the estimated alleles within samples belonging to a trio of CEPH/Utah pedigree 1463 with 11 offspring. CONCLUSIONS: Our proposed approach enables detailed analysis of copy number variations, such as association study between copy unit alleles and phenotypes or biological features including human diseases. PMID- 25707812 TI - Men's experience with penile rehabilitation following radical prostatectomy: a qualitative study with the goal of informing a therapeutic intervention. AB - BACKGROUND: Erectile rehabilitation (ER) following radical prostatectomy (RP) is considered an essential component to help men regain erectile functioning; however, many men have difficulty adhering to this type of program. This qualitative study explored men's experience with ER, erectile dysfunction (ED), and ED treatments to inform a psychological intervention designed to help men adhere to ER post-RP. METHODS: Thirty men, 1-to-3-years post-RP, who took part in an ER program, participated in one of four focus groups. Thematic analysis was used to identify the primary themes. RESULTS: Average age was 59 years (standard deviation = 7); mean time since surgery was 26 months (standard deviation = 6). Six primary themes emerged: (1) frustration with the lack of information about postsurgery ED; (2) negative emotional impact of ED and avoidance of sexual situations; (3) negative emotional experience with penile injections and barriers leading to avoidance; (4) the benefit of focusing on the long-term advantage of ER versus short-term anxiety; (5) using humor to help cope; and (6) the benefit of support from partners and peers. CONCLUSIONS: Men's frustration surrounding ED can lead to avoidance of sexual situations and ED treatments, which negatively impact men's adherence to an ER program. The theoretical construct of acceptance and commitment therapy was used to place the themes into a framework to conceptualize the mechanisms underlying both avoidance and adherence in this population. As such, acceptance and commitment therapy has the potential to serve as a conceptual underpinning of a psychological intervention to help men reduce avoidance to penile injections and adhere to an ER program. PMID- 25707813 TI - Impact of blood transfusions and transfusion practices on long-term outcome following hepatopancreaticobiliary surgery. AB - BACKGROUND: The long-term impact of transfusions with packed red blood cells (PRBC) among patients undergoing hepatopancreaticobiliary (HPB) surgery remains ill-defined. We sought to determine the impact of overall blood utilization, as well as a restrictive transfusion strategy, on long-term outcomes among patients undergoing an HPB resection for a malignancy. METHODS: Data on overall blood utilization and hemoglobin (Hb) levels that triggered a transfusion were obtained for patients with cancer undergoing pancreas or liver surgery between 2009 and 2013. Risk-adjusted recurrence-free (RFS) and overall survival (OS) were assessed based on receipt of PRBC and whether the patient received a transfusion using a restrictive transfusion strategy (intraoperative: Hb <10 g/dL; postoperative: Hb <8 g/dL). RESULTS: Four hundred forty-two patients underwent either a pancreas (58.1 %) or liver (41.9 %) resection. Most tumors were pancreatic in origin (41.8 %), while a subset were primary (23.1 %) or secondary (18.8 %) liver tumors. One hundred seventy-five (39.6 %) patients received >=1 PRBC transfusion either intraoperatively (16.7 %), postoperatively (12.7 %), or both (10.2 %). There was a higher incidence of PRBC transfusion among patients undergoing a pancreas resection, those with higher comorbidities, and those with lower preoperative Hb levels. Perioperative morbidity was higher among patients receiving either 1-2 units (OR 3.14) or 3 or more units of PRBC (OR 8.54). Median OS was 31.9 months. Receipt of a blood transfusion was associated with a worse OS (1-2 units: HR 1.76; 3+units: HR 2.50; both P<0.05), and RFS (3+units: HR 2.91; P=0.02). Utilization of a restrictive transfusion strategy did not impact perioperative morbidity or long-term RFS or OS. CONCLUSIONS: Adoption of a more restrictive transfusion strategy in patients undergoing resection for cancer may preserve a limited resource, reduce costs, as well as avoid exposing oncology patients to the unnecessary risks associated with a transfusion. PMID- 25707814 TI - Bouveret's Syndrome Resulting in Gallstone Ileus. PMID- 25707815 TI - Targeted ultrasound contrast agents for ultrasound molecular imaging and therapy. AB - Ultrasound contrast agents (UCAs) are used routinely in the clinic to enhance contrast in ultrasonography. More recently, UCAs have been functionalised by conjugating ligands to their surface to target specific biomarkers of a disease or a disease process. These targeted UCAs (tUCAs) are used for a wide range of pre-clinical applications including diagnosis, monitoring of drug treatment, and therapy. In this review, recent achievements with tUCAs in the field of molecular imaging, evaluation of therapy, drug delivery, and therapeutic applications are discussed. We present the different coating materials and aspects that have to be considered when manufacturing tUCAs. Next to tUCA design and the choice of ligands for specific biomarkers, additional techniques are discussed that are applied to improve binding of the tUCAs to their target and to quantify the strength of this bond. As imaging techniques rely on the specific behaviour of tUCAs in an ultrasound field, it is crucial to understand the characteristics of both free and adhered tUCAs. To image and quantify the adhered tUCAs, the state of-the-art techniques used for ultrasound molecular imaging and quantification are presented. This review concludes with the potential of tUCAs for drug delivery and therapeutic applications. PMID- 25707816 TI - Intra-abdominal temperature distribution during consolidation hyperthermic intraperitoneal chemotherapy with carboplatin in the treatment of advanced stage ovarian carcinoma. AB - PURPOSE: Hyperthermic intraperitoneal chemotherapy (HIPEC) involves the continuous heating and circulation of chemotherapy throughout the abdominal cavity in an attempt to enhance cytotoxicity. Despite the potential of this chemotherapy procedure, there are scant anatomical temperature distribution studies reporting on this therapeutic process. PATIENTS AND METHODS: We prospectively evaluated the temperature of select anatomical (e.g. upper abdominal, mid-abdominal and supra-pubic) sites in 11 advanced stage ovarian cancer patients who were treated with consolidation HIPEC carboplatin (AUC 10). The temperature of the aforementioned anatomical regions and the inflow/outflow tubing was measured at baseline and at 15-min intervals until the procedure's completion. RESULTS: The lowest observed mean composite temperature was 41.1 degrees C at the supra-pubic site whereas the highest temperature was 42.6 degrees C, in association with the inflow/outflow tubing. During the various time intervals we also ascertained that the lowest composite temperature was 40.9 degrees C at baseline (i.e. time 0), whereas the highest value (41.8 degrees C) occurred at multiple time periods (e.g., 15, 45 and 60 min). CONCLUSION: The HIPEC temperature variation amongst the various abdominal sites and time intervals was minimal. We also discerned that uniform temperature distribution throughout the abdominal cavity was facilitated when the abdomen was both maximally distended with fluid and a high flow rate was maintained. PMID- 25707818 TI - Two strategies for the acute response to cold exposure but one strategy for the response to heat stress. AB - PURPOSE: The main aim of this study was to compare physiological and psychological reactions to heat stress between people who exhibited fast cooling (FC, n = 20) or slow cooling (SC; n = 20) responses to 14 degrees C cold water immersion. METHODS: Forty healthy young men (19-25 years old) were recruited to this study based on their tolerance to cold exposure (FC versus SC). The heat stress was induced using immersion in bath water at 43-44 degrees C. Motor and cognitive performance, immune variables, markers of hypothalamic-pituitary adrenal axis activity (i.e. stress hormone concentrations), and autonomic nervous system activity were monitored. RESULTS: In the FC group, time to warm the body from a resting rectal temperature (Tre) of 37.1 +/- 0.2 degrees C before warming to 39.5 degrees C was 63.7 +/- 22.4 min. In the SC group, the time to warm the body from a Tre 37.1 +/- 0.3 degrees C before warming to 39.5 degrees C was 67.2 +/- 13.8 min (p > 0.05 between groups). The physiological stress index (PSI) after warming was 8.0 +/- 0.6 and 8.2 +/- 1.0 in the FC and SC groups, respectively (p > 0.05 between groups). During warming, the changes in subjective indicators of heat stress did not differ significantly between the FC (7.4 +/- 0.5) and SC (7.1 +/- 1.1) groups, respectively. CONCLUSION: The increase in cortisol, epinephrine, norepinephrine, and corticosterone concentrations after passive body heating did not differ between the FC and SC groups. Heat stress did not change indicators of innate and specific immunity in the FC or the SC group. An interesting finding was that heat stress did not affect motor and cognitive function in either group, although central fatigue during 1-min maximal voluntary contraction increased after heat stress in both groups. PMID- 25707817 TI - Histotripsy methods in mechanical disintegration of tissue: towards clinical applications. AB - In high intensity focused ultrasound (HIFU) therapy, an ultrasound beam is focused within the body to locally affect the targeted site without damaging intervening tissues. The most common HIFU regime is thermal ablation. Recently there has been increasing interest in generating purely mechanical lesions in tissue (histotripsy). This paper provides an overview of several studies on the development of histotripsy methods toward clinical applications. Two histotripsy approaches and examples of their applications are presented. In one approach, sequences of high-amplitude, short (microsecond-long), focused ultrasound pulses periodically produce dense, energetic bubble clouds that mechanically disintegrate tissue. In an alternative approach, longer (millisecond-long) pulses with shock fronts generate boiling bubbles and the interaction of shock fronts with the resulting vapour cavity causes tissue disintegration. Recent preclinical studies on histotripsy are reviewed for treating benign prostatic hyperplasia (BPH), liver and kidney tumours, kidney stone fragmentation, enhancing anti tumour immune response, and tissue decellularisation for regenerative medicine applications. Potential clinical advantages of the histotripsy methods are discussed. Histotripsy methods can be used to mechanically ablate a wide variety of tissues, whilst selectivity sparing structures such as large vessels. Both ultrasound and MR imaging can be used for targeting and monitoring the treatment in real time. Although the two approaches utilise different mechanisms for tissue disintegration, both have many of the same advantages and offer a promising alternative method of non-invasive surgery. PMID- 25707819 TI - On the mechanism of phosphoenolpyruvate synthetase (PEPs) and its inhibition by sodium fluoride: potential magnesium and aluminum fluoride complexes of phosphoryl transfer. AB - Phosphoenolpyruvate synthase (PEPs) catalyzes the conversion of pyruvate to phosphoenolpyruvate (PEP) using a two-step mechanism invoking a phosphorylated His intermediate. Formation of PEP is an initial step in gluconeogenesis, and PEPs is essential for growth of Escherichia coli on 3-carbon sources such as pyruvate. The production of PEPs has also been linked to bacterial virulence and antibiotic resistance. As such, PEPs is of interest as a target for antibiotic development, and initial investigations of PEPs have indicated inhibition by sodium fluoride. Similar inhibition has been observed in a variety of phospho transfer enzymes through the formation of metal fluoride complexes within the active site. Herein we quantify the inhibitory capacity of sodium fluoride through a coupled spectrophotometric assay. The observed inhibition provides indirect evidence for the formation of a MgF3(-) complex within the enzyme active site and insight into the phospho-transfer mechanism of PEPs. The effect of AlCl3 on PEPs enzyme activity was also assessed and found to decrease substrate binding and turnover. PMID- 25707820 TI - (-)-Englerin A is a potent and selective activator of TRPC4 and TRPC5 calcium channels. AB - Current therapies for common types of cancer such as renal cell cancer are often ineffective and unspecific, and novel pharmacological targets and approaches are in high demand. Here we show the unexpected possibility for the rapid and selective killing of renal cancer cells through activation of calcium-permeable nonselective transient receptor potential canonical (TRPC) calcium channels by the sesquiterpene (-)-englerin A. This compound was found to be a highly efficient, fast-acting, potent, selective, and direct stimulator of TRPC4 and TRPC5 channels. TRPC4/5 activation through a high-affinity extracellular (-) englerin A binding site may open up novel opportunities for drug discovery aimed at renal cancer. PMID- 25707821 TI - In vitro assessment of tooth color alteration by two different types of endodontic irrigants. AB - AIM: The purpose of this study was to assess in vitro the tooth color alterations associated with two commonly used endodontic irrigants, the chlorhexidine gluconate (CHX) and the sodium hypochlorite (NaOCl) up to 15 days post-treatment. Additionally, the possible influence of endodontic access preparation on tooth color was investigated. MATERIALS AND METHODS: Thirty intact human anterior teeth were used. Black adhesive tape with a 4 mm diameter window was used to standardize the enamel surface intended for color analysis. After the access cavity, preparation and the initial root canal negotiation with stainless steel hand files, the root canal shaping was completed with rotary nickel-titanium files. The teeth were divided into three groups (n = 10). Conventional syringe irrigation was performed with one irrigant for each group. The enamel surfaces were colorimetrically evaluated before access cavity, after cavity preparation and at 1, 3, 7 and 15 days post-treatment. The CIE color parameters (L*, a*, b*) were recorded and averaged for each material and the corresponding color differences (DeltaE) were calculated and statistically analyzed. RESULTS: The most significant factor in tooth color alteration, during the endodontic treatment, was the access preparation. CHX and NaOCl caused tooth color changes comparable with the saline. CHX and NaOCl did not increase the tooth color changes relative to the values induced by the access preparation. CONCLUSION: The two endodontic irrigants were not able to induce tooth color alteration to a greater extent than the access preparation. CLINICAL SIGNIFICANCE: Chlorhexidine and NaOCl cannot be considered as discoloring endodontic materials. The most contributing factor in tooth color alteration during endodontic treatment in the anterior teeth is access preparation. PMID- 25707822 TI - Clinical trial of an experimental cleaning solution: antibiofilm effect and integrity of a silicone-based denture liner. AB - AIM: This study evaluated the antibiofilm effect of an experimental solution of 2% Ricinus communis (R. communis) on a silicone-based denture liner by means of a randomized clinical trial, as well as the integrity of such liner following a cleansing regimen with such solution. MATERIALS AND METHODS: About 30 complete denture wearers had their lower dentures relined with a silicone-based denture liner and randomly allocated to cleanse their dentures by means of: (A) a specific toothbrush for complete dentures and dentifrice; (B) soaking in an experimental 2% R. communis solution; and (C) association of A and B. Considered outcomes were biofilm coverage area (%), microbial counts by means of the deoxy ribonucleic acid (DNA) checkerboard hybridization technique and physical integrity of the soft liner, assessed during a time interval of 60 days. Mean group values were compared by analysis of variance (ANOVA) and Tukey tests or generalized linear method (alpha = 0.05). RESULTS: The mechanical method presented the lowest biofilm percentage (1.45 +/- 1.03) if compared to the chemical method (2.96 +/- 1.98) and the associated one (2.71 +/- 1.76). After 60 days (3.37 +/- 2.04), biofilm accumulation was higher than at 15 days (1.28 +/- 0.77) and 30 days (2.46 +/- 1.54). The denture liner was less deteriorated and kept its physical integrity when the mechanical method was applied. The chemical method presented higher effectiveness against microorganisms, including some Candida species. CONCLUSION: The 2% R. communis solution presented stronger antimicrobial capacity than brushing on a silicone-based denture liner after immersion. However, it was not superior to the mechanical method in preserving the physical integrity of the material and in biofilm removal. CLINICAL SIGNIFICANCE: Soft denture liners hygiene is a very important issue and not conclusive in the literature. The experimental solution of 2% R. communis evaluated presented promising antimicrobial potential and should be more explored to be recommended as cleanser. PMID- 25707823 TI - Efficacy of Super Slick elastomeric modules in reducing friction during sliding: a comparative in vitro study. AB - AIM: To evaluate and compare the frictional resistance produced by Super Slick modules during sliding with four different types of brackets and four ligature types both in conventional and figure-of-8 ligation method with saliva as lubricant. MATERIALS AND METHODS: The frictional resistance was evaluated by using four different ligatures on 0.019" * 0.025" stainless steel (SS) archwires using four different brackets using an universal testing machine with unstimulated saliva as a lubricant. Mean and SD values were calculated. Data was statistically analyzed using analysis of variance ANOVA with post hoc test. RESULTS: The results showed that self-ligating brackets produced least frictional forces. Among all other tested combinations,Tefon-coated SS ligatures in ceramic with metal slot brackets produced least coefficient of static and kinetic friction and full ceramic brackets ligated with Super Slick elastomeric modules demonstrated the highest, with other combinations falling in between. CONCLUSION: Super Slick elastomeric modules, produced highest coefficient of both static and kinetic friction with the conventional and figure-of-8 ligation technique even in wet conditions using natural fresh human saliva. CLINICAL SIGNIFICANCE: Both static and kinetic frictional resistance play an important role during sliding mechanics. Various factors have been attributed for friction. However, bracket type, archwire material, type of ligature and method of ligation are important variables. Recently polymeric coated slick elastomeric modules were introduced with the claim that they produce very low frictional forces in wet condition. Contrary to the claim made by the manufacturers of Super Slick elastomeric modules, they produced highest coefficient of both static and kinetic friction with the conventional and figure-of-8 ligation technique. PMID- 25707824 TI - Effect of bleaching agents on the flexural strength of bovine dentin. AB - The aim of this study was to evaluate the effect of bleaching on the flexural strength of bovine dentin, using bleaching agents containing calcium (Whiteness HP Blue and Whiteness Class) and not containing calcium (Whiteness HP and Whiteness Perfect). Sixty bovine incisor tooth slices were obtained and divided into fve experimental groups (n = 12), such as G1, untreated control group; G2, Whiteness HP Max [35% hydrogen peroxide (HP)]; G3, Whiteness HP Blue (35% HP); G4, Whiteness Class (7.5% HP) and G5, Whiteness Perfect (22% carbamide peroxide). Samples were submitted to bleaching treatment according to the manufacturers' instructions. The control group remained in artificial saliva during bleaching. After bleaching, the enamel was removed and dentin specimens (7 mm length * 1.7 mm width * 0.5 mm thickness) were prepared. Samples were tested in a universal testing machine (EMIC). Data were analyzed by analysis variance (ANOVA) and Tukey's test. Differences between the groups were identified by ANOVA. The mean values (+/- standard deviation) for the experimental groups, such as (in MPa) G1 = 19.05 +/- 2.68 a; G2 = 12.69 +/- 4.52 b; G3 = 16.39 +/- 3.74 ab; G4 = 14.90 +/- 5.60 ab; and G5 = 12.71 +/- 2.25 b. Groups with the same lowercase letter were significantly different from each other. The presence of calcium in bleaching agents appeared to influence the flexural strength of bovine dentin after bleaching treatment, for both office bleaching (35% HP) and home bleaching (7.5% HP). PMID- 25707825 TI - Effect of chronic stress on ligature-induced periodontitis in inbred and noninbred rats: a radiographic study. AB - AIM: The aim was to compare the effect of chronic stress on ligature-induced periodontitis in inbred and noninbred female rats by means of a radiographic study. MATERIALS AND METHODS: Adult Lewis (inbred) and Wistar (non-inbred) rats were used and divided into the following groups: Ligature/Stress Lewis Group (LSLG, n = 8); Ligature/Stress Wistar Group (LSWG, n = 8); Ligature Lewis Group (LLG, n = 8) and Ligature Wistar Group (LWG, n = 8). The animals were anesthetized and a silk thread was continuously kept around their second upper right molar. Then, groups LSLG and LSWG were subjected to physical stress test (physical restraint for 12 hours). After 15 days of ligature placement, the animals were euthanized. The right hemimaxilla was kept in formalin solution for 48 hours. Radiographs of the hemimaxillae were obtained using the parallelism technique and subsequently submitted to a standardized radiographic processing. The examiner was blinded to the groups and calibrated. The bone height level was measured and the data were subjected to statistical analysis (ANOVA, Tukey, p < 0.05). RESULTS: LSWG showed bone destruction significantly higher than that of LSLG (32.1 +/- 1.45 mm and 23.6 mm +/- 2.13, respectively). Similarly, LWG showed bone destruction significantly higher than that of LLG (28.6 +/- 1.18 mm and 25.2 +/- 2.76 mm, respectively). CONCLUSION: Inbred rats (Lewis) are less susceptible to the effects of chronic stress than are noninbred rats (Wistar) in relation to ligature-induced periodontitis. CLINICAL SIGNIFICANCE: Epidemiological studies have shown a relationship between stress and periodontitis. One of the major difficulties of this type of research is the bias of the exact diagnosis of the patient's emotional state. Inbred lines animals have standards-specific neuroendocrine, this allows answers about the susceptibility of periodontal disease, making knowledge applicable in future clinical trials. PMID- 25707826 TI - Maxillary dental arch changes following the leveling and alignment stage with lingual and labial orthodontic appliances: a preliminary report of a randomized controlled trial. AB - BACKGROUND: No randomized controlled trial has tried to compare transverse dental arch changes between the lingual and labial orthodontic fixed appliances in the early stage of treatment. OBJECTIVE: To compare upper dental arch changes between lingual and labial fixed orthodontic appliances after leveling and alignment. DESIGN, SETTING: Parallel-groups randomized controlled trial on patients with class I moderate crowding teeth treated at the University of Al-Baath Dental School in Hamah, Syria. PARTICIPANTS: About 102 patients with crowded teeth and class I malocclusion were evaluated and 58 patients fulflled the inclusion criteria. Randomization was performed using computer generated tables; allocation was concealed using sequentially numbered opaque and sealed envelopes. About 52 participants were analyzed (mean age 21.5 +/- 3.2 years). They were randomly distributed into two groups with 26 patients in each (1:1 allocation ratio). INTERVENTION: Lingual vs labial fixed orthodontic appliances were used. MAIN OUTCOME MEASURE: Intercanine width, interpremolar width, intermolar width, and arch length were measured on study models before brackets' placement (T1), at the end of leveling and alignment stage (T2). RESULTS: Statistically significant increase was detected in the intercanine width in the lingual group (1.99 mm, p < 0.001) and in the labial group (1.22 mm, p < 0.001). The interpremolar width had a significant decrease in the lingual group (-0.70 mm, p < 0.001), whereas there was a significant increase in this width in the labial group (1.73 mm, p < 0.001). A significant decrease in intermolar width was detected in the lingual group (-0.79 mm, p < 0.001) whereas a significant increase was observed in the labial group (0.81 mm, p < 0.001). The differences between the two groups were significant for all comparisons (p < 0.001). CONCLUSION: The labial appliance produced a significant increase in all horizontal transverse arch dimensions, whereas in the lingual appliance group the intercanine width increased significantly in conjunction with a significant narrowing of posterior segments. FUNDING: The University of Al-Baath Postgraduate Research Budget (UBDS-00786223 PG). PMID- 25707827 TI - Light-activated bleaching: effects on surface mineral change on enamel. AB - AIM: This study evaluated the in vitro effect of 35% hydrogen peroxide (HP) on surface enamel change when activated with different light curing units (LCUs). MATERIALS AND METHODS: Enamel blocks (4 * 4 * 2 mm) were obtained from bovine incisors. The initial microhardness of the enamel was determined for each specimen. After this enamel blocks were randomly divided into four groups (n = 10) and treated as follows: Control, no bleaching procedure performed; HP - LCU, application of 35% HP gel without light activation; HP + QTH, application of 35% HP gel and light activation with a Quartz Tungsten-Halogen (QTH); and HP + Light Emitting Diode, application of 35% HP gel and light-activation with a LED. New microhardness measurements were obtained, immediately, 7 and 14 days after treatment. The percentage of surface mineral change was calculated according to the baseline and post-treatment microhardness values. Additionally, six samples from each group were randomly selected and prepared for scanning electron microscopy (SEM) characterization. The data were analyzed using an analysis of variance (ANOVA) to detect differences between the three time periods, and an ANOVA and Tukey's test with a confidence level of 95%. RESULTS: There was no significant difference between the initial hardness values and hardness values after treatment in any of the groups or time periods (p > 0.05). No major surface alterations were detected with SEM when comparing control groups to those undergoing bleaching treatments. CONCLUSION: The use of 35% HP in combination to QTH or LED light curing units LCU does not have detrimental effect on the enamel surface topography or in the mineral content, when compared with unbleached enamel or enamel submitted to 35% HP treatment alone. PMID- 25707828 TI - Differences in immune response to Porphyromonas gingivalis. AB - About 341 (average age of 38.0 +/- 2.5 years) patients with periodontal disease were included in this study. All the patients were not treated for periodontal disease for a period of 6 months prior to this study. All the patients were not on any hormonal therapy. Antibodies to Porphyromonas gingivalis (P. gingivalis) were determined in blood serum by enzyme-linked immunosorbent assay (ELISA) method. Findings from this study suggest immune response to P. gingivalis is more effective in males than in females. Smoking and obesity tends to reduce effective immune response. PMID- 25707829 TI - The effect of temperature on bisphenol: an elution from dental resins. AB - AIM: Bisphenol A (BPA) elution from baby bottles into content has been of great public interest and debate in recent year. Uncontrolled BPA elution due to temperature increase may create a risk factor for human health. However, dental resins that are used in pediatric dentistry also have BPA derivatives. The aim of this study is to evaluate BPA elution from dental resins and to determine the effect of temperature increase on this elution. MATERIALS AND METHODS: Four dental resins containing BPA derivatives (Filtek Z250, Filtek Supreme XT, Fissurit FX, and Admira) and a control group (BPA free G-aenial) were used in this study. Each specimen was stored in 2 ml of 75% ethanol-water solution at 37 degrees C. Water at a temperature of 59 degrees C +/- 1 degrees C (preferred temperature of hot drinks) was added to the study samples at certain time intervals (1, 6, 24 hours and 2, 3, 4, 5 and 6 days). The methanol samples were analyzed using high-performance liquid chromatography (HPLC). Data was analyzed using multivariate and repeated measures analysis of variance (p < 0.05). RESULTS: The study samples generally eluted more BPA than the control samples (p < 0.05). The greatest amount of BPA for an individual time period was measured after 6 hours for the groups A to D; the same was found after 24 hours for group E. CONCLUSION: While the BPA elution levels evaluated in the study samples were more than control samples, all measured values were under the reference levels and the amounts do not constitute a risk. CLINICAL SIGNIFICANCE: Resin-based dental materials can act as a source of BPA (within safety margins), especially when they react with hot water. PMID- 25707830 TI - Bond strength of fiber-reinforced posts to deproteinized root canal dentin. AB - AIM: This study evaluated the push-out bond strength of cemented fiber posts after deproteinization of root canal dentin walls with NaOCl. The effect of the application of an antioxidant solution (sodium ascorbate) was also evaluated. MATERIALS AND METHODS: A three-step etch-and-rinse (Scotch-bond - 3M Espe) and a one-step self-etching adhesive (Xeno III - Dentsply Caulk) were evaluated. Thirty bovine incisor roots were divided into 3 groups: a. Irrigation with physiologic solution (control). b. Deproteinization with 10 minutes irrigation of 5% NaOCl. c. Deproteinization with NaOCl followed by 10 minutes irrigation with 10% ascorbic acid. Fiber posts were cemented with a dual-cured cement (Rely X ARC - 3M ESPE). The push-out bond strength was evaluated after 24 hours of storage in distilled water. The data were analyzed with three-way ANOVA, one-way ANOVA and Tukey's test (alpha = 0.05). RESULTS: There were significant differences between groups (p < 0.05). The bond strength of Scotchbond was not influenced by the deproteinization. Xeno III showed a decrease in bond strength when deproteinized with 5% NaOCl (p < 0.05). For Xeno III, the subsequent irrigation with ascorbic acid was able to reverse the effect of the deproteinization. Considering the radicular thirds, the bond strength varied in the sequence-apical < middle < coronal. CONCLUSION: Only the all-in-one adhesive was influenced by the deproteinization. Considering the respective control groups, both systems showed similar bond strength results. CLINICAL SIGNIFICANCE: The decreased bond strength of the self-etching adhesive following deproteinization seams to be related to the oxidant effect of the NaOCl solution and the subsequent irrigation with ascorbic acid was able to reverse the effect of the deproteinization. PMID- 25707831 TI - Spectrophotometric evaluation of color changes of bleach-shade resin-based composites after staining and bleaching. AB - Spectrophotometric evaluation of color changes of Bleach-shade resin-based composites after staining and bleaching. AIM: The aim of this study was to evaluate the color stability of two commercially available bleach-shade resin composites (RC) after exposure to 3 storage solutions and the effect of 3 bleaching agents on the color stability and stain removal from stained RC. MATERIALS AND METHODS: Two bleach-shade RC were evaluated in this study, including a nanoflled RC, Filtek(TM) Z350 XT (FZ), and a nanohybrid RC, Tetric((r)) N-Ceram (TC), in the extra-white body (shade) (XWB) and L shades, respectively. Twenty-seven disk-shaped specimens, each measuring 12 mm in diameter and 2 mm in thickness, were prepared for each RC, with a total of 54 specimens. Specimens were randomly allocated into 3 groups of 9 specimens each and immersed in 3 storage solutions (distilled water, tea and coffee) for 7 days period. The 9 specimens in each staining group were further divided into 3 subgroups. Specimens in each subgroup (n = 3) were bleached using one of the bleaching agents (10 and 16% Zoom NiteWhite amorphous calcium phosphate (ACP), and Zoom 2 chairside with light activation) for 5 days period. The specimen colors were measured with spectrophotometer. The measurements were performed on each sample three times at baseline, after staining, and after bleaching. Color was expressed using the commission international de I'Eclairage (CIE) L*a*b* color space. The color differences (DeltaE) between the three measurements were calculated and the results were statistically analyzed using Two-way and Three way analysis of variance (ANOVA) and Tukey's posthoc tests. Level of significance was set at p < 0.05. RESULTS: Tetric((r)) N-ceram materials demonstrated significantly less color change than the FZ and the color change, which was greater after storage in coffee compared to tea, was statistically significant. The bleaching agents significantly influence the color changes of composite specimens. All groups showed (DeltaE) values below 3.3 after bleaching, except for 'Zoom 2 chairside' with light activation groups, which is shown clinically unacceptable lighter shade (DeltaE >3.3). CONCLUSION: Bleach-shade composites showed significant discoloration (DeltaE > 3.3) after being immersed into coffee and tea solutions. Nanoflled composites discolored more than nano-hybrid composites, and carbamide peroxide-based bleaching agents were effective in reducing the discoloration to a clinically acceptable value (DeltaE > 3.3). PMID- 25707832 TI - Resin bonding using etch-and-rinse and self-etch adhesives to decalcified deciduous enamel after bioactive glass air abrasion. AB - PURPOSE: Bioactive glass air abrasion is a conservative technique for removal of initial decalcified enamel superficial layer and caries vs alumina air abrasion. This study evaluated shear bond strength of composite resin to sound and decalcified deciduous enamel using etch-and-rinse and self-etch adhesives after alumina and bioactive glass air abrasion. MATERIALS AND METHODS: Ninety-six fat enamel surfaces, mounted in acrylic resin, were prepared from 48 deciduous molars. Half of the specimens were decalcified with a demineralizing solution. Both intact and decalcified specimens were assigned to two groups for alumina and bioactive glass air abrasion. In each group, the specimens were subdivided into two groups for application of Clearfil SE Bond or Optibond FL adhesives (n = 12). After composite resin bonding, the specimens underwent shear bond test. Data were analyzed using three-way analysis of variance (ANOVA), linear regression model and independent-sample t-test (alpha = 0.05). RESULTS: No significant differences were noted in bond strength of composite resin after alumina or bioactive glass air abrasion (p = 0.272). Optibond FL adhesive and enamel decalcification produced higher bond strength (p = 0.000, p = 0.001 respectively). CONCLUSION: In this study, bioactive glass air abrasion produced bond strength comparable to the conventional method. This technique might be an alternative method for preparation of normal and/or decalcified enamel of deciduous teeth for resin bonding. PMID- 25707833 TI - Antimicrobial activity of root canal irrigants associated with cetrimide against biofilm and planktonic Enterococcus faecalis. AB - AIM: To evaluate the antibacterial activity of sodium hypochlorite (NaOCl) and chlorhexidine (CHX) alone or associated with cetrimide (CTR), and QMiX against biofilm and planktonic Enterococcus faecalis (E. faecalis) [American type culture collection (ATCC) 29212]. MATERIALS AND METHODS: The solutions 2.5% NaOCl, 2.5% NaOCl + 0.2% CTR, 2% CHX, 2% CHX + 0.2% CTR, 0.2% CTR, and QMiX were evaluated. E. faecalis biofilms were induced for 14 days on bovine dentin blocks. The irrigants were evaluated after contact with E. faecalis suspension and biofilm for 1 and 3 minutes. After that, serial decimal dilutions were made and plated on tryptic soy agar (TSA) medium. Plates were incubated for 24 hours at 37 degrees C and the colony-forming unit (CFU) 1 ml was determined. Data were subjected to ANOVA and Tukey's tests at 5% significance. RESULTS: All microorganisms were eliminated by direct contact of the irrigants with planktonic cells. Only NaOCl and NaOCl + CTR were able to completely eliminate the microorganisms by direct contact with E. faecalis biofilm. CHX presented effectiveness similar to CHX + CTR CTR, and QMiX after 1 minute of contact and similar to NaOCl and NaOCl + CTR after 3 minutes (p > 0.05), but was unable to completely eliminate the microorganisms. CTR and QMiX did not differ from each other. CONCLUSION: CTR addition to CHX and NaOCl solutions did not improve the antimicrobial activity against biofilm. All evaluated irrigants and associations presented activity against planktonic E. faecalis. Only NaOCl and NaOCl + CTR eliminated biofilm after 1 and 3 minutes of direct contact. PMID- 25707834 TI - Knowledge awareness and attitude about research ethics among dental faculties in India. AB - AIM: The aim of this study was to assess the level of knowledge, awareness and attitude about research ethics and research ethics committees (RECs) among dental faculties. MATERIALS AND METHODS: This cross-sectional questionnaire study incorporated a self administered questionnaire. Descriptive, Chi-square and logistic regression analysis was used to analyze the data. RESULTS: The overall response rate to the study was 85%. More than half were familiar with research ethics, principles and functions of the research ethics committee. Though there were some faculties whose attitude regarding research ethics principle was not optimal. CONCLUSION: The present study revealed a broad acceptance among the faculties acceptance toward RECs and training in research ethics, though there existed certain gap in knowledge about research among the faculties. CLINICAL SIGNIFICANCE: This will help us to understand the knowledge, awareness and attitudes of dental faculties toward research ethics, which will help the institutional officials to develop better educational programs in the field of research ethics in order to help them conduct better research henceforth. PMID- 25707835 TI - Relationship between oral health status and hematological values in pediatric leukemic patients: an evaluative survey. AB - INTRODUCTION: Leukemia is a malignancy of the bone marrow and constitutes 30% of all childhood cancers. The leukemic condition itself and its therapy cause oral signs and symptoms with significant morbidity. AIMS AND OBJECTIVES: The aim of this study was to review the oral health status in children with leukemia and relate the gingival and periodontal findings to the changes in their hematological values. MATERIALS AND METHOD: The oral health status in 47 pediatric leukemic patients in the age group of 6 to 14 years was assessed using the dmft/DMFT index, OHI(S) index and modified gingival index (MGI). Their hematological reports on the day of examination were obtained. The patients were divided into three groups based on the status of treatment. The relation between the platelet count and the WBC count with the MGI score was checked. RESULTS: The highest dmf and DMF scores were seen in patients who were currently under treatment. Though an inverse relation was seen between the platelet count and the MGI score, a statistically significant value was not obtained. CONCLUSION: A longitudinal follow-up of patients should be carried out in order to establish a relation between the hematological parameters and the gingival inflammation score PMID- 25707836 TI - Assessment of the relationship between the maxillary sinus floor and maxillary posterior teeth roots using cone beam computed tomography. AB - AIM: This study was conducted to assess the vertical and horizontal relationship between the maxillary sinus floor and maxillary posterior teeth roots using cone beam computed tomography. MATERIALS AND METHODS: In this cross-sectional study, the CBCT images presented in the radiology department of Hamadan dental school was used. From 450 observed CBCT, 340 of them did not have the inclusion criteria of the study and ultimately 110 CBCT were selected. Totally 214 first premolars, 217 second premolars, 220 first molars and 220 second molars were included. For evaluating the relationship between the maxillary sinus floor and the posterior maxillary teeth, the classification implemented in the study of Jung in 2009 was used. The relation was evaluated by two radiologists twice with a 2-week time interval. RESULTS: One hundred and ten patients with a mean age of 31.06 +/- 9.7 years were assessed. Type 0 relationship (the maxillary sinus floor is located above the root tip) was most frequently observed with the first and second premolars. The most common type observed in the first and second molars was type 3 (apical protrusion is seen over the maxillary sinus floor). The relation between different types and gender was statistically meaningful, while no statistically significant difference was found between the right and left side assessments. CONCLUSION: This study showed that although most of the teeth did not have contact with the sinus floor, but the more posterior the maxillary teeth, the more probability for root protruding into the maxillary sinus. It also confirmed that protrusion of teeth roots into the maxillary sinus is more common in male than female. CLINICAL SIGNIFICANCE: Knowing the anatomical relation between the posterior teeth and the maxillary sinus, help the clinician in preoperative treatment planning of the posterior maxillary teeth and avoid problems that may occur during dental practice. PMID- 25707837 TI - Measurement of nitrite and nitrate in saliva of children with different caries activity. AB - OBJECTIVE OF THE STUDY: Recently, there has been growing interest in the role of salivary nitrate and nitrite in caries protection. Nitrate is a natural compound found in fruits and vegetables and when secreted in saliva, is reduced to nitrite through bacterial respiration and subsequently reduced to nitric oxide in acidic condition. Nitric oxide takes part in oral non-specific immune system and prevents bacterial growth. The aim of present study was to determine the concentration of nitrite and nitrate in saliva of children with different caries activity. MATERIALS AND METHODS: Ninety three children, 4 to 6 years old, enrolled in this case-control study and were divided into 3 groups; 31 caries free children, 31 with 5 10. Unstimulated saliva was collected and stored in 4 degrees C. Measurement of nitrate and nitrite concentration was performed using Griess reaction. Data were analyzed by T-test, Chi-square, ANOVA and multiple comparisons using SPSS 18. p < 0.05 was considered significant. RESULTS: Mean value of DFS in the first, second and third were 0, 7.12 and 12.61 respectively. Mean value of nitrite and nitrate in the third group was significantly higher than two others (p < 0.05), but the difference between first and second group was not significant. CONCLUSION: Increase in DFS was associated by increase in salivary nitrite and nitrate concentration. CLINICAL SIGNIFICANCE: High concentration of nitrate and nitrite is not enough for caries prevention. PMID- 25707838 TI - A preliminary evaluation of a reusable digital sterilization indicator prototype. AB - BACKGROUND: Sterilization of critical and semicritical instruments used in patient care must undergo a terminal process of sterilization. Use of chemical and physical indicators are important in providing information on the sterilizer's performance during each cycle. Regular and periodic monitoring of sterilizers using biological indicators is necessary in periodically validating performance of sterilizers. Data loggers or independent digital parametric indicators are innovative devices that provide more information than various classes chemical indicators. In this study we evaluated a prototype of an independent digital parametric indicator's use in autoclaves. AIM: The purpose of this study was to evaluate the performance of an independent digital indicator/data logger prototype (DS1922F) that could be used for multiple cycles within an autoclave.MG Materials and methods: Three batches of the DS1922F (150 samples) were used in this study that was conducted in a series. The first batch was challenged with 300 sterilization cycles within an autoclave and the data loggers evaluated to study failures and the reason for failure, make corrections and improve the prototype design. After changes made based on studying the first batch, the second batch of the prototype (150 samples) were challenged once again with 300 sterilization cycles within an autoclave and failure studied again in further improvement of the prototype. The final batch (3rd batch) of the prototype (150 samples) was challenged again but with 600 cycles to see how long they would last. Kaplan-Meier survival analysis analyses of all three batches was conducted (alpha = 0.05) and failed samples qualitatively studied in understanding the variables involved in the failure of the prototype, and in improving quality. RESULTS: Each tested batch provided crucial information on device failure and helped in improvement of the prototype. Mean lifetime survival of the final batch (Batch 3) of prototype was 498 (480, 516) sterilization cycles in an autoclave. CONCLUSION: In this study, the final batch of the DS1922F prototype data logger was found to be robust in withstanding the challenge of 600 autoclave cycles, with a mean lifetime of more than 450 cycles, multiple times more than prescribed number of cycles. CLINICAL SIGNIFICANCE: Instrument reprocessing is among the important aspects of infection control. While stringent procedures are followed in instrument reprocessing within the clinic in assuring patient safety, regular use of sterilization process indicators and periodic biological validation of the sterilizer's performance is necessary. Chemical indicators for use in Autoclaves provide information on whether the particular cycle's parameters were achieved but do not provide at what specific point in time or temperature the failure occurred. Data loggers and associated reader software as the tested prototype in this evaluation (DS1922F), are designed to provide continuous information on time and temperature of the prescribed cycle. Data loggers provide immediate information on the process as opposed to Biological Indicators that take from days to a week in obtaining a confirmatory result. Further, many countries do not have the sterilization monitoring service infrastructure to meet the demands of the end users. In the absence of sterilization monitoring services, use of digital data loggers for each sterilization cycle is more pragmatic. PMID- 25707839 TI - Craniofacial fibrous dysplasia with facial asymmetry, canted occlusion and open bite: a case report with 2 years follow-up. AB - AIM: Fibrous dysplasia is a benign fibro-osseous disorder of unknown etiology that may affect the craniofacial region causing significant impairment of facial esthetics and function. This paper reports a case of a 21-year-old male, which was investigated and diagnosed with craniofacial fibrous dysplasia involving an overgrowth over right maxillary and mandibular region associated with facial asymmetry, severe occlusal cant and anterior open bite. Management of the case included surgical excision, cosmetic contouring and orthodontic intervention. The case was reviewed over a period of two years, which demonstrate stable treatment outcome. PMID- 25707840 TI - Morphologic variations in mandibular premolars: a report of three cases. AB - AIM: To report cases with morphologic variations in mandibular premolars. BACKGROUND: Mandibular premolars have earned the reputation for having aberrant anatomy. The occurrence of three canals with three separate (type V, Vertucci) foramina in mandibular premolars is very rare. In this report, three cases are presented involving the root canal treatment of mandibular premolars with three different root and canal configurations. The present report also emphasizes the use of the dental operating microscope to enhance visualization. CASE DESCRIPTION: Correlation between radiographic findings, use of dental operating microscope and knowledge of aberrant anatomy helps to identify, locate and treat the aberrant anatomy of the tooth. CLINICAL SIGNIFICANCE: The treatment was successful as all canals were identified and filled and also as evidenced by relief of symptoms. CONCLUSION: Success is largely dependent on the use of magnification, which aided in identifying the location of the three individual root canal orifices; thus emphasizing the need to familiarize ourselves with dental microscopy, to obtain maximal anatomic information in endodontic practice. PMID- 25707841 TI - A clinical report of an oral lichen planus associated to epidermoid carcinoma in contact with metallic restorations. AB - The aim of this study was to relate the clinical case of a patient with oral lichen planus (OLP) and a history of epidermoid carcinoma associated with metallic restorations. The etiology of OLP is a mucocutaneous disease, which is poorly understood. Studies point to the potential of malignant transformation of OLP and its association with metallic restorations. The metallic restorations were replaced by crowns with a ceramic covering associated and osseointegrated implants in the edentulous areas. About 1 year later, it was observed a bilateral regression of the tongue lesions. The replacement of metallic restorations can contribute to improvement of OLP. PMID- 25707842 TI - Esthetic and function improvement by direct composite resins and biomimetic concept. AB - AIM: This case report describe a resin layering restorative technique based on biomimetic concept to improve esthetics in a patient with dental defects that affected both enamel and dentin in anterior teeth. BACKGROUND: Severe structural defect in anterior teeth compromises esthetics and it is a high challenge to become the defect imperceptible after the restoration. CASE DESCRIPTION: A clinical sequence of applying different composite resin layers allowed the reproduction of the interaction between hard dental tissues and the restorative material. CONCLUSION: This technique achieved a satisfactory final esthetic outcome, preserving sound teeth structure and at same time, improved the quality of life of the young patient. CLINICAL SIGNIFICANCE: The utilization of the biomimetic concept to increase a disharmonic smile with dental defects is based in a conservative approach, which reached a satisfactory and esthetic outcome. PMID- 25707843 TI - Single gene disorders with craniofacial and oral manifestations. AB - Gene and environmental factors are instrumental in genesis of complex and wide range of disorders and syndromes. The newer gene sequencing and other advanced technologies have made our previous knowledge of genetic etiopathogenesis of various disorders more transparent. Single gene disorders refer to the disorders caused due to mutations in a single gene and a fair number of these manifest as craniofacial defects and anomalies. This review is an attempt to give a detailed insight into the varied single gene disorders and syndromes with an emphasis on dental implications. PMID- 25707844 TI - A time-saving method for transferring occlusal vertical dimension and centric relation of complete denture to a full arch implant prosthesis. AB - AIM: This clinical report describes a time-saving recording procedure for implant prosthesis. BACKGROUND: In implant prosthodontics, a few procedures have been suggested to record jaw relationships. Record bases with occlusion rims supported by healing abutments, or screw retained bases are the conventional methods used for mounting definitive implant casts in the articulator. CONCLUSION: The method described in this article reduces the chair time and is comfortable for both the patient and clinician. CLINICAL SIGNIFICANCE: In this article, a chair side technique is presented for articulating the definitive implant casts that maintains the established OVD and CR of the patient's existing complete dentures. PMID- 25707845 TI - MicroRNA in oral cancer research: future prospects. AB - MicroRNA (miRNA) and related therapeutic approaches hold great promise in the field of cancer managements. Various studies on epithelial malignancies have shown encouraging results on various fronts. Its association with invasion, tumor growth, epithelial mesenchymal transition (EMT), angiogenesis, cancer stem cells (CSCs), metastasis and refects the diversified role of miRNA. Moreover, miRNA plays an important role in determining the prognosis of the patients. MicroRNAs interactions with each other and with external factors [human papilloma virus (HPV) (like oncoproteins)] intrigue us to explore more deep into this fascinating world.(1.) PMID- 25707846 TI - Mammographically screen-detected asymmetric densities with architectural distortion and normal ultrasound at assessment: Value of MRI as a problem-solving tool. AB - Four cases are presented in which asymptomatic clients from an Australian mammography screening programme (BreastScreen ACT) were recalled for assessment of an asymmetric density with possible architectural distortion. In all four women, mammographic work-up was equivocal and ultrasound showed no suspicious correlate for biopsy. It was then doubtful as to whether any significant lesion was present. In all four cases, MRI revealed the presence of malignancy. Breast MRI can be a useful problem-solving tool in the work-up of such cases. PMID- 25707847 TI - Green approach for ultratrace determination of divalent metal ions and arsenic species using total-reflection X-ray fluorescence spectrometry and mercapto modified graphene oxide nanosheets as a novel adsorbent. AB - A new method based on dispersive microsolid phase extraction (DMSPE) and total reflection X-ray fluorescence spectrometry (TXRF) is proposed for multielemental ultratrace determination of heavy metal ions and arsenic species. In the developed methodology, the crucial issue is a novel adsorbent synthesized by grafting 3-mercaptopropyl trimethoxysilane on a graphene oxide (GO) surface. Mercapto-modified graphene oxide (GO-SH) can be applied in quantitative adsorption of cobalt, nickel, copper, cadmium, and lead ions. Moreover, GO-SH demonstrates selectivity toward arsenite in the presence of arsenate. Due to such features of GO-SH nanosheets as wrinkled structure and excellent dispersibility in water, GO-SH seems to be ideal for fast and simple preconcentration and determination of heavy metal ions using methodology based on DMSPE and TXRF measurement. The suspension of GO-SH was injected into an analyzed water sample; after filtration, the GO-SH nanosheets with adsorbed metal ions were redispersed in a small volume of internal standard solution and deposited onto a quartz reflector. The high enrichment factor of 150 allows obtaining detection limits of 0.11, 0.078, 0.079, 0.064, 0.054, and 0.083 ng mL(-1) for Co(II), Ni(II), Cu(II), As(III), Cd(II), and Pb(II), respectively. Such low detection limits can be obtained using a benchtop TXRF system without cooling media and gas consumption. The method is suitable for the analysis of water, including high salinity samples difficult to analyze using other spectroscopy techniques. Moreover, GO-SH can be applied to the arsenic speciation due to its selectivity toward arsenite. PMID- 25707848 TI - Leveraging electrokinetics for the active control of dendritic fullerene-1 release across a nanochannel membrane. AB - General adoption of advanced treatment protocols such as chronotherapy will hinge on progress in drug delivery technologies that provide precise temporal control of therapeutic release. Such innovation is also crucial to future medicine approaches such as telemedicine. Here we present a nanofluidic membrane technology capable of achieving active and tunable control of molecular transport through nanofluidic channels. Control was achieved through application of an electric field between two platinum electrodes positioned on either surface of a 5.7 nm nanochannel membrane designed for zero-order drug delivery. Two electrode configurations were tested: laser-cut foils and electron beam deposited thin films, configurations capable of operating at low voltage (<=1.5 V), and power (100 nW). Temporal, reproducible tuning and interruption of dendritic fullerene 1 (DF-1) transport was demonstrated over multi-day release experiments. Conductance tests showed limiting currents in the low applied potential range, implying ionic concentration polarization (ICP) at the interface between the membrane's micro- and nanochannels, even in concentrated solutions (<=1 M NaCl). The ability of this nanotechnology platform to facilitate controlled delivery of molecules and particles has broad applicability to next-generation therapeutics for numerous pathologies, including autoimmune diseases, circadian dysfunction, pain, and stress, among others. PMID- 25707849 TI - Simultaneous silencing of XIAP and survivin causes partial mesenchymal-epithelial transition of human pancreatic cancer cells via the PTEN/PI3K/Akt pathway. AB - Pancreatic cancer has one of the highest mortality rates among malignant tumors and is characterized by rapid invasion, early metastasis and chemoresistance. X linked inhibitor of apoptosis (XIAP) and survivin are two of the most important members of the IAP family. Previous studies have shown that XIAP and survivin were overexpressed in pancreatic cancer and were closely associated with cell proliferation and chemoresistance to gemcitabine. In the present study, stable inhibition of XIAP and survivin in Panc-1 cells was performed using lentivirus carried short hairpin RNAs. The expression of XIAP, survivin, E-cadherin, Slug, phosphatase and tensin homolog (PTEN) and phosphorylated Akt was then measured. In addition, cell proliferation, apoptosis, invasion and migration were assessed. The results showed that stable inhibition of XIAP and survivin expression in Panc 1 cells significantly reduced cell proliferation, increased apoptosis and partially reversed the epithelial-mesenchymal transition (EMT). Furthermore, the results of the present study demonstrated that the partial reversal of the EMT was accompanied by inhibited cell invasion and migration as well as increased chemosensitivity to gemcitabine in pancreatic cancer cells; this was indicated to be mediated via the PTEN/phosphatidylinositol 3-kinase/Akt signaling pathway. In conclusion, these results suggested that simultaneous inhibition of XIAP and survivin may be a promising strategy for the treatment of pancreatic cancer. PMID- 25707850 TI - Integration of life cycle assessment and regional emission information in agricultural systems. AB - BACKGROUND: Life cycle assessment (LCA) is a compilation and evaluation of the input energy and materials, output emissions and the potential environmental impacts of a product, service or system throughout its life cycle. While methodological issues of LCA are still being developed, much research is being conducted worldwide in order to improve them. One of the important advances in LCA is a regionalised LCA, i.e. the development of regionalised databases, inventories, and impact assessment methods and models. RESULTS: Regional emission information (REI) was developed and integrated with the characterisation results in LCA of an agricultural product in the study area. Comparison of outcomes obtained with LCA characterisation results that did not include REI shows that the characterisation results taking REI into account are much higher as regards human toxicity, from 0.02% to 0.18%, freshwater ecotoxicity from 89% to 99% and terrestrial ecotoxicity from 8.006% to 26.177%. CONCLUSION: Results of current LCA studies on agricultural products and systems that do not include REI are under-estimating the life cycle environmental impact. For the LCA of agricultural products and systems, the REI as well as regionalised life cycle inventory data should be developed and integrated into the current LCA approach. PMID- 25707851 TI - Macroscopic architecture of charge transfer-induced molecular recognition from electron-rich polymer interpenetrated porous frameworks. AB - Fluorescent and electron-rich polymer threaded into porous framework provides a scaffold for sensing acceptor molecules through noncovalent interactions. Herein, poly(9-vinylcarbazole) (PVK) threaded MIL-101 with confined nanospace was synthesized by vinyl-monomer impregnation, in situ polymerization, and interpenetration. The pore size of the resulted hybrid could be controlled by varying the time of polymerization and interpenetration. The interaction of PVK threaded MIL-101 with guest molecules showed a charge-transfer progress with an obvious red shift in the optical spectra. Depending on the degree of the interaction, the solution color changed from blue to green or to yellow. In particular, electron-rich PVK-threaded MIL-101 could effectively probe electron poor nitro compounds, especially 1,3,5-trinitrobenzene (TNP), a highly explosive material. This sensing approach is a colorimetric methodology, which is very simple and convenient for practical analysis and operation. PMID- 25707852 TI - Virus-induced gene silencing-based functional verification of six genes associated with vernalization in wheat. AB - Vernalization requirement is an important characteristic in crop breeding. Wheat is a widely grown crop in the world that possesses enormous economic significance. To better understand the gene networks in vernalization process, we performed a high-throughput RNA sequencing analysis comparing the transcriptomes of spring and winter wheat cultivars, with and without vernalization (unpublished data). In this study, we selected six unigenes (CL14010, CL12788, CL176, Unigene 16777, CL8746 and Unigene10196) from our transcriptome analysis based on their expression differences to further characterize their function. Transient silencing of the six unigenes individually were achieved through virus-induced gene silencing (VIGS) using BSMV vector. The period from germination to spike differentiation were recorded and compared between plants underwent VIGS silencing and the control. Our result showed that VIGS of the six unigenes significantly shortened the period from seedling to double ridge (DR) stage. Resulting in SD period ranging from 59.8 +/- 0.60 to 65.8 +/- 0.48 days, compared to 85.0 +/- 0.73 days in the control. The results indicated that these six unigenes function as suppressors in vernalization process and silence or down regulation of these genes promoted flower development in wheat. Further characterization of these six unigenes and their function in vernalization and flowering control is needed. PMID- 25707854 TI - Regulation of recombinant human insulin-induced maturational events in Clarias batrachus (L.) oocytes in vitro. AB - Regulation of insulin-mediated resumption of meiotic maturation in catfish oocytes was investigated. Insulin stimulation of post-vitellogenic oocytes promotes the synthesis of cyclin B, histone H1 kinase activation and a germinal vesicle breakdown (GVBD) response in a dose-dependent and duration-dependent manner. The PI3K inhibitor wortmannin abrogates recombinant human (rh)-insulin action on histone H1 kinase activation and meiotic G2-M1 transition in denuded and follicle-enclosed oocytes in vitro. While the translational inhibitor cycloheximide attenuates rh-insulin action, priming with transcriptional blocker actinomycin D prevents insulin-stimulated maturational response appreciably, albeit in low amounts. Compared with rh-insulin, human chorionic gonadotrophin (hCG) stimulation of follicle-enclosed oocytes in vitro triggers a sharp increase in 17alpha,20beta-dihydroxy-4-pregnen-3-one (17alpha,20beta-DHP) secreted in the incubation medium at 12 h. Interestingly, the insulin, but not the hCG-induced, maturational response shows less susceptibility to steroidogenesis inhibitors, trilostane or dl-aminoglutethimide. In addition, priming with phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (IBMX) or cell-permeable dbcAMP or adenylyl cyclase activator forskolin reverses the action of insulin on meiotic G2 M1 transition. Conversely, the adenylyl cyclase inhibitor, SQ 22536, or PKA inhibitor H89 promotes the resumption of meiosis alone and further potentiates the GVBD response in the presence of rh-insulin. Furthermore, insulin-mediated meiotic maturation involves the down-regulation of endogenous protein kinase A (PKA) activity in a manner sensitive to PI3K activation, suggesting potential involvement of a cross-talk between cAMP/PKA and insulin-mediated signalling cascade in catfish oocytes in vitro. Taken together, these results suggest that rh-insulin regulation of the maturational response in C. batrachus oocytes involves down-regulation of PKA, synthesis of cyclin B, and histone H1 kinase activation and demonstrates reduced sensitivity to steroidogenesis and transcriptional inhibition. PMID- 25707853 TI - Girdin is phosphorylated on tyrosine 1798 when associated with structures required for migration. AB - The mammalian protein Girdin interacts with several key molecules such as actin, and it functions as a regulator of the cytoskeleton. Silencing of Girdin mRNA results in defective migration in a variety of cultured cells. Moreover, knockout of Girdin causes phenotypes related to defective migration, including hypoplasia of olfactory bulbs and a widened rostral migratory stream (RMS) in mice. To elucidate the molecular basis underlying cellular migration, we generated site- and phosphorylation state-specific antibodies against human Girdin peptides carrying four putative phosphorylation sites (serine1386 [S1386], S1416, tyrosine1764 [Y1764] and Y1798) that had been identified by mutagenesis analyses or mass spectrometric studies. We found that these residues were phosphorylated in an epidermal growth factor (EGF)-dependent manner. Among the four antibodies we developed, the antibody that targeted Girdin when phosphorylated at Y1798 (pY1798) worked well for immunohistochemistry of paraffin-embedded tissues as well as for cultured cells. Immunocytochemistry of HEK293FT cells transfected with an EGF receptor expression plasmid exhibited punctate signals with pY1798. These signals colocalized with those of endocytosed EGF receptors after EGF stimulation. Signals from pY1798 were also observed on lamellipodia, filopodia, focal adhesion and stress fibers in NIH3T3 cells under conventional culture conditions. Immunohistochemistry of paraffin-embedded mouse brain at P14 using anti-pY1798 antibody displayed signals at the hilum-side (internal side) of the dentate gyrus of the hippocampus, the RMS, the accessory olfactory bulb and the olfactory bulb in which Girdin expression was detected. Primary culture of RMS neurons showed punctate signals of pY1798 at the tips of leading processes as well as in the cytoplasm, whereas no signals were observed when neurons were treated with Src inhibitor, PP2. Our data revealed the changes in the phosphorylation status of Y1798 in Girdin when it associated with migration related structures in vitro and in vivo. PMID- 25707855 TI - Protein-protein docking on hardware accelerators: comparison of GPU and MIC architectures. AB - BACKGROUND: The hardware accelerators will provide solutions to computationally complex problems in bioinformatics fields. However, the effect of acceleration depends on the nature of the application, thus selection of an appropriate accelerator requires some consideration. RESULTS: In the present study, we compared the effects of acceleration using graphics processing unit (GPU) and many integrated core (MIC) on the speed of fast Fourier transform (FFT)-based protein-protein docking calculation. The GPU implementation performed the protein protein docking calculations approximately five times faster than the MIC offload mode implementation. The MIC native mode implementation has the advantage in the implementation costs. However, the performance was worse with larger protein pairs because of memory limitations. CONCLUSION: The results suggest that GPU is more suitable than MIC for accelerating FFT-based protein-protein docking applications. PMID- 25707856 TI - Proposing a scientific confidence framework to help support the application of adverse outcome pathways for regulatory purposes. AB - An adverse outcome pathway (AOP) describes the causal linkage between initial molecular events and an adverse outcome at individual or population levels. Whilst there has been considerable momentum in AOP development, far less attention has been paid to how AOPs might be practically applied for different regulatory purposes. This paper proposes a scientific confidence framework (SCF) for evaluating and applying a given AOP for different regulatory purposes ranging from prioritizing chemicals for further evaluation, to hazard prediction, and ultimately, risk assessment. The framework is illustrated using three different AOPs for several typical regulatory applications. The AOPs chosen are ones that have been recently developed and/or published, namely those for estrogenic effects, skin sensitisation, and rodent liver tumor promotion. The examples confirm how critical the data-richness of an AOP is for driving its practical application. In terms of performing risk assessment, human dosimetry methods are necessary to inform meaningful comparisons with human exposures; dosimetry is applied to effect levels based on non-testing approaches and in vitro data. Such a comparison is presented in the form of an exposure:activity ratio (EAR) to interpret biological activity in the context of exposure and to provide a basis for product stewardship and regulatory decision making. PMID- 25707857 TI - Tissue concentrations of sulfamethazine and tetracycline hydrochloride of swine (Sus scrofa domestica) as it relates to withdrawal methods for international export. AB - The use of water medications is a common practice in the US swine industry to treat and prevent infections in swine herds with minimal labor and without risk of needle breakage. There are concerns that FDA-approved withdrawal times (WDT) may be inadequate for several water medications when exporting pork products to countries where MRLs (maximum residue limits) are lower than US tolerance levels. In this study, withdrawal intervals (WDI) were estimated for pigs when dosed with tetracycline and sulfamethazine in water. The WDI were calculated using the FDA tolerance method (TLM) and a population-based pharmacokinetic method (PopPK). The estimated WDIs (14-16 days using TLM) were similar to the approved WDT of 15 days for sulfamethazine. However, the PopPK method extended WDIs for both sulfamethazine (19-20 days) and tetracycline (12 days) compared to the currently approved WDTs in the U.S. This study also identified potential differences in WDI between weanling and finisher pigs. In conclusion, the TLM may not always provide adequate WDT for foreign export markets especially when MRLs differ from tolerance levels approved for US markets. However, PopPK methods can provide conservative WDIs in situations with considerable variability in medication exposure such as with administration in water. PMID- 25707858 TI - Mode of action and human relevance of pronamide-induced rat thyroid tumors. AB - Pronamide, a selective, systemic, pre- and post-emergence herbicide, caused an increased incidence of thyroid follicular cell adenomas in a rat carcinogenicity study. Thyroid tumors, as well as liver and pituitary changes, were limited only to the high-dose group. The evidence for and against specific potential modes of action (MoAs) for rat thyroid follicular cell adenomas and their relevance to humans is discussed. Pronamide is not mutagenic and therefore, direct DNA reactivity is not relevant as a MoA. The hypothesized MoA for this effect is altered homeostasis of the hypothalamic-pituitary-thyroid (HPT) axis mediated by the induction of hepatic enzymes, including uridine diphosphate glucuronosyltransferase (UGT). Evaluation of data from a series of regulatory guideline and MoA studies aimed at identifying the causative and associated key events supported a UGT-mediated MoA in the development of thyroid follicular tumors. This MoA for pronamide-induced thyroid tumors in rats, which involves increased thyroid hormone metabolism/clearance, altered thyroid hormone homeostasis and HPT stimulation is not considered relevant to humans based on quantitative species differences, making rats markedly more sensitive than humans to thyroid perturbations. PMID- 25707859 TI - A pyrazolate-stabilized sodium hydride complex. AB - The reaction of a sterically demanding sodium pyrazolate complex with n butylsodium and diphenylsilane afforded the first well-defined molecular sodium hydride complex [(pz)6Na7H] (pz = 3,5-di-tert-butylpyrazolate) that could be structurally characterised. PMID- 25707860 TI - Bioactivity in an Aggrecan 32-mer Fragment Is Mediated via Toll-like Receptor 2. AB - OBJECTIVE: To determine whether an aggrecan 32-mer fragment derived from dual ADAMTS and matrix metalloproteinase (MMP) cleavage in the aggrecan interglobular domain was bioactive and, if so, to elucidate its mechanism of action. METHODS: Mouse primary chondrocytes, synovial fibroblasts, or peritoneal macrophages, human primary chondrocytes, and cells or cell lines from myeloid differentiation factor 88 (MyD88)-deficient and Toll-like receptor 2 (TLR-2)-deficient mice were stimulated with synthetic mouse 32-mer peptide, human 32-mer peptide, a 32-mer scrambled peptide, or native, glycosylated 32-mer peptide. Cells stimulated with 32-mer peptide were analyzed for changes in messenger RNA (mRNA) expression by quantitative polymerase chain reaction. Conditioned medium was analyzed for levels of interleukin-6 protein by an AlphaLISA or for levels of MMP-3 and MMP-13 protein by Western blotting. NF-kappaB activation was measured in a luciferase reporter assay. RESULTS: Treatment of mouse cells or cartilage explants with 32 mer peptide or scrambled peptide revealed that the 32-mer peptide, but not the scrambled peptide, had antianabolic, procatabolic, and proinflammatory bioactivity in vitro. Chondrocytes, synovial fibroblasts, and macrophages from MyD88-deficient mice failed to respond to 32-mer peptide stimulation. A macrophage cell line derived from TLR-2-deficient mice also failed to respond to 32-mer peptide stimulation. Stimulation of human chondrocytes with human 32-mer peptide increased the expression of catabolic markers at the mRNA and protein levels. Mouse and human 32-mer peptide stimulated NF-kappaB activation in a TLR-2 dependent reporter assay, and the response of chondrocytes from both species to native, glycosylated 32-mer peptide was similar to the response to synthetic peptides. CONCLUSION: The aggrecan 32-mer fragment is a novel endogenous ligand of TLR-2 with the potential to accelerate cartilage destruction in vivo. PMID- 25707861 TI - Heart rate variability and the risk of Parkinson disease: The Atherosclerosis Risk in Communities study. AB - OBJECTIVE: Autonomic dysfunction frequently occurs in the context of Parkinson disease (PD) and may precede onset of motor symptoms. Limited data exist on the prospective association of heart rate variability (HRV), a marker of autonomic function, with PD risk. METHODS: We included 12,162 participants of the Atherosclerosis Risk in Communities study, a community-based cohort, without a diagnosis of PD at baseline (1987-1989) and with available HRV data (mean age = 54 years, 57% women). A 2-minute electrocardiogram was used to measure HRV. Incident PD was identified through 2008 from multiple sources, and adjudicated. Multivariable Cox models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of PD by quartiles of HRV measurements. RESULTS: During a mean follow-up of 18 years, we identified 78 incident PD cases. Lower values of the root mean square of successive differences in normal-to-normal R-R intervals (rMSSD) and standard deviation of normal-to-normal R-R intervals (SDNN), markers of parasympathetic activity and total variability, respectively, were associated with higher PD risk during follow-up. In multivariate models, the HR (95% CI) of PD in the bottom quartiles of rMSSD and SDNN compared to the top quartiles were 2.1 (1.0-4.3) and 2.9 (1.4-6.1), respectively. Other measures of cardiac autonomic function, including mean R-R interval and frequency-domain measurements, were not associated with PD risk. INTERPRETATION: In this prospective cohort, decreased HRV was associated with an increased risk of PD. Assessment of cardiac autonomic function may help identify individuals at risk for PD. PMID- 25707862 TI - Tyrosine O-prenyltransferases TyrPT and SirD displaying similar behavior toward unnatural alkyl or benzyl diphosphate as their natural prenyl donor dimethylallyl diphosphate. AB - Prenyltransferases of the dimethylallyltryptophan synthase (DMATS) superfamily are involved in the biosynthesis of secondary metabolites and contribute as modification enzymes significantly to structural diversity of natural products. They show usually broad specificity toward their aromatic substrates with regiospecific prenylations on aromatic rings. However, most members of this superfamily exhibit a high specificity toward their prenyl donors and usually accept exclusively dimethylallyl diphosphate (DMAPP). Recently, several indole prenyltransferases from this family were also demonstrated to accept unnatural DMAPP analogs such as methylallyl, 2-pentenyl and benzyl diphosphate for alkylation, or benzylation of the indole ring. Partial or complete shift of the substitution position was observed for these enzymes. In this study, we report the acceptance of these DMAPP analogs by two tyrosine O-prenyltransferases TyrPT from Aspergillus niger and SirD from Leptosphaeria maculans for alkylation or benzylation of tyrosine and derivatives. NMR and mass spectrometry (MS) analyses of nine isolated enzyme products confirmed the regiospecific O- or N-alkylation or benzylation at position C-4 of the aromatic ring, which is the same prenylation position of these enzymes in the presence of DMAPP. PMID- 25707863 TI - Overexpression of ribosome elongation factor G and recycling factor increases L isoleucine production in Corynebacterium glutamicum. AB - Ribosome elongation factor G encoded by fusA promotes the translocation step of protein synthesis in bacteria; ribosome recycling factor encoded by frr, together with the elongation factor G, dissociates ribosomes from messenger RNA after the termination of translation. Both factors play important roles during protein synthesis in bacteria. In this study, we found that overexpression of fusA and/or frr led to the increase of L-isoleucine production in Corynebacterium glutamicum IWJ001, an L-isoleucine production strain generated by random mutagenesis. Reverse transcription polymerase chain reaction analysis showed that transcriptional levels of genes lysC, hom, thrB, ilvA, ilvBN, and ilvE encoding the key enzymes in the biosynthetic pathway of L-isoleucine increased in C. glutamicum IWJ001 when fusA and/or frr were overexpressed. Co-overexpression of fusA and frr, together with genes ilvA, ilvB, ilvN, and ppnk in C. glutamicum IWJ001, led to 76.5 % increase of L-isoleucine production in flask cultivation and produced 28.5 g/L L-isoleucine in 72-h fed-batch fermentation. The results demonstrate that overexpressing ribosome elongation factor G and ribosome recycling factor is an efficient approach to enhance L-isoleucine production in C. glutamicum. PMID- 25707864 TI - Combination therapy with TNFR-Fc and CTLA4-FasL using the recombinant adeno associated virus potently suppresses adjuvant-induced arthritis in rats. AB - The complexity of rheumatoid arthritis (RA) pathogenesis makes combined blockade of key pathogenic factors an attractive therapeutic strategy. We have previously reported a novel recombinant adeno-associated virus (AAV) vector, AAV.TFCF, which mediates separate coexpression of TNFalpha antagonist TNFR-Fc and T cell antagonist CTLA4-FasL both in vitro and in vivo (the injected joints). The purpose of this study was to examine the efficacy of TNFR-Fc/CTLA4-FasL combination therapy mediated by AAV.TFCF in experimental model of RA. Adjuvant induced arthritis (AIA) was induced in Lewis rats, and the recombinant AAV.TFCF was injected into rat ankle joints. AAV vector encoding CTLA4-FasL (AAV.CTFA) or TNFR-Fc (AAV.TRFC) was used as the monotherapy control, and an AAV vector mediating the expression of enhanced green fluorescent protein (AAV.EGFP) was used as the negative control. The combination treatment mediated by AAV.TFCF demonstrated a more effective suppression of AIA compared with those monotherapy controls, as reflected in the clinical and histological observations. The synergistic anti-inflammatory effect of TNFR-Fc combining with CTLA4-FasL was proved to be associated with the greater reductions of inflammatory CD4+ T cell infiltration and proinflammatory cytokine TNFalpha level in the arthritic joints. In addition, the combination therapy was found to be able to increase the frequency of CD4 + CD25 + FoxP3+ regulatory T cell population in rat draining lymph nodes and suppress splenic inflammatory responses. These results suggest that combination treatment with TNFR-Fc and CTLA4-FasL may achieve superior efficacy in suppressing RA, and using this novel recombinant AAV.TFCF to obtain the combined counteraction of both pathogenic T cells and the key proinflammatory cytokine TNFalpha may provide a more effective and desirable strategy for treatment of RA. PMID- 25707865 TI - Potential of sequential treatment with minocycline and S. aureus specific phage lysin in eradication of MRSA biofilms: an in vitro study. AB - Lysins are novel class of anti-infectives which are derived from bacteriophage. In the present study, the potential of previously characterised phage borne endolysin MR-10 in eradicating methicillin-resistant Staphylococcus aureus (MRSA) biofilm was evaluated. Scanning electron microscopic examination showed that both ica-positive and ica-negative MRSA formed equally potent mature biofilm. Different approaches were employed to eradicate the young as well as older biofilm formed by both types of MRSA strains. Our results showed a significant decrease (p < 0.01) in biofilm count on sequentially treating the MRSA biofilm with minocycline (4 MUg/ml) for 3 h followed by treatment with endolysin MR-10. Since endolysin can act effectively irrespective of the metabolic status of the cells hence, they are capable of killing the rapidly growing cells (log phase cells) as well as non-dividing (stationary phase) cells. As a result they are effective in eradicating the younger and older biofilm. On staining the ica positive MRSA biofilm with wheat germ agglutinin (WGA)-Alexa Flour 350, reduction in poly-intercellular adhesion (PIA) content was observed in comparison to control biofilm. In addition, a significant decrease (p < 0.01) in extracellular DNA (eDNA) content of ica-negative MRSA biofilm was also observed. Further, Live/Dead BaclightTM staining also showed presence of higher population of dead cells after treatment with minocycline and endolysin MR-10. Hence, our results showed that using minocycline sequentially with endolysin, MR-10 can effectively eradicate both young as well as older biofilm formed by ica-positive and ica negative MRSA. PMID- 25707866 TI - Pyrrole-coupled salicylimine-based fluorescence "turn on" probe for highly selective recognition of Zn2+ ions in mixed aqueous media: Application in living cell imaging. AB - Cation sensing behaviour of a pyrrole-based derivative (2-hydroxyl 3 methyl 6 isopropyl benzaldehyde}-3,4-dimethyl-1H-pyrrole-2-carbohydrazide (receptor 3) has been explored and is found to be selective towards Zn(2+) over a variety of tested cations. The receptor 3 has shown high selectivity and sensitivity towards Zn(2+) over the other alkali, alkaline earth and transition metal ions. In the presence of Zn(2+), absorption band of receptor 3 has shown the red shift. The sensing behaviour has been suggested to continue via enhancement process which has further been supported by UV-vis absorption and theoretical density functional theory (DFT) calculations indicating the formation of a 1:1 complex between the pyrrole based receptor 3 and Zn(2+). The present work is presenting a highly selective dual channel colorimetric sensor for zinc with great sensitivity. The developed sensor was successfully applied to image intracellular Zn(2+) in living cells. PMID- 25707867 TI - Contextual effects on preattentive processing of sound motion as revealed by spatial MMN. AB - The magnitude of spatial distance between sound stimuli is critically important for their preattentive discrimination, yet the effect of stimulus context on auditory motion processing is not clear. This study investigated the effects of acoustical change and stimulus context on preattentive spatial change detection. Auditory event-related potentials (ERPs) were recorded for stationary midline noises and two patterns of sound motion produced by linear or abrupt changes of interaural time differences. Each of the three types of stimuli was used as standard or deviant in different blocks. Context effects on mismatch negativity (MMN) elicited by stationary and moving sound stimuli were investigated by reversing the role of standard and deviant stimuli, while the acoustical stimulus parameters were kept the same. That is, MMN amplitudes were calculated by subtracting ERPs to identical stimuli presented as standard in one block and deviant in another block. In contrast, effects of acoustical change on MMN amplitudes were calculated by subtracting ERPs of standards and deviants presented within the same block. Preattentive discrimination of moving and stationary sounds indexed by MMN was strongly dependent on the stimulus context. Higher MMNs were produced in oddball configurations where deviance represented increments of the sound velocity, as compared to configurations with velocity decrements. The effect of standard-deviant reversal was more pronounced with the abrupt sound displacement than with gradual sound motion. PMID- 25707868 TI - Iatrogenic Petersen's hernia following Roux-en-Y gastric bypass. PMID- 25707869 TI - Evidence-Based Protocols to Guide Pulse Oximetry and Oxygen Weaning in Inpatient Children with Asthma and Bronchiolitis: A Pilot Project. AB - Nurses', respiratory therapists' (RTs), and physicians' concerns about oxygen weaning practices and pulse oximetry use in healthy children during inpatient admissions prompted this multidisciplinary evidence-based project. A nurse-led inter-professional team found lack of consistent oxygen weaning practices and lack of guidelines for nurses or RTs regarding pulse oximetry use with children admitted for acute respiratory illness. The team created and piloted evidence based oxygen weaning and pulse oximetry protocols. After a 6 month pilot, children in the pilot had shorter length of stay, time on oxygen, and time on continuous pulse oximetry. Protocols improved patient outcomes and decreased associated charges. PMID- 25707870 TI - Do we need antiplatelet therapy in thrombocytosis? Pro. Diagnostic and pathophysiologic considerations for a treatment choice. AB - Thrombocytosis (defined as platelets >450 x 109/l) has several aetiologies. After having excluded spurious thrombocytosis (e. g., due to microspherocytes, schistocytes, cryoglobulins, or bacteria), the differential diagnosis of true thrombocytosis encompasses secondary causes (as diverse as inflammation, infection, malignancy, iron deficiency, or asplenia), primary hereditary (rare forms of familial thrombocytosis) and primary acquired entities (either in the context of a myelodysplastic syndrome or more frequently a myeloproliferative neoplasia). This manuscript addresses the following aspects: 1) diagnostic approach to thrombocytosis; 2) various mechanisms leading to a high platelet count; 3) potential of some of these mechanisms to modulate platelet function, producing hyper-reactive platelets and thus exerting a direct impact on the thrombotic risk; 4) indication of anti-thrombotic treatment in patients with thrombocytosis. There is a single prospective randomized clinical trial showing the benefit of acetyl-salicylic acid in polycythaemia vera. For other types of primary thrombocytosis and for secondary forms, treatment decisions have to be individualized according to the patient thrombotic and bleeding risks, taking into account the mechanism causing thrombocytosis. This manuscript discusses experimental and clinical data suggesting that besides patients with essential thrombocythaemia and other forms of primary thrombocytosis also those with thrombocytosis in the context of chronic inflammation, malignancy, or exposure to high altitude might benefit from anti-platelet treatment. PMID- 25707871 TI - Mild encephalopathy with reversible splenial lesion: an important differential of encephalitis. AB - Mild encephalopathy with a reversible splenial lesion (MERS) is a clinico radiological syndrome characterized by a transient mild encephalopathy and a reversible lesion in the splenium of the corpus callosum on MRI. This syndrome has almost universally been described in children from Japan and East Asia. Here we describe seven cases of MERS occurring in Caucasian Australian children from one centre seen over a 3 year period. All patients had a fever-associated encephalopathy (n = 7), which presented with confusion (n = 4), irritability (n = 3), lethargy (n = 3), slurred speech (n = 3), drowsiness (n = 2) and hallucinations (n = 2). Other neurological symptoms included ataxia (n = 5) and seizures (n = 1). These symptoms resolved rapidly over 4-6 days followed by complete neurological recovery. In all patients, MRI performed within 1-3 days of onset of encephalopathy demonstrated a symmetrical diffusion-restricted lesion in the splenium of the corpus callosum. Three patients had additional lesions involving other parts of the corpus callosum and adjacent periventricular white matter. These same three patients had mild persisting white matter changes evident at followup MRI, while the other patients had complete resolution of radiological changes. A potential trigger was present in five of the seven cases: Kawasaki disease, Salmonella, cytomegalovirus, influenza B and adenovirus (all n = 1). Elevated white cell count (n = 4), elevated C reactive protein (n = 5) and hyponatremia (n = 6) were commonly observed. CSF was performed in four patients, which showed no pleocytosis. This case series of MERS demonstrates this condition occurs outside of East Asia and is an important differential to consider in children presenting with acute encephalopathy. PMID- 25707872 TI - Short prolactin profile for monitoring treatment in BH4 deficiency. AB - Tetrahydrobiopterin (BH4) deficiency causes hyperphenylalaninemia and impaired synthesis of serotonin and dopamine, leading to brain degeneration and early death if left untreated. Replacement therapy with neurotransmitters precursors is the cornerstone of treatment, relying on 5-hydroxytryptophan and L-dopa administration. Effective restoration of dopaminergic activity is thickened, like in Parkinson's disease, by the pulsatile pharmacokinetic profile of L-dopa. Monitoring of L-dopa therapy in BH4 deficiency is generally based upon clinical observation and periodical measurement of homovanillic acid (HVA) concentration in the cerebrospinal fluid (CSF). According to the finding that dopamine is the natural inhibitor of prolactin (PRL) incretion, we introduced the use of peripheral PRL measurement as an index of dopaminergic homeostasis, so avoiding the need of repeated lumbar punctures in patients with BH4 deficiency. As a single PRL evaluation can be misleading, due to the dependency of PRL fluctuations on L-dopa administration schedule, here we show that a short PRL profile is suitable for monitoring these patients. Together with the assessment of patients' clinical symptoms, this standardized tool will ensure an objective non-invasive reference to the management of dopaminergic replacement therapy in BH4 deficiency, even in patients treated with dopamine agonists. PMID- 25707873 TI - Do circulating cells transdifferentiate and replenish stem cell pools in the brain and periphery? AB - For nearly two centuries, developmental biologists have known that body organs are derived from distinct germ layers. They have argued that adult stem cells formed in one of these, mesoderm for example, cannot give rise to cells that originate in another. We disagree. An exception to this "rule" has been described in crayfish recently. In this species, hemocytes appear to replenish neurogenic cells. This may happen in humans as well. In women who were given male bone marrow-derived cells, Y chromosome positive cheek cells and brain neurons were detected. While repopulation of these tissues by bone marrow derived cells may not occur normally, and while it does not appear to be terribly efficient, the phenomenon should be studied in more detail. Perhaps cells in the marrow could be used to regenerate tissues elsewhere. PMID- 25707874 TI - Risk factors for carbapenem-resistant Klebsiella pneumoniae infection/colonization and predictors of mortality: a retrospective study. AB - OBJECTIVE: To identify risk factors associated with carbapenem-resistant Klebsiella pneumoniae (CRKP) infection/colonization and death and to investigate the resistance and homology of CRKP. METHODS: A retrospective 1:1 case-control study was conducted at Changhai Hospital, China, from January 2010 to December 2011.The study population included 30 patients with CRKP infection/colonization and 30 matched patients with carbapenem-susceptible K. pneumoniae (CSKP) infection/colonization at the same site. Homology analysis was conducted by multilocus sequence typing (MLST) and pulsed-field gel electrophoresis (PFGE). Potential resistance genes were detected by PCR. RESULTS: Independent risk factors for CRKP infection/colonization were admission to exposure to glycopeptides [Odds ratio (OR): 43.84, 95% confidence interval (CI): 1.73 1111.91, P = 0.020], cefoperazone plus sulbactam (OR: 49.56, 95% CI: 1.42 1726.72, P = 0.030) and tracheostomy (OR: 677.82, 95% CI: 2.76-1667, P = 0.020). Age (OR: 1.07, 95% CI: 1.00-1.14, P = 0.04), renal dysfunction (OR: 17.63, 95% CI: 2.34-132.87, P = 0.005) and exposure to cefoperazone plus sulbactam (OR: 8.87, 95% CI: 1.29-61.07, P = 0.026) were independent risk factors for the death of patients with K. pneumoniae infection/colonization. Older age (OR: 1.16, 95% CI: 1.01-1.39, P = 0.011) was an independent risk factor for the death of patients with CRKP infection/colonization. Thirty CRKP strains were all KPC-2 producing resistant strains with genotype of ST-11. CONCLUSION: Exposure to glycopeptides, cefoperazone plus sulbactam and tracheostomy were independent risk factors for CRKP infection/colonization, and older age was an independent risk factor for CRKP infection/colonization caused death. PMID- 25707875 TI - Daclizumab Versus Rabbit Antithymocyte Globulin in High-Risk Renal Transplants: Five-Year Follow-up of a Randomized Study. AB - We previously reported a randomized controlled trial in which 227 de novo deceased-donor kidney transplant recipients were randomized to rabbit antithymocyte (rATG, Thymoglobulin) or daclizumab if they were considered to be at high immunological risk, defined as high panel reactive antibodies (PRA), loss of a first kidney graft through rejection within 2 years of transplantation, or third or fourth transplantation. Patients treated with rATG had lower incidences of biopsy-proven acute rejection (BPAR) and steroid-resistant rejection at 1 year. Patients were followed to 5 years posttransplant in an observational study; findings are described here. Treatment with rATG was associated with a lower rate of BPAR at 5 years (14.2% vs. 26.0% with daclizumab; p = 0.035). Only one rATG treated patient (0.9%) and one daclizumab-treated patient (1.0%) developed BPAR after 1 year. Five-year graft and patient survival rates, and renal function, were similar between the two groups. Overall graft survival at 5 years was significantly higher in patients without BPAR (81.0% vs. 54.8%; p < 0.001). In conclusion, rATG is superior to daclizumab for the prevention of BPAR among high immunological-risk renal transplant recipients. Overall graft survival at 5 years was approximately 70% with either induction therapy, which compares favorably to low-risk cohorts. PMID- 25707876 TI - Re-defining response and treatment effects for neuro-oncology immunotherapy clinical trials. AB - In much of medical oncology, including neuro-oncology, there is great interest to evaluate the therapeutic potential of immune-based therapies including vaccines, adoptive T cell strategies and modulators of immune checkpoint regulators such as cytotoxic T lymphocyte antigen 4 and programmed death 1. Immune-based treatments exert an indirect anti-tumor effect by generating potent, tumor-targeting immune responses. Robust anti-tumor immune responses have been shown to achieve encouraging radiographic responses across the spectrum of applied immunotherapeutics which are felt to be indicative of a bona fide anti-tumor effect. Conversely, worsening of imaging findings, particularly early in the course of immunotherapy administration, can be challenging to interpret with growing evidence demonstrating that at least a subset of such patients ultimately will derive meaningful clinical benefit. The immune related response criteria were generated to provide guidance regarding the interpretation of such complex imaging findings, for general medical oncologists prescribing immunotherapeutics. An analogous effort that addresses challenges associated with imaging assessment and incorporates nuances associated with neuro-oncology patients is underway and is referred to as the immunotherapy response assessment in neuro-oncology criteria. PMID- 25707878 TI - Osteopoikilosis: an important incidental finding. PMID- 25707877 TI - Semaphorin 4D Contributes to Rheumatoid Arthritis by Inducing Inflammatory Cytokine Production: Pathogenic and Therapeutic Implications. AB - OBJECTIVE: Semaphorin 4D (Sema4D)/CD100 has pleiotropic roles in immune activation, angiogenesis, bone metabolism, and neural development. We undertook this study to investigate the role of Sema4D in rheumatoid arthritis (RA). METHODS: Soluble Sema4D (sSema4D) levels in serum and synovial fluid were analyzed by enzyme-linked immunosorbent assay. Cell surface expression and transcripts of Sema4D were analyzed in peripheral blood cells from RA patients, and immunohistochemical staining of Sema4D was performed in RA synovium. Generation of sSema4D was evaluated in an ADAMTS-4-treated monocytic cell line (THP-1 cells). The efficacy of anti-Sema4D antibody was evaluated in mice with collagen-induced arthritis (CIA). RESULTS: Levels of sSema4D were elevated in both serum and synovial fluid from RA patients, and disease activity markers were correlated with serum sSema4D levels. Sema4D-expressing cells also accumulated in RA synovium. Cell surface levels of Sema4D on CD3+ and CD14+ cells from RA patients were reduced, although levels of Sema4D transcripts were unchanged. In addition, ADAMTS-4 cleaved cell surface Sema4D to generate sSema4D in THP-1 cells. Soluble Sema4D induced tumor necrosis factor alpha (TNFalpha) and interleukin-6 (IL-6) production from CD14+ monocytes. IL-6 and TNFalpha induced ADAMTS-4 expression in synovial cells. Treatment with an anti-Sema4D antibody suppressed arthritis and reduced proinflammatory cytokine production in CIA. CONCLUSION: A positive feedback loop involving sSema4D/IL-6 and TNFalpha/ADAMTS-4 may contribute to the pathogenesis of RA. The inhibition of arthritis by anti Sema4D antibody suggests that Sema4D represents a potential therapeutic target for RA. PMID- 25707880 TI - Towards a methanol economy based on homogeneous catalysis: methanol to H2 and CO2 to methanol. AB - The possibility to implement both the exhaustive dehydrogenation of aqueous methanol to hydrogen and CO2 and the reverse reaction, the hydrogenation of CO2 to methanol and water, may pave the way to a methanol based economy as part of a promising renewable energy system. Recently, homogeneous catalytic systems have been reported which are able to promote either one or the other of the two reactions under mild conditions. Here, we review and discuss these developments. PMID- 25707879 TI - Clinical differences between major burns patients deemed survivable and non survivable on admission. AB - INTRODUCTION: Despite advances in burn care, there is still a group of patients with serious burn injury who fail to respond to therapies or for whom active treatments are unsuccessful. As the demographic and causative factors of burn related mortality may differ between treating units and countries, we aimed to investigate clinical aspects of patients that die whose injuries are considered either survivable or non-survivable on admission. METHODS: A retrospective 11 year medical record review (2000-2011) of patients admitted to the Victorian Adult Burns Service (VABS), Melbourne, Australia, with a fatal burn injury was undertaken. Patient characteristics such as age, gender, total body surface area (TBSA%) burned, type and site of burn, hospital length of stay, receipt of burn care treatments and when withdrawal of care (WOC) took place were identified using hospital databases. For the purposes of categorization, two categories of patients were defined retrospectively. 'Early WOC' patients were those for whom a decision was made within the first 24h following admission that a patient injury was likely non-survivable, or that survival was incompatible with a meaningful quality of life. 'Late WOC' patients were those patients for whom a decision was made within the first 24h following admission that a patient injury was survivable and potentially compatible with a meaningful quality of life. RESULTS: In a study analyzing 70 patients, the average TBSA% burned in the 'Early WOC' group (n=43) was significantly higher with the 'Late WOC' cohort (n=27) (85% vs. 45%; p=0.001) compared. A higher incidence of accelerant use (60% vs. 35%; p=0.07) and facial burns (74% vs. 44%; p=0.02) was found in the 'Early WOC' patients. In the 'Late WOC' group, 92.6% of patients required mechanical ventilation and 78.6% of patients underwent operative intervention (median surgical time 9.25h, inter-quartile range 6.5-18.5). CONCLUSION: A number of clinical differences in major burn patients can be observed at admission between patients for whom a decision is made as to whether an injury is survivable or non survivable. These differences may influence the degree of therapeutic aggression or conservatism as determined by the treating clinical team. As a matter of maintaining standards amongst the burns community, reporting mortality data such as this may also provide a benchmark by which other burns units can assess their own data regarding end-of-life decision-making. PMID- 25707881 TI - Quantitative structure-retardation factor relationship of protein amino acids in different solvent mixtures for normal-phase thin-layer chromatography. AB - A quantitative predictive/descriptive model was proposed for the retardation factors of protein amino acids in normal-phase thin-layer chromatography. The experimental retardation factors of 126 chromatographic mixtures (21 protein amino acids in different mobile phases) were used as the independent variable. The matrix of dependent variables of the model was built using structural descriptors of amino acids and empirical parameters of solvents of the applied mobile phases. After variable selection, a five-parametr model was proposed for the retardation factor of amino acids, which covered about 84 and 77% variance of data in training and cross-validation, respectively. The correlation coefficient of the external test set was 0.80, which shows the prediction potential of proposed model as well as its good applicability domain that was checked using a standardized residual-leverage plot. PMID- 25707882 TI - Role of the Keap1/Nrf2 pathway in neurodegenerative diseases. AB - As the elderly population increases, a growing number of individuals suffer from age-associated neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD). Oxidative stress is considered to play a crucial role in the pathogenesis of age-related diseases. The transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) is activated by oxidative stress and regulates the expression of a variety of antioxidant enzymes and proteins that exert cytoprotective effects against oxidative stress. Numerous studies have addressed the role of Nrf2 in age-related diseases, including neurodegenerative diseases, using animal or in vitro cell culture models. Here, we introduce the role of oxidative stress in the pathogenesis of neurodegenerative diseases and critically examine the recent findings concerning the role for Nrf2 in the amelioration of AD and PD. Nrf2 not only regulates antioxidant proteins but also regulates the genes associated with autophagy and nerve growth factor signaling. Current research unequivocally demonstrates that the activation of the Nrf2 pathway is a promising novel strategy for the prevention and modification of neurodegenerative diseases. PMID- 25707883 TI - [Gorlin syndrome and SUFU germline mutations]. PMID- 25707884 TI - Radiology and social media: are private practice radiology groups more social than academic radiology departments? AB - PURPOSE: This study assesses the prevalence of use of the most commonly used social media sites among private radiology groups (PRGs) and academic radiology departments (ARDs). METHODS: The 50 largest PRGs and the 50 ARDs with the highest level of funding from the National Institutes of Health were assessed for presence of a radiology-specific social media account on Facebook, Twitter, Instagram, Pinterest, YouTube, and LinkedIn. Measures of organizational activity and end-user activity were collected, including the number of posts and followers, as appropriate; between-group comparisons were performed. RESULTS: PRGs adopted Facebook 12 months earlier (P = .02) and Twitter 18 months earlier (P = .02) than did ARDs. A total of 76% of PRGs maintained >=1 account on the social media sites included in the study, compared with 28% of ARDs (P < .0001). The prevalence of having an account on the social media sites for PRGs was: Facebook, 66%; LinkedIn, 56%; Twitter, 42%; YouTube, 20%; Pinterest, 4%; and Instagram, 2%. The prevalence of radiology-specific social media accounts for ARDs was: Facebook, 18%; LinkedIn, 0%; Twitter, 24%; YouTube, 6%; Pinterest, 0%; and Instagram, 0%. There was no significant difference between ARDs and PRGs in measures of end-user or organizational activity on Facebook or Twitter. CONCLUSIONS: Use of social media in health care is emerging as mainstream, with PRGs being early adopters of Facebook and Twitter in comparison with ARDs. Competitive environments and institutional policies may be strong factors that influence how social media is used by radiologists at the group and department levels. PMID- 25707885 TI - What mediators can teach physicians about managing 'difficult' patients. PMID- 25707886 TI - The reply. PMID- 25707887 TI - Quality of care: a long way to tipperary or a long way down. PMID- 25707888 TI - The reply. PMID- 25707889 TI - Is the epidemic of heart disease really over or just evolving? PMID- 25707890 TI - The reply. PMID- 25707891 TI - Fecal microbiota transplantation: the case of immunocompromised patients. PMID- 25707892 TI - Marijuana use in models for health outcomes. PMID- 25707893 TI - Screening for hepatocellular carcinoma: where is the inconsistency? PMID- 25707894 TI - The reply. PMID- 25707895 TI - Thyroid heart disease should include the coincidental association of hypothyroidism and atrial fibrillation. PMID- 25707896 TI - Intestinal absorption and cell transforming potential of PhIP-M1, a bacterial metabolite of the heterocyclic aromatic amine 2-amino-1-methyl-6 phenylimidazo[4,5-b]pyridine (PhIP). AB - Previous studies have shown that in the rat, the colon carcinogen 2-amino-1 methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is only absorbed to a limited extent in the small intestines and that a major fraction of unmetabolised PhIP reaches the colon. Moreover, PhIP is extensively metabolised when incubated with human stool samples to a major derivative, 7-hydroxy-5-methyl-3-phenyl-6,7,8,9 tetrahydropyrido [3',2':4,5]imidazo[1,2-a]pyrimidin-5-ium chloride (PhIP-M1). In the present study, the uptake and transport of PhIP-M1 in Ussing chamber experiments, its cytotoxicity in the different segments of the Fischer 344 rat gut and its transforming potential in the BALB/c 3T3 cell transformation assay were analysed. At the most, 10-20% of the PhIP-M1 amount added to the mucosal compartment of the Ussing chambers per segment were absorbed within 90min. Therefore, the amount of PhIP-M1 detected in the tissues as well as in the serosal compartment of the Ussing chambers was extremely low. Moreover, human relevant concentrations of PhIP-M1 were not cytotoxic and did not induce the malignant transformation of BALB/c 3T3 cells. In conclusion, even if one would assume that 100% of the daily amount of PhIP ingested by a human being is converted into PhIP-M1 in the colon, this concentration most probably would not lead to cytotoxicity and/or carcinogenicity in the colorectal mucosa. PMID- 25707897 TI - Analysis and interpretation of a unique Arabic finger ring from the Viking Age town of Birka, Sweden. AB - In this work we used non-destructive SEM imaging and EDS analysis to characterize the material composition of an Arabic finger ring, which was found in a 9(th) c. woman's grave at the Viking Age (A.D. 793-1066) trading center of Birka, Sweden. The ring is set with a violet stone inscribed with Arabic Kufic writing, here interpreted as reading "il-la-lah", i.e. "For/to Allah". The stone was previously thought to be an amethyst, but the current results show it to be coloured glass. The ring has been cast in a high-grade silver alloy (94.5/5.5 Ag/Cu) and retains the post-casting marks from the filing done to remove flash and mold lines. Thus, the ring has rarely been worn, and likely passed from the silversmith to the woman buried at Birka with few owners in between. The ring may therefore constitute material evidence for direct interactions between Viking Age Scandinavia and the Islamic world. Being the only ring with an Arabic inscription found at a Scandinavian archaeological site, it is a unique object among Swedish Viking Age material. The technical analysis presented here provides a better understanding of the properties and background of this intriguing piece of jewelry. PMID- 25707898 TI - Mental health service users' experiences of mental health care: an integrative literature review. AB - A number of studies have highlighted issues around the relationship between service users and providers. The recovery model is predominant in mental health as is the recognition of the importance of person-centred practice. The authors completed an in-depth search of the literature to answer the question: What are service users' experiences of the mental health service? Three key themes emerged: acknowledging a mental health problem and seeking help; building relationships through participation in care; and working towards continuity of care. The review adds to the current body of knowledge by providing greater detail into the importance of relationships between service users and providers and how these may impact on the delivery of care in the mental health service. The overarching theme that emerged was the importance of the relationship between the service user and provider as a basis for interaction and support. This review has specific implications for mental health nursing. Despite the recognition made in policy documents for change, issues with stigma, poor attitudes and communication persist. There is a need for a fundamental shift in the provider service user relationship to facilitate true service-user engagement in their care. The aim of this integrative literature review was to identify mental health service users' experiences of services. The rationale for this review was based on the growing emphasis and requirements for health services to deliver care and support, which recognizes the preferences of individuals. Contemporary models of mental health care strive to promote inclusion and empowerment. This review seeks to add to our current understanding of how service users experience care and support in order to determine to what extent the principles of contemporary models of mental health care are embedded in practice. A robust search of Web of Science, the Cochrane Database, Science Direct, EBSCO host (Academic Search Complete, MEDLINE, CINAHL Plus Full-Text), PsycINFO, PsycARTICLES, Social Sciences Full Text and the United Kingdom and Ireland Reference Centre for data published between 1 January 2008 and 31 December 2012 was completed. The initial search retrieved 272 609 papers. The authors used a staged approach and the application of predetermined inclusion/exclusion criteria, thus the numbers of papers for inclusion were reduced to 34. Data extraction, quality assessment and thematic analysis were completed for the included studies. Satisfaction with the mental health service was moderately good. However, accessing services could be difficult because of a lack of knowledge and the stigma surrounding mental health. Large surveys document moderate satisfaction ratings; however, feelings of fear regarding how services function and the lack of treatment choice remain. The main finding from this review is while people may express satisfaction with mental health services, there are still issues around three main themes: acknowledging a mental health problem and seeking help; building relationship through participation and care; and working towards continuity of care. Elements of the recovery model appear to be lacking in relation to user involvement, empowerment and decision making. There is a need for a fundamental shift in the context of the provider-service user relationship to fully facilitate service users' engagement in their care. PMID- 25707899 TI - From service quality in organisations to self-determination at home. AB - BACKGROUND: In our proposed model, family members' perceptions of service quality in organisations improve communication about self-determination. In turn, family perceptions of communication openness have a positive relationship with self determination attitudes of family members. Finally, these attitudes predict self determination behaviours of individuals with intellectual disability, as reported by family members. METHOD: We tested this model with a sample of 625 family members (196 using 'day care services' and 429 using 'occupational services'). RESULTS: Multi-sample structural equation modelling (SEM) supported the model. Communication and attitudes fully mediated the link from service quality to self determination behaviours. CONCLUSIONS: Improving family members' perceptions of service quality and opening channels of communication between professionals and family members are useful strategies to facilitate parents' positive attitudes and increase the frequency of self-determination behaviours at home. PMID- 25707900 TI - Apical 4-chamber longitudinal strain by vector velocity imaging: a promising predictor of left ventricular ejection fraction in healthy individuals. PMID- 25707901 TI - The Mediterranean diet and plasma lipid profile. PMID- 25707902 TI - Long-term outcome of cirrhotic patients with severe aortic stenosis treated with transcatheter aortic valve implantation. PMID- 25707903 TI - Atomic scale analysis of the enhanced electro- and photo-catalytic activity in high-index faceted porous NiO nanowires. AB - Catalysts play a significant role in clean renewable hydrogen fuel generation through water splitting reaction as the surface of most semiconductors proper for water splitting has poor performance for hydrogen gas evolution. The catalytic performance strongly depends on the atomic arrangement at the surface, which necessitates the correlation of the surface structure to the catalytic activity in well-controlled catalyst surfaces. Herein, we report a novel catalytic performance of simple-synthesized porous NiO nanowires (NWs) as catalyst/co catalyst for the hydrogen evolution reaction (HER). The correlation of catalytic activity and atomic/surface structure is investigated by detailed high resolution transmission electron microscopy (HRTEM) exhibiting a strong dependence of NiO NW photo- and electrocatalytic HER performance on the density of exposed high-index facet (HIF) atoms, which corroborates with theoretical calculations. Significantly, the optimized porous NiO NWs offer long-term electrocatalytic stability of over one day and 45 times higher photocatalytic hydrogen production compared to commercial NiO nanoparticles. Our results open new perspectives in the search for the development of structurally stable and chemically active semiconductor-based catalysts for cost-effective and efficient hydrogen fuel production at large scale. PMID- 25707904 TI - Inferring the global structure of chromosomes from structural variations. AB - BACKGROUND: Next generation sequencing (NGS) technologies have made it possible to exhaustively detect structural variations (SVs) in genomes. Although various methods for detecting SVs have been developed, the global structure of chromosomes, i.e., how segments in a reference genome are extracted and ordered in an unknown target genome, cannot be inferred by detecting only individual SVs. RESULTS: Here, we formulate the problem of inferring the global structure of chromosomes from SVs as an optimization problem on a bidirected graph. This problem takes into account the aberrant adjacencies of genomic regions, the copy numbers, and the number and length of chromosomes. Although the problem is NP complete, we propose its polynomial-time solvable variation by restricting instances of the problem using a biologically meaningful condition, which we call the weakly connected constraint. We also explain how to obtain experimental data that satisfies the weakly connected constraint. CONCLUSION: Our results establish a theoretical foundation for the development of practical computational tools that could be used to infer the global structure of chromosomes based on SVs. The computational complexity of the inference can be reduced by detecting the segments of the reference genome at the ends of the chromosomes of the target genome and also the segments that are known to exist in the target genome. PMID- 25707905 TI - Pseudobowmanella zhangzhouensis gen. nov., sp. nov., isolated from the surface freshwater of the Jiulong River in China. AB - A strain, JS7-9(T), which was isolated from the surface freshwater of the Jiulong River, China, was subjected to taxonomic study. The bacterium was Gram-negative, facultatively anaerobic, rod-shaped and motile by means of a single polar flagellum. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain JS7-9(T) is affiliated to the family Alteromonadaceae, showing 90.5-94.2 % of 16S rRNA gene sequence similarity with the genera Bowmanella (94.0-94.2 %), Aestuariibacter (93.0-93.5 %), Glaciecola (91.0-93.1 %), Alteromonas (90.5-93.1 %) and Salinimonas (90.6-91.8 %). The major fatty acids were identified as C16:0, Sum In Feature 3 (C16:1 omega7c/omega6c), Sum In Feature 8 (C18:1 omega7c/omega6c) and C17:1 omega8c, and Q-8 as the predominant isoprenoid quinone. Based on the phenotypic, chemotaxonomic and phylogenetic distinctiveness, strain JS7-9(T) is considered to represent a novel species of a novel genus of the family Alteromonadaceae, for which the name Pseudobowmanella zhangzhouensis gen. nov., sp. nov. is proposed, with the type strain JS7-9(T) (=MCCC 1A00758(T) = KCTC 42143(T)). PMID- 25707906 TI - Elastic properties of Thiel-embalmed human ankle tendon and ligament. AB - Thiel embalming is recommended as an alternative to formalin-based embalming because it preserves tissue elasticity, color, and flexibility in the long term, with low infection and toxicity risk. The degree to which Thiel embalming preserves elasticity has so far been assessed mainly by subjective scoring, with little quantitative verification. The aim of this study is to quantify the effect of Thiel embalming on the elastic properties of human ankle tendons and ligament. Biomechanical tensile tests were carried out on six Thiel-embalmed samples each of the peroneus longus, peroneus brevis, and calcaneal tendons, and the calcaneofibular ligament, with strain rates of 0.25%s(-1), 2%s(-1), and 8%s(-1). The stress-strain relationship was calculated from the force-extension response with cross-sectional area and gauge length. Young's modulus was determined from the stress-strain curve. The results showed that the tendon and ligament elasticity were lower after Thiel embalming than the literature values for fresh nonembalmed tendons and ligament. The biomechanical tensile test showed that the measured elasticity of Thiel-embalmed tendons and ligaments increased with the strain rate. The Thiel embalming method is useful for preserving human ankle tendons and ligaments for anatomy and surgery teaching and research, but users need to be aware of its softening effects. The method retains the mechanical strain rate effect on tendons and ligament. PMID- 25707907 TI - Season-dependent associations of circadian rhythm-regulating loci (CRY1, CRY2 and MTNR1B) and glucose homeostasis: the GLACIER Study. AB - AIMS/HYPOTHESIS: The association of single nucleotide polymorphisms (SNPs) proximal to CRY2 and MTNR1B with fasting glucose is well established. CRY1/2 and MTNR1B encode proteins that regulate circadian rhythmicity and influence energy metabolism. Here we tested whether season modified the relationship of these loci with blood glucose concentration. METHODS: SNPs rs8192440 (CRY1), rs11605924 (CRY2) and rs10830963 (MTNR1B) were genotyped in a prospective cohort study from northern Sweden (n = 16,499). The number of hours of daylight exposure during the year ranged from 4.5 to 22 h daily. Owing to the non-linear distribution of daylight throughout the year, season was dichotomised based on the vernal and autumnal equinoxes. Effect modification was assessed using linear regression models fitted with a SNP * season interaction term, marginal effect terms and putative confounding variables, with fasting or 2 h glucose concentrations as outcomes. RESULTS: The rs8192440 (CRY1) variant was only associated with fasting glucose among participants (n = 2,318) examined during the light season (beta = 0.04 mmol/l per A allele, 95% CI -0.08, -0.01, p = 0.02, p interaction = 0.01). In addition to the established association with fasting glucose, the rs11605924 (CRY2) and rs10830963 (MTNR1B) loci were associated with 2 h glucose concentrations (beta = 0.07 mmol/l per A allele, 95% CI 0.03, 0.12, p = 0.0008, n = 9,605, and beta = -0.11 mmol/l per G allele, 95% CI -0.15, -0.06, p < 0.0001, n = 9,517, respectively), but only in participants examined during the dark season (p interaction = 0.006 and 0.04, respectively). Repeated measures analyses including data collected 10 years after baseline (n = 3,500) confirmed the results for the CRY1 locus (p interaction = 0.01). CONCLUSIONS/INTERPRETATION: In summary, these observations suggest a biologically plausible season-dependent association between SNPs at CRY1, CRY2 and MTNR1B and glucose homeostasis. PMID- 25707908 TI - [A patient without intracardiac ECG. Persistent azygos vein]. AB - Interruption of inferior vena cava with azygos continuation is a rare venous anomaly. We report the case of a 17 old male with Wolf-Parkinson-White syndrome and a persistent vena azygos. Despite the complex anatomical situation, it was possible to safely ablate a lateral accessory pathway with radiofrequency energy using a femoral retrograde approach. PMID- 25707909 TI - Validation of an indirect calorimeter using n-of-1 methodology. AB - BACKGROUND: Validation data for currently available indirect calorimeters is limited. The purpose of this investigation was to validate a newer indirect calorimeter system (Vmax Encore) against a criterion device (Deltatrac Metabolic Monitor) in spontaneously breathing mode. MATERIALS AND METHODS: An n-of-1 methodology was used in which both indirect calorimeters were employed in the same subject repeatedly until 15 measurement pairs were generated for oxygen consumption (VO2), carbon dioxide production (VCO2), resting metabolic rate (RMR), and respiratory quotient (RQ). Bias was defined as a 95% confidence interval of differences between devices that excluded zero. A set of intradevice measurement pairs was also obtained to analyze the precision of the Vmax and Deltatrac (precision defined as not more than 5% of measurements being >=5% different). RESULTS: Both Vmax and Deltatrac precisely measured VO2 and RMR. The largest intradevice difference for RMR in the Deltatrac was 4.7% (one of 20 pairs) and in the Vmax 4.8%. On the other hand, VCO2 and RQ were not measured precisely by either device, with 10% or more of the measurement pairs differing by >= 5%. The Vmax was biased toward low measurement of VO2 and RMR relative to the Deltatrac. Oxygen consumption was on average 4.5 +/- 2.4% lower for the Vmax device compared to Deltatrac while RMR was lower by an average of 4.1 +/- 2.2%. CONCLUSIONS: The Vmax Encore indirect calorimeter is a precise instrument for measuring VO2 and RMR in spontaneously breathing individuals, but it is biased toward lower values compared to the Deltatrac. PMID- 25707910 TI - Toward a cancer-specific diet. AB - BACKGROUND & AIMS: It is widely acknowledged that the energy metabolism of cancer cells mainly relies on anaerobic glycolysis and this has prompted many researchers to try to reduce the malignant cells growth of experimental tumours through a programme of calorie restriction. Recently this approach has been proposed also to cancer patients. In the meantime it was demonstrated that the effects of calorie restriction on tumour growth are mediated through the toxic effect of ketone bodies on cancer cells which have a defective mitochondrial function, while these substrates are well-utilized by the normal cells. METHODS: This review analyzes the main available data regarding the tumour growth in patients undergoing a period of starvation or of normal/artificial nutrition as well as the recent approach through special normocaloric ketogenic diets which are well utilized by cancer patients while may be unfavourable for cancer cells. RESULTS: Despite the paucity of data it appears that modulation of tumour growth by the calorie restriction/nutritional support is unlikekly in humans for several reasons: the different tumour cells growth rate and different tumour/host carcass ratio and duration of treatment, between tumour-bearing animals and patients. CONCLUSION: There is a large consensus in literature that maintaining a normal body weight and preserving the lean body mass through an adequate nutrition is beneficial in cancer patients. The nutritional approach through a ketogenic diet which may be toxic for the cancer cells while is well utilized and tolerated by the patient seems promising in a next future. PMID- 25707911 TI - Stereotactic body radiotherapy for prostate cancer. AB - The use of stereotactic body radiotherapy (SBRT) for localised prostate cancer is now supported by a substantial body of non-randomised data, with medium-term outcomes consistent with current standard radiotherapy. The ability to deliver profoundly hypofractionated treatment, combined with the relatively low alpha/beta ratio of prostate cancer, may result in a more favourable therapeutic ratio, presenting an opportunity for isotoxic dose escalation. Furthermore, as treatment can be given in five attendances, SBRT has the potential both to reduce costs and improve patient quality of life. However, in a treatment landscape with many competing options of broadly similar efficacy, randomised trials are essential to define the relative benefits of this approach. SBRT also has an emerging application in oligometastatic prostate cancer, with promising early outcomes for delaying disease progression and deferring the need for androgen deprivation therapy. PMID- 25707912 TI - Converting Inoperable Colorectal Liver Metastases to Operable; Data from a UK Perspective. PMID- 25707914 TI - Parafoveal activation of sign translation previews among deaf readers during the reading of Chinese sentences. AB - In the present study, we manipulated the different types of information available in the parafovea during the reading of Chinese sentences and examined whether deaf readers could activate sign translations of Chinese words during reading. The main finding was that, as compared to unrelated previews, the deaf readers had longer fixation durations on the target words when sign-phonologically related preview words were presented; this preview cost effect due to sign phonological relatedness was absent for reading-level-matched hearing individuals. These results indicate that Chinese deaf readers activate sign language translations of parafoveal words during reading. We discuss the implications for notions of parafoveal processing in reading. PMID- 25707913 TI - Anti-PEG immunity: emergence, characteristics, and unaddressed questions. AB - The modification of protein and nanoparticle therapeutics with polyethylene glycol (PEG), a flexible, uncharged, and highly hydrophilic polymer, is a widely adopted approach to reduce RES clearance, extend circulation time, and improve drug efficacy. Nevertheless, an emerging body of literature, generated by numerous research groups, demonstrates that the immune system can produce antibodies that specifically bind PEG, which can lead to the 'accelerated blood clearance' of PEGylated therapeutics. In animals, anti-PEG immunity is typically robust but short-lived and consists of a predominantly anti-PEG IgM response. Rodent studies suggest that the induction of anti-PEG antibodies (alpha-PEG Abs) primarily occurs through a type 2 T-cell independent mechanism. Although anti-PEG immunity is less well-studied in humans, the presence of alpha-PEG Abs has been correlated with reduced efficacy of PEGylated therapeutics in clinical trials. The prevalence of anti-PEG IgG and reports of memory immune responses, as well as the existence of alpha-PEG Abs in healthy untreated individuals, suggests that the mechanism(s) and features of human anti-PEG immune responses may differ from those of animal models. Many questions, including the incidence rate of pre existing alpha-PEG Abs and immunological mechanism(s) of alpha-PEG Ab formation in humans, must be answered in order to fully address the potential complications of anti-PEG immunity. PMID- 25707916 TI - The role of antibody in enhancing dengue virus infection. AB - Dengue virus has four distinct serotypes whose cross-reactive immune responses contribute to increased disease severity following heterologous infections. It was proposed that non-protective cross-reactive antibodies may play a role in disease enhancement. In this study we develop a mathematical model of host-virus interaction and predict the mechanisms responsible for virus expansion and loss during primary and secondary dengue infections. We use the model to determine the role of cross-reactive antibodies during dengue fever and dengue hemorrhagic fever-inducing secondary infections, and then compare the model to published patient data. We predict that the cross-reactive antibodies interfere with the non-neutralizing antibody effects by reducing the phagocyte-mediated removal of antibody-virus immune complexes. PMID- 25707917 TI - An exploitation-competition system with negative effect of prey on its predator. AB - This paper considers an exploitation-competition system in which exploitation is the dominant interaction when the prey is at low density, while competition is dominant when the prey is at high density due to its negative effect on the predator. The two-species system is characterized by differential equations, which are the combination of Lotka-Volterra competitive and predator-prey models. Global dynamics of the model demonstrate some basic properties of exploitation competition systems: (i) When the growth rate of prey is extremely small, the prey cannot promote the growth of predator. (ii) When the growth rate is small, an obligate predator can survive by preying on the prey, while a facultative predator can approach a high density by the predation. (iii) When the growth rate is intermediate, the predator can approach the maximal density by an intermediate predation. (iv) When the growth rate is large, the predator can persist only if it has a large density and its predation on the prey is big. (v) Intermediate predation is beneficial to the predator under certain parameter range, while over or under-predation is not good. Extremely big/small predation would lead to extinction of species. Numerical simulations confirm and extend our results. PMID- 25707915 TI - The Pronociceptive Effect of Paradoxical Sleep Deprivation in Rats: Evidence for a Role of Descending Pain Modulation Mechanisms. AB - The mechanisms underlying the pronociceptive effect of paradoxical sleep deprivation (PSD) are not known. In this study, we asked whether PSD increases tonic nociception in the formalin test, decreases the antinociceptive effect of morphine administered into the periaqueductal gray matter (PAG), and disrupts endogenous descending pain modulation. PSD for either 24 or 48 h significantly increased formalin-induced nociception and decreased mechanical nociceptive paw withdrawal threshold. The maximal antinociceptive effect induced by morphine (0.9 9 nmol, intra-PAG) was significantly decreased by PSD. The administration of a low dose of the GABAA receptor antagonist, bicuculline (30-300 pmol, intra-PAG), decreased nociception in control rats, but not in paradoxical-sleep-deprived ones. Furthermore, the administration of the cholecystokinin (CCK) 2 receptor antagonist, YM022 (0.5-2 pmol) in the rostral ventral medulla (RVM), decreased nociception in paradoxical-sleep-deprived rats but not in control ones. While a dose of the CCK 2 receptor agonist, CCK-8 (8-24 pmol intra-RVM), increased nociception in control rats, but not in paradoxical-sleep-deprived ones. In addition, the injection of lidocaine (QX-314, 2%, intra-RVM) decreased nociception in sleep-deprived rats, but not in control rats, while the lesion of the dorsolateral funiculus prevented the pronociceptive effect of PSD. Finally, PSD significantly increased c-Fos expression in the RVM. Therefore, PSD increases pain independently of its duration or of the characteristic of the nociceptive stimulus and decreases morphine analgesia at the PAG. PSD appears to increase pain by decreasing descending pain inhibitory activity and by increasing descending pain facilitatory activity. PMID- 25707918 TI - Nationwide time trends and risk factors for in-hospital falls-related major injuries. AB - BACKGROUND: Accidental falls during hospitalisation have a range of complications and more information is needed to improve prevention. We investigated patterns of in-hospital fall-related major injuries in the period 2000-2012 and the association between chronic conditions and in-hospital fall-related major injuries. METHODS: Using administrative databases, patients aged 65+ years with in-hospital falls causing fractures or head injuries with need for surgery or intensive observation were identified as cases and were individually matched with five controls. Joinpoint regression was used to examine time trends and conditional logistic regression was used to analyse odds ratio (OR) for in hospital falls-related major injuries according to a range of comorbidities. RESULTS: Four thousand seven hundred and fifty-four cases were identified from 2000 to 2012 and the most common injury was femur fracture (61.55%). For individuals aged 65-74 and 75+ years, the incidence of in-hospital falls-related major injuries per 100,000 hospital days increased significantly in 2000-2012 (average annual change: 3.2%, CI: 0.6-5.8) and 2007-2012 (average annual change: 11.4%, CI: 5.7-17.5), respectively. Significantly increased OR for in-hospital fall-related major injuries were found for individuals with dementia (OR = 2.34, CI: 1.87-2.92), osteoporosis (OR = 1.68, CI: 1.43-1.99), stroke (OR = 1.63, CI: 1.41-1.88), depression (OR = 1.24, CI: 1.09-1.41), chronic obstructive pulmonary disease (OR = 1.18, CI: 1.01-1.39) and Parkinson disease (OR = 1.17, CI: 1.01 1.34). CONCLUSIONS: In-hospital falls-related major injuries increased significantly during the study period. Elderly with dementia, osteoporosis, stroke, depression, chronic obstructive pulmonary disease and Parkinson disease were associated with increased OR for in-hospital fall-related major injuries. Increased focus on patients with these comorbidities is warranted to decrease the increasing incidence in in-hospital major injuries. PMID- 25707919 TI - Saharan dust, climate variability, and asthma in Grenada, the Caribbean. AB - Saharan dust is transported across the Atlantic and interacts with the Caribbean seasonal climatic conditions, becoming respirable and contributing to asthma presentments at the emergency department. This study investigated the relationships among dust, climatic variables, and asthma-related visits to the emergency room in Grenada. All asthma visits to the emergency room (n = 4411) over 5 years (2001-2005) were compared to the dust cover and climatic variables for the corresponding period. Variation in asthma was associated with change in dust concentration (R(2) = 0.036, p < 0.001), asthma was positively correlated with rainfall (R(2) = 0.055, p < 0.001), and rainfall was correlated with dust (R(2) = 0.070, p = 0.003). Despite the similarities and the short distance between Trinidad, Barbados, and Grenada, they have markedly different geographies, cultures, population sizes, industrialization level, and economies. Therefore, different than from the studies in Trinidad and Barbados, Grenada is a non-industrialized low-income small island without major industrialized air pollution addition; asthma visits were inversely related to mean sea level pressure (R(2) = 0.123, p = 0.006) and positively correlated with relative humidity (R(2) = 0.593, p = 0.85). Saharan dust in conjunction with seasonal humidity allows for inhalable particulate matter that exacerbates asthma among residents in the Caribbean island of Grenada. These findings contribute evidence suggesting a broader public health impact from Saharan dust. Thus, this research may inform strategic planning of resource allocation among the Caribbean public health agencies. PMID- 25707920 TI - Oxytocin in the regulation of social behaviours in medial amygdala-lesioned mice via the inhibition of the extracellular signal-regulated kinase signalling pathway. AB - The neuropeptide oxytocin (OXT) has been implicated in the pathophysiology of behavioural deficits among patients with autism spectrum disorder (ASD). However, the molecular mechanisms underlying its role in ASD remain unclear. In the present study, a murine model with ASD-like phenotypes was induced by intra medial amygdala injection of N-methyl-d-aspartate, and it was used to investigate the role of OXT in behaviour regulation. Behavioural tests were performed to verify the ASD-like phenotypes of N-methyl-d-aspartate-treated mice, and the results showed that mice with bilateral medial amygdala lesions presented significant behavioural deficits, including impaired learning and memory and increased anxiety and depression. We also observed a notably decreased level of OXT in both the plasma and the hypothalamus of medial amygdala-lesioned mice, and the extracellular signal-regulated kinase (ERK) was activated. Further studies demonstrated that the administration of OXT alleviated ASD-like symptoms and significantly inhibited phosphorylation of ERK; the inhibitory effect was similar to that of U0126, an ERK signalling inhibitor. In addition, OXT administration modulated the expression of downstream proteins of the ERK signalling pathway, such as cyclic adenosine monophosphate response element binding and c-fos. Taken together, our data indicate that OXT plays an important role in ameliorating behavioural deficits in an ASD-like mouse model, which was mediated by inhibiting the ERK signalling pathway and its downstream proteins. PMID- 25707921 TI - Characteristics of men classified at high-risk for type 2 diabetes mellitus using the AUSDRISK screening tool. AB - AIMS: The primary aim was to describe characteristics of men identified at high risk for Type 2 diabetes mellitus (T2DM) using the Australian diabetes risk assessment (AUSDRISK) tool. Secondary aims were to determine the prevalence of pre-diabetes and metabolic syndrome in these men. METHODS: Men (n=209) completed the AUSDRISK tool, with 165 identified as high-risk for T2DM (score >= 12, maximum 38). Demographic, anthropometric, physiological and behavioural outcomes were assessed for 101 men. Comparisons (one-way ANOVA) among three AUSDRISK score groups (12-15, 16-19, >= 20) were performed (significance level, P<0.05). RESULTS: Common risk factors (percentages) among high-risk men were waist circumference (>90 cm; 93%), age (>44 years; 79%), physical activity level (< 150 min wk(-1); 59%), family history of diabetes (39%) and previously high blood glucose levels (32%). Men with AUSDRISK scores >= 20 had higher (mean +/- SD) HbA1C (6.0 +/- 0.4% [42 +/- 4.4 mmol.mol(-1)], P<0.001), FPG (5.3 +/- 0.6 mmol.L( 1), P=0.001) and waist circumference (113.2 +/- 9.8 cm, P=0.026) than men with scores of 12-15. Mean FPG for the sample was 5.0 +/- 0.6 mmol.L(-1), whereas mean HbA1C was 5.8 +/- 0.5% [40 +/- 5.5 mmol.mol(-1)]. Pre-diabetes prevalence was 70% and metabolic syndrome prevalence was 62%. CONCLUSIONS: The AUSDRISK tool identified men who were mostly older than 44, and had large waist circumferences and elevated HbA1C. These findings provide evidence supporting the usefulness of the AUSDRISK screening tool for T2DM screening in clinical and research settings. PMID- 25707922 TI - Cisplatin-loaded polymeric nanoparticles: characterization and potential exploitation for the treatment of non-small cell lung carcinoma. AB - Cisplatin-loaded poly(l-glutamic acid)-g-methoxy poly(ethylene glycol 5K) nanoparticles (CDDP-NPs) were characterized and exploited for the treatment of non-small cell lung carcinoma (NSCLC). In vitro metabolism experiments showed that a glutamic acid 5-mPEG ester [CH3O(CH2CH2O)nGlu] was generated when the poly(l-glutamic acid)-g-methoxy poly(ethylene glycol 5K) (PLG-g-mPEG5K) was incubated with HeLa cells. This suggests that the poly(glutamic acid) backbone of the PLG-g-mPEG5K is biodegradable. Furthermore, the size of the CDDP-NPs in an aqueous solution was affected by varying the pH (5.0-8.0) and their degradation rate was dependent on temperature. The CDDP-NPs could also bind to the model nucleotide 2'-deoxyguanosine 5'-monophosphate, indicating a biological activity similar to cisplatin. The CDDP-NPs showed a significantly lower peak renal platinum concentration after a single systemic administration when compared to free cisplatin. In vivo experiments with a Lewis lung carcinoma (LLC) model showed that the CDDP-NPs suppressed the growth of tumors. In addition, LLC tumor bearing mice treated with the CDDP-NPs (5mg/kg cisplatin eq.) showed much longer survival rates (median survival time: 51days) as compared with mice treated with free cisplatin (median survival time: 18days), due to the acceptable antitumor efficacy and low systemic toxicity of CDDP-NPs. These results suggest that the CDDP-NPs may be successfully applied to the treatment of NSCLC. PMID- 25707923 TI - Dynamic inguinal ultrasound: a diagnostic tool for hernia surgeons. PMID- 25707924 TI - Analysis of full-length mitochondrial DNA D-loop sequences from Macaca fascicularis of different geographical origin reveals novel haplotypes. AB - BACKGROUND: Cynomolgus macaques are indigenous to Asia occupying a range of geographical areas. A non-indigenous population established on Mauritius approximately 500 years ago. Mauritian cynomolgus macaques are recognised as having low genetic diversity compared to Indonesian macaques, from which they originated. As cynomolgus macaques are widely used as a biomedical model, there have been many studies of their genetic relationships. However, population diversity and relationships have only been assessed through analysis of either the hypervariable region I or II separately within the D-loop region of the mitochondrial genome in these macaques. METHODS: Using sequencing, we defined haplotypes encompassing the full D-loop sequence for Mauritian and Indonesian cynomolgus macaques. RESULTS: We evaluated the haplotype relationships by constructing a median-joining network based on full-length D-loop sequences, which has not been reported previously. CONCLUSION: Our data allow a complete D loop haplotype, including a hereto unreported polymorphic region, to be defined to aid the resolution of populations of cynomolgus macaques and which highlights the value in analysing both D-loop hypervariable regions in concert. PMID- 25707925 TI - Evaluation of Four Fingerprint Development Methods for Touch Chemistry Using Matrix-Assisted Laser Desorption Ionization/Time-of-Flight Mass Spectrometry(.). AB - Four preparation techniques for MALDI/TOF mass spectrometry were compared to determine the ability to gather intelligence for investigations through the chemical analysis of latent fingerprints, defined as "touch chemistry." Compatible fingerprint development processes used for identification along with new techniques are necessary to evaluate touch chemistry. Ten volunteers deposited fingerprints from solvent residues containing drugs and explosives onto microscope slides. The developers included (A) fingerprint powder, (B) MALDI matrix, (C) fingerprint powder and lifting, and (D) cyanoacrylate fuming with fingerprint powder. Qualitative identification was based on ion images and spectra. The highest average detection rates (88%) were found using methods A and B. Methods C (52%) or D (18%) had limited success. Results demonstrate the importance of imaging coupled to extracted mass spectral data in detecting analytes in deposited fingerprints. Overall, the results suggest continued development of touch chemistry applications could prove useful for gathering intelligence and forensically relevant information. PMID- 25707926 TI - Technology: Bead capture for single-cell transcriptomics. PMID- 25707928 TI - Hypercalcemia and parathyroid hormone-related peptide expression in a dog with thyroid carcinoma and histiocytic sarcoma. AB - A 9.5-year-old, male castrated Walker Hound was presented for evaluation of progressive weakness, anorexia, and weight loss. Imaging revealed multiple abdominal and thoracic masses and ascites; fine-needle aspirates of mesenteric and splenic masses confirmed malignancy, most likely histiocytic sarcoma. Laboratory analyses revealed increased ionized calcium and parathyroid hormone related peptide (PTH-rP) concentrations, and concurrent low-normal parathyroid hormone concentration, consistent with humoral hypercalcemia of malignancy. Necropsy was performed after euthanasia. The dog had disseminated histiocytic sarcoma, including sarcomatosis, as well as bilateral thyroid carcinoma. PTH-rP immunostaining was positive in the thyroid carcinoma but negative in the histiocytic neoplasm. These results suggest that thyroid carcinoma-associated hypercalcemia can be caused by tumor secretion of PTH-rP. PMID- 25707929 TI - Compare the effects of two silicone-hydrogel bandage contact lenses on epithelial healing after photorefractive keratectomy with anterior segment optical coherence tomography. AB - PURPOSE: To evaluate the efficacy of two silicone hydrogel bandage lenses (SiHy) on epithelial healing following photorefractive keratectomy (PRK) with anterior segment optical coherence tomography (AS-OCT). METHODS: Forty-two eyes of 21 patients who underwent PRK were included in a contralateral eye comparison study. At the end of the procedure, one eye of each patient was fitted with a Lotrafilcon B contact lens whereas the fellow eye was fitted with a Comfilicon A lens. Patients were examined on the day of surgery and at days 1-5 postoperatively. Main outcome measures were number of reepithelialized eyes, epithelial defect size, patient discomfort score and average complete reepithelization time. RESULTS: The number of mean reepithelialized eyes was showed no statistical significance between both groups during the follow up. Average epithelial defect size for Comfilcon A and Lotrafilcon B was 32.7+/ 12.2mm(2) vs. 33.3+/-12mm(2) at day 1 (p=0.279) and 13.1+/-6mm(2) vs. 14.5+/ 9mm(2) at day 3 postoperatively (p=0.018). Average re-epithelialization time was 3.1 days for Comfilcon A and 3.6 days for Lotrafilcon B (p=0.03). Mean subjective discomfort score was 2.25+/-0.96 in eyes with Lotrafilcon B and 1.64+/-0.67 in eyes with Comfilcon A on the first exam the day after surgery and until third day the differences were statistically significant (p=0.011 and p=0.012, respectively). CONCLUSIONS: AS-OCT is a reliable and noncontact method for assessment of reepithelialization under contact lenses after PRK. Eyes with Comfilcon A showed a statistically significant better discomfort score and faster reepithelialization time. PMID- 25707930 TI - Characteristics and associations of keratoconus patients. AB - PURPOSE: To determine the characteristics and risk factors of keratoconus (KC) patients and the possible associations between these characteristics and the severity of KC. METHODS: A prospective case-control study was performed in a referral eye hospital, recruiting KC patients and comparing their demographic and clinical characteristics with age and sex-matched control subjects to determine factors associated with KC. Mean keratometry (mean K) and central corneal thickness (CCT) of KC patients were recorded and compared. The severity of KC was further compared with the characteristics of KC patients. RESULTS: A total of 922 KC patients and controls were enrolled in the study. The mean age at the first presentation of KC patients was 21.03+/-6.17 years. The most frequent presenting symptom was blurred vision. The multivariate analysis revealed that KC in relatives, eye rubbing, itchy eyes, and low educational level are independent predictors of KC. Severity of KC was moderate in 43.8% and severe in 41% of the patients. None of the proposed characteristics were significantly associated with mean K and CCT. KC patients with a higher frequency of eye rubbing, family history of KC and more KC members in their family had a more severe KC, while diabetic patients had a less severe KC. CONCLUSION: This study presented an overview of a large population of KC patients in Iran, emphasizing the associated risk factors for this condition. Our findings add weights to the evidences that eye rubbing and positive family history of KC are independent risk factors for developing KC. PMID- 25707931 TI - How applicable are results of systematic reviews and meta-analyses of health behaviour maintenance? A critical evaluation. AB - OBJECTIVE: To evaluate the practical applicability of systematic reviews and meta analyses to the maintenance of physical activity or weight loss by assessing methodological and reporting aspects. METHODS: To identify relevant studies a literature search was conducted in MEDLINE, EMBASE, Cochrane Library, PsycINFO, PSYNDEX, Google scholar, and reference lists. Each article was evaluated for methodological quality, operationalization of maintenance, and practicability following the RE-AIM framework and the PRISMA statement. RESULTS: Twenty-four systematic reviews and meta-analyses were included of which 14 were published in the last four years. There were multiple definitions of maintenance. In addition the instances of redundancy, and neglect of thematic fields are identified. Eighty-seven percent of the reviews showed methodological flaws. The potential practical use of the outcomes was limited. CONCLUSION: The applicability of systematic reviews and meta-analyses regarding health behaviour maintenance is limited with regard to reporting, methodology and thematic coverage. For practitioners, synthesis of quantitative and qualitative evidence with theoretical models is lacking. PMID- 25707932 TI - Principles of all-inclusive public health: developing a public health leadership curriculum. PMID- 25707927 TI - The role of regulatory variation in complex traits and disease. AB - We are in a phase of unprecedented progress in identifying genetic loci that cause variation in traits ranging from growth and fitness in simple organisms to disease in humans. However, a mechanistic understanding of how these loci influence traits is lacking for the majority of loci. Studies of the genetics of gene expression have emerged as a key tool for linking DNA sequence variation to phenotypes. Here, we review recent insights into the molecular nature of regulatory variants and describe their influence on the transcriptome and the proteome. We discuss conceptual advances from studies in model organisms and present examples of complete chains of causality that link individual polymorphisms to changes in gene expression, which in turn result in physiological changes and, ultimately, disease risk. PMID- 25707933 TI - Understanding why people do or do not engage in activities following total joint replacement: a longitudinal qualitative study. AB - OBJECTIVE: Numerous studies report large and significant improvements in basic mobility and activities of daily living following total hip or knee replacement (TJR). Nevertheless, quantitative research has shown minimal increase in participation in activities that benefit overall health. This study explored why people do or do not engage in activities following hip or knee TJR. METHOD: This was a longitudinal qualitative study. Sampling was guided by constructivist grounded theory and data collected using open-ended, semi-structured interviews. Participants were recruited using maximum variation sampling based on age, sex and joint replaced (hip or knee). Data were analysed using a constant comparative approach and coded for thematic patterns and relationships from which overarching themes were constructed. RESULTS: Twenty-nine patients participated in interviews prior to, and 8 and 18 months post following TJR. A high degree of variability with regard to participants' return to activities was found and five emergent themes were identified that accounted for this variability. These themes highlight the importance of issues beyond medical factors alone, such as socio cultural factors that partially determine participants' participation in activity following TJR. CONCLUSION: Findings suggest that multi-faceted experiences impact participation in activity following TJR. These experiences include changes in identity and lifestyle that preclude a 'return to normal'. There is an urgent need for supports to increase people's activity post-TJR in order to facilitate enhancement of post-surgery levels of engagement. Approaches that take into consideration more personalized interventions may be critical to promoting healthy aging in people with TJR. PMID- 25707934 TI - Early postnatal ablation of the microRNA-processing enzyme, Drosha, causes chondrocyte death and impairs the structural integrity of the articular cartilage. AB - OBJECTIVE: In growth plate chondrocytes, loss of Dicer, a microRNA (miRNA) processing enzyme, causes defects in proliferation and differentiation, leading to a lethal skeletal dysplasia. However roles of miRNAs in articular chondrocytes have not been defined in vivo. To investigate the role of miRNAs in articular chondrocytes and to explore the possibility of generating a novel mouse osteoarthritis (OA) model caused by intrinsic cellular dysfunction, we ablated Drosha, another essential enzyme for miRNA biogenesis, exclusively in articular chondrocytes of postnatal mice. DESIGN: First, to confirm that the essential role of miRNAs in skeletal development, we ablated the miRNA biogenesis pathway by deleting Drosha or DGCR8 in growth plate chondrocytes. Next, to investigate the role of miRNAs in articular cartilage, we deleted Drosha using Prg4-CreER(T) transgenic mice expressing a tamoxifen-activated Cre recombinase (CreER(T)) exclusively in articular chondrocytes. Tamoxifen was injected at postnatal days, 7, 14, 21, and 28 to ablate Drosha. RESULTS: Deletion of Drosha or DGCR8 in growth plate chondrocytes caused a lethal skeletal defect similar to that of Dicer deletion, confirming the essential role of miRNAs in normal skeletogenesis. Early postnatal Drosha deletion in articular chondrocytes significantly increased cell death and decreased Safranin-O staining. Mild OA-like changes, including surface erosion and cleft formation, were found in male mice at 6 months of age; however such changes in females were not observed even at 9 months of age. CONCLUSIONS: Early postnatal Drosha deficiency induces articular chondrocyte death and can cause a mild OA-like pathology. PMID- 25707935 TI - Prediction of risk for hepatocellular carcinoma by response of serum alpha fetoprotein to entecavir therapy. AB - BACKGROUND AND AIMS: Serum alpha-fetoprotein (AFP) is frequently elevated in patients with chronic hepatitis B (CHB) who do not have hepatocellular carcinoma (HCC). Entecavir (ETV) treatment reduces AFP levels in these patients, but the clinical significance of AFP response to ETV has not been fully studied. The aims of this study were to elucidate the temporal response of AFP to ETV therapy and to determine the relationship between AFP response and the subsequent development of HCC. METHODS: All consecutive nucleos(t)ide-naive CHB patients who started ETV therapy between March 2007 and February 2009 were selected from an electronic medical record database at a tertiary referral center (BESTCare). Clinical, biochemical, and virologic parameters were evaluated in relation to the serial AFP levels tested during ETV treatment. RESULTS: Among the 244 enrolled patients, 66 had elevated AFP levels before ETV therapy. Low serum albumin was a significant predictor for elevated AFP. During 12 months of ETV therapy, AFP levels normalized in approximately three fourths of these patients. The decrease in AFP was delayed in patients with high baseline hepatitis B virus titers and in patients who subsequently developed HCC during ETV therapy. Incidence of HCC was similar regardless of baseline AFP levels. Among patients with elevated AFP, however, HCC developed exclusively in the subgroup where elevated AFP persisted for more than 6 months of ETV therapy. CONCLUSIONS: Delayed AFP response to ETV may serve as an indicator of high HCC risk. PMID- 25707936 TI - Formation of titanium monoxide (001) single-crystalline thin film induced by ion bombardment of titanium dioxide (110). AB - A plethora of technological applications justify why titanium dioxide is probably the most studied oxide, and an optimal exploitation of its properties quite frequently requires a controlled modification of the surface. Low-energy ion bombardment is one of the most extended techniques for this purpose and has been recently used in titanium oxides, among other applications, to favour resistive switching mechanisms or to form transparent conductive layers. Surfaces modified in this way are frequently described as reduced and defective, with a high density of oxygen vacancies. Here we show, at variance with this view, that high ion doses on rutile titanium dioxide (110) induce its transformation into a nanometric and single-crystalline titanium monoxide (001) thin film with rocksalt structure. The discovery of this ability may pave the way to new technical applications of ion bombardment not previously reported, which can be used to fabricate heterostructures and interfaces. PMID- 25707937 TI - Similarity evaluation of DNA sequences based on frequent patterns and entropy. AB - BACKGROUND: DNA sequence analysis is an important research topic in bioinformatics. Evaluating the similarity between sequences, which is crucial for sequence analysis, has attracted much research effort in the last two decades, and a dozen of algorithms and tools have been developed. These methods are based on alignment, word frequency and geometric representation respectively, each of which has its advantage and disadvantage. RESULTS: In this paper, for effectively computing the similarity between DNA sequences, we introduce a novel method based on frequency patterns and entropy to construct representative vectors of DNA sequences. Experiments are conducted to evaluate the proposed method, which is compared with two recently-developed alignment-free methods and the BLASTN tool. When testing on the beta-globin genes of 11 species and using the results from MEGA as the baseline, our method achieves higher correlation coefficients than the two alignment-free methods and the BLASTN tool. CONCLUSIONS: Our method is not only able to capture fine-granularity information (location and ordering) of DNA sequences via sequence blocking, but also insensitive to noise and sequence rearrangement due to considering only the maximal frequent patterns. It outperforms major existing methods or tools. PMID- 25707938 TI - Describing and understanding depression in spouses of cancer patients in palliative phase. AB - BACKGROUND: The cancer patient's relatives and family constitute one of the patient's main sources of support throughout the disease. In recent years, several studies have emphasized the psychological vulnerability of spouses caregivers with a high proportion suffering from anxiety and depression symptoms. The literature underlines several factors of detrimental outcomes but critical aspects of the spousal relationship as attachment were neglected. OBJECTIVES: This study aims at (1) describing depressive symptoms and depression among spouses who care for palliative cancer patients and (2) highlighting important factors explaining these symptoms. METHODS: We surveyed 60 spouses 1-6 months before the patient's death, (38 men, mean age: 62 years). RESULTS: We found a high frequency of depression symptoms (25%) in the sample. Higher depression scores were associated to insecure-anxious attachment style, more frequent venting of emotion and disengagement through substance use. CONCLUSION: Despite limitations, this description of caregivers' emotional adjustment in the palliative phase is unique. Future support programs could use the present information by focusing on emotional venting and avoidance. It also underlines the benefits for caregivers to develop organizational skills thanks to services that will lessen tasks or care responsibilities. PMID- 25707939 TI - Polymeric electrospun scaffolds: neuregulin encapsulation and biocompatibility studies in a model of myocardial ischemia. AB - Cardiovascular disease represents one of the major health challenges in modern times and is the number one cause of death globally. Thus, numerous studies are under way to identify effective cell- and/or growth factor (GF)-based therapies for repairing damaged cardiac tissue. In this regard, improving the engraftment or survival of regenerative cells and prolonging GF exposure have become fundamental goals in advancing these therapeutic approaches. Biomaterials have emerged as innovative scaffolds for the delivery of both cells and proteins in tissue engineering applications. In the present study, electrospinning was used to generate smooth homogenous polymeric fibers, which consisted of a poly(lactic co-glycolic acid) (PLGA)/NCO-sP(EO-stat-PO) polymer blend encapsulating the cardioactive GF, Neuregulin-1 (Nrg). We evaluated the biocompatibility and degradation of this Nrg-containing biomaterial in a rat model of myocardial ischemia. Histological analysis revealed the presence of an initial acute inflammatory response after implantation, which was followed by a chronic inflammatory phase, characterized by the presence of giant cells. Notably, the scaffold remained in the heart after 3 months. Furthermore, an increase in the M2:M1 macrophage ratio following implantation suggested the induction of constructive tissue remodeling. Taken together, the combination of Nrg encapsulating scaffolds with cells capable of inducing cardiac regeneration could represent an ambitious and promising therapeutic strategy for repairing diseased or damaged myocardial tissue. PMID- 25707940 TI - Construction of LRET-based nanoprobe using upconversion nanoparticles with confined emitters and bared surface as luminophore. AB - Upconversion nanoparticles (UCNPs) are promising energy donors for luminescence resonance energy transfer (LRET) and have widely been used to construct nanoprobes. To improve the LRET efficiency, which is currently a limiting factor for UCNPs-based bioassay, we herein propose a strategy to construct LRET-based nanoprobe using UCNPs with confined emitters and bared surface as the luminophore, with Ca(2+) as the proof-of-concept target. The sandwich-structure upconversion nanoparticles (SWUCNPs) are designed with a core-inner shell-outer shell architecture, in which the emitting ions (Ln(3+)) are precisely located in the inner shell near the particle surface, which is close enough to external energy acceptors. The target receptor (Fluo-4) is directly tagged on bared surface of SWUCNPs, which further reduces the donor-to-acceptor distance. Our strategy contributes to significantly improved LRET efficiency and hence affords an ultrahigh sensitivity for Ca(2+) detection. The as-constructed nanoprobe is structurally stable and exhibits good biocompatibility, which ensures uptake and reliable observation in living cells. The nanoprobe can be used for monitoring the different levels of cytosol [Ca(2+)] in living cells. Furthermore, it is applicable in Ca(2+) imaging in mice liver tissues. PMID- 25707941 TI - The Patient-Centered Medical Home: Preparation of the Workforce, More Questions than Answers. AB - As American medicine continues to undergo significant transformation, the patient centered medical home (PCMH) is emerging as an interprofessional primary care model designed to deliver the right care for patients, by the right professional, at the right time, in the right setting, for the right cost. A review of local, state, regional and national initiatives to train professionals in delivering care within the PCMH model reveals some successes, but substantial challenges. Workforce policy recommendations designed to improve PCMH effectiveness and efficiency include 1) adoption of an expanded definition of primary care, 2) fundamental redesign of health professions education, 3) payment reform, 4) responsiveness to local needs assessments, and 5) systems improvement to emphasize quality, population health, and health disparities. PMID- 25707942 TI - An interpretable rule-based diagnostic classification of diabetic nephropathy among type 2 diabetes patients. AB - BACKGROUND: The prevalence of type 2 diabetes is increasing at an alarming rate. Various complications are associated with type 2 diabetes, with diabetic nephropathy being the leading cause of renal failure among diabetics. Often, when patients are diagnosed with diabetic nephropathy, their renal functions have already been significantly damaged. Therefore, a risk prediction tool may be beneficial for the implementation of early treatment and prevention. RESULTS: In the present study, we developed a decision tree-based model integrating genetic and clinical features in a gender-specific classification for the identification of diabetic nephropathy among type 2 diabetic patients. Clinical and genotyping data were obtained from a previous genetic association study involving 345 type 2 diabetic patients (185 with diabetic nephropathy and 160 without diabetic nephropathy). Using a five-fold cross-validation approach, the performance of using clinical or genetic features alone in various classifiers (decision tree, random forest, Naive Bayes, and support vector machine) was compared with that of utilizing a combination of attributes. The inclusion of genetic features and the implementation of an additional gender-based rule yielded better classification results. CONCLUSIONS: The current model supports the notion that genes and gender are contributing factors of diabetic nephropathy. Further refinement of the proposed approach has the potential to facilitate the early identification of diabetic nephropathy and the development of more efficient treatment in a clinical setting. PMID- 25707944 TI - Erratum: Management of diabetes in the elderly with canagliflozin: A newer hypoglycemic drug on the horizon: Erratum. AB - [This corrects the article on p. 227 in vol. 5, PMID: 25422561.]. PMID- 25707946 TI - Something old, something new. PMID- 25707943 TI - Acetyl-lysine erasers and readers in the control of pulmonary hypertension and right ventricular hypertrophy. AB - Acetylation of lysine residues within nucleosomal histone tails provides a crucial mechanism for epigenetic control of gene expression. Acetyl groups are coupled to lysine residues by histone acetyltransferases (HATs) and removed by histone deacetylases (HDACs), which are also commonly referred to as "writers" and "erasers", respectively. In addition to altering the electrostatic properties of histones, lysine acetylation often creates docking sites for bromodomain containing "reader" proteins. This review focuses on epigenetic control of pulmonary hypertension (PH) and associated right ventricular (RV) cardiac hypertrophy and failure. Effects of small molecule HDAC inhibitors in pre clinical models of PH are highlighted. Furthermore, we describe the recently discovered role of bromodomain and extraterminal (BET) reader proteins in the control of cardiac hypertrophy, and provide evidence suggesting that one member of this family, BRD4, contributes to the pathogenesis of RV failure. Together, the data suggest intriguing potential for pharmacological epigenetic therapies for the treatment of PH and right-sided heart failure. PMID- 25707945 TI - Direct trifluoromethylthiolation of unactivated C(sp(3))-H using silver(I) trifluoromethanethiolate and potassium persulfate. AB - A practical and efficient method for the direct trifluoromethylthiolation of unactivated C(sp(3) )?H bonds by AgSCF3 /K2 S2 O8 under mild conditions is described. The reaction has a good functional-group tolerance and good selectivity. Initial mechanistic investigations indicate that the reaction may involve a radical process in which K2 S2 O8 plays key roles in both the activation of the C(sp(3) )?H bond and the oxidation of AgSCF3 . PMID- 25707947 TI - The effect of vibration on the rate of leveling and alignment. PMID- 25707948 TI - Treatment with the mandibular Arnold expander. PMID- 25707949 TI - Nonsurgical treatment of a mature adult Class III patient. PMID- 25707950 TI - Strategic financial statements for better practice management. PMID- 25707951 TI - 2014 JCO Study of Orthodontic Diagnosis and Treatment Procedures, Part 2: breakdowns of selected variables. PMID- 25707952 TI - Wide field of view CT and acromioclavicular joint instability: A technical innovation. AB - A 21-year-old female with a traumatic shoulder injury is investigated and managed for symptoms relating to this injury. Pathology at the acromioclavicular joint is detected clinically; however, clinical examination and multiple imaging modalities do not reach a unified diagnosis on the grading of this acromioclavicular joint injury. When management appropriate to that suggested injury grading fail to help the patient's symptoms, further investigation methods were utilised. Wide field of view, dynamic CT (4D CT) is conducted on the patient's affected shoulder using a 320 * 0.5 mm detector multislice CT. Scans were conducted with a static table as the patient completed three movements of the affected shoulder. Capturing multiple data sets per second over a z-axis of 16 cm, measurements of the acromioclavicular joint were made, to show dynamic changes at the joint. Acromioclavicular (AC) joint translations were witnessed in three planes (a previously unrecognised pathology in the grading of acromioclavicular joint injuries). Translation in multiple planes was also not evident on careful clinical examination of this patient. AC joint width, anterior posterior translation, superior-inferior translation and coracoclavicular width were measured with planar reconstructions while volume-rendered images and dynamic sequences aiding visual understanding of the pathology. Wide field of view dynamic CT (4D CT) is an accurate and quick modality to diagnose complex acromioclavicular joint injury. It provides dynamic information that no other modality can; 4D CT shows future benefits for clinical approach to diagnosis and management of acromioclavicular joint injury, and other musculoskeletal pathologies. PMID- 25707954 TI - Capillary electrophoresis strategy to monitor the released and remaining nitric oxide from the same single cell using a specially designed water-soluble fluorescent probe. AB - Gasotransmitters including nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S) have attracted more and more attention in the past decades due to their unique signaling and functions. However, as a fundamental issue in the investigations of gasotransmitters, the cell membrane permeability and release behavior of them is controversial in reports because of the lack of an efficient approach to determine gasotransmitters released out of and remaining in the same cells simultaneously. To solve such problem, taking NO as representative, a robust and facile strategy has been reported based on a completely water-soluble fluorescent probe and a commercially available capillary electrophoresis system. A specially designed boron-dipyrromethene (BODIPY)-based fluorescent probe with two sulfonate groups, disodium 2,6-disulfonate-1,3,5,7-tetramethyl-8-(3',4' diaminophenyl) difluoroboradiaza-s-indance (TMDSDAB), has been developed. As a turn-on fluorescent probe, TMDSDAB can react with NO promptly in aqueous media, and 540-fold enhancement of fluorescence is obtained. Using TMDSDAB, the trapping and quantification of NO released out of and remaining in the same single cell was achieved by capillary electrophoresis with laser-induced fluorescence detection. The limit of detection is 0.5 nM for NO. The proposed method has been applied to estimate the release behavior of single macrophages, and the results indicated that the cell membrane should be a barrier to NO diffusion. PMID- 25707953 TI - Synergistic hepatotoxicity by cadmium and chlorpyrifos: disordered hepatic lipid homeostasis. AB - Due to its extensive application, chlorpyrifos (CPF) has contaminated a diverse range of environmental substrates, fruits and vegetables. A number of studies have suggested that CPF may incur adverse effects on human health, including neurotoxicity, hepatotoxicity and endocrine disruption. Additionally, cadmium (Cd) is one of the most prevalent environmental heavy metals, as a result of considerable use in a wide spectrum of industrial fields. Exposure to Cd can cause several lesions in various organs, including the liver, kidneys and lungs. CPF and Cd often co-exist in the environment, food and crops, however, their joint exposure and potential synergistic toxicity are largely neglected and unrecognized. Our previous study characterized an interaction between CPF and Cd, which may occur via bonding between Cd2+ and the nitrogen atom in the pyridine ring of CPF, or the chelation between one Cd2+ and two CPF molecules. Our previous study also identified increased hepatotoxicity induced by CPF and Cd together compared with the individual compounds. In the present study, the effects of the concomitant exposure of CPF and Cd on lipid metabolism in hepatocytes was investigated. The results demonstrated an accumulation of lipids in hepatocytes, induced by the CPF and Cd complex, which was fundamentally distinct from its parental chemicals. Notably, the molecular mechanism by which the CPF-Cd complex significantly induced hepatic lipogenesis was revealed, elevating the concentrations of sterol regulatory element-binding protein-1 and fatty acid synthase. These findings pave the way for future studies in recognizing synergistic biological effects between pollutants. PMID- 25707955 TI - Silver nanocube aggregation gradient materials in search for total internal reflection with high phase sensitivity. AB - We fabricated monolayer coatings of a silver nanocube aggregation to create a step-wise optical strip by applying different surface pressures during slow Langmuir-Blodgett deposition. The varying amount of randomly distributed nanocube aggregates with different surface coverages in gradient manner due to changes in surface pressure allows for continuous control of the polarization sensitive absorption of the incoming light over a broad optical spectrum. Optical characterization under total internal reflection conditions combined with electromagnetic simulations reveal that the broadband light absorption depends on the relative orientation of the nanoparticles to the polarization of the incoming light. By using computer simulations, we found that the electric field vector of the s-polarized light interacts with the different types of silver nanocube aggregations to excite different plasmonic resonances. The s-polarization shows dramatic changes of the plasmonic resonances at different angles of incidence (shift of 64 nm per 10 degrees angle of incidence). With a low surface nanocube coverage (from 5% to 20%), we observed a polarization-selective high absorption of 80% (with an average 75%) of the incoming light over a broad optical range in the visible region from 400 nm to 700 nm. This large-area gradient material with location-dependent optical properties can be of particular interest for broadband light absorption, phase-sensitive sensors, and imaging. PMID- 25707956 TI - Multi-systemic involvement in NGLY1-related disorder caused by two novel mutations. AB - NGLY1-related disorder is a newly described autosomal recessive condition characterized by neurological, hepatic, ophthalmological findings and associated with dysmorphic features, constipation and scoliosis. It is caused by mutations in NGLY1, which encodes an enzyme, N-glycanase 1, involved in deglycosylation of glycoproteins, an essential step in the endoplasmic reticulum-associated degradation (ERAD) pathway. The disorder has been described in eight patients. We investigated the molecular basis and phenotype of NGLY1-related disorder in an additional patient. The proband is a 14-year-old who presented in early infancy with profound hypotonia and elevated transaminases. Liver biopsy showed lipid accumulation with dilated endoplasmic reticulum. He exhibited global developmental delay, acquired microcephaly, seizures, involuntary body movements, muscle atrophy, absent reflexes, and poor growth. He had multiple procedures for lacrimal duct stenosis and strabismus and had intractable blepharitis. He had severe osteopenia and persistent hypocholesterolemia. Whole exome sequencing revealed two novel variants in NGLY1: a truncating mutation, c.347C > G (p.S116X), and a splicing mutation, c.881 + 5G (p.IVS5 + 5G>T), predicted to abolish the splice donor site of exon 5. This study, along with previously reported cases, suggests that mutations in NGLY1 cause a recognizable phenotype and targeted sequencing should be considered in patients with typical presentation. This study expands the molecular spectrum of NGLY1-related condition and suggests that osteopenia and hypocholesterolemia may be part of the phenotype. PMID- 25707957 TI - Peptides, mAbs, bispecifics, oh my! clinical pharmacology challenges in the development of biologics. PMID- 25707958 TI - Challenges and considerations for development of therapeutic proteins in pediatric patients. AB - Target specificity and generally good tolerability of therapeutic proteins (TPs) present desirable treatment opportunities for pediatric patients. However, little is known on the ontogeny of processes related to the pharmacokinetics (PK) and disposition of TPs. The science, regulatory requirements and strategy of developing TPs for children are evolving. Our current review of TPs, (with focus on monoclonal antibodies and fusion proteins) that were approved for pediatric use indicates that dose-selection for pediatric pivotal studies is often based on adult PK information alone. This approach might not be sufficient if more complex PK properties than simple linear PK are present. Body weight-based dosing for pediatric patients directly scaled down from adult dosing can lead to under exposure in young pediatric patients who are usually in the lowest body-weight range. Tiered-fixed dosing can be reasonably effective for TPs in achieving comparable exposure in children over a wide age range. The uniqueness of the pediatric population, the practical challenges in conducting clinical studies in this population, as well as regulations from health authorities warrant including pharmacometrics as an integral component of pediatric drug development. We propose a framework distinct from previous proposals, to guide clinical pharmacology strategy for pediatric drug development specifically for TPs. PMID- 25707959 TI - Considerations for clinical pharmacology studies for biologics in emerging markets. AB - Registration of innovative biologics in Emerging Markets (EMs) poses many opportunities and challenges. The BRIC-MT countries (Brazil, Russia, India, China, Mexico, and Turkey) that are the fastest growing markets and regulators in these countries have imposed certain requirements, including the need for local clinical studies, for registration of biologics. The regulatory landscape in these countries is rapidly evolving, which necessitates an up-to-date understanding of such requirements. There is growing evidence which suggests that race, after accounting for body weight differences, may not influence the pharmacokinetics of biologics to the same extent that it does for small molecules. Thus, the requirements for clinical pharmacology trials in EMs are driven mainly by regulatory needs set forth by local Ministry of Health. In addition to the clinical Phase I to III studies done in the global program that supports registration in large geographies, countries such as China require local single and multiple dose Phase I studies. Participating in global studies with clinical sites within their country may be sufficient for some markets, while other regulators may be satisfied with a Certificate of Pharmaceutical Product. This paper discusses the current requirements for registration of innovative biologics in key EMs. PMID- 25707960 TI - Clinical pharmacology of bispecific antibody constructs. AB - The confluence of rapid scientific advancements especially in protein engineering and recombinant technology, unmet medical needs, and commercial incentives have led to the development of the next generation of therapeutic proteins. Bispecific antibody constructs are one of the novel strategies that is being pursued, combining the ability to bind simultaneously to two distinct targets and the advantages of purpose-designed and optimized antibody-based scaffolds. Their pharmacokinetic and pharmacodynamic properties, including their immunogenic potential, are closely related to their structural features and ability to interact with disposition mechanisms of immunoglobulin molecules. Catumaxomab and blinatumomab are bispecific constructs that are approved for clinical use and have provided clinical pharmacology data for this novel class of therapeutics. This knowledgebase on the clinical behavior of bispecific therapeutic proteins is poised to rapidly evolve over the next few years with many development programs having entered the clinical development stage. PMID- 25707961 TI - Assessments of antibody biodistribution. AB - Monoclonal antibody (mAb) therapeutics are in use for several disease conditions, and have generally shown excellent clinical benefit, in large part due to their high specificity and affinity for target proteins. As this therapeutic class continues to grow in size, improved understanding of the mechanisms controlling mAb biodistribution and protein binding may be expected to allow better prediction of safety and efficacy. Due to the large size and polarity of antibodies, rates of mAb distribution and elimination are typically much slower than those reported for small molecule drugs. Additionally, high affinity interaction with target proteins will often influence mAb pharmacokinetics, leading to complex, nonlinear tissue distribution and elimination. In this report, we summarize key determinants of mAb disposition, methods for assessing antibody exposure and protein binding, and model-based approaches that may be utilized to predict mAb pharmacokinetics. PMID- 25707962 TI - Pharmacokinetics of anti-TNF monoclonal antibodies in inflammatory bowel disease: Adding value to current practice. AB - Since anti-tumor necrosis factor (TNF) antibodies were introduced to treat patients with inflammatory bowel diseases, short- and long-term clinical and endoscopic endpoints can be achieved that were unreachable with conventional anti inflammatory agents. Although a large proportion of patients (70-90%) initially respond to the treatment, remission rates after induction are still low (20-50%) and patients are at risk to lose response to the drug over time. This inter individual variability in response is likely to be influenced by the observed inter-individual variability in pharmacokinetics. By extensively reviewing the literature, we evaluated the potential role of therapeutic drug monitoring to optimize dosing of anti-TNF drugs. Thereby we emphasize some of the pharmacokinetic cornerstones that can help to understand the observed concentration-effect relationship. After discussing some of the most commonly used assays to measure anti-TNF drug and anti-drug antibody concentrations, we reviewed the application of those tests and their potential clinical value in retrospective and prospective studies. PMID- 25707964 TI - Dashboard systems: Pharmacokinetic/pharmacodynamic mediated dose optimization for monoclonal antibodies. AB - Many marketed drugs exhibit high variability in exposure and response. While these drugs are efficacious in their approved indications, finding appropriate dose regimens for individual patients is not straightforward. Similar dose adjustment problems are also seen with drugs that have a complex relationship between exposure and response and/or a narrow therapeutic window. This is particularly true for monoclonal antibodies, where prolonged dosing at a sub therapeutic dose can also elicit anti-drug antibodies which will further compromise safety and efficacy. Thus, finding appropriate doses quickly would represent a substantial improvement in healthcare. Dashboard systems, which are decision-support tools, offer an improved, convenient means of tailoring treatment for individual patients. This article reviews the clinical need for this approach, particularly with monoclonal antibodies, the design, development, and testing of such systems, and the likely benefits of dashboard systems in clinical practice. We focus on infliximab for reference. PMID- 25707965 TI - Clinical impact of concomitant immunomodulators on biologic therapy: Pharmacokinetics, immunogenicity, efficacy and safety. AB - Immune-mediated inflammatory diseases encompass a variety of different clinical syndromes, manifesting as either common diseases such as rheumatoid arthritis (RA), inflammatory bowel disease (IBD) and psoriasis, or rare diseases such as cryopyrin-associated periodic syndromes. The therapy for these diseases often involves the use of a wide range of drugs including nonsteroidal anti inflammatory drugs (NSAIDs), glucocorticoids, immunomodulators, and biologic therapies. Due to the abundance of relevant clinical data, this article provides a general overview on the clinical impact of the concomitant use of immunomodulators and biologic therapies, with a focus on anti-tumor necrosis factor-alpha agents (anti-TNFalpha), for the treatment of RA and Crohn's disease (CD). Compared to biologic monotherapy, concomitant use of immunomodulators (methotrexate, azathioprine, and 6-mercaptopurine) often increases the systemic exposure of the anti-TNFalpha agent and decreases the formation of antibodies to the anti-TNFalpha agent, consequently enhancing clinical efficacy. Nevertheless, long-term combination therapy with immunomodulators and anti-TNFalpha agents may be associated with increased risks of serious infections and malignancies. Therefore, the determination whether combination therapy is suitable for a patient should always be based on an individualized benefit-risk evaluation. More research should be undertaken to identify and validate prognostic markers for predicting patients who would benefit the most and those who are at greater risk from combination therapy with immunomodulators and anti-TNFalpha agents. PMID- 25707966 TI - Utility of free and total target measurements as target engagement and efficacy biomarkers in biotherapeutic development--opportunities and challenges. AB - For biotherapeutics directed against soluble targets, most often monoclonal antibodies (mAbs), their therapeutic efficacy theoretically is driven by the magnitude and duration of free target suppression. However, for soluble targets of rapid turnover and low abundance, it can be technically challenging to directly measure the lowering of free target following treatment with biologics. The opportunities, challenges, and practical approaches to assess free and bound soluble targets and the utility of free and bound target measurements as biomarkers for target engagement and efficacy are covered in this review. In particular, case examples are presented to illustrate the interplay between drug and free/bound target, and how an integrated bioanalytical and pharmacokinetic/target engagement/pharmacodynamic (PK/TE/PD) modeling approach can be used to assess the target engagement for biologics directed against soluble targets with rapid turnover. Important caveats of the modeling approach in the absence of free target measurements are also discussed. PMID- 25707963 TI - Beyond peptides and mAbs--current status and future perspectives for biotherapeutics with novel constructs. AB - Biotherapeutics are attractive anti-cancer agents due to their high specificity and limited toxicity compared to conventional small molecules. Antibodies are widely used in cancer therapy, either directly or conjugated to a cytotoxic payload. Peptide therapies, though not as prevalent, have been utilized in hormonal therapy and imaging. The limitations associated with unmodified forms of both types of biotherapeutics have led to the design and development of novel structures, which incorporate key features and structures that have improved the molecules' abilities to bind to tumor targets, avoid degradation, and exhibit favorable pharmacokinetics. In this review, we highlight the current status of monoclonal antibodies and peptides, and provide a perspective on the future of biotherapeutics using novel constructs. PMID- 25707967 TI - Quantitative pharmacology of denosumab in patients with bone metastases from solid tumors. AB - Denosumab (XGEVA(r)) is a recombinant, fully human IgG2 monoclonal antibody directed against the receptor activator of nuclear factor kappa-B ligand (RANKL) that prevents differentiation of osteoclast precursors into mature osteoclasts and acceleration of bone resorption, resulting in the inhibition of osteoclast activation. Denosumab is indicated for the prevention of skeletal-related events (SREs) in adult patients with bone metastases from solid tumors at the dose of 120 mg administered subcutaneously (SC) every 4 weeks. This review is focused on describing its target-mediated disposition and direct inhibitory effect on bone resorption, as well as the modeling and simulation techniques used to integrate the PKPD information collected during clinical development of denosumab. In addition, this review further discusses the clinical relevance of patient covariate effects on denosumab systemic exposure, target engagement and downstream pharmacodynamics biomarkers, and the rationale for dosing regimen selection for Phase 3 studies. Phase 3 clinical studies demonstrated that denosumab was superior to zoledronic acid in inhibiting bone resorption and, consequently, delaying the time to first SRE by a median of 8.2 months in patients with bone metastases from solid tumors. Thus, denosumab may be considered a better alternative treatment than zoledronic acid for the prevention of SRE in patients with bone metastases from solid tumors. PMID- 25707968 TI - Vaccines: A review of immune-based interventions to prevent and treat disease. AB - The enormous gains made in public health during the 20th century, through the prevention and treatment of infectious disease, have contributed to dramatic improvements in the quality and length of the human lifespan. Continued advances in medicine are dependent on addressing several challenges including the increase in existing and new resistance to antibiotics, the decrease in productivity of the research and development (R&D) ecosystem, uncertain regulatory pathways, and an economic environment that rewards innovation for developing therapeutics that involve long cycle times from idea to a product. In this article, we consider important issues pertaining to the development of vaccines with particular emphasis on preclinical requirements, optimal dose selection, design, execution, and reporting of clinical trials for regulatory submission, planning and implementation of post-approval life-cycle programs, and emerging themes in therapeutic vaccines. PMID- 25707970 TI - Self-assembly of gridlike zinc oxide lamellae for chemical-sensing applications. AB - Hexagonal gridlike ZnO lamellae (GZL) with uniform thickness are synthesized by the o-phthalic acid-assisted hydrothermal method. Here, a systematic study of the assembly behaviors of gridlike ZnO lamellae obtained by the synergistic effect of urea and o-phthalic acid is presented. The morphology evolution and formation mechanism of GZL are also discussed in detail. The as-synthesized samples were characterized by powder X-ray diffraction, scanning electron microscopy, and transmission electron microscopy and electron diffraction spectroscopy. The results show that 2D ZnO lamellae are composed of nanotablets, which are jointed to form grids. The length and width of ZnO lamellae are about 1000 and 500 nm, respectively, and the thickness is about 30 nm. GZL morphology evolves from hexagonal ZnO nanotablets to lamellae with grids. The gas-sensing properties indicate that sensors fabricated from different materials present very different responses to volatile organic compounds. A GZL-based sensor has good response to acetaldehyde, and the response and recovery times are 1 and 6 s, respectively, when it was exposed to 1 ppm of acetaldehyde gas. The possibility of tuning the gas-sensing properties by adjusting the morphology makes GZL a novel candidate for more effective detection of a toxic, volatile gas with low concentration. PMID- 25707971 TI - What are the biological and therapeutic implications of biomolecule corona formation on the surface of inhaled nanomedicines? PMID- 25707972 TI - Highlights from the latest articles in advanced biomanufacturing at micro- and nano-scale. PMID- 25707973 TI - Indocyanine green targeted micelles with improved stability for near-infrared image-guided photothermal tumor therapy. AB - AIM: Indocyanine green (ICG) is a promising near-infrared (NIR) dye for tumor imaging and photothermal therapy; however, the poor stability and lack of targeting limit its application. In this study, ICG was encapsulated into folate conjugated poly(2-ethyl-2-oxazoline)-b-poly(epsilon-caprolactone) micelles to overcome these problems. MATERIALS & METHODS: ICG-loaded micelles were prepared by solvent evaporation method. Cell uptake and in vitro photothermal cytotoxicity were evaluated on KB cells. In vivo NIR imaging and photothermal therapy were conducted on KB tumor-bearing mice. RESULTS: ICG-loaded micelles with favorable sizes and stable NIR optical properties were successfully prepared. These micelles could target to KB tumors and enabled high-resolution NIR imaging. Moreover, they could effectively convert the absorbed NIR laser energy into heat, resulting in significant tumor damage and inhibition. CONCLUSION: This novel micellar system, integrating stable NIR properties, excellent tumor targeting and photothermal capability, showed great potential in tumor imaging and therapy. PMID- 25707974 TI - Surface functionalization of polymeric nanospheres modulates macrophage activation: relevance in leishmaniasis therapy. AB - AIM: To characterize the production and application of carbohydrate functionalized poly(D,L-lactide-co-glycolide) (PLGA) nanospheres as immune modulatory mediators in the treatment of visceral leishmaniasis (VL). MATERIALS & METHODS: PLGA nanospheres were prepared by nanoprecipitation and surface functionalized with mannose, mannan or mannosamine moieties using a carbodiimide reaction. Flow cytometry and fluorescence microscopy revealed the interaction of these nanospheres with macrophages. RESULTS: The nanocarriers were taken up by murine primary macrophages using clathrin-mediated endocytosis. Co-culture of macrophages with carbohydrate-functionalized nanospheres led to their activation and production of pro-inflammatory cytokines. One dose of amphotericin B-loaded on mannan-functionalized nanospheres resulted in an efficacy VL therapy. CONCLUSION: This approach provides a promising therapy for VL and a new therapeutic nanoplatform for obligate intracellular pathogens. PMID- 25707975 TI - Development of amino acid substituted gemini surfactant-based mucoadhesive gene delivery systems for potential use as noninvasive vaginal genetic vaccination. AB - AIM: Recently, we synthesized amino acid- and peptide-substituted gemini surfactants, 'biolipids' that exhibited high transfection efficiency in vitro. In this study, we developed these plasmid DNA and gemini surfactant lipid particles for noninvasive administration in vaginal cavity. MATERIAL & METHODS: Novel formulations of these gene delivery systems were prepared with poloxamer 407 to induce in situ gelling of the formulation and diethylene glycol monoethyl ether to improve their penetration across mucosal tissue. RESULTS: Poloxamer at 16% w/v concentration in diethylene glycol monoethyl ether aqueous solution produced dispersions that gelled near body temperature and had a high yield value, preventing leakage of the formulation from the vaginal cavity. Intravaginal administration in rabbits showed that the glycyl-lysine-substituted gemini surfactant led to a higher gene expression compared with the parent unsubstituted gemini surfactant. CONCLUSION: This provides a proof-of-concept that amino acid substituted gemini surfactants can be used as noninvasive mucosal (vaginal) gene delivery systems to treat diseases associated with mucosal epithelia. PMID- 25707976 TI - Blockade of oral tolerance to ovalbumin in mice by silver nanoparticles. AB - AIM: The authors investigated the effect of silver nanoparticles (Ag NPs) on oral tolerance to dietary antigen ovalbumin (OVA) in mice. MATERIALS & METHODS: Ag NPs were orally administered for 7 days before feeding of OVA and the immunological responses were assayed. RESULTS: Polyvinyl pyrrolidone-coated Ag NPs (Ag NPs-PVP) were found to block the induction of oral tolerance to OVA. The physicochemical properties of the three kinds of Ag NPs were assessed and silver ions were found to inhibit the induction of oral tolerance, which might be the dominating factor in the blockade of oral tolerance by Ag NPs-PVP. CONCLUSION: Ag NPs with certain physicochemical properties can block oral tolerance to dietary antigen that may induce food allergy in humans. PMID- 25707977 TI - Current trends in magnetic particle enrichment for mass spectrometry-based analysis of cardiovascular protein biomarkers. AB - Magnetic particles have traditionally been utilized to isolate and enrich various cardiovascular protein biomarkers for mass spectrometry-based proteomic analysis. The application of functionalized magnetic particles for immunocapture is attractive due to their easy manipulation, large surface area-to-volume ratios for maximal antibody binding, good recovery and high magnetic saturation. Magnetic particle enrichment coupled with mass spectrometry can act as a complementary tool for clinical sandwich-immunoassay development since it can provide improved target specificity and true metrological traceability. The purpose of this review is to summarize current separation methods and technologies that use magnetic particles to enrich protein biomarkers from complex matrices, specifically focusing on cardiovascular disease-related proteins and the advantages of magnetic particles over existing techniques. PMID- 25707979 TI - Nanomedicines against Chagas disease: an update on therapeutics, prophylaxis and diagnosis. AB - Chagas disease is a neglected parasitic infection caused by the protozoan Trypanosoma cruzi. After a mostly clinically silent acute phase, the disease becomes a lifelong chronic condition that can lead to chronic heart failure and thromboembolic phenomena followed by sudden death. Antichagasic treatment is only effective in the acute phase but fails to eradicate the intracellular form of parasites and causes severe toxicity in adults. Although conventional oral benznidazol is not a safe and efficient drug to cure chronic adult patients, current preclinical data is insufficient to envisage if conventional antichagasic treatment could be realistically improved by a nanomedical approach. This review will discuss how nanomedicines could help to improve the performance of therapeutics, vaccines and diagnosis of Chagas disease. PMID- 25707978 TI - The effects of nanoparticle drug loading on the pharmacokinetics of anticancer agents. AB - Major advances in carrier-mediated agents, which include nanoparticles, nanosomes and conjugates, have revolutionized drug delivery capabilities over the past decade. While providing numerous advantages, such as greater solubility, duration of exposure and delivery to the site of action over their small-molecule counterparts, there is substantial variability in systemic clearance and distribution, tumor delivery and pharmacologic effects (efficacy and toxicity) of these agents. This review provides an overview of factors that affect the pharmacokinetics and pharmacodynamics of carrier-mediated agents in preclinical models and patients. PMID- 25707980 TI - Nanoparticle-based caspase sensors. AB - Recent advances in nanotechnology have provided new tools for measuring enzymatic activities that are relevant for the assessment of physiological and pathological processes. Caspases, the enzymes intimately linked with cell death and inflammation, are cysteine-dependent aspartate-directed proteases. The measurement of caspase activity requires assays that can provide data with specificity, precision and sensitivity. Several nanoparticle-based assays are now beginning to emerge. This article will first provide a brief discussion of conventional methods of measuring caspase activity and their limitations, followed by an overview of the advantages and limitations of nanoparticle-based strategies for sensing caspase enzymatic activity in vitro and in vivo. PMID- 25707981 TI - No king without a crown--impact of the nanomaterial-protein corona on nanobiomedicine. AB - Besides the wide use of nanomaterials in technical products, their application spectrum in biotechnology and biomedicine is steadily increasing. Whereas the physico-chemical properties and behavior of nanomaterials can be engineered and characterized accurately under idealized conditions, this is no longer the case in complex physiological environments. In biological fluids, proteins rapidly bind to nanomaterials forming the protein corona, critically affecting the nanomaterials' biological identity. As the corona impacts in vitro and/or in vivo nanomaterial applications, we here review the concept of the protein corona and its analytical dissection. We comment on how corona signatures may be linked to effects at the nano-bio interface and conclude how such knowledge is offering novel opportunities for improved nanomedicine. PMID- 25707982 TI - Mitochondria: a target for bacteria. AB - Eukaryotic cells developed strategies to detect and eradicate infections. The innate immune system, which is the first line of defence against invading pathogens, relies on the recognition of molecular patterns conserved among pathogens. Pathogen associated molecular pattern binding to pattern recognition receptor triggers the activation of several signalling pathways leading to the establishment of a pro-inflammatory state required to control the infection. In addition, pathogens evolved to subvert those responses (with passive and active strategies) allowing their entry and persistence in the host cells and tissues. Indeed, several bacteria actively manipulate immune system or interfere with the cell fate for their own benefit. One can imagine that bacterial effectors can potentially manipulate every single organelle in the cell. However, the multiple functions fulfilled by mitochondria especially their involvement in the regulation of innate immune response, make mitochondria a target of choice for bacterial pathogens as they are not only a key component of the central metabolism through ATP production and synthesis of various biomolecules but they also take part to cell signalling through ROS production and control of calcium homeostasis as well as the control of cell survival/programmed cell death. Furthermore, considering that mitochondria derived from an ancestral bacterial endosymbiosis, it is not surprising that a special connection does exist between this organelle and bacteria. In this review, we will discuss different mitochondrial functions that are affected during bacterial infection as well as different strategies developed by bacterial pathogens to subvert functions related to calcium homeostasis, maintenance of redox status and mitochondrial morphology. PMID- 25707983 TI - The genome as pharmacopeia: association of genetic dose with phenotypic response. AB - The majority of compounds that enter clinical trials fail to meet regulatory standards for marketed therapeutics. Success in clinical trials is increased when therapies are directed against targets for which genetic variants have been linked to disease risk or progression in humans. Here we review how genome-wide association studies (GWAS) have furthered our understanding of the genetic basis of common disease, and how GWAS findings could stimulate development of novel drugs. Genetic screens that associate variants with clinical phenotypes of interest, like pharmacological screens that associate compounds with in vitro responses of interest, establish an intervention-response relationship on which a therapeutic hypothesis can be based. We highlight the similarities between the GWAS approach and well-established principles in early drug discovery, from primary screen through lead identification. We believe that integration of genetic and pharmacological screens will considerably enhance the development of therapeutic interventions with clear benefit to patients. PMID- 25707984 TI - Academic achievement and satisfaction in adolescents with CHD. AB - OBJECTIVES: To evaluate academic achievement and satisfaction in adolescents with CHD. Study design Questionnaires were sent to all adolescents, aged between 17 and 20 years with CHD, currently treated at our hospital (n=326) in order to assess the patients' education and satisfaction with their academic career. Results were compared with the official community statistics. RESULTS: A total of 207 patients completed the questionnaires (participation rate 63.5%), 113 boys and 94 girls; 50% had completed mandatory school at the highest, 37.3% at the middle, and 12.7% at the lowest educational level. The distribution in the general population was comparable: 57.6, 32.5, and 9.9%, respectively (p=0.8). Adolescents with severe CHD were less likely to attain a higher educational level than those with moderate or mild CHD (p=0.03 for school grades 7-9). None of the other examined medical or socio-demographic factors, such as socio-economic status, foreign language, severity of CHD, cyanosis, and open heart surgery, were found to be associated with lower educational attainment. After the mandatory 9 years of schooling, 21.4% (n=44) of the patients with CHD compared with 16.7% in the general population attended higher school levels heading towards university education (p=0.7). From the 165 patients who provided information on career satisfaction, 79% regarded their job or school situation as being their desired one without a difference for those with severe CHD. CONCLUSION: School education in Swiss adolescents with CHD is very similar to the normal population. In addition, the majority of adolescents are satisfied with their educational career. This fact may be due to the good educational support provided during schooling. PMID- 25707985 TI - Possible abilities of dietary factors to prevent and treat diabetes via the stimulation of glucagon-like peptide-1 secretion. AB - There is a pressing need for countermeasures against diabetes, which has increased in incidence, becoming a global issue. Glucagon-like peptide-1 (GLP-1), a molecule secreted in enteroendocrine L cells in the lower small and large intestines, is thought to be one of the most important molecular targets for the prevention and treatment of diabetes. There has been increasing interest in the possible ability of dietary factors to treat diabetes via modulating GLP-1 secretion. There is thought to be a close relationship between incretin and diet, and the purported best approach for using dietary factors to increase GLP-1 activity is promotion of secretion of endogenous GLP-1. It have been reported that nutrients as well as various non-nutrient dietary factors can function as GLP-1 secretogogues. Here, we present our findings on the GLP-1 secretion stimulating functions of two dietary factors, curcumin and extract of edible sweet potato leaves, which contain caffeoylquinic acid derivatives. However, it is necessary to reveal in greater detail the stimulation of GLP-1 secretion by dietary factors for preventing and treating diabetes. It is desirable to clarify the exact GLP-1 secretory pathway, the effect of metabolites derived from dietary factors in gut lumen, and the relationship between incretin and meal. PMID- 25707986 TI - Assessment of biochemical and behavioral effects of carbaryl and methomyl in Brown-Norway rats from preweaning to senescence. AB - Factors impacting life stage-specific sensitivity to chemicals include toxicokinetic and toxicodynamic changes. To evaluate age-related differences in the biochemical and behavioral impacts of two typical N-methyl carbamate pesticides, we systematically compared their dose-response and time-course in preweanling (postnatal day, PND, 18) and adult male Brown Norway rats (n=9 10/dose or time) ranging from adolescence to senescence (1, 4, 12, 24 mo). Carbaryl was administered orally at 3, 7.5, 15, or 22.5mg/kg and data were collected at 40 min after dosing, or else given at 3 or 15 mg/kg and data collected at 30, 60, 120, and 240 min. Methomyl was studied only in adult and senescent rat (4, 12, 24 mo) in terms of dose-response (0.25. 0.6, 1.25, 2.5mg/kg) and time-course (1.25mg/kg at 30, 60, 120, 240 min). Motor activity as well as brain and erythrocyte (RBC) cholinesterase (ChE) activity were measured in the same animals. In the carbaryl dose-response, PND18 rats were the most sensitive to the brain ChE-inhibiting effects of carbaryl, but 12- and 24-mo rats showed more motor activity depression even at similar levels of brain ChE inhibition. We have previously reported that brain ChE inhibition, but not motor activity effects, closely tracked carbaryl tissue levels. There were no age related differences in methomyl-induced ChE inhibition across doses, but greater motor activity depression was again observed in the 12- and 24-mo rats. Carbaryl time-course data showed that motor activity depression reached a maximum later, and recovered slower, in the 12- and 24-mo rats compared to the younger ages; slowest recovery and maximal effects were seen in the 24-mo rats. Acetylcholinesterase sensitivity (concentration-inhibition curves) was measured in vitro using control tissues from each age. Inhibitory concentrations of carbaryl were somewhat lower in PND18, 12-, and 24-mo tissues compared to 1- and 4-mo, but there were no differences with methomyl-treated tissues. Thus, in the dose-response and time-course, there were dissociations between brain ChE inhibition and the magnitude as well as recovery of motor activity changes. The explanation for this dissociation is unclear, and is likely due to early development followed by aging-related decline in both kinetic parameters and neurological responsiveness. PMID- 25707987 TI - Accurate multiple network alignment through context-sensitive random walk. AB - BACKGROUND: Comparative network analysis can provide an effective means of analyzing large-scale biological networks and gaining novel insights into their structure and organization. Global network alignment aims to predict the best overall mapping between a given set of biological networks, thereby identifying important similarities as well as differences among the networks. It has been shown that network alignment methods can be used to detect pathways or network modules that are conserved across different networks. Until now, a number of network alignment algorithms have been proposed based on different formulations and approaches, many of them focusing on pairwise alignment. RESULTS: In this work, we propose a novel multiple network alignment algorithm based on a context sensitive random walk model. The random walker employed in the proposed algorithm switches between two different modes, namely, an individual walk on a single network and a simultaneous walk on two networks. The switching decision is made in a context-sensitive manner by examining the current neighborhood, which is effective for quantitatively estimating the degree of correspondence between nodes that belong to different networks, in a manner that sensibly integrates node similarity and topological similarity. The resulting node correspondence scores are then used to predict the maximum expected accuracy (MEA) alignment of the given networks. CONCLUSIONS: Performance evaluation based on synthetic networks as well as real protein-protein interaction networks shows that the proposed algorithm can construct more accurate multiple network alignments compared to other leading methods. PMID- 25707988 TI - Oxidation of CO on a carbon-based material composed of nickel hydroxide and hydroxyl graphene oxide, (Ni4(OH)3-hGO)--a first-principles calculation. AB - Nickel or nickel hydroxide clusters and graphene oxide (GO) composites are novel nanomaterials in the application of electrochemical catalysts. In this work, we calculated the energy of Ni4 adsorbed onto saturated hydroxyl graphene oxide (hGO), which forms a Ni4(OH)3 cluster on the hydroxyl graphene oxide (Ni4(OH)3 hGO) and releases 4.47 eV (5.22 eV with DFT-D3 correction). We subsequently studied the oxidation of CO on the Ni4(OH)3-hGO system via three mechanisms - LH, ER and carbonated mechanisms. Our results show that the activation energy for oxidation of the first CO molecule according to the ER mechanism is 0.14 eV (0.12 eV with DFT-D3 correction), much smaller than that with LH (Ea = 0.65 eV, 0.61 eV with DFT-D3 correction) and with carbonated (Ea = 1.28 eV, 1.20 eV with DFT-D3 correction) mechanisms. The barrier to oxidation of the second CO molecule to CO2 with the ER mechanism increases to 0.43 eV (0.37 eV with DFT-D3 correction), but still less than that via LH (Ea = 1.09 eV, 1.07 eV with DFT-D3 correction), indicating that CO could be effectively oxidized through the ER mechanism on the Ni4(OH)3/hGO catalyst. PMID- 25707989 TI - Anchorage-dependent binding of integrin I-domain to adhesion ligands. AB - The dynamic interactions between leukocyte integrin receptors and ligands in the vascular endothelium, extracellular matrix, or invading pathogens result in leukocyte adhesion, extravasation, and phagocytosis. This work examined the mechanical strength of the connection between iC3b, a complement component that stimulates phagocytosis, and the ligand-binding domain, the I-domain, of integrin alphaMbeta2. Single-molecule force measurements of alphaM I-domain-iC3b complexes were conducted by atomic force microscope. Strikingly, depending on loading rates, immobilization of the I-domain via its C-terminus resulted in a 1.3-fold to 1.5-fold increase in unbinding force compared with I-domains immobilized via the N-terminus. The force spectra (unbinding force versus loading rate) of the I domain-iC3b complexes revealed that the enhanced mechanical strength is due to a 2.4-fold increase in the lifetime of the I-domain-iC3b bond. Given the structural and functional similarity of all integrin I-domains, our result supports the existing allosteric regulatory model by which the ligand binding strength of integrin can be increased rapidly when a force is allowed to stretch the C terminus of the I-domain. This type of mechanism may account for the rapid ligand affinity adjustment during leukocyte migration. PMID- 25707990 TI - Carbopol improves the early cellular immune responses induced by the modified life vaccine Ingelvac PRRS(r) MLV. AB - Adjuvants enhance both the magnitude and duration of immune responses, therefore representing a central component of vaccines. The nature of the adjuvant can determine the particular type of immune response, which may be skewed toward cytotoxic T cell (CTL) responses, antibody responses, or particular classes of T helper (Th) responses and antibody isotypes. Traditionally, adjuvants have been added to intrinsically poor immunogenic vaccines, such as those using whole killed organisms or subunit vaccines. Here, we have compared cellular immune responses induced by the immunogenic modified life-attenuated vaccine Ingelvac PRRS(r) MLV when administered alone or in combination with carbopol, a widely used adjuvant in veterinary medicine. Using functional readouts (IFN-gamma ELISpot and cell proliferation) and analyzing phenotypical hallmarks of CD4T cell differentiation, we show that carbopol improves cellular immunity by inducing early IFN-gamma-producing cells and by preferentially driving T cell differentiation to effector phenotypes. Our data suggest that adjuvants may enhance and modulate life-attenuated--not only subunit/inactivated--vaccines. PMID- 25707992 TI - Articular ankle fracture results in increased synovitis, synovial macrophage infiltration, and synovial fluid concentrations of inflammatory cytokines and chemokines. AB - OBJECTIVE: The inflammatory response following an articular fracture is thought to play a role in the development of posttraumatic arthritis (PTA) but has not been well characterized. The objective of this study was to characterize the acute inflammatory response, both locally and systemically, in joint synovium, synovial fluid (SF), and serum following articular fracture of the ankle. We hypothesized that intraarticular fracture would alter the synovial environment and lead to increased local and systemic inflammation. METHODS: Synovial tissue biopsy specimens, SF samples, and serum samples were collected from patients with an acute articular ankle fracture (n = 6). Additional samples (normal, ankle osteoarthritis [OA], and knee OA [n = 6 per group]) were included for comparative analyses. Synovial tissue was assessed for synovitis and macrophage count. SF and serum were assessed for cytokines (interferon-gamma [IFNgamma], interleukin-1beta [IL-1beta], IL-6, IL-8, IL-10, IL-12p70, and tumor necrosis factor alpha) and chemokines (eotaxin, eotaxin 3, IFNgamma-inducible 10-kd protein, monocyte chemotactic protein 1 [MCP-1], MCP-4, macrophage-derived chemokine, macrophage inflammatory protein 1beta, and thymus and activation-regulated chemokine). RESULTS: Synovitis scores were significantly higher in ankle fracture tissue compared with normal ankle tissue (P = 0.007), and there was a trend toward an increased abundance of CD68+ macrophages in ankle fracture synovium compared with normal knee synovium (P = 0.06). The concentrations of all cytokines and chemokines were elevated in the SF of patients with ankle fracture compared with those in SF from OA patients with no history of trauma. Only the concentration of IL-6 was significantly increased in the serum of patients with ankle fracture compared with normal serum (P = 0.027). CONCLUSION: Articular fracture of the ankle increased acute local inflammation, as indicated by increased synovitis, increased macrophage infiltration into synovial tissue, and increased SF concentrations of biomarkers of inflammation. Characterizing the acute response to articular fracture provides insight into the healing process and may help to identify patients who may be at greater risk of PTA. PMID- 25707991 TI - Fyn inhibition rescues established memory and synapse loss in Alzheimer mice. AB - OBJECTIVE: Currently no effective disease-modifying agents exist for the treatment of Alzheimer disease (AD). The Fyn tyrosine kinase is implicated in AD pathology triggered by amyloid-beta oligomers (Abetao) and propagated by Tau. Thus, Fyn inhibition may prevent or delay disease progression. Here, we sought to repurpose the Src family kinase inhibitor oncology compound, AZD0530, for AD. METHODS: The pharmacokinetics and distribution of AZD0530 were evaluated in mice. Inhibition of Abetao signaling to Fyn, Pyk2, and Glu receptors by AZD0530 was tested by brain slice assays. After AZD0530 or vehicle treatment of wild-type and AD transgenic mice, memory was assessed by Morris water maze and novel object recognition. For these cohorts, amyloid precursor protein (APP) metabolism, synaptic markers (SV2 and PSD-95), and targets of Fyn (Pyk2 and Tau) were studied by immunohistochemistry and by immunoblotting. RESULTS: AZD0530 potently inhibits Fyn and prevents both Abetao-induced Fyn signaling and downstream phosphorylation of the AD risk gene product Pyk2, and of NR2B Glu receptors in brain slices. After 4 weeks of treatment, AZD0530 dosing of APP/PS1 transgenic mice fully rescues spatial memory deficits and synaptic depletion, without altering APP or Abeta metabolism. AZD0530 treatment also reduces microglial activation in APP/PS1 mice, and rescues Tau phosphorylation and deposition abnormalities in APP/PS1/Tau transgenic mice. There is no evidence of AZD0530 chronic toxicity. INTERPRETATION: Targeting Fyn can reverse memory deficits found in AD mouse models, and rescue synapse density loss characteristic of the disease. Thus, AZD0530 is a promising candidate to test as a potential therapy for AD. PMID- 25707993 TI - Transverse Subtrochanteric Shortening Osteotomy During Cementless Total Hip Arthroplasty in Crowe Type-III or IV Developmental Dysplasia. AB - The purpose of this study was to review the outcomes of transverse subtrochanteric shortening osteotomy during cementless total hip arthroplasty in Crowe Type-III or IV developmental dysplasia. Seventy-three osteotomies were included in our study. Mean follow-up was 61 months. Harris hip score, leg length discrepancy, neurological status, union status of the osteotomy, and femoral component stability were the criteria for evaluation. All complications were noted. The mean Harris hip score improved from 38.6 points to 83.7 points. The mean leg length discrepancy decreased from 56.5 mm to 10.7 at the latest follow up. The mean union time was 5.2 months. We observed 4 non-unions. Transverse subtrochanteric shortening osteotomy is an effective and reliable method in restoration of a more normal limb. PMID- 25707994 TI - Trends in Total Knee Arthroplasty Implant Utilization in the United States. PMID- 25707995 TI - Economic Impact of Orthopedic Adult Reconstruction Office Practice: The Implications of Hospital Employment Models on Local Economies. AB - The purpose of this study was to evaluate the economic attributes of private practice adult reconstruction (AR) offices. 458 AAHKS surgeons responded; 65% were in private practice (fee-for-service, non-salaried, non-employed AR surgeons). 54% had considered hospital employment in the past two years. The average group employs 13.4 orthopedic surgeons (3.4 AR), and 105 other employees. The average total budget is $12.5 million per year with $4 million in salaries, and $238,000 in tax revenue generated. Co-management joint ventures are a better model than hospital employment for aligning AR surgeons and hospitals and realizing the cost effectiveness and quality improvement goals of PPACA and AARA while preserving the economic impact of AR private practice. PMID- 25707996 TI - Effects of experimental insoles on body posture, mandibular kinematics and masticatory muscles activity. A pilot study in healthy volunteers. AB - BACKGROUND: It has been hypothesized that different plantar sensory inputs could influence the whole body posture and dental occlusion but there is a lack of evidence on this possible association. OBJECTIVES: To investigate the effects of experimental insoles redistributing plantar pressure on body posture, mandibular kinematics and electromyographic (EMG) activity of masticatory muscles on healthy subjects. METHODS: A pilot study was conducted on 19 healthy volunteers that wore custom-made insoles normalizing the plantar pressure distribution for 2 weeks. Body posture parameters were measured by means of an optoelectronic stereophotogrammetric analysis; mandibular kinematics was analyzed by means of gothic arch tracings; superficial EMG activity of head and neck muscles was performed. Measurements were carried out 10 days before the insertion of the insoles, immediately before the insertion, the day after, 7 and 14 days after, in four different exteroceptive conditions. RESULTS: The outcomes of the present study show that insoles do not modify significantly over time the parameters of body posture, SEMG activity of head and neck muscles and mandibular kinematics. CONCLUSIONS: In this pilot study the experimental insoles did not significantly influence the body posture, the mandibular kinematics and the activity of masticatory muscles during a 14-day follow up period. PMID- 25707997 TI - Clinical nursing and midwifery research in African countries: a scoping review. AB - BACKGROUND: Globally, the nursing shortage has been deemed a crisis, but African countries have been hit hardest. Therefore, it is of utmost importance nurses use the best available evidence and that nursing research is targeted to address gaps in the evidence. To achieve this, an understanding of what is currently available and identification of gaps in clinical nursing research is critical. OBJECTIVES: We performed a scoping review of existing literature to assess clinical nursing research conducted in all African countries over the past decade, identify gaps in clinical nursing and midwifery research, determine whether they match with health priorities for countries, and define priorities for regional clinical nursing research agendas to improve health outcomes. DESIGN: This is a scoping review of published clinical nursing research conducted in African countries. DATA SOURCES: Systematic searches of literature published between January 01, 2004 and September 15, 2014 were performed in PubMed, Medline, CINHAL, and Embase. REVIEW METHODS: Research was included if it was conducted by nurses, included data obtained in African countries or regions within the African continent, published in a peer-reviewed journal with an abstract, and included patient outcomes. Abstracts were independently reviewed for inclusion by two authors. The following data were extracted: countries of publication and study, study type and design, journal, language, and topics of research. Gaps in the literature were identified. RESULTS: Initially, 1091 papers were identified with a final sample of 73 articles meeting inclusion criteria. Studies used 12 designs, were published in 35 journals published in five countries (including two African countries); 29% of the research was published in a single journal (Curatonis). Research was mostly qualitative (57%) and included twenty countries in Africa (38%). There were 12 major topics of study, most often midwifery/maternal/child health (43%), patient experiences (38%), and human immunodeficiency virus (HIV)/sexually transmitted infections (STIs) (36%). CONCLUSIONS: Areas most often studied were associated with funding sources (e.g., a large influx of funds for HIV-related research). Major and common health care problems in African countries (e.g. infectious disease other than HIV, and noncommunicable diseases such as malnutrition, diarrheal disease, hypertension and diabetes) were not subjects of the published literature, indicating a clear gap between health care needs and problems and the focus of the majority of clinical nursing research. Additionally, the shortage of doctorally prepared nurses may contribute to the lack of clinical nursing and midwifery research in African countries. PMID- 25707998 TI - Different cerebrospinal fluid levels of Alzheimer-type biomarker Abeta42 between general paresis and asymptomatic neurosyphilis. AB - BACKGROUND AND PURPOSE: Neurosyphilis is a neurological disease that involves infection of the central nervous system with Treponema pallidum. With increases in unsafe sexual behaviour, syphilis has re-emerged worldwide. To explore the amyloid and tau metabolism in neurosyphilis patients in different stages, the levels of Alzheimer-type biomarkers in general paresis (GP) and asymptomatic neurosyphilis (ANS) patients in comparison to patients with Alzheimer's disease (AD) and normal controls (NCs) were investigated. METHODS: beta-amyloid peptide 1 42 (Abeta42) and Abeta 1-40 (Abeta40), tau hyperphosphorylated at threonine 181 (p-tau181) and total tau (t-tau) in cerebrospinal fluid (CSF) were measured by enzyme-linked immunosorbent assay kits in 44 patients with GP, 10 patients with ANS, 45 patients with AD and 39 NCs. RESULTS: Alzheimer's disease patients had lower CSF Abeta42 levels combined with higher CSF t-tau and p-tau181 levels than other groups (all P < 0.001). The CSF Abeta42 levels decreased in GP compared to ANS and NCs (P < 0.001). CSF Abeta40, t-tau and p-tau181 levels were not different between the GP, ANS or NC groups. CONCLUSIONS: Our research has demonstrated that GP, ANS and AD patients are characterized by distinct patterns of the CSF biomarkers Abeta and tau. The distinct CSF Abeta pattern in GP suggests the existence of abnormal Abeta metabolism. Furthermore, different levels of CSF Abeta will be helpful for the differentiation between different stages of neurosyphilis. PMID- 25707999 TI - Complete genome sequence of Bifidobacterium animalis subsp. lactis A6, a probiotic strain with high acid resistance ability. AB - Bifidobacterium animalis subsp. lactis A6 (BAA6) (CGMCC No. 9273) was a probiotic strain isolated from the feces of a centenarian. Previous study showed that BAA6 had high acid resistance to low pH which is a critical factor influencing its healthy benefits. Elaborating the stress resistant mechanisms of bifidobacteria is important to extensively exploit this probiotic. Here, we reported the complete genome sequence of BAA6 that contains 1,958,651 bp encoding 1622 CDSs, 16 rRNA genes, 52 tRNA genes. PMID- 25708001 TI - "Bad genes" & criminal responsibility. AB - The genetics of the accused is trying to break into the courts. To date several candidate genes have been put forward and their links to antisocial behavior have been examined and documented with some consistency. In this paper, we focus on the so called "warrior gene", or the low-activity allele of the MAOA gene, which has been most consistently related to human behavior and specifically to violence and antisocial behavior. In preparing this paper we had two objectives. First, to summarize and analyze the current scientific evidence, in order to gain an in depth understanding of the state of the issue and determine whether a dominant line of generally accepted scientific knowledge in this field can be asserted. Second, to derive conclusions and put forward recommendations related to the use of genetic information, specifically the presence of the low-activity genotype of the MAOA gene, in modulation of criminal responsibility in European and US courts. PMID- 25708000 TI - Molecular basis for convergent evolution of glutamate recognition by pentameric ligand-gated ion channels. AB - Glutamate is an indispensable neurotransmitter, triggering postsynaptic signals upon recognition by postsynaptic receptors. We questioned the phylogenetic position and the molecular details of when and where glutamate recognition arose in the glutamate-gated chloride channels. Experiments revealed that glutamate recognition requires an arginine residue in the base of the binding site, which originated at least three distinct times according to phylogenetic analysis. Most remarkably, the arginine emerged on the principal face of the binding site in the Lophotrochozoan lineage, but 65 amino acids upstream, on the complementary face, in the Ecdysozoan lineage. This combined experimental and computational approach throws new light on the evolution of synaptic signalling. PMID- 25708002 TI - Peritoneal metastasis of pancreas cancer mimicking the local recurrence of colon cancer after laparoscopic colectomy. PMID- 25708003 TI - Early outcome of high energy Laser (Excimer) facilitated coronary angioplasty ON hARD and complex calcified and balloOn-resistant coronary lesions: LEONARDO Study. AB - AIM: An innovative xenon-chlorine (excimer) pulsed laser catheter (ELCA X80) has been recently used for the treatment of complex coronary lesions, as calcified stenosis, chronic total occlusions and non-compliant plaques. Such complex lesions are difficult to adequately treat with balloon angioplasty and/or intracoronary stenting. The aim of this study was to examine the acute outcome of this approach on a cohort of patients with coronary lesions. METHODS AND RESULTS: Eighty patients with 100 lesions were enrolled through four centers, and excimer laser coronary angioplasty was performed on 96 lesions (96%). Safety and effectiveness data were compared between patients treated with standard laser therapy and those treated with increased laser therapy. Laser success was obtained in 90 lesions (93.7%), procedural success was reached in 88 lesions (91.7%), and clinical success in was obtained in 87 lesions (90.6%). There was no perforation, major side branch occlusion, spasm, no-reflow phenomenon, dissection nor acute vessel closure. Increased laser parameters were used successfully for 49 resistant lesions without complications. CONCLUSIONS: This study suggests that laser-facilitated coronary angioplasty is a simple, safe and effective device for the management of complex coronary lesions. Furthermore, higher laser energy levels delivered by this catheter improved the device performance without increasing complications. PMID- 25708004 TI - Formulation and characterization of ORMOSIL particles loaded with budesonide for local colonic delivery. AB - In this study, hybrid silica xerogel particles were developed as carriers of budesonide (BDS) for efficient local treatment of inflammatory bowel diseases (IBD). Organically modified silica particles (ORMOSILs) were prepared by co condensation of 3-aminopropyltriethoxysilane (APTES) and tetraethyl orthosilicate (TEOS) by an ambient temperature acid catalysed sol-gel process followed by spray drying. Formulation for preparation of BDS-loaded particles was optimized and their physicochemical parameters and drug release profiles were evaluated in vitro. Optimal formulation had a small particle size (mean diameter of 1.45+/ 0.02MUm) with unimodal narrow size distribution and high encapsulation efficiency (98.0 +/- 1.85%). Due to the positive surface charge originated from amino group of APTES, ORMOSILs showed excessive mucoadhesiveness in comparison to native TEOS particles. The drug release decreased with increasing pH from 2.0 to 7.4. In order to avoid undesirable erroneous performance in the upper GI tract, particles were additionally coated with Eudragit((r)) FS 30D, as a barrier to the drug release at pH range from 2.0 to 7.0. After Eudragit((r)) FS 30D coating, the release of BDS in acidic media was sustained, while no significant differences in drug release were observed at pH 7.4. In conclusion, pH-responsive ORMOSILs showed great potential for efficient BDS delivery to the colon region. PMID- 25708005 TI - Cryopreservation of microencapsulated murine mesenchymal stem cells genetically engineered to secrete erythropoietin. AB - The ability to cryopreserve and store for long term the structure and function of therapeutic cells and tissues plays a pivotal role in clinical medicine. In fact, it is an essential pre-requisite for the commercial and clinical application of stem cells since preserves cells at low temperature and creates a reserve for future uses. This requisite may also affect the encapsulated stem cells. Several parameters should be considered on encapsulated cell cryopreservation such as the time and temperature during the cryopreservation process, or the cryoprotectant solutions used. In this study, we have compared the influence of penetrating and nonpenetrating cryoprotectants on the viability and functionality of encapsulated mesenchymal stem cells genetically modified to secrete erythropoeitin. Several cryoprotectant solutions combining DMSO, glycerol and trehalose at different concentrations were studied. Although almost no differences among the studied cryoprotectant solutions were observed on the differentiation potential of encapsulated mesenchymal stem cells, the penetrating cryoprotectant DMSO at a concentration of 10% displayed the best viability and erythropoietin secretion profile compared to the other cryoprotectant solutions. These results were confirmed after subcutaneous implantation of thawed encapsulated mesenchymal stem cells secreting erythropoeitin on Balb/c mice. The hematocrit levels of these animals increased to similar levels of those detected on animals transplanted with noncryopreserved encapsulated cells. Therefore, DMSO 10% represents the most suitable cryoprotectant solution among the solutions here studied, for encapsulated mesenchymal stem cells cryopreservation and its translation into the clinic. Similar studies should be performed for the encapsulation of other cell types before they can be translated into the clinic. PMID- 25708006 TI - Investigating the interactions of resveratrol with phospholipid vesicle bilayer and the skin: NMR studies and confocal imaging. AB - In this work, phospholipid vesicle-based nanoformulations were developed to deliver antioxidant resveratrol (RSV) to the skin. Penetration enhancer containing vesicles (PEVs) were prepared adding OramixTM CG110 or LauroglycolTM FCC to phosphatidylcholine to favor RSV diffusion through the skin, which was investigated using Franz cells. Vesicles were approximately 100 nm in size, negatively charged and fairly round in shape, as shown via transmission electron microscopy. Nuclear magnetic resonance studies were performed to investigate the RSV/vesicle interactions at the molecular scale, which revealed that RSV was deeply embedded in the bilayer, as shown by the restricted mobility of the drug. Moreover, PEVs improved drug local accumulation 1.7- to 2.1-fold, as compared to the control liposomes. Confocal imaging displayed broadened intercellular spaces in the viable epidermis of PEVs treated skin and high degree of hydration, which are presumably due to the occlusive film formed on the skin surface by the vesicles. These phenomena may be responsible for the higher RSV accumulation achieved when administering PEVs, as compared to control liposomes. Finally, the toxicity of the vesicular formulations was evaluated in vitro against 3T3 fibroblasts, showing no alteration on cell viability after 24h incubation with RSV loaded vesicles. The results from this study suggest that the proposed formulations may be a potential therapeutic alternative to treat skin disorders associated with oxidative stress. PMID- 25708007 TI - Do surface active parenteral formulations cause inflammation? AB - Local irritation and inflammation at the site of administration are a common side effect following administration of parenteral formulations. Biological effects of surface (interfacial) activity in solutions are less well investigated than effects caused by other physico-chemical parameters such as pH and osmolality. The interfacial activity in different systems, including human plasma, typical amphiphilic substances with fundamental biological relevance such as free fatty acids, anesthetic depot formulations and six different antibiotics was measured. The relative interfacial pressure, and/or concentration of active substance, required to obtain 50% of the maximal attainable effect in terms of interfacial pressure were calculated. The aim was to test the hypothesis that these parameters would allow comparison to biological effects reported in in vivo studies on the investigated substances. The highest interfacial activity was found in a triglyceride/plasma system. Among the antibiotic tested, the highest interfacial activities were found in erythromycin and dicloxacillin, which is in accordance with previous clinical findings of a high tendency of infusion phlebitis and cell toxicity. Independently of investigated system, biological effects were minimal below a 15% relative increase of interfacial activity. Above 35-45% the effects were severe. Interfacial activity in parenteral formulations may well cause damages to tissues followed by inflammation. PMID- 25708008 TI - Comparison of CT numbers of organs before and after plastination using standard S 10 technique. AB - Plastination is the art of preserving biological tissues with curable polymers. Imaging with plastinates offers a unique opportunity for radiographic, anatomical, pathological correlation to elucidate complex anatomical relationships. The aim of this study was to make plastinates from cadavers using the standard S-10 plastination technique and to compare the radiological properties of the tissue before and afterwards to examine the suitability of plastinates as phantoms for planning radiotherapy treatment. An above-diaphragm and a below-diaphragm specimen were obtained from a male and a female cadaver, respectively, and subjected to the standard S-10 plastination technique. CT images were obtained before and after plastination and were compared using Treatment Planning System for anatomical accuracy, volume of organs, and CT numbers. The plastinated specimens obtained were dry, robust, and durable. CT imaging of the plastinated specimens showed better anatomical detail of the organs than the preplastinate. Organ volumes were estimated by contouring the organs' outline in the CT images of the preplastinated and postplastinated specimens, revealing an average shrinkage of 25%. CT numbers were higher in the plastinated specimens except in bones and air-filled cavities such as the maxillary air sinus. Although plastination by the standard S-10 technique preserves anatomical accuracy, it increases the CT numbers of the organs because of the density of silicone, making it unsuitable for radiation dosimetry. Further improvements of the technique could yield more suitable plastinated phantoms. PMID- 25708009 TI - Advances in pathology of diabetes from pancreatic islets to neuropathy--a tribute to Paul Langerhans. AB - There emerges a world epidemic of diabetes, afflicting over 3.8 billion people globally. The socio-economic burden of this disorder is tremendous and there is an urgent need to solve the problems incurred from this disorder and to establish an efficient way of prevention and treatment. Fundamental pathology of diabetes has been too diverse to reach a simple etiology and the mechanisms of how the lesions specific to diabetes develop are yet to be clear. Nevertheless, there has been slow but significant advancement in the understanding of the disease based on characterization of the salient features of pathological lesions in human diabetic subjects. Progressive decline of islet beta cells associated with increased alpha cell volume density was found to account for clinical manifestation of hypoinsulinemia and hyperglucagonemia in type 2 diabetes. Concurrently, signs of complications represented by distal nerve fiber loss in the skin commences from the beginning of this disease. Thus the pathological studies disclosed the major attributes in this disorder targeting the islet of pancreas and epidermal nerve, both of which were discovered by Paul Langerhans more than 140 years ago. In this review, I attempt to summarize the progress in pathology of diabetes which Langerhans opened this field. PMID- 25708011 TI - Left ventricular pseudo-mass due to localized turbulence: a novel cardiac CT artifact. PMID- 25708010 TI - Expanding pseudoaneurysm compressing the coronary arteries and causing cardiogenic shock. AB - A 37-year-old man who recently underwent aortic valve replacement after endocarditis presented with cardiogenic shock. A large expansile pseudoaneurysm was subsequently discovered using multiple imaging modalities. Although transesophageal echocardiography is important in diagnosing valve endocarditis, coronary CT angiography of prosthetic valves is feasible and image quality is good. In this case, coronary CT angiography allowed for better understanding of transesophageal echocardiography images and earlier diagnosis of coronary involvement as cause for left ventricular dysfunction. PMID- 25708012 TI - Atresia of the right atrial ostium of the coronary sinus without persistent left superior vena cava. AB - We present a case of atresia of the right atrial ostium of the coronary sinus. Recognizing this anomaly is important during catheter ablation or cardiac surgery, which could be noninvasively evaluated by multidetector CT. PMID- 25708013 TI - SCCT curriculum guidelines for general (level 1) cardiovascular CT training. AB - The Society of Cardiovascular Computed Tomography has developed general (level 1) cardiovascular CT (CCT) training guidelines for radiology resident and cardiology fellow education. As CCT use has expanded over the past decade, it is essential to incorporate such training in both diagnostic radiology residency programs and cardiology fellowship programs. This curriculum will ensure residents and fellows in-training obtain a fundamental understanding of CCT to stay current in the evolving landscape of cardiovascular imaging and know how and when to use CCT. The curriculum will also help narrow the present knowledge and training gap that exists for CCT between different programs and may encourage trainees to pursue additional training in advanced cardiovascular imaging. PMID- 25708014 TI - Meandering pulmonary veins mimicking arteriovenous malformation. AB - We report a case of preoperative incidental finding in a 34-year-old man with a significant aortic insufficiency. Preoperative chest x-ray was suspicious for arteriovenous malformation in the right lung. Chest CT angiography discovered an anomalous course of the left superior pulmonary vein crossing the mediastinum to the contralateral hemithorax, joining the right superior pulmonary vein before entering the right inferior pulmonary vein and forming a common trunk of right inferior pulmonary vein. PMID- 25708015 TI - 2014 SCCT guidelines for the interpretation and reporting of coronary CT angiography: a report of the Society of Cardiovascular Computed Tomography Guidelines Committee. PMID- 25708017 TI - HLA epitopes as viewed by antibodies: what is it all about? AB - The need for new approaches to define HLA antibodies, in the context of organ transplantation, is intensely debated among HLA professionals. In this review, we sought to provide background and perspective to current understanding of the immunogenicity of HLA mismatches with respect to the humoral alloimmune response and the definition of B cell epitopes. Initial data suggest that epitope matching not only assists in defining better matches for the current transplant, but also minimizes the risk of developing de novo HLA-donor-specific-antibodies posttransplant. In other words, other than lowering the risk of current graft rejection, epitope matching is likely to lower overall future sensitization levels and thus increases the likelihood of finding a compatible donor when the need for a retransplantation arises. More detailed knowledge of epitopes makes it possible to investigate what constitutes permissible versus non-permissible HLA mismatches. The currently available evidence suggest that epitope matching is the most rational way to decrease the risk of HLA-linked transplant rejection. This review is aimed at stimulating further and more intense collaborative effort in this field. PMID- 25708016 TI - Role for pro-inflammatory cytokines in regulating expression of GABA transporter type 1 and 3 in specific brain regions of kainic acid-induced status epilepticus. AB - In general, pro-inflammatory cytokines (PICs) contribute to regulation of epilepsy-associated pathophysiological processes in the central nerve system. In this report, we examined the specific activation of PICs, namely IL-1beta, IL-6 and TNF-alpha in rat brain after kainic acid (KA)-induced status epilepticus (SE). Also, we examined the role played by PICs in regulating expression of GABA transporter type 1 and 3 (GAT-1 and GAT-3, respectively), which are the two important subtypes of GATs responsible for the regulation of extracellular GABA levels in the brain. Our results show that IL-1beta, IL-6 and TNF-alpha were significantly increased in the parietal cortex, hippocampus and amygdala of KA rats as compared with sham control animals (P < 0.05, KA rats vs. control rats). KA-induced SE also significantly increased (P < 0.05 vs. controls) the protein expression of GAT-1 and GAT-3 in those brain regions. In addition, central administration of antagonists to IL-1beta and TNF-alpha receptors significantly attenuated amplified GAT-1 and GAT-3 (P < 0.05 vs. vehicle control for each antagonist group). However, antagonist to IL-6 receptor failed to attenuate enhancement in expression of GAT-1 and GAT-3 induced by KA-induced SE. Overall, our data demonstrate that PIC pathways are activated in the specific brain regions during SE which thereby selectively leads to upregulation of GABA transporters. As a result, it is likely that de-inhibition of GABA system is increased in the brain. This support a role for PICs in engagement of the adaptive mechanisms associated with epileptic activity, and has pharmacological implications to target specific PICs for neuronal dysfunction and vulnerability related to epilepsy. PMID- 25708018 TI - The Cologne-Bonn cohort: lessons learned. AB - Much of our knowledge about HIV infection has been obtained from cohort studies, including description of the natural history of infection, identification of CD4 count and viral load as good surrogate markers of clinical progression, identification of co-factors [including older age and viral infections (CMV, HCV)] for progression of HIV-related disease and assessment of impact of highly active antiretroviral therapy on clinical outcomes. The Cologne-Bonn cohort was founded by Gerd Fatkenheuer and Bernd Salzberger after introduction of combination antiretroviral therapy in 1996 and has delivered important findings which have helped to improve treatment strategies as well as quality of overall care in HIV infection in these two cities. Indeed, the first pivotal paper from the cohort reported on an unexpectedly high rate of virological treatment failure of protease inhibitor therapy in an unselected cohort of HIV-infected patients. The subsequent analysis of risk factors for virological failure initiated the development of more potent HIV combination therapy. This review summarizes some of the major findings and contributions from the Cologne-Bonn cohort since 1996. PMID- 25708019 TI - Estimating pi binding energy of N-heterocyclic carbenes: the role of polarization. AB - In this work, the tuneability of the pi acceptor or donor properties of a set of N-heterocyclic carbenes (NHCs) with a wide spectrum of electronic characteristics is established by means of density functional theory and energy decomposition analysis (EDA) tools. Even though the main orbital interaction contribution to the NHC coordination is the sigma donation, a significant contribution of the pi interactions to the bond is observed. By means of carefully selected coordination sites, different contributions to the pi interactions could be identified and isolated. It includes not only the well known back donation and donation interactions, but also the intrafragment polarization, which has not been considered in previous studies. This can be obtained through the use of the extended transition state method for EDA combined with the natural orbitals for chemical valence and the constrained space orbital variation analysis. The contributions vary with the position of the heteroatoms and the presence of exocyclic substituents; the donation/backdonation pi interactions between NHC and the coordination site can range between 2 and 61% of the total pi orbital interactions, while the rest is owed to intrafragment polarization. Our results do not only contribute to the understanding of the electronic structure of NHC based complexes, giving ways to improve their catalytic properties, but also provide comprehension on the modelization methods used to study their donor acceptor interactions. PMID- 25708022 TI - A randomized, placebo-controlled, phase 2 study of the efficacy and safety of droxidopa in patients with intradialytic hypotension. AB - INTRODUCTION: Intradialytic hypotension (IDH) is the most common complication of hemodialysis (HD), and it plays a significant role in the morbidity and mortality associated with maintenance HD. METHODS: This was a placebo-controlled, parallel group study evaluating efficacy and safety of droxidopa in improving intradialytic blood pressure (BP) responses in 85 adults with end-stage renal disease (ESRD) and prone to IDH. Following screening and baseline periods, patients received 400 mg or 600 mg droxidopa, or placebo, orally 1 hour before HD for 4 weeks. Primary outcome endpoint was the change between baseline and last 2 treatment weeks in average mean arterial pressure (MAP) during HD. Also assessed were changes from baseline in systolic BP (SBP) and diastolic BP (DBP) during and after HD; number of hypotension-induced interventions and symptoms; and adverse events. RESULTS: Increase in droxidopa intra-HD MAP were not significantly different from placebo, although droxidopa groups showed significant improvements in mean SBP after HD of +4.8 +/- 11.6 mm Hg (600-mg) and +3.4 +/- 13.1 (400-mg) compared with -4.4 +/- 17.9 mm Hg in placebo, and the drop seen in mean nadir SBP pre- to intra-HD was also reduced. Changes in mean DBP pre- and post-HD, changes in mean nadir SBP post-HD, or intra-HD SBP were not significant over the treatment period. HD terminations decreased 5-fold in the 600-mg group and 2-fold in the 400-mg group, whereas the number of discontinuations stayed unchanged in the placebo group. Overall, treatment with 600-mg or 400-mg droxidopa was well tolerated in this population. CONCLUSION: These data suggest that droxidopa may have a role in reducing IDH complications in patients with ESRD on chronic HD. PMID- 25708023 TI - Testosterone and cardiovascular disease--the controversy and the facts. AB - Since November 2013, there has been a flurry of articles written in the media touting the risk of cardiovascular (CV) disease in men treated with testosterone, based on two recent reports. Since first synthesized in 1935, testosterone therapy has demonstrated substantial benefits for men with testosterone deficiency (also called hypogonadism). Testosterone has an acceptable safety profile and literature spanning more than 30 years, suggesting a decreased CV risk with low levels of testosterone and benefits associated with testosterone therapy. However, nonmedical media outlets have seized on reports of increased CV risk, and published scathing editorials impugning testosterone therapy as a dangerous and overprescribed treatment. Here, we review these recent studies, and find no scientific basis for assertions of increased CV risk. This article is intended to provide the clinician with the facts needed for an informed discussion with men who suffer from testosterone deficiency and who desire treatment for their symptoms. PMID- 25708024 TI - Adult renal cell carcinoma with rhabdoid differentiation: incidence and clinicopathologic features in Chinese patients. AB - Renal cell carcinoma (RCC) with rhabdoid differentiation is a recently described variant of RCC, which has seldom been reported in China. This form of differentiation has been generally associated with a poor prognosis and is often present in tumors with a poorly differentiated morphology. The development of a rhabdoid morphology appears to represent a common dedifferentiation pathway for renal parenchymal malignancies. The aim of this study is to evaluate the incidence and clinicopathologic features of RCC rhabdoid differentiation in Chinese adult patients and to further investigate its origin. We reviewed 723 cases of RCC obtained between January 2012 and March 2014 in Peking University First Hospital. From these cases, 10 (1.4%) were found to have areas of classic rhabdoid morphology. Immunohistochemistry for vimentin, cytokeratin (CK) (pan cytokeratin (AE1/AE3), CK20, CK5/6, CK7, and CK8/18), RCC, CD10, Pax-2, Pax-8, CD117, desmin, muscle-specific actin, CD68, p53, and Ki-67 was performed in each case using the labeled streptavidin-biotin method. Rhabdoid differentiation was identified in association with clear cell RCC, papillary RCC (II type), and sarcomatoid RCC. We compared the morphologic and immunohistochemical features between rhabdoid and nonrhabdoid components. In our cases, rhabdoid differentiation was characterized by the presence of cohesive large epithelioid cells with abundant pink cytoplasm and central eosinophilic intracytoplasmic inclusions and 1 or more large, oval, eccentric, or irregular nuclei containing prominent nucleoli. Most of the rhabdoid areas showed a solid growth pattern. In our series, RCC with rhabdoid differentiation had an aggressive biological behavior, and rhabdoid components were most likely associated with high-grade tumors of advanced stage. In all cases, the rhabdoid and nonrhabdoid tumoral areas without sarcomatoid differentiation exhibited the very similar immunophenotype as follows: vimentin (+/-), AE1/AE3 (+), CK8/18(+), CK7(+/-), CK5/6 (-), CK20 (-), RCC (focal +), CD10 (focal +), Pax-2 (+), Pax-8 (+), CD117 (+/-), desmin (-), muscle-specific actin (-), and CD68 (-). On p53 and Ki-67 immunohistochemistry, the positive rate of rhabdoid cells for both p53 and Ki-67, similar to sarcomatoid cells, was higher than that of nonrhabdoid tumor cells without sarcomatoid differentiation. Our results indicate that the incidence rate of rhabdoid differentiation in Chinese adult RCC patients is lower than that of foreign reports. We support that the rhabdoid and nonrhabdoid tumor cells originate from the same clone, and the rhabdoid components present high proliferative activity and indicate a poor prognosis. PMID- 25708025 TI - Lubricin/Proteoglycan 4 Binding to CD44 Receptor: A Mechanism of the Suppression of Proinflammatory Cytokine-Induced Synoviocyte Proliferation by Lubricin. AB - OBJECTIVE: To evaluate the binding of recombinant human proteoglycan 4 (rhPRG4) to CD44 receptor and its consequences on cytokine-induced synoviocyte proliferation. METHODS: The binding of rhPRG4 to CD44 and competition with high molecular weight (HMW) hyaluronic acid (HA) was evaluated using a direct enzyme linked immunosorbent assay (ELISA) and surface plasmon resonance. Sialidase A and O-glycosidase digestion of rhPRG4 was performed, and CD44 binding was evaluated using ELISA. Rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) were stimulated with interleukin-1beta (IL-1beta) or tumor necrosis factor alpha (TNFalpha) for 48 hours in the presence or absence of rhPRG4 or HMW HA at 20, 40, and 80 MUg/ml, and cell proliferation was measured. The contribution of CD44 was assessed by coincubation with a CD44 antibody (IM7). The antiproliferative effect of rhPRG4 was investigated following treatment of PRG4(-/-) mouse synoviocytes with IL-1beta or TNFalpha in the presence or absence of IM7. RESULTS: Recombinant human PRG4 bound CD44 and interfered with the binding of HMW HA to CD44. Removal of sialic acid and O-glycosylations significantly increased CD44 binding by rhPRG4 (P < 0.001). Both rhPRG4 and HMW HA at 40 and 80 MUg/ml significantly suppressed IL-1beta-induced proliferation of RA FLS (P < 0.05). Recombinant human PRG4 at 20, 40, and 80 MUg/ml significantly suppressed TNFalpha-induced RA FLS proliferation (P < 0.05). CD44 neutralization reversed the effect of rhPRG4 on IL 1beta- and TNFalpha-stimulated RA FLS and the effect of HMW HA on IL-1beta stimulated RA FLS. Recombinant human PRG4 inhibited cytokine-induced proliferation of PRG4(-/-) synoviocytes, which could be prevented by blocking CD44. CONCLUSION: PRG4 (lubricin) is a novel putative ligand for CD44 and may control synoviocyte overgrowth in inflammatory arthropathies via a CD44-mediated mechanism. PMID- 25708026 TI - The effect of antegrade femoral nailing on femoral head perfusion: a comparison of piriformis fossa and trochanteric entry points. AB - INTRODUCTION: Piriformis fossa entry antegrade femoral nailing is a common method for stabilizing diaphyseal femur fractures. However, clinically significant complications such as chronic hip pain, hip abductor weakness, heterotopic ossification and femoral head osteonecrosis have been reported. A recent cadaveric study found that piriformis entry nailing damaged either the deep branch of the medial femoral circumflex artery (MFCA) or its distal superior retinacular artery branches in 100% of specimens and therefore recommended against its use. However, no study has quantitatively assessed the effect of different femoral entry points on femoral head perfusion. MATERIALS AND METHODS: Twelve fresh-frozen cadaveric lower extremity specimens were randomly allocated to either piriformis fossa or trochanteric entry nailing using a 13-mm reamer. The contralateral hip served as an internal matched control. All specimens subsequently underwent gadolinium-enhanced fat-suppressed gradient-echo sequence MRI to assess femoral head perfusion. Gross dissection was also performed to assess MFCA integrity and distance to the opening reamer path. RESULTS: MRI quantification analysis revealed near full femoral head perfusion with no significant difference between the piriformis and trochanteric starting points (95 vs. 97%, p = 0.94). There was no observed damage to the deep MFCA in either group. The mean distance from the reamer path to the deep MFCA was 3.2 mm in the piriformis group compared to 18.5 mm in the trochanteric group (p = 0.001). Additionally, there was a significantly greater number of mean terminal superior retinacular vessels damaged by the opening reamer in the piriformis cohort (1 vs. 0; p = 0.007). CONCLUSIONS: No statistically significant difference in femoral head perfusion was found between the two groups. Therefore, we cannot recommend against the use of piriformis entry femoral nails. However, we caution against multiple errant starting point attempts and recommend meticulous soft tissue protection during the procedure. PMID- 25708027 TI - Anatomy and classification of the posterior tibial fragment in ankle fractures. AB - INTRODUCTION: The aim of this study was to analyze the pathoanatomy of the posterior fragment on the basis of a comprehensive CT examination, including 3D reconstructions, in a large patient cohort. MATERIALS AND METHODS: One hundred and forty one consecutive individuals with an ankle fracture or fracture dislocation of types Weber B or Weber C and evidence of a posterior tibial fragment in standard radiographs were included in the study. The mean patient age was 49 years (range 19-83 years). The exclusion criteria were patients below 18 years of age, inability to provide written consent, fractures of the tibial pilon, posttraumatic arthritis and pre-existing deformities. In all patients, post-injury radiographs were obtained in anteroposterior, mortise and lateral views. All patients underwent CT scanning in transverse, sagittal and frontal planes. 3D CT reconstruction was performed in 91 patients. RESULTS: We were able to classify 137 cases into one of the following four types with constant pathoanatomic features: type 1: extraincisural fragment with an intact fibular notch, type 2: posterolateral fragment extending into the fibular notch, type 3: posteromedial two-part fragment involving the medial malleolus, type 4: large posterolateral triangular fragment. In the 4 cases it was not possible to classify the type of the posterior tibial fragment. These were collectively termed type 5 (irregular, osteoporotic fragments). CONCLUSION: It is impossible to assess the shape and size of the posterior malleolar fragment, involvement of the fibular notch, or the medial malleolus, on the basis of plain radiographs. The system that we propose for classification of fractures of the posterior malleolus is based on CT examination and takes into account the size, shape and location of the fragment, stability of the tibio-talar joint and the integrity of the fibular notch. It may be a useful indication for surgery and defining the most useful approach to these injuries. PMID- 25708028 TI - Pathogenesis and prevention strategies of heterotopic ossification in total hip arthroplasty: a narrative literature review and results of a survey in Germany. AB - INTRODUCTION: Heterotopic ossification (HO) after THA can lead to pain, impaired range of motion and possibly revision surgery. This article summarizes current literature on the pathogenesis of HO in THA and trauma. Second, it presents the results of a survey on prophylactic concepts for HO in Germany. MATERIALS AND METHODS: A narrative literature review was conducted by searching three databases (Pubmed, ScienceDirect, the Cochrane library) on the aetiology of HO. Between 2013 and 2014, a questionnaire was sent to 119 orthopaedic and trauma surgery departments in Germany. RESULTS: The acquired form of HO seems to develop after tissue trauma, which induces a local inflammation. A change in tissue conditions, multiple signalling pathways and involvement of several different cell types seem to promote enchondral ossification and finally HO formation. The feed back rate of the survey was 67%. Eighty-seven percent of all departments currently administer NSAIDs with a mean time span of 3 weeks after surgery for oral prophylaxis. Prophylactic perioperative irradiation is performed in 64% of trauma/orthopaedic departments if the patient is at risk for HO with a mean dosage of 7 Gy. CONCLUSIONS: Basic research detected new pathways and cell signalling mechanisms of HO pathogenesis, which could offer new treatment and prophylaxis options in the near future. So far, there is no uniform strategy for the clinical prophylaxis of HO in THA. Guidelines and new clinical trials need to be developed to further reduce HO rates in THA. PMID- 25708029 TI - A new pathological classification of lumbar disc protrusion and its clinical significance. AB - Lumbar disc protrusion is common. Its clinical manifestations and treatments are closely related to the pathological changes; however, the pathological classification of lumbar disc protrusion is controversial. This article introduces a new pathological classification comprising four types of lumbar disc protrusion according to intraoperative findings. The damage-herniation type is probably caused by injury and is characterized by soft herniation, the capsule can easily be cut and the broken disc tissue blocks overflow or is easily removed. The broken disc substances should be completely removed; satisfactory results can be achieved by minimally invasive endoscopic surgery. The degeneration-protrusion type is characterized by hard and tough protrusions and the pathological process by degeneration and proliferative reaction. The nerve should be decompressed and relaxed with minimally invasive removal of the posterior wall; the bulged or protruded disc often need not be excised. The posterior vertebral osteochondrosis with disc protrusion type is characterized by deformity of the posterior vertebral body, osteochondral nodules and intervertebral disc protrusion. The herniated and fragmented disc tissue should be removed with partially protruding osteochondral nodules. Intervertebral disc cyst is of uncertain pathogenesis and is characterized by a cyst that communicates with the disc. Resection of the cyst under microscopic or endoscopic control can achieve good results; and whether the affected disc needs to be simultaneously resected is controversial. The new pathological classification proposed here is will aid better understanding of pathological changes and pathogenesis of lumbar disc protrusion and provides a reference for diagnosis and treatment. PMID- 25708030 TI - Anatomy, definition, and treatment of the "terrible triad of the elbow" and contemplation of the rationality of this designation. AB - In the realm of orthopaedics, the terrible triad of the elbow is infamous, not simply because the prognosis is poor for most patients, but also, maybe to a greater extent, because the unique name of this malady attracts considerable attention and interest in both doctors and patients. The adjective terrible is bestowed on an elbow triad that comprises three coexisting complicated traumas; namely, radial head and ulnar coronoid process fractures and posterior dislocation of the elbow joint. In this review, the classification, treatment principles and prognosis for different forms of management of the radial head and ulnar coronoid process fractures and the ligaments lesions are introduced sequentially and various surgical procedures and their efficacy are discussed. This triad has long given orthopedic surgeons headaches. Nonetheless, in recent years a series of anatomical mechanical studies on the elbow joint have been published and there have been several breakthroughs in surgical techniques for managing this elbow triad. This review examines some memorable millstones and unveils trends in the current clinical norm for this triad. The accomplishments achieved recently have reportedly resulted in enhanced prognoses in the last two or three years compared with previous years. It is therefore high time to revise our thoughts about the justice and accuracy of defining this triad of the elbow as terrible. Lastly, we may safely conclude that the terrible triad of the elbow is much less terrible than previously, provided the commonly approved clinical approaches are undertaken. PMID- 25708031 TI - No evidence of superiority in reducing outliers of component alignment for patient-specific instrumentation for total knee arthroplasty: a systematic review. AB - Patient-specific instrumentation (PSI) technology has been developed to improve alignment when implanting total knee arthroplasty (TKA) and is a new focus in the orthopaedic community. Current controversial data concerning PSI are discussed. A systematic review to compare PSI with conventional instrumentation and assess the radiographic outcomes was performed. Electronic databases (including PubMed, Medline, Embase, the Cochrane Library and the Science Citation Index database) and conference proceedings from 1950 to 2014 in the English language were searched. Data, including relevant patient characteristics, sample size, radiographic method, PSI system manufacturer and outliers of implant positioning and alignment on radiography were independently extracted from all eligible studies by two of the authors. A total of 2739 TKAs were included (1410 performed with PSI and 1329 with conventional instrumentation). There were more TCA outliers (malalignment >3 degrees ) and tibial slope outliers (malalignment >3 degrees ) in the PSI group than in the conventional group. The other radiographic outcomes assessed, including coronal, sagittal or rotational alignment outliers did not differ between the two groups. With regard to radiographic outcomes, our findings indicate that PSI technology is not superior in reducing outliers of component alignment. PMID- 25708032 TI - Thromboelastography predictive of death in trauma patients. AB - OBJECTIVES: To determine if thromboelastography (TEG) is predictive of patient outcomes following traumatic injury. METHODS: A retrospective review of 131 patients with pelvic trauma admitted to a Level II trauma center was conducted over four years from 1 January 2009 to 31 December 2012. Patients were identified retrospectively from a prospectively collected database of acute pelvic trauma (n = 372). Eligible patients were identified from billing/coding data as having fractures of the acetabulum, iliac wing or sacral alae. Patients with incomplete TEG data were excluded (n = 241), as were patients with pathological fractures. TEG clotting variables and traditional clotting variables were recorded. RESULTS: Evaluation of TEG data revealed 41 patients with abnormal clotting times (TEG R). TEG R > 6 was an independent risk factor for death (OR, 16; 95%CI 5.4-53; P = 0.0001). The death rate was 52% in patients with TEG R values >=6 (n = 13/25). There was no significant association between traditional clotting markers and death rate. CONCLUSIONS: TEG reaction time value, representing the time of initial clot formation, was the only hematologic marker predictive of mortality in patients with pelvic trauma. Delay in reaction time was associated with a significantly increased death rate, independent of injury severity. The death rate association was not observed with traditional markers of clotting. Future prospective studies may be warranted to determine the presentation and significance of TEG abnormalities when resuscitating patients with orthopaedic trauma. PMID- 25708033 TI - Sanders II type calcaneal fractures: a retrospective trial of percutaneous versus operative treatment. AB - OBJECTIVE: The purpose of this study was to compare the clinical results of percutaneous reduction and Steinman pin fixation for Sanders II calcaneal fractures with those of operative management through an extensile lateral approach. METHODS: Fifty-three patients treated with standard open reduction and internal fixation (ORIF group) and 54 patients who had undergone percutaneous reduction and Steinman pin fixation (CRIF group) were retrospectively reviewed. There were no differences between the groups regarding sex, age or fracture classification. Pain and functional outcome were evaluated with a visual analogue scale (VAS) and American Orthopaedic Foot and Ankle Society (AOFAS) scores. Wound complications and radiological results were compared. RESULTS: At a mean follow up of 40.4 months (24 to 56 months), there were no differences between the two groups in mean AOFAS score, VAS score or radiologically determined variables. Two cases of deep infection and six of poor wound healing occurred in the ORIF group and none in the CRIF group. Subtalar and ankle motion was found to be better in the CRIF group. CONCLUSIONS: Percutaneous reduction and Steinman pin fixation minimizes complications and achieves functional outcomes comparable to those of the open techniques in patients with Sanders II calcaneal fractures. PMID- 25708034 TI - Cementless revision for infected hip arthroplasty: an 8.6 years follow-up. AB - OBJECTIVE: To investigate cementless revision for postoperative infection after total hip arthroplasty (THA). METHODS: From November 1997 to December 2009, 10 patients (10 hips; four males, six females) of mean age 58 years (36-73 years) with infection after THA were treated. Six of the 10 hips underwent revision total hip arthroplasty, two only received new acetabular components and two underwent stem revision. One-stage revision was performed in six cases and two stage revision in four. Consecutive radiographs were compared to evaluate component conditions. Harris hip scores were determined before surgery and at final follow-up. Erythrocyte sedimentation rate and C-reactive protein were assessed. RESULTS: All patients were followed up for a mean duration of 8.6 years (6.5-15.6 years). The mean Harris hip score improved from 35 (18-63) points preoperatively to 89 (60-99) points at final follow-up. No re-infection occurred. Femoral component exsertion was occurred in one asymptomatic patient. Hip joint pain resolved in seven cases; three patients had mild pain when walking long distances. At final follow-up, six patients still had slight limps. Heterotopic ossification developed in two hips. Mean polyethylene liner wear was 0.08 mm per year at final follow-up. Deep vein phlebothrombosis and nerve injury did not occur. CONCLUSION: One- or two-stage revisions using cementless prosthesis can produce satisfactory clinical outcomes in patients with infection after THA. Whether the original prosthesis can be partially retained when attached tightly to the femur or acetabular bone needs further investigation. PMID- 25708035 TI - Three-dimensional computed tomography for assessing lung morphology in adolescent idiopathic scoliosis following posterior spinal fusion surgery. AB - OBJECTIVE: To evaluate the changes in lung morphology in subjects with adolescent idiopathic scoliosis (AIS) following posterior spinal fusion surgery. METHODS: From April 2009 to August 2013, 30 AIS patients (nine males and 21 females) were enrolled in this study. All scans were obtained with the patient in the supine position and the breath held in deep inspiration and performed both before and after surgery. Syngo software was used to manage the computed tomography scan imaging and to calculate the lung volume, lung height and pulmonary cross sectional area in the apical vertebral plane. RESULTS: Left lung, right lung and total lung volumes and convex to concave lung volume ratio did not change significantly after corrective surgery. There was a statistically significant improvement in left lung and right lung heights after posterior spinal fusion surgery. However, the pulmonary cross-sectional area in the apical vertebrae plane was smaller postoperatively than preoperatively. CONCLUSIONS: This study showed that lung height in AIS patients increased significantly immediately postoperatively whereas lung volume did not change significantly. Thoracic symmetry was improved postoperatively in these patients. PMID- 25708036 TI - Reconstruction of limb deformities in patients with thrombocytopenia-absent radius syndrome. AB - OBJECTIVE: Developmental abnormalities of the appendicular skeleton are among the most common and easily identified birth defects. The aim of this report was to describe the phenotypic characterization of several patients with thrombocytopenia-absent radius (TAR) syndrome and the orthopaedic interventions performed on them. TAR syndrome is inherited in an autosomal recessive manner and results from compound heterozygosity of RBM8A mutations. METHODS: Reconstructions were designed and performed in five patients with TAR syndrome, mainly comprising orthopaedic interventions to correct their upper limb defects. Additional lower limb deformities (severe internal rotation of the tibiae) was been encountered in one patient. RESULTS: The affected patients' wrists were re-aligned and stabilized and the musculotendinous forces around the wrist rebalanced to reverse the ulnar forearm bow. CONCLUSION: Patients with TAR syndrome who receive optimal treatment can expect to return to most activities of daily living with some limitation of wrist extension and ulnar deviation and, of course, with a reduced total active range of digital motion. PMID- 25708037 TI - Combination treatment with whole body vibration and a kidney-tonifying herbal Fufang prevent osteoporosis in ovariectomized rats. AB - OBJECTIVE: To assess the ability of whole body vibration (WBV) with the kidney tonifying herbal Fufang (Bushen Zhuanggu Granules, BZG) to prevent osteoporosis in ovariectomized rats. METHODS: Fifty 6-month-old female Sprague Dawley rats were divided into five groups: sham-operated (SHAM), ovariectomized (OVX), OVX with WBV (OVX + WBV), OVX with BZG (OVX + BZG), OVX with both WBV and BZG (OVX + WBV + BZG). The SHAM group received normal saline. After 12 weeks of treatment, the rats were killed, their serum concentrations of osteopontin (OPN), receptor activator of nuclear factor kappa-B ligand RANKL and bone turnover markers assayed and bone mineral density (BMD), histomorphometry and bone strength evaluated. RESULTS: Concentrations of OPN were significantly lower in the SHAM, OVX + WBV and OVX + WBV + BZG groups at 12 weeks, whereas concentrations of RANKL had decreased significantly in the SHAM, OVX + WBV, OVX + BZG and OVX + WBV + BZG groups. In the OVX + WBV, OVX + BZG and OVX + WBV + BZG groups the amount of bone turnover had been significantly antagonized. Compared with OVX group, BMD, % trabecular area (Tb.Ar), number of trabeculae (Tb.N) and assessed biomechanical variables were higher in OVX+WBV group, whereas and BMD, %Tb.Ar, Tb.N, maximal load and yield load were higher in the OVX + BZG group. All tested indices were significantly lower in the OVX + WBV and OVX + BZG groups than in the OVX + WBV + BZG group. CONCLUSION: Either WBV or BZG alone prevents OVX-induced bone loss. However, BZG enhances the effect of WBV by further enhancing BMD, bone architecture and strength. PMID- 25708038 TI - Finite element modelling for assessing effect of acetabular component orientation on the basic stress path above acetabular dome. AB - OBJECTIVE: To investigate the effect of acetabular component orientation on the basic stress path above the acetabular dome in the recommended safe zone. METHODS: A subject-specific normal hip finite element model was generated and a convergence study carried out to determine the number of material properties for trabecular bone using a normal hip model. Four abduction angles (35 degrees , 40 degrees , 45 degrees and 50 degrees ) and four anteversion angles (10 degrees , 15 degrees , 20 degrees and 25 degrees ) from the recommended safe zone of acetabular cup orientation were chosen to simulate acetabular reconstruction. The distribution and level of periacetabular stress was assessed using a normal hip model as a control and 16 reconstructed acetabula in simulated single-legged stances. RESULTS: The error of the average stress between plans four and five (50 and 100 materials for trabecular bone respectively) was 4.8%, which is less than the previously defined 5% error. The effect of acetabular component orientation on stress distribution in trabecular bone was not pronounced. When the acetabular component was at 15 degrees anteversion and the abduction angle was 40 degrees or 45 degrees , the stress level on posterolateral cortical bone above the acetabular dome was as stable as that in the normal hip model. CONCLUSIONS: Acetabular component orientation affects the basic stress path above the acetabular dome. Thus, orientation should be considered when attempting to restore normal biomechanics in the main load-bearing area. PMID- 25708039 TI - Intercompartmental giant lipoma of the arm: a case report. PMID- 25708040 TI - Does the necrosis develop simultaneously in patients with bilateral hips necrosis? A case report. PMID- 25708041 TI - Posterior lumbar interbody fusion for grade II spondylolisthesis. PMID- 25708042 TI - Modified resection technique for ventrally-located subdural thoracic extramedullary schwannoma. PMID- 25708043 TI - Mid-head resection of hip using resurfacing prosthesis. PMID- 25708044 TI - Clinical significance of echocardiography in patients supported by venous-venous extracorporeal membrane oxygenation. AB - Although there are extensive published data regarding venous-arterial (VA) ECMO, particularly in the pediatric population, there is a paucity of data (mainly including case reports and observational studies) delineating the role of echocardiography in the management of adult patients supported by venous-venous (VV) ECMO. The present review is aimed at specifically addressing the rationale for echocardiography use in patients supported by VV-ECMO and at summarizing the available evidence on this topic. Based on the available evidence and on the experience of our group, practical considerations on the use of echocardiography in adult patients on VV-ECMO support are reported. To date, echocardiography is mainly used for selecting the type of ECMO (VA vs VV), monitoring cannulation and the early detection of complications, but it is underused in patients supported by VV-ECMO. Nevertheless, in these patients, this methodology can provide useful information in monitoring cardiac function, cannula positioning, pericardial fluid (for early detection of tamponade) during ECMO support, and therefore it can contribute to the integrated assessment and management of these complex patients. There is a clinical need to elaborate shared protocols for echocardiography use during VV ECMO support, particularly at this time when advanced echocardiography is gaining interest among intensivists. PMID- 25708045 TI - IBD: Tracking TNF and anti-TNF agents in inflamed gut tissue. PMID- 25708046 TI - Viral hepatitis: Scaling up HCV treatment in resource-limited countries. PMID- 25708047 TI - Pancreatic cancer: Disrupted lipid metabolic pathways in PDAC identified. PMID- 25708048 TI - Mechanistic analysis elucidating the relationship between Lys96 mutation in Mycobacterium tuberculosis pyrazinamidase enzyme and pyrazinamide susceptibility. PMID- 25708049 TI - Sulfitobacter pacificus sp. nov., isolated from the red alga Pyropia yezoensis. AB - Three Gram-negative, aerobic, halophilic bacterial strains, SCM2-10(T), SCM-4, and 14C-6, were isolated from the algal medium of the red alga Pyropia yezoensis (previously classified as Porphyra yezoensis) grown in laboratory experiments. Phylogenetic analysis based on 16S rRNA gene sequences revealed that the organisms with high similarities to the three isolates are Sulfitobacter geojensis MM-124(T) (98.7%), Sulfitobacter noctilucicola NB-77(T) (98.7%), Sulfitobacter noctilucae NB-68(T) (98.6%), Sulfitobacter mediterraneus CH-B427(T) (97.6%), and Sulfitobacter porphyrae SCM-1(T) (97.6%), and that the three isolates belong to the genus Sulfitobacter, within the class Alphaproteobacteria. The DNA G+C contents of the three isolates were found to be in the range of 56.5 57.1 mol%. DNA-DNA hybridization experiments demonstrated that the genomic relatedness between strain SCM2-10(T) and type strains of other Sulfitobacter species was in the range of 6.2-27.1%. The predominant respiratory quinone of the three isolates was identified as ubiquinone-10. The dominant polar lipids in the three isolates were found to be phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, and an unidentified amino lipid. The major fatty acid in the three isolates is C(18:1)omega7c. Strain SCM2-10(T) demonstrated unique phenotypic characteristics, which differed from those of type strains of other Sulfitobacter species. Based on the phylogenetic, genetic, phenotypic, and chemotaxonomic data, we propose a novel species of the genus Sulfitobacter, which we named as Sulfitobacter pacificus sp. nov. The type strain of this species is strain SCM2-10(T) (=LMG 27113(T) = NBRC 109915(T)). PMID- 25708050 TI - Adhesion patterns in the microvasculature are dependent on bifurcation angle. AB - Particle adhesion in vivo is highly dependent on the microvascular environment comprising of unique anatomical, geometrical, physiological fluid flow conditions and cell-particle and cell-cell interactions. Hence, proper design of vascular targeted drug carriers that efficiently deliver therapeutics to the targeted cells or tissue at effective concentrations must account for these complex conditions observed in vivo. In this study, we build upon our previous results with the goal of characterizing the effects of bifurcations and their corresponding angle on adhesion of functionalized particles and neutrophils to activated endothelium. Our hypothesis is that adhesion is significantly affected by the type of biochemical interactions between particles and vessel wall as well as the presence of bifurcations and their corresponding angle. Here, we investigate adhesion of functionalized particles (2 MUm and 7 MUm microparticles) to protein coated channels as well as adhesion of human neutrophils to human endothelial cells under various physiological flow conditions in microfluidic bifurcating channels comprising of different contained angles (30 degrees , 60 degrees , 90 degrees , or 120 degrees ). Our findings indicate that both functionalized particle and neutrophil adhesion propensity increase with a larger bifurcation angle. Moreover, the difference in the adhesion patterns of neutrophils and rigid, similar sized (7 MUm) particles is more apparent in the junction regions with a larger contained angle. By selecting the right particle size range, enhanced targeted binding of vascular drug carriers can be achieved along with a higher efficacy at optimal drug dosage. Hence, vascular drug particle design needs to be tailored to account for higher binding propensity at larger bifurcation angles. PMID- 25708051 TI - flg2 as a potential biomarker of acute cerebral ischemic-reperfusion injury. AB - Cerebral ischemic-reperfusion injury as an inflammatory and microcirculation dysfunction pathological condition negatively affects the clinical outcome of stroke patients. The novel inflammatory procoagulant protein fgl2 has been reported to play a role in some inflammatory and coagulation dysregulation diseases. This study aimed to examine the relationship between fgl2 expression and infarct size in an acute cerebral ischemic-reperfusion rat model. We studied fgl2 mRNA and protein expressions in cerebral tissue and peripheral macrophages, and the expressions of several inflammatory factors (TNF-alpha, IL-1beta, MCP-1, and IL-8) in serum samples from rats with acute cerebral ischemic-reperfusion injury. Fiber microthrombosis in situ contributed to the microvascular thrombosis in acute cerebral ischemic-reperfusion injury, and fgl2 expression tended to strongly correlate with cerebral infarct size. The expression levels of the other inflammatory factors significantly increased but weakly correlated with cerebral infarct size. These findings support the potential of fgl2 level as a novel biomarker of acute cerebral ischemic-reperfusion injury. PMID- 25708052 TI - The skeletal muscle cross sectional area in long-term bisphosphonate users is smaller than that of bone mineral density-matched controls with increased serum pentosidine concentrations. AB - Bisphosphonates are effective in increasing bone mineral density (BMD), but fragility fractures can still occur despite bisphosphonate treatment. The purpose of this study was to determine if long-term bisphosphonate users have characteristic findings in the musculoskeletal system, which could put them at risk of developing typical or atypical femoral fractures. We recruited 40 female patients who had taken bisphosphonates for more than 3 years. The control group included 60 volunteers who were matched by age, body mass index, and dual-energy X-ray absorptiometry-derived BMDs. We measured the skeletal muscle cross sectional area around the proximal thigh and buckling ratio of the femoral neck using quantitative computed tomography (qCT) and several biochemical markers of bone metabolism. Those parameters were compared between the groups. While no significant differences of buckling ratio derived from qCT were detected, the skeletal muscle cross sectional area was significantly smaller in the long-term bisphosphonate users than in the controls. Furthermore, the serum pentosidine level was significantly higher in the bisphosphonate users than in the controls. To determine if those differences were attributable to bisphosphonate treatment, we further compared those parameters between before and after 3 years of bisphosphonate treatment in 32 patients. After 3 years of bisphosphonate treatment, the BMD of the femoral neck and serum pentosidine level increased but not the skeletal muscle cross sectional area. In the present study, the skeletal muscle mass did not match the bone mass in long-term bisphosphonate users, thus suggesting that increases in BMD by bisphosphonates are unlikely to have secondary positive effects on the surrounding skeletal muscles. Also, serum pentosidine levels were greater in the long-term bisphosphonate users. Further study is necessary to test if such patients are prone to develop typical or atypical femoral fractures. PMID- 25708053 TI - Leonurine hydrochloride inhibits osteoclastogenesis and prevents osteoporosis associated with estrogen deficiency by inhibiting the NF-kappaB and PI3K/Akt signaling pathways. AB - Osteoclasts, the primary bone resorbing cells, are responsible for destructive bone diseases such as postmenopausal osteoporosis, rheumatoid arthritis, and periodontitis. Many plant-derived traditional medicines that might suppress the formation and/or function of osteoclasts are promising treatments for osteoclast related diseases. In this study, we investigated the effects of leonurine hydrochloride (LH) on receptor activator NF-kappaB ligand (RANKL)-induced osteoclastogenesis and ovariectomy-induced bone loss. LH is a synthetic chemical compound based on the structure of leonurine, which is found in motherwort and has been reported to exhibit phytoestrogenic activity. In RAW 264.7 cells and mouse bone marrow monocytes (BMMs), LH suppressed RANKL-induced osteoclastogenesis and actin ring formation in a dose-dependent manner. LH targeted RANKL-induced osteoclastogenesis and bone resorption at an early stage. Molecular analysis demonstrated that LH attenuated RANKL-induced NF-kappaB signaling by inhibiting the phosphorylation and degradation of IkappaBalpha and NF-kappaB p65 nuclear translocation. LH inhibited the RANK-TRAF6 association triggered by RANKL binding and the phosphatidylinositol 3-kinase (PI3K)/Akt axis, without significantly affecting the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) and AP-1 signaling pathways. LH attenuated the RANKL-stimulated expression of osteoclast-related genes including NFATc1, tartrate resistant acid phosphatase (TRAP), cathepsin K, and osteoclast associated receptor (OSCAR). Consistent with the in vitro results, LH administration attenuated osteoclast activity, thus preventing bone loss caused by estrogen deficiency in mice. In this study, LH suppressed RANKL-induced osteoclastogenesis via RANK-TRAF6, NF-kappaB, and PI3K/Akt signaling. These data provide the first evidence that LH might be a promising therapeutic compound to treat osteoclast-related diseases, such as osteoporosis. PMID- 25708054 TI - Quantifying the osteocyte network in the human skeleton. AB - Osteocytes form an extensive cellular network throughout the hard tissue matrix of the skeleton, which is known to regulate skeletal structure. However due to limitations in imaging techniques, the magnitude and complexity of this network remain undefined. We have used data from recent papers obtained by new imaging techniques, in order to estimate absolute and relative quantities of the human osteocyte network and form a more complete understanding of the extent and nature of this network. We estimate that the total number of osteocytes within the average adult human skeleton is ~42 billion and that the total number of osteocyte dendritic projections from these cells is ~3.7 trillion. Based on prior measurements of canalicular density and a mathematical model of osteocyte dendritic process branching, we calculate that these cells form a total of 23 trillion connections with each other and with bone surface cells. We estimate the total length of all osteocytic processes connected end-to-end to be 175,000 km. Furthermore, we calculate that the total surface area of the lacuno-canalicular system is 215 m(2). However, the residing osteocytes leave only enough space for 24 mL of extracellular fluid. Calculations based on measurements in lactation induced murine osteocytic osteolysis indicate a potential total loss of ~16,000 mm(3) (16 mL) of bone by this process in the human skeleton. Finally, based on the average speed of remodelling in the adult, we calculate that 9.1 million osteocytes are replenished throughout the skeleton on a daily basis, indicating the dynamic nature of the osteocyte network. We conclude that the osteocyte network is a highly complex communication network, and is much more vast than commonly appreciated. It is at the same order of magnitude as current estimates of the size of the neural network in the brain, even though the formation of the branched network differs between neurons and osteocytes. Furthermore, continual replenishment of large numbers of osteocytes in the process of remodelling allows therapeutic changes to the continually renewed osteoblast population to be rapidly incorporated into the skeleton. PMID- 25708055 TI - Effects of active and passive smoking on the development of cardiovascular disease as assessed by a carotid intima-media thickness examination in patients with type 2 diabetes mellitus. AB - Carotid intima-media thickness has been widely used as a surrogate end-point for cardiovascular disease, myocardial infarction, and stroke. This study aimed to assess the effects of active and passive smoking exposure on the development of cardiovascular disease in patients with type 2 diabetes mellitus. Seven hundred twenty-two patients with type 2 diabetes mellitus were recruited for the study. A standardized questionnaire on smoking status, pack-years of smoking, and the number of years of smoking cessation was provided to the patients, and their responses were collected for analysis. The carotid intima-media thickness, carotid plaque, and the internal diameter of the common carotid artery were determined by high-resolution B-mode ultrasonography. Compared to non-smokers, passive female smokers had a higher risk of cardiovascular disease (odds ratio = 3.50, 95% confidence interval: 1.29-9.49, P = 0.009); they also had a significantly larger common carotid artery (P = 0.041) and risk of carotid plaque (odds ratio = 2.20, 95% confidence interval: 1.1980-4.0505, P = 0.01). Both active and passive male smokers had a significantly greater carotid intima-media thickness than non-smokers (P = 0.003 and P = 0.005, respectively). Male active smokers had a significantly higher risk of carotid plaque (odds ratio = 2.88, 95% confidence interval: 1.4788-5.6094, P = 0.001). In conclusion, cumulative active and passive smoking exposures are significant risk factors for carotid atherosclerosis in patients with type 2 diabetes mellitus. Our results highlight the importance of endorsing a smoke-free environment for patients with type 2 diabetes mellitus. PMID- 25708056 TI - Exploring the prevalence of and factors associated with pain: a cross-sectional study of community-dwelling people with dementia. AB - Few pain studies have made community-dwelling people with dementia (PWD) their focus. The aim of this study was to determine the prevalence of pain among this patient population and to explore medication use. Moreover, we sought to investigate patient and caregiver variables associated with the presence of pain. Community-dwelling PWD and their caregivers were recruited between May 2009 and July 2012 from outpatient memory clinics in Northern Ireland to take part in a face-to-face structured interview with a researcher. Patients' cognitive status and presence of depression were established. A full medication history was taken. Both patients and caregivers were asked to rate patients' pain, at the time of the interview and on an average day, using a 7-point verbal descriptor scale. From the 206 patients who were eligible to take part, 75 patient-caregiver dyads participated in the study (participation rate = 36.4%). The majority of patients (92.0%) had dementia classed as mild or moderate. Pain was commonly reported among the sample, with 57.3% of patients and 70.7% of caregivers reporting patient pain on an average day. Significant differences were found between patients' and caregivers' reports of pain. Two-fifths of patients (40.0%) were prescribed analgesia. Antipsychotic, hypnotic and anxiolytic drug use was low, whereas antidepressant drugs were prescribed more commonly. Presence of pain was unaffected by dementia severity; however, the use of prescribed analgesic medication was a significant predictor of the presence of pain in these patients, whether reported by the patient or their caregiver 'right now' or 'on an average day' (P < 0.001). Patient and caregiver recruitment was challenging, and remains a barrier to research in this area in the future. PMID- 25708057 TI - Epidemiological and clinical profile of hospitalized children with moderate and severe acute malnutrition in South India. AB - OBJECTIVE: To evaluate the clinico-epidemiological profile, pattern of infections, feeding practices, socio-demographic risk factors and outcome of hospitalized children with moderate acute malnutrition (MAM) and severe acute malnutrition (SAM). METHODS: Cases (children aged 1-60 mo with SAM or MAM) and controls (children with weight for height z score more than -1 SD) were recruited from November 2011 through July 2013. Overall, 126 cases and 126 controls were included. RESULTS: Only 33 % of malnourished children (cases) were exclusively breast fed. Among controls, 71 % were exclusively breast fed for the first 6 mo after birth. Most cases had associated infections (p 0.004) and anemia (p < 0.001). ROC curve revealed 120 mm mid upper arm circumference (MUAC) as the best cut off for predicting SAM. Mothers' education, pre-lacteal feeds and co morbidities were independent predictors of malnutrition (R(2) = 22.1 %) by logistic regression. CONCLUSIONS: Though 11.5 cm MUAC has been mentioned by WHO as the cut off for identifying SAM, a higher cut off (12 cm) may be required to use it as a screening tool. Mothers' education, pre-lacteal feeds and co morbidities were found to be independent determinants for malnutrition in the present patient population, indicating the need towards a targeted approach for modifying these factors. PMID- 25708058 TI - Living Related Liver Transplantation for Biliary Atresia in the Last 5 years: Experience from the First Liver Transplant Program in India. AB - OBJECTIVE: To study the clinical, biochemical profile and outcome of patients with biliary atresia (BA) who underwent living related liver transplantation (LRLT) at authors' institute in the last 5 y (2008-2013). METHODS: Case records of the 20 patients diagnosed with biliary atresia who had undergone living related liver transplantation at authors' centre in the last 5 y were analysed. RESULTS: Eighteen patients with BA with a failed Kasai procedure and 2 without a prior Kasai's portoenterostomy received a liver transplant. At a median follow up of 2 y and 6 mo, both the patient and graft survival rates were 90 %. The median age of the recipients at the time of LRLT was 8 mo and 12 (60 %) of the transplanted children were less than or equal to 1 y of age. The male-female ratio was 1.8:1. The median weight was 7.3 kg (5.8-48 kg); two thirds were less than 10 kg. The median pre-transplant total serum bilirubin (TSB) and international normalized ratio (INR) were 12.98 (0.5-48.3) mg/dl and 1.3 (1.0 3.9) respectively. All patients received a living related graft and there was no donor mortality. The median duration of postoperative ventilation was 14 h. The post-operative complications were infection (30 %), vascular complications (20 %) and acute rejection (20 %). The median duration of postoperative hospital stay was 21 d (17-42). Two patients died of combined hepatic and portal vein thrombosis in the early postoperative period. Late rejection was encountered in 1 patient and another developed chronic kidney disease necessitating a renal transplant. There were no late vascular occlusions or development of post transplant lymphoproliferative disease. CONCLUSIONS: Thus, LRLT for BA with or without a prior portoenterostomy, is a feasible and successful treatment modality with good outcomes attained despite the challenges of age and size. This treatment modality is now well established in India. PMID- 25708059 TI - Correlation of Childhood Obesity and Related Insulin Resistance with Leptin and Retinol Binding Protein 4. AB - OBJECTIVES: To study the correlation of obesity with various metabolic parameters and correlation between insulin resistance and leptin and retinol binding protein 4 (RBP4) levels. METHODS: This is a cross sectional study in a tertiary care children's hospital wherein 98 obese children were included and their metabolic parameters analysed with regards to insulin resistance and RBP4 levels. RESULTS: Leptin levels were abnormal for all children and high RBP4 levels were observed in 69.6 %. There was no significant association between insulin resistance and RBP4 levels (p 0.8). CONCLUSIONS: RBP4, the sole retinol transporter in blood, secreted from adipocytes and liver has been implicated in insulin resistance. The index study however, did not show a significant positive association. PMID- 25708060 TI - Secondary Hemophagocytic Lymphohistiocytosis Associated with Epstein-Barr Virus. PMID- 25708061 TI - 3-HMG Coenzyme A Lyase Deficiency: Macrocephaly and Left Ventricular Noncompaction with a Novel Mutation. AB - 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) lyase deficiency, an inborn error of ketone body synthesis and leucine degradation, is a rare autosomal recessive disease. There are a few reports demonstrating clinical and neuroradiologic findings of this condition. The authors report case of an 8-mo-old infant with HMG-CoA lyase deficiency, who presented with macrocephaly, left ventricular noncompaction, recurrent pulmonary infections, nonketotic hypoglycemia, seizure and metabolic acidosis. There was no significant difference in brain magnetic resonance imaging after leucine-restricted diet and carnitine therapy and neurologic deterioration was not observed. Left ventricular noncompaction is an interesting finding for HMG-CoA lyase deficiency which has not been reported in the literature. The genetic analysis revealed a novel homozygote deletion in exon 3 and 4 in HMGCL gene. HMG-CoA lyase deficiency should be thought in the patients with hypoketotic hypoglycemia, hyperammonemia, elevated liver function tests, noncompaction left ventricle and characteristic white matter changes and in the differential diagnosis of macrocephaly. PMID- 25708062 TI - Clinical Profile of Children with Malformations of Cortical Development. AB - OBJECTIVE: To elucidate the clinical-radiological profile of children with malformations of cortical development. METHODS: This observational study was conducted at a tertiary care child hospital of north India. Clinical-radiological data records were reviewed and assessment of children's functioning in five key areas of physical, adaptive behavior, social emotional, cognitive and communication was performed using Developmental Profile-3. RESULTS: Sixty-four cases of "Malformations of cortical development" were studied. The commonest malformations were lissencephaly (14/64), agyria-pachygyria (14/64) and schizencephaly (14/64). Focal cortical dysplasia (n = 12), hemimegalencephaly (n = 4), polymicrogyria (n = 3) and heterotopias (n = 3) were the other malformations seen. On Developmental Profile-3, 90 % children had developmental delay. CONCLUSIONS: The present study provides important data on the pattern of malformations of cortical development seen in a tertiary care hospital. It emphasizes that all children with developmental delay and seizures should be evaluated with magnetic resonance imaging. PMID- 25708063 TI - Medical photography: current technology, evolving issues and legal perspectives. AB - Medical photographic image capture and data management has undergone a rapid and compelling change in complexity over the last 20 years. This is because of multiple factors, including significant advances in ease of photograph capture, alongside an evolution of mechanisms of data portability/dissemination, combined with governmental focus on health information privacy. Literature to guide medical, legal, governmental and business professionals when dealing with issues related to medical photography is virtually nonexistent. Herein, we will address the breadth of uses of medical photography, device properties/specific devices utilised for image capture, methods of data transfer and dissemination and patient perceptions and attitudes regarding photography in a medical setting. In addition, we will address the legal implications, including legal precedent, copyright and privacy law, informed consent, protected health information and the Health Insurance Portability and Accountability Act (HIPAA), as they pertain to medical photography. PMID- 25708065 TI - Editorial overview: Cell regulation: when you think you know it all, there is another layer to be discovered. PMID- 25708064 TI - Meanings of knowledge and identity in public health nursing in a time of transition: interpretations of public health nurses' narratives. AB - BACKGROUND: A changing healthcare system affects the professional identity of nursing groups. Public health nursing has experienced challenges in balancing the paternalistic expert ideology and the empowerment participation ideology. A strong professional identity can legitimate nursing, and possibly influence the quality of nursing work. Narrations from practice can illuminate the nurses' theoretical and practical knowledge and help illustrate their collective professional identity. AIM: To illuminate the meaning of public health nursing knowledge and professional identity in a continuously changing public health nursing practice. METHOD: A qualitative interview study with a purposeful sample of 23 Norwegian public health nurses was carried out. Data were analysed using phenomenological hermeneutics, a descriptive method inspired by Ricoeur's philosophy of interpretation. FINDINGS: Three themes emerged (i) Being a generalist: emphasising the need for generalised knowledge and using clinical judgement, (ii) Being one who empowers: focusing on resources and coping strategies, (iii) Being occupied with individual problem solving: focusing on individuals with special needs, using standardised techniques and protocols, and lacking specialised knowledge. CONCLUSION: Interpretation of the nurses' stories illuminated their need for generalised evidence-based knowledge, but also the importance of using sound clinical judgement in a diverse complex practice, where service users need encouragement, support and expert advice. Time pressures can limit the nurses' involvement. Many had an individual problem-focus more than a primary prevention focus, in contrast to governmental regulations stating that Norwegian public health nurses should focus on health promotion and primary prevention. Public health nurses have a broad generalised knowledge of their special target group giving them a 'specialist generalist' role. Clarification of this role, in relation to jurisdictional borders, can create a strong identity at a time when healthcare policy promotes economic values, professional neutrality and increased collaboration. PMID- 25708066 TI - Diffusion-weighted MRI in the differential diagnosis of uterine endometrial cavity tumors. AB - BACKGROUND: This study aimed to investigate the efficacy of quantitative apparent diffusion coefficient (ADC) measurement in the differential diagnosis of the uterine endometrial cavity tumors (UECT). METHODS: This study included consecutive 36 female patients with UECT. The groups were formed as follows: group 1, patients with endometrial carcinoma; group 2, patients with endometrial polyp; group 3, patients with submucosal leiomyoma; and additionally group A, patients with malignant lesion; group B patients with benign lesion. Tumoral and outer myometrial ADC values were measured and the tumor-myometrium ADC ratios were calculated in all patients. Kolmogorov-Smirnov tests were used to test the normality of the data distributions. The data were not normally distributed, and therefore, nonparametric tests were performed. The cut-off values, sensitivity, and specificity were determined by the receiver operating characteristic analysis. RESULTS: The mean ADC value and ratio of group 1 were lower than that of group 2 and 3, and the mean ADC value and ratio of group 3 were lower than that of group 2. The sensitivity and specificity for group 1, 2, and 3 were as follows: 90, 100, and 66.7 %; and 81.8, 88, and 58.8 %, respectively, in terms of the ADC values; 90, 100 and 67 %; and 77.3, 96, and 64.7 % in terms of the ADC ratios. Statistically significant differences were demonstrated between group A and B in terms of mean tumoral ADC values and ratios. Sensitivity and specificity were found to be 90 and 81.8 %, respectively, in terms of the ADC values. The sensitivity and specificity were found to be 90 and 77.3 %, respectively, in terms of the ADC ratios. CONCLUSIONS: ADC values and ratios represent a promising parameter in the determination of the tumoral lesions in patients with UECT. PMID- 25708068 TI - Pocket-creation method for the safe, reliable, and efficient endoscopic submucosal dissection of colorectal lateral spreading tumors. PMID- 25708067 TI - Serum paraoxonase activity, total thiols levels, and oxidative status in patients with acute brucellosis. AB - It is well known that paraoxonase-1 (PON1) activity may decrease during the course of infection and inflammation. The aim of this study was to investigate serum PON1 activity, oxidative status, and thiols levels in patients with acute brucellosis. In addition, we investigated the PON1 phenotype in patients with acute brucellosis. Thirty patients with acute brucellosis and 35 healthy controls were enrolled. Serum paraoxonase and arylesterase activities, thiols levels, lipid hydroperoxide levels, total antioxidant capacity (TAC), total oxidant status (TOS) and oxidative stress index (OSI) were determined. Serum basal and salt-stimulated paraoxonase-arylesterase activities, TAC levels and thiols levels were significantly lower in patients with acute brucellosis than controls (for all, p < 0.05), while LOOH levels, TOS levels, and OSI values were significantly higher (for all, p < 0.05). We concluded that oxidative stress is increased, while serum PON1 activity is decreased in patients with acute brucellosis. These results indicate that lower PON1 activity is associated with oxidant-antioxidant imbalance. PMID- 25708069 TI - Introduction: Preterm birth. PMID- 25708070 TI - Preterm birth: An overview of risk factors and obstetrical management. AB - Preterm birth is the leading cause of neonatal mortality and a major public health concern. Risk factors for preterm birth include a history of preterm birth, short cervix, infection, short interpregnancy interval, smoking, and African-American race. The use of progesterone therapy to treat mothers at risk for preterm delivery is becoming more widespread. Tocolytics may not prevent preterm birth but have a role in prolonging pregnancy for administration of medications to benefit the preterm infant. These include antenatal steroids and, if indicated, magnesium sulfate for neuroprotection and intravenous antibiotics for Group B Streptococcus prophylaxis. PMID- 25708071 TI - Advancing evidence in preterm neonatal medicine. AB - Few interventions and treatments for premature infants have undergone the rigors of a randomized controlled trial (RCT), the cornerstone of evidence-based healthcare. Multiple barriers in establishing a quality evidence base for the care of preterm infants are examined including the systematic exclusion of children from drug trials, vulnerability of the infants, burden to families of the consent process for RCTs, and the lack of standard measurements and subgroup definitions that impede systematic reviews. Delays in getting evidence into practice are highlighted, including clinician knowledge of existing evidence, attitudes about the evidence, and behavior. Landmark trials are used as examples. Finally, a call for the research community to develop guidance on good clinical research practice for preterm infants is offered that will allow the synthesis of the totality of evidence. PMID- 25708072 TI - Palliative care for extremely premature infants and their families. AB - Extremely premature infants face multiple acute and chronic life-threatening conditions. In addition, the treatments to ameliorate or cure these conditions often entail pain and discomfort. Integrating palliative care from the moment that extremely premature labor is diagnosed offers families and clinicians support through the process of defining goals of care and making decisions about life support. For both the extremely premature infant who dies soon after birth and the extremely premature infant who experiences multiple complications over weeks and months in the neonatal intensive care unit, palliative care can maintain a focus on infant comfort and family support. This article highlights the ways in which palliative care can be incorporated into intensive care for all critically ill infants. PMID- 25708074 TI - Kindergarten readiness after prematurity: Integrating health, development, and behavioral functioning to optimize educational outcomes of vulnerable children. AB - In the past 20 years, many advances (e.g., maternal steroids and surfactant) have changed the course of neonatal medicine. As a result, extremely preterm infants survive medical complications that were previously fatal. Once they are discharged from the neonatal intensive care unit, preterm infants may continue to experience a spectrum of medical and developmental challenges, and their families are faced with the potentially daunting task of nurturing a vulnerable child. Families may be referred to multiple systems of care, including primary care physicians, pediatric subspecialists, and early intervention services. The ultimate goal for preterm infants is to optimize their motor, communicative, social-emotional, and adaptive development as well as to promote their learning at home, at school, and in the community. As children transition to school, key indicators of their functional status include the amount of developmental, educational, habilitative, and behavioral supports they require to participate in learning activities with their peers. Success may be measured by whether preterm infants are ready for large-group learning with peers and the extent of supports required to make this important transition. The purpose of this review is to describe what is known about certain indicators of school readiness in preterm infants, including neurodevelopmental impairments, social-emotional skills, and social factors. We conclude with guidelines for using this transition as an important indicator of developmental trajectories that may help us to better understand risk and resilience in this vulnerable population of children. PMID- 25708073 TI - Pathogenesis, neuroimaging and management in children with cerebral palsy born preterm. AB - With advances in obstetric and perinatal management, the incidence of intraventricular hemorrhage in premature infants has declined, while periventricular leukomalacia remains a significant concern. It is now known that brain injury in children born preterm also involves neuronal-axonal disease in supratentorial and infratentorial structures. The developing brain is especially vulnerable to white matter (WM) injury from 23 to 34 weeks gestation when blood vessels serving the periventricular WM are immature. Oligodendrocyte progenitors, which are beginning to form myelin during this time, are susceptible to attack from oxygen free radicals, glutamate, and inflammatory cytokines. Advances in imaging techniques such as diffusion tensor imaging provide a more complete picture of the location and extent of injury. Effective management of children born preterm with cerebral palsy is predicated on an understanding of sequential links from etiological antecedents to brain neuropathology as revealed with neuroimaging techniques to clinical phenotypes, toward focused interventions with measurable outcomes. PMID- 25708075 TI - Preterm birth: Transition to adulthood. AB - Preterm birth is associated with greater difficulty with transitions from childhood to adolescence to adulthood. Adolescents and young adults born preterm have higher rates of cerebral palsy, intellectual disability, cognitive impairment, learning disability, executive dysfunction, attention deficit disorder, and social-emotional difficulties than their peers born fullterm. Compared to individuals born fullterm, more preterm survivors have major neurodevelopmental or psychiatric disability and need financial supports and societal resources. Neuroimaging studies of adolescents and adults born preterm report higher rates of brain injury, differences in regional brain structure, and different brain circuits than in those born fullterm. Making the transition to adulthood is more difficult for young adults who were born preterm than their peers born fullterm, in that fewer complete high school and higher education, find and keep meaningful employment, and live independently from their parents. As a group, they do not tend to be risk-takers, and they have lower rates of alcohol abuse, use of illicit drugs, and criminal offenses than do their peers. Despite their many challenges, the majority of adults born preterm function well, form personal relationships, integrate well into their community, and are as satisfied with their quality of life as are their peers. Concerns regarding current preterm infants, with more extremely preterm survivors, overwhelming our medical, educational, and societal resources should serve as an impetus for research on prevention of preterm births and brain injury, as well as how to support and promote their ongoing neuromaturation and recovery from injury. PMID- 25708076 TI - The wicked in court: a neuroscientific primer. AB - The criminal cases of Anders Breivik, the Norwegian shooter, and Bernard Madoff, the fraudulent American financier, are used as prominent examples of the complexity that courts have to explore when judging the severity and responsibility of felonies performed by different types of psychopaths. I outline the brain circuits subserving morally charged decisions in ordinary citizens and in patients with gross lesions in the same areas, along with singularities in these brain systems that have been detected in psychopaths. These neural signatures, combined with thorough neuropsychological examination, will hopefully improve the diagnoses and prognoses of criminals with dangerous psychopathic traits. In this respect, the profiles of incarcerated members of gangs are used to exemplify and distinguish among typical niches and varieties of psychopathy within criminal organizations. A discussion follows, presenting the complexities of novel research that is increasing the sophistication of these challenging but key intersections between neuroscience and law. PMID- 25708077 TI - Sacred values in the Israeli-Palestinian conflict: resistance to social influence, temporal discounting, and exit strategies. AB - Conflicts over sacred values may be particularly difficult to resolve. Because sacred values are nonfungible with material values, standard attempts to negotiate, such as offering material incentives to compromise, often backfire, increasing moral outrage and support for violent action. We present studies with Palestinians in the West Bank and Gaza demonstrating three other ways sacred values may make conflict more intractable, focusing on what we call devoted actors, people who regard issues central to the Israel-Palestine conflict as sacred values. We show that devoted actors (1) were less amenable to social influence, (2) perceived conflict-related events in the past as well as expected events in the future to be temporally closer, and (3) were blind to individual opportunities to escape the conflict. These results suggest that sacred values may affect decision making in a number of ways, which, when combined, contribute to common defense and continuation of conflict. PMID- 25708078 TI - The neuroimaging of sacred values. AB - Sacred (or protected) values (SVs) constitute core beliefs that define primary reference groups. There is significant research on SVs at a behavioral level, but their neural underpinnings are just beginning to be discovered. In this paper, we highlight the current state of neuroimaging research concerning SVs. Given that SVs are considered to be strongly motivated by moral principles, we first provide an outline of the neural circuits that have been found to be involved in moral cognition. We then review various neuroimaging studies that have explored the notion of SVs. Specifically, we concentrate on neuroimaging studies dealing with intergroup bias and those that focus on social norms, since these are two basic dimensions of SVs that have been studied with neuroimaging techniques. Finally, we review two studies that have directly addressed SVs with neuroimaging techniques, and we offer suggestions for further avenues of study. PMID- 25708079 TI - Their pain, our pleasure: stereotype content and schadenfreude. AB - People often fail to empathize with others, and sometimes even experience schadenfreude-pleasure at others' misfortunes. One potent predictor of schadenfreude is envy, which, according to the stereotype content model, is elicited by high-status, competitive targets. Here we review our recent research program investigating the relationships among stereotypes, envy, schadenfreude, and harm. Experiment 1 demonstrates that stereotypes are sufficient to influence affective responses to targets' misfortunes; participants not only report feeling less negative when misfortunes befall high-status, competitive targets as compared to other targets, they also smile more (assessed with facial EMG). Experiment 2 replicates the self-report findings from Experiment 1 and assesses behavioral tendencies toward envied targets; participants are more willing to endorse harming high-status, competitive targets as compared to other targets. Experiment 3 turns off the schadenfreude response by manipulating status and competition-relevant information regarding envied targets. Finally, Experiment 4 investigates affective and neural markers of intergroup envy and schadenfreude in the context of a long-standing sports rivalry and the extent to which neurophysiological correlates of schadenfreude are related to self-reported likelihood of harming rival team fans. We conclude with implications and future directions. PMID- 25708080 TI - Individualistic and social motives for justice judgments. AB - Justice judgments are subjective by nature, and are influenced substantially by motivational processes. In the present contribution, two motives underlying justice judgments are examined: individualistic motives to evaluate solutions to social problems that benefit the self in material or immaterial ways as fair versus social motives to conceptualize justice in terms of the well-being of others, such as a desire for equality, adherence to in-group norms, and a concern for the collective interest. A review of relevant research reveals evidence for both motivations when people make evaluations of justice. Moreover, which motive is most dominant in the justice judgment process depends on perceptual salience: whereas individualistic motives are activated when a perceiver's own needs and goals are perceptually salient, social motives are activated when others' needs and goals are perceptually salient. It is concluded that both individualistic and social motives contribute in predictable ways to justice judgments. PMID- 25708081 TI - The evolutionary roots of human collaboration: coordination and sharing of resources. AB - Humans' ability to collaborate to obtain otherwise inaccessible goals may be one main cause for our success as a species. Comparative psychological research with children and our closest primate relatives is starting to elucidate the phylogenetic roots as well as the unique psychological mechanisms that support our cooperative behavior. For mutually beneficial collaboration, individuals need (1) cognitive mechanisms to coordinate actions with partners and (2) mechanisms to distribute the acquired resources in a way that incentivizes partners to continue collaborating. Several recent studies suggest that we share with chimpanzees many of the cognitive mechanisms required for successful coordination: chimpanzees understand the need to act jointly with a partner, that is, recruiting the partner when the problem requires collaboration and even helping her to perform her role. However, in contrast to very young children, they do not seem well equipped to share resources obtained through joint effort. Chimpanzees' competitive nature around food constrains their sharing behavior, and because they do not share differently after individual or collaborative effort, partners lose motivation to continue collaborating. All this suggests that higher interindividual tolerance around food and mechanisms to counteract bullying behavior and share the spoils after a collaborative effort are probably derived human traits. PMID- 25708082 TI - Trust and cooperation: a new experimental approach. AB - Several theories within different disciplines emphasize the role of trust in fostering cooperation in human social life. Despite differences, the core of these notions of trust is affectively motivated loyalty, which makes the individuals feel mutually committed and willing to accept vulnerability because of positive expectations about each other's behavior. In evolutionary game theory and experimental economics, the notion of trust is much simpler: it is an expectation about another's behavior, a kind of wager, in which the sense of mutual commitment and vulnerability is completely absent. In order to extend the paradigm of trust games typical in those fields to explore the fuller sense of trust relationships, we have developed a new experimental design, in which an iterated prisoner dilemma is played by participants who do or do not hold a trusting personal relationship, while anonymity is preserved. We present here the results of our two pilot studies, which indicate the relevance of personal trust in fostering cooperation and suggest the influence of the structure of social networks on the degree of cooperation achieved. PMID- 25708083 TI - Cognitive mechanisms for the evolution of religious thought. AB - The reasons behind the cultural persistence of religious beliefs throughout human history and prehistory still generate unanswered questions requiring scientific explanations. Within the framework of the cognitive science of religion, this article reviews experimental evidence supporting human predisposition for religious thinking and focuses on the hypothesis that a reason why religious beliefs are successful is their minimal counterintuitiveness. According to this hypothesis, religious concepts or stories would be characterized by containing only a small number of world-knowledge violations, which attracts attention while improving memorizability. We conclude this review by summarizing recent findings from our group using brain electrical activity and delving further into these questions. Our research suggests parallels between the natural tendency of the human cognitive system to use metaphors and the minimal counterintuitiveness of religious beliefs. PMID- 25708084 TI - Neural reality and social convention: do they overlap? AB - Neural reality is part of nature, independent of our cultural agreements. Social conventions are part of culture and fictions created and sustained by our accords. The classical Greeks had already established a difference between physis (nature, reality) and nomos (norm, law). Pain, pleasure, emotion, and compassion belong to the first realm. Rights, duties, guilt, responsibility, and dignity are in the second. Do they overlap anywhere? Perhaps around the emotion of compassion, which is morally relevant but also neurologically real. We briefly consider the relation of compassion to mirror neurons and neuromodulators in the brain. When jumping from neurons to norms, we must beware of the naturalistic fallacy and the moralistic fallacy. PMID- 25708085 TI - Introduction to sociability, responsibility, and criminality: from lab to law. PMID- 25708086 TI - Skin response to epicutaneous application of anticoagulant rodenticide warfarin is characterized by differential time- and dose-dependent changes in cell activity. AB - CONTEXT: Skin is the target of both acute and chronic exposure to warfarin, coumarin anticoagulant. Single exposure of rat skin to this agent induces early (24 h following epicutaneous administration) local response which might be part of inflammatory/reparatory homeostatic program or introduction to pathological events in exposed skin. OBJECTIVE: To examine time-dependent changes in skin of rats exposed to epicutaneously applied warfarin. MATERIALS AND METHODS: The effect of low (10 MUg) and high (100 MUg) doses of warfarin on histologically evident changes of epidermis (epidermal thickness) and dermis (numbers of mesenchymal cells and dermal capillaries), skin cell proliferative activity (Ki67(+) and PCNA(+) cells) and apoptotic (TUNEL(+)) and necrotic (ultra structural appearance) cells was examined one, three and seven days after the application. RESULTS: Both warfarin doses affected the majority of skin cell activity, but with differential time-course of skin epidermal and dermal cells state/activity. The occurrence of necrotic/apoptotic epidermal and dermal cells was noted the first day after the application and the activities which point to tissue reparation/remodeling were observed seven days after skin exposure to this agent. DISCUSSION: The observed pattern of changes (early evidence of cell/tissue injury which was later followed by signs of cell activity characteristic for tissue reparation/remodeling) implied warfarin-induced toxicity in skin cells as stimulus for subsequent activities relevant for tissue homeostasis. CONCLUSION: The data presented provide new and additional information concerning skin responses to warfarin that gains access to this tissue. PMID- 25708087 TI - Systems Thinking Versus Population Thinking: Genotype Integration and Chromosomal Organization 1930s-1950s. AB - This article describes how empirical discoveries in the 1930s-1950s regarding population variation for chromosomal inversions affected Theodosius Dobzhansky and Richard Goldschmidt. A significant fraction of the empirical work I discuss was done by Dobzhansky and his coworkers; Goldschmidt was an astute interpreter, with strong and unusual commitments. I argue that both belong to a mechanistic tradition in genetics, concerned with the effects of chromosomal organization and systems on the inheritance patterns of species. Their different trajectories illustrate how scientists' commitments affect how they interpret new evidence and adjust to it. Dobzhansky was moved to revised views about selection, while Goldschmidt moved his attention to different genetic phenomena. However different, there are significant connections between the two that enrich our understanding of their views. I focus on two: the role of developmental considerations in Dobzhansky's thought and the role of neutrality and drift in Goldschmidt's evolutionary account. Dobzhansky's struggle with chromosomal variation is not solely about competing schools of thought within the selectionist camp, as insightfully articulated by John Beatty, but also a story of competition between selectionist thinking and developmental perspectives. In contraposition, Goldschmidt emphasized the role of low penetrance mutations that spread neutrally and pointed out that drift could result from developmental canalization. This account adds to the dominant story about Goldschmidt's resistance to the splitting of development from genetics, as told by Garland Allen and Michael Dietrich. The story I tell illustrates how developmental thinking and genetic thinking conflicted and influenced researchers with different convictions about the significance of chromosomal organization. PMID- 25708088 TI - Evidence for induction of humoral and cytotoxic immune responses against devil facial tumor disease cells in Tasmanian devils (Sarcophilus harrisii) immunized with killed cell preparations. AB - Tasmanian devils (Sarcophilus harrisii) risk extinction from a contagious cancer, devil facial tumour disease (DFTD) in which the infectious agent is the tumor cell itself. Because devils are unable to produce an immune response against the tumor cells no devil has survived 'infection'. To promote an immune response we immunized healthy devils with killed DFTD tumor cells in the presence of adjuvants. Immune responses, including cytotoxicity and antibody production, were detected in five of the six devils. The incorporation of adjuvants that act via toll like receptors may provide additional signals to break 'immunological ignorance'. One of these devils was protected against a challenge with viable DFTD cells. This was a short-term protection as re-challenge one year later resulted in tumor growth. These results suggest that Tasmanian devils can generate immune responses against DFTD cells. With further optimization of immune stimulation it should be possible to protect Tasmanian devils against DFTD with an injectable vaccine. PMID- 25708089 TI - PNImodeler: web server for inferring protein-binding nucleotides from sequence data. AB - BACKGROUND: Interactions between DNA and proteins are essential to many biological processes such as transcriptional regulation and DNA replication. With the increased availability of structures of protein-DNA complexes, several computational studies have been conducted to predict DNA binding sites in proteins. However, little attempt has been made to predict protein binding sites in DNA. RESULTS: From an extensive analysis of protein-DNA complexes, we identified powerful features of DNA and protein sequences which can be used in predicting protein binding sites in DNA sequences. We developed two support vector machine (SVM) models that predict protein binding nucleotides from DNA and/or protein sequences. One SVM model that used DNA sequence data alone achieved a sensitivity of 73.4%, a specificity of 64.8%, an accuracy of 68.9% and a correlation coefficient of 0.382 with a test dataset that was not used in training. Another SVM model that used both DNA and protein sequences achieved a sensitivity of 67.6%, a specificity of 74.3%, an accuracy of 71.4% and a correlation coefficient of 0.418. CONCLUSIONS: Predicting binding sites in double stranded DNAs is a more difficult task than predicting binding sites in single stranded molecules. Our study showed that protein binding sites in double stranded DNA molecules can be predicted with a comparable accuracy as those in single-stranded molecules. Our study also demonstrated that using both DNA and protein sequences resulted in a better prediction performance than using DNA sequence data alone. The SVM models and datasets constructed in this study are available at http://bclab.inha.ac.kr/pnimodeler. PMID- 25708090 TI - Antibiotic prescribing in medical intensive care units--a comparison between two private sector hospitals in Central India. AB - BACKGROUND: Inappropriate antibiotic prescribing, common in India, contributes to increased risk for development of bacterial resistance. Patients admitted to intensive care units (ICUs) are often prescribed antibiotics. Paucity of local data on antibiotic prescribing hinders development of appropriate interventions. The aim of the study was to describe and compare antibiotic prescribing in medical ICUs (MICUs) at two private sector hospitals, one teaching (TH) and one non-teaching (NTH) in Ujjain, India. METHODS: The study was conducted prospectively for 3 years at MICUs of both hospitals. Patients were compared for demographic variables and diagnosis, prescribed antibiotics, generic name prescribing, and route of administration. Adherence to the World Health Organization list of essential medicines (WHOLEM) and the National List of Essential Medicines of India (NLEMI) was analyzed. RESULTS: In total, 4843 of 6141 patients admitted to the MICUs stayed at least one night. More than 70% were prescribed antibiotics. Generic name prescribing was more common at the TH than at the NTH. Prescriptions at the TH had higher compliance to WHOLEM and NLEMI compared with that at the NTH (p < 0.001). Of the 1371 patients at the TH, 189 (14%) and of 3472 at the NTH, 400 (12%) patients were diagnosed with infections. More than 75% of patients at both hospitals had no infection-associated diagnoses. CONCLUSIONS: Antibiotic prescribing was common at both hospitals. The antibiotic prescriptions at the TH had higher compliance to WHOLEM and NLEMI. However, there is a need to develop appropriate interventions to improve antibiotic prescribing at both hospitals. PMID- 25708091 TI - Sacral insufficiency fractures: an underdiagnosed injury during childbirth? : A case report and review of literature. AB - Insufficiency fractures during pregnancy or childbirth are difficult to diagnose but holds high morbidity for a vulnerable patient group. In documenting the patient's pathway, diagnostic challenges and treatment options, it is hoped that pregnancy-related insufficiency fractures will be better diagnosed and treated. INTRODUCTION: Sacral insufficiency fractures are a poorly understood phenomenon, which poses diagnostic and therapeutic challenges. Peripartum females who suffer from transient osteoporosis of pregnancy have been shown in several reports to be at particular high risk of these fractures. METHOD: This case report details such a case and highlights some of the challenges that this condition presents. Furthermore, it draws on the current literature to offer options for improved techniques for diagnosis and up-to-date management for future practice. PMID- 25708092 TI - The effect of selective REM-sleep deprivation on the consolidation and affective evaluation of emotional memories. AB - Emotion boosts the consolidation of events in the declarative memory system. Rapid eye movement (REM) sleep is believed to foster the memory consolidation of emotional events. On the other hand, REM sleep is assumed to reduce the emotional tone of the memory. Here, we investigated the effect of selective REM-sleep deprivation, SWS deprivation, or wake on the affective evaluation and consolidation of emotional and neutral pictures. Prior to an 9-h retention interval, sixty-two healthy participants (23.5 +/- 2.5 years, 32 female, 30 male) learned and rated their affect to 80 neutral and 80 emotionally negative pictures. Despite rigorous deprivation of REM sleep or SWS, the residual sleep fostered the consolidation of neutral and negative pictures. Furthermore, emotional arousal helped to memorize the pictures. The better consolidation of negative pictures compared to neutral ones was most pronounced in the SWS deprived group where a normal amount of REM sleep was present. This emotional memory bias correlated with REM sleep only in the SWS-deprived group. Furthermore, emotional arousal to the pictures decreased over time, but neither sleep nor wake had any differential effect. Neither the comparison of the affective ratings (arousal, valence) during encoding and recognition, nor the affective ratings of the recognized targets and rejected distractors supported the hypothesis that REM sleep dampens the emotional reaction to remembered stimuli. The data suggest that REM sleep fosters the consolidation of emotional memories but has no effect on the affective evaluation of the remembered contents. PMID- 25708093 TI - [Basic lung ultrasound. Part 2. Parenchymal diseases]. AB - In this second part, an analysis is made of the pathology of lung parenchyma. This text is structured into different sections, including the study of atelectasias, pneumonia and abscess, interstitial/alveolar or Blines patterns, and finally an analysis is made of pulmonary embolism. With this second part, the basic knowledge to develop lung ultrasound in the anesthesia department has been presented. PMID- 25708094 TI - Multiple applications of ion chromatography oligosaccharide fingerprint profiles to solve a variety of sugar and sugar-biofuel industry problems. AB - Sugar crops contain a broad variety of carbohydrates used for human consumption and the production of biofuels and bioproducts. Ion chromatography with integrated pulsed amperometric detection (IC-IPAD) can be used to simultaneously detect mono-, di-, and oligosaccharides, oligosaccharide isomers, mannitol, and ethanol in complex matrices from sugar crops. By utilizing a strong NaOH/NaOAc gradient method over 45 min, oligosaccharides of at least 2-12 dp can be detected. Fingerprint IC oligosaccharide profiles are extremely selective, sensitive, and reliable and can detect deterioration product metabolites from as low as 100 colony-forming units/mL lactic acid bacteria. The IC fingerprints can also be used to (i) monitor freeze deterioration, (ii) optimize harvesting methods and cut-to-crush times, (iii) differentiate between white refined sugar from sugar cane and from sugar beets, (iv) verify the activities of carbohydrate enzymes, (v) select yeasts for ethanol fermentations, and (vi) isolate and diagnose infections and processing problems in sugar factories. PMID- 25708095 TI - Network tuned multiple rank aggregation and applications to gene ranking. AB - With the development of various high throughput technologies and analysis methods, researchers can study different aspects of a biological phenomenon simultaneously or one aspect repeatedly with different experimental techniques and analysis methods. The output from each study is a rank list of components of interest. Aggregation of the rank lists of components, such as proteins, genes and single nucleotide variants (SNV), produced by these experiments has been proven to be helpful in both filtering the noise and bringing forth a more complete understanding of the biological problems. Current available rank aggregation methods do not consider the network information that has been observed to provide vital contributions in many data integration studies. We developed network tuned rank aggregation methods incorporating network information and demonstrated its superior performance over aggregation methods without network information. PMID- 25708096 TI - Stent under-expansion on the procedure day, a predictive factor for poor oral intake after metallic stenting for gastric outlet obstruction. AB - BACKGROUND AND AIM: Self-expandable metallic stents (SEMS) have been widely accepted as palliation therapy for malignant gastric outlet obstruction (GOO). However, the factors predictive of poor oral intake after SEMS placement have not been elucidated sufficiently. We aimed to clarify both the patient and stent related predictive factors. METHODS: We retrospectively reviewed 126 consecutive patients who underwent uncovered SEMS placement for malignant GOO between April 2010 and March 2013 at a university hospital and two tertiary care referral centers. RESULTS: Technical success of SEMS placement was achieved in all 126 (100%) patients. Improved oral intake was observed in 111 (88.1%) patients. A Karnofsky performance status <= 40 (odds ratio [OR], 1.19; 95% confidence interval [CI], 1.02-1.28; P = 0.041), peritoneal dissemination (OR, 1.20; 95% CI, 1.01-1.26; P = 0.038), and under-expansion of the SEMS on the procedure day (OR, 1.55; 95% CI, 1.26-1.62; P < 0.001) were independent predictive factors for poor improvement on the GOO scoring system, according to multivariate analysis. CONCLUSIONS: SEMS under-expansion was a stent related, while poor performance status and peritoneal dissemination were patient related, predictive factors for poor oral intake after SEMS placement for malignant GOO. PMID- 25708098 TI - Corrigendum: The role of drug transporters in the kidney: lessons from tenofovir. AB - [This corrects the article on p. 248 in vol. 5, PMID: 25426075.]. PMID- 25708097 TI - Temperature-controlled bidirectional enantioselectivity in a dynamic catalyst for asymmetric hydrogenation. AB - Asymmetric catalysis using enantiomerically pure catalysts is one of the most widely used methods for the preparation of enantiomerically pure compounds. The separate synthesis of both enantiomerically pure compounds requires tedious and time-consuming preparation of both enantiomerically pure catalysts or chiral separation of the racemic products. Here, we report a stereochemically flexible diastereomeric rhodium(I) catalyst for asymmetric hydrogenations of prochiral (Z) alpha-acetamidocinnamates and alpha-substituted acrylates, which changes its enantioselectivity depending on the temperature to produce each enantiomerically pure compound in high yield with constant high enantioselectivity over time. The same axially chiral rhodium(I) catalyst produces (R)-phenylalanine derivatives in enantiomeric ratios of up to 87:13 (R/S) at low temperature and up to 3:97 (R/S) of the corresponding S enantiomers after re-equilibration of the same catalyst at elevated temperature. PMID- 25708099 TI - A microelectromechanical systems-enabled, miniature triple quadrupole mass spectrometer. AB - Miniaturized mass spectrometers are becoming increasingly capable, enabling the development of many novel field and laboratory applications. However, to date, triple quadrupole tandem mass spectrometers, the workhorses of quantitative analysis, have not been significantly reduced in size. Here, the basis of a field deployable triple quadrupole is described. The key development is a highly miniaturized ion optical assembly in which a sequence of six microengineered components is employed to generate ions at atmospheric pressure, provide a vacuum interface, effect ion guiding, and perform fragmentation and mass analysis. Despite its small dimensions, the collision cell efficiently fragments precursor ions and yields product ion spectra that are very similar to those recorded using conventional instruments. The miniature triple quadrupole has been used to detect thiabendazole, a common pesticide, in apples at a level of 10 ng/g. PMID- 25708100 TI - Duplex kidney: not just a drooping lily. AB - INTRODUCTION: Duplex kidneys are common, mostly asymptomatic and of no clinical significance. However, they can be associated with significant pathology, often with long-term morbidity. There is minimal literature on the review of the duplex kidney, its associated anomalies and complications. The purpose of this paper is to review our experience of imaging the spectrum of abnormalities associated with duplex kidneys in the paediatric population and correlate this with contemporary literature. METHOD: A retrospective review of the radiology database in a tertiary paediatric centre was performed. A word search of the Radiology Information System for 'duplex' of patients under the age of 16 was undertaken and limited to studies performed between 2006 and 2013. RESULTS: Two hundred seventy-four patients were identified (age range 0-16, median 3 years, gender 59.9% female) who had 836 studies: ultrasound 598/836 (71.6%), nuclear medicine 180/836 (21.5%), micturating cystourethrogram 52/836 (6.2%), MRI 5/836 (<1%) and CT scan 1/836 (<1%). Patients were categorised as duplex and no complication (151/274 = 55.1%), upper moiety obstruction, lower moiety reflux/scarring, multicystic dysplastic kidney, abnormal ureteric insertion and other pathology. CONCLUSION: Duplex kidneys are common and often not clinically significant. However, this study demonstrates almost 50% of paediatric patients investigated for duplex kidneys had complications requiring treatment. The most common complications were upper moiety obstruction associated with a ureterocele and lower moiety vesicoureteric reflux. Ultrasound was the most common modality for early detection of these complications. PMID- 25708101 TI - Association with HLA-DRB1 in Egyptian and German pemphigus vulgaris patients. PMID- 25708102 TI - An infant with large fontanelles, aplasia cutis congenita, tessier facial cleft, polydactyly inversus, and toe syndactyly: a previously undescribed syndrome? AB - We report on a 5-month-old female with large and widely spaced anterior and posterior fontanelles, aplasia cutis congenita, Tessier 3 oblique facial cleft, polydactyly, and syndactyly of toes. The polydactyly is unusual as an accessory finger is attached to the left fifth finger with mirrored, end-to-end fusion. We are naming this anomaly "polydactyly inversus." The infant appears to have a previously unreported syndrome of unknown cause. PMID- 25708104 TI - Self-assembling triazolophanes: from croissants through donuts to spherical vesicles. AB - Macrocyclic compounds M1-M3 with different ring sizes containing amide and triazole units were synthesized. These triazolophanes displayed a variety of self assembled structures such as hemi-toroids, toroids, and vesicles in a concentration dependent manner. Detailed ultramicroscopic and crystallographic investigations delineated a hierarchical mechanism of self-assembly. PMID- 25708103 TI - Are the osseous and tendinous-cartilaginous tibial tuberosity-trochlear groove distances the same on CT and MRI? AB - OBJECTIVE: To verify whether the tibial tuberosity-trochlear groove distance (TT TG) and the tendinous-cartilaginous TT-TG (the distance between the patellar tendon and trochlear groove: PT-TG) are identical using computed tomography (CT) and magnetic resonance imaging (MRI) techniques. SUBJECTS AND METHODS: The TT-TG and PT-TG distances were measured on the same knee samples by three observers (two measurements per observer) using CT and MRI scans collected retrospectively. The reproducibility of the measurements was assessed using the interclass correlation coefficient (ICC). The means and standard deviations of four measurements were calculated for each patient. A paired t-test was used to assess differences between measurements. RESULTS: Fifty knee samples (32 with patellar instability and 18 with other conditions) were evaluated. The inter- and intraobserver reliability was excellent for all four measurements (>0.8). On average, the TT-TG distance on MRI was 3.1-3.6 mm smaller than that on CT, and the PT-TG distance on MRI was 1.0-3.4 mm larger than the TT-TG distance on MRI. CONCLUSION: The osseous TT-TG and tendinous-cartilaginous PT-TG distances determined by CT and MRI were not identical. PMID- 25708105 TI - Identification of absorbed constituents and metabolites in rat plasma after oral administration of Shen-Song-Yang-Xin using ultra-performance liquid chromatography combined with quadrupole time-of-flight mass spectrometry. AB - In this study, a rapid and sensitive method by ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry, and Metabolynx(TM) software with mass defect filter technique was developed for screening and identification of the metabolites in rat plasma after oral administration of Shen-Song-Yang-Xin capsule (SSYX). A total of 92 SSYX-related xenobiotics were identified or characterized, including 45 prototypes and 47 metabolites. The results indicated that the absorbed constituents and metabolites mainly came from benzocyclooctadiene lignans, tanshinones, isoquinoline alkaloids and triterpenic acids, while phase I reactions (e.g. hydrogenation, hydroxylation, demethylation) and phase II reaction (glucuronidation) were the main metabolic pathways of these ingredients in SSYX. This is the first study on metabolic profiling of SSYX in rat plasma after oral administration. Furthermore, these findings provide useful information on the potential bioactive compounds, and enhance our understanding of the action mechanism of SSYX. PMID- 25708106 TI - Gene therapy for primary immunodeficiencies. AB - Gene therapy has effectively entered Medicine via the field of primary immunodeficiencies (PID). Because hematopoietic stem cells are accessible and because it was understood that genetic correction of lymphocyte progenitor cells carrying a genetic defect impairing differentiation, could result in the production of long-lived T lymphocytes, it was reasoned that ex vivo gene transfer in hematopoietic cells could lead to disease phenotype correction. Retroviral vectors were designed to ex vivo transduce such cells. This has indeed been shown to lead to sustained correction of the T cell immunodeficiency associated with two forms of severe combined immunodeficiencies (SCID) for now more than ten years. Occurrence in some patients of genotoxicity related to retroviral vectors integration close to and transactivation of oncogenes has led to the development of retroviral vectors devoid of its enhancer element. Results of recent trials performed for several forms of PID indeed suggest that their use is both safe and efficacious. It is thus anticipated that their application to the treatment of many more life threatening PID will be developed over the coming years. PMID- 25708107 TI - Cardiovascular and metabolic risk markers are related to parasympathetic indices in pre-pubertal adolescents. AB - OBJECTIVE: To analyse the relationship between different heart rate variability indices, resting heart rate, and cardiovascular markers in adolescents. METHODS: A cross-sectional study was carried out with information from an ongoing cohort study. The sample was composed of 99 adolescents who complied with the following inclusion criteria: aged between 11 and 14 years; enrolled in a school unit of elementary education; absence of any known diseases; no drug consumption; and a formal consent signed by the parents or legal guardians. Weight, height, heart rate variability, lipid profile, inflammatory markers, blood pressure, resting heart rate, intima-media thickness, blood flow, and trunk fatness were measured. Partial correlation and linear regression (expressed by beta and 95% confidence intervals [95%CI]) analyses were used to analyse the relationships between the variables. RESULTS: In the linear regression analysis, even after adjustments for sex, age, trunk fatness, and somatic maturation, parasympathetic activity presented significant correlations with maximum carotid artery blood flow (beta= 0.111 [95%CI=-0.216; -0.007]), systolic blood pressure (beta=-0.319 [95%CI= 0.638; -0.001]), and resting heat rate (beta=-0.005 [95%CI=-0.009; -0.002]). CONCLUSION: Parasympathetic activity at rest is inversely related to maximum and minimum blood flow, triacylglycerol levels, and systolic blood pressure. These findings suggest that heart rate variability has the potential to discriminate pre-pubertal adolescents at increased risk. PMID- 25708108 TI - The extraction debate. PMID- 25708109 TI - Protocols for combining the Beneslider with lingual appliances in Class II treatment. PMID- 25708110 TI - Extraction treatment, part 1: the extraction vs. nonextraction debate. PMID- 25708111 TI - 2014 JCO Study of Orthodontic Diagnosis and Treatment Procedures, part 3: breakdowns by prescription appliance use. PMID- 25708112 TI - Mandibular arch retraction with retromolar skeletal anchorage in a Class III open bite patient. PMID- 25708113 TI - Clinical evaluation of a new bonded space maintainer. PMID- 25708114 TI - A modified lingual arch for correction of posterior crossbite. PMID- 25708115 TI - Investigating the utility of clinical outcome-guided mutual information network in network-based Cox regression. AB - BACKGROUND: Network-based approaches have recently gained considerable popularity in high- dimensional regression settings. For example, the Cox regression model is widely used in expression analysis to predict the survival of patients. However, as the number of genes becomes substantially larger than the number of samples, the traditional Cox or L2-regularized Cox models are still prone to noise and produce unreliable estimations of regression coefficients. A recent approach called the network-based Cox (Net-Cox) model attempts to resolve this issue by incorporating prior gene network information into the Cox regression. The Net-Cox model has shown to outperform the models that do not use this network information. RESULTS: In this study, we demonstrate an alternative network construction method for the outcome-guided gene interaction network, and we investigate its utility in survival analysis using Net-Cox regression as compared with conventional networks, such as co-expression or static networks obtained from the existing knowledgebase. Our network edges consist of gene pairs that are significantly associated with the clinical outcome. We measure the strength of this association using mutual information between the gene pair and the clinical outcome. We applied this approach to ovarian cancer patients' data in The Cancer Genome Atlas (TCGA) and compared the predictive performance of the proposed approach with those that use other types of networks. CONCLUSIONS: We found that the alternative outcome-guided mutual information network further improved the prediction power of the network-based Cox regression. We expect that a modification of the network regularization term in the Net-Cox model could further improve its prediction power because the properties of our network edges are not optimally reflected in its current form. PMID- 25708116 TI - 'We have to discuss it': cancer patients' advance care planning impressions following educational information about cardiopulmonary resuscitation. AB - OBJECTIVE: Most cancer patients desire information about care options at the end of life, including cardiopulmonary resuscitation (CPR). Communicating such care options can be challenging and is part of advance care planning (ACP). Our prior studies with video educational media produced data on patients' categoric preferences (yes/no/unsure) for CPR; however, the thematic underpinnings of these educated preferences in patients treated for advanced cancer aren't well known. METHODS: Qualitative thematic content analysis of participants' responses in a randomized trial of an educational video (V) or narrative (N) about CPR in patients with advanced gastrointestinal cancers. Responses were independently coded and categorized for thematic content by two reviewers. RESULTS: Of 54 study participants, 26 total (41% of V arm, 56% of N arm) articulated questions, comments, or both. Reviewer analyses demonstrated thematic consensus and resulted in seven distinct themes listed in decreasing order of prevalence: (a) ACP should be started early; (b) educational information about CPR affirmed participants' existing beliefs/knowledge/values about advanced illness; (c) participants were apprehensive about ACP but wanted to discuss it; (d) gaps in knowledge about ACP emerged; (e) CPR information was helpful/acceptable; (f) physicians should be involved in ACP; and (g) medical questions about critical illness arose. CONCLUSIONS: Findings identified that while sometimes difficult to discuss, advance care planning is desired, deemed helpful, and ideally begun early by clinicians, and that video education is an appropriate and affirming initiator of discussions. These themes are incorporated into our ongoing research on cancer patient-specific values and education about care options. PMID- 25708117 TI - Olive oil phenolic extract regulates interleukin-8 expression by transcriptional and posttranscriptional mechanisms in Caco-2 cells. AB - In this study, we investigated the ability of a phenolic extract from extra virgin olive oil (OPE) to modulate the inflammatory response in intestinal epithelial cells. Undifferentiated and differentiated Caco-2 cells were challenged with LPS (50 MUg/mL) or IL-1beta (5 ng/mL) to mimic the early and intermediate phase of intestinal inflammation, respectively. The effects of OPE on nuclear factor-kappaB-driven transcription and IL-8 promoter activity were evaluated in transfection assays, coupled to p65 nuclear translocation. Modulation of IL-8 mRNA levels by OPE was measured by quantitative RT-PCR while effects on protein levels by ELISA. Specific mitogen activated protein kinases inhibitors were used to investigate mRNA stability and the involvement of related signaling pathways. OPE prevented IL-8 expression and secretion in LPS-treated Caco-2 cells. In the presence of IL-1beta OPE exhibited opposing effects on IL-8 gene transcription and mRNA/protein levels. While in IL-1beta-treated cells IL-8 promoter activity was inhibited by treatment with OPE, IL-8 mRNA stability was strongly enhanced, leading to increased protein expression. Inhibitors of p38 and extracellular signal-regulated kinases partly prevented OPE effect on IL-8 mRNA levels. Intestinal epithelial cells represent a direct target of the action of olive oil phenols where they regulate IL-8 expression by transcriptional and posttranscriptional mechanisms. PMID- 25708119 TI - Disease heterogeneity and risk stratification in sepsis-related occult hypoperfusion: A retrospective cohort study. AB - PURPOSE: Occult hypoperfusion is associated with increased mortality in patients with sepsis. We sought to determine the practice patterns and outcomes of patients with sepsis-related occult hypoperfusion and introduce a potential method for risk stratification. MATERIALS AND METHODS: Single-center retrospective study of normotensive patients presenting to an urban tertiary care emergency department with lactate greater than or equal to 4 mmol/L and suspected infection. chi(2) Testing, Spearman, and Wilcoxon coefficients were used to compare binary, parametric, and nonparametric data, respectively. Patients were divided into 4 groups based on lactate clearance (<4 mmol/L) and the presence of respiratory distress while in the emergency department; outcomes were compared using chi(2) test and analysis of variance. RESULTS: Median initial lactate was 4.7 mmol/L (interquartile range, 4.2-6.4), and 34 (45.2%) of 73 exhibited respiratory distress. Hyperlactatemia resolved in 67.1% (49/73) of patients. Mortality was 23.3% (17/73), and 19.1% (14/73) required vasopressors. In patients with lactate clearance and without respiratory distress (n = 27), mortality was 0%, and none required vasopressors. In patients with persistent hyperlactatemia and/or respiratory distress (n = 46), 30.4% required vasopressors, and the mortality was 37.0% (P < .01 and P < .01, respectively). CONCLUSIONS: Patients defined as having occult hypoperfusion comprise a heterogeneous group with a varied degree of illness severity. Identifying those with low risk of clinical deterioration may be important for titration of care. PMID- 25708120 TI - Risk factors for postoperative delirium in patients after coronary artery bypass grafting: A prospective cohort study. AB - PURPOSE: This study was designed to identify the incidence and independent perioperative risk factors associated with postoperative delirium of patients who underwent coronary artery bypass grafting (CABG) in a large intensive care unit setting in China. METHODS: Delirium was diagnosed by the confusion assessment method for the intensive care unit (CAM-ICU). Baseline demographics, perioperative data, and postoperative outcomes of 249 consecutive patients who underwent CABG were recorded prospectively and analyzed via univariate analysis and multivariate logistic regression to determine the independent risk factors of postoperative delirium. RESULTS: Postoperative delirium was detected in 76 patients according to CAM-ICU criteria. The incidence was 30.52%. Patients with and without delirium differed significantly on 34 variables (P < .05). Multivariate logistic regression analysis revealed that preoperative atrial fibrillation (odds ratio [OR], 3.957; 95% confidence interval [CI], 1.727-9.066), elevated European system for cardiac operative risk evaluation (OR, 1.178; 95% CI, 1.018-1.364), cognitive impairment (OR, 3.231; 95% CI, 1.008-10.356), prolonged surgery duration (OR, 1.008; 95% CI, 1.003-1.014), postoperative poor quality of sleep (OR, 5.001; 95% CI, 2.476-10.101), and electrolyte disturbance (OR, 2.095; 95% CI, 1.041-4.216) were independently associated with postoperative delirium after CABG. CONCLUSIONS: Delirium is a frequent complication. Factors independently associated with delirium are preoperative atrial fibrillation, elevated European system for cardiac operative risk evaluation and cognitive impairment, longer surgery duration, postoperative poor quality of sleep, and electrolyte disturbance. The study may be helpful in decreasing the incidence of postoperative delirium after CABG by treating these predictors properly. PMID- 25708121 TI - An Increase in Forearm Cortical Bone Size After Menopause May Influence the Estimated Bone Mineral Loss--A 28-Year Prospective Observational Study. AB - Areal bone mineral density (aBMD) is the most common estimate of bone mass, incorporated in the World Health Organization definition of osteoporosis. However, aBMD depends on not only the amount of mineral but also the bone size. The estimated postmenopausal decline in aBMD could because of this be influenced by changes in bone size.We measured bone mineral content (BMC; mg), aBMD (mg/cm2), and bone width (mm) by single-photon absorptiometry at the cortical site of the forearm in a population-based sample of 105 Caucasian women. We conducted 12 measurements during a 28-yr period from mean 5 yr (range: 2-9) before menopause to mean 24 yr (range: 18-28) after menopause. We calculated individual slopes for changes in the periods before menopause, 0-<8, 8-<16, and 16-28 yr after menopause. Data are presented as means with 95% confidence intervals. The annual BMC changes in the 4 periods were -1.4% (-0.1, -2.6), -1.1% (-0.9, -1.4), -1.2% (-0.9, -1.6), and -1.1% (-0.8, -1.4) and the annual increase in bone width 0.4% (-1.2, 1.9), 0.7% (0.5, 0.9), 0.1% (-0.2, 0.4), and 0.1% ( 0.2, 0.4). BMC loss was similar in all periods, whereas the increase in bone width was higher in the first postmenopausal period than in the second (p=0.003) and the third (p=0.01) postmenopausal periods. Menopause is followed by a transient increase in forearm bone size that will influence the by aBMD estimated cortical loss in bone minerals. PMID- 25708122 TI - Quantitative Assessment of Abdominal Aortic Calcifications Using Lateral Lumbar Radiograph, Dual-Energy X-ray Absorptiometry, and Quantitative Computed Tomography of the Spine. AB - Abdominal aortic calcifications (AACs) represent an independent determinant of cardiovascular events and are strongly associated with cardiovascular disease. To our knowledge, a comparison between lateral lumbar radiography, lateral spine dual-energy x-ray absorptiometry (DXA), and quantitative computed tomography (QCT) in the assessment of AAC has not been performed. Our objective was to compare those methods in the detection and quantification of AAC using a simplified 8-point score system (AAC-8). Three hundred twenty-three postmenopausal women underwent lateral lumbar radiography, lateral spine DXA, and QCT for osteoporosis screening and were scored for AAC using the AAC-8. Lateral lumbar radiographs, lateral spine DXA, and QCT detected AAC in 58%, 55%, and 60% of the subjects, respectively. The nonparametric intraclass correlation coefficient between lateral lumbar radiograph and lateral spine DXA and lateral lumbar radiograph and QCT were 0.699 (95% confidence interval [CI]: 0.638-0.752) and 0.829 (95% CI: 0.783-0.865). Area under operating curve (receiver operating characteristic [ROC]) for lateral spine DXA was 0.826 (95% CI: 0.764-0.888), whereas for QCT was 0.948 (95% CI: 0.922-0.974) considering lateral lumbar radiograph as gold standard. AAC has been shown to be a significant predictive marker of overall cardiovascular disease. DXA may be a screening tool among asymptomatic patients with low radiation exposure to identify an important cardiovascular disease risk factor. QCT represents a reliable technique that may be applied as a future standard to facilitate the detection of abdominal aortic calcification as well as to provide more accurate measurement of bone densitometry. PMID- 25708123 TI - Characterization of patients' requests and pharmacists' professional practice in oropharyngeal condition in Spain. AB - BACKGROUND: A sore throat is the reason behind 4 million visits to health care services per year in Spain. The management of these ailments is usually associated with an inappropriate use of medicines. Community pharmacists are often the first point of contact for patients under the healthcare system and play a major role in the management of minor ailments. OBJECTIVE: To characterize the pharmacists' professional practice in oropharyngeal condition in terms of patients' requests and pharmacists' interventions performed. SETTING: Community pharmacies throughout Spanish territory. METHOD: Cross-sectional multicenter observational study, undertaken between November 2012 and March 2013. Patients were recruited consecutively in the participant pharmacies. Eligible patients were those making a consultation related to an oropharyngeal condition or requesting treatment for an oropharyngeal condition. A univariate descriptive analysis showing the frequency of occurrence of the different variables was performed. This was completed with a multivariate statistical analysis through a multiple correspondence method, in order to analyze the potential association between the pharmacist profile and the intervention provided. MAIN OUTCOME MEASURE: Professional Pharmacy Service requested (dispensing/counselling/medication review with follow-up), reason for consultation, source of the recommendation, Pharmacist's intervention and reason for referral. RESULTS: 710 pharmacies and 3,547 patients participated in the study. The most frequently requested service was dispensing (44.7 %), followed by counselling (31.8 %). Regarding dispensing, the majority of patients requested a throat preparation, mostly antiseptics. Symptoms associated with the pharmacy consultation were mainly throat symptoms (70.8 %), voice symptoms (24.9 %), and mouth/tongue/lip symptoms (10.1 %). The most common pharmacist intervention was "selection of pharmacological treatment", followed by "dispensing the requested medicine"; 6.51 % of the patients were referred to a general practitioner, mainly due to fever and other symptoms associated with infection. No relationship between the pharmacist profile and the intervention performed was found. CONCLUSION: The most frequently requested professional service was the dispensing service, mainly for treating throat symptoms. Community pharmacists play a major role in managing patients with an oropharyngeal condition. They can keep them out of general practice or act as referral agents when a more severe disease is identified. PMID- 25708124 TI - The influence of patients' knowledge on adherence to their chronic medications: a cross-sectional study in Jordan. AB - BACKGROUND: Non-adherence to long-term therapy for chronic illnesses is considered the major reason why patients fail to reach their clinical goals, resulting in suboptimal health outcomes, death, and extra costs on the health care systems. Knowledge about the disease and prescription medications, an understanding of the reason the medication is needed, and good expectations or attitudes toward treatment, all contribute to a better medication-taking behavior and are associated with higher rates of adherence. OBJECTIVE: This study examines the relationship between knowledge and adherence of patients receiving long-term therapy for one or more chronic illnesses in Jordan. SETTINGS: The study was conducted in the out-patient clinics of two Jordanian hospitals (The University of Jordan Hospital and Jordan Hospital). METHODS: This was a cross-sectional study that included 902 patients. The correlation between patients' knowledge about their chronic medications and adherence was assessed. Effects of several sociodemographic characteristics were investigated in regard to knowledge and adherence. MAIN OUTCOME MEASURES: Knowledge was assessed by a modified version of the McPherson index, and the Morisky Medication Adherence Scale was used to assess medication adherence. RESULTS: A significant correlation was found between patients' knowledge and their adherence to medications (r = 0.357, p < 0.001). Most of the participants had low adherence. Younger age, higher education levels, high income, fewer medications and diseases were significant predictors of higher knowledge levels. Knowledgeable patients were found to be twice as likely to have moderate-to-high adherence as their unknowledgeable counterparts. Similarly, high income and higher education were associated with higher adherence scores. CONCLUSION: Forgetfulness and aversion toward medications were the most common barriers to medication adherence. This implicates that clinicians and health care policy makers should direct their effort toward two main strategies to improve adherence increasing awareness and education of effective ways to remind patients about their medications. PMID- 25708125 TI - Successful induction of oestrus, ovulation and pregnancy in adult ewes and ewe lambs out of the breeding season using a GnRH+progesterone oestrus synchronisation protocol. AB - A series of experiments was designed to assess the effect of a treatment protocol (U-synch) for inducing oestrus and ovulation out of the breeding season in adult ewes and ewe lambs. The protocol consisted of a 7-day treatment with an intravaginal progesterone-releasing device (IPRD), administration of GnRH at IPRD insertion on Day 0, and equine chorionic gonadotropin (eCG) and prostaglandin F2alpha at IPRD removal on Day 7. In Experiment 1, 50 or 100 MUg GnRH were sufficient to induce ovulation at the beginning of the protocol in 3/9 and 4/9 ewes, respectively; while the resulting proportion of sheep ovulating after the treatment protocol was 88.9% and 77.8% in ewes initially treated with 50 or 100 MUg GnRH, respectively. In Experiment 2, the proportion of Romney-cross ewe lambs ovulating was greater (P<0.0001) in the U-synch group (95.4%) than in the untreated Control group (3.2%). In Experiment 3, pregnancy rates of Dorset-cross sheep in the U-synch (60.7%) and Standard (12-day IPRD and eCG treatment; 56.5%) groups were greater (P=0.01) than in the untreated Control group (43.4%). The incidence of twin pregnancies was greater (P=0.005) in the U-synch group than in the Control group. A 7-day IPRD treatment including GnRH treatment at device insertion and eCG treatment at device removal induced oestrus and ovulation during the non-breeding season in a high proportion of mature ewes and ewe lambs. High pregnancy rates to natural mating, with a low rate of triplet pregnancies, were also observed. PMID- 25708127 TI - Unique stereocontrol in carborane chemistry: skeletal alkylcarbonation (SAC) versus exoskeletal alkylmethylation (EAM) reactions. AB - Reactions between the arachno-6,9-C2B8H14 (1) dicarbaborane and acyl chlorides, RCOCl (2), are subject to stereocontrol that completely changes the nature of the reaction products. While most chlorides produce the 8-R-nido-7,8,9-C3B8H11 (3) tricarbollides (by skeletal alkylcarbonation=SAC), bulky RCOCls (2; where R=1 adamantyl, 2 a; 1-mesityl, 2 b; 9-anthranyl, 2 c; 1-naphthyl, 2 d) in 1,2 dichloroethane (DCE) in the presence of triethylamine at 40-60 degrees C gave a series of entirely different 1-R-2-CH3-closo-1,6-C2B8H8 (4) dicarbaboranes upon acidification with conc. H2SO4 (by exosleletal alkylmehylation=EAM). Both types of reactions seem to proceed via a common [8-R-nido-7,8,9-C3B8H10](-) (3(-)) anion which in the EAM case is unstable because of steric crowd and undergoes rearrangement via the isomeric [R-nido-7,8,10-C3B8H10](-) tricarbollide structures which, on protonation, undergo reductive extraction of one CH vertex to generate the 2-CH3 substituent in structure 4. PMID- 25708126 TI - Development of a conceptual model to illustrate the impact of multiple myeloma and its treatment on health-related quality of life. AB - PURPOSE: Little qualitative research exploring the impact of multiple myeloma (MM) and its treatment on the health-related quality of life (HRQL) of patients has been published. This study aimed to explore the burden of MM symptoms and treatment and the impact of these on HRQL. A model was developed to illustrate key concepts and their interrelationships. METHODS: Patients with MM were recruited to this cross-sectional, qualitative study through a patient panel and at two clinical sites in the USA. An interview discussion guide was developed using a review of published literature and interviews with experienced MM clinicians. In-depth, semistructured telephone interviews with MM patients were conducted to explore their experiences of the disease and its treatment. Data were analyzed using a thematic analysis approach. RESULTS: Twenty MM patients at various stages of treatment participated in open-ended, semistructured interviews. Patients reported both current and previous MM symptoms; most had experienced fatigue and pain. Other commonly reported symptoms were fractures, anemia, neuropathy, aches, and infections. MM treatment was found to have a negative impact on patients' HRQL; treatment-related adverse events included fatigue, neuropathy, insomnia, and gastrointestinal symptoms. MM treatment placed a substantial psychological and physical burden on patients, disrupting social activities, decreasing independence, and impacting on relationships. A model was developed to illustrate the relationship between these concepts. CONCLUSION: The conceptual model developed in this study illustrates the many aspects of MM and its treatment and how they can have a negative impact on patients' HRQL. PMID- 25708128 TI - One-pot multi-component synthesis of 1,4-dihydropyridines using Zn(2+) @KSF and evaluating their antibacterial and antioxidant activities. AB - New 5-aryl-10-(4-(4-methoxyphenyl)thiazole-2-yl)-9,10-dihydropyrido[2,3-d:5,6 d']dipyrimidinone-2,4,6,8-(1H,3H,5H,7H)-tetraones 6a-d were synthesized through one-pot four-component reaction of aldehydes, barbituric acid, and thiazole using Zn(2+) @KSF under reflux condition. The key features of this reaction are: incorporating four heterocyclic rings, using a heterogeneous and efficient catalyst, high yield, and easy-to-setup reaction. The structure of the products was confirmed by FT-IR, (1)H NMR, and (13)C NMR spectra. The antibacterial activities of compounds 6a-d were screened against Escherichia coli, Micrococcus luteus, Pseudomonas aeruginosa, and Staphylococcus aureus bacterial strains using the zone inhibition method. Also, the 2,2-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activities of compounds 6a-d were evaluated. All compounds showed good antioxidant capacity in comparison to ascorbic acid. The IC50 values of the antioxidant activity were calculated. The proposed mechanism for antioxidant activity is discussed. PMID- 25708129 TI - Tuning into single-band red upconversion luminescence in Yb(3+)/Ho(3+) activated nano-glass-ceramics through Ce(3+) doping. AB - Yb(3+)/Ho(3+) activated glass ceramics containing beta-YF3 nanocrystals were successfully fabricated. The green ((5)S2/(5)F4->(5)I8) upconversion emission is dominant in the glass ceramics and is about 160 times stronger than that of the precursor glass, resulting from the partition of lanthanide activators into a low phonon-energy crystalline lattice and the subsequent low probability of multi phonon nonradiative relaxation from the (5)S2/(5)F4 and (5)I6 states to the lower ones. Upon the introduction of Ce(3+) ions into nano-glass-ceramics, two efficient cross-relaxation processes between Ho(3+) and Ce(3+), i.e., Ho(3+):(5)S2/(5)F4 + Ce(3+):(2)F5/2->Ho(3+):(5)F5 + Ce(3+):(2)F7/2 and Ho(3+):(5)I6 + Ce(3+):(2)F5/2->Ho(3+):(5)I7 + Ce(3+):(2)F7/2, are demonstrated to greatly suppress the population of the green-emitting (5)S2/(5)F4 state and to enhance the population of the red-emitting (5)F5 one, leading to the intense single-band red UC radiation of Ho(3+). PMID- 25708130 TI - Left ventricular assist device thrombosis in the setting of left ventricular recovery. PMID- 25708131 TI - Chronic pelvic pain syndrome: reduction of medication use after pelvic floor physical therapy with an internal myofascial trigger point wand. AB - This study documents the voluntary reduction in medication use in patients with refractory chronic pelvic pain syndrome utilizing a protocol of pelvic floor myofascial trigger point release with an FDA approved internal trigger point wand and paradoxical relaxation therapy. Self-referred patients were enrolled in a 6 day training clinic from October, 2008 to May, 2011 and followed the protocol for 6 months. Medication usage and symptom scores on a 1-10 scale (10 = most severe) were collected at baseline, and 1 and 6 months. All changes in medication use were at the patient's discretion. Changes in medication use were assessed by McNemar's test in both complete case and modified intention to treat (mITT) analyses. 374 out of 396 patients met inclusion criteria; 79.7 % were male, median age of 43 years and median symptom duration of 5 years. In the complete case analysis, the percent of patients using medications at baseline was 63.6 %. After 6 months of treatment the percentage was 40.1 %, a 36.9 % reduction (p < 0.001). In the mITT analysis, there was a 22.7 % overall reduction from baseline (p < 0.001). Medication cessation at 6 months was significantly associated with a reduction in total symptoms (p = 0.03). PMID- 25708132 TI - Medium-term outcomes of bovine jugular vein graft and homograft conduits in children. AB - BACKGROUND: The bovine jugular vein (Contegra) conduit has been described as an alternative to the homograft for right ventricle (RV) to pulmonary artery (PA) connection. We assessed the outcomes of Contegra conduits and homografts at a single institution. METHODS: We conducted a retrospective review of children (n = 249) who underwent RV-to-PA conduit (Contegra or homograft) implantation from 2001 to 2011. RESULTS: Median operation age was 4.8 years (2 days-18 years). Indications for surgery were as follows: primary conduit insertion (n = 131; 53%), previous conduit failure (n = 57; 23%) or Ross procedure (n = 61; 25%). There were 113 (45%) Contegra conduits and 136 (55%) homografts (92 pulmonary, 44 aortic) inserted. Early mortality was 5% (n = 12). Overall survival was 89% (95% confidence interval (CI): 84-92%) at 5 years and 87% (95% CI: 81-92%) at 10 years. Mortality was associated with smaller conduit size (P = 0.044) and syndrome diagnosis (P = 0.012). Freedom from reoperation was 85% (95% CI: 77-91%) and 75% (95% CI: 59-86%) at 5 years for homografts and Contegra conduits, respectively. Patients required conduit replacement (15%) for endocarditis (n = 4; 11%) or graft failure (n = 34; 89%). Eleven patients developed distal conduit stenosis with the majority occurring in Contegra conduits (n = 7; 64%) (P = 0.004). A larger conduit (P = 0.007) was protective against reoperation. There was no difference in reoperation between conduits (P = 0.41). Mean follow-up was 5 +/- 3.2 years (96% complete). Majority of survivors (99%) were in New York Heart Association Class II/I. CONCLUSION: The Contegra conduit and homograft demonstrate similar mid-term outcomes in children. Smaller conduit size is associated with higher graft failure and mortality. PMID- 25708133 TI - Prevalence and risk factors for biopsy-proven non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in a prospective cohort of adult patients with gallstones. AB - BACKGROUND & AIMS: Relationship between gallstones and non-alcoholic fatty liver disease (NAFLD), and largely non-alcoholic steatohepatitis (NASH), is uncertain. AIM: To determine the prevalence, non-invasive fibrosis markers profile and risk factors for biopsy-proven NAFLD and NASH among patients with gallstones. METHODS: Anthropometric and laboratory evaluation, an abdominal ultrasound and a liver biopsy were performed to 215 consecutive patients with gallstones referred for cholecystectomy. RESULTS: Prevalence of NASH was 10.2% whereas that of simple steatosis (SS) was 41.4%. In the cohort of NAFLD patients, negative predictive values for advanced fibrosis of FIB-4 and NAFLD fibrosis score were 96 and 95% respectively. Gallstone patients with NASH had a higher mean homeostatic model assessment (HOMA) score than those with SS (P = 0.015). Noteworthy, NASH was 2.5 fold more frequent in patients with gallstones who had metabolic syndrome than in those who did not (P < 0.001). Fatty liver on ultrasound was observed in 90.9% of gallstone patients with NASH compared with 61.8% of those with SS (P = 0.044). Using multivariate logistic regression, increased HOMA score (OR, 3.47; 95% CI, 1.41-8.52; P = 0.007) and fatty liver on ultrasound (OR, 23.27; 95% CI, 4.15 130.55; P < 0.001) were the only factors independently associated with NASH. CONCLUSIONS: Prevalence of NASH among patients with gallstones is lower than estimated previously, but NASH is frequent particularly in those patients with concurrent metabolic syndrome. The combination of an increased HOMA score with fatty liver on ultrasound has a good accuracy for predicting NASH in patients with gallstones. PMID- 25708134 TI - Resolution of carotid stenosis pre-carotid intervention: A case for selective preoperative duplex ultrasound. AB - INTRODUCTION: Spontaneous resolution of carotid stenosis is a phenomenon that has been described in literature in the past. At present it is not routine practise to scan patients prior to carotid endarterectomy surgery within the UK. PRESENTATION OF CASE: A 58 year old female presented to hospital with a history of sudden onset headache and left sided weakness. CT head showed findings in keeping with an acute right MCA territory infarct. A duplex ultrasound scan showed echolucent material in the right internal carotid artery forming a greater than 95% stenosis. The scan was unable to visualise the patency of the vessel distally due to the position of the mandible. The patient was provisionally listed for carotid endarterectomy. An MRA was requested prior to surgery to assess the patency of the distal internal carotid artery. The MRA of the carotids showed normal appearance of the common carotid, internal and vertebral arteries with no definite stenosis. A repeat duplex ultrasound confirmed there was no significant stenosis. DISCUSSION: The finding of complete resolution of stenosis on MRA was an unexpected event. Had the initial duplex imaging allowed visualisation of the distal vessel patency, our patient would have undergone unnecessary carotid surgery with the associated morbidity and mortality. CONCLUSION: This case report draws attention to the benefits of selective preoperative scanning, in sparing patients from unnecessary surgery as a result of finding occlusion or resolution of a previously diagnosed carotid stenosis. PMID- 25708135 TI - Primary mucinous adenocarcinoma of the scalp: A case report and literature review. AB - INTRODUCTION: Primary mucinous adenocarcinoma or mucinous eccrine carcinoma of the skin is a rare malignant neoplasm showing predilection to the head and neck. Distinguishing between these primary neoplasms and the more frequent metastatic mucinous deposits on the skin from primaries in the breast and gastrointestinal tract constitutes a diagnostic dilemma. PRESENTATION OF CASE: We report a case of a 61-year-old lady who presented with a slow-growing, painless scalp nodule. Upon excision, it was diagnosed as "primary mucinous adenocarcinoma". An extensive work-up in search for another primary tumour failed to show a primary malignancy elsewhere and the diagnosis of a primary eccrine mucinous adenocarcinoma of the skin was rendered. DISCUSSION: A review of the literature on this entity is presented, discussing diagnostic challenges and therapeutic options that of interest to surgeons, pathologists and dermatologists. CONCLUSION: These tumours are indolent and low-grade, with a tendency for local, sometimes multiple, recurrences. Proper patient counselling and follow-up are important in treatment. Sound collaboration between clinicians and pathologists, for good therapeutic results, is of utmost importance. PMID- 25708136 TI - Introduction to British Association of Spinal Surgeons special supplement of The Spine Journal. PMID- 25708137 TI - The rape of the spine. PMID- 25708138 TI - British Association of Spinal Surgeons/British Scoliosis Society President's Travelling Fellowship report 2014. PMID- 25708139 TI - British Association of Spine Surgeons standards of care for cauda equina syndrome. AB - This group of articles looks at the BASS guidelines for CES. TG and AC gave us the background on the long journey taken in publishing this, SA summarized the forum discussion on the BASS Web site, and NT gave us a medicolegal comment. The guidelines are concise, highlighting the need for prompt MRI scanning and as a consequence emergency surgery in appropriate cases. This has resource implication in terms of MRI availability and a comprehensive spinal on-call system. The question of whether operating "in the small hours" carries increased risk or whether we are using this as an excuse not to get out of bed needs to be addressed. CES discs tend to be more difficult than standard ones and probably associated with a higher complication rate. Literature on complications from night-time trauma surgery has considerably reduced out-of-hour operating in trauma. Guidelines on CES will allow the spinal community to prospectively collect data on a national registry which in time will allow us to further improve our understanding and treatment of this condition. Spinal surgery is quickly evolving into a separate specialty. These guidelines further highlight the need for a single spinal society to help set standards, educate, and revalidate our members. It is important that we all engage in this debate to get a consensus opinion to improve spinal practice across the United Kingdom. PMID- 25708140 TI - Definitions, diagnosis, and decompression in spinal surgery: problems and solution. PMID- 25708141 TI - A paper which influenced my practice, and the importance of peer review. PMID- 25708142 TI - Visceral obesity, body mass index and risk of complications after colon cancer resection: A retrospective cohort study. AB - BACKGROUND: The aim of our study was to assess the influence of visceral obesity (VO), as measured by preoperative abdominal CT scan, in relation to body mass index (BMI) on the incidence of postoperative complications and duration of hospital stay after colon cancer surgery. METHODS: Patients who underwent elective resection for colon cancer between January 1, 2006, and December 31, 2013, and had a preoperative CT scan were entered in the study. Visceral fat area (VFA) was determined by using the preoperative CT scan at the L3-L4 level. The effect of VO, defined as a VFA of >100 cm2, on postoperative complications and duration of hospital stay was analyzed. RESULTS: Of 564 included patients, 65% had VO. VO was associated with more anastomotic leakage (P = .04), pneumonia (P = .02), wound infection (P = .03), reoperations (P = .04), and longer duration of hospital stay (P = .05). Of patients with a BMI < 25 kg/m2, 44% had VO. In this group, VO was associated significantly with postoperative complications, cardiac (P < .01) and pulmonary (P = .01) comorbidity, hypertension (P < .01), and diabetes (P < .01). In the overweight (BMI 25-30 kg/m2) and obese (BMI > 30 kg/m2) groups, the rate of VO was much higher (81% and 90%, respectively), but was not associated significantly with complications or comorbidity, except for cardiac comorbidity (P < .02) in the BMI = 25-30 kg/m2 group. After multivariable analysis, VO was shown to be an independent predictor of anastomotic leakage and wound infection. CONCLUSION: The association of VO with worse outcome after colon cancer surgery is most pronounced in patients with a BMI < 25 kg/m2. PMID- 25708143 TI - Tools for identifying gelator scaffolds and solvents. AB - Small molecule gelators are serendipitously discovered more often than they are designed. As a consequence, it has been challenging to develop applications based on the limited set of known materials. This synopsis highlights recent strategies to streamline the process of gelator discovery, with a focus on the role of unidirectional intermolecular interactions and solvation. We present these strategies as a series of tools that can be employed to help identify gelator scaffolds and solvents for gel formation. Overall, we suggest that this guided approach is more efficient than random derivatization and screening. PMID- 25708144 TI - Recent advances in histogenesis research of lung neuroendocrine cancers: Evidence obtained from functional analyses of primitive neural/neuroendocrine cell specific transcription factors. AB - Small cell carcinoma (SmCC) and large cell neuroendocrine carcinoma (LENEC) are categorized as neuroendocrine cancers (NECs) of the lung and have extremely poor prognoses. The lack of an effective therapeutic strategy against SmCC and LCNEC is a serious issue. Because the regulation of the cellular phenotype is complicated by the actions of various transcription factors, investigations into the function of neural/neuroendocrine cell-specific transcription factors are important for elucidating the cellular characteristics and histogenesis of SmCC and LCNEC and for establishing innovative therapeutic strategies against them. In this review, the functions of ASCL1, NeuroD1, REST, TTF1, and class III/IV POU, that are specifically and highly expressed in lung NECs, are introduced. These transcription factors transactivate and/or transrepress various genes and are involved in neural progenitor phenotyping, neuroendocrine and stem cell marker expression, and epithelial-to-mesenchymal transition. Based on the evidence that certain carcinoids express ASCL1, NeuroD1, TTF1, and class III/IV POU and that lung NECs can develop from non-NE cells/non-NEC cells, the relationships among lung NECs, carcinoid tumors, and non-NECs are discussed. Finally, a model of the histogenesis of lung NECs in view of similarities in the expression of primitive neural/neuroendocrine cell-specific transcription factors is proposed. PMID- 25708145 TI - On the packing density of the unbound protein-protein interaction interface and its implications in dynamics. AB - BACKGROUND: Characterizing the interface residues will help shed light on protein protein interactions, which are involved in many important biological processes. Many studies focus on characterizing sequence or structure features of protein interfaces, but there are few studies characterizing the dynamics of interfaces. Therefore, we would like to know whether there is any specific dynamics pattern in the protein-protein interaction interfaces. Thermal fluctuation is an important dynamical property for a residue, and could be quickly estimated by local packing density without large computation since studies have showen closely relationship between these two properties. Therefore, we divided surface of an unbound subunit (free protein subunits before they are involved in forming the protein complexes) into several separate regions, and compared their average thermal fluctuations of different regions in order to characterize the dynamics pattern in unbound protein-protein interaction interfaces. RESULTS: We used weighted contact numbers (WCN), a parameter-free method to quantify packing density, to estimate the thermal fluctuations of residues in the interfaces. By analyzing the WCN distributions of interfaces in unbound subunits from 1394 non homologous protein complexes, we show that the residues in the central regions of interfaces have higher packing density (i.e. more rigid); on the other hand, residues surrounding the central regions have smaller packing density (i.e. more flexible). The distinct distributions of packing density, suggesting distinct thermal fluctuation, reveals specific dynamics pattern in the interface of unbound protein subunits. CONCLUSIONS: We found general trend that the unbound protein-protein interaction interfaces consist of rigid residues in the central regions, which are surrounded by flexible residues. This finding suggests that the dynamics might be one of the important features for the formation of protein complexes. PMID- 25708147 TI - Brief Report: Ultrasonographic Assessment of Salivary Gland Response to Rituximab in Primary Sjogren's Syndrome. AB - OBJECTIVE: To evaluate changes in salivary gland echostructure and vascularization after rituximab treatment in patients with primary Sjogren's syndrome (SS). METHODS: Twenty-eight patients with primary SS included in the multicenter, randomized, double-blind, placebo-controlled Tolerance and Efficacy of Rituximab in Primary Sjogren's Syndrome (TEARS) trial underwent salivary gland ultrasonography before the first placebo or rituximab infusion and then 6 months later. Trial inclusion criteria were scores of >=50 mm on at least 2 of 4 visual analog scales (VAS) evaluating dryness, pain, fatigue, and global disease; and recent-onset (<10 years) biologically active primary SS and/or systemic primary SS. Patients were randomly assigned (1:1) to rituximab (1 gm at weeks 0 and 2) or placebo. Ultrasonography of both parotid and submandibular glands was performed to assess echostructure (using a semiquantitative score of 0-4, with improvement defined as a >=1-point decrease), size of each gland, and vascularization based on the resistive index of the transverse facial artery of the parotid gland before and after lemon juice stimulation. RESULTS: Of the 28 patients, 5 (18%; 3 in the placebo group and 2 in the rituximab group) had clinically detectable bilateral parotid gland enlargement at baseline. Parotid parenchyma echostructure improved in 50% of the rituximab-treated patients versus 7% of the placebo treated patients (P = 0.03). In the submandibular glands, echostructure also improved in a larger proportion of rituximab-treated patients, although the difference was not significant (36% versus 7% of placebo-treated patients; P = 0.16). Gland sizes and resistive index remained unchanged. CONCLUSION: Ultrasonography showed improved salivary gland echostructure in patients with primary SS receiving rituximab, with no changes in salivary gland size or vascularization, 6 months after the first infusion. PMID- 25708146 TI - Atypical hemolytic-uremic syndrome: a case report and literature review. AB - BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is a rare disease characterized by hemolysis, thrombocytopenia, and renal dysfunction. It is a disease related to genetic mutations in the alternative complement pathway and has a distinct pathophysiology but is difficult to differentiate from other thrombotic microangiopathies. CASE REPORT: We present a case of a 59-year-old female patient who presented with accelerated hypertension, acute renal failure, hemolysis, and encephalopathy. She was managed with antihypertensive medication, but her encephalopathy did not improve. Evaluation resulted in our impression of the disease being atypical hemolytic-uremic syndrome. The patient continued to be managed with good blood pressure control and later was started on eculizumab, but evaluation of response to therapy was hindered by the patient's non-compliance with therapy and follow-up appointments. CONCLUSIONS: We have a very limited understanding of the genetics and epidemiology of atypical HUS, and the overlapping clinical features sometimes delay diagnosis and initiation of appropriate treatment of this rare disease. PMID- 25708148 TI - Four central questions about prediction in language processing. AB - The notion that prediction is a fundamental principle of human information processing has been en vogue over recent years. The investigation of language processing may be particularly illuminating for testing this claim. Linguists traditionally have argued prediction plays only a minor role during language understanding because of the vast possibilities available to the language user as each word is encountered. In the present review I consider four central questions of anticipatory language processing: Why (i.e. what is the function of prediction in language processing)? What (i.e. what are the cues used to predict up-coming linguistic information and what type of representations are predicted)? How (what mechanisms are involved in predictive language processing and what is the role of possible mediating factors such as working memory)? When (i.e. do individuals always predict up-coming input during language processing)? I propose that prediction occurs via a set of diverse PACS (production-, association-, combinatorial-, and simulation-based prediction) mechanisms which are minimally required for a comprehensive account of predictive language processing. Models of anticipatory language processing must be revised to take multiple mechanisms, mediating factors, and situational context into account. Finally, I conjecture that the evidence considered here is consistent with the notion that prediction is an important aspect but not a fundamental principle of language processing. This article is part of a Special Issue entitled SI: Prediction and Attention. PMID- 25708149 TI - Transcriptional upregulation of myelin components in spontaneous myelin basic protein-deficient mice. AB - Myelin is essential for efficient signal transduction in the nervous system comprising of multiple proteins. The intricacies of the regulation of the formation of myelin, and its components, are not fully understood. Here, we describe the characterization of a novel myelin basic protein (Mbp) mutant mouse, mbp(jive), which spontaneously occurred in our mouse colony. These mice displayed the onset of a shaking gait before 3 weeks of age and seizure onset before 2 months of age. Due to a progressive increase of seizure intensity, mbp(jive) mice experienced premature lethality at around 3 months of age. Mbp mRNA transcript or protein was undetectable and, accordingly, genetic analysis demonstrated a homozygous loss of exons 3 to 6 of Mbp. Peripheral nerve conductance was mostly unimpaired. Additionally, we observed grave structural changes in white matter predominant structures were detected by T1, T2 and diffusion weighted magnetic resonance imaging. We additionally observed that Mbp-deficiency results in an upregulation of Qkl, Mag and Cnp, suggestive of a regulatory feedback mechanism whereby compensatory increases in Qkl have downstream effects on Mag and Cnp. Further research will clarify the role and specifications of this myelin feedback loop, as well as determine its potential role in therapeutic strategies for demyelinating disorders. PMID- 25708150 TI - OGD induced modification of FAK- and PYK2-coupled pathways in organotypic hippocampal slice cultures. AB - Focal adhesion kinase (FAK) and proline-rich tyrosine kinase (PYK2) are two related non-receptor tyrosine kinases which are thought to play a role in transducing extracellular matrix (ECM)-derived survival signals into cells. The functions of FAK and PYK2 are linked to autophosphorylation of their specific tyrosine residues, Tyr-397 in FAK and Tyr-402 in PYK2, and then association with different signalling proteins which mediate activation of downstream targets such as ERK and JNK mitogen-activated kinase cascades. Thus, modulation of FAK as well as PYK2 autophosphorylation may affect several intracellular pathways and may participate in a variety of pathological settings. The present study provides a systematic investigation of the influence of experimental ischemia, induced by oxygen-glucose-deprivation, on the FAK- and PYK2-mediated signalling in organotypic hippocampal slice cultures. OGD induced primary down-regulation of FAK and PYK2 autophosphorylation (at Tyr 397 and Tyr 402, respectively) at 24-48 h of reoxygenation was accompanied by the diminution of phosphorylation/activation of Src and JNK. In contrast, the activity of Akt and ERK1/2 remained on the control level. It indicates that Akt kinase as well as ERK1/2 does not interfere with OGD-induced neuronal damage. The inhibition of the early step of FAK and PYK2 activation demonstrated by the decrease of tyrosine autophosphorylation may comprise an important portion of the response expressed by modulation of some coupled signal transduction pathways. PMID- 25708151 TI - Novel application method of talcum powder to prevent sticking tendency and modify release of esomeprazole magnesium enteric-coated pellets. AB - Actually, reflecting drug release from polymer-coated pellets remains a challenge. In this study, sticking of pellets caused by Eudragit(r)L30D-55 was observed during the release process, leading to change in drug release. Talcum powder (talc) was used in esomeprazole magnesium pellets to prevent sticking and modify release of pellets. Three methods including talc incorporated in enteric layer, physically mixed and coating resulted pellets were employed to prevent the sticking. The release of pellets was modified by addition talc into subcoat. The dispersion coefficient (Fd) and release profiles were determined in phosphate buffer solution (pH 6.8 and 6.0) and distilled water. It was found that the first manner made Fd increase to about 0.75, but the latter two methods could completely prevent sticking. Also, the second manner was more simple and readily scaled up. In addition, talc in subcoat significantly slowed the drug release in water, but the slowing release effect is less pronounced at pH 6.0 and 6.8. These different effects of talc were attributed to a different release mechanism in three media. The release profiles in water were fitted to Nuttanan model, and the K designated as "diffusive resistance constant" was linearly increased with talc levels in subcoat (R(2)=0.9874). PMID- 25708152 TI - Effect of pepsin on maintaining the supersaturation of the HCl salt of a weakly basic drug: a case study. AB - The impact of pepsin on the maintenance of supersaturated solution of the HCl salt of a weakly basic drug was evaluated in simulated gastric fluid by monitoring the drug solubility in the absence and presence of pepsin. In the presence of pepsin, the HCl salt maintained its apparent solubility through 24 h, whereas, no such solubility advantage was seen in the absence of pepsin. Consequently, a minimum inhibitory concentration of pepsin is required for maintenance of supersaturation. In addition, NMR study seems to indicate a molecular level interaction between pepsin and HCl salt leading to a weak binding between the two. Therefore, for the HCl salts of weak bases having disproportionation potential, it is preferred that preformulation solubility studies are conducted in the presence of pepsin to reflect their in vivo behavior in maintaining supersaturation solubility. PMID- 25708153 TI - e-Rheumatology: are we ready? AB - Advances in technology led to a heightened interest in exploring the use of this technology in the standard rheumatology practice. Tech-Talks will enable the information at the patients' and rheumatologists' fingertips. As e-rheumatology is an idea whose time has come, this review outlines the e-health's developments and its impact on both the patients and the treating rheumatologists. Also it will discuss the strengths and weaknesses of using apps and mobile health in the day-to-day rheumatology service as well as the ethical and financial aspects of this model of care. PMID- 25708154 TI - Intra-tumour 18F-FDG uptake heterogeneity decreases the reliability on target volume definition with positron emission tomography/computed tomography imaging. AB - INTRODUCTION: This study aims to explore whether the intra-tumour (18) F fluorodeoxyglucose (FDG) uptake heterogeneity affects the reliability of target volume definition with FDG positron emission tomography/computed tomography (PET/CT) imaging for nonsmall cell lung cancer (NSCLC) and squamous cell oesophageal cancer (SCEC). METHODS: Patients with NSCLC (n = 50) or SCEC (n = 50) who received (18)F-FDG PET/CT scanning before treatments were included in this retrospective study. Intra-tumour FDG uptake heterogeneity was assessed by visual scoring, the coefficient of variation (COV) of the standardised uptake value (SUV) and the image texture feature (entropy). Tumour volumes (gross tumour volume (GTV)) were delineated on the CT images (GTV(CT)), the fused PET/CT images (GTV(PET-CT)) and the PET images, using a threshold at 40% SUV(max) (GTV(PET40%)) or the SUV cut-off value of 2.5 (GTV(PET2.5)). The correlation between the FDG uptake heterogeneity parameters and the differences in tumour volumes among GTV(CT), GTV(PET-CT), GTV(PET40%) and GTV(PET2.5) was analysed. RESULTS: For both NSCLC and SCEC, obvious correlations were found between uptake heterogeneity, SUV or tumour volumes. Three types of heterogeneity parameters were consistent and closely related to each other. Substantial differences between the four methods of GTV definition were found. The differences between the GTV correlated significantly with PET heterogeneity defined with the visual score, the COV or the textural feature-entropy for NSCLC and SCEC. CONCLUSIONS: In tumours with a high FDG uptake heterogeneity, a larger GTV delineation difference was found. Advance image segmentation algorithms dealing with tracer uptake heterogeneity should be incorporated into the treatment planning system. PMID- 25708155 TI - A Cross-Sectional Study Comparing the Frequency of Drug Interactions After Adding Simeprevir- or Sofosbuvir-Containing Therapy to Medication Profiles of Hepatitis C Monoinfected Patients. AB - INTRODUCTION: This study compares the expected occurrence of contraindicated drug drug interactions (XDDIs) when simeprevir (SIM)- or sofosbuvir (SOF)-containing therapy is added to medication profiles of patients with hepatitis C (HCV) monoinfection to quantify, in relative terms, the population-based risk of XDDIs. Second, this study identified the predictors of XDDIs when HCV therapies are added to medication profiles. METHODS: A cross-sectional study was performed among Veterans' Affairs patients. Inclusion criteria were: (1) age >=18 years, (2) HCV infection, and (3) availability of a medication list. Patients with human immunodeficiency virus were excluded. Demographics, comorbidities, year of HCV diagnosis, and most recent medication list were collected from medical records. The primary outcome was the presence of XDDIs involving HCV therapy and the medications in the patient's home medication list after the addition of either SIM- or SOF-containing regimens. To define XDDIs, Lexi-Interact drug interaction software was used. RESULTS: 4,251 patients were included. The prevalence of XDDIs involving SIM- or SOF-containing therapy were 12.6% and 4.7% (p < 0.001), respectively. In multivariable analyses examining the predictors of XDDIs involving SIM-containing therapy, the only medication-related predictor was use of >=6 home medications (odds ratio OR 4.58, 95% confidence interval CI 3.54 5.20, p < 0.001). Similarly, use of >=6 home medications was also the only variable associated with an increased probability of XDDI involving SOF containing therapy (OR 3.83, 95% CI 2.57-5.70, p < 0.001). CONCLUSIONS: Sofosbuvir-containing therapy had a lower frequency of XDDIs than SIM-containing therapy. Polypharmacy with various classes of home medications predicted XDDIs involving SIM- or SOF-containing therapy. PMID- 25708156 TI - Tedizolid Phosphate: a Next-Generation Oxazolidinone. AB - Treatment of multidrug-resistant Gram-positive infections continues to challenge clinicians as the emergence of new resistance mechanisms outpaces introduction of novel antimicrobial agents. Tedizolid phosphate is a next-generation oxazolidinone with activity against both methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus spp. Tedizolid has consistently shown potency advantages over linezolid against Gram-positive microorganisms including those with reduced susceptibility to linezolid. Of particular significance, minimum inhibitory concentrations of tedizolid appear to be largely unaffected by the chloramphenicol-florfenicol resistance (cfr) gene, which has been implicated in a number of published linezolid-resistant organism outbreaks. Tedizolid phosphate also has been found to have a favorable pharmacokinetic profile allowing for once-daily dosing in both oral and intravenous forms. Potency and pharmacokinetic advantages have allowed for lower total daily doses of tedizolid, compared to linezolid, being needed for clinical efficacy in the treatment of acute bacterial skin and skin structure infections (ABSSSI). The decreased total drug exposure produced may in part be responsible for a decrease in the observed adverse effects including thrombocytopenia. Tedizolid phosphate is currently indicated for the treatment of ABSSSI and under investigation for the treatment of nosocomial pneumonia. Although much of the role of tedizolid remains to be defined by expanding clinical experience, tedizolid is likely a welcomed addition to the mere handful of agents available for the treatment of multidrug-resistant Gram-positive infections. PMID- 25708157 TI - Small cell- versus large cell-sized metal stent in endoscopic bilateral stent-in stent placement for malignant hilar biliary obstruction. AB - BACKGROUND AND AIM: Although the large cell-sized biliary stent facilitates contralateral stent deployment through the mesh of the first metallic stent for stent-in-stent (SIS) technique, there are concerns about its vulnerability to tumor ingrowth. The aim of the present study was to compare the clinical outcomes of endoscopic bilateral SIS placement according to the cell size of a self expandable metallic stent (SEMS). METHODS: A total of 58 patients were enrolled who underwent endoscopic bilateral SIS placement of SEMS for malignant hilar biliary obstruction as a result of cholangiocarcinoma or gallbladder cancer. Finally, 43 patients who underwent successful stent insertion were included in the analysis and divided into the small cell-sized stent (SCS; n = 21) and the large cell-sized stent (LCS; n = 22) groups. We retrospectively compared comprehensive clinical and laboratory data in both groups. RESULTS: There were no significant differences between the two groups in successful drainage (SCS vs LCS, 100% vs 100%, respectively), early complications (38.1% vs 18.2%), late complications (14.3% vs 22.7%), stent occlusion (42.9% vs 45.5%), tumor ingrowth (33.3% vs 45.5%) or overgrowth (9.5% vs 0%). Duration of stent patency and overall survival were not significantly different between the two groups (P = 0.086 and P = 0.320, respectively). CONCLUSIONS: Endoscopic bilateral SIS placement for malignant hilar biliary obstruction shows no differences in stent patency, survival, complications and clinical course according to the cell size of SEMS. PMID- 25708158 TI - A mine is a terrible thing to waste: high content, single cell technologies for comprehensive immune analysis. AB - In recent years, an incredible variety of single cell technologies have become available to analyze immune responses. These technologies include polychromatic flow cytometry, mass cytometry, highly multiplexed single cell qPCR, RNA sequencing, microtools, and high-resolution imaging. In this article, we review these platforms, describing their power and limitations for comprehensive analysis of the immune system. We relate the properties of these technologies to the various cellular states relevant to an immune response, in order to address which technologies are most appropriate for which settings. PMID- 25708159 TI - Can colonic migrating motor complexes occur in mice lacking the endothelin-3 gene? AB - In mammals, colonic migrating motor complexes (CMMC) are a major propulsive contraction responsible for the expulsion of faecal content. Mice with a mutation of the endothelin-3 gene raised on a 129SL background strain have ~70% colonic aganglionosis, lack CMMC, and are lethal within 12 days postpartum. In contrast, endothelin-3 mutant mice raised and maintained on a C57BL6 background strain (lethal-spotted (ls/ls) mice) can live for much longer, but it is unclear whether CMMC generation is preserved in these mice also lacking the endothelin-3 gene. The aim of this study was to determine whether CMMC exist in ls/ls mouse colon and, if so, whether their existence and frequency are related to the length of aganglionosis. Spatiotemporal mapping and mechanical recordings of colonic wall movements were made from isolated whole colons obtained from wild-type and ls/ls mice. Although ls/ls mice had a megacolon, they still generated CMMC in the ganglionic segment, which on some occasions could propagate short distances into the aganglionic region. There was large variability in aganglionosis length, which showed a weak correlation with the existence or frequency of CMMC. Interestingly, CMMC propagation velocity was slower in ls/ls mice when evoked by intraluminal fluid. A myogenic motor pattern was identified in the aganglionic region that was maintained under tonic inhibition. We show that despite megacolon, ls/ls mice still generate CMMC in the ganglionic region. These offspring have sufficient propulsive motility in the ganglionic segment to live a normal murine lifespan and rarely die of bowel obstruction. PMID- 25708160 TI - Stem cell state and the epithelial-to-mesenchymal transition: Implications for cancer therapy. AB - The cancer stem cell paradigm, the epithelial-to-mesenchymal transition and its converse, the mesenchymal-to-epithelial transition, have reached convergence. Implicit in this understanding is the notion that cancer cells can change state, and with such change come bidirectional alterations in motility, proliferative activity, and drug resistance. As such, tumors present a moving target for antineoplastic therapy. This article will review the evolving adult stem cell paradigm and how changes in our understanding of the bidirectional nature of cancer cell differentiation may affect the selection and timing of antineoplastic therapy. The goal is to determine how to best administer therapies potentially targeted against the cancer stem cell state in the context of established treatment regimens, and to evaluate long-term effects beyond tumor regression. PMID- 25708162 TI - A pipeline for completing bacterial genomes using in silico and wet lab approaches. AB - BACKGROUND: Despite the large volume of genome sequencing data produced by next generation sequencing technologies and the highly sophisticated software dedicated to handling these types of data, gaps are commonly found in draft genome assemblies. The existence of gaps compromises our ability to take full advantage of the genome data. This study aims to identify a practical approach for biologists to complete their own genome assemblies using commonly available tools and resources. RESULTS: A pipeline was developed to assemble complete genomes primarily from the next generation sequencing (NGS) data. The input of the pipeline is paired-end Illumina sequence reads, and the output is a high quality complete genome sequence. The pipeline alternates the employment of computational and biological methods in seven steps. It combines the strengths of de novo assembly, reference-based assembly, customized programming, public databases utilization, and wet lab experimentation. The application of the pipeline is demonstrated by the completion of a bacterial genome, Thermotoga sp. strain RQ7, a hydrogen-producing strain. CONCLUSIONS: The developed pipeline provides an example of effective integration of computational and biological principles. It highlights the complementary roles that in silico and wet lab methodologies play in bioinformatical studies. The constituting principles and methods are applicable to similar studies on both prokaryotic and eukaryotic genomes. PMID- 25708161 TI - Exploring the Clinical Benefit of Docetaxel or Enzalutamide After Disease Progression During Abiraterone Acetate and Prednisone Treatment in Men With Metastatic Castration-Resistant Prostate Cancer. AB - BACKGROUND: Abiraterone acetate (AA) has demonstrated improved outcomes in men with metastatic castration-resistant prostate cancer (mCRPC). However, data are lacking on the effect of AA on subsequent efficacy of enzalutamide or docetaxel. PATIENTS AND METHODS: We included men with mCRPC who received AA and subsequent enzalutamide or docetaxel by August 12, 2013. Patients were separated into 3 groups: group A, treated with AA then enzalutamide before chemotherapy; group B, treated with AA then docetaxel; and group C, treated with AA and enzalutamide after chemotherapy. The primary objective was to describe the response and overall survival with subsequent therapy. RESULTS: There were 28 evaluable patients who received enzalutamide after AA (9 in group A and 19 in group C) and 13 patients who received docetaxel after AA (group B). Group A patients had more visceral disease and higher baseline prostate-specific antigen (PSA) levels, and group C men had a higher level of pain and multiple poor prognostic features. Median progression-free survival was 3.6, 5.1, and 2.8 months, respectively, and median overall survival was 8.5, not reached, and 9.6 months, respectively. A >= 50% PSA decline was achieved in 11%, 63%, and 5% of group A, B, and C patients, respectively. Radiographic or clinical progression as best response was noted in 55.5%, 30.8%, and 68.4% in each respective group. CONCLUSION: In this chart review of consecutive men with progressive mCRPC after AA, we found modest activity for enzalutamide and docetaxel, with clear cross-resistance for AA and enzalutamide. These data might inform the complex treatment decisions after AA treatment. PMID- 25708163 TI - Pharmacokinetics of aconitine-type alkaloids after oral administration of Fuzi (Aconiti Lateralis Radix Praeparata) in rats with chronic heart failure by microdialysis and ultra-high performance liquid chromatography-tandem mass spectrometry. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Fuzi [the lateral root of Aconitum carmichaeli Debx (Ranunculaceae)] is a well-known traditional medicinal herb used to treat chronic heart failure (CHF). Aconitine-type alkaloids are major alkaloids that are responsible for the pharmacological activity and toxicity of this herb.To investigate therapeutic effects and pharmacokinetic profiles of aconitine-type alkaloids in CHF rats. MATERIALS AND METHODS: The plasma pharmacokinetic profiles of aconitine, mesaconitine, and hypaconitine were investigated after once treatment of Fuzi extract (containing aconitine 0.086 mg/g, mesaconitine 0.84 mg/g, and hypaconitine 1.97 mg/g) using a rapid and sensitive combinative method of ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC MS/MS) and microdialysis (MD). The cardiac function and antioxidant enzyme activities were also evaluated. RESULTS: Recoveries of MD sampling ranged from 35.06% to 45.74% with RSD below 6.05%. Fuzi extract improved the myocardial function and antioxidant enzymatic activities of rats with CHF. Aconitine, mesaconitine, and hypaconitine exhibited slower absorption into the bloodstream, and yielded 11-fold less values of area under concentration-time curve (AUC) in the CHF rats than those in normal rats. The plasma AUC showed that the maximum blood concentration (Cmax) was 5.561 ng/mL for aconitine, 17.30 ng/mL for mesaconitine, and 17.78 ng/mL for hypaconitine in normal rats, while these were 0.6059 ng/mL, 2.430, and 0.7461 ng/mL in CHF rats, respectively. CONCLUSION: Aconitine-type alkaloids associated with Fuzi's efficacy have lower intake and slower elimination in the CHF rats, indicating a non-interdependent relationship between its efficacy and toxicity. It may contribute to the depth understanding of the toxicological and pharmacological profiles of Fuzi and further benefit the herbal drug development with safety and efficacy for CHF treatment. PMID- 25708164 TI - Protein functional properties prediction in sparsely-label PPI networks through regularized non-negative matrix factorization. AB - BACKGROUND: Predicting functional properties of proteins in protein-protein interaction (PPI) networks presents a challenging problem and has important implication in computational biology. Collective classification (CC) that utilizes both attribute features and relational information to jointly classify related proteins in PPI networks has been shown to be a powerful computational method for this problem setting. Enabling CC usually increases accuracy when given a fully-labeled PPI network with a large amount of labeled data. However, such labels can be difficult to obtain in many real-world PPI networks in which there are usually only a limited number of labeled proteins and there are a large amount of unlabeled proteins. In this case, most of the unlabeled proteins may not connected to the labeled ones, the supervision knowledge cannot be obtained effectively from local network connections. As a consequence, learning a CC model in sparsely-labeled PPI networks can lead to poor performance. RESULTS: We investigate a latent graph approach for finding an integration latent graph by exploiting various latent linkages and judiciously integrate the investigated linkages to link (separate) the proteins with similar (different) functions. We develop a regularized non-negative matrix factorization (RNMF) algorithm for CC to make protein functional properties prediction by utilizing various data sources that are available in this problem setting, including attribute features, latent graph, and unlabeled data information. In RNMF, a label matrix factorization term and a network regularization term are incorporated into the non-negative matrix factorization (NMF) objective function to seek a matrix factorization that respects the network structure and label information for classification prediction. CONCLUSION: Experimental results on KDD Cup tasks predicting the localization and functions of proteins to yeast genes demonstrate the effectiveness of the proposed RNMF method for predicting the protein properties. In the comparison, we find that the performance of the new method is better than those of the other compared CC algorithms especially in paucity of labeled proteins. PMID- 25708165 TI - Development: beta-catenin network controls nephron patterning. PMID- 25708166 TI - Hypertension: Lymphocyte adaptor protein puts the 'brakes' on hypertension. PMID- 25708167 TI - Transplantation: Promising outcomes of HIV-positive-to-HIV-positive kidney transplantation. PMID- 25708168 TI - Serum uric acid and other short-term predictors of electrocardiographic alterations in the Brisighella Heart Study cohort. AB - INTRODUCTION: Recent studies show that serum uric acid (SUA) is a predictor of atrial fibrillation, while its association with other kinds of arrhythmias is not yet established. We aimed to evaluate the incidence of the most common electrocardiographic alterations in a relatively large sample of general population and their association with SUA. MATERIALS AND METHODS: We selected a Brisighella Heart Study cohort sample of 1557 subjects, consecutively visited in the 2004 and 2008 surveys, in a setting of primary prevention for cardiovascular disease and without a known diagnosis of arrhythmia or left ventricular hypertrophy, excluding subjects affected by gout or taking any antihyperuricemic agent or drugs able to interfere with the QT interval. A step-wise Cox regression analysis was used to determine the independent prognostic significance of age, gender, physical activity, smoking, body mass index (BMI), fasting plasma glucose, mean arterial pressure (MAP), heart rate, LDL-cholesterol, HDL cholesterol, triglycerides, SUA and eGFR on ECG alterations during a 4-year follow-up. RESULTS: No one of the considered variables was associated with the incident diagnosis of sinus tachycardia and sinus bradycardia. SUA predicted incident tachyarrhythmias, Q waves and ECG signs of left ventricular hypertrophy; age, female sex and active smoking predicted incident tachyarrhythmias; male sex, active smoking and LDL-cholesterol predicted incident ECG signs of previous myocardial infarction; BMI and MAP predicted incident ECG-diagnosed left ventricular hypertrophy. CONCLUSION: In a cohort of general population, SUA seems to be a significant middle-term predictor of electrocardiographically diagnosed myocardial infarction, left ventricular hypertrophy and tachyarrhythmias. PMID- 25708169 TI - Disclosing genetic risk for coronary heart disease: effects on perceived personal control and genetic counseling satisfaction. AB - We investigated whether disclosure of coronary heart disease (CHD) genetic risk influences perceived personal control (PPC) and genetic counseling satisfaction (GCS). Participants (n = 207, age: 45-65 years) were randomized to receive estimated 10-year risk of CHD based on a conventional risk score (CRS) with or without a genetic risk score (GRS). Risk estimates were disclosed by a genetic counselor who also reviewed how GRS altered risk in those randomized to CRS+GRS. Each participant subsequently met with a physician and then completed surveys to assess PPC and GCS. Participants who received CRS+GRS had higher PPC than those who received CRS alone although the absolute difference was small (25.2 +/- 2.7 vs 24.1 +/- 3.8, p = 0.04). A greater proportion of CRS+GRS participants had higher GCS scores (17.3 +/- 5.3 vs 15.9 +/- 6.3, p = 0.06). In the CRS+GRS group, PPC and GCS scores were not correlated with GRS. Within both groups, PPC and GCS scores were similar in patients with or without family history (p = NS). In conclusion, patients who received their genetic risk of CHD had higher PPC and tended to have higher GCS. Our findings suggest that disclosure of genetic risk of CHD together with conventional risk estimates is appreciated by patients. Whether this results in improved outcomes needs additional investigation. PMID- 25708170 TI - Low-content quantification in powders using Raman spectroscopy: a facile chemometric approach to sub 0.1% limits of detection. AB - A robust and accurate analytical methodology for low-content (<0.1%) quantification in the solid-state using Raman spectroscopy, subsampling, and chemometrics was demonstrated using a piracetam-proline model. The method involved a 5-step process: collection of a relatively large number of spectra (8410) from each sample by Raman mapping, meticulous data pretreatment to remove spectral artifacts, use of a 0-100% concentration range partial least-squares (PLS) regression model to estimate concentration at each pixel, use of a more accurate, reduced concentration range PLS model to calculate analyte concentration at each pixel, and finally statistical analysis of all 8000+ concentration predictions to produce an accurate overall sample concentration. The relative prediction accuracy was ~2.4% for a 0.05-1.0% concentration range, and the limit of detection was comparable to high performance liquid chromatography (0.03% versus 0.041%). For data pretreatment, we developed a unique cosmic ray removal method and used an automated baseline correction method, neither of which required subjective user intervention and thus were fully automatable. The method is applicable to systems which cannot be easily analyzed chromatographically, such as hydrate, polymorph, or solvate contamination. PMID- 25708172 TI - Innate and adaptive genetic pathways in HCV infection. AB - Infection with hepatitis C virus (HCV) leads to a wide spectrum of clinical manifestations. This heterogeneity is underpinned by the host immune response and the genetic factors that govern it. Polymorphisms affecting both the innate and adaptive immunity determine the outcome of exposure. However the innate immune system appears to play a greater role in determining treatment-associated responses. Overall the effects of IFNL3/4 appear dominant over other polymorphic genes. Understanding how host genetics determines the disease phenotype has not been as intensively studied. This review summarizes our current understanding of innate and adaptive immunogenetic factors in the outcome of HCV infection. It focuses on how they relate to resolution and the progression of HCV-related liver disease, in the context of current and future treatment regimes. PMID- 25708171 TI - Graphene Oxide as a Multifunctional Platform for Raman and Fluorescence Imaging of Cells. AB - Fluorescence and Raman bimodal imaging and Raman multifrequency imaging of Hela cells are carried out with the help of two kinds of graphene oxide-based hybrids. As a multifunctional platform, graphene oxide acts as not only a Raman probe, but also as a substrate for Raman and fluorescent probes to load on. PMID- 25708173 TI - ERP evidence of cognitive strategy change in motivational conditions with varying level of difficulty. AB - Recent research suggests that motivation improves cognitive functions but the particular mechanisms and precise behavioural conditions involved in such improvement still remain unknown. Particularly, it is unclear when in time and in which conditions these mechanisms are engaged. In the present study, we aimed to look at the neural markers of cognitive control strategies in different motivational conditions (motivation vs neutral) with different levels of difficulty (high vs low). Twenty-five adults completed a newly designed task in the four conditions above. Three ERP components were analysed: the CNV, LRP and P3b. We found that a motivational situation triggers the use of a proactive strategy when low cognitive control is required. A reactive strategy was used in a non-motivational situation and for difficult trials. Our study is also the first to provide evidence that the difference between proactive and reactive strategies occurs after the first stimulus (cue) is processed. PMID- 25708174 TI - Neural correlates of taste perception in congenital blindness. AB - Sight is undoubtedly important for the perception and the assessment of the palatability of tastants. Although many studies have addressed the consequences of visual impairment on food selection, feeding behavior, eating habits and taste perception, nothing is known about the neural correlates of gustation in blindness. In the current study we examined brain responses during gustation using functional magnetic resonance imaging (fMRI). We scanned nine congenitally blind and 14 age- and sex-matched blindfolded sighted control subjects, matched in age, gender and body mass index (BMI), while they made judgments of either the intensity or the (un)pleasantness of different tastes (sweet, bitter) or artificial saliva that were delivered intra-orally. The fMRI data indicated that during gustation, congenitally blind individuals activate less strongly the primary taste cortex (right posterior insula and overlying Rolandic operculum) and the hypothalamus. In sharp contrast with results of multiple other sensory processing studies in congenitally blind subjects, including touch, audition and smell, the occipital cortex was not recruited during taste processing, suggesting the absence of taste-related compensatory crossmodal responses in the occipital cortex. These results underscore our earlier behavioral demonstration that congenitally blind subjects have a lower gustatory sensitivity compared to normal sighted individuals. We hypothesize that due to an underexposure to a variety of tastants, training-induced crossmodal sensory plasticity to gustatory stimulation does not occur in blind subjects. PMID- 25708175 TI - The effects of homonymous hemianopia in experimental studies of alexia. AB - Pure alexia is characterized by an increased word-length effect in reading. However, this disorder is usually accompanied by right homonymous hemianopia, which itself can cause a mildly increased word-length effect. Some alexic studies have used hemianopic patients with modest word-length effects: it is not clear (a) whether they had pure alexia and (b) if not, whether their results could be explained by the field defect. Our goal was to determine if impairments in visual processing claimed to be related to alexia could be replicated in homonymous hemianopia alone. Twelve healthy subjects performed five experiments used in two prior studies of alexia, under both normal and simulated hemianopic conditions, using a gaze-contingent display generated by an eye-tracker. We replicated the increased word-length effect for reading time with right homonymous hemianopia, and showed a similar effect for a lexical decision task. Simulated hemianopia impaired scanning accuracy for letter or number strings, and slowed object part processing, though the effect of configuration was not greater under hemianopic viewing. Hemianopia impaired the identification of words whose letters appeared and disappeared sequentially on the screen, with better performance on a cumulative presentation in which the letters remained on the screen. The reporting of trigrams was less accurate with hemianopia, though syllabic structure did not influence the results. We conclude that some impairments that have been attributed to the processing defects underlying alexia may actually be due to right homonymous hemianopia. Our results underline the importance of considering the contribution of accompanying low-level visual impairments when studying high-level processes. PMID- 25708176 TI - Increased risk of erectile dysfunction among patients with sleep disorders: a nationwide population-based cohort study. AB - AIMS: Few studies have investigated the relationship between sleep disorders (SD) and erectile dysfunction (ED). Therefore, this study explored whether patients with SD in an Asian population are at an increased risk of developing ED. METHODS: This longitudinal nationwide population-based cohort study investigated the incidence and risk of developing ED in 34,548 men newly diagnosed with SD between 2002 and 2008 from the National Health Insurance Research Database. A total of 138,192 controls without SD were randomly recruited from the general population and frequency matched according to age and sex. The follow-up period began from the date of entering the study cohort until the date of an ED event, censoring, or 31 December 2010. We conducted Cox proportional hazard regression analyses to estimate the effects of SD on the risk of ED. RESULTS: The SD cohort had a 2.11-fold adjusted hazard ratio (HR) of subsequent ED development compared with the non-SD cohort [95% confidence interval (CI) = 1.89-2.37]. The incidence of ED increased with age for both cohorts and was higher for the patients in the SD cohort. Compared with the participants without SD or comorbidities, the patients without SD with any comorbidity exhibited a 1.79-fold risk of developing ED (95% CI = 1.54-2.09); the highest risk was for those with both SD and any comorbidity (HR = 3.34, 95% CI = 2.82-3.95). Furthermore, SD patients who had a particular number of comorbidities showed the dose-response effect of developing ED. CONCLUSION: This nationwide cohort study determined that ED risk evidently increased in SD patients compared with the general population. PMID- 25708177 TI - Both Nsp1beta and Nsp11 are responsible for differential TNF-alpha production induced by porcine reproductive and respiratory syndrome virus strains with different pathogenicity in vitro. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) has been recognized to be one of the most important pathogens severely affecting global swine industry. An increasingly number of studies have paid much attention to the diverse roles of its nonstructural proteins (Nsps) in regulating the innate immune response of host upon PRRSV infection. In the present study, we first discovered that highly pathogenic PRRSV (HP-PRRSV) and low pathogenic PRRSV (LP PRRSV) infection exhibited a differential TNF-alpha expression in pulmonary alveolar macrophages (PAMs), showing that HP-PRRSV infection induces lower TNF alpha production at protein level in PAMs, compared with LP-PRRSV. Next, HP-PRRSV was confirmed to strongly suppress TNF-alpha production by inhibiting ERK signaling pathway. Finally, both Nsp1beta and Nsp11 were demonstrated to be responsible for the inhibitory effect on TNF-alpha production induced by HP-PRRSV and the differential TNF-alpha production in PAMs. These findings contribute to the understanding of the pathogenesis of the Chinese HP-PRRSV. PMID- 25708178 TI - Value of ventilation/perfusion SPECT for diagnosis of pulmonary embolism. PMID- 25708179 TI - Value of ventilation/perfusion SPECT for diagnosis of pulmonary embolism: response to comments by Sinzinger et al. PMID- 25708180 TI - First trimester screening for other trisomies than trisomy 21, 18, and 13. AB - OBJECTIVE: The objective of the study was to evaluate the performance of first trimester combined screening in cases of placental/fetal, mosaic or non-mosaic, autosomal trisomy other than trisomy 21, 18, or 13, and in cases of aneuploidy for a marker chromosome with focus on biochemical markers. METHOD: We identified 66 cases in three large databases including 357 675 pregnancies from October 2003 to January 2014. RESULTS: Seventy-seven percent of the 66 cases were screened positive at the combined first trimester screening (cFTS) for trisomy 21 or trisomy 18 or 13. The multiple of median (MoM) of Pregnancy Associated plasma protein A (PAPP-A) of the different aneuploidy groups ranged from 0.2 to 0.5 MoM, whereas the MoM of maternal serum free - beta - human chorionic gonadotropin (FbetahCG) was approximately 1.0 MoM. The exceptions being 0.2 MoM for cases involving chromosome 8 (n = 7) and 0.5 MoM for cases involving chromosome 9 (n = 3). The nuchal translucency MoM was approximately 1.0 MoM in all aneuploidy groups. CONCLUSION: The cFTS program for trisomy 21, 18, and 13 is also sensitive to a broad range of rare chromosomal trisomies and chromosomal mosaicisms, primarily because of a strong detection capacity of PAPP-A MoM. PMID- 25708181 TI - Development and validation of TLC-densitometric method for determination of lipid A adjuvant as a bulk and in solid fat nanoemulsions. AB - A simple, sensitive, selective and precise high-performance thin-layer chromatographic method was developed for determination of lipid A (MPLA) adjuvant as a bulk and in solid fat nanoemulsions. Chromatographic separations were performed on thin-layer chromatography aluminum plates precoated with silica gel 60 F-254 as stationary phase and chloroform-methanol-ethyl acetate solution (10:2:4, v/v/v) as mobile phase. With this solvent system, compact spots for MPLA at Rf value 0.80 +/- 0.02 were obtained. Densitometric analysis of MPLA was carried out in absorbance mode at 357 nm. Linear regression analysis for the calibration plots showed good linear relationship with r = 0.9996 in the concentration range of 20-100 ng/spot. The mean values (+/-SD) of slope and intercept were found to be 7.355 +/- 0.006 and 109.52 +/- 0.170, respectively. Limits of detection (LOD) and quantitation (LOQ) were observed at 3.096 and 9.382 ng/spot, respectively.The method was validated for precision, accuracy, robustness and recovery as per the International Conference on Harmonization guidelines. Statistical analysis proved that the developed method for quantification of MPLA as a bulk and in solid fat nanoemulsions is reproducible, selective and economical. This method could be applied for quantitative assay of MPLA in lipid-based vaccine formulations. PMID- 25708183 TI - Rapid induction of omega-3 fatty acids (EPA) in Nannochloropsis sp. by UV-C radiation. AB - Omega-3 fatty acids, such as eicosapentaenoic acid (EPA), provide substantial health benefits. As global fish stocks are declining and in some cases are contaminated with heavy metals, there is a need to find more sustainable land based sources of these essential fatty acids. The oleaginous microalga Nannochloropsis sp. has been identified as a highly efficient producer of omega-3 fatty acids. In this study, we present a new process to rapidly induce biosynthesis of essential fatty acids, including EPA in Nannochloropsis sp. BR2. Short exposure to UV-C at a dose of 100 or 250 mJ/cm(2) led to a significant increase in total cellular lipid contents when compared to mock-treated controls. A low dosage of 100 mJ/cm(2) also led to a twofold increase in total EPA content within 24 h that constituted 30% of total fatty acids and up to 12% of total dry weight at higher dosages. UV-C radiation may find uses as an easily applicable external inducer for large-scale production of omega-3 production from microalgae. PMID- 25708182 TI - A sustained-release drug-delivery system of synthetic prostacyclin agonist, ONO 1301SR: a new reagent to enhance cardiac tissue salvage and/or regeneration in the damaged heart. AB - Cardiac failure is a major cause of mortality and morbidity worldwide, since the standard treatment for cardiac failure in the clinical practice is chiefly to focus on removal of insults against the heart or minimisation of additional factors to exacerbate cardiac failure, but not on regeneration of the damaged cardiac tissue. A synthetic prostacyclin agonist, ONO-1301, has been developed as a long-acting drug for acute and chronic pathologies related to regional ischaemia, inflammation and/or interstitial fibrosis by pre-clinical studies. In addition, poly-lactic co-glycolic acid-polymerised form of ONO-1301, ONO-1301SR, was generated to achieve a further sustained release of this drug into the targeted region. This unique reagent has been shown to act on fibroblasts, vascular smooth muscle cells and endothelial cells in the tissue via the prostaglandin IP receptor to exert paracrinal release of multiple protective factors, such as hepatocyte growth factor, vascular endothelial growth factor or stromal cell-derived factor-1, into the adjacent damaged tissue, which is salvaged and/or regenerated as a result. Our laboratory developed a new surgical approach to treat acute and chronic cardiac failure using a variety of animal models, in which ONO-1301SR is directly placed over the cardiac surface to maximise the therapeutic effects and minimise the systemic complications. This review summarises basic and pre-clinical information of ONO-1301 and ONO-1301SR as a new reagent to enhance tissue salvage and/or regeneration, with a particular focus on the therapeutic effects on acute and chronic cardiac failure and underlying mechanisms, to explore a potential in launching the clinical study. PMID- 25708184 TI - Clinical considerations of the glandular branch of the lacrimal artery. AB - The lacrimal artery is classically described as a branch of the ophthalmic artery supplied by the internal carotid. In this study, 25 orbits were dissected to identify variations in glandular branching and to compare them to previously published accounts. The glandular branching patterns of the lacrimal artery fall into two categories, those that branch (56%) and those that do not branch (44%). We found the medial and lateral glandular branches to be equal in diameter with a divergence of 2.67-40.58 mm proximal to the gland parenchyma. The long glandular branches run alongside the superolateral aspect of the orbit. The lateral branch runs lateral to the lateral rectus muscle. The medial branch runs superomedial to the lateral rectus muscle and lateral to the superior rectus muscle. In relation to the lacrimal gland, the medial branch enters the superior aspect of the gland parenchyma and the lateral branch enters its inferior aspect. The average branch lengths were 17.88 mm (medial) and 13.51 mm (lateral) as measured with a Mitutoyo Absolute 1/100 mm caliper. We could not confirm the existence of a third branch supplying the lacrimal gland, as posited by other authors. The key finding in this study is that the lacrimal gland is predominantly supplied by two significant arterial branches, both of which must be identified during procedures involving the lateral orbit. PMID- 25708185 TI - 'False' lambda sign in monochorionic twin pregnancy. PMID- 25708186 TI - Gender disparity in chronic hepatitis B: Mechanisms of sex hormones. AB - Hepatitis B virus (HBV) is a common human pathogen transmitted worldwide, and its chronic infection is a well-known risk factor for hepatocellular carcinoma (HCC). The sex disparity of HBV-related liver diseases has been noticed for a long time, which could be attributed to sex hormone effects, other than gender behaviors or environmental impact. This difference is experimentally confirmed in HBV transgenic mice, as well as in immunocompetent mice receiving hydrodynamic delivery of HBV. Androgen and estrogen pathways were identified to play opposite regulations of HBV transcription by targeting viral enhancer I at molecular level. In addition to the direct effects on HBV life cycle, sex hormones may be also involved in the immune response to HBV infection and the progression of associated liver diseases, although the detailed mechanisms are still unclear. Besides, several unaddressed issues such as HBV entry, microRNA profiles, viral integration, and adaptability in which androgen and estrogen axes might be involved are warranted to be delineated. The comprehensive understanding of the sex disparity in HBV virology and pathogenesis will be helpful to provide newly biomarkers for clinical diagnosis and develop novel drugs to manage HBV-related HCC patients. PMID- 25708187 TI - Can repetitive transcranial magnetic stimulation increase muscle strength in functional neurological paresis? A proof-of-principle study. AB - BACKGROUND AND PURPOSE: Therapeutic options are limited in functional neurological paresis disorder. Earlier intervention studies did not control for a placebo effect, hampering assessment of effectivity. A proof-of-principle investigation was conducted into the therapeutic potential of repetitive transcranial magnetic stimulation (rTMS), using a single-blind two-period placebo controlled cross-over design. METHODS: Eleven patients received active 15 Hz rTMS over the contralateral motor cortex (hand area), in two periods of 5 days, for 30 min once a day at 80% of resting motor threshold, with a train length of 2 s and an intertrain interval of 4 s. Eight of these eleven patients were also included in the placebo treatment condition. Primary outcome measure was change in muscle strength as measured by dynamometry after treatment. Secondary outcome measure was the subjective change in muscle strength after treatment. RESULTS: In patients who received both treatments, active rTMS induced a significantly larger median increase in objectively measured muscle strength (24%) compared to placebo rTMS (6%; P < 0.04). Subjective ratings showed no difference due to treatment, i.e. patients did not perceive these objectively measured motor improvements (P = 0.40). CONCLUSIONS: Our findings suggest that rTMS by itself can potentially improve muscle weakness in functional neurological paresis disorder. Whereas patients' muscle strength increased as measured with dynamometry, patients did not report increased functioning of the affected hand, subjectively. The results may indicate that decreased muscle strength is not the core symptom and that rTMS should be added to behavioral approaches in functional neurological paresis. PMID- 25708188 TI - Serum homocysteine, asymmetric dimethyl arginine (ADMA) and other arginine-NO pathway metabolite levels in patients with psoriasis. AB - Hyperhomocysteinemia, a well-known and independent risk factor for cardiovascular disease, has been related in several studies with psoriasis patients. It has been suggested that homocysteine leads to endothelial dysfunction by causing an accumulation of asymmetrical dimethyl arginine (ADMA), a potent endogenous nitric oxide (NO) synthase inhibitor of the L-arginine-NO pathway. However, limited data is available regarding the psoriasis and ADMA relationship. In this study, we aimed to investigate the serum levels of homocysteine, ADMA and other metabolites from the L-arginine-NO pathway in psoriasis patients. Forty-two patients with chronic plaque psoriasis and 48 controls were enrolled in the study. Serum homocysteine, ADMA, L-monomethyl-L-arginine (L-NMMA), symmetric dimethylarginine (SDMA) and L-arginine levels, and L-arginine/ADMA ratios of psoriasis patients and the control group were measured. The severity of psoriasis was assessed by the psoriasis area and severity index (PASI). The mean ADMA and homocysteine values were significantly higher, and citrulline and L-arginine/ADMA values were significantly lower in psoriasis patients compared to control subjects. However, there were no significant differences among the patient and control groups with respect to mean SDMA, L-NMMA and L-arginine values. PASI scores strongly correlated with the ADMA level and moderately correlated with L-arginine/ADMA ratio. This study suggests that the L-arginine-NO pathway metabolites, especially ADMA, may play an important role in the pathogenesis of psoriasis. Additionally, serum ADMA levels of psoriasis patients may be an indicator of the disease severity. PMID- 25708190 TI - Microvascular abnormalities in adjuvant-induced arthritis: relationship to macrovascular endothelial function and markers of endothelial activation. AB - OBJECTIVE: To determine the time course of microvascular abnormalities and the link with macrovascular endothelial function and circulating markers of endothelial activation in adjuvant-induced arthritis (AIA) in rats. METHODS: Microvascular function/structure and mechanics were studied in third-order mesenteric arteries subjected to flow and/or pressure on day 4 (preclinical arthritis), day 11 (very early arthritis), day 33 (severe disease), and day 90 (when inflammation has resolved) after AIA induction. Macrovascular function was studied in aortic rings, and blood pressure, plasma levels of C-reactive protein (CRP), intercellular adhesion molecule 1 (ICAM-1), and vascular cell adhesion molecule 1 (VCAM-1) were measured at each time point. RESULTS: Mesenteric flow mediated vasodilation was significantly reduced from very early arthritis to chronic disease, whereas increased microvascular arterial stiffness was evident only on day 33. Macrovascular endothelial dysfunction was observed only on day 33. Thus, on day 90, whereas rats with AIA recovered normal macrovascular endothelial function, microvascular endothelial function remained impaired. No correlation was found between micro- and macrovascular endothelial function throughout the course of arthritis (r = 0.180, P = 0.229). Furthermore, no correlation was found between CRP levels, ICAM-1 levels, and endothelial function whatever the vascular bed. AIA was not associated with change in blood pressure or VCAM levels. CONCLUSION: Our findings indicate that microvascular endothelial dysfunction occurs earlier than macrovascular endothelial dysfunction and microvascular arterial stiffness during arthritis, suggesting that microvascular endothelial function would be a valuable tool for the early assessment of cardiovascular risk in RA. Neither the ICAM-1 level nor the CRP level is a good marker of micro- or macrovascular endothelial dysfunction. PMID- 25708189 TI - The role of transcription factor Nrf2 in skin cells metabolism. AB - Skin, which is a protective layer of the body, is in constant contact with physical and chemical environmental factors. Exposure of the skin to highly adverse conditions often leads to oxidative stress. Moreover, it has been observed that skin cells are also exposed to reactive oxygen species generated during cell metabolism particularly in relation to the synthesis of melanin or the metabolism in immune system cells. However, skin cells have special features that protect them against oxidative modifications including transcription factor Nrf2, which is responsible for the transcription of the antioxidant protein genes such as antioxidant enzymes, small molecular antioxidant proteins or interleukins, and multidrug response protein. In the present study, the mechanisms of Nrf2 activation have been compared in the cells forming the various layers of the skin: keratinocytes, melanocytes, and fibroblasts. The primary mechanism of control of Nrf2 activity is its binding by cytoplasmic inhibitor Keap1, while cells have also other controlling mechanisms, such as phosphorylation of Nrf2 and modifications of its activators (e.g., Maf, IKKbeta) or inhibitors (e.g., Bach1, caveolae, TGF-beta). Moreover, there are a number of drugs (e.g., ketoconazole) used in the pharmacotherapy of skin diseases based on the activation of Nrf2, but they may also induce oxidative stress. Therefore, it is important to look for compounds that cause a selective activation of Nrf2 particularly natural substances such as curcumin, sulforaphane, or extracts from the broccoli leaves without side effects. These findings could be helpful in the searching for new drugs for people with vitiligo or even melanoma. PMID- 25708191 TI - Pre-B cell receptor binding to galectin-1 modifies galectin-1/carbohydrate affinity to modulate specific galectin-1/glycan lattice interactions. AB - Galectins are glycan-binding proteins involved in various biological processes including cell/cell interactions. During B-cell development, bone marrow stromal cells secreting galectin-1 (GAL1) constitute a specific niche for pre-BII cells. Besides binding glycans, GAL1 is also a pre-B cell receptor (pre-BCR) ligand that induces receptor clustering, the first checkpoint of B-cell differentiation. The GAL1/pre-BCR interaction is the first example of a GAL1/unglycosylated protein interaction in the extracellular compartment. Here we show that GAL1/pre-BCR interaction modifies GAL1/glycan affinity and particularly inhibits binding to LacNAc containing epitopes. GAL1/pre-BCR interaction induces local conformational changes in the GAL1 carbohydrate-binding site generating a reduction in GAL1/glycan affinity. This fine tuning of GAL1/glycan interactions may be a strategic mechanism for allowing pre-BCR clustering and pre-BII cells departure from their niche. Altogether, our data suggest a novel mechanism for a cell to modify the equilibrium of the GAL1/glycan lattice involving GAL1/unglycosylated protein interactions. PMID- 25708192 TI - Borderline personality disorder and Axis I psychiatric and substance use disorders among women experiencing homelessness in three US cities. AB - PURPOSE: In this study, we report prevalence rates of borderline personality disorder (BPD) and Axis I psychiatric and substance use disorders among randomly selected women who were experiencing episodes of homelessness in three US cities. METHODS: The sample consists of 156 women, 79 from Omaha, NE, 39 from Pittsburgh, PA, and 38 from Portland, OR. It included 140 women from shelters and 16 women from meal locations. Latent class analysis was used to evaluate BPD symptoms. RESULTS: A large majority of the women (84.6 %) met criteria for at least one lifetime psychiatric disorder, about three-fourths (73.1 %) met criteria for a psychiatric disorder in the past year, and 39.7 % met past month criteria for a psychiatric disorder. Approximately three-fourths of the sample (73.7 %) met lifetime criteria for at least two disorders, about half (53.9 %) met criteria for at least three lifetime disorders, and approximately one-third (39.1 %) met criteria for four or more disorders. Latent class analyses indicated that 16.7 % of the women could be categorized as low self-harm BPD and 19.9 % high self-harm BPD. CONCLUSIONS: In shelters and in treatment settings, these women will present with complex histories of multiple serious psychiatric disorders. They are highly likely to manifest symptoms of BPD, post-traumatic stress disorder, and substance abuse disorders in addition to other psychiatric symptoms which will add to clinical complications. PMID- 25708193 TI - Environmental clustering of drug abuse in households and communities: multi-level modeling of a national Swedish sample. AB - PURPOSE: Both epidemiological and genetically informative studies indicate that shared environmental influences contribute to resemblance in siblings for drug abuse (DA). To what degree do these influences arise from living in the same household versus residing in the same community? METHODS: We performed a cross classified multi-level logistic regression on all individuals born in Sweden 1975 1990 (N = 1558,654). We assessed the proportion of the total population variation in DA that was due to household versus community effects controlling for genetic resemblance. DA was assessed from medical, criminal and pharmacy records. RESULTS: Expressed as an intraclass correlation (ICC), the combined household/community effects accounted for ~8 % of the total population variation in DA. The variance attributed to the community was greater than that seen for household (4.5 versus 3.4 %). In males, the variance components were slightly larger and nearly equal at the community (5.3 %) and household level (5.1 %). In females, household effects (4.8 %) were stronger than those arising from the community (3.2 %). CONCLUSION: In the total population and among males, community effects on DA were somewhat more potent than household effects. However, in females, household effects on DA were stronger than community effects. In Sweden, shared environmental effects for DA arise both at the household and at the community level. Community effects on DA are more potent in males than in females. PMID- 25708194 TI - Post-traumatic stress disorder and chronic disease: open questions and future directions. PMID- 25708196 TI - Successful methotrexate treatment of oesophageal pemphigus vulgaris in an immunosuppressed patient with Crohn's disease. PMID- 25708197 TI - Maximal flow at functional residual capacity in asthmatic preschool children. AB - BACKGROUND: Many preschool children will perform correct peak-flow but will not exhale to residual volume, thus limiting the determination of airways obstruction. The maximal flow measured at function residual capacity (V'maxFRC) is independent of lung empting and could potentially serve as a parameter for describing flow at low lung volumes. The study determines the detection of airway obstruction/dilation in asthmatic preschool children by V'maxFRC, compared to FEV1 and FEF25-75. METHODS: Children performed bronchial provocation test (BPT; n = 26) or received bronchodilators (Post-BD; n = 31). V'maxFRC was extracted at inspiratory capacity point of flow/volume maneuvers. The %change of V'maxFRC from baseline was compared with changes in various spirometry indices and to values obtained from our previously studied healthy control children. RESULTS: FEV1, FEF25-75, and V'maxFRC decreased by 30.9 +/- 12.2%, 46.2 +/- 10.9%, and 36.6 +/- 8.0%, respectively, while FRC increased by 37.0 +/- 24.9% at end of the BPT. Post BD spirometry values increased by 17.1 +/- 16.1%, 47.0 +/- 42.2, and 45 +/- 24%, respectively (p < 0.0001). A positive response to bronchodilators was observed in 15/31 (48%) children by FEV1, in 22/31 (71%) children by V'maxFRC, and in 21/31 children by FEF25-75. CONCLUSION: V'maxFRC detects airway obstruction/dilation in young asthmatic children similar to FEF25-75 and FEV1. V'maxFRC may be a valuable index in preschool children who cease exhalation prematurely. Digitally measured V'maxFRC should confirm the actual values in a wider age range in healthy and disease states. PMID- 25708198 TI - Rh(III)-catalyzed direct C-H/C-H cross-coupling of quinones with arenes assisted by a directing group: identification of carbazole quinones as GSKbeta inhibitors. AB - Rh-catalyzed direct C-H/C-H cross-coupling reaction of various (hetero)arenes with quinones is developed. This protocol is effective for a broad range of both quinone and arene substrates and a wide range of directing groups for this reaction, affording structurally diverse aryl-substituted quinones with high synthetic utility. Moreover, the present synthetic route allowed for the rapid construction of the carbazole quinone moiety that was identified as a new inhibitor scaffold for GSKbeta. PMID- 25708199 TI - Accurate inference of isoforms from multiple sample RNA-Seq data. AB - BACKGROUND: RNA-Seq based transcriptome assembly has become a fundamental technique for studying expressed mRNAs (i.e., transcripts or isoforms) in a cell using high-throughput sequencing technologies, and is serving as a basis to analyze the structural and quantitative differences of expressed isoforms between samples. However, the current transcriptome assembly algorithms are not specifically designed to handle large amounts of errors that are inherent in real RNA-Seq datasets, especially those involving multiple samples, making downstream differential analysis applications difficult. On the other hand, multiple sample RNA-Seq datasets may provide more information than single sample datasets that can be utilized to improve the performance of transcriptome assembly and abundance estimation, but such information remains overlooked by the existing assembly tools. RESULTS: We formulate a computational framework of transcriptome assembly that is capable of handling noisy RNA-Seq reads and multiple sample RNA Seq datasets efficiently. We show that finding an optimal solution under this framework is an NP-hard problem. Instead, we develop an efficient heuristic algorithm, called Iterative Shortest Path (ISP), based on linear programming (LP) and integer linear programming (ILP). Our preliminary experimental results on both simulated and real datasets and comparison with the existing assembly tools demonstrate that (i) the ISP algorithm is able to assemble transcriptomes with a greatly increased precision while keeping the same level of sensitivity, especially when many samples are involved, and (ii) its assembly results help improve downstream differential analysis. The source code of ISP is freely available at http://alumni.cs.ucr.edu/~liw/isp.html. PMID- 25708195 TI - CD47 signaling pathways controlling cellular differentiation and responses to stress. AB - CD47 is a widely expressed integral membrane protein that serves as the counter receptor for the inhibitory phagocyte receptor signal-regulatory protein-alpha (SIRPalpha) and as a signaling receptor for the secreted matricellular protein thrombospondin-1. Recent studies employing mice and somatic cells lacking CD47 have revealed important pathophysiological functions of CD47 in cardiovascular homeostasis, immune regulation, resistance of cells and tissues to stress and chronic diseases of aging including cancer. With the emergence of experimental therapeutics targeting CD47, a more thorough understanding of CD47 signal transduction is essential. CD47 lacks a substantial cytoplasmic signaling domain, but several cytoplasmic binding partners have been identified, and lateral interactions of CD47 with other membrane receptors play important roles in mediating signaling resulting from the binding of thrombospondin-1. This review addresses recent advances in identifying the lateral binding partners, signal transduction pathways and downstream transcription networks regulated through CD47 in specific cell lineages. Major pathways regulated by CD47 signaling include calcium homeostasis, cyclic nucleotide signaling, nitric oxide and hydrogen sulfide biosynthesis and signaling and stem cell transcription factors. These pathways and other undefined proximal mediators of CD47 signaling regulate cell death and protective autophagy responses, mitochondrial biogenesis, cell adhesion and motility and stem cell self-renewal. Although thrombospondin-1 is the best characterized agonist of CD47, the potential roles of other members of the thrombospondin family, SIRPalpha and SIRPgamma binding and homotypic CD47 interactions as agonists or antagonists of signaling through CD47 should also be considered. PMID- 25708200 TI - Patients concerns inventory highlights perceived needs and concerns in head and neck cancer survivors and its impact on health-related quality of life. AB - Currently, the head and neck cancer Patients' Concerns Inventory (HNC-PCI), a holistic, self-reported tool to help patients disclose needs and concerns during consultations, is not organised into domains. We used a Delphi approach to generate domains and applied them to an existing HNC-PCI database to assess association with health-related quality of life (HRQoL). The expert panel comprised 10 experts in head and neck cancer who were selected ad hoc. The HNC PCI checklist was analysed and fed back to the panel for 3 rounds until consensus was achieved. Five domains were generated (A=Physical and functional; B=Psychological and emotional or spiritual well-being; C=Social care and well being; D=Treatment-related; and E=Other) and were applied to a database compiled from 674 patients who had completed the PCI on 1276 occasions. On first completing the inventory (median 32 months after treatment) 81% selected items under domain A and 58% under domain B. Fewer items were selected/domain thereafter. Younger patients were more likely to select from domains B and C. Those treated by radiotherapy and adjuvant radiotherapy were more likely to select from domains A and C, respectively. Patients with laryngeal cancer tended to select from domain C, and those with poor HRQoL outcomes were significantly more likely to indicate more items of concern. The items selected under the HNC PCI domains showed that certain clinical, pathological, and HRQoL factors were associated with specific patterns of needs or concerns. PMID- 25708201 TI - Oculomotor capture by irrelevant onsets with and without color contrast. AB - It is widely known that irrelevant onsets (i.e., items appearing in previously empty locations) can automatically capture attention and attract our gaze. Some studies have shown that onset capture is stronger when the onset distractor matches the target feature, indicating that onset capture can be modulated by feature-based (top-down) tuning to the target. However, it is less clear whether and to what extent the perceptual saliency of the distractor can further modulate this effect. This study examined the effects of target similarity, competition between target and distractor, and bottom-up color contrast on the ability of onset distractor to capture the gaze, by varying the color (contrast) and stimulus-onset asynchrony of the onset distractor. The results clearly show that competition and feature-based attention modulate capture by the irrelevant onset to a large extent, whereas bottom-up color contrasts do not modulate onset capture. These results indicate the need to revise current accounts of gaze control. PMID- 25708202 TI - The influence of grass silage-to-maize silage ratio and concentrate composition on methane emissions, performance and milk composition of dairy cows. AB - It is well-established that altering the proportion of starch and fibre in ruminant diets can alter ruminal and post-ruminal digestion, although quantitative evidence that this reduces enteric methane (CH4) production in dairy cattle is lacking. The objective of this study was to examine the effect of varying grass-to-maize silage ratio (70 : 30 and 30 : 70 DM basis), offered ad libitum, with either a concentrate that was high in starch or fibre, on CH4 production, intake, performance and milk composition of dairy cows. A total of 20 cows were allocated to one of the four experimental diets in a two-by-two factorial design run as a Latin square with each period lasting 28 days. Measurements were conducted during the final 7 days of each period. Cows offered the high maize silage ration had a higher dry matter intake (DMI), milk yield, milk energy output and lower CH4 emissions when expressed per kg DMI and per unit of ingested gross energy, but there was no difference in total CH4 production. Several of the milk long-chain fatty acids (FA) were affected by forage treatment with the most notable being an increase in 18:0, 18:1 c9, 18:2 c9 c12 and total mono unsaturated FA, observed in cows offered the higher inclusion of maize silage, and an increase in 18:3 c9 c12 c15 when offered the higher grass silage ration. Varying the composition of the concentrate had no effect on DMI or milk production; however, when the high-starch concentrate was fed, milk protein concentration and milk FAs, 10:0, 14:1, 15:0, 16:1, increased and 18:0 decreased. Interactions were observed for milk fat concentration, being lower in cows offered high-grass silage and high-fibre concentrates compared with the high starch concentrate, and FA 17:0, which was the highest in milk from cows fed the high-grass silage diet supplemented with the high-starch concentrate. In conclusion, increasing the proportion of maize silage in the diets of dairy cows increased intake and performance, and reduced CH4 production, but only when expressed on a DM or energy intake basis, whereas starch-to-fibre ratio in the concentrate had little effect on performance or CH4 production. PMID- 25708203 TI - Commentary: tempo of evolutionary change in ecological systems. AB - As ecology and evolutionary biology developed during the 20th century one thing that frustrated an integration of research programs in these areas was the assumption that ecological and evolutionary processes operated on very different time scales. In 1961 the ecologist Lawrence Slobodkin reflected this assumption in his distinction between "evolutionary time" and "ecological time." This commentary reflects on the four papers in this Special Section that advance our understanding of the history of research at the intersection of phenotypes, genotypes, ecology, and evolution using plants as study organisms. Early in the 20th century at least some researchers, especially in agricultural systems, were already using observations and experiments to show how natural selection could operate over relatively short time periods and small spatial scales. These four studies offer a more nuanced view of the history of our understanding of the rate of phenotypic change via natural selection and the use of experiments to study evolutionary change. They illuminate the route that has led to the current presumption that in many cases ecological and evolutionary processes may indeed operate on similar, not dissimilar, time scales. PMID- 25708205 TI - Amyloid beta-abrogated TrkA ubiquitination in PC12 cells analogous to Alzheimer's disease. AB - Amyloid beta (Abeta) protein is the primary proteinaceous deposit found in the brains of patients with Alzheimer's disease (AD). Evidence suggests that Abeta plays a central role in the development of AD pathology. Here, we show in PC12 cells, Abeta impairs tropomyosin receptor kinase A (TrkA) ubiquitination, phosphorylation, and its association with p75(NTR), p62, and TRAF6 induced by nerve growth factor. The ubiquitination and tyrosine phosphorylation of TrkA was also found to be impaired in postmortem human AD hippocampus compared to control. Interestingly, the nitrotyrosylation of TrkA was increased in AD hippocampus and this explains why the phosphotyrosylation and ubiquitination of TrkA was impaired. In AD brain, the production of matrix metalloproteinase-7 (MMP-7), which cleaves proNGF, was reduced, thereby leading to the accumulation of pro-NGF and a decrease in the level of active NGF. TrkA signaling events, including Ras/MAPK and phosphatidylinositol 3-kinase (PI3K)/Akt pathways, are deactivated with Abeta and in the human AD hippocampus. Findings show that Abeta blocks the TrkA ubiquitination and downstream signaling similar to AD hippocampus. Cell survival and differentiation are essential for living organisms. We propose that under normal conditions, nerve growth factor (NGF) leads to Tropomyosin receptor kinase A (TrkA) phosphorylation, ubiquitination and its association with p75(NTR), p62 and TRAF6, thereby promoting cell survival and differentiation. In diseased conditions such as Alzheimer's, proNGF leads to nitrotyrosylation of TrkA, thereby impairing its ubiquitination and downstream signaling which results in apoptosis. TRAF6 = tumor necrosis factor receptor-associated factor 6; Ub = ubiquitin. PMID- 25708204 TI - Associations of three well-characterized polymorphisms in the IL-6 and IL-10 genes with pneumonia: a meta-analysis. AB - Published data on the associations between three well-characterized polymorphisms in the interleukin 6 and 10 (IL-6 and IL-10) genes and the risk of pneumonia are inconclusive. A meta-analysis was performed to derive a more precise estimate. The electronic databases MEDLINE (Ovid) and PubMed were searched from the earliest possible year to May 2014. A total of 9 articles met the criteria, and these included 3460 patients with pneumonia and 3037 controls. The data were analyzed with RevMan software, and risk estimates are expressed as odds ratios (ORs) and 95% confidence intervals (95% CIs). Analyses of the full data set failed to identify any significant association of pneumonia risk with the IL-6 gene -174C allele (OR = 1.00; 95% CI: 0.98-1.03), the IL-10 gene -592C allele (OR = 1.20; 95% CI: 0.95-1.52), or the IL-10 gene -1082A allele (OR = 1.21; 95% CI: 0.99-1.49). In a subgroup analysis by pneumonia type, ethnicity, sample size and quality score, no significantly increased risk of pneumonia was found for individuals carrying the IL-6 gene -174C allele. There was a low probability of publication bias, as reflected by the fail-safe number. This meta-analysis suggests that there is no significantly increased risk of pneumonia associated with previously reported IL-6 and IL-10 polymorphisms. PMID- 25708206 TI - ImmTACs for targeted cancer therapy: Why, what, how, and which. AB - Overcoming immunosuppression and activating a cytotoxic T cell response has the potential to halt the progression of cancer and, in some circumstances, eradicate it. Designing therapeutic interventions that achieve this goal has proven challenging, but now a greater understanding of the complexities of immune responses is beginning to produce some notable breakthroughs. ImmTACs (immune mobilising monoclonal TCRs against cancer) are a new class of bispecific reagents, based on soluble monoclonal T cell receptors, which have been engineered to possess extremely high affinity for cognate tumour antigen. In this way, ImmTACs overcome the problem of low affinity tumour-specific T cells imposed by thymic selection and provide access to the large number of antigens presented as peptide-HLA complexes. Once bound to tumour cells the anti-CD3 effector end of the ImmTAC drives recruitment of polyclonal T cells to the tumour site, leading to a potent redirected T cell response and tumour cell destruction. Extensive in vitro testing coupled with promising early clinical data has provided an enhanced appreciation of ImmTAC function in vivo and indicates their potential therapeutic benefit in terms of a durable response and ultimately the breaking of T cell tolerance. This review introduces ImmTACs in the context of immunotherapy, and outlines their design, construction and mechanism of action, as well as examining target selection and aspects of preclinical safety testing. PMID- 25708207 TI - Evaluation of hydration effects on tensile properties of bovine corneas. AB - PURPOSE: To determine effects of hydration on tensile stress-relaxation behavior of the bovine cornea. SETTING: Computational Biomechanics Laboratory, School of Mechanical and Aerospace Engineering, Oklahoma State University, Stillwater, Oklahoma, USA. DESIGN: Experimental study. METHODS: Bovine corneal strips were obtained from a local slaughterhouse and divided into 6 groups based on their thickness. The samples were first air dried and then rehydrated to reach the predetermined thickness of each group as follows: 0.4 mm (Group 1), 0.5 mm (Group 2), 0.7 mm (Group 3), 0.9 mm (Group 4), 1.1 mm (Group 5), and 1.5 mm (Group 6). A custom-built tensile machine was used to characterize the stress-relaxation properties. Mineral oil was used as the bathing fluid to prevent hydration variation during the experiments. RESULTS: Hydration significantly affected the immediate and transient tensile behavior of the cornea. With increasing hydration, there was a significant decrease in peak and equilibrium stress (P < .01). At all hydration levels, the tensile stress-strain curves and relaxation behavior were numerically represented with exponential and logarithmic mathematical expressions (R(2) > 0.99), respectively. An exponential relationship was found between the tangent modulus and hydration. CONCLUSIONS: Hydration of the corneal strips significantly affected their tensile and viscoelastic mechanical behavior. Therefore, while careful attention must be taken in interpreting the results in previous studies in which hydration of specimens was not fully controlled, it is important to monitor and report hydration of corneal samples in future studies. FINANCIAL DISCLOSURE: Neither author has a financial or proprietary interest in any material or method mentioned. PMID- 25708208 TI - Intraocular lens power calculation for eyes with an axial length greater than 26.0 mm: comparison of formulas and methods. AB - PURPOSE: To evaluate and compare the accuracy of formulas and methods for calculating the intraocular lens (IOL) power for eyes with an axial length (AL) greater than 26.0 mm. SETTING: Ein-Tal Eye Center, Tel-Aviv, Israel. DESIGN: Retrospective case series. METHODS: The postoperative refraction results in myopic eyes with an AL over 26.0 mm were compared with the predicted refractions calculated using standard formulas (Holladay 1, SRK/T, Hoffer Q, and Haigis) with optical IOL constants, User Group for Laser Interference Biometry constants, and an AL-adjustment method and using new-generation formulas (Barrett Universal II, Holladay 2, and Olsen). RESULTS: In 76 (71.7%) of 106 eyes, the IOL was 6.0 diopters (D) or more (Group A) and in 30 eyes (28.3%) was less than 6.0 D (Group B). In Group A, the SRK/T, Hoffer Q, Haigis, Barrett Universal II, Holladay 2, and Olsen methods met the benchmark criteria of having a prediction error of +/ 0.5 D in at least 71.0% of eyes and +/-1.0 D in 93.0% of eyes. In Group B, only the Barrett Universal II formula and the Holladay 1 and Haigis formulas using the AL-adjusted method met those criteria. CONCLUSION: When selecting IOLs for high and extreme myopia, choosing appropriate formulas and methods can yield accurate refractive results that meet benchmark criteria. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 25708209 TI - Modified capsule expander implantation to reposition and fixate the capsular bag in eyes with subluxated cataractous lenses and phacodonesis: intermediate-term results. AB - PURPOSE: To report the intermediate-term results of capsule stabilization for scleral fixation with implantation of the Yaguchi hook, a modified capsule expander stabilization hook. SETTING: Department of Ophthalmology, School of Medicine, University of Showa, Fujigaoka Rehabilitation Hospital, Yokohama, Japan. DESIGN: Retrospective case series. METHODS: Patients with zonular dialysis and phacodonesis were followed postoperatively for at least 2 years. All eyes had phacoemulsification and aspiration using an ordinary capsule expander and in-the bag implantation of an intraocular lens (IOL). Capsule expanders were removed after the residual cortex was removed, and the capsular bag was fixated to the scleral wall via the ciliary sulcus using the modified capsule expander stabilization hook. Preoperative findings, intraoperative complications, and postoperative courses were examined. RESULTS: The mean age of the 11 patients (11 eyes) was 72.2 years +/- 10.5 (SD); 5 patients were men. The mean postoperative follow-up was 48.6 +/- 13.6 months. The zonular dialysis range was 90 to 180 degrees in 1 eye, 180 degrees in 4 eyes, and 180 to 270 degrees in 1 eye. In 5 eyes, severe phacodonesis was observed without obvious zonular dialysis. In all eyes, the capsular bag and IOL were well centered without severe intraoperative or postoperative complications. CONCLUSION: The modified capsule expander stabilization hook provided good centration and stabilization of the capsule-IOL complex in eyes with severely weak zonular fibers. FINANCIAL DISCLOSURE: Dr. Yaguchi, who is the inventor of the modified capsule expander, has received financial support from Handaya, Tokyo, Japan. No other author has a financial or proprietary interest in any material or method mentioned. PMID- 25708210 TI - Light-distortion analysis as a possible indicator of visual quality after refractive lens exchange with diffractive multifocal intraocular lenses. AB - PURPOSE: To study the perception of light distortion after refractive lens exchange (RLE) with diffractive multifocal intraocular lenses (IOLs). SETTING: Clinica Oftalmologica das Antas, Porto, Portugal. DESIGN: Retrospective comparative study. METHODS: Refractive lens exchange was performed with implantation of an AT Lisa 839M (trifocal) or 909MP (bifocal toric) IOL, the latter if corneal astigmatism was more than 0.75 diopter (D). The postoperative visual and refractive outcomes were evaluated. A prototype light-distortion analyzer was used to quantify the postoperative light-distortion indices. A control group of eyes in which a Tecnis ZCB00 1-piece monofocal IOL was implanted had the same examinations. RESULTS: A trifocal or bifocal toric IOL was implanted in 66 eyes. The control IOL was implanted in 18 eyes. All 3 groups obtained a significant improvement in uncorrected distance visual acuity (UDVA) (P < .001) and corrected distance visual acuity (CDVA) (P = .001). The mean uncorrected near visual acuity (UNVA) was 0.123 logMAR with the trifocal IOL and 0.130 logMAR with the bifocal toric IOL. The residual refractive cylinder was less than 1.00 D in 86.7% of cases with the toric IOL. The mean light-distortion index was significantly higher in the multifocal IOL groups than in the monofocal group (P < .001), although no correlation was found between the light-distortion index and CDVA. CONCLUSIONS: The multifocal IOLs provided excellent UDVA and functional UNVA despite increased light-distortion indices. The light-distortion analyzer reliably quantified a subjective component of vision distinct from visual acuity; it may become a useful adjunct in the evaluation of visual quality obtained with multifocal IOLs. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 25708211 TI - Comparison of multimetric D index with keratometric, pachymetric, and posterior elevation parameters in diagnosing subclinical keratoconus in fellow eyes of asymmetric keratoconus patients. AB - PURPOSE: To compare the multimetric D index and other keratoconus-screening parameters in patients with clinical keratoconus in 1 eye and subclinical keratoconus in the fellow eye. SETTING: Medipol University Hospital and Birinci Eye Hospital, Istanbul, Turkey. DESIGN: Retrospective case-control study. METHODS: Patients with clinical keratoconus in 1 eye and subclinical keratoconus in the fellow eye and eyes of normal subjects were evaluated with a rotating Scheimpflug imaging system (Pentacam). Parameters included anterior curve analysis, keratometry (K) values, minimum corneal thickness, pachymetric progression index, Ambrosio relational thickness, posterior elevation, back difference elevation, and D-index values. The receiver operating characteristic (ROC) curves were analyzed to evaluate the area under curve (AUC), sensitivity, and specificity of each parameter. RESULTS: Forty-five patients and 67 normal subjects were evaluated. The pachymetric progression indices, posterior elevation, and the D-index measurements were statistically significantly higher whereas corneal thickness and Ambrosio relational thickness measurements were significantly lower in eyes with keratoconus or subclinical keratoconus than in eyes of normal subjects (P < .05). Using the ROC analysis, the AUC values of the mean steep K, minimum corneal thickness, pachymetric progression index minimum, Ambrosio relational thickness maximum, posterior elevation, back difference elevation, and D index to distinguish between subclinical keratoconus from control subjects were 0.52, 0.64, 0.71, 0.72, 0.71, 0.76, and 0.83, respectively. CONCLUSION: The new multimetric D index seems to be better than other single metric parameters in diagnosing keratoconus and subclinical keratoconus with good specificity. However, the sensitivity levels of all parameters were relatively limited in the diagnosis of subclinical keratoconus. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 25708212 TI - Imaging techniques for muscle injury in sports medicine and clinical relevance. AB - Magnetic resonance imaging (MRI) and ultrasound are the imaging modalities of choice to assess muscle injuries in athletes. Most authors consider MRI as the reference standard for evaluation of muscle injuries, since it superiorly depicts the extent of injuries independently of its temporal evolution, and due to the fact that MRI seems to be more sensitive for the detection of minimal injuries. Furthermore, MRI may potentially allow sports medicine physicians to more accurately estimate recovery times of athletes sustaining muscle injuries in the lower limbs, as well as the risk of re-injury. However, based on data available, the specific utility of imaging (including MRI) regarding its prognostic value remains limited and controversial. Although high-quality imaging is systematically performed in professional athletes and data extracted from it may potentially help to plan and guide management of muscle injuries, clinical (and functional) assessment is still the most valuable tool to guide return to competition decisions. PMID- 25708213 TI - Hematopoietic cell transplantation for mucopolysaccharidosis patients is safe and effective: results after implementation of international guidelines. AB - Allogeneic hematopoietic cell transplantation (HCT) is the only treatment able to prevent progressive neurodegenerative disease in a selected group of mucopolysaccharidosis (MPS) disorders. However, its use was historically limited by the high risk of graft failure and transplantation-related morbidity and mortality. Therefore, since 2005 new international HCT guidelines for MPS disorders were proposed. The survival and graft outcomes of MPS patients receiving HCT according to these guidelines in 2 European centers of expertise were evaluated. Two consecutive conditioning regimens were used, busulfan/cyclophosphamide or fludarabine/busulfan-based, both with exposure targeted i.v. busulfan. A noncarrier matched sibling donor (MSD), matched unrelated cord blood (UCB), or matched unrelated donor (MUD) were considered to be preferred donors. If not available, a mismatched UCB donor was used. Participants were 62 MPS patients (56 MPS type I-Hurler, 2 MPS type II, 2 MPS type III, and 2 MPS type VI) receiving HCT at median age 13.5 months (range, 3 to 44). Forty-one patients received a UCB donor, 17 MSD, and 4 MUD. High overall survival (95.2%) and event-free survival (90.3%) were achieved with only low toxicity: 13.3% acute graft-versus-host disease aGVHD) grades II to IV and 14.8% chronic GVHD (1.9% extensive). A mismatched donor predicted for lower event-free survival (P = .04). A higher age at HCT was a predictor for both aGVHD (P = .001) and chronic GVHD (P = .01). The use of a mismatched donor was a predictor for aGVHD (P = .01). Higher rates of full-donor chimerism were achieved in successfully transplanted UCB recipients compared with MSD/MUD (P = .002). If complying with the international HCT guidelines, HCT in MPS patients results in high safety and efficacy. This allows extension of HCT to more attenuated MPS types. Because a younger age at HCT is associated with reduction of HCT-related toxicity, newborn screening may further increase safety. PMID- 25708214 TI - Cord Blood Transplantation for Multiple Myeloma: A Study from the Multiple Myeloma Working Group of the Japan Society for Hematopoietic Cell Transplantation. AB - Cord blood has been investigated as an alternative source for hematopoietic stem cell transplantation, but information about its use for multiple myeloma is limited. The purpose of this study was to evaluate the feasibility of cord blood transplantation (CBT) for patients with multiple myeloma. Eighty-six patients with multiple myeloma who underwent a first CBT between 2001 and 2011 were included in this retrospective study. Sixty-two of them had received other types of stem cell transplantation before CBT. The cumulative incidences of neutrophil engraftment at day 50, grade II to IV acute graft-versus-host disease (GVHD), and chronic GVHD were 81.4%, 39.0%, and 19.5%, respectively. The incidence of nonrelapse mortality at 2 years was 39.0%, but it was only 6.2% in patients who underwent planned tandem autologous/reduced-intensity conditioning CBT (auto/RIC CBT). Progression-free survival (PFS) and overall survival (OS) at 6 years were 13.0% and 15.2%, respectively. Less than a partial response before CBT and lack of prior transplantation were independent significant adverse factors for PFS, whereas the presence of prior transplantation and planned tandem transplantation were associated with better OS. OS at 6 years in patients who underwent auto/RIC CBT was 45.9%. In addition, the development of chronic GVHD was associated with superior PFS. In conclusion, we demonstrated that cord blood is feasible as an alternative graft source for myeloma patients. Although CBT provided long-term survival for a fraction of patients, optimal use of this graft requires further clinical studies. PMID- 25708215 TI - Emerging Influence of the Intestinal Microbiota during Allogeneic Hematopoietic Cell Transplantation: Control the Gut and the Body Will Follow. AB - The intestinal microbiota has many critical roles in maintaining gastrointestinal epithelial and gastrointestinal systemic immune homeostasis. This review provides insight into how allogeneic hematopoietic cell transplantation (HCT) and its associated complications and supportive care therapies affect the microbiota. Additionally, the review discusses how preservation and restoration of the microbiota might be advantageous in decreasing HCT-related morbidity and mortality. PMID- 25708217 TI - Neurologic complications after allogeneic hematopoietic stem cell transplantation in children: analysis of prognostic factors. AB - Neurologic complications are serious complications after hematopoietic stem cell transplantation (HSCT) and significantly contribute to morbidity and mortality. The purpose of this study was to investigate the clinical features and prognosis in pediatric patients who had neurologic complications after allogeneic HSCT. We retrospectively reviewed the medical records of children and adolescents (19 years old or younger) who underwent allogeneic HSCT at our institution from 2000 to 2012. A total of 383 patients underwent 430 allogeneic transplantations. Among them, 73 episodes of neurologic complications occurred in 70 patients. The cumulative incidence of neurologic complications at day 400 was 20.0%. Almost two thirds of the episodes (63.0%, 46 of 73) occurred within 100 days after transplantation. Calcineurin inhibitor-related neurotoxicity was observed as the most common cause of neurotoxicity (47.9%, 35 of 73) and was significantly associated with earlier onset neurologic complications, seizure, and tremor. It also showed a significant association with lower probability of headache, abnormality of cranial nerve, and neurologic sequelae. In a multivariate analysis, days to neutrophil engraftment after HSCT, extensive chronic graft versus-host disease (GVHD) and the existence of neurologic sequelae were identified as risk factors for mortality in patients who had neurologic complications (hazard ratio [HR], 1.08; 95% confidence interval [CI], 1.02 to 1.15; P = .011; HR, 5.98; 95% CI, 1.71 to 20.90; P = .005; and HR, 4.37; 95% CI, 1.12 to 17.05; P = .034, respectively). However, there was no significant difference in the 5-year overall survival between the patients who had neurologic complications without sequelae and the patients who did not have any neurologic complications (57.3% versus 61.8%, P = .906). In conclusion, we found that the major significant risk factors for mortality in pediatric recipients with neurologic complications were the existence of neurologic sequelae and extensive chronic GVHD. PMID- 25708216 TI - Phenotypical and functional characterization of bone marrow mesenchymal stem cells in patients with chronic graft-versus-host disease. AB - Chronic graft-versus-host disease (cGVHD) is a critical complication after allogeneic hematopoietic stem cell transplantation. The conditioning therapy has been involved in the impairment of bone marrow (BM) mesenchymal stem/stromal cells (MSCs). However, the potential implication of MSCs in the pathophysiology of cGVHD has not been investigated. We analyzed expanded MSCs from patients with cGVHD and compared them with those from transplantation patients without cGVHD. The MSCs from both groups were of host origin and their reserves were comparable. They showed similar morphology, immunophenotype, population doubling times, self renewal capacity, differentiation, and migration potential. The immunomodulatory potential of the 2 groups was also identical, they were both capable of inhibiting phytohemagglutinin-activated peripheral blood mononuclear cells (PBMCs) proliferation and inducing regulatory T cells after coculturing with CD4(+) T cells, and the immunosuppressive factors were secreted similarly in both MSCs whether in normal culture or coculture with PBMCs. No significant differences were observed in the cellular senescence and apoptosis between 2 groups. In addition, MSCs from patients with cGVHD displayed normal phenotype and function compared with their counterparts from healthy donors, although reduced frequency in BM mononuclear cell fraction was observed in these patients. Taken together, our results suggest that MSCs do not seem to contribute to the pathogenesis of cGVHD and indicate the feasibility of autologous cell therapy in patients who are not completely responding to standard immunosuppressive therapy for cGVHD. PMID- 25708218 TI - Association between thymic function and allogeneic hematopoietic stem cell transplantation outcome: results of a pediatric study. AB - Robust T cell function recovery has been shown to be crucial in determining allogeneic hematopoietic stem cell transplantation (HSCT) outcome, and there is growing evidence that the thymus plays a central role in regulating this process. We performed a long-term analysis of the role of thymic activity recovery in a population of pediatric patients undergoing allogeneic HSCT by signal joint T cell receptor excision circle (sjTREC) quantification. In this study, characterized by a long-term follow-up (median, 72 months), we found patients with higher levels of sjTRECs before transplantation had a statistically significant reduced risk of death compared with patients with lower values (relative risk, .31; 95% confidence interval, .30 to .32; P = .02), showing this different outcome was mainly related to a reduction of relapse incidence (14% versus 43%, P = .02). Unlike previous reports, we observed no correlation between sjTREC levels and lymphocyte recovery. Moreover, we confirmed that only graft versus-host disease influenced thymic activity after transplantation. In conclusion, our results suggest an association between pretransplantation thymic activity and the long-term outcome of pediatric patients undergoing HSCT, mainly through a reduction of relapse opportunities. PMID- 25708220 TI - Effect of graft source on unrelated donor hemopoietic stem cell transplantation in adults with acute myeloid leukemia after reduced-intensity or nonmyeloablative conditioning: a study from the Societe Francaise de Greffe de Moelle et de Therapie Cellulaire. AB - This retrospective report compared the 4-year outcomes of allogeneic stem cell transplantation (allo-SCT) in 651 adult patients with acute myeloid leukemia receiving a reduced-intensity (RIC) or nonmyeloablative conditioning (NMA) regimen according to the type of unrelated donors. These were either umbilical cord blood (UCB, n = 205), a 9/10 mismatched unrelated donor (MisMUD, n = 99), or a 10/10 matched unrelated donor (MUD, n = 347) graft. Neutrophil recovery was slower in UCB (74.5% by day 42) compared with MisMUD (94.8%) and MUD (95.6%) (P < .001). There was no significant difference in nonrelapse mortality between UCB and both MUD (hazard ratio [HR], 1.05; 95% confidence interval [CI], .62 to 1.78; P = .85) and MisMUD (HR, 1.58; 95% CI, .88 to 2.83; P = .13) The relapse/progression was similar between UCB and MisMUD (HR, .62; 95% CI, .37 to 1.03; P = .07), but was significantly lower in MUD compared with UCB (HR, .60; 95% CI, .39 to .92; P = .02). The rate of extensive chronic graft-versus-host disease (GVHD) was similar between UCB and both MUD (HR, 2.15; 95% CI, .93 to 4.97; P = .08) and MisMUD (HR, 1.84; 95% CI, .68 to 4.95; P = .23). The rate of severe grade III and IV acute GVHD was significantly increased in MisMUD compared with UCB (HR, 2.61; 95% CI, 1.30 to 5.23; P = .007). There was no significant difference in overall survival between UCB and both MisMUD (HR, .98; 95% CI, .66 to 1.45; P = .92) and MUD (HR, .74; 95% CI, .52 to 1.03; P = .08). These data suggest that in the setting of RIC/NMA, allo-SCT UCB is a valid alternative graft source, with significantly less chronic GVHD, compared with MisMUD, when there is no MUD available or when urgent transplantation is needed. PMID- 25708219 TI - General and Virus-Specific Immune Cell Reconstitution after Double Cord Blood Transplantation. AB - Cord blood transplantation (CBT) is curative for many patients with hematologic malignancies but is associated with delayed immune recovery and an increased risk of viral infections compared with HLA-matched bone marrow or peripheral blood progenitor cell transplantation. In this study we evaluated the significance of lymphocyte recovery in 125 consecutive patients with hematologic malignancies who underwent double-unit CBT (DUCBT) with an antithymocyte globulin-containing regimen at our institution. A subset of 65 patients was prospectively evaluated for recovery of T, natural killer (NK), and B cells, and in 46 patients we also examined viral-specific T cell recovery against adenovirus, Epstein-Barr virus, cytomegalovirus, BK virus, respiratory syncytial virus, and influenza antigen. Our results indicate that in recipients of DUCBT, the day 30 absolute lymphocyte count is highly predictive of nonrelapse mortality and overall survival. Immune recovery post-DUCBT was characterized by prolonged CD8+ and CD4+ T lymphopenia associated with preferential expansion of B and NK cells. We also observed profound delays in quantitative and functional recovery of viral-specific CD4+ and CD8+ T cell responses for the first year post-CBT. Taken together, our data support efforts aimed at optimizing viral-specific T cell recovery to improve outcomes post-CBT. PMID- 25708221 TI - Efficacy and outcome of allogeneic transplantation in IgD and nonsecretory myeloma. A report on behalf of the Myeloma Subcommittee of the Chronic Malignancies Working Party of the European Group for Blood and Marrow Transplantation. AB - We have recently reported on the outcome of autologous transplantation in the rare myelomas (IgD, IgE, IgM, and nonsecretory [NS]) but there is no real information on the outcome of these conditions after allogeneic transplantation. We used the European Group for Blood and Marrow Transplantation myeloma database to compare the outcomes after allogeneic transplantation of 1354 common myelomas (IgG, IgA, and light chain myeloma) with the outcome in 26 IgD myelomas and 52 NS myelomas. There was little difference between common and the IgD and NS myeloma patients with respect to prognostic factors although the IgD group had a higher beta 2 microglobulin at diagnosis, shorter time to transplantation, and more T cell depletion. IgD and NS patients had a significantly greater achievement of complete remission at conditioning but this did not translate into equivalent progression-free survival and overall survival for the IgD patients although the NS outcome was very similar to that of common myeloma. The PFS and OS of IgD, common, and NS myelomas appear similar after allogeneic transplantation, despite a tendency for higher early relapse rate in IgD myeloma. Allogeneic transplantation may, therefore, be an option to investigate in prospective observational studies. PMID- 25708222 TI - Rapidly progressive hypertrophic cardiomyopathy in an infant with Noonan syndrome with multiple lentigines: palliative treatment with a rapamycin analog. AB - Noonan syndrome with multiple lentigines (NSML) frequently manifests with hypertrophic cardiomyopathy (HCM). Recently, it was demonstrated that mTOR inhibition reverses HCM in NSML mice. We report for the first time on the effects of treatment with a rapamycin analog in an infant with LS and malignant HCM. In the boy, progressive HCM was diagnosed during the first week of life and a diagnosis of NSML was established at age 20 weeks by showing a heterozygous Q510E mutation in PTPN11. Immunoblotting with antibodies against pERK, pAkt, and pS6RP in fibroblasts demonstrated enhanced Akt/mTOR pathway activity. Because of the patient's critical condition, everolimus therapy was started at age 24 weeks and continued until heart transplantation at age 36 weeks. Prior to surgery, heart failure improved from NYHA stage IV to II and brain natriuretic peptide values decreased from 9,600 to <1,000 pg/ml, but no reversal of cardiac hypertrophy was observed. Examination of the explanted heart revealed severe hypertrophy and myofiber disarray with extensive perivascular fibrosis. These findings provide evidence that Akt/mTOR activity is enhanced in NSML with HCM and suggest that rapamycin treatment could principally be feasible for infantile NSML. The preliminary experiences made in this single patient indicate that therapy should start early to prevent irreversible cardiac remodelling. PMID- 25708224 TI - The curriculum prerequisite network: Modeling the curriculum as a complex system. AB - This article advances the prerequisite network as a means to visualize the hidden structure in an academic curriculum. Networks have been used to represent a variety of complex systems ranging from social systems to biochemical pathways and protein interactions. Here, I treat the academic curriculum as a complex system with nodes representing courses and links between nodes the course prerequisites as readily obtained from a course catalogue. I show that the catalogue data can be rendered as a directed acyclic graph, which has certain desirable analytical features. Using metrics developed in mathematical graph theory, I characterize the overall structure of the undergraduate curriculum of Benedictine University along with that of its Biochemistry and Molecular Biology program. The latter program is shown to contain hidden community structure that crosses disciplinary boundaries. The overall curriculum is seen as partitioned into numerous isolated course groupings, the size of the groups varying considerably. Individual courses serve different roles in the organization, such as information sources, hubs, and bridges. The curriculum prerequisite network represents the intrinsic, hard-wired constraints on the flow of information in a curriculum, and is the organizational context within which learning occurs. I explore some applications for advising and curriculum reform. PMID- 25708223 TI - Role of sox9 in growth factor regulation of articular chondrocytes. AB - Chondrogenic polypeptide growth factors influence articular chondrocyte functions that are required for articular cartilage repair. Sox9 is a transcription factor that regulates chondrogenesis, but its role in the growth factor regulation of chondrocyte proliferation and matrix synthesis is poorly understood. We tested the hypotheses that selected chondrogenic growth factors regulate sox9 gene expression and protein production by adult articular chondrocytes and that sox9 modulates the actions of these growth factors. To test these hypotheses, we delivered insulin-like growth factor-I (IGF-I), fibroblast growth factor-2 (FGF 2), bone morphogenetic protein-2 (BMP-2) and/or bone morphogenetic protein-7 (BMP 7), or their respective transgenes to adult bovine articular chondrocytes, and measured changes in sox9 gene expression and protein production. We then knocked down sox9 gene expression with sox9 siRNA, and measured changes in the expression of the genes encoding aggrecan and types I and II collagen, and in the production of glycosaminoglycan, collagen and DNA. We found that FGF-2 or the combination of IGF-I, BMP-2, and BMP-7 increased sox9 gene expression and protein production and that sox9 knockdown modulated growth factor actions in a complex fashion that differed both with growth factors and with chondrocyte function. The data suggest that sox9 mediates the stimulation of matrix production by the combined growth factors and the stimulation of chondrocyte proliferation by FGF-2. The mitogenic effect of the combined growth factors and the catabolic effect of FGF-2 appear to involve sox9-independent mechanisms. Control of these molecular mechanisms may contribute to the treatment of cartilage damage. PMID- 25708225 TI - Obesity and mortality: Is childhood obesity shortening life expectancy? PMID- 25708226 TI - PARP inhibitors: A new era of targeted therapy. AB - Personalized medicine seeks to utilize targeted therapies with increased selectivity and efficacy in preselected patient cohorts. One such molecularly targeted therapy is enabled by inhibiting the enzyme poly(ADP-ribose) polymerase (PARP) by small molecule inhibitors in tumors which have a defect in the homologous DNA recombination pathway, most characteristically due to BRCA mutations. Olaparib, a highly potent PARP inhibitor, has recently been the approved for ovarian cancer therapy by the FDA and European commission in patients with platinum-sensitive, recurrent, high-grade serous ovarian cancer with BRCA1 or BRCA2 mutations. Currently, clinical trials with several PARP inhibitors are being conducted to assess the toxicities, the efficacies and the benefit of the drugs as monotherapies or combined with radiation or other chemotherapeutic agents, in ovarian, breast, prostate, rectal, lung, pancreatic, peritoneal, head and neck, brain, squamous cell carcinomas and sarcomas, to list a few. In this review, our focus is to outline the emerging molecular mechanisms, preclinical evidence and clinical applications of PARP inhibitors especially in nonBRCA cancers, and review the combination strategies compatible with PARP inhibitor therapy. PMID- 25708227 TI - A 9-year prospective population-based study on the association between the APOE*E4 allele and late-life depression in Sweden. AB - BACKGROUND: It is well established that there is an association between the apolipoprotein E (APOE) epsilon4 allele (APOE*E4) and Alzheimer's disease. It is less clear whether there is also an association with geriatric depression. We examined the relationship between APOE*E4 and 5-year incidence of depression in a Swedish population-based sample of older adults without dementia and excluding older adults who developed dementia within 4 years after the diagnosis of depression. METHODS: In 2000-2001, 839 women and men (age range, 70-92 years; mean age, 73.8 years) free from dementia and depression underwent neuropsychiatric and neuropsychological examinations and genotyping of the APOE*E4 allele. Follow-up evaluations were conducted in 2005 and 2009.The association between APOE*E4 allele and 5-year incidence of depression was examined, while avoiding possible confounding effects of clinical or preclinical dementia by excluding participants who had dementia at study entry, subsequently developed dementia during the 9-year follow-up period, or had a decline in Mini Mental State Examination score of >=5 points. RESULTS: Among subjects without depression at study entry and without dementia or significant cognitive decline during the subsequent 9 years, APOE*E4 was prospectively associated with more severe depressive symptoms (b = 1.56, p = .007), incident minor depression (odds ratio = 1.99 [confidence interval = 1.11-3.55], p = .020), and any depression (odds ratio = 1.75 [confidence interval = 1.01-3.03], p = .048). CONCLUSIONS: The presence of the APOE*E4 allele predicted future depression in this Swedish population study, even after excluding depressed individuals who later developed dementia, suggesting that the APOE*E4 allele could potentially identify people at high risk for clinically significant depression. PMID- 25708228 TI - Altered WNT Signaling in Human Induced Pluripotent Stem Cell Neural Progenitor Cells Derived from Four Schizophrenia Patients. PMID- 25708230 TI - The Sustainability of Recovery-Oriented Evidence-Based Practices. PMID- 25708229 TI - Effectiveness of Health System Services and Programs for Youth to Adult Transitions in Mental Health Care: A Systematic Review of Academic Literature. AB - Youth shifting to adult mental health services often report experiencing frustrations with accessing care that adequately replaces the youth services they had received. This systematic review assesses the peer reviewed evidence on services/programs aimed at addressing youth to adult transitions in mental health services. Findings suggest little data exists on the effectiveness of transition services/programs. While the available evidence supports meetings between youth and youth caseworkers prior to transitions occurring, it also verifies that this is not common practice. Other identified barriers to effective transitions were categorized as logistical (ineffective system communication), organizational (negative incentives), and related to clinical governance. PMID- 25708231 TI - Social Constraints are Associated with Negative Psychological and Physical Adjustment in Bereavement. AB - Losing a loved one is a normative life event, yet there is great variability in subsequent interpersonal experiences and adjustment. The Social-Cognitive Processing (SCP) model suggests that social constraints (i.e. limited opportunities to disclose thoughts and feelings in a supportive context) impede emotional and cognitive processing of stressful life events, which may lead to maladjustment. This study investigates personal and loss-related correlates of social constraints during bereavement, the links between social constraints and post-loss adjustment, and whether social constraints moderate the relations between loss-related intrusive thoughts and adjustment. A community sample of bereaved individuals (n = 238) provided demographic and loss-related information and reported on their social constraints, loss-related intrusions, and psychological and physical adjustment. Women, younger people, and those with greater financial concerns reported more social constraints. Social constraints were significantly associated with more depressive symptoms, perceived stress, somatic symptoms, and worse global health. Individuals with high social constraints and high loss-related intrusions had the highest depressive symptoms and perceived life stress. Consistent with the SCP model, loss-related social constraints are associated with poorer adjustment, especially psychological adjustment. In particular, experiencing social constraints in conjunction with loss-related intrusions may heighten the risk for poor psychological health. PMID- 25708232 TI - Gastric lipoma: a rare cause of gastrointestinal bleeding. PMID- 25708233 TI - Horse kick related injury: Significance of the line of impact. PMID- 25708234 TI - 1D, 2D and 3D liquid crystalline phases formed by bent-core mesogens. AB - The type of the mesophase is altered by a small change in the molecular architecture, i.e. increasing the number of alkyl chains attached to the mesogenic core at terminal positions. Lamellar (1D) and columnar (2D) phases are formed for molecules with one and three terminal chains, respectively. For those with two chains 3D phases are observed with either cubic or triclinic symmetry structure. PMID- 25708235 TI - Effects of Early Moderate Loading on Implant Stability: A Retrospective Investigation of 634 Implants with Platform Switching and Morse-Tapered Connections. AB - PURPOSE: This retrospective investigation aimed to evaluate the effect of early moderate loading (EML) on implant stability. MATERIALS AND METHODS: Following 6 weeks of conventional healing, 634 dental implants (Ankylos(r), Dentsply Implants, Mannheim, Germany) inserted in 247 patients were uncovered. Provisional restorations were placed in infra-occlusion in partially edentulous patients and in full occlusion in edentulous patients. Patients were instructed to consume a soft/liquid diet until final restorations were delivered after approximately 6 weeks. Periotest values (PTVs) at the time of uncovering and after EML were assessed in order to calculate the change in PTV (DeltaPTV). Improvement of the PTV was analyzed to account for dependencies between measurements on multiple implants of a single patient, along with other factors. RESULTS: No implant was lost during the EML. After a mean loading time of 3 years (+/- 1.7 years), the implant survival rate was 98.74%. The PTV of 556 implants decreased (improved) over the course of the study. The DeltaPTV was statistically significant (p = .0001), and none of the factors analyzed appeared to influence it. CONCLUSIONS: The EML of implants does not impair the implants' stability, as determined by Periotest. On the contrary, early moderate loading seems to be beneficial at compromised bone qualities. PMID- 25708236 TI - Field testing hot water temperature reduction as an energy-saving measure--does the Legionella presence change in a clinic's plumbing system? AB - Legionella spp. represent a significant health risk for humans. To ensure hygienically safe drinking water, technical guidelines recommend a central potable water hot (PWH) supply temperature of at least 60 degrees C at the calorifier. In a clinic building we monitored whether slightly lowered temperatures in the PWH system led to a systemic change in the growth of these pathogens. In four separate phases we tested different scenarios concerning PWH supply temperatures and disinfection with chlorine dioxide (ClO2). In each phase, we took 5 sets of samples at 17 representative sampling points in the building's drinking water plumbing system. In total we collected 476 samples from the PWH system. All samples were tested (culture-based) for Legionella spp. and serogroups. Additionally, quantitative parameters at each sampling point were collected, which could possibly be associated with the presence of Legionella spp. (Pseudomonas aeruginsoa, heterotrophic plate count at 20 degrees C and 36 degrees C, temperatures, time until constant temperatures were reached, and chlorine dioxide concentration). The presence of Legionella spp. showed no significant reactions after reducing the PWH supply temperature from 63 degrees C to 60 degrees C and 57 degrees C, as long as disinfection with ClO2 was maintained. After omitting the disinfectant, the PWH system showed statistically significant growth rates at 57 degrees C. PWH temperatures which are permanently lowered to less than recommended values should be carefully accompanied by frequent testing, a thorough evaluation of the building's drinking water plumbing system, and hygiene expertise. PMID- 25708237 TI - Corrigendum: Experts bodies, experts minds: how physical and mental training shape the brain. AB - [This corrects the article on p. 280 in vol. 8, PMID: 24847236.]. PMID- 25708238 TI - Laparoscopic conversion to loop duodenojejunal bypass with sleeve gastrectomy for intractable dumping syndrome after Roux-en-Y gastric bypass-two case reports. AB - BACKGROUND: Dumping syndrome is not infrequent after laparoscopic Roux-en-Y gastric bypass (LRYGB) and could result in dreaded complications, such as neuroglycopenia. For those refractory to diet modification or/and medication, regarded as intractable dumping syndrome, revision procedures should be taken into consideration. Herein, we make a video presentation of laparoscopic revision surgery for intractable dumping syndrome with unsatisfactory weight loss. METHODS: Two diabetic, morbidly obese women (initial body mass index 36.6 and 41.4 kg/m(2)) presented with intractable dumping syndrome 2 and 3 years after initial LRYGB, respectively. In addition, these patients had insufficient weight loss (body mass index 29 and 31 kg/m(2)). Laparoscopic revision procedure of loop duodenojejunal bypass with sleeve gastrectomy was conducted to relieve their intractable conditions. RESULTS: The mean operation time was 174 min (160 and 188), and the average blood loss was 60 mL (50 and 70). There was no intraoperative complication. Both patients had uneventful postoperative courses, and the average postoperative hospital stay was 2 days. The uncomfortable symptoms relieved successfully after the revision surgery. The Sigstad's score decreased to 2 points 6 months later, and the body mass index reduced to 26 and 28 kg/m(2). CONCLUSIONS: Though long-term follow-up is warranted to draw a definite conclusion, loop duodenojejunal bypass with sleeve gastrectomy for pyloric restoration and malabsorptive effect remains an acceptable revision procedure to relive intractable dumping syndrome and successfully maintain sustained weight loss in our patients. PMID- 25708239 TI - GERD-Related Questionnaires and Obese Population: Can They Really Reflect the Severity of the Disease and the Impact of GERD on Quality of Patients' Life? AB - INTRODUCTION: There is a strong association between obesity and gastroesophageal reflux disease (GERD). GERD-related questionnaires have been developed in order to objectify symptoms. However, none of them has been tested in obese population. PURPOSE: The purpose of this study is to evaluate if GERD score and GERD-Health Related Quality of Life (HRQL) can reflect severity of the disease and screen obese patients for GERD preoperatively. GERD's impact on the quality of life of obese patients is being assessed with the use of EORTC-QLQ C30. PATIENTS-METHODS: Obese patients during their preoperative evaluation were recruited regardless of the presence of GERD symptoms. A targeted GERD symptom history was obtained. Patients completed GERD score, GERD-HRQL, and EORTC-QLQ C30, and then, a 24-h multichannel intraluminal impedance pHmetry (MIIpH) was conducted. RESULTS: Forty seven consecutive obese patients with mean age 39.91 years and mean BMI 46.94 kg/m(2) were included in the study. GERD score and GERD-HRQL have a positive linear correlation with DeMeester score (p = 0.001 and p < 0.001, respectively). EORTC QLQ-C30 does not correlate with DeMeester score. CONCLUSIONS: GERD-related questionnaires could be used in obese population as preoperative screening tool for GERD. However, our results indicate that the quality of life of obese patients is not affected by the existence of GERD. PMID- 25708240 TI - Laparoscopic revision of gastric bypass for gastrojejunal anastomotic stenosis and trans-mesocolic defect: video report. AB - PURPOSE: Laparoscopic gastric bypass (LRYGB) is considered as the gold standard procedure for morbid obesity because of sustainable weight loss and coexisting conditions improvements (Sjostrom L et al. The New England journal of medicine 351(26):2683-93, 2004 [1]; Thereaux J et al. Surg Obesity Related Dis: Off J Am Soc Bariatric Surg, 2014 [2]). However, there are some concerns with the late risk of gastrojejunal anastomotic stenosis and of small bowel obstruction (Hamdan K et al. 98(10):1345-55, 2011 [3]). MATERIALS AND METHODS: We present the case of a 46-year-old woman (70 kg, 1.67 m) with a body mass index (BMI) of 25.1 kg/m(2) who had undergone LRYGB, 3 years ago (initial BMI 45 kg/m(2)). She was referred to our tertiary care center for dysphagia and abdominal pain. RESULTS: In this multimedia video, we present a step-by-step laparoscopic revision of a LRYGB for gastrojejunal anastomotic stenosis associated with trans-mesocolic defect. Procedure included dissection and resection of the strictured anastomosis, redo gastrojejunal circular anastomosis, and closure of the trans-mesocolic defect. No adverse outcomes occurred during the postoperative period. CONCLUSION: Gastrojejunal anastomosis stenosis should be managed under laparoscopy. All abdominal surgery in patients with a history of LRYGB, especially with trans mesocolic alimentary limb, should include inspection of potential meso-defect. PMID- 25708241 TI - Laparoscopic Adjustable Gastric Banding In Patients with Unexpected Cirrhosis: Safety and Outcomes. AB - BACKGROUND: The safety and efficacy of laparoscopic adjustable gastric banding (LAGB) in the context of cirrhosis have not been established. We hypothesized that LAGB in cirrhotic patients is a safe procedure that may offer positive long term benefits, both in terms of obesity and avoiding progression of liver disease. METHODS: Data were gathered from a prospectively maintained database of 8402 patients who had undergone LAGB from November 1993 and April 2014. RESULTS: Fourteen patients with biopsy-proven cirrhosis were identified in the database. In all cases, cirrhosis was an unexpected macroscopic finding at the time of surgery, confirmed with intraoperative biopsy. All patients were either Child Pugh A or B. No patients had preoperative clinical evidence of decompensated liver disease. The mean initial weight was 116.6 kg and BMI 38.9. There was no operative mortality. Two patients experienced a surgical complication (Clavien Dindo grade II and grade IIIa). At 12 months, the mean excess weight loss was 61.3% giving a mean BMI 31.7. Repeat biopsies were available in three patients. All demonstrated improvement in inflammation and two had fibrosis regression. Baseline liver biochemistry was compared in nine patients who had repeat biochemistry studies after 12 months. There was a significant improvement in alanine transaminase (ALT) (p = 0.04) and aspartate transaminase (AST) (p = 0.02). Two patients developed hepatocellular carcinoma (HCC). One has died as a result of this disease 11 years after LAGB surgery. CONCLUSION: LAGB may be a safe and effective bariatric intervention in patients with compensated cirrhosis. Our findings support the need for a prospective study with paired liver biopsies. PMID- 25708242 TI - Anaplastic lymphoma kinase translocation is correlated with anaplastic lymphoma kinase expression and mutually exclusive with epidermal growth factor receptor mutation in Taiwanese non-small cell lung cancer. AB - The echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) fusion gene is an important biomarker for target therapy. The aim of this study is to better understand the clinical and molecular features of the EML4-ALK fusion gene in lung cancer patients in Taiwan and therefore to generate an efficient algorithm for the detection of ALK translocation. In the first cohort, ALK translocation was identified in 1 adenocarcinoma from 100 lung cancer patients by using break apart fluorescent in situ hybridization (FISH). Next, we detected 6 ALK translocations in another 40 EGFR wild type adenocarcinomas but not in 40 cases with EGFR mutation. Histological analysis revealed that solid growth with signet-ring cells or cribriform glands with extracellular mucin were noted in all the 7 ALK translocated cases. One ALK positive cancer with mucinous cribriform pattern had no ALK expression. ALK expression was correlated with ALK translocation (p < 0.001), but not with ALK gene copy number gain (CNG) (P = 0.838). ALK translocation was also mutually exclusive with EGFR mutation in Taiwanese non-small cell lung cancer (P = 0.033). These results indicate that screening tests for EGFR mutation status and/or ALK expression could help efficiently select ALK translocated patients for target therapy. PMID- 25708244 TI - Prognostic Value of Brachial-Ankle Pulse Wave Velocity in Patients With Takayasu Arteritis With Drug-Eluting Stent Implantation. AB - OBJECTIVE: This study investigates the long-term outcomes of drug-eluting stent (DES) implantation in patients with Takayasu arteritis (TAK). METHODS: Data on 48 TAK patients and 40 age-, sex-, and severity-matched patients with coronary artery disease (CAD) receiving DES implantation and hospitalized in Fuwai Hospital from February 2004 to March 2014 were assessed. The clinical features, laboratory data, coronary angiographic findings, treatment, and followup outcomes were summarized retrospectively. Major adverse cardiac events (MACE), which include all-cause death, nonfatal myocardial infarction, and nonfatal target vessel revascularization, were recorded. RESULTS: TAK patients exhibited increased mean +/- SD brachial-ankle pulse wave velocity (baPWV) compared with patients with CAD (17.0 +/- 3.8 versus 13.8 +/- 3.0 meters/second; P = 0.002). However, CAD patients had higher levels of low-density lipoprotein cholesterol (2.5 +/- 1.0 versus 2.3 +/- 0.8 mmoles/liter; P = 0.04). Multiple linear regression analysis revealed that baPWV was independently associated with the extent of CAD, assessed by the SYNTAX (Synergy Between Percutaneous Coronary Intervention With TAXUS and Cardiac Surgery) score (beta = 0.33, P = 0.03), in TAK patients. DES implantation was deployed in 73 coronary lesions in 48 TAK patients, and restenosis occurred in 48 lesions after an average of 25.6 months (range 9.0-68.0 months) following intervention. Logistic regression analysis identified that a baPWV of 17.00 meters/second or higher (odds ratio 5.50, 95% confidence interval [95% CI] 2.1-16.6, P = 0.008) may be considered as an independent predictor of DES restenosis. Moreover, the multivariate Cox proportional hazards model demonstrated that a baPWV of 17.00 meters/second or higher (hazard ratio 3.36, 95% CI 1.51-7.52, P = 0.003) was significant and may serve as an independent predictor of MACE in TAK patients who underwent DES implantation. CONCLUSION: DES in-stent restenosis remains a challenge, affecting the long-term outcomes of patients with TAK. Measuring increased arterial stiffness through baPWV, with the addition of inflammation status monitoring during followup, would be of great clinical value to identify TAK patients with DES who have a high risk for in-stent restenosis and MACE. PMID- 25708243 TI - SCMPSP: Prediction and characterization of photosynthetic proteins based on a scoring card method. AB - BACKGROUND: Photosynthetic proteins (PSPs) greatly differ in their structure and function as they are involved in numerous subprocesses that take place inside an organelle called a chloroplast. Few studies predict PSPs from sequences due to their high variety of sequences and structues. This work aims to predict and characterize PSPs by establishing the datasets of PSP and non-PSP sequences and developing prediction methods. RESULTS: A novel bioinformatics method of predicting and characterizing PSPs based on scoring card method (SCMPSP) was used. First, a dataset consisting of 649 PSPs was established by using a Gene Ontology term GO:0015979 and 649 non-PSPs from the SwissProt database with sequence identity <= 25%.- Several prediction methods are presented based on support vector machine (SVM), decision tree J48, Bayes, BLAST, and SCM. The SVM method using dipeptide features-performed well and yielded - a test accuracy of 72.31%. The SCMPSP method uses the estimated propensity scores of 400 dipeptides as PSPs and has a test accuracy of 71.54%, which is comparable to that of the SVM method. The derived propensity scores of 20 amino acids were further used to identify informative physicochemical properties for characterizing PSPs. The analytical results reveal the following four characteristics of PSPs: 1) PSPs favour hydrophobic side chain amino acids; 2) PSPs are composed of the amino acids prone to form helices in membrane environments; 3) PSPs have low interaction with water; and 4) PSPs prefer to be composed of the amino acids of electron-reactive side chains. CONCLUSIONS: The SCMPSP method not only estimates the propensity of a sequence to be PSPs, it also discovers characteristics that further improve understanding of PSPs. The SCMPSP source code and the datasets used in this study are available at http://iclab.life.nctu.edu.tw/SCMPSP/. PMID- 25708245 TI - Induction of Osteoarthritis-like Pathologic Changes by Chronic Alcohol Consumption in an Experimental Mouse Model. PMID- 25708246 TI - Guidelines for prevention and treatment of cognitive impairment in the elderly. AB - The aim of this study is to present the available and verified methods of prevention of cognitive decline in healthy older adults and to review clinical trials of therapies to improve impaired cognitive performance. We discuss data about the actual possibility of pharmacological treatment, usefulness of physical exercises, and effectiveness of different cognitive training methods. In a separate chapter we discuss why older people cope much better in life challenges then it would appear from the measurements made by use of neuro-psychological tests. We also discuss the so-called issue of transfers, ie, the question of how certain cognitive characteristics, improved through cognitive training, are transferred to other mental skills. We distinguish between simple and sophisticated (usually computerized) forms of cognitive training and pay particular attention to methods that are simple and easy to use. In particular, we discuss the so-called "learning therapy", which amounts to "reading aloud and simple arithmetic calculations", the method based on "switching between words and imagination", and also the method consisting of personal counseling, support, and assistance in learning, especially in the form of home visits. In the final chapter we formulate practical advice, not only for individuals who want to undertake the preventing or correction activities alone with eventual help of medical professionals, but also for the members of health institutions that wish to implement preventive and therapeutic actions directed to a chosen population. We also discuss the indications and rationale for further research and clinical trials. PMID- 25708247 TI - MicroRNA-424 may function as a tumor suppressor in endometrial carcinoma cells by targeting E2F7. AB - MicroRNAs (miRNAs) are frequently dysregulated in human cancers and can act as potent oncogenes or tumor suppressor genes. Aberrant expression of miR-424 has been identified in some types of cancer, however, its expression and potential biologic role in endometrial cancer are remains to be determined. In the present study, we demonstrated that miR-424 was downregulated in human endometrial cancer and suppressed growth of the human Ishikawa and HEC-1B endometrial cancer cell lines. Bioinformatics analysis indicated that E2F7 was a putative target of miR 424. In a luciferase reporter system, we confirmed that E2F7 was a direct target gene of miR-424. Furthermore, knockdown of E2F7 inhibited Ishikawa and HEC-1B cell growth. These findings indicate that miR-424 targets the E2F7 transcript and suppresses endometrial cancer cell growth, suggesting that miR-424 has a tumor suppressive role in human endometrial cancer pathogenesis. PMID- 25708248 TI - Anxiety related to discharge from inpatient neurorehabilitation: Exploring the role of self-efficacy and internal health control beliefs. AB - The study aimed to determine the prevalence of anxiety related to discharge, among a group of 42 participants who were likely to have sustained an at least moderate to severe ABI and who were due to be discharged home following a period of inpatient neurorehabilitation. Differential relationships between psychological factors (self-efficacy and internal health control beliefs) were examined, alongside the relative influence of demographic and clinical characteristics on discharge anxiety. Data were obtained via self-report measures and retrospective reviews of participant's inpatient medical records. While relatively few participants (n = 6; 14%) reported markedly elevated trait anxiety, almost half the sample (n = 19; 45%) reported clinically significant levels of transient state-anxiety. Notably, state-anxiety was strongly associated with discharge anxiety. Multivariate analyses revealed that age, self-efficacy and internal health control beliefs made independent contributions to self reported discharge anxiety, with perceived self-efficacy alone explaining 69% of the variance and mediating the effects of age and internal health control beliefs. None of the other demographic or clinical characteristics examined was significantly associated with discharge anxiety. While causality cannot be inferred, findings suggest that anxiety related to discharge from rehabilitation might be best predicted by poor perceptions of self-efficacy. Implications for clinical practice and future research are discussed. PMID- 25708249 TI - Evidence of improved immediate verbal memory and diminished category fluency following STN-DBS in Chinese-Cantonese patients with idiopathic Parkinson's disease. AB - The present study investigated the neuropsychological effects of bilateral deep brain stimulation (DBS) on subthalamic nucleus (STN) in Chinese-Cantonese patients with idiopathic Parkinson's disease (PD). Twenty-seven patients were prospectively recruited from the Movement Disorder Clinic at the Hong Kong Prince of Wales Hospital. Neuropsychological evaluations were performed at baseline, 6 and 12 months following the DBS procedure. Assessment battery included standardized tests on global cognitive function, verbal memory, non-verbal memory, confrontation naming, visuospatial organization, attention and executive functions. Anxiety and depressive symptoms were measured by two self-reported questionnaires. Results demonstrated diminished performance on a category fluency task that occurred at 6 months post-operatively and persisted at 12-month re evaluation; 29.6-33.3 % of patients showed reduction of more than 1 SD (standard deviation) at post-operative measure. Conversely, performance on an immediate recall task in a verbal memory test was found to improve significantly at the same time point and persisted through 12 months after surgery; 22.2-25.9 % showed an improvement (>=1 SD). Psychologically, anxiety symptoms were statistically decreased and the significant reduction occurred at 12 months after surgery. Patients who reported a moderate to severe level of anxiety reduced from 51.9 to 18.5 %. Our findings concurred with most evidences on the effects of STN-DBS on verbal fluency; on the other hand, we demonstrated improvement of immediate verbal memory that warranted further investigation. PMID- 25708250 TI - [Attitudes towards anti-depressive therapy: acceptance vs. stigmatization]. AB - OBJECTIVE: The current study investigates the attitude towards antidepressant treatment among general public. METHODS: A total of 234 probands (139 women and 95 men) were asked to complete individually provided questionnaires examining socio-demographic data, psychoeducational levels, as well as personal beliefs concerning antidepressant treatment and levels of present stigmatisation. Three scales were used to quantify stigmatisation levels-"Revised Perceived Devaluation Discrimination Scale"/"Revised Internalized Stigma of Mental Illness Scale"/"Attitudes Toward Mental Health Treatment Scale", "Revised Perceived Devaluation Discrimination Scale". RESULTS: 65 people (27.8 %) reported to have had one or more episodes of depression during their lifetime; 169 people (72.2 %) indicated to have never had any episode of that type before. The words "sickness" and "anxiety" were the terms primarily associated with the word "depression". It was a common belief among interviewees that lonely individuals or those not receiving social support have a higher risk of becoming depressed. We further found that people experience higher levels of internalized stigma when talking about their antidepressant drug-therapy, than the level of perceived stigma would suggest. Opposed to those not indicating depression depressed people indicated that they considered the use of antidepressant medication helpful and a good option, if necessary. Stigma can still be found among those not indicating depression as well as among those with symptoms of depression. Based on the current study we conclude that work in the field of destigmatisation is of great importance. PMID- 25708252 TI - Critical Review on Suicide Among Nurses. AB - Background: Research shows that there is a high prevalence of suicide among nurses. Despite this, it has been 15 years since the last literature review on the subject was published. Aim: The aim of this article is to review the knowledge currently available on the risk of suicide among nurses and on contributory risk factors. Method: A search was conducted in electronic databases using keywords related to prevalence and risk factors of suicide among nurses. The abstracts were analyzed by reviewers according to selection criteria. Selected articles were submitted to a full-text review and their key elements were summarized. Results: Only nine articles were eligible for inclusion in this review. The results of this literature review highlight both the troubling high prevalence of suicide among nurses as well as the persistent lack of studies that examine this issue. Conclusion: Considering that the effects of several factors related to nurses' work and work settings are associated with high stress, distress, or psychiatric problems, we highlight the relevance of investigating work-related factors associated with nurses' risk of suicide. Several avenues for future studies are discussed as well as possible research methods. PMID- 25708251 TI - Improving the quality of colonoscopy bowel preparation using a smart phone application: a randomized trial. AB - BACKGROUND AND AIM: Getting ready for a colonoscopy is difficult and involves many steps. Information given to patients is very important for adherence to treatment. We created a novel smart phone application (SPA) aimed to increase bowel preparation quality and patient satisfaction. METHODS: We carried out a prospective, endoscopist-blinded, randomized, controlled trial. We enrolled 260 outpatient (58% female, age range 21-75 years) owners of a smartphone. Patients were allocated to two different protocols: instructions provided by SPA (SPA group; n = 108) or written instructions with visual aids (control group; n = 152). All procedures were carried out in the afternoon and patients received the same purgative regimen (2 L polyethylene glycol (PEG) solution plus ascorbic acid), in a full-dose same-day regimen. The study was designed to detect an improvement in quality of bowel preparation using the Harefield Cleansing Scale (HCS) scale. Effect of protocol on patient satisfaction was assessed with a specific questionnaire at the time of colonoscopy. RESULTS: Proportion of patients who obtained successful bowel preparation for colonoscopy (HCS A or B) was significantly higher in the SPA group than in the control group (100% vs 96.1%, respectively; P = 0.037). Mean global HCS scores were similar in both groups. Patient-reported tolerability and overall experience with the prescribed bowel preparation were significantly higher for the SPA group than for the control group. CONCLUSION: Successful cleansing and patient acceptability with the use of SPA were superior to written instructions in outpatients submitted for colonoscopy using 2 L PEG solution plus ascorbic acid. PMID- 25708253 TI - Effects of Parliamentary Elections on Suicide Rates in Hungary. AB - Background: Phillips and Feldman reported a decline in suicides leading up to the American presidential elections, but Wasserman argued that elections had no impact on suicide. Aims: The present study explored the impact of elections on suicides in Hungary. Method: The study examined changes in the number of suicides in Hungary during the period 1990-2010 on the days of parliamentary elections, and in the weeks and months surrounding the elections. Results: There was no significant impact from the elections on the number of suicides. Conclusion: The data from Hungary replicated the results of Wasserman rather than those of Phillips and Feldman. PMID- 25708254 TI - Swiss Prison Suicides Between 2000 and 2010. AB - Background: Suicide is the leading cause of death in Swiss prisons. The Federal Statistics Office provides numbers but no further details. Previous studies worldwide have focused on identifying suicide risk factors in prisoners, but very few have looked at the methods used in relation to prevention strategies. Aims: To obtain details of Swiss prison suicides, determine new findings in an international context, and establish prevention strategies based on the information acquired. Method: Retrospective data analysis of prison suicides extracted from the database of all suicides investigated by Swiss institutes of legal medicine between 2000 and 2010, using a standardized assessment sheet. Results: Out of 4,885 suicides investigated in the institutes of legal medicine in Switzerland, we identified 50 (1.02%) inmate suicides. Most were unmarried Swiss men, with a median age of 32 years. The two most common methods used were hanging and tricyclic antidepressant overdose. Two died due to self-immolation. Conclusion: Swiss prison suicides do not differ from those in other countries regarding sociodemographic details and the most common method of hanging. Anchoring devices, even low ones, should be avoided to prevent hanging and medication intake should be monitored. As prisoners use tricyclic antidepressants to die by suicide, we recommend the general monitoring of intake. PMID- 25708255 TI - Sustaining the Effects of Gatekeeper Suicide Prevention Training. AB - Background: Gatekeeper training is a promising suicide prevention strategy that is growing in popularity. Although gatekeeper training programs have been found to improve trainee knowledge, self-efficacy, and perceived skills, researchers have found that the benefit of gatekeeper training may not last over time. Aims: The purpose of this study was to identify strategies for strengthening the long term effects of suicide prevention gatekeeper training. Method: In-depth interviews and focus groups were conducted with gatekeepers (N = 44) and data were analyzed using a qualitative research approach. Results: The results of this study suggest that posttraining interventions may be more effective if they include the following seven themes: (a) social network - connecting with other gatekeepers; (b) continued learning - further education; (c) community outreach - building awareness; (d) accessibility - convenience; (e) reminders - ongoing communication; (f) program improvement -- enhancing previous training; and (g) certification - accreditation. Conclusion: Posttraining interventions that incorporate the themes from this study offer a promising direction in which to sustain the effects of gatekeeper suicide prevention training. PMID- 25708256 TI - The sustainability of healthcare innovations: a concept analysis. AB - AIM: To report on an analysis of the concept of the sustainability of healthcare innovations. BACKGROUND: While there have been significant empirical, theoretical and practical contributions made towards the development and implementation of healthcare innovations, there has been less attention paid to their sustainability. Yet many desired healthcare innovations are not sustained over the long term. There is a need to increase clarity around the concept of innovation sustainability to guide the advancement of knowledge on this topic. DESIGN: Concept analysis. DATA SOURCES: We included literature reviews, theoretical and empirical articles, books and grey literature obtained through database searching (ABI/INFORM, Academic Search Complete, Business Source Complete, CINAHL, Embase, MEDLINE and Web of Science) from 1996-May 2014, reference harvesting and citation searching. METHODS: We examined sources according to terms and definitions, characteristics, preconditions, outcomes and boundaries to evaluate the maturity of the concept. RESULTS: This concept is partially mature. Healthcare innovation sustainability remains a multi dimensional, multi-factorial notion that is used inconsistently or ambiguously and takes on different meanings at different times in different contexts. We propose a broad conceptualization that consists of three characteristics: benefits, routinization or institutionalization, and development. We also suggest that sustained innovations are influenced by a variety of preconditions or factors, which are innovation-, context-, leadership- and process-related. CONCLUSION: Further conceptual development is essential to continue advancing our understanding of the sustainability of healthcare innovations, especially in nursing where this topic remains largely unexplored. PMID- 25708257 TI - Effects of Intrauterine Growth Restriction During Late Pregnancy on the Development of the Ovine Fetal Thymus and the T-Lymphocyte Subpopulation. AB - PROBLEM: The retarded development of fetal thymus in intrauterine growth restriction (IUGR) from maternal undernutrition during late pregnancy destroys the tridimensional structure and modifies the development of fetal T lymphocytes. The mechanisms, however, remain unclear. The objective of this study was to investigate the effect of IUGR during late pregnancy on the development of the ovine fetal thymus and the T-lymphocyte subpopulation. METHOD OF STUDY: Eighteen time-mated ewes with singleton fetuses were allocated to three groups at day 90 of pregnancy: restricted group 1 (RG1, 0.18 MJ ME/BW(0.75) /day, n = 6), restricted group 2 (RG2, 0.33 MJ ME/BW(0.75) /day, n = 6) and a control group (CG, ad libitum, 0.67 MJ ME/BW(0.75) /day, n = 6). Fetuses were recovered at slaughter on day 140. RESULTS: Fetuses in RG1 exhibited decreased (P < 0.05) thymic weight, cortical thickness, cortical:medullary, DNA content, total antioxidant capacity, and superoxide dismutase; intermediate changes were found in RG2 fetuses, including decreased thymic weight, cortical thickness, and DNA content (P < 0.05). The reductions (P < 0.05) of CD4(+) CD8(+) T cells, relative mRNA expression of keratin 8, recombination activating gene 1 (RAG1), and B-cell lymphoma 2 (Bcl-2) were found in both restricted groups. In addition, there was reduced mRNA expression (P < 0.05) of T-cell receptor, apoptosis antigen 1 ligand, and RAG2 in the RG1 group. In contrast, increases in glutathione peroxidase, malondialdehyde, caspase-3, Cytochrome c, and CD4(+) T cells were observed (P < 0.05), and higher mRNA expressions (P < 0.05) of protein 53, Bcl-2 associated X protein (Bax), and apoptosis antigen 1 (Fas) were found in RG1 fetuses; and thymuses of RG2 fetuses had increased caspase-3, and expression of Fas and Bax (P < 0.05), relative to control fetuses. CONCLUSION: These results indicate that reduced cell proliferation, oxidative stress, and increased cell apoptosis were the potential mechanisms for impaired development and microenvironment of IUGR fetal thymus, and for modifying the maturation of CD4(+) CD8(+) thymocytes underlying their reduced numbers . PMID- 25708258 TI - A nurse-led accelerated procedure for infliximab infusion is well tolerated and effective in patients with inflammatory bowel disease. AB - BACKGROUND: Shorter infusions of infliximab for inflammatory bowel disease seem to be as tolerated as standard procedures and nurses may be able to manage them safely. AIMS: To test tolerability and effectiveness of a fast nurse-led infusion procedure and the related patients' satisfaction. METHODS: We retrospectively compared three different regimens adopted in our outpatient infusion unit from 2010 to 2013: Group 1, a standard procedure with two-hour infusions, preceded by hydrocortisone medication (87 patients, 311 infusions); Group 2, a similar regimen without physician supervision (130 patients, 464 infusions); Group 3, a one-hour nurse-led procedure without routine premedication (176 patients, 1356 infusions). Disease characteristics, infusion reactions, infusions per month and patients' satisfaction were recorded. RESULTS: There were significantly fewer infusion reactions in Group 3 than Group 1 (2.2% versus 5.8% respectively; p=0.001). The only significant risk factor for side effects was premedication (odds ratio 4.71, 95% confidence interval 2.21-10.02, p<0.001) which was related to the presence of previous side effects. Number of infusions per month increased by 27% (83 versus 61, p<0.001) without increasing nurses' workload and patients were satisfied. CONCLUSIONS: Our fast nurse-led procedure was well tolerated, effective and satisfactory for patients. PMID- 25708259 TI - Genome-wide analysis of transcription factor binding sites and their characteristic DNA structures. AB - BACKGROUND: Transcription factors (TF) regulate gene expression by binding DNA regulatory regions. Transcription factor binding sites (TFBSs) are conserved not only in primary DNA sequences but also in DNA structures. However, the global relationship between TFs and their preferred DNA structures remains to be elucidated. RESULTS: In this paper, we have developed a computational method to generate a genome-wide landscape of TFs and their characteristic binding DNA structures in Saccharomyces cerevisiae. We revealed DNA structural features for different TFs. The structural conservation shows positional preference in TFBSs. Structural levels of DNA sequences are correlated with TF-DNA binding affinities. CONCLUSIONS: We provided the genome-wide correspondences of TFs to DNA structures. Our findings will have implications in understanding TF regulatory mechanisms. PMID- 25708260 TI - Noninvasive evaluation of the regional variations of GABA using magnetic resonance spectroscopy at 3 Tesla. AB - PURPOSE: Rapid regional fluctuations in GABA may result in inhomogeneous concentrations throughout the brain parenchyma. The goal of this study is to provide further insight into the natural distribution of GABA throughout the brain and thus determine if a surrogate site may be used for spectroscopy when evaluating motor diseases, neurological disorders, or psychiatric dysfunction. MATERIALS AND METHODS: In this prospective study, eight healthy volunteers underwent spectroscopic evaluation of the frontal lobe, occipital lobe, lateral temporal lobe, basal ganglia, and both hippocampi using a spin echo variant of a J-difference editing method. Knowledge of the relative peak intensities of the macromolecule peaks at 3ppm and 0.9ppm was used to correct the contribution of co edited macromolecules to the GABA peak at 3ppm. The GABA values were internally referenced to NAA. Linear regression was used to normalize the effect of regional tissue-fraction variation on the GABA/NAA values. A one-way ANOVA was performed with Tukey's multiple comparison test to compare the normalized GABA/NAA values in each pair of locations. RESULTS: After accounting for the macromolecule contribution to the GABA signal and correction for tissue fraction variation, the normalized GABA/NAA ratios differ significantly between the six brain locations (p<0.001). Pairwise comparisons of the corrected normalized GABA/NAA ratios show statistically significant variation between the frontal lobe and the basal ganglia, frontal and lateral temporal lobes, and frontal lobe and right hippocampus. Variations in the normalized GABA/NAA ratios trend toward significance between the frontal lobe and left hippocampus, occipital lobe and the frontal lobe, occipital lobe and basal ganglia, and occipital lobe and right hippocampus. CONCLUSION: Our study suggests that GABA concentration is inhomogeneous throughout the parenchyma. Studies evaluating the role of GABA must carefully consider voxel placement when incorporating spectroscopy. PMID- 25708261 TI - Bilateral common carotid artery occlusion induced brain lesions in rats: A longitudinal diffusion tensor imaging study. AB - Bilateral common carotid artery occlusion (BCCAO) has been widely used to reproduce the white matter (WM) and gray matter (GM) damage associated with chronic cerebral hypoperfusion (CCH). This study investigated whether diffusion tensor imaging (DTI) could be used at the early stages of disease to assess brain damage induced by BCCAO. To this end, DTI, together with histological methods, was used to evaluate the progression of WM lesions and GM neurodegeneration following BCCAO. The DTI was sufficiently sensitive to detect WM abnormalities in selected regions of the brain at 4weeks after BCCAO. These abnormalities may indicate damage to the myelin and axons in the optic nerve (ON) and optic tract (OT). Our longitudinal results showed that DTI could be used to detect abnormalities of the WM and GM in select regions of the brain as early as 2days after ligation. The DTI parameter patterns of change were region-specific throughout the detection time course. Lesions of the external capsule (EC) and periventricular hypothalamic nucleus (Pe) have not been thoroughly studied before. We found that the EC and Pe were both vulnerable to BCCAO and that the associated lesions could be detected using DTI. The current study demonstrated that in vivo DTI could potentially be used to measure WM damage evolution in a BCCAO rat model as well as early brain injury following CCH. PMID- 25708262 TI - Liver MRI is more precise than liver biopsy for assessing total body iron balance: a comparison of MRI relaxometry with simulated liver biopsy results. AB - PURPOSE: Liver biopsy was long considered the reference standard for measuring liver iron concentration. However, its high sampling variability and invasive nature make it poorly suited for serial analyses. To demonstrate the fallibility of liver biopsy, we use serial estimates of iron chelation efficiency (ICE) calculated by R2 and R2* MRI liver iron concentration (LIC) estimates as well as by simulated liver biopsy (over all physically reasonable sampling variability) to compare the robustness of these three techniques. MATERIALS AND METHODS: R2, R2*, transfusional volume, and chelator compliance were obtained from 49 participants in a phase II clinical trial of deferitazole over two years. Liver biopsy LIC results were simulated using sampling errors of 0%, 10%, 20%, 30%, 40% and iron assay variability of 12%. LIC estimates by R2, R2*, and simulated biopsy were used to calculate ICE over time. Bland-Altman limits of agreement were compared across observation intervals of 12, 24, and 48 weeks. RESULTS: At 48 week intervals, LIC estimates by R2, R2* and "perfect" liver biopsy had comparable accuracy in predicting ICE; both MRI methods were superior to any physically realizable liver biopsy (sampling error 10% or higher). LIC by R2* demonstrated the most robust ICE estimates at monitoring intervals of 24 and 12 weeks, but this difference did not remain significant at 48 week intervals. CONCLUSION: MRI relaxometry is superior to liver biopsy for serial LIC observations, such as used in the care of tranfusional siderosis patients, and should also be considered the new standard of LIC determination for regulatory purposes. Among relaxometry techniques, LIC estimates by R2* are more robust for tracking changes in iron balance over intermediate time scales (<=24 weeks). PMID- 25708263 TI - Cerebrovascular reactivity measured with arterial spin labeling and blood oxygen level dependent techniques. AB - PURPOSE: To compare cerebrovascular reactivity (CVR) quantified with pseudo continuous arterial spin labeling (pCASL) and blood oxygen level dependent (BOLD) fMRI techniques. MATERIALS AND METHODS: Sixteen healthy volunteers (age: 37.8+/ 14.3years; 6 women and 10 men; education attainment: 17+/-2.1years) were recruited and completed a 5% CO2 gas-mixture breathing paradigm at 3T field strength. ASL and BOLD images were acquired for CVR determination assuming that mild hypercapnia does not affect the cerebral metabolic rate of oxygen. Both CVR quantifications were derived as the ratio of the fractional cerebral blood flow (CBF) or BOLD signal change over the change in end-tidal CO2 pressure. RESULTS: The absolute CBF, BOLD and CVR measures were consistent with literature values. CBF derived CVR was 5.11+/-0.87%/mmHg in gray matter (GM) and 4.64+/-0.37%/mmHg in parenchyma. BOLD CVR was 0.23+/-0.04%/mmHg and 0.22+/-0.04%/mmHg for GM and parenchyma respectively. The most significant correlations between BOLD and CBF based CVRs were also in GM structures, with greater vascular response in occipital cortex than in frontal and parietal lobes (6.8%/mmHg versus 4.5%/mmHg, 50% greater). Parenchymal BOLD CVR correlated significantly with the fractional change in CBF in response to hypercapnia (r=0.61, P=0.01), suggesting the BOLD response to be significantly flow driven. GM CBF decreased with age in room air ( 5.58mL/100g/min per decade for GM; r=-0.51, P=0.05), but there was no association of CBF with age during hypercapnia. A trend toward increased pCASL CVR with age was observed, scaling as 0.64%/mmHg per decade for GM. CONCLUSION: Consistent with previously reported CVR values, our results suggest that BOLD and CBF CVR techniques are complementary to each other in evaluating neuronal and vascular underpinning of hemodynamic processes. PMID- 25708264 TI - Accuracy and reproducibility of a quantitative magnetic resonance imaging method for concurrent measurements of tissue relaxation times and proton density. AB - PURPOSE: To evaluate the accuracy and reproducibility of a quantitative magnetic resonance (qMR) imaging method (QRAPMASTER) for simultaneous measurements of T1 and T2 relaxation times, and proton density (PD). MATERIALS AND METHODS: Measurements of T1, T2, and PD with qMR were performed using phantoms with different relaxation times and concentrations of heavy water. Healthy volunteers were examined with different head coils. Regional measurements were performed in normal-appearing white and gray matter from the healthy control subjects, and in multiple sclerosis (MS) patients. RESULTS: In phantom measurements, QRAPMASTER slightly underestimated T1, and T2 variations between repeated measurements were modest. PD was generally overestimated. The overall relative difference was 1.2+/-5.3% (T1), -6.6+/-1.9% (T2), and 0.7+/-5.1% (PD). In healthy volunteers, there were no statistically significant differences of T1, T2 or PD using different head coils. Values of T1, T2, and PD obtained in healthy controls and MS patients were within reference ranges. However, significant differences were found in normal-appearing gray and white matter. CONCLUSION: QRAPMASTER can be considered a sufficiently accurate and reproducible method for use in clinical practice. Neuropathology in normal-appearing brain tissue may be revealed using this MR method, with putative implications for quantification of tissue damage in neurological diseases. PMID- 25708265 TI - Assessment of functional and structural damage in brain parenchyma in patients with vitamin B12 deficiency: A longitudinal perfusion and diffusion tensor imaging study. AB - INTRODUCTION: Vitamin B12 deficiency may cause neural tissue damage. Even in advanced stages, conventional imaging of brain usually appears normal in vitamin B12 deficient patients. The aim of this study was to assess the structural and functional changes in brain of patients with vitamin B12 deficiency before and after six weeks of vitamin B12 supplementation using diffusion tensor imaging and pseudo-continuous arterial spin labelling (PCASL). METHODS: MR imaging including DTI and PCASL and neuropsychological tests (NPT) were performed in 16 patients with vitamin B12 deficiency and 16 controls before and after 6weeks of therapy. Cerebral blood flow (CBF) derived from PCASL and DTI indices was calculated in brain of patients with vitamin B12 deficiency and controls. RESULTS: Patient with vitamin B12 deficiency showed altered neuropsychological scores and altered CBF as well as fractional anisotropy (FA) values in various brain regions as compared with controls. Both CBF values and neuropsychological scores showed complete reversibility at 6weeks post therapy. Though FA values showed significant recovery, it failed to show complete recovery. CONCLUSION: Our results suggest that micro-structural recovery lags behind functional recovery in patients with vitamin B12 deficiency following therapy and CBF change may be used as an early predictor of complete recovery in patients with B12 deficiency. PMID- 25708266 TI - MRI investigation of subcellular water compartmentalization and gas distribution in apples. AB - Water status and distribution at subcellular level in whole apple fruit were evaluated by Magnetic Resonance Imaging (MRI) measurement of the multi exponential transverse (T2) relaxation of water protons. Apparent microporosity, also estimated by MRI, provided mapping of gas distribution in fruit tissues. Measuring for the first time the multi-exponential relaxation of water and apparent tissue microporosity in whole fruit and combining these with histological measurements provided a more reliable interpretation of the origins of variations in the transverse relaxation time (T2) and better characterization of the fruit tissue. Measurements were performed on 54 fruits from 3 different cultivars. Fruits of different sizes were selected for each cultivar to provide tissues with cells of different dimensions. Macrovision measurements were carried out on parenchymal tissue from all fruits to investigate the impact of cell size on T2 value. The results showed that the MRI transverse relaxation signal is well fitted by a tri-exponential decay curve that reflects cell compartmentalization. Variations in cell size partially explained the different T2 observed. This study highlighted the heterogeneity of apple tissues in terms of relaxation parameters, apparent microporosity and cell morphology and in relation to specific variations between fruit of different cultivars. PMID- 25708267 TI - Association of beclin 1 expression with response to neoadjuvant chemoradiation therapy in patients with locally advanced rectal carcinoma. AB - Beclin 1 is an essential regulator of autophagy that is induced in response to cellular stress and serves to maintain cell survival in established tumors. We recently demonstrated that Beclin 1 suppression can sensitize colorectal cancer cells to radiation-induced DNA damage and apoptosis. Therefore, we hypothesized that the level of Beclin 1 expression may be associated with radiation sensitivity in vivo. We determined the association of Beclin 1 expression in pretreatment rectal cancer tissues with response to neoadjuvant chemoradiation in surgical resection specimens. Stages II and III (n = 96) rectal adenocarcinoma patients were treated with neoadjuvant chemoradiation followed by surgical resection with curative intent. Beclin 1 was analyzed by immunohistochemistry and the expression level was dichotomized at the median value with categorization into low and high groups. We identified 56 (58.3%) and 40 (41.7%) patients whose tumors had high- versus low-level Beclin 1 expression, respectively. Rectal cancers with high versus low Beclin 1 expression were significantly less likely to be downstaged after chemoradiation treatment (45% [25/55] vs. 58% [22/38]; p = 0.02). In a multivariable analysis adjusted for age, sex, histological grade and baseline tumor node metastasis (TNM) stage, the impact of Beclin 1 expression on tumor downstaging remained statistically significant (p = 0.03). The association of the level of Beclin 1 expression with the rate of tumor downstaging after chemoradiation is consistent with in vitro data, and suggests that Beclin 1 may be a predictive biomarker for the efficacy of chemoradiation in patients with rectal cancer. PMID- 25708268 TI - Fear of falling in people with chronic obstructive pulmonary disease. AB - BACKGROUND: Increased fear of falling (FOF) has been associated with impaired physical function, reduced physical activity and increased fall risk in older adults. Preliminary evidence suggests that individuals with chronic obstructive pulmonary disease (COPD) may have an increased FOF. This study aims to compare the level of FOF in people with COPD with healthy controls, and to determine the associations between FOF and measures of physical function, physical activity and fall risk in COPD. METHODS: FOF was assessed in 40 participants with COPD and 25 age- and gender-matched controls using the Falls Efficacy Scale-International (FES-I). Physical function was evaluated using quadriceps hand-held dynamometry, the Berg Balance Scale and the Six-minute Walk Test. Associations between FOF, physical activity and fall risk were evaluated using the Physical Activity Scale for the Elderly and the Falls Risk in Older People - Community Setting. Pearson's correlation coefficient and stepwise multivariate linear regression were used. RESULTS: Individuals with COPD (mean +/- SD; age: 71 +/- 8 years, FEV1: 45 +/- 16 %pred) had higher FOF compared to controls (FES-I: 25.0 +/- 7.9 vs 20.2 +/- 5.2, p=0.01). Higher FOF was associated with lower quadriceps strength (p=0.02) and an impaired balance (p < 0.01); these explained 26% of the FOF variance. Reduced levels of physical activity (p=0.01) and a higher fall risk (p < 0.01) were associated with an increased FOF in COPD. CONCLUSION: People with COPD have a higher FOF compared to the healthy peers, which is related to lower quadriceps muscle strength, impaired balance, lower levels of physical activity and an increased fall risk. PMID- 25708269 TI - The globalization of nephrology. PMID- 25708270 TI - Two distinct roles of the yorkie/yap gene during homeostasis in the planarian Dugesia japonica. AB - Adult planarians possess somatic pluripotent stem cells called neoblasts that give rise to all missing cell types during regeneration and homeostasis. Recent studies revealed that the Yorkie (Yki)/Yes-associated protein (YAP) transcriptional coactivator family plays an important role in the regulation of tissue growth during development and regeneration, and therefore we investigated the role of a planarian yki-related gene (termed Djyki) during regeneration and homeostasis of the freshwater planarian Dugesia japonica. We found that knockdown of the function of Djyki by RNA interference (RNAi) downregulated neoblast proliferation and caused regeneration defects after amputation. In addition, Djyki RNAi caused edema during homeostasis. These seemingly distinct defects induced by Djyki RNAi were rescued by simultaneous RNAi of a planarian mats related gene (termed Djmats), suggesting an important role of Djmats in the negative regulation of Djyki, in accordance with the conservation of the functional relationship of these two genes during the course of evolution. Interestingly, Djyki RNAi did not prevent normal protonephridial structure, suggesting that Djyki RNAi induced the edema phenotype without affecting the excretory system. Further analyses revealed that increased expression of the D. japonica gene DjaquaporinA (DjaqpA), which belongs to a large gene family that encodes a water channel protein for the regulation of transcellular water flow, promoted the induction of edema, but not defects in neoblast dynamics, in Djyki(RNAi) animals. Thus, we conclude that Djyki plays two distinct roles in the regulation of active proliferation of stem cells and in osmotic water transport across the body surface in D. japonica. PMID- 25708271 TI - Diagnosis of nephrogenic systemic fibrosis by means of elemental bioimaging and speciation analysis. AB - The combined use of elemental bioimaging and speciation analysis is presented as a novel means for the diagnosis of nephrogenic systemic fibrosis (NSF), a rare disease occurring after administration of gadolinium-based contrast agents (GBCA) for magnetic resonance imaging (MRI), in skin samples of patients suffering from renal insufficiency. As the pathogenesis of NSF is still largely unknown particularly with regard to the distribution and potential retention of gadolinium in the human organism, a skin biopsy sample from a suspected NSF patient was investigated. The combination of inductively coupled plasma mass spectrometry (ICP-MS), laser ablation (LA) ICP-MS for quantitative elemental bioimaging, and hydrophilic interaction liquid chromatography (HILIC) ICP-MS for speciation analysis allowed one to unambiguously diagnose the patient as a case of NSF. By means of ICP-MS, a total gadolinium concentration from 3.02 to 4.58 mg/kg was determined in the biopsy sample, indicating a considerable deposition of gadolinium in the patient's skin. LA-ICP-MS revealed a distinctly inhomogeneous distribution of gadolinium as well as concentrations of up to 400 mg/kg in individual sections of the skin biopsy. Furthermore, the correlation between the distributions of phosphorus and gadolinium suggests the presence of GdPO4 deposits in the tissue section. Speciation analysis by means of HILIC-ICP MS showed the presence of the intact GBCA Gd-HP-DO3A eight years after the administration to the patient. The concentration of the contrast agent in the aqueous extract of the skin biopsy was found to be 1.76 nmol/L. Moreover, evidence for the presence of further highly polar gadolinium species in low concentrations was found. PMID- 25708272 TI - Vitamin D deficiency in Parkinson's disease patients with orthostatic hypotension. AB - OBJECTIVES: The purpose of our study was to investigate the associations between serum vitamin D3 levels and orthostatic hypotension (OH) in patients with Parkinson's disease (PD). MATERIALS AND METHODS: Fifty-five patients with PD were enrolled in this study. Blood pressure (BP) measurements were gathered while the patients were in the supine position and while standing up. Then, the patients were divided into two groups: PD patients with and without OH. We compared the levels of serum 25-hydroxyvitamin D3 and 1, 25-dihydroxyvitamin D3 (calcitriol) between the two groups. RESULTS: Serum 25-hydroxyvitamin D and calcitriol levels were significantly decreased in patients with OH compared with those without OH. The systolic and diastolic BPs and symptom severities significantly negatively correlated with the serum 25-hydroxyvitamin D and calcitriol levels. CONCLUSIONS: Although the underlying mechanism for this association is not fully understood, our results suggest that low vitamin D status is associated with OH in patients with PD. PMID- 25708273 TI - Living donor liver transplantation from a heterozygous parent for classical maple syrup urine disease. AB - MSUD is a hereditary metabolic disorder that is characterized by impaired activity of the BCKADC. Liver transplantation has been approved as a treatment for some MSUD cases in which the control of BCAAs is insufficient. Although there have been several reports about DDLT for MSUD, few LDLT cases have been reported. Because either of parents who are heterozygote of this disease usually applies to be a candidate of donor in LDLT, the impairment of BCKADC activity of graft liver should be concerned. We performed LDLT for 10 month-old girl with a left lateral segment graft from her father. BCKADC activities of the patient and her parents were measured using lysates of lymphocytes isolated from peripheral blood specimen before the transplant. As a consequence, the activity of BCKADC of father was not inferior to a normal range. The patient tolerated the operation well. Postoperative course was uneventful and mixed milk was started at 8th POD. The serum BCAAs levels have remained within normal range. It should be necessary to follow the physical growth and mental development of the recipient in the future. PMID- 25708274 TI - Role of 5-HT2 receptors in diabetes: Swertiamarin seco-iridoid glycoside might be a possible 5-HT2 receptor modulator. AB - In the present review, we are focusing on modulators of 5-HT2 receptors, swertiamarin and their role in diabetes. These drugs possess both central and peripheral actions in various animal models of depression, diabetes and obesity. Swertiamarin and 5-HT2 antagonist are reported antidepressant, hypolipidemic and beneficial in peripheral vasculopathy. In contrast to this, 5-HT2C selective agonist decreases hyperglycemia, hyperlipidemia and insulin secretogogue by action. Selective serotonin reuptake inhibitors (SSRIs) are known antidepressant having weight gain as an adverse effect. Swertiamarin has similar pharmacological actions as 5-HT2 antagonist and 5-HT2C selective agonist. This warrants that swertiamarin might modulate 5-HT2 receptors rather than affecting the uptake of serotonin. In the light of present investigation, the mechanism of these drugs can correlate the role of central and peripheral 5-HT2 receptors in diabetes. PMID- 25708275 TI - 'Four Seasons' in an animal rescue centre; classical music reduces environmental stress in kennelled dogs. AB - On admission to rescue and rehoming centres dogs are faced with a variety of short- and long-term stressors including novelty, spatial/social restriction and increased noise levels. Animate and inanimate environmental enrichment techniques have been employed within the kennel environment in an attempt to minimise stress experienced by dogs. Previous studies have shown the potential physiological and psychological benefits of auditory stimulation, particularly classical music, within the kennel environment. This study determined the physiological/psychological changes that occur when kennelled dogs are exposed to long-term (7 days) auditory stimulation in the form of classical music through assessment of effects on heart rate variability (HRV), salivary cortisol and behaviour. The study utilised a cross over design in which two groups were exposed to two consecutive 7 day treatments; silence (control) and classical music (test). Group A was studied under silent conditions followed by 7 days of test conditions during which a fixed classical music playlist was played from 10:00-16:30 h. Group B received treatment in the reverse order. Results showed that auditory stimulation induced changes in HRV and behavioural data indicative of reduced stress levels in dogs in both groups (salivary cortisol data did not show any consistent patterns of change throughout the study). Specifically, there was a significant increase in HRV parameters such as MURR, STDRR, RMSSD, pNN50, RRTI, SD1 and SD2 and a significant decrease in MUHR and LF/HF from the first day of silence (S1) to the first day of music (M1). Similarly, examination of behavioural data showed that dogs in both groups spent significantly more time sitting/lying and silent and less time standing and barking during auditory stimulation. General Regression Analysis (GRA) of the change in HRV parameters from S1 to M1 revealed that male dogs responded better to auditory stimulation relative to female. Interestingly, HRV and behavioural data collected on the seventh day of music (M2) was similar to that collected on S1 suggesting that the calming effects of music are lost within the 7 days of exposure. A small '9-Day' study was conducted in attempt to determine the time-scale in which dogs become habituated to classical music and examination of the results suggests that this occurs within as soon as the second day of exposure. The results of this study show the potential of auditory stimulation as a highly effective environmental enrichment technique for kennelled dogs. However, the results also indicate the requirement for further investigations into the way in which auditory stimulation should be incorporated within the daily kennel management regime in order to harness the full physiological and psychological benefits of music. PMID- 25708276 TI - My heart is in my hands: the interoceptive nature of the spontaneous sensations felt on the hands. AB - Somatic sensations may arise in the total absence of external stimuli, i.e., spontaneous sensations (SPSs). Because the background of body sensations has been mentioned as a possible contributor to interoceptive functions, such as the perception of the self and the conscious awareness of one's own body, a possible link between SPSs and interoception has been advocated. Yet, no study has provided direct evidence on such a relationship. The aim of the present study was to establish a link between SPSs and interoception. On the basis of the literature, the accuracy of heartbeat perception was taken as an index of general interoception across different bodily modalities. It was found that individuals with good heartbeat perception experienced more numerous and more intense SPSs. Furthermore, taken along with other individual characteristics, heartbeat perception accuracy predicted the perceived intensity of SPSs, their spatial extent, their variety, as well as confidence in their spatial characteristics. However, we also provide evidence that good vs. poor heartbeat perception is not just a matter of degree. We conclude that interoception definitely contributes to the perception of SPSs. PMID- 25708277 TI - Diurnal and circadian regulation of reward-related neurophysiology and behavior. AB - Here, we review work over the past two decades that has indicated drug reward is modulated by the circadian system that generates daily (i.e., 24h) rhythms in physiology and behavior. Specifically, drug-self administration, psychomotor stimulant-induced conditioned place preference, and locomotor sensitization vary widely across the day in various species. These drug-related behavioral rhythms are associated with rhythmic neural activity and dopaminergic signaling in the mesocorticolimbic pathways, with a tendency toward increased activity during the species typical wake period. While the mechanisms responsible for such cellular rhythmicity remain to be fully identified, circadian clock genes are expressed in these brain areas and can function locally to modulate both dopaminergic neurotransmission and drug-associated behavior. In addition, neural and endocrine inputs to these brain areas contribute to cellular and reward-related behavioral rhythms, with the medial prefrontal cortex playing a pivotal role. Acute or chronic administration of drugs of abuse can also alter clock gene expression in reward-related brain regions. Emerging evidence suggests that drug craving in humans is under a diurnal regulation and that drug reward may be influenced by clock gene polymorphisms. These latter findings, in particular, indicate that the development of therapeutic strategies to modulate the circadian influence on drug reward may prove beneficial in the treatment of substance abuse disorders. PMID- 25708279 TI - Abdominopelvic hemorrhage: correlation of CT positivity with the subsequent decision to perform blood transfusion. AB - The purpose of this study is to determine the role of computed tomography (CT) on the decision to administer blood transfusions in patients with abdominopelvic hemorrhage (trauma, surgery, invasive procedure, and spontaneous) and to determine the clinical parameters most likely to influence the decision to administer blood transfusions in patients with spontaneous abdominopelvic hemorrhage. In this IRB approved and HIPPA compliant study, retrospective analysis was performed on 298 patients undergoing abdominal and pelvic CT for suspected abdominopelvic hemorrhage and the CT reports and electronic medical records were reviewed. Odds ratios and 95% CI were calculated to compare the odds of abdominopelvic hemorrhage and transfusion for categorical and continuous predictors. The presence of abdominopelvic hemorrhage by CT was significantly associated with blood transfusions for trauma patients (p-value <0.0001) only. 106 patients with suspected spontaneous abdominopelvic hemorrhage had the lowest CT positivity rate (n = 23, 21.7%) but the highest blood transfusion rate (n = 62, 58.5%) compared to the patients with abdominopelvic hemorrhage from known preceding causes. In patients with spontaneous abdominopelvic hemorrhage, low hemoglobin and hematocrit levels immediately prior to obtaining the CT study were more predictive for receiving a blood transfusion (p-value <0.0001) than the presence of hemorrhage by CT. CT positivity is strongly correlated with the decision to administer blood transfusions for patients with abdominopelvic hemorrhage from trauma, indicating that CT studies play a significant role in determining the clinical management of trauma patients. For patients with spontaneous abdominopelvic hemorrhage, the decision to transfuse depends not on the CT study but on the patient's hemoglobin and hematocrit levels. CT studies should therefore not be performed for the sole purpose of determining the need for blood transfusion in patients with spontaneous abdominopelvic hemorrhage. PMID- 25708278 TI - Male adolescent rats display blunted cytokine responses in the CNS after acute ethanol or lipopolysaccharide exposure. AB - Alcohol induces widespread changes in cytokine expression, with recent data from our laboratory having demonstrated that, during acute ethanol intoxication, adult rats exhibit consistent increases in interleukin (IL)-6 mRNA expression in several brain regions, while showing reductions in IL-1 and TNFalpha expression. Given evidence indicating that adolescence may be an ontogenetic period in which some neuroimmune processes and cells may not yet have fully matured, the purpose of the current experiments was to examine potential age differences in the central cytokine response of adolescent (P31-33days of age) and adult (69-71days of age) rats to either an acute immune (lipopolysaccharide; LPS) or non-immune challenge (ethanol). In Experiment 1, male Sprague-Dawley rats were given an intraperitoneal (i.p.) injection of either sterile saline, LPS (250MUg/kg), or ethanol (4-g/kg), and then trunk blood and brain tissue were collected 3h later for measurement of blood ethanol concentrations (BECs), plasma endotoxin, and central mRNA expression of several immune-related gene targets. In Experiment 2, the response to intragastrically (i.g.) administered ethanol was examined and compared to animals given tap water (i.g.). Results showed that LPS stimulated robust increases in expression of IL-1, IL-6, TNFalpha, and IkappaBalpha in the hippocampus, PVN, and amygdala, and that these increases were generally less pronounced in adolescents relative to adults. Following an i.p. ethanol challenge, IL-6 and IkappaBalpha expression was significantly increased in both ages in the PVN and amygdala, and adults exhibited even greater increases in IkappaBalpha than adolescents. I.g. administration of ethanol also increased IL-6 and IkappaBalpha expression in all three brain regions, with hippocampal IL-6 elevated even more so in adults compared to adolescents. Furthermore, assessment of plasma endotoxin concentrations revealed (i) whereas robust increases in plasma endotoxin were observed in adults injected with LPS, no corresponding elevations were seen in adolescents after LPS; and (ii) neither adolescents nor adults demonstrated increases in plasma endotoxin concentrations following i.p. or i.g. ethanol administration. Analysis of BECs indicated that, for both routes of exposure, adolescents exhibited lower BECs than adults. Taken together, these data suggest that categorically different mechanisms are involved in the central cytokine response to antigen exposure versus ethanol administration. Furthermore, these findings confirm once again that acute ethanol intoxication is a potent activator of brain cytokines, and calls for future studies to identify the mechanisms underlying age-related differences in the cytokine response observed during ethanol intoxication. PMID- 25708280 TI - Non-invasive prenatal diagnosis for cystic fibrosis: detection of paternal mutations, exploration of patient preferences and cost analysis. AB - OBJECTIVES: We aim to develop non-invasive prenatal diagnosis (NIPD) for cystic fibrosis (CF) and determine costs and implications for implementation. METHODS: A next-generation sequencing assay was developed to detect ten common CF mutations for exclusion of the paternal mutation in maternal plasma. Using uptake data from a study exploring views on NIPD for CF, total test-related costs were estimated for the current care pathway and compared with those incorporating NIPD. RESULTS: The assay reliably predicted mutation status in all control and maternal plasma samples. Of carrier or affected adults with CF (n = 142) surveyed, only 43.5% reported willingness to have invasive testing for CF with 94.4% saying they would have NIPD. Using these potential uptake data, the incremental costs of NIPD over invasive testing per 100 pregnancies at risk of CF are L9025 for paternal mutation exclusion, and L26,510 for direct diagnosis. CONCLUSIONS: We have developed NIPD for risk stratification in around a third of CF families. There are economic implications due to potential increased test demand to inform postnatal management rather than to inform decisions around termination of an affected pregnancy. PMID- 25708281 TI - Clinical outcomes of intravenous immunoglobulin therapy in refractory uveitis. AB - Intravenous immunoglobulin (IVIg) therapy has multiple mechanisms of immunomodulatory action. We wished therefore to assess its efficacy in a spectrum of patients with refractory uveitis. Retrospective review of clinical charts was conducted to document response to IVIg treatment in consecutive patients with treatment-refractory uveitis. Main outcome measures were control of intraocular inflammation, visual acuity, progression of the disease, and complications. Four (two male) patients, with a mean age at the beginning of the treatment of 47 years (range: 39-64), were included in the study. Indication for treatment was patients with active non-infectious uveitis refractory to steroids and immunomodulatory therapy. All patients received a course of 0.5 g/kg per day of IVIg for three consecutive days, repeating this course at a mean of 11 week (range: 2-39 weeks) intervals when indicated clinically. The median duration of the IVIg therapy was 7 months (range: 3-14 months). In three patients treatment resulted in stabilisation and prevention of progression of the disease, and additionally in two patients it facilitated a decrease in prednisolone dose. Treatment failed to induce long-term remission in one patient with recurrence of macular oedema. IVIg was well tolerated with neither immediate nor longer-term adverse events observed. In three out of four cases IVIg was an effective adjunctive therapy and well tolerated for the management of treatment-refractory uveitis. PMID- 25708282 TI - Collagen cross-linking in keratoconus in Asian eyes: visual, refractive and confocal microscopy outcomes in a prospective randomized controlled trial. AB - To evaluate the safety and efficacy of collagen cross-linking (CXL) in the treatment of keratoconus. A prospective randomized sham-controlled clinical trial was undertaken and 43 eyes with moderate to severe keratoconus were randomized into two groups that is the treatment (n = 23) and the sham (n = 20) group. CXL was performed with riboflavin (0.1 in 20 % dextran) followed by UVA radiation (365 nm, 3 mW/cm(2), 30 min). In the sham group, only riboflavin was administered without UVA radiation. Uncorrected distance visual acuity (UDVA), corrected distance visual acuity, intraocular pressure, corneal thickness, keratometry, endothelial count, confocal microscopy were evaluated at baseline and at 1 week, 1, 3, and 6 months. In cases where CXL was done, UDVA improved by mean 0.11 +/- 0.06 logMAR units at 6 months (P = 0.01). The refractive cylinder and spherical equivalent decreased by mean of 0.62 D (P = 0.01) and 0.5 D (P = 0.19), respectively. Ultrasonic central corneal thickness decreased by mean 22.7 +/- 10.3 MUm (P = 0.01). The maximum and minimum keratometry decreased by mean of 1.2 +/- 0.8 D (P = 0.01) and 0.83 +/- 1.2 D (P = 0.39), respectively. The specular count and intraocular pressure did not show any significant change. In the sham group, no significant change was observed in any parameter. Confocal analysis showed that the epithelial healing was complete at 1 week after crosslinking. The sub-epithelial plexus showed loss of nerve plexus at 1 month, regeneration of nerve fibers which started at 3 months and was complete at 6 months. The anterior stroma showed loss of keratocytes with honeycomb oedema and apoptotic bodies till 3 months. The regeneration of keratocytes started at 3 months and was complete at 6 months of follow-up. Collagen cross-linking is an effective procedure to halt progression in keratoconus. The confocal microscopic changes correlate with the outcomes in the treatment and the sham groups. PMID- 25708283 TI - Interfacial control toward efficient and low-voltage perovskite light-emitting diodes. AB - High-performance perovskite light-emitting diodes are achieved by an interfacial engineering approach, leading to the most efficient near-infrared devices produced using solution-processed emitters and efficient green devices at high brightness conditions. PMID- 25708284 TI - Unexpected versatility in bacterial riboswitches. AB - Bacterial riboswitches are elements present in the 5'-untranslated regions (UTRs) of mRNA molecules that bind to ligands and regulate the expression of downstream genes. Riboswitches typically regulate the expression of protein-coding genes. However, mechanisms of riboswitch-mediated regulation have recently been shown to be more diverse than originally thought, with reports showing that riboswitches can regulate the expression of noncoding RNAs and control the access of proteins, such as transcription termination factor Rho and RNase E, to a nascent RNA. Riboswitches are also increasingly used in biotechnology, with advances in the engineering of synthetic riboswitches and the development of riboswitch-based sensors. In this review we address the emerging roles and mechanisms of riboswitch-mediated regulation in natura and recent progress in the development of riboswitch-based technology. PMID- 25708286 TI - Protein Science Best Paper awards to Chih-Chia (Jack) Su and Minttu Virkki. PMID- 25708288 TI - Bile acid activated receptors are targets for regulation of integrity of gastrointestinal mucosa. AB - Bile acids are the end product of cholesterol metabolism. Synthesized in the liver, primary bile acids are secreted by hepatocytes and are transformed by intestinal microbiota into secondary bile acids. In addition to their role in cholesterol and lipid absorption, bile acids act as signaling molecules activating a family of nuclear and G-protein-coupled receptors collectively known as bile acid activated receptors (BARs). These receptors are expressed at high density in enterohepatic tissues, but their expression occurs throughout the body and their activation mediates regulatory functions of bile acids on lipids and glucose metabolism and immunity. In the gastrointestinal tract, BARs maintain intestinal integrity, and their deletion makes the intestine more susceptible to the damage caused by acetylsalicylic acid and nonsteroidal anti-inflammatory drugs (NSAIDs). Deficiency in farnesoid X receptor and G-protein-coupled bile acid receptor 1 genes alters the expression/activity of cystathione gamma-lyase and endothelial nitric oxide synthase, two genes involved in the synthesis of hydrogen sulfide and nitric oxide, i.e., two gaseous mediators that have been shown to be essential in maintaining the intestinal homeostasis. In addition, farnesoid X receptor regulates the expression of transporters required for secretion of phospholipid by hepatocytes. Because phospholids attenuate intestinal injury caused by acetylsalicylic acid and NSAIDs, BAR agonism could be exploited to protect the intestinal mucosa against injury caused by anti inflammatory medications. This approach might be useful in the prevention of so called NSAID enteropathy, a common clinical condition occurring in long-term users of NSAIDs, which is not effectively prevented either by cotreatment with proton pump inhibitors or by the use of coxibs. PMID- 25708289 TI - Celebratory message from the Editor-in-Chief on the 50th anniversary of the Journal of Gastroenterology. PMID- 25708290 TI - Evidence-based clinical practice guidelines for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. AB - Nonalcoholic fatty liver disease (NAFLD) is currently the most common cause of chronic liver disease in industrialized countries worldwide, and has become a serious public health issue not only in Western countries but also in many Asian countries including Japan. Within the wide spectrum of NAFLD, nonalcoholic steatohepatitis (NASH) is a progressive form of disease, which often develops into liver cirrhosis and increases the risk of hepatocellular carcinoma. In turn, a large proportion of NAFLD/NASH is the liver manifestation of metabolic syndrome, suggesting that NAFLD/NASH plays a key role in the pathogenesis of systemic atherosclerotic diseases. Currently, a definite diagnosis of NASH requires liver biopsy, though various noninvasive measures are under development. The mainstays of prevention and treatment of NAFLD/NASH include dietary restriction and exercise; however, pharmacological approaches are often necessary. Currently, vitamin E and thiazolidinedione derivatives are the most evidence-based therapeutic options, although the clinical evidence for long-term efficacy and safety is limited. This practice guideline for NAFLD/NASH, established by the Japanese Society of Gastroenterology in cooperation with The Japan Society of Hepatology, covers lines of clinical evidence reported internationally in the period starting from 1983 to January 2012, and each clinical question was evaluated using the GRADE system. Based on the primary release of the full version in Japanese, this English summary provides the core essentials of this clinical practice guideline comprising the definition, diagnosis, and current therapeutic recommendations for NAFLD/NASH in Japan. PMID- 25708291 TI - Prediction of prevalent but not incident non-alcoholic fatty liver disease by levels of serum testosterone. AB - BACKGROUND AND AIMS: The association between testosterone level and development of non-alcoholic fatty liver disease (NAFLD) is not well known. We examined the relationship of total testosterone level with development and regression of NAFLD. METHODS: Among the men who had undergone repeated liver ultrasonography in 2 years or more at a health promotion center, subjects with available serum testosterone level at baseline were included in the study. Alcohol consumers (> 20 g/day) were excluded from the study. RESULTS: Among the 1944 men, 44.3% of subjects were diagnosed with NAFLD. Higher level of testosterone significantly lowered the prevalence of fatty liver (odds ratios per SD increase, 0.686 and 0.795 at baseline and follow-up, respectively). During the median 4.2 years follow-up, 22.4% of subjects in the normal group developed fatty liver, and 21.0% of subjects in the NAFLD group recovered at the follow-up. In longitudinal analyses, higher level of testosterone was significantly associated with the development or regression of fatty liver, before adjustment for obesity and metabolic parameters. However, in the full-adjusted model, testosterone level did not influence the development or regression of fatty liver. CONCLUSIONS: Although testosterone level was significantly low in the subjects with NAFLD in cross sectional analyses, baseline testosterone level did not independently influence the development or regression of fatty liver at the median 4.2 years follow-up. Obesity and metabolic parameters may play key roles in the link between testosterone level and NAFLD. PMID- 25708292 TI - Predictors and impact of early cerebral infarction after aneurysmal subarachnoid hemorrhage. AB - BACKGROUND AND PURPOSE: Cerebral infarction is a frequent and serious complication of aneurysmal subarachnoid hemorrhage (SAH). This study aimed to identify independent predictors of the timing of cerebral infarction and clarify its impact on disease course and patients' outcome. METHODS: All consecutive patients with SAH admitted to our institution from January 2005 to December 2012 were analyzed. Serial computed tomography (CT) scans were evaluated for cerebral infarctions. Demographic, clinical, laboratory and radiological data of patients during hospitalization as well as clinical follow-ups 6 months after SAH were recorded. RESULTS: Of the 632 analyzed patients, 320 (51%) developed cerebral infarction on CT scans. 136 patients (21.5%) with early cerebral infarction (occurring within 3 days after SAH) had a significantly higher risk of unfavorable outcome than patients with late infarction [odds ratio (OR) 2.94; P = 0.008], a higher in-hospital mortality (OR 3.14; P = 0.0002) and poorer clinical outcome after 6 months (OR 0.54; P < 0.0001). The rates of decompressive craniectomy (OR 1.96, P = 0.0265), tracheostomy (OR 1.87, P = 0.0446), the duration of intensive care unit stay and mechanical ventilation were significantly higher in patients with early infarction. In multivariate analysis, Hunt and Hess grades 4 and 5 (OR 2.06, P = 0.008), Fisher grades 3 and 4 (OR 3.99, P = 0.014), sustained elevations of intracranial pressure >20 mmHg (OR 5.95, P < 0.0001) and early vasospasm on diagnostic angiograms (OR 3.01, P = 0.008) were predictors of early cerebral infarction. CONCLUSION: Early cerebral infarction after SAH is associated with severe clinical course and unfavorable outcome and can be reliably predicted by poor initial clinical condition, thick subarachnoid clot, early angiographic vasospasm and sustained elevations of intracranial pressure. PMID- 25708293 TI - Cross sectional imaging of metal-on-metal hip arthroplasties. PMID- 25708294 TI - Changing phenotype of diffuse idiopathic skeletal hyperostosis over time: comment on the article by Saleem and Hawass. PMID- 25708295 TI - Weak linkage between the heaviest rainfall and tallest storms. AB - Conventionally, the heaviest rainfall has been linked to the tallest, most intense convective storms. However, the global picture of the linkage between extreme rainfall and convection remains unclear. Here we analyse an 11-year record of spaceborne precipitation radar observations and establish that a relatively small fraction of extreme convective events produces extreme rainfall rates in any region of the tropics and subtropics. Robust differences between extreme rainfall and convective events are found in the rainfall characteristics and environmental conditions, irrespective of region; most extreme rainfall events are characterized by less intense convection with intense radar echoes not extending to extremely high altitudes. Rainfall characteristics and environmental conditions both indicate the importance of warm-rain processes in producing extreme rainfall rates. Our results demonstrate that, even in regions where severe convective storms are representative extreme weather events, the heaviest rainfall events are mostly associated with less intense convection. PMID- 25708296 TI - Accumulation and biotransformation of vanadium in Opuntia microdasys. AB - The accumulation and biotransformation of vanadium (V) in Opuntia microdasys were investigated under hydroponic conditions to determine the toxicity of pentavalent V [i.e., V(V)] to the plant and the mechanism of tolerance by the plant to V. Results showed that the concentration of V(V) in nutrient solution was negatively correlated to plant biomass. Moreover, the water content of cladodes decreased under V(V) stress. In V(V)-treated plants, most of the adsorbed V remained in the roots and in the cell wall compartment. In the cladodes, the ratios of V(V) to Vtotal were lower in V(V)-treated plants than those in the control plants. These results indicate that a high concentration of V(V) is toxic to O. microdasys but that the plants may limit this toxicity through the compartmentalization of V in the cell wall and the biotransformation of V from V(V) to tetravalent V [i.e., V(IV)]. PMID- 25708297 TI - Effects of (Anti) Androgenic Endocrine Disruptors (DEHP and Butachlor) on Immunoglobulin M (IgM) and Leukocytes Counts of Male Rainbow Trout (Oncorhynchus mykiss). AB - The effect of two anti-androgenic endocrine disrupting compounds, i.e. the plasticizer di (2-ethylhexyl) phthalate (DEHP) and herbicide butachlor, were evaluated for their effects on immunoglobulin M (IgM) and leukocytes in male rainbow trout. Also, plasma testosterone (T) concentration was measured to confirm their anti-androgenic effects. In the first experiment, trout were treated with 50 mg/kg (body weight) DEHP intraperitoneally, and in the second one, fish were exposed to 0.39 mg/L butachlor for 10 days. The results showed that T concentrations and white blood cells were significantly lower in fish exposed to either DEHP or butachlor compared to control fish (p < 0.05). Fish showed significantly elevated neutrophil levels and decreased lymphocyte levels in the butachlor (p < 0.05); however, no significant difference was observed in lymphocyte and neutrophils values in the DEHP treatment (p > 0.05). In addition, no significant differences were found in IgM, eosinophil and monocyte parameters in either DEHP or butachlor treatments (p > 0.05). These results confirmed that leukocytes counts can be considered as a novel marker of immunotoxicity triggered by (anti) androgenic endocrine disruptors. PMID- 25708298 TI - Pruritic Papules Following Lumbar Corset Use: A Quiz. Grover's disease. PMID- 25708299 TI - The catalytic role of the M2 metal ion in PP2Calpha. AB - PP2C family phosphatases (the type 2C family of protein phosphatases; or metal dependent phosphatase, PPM) constitute an important class of signaling enzymes that regulate many fundamental life activities. All PP2C family members have a conserved binuclear metal ion active center that is essential for their catalysis. However, the catalytic role of each metal ion during catalysis remains elusive. In this study, we discovered that mutations in the structurally buried D38 residue of PP2Calpha (PPM1A) redefined the water-mediated hydrogen network in the active site and selectively disrupted M2 metal ion binding. Using the D38A and D38K mutations of PP2Calpha as specific tools in combination with enzymology analysis, our results demonstrated that the M2 metal ion determines the rate limiting step of substrate hydrolysis, participates in dianion substrate binding and stabilizes the leaving group after P-O bond cleavage. The newly characterized catalytic role of the M2 metal ion in this family not only provides insight into how the binuclear metal centers of the PP2C phosphatases are organized for efficient catalysis but also helps increase our understanding of the function and substrate specificity of PP2C family members. PMID- 25708301 TI - Oesophageal perforation during neo-adjuvant brachytherapy for oesophageal squamous cell carcinoma. AB - Neo-adjuvant brachytherapy (NBT) for oesophageal cancer is under rapid development in recent years and more reports are required to elucidate its complications and drawbacks. Here, we report a case treated for NBT whose oesophagus was perforated during the procedure and mention necessary precautions to avoid it. A 73 year old male whose upper gastrointestinal endoscopy showed a lesion extending from 29 cm to 33 cm of the incisors with a histology of poorly differentiated squamous cell carcinoma, without metastases. Endoscopic ultrasonography diagnosed a T3 N0 grade tumour. He was selected for NBT and neo adjuvant chemotherapy. The patient received 5 Gy in the first session of NBT, but in the second session before receiving the same dosage his control chest X-ray showed the tip of the catheter to be out of the oesophageal tract. After confirmation of the perforation by Gastrografin, we performed total oesophagectomy combined with a gastric pull-up procedure. To our best knowledge, our case is the first reported complication related to the direct effect of the catheter and tissue manipulation rather than the radiation beam. Weakness in the oesophageal wall due to tumour involvement makes it prone to perforation by any rigid catheter. PMID- 25708300 TI - Discovering monotonic stemness marker genes from time-series stem cell microarray data. AB - BACKGROUND: Identification of genes with ascending or descending monotonic expression patterns over time or stages of stem cells is an important issue in time-series microarray data analysis. We propose a method named Monotonic Feature Selector (MFSelector) based on a concept of total discriminating error (DEtotal) to identify monotonic genes. MFSelector considers various time stages in stage order (i.e., Stage One vs. other stages, Stages One and Two vs. remaining stages and so on) and computes DEtotal of each gene. MFSelector can successfully identify genes with monotonic characteristics. RESULTS: We have demonstrated the effectiveness of MFSelector on two synthetic data sets and two stem cell differentiation data sets: embryonic stem cell neurogenesis (ESCN) and embryonic stem cell vasculogenesis (ESCV) data sets. We have also performed extensive quantitative comparisons of the three monotonic gene selection approaches. Some of the monotonic marker genes such as OCT4, NANOG, BLBP, discovered from the ESCN dataset exhibit consistent behavior with that reported in other studies. The role of monotonic genes found by MFSelector in either stemness or differentiation is validated using information obtained from Gene Ontology analysis and other literature. We justify and demonstrate that descending genes are involved in the proliferation or self-renewal activity of stem cells, while ascending genes are involved in differentiation of stem cells into variant cell lineages. CONCLUSIONS: We have developed a novel system, easy to use even with no pre existing knowledge, to identify gene sets with monotonic expression patterns in multi-stage as well as in time-series genomics matrices. The case studies on ESCN and ESCV have helped to get a better understanding of stemness and differentiation. The novel monotonic marker genes discovered from a data set are found to exhibit consistent behavior in another independent data set, demonstrating the utility of the proposed method. The MFSelector R function and data sets can be downloaded from: http://microarray.ym.edu.tw/tools/MFSelector/. PMID- 25708302 TI - Radiation induced depigmentation disorder in two patients with breast cancer: Exploring a rare accompaniment. AB - Radiation induced depigmentation disorder is a rare accompaniment. We herein report two patients of bilateral breast cancer developing depigmentation disorder, initially confined to the radiation portal with subsequent generalization within few months of completion of whole breast radiotherapy. Both these patients had no prior history of vitiligo or other autoimmune disorder. This brief report highlights the importance of awareness of this association in appropriate decision making in susceptible patients thereby preventing this morbidity and its psychological ramifications. PMID- 25708303 TI - Holocord low grade astrocytoma--Role of radical irradiation and chemotherapy. AB - Spinal intradural tumors, especially those extending along the entire length of the spinal cord, termed as 'holocord' tumors are uncommon. Most of these are gliomas, with astrocytomas (low grade) predominating in children and ependymomas in adults. Other histologies, though reported, are even rarer. Management is debatable, with both surgery and radiotherapy of such extensive tumors posing challenges. We describe a case of a 14-year-old girl with holocord astrocytoma extending from cervicomedullary junction till lumbar spine, who recovered full neurological function following radical irradiation of entire spine followed by temozolomide-based chemotherapy. No grade 3/4 bone marrow morbidity was seen. Five years following treatment, she maintained normal neurological function and apparently normal pubertal and skeletal growth despite residual disease visible on imaging. Literature review of existing reports of holocord astrocytomas highlighting management and outcome is presented. PMID- 25708304 TI - Understanding the epigenetics of neurodevelopmental disorders and DOHaD. AB - The Developmental Origins of Health and Disease (DOHaD) hypothesis refers to the concept that 'malnutrition during the fetal period induces a nature of thrift in fetuses, such that they have a higher change of developing non-communicable diseases, such as obesity and diabetes, if they grow up in the current well-fed society.' Epigenetics is a chemical change in DNA and histones that affects how genes are expressed without alterations of DNA sequences. Several lines of evidence suggest that malnutrition during the fetal period alters the epigenetic expression status of metabolic genes in the fetus and that this altered expression can persist, and possibly lead to metabolic disorders. Similarly, mental stress during the neonatal period can alter the epigenetic expression status of neuronal genes in neonates. Moreover, such environmental, stress induced, epigenetic changes are transmitted to the next generation via an acquired epigenetic status in sperm. The advantage of epigenetic modifications over changes in genetic sequences is their potential reversibility; thus, epigenetic alterations are potentially reversed with gene expression. Therefore, we potentially establish 'preemptive medicine,' that, in combination with early detection of abnormal epigenetic status and early administration of epigenetic restoring drugs may prevent the development of disorders associated with the DOHaD. PMID- 25708307 TI - Neuroprotection in ischemic stroke: what does the future hold? AB - Neurodegenerative and vascular disease processes are commonly found concurrently in the brains of elderly patients, highlighting the difficulty in determining which processes may be responsible for cognitive impairment. Therapeutically, it may be more sensible to assume that most patients have mixed dementia. Therefore, therapies with multimodal modes of action would be expected to confer neuronal protection. Ischemic stroke is also associated with a complex pathophysiology and a high incidence of post-stroke cognitive impairment, but evidence for the efficacy of neuroprotective treatments in humans is contradictory (mainly due to a failed translation from bench to bedside). Nevertheless, emerging drug therapies continue to undergo testing in prospective, randomized, controlled studies. Natural biologicals, such as Actovegin, or smaller biological molecules with multifaceted effects in the restorative phase of ischemia are likely candidates for efficacy testing. In addition, a number of non-pharmacological interventions, especially lifestyle interventions, are also the subject of current research and would eventually be expected to supplement the treatment and prevention of ischemic stroke. PMID- 25708306 TI - The pathogenesis of pediatric cerebral malaria: eye exams, autopsies, and neuroimaging. AB - Several advances in our understanding of pediatric cerebral malaria (CM) have been made over the past 25 years. Accurate clinical diagnosis is enhanced by the identification of a characteristic retinopathy, visible by direct or indirect ophthalmoscopy, the retinal changes (retinal whitening, vessel color changes, white-centered hemorrhages) being consistently associated with intracerebral sequestration of parasites in autopsy studies. Autopsies have yielded information at tissue levels in fatal CM, but new insights into critical pathogenetic processes have emerged from neuroimaging studies, which, unlike autopsy-based studies, permit serial observations over time and allow comparisons between fatal cases and survivors. Brain swelling has emerged as the major risk factor for death, and, among survivors, brain volume diminishes spontaneously over 24-48 hours. Studies of life-threatening and fatal malaria are suggesting new approaches to identifying and caring for those at highest risk; potential adjuvants should be evaluated and implemented where they are most needed. PMID- 25708305 TI - Analytical workflow profiling gene expression in murine macrophages. AB - Comprehensive and simultaneous analysis of all genes in a biological sample is a capability of RNA-Seq technology. Analysis of the entire transcriptome benefits from summarization of genes at the functional level. As a cellular response of interest not previously explored with RNA-Seq, peritoneal macrophages from mice under two conditions (control and immunologically challenged) were analyzed for gene expression differences. Quantification of individual transcripts modeled RNA Seq read distribution and uncertainty (using a Beta Negative Binomial distribution), then tested for differential transcript expression (False Discovery Rate-adjusted p-value < 0.05). Enrichment of functional categories utilized the list of differentially expressed genes. A total of 2079 differentially expressed transcripts representing 1884 genes were detected. Enrichment of 92 categories from Gene Ontology Biological Processes and Molecular Functions, and KEGG pathways were grouped into 6 clusters. Clusters included defense and inflammatory response (Enrichment Score = 11.24) and ribosomal activity (Enrichment Score = 17.89). Our work provides a context to the fine detail of individual gene expression differences in murine peritoneal macrophages during immunological challenge with high throughput RNA-Seq. PMID- 25708308 TI - Monoclonal antibody therapy in multiple sclerosis: critical appraisal and new perspectives. AB - Monoclonal antibodies (mAbs) have been used as experimental treatments of multiple sclerosis (MS) since the 1980s, with the advantage of a high specificity for their target but disadvantages due to their immunogenicity. A literature review of experimental and disposable mAbs in the treatment of MS was performed, putting into perspective the clinical impact that these novel therapies can have and the main challenges facing their use in the daily practice. mAbs therapy resulted in a clear paradigm shift in MS therapeutics. Their use in early, inflammatory phases could have the potential to prevent or delay disability. However, it is still unclear how and when these powerful biological weapons can be used safely in the management of MS. The challenge then is how to obtain the best benefit-risk ratio and how to monitor and prevent emergent safety concerns. PMID- 25708309 TI - Building a roadmap for developing combination therapies for Alzheimer's disease. AB - Combination therapy has proven to be an effective strategy for treating many of the world's most intractable diseases. A growing number of investigators in academia, industry, regulatory agencies, foundations and advocacy organizations are interested in pursuing a combination approach to treating Alzheimer's disease. A meeting co-hosted by the Accelerate Cure/Treatments for Alzheimer's Disease Coalition, the Critical Path Institute and the Alzheimer's Association addressed challenges in designing clinical trials to test multiple treatments in combination and outlined a roadmap for making such trials a reality. PMID- 25708310 TI - A ruthenium(II) complex inhibits tumor growth in vivo with fewer side-effects compared with cisplatin. AB - The antitumor activity of a ruthenium(II) polypyridyl complex, Delta [Ru(bpy)2(HPIP)](ClO4)2 (Delta-Ru1, where bpy=2,2'-bipyridine, HPIP=2-(2 hydroxyphenyl)imidazo[4,5-f][1,10]phenanthroline), was evaluated. The in vivo experiments showed that Delta-Ru1 inhibited the growth of a human cervical carcinoma cell line (HeLa) xenotransplanted into nude mice with efficiency similar to that of cisplatin. Histopathology examination of the tumors from treated xenograft models was consistent with apoptosis in tumor cells. Importantly, in striking contrast with cisplatin, Delta-Ru1 did not cause any detectable side effects on the kidney, liver, peripheral neuronal system, or the hematological system at the pharmacologically effective dose. The preclinical studies reported here provide support for the clinical use of Delta-Ru1 as an exciting new drug candidate with lower toxicity than cisplatin, endowed with proapoptotic properties. PMID- 25708311 TI - Relationship between hip flexion and ankle dorsiflexion during swing phase in chronic stroke patients. AB - BACKGROUND: During the clinical examination of stroke patients, it is common to observe that involuntary hip flexion occurs during voluntary ankle dorsiflexion (synkinesia). This suggests that there is a relationship between these two joints. We hypothesized that there may be a relationship between hip and ankle flexion during swing phase of the gait cycle. The objective of this study was to determine if there is a biomechanical relationship between peak hip flexion and peak ankle dorsiflexion during the swing phase of the gait cycle following stroke. METHOD: The paretic lower limbs of 60 patients with stroke were evaluated using clinical tests and 3D-gait analysis. The clinical assessment included muscle strength, spasticity and passive range of ankle motion. The gait analysis focused on sagittal frontal and transverse kinematic gait parameters during swing. FINDINGS: A stepwise-linear-regression indicated that peak hip flexion and gait speed were the only 2 parameters which accounted for peak ankle dorsiflexion. There was also a significant negative correlation between peak hip flexion and peak ankle dorsiflexion during swing, and a significant positive correlation between hip flexor and ankle dorsiflexor muscle strength. INTERPRETATION: These results suggest that the biomechanical behaviour of hip and ankle joints during the swing phase of the gait cycle is linked in patients with stroke. They also suggest that two strategies exist: if sufficient ankle dorsiflexion is present, less hip flexion is required (distal-strategy) whereas if dorsiflexion is reduced, it is compensated for by an increase in peak hip flexion (proximal-strategy). PMID- 25708312 TI - Early growth response 1 (Egr-1) directly regulates GABAA receptor alpha2, alpha4, and theta subunits in the hippocampus. AB - The homeostatic regulation of neuronal activity in glutamatergic and GABAergic synapses is critical for neural circuit development and synaptic plasticity. The induced expression of the transcription factor early growth response 1 (Egr-1) in neurons is tightly associated with many forms of neuronal activity, but the underlying target genes in the brain remained to be elucidated. This study uses a quantitative real-time PCR approach, in combination with in vivo chromatin immunoprecipitation, and reveals that GABAA receptor subunit, GABRA2 (alpha2), GABRA4 (alpha4), and GABRQ (theta) genes, are transcriptional targets of Egr-1. Transfection of a construct that over-expresses Egr-1 in neuroblastoma (Neuro2A) cells up-regulates the alpha2, alpha4, and theta subunits. Given that Egr-1 knockout mice display less GABRA2, GABRA4, and GRBRQ mRNA in the hippocampus, and that Egr-1 directly binds to their promoters and induces mRNA expression, the present findings support a role for Egr-1 as a major regulator for altered GABAA receptor composition in homeostatic plasticity, in a glutamatergic activity dependent manner. The early growth response 1 (Egr-1) is an inducible transcription factor to mediate rapid gene expression by neuronal activity. However, its underlying molecular target genes and mechanisms are not fully understood. We suggest that GABAA receptor subunits, GABRA2 (alpha2), GABRA4 (alpha4), and GABRQ (theta) genes are transcriptional targets of Egr-1. Neuronal activity-dependent up-regulation of Egr-1 might lead to altered subtypes of GABAA receptors for the maintenance of homeostatic excitatory and inhibitory balance for the regulation of synaptic strength. PMID- 25708313 TI - Transfusion medicine reviews special edition: focus on Australia. PMID- 25708314 TI - Donald Metcalf, 'Father of CSF' (1929-2014). PMID- 25708316 TI - Microcephaly, ectodermal dysplasia, multiple skeletal anomalies and distinctive facial appearance: delineation of cerebro-dermato-osseous-dysplasia. AB - In 1980, a novel multiple malformation syndrome has been described in a 17-year old woman with micro- and turricephaly, intellectual disability, distinctive facial appearance, congenital atrichia, and multiple skeletal anomalies mainly affecting the limbs. Four further sporadic patients and a couple of affected sibs are also reported with a broad clinical variability. Here, we describe a 4-year old girl strikingly resembling the original report. Phenotype comparison identified a recurrent pattern of multisystem features involving the central nervous system, and skin and bones in five sporadic patients (including ours), while the two sibs and a further sporadic case show significant phenotypic divergence. Marked clinical variability within the same entity versus syndrome splitting is discussed and the term "cerebro-dermato-osseous dysplasia" is introduced to define this condition. PMID- 25708317 TI - Network activity underlying the illusory self-attribution of a dummy arm. AB - Neuroimaging has demonstrated that the illusory self-attribution of body parts engages frontal and intraparietal brain areas, and recent evidence further suggests an involvement of visual body-selective regions in the occipitotemporal cortex. However, little is known about the principles of information exchange within this network. Here, using automated congruent versus incongruent visuotactile stimulation of distinct anatomical locations on the participant's right arm and a realistic dummy counterpart in an fMRI scanner, we induced an illusory self-attribution of the dummy arm. The illusion consistently activated a left-hemispheric network comprising ventral premotor cortex (PMv), intraparietal sulcus (IPS), and body-selective regions of the lateral occipitotemporal cortex (LOC). Importantly, during the illusion, the functional coupling of the PMv and the IPS with the LOC increased substantially, and dynamic causal modeling revealed a significant enhancement of connections from the LOC and the secondary somatosensory cortex to the IPS. These results comply with the idea that the brain's inference mechanisms rely on the hierarchical propagation of prediction error. During illusory self-attribution, unpredicted ambiguous sensory input about one's body configuration may result in the generation of such prediction errors in visual and somatosensory areas, which may be conveyed to parietal integrative areas. PMID- 25708315 TI - Study of correlation between state and composition of lipid phase and change in erythrocytes structure under induction of oxidative processes. AB - We investigated human blood erythrocytes under oxidative stress in vitro and established a correlation between composition and state of lipids and changes in erythrocytes structure under induced oxidative stress. These changes may serve as an indicator of not only the erythrocyte state but of systemic processes that occur at the level of the whole organism, including various pathologies as well. We found that a pyrimidine derivative xymedon used in the present study is an effective inhibitor of oxidative processes. Xymedon may be useful as an antioxidant for preserving the structural and functional characteristics of the erythrocytes in the treatment of organisms exposed to physical and toxic factors causing oxidative stress. PMID- 25708318 TI - Polyparameter linear free energy relationship for wood char-water sorption coefficients of organic sorbates. AB - Black carbons, including soots, chars, activated carbons, and engineered nanocarbons, have different surface properties, but the extent to which these affect their sorbent properties is not known. To evaluate this for an environmentally ubiquitous form of black carbon, biomass char, the surface of a well-studied wood char was probed using 14 sorbates exhibiting diverse functional groups, and the data were fit with a polyparameter linear free energy relationship to assess the importance of the various possible sorbate-char surface interactions. Sorption from water to water-wet char evolved with the sorbate's degree of surface saturation and depended on only a few sorbate parameters: log K(d)L/kg) = [(4.03 +/- 0.14) + (-0.15 +/- 0.04) log a(i)] V + [( 0.28 +/- 0.04) log a(i)] S + (-5.20 +/- 0.21) B, where a(i) is the aqueous saturation of the sorbate i, V is McGowan's characteristic volume, S reflects polarity, and B represents the electron-donation basicity. As is generally observed for activated carbon, the sorbate's size encouraged sorption from water to the char, whereas its electron donation and proton acceptance discouraged sorption from water. The magnitude and saturation dependence differed significantly from what has been seen for activated carbons, presumably reflecting the unique surface chemistries of these 2 black carbon materials and suggesting that black carbon-specific sorption coefficients will yield more accurate assessments of contaminant mobility and bioavailability, as well as evaluation of a site's response to remediation. PMID- 25708319 TI - Expression and specificity profile of the major acetate transporter AcpA in Aspergillus nidulans. AB - AcpA has been previously characterized as a high-affinity transporter essential for the uptake and use of acetate as sole carbon source in Aspergillus nidulans. Here, we follow the expression profile of AcpA and define its substrate specificity. AcpA-mediated acetate transport is detected from the onset of conidiospore germination, peaks at the time of germ tube emergence, and drops to low basal levels in germlings and young mycelia, where a second acetate transporter is also becoming apparent. AcpA activity also responds to acetate presence in the growth medium, but is not subject to either carbon or nitrogen catabolite repression. Short-chain monocarboxylates (benzoate, formate, butyrate and propionate) inhibit AcpA-mediated acetate transport with apparent inhibition constants (Ki) of 16.89+/-2.12, 9.25+/-1.01, 12.06+/-3.29 and 1.44+/-0.13mM, respectively. AcpA is also shown not to be directly involved in ammonia export, as proposed for its Saccharomyces cerevisiae homologue Ady2p. In the second part of this work, we search for the unknown acetate transporter expressed in mycelia, and for other transporters that might contribute to acetate uptake. In silico analysis, genetic construction of relevant null mutants, and uptake assays, reveal that the closest AcpA homologue (AN1839), named AcpB, is the 'missing' secondary acetate transporter in mycelia. We also identify two major short-chain carboxylate (lactate, succinate, pyruvate and malate) transporters, named JenA (AN6095) and JenB (AN6703), which however are not involved in acetate uptake. This work establishes a framework for further exploiting acetate and carboxylate transport in filamentous ascomycetes. PMID- 25708320 TI - Carbon footprint of robotically-assisted laparoscopy, laparoscopy and laparotomy: a comparison. AB - BACKGROUND: To date there have been no comprehensive, comparative assessments of the environmental impact of surgical modalities. Our study seeks to quantify and compare the total greenhouse gas emissions, or 'carbon footprint', attributable to three surgical modalities. METHODS: A review of 150 staging procedures, employing laparotomy (LAP), conventional laparoscopy (LSC) or robotically assisted laparoscopy (RA-LSC), was performed. The solid waste generated (kg) and energy consumed (kWh) during each case were quantified and converted into their equivalent mass of carbon dioxide (kg CO(2) e) release into the environment. The carbon footprint is the sum of the waste production and energy consumption during each surgery (kg CO(2) e). RESULTS: The total carbon footprint of a RA-LSC procedure is 40.3 kg CO(2) e/patient (p < 0.01). This represents a 38% increase over that of LSC (29.2 kg CO(2) e/patient; p < 0.01) and a 77% increase over LAP (22.7 kg CO(2) e/patient; p < 0.01). CONCLUSIONS: Our results provide clinicians, administrators and policy-makers with knowledge of the environmental impact of their decisions to facilitate adoption of sustainable practices. PMID- 25708321 TI - Characterization of site-specific biomechanical properties of human meniscus Importance of collagen and fluid on mechanical nonlinearities. AB - Meniscus adapts to joint loads by depth- and site-specific variations in its composition and structure. However, site-specific mechanical characteristics of intact meniscus under compression are poorly known. In particular, mechanical nonlinearities caused by different meniscal constituents (collagen and fluid) are not known. In the current study, in situ indentation testing was conducted to determine site-specific elastic, viscoelastic and poroelastic properties of intact human menisci. Lateral and medial menisci (n=26) were harvested from the left knee joint of 13 human cadavers. Indentation tests, using stress-relaxation and dynamic (sinusoidal) loading protocols, were conducted for menisci at different sites (anterior, middle, posterior, n=78). Sample- and site-specific axisymmetric finite element models with fibril-reinforced poroelastic properties were fitted to the corresponding stress-relaxation curves to determine the mechanical parameters. Elastic moduli, especially the instantaneous and dynamic moduli, showed site-specific variation only in the medial meniscus (p<0.05 between the sites). The instantaneous and dynamic elastic moduli of the anterior horn were significantly (p<0.05) greater in the medial than lateral meniscus. The phase angle showed no statistically significant variation between the sites (p>0.05). The values for the strain-dependent fibril network modulus (nonlinear behaviour of collagen) were significantly different (p<0.05) between all sites in the medial menisci. Additionally, there was a significant difference (p<0.01) in the strain-dependent fibril network modulus between the lateral and medial anterior horns. The initial permeability was significantly different (p<0.05) in the medial meniscus only between the middle and posterior sites. For the strain dependent permeability coefficient, only anterior and middle sites showed a significant difference (p<0.05) in the medial meniscus. This parameter demonstrated a significant difference (p<0.05) between lateral and medial menisci at the anterior horns. Our results reveal that under in situ indentation loading, medial meniscus shows more site-dependent variation in the mechanical properties as compared to lateral meniscus. In particular, anterior horn of medial meniscus was the stiffest and showed the most nonlinear mechanical behaviour. The nonlinearity was related to both collagen fibrils and fluid. PMID- 25708322 TI - Syntheses and structures of two gold(I) coordination compounds derived from P-S hybrid ligands and their efficient catalytic performance in the photodegradation of nitroaromatics in water. AB - Solvothermal reactions of HAuCl4.4H2O with a P-S hybrid ligand N,N bis(diphenylphosphanylmethyl)-amino-thiocarbamide (dppatc) at 80 degrees C and 115 degrees C produced two Au-P-S complexes, [Au2(dppatc)2]Cl2 (1) and [Au2(dppmt)2]n (2) (dppmtH = (diphenylphosphino)methanethiol). 1 and 2 were characterized by elemental analyses, IR and UV-vis spectra, thermal-gravity analyses, powder X-ray diffraction and single crystal X-ray diffraction analyses. Compound 1 contains a dinuclear [Au2(dppatc)2](2+) dication, while 2 has a one dimensional chain formed by AuAu aurophilic interactions. Compounds 1 and 2 exhibited excellent catalytic activity toward the photodegradation of nitrobenzene, p-nitrophenol and 2,4-dinitrophenol in aqueous solutions. The degradation reactions followed the zero-order kinetic model, in which the three nitroaromatics could be converted into CO2 and H2O in 92-96% yields. PMID- 25708323 TI - Specific anti-IIa activity is a key indicator of safety and efficacy in validation of biosimilarity of unfractioned heparin preparations. AB - We compared anti-IIa activity of a heparin analogue and a reference product was carried out to confirm their biosimilarity. The experiment was based on the method of estimation of anti-IIa activity of a commercial sodium heparin preparation according to United States Pharmacopoeia. High similarity of the two medicinal heparin preparations by this parameter is shown. The method is recommended for the use in comparability studies. PMID- 25708325 TI - Antihypoxic activity of cycloprolylglycine analogs. AB - We studied antihypoxic activity of analogs of endogenous cyclic dipeptide cycloprolylglycine in a mouse model of normobaric hypoxia with hypercapnia and found that antixypoxic effect depends on the structure of the substance. It was shown that different pharmacophores are responsible for the antihypoxic, nootropic, and anxiolytic effects of cycloprolylglycine. PMID- 25708324 TI - Possible role and application of fMRI in the screening of release-active drugs. AB - Functional magnetic resonance imaging (fMRI) of the brain was applied for preclinical evaluation of the efficiency of Divaza preparation intended for the treatment of cerebrovascular disorders. Psychological testing (Stroop task) in the magnetic field of fMRI was performed before and after 12-week treatment course using a double blind placebo-controlled protocol. It was shown that standard psychological and neuropsychological protocols do not allow fully estimate the results of treatment, whereas fMRI targeted the pool of cerebral structures activated during task solution. In the treatment group (in contrast to placebo), active zones in these structures were found only during task solution. Thus, resolution capability of fMRI significantly extends the range of rational screening by identifying active zones and can radically change the procedure of selection and clinical trials. PMID- 25708326 TI - Effects of immunomodulators on functional activity of innate immunity cells infected with Streptococcus pneumoniae. AB - Low activity of bactericidal enzymes was found in innate immunity cells infected with S. pneumonia. The death of these cells was fastened under these conditions. On the contrary, treatment with antibiotic maxifloxacin was followed by an increase in activity of bactericidal enzymes in phagocytes and induced their death via necrosis. Analysis of the therapeutic properties of immunomodulators tinrostim and licopid in combination with maxifloxacin showed that these combinations correct functional activity of cells infected with S. pneumonia. PMID- 25708327 TI - Effects of combined treatment with complex S. typhimurium antigens and factors stimulating osteogenesis (curettage, BMP-2) on multipotent bone marrow stromal cells and serum concentration of cytokines in CBA mice. AB - The content of multipotent stromal cells (MSC) in the bone marrow and efficiency of their cloning (ECF-MSC) increased by 3 times 1 day after administration of complex S. typhimurium antigens to CBA mice, while the relative content of alkaline phosphatase-positive MSC colonies (marker of osteogenesis; P(+) colonies) decreased from 14% (control) to 3%. After administration of the complex S. typhimurium antigens to CBA mice 3 h after (or 3 h before) curettage or treatment with morphogenetic protein (BMP-2), the content of MSC and ECF-MSC decreased on the next day by ~3 times in comparison with animals receiving antigens alone and approached the control level. The relative content of P(+) colonies increased to 20 and 35%, respectively, in comparison with animals receiving antigens (3%), but was significantly lower than after curettage (34%) or BMP-2 (42%) administration. Expression of IL-1beta, IL-6, IL-12, TNF-alpha, and IFN-gamma genes in the primary cultures of stromal bone marrow cells induced by antigen administration was suppressed, while the concentrations of IL-12 and TNF-alpha in the culture medium sharply decreased after antigen treatment in combination with curettage or BMP-2 administration. Administration of complex S. typhimurium antigens after pretreatment with BMP-2 (3 h before) was associated with a decrease in serum levels of IL-2, IFN-gamma, IL-12, and TNF-alpha in mice receiving BMP-2+S. typhimurium group 4 h after treatment in comparison with the animals receiving only S. typhimurium antigens alone by 1.9, 4.4, 1.5, and 6 times, respectively, i.e. to normal level or below it, while the concentration of IL-10 increased by almost 2 times, which probably reflected anti-inflammatory properties of BMP-2. These data probably attest to competitive relations between osteogenesis and immune response at the level of MSC. PMID- 25708328 TI - Chronodependent effect of interleukin-2 on mouse spleen cells in the model of cyclophosphamide immunosuppression. AB - We studied the chronodependent effect of IL-2 in the experimental model of immunodeficiency, cyclophosphamide-induced immunosuppression in mice. IL-2 in a dose of 100 U/ mouse was administered at 10.00 and 16.00 for 3 days after injection of cyclophosphamide. In contrast to the morning treatment with the cytokine, evening administration produced antiapoptotic effect on splenocytes and stimulated proliferation to a greater extent. This was accompanied by an increase in the number of CD4(+), CD25(+) and CD4(+)25(+) cells in the spleen to a level of intact mice. More pronounced effect of the evening mode of IL-2 administration on the proliferation and subpopulation composition of mouse spleen cells in the studied model can be associated with high blood level of CD25(+) cells at this time of the day. PMID- 25708329 TI - Photodynamic inactivation of bacteria in vitro under the effect of blue light. AB - We studied the photodynamic inactivation of E. coli, S. aureus, and P. aeruginosa in vitro. Bacteria suspensions were incubated with riboflavin and exposed to blue light emitted by a diode matrix. Exogenous photosensitizer riboflavin efficiently inactivated bacteria, while methylene blue was ineffective. Under the effect of blue light in a dose of 117 J/cm(2), photoinactivation of E. coli, S. aureus, and P. aeruginosa occurred without photosensitizer riboflavin. PMID- 25708330 TI - Effects of permafrost microorganisms on skin wound reparation. AB - Local application of ointment with Bacillus spp. strain MG8 (15,000-20,000 living bacterial cells), isolated from permafrost specimens, on the skin wound of about 60 mm(2) stimulated the reparation processes in experimental mice. A possible mechanism stimulating the regeneration of the damaged tissues under the effect of MG8 could be modulation of the immune system reactivity with more rapid switchover to humoral immunity anti-inflammatory mechanisms aimed at de novo synthesis of protein. PMID- 25708331 TI - Effects of preventive administration of oxidized dextran on liver injury and reparative regeneration in mice infected with influenza A/H5N1 virus. AB - Intranasal infection of outbred male mice with influenza A/H5N1 A/goose/Krasnoozerskoye/627/05 virus led to high (85%) mortality of animals. Morphological studies of liver specimens showed destructive changes in the parenchyma (93.5% hepatocytes), caused by long persistence of the virus in the liver. The virus persistence was conjugated with activation of cellular immunity, manifesting by an increase in the counts of cells with high expression of proinflammatory cytokines (TNF-alpha) and lysosomal enzymes (lysozyme, cathepsin D). Injections of oxidized dextran 3 and 1 days before infection reduced mortality and 2-fold attenuated destructive changes in the liver, presumably due to prevention of virus penetration into the target cells, modulation of immune reactions, and stimulation of reparative plastic processes. PMID- 25708332 TI - Changes in the serum protein composition in mice with transplanted Ehrlich's carcinoma. AB - Injection of blood serum from mice with Ehrlich's carcinoma stimulates the growth of transplanted tumor, which proves the presence of tumor-specific factors in the serum. Experiments on (CBA*C57Bl/6)F1 male mice with transplanted Ehrlich's carcinoma demonstrated the appearance of new proteins in the serum, some of them are identified. The authors suggest continuing the search for tumor-associated factor by combining proteomic analytical methods and testing of identified candidate proteins for their effects on tumor growth. PMID- 25708333 TI - Autoantibodies to plasminogen and their role in tumor diseases. AB - Plasma level of IgG autoantibodies to plasminogen was measured by ELISA in patients with benign prostatic hyperplasia (n=25), prostatic cancer (n=17), lung cancer (n=15), and healthy volunteers (n=44). High levels of IgG to plasminogen were found in 2 (12%) of 17 healthy women, in 1 (3.6%) of 27 specimens in a healthy man, in 17 (68%) of 25 specimens in prostatic cancer, in 10 (59%) of 17 specimens in lung cancer, and in 5 (30%) of 15 specimens in benign prostatic hyperplasia. Comparison of plasma levels of anti-plasminogen IgG by affinity chromatography showed 3-fold higher levels in patients with prostatic cancer vs. healthy men. PMID- 25708334 TI - P388 leukemia in CDF1 mice as the test system for studies of tumor-associated neoangiogenesis and hypercoagulation. AB - Blood levels of vascular endothelial growth factor, the main marker of angiogenesis activity, and coagulation hemostasis were studied in CDF1 mice with transplanted P-388 lymphocytic leukemia. Blood levels of vascular endothelial growth factor increased by 168% in mice with tumors. The animals developed the hypercoagulation syndrome manifesting in shorter activated partial thromboplastin time and prothrombin time and development of hyperfibrinogenemia. PMID- 25708335 TI - Nanostructure changes in the intervertebral discs after experimental laser irradiation. AB - Laser-induced changes in the intervertebral discs were studied by the method of atomic force microscopy. Alteration of the proximal caudal intervertebral discs was modeled in rats: puncture and exposure to diode laser (2, 3, or 5 W) in constant or pulse regimens or only puncture (control). Nanostructure of disc surface was estimated by surface skewness, root mean square and average roughness, and coefficient of kurtosis. Maximum positive effect and signs of regenerative changes in the surface microstructure of the intervertebral discs were found after exposure to laser (2-3 W) in constant or pulse regimens. PMID- 25708336 TI - Specific role of nitric oxide (NO) in avian embryonic myogenesis. AB - NO plays a specific role in avian embryogenesis stimulating the development of muscle tissue. The main consumer of NO synthesized at the initial stage of avian embryogenesis is presumably a factor stimulating myogenesis. PMID- 25708337 TI - Dihydroquercetin effects on the morphology and antioxidant/prooxidant balance of the prostate in rats with sulpiride-induced benign hyperplasia. AB - A course of dihydroquercetin (antioxidant) injections to 5-month-old Wistar rats with sulpiride-induced benign prostatic hyperplasia led to reduction of proliferative activity in the glandular structures and to attenuation of the inflammatory reaction in the tissue. Prostatic antioxidant/prooxidant balance returned to normal after the treatment. PMID- 25708338 TI - The use of automated system for EEG analysis and feedback cerebral stimulation to stop epileptiform activity in WAG/Rij rats. AB - Original software program is described, which revealed EEG activity characteristic of the onset of epileptic seizure and turned on electrical stimulation of the nucleus basalis of Meynert in WAG/Rij rats with congenital absence epilepsy. The program reliably detected the onset of seizure and automatically stopped it with a high-frequency train of electrical impulses (100 150 Hz). Thus, a feedback system of deep brain stimulation has been developed to stop early manifestations of absence epileptiform seizures. The study can be a base to develop an implanted apparatus to automatically analyze EEG and stimulate the brain to stop the epileptic seizures. PMID- 25708339 TI - Umbilical cord blood for autologous transfusion in the early postnatal ontogeny: analysis of cell composition and viability during long-term culturing. AB - Changes in cell composition and viability as well as the content and functional activity of hemopoietic progenitor cells were analyzed during long-term (up to 1 month at 4 degrees C) storage of human umbilical cord blood cells. No significant quantitative changes in erythrocytes were found during this period. The total content and viability of leukocytes changed, which resulted in the prevalence of mononuclear cells (lymphocytes and monocytes). Analysis of functional activity of hemopoietic stem cells in semisolid culture revealed a decrease in the relative content of CFU during the first week of storage [corrected] and inability of cells to colony formation after 2 weeks. PMID- 25708340 TI - Endogenous progenitors as the source of cell material for ischemic damage repair in experimental myocardial infarction under conditions of changed concentration of vascular endothelial growth factor. AB - We studied the effect of VEGF-A in experimental myocardial infarction on attraction of progenitor cells into the regeneration zone. The appearance of CD34(+)CD45(+) cells known as low-differentiated progenitor cells was observed in the damaged myocardial tissue in the presence of a considerable excess of VEGF-A. These cells can act as precursors of mesenchymal tissues depending on the direction of differentiation. PMID- 25708341 TI - Comparative analysis of the expression of surface markers on fibroblasts and fibroblast-like cells isolated from different human tissues. AB - Expression of 20 surface markers was analyzed in cultures of mesenchymal stromal cells of the umbilical cord, fibroblasts from adult and fetal human skin, and fibroblast-like cells of fetal liver was analyzed by fl ow cytometry. The studied cultures did not express hemopoietic cells markers, but were positive for CD73, CD90, and CD105 markers recommended by the International Society of Cell Therapy for the identification of the multipotent mesenchymal stromal cells. Fetal liver fibroblast-like cells were positive for CD54; this marker was absent in skin fibroblast cultures, but was expressed by umbilical cord mesenchymal stromal cells. Further study of these cells revealed a minor subpopulation of cells co expressing CD24 and CD90 or CD24 and CD54. We hypothesized that these cells probably participate in epithelial mesenchymal transition. PMID- 25708344 TI - Oesophagectomy is a safe option for early adenocarcinoma arising from Barrett's oesophagus. AB - BACKGROUND: Over the last decade, there has been a shift towards endoscopic treatment of high-grade dysplasia (HGD) and T1 stage adenocarcinoma arising in Barrett's oesophagus. Although short-term outcomes are promising, longer-term outcomes remain uncertain and the role of these therapies versus surgery is debated, with surgical mortality rates assumed. However, few studies have specifically determined the outcome for oesophagectomy in the subgroup with HGD or T1 adenocarcinoma. To determine this, we evaluated experience with oesophagectomy for HGD and T1 adenocarcinoma in Barrett's oesophagus. METHODS: Data were analysed from a prospective audit database for oesophagectomy performed at two public and four associated private hospitals in Adelaide, South Australia. Patients with HGD, T1a and T1b adenocarcinoma who underwent oesophagectomy from 20 February 1998 to 17 February 2012 were identified, and their perioperative, post-operative and survival outcomes were determined. RESULTS: From 452 oesophagectomy procedures, 63 (13.9%) individuals who underwent surgery for HGD or T1 adenocarcinoma were identified; HGD - 19 (30.1%), T1a - 18 (28.5 %), T1b - 26 (41.3%). Major complications occurred in eight (12.7%) patients including one (1.6%) death following surgery. Five-year survival for HGD and T1a cancers using Kaplan-Meier analysis was not significantly different from a matched general population without cancer. CONCLUSION: Oesophagectomy for HGD and T1 stage adenocarcinoma in Barrett's oesophagus is associated with favourable outcomes. Outcomes following endoscopic treatments should be benchmarked against these outcomes, not those following oesophagectomy for advanced cancer. PMID- 25708345 TI - From Nutrition to Public Policy: Improving Healthy Food Access by Enhancing Farm to-Table Legislation in Louisiana. PMID- 25708346 TI - Structural and electronic modification of MoS2 nanosheets using S-doped carbon for efficient electrocatalysis of the hydrogen evolution reaction. AB - We discovered the in situ generation of S-doped carbon sandwiched between the MoS2 nano-sheets during pyrolysis of Mo(VI)-polydopamine (PDA) in the presence of elemental sulfur. This causes enrichment of MoS2 with more edge planes (2H -> 1T), also resulting in enhanced charge density and electronic conductivity. The phase transformed MoS2[@S-C(PDA)] exhibits enhanced HER activity with eta = 160 mV at a current density of 10 mA cm(-2). PMID- 25708347 TI - Effects of acute transcranial direct current stimulation in hot and cold working memory tasks in healthy and depressed subjects. AB - Dorsolateral prefrontal cortex (DLPFC) hypoactivity and subcortical hyperactivity have been associated to cognitive impairment for non-emotional ("cold") and emotional ("hot") working memory tasks in major depressive disorder (MDD). We investigated whether an increase of DLPFC activity using transcranial direct current stimulation (tDCS) would differently influence the performance in working memory tasks in depressed and healthy subjects. Forty young adult participants (20 with MDD and 20 healthy controls) were randomized to a single, sham controlled, bifrontal (left anodal/right cathodal), 2mA, 30min tDCS session in a parallel design. The n-back and the internal shift task (IST) were used as proxies of cold and hot working memory performance, respectively. Active tDCS compared to sham promoted more accurate and faster responses to the n-back task for both patients and controls. Conversely, only patients presented an improvement in response times for the IST task. Our findings suggest that the mechanisms of tDCS in MDD involve modulation of both cold and hot working memory. We discuss these findings considering the modulatory top-down effects of tDCS on subcortical structures via prefrontal activation, and how spreading of activation might be different for healthy volunteers versus depressed patients. We also discuss the role of tDCS in cognitive amelioration for depressed patients. Finally, the distinct effects of tDCS in the "hot" cognition task for healthy and depressed participants are indicative that tDCS outcomes are also regulated by differences in baseline activity of the stimulated network. PMID- 25708348 TI - Influence of acoustic energy walk-off on acousto-optic diffraction characteristics. AB - Influence of acoustic beam energy walk-off on characteristics of Bragg diffraction of light is studied theoretically and experimentally by the example of a paratellurite single crystal. Two cases of isotropic and anisotropic light scattering are examined. Angular and frequency characteristics of acousto-optic interaction are calculated in wide ranges of Bragg angles and ultrasound frequencies by means of modified Raman-Nath equations. It is shown that the walk off can substantially change the width of angular and frequency ranges, resulting in their narrowing or broadening subject to position of the operating point in the Bragg angle frequency characteristic. Coefficients of broadening are introduced for characterization of this effect. It is established that frequency dependences of the broadening coefficients are similar to the Bragg angle frequency characteristics. Experimental verification of the calculations is carried out with a paratellurite cell of 10.5 degrees crystal cut. PMID- 25708349 TI - Rotary ultrasonic elliptical machining for side milling of CFRP: tool performance and surface integrity. AB - The rotary ultrasonic elliptical machining (RUEM) has been recognized as a new effective process to machining circular holes on CFRP materials. In CFRP face machining, the application of grinding tools is restricted for the tool clogging and the machined surface integrity. In this paper, we proposed a novel approach to extend the RUEM process to side milling of CFRP for the first time, which kept the effect of elliptical vibration in RUEM. The experiment apparatus was developed, and the preliminary experiments were designed and conducted, with comparison to conventional grinding (CG). The experimental results showed that when the elliptical vibration was applied in RUEM, a superior cutting process can be obtained compared with that in CG, including providing reduced cutting forces (2-43% decrement), an extended tool life (1.98 times), and improved surface integrity due to the intermittent material removal mechanism and the excellent chip removal conditions achieved in RUEM. It was concluded that the RUEM process is suitable to mill flat surface on CFRP composites. PMID- 25708350 TI - Revolutionizing sports medicine with ultrasound. PMID- 25708352 TI - Practice management. Introduction. PMID- 25708351 TI - American Medical Society for Sports Medicine (AMSSM) position statement: interventional musculoskeletal ultrasound in sports medicine. AB - The use of diagnostic and interventional ultrasound has significantly increased over the past decade. A majority of the increased utilization is by nonradiologists. In sports medicine, ultrasound is often used to guide interventions such as aspirations, diagnostic or therapeutic injections, tenotomies, releases, and hydrodissections. This American Medical Society for Sports Medicine (AMSSM) position statement critically reviews the literature and evaluates the accuracy, efficacy, and cost-effectiveness of ultrasound-guided injections in major, intermediate, and small joints, and soft tissues, all of which are commonly performed in sports medicine. New ultrasound-guided procedures and future trends are also briefly discussed. Based upon the evidence, the official AMSSM position relevant to each subject is made. PMID- 25708353 TI - Health technology assessment: at the junction of evidence, policy, and reimbursement. PMID- 25708354 TI - American Medical Society for Sports Medicine (AMSSM) recommended sports ultrasound curriculum for sports medicine fellowships. PMID- 25708355 TI - Variation of exciton-vibrational coupling in photosystem II core complexes from Thermosynechococcus elongatus as revealed by single-molecule spectroscopy. AB - The spectral properties and dynamics of the fluorescence emission of photosystem II core complexes are investigated by single-molecule spectroscopy at 1.6 K. The emission spectra are dominated by sharp zero-phonon lines (ZPLs). The sharp ZPLs are the result of weak to intermediate exciton-vibrational coupling and slow spectral diffusion. For several data sets, it is possible to surpass the effect of spectral diffusion by applying a shifting algorithm. The increased signal-to noise ratio enables us to determine the exciton-vibrational coupling strength (Huang-Rhys factor) with high precision. The Huang-Rhys factors vary between 0.03 and 0.8. The values of the Huang-Rhys factors show no obvious correlation between coupling strength and wavelength position. From this result, we conclude that electrostatic rather than exchange or dispersive interactions are the main contributors to the exciton-vibrational coupling in this system. PMID- 25708357 TI - Resuming anticoagulation after brain hemorrhage while on warfarin treatment: INR at the time of bleeding should be taken into consideration-authors' reply. PMID- 25708356 TI - Fathoming the kynurenine pathway in migraine: why understanding the enzymatic cascades is still critically important. AB - Kynurenine pathway, the quantitatively main branch of tryptophan metabolism, has been long been considered a source of nicotinamide adenine dinucleotide, although several of its products, the so-called kynurenines, are endowed with the capacity to activate glutamate receptors, thus potentially influencing a large group of functions in the central nervous system (CNS). Migraine, a largely unknown pathology, is strictly related to the glutamate system in the CNS pathologic terms. Despite the large number of studies conducted on migraine etio-pathology, the kynurenine pathway has been only recently linked to this disease. Nonetheless, some evidence suggests an intriguing role for some kynurenines, and an exploratory study on the serum kynurenine level might be helpful to better understand possible alterations of the kynurenine pathway in patients suffering from migraine. PMID- 25708358 TI - Low frequency of PAX8-PPARgamma rearrangement in follicular thyroid carcinomas in Japanese patients. AB - Paired-box gene 8 (PAX8)-peroxisome proliferator-activated receptor-gamma (PPARgamma) gene fusion has been identified at significant frequency in follicular thyroid carcinomas (FTCs) with cytogenetically detectable translocation t(2;3)(q13;p25). This represents a possible specific molecular marker for follicular carcinoma. In this study, we examined PAX8-PPARgamma rearrangement in 24 FTC samples from Japanese patients by reverse transcribed polymerase chain reaction (RT-PCR) using two upstream PAX8 primers located in exons 7 and 8 and a downstream primer in exon 1 of PPARgamma. The fusion gene was detected in only one of 24 FTCs (4%). The FTC with PAX8-PPARgamma rearrangement from a 56-year-old man showed a product consistent with fusion between exon 8 of PAX8 and exon 1 of PPARgamma. It was confirmed by direct sequencing. This FTC was histologically encapsulated, composed of trabeculae and small follicles and had complete penetration of the capsule by tumor tissues (minimally invasive type). The frequency of the fusion gene in this study was much lower than the 29-63% noted in reports from other countries suggesting that FTCs in Japanese patients may have a special genetic background, and that the high iodine intake from a typical Japanese diet might influence the frequency of the fusion gene in FTCs. PMID- 25708359 TI - ViralmiR: a support-vector-machine-based method for predicting viral microRNA precursors. AB - BACKGROUND: microRNAs (miRNAs) play a vital role in development, oncogenesis, and apoptosis by binding to mRNAs to regulate the posttranscriptional level of coding genes in mammals, plants, and insects. Recent studies have demonstrated that the expression of viral miRNAs is associated with the ability of the virus to infect a host. Identifying potential viral miRNAs from experimental sequence data is valuable for deciphering virus-host interactions. Thus far, a specific predictive model for viral miRNA identification has yet to be developed. METHODS AND RESULTS: Here, we present ViralmiR for identifying viral miRNA precursors on the basis of sequencing and structural information. We collected 263 experimentally validated miRNA precursors (pre-miRNAs) from 26 virus species and generated sequencing fragments from virus and human genomes as the negative dataset. Support vector machine and random forest models were established using 54 features from RNA sequences and secondary structural information. The results show that ViralmiR achieved a balanced accuracy higher than 83%, which is superior to that of previously developed tools for identifying pre-miRNAs. CONCLUSIONS: The easy-to-use ViralmiR web interface has been provided as a helpful resource for researchers to use in analyzing and deciphering virus-host interactions. The web interface of ViralmiR can be accessed at http://csb.cse.yzu.edu.tw/viralmir/. PMID- 25708361 TI - Erratum: combined conjunctival autograft and overlay amniotic membrane transplantation; a novel surgical treatment for pterygium: erratum. AB - [This corrects the article on p. 399 in vol. 9, PMID: 25667744.]. PMID- 25708360 TI - Three-dimensional biomechanical gait characteristics at baseline are associated with progression to total knee arthroplasty. AB - OBJECTIVE: To determine if baseline 3-dimensional (3-D) biomechanical gait patterns differed between those patients with moderate knee osteoarthritis (OA) who progressed to total knee arthroplasty (TKA) and those that did not, and whether these differences had predictive value. METHODS: Fifty-four patients with knee OA had ground reaction forces and segment motions collected during gait. 3-D hip, knee, and ankle angles and moments were calculated over the gait cycle. Amplitude and temporal waveform characteristics were determined using principal component analysis. At followup 5-8 years later, 26 patients reported undergoing TKA. Unpaired t-tests were performed on baseline demographic and waveform characteristics between TKA and no-TKA groups. Receiver operating curve analysis, stepwise discriminate analysis, and logistic regression analysis determined the combination of features that best classified TKA and no-TKA groups and their predictive ability. RESULTS: Baseline demographic, symptomatic, and radiographic variables were similar, but 7 gait variables differed (P < 0.05) between groups. A multivariate model including overall knee adduction moment magnitude, knee flexion/extension moment difference, and stance-dorsiflexion moment had a 74% correct classification rate, with no overtraining based on cross-validation. A 1 unit increase in model score increased by 6-fold the odds of progression to TKA. CONCLUSION: In addition to the link between higher overall knee adduction magnitude and future TKA, an outcome of clear clinical importance, novel findings include altered sagittal plane moment patterns indicative of reduced ability to unload the joint during midstance. This combination of dynamic biomechanical factors had a 6-fold increased odds of future TKA; adding baseline demographic and clinical factors did not improve the model. PMID- 25708364 TI - Salami slicing--how thin is the slice? PMID- 25708365 TI - Physical activity and stress in adult Hispanics. AB - PURPOSE: Physical inactivity and obesity are major U.S. health concerns. Hispanics have higher rates of obesity and lower incidence of meeting physical activity (PA) recommendations, however most studies on PA focus on non-Hispanic Whites. This study examined type and amount of physical activities, and their relationship to age, BMI, employment, and stress in adult female Hispanics. DATA SOURCES: Sixty-three female Hispanics (mean age 34 years, SD = 10.5) were recruited in the Miami community. By BMI, of 47 women reporting both weight and height, 8.5% were underweight, 38.3% were normal weight, 27.2% were overweight, and 26.0% were obese. Women completed two instruments measuring PA and two measuring stress. CONCLUSIONS: Attitudes toward PA were positive; greatest concerns were job security and finances not exercise. Leisure walking (14.3%) was the most common type of PA followed by activities watching TV (32.8%) and using video games (32.8%). Women with greater stress had higher BMIs and were less physically active (p < .05). IMPLICATIONS FOR PRACTICE: In this sample, exercise was not a main priority although 53% were overweight/obese. Stress related to employment and finances was a major concern. Interventions on stress reduction and incorporating exercise within their daily lives are important strategies. PMID- 25708367 TI - Thimerosal: clinical, epidemiologic and biochemical studies. AB - INTRODUCTION: Thimerosal (or Thiomersal) is a trade name for an organomercurial compound (sodium ethyl-mercury (Hg) thiosalicylate) that is 49.55% Hg by weight, which rapidly decomposes in aqueous saline solutions into ethyl-Hg hydroxide and ethyl-Hg chloride. Developed in 1927, it has been and is still being used as a preservative in some cosmetics, topical pharmaceuticals, and biological drug products, including vaccines. Concerns have been voiced about its use because it is toxic to human cells. Although it is banned in several countries, it continues to be added to some vaccines in the United States and many vaccines in the developing world. DISCUSSION: This critical review focuses on the clinical, epidemiological, and biochemical studies of adverse effects from Thimerosal in developing humans. This review will include research that examines fetal, infant, and childhood death; birth defects; neurodevelopmental testing deficits in children; and neurodevelopmental disorders (attention deficit/hyperactivity disorder, autism spectrum disorder, tic disorder, and specific developmental delays). The review will also look at the research that examined the outcomes of acute accidental ethyl-Hg poisoning in humans. The studies that examine the underlying biochemical insights into the neuronal cellular damage will also be explored. CONCLUSION: The culmination of the research that examines the effects of Thimerosal in humans indicates that it is a poison at minute levels with a plethora of deleterious consequences, even at the levels currently administered in vaccines. PMID- 25708366 TI - ADAR1 is required for differentiation and neural induction by regulating microRNA processing in a catalytically independent manner. AB - Adenosine deaminases acting on RNA (ADARs) are involved in adenosine-to-inosine RNA editing and are implicated in development and diseases. Here we observed that ADAR1 deficiency in human embryonic stem cells (hESCs) significantly affected hESC differentiation and neural induction with widespread changes in mRNA and miRNA expression, including upregulation of self-renewal-related miRNAs, such as miR302s. Global editing analyses revealed that ADAR1 editing activity contributes little to the altered miRNA/mRNA expression in ADAR1-deficient hESCs upon neural induction. Genome-wide iCLIP studies identified that ADAR1 binds directly to pri miRNAs to interfere with miRNA processing by acting as an RNA-binding protein. Importantly, aberrant expression of miRNAs and phenotypes observed in ADAR1 depleted hESCs upon neural differentiation could be reversed by an enzymatically inactive ADAR1 mutant, but not by the RNA-binding-null ADAR1 mutant. These findings reveal that ADAR1, but not its editing activity, is critical for hESC differentiation and neural induction by regulating miRNA biogenesis via direct RNA interaction. PMID- 25708369 TI - Outcome prediction in home- and community-based brain injury rehabilitation using the Mayo-Portland Adaptability Inventory. AB - The objective of the study was to develop statistical formulas to predict levels of community participation on discharge from post-hospital brain injury rehabilitation using retrospective data analysis. Data were collected from seven geographically distinct programmes in a home- and community-based brain injury rehabilitation provider network. Participants were 642 individuals with post traumatic brain injury. Interventions consisted of home- and community-based brain injury rehabilitation. The main outcome measure was the Mayo-Portland Adaptability Inventory (MPAI-4) Participation Index. Linear discriminant models using admission MPAI-4 Participation Index score and log chronicity correctly predicted excellent (no to minimal participation limitations), very good (very mild participation limitations), good (mild participation limitations), and limited (significant participation limitations) outcome levels at discharge. Predicting broad outcome categories for post-hospital rehabilitation programmes based on admission assessment data appears feasible and valid. Equations to provide patients and families with probability statements on admission about expected levels of outcome are provided. It is unknown to what degree these prediction equations can be reliably applied and valid in other settings. PMID- 25708368 TI - Podocalyxin promotes glioblastoma multiforme cell invasion and proliferation by inhibiting angiotensin-(1-7)/Mas signaling. AB - Podocalyxin (PODX) reportedly enhances invasion in many human cancers including glioblastoma multiforme (GBM). Recent studies have shown that the local renin angiotensin system (RAS) in tumor environment contributes significantly to tumor progression. As a counter-regulatory axis in RAS, angiotensin (Ang)-(1-7)/Mas signaling has been shown to inhibit the growth and invasiveness of several human cancers including GBM. In the present study, we examined the crosstalk between PODX and Ang-(1-7)/Mas signaling in GBM cells, and assessed its impact on GBM cell invasion and proliferation. A strong negative correlation between the expression of PODX and Mas in GBM tumor tissues from 10 consecutive patients (r= 0.768, p<0.01) was observed. The stable overexpression of PODX in LN-229 and U 118 MG human GBM cells decreased the expression of Mas at the mRNA and protein levels, which led to decreased density of Ang-(1-7)-binding Mas on the cell membrane. This effect was completely abolished by selective phosphatidylinositol 3-kinase (PI3K) inhibitor BKM120. By contrast, the stable knockdown of PODX in LN 229 and U-118 MG cells increased the expression of Mas and the density of Ang-(1 7)-binding Mas on the cell membrane. Overexpression and knockdown of PODX respectively reversed and enhanced the inhibitory effects of Ang-(1-7) on the expression/activity of matrix metalloproteinase-9 and cell invasion and proliferation in GBM cells. Although the overexpression of Mas showed no significant effect on the promoting effect of PODX on GBM cell invasion and proliferation in the absence of Ang-(1-7), it completely eliminated the effect of PODX in the presence of Ang-(1-7). In conclusion, to the best of our knowledge, the present study provided the first evidence that PODX inhibits Ang-(1-7)/Mas signaling by downregulating the expression of Mas through a PI3K-dependent mechanism in GBM cells. This effect led to enhanced GBM cell invasion and proliferation. The results of this study add new insight into the biological functions of PODX and the molecular mechanisms underlying GBM progression. PMID- 25708370 TI - Skip lymph node metastasis in gastric cancer: is it skipping or skipped? AB - BACKGROUND: Skip metastasis is the presence of a metastatic lymph node (LN) in an extraperigastric (EP) area without perigastric (PG) involvement. The mechanism and prognosis of skip metastasis are still unknown. The purpose of this study was to scrutinize the clinical significance of skip metastasis in gastric cancer. METHODS: Data were reviewed from 6,025 patients who had undergone gastrectomy for primary gastric cancer. Patients were categorized as a PG-only group when the metastatic LNs were limited to only the PG area, as a PG + EP group if metastatic LNs extended to both the PG area and the EP area, and as a skip group if metastatic LNs were in the EP area but there were no metastatic LNs in the PG area. RESULTS: After we had performed matching, the prognosis of the skip group was worse than that of the PG-only group (adjusted hazard ratio 1.69, 95% confidence interval 1.13-2.54) and was similar to that of the PG + EP group (adjusted hazard ratio: 1.54, 95% confidence interval 0.92-2.59). The number of retrieved LNs was less in the skip group than in the other groups, especially from the PG area (p < 0.001). CONCLUSIONS: The prognosis of the skip group was worse than that of the PG-only group and was similar to that of the PG + EP group when the tumor stage was considered. It is difficult to conclude whether skip metastasis is real skipping of cancer cells or a result of inadequate LN sampling. Further evaluation of LNs in the PG area of the skip group could provide more clues for the mechanism of skip metastasis. PMID- 25708371 TI - The medical and laser management of hidradenitis suppurativa. AB - Hidradenitis suppurativa (HS) is a chronic, debilitating skin disease characterized by painful recurrent nodules and abscesses. In advanced stages, sinus tracts form, with resulting fibrotic and cribriform scar formation, leading to dermal contractures and induration of the affected skin. The epidemiology of HS is poorly described, and few population-based studies exist. The reported incidence varies from 0.0003 to 4%. Effective treatment options for HS are limited, and randomized controlled trials addressing the safety and/or efficacy of available treatments are scarce. No medical treatment to date has been approved by the US FDA specifically for the treatment of HS. While some evidence of disease improvement exists with agents including clindamycin and rifampicin, metformin, fumarates, infliximab, and adalimumab, no single treatment has shown overwhelmingly positive outcomes. The lack of randomized controlled trials for most treatments and often disappointing treatment outcomes is disheartening. This study reviews the published evidence for treatment options for HS. PMID- 25708372 TI - Oral direct thrombin inhibitor as an alternative in the management of cerebral venous thrombosis: a series of 15 patients. AB - BACKGROUND: Cerebral vein thrombosis is a rare cause of stroke with significant risk of death and long-term dependency. Anticoagulation has been associated with better long-term prognosis, and vitamin K antagonists are usually prescribed in this setting. AIM: The aim of this study was to present a series of 15 cerebral vein thrombosis patients treated with dabigatran. METHODS: Retrospective study of clinical, imaging, and follow-up characterization of all patients admitted with cerebral vein thrombosis and treated with dabigatran in a tertiary neurology department between June 2011 and December 2013 was conducted. Complications and adverse effects were recorded. Modified Rankin Scale was used to assess clinical severity; excellent outcome was defined as modified Rankin Scale at six-months of 0 to 1. Recanalization was assessed with an angiographic method (computer tomography, magnetic resonance imaging, or digital subtraction angiography). RESULTS: Eighteen patients were admitted for cerebral vein thrombosis. Dabigatran was started in 11 patients, and warfarin was started in 7. Four patients on warfarin were switched to dabigatran because of adverse effects at 0.5, 1, 3.5, and 4 months. A total of 15 patients were treated with dabigatran with median follow-up time of 19 months. Excellent outcome was observed in 87% of patients and recanalization in 80%. CONCLUSIONS: We report the largest series of cerebral vein thrombosis patients treated with dabigatran. Clinical outcome was excellent in most patients and not different from other studies. Dabigatran could possibly be considered an alternative to warfarin; nevertheless, further prospective assessment with randomized controlled studies is warranted. PMID- 25708373 TI - Topical propranolol 1% cream for pyogenic granulomas of the nail: open-label study in 10 patients. PMID- 25708374 TI - An exploratory study on a chest-worn computer for evaluation of diet, physical activity and lifestyle. AB - Recently, wearable computers have become new members in the family of mobile electronic devices, adding new functions to those provided by smart-phones and tablets. As "always-on" miniature computers in the personal space, they will play increasing roles in the field of healthcare. In this work, we present our development of eButton, a wearable computer designed as a personalized, attractive, and convenient chest pin in a circular shape. It contains a powerful microprocessor, numerous electronic sensors, and wireless communication links. We describe its design concepts, electronic hardware, data processing algorithms, and its applications to the evaluation of diet, physical activity and lifestyle in the study of obesity and other chronic diseases. PMID- 25708375 TI - Monitoring of infant feeding behavior using a jaw motion sensor. AB - Rapid weight gain during infancy increases the risk of obesity. Given that infant feeding may contribute to rapid weight gain, it would be useful to develop objective tools which can monitor infant feeding behavior. This paper presents an objective method for examining infant sucking count during meals. A piezoelectric jaw motion sensor and a video camera were used to monitor jaw motions of 10 infants during a meal. Videotapes and sensor signals were annotated by two independent human raters, counting the number of sucks in each 10 second epoch. Annotated data were used as a gold standard for the development of the computer algorithms. The sensor signal was de-noised and normalized prior to computing the per-epoch sucking counts. A leave-one-out cross-validation scheme resulted in a mean error rate of -9.7% and an average intra-class correlation coefficient value of 0.86 between the human raters and the algorithm. PMID- 25708376 TI - Geoprocessing via google maps for assessing obesogenic built environments related to physical activity and chronic noncommunicable diseases: validity and reliability. AB - This study analyzes the reliability and validity of obesogenic built environments related to physical activity and chronic noncommunicable diseases through Google Maps in a heterogeneous urban area (i.e., residential and commercial, very poor and very rich) in Sao Paulo (SP), Brazil. There are no important differences when comparing virtual measures with street audit. Based on Kappa statistic, respectively for validity and reliability, 78% and 80% of outcomes were classified as nearly perfect agreement or substantial agreement. Virtual measures of geoprocessing via Google Maps provided high validity and reliability for assessing built environments. PMID- 25708378 TI - Review of information and communication technology devices for monitoring functional and cognitive decline in Alzheimer's disease clinical trials. AB - Detecting and monitoring early cognitive impairment in Alzheimer's disease (AD) is a significant need in the field of AD therapeutics. Successful AD clinical trial designs have to overcome challenges related to the subtle nature of early cognitive changes. Continuous unobtrusive assessments using Information and Communication Technology (ICT) devices to capture markers of intra-individual change over time to assess cognitive and functional disability therefore offers significant benefits. We review the literature and provide an overview on randomized clinical trials in AD that use intelligent systems to monitor functional decline, as well as strengths, weaknesses, and future directions for the use of ICTs in a new generation of AD clinical trials. PMID- 25708377 TI - Discrimination of mild cognitive impairment and Alzheimer's disease using transfer entropy measures of scalp EEG. AB - Mild cognitive impairment (MCI) is a neurological condition related to early stages of dementia including Alzheimer's disease (AD). This study investigates the potential of measures of transfer entropy in scalp EEG for effectively discriminating between normal aging, MCI, and AD participants. Resting EEG records from 48 age-matched participants (mean age 75.7 years)-15 normal controls, 16 MCI, and 17 early AD-are examined. The mean temporal delays corresponding to peaks in inter-regional transfer entropy are computed and used as features to discriminate between the three groups of participants. Three-way classification schemes based on binary support vector machine models demonstrate overall discrimination accuracies of 91.7- 93.8%, depending on the protocol condition. These results demonstrate the potential for EEG transfer entropy measures as biomarkers in identifying early MCI and AD. Moreover, the analyses based on short data segments (two minutes) render the method practical for a primary care setting. PMID- 25708379 TI - Modeling hospitals' adaptive capacity during a loss of infrastructure services. AB - Resilience in hospitals - their ability to withstand, adapt to, and rapidly recover from disruptive events - is vital to their role as part of national critical infrastructure. This paper presents a model to provide planning guidance to decision makers about how to make hospitals more resilient against possible disruption scenarios. This model represents a hospital's adaptive capacities that are leveraged to care for patients during loss of infrastructure services (power, water, etc.). The model is an optimization that reallocates and substitutes resources to keep patients in a high care state or allocates resources to allow evacuation if necessary. An illustrative example demonstrates how the model might be used in practice. PMID- 25708380 TI - Experimental feasibility study of estimation of the normalized central blood pressure waveform from radial photoplethysmogram. AB - The feasibility of a novel system to reliably estimate the normalized central blood pressure (CBPN) from the radial photoplethysmogram (PPG) is investigated. Right-wrist radial blood pressure and left-wrist PPG were simultaneously recorded in five different days. An industry-standard applanation tonometer was employed for recording radial blood pressure. The CBP waveform was amplitude-normalized to determine CBPN. A total of fifteen second-order autoregressive models with exogenous input were investigated using system identification techniques. Among these 15 models, the model producing the lowest coefficient of variation (CV) of the fitness during the five days was selected as the reference model. Results show that the proposed model is able to faithfully reproduce CBPN (mean fitness = 85.2% +/- 2.5%) from the radial PPG for all 15 segments during the five recording days. The low CV value of 3.35% suggests a stable model valid for different recording days. PMID- 25708382 TI - Intrathecal Pharmacology Update: Novel Dosing Strategy for Intrathecal Monotherapy Ziconotide on Efficacy and Sustainability. AB - INTRODUCTION: Intrathecal drug delivery is a well-defined strategy to treat malignant and nonmalignant pain. Ziconotide is a well-studied intrathecal medicine option that has many attractive qualities, as it is non-granulomagenic, overdose or underdose is not associated with cardiopulmonary compromise or death, and is a non-opoid analgesic. However, it has had slow adoption into pain care algorithms because it has been historically plagued with the connotation of having a narrow therapeutic window and a low sustainability rate. We introduce a novel dosing strategy to improve patient outcomes and sustainability. METHODS: Patients were identified as being an intrathecal candidate and trialed with ziconotide based on the current standard of care. Patient demographics, diagnosis, previous treatment failures, and pre-implant visual analog scale (VAS) scores were recorded. Once the trial was deemed successful, based on the dual bolusing strategy, the patient underwent device implantation. Consecutive patients were prospectively followed. Ziconotide was then initiated with a flex dosing strategy, weighted during nocturnal dosing. Outcome endpoints included: reduction in VAS, side effects, durability of therapy, and systemic opioid use prior to implant and at last visit were noted (calculated to daily morphine equivalents). Primary endpoint was tolerability of ziconotide at three months following new dosing strategy. No industry support or funding was obtained for this project. RESULTS: All enrolled patients met the endpoint of the study of tolerability of ziconotide at three months. Numbers declined to 75% of patients at four months, and 70% of patients at six months. The discontinuing side-effects were most commonly urinary retention and visual hallucinations. There were no serious adverse events and no unresolved complications reported. Numerical rating scale (NRS) decreased on average from 9.06 to 1.8. Opioid reduction in morphine equivalents averaged 91.5% DISCUSSION: The efficacy and tolerability of monotherapy ziconotide may be improved by using a weighted bolus flex dosing strategy as compared with slow continuous infusions. CONCLUSION: We present a novel strategy to deliver ziconotide using a unique continuous infusion flex dosing strategy. Further randomized, prospective, higher-powered studies are needed to critically evaluate the conclusions suggested by this limited prospective case series. PMID- 25708381 TI - A systems biology approach toward understanding seed composition in soybean. AB - BACKGROUND: The molecular, biochemical, and genetic mechanisms that regulate the complex metabolic network of soybean seed development determine the ultimate balance of protein, lipid, and carbohydrate stored in the mature seed. Many of the genes and metabolites that participate in seed metabolism are unknown or poorly defined; even more remains to be understood about the regulation of their metabolic networks. A global omics analysis can provide insights into the regulation of seed metabolism, even without a priori assumptions about the structure of these networks. RESULTS: With the future goal of predictive biology in mind, we have combined metabolomics, transcriptomics, and metabolic flux technologies to reveal the global developmental and metabolic networks that determine the structure and composition of the mature soybean seed. We have coupled this global approach with interactive bioinformatics and statistical analyses to gain insights into the biochemical programs that determine soybean seed composition. For this purpose, we used Plant/Eukaryotic and Microbial Metabolomics Systems Resource (PMR, http://www.metnetdb.org/pmr, a platform that incorporates metabolomics data to develop hypotheses concerning the organization and regulation of metabolic networks, and MetNet systems biology tools http://www.metnetdb.org for plant omics data, a framework to enable interactive visualization of metabolic and regulatory networks. CONCLUSIONS: This combination of high-throughput experimental data and bioinformatics analyses has revealed sets of specific genes, genetic perturbations and mechanisms, and metabolic changes that are associated with the developmental variation in soybean seed composition. Researchers can explore these metabolomics and transcriptomics data interactively at PMR. PMID- 25708383 TI - Successful treatment of hepatitis E virus-associated cryoglobulinemic membranoproliferative glomerulonephritis with ribavirin. AB - Hepatitis E virus genotype-3 (HEV3) infection can cause chronic hepatitis in immunosuppressed patients and induce extra-hepatic manifestations, such as neurological symptoms, kidney injuries, and immune-mediated thrombocytopenia. Very few cases of HEV-induced kidney manifestations have been reported. Herein, we report, for the first time, a case of de novo membranoproliferative glomerulonephritis that occurred in a kidney transplant patient who developed a chronic HEV3 infection, which was successfully treated with ribavirin. PMID- 25708384 TI - The ABA-deficiency suppressor locus HAS2 encodes the PPR protein LOI1/MEF11 involved in mitochondrial RNA editing. AB - The hot ABA-deficiency suppressor2 (has2) mutation increases drought tolerance and the ABA sensitivity of stomata closure and seed germination. Here we report that the HAS2 locus encodes the mitochondrial editing factor11 (MEF11), also known as lovastatin insensitive1. has2/mef11 mutants exhibited phenotypes very similar to the ABA-hypersensitive mutant, hai1-1 pp2ca-1 hab1-1 abi1-2, which is impaired in four genes encoding type 2C protein phosphatases (PP2C) that act as upstream negative regulators of the ABA signaling cascade. Like pp2c, mef11 plants were more resistant to progressive water stress and seed germination was more sensitive to paclobutrazol (a gibberellin biosynthesis inhibitor) as well as mannitol and NaCl, compared with the wild-type plants. Phenotypic alterations in mef11 were associated with the lack of editing of transcripts for the mitochondrial cytochrome c maturation FN2 (ccmFN2) gene, which encodes a cytochrome c-heme lyase subunit involved in cytochrome c biogenesis. Although the abundance of electron transfer chain complexes was not affected, their dysfunction could be deduced from increased respiration and altered production of hydrogen peroxide and nitric oxide in mef11 seeds. As minor defects in mitochondrial respiration affect ABA signaling, this suggests an essential role for ABA in mitochondrial retrograde regulation. PMID- 25708385 TI - Engagement of signaling pathways of protease-activated receptor 2 and MU-opioid receptor in bone cancer pain and morphine tolerance. AB - Pain is one of the most common and distressing symptoms suffered by patients with progression of cancer. Using a rat model of bone cancer, recent findings suggest that proteinase-activated receptor 2 (PAR2) signaling pathways contribute to neuropathic pain and blocking PAR2 amplifies antinociceptive effects of systemic morphine. The purpose of our study was to examine the underlying mechanisms responsible for the role of PAR2 in regulating bone cancer-evoked pain and the tolerance of systemic morphine. Breast sarcocarcinoma Walker 256 cells were implanted into the tibia bone cavity of rats and this evoked significant mechanical and thermal hyperalgesia. Our results showed that the protein expression of PAR2 and its downstream pathways (protein kinases namely, PKCepsilon and PKA) and transient receptor potential vanilloid 1 (TRPV1) were amplified in the dorsal horn of the spinal cord of bone cancer rats compared to control rats. Blocking spinal PAR2 by using FSLLRY-NH2 significantly attenuated the activities of PKCepsilon/PKA signaling pathways and TRPV1 expression as well as mechanical and thermal hyperalgesia. Also, inhibition of PKCepsilon/PKA and TRPV1 significantly diminished the hyperalgesia observed in bone cancer rats. Additionally, blocking PAR2 enhanced the attenuations of PKCepsilon/PKA and cyclic adenosine monophosphate induced by morphine and further extended analgesia of morphine via MU-opioid receptor (MOR). Our data revealed specific signaling pathways, leading to bone cancer pain, including the activation of PAR2, downstream PKCepsilon/PKA, TRPV1 and resultant sensitization of MOR. Targeting one or more of these signaling molecules may present new opportunities for treatment and management of bone cancer pain often observed in clinics. PMID- 25708386 TI - Biotransformations and biological activities of hop flavonoids. AB - Female hop cones are used extensively in the brewing industry, but there is now increasing interest in possible uses of hops for non-brewing purposes, especially in the pharmaceutical industry. Among pharmaceutically important compounds from hops are flavonoids, having proven anticarcinogenic, antioxidant, antimicrobial, anti-inflammatory and estrogenic effects. In this review we aim to present current knowledge on the biotransformation of flavonoids from hop cones with respect to products, catalysis and conversion. A list of microbial enzymatic reactions associated with gastrointestinal microbiota is presented. A comparative analysis of the biological activities of hop flavonoids and their biotransformation products is described, indicating where further research has potential for applications in the pharmaceutical industry. PMID- 25708387 TI - Current approaches in SELEX: An update to aptamer selection technology. AB - Systematic evolution of ligands by exponential enrichment (SELEX) is a well established and efficient technology for the generation of oligonucleotides with a high target affinity. These SELEX-derived single stranded DNA and RNA molecules, called aptamers, were selected against various targets, such as proteins, cells, microorganisms, chemical compounds etc. They have a great potential in the use as novel antibodies, in cancer theragnostics and in biomedical research. Vast interest in aptamers stimulated continuous development of SELEX, which underwent numerous modifications since its first application in 1990. Novel modifications made the selection process more efficient, cost effective and significantly less time-consuming. This article brings a comprehensive and up-to-date review of recent advances in SELEX methods and pinpoints advantages, main obstacles and limitations. The post-SELEX strategies and examples of application are also briefly outlined in this review. PMID- 25708388 TI - A probabilistic method to report predictions from a human liver microsomes stability QSAR model: a practical tool for drug discovery. AB - Using data from the in vitro liver microsomes metabolic stability assay, we have developed QSAR models to predict in vitro human clearance. Models were trained using in house high-throughput assay data reported as the predicted human hepatic clearance by liver microsomes or pCLh. Machine learning regression methods were used to generate the models. Model output for a given molecule was reported as its probability of being metabolically stable, thus allowing for synthesis prioritization based on this prediction. Use of probability, instead of the regression value or categories, has been found to be an efficient way for both reporting and assessing predictions. Model performance is evaluated using prospective validation. These models have been integrated into a number of desktop tools, and the models are routinely used to prioritize the synthesis of compounds. We discuss two therapeutic projects at Genentech that exemplify the benefits of a probabilistic approach in applying the models. A three-year retrospective analysis of measured liver microsomes stability data on all registered compounds at Genentech reveals that the use of these models has resulted in an improved metabolic stability profile of synthesized compounds. PMID- 25708389 TI - Enolase is regulated by Liver X Receptors. AB - Enolase is a glycolytic enzyme known to inhibit cholesteryl ester hydrolases (CEHs). Cholesteryl ester loading of macrophages, as occurs during atherosclerosis, is accompanied by increased Enolase protein and activity. Here, we describe that J774 macrophages treated with LXR agonists exhibit reduced Enolase transcript and protein abundance. Moreover, we show that this reduction is further potentiated by activation of the LXR/RXR heterodimer with the RXR ligand 9-cis retinoic acid. Enolase levels are also reduced in vivo following activation of LXRs in the intestine, but not in the liver. This effect is lost in Lxralphabeta-/- mice. In aggregate, our study identified Enolase as a new target of LXRs in vivo, which may promote cholesterol mobilization for subsequent efflux. PMID- 25708392 TI - Parkinson disease: treatment needs vary between Parkinson disease subtypes. PMID- 25708399 TI - Intrinsic regulations in neural fate commitment. AB - Neural fate commitment is an early embryonic event that a group of cells in ectoderm, which do not ingress through primitive streak, acquire a neural fate but not epidermal or mesodermal lineages. Several extracellular signaling pathways initiated by the secreted proteins bone morphogenetic proteins (BMPs), fibroblast growth factors (FGFs), wingless/int class proteins (WNTs) and Nodal play essential roles in the specification of the neural plate. Accumulating evidence from the studies on mouse and pluripotent embryonic stem cells reveals that except for the extracellular signals, the intracellular molecules, including both transcriptional and epigenetic factors, participate in the modulation of neural fate commitment as well. In the review, we mainly focus on recent findings that the initiation of the nervous system is elaborately regulated by the intrinsic programs, which are mediated by transcriptional factors such as Sox2, Zfp521, Sip1 and Pou3f1, as well as epigenetic modifications, including histone methylation/demethylation, histone acetylation/deacetylation, and DNA methylation/demethylation. The discovery of the intrinsic regulatory machineries provides better understanding of the mechanisms by which the neural fate commitment is ensured by the cooperation between extracellular factors and intracellular molecules. PMID- 25708400 TI - The future role of metal-on-metal hip resurfacing. AB - PURPOSE: The purpose of this review was to assess the ten to 15-year outcomes of metal-on-metal hip resurfacing (MoM HR) when performed at designing and independent centres, and make recommendations for the future use of MoM HR. METHODS: Studies reporting ten to 15-year outcomes for modern MoM HR devices from both designing and independent centres were reviewed. Outcomes from these studies were assessed to allow the formulation of recommendations for the future use of MoM HR. RESULTS: Two MoM HR designs, the Birmingham Hip Resurfacing (BHR) and Conserve Plus, have outcomes reported at a minimum of ten years. The BHR was the only device with outcomes reported at a minimum of ten years by both designing (overall survival of up to 95.8 % at 15 years) and independent surgeons (overall survival of 87.1-94.5 % at ten years). Implant survival in these seven BHR studies was influenced by the pre-operative diagnosis (primary osteoarthritis had better outcomes), gender (male patients had better outcomes), and femoral component head size (larger sizes had better outcomes). In contrast to independent centres, designing surgeons reported acceptable outcomes in female patients undergoing BHR. CONCLUSIONS: There remains a role for MoM HR in young active male patients with primary osteoarthritis, provided the surgeon has sufficient experience in the procedure, the implant has an established record, and the patient is aware of the potential risks associated with MoM bearings and HR. Very experienced HR surgeons may also consider this procedure in females provided they meet the refined inclusion criteria described (including femoral head sizes of 46 mm and above). PMID- 25708401 TI - High functional diversity within species of arbuscular mycorrhizal fungi is associated with differences in phosphate and nitrogen uptake and fungal phosphate metabolism. AB - Plant growth responses following colonization with different isolates of a single species of an arbuscular mycorrhizal (AM) fungus can range from highly beneficial to detrimental, but the reasons for this high within-species diversity are currently unknown. To examine whether differences in growth and nutritional benefits are related to the phosphate (P) metabolism of the fungal symbiont, the effect of 31 different isolates from 10 AM fungal morphospecies on the P and nitrogen (N) nutrition of Medicago sativa and the P allocation among different P pools was examined. Based on differences in the mycorrhizal growth response, high, medium, and low performance isolates were distinguished. Plant growth benefit was positively correlated to the mycorrhizal effect on P and N nutrition. High performance isolates increased plant biomass by more than 170 % and contributed substantially to both P and N nutrition, whereas the effect of medium performance isolates particularly on the N nutrition of the host was significantly lower. Roots colonized by high performance isolates were characterized by relatively low tissue concentrations of inorganic P and short chain polyphosphates and a high ratio between long- to short-chain polyphosphates. The high performance isolates belonged to different morphospecies and genera, indicating that the ability to contribute to P and N nutrition is widespread within the Glomeromycota and that differences in symbiotic performance and P metabolism are not specific for individual fungal morphospecies. PMID- 25708402 TI - Comparative assessment of heavy metals content during the composting and vermicomposting of Municipal Solid Waste employing Eudrilus eugeniae. AB - This study was undertaken to have comparative assessment of heavy metals content during composting and vermicomposting processing of Municipal Solid Waste (MSW). Six scenarios were set up in which three experiments were for composting (controls) denoted as S1 for food waste, S2 for paper waste and S3 for yard waste and the corresponding replicates for vermicomposting processes were S4, S5 and S6. Vermicomposting caused significant reduction in Cd (43.3-73.5%), Cr (11.3 52.8%), Cu (18.9-62.5%), Co (21.4-47.6%), Zn (34.6%) and Ni (19.9-49.6%) compared to composting which showed a progressive increase. Addition of worms did not show any effect on Fe and Mn, most probably from the genesis of organic-bound complexes. The efficacy of utilizing Eudrilus eugeniae was indicated by the high values of bioconcentration factors (BCFs) which were in the order of Cd>Ni>Cu>Co>Cr>Zn and the increase amount of these metals in the earthworms' tissue after the vermicomposting processes. Different values of BCFs were obtained for different heavy metals and this accounted that earthworms exert different metabolic mechanisms. Regression analysis of the reduction percentages (R) in relation to BCF showed that RCdtot.S6, RCrtot.S5 and RCutot.S6 were significantly correlated with BCFCd.S6, BCFCr.S5 and BCFCu.S6 respectively. Thus, in comparison to simple composting processes, data analysis suggested the feasibility of inoculating E. eugeniae to MSW in order to mitigate the content of toxic heavy metals. PMID- 25708403 TI - Assessment of environmental and economic feasibility of Enhanced Landfill Mining. AB - This paper addresses the environmental and economic performance of Enhanced Landfill Mining (ELFM). Based on life cycle assessment and life cycle costing, a detailed model is developed and is applied to a case study, i.e. the first ELFM project in Belgium. The environmental and economic analysis is performed in order to study the valorisation of different waste types in the landfill, such as municipal solid waste, industrial waste and total waste. We found that ELFM is promising for the case study landfill as greater environmental benefits are foreseen in several impact categories compared to the landfill's current situation (the 'Do-nothing' scenario). Among the considered processes, the thermal treatment process dominates both the environmental and economic performances of ELFM. Improvements in the electrical efficiency of thermal treatment process, the calorific value of refuse derived fuel and recovery efficiencies of different waste fractions lead the performance of ELFM towards an environmentally sustainable and economically feasible direction. Although the environmental and economic profiles of ELFM will differ from case to case, the results of this analysis can be used as a benchmark for future ELFM projects. PMID- 25708404 TI - Life Cycle Assessment of mechanical biological pre-treatment of Municipal Solid Waste: a case study. AB - The environmental performance of mechanical biological pre-treatment (MBT) of Municipal Solid Waste is quantified using Life Cycle Assessment (LCA), considering one of the 57 French plants currently in operation as a case study. The inventory is mostly based on plant-specific data, extrapolated from on-site measurements regarding mechanical and biological operations (including anaerobic digestion and composting of digestate). The combined treatment of 46,929 tonnes of residual Municipal Solid Waste and 12,158 tonnes of source-sorted biowaste (as treated in 2010 at the plant) generates 24,550 tonnes CO2-eq as an impact on climate change, 69,943kg SO2-eq on terrestrial acidification and 19,929kg NMVOC eq on photochemical oxidant formation, in a life-cycle perspective. On the contrary MBT induces environmental benefits in terms of fossil resource depletion, human toxicity (carcinogenic) and ecotoxicity. The results firstly highlight the relatively large contribution of some pollutants, such as CH4, emitted at the plant and yet sometimes neglected in the LCA of waste MBT. Moreover this study identifies 4 plant-specific operation conditions which drive the environmental impact potentials induced by MBT: the conditions of degradation of the fermentable fraction, the collection of gaseous flows emitted from biological operations, the abatement of collected pollutants and NOx emissions from biogas combustion. Finally the results underline the relatively large influence of the operations downstream the plant (in particular residuals incineration) on the environmental performance of waste MBT. PMID- 25708405 TI - Potential of compost mixed with tuff and pozzolana in site restoration. AB - The present research is aimed at evaluating the potential of mixtures made of different percentages of compost (10%, 20% and 30% by volume) and inorganic waste from extraction activities (tuff and pozzolana) for site restorations. The materials alone and the mixtures were characterised from a geotechnical point of view, in order to determine the optimal percentage to be used. In particular, the oedometric test and the direct shear test were performed. Also the environmental quality of the materials was investigated through chemical characterisation and a leaching test. In addition, a lab-scale seeding test was carried out to assess the potential phytotoxicity of the mixture. Finally, at the end of the experimentation the accumulation of heavy metals in the plants was determined and the plants+artificial soil system underwent a shear stress test. The presence of compost in the percentages tested did not reduce the mechanical performances of the inorganic residues, guaranteeing good resistance and stability. In fact, the response to oedometric compression, the compression coefficient and the internal friction angle of the mixtures were quite similar to those obtained for tuff and pozzolana alone. The mixtures selected as optimal from a mechanical point of view (30% by volume of compost and 70% by volume of tuff/pozzolana), did not represent a potential hazard for the environment due to the low content and negligible leachability of heavy metals. In addition, such mixtures can provide a good substrate for revegetation thanks to the high content of organic matter and the absence of phytotoxic effects in the conditions tested. PMID- 25708406 TI - Sewage sludge, compost and other representative organic wastes as agricultural soil amendments: Benefits versus limiting factors. AB - Nine different samples of sewage sludges, composts and other representative organic wastes, with potential interest to be used as agricultural soil amendments, were characterized: municipal sewage sludge (SS1 and SS2), agro industrial sludge (AIS), municipal slaughterhouse sludge (MSS), mixed municipal solid waste compost (MMSWC), agricultural wastes compost (AWC), compost produced from agricultural wastes and sewage sludge (AWSSC), pig slurry digestate (PSD) and paper mill wastes (PMW). The characterization was made considering their: (i) physicochemical parameters, (ii) total and bioavailable heavy metals (Cd, Cr, Cu, Ni, Pb, Zn and Hg), (iii) organic contaminants, (iv) pathogenic microorganisms and (v) stability and phytotoxicity indicators. All the sludges, municipal or other, comply with the requirements of the legislation regarding the possibility of their application to agricultural soil (with the exception of SS2, due to its pathogenic microorganisms content), with a content of organic matter and nutrients that make them interesting to be applied to soil. The composts presented, in general, some constraints regarding their application to soil, and their impairment was due to the existence of heavy metal concentrations exceeding the proposed limit of the draft European legislation. As a consequence, with the exception of AWSSC, most compost samples were not able to meet these quality criteria, which are more conservative for compost than for sewage sludge. From the results, the composting of sewage sludge is recommended as a way to turn a less stabilized waste into a material that is no longer classified as a waste and, judging by the results of this work, with lower heavy metal content than the other composted materials, and without sanitation problems. PMID- 25708407 TI - Biodiesel production from waste frying oil using waste animal bone and solar heat. AB - A two-step catalytic process for the production of biodiesel from waste frying oil (WFO) at low cost, utilizing waste animal-bone as catalyst and solar radiation as heat source is reported in this work. In the first step, the free fatty acids (FFA) in WFO were esterified with methanol by a catalytic process using calcined waste animal-bone as catalyst, which remains active even after 10 esterification runs. The trans-esterification step was catalyzed by NaOH through thermal activation process. Produced biodiesel fulfills all the international requirements for its utilization as a fuel. A probable reaction mechanism for the esterification process is proposed considering the presence of hydroxyapatite at the surface of calcined animal bones. PMID- 25708408 TI - Transpiration as landfill leachate phytotoxicity indicator. AB - An important aspect of constructed wetlands design for landfill leachate treatment is the assessment of landfill leachate phytotoxicity. Intravital methods of plants response observation are required both for lab scale toxicity testing and field examination of plants state. The study examined the toxic influence of two types of landfill leachate from landfill in Zakurzewo (L1) and landfill in Wola Pawlowska (L2) on five plant species: reed Phragmites australis (Cav.) Trin. ex Steud, manna grass Glyceria maxima (Hartm.) Holmb., bulrush Schoenoplectus lacustris (L.) Palla, sweet flag Acorus calamus L., and miscanthus Miscanthus floridulus (Labill) Warb. Transpiration measurement was used as indicator of plants response. The lowest effective concentration causing the toxic effect (LOEC) for each leachate type and plant species was estimated. Plants with the highest resistance to toxic factors found in landfill leachate were: sweet flag, bulrush, and reed. The LOEC values for these plants were, respectively, 17%, 16%, 9% in case of leachate L1 and 21%, 18%, 14% in case of L2. Leachate L1 was more toxic than L2 due to a higher pH value under similar ammonia nitrogen content, i.e. pH 8.74 vs. pH 8.00. PMID- 25708409 TI - Lactic acid production from potato peel waste by anaerobic sequencing batch fermentation using undefined mixed culture. AB - Lactic acid (LA) is a necessary industrial feedstock for producing the bioplastic, polylactic acid (PLA), which is currently produced by pure culture fermentation of food carbohydrates. This work presents an alternative to produce LA from potato peel waste (PPW) by anaerobic fermentation in a sequencing batch reactor (SBR) inoculated with undefined mixed culture from a municipal wastewater treatment plant. A statistical design of experiments approach was employed using set of 0.8L SBRs using gelatinized PPW at a solids content range from 30 to 50 g L(-1), solids retention time of 2-4 days for yield and productivity optimization. The maximum LA production yield of 0.25 g g(-1) PPW and highest productivity of 125 mg g(-1) d(-1) were achieved. A scale-up SBR trial using neat gelatinized PPW (at 80 g L(-1) solids content) at the 3 L scale was employed and the highest LA yield of 0.14 g g(-1) PPW and a productivity of 138 mg g(-1) d(-1) were achieved with a 1 d SRT. PMID- 25708410 TI - Histopathologic classification of parapharyngeal space tumors: a case series and review of the literature. AB - The objective of the study is to present a large case series of parapharyngeal space tumors (PPST) and the most comprehensive literature review of tumor histopathologic distribution. The study was designed as internal case series and full Pubmed/MEDLINE electronic database review in a tertiary academic medical center. Tumor histopathology and patient demographics were obtained from a comprehensive Pubmed/MEDLINE database review, as well from an internal case series of 117 patients referred to our center between 1993 and 2013. Main outcome and measures of the study were to define the age, gender, and histopathology of PPST within a large internal case series and among the current body of published literature, and to propose a diagnostic and treatment algorithm for these tumors. Our cohort included 117 cases, 58 females and 59 males, with benign tumors comprising 85 % (n = 99) and malignant tumors 15 % (n = 18). A systematic review of published literature from 1963 to the present revealed 37 case series, and when combined with our present series, yielded a total of 2160 cases. Benign tumors are most common (78.8 %), with tumors of salivary gland (44.4 %), neural (34.4 %), and vascular (2.64 %) origin representing the largest subtypes. Pleomorphic adenomas (30.9 %), paragangliomas (13.1 %), and schwannomas (12.3 %) comprised the majority of all cases. Due to their rarity, data regarding the histopathologic distribution of PPST is scarce. We provide one of the largest case series and the most comprehensive review of these tumors in the literature to date, and offer our algorithm for evaluation and treatment. PMID- 25708411 TI - Surgical results of different palate techniques to treat oropharyngeal collapse. AB - The aim of this study was to assess the surgical success rate of patients undergoing oropharyngeal surgery, selected through drug-induced sleep endoscopy. Secondly, to compare outcomes of the different oropharyngeal surgery techniques applied. The study design was retrospective case series of surgically treated patients from 2006 to 2013. All patients were diagnosed with either moderate or severe obstructive sleep apnea and did not tolerate conventional positive airway pressure. We performed five different surgical techniques to treat oropharyngeal collapse: partial palate resection, uvulopalatopharyngoplasty, Z-palatoplasty, lateral pharyngoplasty and expansion pharyngoplasty. Patients in whom multilevel surgery was performed were excluded. 53 patients were included in our study, 52.8 % were severe obstructive sleep apnea patients, mean age was 43.9 years, mean body mass index 27.5. The surgical success rate according to Sher's criteria was 71.7 %. 47.2 % had a postoperative apnea hypopnea index lower than 10. The highest success rate was measured in patients who underwent expansion pharyngoplasty (90 % according to Sher's criteria, 80 % with a postoperative apnea hypopnea index lower than 10) although it did not reach statistical significance. Our conclusion is that drug-induced sleep endoscopy is a good tool to select surgical candidates in patients with moderate-to-severe obstructive sleep apnea who are not compliant with the optimal therapy. Expansion pharyngoplasty was the surgical technique with the highest success rates. PMID- 25708412 TI - Recurrent neck lesions secondary to pyriform sinus fistula. AB - Recurrent neck lesions associated with third or fourth branchial arch fistula are much less common than those of second arch and usually present with acute suppurative thyroiditis or neck abscess. Our aim is to describe clinical features, management and treatment outcomes of 64 cases of congenital pyriform sinus fistula (PSF). Medical record of these 64 patients (33 males, 31 females) treated at the First Affiliated Hospital of Zhengzhou University from 2011 to 2014 were reviewed. The patients comprised 33 males and 31 females, and their ages ranged from 18 months to 47 years (median 10 years, mean 12.7 years). Neck abscess and recurrent infection was the mode of presentation in 37 cases (57.8 %), 4 patients (6.3 %) presented with acute suppurative thyroiditis, neck mass was the mode of presentation in 17 cases (26.6 %), 2 patients (3.1 %) presented with neck mass with respiratory distress, and cutaneous discharging fistula was the mode of presentation in 1 cases (1.6 %). The remaining 3 patients (4.7 %) presented with cutaneous discharging fistula with neck infection. Investigations performed include barium swallow, CT scan, and ultrasound which were useful in delineating PSF tract preoperatively. Barium swallow was taken as the gold standard for diagnosis. Our patients were treated by fistulectomy with hemithyroidectomy, fistulectomy, fistulectomy with endoscopic electric cauterization, endoscopic electric cauterization or endoscopic coblation cauterization, respectively. Histopathologic examination of the surgical specimens revealed that they were lined with ciliated epithelium, stratified cuboid epithelium with chronic inflammatory cell infiltration and fibrosis. Voice hoarseness occurred after operation in seven patients, but disappeared 1 week later. PSF recurred in 6 patients, 4 of them were cured by a successful re excision. One patient was cured by successful endoscopic electric cauterization. The other 1 has remained asymptomatic for 5 months. In our series, mean follow-up period was 13.3 months and median follow-up period was 12.5 months (range 2-40 months). Presence of congenital PSF should be suspected when intra-thyroidal abscess formation occurs as the gland is resistant to infection. Strong clinical suspicion, barium swallow study, CT scan and ultrasound are the key to diagnosis. Both fistulectomy with hemithyroidectomy and endoscopic treatment have comparable success rate. Endoscopic coblation cauterization may prove a useful and equally effective method of treatment for PSF in future. PMID- 25708413 TI - The use of subtotal petrosectomy in cochlear implant candidates with chronic otitis media. AB - Cochlear implants (CI) candidates with chronic otitis media require special attention and management. The need of opening of the inner ear creates potential routes of spread of infection to subarachnoid spaces and lead to meningitis. The aim of the study was to analyse the technique and complications of subtotal petrosectomy (SP) in cochlear implant candidates with chronic otitis media at three different CI centres. A retrospective study was carried out in three Territory Referral Hospitals. The centres follow Fisch's philosophy and surgical techniques of SP. The study group consisted of 19 patients, 4 men and 15 women, aged 12-82 years. All patients underwent SP with either primary or staged CI implantation. Indications for single or a staged management, difficulties during surgery and complications were analysed. Skin and muscle flap design in primary and revision cases as well as imaging follow-up strategy are discussed. In 14 patients implantation was performed in a single stage and in 5 cases in two stages. Follow-up ranged from 8 months to 10 years. All the patients use their implants and there were no major nor minor complications. The use of subtotal petrosectomy with cochlear implants is a safe and efficient technique when strict surgical steps and rules are applied. Closure of the external ear canal after previous meatoplasty can be challenging and extreme care dissecting the skin flaps is required. In patients with extensive cholesteatoma, active discharge from the ear with resistant bacteria or an "unstable" situation, the procedure can be staged. PMID- 25708414 TI - Placental pathology in relation to stillbirth and neonatal outcome in an extremely preterm population: a prospective cohort study. AB - OBJECTIVE: To study associations between placental histopathology and stillbirth as well as neonatal outcome in a population born extremely preterm. DESIGN: Prospective cohort study. SETTING: Stockholm, Sweden. POPULATION: 167 infants born <27 gestational weeks during 2004-2007. METHODS: One senior perinatal pathologist, blinded to outcome data, evaluated all placental slides. MAIN OUTCOME MEASURES: Intrauterine fetal death, small-for-gestational age, major neonatal morbidity (intraventricular hemorrhage >=grade 3, retinopathy of prematurity >=grade 3, necrotizing enterocolitis, cystic periventricular leukomalacia or severe bronchopulmonary dysplasia) and neonatal mortality. Additional outcome variables were Apgar score at 5 min, sepsis, and treated patent ductus arteriosus. RESULTS: Accelerated villous maturation was associated with a decreased risk for Apgar score <7 at 5 min (p = 0.041). Fetal thrombosis and low placental weight were associated with an increased risk for both intrauterine fetal death (p < 0.001 and p = 0.011, respectively) and small-for gestational age (p < 0.001 and p < 0.001, respectively). CONCLUSION: Placental histology may have prognostic value as it appears to be associated with intrauterine fetal death, as well as with being small-for-gestational age and assignment of a low Apgar score at birth. PMID- 25708415 TI - Two-dimensional separation of ionic species by hyphenation of capillary ion chromatography * capillary electrophoresis-mass spectrometry. AB - The separation of complex mixtures such as biological or environmental samples requires high peak capacities, which cannot be established with a single separation technique. Therefore, multidimensional systems are in demand. In this work, we present the hyphenation of the two most important (orthogonal) techniques in ion analysis, namely, ion chromatography (IC) and capillary electrophoresis (CE), in combination with mass spectrometry. A modulator was developed ensuring a well-controlled coupling of IC and CE separations. Proof-of concept measurements were performed using a model system consisting of nucleotides and cyclic nucleotides. The data are presented in a multidimensional contour plot. Analyte stacking in the CE separation could be exploited on the basis of the fact that the suppressed IC effluent is pure water. PMID- 25708416 TI - Reassessment of endothelin receptor A expression in normal and neoplastic human tissues using the novel rabbit monoclonal antibody UMB-8. AB - The endothelins ET-1, ET-2 and ET-3 are a family of peptides, which exert their actions via two G protein-coupled receptor subtypes, ETA and ETB. ET-1 is a potent vasoconstrictor and is involved in the development of different cardiovascular and renal disorders. Additionally, ET-1 and the ETA receptor have been shown to be important mediators of cancer growth and metastasis. We have extensively characterized the novel monoclonal rabbit anti-ETA antibody UMB-8 using transfected cells as well as mouse, rat and human tissues. UMB-8 was then tested in a large series of formalin-fixed and paraffin-embedded human normal and neoplastic tissue specimens. Specificity of UMB-8 was demonstrated by detection of a broad band migrating at 70-80kDa in Western blot analyses of ETA-transfected HEK-293 cells and of different mouse tissues and by agonist-dependent translocation of the immunosignal from the surface of ETA-transfected cells into the cytosol. In tissue samples, UMB-8 yielded an efficient immunostaining of distinct cell populations with a predominance of plasma membrane staining, which was abolished after preadsorption of the antibody with its immunizing peptide. In normal tissue, ETA was present in the heart, blood vessels, gut and kidneys. ETA was also detected with a hitherto unappreciated high prevalence in all types of sarcomas and in glioblastomas, but also in various epithelial tumor entities and in tumor stroma. All in all, UMB-8 may prove of great value in the identification of ETA-expressing tumors during routine histopathological examinations. PMID- 25708417 TI - Biphalin analogs containing beta(3)-homo-amino acids at the 4,4' positions: Synthesis and opioid activity profiles. AB - Biphalin, a synthetic opioid octapeptide with a palindromic sequence has high analgesic activity. Biphalin displays a strong affinity for MU and delta-opioid receptors, and a significant to kappa-receptor. The paper reports the synthesis of novel analogs of biphalin containing beta(3)-homo-amino acid residues at the 4,4' positions and a hydrazine or 1,2-phenylenediamine linker. The potency and selectivity of the peptides were evaluated by a competitive receptor-binding assay in rat brain homogenate using [(3)H]DAMGO (a MU ligand) and [(3)H]DELT (a delta ligand). Analogs with beta(3)-h-p-NO2Phe in positions 4 and 4' are the most active compounds. Selectivity depends on the degree of freedom between the two pharmacophore moieties. Analogs with a hydrazine linker show noticeable binding selectivity to MU receptors (IC50(MU)=0.72nM; IC50(delta)=4.66nM), while the peptides with a 1,2-phenylenediamine linker show slight delta selectivity (IC50(MU)=10.97nM; IC50(delta)=1.99nM). Tyr-d-Ala-Gly-beta(3)-h-p-NO2PheNHNH beta(3)-h-p-NO2Phe (1) and (Tyr-d-Ala-Gly-beta(3)-h-p-NO2PheNH)2 (2) produced greater antinociceptive effect compared to morphine after i.t. administration. PMID- 25708418 TI - Comments on Shemie et al.: international guideline development for the determination of death. PMID- 25708419 TI - Probiotic prophylaxis to prevent ventilator associated pneumonia (VAP) in children on mechanical ventilation: an open-label randomized controlled trial. AB - PURPOSE: Ventilator associated pneumonia (VAP) is one of the most common nosocomial infections in the pediatric intensive care unit (PICU). It is associated with increased mortality and prolonged hospital stay. Several preventive strategies have been introduced to reduce VAP. One novel intervention is prophylactic administration of probiotics. Studies on the effect of probiotics on VAP in pediatric populations are lacking. METHODS: This was an open-label randomized controlled trial. A total of 150 children no older than 12 years admitted to the PICU were recruited from November 2011 to July 2013. Children who were likely to require ventilation for more than 48 h were eligible for inclusion in the study. Patients were randomized into two groups after stratification based on age groups. Children in the intervention group received probiotic preparation twice a day beginning from the day of ICU admission till 7 days or discharge from ICU, whichever was earlier. The control group did not receive any placebo. Children were examined daily for evidence of VAP and were followed up till discharge from hospital. Incidence of VAP, duration of hospital stay, and mortality were compared. RESULTS: Children who received prophylactic probiotics had a lower incidence of VAP compared to the control group (17.1 % in the probiotics group vs 48.6 % in the control group, p < 0.001; 22 per 1,000 ventilated days vs 39 per 1,000 ventilated days, p = 0.02). On multiple logistic regression analysis, use of prophylactic probiotics decreased the incidence of VAP by 77 % and reduced the duration of ICU and hospital stays by an average of 2.1 and 3.3 days, respectively, after adjusting for the other confounders. No complications due to administration of probiotics were observed in the study. CONCLUSION: Prophylactic probiotics administration resulted in reduction of the incidence of VAP in critically ill children in a setting where baseline VAP rates are high. The intervention was found to be safe. PMID- 25708420 TI - What's new in sedation strategies? PMID- 25708421 TI - When intra-aortic balloon pump is intra-abdominal balloon pump. PMID- 25708422 TI - Erratum to: plasma soluble thrombomodulin levels are associated with mortality in the acute respiratory distress syndrome. PMID- 25708423 TI - Incorporation of a hemofilter circuit into venoarterial extracorporeal membrane oxygenation: a novel approach to provide more oxygenation. PMID- 25708424 TI - Deep venous thrombosis was not detected after total knee arthroplasty in Japanese patients with haemophilia. AB - Combined thrombo-prophylaxis with mechanical and pharmacological methods is recommended in patients undergoing total knee or hip arthroplasty. As patients with 'untreated inherited bleeding disorders such as haemophilia' are at risk of bleeding, no prophylaxis has been prescribed for these patients. However, a retrospective study reported subclinical deep venous thrombosis (DVT) in 10% of patients with haemophilia undergoing major orthopaedic surgery. In this study, we aimed to evaluate the risk of DVT after total knee arthroplasty (TKA). We examined 38 TKA in 33 Japanese patients with haemophilia using ultrasonography. We did not detect DVT. The risk of DVT in patients with haemophilia after TKA may be lower than that in the general population. However, as patients with haemophilia progress in age, venous thromboembolism should be considered as a potential problem. PMID- 25708425 TI - A hybrid electro-optic polymer and TiO2 double-slot waveguide modulator. AB - An electro-optic (EO) modulator using a TiO2 slot hybrid waveguide has been designed and fabricated. Optical mode calculations revealed that the mode was primarily confined within the slots when using a double-slot configuration, thus achieving a high EO activity experimentally. The TiO2 slots also acted as an important barrier to induce an enhanced DC field during the poling of the EO polymer and the driving of the EO modulator. The hybrid phase modulator exhibited a driving voltage (Vpi) of 1.6 V at 1550 nm, which can be further reduced to 0.8 V in a 1 cm-long push-pull Mach-Zehnder interferometer (MZI) structure. The modulator demonstrated a low propagation loss of 5 dB/cm and a relatively high end-fire coupling efficiency. PMID- 25708427 TI - No clinical benefit of gender-specific total knee arthroplasty: A systematic review and meta-analysis of 6 randomized controlled trials. PMID- 25708426 TI - Observational study on adjuvant trastuzumab in HER2-positive early breast cancer patients. AB - AIM: This observational study investigates the use of adjuvant trastuzumab (AT) in HER2-positive breast cancer patients in a real-life setting, focusing on relapse and discontinuation rates. PATIENTS & METHODS: Data on a group of HER2 positive patients collected from 13 oncology centers of northeast Italy were analyzed. RESULTS: In total, 1245 patients were analyzed. 13.1% of patients were excluded from AT because of comorbidities, age, tumor stage, refusal or other reasons; 8.2% of patients who received AT interrupted the therapy, mainly for toxicity. Overall the relapse rate was 10.9% in the AT-treated population versus 22.6% in nontreated patients (follow-up: 37.4 and 62.1 months, respectively). Disease-free survival (DFS) was lower in AT-relapsed patients than in not relapsed. Statistical analysis showed a correlation between DFS and estrogen receptor status in AT-treated patients. CONCLUSION: Relapse rates are lower in clinical setting compared to clinical trials. Overall, AT is effective in HER2 positive early-stage breast cancer patients. PMID- 25708428 TI - In-situ formation of growth-factor-loaded coacervate microparticle-embedded hydrogels for directing encapsulated stem cell fate. AB - The spontaneous formation of coacervate microdroplet-laden photo-crosslinked hydrogels derived from the simple mixing of oxidized, methacrylated alginate (OMA) and methacrylated gelatin (GelMA) enables simultaneous creation of drug laden microdroplets and encapsulation of stem cells in photopolymerized coacervate hydrogels under physiological conditions. This can be utilized as a novel platform for in situ formation of localized, sustained bioactive molecule delivery to encapsulate stem cells for therapeutic applications. PMID- 25708429 TI - Primordial germ cell migration in the yellowtail kingfish (Seriola lalandi) and identification of stromal cell-derived factor 1. AB - Primordial germ cells (PGCs) are progenitors of the germ cell lineage, giving rise to either spermatogonia or oogonia after the completion of gonadal differentiation. Currently, there is little information on the mechanism of PGCs migration leading to the formation of the primordial gonad in perciform fish. Yellowtail kingfish (Seriola lalandi) (YTK) (order Perciforms) inhabit tropical and temperate waters in the southern hemisphere. Fundamental details into the molecular basis of larval development in this species can be easily studied in Australia, as they are commercially cultured and readily available. In this study, histological analysis of YTK larvae revealed critical time points for the migration of PGCs to the genital ridge, resulting in the subsequent development of the primordial gonad. In YTK larvae at 3, 5, 7 and 10 days post hatch (DPH), PGCs were not yet enclosed by somatic cells, indicating the primordial gonad had not yet started to form. While at 15, 18 and 20 DPH PGCs had already settled at the genital ridge and started to become enclosed by somatic cells indicating the primordial gonad had started to develop. A higher number of PGCs were observed in the larvae at 15 and 18 DPH indicating PGCs proliferation, which corresponds with them becoming enclosed by the somatic cells. Directional migration of PGCs toward the genital ridge is a critical event in the subsequent development of a gonad. In zebrafish, mouse and chicken, stromal-cell derived factor (SDF1) signalling is one of the key molecules for PGC migration. We subsequently isolated from YTK the SDF1 (Slal-SDF1) gene, which encodes for a 98-residue precursor protein with a signal peptide at the N-terminus. There is spatial conservation between fish species of four cysteine residues at positions C9, C11, C34 and C49, expected to form disulphide bonds and stabilize the SDF structure. In YTK, Slal-SDF1 gene expression analyses shows that this gene is expressed in larvae from 1 to 22 DPH and demonstrates distinct spatial localisation in the larvae at 7 DPH. These results provide a platform for further studies into the molecular machinery of PGC migration in yellowtail kingfish, as well as other perciform fish species. PMID- 25708430 TI - Anti-diabetic and neuroprotective effects of pancreatic islet transplantation into the central nervous system. AB - During the last decades, the central nervous system (CNS) was intensively tested as a site for islet transplantation in different animal models of diabetes. Immunoprivilege properties of intracranial and intrathecal sites were found to delay and reduce rejection of transplanted allo-islets and xeno-islets, especially in the form of dispersed single cells. Insulin released from islets grafted in CNS was shown to cross the blood-brain barrier and to act as a regulator of peripheral glucose metabolism. In diabetic animals, sufficient nutrition and oxygen supply to islets grafted in the CNS provide adequate insulin response to increase glucose level resulting in rapid normoglycemia. In addition to insulin, pancreatic islets produce and secrete several other hormones, as well as neurotrophic and angiogenic factors with potential neuroprotective properties. Recent experimental studies and clinical trials provide a strong support for delivery of islet-derived macromolecules to CNS as a promising strategy to treat various brain disorders. This review article focuses mainly on analysis of current status of intracranial and intrathecal islet transplantations for treatment of experimental diabetes and discusses the possible neuroprotective properties of grafted islets into CNS as a novel therapeutic approach to brain disorders with cognitive dysfunctions characterized by impaired brain insulin signalling. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 25708431 TI - The value of the tender muscle sign in detecting motor recovery after peripheral nerve reconstruction. AB - PURPOSE: Squeezing a denervated muscle a few weeks after nerve repair produces a characteristic response in patients. This response is observed before any clinical evidence of motor recovery. We called this response the tender muscle sign (TMS) and wanted to determine whether this sign was related to the recovery of motor power. METHODS: We studied 31 adults with unilateral brachial plexus injuries who underwent 50 procedures for reinnervation of the supraspinatus, deltoid, and biceps. Follow-up was monthly for the first year and at 3-monthly intervals thereafter. Average duration of follow-up was 3.3 years. The TMS was sought at each visit. The presence of the TMS, when it was first observed, and time to Medical Research Council (MRC) grade 1 and 3 recoveries were recorded. The sensitivity, specificity, and predictive values of TMS for motor recovery were calculated. RESULTS: The TMS was always detected earlier than palpable muscle contraction. It was significantly associated with recovery of MRC grade 1 and 3 motor power. The sensitivity of TMS for MRC grade 1 recovery was 96% and specificity was 100%. For MRC grade 3 recovery, it had 97% sensitivity and 27% specificity. The positive predictive value was 100% for MRC grade 1 recovery and 83% for MRC grade 3. The negative predictive value was 50% for MRC grade 1 recovery and 75% for MRC grade 3. CONCLUSIONS: Previous studies have demonstrated the presence of nocioceptive receptors in human skeletal muscle. The reinnervation of these receptors by the regenerating axons results in cramp-like tenderness when the muscle is squeezed. This response is specific to a reinnervated muscle and cannot be elicited in denervated or normally innervated muscle. The TMS is a simple, clear, and early indicator of muscle reinnervation that is useful in monitoring motor recovery after nerve regeneration. TYPE OF STUDY/LEVEL OF EVIDENCE: Diagnostic IV. PMID- 25708432 TI - The benefit of carpal tunnel release in patients with electrophysiologically moderate and severe disease. AB - PURPOSE: To compare change in numbness and pain after carpal tunnel release in patients with electrophysiologically moderate and severe disease. METHODS: We tested the primary null hypothesis that there is no difference in the total Carpal Tunnel Symptoms Scale score 3 months after surgery between patients with moderate and those with severe disease. Ninety-five patients (47 in the moderate cohort, and 48 in the severe cohort) who had miniopen carpal tunnel release between November 2011 and November 2013 were identified from our prospectively collected database. For each patient, the total Carpal Tunnel Symptoms Scale score, as well the numbness and pain subscale scores, at the preoperative and postoperative (2-wk, 1-mo, 2-mo, 3-mo, >= 1-y) visits were documented. The data were analyzed with repeated-measures analysis of variance. RESULTS: Three months after surgery, patients with moderate carpal tunnel syndrome (CTS) reported, on average, no symptoms, and patients with severe disease had reduced but unresolved symptoms. Although symptoms diminished in both groups from the preoperative assessment to the 2-week postoperative assessment, patients with severe CTS had comparatively more severe symptoms at all time points with the exception of pain at 2 weeks and 1 year or longer after surgery, at which times there was no significant difference. At 1 year or longer after surgery, 1 (2%) patient with moderate CTS and 9 (19%) patients with severe CTS reported continued symptoms. Preoperative electrodiagnostic severity was the factor most predictive of symptom scores. CONCLUSIONS: Patients with severe CTS experience considerable reduction in symptoms after surgery but should be informed that recovery may be more prolonged and, in some cases, incomplete 1 year after carpal tunnel release, particularly with regard to numbness. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic III. PMID- 25708433 TI - Bullosis diabeticorum in median nerve innervated fingers shortly after carpal tunnel release: case report. AB - Bullosis diabeticorum is a cutaneous manifestation of diabetes mellitus, mainly observed in the lower extremities in patients with longstanding disease. The etiology is unknown, but an association with neurologic or vascular disturbances has been suggested. We have reviewed a case of a 70-year-old man with rapid development of bullae in median nerve innervated fingertips following carpal tunnel release. PMID- 25708434 TI - Pyrolytic carbon hemiarthroplasty in the management of proximal interphalangeal joint arthritis. AB - PURPOSE: To review clinical, subjective, and radiographic results of pyrocarbon hemiarthroplasty for proximal interphalangeal (PIP) joint arthritis. METHODS: A total of 42 fingers in 38 patients underwent PIP joint hemiarthroplasty between 2005 and 2011. Preoperative diagnoses included 28 with osteoarthritis or posttraumatic arthritis and 10 with inflammatory arthritis. Average age at the time of surgery was 56 years. Digits treated included: index (10), middle (20), ring (9), and little (3). Average follow-up was 4.6 years (minimum, 2 y). RESULTS: There was considerable improvement in patient satisfaction measures including Canadian Occupational Performance Measure for both performance and satisfaction and Disabilities of the Arm, Shoulder, and Hand and visual analog scale pain scores. There was no significant change in motion or grip and pinch strength after surgery. Four joints were revised for failure: 3 underwent arthrodesis and 1 was converted to a silicone PIP joint arthroplasty. Radiographic outcomes in surviving implants demonstrated a Sweets and Stern grade 0 in 37 implants and grade 3 in 1. CONCLUSIONS: Pyrocarbon hemiarthroplasty appears to be a viable alternative to total joint arthroplasty in the treatment of PIP joint arthritis. Clinical and patient satisfaction outcomes compared favorably with published outcomes of arthroplasty. Radiographic outcomes of PIP joint hemiarthroplasty were encouraging with respect to implant position and loosening. Compared with total joint arthroplasty, proximal hemiarthroplasty is a simple procedure that preserves more bone stock and would allow for better success of salvage options such as arthrodesis and revision arthroplasty. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 25708435 TI - Commentary regarding "Evaluation of expectations and expectation fulfillment in patients treated for trapeziometacarpal osteoarthritis". PMID- 25708436 TI - Correlation between distal radial cortical thickness and bone mineral density. AB - PURPOSE: To determine interobserver reliability in measuring the cortical thickness of distal radiuses on posteroanterior radiographs obtained at the time of injury and to determine whether there is a correlation between distal radius cortical thickness and hip and lumbar spine scores on dual-energy x-ray absorptiometry (DXA). METHODS: Four orthopedic surgeons at 2 academic institutions who were blinded to the study protocol reviewed standard posteroanterior wrist radiographs of 80 women over age 50 years with distal radius fractures with DXA data obtained within the past 2 years. Radial bicortical widths were measured at 50 and 70 mm proximal to the distal ulnar articular surface, and mean bicortical thickness was calculated from radiographs of the injured wrist. Average bicortical width was compared with each patient's femoral and lumbar spine bone density measures. Data were analyzed using Pearson correlation coefficients and simple linear regression. Inter-rater reliability was evaluated using intra-class correlation coefficients. RESULTS: The inter rater reliability for average bicortical thickness had a high intra-class correlation coefficient value of 0.91. Average bicortical thickness showed a statistically significant positive relationship with femoral bone density. Average bicortical thickness was statistically correlated with femoral bone density values, with a 1-mm increase in average bicortical thickness associated with a 0.05 g/cm(2)-increase in femoral density. Average bicortical thickness was not associated with lumbar bone density. CONCLUSIONS: Bicortical thickness of the distal radius was positively correlated with femoral bone density but not with lumbar spine density. This may reflect similarity in quality and loading properties of the femur and radius as appendicular bones, compared with the axial spine. Identification of thinned distal radial cortices in association with distal radius fracture is a simple qualitative observation that should prompt further evaluation with DXA and medical management of bone insufficiency. TYPE OF STUDY/LEVEL OF EVIDENCE: Diagnostic II. PMID- 25708437 TI - Wrist ganglion treatment: systematic review and meta-analysis. AB - PURPOSE: To review the clinical outcomes of treatment for adult wrist ganglions and to conduct a meta-analysis comparing the 2 most common options: open surgical excision and aspiration. METHODS: The review methodology was registered with PROSPERO. We performed a systematic search of MEDLINE and EMBASE for articles published between 1990 and 2013. Included studies reported treatment outcomes of adult wrist ganglions. Two independent reviewers performed screening and data extraction. We evaluated the methodological quality of randomized controlled trials (RCT) and cohort studies using the Cochrane Handbook for Systematic Reviews and the Newcastle-Ottawa Scale, respectively; Grading of Recommendations, Assessment, Development, and Evaluation was used to evaluate the quality of evidence. RESULTS: A total of 753 abstracts were identified and screened; 112 full-text articles were reviewed and 35 studies (including 2,239 ganglions) met inclusion criteria for data extraction and qualitative synthesis. Six studies met criteria for meta-analysis, including 2 RCTs and 4 cohort studies. In RCTs surgical excision was associated with a 76% reduction in recurrence compared with aspiration. Randomized controlled trial quality was moderate. In cohort studies surgical excision was associated with a 58% reduction in recurrence compared with aspiration. Cohort study quality was very low. In cohort studies aspiration was not associated with a significant reduction in recurrence compared with reassurance. Across all studies mean recurrence for arthroscopic surgical excision (studies, 11; ganglions, 512), open surgical excision (studies, 14; ganglions, 809), and aspiration (studies, 12; ganglions, 489) was 6%, 21%, and 59%, respectively. Mean complication rate for arthroscopic surgical excision (studies, 6; ganglions, 221), open surgical excision (studies, 6; ganglions, 341), and aspiration (studies, 3; ganglions, 134) was 4%, 14%, and 3%, respectively. CONCLUSIONS: Open surgical excision offers significantly lower chance of recurrence compared with aspiration in the treatment of wrist ganglions. Arthroscopic excision has yielded promising outcomes but data from comparative trials are limited and have not demonstrated its superiority. Further RCTs are needed to increase confidence in the estimate of effect and to compare complications and recovery. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic I. PMID- 25708438 TI - Management of thumb tip injuries. AB - The management of thumb tip injuries has undergone great changes in recent years. The traditional armamentarium of flaps has been expanded and replaced by a wide variety of flaps with more versatility and less donor side morbidity. Parallel to the development of new flaps, the conservative treatment of thumb tip injuries with semi-occlusive dressing has gained ground in the treatment of these injuries. Although tedious and time-consuming, and requiring intensive communication with the patient to explain the look and occasionally fetid smell of the wound, this technique yields excellent results with respect to restoring contour and sensibility in pulp injuries. The article gives an update on the current options for treating thumb tip injuries including the most commonly applied flaps. PMID- 25708439 TI - George E. Omer, Jr, MD December 23, 1922--November 20, 2014. PMID- 25708440 TI - Letter to the editor regarding Phillips BZ, Franco MJ, Yee A, Tung TH, Mackinnon SE, Fox IK. Direct radial to ulnar nerve transfer to restore intrinsic muscle function in combined proximal median and ulnar nerve injury: case report and surgical technique. J Hand Surg Am. 2014;39(7):1358-1362. PMID- 25708441 TI - In reply. PMID- 25708442 TI - Reduction and association of the scaphoid and lunate procedure: short-term outcomes. PMID- 25708443 TI - In reply. PMID- 25708444 TI - Letter regarding Patel SP, Anthony SG, Zurakowski D, et al. Radiographic scoring system to evaluate union of distal radius fractures. J Hand Surg Am. 2014;39(8):1471-1479. PMID- 25708445 TI - In reply. PMID- 25708446 TI - Association of colonic regulatory T cells with hepatitis C virus pathogenesis and liver pathology. AB - BACKGROUND AND AIM: Forkhead box protein P3 (FoxP3)(+) regulatory T (Treg ) cells play a fundamental role in maintaining the balance between the tissue-damaging and protective immune response to chronic hepatitis C (CHC) infection. Herein, we investigated the frequency of Treg cells in the colon and their potential relationship to the various CHC outcomes and hepatic histopathology. METHODS: Colonic biopsies were collected from three groups with CHC: treatment naive (TN; n = 20), non-responders (NR; n = 20), sustained virologic response (SVR; n = 20), and a fourth healthy control group (n = 10). The plasma viral loads and cytokines levels were determined by quantitative real-time polymerase chain reaction, and ELISA, respectively. Liver biopsies were examined to assess inflammatory score and fibrosis stage. Colonic Treg frequency was estimated by immunohistochemistry using confocal microscopy. RESULTS: A significant increase in the frequency of colonic Treg was found in TN, and NR groups compared with the control and SVR group. The frequency of colonic Treg , plasma interleukin (IL)-10 and IL-4 levels were significantly positively correlated with viral load and negatively correlated with METAVIR inflammatory score, and fibrosis stages. CONCLUSION: Colonic Treg cells are negatively correlated with liver inflammation and hepatitis C virus (HCV) viral load, which suggests a strong linkage between gut derived Treg cell populations and HCV infection. PMID- 25708448 TI - Low-intensity pulsed ultrasound (LIPUS) can decrease the economic burden of fracture non-union. AB - OBJECTIVES: Few studies have evaluated the economic burden of surgical and conservative treatment of fracture non-union. An analysis was undertaken of aggregated payer data to determine economic costs of non-unions treated with surgery only vs non-unions treated conservatively with low-intensity pulsed ultrasound (LIPUS) only. METHODS: This study used administrative claims from a health plan database including nearly 80 million people. Patients with a claim for non-union surgery or LIPUS for non-union were identified, from April 2007 until April 2010. A retrospective cohort was formed by pairwise demographic matching among patients who received 'Surgery Only' or 'LIPUS Only'. Date of the first non-union intervention (surgery or LIPUS) was defined as the index date. All medical costs were assessed over 12 months following the index date for the 'Surgery Only' and 'LIPUS Only' cohorts. RESULTS: A total of 1158 matched patients were identified. 'Surgery Only' patients used significantly more healthcare services. In the year following intervention, 'Surgery Only' patients had total medical costs $6289 higher than 'LIPUS Only' patients (Mean = $11,276 vs $4986; p < 0.0001). Outpatient costs accounted for >68% of overall costs in both cohorts, and outpatient costs were significantly higher among the 'Surgery Only' cohort (Mean = $7682 vs $4196; p < 0.0001). Total inpatient costs were also significantly higher among the 'Surgery Only' cohort (Mean = $3302 vs $381; p < 0.0001). LIMITATIONS: Limitations of this work are typical of all studies based on administrative claims data: errors in the database are assumed to distribute randomly between cohorts, and some patients may have been miscoded as to treatment received or costs billed. CONCLUSIONS: 'Surgery Only' patients used significantly and substantially more healthcare services in treatment of fracture non-union. Conservative treatment with 'LIPUS only' for fracture non-union could potentially result in cost savings projected to roughly $1 billion dollars [corrected]. PMID- 25708449 TI - Microwave-assisted solid-phase peptide synthesis of neurosecretory protein GL composed of 80 amino acid residues. AB - We recently identified a novel cDNA encoding a small secretory protein of 80 amino acid residues, termed neurosecretory protein GL (NPGL), from the chicken hypothalamus. Homologs of NPGL have been reported to be present in mammals, such as human and rat. NPGL is amidated at its C-terminus, contains an intramolecular disulfide bond, and is hydrophobic in nature. In this study, we have optimized the synthesis of the entire 80-amino acid peptide sequence of rat NPGL by microwave-assisted solid-phase peptide synthesis. NPGL was obtained with a 10% yield when the coupling reactions were performed using 1 [Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxid hexafluorophosphate (HATU) at 50 degrees C for 5 min, and Fmoc deprotections were performed using 40% piperidine containing 0.1 M HOBt. Furthermore, the disulfide bond of NPGL was formed with 20% yield with the use of glutathione containing redox buffer and 50% acetonitrile. PMID- 25708447 TI - Uptake and metabolism of fructose by rat neocortical cells in vivo and by isolated nerve terminals in vitro. AB - Fructose reacts spontaneously with proteins in the brain to form advanced glycation end products (AGE) that may elicit neuroinflammation and cause brain pathology, including Alzheimer's disease. We investigated whether fructose is eliminated by oxidative metabolism in neocortex. Injection of [(14) C]fructose or its AGE-prone metabolite [(14) C]glyceraldehyde into rat neocortex in vivo led to formation of (14) C-labeled alanine, glutamate, aspartate, GABA, and glutamine. In isolated neocortical nerve terminals, [(14) C]fructose-labeled glutamate, GABA, and aspartate, indicating uptake of fructose into nerve terminals and oxidative fructose metabolism in these structures. This was supported by high expression of hexokinase 1, which channels fructose into glycolysis, and whose activity was similar with fructose or glucose as substrates. By contrast, the fructose-specific ketohexokinase was weakly expressed. The fructose transporter Glut5 was expressed at only 4% of the level of neuronal glucose transporter Glut3, suggesting transport across plasma membranes of brain cells as the limiting factor in removal of extracellular fructose. The genes encoding aldose reductase and sorbitol dehydrogenase, enzymes of the polyol pathway that forms glucose from fructose, were expressed in rat neocortex. These results point to fructose being transported into neocortical cells, including nerve terminals, and that it is metabolized and thereby detoxified primarily through hexokinase activity. We asked how the brain handles fructose, which may react spontaneously with proteins to form 'advanced glycation end products' and trigger inflammation. Neocortical cells took up and metabolized extracellular fructose oxidatively in vivo, and isolated nerve terminals did so in vitro. The low expression of fructose transporter Glut5 limited uptake of extracellular fructose. Hexokinase was a main pathway for fructose metabolism, but ketohexokinase (which leads to glyceraldehyde formation) was expressed too. Neocortical cells also took up and metabolized glyceraldehyde oxidatively. PMID- 25708450 TI - A case of mediastinal fibrosis due to radiotherapy and 'downhill' esophageal varices: a rare cause of upper gastrointestinal bleeding. AB - 'Downhill' varices are located in the proximal part of the esophagus. Their etiology differs from the distal types, with most of them usually being related to superior vena cava obstruction. Although bleeding due to 'downhill' varices is very rare, it can be life-threatening. Here, we present a case of upper gastrointestinal bleeding due to mediastinal fibrosis associated with chest radiotherapy for seminoma metastasis sixteen years previously, which was successfully treated conservatively. PMID- 25708451 TI - Effectiveness of endoscopic self-expandable metal stent placement for afferent loop obstruction caused by pancreatic cancer recurrence after pancreaticoduodenectomy. AB - Afferent loop obstruction caused by cancer recurrence after pancreaticoduodenectomy (PD) can be managed by either surgical or nonsurgical treatment. The general condition of patients with recurrent pancreaticobiliary cancer is often not good enough for them to undergo surgery, so less invasive nonsurgical treatment is desirable. We report a case of a 66-year-old male who had undergone PD for pancreatic head adenocarcinoma 10 months previously and who presented at our hospital with fever and jaundice due to afferent loop obstruction caused by pancreatic cancer recurrence. An endoscopic self-expandable metal stent (SEMS) was placed for afferent loop obstruction without any complications. He quickly recovered after SEMS placement. He retained a good quality of life by receiving chemotherapy until his death due to cancer progression. Our case indicates that this method could be an easy, effective, safe, and less invasive treatment, which may confer a better quality of life for patients with afferent loop obstruction due to cancer recurrence after PD. PMID- 25708452 TI - Alternative Ways to Quantify Sustained Remission: Applying the Continuity Rewarded Score and Patient Vector Graph. AB - OBJECTIVE: Although the Computer Assisted Management in Early Rheumatoid Arthritis Trial-II (CAMERA-II) showed favorable clinical effects in the most intensive methotrexate (MTX)-based strategy with prednisone (MTX +/- prednisone) compared to that with placebo (MTX + placebo), this beneficial difference was only seen in 1 of the 3 analyses of remission. Our objective was to investigate whether the Continuity Rewarded (ConRew) score and a simple sum score would better reveal differences regarding remission between the 2 treatment arms of CAMERA-II. Furthermore, we investigated whether the patient vector graph, which plots on patient level, would add visual information on remission compared to a conventional box plot only, which displays data on the group level. METHODS: The ConRew method, which awards continuous periods of remission with a higher score, was applied, in addition to a simple sum score of remission periods of 4 weeks. A patient vector graph was compared with box plots. RESULTS: Both the mean +/- SD simple sum score and the ConRew score of remission were significantly higher (favorable) in the MTX + prednisone strategy group versus the MTX + placebo group, respectively: 9 +/- 7 versus 12 +/- 8; P = 0.003, and 23 +/- 16 versus 17 +/- 14; P = 0.004. The patient vector graphs show a visual pattern of more and longer periods of remission in the MTX + prednisone strategy and visually add information to the box plots. CONCLUSION: The simple sum of remission periods, the ConRew score, and the patient vector graph add understanding and discrimination to the analysis of the remission outcome in CAMERA-II. PMID- 25708453 TI - Impact of Experience Corps((r)) participation on school climate. AB - We examined the impact of the Experience Corps((r)) (EC) program on school climate within Baltimore City public elementary schools. In this program, teams of older adult volunteers were placed in high intensity (>15 h per week), meaningful roles in public elementary schools, to improve the educational outcomes of children as well as the health and well-being of volunteers. During the first year of EC participation, school climate was perceived more favorably among staff and students in EC schools as compared to those in comparison schools. However, with a few notable exceptions, perceived school climate did not differ for staff or students in intervention and comparison schools during the second year of exposure to the EC program. These findings suggest that perceptions of school climate may be altered by introducing a new program into elementary schools; however, research examining how perceptions of school climate are impacted over a longer period is warranted. PMID- 25708454 TI - Experience in therapeutic plasma exchange by membrane filtration at an academic center in Colombia: Registry of the first 500 sessions. AB - INTRODUCTION: Therapeutic plasma exchange (TPE) is an extracorporeal blood purification therapy that is part of the treatment of various diseases. Plasma and blood cells can be separated by centrifugation or using membrane separators. MATERIALS AND METHODS: A descriptive analysis, in which the first 500 TPE sessions using membrane filtration without anticoagulation of the extracorporeal circuit are described. RESULTS: Five hundred (500) TPE sessions were performed on 68 patients over a period of 5 years. Therapeutic indications were 17 different diseases. 5% albumin was the most frequent replacement solution used in 62% of sessions. The mean number of plasma volume replacements was 1.33. Complications occurred in 7.6% of the sessions. Arterial hypotension was the most common event and clotting of the extracorporeal circuit was documented in just one TPE session. Electrolyte tests performed in patients during the procedure showed: 11% hypocalcemia, with a similar distribution of hypokalemia. Twenty-two percent (22%) and 37% of phosphorus and magnesium records, respectively, were higher than normal. No symptoms associated with electrolyte abnormalities were documented. CONCLUSIONS: TPE by membrane filtration is one of the techniques by which it is possible to perform such therapy. In this registry, a low rate of complications was documented. While the need for anticoagulation may be related not only to clotting of the circuit but also to the efficiency of the therapy, clinical response in this series of patients was as expected for each disease. Continuous monitoring and an individualized analysis of electrolytes should be performed in TPE patients. PMID- 25708455 TI - Cerebellar contributions to neurological soft signs in healthy young adults. AB - Neurological soft signs (NSS) are frequently found in psychiatric disorders of significant neurodevelopmental origin, e.g., in patients with schizophrenia and autism. Yet NSS are also present in healthy individuals suggesting a neurodevelopmental signature of motor function, probably as a continuum between health and disease. So far, little is known about the neural mechanisms underlying these motor phenomena in healthy persons, and it is even less known whether the cerebellum contributes to NSS expression. Thirty-seven healthy young adults (mean age = 23 years) were studied using high-resolution structural magnetic resonance imaging (MRI) and "resting-state" functional MRI at three Tesla. NSS levels were measured using the "Heidelberg Scale." Cerebellar gray matter volume was investigated using cerebellum-optimized voxel-based analysis methods. Cerebellar function was assessed using regional homogeneity (ReHo), a measure of local network strength. The relationship between cerebellar structure and function and NSS was analyzed using regression models. There was no significant relationship between cerebellar volume and NSS (p < 0.005, uncorrected for height, p < 0.05 corrected for spatial extent). Positive associations with cerebellar lobule VI activity were found for the "motor coordination" and "hard signs" NSS domains. A negative relationship was found between lobule VI activity and "complex motor task" domain (p < 0.005, uncorrected for height, p < 0.05 corrected for spatial extent). The data indicate that in healthy young adults, distinct NSS domains are related to cerebellar activity, specifically with activity of cerebellar subregions with known cortical somatomotor projections. In contrast, cerebellar volume is not predictive of NSS in healthy persons. PMID- 25708456 TI - A step forward in elucidating the mystery of OCD. AB - Obsessive-compulsive disorder represents one of the most disabling psychiatric disorders. The underlying pathophysiology is not fully understood. In a recent Science article, Ahmari and colleagues enlighten fundamental aspects of obsessive compulsive disorder by means of optogenetic stimulation, thereby also elucidating the usefulness of SSRI in the treatment for OCD. PMID- 25708457 TI - Psychiatrists' self-stigma, the DGPPN guideline for psychosocial interventions, and contemporary treatment strategies. PMID- 25708458 TI - Robust strand exchange reactions for the sequence-specific, real-time detection of nucleic acid amplicons. AB - Loop-mediated isothermal amplification (LAMP) of DNA is a powerful isothermal nucleic acid amplification method that can generate upward of 10(9) copies from less than 100 copies of template DNA within an hour. Unfortunately, although the amplification reactions are extremely powerful, real-time and specific detection of LAMP products remains analytically challenging. In order to both improve the specificity of LAMP detection and to make readout simpler and more reliable, we have replaced the intercalating dye typically used for monitoring in real-time fluorescence with a toehold-mediated strand exchange reaction termed one-step strand displacement (OSD). Due to the inherent sequence specificity of toehold mediated strand exchange, the OSD reporter could successfully distinguish side products from true amplicons arising from templates corresponding to the biomedically relevant M. tuberculosis RNA polymerase (rpoB) and the melanoma related biomarker BRAF. OSD allowed the Yes/No detection of rpoB in a complex mixture such as synthetic sputum and also demonstrated single nucleotide specificity in Yes/No detection of a mutant BRAF allele (V600E) in the presence of 20-fold more of the wild-type gene. Real-time detection of different genes in multiplex LAMP reactions also proved possible. The development of simple, readily designed, modular equivalents of TaqMan probes for isothermal amplification reactions should generally improve the applicability of these reactions and may eventually assist with the development of point-of-care tests. PMID- 25708459 TI - Vitamin D status is inversely associated with obesity in a clinic-based sample in Puerto Rico. AB - Studies show that vitamin D status is associated to obesity but data in Hispanic individuals is scarce. The aim of this study was to assess the association between vitamin D status and obesity in a clinic-based sample in Puerto Rico. We hypothesized that subjects with a higher adiposity would have a lower vitamin D status. We extracted the following data from medical records of a private clinic: age, gender, serum 25(OH)D levels, weight, height, and waist circumference. Body mass index (BMI) (kg/m(2)) and waist-to-height ratio were calculated and categorized according to standard guidelines. Statistical analyses included analysis of covariance, Pearson correlations and chi(2) test. From 797 individuals (mean age 53.7 +/- 15.4 years; 63.5% females), 35.6% were overweight and 43.7% obese. Mean 25(OH)D levels were 24.7 +/- 8.7 ng/mL; 5.3% had levels <12 ng/mL, 30.6% had levels 12 to 20 ng/mL, and 43.5% had levels 21 to 30 ng/mL. Mean 25(OH)D levels were significantly higher in normal weight and overweight males compared to obese males (P < .05) and in overweight females compared to obese females (P < .05). Levels were also higher in those with low risk compared to high risk of waist circumference and waist-to-height ratio (P < .001). BMI, waist circumference, and waist-to-height ratio were inversely correlated to 25(OH)D levels (P < .001). A greater proportion of obese individuals (41.4%) were vitamin D deficient or insufficient compared to the normal weight (33.9%) and overweight individuals (30.3%) (P < .05). In conclusion, in this clinic-based sample of Puerto Rican adults, those with higher BMI, waist circumference, and waist-to height ratio had a significantly lower vitamin D status. PMID- 25708461 TI - Amyotrophic lateral sclerosis as a spatiotemporal mislocalization disease: location, location, location. AB - Spatiotemporal localization of signals is a fundamental feature impacting cell survival and proper function. The cell needs to respond in an accurate manner in both space and time to both intra- and intercellular environment cues. The regulation of this comprehensive process involves the cytoskeleton and the trafficking machinery, as well as local protein synthesis and ligand-receptor mechanisms. Alterations in such mechanisms can lead to cell dysfunction and disease. Motor neurons that can extend over tens of centimeters are a classic example for the importance of such events. Changes in spatiotemporal localization mechanisms are thought to play a role in motor neuron degeneration that occurs in amyotrophic lateral sclerosis (ALS). In this review we will discuss these mechanisms and argue that possible misregulated factors can lead to motor neuron degeneration in ALS. PMID- 25708460 TI - How Rab proteins determine Golgi structure. AB - Rab proteins, small GTPases, are key regulators of mammalian Golgi apparatus organization. Based on the effect of Rab activation state, Rab proteins fall into two functional classes. In Class1, inactivation induces Golgi ribbon fragmentation and/or redistribution of Golgi enzymes to the Endoplasmic Reticulum, while overexpression of wild type or activation has little, if any, effect on Golgi ribbon organization. In Class 2, the reverse is true. We give emphasis to Rab6, the most abundant Golgi-associated Rab protein. Rab6 depletion in HeLa cells causes an increase in Golgi cisternal number, longer, more continuous cisternae, and a pronounced accumulation of vesicles; the effect of Rab6 on Golgi ribbon organization is probably through regulation of vesicle transport. In effector studies, motor proteins and their regulators are found to be key Rab6 effectors. A related Rab, Rab41, affects Golgi ribbon organization in a contrasting manner. The balance between minus- and plus-end directed motor recruitment may well be the major Rab-dependent factor in Golgi ribbon organization. PMID- 25708463 TI - Heredity and self-organization: partners in the generation and evolution of phenotypes. AB - In this review we examine the role of self-organization in the context of the evolution of morphogenesis. We provide examples to show that self-organized behavior is ubiquitous, and suggest it is a mechanism that can permit high levels of biodiversity without the invention of ever-increasing numbers of genes. We also examine the implications of self-organization for understanding the "internal descriptions" of organisms and the concept of a genotype-phenotype map. PMID- 25708462 TI - Malleable mitochondrion of Trypanosoma brucei. AB - The importance of mitochondria for a typical aerobic eukaryotic cell is undeniable, as the list of necessary mitochondrial processes is steadily growing. Here, we summarize the current knowledge of mitochondrial biology of an early branching parasitic protist, Trypanosoma brucei, a causative agent of serious human and cattle diseases. We present a comprehensive survey of its mitochondrial pathways including kinetoplast DNA replication and maintenance, gene expression, protein and metabolite import, major metabolic pathways, Fe-S cluster synthesis, ion homeostasis, organellar dynamics, and other processes. As we describe in this chapter, the single mitochondrion of T. brucei is everything but simple and as such rivals mitochondria of multicellular organisms. PMID- 25708464 TI - Nuclear compartments, genome folding, and enhancer-promoter communication. AB - The eukaryotic genome has an extremely complex spatial organization. The physical distances between regulatory elements of the genome, such as enhancers, promoters, insulators, and CpG-islands, do not necessarily reflect genomic distances. Some remote regulatory elements appear to interact physically with target promoters in the 3D nuclear space. These spatial contacts are thought to play a crucial role in the regulation of transcription. Recent studies performed using 3C (chromosome conformation capture)-based methods, FISH (fluorescence in situ hybridization) coupled with confocal microscopy, and other experimental approaches have revealed that the spatial interactions of distant genomic elements within a folded chromosome are specific and functionally relevant. Additionally, the spatial organization of the eukaryotic genome is linked to the functional compartmentalization of the cell nucleus. In this review, we discuss the current state of research on the functional architecture of the eukaryotic genome. Special emphasis is given to the role of the spatial organization of the genome in establishing communication between enhancers and promoters. The driving forces of the juxtaposition of remote genomic elements are also considered. PMID- 25708465 TI - Modifiers of membrane dipole potentials as tools for investigating ion channel formation and functioning. AB - Electrostatic fields generated on and within biological membranes play a fundamental role in key processes in cell functions. The role of the membrane dipole potential is of particular interest because of its powerful impact on membrane permeability and lipid-protein interactions, including protein insertion, oligomerization, and function. The membrane dipole potential is defined by the orientation of electric dipoles of lipid headgroups, fatty acid carbonyl groups, and membrane-adsorbed water. As a result, the membrane interior is several hundred millivolts more positive than the external aqueous phase. This potential decrease depends on the lipid, and especially sterol, composition of the membrane. The adsorption of certain electroneutral molecules known as dipole modifiers may also lead to significant changes in the magnitude of the potential decrease. These agents are widely used to study the effects of the dipole potential on membrane transport. This review presents a critical analysis of a variety of data from studies dedicated to ion channel formation and functioning in membranes with different dipole potentials. The types of ion channels found in cellular membranes and pores formed by antimicrobial agents and toxins in artificial lipid membranes are summarized. The mechanisms underlying the influence of the membrane dipole potential on ion channel activity, including dipole-dipole and charge-dipole interactions in the pores and in membranes, are discussed. A hypothesis, in which lipid rafts in both model and cellular membranes also modulate ion channel activity by virtue of an increased or decreased dipole potential, is also considered. PMID- 25708466 TI - Link between aneuploidy and chromosome instability. AB - Aneuploidy is widely acknowledged as a leading cause of miscarriage and birth defects in humans, and is generally known to be deleterious to the survival of individual cells. However, aneuploidy is also ubiquitous in cancer and is found to arise as an adaptive response in certain contexts. This dichotomy of aneuploidy has attracted the interest of researchers for over a century, but many studies have reached conflicting conclusions. The emergence of new technology has allowed scientists to revisit the aneuploidy problem and has fueled a number of recent studies aimed at understanding the effects of aneuploidy on cell physiology. Here, we review these studies, in light of previous observations and knowledge, specifically focusing on the effects of aneuploidy on cellular homeostasis, chromosome stability, and adaptation. PMID- 25708467 TI - The management of alcohol withdrawal in pregnancy--case report, literature review and preliminary recommendations. AB - Pregnant women are advised to stop drinking alcohol, but there is very little evidence-based guidance on the management of alcohol withdrawal. We describe a case of alcohol withdrawal during pregnancy and summarize available information on treatment. PMID- 25708468 TI - Simultaneous determination of perfluorinated compounds and their potential precursors in mussel tissue and fish muscle tissue and liver samples by liquid chromatography-electrospray-tandem mass spectrometry. AB - An analytical method for the simultaneous determination in fish liver and muscle tissue and mussel samples of 14 perfluorinated compounds (PFCs), including three perfluoroalkylsulfonates (PFSAs), seven perfluorocarboxylic acids (PFCAs), three perfluorophosphonic acids (PFPAs) and perfluorooctanesulfonamide (PFOSA), and 10 potential precursors, including four polyfluoroalkyl phosphates (PAPs), four fluorotelomer saturated acids (FTCAs) and two fluorotelomer unsaturated acids (FTUCAs), was developed in the present work. Different clean-up strategies by means of solid-phase extraction (SPE) using a mix-mode weak anion exchanger (WAX), reverse phase Envi-Carb or a combination of them was optimized and evaluated for the clean-up of focused ultrasonic solid-liquid (FUSLE) extracts before the analysis by liquid chromatography-triple quadrupole tandem mass spectrometry (LC-MS/MS). Mix-mode WAX coupled in-line to Envi-Carb was finally selected since it rendered the cleanest extracts and minimum matrix effect. The FUSLE-SPE-LC-MS/MS methodology was validated in terms of recovery, precision and method detection limits (MDLs). Apparent recovery values in the 65-116%, 59-119% and 67-126% range and MDLs in the 0.1-2.7 ng/g, 0.1-3.8 ng/g and 0.2-3.1ng/g range were obtained for liver, mussel and fish muscle tissue samples, respectively. The method developed was applied to the analysis of grey mullet liver (Chelon labrosus) and mussel (Mytilus galloprovincialis) samples from the Basque Coast (North of Spain) and Yellowfin tuna muscle tissue (Thunnus albacares) samples from the Indian Ocean. To the best of our knowledge this is the first method that describes the simultaneous determination of 14 PFCs and 10 potential precursors in fish liver, fish muscle tissue and mussel samples. Besides, this is the first time that 8:2 monosubstituted polyfluorodecyl phosphate (8:2 monoPAP) and 8:2 disubstituted polyfluorodecyl phosphate (8:2 diPAP) were detected in mussel and tuna samples, respectively. PMID- 25708469 TI - Onflow liquid chromatography at critical conditions coupled to (1)H and (2)H nuclear magnetic resonance as powerful tools for the separation of poly(methylmethacrylate) according to isotopic composition. AB - The present work addresses a major challenge in polymer chromatography by developing a method to separate and analyze polymers with identical molar masses, chemical structures and tacticities that is solely based on differences in isotope composition. For the first time, liquid chromatography at critical conditions (LCCC) was used to separate PMMA regarding the H and D isotopes. At critical conditions of H-PMMA, D-PMMA eluted in the adsorption mode and vice versa. By online onflow LCCC-NMR, both PMMA species were clearly identified. Different from other detectors, NMR can distinguish between H and D. Onflow LCCC H/NMR and LCCC-D/NMR measurements were carried out and the H/D-blend components were detected. (1)H and (13)C NMR provided the tacticity of protonated PMMA. Double resonance (13)C{H} and triple resonance (13)C{H,D} provided the tacticity of the deuterated samples. Samples with similar tacticities were used to ensure that separation occurs solely regarding the isotope labeling. PMID- 25708470 TI - Responses of proteins to different ionic environment are linearly interrelated. AB - Protein partitioning in aqueous two-phase systems (ATPS) is widely used as a convenient, inexpensive, and readily scaled-up separation technique. Protein partition behavior in ATPS is known to be readily manipulated by ionic composition. However, the available data on the effects of salts and buffer concentrations on protein partitioning are very limited. To fill this gap, partitioning of 15 proteins was examined in dextran-poly(ethylene glycol) ATPSs with different salt additives (Na2SO4, NaClO4, NaSCN, CsCl) in 0.11 M sodium phosphate buffer, pH 7.4. This analysis reveals that there is a linear relationship between the logarithms of the protein partition coefficients determined in the presence of different salts. This relationship suggests that the protein response to ionic environment is determined by the protein structure and type and concentrations of the ions present. Analysis of the differences between protein structures (described in terms of proteins responses to different salts) and that of cytochrome c chosen as a reference showed that the peculiarities of the protein surface structure and B-factor used as a measure of the protein flexibility are the determining parameters. Our results provide better insight into the use of different salts in manipulating protein partitioning in aqueous two-phase systems. These data also demonstrate that the protein responses to different ionic environments are interrelated and are determined by the structural peculiarities of protein surface. It is suggested that changes in ionic microenvironment of proteins may regulate protein transport and behavior in biological systems. PMID- 25708472 TI - Overall survival in patients with metastatic melanoma. AB - INTRODUCTION: Patients with regionally or distantly metastatic melanoma have poor long-term prognosis. The objective of this analysis was to describe survival rates among patients diagnosed with unresectable stage IIIB/C or stage IV melanoma. METHODS: Using data from the Surveillance, Epidemiology, and End Results (SEER) database, patients diagnosed with unresectable stage IIIB/C and stage IV (M1a, M1b, M1c) melanoma between 2004 and 2009 were selected. Patients' demographic and clinical characteristics were reported at the time of diagnosis. The outcome of the analysis was time from melanoma diagnosis to death. Survival was presented as 1 year, 2 year, and 3 year survival rates, and median overall survival. RESULTS: A total of 1682 patients met the study criteria, with 4.4% at stage IIIB/IIIC, 12.6% at M1a, 17.4% at M1b, and 65.6% at M1c. The mean age was 64 years, 49.5% of patients were 64 years old or younger, 68.0% were male, and 91.7% were white. Patients at stage IIIB/IIIC had a median overall survival (OS) of 24.3 months, with a survival rate of 67.2% at 1 year, 42.9% at 2 years, and 32.1% at 3 years. For patients at stage M1a, the median OS was 22.3 months, 1 year, 2 year, and 3 year survival rates were 64.5%, 40.4%, and 26.4%, respectively; for patients at stage M1b, median OS was 11.2 months, 1 year, 2 year, and 3 year survival rates were 43.8%, 23.4%, and 13.8%, respectively; for patients at stage M1c, median OS was 5.1 months, and 1 year, 2 year, and 3 year survival rates were 22.3%, 8.9%, and 4.7%, respectively. CONCLUSIONS: Among patients diagnosed with unresectable metastatic melanoma from 2004 to 2009, patients at later stages had lower median overall survival and higher mortality rates than patients at earlier stages. Limitations of this analysis include the lack of information on disease progression, therapies used, and genetic factors. PMID- 25708473 TI - Pinpointing disease genes through phenomic and genomic data fusion. AB - BACKGROUND: Pinpointing genes involved in inherited human diseases remains a great challenge in the post-genomics era. Although approaches have been proposed either based on the guilt-by-association principle or making use of disease phenotype similarities, the low coverage of both diseases and genes in existing methods has been preventing the scan of causative genes for a significant proportion of diseases at the whole-genome level. RESULTS: To overcome this limitation, we proposed a rigorous statistical method called pgFusion to prioritize candidate genes by integrating one type of disease phenotype similarity derived from the Unified Medical Language System (UMLS) and seven types of gene functional similarities calculated from gene expression, gene ontology, pathway membership, protein sequence, protein domain, protein-protein interaction and regulation pattern, respectively. Our method covered a total of 7,719 diseases and 20,327 genes, achieving the highest coverage thus far for both diseases and genes. We performed leave-one-out cross-validation experiments to demonstrate the superior performance of our method and applied it to a real exome sequencing dataset of epileptic encephalopathies, showing the capability of this approach in finding causative genes for complex diseases. We further provided the standalone software and online services of pgFusion at http://bioinfo.au.tsinghua.edu.cn/jianglab/pgfusion. CONCLUSIONS: pgFusion not only provided an effective way for prioritizing candidate genes, but also demonstrated feasible solutions to two fundamental questions in the analysis of big genomic data: the comparability of heterogeneous data and the integration of multiple types of data. Applications of this method in exome or whole genome sequencing studies would accelerate the finding of causative genes for human diseases. Other research fields in genomics could also benefit from the incorporation of our data fusion methodology. PMID- 25708474 TI - Histology of a cerebral hemorrhage: AVM as a seat of a metastatic choriocarcinoma. AB - INTRODUCTION: There are published cases of cerebral hemorrhage secondary to vascular alterations caused by choriocarcinoma metastases. However, it is extremely rare to find this type of bleeding secondary to an association of such a metastasis with a brain arteriovenous malformation (AVM). CLINICAL CASE: We present the case of a 19-year-old male who came to the Emergency Department complaining of intense headache of abrupt onset. His physical examination revealed a striking increase in size of the right testicle of tumoral origin. Chest X-ray evidenced metastasis to the lungs and a brain CT showed a frontal hemorrhage of probably metastatic origin. The latter eventually progressed to cause the death of the patient. Pathology of the brain hematoma disclosed a choriocarcinoma within the brain AVM nidus. CONCLUSIONS: The case presented is an extremely rare confluence of choriocarcinoma brain metastasis within an AVM. The hemorrhagic onset could have been secondary to bleeding from either of the two histological components of the subjacent mixed pathological lesion. PMID- 25708475 TI - Michael foundation forum 2014, bonn, Germany. PMID- 25708476 TI - Nonadherence to treatment causing acute hospitalizations in people with epilepsy. PMID- 25708477 TI - Research using archival health care data: Let the buyer beware. PMID- 25708478 TI - In response: Research using archival health care data: Let the buyer beware. PMID- 25708479 TI - Vagus nerve stimulation for epilepsy treatment in children. PMID- 25708480 TI - In response: Vagus nerve stimulation for epilepsy treatment in children. PMID- 25708481 TI - Maternal restraint stress during pregnancy in mice induces 11beta-HSD1-associated metabolic changes in the livers of the offspring. AB - In rats, maternal exposure to restraint stress during pregnancy can induce abnormalities in the cardiovascular and central nervous systems of the offspring. These effects are mediated by long-lasting hyperactivation of the hypothalamic pituitary-adrenal axis. However, little is known about the potential effects of stress during pregnancy on metabolic systems. We examined the effect of restraint stress in pregnant mice on the liver function of their offspring. The offspring of stressed mothers showed significantly higher lipid accumulation in the liver after weaning than did the controls; this accumulation was associated with increased expression of lipid metabolism-related proteins such as alanine aminotransferase 2 diglyceride acyltransferase 1, peroxisome proliferator activated receptor gamma and glucocorticoid receptor. Additionally, we observed increased levels of 11beta-hydroxysteroid dehydrogenase type 1, an intercellular mediator that converts glucocorticoid from the inactive to the active form, in the foetal and postnatal periods. These results indicate that restraint stress in pregnancy in mice induces metabolic abnormalities via 11beta-hydroxysteroid dehydrogenase type 1-related pathways in the foetal liver. It is therefore possible that exposure to stress in pregnant women may be a risk factor for metabolic syndromes (e.g. fatty liver) in children. PMID- 25708482 TI - Expectation violations in sensorimotor sequences: shifting from LTM-based attentional selection to visual search. AB - Long-term memory (LTM) delivers important control signals for attentional selection. LTM expectations have an important role in guiding the task-driven sequence of covert attention and gaze shifts, especially in well-practiced multistep sensorimotor actions. What happens when LTM expectations are disconfirmed? Does a sensory-based visual-search mode of attentional selection replace the LTM-based mode? What happens when prior LTM expectations become valid again? We investigated these questions in a computerized version of the number connection test. Participants clicked on spatially distributed numbered shapes in ascending order while gaze was recorded. Sixty trials were performed with a constant spatial arrangement. In 20 consecutive trials, either numbers, shapes, both, or no features switched position. In 20 reversion trials, participants worked on the original arrangement. Only the sequence-affecting number switches elicited slower clicking, visual search-like scanning, and lower eye-hand synchrony. The effects were neither limited to the exchanged numbers nor to the corresponding actions. Thus, expectation violations in a well-learned sensorimotor sequence cause a regression from LTM-based attentional selection to visual search beyond deviant-related actions and locations. Effects lasted for several trials and reappeared during reversion. PMID- 25708483 TI - Controlling the exciton energy of zinc oxide (ZnO) quantum dots by changing the confinement conditions. AB - ZnO nanoparticles were synthesized by solid state and hydrolysis methods based on the conventional precipitation. In situ growth of ZnO nanoparticles were monitored by photoluminescence spectroscopy (PL). By the help of electron paramagnetic resonance (EPR) technique, detailed analysis of intrinsic defect structure of ZnO was given with respect to mean particle size. In nanoscale concentration of surface defects enormously increased and core defects reduced. In addition, blue-shift was observed in PL spectra at near-band-edge UV region due to e-h recombination. Calculation of band gap energies by the aid of Brus equation revealed consistent results with the experimental observations. PMID- 25708484 TI - Modulation of human gamma/delta T-cell activation and phenotype by histone deacetylase inhibitors. AB - Histone deacetylase inhibitors have been shown to possess therapeutic potential in various pathophysiological conditions. Valproic acid (VPA), a known histone deacetylase class I inhibitor, has been studied for its influence on immune cell functions. However, the potential impact of VPA on human gammadelta T-cells remains unknown. Here we investigated the effects of VPA on the proliferation and the immunophenotype of human gammadelta T-cells. We observed dose-dependent inhibition of proliferation, associated with significant cell death as revealed by flow cytometry. The cellular response to VPA clearly showed differential modulation of cell surface markers on gammadelta T-cells when compared to alphabeta T-cells. Furthermore, histone H3 acetylation was detected in gammadelta T-cells even at toxic concentrations of VPA. Our investigations focusing on the impact of VPA on human gammadelta T-cells will be helpful in understanding its safety profile in clinical application, particularly in the context of gammadelta T-cell-targeted immunotherapy. PMID- 25708485 TI - Suppressive effects of androgens on the immune system. AB - Sex-based disparities in immune responses are well known phenomena. The two most important factors accounting for the sex-bias in immunity are genetics and sex hormones. Effects of female sex hormones, estrogen and progesterone are well established, however the role of testosterone is not completely understood. Evidence from unrelated studies points to an immunosuppressive role of testosterone on different components of the immune system, but the underlying molecular mechanisms remains unknown. In this review we evaluate the effect of testosterone on key cellular components of innate and adaptive immunity. Specifically, we highlight the importance of testosterone in down-regulating the systemic immune response by cell type specific effects in the context of immunological disorders. Further studies are required to elucidate the molecular mechanisms of testosterone-induced immunosuppression, leading the way to the identification of novel therapeutic targets for immune disorders. PMID- 25708486 TI - Incidental findings in surgery. PMID- 25708487 TI - Multimode optomechanical dynamics in a cavity with avoided crossings. AB - Cavity optomechanics offers powerful methods for controlling optical fields and mechanical motion. A number of proposals have predicted that this control can be extended considerably in devices where multiple cavity modes couple to each other via the motion of a single mechanical oscillator. Here we study the dynamic properties of such a multimode optomechanical device, in which the coupling between cavity modes results from mechanically induced avoided crossings in the cavity's spectrum. Near the avoided crossings we find that the optical spring shows distinct features that arise from the interaction between cavity modes. Precisely at an avoided crossing, we show that the particular form of the optical spring provides a classical analogue of a quantum non-demolition measurement of the intracavity photon number. The mechanical oscillator's Brownian motion, an important source of noise in these measurements, is minimized by operating the device at cryogenic temperature (500 mK). PMID- 25708488 TI - Prophylactic fluconazole in very low birth weight infants admitted to neonatal intensive care unit: randomized controlled trial. AB - OBJECTIVE: To evaluate the effect of fluconazole prophylaxis on invasive fungal infection (IFI) in very low birth weight (VLBW) infants in the Neonatal Intensive Care Unit (NICU). METHODS: VLBW infants receiving antibiotics for more than 3 days were randomized to receive either fluconazole (6 mg/kg) or placebo, every other day for 7 days followed by everyday till day 28 or discharge whichever was earlier. The primary outcome was IFI, and secondary outcome was fungal attributable mortality and all-cause mortality. RESULTS: The incidence of IFI was significantly lower (21%) in the fluconazole group compared to the control group (43.2%, 95%CI 0.09-0.37, p < 0.05). The ARR (absolute risk reduction) was 22.2% and the NNT (number needed to treat) was 5. Fungal attributable mortality was also lower in the fluconazole group (2.6% versus 18.9%, 95%CI 0.003-0.52, p < 0.05). CONCLUSION: In VLBW neonates on the NICU, use of fluconazole prophylaxis decreases IFI and fungal attributable mortality. PMID- 25708489 TI - Evaluation of the effects of fasting associated dehydration on maternal NGAL levels and fetal renal artery Doppler parameters. AB - OBJECTIVE: The aim of this study was to evaluate maternal neutrophil gelatinase asssociated lipocalin (NGAL) levels and fetal renal artery (fRA) Doppler flow indices in pregnant women fasting in Ramadan in respect of dehydration in long hot summer days as a marker of hypoperfusion and early renal injury. METHODS: A cross-sectional observational study was carried out at a University Hospital. Fasting pregnant women and non-fasting age, gravidity and gestational age-matched women were evaluated for hematologic, blood biochemistry and urine parameters in the first and fourth weeks of the Ramadan. Umbilical artery and fRA Doppler flows were studied in each evaluation. RESULTS: Blood urea nitrogen, potassium and hematocrit levels, blood and urine NGAL levels were significantly higher, and fRA Doppler indices increased in fasting women (p < 0.05) during the second visit in the last week of the Ramadan, while non-fasting women had no significant alterations in each evaluation (p > 0.05). CONCLUSIONS: Adequate maternal vascular volume is essential for the maintenance of healthy pregnancy. Fasting during the long and hot summer days leads to fluid deprivation and dehydration which was found to be related to subclinical maternal renal dysfunction and increased fRA Doppler indices. PMID- 25708490 TI - Fetal ductus arteriosus constriction and closure: analysis of the causes and perinatal outcome related to 45 consecutive cases. AB - OBJECTIVE: The aim of this study was to analyze the causes and perinatal outcome related to fetal ductus arteriosus constriction or closure at a single center over a 26-year period. METHODS: This was a retrospective analysis of 45 consecutive cases of constriction (n = 41) and closure (n = 4) from 1987 through 2013. Patients were divided into Group A (maternal use of non-steroidal anti inflammatory drugs (NSAID), n = 29), Group B (idiopathic, n = 8), and Group C (other drugs not previously described, n = 8). RESULTS: The median gestational age at diagnosis was 34 weeks (range, 27-38), mean systolic and diastolic velocity in the ductus arteriosus was 2.01 +/- 0.66 m/s and 0.71 +/- 0.46 m/s, respectively. Among the 29 cases of NSAIDs, 27.5% (8/29) have taken a single day use and 75% multiple days/doses. Right ventricular dilatation was present in 82.2% of the fetuses, tricuspid insufficiency in 86.6%, and heart failure in 22.2%. Neonatal persistent pulmonary hypertension occurred in 17.7% of the patients. Late follow-up showed all 43 survivors alive and healthy with only two deaths from unrelated causes. CONCLUSIONS: The results of this study indicate that clinically significant ductal constriction may follow maternal exposure to single doses of NSAIDs. Unknown causes or other new substances were also described, such as naphazoline, fluoxetine, isoxsuprine, caffeine and pesticides. Echocardiographic diagnosis of ductal constriction led to an active medical approach that resulted in low morbidity of this group of patients. PMID- 25708491 TI - Fetal surgery and maternal cortisol response to stress. The myelomeningocele sheep model. AB - BACKGROUND: Prenatal surgery represents a multifactorial stressor event for mother and fetus. The stress response to fetal surgery was evaluated by measuring maternal plasma and amniotic fluid (AF) cortisol levels in the myelomeningocele (MMC) sheep model. SUBJECTS AND METHODS: Pregnant ewes (n = 8) underwent general anesthesia for MMC-induction (step 1: 75 d gestation), surgical defect repair (step 2: 110 d gestation), and delivery (step 3: 140 d gestation). Maternal blood samples were taken before surgery (surgical stage T1), after laparotomy and uterine exposure (surgical stage T2), at the end of the procedure (surgical stage T3). Fetal stress was evaluated by measuring cortisol levels in AF after hysterotomy at steps 1-3. RESULTS: Maternal cortisol concentrations at T2 and T3 increased compared with T1 (p = 0.019 and p = 0.046). AF cortisol response increased from 1 to 3 surgical steps and during pregnancy. The AF cortisol level was lower than maternal serum levels (induction p < 0.001; repair p < 0.001; caesarean section p < 0.001). CONCLUSIONS: Hysterotomy was the most stressful event in the ewes. Fetuses seemed to be partially protected from the high maternal cortisol levels. The fetal stress response to prenatal surgery increased with gestational age. Pain perception development, fetal maturation, and "pain memory" are probably associated with this increase. PMID- 25708492 TI - Predictive value of angiogenic factors, clinical risk factors and uterine artery Doppler for pre-eclampsia and fetal growth restriction in second and third trimester pregnancies in an Ecuadorian population. AB - OBJECTIVE: To evaluate the performance of angiogenic factors, maternal risks and uterine artery Doppler (UAD) in the prediction of pre-eclampsia (PE) and fetal growth restriction (FGR) in a high-risk Ecuadorian population. METHODS: Patients with singleton pregnancies (n = 346) were investigated at two clinical visits (18 25 weeks and 28-32 weeks). Mean uterine artery (UA), pulsatility index (PI) and maternal biomarkers (soluble fms-like tyrosine kinase-1, placental growth factor, sFlt-1/PLGF ratio) were obtained. The main endpoints were PE and FGR. UA PI and angiogenic factor levels were compared for the groups with PE (n = 34), FGR (n = 26), PE & FGR (n = 14) and controls (n = 272). Multivariable stepwise logistic regression was used to construct prediction models. RESULTS: Pregnancies with either FGR or PE & FGR exhibited in the second trimester a significantly higher mean UA PI and sFlt-1/PLGF ratio and lower PLGF values compared to controls. In the third trimester, all groups with adverse outcome demonstrated significantly lower PLGF levels and a higher sFlt-1/PLGF ratio compared to normal pregnancies. Differences were most pronounced for pregnancies that developed PE and FGR for both time intervals. The combination of UAD and sFlt-1/PLGF ratio improved the predictive capacity for PE and FGR compared to each parameter alone. The best performance was obtained by integrating anamnestic risk factors, resulting in an area under the receiver operating curve for PE of 0.85 and 0.89 and for FGR of 0.79 and 0.77 in the second and third trimester, respectively. CONCLUSION: In a high-altitude Ecuadorian population, angiogenic factors and UA PI were useful tools in the prediction of PE and/or FGR. The highest performance was achieved by the combination of these factors, including obstetric and medical history. PMID- 25708493 TI - The effects of maternal weight and age on pre-eclampsia and eclampsia in Haiti. AB - OBJECTIVE: Patient data from Maison de Naissance (MN), a rural maternity clinic in Haiti, were analyzed to determine the prevalence of pregnancy-related hypertensive disorders and the extent to which maternal weight and age are associated with these disorders in the MN population. METHODS: A case-control study design was used with cases defined as pregnant women who were presented at MN with pregnancy-related hypertensive disorders (pregnancy-induced hypertension, pre-eclampsia or eclampsia) and controls defined as those women who delivered babies at MN and were not diagnosed with a pregnancy-related hypertensive disorder. The final cohort size was 622 controls and 67 cases. Odds ratios were calculated using multivariate logistic regression. RESULTS: The incidence of pre eclampsia and eclampsia was 7.0%. Older maternal age at delivery (OR = 3.18; 95%CI: 1.31, 7.76) and higher maternal weight (OR = 3.24; 95%CI: 1.76, 5.98) measured during prenatal care were significantly associated with pregnancy related hypertensive disorders. Prenatal care was not significantly associated with reduced risk of pre-eclampsia/eclampsia. CONCLUSIONS: The prevalence of pregnancy-related hypertensive disorders was high relative to rates in other developing countries. More is required to reduce the rate of pre-eclampsia perhaps by targeting older and women with high weight for preconception and more intensive prenatal care. PMID- 25708494 TI - The effect of peritoneal cavity saline irrigation at cesarean delivery on maternal morbidity and gastrointestinal system outcomes. AB - OBJECTIVE: The objective of this study is to investigate the effect of peritoneal cavity saline irrigation during cesarean section (CS) on gastrointestinal disturbance and postoperative infectious morbidity (PIM). METHODS: This prospective randomized clinic trial included 430 women who underwent elective or primary CS. The participants were randomized to either an irrigation of the abdominal cavity or the control group. The primary outcome measured was the rate of antiemetic drugs required in the postoperative period following CS. Secondary outcome measures included the rate of PIM. RESULTS: Participants in both groups had similar demographic and clinical characteristics. The rate of antiemetic drugs required by patients was significantly higher in the irrigation group when compared with the control group (15.8% versus 8.4%, p = 0.018). The rate of intraoperative nausea and emesis (p <= 0.001) and the rate of postoperative nausea and emesis (p <= 0.001 and p = 0.018, respectively) were significantly higher in the irrigation group compared with the control group. CONCLUSIONS: Irrigation with saline at the time of CS increases both intraoperative and postoperative nausea and emesis without any beneficial effects on PIM. Routine use of saline irrigation in the abdominal cavity does not seem to be reasonable. PMID- 25708495 TI - Re-laparotomy following cesarean delivery - risk factors and outcomes. AB - INTRODUCTION: Re-laparotomy following caesarean delivery (CD) is a rare yet serious complication. The aim of this study was to identify risk factors, diagnostic features and outcomes following re-laparotomy. MATERIALS AND METHODS: This retrospective cohort study reviewed cases of re-laparotomy following CD performed at Hadassah-Hebrew University Medical Center. Occurrences were identified via the electronic medical record database. RESULTS: During the study period, 17,213 women underwent CD, of which 55 (0.3%) underwent re-laparotomy during the same hospitalization. Main indications for re-laparotomy were intra peritoneal bleeding (62%) and wound infection/dehiscence (22%). During re laparotomy, the bleeding source was found and ligated in 85% of the cases. Age, parity, previous CD, induction of labor, anesthesia type and operative duration were significant risk factors for re-laparotomy. In a selected group of patients, trial of conservative treatment was made. However, in 76% of these women a re laparotomy was required. DISCUSSION: Risk factors for re-laparotomy following CD should be identified, thus enabling more intensified monitoring of patients considered at risk for this complication. When intra-peritoneal bleeding following CD is suspected, conservative management has a high failure rate and should be reserved for a selected group of stable patients. PMID- 25708496 TI - Intramolecular N-coordination in ketiminoboranes. AB - Treatment of the imine PhC(=NSiMe3)py with Et2BOMe or BF3.Et2O afforded bicyclic ketiminoboranes and via intramolecular N-coordination. The basicity of the imine N is evidenced by their reactivity towards Bronsted and Lewis acids and the structures of .HCl and .BF3 are reported as well as the dipyridyl imine derivative .HCl. PMID- 25708498 TI - Therapy. Targeted delivery of packaged siRNA promotes osteogenesis. PMID- 25708497 TI - Stem cell therapy for intervertebral disc regeneration: obstacles and solutions. AB - Intervertebral disc (IVD) degeneration is frequently associated with low back and neck pain, which accounts for disability worldwide. Despite the known outcomes of the IVD degeneration cascade, the treatment of IVD degeneration is limited in that available conservative and surgical treatments do not reverse the pathology or restore the IVD tissue. Regenerative medicine for IVD degeneration, by injection of IVD cells, chondrocytes or stem cells, has been extensively studied in the past decade in various animal models of induced IVD degeneration, and has progressed to clinical trials in the treatment of various spinal conditions. Despite preliminary results showing positive effects of cell-injection strategies for IVD regeneration, detailed basic research on IVD cells and their niche indicates that transplanted cells are unable to survive and adapt in the avascular niche of the IVD. For this therapeutic strategy to succeed, the indications for its use and the patients who would benefit need to be better defined. To surmount these obstacles, the solution will be identified only by focused research, both in the laboratory and in the clinic. PMID- 25708499 TI - Spondyloarthropathies. The devil is in the details--teasing out PsA genetics. PMID- 25708500 TI - Recurrent ancient schwannoma. PMID- 25708501 TI - POTS following traumatic stress: interacting central and intracardiac neural control? AB - Cardiovascular autonomic dysfunction is one of the most overlooked complications in patients with diabetes. We report the case of a 19-year-old woman with a 4 year history of diabetes referred due to palpitations and light-headedness following traumatic stress. Rise of heart rate and blood pressure during tilt table testing indicated hyperadrenergic postural orthstatic tachycardia syndrome (POTS). Elevated blood pressure variability, an indirect parameter of increased sympathetic activity, remained almost stable during orthostatic stress. Short term treatment with ivabradine in combination with psychosocial support alleviated POTS-related symptoms. Our findings suggest that traumatic stress in patients with type 1 diabetes mellitus might translate into disturbed neural heart rate control due to a central, ephemeral alteration in autonomic balance. PMID- 25708503 TI - Safe and cost-effective ultrasound guided removal of retained intrauterine device: our experience. AB - OBJECTIVES: To evaluate the efficacy and difference in cost of ultrasound guided removal of retained intrauterine device (IUD). STUDY DESIGN: A total of 23 women underwent ultrasound-guided retrieval of retained IUDs between January 2013 and March 2014. Transvaginal ultrasound was performed in all cases to assess the localization of the IUD. Under transabdominal ultrasound guidance, either the crochet type IUD hook (Gyneas, Goussainville, France) or Alligator forceps were used to grasp the IUD and remove it from the uterine cavity. The costs of the ultrasound guided procedure and the hysteroscopic removal of the IUD were compared. RESULTS: Twenty-three patients who failed IUD removal in the clinic were referred to our department for ultrasound-guided removal. All patients had an IUD present in the uterine cavity. Eleven patients had Paragard IUDs (48%), eight had Mirena IUDs (35%), three had Lippes loop (13%), and one had a ring IUD (4%). The patients' ages ranged from 20-56 years. The IUDs were in place for 8 months to 23 years. Of the 23 patients with retained IUDs, 19 were successfully removed (83%), and 4 underwent hysteroscopic removal of IUD. The IUD removal cost in the operating room on average was $3562 US dollars and the cost of ultrasound guided removal was $465 US dollars. CONCLUSIONS: Retained intrauterine devices with or without strings can often be safely removed in an office-based setting under ultrasound guidance at less cost than in the operating room, even in cases with embedded IUDs. IMPLICATIONS: Our experience leads us to propose in-office IUD removal under ultrasound guidance as the first line in management of retained IUDs after failed removal by conventional practices. Ultrasound provides numerous advantages including direct visualization in a less invasive manner than hysteroscopy. Three-dimensional imaging can also be used for enhanced perspective. PMID- 25708502 TI - Hormonal contraception does not increase women's HIV acquisition risk in Zambian discordant couples, 1994-2012. AB - OBJECTIVE: To determine the impact of hormonal contraceptive methods on risk of HIV acquisition among HIV-negative women cohabiting with HIV-positive male partners. STUDY DESIGN: From 1994-2012, HIV discordant couples recruited from a couples' voluntary HIV counseling and testing center in Lusaka, Zambia were followed longitudinally. HIV-negative partners were tested quarterly. This analysis is restricted to couples in which the man was HIV-positive and the woman was HIV-negative at enrollment and the man was not on antiretroviral treatment. Multivariate Cox models evaluated associations between time-varying contraceptive methods and HIV acquisition among women. Sensitivity analyses explored exposure misclassification and time-varying confounder mediation. RESULTS: Among 1393 couples, 252 incident infections occurred in women over 2842 couple-years (8.9 infections per 100 couple-years; 95% CI, 7.8-10.0). Multivariate Cox models indicated that neither injectable [adjusted hazard ratio (aHR)=1.2; 95% CI, 0.8 1.7], oral contraceptive pill (OCP, aHR=1.3; 95% CI, 0.9-1.8), or implant (aHR=1.1; 95% CI, 0.5-2.2) use was significantly associated with HIV acquisition relative to non-hormonal contraception controlling for woman's age, literacy and time-varying measures of genital ulceration/inflammation. This remained true when only looking at the subset of infections acquired from the spouse (82% of infections) and additionally controlling for baseline HIV viral load of the male partner, pregnancy status, and time-varying measures of sperm on a vaginal swab wet prep and self-reported unprotected sex. OCP and injectable users reported more unprotected sex (p<.001), and OCP users were more likely to have sperm on vaginal swab (p=.1) than nonhormonal method users. CONCLUSIONS: We found no association between hormonal contraception and HIV acquisition risk in women. Condom use and reinforced condom counseling should always be recommended for HIV discordant couples. HIV testing of sex partners together is critical to establish HIV risk, ascertain couple fertility intentions and counsel appropriately. IMPLICATIONS: These findings add to a controversial literature and uniquely address several common design and analytic challenges faced by previous studies. After controlling for confounders, we found no association between hormonal contraception and HIV acquisition risk in women. We support promoting condoms for HIV prevention and increasing the contraceptive method mix to decrease unintended pregnancy. PMID- 25708505 TI - Recruitment and retention strategies for expert nurses in abortion care provision. AB - OBJECTIVE(S): The purpose of this thematic analysis is to describe recruitment, retention and career development strategies for expert nurses in abortion care provision. STUDY DESIGN: Thematic analysis influenced by grounded theory methods were used to analyze interviews, which examined cognitive, emotional, and behavioral processes associated with how nurses make decisions about participation in abortion care provision. The purposive sample consisted of 16 nurses, who were interviewed between November 2012 and August 2013, who work (or have worked) with women seeking abortions in abortion clinics, emergency departments, labor and delivery units and post anesthesia care units. RESULTS: Several themes emerged from the broad categories that contribute to successful nurse recruitment, retention, and career development in abortion care provision. All areas were significantly influenced by engagement in leadership activities and professional society membership. The most notable theme specific to recruitment was exposure to abortion through education as a student, or through an employer. Retention is most influenced by flexibility in practice, including: advocating for patients, translating one's skill set, believing that nursing is shared work, and juggling multiple roles. Lastly, providing on the job training opportunities for knowledge and skill advancement best enables career development. CONCLUSION(S): Clear mechanisms exist to develop expert nurses in abortion care provision. IMPLICATIONS: The findings from our study should encourage employers to provide exposure opportunities, develop activities to recruit and retain nurses, and to support career development in abortion care provision. Additionally, future workforce development efforts should include and engage nursing education institutions and employers to design structured support for this trajectory. PMID- 25708506 TI - Initial improvements when converting eyes with treatment-resistant exudative AMD to aflibercept are substantially diminished after increasing treatment intervals from 4 to 8 weeks. PMID- 25708504 TI - How does intimate partner violence affect condom and oral contraceptive Use in the United States?: A systematic review of the literature. AB - INTRODUCTION: Intimate partner violence (IPV) is estimated to affect 25% of adult women in the United States alone. IPV directly impacts women's ability to use contraception, resulting in many of unintended pregnancies and STIs. This review examines the relationship between IPV and condom and oral contraceptive use within the United States at two levels: the female victim's perspective on barriers to condom and oral contraceptive use, in conjunction with experiencing IPV (Aim 1) and the male perpetrator's perspective regarding condom and oral contraceptive use (Aim 2). STUDY DESIGN: We systematically reviewed and synthesized all publications meeting the study criteria published since 1997. We aimed to categorize the results by emerging themes related to each study aim. RESULTS: We identified 42 studies that met our inclusion criteria. We found 37 studies that addressed Aim 1. Within this we identified three themes: violence resulting in reduced condom or oral contraceptive use (n=15); condom or oral contraceptive use negotiation (n=15); which we further categorized as IPV due to condom or oral contraceptive request, perceived violence (or fear) of IPV resulting in decreased condom or oral contraceptive use, and sexual relationship power imbalances decreasing the ability to use condoms or oral contraceptives; and reproductive coercion (n=7). We found 5 studies that addressed Aim 2. Most studies were cross-sectional, limiting the ability to determine causality between IPV and condom or oral contraceptive use; however, most studies did find a positive relationship between IPV and decreased condom or oral contraceptive use. CONCLUSIONS: Quantitative, qualitative, and mixed methods research has demonstrated the linkages between female IPV victimization/male IPV perpetration and condom or oral contraceptive use. However, additional qualitative and longitudinal research is needed to improve the understanding of dynamics in relationships with IPV and determine causality between IPV, intermediate variables (e.g., contraceptive use negotiation, sexual relationship power dynamics, reproductive coercion), and condom and oral contraceptive use. Assessing the relationship between IPV and reproductive coercion may elucidate barriers to contraceptive use as well as opportunities for interventions to increase contraceptive use (such as forms of contraception with less partner influence) and reduce IPV and reproductive coercion. PMID- 25708507 TI - Drug resistance of bacterial dental biofilm and the potential use of natural compounds as alternative for prevention and treatment. AB - Oral diseases, such as dental caries and periodontal disease are directly linked with the ability of bacteria to form biofilm. The development of dental caries involves acidogenic and aciduric Gram-positive bacteria colonizing the supragingival biofilm (Streptococcus, Lactobacillus and Actinomycetes). Periodontal diseases have been linked to anaerobic Gram-negative bacteria forming a subgingival plaque (Porphyromonas gingivalis, Actinobacillus, Prevotella and Fusobacterium). Cells embedded in biofilm are up to 1000-fold more resistant to antibiotics compared to their planctonic ones. Several mechanisms have been proposed to explain biofilms drug resistance. Given the increased bacterial resistance to antibiotics currently used in dentistry, a great importance is given to natural compounds for the prevention of oral bacterial growth, adhesion and colonization. Over the past decade, interest in drugs derived from medicinal plants has markedly increased. It has been well documented that medicinal plants and natural compounds confer considerable antibacterial activity against various microorganisms including cariogenic and periodontal pathogens. This paper provides a review of the literature focusing on the studies on (i) biofilm in the oral cavity, (ii) drug resistance of bacterial biofilm and (iii) the potential use of plant extracts, essential oils and natural compounds as biofilm preventive agents in dentistry, involving their origin and their mechanism of biofilm inhibition. PMID- 25708508 TI - Higher frequency of anastomotic leakage with stapled compared to hand-sewn ileocolic anastomosis in a large population-based study. AB - BACKGROUND: The stapling technique was recommended in a recent Cochrane analysis based on relatively small randomized trials between 1970 and 2009. Data from a large Swedish population-based quality register were analyzed in order to compare the leakage frequency between stapled and hand-sewn ileocolic anastomoses in colon cancer surgery. METHODS: Three-thousand four-hundred and twenty-eight patients with an ileocolic anastomosis were entered in a Swedish regional quality register for colon cancer, including the type of anastomosis used. The patients were analyzed by logistic regression regarding risk for leakage, and Cox proportional hazard regression for survival associated with the technique used for anastomosis. Analyses were made for gender, age, elective or emergency surgery, duration of surgery, bleeding, cancer stage, and local radicality. RESULTS: Most anastomoses were hand sewn (1,908 of 3,428, 55.7 %, p < 0.001), whereas stapling was more common among emergency cases (342 of 618, 55.3 %, p < 0.001). Clinically relevant leakage appeared in 58 patients (1.7 %), of whom 51 (87.9 %) were re-operated. Leakage was found to be more frequent after stapled anastomosis (2.4 vs. 1.2 %, p = 0.006), and in multivariate analysis, stapled anastomosis was the only risk factor (OR = 2.04 95 % CI 1.19-3.50). There was no difference in overall survival related to the technique. CONCLUSION: Hand-sewn anastomosis is not associated with a higher leakage rate when comparing to a stapling procedure and is recommended for routine and emergency right-sided colon cancer surgery. This recommendation is based on what appears to be a lower leakage rate, similar survival and lower material cost. PMID- 25708509 TI - Survival after surgical drainage of malignant pericardial effusion. AB - OBJECTIVES: Management of malignant pericardial effusion (PE) is complex. Cardiac surgeons are not necessarily familiar with or are challenged by the many underlying etiologies. Analyzing risk factors for mortality may help to estimate the benefit of surgery in high-risk patients. METHODS: Patients undergoing a surgical pericardiotomy for malignant PE, between 2001 and 2011, were included. The influence of tumor type, disease extension, intra-pericardial tumor infiltration on early mortality and long-term survival as well as freedom from symptoms after drainage, and the use of sclerosing agents on PE recurrence rates was analyzed. RESULTS: PE drainage was performed on 46 patients 12 +/- 30 months after tumor diagnosis. Malignant diseases were lung cancers (50 %), breast cancers (15 %), lymphoma and leukemia (13 %), cancers of the digestive tract (13 %), and others (9 %). 80 % of patients were symptomatic and symptom relief was achieved in 65 %. Nobody died during surgery. Recurrence rate was 4 %. Early in hospital mortality was 22 %. After 1 year, 29 % of patients were alive. Eleven patients (24 %) had a complete tumor regression. Metastatic spread (p < 0.001), pericardial infiltration (p = 0.02), and intra-pericardial Bleomycin (p = 0.01) injection were associated with increased mortality. Hematological malignancies had a better prognosis for survival. CONCLUSION: Surgical pericardiotomy is safe, associated with a low recurrence rate and symptom relief in the majority of dyspneic patients. Intra-pericardial Bleomycin may reduce recurrent effusion but does not ameliorate survival. Long-term survival rate was low with an increased mortality in cases of metastatic spreading, pericardial infiltration, and as the tumor of origin: breast cancers. Leukemic and lymphatic tumors have better prognosis. PMID- 25708510 TI - Seminal parameters of chronic male genital inflammation are associated with disturbed sperm DNA integrity. AB - Definition of chronic male genital tract inflammation and its impact on male infertility is still a matter of debate. In particular, DNA integrity has been reported to be disturbed in subfertile men. Thus, the aim of this study was to investigate an association of DNA integrity to altered standard semen parameters as well as inflammatory parameters such as peroxidase-positive cells, macrophages and seminal interleukin-6 concentration. Macrophages were detected by CD18/HLA-Dr staining, and DNA integrity was analysed by acridine orange staining using flow cytometry. Interleukin-6 was detected by ELISA. Normal DNA integrity showed a significant correlation to sperm number and progressive motility. Moreover, a significant inverse correlation of DNA integrity to Interleukin-6 and macrophages could be demonstrated. Further on, seminal interleukin-6 also significantly correlated to macrophages. No association has been observed between the number of peroxidase-positive cells and normal DNA integrity. As disturbed DNA integrity has been reported to negatively influence spermatozoon-egg interaction and even fertilisation rates following ICSI, and as early miscarriages have been associated with sperm DNA damage, it should be screened very carefully for male genital tract inflammations in couples undergoing infertility treatment. Measuring Interleukin-6 seems superior to assessment of the number of leucocytes alone and additional assessment of DNA integrity into the diagnostic work-up should be considered. PMID- 25708511 TI - Hysteresis in coral reefs under macroalgal toxicity and overfishing. AB - Macroalgae and corals compete for the available space in coral reef ecosystems.While herbivorous reef fish play a beneficial role in decreasing the growth of macroalgae, macroalgal toxicity and overfishing of herbivores leads to proliferation of macroalgae. The abundance of macroalgae changes the community structure towards a macroalgae-dominated reef ecosystem. We investigate coral macroalgal phase shifts by means of a continuous time model in a food chain. Conditions for local asymptotic stability of steady states are derived. It is observed that in the presence of macroalgal toxicity and overfishing, the system exhibits hysteresis through saddle-node bifurcation and transcritical bifurcation. We examine the effects of time lags in the liberation of toxins by macroalgae and the recovery of algal turf in response to grazing of herbivores on macroalgae by performing equilibrium and stability analyses of delay-differential forms of the ODE model. Computer simulations have been carried out to illustrate the different analytical results. PMID- 25708512 TI - CD56+ lymphocyte counts remain low in the livers of human immunodeficiency virus/hepatitis C virus patients commencing ART. PMID- 25708513 TI - A stepwise increase in pristinamycin II biosynthesis by Streptomyces pristinaespiralis through combinatorial metabolic engineering. AB - Pristinamycin, which is a streptogramin antibiotic produced by Streptomyces pristinaespiralis, contains two chemically unrelated compounds, pristinamycin I (PI) and pristinamycin II (PII). Semi-synthetic derivatives of PI and PII have been approved for use in human medicine to treat a broad range of drug-resistant pathogens. In this study, we design and implement a combinatorial metabolic engineering strategy for improving PII production. First, an extra copy of the PII biosynthetic gene cluster, which was assembled using a modified Gibson assembly method for cloning large DNA fragments with high GC contents, was introduced into a high-producing strain S. pristinaespiralis HCCB10218. This duplication of the PII biosynthetic gene cluster resulted in a maximum increase in PII titer by 45%. Second, all seven cluster-situated regulatory genes (from papR1 to papR6 and spbR) were systematically manipulated. Higher PII titers were achieved by deleting either one of the two repressor genes papR3 or papR5 in combination with overexpression of both activator genes papR4 and papR6, and the resulting strains ?papR3+R4R6 and ?papR5+R4R6 showed maximum increases in PII production by 99% and 75%, respectively. A combination of the above two different approaches was employed. Integration of the assembled PII gene cluster (BAC F1F15) into ?papR5+R4R6 led to the highest PII titer improvement, which was approximately 1.5-fold higher than the parental strain. By adding the macroreticular resin, which can separate pristinamycin in situ and thereby lessen end-product feedback inhibition and toxic effects, PII titers of the final engineered strain ?papR5+R4R6/BAC-F1F15 reached 1.13 and 1.16g/L in the Erlenmeyer flask and 5-L bioreactor, respectively, with 5.13- and 5.26-fold improvements over the parental strain. Taken together, this combinatorial strategy is an efficient method to optimize PII biosynthesis of S. pristinaespiralis and may be extended to other industrially used streptomycetes for strain improvement. PMID- 25708514 TI - Mitochondrial engineering of the TCA cycle for fumarate production. AB - Microbial fumarate production from renewable feedstock is a promising and sustainable alternative to petroleum-based chemical synthesis. Here, mitochondrial engineering was used to construct the oxidative pathway for fumarate production starting from the TCA cycle intermediate alpha-ketoglutarate in Candida glabrata. Accordingly, alpha-ketoglutarate dehydrogenase complex (KGD), succinyl-CoA synthetase (SUCLG), and succinate dehydrogenase (SDH) were selected to be manipulated for strengthening the oxidative pathway, and the engineered strain T.G-K-S-S exhibited increased fumarate biosynthesis (1.81 g L( 1)). To further improve fumarate production, the oxidative route was optimized. First, three fusion proteins KGD2-SUCLG2, SUCLG2-SDH1 and KGD2-SDH1 were constructed, and KGD2-SUCLG2 led to improved fumarate production (4.24 g L(-1)). In addition, various strengths of KGD2-SUCLG2 and SDH1 expression cassettes were designed by combinations of promoter strengths and copy numbers, resulting in a large increase in fumarate production (from 4.24 g L(-1) to 8.24 g L(-1)). Then, through determining intracellular amino acids and its related gene expression levels, argininosuccinate lyase in the urea cycle was identified as the key factor for restricting higher fumarate production. Correspondingly, after overexpression of it, the fumarate production was further increased to 9.96 g L( 1). Next, two dicarboxylic acids transporters facilitated an improvement of fumarate production, and, as a result, the final strain T.G-KS(H)-S(M)-A-2S reached fumarate titer of 15.76 g L(-1). This strategy described here paves the way to the development of an efficient pathway for microbial production of fumarate. PMID- 25708515 TI - Depression and quality of life before and after breast cancer diagnosis in older women from the Women's Health Initiative. AB - PURPOSE: Distress and reduced quality of life (QOL) are common among people with cancer. No study has compared these variables after breast cancer diagnosis to pre-cancer diagnosis levels. METHODS: Data on women with breast cancer 50 years of age or older (n = 6949) were analyzed from the Women's Health Initiative (1993 2013). Health-related QOL (physical function, mental health) was measured using Rand-36. Depressive symptoms were measured with the six-item Center for Epidemiologic Studies Depression scale. Assessments occurred before and after the cancer diagnosis. Hierarchical linear modeling compared pre-cancer QOL and depressive symptoms to levels post-diagnosis and tested whether pre-cancer physical activity, stressful life events, sleep disturbance, and pain predicted post-diagnosis outcomes. RESULTS: Compared with pre-cancer levels, depressive symptoms increased (20.0% increase at 0-6 months, 12.9% increase at 6-12 months), while physical function (-3.882 points at 0-6 months, -3.545 at 6-12 months) and mental health decreased (-2.899 points at 0-6 months, -1.672 at 6-12 months) in the first year after diagnosis (all p < .01). Depressive symptoms returned to pre cancer levels after 10 years, but QOL remained significantly lower. At more than 10 years post-diagnosis, physical function was 2.379 points lower than pre-cancer levels (p < 0.01) while mental health was 1.922 points lower (p < 0.01). All pre cancer predictors were associated with all outcomes. Pain predicted uniquely greater decreases in physical function post-diagnosis. CONCLUSIONS: Depressive symptoms increased and QOL decreased following breast cancer diagnosis compared with pre-cancer levels, particularly in the first year. IMPLICATIONS FOR CANCER SURVIVORS: QOL may remain lower for years after breast cancer diagnosis, although decreases are small. PMID- 25708516 TI - Neonatal diabetes mellitus due to a novel mutation in the GATA6 gene accompanying renal dysfunction: a case report. PMID- 25708517 TI - Design and application of a novel high-throughput screening technique for 1 deoxynojirimycin. AB - High-throughput screening techniques for small molecules can find intensive applications in the studies of biosynthesis of these molecules. A sensitive, rapid and cost-effective technique that allows high-throughput screening of endogenous production of the natural iminosugar 1-deoxynojirimycin (1-DNJ), an alpha-glucosidase inhibitor relevant to the pharmaceutical industry, was developed in this study, based on the inhibitory effects of 1-DNJ on the activity of the beta-glycosidase LacS from Sulfolobus solfataricus. This technique has been demonstrated effective in engineering both the key enzyme and the expression levels of enzymes in the 1-DNJ biosynthetic pathway from Bacillus atrophaeus cloned in E. coli. Higher biosynthetic efficiency was achieved using directed evolution strategies. PMID- 25708518 TI - Assessment of Genetic Variability in the Coding Sequence of Melatonin Receptor Gene (MTNR1A) in Tropical Arid Sheep Breeds of India. AB - Seasonal behaviour in sheep, which varies in tropical and temperate environmental conditions, is a matter of study, because it can provide a clue to address the problem of seasonality in sheep. Melatonin receptor is the membrane-bound G coupled receptor, sensing the message of photoperiodic cues thorough melatonin. Restriction fragment length polymorphism (RFLP) studies were carried out to assess the variability of gene at G612A and C606T SNPs in MTNR1A gene, which have been studied to be markers for out-of-season breeding. Allelic frequency distribution corresponded to higher frequency of GG and CC genotype, in tropical arid sheep breed in comparison with temperate region sheep breed. PCR amplification of MTNR1A gene of 30 animals was performed and single nucleotide polymorphisms (SNPs) identification was carried out using Lasergene software. Seven SNPs/mutations were identified, but most of them were synonymous, except the one G706A, leading to substitution of valine by isoleucine. Polyphen-2 analysis of G706A mutation revealed that it is a benign mutation. Two important SNPs C426T and G555A, which were identified in temperate sheep breeds, could not be traced in Magra and Marwari breeds of sheep. Thus, the Magra and Marwari breeds of tropical, arid region demonstrated the presence of both polymorphic SNPs markers G612A and C606T, associated with out-of-season breeding. GG and CC genotypes were having a higher prevalence in the studied population. PMID- 25708519 TI - A QM:MM model for the interaction of DNA nucleotides with carbon nanotubes. AB - Hybrid materials formed by DNA and carbon nanotubes (CNTs) have shown very interesting properties, but their simulation in solution using quantum mechanical approaches is still a challenge in the computational chemistry community. In this paper, we developed a QM:MM model to study the interactions between charged DNA nucleotides and carbon nanotubes in solution. All four types of DNA nucleotides were taken to interact with two CNTs of similar diameter but different chiralities: (4,4) and (7,0). The nucleotides and CNTs were treated at the QM level, while added water and neutralizing ions were modeled at the MM level. ONIOM simulations were performed at the (M06-2X/6-31G(d):Amber) level for the hybrids, as well as for individually solvated CNTs and nucleotides, which allowed us to evaluate the energy of binding. Our binding energy (BE) values range from 146.60 to 503.43 kJ mol(-1), indicating strong physisorption of nucleotides on CNTs. The relatively large BE, compared with past studies on nucleobase-CNT binding in a vacuum, could be due to the larger size of nucleotides compared with nucleobases, the charges on the nucleotides, and the inclusion of solution which causes the release of water molecules upon hybridization. PMID- 25708520 TI - Pemphigoid with antibodies to laminin gamma1, BP180 and BP230, associated with psoriasis vulgaris: successful disease control with cyclosporin. AB - Both anti-laminin gamma1 pemphigoid and bullous pemphigoid are autoimmune subepidermal blistering diseases. The former is rare and characterized by autoantibodies to laminin gamma1, a 200-kDa dermal protein, while the latter is common among the elderly and characterized by autoantibodies to BP180 and BP230, both of which are hemidesmosomal proteins. We experienced a 69-year-old Japanese male patient with blister formation secondary to erythrodermic psoriasis, which was successfully treated with cyclosporin. The histopathology of erythema corresponded with psoriasis and that of a blistering lesion showed infiltration of neutrophils and eosinophils in and around the subepidermal blisters. Patient immunoglobulin G antibodies labeled both the epidermal and dermal sides of 1 mol/L NaCl-split human skin by indirect immunofluorescent microscopy and recognized laminin gamma1, BP180 and BP230 by immunoblotting. To the best of our knowledge, this is the first report of coexistence of psoriasis and atypical pemphigoid with these three autoantibodies. PMID- 25708521 TI - Temperature dependence of the evaporation lengthscale for water confined between two hydrophobic plates. AB - Liquid water in a hydrophobic confinement is the object of high interest in physicochemical sciences. Confined between two macroscopic hydrophobic surfaces, liquid water transforms into vapor if the distance between surfaces is smaller than a critical separation, referred to as the evaporation lengthscale. To investigate the temperature dependence of the evaporation lengthscale of water confined between two hydrophobic parallel plates, we use the combination of the density functional theory (DFT) with the probabilistic hydrogen bond (PHB) model for water-water hydrogen bonding. The PHB model provides an analytic expression for the average number of hydrogen bonds per water molecule as a function of its distance to a hydrophobic surface and its curvature. Knowing this expression, one can implement the effect of hydrogen bonding between water molecules on their interaction with the hydrophobe into DFT, which is then employed to determine the distribution of water molecules between two macroscopic hydrophobic plates at various interplate distances and various temperatures. For water confined between hydrophobic plates, our results suggest the evaporation lengthscale to be of the order of several nanometers and a linearly increasing function of temperature from T=293 K to T=333 K, qualitatively consistent with previous results. PMID- 25708522 TI - Interactions between quaternary ammonium surfactants and polyethylenimine at high pH in film forming systems. AB - HYPOTHESIS: Film formation and film structure in films formed on solutions of cationic surfactants with polyethylenimine is influenced by the surfactant structure, including both the tail length and the nature of the headgroup, which alter the micelle properties. EXPERIMENTS: A series of cationic surfactants were synthesized and conductivity measurements were used to compare the critical micelle concentrations for these surfactants and their behaviour with and without polyethylenimine at high pH. Small angle neutron scattering measurements were used to characterise the size and shape of the micelles in the presence and absence of the polymer. Film formation between polyethylenimine and the various surfactants was trialled, and the interfacial film structures measured using neutron reflectivity. FINDINGS: Film formation is shown to depend on surfactant tail length, with thicker films forming for surfactants with longer hydrophobic tails. The surfactant headgroup structure affects counterion binding to the micelles, and in the case of the aromatic headgroups, the headgroup affects the extent of micellar growth when polymer is added. Films with the greatest mesostructural ordering were grown using hexadecylpyridinium bromide surfactants. PMID- 25708523 TI - Ghrelin regulates phasic dopamine and nucleus accumbens signaling evoked by food predictive stimuli. AB - Environmental stimuli that signal food availability hold powerful sway over motivated behavior and promote feeding, in part, by activating the mesolimbic system. These food-predictive cues evoke brief (phasic) changes in nucleus accumbens (NAc) dopamine concentration and in the activity of individual NAc neurons. Phasic fluctuations in mesolimbic signaling have been directly linked to goal-directed behaviors, including behaviors elicited by food-predictive cues. Food-seeking behavior is also strongly influenced by physiological state (i.e., hunger vs. satiety). Ghrelin, a stomach hormone that crosses the blood-brain barrier, is linked to the perception of hunger and drives food intake, including intake potentiated by environmental cues. Notwithstanding, whether ghrelin regulates phasic mesolimbic signaling evoked by food-predictive stimuli is unknown. Here, rats underwent Pavlovian conditioning in which one cue predicted the delivery of rewarding food (CS+) and a second cue predicted nothing (CS-). After training, we measured the effect of ghrelin infused into the lateral ventricle (LV) on sub-second fluctuations in NAc dopamine using fast-scan cyclic voltammetry and individual NAc neuron activity using in vivo electrophysiology in separate groups of rats. LV ghrelin augmented both phasic dopamine and phasic increases in the activity of NAc neurons evoked by the CS+. Importantly, ghrelin did not affect the dopamine nor NAc neuron response to the CS-, suggesting that ghrelin selectively modulated mesolimbic signaling evoked by motivationally significant stimuli. These data demonstrate that ghrelin, a hunger signal linked to physiological state, can regulate cue-evoked mesolimbic signals that underlie food-directed behaviors. Cues that predict food availability powerfully regulate food-seeking behavior. Here we show that cue-evoked changes in both nucleus accumbens (NAc) dopamine (DA) and NAc cell activity are modulated by intra cranial infusions of the stomach hormone ghrelin--a hormone known to act centrally to promote food intake. These data demonstrate that hormones associated with physiological state (i.e., hunger) can affect encoding of food-predictive cues in brain regions that drive food-motivated behavior. PMID- 25708524 TI - Causes of metabolic syndrome and obesity-related co-morbidities Part 1: A composite unifying theory review of human-specific co-adaptations to brain energy consumption. AB - The medical, research and general community is unable to effect significantly decreased rates of central obesity and related type II diabetes mellitus (TIIDM), cardiovascular disease (CVD) and cancer. All conditions seem to be linked by the concept of the metabolic syndrome (MetS), but the underlying causes are not known. MetS markers may have been mistaken for causes, thus many treatments are destined to be suboptimal. The current paper aims to critique current paradigms, give explanations for their persistence, and to return to first principles in an attempt to determine and clarify likely causes of MetS and obesity related comorbidities. A wide literature has been mined, study concepts analysed and the basics of human evolution and new biochemistry reviewed. A plausible, multifaceted composite unifying theory is formulated. The basis of the theory is that the proportionately large, energy-demanding human brain may have driven co adaptive mechanisms to provide, or conserve, energy for the brain. A 'dual system' is proposed. 1) The enlarged, complex cortico-limbic-striatal system increases dietary energy by developing strong neural self-reward/motivation pathways for the acquisition of energy dense food, and (2) the nuclear factor erythroid 2-related factor 2 (NRF2) cellular protection system amplifies antioxidant, antitoxicant and repair activity by employing plant chemicals, becoming highly energy efficient in humans. The still-evolving, complex human cortico-limbic-striatal system generates strong behavioural drives for energy dense food procurement, including motivating agricultural technologies and social system development. Addiction to such foods, leading to neglect of nutritious but less appetizing 'common or garden' food, appears to have occurred. Insufficient consumption of food micronutrients prevents optimal human NRF2 function. Inefficient oxidation of excess energy forces central and non-adipose cells to store excess toxic lipid. Oxidative stress and metabolic inflammation, or metaflammation, allow susceptibility to infectious, degenerative atherosclerotic cardiovascular, autoimmune, neurodegenerative and dysplastic diseases. Other relevant human-specific co-adaptations are examined, and encompass the unusual ability to store fat, certain vitamin pathways, the generalised but flexible intestine and microbiota, and slow development and longevity. This theory has significant past and future corollaries, which are explored in a separate article by McGill, A-T, in Archives of Public Health, 72: 31. PMID- 25708525 TI - A longitudinal evaluation of anti-FVIII antibodies demonstrated IgG4 subclass is mainly correlated with high-titre inhibitor in haemophilia A patients. AB - The development of inhibitory antibodies against factor VIII (FVIII) (inhibitor) is the major complication in haemophilia A patients. The FVIII-binding antibodies development comprises a polyclonal immunoglobulin (Ig) G response. Recent studies showed strong correlation between the presence of neutralizing anti-FVIII antibodies (inhibitors) and IgG4 subclass. The aim of this study was to evaluate anti-FVIII IgG subclasses in haemophilia A patients with inhibitor both in a cross-sectional and in a longitudinal analysis. Inhibitors were determined by Nijmegen-Bethesda assay. Anti-FVIII IgG subclasses were performed by ELISA, and samples from 20 healthy individuals were used to validate the test. We studied 25 haemophilia A patients with inhibitor, previously treated exclusively with plasma derived FVIII concentrates or bypassing agents. The IgG subclasses distributions were evaluated in two groups of patients classified according to inhibitor response. IgG1 and IgG4 antibodies were most prominent in haemophilia A patients with inhibitors when compared with IgG2 and IgG3. This study reports for the first time the behaviour of FVIII-binding IgG1 and IgG4 subclasses in a longitudinal analysis, in a clinical setting, of high-response inhibitor haemophilia A patients, showing the correlation of IgG4 and the inhibitor titres. In spite of being considered a non-pathologic antibody subclass with anti inflammatory properties in other situations, IgG4 is correlated with the presence of high-titre inhibitor in the haemophilia setting. The comprehension of the IgG4 role in immune response may be crucial to establish the process for designing specific tolerance to FVIII. PMID- 25708526 TI - High incidence of acute full-thickness rotator cuff tears. AB - BACKGROUND AND PURPOSE: Epidemiological studies of full-thickness rotator cuff tears (FTRCTs) have mainly investigated degenerative lesions. We estimated the population-based incidence of acute FTRCT using a new diagnostic model. PATIENTS AND METHODS: During the period November 2010 through October 2012, we prospectively studied all patients aged 18-75 years with acute onset of pain after shoulder trauma, with limited active abduction, and with normal conventional radiographs. 259 consecutive patients met these inclusion criteria. The patients had a median age of 51 (18-75) years. 65% were males. The patients were divided into 3 groups according to the clinical findings: group I, suspected FTRCT; group II, other specific diagnoses; and group III, sprain. Semi-acute MRI was performed in all patients in group I and in patients in group III who did not recover functionally. RESULTS: We identified 60 patients with FTRCTs. The estimated annual incidence of MRI-verified acute FTRCT was 16 (95% CI: 11-23) per 10(5) inhabitants for the population aged 18-75 years and 25 (CI: 18-36) per 10(5) inhabitants for the population aged 40-75 years. The prevalence of acute FTRCT in the study group was 60/259 (23%, CI: 18-28). The tears were usually large and affected more than 1 tendon in 36 of these 60 patients. The subscapularis was involved in 38 of the 60 patients. INTERPRETATION: Acute FTRCTs are common shoulder injuries, especially in men. They are usually large and often involve the subscapularis tendon. PMID- 25708527 TI - The meaning of 'life' and other abstract words: Insights from neuropsychology. AB - There are a number of long-standing theories on how the cognitive processing of abstract words, like 'life', differs from that of concrete words, like 'knife'. This review considers current perspectives on this debate, focusing particularly on insights obtained from patients with language disorders and integrating these with evidence from functional neuroimaging studies. The evidence supports three distinct and mutually compatible hypotheses. (1) Concrete and abstract words differ in their representational substrates, with concrete words depending particularly on sensory experiences and abstract words on linguistic, emotional, and magnitude-based information. Differential dependence on visual versus verbal experience is supported by the evidence for graded specialization in the anterior temporal lobes for concrete versus abstract words. In addition, concrete words have richer representations, in line with better processing of these words in most aphasic patients and, in particular, patients with semantic dementia. (2) Abstract words place greater demands on executive regulation processes because they have variable meanings that change with context. This theory explains abstract word impairments in patients with semantic-executive deficits and is supported by neuroimaging studies showing greater response to abstract words in inferior prefrontal cortex. (3) The relationships between concrete words are governed primarily by conceptual similarity, while those of abstract words depend on association to a greater degree. This theory, based primarily on interference and priming effects in aphasic patients, is the most recent to emerge and the least well understood. I present analyses indicating that patterns of lexical co occurrence may be important in understanding these effects. PMID- 25708528 TI - Fatty acid synthase-positive hepatocytes and subsequent steatosis in rat livers by irinotecan. AB - Using a rat model, we investigated factors contributing to the pathogenesis of irinotecan-associated fatty liver disease. Male Sprague-Dawley rats were administered 200 mg/kg irinotecan by intraperitoneal injection on days 1-4, but not on days 5-7. This schedule was repeated 3 times. Rats were sacrificed 4, 18 and 25 days after the last injection, and liver steatosis was evaluated by hematoxylin and eosin (H&E) staining, microarray analysis and immunohistochemistry. Panacinar intrahepatocyte vacuoles were absent on days 4 and 25, but present on day 18, and this alteration was more prominent around the bile ducts than the central veins. Microarray analysis showed that the expression of genes involved in the synthesis of cholesterol and fatty acids was upregulated on day 4. Immunohistochemistry detected fatty acid synthase (Fasn)-strongly positive hepatocytes as well as the activation of liver progenitor cells on day 4, whereas intracellular vacuoles were evident in carbonic anhydrase 3 (CA3) positive hepatocytes on day 18. Thus, irinotecan-induced liver steatosis was preceded by Fasn-strongly-positive hepatocytes and liver progenitor cell activation. The magnitude of the decrease in the number of Fasn-strongly positive hepatocytes between days 4 and 18 was similar to that of the increase in the number of CA3-positive hepatocytes accompanying vacuoles. PMID- 25708529 TI - HER2 expression and markers of phosphoinositide-3-kinase pathway activation define a favorable subgroup of metastatic pulmonary adenocarcinomas. AB - OBJECTIVES: Pulmonary adenocarcinomas (ADC) can be sub-grouped based on dominant oncogenic drivers. EGFR mutations define an entity of metastatic ADC with favorable prognosis and high susceptibility to EGFR tyrosine kinase inhibition. In contrast, the clinical impact of additional ERBB family members in ADC is less defined. To this end we prospectively studied HER2 expression, gene amplification, and mutation in relation to outcome of patients with advanced or metastatic ADC. MATERIALS AND METHODS: Diagnostic tumor biopsies from 193 sequential patients with stage III/IV ADC were prospectively studied for HER2 expression by immunohistochemistry (IHC). Cases with IHC scores 2+ or 3+ were analyzed by HER2 chromogenic in situ hybridization (CISH), and sequencing of HER2 exons 20 and 23. Additional prospectively determined biomarkers included PTEN, cMET, pAKT, and pERK expression, KRAS, EGFR, BRAF and PIK3CA mutations, and ALK fluorescence ISH (FISH). RESULTS AND CONCLUSION: HER2-IHC was feasible in 176 (91.2%) cases. Of 53 (30%) cases with IHC scores 2+/3+, 45 (85%) could be studied by CISH and 34 (64%) by sequencing. The lower number of HER2-mutational analyses resulted from exhaustion of tumor tissue and DNA following mutational analysis of KRAS, EGFR, BRAF and PIK3CA. HER2 amplification was detected in 4 cases (2.3%), while no mutation was found. HER2 expression correlated with expression of pAKT and cMET. Expression of HER2 and pAKT was associated with favorable overall survival in stage IV disease. HER2-expressing ADC more frequently harbored KRAS mutations, while HER2 expression was absent in all 4 cases with BRAF mutation. HER2-IHC was not predictive of HER2 gene amplification or mutation, which both were rare events in prospectively studied patients with advanced or metastatic ADC. Expression of HER2 and pAKT define a population of patients with stage IV ADC with a distinct disease course, who could benefit from specifically tailored pharmacotherapies. PMID- 25708530 TI - Effects of dehulling, steam-cooking and microwave-irradiation on digestive value of white lupin (Lupinus albus) seed meal for rainbow trout (Oncorhynchus mykiss) and Atlantic salmon (Salmo salar). AB - A digestibility trial was conducted to assess the effect of dehulling, steam cooking and microwave-irradiation on the apparent digestibility of nutrients in white lupin (Lupinus albus) seed meal when fed to rainbow trout (Oncorhynchus mykiss) and Atlantic salmon (Salmo salar). Six ingredients, whole lupin seed meal (LSM), dehulled LSM, dehulled LSM steam-cooked for 15 or 45 min (SC15 and SC45, respectively) and LSM microwave-irradiated at 375 or 750 W (MW375 and MW750, respectively), were evaluated for digestibility of dry matter, crude protein (CP), lipids, nitrogen-free extractives (NFE) and gross energy (GE). The diet substitution approach was used (70% reference diet + 30% test ingredient). Faeces from each tank were collected using a settlement column. Dehulled LSM showed higher levels of proximate components (except for NFE and crude fibre), GE and phosphorus in comparison to whole LSM. Furthermore, SC15, SC45, MW375 and MW750 showed slight variations of chemical composition in comparison to dehulled LSM. Results from the digestibility trial indicated that dehulled LSM, SC15, SC45 and MW375 are suitable processing methods for the improvement of nutrients' apparent digestibility coefficient (ADC) in whole LSM. MW750 showed a lower ADC of nutrients (except for CP and lipids for rainbow trout) in comparison with MW350 for rainbow trout and Atlantic salmon, suggesting a heat damage of the ingredient when microwave-irradiation exceeded 350 W. PMID- 25708531 TI - Efficacy of an innovative aerosol foam formulation of fixed combination calcipotriol plus betamethasone dipropionate in patients with psoriasis vulgaris. AB - BACKGROUND AND OBJECTIVE: The antipsoriatic effect of an innovative aerosol foam formulation of fixed combination calcipotriol 50 MUg/g (as hydrate; Cal) and betamethasone 0.5 mg/g (as dipropionate; BD) was explored in order to compare the effect with that of the first-line treatment Cal/BD ointment. METHODS: This was a Phase IIa, single-centre, investigator-blinded, exploratory study, with intra individual comparison using a modified psoriasis plaque test. Patients were treated once daily (6 days/week) for 4 weeks with Cal/BD foam, Cal/BD ointment, BD foam and Cal/BD foam vehicle, randomized to four plaque test sites (5 cm(2) each). The primary efficacy endpoint was change in total clinical score (TCS; sum of erythema, scaling and lesional thickness). Secondary endpoints included ultrasonographic changes in total skin thickness and echo-poor band thickness, and adverse events. RESULTS: Twenty-four patients, median age 52.5 years (range 21-75), completed this study. At week 4, test sites treated with Cal/BD foam had a significantly greater decrease in mean (+/-SD) TCS (-6.00 +/- 1.27) versus those treated with Cal/BD ointment (-5.25 +/- 1.78; difference -0.75; 95 % CI 1.46 to -0.04; p = 0.038), BD foam (-4.96 +/- 1.85; difference -1.04; 95 % CI 1.75 to -0.33; p = 0.005) or foam vehicle (-1.88 +/- 1.12; difference -4.13; 95 % CI -4.83 to -3.42; p < 0.001). Total skin thickness and echo-poor band thickness of Cal/BD foam-treated sites were reduced to a greater extent than those treated with comparators. Eleven patients reported 17 adverse events, the most frequent being headache (five patients). There were no lesional/perilesional adverse events or adverse drug-related events. CONCLUSIONS: Cal/BD foam demonstrated a significant improvement in antipsoriatic effect over Cal/BD ointment, BD foam and foam vehicle alone. PMID- 25708532 TI - Effect of age and sex on lacosamide pharmacokinetics in healthy adult subjects and adults with focal epilepsy. AB - BACKGROUND AND OBJECTIVE: Age- and sex-related differences in body composition could affect the pharmacokinetic parameters of administered drugs. The purpose of this post hoc analysis was to investigate the influences of age and sex on the pharmacokinetics of lacosamide. METHODS: This post hoc analysis used pharmacokinetic data taken at steady state from (i) two phase I studies of oral lacosamide in healthy adult subjects (n = 66), and (ii) a population pharmacokinetic analysis carried out using data from two phase III studies of adjunctive oral lacosamide in adults (n = 565) with focal epilepsy taking 1-3 concomitant anti-epileptic drugs. Phase I data were stratified by age and sex as 'younger female' (aged 18-40 years), 'younger male' (aged 18-45 years) or 'elderly male/female' (aged >=65 years), then normalized by body weight (lean body weight or fat-free mass), height or volume of distribution, and analysed using non-compartmental analysis. Population pharmacokinetic data were stratified by sex and analysed using a one-compartment model. RESULTS: Minor numerical differences between lacosamide exposure [the area under the concentration-time curve at steady state over the dosage interval (AUCtau,ss)] and the maximum plasma concentration at steady state (C max,ss) in subjects of different ages or sexes were noted. The differences could be explained by a scaling factor between the drug applied and the plasma concentration. Following normalization by lean body weight or volume of distribution, an analysis of relative bioavailability resulted in 90 % confidence intervals of the ratios for AUCtau,ss and C max,ss for age (elderly to younger) or sex (male to female) falling within the range accepted for equivalence (80-125 %); without normalization, the 90 % confidence intervals were outside this range. Minor numerical differences in lacosamide plasma concentrations were noted in the comparison between male and female patients (aged 16-71 years) with focal epilepsy. Simulations using different body weights demonstrated a minimal effect of body weight on lacosamide plasma concentrations in adult patients with focal epilepsy. CONCLUSION: Age and sex had no relevant effects on the rates of absorption and elimination of lacosamide in this post hoc analysis, as the minor numerical differences could be explained by the main scaling factor for body weight or volume of distribution. The pharmacokinetic profile of lacosamide was unaffected by age or sex in adults with focal epilepsy. PMID- 25708533 TI - Where and when should natural killer cells be tested in women with repeated implantation failure? AB - The aim of this study was to identify the candidates for natural killer (NK) testing and to define the best methodology. For this purpose a prospective study was performed on 73 women with repeated implantation failure (RIF). RIF was considered to exist in patients not achieving clinical pregnancy after three transfers with at least one good-quality embryo. Idiopathic RIF was considered to exist in patients in whom thrombophilia, hysteroscopy and endometrial culture were normal, and no chromosomal factor was suspected. Thirty-two of the 73 patients were considered to have idiopathic RIF, and 17 fertile women with children were taken as controls. Immunohistochemical staining for endometrial CD56+ and blood CD56+ or CD16+ NK cells measured using flow cytometry were compared during the mid-luteal phase in both patients and controls. Seventeen out of the 32 patients with idiopathic RIF and only one of the controls had >250 CD56 cells per high power field 400* in endometrial biopsy (p<0.001). The percentage of blood NK cells out of the total lymphocyte population was higher in women with idiopathic RIF (13.4+/-1.2%; range, 2.63-29.01) than in controls (8.4+/-0.7%; range, 5.72-13.28; p=0.026). There was a positive correlation between blood and endometrial CD56 cells (rho=0.707; p<0.001). No significant differences were found between patients with other types of RIF and controls. This study suggested that testing for NK cells might be useful in women with idiopathic RIF during the mid-luteal phase. PMID- 25708534 TI - Highlights from the tenth ISCB Student Council Symposium 2014. AB - This report summarizes the scientific content and activities of the annual symposium organized by the Student Council of the International Society for Computational Biology (ISCB), held in conjunction with the Intelligent Systems for Molecular Biology (ISMB) conference in Boston, USA, on July 11th, 2014. PMID- 25708535 TI - Interrelationships of Physical Activity and Sleep with Cardiovascular Risk Factors: a Person-Oriented Approach. AB - PURPOSE: Associations of behaviorally modifiable factors like physical activity (PA), sedentary behaviors, and sleep with cardiovascular diseases (CVDs) are complicated. We examined whether membership in latent classes (LCs) differentiated by PA and sleep profiles (real-life clustering of behaviors in population subgroups) associate with metabolic risk factors and CVD risk. METHODS: The National FINRISK 2012 Study comprise a cross-sectional sample of 10,000 Finns aged 25 to 74 years. Analyses included participants with complete data on a health questionnaire, a health examination, who had no prevalent CVD (n = 4031). LCs with PA and sleep profiles were previously defined using latent class analysis. Ten metabolic risk factors and the Framingham 10-year CVD risk score were compared between the LCs. RESULTS: PA and sleep class profiles were substantially similar for genders. Compared to LC-1, with a profile including high PA and sufficient sleep, membership in LC-4, with a profile including sedentariness and insufficient sleep was associated with high metabolic risk factors in women but not in men. In women, also membership in LC-2, with a profile including light PA, sufficient sleep, and high sedentariness was associated with high metabolic risk factors. The Framingham 10-year CVD risk score was highest in LCs 2 and 4 in both genders. CONCLUSIONS: Membership in LCs differentiated by PA and sleep profiles was associated with metabolic risk factors merely in women, suggesting gender differences in the interrelationships of health behaviors and metabolic risk factors. Total CVD risk differed between the LCs despite of gender; however, the effect was small. PMID- 25708537 TI - Deciphering complex patterns of class-I HLA-peptide cross-reactivity via hierarchical grouping. AB - T-cell responses in humans are initiated by the binding of a peptide antigen to a human leukocyte antigen (HLA) molecule. The peptide-HLA complex then recruits an appropriate T cell, leading to cell-mediated immunity. More than 2000 HLA class-I alleles are known in humans, and they vary only in their peptide-binding grooves. The polymorphism they exhibit enables them to bind a wide range of peptide antigens from diverse sources. HLA molecules and peptides present a complex molecular recognition pattern, as many peptides bind to a given allele and a given peptide can be recognized by many alleles. A powerful grouping scheme that not only provides an insightful classification, but is also capable of dissecting the physicochemical basis of recognition specificity is necessary to address this complexity. We present a hierarchical classification of 2010 class-I alleles by using a systematic divisive clustering method. All-pair distances of alleles were obtained by comparing binding pockets in the structural models. By varying the similarity thresholds, a multilevel classification was obtained, with 7 supergroups, each further subclassifying to yield 72 groups. An independent clustering performed based only on similarities in their epitope pools correlated highly with pocket-based clustering. Physicochemical feature combinations that best explain the basis of clustering are identified. Mutual information calculated for the set of peptide ligands enables identification of binding site residues contributing to peptide specificity. The grouping of HLA molecules achieved here will be useful for rational vaccine design, understanding disease susceptibilities and predicting risk of organ transplants. PMID- 25708536 TI - Chemokine and chemokine receptor structure and interactions: implications for therapeutic strategies. AB - The control of cell migration by chemokines involves interactions with two types of receptors: seven transmembrane chemokine-type G protein-coupled receptors and cell surface or extracellular matrix-associated glycosaminoglycans. Coordinated interaction of chemokines with both types of receptors is required for directional migration of cells in numerous physiological and pathological processes. Accumulated structural information, culminating most recently in the structure of a chemokine receptor in complex with a chemokine, has led to a view where chemokine oligomers bind to glycosaminoglycans through epitopes formed when chemokine subunits come together, while chemokine monomers bind to receptors in a pseudo two-step mechanism of receptor activation. Exploitation of this structural knowledge has and will continue to provide important information for therapeutic strategies, as described in this review. PMID- 25708538 TI - Chitosan hydrogel vaccine generates protective CD8 T cell memory against mouse melanoma. AB - CD8(+) T cells are important in the control of viral infections and cancers because of their cytolytic activity. A vaccine able to generate these cells could be beneficial in the prevention or treatment of these diseases. Chitosan hydrogel is a promising vaccine formulation that has previously been shown to generate effector CD8(+) T cells in a mouse model. This vaccine promotes sustained release of antigen and adjuvant, which generates a robust effector response. For longer lasting immunity, a memory population of these CD8(+) T cells is required to control further disease. We found that vaccination with chitosan hydrogel or dendritic cells using ovalbumin protein as a model antigen and Quil-A adjuvant provided protection in a subcutaneous melanoma challenge 30 days later. Ovalbumin specific memory CD8(+) T cells were detectable following vaccination with the chitosan hydrogel but not the dendritic cell vaccine and an in vivo cytotoxicity assay demonstrated specific lysis of target cells in chitosan hydrogel vaccinated mice but not those receiving dendritic cell vaccination. These results demonstrate that vaccination with chitosan hydrogel is equally effective as dendritic cell vaccination in tumour protection but has more readily detectable immune correlates of protection. This may be advantageous in predetermining protection in vaccinated individuals. PMID- 25708539 TI - Receptor binding proteins of Listeria monocytogenes bacteriophages A118 and P35 recognize serovar-specific teichoic acids. AB - Adsorption of a bacteriophage to the host requires recognition of a cell wall associated receptor by a receptor binding protein (RBP). This recognition is specific, and high affinity binding is essential for efficient virus attachment. The molecular details of phage adsorption to the Gram-positive cell are poorly understood. We present the first description of receptor binding proteins and a tail tip structure for the siphovirus group infecting Listeria monocytogenes. The host-range determining factors in two phages, A118 and P35 specific for L. monocytogenes serovar 1/2 have been determined. Two proteins were identified as RBPs in phage A118. Rhamnose residues in wall teichoic acids represent the binding ligands for both proteins. In phage P35, protein gp16 could be identified as RBP and the role of both rhamnose and N-acetylglucosamine in phage adsorption was confirmed. Immunogold-labeling and transmission electron microscopy allowed the creation of a topological model of the A118 phage tail. PMID- 25708540 TI - Antibacterial, antifungal and in vitro antileukaemia activity of metal complexes with thiosemicarbazones. AB - 1-phenyl-3-methyl-4-benzoyl-5-pyrazolone 4-ethyl-thiosemicarbazone (HL) and its copper(II), vanadium(V) and nickel(II) complexes: [Cu(L)(Cl)].C2H5OH.(1), [Cu(L)2].H2O (2), [Cu(L)(Br)].H2O.CH3OH (3), [Cu(L)(NO3)].2C2H5OH (4), [VO2(L)].2H2O (5), [Ni(L)2].H2O (6), were synthesized and characterized. The ligand has been characterized by elemental analyses, IR, (1) H NMR and (13) C NMR spectroscopy. The tridentate nature of the ligand is evident from the IR spectra. The copper(II), vanadium(V) and nickel(II) complexes have been characterized by different physico-chemical techniques such as molar conductivity, magnetic susceptibility measurements and electronic, infrared and electron paramagnetic resonance spectral studies. The structures of the ligand and its copper(II) (2, 4), and vanadium(V) (5) complexes have been determined by single-crystal X-ray diffraction. The composition of the coordination polyhedron of the central atom in 2, 4 and 5 is different. The tetrahedral coordination geometry of Cu was found in complex 2 while in complex 4, it is square planar, in complex 5 the coordination polyhedron of the central ion is distorted square pyramid. The in vitro antibacterial activity of the complexes against Escherichia coli, Salmonella abony, Staphylococcus aureus, Bacillus cereus and the antifungal activity against Candida albicans strains was higher for the metal complexes than for free ligand. The effect of the free ligand and its metal complexes on the proliferation of HL-60 cells was tested. PMID- 25708541 TI - Cascade enzymatic reactions for efficient carbon sequestration. AB - Thermochemical processes developed for carbon capture and storage (CCS) offer high carbon capture capacities, but are generally hampered by low energy efficiency. Reversible cascade enzyme reactions are examined in this work for energy-efficient carbon sequestration. By integrating the reactions of two key enzymes of RTCA cycle, isocitrate dehydrogenase and aconitase, we demonstrate that intensified carbon capture can be realized through such cascade enzymatic reactions. Experiments show that enhanced thermodynamic driving force for carbon conversion can be attained via pH control under ambient conditions, and that the cascade reactions have the potential to capture 0.5 mol carbon at pH 6 for each mole of substrate applied. Overall it manifests that the carbon capture capacity of biocatalytic reactions, in addition to be energy efficient, can also be ultimately intensified to approach those realized with chemical absorbents such as MEA. PMID- 25708543 TI - Exploratory methodology for retrieving oxidation state information from X-ray resonant Raman scattering spectrometry. AB - It has been observed recently that the resonant Raman scattering (RRS) peak of an X-ray spectrum contains information about the chemical environment of the irradiated matter. This information is extracted with complex processing of the spectrum data. Principal component analysis (PCA) is a statistical multivariate technique that allows exploring the variance-covariance structure of a set of data, through a few linear combinations of the original variables. This methodology can be applied to obtain information from RRS spectra. To analyze its potentiality, several measurements of different oxides in surface nanolayers were measured in total reflection conditions using synchrotron radiation. Multivariate analysis techniques, in particular, PCA, were used to obtain the information encrypted in the RRS peak, and to establish a new methodology, simpler and more accurate. The results show that multivariate analysis techniques are suitable for the analysis of this kind of spectra, foreseeing its application in future research. PMID- 25708544 TI - Response to Jackson. PMID- 25708542 TI - The crossroads between cancer stem cells and aging. AB - The cancer stem cell (CSC) hypothesis suggests that only a subpopulation of cells within a tumour is responsible for the initiation and progression of neoplasia. The original and best evidence for the existence of CSCs came from advances in the field of haematological malignancies. Thus far, putative CSCs have been isolated from various solid and non-solid tumours and shown to possess self renewal, differentiation, and cancer regeneration properties. Although research in the field is progressing extremely fast, proof of concept for the CSC hypothesis is still lacking and key questions remain unanswered, e.g. the cell of origin for these cells. Nevertheless, it is undisputed that neoplastic transformation is associated with genetic and epigenetic alterations of normal cells, and a better understanding of these complex processes is of utmost importance for developing new anti-cancer therapies. In the present review, we discuss the CSC hypothesis with special emphasis on age-associated alterations that govern carcinogenesis, at least in some types of tumours. We present evidence from the scientific literature for age-related genetic and epigenetic alterations leading to cancer and discuss the main challenges in the field. PMID- 25708545 TI - 18FDG-PET in different subtypes of temporal lobe epilepsy: SEEG validation and predictive value. AB - OBJECTIVE: The objective of the study was to characterize interictal 18 fluorodeoxyglucose-positron emission tomography ((18) FDG-PET) whole-brain voxel based metabolic patterns among distinct subtypes of temporal lobe epilepsy (TLE), as defined by stereo-electroencephalography (SEEG) and to determine predictive value of PET result on postoperative outcome. METHODS: Fifty-four consecutive patients with pharmacoresistant TLE were enrolled retrospectively after a comprehensive presurgical evaluation. This evaluation defined: 7 lateral TLE, 17 mesial TLE, 14 "plus" TLE, and 16 bilateral TLE. Whole-brain voxel-based brain metabolism was studied in each group of patients, in comparison to 23 healthy subjects, and individual classification was evaluated by cross-validation using the found clusters. An (18) FDG-PET index was moreover calculated for each patient, based on the individual Z-score of the most significant cluster extracted on the comparison between patients' subgroup and healthy subjects. Logistic regression analysis was used to estimate factors associated with postoperative outcome (Engel's classes III-IV vs. I-II), including age, gender, disease duration, seizure frequency, as well as magnetic resonance imaging (MRI) and PET findings. RESULTS: Different patterns of hypometabolism were found inside and outside the epileptogenic zone, among patients with distinct subgroups of TLE, in comparison to healthy subjects (p < 0.001, corrected for the cluster). At individual level, cross-validation showed satisfactory discrimination between the four groups with 71.4-88.2% overall accuracy. Multivariate analysis shows that (18) FDG-PET index was the only significant predictor of postoperative outcome to distinguish between Engel's classes I-II and III-IV (p = 0.037). SIGNIFICANCE: Overall, this whole-brain voxel-based analysis validates specific patterns of hypometabolism, inside and outside the EZ, in distinct subgroups of patients with TLE, as defined by SEEG gold standard, and in relation with postoperative outcome. PMID- 25708546 TI - Lymphoma Risk in Japanese Patients With Rheumatoid Arthritis: Comment on the Article by Kameda et al. PMID- 25708547 TI - On the universality of the attribution-affect model of helping. AB - Although Pilati et al.'s (2014) findings question the strong quantitative universality of the attribution-affect model of helping, they are consistent with a weak form of quantitative universality, as well as with the qualitative universality of the theory. However, universality is put into question by previous studies revealing significant and sizeable between-study differences in the strength of the causal paths postulated by the theory. These differences may in part reflect differences in the type of helping situations studied. PMID- 25708548 TI - Acute diarrhoea: new perspectives. PMID- 25708550 TI - Tigecycline dosing is critical in preventing tigecycline resistance because relative resistance is, in part, concentration dependent. PMID- 25708549 TI - ST2249-MRSA-III: a second major recombinant methicillin-resistant Staphylococcus aureus clone causing healthcare infection in the 1970s. AB - Typing of healthcare-associated methicillin-resistant Staphylococcus aureus (MRSA) from Australia in the 1970s revealed a novel clone, ST2249-MRSA-III (CC45), present from 1973 to 1979. This clone was present before the Australian epidemic caused by the recombinant clone, ST239-MRSA-III. This study aimed to characterize the genome of ST2249-MRSA-III to establish its relationship to other MRSA clones. DNA microarray analysis was conducted and a draft genome sequence of ST2249 was obtained. The recombinant structure of the ST2249 genome was revealed by comparisons to publicly available ST239 and ST45 genomes. Microarray analysis of genomic DNA of 13 ST2249 isolates showed gross similarities with the ST239 chromosome in a segment around the origin of replication and with ST45 for the remainder of the chromosome. Recombination breakpoints were precisely determined by the changing pattern of nucleotide polymorphisms in the genome sequence of ST2249 isolate SK1585 compared with ST239 and ST45. One breakpoint was identified to the right of oriC, between sites 1014 and 1065 of the gene D484_00045. Another was identified to the left of oriC, between sites 1185 and 1248 of D484_01632. These results indicate that ST2249 inherited approximately 35.3% of its chromosome from an ST239-like parent and 64.7% from an ST45-like parent. ST2249 MRSA-III resulted from a major recombination between parents that resemble ST239 and ST45. Although only limited Australian archival material is available, the oldest extant isolate of ST2249 predates the oldest Australian isolate of ST239 by 3 years. It is therefore plausible that these two recombinant clones were introduced into Australia separately. PMID- 25708552 TI - Partial oxidation of light alkanes by periodate and chloride salts. AB - The efficient and selective partial oxidation of light alkanes using potassium periodate and potassium chloride is reported. Yields of methane functionalization in trifluoroacetic acid reach >40% with high selectivity for methyl trifluoroacetate. Periodate and chloride also functionalize ethane and propane in good yields (>20%). PMID- 25708551 TI - Management of emerging multidrug-resistant tuberculosis in a low-prevalence setting. AB - Multidrug-resistant (MDR) tuberculosis (TB) is an emerging concern in communities with a low TB prevalence and a high standard of public health. Twenty-three consecutive adult MDR TB patients who were treated at our institution between 2007 and 2013 were reviewed for demographic characteristics and anti-TB treatment management, which included surgical procedures and long-term patient follow-up. This report of our experience emphasizes the need for an individualized approach as MDR TB brings mycobacterial disease management to a higher level of expertise, and for a balance to be found between international current guidelines and patient-tailored treatment strategies. PMID- 25708553 TI - Niacin and progression of CKD. AB - Niacin is the oldest drug available for the treatment of dyslipidemia. It has been studied extensively and tested in clinical trials of atherosclerotic cardiovascular disease prevention and regression in the general population, but not specifically in patients with chronic kidney disease (CKD), who are at extremely high residual risk despite current therapy. Despite the current controversy about recent trials with niacin, including their limitations, there may be a place for this agent in select patients with CKD with dyslipidemia. Niacin has a favorable unique impact on factors affecting the rate of glomerular filtration rate decline, including high-density lipoprotein (HDL) particle number and function, triglyceride levels, oxidant stress, inflammation and endothelial function, and lowering of serum phosphorus levels by reducing dietary phosphorus absorption in the gastrointestinal tract. These effects may slow glomerular filtration rate decline and ultimately improve CKD outcomes and prevent cardiovascular risk. This review presents the clinically relevant concept that niacin holds significant potential as a renoprotective therapeutic agent. In addition, this review concludes that clinical investigations to assess the effect of niacin (in addition to aggressive low-density lipoprotein cholesterol lowering) on reduction of cardiovascular events in patients with CKD with very low HDL cholesterol (or those with identified dysfunctional HDL) and elevated triglyceride levels need to be considered seriously to address the high residual risk in this population. PMID- 25708554 TI - The need for enhanced training in nephrology medical education research. PMID- 25708555 TI - Combination of attentional and spatial working memory deficits in Balint-Holmes syndrome. AB - This study aims to investigate whether attention and spatiotemporal integration deficits are dissociated in patients with bilateral posterior cortical atrophy (PCA), and whether it is their combination that leads to a severe clinical handicap. We recorded performance and ocular behavior of four PCA patients and four age-matched controls in visual search and counting tasks. We measured the percentage of targets detected and the mean detection time in a "pop-out" search. We also compared counting ability when a set of dots is presented briefly (in healthy individuals, the automatic deployment of attention over space allows a fast estimation of quantity) or for unlimited duration (favoring sequential counting, hence spatiotemporal integration). All patients showed reduced deployment of attention over space (simultanagnosia), resulting in increased visual search times and underestimations of the number of briefly presented dots. Only two patients showed ocular revisiting behavior that caused frequent omissions in visual search and overestimations of the number of dots presented for unlimited duration. The impairment to deploy attention is considered here as a bilateral covert attention deficit. Disorganized ocular exploration appears to be independent and is hypothesized to result from processes maintaining a salience map over time (spatial working memory) and especially across saccades. PMID- 25708556 TI - Design for human factors (DfHF): a grounded theory for integrating human factors into production design processes. AB - The 'design for human factors' grounded theory explains 'how' human factors (HF) went from a reactive, after-injury programme in safety, to being proactively integrated into each step of the production design process. In this longitudinal case study collaboration with engineers and HF Specialists in a large electronics manufacturer, qualitative data (e.g. meetings, interviews, observations and reflections) were analysed using a grounded theory methodology. The central tenet in the theory is that when HF Specialists acclimated to the engineering process, language and tools, and strategically aligned HF to the design and business goals of the organisation, HF became a means to improve business performance. This led to engineers 'pulling' HF Specialists onto their team. HF targets were adopted into engineering tools to communicate HF concerns quantitatively, drive continuous improvement, visibly demonstrate change and lead to benchmarking. Senior management held engineers accountable for HF as a key performance indicator, thus integrating HF into the production design process. Practitioner Summary: Research and practice lack explanations about how HF can be integrated early in design of production systems. This three-year case study and the theory derived demonstrate how ergonomists changed their focus to align with design and business goals to integrate HF into the design process. PMID- 25708557 TI - Association between metformin therapy and incidence, recurrence and mortality of prostate cancer: evidence from a meta-analysis. AB - OBJECTIVE: Previous studies suggested that metformin is associated with decreased risk of cancer; however, results specifically addressing the potential association with prostate cancer were limited and contradictory. This study considers the association between metformin and the incidence, mortality and recurrence of prostate cancer by performing a meta-analysis of observational studies. METHODS: Literatures published before January 2014 were searched by using databases of PubMed and Embase. Pooled relative risks (RRs) were determined using a random effects model to evaluate the strength of association between metformin therapy and risk of prostate cancer. RESULTS: Thirteen studies involving a total of 334 532 participants were included in this meta-analysis. Compared with the control group, metformin therapy was associated with significantly decreased incidence of prostate cancer [RR = 0.88, 95% confidence interval (CI) [0.78, 0.99], p = 0.03, I(2) = 74.7%]. However, metformin therapy was not associated with decreased all-cause mortality (RR = 1.07, 95% CI [0.86, 1.32], p = 0.55, I(2) = 58.2%) or decreased recurrence of prostate cancer (RR = 0.90, 95% CI [0.75, 1.09], p = 0.27, I(2) = 0.0%). No publication bias was detected (pBegg = 0.55, pEgger = 0.46). CONCLUSIONS: The present study suggested that metformin therapy may decrease the incidence of prostate cancer but that there was no association between the treatment and all-cause mortality or recurrence. It is recommended that this finding should be considered carefully and confirmed with further studies. PMID- 25708558 TI - On "using a team-centered approach to evaluate effectiveness of nurse-physician communications". PMID- 25708559 TI - Ophthalmic artery visualization and morphometry by computed tomography angiography. AB - We assessed the feasibility of using computed tomography angiography (CTA) to visualize the opthalmic artery (OA) and conducted three-dimensional (3D) morphometry. A retrospective analysis of 171 patients was performed using CTA confirmed normal internal carotid arteries. To identify the OA, multiplanar CT reformations were performed. The OA diameter was compared in patients of different age groups and between males and females. All ophthalmic arteries were detected by 3D volume-rendering (VR) CTA. Bone subtraction was successful in all patients. The mean OA diameter was 1.37 +/-0.25 mm in men, 1.35 +/-0.16 mm in women (P = 0.188 for gender), 1.38 +/-0.25 mm in the <40 years-old group, 1.37 +/ 0.14 mm in the 40-49 years-old group, 1.36 +/-0.16 mm in the 50-59 years-old group, 1.38 +/-0.19 mm in the 60-69 years-old group, and 1.34 +/-0.17 mm in the > 70 years-old group (P = 0.662 for age group). CTA is a reliable method for visualizing the ophthalmic artery (OA). There are no major differences in OA diameter among gender or age. PMID- 25708560 TI - Ocular complications in children after hematopoietic stem cell transplantation without total body irradiation. AB - PURPOSE: The purpose of the study was to evaluate whether hematopoietic stem cell transplantation (HSCT) without conditioning Total Body Irradiation (TBI) had lower or milder ocular complication rates in the pediatric population. METHODS: This study included all children who underwent HSCT without conditioning TBI at the Chaim Sheba Medical Center between the years 2001 and 2008. All children had an ophthalmic evaluation prior to and every four months after HSCT. RESULTS: Of the 33 children who initially comprised this study, ten did not complete the minimal follow-up of four months, and were, thus, excluded from the study. Follow up of the remaining 23 children ranged from four to 117 months. Dry eye related to chronic graft-versus-host disease (cGVHD) developed in eight children (35 %). In three cases, an additional complication was observed : corneal abscess, herpes zoster ophthalmicus, and bilateral subcapsular cataract (one case each). Posterior segment or neuro-ophthalmological complications were not observed in any patient. CONCLUSION: In our study group, the preclusion of conditioning TBI before HSCT did not result in a decreased ocular complication rate compared to past publications, but complications were relatively mild and confined only to the anterior segment. PMID- 25708561 TI - Impaired anticipatory postural adjustments due to experimental infrapatellar fat pad pain. AB - BACKGROUND: Anticipatory postural adjustments (APAs) are motor responses generated to stabilize balance prior to voluntary movement. This study investigated how infrapatellar fat pad pain induces reorganization of APAs during reaction time tasks. It has been hypothesized that knee pain may cause insufficient APAs, thereby impairing the balance. METHODS: While standing, 12 healthy men performed two reaction time tasks (shoulder flexion of the dominant side and bilateral heel lift, respectively) before, during and after experimental infrapatellar fat pad pain induced in the dominant side by injections of hypertonic saline. Isotonic saline was injected as control. The reaction time task performance was assessed by peak angle and peak angular velocity. Timing and intensity of the postural muscle activity were recorded by surface electromyography. RESULTS: The reaction time task performance was not significantly affected by experimental pain. The onset of muscle activity in vastus medialis, vastus lateralis and tibialis anterior muscles on the dominant side during the bilateral heel lift task was significantly delayed during pain, and their muscle activity was reduced when compared with non-painful sessions (p < 0.05). The contralateral vasti muscles demonstrated early onset during pain compared with the non-painful session of the same task (p <= 0.05). CONCLUSIONS: This study demonstrates that knee pain reorganizes the APAs which may destabilize the balance control. The knee pain-related reorganization of postural muscle activity during APA may be a part of the central modulation to maintain posture and protect the painful limb while preserving the reaction task movement performance. PMID- 25708562 TI - Marginal artery stump pressure in left colic artery-preserving rectal cancer surgery: a clinical trial. AB - BACKGROUND: The aim of this clinical trial is to evaluate the influence of high and low ligation of the inferior mesenteric artery with apical lymph node dissection on the anastomotic blood supply, lymph node retrieval rate, operative time and anastomotic leakage rate in rectal cancer surgery. METHODS: A total of 57 Chinese patients were randomly distributed into group A and group B and underwent radical resection of rectal cancer. Patients in group A underwent high ligation of the inferior mesenteric artery, and patients in group B underwent apical lymph node resection around the root of the inferior mesenteric artery with preservation of the left colic artery. The marginal artery stump pressure was measured after colon and artery reconstruction. Systemic pressure, distal colon length, operative time and lymph node retrieval rate were measured and recorded. The results were analysed and related to patient characteristics and post-operative complications. RESULTS: The anastomotic blood supply negatively and linearly correlated with age and distal colon length and showed a positive linear correlation with systemic pressure. Patients who received low ligation with apical lymph node dissection had a better anastomotic blood supply than those who received high ligation. No differences were found in lymph node retrieval rate, operative time and anastomotic leakage rate. Anastomotic leakage was associated with a worse anastomotic blood supply. CONCLUSIONS: Low ligation with apical lymph node dissection in rectal cancer treatment provides better anastomotic blood supply but is not associated with differences in node retrieval rate or operation time. PMID- 25708563 TI - Junctional epidermolysis bullosa with LAMB3 splice-site mutations. PMID- 25708564 TI - Six-minute walk test in Chinese adults with clinically stable bronchiectasis: association with clinical indices and determinants. AB - BACKGROUND: The profiles of 6-minute walk distance (6MWD) in adults with clinically stable bronchiectasis in Chinese adult patients with bronchiectasis are unclear. OBJECTIVES: To delineate the 6MWD by stratification of clinical indices, and to investigate the factors associated with reduced 6MWD in Chinese adults with clinically stable bronchiectasis. METHODS: We recruited 141 adult bronchiectasis patients (mean age: 44.3 +/- 13.9 years). Demography, radiology, spirometry, diffusing capacity, etiology, sputum bacteriology, modified Medical Research Council dyspnea scale (MMRC) and quality of life were assessed. The safety profile of the measurement was also examined. RESULTS: Lower levels of 6MWD were associated with older age (>50 years), higher HRCT total score, presence of cystic bronchiectasis, bilateral bronchiectasis, reduced diffusing capacity, higher MMRC score, and higher SGRQ scores. Correlation coefficients between 6MWD and spirometry and quality of life scores were different in patients with 6MWD higher and lower than lower limit of normal. DLCO being less than 80% predicted (OR = 3.13, 95% CI: 1.32-7.43, P = 0.01) and MMRC scale between 1 and 4 (OR = 6.42, 95% CI: 2.27-18.18, P < 0.01) were the factors associated with 6MWD being less than the lower limit of normal (80% predicted value). No severe adverse events were reported. CONCLUSION: The 6MWD could be safely measured in adult patients with bronchiectasis and is poorly associated with clinical parameters. DLCO less than 80% predicted and higher MMRC scale are independent predictors of 6MWD below the lower limit of normal. Our findings will provide a reference for management of bronchiectasis patients in mainland China. PMID- 25708565 TI - Calf's sex, parity and the hour of harvest after calving affect colostrum quality of dairy cows grazing under high tropical conditions. AB - High-quality colostrum is an important factor influencing neonatal calf health, and quality assessment is essential to obtain good health results. This research evaluated the effects of the calf's sex, the parity of the cow and the hour of colostrum harvest after parity on the fat, nonfat solids, protein and Ig contents in Holstein colostrum for cows under high grazing conditions in the tropics. The effects of the calf's sex and parity on somatic cell count (SCC) at the first milking postpartum were determined. A comparison was made between a laboratory method and a farm method for the estimation of the fat and protein content of colostrum. Thirty-three cows were sampled in the study. The calf's sex was shown to have an effect on the amount of colostrum, on the concentration of fat, and on the amount of milk produced by lactating Holstein cows; all were higher in cows that gave birth to a female calf. Colostrum protein decreased after the first hour postpartum, and the Ig concentration had a tendency to decrease after 4 h. The cows that had parity 1-2 had lower Ig concentrations and total production of Igs, and higher SCC at the first milking postpartum. Ekomilk was a reliable method to measure the colostrum fat on the farm. PMID- 25708566 TI - An 8-year longitudinal sero-epidemiological study of bovine leukaemia virus (BLV) infection in dairy cattle in Turkey and analysis of risk factors associated with BLV seropositivity. AB - Enzootic bovine leukosis (EBL) which is caused by bovine leukaemia virus (BLV) has an important economic impact on dairy herds due to reduced milk production and restrictions on livestock exports. This study was conducted to determine the BLV infection status in Central Anatolia Region of Turkey, an important milk production centre, and to examine the risk factors such as purchasing cattle, increasing cattle age, cattle breed and herd size associated with transmission of BLV infection. To estimate the rate of BLV infection, a survey for specific antibodies in 28,982 serum samples from animals belonging to 1116 different herds situated in Central Anatolia Region of Turkey were tested from January 2006 to December 2013. A generalized mixed linear model was used to evaluate the risk factors that influenced BLV seroprevalence. Antibodies against BLV were detected in 431 (2.28 %) of 18,822 Holstein and 29 (0.28 %) of 10,160 Brown Swiss cows. Among 1116 herds, 132 herds (11.82 %) had one or more positive animals. Also results of our study show that the prevalence of BLV infection increased from 2006 to 2011, and it tends to reduce with BLV control programme. Furthermore, we found positive associations between percentage of seropositive animal and increasing cattle age, herd size, cattle breed and purchased cattle. Age-specific prevalence showed that BLV prevalence increased with age. These factors should be taken into consideration for control of BLV infection. PMID- 25708567 TI - December 2014 HeartWeek issue of cardiology in the young: highlights of HeartWeek 2014: diseases of the cardiac valves from the foetus to the adult. AB - This December Issue of Cardiology in the Young represents the 12th annual publication generated from the two meetings that compose "HeartWeek in Florida". "HeartWeek in Florida", the joint collaborative project sponsored by the Cardiac Center at the Children's Hospital of Philadelphia, Pennsylvania, together with Johns Hopkins All Children's Heart Institute of Saint Petersburg, Florida, averages over 1000 attendees every year and is now recognised as one of the major planks of continuing medical and nursing education for those working in the fields of diagnosis and treatment of cardiac disease in the foetus, neonate, infant, child, and adult. "HeartWeek in Florida" combines the International Symposium on Congenital Heart Disease, organised by All Children's Hospital and Johns Hopkins Medicine and entering its 15th year, with the Annual Postgraduate Course in Pediatric Cardiovascular Disease, organised by The Children's Hospital of Philadelphia and entering its 18th year. This December, 2014 Issue of Cardiology in the Young features highlights of Johns Hopkins All Children's Heart Institute's 14th Annual International Symposium on Congenital Heart Disease, which was held at the Renaissance Vinoy Resort & Golf Club, Saint Petersburg, Florida, from 15-18 February, 2014. This Symposium was co-sponsored by The American Association for Thoracic Surgery (AATS) and had as its special focus " Diseases of the Cardiac Valves from the Fetus to the Adult ". We acknowledge the tremendous contributions made to paediatric and congenital cardiac care by Duke Cameron and Joel Brenner, and therefore we dedicate this December, 2014 HeartWeek Issue of Cardiology in the Young to them. Duke Cameron is Professor of Surgery at Johns Hopkins University and Cardiac Surgeon-in-Charge at The Johns Hopkins Hospital. Joel Brenner is Professor of Pediatrics at Johns Hopkins University and Director of the Taussig Heart Center at Bloomberg Children's Center, The Johns Hopkins Hospital. Together, Joel and Duke lead the proud paediatric and congenital cardiac programme at The Johns Hopkins Hospital. PMID- 25708568 TI - Reply to the article "Adjusting the focus of transoral robotic surgery". PMID- 25708569 TI - Physician Beliefs about Physical and Mental Competency of Patients Applying for Concealed Weapon Permits. AB - Law enforcement officials have asked health care providers to evaluate patient applications for concealed weapon permits. The current study was designed to examine physician beliefs regarding competency to carry a concealed weapon for patients with specific physical and mental conditions. Among 222 North Carolina physicians who participated in this survey (40% response rate), large variation and uncertainty existed for determining competency. Physicians most frequently chose mild dementia, post-traumatic stress disorder, and recent depression as conditions that would render a patient not competent to carry a concealed weapon. Male physicians and those owning a gun were more likely to deem a patient competent. Almost a third of physicians were unsure about competence for most conditions. Physicians asked to assess competency of patients to carry a concealed weapon have quite disparate views on competency and little confidence in their decisions. If physicians are expected to assess patient competence to carry a concealed weapon, more objective criteria and training are needed. PMID- 25708570 TI - Superamphiphobic polymeric surfaces sustaining ultrahigh impact pressures of aqueous high- and low-surface-tension mixtures, tested with laser-induced forward transfer of drops. AB - Superamphiphobic, (quasi-)ordered plasma-textured surfaces, coated with a perfluorinated monolayer, exhibit extreme resistance against drop-pinning for both water-like and low-surface-tension mixtures (36 mN m(-1)). The highest values reported here are 36 atm for a water-like mixture, 5 times higher than previously reported in the literature, and 7 atm for a low-surface-tension mixture, the highest ever reported value for lotus-leaf-inspired surfaces. PMID- 25708571 TI - Integrating experimental and literature protein-protein interaction data for protein complex prediction. AB - BACKGROUND: Accurate determination of protein complexes is crucial for understanding cellular organization and function. High-throughput experimental techniques have generated a large amount of protein-protein interaction (PPI) data, allowing prediction of protein complexes from PPI networks. However, the high-throughput data often includes false positives and false negatives, making accurate prediction of protein complexes difficult. METHOD: The biomedical literature contains large quantities of PPI data that, along with high-throughput experimental PPI data, are valuable for protein complex prediction. In this study, we employ a natural language processing technique to extract PPI data from the biomedical literature. This data is subsequently integrated with high throughput PPI and gene ontology data by constructing attributed PPI networks, and a novel method for predicting protein complexes from the attributed PPI networks is proposed. This method allows calculation of the relative contribution of high-throughput and biomedical literature PPI data. RESULTS: Many well characterized protein complexes are accurately predicted by this method when apply to two different yeast PPI datasets. The results show that (i) biomedical literature PPI data can effectively improve the performance of protein complex prediction; (ii) our method makes good use of high-throughput and biomedical literature PPI data along with gene ontology data to achieve state-of-the-art protein complex prediction capabilities. PMID- 25708572 TI - Meta-analysis of internal herniation after gastric bypass surgery. AB - BACKGROUND: The aim of this study was to provide a systematic and quantitative summary of the association between laparoscopic Roux-en-Y gastric bypass (LRYGB) and the reported incidence of internal herniation (IH). The route of the Roux limb and closure of mesenteric and/or mesocolonic defects are described as factors of influence. METHODS: MEDLINE, Embase, the Cochrane Library and Web of Science were searched for relevant literature, references and citations according to the PRISMA statement. Two independent reviewers selected studies that evaluated incidence of IH after LRYGB and possible techniques for prevention. Data were pooled by route of the Roux limb and closure/non-closure of the mesenteric and/or mesocolonic defects. RESULTS: Forty-five articles included data on 31 320 patients. Lowest IH incidence was in the antecolic group, with closure of all defects (1 per cent; P < 0.001), followed by the antecolic group, with all defects left open and the retrocolic group with closure of the mesenteric and mesocolonic defect (both 2 per cent; P < 0.001). The incidence of IH was highest in the antecolic group, with closure of the jejunal defect, and in the retrocolic group, with closure of all defects (both 3 per cent). CONCLUSION: The present systematic review includes a random-effects meta-analysis. The antecolic procedure, with closure of both the mesenteric and Petersen defects, has the lowest internal herniation incidence following laparoscopic Roux-en-Y gastric bypass. PMID- 25708573 TI - Biosimilars advancements: Moving on to the future. AB - Many patents for the first biologicals derived from recombinant technology and, more recently, monoclonal antibodies (mAbs) are expiring. Naturally, biosimilars are becoming an increasingly important area of interest for the pharmaceutical industry worldwide, not only for emergent countries that need to import biologic products. This review shows the evolution of biosimilar development regarding regulatory, manufacturing bioprocess, comparability, and marketing. The regulatory landscape is evolving globally, whereas analytical structure and functional analyses provide the foundation of a biosimilar development program. The challenges to develop and demonstrate biosimilarity should overcome the inherent differences in the bioprocess manufacturing and physicochemical and biological characterization of a biosimilar compared to several lots of the reference product. The implementation of approaches, such as Quality by Design (QbD), will provide products with defined specifications in relation to quality, purity, safety, and efficacy that were not possible when the reference product was developed. Actually, the need to prove comparability to the reference product by the biosimilar industry has increased the knowledge about the product and the production-process associated by the use of powerful analytical tools. The technological challenges to make copies of biologic products while attending regulatory and market demands are expected to help innovation in the direction of attaining more productive manufacturing processes. PMID- 25708574 TI - Perioperative pharmacological management of choroidal detachment associated with rhegmatogenous retinal detachment. AB - PURPOSE: To compare subtenon triamcinolone versus systemic dexamethasone for perisurgical management of primary rhegmatogenous retinal detachment presenting with a choroidal detachment (RRD/CD). METHODS: Thirty consecutive primary RRD/CD patients were prospectively studied. Sixteen RRD/CD patients were injected with a 40 mg subtenon triamcinolone acetonide (TA) 5 days before a scheduled vitrectomy (TA group) while the other 14 RRD/CD patients were intravenously infused daily with 10 mg dexamethasone (Dex) for 5 days before a scheduled vitrectomy (Dex group). All patients were followed up for 6 months. Changes of choroid detachment on B ultrasonography and preoperative intraocular pressure (IOP), systemic and ocular steroid level, blood sugar, and postoperative macular oedema were compared between the two groups. RESULTS: During 5 days of presurgical treatment, the IOP recovery from the baseline was 3.29 +/- 4.56 mmHg for the TA group versus 1.16 +/ 1.60 mmHg for the Dex group (p = 0.021). The height of CD decreased significantly more for the TA group (3.55 +/- 1.33 versus 1.84 +/- 1.5 mm, p = 0.0029). The physiological cortisol level in the plasma was significantly suppressed for the Dex group (8.35 +/- 10.35 versus 51.9 +/- 35.9 ng/ml, p = 0.01). Postoperative 1-month macula was less oedematous for TA group (401 +/- 196 versus 256 +/- 66 MUm, p = 0.0498). CONCLUSION: Subtenon TA seems to be a better option for perisurgical management of RRD/CD patients than systemic steroid application. Subtenon TA is more convenient for patients and imposes much less stress to patients' hormones homeostasis. This is especially important for those who are suffering metabolic disorders and need vitrectomy surgery for repairing RRD/CD. PMID- 25708575 TI - Prostate cancer: Fetuin-A--a marker for metastatic disease? PMID- 25708576 TI - Immunotherapy: Sipuleucel-T induces humoral antigen spread in patients with mCRPC. PMID- 25708577 TI - Prostate cancer: Breaking AKR1C3-mediated enzalutamide resistance by inhibiting androgen synthesis. PMID- 25708578 TI - Radiotherapy for high-risk prostate cancer. AB - The combination of radiation treatment and long-term androgen deprivation therapy (ADT) has been shown in multiple clinical trials to prolong overall survival in men with high-risk prostate cancer compared with either treatment alone. New radiation technologies enable the safe delivery of high radiation doses that improve cancer control compared with lower radiation doses. Based on the results of multiple randomized trials, clinical practice guidelines for high-risk prostate cancer recommend total radiation doses of at least 75.6 Gy, with long term (2-3 years) ADT. Ongoing research into hypofractionated radiation treatment, whole-pelvic radiation, and combinations of radiation with novel hormonal agents could further improve cancer control and survival outcomes for patients with high risk prostate cancer. PMID- 25708580 TI - Penile cancer: Advanced penile cancer continues to elude systemic therapy. PMID- 25708579 TI - Risk-adapted strategy for the kidney-sparing management of upper tract tumours. AB - The conservative management of upper tract urothelial carcinoma (UTUC) was traditionally restricted to patients with imperative indications only. However, current recommendations suggest selected patients with normal, functioning contralateral kidneys should also be considered for such an approach. A risk adapted strategy to accurately select patients who could benefit from kidney sparing surgery without compromising their oncological safety has been advocated. A number of kidney-sparing surgical procedures are available. Despite the advent of ureteroscopic management, segmental ureterectomy and the percutaneous approach both have specific indications for use that predominantly depend on the tumour location and progression risk. These kidney-sparing procedures are cost effective, and when used to treat patients with low-risk UTUC, are associated with oncological outcomes similar to radical nephroureterectomy. Systematic second-look endoscopy combined with upper tract instillations of topical chemotherapeutic agents after ureteroscopic or percutaneous surgery and a single early intravesical instillation of mitomycin C after any kidney-sparing procedure might decrease the risks of local recurrence and progression. Meticulous and stringent endoscopic monitoring of the upper and lower urinary tract is a key component of the conservative management of UTUC. Local recurrences are often suitable for repeat conservative therapy, whereas disease progression should be treated with delayed radical nephroureterectomy. PMID- 25708581 TI - In vitro pro-oxidant/antioxidant role of carvacrol, thymol and their mixture in the intestinal Caco-2 cell line. AB - The food industry needs to provide consumers with fresh and healthy products. In this context, food packaging plays an important role. Thus, certain essential oils are being incorporated into plastic polymers to confer better preservative properties. The oregano essential oil contains carvacrol and thymol, two important polyphenols. Considering their increasing use in active food packaging, the evaluation of their suitability and safety is of great interest. In the present work, a concentration-dependent increase in the antioxidant effects of carvacrol, thymol, and their mixture (10:1) was determined using DPPH and ABTS assays. In addition, the safety of these compounds was tested in vitro. Reactive oxygen species and glutathione levels were measured after exposing cells for 24 and 48 h to different concentrations of carvacrol, thymol and their mixture. The abilities of these compounds to protect against or revert the effects of H2O2 on cells were also studied. The results showed that oxidative stress plays a role in the damage induced by carvacrol and the mixture at high concentrations. However, at lower concentrations, both compounds and their mixture were shown, for the first time, to protect cells against the damage induced by the H2O2. PMID- 25708582 TI - Diversity of human-associated Methanobrevibacter smithii isolates revealed by multispacer sequence typing. AB - Methanobrevibacter smithii is the main archaea in human, detoxifying molecular hydrogen resulting from anaerobic bacteria fermentations into gaseous methane. Its identification relies on gene sequencing, but no method is available to discriminate among genetic variants of M. smithii. Here, we developed a multispacer sequence typing (MST) for genotyping the genetic variants of M. smithii. Four intergenic spacers recovered from the M. smithii reference genome were PCR amplified and sequenced in three M. smithii reference strains and in a collection of 22 M. smithii isolates from the oral cavity in two individuals and the gut of 10 additional individuals. Sequencing yielded 216 genetic polymorphisms including 89 single nucleotide polymorphisms (41.2 %), 83 insertions (38.4 %), and 44 deletions (20.4 %). Combining these genetic polymorphisms yielded 15 genotypes with an index of discrimination of 0.942 (confidence interval 0.9-0.984; P < 0.05). Five M. smithii isolates made from the oral cavity yielded five different genotypes; seven gut isolates yielded nine different genotypes; genotypes MST5 and MST6 were found both in the oral cavity and the gut. Multiple genotypes were identified in some individuals at the same anatomical site. MST is a sequencing-based method which discriminates several genetic variants within M. smithii. Individuals may harbor several contemporary genetic variants of M. smithii in the oral cavity and gut. MST will allow studying population dynamics of M. smithii and tracing its circulation between individuals and their environment. PMID- 25708583 TI - The effect of CbbR-binding affinity to the upstream of cbbF and cfxB on the metabolic effector in Rhodobacter sphaeroides. AB - Rhodobacter sphaeroides is a non-sulfur photosynthetic bacterium that possesses two cbb operons, cbb I and cbb II , encoding enzymes involved in the Calvin Bensom-Bassham reductive pentose phosphate pathway of carbon dioxide fixation. In the present study, a number of molecules have been identified that have the ability to alter the in vivo DNA-binding properties of CbbR protein in R. sphaeroides. The CbbR-binding sites on the cbb operon in R. sphaeroides were characterized by chromatin immunoprecipitation (ChIP) assay. The ChIP assay indicated that the CbbR protein binds specifically to the upstream regions cbbF in cbb I operon and cfxB in cbb II operon. The change in the binding of CbbR to the upstream of cbbF and cfxB in the presence of RuBP, fructose 1,6-bisphosphate, NADPH, KH2PO4 was observed under anaerobic, aerobic, aerobic light-dark, and aerobic dark conditions, respectively. From these results, the role of different co-inducer molecules in influencing the interactions of CbbR with the binding site within cbb operon has been ascertained. The biosynthetic intermediates and other potential metabolic effectors have been observed to play an important role in the regulatory mechanism. PMID- 25708584 TI - ECEL1 mutation causes fetal arthrogryposis multiplex congenita. AB - Arthrogryposis multiplex congenita (AMC) is a descriptor for the clinical finding of congenital fixation of multiple joints. We present a consanguineous healthy couple with two pregnancies described with AMC due to characteristic findings on ultrasonography of fixated knee extension and reduced fetal movement at the gestational age of 13 weeks + 2 days and 12 weeks + 4 days. Both pregnancies were terminated and postmortem examinations were performed. The postmortem examinations confirmed AMC and suggested a diagnosis of centronuclear myopathy (CNM) due to characteristic histological findings in muscle biopsies. Whole exome sequencing (WES) was performed on all four individuals and the outcome was filtered by application of multiple filtration parameters satisfying a recessive inheritance pattern. Only one gene, ECEL1, was predicted damaging and had previously been associated with neuromuscular disease or AMC. The variant found ECEL1 is a missense mutation in a highly conserved residue and was predicted pathogenic by prediction software. The finding expands the molecular basis of congenital contractures and the phenotypic spectrum of ECEL1 mutations. The histological pattern suggestive of CNM in the fetuses can expand the spectrum of genes causing CNM, as we propose that mutations in ECEL1 can cause CNM or a condition similar to this. Further investigation of this is needed and we advocate that future patients with similar clinical presentation or proven ECEL1 mutations are examined with muscle biopsy. Secondly, this study illustrates the great potential of the clinical application of WES in couples with recurrent abortions or stillborn neonates. PMID- 25708585 TI - Overlap of familial Mediterranean fever and hyper-IgD syndrome in an Arabic kindred. AB - Hyperimmunoglobulinemia D Syndrome (HIDS) has rarely been reported in Arabs. Moreover, the simultaneous presence of mutations in MEFV and MVK segregating in the same family is exceptional. We report an Arabic girl presenting since the age of 8-years with two patterns of recurrent episodes of fever, and associated with a spectrum of clinical features suggestive of overlap between familial Mediterranean fever (FMF) and HIDS. Her 19-year old brother presented since the age of 1 year with prolonged episodes of fever and was diagnosed with HIDS at the age of 7 years based on clinical features and homozygosity for p.V377I mutation in MVK. Shorter episodes of fever and abdominal pain more consistent with FMF ensued since the age of 17 years. Genetic testing done for both patients and all other family members revealed simultaneous presence of mutations in MEFV and MVK but with a variable clinical spectrum ranging from asymptomatic to severe manifestations. Both of our patients are homozygous for p.V377I MVK mutation; the girl is a compound heterozygote for p.E148Q/p.P369S/p.R408G and p.E167D/p.F479L MEFV mutations whereas the brother is a compound heterozygote for p.E148Q/p.P369S/p.R408G and p.M680I MEFV mutations. The clinical implications of having more than one mutation in different genes of monogenic autoinflammatory diseases in the same individual are not clear but may explain atypical clinical manifestations such as the overlap features of both FMF and HIDS in this family. PMID- 25708586 TI - Familial hepatopulmonary syndrome in common variable immunodeficiency. AB - Common Variable Immunodeficiency (CVID) comprises a heterogeneous group of primary antibody deficiencies which lead to a range of complications, including infectious, neoplastic and inflammatory disorders. This report describes monozygotic twin brothers with CVID who developed cryptogenic liver disease and subsequently hepatopulmonary syndrome (HPS). This is the second report of the association of HPS and CVID. Its occurrence in two identical twins implicates a genetic basis. PMID- 25708587 TI - Lipoprotein(a) hyperlipidemia as cardiovascular risk factor: pathophysiological aspects. AB - Lipoprotein (a) [Lp(a)] is a modified LDL particle with an additional apolipoprotein [apo(a)] protein covalently attached by a thioester bond. Multiple isoforms of apo(a) exist that are genetically determined by differences in the number of Kringle-IV type-2 repeats encoded by the LPA gene. Elevated plasma Lp(a) is an independent risk factor for cardiovascular disease.The phenotypic diversity of familial Lp(a) hyperlipidemia [Lp(a)-HLP] and familial hypercholesterolemia [FH], as defined risks with genetic background, and their frequent co-incidence with additional cardiovascular risk factors require a critical revision of the current diagnostic and therapeutic recommendations established for isolated familial Lp(a)-HLP or FH in combination with elevated Lp(a) levels.Lp(a) assays still suffer from poor standardization, comparability and particle variation. Further evaluation of the current biomarkers and establishment of novel comorbidity biomarkers are necessary for extended risk assessment of cardiovascular disease in FH or Lp(a)-HLP and to better understand the pathophysiology and to improve patient stratification of the Lp(a) syndrome complex.Lp(a) promotes vascular remodeling, increased lesion progression and intima media thickening through induction of M1-macrophages, antiangiogenic effects (e.g. vasa vasorum) with secretion of the antiangiogenic chemokine CXCL10 (IP10) and CXCR3 mediated activation of Th1- and NK-cells.In addition inhibition of serine proteases causing disturbances of thrombosis/ hemostasis/ fibrinolysis, TGFb-activation and acute phase response (e.g. CRP, anti-PL antibodies) are major features of Lp(a) pathology. Anti-PL antibodies (EO6 epitope) also bind to oxidized Lp(a).Lipoprotein apheresis is used to reduce circulating lipoproteins in patients with severe FH and/or Lp(a)-HLP, particularly with multiple cardiovascular risks who are intolerant or insufficiently responsive to lipid lowering drugs. PMID- 25708589 TI - Merkel cell carcinoma showing regression after biopsy: Evaluation of programmed cell death 1-positive cells. AB - We present a cases of Merkel cell carcinoma (MCC) with Merkel cell polyomavirus that showed complete regression after biopsy. The exact mechanism of regression in MCC has remained unclear. It has been reported that apoptosis caused by T-cell immunity was implicated in the regression, and programmed cell death 1 (PD-1), an inhibitory receptor, was expressed in approximately half of tumor-infiltrating T cells in MCC. However, the contribution of PD-1-positive cells for the regression of MCC has not been evaluated. We examined the rate of PD-1-positive cells among the peritumoral mononuclear cells, which showed that the percentage of PD-1 positive cells in the case was significantly lower compared with in MCC without regression. We propose that PD-1-positive cells suppress tumor immunity for MCC, and that reduction of PD-1-positive cells may be associated with tumor regression. PMID- 25708588 TI - Expression variations of connective tissue growth factor in pulmonary arteries from smokers with and without chronic obstructive pulmonary disease. AB - Cigarette smoking contributes to the development of pulmonary hypertension (PH) complicated with chronic obstructive pulmonary disease (COPD), and the pulmonary vascular remodeling, the structural basis of PH, could be attributed to abnormal proliferation of pulmonary artery smooth muscle cells (PASMCs).In this study, morphometrical analysis showed that the pulmonary vessel wall thickness in smoker group and COPD group was significantly greater than in nonsmokers. In addition, we determined the expression patterns of connective tissue growth factor (CTGF) and cyclin D1 in PASMCs harvested from smokers with normal lung function or mild to moderate COPD, finding that the expression levels of CTGF and cyclin D1 were significantly increased in smoker group and COPD group. In vitro experiment showed that the expression of CTGF, cyclin D1 and E2F were significantly increased in human PASMCs (HPASMCs) treated with 2% cigarette smoke extract (CSE), and two CTGF siRNAs with different mRNA hits successfully attenuated the upregulated cyclin D1 and E2F, and significantly restored the CSE-induced proliferation of HPASMCs by causing cell cycle arrest in G0. These findings suggest that CTGF may contribute to the pathogenesis of abnormal proliferation of HPASMCs by promoting the expression of its downstream effectors in smokers with or without COPD. PMID- 25708590 TI - Yarrowia lipolytica NCIM 3589, a tropical marine yeast, degrades bromoalkanes by an initial hydrolytic dehalogenation step. AB - The widespread industrial use of organobromines which are known persistent organic pollutants has led to their accumulation in sediments and water bodies causing harm to animals and humans. While degradation of organochlorines by bacteria is well documented, information regarding degradation pathways of these recalcitrant organobromines is scarce. Hence, their fates and effects on the environment are of concern. The present study shows that a tropical marine yeast, Yarrowia lipolytica NCIM 3589 aerobically degrades bromoalkanes differing in carbon chain length and position of halogen substitution viz., 2-bromopropane (2 BP), 1-bromobutane (1-BB), 1,5 dibromopentane (1,5-DBP) and 1-bromodecane (1-BD) as seen by an increase in cell mass, release of bromide and concomitant decrease in concentration of brominated compound. The amount of bromoalkane degraded was 27.3, 21.9, 18.0 and 38.3 % with degradation rates of 0.076, 0.058, 0.046 and 0.117/day for 2-BP, 1-BB, 1,5-DBP and 1-BD, respectively. The initial product formed respectively were alcohols viz., 2-propanol, 1-butanol, 1-bromo, 5 pentanol and 1-decanol as detected by GC-MS. These were further metabolized to fatty acids viz., 2-propionic, 1-butyric and 1-decanoic acid eventually leading to carbon dioxide formation. Neither higher chain nor brominated fatty acids were detected. An inducible extracellular dehalogenase responsible for removal of bromide was detected with activities of 21.07, 18.82, 18.96 and 26.67 U/ml for 2 BP, 1-BB, 1,5-DBP and 1-BD, respectively. We report here for the first time the proposed aerobic pathway of bromoalkane degradation by an eukaryotic microbe Y. lipolytica 3589, involving an initial hydrolytic dehalogenation step. PMID- 25708591 TI - Detection of circulating tumor cell-specific markers in breast cancer patients using the quantitative RT-PCR assay. AB - BACKGROUND: Breast cancer is a highly prevalent disease among women worldwide. While the expression of certain proteins within breast cancer tumors is used to determine the prognosis and select therapies, additional markers need to be identified. Circulating tumor cells (CTCs) are constituent cells that have detached from a primary tumor to circulate in the bloodstream. CTCs are considered the main source of breast cancer metastases; therefore, detection of CTCs could be a promising diagnostic method for metastatic breast cancer. METHODS: In this study, the CircleGen CTC RT-qDx assay was used to analyze the mRNA expression levels of six CTC-specific markers including EpCAM, CK19, HER2, Ki67, hTERT, and vimentin with a total of 692 peripheral whole blood samples from 221 breast cancer patients and 376 healthy individuals. RESULTS: This assay showed high specificity with multiple markers; none of the healthy controls were detected positive, whereas 21.7 and 14 % of breast cancer patients were positive for EpCAM and CK19, respectively. Of the 221 breast cancer patients, 84 (38 %), 46 (20.8 %), 83 (37.6 %), and 39 (17.6 %) were positively for HER2, Ki67, hTERT, and vimentin mRNA, respectively. Of the 84 patients who were HER2 positive, nine (4 %) were also positive for EpCAM, CK19, Ki67, hTERT, and vimentin. Of the 139 breast cancer patients who were HER2 negative, 65 (29.1 %) were negative for EpCAM, CK19, Ki67, hTERT, and vimentin. Furthermore, the EpCAM-positive population decreased from 21.5 to 8.3 % after completion of anti-tumor treatment (TP4). Similarly, the CK19, HER2, hTERT, and vimentin positives also decreased from 13.9 to 9.5 %, from 37.7 to 21.4 %, from 37.2 to 33.3 %, and from 17.5 to 14.3 %, respectively, after completion of anti-tumor treatment. In contrast, the Ki67 positives increased from 20.6 to 41.7 % after completion of anti-tumor treatment. CONCLUSIONS: mRNA overexpression of six CTC-specific markers was detected by the CircleGen CTC RT-qDx assay with high specificity, and the obtained mRNA expression levels of CTC-specific markers might provide useful criteria to select appropriate anti-tumor treatment for breast cancer patients. PMID- 25708592 TI - Combination of molecular-targeted drugs with endocrine therapy for hormone resistant breast cancer. AB - Overcoming resistance to endocrine therapy is the most intensive research area in estrogen receptor (ER)-positive breast cancer. A strategy to restore endocrine sensitivity using molecular-targeted drugs such as mammalian target of rapamycin inhibitor everolimus along with endocrine therapy has already been used as a treatment option after the progression of previous aromatase inhibitor therapy. Phase II/III clinical trials of several signal pathway inhibitors and cyclin dependent kinase 4/6 inhibitors are underway. In addition, a randomized phase II trial of the histone deacetylase inhibitor entinostat showed interesting findings. In this review, we summarize the mechanistic principles of combination therapy of molecular-targeted drugs with endocrine therapy by using a hybrid car model. PMID- 25708593 TI - Investigation of the clinicopathological features of squamous cell carcinoma of the vulva: a retrospective survey of the Tohoku Gynecologic Cancer Unit. AB - BACKGROUND: This multi-institutional study was conducted to clarify the clinicopathological features of squamous cell carcinomas of the vulva. METHODS: The medical records of vulvar cancer patients treated between 2002 and 2012 were retrospectively reviewed following approval by the Institutional Review Board of each institution. RESULTS: One hundred and eleven patients with vulvar malignancies were included. Of these, 63 patients had squamous cell carcinoma (57 %). Initial treatment was surgery, radiation therapy (RT), and concurrent chemoradiotherapy (CCRT) in 34 (54 %), 15 (24 %), and 11 (17 %) patients, respectively. Nineteen, 11, 26, and 7 patients had stage I, II, III, and IV disease, respectively. Of the 34 patients who had surgical treatment, 50 % had stage I disease, while 74 % of those who received CCRT had stage III or IV disease. Complete response (CR) rates for the surgery, RT, and CCRT groups were 73, 60, and 64 %, respectively. The 5-year survival rates for stage I/II and III/IV disease were 64 and 39 %, respectively (P = 0.019). The 5-year survival rates for the surgery, RT, and CCRT groups were 53, 38, and 50 %, respectively, and the prognosis of patients treated with surgery or CCRT was significantly better than that of patients who received RT (P < 0.05). In multivariate analysis, clinical response to initial treatment was an independent prognostic factor (P < 0.001). CONCLUSIONS: Although many patients had advanced-stage disease in the CCRT group, the therapeutic outcome for the surgery and CCRT groups was similar. Thus, CCRT may be a promising treatment for squamous cell carcinoma of the vulva. PMID- 25708597 TI - Usefulness of an in vitro cellular expression model for haemophilia A carrier diagnosis: illustration with five novel mutations in the F8 gene in women with isolated factor VIII:C deficiency. AB - This study aims to determine the way to predict the haemophilia A (HA) carrier status and the potential severity in six females with low FVIII: C levels (<0.50 IU mL(-1) ), F8 gene variations and without family history of HA. Except p.Ser577Tyr, F8 gene variations that we reported have never been described (p.Leu107His, p.Pro521Leu, p.Val682Leu, p.Leu2032Pro, p.Ala315dup). Prediction of their potential causal impact was studied by two strategies: bioinformatics approaches and site-directed mutagenesis followed by FVIII cellular expression into COS-1 cell. FVIII clotting assay ( FVIII: C) and antigen ( FVIII: Ag) were assayed in vitro. In silico analysis showed the probably damaging effect of all substitutions and the full conservation of the residues across mammalian species, except for p.Leu2032Pro. The in vitro variant expression model showed abnormal intra and/or extracellular FVIII: C and FVIII: Ag levels for five mutations, which suggest their causality in HA and provide informations about the involved mechanism. We suspect a defect in synthesis and secretion for p.Leu107His, p.Ala315dup and p.Pro521Leu. The mutation p.Val682Leu only affects the FVIII function while p.Ser577Tyr alters function and synthesis. The variant p.Leu2032Pro is probably a polymorphism because no alteration of the FVIII protein expression was observed in vitro. In vitro results suggest that mutations p.Ser577Tyr and p.Ala315dup could led to a severe HA in men. This study demonstrates the ability of this in vitro cellular expression model to contribute to the diagnosis strategy for female suspected of being HA carrier, without HA family history and with a novel F8 gene variation and to provide new criteria for the genetic counselling. PMID- 25708596 TI - Recombinant adeno-associated viral (rAAV) vectors mediate efficient gene transduction in cultured neonatal and adult microglia. AB - Microglia are a specialized population of myeloid cells that mediate CNS innate immune responses. Efforts to identify the cellular and molecular mechanisms that regulate microglia behaviors have been hampered by the lack of effective tools for manipulating gene expression. Cultured microglia are refractory to most chemical and electrical transfection methods, yielding little or no gene delivery and causing toxicity and/or inflammatory activation. Recombinant adeno-associated viral (rAAVs) vectors are non-enveloped, single-stranded DNA vectors commonly used to transduce many primary cell types and tissues. In this study, we evaluated the feasibility and efficiency of utilizing rAAV serotype 2 (rAAV2) to modulate gene expression in cultured microglia. rAAV2 yields high transduction and causes minimal toxicity or inflammatory response in both neonatal and adult microglia. To demonstrate that rAAV transduction can induce functional protein expression, we used rAAV2 expressing Cre recombinase to successfully excise a LoxP-flanked miR155 gene in cultured microglia. We further evaluated rAAV serotypes 5, 6, 8, and 9, and observed that all efficiently transduced cultured microglia to varying degrees of success and caused little or no alteration in inflammatory gene expression. These results provide strong encouragement for the application of rAAV-mediated gene expression in microglia for mechanistic and therapeutic purposes. Neonatal microglia are functionally distinct from adult microglia, although the majority of in vitro studies utilize rodent neonatal microglia cultures because of difficulties of culturing adult cells. In addition, cultured microglia are refractory to most methods for modifying gene expression. Here, we developed a novel protocol for culturing adult microglia and evaluated the feasibility and efficiency of utilizing Recombinant Adeno-Associated Virus (rAAV) to modulate gene expression in cultured microglia. PMID- 25708598 TI - Flexible endosopic management of Zenker's diverticulum: characteristics and outcomes of 52 cases at a tertiary referral center. AB - Zenker's diverticulum causes substantial morbidity among affected elderly patients. In the United States, rigid endoscopic cricopharyngeal myotomy is the mainstay of management and the flexible endoscopic technique is reserved for those not deemed candidates for rigid endoscopy due to an inability to extend the neck and/or medical comorbidities. Short- and long-term outcomes following flexible endoscopic cricopharyngeal myotomy in the United States are limited. We reviewed the patient characteristics and outcomes of 58 consecutive flexible endoscopic cricopharyngeal myotomies performed at Mayo Clinic, Rochester, between March 2006 and November 2013. There were 58 procedures performed on 52 unique patients. The median age was 77 years, and 48% of patients were female. More than one third of patients had either failed previous rigid therapy or were deemed inoperable by the referring surgeon. Size of the diverticulum ranged from 1 cm to 5 cm with a mean of 2.8 cm. Most procedures (67%) were performed under general anesthesia. Initial procedural success was achieved in all patients. Of the patients, 77% reported complete symptom resolution at mean follow-up time of 26 months. Of the procedures, 71% were not associated with any adverse event, but esophageal microperforation occurred during 11 procedures (19%). Of these, nine resolved with conservative management, one required an endoscopic stent, and one developed a neck abscess that required drainage. Our data show in a group of elderly patients with preexisting comorbidities flexible endoscopy therapy for Zenker's diverticulum is feasible. Initial symptomatic improvement was universal, and long-term response appears durable. The most common adverse event was esophageal microperforation, and the majority (82%) of these resolved with conservative management. Direct comparison with outcomes of rigid endoscopic or open surgical techniques has not been performed, but these data suggest that a randomized trial is warranted to assess the efficacy and safety of a flexible endoscopic technique. PMID- 25708599 TI - Past and future corollaries of theories on causes of metabolic syndrome and obesity related co-morbidities part 2: a composite unifying theory review of human-specific co-adaptations to brain energy consumption. AB - Metabolic syndrome (MetS) predicts type II diabetes mellitus (TIIDM), cardiovascular disease (CVD) and cancer, and their rates have escalated over the last few decades. Obesity related co-morbidities also overlap the concept of the metabolic syndrome (MetS). However, understanding of the syndrome's underlying causes may have been misapprehended. The current paper follows on from a theory review by McGill, A-T in Archives of Public Health, 72: 30. This accompanying paper utilises research on human evolution and new biochemistry to theorise on why MetS and obesity arise and how they affect the population. The basis of this composite unifying theory is that the proportionately large, energy-demanding human brain may have driven co-adaptive mechanisms to provide, or conserve, energy for the brain. A 'dual system' is proposed. 1) The enlarged, complex cortico-limbic-striatal system increases dietary energy by developing strong neural self-reward/motivation pathways for the acquisition of energy dense food, and (2) the nuclear factor-erythroid 2-related factor 2 (NRF2) cellular protection system amplifies antioxidant, antitoxicant and repair activity by employing plant chemicals. In humans who consume a nutritious diet, the NRF2 system has become highly energy efficient. Other relevant human-specific co adaptations are explored. In order to 'test' this composite unifying theory it is important to show that the hypothesis and sub-theories pertain throughout the whole of human evolution and history up till the current era. Corollaries of the composite unifying theory of MetS are examined with respect to past under nutrition and malnutrition since agriculture began 10,000 years ago. The effects of man-made pollutants on degenerative change are examined. Projections are then made from current to future patterns on the state of 'insufficient micronutrient and/or unbalanced high energy malnutrition with central obesity and metabolic dysregulation' or 'malnubesity'. Forecasts on human health are made on positive, proactive strategies using the composite unifying theory, and are extended to the wider human ecology of food production. A comparison is made with the outlook for humans if current assumptions and the status quo on causes and treatments are maintained. Areas of further research are outlined. A table of suggestions for possible public health action is included. PMID- 25708600 TI - Inhibitory effects of niclosamide on inflammation and migration of fibroblast like synoviocytes from patients with rheumatoid arthritis. AB - OBJECTIVES: This study evaluated the anti-inflammatory effect of niclosamide in tumor necrosis factor (TNF)-alpha-stimulated human rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) and inhibitory effects on migration and invasion in RA FLS and investigated the signal mechanism, and further explored the treatment activity of niclosamide on collagen-induced arthritis (CIA). METHODS: The levels of interleukin (IL)-1beta, IL-6, IL-8, IL-10,IL-17A and interferon (IFN)-gamma in cultural supernatants were measured by multiplex cytokine assay kits. RA FLS migration and invasion in vitro were measured by the Boyden chamber method and the scratch assay. Signal transduction proteins expression was measured by western blot. The in vivo suppressive effects of niclosamide were elucidated on CIA in a mouse model. RESULTS: Niclosamide reduced the secretion of IL-1beta, IL-6, IL-8, IL-17A and IFN-gamma from TNF-alpha induced RA FLS in a dose-dependent manner. Niclosamide inhibits FBS-induced migration and invasion and exhibits F-actin alterations in RA FLS. Niclosamide decreased the phosphorylation of c-Jun N-terminal kinase and ERK in TNF-alpha stimulated RA FLS and blocked TNF-alpha-induced IKK, IkappaBalpha phosphorylation and translocation of p65. Niclosamide treatments reduced the severity of CIA model. CONCLUSIONS: Our data suggest for the first time that niclosamide posses the anti-inflammatory effect in RA both in vitro and in vivo. PMID- 25708601 TI - Measuring the reactivity of commercially available zero-valent iron nanoparticles used for environmental remediation with iopromide. AB - The high specific surface area and high reactivity of nanoscale zero-valent iron (nZVI) particles have led to much research on their application to environmental remediation. The reactivity of nZVI is affected by both the water chemistry and the properties of the particular type of nZVI particle used. We have investigated the reactivity of three types of commercially available Nanofer particles (from Nanoiron, s.r.o., Czech Republic) that are currently either used in, or proposed for use in full scale environmental remediation projects. The performance of one of these, the air-stable and thus easy-to-handle Nanofer Star particle, has not previously been reported. Experiments were carried out first in batch shaking reactors in order to derive maximum reactivity rates and provide a rapid estimate of the Nanofer particle's reactivity. The experiments were performed under near natural environmental conditions with respect to the pH value of water and solute concentrations, and results were compared with those obtained using synthetic water. Thereafter, the polyelectrolyte-coated Nanofer 25S particles (having the highest potential for transport within porous media) were chosen for the experiments in column reactors, in order to elucidate nanoparticle reactivity under a more field-site realistic setting. Iopromide was rapidly dehalogenated by the investigated nZVI particles, following pseudo-first-order reaction kinetics that was independent of the experimental conditions. The specific surface area normalized reaction rate constant (kSA) value in the batch reactors ranged between 0.12 and 0.53Lm(-2)h(-1); it was highest for the uncoated Nanofer 25 particles, followed by the polyacrylic acid-coated Nanofer 25S and air-stable Nanofer Star particles. In the batch reactors all particles were less reactive in natural water than in synthetic water. The kSA values derived from the column reactor experiments were about 1000 times lower than those from the batch reactors, ranging between 2.6*10(-4) and 5.7*10(-4)Lm(-2)h(-1). Our results revealed that the easy-to-handle and air-stable Nanofer Star particles are the least reactive of all the Nanofer products tested. The reaction kinetics predicted by column experiments were more realistic than those predicted by batch experiments and these should therefore be used when designing a full-scale field application of nanomaterials for environmental remediation. PMID- 25708602 TI - Defective innate immune responses to respiratory syncytial virus infection in ovalbumin-sensitized mice. AB - BACKGROUND/PURPOSE: Respiratory viral infections have frequently been reported to closely correlate with asthma exacerbations. Distinctive expression of cytokine/chemokine and anomalous responses of innate immunity induced by respiratory viral infections were suggested to play a key role. This study further evaluates the effects of airway sensitization on innate immunity in response to different viruses. METHODS: Murine sensitization was established using an ovalbumin (OVA) sensitization model. Mice were subsequently infected with either respiratory syncytial virus (RSV) or human metapneumovirus (hMPV). Type I interferon (IFN), cytokines, and chemokines were measured in bronchoalveolar lavage (BAL) fluid. Pulmonary tissue samples were collected for the analysis of viral titers and type I IFN signal transcriptors. RESULTS: Distinct expressions of cytokine/chemokine responses after viral infection were also found in mice with OVA sensitization. A significant increase of virus replication was found in lungs of RSV-infected sensitized mice. The increment of RSV titer was associated with the decreased levels of type I IFN. Although Toll like receptor 3 (TLR3) expression was significantly increased in the lungs, the key signal transcriptor, IFN regulatory factor 3, was significantly suppressed in the RSV-infected sensitized mice. CONCLUSION: A defective antiviral innate response was observed in the murine respiratory allergy model. Suppressed expression of IFN signal transcriptor contributes to decreased production of type I IFN. The defective innate immune response might result in acute viral exacerbations of allergic airway diseases. PMID- 25708603 TI - Effects of elevated parameters of subclinical ketosis on the immune system of dairy cows: in vivo and in vitro results. AB - Using an established model in which subclinical ketosis is induced, the response of differential blood counts and levels of various haematological variables, including the inflammatory marker haptoglobin (Hp), were tested over the last six weeks of parturition until the 56th day post-partum in cows with lower or higher body condition scores (LBC and HBC, respectively; n = 9/group). Animals in the HBC group evidenced subclinical ketosis whereas LBC animals were metabolically healthy. For in vitro examination with beta-hydroxybutyrate (BHB) as a further stimulus, peripheral blood mononuclear cell (PBMC) counts of cows with and without subclinical ketosis (n = 5/group) were observed. Counts of leucocytes, granulocytes and lymphocytes (LY) peaked at day 1 post-partum in HBC cows, with a more marked increase in heifers. In subclinical ketosis LY count increased again, with significantly higher values in the HBC group. The red blood cell (RBC) profile was affected by parity (counts were higher in heifers). Hp showed a positive linear correlation with BHB and non-esterified fatty acids (NEFA; R(2) = 0.41). PBMC from cows that were not pre-stressed with subclinical ketosis were more sensitive to increasing levels of BHB in vitro, as evidenced by both their higher proliferative capability and increased release of nitric oxide (NO). In summary, cows with subclinical ketosis showed a heightened immune response compared with metabolically healthy individuals, based on increased LY counts, increasing stimulative properties of PBMC and a relationship between Hp and typically increased values of BHB and NEFA. Concentrations of BHB in vivo during subclinical ketosis did not alter the proliferative capability of bovine PBMC in vitro, which was first significantly decreased at a dosage of 5 mM BHB. PMID- 25708605 TI - Latest developments in the assessment and treatment of lower urinary tract symptoms suggestive of benign prostatic hyperplasia: what is clinically relevant? PMID- 25708606 TI - The diagnosis and treatment of lower urinary tract symptoms due to benign prostatic hyperplasia with alpha-blockers: focus on silodosin. AB - Lower urinary tract symp toms due to benign prostatic hyperplasia (LUTS/BPH) are common in aging men and can progress to acute urinary retention. Among the classes of agents recommended for patients with moderate to severe symptoms are alpha-adrenergic receptor (adrenoceptor) antagonists (alpha-blockers) and 5alpha reductase inhibitors (5ARIs). This review provides a brief overview of the diagnosis and management of LUTS/BPH, focusing on the efficacy and tolerability of alpha-blockers approved for the treatment of LUTS/BPH, with particular emphasis on silodosin, a novel alpha-blocker. Of the older alpha1-blockers, alfuzosin, doxazosin and terazosin show little selectivity for the alpha1 adrenoceptor subtypes, while tamsulosin is moderately and silodosin is highly selective for the alpha1A subtype in preference to the alpha1B subtype. Highly selective alpha1A-receptor antagonists such as silodosin were developed specifically for the treatment of LUTS because non-selective antagonists were associated with cardiovascular adverse effects. Since alpha1A is predominantly expressed in the prostate, higher selectivity for alpha1A may account for lower blood pressure-related adverse effects. Silodosin is administered once daily and provides rapid improvements in the signs and symptoms of moderate to severe LUTS/BPH in male patients. As with other alpha-blockers, silodosin is generally well-tolerated and the most common adverse events seen are abnormal ejaculation, dizziness, headache, diarrhoea, nasal congestion and orthostatic hypotension. Unlike 5ARIs, alpha-blockers do not impair libido. Given the prevalence of LUTS/BPH and the efficacy and tolerability concerns with existing therapies, silodosin is a welcome addition to the pharmacological options for these patients. PMID- 25708607 TI - The diagnosis and treatment of lower urinary tract symptoms due to benign prostatic hyperplasia by primary care family physicians in Portugal. AB - BACKGROUND: The shift towards primarily pharmacological management of lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH) has led to an increasing proportion of patients being treated in the primary care setting. METHOD: Two related studies were undertaken in Portugal. The first was a survey of primary care family physicians regarding the management of LUTS/BPH. The second was a cross-sectional study of the records of patients with suspected or confirmed LUTS/BPH managed by the surveyed physicians. RESULTS: One hundred and sixty-three physicians were surveyed between 16 June 2012 and 10 February 2013 and 2,988 patients were identified (mean age 68 years). While 80 % of physicians would order diagnostic tests for patients reporting symptoms, only 2.5 % would initiate treatment based on reported symptoms alone. Only 1 % would refer patients directly to a urologist for diagnosis, and 75 % would only refer patients after an inadequate response to treatment in the primary care setting. Management practices varied according to physicians' age and experience. Nocturia was both the most common and the most bothersome symptom. Erectile dysfunction was reported by 51 % of patients and 81 % had hypertension, hypercholesterolaemia and/or diabetes mellitus. Diagnosis and treatment of LUTS/BPH differed for older patients, those with comorbidities and those with more severe nocturia at presentation. CONCLUSION: Primary care physicians in Portugal usually diagnose and treat patients with LUTS/BPH rather than refer them to a urologist. Physicians' age and experience, and patients' age, comorbidities and symptom severity affect the management of LUTS/BPH in primary care in Portugal. PMID- 25708608 TI - Behavioral and molecular responses to electroconvulsive shock differ between genetic and environmental rat models of depression. AB - Depression's causes play a role in individuals' different responses to antidepressant treatments, which require advancements. We investigated the mechanisms behind and responses to a highly effective antidepressant treatment, electroconvulsive therapy (ECT), in rat models with different (genetic or environmental) depression causes. Wistar Kyoto (WKY) rats and Wistar rats treated with chronic unpredictable mild stresses (CUMS) were used as genetic and environmental rat models of depression, respectively. The rats underwent electroconvulsive shock (ECS, the animal analog of ECT) or sham ECS. We performed a sucrose preference test, open field test, and Morris water maze to assess behavior. Hippocampal neuron numbers were measured with Nissl stain. Hippocampal BDNF, CREB, and p-CREB proteins were assayed with ELISA or western blotting. The main results showed that ECS impaired WKY rats' memories but improved CUMS rats' memories. It elevated hippocampal BDNF and CREB proteins only in CUMS rats, while it improved depressive behavior and hippocampal p-CREB protein levels in both rats, with more effective regulations in the CUMS rats. ECS did not change the hippocampal neuron number in both rats. These findings suggest that ECS exerted up-regulating effects on hippocampal BDNF and CREB (and its phosphorylation) in depressed rats, and the environmental model responded better. PMID- 25708610 TI - Implementing and measuring change to enhance perioperative outcomes. PMID- 25708609 TI - Potential of extracellular microRNAs as biomarkers of acetaminophen toxicity in children. AB - Developing biomarkers for detecting acetaminophen (APAP) toxicity has been widely investigated. Recent studies of adults with APAP-induced liver injury have reported human serum microRNA-122 (miR-122) as a novel biomarker of APAP-induced liver injury. The goal of this study was to examine extracellular microRNAs (miRNAs) as potential biomarkers for APAP liver injury in children. Global levels of serum and urine miRNAs were examined in three pediatric subgroups: 1) healthy children (n=10), 2) hospitalized children receiving therapeutic doses of APAP (n=10) and 3) children hospitalized for APAP overdose (n=8). Out of 147 miRNAs detected in the APAP overdose group, eight showed significantly increased median levels in serum (miR-122, -375, -423-5p, -30d-5p, -125b-5p, -4732-5p, -204-5p, and -574-3p), compared to the other groups. Analysis of urine samples from the same patients had significantly increased median levels of four miRNAs (miR-375, 940, -9-3p and -302a) compared to the other groups. Importantly, correlation of peak serum APAP protein adduct levels (an indicator of the oxidation of APAP to the reactive metabolite N-acetyl-para-quinone imine) with peak miRNA levels showed that the highest correlation was observed for serum miR-122 (R=0.94; p<0.01) followed by miR-375 (R=0.70; p=0.05). CONCLUSION: Our findings demonstrate that miRNAs are increased in children with APAP toxicity and correlate with APAP protein adducts, suggesting a potential role as biomarkers of APAP toxicity. PMID- 25708611 TI - Highlights from the Third International Society for Computational Biology (ISCB) European Student Council Symposium 2014. AB - In this meeting report, we give an overview of the talks, presentations and posters presented at the third European Symposium of the International Society for Computational Biology (ISCB) Student Council. The event was organized as a satellite meeting of the 13th European Conference for Computational Biology (ECCB) and took place in Strasbourg, France on September 6th, 2014. PMID- 25708612 TI - Observation of long-lived interlayer excitons in monolayer MoSe2-WSe2 heterostructures. AB - Van der Waals bound heterostructures constructed with two-dimensional materials, such as graphene, boron nitride and transition metal dichalcogenides, have sparked wide interest in device physics and technologies at the two-dimensional limit. One highly coveted heterostructure is that of differing monolayer transition metal dichalcogenides with type-II band alignment, with bound electrons and holes localized in individual monolayers, that is, interlayer excitons. Here, we report the observation of interlayer excitons in monolayer MoSe2-WSe2 heterostructures by photoluminescence and photoluminescence excitation spectroscopy. We find that their energy and luminescence intensity are highly tunable by an applied vertical gate voltage. Moreover, we measure an interlayer exciton lifetime of ~1.8 ns, an order of magnitude longer than intralayer excitons in monolayers. Our work demonstrates optical pumping of interlayer electric polarization, which may provoke further exploration of interlayer exciton condensation, as well as new applications in two-dimensional lasers, light-emitting diodes and photovoltaic devices. PMID- 25708613 TI - Identification of transcriptionally active HPV infection in formalin-fixed, paraffin-embedded biopsies of oropharyngeal carcinoma. AB - Human papillomavirus (HPV) oncogenic activity is the result of viral oncogene E6 and E7 expression in infected cells. Oncogene expression analysis is, however, not part of the routine diagnostic evaluation of HPV-associated oropharyngeal squamous cell carcinoma (OPSCC) since it requires fresh tumor tissue. We compared the diagnostic accuracy of several methods commonly employed for HPV characterization in OPSCC with the results of the newly available HPV E6/E7 mRNA in situ hybridization (ISH) on formalin-fixed, paraffin-embedded biopsy samples, in order to establish if the latter should be introduced in the diagnostic routine to increase accuracy when fresh tissue is not available. p16 immunostain, DNA ISH for high-risk HPV genotypes, SPF LiPA amplification and genotyping, and HPV16 E6 amplification were performed on 41 consecutive OPSCC samples. Twenty (48.7%) cases were positive by mRNA ISH; sensitivity and specificity were 100% and 90% for p16, 90% and 100% for DNA ISH, 70% and 76% for SPF10 LiPA, 90% and 76% for E6 amplification. A diagnostic algorithm considering p16 immunostain as first step followed by either high-risk HPV DNA ISH or HPV16 E6 amplification in p16-positive cases correctly characterized 90% of mRNA-positive and all mRNA negative cases; combining the 3 tests correctly identified all cases. While no stand-alone test was sufficiently accurate for classifying HPV-associated OPSCC, the high sensitivity and specificity of the established combination of p16 immunostain, DNA ISH, and HPV16 DNA amplification suggests that the introduction of labour- and cost-intensive mRNA ISH, is not necessary in the diagnostic routine of oropharyngeal tumors. PMID- 25708615 TI - Adult primary central nervous system vasculitis treatment and course: analysis of one hundred sixty-three patients. AB - OBJECTIVE: To describe the treatment and outcomes of patients with primary central nervous system (CNS) vasculitis. METHODS: We retrospectively studied a cohort of 163 consecutive patients with primary CNS vasculitis who were seen at the Mayo Clinic over a 29-year period. We analyzed treatments, treatment responses, and factors predictive of outcomes. RESULTS: A favorable response was observed in 85% of patients treated with prednisone alone and in 80% of patients treated with prednisone and cyclophosphamide. Relapses were observed in 27% of patients, and 25% of patients had discontinued therapy by the time of the last followup visit. Treatment with prednisone alone was associated with more frequent relapses (odds ratio [OR] 2.90), while large vessel involvement (OR 6.14) and cerebral infarcts at the time of diagnosis (OR 3.32) were associated with a poor response to treatment. Prominent gadolinium-enhanced cerebral lesions or meninges were linked with continued treatment at the last followup encounter (OR 2.28). Higher disability scores at the last followup visit were associated with increasing age at the time of diagnosis (OR 1.44) and cerebral infarctions (OR 3.74), while lower disability scores were associated with gadolinium-enhanced cerebral lesions or meninges (OR 0.35) and cerebral amyloid angiopathy (OR 0.24). Increased mortality was associated with increasing age at diagnosis (hazard ratio [HR] 1.39), diagnosis by angiography (HR 3.28), cerebral infarction (HR 4.44), and large vessel involvement (HR 4.98), while reduced mortality was associated with gadolinium-enhanced cerebral lesions or meninges (HR 0.20). CONCLUSION: The majority of patients with primary CNS vasculitis responded to treatment. Recognition of findings at diagnosis that predict the course or outcome may aid in decision-making regarding therapy. PMID- 25708614 TI - Class-specific histone/protein deacetylase inhibition protects against renal ischemia reperfusion injury and fibrosis formation. AB - Renal ischemia-reperfusion injury (IRI) is a common cause of renal dysfunction and renal failure. Histone/protein deacetylases (HDACs) regulate gene accessibility and higher order protein structures and may alter cellular responses to a variety of stresses. We investigated whether use of pan- and class specific HDAC inhibitors (HDACi) could improve IRI tolerance in the kidney. Using a model of unilateral renal IRI, we investigated early renal function after IRI, and calculated fibrosis after IRI using an automated scoring system. We found that pan-HDAC inhibition using trichostatin (TSA) yielded significant renal functional benefit at 24-96 hours (p < 0.001). Treated mice developed significantly less fibrosis at 30 days (p < 0.0004). Class I HDAC inhibition with MS-275 yielded similar effects. Protection from fibrosis formation was also noted in a cold ischemia transplant model (p < 0.008) with a trend toward improved cold ischemic survival in TSA-treated mice. These effects were not accompanied by induction of typical ischemic tolerance pathways or by priming of heat shock protein expression. In fact, heat shock protein 70 deletion or overexpression did not alter renal ischemia tolerance. Micro-RNA 21, known to be enhanced in vitro in renal tubular cells that survive stress, was enhanced by treatment with HDACi, pointing to possible mechanism. PMID- 25708616 TI - Environmentally benign synthesis, molecular properties prediction and anti inflammatory activity of novel isoxazolo[5,4-d]isoxazol-3-yl-aryl-methanones via vinylogous Henry nitroaldol adducts as synthons. AB - Synthesis of novel 6-methylisoxazolo[5,4-d]isoxazol-3-yl-aryl-methanones 5 has been achieved via nitro-nitrite rearrangement by utilizing vinylogous nitroaldol adducts as synthons under mild conditions. Furthermore, the new series of compounds 5a-i were assessed for molecular properties prediction, drug-likeness by Molinspiration (Molinspiration, 2008) & MolSoft (MolSoft, 2007) softwares, lipophilicity and solubility parameters using ALOGPS 2.1 program. The new series of compounds 5a-i were screened for their anti-inflammatory activity. PMID- 25708617 TI - Minimization of drug-drug interaction risk and candidate selection in a natural product-based class of gamma-secretase modulators. AB - Early lead compounds in this gamma secretase modulator series were found to potently inhibit CYP3A4 and other human CYP isoforms increasing their risk of causing drug-drug-interactions (DDIs). Using structure-activity relationships and CYP3A4 structural information, analogs were developed that minimized this DDI potential. Three of these new analogs were further characterized by rat PK, rat PK/PD and rat exploratory toxicity studies resulting in selection of SPI-1865 (14) as a preclinical development candidate. PMID- 25708618 TI - Discovery and evaluation of a novel monocyclic series of CXCR2 antagonists. AB - Antagonism of the chemokine receptor CXCR2 has been proposed as a strategy for the treatment of inflammatory diseases such as arthritis, chronic obstructive pulmonary disease and asthma. Earlier series of bicyclic CXCR2 antagonists discovered at AstraZeneca were shown to have low solubility and poor oral bioavailability. In this Letter we describe the design, synthesis and characterisation of a new series of monocyclic CXCR2 antagonists with improved solubility and good pharmacokinetic profiles. PMID- 25708619 TI - CT-guided infiltration saves surgical intervention and fastens return to work compared to anatomical landmark-guided infiltration in patients with lumbosciatica. AB - BACKGROUND: Infiltration procedures are a common treatment of lumbar radiculopathy. There is a wide variety of infiltration techniques without an established gold standard. Therefore, we compared the effectiveness of CT-guided transforaminal infiltrations versus anatomical landmark-guided transforaminal infiltrations at the lower lumbar spine in case of acute sciatica at L3-L5. METHODS: A retrospective chart review was conducted of 107 outpatients treated between 2009 and 2011. All patients were diagnosed with lumbar radiculopathic pain secondary to disc herniation in L3-L5. A total of 52 patients received CT guided transforaminal infiltrations; 55 patients received non-imaging-guided nerve root infiltrations. The therapeutic success was evaluated regarding number of physician contacts, duration of treatment, type of analgesics used and loss of work days. Defined endpoint was surgery at the lower lumbar spine. RESULTS: In the CT group, patients needed significantly less oral analgesics (p < 0.001). Overall treatment duration and physician contacts were significantly lower in the CT group (p < 0.001 and 0.002) either. In the CT group, patients lost significant fewer work days due to incapacity (p < 0.001). Surgery had to be performed in 18.2 % of the non-imaging group patients (CT group: 1.9 %; p = 0.008). CONCLUSION: This study shows that CT-guided periradicular infiltration in lumbosciatica caused by intervertebral disc herniation is significantly superior to non-imaging, anatomical landmark-guided infiltration, regarding the parameters investigated. The high number of treatment failures in the non-imaging group underlines the inferiority of this treatment concept. PMID- 25708620 TI - Is it possible to eliminate the plate-related problems and still achieve satisfactory outcome after multilevel anterior cervical discectomy? AB - BACKGROUND: Stand-alone cage-assisted anterior cervical discectomy and fusion (ACDF) has proved to be safe and effective procedure for treatment of mono segmental cervical degenerative stenosis (CDS). However, the success rate has reported to decline as the number of levels increases. The aim of this prospective study was to evaluate the short-term results of multilevel ACDF using stand-alone polyetheretherketone (PEEK) cages. PATIENTS AND METHODS: Twenty-eight patients (16 males and 12 females; mean age 40.5 years) of symptomatic multilevel CDS were enroled in this study and completed a 2-year post-operative follow-up. All patients underwent contiguous multilevel ACDF, using indirect decompression and stand-alone PEEK cages, between 2009 and 2012. Ten patients underwent two level fusions (group I), ten underwent three-level fusions (group II), and eight underwent four-level fusions (group III). The visual analogue scales of neck and arm pain and Odom's criteria were used to evaluate clinical outcomes. Radiological evaluation was done to evaluate: fusion, cervical sagittal angle (CSA) and cage subsidence. RESULTS: There was a statistical significant improvement in clinical parameters and radiological CSA values in all groups post operatively. This improvement was well maintained till final follow-up. Subsidence and non-union were encountered in seven and two fusion levels, respectively, with no significant differences between groups. All patients were satisfied and none of them had major complications or required revision surgery. CONCLUSION: With proper patient selection, meticulous surgical technique and strict post-operative cervical bracing, the less-invasive indirect anterior cervical decompression technique augmented with stand-alone PEEK cage-assisted ACDF is an efficient and safe method for the treatment of multilevel CDS. PMID- 25708622 TI - Geomagnetic and strong static magnetic field effects on growth and chlorophyll a fluorescence in Lemna minor. AB - The geomagnetic field (GMF) varies over Earth's surface and changes over time, but it is generally not considered as a factor that could influence plant growth. The effects of reduced and enhanced GMFs and a strong static magnetic field on growth and chlorophyll a (Chl a) fluorescence of Lemna minor plants were investigated under controlled conditions. A standard 7 day test was conducted in extreme geomagnetic environments of 4 uT and 100 uT as well as in a strong static magnetic field environment of 150 mT. Specific growth rates as well as slow and fast Chl a fluorescence kinetics were measured after 7 days incubation. The results, compared to those of controls, showed that the reduced GMF significantly stimulated growth rate of the total frond area in the magnetically treated plants. However, the enhanced GMF pointed towards inhibition of growth rate in exposed plants in comparison to control, but the difference was not statistically significant. This trend was not observed in the case of treatments with strong static magnetic fields. Our measurements suggest that the efficiency of photosystem II is not affected by variations in GMF. In contrast, the strong static magnetic field seems to have the potential to increase initial Chl a fluorescence and energy dissipation in Lemna minor plants. PMID- 25708621 TI - pecific nutrient combination effects on tax, NF- kappaB and MMP-9 in human T-cell lymphotropic virus -1 positive malignant T-lymphocytes. AB - BACKGROUND: Adult T-cell Leukemia (ATL) is a disease with no known cure. The disease manifests itself as an aggressive proliferation of CD4+ cells with the human T-cell Lymphotropic virus type 1 (HTLV-1). The leukemogenesis of the virus is mainly attributed to the viral oncoprotein. Tax activates the Nuclear Factor kappa B (NF-kappaB) which stimulates the activity and expression of the matrix metalloproteinase-9 (MMP-9). The objective of this study was to investigate the efficacy of a specific nutrient synergy (SNS) on proliferation, Tax expression, NF-kappaB levels as well as on MMP-9 activity and expression both at the transcriptional and translational levels in two HTLV-1 positive cell lines, HuT 102 and C91-PL at 48h and 96h of incubation. Cytotoxicity of Epigallocatechin-3 gallate (EGCG) was assayed using CytoTox 96 Non-radioactive and proliferation was measured using Cell Titer96TM Nonradioactive Cell Proliferation kit (MTT- based assay). Enzyme linked immunosorbant assay (ELISA) and electrophoretic mobility shift assay (EMSA) were used to assess the effect of SNS on NF-kappaB mobility. Zymography was used to determine the effects of SNS on the activity and secretion of MMP-9. The expression of MMP-9 was done using RT-PCR at the translational level and Immunoblotting at the transcriptional level. RESULTS: A significant inhibition of proliferation was seen in both cell lines starting at a concentration of 200MUg/ml and in a dose dependent manner. SNS induced a dose dependent decrease in Tax expression, which was paralleled by a down-regulation of the nuclearization of NF-kappaB. This culminated in the inhibition of the activity of MMP-9 and their expression both at the transcriptional and translational levels. CONCLUSIONS: The results of this study indicate that a specific nutrient synergy targeted multiple levels pertinent to the progression of ATL. Its activity was mediated through the NF-kappaB pathway, and hence has the potential to be integrated in the treatment of this disease as a natural potent anticancer agent. PMID- 25708623 TI - Measurement of temperature-dependent stability constants of Cu(I) and Cu(II) chloride complexes by voltammetry at a Pt ultramicroelectrode. AB - Cu(II)Cl complexes can undergo stepwise electrochemical reduction to Cu(I)Cl and then to Cu. In this paper, the Nernst equation is used to simultaneously calculate the temperature-dependent stability constants of both mononuclear Cu(II)Cl and Cu(I)Cl complexes for the first time. First, voltammograms were recorded at a Pt ultramicroelectrode (UME) with a variable of free chloride concentration at a given temperature. Using the equilibrium of Ag/AgCl redox couple, the free chloride activities were measured on an Ag electrode in different NaCl solutions, adjusting for the influence of ionic strength. This electrochemical technique was proved to be feasible at 25 and 90 degrees C. With increasing temperature, the Cu(II)Cl complex favored a lower coordination number and the CuCl2 complex prevailed, whereas the CuCl4(2-) was predicted to be unstable. The CuCl2(-) and CuCl3(2-) complexes were still the primary species for the Cu(I)Cl complex. PMID- 25708625 TI - Presurgery resting-state local graph-theory measures predict neurocognitive outcomes after brain surgery in temporal lobe epilepsy. AB - OBJECTIVE: This study determined the ability of resting-state functional connectivity (rsFC) graph-theory measures to predict neurocognitive status postsurgery in patients with temporal lobe epilepsy (TLE) who underwent anterior temporal lobectomy (ATL). METHODS: A presurgical resting-state functional magnetic resonance imaging (fMRI) condition was collected in 16 left and 16 right TLE patients who underwent ATL. In addition, patients received neuropsychological testing pre- and postsurgery in verbal and nonverbal episodic memory, language, working memory, and attention domains. Regarding the functional data, we investigated three graph-theory properties (local efficiency, distance, and participation), measuring segregation, integration and centrality, respectively. These measures were only computed in regions of functional relevance to the ictal pathology, or the cognitive domain. Linear regression analyses were computed to predict the change in each neurocognitive domain. RESULTS: Our analyses revealed that cognitive outcome was successfully predicted with at least 68% of the variance explained in each model, for both TLE groups. The only model not significantly predictive involved nonverbal episodic memory outcome in right TLE. Measures involving the healthy hippocampus were the most common among the predictors, suggesting that enhanced integration of this structure with the rest of the brain may improve cognitive outcomes. Regardless of TLE group, left inferior frontal regions were the best predictors of language outcome. Working memory outcome was predicted mostly by right-sided regions, in both groups. Overall, the results indicated our integration measure was the most predictive of neurocognitive outcome. In contrast, our segregation measure was the least predictive. SIGNIFICANCE: This study provides evidence that presurgery rsFC measures may help determine neurocognitive outcomes following ATL. The results have implications for refining our understanding of compensatory reorganization and predicting cognitive outcome after ATL. The results are encouraging with regard to the clinical relevance of using graph-theory measures in presurgical algorithms in the setting of TLE. PMID- 25708624 TI - Time-dependent changes in the mouse hippocampal synaptic membrane proteome after contextual fear conditioning. AB - A change in efficacy of hippocampal synapses is critical for memory formation. So far, the molecular analysis of synapses during learning has focused on small groups of proteins, whereas the dynamic global changes at these synapses have remained unknown. Here, we analyzed the temporal changes of the mouse hippocampal synaptic membrane proteome 1 and 4 h after contextual fear learning, comparing two groups; (1) a fear memory forming "delayed-shock" group and (2) a fear memory deficient "immediate-shock" group. No changes in protein expression were observed 1 h after conditioning between the two experimental groups. However, 423 proteins were significantly regulated 4 h later of which 164 proteins showed a temporal regulation after a delayed shock and 273 proteins after the stress of an immediate shock. From the proteins that were differentially regulated between the delayed- and the immediate-shock groups at 4 h, 48 proteins, most prominently representing endocytosis, (amphiphysin, dynamin, and synaptojanin1), glutamate signaling (glutamate [NMDA] receptor subunit epsilon-1, disks large homolog 3), and neurotransmitter metabolism (excitatory amino acid transporter 1, excitatory amino acid transporter 2, sodium- and chloride-dependent GABA transporter 3) were regulated in both protocols, but in opposite directions, pointing toward an interaction of learning and stress. Taken together, this data set yields novel insight into diverse and dynamic changes that take place at hippocampal synapses over the time course of contextual fear-memory learning. PMID- 25708626 TI - Barriers to and Facilitators of a Career as a Physician-Scientist Among Rheumatologists in the US. AB - OBJECTIVE: To determine perceived barriers to and facilitators of a career in rheumatology research, examine factors leading rheumatologists to leave an academic research career, and solicit ways to best support young physician scientists. METHODS: A web-based survey was conducted among the domestic American College of Rheumatology (ACR) membership from January through March 2014. Inclusion criteria were ACR membership and an available e-mail address. Non rheumatologists were excluded. The survey assessed demographics, research participation, barriers to and facilitators of a career in research, reasons for leaving a research career (when applicable), and ways in which the ACR could support junior investigators. Content analysis was used to extract relevant themes. RESULTS: Among 5,448 domestic ACR members, 502 responses were obtained (9.2% response rate). After exclusions (38 incomplete, 2 duplicates, 32 non rheumatologists), 430 responses were analyzed. Participants included fellows, young investigators, established investigators, mentors, clinicians, and those who previously pursued a research career but have chosen a different career path. Funding and mentoring were the most highly ranked barriers and facilitators. Protection from clinical and administrative duties, institutional support, and personal characteristics such as resilience and persistence were also ranked highly. The most commonly cited reasons for leaving an academic research career were difficulty obtaining funding and lack of department or division support. CONCLUSION: This is the first study to examine barriers to and facilitators of a career in rheumatology research from the perspectives of diverse groups of rheumatologists. Knowledge of such barriers and facilitators may assist in designing interventions to support investigators during vulnerable points in their career development. PMID- 25708627 TI - Students' online collaborative intention for group projects: Evidence from an extended version of the theory of planned behaviour. AB - Given the increasing use of web technology for teaching and learning, this study developed and examined an extended version of the theory of planned behaviour (TPB) model, which explained students' intention to collaborate online for their group projects. Results indicated that past experience predicted the three antecedents of intention, while past behaviour was predictive of subjective norm and perceived behavioural control. Moreover, the three antecedents (attitude towards e-collaboration, subjective norm and perceived behavioural control) were found to significantly predict e-collaborative intention. This study explored the use of the "remember" type of awareness (i.e. past experience) and evaluated the value of the "know" type of awareness (i.e. past behaviour) in the TPB model. PMID- 25708628 TI - Biomedical studies by TOF-SIMS imaging. AB - Imaging by secondary ion mass spectrometry coupled to time-of-flight mass analysis (TOF-SIMS) is a method of which the applications have greatly increased since 10 years. Taking advantage of the development of cluster ion sources, TOF SIMS offers images of molecular ions at a micrometer lateral resolution or slightly below and does not require complex sample preparation. Although TOF-SIMS has been primarily dedicated to surface analysis of inorganic or polymeric samples, several groups have successfully demonstrated that TOF-SIMS imaging is also perfectly suited for mapping organic compounds, such as drugs or lipids, directly on tissue sections from animals or from human biopsies. This minireview will enlighten some of these developments in the field of biomedical applications. PMID- 25708629 TI - Synthesis and optimization of fluorescent poly(N-isopropyl acrylamide)-coated surfaces by atom transfer radical polymerization for cell culture and detachment. AB - Although there are many stimulus-responsive polymers, poly(N-isopropyl acrylamide) (pNIPAM) is of special interest due to the phase change it undergoes in a physiologically relevant temperature range that leads to the release of cells and proteins. The nondestructive release of cells opens up a wide range of applications, including the use of pNIPAM for cell sheet and tissue engineering. In this work, pNIPAM surfaces were generated that can be distinguished from the extracellular matrix. A polymerization technique was adapted that was previously used by Mendez, and the existing protocol was optimized for the culture of mammalian cells. The resulting surfaces were characterized with X-ray photoelectron spectroscopy and goniometry. The developed pNIPAM surfaces were further adapted by incorporation of 5-acrylamidofluorescein to generate fluorescent pNIPAM-coated surfaces. Both types of surfaces (fluorescent and nonfluorescent) sustained cellular attachment and produced cellular detachment of ~90%, and are therefore suitable for the generation of cell sheets for engineered tissues and other purposes. These surfaces will be useful tools for experiments investigating cellular detachment from pNIPAM and the pNIPAM/cell interface. PMID- 25708630 TI - Drug delivery and cell interaction of adhesive poly(ethyleneimine)/sulfated polysaccharide complex particle films. AB - Herein, the authors report and review polyelectrolyte complex (PEC) nanoparticles (NPs) loaded with zoledronate (ZOL) and simvastatin and their effects on bone cells. PEC NPs are intended for modification of bone substitute materials. For characterization, they can be solution casted on germanium (Ge) substrates serving as analytically accessible model substrate. PEC NPs were generated by mixing poly(ethyleneimine) (PEI) either with linear cellulose sulfate (CS) or with branched dextransulfate (DS). Four important requirements for drug loaded PEC NPs and their films are addressed herein, which are the colloidal stability of PEC dispersions (1), interfacial stability (2), cytocompatibility (3), and retarded drug release (4). Dynamic light scattering measurements (DLS) showed that both PEI/CS and PEI/DS PEC NP were obtained with hydrodynamic radii in the range of 35-170 nm and were colloidally stable up to several months. Transmission FTIR spectroscopy evidenced that films of both systems were stable in contact to the release medium up to several days. ZOL-loaded PEI/CS nanoparticles, which were immobilized on an osteoblast-derived extracellular matrix, reduced significantly the resorption and the metabolic activity of human monocyte-derived osteoclasts. FTIR spectroscopy at cast PEC/drug films at Ge substrates revealed retarded drug releases in comparison to the pure drug films. PMID- 25708631 TI - Latest applications of 3D ToF-SIMS bio-imaging. AB - Time-of-flight secondary ion mass spectrometry (ToF-SIMS) is a rapidly developing technique for the characterization of a wide range of materials. Recently, advances in instrumentation and sample preparation approaches have provided the ability to perform 3D molecular imaging experiments. Polyatomic ion beams, such as C60, and gas cluster ion beams, often Arn (n = 500-4000), substantially reduce the subsurface damage accumulation associated with continued bombardment of organic samples with atomic beams. In this review, the capabilities of the technique are discussed and examples of the 3D imaging approach for the analysis of model membrane systems, plant single cell, and tissue samples are presented. Ongoing challenges for 3D ToF-SIMS imaging are also discussed along with recent developments that might offer improved 3D imaging prospects in the near future. PMID- 25708633 TI - Mass spectrometric metabolomic imaging of biofilms on corroding steel surfaces using laser ablation and solvent capture by aspiration. AB - Ambient laser ablation and solvent capture by aspiration (LASCA) mass spectrometric imaging was combined with metabolomics high-performance liquid chromatography (HPLC) mass spectrometry analysis and light profilometry to investigate the correlation between chemical composition of marine bacterial biofilms on surfaces of 1018 carbon steel and corrosion damage of steel underneath the biofilms. Pure cultures of Marinobacter sp. or a wild population of bacteria present in coastal seawater served as sources of biofilms. Profilometry data of biofilm-free surfaces demonstrated heterogeneous distributions of corrosion damage. LASCA data were correlated with areas on the coupons varying in the level of corrosion attack, to reveal differences in chemical composition within biofilm regions associated with corroding and corrosion-free zones. Putative identification of selected compounds was carried out based on HPLC results and subsequent database searches. This is the first report of successful ambient chemical and metabolomic imaging of marine biofilms on corroding metallic materials. The metabolic analysis of such biofilms is challenging due to the presence in the biofilm of large amounts of corrosion products. However, by using the LASCA imaging interface, images of more than 1000 ions (potential metabolites) are generated, revealing striking heterogeneities within the biofilm. In the two model systems studied here, it is found that some of the patterns observed in selected ion images closely correlate with the occurrence and extent of corrosion in the carbon steel substrate as revealed by profilometry, while others do not. This approach toward the study of microbially influenced corrosion (MIC) holds great promise for approaching a fundamental understanding of the mechanisms involved in MIC. PMID- 25708632 TI - Experimental characterization of adsorbed protein orientation, conformation, and bioactivity. AB - Protein adsorption on material surfaces is a common phenomenon that is of critical importance in many biotechnological applications. The structure and function of adsorbed proteins are tightly interrelated and play a key role in the communication and interaction of the adsorbed proteins with the surrounding environment. Because the bioactive state of a protein on a surface is a function of the orientation, conformation, and accessibility of its bioactive site(s), the isolated determination of just one or two of these factors will typically not be sufficient to understand the structure-function relationships of the adsorbed layer. Rather a combination of methods is needed to address each of these factors in a synergistic manner to provide a complementary dataset to characterize and understand the bioactive state of adsorbed protein. Over the past several years, the authors have focused on the development of such a set of complementary methods to address this need. These methods include adsorbed-state circular dichroism spectropolarimetry to determine adsorption-induced changes in protein secondary structure, amino-acid labeling/mass spectrometry to assess adsorbed protein orientation and tertiary structure by monitoring adsorption-induced changes in residue solvent accessibility, and bioactivity assays to assess adsorption-induced changes in protein bioactivity. In this paper, the authors describe the methods that they have developed and/or adapted for each of these assays. The authors then provide an example of their application to characterize how adsorption-induced changes in protein structure influence the enzymatic activity of hen egg-white lysozyme on fused silica glass, high density polyethylene, and poly(methyl-methacrylate) as a set of model systems. PMID- 25708634 TI - Nanomechanical properties of the sea-water bacterium Paracoccus seriniphilus--a scanning force microscopy approach. AB - The measurement of force-distance curves on a single bacterium provides a unique opportunity to detect properties such as the turgor pressure under various environmental conditions. Marine bacteria are very interesting candidates for the production of pharmaceuticals, but are only little studied so far. Therefore, the elastic behavior of Paracoccus seriniphilus, an enzyme producing marine organism, is presented in this study. After a careful evaluation of the optimal measurement conditions, the spring constant and the turgor pressure are determined as a function of ionic strength and pH. Whereas the ionic strength changes the turgor pressure passively, the results give a hint that the change to acidic pH increases the turgor pressure by an active mechanism. Furthermore, it could be shown, that P. seriniphilus has adhesive protrusions outside its cell wall. PMID- 25708635 TI - Multivariate ToF-SIMS image analysis of polymer microarrays and protein adsorption. AB - The complexity of hyperspectral time of flight secondary ion mass spectrometry (ToF-SIMS) datasets makes their subsequent analysis and interpretation challenging, and is often an impasse to the identification of trends and differences within large sample-sets. The application of multivariate data analysis has become a routine method to successfully deconvolute and analyze objectively these datasets. The advent of high-resolution large area ToF-SIMS imaging capability has enlarged further the data handling challenges. In this work, a modified multivariate curve resolution image analysis of a polymer microarray containing 70 different poly(meth)acrylate type spots (over a 9.2 * 9.2 mm area) is presented. This analysis distinguished key differences within the polymer library such as the differentiation between acrylate and methacrylate polymers and variance specific to side groups. Partial least squares (PLS) regression analysis was performed to identify correlations between the ToF-SIMS surface chemistry and the protein adsorption. PLS analysis identified a number of chemical moieties correlating with high or low protein adsorption, including ions derived from the polymer backbone and polyethylene glycol side-groups. The retrospective validation of the findings from the PLS analysis was also performed using the secondary ion images for those ions found to significantly contribute to high or low protein adsorption. PMID- 25708636 TI - Surface analysis of zinc-porphyrin functionalized carbon nano-onions. AB - Multishell fullerenes, known as carbon nano-onions (CNOs), are an interesting class of carbon-based nanomaterials. They display several unique properties, such as a large surface area to volume ratio, a low density, and a graphitic multilayer morphology, which have made them appealing for several applications in many fields, including biology. Chemical functionalization of CNOs dramatically enhances their solubility and attenuates their inflammatory properties, thereby increasing their applicability especially in the fields of biology and medicine. CNOs functionalized with fluorescent probes can be used for cellular imaging. In this article, detailed surface characterization of CNOs functionalized with a zinc porphyrin (ZnTPP) as the fluorescent probe is presented. In particular, time of-flight secondary ion mass spectrometry and x-ray photoelectron spectroscopy provide a detailed surface characterization of the organic functionalities introduced via "click chemistry" and clearly demonstrate the success of the CNOs functionalization process. XPS data reveal the presence of Zn and N, whilst ToF SIMS is able to identify specific fragments related to the presence of the ZnTPP, such as the quasimolecular mass peak [C32N4H20Zn](+) and the molecular mass peak [C44N4H28Zn](+). Moreover, ions fragments deriving from the triazole ring formed by the click chemistry reaction have been identified by ToF-SIMS analysis, proving unambiguously the covalent binding of the fluorescent molecules to the CNOs surfaces. PMID- 25708637 TI - Cleaning of titanium substrates after application in a bioreactor. AB - Plain and microstructured cp-titanium samples were studied as possible biofilm reactor substrates. The biofilms were grown by exposition of the titanium samples to bacteria in a flow cell. As bacteria the rod shaped gram negative Pseudomonas fluorescens and the spherical gram negative Paracoccus seriniphilus were chosen. Afterward, the samples were cleaned in subsequent steps: First, with a standard solvent based cleaning procedure with acetone, isopropanol, and ultrapure water and second by oxygen plasma sputtering. It will be demonstrated by means of x-ray photoelectron spectroscopy, fluorescence microscopy, and confocal laser scanning microscopy that oxygen plasma cleaning is a necessary and reliant tool to fully clean and restore titanium surfaces contaminated with a biofilm. The microstructured surfaces act beneficial to biofilm growth, while still being fully restorable after biofilm contamination. Scanning electron microscopy images additionally show, that the plasma process does not affect the microstructures. The presented data show the importance of the cleaning procedure. Just using solvents does not remove the biofilm and all its components reliably while a cleaning process by oxygen plasma regenerates the surfaces. PMID- 25708640 TI - Time of flight secondary ion mass spectrometry surface and in-depth study of degradation of nanosheet poly(L-lactic acid) films. AB - With the advent of novel fabrication technologies, free-standing poly(l-lactic acid) (PLLA) nanosheets have been shown to have enhanced performance over their micro- or macroscale equivalents as tissue engineering and drug delivery constructs. In the present research, the authors investigated the surface degradation behavior of PLLA films as a function of confinement to a quasi-two dimensional structure, and the degradation behavior of nanoscale PLLA films as a function of the initial molecular weight and depth, using time-of-flight secondary ion mass spectrometry. The authors found that nanofilms exhibit less segregation of shorter chains to the surface than microfilms, due to the constrained geometries of these morphologies. It was also concluded that the degradation rate at the surface of nanofilms related to the inverse of the initial molecular weight, as is the case in bulk-scale systems. PMID- 25708639 TI - Full membrane spanning self-assembled monolayers as model systems for UHV-based studies of cell-penetrating peptides. AB - Biophysical studies of the interaction of peptides with model membranes provide a simple yet effective approach to understand the transport of peptides and peptide based drug carriers across the cell membrane. Herein, the authors discuss the use of self-assembled monolayers fabricated from the full membrane-spanning thiol (FMST) 3-((14-((4'-((5-methyl-1-phenyl-35-(phytanyl)oxy 6,9,12,15,18,21,24,27,30,33,37-undecaoxa-2,3-dithiahenpentacontan-51-yl)oxy) [1,1'-biphenyl]-4-yl)oxy)tetradecyl)oxy)-2-(phytanyl)oxy glycerol for ultrahigh vacuum (UHV) based experiments. UHV-based methods such as electron spectroscopy and mass spectrometry can provide important information about how peptides bind and interact with membranes, especially with the hydrophobic core of a lipid bilayer. Near-edge x-ray absorption fine structure spectra and x-ray photoelectron spectroscopy (XPS) data showed that FMST forms UHV-stable and ordered films on gold. XPS and time of flight secondary ion mass spectrometry depth profiles indicated that a proline-rich amphipathic cell-penetrating peptide, known as sweet arrow peptide is located at the outer perimeter of the model membrane. PMID- 25708638 TI - ToF-SIMS of tissues: "lessons learned" from mice and women. AB - The ability to image cells and tissues with chemical and molecular specificity could greatly expand our understanding of biological processes. The subcellular resolution mass spectral imaging capability of time of flight secondary ion mass spectrometry (ToF-SIMS) has the potential to acquire chemically detailed images. However, the complexities of biological systems combined with the sensitivity of ToF-SIMS require careful planning of experimental methods. Tissue sample preparation methods of formalin fixation followed by paraffin embedding (FFPE) and OCT embedding are compared. Results show that the FFPE can potentially be used as a tissue sample preparation protocol for ToF-SIMS analysis if a cluster ion pre-sputter is used prior to analysis and if nonlipid related tissue features are the features of interest. In contrast, embedding tissue in OCT minimizes contamination and maintains lipid signals. Various data acquisition methodologies and analysis options are discussed and compared using mouse breast and diaphragm muscle tissue. Methodologies for acquiring ToF-SIMS 2D images are highlighted along with applications of multivariate analysis to better identify specific features in a tissue sections when compared to H&E images of serial sections. Identification of tissue features is necessary for researchers to visualize a molecular map that correlates with specific biological features or functions. Finally, lessons learned from sample preparation, data acquisition, and data analysis methods developed using mouse models are applied to a preliminary analysis of human breast tumor tissue sections. PMID- 25708641 TI - [Persistent Mullerian ducts syndrome: one case of late hypofertility]. AB - We report the case of a 35-year-old patient with a syndrome of persistent Mullerian ducts (PMDS) of the female type (group A). The diagnosis was made in adulthood during an infertility workup. Clinical examination revealed an empty scrotum, a normal penis and bilateral inguinal cystic masses. The spermogram found azoospermia. Imaging using MRI and tomotensidometry found the presence of an uterus, two fallopian tubes and two inguinal positions of polycystic testes. A surgical management was performed for surgical testicular biopsy. Histological examination then found a cystic formation of multi-celled mesothelial origin, with atrophic testis Sertoli cell involution and without sperm. PMDS is a rare form of pseudo-internal hermaphroditism characterized by the presence in a man of the uterus, fallopian tubes and upper vagina with external male genitalia and virilized characters. About 200 cases are reported in the literature. The diagnosis is often made in children intraoperatively during a cure of testicular ectopia. The karyotype is 46 XY type. The pathogenesis is related to a deficiency of anti-Mullerian hormone (AMH) or tissue resistance to its action by receptor abnormalities. The regression of the Mullerian duct derivatives can give three types of PMDS : masculine type, feminine type and a transverse type. Surgical treatment is difficult but necessary because of the risk of infertility and ectopic testicular degeneration. PMID- 25708642 TI - Low serum factor V level: early predictor of allograft failure and death following liver transplantation. AB - PURPOSE: According to the current criteria, the diagnosis of early allograft dysfunction usually cannot be established before the end of the first week after liver transplantation. Thus, early predictive tests for detecting allograft dysfunction are still warranted to prevent allograft failure. This study was undertaken to assess the role of low serum factor V activity as an early prognostic factor (postoperative day 2) after liver transplantation. METHODS: A retrospective review of all consecutive adult patients who underwent first orthotopic whole-graft liver transplant at our institution between March 2002 and June 2011 was undertaken. Primary endpoint was graft failure within 90 days after transplantation. RESULTS: Of all 105 patients analyzed in this study, 39 (37.1 %) were female and 66 (62.9 %) were male. Mean age was 52.7 +/- 11.7 years, and median follow-up period was 2474 +/- 164 days. There were overall 33 (31.4 %) deaths, 13 of those occurring on the first 90 post-transplant days. Multivariate analysis demonstrated that serum factor V lower than 41.5 % and female gender had a negative impact not only on allograft failure/death within 90 days after transplantation (RR = 5.30, CI = 1.40-20.2, p = 0.015 and RR = 5.23, CI = 1.53 21.33, p = 0.008) but also on overall mortality. For prediction of allograft failure/death occurring during the first 3 months, serum factor V level of 41.5 % or lower exhibited a specificity of 87.9 %, a sensitivity of 42.9 %, an accuracy of 81.9 %, a positive predictive value of 35.3 %, and a negative predictive value of 90.9 %. CONCLUSIONS: Assessment of serum factor V levels on postoperative day 2 might be a promising prognostic tool for early prediction of inferior outcomes after liver transplantation. PMID- 25708643 TI - Emergency Department Use in the US-Mexico Border Region and Violence in Mexico: Is There a Relationship? AB - PURPOSE: This study assessed the association between homicide rates in northern Mexico and potentially avoidable use of emergency departments (ED) in the US Mexico border region. The border region is largely rural and underserved, making the identification and correction of potential barriers to access crucial. METHODS: We used secondary data from state inpatient and ED discharge databases for California and Arizona for 2005-2010. A retrospective observational analysis using generalized linear models was used to determine whether the probability that an ED encounter was potentially avoidable was associated with homicide rates in the nearest Mexican municipality. To conduct the analysis, the location of ED encounters were identified and matched with homicide rates in the nearest Mexican municipality and regional characteristics. The probability that an ED encounter was potentially avoidable was calculated using the Billings ED algorithm. FINDINGS: We found that 77% of ED encounters were potentially avoidable, with a higher percentage in border counties. There was no statistically significant relationship between homicide rates and the probability that an ED encounter was for a potentially avoidable condition for the full analytic sample (n = 24,859,273) and the uninsured and underinsured in the sample (n = 11,700,123). CONCLUSION: A substantial majority of ED encounters in the US-Mexico border region were potentially avoidable. However, there was not a strong relationship between homicide rates in northern Mexico and the distribution of ED discharges in Arizona and California. Given the large percentage of potentially avoidable ED encounters and the ongoing violence in Mexico, continuing to monitor this relationship is important. PMID- 25708645 TI - Osteoprotegerin protects against muscular dystrophy. AB - Receptor-activator of NF-kappaB, its ligand RANKL, and the soluble decoy receptor osteoprotegerin are the key regulators of osteoclast differentiation and bone remodeling. Although there is a strong association between osteoporosis and skeletal muscle atrophy/dysfunction, the functional relevance of a particular biological pathway that synchronously regulates bone and skeletal muscle physiopathology still is elusive. Here, we show that muscle cells can produce and secrete osteoprotegerin and pharmacologic treatment of dystrophic mdx mice with recombinant osteoprotegerin muscles. (Recombinant osteoprotegerin-Fc mitigates the loss of muscle force in a dose-dependent manner and preserves muscle integrity, particularly in fast-twitch extensor digitorum longus.) Our data identify osteoprotegerin as a novel protector of muscle integrity, and it potentially represents a new therapeutic avenue for both muscular diseases and osteoporosis. PMID- 25708646 TI - Metagenomic characterization of viral communities in corals: mining biological signal from methodological noise. AB - Reef-building corals form close associations with organisms from all three domains of life and therefore have many potential viral hosts. Yet knowledge of viral communities associated with corals is barely explored. This complexity presents a number of challenges in terms of the metagenomic assessments of coral viral communities and requires specialized methods for purification and amplification of viral nucleic acids, as well as virome annotation. In this minireview, we conduct a meta-analysis of the limited number of existing coral virome studies, as well as available coral transcriptome and metagenome data, to identify trends and potential complications inherent in different methods. The analysis shows that the method used for viral nucleic acid isolation drastically affects the observed viral assemblage and interpretation of the results. Further, the small number of viral reference genomes available, coupled with short sequence read lengths might cause errors in virus identification. Despite these limitations and potential biases, the data show that viral communities associated with corals are diverse, with double- and single-stranded DNA and RNA viruses. The identified viruses are dominated by double-stranded DNA-tailed bacteriophages, but there are also viruses that infect eukaryote hosts, likely the endosymbiotic dinoflagellates, Symbiodinium spp., host coral and other eukaryotes in close association. PMID- 25708647 TI - A case of neonatal linear IgA bullous dermatosis with severe eye involvement. PMID- 25708648 TI - Osteoporotic fracture rate among women with at least 1 year of adherence to osteoporosis treatment. AB - PURPOSE: In clinical trials, bisphosphonate therapy reduces but does not eliminate the risk of fracture. The objective of this retrospective observational study was to examine fracture rates among women who were adherent to bisphosphonate therapy for at least 1 year. METHODS: We studied outcomes for women >=50 years old who received their first osteoporosis therapy as an oral bisphosphonate during 2002-2008 and were enrolled in a large claims database for >=3 consecutive years, including a baseline year before and 2 years after the index prescription (thus, the full study period was 2001-2010). Adherence during the first year of therapy was defined as a medication possession ratio (MPR) >=80% (total number of days' supply/365 days * 100%). RESULTS: Of the 62,446 women who met the eligibility criteria, 26,852 (43%) had an MPR >=80% for osteoporosis therapy during year 1. In year 2, the fracture rate was 52/1000 patient-years. Fragility fractures were recorded for 1292 patients (4.8%) during the baseline year (before initiating therapy); for 1051 patients (3.9%) during year 1 (adherence year); and for 871 patients (3.2%) during year 2. Significant predictors of fracture in year 2 were older age, higher comorbidity score, comorbid inflammatory joint disease, and prior fragility fracture during the baseline year or first year of treatment. The primary limitation of these results is the scope of the claims database, which did not provide information on bone mineral density, supplemental use of calcium or vitamin D, or reasons for initiating oral bisphosphonates. CONCLUSIONS: Despite being adherent to bisphosphonate treatment for 1 year, 3.2% of women experienced a fracture in the subsequent year. These results suggest an unmet need in patients with osteoporosis and an opportunity for newer therapies to help address this need. PMID- 25708649 TI - Inbreeding effects on reproductive traits in Iranian Guilan sheep. AB - The objective of the present study was to evaluate the effects of inbreeding on reproductive traits in Guilan sheep. Traits included were litter size at birth (LSB), litter size at weaning (LSW), litter mean weight per lamb born (LMWLB), litter mean weight per lamb weaned (LMWLW), total litter weight at birth (TLWB), and total litter weight at weaning (TLWW). Data and pedigree information used in this study were collected during 1994 to 2011 by the Agriculture Organization of Guilan Province in the north of Iran. Data were comprised of 14,534 records of lambs from 136 sires and 2021 dams. All the animals were grouped into three classes according to the inbreeding coefficients (F) obtained by their pedigree: the first class included non-inbred animals (F = 0%), and the second and third classes included inbred animals (0 < F <= 5% and F > 5%, respectively). The regression coefficients of LSB, LSW, LMWLB, LMWLW, TLWB, and TLWW on lamb inbreeding for a change of 1% in inbreeding were estimated to be 0.035 +/- 0.0038 (P < 0.001), -0.029 +/- 0.0077 (P < 0.05), -0.333 +/- 0.009 (P < 0.001), -2.21 +/ 0.071 (P < 0.001), -0.254 +/- 0.013 (P < 0.001), and -1.95 +/- 0.093 (P < 0.001), respectively. Effect of inbreeding on reproductive traits in Guilan sheep was very pronounced in the flock. The utilization of a program for planned mating system, in the present flock, suggested keeping the level of inbreeding under control and avoiding appearance of its detrimental effects. PMID- 25708650 TI - Psychometric properties of the Turkish version of the Sleep Hygiene Index in clinical and non-clinical samples. AB - OBJECTIVE: Sleep is one of the most significant of human behaviors, occupying roughly one third of human life. Sleep is a process the brain requires for proper functioning. Sleep hygiene can be described as practices to ease sleep and to avoid factors which decrease sleep quality. Inadequate sleep hygiene generally results in disturbance of daily life activities due to inability to sustain sleep quality and daytime wakefulness. Therefore, the importance of development and utilization of measures of sleep hygiene increases. The aim of the study was to assess psychometric properties of the Sleep Hygiene Index (SHI) in clinical and non-clinical Turkish samples. METHOD: Data were collected from 106 patients with major depression consecutively admitted to the psychiatry clinic of Yuzuncu Yil University School of Medicine and 200 were volunteers recruited from community sample who were enrolled at the university. The SHI, Pittsburgh Sleep Quality Index (PSQI), Insomnia Severity Index (ISI) and Epworth Sleepiness Scale (ESS) were administered to the subjects. Factor structure of the SHI was evaluated with explanatory and multi-sample confirmatory factor analyses. Pearson product-moment correlation coefficients of the SHI with the PSQI, ISI and ESS were computed. Item analyses, internal consistency coefficients and intra-class correlations between two repeated applications in both patient and healthy subjects were calculated. RESULTS: The SHI revealed a unidimensional factor structure. Significant strong partial associations of the SHI with depression, insomnia and poor sleep quality and a modest partial association with sleepiness were detected. Cronbach's alphas for the SHI in community sample and patients with major depression were 0.70 and 0.71, respectively. Additionally, we found acceptable three-week temporal reliability in terms of intra-correlation coefficients of r=0.62, p<0.01 for the community sample and of r=0.67, p<0.01 among patients with major depression. CONCLUSION: The SHI revealed adequate validity and reliability to be used by researchers in Turkish sample. Current results were discussed in light of previous findings and theoretical considerations. PMID- 25708651 TI - Genome-wide microarray analysis of gene expression profiling in major depression and antidepressant therapy. AB - Major depressive disorder (MDD) is a serious health concern worldwide. Currently there are no predictive tests for the effectiveness of any particular antidepressant in an individual patient. Thus, doctors must prescribe antidepressants based on educated guesses. With the recent advent of scientific research, genome-wide gene expression microarray studies are widely utilized to analyze hundreds of thousands of biomarkers by high-throughput technologies. In addition to the candidate-gene approach, the genome-wide approach has recently been employed to investigate the determinants of MDD as well as antidepressant response to therapy. In this review, we mainly focused on gene expression studies with genome-wide approaches using RNA derived from peripheral blood cells. Furthermore, we reviewed their limitations and future directions with respect to the genome-wide gene expression profiling in MDD pathogenesis as well as in antidepressant therapy. PMID- 25708652 TI - ERK1/2: Function, signaling and implication in pain and pain-related anxio depressive disorders. AB - Despite the increasing knowledge regarding pain modulation, the understanding of the mechanisms behind a complex and pathologic chronic pain condition is still insufficient. These knowledge gaps might result in ineffective therapeutic approaches to relieve painful sensations. As a result, severe untreated chronic pain frequently triggers the onset of new disorders such as depression and/or anxiety, and therefore, both the diagnosis and treatment of patients suffering from chronic pain become seriously compromised, prompting a self-perpetuating cycle of symptomatology. The extracellular signal-regulated kinases 1 and 2 (ERK1/2) are molecules strongly implicated in the somatic component of pain at the spinal cord level and have been emerging as mediators of the emotional affective component as well. Although these molecules might represent good biomarkers, their use as pharmacological targets is still open to discussion as paradoxical information has been obtained. Here we review the current scientific literature regarding ERK1/2 signaling in the modulation of pain, depression and anxiety, including the emotional-affective spheres of the pain experience. PMID- 25708654 TI - Usefulness of High-Frequency Ultrasound in the Diagnosis of Piezogenic Pedal Papules. PMID- 25708653 TI - Can atopic dermatitis be prevented? AB - Atopic dermatitis has become a health problem in our setting due to its rising prevalence, impact on quality of life, associated costs, and role in the progression to other atopic diseases. Furthermore, atopic dermatitis has no definitive cure and therefore preventive measures are important. In this article, we review the latest advances in both primary prevention (reduction of the incidence of atopic dermatitis) and secondary prevention (reduction of associated morbidity and reduction of the atopic march). We analyze the different preventive strategies available, including modification of the immune system through microbial exposure, induction of immune tolerance through antigen exposure, and restoration of skin barrier function to halt the atopic march. Dermatologists need to be familiar with these strategies in order to apply them where necessary and to accurately inform patients and their relatives to prevent misguided or inappropriate actions. PMID- 25708655 TI - Telepsychiatry for Neurocognitive Testing in Older Rural Latino Adults. AB - As the population of older Latinos in the U.S. increases, availability of culturally adapted geriatric psychiatry services is becoming a growing concern. This issue is exacerbated for rural Latino populations. In this study, we assessed whether neurocognitive assessment via telepsychiatry (TP) using a Spanish-language battery would be comparable to in-person (IP) testing using the same battery in a sample of Spanish-speaking older adults in a rural setting. Patients (N = 22) received IP and TP testing 2 weeks apart. The order of IP and TP test administrations in individual subjects was determined randomly. Comparison of scores indicated that there were no significant differences between IP and TP test performance though both groups scored non-significantly higher at the second visit. This study demonstrates feasibility and utility of neurocognitive testing in Spanish using TP among older rural Latinos. PMID- 25708656 TI - Melittin has a chondroprotective effect by inhibiting MMP-1 and MMP-8 expressions via blocking NF-kappaB and AP-1 signaling pathway in chondrocytes. AB - Bee venom is a natural ingredient produced by the honey bee (Apis mellifera), and has been widely used in China, Korea and Japan as a traditional medicine for various diseases such as arthritis, rheumatism, and skin diseases However, the regulation of the underlying molecular mechanisms of the anti-arthritis by bee venom and its major peptides is largely unknown. In this study, we investigated the potential molecular mechanisms underlying the anti-arthritis effect of bee venom and its major peptides, melittin and apamin, in tumor necrosis factor-alpha (TNF-alpha) responsive C57BL/6 mice chondrocyte cells. The bee venom and melittin significantly and selectively suppressed the TNF-alpha-mediated decrease of type II collagen expression, whereas the apamin had no effects on the type II collagen expression. We, furthermore, found that the bee venom and melittin inhibited the protein expression of matrix metalloproteinase (MMP)-1 and MMP-8, which suggests that the chondroprotective effect of bee venom may be caused by melittin. The inhibitory effects of melittin on the TNF-alpha-induced MMP-1 and MMP-8 protein expression were regulated by the inhibition of NF-kB and AP-1. In addition, melittin suppressed the TNF-alpha-induced phosphorylation of Akt, JNK and ERK1/2, but did not affect the phosphorylation of p38 kinase. These results suggest that melittin suppresses TNF-alpha-stimulated decrease of type II collagen expression by the inhibiting MMP-1 and MMP-8 through regulation of the NF-kB and AP-1 pathway and provision of a novel role for melittin in anti-arthritis action. PMID- 25708657 TI - Foxp3 gene polymorphisms and haplotypes associate with susceptibility of Graves' disease in Chinese Han population. AB - BACKGROUND: Foxp3 plays important roles in the pathogenesis of autoimmune diseases. To investigate the association between Foxp3 gene polymorphisms and the susceptibility to Graves' disease (GD) in Chinese Han population, four single nucleotide polymorphisms (SNPs) including -2383, -3279, -3499 in the promoter and IVS9+459 in the intron were genotyped. METHODS: Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 308 GD patients and 306 healthy controls. The relative expression level of Foxp3 gene was measured by qRT-PCR. RESULTS: The frequencies of AA/CA genotype of -3279 and CC genotype of IVS9+459 were significantly higher in GD patients than healthy controls. The AA/CA genotype of -3279 in female GD patients was more frequent than the male. For -3279, GD patients with higher TSH level or/and lower TRAb level were more frequent to carry A allele. We further analyzed the haplotypes of three SNPs and found that the haplotype CCA played a protective role in the susceptibility to GD. In contrast, the CAA and TCA haplotypes were associated with an increased susceptibility to GD. In addition, the mutation from C to A at the position of -3279 reduced the relative luciferase activity of Foxp3 promoter and decreased the expression of Foxp3 in GD patients. CONCLUSION: Our findings indicated that Foxp3 functional polymorphisms and haplotypes in promoter were associated with the susceptibility to GD in Chinese Han population. PMID- 25708658 TI - Highly conductive all-plastic electrodes fabricated using a novel chemically controlled transfer-printing method. AB - A novel transfer-printing method for high-performance all-plastic transparent electrodes is demonstrated. A solution process using H2 SO4 not only dramatically enhances the electrical conductivity of poly(3,4-ethylenedioxythiophene):poly(4 styrenesulfonate) (PEDOT:PSS) over 4000 S cm(-1) but also chemically modifies its adhesion properties, thereby enabling expeditious "pick-and-place" transfer onto arbitrary surfaces using elastomeric stamps. Flexible and transparent optoelectronic devices with transferred PEDOT:PSS electrodes show superb performances. PMID- 25708660 TI - Comprehensive Geriatric Assessment and predicted 3-year survival in treatment planning for frail patients with early breast cancer. AB - BACKGROUND: Endocrine therapy alone has been a popular treatment for oestrogen receptor-positive breast cancer in elderly patients, although it may be inadequate in those surviving more than 2-3 years. The aim of this study was to estimate 3-year survival in frail patients with early breast cancer, to inform treatment decisions. METHODS: A risk score was created to estimate 3-year survival in individual patients using data from patients who had Comprehensive Geriatric Assessment (CGA) in a specialist clinic before decisions about their breast cancer treatment were made. The data were analysed using logistic regression. RESULTS: Ninety-seven (29.6 per cent) of the 328 patients had died by 3 years. Four components of the assessment proved strongly associated with survival: Mini Mental State Examination, Barthel Index of Activities of Daily Living, instrumental Activities of Daily Living and American Association of Anesthesiologists fitness grade. The derived CGA risk score gave an adequate level of discrimination and calibration, with an area under the receiver operating characteristic (ROC) curve of 0.75 (95 per cent c.i. 0.67 to 0.82) (Hosmer-Lemeshow statistic chi(2) = 7.9, P = 0.448). CONCLUSION: Detailed assessment can allow prediction of survival probability in frail elderly patients. Good scores indicate good survival prospects and a likely benefit from surgery; poor scores are associated with reduced survival, although with wide variation. CGA is recommended before making decisions on best treatment. PMID- 25708661 TI - Low-grade fibromyxoid sarcoma of the sigmoid colon. AB - Low-grade fibromyxoid sarcoma (LGFMS) is a rare soft tissue tumor with a slight male predominance. The tumor has a tendency to arise from deep soft tissue of the trunk and lower extremities. Rare cases are reported to arise from the mediastinal and retroperitoneal areas. Its deceptively bland histologic appearance makes this tumor difficult to diagnose. Also, there are several histologic mimics that may hinder in its diagnosis. We report a case of low-grade fibromyxoid sarcoma from a 48-year-old woman, first documented herein to arise from the sigmoid. We also report the value of CD99, BCL2 and MUC4 stains in the diagnosis of this tumor. PMID- 25708662 TI - Genome-wide association data classification and SNPs selection using two-stage quality-based Random Forests. AB - BACKGROUND: Single-nucleotide polymorphisms (SNPs) selection and identification are the most important tasks in Genome-wide association data analysis. The problem is difficult because genome-wide association data is very high dimensional and a large portion of SNPs in the data is irrelevant to the disease. Advanced machine learning methods have been successfully used in Genome-wide association studies (GWAS) for identification of genetic variants that have relatively big effects in some common, complex diseases. Among them, the most successful one is Random Forests (RF). Despite of performing well in terms of prediction accuracy in some data sets with moderate size, RF still suffers from working in GWAS for selecting informative SNPs and building accurate prediction models. In this paper, we propose to use a new two-stage quality-based sampling method in random forests, named ts-RF, for SNP subspace selection for GWAS. The method first applies p-value assessment to find a cut-off point that separates informative and irrelevant SNPs in two groups. The informative SNPs group is further divided into two sub-groups: highly informative and weak informative SNPs. When sampling the SNP subspace for building trees for the forest, only those SNPs from the two sub-groups are taken into account. The feature subspaces always contain highly informative SNPs when used to split a node at a tree. RESULTS: This approach enables one to generate more accurate trees with a lower prediction error, meanwhile possibly avoiding overfitting. It allows one to detect interactions of multiple SNPs with the diseases, and to reduce the dimensionality and the amount of Genome-wide association data needed for learning the RF model. Extensive experiments on two genome-wide SNP data sets (Parkinson case-control data comprised of 408,803 SNPs and Alzheimer case-control data comprised of 380,157 SNPs) and 10 gene data sets have demonstrated that the proposed model significantly reduced prediction errors and outperformed most existing the-state-of-the-art random forests. The top 25 SNPs in Parkinson data set were identified by the proposed model including four interesting genes associated with neurological disorders. CONCLUSION: The presented approach has shown to be effective in selecting informative sub-groups of SNPs potentially associated with diseases that traditional statistical approaches might fail. The new RF works well for the data where the number of case-control objects is much smaller than the number of SNPs, which is a typical problem in gene data and GWAS. Experiment results demonstrated the effectiveness of the proposed RF model that outperformed the state-of-the-art RFs, including Breiman's RF, GRRF and wsRF methods. PMID- 25708663 TI - Intravitreal triamcinolone acetonide, retinal microglia and retinal ganglion cell apoptosis in the optic nerve crush model. AB - PURPOSE: To evaluate the effect of intravitreal triamcinolone acetonide (TA) on the activation of retinal microglia cells (RMGCs) and survival of retinal ganglion cells (RGCs) in an optic nerve crush (ONC) model. METHODS: Adult female Sprague-Dawley rats underwent a standardized ONC and either received an intravitreal injection of TA (TA group) or of phosphate-buffered saline (PBS, PBS group) in the right eyes. At 1, 3, 7, 14 and 28 days after the ONC, the animals were killed. The retinas were examined by immunohistochemistry, light microscopy, Western blot or retrograde labelling of RGCs by fluorogold injected into the superior colliculi. RESULTS: The TA group as compared to the PBS control group showed a significantly (p < 0.0001) lower density of activated RMGCs, at 14 days [4.2 +/- 1.6 versus 9.3 +/- 2.2 cells/high-power microscopic field (HPF)] and at 28 days (2.3 +/- 1.1 versus 4.4 +/- 1.5 cells/HPF), and with a significantly lower expression of inflammatory factors. Central density of RGCs as stained by haematoxylin-eosin or by fluorogold was significantly (all p < 0.05) more reduced in the PBS group than in the TA group at days 14 and 28 after baseline. The survival rate (cell density in the study eye as compared to cell density in the contralateral unaffected eye) was significantly higher in the TA group than in the PBS group on days 14 (58% versus 45%; p = 0.003) and 28 (52% versus 41%; p = 0.022). CONCLUSIONS: Intravitreal TA as compared to intravitreal PBS was associated with a lower density of activated RMGCs and a higher density of surviving RGCs in an ONC model. PMID- 25708664 TI - The effects of repeated filling cystometries on cystometric variables in spinal cord-injured patients with overactive detrusor, who utilize different type of urine drainage methods. AB - STUDY DESIGN: Cross-sectional study. OBJECTIVES: Our aim was to compare the effects of repeated cystometric measurements in spinal cord injury (SCI) patients with neurogenic detrusor overactivity (NDO) who use indwelling catheters (IDC) or intermittent catheterization (IC). SETTING: Turkey. METHODS: A total of 20 SCI patients with NDO, 9 patients on IC and 11 on IDC for at least two consecutive months were included. After emptying the bladder, first involuntary detrusor contraction volume (1stIDCV), cystometric bladder capacity (CC), bladder compliance and maximum detrusor pressure (MPdet) were assessed by filling it with sterile physiological saline at room temperature at a continuous rate of 30 ml min(-1). The bladder was re-emptied after the process and a second filling cystometry was performed in the same way. RESULTS: When all study population were taken into account, 1stIDCV and CC measures were significantly increased in the second cystometry compared with the first cystometry (P=0.001 and P=0.022, respectively), whereas there was no statistically significant difference on bladder compliance and MPdet measures between the first and the repeated cystometry. There was no statistically significant difference on 1stIDCV, CC and bladder compliance measures between the first and the repeated cystometries for IC group, whereas there was statistically significant increase on these measures in the IDC group (P=0.003, P=0.008 and P=0.022, respectively). In addition there was no statistically significant difference on MP(det) measures between the first and the repeated cystometries for both the urine drainage methods. When IC and IDC groups were compared according to mean values of differences in 1stIDCV, CC and bladder compliance measures between the two cystometries, the IDC group had a statistically significant increase in all parameters when compared with the IC group in the second cystometry performed (P=0.001, P=0.003 and P=0.048, respectively). CONCLUSION: Repeated cystometric measurements in SCI patients with NDO lead to an increase in 1stIDCV and CC. However, when the type of urine drainage method is taken into account, although repeated filling cystometry leads to an increase in 1stIDCV, MCC and bladder compliance in patients with IDC, it does not cause a difference in patients on IC. PMID- 25708665 TI - Use of complementary and alternative medicine in persons with spinal cord injury in Switzerland: a survey study. AB - STUDY DESIGN: Questionnaire-based survey study. OBJECTIVES: To evaluate the use of and the satisfaction with complementary and alternative medicine (CAM) techniques in patients with spinal cord injury (SCI). SETTING: Rehabilitation Center, Switzerland. METHODS: Between May and September 2014, all patients with chronic (>1 year) SCI attending the urologic outpatient clinic were asked to fill in a questionnaire regarding the use of CAM. RESULTS: Of the 103 participants (66 men and 37 women), 73.8% stated that they have used some form of CAM since SCI, with acupuncture and homeopathy being the two techniques that were used most frequently (31% each). The most common indications for CAM use were pain and urinary tract infections (UTIs). CAM was used supplementarily rather than exclusively. Overall satisfaction (85.1%) as well as satisfaction rates for the different indications (pain: 85%; UTI: 90.5%) and for the most frequently used forms of CAM (homeopathy: 90.6%; acupuncture: 78.1%) were high. CONCLUSION: According to our data, there is a demand for adjunctive CAM procedures for the treatment of medical complications by persons with SCI. CAM led to high satisfaction levels. On the basis of these results, future research should systematically evaluate the therapeutic potential of the most popular CAM techniques, for example, acupuncture and homeopathy, for the treatment of secondary medical complications of SCI. PMID- 25708666 TI - Factors predicting resilience in people with spinal cord injury during transition from inpatient rehabilitation to the community. AB - STUDY DESIGN: This is a longitudinal design study. OBJECTIVES: The objective of this study was to determine factors that predict resilience in people with spinal cord injury (SCI) at discharge from inpatient rehabilitation and after reintegration into the community 6 months post discharge. SETTING: This study was conducted in SCI rehabilitation units and the community in New South Wales, Australia. METHODS: Participants included 88 adults with SCI admitted over almost 3 years into three SCI Units in Sydney. Standardized self-report and clinician based measures were used. Longitudinal assessment occurred up to 6 months post discharge. Sociodemographic, injury and psychological variables were assessed at admission, before discharge and 6 months post discharge. Standard multiple regression was used to determine factors that predict resilience at discharge from hospital and 6 months post discharge. RESULTS: Almost 70% of the participants were classified as resilient at discharge and 66% after 6 months of living in the community. Multiple factors significantly predicted resilience at discharge and 6 months post discharge, including self-efficacy, low levels of negative mood and lower functional independence, whereas social support and low severity of secondary conditions trended to significance. Demographic and injury variables did not contribute significantly. CONCLUSION: Self-efficacy and low levels of negative mood states strongly contribute to resilience. The determination of these predictors will assist in improving rehabilitation programs to strengthen the resilience of people with SCI. However, given that 40 44% of the variance in resilience was explained by the group of factors entered, future longitudinal research is needed to determine not only whether resilience correlates but also whether these associations change over time. PMID- 25708667 TI - Maruyama's allelic age revised by whole-genome GEMA simulations. AB - In 1974, Takeo Maruyama deduced that neutral mutations should, on average, be older than deleterious or beneficial ones. This theory is based on the diffusion approximation for a branching process, which considers mutations independently of one another and not as multiple groups of interconnected mutations with strong linkage disequilibrium (haplotypes). However, mammalian genomes contain thousands of haplotypes, in which beneficial, neutral, and deleterious mutations are tightly linked to each other. This complex haplotype organization should not be ignored for estimation of allelic ages. We employed our GEMA computer simulation program for genome evolution to re-evaluate Maruyama's phenomenon in modeled populations that include haplotypes approximating real genomes. We determined that only under specific conditions (high recombination rates and abundance of neutral mutations), the deleterious and beneficial mutations are younger than neutral ones as predicted by Maruyama. Under other conditions, the ages of negative, neutral, and beneficial mutations were almost the same. PMID- 25708668 TI - Pathological features of preclinical or early clinical stages of corticobasal degeneration: a comparison with advanced cases. AB - AIMS: The manner in which pathological lesions of corticobasal degeneration (CBD) progress remains poorly understood. Because the pathology of early disease stages may be fundamental for elucidating a border between clinical and preclinical states of CBD, the present study aimed to detect preclinical or early clinical CBD cases by examining a series of forensic autopsy cases. METHODS: A series of 887 brains from medicolegal autopsies was examined. Immunohistochemistry for tau (AT8, 3, and 4-repeat-tau) and Gallyas-Braak was applied for diagnosis. Neuropathological diagnosis of CBD followed criteria updated in 2002 by a working group. RESULTS: Three autopsy cases (0.34%) were identified that fulfilled CBD pathological criteria. Two cases were preclinical or very early clinical cases without brain atrophy; the other case had exhibited a 5-year history of advanced frontotemporal dementia. Significant microscopic differences between the subclinical and clinical cases included occurrence of neuronal loss with spongiosis and gliosis, as well as a difference in degree of tau pathology in the superficial layer of the neocortical areas and white matter. Anatomical hierarchy of tau pathology in the brain was not evident, but asymmetric neocortical tau pathology that might influence the clinical phenotype was found in preclinical and early clinical cases. CONCLUSIONS: The results revealed the pathological features of subclinical and early clinical CBD cases. Comparison with clinical CBD cases showed that neuronal loss, cortical atrophy and volume reduction of white matter may be involved in the occurrence of clinical symptoms of CBD. Additionally, immunohistochemistry is essential for detecting preclinical CBD cases, regardless of case selection. PMID- 25708669 TI - Sex-discordant monochorionic twins with blood and tissue chimerism. AB - We report on a pair of normally conceived monochorionic/dizygotic (MC/DZ) sex discordant twins. The comparison of blood and skin genotypes revealed that the chimerism was also present in the skin. We conjecture about the developmental origins of this case. PMID- 25708670 TI - Ropivacaine plasma levels following high-dose local infiltration analgesia for total knee arthroplasty. AB - We measured total and free plasma concentrations of ropivacaine following high volume, high-dose local infiltration analgesia in 28 patients aged 65 years or over undergoing unilateral total knee arthroplasty. Patients received infiltration of ropivacaine 400 mg followed by infusion at 20 mg.h(-1) through an intra-articular catheter. Total and free plasma levels of ropivacaine were measured at specified time intervals during a 24-h period after tourniquet release. Patients were monitored for symptoms and signs of local anaesthetic toxicity. Total levels of plasma ropivacaine varied from 0.147 to 3.093 MUg.ml( 1) (mean (SD) 1.105 (0.518) MUg.ml(-1) ). Free levels of plasma ropivaca-ine varied from 0.001 to 0.104 MUg.ml(-1) (mean (SD) 0.037 (0.020) MUg.ml(-1) ). Six samples had total plasma ropivacaine levels greater the toxic threshold of 2.2 MUg.ml(-1) . No samples reached the toxic threshold for free venous ropivacaine concentration. We conclude that the use of high-dose ropivacaine infiltration and catheter infusion for total knee arthroplasty in an elderly population does not result in free plasma ropivacaine levels previously associated with toxicity but that raised total plasma levels may be observed. PMID- 25708671 TI - Bacterial-resistance among outpatients of county hospitals in China: significant geographic distinctions and minor differences between central cities. AB - The purpose of this study was to survey antibacterial resistance in outpatients of Chinese county hospitals. A total of 31 county hospitals were selected and samples continuously collected from August 2010 to August 2011. Drug sensitivity testing was conducted in a central laboratory. A total of 2946 unique isolates were collected, including 634 strains of Escherichia coli, 606 Klebsiella pneumoniae, 476 Staphylococcus aureus, 308 Streptococcus pneumoniae, and 160 Haemophilus influenzae. Extended-spectrum beta-lactamases were detected in E. coli (42.3% strains), K. pneumoniae (31.7%), and Proteus mirabilis (39.0%). Ciprofloxacin-resistance was detected in 51.0% of E. coli strains. Salmonella spp. and Shigella spp. were sensitive to most antibacterial agents. Less than 8.0% of Pseudomonas aeruginosa isolates were resistant to carbapenem. For S. aureus strains, 15.3% were resistant to methicillin, and some strains of S. pneumoniae showed resistance to penicillin (1.6%), ceftriaxone (13.0%), and erythromycin (96.4%). beta-lactamase was produced by 96.5% of Moraxella catarrhalis strains, and 36.2% of H. influenzae isolates were resistant to ampicillin. Azithromycin-resistant H. influenzae, imipenem-resistant but meropenem-sensitive Proteus, and ceftriaxone- and carbapenem non-sensitive M. catarrhalis were recorded. In conclusion, cephalosporin- and quinolone-resistant strains of E. coli and Klebsiella pneumonia and macrolide-resistant Gram-positive cocci were relatively prominent in county hospitals. The antibacterial resistance profiles of isolates from different geographical locations varied significantly, with proportions in county hospitals lower than those in their tertiary counterparts in the central cities, although the difference is diminishing. PMID- 25708672 TI - Photoplethysmography variability as an alternative approach to obtain heart rate variability information in chronic pain patient. AB - Heart rate variability (HRV) is a well-known method for the assessment of autonomic nervous function of the heart. Previous study suggested that pulse rate variability (PRV) determined by photoplethysmography could be used instead of HRV to more simply assess autonomic nervous function. However, most research studies included healthy subjects. Thus, the aim of this study was to investigate the feasibility for PRV as a surrogate index for patients with chronic pain. This study investigated the correlation coefficient (by Pearson correlation) and agreement (by Bland-Altman analysis) between PRV and HRV in chronic pain patients in the clinical setting. The results showed high significant correlations (p < 0.001, r > 0.86) between all the HRV and PRV parameters and good agreements (ratio < 0.1) between the parameters in terms of HR, mean RR, VLF, LF, nLF, nHF, and SD1/SD2. Our study suggests that HRV can also be reliably estimated using the photoplethysmography-based PP interval in elderly patients with chronic pain. PMID- 25708673 TI - Behavioral treatments for migraine management: useful at each step of migraine care. AB - Migraine is a disabling and prevalent disorder. Migraine is most effectively treated with a stepped care approach, where patients initially receive a broad level of care (primary care) and proceed to receive increasingly specialized care throughout the course of treatment. Behavioral treatments for migraine modify behaviors of people with migraine with the intention to prevent migraine episodes and secondary consequence of migraine. Behavioral treatments can be incorporated into each level of the stepped care approach for migraine treatment. In this article, we provide a rationale for including behavioral treatment strategies in the treatment of migraine. We then describe and review the evidence for behavioral treatment strategies for migraine, including patient education, relaxation strategies, biofeedback, and cognitive behavioral treatment strategies. Finally, we describe how behavioral treatments can be integrated into a stepped care approach for migraine care. PMID- 25708674 TI - Dietary interventions to lower the risk of stroke. AB - Stroke is a major cause of death and permanent disability in the USA; primary prevention and risk reduction are a critical health concern. A wealth of research investigated stroke risk factors, including primary hypertension, diabetes, and atrial fibrillation. Research has expanded to examine lifestyle factors, such as diet/dietary patterns, physical activity, cigarette smoking, and obesity distribution, as critical modifiable risk factors. Emerging evidence suggests diet/dietary patterns may lead to heightened risk of stroke. Despite a growing literature, research has yet to implement dietary interventions to explore this relationship within a US sample. This review discusses available clinical research findings reporting on the relationship among diet/dietary patterns, cardiovascular disease, and risk of stroke. We will assess challenges, limitations, and controversies, and address future research directions. PMID- 25708675 TI - The melt-recrystallization behavior of highly oriented alpha-iPP fibers embedded in a HIPS matrix. AB - The melt-recrystallization behavior of alpha-iPP fibers embedded in an amorphous HIPS matrix has been studied by means of optical microscopy. The amorphous HIPS serving as a supporter of iPP fibers does not become involved in the nucleation and crystallization process of the molten highly oriented iPP fibers. It also does not provide any birefringence under the optical microscope with crossed polarizers. This enables the study of orientation-induced beta-iPP crystallization through a control of the melting status of the fibers. Through melting the fibers at different temperatures above 175 degrees C and subsequent recrystallization, some beta-iPP crystals were always produced. The content of the beta-iPP crystal depends strongly on the melting temperature and melting time of the iPP fibers. It was confirmed that melting the iPP fibers at relatively lower temperature, e.g. 176 degrees C, less amount of beta-iPP crystals were observed. The content of beta-iPP crystal enhances first with increasing melting temperature and then decreases with further increase of the fiber melting temperature. The beta-iPP crystallization is found to be most favorable upon melting the fibers at 178 degrees C for 2 min. This demonstrates the requirement of a certain chain or chain segment orientation for generating beta-iPP crystallization on the one hand, while higher orientation of the iPP chains or chain segments encourages the growth of iPP crystals in the alpha-form on the other hand. This has been further confirmed by varying the melting time of the fiber at different temperatures, since relaxation of the iPP molecular chains at a fixed temperature is time dependent. Moreover, the complete transformation of alpha-iPP fibers in some local places into beta-iPP crystals implies that the alphabeta-transition may not be required for the orientation-induced beta-iPP crystallization. PMID- 25708677 TI - Clustering of pelvic floor disorders 20 years after one vaginal or one cesarean birth. AB - INTRODUCTION AND HYPOTHESIS: The objective was to assess the prevalence and risk factors for co-occurring pelvic floor disorders (PFDs): urinary incontinence (UI), symptomatic pelvic organ prolapse (sPOP), and fecal incontinence (FI), 20 years after one vaginal (VD) or one cesarean (CS) delivery. METHODS: We carried out a registry-based national cohort study of primiparae who delivered during the period 1985-1988 and had no further deliveries. Medical Birth Registry data were linked to data from postal questionnaires distributed 20 years post-partum (response rate 65.2%, n = 5,236). Main outcome measures were prevalence and risk factors for combined and isolated PFDs. RESULTS: The prevalence of any PFD was 46.5; 31.7% had one symptom and 14.8% had two or more. Co-occurring symptoms doubled after VD (17.1%) compared with CS (8.4%) (adjOR 2.26; 95% CI 1.84-2.79). The strongest association was observed between VD and having all three symptoms (adjOR 5.20; 95% CI 2.73-9.91), followed by the combination of sPOP and UI (adjOR 3.38; 95% CI 2.24-5.10). The degree of frustration perceived by the women because of pelvic floor dysfunction increased with each additional co-occurring PFD (p < 0.001). The strongest risk factors for clustering of PFDs were: VD (OR 2.19; 95% CI 1.75-2.73), family history (OR 2.03; 95% CI 1.73-2.34), and >=2 degree tear (OR 1.78; 95% CI 1.24-2.55). Vacuum extraction and episiotomy were not risk factors. CONCLUSIONS: The prevalence of co-occurring PFDs was high and was doubled in women after VD compared with CS. Women with UI most likely had it as an isolated symptom, whereas FI and sPOP more often occurred in combination. PMID- 25708678 TI - Quantum metrology with unitary parametrization processes. AB - Quantum Fisher information is a central quantity in quantum metrology. We discuss an alternative representation of quantum Fisher information for unitary parametrization processes. In this representation, all information of parametrization transformation, i.e., the entire dynamical information, is totally involved in a Hermitian operator H. Utilizing this representation, quantum Fisher information is only determined by H and the initial state. Furthermore, H can be expressed in an expanded form. The highlights of this form is that it can bring great convenience during the calculation for the Hamiltonians owning recursive commutations with their partial derivative. We apply this representation in a collective spin system and show the specific expression of H. For a simple case, a spin-half system, the quantum Fisher information is given and the optimal states to access maximum quantum Fisher information are found. Moreover, for an exponential form initial state, an analytical expression of quantum Fisher information by H operator is provided. The multiparameter quantum metrology is also considered and discussed utilizing this representation. PMID- 25708679 TI - Tackling the bottleneck in bacterial signal transduction research: high throughput identification of signal molecules. AB - Signal transduction processes are typically initiated by the interaction of signal molecules with sensor domains. The current lack of information on the signal molecules that feed into regulatory circuits forms a major bottleneck that hampers the understanding of regulatory processes. McKellar et al. report a high throughput approach for the identification of signal molecules, which is based on thermal shift assays of recombinant sensor domains in the absence and presence of compounds from commercially available ligand collections. Initial binding studies with the sensor domain of the PctA chemoreceptor of Pseudomonas aeruginosa showed a close match between thermal shift assay results and microcalorimetric studies reported previously. Using thermal shift assays the authors then identify signals that bind to three chemoreceptors of the kiwifruit pathogen P. syringae pv. Actinidiae NZ-V13. Microcalorimetric binding studies and chemotaxis assays have validated the relevance of these ligands. The power of this technique lies in the combination of a high-throughput analytical tool with commercially available compound collections. The approach reported is universal since it can be employed to identify signal molecules to any type of sensor domain. There is no doubt that this technique will facilitate the identification of many signal molecules in future years. PMID- 25708680 TI - Serum vaspin levels: A possible correlation with digital ulcers in patients with systemic sclerosis. AB - Vaspin is an adipokine implicated in vascular inflammation and remodeling. We herein evaluated the clinical correlation of serum vaspin levels in systemic sclerosis (SSc). Consistent with previous reports, 12% of subjects exhibited serum vaspin levels over 10 ng/mL, likely due to genetic effects. Excluding these subjects, despite no difference between SSc and control subjects, serum vaspin levels were significantly decreased in SSc patients with digital ulcers compared with those without, suggesting the potential contribution of vaspin to digital ulcers of this disease. PMID- 25708681 TI - Palliation of a gastrocolic fistula secondary to colon cancer with a covered colonic stent using a simultaneous dual-scope approach. PMID- 25708682 TI - Robotic transanal surgery for local excision of rectal neoplasia, transanal total mesorectal excision, and repair of complex fistulae: clinical experience with the first 18 cases at a single institution. AB - BACKGROUND: Robotic transanal surgery represents a natural evolution of transanal minimally invasive surgery. This new approach to rectal surgery provides the ability to perform local excision of rectal neoplasia with precision. Robotic transanal surgery can also be used to perform more advanced procedures including repair of complex fistulae and transanal total mesorectal excision. METHODS: Data from patients who underwent transanal robotic surgery over a 33-month period were retrospectively reviewed. Patients underwent three types of procedures using this approach: (a) local excision of rectal neoplasia, (b) transanal total mesorectal excision, and (c) closure of complex fistulae, such as rectourethral fistulae. RESULTS: Eighteen patients underwent robotic transanal surgery during the 33 month study period. Of these, nine patients underwent local excision of rectal neoplasia; four patients underwent transanal total mesorectal excision; four patients underwent repair of rectourethral fistulae; and one patient underwent repair of an anastomotic fistula. Of the patients undergoing robotic transanal surgery for local excision, 6/9 were resections of benign neoplasia, while 3/9 were resections for invasive adenocarcinoma. There was no fragmentation (0/9) noted on any of the locally excised specimens, while one patient (1/9) had a positive lateral margin. During the mean follow-up of 11.4 months, no recurrence was detected. Four patients underwent robotic-assisted transanal total mesorectal excision for curative intent resection of rectal cancer confined to the distal rectum. Mesorectal quality was graded as complete or near complete, and an R0 resection was performed in all four cases. Other transanal robotic procedures performed were the repair of rectourethral fistulae (n = 3) and anastomotic fistula (n = 1). This approach was met with limited success, and only half of the rectourethral fistulae were closed. CONCLUSIONS: Robotic transanal surgery for local excision, transanal total mesorectal excision, and repair of fistulae is feasible, although these new approaches represent a work-in-progress. Improvement in platform design will likely facilitate the ability to perform more complex procedures. Further research with robotic transanal approaches is necessary to determine whether or not this approach can provide patients with significant benefit. PMID- 25708683 TI - Tying up loose ends. PMID- 25708684 TI - Graphene oxide selectively targets cancer stem cells, across multiple tumor types: implications for non-toxic cancer treatment, via "differentiation-based nano-therapy". AB - Tumor-initiating cells (TICs), a.k.a. cancer stem cells (CSCs), are difficult to eradicate with conventional approaches to cancer treatment, such as chemo-therapy and radiation. As a consequence, the survival of residual CSCs is thought to drive the onset of tumor recurrence, distant metastasis, and drug-resistance, which is a significant clinical problem for the effective treatment of cancer. Thus, novel approaches to cancer therapy are needed urgently, to address this clinical need. Towards this end, here we have investigated the therapeutic potential of graphene oxide to target cancer stem cells. Graphene and its derivatives are well-known, relatively inert and potentially non-toxic nano materials that form stable dispersions in a variety of solvents. Here, we show that graphene oxide (of both big and small flake sizes) can be used to selectively inhibit the proliferative expansion of cancer stem cells, across multiple tumor types. For this purpose, we employed the tumor-sphere assay, which functionally measures the clonal expansion of single cancer stem cells under anchorage-independent conditions. More specifically, we show that graphene oxide effectively inhibits tumor-sphere formation in multiple cell lines, across 6 different cancer types, including breast, ovarian, prostate, lung and pancreatic cancers, as well as glioblastoma (brain). In striking contrast, graphene oxide is non-toxic for "bulk" cancer cells (non-stem) and normal fibroblasts. Mechanistically, we present evidence that GO exerts its striking effects on CSCs by inhibiting several key signal transduction pathways (WNT, Notch and STAT signaling) and thereby inducing CSC differentiation. Thus, graphene oxide may be an effective non-toxic therapeutic strategy for the eradication of cancer stem cells, via differentiation-based nano-therapy. PMID- 25708685 TI - Prelamin A and Oct-1: a puzzle of aging. PMID- 25708686 TI - Efficacy and safety of fosphenytoin for benign convulsions with mild gastroenteritis. AB - OBJECTIVE: To clarify the efficacy and safety of fosphenytoin for seizures in children with benign convulsions and mild gastroenteritis. METHODS: Using the mailing list of the Annual Zao Conference on Pediatric Neurology, we recruited patients who met the following criteria: (1) clinical diagnosis of benign convulsions with mild gastroenteritis and (2) treatment with intravenous fosphenytoin. Benign convulsions with mild gastroenteritis were defined as a condition of (a) seizures associated with gastroenteritis without electrolyte imbalance, hypoglycemia, or dehydration in patients (b) between 6 months and 3 years of age with (c) no preexisting neurological disorders, (d) no impaired consciousness, and (e) a body temperature less than 38.0 degrees C before and after the seizures. The efficacy of fosphenytoin was categorized as effective when cessation of seizures was achieved. RESULTS: Data from 16 child patients were obtained (median age, 20 months). Seizures were completely controlled after the initial dose of fosphenytoin in 14 of 16 patients. The median loading dose of fosphenytoin was 22.5 mg/kg. In 10 patients, fosphenytoin was administered after other antiepileptic drugs such as diazepam and midazolam were used. Adverse effects of fosphenytoin, excessive sedation, or intravenous fluid incompatibility were not observed in any patients. CONCLUSION: Fosphenytoin is effective and well tolerated among children with benign convulsions with mild gastroenteritis. PMID- 25708687 TI - The effect of diet composition on serum leptin levels. PMID- 25708688 TI - Pneumomediastinum after nose blowing. PMID- 25708689 TI - Chest wall abscess as a complication of bacilli Calmette-Guerin vaccination in an immunocompetent child. PMID- 25708690 TI - Integration of ultrasound findings and a clinical score in the diagnostic evaluation of pediatric appendicitis. AB - OBJECTIVE: To determine the predictive value of ultrasonography (US) for appendicitis in children when combined with clinical assessment based on the Pediatric Appendicitis Score (PAS). STUDY DESIGN: Observational study of children aged 3-18 years who had an US examination for possible appendicitis. A PAS was calculated on the basis of historical elements, examination, and laboratory studies and was used to classify patients into 3 risk groups (low, medium, high). The predictive value of the PAS for appendicitis was calculated and stratified by the result of the US (positive, negative, or equivocal). RESULTS: A total of 728 children with a median age 11.7 (IQR 7.8-14.9) years were studied; 29% had appendicitis. The negative predictive value of US decreased with increasing PAS based risk assignment: low risk 1.00 (95% CI, 0.97-1.00), medium risk 0.94 (0.91 0.97), and high risk 0.81 (0.73-0.89). With increasing PAS, the positive predictive value increased: low risk 0.73 (0.47-0.99), medium risk 0.90 (0.82 0.98), and high risk 0.97 (0.95-1.0). Among children with equivocal ultrasound results, the proportion with appendicitis ranged from 0.09 (0.0-0.19) for low risk patients to 0.47 (0.33-0.61) among for high-risk patients. CONCLUSION: Ultrasound findings in children with possible appendicitis should be integrated with clinical assessment, such as a clinical score, to determine next steps in management. Rates of false-negative US increase with increasing PAS, and false positive US results occur more often with lower PAS. When discordance exists between US results and the clinical assessment, serial examinations or further imaging are warranted. PMID- 25708691 TI - Intravenous acyclovir and renal dysfunction in children: a matched case control study. AB - OBJECTIVES: A cluster of children receiving intravenous (IV) acyclovir for meningoencephalitis developed acute renal failure in April-May 2008, which prompted a retrospective case-control study to determine the rate of and risk factors for acute nephrotoxicity during IV acyclovir treatment in children. STUDY DESIGN: The percentage decrease in glomerular filtration rate in children receiving IV acyclovir who had >= 1 creatinine measurement after acyclovir initiation from October 2006 to January 2009 was classified as renal risk, injury, or failure according to modified Pediatric Risk Injury, Failure, Loss, End-Stage Renal Disease criteria. Univariate and multivariate matched analyses were conducted to identify risk factors contributing to nephrotoxicity. RESULTS: In the selected study group, renal dysfunction was seen in 131 of 373 (35%) treatment courses studied: 81 of 373 (22%) risk, 36 of 373 (9.7%) injury, and 14 of 373 (3.8%) failure. Most renal dysfunction occurred within 48 hours of the initiation of acyclovir. Renal function returned to the normal range but not to baseline in most cases during the follow-up period. Risk factors for renal dysfunction included acyclovir dose >15 mg/kg (OR 3.81, 95% CI 1.55-9.37) for risk; cumulative exposure greater than calculated cumulative exposure based on 500 mg/m(2)/dose (OR 6.00, 95% CI 1.95-18.46) for injury; and age >8 years (OR 21.5, 95% CI 2.2, >1000) and ceftriaxone coadministration (OR 19.3, 95% CI 1.8, >1000) for failure. CONCLUSIONS: Nephrotoxicity associated with IV acyclovir is common and necessitates renal function monitoring. Risk factors include greater dose, older age, and concomitant ceftriaxone administration. Outside the neonatal period, renal dysfunction may be minimized by dosing IV acyclovir below thresholds associated with nephrotoxicity (ie, <= 500 mg/m(2)/dose or <= 15 mg/kg/dose), particularly in older patients. PMID- 25708692 TI - Emotional response inhibition in children with attention-deficit/hyperactivity disorder: neural and behavioural data. AB - BACKGROUND: Although both emotion and response inhibition are thought to be important in attention-deficit/hyperactivity disorder (ADHD), little is known about the neural mechanisms that underlie the interaction between these two processes in patients with this disorder. This study aimed at examining how emotional contexts affect inhibitory control in children with ADHD. METHOD: A total of 24 ADHD children and 24 healthy comparison subjects performed a modified go/no-go task during three different emotionally laden contexts: negative, neutral and positive. To explore the timing and the underlying neural substrates of emotion-modulated response inhibition, event-related potentials were measured and further analysed both at the scalp and at the voxel level. RESULTS: Patients with ADHD showed greater activation of inhibition-related neural mechanisms (i.e. no-go P3 amplitudes and orbitofrontal cortex activity) to maintain a similar level of performance as healthy comparison subjects, especially during the emotionally arousing contexts (negative and positive). CONCLUSIONS: This study provides plausible neural mechanisms for the difficulty that ADHD children have in controlling their behaviour in highly emotional situations. Such emotional contexts might increase the need for top-down inhibitory control and put ADHD children at greater risk for impulsive behaviours and emotional dysregulation. PMID- 25708693 TI - Improving T cell-induced response to subunit vaccines: opportunities for a proteomic systems approach. AB - Prophylactic vaccines are an effective strategy to prevent development of many infectious diseases. With new and re-emerging infections posing increasing risks to food stocks and the health of the population in general, there is a need to improve the rationale of vaccine development. One key challenge lies in development of an effective T cell-induced response to subunit vaccines at specific sites and in different populations. OBJECTIVES: In this review, we consider how a proteomic systems-based approach can be used to identify putative novel vaccine targets, may be adopted to characterise subunit vaccines and adjuvants fully. KEY FINDINGS: Despite the extensive potential for proteomics to aid our understanding of subunit vaccine nature, little work has been reported on identifying MHC 1-binding peptides for subunit vaccines generating T cell responses in the literature to date. SUMMARY: In combination with predictive and structural biology approaches to mapping antigen presentation, proteomics offers a powerful and as yet un-tapped addition to the armoury of vaccine discovery to predict T-cell subset responses and improve vaccine design strategies. PMID- 25708695 TI - Self-expandable metal stents for malignant esophageal obstruction: a comparative study between extrinsic and intrinsic compression. AB - Self-expandable metal stents (SEMSs) are effective for malignant esophageal obstruction, but usefulness of SEMSs in extrinsic lesions is yet to be elucidated. This study is aimed at evaluating the clinical usefulness of SEMSs in the extrinsic compression compared with intrinsic. A retrospective review was conducted for 105 patients (intrinsic, 85; extrinsic, 20) with malignant esophageal obstruction who underwent endoscopic SEMSs placement. Technical and clinical success rates were evaluated and clinical outcomes were compared between extrinsic and intrinsic group. Extrinsic group was mostly pulmonary origin. Overall technical and clinical success rate was 100% and 91%, respectively, without immediate complications. Extrinsic and intrinsic group did not differ significantly in clinical success rate. The median stent patency time was 131.3 +/- 85.8 days in intrinsic group while that of extrinsic was 54.6 +/- 45.1 due to shorter survival after stent insertion. The 4-, 8-, and 12-week patency rates were 90.5%, 78.8%, and 64.9% respectively in intrinsic group, while stents of extrinsic group remained patent until death. Uncovered, fully covered, and double layered stent were used evenly and the types did not influence patency in both groups. In conclusion, esophageal SEMSs can safely and effectively be used for malignant extrinsic compression as well as intrinsic. PMID- 25708694 TI - Effect of rotational alignment on outcome of total knee arthroplasty. AB - BACKGROUND AND PURPOSE: Poor outcomes have been linked to errors in rotational alignment of total knee arthroplasty components. The aims of this study were to determine the correlation between rotational alignment and outcome, to review the success of revision for malrotated total knee arthroplasty, and to determine whether evidence-based guidelines for malrotated total knee arthroplasty can be proposed. PATIENTS AND METHODS: We conducted a systematic review including all studies reporting on both rotational alignment and functional outcome. Comparable studies were used in a correlation analysis and results of revision were analyzed separately. RESULTS: 846 studies were identified, 25 of which met the inclusion criteria. From this selection, 11 studies could be included in the correlation analysis. A medium positive correlation (rho = 0.44, 95% CI: 0.27-0.59) and a large positive correlation (rho = 0.68, 95% CI: 0.64-0.73) were found between external rotation of the tibial component and the femoral component, respectively, and the Knee Society score. Revision for malrotation gave positive results in all 6 studies in this field. INTERPRETATION: Medium and large positive correlations were found between tibial and femoral component rotational alignment on the one hand and better functional outcome on the other. Revision of malrotated total knee arthroplasty may be successful. However, a clear cutoff point for revision for malrotated total knee arthroplasty components could not be identified. PMID- 25708696 TI - ZNF804A variants confer risk for heroin addiction and affect decision making and gray matter volume in heroin abusers. AB - Drug addiction shares common neurobiological pathways and risk genes with other psychiatric diseases, including psychosis. One of the commonly identified risk genes associated with broad psychosis has been ZNF804A. We sought to test whether psychosis risk variants in ZNF804A increase the risk of heroin addiction by modulating neurocognitive performance and gray matter volume (GMV) in heroin addiction. Using case-control genetic analysis, we compared the distribution of ZNF804A variants (genotype and haplotype) in 1035 heroin abusers and 2887 healthy subjects. We also compared neurocognitive performance (impulsivity, global cognitive ability and decision-making ability) in 224 subjects and GMV in 154 subjects based on the ZNF804A variants. We found significant differences in the distribution of ZNF804A intronic variants (rs1344706 and rs7597593) allele and haplotype frequencies between the heroin and control groups. Decision-making impairment was worse in heroin abusers who carried the ZNF804A risk allele and haplotype. Subjects who carried more risk alleles and haplotypes of ZNF804A had greater GMV in the bilateral insular cortex, right temporal cortex and superior parietal cortex. The interaction between heroin addiction and ZNF804A variants affected GMV in the left sensorimotor cortex. Our findings revealed several ZNF804A variants that were significantly associated with the risk of heroin addiction, and these variants affected decision making and GMV in heroin abusers compared with controls. The precise neural mechanisms that underlie these associations are unknown, which requires future investigations of the effects of ZNF804A on both dopamine neurotransmission and the relative increases in the volume of various brain areas. PMID- 25708697 TI - Quantitative meta-analysis of grey matter anomalies in neuropathic pain. AB - BACKGROUND: Increasing neuroimaging studies have revealed grey matter (GM) anomalies of several brain regions by voxel-based morphometry (VBM) studies in patients with neuropathic pain. The changes have been suggested to be related to central sensitization. Our aim was to investigate concurrence across VBM studies to identify whether different subtypes of neuropathic pain share a common pathophysiological basis revealed by structural abnormalities. METHODS: A systematic search of VBM studies of patients with neuropathic pain and healthy controls published in PubMed and Embase databases from January 2000 to March 2014 was conducted. A quantitative meta-analysis of whole-brain VBM studies in patients with neuropathic pain compared with healthy controls was performed by means of effect-size signed differential mapping. RESULTS: Ten studies comprising 240 patients with neuropathic pain and 263 healthy subjects were systematically included in the present study. Compared to healthy controls, the patients showed consistent decreased GM in bilateral anterior insula and thalamus, right superior frontal gyrus and left postcentral gyrus, and increased GM in right medial frontal gyrus and right posterior insula. The results remained largely unchanged in the following jackknife sensitivity analysis. CONCLUSIONS: This meta-analysis shows strong evidence of brain GM anomalies within the pain matrix in patients with neuropathic pain compared with healthy subjects. Further studies are needed to determine whether the reported changes are specific to neuropathic pain or whether they may be common to other chronic pain. PMID- 25708698 TI - The impact of human papillomavirus infection on the survival and treatment response of patients with esophageal cancers. AB - OBJECTIVE: This study aimed to investigate the impact of human papillomavirus (HPV) infection on the prognosis and treatment response of esophageal squamous cell carcinoma (ESCC). METHODS: We examined the presence and subtypes of HPV in the tumors by polymerase chain reaction and sequencing in 150 ESCC patients. Their clinicopathological characteristics, treatment response and survival were further analyzed according to the presence of HPV infection. RESULTS: Of 150 ESCC tumor samples, 27 (18.0%) were HPV-positive, of which 22 (81.5%) had HPV-16 infection. The risk of developing multifocal ESCC was not significantly different in the HPV-positive and HPV-negative groups (29.6% vs 28.5%, P = 0.90). In subgroup analysis, patients with HPV-16-positive advanced ESCC had a significantly better survival than those with HPV-negative ESCC (3-year survival: 55% vs 21%, log-rank P = 0.03). Cox proportional hazards model showed that the presence of HPV-16 was associated with a significant reduction in the mortality rate (hazard ratio 0.41, 95% CI 0.18-0.96). Patients with HPV-16 infection had better response to chemoradiotherapy (CRT) than those without HPV-16 infection (P = 0.026). CONCLUSIONS: In patients with advanced ESCC, HPV-16-positive patients had a significantly favorable survival, especially those who received CRT. Larger scale studies are needed to determine the causal relationship. PMID- 25708699 TI - Retraction of "novel 2-aminobenzamides as potential orally active antithrombotic agents". AB - [This retracts the article DOI: 10.1021/ml300217f.]. PMID- 25708701 TI - Erratum to: IKK-related genetic diseases: probing NF-kappaB functions in humans and other matters. PMID- 25708700 TI - Mitochondrial fusion provides an 'initial metabolic complementation' controlled by mtDNA. AB - Heteroplasmic cells, harboring both mutant and normal mitochondrial DNAs (mtDNAs), must accumulate mutations to a threshold level before respiratory activity is affected. This phenomenon has led to the hypothesis of mtDNA complementation by inter-mitochondrial content mixing. The precise mechanisms of heteroplasmic complementation are unknown, but it depends both on the mtDNA nucleoid dynamics among mitochondria as well as the mitochondrial dynamics as influenced by mtDNA. We tracked nucleoids among the mitochondria in real time to show that they are shared after complete fusion but not 'kiss-and-run'. Employing a cell hybrid model, we further show that mtDNA-less mitochondria, which have little ATP production and extensive Opa1 proteolytic cleavage, exhibit weak fusion activity among themselves, yet remain competent in fusing with healthy mitochondria in a mitofusin- and OPA1-dependent manner, resulting in restoration of metabolic function. Depletion of mtDNA by overexpression of the matrix targeted nuclease UL12.5 resulted in heterogeneous mitochondrial membrane potential (DeltaPsim) at the organelle level in mitofusin-null cells but not in wild type. In this system, overexpression of mitofusins or application of the fusion-promoting drug M1 could partially rescue the metabolic damage caused by UL12.5. Interestingly, mtDNA transcription/translation is not required for normal mitochondria to restore metabolic function to mtDNA-less mitochondria by fusion. Thus, interplay between mtDNA and fusion capacity governs a novel 'initial metabolic complementation'. PMID- 25708702 TI - Increased migration of olfactory ensheathing cells secreting the Nogo receptor ectodomain over inhibitory substrates and lesioned spinal cord. AB - Olfactory ensheathing cell (OEC) transplantation emerged some years ago as a promising therapeutic strategy to repair injured spinal cord. However, inhibitory molecules are present for long periods of time in lesioned spinal cord, inhibiting both OEC migration and axonal regrowth. Two families of these molecules, chondroitin sulphate proteoglycans (CSPG) and myelin-derived inhibitors (MAIs), are able to trigger inhibitory responses in lesioned axons. Mounting evidence suggests that OEC migration is inhibited by myelin. Here we demonstrate that OEC migration is largely inhibited by CSPGs and that inhibition can be overcome by the bacterial enzyme Chondroitinase ABC. In parallel, we have generated a stable OEC cell line overexpressing the Nogo receptor (NgR) ectodomain to reduce MAI-associated inhibition in vitro and in vivo. Results indicate that engineered cells migrate longer distances than unmodified OECs over myelin or oligodendrocyte-myelin glycoprotein (OMgp)-coated substrates. In addition, they also show improved migration in lesioned spinal cord. Our results provide new insights toward the improvement of the mechanisms of action and optimization of OEC-based cell therapy for spinal cord lesion. PMID- 25708703 TI - Trends in the management of pediatric peritonsillar abscess infections in the U.S., 2000-2009. AB - OBJECTIVES: To analyze temporal trends in the incidence and surgical management of children with peritonsillar abscesses (PTAs), and to examine whether there has been concurrent changes in hospital charges or length of stay. METHODS: The Kids' Inpatient Database (KID) from 2000 to 2009 was examined for children less than 18 years old with ICD-9-CM diagnostic codes for PTA (475). Survey weighted frequency and regression analyses were performed across the entire study period on variables of interest in order to determine estimates of national incidence, demographics and outcomes. RESULTS: A total of 20,546 weighted cases of PTA were identified during the study period. There was no significant change in the incidence of pediatric PTA across the study period (p=0.63) or in the rate of nonsurgical management (p=0.85). There was a significant increase in the rates of I&D from 26.4% to 33.7% (p<0.001) and a significant decrease in the rate of tonsillectomy from 13.0% to 7.8% (p<0.001). Mean inflation-adjusted charges significantly increased from approximately $8400 in 2000 to $13,300 in 2009 (p<0.001), and average length of stay was 2.15 days with no significant change during the study period (p=0.164). Mean inflation-adjusted charges for patients undergoing tonsillectomy alone were approximately $1800 greater than mean charges for those undergoing I&D alone (p=0.003) and length of stay was also significantly longer for tonsillectomy patients versus I&D patients [I&D 1.99 days versus tonsillectomy 2.23 days (p<0.001)]. CONCLUSIONS: There was no change in the incidence of pediatric PTAs from 2000 to 2009 but there was a change in surgical management, with a significant decrease in the rate of tonsillectomy and significant increase in the rate of incision and drainage procedures. Hospital charges during this period increased nearly 60% despite no change in rates of CT imaging, surgical intervention or length of stay. PMID- 25708704 TI - A new compound heterozygous mutation in GJB2 causes nonsyndromic hearing loss in a consanguineous Iranian family. AB - OBJECTIVE: To investigate mutations in GJB2 in a consanguineous Iranian family with multiple members affected by non-syndromic hearing loss. METHODS: DNA was extracted from blood samples and the coding region of the conexin 26 gene was amplified using PCR. Bidirectional sequencing was carried out on PCR products. RESULTS: Direct sequencing of the PCR products led to the identification of a novel compound heterozygous mutation of c.551G>C/c.397T>G (p.R184P/p.W133G) and a previously reported homozygous mutation c.551G>C (R184P/R184P). Compound heterozygous mutation was identified in the father and his daughter and homozygous mutation was identified in his affected son. In silico analysis of p.W133G predicted mutation has deleterious effect on protein structure. CONCLUSION: These results show the usefulness of GJB2 mutation screening and bioinformatic analysis for genetic diagnosis and counseling of non-syndromic hearing loss. PMID- 25708705 TI - Development and characterization of a panel of cross-reactive monoclonal antibodies generated using H1N1 influenza virus. AB - To characterize the antigenic epitopes of the hemagglutinin (HA) protein of H1N1 influenza virus, a panel consisting of 84 clones of murine monoclonal antibodies (mAbs) were generated using the HA proteins from the 2009 pandemic H1N1 vaccine lysate and the seasonal influenza H1N1(A1) vaccines. Thirty-three (39%) of the 84 mAbs were found to be strain-specific, and 6 (7%) of the 84 mAbs were subtype specific. Twenty (24%) of the 84 mAbs recognized the common HA epitopes shared by 2009 pandemic H1N1, seasonal A1 (H1N1), and A3 (H3N2) influenza viruses. Twenty five of the 84 clones recognized the common HA epitopes shared by the 2009 pandemic H1N1, seasonal A1 (H1N1) and A3 (H3N2) human influenza viruses, and H5N1 and H9N2 avian influenza viruses. We found that of the 16 (19%) clones of the 84 mAbs panel that were cross-reactive with human respiratory pathogens, 15 were made using the HA of the seasonal A1 (H1N1) virus and 1 was made using the HA of the 2009 pandemic H1N1 influenza virus. Immunohistochemical analysis of the tissue microarray (TMA) showed that 4 of the 84 mAb clones cross-reacted with human tissue (brain and pancreas). Our results indicated that the influenza virus HA antigenic epitopes not only induce type-, subtype-, and strain-specific monoclonal antibodies against influenza A virus but also cross-reactive monoclonal antibodies against human tissues. Further investigations of these cross-reactive (heterophilic) epitopes may significantly improve our understanding of viral antigenic variation, epidemics, pathophysiologic mechanisms, and adverse effects of influenza vaccines. PMID- 25708706 TI - Reply to the article "Comparing demographics, clinical presentation, treatments and outcome between sle patients treated in a public and private health system in Santa Fe, Argentina". PMID- 25708707 TI - Outcome of venous stenting following catheter directed thrombolysis for acute proximal lower limb venous thrombosis: a prospective study with venous Doppler follow-up at 1-year. AB - Functional outcome of venous stent placement for the management of acute iliofemoral deep vein thrombosis (DVT) following catheter-directed thrombolysis (CDT), remain undefined. The purpose of this study was to assess immediate and intermediate term outcomes among patients treated with venous stenting following CDT in patients with proximal lower limb DVT. Thirty consecutive patients aged between 20-70 years with proximal lower limb DVT formed the study group. The mean duration of CDT done with streptokinase was 4.5 +/- 1.3 days. Patients with residual venous obstruction and/or large clot burden were treated further with venous angioplasty and/or stenting. Primary endpoint was to evaluate the safety, efficacy and patency of venous stenting in the management of incomplete result following CDT. After 12 months, post-thrombotic syndrome (PTS) was assessed clinically using Villalta scale and deep venous patency was assessed through duplex ultrasound. We studied 8 (5 female and 3 male) patients with 9 (3 left and 6 right) limb involvement and 13 stent (4 balloon expandable and 9 self expandable) placement. All patients improved clinically immediately following venous stenting. Technical success was achieved in all patients. One patient developed pulmonary embolism during course of hospital stay. One patient had stent thrombosis and PTS and another patient died due to carcinoma breast during follow-up. Deep venous stenting is an effective mode of treatment in proximal acute lower limb DVT with high late patency rate up to 1-year. PMID- 25708708 TI - A rare instructive complication of balloon catheter fracture during percutaneous coronary intervention. AB - The entrapment, fracture, and dislodgement of catheterization devices during percutaneous coronary intervention (PCI) are rare complications, for which cardiac surgery is sometimes required. Here, we encountered a rare but instructive case of balloon catheter fracture during PCI. Although there have been some reports of guidewire fracture in PCI, reports on balloon catheter fracture are very rare to our knowledge. A simulation test to examine the mechanism of balloon catheter fracture revealed that overuse of the balloon catheter, both for kissing balloon inflation and balloon anchor, was highly likely to have been the cause of the fracture. PMID- 25708709 TI - Diterpene glycosides from the ethanol extract of Diplopterygium rufopilosum. AB - A phytochemical investigation on the 70% EtOH extract from the dry fronds of Diplopterygium rufopilosum afforded two new labdane-type diterpene glycosides, (3beta,13S)-3-O-beta-d-glucopyranosyl-13-O-alpha-l-rhamnopyranosyl-labda-8(17),14 diene (1) and (3beta,13S)-3-O-alpha-l-rhamnopyranosyl-13-O-[6-O-acetyl-beta-d glucopyranosyl-(1 -> 4)-2-O-acetyl-alpha-l-rhamnopyranosyl]-labda-8(17),14-diene (2). Their structures were determined on the basis of chemical method and spectroscopic analyses, including 1D and 2D NMR (COSY, HMQC, HMBC, and NOESY) and HR-ESI-MS analyses. PMID- 25708710 TI - Inferring bacteriophage infection strategies from genome sequence: analysis of bacteriophage 7-11 and related phages. AB - BACKGROUND: Analyzing regulation of bacteriophage gene expression historically lead to establishing major paradigms of molecular biology, and may provide important medical applications in the future. Temporal regulation of bacteriophage transcription is commonly analyzed through a labor-intensive combination of biochemical and bioinformatic approaches and macroarray measurements. We here investigate to what extent one can understand gene expression strategies of lytic phages, by directly analyzing their genomes through bioinformatic methods. We address this question on a recently sequenced lytic bacteriophage 7 - 11 that infects bacterium Salmonella enterica. RESULTS: We identify novel promoters for the bacteriophage-encoded sigma factor, and test the predictions through homology with another bacteriophage (phiEco32) that has been experimentally characterized in detail. Interestingly, standard approach based on multiple local sequence alignment (MLSA) fails to correctly identify the promoters, but a simpler procedure that is based on pairwise alignment of intergenic regions identifies the desired motifs; we argue that such search strategy is more effective for promoters of bacteriophage-encoded sigma factors that are typically well conserved but appear in low copy numbers, which we also verify on two additional bacteriophage genomes. Identifying promoters for bacteriophage encoded sigma factors together with a more straightforward identification of promoters for bacterial encoded sigma factor, allows clustering the genes in putative early, middle and late class, and consequently predicting the temporal regulation of bacteriophage gene expression, which we demonstrate on phage 7-11. CONCLUSIONS: While MLSA algorithms proved highly useful in computational analysis of transcription regulation, we here established that a simpler procedure is more successful for identifying promoters that are recognized by bacteriophage encoded sigma factor/RNA polymerase. We here used this approach for predicting sequence specificity of a novel (bacteriophage encoded) sigma factor, and consequently inferring phage 7-11 transcription strategy. Therefore, direct analysis of bacteriophage genome sequences is a plausible first-line approach for efficiently inferring phage transcription strategies, and may provide a wealth of information on transcription initiation by diverse sigma factors/RNA polymerases. PMID- 25708711 TI - Serotonin-norepinephrine reuptake inhibitor and selective serotonin reuptake inhibitor use and risk of fractures: a new-user cohort study among US adults aged 50 years and older. AB - BACKGROUND: Antidepressants may increase the risk of fractures by disrupting sensory-motor function, thereby increasing the risk of falls, and by decreasing bone mineral density and consequently increasing the fall- or impact-related risk of fracture. Selective serotonin reuptake inhibitor (SSRI) antidepressants appear to increase fracture risk relative to no treatment, while less is known about the effect of serotonin-norepinephrine reuptake inhibitor (SNRI) antidepressants, despite SNRIs being prescribed with increasing frequency. No prior study has directly examined how fracture risk differs among patients initiating SNRIs versus those initiating SSRIs. OBJECTIVE: The objective of this study was to assess the effect of SNRI versus SSRI initiation on fracture rates. DATA SOURCE: Data were derived from a PharMetrics claims database, 1998-2010, which is comprised of commercial health plan information obtained from managed care plans throughout the US. METHODS: We constructed a cohort of patients aged 50 years or older initiating either of the two drug classes (SSRI, N = 335,146; SNRI, N = 61,612). Standardized mortality weighting and Cox proportional hazards regression were used to estimate hazard ratios (HRs) for fractures by antidepressant class. RESULTS: In weighted analyses, the fracture rates were approximately equal in SNRI and SSRI initiators: HRs for the first 1- and 5-year periods following initiation were 1.11 [95 % confidence interval (CI) 0.92-1.36] and 1.06 (95 % CI 0.90-1.26), respectively. For the subgroup of patients with depression who initiated on either SNRIs or SSRIs, those initiating SNRIs had a modestly, but not significantly, elevated fracture risk compared with those who initiated on SSRIs [HR 1.31 (95 % CI 0.95-1.79)]. CONCLUSIONS: We found no evidence that initiating SNRIs rather than SSRIs materially influenced fracture risk among a cohort of middle-aged and older adults. PMID- 25708712 TI - Effects of Water-Based Training on Static and Dynamic Balance of Older Women. AB - OBJECTIVE: The aim of this study was to evaluate the effects of a water-based exercise program on static and dynamic balance. METHOD: Thirty-six older women were randomly assigned to a water-based training (3 days/week for 12 weeks) or control group. Water level was kept at the level of the xiphoid process and temperature at ~28-30 degrees C. Each session included aerobic activities and lower limb strength exercises. The medial-lateral, the anterior-posterior amplitude, and displacement of the center of pressure (CP-D) were measured in a quiet standing position (60 sec eyes opened and closed). The dynamic balance and 8-Foot Up-and-Go tests were also applied. Group comparisons were made using two way analysis of variance (ANOVA) with repeated measures. RESULTS: No differences were found in the center of pressure variables; however, the WBT group showed better performance in the 8 Foot Up-and-Go Test after training (5.61+/-0.76 vs. 5.18+/-0.42; p<0.01). CONCLUSION: The water-based training was effective in improving dynamic balance, but not static balance. PMID- 25708714 TI - Engineered pairs of distinct photoswitches for optogenetic control of cellular proteins. AB - Optogenetic methods take advantage of photoswitches to control the activity of cellular proteins. Here, we completed a multi-directional engineering of the fungal photoreceptor Vivid to develop pairs of distinct photoswitches named Magnets. These new photoswitches were engineered to recognize each other based on the electrostatic interactions, thus preventing homodimerization and enhancing light-induced heterodimerization. Furthermore, we tuned the switch-off kinetics by four orders of magnitude and developed several variants, including those with substantially faster kinetics than any of the other conventional dimerization based blue spectrum photoswitches. We demonstrate the utility of Magnets as powerful tools that can optogenetically manipulate molecular processes in biological systems. PMID- 25708713 TI - Pharmacokinetics and dose recommendations for cyclosporine and tacrolimus when coadministered with ABT-450, ombitasvir, and dasabuvir. AB - ABT-450, ombitasvir, and dasabuvir are direct-acting antiviral agents (DAAs) that have been developed for combination treatment of chronic hepatitis C virus (HCV) infection. Because these DAAs have metabolic and transporter profiles that overlap with cyclosporine and tacrolimus disposition, there is potential for drug interactions. Two Phase 1 studies assessed effects of ABT-450 (150 mg coadministered with ritonavir 100 mg once daily), ombitasvir (25 mg once daily), and dasabuvir (400 mg twice daily) on the pharmacokinetics, safety, and tolerability of a single dose of cyclosporine (30 mg) or tacrolimus (2 mg) in healthy volunteers (N = 12 per study). In the presence of steady-state concentrations of all 3 DAAs, dose-normalized cyclosporine concentration at 24 hours (C24), and area under the concentration-time curve from time 0 to infinity (AUC(infinity)) were 15.8-fold and 5.8-fold, respectively, and dose-normalized tacrolimus C24 and AUC(infinity) were 17-fold and 57-fold, respectively, of either agent alone. Cyclosporine and tacrolimus half-lives increased from 7 to 25 h and 32 to 232 h, respectively. There were no major safety or tolerability issues in these studies. The results suggest that cyclosporine and tacrolimus doses and dosing frequency should be reduced in HCV-infected posttransplant patients being treated with this 3-DAA regimen. PMID- 25708715 TI - Determinants of virtual water flows in the Mediterranean. AB - The aim of the paper is to investigate the main determinants of the bilateral virtual water (water used in the production of a commodity or service) flows associated with international trade in agricultural goods across the Mediterranean basin. We consider the bilateral gross flows of virtual water in the area and study what export-specific and import-specific factors are significantly associated with virtual water flows. We follow a sequential approach. Through a gravity model of trade, we obtain a "refined" version of the variable we aim to explain, one that is free of the amount of flows due to pair specific factors affecting bilateral trade flows and that fully reflects the impact of country-specific determinants of virtual water trade. A number of country-specific potential explanatory variables, ranging from water endowments to trade barriers, from per capita GDP to irrigation prices, is presented and tested. To identify the variables that help to explain the bilateral flows of virtual water, we adopt a model selection procedure based on model averaging. Our findings confirm one of the main controversial results in the literature: larger water endowments do not necessarily lead to a larger 'export' of virtual water, as one could expect. We also find some evidence that higher water irrigation prices reduce (increase) virtual water 'exports' ('imports'). PMID- 25708716 TI - Colony-stimulating factor-3 receptor, watch out for polymorphisms. PMID- 25708717 TI - Adjusting the frequency of mammography screening on the basis of genetic risk: Attitudes among women in the UK. AB - PURPOSE: To explore public attitudes towards modifying frequency of mammography screening based on genetic risk. METHODS: Home-based interviews were carried out with a population-based sample of 942 women aged 18-74 years in the UK. Demographic characteristics and perceived breast cancer (BC) risk were examined as predictors of support for risk-stratified BC screening and of the acceptability of raised or lowered screening frequency based on genetic risk, using multivariate logistic regression. RESULTS: Over two-thirds of respondents (65.8%) supported the idea of varying screening frequency on the basis of genetic risk. The majority (85.4%) were willing to have more frequent breast screening if they were found to be at higher risk, but fewer (58.8%) were willing to have less frequent screening if at lower risk (t (956) = 15.6, p < 0.001). Ethnic minority status was associated with less acceptability of more frequent screening (OR = 0.40, 95% CI = 0.21-0.74), but there were no other significant demographic correlates. Higher perceived risk of BC was associated with greater acceptability of more frequent screening (OR = 1.71, 95%CI = 1.27-2.30). CONCLUSION: Women were positive about adjusting the frequency of mammography screening in line with personal genetic risk, but it will be important to develop effective communication materials to minimise resistance to reducing screening frequency for those at lower genetic risk. PMID- 25708718 TI - Glucocorticoid-induced leucine zipper governs the therapeutic potential of mesenchymal stem cells by inducing a switch from pathogenic to regulatory Th17 cells in a mouse model of collagen-induced arthritis. AB - OBJECTIVE: Mesenchymal stem cells (MSCs) are potent immunosuppressive cells that have shown promise in the treatment of rheumatoid arthritis (RA). Deciphering the intrinsic characteristics of MSCs that correlate with their biologic activity will facilitate their clinical use. Recently, the role of glucocorticoid-induced leucine zipper (GILZ) in the development of RA has been documented. The aim of this study was to evaluate whether GILZ expression by MSCs may contribute to their therapeutic effect. METHODS: MSCs were isolated from GILZ-deficient (GILZ( /-) ) mice and wild-type mice. MSCs (1 * 10(6) cells) were injected twice via the tail vein into mice with collagen-induced arthritis (CIA). RESULTS: In vitro, we showed that GILZ is a key factor involved in the immunosuppressive potential of MSCs. MSCs derived from GILZ(-/-) mice did not suppress the proliferation of CD4+ T cells and were less efficient than MSCs derived from WT mice in altering Th17 cell polarization. Thus, we investigated the role of GILZ in an experimental model of arthritis and demonstrated that although WT MSCs significantly reduced paw swelling in arthritic mice, GILZ(-/-) MSCs did not. Moreover, the magnitude of the effects of GILZ(-/-) MSCs on Th17 cell frequency was significantly lower than that of WT MSCs. The therapeutic effect of MSCs correlated with the generation of Treg cells bearing the CD4 + RORgammat+IL-17(low) IL-10+ signature, and Th17 cell polarization was GILZ dependent. CONCLUSION: This study demonstrates that GILZ has an essential role in the therapeutic effectiveness of MSCs in arthritis by favoring Th17 cell polarization toward a regulatory phenotype. Therefore, potentiation of GILZ expression in MSCs could represent a means to enhance their therapeutic effect in autoimmune diseases. PMID- 25708719 TI - Erratum to: Impact of Surgical Infection Society/Infectious Disease Society of America-recommended antibiotics on postoperative intra-abdominal abscess with image-guided percutaneous abscess drainage following gastrointestinal surgery. PMID- 25708720 TI - A novel technique for managing open abdomen with the combined use of mesh mediated traction and the bilateral anterior rectus abdominis sheath turnover flap method: how to do it. AB - Proper management of abdominal compartment syndrome and open abdomen is important for improving the survival of critically ill patients. However, in cases requiring a prolonged period of open abdomen, it is frequently difficult to perform definitive fascial closure due to lateralization of the abdominal musculature. We herein present a novel combined technique for managing open abdomen. A 74-year-old male with diffuse peritonitis was transferred to our department, after which a long period of open abdomen made it difficult to achieve fascial closure. Polypropylene mesh was sutured to the fascial edges to reduce the gap, which was then serially tightened under negative pressure wound therapy. However, since it was not possible to accomplish definitive fascial closure, abdominal closure was performed using the bilateral anterior rectus abdominis sheath turnover flap method after removing the mesh, without any complications. This combined technique may be an effective alternative in patients requiring open abdomen with subsequent difficulty in achieving definitive fascial closure. PMID- 25708721 TI - Sleepwalking episodes are preceded by arousal-related activation in the cingulate motor area: EEG current density imaging. AB - OBJECTIVE: To investigate local arousal fluctuations in adults who received ICSD 2 diagnosis of somnambulism. METHODS: EEG neuroimaging (eLORETA) was utilized to compare current density distribution for 4s epochs immediately preceding sleepwalking episode (from -4.0 s to 0 s) to the distribution during earlier 4s epochs (from -8.0 s to -4.0 s) in 20 EEG segments from 15 patients. RESULTS: Comparisons between eLORETA images revealed significant (t>4.52; p<0.05) brain activations before onset of sleepwalking, with greater current density within beta 3 frequency range (24-30 Hz) in Brodmann areas 33 and 24. CONCLUSIONS: Sleepwalking motor events are associated with arousal-related activation of cingulate motor area. SIGNIFICANCE: These results support the notion of blurred boundaries between wakefulness and NREM sleep in sleepwalking. PMID- 25708722 TI - Polyneuropathy in POEMS syndrome: Alterations in nerve function and morphology. PMID- 25708723 TI - Abstracts of the 2015 SCMR/EuroCMR Joint Scientific Sessions, February 4-7, 2015, Nice, France. PMID- 25708724 TI - Dosimetry of infant exposure to power-frequency magnetic fields: variation of 99th percentile induced electric field value by posture and skin-to-skin contact. AB - Infant exposure to 50 Hz magnetic fields from power lines was numerically analyzed in this study. Dosimetric variability due to posture and skin-to-skin contact was evaluated using human anatomical models including a recently developed model of a 12-months-old infant. As proposed by the International Commission on Non-Ionizing Radiation Protection, the induced E-field strength (99th percentile value, E99 ) for the central nerve systems (E99_CNS ) and peripheral nerve system (E99_PNS ), were used as metrics. Results showed that the single (free of contact with others) infant model has lower E99 (E99_CNS and E99_PNS inclusive) compared with single adult and child models when exposed to the same power-frequency magnetic field. Also, studied postures of sitting, standing, or arm-up, would not change E99 _PNS . However, skin-to-skin contact with other models could significantly raise induced E-field strength in the infant (e.g., contact on 0.93% of the infant's total surface increased E99_PNS by 213%). Simulations with canonical models were conducted to assess different factors contributing to the E99 enhancement. Results indicated the importance of thoroughly investigating the conservativeness of current safety guidelines in the case of skin-to-skin contact, especially with infants. PMID- 25708725 TI - Estimation of human leptin concentration in the subcutaneous adipose and skeletal muscle tissues. AB - BACKGROUND: Interstitial leptin concentrations in subcutaneous adipose and skeletal muscle tissues were determined by open-flow microperfusion. METHOD: In 12 lean male subjects (age: 25.6 +/- 1.1 years), a zero flow rate experiment using different flow rates was applied. Recovery was determined by urea as an internal reference. In the no-net-flux experiments, catheters were perfused with five solutions containing different concentrations of leptin. Concentrations of interstitial leptin were calculated by applying linear regression analysis to perfusate as opposed to sampled leptin concentrations. RESULTS: The zero flow rate protocol showed significantly higher concentrations of leptin in the interstitial fluid of subcutaneous adipose compared to skeletal muscle tissue [36.8 +/- 10.32 vs. 7.1 +/- 2.5% of the corresponding plasma level (P = 0.018)]. The recovery of urea in the samples was comparable for all catheters [79.4 +/- 6.8 vs. 83.0 +/- 5.8 of the corresponding plasma level, flow rate of 0.3 MUL/min; (P = ns)] and was higher when compared to leptin. In the no-net-flux protocol, the concentration of leptin in subcutaneous adipose tissue was almost identical to plasma [90. 5 +/- 7.0%] and the skeletal muscle tissue concentration of leptin was 23.7 +/- 2.5% of the corresponding plasma level. CONCLUSION: Open-flow microperfusion enables the estimation of leptin concentrations in subcutaneous adipose and skeletal muscle tissues in humans in vivo. This is the first documentation on the use of open-flow microperfusion to demonstrate that relevant amounts of leptin are also found in skeletal muscle tissue. PMID- 25708726 TI - How do lesion studies elucidate the role of the hippocampus in intertemporal choice? PMID- 25708727 TI - Sustaining the Rheumatology Research Enterprise. PMID- 25708728 TI - Autophagy Mediates HBx-Induced Nuclear Factor-kappaB Activation and Release of IL 6, IL-8, and CXCL2 in Hepatocytes. AB - Hepatitis B virus (HBV) and one of its encoded proteins, HBV X protein (HBx), have been shown to induce autophagy in hepatoma cells. Substantial evidence indicates that autophagy is a potent suppressor of inflammation. However, sporadic reports suggest that autophagy could promote pro-inflammatory cytokine expression and inflammation in some biological contexts. Here, we show that overexpression of HBx induces LC3B-positive autophagosome formation, increases autophagic flux and enhances the expression of ATG5, ATG7, and LC3B-II in normal hepatocytes. Abrogation of autophagy by small interfering RNA against ATG5 and ATG7 prevents HBx-induced formation of autophagosomes. Autophagy inhibition also abrogates HBx-induced activation of nuclear factor-kappaB (NF-kappaB) and production of interleukin-6 (IL-6), IL-8, and CXCL2. These findings suggest that autophagy is required for HBx-induced NF-kappaB activation and pro-inflammatory cytokine production and could shed new light on the complex role of autophagy in the modulation of inflammation. PMID- 25708729 TI - Melorheostosis involving the hand. PMID- 25708730 TI - [Correction of the position of the cilia in facial paralysis: Technical note]. AB - Facial paralysis is a incapacitating pathology that we treat with lengthening temporalis myoplasty for reanimation of the smile. To treat lagophthalmia, we use the extension of the levator of the upper eyelid according Tessier and the asymmetric external blepharorraphy. These techniques can optionally be combined with other techniques, as needed. However, many patients are embarrassed by the appearance of the lashes of the upper eyelid homolateral side facial paralysis. The cilia are lowered and horizontalised, creating a functional disorder by partial "amputation" of the visual field and aesthetic inconvenience. We describe a surgical technique to correct the malposition of the lashes. This technique can be carried out independently or in the lengthening of the temporal myoplasty or another surgical procedure on the eye. In case of extension of the levator of the upper eyelid, the technique we propose requires no additional incision. This is a simple technique and increases very little surgical time. It is fast, little or no morbid, reproducible and provides a significant improvement in the aesthetic and functional patient. This simple technique allows to provide both aesthetic and functional refinement for patients with facial paralysis sequelae. PMID- 25708731 TI - [Review of clinical experience for a new preputioplasty technique as circumcision alternative]. AB - Surgery is required for phimosis with a contracted fibrous ring or when the medical treatment with steroids has been unsuccessful. Surgical teams often opt for circumcision when a conservative technique can be used. This surgery could have some psychologic consequences, and when the circumcision in not according to religious convictions, it cannot be live well for the patient and his family. Furthermore, some surgery procedures for prepuce conservation seem to give some unaesthesics aspects with cutaneous excess. The objective of this study was to evaluate our new preputioplasty technique according to the initial diagnosis (phimosis with scarred foreskin or long and narrow foreskin), in situation where circumcision is required currently. Outcome evaluated was: easy and painless foreskin retraction, absence of postoperative phimosis as well as cosmetic aspects of the penis. In this study, 90 children benefited from this technique and subsequent follow-up. The mean age was 7.9 years for the 32 children in the sclerotic phimosis group and 6.8 years for the 58 children in the long and narrow foreskin group. We observed complete foreskin retraction without any recurrence in 100% of children with a phimosis resistant to medical treatment which consisted of progressive foreskin retraction and application of topical steroids, with a mean postoperative follow-up of 1.4 years. Results showed an excellent cosmetic aspect of the penis with absence of enlarged foreskin in all our subjects. This study underlines the relevance of this surgical technique. PMID- 25708732 TI - [Locally advanced basal-cell carcinoma: Combined alternative treatments beyond surgery]. AB - The vismodegib, inhibitor of the hedgehog signaling pathway, is a new therapeutic option in locally advanced BCC when surgery or radiotherapy are inappropriate. If the response rate is high with rapid and sustained efficacy, complete responses are rare. Furthermore, the common side effects may limit continuous and prolonged treatment and lead to discuss sequential treatments. We report two cases that illustrate the severity of LaCBC, tumors neglected by patients and their families limiting therapeutic choice especially surgery that become impossible and for which vismodegib is indicated. These observations illustrate the possible interest of radiotherapy in combination or after tumor debulking by vismodegib. Vismodegib must be known by surgeons for LaCBC, mainly as an alternative beyond surgery but also as a possible neoadjuvant treatment to surgery that have to be evaluated. PMID- 25708733 TI - Percutaneous transcatheter closure of a large systemic to pulmonary venous fistulae in an adult patient after extracardiac fontan. AB - Vascular fistulae are frequent complications in patients who have undergone a Fontan operation for palliation of single ventricle physiology. Fistulae involving the pulmonary vasculature may result in progressive hypoxemia, pulmonary hemorrhage, and clinical symptoms. These are commonly managed by percutaneous transcatheter embolization utilizing coils, and more recently, vascular plugs and septal occluders. We present a clinical case of an adult patient who underwent an extracardiac Fontan procedure in childhood for univentricular physiology and presented with symptoms of systemic desaturation 10 years after his surgery. The patient was found to have a large fistula from the inferior vena cava to the right inferior pulmonary vein. The fistula was attempted to be closed with a 12 mm Amplatzer Septal Occluder (St. Jude Medical, St. Paul, MN). Angiography showed continued flow across the fistula, which was then successfully occluded with an 18 mm Amplatzer "Cribriform" Septal Occluder (St. Jude Medical, St. Paul, MN). The patient experienced immediate improvement in his systemic saturation, and demonstrates continued resolution of his symptomatic hypoxia on follow-up. This case illustrates an uncommon systemic to pulmonary vein fistula after Fontan, and a unique, successful embolization with two septal occluders, resulting in sustained symptomatic improvement. PMID- 25708734 TI - Nanoparticulates with drug release based on temperature change. AB - The stimuli-induced release systems are able to respond to an external stimulus resulting in drug release in a controlled pattern. The origin of the external stimuli may be of physical, chemical or biological nature. Thermo-responsive delivery systems respond to the change in temperature and they were mainly designed in order to be used in the cancer treatment method using elevated temperature, i.e. hyperthermia. The thermo-responsive systems can be divided into several groups, such as thermo-responsive hydrogel polymer systems, liposomes, nano- or microparticles, and polypeptide-drug conjugates. While liposomes are temperature-sensitive by their nature, the other systems are usually based on thermo-sensitive polymers, namely poly-(N-isopropyl-acrylamide). This article summarizes recently available items of information regarding thermo-responsive drug delivery. KEYWORDS: drug delivery system thermo-responsive system poly-(N isopropyl-acrylamide) liposome nanoparticle polypeptide-drug conjugate. PMID- 25708735 TI - An overview of urease and its relation to the ureolytic bacteria and the search for new urease inhibitors. AB - In this review, an overview of the available literature on urease is presented. Urease is an enzyme which catalyzes the hydrolysis of urea. The occurrence of ureases and their functions are discussed thoroughly. The relationship of urease to ureolytic bacteria is examined, and the currently available urease inhibitors, both inorganic and natural, are presented. Finally, the importance of urease and current and future applications of new inhibitors and explored. KEYWORDS: bacteria inhibitor urease. PMID- 25708736 TI - [Clinical trials in the European Union and the Czech Republic in the years 2006, 2009 and 2012]. AB - The aim of this paper is to analyze clinical trials conducted in the European Union and the Czech Republic in the years 2006, 2009 and 2012. The analysis has two main points of interest: characterization of the study population (the attention is paid to the age and gender profile of the subjects population as well as to the fact whether healthy volunteers and/or patients were enrolled) and clinical trials focus (the phases of clinical trials and therapeutic areas the trials were focused on). In addition, the aim of this paper is to discover possible differences between the EU and the CR and to find out if the implementation of Directive 2001/20/EC of the European Parliament and Council from 4th of April 2001 had any influence on the number of clinical trials being conducted (per therapeutic area and time). KEYWORDS: clinical trials focus participant population healthy volunteers placebo. PMID- 25708737 TI - [Examples of off-label use of human medicinal preparations in veterinary medicine]. AB - The paper presents several examples of the use of human medicinal preparations (MP) in veterinary medicine, aiming to compare the indications listed in the summary of product characteristics (SmPC) and the indications in which these MPs are used by veterinarians. For the sake of illustration, two human MPs were selected, which, on the basis of a preceding analysis, were found to be those most widely used in veterinary medicine. A questionnaire survey was employed to find information on the indications in which human MPs are prescribed by veterinarians. The set consisted of 200 veterinary surgeries specializing mainly in small animals. The returnability of the questionnaires was 40%. KEYWORDS: human medicinal preparation veterinary medicine summary of product characteristics off-label use indication questionnaire. PMID- 25708738 TI - [Influence of excipients on caffeine permeation from gels]. AB - The subject of this paper is a study of the influence of excipients on caffeine permeation from dermal semisolids drugs. Due to its advantageous properties, caffeine can be successfully used in dermal hydrogels. The choice of excipients from the group of humectants and cationic surfactants also plays an important role. The excipients should ensure long-term stability of hydrogels and the best permeation of the drug from gels. In particular, the influence of various excipients on caffeine permeation from gels and at the same time their influence on rheological properties of hydrogels were investigated. Based on the obtained results, the following optimal composition of caffeine gel was determined: 2.5 % chitosan + 0.1 % caffeine + 10 % propylenglycol + 0.1 % benzyldimethylhexadecylammonium chloride. KEYWORDS: caffeine hydrogels permeation rheological parameters. PMID- 25708739 TI - Accumulation of silymarin in milk thistle seeds under drought stress. AB - MAIN CONCLUSION: According to the results obtained in this study, drought stress can enhance the accumulation of silymarin in milk thistle seeds. Moreover, under drought stress, the share of silybin increased which possess the greatest degree of biological activity among the silymarin components. Silymarin, an isomeric mixture of flavonolignans found in milk thistle (Silybum marianum (L.) Gaertn) seeds, has been used for its hepatoprotective effects for more than 2,000 years. Biosynthesis and accumulation of active substances like silymarin in plant tissues highly interacts with the environmental conditions. Effects of moderate and severe drought stress (based on soil moisture depletion) on silymarin content and composition in milk thistle seeds were evaluated in a field study. Averaged across treatments, milk thistle seeds contained 19.3 g kg(-1) silymarin. Drought stress enhanced silymarin accumulation in milk thistle seeds. Plants grown under moderate and severe drought stress treatments contained 4 and 17 % greater silymarin than those grown in well-watered condition, respectively. Greater content of sylimarin in stressed plants was attributed to more contents of silybin, isosilybin and silychristin, while silydianin content was lower under drought condition. According to the results obtained in this study, drought stress enhanced accumulation of silymarin in milk thistle seeds and improved its quality by increasing the share of silybin, which possess the greatest degree of biological activity among the silymarin components. PMID- 25708740 TI - Erratum to: Mining NGS transcriptomes for miRNAs and dissecting their role in regulating growth, development, and secondary metabolites production in different organs of a medicinal herb, Picrorhiza kurroa. PMID- 25708741 TI - Hyperplastic polyps of the colon and rectum - reclassification, BRAF and KRAS status in index polyps and subsequent colorectal carcinoma. AB - Hyperplastic polyps (HP) of the colon and rectum were previously considered benign. Newer studies have suggested that colorectal HP are different entities. The aim of this study was to reclassify lesions from a 5-year period previously classified as colorectal HP into traditional hyperplastic polyp (THP), sessile serrated lesions (SSL), and other lesions. All patients were confirmed in the Danish National Pathology Database for the occurrence of metachronous polyps/adenomas, colorectal cancer (CRC), and other gastrointestinal malignancies. Molecular pathology of the CRC were characterized and correlated with the index lesion. In total, 591 HP biopsy specimens were obtained from 480 patients. The lesions were reclassified as: 358 THP, 109 SSL, 35 TA, 81 unspecified non-neoplastic lesions, four traditional serrated adenoma, and 4 SSL with cytological dysplasia. Seven patients developed CRC in the follow-up period (1 patient had SSL, 4 had THP, and 2 had unspecified non-neoplastic lesions). Ten patients developed other gastrointestinal malignancies. The patient with SSL as index lesions who developed CRC harbored V600E BRAF mutation in both index lesion and the carcinoma. Sixteen percent of patients with SSL subsequently developed a neoplastic lesion. Further studies are needed to clarify the cancer risk of SSL. PMID- 25708742 TI - Verbal memory impairment in new onset bipolar disorder: Relationship with frontal and medial temporal morphology. AB - OBJECTIVES: Verbal memory (VM) impairment is a trait feature of bipolar I disorder (BDI) that is present at illness onset and associated with functional outcome. However, little is known about the morphological abnormalities underlying this deficit early in the disease course. This study examined the neurobiological correlates of VM impairment in euthymic newly diagnosed patients, with attention to frontal and medial temporal (MT) structures known to contribute to VM. METHODS: Euthymic patients with BDI recently recovered from their first episode of mania (n = 42) were compared with healthy subjects (n = 37) using measures of the California Verbal Learning Test (CVLT-II) associated with frontal and MT functioning. A subset of participants had 3T MRI scan (n = 31 patient group, n = 30 healthy subject group). Hippocampal and prefrontal volumes were analyzed using FreeSurfer 5.1 and correlated with their corresponding CVLT-II subscores. RESULTS: Patients showed decreased performance in total learning as well as short and long delay verbal recall. Consistent with MT dysfunction, they also showed deficits in recognition discriminability and learning slope. In the patient group only, left hippocampal volumes were negatively correlated with these measures. CONCLUSIONS: These results suggest that anomalous MT functioning is involved with VM impairment early in the course of BDI. PMID- 25708743 TI - Review of patient-reported outcome instruments measuring health-related quality of life and satisfaction in patients with type 2 diabetes treated with oral therapy. AB - OBJECTIVE: Treatments and their mode of administration may represent a burden for patients and can therefore impact their health-related quality of life (HRQL) or treatment/health satisfaction. Patients with type 2 diabetes mellitus (T2DM) can be treated with oral hypoglycemic agents (OHAs), injectable medications (such as insulin), or a combination of agents. This review aimed to identify patient reported outcome (PRO) instruments measuring HRQL and/or satisfaction that could differentiate between oral medications based on medication related attributes such as efficacy, tolerability, weight loss, dosing frequency and pill burden. RESEARCH DESIGN AND METHODS: Medline, Embase, PsycINFO, Cochrane Library and the Patient-Reported Outcome and Quality of Life Questionnaires (PROQOLID) biomedical databases were searched to identify instruments and document their development methodology, content and psychometric properties (i.e. validity, reliability), responsiveness and ability to detect changes between treatments. RESULTS: Nineteen instruments were retained based on their potential to differentiate between OHAs. Ten instruments assessed HRQL, amongst which the Audit of Diabetes Dependent Quality of Life, Diabetes 39, Diabetes Health Profile and Impact of Weight on Quality of Life displayed good psychometric properties in T2DM populations and comprehensive HRQL content. Nine instruments assessed satisfaction. Both the Oral Hypoglycemic Agent Questionnaire (OHAQ) and Diabetes Medication Satisfaction (DiabMedSat) Questionnaire have highly relevant content regarding drug attributes. The OHAQ is specific to oral treatment and the DiabMedSat includes HRQL items. The Diabetes Treatment Satisfaction Questionnaire is a standard instrument that is extensively used and provides conclusive results in studies of patients with T2DM. CONCLUSIONS: Very few of the existing PRO instruments are specific to OHAs. Despite satisfaction instruments being recommended to differentiate between OHAs in studies of T2DM based on medication attributes, we find that none of the existing instruments appear to be useful in detecting differences between treatments, therefore limiting their use in clinical and observational research. PMID- 25708744 TI - [(18)F]VM4-037 MicroPET Imaging and Biodistribution of Two In Vivo CAIX Expressing Tumor Models. AB - PURPOSE: [(18)F]VM4-037 was recently developed as a positron emission tomography (PET) tracer for the detection of carbonic anhydrase IX (CAIX), a tumor-specific protein upregulated under hypoxic conditions. In this study, the accumulation of [(18)F]VM4-037 was determined in two CAIX-expressing preclinical human tumor models. PROCEDURES: U373 and HT29 tumor-bearing animals were injected with [(18)F]VM4-037 and underwent microPET imaging up to 4 h post-injection (p.i.). Biodistribution throughout the different organs was assessed at 2 and 4 h p.i. using gamma counting. RESULTS: MicroPET imaging showed high [(18)F]VM4-037 uptake in the abdominal region, and biodistribution revealed high radioactivity in the kidney, ileum, colon, liver, stomach, and bladder. Although high CAIX expression was confirmed in both tumor models, tumor uptake assessed with microPET and biodistribution experiments was comparable to background tissues. CONCLUSIONS: In this study, [(18)F]VM4-037 does not specifically accumulate in CAIX-expressing tumors, indicating that the tracer is not suitable for the detection of CAIX. PMID- 25708745 TI - Discovery of novel candidate urinary protein biomarkers for prostate cancer in a multiethnic cohort of South African patients via label-free mass spectrometry. AB - PURPOSE: Improvement in diagnostic accuracy of prostate cancer (PCa) progression using MS-based methods to analyze biomarkers in our African, Caucasian, and Mixed Ancestry patients can advance early detection and treatment monitoring. EXPERIMENTAL DESIGN: MS-based proteomic analysis of pooled (N = 36) and individual samples (N = 45) of PCa, benign prostatic hyperplasia, normal healthy controls, and patients with other uropathies was used to identify differences in proteomics profile. Samples were analyzed for potential biomarkers and proteome coverage in African, Caucasian, and Mixed Ancestry PCa patients. RESULTS: A total of 1102 and 5595 protein groups and nonredundant peptides, respectively, were identified in the pooling experiments (FDR = 0.01). Twenty potential biomarkers in PCa were identified and fold differences +/- 2SD were observed in 17 proteins using intensity-based absolute quantification. Analysis of 45 individual samples yielded 1545 and 9991 protein groups and nonredundant peptides, respectively. Seventy-three (73) proteins groups, including existing putative PCa biomarkers, were found to be potential biomarkers of PCa by label-free quantification and demonstrated ethnic trends within our PCa cohort. CONCLUSION AND CLINICAL RELEVANCE: Urinary proteomics is a promising route to PCa biomarker discovery and may serve as source of ethnic-related biomarkers of PCa. PMID- 25708746 TI - Understanding nanoparticle cellular entry: A physicochemical perspective. AB - Understanding interactions between nanoparticles (NPs) with biological matter, particularly cells, is becoming increasingly important due to their growing application in medicine and materials, and consequent biological and environmental exposure. For NPs to be utilised to their full potential, it is important to correlate their functional characteristics with their physical properties, which may also be used to predict any adverse cellular responses. A key mechanism for NPs to impart toxicity is to gain cellular entry directly. Many parameters affect the behaviour of nanomaterials in a cellular environment particularly their interactions with cell membranes, including their size, shape and surface chemistry as well as factors such as the cell type, location and external environment (e.g. other surrounding materials, temperature, pH and pressure). Aside from in vitro and in vivo experiments, model cell membrane systems have been used in both computer simulations and physicochemical experiments to elucidate the mechanisms for NP cellular entry. Here we present a brief overview of the effects of NPs physical parameters on their cellular uptake, with focuses on 1) related research using model membrane systems and physicochemical methodologies; and 2) proposed physical mechanisms for NP cellular entrance, with implications to their nanotoxicity. We conclude with a suggestion that the energetic process of NP cellular entry can be evaluated by studying the effects of NPs on lipid mesophase transitions, as the molecular deformations and thus the elastic energy cost are analogous between such transitions and endocytosis. This presents an opportunity for contributions to understanding nanotoxicity from a physicochemical perspective. PMID- 25708747 TI - Use of White Blood Cell Count and Polymorphonuclear Leukocyte Differential to Improve the Predictive Value of Ultrasound for Suspected Appendicitis in Children. AB - BACKGROUND: The objective of this study was to examine the use of WBC count and polymorphonuclear leukocyte differential (PMN%) for improving the predictive value of ultrasound (US) in children with suspected appendicitis. STUDY DESIGN: We conducted a retrospective cohort study of children undergoing US for suspected appendicitis between January 1, 2010 and December 31, 2012 at a single children's hospital (n=845). Negative (NPV) and positive predictive values (PPV) for appendicitis were calculated for common constellations of US findings and compared with and without the use of laboratory thresholds (WBC>9*10(3)/MUL and PMN%>65% for PPV; WBC<=9*10(3)/MUL and PMN%<=65% for NPV). RESULTS: Fifty-one percent of US were considered "equivocal" (ie, appendix incompletely visualized, no primary or secondary signs, or presence of fluid only) and NPV increased significantly for this cohort using laboratory thresholds (41.9% vs 95.8%; p<0.001). Primary signs of appendicitis, without secondary signs, were documented in 18% of examinations, and the PPV associated with this cohort increased from 79.1% to 91.3% (p<0.001) using laboratory thresholds. Secondary signs with or without primary signs were documented in 24% of examinations, and laboratory thresholds improved the PPV in this cohort from 89.1% to 96.8% (p<0.001). Guidelines recommending against the use of CT for very high-risk and low-risk categories (NPV>95% and PPV>95%) on the basis of combined US and laboratory data could have reduced the number of CTs by 27.1% (101 of 373) during the study period. CONCLUSIONS: The incorporation of WBC count and PMN% can substantially improve the predictive value of US in the diagnosis of suspected appendicitis in children. PMID- 25708748 TI - Copper-mediated aromatic radiofluorination revisited: efficient production of PET tracers on a preparative scale. AB - Two novel methods for copper-mediated aromatic nucleophilic radiofluorination were recently reported. Evaluation of these methods reveals that, although both are efficient in small-scale experiments, they are inoperative for the production of positron emission tomography (PET) tracers. Since high base content turned out to be responsible for low radiochemical conversions, a "low base" protocol has been developed which affords (18)F-labeled arenes from diaryliodonium salts and aryl pinacol boronates in reasonable yields. Furthermore, implementation of our "minimalist" approach to the copper-mediated [(18)F]-fluorination of (mesityl)(aryl)iodonium salts allows the preparation of (18)F-labeled arenes in excellent RCCs. The novel radiofluorination method circumvents time-consuming azeotropic drying and avoids the utilization of base and other additives, such as cryptands. Furthermore, this procedure enables the production of clinically relevant PET tracers; [(18)F]FDA, 4-[(18)F]FPhe, and [(18)F]DAA1106 are obtained in good isolated radiochemical yields. Additionally, [(18)F]DAA1106 has been evaluated in a rat stroke model and demonstrates excellent potential for visualization of translocator protein 18 kDa overexpression associated with neuroinflammation after ischemic stroke. PMID- 25708749 TI - Characterization of a new Kunitz-type serine protease inhibitor from the hard tick Rhipicephalus hemaphysaloides. AB - A new Kunitz-type serine protease inhibitor, Rhipilin-2, was identified in the tick Rhipicephalus hemaphysaloides. The cDNA sequence of Rhipilin-2 is 693 bp, and it encodes a deduced 195 amino acid protein with a size of 22 kDa. Bioinformatic analysis shows that Rhipilin-2 belongs to the Kunitz-type family of inhibitors, containing one Kunitz domain with homology to the tissue factor pathway inhibitor. Using Real time polymerase chain reaction (Real time-PCR), Rhipilin-2 mRNA transcripts were detected in tick salivary glands and midgut. Blood feeding induced transcript expression. The recombinant protein was expressed in insect Sf9 cells and confirmed by immunofluorescence test and Western blot analysis with an anti-His antibody. The purified recombinant Rhipilin-2 inhibited serine protease trypsin and elastase, but not thrombin. The anticoagulant activity of Rhipilin-2 was shown by delaying normal clotting of rabbit plasma in the activated partial thromboplastin time tests. These results indicate that Rhipilin-2 is a novel Kunitz-type serine protease inhibitor involved in tick blood feeding. PMID- 25708753 TI - Skill and colonoscopy: even the pros take lessons. PMID- 25708751 TI - Mitosis, microtubule dynamics and the evolution of kinesins. PMID- 25708752 TI - SCENIC international consensus statement on surveillance and management of dysplasia in inflammatory bowel disease. PMID- 25708754 TI - Improving complete EMR of colorectal neoplasia: a randomized trial comparing snares and injectate in the resection of large sessile colon polyps. AB - BACKGROUND: There are few randomized studies examining efficacy of snares and agents in EMR. OBJECTIVE: To compare the use of a combined needle and snare unit with injectate versus a spiral wire and injectate (primary); saline solution versus hydroxypropyl methylcellulose (secondary). DESIGN: Prospective, randomized, factorial, single center. SETTING: Tertiary-care academic medical center. PATIENTS: A total of 140 patients with large (>15 mm), sessile, colorectal polyps. INTERVENTIONS: Polyps randomized to either 1 of 2 snare types and 1 of 2 injectates. MAIN OUTCOME MEASUREMENTS: Primary-the Sydney resection quotient (SRQ), defined as the size of the polyp divided by the number of pieces resected and the amount of tissue per snare attempt. Secondary-procedure time, adverse events, residual neoplasia at follow-up. RESULTS: The SRQ was higher with the combined unit (median 13.8 mm vs 7.1 mm; P = .019); additionally, procedure time was less (median 6 vs 11 minutes; P < .001). Resection was considered complete after the EMR in 62% (42/68) with the combined needle and snare unit versus 51% (37/72; P = .22) with the spiral wire. Rates of adverse events were similar. Residual neoplasia was found at follow-up in 22% (10/46) with the combined needle and snare unit versus 21% (10/48; P = .89) with the spiral wire. There was no evidence of differences in outcomes by lifting agent. LIMITATIONS: The SRQ is only a surrogate marker. CONCLUSION: This study provides evidence that the integrated needle-snare may be superior to the snare alone for the removal of large, flat polyps. Additionally, the type of injectate appears to have no impact on outcome. PMID- 25708755 TI - Diagnostic performance of EUS for evaluating the invasion depth of early colorectal cancers. AB - BACKGROUND: EUS is one technique used to estimate the invasion depth of early colorectal cancer (CRC), but its diagnostic accuracy remains a matter of debate. OBJECTIVE: To assess the accuracy of EUS for estimating the invasion depth of early CRC. DESIGN: Retrospective analysis. SETTING: Tertiary-care academic medical center. PATIENTS: The invasion depth of early CRC was estimated by EUS from 1989 through 2012. INTERVENTIONS EUS MAIN OUTCOME MEASUREMENTS: Accuracy of EUS diagnosis, risk factors for misdiagnosis, and characteristics of lesions that were difficult to image. RESULTS: We estimated the invasion depth of 714 cases of early CRC on EUS. Of the lesions able to be visualized on EUS, the overall diagnostic accuracy of EUS for differentiating between lesions that could be resected endoscopically (Tis and T1a cancers), and those that required colectomy (T1b cancers) was 89%. Submucosal cancer and a macroscopic classification of superficial type were independent risk factors for misdiagnosis. Ninety lesions (13%) were difficult to image. Risk factors for difficulty in imaging were protruding-type morphology and tumor location in the sigmoid colon or from the descending colon to the cecum. LIMITATIONS: Single center, retrospective. Experienced endoscopists performed EUS. CONCLUSIONS: Although some lesions that were protruding or located in the proximal colon were difficult to visualize, EUS is considered a useful technique for the diagnosis of invasion depth and the selection of treatment in patients with early CRC. PMID- 25708756 TI - Good is better than excellent: bowel preparation quality and adenoma detection rates. AB - BACKGROUND: Inadequate bowel cleansing is associated with missed lesions, yet whether polyp and adenoma detection rates (PDR, ADR) increase at the highest levels of bowel cleanliness is unknown. OBJECTIVE: To evaluate the association between bowel preparation quality by using the Boston Bowel Preparation Scale (BBPS) and PDR and ADR among colonoscopies with adequate preparation. DESIGN: Cross-sectional analysis. SETTING: Boston Medical Center (BMC) and the Clinical Outcomes Research Initiative (CORI). PATIENTS: Average-risk ambulatory patients attending screening colonoscopy with adequate bowel preparation defined as BBPS score >=6. INTERVENTIONS: Colonoscopy. MAIN OUTCOME MEASUREMENTS: PDR and ADR stratified by BBPS score. RESULTS: Among the 3713 colonoscopies at BMC performed by 19 endoscopists, the PDR, ADR, and advanced ADR were 49.8%, 37.7%, and 6.0%, respectively. Among the 5532 colonoscopies in CORI performed by 85 endoscopists at 41 different sites, the PDR was 44.5%, and the PDR for polyps >9 mm (surrogate for advanced ADR) was 6.2%. The PDR associated with total BBPS scores of 6, 7, and 8 were higher than those associated with a BBPS score of 9 at BMC (BBPS 6, 51%; BBPS 7, 53%; BBPS 8, 52% vs BBPS 9, 46%; P = .002) and CORI (BBPS 6, 51%; BBPS 7, 48%; BBPS 8, 45% vs BBPS 9, 40%; P < .0001). This trend persisted after we adjusted for age, sex, and race and/or ethnicity and was observed for ADR and advanced ADR. PDR was higher among good compared with excellent preparations at BMC (odds ratio [OR] 1.3; 95% confidence interval [CI], 1.0-1.5) and CORI (OR 4.7; 95% CI, 3.1-7.1). LIMITATIONS: Retrospective study. CONCLUSION: The PDR and ADR decreased at the highest levels of bowel cleanliness. Endoscopists finding a pristine bowel preparation should avoid a sense of overconfidence for polyp detection during the inspection phase of screening colonoscopy and still perform a careful evaluation for polyps. Furthermore, endoscopists expending additional effort to maximize cleansing of the bowel should never sacrifice on their inspection technique or inspection time. PMID- 25708758 TI - Colorectal cancer screening: what program is most effective? PMID- 25708757 TI - Comparing the effectiveness of competing tests for reducing colorectal cancer mortality: a network meta-analysis. AB - BACKGROUND: Comparative effectiveness data pertaining to competing colorectal cancer (CRC) screening tests do not exist but are necessary to guide clinical decision making and policy. OBJECTIVE: To perform a comparative synthesis of clinical outcomes studies evaluating the effects of competing tests on CRC related mortality. DESIGN: Traditional and network meta-analyses. Two reviewers identified studies evaluating the effect of guaiac-based fecal occult blood testing (gFOBT), flexible sigmoidoscopy (FS), or colonoscopy on CRC-related mortality. INTERVENTIONS: gFOBT, FS, colonoscopy. MAIN OUTCOME MEASUREMENTS: Traditional meta-analysis was performed to produce pooled estimates of the effect of each modality on CRC mortality. Bayesian network meta-analysis (NMA) was performed to indirectly compare the effectiveness of screening modalities. Multiple sensitivity analyses were performed. RESULTS: Traditional meta-analysis revealed that, compared with no intervention, colonoscopy reduced CRC-related mortality by 57% (relative risk [RR] 0.43; 95% confidence interval [CI], 0.33 0.58), whereas FS reduced CRC-related mortality by 40% (RR 0.60; 95% CI, 0.45 0.78), and gFOBT reduced CRC-related mortality by 18% (RR 0.82; 95% CI, 0.76 0.88). NMA demonstrated nonsignificant trends favoring colonoscopy over FS (RR 0.71; 95% CI, 0.45-1.11) and FS over gFOBT (RR 0.74; 95% CI, 0.51-1.09) for reducing CRC-related deaths. NMA-based simulations, however, revealed that colonoscopy has a 94% probability of being the most effective test for reducing CRC mortality and a 99% probability of being most effective when the analysis is restricted to screening studies. LIMITATIONS: Randomized trials and observational studies were combined within the same analysis. CONCLUSION: Clinical outcomes studies demonstrate that gFOBT, FS, and colonoscopy are all effective in reducing CRC-related mortality. Network meta-analysis suggests that colonoscopy is the most effective test. PMID- 25708759 TI - Attempted underwater en bloc resection for large (2-4 cm) colorectal laterally spreading tumors (with video). AB - OBJECTIVE: To evaluate the feasibility and outcomes of attempted underwater en bloc resection (UEBR) of large colorectal laterally spreading tumors (LSTs). DESIGN: Prospective, observational study. SETTING: Tertiary academic referral center. PATIENTS: Fifty patients meeting the inclusion and exclusion criteria. INTERVENTIONS: Standardized UEBR technique involving attempted en bloc resection without submucosal injection by using a large 33-mm snare. MAIN OUTCOME MEASUREMENTS: Complete endoscopic en bloc resection, histologic complete resection, procedure time, adverse events, and follow-up data. RESULTS: Over 13 months, UEBR was attempted in 50 patients (median age, 68 years) with 53 LSTs 2 to 4 cm in size. The median LST size was 30 mm (range 20-40 mm). The median procedure and resection times were 38 minutes (range 17-87 minutes) and 3 minutes (range 1-32 minutes), respectively. Complete endoscopic en bloc resection with the 33-mm snare was successful in 29 of 53 lesions (55%). Of these, histology showed neoplasia-free margins in 79%. Final histology was tubular adenoma (n = 26), sessile serrated adenoma (n = 10), tubulovillous adenoma (n = 14), villous adenoma (n = 2), and intramucosal carcinoma (n = 1). Adverse events (4%) were delayed bleeding in 1 and abdominal pain in 1 patient each. There were no perforations. Forty patients with a total of 43 adenomas had follow-up colonoscopy with biopsies of the resection site after a median of 31 weeks (range 7-71 weeks) after resection. Residual adenoma was found in 2 of 43 (5%). LIMITATIONS: Single-center, limited follow-up. CONCLUSION: On an intention-to treat basis, complete endoscopic en bloc resection was achieved in 55% of lesions with complete histologic resection verified in 79% of the en bloc specimens. UEBR without submucosal injection appears safe. Refinements are needed to improve UEBR success rates. PMID- 25708760 TI - A combination of clinical risk stratification and fecal immunochemical test results to prioritize colonoscopy screening in asymptomatic participants. AB - BACKGROUND: Stool-based colonoscopy is the preferred strategy for colorectal cancer (CRC) screening. The Asia-Pacific Colorectal Screening System (APCS) score also is helpful in stratifying the risk for advanced neoplasia in the asymptomatic population. The combination of the fecal immunochemical test (FIT) result and clinical risk stratification may be more helpful in stratifying the risk. OBJECTIVE: To evaluate the value of the combination of FIT and APCS scores in stratifying asymptomatic participants for colonoscopy. DESIGN: Cross-sectional study. SETTING: University hospital. PATIENTS: A total of 948 asymptomatic participants eligible for screening colonoscopy. INTERVENTIONS: FIT, APCS score evaluation, screening colonoscopy. MAIN OUTCOME MEASUREMENTS: The prevalence of colorectal neoplasia in 4 different groups of participants according to FIT and APCS score evaluations. RESULTS: The prevalence of non-advanced and advanced neoplasia in the 4 groups (high risk with positive FIT result, high risk with negative FIT result, moderate risk with positive FIT result, and moderate risk with negative FIT result) was 44% versus 36.9%, 30.1% versus 11.6%, 27.1% versus 12%, and 22.6% versus 6.4%, respectively (P < .001). Participants with both high risk scores and positive FIT results had a significantly higher detection rate of advanced neoplasia (6.15-fold, 95% confidence interval, 3.72-10.17) compared with the other 3 groups. Seven cancers were discovered; 4 were in the high-risk with positive FIT result group. LIMITATIONS: Hospital-based study. CONCLUSION: In countries with limited resources, participants with positive FIT results and high risk scores by APCS should be given priority for colonoscopy because this group is most likely to have advanced neoplasia. However, this strategy needs to be confirmed for its cost-effectiveness in a large, population-based study. ( CLINICAL TRIAL REGISTRATION NUMBER: TCTR20140228001.). PMID- 25708761 TI - Diminutive polyps among black and Latino populations undergoing screening colonoscopy: evidence supporting a resect and discard approach. AB - BACKGROUND: A resect and discard strategy for diminutive (<=5 mm) colon polyps has been proposed to save costs of screening colonoscopy (SC). Prior studies on neoplasia prevalence based on polyp size have involved mostly white patients. OBJECTIVE: To determine the prevalence of adenomas and advanced histologic features by size among primarily black and Latino patients enrolled in a prospective SC study. DESIGN: Retrospective analysis of data from a prospective clinical trial. SETTING: Urban academic medical center. PATIENTS: Average risk, asymptomatic, minority patients aged >=50 years undergoing SC. INTERVENTIONS: Screening colonoscopy. MAIN OUTCOME MEASUREMENTS: Rates of neoplasia and advanced histologic features (villous histology, high-grade dysplasia, or cancer) by polyp size and location. RESULTS: A total of 566 polyps from 295 patients were analyzed. Diminutive polyps and small (6-9 mm) polyps had lower prevalence of >=1 advanced feature compared with large (>=10 mm) polyps (0.9% and 2.7%, respectively, vs 13.6%; P < .001 for both comparisons). Distal polyps were less likely to be neoplastic (31.7% vs 61.4%; P < .001) than proximal polyps in all size categories (P < .001 for all comparisons). After adjusting for sex, ethnicity, age, and location, large polyps were more likely to have >=1 advanced feature than diminutive polyps (adjusted odds ratio [OR] 19.5; 95% CI, 4.4-85.6) or small polyps (adjusted OR 6.1; 95% CI, 2.2-16.9). LIMITATIONS: Use of pathology reports for polyp size. CONCLUSION: Among a cohort of minority patients, advanced histologic features were very rare in diminutive polyps. Distal polyps were less likely to be neoplastic than proximal polyps in all size categories. This supports a resect and discard strategy for diminutive polyps, especially in the distal colon. PMID- 25708762 TI - Endoscopic and surgical treatment of malignant colorectal polyps: a population based comparative study. AB - BACKGROUND: Long-term population-based data comparing endoscopic therapy (ET) and surgery for management of malignant colorectal polyps (MCPs) are limited. OBJECTIVE: To compare colorectal cancer (CRC)-specific survival with ET and surgery. DESIGN AND SETTING: Population-based study. PATIENTS: Patients with stage 0 and stage 1 MCPs were identified from the Surveillance Epidemiology and End Results (SEER) database (1998-2009). Demographic characteristics, tumor size, location, treatment modality, and survival were compared. Propensity-score matching and Cox proportional hazards regression models were used to evaluate the association between treatment and CRC-specific survival. INTERVENTIONS: ET and surgery. MAIN OUTCOME MEASUREMENTS: Mid-term (2.5 years) and long-term (5 years) CRC-free survival rates and independent predictors of CRC-specific mortality. RESULTS: Of 10,403 patients with MCPs, 2688 (26%) underwent ET and 7715 (74%) underwent surgery. Patients undergoing ET were more likely to be older white men with stage 0 disease. Surgical patients had more right-sided lesions, larger MCPs, and stage 1 disease. There was no difference in the 2.5-year and 5-year CRC free survival rates between the 2 groups in stage 0 disease. Surgical resection led to higher 2.5-year (97.8% vs 93.2%; P < .001) and 5-year (96.6% vs 89.8%; P < .001) CRC-free survival in stage 1 disease. These results were confirmed by propensity-score matching. ET was a significant predictor for CRC-specific mortality in stage 1 disease (hazard ratio 2.40; 95% confidence interval, 1.75 3.29; P < .001). LIMITATIONS: Comorbidity index not available, selection bias. CONCLUSIONS: ET and surgery had comparable mid- and long-term CRC-free survival rates in stage 0 disease. Surgical resection is the recommended treatment modality for MCPs with submucosal invasion. PMID- 25708763 TI - Cold snare polypectomy versus cold forceps polypectomy for diminutive and small colorectal polyps: a randomized controlled trial. AB - BACKGROUND: The optimal technique for removal of diminutive or small colorectal polyps is debatable. OBJECTIVE: To compare the complete resection rates of cold snare polypectomy (CSP) and cold forceps polypectomy (CFP) for the removal of adenomatous polyps <=7 mm. DESIGN: Prospective randomized controlled study. SETTING: A university hospital. PATIENTS: A total of 139 patients who were found to have >=1 colorectal adenomatous polyps <=7 mm. INTERVENTIONS: Polyps were randomized to be treated with either CSP or CFP. After the initial polypectomy, additional EMR was performed at the polypectomy site to assess the presence of residual polyp tissue. MAIN OUTCOME MEASUREMENTS: Absence of residual polyp tissue in the EMR specimen of the polypectomy site was defined as complete resection. RESULTS: Among a total of 145 polyps, 128 (88.3%) were adenomatous polyps. The overall complete resection rate for adenomatous polyps was significantly higher in the CSP group compared with the CFP group (57/59, 96.6% vs 57/69, 82.6%; P = .011). Although the complete resection rates for adenomatous polyps <=4 mm were not different (27/27, 100% vs 31/32, 96.9%; P = 1.000), the complete resection rates for adenomatous polyps sized 5 to 7 mm was significantly higher in the CSP group compared with the CFP group (30/32, 93.8% vs 26/37, 70.3%; P = .013). LIMITATIONS: Single-center study. CONCLUSION: CSP is recommended for the complete resection of colorectal adenomatous polyps <=7 mm. ( CLINICAL TRIAL REGISTRATION NUMBER: NCT01665898.). PMID- 25708764 TI - Colonic Dieulafoy's lesion. PMID- 25708765 TI - Solitary polypoid colonic neuromatosis. PMID- 25708766 TI - Analysis of fiducials implanted during EUS for patients with localized rectal cancer receiving high-dose rate endorectal brachytherapy. PMID- 25708767 TI - Efficacy and safety of endoscopic radial incision and cutting for benign severe anastomotic stricture after surgery for lower rectal cancer (with video). PMID- 25708768 TI - Response. PMID- 25708769 TI - The optimal interval of endoscopic variceal ligation: an issue of controversy. PMID- 25708770 TI - Inflammatory gastric outlet obstruction after acute pancreatitis: a novel method of treatment. PMID- 25708771 TI - Continuous-flow left ventricular assist devices as a cause of acquired von Willebrand syndrome and GI bleeding. PMID- 25708772 TI - Response. PMID- 25708773 TI - A comparison of oral sulfate solution with sodium picosulfate and magnesium citrate in split doses as bowel preparation for colonoscopy. PMID- 25708774 TI - Response. PMID- 25708775 TI - EXPath: a database of comparative expression analysis inferring metabolic pathways for plants. AB - BACKGROUND: In general, the expression of gene alters conditionally to catalyze a specific metabolic pathway. Microarray-based datasets have been massively produced to monitor gene expression levels in parallel with numerous experimental treatments. Although several studies facilitated the linkage of gene expression data and metabolic pathways, none of them are amassed for plants. Moreover, advanced analysis such as pathways enrichment or how genes express under different conditions is not rendered. DESCRIPTION: Therefore, EXPath was developed to not only comprehensively congregate the public microarray expression data from over 1000 samples in biotic stress, abiotic stress, and hormone secretion but also allow the usage of this abundant resource for coexpression analysis and differentially expression genes (DEGs) identification, finally inferring the enriched KEGG pathways and gene ontology (GO) terms of three model plants: Arabidopsis thaliana, Oryza sativa, and Zea mays. Users can access the gene expression patterns of interest under various conditions via five main functions (Gene Search, Pathway Search, DEGs Search, Pathways/GO Enrichment, and Coexpression analysis) in EXPath, which are presented by a user-friendly interface and valuable for further research. CONCLUSIONS: In conclusion, EXPath, freely available at http://expath.itps.ncku.edu.tw, is a database resource that collects and utilizes gene expression profiles derived from microarray platforms under various conditions to infer metabolic pathways for plants. PMID- 25708777 TI - Influence of the vitreomacular interface on the efficacy of intravitreal therapy for uveitis-associated cystoid macular oedema. AB - PURPOSE: To evaluate the effect of the vitreomacular interface (VMI) on treatment efficacy of intravitreal therapy in uveitic cystoid macular oedema (CME). METHODS: Retrospective analysis of CME resolution, CME recurrence rate and monthly course of central retinal thickness (CRT), retinal volume (RV) and best corrected visual acuity (BCVA) after intravitreal injection with respect to the VMI configuration on spectral-domain OCT using chi-squared test and repeated measures anova adjusted for confounding covariates epiretinal membrane, administered drug and subretinal fluid. RESULTS: Fifty-nine eyes of 53 patients (mean age: 47.4 +/- 16.9 years) were included. VMI status had no effect on complete CME resolution rate (p = 0.16, corrected p-value: 0.32), time until resolution (p = 0.09, corrected p-value: 0.27) or CME relapse rate (p = 0.29, corrected p-value: 0.29). Change over time did not differ among the VMI configuration groups for BVCA (p = 0.82) and RV (p = 0.18), but CRT decrease was greater and faster in the posterior vitreous detachment (PVD) group compared to the posterior vitreous attachment (PVA) and vitreous macular adhesion (VMA) groups (p = 0.04). Also, the percentage of patients experiencing a >= 20% CRT thickness decrease after intravitreal injection was greater in the PVD group (83%) compared to the VMA (64%) and the PVA (16%) group (p = 0.027), however, not after correction for multiple testing (corrected p-value: 0.11). CONCLUSION: The VMI configuration seems to be a factor contributing to treatment efficacy in uveitic CME in terms of CRT decrease, although BCVA outcome did not differ according to VMI status. PMID- 25708778 TI - Photonic lattice simulation of dissipation-induced correlations in bosonic systems. AB - We propose an optical simulation of dissipation-induced correlations in one dimensional (1D) interacting bosonic systems, using a two-dimensional (2D) array of linear photonic waveguides and only classical light. We show that for the case of two bosons in a 1D lattice, one can simulate on-site two-body dissipative dynamics using a linear 2D waveguide array with lossy diagonal waveguides. The intensity distribution of the propagating light directly maps out the wave function, allowing one to observe the dissipation-induced correlations with simple measurements. Beyond the on-site model, we also show that a generalised model containing nearest-neighbour dissipative interaction can be engineered and probed in the proposed set-up. PMID- 25708779 TI - Mitochondrial free radical overproduction due to respiratory chain impairment in the brain of a mouse model of Rett syndrome: protective effect of CNF1. AB - Rett syndrome (RTT) is a pervasive neurodevelopmental disorder mainly caused by mutations in the X-linked MECP2 gene associated with severe intellectual disability, movement disorders, and autistic-like behaviors. Its pathogenesis remains mostly not understood and no effective therapy is available. High circulating levels of oxidative stress markers in patients and the occurrence of oxidative brain damage in MeCP2-deficient mouse models suggest the involvement of oxidative stress in RTT pathogenesis. However, the molecular mechanism and the origin of the oxidative stress have not been elucidated. Here we demonstrate that a redox imbalance arises from aberrant mitochondrial functionality in the brain of MeCP2-308 heterozygous female mice, a condition that more closely recapitulates that of RTT patients. The marked increase in the rate of hydrogen peroxide generation in the brain of RTT mice seems mainly produced by the dysfunctional complex II of the mitochondrial respiratory chain. In addition, both membrane potential generation and mitochondrial ATP synthesis are decreased in RTT mouse brains when succinate, the complex II respiratory substrate, is used as an energy source. Respiratory chain impairment is brain area specific, owing to a decrease in either cAMP-dependent phosphorylation or protein levels of specific complex subunits. Further, we investigated whether the treatment of RTT mice with the bacterial protein CNF1, previously reported to ameliorate the neurobehavioral phenotype and brain bioenergetic markers in an RTT mouse model, exerts specific effects on brain mitochondrial function and consequently on hydrogen peroxide production. In RTT brains treated with CNF1, we observed the reactivation of respiratory chain complexes, the rescue of mitochondrial functionality, and the prevention of brain hydrogen peroxide overproduction. These results provide definitive evidence of mitochondrial reactive oxygen species overproduction in RTT mouse brain and highlight CNF1 efficacy in counteracting RTT-related mitochondrial defects. PMID- 25708780 TI - Structure-function analysis of peroxidasin provides insight into the mechanism of collagen IV crosslinking. AB - Basement membranes provide structural support and convey regulatory signals to cells in diverse tissues. Assembly of collagen IV into a sheet-like network is a fundamental mechanism during the formation of basement membranes. Peroxidasin (PXDN) was recently described to catalyze crosslinking of collagen IV through the formation of sulfilimine bonds. Despite the significance of this pathway in tissue genesis, our understanding of PXDN function is far from complete. In this work we demonstrate that collagen IV crosslinking is a physiological function of mammalian PXDN. Moreover, we carried out structure-function analysis of PXDN to gain a better insight into its role in collagen IV synthesis. We identify conserved cysteines in PXDN that mediate the oligomerization of the protein into a trimeric complex. We also demonstrate that oligomerization is not an absolute requirement for enzymatic activity, but optimal collagen IV coupling is only catalyzed by the PXDN trimers. Localization experiments of different PXDN mutants in two different cell models revealed that PXDN oligomers, but not monomers, adhere on the cell surface in "hot spots," which represent previously unknown locations of collagen IV crosslinking. PMID- 25708781 TI - The clinical usefulness of ESR, CRP, and disease duration in ankylosing spondylitis: the product of these acute-phase reactants and disease duration is associated with patient's poor physical mobility. AB - We evaluated the clinical usefulness of ESR, CRP, and disease duration in ankylosing spondylitis (AS) disease severity. There were 156 Chinese AS patients included in Taiwan. Patients completed the questionnaires, containing demographic data, disease activity (BASDAI), functional status (BASFI), and patient's global assessment (BASG). Meanwhile, patient's physical mobility (BASMI) and acute-phase reactants, including ESR and CRP levels were measured. Receiver operating characteristic (ROC) plot analysis was used to evaluate the performance of ESR, CRP, and disease duration in the AS patients. ESR mildly correlated with BASFI (r = 0.176, p = 0.028) and disease duration (r = 0.214, p = 0.008), and moderately correlated with BASMI (r = 0.427, p < 0.001). CRP moderately correlated with BASMI (r = 0.410, p < 0.001). By using ROC plot analysis, ESR, CRP, and disease duration showed the best and significant "area under the curve (AUC)", in distinguishing the AS patients with poor physical mobility (BASMI >= 3.6, the Median) (AUC = 0.748, 0.751 and 0.738, respectively, all p < 0.001), as compared to BASDAI, BASFI, and BASG. ESR * disease duration (AUC = 0.801, p < 0.001) and CRP * disease duration (AUC = 0.821, p < 0.001) showed higher AUC values than ESR or CRP alone in indicating poor physical mobility. For detecting poor physical mobility (BASMI >= 3.6) in the AS patients: ESR * disease duration (>=60.0 mm/h * year): sensitivity = 72.7 % and specificity = 72.8 %; CRP * disease duration (>=8.3 mg/dl * year): sensitivity = 72.7 % and specificity = 74.6 %. ESR, CRP, and disease duration are particularly related to AS patient's poor physical mobility. Combining the usefulness of acute-phase reactants and disease duration, the values of ESR * disease duration and CRP * disease duration demonstrate better association with poor physical mobility in AS patients. PMID- 25708782 TI - Common mental disorders among women, social circumstances and toddler growth in rural Vietnam: a population-based prospective study. AB - BACKGROUND: Common mental disorders (CMD) and adverse social circumstances are widespread among mothers of infants and toddlers in resource-constrained settings. These can undermine early childhood development through compromised caregiving and insufficient access to essential resources. The aim was to examine the effect of maternal CMD and social adversity in the post-partum year on toddler's length-for-age index in a rural low-income setting. METHODS: A population-based prospective cohort study of women in Ha Nam province, Vietnam who completed baseline assessments in either late pregnancy or 4-6 weeks post partum and were followed up, with their toddlers, 15 months later. CMD were assessed at both points by psychiatrist-administered Structured Clinical Interviews for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Diagnoses. Anthropometric indices were calculated from toddler's age, sex, weight and length using World Health Organization Child Growth Standards. Social adversities were assessed by study-specific questions and locally validated psychometric instruments. The hypothesized model of factors governing toddler's length-for-age Z score (LAZ) was tested using path analysis. RESULTS: In total, 211/234 (90.1%) mother-toddler pairs provided complete data. Baseline prevalence of CMD among women was 33.6% and follow-up was 18.5%. The mean LAZ among toddlers was -1.03 and stunting prevalence (LAZ < -2) was 15.6%. Maternal CMD at baseline were indirectly related to toddler LAZ via maternal CMD at follow up (regression coefficient = -0.05, 95% CI -0.11 to -0.01). Maternal CMD at follow-up was associated significantly with toddler LAZ (regression coefficient = -0.15, 95% CI -0.28 to -0.05). Poorer quality of marital relationship, mothers' experiences of childhood abuse and <30 days dedicated post-partum care were associated indirectly with lower toddler LAZ via maternal CMD. CONCLUSIONS: Maternal post-natal CMD are associated with child growth measured by LAZ in this resource-constrained setting. Social adversities affect child growth indirectly through increasing the risk of maternal CMD. Interventions to reduce stunting in low-income settings may need to address maternal CMD and social adversities in order to improve impact. PMID- 25708783 TI - DNA amplification and repair: Further insights by cytometry. PMID- 25708787 TI - A case of Murray Valley encephalitis in a 2-year-old Australian Stock Horse in south-east Queensland. AB - CASE REPORT: This report summarises the findings from a case of naturally occurring Murray Valley encephalitis in a 2-year-old filly presenting with acute onset of depression and weakness. Serum samples tested at the onset of clinical signs were negative for Hendra and Kunjin virus antibodies, but positive for Murray Valley encephalitis virus (MVEV) using IgM-capture ELISA (1 : 300 dilution). A virus neutralisation assay performed 4 weeks later confirmed a titre of 1 : 160. Sera collected in the weeks preceding neurological signs returned a negative titre for MVEV 2 weeks prior followed by a titre of 1:80 in the week prior to illness. Serological surveillance conducted on 67 co-located horses returned a positive titre of 1 : 20 in one in-contact horse. There was no history of clinical disease in that horse. At 3 months after the onset of clinical signs in the index case, the filly continued to show mild facial paresis and hypermetria; the owners elected euthanasia and gave permission for necropsy. Histopathological analysis of the brain showed a mild meningoencephalitis. CONCLUSION: The progression of a naturally-occurring MVEV infection in a horse has been documented in this case. PMID- 25708789 TI - Right-sided congestive heart failure in a dog because of a primary intracavitary myocardial lymphoma. AB - CASE REPORT: A 9-year-old female intact Cocker Spaniel was presented with a history of acute-onset dyspnoea and abdominal distension of 3 days' duration. Ultrasonography revealed pleural, peritoneal and pericardial effusions. Abdominal fluid analysis was consistent with a modified transudate. Echocardiography revealed a large, hypoechoic space-occupying mass within the right atrium. The dog was euthanased and the postmortem examination showed a solid, 40 * 35 * 20 mm broad-based mass arising from the right atrial wall and occluding approximately 90% of the right atrial lumen. Histopathology revealed myocardial lymphoma. There were histologically similar, focal nodules in the lung parenchyma without involvement of other extracardiac sites. There was gross and histological evidence of hepatic congestion and marked distension of the caudal vena cava, consistent with secondary right-sided congestive heart failure. CONCLUSION: This case highlights the need to consider lymphoma as a differential diagnosis for an intra-atrial mass and as a cause of congestive heart failure in the dog. PMID- 25708788 TI - Canine tick-borne pathogens and associated risk factors in dogs presenting with and without clinical signs consistent with tick-borne diseases in northern Australia. AB - OBJECTIVES: To estimate the proportion of canine tick-borne disease (CTBD) pathogens in dogs from northern states of Australia presenting with and without clinical signs/laboratory abnormalities suggestive of CTBD and to evaluate associated risk factors. DESIGN: Client-owned dogs presented to a general practice clinic in the Northern Territory (NT; n = 138) and five referral hospitals in south-east Queensland (SEQ; n = 100) were grouped into CTBD-suspect and -control groups based on clinical and laboratory criteria. Blood and sera were screened for haemotropic Mycoplasma spp., Babesia spp., Anaplasma spp., Ehrlichia spp. and Hepatozoon spp. using microscopic examination, in-clinic ELISA testing and PCR assays. Dog-specific risk factors associated with the presence of CTBD pathogens were evaluated. RESULTS: Overall, 24.4% of the suspect group and 12.2% of the control group dogs were infected. The proportions of M. haemocanis, B. vogeli, A. platys, Candidatus Mycoplasma haematoparvum, and C. Mycoplasma haemobos were 7.1%, 5.0%, 3.8%, 1.7% and 0.4%, respectively. Dogs originating from the NT were 3.6-fold (95% confidence interval (CI) 1.51-8.62; P = 0.004) more likely to be infected with CTBD pathogens than those from SEQ. Male dogs were 2.3-fold (95% CI 1.17-4.80, P = 0.024) more likely to be PCR-positive to CTBD pathogens than female dogs. Dogs presenting with clinical signs consistent with CTBD and thrombocytopenia were more likely to be infected by CTBD pathogens (odds ratio 2.85; 95% CI 1.16, 7.02; P = 0.019). CONCLUSIONS: Haemotropic mycoplasmas were the most common tick-borne pathogen infecting client-owned dogs. Subclinical cases were common in dogs from the NT. Veterinary practitioners should be aware of the proportion of CTBD pathogens and the presenting features of clinical and subclinical disease in their area. PMID- 25708790 TI - An investigation into exposure of pigs to lead from contaminated zinc oxide in 2007-2008. AB - BACKGROUND: High levels of lead, up to 3.3 mg/kg fresh weight, were detected in pig liver in Western Australia at the beginning of 2008. This followed the detection of lead at above the maximum level (ML) in a pig liver through the National Residue Survey (NRS). The contamination source was traced back to a zinc oxide feed additive used early post-weaning that contained in excess of 8% lead. METHODS AND RESULTS: Confirmation of the source of lead contamination was obtained by comparing lead isotope ratios for the zinc oxide and the pig livers. The investigation demonstrated the importance of verifying the safety of feed and feed ingredients prior to incorporation in feed. Retrospective analysis of NRS data indicated that the level of lead needed to trigger an investigation for intensively housed pigs should be considerably lower than the ML. As a result, investigations in Australia will now be conducted when levels of lead in pig liver exceed 0.1 mg/kg fresh weight. CONCLUSIONS: Despite the potential for small amounts of non-compliant kidney and liver to enter the human food chain, there was no significant increase in the risk to consumers. PMID- 25708791 TI - Molybdenum deprivation, purine ingestion and an astrocyte-associated motor neurone syndrome in sheep: assumed clinical effects of inosine. AB - BACKGROUND: An astrocyte-associated motor neurone syndrome was produced in molybdenum-deprived sheep fed xanthosine. Mo-deprived sheep fed inosine, adenosine or guanosine would be also expected to develop astrocyte-associated motor neurone syndromes, because all these purine nucleosides can act as neuromodulators and all depend on the Mo-associated enzyme xanthine oxidase dehydrogenase for their catabolism. DESIGN: To investigate the relationship between inosine ingestion and low Mo concentration, eight sheep were fed lucerne chaff with a Mo value <0.10 ppm and the Mo antagonist, sodium tungstate, for 21 weeks, with inosine (35 mg/kg/day) fed for the last 18 of these weeks. This clinical study was uncontrolled. RESULTS: An astrocyte-associated motor neurone syndrome was produced in three sheep 18-27 months later. It was characterised by diaphragmatic, laryngeal, lingual and pharyngeal muscle weakness. The diaphragmatic muscle weakness was the most severe and potentially lethal. CONCLUSION: These findings suggest that purinergic neuromodulation of respiration, vocalisation and swallowing is different to that of limb movement. The syndrome produced, and assumed to be caused by the treatment given, has not been reported in livestock. A similar syndrome is seen in human motor neurone disease, but not in equine motor neurone disease, and this is consistent with it being an upper, not a lower, motor neurone effect. PMID- 25708792 TI - Tooth wear, body mass index and management options for edentulous black flying foxes (Pteropus alecto Gould) in the Townsville district, north Queensland, Australia. AB - OBJECTIVE: We investigated the relationship between a body mass index and tooth wear in the black flying-fox (Pteropus alecto Gould) to provide guidance on management of edentulous individuals by wildlife carers and veterinarians. METHODS: Flying-foxes brought into care because of injury were weighed, their forearms measured and the state of their teeth evaluated. Measurements were analysed by Chi-square, ANOVA, t-tests and regression to identify any relationship between the body mass index and the condition of canine and molar teeth, as well as in relation to sex and season. RESULTS: There was no statistically significant relationship between a bat's dentition state and the body mass index being used. CONCLUSIONS: In Townsville, the black flying-fox appears to experience a rapid decline in dental condition over time. Despite this, there is little indication that loss of teeth results in a decline in body condition. We attribute this to the dominance of floral foods in the bats' diet in Townsville and a lesser importance of hard fruit that requires intact dentition for consumption. Edentulousness on its own is not sufficient reason to euthanase black flying-foxes in either Townsville or similar relatively dry localities where blossom dominates the flying-fox diet. PMID- 25708793 TI - Horse welfare is the issue with use of cobalt. PMID- 25708794 TI - Sex life and the Oswestry Disability Index. AB - BACKGROUND CONTEXT: Despite the option to not answer, there is widespread anecdotal belief that the Oswestry Disability Index (ODI) Section 8 (ODI-8/sex life) is answered inaccurately (ie, in relation to psychosocial factors, not pain) or that it repels ODI participation. Oswestry Disability Index versions have therefore been created that omit ODI-8; however, no evidence base justifies this. Interestingly, one recent study reported an ODI-8 response rate (RR) of 97%. PURPOSE: The aims of this study were to measure RR to sex life questions in patients with chronic low back pain (CLBP) and to validate that ODI-8 is answered appropriately and represents a specific measure of CLBP-mediated sexual inactivity. STUDY DESIGN: Original. PATIENT SAMPLE: Eighty-eight patients. OUTCOME MEASURES: The outcome measures used in this study were the ODI, the Sexual Quality of Life Scale-version 2 (SQOL-2), the Short Form-12 version 2 (mental and physical), the Depression Anxiety and Stress Scale, the Coping Strategies Questionnaire, the Short-Form McGill Pain Questionnaire-version 2, the Opioid Risk Tool, and the Fear-Avoidance Beliefs Questionnaire (work and physical). METHOD: Chronic low back pain patients older than 18 years attending a multicultural Western spinal clinic were prospectively offered the aforementioned questionnaires. Sex life disability questions--pain dependent (ODI-8) and pain independent (SQOL-2)--appeared first and fifth in every sequence. RESULTS: Results were obtained in 65 patients (male 29, female 36). Despite expected response attrition with battery progression (RRs for the first and eighth questionnaires were 100% and 64.61%, respectively), RRs for ODI-8 (52.31%) and SQOL-2 (52.31%) were equal and significantly lower than others (p<.001). Nonresponders to ODI-8 (60.57+/-13.3 years) and SQOL-2 (59.68+/-13.34 years) were significantly older than responders (ODI-8: 47.82+/-12.17 years, p<.001; SQOL-2: 48.27+/-12.76 years, p=.001). Among ODI-8 or SQOL-2 responders, ODI-8 and SQOL-2 were not correlated (r=-0.340, p=.104). Although ODI-8 significantly correlated with prospectively identified pain-correlated questionnaires, ODI-8 did not correlate significantly with non-pain-correlated questionnaires. CONCLUSION: Contrary to previous findings, 47.69% of CLBP patients specifically ignored ODI 8; however, 100% completed the ODI remainder. Among "responders," ODI-8 was validated as having measured CLBP-mediated sexual inactivity. The ODI-8 was therefore treated consistently, as directed: It was either answered appropriately (ie, in relation to pain) or it was ignored (respecting the clause "if applicable"). No ODI modification therefore appears required for adults older than 18 years attending a multicultural Western CLBP clinic: One standard form including ODI-8 appears to yield appropriate ODI-8 response-treatment, with unaffected ODI participation. Multiple ODIs circumventing ODI-8 appear unnecessary and redundant in this population. PMID- 25708795 TI - Advances in tandem reactions with organozinc reagents. AB - The design and implementation of tandem reactions provides organic chemists with numerous challenges, in particular that of undesired cross-reactivity between substrates. Among organometallics, the use of organozinc reagents in tandem reactions provides several advantages as a result of their broad functional group tolerance and compatibility with transition metals. This review highlights prominent examples of recent advances in tandem reactions with organozinc reagents that illustrate their potential in organic synthesis. PMID- 25708796 TI - A novel 3D-printed device for localization and extraction of trabeculae from human femoral heads: a comparison with traditional visual extraction. AB - In this study, we propose a novel method for accurate trabeculae extraction from human femoral heads using 3D-printing techniques and compare spatial deviation errors between this novel method and the conventional method. We found that spatial deviation errors, which indicate inaccuracy and unreliability, were significantly higher with the conventional method. INTRODUCTION: Assessment of structural and mechanical properties of local bone is important in the study of pathological changes associated with musculoskeletal degenerative diseases. However, the widely used visual extraction method (VIS) for trabecular columns showed large deviations from veridicality, referred to as spatial deviation errors (SDE). Here, we propose a novel method for accurately locating and trephining trabeculae using a 3D-printed (3DP) positioning device and also evaluate the SDE of the VIS. METHODS: Twenty femoral heads were obtained from osteoporotic patients, and the trabecular columns were extracted from the principal compressive trabeculae by VIS (n = 10) or the 3DP (n = 10) method. Morphological, structural, and mechanical properties were compared between both groups along with the recorded errors in spatial deviation. RESULTS: Compared with the 3DP group, the average angle of central axis deflection in the VIS group was significantly greater; SDE in the VIS group was 26.1, 8.8, 4.1, 9.8, 7.2, 8.1, and 10.1 % greater for bone mineral density, bone volume/tissue volume ratio, trabecular thickness, trabecular number, Young's modulus, yield strength, and ultimate strength. CONCLUSION: In this study, a high degree of SDE was demonstrated in the VIS, which indicates that the conventional technique is unreliable. Additionally, accurate sample fabrication and credible quantitative analysis of local trabeculae among individuals can be achieved with the aid of computed tomography and the 3DP device, thus providing a more objective method for researching musculoskeletal degenerative diseases and possibly a better clinical understanding of these disorders. PMID- 25708797 TI - Normal bone mass and normocalcemia in adulthood despite homozygous vitamin D receptor mutations. AB - Adding to the debate around vitamin D's effects on skeletal health, we report the long-term follow-up of two patients with severe vitamin D receptor mutations, who had normal bone mass acquisition and normalization of calcemia around puberty, suggesting that vitamin D might not be essential for skeletal health in adulthood. INTRODUCTION: Vitamin D plays a pivotal role in calcium homeostasis, and the consequences of vitamin D insufficiency for skeletal health, as well as the importance of its supplementation, are a matter of great interest. Individuals bearing homozygous vitamin D receptor (VDR) defects present with severe hypocalcemic rickets in early infancy due to vitamin D resistance. METHODS: Here, we report the follow-up of two patients with hereditary vitamin D resistant rickets (HVDRR), focusing on bone mass acquisition and evolution of calcemia. RESULTS: Patient 1 is a 30-year-old male bearing a homozygous p.Arg30* nonsense mutation in the VDR DNA-binding domain, who presented at 6 months. From 9 years of age, treatment requirement decreased progressively. Follow-up with DXA showed normal bone mass acquisition. In adulthood, he maintains normocalcemia without calcium supplementation and has no signs of bone fragility. Patient 2 is a 37-year-old female with milder HVDRR and alopecia due to a homozygous p.Gly319Val mutation in the VDR ligand-binding domain. Around puberty, hypercalciuria and kidney stones were detected, resulting in suspension of treatment. Follow-up with DXA revealed normal bone mass, and she maintained normocalcemia without supplementation during gestation and lactation. CONCLUSIONS: The long-term follow-up of HVDRR provides insights into the role of vitamin D in human calcium homeostasis and bone health. The normalization of calcemia and normal bone mass acquisition despite a permanently dysfunctional VDR suggest that vitamin D might not be essential for skeletal health in adulthood. Extrapolation of these findings may have implications in broader clinical settings, especially considering widespread vitamin D supplementation. PMID- 25708798 TI - Contemporary surgical options for metastatic colorectal cancer. AB - The diagnosis of stage IV colorectal cancer was once associated with a uniformly grim prognosis. Over the last 20 years, advances in chemotherapeutics, surgical technique, and surgical adjuncts have dramatically broadened treatment options and improved outcomes. Among current treatment options, surgery remains the key component of any multidisciplinary approach with surgical data demonstrating the longest survivorship. This review will summarize current and developing surgical advances in the treatment of metastatic colorectal cancer. Specifically, we will discuss how surgical interventions fit within the greater context of a multi modality approach, as well as, the specific, recent innovations in the surgical management of hepatic and extrahepatic metastases. PMID- 25708800 TI - Radical surgery in ovarian cancer. AB - While there is an ongoing debate regarding the timing of the maximal surgical effort in epithelial ovarian cancer, it is well established that patients with suboptimal tumor debulking derive no benefit from the surgical procedure. The amount of residual disease after cytoreductive surgery has been repeatedly identified as a strong predictor of survival, and accordingly, the surgical effort to achieve the goal of complete gross tumor resection has been constantly evolving. Centers that have adopted the concept of radical surgery in patients with advanced ovarian cancer have reported improvements in their patients' survival. In addition to the expected improvements in the pharmacologic treatment of this disease, some of the next challenges in the surgical management of ovarian cancer include the preoperative prediction of suboptimal debulking, improving the drug delivery to the tumor, and increasing access to centers of excellence in ovarian cancer regardless of geographical, financial, or other social barriers. This review will discuss an update on the role of surgery in the treatment of primary epithelial ovarian cancer as it has evolved since the emergence of the concept of surgical cytoreduction. PMID- 25708799 TI - Precision medicine in breast cancer: genes, genomes, and the future of genomically driven treatments. AB - Remarkable progress in sequencing technology over the past 20 years has made it possible to comprehensively profile tumors and identify clinically relevant genomic alterations. In breast cancer, the most common malignancy affecting women, we are now increasingly able to use this technology to help specify the use of therapies that target key molecular and genetic dependencies. Large sequencing studies have confirmed the role of well-known cancer-related genes and have also revealed numerous other genes that are recurrently mutated in breast cancer. This growing understanding of patient-to-patient variability at the genomic level in breast cancer is advancing our ability to direct the appropriate treatment to the appropriate patient at the appropriate time--a hallmark of "precision cancer medicine." This review focuses on the technological advances that have catalyzed these developments, the landscape of mutations in breast cancer, the clinical impact of genomic profiling, and the incorporation of genomic information into clinical care and clinical trials. PMID- 25708801 TI - Adenocarcinoma of the cervix: should we treat it differently? AB - Worldwide, cervical cancer is a leading cause of mortality among women, causing 265,653 deaths annually. Squamous cell carcinoma (SCC) accounts for 75% of cervical cancer cases in the USA, while adenocarcinoma (AC) accounts for 25%. The incidence of SCC is decreasing in the USA, yet AC is increasing. Many differences exist between cervical SCC and AC including anatomic origin, risk factors, prognosis, dissemination, sites of recurrence, and rates of metastasis. Despite differences, current treatment algorithms do not distinguish between cervical SCC and AC. To date, prospective research directed toward AC is limited. We review published differences in response to neoadjuvant chemotherapy and concomitant chemotherapy with radiation, the role of adjuvant radical hysterectomy, and optimal chemotherapy for cervical AC. Cervical AC is sufficiently distinct from SCC to warrant specific treatment recommendations; however, lack of data evaluating AC limit recommendations. Additional prospective AC cervix specific research is needed. PMID- 25708802 TI - Activin receptor inhibitors--dalantercept. AB - Development of anti-angiogenic therapy including the vascular endothelial growth factor (VEGF) antibodies and VEGF-tyrosine kinase receptors has been a major landmark in cancer therapy leading improvement in survival in several cancers. While anti-angiogenic therapy is effective in some settings, resistance often develops owing to evasive, alternative pathways. Novel targets for anti angiogenic therapy are urgently required to provide treatment alternatives in patients whose tumors are unresponsive to approved anti-angiogenic agents; one such pathway is the bone morphogenetic proteins (BMP 9 and BMP 10) that activate the type I activin receptor-like kinase-1 (ALK1), which has been implicated in the development of functional vasculature. Dalantercept (ACE-041) is a novel anti angiogenic agent, which is a soluble form of ALK1, and acts as a ligand trap for BMP 9 and BMP 10, inhibiting their interaction with ALK1, which further disrupts the process of vascular development. This review will discuss the preclinical and clinical development of dalantercept as a novel anti-angiogenic therapy in treating a variety of cancers and its distinct safety profile compared to other anti-VEGF agents. We will also discuss the ongoing and completed studies of dalantercept, including combination studies with other VEGF-directed therapies. PMID- 25708803 TI - Adjuvant and neoadjuvant options in resectable gastric cancer: is there an optimal treatment approach? AB - Gastric cancer is one of the most prevalent and deadliest forms of cancer worldwide. Even though neoadjuvant, perioperative, and adjuvant chemotherapy and/or radiation therapy may improve outcomes compared with surgery alone, the optimal combination of treatment modalities remains controversial. While European and North American trials established perioperative chemotherapy and adjuvant chemoradiation regimens for gastric cancer, Asian countries have focused on the use of adjuvant chemotherapy. This review summarizes results from contemporary randomized controlled trials and meta-analyses to elucidate the relative merits of each treatment approach. PMID- 25708804 TI - Genome-wide profiling of DNA methylation provides insights into epigenetic regulation of fungal development in a plant pathogenic fungus, Magnaporthe oryzae. AB - DNA methylation is an important epigenetic modification that regulates development of plants and mammals. To investigate the roles of DNA methylation in fungal development, we profiled genome-wide methylation patterns at single nucleotide resolution during vegetative growth, asexual reproduction, and infection-related morphogenesis in a model plant pathogenic fungus, Magnaporthe oryzae. We found that DNA methylation occurs in and around genes as well as transposable elements and undergoes global reprogramming during fungal development. Such reprogramming of DNA methylation suggests that it may have acquired new roles other than controlling the proliferation of TEs. Genetic analysis of DNA methyltransferase deletion mutants also indicated that proper reprogramming in methylomes is required for asexual reproduction in the fungus. Furthermore, RNA-seq analysis showed that DNA methylation is associated with transcriptional silencing of transposable elements and transcript abundance of genes in context-dependent manner, reinforcing the role of DNA methylation as a genome defense mechanism. This comprehensive approach suggests that DNA methylation in fungi can be a dynamic epigenetic entity contributing to fungal development and genome defense. Furthermore, our DNA methylomes provide a foundation for future studies exploring this key epigenetic modification in fungal development and pathogenesis. PMID- 25708805 TI - The conserved histone deacetylase Rpd3 and the DNA binding regulator Ume6 repress BOI1's meiotic transcript isoform during vegetative growth in Saccharomyces cerevisiae. AB - BOI1 and BOI2 are paralogs important for the actin cytoskeleton and polar growth. BOI1 encodes a meiotic transcript isoform with an extended 5'-untranslated region predicted to impair protein translation. It is, however, unknown how the isoform is repressed during mitosis, and if Boi1 is present during sporulation. By interpreting microarray data from MATa cells, MATa/alpha cells, a starving MATalpha/alpha control, and a meiosis-impaired rrp6 mutant, we classified BOI1's extended isoform as early meiosis-specific. These results were confirmed by RNA Sequencing, and extended by a 5'-RACE assay and Northern blotting, showing that meiotic cells induce the long isoform while the mitotic isoform remains detectable during meiosis. We provide evidence via motif predictions, an in vivo binding assay and genetic experiments that the Rpd3/Sin3/Ume6 histone deacetylase complex, which represses meiotic genes during mitosis, also prevents the induction of BOI1's 5'-extended isoform in mitosis by direct binding of Ume6 to its URS1 target. Finally, we find that Boi1 protein levels decline when cells switch from fermentation to respiration and sporulation. The histone deacetylase Rpd3 is conserved, and eukaryotic genes frequently encode transcripts with variable 5'-UTRs. Our findings are therefore relevant for regulatory mechanisms involved in the control of transcript isoforms in multi-cellular organisms. PMID- 25708806 TI - Multiscale impact of nucleotides and cations on the conformational equilibrium, elasticity and rheology of actin filaments and crosslinked networks. AB - Cells are able to respond to mechanical forces and deformations. The actin cytoskeleton, a highly dynamic scaffolding structure, plays an important role in cell mechano-sensing. Thus, understanding rheological behaviors of the actin cytoskeleton is critical for delineating mechanical behaviors of cells. The actin cytoskeleton consists of interconnected actin filaments (F-actin) that form via self-assembly of actin monomers. It has been shown that molecular changes of the monomer subunits impact the rigidity of F-actin. However, it remains inconclusive whether or not the molecular changes can propagate to the network level and thus alter the rheological properties of actin networks. Here, we focus on how cation binding and nucleotide state tune the molecular conformation and rigidity of F actin and a representative rheological behavior of actin networks, strain stiffening. We employ a multiscale approach by combining established computational techniques: molecular dynamics, normal mode analysis and Brownian dynamics. Our findings indicate that different combinations of nucleotide (ATP, ADP or ADP-Pi) and cation [Formula: see text] or [Formula: see text] at one or multiple sites) binding change the molecular conformation of F-actin by varying inter- and intra-strand interactions which bridge adjacent subunits between and within F-actin helical strands. This is reflected in the rigidity of actin filaments against bending and stretching. We found that differences in extension and bending rigidity of F-actin induced by cation binding to the low-, intermediate- and high-affinity sites vary the strain-stiffening response of actin networks crosslinked by rigid crosslinkers, such as scruin, whereas they minimally impact the strain-stiffening response when compliant crosslinkers, such as filamin A or [Formula: see text]-actinin, are used. PMID- 25708807 TI - Erythema papulatum centrifugum developing around melanoma. PMID- 25708808 TI - Wide field of view computed tomography and mid-carpal instability: the value of the sagittal radius-lunate-capitate axis--preliminary experience. AB - PURPOSE: Dynamic four dimensional (4D) computed tomography (CT) has recently emerged as a practical method for evaluating complex functional abnormality of joints. We retrospectively analysed 4D CT studies undertaken as part of the clinical management of hand and wrist symptoms. We present our initial experience of 4D CT in the assessment of functional abnormalities of the wrist in a group of patients with mid carpal instability (MCI), specifically carpal instability non dissociative. We aim to highlight unique features in assessment of the radius lunate-capitate (RLC) axis which allows insight and understanding of abnormalities in function, not just morphology, which may be contributing to symptoms. MATERIALS AND METHODS: Wide field of view multi-detector CT scanner (320 slices, 0.5 mm detector thickness) was used to acquire bilateral continuous motion assessment in hand flexion and extension. A maximum z-axis coverage of 16 cm was available for each acquisition, and a large field of view (FOV) was used. Due to the volume acquisition during motion, reconstructions at multiple time points were undertaken. Dynamic and anatomically targeted multi-planar reconstructions (MPRs) were then used to establish the kinematic functionality of the joint. RESULTS: Our initial cohort of 20 patients was reviewed. Three findings were identified which were present either in isolation or in combination. These are vacuum phenomenon, triggering of the lunate and capitate subluxation. We provide 4D CT representations of each and highlight features considered of clinical importance and their significance. We also briefly discuss how the current classifications of dynamic wrist abnormalities may alter with the supplementary information provided by dynamic 4D CT MSK acquisitions. CONCLUSION: 4D CT has provided a unique insight into motion disorders. We highlight our early experience with the ability of 4D CT to investigate the RLC axis and three signs which have provided a unique assessment of MCI. This improved assessment of wrist motion disorders has highlighted sufficient differences in the dynamic CT classifications we have described and suggests that further research may result in refinement of the MCI classification system. PMID- 25708809 TI - MicroRNA-153 promotes Wnt/beta-catenin activation in hepatocellular carcinoma through suppression of WWOX. AB - Persistent activation of Wnt/beta-catenin signaling plays crucial roles in the development of human cancers, including hepatocellular carcinoma (HCC). Here, we performed a MicroRNA-based genetic screen, which revealed a novel diversion in beta-catenin signaling triggered by MicroRNA-153 (miR-153). Overexpression of miR 153 was able to promote beta-catenin transcriptional activity, leading to cell cycle progression, proliferation and colony formation of HCC cells. Additionally, systemic administration of miR-153 antigomir suppressed hepatocellular carcinogenesis in a murine liver cancer model. At the molecular level, we found that miR-153 inhibited protein level of WWOX, a tumor suppressor and inhibitor of beta-catenin signaling, through targeting its 3'-untranslated region. Therefore, our study highlights the importance of MicroRNA-153/WWOX/beta-catenin regulatory axis in the HCC tumorigenesis. PMID- 25708810 TI - The art of common ground: emergence of a complex pragmatic language skill in adolescents with autism spectrum disorders. AB - Deficits in pragmatic language are central to autism spectrum disorder (ASD). Here we investigate common ground, a pragmatic language skill in which speakers adjust the contents of their speech based on their interlocutor's perceived knowledge, in adolescents with ASD and typical development (TD), using an experimental narrative paradigm. Consistent with prior research, TD participants produced shorter narrations when they shared knowledge with an interlocutor, an effect not observed at the group level in ASD. This effect was unrelated to general skills such as IQ or receptive vocabulary. In ASD, the effect was correlated with age and symptom severity: older and less severely affected participants did shorten their narratives. Several metrics (including explicit references to common ground, speech disfluencies, and communicative quality ratings) suggested that, although adolescents with ASD did not show implicit reductions in their narrative length, they were aware of common ground, and communicated differently in its presence. PMID- 25708811 TI - Belching during gastroscopy and its association with gastroesophageal reflux disease. AB - Belching may result from transient lower esophageal sphincter relaxation; therefore, it has been proposed that belching may be a manifestation of gastroesophageal reflux disease (GERD). This study was conducted to investigate the frequency of belching during esophagogastroduodenoscopy (EGD) and its association with GERD. A retrospective review was performed on prospectively collected clinical and endoscopic data from 404 subjects who underwent EGD without sedation from December 2012 to May 2013 in a training hospital in Korea. All detectable belching events during endoscopy were counted. Frequency and severity of belching events were compared between the group with and without GERD using an ordinal logistic regression model. There were 145 GERD patients (26 erosive reflux disease and 119 nonerosive reflux disease [NERD]). In the multivariable analysis, GERD was significantly associated with a higher frequency of belching events (odds ratio = 6.59, P < 0.001). Central obesity, female, and younger age were also risk factors for frequent belching during EGD. Subgroup analyses were performed in subjects without erosive reflux disease (n = 378) and NERD (n = 293). NERD was also a predictive factor for frequent belching during EGD (odds ratio = 6.61, P < 0.001), and the frequency of belching was significantly correlated with GERD severity according to the Los Angeles classification (P < 0.05). Frequent belching during EGD was associated with GERD, including NERD. Future research should focus on its adjuvant role in the diagnosis of GERD/NERD and the necessity for applying differentiated endoscopy strategies for GERD patients, leading to less discomfort during EGD in patients at risk for intolerability. PMID- 25708812 TI - Ocean acidification decreases the light-use efficiency in an Antarctic diatom under dynamic but not constant light. AB - There is increasing evidence that different light intensities strongly modulate the effects of ocean acidification (OA) on marine phytoplankton. The aim of the present study was to investigate interactive effects of OA and dynamic light, mimicking natural mixing regimes. The Antarctic diatom Chaetoceros debilis was grown under two pCO2 (390 and 1000 MUatm) and light conditions (constant and dynamic), the latter yielding the same integrated irradiance over the day. To characterize interactive effects between treatments, growth, elemental composition, primary production and photophysiology were investigated. Dynamic light reduced growth and strongly altered the effects of OA on primary production, being unaffected by elevated pCO2 under constant light, yet significantly reduced under dynamic light. Interactive effects between OA and light were also observed for Chl production and particulate organic carbon quotas. Response patterns can be explained by changes in the cellular energetic balance. While the energy transfer efficiency from photochemistry to biomass production (Phie,C ) was not affected by OA under constant light, it was drastically reduced under dynamic light. Contrasting responses under different light conditions need to be considered when making predictions regarding a more stratified and acidified future ocean. PMID- 25708813 TI - High treatment modification rates with lamivudine therapy in HBV-infected patients with low baseline viremia and early virological response: A multicenter study. AB - OBJECTIVE: Low baseline viremia and an early treatment response predict the best outcomes in hepatitis B virus (HBV)-infected patients treated with nucleoside analogues with low barriers to resistance. The aim of this study was to assess the long-term results and effectiveness of lamivudine in patients with low baseline viremia and early virological treatment response. METHODS: In this multicenter, real-life setting study, 111 antiviral-naive patients with low baseline viremia (HBV DNA <10(7) copies/mL) plus an early virological response (HBV DNA <300 copies/mL at week 24) treated with lamivudine were enrolled. The primary end-point was treatment failure, defined as the re-emergence of detectable viremia or at least a 1 log increase in HBV DNA, resulting in a titer of >= 300 copies/mL with lamivudine treatment after week 24, which required treatment modification. RESULTS: Altogether 111 patients, including 78 non cirrhotic and 33 cirrhotic patients, were included in the study. Treatment failure occurred in 30.8% of the non-cirrhotic patients over a median follow-up period of 32.5 months, and the 1-, 2-, 3-, 4- and 5-year treatment failure rates were 6.5%, 14.0%, 31.4%, 39.6% and 43.1%, respectively. Treatment failure occurred in 28.8% of the whole group. There were no differences between the cirrhotic and non-cirrhotic patients. CONCLUSIONS: Lamivudine treatment had a high treatment modification rate in patients with low baseline viremia and early virological response over a long-term follow-up in a real-life setting. The pretreatment and on-treatment favorable characteristics found in the studies with telbivudine appeared to be inapplicable to lamivudine. PMID- 25708814 TI - Community effectiveness of copepods for dengue vector control: systematic review. AB - OBJECTIVE: Vector control remains the only available method for primary prevention of dengue. Several interventions exist for dengue vector control, with limited evidence of their efficacy and community effectiveness. This systematic review compiles and analyses the existing global evidence for community effectiveness of copepods for dengue vector control. METHODS: The systematic review follows the PRISMA statement, searching six relevant databases. Applying all inclusion and exclusion criteria, 11 articles were included. RESULTS: There is evidence that cyclopoid copepods (Mesocyclops spp.) could potentially be an effective vector control option, as shown in five community effectiveness studies in Vietnam. This includes long-term effectiveness for larval and adult control of Ae. aegypti, as well as dengue incidence. However, this success has so far not been replicated elsewhere (six studies, three community effectiveness studies- Costa Rica, Mexico and USA, and three studies analysing both efficacy and community effectiveness--Honduras, Laos and USA), probably due to community participation, environmental and/or biological factors. Judging by the quality of existing studies, there is a lack of good study design, data quality and appropriate statistics. CONCLUSION: There is limited evidence for the use of cyclopoid copepods as a single intervention. There are very few studies, and more are needed in other communities and environments. Clear best practice guidelines for the methodology of entomological studies should be developed. PMID- 25708815 TI - The 12/15-lipoxygenase as an emerging therapeutic target for Alzheimer's disease. AB - Alzheimer's disease (AD) is a chronic neurodegenerative condition characterized by progressive memory loss. Mutations in genes involved in the production of amyloid-beta (Abeta) are linked to the early-onset variant of AD. However, the most common form, sporadic AD, is considered to be the result of an interaction between environmental risk factors and various genes. Among them, recent work has highlighted the potential role that the 12/15-lipoxygenase (12/15LO) pathway may play in AD pathogenesis. 12/15LO is widely distributed in the central nervous system, and its levels are upregulated in patients with AD or mild cognitive impairments. Studies using animal models have implicated 12/15LO in the molecular pathology of AD, including the metabolism of Abeta and tau, synaptic integrity, and cognitive functions. We provide an overview of this pathway and its relevance to AD pathogenesis, discuss the mechanism(s) involved, and provide an assessment of how targeting 12/15LO could lead to novel AD therapeutics. PMID- 25708816 TI - Efficient information for recognizing pain in facial expressions. AB - BACKGROUND: The face as a visual stimulus is a reliable source of information for judging the pain experienced by others. Until now, most studies investigating the facial expression of pain have used a descriptive method (i.e. Facial Action Coding System). However, the facial features that are relevant for the observer in the identification of the expression of pain remain largely unknown despite the strong medical impact that misjudging pain can have on patients' well-being. METHODS: Here, we investigated this question by applying the Bubbles method. Fifty healthy volunteers were asked to categorize facial expressions (the six basic emotions, pain and neutrality) displayed in stimuli obtained from a previously validated set and presented for 500 ms each. To determine the critical areas of the face used in this categorization task, the faces were partly masked based on random sampling of regions of the stimuli at different spatial frequency ranges. RESULTS: Results show that accurate pain discrimination relies mostly on the frown lines and the mouth. Finally, an ideal observer analysis indicated that the use of the frown lines in human observers could not be attributed to the objective 'informativeness' of this area. CONCLUSIONS: Based on a recent study suggesting that this area codes for the affective dimension of pain, we propose that the visual system has evolved to focus primarily on the facial cues that signal the aversiveness of pain, consistent with the social role of facial expressions in the communication of potential threats. PMID- 25708818 TI - Recurrent facial palsy in Melkersson Rosenthal syndrome: total facial nerve decompression is effective to prevent further recurrence. AB - OBJECTIVE: To study the role of total facial nerve decompression in preventing further recurrence of facial palsy in Melkersson Rosenthal syndrome (MRS). METHODS: Total facial nerve decompression was performed on nine patients with recurrent facial palsy in MRS, and prednisolone treatment was given to 6 cases who declined surgery. They were incorporated into surgery group and control group, respectively. Patients in surgery group and control group were followed up for 5.4 +/- 1.4 years (range, 4 to 8 years) and 6.0 +/- 1.4 years (range, 4 to 8 years), respectively. RESULTS: Further episodes of facial palsy affected none of 9 cases (0.0%) in surgery group, while they affected 3 of 6 cases (50.0%) in control group, with significant difference (p<0.05). CONCLUSIONS: Total facial nerve decompression was effective to prevent further episodes of facial palsy in MRS. PMID- 25708817 TI - Preliminary investigation of miRNA expression in individuals at high familial risk of bipolar disorder. AB - Bipolar disorder (BD) is a highly heritable psychiatric disorder characterised by recurrent episodes of mania and depression. Many studies have reported altered gene expression in BD, some of which may be attributable to the dysregulated expression of miRNAs. Studies carried out to date have largely studied medicated patients, so it is possible that observed changes in miRNA expression might be a consequence of clinical illness or of its treatment. We sought to establish whether altered miRNA expression might play a causative role in the development of BD by studying young, unmedicated relatives of individuals with BD, who are at a higher genetic risk of developing BD themselves (high-risk individuals). The expression of 20 miRNAs previously implicated in either BD or schizophrenia was measured by qRT-PCR in whole-blood samples from 34 high-risk and 46 control individuals. Three miRNAs, miR-15b, miR-132 and miR-652 were up-regulated in the high-risk individuals, consistent with previous reports of increased expression of these miRNAs in patients with schizophrenia. Our findings suggest that the altered expression of these miRNAs might represent a mechanism of genetic susceptibility for BD. Moreover, our observation of altered miRNA expression in the blood prior to the onset of illness provides hope that one day blood-based tests may aid in the risk-stratification and treatment of BD. PMID- 25708819 TI - Primary cutaneous vs. parotid mucoepidermoid carcinoma of the scalp: A case report. AB - Primary cutaneous mucoepidermoid carcinoma remains a rare occurrence. This is the first report of a case of primary cutaneous mucoepidermoid carcinoma originating on the scalp and subsequently metastasizing to the parotid gland. The patient was a 53-year-old female who presented with a purple mass on her scalp since 5 months prior to examination. Histopathology revealed nests and islands of atypical epithelioid cells with pleomorphism, medium to prominent nucleoli, and scattered mucin deposition highlighting with a mucicarmine stain. The atypical cells demonstrated intravascular involvement. These findings were compatible with metastatic adenocarcinoma. Later, fine needle aspiration of the patient's parotid lesion revealed malignant cells from a poorly differentiated carcinoma that appeared similar to the patient's previously excised scalp lesion. In addition to summarizing this patient's presentation, clinical course, and management, we discuss the diagnostic challenges posed by this atypical presentation. Primary cutaneous mucoepidermoid carcinoma should be considered in the differential diagnosis of patients presenting with a scalp mass. Moreover, patients with primary cutaneous mucoepidermoid carcinoma originating on the scalp should be evaluated for possible metastases. PMID- 25708820 TI - Sublingual gland is the origin of giant submandibular mucocele. PMID- 25708821 TI - Assessment of retinal pigment epithelial cells in epiretinal membrane formation. AB - BACKGROUND: The definite etiology of epiretinal membrane (ERM) is unknown. Clinically, ERM may cause metamorphopsia and decreased vision during the disease exacerbation. Several theories of pathogenesis emphasize a glial tissue origin. However, in some studies, surgically removed ERM specimens were found to contain retinal pigment epithelial (RPE) cells. The actual mechanism by which RPE cells gain access into the inner retina and what roles they play in the formation of ERM remain controversial. The purpose of this study was to evaluate the incidence of RPE cells in ERM and discuss the possible mechanisms. METHODS: A retrospective review of the histological findings in 23 surgically removed specimens of ERM was done. The samples were studied using light microscopy and immunohistochemistry. RESULTS: Glial cells were the main components in all 23 cases, and RPE cells were found in five of the specimens. Two of these five cases were clinically diagnosed as idiopathic macular pucker, whereas the other three cases were identified as macular pucker associated with previous retinal detachment. A much higher density of myofibroblasts was noted in these five specimens than in the other 18 cases. CONCLUSION: The incidence of RPE cells found in ERM is 21.7% (5 out of 23 specimens). A strong association between RPE cells and myofibroblasts in cases of ERM with or without retinal detachment indicates that RPE cells may contribute to the formation of ERM via a wound healing process. PMID- 25708822 TI - Clinical application of dehydroepiandrosterone in reproduction: A review of the evidence. AB - The effect of dehydroepiandrosterone (DHEA) therapy on improvement of reproduction outcome is uncertain. Many earlier studies have shown conflicting results. Therefore, a review of the literature is needed to explore the role of DHEA in reproduction. We conducted a literature search of MEDLINE (Ovid) and Pub Med (2000-June 2014) for all relevant articles that included the terms "dehydroepiandrosterone," "DHEA," and "in vitro fertilization." Among the search identified articles, seven prospective self-controlled studies and four retrospective case-control studies showed DHEA as an adjuvant therapy able to improve in vitro fertilization outcomes in poor responders (women with diminished ovarian reserve and/or poor ovarian response). However, four randomized controlled trials did not support the benefit of DHEA therapy for poor responders. By contrast, one prospective randomized study showed that DHEA might be beneficial to reproduction in women without diminished ovarian reserve (normal responders). In summary, a review of the previously published studies does not provide clear evidence that DHEA can be a useful treatment to improve ovarian function in poor responders. PMID- 25708824 TI - New chalcones bearing a long-chain alkylphenol from the rhizomes of Alpinia galanga. AB - Three novel chalcones bearing a long-chain alkylphenol, galanganones A-C (1-3), were isolated from the rhizomes of Alpinia galanga. Their structures were elucidated by extensive spectroscopic analysis including 2D NMR experiments. Compounds 1-3 represent the first examples of long-chain alkylphenol-coupled chalcone. PMID- 25708823 TI - Investigation of changes in apelin receptor mRNA and protein expression in the myocardium and aorta of rats with two-kidney, one-clip (2K1C) Goldblatt hypertension. AB - Experimental and clinical evidences suggest that apelin and its receptor APJ are involved in the pathogenesis of cardiovascular complications. However, the role of apelin/APJ in hypertension is not sufficiently understood. Because chronic kidney diseases lead to hypertension and cardiac failure, we investigated the changes in apelin receptor gene expression in the myocardium and aorta of rat models of kidney disease hypertension. Two-kidney, one-clip (2K1C) hypertension was produced by placing a clip around the renal artery. Four and 16 weeks later, blood pressure, left ventricular end-diastolic pressure (LVEDP), serum apelin, and angiotensin II were measured. The messenger RNA (mRNA) and protein of APJ were determined by reverse transcription polymerase chain reaction (RT-PCR) and Western blotting. Chronic hypertensive rats had approximately 10 times higher LVEDP (P < 0.001). 2K1C decreased serum apelin from 220 +/- 11 to 170 +/- 10 pg/mL in 16 weeks (P < 0.05). The mRNA expression of APJ significantly decreased in the heart and aorta at 4 weeks. At 16 weeks, the reduction was not significant in the heart but was significant in the aorta. At 4 weeks, the expression of the APJ protein significantly decreased in the heart but not in the aorta. At 16 weeks, APJ protein was significantly decreased only in the aorta. Reduction of serum apelin and downregulation of apelin receptors in both the heart and aorta may play a role in the pathophysiology of hypertension and cardiac failure in 2K1C hypertensive rats. PMID- 25708825 TI - Role of the horizontal gene exchange in evolution of pathogenic Mycobacteria. AB - BACKGROUND: Mycobacterium tuberculosis is one of the most dangerous human pathogens, the causative agent of tuberculosis. While this pathogen is considered as extremely clonal and resistant to horizontal gene exchange, there are many facts supporting the hypothesis that on the early stages of evolution the development of pathogenicity of ancestral Mtb has started with a horizontal acquisition of virulence factors. Episodes of infections caused by non tuberculosis Mycobacteria reported worldwide may suggest a potential for new pathogens to appear. If so, what is the role of horizontal gene transfer in this process? RESULTS: Availing of accessibility of complete genomes sequences of multiple pathogenic, conditionally pathogenic and saprophytic Mycobacteria, a genome comparative study was performed to investigate the distribution of genomic islands among bacteria and identify ontological links between these mobile elements. It was shown that the ancient genomic islands from M. tuberculosis still may be rooted to the pool of mobile genetic vectors distributed among Mycobacteria. A frequent exchange of genes was observed between M. marinum and several saprophytic and conditionally pathogenic species. Among them M. avium was the most promiscuous species acquiring genetic materials from diverse origins. CONCLUSIONS: Recent activation of genetic vectors circulating among Mycobacteria potentially may lead to emergence of new pathogens from environmental and conditionally pathogenic Mycobacteria. The species which require monitoring are M. marinum and M. avium as they eagerly acquire genes from different sources and may become donors of virulence gene cassettes to other micro-organisms. PMID- 25708826 TI - Reconfiguration of DNA methylation in aging. AB - A complex interplay between multiple biological effects shapes the aging process. The advent of genome-wide quantitative approaches in the epigenetic field has highlighted the effective impact of epigenetic deregulation, particularly of DNA methylation, on aging. Age-associated alterations in DNA methylation are commonly grouped in the phenomenon known as "epigenetic drift" which is characterized by gradual extensive demethylation of genome and hypermethylation of a number of promoter-associated CpG islands. Surprisingly, specific DNA regions show directional epigenetic changes in aged individuals suggesting the importance of these events for the aging process. However, the epigenetic information obtained until now in aging needs a re-consideration due to the recent discovery of 5 hydroxymethylcytosine, a new DNA epigenetic mark present on genome. A recapitulation of the factors involved in the regulation of DNA methylation and the changes occurring in aging will be described in this review also considering the data available on 5 hmC. PMID- 25708827 TI - Economic and social impact of upper extremity fragility fractures in elderly patients. AB - BACKGROUND: Fragility fractures of the proximal humerus and distal radius can have a significant impact on the elderly population, both economically and physically. Limited data are available to demonstrate the functional and economic impact of upper extremity fragility fractures. AIMS: To investigate the economic and social impact that proximal humerus fragility fractures may have on an older population. METHODS: A retrospective chart review for patients >=50 years old treated as an inpatient at a local hospital between 2006 and 2012 for a proximal humerus or a distal radius fracture was done. Patients were divided into two groups to show age impact; Group 1 = 50-79 years old and Group 2 = 80 years and older. Eighty-six charts were reviewed, 38 for Group 1 and 48 for Group 2. Demographic, admission, inpatient, and discharge data were compared between groups. RESULTS: A third of patients in each group had a previous fragility fracture. Inpatient length of stay was comparable between groups. Surgical treatment was used at a higher rate in the younger cohort (p = 0.06). Approximate average hospital charges for an inpatient surgical treatment were about twice those of the non-surgically treated patients. DISCUSSION: Our results illustrate the significant burden of upper extremity fractures in terms of loss of independence, inpatient hospitalizations and prolonged nursing home or rehabilitation needs, which account for considerable health care costs. CONCLUSION: Fractures of the humerus, forearm and wrist account for one-third of the total incidence of fractures and can be a significant burden to individuals and the community. PMID- 25708828 TI - Effect of dementia on outcomes of elderly patients with hemorrhagic peptic ulcer disease based on a national administrative database. AB - BACKGROUND: Little information is available on the effect of dementia on outcomes of elderly patients with hemorrhagic peptic ulcer disease at the population level. AIMS: This study aimed to investigate the effect of dementia on outcomes of elderly patients with hemorrhagic peptic ulcer based on a national administrative database. METHODS: A total of 14,569 elderly patients (>=80 years) who were treated by endoscopic hemostasis for hemorrhagic peptic ulcer were referred to 1073 hospitals between 2010 and 2012 in Japan. We collected patients' data from the administrative database to compare clinical and medical economic outcomes of elderly patients with hemorrhagic peptic ulcers. Patients were divided into two groups according to the presence of dementia: patients with dementia (n = 695) and those without dementia (n = 13,874). RESULTS: There were no significant differences in in-hospital mortality within 30 days and overall mortality between the groups (odds ratio; OR 1.00, 95 % confidence interval; CI 0.68-1.46, p = 0.986 and OR 1.02, 95 % CI 0.74-1.41, p = 0.877). However, the length of stay (LOS) and medical costs during hospitalization were significantly higher in patients with dementia compared with those without dementia. The unstandardized coefficient for LOS was 3.12 days (95 % CI 1.58-4.67 days, p < 0.001), whereas that for medical costs was 1171.7 US dollars (95 % CI 533.8 1809.5 US dollars, p < 0.001). CONCLUSIONS: Length of stay and medical costs during hospitalization are significantly increased in elderly patients with dementia undergoing endoscopic hemostasis for hemorrhagic peptic ulcer disease. PMID- 25708829 TI - Addressing morbid obesity as a barrier to renal transplantation with laparoscopic sleeve gastrectomy. AB - Morbid obesity is a barrier to renal transplantation and is inadequately addressed by medical therapy. We present results of a prospective evaluation of laparoscopic sleeve gastrectomy (LSG) for patients failing to achieve significant weight loss with medical therapy. Over a 25-month period, 52 obese renal transplant candidates meeting NIH guidelines for metabolic surgery underwent LSG. Mean age was 50.0 +/- 10.0 years with an average preoperative BMI of 43.0 +/- 5.4 kg/m(2) (range 35.8-67.7 kg/m(2)). Follow-up after LSG was 220 +/- 152 days (range 26-733 days) with last BMI of 36.3 +/- 5.3 kg/m(2) (range 29.2-49.8 kg/m(2)) with 29 (55.8%) patients achieving goal BMI of <35 kg/m(2) at 92 +/- 92 days (range 13-420 days). The mean percentage of excess weight loss (%EWL) was 32.1 +/- 17.6% (range 6.7-93.8%). A segmented regression model was used to compare medical therapy versus LSG. This revealed a statistically significant increase in the BMI reduction rate (0.3 kg/m(2)/month versus 1.1 kg/m(2)/month, p < 0.0001). Patients also experienced a 40.9% decrease in anti-hypertensive medications (p < 0.001) and a 49.7% decrease in total daily insulin dose (p < 0.001). LSG is a safe and effective means for addressing obesity in kidney transplant candidates in the context of a multidisciplinary approach. PMID- 25708830 TI - Enhancing HOTAIR/MiR-10b Drives Normal Liver Stem Cells Toward a Tendency to Malignant Transformation Through Inducing Epithelial- to-Mesenchymal Transition. AB - Previously, other groups and our team consistently have demonstrated that the possible origination of liver cancer stem cells (LCSCs) is the malignant transformation from liver normal stem cells (LNSCs). However, this complex and multi-step process is far from clear due to the accumulation of various gene dysregulations. Because non-coding RNAs (ncRNAs) could regulate multiple genes, a family of genes, and even whole chromosomes, this study further investigated the effect of dysregulated short ncRNA microRNA-10b and long ncRNA HOX transcript antisense RNA (HOTAIR) between LNSCs and LCSCs on phenotype reversion. To clarify the role of ncRNA in malignant transformation of LNSCs, we used lentivirus transduction to enhance the miR-10b and HOTAIR expression levels in our previously isolated rat LNSCs. The malignant abilities of proliferation, invasiveness, and tumorigenesis were observed and compared in cells before and after ncRNAs enhancement. After microRNA-10b and HOTAIR were enhanced separately, several cancer stem cell (CSC)-like traits appeared in these LNSCs, including in vitro-enhanced proliferative capacity, expression of putative LCSC markers, progressive invasive ability, and even in vivo aggravation into and taking the place of normal liver tissue. Furthermore, strengthened expression of these ncRNAs partially degraded E-cadherin in LNSCs, which is one of the classic markers in epithelial-to-mesenchymal transition (EMT). HOTAIR or miR-10b enhanced in LNSCs may drive the LNSCs to a tendency toward malignant transformation. This study partially uncovers the mechanism by which miR-10b or HOTAIR promotes malignant transformation of LNSCs through down-regulating E-cadherin and inducing EMT. PMID- 25708831 TI - Activity-driven relaxation of the cortical actomyosin II network synchronizes Munc18-1-dependent neurosecretory vesicle docking. AB - In neurosecretory cells, secretory vesicles (SVs) undergo Ca(2+)-dependent fusion with the plasma membrane to release neurotransmitters. How SVs cross the dense mesh of the cortical actin network to reach the plasma membrane remains unclear. Here we reveal that, in bovine chromaffin cells, SVs embedded in the cortical actin network undergo a highly synchronized transition towards the plasma membrane and Munc18-1-dependent docking in response to secretagogues. This movement coincides with a translocation of the cortical actin network in the same direction. Both effects are abolished by the knockdown or the pharmacological inhibition of myosin II, suggesting changes in actomyosin-generated forces across the cell cortex. Indeed, we report a reduction in cortical actin network tension elicited on secretagogue stimulation that is sensitive to myosin II inhibition. We reveal that the cortical actin network acts as a 'casting net' that undergoes activity-dependent relaxation, thereby driving tethered SVs towards the plasma membrane where they undergo Munc18-1-dependent docking. PMID- 25708832 TI - Acetone as a greener alternative to acetonitrile in liquid chromatographic fingerprinting. AB - A considerable amount of chemical waste from liquid chromatography analysis is generated worldwide. Acetonitrile is the most employed solvent in liquid chromatography analyses since it exhibits favorable physicochemical properties for separation and detection, but it is an unwelcome solvent from an environmental point of view. Acetone might be a much greener alternative to replace acetonitrile in reversed-phase liquid chromatography, since both share similar physicochemical properties, but its applicability with ultraviolet absorbance-based detectors is limited. In this work, a reference method using acetonitrile and high-performance liquid chromatography coupled to an ultraviolet photodiode array detector coupled to a corona charged aerosol detector system was developed to fingerprint a complex sample. The possibility of effectively substituting acetonitrile with acetone was investigated. Design of experiments was adopted to maximize the number of peaks acquired in both fingerprint developments. The methods with acetonitrile or acetone were successfully optimized and proved to be statistically similar when only the number of peaks or peak capacity was taken into consideration. However, the superiority of the latter was evidenced when parameters of separation and those related to greenness were heuristically combined. A green, comprehensive, time- and resource-saving approach is presented here, which is generic and applicable to other complex matrices. Furthermore, it is in line with environmental legislation and analytical trends. PMID- 25708833 TI - The measurement of in vivo joint angles during a squat using a single camera markerless motion capture system as compared to a marker based system. AB - Markerless motion capture may have the potential to make motion capture technology widely clinically practical. However, the ability of a single markerless camera system to quantify clinically relevant, lower extremity joint angles has not been studied in vivo. Therefore, the goal of this study was to compare in vivo joint angles calculated using a marker-based motion capture system and a Microsoft Kinect during a squat. Fifteen individuals participated in the study: 8 male, 7 female, height 1.702+/-0.089m, mass 67.9+/-10.4kg, age 24+/ 4 years, BMI 23.4+/-2.2kg/m(2). Marker trajectories and Kinect depth map data of the leg were collected while each subject performed a slow squat motion. Custom code was used to export virtual marker trajectories for the Kinect data. Each set of marker trajectories was utilized to calculate Cardan knee and hip angles. The patterns of motion were similar between systems with average absolute differences of <5 deg. Peak joint angles showed high between-trial reliability with ICC>0.9 for both systems. The peak angles calculated by the marker-based and Kinect systems were largely correlated (r>0.55). These results suggest the data from the Kinect can be post processed in way that it may be a feasible markerless motion capture system that can be used in the clinic. PMID- 25708834 TI - Anti-CD22 and anti-CD79B antibody drug conjugates are active in different molecular diffuse large B-cell lymphoma subtypes. AB - Antibody drug conjugates (ADCs), in which cytotoxic drugs are linked to antibodies targeting antigens on tumor cells, represent promising novel agents for the treatment of malignant lymphomas. Pinatuzumab vedotin is an anti-CD22 ADC and polatuzumab vedotin an anti-CD79B ADC that are both linked to the microtubule disrupting agent monomethyl auristatin E (MMAE). In the present study, we analyzed the activity of these agents in different molecular subtypes of diffuse large B-cell lymphoma (DLBCL) both in vitro and in early clinical trials. Both anti-CD22-MMAE and anti-CD79B-MMAE were highly active and induced cell death in the vast majority of activated B-cell-like (ABC) and germinal center B-cell-like (GCB) DLBCL cell lines. Similarly, both agents induced cytotoxicity in models with and without mutations in the signaling molecule CD79B. In line with these observations, relapsed and refractory DLBCL patients of both subtypes responded to these agents. Importantly, a strong correlation between CD22 and CD79B expression in vitro and in vivo was not detectable, indicating that patients should not be excluded from anti-CD22-MMAE or anti-CD79B-MMAE treatment because of low target expression. In summary, these studies suggest that pinatuzumab vedotin and polatuzumab vedotin are active agents for the treatment of patients with different subtypes of DLBCL. PMID- 25708835 TI - Dinaciclib is a novel cyclin-dependent kinase inhibitor with significant clinical activity in relapsed and refractory chronic lymphocytic leukemia. AB - Dinaciclib (SCH727965) is a selective CDKi chosen for clinical development based upon a favorable therapeutic index in cancer xenograft models. We performed a phase I dose escalation study of dinaciclib in relapsed and refractory chronic lymphocytic leukemia (CLL) patients with intact organ function and WBC<200 * 10(9) /l. Five separate dose levels (5 mg/m(2), 7 mg/m(2), 10 mg/m(2), 14 mg/m(2) and 17 mg/m(2)) were explored dosing on a weekly schedule * 3 with 1 week off (4 week cycles) using a standard 3+3 design with expansion cohorts to optimize safety. Fifty-two patients were enrolled with relapsed and refractory CLL. Escalation through cohorts occurred with two dose-limiting toxicity (DLTs) at the 17 mg/m(2) dose (tumor lysis syndrome (TLS) and pneumonia). The phase II expansion occurred at 14 mg/m(2) with 16 patients receiving this dose with one DLT (TLS). Additional stepped up dosing to the maximum tolerated dose was examined in 19 patients at this dose. Adverse events included cytopenias, transient laboratory abnormalities and TLS. Responses occurred in 28 (54%) of patients independent of del(17)(p13.1) with a median progression-free survival of 481 days. Dinaciclib is clinically active in relapsed CLL including those patients with high risk del(17)(p13.1) disease and warrants future study. PMID- 25708836 TI - The relationship of autophagy defects to cartilage damage during joint aging in a mouse model. AB - OBJECTIVE: Aging is a main risk factor for osteo arthritis (OA), the most prevalent musculoskeletal disorder. Defects in autophagy, an essential cellular homeostasis mechanism, have recently been observed in OA articular cartilage. The objectives of this study were to establish the constitutive level of autophagy activation in normal cartilage and to monitor the temporal relationship between changes in autophagy and aging-related degradation of cartilage in a mouse model. METHODS: In GFP-LC3-transgenic mice, green fluorescent protein (GFP)-light chain 3 (LC3) is ubiquitously expressed, and the accumulation of GFP puncta, representing autophagosomes, was quantified by confocal microscopy as a measure of autophagy activation. Expression of the autophagy proteins autophagy-related protein 5 (ATG-5) and microtubule-associated protein 1 light chain 3 (LC3) was analyzed by immunohistochemistry. Cartilage cellularity, apoptotic cell death, and cartilage structural damage and changes in synovium and bone were examined by histology and immunohistochemistry. RESULTS: Basal autophagy activation was detected in liver and knee articular cartilage from young (6-month-old) mice, with higher levels in cartilage than in liver in the same animals. In 28-month old mice, there was a statistically significant reduction in the total number of autophagic vesicles per cell (P < 0.01) and in the total area of vesicles per cell (P < 0.01) in the articular cartilage as compared to that from young 6-month old mice. With increasing age, the expression of ATG-5 and LC3 decreased, and this was followed by a reduction in cartilage cellularity and an increase in the apoptosis marker poly(ADP-ribose) polymerase p85. Cartilage structural damage progressed in an age-dependent manner subsequent to the autophagy changes. CONCLUSION: Autophagy is constitutively activated in normal cartilage. This is compromised with aging and precedes cartilage cell death and structural damage. PMID- 25708837 TI - Pneumocystis jirovecci pneumonia in connective tissue diseases: Comparison with other immunocompromised patients. AB - INTRODUCTION: Pneumocystis jirovecci pneumonia (PJP) is an opportunistic fungal infection occurring in immunocompromised patients, such as those with human immunodeficiency virus (HIV), organ transplantation, malignancies and connective tissue diseases (CTDs). Risk factors for PJP are not well characterised, leading to uncertainty regarding the indications for antimicrobial prophylaxis and monitoring. This study compared differences between patients with and without CTDs who developed PJP. METHODS: Retrospective data was collected for all subjects with a positive toludine blue O stain or a positive P. jirovecci PCR and a concurrent respiratory illness that was clinically consistent with PJP between 2002 and 2013 at the Royal Melbourne Hospital, Australia. Sub-groups were assigned according to the underlying disease. Peripheral blood results were retrieved from an in-house pathology database. RESULTS: Eleven of 90 subjects (12.2%) diagnosed with PJP had underlying CTDs. The CTDs group was more likely to have been exposed to corticosteroids (100% versus 35.2%, p < 0.001) and other iatrogenic immunosuppression (90.9% versus 24.6%, p < 0.001). After adjusting for age and gender, the CTDs group had greater lymphopaenia (0.17 versus 0.58 * 10(9)/L; p = 0.034) and were older (69.6 versus 50.6 years; p < 0.001) than the non-CTD group. Excluding renal transplant recipients, people with CTDs also had lower eGFR than the non-CTD group (65 versus 80; p = 0.015). CONCLUSIONS: CTDs contributed to a significant proportion of total PJP diagnoses. Clinicians treating CTDs must be vigilant for PJP, particularly in older patients with exposure to corticosteroids or other iatrogenic immunosuppression, lymphopaenia and renal impairment; factors which may lower the clinical threshold for initiating prophylaxis. PMID- 25708838 TI - Whole-genome sequence analysis of G3 and G14 equine group A rotaviruses isolated in the late 1990s and 2009-2010. AB - Equine group A rotavirus (RVA) G3P[12] and G14P[12] strains cause gastroenteritis in foals worldwide. Both of these strains have been co-circulating in Japan since G14P[12] strains emerged in the late 1990s. Although it is important to comprehensively understand the evolution of RVA strains, whole-genome sequence data on recent equine RVA strains in Japan are lacking. Therefore, in this study, whole-genome analysis of 23 equine RVA isolates from the late 1990s and 2009-2010 and the vaccine strain RVA/Horse-tc/JPN/HO-5/1982/G3P[12] (HO-5) was performed. The G3 strains, including strain HO-5, shared a G3-P[12]-I6-R2-C2-M3-A10-N2-T3-E2 H7 genotype constellation, and all of their 11 gene segments were highly conserved, regardless of the year of isolation. G14 strains also exhibited an identical genotype constellation (G14-P[12]-I2-R2-C2-M3-A10-N2-T3-E2-H7), but, phylogenetically, segregated into two lineages within the VP7-G14 and NSP4-E2 genotypes. G14 strains were closely related to G3 strains in their VP4, VP1-3, NSP1-3 and NSP5 gene segments. Interestingly, the NSP4 gene of all G3 and G14 strains isolated in the late 1990s branched into a bovine-RVA-like NSP4 gene cluster. These results indicate that, apart from VP7, VP6, and NSP4 genes, the Japanese equine RVA strains share a highly conserved genetic backbone, and that strains possessing a bovine-RVA-like NSP4 gene were predominant in the late 1990s in Japan. PMID- 25708839 TI - Tracking the changes in virus taxonomy. AB - A database and website ( http://www.ictvonline.org/taxonomyReleases.asp ) have been established where the history of changes in virus taxonomy from 1971 to the present day can easily be traced. Each change is linked to a source document confirming the change or, for most changes since 2002, to the taxonomic proposal approved by the International Committee on Taxonomy of Viruses (ICTV). PMID- 25708840 TI - cisPath: an R/Bioconductor package for cloud users for visualization and management of functional protein interaction networks. AB - BACKGROUND: With the burgeoning development of cloud technology and services, there are an increasing number of users who prefer cloud to run their applications. All software and associated data are hosted on the cloud, allowing users to access them via a web browser from any computer, anywhere. This paper presents cisPath, an R/Bioconductor package deployed on cloud servers for client users to visualize, manage, and share functional protein interaction networks. RESULTS: With this R package, users can easily integrate downloaded protein protein interaction information from different online databases with private data to construct new and personalized interaction networks. Additional functions allow users to generate specific networks based on private databases. Since the results produced with the use of this package are in the form of web pages, cloud users can easily view and edit the network graphs via the browser, using a mouse or touch screen, without the need to download them to a local computer. This package can also be installed and run on a local desktop computer. Depending on user preference, results can be publicized or shared by uploading to a web server or cloud driver, allowing other users to directly access results via a web browser. CONCLUSIONS: This package can be installed and run on a variety of platforms. Since all network views are shown in web pages, such package is particularly useful for cloud users. The easy installation and operation is an attractive quality for R beginners and users with no previous experience with cloud services. PMID- 25708841 TI - Pre-exposure of neuroblastoma cell line to pulsed electromagnetic field prevents H2 O2 -induced ROS production by increasing MnSOD activity. AB - Electromagnetic fields (EMFs) have been linked to increased risk of cancers and neurodegenerative diseases; however, EMFs can also elicit positive effects on biological systems, and redox status seems crucially involved in EMF biological effects. This study aimed to assess whether a short and repeated pulsed EMF (PEMF) could trigger adaptive responses against an oxidative insult in a neuronal cellular model. We found that a 40 min overall (four times a week, 10 min each) pre-exposure to PEMF did not affect major physiological parameters and led to a significant increase of Mn-dependent superoxide dismutase activity in the human neuroblastoma SH-SY5Y cell line. In addition, we found PEMF-pre-exposed cells exhibited decreased reactive oxygen species production following a 30 min H2 O2 challenge, with respect to non pre-exposed cells. Our findings might provide new insights on the role played by short and repeated PEMF stimulations in the enhancement of cellular defenses against oxidative insults. Although studies in normal neuronal cells would be useful to further confirm our hypothesis, we suggest that specific PEMF treatments may have potential biological repercussions in diseases where oxidative stress is implicated. PMID- 25708842 TI - Plasma zinc alpha2-glycoprotein levels are elevated in smokers and correlated with metabolic syndrome. AB - BACKGROUND: Smoking is a strong risk factor of metabolic syndrome. Zinc alpha2 glycoprotein (ZAG) is a protein involved in metabolic syndrome. This study aims to investigate the effect of smoking on plasma ZAG levels and its relations to metabolic syndrome. MATERIALS AND METHODS: A group of 41 cigarette smokers and 47 non-smokers were enrolled. ZAG levels were measured to correlate to participants' demographic and metabolic parameters. RESULTS: Plasma ZAG levels of smokers were higher than those of controls (P < 0.0001). Plasma ZAG levels were positively correlated with male gender (P = 0.0002), number of cigarettes smoked per day (P < 0.0001), smoking duration in years (P < 0.0001), smoking index (P < 0.0001) and nicotine dependence score (P < 0.0001). In the multiple regression analysis, smoking was a strong independent factor affecting plasma ZAG levels (P = 0.0034). Plasma ZAG levels elevated progressively with the number of metabolic syndrome components (P = 0.0143). In the multiple regression analysis, plasma ZAG was an independent factor for metabolic syndrome. CONCLUSIONS: Plasma ZAG levels are high in smokers and correlate with metabolic syndrome. Our results indicate ZAG is an independent risk factor, but also interacted with smoking, for the metabolic syndrome. PMID- 25708843 TI - Striatal and midbrain connectivity with the hippocampus selectively boosts memory for contextual novelty. AB - The role of contextual expectation in processing familiar and novel stimuli was investigated in a series of experiments combining eye tracking, functional magnetic resonance imaging, and behavioral methods. An experimental paradigm emphasizing either familiarity or novelty detection at retrieval was used. The detection of unexpected familiar and novel stimuli, which were characterized by lower probability, engaged activity in midbrain and striatal structures. Specifically, detecting unexpected novel stimuli, relative to expected novel stimuli, produced greater activity in the substantia nigra/ventral tegmental area (SN/VTA), whereas the detection of unexpected familiar, relative to expected, familiar stimuli, elicited activity in the striatum/globus pallidus (GP). An effective connectivity analysis showed greater functional coupling between these two seed areas (GP and SN/VTA) and the hippocampus, for unexpected than for expected stimuli. Within this network of midbrain/striatal-hippocampal interactions two pathways are apparent; the direct SN-hippocampal pathway sensitive to unexpected novelty and the perirhinal-GP-hippocampal pathway sensitive to unexpected familiarity. In addition, increased eye fixations and pupil dilations also accompanied the detection of unexpected relative to expected familiar and novel stimuli, reflecting autonomic activity triggered by the functioning of these two pathways. Finally, subsequent memory for unexpected, relative to expected, familiar, and novel stimuli was characterized by enhanced recollection, but not familiarity, accuracy. Taken together, these findings suggest that a hippocampal-midbrain network, characterized by two distinct pathways, mediates encoding facilitation and most critically, that this facilitation is driven by contextual novelty, rather than by the absolute novelty of a stimulus. This contextually sensitive neural mechanism appears to elicit increased exploratory behavior, leading subsequently to greater recollection of the unexpected stimulus. PMID- 25708845 TI - [Quilting suture after mastectomy in prevention of postoperative seroma: a prospective observational study]. AB - OBJECTIVES: The occurrence of a postoperative seroma is the main complication of mastectomy. In 2011, Ouldamer et al. adapted a quilting technique used in reconstructive surgery in mastectomy closure. The aim of this study is to evaluate the impact of quilting in the prevention of postoperative seroma. PATIENTS AND METHODS: This is an observational prospective study to the Centre Hospital-University of Tours. Hundred and forty-four patients who underwent a mastectomy between January 1st, 2011 and October 1st, 2012 were included. Patients were divided into 2 groups, one with a classic wound closure with drainage and the second with quilting suture of skin flaps to the underlying musculature after mastectomy without drainage. RESULTS: Quilting suture significantly reduces the postoperative seroma appearance (OR=0.15; CI95% [0.06 0.39]; P<0.001). Operative time is increased by 20minutes in the quilted group (P<0.001). Postoperative pain is not changed by quilting. The duration of hospitalization is significantly shorter (5.09+/-1.46 days versus 6.49+/-2.77 days; P<0.001). Quality of the healing and appearance of the scar, rated by patients, are identical in both groups. CONCLUSION: Quilting is an effective method not only for prevention of seroma, but also for reducing of hospitalization duration, without increasing of postoperative pain and complications. PMID- 25708844 TI - Cognitive Performance Scores for the Pediatric Automated Neuropsychological Assessment Metrics in Childhood-Onset Systemic Lupus Erythematosus. AB - OBJECTIVE: To develop and initially validate a global cognitive performance score (CPS) for the Pediatric Automated Neuropsychological Assessment Metrics (PedANAM) to serve as a screening tool of cognition in childhood lupus. METHODS: Patients (n = 166) completed the 9 subtests of the PedANAM battery, each of which provides 3 principal performance parameters (accuracy, mean reaction time for correct responses, and throughput). Cognitive ability was measured by formal neurocognitive testing or estimated by the Pediatric Perceived Cognitive Function Questionnaire-43 to determine the presence or absence of neurocognitive dysfunction (NCD). A subset of the data was used to develop 4 candidate PedANAM CPS indices with supervised or unsupervised statistical approaches: PedANAM CPSUWA , i.e., unweighted averages of the accuracy scores of all PedANAM subtests; PedANAM-CPSPCA , i.e., accuracy scores of all PedANAM subtests weighted through principal components analysis; PedANAM-CPSlogit , i.e., algorithm derived from logistic models to estimate NCD status based on the accuracy scores of all of the PedANAM subtests; and PedANAM-CPSmultiscore , i.e., algorithm derived from logistic models to estimate NCD status based on select PedANAM performance parameters. PedANAM-CPS candidates were validated using the remaining data. RESULTS: PedANAM-CPS indices were moderately correlated with each other (|r| > 0.65). All of the PedANAM-CPS indices discriminated children by NCD status across data sets (P < 0.036). The PedANAM-CPSmultiscore had the highest area under the receiver operating characteristic curve (AUC) across all data sets for identifying NCD status (AUC >0.74), followed by the PedANAM-CPSlogit , the PedANAM-CPSPCA , and the PedANAM-CPSUWA , respectively. CONCLUSION: Based on preliminary validation and considering ease of use, the PedANAM-CPSmultiscore and the PedANAM-CPSPCA appear to be best suited as global measures of PedANAM performance. PMID- 25708846 TI - [Comparison of frozen embryo transfer outcomes at blastocyst stage according to freezing method and type of endometrial preparation]. AB - OBJECTIVE: This study intended to compare frozen embryo transfer (FET) outcomes at blastocyst stage according to freezing methods, slow freezing versus vitrification and according to the type of endometrial preparation. PATIENTS AND METHODS: A total of 172 FET at blastocyst stage (day 5 or 6) were included retrospectively from April, 2007 to December, 2012. The FET outcomes from slow freezing (group 1, n=86) were compared with those from vitrification (group 2, n=86). More particularly, the survival rate after thawing, as well as implantation and pregnancy rates (clinical and ongoing pregnancy rates) were compared respectively between these two groups, after matching on women's age at freezing day, embryo number and embryo development stage for transfer. Furthermore, for each freezing method, FET outcomes were compared according to the type of endometrial preparation, i.e. natural cycle (group N) versus stimulated cycle (group S). RESULTS: The survival rate as well as implantation and clinical pregnancy rates were significantly higher for FET after vitrification compared to FET after slow freezing (97% vs 85%, P<0.0001; 32% vs 20%, P=0.02; 43% vs 28%, P=0.04, respectively). By taking into account the number of transferred embryos for each group, the multiple pregnancy rate was three-fold higher in the group of FET after vitrification compared to the group of FET after slow freezing but not significantly (27.3% vs 8.3%, NS). However, FET outcomes were not affected significantly by the type of endometrial preparation whatever freezing methods. Nevertheless, the early spontaneous abortion (ESA) rate was lower in the case of embryos that were frozen by vitrification and transferred in natural cycle (group N2 vs group S2: 20% vs 47%, NS). DISCUSSION AND CONCLUSION: Our study confirms that the survival rate after thawing at blastocyst stage (day 5 or 6) is significantly improved after freezing by vitrification compared to slow freezing method. Likewise, implantation and clinical pregnancy rates are significantly increased in the case of FET at blastocyst stage when these embryos were frozen by vitrification. The results obtained by vitrification are very satisfactory but are also associated with an increased multiple pregnancy rate. Moreover, FET associated with natural or stimulated cycle does not modify significantly the outcomes of attempts, whatever the freezing method. However, the risk of ESA is reduced in the case of FET with natural cycle and after embryo vitrification. PMID- 25708847 TI - [Extended endometrial ablation risks in the fertility sparing management of adenocarcinoma and atypical hyperplasia of the endometrium]. PMID- 25708848 TI - [Anticoagulation and peripartum management]. AB - OBJECTIVE: To compare peripartum management of anticoagulated patients concerning locoregional analgesia, post-partum hemorrhage and thrombotic events according to planified interruption or not of antithrombotic therapy. PATIENTS AND METHODS: We conducted a single tertiary care center retrospective study of all deliveries associated with antithrombotic therapy from January 2005 to September 2011. RESULTS: We identified 120 cases with prophylactic (71%) or curative (29%) anticoagulation. Two thrombotic events occurred. In case of curative therapy, the use of locoregional analgesia was lower (P<0.0001) and post-partum hemorrhage occurred more frequently (P=0.07) compared to prophylactic therapy. According to planified interruption or not of antithrombotic therapy, we observed a more prolonged duration of therapeutic interruption before delivery (55.6h+/-63.3 vs 26.4 h+/-11.6, P<0.0001), higher use of locoregional analgesia (83% vs 71%, P=0.02) but no difference concerning cesarean rate (35% vs 39%, P=0.8) or post partum hemorrhage (13% vs 14%, P=0.9). CONCLUSION: In case of curative anticoagulation, plannified interruption favours the use of perimedullar analgesia after 24hour delay. In case of preventive anticoagulation, plannified interruption appears unnecessary as the 12hour delay is easier to reach. PMID- 25708849 TI - Abdominal findings in lymphangioleiomyomatosis: a report of two cases. PMID- 25708850 TI - Two-year results of a low-dose drug-coated balloon for revascularization of the femoropopliteal artery: outcomes from the ILLUMENATE first-in-human study. AB - OBJECTIVES: To assess the safety and effectiveness of the StellarexTM drug-coated angioplasty balloon (DCB) to inhibit restenosis in the superficial femoral and/or popliteal artery. BACKGROUND: Treatment of peripheral arterial disease is challenged by restenosis, requiring revascularization procedures to maintain patency. DCBs are designed to deliver an anti-proliferative drug to the vessel wall to diminish smooth muscle cell proliferation and maintain patency. METHODS: This prospective, single-arm, multicenter study enrolled 50 patients with 58 lesions in the first cohort that required pre-dilatation with an uncoated angioplasty balloon prior to inflation of the DCB. The primary effectiveness endpoint was 6-month late lumen loss (LLL). The major secondary endpoint was major adverse event (MAE) rate at 6 months, defined as cardiovascular death, amputation, and/or ischemia-driven target lesion revascularization. RESULTS: The mean lesion length was 7.2 cm and baseline stenosis was 75.1%. Calcification was present in 62.1% of lesions and 12.1% were occluded. Both endpoints met their prespecified performance goals; at 6 months, the MAE rate was 4% and the mean LLL was 0.54 mm. The primary patency rate was 89.5% at 12 months and 80.3% at 24 months. The freedom from clinically-driven target lesion revascularization rate, per Kaplan-Meier estimate, was 90.0% at 12 months and 85.8% at 24 months. Additionally, there were no amputations or cardiovascular deaths reported through 24 months. CONCLUSIONS: The Stellarex DCB provides safe and durable clinical outcomes for treatment of femoropopliteal artery disease through 24 months. PMID- 25708851 TI - Is subjective perception of negative body image among adolescents associated with bullying? AB - Adolescents' body image dissatisfaction has an adverse effect on peer relationships. It may lead to changes in behaviour (aggressive or passive) and consequently to bullying behaviour. Our aim was to assess the association between body image dissatisfaction and involvement in bullying and whether this differs by gender. We used data from the Slovak part of the 2010 Health Behaviour in School-aged Children study. The final sample comprised 8050 adolescents aged 11 to 15 years old (mean age 13.57), less than half of whom were boys. The association between self-reported body image and involvement in bullying was determined using multinomial logistic regression. We found a significant association between body dissatisfaction and involvement in bullying. Adolescents dissatisfied with their bodies because due to feeling overweight were more likely to become passive or reactive victims. Self-reported thinness was found to be significantly associated with bully-victims only in boys. CONCLUSION: Adolescent body dissatisfaction is strongly associated with bullying behaviour. Our findings point out the importance of incorporating at schools different types of intervention programmes supporting positive self-perceptions of adolescents and reducing bullying behaviour. PMID- 25708852 TI - Risk of mucocutaneous toxicities in patients with solid tumors treated with lapatinib: a systematic review and meta-analysis. AB - BACKGROUND: We performed a systematic review and meta-analysis to determine the risk of mucocutaneous adverse events associated with lapatinib. PATIENTS AND METHODS: Eligible studies included randomized phase II and III trials of patients with solid tumors on lapatinib; describing events of stomatitis, skin rash, hand foot syndrome, pruritus and alopecia. RESULTS: Our search strategy yielded 380 potentially relevant citations on lapatinib from PubMed/Medline, CENTRAL Cochrane Registry and ASCO Meeting Library. After exclusion of ineligible studies, a total of 19 clinical trials were considered eligible for the meta-analysis. The RRs of all-grade skin rash, stomatitis, hand foot syndrome and pruritus were 3.04 (95% CI 2.33-3.96; p < 0.00001), 1.67 (95% CI 1.02-2.3; p < 0.04), 4.45 (95% CI 1.15 17.19; p = 0.03), and 2.02 (95% CI 1.46-2.8; p < 0.0001), respectively. Exploratory subgroup analysis showed no effect of treatment regimen on the RRs of the relevant adverse events. CONCLUSIONS: Our meta-analysis has demonstrated that lapatinib is associated with a significantly increased risk of all-grade skin rash, hand foot skin reaction and pruritus. Clinicians should be aware of these risks and perform regular clinical monitoring. PMID- 25708854 TI - Yrjo Tapio Konttinen 1952-2014. PMID- 25708855 TI - Proteomic tools for the characterization of cell death mechanisms in drug discovery. AB - This review focuses on the use of proteomic tools for the characterization of cell death mechanisms that have contributed to drug discovery efforts. Resistance to cell death plays a major role in the development of many diseases, including numerous types of malignancies. Using a multitude of proteomic approaches, including protein-protein interaction studies, phosphorylation site mapping, ubiquitination site identification, and differential quantitative approaches, various cellular death pathways such as apoptosis and necroptosis have been investigated. These studies have aided in the development of therapeutic strategies or allowed dissection of clinical results to evaluate the success of clinical trials in addition to contributing to our understanding of these biological pathways. Here, we address the new wave of discoveries enabled by advancements in mass spectrometric technology and bioinformatic infrastructure that will hopefully lead to clinically efficacious strategies to overcome resistance to apoptosis and therefore offer improved treatment options for patients. PMID- 25708853 TI - Occurrence of selected pharmaceuticals in water and sediment of Umgeni River, KwaZulu-Natal, South Africa. AB - Selected pharmaceuticals including antibiotics, antipyretics, a stimulant, an antiepileptic and an antipsychotic drug were determined in wastewater, surface water and sediment along the Umgeni River which is the main source of water to Durban City in KwaZulu-Natal, South Africa. Samples were analysed using high performance liquid chromatography coupled to a mass spectrometer (HPLC-MS/MS) after clean up and pre-concentration by solid phase extraction (SPE). At the wastewater treatment plant outlet, the antipyretic ibuprofen was detected in concentrations up to 12.94 MUg/L and 15.96 ng/g in wastewater and bio-solids, respectively. The antipsychotic clozapine was detected in concentrations up to 14.43 MUg/L and 18.75 ng/g in wastewater and bio-solids, respectively. Other pharmaceuticals namely sulfamethazine, sulfamethoxazole, erythromycin, metronidazole, trimethoprim, acetaminophen, caffeine and carbamazepine were also detected but in lower concentration compared to clozapine and ibuprofen (<10 MUg/L or 10 ng/g). Clozapine and ibuprofen were detected at high concentrations in the surface water and sediment of Umgeni River. The highest concentration of clozapine (78.33 MUg/L) was detected at the business park, while that for ibuprofen (62.0 MUg/L) was detected at the point where a tributary, Msunduzi, joins Umgeni. Metronidazole was only detected in sediment, and caffeine (2243.52 ng/g) was detected at the highest concentration in the sediment at the blue lagoon sampling site. The antibiotic sulfamethoxazole was also detected in appreciable amounts up to 507.34 ng/g in the sediment at the Msunduzi tributary sampling site. The data collected implies that while insufficiently treated wastewater contributes to surface water contamination, human activities also contribute appreciably to the pharmaceutical loading of River Umgeni. PMID- 25708856 TI - Trans-anethole, a terpenoid ameliorates hyperglycemia by regulating key enzymes of carbohydrate metabolism in streptozotocin induced diabetic rats. AB - Trans-anethole (TA), a terpenoid and a principle constituent of many essential oils from medicinal plants possess hypoglycemic and antioxidant activities. This study was undertaken to explore beneficial effects of TA on key enzymes of carbohydrate metabolism in streptozotocin (STZ)-induced type 2 diabetic rats. Diabetes was induced in male albino Wistar rats by intraperitoneal administration of STZ (40 mg/kg BW). TA was administered to diabetic rats at a dose of 20, 40 and 80 mg/kg BW for 45 days. However, the dose at 80 mg/kg BW, resulted in a significant reduction in the levels of plasma glucose, glycosylated haemoglobin (HbA1c) and increase in the levels of insulin and haemoglobin (Hb). Upon administration of TA, the altered levels of liver glycolytic enzyme (hexokinase), hepatic shunt enzyme (glucose-6-phosphate dehydrogenase) and gluconeogenic enzymes (glucose-6-phosphatase and fructose-1,6-bisphosphatase) in the liver and kidney of diabetic rats significantly reverted to near normal levels. In addition to this, TA also improved the hepatic and muscle glycogen content in diabetic rats. The histological studies showed the ameliorative effect of TA on the beta cells of pancreas in diabetic rats. The results were compared with glibenclamide, a standard oral hypoglycemic drug. These encouraging findings suggest that TA may be used as a propitious bioactive compound in the development of therapeutic agents against type 2 diabetes mellitus. PMID- 25708857 TI - Mechanisms of mRNA frame maintenance and its subversion during translation of the genetic code. AB - Important viral and cellular gene products are regulated by stop codon readthrough and mRNA frameshifting, processes whereby the ribosome detours from the reading frame defined by three nucleotide codons after initiation of translation. In the last few years, rapid progress has been made in mechanistically characterizing both processes and also revealing that trans acting factors play important regulatory roles in frameshifting. Here, we review recent biophysical studies that bring new molecular insights to stop codon readthrough and frameshifting. Lastly, we consider whether there may be common mechanistic themes in -1 and +1 frameshifting based on recent X-ray crystal structures of +1 frameshift-prone tRNAs bound to the ribosome. PMID- 25708858 TI - Regulation of pyruvate kinase isozyme M2 is mediated by the ubiquitin-specific protease 20. AB - USP20, one of deubiquitinating enzymes (DUBs) belonging to the subfamily of ubiquitin-specific protease (USP), regulates ubiquitin-mediated protein degradation. So far, USP20 has been identified as a binding protein and a regulator of hypoxia-inducible factor (HIF)-1alpha, beta-adrenergic receptor, and tumor necrosis factor (TNF) receptor associated factor 6 (TRAF6). In order to investigate other biological functions of USP20 with its novel substrates, we searched for putative substrates through two-dimensional electrophoresis (2-DE) and matrix-assisted laser desorption-ionization time-of-flight mass spectrometry (MALDI-TOF/MS) analysis. We found several putative substrates, some of which are related to cancer metabolism or neural disorders. Among these, the pyruvate kinase isoenzyme M2 (PKM2) had a high identity score. Most cancer cells contain a specific metabolic pathway, referred to as the Warburg effect. One well-known function of PKM2 is a main regulator in cancer metabolic pathways, and PKM2 promotes the Warburg effect and tumor growth. In addition, both PKM2 and HIF 1alpha upregulate the expression of target genes. From this evidence, it is expected that USP20 would be associated with the metabolic pathway through the regulation of PKM2 ubiquitination. Despite various roles of DUBs, the biological functions of USP20 in cellular mechanisms are poorly understood. Herein, we investigated the inter-action between PKM2 and USP20. Our results suggest a new molecular pathway in cancer metabolism through the regulation of PKM2. PMID- 25708859 TI - French firefighter mortality: analysis over a 30-year period. AB - OBJECTIVE: To explore mortality of French professional male firefighters. METHODS: Standardized mortality ratios (SMR) were calculated for 10,829 professional male firefighters employed in 1979 and compared with the French male population between 1979-2008. Firefighters were identified from 89 French administrative departments (93% of population). RESULTS: One thousand six hundred forty two deaths were identified, representing significantly lower all-cause mortality than in the general population (SMR = 0.81; 95%CI: 0.77-0.85). SMR increased with age and was not different from 1 for firefighters >70 years. No significant excess of mortality was observed for any specific cause, but a greater number of deaths than expected were found for various digestive neoplasms (rectum/anus, pancreas, buccal-pharynx, stomach, liver, and larynx). CONCLUSION: We observed lower all and leading-cause mortality likely due to the healthy worker effect in this cohort, with diseases of the respiratory system considerably lower (SMR = 0.57). Non-significant excesses for digestive neoplasms are notable, but should not be over-interpreted at this stage. PMID- 25708860 TI - Effect of minor liver function test abnormalities and values within the normal range on survival in heart failure. AB - Liver function test (LFT) abnormalities are often observed in patients with heart failure (HF). However, the relation of LFTs with outcomes has not been well described. Patients of the VA Palo Alto Health Care System (3 inpatient facilities and 7 community clinics) with a complete set of LFTs in the 60 days before a first HF diagnosis were included in the analysis from January 2005 to April 2013. A total of 2,096 patients met inclusion criteria. Patients were a mean of 71 +/- 12 years old, 97% were men, 57% had a previous diagnosis of ischemic heart disease, and the mean left ventricular ejection fraction was 51 +/ 12%. The median (twenty fifth and seventy fifth) values were albumin 3.6 g/dl (3.3, 3.9), alanine transaminase 21 IU/L (16, 30), aspartate transaminase 24 IU/L (20,31), AP 70 IU/L (57, 87), and total bilirubin 0.8 mg/dl (0.6, 1.0). There were 851 deaths (41%) over a mean duration of 41 +/- 27 months. Mortality significantly increased with lower values of albumin and alanine transaminase and higher levels of aspartate transaminase and AP. The association with total bilirubin was not significant. In conclusion, many LFT values in the "normal" range are independently associated with decreased survival beyond traditional risk factors for mortality in HF. PMID- 25708861 TI - Meta-analysis of the effects of carvedilol versus metoprolol on all-cause mortality and hospitalizations in patients with heart failure. AB - Long-term treatment with appropriate doses of carvedilol or metoprolol is currently recommended for patients with heart failure with reduced ejection fraction (HFrEF) to decrease the risk of death, hospitalizations, and patients' symptoms. It remains unclear if the beta blockers used in patients with HFrEF are equal or carvedilol is superior to metoprolol types. We performed a meta-analysis of the comparative effects of carvedilol versus metoprolol tartrate and succinate on all-cause mortality and/or hospitalization. We conducted an Embase and MEDLINE search for prospective controlled trials and cohort studies of patients with HFrEF who were received to treatment with carvedilol versus metoprolol. We identified 4 prospective controlled and 6 cohort studies with 30,943 patients who received carvedilol and 69,925 patients on metoprolol types (tartrate and succinate) with an average follow-up duration of 36.4 months. All-cause mortality was reduced in prospective studies with carvedilol versus metoprolol tartrate. Neither all-cause mortality nor hospitalizations were significantly different between carvedilol and metoprolol succinate in the cohort studies. In conclusion, in patients with HFrEF, carvedilol and metoprolol succinate have similar effects in reducing all-cause mortality. PMID- 25708862 TI - Effect of preoperative angina pectoris on cardiac outcomes in patients with previous myocardial infarction undergoing major noncardiac surgery (data from ACS NSQIP). AB - The impact of preoperative stable angina pectoris on postoperative cardiovascular outcomes in patients with previous myocardial infarction (MI) who underwent major noncardiac surgery is not well studied. We studied patients with previous MI who underwent elective major noncardiac surgeries within the American College of Surgeons-National Surgical Quality Improvement Program (2005 to 2011). Primary outcome was occurrence of an adverse cardiac event (MI and/or cardiac arrest). Multivariable logistic regression models evaluated the impact of stable angina on outcomes. Of 1,568 patients (median age 70 years; 35% women) with previous MI who underwent major noncardiac surgery, 5.5% had postoperative MI and/or cardiac arrest. Patients with history of preoperative angina had significantly greater incidence of primary outcome compared to those without anginal symptoms (8.4% vs 5%, p = 0.035). In secondary outcomes, reintervention rates (22.5% vs 11%, p <0.001) and length of stay (median 6-days vs 5-days; p <0.001) were also higher in patients with preoperative angina. In multivariable analyses, preoperative angina was a significant predictor for postoperative MI (odds ratio 2.49 [1.20 to 5.58]) and reintervention (odds ratio 2.40 [1.44 to 3.82]). In conclusion, our study indicates that preoperative angina is an independent predictor for adverse outcomes in patients with previous MI who underwent major noncardiac surgery, and cautions against overreliance on predictive tools, for example, the Revised Cardiac Risk Index, in these patients, which does not treat stable angina and previous MI as independent risk factors during risk prognostication. PMID- 25708863 TI - Usefulness of thrombocytopenia at admission as a prognostic marker in native valve left-sided infective endocarditis. AB - In-hospital mortality of patients with infective endocarditis (IE) remains exceedingly high. Quick recognition of parameters accurately identifying high risk patients is of paramount importance. The objective of this study was to analyze the incidence and severity of thrombocytopenia at presentation and its prognostic impact in patients with native valve left-sided IE. We studied a cohort of 533 consecutive episodes of native valve left-sided IE prospectively recruited. We distinguished 2 groups: group I (n = 175), episodes who had thrombocytopenia at admission, and group II (n = 358) gathered all the episodes who did not. Thrombocytopenia at admission was defined as a platelet count of <150,000/MUl. No differences were found in the need for surgery, but in-hospital mortality was significantly higher in patients with thrombocytopenia (p <0.001). Mortality rate was associated with the degree of thrombocytopenia (p <0.001). In the multivariable analysis, thrombocytopenia at admission was an independent predictor of higher mortality (p = 0.002). A synergistic interaction between thrombocytopenia and Staphylococcus aureus on mortality risk was also observed (p = 0.04). In conclusion, thrombocytopenia at admission is an early risk marker of increased mortality in patients with native valve left-sided IE. Mortality rates increased with increasing severity of thrombocytopenia. Thrombocytopenia at admission should be used as an early marker for risk stratification in patients with native valve IE to identify those at risk of complicated in-hospital evolution and increased mortality. PMID- 25708864 TI - Host-guest chemistry of a bis-calix[4]pyrrole derivative containing a trans/cis switchable azobenzene unit with several aliphatic bis-carboxylates. AB - The azobenzene unit used as a photochemically and thermally switchable linker in the assembly of a bis-calix[4]pyrrole receptor provides a means to modulate the binding of bis-carboxylates of significant biological importance in cancer research. Conversely, the complexation of different bis-anionic guests has significant kinetic effects on both the photochemical and thermal trans/cis isomerization of the azobenzene unit. PMID- 25708865 TI - Ultrasonic Assisted Synthesis of Chromenes Catalyzed by Sodium Carbonate in Aqueous Media. AB - A simple, efficient, and environmentally benign procedure for the synthesis of 2 amino-4H-chromene ring has been achieved by the three-component reaction of an aromatic aldehyde, malononitrile and diverse enolizable C-H activated compound under ultrasound irradiation using sodium carbonate as a catalyst in aqueous media. Sodium carbonate as a natural salt, being available as an inexpensive catalyst combined with ultrasound method promoted this protocol in comparison to other methods and catalysts. PMID- 25708866 TI - A pilot trial to examine the effect of high-dose niacin on arterial wall inflammation using fluorodeoxyglucose positron emission tomography. AB - RATIONALE AND OBJECTIVES: Although studies have reported direct inhibition of inflammatory pathways with niacin, the effect of niacin on arterial wall inflammation remains unknown. We examined the effect of niacin on arterial (18)F fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT). MATERIALS AND METHODS: Nine statin-treated patients with coronary disease were randomized to niacin 6000 mg/day or placebo. FDG-PET/CT and lipids were assessed at baseline and at 12 weeks. FDG was quantified in the aorta, right carotid artery, and left carotid artery as the target-to-background ratio (TBR) and target-to-background difference (TBD). RESULTS: Eight patients completed the study. No significant changes in FDG measured by aortic, left carotid, or right carotid TBR or TBD were seen in either group. Compared to baseline, niacin treated subjects exhibited a significant 29% reduction in low-density lipoprotein cholesterol (LDL-C; 95% confidence interval [CI], -50% to 8%; P = .01) and a nonsignificant 29% reduction in LDL particle number (LDL-P; 95% CI, -58% to 0.2%; P = .07). A nonsignificant 11% increase in HDL-C (95% CI, -15% to 37%; P = .30) and 8% decrease in HDL-P (95% CI, -44% to 28%; P = .51) were observed with niacin treatment. In a pooled analysis, changes in LDL-P were positively correlated with FDG uptake in the aorta (TBR r = 0.66, P = .08; TBD r = 0.75, P = .03), left carotid (TBR r = 0.65, P = .08; TBD r = 0.74, P = .03), and right carotid (TBR r = 0.54, P = .17; TBD r = 0.61, P = .11). CONCLUSIONS: In this pilot study, adding niacin to statin therapy did not affect arterial wall inflammation measured by FDG-PET/CT. However, an association between changes in arterial FDG uptake and LDL-P was observed. Larger studies are needed to definitively examine the effect of niacin on arterial wall inflammation. PMID- 25708867 TI - Comparison of prostate volume measured by endorectal coil MRI to prostate specimen volume and mass after radical prostatectomy. AB - RATIONALE AND OBJECTIVES: To compare prostate volume measurements from 3-Tesla endorectal coil magnetic resonance imaging (ERC MRI) obtained with the prolate ellipsoid volume formula (EVF) and volumetry to pathology-based volume measurements. METHODS: The institutional review board waived informed consent for this retrospective, health insurance portability and accountability act (HIPAA) compliant study, which included 195 patients who underwent 3-T ERC MRI between January 2008 and October 2011 and had pathologic prostate measurements available. Two readers in consensus measured the prostate length, height, and width on each MRI. They estimated prostate volumes using the prolate EVF (length * height * width * [pi/6]) and also by performing three-dimensional volumetry. Pathologic specimen mass and dimensions were used to calculate prostate volume. Agreement was measured with Lin's concordance correlation coefficient (CCC). Volume differences were assessed using the Wilcoxon signed-rank test. Correct prostate specific antigen (PSA) density classification rates were compared between EVF based and volumetry-based PSA density levels using the exact McNemar test, with pathology-based PSA density as the reference standard. RESULTS: Concordance was high between EVF and volumetry measurements (CCC, 0.950 [95% confidence interval, 0.935-0.962]) and between both kinds of MRI measurements and pathology (both CCC > 0.80). Based on a cut-off of <=0.15 ng/mL/cm(3), use of EVF-based volume produced correct classification of 46 of 48 PSA density levels >15 ng/mL/cm(3) and 113 of 147 PSA density levels <=15 ng/mL/cm(3); use of volumetry-based volume produced correct classification of 47 of 48 PSA density levels >15 ng/mL/cm(3) and 121 of 147 PSA density levels <=15 ng/mL/cm(3). Rates of underclassification (P > .95) and overclassification (P = .10) did not differ significantly between EVF and volumetry. CONCLUSIONS: EVF appears to be suitable for measuring prostate volume from ERC-MRI. PMID- 25708868 TI - Plasma rich in growth factors (PRGF) eye drops stimulates scarless regeneration compared to autologous serum in the ocular surface stromal fibroblasts. AB - Autologous serum (AS) eye drops was the first blood-derived product used for the treatment of corneal pathologies but nowadays PRGF arises as a novel interesting alternative to this type of diseases. The purpose of this study was to evaluate and compare the biological outcomes of autologous serum eye drops or Plasma rich in growth factors (PRGF) eye drops on corneal stromal keratocytes (HK) and conjunctival fibroblasts (HConF). To address this, blood from healthy donors was collected and processed to obtain autologous serum (AS) eye drops and plasma rich in growth factors (PRGF) eye drops. Blood-derivates were aliquoted and stored at 80 degrees C until use. PDGF-AB, VEGF, EGF, FGFb and TGF-beta1 were quantified. The potential of PRGF and AS in promoting wound healing was evaluated by means of proliferation and migration assays in HK and HConF. Fibroblast cells were induced to myofibroblast differentiation after treatment with 2.5ng/mL of TGF-beta1. The capability of PRGF and AS to prevent and inhibit TGF-beta1-induced differentiation was evaluated. Results showed significant higher levels of all growth factors analyzed in PRGF eye drops compared to AS. Moreover, PRGF eye drops enhanced significantly the biological outcomes of both HK and HConF, and reduced TGF-beta1-induced myofibroblast differentiation in contrast to autologous serum eye drops (AS). In summary, these results suggest that PRGF exerts enhanced biological outcomes than AS. PRGF may improve the treatment of ocular surface wound healing minimizing the scar formation compared to AS. Results obtained herein suggest that PRGF protects and reverses the myofibroblast phenotype while promotes cell proliferation and migration. PMID- 25708870 TI - HLA-VBSeq: accurate HLA typing at full resolution from whole-genome sequencing data. AB - BACKGROUND: Human leucocyte antigen (HLA) genes play an important role in determining the outcome of organ transplantation and are linked to many human diseases. Because of the diversity and polymorphisms of HLA loci, HLA typing at high resolution is challenging even with whole-genome sequencing data. RESULTS: We have developed a computational tool, HLA-VBSeq, to estimate the most probable HLA alleles at full (8-digit) resolution from whole-genome sequence data. HLA VBSeq simultaneously optimizes read alignments to HLA allele sequences and abundance of reads on HLA alleles by variational Bayesian inference. We show the effectiveness of the proposed method over other methods through the analysis of predicting HLA types for HLA class I (HLA-A, -B and -C) and class II (HLA-DQA1, DQB1 and -DRB1) loci from the simulation data of various depth of coverage, and real sequencing data of human trio samples. CONCLUSIONS: HLA-VBSeq is an efficient and accurate HLA typing method using high-throughput sequencing data without the need of primer design for HLA loci. Moreover, it does not assume any prior knowledge about HLA allele frequencies, and hence HLA-VBSeq is broadly applicable to human samples obtained from a genetically diverse population. PMID- 25708871 TI - Swimming droplets driven by a surface wave. AB - Self-propelling motion is ubiquitous for soft active objects such as crawling cells, active filaments, and liquid droplets moving on surfaces. Deformation and energy dissipation are required for self-propulsion of both living and non-living matter. From the perspective of physics, searching for universal laws of self propelled motions in a dissipative environment is worthwhile, regardless of the objects' details. In this article, we propose a simple experimental system that demonstrates spontaneous migration of a droplet under uniform mechanical agitation. As we vary control parameters, spontaneous symmetry breaking occurs sequentially, and cascades of bifurcations of the motion arise. Equations describing deformable particles and hydrodynamic simulations successfully describe all of the observed motions. This system should enable us to improve our understanding of spontaneous motions of self-propelled objects. PMID- 25708872 TI - Growth arrest in the ribosomopathy, Bowen-Conradi syndrome, is due to dramatically reduced cell proliferation and a defect in mitotic progression. AB - Bowen-Conradi syndrome (BCS) is a ribosomopathy characterized by severe developmental delay and growth failure that typically leads to death by one year of age. It is caused by a c.257A>G, p.D86G substitution in the ribosomal biogenesis protein, Essential for Mitotic Growth 1 (EMG1). We generated a knock in of the D86G substitution in mice to characterize the effects of EMG1 deficiency, particularly in the brain, where EMG1 expression is high. Embryos homozygous for the mutation in Emg1 were small for gestational age with neural tube defects, and died between embryonic days 8.5 and 12.5. These embryos exhibited dramatically reduced cell proliferation, which we also detected in autopsy brain tissue and bone marrow of BCS patients, consistent with a requirement for high levels of EMG1 in tissues with rapid cell proliferation. In fibroblasts derived from the BCS mouse embryos, we detected a high proportion of binucleated cells, indicating that a mitotic defect underlies the growth arrest in BCS. These studies add to growing evidence of a link between ribosome biogenesis, mitotic progression, and brain development that is currently unexplored. PMID- 25708874 TI - The cross-lagged relationship between father absence and child problem behaviour in the early years. AB - BACKGROUND: Father absence has negative consequences for children's behaviour. Yet research has not examined how father absence and child behaviour may influence each other. This study models the cross-lagged relationship between father absence (non-residence) and child problem behaviour in the early years. METHODS: We used data from the UK's Millennium Cohort Study, at children's ages 3, 5 and 7 years (Sweeps 2-4). The sample was 15,293 families in which both biological parents were co-resident at Sweep 1, when the child was aged 9 months. Child problem behaviour was assessed using the clinical cut-offs of the Strengths and Difficulties Questionnaire (SDQ). We also investigated gender differences in the association between father absence and problem behaviour. RESULTS: Father absence at age 3 predicted a higher probability of the child scoring above cut off for total difficulties at age 5, as did father absence at age 5 for total difficulties at age 7. There were no significant effects for total difficulties on father absence. Similar father absence effects were found for individual SDQ subscales. Using these subscales, we found few child behaviour effects, mostly during the preschool years: children's severe externalizing and social (but not emotional) problems were associated with a greater probability of the father being absent in the next sweep. All cross-lagged relationships were similar for boys and girls. CONCLUSIONS: Father absence seems to be mainly the cause rather than the outcome of child problem behaviour in young UK families, and to affect boys and girls similarly. There were some child (mostly externalizing) behaviour effects on father absence, particularly in the early years. PMID- 25708876 TI - Fabrication of fibrillized collagen microspheres with the microstructure resembling an extracellular matrix. AB - Microspheres using artificial or natural materials have been widely applied in the field of tissue engineering and drug delivery systems. Collagen is being widely used for microspheres because of its abundancy in the extracellular matrix (ECM), and its good biocompatibility. The purpose of this study is to establish the appropriate condition for preparing collagen microspheres (CMS) and fibrillized collagen microspheres (fCMS) using water-in-oil (W/O) emulsion. Collagen can be tailored to mimic the native cell environment possessing a similar microstructure to that of the ECM by conditioning the aqueous solution. We focused on the preparation of stable and injectable CMS and fCMS which is stable and would promote the healing response. Controlling the interfacial properties of hydrophilic-lipophilic balance (HLB), we obtained CMS and fCMS with various sizes and various morphologies. The microsphere prepared with wetting agents showed good microsphere formation, but too low or too high HLB value caused low yield and uncontrollable size distribution. The change in the surfactant amount and the rotor speed also affected the formation of the CMS and fCMS, where the low surfactant amount and fast rotor speed produced smaller CMS and fCMS. In the case of fCMS, the presence of NaCl made it possible to prepare stable fCMS without using any cross-linker due to fibrillogenesis and gelling of collagen molecules. The microstructure of fCMS was similar to that of the native tissue indicating that the fCMS would replicate its function in vivo. PMID- 25708873 TI - The NPR1 homolog GhNPR1 plays an important role in the defense response of Gladiolus hybridus. AB - KEY MESSAGE: GhNPR1 shares similar functions as Arabidopsis NPR1 . Silencing of GhNPR1 in Gladiolus results in an enhanced susceptibility to Curvularia gladioli. We propose that GhNPR1 plays important roles in plant immunity. Gladiolus plants and corms are susceptible to various types of pathogens including fungi, bacteria and viruses. Understanding the innate defense mechanism in Gladiolus is a prerequisite for the development of new protection strategies. The non-expressor of pathogenesis-related gene 1 (NPR1) and bzip transcription factor TGA2 play a key role in regulating salicylic acid (SA)-mediated systemic acquired resistance (SAR). In this study, the homologous genes, GhNPR1 and GhTGA2, were isolated from Gladiolus and functionally characterized. Expression of GhNPR1 exhibited a 3.8 fold increase in Gladiolus leaves following salicylic acid treatment. A 1332 bp fragment of the GhNPR1 promoter from Gladiolus hybridus was identified. Inducibility of the GhNPR1 promoter by SA was demonstrated using transient expression assays in the leaves of Nicotiana benthamiana. The GhNPR1 protein is located in the nucleus and cytomembrane. GhNPR1 interacts with GhTGA2, as observed using the bimolecular fluorescence complementation system. Overexpression of GhNPR1 in an Arabidopsis npr1 mutant can restore its basal resistance to Pseudomonas syringae pv. tomato DC3000. Silencing of GhNPR1, using a tobacco rattle virus-based silencing vector, resulted in an enhanced susceptibility to Curvularia gladioli. In conclusion, these results suggest that GhNPR1 plays a pivotal role in the SA-dependent systemic acquired resistance in Gladiolus. PMID- 25708877 TI - Differences in vulnerability to traumatic stress among patients with psychiatric disorders: One-year follow-up study after the Great East Japan Earthquake. AB - AIMS: The aim of this study was to evaluate differences in vulnerability to traumatic stress and the 1-year course of post-traumatic stress symptoms among patients with pre-existing psychiatric disorders after the Great East Japan Earthquake. METHODS: The Impact of Event Scale-Revised (IES-R) was used to assess post-traumatic stress symptoms in 612 patients with schizophrenic (ICD-10 F2; n = 163), mood (F3; n = 299), or neurotic disorders (F4; n = 150) at 1-4 months and again at 13-16 months after the disaster (retention rate: 68%). RESULTS: The mean IES-R total score for all diagnostic groups was 18.6 at index and 13.4 at follow up. The mean IES-R total score for patients with neurotic disorders (22.5) was significantly higher than that of patients with mood disorders (18.1) and schizophrenic disorders (15.9). At follow up, these scores decreased for all groups and inter-group differences were not observed. CONCLUSIONS: Vulnerability to traumatic stress after a disaster was most severe in patients with neurotic disorders, followed by mood disorders, and, lastly, schizophrenic disorders. This difference among the three diagnostic groups was not found 1 year after the disaster. PMID- 25708878 TI - Additional review of Mohs slides to optimize Mohs micrographic surgery. AB - BACKGROUND: One significant risk factor for recurrence after Mohs surgery is misinterpretation of slides. OBJECTIVES: To determine how often pathologists detected incompletely excised basal cell carcinoma (BCC) on Mohs slides and to determine risk factors for incompletely excised BCCs. METHODS: This retrospective study included 1653 BCCs treated with Mohs surgery in a university hospital between 2007 and 2011. For routine quality assurance, all slides were additionally reviewed by a pathologist within 1 week of the procedure. For this study, all cases that had divergent interpretations were re-evaluated by a Mohs surgeon and a pathologist. Mixed-effects logistic regression models with Mohs surgeon effects as random effects were used to determine risk factors for incompletely excised BCC. RESULTS: Incompletely excised BCCs were detected in 31 cases (2%), in which defects > 20 mm in diameter were an independent risk factor (odds ratio 3.58, 95% confidence interval 1.55-8.28). Other studied variables (i.e. aggressive subtype, previously treated BCC, location on nose and > 2 Mohs stages) did not affect the risk of incompletely excised BCCs. CONCLUSIONS: The additional review of Mohs slides might increase accurate interpretation, especially in large BCCs. PMID- 25708879 TI - Assessing mitral regurgitation in the prediction of clinical outcome after cardiac resynchronization therapy. AB - BACKGROUND: Cardiac resynchronization therapy (CRT) has been shown to reduce mitral regurgitation (MR), although the clinical impact of this improvement remains uncertain. OBJECTIVES: We sought to evaluate the impact of MR improvement on clinical outcome after CRT and to assess predictors and mechanism for change in MR. METHODS: This was a cohort study of patients undergoing CRT for conventional indications with baseline and follow-up echocardiography (at 6 months). MR severity was classified into 4 grades. The primary end point was time to all-cause death or time to first heart failure (HF) hospitalization assessed at 3 years. RESULTS: A total of 439 patients were included: median age was 70.2 years, 90 (20.5%) were women, 255 (58.1%) with ischemic cardiomyopathy, and mean QRS width was 162 ms. Worsening severity of baseline MR was independently predictive of HF or all-cause mortality (hazard ratio 1.33; 95% confidence interval 1.01-1.75; P = .042). Reduction in MR after CRT was significantly associated with lower HF hospitalization and improved survival (hazard ratio 0.65; 95% confidence interval 0.49-0.85; P = .002). Degree of baseline MR and longer surface QRS to left ventricular lead time were significant predictors of MR change. Patients with MR reduction exhibited lower mitral valve tenting area (P < .001) and coaptation height (P < .001) than those with stable or worsening MR, suggestive of improved ventricular geometry as a mechanism for change in MR. CONCLUSION: Degree of baseline MR and change in MR after CRT predicted all-cause mortality and HF hospitalization at 3 years. Longer surface QRS to left ventricular lead time at implant may be a means to target MR improvement. PMID- 25708880 TI - Antitachycardia pacing for reduction of implantable cardioverter-defibrillator shocks. AB - Antitachycardia pacing (ATP) strategies represent safe, effective, and painless therapy for ventricular tachyarrhythmias, with a large body of clinical evidence supporting their routine use in both primary and secondary implantable cardioverter-defibrillator recipients. This article details the evidence supporting the use of standardized and validated ATP strategies for primary prevention patients and the conceptual framework to design effective ATP strategy for secondary prevention patients. PMID- 25708881 TI - An unusual interaction between an abandoned pacing lead and an ICD lead. PMID- 25708882 TI - Comparison of delayed transvenous reimplantation and immediate surgical epicardial approach in pacing-dependent patients undergoing extraction of infected permanent pacemakers. AB - BACKGROUND: Pacemaker infection in pacing-dependent patients is challenging. After extraction, temporary pacing usually is utilized before delayed reimplantation (after an appropriate course of antibiotics), resulting in prolonged hospital stays. A single combined procedure of epicardial (EPI) pacemaker implantation and system extraction may prevent this. OBJECTIVE: The purpose of this study was to evaluate the feasibility and safety of these 2 approaches by comparing clinical outcome for both strategies over 1 year. METHODS: In center 1, 80 consecutive pacemaker-dependent patients underwent extraction with an externalized pacemaker and delayed implantation on the contralateral side (ENDO group). In center 2, 80 consecutive patients had 2 epicardial ventricular leads surgically implanted with extraction of the infected pacemaker during the same procedure (EPI group). Patients were followed-up for 12 months. RESULTS: One hundred sixty pacing-dependent patients were successfully implanted and extracted (ENDO group 71 +/- 13 years vs EPI group 73 +/- 14, P = NS). In the EPI group, 2 patients developed significant pericardial bleeding. In hospital mortality was 0% in the ENDO group and 2.5% in the EPI group. Total hospitalization time was 15 +/- 7 days in the ENDO group vs 9 +/- 6 days in the EPI group (P <.001). At 1 year, no infection recurrences occurred in either group, and mortality was equal (5% in each group). Median 1-year pacing thresholds were lower in the ENDO vs the EPI group (0.8 +/- 0.6 V vs 1.1 +/- 0.6 V, P = .02). CONCLUSION: The ENDO and EPI strategies had an excellent success rate and low risk of complications. A single procedure using surgical epicardial lead implantation was associated with a shorter duration of hospital stay. PMID- 25708883 TI - Risk of stroke after catheter ablation versus cardioversion for atrial fibrillation: A propensity-matched study of 24,244 patients. AB - BACKGROUND: Stroke is the major cause of morbidity and mortality related to atrial fibrillation (AF). Catheter ablation for AF is effective in reducing AF burden, but its impact on long-term stroke risk is unknown. OBJECTIVE: We sought to evaluate the periprocedural and long-term stroke risk after catheter ablation or cardioversion for AF. METHODS: This retrospective, propensity-matched study using a national administrative claims database identified patients with AF who underwent catheter ablation and a comparison group (matched on age, sex, year of treatment, CHA2DS2-Vasc score, and Charlson index) who underwent cardioversion between 2005 and 2012. The primary end points were (1) time to first ischemic or hemorrhagic stroke or transient ischemic attack (TIA) and (2) time to first ischemic or hemorrhagic stroke excluding TIA. We compared periprocedural incident stroke (within 30 days of ablation or cardioversion) as well as total strokes between the 2 groups. RESULTS: A total of 24,244 patients (12,122 patients undergoing ablation and 12,122 patients undergoing cardioversion) were included in the analysis. Incident periprocedural stroke or TIA occurred in 0.5% of the ablation group and 0.3% of the cardioversion group (P = .04). There was a significant initial risk of stroke/TIA with ablation within the first 30 days (rate ratio 1.53; P = .05). After 30 days, this risk was significantly lower in the ablation group (rate ratio 0.78; P = .03). CONCLUSION: In patients with AF, there is a small periprocedural stroke risk with ablation in comparison to cardioversion. However, over longer-term follow-up, ablation is associated with a slightly lower rate of stroke. PMID- 25708884 TI - Connecting the dots from radiographic to electrophysiologic substrate in hypertrophic cardiomyopathy. PMID- 25708885 TI - Women in Free Clinics: An Assessment of Health-Related Quality of Life for Prevention and Health Education. AB - Understanding gender influences on health-related quality of life (HRQoL) is important to improve women's health when considering diseases that afflict women specifically. The target population of this study was uninsured female free clinic patients who are low socio-economic status and lack access to healthcare resources. Free clinics provide free or reduced fee healthcare to individuals who lack access to primary care and are socio-economically disadvantaged. While approximately half of free clinic patients are women, there is a paucity of comprehensive health-related data for female free clinic patients. US born English, non-US born English, and Spanish speaking female free clinic patients completed a self-administered survey using a standardized women's HRQoL measure in Fall 2014 (N = 389). Female free clinic patients reported lower HRQoL on all aspects of women's health compared to the US baseline scores, and were less likely to utilize preventive care including: mammograms, Pap smear, and HPV vaccination compared to the US general population. Spanish speakers reported a higher percentage of having had mammography and Pap smear, and heard about HPV compared to the other two groups. US born English speakers reported lower levels of HRQoL in vasomotor symptoms and sleep symptoms, and the lowest percentage of breast health and Pap smear screenings compared to non-US born English and Spanish speakers. Non-US born English speakers reported higher preference for female physician compared to US born English speakers and Spanish speakers. Free clinic female patients need preventative interventions and educational opportunities to improve their overall HRQoL. PMID- 25708886 TI - Gold nanostars co-coated with the Cu(II) complex of a tetraazamacrocyclic ligand. AB - The twelve-membered tetraazamacrocyclic ligand L1 bears an appended lipoic acid unit, whose disulphide ring is an efficient grafting moiety for the surface of gold nanostars (GNS). The GNS that were used featured a localized surface plasmon resonance (LSPR) absorption at ~800 nm, i.e. in the near infrared (NIR). We investigated different approaches for coating them with the Cu(2+) complex of L1. While the direct reaction of [CuL1](2+) with as-prepared GNS led to aggregation, an initial coating step with polyethyleneglycol-thiol (PEG-SH) was found to be advantageous. Displacement reactions were carried out on pegylated GNS either with [CuL1](2+), directly generating [Cun(L1@GNS)](2n+), or with void L1, thus obtaining @GNS that coordinates Cu(2+) in a second step. In both cases, even with a large excess of the competing disulphide moiety, only partial displacement of PEG-SH is observed, obtaining ca. 500-1500 [CuL1](2+) per GNS depending on the conditions, with PEG-SH remaining in the [Cun(L1@GNS)](2n+) hybrids and imparting them with remarkable stability. Comparison of the photothermal and two-photon luminescence (TPL) properties of the GNS between the pegylated GNS and [Cun(L1@GNS)](2n+) revealed that the grafted copper complex does not change them to any extent. Finally, the stability against demetallation and transmetallation of the complexes, as well as the fast kinetics of complexation of the monodispersed macrocycle and of L1@GNS, have been examined, suggesting [Cun(L1@GNS)](2n+) as a device capable of TPL optical tracking and NIR photothermal therapy and as a possible agent for PET imaging. PMID- 25708887 TI - Supersymmetry-inspired non-Hermitian optical couplers. AB - Supersymmetry has been shown to provide a systematic and effective framework for generating classes of isospectral optical structures featuring perfectly-phase matched modes, with the exception of one (fundamental) mode which can be removed. More recently, this approach has been extended to non-Hermitian scenarios characterized by spatially-modulated distributions of optical loss and gain, in order to allow the removal of higher-order modes as well. In this paper, we apply this approach to the design of non-Hermitian optical couplers with higher-order mode-selection functionalities, with potential applications to mode-division multiplexing in optical links. In particular, we highlight the critical role of the coupling between non-Hermitian optical waveguides, which generally induces a phase transition to a complex eigenspectrum, thereby hindering the targeted mode selection functionality. With the specific example of an optical coupler that selects the second-order mode of a given waveguide, we illustrate the aforementioned limitations and propose possible strategies to overcome them, bearing in mind the practical feasibility of the gain levels required. PMID- 25708888 TI - The targeted recognition of Lactococcus lactis phages to their polysaccharide receptors. AB - Each phage infects a limited number of bacterial strains through highly specific interactions of the receptor-binding protein (RBP) at the tip of phage tail and the receptor at the bacterial surface. Lactococcus lactis is covered with a thin polysaccharide pellicle (hexasaccharide repeating units), which is used by a subgroup of phages as a receptor. Using L. lactis and phage 1358 as a model, we investigated the interaction between the phage RBP and the pellicle hexasaccharide of the host strain. A core trisaccharide (TriS), derived from the pellicle hexasaccharide repeating unit, was chemically synthesised, and the crystal structure of the RBP/TriS complex was determined. This provided unprecedented structural details of RBP/receptor site-specific binding. The complete hexasaccharide repeating unit was modelled and found to aptly fit the extended binding site. The specificity observed in in vivo phage adhesion assays could be interpreted in view of the reported structure. Therefore, by combining synthetic carbohydrate chemistry, X-ray crystallography and phage plaquing assays, we suggest that phage adsorption results from distinct recognition of the RBP towards the core TriS or the remaining residues of the hexasacchride receptor. This study provides a novel insight into the adsorption process of phages targeting saccharides as their receptors. PMID- 25708889 TI - Pathophysiology of cardiac hypertrophy and heart failure: signaling pathways and novel therapeutic targets. AB - The onset of heart failure is typically preceded by cardiac hypertrophy, a response of the heart to increased workload, a cardiac insult such as a heart attack or genetic mutation. Cardiac hypertrophy is usually characterized by an increase in cardiomyocyte size and thickening of ventricular walls. Initially, such growth is an adaptive response to maintain cardiac function; however, in settings of sustained stress and as time progresses, these changes become maladaptive and the heart ultimately fails. In this review, we discuss the key features of pathological cardiac hypertrophy and the numerous mediators that have been found to be involved in the pathogenesis of cardiac hypertrophy affecting gene transcription, calcium handling, protein synthesis, metabolism, autophagy, oxidative stress and inflammation. We also discuss new mediators including signaling proteins, microRNAs, long noncoding RNAs and new findings related to the role of calcineurin and calcium-/calmodulin-dependent protein kinases. We also highlight mediators and processes which contribute to the transition from adaptive cardiac remodeling to maladaptive remodeling and heart failure. Treatment strategies for heart failure commonly include diuretics, angiotensin converting enzyme inhibitors, angiotensin II receptor blockers and beta-blockers; however, mortality rates remain high. Here, we discuss new therapeutic approaches (e.g., RNA-based therapies, dietary supplementation, small molecules) either entering clinical trials or in preclinical development. Finally, we address the challenges that remain in translating these discoveries to new and approved therapies for heart failure. PMID- 25708890 TI - Bioavailability of cyanide after consumption of a single meal of foods containing high levels of cyanogenic glycosides: a crossover study in humans. AB - The acute toxicity of cyanide is determined by its peak levels reached in the body. Compared to the ingestion of free cyanide, lower peak levels may be expected after consumption of foods containing cyanogenic glycosides with the same equivalent dose of cyanide. This is due to possible delayed and/or incomplete release of cyanide from the cyanogenic glycosides depending on many factors. Data on bioavailability of cyanide after consumption of foods containing high levels of cyanogenic glycosides as presented herein were necessary to allow a meaningful risk assessment for these foods. A crossover study was carried out in 12 healthy adults who consumed persipan paste (equivalent total cyanide: 68 mg/kg), linseed (220 mg/kg), bitter apricot kernels (about 3250 mg/kg), and fresh cassava roots (76-150 mg/kg), with each "meal" containing equivalents of 6.8 mg cyanide. Cyanide levels were determined in whole blood using a GC-MS method with K(13)C(15)N as internal standard. Mean levels of cyanide at the different time points were highest after consumption of cassava (15.4 uM, after 37.5 min) and bitter apricot kernels (14.3 uM, after 20 min), followed by linseed (5.7 uM, after 40 min) and 100 g persipan (1.3 uM, after 105 min). The double dose of 13.6 mg cyanide eaten with 200 g persipan paste resulted in a mean peak level of 2.9 uM (after 150 min). An acute reference dose of 0.075 mg/kg body weight was derived being valid for a single application/meal of cyanides or hydrocyanic acid as well as of unprocessed foods with cyanogenic glycosides also containing the accompanying intact beta-glucosidase. For some of these foods, this approach may be overly conservative due to delayed release of cyanide, as demonstrated for linseed. In case of missing or inactivated beta-glucosidase, the hazard potential is much lower. PMID- 25708892 TI - Symmetry-Based Biomedical Image Compression. AB - Image compression techniques aim at reducing the amount of data needed to accurately represent an image, such that the image can be economically transmitted or archived. This paper deals with employing symmetry as a parameter for compression of biomedical images. The approach presented in this paper offers great potential in complete lossless compression of the biomedical image under consideration, with the reconstructed image being mathematically identical to the original image. The method comprises getting rid of the redundant data and encoding the non-redundant data for the purpose of regenerating the image at the receiver section without any observable change in the image data. PMID- 25708891 TI - Toward Understanding the Size Dependence of Shape Features for Predicting Spiculation in Lung Nodules for Computer-Aided Diagnosis. AB - We analyze the importance of shape features for predicting spiculation ratings assigned by radiologists to lung nodules in computed tomography (CT) scans. Using the Lung Image Database Consortium (LIDC) data and classification models based on decision trees, we demonstrate that the importance of several shape features increases disproportionately relative to other image features with increasing size of the nodule. Our shaped-based classification results show an area under the receiver operating characteristic (ROC) curve of 0.65 when classifying spiculation for small nodules and an area of 0.91 for large nodules, resulting in a 26% difference in classification performance using shape features. An analysis of the results illustrates that this change in performance is driven by features that measure boundary complexity, which perform well for large nodules but perform relatively poorly and do no better than other features for small nodules. For large nodules, the roughness of the segmented boundary maps well to the semantic concept of spiculation. For small nodules, measuring directly the complexity of hard segmentations does not yield good results for predicting spiculation due to limits imposed by spatial resolution and the uncertainty in boundary location. Therefore, a wider range of features, including shape, texture, and intensity features, are needed to predict spiculation ratings for small nodules. A further implication is that the efficacy of shape features for a particular classifier used to create computer-aided diagnosis systems depends on the distribution of nodule sizes in the training and testing sets, which may not be consistent across different research studies. PMID- 25708893 TI - Robust Intensity Standardization in Brain Magnetic Resonance Images. AB - The paper is focused on a tiSsue-Based Standardization Technique (SBST) of magnetic resonance (MR) brain images. Magnetic Resonance Imaging intensities have no fixed tissue-specific numeric meaning, even within the same MRI protocol, for the same body region, or even for images of the same patient obtained on the same scanner in different moments. This affects postprocessing tasks such as automatic segmentation or unsupervised/supervised classification methods, which strictly depend on the observed image intensities, compromising the accuracy and efficiency of many image analyses algorithms. A large number of MR images from public databases, belonging to healthy people and to patients with different degrees of neurodegenerative pathology, were employed together with synthetic MRIs. Combining both histogram and tissue-specific intensity information, a correspondence is obtained for each tissue across images. The novelty consists of computing three standardizing transformations for the three main brain tissues, for each tissue class separately. In order to create a continuous intensity mapping, spline smoothing of the overall slightly discontinuous piecewise-linear intensity transformation is performed. The robustness of the technique is assessed in a post hoc manner, by verifying that automatic segmentation of images before and after standardization gives a high overlapping (Dice index >0.9) for each tissue class, even across images coming from different sources. Furthermore, SBST efficacy is tested by evaluating if and how much it increases intertissue discrimination and by assessing gaussianity of tissue gray-level distributions before and after standardization. Some quantitative comparisons to already existing different approaches available in the literature are performed. PMID- 25708894 TI - A Quantification Method for Breast Tissue Thickness and Iodine Concentration Using Photon-Counting Detector. AB - The purpose of contrast-enhanced digital mammography (CEDM) is to facilitate detection and characterization of the lesions in the breast using intravenous injection of an iodinated contrast agent. CEDM produces iodine images with gray levels proportional to iodine concentration at each pixel, which can be considered as quantification of iodine. While dual-energy CEDM requires an accurate knowledge of the thickness of compressed breast for the quantification, it is known that the accuracy of the built-in thickness measurement is not satisfactory. Triple-energy CEDM, which can provide a third image, can alleviate the limitation of dual-energy CEDM. If triple exposure technique is applied, it can lead to increased risk of motion artifact. An energy-resolving photon counting detector (PCD) that can acquire multispectral X-ray images can reduce the risk of motion artifact. In this research, an easily implementable method for iodine quantification in breast imaging was suggested, and it was applied to the images of breast phantom with various iodine concentrations. The iodine concentrations in breast phantom simulate lesions filled with different iodine concentrations in the breast. The result shows that the proposed method can quantify the iodine concentrations in breast phantom accurately. PMID- 25708895 TI - Multiple primary syphilis on the lip, nipple-areola and penis: An immunohistochemical examination of Treponema pallidum localization using an anti T. pallidum antibody. AB - Primary syphilis caused by Treponema pallidum usually develops after sexual contact as an initial solitary sclerosis or hard chancre in the genital region. We describe a case of primary syphilis at three sites in genital and extragenital regions of a man who had sex with men. A 29-year-old man visited our hospital for skin lesions on his lower lip, nipple-areola and penis. A positive syphilis serological test for rapid plasma reagin had a titer of 1:16; the patient also tested positive for specific antibodies against T. pallidum, with a cut-off index of 39.0. Histopathological examination of a nipple-areola biopsy specimen revealed a thickened epidermis and dense infiltration of inflammatory cells extending from the upper dermal layers to the deep dermis. The inflammatory cells were composed of abundant lymphocytes, plasma cells, histiocytes and neutrophils. Immunohistochemical staining for T. pallidum using an anti-T. pallidum antibody showed numerous spirochetes in the lower portion of the epidermis, scattered inside inflammatory cell infiltrate and perivascular sites throughout the dermis. Based on these findings, the patient was diagnosed with primary syphilis. Treatment with oral amoxicillin hydrate was started. Five days after starting treatment, a diffuse maculopapular rash (syphilitic roseola) occurred on his trunk and extremities. Perivascular cuffing due to T. pallidum was present throughout the dermis in the biopsy specimen of a localized lesion of primary syphilis. Moreover, syphilitic roseola, which indicates generalized dissemination of T. pallidum, developed during the course of treatment for primary syphilis. Therefore, we considered perivascular cuffing to be indicative of the dissemination phase. PMID- 25708896 TI - Antimicrobial activity of ceftaroline tested against bacterial isolates causing respiratory tract and skin and skin structure infections in US medical centers in 2013. AB - A total of 4533 isolates from community-acquired respiratory tract infections (CARTIs) and 8446 from skin and skin structure infections (SSSIs) were consecutively collected in 149 US medical centers in 2013. Strains were susceptibility tested by broth microdilution method against ceftaroline and numerous comparators. Ceftaroline (MIC(50/90), <=0.015/0.12 MUg/mL) was more potent than ceftriaxone (MIC(50/90), <=0.06/1 MUg/mL) against Streptococcus pneumoniae and highly active against ceftriaxone-nonsusceptible strains (n=201; MIC(90), 0.25 MUg/mL). Ceftaroline was also very active against Haemophilus influenzae (MIC(50/90), 0.008/0.015 MUg/mL), methicillin-susceptible (MIC(50/90), 0.25/0.25 MUg/mL) and methicillin-resistant Staphylococcus aureus (MIC(50/90), 1/1 MUg/mL), and beta-hemolytic streptococci (highest MIC, 0.03 MUg/mL). Ceftaroline exhibited good activity against non-extended-spectrum beta-lactamase (ESBL) phenotype isolates of Klebsiella spp. and Escherichia coli (96.7% susceptible and MIC(90) of 0.25 MUg/mL for both) but limited activity against ESBL phenotype isolates. In summary, ceftaroline exhibited potent in vitro activity against a large collection of bacterial isolates causing CARTI and SSSI in US medical centers. PMID- 25708897 TI - Age impacts ability of aspartate-alanine aminotransferase ratio to predict advanced fibrosis in nonalcoholic Fatty liver disease. AB - BACKGROUND AND AIM: While histological differences have been reported between pediatric and adult nonalcoholic fatty liver disease (NAFLD), potential age related changes in serum transaminases and liver histology remain largely unexplored. Our study sought to investigate the clinical and histological characteristics of NAFLD across age. METHODS: This was a prospective cross sectional study of 502 biopsy-proven NAFLD patients. Clinical data were evaluated and compared among different age groups; group A (ages 18-44), B (ages 45-64), and C (>= ages 65). RESULTS: 34.9, 56.0, and 9.1 % of the cohort were distributed among group A, B, and C, respectively. While the prevalence of nonalcoholic steatohepatitis (NASH) was comparable across age groups, the prevalence of advanced fibrosis increased with age (p = 0.000). Although the mean ALT progressively decreased with age; 87, 64, 56 U/L in group A, B, and C, respectively (p = 0.000), there was no difference in mean AST (p = 0.939) across age. The AST:ALT ratio (AAR) progressively increased from 0.7, 0.9, and 1.1 in group A, B, and C, respectively (p = 0.000). In group C, an AAR >= 1 was found in 74 and 40 % of patients with and without advanced fibrosis. CONCLUSION: With advancing age, ALT levels progressively declined while AST levels remained stable, leading to a higher AAR. Although higher AAR is often used as a surrogate measure of advanced fibrosis, advancing age can also contribute to increased AAR. In fact, an AAR >= 1 was found in significant number of elderly patients without advanced fibrosis. Consequently, an increased AAR may be a function of decreasing ALT with age in addition to progressive fibrosis. PMID- 25708898 TI - The Protective Effects of Exclusive Enteral Nutrition Formulas on Growth Factor Expression and the Proximal Tibial Epiphyseal Growth Plate in a TNBS-Induced IBD Rat Model. AB - OBJECTIVE: This study aimed to evaluate the effectiveness of different types of nutritional formulas in a rat model of TNBS-induced IBD. METHODS: IBD was induced with TNBS in 4-week-old rats that were then fed different exclusive enteral nutrition diets for 7 days. The length of the tibia and the number of chondrocytes in the proximal tibias were analyzed at 7 days after supplementation. Immunohistochemical analysis, ELISA and real-time PCR were performed to evaluate the levels of growth hormone receptor (GHR) and insulin like growth factor-I receptor (IGF-IR), the growth factors IGF-I and insulin-like growth factor-binding protein-3 (IGFBP3) , bone morphogenetic protein (BMP)-2 and BMP-6 respectively. RESULTS: The results demonstrated that the tibia length of the peptide formula group was longer than that of the IBD-Modulen((r)) formula and normal diet groups (P < 0.05). Furthermore, the number of chondrocytes of the proximal tibial was more pronounced in the peptide formula group compared to the other groups (P < 0.05). The peptide formula was also more effective in increasing the expression of GHR compared to the other groups (P < 0.05), while the expression of IGF-IR was not significantly different (P > 0.05). In addition, the IGF-I and IGFBP3 levels were more pronounced in the peptide formula supplement group (P < 0.05), and the expression of BMP-2 and BMP-6 mRNA in the proximal tibia growth plate from the peptide formula group was higher than that in the ordinary formula and normal diet groups (P < 0.05). CONCLUSIONS: EEN, and particularly a peptide formula, exerted protective effects on the proximal tibial epiphyseal growth plate in a TNBS-induced IBD model. PMID- 25708899 TI - Clinical Characteristics and Treatment Outcomes of Cryptogenic Multifocal Ulcerous Stenosing Enteritis in Korea. AB - BACKGROUND: Cryptogenic multifocal ulcerous stenosing enteritis (CMUSE) is a rare disease that is characterized by multiple, recurring small intestinal ulcers with stenosis of unknown causes. The aim of this study was to investigate the clinical characteristics and the treatment outcomes of patients with CMUSE in Korea. METHODS: We performed a multicenter study to retrospectively analyze clinical data from 20 patients who suffered from CMUSE between 1984 and 2012. Their clinical characteristics and long-term disease courses were investigated. RESULTS: The most common initial symptom of CMUSE was abdominal pain (14/20, 70 %). Small bowel series (13/20, 65 %), double-balloon enteroscopy (12/20, 60 %), CT enterography (12/20, 60 %), and capsule endoscopy (10/20, 50 %) were used to diagnose CMUSE. The strictures of the patients were located in the jejunum (5/20, 25 %), ileum (7/20, 35 %), and both jejunum and ileum (6/20, 30 %). The number of patients in a state of remission, persistent disease, and relapse at the end of follow-up were 13/20 (65 %), 2/20 (10 %), and 5/20 (25 %), respectively. The median relapse-free survival was of 67.1 months. Seventy-five percent relapse free survivals for female and male patients were 93 and 9 months, respectively (P = 0.031). CONCLUSION: CMUSE is difficult to diagnose and is an easily relapsing disease. Female patients might have a better prognosis than male patients in terms of the relapse-free time. PMID- 25708900 TI - Volatile Organic Compounds in Urine for Noninvasive Diagnosis of Malignant Biliary Strictures: A Pilot Study. AB - BACKGROUND: The use of volatile organic compounds (VOCs) in bile was recently studied and appeared promising for diagnosis of malignancy. Noninvasive diagnosis of malignant biliary strictures by using VOCs in urine has not been studied. AIM: To identify potential VOCs in urine to diagnose malignant biliary strictures. METHODS: In this prospective cross-sectional study, urine was obtained immediately prior to ERCP from consecutive patients with biliary strictures. Selected-ion flow-tube mass spectrometry was used to analyze the concentration of VOCs in urine samples. RESULTS: Fifty-four patients with biliary strictures were enrolled. Fifteen patients had malignant stricture [six cholangiocarcinoma (CCA) and nine pancreatic cancer], and 39 patients had benign strictures [10 primary sclerosing cholangitis (PSC) and 29 with benign biliary conditions including chronic pancreatitis and papillary stenosis]. The concentration of several compounds (ethanol and 2-propanol) was significantly different in patients with malignant compared with benign biliary strictures (p < 0.05). Using receiver operating characteristic curve analysis, we developed a model for the diagnosis of malignant biliary strictures adjusted for age and gender based on VOC levels of 2-propranol, carbon disulfide, and trimethyl amine (TMA). The model [-2.4191 * log(2-propanol) + 1.1617 * log(TMA) - 1.2172 * log(carbon disulfide)] >= 7.73 identified the patients with malignant biliary stricture [area under the curve (AUC = 0.83)], with 93.3 % sensitivity and 61.5 % specificity (p = 0.009). Comparing patients with CCA and PSC, the model [38.864 * log(ethane) - 3.989 * log(1-octene)] <= 169.9 could identify CCA with 80 % sensitivity and 100 % specificity (AUC = 0.9). CONCLUSIONS: Measurement of VOCs in urine may diagnose malignant biliary strictures noninvasively. PMID- 25708901 TI - Estimating the latent number of types in growing corpora with reduced cost accuracy trade-off. AB - The number of unique words in children's speech is one of most basic statistics indicating their language development. We may, however, face difficulties when trying to accurately evaluate the number of unique words in a child's growing corpus over time with a limited sample size. This study proposes a novel technique to estimate the latent number of words from a series of words uttered by children. This technique utilizes statistical properties of the number of types as a function of the number of sampled tokens. We tested the practical effectiveness of the proposed method in the empirical data analysis of the cross sectional and longitudinal samples. The converging empirical evidence indicates that the proposed estimator improves the accuracy of vocabulary size estimation over a set of existing estimators. Utilizing this efficient estimator, we propose a new sampling scheme for vocabulary assessment that has lower cost and higher accuracy compared to existing methods. PMID- 25708902 TI - Topography as a driver of diversification in the Cape Floristic Region of South Africa. AB - The rugged topography of the Cape Floristic Region (CFR), South Africa, is frequently invoked to explain the spectacular radiation of the Cape flora, but the mechanisms involved remain unclear. Where recent authors emphasize the importance of elevation gradients as stimuli for ecological speciation, earlier workers stressed the role of topography as an isolating mechanism, particularly in montane lineages. Using six Cape plant lineages, we tested whether elevation niches are phylogenetically conserved. We then assessed whether high-elevation species are more consistently range-restricted than low-elevation species, and whether high-elevation sisters show stronger range exclusivity (allopatry) and weaker ecological and phenotypic differentiation, suggestive of nonecological speciation. Elevation niches tend to be phylogenetically conserved. Also, high elevation species are more consistently range-restricted than low-elevation species, potentially explaining the generally stronger range exclusivity of high elevation sisters. While the high-elevation zone is less homogeneous ecologically, more data are required to demonstrate that high-elevation sister species show generally weaker ecological and phenotypic differentiation. Topographic complexity promotes geographical isolation at high elevations, thereby providing opportunities for nonecological, vicariant speciation. While recognizing the need for additional data, we suggest that the upland and lowland floras of the CFR may differ with regard to predominant speciation mode. PMID- 25708903 TI - Safety and efficacy of endoscopic spray cryotherapy for Barrett's dysplasia: results of the National Cryospray Registry. AB - Retrospective series have shown the efficacy of endoscopic spray cryotherapy in eradicating high-grade dysplasia (HGD) in Barrett's esophagus (BE); however, prospective data are lacking, and efficacy for low-grade dysplasia (LGD) is unclear. The aim of this study was to assess the efficacy and safety of spray cryotherapy in patients with LGD or HGD. A multicenter, prospective open-label registry enrolled patients with dysplastic BE. Spray cryotherapy was performed every 2-3 months until there was no endoscopic evidence of BE and no histological evidence of dysplasia, followed by surveillance endoscopies up to 2 years. Primary outcome measures were complete eradication of dysplasia (CE-D) and complete eradication of all intestinal metaplasia (CE-IM). Ninety-six subjects with Barrett's dysplasia (67% HGD; 65% long-segment BE; mean length 4.5 cm) underwent 321 treatments (mean 3.3 per subject). Mean age was 67 years, 83% were male. Eighty patients (83%) completed treatment with follow-up endoscopy (mean duration 21 months). In patients with LGD, rate of CE-D was 91% (21/23) and rate of CE-IM was 61% (14/23). In HGD, CE-D rate was 81% (46/57) and CE-IM was 65% (37/57). In patients with short-segment BE (SSBE) with any dysplasia, CE-D was achieved in 97% (30/31) and CE-IM in 77% (24/31). There were no esophageal perforations or related deaths. One subject developed a stricture, which did not require dilation. One patient was hospitalized for bleeding in the setting of non steroidal anti-inflammatory drug use. In the largest prospective cohort to date, data suggest endoscopic spray cryotherapy is a safe and effective modality for eradication of BE with LGD or HGD, particularly with SSBE. PMID- 25708904 TI - The genotype CC of IL-28B SNP rs12979860 is significantly associated with a sustained virological response in chronic HCV-infected Pakistani patients. AB - OBJECTIVE: To evaluate the association of genetic variation in interleukin 28B (IL-28B) gene and viral factors with treatment outcome in chronic hepatitis C virus (HCV)-infected patients in Pakistan. METHODS: Patients with chronic HCV infection who received interferon plus ribavirin combination therapy were enrolled in the study. The viral loads were checked at the third and sixth month of treatment and 6 months after the completion of the treatment. Genotyping of single-nucleotide polymorphism (SNP) rs12979860 of IL-28B gene was performed by the restriction fragment length polymorphism method and direct sequence analysis. RESULTS: A total of 111 patients successfully completed antiviral therapy and the follow-up period. Early virological response (EVR) and a sustained virological response (SVR) were achieved in 92 and 91 patients, respectively. Patients infected with HCV genotype 3a had a higher SVR rate compared with other HCV genotypes. A higher C allele frequency (81.9%) was observed in patients with SVR than those with non-SVR (P = 0.00001). The odds ratio of achieving SVR was more than 10-fold greater for the CC genotype than the CT/TT genotypes of SNP rs12979860 (OR 10.351, 95% CI 1.925-55.653, P = 0.006). Other positive predictors observed for SVR were female gender and EVR. CONCLUSION: The CC genotype of IL 28B SNP rs12979860 is an independent predictive factor for SVR in chronic HCV infected patients in Pakistan. PMID- 25708905 TI - Knowledge and practice of primary eye care among primary healthcare workers in northern Nigeria. AB - OBJECTIVE: To assess knowledge and practice of primary eye care among primary healthcare workers known as community health extension workers in Funtua district of Nigeria. METHODS: Cross-sectional mixed method study among health workers employed in government-owned primary healthcare facilities. Quantitative data were obtained using self-administered questionnaires and checklists, while qualitative data by modified Delphi technique, role plays and observation. A score of 1 was given for each correct answer, while a total score of >=60% was considered 'good'. RESULTS: Eighty three of 88 health workers participated (94%) in the questionnaire survey; while 16 of them were selected for the qualitative survey. Good scores regarding the knowledge of common eye diseases were obtained by 68.7%, but only 26.4% of them could identify their most important features. Participants could undertake 3 of 5 steps in visual acuity testing. Skills in recognising common eye diseases and their management were weak; while practice was often not according to the guidelines. CONCLUSION: Community health extension workers displayed good knowledge of common eye diseases. Areas of weakness are recognition and interpretation of eye signs, and practice rarely follows the guidelines. Preventive medicine was neglected; community health extension workers require practical retraining and supervision to achieve integration of primary eye care into primary healthcare services. PMID- 25708906 TI - Biomechanical and biochemical remodeling of stromal extracellular matrix in cancer. AB - The extracellular matrix (ECM) provides structural and biochemical signals that regulate cell function. A well-controlled balance between cells and surroundings (i.e., dynamic reciprocity) is crucial for regulating ECM architecture. During cancer progression, epithelial cells undergo genetic alterations which, together with stromal changes including ECM remodeling, disturb the homeostatic dynamics of the epithelium. A parallel organization of stromal ECM fibrils is associated with tumorigenic responses. In an emerging paradigm, continuous and progressive regulation via mechanical forces and aberrant signaling are believed to be responsible for tumor-associated ECM remodeling. In this review we discuss the discrete biomechanical and biochemical mechanisms that underlie these architectural changes and highlight their particular relevance to the regulation of the alignment of ECM in the mesenchymal stroma. PMID- 25708907 TI - Deformation and pressure propagation in deep somatic tissue during painful cuff algometry. AB - BACKGROUND: Cuff algometry is used for quantitative pain assessment although it is not clarified which tissues are actually challenged by the stimulation. This study investigated the mechanical stress and strain distribution in superficial and deep tissues during cuff algometry applied on the lower leg at three different intensities (mild pressure, pain threshold and supra pain threshold). METHODS: A computational three-dimensional finite element model of the lower leg with three different layers of soft tissue was developed based on magnetic resonance imaging (MRI) recorded during cuff stimulation. Tissue indentation maps were extracted from the MRI scans and transferred into the model as displacement of boundary condition. In all stimulation conditions, the mean stress of subcutaneous adipose and muscle tissue below the cuff decreased compared with the skin while the mean strain peaked in subcutaneous adipose and decreased in other tissues. RESULTS: At pain threshold stimulation intensity, the mean muscle stress was 2.9% of mean skin stress and the mean muscle strain was 55.1% of mean strain in adipose layer. The mean stress and strain increased by 30.4% and 27.1%, respectively, in muscle tissue from painful to supra pain threshold stimulation. The stress and strain was mainly focused around the bones and superficially under cuff. CONCLUSIONS: This study shows the better capability of cuff algometry for stimulation of deep somatic tissue in terms of generation of mechanical stress and strain in contrast to the more superficial muscle tissue previously demonstrated to be strained by single-point pressure algometry. PMID- 25708909 TI - [Disease management programs: Difficulties in the analysis of benefit]. AB - After an introduction to the theme with an overview of the implementation of the Disease Management Programs (DMP), accompanying documentation, present utilization and costs of the programs, the present article is primarily devoted to the issue of the analysis of the benefits of DMP. Following an assessment of the legally specified evaluation requirements, in the absence of a prospective, randomized, controlled trial (RCT), the results of three studies are first summarized, which, with the application of propensity score matching, utilize the routine data of the statutory health insurance schemes to form a control group. The overview concludes with a look at the planned changes in evaluation and the intended expansion of the DMP to programs for other chronic illnesses. PMID- 25708908 TI - Task-evoked fMRI changes in attention networks are associated with preclinical Alzheimer's disease biomarkers. AB - There is a growing emphasis on examining preclinical levels of Alzheimer's disease (AD)-related pathology in the absence of cognitive impairment. Previous work examining biomarkers has focused almost exclusively on memory, although there is mounting evidence that attention also declines early in disease progression. In the current experiment, 2 attentional control tasks were used to examine alterations in task-evoked functional magnetic resonance imaging data related to biomarkers of AD pathology. Seventy-one cognitively normal individuals (females = 44, mean age = 63.5 years) performed 2 attention-demanding cognitive tasks in a design that modeled both trial- and task-level functional magnetic resonance imaging changes. Biomarkers included amyloid beta42, tau, and phosphorylated tau measured from cerebrospinal fluid and positron emission tomography measures of amyloid deposition. Both tasks elicited widespread patterns of activation and deactivation associated with large task-level manipulations of attention. Importantly, results from both tasks indicated that higher levels of tau and phosphorylated tau pathologies were associated with block-level overactivations of attentional control areas. This suggests early alteration in attentional control with rising levels of AD pathology. PMID- 25708910 TI - Evaluation of an Interdisciplinary Curriculum Teaching Team-Based Palliative Care Integration in Oncology. AB - For students of the health care professions to succeed in today's health care environment, they must be prepared to collaborate with other professionals and practice on interdisciplinary teams. As most will care for patients with cancer, they must also understand the principles of palliative care and its integration into oncology. This article reports the success of one university's effort to design and implement an interdisciplinary curriculum teaching team-based palliative care in oncology which was mandatory for medical, nursing, social work, and chaplaincy students. Quantitative evaluation indicated that students made significant improvements related to palliative care knowledge and skills and readiness for interprofessional education. Qualitative feedback revealed that students appreciated the experiential aspects of the curriculum most, especially the opportunity to observe palliative teams at work and practice team-based skills with other learners. While there exist many obstacles to interprofessional education and hands-on learning, the value of such experiences to the learners justifies efforts to initiate and continue similar programs in the health sciences. PMID- 25708912 TI - Improving public health by respecting autonomy: using social science research to enfranchise vulnerable prison populations. AB - It is widely recognised that prisoners constitute a vulnerable population that is subject to numerous health inequalities and merits special protection. Improving prisoners' access to healthcare by ensuring adherence to the principle of equivalence has been the main focus of efforts to ensure that their health is not jeopardised. However, another means of respecting prisoners' autonomy and improving their health is to involve them (and prison staff) in social science research within prisons. Such research not only produces valuable data which can be used to assess whether the principle of equivalence is being respected; it also enfranchises prisoners by allowing them to air concerns about perceived ill treatment and influence their environment. If prison authorities enable such research and adjust policy accordingly, both they and prisoners will benefit from the increased level of respect for prisoners' autonomy, and the improvements in individual and public health that flow from this. Conducting social science research in prisons enables the creation of a virtuous cycle of respect that makes prisons safer and healthier places. PMID- 25708911 TI - Modeling evolution of spatially distributed bacterial communities: a simulation with the haploid evolutionary constructor. AB - BACKGROUND: Multiscale approaches for integrating submodels of various levels of biological organization into a single model became the major tool of systems biology. In this paper, we have constructed and simulated a set of multiscale models of spatially distributed microbial communities and study an influence of unevenly distributed environmental factors on the genetic diversity and evolution of the community members. RESULTS: Haploid Evolutionary Constructor software http://evol-constructor.bionet.nsc.ru/ was expanded by adding the tool for the spatial modeling of a microbial community (1D, 2D and 3D versions). A set of the models of spatially distributed communities was built to demonstrate that the spatial distribution of cells affects both intensity of selection and evolution rate. CONCLUSION: In spatially heterogeneous communities, the change in the direction of the environmental flow might be reflected in local irregular population dynamics, while the genetic structure of populations (frequencies of the alleles) remains stable. Furthermore, in spatially heterogeneous communities, the chemotaxis might dramatically affect the evolution of community members. PMID- 25708913 TI - Efficacy of everolimus with reduced-exposure cyclosporine in de novo kidney transplant patients at increased risk for efficacy events: analysis of a randomized trial. AB - The efficacy of de novo everolimus with reduced-exposure calcineurin inhibitor (CNI) was examined in kidney transplant subpopulations from the A2309 study that were identified to be at increased risk for efficacy events. A2309 was a 24 month, multicenter, open-label trial in which 833 de novo kidney transplant recipients were randomized to everolimus targeting 3-8 or 6-12 ng/ml with reduced exposure cyclosporine (CsA), or mycophenolic acid (MPA) with standard-exposure CsA, all with basiliximab induction. The composite efficacy endpoint was treated biopsy-proven acute rejection (BPAR), graft loss, death, or loss to follow-up. Cox proportional hazard modeling showed male gender, younger recipient age, black race, delayed graft function, human leukocyte antigen (HLA) mismatch >=3 and increasing donor age to be significantly predictive for the composite efficacy endpoint at months 12 or 24 post-transplant. CsA exposure was 53-75 % lower, and 46-75 % lower, in patients receiving everolimus 3-8 ng/ml or receiving everolimus 6-12 ng/ml, respectively, versus MPA-treated patients. The incidence of the composite endpoint was similar in all three treatment groups within each subpopulation analyzed. The incidence of treated BPAR was similar with everolimus 3-8 ng/ml or MPA in all subpopulations, but less frequent with everolimus 6-12 ng/ml versus MPA in patients with HLA mismatch >=3 (p = 0.049). This post hoc analysis of a large, randomized trial suggests that a de novo regimen of everolimus with reduced-exposure CsA maintains immunosuppressive efficacy even in kidney transplant patients at increased risk for efficacy events despite substantial reductions in CsA exposure. PMID- 25708916 TI - Sympathy for the ganglion. PMID- 25708915 TI - Quality evaluation of Salvia miltiorrhiza Bge. by ultra high performance liquid chromatography with photodiode array detection and chemical fingerprinting coupled with chemometric analysis. AB - An ultra high performance liquid chromatography with photodiode array detection method is developed for the simultaneous quantitative determination of five water soluble compounds including danshensu, protocatechualdehyde, rosmarinic acid, salvianolic acid B, and salvianolic acid A in Salvia miltiorrhiza Bge. SAMPLES: Through method optimization, the five compounds all expressed good linearity (R(2) > 0.9990) in a wide concentration range together with satisfactory accuracy, precision, and stability. Moreover, through qualitative analysis of the chemical fingerprint combined with similarity analysis, hierarchical cluster analysis, principle component analysis, and partial least-squares discriminate analysis, we determined that the 13 batches of Salvia miltiorrhiza Bge. were similar in internal quality and the differences resulted from various cultivation environments, recovery elements, and others. Seen from the results of hierarchical cluster analysis and principle component analysis, the classification of 13 batches was in accordance, and partial least-squares discriminate analysis technique was more suitable than the principle component analysis model to provide a distinct classification of test samples on the basis of their different components. Moreover, a permutation test verified the rationality of partial least-squares discriminate analysis and variable importance plot showed that peaks 37 and 38 were the most significant variables in distinguishing the Salvia miltiorrhiza Bge. SAMPLES: The idea of the quantitative and qualitative analysis of Salvia miltiorrhiza Bge. was convenient, sensitive, and comprehensive, which could be applied to evaluate the quality of more traditional Chinese medicines. PMID- 25708914 TI - Norepinephrine, left ventricular disorders and volume excess in ESRD. AB - BACKGROUND: Sympathetic over-activity is a hallmark of end stage renal disease (ESRD). Left ventricular (LV) disorders and volume overload are pervasive in ESRD and sympathetic over-activity may be a relevant mediator of the cardiovascular (CV) risk by these alterations in this population. DESIGN: We investigated the relationship between a combined biomarker of LV disorders and volume excess, atrial natriuretic peptide (ANP), and the plasma concentration of nor-epinephrine (NE) in 227 ESRD patients without heart failure at baseline and modelled the risk for incident CV events by these biomarkers over a 3.5 years follow-up. RESULTS: Plasma NE was strongly and independently related to ANP (beta = 0.31, P < 0.001). In a multivariate Cox's regression analysis, ANP was an independent predictor of these events [HR (1-SD) 1.25, 95 % CI 1.01-1.54]. However, when NE was introduced into the multivariate model, HR by ANP reduced substantially (1.14, 95% CI 0.91 1.42) and was no longer significant (P = 0.25) while the CV risk signalled by NE was clinically relevant (HR 1.29, 95% CI 1.05-1.59) and statistically significant (P = 0.02). CONCLUSIONS: In ESRD patients without heart failure, NE is strongly and independently related to ANP. The predictive power of ANP for CV events is largely captured by NE in a statistical model including both biomarkers. These data suggest that sympathetic over-activity may be a relevant mediator of the high risk of CV events triggered by LV disorders and volume excess in this population. However, further mechanistic and intervention studies are needed to prove the nature (causal/non causal) of these findings. PMID- 25708917 TI - T-types make your clock tick. PMID- 25708918 TI - High on 'chronic': an unexpected route to cannabinoid-induced synaptic plasticity. PMID- 25708919 TI - NAVigating a transition from single action potential firing to bursting in chromaffin cells. PMID- 25708920 TI - Risk of hospitalized infection among rheumatoid arthritis patients concurrently treated with a biologic agent and denosumab. AB - OBJECTIVE: Denosumab is a biologic agent used to treat osteoporosis. Its safety profile given concurrently with biologic drugs for rheumatoid arthritis (RA) has not been well studied. We evaluated hospitalized infections among patients treated with biologic agents for RA who initiated denosumab or zoledronic acid (ZA), a parenteral bisphosphonate without known associations with infection. We hypothesized that the rate of hospitalized infection with denosumab would be noninferior to ZA. METHODS: We identified RA patients enrolled in Medicare in 2006-2012 treated with biologic agents who initiated denosumab or ZA. Cox proportional hazards models compared the risk for hospitalized infection, comparing denosumab users to ZA users and adjusting for potentially confounding factors. A noninferiority margin was specified a priori to demonstrate that denosumab had no greater infection risk than ZA if the upper bound of the 95% confidence interval (95% CI) of the hazard ratio (HR) was <1.5. RESULTS: Eligible RA patients receiving biologic agents initiated denosumab (n = 1,354) or ZA (n = 4,460). Characteristics of the denosumab users were as follows: mean +/- SD age 73.0 +/- 8.9, 98.2% women, with a majority receiving infliximab (35.7%) or abatacept (18.6%). Denosumab users had a higher prevalence of prior infections (11.5% hospitalized and 48.3% outpatient) and infection-related risk factors. The crude rate of hospitalized infections for denosumab (14.9/100 person-years [95% CI 12.2-18.1]) was comparable to that for ZA (13.9/100 person-years [95% CI 12.5 15.4]). After adjustment, the HR of hospitalized infection for denosumab users was noninferior to that for ZA users (HR 0.89 [95% CI 0.69-1.15]). CONCLUSION: The rate of hospitalized infection among RA patients receiving denosumab concurrently with biologic agents for RA was not increased compared to those receiving zoledronate. PMID- 25708922 TI - Silicon-chip mid-infrared frequency comb generation. AB - Optical frequency combs are a revolutionary light source for high-precision spectroscopy because of their narrow linewidths and precise frequency spacing. Generation of such combs in the mid-infrared spectral region (2-20 MUm) is important for molecular gas detection owing to the presence of a large number of absorption lines in this wavelength regime. Microresonator-based frequency comb sources can provide a compact and robust platform for comb generation that can operate with relatively low optical powers. However, material and dispersion engineering limitations have prevented the realization of an on-chip integrated mid-infrared microresonator comb source. Here we demonstrate a complementary metal-oxide-semiconductor compatible platform for on-chip comb generation using silicon microresonators, and realize a broadband frequency comb spanning from 2.1 to 3.5 MUm. This platform is compact and robust and offers the potential to be versatile for use outside the laboratory environment for applications such as real-time monitoring of atmospheric gas conditions. PMID- 25708921 TI - Plasmodium falciparum XPD translocates in 5' to 3' direction, is expressed throughout the blood stages, and interacts with p44. AB - XPD helicase, a TFIIH subunit, is essential for several processes including transcription, NER, cell cycle regulation, and apoptosis in eukaryotes. Another component of TFIIH, namely p44, is among the well-known interacting partners of XPD and is vital in regulating the helicase activities of latter. However, none of the above mentioned proteins have been functionally characterized in Plasmodium falciparum. Consequently, in this study, we performed detailed studies on XPD and its interacting partner, p44, from P. falciparum 3D7 strain. Accordingly, we expressed and purified recombinant PfXPD and its fragments and Pfp44 proteins and characterized the enzymatic activities of PfXPD and its fragments. The in vivo stage-specific expression and subcellular localizations of PfXPD and Pfp44 proteins were studied using the specific antibodies in the intraerythrocytic developmental stages of P. falciparum 3D7 strain. Our results suggest that PfXPD displays the characteristic ssDNA-dependent ATPase and 5'-3' DNA helicase activities. We also report the existence of two high molecular weight forms of p44 in P. falciparum 3D7 strain. Both PfXPD and Pfp44 colocalize in the nucleus and interact with each other, which suggest that they are most likely components of the same complex apparently, TFIIH. Furthermore, during trophozoite and schizont stages, both proteins exhibit a distinct cytoplasmic distribution pattern which implies that PfXPD and Pfp44 might also be involved in other functions. These studies will aid in understanding the basic biology of malaria parasite. PMID- 25708923 TI - Congenital heart disease assessment with 4D flow MRI. AB - With improvements in surgical and medical management, patients with congenital heart disease (CHD) are often living well into adulthood. MRI provides critical data for diagnosis and monitoring of these patients, yielding information on cardiac anatomy, blood flow, and cardiac function. Though historically these exams have been complex and lengthy, four-dimensional (4D) flow is emerging as a single fast technique for comprehensive assessment of CHD. The 4D flow consists of a volumetric time-resolved acquisition that is gated to the cardiac cycle, providing a time-varying vector field of blood flow as well as registered anatomic images. In this article, we provide an overview of MRI evaluation of congenital heart disease by means of example of three relatively common representative conditions: tetralogy of Fallot, aortic coarctation, and anomalous pulmonary venous drainage. Then 4D flow data acquisition, data correction, and postprocessing techniques are reviewed. We conclude with several examples that highlight the comprehensive nature of the evaluation of congenital heart disease with 4D flow. PMID- 25708924 TI - PDGF signalling in the dermis and in dermal condensates is dispensable for hair follicle induction and formation. AB - Embryonic hair follicle (HF) induction and formation is dependent on signalling crosstalk between the dermis and specialized dermal condensates on the mesenchymal side and epidermal cells and incipient placodes on the epithelial side, but the precise nature and succession of signals remain unclear. Platelet derived growth factor (PDGF) signalling is involved in the development of several organs and the maintenance of adult tissues, including HF regeneration in the hair cycle. As both PDGF receptors, PDGFRalpha and PDGFRbeta, are expressed in embryonic dermis and dermal condensates, we explored in this study the role of PDGF signalling in HF induction and formation in the developing skin mesenchyme. We conditionally ablated both PDGF receptors with Tbx18(Cre) in early dermal condensates before follicle formation, and with Prx1-Cre broadly in the ventral dermis prior to HF induction. In both PDGFR double mutants, HF induction and formation ensued normally, and the pattern of HF formation and HF numbers were unaffected. These data demonstrate that mesenchymal PDGF signalling, either in the specialized niche or broadly in the dermis, is dispensable for HF induction and formation. PMID- 25708925 TI - Influenza vaccination during pregnancy and its usefulness to mothers and their young infants. AB - The current approach to protecting pregnant women from influenza infection and serious influenza-related complications is vaccination. It is, therefore, critical to evaluate the vaccine's safety, immunogenicity, and protection efficacy during pregnancy. However, because it is affected by previous influenza vaccination or infection, the efficacy of the seasonal trivalent inactivated influenza vaccine is difficult to evaluate in pregnant women. The A/H1N1pdm pandemic in 2009 provided us with the opportunity to evaluate the immunogenicity of the influenza vaccine unaffected by previous vaccinations or infections. Vaccination with inactivated influenza virus during pregnancy elicited neutralizing antibody titers that were sufficient and comparable to those of naturally infected individuals. Furthermore, post-pandemic surveys provided a wealth of definitive information on vaccine efficacy and safety. In addition, transplacental transfer of antibodies following vaccination protected newborn infants against influenza infection. With reports showing the effectiveness of influenza vaccine during pregnancy, it is suggested that influenza vaccination benefits both mothers and their young infants. PMID- 25708926 TI - Duration of anticoagulation after venous thromboembolism in real world clinical practice. AB - INTRODUCTION: Venous thromboembolism (VTE) carries a considerable risk of recurrence and anticoagulants should be administered for a minimum of three months. Since little is known about real life management of VTE, we aimed to describe current practice in the secondary prevention of VTE. MATERIALS AND METHODS: Using the database of an international, prospective registry on patients treated for VTE, RIETE, information was collected on risk factors for VTE and bleeding, anticoagulant treatment, and clinical outcomes during follow up. Multivariate analysis using logistic regression was performed to identify predictors of treatment duration. RESULTS: Of 6944 patients with a first episode of VTE 41.1% had unprovoked VTE, 31.8% had transient risk factors, 27.1% had cancer. After the exclusion of patients who died during the first year of observation, the rate of patients treated for >12 months was 55.1%, 41.9%, and 43.2%, respectively (p<0.001). Pulmonary embolism at presentation, recurrence while on treatment, chronic heart failure and age >65 years were independently associated with treatment for >12 months. Body weight <75 kg, anemia, cancer, and the presence of transient risk factors were associated with treatment for 12 months or less. Major bleeding occurred more frequently than recurrent VTE in patients with VTE secondary to transient risk factors and cancer; fatal bleeding was more frequent than fatal recurrent PE in all subgroups. CONCLUSIONS: We observed heterogeneous duration of anticoagulant treatment for the secondary prevention of VTE. A substantial proportion of patients, in particular those with VTE secondary to transient risk factors, may be exposed to a possibly unnecessary risk of bleeding. PMID- 25708927 TI - Expression of Interferon-gamma Receptor Genes in Peripheral Blood Mononuclear Cells Is Associated With Rheumatoid Arthritis and Its Radiographic Severity in African Americans. AB - OBJECTIVE: The factors responsible for radiographic severity in African American patients with rheumatoid arthritis (RA) are poorly understood. We sought to identify genes whose expression in peripheral blood mononuclear cells is associated with radiographic severity in RA. METHODS: In the first phase of the study, we performed real-time quantitative polymerase chain reaction to analyze the expression of 182 candidate genes in 40 African American RA patients with extremes of radiographic damage (low versus high radiographic scores) and disease duration (<=2 years versus >2 years) and 20 healthy African American control subjects; the genes were selected based on plausible immune pathways. In the second phase, we analyzed the expression of the genes that were shown to be significantly associated with radiographic scores in 576 African American patients with RA and 51 African American control subjects who had not been studied previously, accounting for autoantibody status and disease duration. RESULTS: We observed significant differences in IFNGR1 expression between patients with RA and control subjects (adjusted P [P(adj)] = 6 * 10(-14)) and in IFNGR2 expression between RA patients with erosions and those with no erosions (P(adj) = 0.01 by Wilcoxon's rank sum test). We also observed significant correlations between IFNGR2 expression and radiographic scores (P(adj) = 0.03 for erosions, P(adj) = 0.04 for joint space narrowing, and P(adj) = 0.03 for total radiographic score [zero-inflated negative binomial regression model]) and annualized progression rate (P(adj) = 0.0024 by Spearman's correlation analysis). CONCLUSION: These findings have important implications with respect to the role of interferon-gamma (IFNgamma) in the pathogenesis of RA and may lead to identification of a biomarker for radiographic damage. Additional studies are needed to define the cell subsets responsible for the association of IFNgamma receptor gene expression with radiographic findings, which downstream mechanisms are involved, and generalizability to other RA populations. PMID- 25708928 TI - Identifying DNA-binding proteins by combining support vector machine and PSSM distance transformation. AB - BACKGROUND: DNA-binding proteins play a pivotal role in various intra- and extra cellular activities ranging from DNA replication to gene expression control. Identification of DNA-binding proteins is one of the major challenges in the field of genome annotation. There have been several computational methods proposed in the literature to deal with the DNA-binding protein identification. However, most of them can't provide an invaluable knowledge base for our understanding of DNA-protein interactions. RESULTS: We firstly presented a new protein sequence encoding method called PSSM Distance Transformation, and then constructed a DNA-binding protein identification method (SVM-PSSM-DT) by combining PSSM Distance Transformation with support vector machine (SVM). First, the PSSM profiles are generated by using the PSI-BLAST program to search the non redundant (NR) database. Next, the PSSM profiles are transformed into uniform numeric representations appropriately by distance transformation scheme. Lastly, the resulting uniform numeric representations are inputted into a SVM classifier for prediction. Thus whether a sequence can bind to DNA or not can be determined. In benchmark test on 525 DNA-binding and 550 non DNA-binding proteins using jackknife validation, the present model achieved an ACC of 79.96%, MCC of 0.622 and AUC of 86.50%. This performance is considerably better than most of the existing state-of-the-art predictive methods. When tested on a recently constructed independent dataset PDB186, SVM-PSSM-DT also achieved the best performance with ACC of 80.00%, MCC of 0.647 and AUC of 87.40%, and outperformed some existing state-of-the-art methods. CONCLUSIONS: The experiment results demonstrate that PSSM Distance Transformation is an available protein sequence encoding method and SVM-PSSM-DT is a useful tool for identifying the DNA-binding proteins. A user-friendly web-server of SVM-PSSM-DT was constructed, which is freely accessible to the public at the web-site on http://bioinformatics.hitsz.edu.cn/PSSM-DT/. PMID- 25708929 TI - Early onset pancreatic cancer: risk factors, presentation and outcome. AB - BACKGROUND: About 10% of pancreatic cancer patients are aged <=50 at diagnosis and defined as Early Onset Pancreatic Cancer (EOPC). There is limited information regarding risk factors for EOPC occurrence and their outcome. AIM: To investigate risk factors, presentation features and outcome of EOPC patients. METHODS: Consecutive, histologically confirmed, pancreatic cancer patients enrolled. Data regarding environmental and genetic risk factors, clinical and pathological information, treatment and survival were recorded. EOPC patients (aged <=50 at diagnosis) were compared to older subjects. RESULTS: Twenty-five of 293 patients (8.5%) had EOPC. There was no difference regarding sex distribution, medical conditions and alcohol intake between EOPC and older subjects. EOPC patients were more frequently current smokers (56% vs 28% p = 0.001) and started smoking at a significantly lower mean age (19.8 years, 95%CI 16.7-22.9) as compared to older patients (26.1, 95%CI 24.2-28) (p = 0.001). Current smoking (OR 7.5; 95%CI 1.8 30; p = 0.004) and age at smoking initiation (OR 0.8 for every increasing year; 95%CI 0.7-0.9; p = 0.01) were significant and independent risk factors for diagnosis of EOPC. There were no differences regarding genetic syndromes and pancreatic cancer family history. EOCP presented less frequently with jaundice (16% vs 44%, p = 0.006) and had a higher rate of unresectable disease, albeit not significantly (84% vs 68%, p = 0.1). EOPC patients were more frequently fit for surgery or chemotherapy than their counterpart, resulting in similar stage specific survival probability. CONCLUSION: EOPC seems related to active and early smoking but not to familial syndromes. Young patients display aggressive disease but not worse outcome. PMID- 25708930 TI - Increased expression of Nodal correlates with reduced patient survival in pancreatic cancer. AB - BACKGROUND: Nodal (nodal growth differentiation factor) and its inhibitor Lefty (left right determination factor), which are ligands of the TGF (transforming growth factor) beta superfamily, are responsible for the determination of left right asymmetry in vertebrates. Nodal/Lefty signaling has been suggested to play a role in the development of metastatic melanoma and breast cancer. However, it remains unclear whether this pathway is also involved in human pancreatic ductal adenocarcinoma (PDAC). METHODS: Pancreatic cancer patient specimens with clinical data (n = 54) were used to investigate the clinical significance of Nodal-Lefty signaling. A set of in vitro assays were carried out in a human pancreatic cancer cell line (Colo-357) to assess the functional relevance of Nodal-Lefty signaling. RESULTS: Nodal was absent in the human normal pancreas, while Lefty was present in islet cells. Though Nodal and Lefty expression were found in cancer cells at various expression levels, the cancer-associated tubular complexes were particularly positive for Lefty. Survival analysis revealed that high expression of Nodal correlated with reduced patient survival (median survival 17.8 vs 33.0 months, p = 0.013). Cultured pancreatic cancer cell lines expressed Nodal and Lefty at different levels. In vitro functional assays revealed that treatment with human recombinant Nodal inhibited cell growth and increased invasion of Colo 357 pancreatic cancer cells whereas no effect was found upon treatment with recombinant Lefty. CONCLUSION: Nodal-Lefty signaling might be involved in the pathogenesis of PDAC as Nodal expression marks a subtype of PDAC with unfavorable prognosis. PMID- 25708931 TI - Quality of life in patients with long-standing chronic non-pathological pancreatic hyperenzymemia. AB - BACKGROUND: Chronic non-pathological pancreatic hyperenzymemia is a benign condition characterized by the persistent elevation of serum pancreatic enzymes without morphological alterations of the pancreas. No information is available regarding the quality of life of these subjects. AIM: To evaluate the physical, mental and psychological status of these subjects using SF-12 Health Survey questionnaire and the 12-item General Health Questionnaire. METHODS: Fifty-one consecutive subjects having long-standing chronic non-pathological pancreatic hyperenzymemia (duration: 11.0 years, range 5-21) were studied. The Italian version of the SF-12 questionnaire and the General Health Questionnaire were compiled by the subjects studied. RESULTS: Regarding the SF-12 questionnaire, the physical component scores and the mental component scores were 50.1 +/- 8.0 and 44.7 +/- 11.7, respectively and these figures were not statistically different from those of reference Italian population. Regarding the psychological status, seven subjects (13.7%) had non-psychotic-psychiatric problems. No statistical differences in the physical component score, mental component score and general health questionnaire were found between patients having non-familial or familial chronic non-pathological pancreatic hyperenzymemia. CONCLUSIONS: Subjects with long-standing chronic non-pathological pancreatic hyperenzymemia had a quality of life no different from that of the Italian population. The explanation provided by the physician regarding the benignity of long-standing chronic non pathological pancreatic hyperenzymemia is enough to reassure this type of patient. PMID- 25708932 TI - C-MYC modulation induces responsiveness to paclitaxel in adrenocortical cancer cell lines. AB - C-MYC is overexpressed in many types of cancer linked to poor prognosis. We examined the c-Myc protein expression in adrenocortical cancer (ACC) cells to investigate the role of this protein in the neoplasm, its involvement in chemotherapy and finally to determine whether c-Myc could be considered a prognostic factor in patients with ACC. H295R and SW13 cell lines were treated with paclitaxel. c-Myc overexpressing cell clones were achieved by transfecting the H295R cell line with the pcDNA3-hMYC plasmid expressing the full-lengh C-MYC coding sequence. The SW13 cell line was transfected with siRNA oligonucleotides for C-MYC. Cell cycle analysis was evaluated by flow cytometry. c-Myc, cyclin B1 and pro caspase expression levels were evaluated by western blot analysis. We found that expression of c-Myc was highly expressed in the SW13 cells, whereas the protein was undetectable in the H295R cells. Different doses of paclitaxel were required in the two ACC cell line to induce a block in the G2 phase, characterized by increased cyclin B1 levels and to induce apoptosis by pro caspase-3 activation. Interestingly, the silencing of C-MYC mRNA prevented paclitaxel induced apoptosis in SW13 cells, whereas in the H295R cells the overexpression of C-MYC rendered the cells more prone to growth inhibition after paclitaxel exposure. The present study directly demonstrates that C-MYC plays a central role in controlling proliferation in ACC cells after paclitaxel treatment and that c-Myc could be considered as a marker for predicting response to chemotherapeutic agents in ACC cell lines. PMID- 25708933 TI - Revisiting phage therapy: new applications for old resources. AB - The success of phage therapy is dependent on the development of strategies able to overcome the limitations of bacteriophages as therapeutic agents, the creation of an adequate regulatory framework, the implementation of safety protocols, and acceptance by the general public. Many approaches have been proposed to circumvent phages' intrinsic limitations but none have proved to be completely satisfactory. In this review we present the major hurdles of phage therapy and the solutions proposed to circumvent them. A thorough discussion of the advantages and drawbacks of these solutions is provided and special attention is given to the genetic modification of phages as an achievable strategy to shape bacteriophages to exhibit desirable biological properties. PMID- 25708934 TI - Six SQSTM1 mutations in a Chinese amyotrophic lateral sclerosis cohort. AB - The purpose of this study was to identify SQSTM1 gene mutations, estimate survival based on the progression rate of the revised amyotrophic lateral sclerosis functional rating scale (ALSFRS-R) score (DeltaFS), and characterize the relationships between SQSTM1 mutations and clinical phenotypes in Chinese ALS patients. We sequenced the SQSTM1 gene in 35 familial ALS patients, 436 sporadic ALS patients, and 384 healthy controls. SQSTM1 gene mutations were screened with PCR and direct sequencing; the correlations between genotype and phenotype and the progressive ALSFRS-R ratio were analyzed. Results revealed six heterozygous missense mutations in 471 ALS patients: c.241 G> A (p.E81K), c.717 C> A (p.N239K), c.889 G> A (p.G297S), c.1116 G> C (p.E372D), c.1162 C> T (p.P388S) and c.1175 C> T (p.P392 L). The gender ratio was 1:1, and the limb was the site of disease onset in mutation-positive patients. Notably, the DeltaFS analysis revealed that the risk of death or tracheostomy was significantly increased in SQSTM1 mutation carriers (p < 0.05). In conclusion, E81K, N239K, G297S, E372D, P388S and P392 L were detected in the PB1, TRAF6, PEST and UBA domains, which are important to p62 function and prone to ALS. The incidence of ALS caused by the SQSTM1 mutation has increased from 30 to 35 worldwide. PMID- 25708935 TI - Mitigation of chemical membrane degradation in fuel cells: understanding the effect of cell voltage and iron ion redox cycle. AB - Chemical membrane degradation through the Fenton's reaction is one of the main lifetime-limiting factors for polymer-electrolyte fuel cells. In this work, a comprehensive, transient membrane degradation model is developed to capture and elucidate the complex in situ degradation mechanism. A redox cycle of iron ions is discovered within the membrane electrolyte assembly, which sustains the Fe(II) concentration and results in the most severe chemical degradation at open circuit voltage. The cycle strength is critically reduced at lower cell voltages, which leads to an exponential decrease in Fe(II) concentration and associated membrane degradation rate. When the cell voltage is held below 0.7 V, a tenfold reduction in cumulative fluoride release is achieved, which suggests that intermediate cell voltage operation would efficiently mitigate chemical membrane degradation and extend the fuel cell lifetime. PMID- 25708937 TI - Pharmacokinetics and tissue disposition of meloxicam in beef calves after repeated oral administration. AB - The objective of this study was to investigate the pharmacokinetics and tissue disposition of meloxicam after repeated oral administration in calves. Thirteen male British * Continental beef calves aged 4 to 6 months and weighing 297-392 kg received 0.5 mg/kg meloxicam per os once daily for 4 days. Plasma meloxicam concentrations were determined in 8 calves over 6 days after first treatment. Calves were randomly assigned to be euthanized at 5, 10, 15 (n = 3/timepoint), and 19 days (n = 4) after final administration. Meloxicam concentrations were determined in plasma (LOQ= 0.025 MUg/mL) and muscle, liver, kidney, and fat samples (LOQ = 2 ng/g) after extraction using validated LC-MS-MS methods. The mean (+/- SD) Cmax , Cmin , and Caverage plasma meloxicam concentrations were 4.52 +/- 0.87 MUg/mL, 2.95 +/- 0.77 MUg/mL, and 3.84 +/- 0.81 MUg/mL, respectively. Mean (+/- SD) tissue meloxicam concentrations were highest in liver (226.67 +/- 118.16 ng/g) and kidney samples (52.73 +/- 39.01 ng/g) at 5 days after final treatment. Meloxicam concentrations were below the LOQ in all tissues at 15 days after treatment. These findings suggest that tissue from meloxicam treated calves will have low residue concentrations by 21 days after repeated oral administration. PMID- 25708938 TI - SecG is required for antibiotic activities of Pseudomonas sp. YL23 against Erwinia amylovora and Dickeya chrysanthemi. AB - Strain YL23 was isolated from soybean root tips and identified to be Pseudomonas sp. This strain showed broad-spectrum antibacterial activity against bacterial pathogens that are economically important in agriculture. To characterize the genes dedicated to antibacterial activities against microbial phytopathogens, a Tn5-mutation library of YL23 was constructed. Plate bioassays revealed that the mutant YL23-93 lost its antibacterial activities against Erwinia amylovora and Dickeya chrysanthemi as compared with its wild type strain. Genetic and sequencing analyses localized the transposon in a homolog of the secG gene in the mutant YL23-93. Constitutive expression plasmid pUCP26-secG was constructed and electroporated into the mutant YL23-93. Introduction of the plasmid pUCP26-secG restored antibacterial activities of the mutant YL23-93 to E. amylovora and D. chrysanthemi. As expected, empty plasmid pUCP26 could not complement the phenotype of the antibacterial activity in the mutant. Thus the secG gene, belonging to the Sec protein translocation system, is required for antibacterial activity of strain YL23 against E. amylovora and D. chrysanthemi. PMID- 25708939 TI - Osteotomy Healing in Children With Osteogenesis Imperfecta Receiving Bisphosphonate Treatment. AB - A decade ago our group had reported that osteotomy healing was commonly delayed in children with moderate to severe osteogenesis imperfecta (OI) who were treated with intravenous pamidronate infusions. We subsequently maintained a bisphosphonate infusion-free interval of 4 months after osteotomy and changed the surgical approach (use of an osteotome instead of a power saw). In addition, zoledronic acid has become the standard intravenous bisphosphonate for treatment of OI at our institution. In the present study, we compared osteotomy healing before and after these changes were instituted. We evaluated bone healing post osteotomy on standard radiographs after 261 intramedullary rodding procedures involving osteotomies (139 femur, 112 tibia) in 110 patients (age at surgery 1.2 to 20.4 years). Delayed healing was diagnosed when the osteotomy line was visible 12 months after the event. We observed delayed bone healing after 48 of the 114 osteotomies (42%) performed with the new approach, and in 106 of the 147 osteotomies (72%) using the previous approach (p = 0.001). The odds for delayed osteotomy healing were significantly lower with the new approach even after adjustment for age, sex, height Z-score, weight Z-score, OI type, and bone involved (odds ratio = 0.17; 95% confidence interval 0.16-0.47). Thus, delayed osteotomy healing occurred less frequently in the past 10 years than in the decade before that. It is likely that this improved result is attributable to the implemented changes in both medical and surgical management. PMID- 25708940 TI - Engineering of a hybrid polymer-lipid nanocarrier for the nasal delivery of tenofovir disoproxil fumarate: physicochemical, molecular, microstructural, and stability evaluation. AB - PURPOSE: To engineer a hybrid nanocarrier system based on lipid and polymer for the nasal delivery of tenofovir disoproxil fumarate (TDF), and further to investigate its physicochemical, molecular, microstructural, and stability aspects. METHODS: Nanoparticles were prepared by melt emulsification-probe sonication technique. A 3(2) factorial design was used to identify key formulation variables influencing the characteristics of drug-loaded carrier. FT IR, mass spectroscopy (MS) and (1)H NMR was used to probe molecular interactions among the components of the system, while the surface morphology was imagined through electron microscopy (TEM and SEM). Thermal analysis and powder X-ray diffraction (PXRD) was used to explore melting and crystallization behavior of drug and the carrier lipid. PLN-9 GEL was studied for its rheology, drug release, ex-vivo permeation, histopathology, and stability. RESULTS: Batch PLN-9 had size of 239 nm, drug encapsulation of 87.14% and revealed spherical morphology. MS, FT IR and (1)H NMR established compatibility between the drug (TDF) and the carrier lipid (Lauric acid), while, a strong H-bonding was identified between the amino ( NH2) group of drug and the carboxyl (-COOH) group of pemulen polymer. Thermal analysis confirmed an amorphous TDF within the carrier matrix. PXRD analysis indicated substantial change in the molecular packing and subcell structure of carrier lipid during the PLN processing. PLN-9 GEL had shear thinning rheology, an anomalous type (n>0.5) of drug release and possessed potential to transport TDF across the nasal mucosa with an average flux of 135.36 MUg/cm(2)/h. CONCLUSION: The designed carrier can encapsulate TDF and accentuates its transnasal flux, thus could be used as a carrier for an effective nasal delivery of TDF. PMID- 25708941 TI - Antimicrobial activity of ibuprofen: new perspectives on an "Old" non-antibiotic drug. AB - Pharmaceutical industry has been encountering antimicrobial activity of non antibiotics during suitability tests carried out prior to routine pharmacopoeial microbiological purity analysis of finished dosage forms. These properties are usually ignored or perceived as a nuisance during pharmaceutical analysis. The aim of this study was: (i) to compare the available data to our method suitability test results carried out on products containing ibuprofen, i.e. to demonstrate that method suitability can be a valuable tool in identifying new antimicrobials, (ii) to demonstrate the antimicrobial activity of ibuprofen and ibuprofen lysine. Microbiological purity method suitability testing was carried out according to European Pharmacopoeia (EP), chapters 2.6.12. and 2.6.13. Antimicrobial activity of ibuprofen and ibuprofen lysine was demonstrated by a disk diffusion method, a modification of the European Committee for Antimicrobial Susceptibility Testing method (EUCAST), against test microorganisms recommended in the EP. It was confirmed that ibuprofen may be responsible for the broad spectrum of antimicrobial activity of the tested products, and that method suitability tests according to the EP can indeed be exploited by the scientific community in setting guidelines towards future research of new antimicrobials. In the disk diffusion assay, inhibition zones were obtained with more than 62.5 MUg and 250 MUg for Staphylococcus aureus, 125 MUg and 250 MUg for Bacillus subtilis, 31.3 MUg and 125 MUg for Candidaalbicans, 31.3 MUg and 62.5 MUg for Aspergillusbrasiliensis, of ibuprofen/disk, and ibuprofen lysine/disk, respectively. For Escherichiacoli, Pseudomonasaeruginosa and Salmonellatyphimurium inhibition zones were not obtained. Antimicrobial activity of ibuprofen is considered merely as a side effect, and it is not mentioned in the patient information leaflets of ibuprofen drugs. As such, for the patient, it could represent an advantage, but, it could also introduce additional risks during usage. Further microbiological, pharmacological and clinical trials are of great importance. PMID- 25708942 TI - Reduction of inappropriate exit prescriptions for proton pump inhibitors: A before-after study using education paired with a web-based quality-improvement tool. AB - BACKGROUND: Proton pump inhibitors (PPIs) are overprescribed despite concerns regarding associated adverse drug events. OBJECTIVE: To reduce inappropriate PPI prescriptions using hospitalization as the point of contact to effect meaningful change. DESIGN: Before-after study design. SETTING: Forty-six-bed medical clinical teaching unit in a 417-bed university teaching hospital in Montreal, Canada. PATIENTS: Four hundred sixty-four consecutively admitted patients in the preintervention control group, and 640 consecutively admitted patients in the intervention group. INTERVENTION: A monthly educational intervention paired with a Web-based quality improvement tool. MEASUREMENTS: We determined the proportion of patients admitted on PPIs, their indications, and appropriateness of use. We then compared the proportion of patients whose PPIs were discontinued at discharge before and after our intervention. RESULTS: Forty-four percent of patients were already using a PPI prior to their hospitalization. In evaluated patients, only 54% of these patients had an evidence-based indication for ongoing use. The proportion of PPIs discontinued at hospital discharge increased from 7.7% per month in the 6 months prior to intervention, to 18.5% per month postintervention (P = 0.03). CONCLUSIONS: Strategies to combat PPI overuse are needed to improve the overall quality of patient care. We significantly reduced discharge prescriptions for PPIs through the implementation of an educational initiative paired with a Web-based quality improvement tool. An active interventional strategy is likely required considering the increasingly recognized and preventable adverse events associated with PPI misuse. PMID- 25708943 TI - An optically and thermally switchable electronic structure based on an anthracene BODIPY conjugate. AB - An optically and thermally responsive boron dipyrromethene (BODIPY) dye, namely, meso-2-(9,10-dihydro-9,10-ethanoanthracene-11,12-dione) (DK)-linked, bicyclo[2.2.2]octadiene (BCOD)-fused BODIPY (BCOD-DK), was synthesized. The weakly luminous structure of BCOD-DK can be changed quantitatively to that of the strongly fluorescent BODIPY BCOD-Ant by optical excitation at the DK unit, which induces double decarbonylation of the DK unit to give an anthracene unit. The solvent effect on the fluorescence properties of BCOD-DK suggests that the dramatic change in fluorescence intensity is controlled by intramolecular electron transfer from the BODIPY moiety to the meso-DK substituent. BCOD-DK is converted to meso-DK benzene-fused BODIPY (Benzo-DK) by heating at 220 degrees C with 64-70 nm redshift of absorption and fluorescence peaks without changing the fluorescence quantum yield of PhiF =0.08 in dichloromethane. Benzo-DK can be converted to strongly fluorescent meso-anthracene benzene-fused BODIPY Benzo-Ant by optical excitation. Thus, BCOD-DK can show four different optical performances simply by irradiation and heating, and hence may be applicable for optical data storage and security data encryption. PMID- 25708944 TI - Circulating tumor cells versus objective response assessment predicting survival in metastatic castration-resistant prostate cancer patients treated with docetaxel chemotherapy. AB - PURPOSE: Circulating tumor cell (CTC) counts might display a superior prognostic value for overall survival (OS) compared to objective response criteria (OR) in metastatic castration-resistant prostate cancer (mCRPC) patients. METHODS: CTCs were detected using the CellSearchTM System out of 122 samples during docetaxel chemotherapy (75 mg/m(2)) at baseline (q0) and after 1 (q1), 4 (q4) and 10 (q10) cycles, in mCRPC patients (n = 33). OR was evaluated by morphologic RECIST and clinical criteria after 4 (q4) and 10 (q10) cycles. RESULTS: For OS, analyses revealed a significant prognostic value for categorical (<5 vs. >=5) CTC counts (q0, p = 0.005; q1, p = 0.001; q4, p < 0.001; q10, p = 0.002), RECIST (q4, p < 0.001; q10, p = 0.02) and clinical criteria (q4, p < 0.001; q10, p = 0.02). Concordance of CTC counts with OR revealed a sensitivity of 83.3-87.5 % and a specificity of 68.0-76.5 % with complementary discriminatory power for OS. Comparing CTC counts with concomitant OR at q4 in multivariate analyses, an independent prognostic value for OS was found for CTC counts (HR 3.3; p = 0.02) similar to clinical (HR 4.9; p = 0.02) and radiologic response (HR 3.4; p = 0.051). Comparing the predictive value for death, early post-treatment CTC counts at q1 demonstrated significant accuracy with an area under the curve of 79.5 % (p = 0.004) similar to CTC counts at q4 (76.7 %; p = 0.009). Radiologic and clinical response at q4 displayed accuracy similar to early CTC counts at q1 (72.2 %; p = 0.03 and 75.0 %; p = 0.02) despite low sensitivities. CONCLUSIONS: CTC counts appear to be an earlier and more sensitive predictor for survival and treatment response than current OR approaches and may provide complementary information toward individualized treatment strategies. PMID- 25708945 TI - Paraoxonase-2 (PON2) protects oral squamous cell cancer cells against irradiation induced apoptosis. AB - PURPOSE: Patients with oral squamous cell carcinomas (OSCC) often receive radiotherapy to preferentially induce apoptosis of cancer cells through generation of overwhelming DNA damage. This is amplified by generation of reactive oxygen species (ROS), thereby causing oxidative stress and cell death. However, tumors resist through different mechanisms, including upregulation of anti-apoptotic factors and enhanced ROS resistance. We recently reported that the antioxidative enzyme PON2 significantly enhances cellular stress resistance by attenuating mitochondrial ROS-mediated apoptosis. Further, PON2 is often upregulated in cancer. This prompted us to investigate its yet unknown role in the protection of OSCC against irradiation-induced cell death. METHODS: PON2 expression was determined after 7 Gy singular irradiation in four OSCC cell lines (PCI-13, PCI-52, SCC-4, SCC-68) accompanied by the detection of caspase 3/7 activity. A direct role of PON2 was tested by siRNA-mediated knockdown. In vivo PON2 expression was tested in five patients with oral carcinoma and compared with healthy mucosa for the evaluation of clinical significance. RESULTS: PON2 is variably expressed in OSCC in vitro and in vivo. Compared with the other cell lines, SCC-4 cells showed twofold more basal PON2 (p <= 0.05) and the lowest caspase 3/7 activity after singular irradiation (p <= 0.05). Contrarily, irradiation led to 1.2-fold induction of PON2 in PCI-13 with no effect on SCC-4 (<=0.05), suggesting that PON2 levels reflect the cells' irradiation sensitivity. In agreement, PON2 knockdown resulted in significant higher apoptosis rates (p <= 0.05). CONCLUSION: Our findings give first evidence that upregulation of PON2 may protect OSCC against irradiation-induced apoptosis. PMID- 25708946 TI - Changes in physical activity and cognitive decline in older adults living in the community. AB - Accumulating evidence suggests that physical activity may be beneficial in preserving cognition in late life. This study examined the association between baseline and changes in physical activity and cognitive decline in community dwelling older people. Data were from the Korean Longitudinal Study of Aging, with 2605 aged 65 years and older subjects interviewed in 2006 and followed up for 2 years. Cognitive decline was defined by calculating the Reliable Change Index using the Mini-Mental State Examination. Physical activity levels were categorized as sedentary, low, or high. Changes in physical activity were classified as inactive, decreaser, increaser, or active. Logistic regression analysis of baseline and changes in physical activity with cognitive decline was performed. Compared with the sedentary group at baseline, both the low and high activity groups were less likely to experience cognitive decline. The active (odds ratio [OR] = 0.40, 95 % confidence interval [CI] 0.23-0.68) and increaser (OR = 0.45, 95 % CI 0.27-0.74) group, compared with the inactive counterpart, demonstrated a significantly lower likelihood of cognitive decline. Older adults who remained active or increased activity over time had a reduced risk of cognitive decline. Engagement in physical activity in late life may have cognitive health benefits. PMID- 25708947 TI - A linear time algorithm for detecting long genomic regions enriched with a specific combination of epigenetic states. AB - BACKGROUND: Epigenetic modifications are essential for controlling gene expression. Recent studies have shown that not only single epigenetic modifications but also combinations of multiple epigenetic modifications play vital roles in gene regulation. A striking example is the long hypomethylated regions enriched with modified H3K27me3 (called, "K27HMD" regions), which are exposed to suppress the expression of key developmental genes relevant to cellular development and differentiation during embryonic stages in vertebrates. It is thus a biologically important issue to develop an effective optimization algorithm for detecting long DNA regions (e.g., >4 kbp in size) that harbor a specific combination of epigenetic modifications (e.g., K27HMD regions). However, to date, optimization algorithms for these purposes have received little attention, and available methods are still heuristic and ad hoc. RESULTS: In this paper, we propose a linear time algorithm for calculating a set of non overlapping regions that maximizes the sum of similarities between the vector of focal epigenetic states and the vectors of raw epigenetic states at DNA positions in the set of regions. The average elapsed time to process the epigenetic data of any of human chromosomes was less than 2 seconds on an Intel Xeon CPU. To demonstrate the effectiveness of the algorithm, we estimated large K27HMD regions in the medaka and human genomes using our method, ChromHMM, and a heuristic method. CONCLUSIONS: We confirmed that the advantages of our method over those of the two other methods. Our method is flexible enough to handle other types of epigenetic combinations. The program that implements the method is called "CSMinfinder" and is made available at: http://mlab.cb.k.u tokyo.ac.jp/~ichikawa/Segmentation/ PMID- 25708948 TI - Repression of Nrf2 enhances antitumor effect of 5-fluorouracil and gemcitabine on cholangiocarcinoma cells. AB - Resistance to chemotherapy is the major problem in cancer treatment. Cholangiocarcinoma (CCA) is the tumor arising from the bile duct epithelium. The disease is characterized by very poor prognosis and rarely responds to current radiotherapy or chemotherapy. Transcription factor Nrf2 is activated by oxidative stress and electrophiles and contributes to cytoprotection in normal cells as well as cancer cells. Inhibition of Nrf2 can enhance the sensitivity of cancer cells to chemotherapeutic agents, although this sensitizing effect is variable depending on the cancers. In this study, we selected three CCA cell lines with different Nrf2 expression levels, detected by immunocytofluorescent staining. Chemotherapeutic agents variably induced the expression of antioxidant and xenobiotic metabolizing genes including Nrf2, NQO1, HO-1, GCLC, and GSTP1. Knockdown of Nrf2 expression by siRNA suppressed protein expression of Nrf2 regulated genes and enhanced the sensitivity to 5-fluorouracil and gemcitabine of CCA cells in both high and low basal Nrf2 expression. Cells with more resistance to chemotherapeutic agents gained more chemosensitizing effect by Nrf2 inhibition than the sensitive cells. The IC50 of the chemotherapeutic agents was also significantly reduced and the maximal cytotoxic effect was increased. Suppression of Nrf2 signaling may be a strategy to increase the efficacy of chemotherapy to CCA. PMID- 25708949 TI - Protective effect of boswellic acids versus pioglitazone in a rat model of diet induced non-alcoholic fatty liver disease: influence on insulin resistance and energy expenditure. AB - Non-alcoholic fatty liver disease (NAFLD) is closely linked to insulin resistance, oxidative stress, and cytokine imbalance. Boswellic acids, a series of pentacyclic triterpene molecules that are produced by plants in the genus Boswellia, has been traditionally used for the treatment of a variety of diseases. This study aimed at evaluating the protective effect of boswellic acids in a model of diet-induced NAFLD in rats in comparison to the standard insulin sensitizer, pioglitazone. Rats were fed with a high-fat diet (HFD) for 12 weeks to induce NAFLD. Starting from week 5, rats received boswellic acids (125 or 250 mg/kg) or pioglitazone parallel to the HFD. Feeding with HFD induced hepatic steatosis and inflammation in rats. In addition, liver index, insulin resistance index, activities of liver enzymes, and serum lipids deviated from normal. Further, serum tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and cyclooxygenase 2 were elevated; this was associated with an increase in hepatic expression of inducible nitric oxide synthase (iNOS) and formation of 4-hydroxy-2 nonenal (HNE). Rats treated with boswellic acids (125 or 250 mg/kg) or pioglitazone showed improved insulin sensitivity and a reduction in liver index, activities of liver enzymes, serum TNF-alpha and IL-6 as well as hepatic iNOS expression and HNE formation compared to HFD group. Furthermore, at the cellular level, boswellic acids (250 mg/kg) ameliorated the expression of thermogenesis related mitochondrial uncoupling protein-1 and carnitine palmitoyl transferase-1 in white adipose tissues. Data from this study indicated that boswellic acids might be a promising therapy in the clinical management of NAFLD if appropriate safety and efficacy data are available. PMID- 25708950 TI - Paradoxical effects of the autophagy inhibitor 3-methyladenine on docetaxel induced toxicity in PC-3 and LNCaP prostate cancer cells. AB - Docetaxel was the first chemotherapeutic agent to increase survival time in patients with androgen-resistant prostate cancer. However, it provides only a modest increase in survival and is associated with significant toxicity. Therefore, there is an urgent need to identify potential adjunct therapies. Given the key role of autophagy in both tumour survival and chemoresistance, the impact of autophagy modulation on docetaxel toxicity was tested in vitro. PC-3 and LNCaP cells were pre-treated with the autophagy inhibitor 3-methyladenine (5 mM) and then exposed to various concentrations (0-100 MUM) of docetaxel. Cytoxic effects of docetaxel were measured using resazurin reduction to resorufin, whilst autophagy and apoptosis was measured using monodansylcadaverine, annexin V and caspase-3, respectively. Docetaxel produced significant toxicity in PC-3 cells but was not toxic to LNCaP cells. Pre-treatment with the autophagy inhibitor, 3 methyladenine (5 mM) significantly protected PC-3 cells against docetaxel-induced cytotoxicity, increased autophagosome formation and apoptosis measured using monodansylcadaverine, annexin V and caspase-3 fluorescence, respectively. In contrast, 3-methyladenine was toxic by itself in LNCaP cells and also increased autophagic vesicle formation and apoptosis but did not influence docetaxel toxicity in these cells. These paradoxical effects of 3-methyladenine were largely independent of reactive oxygen species production. We show here that modulation of autophagy may influence docetaxel-induced toxicity in prostate cancer cells and these effects may differ between cell lines. PMID- 25708951 TI - Step-by-step Type C Laparoscopic Radical Hysterectomy With Nerve-sparing Approach. AB - STUDY OBJECTIVE: To show the laparoscopic technique to perform type C radical hysterectomy with a nerve-sparing approach and pelvic lymphadenectomy. DESIGN: Educational video with step-by-step explanation of the technique using videos and pictures to highlight the anatomic landmark that guides the procedure. SETTING: The goal of this procedure is to enlarge the resection of the paracervix at the junction with internal iliac vascular system, leaving the neural part of the structure under the deep uterine vein untouched. Type C consists in the resection of the uterosacral ligament at the rectum level and the vesicouterine ligament at the bladder level. The ureter is mobilized completely, and 15 to 20 mm of the vagina from the tumor or cervix is resected. Performing such an enlarged hysterectomy, the preservation of the nerve supply to the bladder is crucial, leading to the creation of the subclasses. Type C1 conserves a nerve-sparing approach remaining above the deep uterine vein, whereas in type C2 a resection beyond this landmark including the neural part of the paracervix is performed. INTERVENTIONS: Total laparoscopic type C1 radical hysterectomy with pelvic lymphadenectomy. CONCLUSION: This video shows the feasibility of type C radical hysterectomy through a minimally invasive approach. The possibility to perform this type of procedure laparoscopically matches with the more conservative approach to cervical cancer, bringing all the advantages of this technique into this field of gynecologic surgery. PMID- 25708953 TI - Population-based analysis of salvage radical prostatectomy with examination of factors associated with adverse perioperative outcomes. AB - INTRODUCTION: Salvage radical prostatectomy (SRP) is a potentially curative operation performed for recurrent prostate cancer after radiation therapy (RT). The purpose of this study was to examine perioperative and pathologic outcomes of SRP in a national cohort. MATERIALS AND METHODS: The National Cancer Database from 1998 to 2011 was used to identify 408 patients who underwent SRP. We evaluated the demographic data, clinical variables, and pathologic and perioperative outcomes. Primary outcomes of interest were length of stay (LOS) and positive surgical margins (PSM). A multivariable logistic regression model was employed to identify preoperative predictors of LOS >= 3 days and PSM following SRP. RESULTS: Among patients undergoing SRP, the mean age was 62.5 +/- 6.8 years, mean prostate-specific antigen (PSA) level was 12.6 +/- 15.6 ng/ml, and 64% were categorized as clinical stage T1. External beam RT (89%), followed by brachytherapy (11%), was the most common modalities for primary RT. Most SRPs were performed at high-volume centers (57%) in metropolitan locations (83%). Most patients underwent a lymph node dissection (75%) and the mean node count was 15.0 +/- 30.1. On final pathology, 73% had intermediate- or high-grade disease (Gleason score 7 in 43% and Gleason score 8-10 in 30%), 49% had pT3 or pT4 disease, 6.2% had positive lymph nodes, and 34% had PSM. The mean LOS was 3.5 +/- 9.9 days, and 43% of patients had a LOS >= 3 days. The 30-day readmission rate was 6.5% after SRP, and 30- and 90-day postoperative mortality rates were extremely low at 0.4% (n = 1). On multivariable analysis of the entire cohort, PSA level > 20 ng/ml was an independent predictor of PSM (OR = 3.68, 95% CI: 1.2 10.9, P = 0.018). PSA level > 20 ng/ml (OR = 4.37, 95% CI: 1.2-16.2, P = 0.027) and cT2 or greater disease (OR = 2.52, 95% CI: 1.0-6.2, P = 0.046) were associated with prolonged LOS (LOS >= 3d), whereas surgery at an academic facility (OR = 0.30, 95% CI: 0.1-0.8, P = 0.02) reduced the odds of LOS >= 3 days. CONCLUSIONS: In select patients derived from a population-based cohort, SRP results in effective local cancer control with acceptable perioperative outcomes. PSA level > 20 ng/ml is independently associated with PSM and prolonged LOS after SRP. Clinical stage T2 or greater disease is also associated with prolonged LOS, whereas surgery at an academic facility reduced this risk. PMID- 25708952 TI - The role of families in decisions regarding cancer treatments. AB - BACKGROUND: Shared decision-making is an important component of patient-centered care and is associated with improved outcomes. To the authors' knowledge, little is known concerning the extent and predictors of the involvement of a patient's family in decisions regarding cancer treatments. METHODS: The Cancer Care Outcomes Research and Surveillance (CanCORS) Consortium is a large, multiregional, prospective cohort study of the cancer care and outcomes of patients with lung and colorectal cancer. Participants reported the roles of their families in decision-making regarding treatment. Multinomial logistic regression was used to assess patient factors associated with family roles in decisions. RESULTS: Among 5284 patients, 80 (1.5%) reported family-controlled decisions, with the highest adjusted rates (12.8%) noted among non-English speaking Asians. Among the 5204 remaining patients, 49.4% reported equally sharing decisions with family, 22.1% reported some family input, and 28.5% reported little family input. In adjusted analyses, patients who were married, female, older, and insured more often reported equally shared decisions with family (all P <.001). Adjusted family involvement varied by race/ethnicity and language, with Chinese-speaking Asian (59.8%) and Spanish-speaking Hispanic (54.8%) patients equally sharing decisions with family more often than white individuals (47.6%). Veterans Affairs patients were least likely to report sharing decisions with family, even after adjustment for marital status and social support (P <.001). CONCLUSIONS: The majority of patients with newly diagnosed lung or colorectal cancer involve family members in treatment decisions. Non-English-speaking Asians and Hispanics rely significantly on family. Further studies are needed to determine the impact of family involvement in treatment decisions on outcomes; until then, physicians should consider eliciting patients' preferences for family involvement. PMID- 25708954 TI - Battling resistance mechanisms in antihormonal prostate cancer treatment: Novel agents and combinations. AB - Prostate cancer (PCa) is a hormone-sensitive disease. Androgen deprivation therapy lowers serum testosterone levels (castration) or blocks the androgen receptor (AR) ligand-binding domain. Especially in metastatic disease, hormonal therapy has been able to delay disease progression, reduce symptoms, and improve overall survival. Despite subsequent disease progression and development of castration resistance, PCa remains AR driven. Secondary hormonal treatments such as abiraterone acetate or enzalutamide have demonstrated increased overall survival. However, new resistance mechanisms to these agents have been identified, and systemic chemotherapy is still needed especially in fast progressing castration-resistant PCa. Several promising androgen synthesis inhibitors (orteronel and galeterone), AR inhibitors (ARN-509, EPI-001, AZD3514, and ODM-201), and heat shock protein modulators (AT11387, 17-DMAG, STA-9090, and OGX-427) are currently under investigation. The wide variety in upcoming systemic agents underlines the molecular heterogeneity of castration-resistant PCa. This article reviews antihormonal therapy in PCa and resistance mechanisms and focuses on novel and upcoming agents currently in clinical testing. PMID- 25708955 TI - Ultrasensitive biosensors using enhanced Fano resonances in capped gold nanoslit arrays. AB - Nanostructure-based sensors are capable of sensitive and label-free detection for biomedical applications. However, plasmonic sensors capable of highly sensitive detection with high-throughput and low-cost fabrication techniques are desirable. We show that capped gold nanoslit arrays made by thermal-embossing nanoimprint method on a polymer film can produce extremely sharp asymmetric resonances for a transverse magnetic-polarized wave. An ultrasmall linewidth is formed due to the enhanced Fano coupling between the cavity resonance mode in nanoslits and surface plasmon resonance mode on periodic metallic surface. With an optimal slit length and width, the full width at half-maximum bandwidth of the Fano mode is only 3.68 nm. The wavelength sensitivity is 926 nm/RIU for 60-nm-width and 1,000-nm-period nanoslits. The figure of merit is up to 252. The obtained value is higher than the theoretically estimated upper limits of the prism-coupling SPR sensors and the previously reported record high figure-of-merit in array sensors. In addition, the structure has an ultrahigh intensity sensitivity up to 48,117%/RIU. PMID- 25708956 TI - Quality of cardiopulmonary resuscitation by lifeguards on a small inflatable boat. PMID- 25708957 TI - Time to incorporate real-time CPR feedback and CPR debriefings into advanced life support courses. PMID- 25708958 TI - Derivation and initial application of a standard population for out-of-hospital cardiac arrest (SPOHCA). AB - AIM: While adjusting data for age, sex, race and/or socio-economic status is well established in out-of-hospital cardiac arrest (OHCA) research, there are shortcomings to reporting and comparing population-based OHCA outcomes. The purpose of this study was to derive a case-based standard population specific to EMS treated adult OHCA (SPOHCA) in the U.S., and demonstrate its application. METHODS: The proposed SPOHCA was developed from three sources of multi-site OHCA data: the Cardiac Arrest Registry to Enhance Survival (CARES); the National EMS Information System (NEMSIS); and a published report from the Resuscitation Outcomes Consortium (ROC). OHCA data from a single EMS system were then used to demonstrate the application of SPOHCA. We report raw survival, population-based survival adjusted to the U.S. population, and the new SPOHCA-adjusted survival. RESULTS: Observed raw survival was 12.3%. Adjustment to the demographic make-up of the adult U.S. population produced an adjusted incidence of 94.2 OHCA per 100,000 p-y, with a survival rate of 9.8 per 100,000 p-y. Using the proposed SPOHCA to adjust survival data produced an adjusted survival rate of 12.4%. CONCLUSION: A case-based standard population provides for more practical interpretation of reported OHCA outcomes. We encourage a more widespread effort involving multiple stakeholders to further explore the effects of adjusting OHCA outcomes using the proposed SPOHCA instead of population-based demographics. PMID- 25708959 TI - Incidence of difficult airway situations during prehospital airway management by emergency physicians--a retrospective analysis of 692 consecutive patients. AB - INTRODUCTION: In the prehospital setting, advanced airway management is challenging as it is frequently affected by facial trauma, pharyngeal obstruction or limited access to the patient and/or the patient's airway. Therefore, incidence of prehospital difficult airway management is likely to be higher compared to the in-hospital setting and success rates of advanced airway management range between 80 and 99%. METHODS: 3961 patients treated by an emergency physician in Zurich, Switzerland were included in this retrospective analysis in order to determine the incidence of a difficult airway along with potential circumstantial risk factors like gender, necessity of CPR, NACA score, GCS, use and type of muscle relaxant and use of hypnotic drugs. RESULTS: 692 patients underwent advanced prehospital airway management. Seven patients were excluded due to incomplete or incongruent documentation, resulting in 685 patients included in the statistical analysis. Difficult intubation was recorded in 22 patients, representing an incidence of a difficult airway of 3.2%. Of these 22 patients, 15 patients were intubated successfully, whereas seven patients (1%) had to be ventilated with a bag valve mask during the whole procedure. CONCLUSION: In this physician-led service one out of five prehospital patients requires airway management. Incidence of advanced prehospital difficult airway management is 3.2% and eventual success rate is 99%, if performed by trained emergency physicians. A total of 1% of all prehospital intubation attempts failed and alternative airway device was necessary. PMID- 25708960 TI - Familial periodontal disease in the Cayo Santiago rhesus macaques. AB - Substantial ongoing research continues to explore the contribution of genetics and environment to the onset, extent and severity of periodontal disease(s). Existing evidence supports that periodontal disease appears to have an increased prevalence in family units with a member having aggressive periodontitis. We have been using the nonhuman primate as a model of periodontal disease for over 25 years with these species demonstrating naturally occurring periodontal disease that increases with age. This report details our findings from evaluation of periodontal disease in skulls from 97 animals (5-31 years of age) derived from the skeletons of the rhesus monkeys (Macaca mulatta) on Cayo Santiago. Periodontal disease was evaluated by determining the distance from the base of the alveolar bone defect to the cemento-enamel junction on 1st/2nd premolars and 1st/2nd molars from all four quadrants. The results demonstrated an increasing extent and severity of periodontitis with aging across the population of animals beyond only compensatory eruption. Importantly, irrespective of age, extensive heterogeneity in disease expression was observed among the animals. Linking these variations to multi-generational matriarchal family units supported familial susceptibility of periodontitis. As the current generations of animals that are descendants from these matrilines are alive, studies can be conducted to explore an array of underlying factors that could account for susceptibility or resistance to periodontal disease. PMID- 25708961 TI - MDCT evaluation of aortic root and aortic valve prior to TAVI. What is the optimal imaging time point in the cardiac cycle? AB - OBJECTIVES: To determine the optimal imaging time point for transcatheter aortic valve implantation (TAVI) therapy planning by comprehensive evaluation of the aortic root. METHODS: Multidetector-row CT (MDCT) examination with retrospective ECG gating was retrospectively performed in 64 consecutive patients referred for pre-TAVI assessment. Eighteen different parameters of the aortic root were evaluated at 11 different time points in the cardiac cycle. Time points at which maximal (or minimal) sizes were determined, and dimension differences to other time points were evaluated. Theoretical prosthesis sizing based on different measurements was compared. RESULTS: Largest dimensions were found between 10 and 20% of the cardiac cycle for annular short diameter (10%); mean diameter (10%); effective diameter and circumference-derived diameter (20%); distance from the annulus to right coronary artery ostium (10%); aortic root at the left coronary artery level (20%); aortic root at the widest portion of coronary sinuses (20%); and right leaflet length (20%). Prosthesis size selection differed depending on the chosen measurements in 25-75% of cases. CONCLUSION: Significant changes in anatomical structures of the aortic root during the cardiac cycle are crucial for TAVI planning. Imaging in systole is mandatory to obtain maximal dimensions. KEY POINTS: * Most aortic root structures undergo significant dimensional changes throughout the cardiac cycle. * The largest dimensions of aortic parameters should be determined to optimize TAVI. * Circumference-derived diameter showed maximum dimension at 20% of the cardiac cycle. PMID- 25708962 TI - CT findings suggesting anastomotic leak and predicting the recovery period following gastric surgery. AB - OBJECTIVE: To assess diagnostic performance of routine CT for detecting anastomotic leak after gastric surgery, and analyse the relationship between recovery period and CT findings. METHODS: We included 179 patients who underwent immediate CT and fluoroscopy after gastric surgery. Two reviewers retrospectively rated the possibility of leak on CT using a five-point scale focused on predefined CT findings. They also evaluated CT findings. Patients were categorised as: Group I, leak on fluoroscopy; Group II, possible leak on CT but negative on fluoroscopy; Group III, no leak. We analysed the relationship between recovery period and group. RESULTS: Area under the curve for detecting leak on CT was 0.886 in R1 and 0.668 in R2 with moderate agreement (k = 0.482). Statistically common CT findings for leak included discontinuity, large amount of air-fluid and wall thickening at anastomosis site (p < 0.05). Discontinuity at anastomosis site and a large air-fluid collection were independently associated with leak (p < 0.05). The recovery period including hospitalisation and postoperative fasting period was longer in Group I than Group II or III (p < 0.05). Group II showed a longer recovery period than Group III (p < 0.05). CONCLUSIONS: Postoperative routine CT was useful for predicting anastomotic leak using specific findings, and for predicting length of recovery period. KEY POINTS: * Anastomotic leakage remains a significant clinical problem following gastric surgery. * Routine CT without oral contrast is useful for predicting anastomotic leaking. * Wall discontinuity at anastomosis sites was an independent predictor for leaking. * CT is also useful for predicting recovery period following gastric surgery. PMID- 25708963 TI - Fairly direct hit! Advances in imaging of shotgun projectiles in MRI. AB - OBJECTIVES: To investigate the magnetic properties of different types of projectiles and qualify the metal artefact reduction technique for diagnostic and/or forensic MRI. MATERIALS AND METHODS: Ten different projectiles embedded in ordnance gelatine blocks underwent an in vitro 1.5-T MR study with seven sequences including a recently developed metal artefact reduction sequence (Advanced WARP) combining VAT (view-angle-tilting) and SEMAC (slice-encoding metal-artefact-correction). Resulting image quality (five-point scale: 1=best; 5=worst) was scored. Quantifiable magnetic characteristics were correlated with qualitative rating of the MR sequences and torque dislodgment. RESULTS: Metal artefact reduction sequence (median: 2.5) significantly (p < 0.001) improves depiction of projectiles in comparison to all other MR pulse sequences (median: 4.75). Images from diamagnetic composed bullets (median: 2) are much less disturbed compared to magnetic attracted ones (median: 5). Correlation (0.623) between deflection angle measurement (ferromagnetic mean 84.2 degrees ; paramagnetic 62 degrees ; diamagnetic mean 0 degrees ) and median qualitative image quality was highly significant (p = 0.027). Torque dislodgement was distinct for elongated magnetic attracted projectiles. CONCLUSIONS: Significant improvement of MR imaging of projectiles using metal artefact reduction techniques has important implications for diagnostic/forensic work-up. The correlations between magnetic attraction force, deflection-angle results and image properties demonstrate that the MR safety of projectiles can be estimated with one of these methods. KEY POINTS: * Metal artefact reduction sequence improves overall image quality of bullets (p < 0.001). * Deflection angle assessment significantly predicts image quality of bullets (p = 0.027). * Classification of projectiles' magnetic properties based on artefacts' characteristics is possible. * Classifying of bullets has important implications in diagnostic and forensic imaging. * Identification of projectiles' magnetic attributes improves estimation of patients' injury risk. PMID- 25708964 TI - Use of electroconvulsive therapy for Asian patients with schizophrenia (2001 2009): Trends and correlates. AB - AIMS: Little is known about electroconvulsive therapy (ECT) use in Asian inpatients with schizophrenia. This study examined trends of ECT use for schizophrenia patients in Asia between 2001 and 2009 and its independent demographic and clinical correlates. METHODS: Data on 6761 hospitalized schizophrenia patients (2001 = 2399, 2004 = 2136, and 2009 = 2226) in nine Asian countries and territories were collected by either chart review or interviews during a 1-month period. Patients' sociodemographic and clinical characteristics, prescriptions of psychotropic drugs and ECT use were recorded using a standardized protocol and data-collection procedure. RESULTS: The frequency of ECT was 3.3% in the whole sample; rising from 1.8% in 2001 to 3.3% in 2004 and 4.9% in 2009 (P < 0.0001). However, this increased trend was driven solely by increased ECT use in China (P < 0.0001), and the inclusion of India in the 2009 survey. There were wide inter-country variations: 2001, 0% (Hong Kong, Korea) to 5.9% (China); 2004, 0% (Singapore) to 11.1% (China); 2009, 0% (Hong Kong) to 13.8% (India) and 15.2% (China). Multiple logistic regression analysis of the whole sample revealed that patients receiving ECT were less likely in the 35-64 year age group, had shorter length of current hospitalization and fewer negative symptoms, and were more likely to receive second-generation antipsychotic medications compared to those who were not treated with ECT (R(2) = 0.264, P < 0.001). CONCLUSIONS: ECT use for schizophrenia has increased over the past decade in China, being low/relatively stable in other Asian countries/regions. Reasons for substantial variations in ECT frequency in Asia require further study. PMID- 25708965 TI - Image Schemas in Verb-Particle Constructions: Evidence from a Behavioral Experiment. AB - Cognitive linguists claim that verb-particle constructions are compositional and analyzable, and that the particles contribute to the overall meaning in the form of image schemas. This article examined this claim with a behavioral experiment, in which participants were asked to judge the sensibility of short sentences primed by image-schematic pictures. Results showed that for sentences containing spatial VP constructions, the latency followed the order of "agreement primes < neutral primes < disagreement primes", while for sentences of non-spatial VP constructions, the order was "neutral primes < agreement primes < disagreement primes". This suggests that the activation of the corresponding image schemas influences both types of VP constructions, providing new evidence for the embodied account of language and thought. The different processing patterns between the spatial and non-spatial VP constructions are also discussed in the theoretical framework of Construction Grammar. PMID- 25708966 TI - The Effect of Bipolar Mood Disorder on Sadegh Hedayat's Letters. AB - This paper studies linguistic characteristics of bipolar mood disorder in Sadegh Hedayat's letters. It attempts to explore the possibility of diagnosing bipolar disorder through qualitative analysis of text. The personal letters of Iranian author Sadegh Hedayat addressed to Shahid Nouraie are studied. The addressee is fixed to reduce effective factors, including linguistic differences among different registers and styles. Therefore, interpersonal variation is also neutralized. Letters are chosen to reduce the potential effects of aesthetic manipulation used in the author's narratives and published works. To analyze the data, semantic fields used in the letters are studied, and to find any instance of pressured speech and poverty of speech, topical shifts and moves are analyzed as well. Linguistic study of each letter reveals that different types of bipolar mood episodes (i.e., hypomanic, depressed, euthymic and mixed) can be diagnosed with this methodology. Other semantic criteria are explored, including themes of humiliation and ridicule. PMID- 25708967 TI - Letter in response to: therapeutic hypothermia after cardiac arrest caused by self-inflicted intoxication: a multicenter retrospective cohort study. PMID- 25708968 TI - Pseudomyocardial infarction caused by adrenocortical adenoma. PMID- 25708969 TI - Takotsubo's cardiomyopathy: the spectrum expands. PMID- 25708970 TI - Lengths of stay for involuntarily held psychiatric patients in the ED are affected by both patient characteristics and medication use. AB - BACKGROUND: Psychiatric patients experience longer treatment times (length of stay [LOS]) in the emergency department (ED) compared to nonpsychiatric patients. Although patients on involuntary mental health holds are relatively understudied, common wisdom would hold that times for these patients can only be affected by addressing systems issues because they are not free to leave. The objective of this study was to determine whether both selected ED and patient-specific factors were associated with longer LOS. We hypothesized that nonmodifiable factors (age, sex, agitation, presentation during evenings/nights, presentation during weekends, suicidal ideation) would prolong LOS but that potentially modifiable factors (such as use of medication) would reduce LOS. METHODS: A historical cohort of patients (January 1, 2009-August 16, 2010) placed on involuntary mental health holds was studied in 2 general EDs. A regression model was used to calculate the effects of modifiable and nonmodifiable factors on LOS. RESULTS: Six hundred forty patient visits met all inclusion/exclusion criteria. Longer LOSs were significantly associated with suicidal ideation, use of antipsychotics, and use of benzodiazepines, although agitation did not predict longer LOSs. Longer LOSs were also longer with presentation on the weekends. CONCLUSIONS: Lengths of stay for patients on involuntary mental health holds are associated with several factors outside the control of the typical ED clinician such as the ability to clear holds quickly due to day of week or placement of the hold for suicidal ideation. Lengths of stay are also increased by factors within the control of the typical ED clinician, such as administration of calming medication. PMID- 25708971 TI - Wearing the mask of ST-elevation myocardial infarction: postpericardiotomy syndrome. AB - INTRODUCTION: Postpericardiotomy syndrome (PPS) is an inflammatory process, affecting 15% to 20% of patients, after surgery involving pleura, pericardium, or both. The role of electrocardiogram (ECG) in diagnosing PPS is uncertain because ECG is rarely normal (especially after cardiac surgery). We report a case of PPS that presented initially with localized ST-segment elevation and also discuss proposed mechanisms. CLINICAL CASE: A 60-year-old White man presented to the emergency department (ED) after having chest pain, shortness of breath, and palpitation for approximately 2 hours. Patient had known coronary artery disease, status postcoronary artery bypass graft a month earlier with a graft to right coronary artery, and 2 grafts to marginal arteries. In the ED, ECG revealed localized ST-segment elevations in leads II, III, and aVF. Coronary angiography did not reveal significant coronary artery stenosis, and all the grafts were found to be patent. Following ECG showed PR depression along with diffuse ST elevation consistent with pericarditis. Patient was started on nonsteroidal anti inflammatory drugs and colchicine with significant improvement of his symptoms in a few days. DISCUSSION: In our patient, injury or surgical manipulation to the area perfused by right coronary artery might have initiated a process, initially localized to the inferior wall with subsequent diffuse involvement of the entire pericardium. The presentation of our patient shortly after the development of chest pain and availability of 2 ECGs a few minutes apart may have shed light on the pathophysiology of PPS. PMID- 25708972 TI - Case Presentation: Trick or Treat? PMID- 25708973 TI - Methylisothiazolinone in rinse-off products causes allergic contact dermatitis: a repeated open-application study. AB - BACKGROUND: In recent years, the prevalence of contact allergy to the preservative methylisothiazolinone (MI) has increased dramatically. Cosmetic products are one of the major sources of exposure. OBJECTIVES: To examine whether allowed concentrations of MI in cosmetic rinse-off products have the potential to cause allergic contact dermatitis. METHODS: Nineteen MI-allergic subjects and 19 controls without MI allergy applied two liquid hand soaps five times per day on areas of 5 * 10 cm(2) on the ventral side of their forearms. One soap contained 100 ppm MI, the maximum allowed concentration in cosmetics, and was used by 10 allergic subjects and all controls. Another liquid soap with 50 ppm MI was used by nine allergic subjects. As the negative control, all subjects used a similar soap that did not contain MI. The repeated open applications proceeded until a positive reaction occurred or up to 21 days. The study was conducted in a randomized and blinded fashion. RESULTS: Ten out of 10 MI-allergic subjects developed positive reactions to the soap with 100 ppm and seven out of nine reacted to the 50 ppm soap, while none of the 19 controls had a positive reaction during 21 days of application. No reactivity was seen to the soap without MI. The difference in reactivity to MI between MI-allergic subjects and controls was statistically significant (Fisher's exact test, P ? 0.0001). CONCLUSIONS: Rinse off products preserved with 50 ppm MI or more are not safe for consumers. No safe level has yet been identified. PMID- 25708974 TI - Long-term outcome of esophagectomy for primary malignant melanoma of the esophagus: a single-institute retrospective analysis. AB - Primary malignant melanoma of the esophagus (PMME) is a highly malignant tumor with a poor prognosis. Because PMME is an extremely rare disease, therapeutic strategies against the tumor have yet to be established, and the efficacy of esophagectomy remains unclear. The objective of this study was to evaluate the post-esophagectomy survival of PMME patients. Ten patients who underwent esophagectomy for PMME between March 2005 and April 2013 at the Department of Gastroenterological Surgery, Cancer Institute Hospital, Tokyo, Japan, were identified from the institutional database. We retrospectively retrieved clinical information and data on the long-term outcomes from the patients' records. Survival rates after esophagectomy were calculated by the Kaplan-Meier method, and the hazard ratios of mortality were determined using the Cox's model. A follow-up study of the 10 patients revealed 7 cancer recurrences and 5 deaths. Median survival time was 34.5 months, and 5 of 10 patients survived longer than 2 years. The 1-year disease-free survival rate was 40%, and the 1- and 3-year overall survival rates were 70% and 60%, respectively. Importantly, all three of the non-relapsing patients were histologically confirmed as free of lymph node involvement. The four patients with lymph node metastasis relapsed within 1 year. The disease-free survival was significantly shorter in patients with lymph node involvement than in those without lymph node involvement (univariate hazard ratio = 13.3, 95% confidence interval 1.85-266.4; P = 0.009). In conclusion, esophagectomy might benefit PMME patients with no lymph node metastasis. Further large-scale cohort studies are needed to establish the treatment strategy for PMME. PMID- 25708975 TI - Hybrid coronary revascularization: present indications and future perspective. AB - OPINION STATEMENT: Hybrid coronary revascularization (HCR) strategy consists of minimal invasive left internal mammary artery to left anterior descending bypass grafting and percutaneous coronary intervention (PCI) of the remaining lesions. HCR combines the known benefits of the LIMA-to-LAD graft (LIMA: left internal mammary artery, LAD: left anterior descending) and drug eluting stent (DES) to non-LAD regions and is currently reserved for particularly high-risk patients with favorable anatomy. Despite the lack of multicenter randomized trials, several small non-randomized studies have shown that HCR is safe with low mortality rates, low morbidity, and shorter intensive care unit and hospital stay. Up to date, HCR appears to be a promising and cost-effective alternative for CABG in the treatment of multivessel coronary artery disease in a selected patient population. PMID- 25708976 TI - Stent thrombosis: current management and outcomes. AB - OPINION STATEMENT: Stent thrombosis (ST) is an uncommon but highly morbid complication of percutaneous coronary interventions. The mechanisms leading to ST are heterogeneous, likely accounting for the variable timing and outcomes of ST. For the clinician, it is important to recognize major risk factors for ST, including discontinuation of dual antiplatelet therapy. Once ST occurs, management includes intensive antithrombotic and antiplatelet therapies. Newer antiplatelet agents may reduce the risk of ST and possibly minimize adverse outcomes after presentation with ST. PMID- 25708977 TI - Complete versus incomplete coronary revascularization of patients with multivessel coronary artery disease. AB - OPINION STATEMENT: The treatment of patients with multivessel coronary artery disease in need of a revascularization procedure is influenced by the clinical situation (stable vs. unstable), comorbid conditions (diabetes mellitus), and anatomical variables (proximal left anterior artery stenosis, left ventricular dysfunction). Given the invasive nature of coronary artery bypass graft (CABG) operations, surgeons have embraced the concept of complete anatomical revascularization in one procedural stage since the inception of CABG surgery. However, achieving complete coronary revascularization has been more challenging with percutaneous coronary intervention (PCI), and as a result, incomplete procedures are far more common than complete ones. Data continue to emerge on the potential benefits of complete revascularization on clinical outcomes and suggest that complete revascularization should be the goal of therapy whenever possible. The heart team should carefully review the degree to which each revascularization modality can achieve this goal during procedural planning. PMID- 25708978 TI - Functional analysis of drug resistance-associated mutations in the Trypanosoma brucei adenosine transporter 1 (TbAT1) and the proposal of a structural model for the protein. AB - The Trypanosoma brucei aminopurine transporter P2/TbAT1 has long been implicated in the transport of, and resistance to, the diamidine and melaminophenyl arsenical classes of drugs that form the backbone of the pharmacopoeia against African trypanosomiasis. Genetic alterations including deletions and single nucleotide polymorphisms (SNPs) have been observed in numerous strains and clinical isolates. Here, we systematically investigate each reported mutation and assess their effects on transporter function after expression in a tbat1(-/-) T. brucei line. Out of a set of six reported SNPs from a reported 'resistance allele', none significantly impaired sensitivity to pentamidine, diminazene or melarsoprol, relative to the TbAT1-WT allele, although several combinations, and the deletion of the codon for residue F316, resulted in highly significant impairment. These combinations of SNPs, and DeltaF316, also strongly impaired the uptake of [(3)H]-adenosine and [(3)H]-diminazene, identical to the tbat1(-/-) control. The TbAT1 protein model predicted that residues F19, D140 and F316 interact with the substrate of the transporter. Mutation of D140 to alanine resulted in an inactive transporter, whereas the mutation F19A produced a transporter with a slightly increased affinity for [(3)H]-diminazene but reduced the uptake rate. The results presented here validate earlier hypotheses of drug binding motifs for TbAT1. PMID- 25708979 TI - Multimodal imaging of a case of peripheral cone dystrophy. AB - PURPOSE: To characterize the peripheral cones in the images obtained by spectral domain optical coherence tomography (OCT), swept source OCT, and adaptive optics fundus camera in a patient with peripheral cone dystrophy. METHODS: A 28-year-old Japanese man underwent detailed ophthalmic evaluations including high-resolution imaging of the fundus of both eyes. RESULTS: The decimal best-corrected visual acuity was 1.2 in both eyes. The results of slit-lamp biomicroscopy and ophthalmoscopy were essentially normal. Fluorescein and indocyanine green angiographies did not show any hyper- or hypofluorescent areas of the retina. Goldmann perimetry showed full peripheral visual fields but relative central scotomas within the central 20 degrees . The results of the Humphrey Visual Field Analyzer showed a limited preservation of the central sensitivity. Color vision tests showed no errors in both eyes. Spectral-domain OCT showed attenuation of both the ellipsoid and interdigitation zones throughout the macular region except the center of the fovea. The scotopic full-field ERGs were normal, but the photopic ERGs were markedly reduced. Regular cone mosaics were not observed especially more than 450 MUm radius from the fovea in the adaptive optics retinal images. The parafoveal cone densities were severely decreased in both eyes. CONCLUSIONS: Our findings indicate that the peripheral cone dystrophy diagnosed by full-field ERGs and perimetry is due to a reduction in the density of parafoveal and peripheral cones. PMID- 25708980 TI - Triggered-release polymeric conjugate micelles for on-demand intracellular drug delivery. AB - Nanoscale drug delivery platforms have been developed over the past four decades that have shown promising clinical results in several types of cancer and inflammatory disorders. These nanocarriers carrying therapeutic payloads are maximizing the therapeutic outcomes while minimizing adverse effects. Yet one of the major challenges facing drug developers is the dilemma of premature versus on demand drug release, which influences the therapeutic regiment, efficacy and potential toxicity. Herein, we report on redox-sensitive polymer-drug conjugate micelles for on-demand intracellular delivery of a model active agent, curcumin. Biodegradable methoxy poly(ethylene glycol)-poly(lactic acid) copolymer (mPEG PLA) was conjugated with curcumin via a disulfide bond or ester bond (control), respectively. The self-assembled redox-sensitive micelles exhibited a hydrodynamic size of 115.6 +/- 5.9 (nm) with a zeta potential of -10.6 +/- 0.7 (mV). The critical micelle concentration was determined at 6.7 +/- 0.4 (MUg mL( 1)). Under sink conditions with a mimicked redox environment (10 mM dithiothreitol), the extent of curcumin release at 48 h from disulfide bond linked micelles was nearly three times higher compared to the control micelles. Such rapid release led to a lower half maximal inhibitory concentration (IC50) in HeLa cells at 18.5 +/- 1.4 (MUg mL(-1)), whereas the IC50 of control micelles was 41.0 +/- 2.4 (MUg mL(-1)). The cellular uptake study also revealed higher fluorescence intensity for redox-sensitive micelles. In conclusion, the redox sensitive polymeric conjugate micelles could enhance curcumin delivery while avoiding premature release, and achieving on-demand release under the high glutathione concentration in the cell cytoplasm. This strategy opens new avenues for on-demand drug release of nanoscale intracellular delivery platforms that ultimately might be translated into pre-clinical and future clinical practice. PMID- 25708981 TI - Concentration- and roughness-dependent antibacterial and antifungal activities of CuO thin films and their Cu ion cytotoxicity and elution behavior. AB - In this study, we aimed to evaluate the antibacterial and antifungal properties, cytotoxicity, and elution behavior of copper oxide (CuO) thin films with varying concentrations and roughness values. CuO films greater than 0.2 mol % showed 99.9 % antimicrobial activity against Escherichia coli, Staphylococcus aureus, Campylobacter jejuni, and Penicillium funiculosum. Cu ions were found to be noncytotoxic in New Zealand white rabbits. The concentration of Cu ions from CuO thin films eluted in drinking water in 24 h at 100 degrees C was 0.014 MUg L( 1), which was below the standard acceptable level of 0.02 MUg L(-1). The transmittance of CuO thin film-coated glass was similar to that of parent glass. The antimicrobial activity, cytotoxicity, elution behavior, and transmittance of CuO deposited on glass suggest that these films could be useful in household devices and display devices. PMID- 25708983 TI - The pattern of Fos expression in the rat auditory brainstem changes with the temporal structure of binaural electrical intracochlear stimulation. AB - The immediate-early-gene c-fos with its protein product Fos has been used as a powerful tool to investigate neuronal activity and plasticity following sensory stimulation. Fos combines with Jun, another IEG product, to form the dimeric transcription factor activator protein 1 (AP-1) which has been implied in a variety of cellular functions like neuronal plasticity, apoptosis, and regeneration. The intracellular emergence of Fos indicates a functional state of nerve cells directed towards molecular and morphological changes. The central auditory system is construed to detect stimulus intensity, spectral composition, and binaural balance through neurons organized in a complex network of ascending, descending and commissural pathways. Here we compare monaural and binaural electrical intracochlear stimulation (EIS) in normal hearing and early postnatally deafened rats. Binaural stimulation was done either synchronously or asynchronously. The auditory brainstem of hearing and deaf rats responds differently, with a dramatically increasing Fos expression in the deaf group so as if the network had no pre-orientation for how to organize sensory activity. Binaural EIS does not result in a trivial sum of 2 independent monaural EIS, as asynchronous stimulation invokes stronger Fos activation compared to synchronous stimulation almost everywhere in the auditory brainstem. The differential response to synchronicity of the stimulation puts emphasis on the importance of the temporal structure of EIS with respect to its potential for changing brain structure and brain function in stimulus-specific ways. PMID- 25708982 TI - The TLR4 agonist fibronectin extra domain A is cryptic, exposed by elastase-2; use in a fibrin matrix cancer vaccine. AB - Fibronectin (FN) is an extracellular matrix (ECM) protein including numerous fibronectin type III (FNIII) repeats with different functions. The alternatively spliced FN variant containing the extra domain A (FNIII EDA), located between FNIII 11 and FNIII 12, is expressed in sites of injury, chronic inflammation, and solid tumors. Although its function is not well understood, FNIII EDA is known to agonize Toll-like receptor 4 (TLR4). Here, by producing various FN fragments containing FNIII EDA, we found that FNIII EDA's immunological activity depends upon its local intramolecular context within the FN chain. N-terminal extension of the isolated FNIII EDA with its neighboring FNIII repeats (FNIII 9-10-11) enhanced its activity in agonizing TLR4, while C-terminal extension with the native FNIII 12-13-14 heparin-binding domain abrogated it. In addition, we reveal that an elastase 2 cleavage site is present between FNIII EDA and FNIII 12. Activity of the C-terminally extended FNIII EDA could be restored after cleavage of the FNIII 12-13-14 domain by elastase 2. FN being naturally bound to the ECM, we immobilized FNIII EDA-containing FN fragments within a fibrin matrix model along with antigenic peptides. Such matrices were shown to stimulate cytotoxic CD8(+) T cell responses in two murine cancer models. PMID- 25708984 TI - NMDA receptor triggered molecular cascade underlies compression-induced rapid dendritic spine plasticity in cortical neurons. AB - Compression causes the reduction of dendritic spines of underlying adult cortical pyramidal neurons but the mechanisms remain at large. Using a rat epidural cerebral compression model, dendritic spines on the more superficial-lying layer III pyramidal neurons were found quickly reduced in 12h, while those on the deep located layer V pyramidal neurons were reduced slightly later, starting 1day following compression. No change in the synaptic vesicle markers synaptophysin and vesicular glutamate transporter 1 suggest no change in afferents. Postsynaptically, N-methyl-d-aspartate (NMDA) receptor trafficking to synaptic membrane was detected in 10min and lasting to 1day after compression. Translocation of calcineurin to synapses and enhancement of its enzymatic activity were detected within 10min as well. These suggest that compression rapidly activated NMDA receptors to increase postsynaptic calcium, which then activated the phosphatase calcineurin. In line with this, dephosphorylation and activation of the actin severing protein cofilin, and the consequent depolymerization of actin were all identified in the compressed cortex within matching time frames. Antagonizing NMDA receptors with MK801 before compression prevented this cascade of events, including NR1 mobilization, calcineurin activation and actin depolymerization, in the affected cortex. Morphologically, MK801 pretreatment prevented the loss of dendritic spines on the compressed cortical pyramidal neurons as well. In short, we demonstrated, for the first time, mechanisms underlying the rapid compression-induced cortical neuronal dendritic spine plasticity. In addition, the mechanical force of compression appears to activate NMDA receptors to initiate a rapid postsynaptic molecular cascade to trim dendritic spines on the compressed cortical pyramidal neurons within half a day. PMID- 25708985 TI - TGF-beta1 prevents blood-brain barrier damage and hemorrhagic transformation after thrombolysis in rats. AB - Transforming growth factor-beta1 (TGF-beta1) is well known to promote extracellular matrix accumulation. Recent studies demonstrated that TGF-beta1 protects against blood-brain barrier (BBB) disruption in the condition of inflammatory pain and stroke. In the present study, we investigated whether TGF beta1 can maintain BBB integrity and prevent hemorrhagic transformation (HT) after recombinant tissue plasminogen activator (rt-PA) treatment in a rat model of thromboembolic middle cerebral artery occlusion (MCAO). Three hours after MCAO, rats were given saline, rt-PA alone or rt-PA combined with TGF-beta1 intravenously. Animals were sacrificed 24h after surgery. HT was calculated as hemorrhagic score. Evans blue dye extravasation was measured for BBB disruption. Basement membrane damage was observed by electron microscopy and quantified by collagen IV and laminin immunostaining. Gelatin zymography was used to measure the activities of matrix metalloproteinase (MMP)-2 and MMP-9. Western blot was performed for the expressions of MMP-2, MMP-9 and plasminogen activator inhibitor type-1 (PAI-1). Rats treated with rt-PA showed elevations in basement membrane damage, BBB disruption and HT. These phenomena were reduced in rats treated by TGF-beta1. We also showed that TGF-beta1 inhibited rt-PA mediated induction of MMP-2 and MMP-9. Meanwhile, TGF-beta1 upregulated PAI-1 expression which was reduced by rt-PA. Taken together, these results suggest that TGF-beta1 can reduce rt-PA induced basement membrane degradation, BBB disruption and HT. One possible mechanism is associated with the elevation of PAI-1. Suppression of MMP-2 and MMP 9 elevated by rt-PA may be another mechanism contributing to the protective effects of TGF-beta1. PMID- 25708988 TI - Flies with Parkinson's disease. AB - Parkinson's disease is an incurable neurodegenerative disease. Most cases of the disease are of sporadic origin, but about 10% of the cases are familial. The genes thus far identified in Parkinson's disease are well conserved. Drosophila is ideally suited to study the molecular neuronal cell biology of these genes and the pathogenic mutations in Parkinson's disease. Flies reproduce quickly, and their elaborate genetic tools in combination with their small size allow researchers to analyze identified cells and neurons in large numbers of animals. Furthermore, fruit flies recapitulate many of the cellular and molecular defects also seen in patients, and these defects often result in clear locomotor and behavioral phenotypes, facilitating genetic modifier screens. Hence, Drosophila has played a prominent role in Parkinson's disease research and has provided invaluable insight into the molecular mechanisms of this disease. PMID- 25708986 TI - A blinded, randomized study of L-arginine in small clot embolized rabbits. AB - OBJECTIVE: Tissue plasminogen activator (tPA) is administered to acute ischemic stroke victims in a vehicle formulation containing high concentrations of L arginine (3.5g/100mg vial), a well-known nitric oxide synthase (NOS) substrate and precursor to nitric oxide (NO), as well as an enhancer of cerebral blood flow. METHODS: We studied the effects of tPA vehicle compared to tPA (3.3mg/kg) formulated in the same vehicle containing L-arginine, normal saline or normal saline containing L-arginine, on behavioral function following small clot embolic strokes in rabbits using clinical rating scores and quantal analysis curves as the primary end point. Treatments were administered intravenously (1ml/kg; 20% bolus/80% infused over 30min) starting 1h following the injection of small-sized blood clots into the brain vasculature and terminal behavior was measured 2days following embolization. Behavioral rating scores were used to calculate the effective stroke dose (P50 in mg) that produces neurological deficits in 50% of the rabbits. RESULTS: In this study, tPA significantly (p=0.001) improved behavior compared to all other treatments including tPA vehicle, saline and saline-L-arginine, increasing the P50 by 141% over tPA vehicle. Saline-L-arginine was not significantly different from either saline or tPA vehicle (p>0.05). CONCLUSION: This study demonstrates that the L-arginine component of the tPA vehicle does not contribute to the reproducible clinical improvement observed following tPA administration in rabbits. Moreover, the administration of L arginine was not an effective method to promote behavioral recovery following embolic strokes in the stringent rabbit small clot stroke model, nor did L arginine exacerbate behavioral deficits or intracerebral hemorrhage in embolized rabbits. PMID- 25708987 TI - Focal transient CNS vessel leak provides a tissue niche for sequential immune cell accumulation during the asymptomatic phase of EAE induction. AB - Peripheral immune cells are critical to the pathogenesis of neurodegenerative diseases including multiple sclerosis (MS) (Hendriks et al., 2005; Kasper and Shoemaker, 2010). However, the precise sequence of tissue events during the early asymptomatic induction phase of experimental autoimmune encephalomyelitis (EAE) pathogenesis remains poorly defined. Due to the spatial-temporal constrains of traditional methods used to study this disease, most studies had been performed in the spine during peak clinical disease; thus the debate continues as to whether tissue changes such as vessel disruption represent a cause or a byproduct of EAE pathophysiology in the cortex. Here, we provide dynamic, high-resolution information on the evolving structural and cellular processes within the gray matter of the mouse cortex during the first 12 asymptomatic days of EAE induction. We observed that transient focal vessel disruptions precede microglia activation, followed by infiltration of and directed interaction between circulating dendritic cells and T cells. Histamine antagonist minimizes but not completely ameliorates blood vessel leaks. Histamine H1 receptor blockade prevents early microglia function, resulting in subsequent reduction in immune cell accumulation, disease incidence and clinical severity. PMID- 25708989 TI - Meningeal cells influence midbrain development and the engraftment of dopamine progenitors in Parkinsonian mice. AB - Dopaminergic neuroblasts, isolated from ventral midbrain fetal tissue, have been shown to structurally and functionally integrate, and alleviate Parkinsonian symptoms following transplantation. The use of donor tissue isolated at an age younger than conventionally employed can result in larger grafts - a consequence of improved cell survival and neuroblast proliferation at the time of implantation. However studies have paid little attention to removal of the meninges from younger tissue, due to its age-dependent tight attachment to the underlying brain. Beyond the protection of the central nervous system, the meninges act as a signaling center, secreting a variety of trophins to influence neural development and additionally impact on neural repair. However it remains to be elucidated what influence these cells have on ventral midbrain development and grafted dopaminergic neuroblasts. Here we examined the temporal role of meningeal cells in graft integration in Parkinsonian mice and, using in vitro approaches, identified the mechanisms underlying the roles of meningeal cells in midbrain development. We demonstrate that young (embryonic day 10), but not older (E12), meningeal cells promote dopaminergic differentiation as well as neurite growth and guidance within grafts and during development. Furthermore we identify stromal derived factor 1 (SDF1), secreted by the meninges and acting on the CXCR4 receptor present on dopaminergic progenitors, as a contributory mediator in these effects. These findings identify new and important roles for the meningeal cells, and SDF1/CXCR4 signaling, in ventral midbrain development as well as neural repair following cell transplantation into the Parkinsonian brain. PMID- 25708990 TI - LRIG3 modulates proliferation, apoptosis and invasion of glioblastoma cells as a potent tumor suppressor. AB - Leucine-rich repeats and immunoglobulin-like domains (LRIG) 3 gene is mapped to chromosome 12q13.2, a region that is frequently deleted in a subset of glioblastoma multiforme (GBM). It has been reported that perinuclear LRIG3 staining correlated with low WHO grade of glioma and better survival of the patients. However, the relationship between LRIG3 and glioma is not very clear. The purpose of this study is to demonstrate the impacts of LRIG3 on biological characteristics of glioma and its possible mechanisms. We found that transduction of LRIG3 into glioblastoma cells inhibited cell growth in vitro and in vivo, promoted cell apoptosis, and restrained cell invasion and migration. Further studies demonstrated that LRIG3 negatively regulated the epidermal growth factor receptor (EGFR) signaling pathway. Inhibition of EGFR could reduce the effects of LRIG3 knockdown on cell proliferation and EGFR signaling pathway. In conclusion, LRIG3 functions as a tumor suppressor by attenuating EGFR signaling pathway and the restoration of LRIG3 may offer therapeutic potential against malignant gliomas. PMID- 25708991 TI - Quantitative evaluation of the clinical efficacy of attention bias modification treatment for anxiety disorders. AB - BACKGROUND: Attention bias modification treatment (ABMT) is a novel treatment for anxiety disorders. Although a number of other meta-analytic reviews exist, the purpose of the present meta-analysis is to examine issues unaddressed in prior reviews. Specifically, the review estimates the efficacy of ABMT in clinically anxious patients and examines the effect of delivery context (clinic vs. home) on symptom reduction. METHODS: A literature search using PsychInfo and Web of Science databases was performed. Only randomized controlled trials (RCTs) examining dot-probe-based ABMT in clinically diagnosed anxious patients were included. From 714 articles located through the search, 36 ABMT studies were identified and 11 studies met inclusion criteria (N = 589 patients). RESULTS: ABMT was associated with greater clinician-rated reductions in anxiety symptoms relative to control training: between-groups effect (d = 0.42, P = .001, confidence interval (CI) = 0.18-0.66), contrast of within-group effects (Q = 7.25, P < .01). More patients in the treatment group no longer met formal diagnostic criteria for their anxiety disorder posttreatment relative to patients in the control condition (P < .05). Analyses of patients' self-reported anxiety were nonsignificant for the between-groups contrast (P = .35), and were at a trend level of significance for the contrast between the within-group effects (P = .06). Moderation analysis of the between-groups effect revealed a significant effect for ABMT delivered in the clinic (d = 0.34, P = 0.01, CI = 0.07-0.62), and a nonsignificant effect for ABMT delivered at home (d = -0.10, P = 0.40, CI = 0.33-0.13). CONCLUSIONS: The current meta-analysis provides support for ABMT as a novel evidenced-based treatment for anxiety disorders. Overall, ABMT effects are mainly evident when it is delivered in the clinic and when clinical outcome is evaluated by a clinician. More RCTs of ABMT in specific anxiety disorders are warranted. PMID- 25708993 TI - ECR 2015 Book of Abstracts - A - Postgraduate Educational Programme. PMID- 25708992 TI - Robust optimization in intensity-modulated proton therapy to account for anatomy changes in lung cancer patients. AB - BACKGROUND AND PURPOSE: Robust optimization for IMPT takes setup and range uncertainties into account during plan optimization. However, anatomical changes were not prospectively included. The purpose of this study was to examine robustness and dose variation due to setup uncertainty and anatomical change in IMPT of lung cancer. MATERIAL AND METHODS: Plans were generated with multi-field optimization based on planning target volume (MFO-PTV) and worst-case robust optimization (MFO-RO) on simulation computed tomography scans (CT0) for nine patients. Robustness was evaluated on the CT0 by computing the standard deviation of DVH (SD-DVH). Dose variations calculated on weekly CTs were compared with SD DVH. Equivalent uniform dose (EUD) change from the original plan on weekly dose was also calculated for both plans. RESULTS: SD-DVH and dose variation on weekly CTs were both significantly lower in the MFO-RO plans than in the MFO-PTV plans for targets, lungs, and the esophagus (p<0.05). When comparing EUD for ITV between weekly and planned dose distributions, three patients and 28% of repeated CTs for MFO-RO plans, and six patients and 44% of repeated CTs for MFO-PTV plans, respectively, showed an EUD change of >5%. CONCLUSIONS: RO in IMPT reduces the dose variation due to setup uncertainty and anatomy changes during treatment compared with PTV-based planning. However, dose variation could still be substantial; repeated imaging and adaptive planning as needed are highly recommended for IMPT of lung tumors. PMID- 25708994 TI - ECR 2015 Book of Abstracts - B - Scientific Sessions and Late-Breaking Clinical Trials. PMID- 25708995 TI - ECR 2015 Book of Abstracts - C - Scientific and Educational Exhibits. PMID- 25708996 TI - ECR 2015 Book of Abstracts - D - Satellite Symposia. PMID- 25708998 TI - ECR 2015 Book of Abstracts - F - List of Authors & Co-Authors. PMID- 25708999 TI - ECR 2015 Book of Abstracts - G - List of Moderators. PMID- 25709000 TI - [Regenerative therapy approaches in plastic surgery]. AB - BACKGROUND: The regeneration of tissue lost due to trauma or disease is considered as being ideal for reconstruction with respect to repair in which a donor defect arises in a different part of the body. Through a better understanding of the cellular and molecular mechanisms of healing, possibilities for regenerative therapies have been developed in recent years. OBJECTIVES: To give an exemplary representation of current regenerative therapy approaches and their effect and clinical application. MATERIAL AND METHODS: The PubMed database was searched for different regenerative approaches in plastic surgery and various methods are presented in this article. RESULTS: Cell-based approaches, in which autologous mesenchymal stem cells from adipose tissue are preferably used, led to excellent healing results with minimal donor site morbidity. Likewise, growth factor-based approaches or the use of platelet-rich plasma achieve very good results in the field of wound and bone healing. DISCUSSION: By using different cells or molecules and thus taking advantage of biological mechanisms, the regenerative capabilities of adult organisms could be improved. Many methods have already been implemented in clinical practice, not only in reconstructive but also in aesthetic surgery. However, the success should not conceal the potential risk that is inherent in both cell and growth factor-based approaches. Until long term experiences of such therapies have been acquired, they should be used cautiously. PMID- 25709001 TI - [Soft tissue plastic surgery for complications in the skull region]. AB - Tumor resection and trauma may leave devastating defects in the head and neck area complicating and preventing patient rehabilitation; therefore, plastic surgery methods are required which are able to prevent further complications and provide efficient functional and aesthetic reconstruction. In this review article typical cases and the interdisciplinary management of plastic surgery are presented. PMID- 25709002 TI - Calcium and phosphorus metabolism and lithogenic factors in patients with osteoporotic fracture. AB - OBJECTIVES: To demonstrate the attendance of mineral metabolism disorders and lithogenic factors in patients' urine with osteoporotic fracture without previously known stones MATERIAL AND METHODS: 67 patients with osteoporotic fractures surgically treated in trauma service are included. The area of the fracture site, fracture mechanism and the presence of osteoporosis were the factors taken into account to diagnose osteoporotic fracture. Mineral metabolism, calciuria, oxaluria, uricosuria and citraturia in 24hours urine were analyzed. The presence of abnormal calcium and phosphorus metabolism was proved comparing hypercalciuria patients with normocalciuria ones. RESULTS: 12 men and 55 women with mean age 68.8+/-14.5 years old were included. Mean Body Mass Index (BMI) was 27.4+/-4.1kg/m2. 42% of patients showed hypercalciuria, 34% hyperoxaluria, 34% hypocitraturia and 7% hyperuricosuria. Statistically significant differences were observed only in fasting calcium/creatinine ratio (0.17 vs. 0.08; P<.0001) when comparing patients with hypercalciuria with those with normocalciuria. CONCLUSIONS: Patients with osteoporotic fractures show different lithogenic factors in urine, mainly hypercalciuria, always in fasting conditions. PMID- 25709003 TI - Chyle leak after axillary lymph node dissection. PMID- 25709004 TI - Hands-free vein visualizer for selection of recipient vein with an intact valve in lymphatic supermicrosurgery. PMID- 25709005 TI - All-star lymphatic supermicrosurgery: Multiple lymph flow diversion using end-to end, end-to-side, side-to-end, and side-to-side lymphaticovenular anastomoses in a surgical field. PMID- 25709006 TI - Optimizing donor site outcomes after microsurgical proximal interphalangeal joint transfer using the bone-peg technique. PMID- 25709007 TI - Does upper blepharoplasty affect frontalis tonicity? AB - BACKGROUND: Frontalis hypertonicity has long been implicated in patients with significant dermatochalasia or blepharoptosis, as evidenced by eyebrow changes that occur after the resection of redundant skin or after blepharoptosis operation. However, whether upper blepharoplasty affects the forehead muscle has not been reported. Thus, this study investigated electrophysiology of the frontalis muscle and eyebrow morphology in a population of patients undergoing double-eyelid blepharoplasty. METHOD: Patients wishing to undergo upper blepharoplasty were recruited for this prospective study between June 2011 and February 2012. The subjects were excluded for complaints of visual obstruction, trauma history, and for any underlying medical condition that would affect eyebrow height or electromyogram (EMG) findings. Eyebrow morphology was ascertained in a standardized photogrammetric evaluation, and the frontalis muscle activity was recorded with needle EMG. These assessments were carried out at preoperation and at 2 weeks, 3 months, and 6 months. Root-mean-square (RMS) indices of various facial expressions were used to normalize the frontalis activity values across individuals. RESULTS: Thirteen patients with a mean age of 55.5 years were recruited. No statistical significance was observed for eyebrow heights at various assessment points. However, EMG recordings have demonstrated a gradual decrease in the proportional RMS index of the frontalis muscle activity. This difference was statistically significant between preoperation and 6 months postoperation (p < 0.05). CONCLUSION: Upper blepharoplasty was associated with gradual decreases in the frontalis muscle activity. A longer follow-up study is needed to evaluate whether this decreased tonicity results in morphologic changes such as decreased forehead wrinkles and depressed eyebrows. This research indicates that upper blepharoplasty has the potential to interfere with those human-computer interaction designs with facial EMG readings as an input. PMID- 25709009 TI - Bone formation of a porous Gelatin-Pectin-biphasic calcium phosphate composite in presence of BMP-2 and VEGF. AB - A composite scaffold of gelatin (Gel)-pectin (Pec)-biphasic calcium phosphate (BCP) was fabricated for the successful delivery of growth factors. Bone morphogenetic protein-2 (BMP-2) and vascular endothelial growth factor (VEGF) were coated on the Gel-Pec-BCP surface to investigate of effect of them on bone healing. Surface morphology was investigated by scanning electron microscopy, and BCP dispersion in the hydrogel scaffolds was measured by energy dispersive X-ray spectroscopy. The results obtained from Fourier transform infrared spectroscopy showed that BMP-2 and VEGF were successfully coated on Gel-Pec-BCP hydrogel scaffolds. MC3T3-E1 preosteoblasts were cultivated on the scaffolds to investigate the effect of BMP-2 and VEGF on cell viability and proliferation. VEGF and BMP-2 loaded on Gel-Pec-BCP scaffold facilitated increased cell spreading and proliferation compared to Gel-Pec-BCP scaffolds. In vivo, bone formation was examined using rat models. Bone formation was observed in Gel-Pec BCP/BMP-2 and Gel-Pec-BCP/VEGF scaffolds within 4 weeks, and was greatest with Gel-Pec-BCP/BMP-2 scaffolds. In vitro and in vivo results suggest that Gel-Pec BCP/BMP-2 and Gel-Pec-BCP/VEGF scaffolds could enhance bone regeneration. PMID- 25709008 TI - Real-time tracking of cell cycle progression during CD8+ effector and memory T cell differentiation. AB - The precise pathways of memory T-cell differentiation are incompletely understood. Here we exploit transgenic mice expressing fluorescent cell cycle indicators to longitudinally track the division dynamics of individual CD8(+) T cells. During influenza virus infection in vivo, naive T cells enter a CD62L(intermediate) state of fast proliferation, which continues for at least nine generations. At the peak of the anti-viral immune response, a subpopulation of these cells markedly reduces their cycling speed and acquires a CD62L(hi) central memory cell phenotype. Construction of T-cell family division trees in vitro reveals two patterns of proliferation dynamics. While cells initially divide rapidly with moderate stochastic variations of cycling times after each generation, a slow-cycling subpopulation displaying a CD62L(hi) memory phenotype appears after eight divisions. Phenotype and cell cycle duration are inherited by the progeny of slow cyclers. We propose that memory precursors cell-intrinsically modulate their proliferative activity to diversify differentiation pathways. PMID- 25709010 TI - Effect of diameter of poly(lactic acid) fiber on the physical properties of poly(E-caprolactone). AB - Biodegradable polymer composites based on poly(E-caprolactone) (PCL) and poly(lactic acid) (PLA) fibers with diameters of 18, 26, 180 MUm were prepared by melt compounding. The PLA fiber content in the composites was constant at 20% by weight. The effects of fibers with different diameters on the physical properties and enzymatic degradation of PCL were investigated. The morphological analysis indicated good interfacial adhesion between PCL and PLA fiber, which was beneficial to improve the physical properties of PCL. With increasing PLA fiber diameter, the complex viscosity and modulus of PCL were significantly increased, especially at low frequencies, indicating that the hindered effect of the fiber on the mobility of the PCL molecular chains was more obvious when PLA fiber diameter was thicker. However, as for the mechanical properties, the reinforcement was more obvious to PCL with the smaller PLA fiber diameter. This was because increasing efficient load transfer may be appeared due to the larger surface area and better interface bonding force of the fiber with thinner diameters. The enzymatic degradation of PCL was accelerated with the addition of large PLA fiber diameter of 26 and 180 MUm, and hardly changed with the small PLA fiber diameter of 18 MUm. PMID- 25709011 TI - Prevention effects of Schisandra polysaccharide on radiation-induced immune system dysfunction. AB - In this study, we investigate the efficacy of SP (Schisandra polysaccharide) in prevention of radiation-induced immune dysfunction and discussed the underlying mechanisms with a Bal/bc mouse model. The data demonstrated that SP could reverse the decreases in the number of white blood cells and lymphocytes in peripheral blood. In addition, the immunoglobulin G (IgG) and complement C3 in blood serum were all decreased after radiation and SP could restore this radiation disorder. Furthermore, SP could reverse the deregulation of CD3(+)CD4(+) and CD3(+)CD8(+) T cell subsets in peripheral blood and thymus of mice after radiotherapy. We also performed terminal dexynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) and Immunohistochemistry (IHC) to investigate the apoptosis and underlying mechanisms of SP in thymus. Data showed that radiation-induced apoptosis of thymocytes could be reversed by SP through inducing upregulation of Bcl-2 expression and downregulation of Fas and Bax levels. Furthermore, SP has no any side-effects on immunity of normal mice. In conclusion, our results indicated that SP could effectively prevent immune injury during radiotherapy by protecting the immune system. This valuable information should be of assistance in choosing a rational design for therapeutic interventions of prevention immune system damage in the radiation treatment. PMID- 25709012 TI - Design and characterization of self-assembled fish sarcoplasmic protein-alginate nanocomplexes. AB - Macrostructures based on natural polymers are subject to large attention, as the application range is wide within the food and pharmaceutical industries. In this study we present nanocomplexes (NCXs) made from electrostatic self-assembly between negatively charged alginate and positively charged fish sarcoplasmic proteins (FSP), prepared by bulk mixing. A concentration screening revealed that there was a range of alginate and FSP concentrations where stable NCXs with similar properties were formed, rather than two exact concentrations. The size of the NCXs was 293 +/- 3 nm, and the zeta potential was -42 +/- 0.3 mV. The NCXs were stable in water, gastric buffer, intestinal buffer and HEPES buffered glycose, and at all pH values from 2 to 9 except pH 3, where they aggregated. When proteolytic enzymes were present in the buffer, the NCXs were degraded. Only at high concentrations the NCXs caused a decreased viability in HeLa and U2OS cell lines. The simple processing procedure and the high stability of the NCXs, makes them excellent candidates for use in the food and pharmaceutical industry. PMID- 25709013 TI - A novel non-blue laccase from Bacillus amyloliquefaciens: secretory expression and characterization. AB - Laccases are copper-containing enzymes which possess a promising potential in many industrial and environmental applications. Here we describe the cloning, extracellular expression and characterization of a novel non-blue laccase from Bacillus amyloliquefaciens in Pichia pastoris. The recombinant enzyme was secreted into the culture supernatant with high activity. It lacks the absorption band at 610 nm typical for blue laccases. However, electron paramagnetic resonance (EPR) spectrum proved the existence of type 1 copper center that was not detectable in the UV-visible spectrum. Metal content analysis revealed that the enzyme contains two copper ions, one iron ion and one zinc ion per protein molecular, suggesting that it is a novel non-blue laccase. The pH and temperature optima of the recombinant laccase were 6.6 and 60 degrees C, respectively, and it was stable at pH 9.0 for 10 days. The enzyme activity was slightly activated by NaCl with concentration up to 200 mM. The purified laccase showed high efficiency in decolorizing reactive black 5 and indigo carmine, achieving more than 93% decolorization after 1h. The extreme robustness of the recombinant B. amyloliquefaciens laccase offers several advantages over most fungal laccases in various industrial applications. PMID- 25709014 TI - Nano-composite of silk fibroin-chitosan/Nano ZrO2 for tissue engineering applications: fabrication and morphology. AB - A scaffold possessing certain desired features such as biodegradation, biocompatibility, and porous structure could serve as a template for tissue engineering. In the present study, silk fibroin (SF), chitosan (CS) and zirconia (Nano ZrO2) were all combined using the freeze drying technique to fabricate a bio-composite scaffold. The composite scaffold (SF/CS/Nano ZrO2) was characterized by SEM, XRD, TGA, BET and FT-IR studies. The scaffold was found to possess a porous nature with pore dimensions suitable for cell infiltration and colonization. The presence of zirconia in the SF/CS/Nano ZrO2 scaffold led to an increase in compressive strength and water uptake capacity while at the same time decreasing the porosity. Cytocompatibility of the SF/CS/Nano ZrO2 scaffold, assessed by MTT assay, revealed non-toxicity to the Human Gingival Fibroblast (HGF, NCBI: C-131). Thus, we suggest that SF/CS/Nano ZrO2 composite scaffold is a potential candidate to be used for tissue engineering. PMID- 25709016 TI - Mechanical and antibacterial properties of novel high performance chitosan/nanocomposite films. AB - Zinc oxide (ZnO) nanoparticle was successfully synthesized using hydrothermal method as well as, silver (Ag) nanoparticle was direct prepared during chitosan nanocomposites preparation. Chitosan films were investigated by recognized the effect of kinds of acids (formic or acetic acid). Correspondingly, using of concentrated NaOH was checking for facilitating de-casting of the films. Utilization of formic acid arisen higher quality films than those films produced using acetic acid as solvent. Optimization was based on the mechanical properties for both types of acids solvent. Furthermore, the elasticity of the prepared films was enhanced by blending hydroxyl ethylcellulose (HEC) with chitosan. Loading the films by silver and zinc oxide nanoparticles (Ag-NPs and ZnO) was achieved during the preparation of films under the optimum conditions. Characterizations of the prepared ZnO nanoparticles and the prepared nanocomposites films were investigated by FT-IR, XRD, SEM, TEM and EDAX. Chitosan nanocomposite films displayed good Antimicrobial activity against Staphylococcus aureus, Escherichia coli, Salmonella typhamrium, Bacillus cereus, and Listeria monocyte. Therefore, these films can be used for packaging applications. PMID- 25709015 TI - Infection-mimicking poly(gamma-glutamic acid) as adjuvant material for effective anti-tumor immune response. AB - Bio-derived low molecular weight poly(gamma-glutamic acid) (gamma-PGA) was suggested as a novel adjuvant material for use in cancer vaccines. When the infection-mimicking gamma-PGA was immunized with ovalbumin (OVA) as a model antigen, increase in the dendritic cell (DC)-mediated functions such as activation, maturation, antigen uptake, migration to lymph nodes, and priming of lymphocytes, which included cross-presentation, was observed. These DC-mediated functions were found to be facilitated by gamma-PGA in a dose-dependent manner, with stimulation of toll-like receptor 4 (TLR4) being one of the underlying mechanisms. The in vivo efficacy of gamma-PGA was tested in a mouse tumor model where both arms of adaptive immunity (humoral and cell-mediated) were found to be significantly enhanced in the presence of gamma-PGA, indicating efficient priming of B and T cells. Moreover, immunization of mice with gamma-PGA followed by EG7 OVA tumor challenge led to dramatic inhibition of tumor growth. After 71 days, the cured mice were rechallenged with tumor cells at a distant site in order to test the memory effect. No tumor growth was observed, which indicates the presence of a systemic, long-lasting immune response. Based on these results, low molecular weight gamma-PGA is expected to have tremendous potential for applications in cancer immunotherapy. PMID- 25709017 TI - Effect of Ca2+ and Mg2+ ions on oligomeric state and chaperone-like activity of alphaB-crystallin in crowded media. AB - The main function of small heat shock proteins acting as suppressors of aggregation of non-native proteins is greatly influenced by crowded environment in the cell and the presence of divalent metal ions. The goal of the present work was to study the effects of Ca(2+) and Mg(2+) ions on the quaternary structure and anti-aggregation activity of alphaB-crystallin under crowding conditions. We showed that Ca(2+) and Mg(2+) ions induced formation of suboligomeric forms of alphaB-crystallin. This effect was retained in the presence of crowder (polyethylene glycol), although to a lesser degree. The chaperone-like activity of alphaB-crystallin was analyzed using heat-induced aggregation of myosin subfragment 1 (S1) at 40 degrees C. In the absence of crowding agents chaperone like activity of alphaB-crystallin exhibited low sensitivity to the presence of Ca(2+) and Mg(2+) ions. The addition of the crowding agents (polyethylene glycol 20000, Ficoll 70) dramatically increased S1 aggregation rates and significantly depressed anti-aggregation activity of alphaB-crystallin. Low concentrations of Ca(2+) (0.1mM) and Mg(2+) (10mM) partially restored the chaperone-like activity of alphaB-crystallin in the presence of crowders. This effect was observed at relatively low values of [alphaB-crystallin]/[S1] molar ratio, however, at [alphaB-crystallin]/[S1]>0.2 the stimulating effect of Ca(2+) became less pronounced. These findings might indicate that under crowded cell conditions different factors, including divalent cations, can effectively modulate chaperone like activity of protein chaperones, which otherwise cannot properly cope with crowding-provoked accelerated rates of substrates aggregation. PMID- 25709018 TI - Hepatoprotective effects of polysaccharides extracted from Zizyphus jujube cv. Huanghetanzao. AB - Jujube polysaccharides have been proved to have various bioactivities. This study was designed to evaluate the chemical composition and hepatoprotective function of the polysaccharides extracted from Zizyphus jujube cv. Huanghetanzao (HJP). The composition of HJP was determined as heteropolysaccharides with galactose and arabinose being the main components. The pretreatment of mice with HJP significantly (p<0.01) reduced the activities of serum hepatic AST, ALT, and LDH induced by CCl4 or acetaminophen (APAP) while the commercial liver-injury treatment drug silybin did not show any prevention effects. Mechanistic study results indicate that the administration of the CCl4- or APAP-injured mice with HJP enhanced SOD and GSH-Px and decreased MDA, indicating that anti-oxidation and detoxification could be the pathways for the liver protection observed. In addition, the liver prevention and treatment effects of HJP on the liver damage induced by CCl4 or APAP obtained from the liver enzyme analyses were confirmed by the hepatic histopathology studies in mice. Therefore, HJP could be used as a prevention and treatment agent for liver injury induced by liver toxic chemicals and drugs. PMID- 25709019 TI - Inhibitory effect of polysaccharide peptide (PSP) against Tobacco mosaic virus (TMV). AB - Polysaccharides are essential macromolecules present in all living organisms, and have many kinds of biological activities, such as anti-oxidation, hypoglycemic, enhancing immunity, anti-aging, anti-rheumatism, anti-cancer and so on. In this study, the antiviral activity of polysaccharide peptide (PSP) was tested, compared with Ningnanmycin, and firstly found it has a stronger antiviral activity by using half-leaf method and leaf disk method. Subsequently, the mechanism of antiviral activity of PSP was preliminarily studied. As a result, its antiviral effect was better than the commercial agent Ningnanmycin, despite of protective effect, curative effect and inactivation effect. On the other hand, PSP as a commercial anti-cancer drug could easily and rapidly get in large quantities by liquid fermentation, which makes the industrialized production feasible. Also PSP is less toxic, easily biodegradable and ecofriendly. All the results are suggesting that PSP has potential as a pesticide to be used for the control of plant virus in the future. PMID- 25709020 TI - Evidence of two oxidation states of copper during aggregation of hen egg white lysozyme (HEWL). AB - In vitro fibrillation of hen egg white lysozyme (HEWL) causes complete reduction of Cu(II) to Cu(I) at pH 7. Here in the present article, we have shown the presence of both Cu(II) and Cu(I) at pH 11 during fibrillation of HEWL using electron paramagnetic resonance and Raman spectroscopy. Our results suggest the existence of a partially reducing environment during fibrillation of hen egg white lysozyme at pH 11. The fibrillation process is governed by the pH of the solution and maximum fibrillation is found to occur at pH 11. Fibrils formed in the absence of Cu(II) were also found to cause significant hemolysis of RBC. PMID- 25709021 TI - Liposomal thymoquinone effectively combats fluconazole-resistant Candida albicans in a murine model. AB - The aim of the present study was to develop a novel liposomal formulation of thymoquinone (TQ) to treat fluconazole-susceptible and -resistant Candida albicans (C. albicans) infections. The liposomal preparation of TQ (Lip-TQ) was used against a fluconazole-susceptible or -resistant isolate of C. albicans. Various doses of fluconazole (0, 5, 10, 20 and 40 mg/kg) or free TQ or Lip-TQ (0, 1, 2 and 5mg/kg) were used to treat C. albicans infected mice. Mice were observed for 40 days post C. albicans infection, and their kidneys were assessed for the fungal load. Fluconazole showed anti-fungal activity against the drug susceptible, but not against the -resistant isolate of C. albicans. Free TQ showed its activity against both fluconazole-susceptible or -resistant C. albicans, however, Lip-TQ was found to be the most effective and imparted ~ 100% and ~ 90% survival of mice infected with fluconazole-susceptible and -resistant isolates of C. albicans, respectively. Mice treated with Lip-TQ showed highly reduced severity of infection in their tissue homogenates. Therefore, Lip-TQ may effectively be used in the treatment of C. albicans infections, including those which are not responding to fluconazole. PMID- 25709022 TI - Characterization of polycaprolactone/collagen fibrous scaffolds by electrospinning and their bioactivity. AB - Fibrous scaffolds for tissue engineering were fabricated using collagen extracted from Nile tilapia skin and polycaprolactone (PCL) by electrospinning. The scaffolds were characterized by scanning electron microscopy (SEM), ATR-Fourier transform infrared, X-ray diffraction, and differential scanning calorimetry. Diameters of PCL/collagen fibrous scaffolds (PCFSs) decreased from 987 +/- 274 to 689 +/- 299 nm with an increase in collagen content, crystallinity was low, and crystal size was small. All of the characteristic bands of PCL and collagen could be observed in PCFSs. Furthermore, PCFSs had a higher dehydration temperature (50 60 degrees C) than native collagen (32.5 degrees C). The ultimate tensile strength of PCFSs increased with an increase in collagen content. Circular dichroism and a degradation assay in vitro indicated that PCFSs had good stability and a low degradation rate. Cellular behavior on PCFSs was investigated by a MTT assay, SEM, and laser scanning confocal microscopy. The results indicated that the PCFSs could provide a suitable environment for the growth and viability of L929 fibroblasts, maintain good cell adhesion, and retain good biocompatibility. It implied the possibility of using PCFSs as a promising candidate for tissue engineering. PMID- 25709023 TI - Novel preparation and characterization of human hair-based nanofibers using electrospinning process. AB - Human hair-based biocomposite nanofibers (NFs) have been fabricated by an electrospinning technique. Aqueous keratin extracted from human hair was successfully blended with poly(vinyl alcohol) (PVA). The focus here is on transforming into keratin/PVA nanofibrous membranes and insoluble property of electrospun NFs. The resulting hair-based NFs were characterized using Fourier transform infrared (FT-IR) spectroscopy, scanning electron microscopy (SEM), X ray diffraction (XRD), differential scanning colorimetry (DSC), and thermogravimetric analysis (TGA). Toward the potential use of these NFs after cross-linking with various weight fractions of glyoxal, its physicochemical properties, such as morphology, mechanical strength, crystallinity, and chemical structure were investigated. Keratin/PVA ratio of 2/1 NFs with 6 wt%-glyoxal showed good uniformity in fiber morphology and suitable mechanical properties, and excellent antibacterial activity providing a potential application of hair based NFs in biomedical field. PMID- 25709024 TI - Catalytic and thermodynamic properties of glycosylated Bacillus cereus cyclodextrin glycosyltransferase. AB - Cyclodextrin glycosyltransferase (CGTase) was covalently coupled to five oxidized polysaccharides differing in structure and chemical nature. The conjugates were evaluated for the retained activity, kinetic and thermodynamic stability. The conjugated CGTase with oxidized dextran (MW 47000) had the highest retained specific activity (70.05%) and the highest half-life (T1/2) at 80 degrees C. Compared to the native enzyme, the conjugated preparation exhibited higher optimum temperature, lower activation energy (Ea), lower deactivation constant rate (kd), higher T1/2, and higher D values (decimal reduction time) within the temperature range of 60-80 degrees C. The values of thermodynamic parameters for irreversible inactivation of native and conjugated CGTase indicated that conjugation significantly decreased entropy (DeltaS*) and enthalpy of deactivation (DeltaH*). The results of thermodynamic analysis for cyclodextrin production from starch indicated that The enthalpy of activation (DeltaH*) and free energy of activation (DeltaG*), (free energy of transition state) DeltaG*E-T and (free energy of substrate binding) DeltaG*E-S values were lower for the conjugated CGTase. Similarly, there was significant impact on improvement of kcat, kcat/Km values. Both native and conjugated enzyme produce alpha cyclodextrin from starch. PMID- 25709025 TI - Ribotoxin restrictocin manifests anti-HIV-1 activity through its specific ribonuclease activity. AB - Restrictocin, a highly specific ribonuclease produced by Aspergillus restrictus, cleaves a single phosphodiester bond in a universally conserved stem and loop structure termed sarcin/ricin loop within the large ribosomal RNA of all organisms. In the current study, we demonstrate restrictocin to manifest anti-HIV 1 activity in two model cell systems. Using two mutants of restrictocin, we further show that the anti-HIV-1 activity of restrictocin is due to its specific ribonucleolytic activity. The study suggests that restrictocin is able to recognize region(s) within HIV-1 genome as its target. Restrictocin appears to have potential as a therapeutic antiviral agent against HIV-1. PMID- 25709028 TI - Solvation methods for protein-ligand docking. AB - Hydration has a significant impact on ligand binding within protein active sites. Specific water molecules and their placement within protein active sites have been shown to make specific contributions to the energetics of protein-ligand binding and need consideration in the design of efficient binding ligands. These specific nonbulk water molecules and their interactions are different and have more significant impact in ligand design than the generalized bulk solvation of ligand-protein systems. Proper theoretical description of the solvation effects of water within a ligand-binding pocket is a significant computational challenge. Recently, new computational methods have been developed which can more accurately describe the contribution of waters within a protein ligand site and lead to improved and enhanced ligand design and ranking in computational docking and to greater enrichment. PMID- 25709027 TI - Prognostic and Prediction Tools in Bladder Cancer: A Comprehensive Review of the Literature. AB - CONTEXT: This review focuses on risk assessment and prediction tools for bladder cancer (BCa). OBJECTIVE: To review the current knowledge on risk assessment and prediction tools to enhance clinical decision making and counseling of patients with BCa. EVIDENCE ACQUISITION: A literature search in English was performed using PubMed in July 2013. Relevant risk assessment and prediction tools for BCa were selected. More than 1600 publications were retrieved. Special attention was given to studies that investigated the clinical benefit of a prediction tool. EVIDENCE SYNTHESIS: Most prediction tools for BCa focus on the prediction of disease recurrence and progression in non-muscle-invasive bladder cancer or disease recurrence and survival after radical cystectomy. Although these tools are helpful, recent prediction tools aim to address a specific clinical problem, such as the prediction of organ-confined disease and lymph node metastasis to help identify patients who might benefit from neoadjuvant chemotherapy. Although a large number of prediction tools have been reported in recent years, many of them lack external validation. Few studies have investigated the clinical utility of any given model as measured by its ability to improve clinical decision making. There is a need for novel biomarkers to improve the accuracy and utility of prediction tools for BCa. CONCLUSIONS: Decision tools hold the promise of facilitating the shared decision process, potentially improving clinical outcomes for BCa patients. Prediction models need external validation and assessment of clinical utility before they can be incorporated into routine clinical care. PATIENT SUMMARY: We looked at models that aim to predict outcomes for patients with bladder cancer (BCa). We found a large number of prediction models that hold the promise of facilitating treatment decisions for patients with BCa. However, many models are missing confirmation in a different patient cohort, and only a few studies have tested the clinical utility of any given model as measured by its ability to improve clinical decision making. PMID- 25709026 TI - Recurrence patterns after open and robot-assisted radical cystectomy for bladder cancer. AB - BACKGROUND: Concerns remain whether robot-assisted radical cystectomy (RARC) compromises survival because of inadequate oncologic resection or alteration of recurrence patterns. OBJECTIVE: To describe recurrence patterns following open radical cystectomy (ORC) and RARC. DESIGN, SETTING, AND PARTICIPANTS: Retrospective review of 383 consecutive patients who underwent ORC (n=120) or RARC (n=263) at an academic institution from July 2001 to February 2014. INTERVENTION: ORC and RARC. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Recurrence-free survival estimates were illustrated using the Kaplan-Meier method. Recurrence patterns (local vs distant and anatomic locations) within 2 yr of surgery were tabulated. Cox regression models were built to evaluate the effect of surgical technique on the risk of recurrence. RESULTS AND LIMITATIONS: The median follow-up time for patients without recurrence was 30 mo (interquartile range [IQR] 5-72) for ORC and 23 mo (IQR 9-48) for RARC (p=0.6). Within 2 yr of surgery, there was no large difference in the number of local recurrences between ORC and RARC patients (15/65 [23%] vs 24/136 [18%]), and the distribution of local recurrences was similar between the two groups. Similarly, the number of distant recurrences did not differ between the groups (26/73 [36%] vs 43/147 [29%]). However, there were distinct patterns of distant recurrence. Extrapelvic lymph node locations were more frequent for RARC than ORC (10/43 [23%] vs 4/26 [15%]). Furthermore, peritoneal carcinomatosis was found in 9/43 (21%) RARC patients compared to 2/26 (8%) ORC patients. In multivariable analyses, RARC was not a predictor of recurrence. Limitations of the study include selection bias and a limited sample size. CONCLUSIONS: Within limitations, we found that RARC is not an independent predictor of recurrence after surgery. Interestingly, extrapelvic lymph node locations and peritoneal carcinomatosis were more frequent in RARC than in ORC patients. Further validation is warranted to better understand the oncologic implications of RARC. PATIENT SUMMARY: In this study, the locations of bladder cancer recurrences following conventional and robotic techniques for removal of the bladder are described. Although the numbers are small, the results show that the distribution of distant recurrences differs between the two techniques. PMID- 25709029 TI - Binding site druggability assessment in fragment-based drug design. AB - Target druggability refers to the propensity that a particular target is amenable to bind high-affinity drug-like molecules. A robust yet accurate computational assessment of target druggability would greatly benefit the fields of chemical genomics and drug discovery. Here, we illustrate a structure-based computational protocol to quantitatively assess the target binding-site druggability via in silico screening a fragment-like compound library. In particular, we provide guidelines, suggestions, and critical thoughts on different aspects of this computational protocol, including: construction of fragment library, preparation of target structure, in silico fragment screening, and analysis of druggability. PMID- 25709030 TI - Generating "fragment-based virtual library" using pocket similarity search of ligand-receptor complexes. AB - As the number of available ligand-receptor complexes is increasing, researchers are becoming more dedicated to mine these complexes to aid in the drug design and development process. We present free software which is developed as a tool for performing similarity search across ligand-receptor complexes for identifying binding pockets which are similar to that of a target receptor. The search is based on 3D-geometric and chemical similarity of the atoms forming the binding pocket. For each match identified, the ligand's fragment(s) corresponding to that binding pocket are extracted, thus forming a virtual library of fragments (FragVLib) that is useful for structure-based drug design. The program provides a very useful tool to explore available databases. PMID- 25709031 TI - Virtual fragment preparation for computational fragment-based drug design. AB - Fragment-based drug design (FBDD) has become an important component of the drug discovery process. The use of fragments can accelerate both the search for a hit molecule and the development of that hit into a lead molecule for clinical testing. In addition to experimental methodologies for FBDD such as NMR and X-ray Crystallography screens, computational techniques are playing an increasingly important role. The success of the computational simulations is due in large part to how the database of virtual fragments is prepared. In order to prepare the fragments appropriately it is necessary to understand how FBDD differs from other approaches and the issues inherent in building up molecules from smaller fragment pieces. The ultimate goal of these calculations is to link two or more simulated fragments into a molecule that has an experimental binding affinity consistent with the additive predicted binding affinities of the virtual fragments. Computationally predicting binding affinities is a complex process, with many opportunities for introducing error. Therefore, care should be taken with the fragment preparation procedure to avoid introducing additional inaccuracies.This chapter is focused on the preparation process used to create a virtual fragment database. Several key issues of fragment preparation which affect the accuracy of binding affinity predictions are discussed. The first issue is the selection of the two-dimensional atomic structure of the virtual fragment. Although the particular usage of the fragment can affect this choice (i.e., whether the fragment will be used for calibration, binding site characterization, hit identification, or lead optimization), general factors such as synthetic accessibility, size, and flexibility are major considerations in selecting the 2D structure. Other aspects of preparing the virtual fragments for simulation are the generation of three-dimensional conformations and the assignment of the associated atomic point charges. PMID- 25709032 TI - Fragment library design: using cheminformatics and expert chemists to fill gaps in existing fragment libraries. AB - Fragment based screening (FBS) has emerged as a mainstream lead discovery strategy in academia, biotechnology start-ups, and large pharma. As a prerequisite of FBS, a structurally diverse library of fragments is desirable in order to identify chemical matter that will interact with the range of diverse target classes that are prosecuted in contemporary screening campaigns. In addition, it is also desirable to offer synthetically amenable starting points to increase the probability of a successful fragment evolution through medicinal chemistry. Herein we describe a method to identify biologically relevant chemical substructures that are missing from an existing fragment library (chemical gaps), and organize these chemical gaps hierarchically so that medicinal chemists can efficiently navigate the prioritized chemical space and subsequently select purchasable fragments for inclusion in an enhanced fragment library. PMID- 25709033 TI - Protocol for fragment hopping. AB - Fragment hopping is a fragment-based approach to designing biologically active small molecules. The key of this approach is the determination of the minimal pharmacophoric elements in the three-dimensional space. Based on the derived minimal pharmacophoric elements, new fragments with different chemotypes can be generated and positioned to the active site of the target protein. Herein, we detail a protocol for performing fragment hopping. This approach can not only explore a wide chemical space to produce new ligands with novel scaffolds but also characterize and utilize the delicate differences in the active sites between isofunctional proteins to produce new ligands with high target selectivity/specificity. PMID- 25709035 TI - A computational fragment-based de novo design protocol guided by ligand efficiency indices (LEI). AB - We present a new protocol aimed at the structure-based design of drug-like molecules using a fragment approach. It starts from a suitably placed and well defined "base fragment" and then uses an incremental construction algorithm and a scoring function to grow the molecule into prioritized candidates. The selection of the most promising solutions for synthesis and validation is guided by the optimization of the calculated ligand efficiency indices known as binding efficiency index (BEI) and surface efficiency index (SEI), which allow the user to navigate proficiently in chemico-biological space. A test case for the protocol is exemplified here using published data for inhibitors of protein kinase B, aka AKT, a key enzyme in several signal transduction pathways. Our procedure was able to identify the main features responsible for the binding of inhibitors and guided the selection process towards molecules that included or resembled those shown as the most active in the original studies. PMID- 25709034 TI - Site Identification by Ligand Competitive Saturation (SILCS) simulations for fragment-based drug design. AB - Fragment-based drug design (FBDD) involves screening low molecular weight molecules ("fragments") that correspond to functional groups found in larger drug like molecules to determine their binding to target proteins or nucleic acids. Based on the principle of thermodynamic additivity, two fragments that bind nonoverlapping nearby sites on the target can be combined to yield a new molecule whose binding free energy is the sum of those of the fragments. Experimental FBDD approaches, like NMR and X-ray crystallography, have proven very useful but can be expensive in terms of time, materials, and labor. Accordingly, a variety of computational FBDD approaches have been developed that provide different levels of detail and accuracy.The Site Identification by Ligand Competitive Saturation (SILCS) method of computational FBDD uses all-atom explicit-solvent molecular dynamics (MD) simulations to identify fragment binding. The target is "soaked" in an aqueous solution with multiple fragments having different identities. The resulting computational competition assay reveals what small molecule types are most likely to bind which regions of the target. From SILCS simulations, 3D probability maps of fragment binding called "FragMaps" can be produced. Based on the probabilities relative to bulk, SILCS FragMaps can be used to determine "Grid Free Energies (GFEs)," which provide per-atom contributions to fragment binding affinities. For essentially no additional computational overhead relative to the production of the FragMaps, GFEs can be used to compute Ligand Grid Free Energies (LGFEs) for arbitrarily complex molecules, and these LGFEs can be used to rank order the molecules in accordance with binding affinities. PMID- 25709036 TI - Scoring functions for fragment-based drug discovery. AB - Fragment-based drug design represents a challenge for computational drug design because almost inevitably fragments will be weak binders to the biomolecular targets of a specific disease, and the performances of the scoring functions for weak binders are usually poorer than those for the stronger binders. This protocol describes how to predict the binding modes and binding affinities of fragments towards their binding partner with our refined AutoDock scoring function incorporating a quantum chemical charge model, namely, the restrained electrostatic potential (RESP) model. This scoring function was calibrated by robust regression analysis and has been demonstrated to perform well for general classes of protein-ligand interactions and for weak binders (with root-mean square of error of about 2.1 kcal/mol). PMID- 25709037 TI - Computational methods for fragment-based ligand design: growing and linking. AB - Fragment-based drug design has proved itself as a powerful technique for increasing the sampling and diversity of chemical space and enabling the design of novel leads and compounds. Computational techniques for identifying fragments, binding sites and particularly for linking, growing, and evolving fragments play a significant role in the process. Information from ADME studies and clustering property information in the form of toxicophores and chemotypes can play a significant role in aiding the design of novel, selective fragments with good activity profiles. PMID- 25709038 TI - Design strategies for computational fragment-based drug design. AB - The computational design method described in this chapter is an approach to de risking the design process due to the limitations of current computational algorithms with respect to predictive accuracy. The method takes advantage of the crystallographically demonstrated interactions between a ligand and its protein target, and through systematic, one fragment replacements allows for quick feedback on the direction of the designs. This design approach can still be useful in the future as computational algorithms improve and become more predictive and reliable. PMID- 25709039 TI - Protein binding site analysis for drug discovery using a computational fragment based method. AB - One of the most powerful tools for designing drug molecules is an understanding of the target protein's binding site. Identifying key amino acids and understanding the electronic, steric, and solvation properties of the site enables the design of potent ligands. Of equal importance for the success of a drug discovery program is the evaluation of binding site druggability. Determining, a priori, if a particular binding site has the appropriate character to bind drug-like ligands saves research time and money.While there are a variety of experimental and computational techniques to identify and characterize binding sites, the focus of this chapter is on Binding Site Analysis (BSA) using virtual fragment simulations. The methodology of the technique is described, along with examples of successful application to drug discovery programs. BSA both indicates if a protein is a viable target for drug discovery and provides a roadmap for designing ligands. Using a computational fragment-based method is a effective means of understanding of a binding site. PMID- 25709040 TI - Fragment-based design of kinase inhibitors: a practical guide. AB - Fragment-based drug design has become an important strategy for drug design and development over the last decade. It has been used with particular success in the development of kinase inhibitors, which are one of the most widely explored classes of drug targets today. The application of fragment-based methods to discovering and optimizing kinase inhibitors can be a complicated and daunting task; however, a general process has emerged that has been highly fruitful. Here a practical outline of the fragment process used in kinase inhibitor design and development is laid out with specific examples. A guide to the overall process from initial discovery through fragment screening, including the difficulties in detection, to the computational methods available for use in optimization of the discovered fragments is reported. PMID- 25709041 TI - Designing a small molecule erythropoietin mimetic. AB - Erythropoietin (EPO) is a protein made by the kidneys in response to low red blood cell count that is secreted into the bloodstream and binds to a receptor on hematopoietic stem cells in the bone marrow inducing them to become new red blood cells. EPO made with recombinant DNA technology was brought to market in the 1980s to treat anemia caused by kidney disease and cancer chemotherapy. Because EPO infusion was able to replace blood transfusions in many cases, it rapidly became a multibillion dollar per year drug and as the first biologic created with recombinant technology it launched the biotech industry. For many years intense research was focused on creating a small molecule orally available EPO mimetic. The Robert Wood Johnson (RWJ) group seemed to definitively establish that only large peptides with a minimum of 60 residues could replace EPO, as anything less was not a full agonist. An intense study of the published work led me to hypothesize that the size of the mimetic is not the real issue, but the symmetry making and breaking of the EPO receptor induced by the ligand is the key to activating the stem cells. This analysis meant that residues in the binding site of the receptor deemed absolutely essential for ligand binding and activation from mutagenesis experiments, were probably not really that important. My fundamental hypotheses were: (a) the symmetric state of the homodimeric receptor is the most stable state and thus must be the off-state, (b) a highly localized binding site exists at a pivot point where the two halves of the receptor meet, (c) small molecules can be created that have high potency for this site that will be competitive with EPO and thus can displace the protein-protein interaction, (d) small symmetric molecules will stabilize the symmetric off-state of the receptor, and (e) a key asymmetry in the small molecule will stabilize a mirror image asymmetry in the receptor resulting in the stabilization of the on-state and proliferation of the stem cells into red blood cells. Researchers at Amgen published a co-crystal structure of EPO bound to the EPO receptor, which has a beautiful twofold symmetry-it was argued that this is the active state of the receptor. Activating the EPO receptor with EPO induces an almost instantaneous shutdown mechanism to sharply curtail any proliferative signal transduction, and thus, my hypotheses lead to the conclusion that the Amgen co-crystal is actually the state after receptor downregulation and thus an off-state. To put these hypotheses to the test, my computational method of Simulated Annealing of Chemical Potential was run using the co-crystal created at RWJ, which is the receptor trapped in a partial agonist state. The simulations predicted a previously unknown high affinity binding site at the pivot point where the two halves of the dimeric receptor meet, and detailed analysis of the fragment patterns led to the prediction of a molecule less than 300 MW that is basically twofold symmetric with a chiral center on one side and not the other. Thus, to the degree that computer simulations can be taken seriously, these results support my hypotheses on small molecule receptor activation. When this small molecule was synthesized and tested it indeed induced human hematopoietic stems cells to become red blood cells. When the predicted chiral center of this molecule was removed eliminating its one asymmetric feature, the resulting molecule was an antagonist-it could potently displace hot EPO but could no longer induce stem cell proliferation and differentiation. These results provided strong support for my theories on how to create potent small molecule EPO agonists and were used to launch the new company Locus Pharmaceuticals. These molecules, however, required significant chemical changes in order to make them stable in other in vitro assays and to be in vivo active, but these alterations had to be done in a way that maintained the symmetry-asymmetry considerations that led to the creation of an in vitro active molecule. The combination of changing functional groups to enable good pharmacokinetics, while not changing the key intrinsic symmetry properties were never seriously pursued at Locus and the program died. Investigations into how red blood cells are created have occupied many prominent researchers for the entire twentieth century. In the second half of the century EPO was discovered and by the end of the century it became a blockbuster commercial product that launched the biotech revolution. PMID- 25709042 TI - Designing an orally available nontoxic p38 inhibitor with a fragment-based strategy. AB - The MAPK p38 became a focal point of inflammatory research when it was recognized that it played a key role in the production of the pro-inflammatory molecules TNF alpha, IL-beta, and cyclooxygenase-2 (COX-2). The pharmaceutical industry devoted enormous efforts to creating p38 inhibitors, because blocking p38 had the potential of downregulating a group of pro-inflammatory mediators, and thus, one drug could have a cocktail effect. The market potential seemed to be clearly established (Bonafede et al., Clinicoecon Outcomes Res 6:381-388, 2014) with a multiplicity of TNF-alpha antibodies and a soluble receptor (Mewar and Wilson, Br J Pharmacol 162:785-791, 2011) already on the market, although the relationship between TNF-alpha production and p38 activation is a complicated two-way (Sabio and Davis, Semin Immunol 26:237-245, 2014) signal transduction process. With the discovery that activated p38 stabilizes (Mancini and Di Battista, Inflamm Res 60:1083-1092, 2011) COX-2 mRNA and upregulates expression of IL-beta (Bachstetter and Van Eldik, Aging Dis 1:199-211, 2010) probably in a similar manner, inhibiting p38 appeared to be a way of blocking TNF-alpha, COX-2, and IL-beta simultaneously. At Locus Pharmaceuticals we jumped on this opportunity, because we believed that our fragment-based drug discovery approach was ideally suited for making a potent small molecule p38 inhibitor that did not bind in the ATP site, but also had the solubility, lack of planarity, and low molecular weight required of a clinical candidate. Just to be clear, in our experience highly planar compounds often result in poor pharmacokinetics, because they tend to bind strongly to plasma proteins. At Locus we typically repeated assays by adding increasing amounts of plasma to check for potency degradation in the presence of blood. We found this to be a useful early indicator of pharmacokinetics and in vivo behavior. It became clear from our work and the work of others that binding to the ATP site resulted in nonspecific isoform toxicities, but binding in the adjacent allosteric DFG-site resulted in molecules that were too planar and too hydrophobic. Applying the computational method of Simulated Annealing of Chemical Potential (SACP) to this problem, we at Locus were able to come up with surprising fragment substitution patterns that led to potent non-ATP p38 inhibitors with the solubility and lack of planarity that resulted in potent in vivo efficacy in rodents with 33 % oral bioavailability. By using the simulations, we made only a small number of molecules and created a high quality clinical candidate. We also did extensive co-crystallography work, which demonstrated that the compounds bound in the mode predicted by the simulations. Unfortunately, all p38 programs ultimately shut down, because compelling evidence emerged that inhibiting p38 had no long-term clinical (Genovese, Arthritis Rheum 60:317-320, 2009) benefit. Devoting a large amount of limited resources to a target that ultimately turns out to be a mistake because it was not properly validated is a fatal error for a small company, and this is one of the reasons that Locus ultimately failed. PMID- 25709043 TI - Association between autoantibodies and neuropsychiatric manifestations of autoimmune disease: comment on the article by Lauvsnes et al. PMID- 25709044 TI - Feasibility study and pilot randomised trial of an antenatal depression treatment with infant follow-up. AB - Substantial evidence links antenatal depression, anxiety and stress with negative effects on foetal development, resulting in enduring problems in child development. Despite this, there is a paucity of research on intervention programmes designed to address depression and anxiety, and none that include infant outcomes. We aimed to evaluate the efficacy of a brief treatment for maternal depression and anxiety in pregnancy in a sample of women with a diagnosed depressive disorder. We developed a cognitive behavioural therapy treatment for antenatal depression and anxiety and evaluated it in a feasibility trial. This was followed by a pilot randomised controlled trial (RCT) which collected data on the efficacy of the brief intervention and follow-up data on infants. The feasibility study (n = 25) yielded promising results for adherence, acceptability and improvements in depression and anxiety (Beck Depression Inventory and Beck Anxiety Inventory). The RCT (n = 54) again showed excellent adherence and acceptability and supported the efficacy of the treatment. Strong reductions in anxiety were observed during pregnancy, and improvements in depression were maintained at 9 months representing a moderately large effect size. Nine-month infant outcomes showed several medium to large effects favouring the intervention in domains including problem solving, self-regulation and stress reactivity, which were independent of maternal postnatal mood. Treating severe depression and anxiety during pregnancy with a brief cognitive behavioural therapy (CBT) intervention appears feasible and worthwhile. To reliably detect clinically meaningful effects on infant outcomes, larger RCTs are likely to be required. PMID- 25709045 TI - Family history of prostate cancer in men being followed by active surveillance does not increase risk of being diagnosed with high-grade disease. AB - OBJECTIVE: To assess whether men with a family history of prostate cancer are more likely to fail active surveillance because of recategorization of their tumors on subsequent surveillance biopsies. METHODS: Men enrolled in an institutional review board-approved active surveillance program were studied, and data on first- and/or second-degree family history of prostate cancer was collected. Analyses were performed to compare the frequency of family history with recategorization (higher grade or volume disease) on surveillance biopsies. RESULTS: Men with and without family history were recategorized with higher grade disease at a similar frequency (30.9% vs 32.8%). There was no evidence that men with a family history with higher grade disease had more aggressive pathology at the time of radical prostatectomy than men without a family history. Although those with a family history tended to have a shorter time period to recategorization with more positive cores, the difference was not significant. CONCLUSION: Our results suggest that men with a family history of prostate cancer are not at an increased risk for recategorization on active surveillance. Men with a family history of prostate cancer should not be deterred from considering active surveillance as a treatment option. PMID- 25709046 TI - Ureteral reimplantation before bladder neck reconstruction in modern staged repair of exstrophy patients: indications and outcomes. AB - OBJECTIVE: To evaluate a single referral center's experience with vesicoureteral reflux (VUR) and its role in management before bladder neck reconstruction (BNR) in exstrophy patients after modern staged repair of exstrophy (MSRE). VUR after primary closure of bladder exstrophy can usually be managed conservatively until ureteral reimplantation (UR) at the time of BNR. However, VUR in these patients is occasionally associated with febrile urinary tract infection and worsening renal function necessitating UR before BNR. MATERIALS AND METHODS: A total of 199 patients who underwent MSRE were identified from an institutional review board approved database. Patient demographics, closure history, postprimary closure VUR, history of urinary tract infection, cystography outcomes, renal function, history of UR before BNR, and UR outcomes were recorded. Univariate and multivariate analyses were performed to determine factors predicting high-grade VUR and the need for pre-BNR UR. RESULTS: After primary closure, VUR was observed in 150 patients (75.4%) of whom 31 (15.58%) had high-grade VUR. Closure without osteotomy and postclosure outlet obstruction were independently associated with postprimary closure high-grade VUR (P <.05). Twenty-two patients (11.06%) required pre-BNR UR. Female gender and those with high-grade VUR were more likely to require UR before BNR (P <.05). Early UR did not affect the continence rate. CONCLUSION: VUR after exstrophy closure can generally be managed with conservative treatment and periodic monitoring of the upper urinary tracts. About 11% of patients undergoing MSRE will require UR before BNR. Closure without osteotomy and patients who develop outlet obstruction after closure are at increased risk for developing high-grade VUR. PMID- 25709047 TI - Editorial comment. PMID- 25709048 TI - Reply: To PMID 25709045. PMID- 25709049 TI - Microsurgical varicocelectomy with transfixing of the difficult-to-isolate periarterial vein using microsutures. AB - OBJECTIVE: To address difficulty in isolating the adhered periarterial vein in microsurgical subinguinal varicocelectomy, we introduced the transfixing microsuture method as well as to evaluate the impact of this technical modification on the surgical success of varicocele repair. MATERIALS AND METHODS: We retrospectively evaluated 4 patients with a mean age of 31.5 years who underwent subinguinal varicocelectomy with transfixion of the difficult-to isolate periarterial vein (a 9-0 transfixing microsuture was placed transversely through the periarterial vein as near to the adjacent border between the testicular artery and adherent vein as possible; then, it was knotted to nick or completely ligate the lumen.) The incidence of recurrence or persistence, postoperative hydrocele formation, sperm improvement, and symptom release was analyzed. RESULTS: In 4 cases, the periarterial vein transfixing procedures were performed with a mean follow-up of 6 months. No postoperative recurrence or hydrocele was identified postoperatively. One patient reported no symptom improvement, but there was significant improvement in the symptoms and/or semen parameters in the other 3 patients. Postoperative ultrasonography evaluation revealed that there was no postoperative varicocele recurrence or persistence, no hydrocele formation, and no testicular atrophy. CONCLUSION: When the adhered periarterial vein is difficult to isolate and ligate, transfixing the vein with a microsuture in microsurgical subinguinal varicocelectomy is a viable compromise that reduces the incidence of postoperative recurrence or persistence without serious complications. PMID- 25709050 TI - Urodynamic evaluation of the efficacy of mirabegron on storage and voiding functions in women with overactive bladder. AB - OBJECTIVE: To investigate the effects of mirabegron (50 mg once daily for 12 weeks) in treatment-naive women with overactive bladder (OAB) based on urodynamic studies. METHODS: This was an open-labeled, single-center, prospective study involving 65 recruited outpatients. The OAB symptom score was used for assessing the severity of subjective symptoms. Urodynamic studies, including uroflowmetry, cystometry, and pressure flow study, were conducted to evaluate objective symptoms. The first desire to void, maximum cystometric capacity, and occurrence of detrusor overactivity were measured as storage function parameters, whereas maximum flow rate, detrusor pressure at Qmax, and postvoid residual urine volume were assessed as voiding function parameters. RESULTS: A total of 60 patients with a mean age of 72.3 years (50-86 years) were included in the analysis. The subjective symptom parameter (ie, the mean OAB symptom score) decreased significantly from 9.4 to 6.2 points (P <.001). In objective symptom parameters, both the first desire to void and maximum cystometric capacity significantly improved after treatment, and detrusor overactivity disappeared in 14 of 35 patients (40.0%) compared with that at baseline (P <.01). The voiding function parameters (ie, mean maximum flow rate, detrusor pressure at Qmax, and postvoid residual urine volume) did not significantly change, demonstrating that mirabegron does not inhibit voiding function. CONCLUSION: Mirabegron improves storage function and subjective symptoms, without influencing voiding function, in women with OAB. PMID- 25709051 TI - Current and Emerging Immunotherapies for Castration-resistant Prostate Cancer. AB - Despite advances in castration-resistant prostate cancer (CRPC) treatment, therapies that provide long-term survival are still needed. In 2010, sipuleucel-T was approved for CRPC on the basis of improved overall survival. Recently, new immunotherapeutic approaches have emerged with perhaps the most exciting being immune-checkpoint inhibition. Here, we provide an overview of immunotherapies for CRPC, with a focus on immune-checkpoint inhibition with ipilimumab. We consider how experience with ipilimumab in melanoma might inform future use in CRPC and describe ongoing phase 3 trials. Finally, we discuss the potential for improved antitumor activity when ipilimumab is combined with hormonal or bone-targeted agents. PMID- 25709052 TI - Antidiabetic drug metformin inhibits esophageal adenocarcinoma cell proliferation in vitro and in vivo. AB - Esophageal carcinoma is the eighth most common cancer worldwide and the sixth leading cause of cancer-related deaths, with one of the worst prognoses of any form of cancer. Treatment with the anti-diabetic drug metformin has been associated with reduced cancer incidence in patients with type 2 diabetes. This study therefore evaluated the effects of metformin on the proliferation, in vitro and in vivo, of human esophageal adenocarcinoma cells, as well as the microRNAs associated with the antitumor effects of metformin. Metformin inhibited the proliferation of the esophageal adenocarcinoma cell lines OE19, OE33, SK-GT4 and OACM 5.1C, blocking the G0 to G1 transition in the cell cycle. This was accompanied by strong reductions in G1 cyclins, especially cyclin D1, cyclin dependent kinase (Cdk)4, and Cdk6, and decreases in retinoblastoma protein phosphorylation. In addition, metformin reduced the phosphorylation of epidermal growth factor receptor and insulin-like growth factor and insulin-like growth factor-1 receptor, as well as angiogenesis-related proteins, such as vascular endothelial growth factor, tissue inhibitor of metalloproteinases (TIMP)-1, and TIMP-2. Metformin also markedly altered microRNA expression. Treatment with metformin of athymic nude mice bearing xenograft tumors reduced tumor proliferation. These findings suggest that metformin may have clinical use in the treatment of esophageal adenocarcinoma. PMID- 25709053 TI - Phylogenetic diversity of Archaea in the intestinal tract of termites from different lineages. AB - Termites are among the few arthropods that emit methane to the atmosphere, which is a significant source of global greenhouse gas due to their huge biomass on earth. In this study, phylogenetic diversity of Archaea of five termite species from different lineages were analyzed based on 16S rRNA genes. Archaea associated with wood-feeding lower termite, R. chinensis were exclusively Methanobrevibacter in the order Methanobacteriales. This type of methanogens was also found in Nasutitermes sp. and Microcerotermes sp. but not in the fungus-cultivating termites, Odontotermes formosanus and Macrotermes barneyi, which harbor Archaea of the order Methanoplasmatales and Methanosarcinales in their guts. Archaeal diversity of wood-feeding higher termites was higher than wood-feeding lower termites. The highest archaeal diversity was found in Nasutitermes sp. In addition to methanogens affiliated with the orders Methanobacteriales, Methanomicrobiales, and Methanoplasmatales, 37% of archaeal clones were affiliated with non-methanogenic Thaumarchaeota. The results of this study will be significant for further understanding of symbiotic relationship between intestinal microbiota and termites. PMID- 25709054 TI - Comparison of resistance training progression models on maximal strength in sub elite adolescent rugby union players. AB - OBJECTIVES: To determine changes in maximal strength between two different resistance training progression models, linear (LP) and daily undulating (DUP), over a 12-week resistance training programme in sub-elite adolescent rugby union players. DESIGN: The study used a quasi-experimental study design. Following baseline assessments, participants from Squad 1 were randomised to either LP or DUP; participants from Squad 2 formed a non-randomised comparison group (CON). METHODS: Participants were 26 sub-elite adolescent rugby union players who were assessed at baseline and after 12 weeks. Outcomes included 5 repetition maximum (RM) box squat and bench press, height, body weight, skeletal muscle mass, percentage body fat and maturation status. RESULTS: Participants in both the LP and DUP groups significantly increased their squat and bench press strength from baseline to 12 weeks. There were no significant differences between groups for squat and bench press increases after 12 weeks (p>0.05). No significant increases in squat or bench press strength were observed after 12 weeks in the CON group. Increases in lower body strength were large in the LP group (ES: 1.64) and very large in the DUP group (ES: 2.33). Upper body strength changes were small in both groups (LP, ES: 0.57; DUP, ES: 0.31). CONCLUSIONS: Twelve weeks of LP or DUP resistance training are both effective at increasing maximal lower and upper body strength in adolescent rugby athletes. Additionally, twice weekly frequency of resistance training in adolescent rugby athletes with greater than 6-months resistance training experience is sufficient to elicit substantial increases in maximal strength. PMID- 25709055 TI - Enhanced Exercise Therapy in Parkinson's disease: A comparative effectiveness trial. AB - OBJECTIVES: Exercise can improve motor function in people with Parkinson's disease but depression reduces the motivation to participate in regular exercise. The aim of this study was to develop a novel Enhanced Exercise Therapy program that uses manual-driven guided exercise and peer-facilitated psychoeducation for individuals with Parkinson's disease and depression. DESIGN: 24 week randomized controlled design. METHODS: Thirty individuals were randomized to Enhanced Exercise Therapy or self-guided therapy, and evaluated at baseline, 12-weeks and at 24-weeks. Enhanced Exercise Therapy included group exercise and group psychoeducation for 12 weeks. Between 13 and 24 weeks, individuals had access to the fitness facility but group sessions were not held. Self-guided therapy included written guidelines for a self-paced exercise program and psychoeducation. Primary outcome measures included the number of exercise sessions and International Physical Activity Questionnaire score. Secondary measures included resting heart rate, supine blood pressure, estimated VO2max and incidence of orthostatic hypotension. RESULTS: Twenty four individuals completed the study (80% retention) and both groups attended similar number of exercise sessions. There were no significant changes in cardiovascular fitness measures but there was a significant increase in the amount of physical activity in the Enhanced Exercise Therapy group and a decrease in the self-guided therapy group during the post-intervention period. CONCLUSIONS: Enhanced Exercise Therapy appears to promote engagement in an exercise program and more physical activity, even after group sessions were concluded in individuals with Parkinson's disease and depression. PMID- 25709056 TI - Ischemic stroke related to an amniotic fluid embolism during labor. AB - We report a young woman who survived multiple cerebral infarctions related to an amniotic fluid embolism (AFE) during labor. To our knowledge, an embolic stroke due to the coexistence of an AFE and patent foramen ovale (PFO) has not been reported. We describe the patient's clinical and radiological features and discuss the stroke mechanism in relation to our AFE hypothesis. A 32-year-old woman presented to the emergency room after experiencing convulsions during labor (blood pressure, 64/28mmHg; oxygen saturation, 67%). She was in a stupor, and her response to painful stimuli on the right side was weaker than on the left side. Acute stroke was considered as a possible cause. Additionally, an AFE was suspected due to cardiopulmonary arrest during labor. Brain MRI revealed multiple territory embolic infarctions. The transcranial Doppler with bubble study demonstrated a right-to-left shunt during the Valsalva maneuver. A transesophageal echocardiogram revealed a PFO with a right-to-left shunt. The elevated intrathoracic pressure during labor may have caused blood to flow backward through the heart, shunting blood from the right side to the left through the PFO. In cases such as this, an amniotic fluid embolus may travel directly from the venous to the arterial circulation via the PFO, leading to multiple cerebral infarctions. PMID- 25709057 TI - Intracardiac migration and knotting of a ventriculoperitoneal shunt. AB - We report a patient with delayed migration of the distal ventriculoperitoneal shunt catheter from the peritoneum to the right atrium with associated knotting of the catheter complicating removal. We also review the literature on this topic. PMID- 25709059 TI - Investigation of the utility of complementary electrochemical detection techniques to examine the in vitro affinity of bacterial flagellins for a toll like receptor 5 biosensor. AB - An initial investigation of the fabrication of a novel biosensor utilizing toll like receptor 5 (TLR5) has been conducted. The detection assay using this sensor platform has been carried out using two complementary electrochemical techniques. The electrochemical properties of the modified bare gold surface following TLR5 immobilization were characterized. The electrochemical response to changes in the sensor film resistance and electron charge-transfer permittivity triggered by independent exposures to flagellins from Salmonella typhimurium (S. typhimurium) and Bacillus subtilis (B. subtilis) were examined and observed. The quantified film resistance data gathered using electrochemical impedance spectroscopy (EIS) over a macroscopic scale are in significant agreement with the corresponding electron charge-transfer permittivity measured locally by scanning electrochemical microscopy (SECM). Unlike other sensors that exploit pathogen recognition elements, TLR5 biosensors have the potential to carry out broad spectrum detection of flagellated bacterial pathogens in near real time. This broad-spectrum detection platform is a significant step toward the development of fast, inexpensive clinical tools for early warning diagnoses and immediate on site treatment. PMID- 25709060 TI - Transdermal delivery of testosterone. AB - Male hypogonadism has been treated with exogenous testosterone since the 1930s. The early transdermal patches of testosterone became available in the 1980s with gel and solution preparations following subsequent decades. This review focusses on the skin permeation characteristics of testosterone, pharmacokinetics following application of transdermal formulations and formulations currently available. At present, gels dominate the market for transdermal testosterone replacement therapy, presumably because of their greater patient acceptability and non-occlusive nature compared with patches. However, specific incidences of secondary transfer of gels to children with consequent unwanted effects such as precocious puberty have been reported. A regulatory review of all testosterone replacement therapies is currently underway which may have implications for future prescribing practices of transdermal testosterone products. PMID- 25709061 TI - Barrier or carrier? Pulmonary surfactant and drug delivery. AB - To consider the lung as a target for drug delivery and to optimise strategies directed at the pulmonary route, it is essential to consider the role of pulmonary surfactant, a thin lipid-protein film lining the respiratory surface of mammalian lungs. Membrane-based surfactant multilayers are essential for reducing the surface tension at the respiratory air-liquid interface to minimise the work of breathing. Different components of surfactant are also responsible for facilitating the removal of potentially pathological entities such as microorganisms, allergens or environmental pollutants and particles. Upon inhalation, drugs or nanoparticles first contact the surfactant layer, and these interactions critically affect their lifetime and fate in the airways. This review summarises the current knowledge on the possible role and effects of the pulmonary surfactant system in drug delivery strategies. It also summarises the evidence that suggests that pulmonary surfactant is far from being an insuperable barrier and could be used as an efficient shuttle for delivering hydrophobic and hydrophilic compounds deep into the lung and the organism. PMID- 25709062 TI - Catalyst activation, deactivation, and degradation in palladium-mediated Negishi cross-coupling reactions. AB - Pd-mediated Negishi cross-coupling reactions were studied by a combination of kinetic measurements, electrospray-ionization (ESI) mass spectrometry, (31)P NMR and UV/Vis spectroscopy. The kinetic measurements point to a rate-determining oxidative addition. Surprisingly, this step seems to involve not only the Pd catalyst and the aryl halide substrate, but also the organozinc reagent. In this context, the ESI-mass spectrometric observation of heterobimetallic Pd-Zn complexes [L2 PdZnR](+) (L=S-PHOS, R=Bu, Ph, Bn) is particularly revealing. The inferred presence of these and related neutral complexes with a direct Pd-Zn interaction in solution explains how the organozinc reagent can modulate the reactivity of the Pd catalyst. Previous theoretical calculations by Gonzalez Perez et al. (Organometallics- 2012, 31, 2053) suggest that the complexation by the organozinc reagent lowers the activity of the Pd catalyst. Presumably, a similar effect also causes the rate decrease observed upon addition of ZnBr2 . In contrast, added LiBr apparently counteracts the formation of Pd-Zn complexes and restores the high activity of the Pd catalyst. At longer reaction times, deactivation processes due to degradation of the S-PHOS ligand and aggregation of the Pd catalyst come into play, thus further contributing to the appreciable complexity of the title reaction. PMID- 25709063 TI - Flat irregular retinal pigment epithelium detachments in chronic central serous chorioretinopathy and choroidal neovascularization. AB - PURPOSE: To evaluate the incidence of flat, irregular pigment epithelium detachments (PEDs) in chronic central serous chorioretinopathy (CSC) and to determine whether they are consistent with active choroidal neovascularization (CNV). DESIGN: Retrospective case series. METHODS: Review of medical records of patients with chronic CSC who were examined in the Ophthalmology Department of Lariboisiere Hospital between June 1, 2007 and May 31, 2013. Multimodal imaging of the fundus, including optical coherence tomography (OCT), fundus autofluorescence, and indocyanine green and fluorescein angiography, was available in most cases. RESULTS: One hundred and ten patients with chronic CSC were identified. Fifty-three eyes of 38 patients showed flat irregular PED on macular OCT examination. Mean age was 58.6 +/- 13.2 years. Twenty-eight patients (73.6%) patients were male. Fifteen patients (39.4%) had bilateral flat irregular PEDs. The mean follow-up duration was 14.6 years (range: 2-39 years). PEDs were suggestive of type 1 CNV in 10 eyes, but no other signs of AMD, specifically no drusen, were present. In the remaining 43 eyes, flat irregular PEDs were stable over time (mean follow-up duration: 15 years) with no evidence of active neovascularization. CONCLUSION: Although the possible occurrence of type 1 CNV complicating the course of chronic CSC should not be ignored, all cases of flat irregular PED should not be mistaken for active CNV and systematically treated with anti-VEGF. Nevertheless, in some cases with worsened vision not responding to usual CSC therapy, anti-VEGF could be considered as a therapeutic test to rule out the presence of secondary CNV. PMID- 25709064 TI - Quantitative analysis of peripheral vasculitis, ischemia, and vascular leakage in uveitis using ultra-widefield fluorescein angiography. AB - PURPOSE: To investigate the relationships between peripheral vasculitis, ischemia, and vascular leakage in uveitis using ultra-widefield fluorescein angiography (FA). DESIGN: Cross-sectional, consecutive case series. METHODS: Consecutive ultra-widefield FA images were collected from 82 uveitis patients (82 eyes) in a single center. The extent of peripheral vasculitis, capillary nonperfusion, and vessel leakage were quantified. Parameters included: (1) foveal avascular zone area and macular leakage, (2) peripheral diffuse capillary leakage and ischemia, (3) peripheral vasculitis, and (4) leakage from neovascularization. Central macular thickness measurements were derived with optical coherence tomography. Main outcome measures were correlations between central and peripheral fluorangiographic changes as well as associations between visual function, ultra-widefield FA-derived metrics, and central macular thickness. RESULTS: Although central leakage was associated with peripheral leakage (r = 0.553, P = .001), there was no association between foveal avascular zone size and peripheral ischemia (r = 0.114, P = .324), regardless of the underlying uveitic diagnosis. Peripheral ischemia was, however, correlated to neovascularization related leakage (r = 0.462, P = .001) and focal vasculitis (r = 0.441, P = .001). Stepwise multiple regression analysis revealed that a poor visual acuity was independently associated with foveal avascular zone size and central macular thickness (R(2)-adjusted = 0.45, P = .001). CONCLUSIONS: We present a large cohort of patients with uveitis imaged with ultra-widefield FA and further describe novel methods for quantification of peripheral vascular pathology, in an attempt to identify visually significant parameters. Although we observed that relationships exist between peripheral vessel leakage, vasculitis, and ischemia, it was only macular ischemia and increased macular thickness that were independently associated with a reduced visual acuity. PMID- 25709065 TI - Erratum to: Determination of omega-6 and omega-3 PUFA metabolites in human urine samples using UPLC/MS/MS. PMID- 25709066 TI - Automated solid-phase extraction coupled online with HPLC-FLD for the quantification of zearalenone in edible oil. AB - Established maximum levels for the mycotoxin zearalenone (ZEN) in edible oil require monitoring by reliable analytical methods. Therefore, an automated SPE HPLC online system based on dynamic covalent hydrazine chemistry has been developed. The SPE step comprises a reversible hydrazone formation by ZEN and a hydrazine moiety covalently attached to a solid phase. Seven hydrazine materials with different properties regarding the resin backbone, pore size, particle size, specific surface area, and loading have been evaluated. As a result, a hydrazine functionalized silica gel was chosen. The final automated online method was validated and applied to the analysis of three maize germ oil samples including a provisionally certified reference material. Important performance criteria for the recovery (70-120 %) and precision (RSDr <25 %) as set by the Commission Regulation EC 401/2006 were fulfilled: The mean recovery was 78 % and RSDr did not exceed 8 %. The results of the SPE-HPLC online method were further compared to results obtained by liquid-liquid extraction with stable isotope dilution analysis LC-MS/MS and found to be in good agreement. The developed SPE-HPLC online system with fluorescence detection allows a reliable, accurate, and sensitive quantification (limit of quantification, 30 MUg/kg) of ZEN in edible oils while significantly reducing the workload. To our knowledge, this is the first report on an automated SPE-HPLC method based on a covalent SPE approach. PMID- 25709067 TI - Microquantification of inorganic and organic phosphate by negative ion electrospray tandem mass spectrometry. AB - A new method for inorganic phosphate microquantification is introduced based on negative ion electrospray tandem mass spectrometry and stable isotope dilution by (18)O4-labeled phosphate. Quantification is performed using the non-labeled and (18)O3-labeled [P(18)O3](-) fragment ions at m/z 79 and 85, respectively, formed by dissociation of the [H2PO4](-) ion at m/z 97 and 105, respectively, visible in negative ion electrospray ionization mass spectrometry (ESI-MS) spectra. Tandem mass spectrometry was selected to remove an overlap with the isobaric [HSO4](-) ion at m/z 97 of sulfate and to establish an optimal sensitivity of the quantification assay. It is demonstrated that the assay can also measure the sum of inorganic and phosphoryl phosphate by prior enzymatic hydrolysis of phosphoryl phosphate. The assay works with phosphate concentrations in the micromolar range and, in combination with nano-ESI, is capable to quantitate absolute amounts of phosphate in the low nanogram range from complex samples. PMID- 25709068 TI - Isolation, identification, and pathogenicity of O142 avian pathogenic Escherichia coli causing black proventriculus and septicemia in broiler breeders. AB - Avian colibacillosis, characterized by black proventriculus and caused by avian pathogenic Escherichia coli (APEC) with an uncommon O142 serogroup, was diagnosed in young broiler breeders. Colonization and persistence assays performed in 7-day old broilers showed that the bacterial load of the APEC 4d/9-1 O142 proventricular isolate in the lung was about 10-fold higher than that of the APEC 4d/9-1 O142 heart blood isolate (P<0.01), and about 100-fold higher in the heart blood, livers, spleens, kidneys, and proventriculi of inoculated broilers (P<0.001). When 32 common virulence genes of APEC were tested, the two isolates had nearly identical profiles, except that only the APEC 4d/9-1 O142 proventricular isolate carried the feoB gene. Furthermore, 100% mortality was observed in both 1-day-old Arbor Acres (AA) broilers and 1-day-old specific pathogen-free (SPF) chickens inoculated with 10(6) colony-forming units of the APEC 4d/9-1 O142 proventricular isolate. However, black proventriculus was only observed in the dead AA broilers, consistent with the clinical occurrence of the disease. This implies that the black proventriculi seen in the dead birds, caused by the APEC 4d/9-1 O142 proventricular isolate, was breed-specific. Both the APEC 4d/9-1 O142 proventricular and heart blood isolates belong to phylogroup B2. However, the former was assigned to ST131 and the latter to ST2704 with multilocus sequence typing, demonstrating the genetic heterogeneity of these two bacterial isolates, although they were derived from the same dead broiler. These results suggest that the O142 APEC isolate was the main pathogenic agent for black proventriculi in 7-day-old broiler breeders. PMID- 25709069 TI - Mycobacterium tuberculosis effectors involved in host-pathogen interaction revealed by a multiple scales integrative pipeline. AB - BACKGROUND: Mycobacterium tuberculosis (Mtb) has evolved multiple strategies to counter host immunity. Proteins are one important player in the host-pathogen interaction. A comprehensive list of such proteins will benefit our understanding of pathogenesis of Mtb. METHODS: A genome-scale dataset was created from different sources of published data: global gene expression studies in disease models; genome-wide insertional mutagenesis defining gene essentiality under different conditions; genes lost in clinical isolates; subcellular localization analysis and non-homology analysis. Using data mining and meta-analysis, expressed proteins critical for intracellular survival of Mtb are first identified, followed by subcellular localization analysis, finally filtering a series of subtractive channel of analysis to find out promising drug target candidates. RESULTS: The analysis found 54 potential candidates essential for the intracellular survival of the pathogen and non-homologous to host or gut flora, and might be promising drug targets. CONCLUSION: Based on our meta-analysis and bioinformatics analysis, 54 hits were found from Mtb around 4000 open reading frames. These hits can be good candidates for further experimental investigation. PMID- 25709070 TI - Reply to "in response to wilderness search strategy and tactics". In reply to Dr Cooper and Mr Frost. PMID- 25709071 TI - Shark attacks and shark diving. PMID- 25709073 TI - Reply to the letter to the editor: minimally invasive surgical approaches in the management of tuberculosis of the thoracic and lumbar spine. PMID- 25709072 TI - High cardiac vagal control is related to better subjective and objective sleep quality. AB - Cardiac vagal control (CVC) has been linked to both physical and mental health. One critical aspect of health, that has not received much attention, is sleep. We hypothesized that adults with higher CVC--operationalized by high-frequency heart rate variability (HF-HRV)--will exhibit better sleep quality assessed both subjectively (i.e., with Pittsburgh Sleep Quality Index) and objectively (i.e., with polysomnography). HF-HRV was measured in 29 healthy young women during an extended neutral film clip. Participants then underwent full polysomnography to obtain objective measures of sleep quality and HF-HRV during a night of sleep. As expected, higher resting HF-HRV was associated with higher subjective and objective sleep quality (i.e., shorter sleep latency and fewer arousals). HF-HRV during sleep (overall or separated by sleep phases) showed less consistent relationships with sleep quality. These findings indicate that high waking CVC may be a key predictor of healthy sleep. PMID- 25709074 TI - CORR Insights((r)): Is the Induced-membrane Technique Successful for Limb Reconstruction After Resecting Large Bone Tumors in Children? PMID- 25709075 TI - Cochrane in CORR ((r)): Platelet-rich Therapies for Musculoskeletal Soft Tissue Injuries (Review). PMID- 25709076 TI - Electronic prompts significantly increase response rates to postal questionnaires: a randomized trial within a randomized trial and meta-analysis. AB - OBJECTIVES: To assess the effectiveness of sending electronic prompts to randomized controlled trial participants to return study questionnaires. STUDY DESIGN AND SETTING: A "trial within a trial" embedded within a study determining the effectiveness of chronic obstructive pulmonary disease (DOC) screening on smoking cessation. Those participants taking part in DOC who provided a mobile phone number and/or an electronic mail address were randomized to either receive an electronic prompt or no electronic prompt to return a study questionnaire. The results were combined with two previous studies in a meta-analysis. RESULTS: A total of 437 participants were randomized: 226 to the electronic prompt group and 211 to the control group. A total of 285 (65.2%) participants returned the follow up questionnaire: 157 (69.5%) in the electronic prompt group and 128 (60.7%) in the control group [difference 8.8%; 95% confidence interval (CI): -0.11%, 17.7%; P = 0.05]. The mean time to response was 23 days in the electronic prompt group and 33 days in the control group (hazard ratio = 1.27; 95% CI: 1.105, 1.47). The meta-analysis of all three studies showed an increase in response rate of 7.1% (95% CI: 0.8%, 13.3%). CONCLUSION: The use of electronic prompts increased response rates and reduces the time to response. PMID- 25709078 TI - Synergetic effects of Al3+ doping and graphene modification on the electrochemical performance of V2O5 cathode materials. AB - A series of V2O5-based cathode materials that include V2O5 and Al0.14 V2O5 nanoparticles, V2O5/reduced graphene oxide (RGO), and Al0.16 V2O5/RGO nanocomposites are prepared by a simple soft chemical method. XRD and Raman scattering show that the Al ions reside in the interlayer space of the materials. These doping ions strengthen the V-O bonds of the [VO5] unit and enhance the linkage of the [VO5] layers, which thus increases the structural stability of V2O5. SEM and TEM images show that the V2O5 nanoparticles construct a hybrid structure with RGO that enables fast electron transport in the electrode matrix. The electrochemical properties of the materials are studied by charge-discharge cycling, cyclic voltammetry, and electrochemical impedance spectroscopy. Of all the materials tested, the one that contained both Al ions and RGO (Al0.16 V2O5/RGO) exhibited the highest discharge capacity, the best rate capability, and excellent capacity retention. The superior electrochemical performance is attributed to the synergetic effects of Al(3+) doping and RGO modification, which not only increase the structural stability of the V2O5 lattice but also improve the electrochemical kinetics of the material. PMID- 25709077 TI - EFFECT OF THE APOE epsilon4 ALLELE AND COMBAT EXPOSURE ON PTSD AMONG IRAQ/AFGHANISTAN-ERA VETERANS. AB - BACKGROUND: The apolipoprotein E (APOE) epsilon4 allele has been implicated in a range of neuropsychiatric conditions. The present research examined if the epsilon4 allele of the APOE gene moderated the effect of combat exposure on posttraumatic stress disorder (PTSD) among Iraq/Afghanistan-era veterans. METHOD: Participants included 765 non-Hispanic White (NHW) and 859 non-Hispanic Black (NHB) Iraq/Afghanistan-era veterans. A structured interview established psychiatric diagnoses. Combat exposure and PTSD symptom severity were assessed via self-report. RESULTS: The most common lifetime diagnoses were depression (39.2%), PTSD (38.4%), and alcohol dependence (24.38%). After correcting for multiple comparisons, no significant effects were observed on any of the outcomes among the NHW sample; however, within the NHB sample, significant gene * environment (G * E) interactions were observed for lifetime PTSD (P = .0029) and PTSD symptom severity (P = .0009). In each case, the APOE epsilon4 allele had no effect on the outcomes when combat exposure was low; however, when combat exposure was high, an additive effect was observed such that epsilon4 homozygotes exposed to high levels of combat reported the highest rates of PTSD (92%) and the worst symptom severity scores on the Davidson Trauma Scale (M = 79.5). CONCLUSIONS: Although preliminary, these findings suggest that the APOE epsilon4 allele, in conjunction with exposure to high levels of combat exposure, may increase veterans' risk for developing PTSD. PMID- 25709080 TI - Ricolinostat (ACY-1215) induced inhibition of aggresome formation accelerates carfilzomib-induced multiple myeloma cell death. AB - Proteasome inhibition induces the accumulation of aggregated misfolded/ubiquitinated proteins in the aggresome; conversely, histone deacetylase 6 (HDAC6) inhibition blocks aggresome formation. Although this rationale has been the basis of proteasome inhibitor (PI) and HDAC6 inhibitor combination studies, the role of disruption of aggresome formation by HDAC6 inhibition has not yet been studied in multiple myeloma (MM). The present study aimed to evaluate the impact of carfilzomib (CFZ) in combination with a selective HDAC6 inhibitor (ricolinostat) in MM cells with respect to the aggresome proteolysis pathway. We observed that combination treatment of CFZ with ricolinostat triggered synergistic anti-MM effects, even in bortezomib-resistant cells. Immunofluorescent staining showed that CFZ increased the accumulation of ubiquitinated proteins and protein aggregates in the cytoplasm, as well as the engulfment of aggregated ubiquitinated proteins by autophagosomes, which was blocked by ricolinostat. Electron microscopy imaging showed increased autophagy triggered by CFZ, which was inhibited by the addition of ACY-1215. Finally, an in vivo mouse xenograft study confirmed a decrease in tumour volume, associated with apoptosis, following treatment with CFZ in combination with ricolinostat. Our results suggest that ricolinostat inhibits aggresome formation, caused by CFZ induced inhibition of the proteasome pathway, resulting in enhanced apoptosis in MM cells. PMID- 25709081 TI - Strain-induced conduction gap in vertical devices made of misoriented graphene layers. AB - We investigate the effects of uniaxial strain on the transport properties of vertical devices made of two misoriented (or twisted) graphene layers, which partially overlap each other. We find that because of the different orientations of the two graphene lattices, their Dirac points can be displaced and separated in the k-space by the effects of strain. Hence, a finite conduction gap as large as a few hundred meV can be obtained in the device with a small strain of only a few percent. The dependence of this conduction gap on the strain magnitude, strain direction, channel orientation and twist angle are clarified and presented. On this basis, the strong modulation of conductance and significant improvement of Seebeck coefficient are shown. The suggested devices therefore may be very promising for improving applications of graphene, e.g., as transistors or strain and thermal sensors. PMID- 25709079 TI - Care trajectories are associated with quality improvement in the treatment of patients with uncontrolled type 2 diabetes: A registry based cohort study. AB - AIMS: To analyse whether care trajectories (CT) were associated with increased prevalence of parenteral hypoglycemic treatment (PHT=insulin or GLP-1 analogues), statin therapy or RAAS-inhibition. Introduced in 2009 in Belgium, CTs target patients with type 2 diabetes mellitus (T2DM), in need for or with PHT. METHODS: Retrospective study based on a registry with 97 general practitioners. The evolution in treatment since 2006 was compared between patients with vs. without a CT, using longitudinal logistic regression. RESULTS: Comparing patients with (N=271) vs. without a CT (N=4424), we noted significant differences (p<0.05) in diabetes duration (10.1 vs. 7.3 years), HbA1c (7.5 vs. 6.9%), LDL-C (85 vs. 98mg/dl), microvascular complications (26 vs. 16%). Moreover, in 2006, parenteral treatment (OR 52.1), statins (OR 4.1) and RAAS-inhibition (OR 9.6) were significantly more prevalent (p<0.001). Between 2006 and 2011, the prevalence rose in both groups regarding all three treatments, but rose significantly faster (p<0.05) after 2009 in the CT-group. CONCLUSIONS: Patients enrolled in a CT differ from other patients even before the start of this initiative with more intense hypoglycemic and cardiovascular treatment. Yet, they presented higher HbA1c-levels and more complications. Enrolment in a CT is associated with additional treatment intensification. PMID- 25709082 TI - Aluminum-centered tetrahedron-octahedron transition in advancing Al-Sb-Te phase change properties. AB - Group IIIA elements, Al, Ga, or In, etc., doped Sb-Te materials have proven good phase change properties, especially the superior data retention ability over popular Ge2Sb2Te5, while their phase transition mechanisms are rarely investigated. In this paper, aiming at the phase transition of Al-Sb-Te materials, we reveal a dominant rule of local structure changes around the Al atoms based on ab initio simulations and nuclear magnetic resonance evidences. By comparing the local chemical environments around Al atoms in respective amorphous and crystalline Al-Sb-Te phases, we believe that Al-centered motifs undergo reversible tetrahedron-octahedron reconfigurations in phase transition process. Such Al-centered local structure rearrangements significantly enhance thermal stability of amorphous phase compared to that of undoped Sb-Te materials, and facilitate a low-energy amorphization due to the weak links among Al-centered and Sb-centered octahedrons. Our studies may provide a useful reference to further understand the underlying physics and optimize performances of all IIIA metal doped Sb-Te phase change materials, prompting the development of NOR/NAND Flash like phase change memory technology. PMID- 25709083 TI - Ambipolar zinc-polyiodide electrolyte for a high-energy density aqueous redox flow battery. AB - Redox flow batteries are receiving wide attention for electrochemical energy storage due to their unique architecture and advantages, but progress has so far been limited by their low energy density (~25 Wh l(-1)). Here we report a high energy density aqueous zinc-polyiodide flow battery. Using the highly soluble iodide/triiodide redox couple, a discharge energy density of 167 Wh l(-1) is demonstrated with a near-neutral 5.0 M ZnI2 electrolyte. Nuclear magnetic resonance study and density functional theory-based simulation along with flow test data indicate that the addition of an alcohol (ethanol) induces ligand formation between oxygen on the hydroxyl group and the zinc ions, which expands the stable electrolyte temperature window to from -20 to 50 degrees C, while ameliorating the zinc dendrite. With the high-energy density and its benign nature free from strong acids and corrosive components, zinc-polyiodide flow battery is a promising candidate for various energy storage applications. PMID- 25709084 TI - Inconclusive evidence for non-inferior immunogenicity of two- compared with three dose HPV immunization schedules in preadolescent girls: A systematic review and meta-analysis. AB - BACKGROUND: The European Medicines Agency (EMA) recently approved two-dose immunization schedules for bivalent (HPV 16/18) and quadrivalent (HPV 6/11/16/18) human papillomavirus (HPV) vaccines in nine to fourteen and thirteen year-old girls, respectively. Registration was based on trials comparing immunogenicity of two-dose schedules in girls 9-14 years to three-dose schedules in young women 15 26 years. We evaluate comparability of antibody levels between and within age groups and discuss potential implications for monitoring the effectiveness of HPV vaccination. METHODS: A systematic literature search was performed for studies comparing immunogenicity of two- to three-dose schedules of HPV vaccination. We compared geometric mean concentrations (GMCs) of vaccine-type antibodies between different dosing schedules across different age groups. Meta-analysis was used to estimate pooled GMC ratios (bivalent vaccine) of two- compared with three-dose schedules within girls. FINDINGS: For both vaccines, two-dose immunization of girls yielded non-inferior GMCs relative to a three-dose schedule in young women up to respectively 36 and 48 months follow-up. Pooled GMC ratios for the bivalent vaccine within girls showed the two-dose schedule becoming inferior to the three dose schedule in girls for HPV 16 at approximately two years after the first dose. For the quadrivalent vaccine, antibody responses for HPV-18 became inferior from 18 months follow-up onwards when comparing the two-dose schedule with the three-dose schedule within girls. IMPLICATIONS: Two-dose immunization of girls has non-inferior immunogenicity compared to a three-dose schedule among young women. However, non-inferior immunogenicity of two- compared with three-dose schedules within girls has not been shown at all time points. Due to this inconclusive evidence, implementation of two-dose HPV vaccination needs to be monitored closely. PMID- 25709086 TI - Cloning, expression, and characterization of a novel xylose reductase from Rhizopus oryzae. AB - Rhizopus oryzae is valuable as a producer of organic acids via lignocellulose catalysis. R. oryzae metabolizes xylose, which is one component of lignocellulose hydrolysate. In this study, a novel NADPH-dependent xylose reductase gene from R. oryzae AS 3.819 (Roxr) was cloned and expressed in Pichia pastoris GS115. Homology alignment suggested that the 320-residue protein contained domains and active sites belonging to the aldo/keto reductase family. SDS-PAGE demonstrated that the recombinant xylose reductase has a molecular weight of approximately 37 kDa. The optimal catalytic pH and temperature of the purified recombinant protein were 5.8 and 50 degrees C, respectively. The recombinant protein was stable from pH 4.4 to 6.5 and at temperatures below 42 degrees C. The recombinant enzyme has bias for D-xylose and L-arabinose as substrates and NADPH as its coenzyme. Real time quantitative reverse transcription PCR tests suggested that native Roxr expression is regulated by a carbon catabolite repression mechanism. Site directed mutagenesis at two possible key sites involved in coenzyme binding, Thr(226) -> Glu(226) and Val(274) -> Asn(274), were performed, respectively. The coenzyme specificity constants of the resulted RoXR(T226E) and RoXR(V274N) for NADH increased 18.2-fold and 2.4-fold, which suggested possibility to improve the NADH preference of this enzyme through genetic modification. PMID- 25709085 TI - Meningococcal carriage in adolescents in the United Kingdom to inform timing of an adolescent vaccination strategy. AB - OBJECTIVES: Recent development of serogroup B meningococcal (MenB) vaccines highlights the importance of pharyngeal carriage data, particularly in adolescents and young adults, to inform implementation strategies. We describe current UK carriage prevalence in this high risk population and compare methods of carriage detection. METHODS: In this multisite study, pharyngeal swabs were collected on 3-4 occasions over 6-12 months, from 1040 school and university students, aged 10-25 years. Meningococcal carriage was detected by standard culture combined with seroagglutination or PCR of cultured isolates, or by direct PCR from swab. The factor H binding protein (fHBP) variants present in meningococcal isolates were determined. RESULTS: Meningococcal serogroups B and Y were most common, with carriage up to 6.5% and 5.5% respectively, increasing throughout adolescence. Identification by seroagglutination was often unreliable, and the sensitivity of direct PCR detection was 66% compared to culture combined with PCR. Of MenB isolates, 89.1% had subfamily A variants of fHBP. The acquisition rate of MenB carriage was estimated at 2.8 per 1000 person-months. CONCLUSIONS: If vaccination is to precede the adolescent rise in MenB carriage, these data suggest it should take place in early adolescence. Studies assessing vaccine impact should use molecular methods to detect carriage. PMID- 25709087 TI - CCN1 (Cyr61) Is Overexpressed in Human Osteoarthritic Cartilage and Inhibits ADAMTS-4 (Aggrecanase 1) Activity. AB - OBJECTIVE: ADAMTS-4, also called aggrecanase 1, is considered to play a key role in aggrecan degradation in human osteoarthritic (OA) cartilage, but information about regulators of ADAMTS-4 aggrecanase activity remains limited. We undertook this study to search for molecules that modulate ADAMTS-4 activity. METHODS: Molecules copurified with ADAMTS-4 from ADAMTS-4-transfected chondrocytic cells were sequenced by nanoscale liquid chromatography tandem mass spectrometry. Binding activity was determined by immunoprecipitation and solid-phase binding assay. Effects on ADAMTS-4 activity were examined by aggrecan digestion assay. Expression of the binding molecule in OA cartilage and chondrocytes was examined by immunohistochemistry and reverse transcription-polymerase chain reaction. RESULTS: We identified CCN1 (Cyr61) as an ADAMTS-4-binding protein and showed specific binding to the ADAMTS-4 cysteine-rich domain. Aggrecanase activity of ADAMTS-4 was inhibited by interaction with CCN1. Expression of messenger RNA for CCN1 was significantly higher in human OA cartilage than in normal cartilage. CCN1 was immunolocalized to chondrocytes in OA cartilage, showing direct correlations of immunoreactivity with the Mankin score of cartilage lesions and chondrocyte cloning. CCN1 and ADAMTS-4 were commonly coexpressed in clustered chondrocytes. CCN1 expression in OA chondrocytes was down-regulated by interleukin-1alpha (IL-1alpha) and up-regulated by transforming growth factor beta (TGFbeta). ADAMTS-4 expression was induced by treatment with IL-1alpha or TGFbeta, but aggrecanase activity was detected only under stimulation with IL 1alpha. TGFbeta-treated chondrocytes exhibited aggrecanase activity when CCN1 expression was knocked down. CONCLUSION: Our findings provide the first evidence that CCN1 suppresses ADAMTS-4 activity and that CCN1 overexpression is directly correlated with chondrocyte cloning in OA cartilage. Our results suggest that the TGFbeta/CCN1 axis plays a role in chondrocyte cluster formation through inhibition of ADAMTS-4. PMID- 25709088 TI - Effects of perturbation training on knee flexion angle and quadriceps to hamstring cocontraction of female athletes with quadriceps dominance deficit: Pre post intervention study. AB - BACKGROUND: Knee joint stability through co-contraction (CC) of hamstrings and quadriceps may be necessary for females with Quadriceps Dominance (Q.D) neuromuscular deficit. Unbalanced CC of medial and lateral portion of the knee can predispose women to extended knee position that exaggerate ACL injury. The purpose of this study was to determine the effects of perturbation training on knee flexion angle and neuromuscular characteristics in female athletes with quadriceps dominance deficit. METHODS: EMG data of quadriceps and hamstrings (during single limb drop-landing), and knee flexion angles (during tuck-jump test) of 29 (14 control and 15 experimental) female athletes with quadriceps dominance deficit were completed at baseline and after six weeks. Six weeks of perturbation training in the experimental group was applied over 18 sessions under the supervision of a physiotherapist. RESULTS: The VL-LH and VM-MH cocontraction in feed-forward and feedback phases significantly increased after perturbation training. Also peak knee flexion angle significantly increased and reaches from 26.24 degrees +/-3.54 degrees in pretest to 48.92 degrees +/-6.18 degrees in posttest due to perturbation training effects on Q.D deficit women (p<0.01). CONCLUSIONS: Finally because the Q.D neuromuscular deficit is one of the important mechanisms of noncontact ACL injuries in female athletes and the effect of perturbation training in solving this problem indicated in this study, so the use of perturbation trainings is recommended to women athlete coaches to eliminate this defect and improve athletic performance (functional tuck jump test). CLINICAL RELEVANCE: The balanced cocontraction ratios produced after the perturbation training may benefit in anterior cruciate ligament injury prevention. PMID- 25709089 TI - The torch of Koan: passing on the flame to the future. PMID- 25709090 TI - Levofolene modulates apoptosis induced by 5-fluorouracil through autophagy inhibition: clinical and occupational implications. AB - 5-Fluorouracil (5-FU), often used in combination with levofolene (LF), can induce, as an important side effect, the hand-foot syndrome (HFS) due to toxicity on keratinocytes. This can also damage workers involved in its handling. In the present study, we investigated the mechanisms of the toxicity induced by 5-FU alone or together with LF on human keratinocytes in culture. We found that the two drugs, as expected, had potentiating activity on keratinocyte growth inhibition and that this effect was mediated by induction of apoptosis. In our experimental model, an increased autophagic vacuole accumulation was observed in keratinocytes treated with 5-FU as a significant increase of the monodansylcadaverine (MDC) labeling (marker of late autophagy vacuoles) was recorded. However, the synergism of 5-FU with LF on apoptotic occurrence was not paralleled by a similar increase in autophagic vacuoles at 72 h suggesting an antagonistic effect of LF on autophagy elicited by 5-FU. Differential effects on reactive oxygen species (ROS) elevation in cells treated with 5-FU alone or the combination between 5-FU and LF were also observed. 5-FU induced a time-dependent increase of both O2- and lipid peroxidation while the combination of 5-FU and LF caused a stronger intracellular O2- increase only at 24 h while at 48 and 72 h its effect was lower when compared with that one of 5-FU alone. On the other hand, the addition of LF to 5-FU caused a stronger increase of lipid peroxidation at 48 and 72 h, but its effects were significantly lower at 24 h. These results suggest for the first time that LF potentiates the cytotoxicity of 5-FU on keratinocytes likely through the antagonism on autophagy escape pathway and consequent apoptosis potentiation. PMID- 25709091 TI - Enhanced photovoltaics inspired by the fovea centralis. AB - The fovea centralis is a closely-packed vertical array of inverted-cone photoreceptor cells located in the retina that is responsible for high acuity binocular vision. The cones are operational in well-lit environments and are responsible for trapping the impinging illumination. We present the vertical light-funnel silicon array as a light-trapping technique for photovoltaic applications that is bio-inspired by the properties of the fovea centralis. We use opto-electronic simulations to evaluate the performance of light-funnel solar cell arrays. Light-funnel arrays present ~65% absorption enhancement compared to a silicon film of identical thickness and exhibit power conversion efficiencies that are 60% higher than those of optimized nanowire arrays of the same thickness although nanowire arrays consist of more than 2.3 times the amount of silicon. We demonstrate the superior absorption of the light-funnel arrays as compared with recent advancements in the field. Fabrication of silicon light-funnel arrays using low-cost processing techniques is demonstrated. PMID- 25709092 TI - Prevalence and seasonality of bulk milk antibodies against Dictyocaulus viviparus and Ostertagia ostertagi in Irish pasture-based dairy herds. AB - Infections with Dictyocaulus viviparus and Ostertagia ostertagi nematode parasites are of importance to bovine health and production in temperate areas across the world. Losses due to these parasites in dairy herds can be considerable due to decreased milk productivity and fertility. However, information on current epidemiological patterns in Irish dairy herds is limited. Bulk milk samples were collected from a total of 319 dairy farms across the Republic of Ireland. The D. viviparus samples were tested with an ELISA based on recombinant major sperm protein, while the O. ostertagi samples were tested with an ELISA based on crude saline extract, whole worm O. ostertagi antigen. Management data were collected from the farms using a questionnaire. Logistic regression was used to find significant associations between the presence of antibodies against D. viviparus and O. ostertagi and management factors. The overall prevalence of D. viviparus infection was 62.8%, while over 98% of herds had antibodies to O. ostertagi at the specified cut-off. Both D. viviparus and O. ostertagi antibodies were highest in November, which could be explained by the accumulated uptake of larvae through the grazing season. In herds of farmers that dosed their in-calf heifers with anthelmintics were significantly more likely to be positive for antibodies against D. viviparus infection. This study highlights that both D. viviparus and O. ostertagi infections are widespread in dairy herds in Ireland throughout the grazing season. PMID- 25709094 TI - A population-based study of prognosis in advanced stage follicular lymphoma managed by watch and wait. AB - Watch and wait (WAW) is a common approach for asymptomatic, advanced stage follicular lymphoma (FL), but single-agent rituximab is an alternative for these patients. In this nationwide study we describe the outcome of patients selected for WAW. A cohort of 286 out of 849 (34%) stage III-IVA FL patients seen between 2000 and 2011, were managed expectantly and included. The 5-year progression-free survival (PFS) was 35% [95% confidence interval (CI) 29-42]. The 10-year overall survival (OS) was 65% (95%CI 54-78), and the cumulative risk of dying from lymphoma within 10 years of diagnosis was 13% (95%CI 7-20). Elevated lactate dehydrogenase and > four nodal regions involved were associated with a higher risk of lymphoma treatment and death from lymphoma. The WAW patients and a matched background population had similar OS during the first 50 months after diagnosis (P = 0.7), but WAW patients had increased risk of death after 50 months (P < 0.001). The estimated loss of residual life after 10 years was 6.8 months. The 10-year cumulative risk of histological transformation was 22% (95%CI 15-29) and the 3-year OS after transformation was 71% (95%CI 58-87%). In conclusion, advanced stage FL managed by WAW had a favourable outcome and abandoning this strategy could lead to overtreatment in some patients. PMID- 25709093 TI - RNA degradation in antiviral immunity and autoimmunity. AB - Post-transcriptional control determines the fate of cellular RNA molecules. Nonsense-mediated decay (NMD) provides quality control of mRNA, targeting faulty cellular transcripts for degradation by multiple nucleases including the RNA exosome. Recent findings have revealed a role for NMD in targeting viral RNA molecules, thereby restricting virus infection. Interestingly, NMD is also linked to immune responses at another level: mutations affecting the NMD or RNA exosome machineries cause chronic activation of defence programmes, resulting in autoimmune phenotypes. Here we place these observations in the context of other links between innate antiviral immunity and type I interferon mediated disease and examine two models: one in which expression or function of pathogen sensors is perturbed and one wherein host-derived RNA molecules with a propensity to activate such sensors accumulate. PMID- 25709095 TI - Nutritional modulation of IGF-1 in relation to growth and body condition in Sceloporus lizards. AB - Nutrition and energy balance are important regulators of growth and the growth hormone/insulin-like growth factor (GH/IGF) axis. However, our understanding of these functions does not extend uniformly to all classes of vertebrates and is mainly limited to controlled laboratory conditions. Lizards can be useful models to improve our understanding of the nutritional regulation of the GH/IGF-1 axis because many species are relatively easy to observe and manipulate both in the laboratory and in the field. In the present study, the effects of variation in food intake on growth, body condition, and hepatic IGF-1 mRNA levels were measured in (1) juveniles of Sceloporus jarrovii maintained on a full or 1/3 ration and (2) hatchlings of Sceloporus undulatus subjected to full or zero ration with or without re-feeding. These parameters plus plasma IGF-1 were measured in a third experiment using adults of S. undulatus subjected to full or zero ration with or without re-feeding. In all experiments, plasma corticosterone was measured as an anticipated indicator of nutritional stress. In S. jarrovii, growth and body condition were reduced but lizards remained in positive energy balance on 1/3 ration, and hepatic IGF-1 mRNA and plasma corticosterone were not affected in comparison to full ration. In S. undulatus, growth, body condition, hepatic IGF-1 mRNA, and plasma IGF-1 were all reduced by zero ration and restored by refeeding. Plasma corticosterone was increased in response to zero ration and restored by full ration in hatchlings but not adults of S. undulatus. These data indicate that lizards conform to the broader vertebrate model in which severe food deprivation and negative energy balance is required to attenuate systemic IGF-1 expression. However, when animals remain in positive energy balance, reduced food intake does not appear to affect systemic IGF-1. Consistent with other studies on lizards, the corticosterone response to reduced food intake is an unreliable indicator of nutritional stress. Further studies on ecologically relevant variation in food intake are required to establish the importance of nutrition as an environmental regulator of the GH/IGF axis. Within the range of positive energy balance, the potential involvement of molecular signals in growth regulation requires further investigation. PMID- 25709096 TI - Where are we going in the management of interstitial lung disease in patients with systemic sclerosis? AB - Interstitial lung disease (ILD) affects about 90% of patients with systemic sclerosis (SSc). It is associated with a restrictive lung disease in only 30% of patients and is progressive in an even lower percentage. A low forced vital capacity at presentation, an extent of lung fibrosis >20% as detected by lung high-resolution computed tomography, high serum interleukin-6 levels, anti topoisomerase I antibody positivity and diffuse cutaneous SSc are each associated with SSc-ILD progression. However, no such association is absolute. Treating patients with a recent deterioration of lung function may allow to capture those with active disease. To date, cyclophosphamide (CYC) is the only drug found to stabilize or improve lung function in randomized clinical trials, but its small beneficial effect is short lived. Therefore, immunosuppressive maintenance therapy after CYC treatment is warranted. At present, however, the best therapeutical strategy after CYC therapy both in responders and in non-responders to CYC is still controversial. Based on a review of the literature, we suggest an approach to the management of SSc-ILD. PMID- 25709098 TI - The clinical application of mesenchymal stem cells and cardiac stem cells as a therapy for cardiovascular disease. AB - Cardiovascular disease (CVD) can be separated into two broad etiological categories, based on the presence or absence of ischemia as a causative factor. In both ischemic and non-ischemic heart disease, myocardial dysfunction or damage frequently results in the development of heart failure, characterized by dyspnea, fatigue and reduced survival. As one of the least regenerative organs in the human body, current standards of care are limited to mitigating loss and preventing recurrence of damage, rather than stimulating actual regeneration of functional heart tissue. Cell based therapies using progenitor cells from bone marrow and the heart itself have been evaluated in preclinical models, and have demonstrated some promise. Accordingly, several clinical trials using autologous stem and progenitor cells have been performed, showing that these cells can be used safely in humans, and suggesting that they may improve relevant clinical parameters in patients with heart disease. Two specific cell populations that are particularly promising are the bone marrow derived mesenchymal stem cell (MSC) and the heart muscle derived cardiac stem cell (CSC). This review will summarize preclinical studies evaluating these stem cell populations and will discuss the clinical application of these cells in contemporary clinical trials, and potential future investigations. PMID- 25709097 TI - Delta9-THC Disrupts Gamma (gamma)-Band Neural Oscillations in Humans. AB - Gamma (gamma)-band oscillations play a key role in perception, associative learning, and conscious awareness and have been shown to be disrupted by cannabinoids in animal studies. The goal of this study was to determine whether cannabinoids disrupt gamma-oscillations in humans and whether these effects relate to their psychosis-relevant behavioral effects. The acute, dose-related effects of Delta-9-tetrahydrocannabinol (Delta(9)-THC) on the auditory steady state response (ASSR) were studied in humans (n=20) who completed 3 test days during which they received intravenous Delta(9)-THC (placebo, 0.015, and 0.03 mg/kg) in a double-blind, randomized, crossover, and counterbalanced design. Electroencephalography (EEG) was recorded while subjects listened to auditory click trains presented at 20, 30, and 40 Hz. Psychosis-relevant effects were measured with the Positive and Negative Syndrome scale (PANSS). Delta(9)-THC (0.03 mg/kg) reduced intertrial coherence (ITC) in the 40 Hz condition compared with 0.015 mg/kg and placebo. No significant effects were detected for 30 and 20 Hz stimulation. Furthermore, there was a negative correlation between 40 Hz ITC and PANSS subscales and total scores under the influence of Delta(9)-THC. Delta(9)-THC (0.03 mg/kg) reduced evoked power during 40 Hz stimulation at a trend level. Recent users of cannabis showed blunted Delta(9)-THC effects on ITC and evoked power. We show for the first time in humans that cannabinoids disrupt gamma-band neural oscillations. Furthermore, there is a relationship between disruption of gamma-band neural oscillations and psychosis-relevant phenomena induced by cannabinoids. These findings add to a growing literature suggesting some overlap between the acute effects of cannabinoids and the behavioral and psychophysiological alterations observed in psychotic disorders. PMID- 25709099 TI - Inhibition of nicotinamide phosphoribosyltransferase (NAMPT) as a therapeutic strategy in cancer. AB - NAD is a metabolite that is an important cofactor and second messenger for a number of cellular processes such as genomic stability and metabolism that are essential for survival. NAD is generated de novo from tryptophan or recycled from NAM through the NAMPT-dependent salvage pathway. Alternatively, cells can convert NA to NAD through the NAPRT1-dependent salvage pathway. Tumor cells rapidly turn over NAD but do not efficiently utilize the de novo synthesis pathway. Hence, they are more reliant on the NAMPT salvage pathway for NAD regeneration making this enzyme an attractive therapeutic target for cancer. NAMPT is over-expressed in a number of cancer types such as colorectal, ovarian, breast, gastric, prostate, gliomas as well as B-cell lymphomas. A number of novel, potent and selective NAMPT small molecule inhibitors have been synthesized to date that have displayed robust anti-tumor activity in tumor models in vitro and in vivo. These inhibitors efficiently suppress NAD production in a time dependent manner and sustained reduction of NAD levels leads to loss of ATP and ultimately cell death. This review will summarize the chemical properties of these unique NAMPT inhibitors as well as their mechanism of action, pharmacodynamic activity and efficacy in tumor models in vitro and in vivo. An overview of biomarkers that predict response to treatment and mechanisms of resistance to NAMPT inhibitors will also be provided. Additionally, NAMPT inhibitors that have advanced into clinical trials will be reviewed along with experimental strategies tested to potentially increase the therapeutic index of these inhibitors. PMID- 25709100 TI - Flexible integrated circuits and multifunctional electronics based on single atomic layers of MoS2 and graphene. AB - Two-dimensional materials, such as graphene and its analogues, have been investigated by numerous researchers for high performance flexible and conformal electronic systems, because they offer the ultimate level of thickness scaling, atomically smooth surfaces and high crystalline quality. Here, we use layer-by layer transfer of large area molybdenum disulphide (MoS2) and graphene grown by chemical vapor deposition (CVD) to demonstrate electronics on flexible polyimide (PI) substrates. On the same PI substrate, we are able to simultaneously fabricate MoS2 based logic, non-volatile memory cells with graphene floating gates, photo-detectors and MoS2 transistors with tunable source and drain contacts. We are also able to demonstrate that these flexible heterostructure devices have very high electronic performance, comparable to four point measurements taken on SiO2 substrates, with on/off ratios >10(7) and field effect mobilities as high as 16.4 cm(2) V(-1) s(-1). Additionally, the heterojunctions show high optoelectronic sensitivity and were operated as photodetectors with responsivities over 30 A W(-1). Through local gating of the individual graphene/MoS2 contacts, we are able to tune the contact resistance over the range of 322-1210 Omega mm for each contact, by modulating the graphene work function. This leads to devices with tunable and multifunctional performance that can be implemented in a conformable platform. PMID- 25709102 TI - [Management of iodine-131 ablation therapy for thyroid carcinoma in a patient on chronic hemodialysis]. AB - Iodine-131 ablation therapy for thyroid cancer in the patient on chronic hemodialysis represents a real problem since the main route of elimination of radioiodine is urinary. There is no recommendation on the management of this treatment in the patient on hemodialysis. We report our experience of management of this treatment in a patient aged 38 years, undergoing hemodialysis for chronic renal failure, and who have been indicated the treatment with iodine-131 for papillary thyroid carcinoma high risk. After multidisciplinary discussions (nephrologists and specialists in nuclear medicine and radiation safety), it has been decided to treat the patient with continuous ambulatory peritoneal dialysis therapy (CAPD). Because of the low but continuous elimination of iodine in the case of CAPD, the patient received a reduced ablative (131)I dose of 1850 MBq, which is 30% of the usual dose delivered in subjects with normal renal function. The patient was hospitalized for four days in nuclear medicine unit and the (131)I radioactivity emitted from him was 2.5 MUSv/h at one meter at his hospital discharge. In conclusion, CAPD in relay of hemodialysis is a technique of renal replacement therapy that can be suggested to minimize exposure to radioactivity to the patient, his family and the medical staff. PMID- 25709103 TI - [Renal lymphangiectasia, a rare case of perirenal infiltration]. AB - Renal lymphangiectasia is a bilateral cystic infiltration of the perirenal and parapelvic space which is caused by the obstruction of the renal lymphatic tissue. To our knowledge only numbers have been reported in the literature. Renal lymphangiectasia usually asymptomatic and incidentally diagnosed has absolutely no effect on the patient outcome. Radiological imaging is typical so that the diagnosis does not need to be confirmed by a cyst punction. The lack of knowledge concerning renal lymphangiectasia make it usually confused with another cause of polycystic renal infiltration, such as the polycystic kidney disease. We report herein a case of renal lymphangiectasia diagnosed incidentally by an abdominal ultrasonography. PMID- 25709101 TI - Hypothalamic-pituitary-adrenal axis and behavioral dysfunction following early binge-like prenatal alcohol exposure in mice. AB - The range of defects that fall within fetal alcohol spectrum disorder (FASD) includes persistent behavioral problems, with anxiety and depression being two of the more commonly reported issues. Previous studies of rodent FASD models suggest that interference with hypothalamic-pituitary-adrenal (HPA) axis structure and/or function may be the basis for some of the prenatal alcohol (ethanol) exposure (PAE)-induced behavioral abnormalities. Included among the previous investigations are those illustrating that maternal alcohol treatment limited to very early stages of pregnancy (i.e., gestational day [GD]7 in mice; equivalent to the third week post-fertilization in humans) can cause structural abnormalities in areas such as the hypothalamus, pituitary gland, and other forebrain regions integral to controlling stress and behavioral responses. The current investigation was designed to further examine the sequelae of prenatal alcohol insult at this early time period, with particular attention to HPA axis associated functional changes in adult mice. The results of this study reveal that GD7 PAE in mice causes HPA axis dysfunction, with males and females showing elevated corticosterone (CORT) and adrenocorticotropic hormone (ACTH) levels, respectively, following a 15-min restraint stress exposure. Males also showed elevated CORT levels following an acute alcohol injection of 2.0 g/kg, while females displayed blunted ACTH levels. Furthermore, analysis showed that anxiety like behavior was decreased after GD7 PAE in female mice, but was increased in male mice. Collectively, the results of this study show that early gestational alcohol exposure in mice alters long-term HPA axis activity and behavior in a sexually dimorphic manner. PMID- 25709104 TI - [Tumour markers in chronic kidney disease]. AB - Tumour markers are high molecular weight glycoproteins whose interpretation in the presence of chronic renal disease may be disturbed. Apart from the prostate specific antigen, human chorionic gonadotropin and alpha-fetoprotein, their levels rise with chronic renal failure. For some markers, such as carcinoembryonic antigen, carcinogen antigen (CA) 15-3, cytokeratin fragment 21-1 or calcitonin, a threshold may be defined in a population with chronic renal failure, which may allow their use in cancer surveillance. Others, such as CA125, CA19-9, squamous cell carcinoma and neurospecific enolase, have a high variability and their use in patients with chronic renal disease remains difficult. PMID- 25709105 TI - The association between depression and leukocyte telomere length: a meta analysis. AB - BACKGROUND: Telomeres protect the ends of chromosomes, and shorter leukocyte telomeres are associated with poor health. Depression may be associated with the shortening of leukocyte telomeres. The present study set out to consolidate the varying effect sizes found so far in studies of depression and telomere length and to identify moderators of the relationship between depression and telomere length. METHODS: A meta-analytic investigation of the relationship between depression and leukocyte telomere length used information from 21,040 participants. RESULTS: A significant effect size, r = -.12, P < .001, indicated that depression was associated with shorter telomere length. Several variables significantly moderated effect size. Concurrent associations (k = 25) between depression and telomere length were significantly stronger than longitudinal associations (k = 5). Studies that used the Southern blot (k = 3) and fluorescent in situ hybridization (FISH; k = 2) assays to measure telomere length showed larger effect sizes than studies that used quantitative polymerase chain reaction (qPCR; k = 25). Finally, study reports that indicated that the telomere assays were conducted blind to depression level of participants (k = 11) had significantly lower effect sizes than those of other studies (k = 19). CONCLUSIONS: The significant relationship between depression and shorter telomere length is consistent with a theoretical model positing that distress, such as experienced in depression, results in physiological changes leading to shortened telomeres. PMID- 25709106 TI - Pathogenicity of lupus anti-ribosomal P antibodies: role of cross-reacting neuronal surface P antigen in glutamatergic transmission and plasticity in a mouse model. AB - OBJECTIVE: To assess whether autoantibodies against ribosomal P (anti-P), which are possibly pathogenic in neuropsychiatric systemic lupus erythematosus (NPSLE), alter glutamatergic synaptic transmission and to what extent the cross-reacting neuronal surface P antigen (NSPA) is involved. METHODS: We analyzed glutamatergic transmission and long-term potentiation (LTP) mediated by AMPA receptor (AMPAR) and N-methyl-d-aspartate receptor (NMDAR) by field excitatory postsynaptic potential (EPSP) at the CA3-CA1 synapse. AMPAR activation by patch-clamp recordings in primary ventral spinal cord neurons was analyzed. In primary hippocampal neurons, NSPA distribution was assessed by double immunofluorescence, and intracellular calcium changes were evaluated using Fura-2 AM. NSPA-LacZ reporter-knockin mice expressing a truncated NSPA were used to assess NSPA expression pattern and function in the brain using beta-galactosidase staining and comparative electrophysiology, calcium responses, and water maze memory tests. RESULTS: NSPA was expressed in the brain in hippocampal CA1, dentate gyrus and ventral, but not dorsal, CA3 regions, encompassing postsynaptic regions and partial colocalization with NMDAR. Notably, NSPA-LacZ reporter-knockin mice showed impaired memory, and decreased NMDAR activity and LTP, with neurons insensitive to anti-P autoantibodies. Anti-P autoantibodies enhanced CA1 postsynaptic transmission, increasing AMPAR and NMDAR activity and leading to LTP abrogation after prolonged (20-minute) incubation. CONCLUSION: Our findings indicate that the neuronal cell surface target of anti-P, NSPA, is involved in glutamatergic synaptic transmission and plasticity related to memory in the hippocampus, and mediates the deleterious effects of anti-P on these processes. Cognitive impairment, as well as other diffuse NPSLE manifestations, may develop when anti-P autoantibodies have access to brain regions coexpressing NSPA, AMPAR, and NMDAR. PMID- 25709107 TI - [Upper endoscopy findings in obese morbid patients candidates for bariatric surgery]. AB - INTRODUCTION: Body mass index has been associated with the presence and severity of various gastrointestinal symptoms. The aim of the study was to analyze the endoscopic findings and gastric histology of morbidly obese candidates for bariatric surgery. METHODS: We retrospectively included patients undergoing bariatric surgery at the Hospital de Leon from March 2005 to April 2013. The findings of upper gastrointestinal endoscopy and antral histology were collected. The relationship of body mass index (BMI) with gastroscopy findings and the presence of Helicobacter pylori were assessed. RESULTS: A total of 194 patients were included. An abnormality on endoscopy or antral biopsy was found in 48.7% and 78.9% of the patients, respectively. Three patients had gastric peptic ulcer, and consequently the intervention was postponed until healing. H.pylori infection was found in 63.9% of the patients. The presence of H.pylori and endoscopic findings were not related to BMI. CONCLUSION: Gastroesophageal disease is common in morbidly obese patients and approximately half of the patients had some kind of alteration on endoscopy. Gastroscopy and H.pylori testing prior to surgery is required to rule out disease that could delay or contraindicate surgery. PMID- 25709108 TI - [Should H. pylori be eradicated before bariatric surgery?]. PMID- 25709109 TI - Emerging infectious diseases of wildlife: a critical perspective. AB - We review the literature to distinguish reports of vertebrate wildlife disease emergence with sufficient evidence, enabling a robust assessment of emergence drivers. For potentially emerging agents that cannot be confirmed, sufficient data on prior absence (or a prior difference in disease dynamics) are frequently lacking. Improved surveillance, particularly for neglected host taxa, geographical regions and infectious agents, would enable more effective management should emergence occur. Exposure to domestic sources of infection and human-assisted exposure to wild sources were identified as the two main drivers of emergence across host taxa; the domestic source was primary for fish while the wild source was primary for other taxa. There was generally insufficient evidence for major roles of other hypothesized drivers of emergence. PMID- 25709110 TI - Subsolid pulmonary nodules: CT-pathologic correlation using the 2011 IASLC/ATS/ERS classification. AB - Adenocarcinoma is the most common histologic subtype of lung cancer. Recent advances in oncology, molecular biology, pathology, imaging, and treatment have led to an increased understanding of this disease. In 2011, the International Association for the Study of Lung Cancer, the American Thoracic Society, and the European Respiratory Society published a new international multidisciplinary classification. Using this taxonomy, we review the spectrum of subsolid pulmonary nodules seen on computed tomography together with their histopathologic correlates and current management guidelines. PMID- 25709111 TI - Fenoldopam for the prevention of contrast-induced nephropathy (CIN)-do we need more trials? A meta-analysis. AB - We conducted a pooled analysis of clinical trials comparing intravenous Fenoldopam (FP) with Saline/Placebo/N-acetyl cysteine (NAC) for the prevention of contrast-induced nephropathy (CIN). Five studies were eligible. Quantitative analyses were done with Review Manager (RevMan version 5.2.). A total of 85 out of 353 patients in Fenoldopam group while 73 among 366 in the control group were affected due to CIN. The risk ratio for the development of CIN in the Fenoldopam group was 1.19 compared to the control group. This was not statistically significant. Fenoldopam is no better than Placebo/Saline or NAC in preventing CIN, but more studies are required. PMID- 25709114 TI - DNA repair: a new tool to target DNA repair. PMID- 25709112 TI - Effect of R-CHOP chemotherapy on liver and mediastinal blood pool (18)F-FDG standardized uptake values in patients with non-Hodgkin's lymphoma. AB - AIM: We aimed to investigate the impact of chemotherapy on (18)F-FDG uptake in the liver and mediastinal blood pool (MBP) among patients with non-Hodgkin's lymphoma. METHODS: Twenty-three patients with NHL underwent baseline, interim, and postchemotherapy (18)F-FDG PET/CT. SUVmax and SUVmean values of the liver and MBP at imaging time were compared statistically. RESULTS: We did not find any significant differences between the liver and mediastinum SUVmean and SUVmax values (P>.05). CONCLUSIONS: Our study demonstrates that the (18)F-FDG uptake in the liver and MBP are not significantly affected by R-CHOP chemotherapy in patients with NHL. PMID- 25709119 TI - Of cholera and Ebola virus disease in Ghana. PMID- 25709118 TI - Therapeutic opportunities within the DNA damage response. AB - The DNA damage response (DDR) is essential for maintaining the genomic integrity of the cell, and its disruption is one of the hallmarks of cancer. Classically, defects in the DDR have been exploited therapeutically in the treatment of cancer with radiation therapies or genotoxic chemotherapies. More recently, protein components of the DDR systems have been identified as promising avenues for targeted cancer therapeutics. Here, we present an in-depth analysis of the function, role in cancer and therapeutic potential of 450 expert-curated human DDR genes. We discuss the DDR drugs that have been approved by the US Food and Drug Administration (FDA) or that are under clinical investigation. We examine large-scale genomic and expression data for 15 cancers to identify deregulated components of the DDR, and we apply systematic computational analysis to identify DDR proteins that are amenable to modulation by small molecules, highlighting potential novel therapeutic targets. PMID- 25709120 TI - Aflatoxins and fumonisins contamination of home-made food (weanimix) from cereal legume blends for children. AB - BACKGROUND: Weanimix is an important food for children in Ghana. Mothers are trained to prepare homemade weanimix from beans, groundnuts and maize for their infants. Groundnuts and maize are prone to aflatoxin contamination while fumonisin contaminates maize. Aflatoxin, is produced by the Asperguillus fungi while fumonisin, is produced by Fusarium fungi. These mycotoxins occur in tropical areas worldwide due to favorable climate for their growth. OBJECTIVE: The objective of the study was to determine the levels of aflatoxin and fumonisin in homemade weanimix in the Ejura-Sekyedumase district in the Ashanti Region of Ghana. METHODS: Thirty six homemade weanimix samples (50g each) were collected from households. Aflatoxin and fumonisin were measured using a fluorometric procedure described by the Association of Official Analytical Chemist (AOAC official method 993.31, V1 series 4). RESULTS: Aflatoxin and fumonisin were detected in all 36 samples, range 7.9-500ppb. Fumonisin levels range: 0.74 11.0ppm). Thirty (83.3%) of the thirty six samples were over the action limit of 20ppb for aflatoxin with an overall mean of 145.2 ppb whiles 58.3% of the samples had fumonisins above the action limit of 4 ppm with an overall mean of 4.7 ppm. CONCLUSION: There were significant aflatoxin and fumonisin contamination of homemade weanimix. Children fed on this nutritional food were being exposed to unacceptable levels of aflatoxin and fumonisin. Therefore there is a critical need to educate mothers on the dangers of mycotoxin exposure and to develop strategies to eliminate exposure of children fed homemade weanimix to aflatoxin and fumonisin. PMID- 25709121 TI - The profile of risk factors and in-patient outcomes of stroke in Kumasi, Ghana. AB - BACKGROUND: Stroke is an emerging public health challenge in Ghana requiring urgent attention for its control. Because some of the risk factors for stroke are modifiable, characterisation of these risk factors in the Ghanaian population as well as outcomes of stroke are urgently needed to guide policy for non communicable diseases. We therefore conducted this study to evaluate the frequencies of the traditional risk factors and outcomes of stroke at the main tertiary referral centre in the middle belt of Ghana in a prospective observational study. METHODS AND RESULTS: Patients with a clinical diagnosis of stroke were consecutively recruited and vascular risk factors were assessed as well as markers of severity of stroke and in-patient treatment outcomes. 265 patients were recruited, 56.6% were females and mean +/- SD age of 64.6 +/- 14.54 years. 85%, 73% and 58% of patients had systemic arterial hypertension, physical inactivity and obesity respectively as common risk factors. We identified that patients with stroke had a median of 3 traditional risk factors, were unaware of the presence of these risk factors or were poorly controlled if known. Stroke was associated with a high in-patient case fatality rate of 43% principally among patients with haemorrhagic stroke. CONCLUSIONS: Our findings indicate that urgent concerted efforts are required to improve public awareness and management of the prevailing risk factors of stroke in Ghana. PMID- 25709122 TI - Therapeutic effect of continuous exercise training program on serum creatinine concentration in men with hypertension: a randomized controlled trial. AB - BACKGROUND: Creatinine (Cr) has been implicated as an independent predictor of hypertension and exercise has been reported as adjunct therapy for hypertension. The purpose of the present study was to investigate the effect of continuous training programme on blood pressure and serum creatinine concentration in black African subjects with hypertension. METHODS: Three hundred and fifty seven male patients with mild to moderate (systolic blood pressure [SBP] between 140-180 & diastolic blood pressure [DBP] between 90-109 mmHg) essential hypertension were age matched and randomly grouped into continuous & control groups. The continuous group involved in an 8 weeks continuous training (60-79% HR reserve) of between 45 minutes to 60 minutes, 3 times per week, while the control group remain sedentary. SBP, DBP, VO2max, serum Cr, body mass index (BMI), waist hip ratio (WHR) and percent (%) body fat. Analysis of covariance (ANCOVA) and Pearson correlation tests were used in data analysis. RESULTS: Findings of the study revealed significant decreased effects of continuous training programme on SBP, DBP, Cr, BMI, WHR, % body fat and significant increase in VO2max at p< 0.05. Serum Cr is significantly and negatively correlated with SBP (-.335), DBP (.194), BMI (.268), WHR (-.258) and % body fat (-.190) at p<0.05. CONCLUSION: The present study demonstrated a rationale bases for the adjunct therapeutic role of moderate intensity continuous exercise training as a multi-therapy in the down regulation of blood pressure, serum Cr, body size and body fat in hypertension. PMID- 25709123 TI - Presentation of glaucoma in the greater Accra metropolitan area of Ghana. AB - BACKGROUND: This study addresses the prevalence and clinical presentation of patients with primary open angle glaucoma (POAG) in the greater Accra metropolitan area. METHODS: This is a retrospective case series of 455 patients (813 eyes) at the Emmanuel Eye Clinic. Patients were diagnosed from May 2008 to Nov 2011. The definition of POAG conformed to the International Society of Geographical and Epidemiological Ophthalmology (ISGEO) criteria. Information collected included basic demographic data, distribution of glaucoma subtypes, measured intraocular pressure (IOP), best corrected visual acuity (BCVA) and optic disc measurements. RESULTS: Nearly 24% presented blind in at least one eye. The average age was 56.7 +/-16.7 years and the average IOP was 33.9 mmHg +/- 12.7 mmHg for right eyes and 33.5 mmHg +/-12.0 mmHg for left eyes. The mean vertical cup to disc ratio (vCDR) was 0.83 for right eyes versus 0.82 for left eyes. A total of 32 patients (53 eyes) were diagnosed with normal tension glaucoma (NTG). Statistically significant differences between the NTG and high tension groups included age (45.3 +/- 16.7 vs. 56.7 +/-16.7, p<0.001), mean IOP (19.1 mmHg +/- 4.5 mmHg vs. 33.7 +/- 12.4 mmHg, p<0.001) and mean vCDR (0.76 +/- 0.17 vs. 0.83 +/-0.10, p<0.01). Comparing age-matched NTG patients with high tension glaucoma patients showed no significant difference in vCDR. CONCLUSIONS: The clinical presentation of POAG at the Emmanuel Eye Center is characterized by elevated IOP and grossly advanced optic neuropathy. Significant differences between high tension glaucoma and NTG were identified. PMID- 25709124 TI - The effect of medical therapy on IOP control in Ghana. AB - BACKGROUND: To investigate IOP control following twelve months of continuous medical therapy in Ghana. METHODS: This retrospective case series included 163 glaucoma patients diagnosed at a referral eye center between 1996 and 2006. Information collected included age, gender, IOP at presentation, six months and one year post treatment and types of anti-glaucoma medications prescribed. Optimal IOP control was defined according to results from the Advanced Glaucoma Intervention Study (AGIS), which demonstrated arrest of visual field progression in patients with IOP < 18 mmHg at all visitations: Level 1 (post-treatment IOP <= 21 mmHg); Level 2 (<= 18 mmHg) and level 3 (<= 16 mmHg). The principal outcome measure was the achievement of IOP <18 mmHg at six months and twelve month visitations. RESULTS: One hundred sixty three patients were analyzed. These included 68 males (41.7%) and 95 females (58.3%). The mean age was 57+/-16 (median 59 years; range 7 - 95 years). There was no significant difference in age (p=0.35) or mean IOP (p=0.08) between genders. The mean pre-treated IOP of 31.9+/ 8.9 mmHg significantly decreased to 21.3+/-6.6 mmHg at 6 months (p=0.001), with 57.4% of eyes at Level 1 IOP control, 25.3% at Level 2 and 15.4% at Level 3 and decreased further at 12 months to 20.7+/-6.9 mmHg (p=0.48) with 69.7% of eyes at Level 1, 34.4% at Level 2, and 12.4% at Level 3. CONCLUSIONS: Current medical regimen is insufficient to reduce IOP to target levels as defined in the Advanced Glaucoma Intervention Study. PMID- 25709125 TI - Prevalence and severity of pterygium among commercial motorcycle riders in south eastern Nigeria. AB - BACKGROUND: Pterygium is common among outdoor workers who are daily exposed to sunlight and dust due to repeated conjunctival /corneal drying and micro-trauma especially in the tropics. Commercial motorcyclists in Nigeria are outdoor workers who spend the greater part of the day outdoors under the intense heat and dust characteristic of this part of the world and would therefore be largely predisposed to developing this conjunctival disorder. OBJECTIVE: The aim of this study is to determine the prevalence and severity of pterygium among these workers and relate these findings to their duration of work. METHODS: A cross sectional study with a multi stage random sampling design was used to choose the 615 subjects enrolled in the study. RESULTS: The prevalence for pterygium was 19.3% (206 eyes) with stage 1 occurring mostly (52%) followed by stage 2(46%). Pterygium was common among riders who had been riding for 5 years or less. The relationship between duration of riding and pterygium severity was significant (p=0.009). This prevalence was unaffected by the use of regular sun glasses (p=0.188). CONCLUSION: A strong relationship exists between commercial motorcycle riding and development of pterygium not affected by using regular sunglasses. We recommend that helmets with full face shields and/or proper UV protected riding goggles where the helmets have no face shield be enforced by the regulation bodies so as to reduce the prevalence of these disorders. PMID- 25709126 TI - Pre-donation screening of blood for transfusion transmissible infections: the gains and the pains - experience at a resource limited blood bank. AB - OBJECTIVE: To determine whether or not pre-donation testing of blood donors affords substantial cost savings without compromise to blood transfusion safety. Pre-donation testing of blood donors for Transfusion Transmissible Infections (TTIs) is done in most developing countries because substantial cost savings are made from resources, materials and man-hours which would have been spent to procure infected blood units. Simple rapid test kits used in pre-donation testing is not as sensitive as the Enzyme Linked Immuno-sorbent Assay (ELISA) method used in post-donation screening in a quality assured manner. DESIGN: It is a retrospective study where records of pre- and post-donation tests done in donor clinic of University of Ilorin Teaching Hospital, between January and December 2010 were retrieved. All processes and inputs were evaluated and costs calculated for pre-donation testing by simple rapid techniques and post donation screening by ELISA. RESULTS: 5000 prospective donors were tested in the study period. The cost of single rapid Pre-donation testing was less than that of single ELISA Post donation screen. The cost of double rapid Pre-donation and Post donation ELISA screen exceeded the cost of single post donation ELISA screen. Substantial cost savings were made when single rapid Pre-donation testing is relied on. More blood units were found reactive for the TTIs with the more expensive Post-donation ELISA. CONCLUSION: Pre-donation testing of blood donors was not cost effective. Although, there is an apparent savings if pre-donation testing is not followed by post-donation ELISA testing, it is done at a compromise to blood transfusion safety. PMID- 25709127 TI - A review of 156 odontogenic tumours in Calabar, Nigeria. AB - BACKGROUND: Odontogenic tumours occur in our environment and because of late treatment, cause considerable disabilities. OBJECTIVE: To review cases of odontogenic tumours in our centre in order to obtain a baseline data and subsequently compare the results with that obtained elsewhere. PATIENTS AND METHODS: Using hospital case files and register, we carried out a 15-year retrospective study of odontogenic tumours at the Dental and Maxillofacial Clinic, University of Calabar Teaching Hospital, Nigeria. The data documented include age, gender, duration of lesion, type of tumour, socio-economic class, type of surgery, and complaints during follow-up reviews. RESULTS: Majority of the patients (n=49, 31.4%) were in the third decade of life. There were 85 (54.5%) males and 71 (45.5%) females, giving male to female ratio of 1.2:1. There was a significant association between the type of odontogenic tumour and the age of occurrence (p=0.000). The longer the duration of symptoms before presentation, the larger the tumours (p=0.000). The benign odontogenic tumours were 151 (96.8%), ameloblastoma (n=74, 47.4%) being the commonest. Jaw resection (54.5%) was the predominant treatment. Majority (58.0%) of the complications following treatment were Facial deformity, malocclusion and impaired mastication. CONCLUSION: Majority of the patients was in the lower socio-economic class, presented late for treatment and a few with aesthetic and functional impairment returned for secondary surgery. The intervention of agencies of government and non-governmental organizations is required to assist these patients if we are to accomplish the core healthcare system values in our environment. PMID- 25709128 TI - A systems view and lessons from the ongoing Ebola Virus Disease (EVD) outbreak in West Africa. AB - This article analyses the on-going (2014) Ebola Virus Disease (EVD) outbreak in West Africa from a systems perspective; and draws out lessons for West Africa in general and Ghana in particular. PMID- 25709129 TI - Non-syndromic oligodontia in permanent dentition: a case report. AB - Tooth agenesis is one of the most common congenital anomalies seen in humans. Although absence of one or more teeth is common but absence of multiple teeth is rare. Oligodontia is a rare developmental anomaly, involving agenesis of six or more permanent teeth, excluding the third molars. The reported prevalence of oligodontia in permanent dentition is 0.14%. Oligodontia can present as an isolated condition or as a part of a syndrome. The present case report highlights a unique case of non syndromic oligodontia, with agenesis of four permanent incisors, left permanent canine and right second premolar in the mandibular arch and its management with a novel fixed functional prosthetic appliance. Prosthetic rehabilitation is an urgent need for these kind of patients so that they do not suffer from masticatory and esthetic problems which can eventually lower the self esteem of individuals. PMID- 25709130 TI - Problems with use of medicines. PMID- 25709131 TI - Predictors of subjective well-being among older Ghanaians. AB - BACKGROUND: Later years of life are accompanied by many physical, emotional and environmental changes which may impact on the well-being of the individual. Many factors are known to influence the subjective well-being of older adults, but most, if not all of this information was the result of studies in the Western world. This study aimed at obtaining and documenting the predictors of subjective well-being (SWB) among older Ghanaians. METHODS: Data for the study was obtained from the WHO SAGE study. The single item measure of life satisfaction was used to determine subjective well-being. Descriptive statistics as well as logistic regression analysis were carried out to determine the predictors of SWB. RESULTS: A total of 4724 individuals aged 50 years and above responded to the questionnaires. Of these 50.4% were males. Following multivariate logistic regression analysis, age, sex, educational level, income and ethnic background were found to significantly affect the SWB of older Ghanaians. Being male was associated with higher level of SWB (OR=1.68; CI: 1.39 - 2.03). For those 50 years and above, being younger (50-59 years) was also associated with a high level of SWB (OR=17.72; CI: 10.13-30.98). Earning a low income and having low educational level were both associated with low levels of SWB (OR=0.304; CI: 0.22 0.42; and OR=0.47; CI: 0.37-0.60 respectively). Ewes (p=0.027), Grumas (p=0.002) and Mole-Dagbons (p=0.04) had significantly higher SWB compared to the other ethnic groups. CONCLUSION: Among older Ghanaians, factors that positively influence SWB are younger age, male sex, high educational level and high income. PMID- 25709133 TI - Adverse drug reaction reporting by doctors in a developing country: a case study from Ghana. AB - BACKGROUND: Spontaneous adverse drug reaction reporting is the most widely used and cost effective method of monitoring the safety of drugs. This method is heavily afflicted by underreporting by healthcare professionals. The study aims at assessing adverse drug reaction (ADR) reporting rate by doctors, knowledge of the reporting system and attitudes to SADR in the Greater Accra region. METHODS: This was a cross sectional survey of 259 doctors randomly selected from 23 hospitals classified as government 199 (76.8%), quasi-governmental 43(16.6%) and private 17 (6.6%) hospitals in the Greater Accra Region of Ghana. Data collection was by self-administered questionnaire from May 5, 2012-July 6, 2012. Descriptive statistics was used to describe the background characteristics of the doctors and the outcome measures like training and reasons for ADR reporting were summarized as frequencies and percentages. RESULTS: One-third (27.4%) of doctors surveyed had received previous training on drug safety monitoring and ADR reporting; training and knowledge of the reporting system was found to improve reporting. More than half 154 (59.5%) of the doctors had seen a patient with suspected ADR in the past one year although only 31 (20%) had reported it by completing the SADR reporting form. Doctors working in government hospitals were about 5 times more likely to report than those in private hospitals [OR=4.94, 95%CI (1.55 15.69)]. CONCLUSION: Training and knowledge of the ADR reporting system were found to be associated with the likelihood of reporting an ADR. Most of the doctors had not previously received training on ADR reporting. PMID- 25709132 TI - Comparing performance of amoxicillin and intramuscular benzathine penicillin in relieving manifestations of streptococcal pharyngitis in children. AB - OBJECTIVE: To compare clinical and bacteriologic responses to intramuscular benzathine penicillin G (BPG) and single dose of amoxicillin in Group A streptococcal (GAS) pharyngitis. DESIGN: This study included 571 children from 6 to 15 years old age, with pharyngitis, who were admitted to 45 elementary and guidance schools from 7 regions of Education Organization in North-East of Iran, Mashhad. They were screened for enrollment and if he/she presented pharyngitis with clinical criteria of sore throat, erythema, exudate and tender or enlarged anterior cervical lymph nodes. Exclusion criteria included reports of antibiotic use, negative throat culture for GAS and history of allergy to the drugs. Clinical and bacteriologic responses to BPG and once daily orally amoxicillin were considered and compared. RESULTS: In the amoxicillin group, treatment failure was more than the penicillin group (18.9% vs. 6.4%, respectively) but the difference was not statistically significant (p < 0.05). Both drugs were significantly effective in reducing pharyngitis manifestations but penicillin was significantly more effective in reducing exudate than amoxicillin. CONCLUSION: Our study was in line with studies comparing the two drugs. The results show that once-daily therapy with amoxicillin is as effective as intramuscular benzathine penicillin G for the treatment of GAS pharyngitis, but penicillin was significantly more effective in reducing exudate and concurrent signs vs. amoxicillin. PMID- 25709134 TI - Pharmacoepidemiology of antiretroviral drugs in a teaching hospital in Lagos, Nigeria. AB - OBJECTIVE: Prescribing, adherence, and adverse drug events to HAART in a large antiretroviral programme in Lagos was evaluated. DESIGN: A retrospective 5 year open cohort study. SETTING: The AIDS Prevention Initiative in Nigeria (APIN) clinic at LUTH is one of the United States Presidential Emergency Plan for AIDS Relief (PEP-FAR) funded centers for HIV relief program in Nigeria Participants The case files of 390 patients on HAART and attending the APIN clinic were reviewed sequel to random selection. MAIN OUTCOME MEASURES: Demographics of the patients and pattern of antiretroviral (ARV) combination drugs prescribed were extracted from their case files. The details of the adverse drug events (ADEs) were extracted from drug toxicity forms regularly filled for each patient. A Chi square test with Yates correction was used to determine the association between adherence and therapeutic outcome. RESULTS: A total of 2944 prescriptions were assessed. Zidovudine + lamivudine + nevirapine (35.87%) and stavudine + lamivudine + nevirapine (35.63%) were the most frequently prescribed combinations. Over 2000 ADEs were reported with cough (13.3%), fever (8.75%) and skin rashes (8.01%) being the most frequently reported. Drug adherence was associated with good therapeutic outcome (chi(2) = 115.60, p<0.0001). CONCLUSIONS: Zidovudine + lamivudine + nevirapine was the most frequently prescribed ARV combination. Cough was the most frequently reported ADE. Interventions aimed at rational prescribing of ARV drugs and improving adherence to antiretroviral drugs is essential for good therapeutic outcome in the treatment of HIV infection. PMID- 25709135 TI - Dermis-fat grafts and enucleation in Ghanaian children: 5 years' experience. AB - BACKGROUND: Enucleation in young children often results in retarded orbital growth ipsilaterally. The need for an implant that will naturally grow with the child, like Dermis-fat Graft (DFG), for managing the anophthalmia has been of interest over the years. OBJECTIVE: To evaluate the use of DFG as an implant for volume replacement post-enucleation. STUDY DESIGN: A prospective non-comparative case series involving 18 consecutive children who had DFG either primarily or secondarily in conjunction with enucleation for intraocular pathologies, from December 2007 to September 2012, at the ophthalmology unit, Korle-Bu. Data from patients who had a minimum of three months follow up(FUP) were analysed. OUTCOME MEASURES: Complete covering of DFG with healthy conjunctiva, increase in volume of DFG, and presence or absence of complications. RESULTS: Fifteen patients were analysed, aged nine months to ten years (mean (SD), 3.7+/-2.7years). Eight (53.3%) were females. Thirteen (86.7%) DFGs were secondary and 2(13.3%) primary. Indications for enucleation were intraocular retinoblastoma (n=10, 66.7%), unexplained retinal detachment mimicking retinoblastoma (n=3,20.0%), anterior staphyloma (n=1,6.7%) and medulloepithelioma (n=1,6.7%). Fourteen (93.3%) patients showed increase in volume of DFG. Time for Conjunctival reepithelialisation of the dermal surface was four to fourteen weeks (mean/median=5.5/4.0). Complications encountered were infection (n=1,6.7%), infection with necrosis (n=1,6.7%), melanosis /keratinization (n=2, 13.3%) and cysts(n=2,13.3%). The patients were followed up for 3 to 54 months (mean/median 20.13 /16.00). CONCLUSION: DFG for management of post-enucleation anophthalmia in Ghanaian children showed 93.3% success. PMID- 25709136 TI - Social demographic characteristics of women with pelvic organ prolapse at the Tamale Teaching Hospital, Ghana. AB - OBJECTIVE: To determine the prevalence, social demographic characteristics and types of pelvic organ prolapse that patients present with at the Tamale Teaching Hospital (TTH). METHODS: A descriptive study of pelvic organ prolapses at the Tamale Teaching Hospital from 1(st) January 2010 to 31(st) December 2011. RESULTS: The 118 pelvic organ prolapse cases constituted (2.68%) of the 4403 gynaecological out-patient cases seen during the two year study period. The mean age and standard deviation was (45.9+/- 15.1) and the modal age group was 30-39 years with 32 (27.1%) of cases. There were 112 (94.9%) cases of uterine prolapse, 95 (80.5%) had cystocele, 16 (13.5%) patients had rectoceles and 3 (2.5%) had enterocele. Their main occupations were trading 66 (55.9%) and farming 44 (37.3%), seventy (62.5%) of the patients with uterine prolapse were premenopausal while (10) 14.3% of the premenopausal cases had an ongoing pregnancy. The parity ranged from zero to 13 with mean and standard deviation of (4.4+/-1.7). Fifty five (46.6%) were from the Tamale metropolis and only 12 (10.5%) had all their deliveries in hospital. The commonest complication was decubitus ulcer present in 20 (16.9%) patients, 16(80%) of it in patients with procedentia. CONCLUSION: Pelvic organ prolapse is not a rare gynaecological condition at the Tamale Teaching Hospital. The patients are relatively young and are from various districts in the northern region. Some occupational, socio-cultural practices and reproductive characteristics may be contributory to severity of pelvic organ prolapse. PMID- 25709137 TI - Pain, range of motion and activity level as correlates of dynamic balance among elderly people with musculoskeletal disorder. AB - BACKGROUND: Assessment of impairment and disability measures on dynamic balance status of elderly patients is well documented in the rehabilitation of neuromuscular disorders. Few studies however considered similar evaluation in musculoskeletal disorders. OBJECTIVE: To determine the influence of pain, hip range of motion and level of activity on dynamic balance among elderly people with hip osteoarthritis (OA). METHODS: Elderly patients with hip OA participated in the cross-sectional survey. The impairment measures were assessed using the visual analogue scale and double-arm universal goniometer whilst their levels of activity were assessed with the Barthel Index. Participants performed Turn-180 on two trials by taking steps clockwise and anti-clockwise round a sturdy arm chair. The total number of steps taken to complete each Turn- 180 was determined. Descriptive statistics were used to summarize data whilst Pearson moment correlation coefficient determined the correlations of the variables at 95% confidence interval. RESULTS: The study involved 87 participants comprising 40(46%) males and 47(54%) females. The age of the participants ranged from 60 to 74 years with a mean of 65.8+/-4.5 years. There was a positive and significant correlation (r=0.596; p<0.001) between the participants' pain and steps taken to complete Turn-180. The participants' hip flexibility and the level of activity were also significantly and inversely correlated with the performance of Turn 180. CONCLUSION: The dynamic balance of the sampled elderly patients was considerably influenced by pain, hip flexibility and level of activity, thereby putting premium on the assessment of the variables during musculoskeletal rehabilitation of elderly patients. PMID- 25709138 TI - State of dietetics practice in Ghana. AB - OBJECTIVE: Prevalence of obesity and related diseases has increased in Ghana. Dietitians have essential skills to prevent and manage dietary diseases. However, little is known about dietetic practice in Ghana. This paper describes the history and current state of dietetics practice in Ghana. METHODS: A questionnaire was administered to 13 dietitians and six dietetic interns in February 2012. The questionnaire collected data on perceptions about dietetics practice, career progression, and challenges in dietetics practice in Ghana. Key informant interviews (KII) on history of dietetics in Ghana were also held with four retired dietitians, and two dietetics educators. Additional KII were conducted with the Chief dietitian, two officers of the Ghana Dietetic Association, and three other dietitians. Most KII were conducted face-to-face but a few were only possible via telephone. Some of the KII were audio-recorded, in addition to handwritten notes. Following transcription of audiorecorded interviews, all data were subjected to content analysis. RESULTS: Dietetic practice in Ghana has evolved from low-skilled cadre (catering officers) offering hospital-based meal services to the current era of available trained dietitians providing diet therapy in diverse settings. However, 80% of the 35 dietitians identified are working in Accra. In three regions of Ghana, there are no dietitians. There remain limited opportunities for continuous learning and professional career advancement. Additionally, there are many unqualified dietitians in practice. CONCLUSION: A huge unmet need for dietitians exists in all regions of Ghana, except Greater Accra. Bridging this gap is essential to increase access to dietetic care throughout Ghana. PMID- 25709139 TI - Endomyocardial fibrosis associated with Schistosoma haematobium infection. AB - Endomyocardial fibrosis (EMF) is a form of restrictive cardiomyopathy common in the tropics and subtropics. The aetiology of EMF is unknown but helminth infestations such as schistosomiasis have been implicated. Two boys aged 8 and 10 years with EMF associated with Schistosoma haematobium, are described. The schistosomes in both cases may have been acquired from contact with contaminated water collected and stored in containers and subsequently used for bathing. Both patients were managed conservatively. Overall prognosis of EMF is poor and this report emphasizes the importance of public health interventions in the control of schistosomiasis. PMID- 25709140 TI - The unacknowledged impact of urinary schistosomiasis in children: 5 cases from Kumasi, Ghana. AB - Urinary schistosomiasis is a parasitic disease caused by Shistosoma haematobium. It is prevalent in several parts of Africa particularly in areas where there are large water bodies. In most affected communities, the condition is often accepted as normal since to them, all growing children pass blood in their urine and "grow out of it". Mass treatment of school children has been a regular exercise often undertaken by stake holders to decrease the disease burden and reduce transmission in selected communities. Urinary schistosomiasis can have devastating impact on the urinary tract which is often unacknowledged and unevaluated. Such omission could have implication for progressive renal damage which, if not detected and treated, could lead to end stage renal failure and death. We present five (5) cases of urinary schistosomiasis with severe obstructive uropathy seen at the paediatric nephrology/urology units of Komfo Anokye Teaching Hospital, Ghana. All five cases had some degree of anaemia and hypertension. Two of the five cases presented with end stage renal failure and died subsequently whilst two underwent successful surgery. One made a spontaneous recovery from the urinary obstruction though still has significant renal impairment. This potential devastating effect of urinary schistosomiasis on the kidneys calls for thorough evaluation and assessment of each confirmed case to include blood pressure measurement, full blood count, and ultrasonography of the urinary system. Mass screening programmes should be combined with portable ultrasonography of the kidneys, ureters and bladder. PMID- 25709141 TI - Poly(ethylene glycol) Corona Chain Length Controls End-Group-Dependent Cell Interactions of Dendron Micelles. AB - To systematically investigate the relationship among surface charge, PEG chain length, and nano-bio interactions of dendron-based micelles (DMs), a series of PEGylated DMs with various end groups (-NH2, -Ac, and -COOH) and PEG chain lengths (600 and 2000 g/mol) are prepared and tested in vitro. The DMs with longer PEG chains (DM2K) do not interact with cells despite their positively charged surfaces. In sharp contrast, the DMs with shorter PEG chains (DM600) exhibit charge-dependent cellular interactions, as observed in both in vitro and molecular dynamics (MD) simulation results. Furthermore, all DMs with different charges display enhanced stability for hydrophobic dye encapsulation compared to conventional linear-block copolymer-based micelles, by allowing only a minimal leakage of the dye in vitro. Our results demonstrate the critical roles of the PEG chain length and polymeric architecture on the terminal charge effect and the stability of micelles, which provides an important design cue for polymeric micelles. PMID- 25709142 TI - Remote Acculturation of Early Adolescents in Jamaica towards European American Culture: A Replication and Extension. AB - Remote acculturation is a modern form of non-immigrant acculturation identified among early adolescents in Jamaica as "Americanization". This study aimed to replicate the original remote acculturation findings in a new cohort of early adolescents in Jamaica (n = 222; M = 12.08 years) and to extend our understanding of remote acculturation by investigating potential vehicles of indirect and intermittent intercultural contact. Cluster analyses replicated prior findings: Relative to Traditional Jamaican adolescents (62%), Americanized Jamaican adolescents (38%) reported stronger European American cultural orientation, lower Jamaican orientation, lower family obligations, and greater conflict with parents. More U.S. media (girls) and less local media and local sports (all) were the primary vehicles of intercultural contact predicting higher odds of Americanization. U.S. food, U.S. tourism, and transnational communication were also linked to U.S. orientation. Findings have implications for acculturation research and for practice and policy targeting Caribbean youth and families. PMID- 25709143 TI - Female access and diet affect insemination success, senescence, and the cost of reproduction in male Mexican fruit flies Anastrepha ludens. AB - Hypotheses exploring the influence of dietary conditions on the life history trade-off between survival and reproductive success are extensively tested in female insects, but are rarely explored in males. Here, the impact of dietary quality and female access on age-specific reproduction and survival of male Mexican fruit flies, Anastrepha ludens Loew (Diptera: Tephritidae), are examined. There is a clear cost of female access for males with access to dietary protein, measurable as a decrease in life expectancy, which is further influenced by the age when females are introduced. A protein deficient diet reduces the lifespan benefit of virginity and masks the detrimental effect of female access on male life expectancy. Dietary protein is not necessary for reproductive success, but access to protein at eclosion improves the lifetime reproductive success of males compared to when it is delayed. Overall, reproductive success diminishes as the male flies age, regardless of the dietary conditions, providing evidence for reproductive senescence in males. Delaying the males' access to a protein source fails to influence the negative effect of age on reproductive ability. Because age specific reproductive rates decline with age, regardless of diet, male fitness does not benefit from lifespan extension. Therefore, males can be expected to allocate available resources towards reproductive effort in favour of extended lifespan, regardless of mate and protein availability. PMID- 25709144 TI - Gender Differences in Child and Adolescent Social Withdrawal: A Commentary. AB - In a manuscript entitled, "Bashful boys and coy girls: A review of gender differences in childhood shyness" Doey et al. (2013) suggest that shyness and its related constructs pose a greater developmental risk for boys compared to girls. They support this claim by citing empirical evidence suggesting that shy and anxiously withdrawn boys are responded to more negatively by important others (i.e., parents, peers, and teachers) and that the relationship between internalizing problems and anxious withdrawal is stronger for boys compared to girls. The principal aim of our commentary is to provide a critical examination of Doey et al.'s conclusions vis-a-vis gender differences in child and adolescent shyness. In this response, we begin by providing important theoretical background regarding shyness and its related constructs. Next, we critically examine the two main arguments the authors use in support of their conclusion through a review of existing empirical and theoretical work as well as the presentation of data from The Friendship Project. These data were analyzed with the specific purpose of providing an empirical test of the hypotheses implicit in Doey et al.'s primary arguments: 1) shy and anxiously withdrawn boys are responded to more negatively than girls and 2) the association between anxious withdrawal and internalizing problems is stronger for boys compared to girls. Our results indicate mixed support for these two claims. Finally, we conclude by suggesting new directions for future researchers interested in clarifying the relationship between gender and both the correlates and outcomes of childhood shyness. PMID- 25709146 TI - Parapharyngeal space tumours: the efficiency of a transcervical approach without mandibulotomy through review of 44 cases. AB - The aim of this study was to describe our experience with benign parapharyngeal space tumours resected via a transcervical route without mandibulotomy and to investigate associated postoperative sequelae and complications. The study investigated and analysed the retrospective charts of 44 patients who underwent surgery for benign parapharyngeal space tumours over a 10-year period. The diagnosis was reached in all patients with clinical and radiologic findings; preoperative fine-needle aspiration biopsy was not performed in any case. The preferred means of accessing the parapharyngeal space in all patients was a transcervical route. In 5 of these patients, transparotid extension was performed due to the position of the tumour. Tumours were classified radiologically as poststyloid in 27 cases and prestyloid in 17 cases. The final histopathologic diagnosis was vagal paraganglioma in 16 cases, pleomorphic adenoma in 13 cases, schwannoma in 10 cases and comparatively rarer tumours in the remaining 5 cases. In three patients, cranial nerve paralysis was observed during preoperative evaluation. Permanent cranial nerve paralysis occurred in 19 cases (43.2%) in the postoperative period, the majority of which were neurogenic tumours such as vagal paraganglioma (n = 16) and schwannoma (n = 2), and one case of non-neurogenic parapharyngeal tumour. The median duration of follow-up was 61 +/- 33 months. There was no local recurrence in any patient during the follow-up period. A transcervical approach should be the first choice for excision of parapharyngeal space tumours, except for recurrent or malignant tumours, considering its advantages of providing direct access to the neoplasm, adequate control of neurovascular structures from the neck and optimal aesthetic outcomes due to preservation of mandibular continuity with minimal morbidity and hospitalisation time. PMID- 25709145 TI - HPV in oropharyngeal cancer: the basics to know in clinical practice. AB - The incidence of oropharyngeal squamous cell carcinoma (OPSCC) is rising in contrast to the decreasing incidence of carcinomas in other subsites of the head and neck, in spite of the reduced prevalence of smoking. Human papilloma virus (HPV) infection, and in particular type 16 (HPV-16), is now recognized as a significant player in the onset of HPV positive OPSCC, with different epidemiological, clinical, anatomical, radiological, behavioural, biological and prognostic characteristics from HPV negative OPSCC. Indeed, the only subsite in the head and neck with a demonstrated aetiological viral link is, at present, the oropharynx. These observations lead to questions regarding management choices for patients based on tumour HPV status with important consequences on treatment, and on the role of vaccines and targeted therapy over the upcoming years. PMID- 25709147 TI - Supracricoid laryngectomies: oncological and functional results for 152 patients. AB - The purpose of this study was to evaluate the oncological and functional outcomes in patients who underwent supracricoid laryngectomies with a crico-hyoidopexy (SCL-CHP) or a crico-hyoido-epiglottopexy (SCL-CHEP) for the treatment of primary and reccurent laryngeal cancer. A retrospective study was conducted on 152 consecutive patients seen from January 1996 to December 2006. Overall survival (OS) and disease-free survival (DFS) were analysed using the Kaplan-Meier method, and were compared according to the type of surgery and clinical stage of the tumour. The mean period before decannulation, nasogastric tube (NGT) removal and recovery of a normal diet and speech were evaluated, and statistical analyses were performed regarding the association with the type of surgery and arytenoidectomy. The median follow-up period was 49.9 months (range: 10-110 months). The 3- and 5-year OS were 87.5 and 83.5%, respectively, and 3- and 5 year DFS were 78.3 and 73.7%, respectively. For patients with early stages tumours, the 5-year OS and DFS were 92.3 and 84.6% respectively, whereas for patients with locally advanced stage tumours, the OS and DFS were 74.3 and 62.2%, respectively. Significant differences in OS and DFS for patients who had early or locally advanced cancers were found (p = 0.0004 and p = 0.0032, respectively). The rate of overall local control was 92.1%, while the mean period until decannulation or NGT removal was 25.1 and 16.6 days, respectively. The mean period until NGT removal was significantly different according to the type of surgery (p = 0.0001) and whether arytenoidectomy was performed (p = 0.0001). The reliable oncological and functional results of SCL for early and locally advanced laryngeal cancers are confirmed by our series of patients. PMID- 25709149 TI - Technical refinements in mandibular reconstruction with free fibula flaps: outcome-oriented retrospective review of 99 cases. AB - Congenital disease, major trauma, tumour resection and biphosphonate-related osteonecrosis can lead to partial, subtotal, or total loss of the mandibular bone. Minor defects can be easily reconstructed using bone grafts, whereas microvascular free tissue transfer may be unavoidable in the case of major bone loss or poor quality of soft tissue. Simple bone or composite osteocutaneous fibula free flaps have proven invaluable and remain the workhorse for microvascular mandibular reconstruction in daily practice. Our experience with 99 consecutive fibular free flaps confirms the available data in terms of high success rate. In these cases, 90% had total success, while 7 had complete flap failures. Three of our patients showed skin paddle necrosis with bony conservation. This report focuses on the technical refinements used by the authors that can prove valuable in obtaining predictable and precise results: in particular, we discuss surgical techniques that avoid vascular pedicle ossification by removing the fibular periosteum from the vascular pedicle itself and reduce donor site morbidity and aid in management of the position in the new condylar fossa. Finally, new technologies such as intraoperative CT and custom premodelled fixation plates may also increase the predictability of morpho functional results. PMID- 25709148 TI - Contemporary role of pectoralis major regional flaps in head and neck surgery. AB - Countless disadvantages of the "old" pectoralis major have been listed while the amazing versatility of the free flap armamentarium gives the opportunity to suit the defect deriving from virtually every ablative head and neck surgery with a tailored reconstruction. Nevertheless, pectoralis major is still the "workhorse" for head and neck reconstruction in developing countries thanks to its ease of harvest, and minimal requirements in term of instrumentation. Furthermore, even in facilities with a high volume of reconstructions by free flaps, a certain number of pectoralis major flaps is still raised every year. The history, present role and current indications of the most widely head and neck reconstructive procedure ever has been reviewed. PMID- 25709151 TI - Long-term surgical and functional outcomes of the intact canal wall technique for middle ear cholesteatoma in the paediatric population. AB - In this paper, we report the postoperative outcomes in canal wall up procedures with second stage surgery in 40 children undergoing intervention for cholesteatoma of the middle ear. The residuals, recurrences and the hearing results were analysed. All 40 patients had a follow-up of at least five years. Of the 39 patients who underwent two staged surgery, 18 (46.1%) had a residual lesion that was identified and excised during the second surgery. Over a five year follow-up period, there were five (12.5%) patients with recurrences, all belonging to the group in whom a residual cholesteatoma was identified during the second staged surgery. The rate of residual cholesteatoma tends to decrease as age increases. The type of cholesteatoma, acquired or congenital middle ear, were not statistically related to the incidence of residual cholesteatoma. Hearing analysis showed that hearing recovery was excellent with canal wall up procedures and remained stable over five years. PMID- 25709150 TI - Association of cinnarizine and betahistine in prophylactic therapy for Meniere's disease with and without migraine. AB - Prophylactic therapy of Meniere's disease (MD) includes betahistine and calcium blockers (the latter also useful for migraine prevention). The aim of our work was to assess the efficacy of combined therapy with cinnarizine and betahistine in MD subjects both with and without migraine and poorly responsive to betahistine alone. Fifty-two MD subjects were included who were poorly responsive to betahistine during 6 months of follow-up; 29 were migraineurs. Combined therapy was administered with betahistine 48 mg/day and cinnarizine 20 mg BID for 1 month, 20 mg/day for 2 weeks and 20 mg every 2 days for 2 more weeks, and then repeated. Results were collected over 6 months of follow-up. MD subjects with and without migraine demonstrated a decrease in both vertigo spells and migrainous attacks during combined therapy (from 9.4 to 3.8 and from 6.8 to 5.9 in 6 months, respectively, for vertigo spells, while migraine decreased from 3.8 to 1 in 6 months, respectively). A correlation was seen between decrease of vertigo spells and headaches in the sample of MD subjects with migraine. Our data support a proactive role for cinnarizine in preventing vertigo spells, especially in MD patients with migraine. PMID- 25709152 TI - Hyoid myotomy without suspension: a surgical approach to obstructive sleep apnoea syndrome. AB - The aim of this study was to verify if hyoid myotomy without hyoid suspension is effective in surgical treatment of obstructive sleep apnoea syndrome (OSAS). We recruited six patients with OSAS, aged between 34 to 60 years, with retropalatal and retrolingual upper airway obstruction, non-obese (BMI < 27) and non-compliant to continuous positive airway pressure therapy. Pre-surgical clinical and instrumental evaluations included clinical examination, cephalometry, polysomnography (PSG) and sleep endoscopy. Surgical treatment included nasal surgery, uvulopalatopharyngoplasty, tonsillectomy and hyoid myotomy without hyoid suspension. Follow-up evaluations were performed with serial PSGs, performed early (one week after surgery), and at 1, 6 and 18 months after surgery. We observed that surgery was followed by immediate normalisation of breathing parameters evaluated by PSG that persisted after 18 months. Thus, hyoid myotomy without suspension combined with nasal and palatal surgery may be considered a valid treatment of non-obese OSAS patients with retrolingual and retropalatal collapse. Furthermore, we suggest that hyoid bone suspension, binding it to mandibular or to thyroid cartilage, might be unnecessary in selected cases. PMID- 25709153 TI - Arterial microanastomoses on the reverse flow of the internal carotid artery reverse flow: an extreme solution in free-flap revascularisation. How we do it. AB - Microvascular free tissue transfer in head and neck reconstruction requires suitable recipient vessels, which are frequently compromised by prior surgery, radiotherapy, or size of the tumour. A surgical description of an arterial free flap pedicle anastomosis on the reverse internal carotid arterial flow in a vessel-depleted neck is presented. A 66-year-old male with a relapse of hypopharyngeal squamous cell carcinoma previously treated with both surgical and radiation therapy for carcinoma of the tongue and the larynx was successfully reconstructed using a free forearm flap with reverse internal carotid arterial flow. The involvement of the carotid glomus and prior surgery excluded the other vessels as recipients. The forearm free flap survived without any complications. This procedure can be considered an alternative rescue technique for salvage reconstruction in a vessel-depleted neck. PMID- 25709156 TI - The patient connexion.... PMID- 25709155 TI - Anti-HMGB1 monoclonal antibody ameliorates immunosuppression after peripheral tissue trauma: attenuated T-lymphocyte response and increased splenic CD11b (+) Gr-1 (+) myeloid-derived suppressor cells require HMGB1. AB - Although tissue-derived high mobility group box 1 (HMGB1) is involved in many aspects of inflammation and tissue injury after trauma, its role in trauma induced immune suppression remains elusive. Using an established mouse model of peripheral tissue trauma, which includes soft tissue and fracture components, we report here that treatment with anti-HMGB1 monoclonal antibody ameliorated the trauma-induced attenuated T-cell responses and accumulation of CD11b(+)Gr-1(+) myeloid-derived suppressor cells in the spleens seen two days after injury. Our data suggest that HMGB1 released after tissue trauma contributes to signaling pathways that lead to attenuation of T-lymphocyte responses and enhancement of myeloid-derived suppressor cell expansion. PMID- 25709157 TI - Pressure injectors for radiologists: A review and what is new. AB - Pressure Injectors are used routinely in diagnostic and interventional radiology. Advances in medical science and technology have made it is imperative for both diagnostic as well as interventional radiologists to have a thorough understanding of the various aspects of pressure injectors. Further, as many radiologists may not be fully conversant with injections into ports, central lines and PICCs, it is important to familiarize oneself with the same. It is also important to follow stringent operating protocols during the use of pressure injectors to prevent complications such as contrast extravastion, sepsis and air embolism. This article aims to update existing knowledge base in this respect. PMID- 25709158 TI - Cryoablation of lung malignancies recurring close to surgical clips following surgery: Report of three cases. AB - BACKGROUND: Minimally ablative therapies are now available for the treatment of lung malignancies. However, selection of the appropriate technique is not always easy and requires accurate preoperative planning. AIMS: To describe the treatment of lung tumors with cryoablation. SETTINGS AND DESIGN: We report three cases of lung malignancies that recurred close to surgical clips after surgical treatment, successfully treated by cryoablation. MATERIALS AND METHODS: An initial freezing cycle was performed for 10 min, followed by a 5-min thawing cycle, and an additional 10-min freezing cycle. A final 5-min thaw was necessary to remove the needle from the iceball formed during the freezing cycle. RESULTS: The procedures were completed successfully with no signs of surgical-clip misplacement, and excellent ablation of the lesions. CONCLUSION: Cryoablation is a relatively new procedure that potentially permits the local treatment of lung tumors with minimal loss of lung parenchyma. PMID- 25709159 TI - Superior thyroid artery pseudoaneurysm and arteriovenous fistula following attempted internal jugular venous access and its management. AB - Vascular injury during common jugular venous (IJV) access is a rare complication, usually involving injury to the common carotid artery. We describe a previously unreported complication of iatrogenic injury of IJV access involving a branch of the superior thyroid artery, and its endovascular management. PMID- 25709154 TI - Transforming growth factor Beta family: insight into the role of growth factors in regulation of fracture healing biology and potential clinical applications. AB - The transforming growth factor beta (TGF-beta) family forms a group of three isoforms, TGF-beta1, TGF-beta2, and TGF-beta3, with their structure formed by interrelated dimeric polypeptide chains. Pleiotropic and redundant functions of the TGF-beta family concern control of numerous aspects and effects of cell functions, including proliferation, differentiation, and migration, in all tissues of the human body. Amongst many cytokines and growth factors, the TGF beta family is considered a group playing one of numerous key roles in control of physiological phenomena concerning maintenance of metabolic homeostasis in the bone tissue. By breaking the continuity of bone tissue, a spread-over-time and complex bone healing process is initiated, considered a recapitulation of embryonic intracartilaginous ossification. This process is a cascade of local and systemic phenomena spread over time, involving whole cell lineages and various cytokines and growth factors. Numerous in vivo and in vitro studies in various models analysing cytokines and growth factors' involvement have shown that TGF beta has a leading role in the fracture healing process. This paper sums up current knowledge on the basis of available literature concerning the role of the TGF-beta family in the fracture healing process. PMID- 25709160 TI - Endovascular management of spontaneous vertebrovertebral arteriovenous fistula associated with neurofibromatosis 1. AB - Extra cranial vertebrovertebral arteriovenous fistulas (VV AVF) are commonly associated with trauma. Their presentation may vary from palpable thrill and myelopathy or myeloradiculopathy. Sudden onset paraparesis is rare. PMID- 25709161 TI - Balloon dilatation of a benign biliary stricture through a T-tube tract. AB - Percutaneous cholangioplasty is a commonly performed procedure for both benign and malignant diseases. The most common route for accessing the biliary tree is transhepatic, following ultrasound or fluoroscopic-guided percutaneous puncture. There are situations when alternative routes can be utilized to access the common bile duct (CBD). We accessed the CBD via T-tube placed surgically in a 57-year old man who had obstructive jaundice of obscure etiology which was likely inflammatory. PMID- 25709162 TI - MR defecography for obstructed defecation syndrome. AB - Patients with obstructed defecation syndrome (ODS) form an important subset of patients with chronic constipation. Evaluation and treatment of these patients has traditionally been difficult. Magnetic resonance defecography (MRD) is a very useful tool for the evaluation of these patients. We evaluated the scans and records of 192 consecutive patients who underwent MRD at our center between January 2011 and January 2012. Abnormal descent, rectoceles, rectorectal intussusceptions, enteroceles, and spastic perineum were observed in a large number of these patients, usually in various combinations. We discuss the technique, its advantages and limitations, and the normal findings and various pathologies. PMID- 25709163 TI - Bouveret syndrome: Primary demonstration of cholecystoduodenal fistula on MR and MRCP study. AB - Bouveret syndrome is an unusual complication of cholelithiasis which results in upper gastrointestinal obstruction due to a gallstone impacted in the duodenum through a bilio-enteric fistula. We present this rare entity which was primarily diagnosed on magnetic resonance (MR) and MR cholangiopancreaticography (MRCP) study. PMID- 25709164 TI - Congenital bronchopulmonary vascular malformations, "sequestration" and beyond. AB - Congenital bronchopulmonary vascular malformations (BPVMs) include a broad spectrum of disorders that involve abnormalities in the form of disruptions of normal communication and/or presence of abnormal communication between one or more of the three main systems of the lung, namely, the airways, arteries, and veins. The establishment of abnormal communications by means of small openings or anastomoses is termed as malinosculation. The aim of this pictorial essay is to illustrate the imaging appearances of the various types of pulmonary malinosculation. PMID- 25709165 TI - HRCT in cystic fibrosis in patients with CFTR I1234V mutation: Assessment of scoring systems with low dose technique using multidetector system and correlation with pulmonary function tests. AB - BACKGROUND AND AIMS: Pulmonary changes in patients with cystic fibrosis (CF) with CFTR I1234V mutation have not been extensively documented. Impact of geographic influence on phenotypical expression is largely unknown. This descriptive clinical study presents the high-resolution computed tomography (HRCT) pulmonary findings and computed tomography (CT) scoring with respect to pulmonary function tests (PFT) in a small subset of CF group. MATERIALS AND METHODS: We examined 29 patients between 2 and 31 years of age with CFTR I1234V mutation. HRCT and PFT were performed within 2 weeks of each other. Imaging abnormalities on HRCT were documented and analyzed by utilizing the scoring system described by Bhalla et al., Brody et al., Helbich et al.,and Santamaria et al. Efficacy of the scoring system with respect to PFT was compared. STATISTICAL ANALYSIS: Inter-observer reliability of the scoring systems was tested using intraclass correlation (ICC) between the two observers. Spearman correlation coefficients were calculated between the scoring systems and between the scoring systems and PFT results. RESULTS: In our study, right upper and middle lobes were the most frequently involved sites of involvement. Bronchiectasis and peribronchial thickening were the most frequent imaging findings. Scores with all four scoring systems were reproducible, with good ICC coefficient of 0.69. There was good agreement between senior radiologists in all scoring systems. CONCLUSION: We noted pulmonary imaging abnormalities in a large majority (96%) of our CF patients. There was no significant difference in the CT scores observed from various systems. The CT evaluation system by Broody is detailed and time consuming, and is ideal for research and academic setup. On the other hand, the systems by Bhalla and Santamaria are easy to use, quick, and equally informative. We found the scoring system by Santamaria preferable over that of Bhalla by virtue of additional points of evaluation and ease of use, and therefore better suited for busy clinical practice. PMID- 25709166 TI - Acute hemorrhagic encephalitis: An unusual presentation of dengue viral infection. AB - Dengue is a common viral infection worldwide with presentation varying from clinically silent infection to dengue fever, dengue hemorrhagic fever, and severe fulminant dengue shock syndrome. Neurological manifestation usually results from multisystem dysfunction secondary to vascular leak. Presentation as hemorrhagic encephalitis is very rare. Here we present the case of a 13-year-old female admitted with generalized tonic clonic seizures. Plain computed tomography (CT) scan of head revealed hypodensities in bilateral deep gray matter nuclei and right posterior parietal lobe without any hemorrhage. Cerebrospinal fluid (CSF) and serology were positive for IgM and IgG antibodies to dengue viral antigen. Contrast-enhanced magnetic resonance imaging (MRI) revealed multifocal T2 and fluid attenuated inversion recovery (FLAIR) hyperintensities in bilateral cerebral parenchyma including basal ganglia. No hemorrhage was seen. She was managed with steroids. As her clinical condition deteriorated, after being stable for 2 days, repeat MRI was done which revealed development of hemorrhage within the lesions, and diagnosis of acute hemorrhagic encephalitis of dengue viral etiology was made. PMID- 25709167 TI - Clinical, imaging and histopathological features of isolated CNS lymphomatoid granulomatosis. AB - Lymphomatoid granulomatosis is a rare systemic angiocentric/angiodestructive, B cell lymphoproliferative disorder. Central nervous system involvement occurs as part of systemic disease. Isolated central nervous system disease is rare with only few case reports. A 53-year-old male presented with progressive cognitive decline, extrapyramidal features, and altered sensorium with seizures over the last 4 years. His magnetic resonance imaging (MRI) of brain showed multiple small enhancing nodules in subependymal/ependymal regions and along the vessels. Brain biopsy showed atypical lymphohistiocytic infiltrate suggestive of lymphomatoid granulomatosis. There was no evidence of systemic disease; thus, isolated central nervous system lymphomatoid granulomatosis was diagnosed. PMID- 25709168 TI - PVNS or pseudo aneurysm: MRI-problem solving or misleading? AB - Pigmented villonodular synovitis (PVNS) is a benign neoplastic process affecting the synovium. Magnetic resonance imaging (MRI) is considered as the imaging modality of choice, where PVNS is seen as a soft tissue lesion affecting the synovium with characteristic hypointense signal on T2-weighted images (T2WI) and typically blooming on gradient echo (GRE) sequences. MRI can sometimes be misleading, with many non-neoplastic pathologies having a tendency of recurrent bleeding closely mimicking PVNS. We report a case of pseudoaneurysm from posterior circumflex humeral artery, a branch of axillary artery, secondary to recurrent shoulder dislocation mimicking PVNS on MRI. PMID- 25709169 TI - Hypophosphatemic osteomalacia in von Recklinghausen neurofibromatosis: Case report and literature review. AB - Osteomalacia in neurofibromatosis is a rare entity and distinct from more common dysplastic skeletal affections of this disease. As a rule, it is characterized by later onset in adulthood. There is renal phosphate loss with hypophosphatemia and multiple pseudofractures in the typical cases. The hypophosphatemic conditions that interfere in bone mineralization comprise many hereditary or acquired diseases, all of them sharing the same pathophysiological mechanism-reduction in phosphate reabsorption by the renal tubuli. This process leads to chronic hyperphosphaturia and hypophosphatemia, associated with inappropriately normal or low levels of calcitriol, causing rickets in children and osteomalacia in adults. PMID- 25709170 TI - Prenatal diagnosis of body stalk complex: A rare entity and review of literature. AB - Body stalk anomalies are a group of massively disfiguring abdominal wall defects in which the abdominal organs lie outside of the abdominal cavity in a sac of amnioperitoneum with absence of or very small umbilical cord. Various hypotheses proposed to explain the pathogenesis of limb body wall complex include early amnion disruptions, embryonic dysplasia, and vascular disruption in early pregnancy. Body stalk anomaly is an accepted fatal anomaly and, hence, its early diagnosis aids in proper management of the patient. PMID- 25709171 TI - A rare newly described overgrowth syndrome with vascular malformations-Cloves syndrome. AB - There are many overgrowth syndromes described in the literature. Few are associated with vascular malformations. We describe a rare, newly described syndrome with features of overgrowth and vascular malformations. PMID- 25709172 TI - Intratesticular and scrotal wall air: Emphysematous epididymo-orchitis or Fournier's gangrene: A dilemma. PMID- 25709173 TI - Emphysematous epididymo-orchitis. PMID- 25709175 TI - Palliative medicine and people. PMID- 25709174 TI - Author's reply. PMID- 25709177 TI - Origin, Maintenance and Future of Do-Not-Resuscitate (DNR). PMID- 25709176 TI - Ban on Dextropropoxyphene is Unjustifiable. PMID- 25709178 TI - Acute Palliative Care - Is it a Workable Concept in India? PMID- 25709179 TI - Views and attitudes towards sexual functioning in men living with spinal cord injury in kerala, South India. AB - CONTEXT: Sexual dysfunction is a major concern for Indian men living with a spinal cord injury. Few first-hand reports exist about the experience of living with an altered sense of sexual identity and the inability to express sexual concerns. AIMS: In this qualitative study, the authors explore views and attitudes towards sexual functioning in men living with a spinal cord injury in Kerala, India. MATERIALS AND METHODS: Semi-structured and open-ended interviews were conducted with seven participants according to IE Seidman's phenomenological approach. Thematic analysis followed the analytic process outlined by Moustakas (1990). RESULTS: Identification of seven interconnected themes included: Recalling an active sexual life, disconnection with sexual identity, incongruence between emotional and physical capability, spousal isolation, social readjustment of spouse, physical barriers to sexual functioning, coping, and reintegration. CONCLUSIONS: Patient's descriptions of suffering demonstrate complexities of experience in sexual functioning. All patients were sexually active prior to the injury. This was now lost causing anxiety, distress, and sadness. A huge gap existed between sexual desire and physical capability. The patient and spouse were now isolated emotionally, socially, and physically. Physical barriers included urinary incontinence and indwelling catheters. While several self evolved coping strategies were identified, support from palliative care services was not evident. Two important gaps exist in research and practice: (1) Attention to sexual issues and whole-person care. (2) Attention to quality of sexual life. Future qualitative studies on sexual dysfunction could provide a useful adjunct to current literature which is predominantly biomedical in its approach. PMID- 25709180 TI - Evaluation of Factors in Relation with the Non-Compliance to Curative Intent Radiotherapy among Patients of Head and Neck Carcinoma: A Study from the Kumaon Region of India. AB - INTRODUCTION: Radiotherapy (RT)-based curative regimens for head and neck squamous cell carcinomas (HNSCC) deliver a dose of 66-70 Gray (Gy) over a period of 6-7 weeks, and incomplete treatments are unlikely to result in cure. Non compliance to RT is major contributory factor to treatment failure. AIMS: To assess the proportion of patients who do not complete planned treatment after initiation of curative RT. This study also aims to explore a possible relationship of non-compliance due to socio-economic, disease-related and treatment-related factors. MATERIALS AND METHODS: The records of HNSCC patients treated from January 2012-December 2013 were audited. Data from the treatment records were to collect patient-related, disease-related, and social demographic parameters. Of the patients who had not completed treatment, the reasons behind the same were investigated. RESULTS: Of the 324 patients of HNSCC who were initiated on radical RT, a total of 76 patients were found to have discontinued treatment without authorization of the treating clinician. There was no significant predilection for treatment non-compliance with regards to patient age, educational status, religion, site of the disease, use of neoadjuvant chemotherapy, or use of concurrent chemotherapy. There tended to be a higher association of treatment non-compliance among patients residing >100 km away from the treatment center, patients hailing from hilly regions, patients without the below poverty line (BPL) card, unemployed patients, and patients with stage IV A/B disease. Of the 76 patients who did not complete treatment, telephonic questionnaire could be obtained from 54 patients. Causes for non-compliance included preference for traditional healers (22.2%), fear of toxicity (7.4%), logistic reasons (18.5%), financial reasons (24.1%), and lack of interest/faith in RT (5.6%). CONCLUSION: There is a high incidence of treatment default among patients of HNSCC during RT in this region. The revelation of the higher propensity for treatment default among patients from distant, hilly regions, unemployed, patients without BPL cards, and stages-IVA/IVB highlights the need for specific interventions for these special populations. PMID- 25709181 TI - Commentary. PMID- 25709182 TI - Impact of specialist home-based palliative care services in a tertiary oncology set up: a prospective non-randomized observational study. AB - BACKGROUND: Home-based specialist palliative care services are developed to meet the needs of the patients in advanced stage of cancer at home with physical symptoms and distress. Specialist home care services are intended to improve symptom control and quality of life, enable patients to stay at home, and avoid unnecessary hospital admission. MATERIALS AND METHODS: Total 690 new cases registered under home-based palliative care service in the year 2012 were prospectively studied to assess the impact of specialist home-based services using Edmonton symptom assessment scale (ESAS) and other parameters. RESULTS: Out of the 690 registered cases, 506 patients received home-based palliative care. 50.98% patients were cared for at home, 28.85% patients needed hospice referral and 20.15% patients needed brief period of hospitalization. All patients receiving specialist home care had good relief of physical symptoms (P < 0.005). 83.2% patients received out of hours care (OOH) through liaising with local general practitioners; 42.68% received home based bereavement care and 91.66% had good bereavement outcomes. CONCLUSION: Specialist home-based palliative care improved symptom control, health-related communication and psychosocial support. It promoted increased number of home-based death, appropriate and early hospice referral, and averted needless hospitalization. It improved bereavement outcomes, and caregiver satisfaction. PMID- 25709183 TI - Breaking bad news in cancer patients. AB - OBJECTIVE: In a regional hospital, many patients are newly diagnosed with cancer. Breaking the bad news in these patients and their relatives is a tough task. Many doctors are not experienced in talking to patients about death or death-related diseases. In recent years, there have been great efforts to change the current situation. The aim of this study was to investigate the experience and education of medical personnel in breaking bad news in a secondary hospital. MATERIALS AND METHODS: 59 doctors from General Hospital of Komotini, Greece were included in the study. All the doctors were in clinical specialties that treated cancer patients. A brief questionnaire was developed based on current guidelines such as Baile/SPIKES framework and the ABCDE mnemonic. RESULTS: Residents are involved in delivering bad news less frequently than specialists. Only 21 doctors (35.59%) had specific training on breaking bad news. 20 doctors (33.90%) were aware of the available techniques and protocols on breaking bad news. 47 doctors (79.66%) had a consistent plan for breaking bad news. 57 (96.61%) delivered bad news in a quiet place, 53 (89.83%) ensured no interruptions and enough time, 53 (89.83%) used simple words and 54 (91.53%) checked for understanding and did not rush through the news. 46 doctors (77.97%) allowed relatives to determine patient's knowledge about the disease. CONCLUSIONS: There were low rates of specific training in breaking bad news. However, the selected location, the physician's speech and their plan were according to current guidelines. PMID- 25709184 TI - Role of social, cultural and economic capitals in perceived quality of life among old age people in kerala, India. AB - OBJECTIVE: To find out the relationship of collective social, economic, and cultural properties of a population on the perceived quality of life (QOL) among old age people. MATERIALS AND METHODS: In a community-based cross-sectional study, we analyzed information on a representative sample of 900 old age (aged > 60 years) from 28 villages in Kollam district of Kerala. WHO-Quality of Life - BREF questionnaire was used. Ethical clearance from Institutional Ethics Committee was obtained. The mean scores for perceived QOL for domains such as physical health, psychological health, social relations, and control of environments were calculated. The three scales (social capital, cultural capital, and economic capital) were standardized using z-score transformation to make them comparable. Using multiple linear regression, we calculated the independent effect of economic capital, social capital, and cultural capital on perceived QOL among old people adjusted for age, sex, and the presence of chronic disease. RESULTS: For overall QOL, only cultural capital contributed significantly. An increase of one unit z-score cultural capital led to three units increase in overall QOL score (beta = 3.362; 95% CI: 2.645-4.078). Social capital and cultural capital contributed significantly to the physical health domain of QOL. With one z-score increase in social capital and cultural capital, QOL score of physical health domain increased by 0.2 units (beta = 0. 227; 95% CI: 0.020 0.434), and 0.5 (beta = 0. 596; 95% CI: 0.384-0.808) units, respectively. Psychological health domain and environmental domain were affected by all three capitals significantly. But, the social relations domain was significantly affected only by cultural capital (beta = 0. 576; 95% CI: 0.373-0.779). CONCLUSION: Hence, the policies for old people should envision retaining our cultural and social norms along with the economic interventions for a better palliative care. PMID- 25709185 TI - Comparison of single versus multiple fractions for palliative treatment of painful bone metastasis: first study from north west India. AB - BACKGROUND: Bone metastasis is a usual cause of pain in advanced cancer. Conventional radiation schedules require larger hospital stay and thus are not suitable for patients with poor general condition. This prospective observational study aims to compare the pain-relieving efficacy of different radiation fractionation schedules, i.e., 8 Gy administered in a single fraction versus 30 Gy administered in 10 fractions. MATERIALS AND METHODS: Two hundred and fifty consecutive patients of bone metastasis were evaluated for the study, with 63 patients being excluded due to non-fulfillment of the inclusion criteria. The response to radiotherapy leading to pain relief as per the Visual Analog Scale was recorded at the end of treatment, 8 days, 15 days and 1 month during the follow-up visits. RESULTS: Sixty-two percent of the patients received a single fraction while the remaining received 10 fractions. In the 10-fraction group, overall response was present in 60% of the patients. Stable pain was present in 23% of the patients while 9% patients had progressive pain. At 1 month of completion of treatment, 9% patients were lost to follow-up. In the single fraction arm, overall response was seen in 58%, stable pain in 27% and progressive pain in 7% of the patients. Six percent of the patients were lost to follow-up. CONCLUSIONS: Single-fraction treatment for bony metastasis is as effective as multiple fractions to relieve bony pain and provides treatment convenience to both the patient and the caregiver. PMID- 25709186 TI - Current Clinical Opinions, Attitudes and Awareness of Interns Regarding Post operative and Cancer Pain Management in A Tertiary Care Centre. AB - AIM: This prospective study was aimed to assess the opinion, awareness and attitude of interns regarding pain assessment, pain management and common barriers in effective pain therapy for patients experiencing pain. MATERIALS AND METHODS: A questionnaire including demographic details, knowledge of the tools of pain assessment, choice of drugs used, side effects, lacunae in existing knowledge and barriers in pain management was designed. A total of 160 interns were approached, out of which 149 returned the completed questionnaire. Only a few of them had a chance exposure to cancer pain management but none of them had undergone any formal training, teaching or classes in this field. RESULTS: Most respondents knew that the pain can be measured and the ways to do it. A significant number considered morphine as the preferred drug for managing cancer pain and thought morphine is responsible for addiction and respiratory depression. About 72% interns knew about transdermal preparation of fentanyl and its usage in malignancy but only a few were aware of buprenorphine transdermal patch. Though they were enthusiastic about relieving the cancer patients from suffering, they had limited knowledge of how to achieve this. The common barriers identified by them were lack of adequate knowledge and training and limited availability of opioids. CONCLUSIONS: The results of this study emphasize the need of special training programs pain management in order to change the current prevailing situation and improve the quality of analgesia provided to the patients. PMID- 25709187 TI - Perspectives of Cardiac Care Unit Nursing Staff about Developing Hospice Services in Iran for Terminally ill Cardiovascular Patients: A Qualitative Study. AB - INTRODUCTION: The present study was conducted aiming to determine the points of view of cardiac care units' nursing staff about designing and providing Hospice services in Iran for cardiovascular patients in the final stages of life. MATERIALS AND METHODS: In this qualitative study, the perspectives of 16 Cardiac Care Unit (CCU) nurses selected purposefully among hospitals of Tabriz-Iran University of Medical Sciences were investigated using semi-structured interviews and were analyzed in content analysis method. RESULTS: 33 themes were finally extracted. Some nurses were for and some were against designing and providing Hospice services in Iran. The main reasons identified for supporting this plan included: Possibility of designing and providing these services consistent with high ethical values of Iranian society; approval of authorities due to increasing the load of chronic diseases and aged population; need of families due to the problems in taking care of patients and life concerns; better pain relief and respectful death; decrease of costs as a result of lower usage of diagnostic therapeutic services, less use of expensive facilities and drugs, and better usage of hospital beds. CONCLUSION: Growing load of chronic diseases has made the need for Hospice as a necessary issue in Iran. In order to provide these services, studying the viewpoints of health service providers is inevitable. Therefore using and applying the results of this study in planning and policy making about designing and providing these services in Iran for cardiovascular patients in their final stages of lives could be helpful. PMID- 25709188 TI - Spiritual needs of cancer patients: a qualitative study. AB - INTRODUCTION: Diagnosis of cancer can cause huge spiritual crisis in a person and affect different aspects of life. At this stage, patients have certain spiritual needs. AIM: This study was conducted to explain spiritual needs of cancer patients in Iran. MATERIALS AND METHODS: In this qualitative study, 18 cancer patients, referred to the Cancer Institute of Imam Khomeini Hospital in Tehran were selected using purposive sampling method, and their spiritual needs emerged out of conventional content analysis of interviews conducted with them. RESULTS: From 1850 initial codes, 4 themes (connection, peace, meaning and purpose, and transcendence) were identified that contained categories of social support, normal behavior, inner peace, seeking forgiveness, hope, acceptance of reality, seeking meaning, ending well, change of life meaning, strengthening spiritual belief, communication with God, and prayer. CONCLUSIONS: Spiritual needs of cancer patients should be recognized, realized, and considered in care of patients by the medical team. An all-out support of health system policy makers to meet patients' spiritual needs is particularly important. PMID- 25709189 TI - Impact of cancer support groups on childhood cancer treatment and abandonment in a private pediatric oncology centre. AB - AIMS: To analyze the impact of two cancer support groups in the treatment and abandonment of childhood cancer. MATERIALS AND METHODS: This is a retrospective review of children with cancer funded and non-funded who were treated at Kanchi Kamakoti CHILDS Trust Hospital from 2010 to 2013. A total of 100 patients were funded, 57 by Ray of Light Foundation and 43 by Pediatric Lymphoma Project and 70 non-funded. RESULTS: The total current survival of 80%, including those who have completed treatment and those currently undergoing treatment, is comparable in both the groups. Abandonment of treatment after initiating therapy was not seen in the financially supported group whereas abandonment of treatment after initiation was seen in one child in the non-funded group. CONCLUSIONS: Besides intensive treatment with good supportive care, financial support also has an important impact on compliance and abandonment in all socioeconomic strata of society. Financial support from private cancer support groups also has its impact beyond the patient and family, in reducing the burden on government institutions by non-governmental funding in private sector. Improvement in the delivery of pediatric oncology care in developing countries could be done by financial support from the private sector. PMID- 25709190 TI - Management of hemichorea hemiballismus syndrome in an acute palliative care setting. AB - Hemichorea hemiballismus (HCHB) is a rare and debilitating presentation of hyperglycemia and subcortical stroke. Early identification, proper assessment and management of HCHB can lead to complete symptom relief. We describe a case of HCHB presenting to a palliative care setting. A 63-year-old diabetic and hypertensive lady, with history of ovarian cancer presented to Palliative Medicine outpatient clinic with two days history of right HCHB. Blood investigations and brain imaging showed high blood sugar levels and lacunar subcortical stroke. Blood sugar levels were controlled with human insulin and Aspirin. Clopidogrel and Atorvastatin were prescribed for the management of lacunar stroke. HCHB reduced markedly post-treatment, leading to significant reduction in morbidity and improvement in quality of life. The symptoms completely resolved within one week of starting the treatment and the patient was kept on regular home and outpatient follow up for further monitoring. Acute palliative care (APC) approach deals with the management of comorbidities and their complications along with supportive care. Prompt assessment and management of such complications lead to better patient outcomes. PMID- 25709191 TI - Management of levofloxacin induced anaphylaxis and acute delirium in a palliative care setting. AB - Levofloxacin is a commonly prescribed antibiotic for managing chest and urinary tract infections in a palliative care setting. Incidence of Levofloxacin associated anaphylaxis is rare and delirium secondary to Levofloxacin is a seldom occurrence with only few published case reports. It is an extremely rare occurrence to see this phenomenon in combination. Early identification and prompt intervention reduces both mortality and morbidity. A 17-year-old male with synovial sarcoma of right thigh with chest wall and lung metastasis and with no prior psychiatric morbidity presented to palliative medicine outpatient department with community-acquired pneumonia. He was initiated on intravenous (IV) Ceftriaxone and IV Levofloxacin. Post IV Levofloxacin patient developed anaphylaxis and acute delirium necessitating IV Hydrocortisone, IV Chlorpheneramine, Oxygen and IV Haloperidol. Early detection and prompt intervention helped in complete recovery. Patient was discharged to hospice for respite after 2 days of hospitalization and then discharged home. Acute palliative care approach facilitated management of two life-threatening medical complications in a palliative care setting improving both quality and length of life. PMID- 25709192 TI - Management of ramsay hunt syndrome in an acute palliative care setting. AB - INTRODUCTION: The Ramsay Hunt syndrome is characterized by combination of herpes infection and lower motor neuron type of facial nerve palsy. The disease is caused by a reactivation of Varicella Zoster virus and can be unrepresentative since the herpetic lesions may not be always be present (zoster sine herpete) and might mimic other severe neurological illnesses. CASE REPORT: A 63-year-old man known case of carcinoma of gall bladder with liver metastases, post surgery and chemotherapy with no scope for further disease modifying treatment, was referred to palliative care unit for best supportive care. He was on regular analgesics and other supportive treatment. He presented to Palliative Medicine outpatient with 3 days history of ipsilateral facial pain of neuropathic character, otalgia, diffuse vesciculo-papular rash over ophthalmic and maxillary divisions of left trigeminal nerve distribution of face and ear, and was associated with secondary bacterial infection and unilateral facial edema. He was clinically diagnosed to have Herpes Zoster with superadded bacterial infection. He was treated with tablet Valacyclovir 500 mg four times a day, Acyclovir cream for local application, Acyclovir eye ointment for prophylactic treatment of Herpetic Keratitis, low dose of Prednisolone, oral Amoxicillin and Clindamycin for 7 days, and Pregabalin 150 mg per day. After 7 days of treatment, the rash and vesicles had completely resolved and good improvement of pain and other symptoms were noted. CONCLUSION: Management of acute infections and its associated complications in an acute palliative care setting improves both quality and length of life. PMID- 25709193 TI - Is mechanism and symptom-based analgesia an answer to opioid-induced hyperalgesia? AB - "Cancer Pain" and "Pain in cancer patient" are not synonymous. Opioid-induced Hyperalgesia (OIH) is a paradoxical state of nociceptive sensitization caused by exposure to opioids. Neuropathic pain is only partially responsive to opioids; injudicious increase in dose of opioids in neuropathic pain may not only result in inadequate pain relief but also OIH. Majority of literature on OIH is in non cancer pain with systemic use of opioids. We describe the development and successful treatment of OIH in a 55-year-old male patient with Small cell Carcinoma Lung. Opioid tapering, rotation, systemic desensitization helps in combatting OIH. The use of anti-neuropathic adjuvant analgesics helps not only in preventing and treating OIH but also in understanding putative mechanisms underlying neuropathic pain and OIH. PMID- 25709194 TI - Long-Term High-dose Oral Morphine in Phantom Limb Pain with No Addiction Risk. AB - Chronic phantom limb pain (PLP) is a type of neuropathic pain, which is located in the missing/amputated limb. Phantom pain is difficult to treat as the exact basis of pain mechanism is still unknown. Various methods of treatment for PLP have been described, including pharmacological (NSAIDs, opioids, antiepileptic, antidepressants) and non-pharmacological (TENS, sympathectomy, deep brain stimulation and motor cortex stimulation). Opioids are used for the treatment of neuropathic pain and dose of opioid is determined based on its effect and thus there is no defined ceiling dose for opioids. We report a case where a patient receiving high-dose oral morphine for chronic cancer pain did not demonstrate signs of addiction. PMID- 25709195 TI - Smartphone applications in palliative homecare. AB - Smartphone applications in healthcare delivery are a novel concept and is rapidly gaining ground in all fields of medicine. The modes of e-communications such as e mail, short message service (SMS), multimedia messaging service (MMS) and WhatsApp in palliative care provides a means for quick tele-consultation, information sharing, cuts the waiting time and facilitates initiation of the treatment at the earliest. It also forms a means of communication with local general practitioner and local health care provider such that continuity of the care is maintained. It also minimizes needless transport of the patient to hospital, prevents needless hospitalization and investigations and minimizes cost and logistics involved in the care process. The two case studies provided highlights the use of smartphone application like WhatsApp in palliative care practice and demonstrates its utility. PMID- 25709196 TI - Oral myiasis. AB - Myiasis is a pathologic condition in humans occurring because of parasitic infestation. Parasites causing myiasis belong to the order Diptera. Oral myiasis is seen secondary to oral wounds, suppurative lesions, and extraction wounds, especially in individuals with neurological deficit. In such cases, neglected oral hygiene and halitosis attracts the flies to lay eggs in oral wounds resulting in oral myiasis. We present a case of oral myiasis in 40-year-old male patient with mental disability and history of epilepsy. PMID- 25709197 TI - Future of palliative medicine. AB - A 'need-supply' and 'requirement-distribution mismatch' along with a continuingneed explosion are the biggest hurdles faced by palliative medicine today. It is the need of the hour to provide an unbiased, equitable and evidence based palliative care to those in need irrespective of the diagnosis, prognosis, social and economic status or geographical location. Palliative care as a fundamental human right, ensuring provision throughout the illness spectrum, global as well as region-specific capacity building, uniform availability of essential drugs at an affordable price, a multidisciplinary team approachand caregiver-support are some of the achievable goals for the future. This supplanted with a strong political commitment, professional dedication and 'public-private partnerships' are necessaryto tackle the existing hurdles and the exponentially increasing future need. For effectively going ahead it is of utmost importance to integrate palliative medicine into medical education, healthcare system and societal framework. PMID- 25709198 TI - Complementary and alternative medicine in cancer pain management: a systematic review. AB - Quality of life (QoL) encompasses the physical, psychosocial, social and spiritual dimensions of life lived by a person. Cancer pain is one of the physical component has tremendous impact on the QoL of the patient. Cancer pain is multifaceted and complex to understand and managing cancer pain involves a tool box full of pharmacological and non pharmacological interventions but still there are 50-70% of cancer patients who suffer from uncontrolled pain and they fear pain more than death. Aggressive surgeries, radiotherapy and chemotherapy focus more on prolonging the survival of the patient failing to realize that the QoL lived also matters equally. This paper reviews complementary and alternative therapy approaches for cancer pain and its impact in improving the QoL of cancer patients. PMID- 25709199 TI - Application of low frequency and medium frequency currents in the management of acute and chronic pain-a narrative review. AB - Trancutaneous electrical nerve stimulation (TENS) and interferential therapy (IFT) have been a regular line of treatment for various types of acute and chronic pain. This review aims to compile the latest literature in pain management using these modalities which use low-frequency and medium-frequency currents. The Cochrane Library, Scopus, PubMed, MEDLINE, and CINAHL were searched and studies were examined from their inception till October 2013. After title and abstract screening the relevant studies were included for this review. We found through this review that even though TENS and IFT are used in management of pain, there is limited amount of high quality research available in this area. Most of the studies lack methodological quality and have a low sample size. PMID- 25709200 TI - Preference of the place of death. PMID- 25709201 TI - Musculoskeletal complaints and predictors of musculoskeletal pain among adults in rural puducherry. PMID- 25709202 TI - Telephone triage in palliative care: looking forward to move forward.... PMID- 25709203 TI - Simultaneous determination of nine analytes in Clausena harmandiana Pierre. by new developed high-performance liquid chromatography method and the influence of locations in Thailand on level of nordentatin and dentatin. AB - BACKGROUND: Clausena harmandiana Pierre. (CH) contains various bioactive analytes with pharmacological benefits. Most researches were focused on carbazole analytes determined by isocratic high-performance liquid chromatography (HPLC), only few were focused on coumarin analytes and harvested location. OBJECTIVE: To develop and validate gradient HPLC method to analyze the variance of nine target analytes contained in roots of CH grown naturally in four different provinces of Thailand. MATERIALS AND METHODS: The analytical method was undertaken by gradient HPLC with 3% tetrahydrofuran in acetonitrile, and 0.05% phosphoric acid in water as mobile phases, on Hypersil ODS column (4.0 * 250 mm, 5 MUm), at flow rate 1.0 mL/min and detected at wavelength 280 nm. The method was validated for system linearity, limit of detection, limit of quantitation, precision and accuracy. RESULTS: The new-developed method was able to detect the nine target analytes in CH root. The validation showed the reliability of the method. All system suitability parameters were within the satisfied limits. The linear responses of method were observed at r (2) >= 0.999 for all analytes. The obtained amount of nine analytes showed the biodiversity of contents in different provinces. Of the nine target analytes, the level of nordentatin and dentatin in coumarin groups were considerably high in plants collected from one specific province of Thailand. CONCLUSION: This study has shown that the new-developed method is reliable, precise, accurate and sensitive to determine and quantify the nine target analytes in CH. Nordentatin and dentatin obviously show the higher level in one specific province of Thailand. PMID- 25709204 TI - Near-infrared for on-line determination of quality parameter of Sophora japonica L. (formula particles): From lab investigation to pilot-scale extraction process. AB - BACKGROUND: Extraction process of dried flowers of formula particles should be investigated from lab investigation to pilot-scale because of good water absorbing capacity and obscure active pharmaceutical ingredients (API) dissolution. OBJECTIVE: Reliable analysis of on-line near-infrared (NIR) technique and novel application in fascinating modern, traditional Chinese medicine production (formula particles) was proved. MATERIALS AND METHODS: The extraction process of Sophora japonica L. (formula particles) was used as an example, the rutin was regarded as API. On-line NIR technology was used to monitor the variation of rutin in the extraction process. High-performance liquid chromatography (HPLC) was used as a reference method to determine the content of rutin during the extraction process. The sample set was selected by Kennard-Stone (KS) algorithm. Different pretreatment methods were compared. The synergy interval partial least square (SiPLS) algorithm was applied. Chemometrics indicators and multivariate detection limits method were mutually used to assess the model. RESULTS: According to both errors alpha (0.05) and beta (0.05), rutin content could be detected by on-line NIR, which was more than 0.181 mg/mL. CONCLUSIONS: This work demonstrated the feasibility of NIR for on-line determination of rutin in the pilot-scale extraction process of S. japonica. L. It provided technical support for the NIR application in the extraction process of formula particles. PMID- 25709205 TI - Flavonoid profiles of three Bupleurum species and in vitro hepatoprotective of activity Bupleurum flavum Forsk. AB - BACKGROUND: Bupleurum L. (Aspiaceae) species are used as herbal remedy in Chinese traditional medicine. OBJECTIVE: The aim was to investigate the flavonoids in three annual European Bupleurum species, including B. baldense, B. affine and B. flavum, and to test their antioxidant and possible hepatoprotective effects. MATERIALS AND METHODS: Flavonoids from the methanol-aqueous extracts were quantified by solid-phase extraction-high-performance liquid chromatography. Bupleurum extracts (1-220 mg/ml) were tested for their antioxidant activity in DPPH and ABTS assays, as well as on isolated liver rat microsomes. In vitro hepatoprotective activity of B. flavum flavonoid (BFF) mixture and rutin, and narcissin, isolated from the same mixture, were evaluated on carbon tetrachloride (CCl4) and tert-butyl hydroperoxide (t-BuOOH) toxicity models in isolated rat hepatocytes. RESULTS: Narcissin was the dominant flavonol glycoside in B. flavum being present at 24.21 +/- 0.19 mg/g, whilst the highest content of rutin (28.63 +/- 1.57 mg/g) was found in B. baldense. B. flavum possessed the strongest DPPH (IC50 22.12 MUg/ml) and ABTS (IC50 118.15 MUg/ml) activity. At a concentration 1 mg/ml of BFF (rutin 197.58 mg/g, narcissin 75.74 mg/g), a stronger antioxidant effect in microsomes was evidenced in comparison with silymarin, rutin and narcissin. The hepatoprotective effect of BFF significantly reduced the elevated levels of lactate dehydrogenase and malondialdehyde, and ameliorated glutathione, being most active in t-BuOOH-induced injury model when compared with CCl4 toxicity (P < 0.001). CONCLUSION: In BFF, synergism of rutin and narcissin could be responsible for stronger protection against mitochondrial induced oxidative stress. PMID- 25709206 TI - Hepatoprotective and antibacterial activity of Lippia nodiflora Linn. against lipopolysaccharides on HepG2 cells. AB - BACKGROUND: Lippia nodiflora (LN) Linn is a small herb distributed throughout the world. The plant extracts of LN is used traditionally as an analgesic, anti inflammatory, antioxidant, antibacterial, antimicrobial, antipyretic, antitumor, antidiabetic, and possess hepatoprotective properties. MATERIALS AND METHODS: To study the antibacterial and hepatoprotective effect of LN, we used methanolic extracts of leaves on HepG2 cells. Lipopolysaccharides (LPS) is a well characterized hepatotoxin, so toxicity was induced on liver cells using LPS. Up regulation of inflammation genes were quantified. RESULTS AND CONCLUSIONS: In our present study, we have showed that LN reduced reactive oxygen species (ROS) production against LPS induced toxicity on HepG2 cells, and ther by decreased the apoptotic gene expression and protect the liver cells against toxicity. PMID- 25709207 TI - Peptides from two sanguinovorous leeches analyzed by ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometric detector. AB - BACKGROUND: Hirudo nipponica Whitman and Poecilobdella manillensis Lesson fall into the family of Hirudinidae Whitman, both of them are sanguinovorous leeches and used a anticoagulant medicines in China. Their medicinal parts are the dried bodies. However, the peptides in the dried body of the two leeches have not been very clear up to now. OBJECTIVE: To analyze the peptides from two sanguinovorous leeches, H. nipponica and P. manillensis. MATERIALS AND METHODS: In this article it is reported that the peptides were obtained from anticoagulant active extracted parts of dried bodies of the two leeches and their molecular weights were analyzed by ultra-performance liquid chromatography with electrospray ionization quadrupole time-of-flight mass spectrometry mass spectrometric detector online. RESULTS: Three peptide components were identified from H. nipponica with their molecular weight separately 14998, 15988, and 15956, six peptide components were identified from P. manillensis with molecular weight 9590, 13642, 14998, 17631, 15988, and 16567. Two of peptides from P. manillensis have the same molecular weight 14998 and 15988 as that in H. nipponica. CONCLUSION: And the two peptides are the main peaks in the base peak ion chromatogram because they occupied a large ratio of total base peak area. Hence the composition of the extracted active part of the two leeches are very close, difference is in that the extract of P. manillensis has more small peptide peaks, but the extract of H. nipponica has not. Furthermore, the tryptic digestion hydrolysates of the extracted active part of each sample were analyzed and the results showed that there were four peaks which only exist in P. manillensis, but not in Hirudo nipponia. They may be the identified peak between the two leeches. This work support the viewpoint that P. manillensis can be used as a medicinal leech as H. nipponia and these peptide components of dried bodies of the two species leeches are a basis for their chemical identification and further investigations in active action. PMID- 25709209 TI - Terpenoids from Ligularia kangtingensis. AB - BACKGROUND: Ligularia kangtingensis, a species from the genus Ligularia (Compositae), is an indigenous plant in Southwest China and more than 20 species in this genus have been used as folk medicines in China. OBJECTIVE: The chemical constituents of the whole plant of L. kangtingensis were studied. MATERIALS AND METHODS: The dried whole plants were extracted with ethanol. Its chemical constituents were mainly isolated and purified by silica gel and Sephadex LH-20 column chromatography and their structures were identified on the basis of spectral analysis. RESULTS: Twelve known terpenoids, including two monoterpenoids, five sesquiterpenoids and five triterpenoids, were isolated and identified from the whole plant of L. kangtingensis. CONCLUSION: All of the 12 known compounds were isolated for the first time from L. kangtingensis. PMID- 25709208 TI - Photoprotective and toxicological activities of extracts from the Antarctic moss Sanionia uncinata. AB - BACKGROUND: The Antarctic moss Sanionia uncinata (Hedw.) Loeske has shown high ultraviolet (UV)-absorbers content after exposition to high levels of UV-B radiation and can be an important source of antioxidants. OBJECTIVE: The aim was to investigate photoprotection and mutagenicity by the aqueous extract (AE) and hydroethanolic extract (HE) from the Antarctic moss S. uncinata. MATERIALS AND METHODS: Photoprotective activities were determined through survival curves of Escherichia coli strains, after UV irradiation in an aqueous solution of thymine and in vitro sun protection factor (SPF). The Salmonella/microsome assays were applied to assess the mutagenicity. RESULTS: Both extracts induced photoprotection against UV-C radiation. The AE showed a higher protection than the hydroethanolic one against UV-induced thymine dimerization. The SPFs were low in both extracts. In association to benzophenone-3 a significant increase in the SPF was detected for the AE, and a significant decrease was induced by the HE. No mutagenicity was found in the both extracts. Furthermore, it was observed absence of cytotoxicity. CONCLUSION: Water-extractable compounds seem to contribute on photoprotection of this Antarctic moss. PMID- 25709210 TI - Antioxidant and anti-lipoxygenase activities of extracts from different parts of Lavatera cretica L. grown in Algarve (Portugal). AB - BACKGROUND: Lavatera cretica L. was used in folk medicine as anti-inflammatory among other applications. As inflammation is many times associated with oxidative processes, the aim of the present work was to evaluate the ability of aqueous extracts obtained from different parts of L. cretica to prevent oxidation or inflammation using several methods in vitro. MATERIALS AND METHODS: The capacity of samples for preventing lipid peroxidation, scavenging free radicals, chelating metal ions, reducing power, and inhibiting lipoxygenase activity was investigated. This last assay also permits to evaluate the anti-inflammatory activity. The quantification of total phenols was performed using Folin Chiocalteu reagent. RESULTS: The highest concentrations of total polyphenols and flavonoids were found in the leaf extract (254.62 +/- 6.50 mg gallic acid equivalent/gram; dry weight). Leaf and flower extracts were the most active for scavenging 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt free radicals [Inhibition concentration (IC 50 = 2.88 +/- 0.54 and IC50 = 4.37 +/- 0.54 ?g/mL, respectively)], and leaf extract was also the best for scavenging hydroxyl radicals (IC50 = 0.81 +/- 0.05 MUg/mL). Bract plus sepal extract possessed the best capacity for preventing lipid peroxidation when lecithin liposome was the lipid substrate (IC50 = 0.19 +/- 0.03 MUg/mL) and scavenging superoxide anion radicals (IC50 = 1.13 +/- 0.48 MUg/mL). Leaf and flower extracts were the best lipoxygenase inhibitors (IC50 = 0.013 +/- 0.0034 MUg/mL in both extracts). CONCLUSIONS: L. cretica extracts were able to scavenge free radicals, inhibit lipid peroxidation and lipoxygenase activity. With these attributes, this plant can have an important role in the treatment of neurodegenerative disorders. PMID- 25709211 TI - Hepatoprotective constituents of Firmiana simplex stem bark against ethanol insult to primary rat hepatocytes. AB - BACKGROUND: Ethanol causes hepatic cellular damage by alterations in biological functions. This study evaluated the hepatoprotective potential of the methanolic extract originating from Firmiana simplex (Sterculiaceae) stem bark against the ethanol-induced hepatotoxicity in rat primary hepatocytes. MATERIALS AND METHODS: The extract of F. simplex stem bark was successively fractionated into n-hexane, chloroform, ethyl acetate (EtOAc), and n-butanol. Column chromatography with silica gel and sephadex LH-20 was used to isolate the EtOAc fraction. Rat primary hepatocytes were cultured to study the hepatoprotective activity of isolated substances against ethanol-induced toxicity. Intracellular reactive oxygen species (ROS) levels, the antioxidant activities of glutathione reductase (GR) and glutathione peroxidase (GSH-PX) enzymes, and the GSH content were measured to examine the antioxidative property of the isolated compounds. RESULTS: Two flavonoid glycosides, quercitrin (1) and tamarixetin 3-O-rhamnopyranoside (2), were isolated from the active EtOAc fraction. Compound 1 significantly protected rat primary hepatocytes against ethanol-induced oxidative stress by reducing the intracellular ROS level and preserving antioxidative defense systems such as GR, GSH-PX, and total GSH. CONCLUSION: This is the first report on the hepatoprotective activities of the extract of F. simplex. The EtOAc fraction of F. simplex stem bark and its major constituent quercitrin (1) could function as hepatoprotective agents to attenuate the development of alcoholic liver disease. PMID- 25709212 TI - Simultaneous Quantitative Determination of 12 Active Components in Yuanhu Zhitong Prescription by RP-HPLC Coupled with Photodiode Array Detection. AB - BACKGROUND: Yuanhu Zhitong prescription (YZP) is a famous traditional Chinese medicine formula, which is officially recorded in Chinese Pharmacopoeia for the treatment of stomach pain, hypochondriac pain, headache and dysmenorrhea caused by qi-stagnancy and blood stasis. It is the first report for the simultaneous determination of 12 active components in YZP. OBJECTIVE: A newly, simple, accurate and reliable method for the separation and determination of 12 active components (protopine, alpha-allocryptopine, coptisine, xanthotol, palmatine, dehydrocorydaline, glaucine, tetrahydropalmatine, tetrahydroberberine, imperatorin, corydaline, isoimperatorin) in YZP was developed and validated using HPLC-PAD. MATERIALS AND METHODS: The analytes were performed on a Phenomenex Luna C18 (2) column (250*4.6 mm, 5.0 MUm) with a gradient elution program using a mixture of acetonitrile and 0.1% phosphoric acid water solution (adjusted with triethylamine to pH 5.6) as mobile phase. Analytes were performed at 30 degrees C with a flow rate of 1.0 mL/min. RESULTS: The validated method was applied to analyze four major dosage forms of YZP coming from different manufacturers with good linearity (r(2), 0.9981~0.9999), precision (RSD, 0.24~2.89%), repeatability (RSD, 0.15~3.34%), stability (RSD, 0.14~3.35%), recovery (91.13~110.81%) of the 12 components. CONCLUSION: The proposed method enables the separation and determination of 12 active components in a single run for the quality control of YZP. PMID- 25709213 TI - Studies on the active constituents in radix salviae miltiorrhizae and their protective effects on cerebral ischemia reperfusion injury and its mechanism. AB - BACKGROUND: To extract, purify and identify the active constituents in ethanol extract of Radix Salviae Miltiorrhizae, and to analyze the protective effects of tanshinone IIA on cerebral ischemia-reperfusion injury in rats. MATERIALS AND METHODS: Radix Salviae Miltiorrhizae was extracted by ultrasonic extraction, effective parts were extracted by extraction method, compounds were isolated by preparative TLC and preparative HPLC, and structures of compounds were identified by (1)H NMR and (13)C NMR; the effects of tanshinone IIA on cerebral ischemia reperfusion injury in rats were determined by establishing rat model of middle cerebral artery occlusion (MCAO). RESULTS: The experimental data show four compounds were isolated, namely tanshinone IIB, hydroxymethylene tanshinone, salvianolic acid B and 9"'-methyl lithospermate B. Tanshinone IIA could alleviate the symptoms of neurological deficit in rats, the neurological deficit alleviating effect became more obvious with the increase of dose; tanshinone IIA experimental groups could reduce the cerebral infarction size and brain water content in rats, different concentrations of tanshinone IIA could decrease the SOD content and increase the MDA content in the frontal and parietal cortices of ischemic hemisphere in the ischemia reperfusion group, the differences were statistically significant compared with the ischemia reperfusion group. CONCLUSION: Radix Salviae Miltiorrhizae has the protective effects on cerebral ischemia reperfusion injury in rats. PMID- 25709214 TI - The molecular basis of the antidiabetic action of quercetin in cultured skeletal muscle cells and hepatocytes. AB - BACKGROUND: Quercetin is universally distributed in the plant kingdom and is the most abundant flavonoid in the human diet. In a previous study, we have reported that quercetin stimulated glucose uptake in cultured C2C12 skeletal muscle through an insulin-independent mechanism involving adenosine monophosphate activated protein kinase (AMPK). AMPK is a key regulator of the whole body-energy homeostasis. In skeletal muscle, activation of AMPK increases glucose uptake through the stimulation of the glucose transporter GLUT4 translocation to the plasma membrane. In liver, AMPK decreases glucose production mainly through the downregulation of the key gluconeogenesis enzymes such as phosphoenolpyruvate carboxylase (PEPCK) and Glucose -6-phosphate (G6Pase). OBJECTIVE: To study the effect of quercetin on glucose homeostasis in muscle and liver. MATERIALS AND METHODS: L6 skeletal muscle cells, murine H4IIE and human HepG2 hepatocytes were treated with quercetin (50 MUM) for 18 h. RESULTS: An 18 h treatment with quercetin (50 MUM) stimulated AMPK and increased GLUT4 translocation and protein content in cultured rat L6 skeletal muscle cells. On the other hand, we report that quercetin induced hepatic AMPK activation and inhibited G6pase in H4IIE hepatocytes. Finally, we have observed that quercetin exhibited a mild tendency to increase the activity of glycogen synthase (GS), the rate-limiting enzyme of glycogen synthesis, in HepG2 hepatocytes. CONCLUSIONS: Overall, these data demonstrate that quercetin positively influences glucose metabolism in the liver and skeletal muscle, and therefore appear to be a promising therapeutic candidate for the treatment of in type 2 diabetes. PMID- 25709215 TI - Effects of iriflophenone 3-C-beta-glucoside on fasting blood glucose level and glucose uptake. AB - BACKGROUND: One of the biological activities of agar wood (Aquilaria sinensis Lour., Thymelaeaceae), is anti-hyperglycemic activity. The methanolic extract (ME) was proven to possess the fasting blood glucose activity in rat and glucose uptake transportation by rat adipocytes. OBJECTIVE: To determine the decreasing fasting blood glucose level of constituents affordable for in vivo test. If the test was positive, the mechanism which is positive to the ME, glucose transportation, will be performed. MATERIALS AND METHODS: The ME was separated by column chromatography and identified by spectroscopic methods. Mice was used as an animal model (in vivo), and rat adipocytes were used for the glucose transportation activity (in vitro). RESULT: Iriflophenone 3-C-beta-glucoside (IPG) was the main constituent, 3.17%, and tested for the activities. Insulin and the ME were used as positive controls. The ME, IPG and insulin lowered blood glucose levels by 40.3, 46.4 and 41.5%, respectively, and enhanced glucose uptake by 152, 153, and 183%, respectively. CONCLUSION: These findings suggest that IPG is active in lowering fasting blood glucose with potency comparable to that of insulin. PMID- 25709216 TI - Evaluating Nothapodytes nimmoniana population from three localities of Western Ghats using camptothecin as phytochemical marker and selection of elites using a new-content range chart method. AB - BACKGROUND: Nothapodytes nimmoniana (Grah.) Mabb. is a high valued medicinal plant endemic to Western Ghats of India, distributed in fragmented populations. The plant is valued for potent anticancer drug camptothecin (CPT). OBJECTIVE: The study compares and expounds variation in CPT content from leaves and stems of N. nimmoniana obtained from three populations of Western Ghats, India. The study also describes a method for categorizing these populations using content range chart (CRC) method for percent yield of CPT. MATERIALS AND METHODS: A total of 60 samples were investigated including ten each of leaves and stems from three localities. Micro-extraction method was implemented to extract CPT. reversed phase ultra-performance liquid chromatography photo diode array technique was used to quantify CPT. RESULTS: Leaf samples of an individual collected from Joida, yielded lowest CPT content (0.002 +/- 0.000 g/100 g), whereas a stem sample from Amgaon, yielded highest CPT content (0.123 +/- 0.006 g/100 g). The findings suggest great variation in individuals producing and accumulating CPT. Using this data along with earlier published work, five categories of CPT yielding plants were made viz. I: Very low: <0.020, II: Low: 0.021-0.039, III: Moderate: 0.040-0.059, IV: High: 0.060-0.079 and V: Very high: >0.080. Based on CPT content in leaves, majority of individuals were under very low category (I(st)) and on the other hand stem samples were in 'II' category. Besides, very few individuals were observed in category 'V'. CONCLUSION: The study expounds use of CRC method for identifying elite population and suggests the need for its conservation. PMID- 25709217 TI - Spectrophotometric determination of the total flavonoid content in Ocimum basilicum L. (Lamiaceae) leaves. AB - BACKGROUND: The chemical characterization is essential to validate the pharmaceutical use of vegetable raw materials. Ultraviolet spectroscopy is an important technique to determine flavonoids, which are important active compounds from Ocimum basilicum. OBJECTIVE: The objective of this work was to optimize a spectrophotometric method, based on flavonoid-aluminum chloride (AlCl3) complexation to determine the total flavonoid content (TFC) in leaves of O. basilicum (herbal material), using response surface methodology. MATERIALS AND METHODS: The effects of (1) the herbal material: Solvent ratio (0.02, 0.03, 0.05, 0.07, and 0.08 g/mL), (2) stock solution volume (0.8, 2.3, 4.4, 6.5, and 8.0 mL) and (3) AlCl3 volume (0.8, 1.0, 1.2, 1.4, and 1.6 mL) on the TFC were evaluated. The analytical performance parameters precision, linearity and robustness of the method were tested. RESULTS: The herbal material: Solvent ratio and stock solution volume showed an important influence on the method response. After choosing the optimized conditions, the method exhibited a precision (RSD%) lower than 6% for repeatability (RSD%) and lower than 8% for intermediate precision (on the order of literature values for biotechnological methods), coefficient of correlation of 0.9984, and no important influence could be observed for variations of the time of complexation with AlCl3. However, the time and temperature of extraction were critical for TFC method and must be carefully controlled during the analysis. CONCLUSION: Thus, this study allowed the optimization of a simple, fast and precise method for the determination of the TFC in leaves of O. basilicum, which can be used to support the quality assessment of this herbal material. PMID- 25709218 TI - Bioactive fraction of Saraca indica prevents diabetes induced cataractogenesis: An aldose reductase inhibitory activity. AB - BACKGROUND: The present study was designed to investigate the effect of Saraca indica (SI) flowers extract and different bioactive fraction on in vitro aldose reductase (AR) inhibitory activity, high glucose-induced cataract in goat lens and in vivo streptozotocin (STZ; 45 mg/kg, i.p) induced cataract in rats. METHODS: Extract of flowers of SI tested for inhibition against rat lens AR. Furthermore, bioactive fraction was investigated against high glucose-induced opacification of the lens in vitro lens culture and STZ induced diabetic cataract in rats. Identification of the bioactive component was attempted through high performance thin-layer chromatography, high-performance liquid chromatography and liquid chromatography-mass spectrometry analysis. RESULTS: Ethyl acetate fraction of S. indica (EASI) produced maximum inhibition that may be due to high phenolic content. Goat lenses in media containing glucose developed a distinctly opaque ring in 72 h and treatment with EASI fraction lowered lens opacity in 72 h. Prolonged treatment with EASI to STZ-induced diabetic rats inhibited the AR activity and delayed cataract progression in a dose dependent manner. CONCLUSION: Ethyl acetate fraction of S. indica fraction has potential to inhibit rat lens AR enzyme and prevent cataractogenesis not only in goat lens model (in vitro), but also in STZ induced diabetic rats (in vivo). This study is suggestive of the anticataract activity of EASI fraction that could be attributed to the phytoconstituents present in the same. PMID- 25709219 TI - Hepatoprotective and in vivo antioxidant activity of Olax subscorpioidea Oliv. (Olacaceae) and Distemonathus benthamianus Baill. (Caesalpiniaceae). AB - BACKGROUND: Liver diseases are on rise and remain a serious health problem. Olax subscorpioidea and Distemonanthus benthamianus are two plants used in Ivorian traditional medicine in the treatment of many diseases including jaundice and hepatitis. OBJECTIVE: The present study was carried out to assess the hepatoprotective and in vivo antioxidant potentials of the hydro-ethanolic leaf extracts of these plants in carbon tetrachloride (CCl4)-induced hepatotoxicity in rats. MATERIALS AND METHODS: The plant extracts at doses of 25 and 100 mg/kg bw, and silymarin (25 mg/kg bw) were intraperitoneally (i.p.) injected once daily for 7 days to different groups of rats. Hepatotoxicity was induced on the 7(th) day in all the group animals except control. Rats were sacrificed on the 8(th) day and blood was collected. Serum biochemical parameters and antioxidant activity were measured using standard procedures. Histopathological examinations of liver rats were also performed. RESULTS AND DISCUSSION: Hepatotoxicity induced with CCl4 was well manifested by significant increase in serum activities of GOT, GPT, ALP and GGT, and enhancement of total bilirubin and TBARS levels. On the other hand, the level of total protein, albumin, alpha1-globulin significantly decreased, and DPPH-free radical scavenging activity and TAP were lowered. Pretreatment with plant extracts and silymarin prevent the toxic effects of CCl4 by decreasing serum enzyme activities, total bilirubin and TBARS levels and improving serum TAP and DPPH-free radical scavenging potential. Histopathological observations showed almost normal hepatic cells with a mild degree of inflammation, lesser fatty infiltration and absence of necrosis among the rats treated at 100 mg/kg of extracts of both the plants. CONCLUSION: The results suggest that the hydro-ethanolic leaf extracts of O. subscorpioidea and D. benthamianus possesses hepatoprotective and in vivo antioxidant activity. PMID- 25709220 TI - Antihyperglycemic effects of Pandanus amaryllifolius Roxb. leaf extract. AB - BACKGROUND: Diabetes mellitus is one of the leading chronic diseases worldwide. In patients with poor glycemic control, high blood glucose level may lead to other life-threatening complications. Pandanus amaryllifolius Roxb. (PA) leaves are used in traditional medicine for the treatment of diabetes. OBJECTIVE: This study evaluated the effect of crude extract from PA leaves on blood glucose level and the hypoglycemic mechanisms. MATERIALS AND METHODS: Thirty healthy volunteers were asked to drink PA tea (test-group) or hot water (control group) 15 min after glucose loading (75 g) in a standard oral glucose tolerance test. To study hypoglycemic mechanisms, PA leaves were extracted using two different methods. Method 1; dried PA leaves were extracted with distilled water at 90 degrees C for 15 min, and method 2; dried PA leaves were extracted with 95% ethanol. Both PA extracts were tested for alpha-glucosidase enzyme inhibition, insulin stimulation, and glucose uptake stimulation. RESULTS: The average of blood glucose level in the control group was 5.55 +/- 0.98 mmol/l, while in PA treated group was 6.16 +/- 0.79 mmol/l which were statistically different (P < 0.001). The results of antihyperglycemic mechanism showed that PA extracts, prepared both methods, could inhibit alpha-glucosidase enzyme and induce insulin production in rat pancreatic cell (RINm5F) in dose-dependent manner (P < 0.05). CONCLUSIONS: The knowledge gained from this research can be used as a basis for a new drug discovery for the treatment of diabetes. PMID- 25709221 TI - Gastroprotective effect of alpha-pinene and its correlation with antiulcerogenic activity of essential oils obtained from Hyptis species. AB - BACKGROUND: Alpha-pinene (alpha-pinene) is a monoterpene commonly found in essential oils with gastroprotective activity obtained from diverse medicinal plants, including Hyptis species. The genus Hyptis (lamiaceae) consists of almost 400 species widespread in tropical and temperate regions of America. In the north and northeastern Brazil, some Hyptis species are used in traditional medicine to treat gastrointestinal disturbances. OBJECTIVE: The present study has investigated the gastoprotective effect of purified alpha-pinene in experimental gastric ulcer induced by ethanol and indomethacin in mice. MATERIALS AND METHODS: Gastric ulcers were induced in male Swiss mice (20-30 g) by oral administration of absolute ethanol or indomethacin 45 min after oral pretreatment with vehicle, standard control drugs or alpha-pinene (10, 30, and 100 mg/kg). One hour after the ulcerative challenges, the stomach were removed, and gastric lesions areas measured. The effects of alpha-pinene on the gastric juice acidity were determined by pylorus ligation model. The gastrointestinal motility and mucus depletion were determined by measuring the gastric levels of phenol red and alcian blue, respectively. Hematoxylin and eosin stained sections of gastric mucosa of the experimental groups were used for histology analysis. RESULTS: alpha-pinene pretreatment inhibited ethanol-induced gastric lesions, reduced volume and acidity of the gastric juice and increased gastric wall mucus (P < 0.05). Furthermore, we showed an interesting correlation between concentration of alpha-pinene and gastroprotective effect of Hyptis species (P Pearson = 0.98). CONCLUSION: Our data showed that the alpha-pinene exhibited significant antiulcerogenic activity and a great correlation between concentration of alpha pinene and gastroprotective effect of Hyptis species was also observed. PMID- 25709222 TI - Isolation and purification of schisandrol A from the stems of Schisandra chinensis and cytotoxicity against human hepatocarcinoma cell lines. AB - BACKGROUND: Schisandrol A, a lignan with anticancer effects, is one of the representative components that identifies Schisandra chinensis. OBJECTIVE: A method for purifying schisandrol A from the stems of S. chinensis was established using an octadecylsilyl (ODS) column combined with preparative high-performance liquid chromatography (HPLC). MATERIALS AND METHODS: Crude extracts obtained from the stems of S. chinensis using 70% ethanol were separated on an AB-8 macroporous resin column and then eluted with a graded ethanol series. After 70% methanol was used in an ODS column separation, preparative HPLC was used for subsequent purification. The structure was identified by electrospray ionization-mass spectrometry, (1)H-nuclear magnetic resonance, and (13)C-nuclear magnetic resonance. HepG2 and Bel-7402 hepatocellular carcinoma cell lines were used for toxicological evaluation. RESULTS: 21.4 mg of schisandrol A with a purity of 95.2% were collected. The cytotoxicity of the ODS-purified sample and schisandrol A were significantly stronger than that of a resin-purified sample. CONCLUSION: Schisandrol A was successfully extracted from the stems of S. chinensis and separated with an ODS column combined with preparative HPLC. The samples obtained during the purification process showed different levels of cytotoxicity on the HepG2 and Bel-7402 hepatocellular carcinoma cell lines. PMID- 25709223 TI - AMPK-activated protein kinase activation by Impatiens balsamina L. is related to apoptosis in HSC-2 human oral cancer cells. AB - OBJECTIVE: In the present study, we investigated the efficacy of a methanol extract from Impatiens balsamina L. (MEIB) against HSC-2 human oral cancer cells. MATERIALS AND METHODS: The anti-cancer efficacies of MEIB were performed by methanethiosulfonate assay, phospho-kinase array, Western blot, 4'-6-diamidino-2 phenylindole staining, trypan blue exclusion assay and 5,5',6,6'-tetrachloro 1,1',3,3'-tetraethylbenzimidazolylcarbocyanine iodide assay. RESULTS: MEIB decreased the cell viability of HSC-2 cells. According to phospho-kinase arrays, MEIB markedly activated AMP-activated protein kinase (AMPK) signaling, but inactivated mammalian target of rapamycin signaling. MEIB induced apoptosis as evidenced by activation of caspase-3, poly (ADP-ribose) polymerase cleavage and nuclear condensation. In addition, AMPK activation by two known activators (5 aminoimidazole-4-carboxamide-1-beta-ribofuranoside and metformin) decreased cell viability and induced apoptosis. Moreover, MEIB increased the expression levels of mitochondria-related proteins (t-Bid, Bak and Bad), which contributed to the disruption of mitochondrial membrane potential, cytochrome C release and activation of caspase-9. Metformin also increased t-Bid expression and the subsequent release of cytochrome C into the cytosol. CONCLUSION: These results suggest that MEIB may be of therapeutic value for treating oral cancer and that its mechanism of action occurs through AMPK and t-Bid. PMID- 25709224 TI - Effects of aqueous extract from Silybum marianum on adenosine deaminase activity in cancerous and noncancerous human gastric and colon tissues. AB - OBJECTIVE: Investigation of possible effects of Silybum marianum extract (SME) on adenosine deaminase (ADA) activity in cancerous and noncancerous human gastric and colon tissues to obtain information about possible mechanism of anticancer action of S. marianum. MATERIALS AND METHODS: Cancerous and noncancerous human gastric and colon tissues removed from patients by surgical operations were used in the studies. The extract was prepared in distilled water. Before and after treatment with the extract, ADA activities in the samples were measured. RESULTS: ADA activity was found to be lowered significantly in cancerous gastric tissues but not in noncancerous gastric tissues after treatment with the SME. In the colon tissues, ADA activities were however found to increase after the treatment of SME. CONCLUSION: Our results suggest that the aqueous extract from S. marianum inhibits ADA activity in cancerous gastric tissues significantly. It is suggested that in addition to other proposed mechanisms, accumulated adenosine due to the inhibition of ADA might also play a part in the anticancer properties of the S. marianum. PMID- 25709225 TI - Physicochemical characterization, fatty acid composition, and thermal analysis of Bertholletia excelsa HBK oil. AB - The present study aimed at characterizing the oil extracted from Bertholletia excelsa H.B.K. almond, a native species from the Amazon region. Analytical methods used for oils and fats were employed through pharmacopoeia assays, AOCS (American Oil Chemists Society) standard methods as well as those recommended by ANVISA (National Health Surveillance Agency) such as acidity, peroxide value, saponification index, iodine value and refractive index, pH and relative density, and also thermoanalytical analyses (thermogravimetry, differential thermogravimetry and differential thermal analysis) as well as chromatographic analysis (gas chromatography). The characterization assessments of B. excelsa oil showed results indicating that the oil contains polyunsaturated fatty acids in large proportion. The termoanalytical tests indicated that B.excelsa oil showed thermal stability up to 220 degrees C, These results showed that the oil extracted from B. excelsa has acceptable characteristics and is of good quality. PMID- 25709226 TI - Microsatellite analysis in the genome of Acanthaceae: An in silico approach. AB - BACKGROUND: Acanthaceae is one of the advanced and specialized families with conventionally used medicinal plants. Simple sequence repeats (SSRs) play a major role as molecular markers for genome analysis and plant breeding. The microsatellites existing in the complete genome sequences would help to attain a direct role in the genome organization, recombination, gene regulation, quantitative genetic variation, and evolution of genes. OBJECTIVE: The current study reports the frequency of microsatellites and appropriate markers for the Acanthaceae family genome sequences. MATERIALS AND METHODS: The whole nucleotide sequences of Acanthaceae species were obtained from National Center for Biotechnology Information database and screened for the presence of SSRs. SSR Locator tool was used to predict the microsatellites and inbuilt Primer3 module was used for primer designing. RESULTS: Totally 110 repeats from 108 sequences of Acanthaceae family plant genomes were identified, and the occurrence of dinucleotide repeats was found to be abundant in the genome sequences. The essential amino acid isoleucine was found rich in all the sequences. We also designed the SSR-based primers/markers for 59 sequences of this family that contains microsatellite repeats in their genome. CONCLUSION: The identified microsatellites and primers might be useful for breeding and genetic studies of plants that belong to Acanthaceae family in the future. PMID- 25709227 TI - Development and validation of an high-performance liquid chromatography-diode array detector method for the simultaneous determination of six phenolic compounds in abnormal savda munziq decoction. AB - AIMS: Given the high-effectiveness and low-toxicity of abnormal savda munziq (ASMQ), its herbal formulation has long been used in traditional Uyghur medicine to treat complex diseases, such as cancer, diabetes, and cardiovascular diseases. SETTINGS AND DESIGN: ASMQ decoction by reversed-phase high-performance liquid chromatography coupled with a diode array detector was successfully developed for the simultaneous quality assessment of gallic acid, protocatechuic acid, caffeic acid, rutin, rosmarinic acid, and luteolin. The six phenolic compounds were separated on an Agilent TC-C18 reversed-phase analytical column (4.6 * 250 mm, 5 MUm) by gradient elution using 0.3% aqueous formic acid (v/v) and 0.3% methanol formic acid (v/v) at 1.0 mL/min. MATERIALS AND METHODS: The plant material was separately ground and mixed at the following ratios (10): Cordia dichotoma (10.6), Anchusa italic (10.6), Euphorbia humifusa (4.9), Adiantum capillus veneris (4.9), Ziziphus jujube (4.9), Glycyrrhiza uralensis (7.1), Foeniculum vulgare (4.9), Lavandula angustifolia (4.9), Dracocephalum moldavica L. (4.9), and Alhagi pseudoalhagi (42.3). STATISTICAL ANALYSIS USED: The precisions of all six compounds were <0.60%, and the average recoveries ranged from 99.39% to 104.85%. Highly significant linear correlations were found between component concentrations and specific chromatographic peak areas (R (2) > 0.999). RESULTS: The proposed method was successfully applied to determine the levels of six active components in ASMQ. CONCLUSIONS: Given the simplicity, precision, specificity, and sensitivity of the method, it can be utilized as a quality control approach to simultaneously determining the six phenolic compounds in AMSQ. PMID- 25709228 TI - Vasorelaxant and blood pressure lowering effects of alchemilla vulgaris: A comparative study of methanol and aqueous extracts. AB - BACKGROUND: In the last decade, a growing interest particularly in determining the cardiovascular effects of herbal extracts took place among researchers. OBJECTIVE: Herein, we aimed to investigate the microvascular and blood pressure lowering effects of two differently processed extracts of the same herb, Alchemilla vulgaris (Rosaceaea), which was revealed to contain high levels of vasoactive compounds. MATERIALS AND METHODS: For the purpose, endothelium intact rat mesenteric arteries were mounted in a myograph system and contracted with prostaglandin F2alpha (PGF2alpha: 3 * 10(-5) M) or potassium chloride (K(+): 40 mM). Then, aqueous and methanol extracts were added at 0.01-10 mg/ml concentrations in a cumulative manner. RESULTS: Both extracts produced relaxations in PGF2alpha (3 * 10(-5) M) precontracted arteries which were insensitive to the inhibitors of endothelium derived vasoactive substances namely, L(G)-nitro-L-arginine (10(-4) M), ODQ (10(-5) M) and indomethacin (10(-5) M) or removal of endothelium. Opposite vascular effects were observed when extracts were applied in K(+) precontracted arteries. In addition, oral administration of the methanol extract of Alchemilla vulgaris, but not the aqueous extract, reduced blood pressure significantly in L-NAME hypertensive rats. CONCLUSION: Our results demonstrated that the methanol extract of Alchemilla vulgaris has more prominent and favourable vascular effects in normal and experimental hypertensive conditions reinforcing its traditional use in cardiovascular disorders, in particular hypertension. These results most likely give rise to further studies to reveal its mechanism of action and clinical value of this herb. PMID- 25709229 TI - Obtainment of pellets using the standardized liquid extract of Brosimum gaudichaudii Trecul (Moraceae). AB - BACKGROUND: The standardized liquid extract of Brosimum gaudichaudii Trecul is an alternative for the treatment of vitiligo. There is a shortage of solid oral dosage forms developed from standardized extracts of this plant specie. OBJECTIVE: This study is aimed to obtain pellets with a standardized liquid extract of B. gaudichaudii. RESULTS: The standardized liquid extract of B. gaudichaudii was obtained through maceration and percolation with a 55% ethanol water solution (v/v). Pellets were obtained through a mixture of extract of 500 g of B. gaudichaudii standardized extract, 500 g of microcrystalline cellulose PH101 and 10 g of hydroxypropyl methylcellulose K100. The pellets obtained presented a homogeneity yield of 92%, aspect ratio of 1.16 +/- 0.65, shape fator e R of 0.35 +/- 0.09 and Feret diammeter of 0.87 +/- 0.27. These pellets were coated with a suspension composed of titanium dioxide, aluminum red lacquer, ethyl cellulose, talc and magnesium stearate. Before the photostability test, the uncoated pellets showed psoralen content equal to 0.13 +/- 0.01% and to the 5-MOP was 1.40 +/- 0.27%. After exposure to one level (3 J.cm(-2)) of UVB irradiation the uncoated pellets presented a degradation of 2.16% of psoralen and 8.1% of 5 MOP. After exposure to three levels (10, 20 and 30 J.cm(-2)) of UVA irradiation the uncoated pellets exhibited photodegradation of 9.78, 17.64, 24.21% of psoralen and 18.95, 23.68, 28.48% for 5-MOP. The coated pellets where unaffected after photostability test. CONCLUSION: Pellets were obtained with the standardized liquid extract of B. gaudichaudii and coating is a technological alternative to ensure the stability of the formula. PMID- 25709230 TI - Chromatographic method for determination of the free amino acid content of chamomile flowers. AB - OBJECTIVE: To determine the free amino acid contents of chamomile flowers using reverse-phase high-performance column chromatography preceded by pre-column derivatization with 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate (AQC), and to determine the reliability of this method. MATERIALS AND METHODS: Derivatization with reconstituted AQC was used to prepare the samples and standards for injection into the chromatography column. The peaks were analyzed by fluorescence detection (lambda excitation, 250 nm; lambda emission, 395 nm. RESULTS: Alanine, proline, and leucine were the most abundant amino acids, whereas tyrosine and methionine were the least abundant. The linearity of the method was found to be good with amino acid concentrations of 0.012-0.36 MUM. The precision was 0.05 1.36%; average recovery, 91.12-129.41%; and limit of detection, 0.006-0.058 MUM. CONCLUSION: The method is reliable for determining the free amino acid content of different types of chamomile flowers. PMID- 25709231 TI - Estimation of Costunolide and Dehydrocostus Lactone in Saussurea lappa and its Polyherbal Formulations followed by their Stability Studies Using HPLC-DAD. AB - BACKGROUND: Saussurea lappa is one of the popular Ayurvedic herb; costunolide and dehydrocostus lactones are well-known sesquiterpene lactones contained in many plants used as popular herbs, such as S. lappa, and have been considered as potential candidates for the treatment of various types of tumor. OBJECTIVE: The present study was used for the quantification of costunolide and dehydrocostus lactone in S. lappa and its polyherbal formulations, stability studies of markers and characterization of their degradants. MATERIALS AND METHODS: HPLC analysis was performed on Waters NOVAPAK HR C18 column (300 mm * 3.9 mm i.d., 6 MUm) using isocratic elution with acetonitrile and water (60:40% v/v). RESULTS: The calibration curves of both analytes showed good linearity within the established range 5-100 MUg/ml. The limits of detection (LOD) and quantification (LOQ) were 1.5 and 4.6 MUg/ml for costunolide and 1.3 and 4.0 MUg/ml for dehydrocostus lactone, respectively. Good results were achieved with respect to repeatability (%RSD < 2.0) and recovery (99.3-101.8%). CONCLUSION: The method was found to be precise, accurate, specific, and was successfully used for analyzing costunolide and dehydrocostus lactone in S. lappa and its polyherbal formulations. The developed method was found to be suitable for stability studies of markers and characterization of their degradation products. PMID- 25709232 TI - A New Lignan Glucoside from Lagochilus ilicifolius. AB - BACKGROUND: The whole herb of Lagochilus ilicifolius has been used as a folk medicine for treating hemostatic, inflammation and ulcer in China. There were only limited reports on its chemical constituents, and no reports on its pharmacology study. OBJECTIVE: To isolate compounds from the whole herb of L. ilicifolius and evaluate their cytotoxic activity. MATERIALS AND METHODS: The column chromatographic techniques were used for separating the constituents of the n-butanol-soluble fraction of the 95% ethanol extract from the whole plant of L. ilicifolius. The structures of one new lignan and two known lignans were elucidated on the basis of spectroscopic analyses and comparison with literature data. The cytotoxic activities of these three lignans were evaluated using the MTT-assay against PC12 cell line derived from rat adrenal pheochromocytoma. RESULTS: The new lignan was identified as erythro-1-[(4-O-beta-D-glucopyranosyl-3 methoxyl)-phenyl]-2-[(5'-methoxyl)-pinoresinol]-propane-1,3-diol (1), and two known lignans were identified as tortoside C (2) and sisymbrifolin (3). The new lignan exhibited significant cytotoxic activity against PC12 cell line with IC50 value of 1.22 +/- 0.03 MUmol/L. CONCLUSIONS: A new lignan, erythro-1-[(4-O-beta-D glucopyranosyl-3-methoxyl)-phenyl]-2-[(5'-methoxyl)-pinoresinol]-propane-1,3-diol and two known lignans were isolated from the whole herbs of L. ilicifolius. The two known lignans were reported for the first time in the genus Lagochilus. Three lignans were evaluated for in vitro cytotoxic activity. The new lignan showed relatively strong cytotoxicity against PC12 cell line, while sisymbrifolin and tortoside C exibited no cytotoxicity. PMID- 25709233 TI - Qualitative and quantitative determination of 15 main active constituents in Fructus Sophorae pill by liquid chromatography tandem mass spectrometry. AB - BACKGROUND: Fructus Sophorae pill, one of the traditional Chinese medicine, was widely used for hemorrhoids, hypertension and odontalgia. This paper describes a sensitive and specific assay for the determination of the 15 active constituents (sophoricoside, genistin, genistein, rutin, quercetin, kaempferol, baicalein, baicalin, naringin, naringenin, hesperidin, neohesperidin, wogonin and cimifugin, prim-O-glucosylcimifugin) in Fructus Sophorae pill. MATERIALS AND METHODS: Chromatographic separation was performed on a C18 column with acidified aqueous methanol gradients at a flow rate of 0.8 mL/min. The identification and quantification of the analytes were achieved by use of a hybrid quadrupole linear ion trap mass spectrometer. Multiple-reaction monitoring scanning was applied to quantification with switching electrospray ion source polarity between positive and negative modes. RESULTS: The proposed method was used to analyze 40 batches of samples with good linearity (r, 0.9990-0.9999), intraday precisions (RSD, 0.14 2.55%), interday precisions (RSD, 0.51-2.81%), stability (RSD, 0.31-2.65%), and recovery (RSD, 1.29-2.95%) of the 15 compounds. In addition, the hierarchical cluster analysis, including a method called furthest neighbor and nearest neighbor, was employed to classify samples according to characteristics of the 15 constituents. CONCLUSION: The results indicated that the analytical method was rapid, reliable, simple and suitable for the quality evaluation of Fructus Sophorae pill. PMID- 25709234 TI - A comparison of the antimicrobial activity and toxicity of six combretum and two terminalia species from southern Africa. AB - BACKGROUND: Plants of the family Combretaceae are amongst the most widely used plants for traditional medicinal purposes in southern Africa. In particular, many species of Combretum and Terminalia are used for their antibacterial, antifungal, antiprotozoal, antiviral, antidiarrhoeal, analgesic, antimalarial, antioxidant, anti-inflammatory and anticancer activities, yet their antimicrobial potential has not been rigorously studied and compared. MATERIALS AND METHODS: A survey of antimicrobial activity was undertaken on selected South African Combretum and Terminalia species. Sixteen extracts from 6 Combretum and 2 Terminalia plant species with a history of medicinal usage were investigated by disc diffusion assay against a panel of bacteria and fungi and their MIC values were determined. Toxicity was determined using the Artemia franciscana nauplii bioassay. RESULTS: All extracts tested displayed broad spectrum antibacterial activity, inhibiting the growth of 12-16 (75-100%) of the bacteria tested, with Gram-positive and Gram negative bacteria being approximately equally susceptible. Potent antibacterial activities (generally in the range 200-5000 MUg/ml) were evident for all Combretaceae extracts against both Gram-positive and Gram-negative bacteria. Similarly, the extracts also displayed good antifungal activity, inhibiting the growth of 2-3 (66.7-100%) of the fungal species tested, with fungal growth inhibition activities generally in the range 200-4000 MUg/ml. In general, the Terminalia extracts had better efficacies than the Combretum extracts. Furthermore, the methanol extracts were generally better antimicrobial agents than the water extracts. All extracts were also shown to be non-toxic in the Artemia nauplii bioassay. CONCLUSION: The lack of toxicity of these extracts and their inhibitory bioactivity against a panel of bacteria and fungi indicate their potential as medicinal agents and partially validate their usage in multiple South African traditional medicinal systems. PMID- 25709235 TI - Promoting effect of triterpenoid compound from Agrimonia pilosa Ledeb on preadipocytes differentiation via up-regulation of PPARgamma expression. AB - BACKGROUND: Agrimonia Pilosa Ledeb (APL), a traditional Chinese medicine, has been reported a variety of biological activities, including treating T2DM. OBJECTIVE: Triterpenoid compound (TC) was collected from APL. The aim of this study was to investigate the effects of TC on 3T3-L1 preadipocytes differentiation and genes related to differentiation and IR. MATERIALS AND METHODS: Column chromatography was used to collect TC from ALP. 3T3-L1 cell differentiation was induced typically in the presence of various concentrations of TC or pioglitazone. Oil red O staining and measurement of intracellular TG content were performed on the seventh day of differentiation. Then quantitative polymerase chain reaction (Q-PCR) was used to test the expressions of three transcription factors (PPARgamma, CCAAT enhancer binding protein-alpha (C/EBP alpha), and sterol regulatory element-binding protein 1 (SREBP-1)) and the target genes of PPARgamma including glucose transporter (GLUT4), lipoprotein lipase (LPL), fat acid binding protein (AP2), and adiponectin in 3T3-L1 cells. RESULTS: At the concentration of 5, 25 and 125 MUg/mL, TC significantly promoted triglyceride accumulation. Further study showed that TC could promote the expression of PPARgamma, C/EBPalpha and ADD1/SREBP1 significantly at 125 MUg/mL. As for downstream genes controlled by PPARgamma, TC at 25 and 125 MUg/mL could significantly promote the expression of GLUT4 and adiponectin. However, the expression of aP2 related to lipid metabolism and adiposity in the TC group was significantly lower than that in the pioglitazone group. CONCLUSION: TC could promote preadipocytes differentiation through activating PPARgamma and downstream controlled genes. TC has the ideal insulin sensitization with lower adipogenic action than classical TZDs in vitro. So TC from Agrimonia Pilosa Ledeb has a good prospect as a natural drug for IR and T2DM. PMID- 25709236 TI - Technical aspects on production of fluid extract from Brosimum gaudichaudii Trecul roots. AB - INSTRUCTION: Despite the increased use of Brosimum gaudichaudii roots as raw material on medicine to treatment of vitiligo, there are not studies that showing the impact of unit operations on the quality and standardized of the extract of B. gaudichaudii. The quality of the herbal extract is essential to ensure the safety and efficacy of pharmaceutical product. Due the medical and commercial importance, this study aimed to evaluate the impact of the extraction method (ultrasound or percolation) on the quality of herbal extract and optimize the extraction of psoralen and 8-methoxypsoralen (8-MOP) from B. gaudichaudii. MATERIALS AND METHODS: The extraction recovery was evaluate by high-performance liquid chromatography (C8 reverse phase column and acetonitrile: Water 45:55 and flow rate 0.6 mL/min). The extraction was performed by ultrasound-assisted extraction (UEA) or percolation using a Box-Behnken design. RESULTS: From both chemical markers (psoralen and bergapten), the optimal conditions for the UEA were an extraction time of 25 min, the mean particle size of 100 MUm, and an ethanol: Water ratio of 55:45 (v/v). CONCLUSION: The extraction by percolation revealed that ethanol 55% was more efficient than ethanol 80% to extract psoralen and bergapten. PMID- 25709237 TI - Increasing preoperative dislocations and total time of dislocation affect surgical management of anterior shoulder instability. AB - PURPOSE: Our purpose was to determine the relationship between number of preoperative shoulder dislocations and total dislocation time and the need to perform bone deficiency procedures at the time of primary anterior instability surgery. Our hypothesis was that need for bone deficiency procedures would increase with the total number and hours of dislocation. MATERIALS AND METHODS: A retrospective review was performed of primary instability surgeries performed by a single surgeon. Patients with <25% glenoid bone loss were treated with an isolated arthroscopic Bankart repair. Those who also had an engaging Hill-Sachs lesion underwent arthroscopic Bankart repair with remplissage. Patients with >25% glenoid bone loss were treated with Latarjet reconstruction. Number of dislocations and total dislocation time were examined for their relationship with the treatment method. RESULTS: Ten arthroscopic Bankart repairs, 13 arthroscopic Bankart plus remplissage procedures, and 9 Latarjet reconstructions were available for review. Total dislocations (P = 0.012) and total hours of dislocation (P = 0.019) increased from the Bankart, to the remplissage, to the Latarjet groups. Patients with a total dislocation time of 5 h or more were more likely to require a Latarjet reconstruction (P = 0.039). Patients with only 1 preoperative dislocation were treated with an isolated Bankart repair in 64% (7 of 11) of cases, whereas those with 2 or more dislocations required a bone loss procedure in 86% (18 of 21) of cases (P = 0.013). CONCLUSION: Increasing number of dislocations and total dislocation time are associated with the development of glenoid and humeral head bony lesions that alter surgical management of anterior shoulder instability. The necessity for the addition of a remplissage to an arthroscopic Bankart repair or the use of a Latarjet reconstruction increases with only 1 recurrent dislocation. LEVEL OF EVIDENCE: Level III, retrospective comparative study. PMID- 25709238 TI - Reinterpretation of O'Brien test in posterior labral tears of the shoulder. AB - BACKGROUND: Injuries to the posterior labrum are less common and more difficult to diagnose compared to anterior labral pathology. This may be in part due to difficulties in preoperative diagnosis. Posterior labral injuries cause abnormal loading of the rotator cuff with subsequent weakness. Examination using the O'Briens test tightens the posterior capsule and posteriorly translates the humeral head, stressing the labrum resulting in pain and weakness. METHOD: A retrospective study. RESULTS: Of 74 patients diagnosed with a posterior labral tear at arthroscopy 55 had subjective weakness on performing a O'Briens test, a sensitivity of 83% and a positive predictive value (PPV) of 90%. CONCLUSION: Multiple tests have been described for posterior labral pathology and none of these, on their own, have a high sensitivity rate. Posterior labral injuries can often be missed on magnetic resonance imaging scanning and also at surgery if not specifically looked for. Using a sign of clinically demonstrated weakness when performing the O'Briens test, and hence reinterpretation of the test, is sensitive, with a high PPV for posterior labral pathology and can help guide further treatment. PMID- 25709239 TI - A new tear pattern of the rotator cuff and its treatment: Fosbury flop tears. AB - PURPOSE: The purpose of this report is to describe a new full-thickness tear pattern of the posterosuperior rotator cuff with reversal healing. We describe the specific radiologic signs associated with this tear pattern and the arthroscopic rotator cuff repair technique. MATERIALS AND METHODS: A prospective radiologic and clinical study collected all patients with a magnetic resonance imaging arthrogram that underwent an arthroscopic rotator cuff repair over a 1 year period. RESULTS: Among 97 patients, five demonstrated a tear of the posterosuperior rotator cuff with reversal healing. Characteristic radiographic findings included a thicker tendon than normal, the presence of a stump and accumulation of liquid in the superior-medial part of the subacromial bursa, and adhesions between the supraspinatus tendon and the wall of the subacromial bursa. CONCLUSION: Avulsion of the posterosuperior rotator cuff with reversal healing on its bursal-side is a less common condition. This type of lesion and distinct radiographic signs that can be recognized to facilitate anatomic repair of the rotator cuff. LEVEL OF EVIDENCE: Level IV. PMID- 25709240 TI - The isolated inferior glenohumeral labrum injury, anterior to posterior (the ILAP): A case series. AB - INTRODUCTION: We describe the presentation, exam findings, surgical repair techniques, and short-term outcomes in a series of patients with isolated inferior labral tears. MATERIALS AND METHODS: A retrospective chart review was performed at a large academic medical center. Isolated inferior labral tears were defined as between the 4 o'clock and 8 o'clock position of the glenoid as determined by direct arthroscopic visualization. Tears that were smaller were also included but were required to cross the 6 o'clock point, having anterior and posterior components. Patients were excluded if they had any other pathology or treatment of the shoulder. 1-year follow-up was required. RESULTS: Of the 17 patients who met inclusion criteria for review, 12 were available for a minimum 1 year follow-up. Average total follow-up for patients to complete the phone interview/Oxford Shoulder Instability Score (OSIS) was an average of 37.7 months (range: 16-79 months). Postoperatively, all reported symptom improvement or resolution since surgery. The mean preoperative pain on a scale of 0-10 was 6.3 (range: 0-10). Mean postoperative pain on a scale of 0-10 was 2.25 (range: 0-5). Eleven of 12 patients (91.7%) had returned to the level of activity desired. The mean OSIS was 41.4 (median: 43; range: 27-47). Eleven of 12 patients (91.7%) had good or excellent scores. Ten of 12 patients (83.3%) had a feeling of stability in the shoulder. All 12 patients reached were satisfied with the procedure and would undergo surgery again in a similar situation. CONCLUSIONS: We have presented our series of patients with isolated inferior labral injury, and have shown that when surgically treated, outcomes of this uncommon injury are good to excellent and a full return to sports can be expected. PMID- 25709241 TI - Pectoralis major transosseous equivalent repair with knotless anchors: Technical note and literature review. AB - INTRODUCTION: Rupture of the pectoralis major (PM) tendon was initially described almost 2 centuries ago, but most of the reported injuries have occurred within the last 30 years. Options for repair have varied widely. The most common methods for repair depend on either transosseous sutures or suture anchors for fixation. Transosseous suture repair allows for docking the tendon into a trough at its anatomic insertion, but risks cortical breakage during suture passing. Our experience has confirmed the value and potential advantages of anchors for a secure fixation. AIMS: To describe a variation of repair using knotless suture anchors and a burred trough to dock the tendon into its anatomic insertion. CONCLUSION: We describe a technique of a transosseous equivalent PM repair technique. To our knowledge, this is the first paper describing such a repair technique for PM rupture. PMID- 25709243 TI - Whats new in emergencies, trauma and shock? Shock, Sonography and survival in emergency care! PMID- 25709244 TI - Alcohol related work place injuries: More Questions than Answers! PMID- 25709242 TI - Reverse shoulder arthroplasty. Part 1: Systematic review of clinical and functional outcomes. AB - Many factors influence the outcomes of reverse shoulder arthroplasty (RSA). The purpose of this study was to compare the clinical and functional outcomes of RSA depending on the surgical approach, type of prosthesis, and indication for surgery through a comprehensive, systematic review. A literature search was conducted (1985 to June 2012) using PubMed, CINAHL, EBSCO-SPORTDiscus, and Cochrane Central Register of Controlled Trials. Levels I-IV evidence, in-vivo human studies (written in English with minimum of 2 years of follow-up and sample size of 10 patients) reporting clinical and/or functional outcomes after RSA were included. The outcomes were analyzed depending on the surgical approach, type of prosthesis (with medialized or lateralized center of rotation), or indication for surgery. A total of 35 studies were included involving 2049 patients (mean [SD] percentage of females, age, and follow-up of 71.6% [13.4], 71.5 years [3.7], and 43.1 months [18.8], respectively). Studies using deltopectoral approach with lateralized prostheses demonstrated greater improvement in external rotation compared with medialized prostheses with the same approach (mean 22.9 degrees and 5 degrees , respectively). In general, RSA for cuff tear arthropathy demonstrated higher improvements in Constant and American Shoulder and Elbow Society scores, and range of motion compared with revision of anatomic prosthesis, failed rotator cuff repair, and fracture sequelae. Lateralized prostheses provided more improvement in external rotation compared to medialized prostheses. Indications of RSA for cuff tear arthropathy demonstrated higher improvements in the outcomes compared with other indications. RSA demonstrated high patient's satisfaction regardless of the type of prosthesis or indication for surgery. LEVEL OF EVIDENCE: Level IV. PMID- 25709245 TI - Accuracy of early rapid ultrasound in shock (RUSH) examination performed by emergency physician for diagnosis of shock etiology in critically ill patients. AB - BACKGROUND: Rapid Ultrasound in Shock (RUSH) is a recently reported emergency ultrasound protocol designed to help clinicians better recognize distinctive shock etiologies in a short time. We tried to evaluate the accuracy of early RUSH protocol performed by emergency physicians to predict the shock type in critically ill patients. MATERIALS AND METHODS: Our prospective study was approved by the ethics committee of trauma research center, Baqiyatallah University of Medical Science, Iran. We enrolled 52 patients with shock state in the emergency department from April 2013 to October 2013. We performed early bed side sonographic examination for participants based on RUSH protocol. Patients received all needed standard therapeutic and diagnostic interventions without delay and were followed to document their final diagnosis. Agreement (Kappa index) of initial impression provided by RUSH with final diagnosis, and also sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of RUSH for diagnosis of each shock type were calculated. RESULTS: Fifty-two patients were enrolled in our study. Kappa index was 0.7 (P value = 0.000), reflecting acceptable general agreement between initial impression and final diagnosis. For hypovolemic and obstructive shocks, the protocol had sensitivity of 100% but had lower PPV. For shocks with distributive or mixed etiology, RUSH showed PPV of 100% but had low sensitivity. For cardiogenic shocks, all reliability indices were above 90%. CONCLUSION: We highlight the role of RUSH examination in the hands of an emergency physician in making a rapid diagnosis of shock etiology, especially in ruling out obstructive, cardiogenic, and hypovolemic types. PMID- 25709246 TI - Ketamine for continuous sedation of mechanically ventilated patients. AB - CONTEXT: Long-term sedation with midazolam or propofol has been demonstrated to have serious adverse side effects, such as toxic accumulation or propofol infusion syndrome. Ketamine remains a viable alternative for continuous sedation as it is inexpensive and widely available, however, there are few analyses regarding its safety in this clinical setting. OBJECTIVE: To review the data related to safety and efficacy of ketamine as a potential sedative agent in mechanically ventilated patients admitted to the intensive care unit (ICU). MATERIALS AND METHODS: This was a single-center retrospective study from September 2011 to March 2012 of patients who required sedation for greater than 24 hours, in whom ketamine was selected as the primary sedative agent. All patients greater than 18 years of age, regardless of admitting diagnosis, were eligible for inclusion. Patients that received ketamine for continuous infusion but died prior to receiving it for 24 hours were not included. RESULTS: Thirty patients received ketamine for continuous sedation. In four patients, ketamine was switched to another sedative agent due to possible adverse side effects. Of these, two patients had tachydysrhythmias, both with new onset atrial fibrillation and two patients had agitation believed to be caused by ketamine. The adverse event rate in our patient population was 13% (4/30). CONCLUSIONS: Among ICU patients receiving prolonged mechanical ventilation, the use of ketamine appeared to have a frequency of adverse events similar to more common sedative agents, like propofol and benzodiazepines. PMID- 25709247 TI - Salvageability of kidney in Grade IV renal trauma by minimally invasive treatment methods. AB - CONTEXT: Renal trauma is increasingly being managed conservatively. Grade I-III injuries are managed conservatively whereas Grade V injuries may end in surgery. Managing Grade IV renal trauma is individualized and managed accordingly. AIMS: To evaluate retrospectively all Grade IV renal injuries managed in our institute over five years and to review the available literature. SETTINGS AND DESIGN: Reviewing the records of patients who sustained renal trauma and study all Grade IV renal injuries. MATERIALS AND METHODS: We retrospectively analyzed all Grade IV renal injuries (16) managed at our institute between July 2008-August 2013. All patients were treated conservatively initially by hemodynamic stabilization, strict bed rest, if required endoscopic procedures. These patients were followed up with CECT. STATISTICAL ANALYSIS: Descriptive statistics was performed using Microsoft excel spreadsheet 2007. Continuous data were described as mean and range. Categorical data was described as percentages. RESULTS: Sixteen patients with Grade IV renal injury were included in the study. All patients had gross hematuria and 15 had urinary extravasation. D-J Stenting was done in 7 patients; perinephric tube drainage with D-J stentingwas done in 2 patients. One required selective upper pole arterial embolisation. Nephrectomy was not required in any of the patients. In the follow-up period, no patient had delayed complications. CONCLUSIONS: Successful conservative management of Grade IV renal trauma requires constant monitoring both clinically and radiologically, and if properly managed, kidneys can be salvaged in all stable patients as reinforced by our study. PMID- 25709248 TI - Warm fresh whole blood and thoracic traumain iraq and afghanistan. AB - BACKGROUND: Thoracic trauma occurred in 10% of the patients seen at US military treatment facilities in Iraq and Afghanistan and 52% of those patients were transfused. Among those transfused, 281 patients received warm fresh whole blood. A previous report documented improved survival with warm fresh whole blood in patients injured in combat without stratification by injury pattern. A later report described an increase in acute lung injuries after its administration. Survivorship and warm fresh whole blood have never been analyzed in a subpopulation at highest risk for lung injuries, such as patients with thoracic trauma. There may be a heterogeneous relationship between whole blood and survival based on likelihood of a concomitant pulmonary injury. In this report, the relationship between warm fresh whole blood and survivorship was analyzed among patients at highest risk for concomitant pulmonary injuries. MATERIALS AND METHODS: Patients with thoracic trauma who received a transfusion were identified in the Joint Theater Trauma Registry. Gross mortality rates were compared between whole blood recipients and patients transfused with component therapy only. The association between each blood component and mortality was determined in a regression model. The overall mortality risk was compared between warm fresh whole blood recipients and non-recipients. RESULTS: Patients transfused with warm fresh whole blood in addition to component therapy had a higher mortality rate than patients transfused only separated blood components (21.3% vs. 12.8%, P < 0.001). When controlling for covariates, transfusion of warm fresh whole blood in addition to component therapy was not associated with increased mortality risk compared with the transfusion of component therapy only (OR 1.247 [95% CI 0.760 2.048], P = 0.382). CONCLUSION: Patients with combat related thoracic trauma transfused with warm fresh whole blood were not at increased risk for mortality compared to those who received component therapy alone when controlling for covariates. PMID- 25709249 TI - Analysis of patients with decompression illness transported via physician-staffed emergency helicopters. AB - CONTEXT: There have been few reports investigating the effects of air transportation on patients with decompression illness (DCI). AIMS: To investigate the influence of air transportation on patients with DCI transported via physician-staffed emergency helicopters (HEMS: Emergency medical system of physician-staffed emergency helicopters). SETTINGS AND DESIGN: A retrospective medical chart review in a single hospital. MATERIALS AND METHODS: A medical chart review was retrospectively performed in all patients with DCI transported via HEMS between July 2009 and June 2013. The exclusion criteria included cardiopulmonary arrest on surfacing. STATISTICAL ANALYSIS USED: The paired Student's t-test. RESULTS: A total of 28 patients were treated as subjects. Male and middle-aged subjects were predominant. The number of patients who suddenly surfaced was 15/28. All patients underwent oxygen therapy during flight, and all but one patient received the administration of lactate Ringer fluid. The subjective symptoms of eight of 28 subjects improved after the flight. The range of all flights under 300 m above sea level. There were no significant differences between the values obtained before and after the flight for Glasgow coma scale, blood pressure, and heart rate. Concerning the SpO2, statistically significant improvements were noted after the flight (96.2 +/- 0.9% versus 97.3 +/- 0.7%). There were no relationships between an improvement in subjective symptoms and the SpO2. CONCLUSION: Improvements in the subjective symptoms and/or SpO2 of patients with DCI may be observed when the patient is transported via HEMS under flights less than 300 m in height with the administration of oxygen and fluids. PMID- 25709250 TI - Preoperative evaluation of penetrating esophageal trauma in the current era: An analysis of the National Trauma Data Bank. AB - BACKGROUND: Preoperative diagnostic evaluation (PDE) of penetrating esophageal injury (PeEsIn) can delay treatment and increase morbidity. We sought to study the relationship among PDE, delay in definitive treatment, and patient mortality in PeEsIn. MATERIALS AND METHODS: The 2008-2010 National Trauma Data Banks were queried for PeEsIn. Exclusion criteria were death within 1 day of injury, and missing data about survival to discharge or operative intervention. Data extracted included demographics, vital signs, injury severity, diagnostic procedures (endoscopy, computed tomography, and fluoroscopy), time to procedures and/or operation, hospital-free days, and mortality. RESULTS: Of 280 patients, 75 underwent PDE and 205 did not. There were no significant differences in baseline demographics, vital signs or injury severity between the two groups. The median time to the first operation was shorter in the nonPDE cohort compared to the PDE cohort (2 vs. 3 h; P = 0.018). Median hospital-free days at day 60 were significantly less in nonPDE (42 days, interquartile range ([IQR] = [28, 50]) versus PDE patients (47 days, IQR = [38, 51]) (P = 0.007). Mortality was not statistically different. CONCLUSIONS: PDE in PeEsIn slightly delays the time to operation without worsening mortality, and is a predictor of more hospital-free days. PMID- 25709251 TI - Goal-directed diuresis: A case - control study of continuous furosemide infusion in critically ill trauma patients. AB - BACKGROUND: Excessive crystalloid administration is common and associated with negative outcomes in critically ill trauma patients. Continuous furosemide infusion (CFI) to remove excessive fluid has not been previously described in this population. We hypothesized that a goal-directed CFI is more effective for fluid removal than intermittent bolus injection (IBI) diuresis without excess incidence of hypokalemia or renal failure. MATERIALS AND METHODS: CFI cases were prospectively enrolled between November 2011 and August 2012, and matched to historic IBI controls by age, gender, Injury Severity Score (ISS), and net fluid balance (NFB) at diuresis initiation. Paired and unpaired analyses were performed to compare groups. The primary endpoints were net fluid balance, potassium and creatinine levels. Secondary endpoints included intensive care unit (ICU) and hospital length of stay (LOS), ventilator-free days (VFD), and mortality. RESULTS: 55 patients were included, with 19 cases and 36 matched controls. Mean age was 54 years, mean ISS was 32.7, and mean initial NFB was +7.7 L. After one day of diuresis with CFI vs. IBI, net 24 h fluid balance was negative (-0.55 L vs. +0.43 L, P = 0.026) only for the CFI group, and there was no difference in potassium and creatinine levels. Cumulative furosemide dose (59.4mg vs. 25.4mg, P < 0.001) and urine output (4.2 L vs. 2.8 L, P < 0.001) were also significantly increased with CFI vs. IBI. There were no statistically significant differences in ICU LOS, hospital LOS, VFD, or mortality. CONCLUSIONS: Compared to IBI, goal directed diuresis by CFI is more successful in achieving net negative fluid balance in patients with fluid overload with no detrimental side effects on renal function or patient outcome. PMID- 25709252 TI - Analysis of patients with bodyboarding injuries transported by physician-staffed emergency helicopter. AB - CONTEXT: There have been no reports that have studied the characteristics specific to bodyboard injuries. AIMS: To clarify characteristics to bodyboard injuries. SETTINGS AND DESIGN: A retrospective medical chart review. MATERIALS AND METHODS: A medical chart review was retrospectively performed for all patients with spinal cord injuries transported via physician-staffed emergency helicopters between January 2009 and October 2013. The subjects were divided into two groups based on whether they had a spinal cord injury induced by bodyboarding (Bodyboard group, n = 14) or not (Control group, n = 14). STATISTICAL ANALYSIS USED: Using a chi(2)-test, Mann-Whitney U-test and non-paired Student's t-test. RESULTS: All but one of the subjects had spinal canal stenosis. The age of the patients in the Bodyboard group was younger than that of the Control group. The ratio of males and Glasgow Coma Scale of the Bodyboard group were higher than those on the Control group. The spinal cord injury induced by bodyboarding typically occurred after impacts of the head or face with the sea bottom while the subject was being buffeted by the waves. The severity of the spinal cord injury in the Bodyboard group was lower than that in the Control group. CONCLUSION: Bodyboarding tended to induce spinal cord injuries after the head or face collided with the sea bottom, and was more common in middle-aged males during the summer season, and was associated with a favorable outcome. PMID- 25709253 TI - Luxatio erecta humeri: Report of a swimming injury with analysis of the mechanism of the injury and associated injuries in literature. AB - Inferior shoulder dislocation also referred to as luxatio erecta is an unusual and rare type of shoulder dislocation. Its incidence is about 0.5% among all shoulder dislocations. After an exhaustive search of all the available literature we were unable to find a swimming accident case that did not have other associated injuries and an uneventful reduction. The mechanism of the injury was mostly related to direct axial loading and indirect hyperabduction lever arm. We would like to emphasize the importance of this being a swimming accident, a type of accident that requires awareness of the possibility of dangerous asphyxia injuries caused by panic in the water (swimming pool, river, lake, sea, etc.). We described the nature of the injury and review the literature concerning the mechanism of the injury and associated neurovascular impairment at admission time. We also presented a supplemental video to contribute to the education of young residents and orthopedic surgeons. PMID- 25709254 TI - Delayed recurrent pericarditis complicated by pericardial effusion and cardiac tamponade in a blunt trauma patient. AB - A 19-year-old male suffered orthopedic fractures, blunt solid organ injury and pneumopericardium after a fall from 40 feet. With the exception of an external fixation device, he was managed non-operatively and discharged to a rehabilitation unit after 8 days. He was readmitted 4 days later with chest pain and clinical evidence of pericardititis that resolved with the initiation of non steroidal anti-inflammatory drugs and colchicine. He returned to the rehabilitation hospital, but was readmitted once again for chest pain and hypotension. Echocardiogram revealed cardiac tamponade that required emergent drainage. He tolerated the procedure well and was discharged home from the hospital to continue treatment for his pericarditis. He is doing well at 3 months of follow-up. PMID- 25709256 TI - Salvage intraosseous thrombolysis and extracorporeal membrane oxygenation for massive pulmonary embolism. AB - Intraosseous access is an alternative route of pharmacotherapy during cardiopulmonary resuscitation. Extracorporeal membrane oxygenation (ECMO) provides cardiac and respiratory support when conventional therapies fail. This case reports the use of intraosseous thrombolysis and ECMO in a patient with acute massive pulmonary embolism (PE). A 34-year-old female presented to the emergency department with sudden onset severe shortness of breath. Due to difficulty establishing intravenous access, an intraosseous needle was inserted into the left tibia. Echocardiography identified severe right ventricular dilatation with global systolic impairment and failure, indicative of PE. Due to the patient's hemodynamic compromise a recombinant tissue plasminogen activator (Alteplase) bolus was administered through the intraosseous route. After transfer to the intensive care unit, venous-arterial ECMO was initiated as further therapy. The patient recovered and was discharged 36 days after admission. This is the first report of combination intraosseous thrombolysis and ECMO as salvage therapy for massive PE. PMID- 25709255 TI - Marchiafava-Bignami disease in a trauma patient. AB - Marchiafava-Bignami disease (MBD) is a rare pathological condition affecting the corpus callosum (CC), characterized by progressive demyelination and necrosis. While usually found in patients with chronic alcoholism, it has rarely been characterized in non-alcoholics. We describe a trauma patient with an unknown mechanism of injury, who was found to have MBD after remaining comatose for a prolonged period of time. Magnetic resonance imaging (MRI) demonstrated restricted diffusion involving the genu, body, and splenium of the CC. The patient eventually awoke but was non-communicative and uncomprehending prior to discharge to a nursing facility. We reviewed the literature and report here the first case of MBD encountered in a trauma patient. In conclusion, MBD is an extremely rare condition in non-alcoholic patients, and the use of MRI is crucial for its identification. PMID- 25709257 TI - Continuous intravenous flumazenil infusion in a patient with chlordiazepoxide toxicity and hepatic encephalopathy. AB - Flumazenil, a benzodiazepine receptor antagonist, is the drug of choice for the diagnosis and treatment of benzodiazepine overdose. We are presenting a patient with chronic alcoholism and alcoholic liver disease, who came with alcohol withdrawal symptoms and treated chlordiazepoxide. Subsequently he developed a prolonged change in mental status that required treatment for benzodiazepine overdose and hepatic encephalopathy with flumazenil infusion for 28 days. PMID- 25709258 TI - Emergency department external fixation for provisional treatment of pilon and unstable ankle fractures. AB - Unstable ankle fractures and impacted tibial pilon fractures often benefit from provisional external fixation as a temporizing measure prior to definitive fixation. Benefits of external fixation include improved articular alignment, decreased articular impaction, and soft tissue rest. Uniplanar external fixator placement in the Emergency Department (ED ex-fix) is a reliable and safe technique for achieving ankle reduction and stability while awaiting definitive fixation. This procedure involves placing transverse proximal tibial and calcaneal traction pins and connecting the pins with two external fixator rods. This technique is particularly useful in austere environments or when the operating room is not immediately available. Additionally, this bedside intervention prevents the patient from requiring general anesthesia and may be a cost-effective strategy for decreasing valuable operating time. The ED ex-fix is an especially valuable procedure in busy trauma centers and during mass casualty events, in which resources may be limited. PMID- 25709259 TI - Chloramphenicol and acute esophagitis in the emergency department. AB - Even with its broad spectrum and low cost, concern over chloramphenicol's adverse effects limited its use in the United States during the 1980s. Reports from United Kingdom and China in the 1990s demonstrated a low incidence of blood dyscrasias with the topical preparation of chloramphenicol, and showed continued good efficacy and low cost. Today, topical chloramphenicol is being used by some groups within otolaryngology and ophthalmology in the United States. As a result, emergency physicians are once again considering chloramphenicol-induced side effects in patients presenting to the emergency department. To date, there have been no published reports associating chest pain, dyspnea with chloramphenicol use, and there has only been one report of fungal esophagitis associated with topical chloramphenicol. We present a 31-year-old woman, 4 months status post tympanoplasty with a modified radical canal wall down mastoidectomy due to a cholesteatoma involving the epitympanum who had a residual tympanic membrane defect. She presented to the emergency department with chest "burning", with no other symptoms shortly after starting treatment with an insufflated combination antibiotic containing chloramphenicol. After ruling out cardiopulmonary or vascular etiology, she was treated successfully with a gastrointestinal cocktail cocktail for presumed esophagitis secondary to newly prescribed chloramphenicol. PMID- 25709260 TI - Availability of Swasthya Vahan Sewa (102 services) and constraints in its utilization in a rural block of Haryana, India. PMID- 25709261 TI - A case of Stanford B type aortic dissection in a patient whose initial complaints were a toothache and left shoulder pain. PMID- 25709262 TI - Treatment of hemodynamically stable penetrating mediastinal gunshot wounds in chile: Comparison of 3 cases and literature review. PMID- 25709263 TI - Ultrasound guided supraclavicular subclavian cannulation: A novel technique using "hockey stick" probe. PMID- 25709264 TI - Gillen-Hackstadt maneuver. PMID- 25709265 TI - Epidemiology of diabetic retinopathy in Oman: Two decades of research. PMID- 25709266 TI - Gene therapy in keratoconus. AB - Keratoconus (KC) is the most common ectasia of the cornea and is a common reason for corneal transplant. Therapeutic strategies that can arrest the progression of this disease and modify the underlying pathogenesis are getting more and more popularity among scientists. Cumulating data represent strong evidence of a genetic role in the pathogenesis of KC. Different loci have been identified, and certain mutations have also been mapped for this disease. Moreover, Biophysical properties of the cornea create an appropriate candidate of this tissue for gene therapy. Immune privilege, transparency and ex vivo stability are among these properties. Recent advantage in vectors, besides the ability to modulate the corneal milieu for accepting the target gene for a longer period and fruitful translation, make a big hope for stupendous results reasonable. PMID- 25709267 TI - Trans-epithelial versus conventional corneal collagen crosslinking: A randomized trial in keratoconus. AB - PURPOSE: The purpose was to compare transepithelial versus epithelium off technique of corneal collagen crosslinking (CXL) in patients of keratoconus. MATERIALS AND METHOD: Totally, 40 eyes (40 patients) with progressive keratoconus were subjected to transepithelial CXL (20 eyes; Group I), and conventional CXL (20 eyes; Group II). Patients were evaluated for uncorrected distance visual acuity, best corrected visual acuity (BCVA), slit lamp-biomicroscopy, keratometry, 9-point pachymentry, orbscan II, and endothelial cell count at baseline and post CXL at 1, 3, and 6 months. RESULTS: The two groups were similar with respect to the evaluated parameters both at baseline and at the end of 6 months. There was an improvement in mean BCVA from Log Mar 0.327 +/- 0.1 (Group 1), 0.36 +/- 0.08 (Group 2) to 0.23 +/- 0.08 (Group 1; P < 0.001), 0.22 +/- 0.06 (Group 2; P < 0.001), respectively, at 6 months. Mean Sim K astigmatism decreased from 6.6 +/- 1.93 D (Group 1), 6.64 +/- 1.93 D (Group 2) to 5.14 +/- 1.86 D (Group 1; P = 0.001), and 4.77 +/- 0.06 (Group 2; P = 0.001), respectively, at 6 months. The mean pachymetry increased from 432.05 +/- 19.36 MUm (Group 1), 429.91 +/- 16.66 MUm (Group 2) to 447.8 +/- 16.09 MUm (Group 1; P < 0.001), 440.25 +/- 11.18 um (Group 2; P = 0.002), respectively, at 6 months. All cases showed stabilization of keratoconus two eyes in epithelium off group developed persistent stromal haze. Most of the patients in Group II experienced pain and photophobia during first 2 days, but not of Group I. CONCLUSION: Trans-epithelial technique offers visual and topographic outcomes similar to the conventional method with superior patient comfort postintervention. PMID- 25709268 TI - Normative data for near point of convergence, accommodation, and phoria. AB - BACKGROUND: Measurement of for near point of convergence (NPC), amplitude of accommodation (AA) and phoria are important components of diagnosing nonstrabismic binocular vision anomalies. There is a huge variation in the normative data established for orthoptic parameters because of the variation in measurement technique. There are only limited studies for normative data based on nonclinical population in Indian population. Therefore, we aim estimate the normative values for NPC, AA, and phoria measurement in Indian population using techniques, which has good repeatability and reliability. MATERIALS AND METHODS: Subjects between the age group 10-35 years participated in this prospective cross sectional study. A self-administered symptom questionnaire was used to exclude patients with asthenopic symptoms. Clinical techniques which have good repeatability and reliability were used. NPC was measured using pen light red, green glass test. AA was measured using minus lens technique. Horizontal and vertical phoria at distance and near was measured using modified Thorington method. RESULTS: One hundred and fifty subjects participated in the study. We found that NPC receded with age, which could because of the increase in horizontal phoria at near with age. The mean normative value for objective NPC, break and recovery of subjective NPC, monocular and binocular AA, horizontal and vertical phoria at distance and near for the three age groups are reported in the study. CONCLUSION: The data presented in this study can be used as a cut-off by eye care practitioners while diagnosing convergence, accommodation related anomalies in Indian population. PMID- 25709269 TI - Magnitude and determinants of glaucoma in type II diabetics: A hospital based cross-sectional study in Maharashtra, India. AB - BACKGROUND: Glaucoma and diabetes have a common pathogenesis. We estimated the magnitude and determinants of glaucoma in adults with type II diabetes who presented to a tertiary level eye center in 2010. STUDY TYPE: A cross-sectional survey. METHODS: Diabetes was diagnosed by history and measurement of blood sugar levels. Glaucoma was diagnosed by assessing optic disc morphology, visual fields, and intraocular pressure. Data were collected on patient demographics, clinical characteristics of diabetes and ocular status through interviews and measurements. The prevalence of glaucoma in diabetics was estimated, and variables were analyzed for an association to glaucoma. The 95% confidence intervals (CIs) were calculated. Statistical significance was indicated by P < 0.05. RESULTS: The study cohort was comprised of 841 diabetics. The mean age of the cohort was 53.8 +/- 10.7 years. There were 320 (38%) females. The prevalence of glaucoma was 15.6% (95% CI: 13.1-18.1). More than 75% of the diabetics had no evidence of diabetic retinopathy (DR). Half of the diabetics with glaucoma had primary open angle glaucoma. The presence of glaucoma was significantly associated to the duration of diabetes (Chi-square = 10.1, degree of freedom = 3, P = 0.001). The presence of DR was not significantly associated to the presence of glaucoma (odds ratio [OR] = 1.4 [95% CI: 0.88-1.2]). The duration of diabetes (adjusted OR = 1.03) was an independent predictor of glaucoma in at least one eye. CONCLUSIONS: More than one-sixth of diabetics in this study had glaucoma. Opportunistic screening for glaucoma during DR screening results in an acceptable yield of glaucoma cases. PMID- 25709270 TI - Photorefractive keratectomy results in myopic patients with thin cornea eyes. AB - BACKGROUND: To evaluate the results of visual acuity and quality, and corneal integrity in myopic patients with a thin cornea who received photorefractive keratectomy (PRK). MATERIALS AND METHODS: In this before-after interventional study, 30 myopic eyes with a myopia -3.76 +/- 1.72 (-6.50 to -1.25) D and a corneal thickness of 486.03 +/- 11.93 (452-499) MUm at the thinnest point received PRK. In myopia was more than 4D, mitomycin C was used with PRK. The surgery was performed with an excimer laser (VISX STAR, Abbott Medical Optics, Abbott Park, US). RESULTS: The safety and the efficacy index of the surgery was 1.01 +/- 0.05 and 1.00 +/- 0.05 in these patients, respectively. All the patients were within +/-0.5D of emmetropia 1 year after the surgery. Mesopic contrast sensitivity (CS) had a significant increase in two spatial frequencies of six (P = 0.003) and 12 (P = 0.003). Total coma (P < 0.001), spherical aberration (P < 0.001), and total higher-order aberrations (HOA) (P < 0.001) also showed a significant increase. Corneal hysteresis (P < 0.001) and corneal resistance factor (P < 0.001) showed a significant decrease after 1 year. CONCLUSION: PRK is a safe, effective, and predictable procedure with desirable effects on mesopic CS in patients with corneal thickness <500 MUm, which increases HOAs and decreases corneal integrity proportionate to its value before the procedure. PMID- 25709271 TI - Role of optometry school in single day large scale school vision testing. AB - BACKGROUND: School vision testing aims at identification and management of refractive errors. Large-scale school vision testing using conventional methods is time-consuming and demands a lot of chair time from the eye care professionals. A new strategy involving a school of optometry in single day large scale school vision testing is discussed. AIM: The aim was to describe a new approach of performing vision testing of school children on a large scale in a single day. MATERIALS AND METHODS: A single day vision testing strategy was implemented wherein 123 members (20 teams comprising optometry students and headed by optometrists) conducted vision testing for children in 51 schools. School vision testing included basic vision screening, refraction, frame measurements, frame choice and referrals for other ocular problems. RESULTS: A total of 12448 children were screened, among whom 420 (3.37%) were identified to have refractive errors. 28 (1.26%) children belonged to the primary, 163 to middle (9.80%), 129 (4.67%) to secondary and 100 (1.73%) to the higher secondary levels of education respectively. 265 (2.12%) children were referred for further evaluation. CONCLUSION: Single day large scale school vision testing can be adopted by schools of optometry to reach a higher number of children within a short span. PMID- 25709272 TI - Graft rejection in pediatric penetrating keratoplasty: Clinical features and outcomes. AB - PURPOSE: Early presentation of rejection facilitates early initiation of treatment which can favor a reversible rejection and better outcome. We analyzed the incidence, clinical features including rejection-treatment period and outcomes following graft rejection in our series of pediatric corneal graft. MATERIALS AND METHODS: Case records of pediatric penetrating keratoplasty (PK) were reviewed retrospectively, and parameters noted demographic profile, indication of surgery, surgery-rejection period, rejection-treatment interval, graft outcome, and complications. RESULTS: PK was performed in 66 eyes of 66 children <12 years, with an average follow-up of 21.12 +/- 11.36 months (range 4 48 month). The median age at the time of surgery was 4.0 years (range 2 months to 12 years). Most of the children belonged to rural background. Scarring after keratitis (22, 33.4%) was the most common indication. Graft rejection occurred in eight eyes (12.12%) (acquired nontraumatic - 3, congenital hereditary endothelial dystrophy [CHED] - 2, nonCHED - 1, congenital glaucoma - 1, regraft - 1). The mean surgery-rejection period was 10.5 +/- 7.3 months and mean rejection treatment interval was 10.9 +/- 7.02 days. CONCLUSION: This study showed irreversible graft rejection was the leading cause of graft failure of pediatric PK. Though, the incidence (12.1%) of graft rejection in current study was not high, but the percentage of reversal (25%) was one of the lowest in literature because of delayed presentation and longer interval between corneal graft rejection and treatment. In addition, categorization of the type of graft rejection was very difficult and cumbersome in pediatric patients. PMID- 25709273 TI - The use of toric intraocular lens to correct astigmatism at the time of cataract surgery. AB - BACKGROUND: To evaluate the visual and refractive outcomes of cataract surgery with toric intraocular lens (IOL) implantation at a teaching hospital of the United Kingdom. DESIGN: Prospective interventional case series. MATERIALS AND METHODS: This study compared the outcome of 3 groups of patients: Group 1 included 25 eyes with cataract and more than 2.5 diopters (D) of corneal astigmatism receiving a toric monofocal IOL; Group 2 had 18 patients with cataract and more than 2.5 D of astigmatism but receiving a non-toric monofocal IOL; while Group 3 had 25 patients with cataract and less than 1.5 D of astigmatism and receiving a non-toric monofocal IOL. Data collected included uncorrected (UDVA) and corrected (CDVA) distance visual acuities, refraction and corneal keratometry. Postoperative examinations were scheduled at 1 and 6 weeks. RESULTS: Postoperatively the mean UDVA was LogMAR 0.27 +/- 0.20 (equivalent snellen acuity of 20/37) in Group 1, 0.54 +/- 0.22 (20/69) in Group 2 and 0.16 +/ 0.20 (20/29) in Group 3. The mean CDVA was LogMAR 0.08 +/- 0.13 (20/24) in Group 1, 0.23 +/- 0.16 (20/34) in Group 2 and 0.04 +/- 0.13 in Group 3 (20/22). The mean preoperative keratometric cylinder was 3.78 +/- 1.0 D in Group 1, 3.41 +/- 1.47 D in Group 2 and 0.97 +/- 0.43D in Group 3; the mean postoperative subjective cylinder was 1.2 +/- 0.68 D in Group 1, 3.23 +/- 1.41 D in Group 2 and 0.95 +/- 0.58 D in Group 3. The difference was statistically significant for the postoperative refractive cylinder values when comparing Group 1 to Group 2 (P = <0.0001) but the difference was insignificant between Group 1 and Group 3 (P = 0.23). CONCLUSION: Toric IOL implantation is an effective option to manage corneal astigmatism at the time of cataract surgery and to optimise visual outcomes for astigmatic patients when comparing to outcomes for their non astigmatic counterparts. PMID- 25709274 TI - Full-thickness macular hole in Bartonella henselae neuroretinitis in an 11-year old girl. AB - Cat scratch disease is a febrile illness caused by Bartonella henselae and is associated with rash at the site of cat bite or scratch and regional lymphadenopathy. Various ocular manifestations of cat scratch disease have been described, mainly retinochoroiditis, optic disc swelling, neuroretinitis, vascular occlusive events, serous retinal detachment, vitreous hemorrhage, intermediate uveitis, inflammatory lesions of the optic nerve head and rarely full thickness macular hole. We describe a case of an 11-year-old girl who presented 2 weeks after the onset of symptoms, with B. Henselae neuroretinitis with full thickness macular hole at presentation. PMID- 25709275 TI - A rare presentation of pigmented paravenous retinochoroidal atrophy. AB - A 21-year-old female patient presented with gradual progressive loss of vision in both eyes of 12 years duration. Funduscopic examination revealed bone-spicule pigmentation and choroidal and retinal pigment epithelium atrophy along the vascular arcades, with macular involvement in both eyes. The patient was diagnosed with pigmented paravenous retinochoroidal atrophy which is rare disease, uncommon in females, more commonly affecting the paravascular fundus. Very few cases of macular involvement have been reported. PMID- 25709276 TI - A rare case of anterior chamber dirofilariasis. AB - We report a rare case of anterior chamber live dirofilariasis presenting as anterior uveitis. A 60-year-old man presented with dimness of vision in the right eye for 1 month. Vision recorded was 6/18 P, N 18 in the right eye. Slit lamp examination of the right eye revealed anterior uveitis with a moving nemathelminthes. The worm was removed live from the anterior chamber under local anesthesia with assisted methyl cellulose delivery and post-operatively, the worm was examined directly under light microscope. Morphometric measurement showed length of the worm was 6.061 mm. A thin, pale, slender worm was diagnosed as immature female Dirofilaria repens and was documented completely. Patient had made an excellent recovery of vision and intraocular inflammation after the surgical removal of the worm. Intraocular infection of dirofilaria is a rare presentation and successful surgical removal of the worm resulted in complete recovery of uveitis and visual status in the affected eye. PMID- 25709277 TI - Nodular scleritis as the eye manifestation in Behcet's syndrome. AB - We report a case of a 45-year-old female, who was diagnosed as Behcet's disease and presented to us with nodular scleritis in her right eye. PMID- 25709278 TI - Subepidermal calcified nodule in upper eyelid: A case report and review of the literature. AB - Calcinosis cutis involves the inappropriate deposition of calcium within the dermis layer of the skin and is often associated with autoimmune diseases. A 3 year-old healthy Omani child presented for evaluation of asymptomatic hard nodule on the left upper eyelid. Pathological examination identified the mass as subepidermal calcified nodule. The patient had no history of trauma or metabolic disturbances. Serum levels of calcium and phosphate were normal. Idiopathic calcinosis cutis should be included in the differential diagnosis for eye lid mass. PMID- 25709279 TI - Choriovitreal ingrowth of a large choroidal vessel after scatter retinal photocoagulation. AB - Choriovitreal ingrowth of a large choroidal vessel is a known complication of intense focal retinal laser photocoagulation. With a standard grey-white burn in panretinal photocoagulation where the power density used is low, such an invasion is rarely reported. We came across the complication in a clinical scenario where a patient with proliferative diabetic retinopathy and associated ocular ischemic syndrome developed the neovascular ingrowth after scatter retinal photocoagulation. PMID- 25709280 TI - Tremendous result of bevacizumab in malignant hypertensive retinopathy. AB - Signs of hypertensive retinopathy are common and are correlated with elevated blood pressure. Patients who have swelling of both optic discs and very high blood pressure (i.e., malignant retinopathy) need urgent antihypertensive treatment. A patient was reported with malignant hypertensive retinopathy who recovered promptly following single intravitreal bevacizumab injection. Intravitreal bevacizumab (1.25 mg/0.05 mL) was injected in two eyes of a patient having malignant hypertensive retinopathy with optic disc edema, macular edema, and retinal exudates. A complete ophthalmic examination, including the best corrected visual acuity (BCVA), central macular thickness on optical coherence tomography (OCT), and fluorescein angiography (FAG), was performed before and after the treatments. Two eyes in a patient received a single intravitreal injection of bevacizumab had improvement of macular edema on OCT at 1 month and decreased fluorescein leakage on FAG 3 months after the treatment, which led to improvements in the BCVA both eyes. The results suggest that intravitreal bevacizumab injections might be a useful and safe adjunctive treatment of malignant hypertensive retinopathy, in addition to proper medical management of malignant hypertension. PMID- 25709281 TI - Periorbital varicella gangrenosa: A rare complication of chicken pox. AB - A previously healthy six year old male child presented in pediatrics ICU in state of shock with history of fever and rashes and later was diagnosed as chicken pox. He developed right sided periorbital varicella gangrenosa which is a form of necrotizing fasciitis secondary to skin infection. Patient was treated with intravenous acyclovir, antibiotics, amphotericin B, extensive debridement and later reconstruction of upper eyelid with skin grafting. Aggressive treatment helped preventing the eyeball and orbital involvement which would have necessitated orbital exenteration. However delayed presentation resulted in necrosis of orbicularis oculi and underlying tissue which resulted in graft retraction and lid dysfunction. Clinicians should be aware of this rare but fulminating condition to minimise the sight and life threatening complications associated with it. PMID- 25709282 TI - Retained intracorneal human hair fragment: An unusual case of occupational trauma. AB - A 32-year old male hairdresser presented with redness and irritation of the left eye for past 15 days. A fragment of hair was found embedded in deep corneal stroma with minimal scarring. No evidence was found of previous or current inflammation incited by this foreign body. The position and depth of the hair fragment was documented by anterior segment optical coherence tomography (AS-OCT) and its effect on the corneal endothelium was assessed by specular microscopy. Hairdressers should take adequate precautions to prevent ocular injury although human hair appears to be well tolerated by the cornea. PMID- 25709283 TI - Acute onset bilateral myopia in convalescence phase of varicella infection. AB - A 13 year old boy presented with sudden onset of painless blurring of vision in his both eye, twenty days following varicella infection. Ocular examination revealed -3.00 DS refractive error; and cilio-choroidal effusion. After treatment at 1 months he had unaided 6/6; N-6 vision in both eyes. PMID- 25709284 TI - Serial ultra wide field imaging for following up acute retinal necrosis cases. AB - We describe two cases of acute retinal necrosis (ARN) in a post renal transplant diabetic patient and a pregnant female in the first trimester. Serial ultra wide field imaging (UWFI) with comprehensive ocular examination was done to monitor the progression of the disease. All the cases responded favorably with intravenous followed by oral acyclovir, which was captured with UWFI. UWFI provides objective proof of response to therapy in ARN. UWFI may also improve patient education and counseling for this peripheral retinal disorder. PMID- 25709285 TI - A case of absent foveal reflex. PMID- 25709286 TI - Waardenburg Shah syndrome: A rare case from India. PMID- 25709287 TI - Role of total dose and hyperfractionation in reducing risk of radiation-induced optic neuropathy. PMID- 25709288 TI - An unusual case of unilateral scleral icterus. PMID- 25709289 TI - Bilateral Sturge-Weber syndrome presenting with early onset convulsion and high myopia. PMID- 25709290 TI - Vitreous hemorrhage following inadvertent intra-ocular injection of botulinum toxin. PMID- 25709291 TI - Stress Reduction through Audio Distraction in Anxious Pediatric Dental Patients: An Adjunctive Clinical Study. AB - AIM: The purpose of the present study was to evaluate the eff-cacy of 'audio distraction' in anxious pediatric dental patients. MATERIALS AND METHODS: Sixty children were randomly selected and equally divided into two groups of thirty each. The first group was control group (group A) and the second group was music group (group B). The dental procedure employed was extraction for both the groups. The children included in music group were allowed to hear audio presentation throughout the treatment procedure. Anxiety was measured by using Venham's picture test, pulse rate, blood pressure and oxygen saturation. RESULTS: 'Audio distraction' was found efficacious in alleviating anxiety of pediatric dental patients. CONCLUSION: 'Audio distraction' did decrease the anxiety in pediatric patients to a significant extent. How to cite this article: Singh D, Samadi F, Jaiswal JN, Tripathi AM. Stress Reduction through Audio Distraction in Anxious Pediatric Dental Patients: An Adjunctive Clinical Study. Int J Clin Pediatr Dent 2014;7(3):149-152. PMID- 25709292 TI - Acceptability and Efficacy of Commercial Oral Preparation of Midazolam for brief Painful Procedure: A Randomized Double Blind Clinical Trial. AB - AIM: To compare the acceptability and efficacy of orally administered commercially available midazolam syrup and injection midazolam mixed in honey for performing venepuncture. MATERIALS AND METHODS: This double blind randomized controlled trial enrolled 40 anxious and healthy 2 to 6 years olds. All subjects received either syrup midazolam or injection midazolam mixed in honey (0.5 mg/kg) per orally, prior to venepuncture as per their group assignment. Primary outcome measures in this trial was acceptability of midazolam. Secondary outcome measures included sedation depth, success of venepuncture, observer and parental satisfaction and parental perception of child's pain. RESULTS: Although the acceptability of syrup midazolam (95%) was higher than injection midazolam (80%), there was no significant difference among two groups with respect to any primary or secondary outcome (p > 0.05). CONCLUSION: Syrup midazolam can serve as a suitable alternative to injection midazolam; thus, eliminating the procedural steps of mixing injection midazolam with any vehicle. How to cite this article: Srivastava B, Mittal N, Mittal P. Acceptability and Efficacy of Commercial Oral Preparation of Midazolam for brief Painful Procedure: A Randomized Double Blind Clinical Trial. Int J Clin Pediatr Dent 2014;7(3):153-156. PMID- 25709293 TI - A Comparison of Canal-centering ability of Two Nickel-Titanium Rotary Systems with Nickel Hand Instrumentation with Stainless Steel Hand Instrumentation in 10 to 25 degrees Curved Canals using Kuttler's Cube. AB - AIMS: The purpose of this study was to compare the canal centering abilities of rotary nickel-titanium (NiTi) files (ProFile 0.04 and 0.06 and Lightspeed LSX) and NiTi hand K-files in 10 degrees to 25 degrees curved canals. This was compared with the canal centering ability of stainless steel hand K-files using Kuttler's endodontic cube. SETTINGS AND DESIGN: The teeth with a 10 degrees to 25 degrees of clinical mesiodistal curvature were used for this study. Each tooth was immersed in methylene blue dye for a period of 10 seconds, as recommended by Kuttler. MATERIALS AND METHODS: The study sample comprised of 60 intact freshly extracted single rooted human mandibular premolars. The radiographs were traced on a tracing paper and the canal curvature was determined according to methodology introduced by Schneider. STATISTICAL ANALYSIS USED: The statistical package SPSS PC + (Statistical package for social service, Version 4.01) was used for analysis. RESULTS: Overall, Lightspeed LSX instruments showed superior canal centering ability and performed better than Profile series, hand NiTi K-files and hand stainless steel K-files. CONCLUSION: The endodontic cube can be used as an effective method for analyzing the canal-centering ability of different endodontic instruments. Both the NiTi rotary instruments showed superior canal-centering ability than NiTi and stainless steel hand K-files. How to cite this article: Swarnkar A. A Comparison of Canal-centering ability of Two Nickel-Titanium Rotary Systems with Nickel Hand Instrumentation with Stainless Steel Hand Instrumentation in 10 to 25 degrees Curved Canals using Kuttler's Cube. Int J Clin Pediatr Dent 2014;7(3):157-162. PMID- 25709294 TI - Comparison of Proximal Caries Detection in Primary Teeth between Laser Fluorescence and Bitewing Radiography: An in vivo Study. AB - BACKGROUND AND OBJECTIVE: Proximal caries detection is of great importance because of the rapid rate of caries progression and the difficulty in determining the absence or presence of a lesion in primary dentition. Although, various methods for caries diagnosis offer good diagnostic performances, they provide varying sensitivities for detecting proximal carious lesions. The objective of this study was to compare, in vivo, the accuracy of DIAGNOdent and bitewing radiography at detecting proximal caries in primary teeth. MATERIALS AND METHODS: One Hundred and one primary maxillary and mandibular molars without obvious cavities of children between the age group of 3 and 10 years were included. The teeth were first subjected to DIAGNOdent examination followed by bitewing radiography. The specificity and sensitivity of the systems were calculated. RESULTS: At the dentin caries (D3) level, the sensitivity of DIAGNOdent and bitewing radiography was 78.5%; at the enamel caries (D1 and D2) level it was 39.12% and for the sound teeth (D0) it was found to be 76.52%. A strong association was observed between the DIAGNOdent and the bitewing radiograph (p < 0.001). CONCLUSION: The DIAGNOdent can be used as an alternative diagnostic method in detection of proximal caries in primary teeth. But when seen at the each caries level, the DIAGNOdent is more accurate at the D0 and D3 threshold. How to cite this article: Mepparambath R, Bhat SS, Hegde SK, Anjana G, Sunil M, Mathew S. Comparison of Proximal Caries Detection in Primary Teeth between Laser Fluorescence and Bitewing Radiography: An in vivo Study. Int J Clin Pediatr Dent 2014;7(3):163-167. PMID- 25709295 TI - Comparative evaluation of prevalence of upper cervical vertebrae anomalies in cleft lip/palate patients: a retrospective study. AB - PURPOSE: The patients with cleft lip and palate have a higher risk of cervical vertebrae anomalies than do patients in general population. The aim of present study was to determine the prevalence of various upper cervical spine anomalies in different type of clefts. PROCEDURES: Lateral cephalograms of 128 patients (66 males, 62 females) with cleft lip and palate, and 125 (60 males, 65 females) non syndromic patients without cleft lip and palate were selected at random from archive. Cephalograms of the patients were traced and the diagnosis of any cervical vertebrae anomaly was noted. Anomalies were categorized as either: posterior arch deficiency or fusions. MAIN FINDINGS: Prevalence of cervical vertebrae anomalies in the c lef t group was 20. 3% while it was 6.4% in the control group. Further cervical vertebrae anomalies were 16.6% in the CPO group, 19.1% in the BCLP group, and 22.2% in the UCLP group. CONCLUSION: A higher prevalence of cervical vertebrae anomalies was observed in cleft lip and palate patients. The prevalenc e obser ved is 3 times more in clef t group than c ontrol group. How to cite this article: Datana S, Bhalla A, Kumar P, Roy SK, Londhe S. Comparative Evaluation of Prevalence of Upper Cervical Vertebrae Anomalies in Cleft Lip/Palate Patients: A Retrospective Study. Int J Clin Pediatr Dent 2014;7(3):168-171. PMID- 25709296 TI - Comparative Evaluation of Microleakage in Conventional and RMGIC Restorations following Conventional and Chemomechanical Caries Removal: An in vitro Study. AB - BACKGROUND: Conventional caries removal involves use of high-speed handpiece. Current concepts of caries excavation in cavitated lesions consist of manual excavators. Principles of minimal invasive approach indicate the need to excavate only carious tissue. AIM: The aim of this study was to compare the microleakage in conventional and resin modified glass ionomer cement restorations following conventional and chemomechanical caries removal. DESIGN: Hundred class I carious human mandibular first molar s were collected and divided into two groups: I and II (50 each). Each group was further divided into subgroups, i.e. (IA, IB and IIA, IIB). Caries was completely removed using conventional method in group one and chemomechanically in group two. The teeth in group IA, IIA are restored with conventional glass ionomer comment (GIC) and in group IB, IIB restored with resign-modified glass ionomer comments (RMGIC), followed by fnishing and polishing. Subsequently, the specimens were thermocycled and then placed in dye solution. The teeth were sectioned through the restorations and evaluated for microleakage scores using a stereomicroscope. The data were analyzed using Mann Whitney U-test. RESULTS: Statistical analysis showed no significant difference in microleakage between the conventional GIC and RMGIC following conventional and chemomechanical caries removal method. CONCLUSION: Carisolv is minimally invasive and an effective alternative treatment for the removal of occlusal caries. How to cite this article: Pavuluri C, Nuvvula S, Kamatham RL, Nirmala SVSG. Comparative Evaluation of Microleakage in Conventional and RMGIC Restorations following Conventional and Chemomechanical Caries Removal: An in vitro Study. Int J Clin Pediatr Dent 2014;7(3):172-175. PMID- 25709297 TI - Effect of Exposure to Positive Images of Dentistry on Dental Anxiety among 7 to 12 Years Old Children. AB - AIM: To evaluate the effect of exposure to positive images of dentistry on dental anxiety among 7 to 12 years old children. MATERIALS AND METHODS: Controlled trial. Assessment of anxiety and analysis of data were conducted blind to experimental condition. Assessment of anxiety was carried out in the waiting room prior intervention, postintervention into the operatory during the treatment and again after the completion of treatment. Anticipatory anxiety was recorded by Venham's picture test (VPT). PARTICIPANTS: Sixty children of 7 to 12 years age group. INTERVENTION: PARTICIPANTS were randomly assigned to one of two conditions. In both conditions the participant was asked to look at photographs for 2 minutes in the waiting area prior to their appointment. The intervention consisted of viewing positive images of dentistry and dental treatment (study group), the (control group) consisted of neutral images. The assessment of anticipatory dental anxiety was made blind to experimental condition and statistical analysis was conducted blind to group membership. Anticipatory anxiety assessed by the VP T. RESULTS: A total of 60 subjects participated in the study and were equally and randomly allotted to study group (positive image) and control group (neutral image). The mean anxiety score found at waiting area before intervention, after intervention (OPD) and postoperative was statistically significant in study group. Post hoc comparison of anxiety score in study group showed high statistical significance. CONCLUSION: Positive dental images have an effect on reducing anxiety as compared to neutral images when measured by the VPT. How to cite this article: Gangwal RR, Badjatia SR, Dave BH. Effect of Exposure to Positive Images of Dentistry on Dental Anxiety among 7 to 12 Years Old Children. Int J Clin Pediatr Dent 2014;7(3):176 -179. PMID- 25709298 TI - Mercury exposure levels in children with dental amalgam fillings. AB - OBJECTIVES: Mercury combined with other metals to form solid amalgams has long been used in reconstructive dentistry but its use has been controversial since at least the middle of the 19th century. The exposure and body burden of mercury reviews have consistently stated that there is a deficiency of adequate epidemiological studies addressing this issue. Fish and dental amalgam are two major sources of human exposure to organic (MeHg) and inorganic Hg respectively. MATERIALS AND METHODS: A total of 150 subjects aged between 9 and 14 years were divided into two groups of 75 subjects each depending on their diet, i.e. seafood or nonseafood consuming. Each category was subdivided into three groups based on number of restorations. Scalp hair and urine samples were collected at baseline and 3 months later to assess the organic and inorganic levels of mercury respectively by atomic absorption spectrophotometer (AAS). RESULTS: The mean values of urinary mercury (inorganic mercury) in the group of children with restorations were 1.5915 MUg/l as compared to 0.0130 MUg/l in the groups with no amalgam restorations (p < 0.001) (Wilcoxon sign rank test and paired t-test). The hair mercury levels (organic mercury) varied signi-ficantly between the fsh eating group and nonfsh-eating group, the average values being 1.03 MUg/l and 0.84 MUg/l respectively (p < 0.001) (Mann-Whitney U-test and paired t-test). CONCLUSION AND SIGNIFICANCE: The notion about the mercury being released from the amalgam restorations as a sole exposure source needs to be put to a rest, as environmental factors collectively overpower the exposure levels from restorations alone. How to cite this article: Varkey IM, Shetty R, Hegde A. Mercury Exposure Levels in Children with Dental Amalgam Fillings. Int J Clin Pediatr Dent 2014;7(3):180-185. PMID- 25709299 TI - Evaluating the reliability of three different dental age estimation methods in visakhapatnam children. AB - Dental age is important for treatment planning in the specialities of pedodontics and orthodontics. Although, Demirjian's method was considered standard for dental age estimation, it may not be reliable for all population. AIM: The goal of the study was to evaluate the reliability of Demir-jian's, Haavikko's and Willems method of dental age estimation methods in Visakhapatnam (Andhra Pradesh, India) children. STUDY DESIGN: One hundred and two children of 6 to 14 years old who underwent panaromic digital radiography for routine diagnostic purposes were included. Dental age was calculated using Demirjian's, Haavikko's and Willems methods and compared with chronologic age for each patient. RESULTS: Dental age showed a significant overestimation by Demirjian's method with a mean difference of 0.55 year and underestimation by Haavikko's and Willems methods with a mean difference of 1.95 and 0.20 year respectively when compared with chronologic age. The mean difference between dental age and chronologic age was not significant in Willems method which shows a close relation between dental and chronologic ages. CONCLUSION: The dental age estimation by Willems method is found to be more accurate than Demirjian's and Haavikko's methods in Visakhapatnam children. How to cite this article: Patnana AK, Vabbalareddy RS, Vanga NRV. Evaluating the Reliability of Three Different Dental Age Estimation Methods in Visakhapatnam Children. Int J Clin Pediatr Dent 2014;7(3):186-191. PMID- 25709300 TI - A Comparative Evaluation of Effect of Different Chemical Solvents on the Shear Bond Strength of Glass Fiber reinforced Post to Core Material. AB - AIM: To compare the effect of different chemical solvents on glass fiber reinforced posts and to study the effect of these solvents on the shear bond strength of glass fiber reinforced post to core material. MATERIALS AND METHODS: This study was conducted to evaluate the effect of three chemical solvents, i.e. silane coupling agent, 6% H2O2 and 37% phosphoric acid on the shear bond strength of glass fiber post to a composite resin restorative material. The changes in post surface characteristics after different treatments were also observed, using scanning electron microscopy (SEM) and shear bond strength was analyzed using universal testing machine (UTM). RESULTS: Surface treatment with hydrogen peroxide had greatest impact on the post surface followed by 37% phosphoric acid and silane. On evaluation of the shear bond strength, 6% H2O2 exhibited the maximum shear bond strength followed in descending order by 37% phosphoric acid and silane respectively. CONCLUSION: The surface treatment of glass fiber post enhances the adhesion between the post and composite resin which is used as core material. Failure of a fiber post and composite resin core often occurs at the junction between the two materials. This failure process requires better characterization. How to cite this article: Sharma A, Samadi F, Jaiswal JN, Saha S. A Comparative Evaluation of Effect of Different Chemical Solvents on the Shear Bond Strength of Glass Fiber Reinforced Post to Core Material. Int J Clin Pediatr Dent 2014;7(3):192-196. PMID- 25709301 TI - Biological restoration in pediatric dentistry: a brief insight. AB - Dental caries is the most prevalent disease in humans, especially during early childhood. The restoration of such an extensive carious lesion should be done properly to reestablish their anatomy and hence their masticatory, phonetic, esthetic and space-maintainer functions in the dental arches. The consequences of premature loss of primary teeth are well known, namely the loss of vertical dimension of occlusion, tongue thrusting and mouth breathing habits, which can be the sources of future malocclusion. Satisfactory restoration of these teeth, improving esthetics, along with the management of space and function has always been a challenge for pediatric dentist. An ever increasing demand for esthetics has led to innovation and development of newer treatment modalities for these problems. In an attempt to widen the treatment options as biologically and conservatively as possible, tooth structure is used as a restorative material to rehabilitate severely destroyed tooth crowns. This technique consists of bonding sterile dental fragments, obtained either from the patient or from a tooth bank, to the teeth. Such a technique was termed as 'biological restoration'. This article aims at reviewing the evolution, techniques and outcome of such biological restorations. How to cite this article: MD Indira, Dhull KS, Nandlal B, Kumar PSP, Dhull RS. Biological Restoration in Pediatric Dentistry: A Brief Insight. Int J Clin Pediatr Dent 2014;7(3):197-201. PMID- 25709302 TI - Accessory Central Cusp in the Maxillary Second Primary Molars: A Rare Entity among the Rare. AB - Central accessory cusp in primary molars is an extremely rare condition which is due to abnormal proliferation and folding of inner enamel epithelium during morphodifferentiation stage of tooth development. The extension of the pulp in the cuspal area is often the reason for early involvement of pulp by the caries process. Therefore, early diagnosis and treatment planning is necessary to maintain the integrity of primary dental arch. This article reports such a case of central accessory cusps involving maxillary second primary molars. How to cite this article: Chandra B, Das M. Accessory Central Cusp in the Maxillary Second Primary Molars: A Rare Entity among the Rare. Int J Clin Pediatr Dent 2014;7(3):202-205. PMID- 25709303 TI - Adenoid cystic carcinoma of child: a rare case. AB - Adenoid cystic carcinoma (ACC) is the second most common malignant tumor affecting both major and minor salivary glands. Clinically, it is a slowly growing tumor with high propensity for local invasion, recurrence and distant metastasis. It is predominantly seen in the ffith and sixth decades of life. Here, we report a rare case of ACC affecting the right maxilla of a 12-year-old girl. How to cite this article: Mathai M, Sherubin JE, Agnihotri PG, Sangeetha GS. Adenoid Cystic Carcinoma of Child: A Rare Case. Int J Clin Pediatr Dent 2014;7(3):206-208. PMID- 25709304 TI - Prosthetic Rehabilitation of Ocular Defect resulting from Pediatric Retinoblastoma. AB - Ocular defects result from tumor, congenital anomaly and external injury not only lead to serious impairment of function and esthetics but also make the patient psychologically disabled. Prosthetic rehabilitation attempts to restore these disfgurements may improve esthetic, level of function, general psychologic improvement and quality of life. This clinical report details an attempt to rehabilitate a pediatric patient who has undergone orbital enucleation resulting from retinoblastoma with the aid of custom ocular prosthesis using commercially available prefabricated eye shell. How to cite this article: Janya S, Gubrellay P, Purwar A, Khanna S. Prosthetic Rehabilitation of Ocular Defect resulting from Pediatric Retinoblastoma. Int J Clin Pediatr Dent 2014; 7(3):209-212. PMID- 25709305 TI - Management of a nonvital young permanent tooth by pulp revascularization. AB - This report presents the case of a 10-year-old patient with a nonvital young permanent tooth which was managed by pulp revascularization. Following disinfection of the canal by irrigation with NaOCl and use of a triantibiotic paste, a scaffold was created by inducing the formation of a blood clot within the canal. At the subsequent follow-up visits, the patient was asymptomatic, with normal response to percussion, normal periodontal probing depths, and no abnormal mobility. The radiographs showed evidence of continued apical root development with increase in root length, signs of apical closure and increase in thickness of dentinal walls. Thus, this case adds to the growing evidence supporting the revascularization approach as an option for management of nonvital young permanent teeth. How to cite this article: Chandran V, Chacko V, Sivadas G. Management of a Nonvital Young Permanent Tooth by Pulp Revascularization. Int J Clin Pediatr Dent 2014;7(3):213-216. PMID- 25709306 TI - Severe periodontal disease manifested in chronic disseminated type of langerhans cell histiocytosis in a 3-year old child. AB - Langerhans cell histiocytosis (LCH), previously known as histio-cytosis X, is a rare idiopathic disorder of reticulo-endothelial system with abnormal proliferation of bone marrow derived Langerhans cells along with a variable number of leukocytes, such as eosinophils, neutrophils, lymphocytes and plasma cells. Three years old male child presented with multifocal osteolytic lesions and papulosquamous skin lesions. Clinical and radio-graphic features, such as severe alveolar bone loss, mobility of teeth, precocious eruption of teeth, foating appearance of teeth in orthopantomogram (OPG), osteolytic lesion in skull and cutaneous lesions were highly suggestive of LCH disease. Skin biopsy confirmed a diagnosis of LCH. Induction chemotherapy with oral prednisolone and intravenous vinblastine was started. Child responded well to chemotherapy. The clinical significance of the presented case is to diagnose the case of LCH on the basis of the manifestation of severe periodontal disease as this can be first or only manifestation of LCH. A dentist plays a major role in the multidisciplinary treatment of LCH through routine examination and periodic follow-up. How to cite this article: Bansal M, Srivastava VK, Bansal R, Gupta V, Bansal M, Patne S. Severe Periodontal Disease Manifested in Chronic Disseminated Type of Langerhans Cell Histiocytosis in a 3-Year Old Child. Int J Clin Pediatr Dent 2014;7(3):217 219. PMID- 25709307 TI - Can Milk Teeth be Impacted? Why Not: A Case of Six Impacted Primary Teeth. AB - The prevalence rate of impacted primary teeth is rare, still we can see impacted teeth in ectodermal dysplasia anhydrotic (EDA), endocrine deficiencies, metabolic disorders and local factors like cysts, tumors, trauma and thickened overlying bone or soft tissue. In cases of EDA, delayed tooth eruption is one of the characteristic finding. Present case report related to a rare case of primary teeth impaction of a 3 years old male child along with EDA. Intraoral examination and radiographs confirmed impacted primary maxillary and mandibular centrals and mandibular lateral incisors. Treatment carried out was surgical exposure of impacted primary teeth, then after patient was followed up for regular visits to check eruption status of the teeth. How to cite this article: Yadiki JV, Kategari YB, Chada P, Vallakatla V. Can Milk Teeth be Impacted? Why Not: A Case of Six Impacted Primary Teeth. Int J Clin Pediatr Dent 2014; 7(3):220-222. PMID- 25709308 TI - Visible epiglottis in children. AB - Visible epiglottis is a rare anatomical variant which is usually asymptomatic without the need of any medical or surgical intervention. It is most commonly seen in children but there are some reports of its prevalence in adults too. Cases of visible epiglottis seem to be unfamiliar among dental professionals. In this report, we have attempted to present this anatomical variant of epiglottis in the feld of dentistry by describing a case of an 8-year-old girl who presented to the department of pediatric dentistry for normal dental check-up unaware of the existence of the visible epiglottis. How to cite this article: Ahmed FJ, Shinohara AL, da Silva SMB, Andreo JC, de Castro Rodrigues A. Visible Epiglottis in Children. Int J Clin Pediatr Dent 2014;7(3):223-224. PMID- 25709309 TI - Simple fixed functional space maintainer. AB - Premature loss of a primary tooth is one of the most common etiology for malocclusion. Space maintainers are employed to prevent this complication. In anterior region, esthetics is an important concern along with function and space management. Fiber-reinforced composite (FRC) retained space maintainer solves all these purposes ef ficiently and ef fectively. In addition, the technique is simple and the appliance is very comfortable inside the oral cavity. Here is a case of premature loss of anterior primary tooth which was replaced by FRC retained esthetic functional space maintainer. The appliance was found to be functioning satisfactorily inside the oral cavity till the last visit (1 Year). How to cite this article: Goenka P, Sarawgi A, Marwah N, Gumber P, Dutta S. Simple Fixed Functional Space Maintainer. Int J Clin Pediatr Dent 2014;7(3):225 228. PMID- 25709310 TI - Cysts in periradicular region of deciduous molars in mixed dentition: retrospective study of five cases. AB - The cyst in mixed dentition stage cause expansion of buccal cortex, displacement of teeth and may present as case of infection. The cyst in periradicular region of deciduous molar are of frequent occurrence. The differential diagnosis of this lesion is radicular cysts of deciduous molar: developmental or infammatory dentigerous cyst of corresponding unerupted premolar. After going through the available literature of radicular cyst of deciduous molars and dentigerous cysts of developing premolars in mixed dentition we studied the five cases of cyst in periradicular region of deciduous molars in mixed dentition retrospectively for the diagnostic dilemma of radicular cyst verses dentigerous cyst. In conclusion, we can set some criteria for the diagnosis which is particularly important for treatment and for conservation of developing premolar. How to cite this article: Manekar VS, Chavan A, Wadde K, Dewalwar V. Cysts in Periradicular Region of Deciduous Molars in Mixed Dentition: Retrospective Study of Five Cases. Int J Clin Pediatr Dent 2014;7(3):229-235. PMID- 25709311 TI - Guest editorial. AB - At the start of this New Year, I would like to draw attention of pediatric dental fraternity at large toward Raven Maria Blanco Foundation, United States. This is a foundation established by parents of a young girl called Maria, who lost her life in pediatric dental Office, which was not prepared to handle an emergency arising from a procedural sedation for dental treatment. This is very heartening for any parent. It was so heart rending that Grammy award singer Michael Crawford popularly known as 'Magnedo7' penned a song called Raven's Song in her memory. This brings the focus on two important issues: sedation and emergency preparedness in our practices.(1.) PMID- 25709312 TI - Intercanine width as a tool in two dimensional reconstruction of face: An aid in forensic dentistry. AB - CONTEXT: Dental evidence is a valuable tool in identifying individuals, especially when disasters befall. Reference points in faciomaxillary region such as interpupillary distance, intercanthal distance, interalar distance and bizygomatic width can significantly contribute toward reconstruction of two dimensional (2D) facial profiles. This study was researched upon to determine the relationship between the maxillary intercanine width and the different reference points of the face. AIM: The aim of the following study is to ascertain whether maxillary intercanine width can be used to detect interpupillary distance, intercanthal distance, interalar distance and bizygomatic distance and to evaluate the role of maxillary intercanine width in the 2D reconstruction of the face. MATERIALS AND METHODS: The study was carried out by consent and involved 90 subjects-45 males and 45 females who satisfied the inclusion criteria. Subjects were divided into three age groups, i.e. 18-24, 25-28, 29-35. Four parameters were measured- intercanine width, interpupillary distance, intercanthal distance and interalar distance. All the measurements were carried out with a digital Vernier caliper. The bizygomatic width was measured from posterior-anterior view. Two empiricists were assigned for the task. Each test was carried out twice to validate the soundness of the findings and to reduce bias. STATISTICAL ANALYSIS: Analysis of variance and Pearson correlation was established. Regression analysis was performed to predict the study variables by intercanine width. RESULTS: Intercanine width showed a significant relationship with different points. The width varied with age and gender. CONCLUSION: Inter canine width can be used as a valuable parameter in the reconstruction of face in two dimensional as it shows significant relationship with faciomaxillary reference point such as interpupillary distance, intercanthal distance, interalar distance and bizygomatic width. PMID- 25709313 TI - Transverse changes in lateral and medial aspects of palatal rugae after mid palatal expansion: A pilot study. AB - INTRODUCTION: Palatal rugae has established role in forensic identification of an individual due to its stability in growth as well as orthodontic treatment. However effect of orthodontic mid-palatal expansion on rugae stability still requires further investigation. Hence, this study was aimed at evaluating the stability of palatal rugae in transverse dimension in adolescent patients of mid palatal expansion. MATERIALS AND METHODS: The study sample consists of 14 subjects (10F,4M, age 12.4 +/- 2.0 years) with transverse maxillary constriction, treated with bonded and banded rapid maxillary expansion (RME) appliance. 1(st) to 3(rd) rugae on pre- and post-expansion casts were recorded synchronously. Inter-medial and inter-lateral rugae distance were measured with digital calipers to record the transverse positional rugae changes. RESULTS: There was a statistically significant (p < 0.05) increase in values after expansion between medial aspects of 2(nd) (p = 0.002) and 3(rd) rugae (p = 0.005) and lateral aspects of 1(st) (p = 0.015), 2(nd) (p = 0.006) and 3(rd) (p = 0.001) rugae. The transverse changes were recorded in the order of 3(rd) rugae >2(nd) rugae >1(st) rugae. CONCLUSION: This pilot study does not support stability of medial and lateral ruga points of 2(nd) and 3(rd) primary rugae for forensic identification in individuals treated with mid palatal expansion. PMID- 25709314 TI - Evaluation of adult dental patterns on orthopantomograms and its implication for personal identification: A retrospective observational study. AB - BACKGROUND: Establishing a person's identity is a very complex process and is one of the main objectives of the forensic science also. Dental radiographs are certainly one of the most desirable pieces of antemortem evidence because of their highly objective nature as compared with other records. The aim of the present study is to establish the utility of orthopantomography for human identification. MATERIALS AND METHODS: A total of 300 digital orthomopantographs were randomly selected from those stored at Oral Medicine and Radiology Department of Dr. D.Y. Patil Dental College and Hospital, Pimpri, Pune. Dental patterns were classified into nine types which are commonly observed in dental radiography. The diversity of dental patterns was calculated for full dentition, maxilla and mandible respectively. RESULTS: Diversity of dental patterns observed for full dentition, maxilla and mandible were found to be 99.9%, 98.2% and 98.4% respectively. CONCLUSION: Findings suggests that orthopantomograms prove to be valuable aid in human identification. PMID- 25709315 TI - Accuracy of two dental and one skeletal age estimation methods in 6-16 year old Gujarati children. AB - INTRODUCTION: Age estimation is of immense importance not only for personal identification but also for treatment planning in medicine and dentistry. Chronologic age conveys only a rough approximation of the maturational status of a person, hence dental and skeletal ages have been explored as maturity indicators since decades. The tooth maturation provides a valuable indicator of dental age and serves as a better index of the maturation of a child as compared to other maturity indicators. AIMS AND OBJECTIVES: To test the applicability of Demirjian's and Willem's dental age assessment methods as well as Greulich and Pyle skeletal age assessment method in children residing in Gandhinagar district. MATERIALS AND METHODS: The study consisted of randomly selected 180 subjects (90 males and 90 females) ranging from 6 to 16 years age and residing in Gandhinagar district. Dental age estimation was performed from radiovisuograph (RVG) images of mandibular teeth of left quadrant by both Demirjian's and Willem's methods. Skeletal age estimation was done from right hand wrist radiograph by Greulich and Pyle method. The differences between the chronological age and the estimated dental and skeletal ages were statistically tested using paired 't' test. The correlation between chronological age, dental and skeletal age estimation methods was confirmed statistically by Pearson's correlation. The reproducibility of the estimations was statistically tested using the Pearson's Chi-square test. RESULTS: Amongst the age estimation methods used in this study, the Willem's dental age estimation method proved to be the most accurate and consistent. CONCLUSION: Although various age estimation methods do exist, the results are varied in different populations due to ethnic differences. However, till new tables are formulated, the Willem's method (Modified Demirjian method) can be accurately applied to estimate chronological age for the population residing in Gandhinagar district. PMID- 25709316 TI - Applicability of Berry's index in bite mark analysis. AB - OBJECTIVES: This study attempts to highlight the usefulness of applying Berry's Index as an adjuvant to support and aid in bite analysis. MATERIALS AND METHODS: This study was conducted among 100 students between the ages of 18-30 from Mar Baselios Dental Collage, Kothamangalam. Out of the 100 subjects, there were 50 males and 50 females. The data obtained was tabulated and analyzed using Statistical Package for Social Sciences, Version 16 (SPSS). RESULTS: The mean value of the width of the upper central incisor for male and female was 0.7602 cm and 0.7765 cm respectively. The mean value of the bizygomatic width for male and female was 12.54 cm and 12.42 cm respectively. The correlation between the upper central incisor width and the bizygomatic width was inferred to have a good positive correlation with a value 0f 0.613. Pearson correlation coefficient with greater correlation between the upper central incisor width and the bizygomatic width in female patient (r = 0.678) compared with male patient (r = 0. 525). CONCLUSION: Berry's Index can be a useful adjuvant to bite analysis by providing a means of determining the facial proportions of an individual from the width of the central incisors. PMID- 25709317 TI - Dimorphic Mandibular canines in gender determination in Moradabad population of Western Uttar Pradesh. AB - BACKGROUND AND OBJECTIVES: Among morphological characteristics that differentiate a male from a female, tooth size has also been evaluated in various populations for its applicability in anthropologic and forensic investigations to identify the gender from dental remains. The present study was undertaken to investigate the accuracy of mesio-distal width of the mandibular canines, inter-canine arch width, and Mandibular Canine Index (MCI) with which gender can be differentiated in Moradabad population and to correlate the results with other available data. MATERIALS AND METHODS: A cross-sectional study was conducted on the casts of 30 males and 30 females between the age group of 19-30 years. RESULTS: The mean right and left canine dimension (RCW and LCW) for females was between 6.28 mm and 6.54 mm while that of males was 7.06 mm and 7.45 mm. The mean inter-canine arch width (ICW) in males was 27.64 mm, whereas in females was 23.42 mm. Area under curve (AUC) of ICW, RCW, and LCW had 100%, 98%, and 99.7%. The predicted sensitivity and specificity observed of three criteria was 100% for ICW, 93.3% and 93.3% for RCW, and 96.7% and 100% for LCW, which were found to be highly statistically significant. The mean values of right and left CMI were significantly higher in females as compared to males (P < 0.001). CONCLUSION: The MCI parameter in the present study was a quick and reliable method for sexual identification and showed sexual dimorphism by both the RMCI and LMCI with greater significance in identifying females by using RMCI. PMID- 25709318 TI - Determination of sex by discriminant function analysis of mandibles from a Central Indian population. AB - CONTEXT: Identification of sex from skeletal remains is one of the important forensic considerations. Discriminant function analysis is increasingly used to determine the sex from skeleton. AIMS: To develop discriminant function to determine sex from mandible in a Central Indian population. SETTINGS AND DESIGN: This was a prospective study done at the Department of Anatomy. MATERIALS AND METHODS: The mandibles used in the present study were from the museum specimens. Only 82 adult mandibles (55 male and 27 female) that had been preserved were selected. Ten mandibular parameters were measured. STATISTICAL ANALYSIS USED: Statistical analysis was conducted using Statistical Package for Social Sciences (SPSS) for Windows, version 16. The level of statistical significance was set at P < 0.05. RESULTS: Using stepwise discriminant function analysis, only six variables were selected as the best discriminant between sexes, with the projection length of corpus mandibulae being the most dimorphic. It was observed that sex classification accuracy of the discriminant functions ranged from 57.3 to 80.5% for the individual variables, 81.7% for the stepwise method, and 85.4% for the direct method. CONCLUSION: The results of the study show that mandibles can be used for determining sex and the results are comparable with other similar studies. The studied mandibular variables showed sexual dimorphism with an accuracy comparable with other skeletal remains, next to cranium and pelvis. PMID- 25709319 TI - Radiographic evaluation of dental age using Demirjian's eight-teeth method and its comparison with Indian formulas in South Indian population. AB - AIM: The study was conducted to evaluate the applicability of Demirjian method and its comparison with Indian formulas for estimation of dental age in subjects attending a dental school in South India. MATERIALS AND METHODS: A total of 250 individuals (130 males and 120 females) between 7 and 18 years, with orthopantamographs were included in the study. Chronological age was recorded based on subject's date of birth. Dental age was estimated using Demirjian's and Indian formulas. All the data obtained was entered into spreadsheet and subjected to statistical analysis. RESULTS: The mean chronological age of the study sample was 12.39 +/- 3.32 years; while the mean age obtained from Demirjian's method and Indian-specific regression formula were 11.56 +/- 3.17 years and 14.20 +/- 3.24 years, respectively. In the present study, the Demirjian's method under estimated dental age by 0.84 years in males and 0.83 years in females (P < 0.05). Indian specific regression formulas overestimated dental age by 1.72 years in males and 1.91 years in females (P < 0.05). CONCLUSION: The published Demirjian's and Indian-specific regression formulas are not applicable to the present study group. Hence population-specific cubic regression formulas were developed for males and females in Bhimavaram town (South India). PMID- 25709320 TI - The study of inheritance analysis and evaluation of lip prints in individuals. AB - CONTEXT: Identification of an individual is a pre-requisite for certification of death and for personal, social, and legal reasons. The study of lip prints (cheiloscopy) was thought as a method for identification of a person. It is safe to assume that cheiloscopy, in its present stage of development, has become a means of criminalistic identification dealing with lip prints. AIM: The first aim of the study was to evaluate the visible lip patterns in Rajasthan population in relation to the gender and to ascertain the existence of hereditary pattern followed among parents and offsprings. The second aim was to compare visible and latent lip print patterns on non-biological materials like tracing paper, microscopic glass slides and stainless steel tumblers. MATERIALS AND METHODS: The lip prints of 300 subjects including 25 families were obtained using lipstick. Out of these 300 individuals, 60 were selected for latent lip prints. In order to prevent any intra- and inter-observer variability single observer carried out all the observations. The lip prints were analyzed using magnifying lens and were classified using the criteria given by Suzuki and Tsuchihashi. The determination of the pattern in each segment of the lip was based on the numerical superiority of properties of the lines on the fragment. STATISTICAL ANALYSIS USED: After recording all the values for various parameters, data obtained were statistically analyzed with the help of the Statistical Package for Social Sciences software version-13 using independent t-test. For all the tests, a P value of 0.05 or less was considered. RESULTS: In the present study, most predominant pattern in the entire study population among upper and lower lips considering both males and females was type III lip pattern. Hereditary resemblance was observed between parents and offsprings in 37.66%. The latent lip prints were better visualized on microscopic glass slide when compared to stainless steel tumblers. CONCLUSION: Lip prints have a good potential for use in criminal investigations. They have been used only occasionally despite their frequent occurrence at crime scenes. A place for cheiloscopy is recommended within the scope of forensic odontology, along with other means of forensic identification. PMID- 25709321 TI - Sex assessment by molar odontometrics in North Indian population. AB - INTRODUCTION: Human identification is based on scientific principles, mainly involving dental records, fingerprints, estimation of age, postmortem reports, differentiation by blood groups, and DNA comparisons. Sex assessment is one of the prime factors employed to assist with the identification of an individual. AIMS AND OBJECTIVE: To investigate univariate sex differences in the dimensions of permanent first molars and to assess sex, based on buccolingual (BL) and mesiodistal (MD) dimensions of permanent first molars in a population of north India. In addition, the study intended to evaluate the reliability of dimensional variation of these teeth in assessment of sex among the population. MATERIALS AND METHODS: The study sample consists of 410 adult individuals (200 males and 210 females), from a north Indian population. The BL and MD diameters of the permanent first molars were measured using digital vernier callipers. RESULTS: It was observed statistically significant difference between males and females with P < 0.05, in maxillary casts in both BL and MD dimensions; but only in the MD dimension in mandibular casts. A high level of sexual dimorphism of 7.7% was found in the BL dimension of the maxillary right first molar. The accuracy of sex assessment by each dimension was deliberated by univariate analyses with an overall accuracy ranging from 67.5 to 88% for various dimensions. CONCLUSION: Sexual dimorphism of teeth is population specific and among north Indian population, BL and MD dimensions in maxillary first molar and MD dimension in mandibular first molar can be used for sex assessment. PMID- 25709322 TI - Evaluation of the efficacy of titanium plates as denture markers under various heat sources and pressure - An in vitro study. AB - INTRODUCTION: Denture Markers are used as one of the main identifying aid in mass disasters. Dental description of missing person in mass disasters plays a vital role in forensic research. Difficulties arise when the teeth are missing. In such situation the prosthodontic identification (ID) of replaced teeth becomes the priority. Till recently, there was no development of denture marker that could withstand massive fire accidents. AIM: To determine the use of titanium chips with identity code engraved on it as denture markers that could withstand high temperature and pressure. MATERIALS AND METHODS: Wax patterns were fabricated with identity code moulded on a rubber stamp. It was invested and casted with titanium. Titanium chips were inserted into the polymethylmethacrylate (PMMA) block and subjected to various heat treatments. RESULTS: There was no loss of identity when subjected to 1,500 degrees C overnight but only residues left under pressure of 200 kg/cm(3). CONCLUSION: The literature recommends the metallic denture markers in order to withstand the post morten assaults. Titanium denture markers could be a preferred option as it can withstand high temperatures under pressure also. PMID- 25709323 TI - Exfoliative cytology: A possible tool in age estimation in forensic odontology. AB - INTRODUCTION: Age determination of unknown human bodies is important in the setting of a crime investigation or a mass disaster because the age at death, birth date, and year of death as well as gender can guide investigators to the correct identity among a large number of possible matches. OBJECTIVE: The study was undertaken with an aim to estimate the age of an individual from their buccal smears by comparing the average cell size using image analysis morphometric software. MATERIALS AND METHODS: Buccal smears were collected from 100 apparently healthy individuals. After fixation in 95% alcohol, the smears were stained using standard Papanicolaou laboratory procedure. The average cell size was measured using Dewinter's image analysis software version 4.3. Statistical analysis of the data was done using one-way ANOVA, Bonferroni procedures. RESULTS: The results showed significant decrease in average cell size of individual with increase in age. The difference was highly significant in age group of above 60 years. CONCLUSION: Age-related alterations are observed in buccal smears. PMID- 25709324 TI - A study of lip print patterns among adults of Sebha city, Libya. AB - INTRODUCTION: Lip print patterns are individualistic and unique and can be used for identification of individuals. OBJECTIVES: The objective of this study was to find out the different types of lip patterns, know the most common one and to know whether it has any gender predilection among adults of Sebha city. MATERIALS AND METHODS: A total of 104 adults aged 18-35 years participated in this study. Lip prints were recorded and analyzed for lip print patterns. Statistical analysis was carried out using the computer software Statistical Program for Social Sciences (SPSS) 17.0 (Chicago, Illinos, USA). RESULTS: Type I lip print pattern was seen in 53.37% and 60.07% of lip quadrants in males and females, respectively. 27 (25.96%) subjects had same lip print pattern in all the four quadrants. CONCLUSION: Suzuki and Tsuchihashi's Type I lip print pattern was most common type of lip print pattern in the studied population, whereas Type I' was found to be the least common. PMID- 25709325 TI - Comparative study of age estimation using dentinal translucency by digital and conventional methods. AB - INTRODUCTION: Estimating age using the dentition plays a significant role in identification of the individual in forensic cases. Teeth are one of the most durable and strongest structures in the human body. The morphology and arrangement of teeth vary from person-to-person and is unique to an individual as are the fingerprints. Therefore, the use of dentition is the method of choice in the identification of the unknown. Root dentin translucency is considered to be one of the best parameters for dental age estimation. Traditionally, root dentin translucency was measured using calipers. Recently, the use of custom built software programs have been proposed for the same. OBJECTIVES: The present study describes a method to measure root dentin translucency on sectioned teeth using a custom built software program Adobe Photoshop 7.0 version (Adobe system Inc, Mountain View California). MATERIALS AND METHODS: A total of 50 single rooted teeth were sectioned longitudinally to derive a 0.25 mm uniform thickness and the root dentin translucency was measured using digital and caliper methods and compared. The Gustafson's morphohistologic approach is used in this study. RESULTS: Correlation coefficients of translucency measurements to age were statistically significant for both the methods (P < 0.125) and linear regression equations derived from both methods revealed better ability of the digital method to assess age. CONCLUSION: The custom built software program used in the present study is commercially available and widely used image editing software. Furthermore, this method is easy to use and less time consuming. The measurements obtained using this method are more precise and thus help in more accurate age estimation. Considering these benefits, the present study recommends the use of digital method to assess translucency for age estimation. PMID- 25709326 TI - Molecular insights of saliva in solving paternity dispute. AB - Everyone is born with a unique genetic blueprint i.e. its own genome. Special locations called loci on different chromosomes display predictable inheritance patterns that could be used to determine biological relationships. These locations contain specific DNA sequences, called markers, which forensic scientists use as identifying marks for individuals. Saliva is a potentially useful source of genomic DNA for genetic studies. Paternity testing is based on the premise that we inherit half our DNA from our father and half from our mother. Therefore, persons who are biologically related must share similar DNA profile. Conversely, the absence of similarities in the DNA profiles of the child and the alleged father is used as proof that no biological relationship exists. In this paper, a female complained for being raped a year back by Mr. X and accused him of being father of her 3-months-old baby girl. DNA testing was done using saliva for the child and blood sample from the mother and the suspected father. The finding presented here allows the use of saliva as an alternative source of blood. PMID- 25709327 TI - Forensic dental workshop. PMID- 25709328 TI - Journal of the pharmacy and bioallied sciences. PMID- 25709329 TI - Stem cell therapy: A novel treatment approach for oral mucosal lesions. AB - Stem cells have enormous potential to alleviate sufferings of many diseases that currently have no effective therapy. The research in this field is growing at an exponential rate. Stem cells are master cells that have specialized capability for self-renewal, potency and capability to differentiate to many cell types. At present, the adult mesenchymal stem cells are being used in the head and neck region for orofacial regeneration (including enamel, dentin, pulp and alveolar bone) in lieu of their proliferative and regenerative properties, their use in the treatment of oral mucosal lesions is still in budding stages. Moreover, there is scanty literature available regarding role of stem cell therapy in the treatment of commonly seen oral mucosal lesions like oral submucous fibrosis, oral lichen planus, oral ulcers and oral mucositis. The present review will focus on the current knowledge about the role of stem cell therapies in oral mucosal lesions and could facilitate new advancements in this area (articles were obtained from electronic media like PubMed, EBSCO, Cochrane and Medline etc., from year 2000 to 2014 to review the role of stem cell therapy in oral mucosal lesions). PMID- 25709330 TI - An alternative in situ gel-formulation of levofloxacin eye drops for prolong ocular retention. AB - INTRODUCTION: Delivering drugs to ocular region is a challenging task. Eye physiological barriers lead to relatively less therapeutic and bioavailability effect by the conventional eye drops. This may be overcome by the use of in situ gel delivery system. OBJECTIVE: The objective of our work was to formulate an ocular delivery system of levofloxacin, based on the concept of ion (sodium alginate) and pH (chitosan) activated in situ gelation concept. Due to its elastic properties, in situ gels resist the ocular drainage of drug leading to longer contact times with ocular surface. MATERIALS AND METHODS: The formulation was evaluated for physicochemical characteristics, in vitro drug release. Ocular retention studies were carried out by Gamma scintigraphy. Time activity curve was plotted between marketed formulation and developed formulation for comparing drug drainage from the eye with time. Ocular tolerance test was performed by handheld infra-red camera. RESULTS AND DISCUSSION: The formulations showed a first-order release pattern over 12 h. Both in vitro release studies and in vivo gamma scintigraphy precorneal retention studies indicated better therapeutic efficacy compared with standard eye drops. CONCLUSION: The results demonstrated that the developed in situ gel of levofloxacin is nonirritant, has prolonged action and is a better option in terms of retention, ocular bioavailability and patient compliance when compared with plain eye drops formulation. PMID- 25709331 TI - Anti-Candida activity of Quercus infectoria gall extracts against Candida species. AB - BACKGROUND: Galls of Quercus infectoria have been traditionally used to treat common ailments, including yeast infections caused by Candida species. OBJECTIVE: This study aimed to evaluate the in vitro anti-Candida activity of Q. infectoria gall extracts against selected Candida species. MATERIALS AND METHODS: Methanol and aqueous extracts of Q. infectoria galls were tested for anti-Candida activity against Candida albicans, Candida krusei, Candida glabrata, Candida parapsilosis and Candida tropicalis. The minimum inhibitory concentrations were determined using the two-fold serial dilution technique of concentrations ranging from 16 mg/ml to 0.03 mg/ml. After 24 h, the minimum fungicidal concentrations were determined by subculturing the wells, which showed no turbidity on the agar plate. Potential phytochemical group in the crude extracts was screened by phytochemical qualitative tests and subsequently subjected to the gas chromatography-mass spectrometry analysis. RESULTS: Both methanol and aqueous extracts displayed substantial anti-Candida activity and pyrogallol was the major component of both crude extracts. CONCLUSIONS: Data from current study suggested that Q. infectoria gall extracts are a potential source to be developed as anti candidiasis. PMID- 25709332 TI - Prediction of anticancer property of bowsellic acid derivatives by quantitative structure activity relationship analysis and molecular docking study. AB - CONTEXT: Boswellic acid consists of a series of pentacyclic triterpene molecules that are produced by the plant Boswellia serrata. The potential applications of Bowsellic acid for treatment of cancer have been focused here. AIMS: To predict the property of the bowsellic acid derivatives as anticancer compounds by various computational approaches. MATERIALS AND METHODS: In this work, all total 65 derivatives of bowsellic acids from the PubChem database were considered for the study. After energy minimization of the ligands various types of molecular descriptors were computed and corresponding two-dimensional quantitative structure activity relationship (QSAR) models were obtained by taking Andrews coefficient as the dependent variable. STATISTICAL ANALYSIS USED: Different types of comparative analysis were used for QSAR study are multiple linear regression, partial least squares, support vector machines and artificial neural network. RESULTS: From the study geometrical descriptors shows the highest correlation coefficient, which indicates the binding factor of the compound. To evaluate the anticancer property molecular docking study of six selected ligands based on Andrews affinity were performed with nuclear factor-kappa protein kinase (Protein Data Bank ID 4G3D), which is an established therapeutic target for cancers. Along with QSAR study and docking result, it was predicted that bowsellic acid can also be treated as a potential anticancer compound. CONCLUSIONS: Along with QSAR study and docking result, it was predicted that bowsellic acid can also be treated as a potential anticancer compound. PMID- 25709333 TI - Phytotherapy of experimental depression: Kalanchoe integra Var. Crenata (Andr.) Cuf Leaf Extract. AB - CONTEXT: Kalanchoe sp. have been used since 1921 for central nervous system (CNS) disorders such as psychosis and depression. It is known to possess CNS depressant effects. AIMS: To investigate the antidepressant properties of the aqueous leaf extract of Kalanchoe integra. SETTINGS AND DESIGN: The study was carried out at the Kwame Nkrumah University of Science and Technology between 6 a.m. and 3 p.m. MATERIALS AND METHODS: ICR mice were subjected to the forced swimming test (FST) and tail suspension test (TST) after they had received extract (30-300 mg/kg), fluoxetine (3-30 mg/kg), desipramine (3-30 mg/kg) orally, or water (as vehicle). In a separate experiment, mice were pre-treated with reserpine (1 mg/kg), alpha methyl paratyrosine (AMPT; 400 mg/kg), both reserpine (1 mg/kg) and AMPT (200 mg/kg) concomitantly, or p-chlorophenylalanine (pCPA; 200 mg/kg) to ascertain the role of the noradrenergic and serotoninergic systems in the mode of action of the extract. STATISTICAL ANALYSIS USED: Means were analyzed by analysis of variance (ANOVA) followed by Newman-Keuls' post hoc test. P < 0.05 was considered significant. RESULTS: In both FST and TST, the extract induced a decline in immobility, indicative of antidepressant-like effect. This diminution in immobility was reversed by pCPA, but not by reserpine and/or AMPT. The extract increased the swimming and climbing scores in the FST, suggestive of possible interaction with serotoninergic and noradrenergic systems. In the TST, the extract produced increases in both curling and swinging scores, suggestive of opioidergic monoaminergic activity, respectively. CONCLUSIONS: The present study has demonstrated the antidepressant potential of the aqueous leaf extract of K. integra is mediated possibly by a complex interplay between serotoninergic, opioidergic, and noradrenergic systems. PMID- 25709334 TI - In vitro acetylcholinesterase inhibition by psoralen using molecular docking and enzymatic studies. AB - INTRODUCTION: Alzheimer's disease (AD) has increased at an alarming rate and is now a worldwide health problem. Inhibitors of acetylcholinesterase (AChE) leading to inhibition of acetylcholine breakdown constitute the main therapeutic strategy for AD. Psoralen was investigated as inhibitor of AChE enzyme in an attempt to explore its potential for the management of AD. MATERIALS AND METHODS: Psoralen was isolated from powdered Psoralea corylifolia fruits. AChE enzyme inhibitory activity of different concentrations of psoralen was investigated by use of in vitro enzymatic and molecular docking studies. Further, the enzyme kinetics were studied using Lineweaver-Burk plot. RESULTS: Psoralen was found to inhibit AChE enzyme activity in a concentration-dependent manner. Kinetic studies showed psoralen inhibits AChE in a competitive manner. Molecular docking study revealed that psoralen binds well within the binding site of the enzyme showing interactions such as pi-pi stacking and hydrogen bonding with residues present therein. CONCLUSION: The result of AChE enzyme inhibitory activity of the psoralen in this study is promising. It could be further explored as a potential candidate for further development of new drugs against AD. PMID- 25709335 TI - Development of a novel 3-month drug releasing risperidone microspheres. AB - OBJECTIVE: The purpose of this study was to develop an ideal microsphere formulation of risperidone that would prolong the drug release for 3 months in vivo and avoid the need for co-administration of oral tablets. MATERIALS AND METHODS: Polycaprolactones (PCL) were used as polymers to prepare microspheres. The research included screening and optimizing of suitable commercial polymers of variable molecular weights: PCL-14000, PCL-45000, PCL-80000 or the blends of these polymers to prepare microspheres with zero-order drug-releasing properties without the lag phase. In the present study, the sustained release risperidone microspheres were prepared by o/w emulsion solvent evaporation technique and the yield was determined. Microspheres were evaluated for their drug content and in vitro drug release. Microspheres prepared using a blend of PCL-45000 and PCL 80000 at a ratio of 1:1 resulted in the release of the drug in a time frame of 90 days, demonstrated zero-order drug release without lag time and burst release. This formulation was considered optimized formulation. Optimized formulation was characterized for solid state of the drug using differential scanning calorimetry, surface morphology using scanning electron microscopy and in vivo drug release in rats. RESULTS: The surface of the optimized formulation was smooth, and the drug changed its physical form in the presence of blends of polymers and upon fabrication of microspheres. The optimized formulation also released the drug in vivo for a period of 90 days. CONCLUSIONS: From our study, it was concluded that these optimized microspheres showed great potential for a better depot preparation than the marketed Risperdal ConstaTM and, therefore, could further improve patient compliance. PMID- 25709336 TI - Hepatoprotective potential of ethanolic extract of Pandanus odoratissimus root against paracetamol-induced hepatotoxicity in rats. AB - BACKGROUND: Pandanus odoratissimus (Pandanaceae) is popular in the indigenous system of medicines like Ayurveda, Siddha, Unani and Homoeopathy. In the traditional system of medicine various plant parts such as leaves, root, flowers, and oils are used as anthelmintic, tonic, stomachic, digestive and in the treatment of jaundice and various liver disorders. OBJECTIVE: The aim was to investigate the hepatoprotective activity of ethanolic extract of the root of P. odoratissimus against paracetamol (PCM) induced hepatotoxicity in rats. MATERIALS AND METHODS: Hepatotoxicity was induced in male Wistar rat by PCM (2 g/kg b.w. p.o. for 7 days). The ethanolic extract of P. odoratissimus root was administered at the dose level of 200 mg/kg and 400 mg/kg b.w. orally for 7 days and silymarin (100 mg/kg b.w. p.o.) as standard drug was administered once daily for a week. The hepatoprotective effect of ethanolic extract was evaluated by assessment of biochemical parameters such as serum glutamic oxaloacetic transaminase, serum glutamic-pyruvic transaminase, serum alkaline phosphatase, total and direct bilirubin and triglycerides. Histopathological study of rat liver was also done. RESULTS: Experimental findings revealed that the extract at dose level of 200 mg/kg and 400 mg/kg of b.w. showed dose dependant hepatoprotective effect against PCM induced hepatotoxicity by significantly restoring the levels of serum enzymes to normal that was comparable to that of silymarin, but the extract at dose level of 400 mg/kg was found to be more potent when compared to that of 200 mg/kg. Besides, the results obtained from histopathological study also support the study. CONCLUSION: From the results, it can be concluded that ethanolic extract of the root of P. odoratissimus afforded significant protection against PCM induced hepatotoxicity in rats. PMID- 25709337 TI - Assesment of endocrinal and biochemical entities through liquid chromatography tandem mass spectrometry/mass spectrometer: Inter-relative investigation of the interaction based cardiovascular formulation. AB - BACKGROUND: Combinatory oral dosage treatment of atorvastatin (ATVS) and olmesartan (OLM) drugs to cardiovascular patients reflects unpredicted results instead of its individual therapy, which was accessed on quantification of endocrinal and biochemicals of plasma through liquid chromatography-tandem mass spectrometry/mass spectrometer (LCMS/MS). OBJECTIVE: Mission was to track the remarkable biochemical variation in the plasma after induction of the combined formulation, to evaluate the pharma-market rumor on its efficiency. METHODS: To fulfil undergoing research objectives for digging-up of market insult, human patient volunteers were chosen according to the required criteria along with bioethical regulation. A sensitive, rapid and precise method was developed and validated to estimate aldosterone (ALD), angiotensin (ANG-II) and the Mevalonate (MVA) not Mevalonic acid through LCMS/MS over least samples of cardiovascular patients. Level of each endogenous biochemicals were determined in three stages - without drugs, with a single drug (OLM/ATVS) and with their combination that was then correlate with blood pressure of respective volunteers. RESULT AND DISCUSSION: Comparative and correlative studies panaroma among these analytes was detected. The selectivity, specificity, linearity, precision, accuracy, extraction recovery, limit of detection and limit of quantification, stability were the essential points of validation of the developed methodology. And the significance of each endogenous analyte data were based on P >= 0.001. Thus, low value of ALD and reciprocally higher in ANG-II on administered single drug than its combination and equal concentration of mevalonate in both stages, was discovered. CONCLUSION: This concludes that the cardiovascular dosage formulation entrenched in the market are not synergistic and effective compared with a single drug as antihypertensive drug. PMID- 25709338 TI - Ulcer healing activity of Mumijo aqueous extract against acetic acid induced gastric ulcer in rats. AB - OBJECTIVE: Gastric ulcer is an important clinical problem, chiefly due to extensive use of some drugs. The aim was to assess the activity of Mumijo extract (which is used in traditional medicine) against acetic acid induced gastric ulcer in rats. MATERIALS AND METHODS: The aqueous extract of Mumijo was prepared. Animals were randomly (n = 10) divided into four groups: Control, sham-operated group (received 0.2 ml of acetic acid to induce gastric ulcer), Mumijo (100 mg/kg/daily) were given for 4 days postacetic acid administration, and ranitidine group (20 mg/kg). The assessed parameters were pH and pepsin levels (by Anson method) of gastric contents and gastric histopathology. Ranitidine was used as reference anti-ulcer drug. RESULTS: The extract (100 mg/kg/daily, p.o.) inhibited acid acetic-induced gastric ulceration by elevating its pH versus sham group (P < 0.01) and decreasing the pepsin levels compared to standard drug, ranitidine (P < 0.05). The histopathology data showed that the treatment with Mumijo extract had a significant protection against all mucosal damages. CONCLUSION: Mumijo extract has potent antiulcer activity. Its anti-ulcer property probably acts via a reduction in gastric acid secretion and pepsin levels. The obtained results support the use of this herbal material in folk medicine. PMID- 25709339 TI - Effects of methanol in blood pressure and heart rate in the rat. AB - INTRODUCTION: Methanol ingestion is an uncommon form of poisoning that can cause severe metabolic disturbances, blindness, permanent neurologic dysfunction and death. While methanol itself may be harmless, it converts, in vivo, to highly toxic formic acid. Methanol intoxication clinically manifests as ocular toxicity. The present study investigated the cardiovascular effects of methanol. MATERIALS AND METHODS: On the day of the experiment, Wistar rats were anesthetized with urethane. The femoral artery on one side was exposed, and a polyethylene catheter was inserted into the artery for recording arterial blood pressure (ABP). The catheter was attached to a pressure transducer (Statham - P23D). Systolic blood pressure (BP), mean ABP, and heart rate were recorded on a power-lab data acquisition system with a computerized analysis program. Rats were administered with different dilutions (9.5%, 19.0%, 28.5%, 38.0%, 47.5%, 57.0%, 66.5%, 76%) of methanol (95% v/v, i.v.). RESULTS: Of all dilutions of methanol, 66.5% dilution showed maximum decrease of diastolic BP from 124.64 +/- 5.39 to 62.30 +/- 11.90 mmHg; 76.0% dilution showed maximum decrease of systolic BP from 165.70 +/- 5.57 to 112.11 +/- 12.0 mmHg, and mean ABP from 160.61 +/- 12.45 to 86.14 +/- 4.11 mmHg. The heart rate increased (from 250 beats/s to near about 275 beats/s) following administration of methanol dilution from 19.0% till 76.0%. CONCLUSION: The present study is consistent with previous studies suggesting that methanol ingestion leads to severe hypotension as observed from decrease in diastolic BP, systolic BP, and mean ABP. However, severe increase of heart rate suggests activation of a compensatory mechanism to offset hypotension that eventually leads to death in methanol poisoning. Hence, this study emphasizes the need to monitor all the hemodynamic parameters in accidental methanol poisoning. PMID- 25709340 TI - Evaluating the reliability and accuracy of the promotional brochures for the generic pharmaceutical companies in Iraq using World Health Organization guidelines. AB - BACKGROUND: Pharmaceutical industries worldwide are heavily involved in aggressive drug promotions. Physician targeted promotion through medical representatives is one of the most common tactic for drug promotion by pharmaceutical drug companies. WHO states that medical representatives to work in an ethical way should make available to prescribers and dispensers complete and unbiased information for each product discussed; therefore this study aimed to evaluate the ethics in the medical brochures of generic pharmaceutical companies that are given through medical representatives to physicians in Iraq. MATERIALS AND METHODS: An observational, cross-sectional study was conducted in Iraq - Baghdad from February to April 2014. Promotional drug brochures were collected mainly from pharmaceutical exhibition during attendance of medical conferences that were sponsored by generic pharmaceutical companies. Evaluation of each brochure was based primarily on WHO criteria for ethical medicinal drug promotion. The availability of emotional pictures in each brochure was also examined. Furthermore, references were checked to find their retrievability, source, and authenticity of presentations. RESULTS: Most medical brochures were for antibiotics, and drugs for cardiovascular diseases. All brochures mention drug name, with its active ingredient and indication, but there is a significant absence for drug interaction, while drug side effects and contraindications if present were written in a small font. Emotional picture presented in 70% of brochures. Reference citation was present in 72% of brochures, however only 75% of references in these brochures were correct. CONCLUSIONS: The information that is provided in medical brochures is biased and mainly persuasive since it is mainly focusing on the positive aspect of drug therapy. PMID- 25709341 TI - In vitro antimicrobial and cytotoxic effects of Anacardium occidentale and Mangifera indica in oral care. AB - BACKGROUND: Oral health is an integral and important component of general health. Infectious diseases such as caries, periodontal, and gingivitis indicate the onset of imbalance in homeostasis between oral micro biota and host. The present day medicaments used in oral health care have numerous side effects. The uses of herbal plants as an alternative have gained popularity due to side effects of antibiotics and emergence of multidrug resistant strains. Anacardium occidentale (cashew) and Mangifera indica (mango) have been used as traditional oral health care measures in India since time immemorial. MATERIALS AND METHODS: The ethanol extracts of cashew and mango leaves were obtained by maceration method. The antimicrobial activity was evaluated by clear zone produced by these plant extracts against Enterococcus faecalis, Staphylococcus aureus, Streptococcus mutans, Escherichia coli, and Candida albicans in agar plate method, determination of minimum inhibitory concentration (MIC), minimum bactericidal/fungicidal concentration (MBC/MFC), and suppression of biofilm. The cytotoxic effects of plants extract was determined by microculture tetrazolium assay on human gingival fibroblast and Chinese hamster lung fibroblast (V79) cell lines. RESULTS: Cashew and mango leaf extract significantly (P < 0.05) produced larger zone of inhibition against test pathogens when compared to povidone-iodine based mouth rinses. Although the MIC and MBC/MFC values of mouth rinses were effective in lower concentrations; plant extracts significantly (P < 0.001) suppressed the biofilms of oral pathogens. The leaf extracts were less cytotoxic (P < 0.001) compared to mouth rinses. CONCLUSIONS: Plant extracts are superior to the mouth rinses and have a promising role in future oral health care. PMID- 25709343 TI - Synthesis and antimicrobial activity of some new diphenylamine derivatives. AB - In search of new leads toward potent antimicrobial agent, an array of novel derivatives of 2-hydrazinyl-N-N, diphenyl acetamide has been synthesized from the chloroacetylation reaction of diphenylamine (DPA). For this, a series of DPA derivatives were prepared by replacing chlorine with hydrazine hydrate in alcoholic medium and 2-hydrazino-N, N-diphenylacetamide was synthesized. The 2 hydrazino-N, N-diphenylacetamide was further subjected to reaction with various aromatic aldehydes in presence of glacial acetic acid in methanol. The synthesized compounds were characterized by their IR, 1HNMR spectral data and elemental analysis. The compounds were screened for antibacterial and antifungal activity by cup plate method. 2-(2-Benzylidenehydrazinyl)-N, N-diphenylacetamide (A1); 2-(2-(3-methylbenzylidene) hydrazinyl)-N, N-diphenyl-acetamide (A5) and 2 (2-(2-nitrobenzylidine) hydrazinyl)-N, N-diphenyl-acetamide compounds (A7) showed significant antimicrobial as well as antifungal activity. Diphenylamine compounds may be explored as potent antimicrobial and antifungal compounds. PMID- 25709342 TI - The effects of female sexual steroids on gastric function and barrier resistance of gastrointestinal tract following traumatic brain injury. AB - AIM: The aim was to assess the alteration of gastric function and barrier function of gastrointestinal (GI) tract following diffuse brain injury in varying ovarian hormone status. MATERIALS AND METHODS: Diffuse traumatic brain injury (TBI) was induced by Marmarou method. Rats were randomly assigned into 10 groups: Intact, sham + ovariectomized female (OVX), TBI, TBI + OVX, vehicle, estradiol (E2), progesterone (P), E2 + P, estrogen receptor alpha agonist and estrogen receptor beta agonist (DPN). Endotoxin levels were measured using enzyme-linked immunosorbent assay method. All the parameters were measured 5 days after TBI. RESULTS: Intragastric pressure was significantly decreased in TBI as compared to the intact group (P < 0.001) and this was lower in TBI group versus TBI + OVX group (P < 0.05). Pretreatment with steroid hormones and their agonists did not have any effect on the gastric pressure compared to TBI + OVX or vehicle groups. Inflammation, congestion, ulcer and erosion were seen in the TBI rats. All treatment groups worsen the tissue condition so that the presence of thrombosis also was seen. The trauma induction did not have any effect on the serum and intestinal endotoxin levels. DPN had caused a significant reduction in serum levels of endotoxin compared with OVX + TBI group (P < 0.05). CONCLUSION: Pretreatment with sexual steroids is not useful in the treatment of GI dysfunction induced by TBI. The treatment with all sexual female hormones worsens the gastric tissue condition. Furthermore, the applied weight was not enough for releasing of endotoxin. It seems that estrogen reduced the endotoxin levels by estrogen beta receptor. PMID- 25709344 TI - Boosting the brand image. PMID- 25709345 TI - Riociguat: Something new in pulmonary hypertension therapeutics? AB - Pulmonary hypertension (PH) continues to be a disease that is associated with woeful outcomes. The search for an ideal drug molecule for PH led to the discovery of riociguat, which is a first-in-class drug molecule that activates soluble guanylate cyclase. We conducted a systematic literature search using databases such as PubMed, Science Direct, Springer, Cochrane Reviews and Google Scholar to gather evidence generated from published clinical trials on the efficacy, safety, pharmacokinetics and regulatory status of riociguat. CHEST-1 and the PATENT-1 were phase-3 pivotal clinical trials that showed that riociguat was able to significantly improve the 6-min walk distance with 16 weeks of therapy as compared with the placebo arm. The drug also showed improvement in secondary outcome measures such as improvement in the pulmonary vascular resistance, N-terminal pro-brain natriuretic peptide levels, World Health Organization functional class, time to clinical worsening and Borg dyspnea score. The drug had a modest safety profile, with hypotension being the most bothersome adverse effect. These findings led to various regulatory agencies around the world granting approval for riociguat for the treatment of pulmonary arterial hypertension (PAH) and inoperable chronic thromboembolic pulmonary hypertension (CTEPH). The entry of a new class of drug for PAH and CTEPH therapy portends some hope for patients with a disease that is traditionally linked with a poor prognosis. PMID- 25709346 TI - The mechanism of antidepressant-like effects of piroxicam in rats. AB - OBJECTIVE: To investigate the antidepressant-like effect of piroxicam with a focus on serotonergic neurotransmission. MATERIALS AND METHODS: Rats were randomly distributed into the following groups: 0.9% saline control; 3 mg/kg pizotifen; 10 mg/kg sertraline; 10 mg/kg piroxicam; 10 mg/kg sertraline + 10 mg/kg piroxicam; 10 mg/kg sertraline + 3 mg/kg pizotifen; and 10 mg/kg piroxicam + 3 mg/kg pizotifen. All the drugs were dissolved in 0.9% saline. Three administrations of the drugs (piroxicam and sertraline) were performed 1, 5 and 24 h before testing the animals in the open field followed by the forced swim test (FST). Piroxicam and sertraline were administered orally by gavage and pizotifen was administered intraperitoneally 30 min before gavage. Immediately after the FST, the hippocampi were rapidly dissected for neurochemical analysis in high-performance liquid chromatography. RESULTS: Acute treatment with piroxicam promoted an antidepressant-like effect in the FST, which was associated with an increase in serotonin levels in the hippocampus. This effect was potentiated in the piroxicam + sertraline group but counteracted by administration of the non-selective serotonin receptor antagonist pizotifen. CONCLUSION: These results suggest that the antidepressant-like effect of piroxicam in the FST is mediated by the serotonin system; however, by different mechanisms from those of sertraline. PMID- 25709347 TI - Phosphodiesterase-4 inhibition with rolipram attenuates hepatocellular injury in hyperinflammation in vivo and in vitro without influencing inflammation and HO-1 expression. AB - OBJECTIVE: To investigate the impact of the phophodiesterase-4 inhibition (PD-4 I) with rolipram on hepatic integrity in lipopolysaccharide (LPS) induced hyperinflammation. MATERIALS AND METHODS: Liver microcirculation in rats was obtained using intravital microscopy. Macrohemodynamic parameters, blood assays, and organs were harvested to determine organ function and injury. Hyperinflammation was induced by LPS and PD-4-I rolipram was administered intravenously one hour after LPS application. Cell viability of HepG2 cells was measured by EZ4U-kit based on the dye XTT. Experiments were carried out assessing the influence of different concentrations of tumor necrosis factor alpha (TNF alpha) and LPS with or without PD-4-I. RESULTS: Untreated LPS-induced rats showed significantly decreased liver microcirculation and increased hepatic cell death, whereas LPS + PD-4-I treatment could improve hepatic volumetric flow and cell death to control level whithout influencing the inflammatory impact. In HepG2 cells TNF-alpha and LPS significantly reduced cell viability. Coincubation with PD-4-I increased HepG2 viability to control levels. The heme oxygenase 1 (HO-1) pathway did not induce the protective effect of PD-4-I. CONCLUSION: Intravenous PD-4-I treatment was effective in improving hepatic microcirculation and hepatic integrity, while it had a direct protective effect on HepG2 viability during inflammation. PMID- 25709348 TI - Antibiotic prophylaxis in the prevention of rebleeding in acute variceal hemorrhage: A randomized trial. AB - OBJECTIVE: To assess the role of antibiotic prophylaxis in the prevention of rebleeding in acute variceal hemorrhage. MATERIALS AND METHODS: A total of 60 patients who underwent endoscopic therapy for bleeding esophageal varices were randomized into the prophylaxis group and the on-demand group. Patients in the prophylaxis group received antibiotic prophylaxis using intravenous ofloxacin till the patient resumed oral fluids, followed by oral ofloxacin tablet for a total of 7 days. In the on-demand group, antibiotics were used only when infection was evident. Patients were monitored for rebleeding and infection during the hospital stay. RESULTS: A total of 30 patients in the prophylaxis group and 26 patients in the on-demand group were analyzed. The clinical characteristics in both the groups were similar. The Child-Pugh score was around 7 in both the groups. The incidence of infection was 5/30 (16.7%) in the prophylaxis group and 7/26 (26.9%) in the on-demand group (P = 0.52). The incidence of early rebleeding in the prophylaxis vs. the on-demand group was 3 vs. 5 (P = 0.69), and the incidence of late rebleeding was 6 vs. 8 (P = 0.48). The differences were not significant. CONCLUSION: The present study shows a trend toward lower rate of early and late rebleeding, infection rate and mortality in the prophylaxis group; hence, routine use of antibiotics in all such patients may not be necessary. Further studies with a larger sample size and a longer follow up period are required to validate the usefulness of antibiotics in these patients. PMID- 25709349 TI - Adverse drug reactions of imatinib in patients with chronic myeloid leukemia: A single-center surveillance study. AB - OBJECTIVE: To monitor the adverse drug reactions (ADRs) associated with imatinib treatment in patients with chronic myeloid leukemia (CML) in a tertiary care hospital. MATERIALS AND METHODS: The study was carried out by the Departments of Pharmacology and Medical Oncology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, India. The study was carried out from March 2012 to February 2014. The ADRs were reported in a suspected Adverse Drug Reaction Reporting form, provided by the Central Drugs Standard Control Organization (CDSCO), Ministry of Health and Family Welfare, Government of India. The ADRs were analyzed for their pattern, causality and severity. RESULTS: A total of 326 ADRs from 81 patients were reported during the study period. The hematological toxicities were much more prominent than the non-hematological toxicities in this study. The prevalence of thrombocytopenia (21.17%) was higher compared with other reactions. Further analysis showed that most of the ADRs were mild to moderate in nature. The causality assessment revealed that the majority of the ADRs belonged to the possible category. CONCLUSION: The present study in a tertiary care hospital suggests that hematological toxicities are predominant in CML patients treated with imatinib mesylate. The blood and lymphatic system (38.96%) was the most affected, with imatinib therapy and thrombocytopenia (21.17%) being the most commonly encountered ADRs in the present study. Thorough monitoring of ADRs is warranted for better treatment outcomes. PMID- 25709350 TI - Structural aberration in R282K genetic mutation and antiviral drug-resistant H7N9 bird flu. PMID- 25709351 TI - Stevens-Johnson syndrome caused by cefepime? PMID- 25709352 TI - Pindolol augmentation of selective serotonin reuptake inhibitors and clomipramine for the treatment of obsessive-compulsive disorder: A meta-analysis. PMID- 25709353 TI - Recurrence of atrial fibrillation after switching from brand to generic atenolol. AB - Beta blockers are the initial treatment for rate control of supraventricular tachyarrhythmia in patients without a history of myocardial infarction or left ventricular dysfunction. In this article we report the recurrence of atrial fibrillation after switching to the generic formulation of atenolol. PMID- 25709354 TI - Isolated sinus tachycardia following reinitiation of risperidone in a patient with suspected autonomic hypersensitivity. AB - The second generation antipsychotic risperidone is generally considered to have low cardiac adverse events, with an increased risk of ventricular arrhythmias being reported only rarely in literature. We report here the case of a patient with a significant history of alcohol dependence, yet with no previous cardiac history, who had previously tolerated risperidone well, but had experienced isolated sinus tachycardia in the post detox period, following the reinitiation of risperidone therapy. The Naranjo Adverse Drug Reaction (ADR) probability scale rating for this being a medication adverse event (AE) was 4, thus indicating that this patient's AE was associated with risperidone therapy. This case report will contribute to the limited evidence of adverse cardiac events associated with risperidone therapy, with particular emphasis on the susceptibility of patients in a state of autonomic hypersensitivity. PMID- 25709355 TI - Hypoglycemia, polycythemia and hyponatremia in a newborn exposed to nebivolol during pregnancy. AB - Nebivolol is a third-generation beta blocker that exerts selective antagonistic activity on beta1 receptors. It has vasodilating properties that result from direct stimulation of endothelial nitric oxide synthase. Nebivolol is indicated for the treatment of hypertension and heart failure, and is generally well tolerated. In this article, we report a case of an infant who was admitted to the Pediatrics and Neonatology Unit of the Moscati Hospital (Aversa, Italy) about 24 hours after birth. The reason for hospitalization was persistent severe hypoglycemia (blood glucose = 30 mg/dL) and jaundice (total bilirubin = 12.5 mg/dL, indirect bilirubin 11.75 mg/dL). He was born by spontaneous delivery after a normal term pregnancy. Birth weight was 3040 g and the Apgar score was 6-9. The mother reported taking nebivolol 5 mg/day for unspecified tachycardia in the last 4 months of pregnancy. Clinical and instrumental investigations carried out during hospitalization did not reveal any congenital or perinatal abnormalities. After treatment for metabolic and electrolyte imbalance, he was discharged on the 10(th) day of hospitalization, in good clinical condition and with normalization of clinical and laboratory parameters. Currently, there are no specific studies on nebivolol tolerability during pregnancy. Our data suggest that the risk profile of nebivolol during pregnancy is the same as that of other beta-blockers. Therefore, further studies are required to determine the safety of beta-blockers during pregnancy and the risks to the unborn child. PMID- 25709356 TI - A rare case modafinil dependence. AB - Modafinil, a non-amphetamine psychostimulant, is indicated for narcolepsy, shift work sleep disorder and severe obstructive sleep apnea syndrome. Modafinil is prescribed at the dose of 100 mg once in a day or as two doses, 12 h apart in a day. It has also been found that it reduces cocaine dependence and withdrawal phenomenon. Modafinil is claimed to have very low liability for abuse and dependence. Here we report a rare case of modafinil dependence. PMID- 25709357 TI - Macitentan: An important addition to the treatment of pulmonary arterial hypertension. AB - Macitentan is an orphan drug for the treatment of pulmonary arterial hypertension (PAH). Endothelin-1 (ET-1) plays a critical role of pathophysiology of PAH. Macitentan, a new dual endothelin receptor antagonist, has reportedly improved prognosis of PAH patients by delaying the progression of disease. It prevents the binding of ET-1 to both endothelin A (ETA) and endothelin B (ETB) receptors. Macitentan displays higher efficacy, lesser adverse effects and drug interactions. It has completed phase III trials in 2012 for treatment of PAH and has been tried for ischemic digital ulcers in systemic sclerosis, recurrent glioblastoma and combination with chemotherapeutic agents against various cancers. Safety data for macitentan were obtained primarily from a placebo controlled clinical study in 742 patients with PAH. The Food and Drug Administration (FDA) approved the drug on 13 October 2013. It is an important addition to long-term treatment of PAH. PMID- 25709358 TI - Fluoride release and uptake of five dental restoratives from mouthwashes and dentifrices. AB - BACKGROUND: This study evaluated the fluoride release and uptake of five common dental restoratives mainly glass ionomer formulations, including a conventional glass ionomer, a relatively new caries stabilization glass ionomer and resin modified glass ionomer (Fuji II, Fuji VII and Fuji II LC); one compomer (F2000); and one fluoride releasing composite resin (tetric ceram). MATERIALS AND METHODS: A total of 12 cylindrical specimens for each of the five materials were prepared following manufacturer's instructions for manipulation and immersed independently in 25 ml of artificial saliva and stored as five groups Group I-V. Each group was further divided into three sub Groups A, B, C. The saliva was changed every day in all the specimens. No treatment was carried out for the specimens in subgroup A. The specimens were immersed in 2% sodium fluoride for 1 min before changing saliva in sub group B and the specimens were treated by brushing with a fluoridated dentifrice for 2 min before changing saliva in sub Group C. The fluoride release was evaluated on the 1(st), 7(th) and 28(th) day using a fluoride ion specific electrode. RESULTS: The results demonstrated that the conventional glass ionomer and the recently introduced caries stabilizing glass ionomer showed similar patterns and quantity of fluoride release, which was significantly higher than the resin-modified glass ionomer, the compomer and the composite resin. The resin-modified glass ionomer showed higher fluoride release than the compomer and the composite resin. All the formulations of glass ionomers showed fluoride uptake from the neutral sodium fluoride and the fluoridated dentifrice, by releasing increased amounts of fluoride after treatment, in comparison with the untreated group. However, the compomer and the composite resin showed no fluoride uptake. CONCLUSION: The fluoride released by the glass ionomer cements (GICs) was found to be highest during the first 24 h and decreased significantly over the 1(st) week with lower levels obtained on the 7(th) and 28(th) day, thus demonstrating the phenomenon of "initial burst." The composite resin and compomer used in this study did not show this phenomenon of the initial burst. The resin-modified GICs released more fluoride than the compomer, and the composite resin. PMID- 25709359 TI - An Assessment of Oral Hygiene in 7-14-Year-Old Children undergoing Orthodontic Treatment. AB - BACKROUND: The study is focused on increased risk of dental plaque accumulation among the children undergoing orthodontic treatment in consideration of individual hygiene and dietary habits. MATERIALS AND METHODS: The study was conducted among 91 children aged 7-14 including 47 girls and 44 boys. The main objectives of the study were: API index, plaque pH, DMF index, proper hygiene and dietary habits. Statistical analysis was provided in Microsoft Office Exel spreadsheet and STATISTICA statistical software. RESULTS: The average API index among the children wearing removable appliance was 9 (SD = 13), and among children without appliances was 16 (SD = 21). DMF index for patients using appliances was 5 (SD = 3) and for those without appliances was 4 (SD = 2). The average plaque pH was 6 for children with appliances (SD = 0.9) and 6.2 without ones (SD = 0.3). CONCLUSION: In patients in whom there is a higher risk of dental plaque accumulating, correct oral hygiene supported with regular visits to the dentist is one of the best ways to control dental caries. In the fight against caries the most effective and only approach is to promote awareness of the problem, foster proper hygiene and nutritional habits, as well as educate children from a very young age in how to maintain proper oral hygiene. PMID- 25709360 TI - A comparative study of bio degradation of various orthodontic arch wires: an in vitro study. AB - BACKGROUND: Orthodontic wires are the corner stones of the science and art of orthodontics and they remain in the patient's mouth for a prolonged period of 18 24 months. It is but natural to expect that they will undergo some biodegradation when in the oral environment during that period. This study aims to compare the biodegradation characteristics of four different orthodontic wires, stainless steel, nickel titanium (NiTi), titanium molybdenum alloy (TMA), and copper NiTi and to assess whether these biodegradation products, are within acceptable limits. MATERIALS AND METHODS: This study involved the incubation of four different wires in artificial saliva and analyzing the amount of metal released from them at the end of a 28 days study period. The metals analyzed for where nickel, chromium, copper, cobalt, manganese, iron, molybdenum, and titanium. The artificial saliva was changed on days 7, 14, and 21 to prevent the saturation of metals in the artificial saliva. At the end of 28 days, these four samples of artificial saliva of each wire were mixed together and analyzed for the eight metals using an inductively coupled plasma spectroscope. RESULTS: The results showed only the release of nickel, chromium, and iron from stainless steel wire, nickel from NiTi wire, nickel, and chromium from copper NiTi and none from TMA wire. CONCLUSION: The metals released from arch wires are of such minute quantities to be of any biologic hazard. The amount of metals released is well within acceptable biocompatible limits. Though this study has analyzed the biodegradation of various orthodontic wires, orthodontic wires are never used alone in mechanotherapy. Orthodontic wires along with multiband appliance system with which it is always used and in combination with accessories like face bows may release more metals. PMID- 25709361 TI - Epidemiology and Relationships between CD4+ Counts and Oral Lesions among 50 Patients Infected with Human Immunodeficiency Virus. AB - BACKGROUND: The aim of this study was to evaluate the clinical lesions of human immunodeficiency virus (HIV)/acquired immune deficiency syndrome patients in the oral cavity, head and neck region and to determine their associations with level of immune suppression as measured by the CD4+ count. MATERIALS AND METHODS: In a descriptive cross-sectional study, 50 patients with a proven HIV infection were evaluated. Based on the clinical findings and CD4+ counts, the relationships between oral lesions and CD4+ cell count were investigated. RESULTS: The CD4+ count (cells/mm(3)) was <200, 200-500, and >500 in 32 cases (64%), 16 cases (32%) and 2 cases (4%) respectively, and the mean CD4+ count was 169.82 cells/mm(3) in males and 142.8 cells/mm(3) in females. All patients showed at least one oral manifestation. The most common oral lesion identified was pseudomembranous candidiasis accounting for 76% (38/50) followed by periodontal disease 34% (17/50), herpetic lesions and hairy leukoplakia 10% for each (5/50), gingivitis 8% (4/50), oral ulceration 8% (4/50), Kaposi's sarcoma 6% (3/50), and Non-Hodgkin lymphoma 2% (1/50). CONCLUSION: The CD4+ count was decreasing the presence, and the severity of oral lesions was increasing in this study. The presence of oral lesions may lead to a positive diagnostic of HIV. Disease progression is characterized by increased prevalence of some oral lesions as candidiasis, hairy leukoplakia, and Kaposi sarcoma. The severity of oral lesions was more pronounced with a CD4+ count <200 cells/mm(3). PMID- 25709362 TI - Patient receptivity to tobacco cessation counseling and services in a dental teaching institute: a patient review. AB - BACKGROUND: The dentists are in a unique position to render tobacco cessation counseling to their patients. The current study is set to assess the attitudes of tobacco users toward tobacco cessation counseling attending a dental teaching institute and hospital in Andhra Pradesh. MATERIALS AND METHODS: A systematic random sampling method was used to select the sample. Survey was conducted among 660 patients attending a dental teaching institute. Patients who have completed oral examination in the department of oral medicine and radiology were asked to complete pretested questionnaire. The questionnaire was designed in both English and Telugu (local language). RESULTS: Among the study subjects 88.9% were planning to quit the habit, 72.27% had agreed that they discussed about ill effects of tobacco, 82% of the subjects said that dentist should routinely offer quit tobacco assistance and services. CONCLUSION: The present study indicates the majority of patients are receptive towards tobacco counseling and services in the dental setting. In this study, the majority of tobacco users were planning to quit. Majority of patients were unaware of the resources available to help them to quit. Dentists have a significant opportunity to disseminate information to patients who need assistance in quitting the habit of tobacco usage. PMID- 25709363 TI - A Comparison of Parental Satisfaction in the Quality of their Child's Orthodontic Treatment by Orthodontists and Pedodontists. AB - BACKGROUND: The aim was to evaluate satisfaction of the parents of children who have undergone orthodontic treatment provided by their orthodontists and pediatric dentists in their private practice. MATERIALS AND METHODS: A total of 412 parents were interviewed with the help of a questionnaire containing information such as demographic part, experience of braces, motives for orthodontic treatment, complications faced during the procedure and reasoning for satisfaction. Student's t-test was applied to analyze the results. The level of significance was set at P = 0.05. RESULTS: A higher level of satisfaction was seen in parents of children treated by pedodontists (mean score of satisfaction = 0.752) when compared with those treated by orthodontists (mean score of satisfaction = 0.631) which was statistically significant. Parents of girl patients showed a higher mean score of satisfaction (1.021) when compared with those of boy patients (0.321), which was also statistically significant. CONCLUSION: It can be concluded that the pedodontists performed orthodontic treatment to a similar standard as orthodontists, in fact they proved to be better in terms of patient care and behavior management as the parental satisfaction in the quality of orthodontic care was more with pediatric dentists than with orthodontists in this study. PMID- 25709364 TI - Fluoride varnish effect on preventing dental caries in a sample of 3-6 years old children. AB - BACKGROUND: Early childhood caries is one of the most prevalent chronic diseases of children that affect their life and their family in different aspects. Using different types of fluoride is one of the most effective ways for preventing the disease. Fluoride varnish is a topical fluoride product which could use in the community even by non-professional. This study aimed to assess the effect of fluoride varnish on dental caries in a group of children aged 3-6 years old in Kerman kindergarten during 6 month's period. MATERIALS AND METHODS: This community interventional study recruited a sample of volunteer children from 12 kindergartens through a cluster sampling. Kindergarten randomly allocated to test and control group after matching. Dental examination was performed in three phases of the study by a trained dentist using criteria of Intentional Caries Detection and Assessment System. Fluoride varnish was applied for test group in the first phase after dental examination and also 3 and 6 months after this phase. Control group has received varnish product just after 3 and 6 months after the first dental exam. Mean decayed, missed and filled teeth (dmft) were compared between and within groups using T-test. RESULTS: From 476 children who participated in the study 55% were boys and the 6 years group was the most frequent group with 35% (166). Mean dmft difference was significant between Phase 1 and 2 (P = 0.05) in the test group but there was no significant difference between Phase 2 and 3 (P = 0.07). The difference was not significant between Phase 1 and 2 (P = 0.09) but it was significant between Phase 1 and 3 (P = 0.03) in the control group. CONCLUSION: The study results showed a decrease in mean dmft after applying the fluoride varnish which confirms previous studies. PMID- 25709365 TI - Knowledge, Attitude and Practice of Paediatricians toward Long-Term Liquid Medicaments Associated Oral Health. AB - BACKGROUND: A pediatrician is a primary care physician who deals with the medical care of infants, children and adolescents. Oral health care for the subgroups detailed is certainly substantiated as an integral part of general health. There are conflicting results presented till date on the subject of knowledge, attitude and practice (KAP) of pediatricians on the consumption of pediatric liquid medicaments and the results can be divergent based on the geographical adjustments specifically with significance for industrial areas. Hence, the present study was carried out to evaluate the KAP of pediatricians toward oral health of children taking long-term pediatric liquid medicaments in Pimpri Chinchwad area deemed and identified as Asia's largest industrial area. MATERIALS AND METHODS: A questionnaire was distributed among 50 pediatriacians practicing in Pimpri-Chinchwad, Pune city area, which consisted of questions seeking knowledge of pediatricians regarding awareness of detrimental effects of long term pediatricians toward long-term liquid medicaments use on oral cavity, including delivery of oral hygiene instructions and regular dental checkup. The results as obtained were subjected to statistical analysis using SPSS version 16.0 for windows (Chicago Inc., USA). The statistical significance of difference was tested using Chi-square test for independence of attributes. RESULTS: About 68% were aware that long-term use of pediatric liquid medicaments can cause tooth structure defects. But only 58% advised regular dental checkups for these patients. 50% of the pediatricians prescribed the liquid medications to be taken in between two meals and 74% of the pediatricians advised rinsing mouth with water immediately after consuming pediatric liquid medicaments. However, there was no statistically significant difference seen among the values observed. CONCLUSION: The pediatricians showed reasonable awareness regarding the ill effects of the long-term use of pediatric liquid medicaments and took precautions regarding the same. However, proper oral hygiene maintenance instructions were lacking as a skill in their offerings. PMID- 25709366 TI - Apoptotic index and proliferative index in premalignant and malignant squamous cell lesions of the oral cavity. AB - BACKGROUND: Oral squamous cell lesions are most commonly diagnosed lesions in India. Both premalignant and malignant lesions are frequently encountered. In this study, we evaluated the role and significance of apoptotic indices (AI) and proliferative indices (PI) in premalignant and malignant squamous cell lesions of the oral cavity. MATERIALS AND METHODS: A total of 62 histologically proven cases of premalignant and malignant oral squamous cell lesions were analyzed. The biopsies were stained with hematoxylin and eosin and also with monoclonal antibody Ki-67. AI and PI were assessed using a light microscope. RESULTS: AI was found to increase gradually from normal to dysplasia to carcinoma. The highest AI was seen in well-differentiated squamous cell carcinomas (SCCs). PI also was found to increase significantly from normal to dysplasia to carcinoma. The highest PI was seen in poorly differentiated SCC. CONCLUSION: AI in conjunction with the PI offers an accurate idea as to the nature and course of the lesion and may help to plan timely surgical intervention that results in better clinical prognosis and outcome. PMID- 25709367 TI - Association of Periodontal Health with Orthodontic Appliances among Indian Patients. AB - BACKGROUND: To assess the association of periodontal status of the patients with and without orthodontic treatment. MATERIALS AND METHODS: This cross-sectional study was conducted among 520 patients (220 undergoing orthodontic procedure and 300 non-orthodontic patients). Periodontal health status was assessed using community periodontal index and loss of attachment. Data were analyzed using SPSS version 16 and level of significance used was 5% level. RESULT: Overall mean number of segments for bleeding component (Score 1) was 0.86 +/- 0.708, that of calculus (Score 2) 0.30 +/- 0.460, for shallow pockets (4-5 mm) (Score 3) 0.33 +/ 0.744 and for deep pockets (6 mm or more) (Score 4) 0.38 +/- 0.476. Patients with orthodontic appliances had poor periodontal status than the non-orthodontic patients (P < 0.05). CONCLUSION: Patients undergoing orthodontic treatment have increased the level of periodontal status as it leads to more retention of food debris. Hence, these patients should be motivated to maintain good oral hygiene. PMID- 25709368 TI - Evaluation and Comparison of Vascular Endothelial Growth Factor Expression between Ameloblastoma and Keratocystic Odontogenic Tumor. AB - BACKGROUND: Odontogenic keratocyst (OKC) is a developmental odontogenic cyst with an aggressive clinical behavior suggesting a change in its terminology from a cyst to a tumor and has now been renamed as keratocystic odontogenic tumor (KCOT). The purpose of this study was to assess and compare angiogenesis in ameloblastoma and OKC. MATERIALS AND METHODS: Angiogenesis was assessed by studying the immunohistochemical expression of vascular endothelial growth factor (VEGF). The study samples included 15 ameloblastomas and 15 KCOTs. The immunoreactivity was statistically evaluated using Mann-Whitney U-test. RESULTS: VEGF expression was higher in ameloblastoma than KCOTs. However, a non significant difference of VEGF expression was noted between ameloblastoma and KCOTs (P = 0.345). CONCLUSION: The results suggest that tumor angiogenesis may play a significant role in aggressive biologic behavior of KCOT. Thus, angiogenesis could be a potent target for developing anatiangiogenic therapeutic strategies. PMID- 25709369 TI - Evaluation of bacterial contamination in a clinical environment. AB - BACKGROUND: Although the contamination of the dental environment and personnel through aerosol contamination is a definite source of cross contamination; there is little data on the microbial involvement of the dental environment. MATERIALS AND METHODS: A total of 100 samples were taken from various inanimate surfaces in the clinical dental setting were collected aseptically by rotating sterile swabs moistened with peptone water over the surfaces of the samples and then inoculated into brain heart infusion broth and incubated at 37 degrees C aerobically overnight. Subcultures were made on 5% sheep blood agar and MacConkey agar plates and incubated at 37 degrees C for 24 h. Growth in the plates was observed. RESULTS: Out of the 100 samples screened in this study, a bacterial agent was observed in 38 samples, and 62 samples showed no growth. A higher percentage of contamination was seen on the dental chair light handles, suction tips and the pens used by the dental health care personnel's, followed by the instruments and the laboratory equipment. CONCLUSION: Establishing an effective preventive strategies for well-practiced infection control is essential to prevent nosocomial infections and promote a safe environment in the dental clinics. PMID- 25709370 TI - Diagnostic and surgical aspects of central hemangioma of mandible: a surgical approach for the reconstruction of mandible. AB - Intraosseous vascular lesions are rare lesions, accounting for 0.5-1% of all intraosseous tumors. They were found to be affecting the second decade of life, more frequent in women. The frequency found affecting the vertebral column and skull; the mandible is a quite rare location. At present, according to the World Health Organization, these lesions are now considered as benign vasoformative neoplasms of endothelial origin. However, the origin of the central hemangioma is debatable. Some authors state it as a true neoplasm, few state it is a hamartoma. On examination, the patient may or may not show any symptoms, some present discomfort, blood discharge, bluish discoloration, mobility of the teeth. The radiographic finding is a multilocular radiolucenies with classic honeycombs or soap bubble appearance. Differential diagnosis includes odontogenic lesions like ameloblastoma, cystic lesions such as residual cyst, central giant cell tumor, fibrous dysplasia. The wide surgical excision along with the reconstruction is choice of treatment of hemangioma. We present a case report of a 24-year-old female diagnosed with intraosseous mandibular hemangioma and surgical reconstruction of mandible with rib graft. PMID- 25709371 TI - Fistulectomy of the parotid fistula secondary to suppurative parotitis: a case report. AB - A parotid fistula is a communication between the skin and a parotid duct or gland through which saliva is discharged. The most common cause of the parotid fistula is trauma. The major causes of parotid trauma in a civilian practice are penetrating injury to the parotid gland from an assault weapon or injury due to shattered glass after a motor vehicle accident. Acute suppurative parotitis can rarely produce a parotid fistula, and it will be difficult to manage successfully. In this article we have described diagnosis by fistulography, meticulous dissection, and complete excision of the fistulous tract with layered closure of the parotid fascia followed by application of a post-operative pressure bandage, use of anticholinergic agents and antibiotics contribute significantly to the successful management of this difficult clinical condition. PMID- 25709372 TI - Molluscum contagiosum in a 12-year-old child - report of a case and review of literature. AB - Molluscum contagiosum (MC) is an infection of the skin and mucous membrane caused by a DNA virus from the poxvirus family. It usually affects any part of the body and presents as pearly, flesh colored dome shaped nodule with a central umbilication. Clinical diagnosis can be supplemented with histopathology for the confirmed diagnosis of MC. This article presents a case of 12-year-old male child afflicted with MC along with a review of the literature on MC. PMID- 25709373 TI - Quorum sensing inhibition, relevance to periodontics. AB - Quorum sensing helps bacteria to communicate with each other and in coordinating their behavior. Many diseases of human beings, plants, and animals are mediated by quorum sensing. Various approaches are being tried to inhibit this communication to control the diseases caused by bacteria. Periodontal pathogens also communicate through quorum sensing and new approaches to treat periodontal disease using quorum sensing inhibition need to explored. PMID- 25709374 TI - Effect of mobile phone radiations on oral health. PMID- 25709375 TI - Early Numeracy Assessment: The Development of the Preschool Numeracy Scales. AB - RESEARCH FINDINGS: The focus of this study was to construct and validate twelve brief early numeracy assessment tasks that measure the skills and concepts identified as key to early mathematics development by the National Council of Teachers of Mathematics (2006) and the National Mathematics Advisory Panel (2008) as well as critical developmental precursors to later mathematics skill by the Common Core State Standards (CCSS; 2010). Participants were 393 preschool children ages 3 to 5 years old. Measure development and validation occurred through three analytic phases designed to ensure that the measures were brief, reliable, and valid. These measures included: one-to-one counting, cardinality, counting subsets, subitizing, number comparison, set comparison, number order, numeral identification, set-to-numerals, story problems, number combinations, and verbal counting. PRACTICE OR POLICY: Teachers have extensive demands on their time, yet, they are tasked with ensuring that all students' academic needs are met. To identify individual instructional needs and measure progress, they need to be able to efficiently assess children's numeracy skills. The measures developed in this study are not only reliable and valid, but also easy to use and can be utilized for measuring the effects of targeted instruction on individual numeracy skills. PMID- 25709376 TI - Synthesis of novel spin-labeled podophyllotoxin derivatives as potential antineoplastic agents: Part XXV. AB - A series of novel spin-labeled 4beta-[(4-substituted)-1,2,3-triazol-1 yl]podophyllotoxin derivatives (17a-h) were firstly designed and synthesized with significant regioselectivity by employing Cu(I) catalyzed click approach, and evaluated for cytotoxicity against four human tumor cell lines (A-549, DU145, KB, and KBvin). Among them, compound 17h displayed the highest cytotoxic activity against the tumor cell lines tested. Significantly, compound 17h showed superior cytotoxic activity compared with etoposide (IC50 6.30 to>10 MUM), a clinically available anticancer drug. Significant activity toward the drug resistant KBvin cell line revealed promising future for compound 17h as a new generation of epipodophyllotoxin-derived antitumor clinical trial candidate. PMID- 25709377 TI - Myology: the passion of a lifetime. PMID- 25709378 TI - Mitochondrial disease heterogeneity: a prognostic challenge. AB - Mitochondrial diseases are a heterogeneous group of progressive, genetically transmitted, multisystem disorders caused by impaired mitochondrial function. The disease course for individuals with mitochondrial myopathies varies greatly from patient to patient because disease progression largely depends on the type of disease and on the degree of involvement of various organs which makes the prognosis unpredictable both within the same family and among families with the same mutation. This is particularly, but not exclusively, true for mitochondrial disorders caused by mtDNA point mutations, which are maternally inherited and subject to the randomness of the heteroplasmy. For this reason, the prognosis cannot be given by single mitochondrial disease, but should be formulated by any single mitochondrial disease-related event or complication keeping in mind that early recognition and treatment of symptoms are crucial for the prognosis. The following approach can help prevent severe organ dysfunctions or at least allow early diagnosis and treatment of disease-related complications. PMID- 25709379 TI - Far field R-wave sensing in Myotonic Dystrophy type 1: right atrial appendage versus Bachmann's bundle region lead placement. AB - Aim of the present study was to investigate far field R-wave sensing (FFRS) timing and characteristics in 34 Myotonic Dystrophy type 1 (DM1) patients undergoing dual chamber pacemaker implantation, comparing Bachmann's bundle (BB) stimulation (16 patients) site with the conventional right atrial appendage (RAA) pacing site (18 patients). All measurements were done during sinus rhythm and in supine position, with unipolar (UP) and bipolar (BP) sensing configuration. The presence, amplitude threshold (FFRS trsh) and FFRS timing were determined. There were no differences between both atrial sites in the Pmin and Pmean values of sensed P-wave amplitudes, as well as between UP and BP sensing configurations. The FFRS trsh was lower at the BB region in comparison to the RAA site. The mean BP FFRS trsh was significantly lower than UP configuration in both atrial locations. There were no significant differences in atrial pacing threshold, sensing threshold and atrial lead impedances at the implant time and at FFRS measurements. Bachmann's bundle area is an optimal atrial lead position for signal sensing as well as conventional RAA, but it offers the advantage of reducing the oversensing of R-wave on the atrial lead, thus improving functioning of standard dual chamber pacemakers in DM1 patients. PMID- 25709380 TI - Sleep breathing disorders and nocturnal respiratory pattern in patients with glycogenosis type II. AB - Patients affected by glycogenosis type II frequently present sleep disordered breathing. The presence of symptoms suggestive of sleep breathing disorders was investigated, by a questionnaire, in 10 patients, affected by adult or juvenile forms of glycogenosis type II. Diurnal respiratory function, diaphragm weakness and nocturnal respiratory pattern were evaluated at the enrolment. In patients presenting sleep disordered breathing, the same parameters were re-evaluated after treatment with assisted non invasive ventilation. Out of 10 patients, 5 presented symptoms suggestive of sleep-disordered breathing at the baseline, 2 a pattern of sleep apnea syndrome and 3 nocturnal hypoventilation. All patients presented diaphragmatic weakness. No correlation was found between forced vital capacity values (FVC) in sit position and nocturnal respiratory disorders. Five patients with respiratory disorders were treated with non invasive ventilation. All patients - after one month of treatment - showed an improvement in symptoms with reduced diurnal hypersomnia (ESS < 10), absence of morning headaches and nocturnal awakenings, and reduced nicturia regardless the modality of ventilation. We recommend that all patients with glycogenosis type II, once diagnosed, are carefully monitored for the development of respiratory involvement, even in the absence of reduced FVC values and in the early stages of the disease, to receive appropriate therapy. PMID- 25709381 TI - Adenosine-induced sinus tachycardia in a patient with Myotonic Dystrophy type 1. AB - We report the case of a 32-year-old man with Myotonic Dystrophy type 1 showing adenosine-induced sinus tachycardia during transesophageal electrophysiological evaluation. PMID- 25709382 TI - GNE myopathy: a personal trip from bedside observation to therapeutic trials. AB - The trip is not over yet as definite therapy for GNE myopathy is not yet available. Also the exact mechanisms by which GNE defects lead to isolated muscle disease in humans are not fully recognized. But in the Gaetano Conte lecture of 2013 I have tried to describe how much a progress was made in several research laboratories and clinical institutes in the investigation of this unique myopathy. PMID- 25709383 TI - How we developed, at the Centre/Institute for Neuromuscular Diseases, differential diagnostics of Spinal Muscle Atrophies / Amyotrophic Lateral Sclerosis (SMA/ALS) and tried to influence the development of the disease. AB - In our research, we placed the emphasis on delimiting fatal diseases against those that have some similar symptoms, but can be improved, even completely cured. More often we succeeded in differentiating the local compressive factor. In our search for early symptoms, we also found physiological, although quite unusual EMG phenomena. High amplitude neural potentials confirmed the malignant disease diagnosis. The spinal angiography discovered arterial pathology, while CT demonstrated localised hydromyelia. Amyotrophic syndromes caused by chronic led intoxications represented a separate group. Patients would recover significantly on d-penicillamine. We applied it successfully in amyotrophic syndromes with laboratory confirmed copper metabolism disorders. A very significant therapeutic effect was obtained in a patient with SMA without similar laboratory, even in recidivism. Exceptionally, we were able to achieve significant remission with corticosteroids, too. The remaining patients, differentiated as certainly fatal, represented a separate group. We tried to elaborate the special psychosocial and ethical problems connected with its outcome in "round table discussions". The first one was in 1989, at the workshop with King Engel, and the second in 1990, on the Fourth Yugoslav Symposium on Neuromuscular Diseases. In 1990, I visited Cicely Saunders and the St. Christopher's hospice in London, and in 1994 I started to organised hospice movement in Croatia. PMID- 25709384 TI - An evaluation of RetaineTM ophthalmic emulsion in the management of tear film stability and ocular surface staining in patients diagnosed with dry eye. AB - A single-center, open-label study consisting of two visits over the course of approximately 2 weeks was conducted to evaluate the efficacy of RetaineTM ophthalmic emulsion in improving the signs and symptoms of dry eye. Forty-two subjects were enrolled and received 1-2 drops twice daily of RetaineTM beginning at the first visit (day 1) and ending at the second visit. Subjects were instructed to complete a symptomatology diary twice daily prior to drop instillation through the morning of the second visit. Ocular sign and symptom assessments, visual acuity procedures, and comfort assessments were conducted during both visits. A statistically significant reduction was observed in mean breakup area on the second visit between the predose time and the postdose time (P=0.026). On the second visit, subjects had significantly less corneal fluorescein staining in the superior (P=0.002), central (P=0.017), corneal sum (P=0.011), and all ocular regions combined (P=0.038) than on the first visit. On the second visit, statistically significant reductions in dryness (P<0.001), grittiness (P=0.0217), ocular discomfort (P=0.0017), and all symptoms (P<0.001) were also seen as measured by the Ora CalibraTM Ocular Discomfort and 4-Symptom Questionnaire (0-5 scale). Subjects reported a statistically significant improvement in their abilities to work with a computer at night (P=0.044). Mean drop comfort scores ranged from 1.29-1.81 on the Ora CalibraTM 0-10 Drop Comfort Scale, on which 0 is very comfortable and 10 is very uncomfortable. RetaineTM demonstrates promising results as a novel artificial tear option for individuals suffering from dry eye. The unique mechanism of action of RetaineTM provides enhanced comfort and improves the quality of life of dry eye subjects while reducing the ocular signs of dry eye. PMID- 25709385 TI - Color light-emitting diode reflection topography: validation of keratometric repeatability in a large sample of wide cylindrical-range corneas. AB - PURPOSE: To investigate repeatability of steep and flat keratometry measurements, as well as astigmatism axis in cohorts with normal range and regular astigmatic such as: eyes following laser-assisted in situ keratomileusis (LASIK) and normal population, as well as cohorts of high and irregular astigmatism such as keratoconic eyes, and keratoconic eyes following corneal collagen cross-linking, employing a novel corneal reflection topography device. METHODS: Steep and flat keratometry and astigmatism axis measurement repeatability was investigated employing a novel multicolored-spot reflection topographer (Cassini) in four study groups, namely a post myopic LASIK-treated Group A, a keratoconus Group B, a post-CXL keratoconus Group C, and a control Group D of routine healthy patients. Three separate, maps were obtained employing the Cassini, enabling investigation of the intra-individual repeatability by standard deviation. Additionally we investigated in all groups,the Klyce surface irregularity indices for keratoconus, the SAI (surface asymmetry index) and the SRI (surface regularity index). RESULTS: Flat keratometry repeatability was 0.74+/-0.89 (0.03 to 5.26) diopters (D) in the LASIK Group A, 0.88+/-1.45 (range minimum to maximum, 0.00 to 7.84) D in the keratoconic Group B, and 0.71+/-0.94 (0.02 to 6.23) D in the cross-linked Group C. The control Group D had flat keratometry repeatability 0.36+/-0.46 (0.00 to 2.71) D. Steep keratometry repeatability was 0.64+/-0.82 (0.01 to 4.81) D in the LASIK Group A, 0.89+/-1.22 (0.02 to 7.85) D in the keratoconic Group B, and 0.93+/-1.12 (0.04 to 5.93) D in the cross-linked Group C. The control Group D had steep keratometry repeatability 0.41+/-0.50 (0.00 to 3.51) D. Axis repeatability was 3.45+/-1.62 degrees (0.38 to 7.78 degrees ) for the LASIK Group A, 4.12+/-3.17 degrees (0.02 to 12.13 degrees ) for the keratoconic Group B, and 3.20+/-1.99 degrees (0.17 to 8.61 degrees ) for the cross-linked Group C. The control Group D had axis repeatability 2.16+/-1.39 degrees (0.05 to 5.86 degrees ). The SAI index measurement repeatability was 0.33+/-0.40 (0.01 to 2.31) in the post-LASIK Group A, 0.39+/-0.75 (0.00 to 7.15) in the keratoconic Group B, and 0.43+/-0.56 (0.05 to 3.50) in the keratoconus post-CXL Group C. The control group had SAI measurement repeatability of 0.26+/ 0.30 (0.00 to 2.39). The SRI index repeatability was 0.22+/-0.17 (0.01 to 0.96) for post-LASIK Group A, 0.20+/-0.18 (0.00 to 1.07) in keratoconic Group B, and 0.13+/-0.09 (0.00 to 0.45) in the keratoconus post-CXL Group C. The control Group D had SRI measurement repeatability of 0.23+/-0.16 (0.00 to 0.75). CONCLUSION: This novel corneal topography device appears to offer very high specificity in estimating corneal keratometry and specific corneal irregularity indices, even in topographically challenging corneas such as LASIK treated, keratoconic, and cross linked. PMID- 25709386 TI - Vitreous flow rates through dual pneumatic cutters: effects of duty cycle and cut rate. AB - PURPOSE: We aimed to investigate effects of instrument settings on porcine vitreous flow rates through dual pneumatic high-speed vitrectomy probes. METHODS: The CONSTELLATION((r)) Vision System was tested with 250, 450, and 650 mmHg of vacuum using six ULTRAVIT((r)) vitrectomy probes of each diameter (25+((r)), 25, 23, and 20 gauge) operated from 500 cuts per minute (cpm) up to 5,000 cpm. Duty cycle modes tested included biased open, 50/50, and biased closed. Flow rates were calculated by assessing the change in weight of porcine eyes during vitreous aspiration. Volumetric flow rate was measured with a computer-connected electronic scale. RESULTS: At lower cut rates, the biased open mode produced higher flow than did the 50/50 mode, which produced higher flow than did the biased closed mode. In the biased closed and 50/50 modes, vitreous flow rates tended to increase with increasing cut rate. Vitreous flow rates in the biased open duty cycle mode remained relatively constant across cut rates. CONCLUSION: Vitreous flow rates through dual pneumatic vitrectomy probes could be manipulated by changing the duty cycle modes on the vitrectomy system. Differences in duty cycle behavior suggest that high-speed cut rates of 5,000 cpm may optimize vitreous aspiration. PMID- 25709387 TI - Simulation of airbag impact on eyes with different axial lengths after transsclerally fixated posterior chamber intraocular lens by using finite element analysis. AB - PURPOSE: To determine the biomechanical response of an impacting airbag on eyes with different axial lengths with transsclerally fixated posterior chamber intraocular lens (PC IOL). MATERIALS AND METHODS: Simulations in a model human eye were performed with a computer using a finite element analysis program created by Nihon, ESI Group. The airbag was set to be deployed at five different velocities and to impact on eyes with three different axial lengths. These eyes were set to have transsclerally fixated PC IOL by a 10-0 polypropylene possessing a tensile force limit of 0.16 N according to the United States Pharmacopeia XXII. RESULTS: The corneoscleral opening was observed at a speed of 40 m/second or more in all model eyes. Eyes with the longest axial length of 25.85 mm had the greatest extent of deformity at any given impact velocity. The impact force exceeded the tensile force of 10-0 polypropylene at an impact velocity of 60 m/second in all eyes, causing breakage of the suture. CONCLUSION: Eyes with transsclerally fixated PC IOL could rupture from airbag impact at high velocities. Eyes with long axial lengths experienced a greater deformity upon airbag impact due to a thinner eye wall. Further basic research on the biomechanical response for assessing eye injuries could help in developing a better airbag and in the further understanding of ocular traumas. PMID- 25709388 TI - Correlation between optic nerve involvement and chronic obstructive pulmonary disease. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a major public health problem worldwide. The aim of this study was to evaluate the rate of optic neuropathy in COPD patients. METHODS: Forty patients diagnosed with COPD and 60 healthy subjects as control group enrolled. After examination by a pulmonary subspecialist, patients were ranked by Global initiative for chronic Obstructive Lung Disease (GOLD) criteria, and patients with zero grades on GOLD criteria were excluded. Visual evoked potential by checkerboard (raster background) method with a frequency of 2 Hz were done for all participants. P-values less than 0.05 were considered as significant. RESULTS: Fifty-five percent of COPD patients had visual evoked potential abnormalities. Mean P100 latency in both eyes was significantly longer in COPD patients. Average P100/N140 amplitude in both eyes were insignificantly higher in COPD. CONCLUSION: Higher P100 latency in COPD patients shows demyelinating type of optic nerve involvement; however, further investigation in this area is needed. PMID- 25709389 TI - Opacification of hydrophilic intraocular lenses after Descemet stripping automated endothelial keratoplasty. AB - PURPOSE: Opacification of hydrophilic acrylic intraocular lenses (IOLs) is an emerging complication following Descemet stripping automated endothelial keratoplasty (DSAEK). We report six cases and review the current literature. METHODS: In this retrospective, noncomparative, observational case series, patients with IOL opacification after previous DSAEK surgery were identified from corneal clinic records. Case notes were reviewed for demographic details, indication for DSAEK, IOL model, incidence of rebubbling, and postoperative course. RESULTS: Six patients developed IOL opacification after DSAEK. All patients had Fuchs' endothelial dystrophy and had previously received hydrophilic acrylic IOL models. Central anterior IOL opacification was noted in all six cases. Five cases (83%) had required rebubbling due to dislocated graft tissue, and one had an early postoperative intraocular pressure (IOP) rise. Five cases (83%) were managed conservatively, and one case with a failed graft underwent redo DSAEK and IOL exchange. CONCLUSION: Repeated exposure to intracameral air, raised IOP, and other patient influences may be major etiological factors for IOL opacification after DSAEK. We advise avoiding hydrophilic acrylic IOL models in patients who may require future endothelial keratoplasty. PMID- 25709390 TI - Ophthalmology on social networking sites: an observational study of Facebook, Twitter, and LinkedIn. AB - BACKGROUND: The use of social media in ophthalmology remains largely unknown. Our aim was to evaluate the extent and involvement of ophthalmology journals, professional associations, trade publications, and patient advocacy and fundraising groups on social networking sites. METHODS: An archived list of 107 ophthalmology journals from SCImago, trade publications, professional ophthalmology associations, and patient advocacy organizations were searched for their presence on Facebook, Twitter, and LinkedIn. Activity and popularity of each account was quantified by using the number of "likes" on Facebook, the number of followers on Twitter, and members on LinkedIn. RESULTS: Of the 107 journals ranked by SCImago, 21.5% were present on Facebook and 18.7% were present on Twitter. Journal of Community Eye Health was the most popular on Facebook and JAMA Ophthalmology was most popular on Twitter. Among the 133 members of the International Council of Ophthalmology, 17.3% were present on Facebook, 12.8% were present on Twitter, and 7.5% were present on LinkedIn. The most popular on Facebook was the International Council of Ophthalmology, and the American Academy of Ophthalmology was most popular on Twitter and LinkedIn. Patient advocacy organizations were more popular on all sites compared with journals, professional association, and trade publications. Among the top ten most popular pages in each category, patient advocacy groups were most active followed by trade publications, professional associations, and journals. CONCLUSION: Patient advocacy groups lead the way in social networking followed by professional organizations and journals. Although some journals use social media, most have yet to engage its full potential and maximize the number of potential interested individuals. PMID- 25709391 TI - Keratopathy, cataract, and dry eye in a survey of aniridia subjects. AB - PURPOSE: To determine the prevalence of keratopathy, cataract, and dry eye in a group of individuals with aniridia. METHODS: We reviewed survey data from the Aniridia Foundation International (AFI) registry, which included 99 subjects who self-reported on corneal disease, cataract, and dry eye disease. RESULTS: The average age of respondents was 25.3+/-18.6 years, with a range of 0 to 67. Of 99 subjects, 46% stated they have corneal disease, 32% stated they did not, and 22% were unsure. The average age of diagnosis of keratopathy was 20.0+/-12.2 years. Keratolimbal allograft was reported in 20% and penetrating keratoplasty in 9%. Cataract was reported in 65%, with an average age of 9.4+/-14.0 years at time of diagnosis, and cataract surgery was reported in 32%. The average age of subjects at the time of cataract and corneal surgery was 28.4+/-13.7 and 33.5+/-11.4 years, respectively. Symptomatic dry eye was reported in 56% of subjects, with an average age at diagnosis of 23.8+/-13.3 years. CONCLUSION: There is a high prevalence of corneal disease in aniridia, with diagnosis in late childhood or early adulthood in nearly one-half of subjects, often requiring corneal surgery. Cataract and dry eye are commonly associated with aniridia. Although aniridia subjects may have been aware of the diagnosis of cataract at an early age, they usually were treated for cataract and keratopathy as adults. PMID- 25709392 TI - Widespread choroidal thickening and abnormal midperipheral fundus autofluorescence characterize exudative age-related macular degeneration with choroidal vascular hyperpermeability. AB - PURPOSE: To investigate the clinical findings that characterize exudative age related macular degeneration (AMD) with choroidal vascular hyperpermeability (CVH). DESIGN: Retrospective comparative study. PARTICIPANTS: Forty-eight consecutive patients attending the outpatient clinic of Tokyo University Hospital between May 2013 and July 2013. METHODS: The presence or absence of CVH was determined with indocyanine green angiography performed at the latest visit. When CVH was observed, the eye was categorized as CVH(+) AMD, otherwise it was categorized as CVH(-) AMD. Using high-penetration optical coherence tomography, we measured choroidal thickness at the fovea and at four midperipheral areas (mean choroidal thickness at points on 6- and 9-papilla diameter circles superior, inferior, temporal, and nasal to the fovea). Ultrawide field retinal imaging was used to investigate abnormalities in midperipheral fundus autofluorescence (FAF). Choroidal thickness and the proportion of FAF abnormalities were compared between the CVH(+) AMD and CVH(-) AMD eyes and between eyes with polypoidal choroidal vasculopathy and typical AMD. Multiple regression analysis was used to control for treatment history and other characteristics. RESULTS: CVH was observed in 17 cases. Choroidal thickness was higher in the CVH(+) AMD eyes than in the CVH(-) AMD eyes at the fovea (325 MUm versus 229 MUm, respectively; P=0.0010, t-test), superior point (277 MUm versus 215 MUm, respectively; P=0.0021, t-test), inferior point (225 MUm versus 161 MUm, respectively; P=0.0002, t-test), and nasal point (202 MUm versus 165 MUm, respectively; P=0.042, t-test). The significance was maintained after controlling for possible confounders. The choroid was thicker at the fovea and at the inferior point in polypoidal choroidal vasculopathy than in typical AMD. The rate of midperipheral FAF abnormality was significantly higher in the CVH(+) AMD eyes than in the CVH(-) AMD eyes (82% versus 48%, respectively; P=0.031). CONCLUSION: AMD with CVH is associated with widespread choroidal thickening and peripheral FAF abnormalities. PMID- 25709393 TI - Effects of laser in situ keratomileusis (LASIK) on corneal biomechanical measurements with the Corvis ST tonometer. AB - PURPOSE: This study was initiated to evaluate biomechanical changes using the Corvis ST tonometer (CST) on the cornea after laser in situ keratomileusis (LASIK). SETTING: University Medical Center Hamburg-Eppendorf, Germany, and Care Vision Refractive Centers, Germany. DESIGN: Retrospective cohort study. METHODS: This retrospective study included 37 eyes of 37 refractive patients. All CST measurements were performed 1 day before surgery and at the 1-month follow-up examination. The LASIK procedure included mechanical flap preparation using a Moria SBK microkeratome and an Allegretto excimer laser platform. RESULTS: Statistically significant differences were observed for mean first applanation length, mean first and second deflection lengths, mean first and second deflection amplitudes, radius of curvature, and peak distance. Significant positive correlations were found between the change (Delta) of radius of curvature and manifest refraction spherical equivalent (MRSE), ablation depth, and Deltaintraocular pressure as well as between AD and DeltaHC-time. Each diopter of myopic correction in MRSE resulted in an increase in Deltaradius of curvature of 0.2 mm. CONCLUSION: Several CST parameters were statistically significantly altered by LASIK, thereby indicating that flap creation, ablation, or both, significantly change the ability of the cornea to absorb or dissipate energy. PMID- 25709394 TI - Unilateral transient mydriasis and ptosis after botulinum toxin injection for a cosmetic procedure. AB - We report a case of unilateral transient mydriasis and ptosis after botulinum toxin injection applied by a medical doctor for a cosmetic procedure. A 36-year old nurse was referred to our eye clinic with unilateral mydriasis and ptosis in the right eye 3 days after botulinum toxin injection for a cosmetic procedure. Botulinum toxin was applied to her eye by a doctor at her hospital who was not an ophthalmologist. She was treated with topical apraclonidine 0.5% ophthalmic solution. Her ptosis decreased to 2 mm with apraclonidine and her visual axis improved. Mydriasis was present for 3 weeks and then disappeared. Mild ptosis continued for 3 months, then resolved completely. Patients seeking treatment with botulinum toxin A for cosmetic purposes should be warned about the possibility of ptosis and mydriasis after injection. If these side effects are seen, the patient must be referred to an ophthalmologist for appropriate management. PMID- 25709396 TI - Targeted photocoagulation of peripheral ischemia to treat rebound edema. AB - INTRODUCTION: Peripheral retinal ischemia not detectable by conventional fluorescein angiography has been proposed to be a driving force for rebound edema in retinal vein occlusions. In this report, we examine the treatment of peripheral retinal ischemia with targeted retinal photocoagulation (TRP) to manage a patient's rebound edema. METHODS: To assess the extent of peripheral nonperfusion, an Optos 200Tx device was used. To target the treatment to peripheral ischemia areas, a Navilas Panretinal Laser was used. RESULTS: A 64 year-old male with a central retinal vein occlusion and a visual acuity 20/300, and central macular thickness 318 MUm presented with rubeosis. Angiography revealed extensive peripheral nonperfusion. Despite TRP to areas of irreversible ischemia, after 2 months, he continued show rubeosis and rebound edema. Additional TRP laser was repeatedly added more posteriorly to areas of reversible nonperfusion, resulting in eventual resolution of rubeosis and edema. CONCLUSION: In this study, we demonstrate the use of widefield imaging with targeted photo coagulation of peripheral ischemia to treat rebound edema, while preserving most peripheral vision. In order to treat rebound edema, extensive TRP, across reversible and nonreversible areas of ischemia, had to be performed - not just in areas of nonreversible peripheral ischemia. These areas need to be mapped during episodes of rebound edema, when ischemia is at its maximum. In this way, by doing the most TRP possible, the cycle of rebound edema can be broken. PMID- 25709395 TI - Incidence of bleb-associated endophthalmitis in the United States. AB - PURPOSE: To evaluate the 5-year incidence rate of blebitis and bleb-associated endophthalmitis in the United States. METHODS: In this retrospective cross sectional study, we utilized a large commercial health insurance claim-based database during 2007-2011 and identified all patients who had a record of trabeculectomy in 2007. These patients were followed until the end of 2011. During the follow-up period, all incidences of blebitis, confirmed bleb associated endophthalmitis, and presumed bleb-associated endophthalmitis were recorded. Kaplan-Meier survival analysis was utilized to calculate 5-year cumulative incidence rates of blebitis and bleb-associated endophthalmitis following trabeculectomy procedures. RESULTS: Among the 1,461 trabeculectomies included in our analysis, eight cases of blebitis, five cases of confirmed bleb associated endophthalmitis, and eight cases of presumed bleb-associated endophthalmitis were identified. We found that the 5-year cumulative incidence of blebitis was 0.55%+/-0.19%. The 5-year cumulative incidence of bleb-associated endophthalmitis was 0.45%+/-0.2% when only confirmed cases were included and 1.3%+/-0.34% when presumed cases were also added to the analysis. The mean time from procedure to diagnosis was 45 months for blebitis and 33 months for bleb associated endophthalmitis. CONCLUSION: Blebitis and bleb-related endophthalmitis are uncommon in the United States. The 5-year cumulative incidence was 0.55% for blebitis and 0.45%-1.3% for bleb-associated endophthalmitis. PMID- 25709397 TI - Scleral buckle hemorrhagic cyst masquerading as an orbital tumor. AB - We present a case of a 41-year-old man who was referred for evaluation of a choroidal tumor with a remote history of scleral buckle placement for traumatic retinal detachment. Ocular imaging, echography, and magnetic resonance imaging could not rule out a neoplastic process so the patient was taken for surgical exploration where a hemorrhagic cyst was discovered. This is the first case in the literature of a silicone scleral buckle-associated hemorrhagic cyst presenting as orbital mass. PMID- 25709398 TI - Apparent histological changes of adipocytes after treatment with CL 316,243, a beta-3-adrenergic receptor agonist. AB - BACKGROUND AND OBJECTIVES: The objective of this experiment was to study the effect of CL 316,243 (CL) (a highly selective beta3-adrenergic receptor agonist) on cellular changes occurring in retroperitoneal white adipose tissue (RWAT) of lean and obese rats. METHODS: Ten-month-old lean and obese Zucker rats were implanted subcutaneously with osmotic mini-pumps, infusing either saline or CL (1 mg/kg body weight/day) for 4 weeks. RESULTS: There was no effect of CL on food intake. However, the resting metabolic rate in lean and obese rats increased by 55% and 96% per rat, respectively. Total RWAT weight decreased in both lean and obese rats under influence of CL treatment by 65% and 38%, respectively. Total body weight and body fat were lower in CL treated rats. Detection of uncoupling protein 1 (UCP1) in RWAT was confirmed qualitatively by both immunohistochemistry and immunofluorescence using a rabbit anti rat UCP1 antibody which showed the appearance of a marked increase of this protein in the adipose tissue. Stained semi-thin sections (0.5 MUm) also demonstrated abundant nuclei in multilocular adipocytes, in endothelial cells associated with the vasculature, and in interstitial cells. In CL-treated obese rats, a clustering of several multilocular cells around the periphery of a white adipocyte was seen. CONCLUSION: These results indicate that treatment of both lean and obese Zucker rats with CL induces extensive remodeling of RWAT that includes shrinkage of white adipose tissue, appearance of abundant multilocular cells in RWAT together with the appearance of a marked increase of UCP, preferentially in lean rats. PMID- 25709399 TI - Clinical pharmacokinetics of AZD3199, an inhaled ultra-long-acting beta2 adrenoreceptor agonist (uLABA). AB - OBJECTIVE: The clinical pharmacokinetics of AZD3199, an ultra-long-acting beta2 agonist, were investigated in healthy volunteers and patients with asthma or chronic obstructive pulmonary disease (COPD). MATERIALS AND METHODS: Five studies are presented: one single ascending dose study in healthy Caucasian males; two multiple ascending dose studies in healthy males, one in Caucasians and one in Japanese; a Phase IIA asthma study; and a Phase IIB COPD study. Subjects received AZD3199 via a Spira nebulizer (Turbuhaler; equivalent delivered doses 5-3200 MUg) or Turbuhaler (single delivered doses of 120-1920 MUg or repeated delivered once daily doses 240-1,680 MUg). AZD3199 pharmacokinetics were assessed using total plasma concentration and urinary excretion, and tolerability using adverse events, clinical laboratory tests, and physical examinations. RESULTS: AZD3199 appeared rapidly in the systemic circulation following single and multiple dosing in healthy volunteers and patients (maximum plasma concentration within 30 minutes), with dose-proportional time-independent pharmacokinetics. Plasma exposure to unmetabolized drug was similar in healthy volunteers and patients with asthma, but relatively lower in patients with COPD. Estimated terminal half life was up to 142 hours in healthy Caucasian males. AZD3199 was well tolerated and showed no or at most mild systemic effects. CONCLUSION: AZD3199 plasma exposure in healthy volunteers and patients suggested linear pharmacokinetics and a long half-life. Systemic availability was similar in healthy subjects and patients with asthma, but was lower in patients with COPD. These clinical trials suggest that AZD3199 is well-tolerated in healthy male volunteers and patients, with no safety concerns identified to preclude further evaluation. PMID- 25709400 TI - Effect and mechanism of fluoxetine on electrophysiology in vivo in a rat model of postmyocardial infarction depression. AB - BACKGROUND: Major depression is diagnosed in 18% of patients following myocardial infarction (MI), and the antidepressant fluoxetine is shown to effectively decrease depressive symptoms and improve coronary heart disease prognosis. We observed the effect of fluoxetine on cardiac electrophysiology in vivo in a rat model of post-MI depression and the potential mechanism. METHODS AND RESULTS: Eighty adult male Sprague Dawley rats (200-250 g) were randomly assigned to five groups: normal control (control group), MI (MI group), depression (depression group), post-MI depression (model group), and post-MI depression treated with intragastric administration of 10 mg/kg fluoxetine (fluoxetine group). MI was induced by left anterior descending coronary artery ligation. Depression was developed by 4-week chronic mild stress (CMS). Behavior measurement was done before and during the experiment. Electrophysiology study in vivo and Western blot analysis were carried on after 4 weeks of CMS. After 4 weeks of CMS, depression-like behaviors were observed in the MI, depression, and model groups, and chronic fluoxetine administration could significantly improve those behaviors (P<0.05 vs model group). Fluoxetine significantly increased the ventricular fibrillation threshold compared with the model group (20.20+/-9.32 V vs 14.67+/ 1.85 V, P<0.05). Expression of Kv4.2 was significantly reduced by 29%+/-12%, 24%+/-6%, and 41%+/-15%, respectively, in the MI group, CMS group, and model group, which could be improved by fluoxetine (30%+/-9%). But fluoxetine showed no improvement on the MI-induced loss of Cx43. CONCLUSION: The susceptibility to ventricular arrhythmias was increased in depression and post-MI depression rats, and fluoxetine may reduce the incidence of ventricular arrhythmia in post-MI depression rats and thus improve the prognosis. This may be related in part to the upregulation of Kv4.2 by fluoxetine. PMID- 25709401 TI - The role of dasatinib in the management of chronic myeloid leukemia. AB - Dasatinib is a second-generation tyrosine kinase inhibitor (TKI) for chronic, blastic, or accelerated phase chronic myeloid leukemia (CML) patients who are resistant or intolerant to previous treatment. It potently inhibits BCR/ABL and SRC-family kinases (SRC, LCK, HCK, YES, FYN, FGR, BLK, LYN, FRK), as well as c KIT, PDGFR-a and -b, and ephrin receptor kinase. Various clinical trials have provided evidence that it has more durable complete hematologic and cytogenetic responses, as well as more potency in imatinib-resistant or -intolerant CML, and it has also shown its advantages in newly diagnosed CML compared to imatinib. In this review, we mainly focus on the structure, mechanisms, pharmacokinetics, and pharmacogenetics of dasatinib. We also summarize clinical trials with dasatinib on CML and provide our recommendations for dasatinib in the treatment of CML. PMID- 25709402 TI - Clinical utility of eslicarbazepine: current evidence. AB - Eslicarbazepine acetate (ESL) is a new antiepileptic drug whose mechanism of action is blockade of the voltage-gated sodium channel (VGSC). However, in respect to carbamazepine and oxcarbazepine, the active ESL metabolite (eslicarbazepine) affects slow inactivation of VGSC and has a similar affinity for the inactivated state and a lower affinity for the resting state of the channel. This new antiepileptic drug has been recently approved in Europe (trade name Zebinix) and in the United States (trade name Stedesa) for adjunctive treatment in adult subjects with partial-onset seizures, with or without secondary generalization. Following oral administration, ESL is rapidly and extensively metabolized by hepatic esterases to eslicarbazepine. This active metabolite has a linear pharmacokinetic profile, a low binding to plasma proteins (<40%), and a half-life of 20-24 hours and is mainly excreted by kidneys in an unchanged form or as glucuronide conjugates. ESL is administered once a day and has a low potential for drug-drug interactions. Efficacy and safety of this drug in patients with focal seizures have been assessed in four randomized clinical trials, and responder rates (percentage of patients with a >=50% improvement of their seizures) ranged between 17% and 43%. Adverse events were usually mild to moderate, and the most common were dizziness, somnolence, diplopia, abnormal coordination, blurred vision, vertigo, headache, fatigue, nausea, and vomiting. ESL may be considered an interesting alternative to current antiepileptic drugs for the treatment of drug-resistant focal epilepsies. Additionally, it is under investigation in children with focal epilepsies, in patients with newly diagnosed focal epilepsies, and also in other neurological and psychiatric disorders. PMID- 25709403 TI - Development of lovastatin-loaded poly(lactic acid) microspheres for sustained oral delivery: in vitro and ex vivo evaluation. AB - BACKGROUND: A novel lovastatin (LVT)-loaded poly(lactic acid) microsphere suitable for oral administration was developed in this study, and in vitro and in vivo characteristics were evaluated. METHODS: The designed microspheres were obtained by an improved emulsion-solvent evaporation method. The morphological examination, particle size, encapsulation ratio, drug loading, and in vitro release were characterized. Pharmacokinetics studies were used to show that microspheres possess more advantages than the conventional formulations. RESULTS: By using the emulsion-solvent evaporation method, it was simple to prepare microspheres and easy to scale up production. The morphology of formed microspheres showed a spherical shape with a smooth surface, without any particle aggregation. Mean size of the microspheres was 2.65+/-0.69 MUm; the encapsulation efficiency was 92.5%+/-3.6%, and drug loading was 16.7%+/-2.1%. In vitro release indicated that the LVT microspheres had a well-sustained release efficacy, and ex vivo studies showed that after LVT was loaded to microspheres, the area under the plasma concentration-time curve from zero to the last measurable plasma concentration point and the extrapolation to time infinity increased significantly, which represented 2.63-fold and 2.49-fold increases, respectively, compared to suspensions. The rate of ex vivo clearance was significantly reduced. CONCLUSION: This research proved that poly(lactic acid) microspheres can significantly prolong the drug circulation time in vivo and can also significantly increase the relative bioavailability of the drug. PMID- 25709404 TI - Efficacy and safety of a herbal mixture (Viron(r) tablets) in the treatment of patients with chronic hepatitis C virus infection: a prospective, randomized, open-label, proof-of-concept study. AB - BACKGROUND: Development of an optimal interferon-free regimen for chronic hepatitis C virus infection is believed to require the combination of different drug classes to provide good antiviral efficacy, clinical and quality of life benefits, as well as a high barrier to resistance. Viron((r)) is a new herbal drug in film-coated tablet form, and is based on a mixture of herbs with known hepatoprotective and antiviral properties. We conducted this study to explore the safety and the potential clinical and quality of life benefits of this product in patients with chronic hepatitis C infection. METHODS: Eighty-two consecutive patients presenting to our outpatient clinics as already-known or newly-diagnosed cases of chronic hepatitis C virus (HCV) infection, were entered into the study and randomized to three groups to receive escalating doses of Viron for 6 months. Virological, clinical, and enzyme responses, as well as quality of life index scores for chronic liver disease were compared between the groups. RESULTS: Of the 20 patients treated with the highest dose of Viron (three tablets twice daily), two (10%) had a complete virological response at the end of treatment (ETR) and two (10%) had a partial ETR, defined as a decrease in viral load of at least 2-log10 at the end of 6 months of treatment, whereas patients treated with the medium dose (two tablets twice daily) and the lowest dose (one tablet twice daily) showed a significantly lower ETR (P=0.043). Alanine aminotransferase levels and scores on the Chronic Liver Disease Questionnaire improved to a significantly greater extent in the highest dose group (P=0.007 and P=0.021, respectively). No serious adverse effects attributable to the herbal formulation were reported in any of the groups, apart from mild transient nausea, bloating, giddiness, and headache in two patients in the group receiving two tablets twice daily and in three patients in the group receiving three tablets twice daily. CONCLUSION: We conclude that this herbal formulation is potentially safe and may offer some added clinical and quality of life benefits when used in the treatment of patients with chronic hepatitis C virus infection. Larger studies could be warranted to evaluate the effects of using this formulation as an add-on therapy to an all-oral combination of a directly acting antiviral drug protocol in the treatment of chronic hepatitis C. PMID- 25709405 TI - Borreliacidal activity of Borrelia metal transporter A (BmtA) binding small molecules by manganese transport inhibition. AB - Borrelia burgdorferi, the causative agent of Lyme disease, utilizes manganese (Mn) for its various metabolic needs. We hypothesized that blocking Mn transporter could be a possible approach to inhibit metabolic activity of this pathogen and eliminate the infection. We used a combination of in silico protein structure prediction together with molecular docking to target the Borrelia metal transporter A (BmtA), a single known Mn transporter in Borrelia and screened libraries of FDA approved compounds that could potentially bind to the predicted BmtA structure with high affinity. Tricyclic antihistamines such as loratadine, desloratadine, and 3-hydroxydesloratadine as well as yohimbine and tadalafil demonstrated a tight binding to the in silico folded BmtA transporter. We, then, tested borreliacidal activity and dose response of the shortlisted compounds from this screen using a series of in vitro assays. Amongst the probed compounds, desloratadine exhibited potent borreliacidal activity in vitro at and above 78 MUg/mL (250 MUM). Borrelia treated with lethal doses of desloratadine exhibited a significant loss of intracellular Mn specifically and a severe structural damage to the bacterial cell wall. Our results support the possibility of developing a novel, targeted therapy to treat Lyme disease by targeting specific metabolic needs of Borrelia. PMID- 25709406 TI - Development of a test for recording both visual and auditory reaction times, potentially useful for future studies in patients on opioids therapy. AB - OBJECTIVE: Italian Road Law limits driving while undergoing treatment with certain kinds of medication. Here, we report the results of a test, run as a smartphone application (app), assessing auditory and visual reflexes in a sample of 300 drivers. The scope of the test is to provide both the police force and medication-taking drivers with a tool that can evaluate the individual's capacity to drive safely. METHODS: The test is run as an app for Apple iOS and Android mobile operating systems and facilitates four different reaction times to be assessed: simple visual and auditory reaction times and complex visual and auditory reaction times. Reference deciles were created for the test results obtained from a sample of 300 Italian subjects. Results lying within the first three deciles were considered as incompatible with safe driving capabilities. RESULTS: Performance is both age-related (r>0.5) and sex-related (female reaction times were significantly slower than those recorded for male subjects, P<0.05). Only 21% of the subjects were able to perform all four tests correctly. CONCLUSION: We developed and fine-tuned a test called Safedrive that measures visual and auditory reaction times through a smartphone mobile device; the scope of the test is two-fold: to provide a clinical tool for the assessment of the driving capacity of individuals taking pain relief medication; to promote the sense of social responsibility in drivers who are on medication and provide these individuals with a means of testing their own capacity to drive safely. PMID- 25709407 TI - Recent advances in combinatorial biosynthesis for drug discovery. AB - Because of extraordinary structural diversity and broad biological activities, natural products have played a significant role in drug discovery. These therapeutically important secondary metabolites are assembled and modified by dedicated biosynthetic pathways in their host living organisms. Traditionally, chemists have attempted to synthesize natural product analogs that are important sources of new drugs. However, the extraordinary structural complexity of natural products sometimes makes it challenging for traditional chemical synthesis, which usually involves multiple steps, harsh conditions, toxic organic solvents, and byproduct wastes. In contrast, combinatorial biosynthesis exploits substrate promiscuity and employs engineered enzymes and pathways to produce novel "unnatural" natural products, substantially expanding the structural diversity of natural products with potential pharmaceutical value. Thus, combinatorial biosynthesis provides an environmentally friendly way to produce natural product analogs. Efficient expression of the combinatorial biosynthetic pathway in genetically tractable heterologous hosts can increase the titer of the compound, eventually resulting in less expensive drugs. In this review, we will discuss three major strategies for combinatorial biosynthesis: 1) precursor-directed biosynthesis; 2) enzyme-level modification, which includes swapping of the entire domains, modules and subunits, site-specific mutagenesis, and directed evolution; 3) pathway-level recombination. Recent examples of combinatorial biosynthesis employing these strategies will also be highlighted in this review. PMID- 25709409 TI - Assessment of selected quality fields of nursing care in neurosurgical wards. PMID- 25709408 TI - In vivo determination of the diclofenac skin reservoir: comparison between passive, occlusive, and iontophoretic application. AB - AIM: There is scarce information concerning the pharmacodynamic behavior of topical substances used in the physiotherapy setting. The aim of the present study was to estimate the formation and emptying of the diclofenac (DF) skin reservoir after passive, semiocclusive, and electrically assisted applications of DF. SUBJECTS AND METHODS: Five different groups of healthy volunteers (ntotal=60, 23 male and 37 female), participated in this study. A 1% DF (Voltaren Emulgel) formulation (12 mg) was applied on the volar forearms on randomized defined circular skin areas of 7 cm(2). DF was applied for 20 minutes under three different conditions at the same time. The presence of DF in the skin results in a reduction of the methyl nicotinate (MN) response. To estimate the bioavailability of DF in the skin, MN responses at different times following initial DF application (1.5, 6, 24, 32, 48, 72, 96, and 120 hours) were analyzed. RESULTS: At 1.5 hours after the initial DF application, a significant decrease in MN response was detected for the occluded and iontophoretic delivery. Passive application resulted in a decrease of the MN response from 6 hours post-DF application. The inhibition remained up to 32 hours post-DF application for the iontophoretic delivery, 48 hours for the occluded application, and 72 hours for the passive delivery. At 96 and 120 hours post-DF application none of the MN responses was inhibited. CONCLUSION: The formation and emptying of a DF skin reservoir was found to be dependent on the DF-application mode. Penetration enhanced delivery resulted in a faster emptying of the reservoir. PMID- 25709410 TI - Motivation of adult female patients seeking orthodontic treatment: an application of Q-methodology. AB - BACKGROUND: Motivation is the impetus for patients to seek orthodontic treatment, affecting adherence, treatment outcomes, and satisfaction. The aim of this study was to assess the motivation of adult female patients seeking orthodontic treatment, and classify the patients according to their motivations. METHODS: This study used Q-methodology as the main tool. Q-samples were collected and categorized (35 items). Forty-two adult female patients were interviewed before treatment as the P-sample, and their responses were categorized into the Q methodology grid. Participants were asked to rank-order a set of 35 statements (Q sample) from "agree most" to "disagree most" (Q-sorting). The finished Q-grids were analyzed using PQ method 2.35. RESULTS: Four main factors were identified based on how adult female patients ranked statements: factor 1, patients who focus on their self-perception of their appearance; factor 2, patients who are concerned about the esthetics and function of their teeth; factor 3, patients who are easily influenced by others; factor 4, patients who want to improve their confidence and avoid negative thoughts caused by their teeth. The remaining patients who had other views did not match any of the above four groups. CONCLUSION: The motivations of adult female patients seeking orthodontic treatment are complex. This study found that most adult female patients fell into one of four typical factor groups. Our findings may improve the adherence of adult female patients by developing a more ideal treatment program. PMID- 25709411 TI - Patients' satisfaction and prevalence of complications on surgical extraction of third molar. AB - OBJECTIVES: To study patients' satisfaction and prevalence of complications in surgical extraction of impacted third molar by senior dentists and recently graduated dentists in a university dental clinic. METHOD: Patients who had impacted third molar extraction in a university dental clinic by two associate dentists who had <2 years of experience and two senior dentists who had >15 years of experience were evaluated in this study. Patients' age, sex, history of pericoronitis, tooth extracted, and radiographic assessment of the impacted tooth were recorded. Immediately after suture removal, the patients were invited to indicate their satisfaction on a Likert scale of 1-5. RESULTS: A total of 546 patients received extraction, and 251 patients were operated by associate dentists. Patient satisfaction was higher among those who had noncomplicated surgery (P=0.007), short treatment time (P<0.001), and had no postsurgical emergency appointments (P<0.001). The prevalence of seeking postsurgical emergency appointments was 9.2%. The reasons were severe pain (4.8%), swelling (2.6%), bleeding (2.4%), alveolar osteitis (0.9%), paresthesia (0.9), and trismus (0.5%). The prevalence of postsurgical complication(s) in associate dentists and senior dentists was 11.6% and 7.1%, respectively (P=0.050). The mean satisfaction scores for associate dentists and senior dentists were 4.17 and 3.95, respectively (P=0.002). CONCLUSION: Although a higher rate of postsurgical complications was observed among the patients treated by the recently graduated dentists, their patients' satisfaction scores were higher than that of the senior dentists. Around 9% of patients attended postsurgical emergency appointments, and their common reason was severe pain. PMID- 25709412 TI - Teriflunomide for the treatment of relapsing-remitting multiple sclerosis: patient preference and adherence. AB - Multiple sclerosis (MS), a chronic demyelinating neuroinflammatory disease of the central nervous system, is the most common neurological disorder leading to disability in young adulthood. In the last 2 decades, numerous treatments for relapsing-remitting MS have been approved with eleven treatment options available worldwide. One of the determinants in treatment selection is disease activity in the individual patient. However, patient preferences play an increasingly major role in treatment decision making. With teriflunomide, a reversible inhibitor of the enzyme dihydroorotate dehydrogenase, a new oral therapeutic option, given once daily, has been approved within the last 2 years by the regulatory agencies. The current review focuses on characteristics of the drug relevant for patients' preferences in the treatment decision process in the light of the available medications. Perceiving and considering patients' preferences will have an effect on treatment adherence, which is known to be often low in MS patients. Teriflunomide-related adherence issues will also be discussed regarding mode of application, dosing, and potential side effects. PMID- 25709413 TI - Patronage of traditional bonesetters in Makurdi, north-central Nigeria. AB - BACKGROUND: Despite the numerous complications associated with traditional bonesetters' (TBS) practices, their patronage has remained high in developing countries. The aim was to study the reasons patients seek TBS treatment. METHODS: This was a descriptive hospital-based study of 120 patients who were treated by TBS. The sociodemographic profile of the patients, details of injuries sustained, reasons for TBS patronage, duration of TBS treatment, the number of TBS visited, the reason for abandoning TBS treatment, patients' belief about the TBS practice, and outcome of their treatment were studied. RESULTS: Out of 418 patients who presented with musculoskeletal injuries, 120 patients who had been treated by TBS before presentation met the inclusion criteria. The mean age of the patients was 37.4+/-10.5 years. Advice of relatives and friends, as seen in 35 (29.2%) patients, was the most common reason for TBS patronage. Other reasons were cheaper cost (number [n]=30; 25%), sociocultural belief (n=17; 14.2%), easy accessibility (n=15; 12.5%), fear of amputation (n=13; 108%), and fear of operation (n=10; 8.3%). There was no correlation between these factors and age, marital status, occupation, and educational status (P=0.41). Forty-two (35%) patients believed TBS were not useful, a nuisance (n=30; 25%), useful (n=38; 31.7%), or indispensable (n=10; 8.3%). The opinion of patients about the outcome of TBS practice was: very satisfactory (n=0; 0%); satisfactory but with deficiencies (n=24; 20%); unsatisfactory (n=80; 66.7%); and no idea (n=16; 13.3%). CONCLUSION: Advice of relatives and friends was the main reason for patronizing TBS. The majority of patients lost confidence in the TBS practice after patronizing them due to the high complication rate. PMID- 25709414 TI - Clinical utility and patient considerations in the use of the sitagliptin metformin combination in Chinese patients. AB - The prevalence of diabetes mellitus (DM) continues to increase each year. However, the efficacy of glucose-lowering therapies remains unsatisfactory. Moreover, the clinical characteristics and manifestations of DM in Chinese patients are different from those in Western patients. Thus, it is imperative to develop an optimal treatment protocol for lowering blood glucose levels in Chinese patients with DM. Sitagliptin has been used in People's Republic of China, and sitagliptin and metformin combination therapy may not alter their individual pharmacokinetics. To date, several clinical trials undertaken to investigate the efficacy of sitagliptin and metformin combination therapy have revealed that it effectively controlled glycated hemoglobin, fasting plasma glucose, and postprandial plasma glucose levels to a greater extent than sitagliptin or metformin alone. In addition, the combined therapy was well tolerated and induced few side effects, which were largely mild. Furthermore, the combined therapy was easy to administer, and the patients receiving this therapy showed good compliance. Therefore, for Chinese patients with type 2 DM, sitagliptin and metformin combination therapy is preferred. PMID- 25709415 TI - The multinational second Diabetes, Attitudes, Wishes and Needs study: results of the French survey. AB - AIM: The second Diabetes, Attitudes, Wishes and Needs (DAWN2TM) multinational cross-sectional study was aimed at generating insights to facilitate innovative efforts by people with diabetes (PWD), family members (FMs), and health care professionals (HCPs) to improve self-management and psychosocial support in diabetes. Here, the French data from the DAWN2TM study are described. METHODS: In France, 500 PWD (80 with type 1 diabetes [T1] and 420 with type 2 diabetes [T2]), 120 FMs, and 288 HCPs were recruited. The questionnaires assessed the impact of diabetes on quality of life and mood, self-management, attitudes/beliefs, and care/support. RESULTS: Diabetes negatively impacted the emotional well-being of 59% of people with T1 versus 45% of people with T2 (P<0.05) and about half of FMs. A high level of distress was felt by about half of PWD and FMs. About half of HCPs reported assessing depression in their patients. Sixty-two percent of FMs considered managing diabetes to be a burden. Hypoglycemia was a source of concern for 64% of people with T1 and 73% of FMs of insulin users. About two-thirds of non-insulin-medicated people with T2 agreed to start insulin if prescribed, while half of HCPs preferred to delay insulin initiation. A discrepancy between HCPs' perceptions of their interactions with their patients and PWD's recollection of these interactions with regard to patients' personal needs and distress was also observed. CONCLUSION: While distress remains under-assessed by HCPs, the negative impact of diabetes on the lives of PWD and FMs clearly induces distress on both groups. These findings provide new understanding of barriers precluding optimal management of diabetes. Developing strategies to overcome these barriers is now warranted. PMID- 25709417 TI - Hearing aid fitting in older persons with hearing impairment: the influence of cognitive function, age, and hearing loss on hearing aid benefit. AB - PURPOSE: To examine the association of cognitive function, age, and hearing loss with clinically assessed hearing aid benefit in older hearing-impaired persons. METHODS: Hearing aid benefit was assessed using objective measures regarding speech recognition in quiet and noisy environments as well as a subjective measure reflecting everyday situations captured using a standardized questionnaire. A broad range of general cognitive functions such as attention, memory, and intelligence were determined using different neuropsychological tests. Linear regression analyses were conducted with the outcome of the neuropsychological tests as well as age and hearing loss as independent variables and the benefit measures as dependent variables. Thirty experienced older hearing aid users with typical age-related hearing impairment participated. RESULTS: Most of the benefit measures revealed that the participants obtained significant improvement with their hearing aids. Regression models showed a significant relationship between a fluid intelligence measure and objective hearing aid benefit. When individual hearing thresholds were considered as an additional independent variable, hearing loss was the only significant contributor to the benefit models. Lower cognitive capacity - as determined by the fluid intelligence measure - was significantly associated with greater hearing loss. Subjective benefit could not be predicted by any of the variables considered. CONCLUSION: The present study does not give evidence that hearing aid benefit is critically associated with cognitive function in experienced hearing aid users. However, it was found that lower fluid intelligence scores were related to higher hearing thresholds. Since greater hearing loss was associated with a greater objective benefit, these results strongly support the advice of using hearing aids regardless of age and cognitive function to counter hearing loss and the adverse effects of age-related hearing impairment. Still, individual cognitive capacity might be relevant for hearing aid benefit during an initial phase of hearing aid provision if acclimatization has not yet taken place. PMID- 25709416 TI - Effectiveness of exercise programs to reduce falls in older people with dementia living in the community: a systematic review and meta-analysis. AB - OBJECTIVE: The objective of this systematic review and meta-analysis is to evaluate the effectiveness of exercise programs to reduce falls in older people with dementia who are living in the community. METHOD: Peer-reviewed articles (randomized controlled trials [RCTs] and quasi-experimental trials) published in English between January 2000 and February 2014, retrieved from six electronic databases - Medline (ProQuest), CINAHL, PubMed, PsycInfo, EMBASE and Scopus - according to predefined inclusion criteria were included. Where possible, results were pooled and meta-analysis was conducted. RESULTS: Four articles (three RCT and one single-group pre- and post-test pilot study) were included. The study quality of the three RCTs was high; however, measurement outcomes, interventions, and follow-up time periods differed across studies. On completion of the intervention period, the mean number of falls was lower in the exercise group compared to the control group (mean difference [MD] [95% confidence interval {CI}] =-1.06 [-1.67 to -0.46] falls). Importantly, the exercise intervention reduced the risk of being a faller by 32% (risk ratio [95% CI] =0.68 [0.55 0.85]). Only two other outcomes were reported in two or more of the studies (step test and physiological profile assessment). No between-group differences were observed in the results of the step test (number of steps) (MD [95% CI] =0.51 [ 1.77 to 2.78]) or the physiological profile assessment (MD [95% CI] =-0.10 [-0.62 to 0.42]). CONCLUSION: Findings from this review suggest that an exercise program may potentially assist in preventing falls of older people with dementia living in the community. However, further research is needed with studies using larger sample sizes, standardized measurement outcomes, and longer follow-up periods, to inform evidence-based recommendations. PMID- 25709418 TI - Proliferative effect of Hachimijiogan, a Japanese herbal medicine, in C2C12 skeletal muscle cells. AB - BACKGROUND: Hachimijiogan (HJG), Ba-Wei-Di-Huang-Wan in Chinese, is one of the most popular herbal medicines in Japanese Kampo. HJG is often prescribed for the prevention and treatment of age-related diseases. Muscle atrophy plays an important role in aging-related disabilities such as sarcopenia. The purpose of this study was to investigate the possible beneficial effect of HJG on skeletal muscle. METHODS: Cells of murine skeletal muscle myoblast cell line C2C12 were used as an in vitro model of muscle cell proliferation and differentiation. The effect of HJG on C2C12 cell proliferation and differentiation was assessed. We counted the number of myotubes morphologically to assess the degree of differentiation. RESULTS: HJG treatment (200 MUg/mL) for 3 days significantly increased C2C12 cell number by 1.23-fold compared with that of the control. HJG promoted the proliferation of C2C12 cells through activation of the ERK1/2 signaling pathway without affecting the Akt signaling pathway. HJG did not affect the differentiation of C2C12 cells. CONCLUSION: HJG had beneficial effects on skeletal muscle myoblast proliferation. These findings may provide a useful intervention for the prevention and treatment of sarcopenia. PMID- 25709419 TI - Effect of computerized cognitive training with virtual spatial navigation task during bed rest immobilization and recovery on vascular function: a pilot study. AB - We investigated the effects of bed rest (BR) immobilization, with and without computerized cognitive training with virtual spatial navigation task (CCT), on vascular endothelium on older subjects. The effects of 14-day BR immobilization in healthy older males (n=16) of ages 53-65 years on endothelial function were studied using EndoPAT((r)), a noninvasive and user-independent method. From the group of 16 older men, 8 randomly received CCT during the BR, using virtual navigation tasks in a virtual environment with joystick device. In all the cases, EndoPAT assessments were done at pre- and post-BR immobilization as well as following 28 days of ambulatory recovery. The EndoPAT index increased from 1.53+/ 0.09 (mean +/- standard error of the mean) at baseline to 1.61+/-0.16 following immobilization (P=0.62) in the group with CCT. The EndoPAT index decreased from 2.06+/-0.13 (mean +/- standard error of the mean) at baseline to 1.70+/-0.09 at the last day of BR study, day 14 (BR14) (P=0.09) in the control group. Additionally, there were no statistically significant differences between BR14 and at 28 days of follow-up (rehabilitation program) (R28). Our results show a trend of immobilization in older persons affecting the vasoconstrictory endothelial response. As the control subjects had a greater increase in EndoPAT index after R28 (+0.018) compared to subjects who had cognitive training (+0.11) (calculated from the first day of BR study), it is possible that cognitive training during BR does not improve endothelial function but rather contributes to slowing down the impairment of endothelial function. Finally, our results also show that EndoPAT may be a useful noninvasive tool to assess the vascular reactivity. PMID- 25709420 TI - Oral health in the elderly patient and its impact on general well-being: a nonsystematic review. AB - Data on the oral health of the elderly depict a worrying situation, with an elevated prevalence of caries and moderate periodontal disease, frequent edentulism, and numerous cases of dry mouth and oral cancer. There is wide evidence that periodontitis is a risk factor for certain systemic diseases, and impaired oral health has been associated with mastication and nutritional problems, especially among the elderly, with highly negative effects on their quality of life. In this nonsystematic review, the authors discuss the importance of evaluating the oral health of the geriatric population in a comprehensive manner, beyond simple clinical assessments. PMID- 25709421 TI - Drug therapies and presence of coronary artery disease may affect aortic stiffness in Alzheimer's disease. PMID- 25709422 TI - A new delirium phenotype with rapid high amplitude onset and nearly as rapid reversal: Central Coast Australia Delirium Intervention Study. AB - BACKGROUND: Traditional models for delirium based on the Diagnostic and Statistical Manual for Mental Disorders and its 1990 offspring, the Confusion Assessment Method (CAM), were not designed to distinguish behavioral and psychological symptoms of dementia from rapid cognitive decline. We examined a new diagnostic criterion for delirium plus exclusion of behavioral and psychological symptoms of dementia and recent inattention with a 25% decline in digit span forward (DSF). METHODS: This was a prospective, randomized controlled trial comparing management of prevalent delirium in general medical with that in geriatric medical wards in a 370-bed hospital north of Sydney. Inclusion criteria were age >=65 years and prevalent delirium in the emergency department based on: CAM; proof that CAM elements were not better explained by behavioral and psychological symptoms of dementia; proof of recent inattention on DSF; evidence of cognitive decline not due to sedatives or antipsychotics in the emergency department. Measurements included the Instrumental Activities of Daily Living (IADL, 22-item), Selective IADL (8-item), Mini-Mental State Examination, DSF daily, Delirium Index daily, and Apathy Evaluation Scale. Pre-delirium scores from past cognitive tests and best scores were imputed after admission. Relative change (RC) was calculated as absolute change/test range and RC/MPC ratio was calculated as RC after admission/maximal possible change. RESULTS: A total of 130 subjects were recruited but 14 with subsyndromal delirium were excluded, leaving 116 subjects (mean age 83.6 years). Forty-eight percent had prior dementia. RC from pre-delirium to admission was 42% for the Mini-Mental State Examination, 41% for Selective IADL, 34% for 5-DSF, 54% for 6-DSF, and 37% for the Apathy Evaluation Scale. Improvements after admission (RC and RC/MPC ratios) were 32%/98% for 5-DSF, 54%/82% for 6-DSF, and 45%/80% for the Delirium Index. General medicine and geriatric medicine groups had similar outcomes. CONCLUSION: This delirium phenotype selects for a rapid high amplitude critical decline in attention, executive function, IADL, and apathy that recovers almost as rapidly. PMID- 25709423 TI - Tiotropium HandiHaler((r)) and Respimat((r)) in COPD: a pooled safety analysis. AB - INTRODUCTION: Tiotropium is prescribed for the treatment of chronic obstructive pulmonary disease (COPD) and delivered via HandiHaler((r)) (18 MUg once daily) or Respimat((r)) Soft MistTM inhaler (5 MUg once daily). The recent TIOtropium Safety and Performance In Respimat((r)) (TIOSPIRTM) study demonstrated that both exhibit similar safety profiles. This analysis provides an updated comprehensive safety evaluation of tiotropium((r)) using data from placebo-controlled HandiHaler((r)) and Respimat((r)) trials. METHODS: Pooled analysis of adverse event (AE) data from tiotropium HandiHaler((r)) 18 MUg and Respimat((r)) 5 MUg randomized, double-blind, parallel-group, placebo-controlled, clinical trials in patients with COPD (treatment duration >=4 weeks). Incidence rates, rate ratios (RRs), and 95% confidence intervals (CIs) were determined for HandiHaler((r)) and Respimat((r)) trials, both together and separately. RESULTS: In the 28 HandiHaler((r)) and 7 Respimat((r)) trials included in this analysis, 11,626 patients were treated with placebo and 12,929 with tiotropium, totaling 14,909 (12,469 with HandiHaler((r)); 2,440 with Respimat((r))) patient-years of tiotropium exposure. Mean age was 65 years, and mean prebronchodilator forced expiratory volume in 1 second (FEV1) was 1.16 L (41% predicted). The risk (RR [95% CI]) of AEs (0.90 [0.87, 0.93]) and of serious AEs (SAEs) (0.94 [0.89, 0.99]) was significantly lower in the tiotropium than in the placebo group (HandiHaler((r)) and Respimat((r)) pooled results), and there was a numerically lower risk of fatal AEs (FAEs) (0.90 [0.79, 1.01]). The risk of cardiac AEs (0.93 [0.85, 1.02]) was numerically lower in the tiotropium group. Incidences of typical anticholinergic AEs, but not SAEs, were higher with tiotropium. Analyzed separately by inhaler, the risks of AE and SAE in the tiotropium groups remained lower than in placebo and similarly for FAEs. CONCLUSION: This analysis indicates that tiotropium is associated with lower rates of AEs, SAEs, and similar rates of FAEs than placebo when delivered via HandiHaler((r)) or Respimat((r)) (overall and separately) in patients with COPD. PMID- 25709424 TI - Systematic literature review of patient-reported outcome measures used in assessment and measurement of sleep disorders in chronic obstructive pulmonary disease. AB - BACKGROUND: Sleep problems are common in patients with chronic obstructive pulmonary disease (COPD), but the validity of patient-reported outcome measures (PROMs) that measure sleep dysfunction has not been evaluated. We have reviewed the literature to identify disease-specific and non-disease-specific sleep PROMs that have been validated for use in COPD patients. The review also examined the psychometric properties of identified sleep outcome measures and extracted point and variability estimates of sleep instruments used in COPD studies. METHODS: The online EMBASE, MEDLINE, PsycINFO, and SCOPUS databases for all years to May 2014 were used to source articles for the review. The review was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Criteria from the Medical Outcomes Trust Scientific Advisory Committee guidelines were used to evaluate the psychometric properties of all sleep PROMs identified. RESULTS: One COPD-specific and six non-COPD-specific sleep outcome measures were identified and 44 papers met the review selection criteria. We only identified one instrument, the COPD and Asthma Sleep Impact Scale, which was developed specifically for use in COPD populations. Ninety percent of the identified studies used one of two non-disease-specific sleep scales, ie, the Pittsburgh Sleep Quality Index and/or the Epworth Sleep Scale, although neither has been tested for reliability or validity in people with COPD. CONCLUSION: The results highlight a need for existing non-disease-specific instruments to be validated in COPD populations and also a need for new disease-specific measures to assess the impact of sleep problems in COPD. PMID- 25709425 TI - Relationship between serum cardiac troponin T level and cardiopulmonary function in stable chronic obstructive pulmonary disease. AB - BACKGROUND: High-sensitivity cardiac troponin T (hs-cTnT) in serum is a useful marker of acute myocardial injury, yet information is limited in patients with chronic obstructive pulmonary disease. We aimed to explore the association between hs-cTnT levels and cardiac and pulmonary dysfunction in patients with stable chronic obstructive pulmonary disease and at-risk individuals. METHODS: We examined community-dwelling adults with/without chronic obstructive pulmonary disease, with a life-long smoking history, current symptoms of dyspnea during exertion, prolonged coughing, and/or sputum. Serum hs-cTnT concentrations were measured, and subjects underwent pulmonary function tests, high-resolution computed tomography of the chest, an echocardiogram, and a 6-minute walking test. RESULTS: Eighty-six stable patients were identified (mean age 65.5 years; predicted forced expiratory volume in 1 second [FEV1% predicted] 75.0%). Their overall mean hs-cTnT level was 0.008 ng/mL. Logarithmically transformed hs-cTnT levels significantly and positively correlated with age, smoking index, serum high-sensitivity C-reactive protein levels, right ventricle systolic pressure, low attenuation area percentage, and brain natriuretic peptide levels (range r=0.231-0.534, P=0.000 to P=0.042). Further, logarithmically transformed hs-cTnT values significantly and negatively correlated with forced vital capacity, FEV1% predicted, diffusion capacity, arterial oxygen tension, and 6-minute walking distance (range r= -0.482 to -0.377, P=0.000 to P=0.002). Multivariate analyses showed that hs-cTnT values varied independently according to the following three parameters: high-sensitivity C-reactive protein levels (B=0.157, beta=0.450, t=3.571, P=0.001), age (B=0.008, beta=0.352, t=2.789, P=0.009), and right ventricular systolic pressure (B=0.008, beta=0.280, t=2.202, P=0.035). CONCLUSION: Even in patients with stable chronic obstructive pulmonary disease, the serum troponin T concentration was controlled by at least three major factors, ie, systemic inflammation, advancing age, and right cardiac overload. PMID- 25709426 TI - Iterative reconstruction for quantitative computed tomography analysis of emphysema: consistent results using different tube currents. AB - PURPOSE: To assess the advantages of iterative reconstruction for quantitative computed tomography (CT) analysis of pulmonary emphysema. MATERIALS AND METHODS: Twenty-two patients with pulmonary emphysema underwent chest CT imaging using identical scanners with three different tube currents: 240, 120, and 60 mA. Scan data were converted to CT images using Adaptive Iterative Dose Reduction using Three Dimensional Processing (AIDR3D) and a conventional filtered-back projection mode. Thus, six scans with and without AIDR3D were generated per patient. All other scanning and reconstruction settings were fixed. The percent low attenuation area (LAA%; < -950 Hounsfield units) and the lung density 15th percentile were automatically measured using a commercial workstation. Comparisons of LAA% and 15th percentile results between scans with and without using AIDR3D were made by Wilcoxon signed-rank tests. Associations between body weight and measurement errors among these scans were evaluated by Spearman rank correlation analysis. RESULTS: Overall, scan series without AIDR3D had higher LAA% and lower 15th percentile values than those with AIDR3D at each tube current (P<0.0001). For scan series without AIDR3D, lower tube currents resulted in higher LAA% values and lower 15th percentiles. The extent of emphysema was significantly different between each pair among scans when not using AIDR3D (LAA%, P<0.0001; 15th percentile, P<0.01), but was not significantly different between each pair among scans when using AIDR3D. On scans without using AIDR3D, measurement errors between different tube current settings were significantly correlated with patients' body weights (P<0.05), whereas these errors between scans when using AIDR3D were insignificantly or minimally correlated with body weight. CONCLUSION: The extent of emphysema was more consistent across different tube currents when CT scans were converted to CT images using AIDR3D than using a conventional filtered-back projection method. PMID- 25709427 TI - Cardiovascular and respiratory dysfunction in chronic obstructive pulmonary disease complicated by impaired peripheral oxygenation. AB - BACKGROUND: Impaired peripheral oxygenation (IPO)-related variables readily achieved with cardiopulmonary exercise testing (CPET) represent cardiovascular dysfunction. These variables include peak oxygen uptake ( [Formula: see text] predicted, anaerobic threshold [Formula: see text] predicted, [Formula: see text] rate slope <8.6 mL/watt, oxygen pulse <80% predicted, and ventilatory equivalents for O2 and CO2 at nadir of >31 and >34, respectively. Some of these six variables may be normal while the others are abnormal in patients with chronic obstructive pulmonary disease (COPD). This may result in confusion when using the interpretation algorithm for diagnostic purposes. We therefore hypothesized that patients found to have abnormal values for all six variables would have worse cardiovascular function than patients with abnormal values for none or some of these variables. METHODS: In this cross-sectional comparative study, 58 COPD patients attending a university teaching hospital underwent symptom-limited CPET with multiple lactate measurements. Patients with abnormal values in all six IPO related variables were assigned to an IPO group while those who did not meet the requirements for the IPO group were assigned to a non-IPO group. Cardiovascular function was measured by two-dimensional echocardiography and [Formula: see text], and respiratory dynamics were compared between the two groups. RESULTS: Fourteen IPO and 43 non-IPO patients were entered into the study. Both groups were similar with regard to left ventricular ejection fraction and right ventricular morphology (P>0.05 for both). At peak exercise, both groups reached a similar heart rate level and [Formula: see text]. The IPO patients had an unfavorable dead space to tidal volume ratio, mean inspiratory tidal flow, and shallow breathing (P<0.05-P<0.001). CONCLUSION: Our IPO and non-IPO patients with COPD had similar cardiovascular performance at rest and at peak exercise, indicating that IPO variables are non-specific for cardiovascular function in these patients. COPD patients with full IPO variables have more deranged ventilatory function. PMID- 25709428 TI - Heart rate and blood pressure responses during hypoxic cycles of a 3-week intermittent hypoxia breathing program in patients at risk for or with mild COPD. AB - The aim of this study was to provide information on heart rate and blood pressure responses during a 3-week intermittent hypoxia breathing program in COPD patients. Sixteen participants with COPD symptoms were randomly assigned to a hypoxia or control group and completed a 3-week intermittent hypoxia breathing program (five sessions per week, each consisting of three to five breathing cycles, each cycle lasting 3-5 minutes with 3-minute breaks between cycles). During the breathing cycles, the hypoxia group received hypoxic air (inspired fraction of oxygen 15%-12%), whereas the control group received normal air (sham hypoxia). During the breaks, all participants breathed normoxic room air. Arterial oxygen saturation, systolic and diastolic blood pressure, and heart rate were measured during the normoxic and hypoxic/sham hypoxic periods. For each breathing cycle, changes from normoxia to hypoxia/sham hypoxia were calculated, and changes were averaged for each of the 15 sessions and for each week. Changes in arterial oxygen saturation were significantly different between groups in the course of the 3 weeks (two-way analysis of variance for repeated measures), with post hoc differences in weeks 1, 2, and 3. During the course of the intermittent hypoxia application, no between-group differences were detected for blood pressure or rate pressure product values. Changes in heart rate were significantly different between groups in the course of the 3 weeks (two-way analysis of variance for repeated measures), with post hoc differences only in week 3. Averages over all 15 sessions were significantly higher in the hypoxia group for heart rate and rate pressure product, and tended to be increased for systolic blood pressure. The applied intermittent hypoxia breathing program resulted in specific and moderate heart rate and blood pressure responses, and did not provoke a progressive increase in blood pressure during the hypoxic cycles in the course of the application. PMID- 25709429 TI - Caregivers' burden in patients with COPD. AB - OBJECTIVE: Chronic obstructive pulmonary disease (COPD) is a very prevalent and invalidating disease. The aim of this study was to analyze the burden borne by informal caregivers of patients with COPD. METHODS: We used the Survey on Disabilities, Personal Autonomy, and Dependency Situations (Encuesta sobre Discapacidad, Autonomia personal y Situaciones de Dependencia [EDAD]-2008) to obtain information on the characteristics of disabled individuals with COPD and their caregivers in Spain. Additionally, statistical multivariate analyses were performed to analyze the impact that an increase in dependence would have on the problems for which caregivers provide support, in terms of health, professional, and leisure/social dimensions. RESULTS: A total of 461,884 individuals with one or more disabilities and with COPD were identified, and 220,892 informal caregivers were estimated. Results showed that 35% of informal caregivers had health-related problems due to the caregiving provided; 83% had leisure/social related problems; and among caregivers of working age, 38% recognized having profession-related problems. The probability of a problem arising was significantly associated with the degree of dependence of the patient receiving care. Caregivers of patients with great dependence showed a 39% higher probability of presenting health-related problems, 27% more professional problems, and 23% more leisure problems compared with those with nondependent patients. CONCLUSION: The results show the large impact on society in terms of the welfare of informal caregivers of patients with COPD. A higher level of dependence was associated with more severe problems in caregivers, in all dimensions. PMID- 25709430 TI - Soluble urokinase-type plasminogen activator receptor is a novel biomarker predicting acute exacerbation in COPD. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory condition, and progresses with acute exacerbations. (AE). During AE, levels of acute phase reactants such as C-reactive protein (CRP) and inflammatory cells in the circulation increase. Soluble urokinase-type plasminogen activator receptor (suPAR) levels increase in acute viral and bacterial infections and in diseases involving chronic inflammation. The purpose of this study was to investigate the effectiveness of suPAR in predicting diagnosis of AE of COPD (AE COPD) and response to treatment. METHODS: The study population consisted of 43 patients diagnosed with AE-COPD and 30 healthy controls. suPAR, CRP, and fibrinogen levels were measured on the first day of hospitalization and on the seventh day of treatment. RESULTS: We found that fibrinogen (P<0.001), CRP (P<0.001), and suPAR (P<0.001) were significantly higher in patients with AE-COPD than in healthy controls. Fibrinogen (P<0.001), CRP (P=0.001), and suPAR (P<0.001) were significantly decreased by the seventh day of treatment. However, the area under receiver operator characteristic curve showed that suPAR is superior to CRP and fibrinogen in distinguishing AE-COPD. There was a correlation between fibrinogen, CRP, and suPAR. However, only fibrinogen was a powerful predictor of suPAR in multiple linear regression. In multiple logistic regression, only suPAR and fibrinogen were strong predictors of AE-COPD (P=0.002 and P=0.014, respectively). Serum suPAR was negatively correlated with forced expiratory volume in 1 second (r=-478, P=0.001). CONCLUSION: suPAR is a marker of acute inflammation. It is well correlated with such inflammation markers as CRP and fibrinogen. suPAR can be used as a predictor of AE-COPD and in monitoring response to treatment. PMID- 25709431 TI - A novel chemosynthetic peptide with beta-sheet motif efficiently kills Klebsiella pneumoniae in a mouse model. AB - Klebsiella pneumoniae (Kp) is one of the most common pathogens in nosocomial infections and is increasingly becoming multiple drug resistant. However, the molecular pathogenesis of Kp in causing tissue injury and dysregulated host defense remains elusive, further dampening the development of novel therapeutic measures. We have previously screened a series of synthetic antimicrobial beta sheet forming peptides and identified a peptide (IRIKIRIK; ie, IK8L) with a broad range of bactericidal activity and low cytotoxicity in vitro. Here, employing an animal model, we investigated the antibacterial effects of IK8L in acute infection and demonstrated that peritoneal injection of IK8L to mice down regulated inflammatory cytokines, alleviated lung injury, and importantly, decreased mortality compared to sham-injected controls. In addition, a math model was used to evaluate in vivo imaging data and predict infection progression in infected live animals. Mechanistically, IK8L can kill Kp by inhibiting biofilm formation and modulating production of inflammatory cytokines through the STAT3/JAK signaling both in vitro and in vivo. Collectively, these findings reveal that IK8L may have potential for preventing or treating Kp infection. PMID- 25709432 TI - A living thick nanofibrous implant bifunctionalized with active growth factor and stem cells for bone regeneration. AB - New-generation implants focus on robust, durable, and rapid tissue regeneration to shorten recovery times and decrease risks of postoperative complications for patients. Herein, we describe a new-generation thick nanofibrous implant functionalized with active containers of growth factors and stem cells for regenerative nanomedicine. A thick electrospun poly(epsilon-caprolactone) nanofibrous implant (from 700 MUm to 1 cm thick) was functionalized with chitosan and bone morphogenetic protein BMP-7 as growth factor using layer-by-layer technology, producing fish scale-like chitosan/BMP-7 nanoreservoirs. This extracellular matrix-mimicking scaffold enabled in vitro colonization and bone regeneration by human primary osteoblasts, as shown by expression of osteocalcin, osteopontin, and bone sialoprotein (BSPII), 21 days after seeding. In vivo implantation in mouse calvaria defects showed significantly more newly mineralized extracellular matrix in the functionalized implant compared to a bare scaffold after 30 days' implantation, as shown by histological scanning electron microscopy/energy dispersive X-ray microscopy study and calcein injection. We have as well bifunctionalized our BMP-7 therapeutic implant by adding human mesenchymal stem cells (hMSCs). The activity of this BMP-7-functionalized implant was again further enhanced by the addition of hMSCs to the implant (living materials), in vivo, as demonstrated by the analysis of new bone formation and calcification after 30 days' implantation in mice with calvaria defects. Therefore, implants functionalized with BMP-7 nanocontainers associated with hMSCs can act as an accelerator of in vivo bone mineralization and regeneration. PMID- 25709433 TI - Sustained-release nanoART formulation for the treatment of neuroAIDS. AB - A novel approach was developed for the coencapsulation of an anti-HIV drug (tenofovir) and a latency-breaking agent (vorinostat), using magnetically guided layer-by-layer (LbL) assembled nanocarriers for the treatment of neuroAIDS. Ultrasmall iron oxide (Fe3O4) nanoparticles (10+/-3 nm) were synthesized and characterized. The LbL technique was used to achieve a sustained release profile, and application of 2 bilayers ([tenofovir+dextran sulphate]2+vorinostat) to magnetic nanoparticles resulted in a 2.8 times increase in drug (tenofovir) loading and also resulted in an increase in the drug release period by 30-fold, with 100% drug release in sustained manner over a period of 5 days with the simultaneous stimulation of latent HIV expression. Nanoformulation showed a good blood-brain barrier transmigration ability (37.95%+/-1.5%) with good in vitro antiviral efficacy (~33% reduction of p24 level) over a period of 5 days after HIV infection in primary human astrocytes, with good cell viability (>90%). Hence, LbL arrangements of drugs on magnetic nanoparticles provides sustained release and, therefore, may improve the patient's adherence to therapy and lead to better compliance. PMID- 25709434 TI - Titanium dioxide nanoparticles enhance production of superoxide anion and alter the antioxidant system in human osteoblast cells. AB - Titanium dioxide (TiO2) nanoparticles (NPs) are manufactured worldwide for a variety of engineering and bioengineering applications. TiO2NPs are frequently used as a material for orthopedic implants. However, to the best of our knowledge, the biocompatibility of TiO2NPs and their effects on osteoblast cells, which are responsible for the growth and remodeling of the human skeleton, have not been thoroughly investigated. In the research reported here, we studied the effects of exposing hFOB 1.19 human osteoblast cells to TiO2NPs (5-15 nm) for 24 and 48 hours. Cell viability, alkaline phosphatase (ALP) activity, cellular uptake of NPs, cell morphology, superoxide anion (O2 (*-2)) generation, superoxide dismutase (SOD) activity and protein level, sirtuin 3 (SIR3) protein level, correlation between manganese (Mn) SOD and SIR, total antioxidant capacity, and malondialdehyde were measured following exposure of hFOB 1.19 cells to TiO2NPs. Exposure of hFOB 1.19 cells to TiO2NPs resulted in: (1) cellular uptake of NPs; (2) increased cytotoxicity and cell death in a time- and concentration-dependent manner; (3) ultrastructure changes; (4) decreased SOD and ALP activity; (5) decreased protein levels of SOD1, SOD2, and SIR3; (6) decreased total antioxidant capacity; (7) increased O2 (*-) generation; and (8) enhanced lipid peroxidation (malondialdehyde level). The linear relationship between the protein level of MnSOD and SIR3 and between O2 (*-) content and SIR3 protein level was observed. Importantly, the cytotoxic effects of TiO2NPs were attenuated by the pretreatment of hFOB 1.19 cells with SOD, indicating the significant role of O2 (*-) in the cell damage and death observed. Thus, decreased expression of SOD leading to increased oxidizing stress may underlie the nanotoxic effects of TiO2NPs on human osteoblasts. PMID- 25709435 TI - Effects of homogenization process parameters on physicochemical properties of astaxanthin nanodispersions prepared using a solvent-diffusion technique. AB - Nanodispersion systems allow incorporation of lipophilic bioactives, such as astaxanthin (a fat soluble carotenoid) into aqueous systems, which can improve their solubility, bioavailability, and stability, and widen their uses in water based pharmaceutical and food products. In this study, response surface methodology was used to investigate the influences of homogenization time (0.5-20 minutes) and speed (1,000-9,000 rpm) in the formation of astaxanthin nanodispersions via the solvent-diffusion process. The product was characterized for particle size and astaxanthin concentration using laser diffraction particle size analysis and high performance liquid chromatography, respectively. Relatively high determination coefficients (ranging from 0.896 to 0.969) were obtained for all suggested polynomial regression models. The overall optimal homogenization conditions were determined by multiple response optimization analysis to be 6,000 rpm for 7 minutes. In vitro cellular uptake of astaxanthin from the suggested individual and multiple optimized astaxanthin nanodispersions was also evaluated. The cellular uptake of astaxanthin was found to be considerably increased (by more than five times) as it became incorporated into optimum nanodispersion systems. The lack of a significant difference between predicted and experimental values confirms the suitability of the regression equations connecting the response variables studied to the independent parameters. PMID- 25709436 TI - Dimensionality reduction, and function approximation of poly(lactic-co-glycolic acid) micro- and nanoparticle dissolution rate. AB - Prediction of poly(lactic-co-glycolic acid) (PLGA) micro- and nanoparticles' dissolution rates plays a significant role in pharmaceutical and medical industries. The prediction of PLGA dissolution rate is crucial for drug manufacturing. Therefore, a model that predicts the PLGA dissolution rate could be beneficial. PLGA dissolution is influenced by numerous factors (features), and counting the known features leads to a dataset with 300 features. This large number of features and high redundancy within the dataset makes the prediction task very difficult and inaccurate. In this study, dimensionality reduction techniques were applied in order to simplify the task and eliminate irrelevant and redundant features. A heterogeneous pool of several regression algorithms were independently tested and evaluated. In addition, several ensemble methods were tested in order to improve the accuracy of prediction. The empirical results revealed that the proposed evolutionary weighted ensemble method offered the lowest margin of error and significantly outperformed the individual algorithms and the other ensemble techniques. PMID- 25709437 TI - Positive impact of IGF-1-coupled nanoparticles on the differentiation potential of human chondrocytes cultured on collagen scaffolds. AB - PURPOSE: In the present study, silica nanoparticles (sNP) coupled with insulin like growth factor 1 (IGF-1) were loaded on a collagen-based scaffold intended for cartilage repair, and the influence on the viability, proliferation, and differentiation potential of human primary articular chondrocytes was examined. METHODS: Human chondrocytes were isolated from the hyaline cartilage of patients (n=4, female, mean age: 73+/-5.1 years) undergoing primary total knee joint replacement. Cells were dedifferentiated and then cultivated on a bioresorbable collagen matrix supplemented with fluorescent sNP coupled with IGF-1 (sNP-IGF-1). After 3, 7, and 14 days of cultivation, cell viability and integrity into the collagen scaffold as well as metabolic cell activity and synthesis rate of matrix proteins (collagen type I and II) were analyzed. RESULTS: The number of vital cells increased over 14 days of cultivation, and the cells were able to infiltrate the collagen matrix (up to 120 MUm by day 7). Chondrocytes cultured on the collagen scaffold supplemented with sNP-IGF-1 showed an increase in metabolic activity (5.98-fold), and reduced collagen type I (1.58-fold), but significantly increased collagen type II expression levels (1.53-fold; P=0.02) after 7 days of cultivation compared to 3 days. In contrast, chondrocytes grown in a monolayer on plastic supplemented with sNP-IGF-1 had significantly lower metabolic activity (1.32-fold; P=0.007), a consistent amount of collagen type I, and significantly reduced collagen type II protein expression (1.86-fold; P=0.001) after 7 days compared to 3 days. CONCLUSION: Collagen-based scaffolds enriched with growth factors, such as IGF-1 coupled to nanoparticles, represent an improved therapeutic intervention for the targeted and controlled treatment of articular cartilage lesions. PMID- 25709438 TI - Improved osseointegration of dental titanium implants by TiO2 nanotube arrays with recombinant human bone morphogenetic protein-2: a pilot in vivo study. AB - TiO2 nanotube arrays on the surface of dental implants were fabricated by two step anodic oxidation. Their effects on bone-implant contact were researched by a pilot in vivo study. The implants were classified into four groups. An implant group with TiO2 nanotube arrays and recombinant human bone morphogenetic protein 2 (rhBMP-2) was compared with various surface implants, including machined surface, sandblasted large-grit and acid-etched surface, and TiO2 nanotube array surface groups. The diameter of the TiO2 nanotube window and TiO2 nanotube were ~70 nm and ~110 nm, respectively. The rhBMP-2 was loaded into TiO2 nanotube arrays and elution was detected by an interferometric biosensing method. A change in optical thickness of ~75 nm was measured by flow cell testing for 9 days, indicating elution of rhBMP-2 from the TiO2 nanotube arrays. For the in vivo study, the four groups of implants were placed into the proximal tibia of New Zealand White rabbits. In the implant group with TiO2 nanotube arrays and rhBMP 2, the bone-to-implant contact ratio was 29.5% and the bone volume ratio was 77.3%. Bone remodeling was observed not only in the periosteum but also in the interface between the bone and implant threads. These values were higher than in the machined surface, sandblasted large-grit and acid-etched surface, and TiO2 nanotube array surface groups. Our results suggest that TiO2 nanotube arrays could potentially be used as a reservoir for rhBMP-2 to reinforce osseointegration on the surface of dental implants. PMID- 25709439 TI - High molecular weight chitosan derivative polymeric micelles encapsulating superparamagnetic iron oxide for tumor-targeted magnetic resonance imaging. AB - Magnetic resonance imaging (MRI) contrast agents based on chitosan derivatives have great potential for diagnosing diseases. However, stable tumor-targeted MRI contrast agents using micelles prepared from high molecular weight chitosan derivatives are seldom reported. In this study, we developed a novel tumor targeted MRI vehicle via superparamagnetic iron oxide nanoparticles (SPIONs) encapsulated in self-aggregating polymeric folate-conjugated N-palmitoyl chitosan (FAPLCS) micelles. The tumor-targeting ability of FAPLCS/SPIONs was demonstrated in vitro and in vivo. The results of dynamic light scattering experiments showed that the micelles had a relatively narrow size distribution (136.60+/-3.90 nm) and excellent stability. FAPLCS/SPIONs showed low cytotoxicity and excellent biocompatibility in cellular toxicity tests. Both in vitro and in vivo studies demonstrated that FAPLCS/SPIONs bound specifically to folate receptor-positive HeLa cells, and that FAPLCS/SPIONs accumulated predominantly in established HeLa derived tumors in mice. The signal intensities of T2-weighted images in established HeLa-derived tumors were reduced dramatically after intravenous micelle administration. Our study indicates that FAPLCS/SPION micelles can potentially serve as safe and effective MRI contrast agents for detecting tumors that overexpress folate receptors. PMID- 25709441 TI - Thickness-controllable electrospun fibers promote tubular structure formation by endothelial progenitor cells. AB - Controlling the thickness of an electrospun nanofibrous scaffold by altering its pore size has been shown to regulate cell behaviors such as cell infiltration into a three-dimensional (3D) scaffold. This is of great importance when manufacturing tissue-engineering scaffolds using an electrospinning process. In this study, we report the development of a novel process whereby additional aluminum foil layers were applied to the accumulated electrospun fibers of an existing aluminum foil collector, effectively reducing the incidence of charge buildup. Using this process, we fabricated an electrospun scaffold with a large pore (pore size >40 MUm) while simultaneously controlling the thickness. We demonstrate that the large pore size triggered rapid infiltration (160 MUm in 4 hours of cell culture) of individual endothelial progenitor cells (EPCs) and rapid cell colonization after seeding EPC spheroids. We confirmed that the 3D, but not two-dimensional, scaffold structures regulated tubular structure formation by the EPCs. Thus, incorporation of stem cells into a highly porous 3D scaffold with tunable thickness has implications for the regeneration of vascularized thick tissues and cardiac patch development. PMID- 25709440 TI - Microemulsion-based synergistic dual-drug codelivery system for enhanced apoptosis of tumor cells. AB - A microemulsion-based synergistic dual-drug codelivery system was developed for enhanced cell apoptosis by transporting coix seed oil and etoposide into A549 (human lung carcinoma) cells simultaneously. Results obtained by dynamic light scattering showed that an etoposide (VP16)-loaded coix seed oil microemulsion (EC ME) delivery system had a small size around 35 nm, a narrow polydispersity index, and a slightly negative surface charge. The encapsulating efficiency and total drug loading rate were 97.01% and 45.48%, respectively, by high-performance liquid chromatography. The release profiles at various pH values showed an obvious pH-responsive difference, with the accumulated amount of VP16 released at pH 4.5 (and pH 5.5) being 2.7-fold higher relative to that at pH 7.4. Morphologic alteration (particle swelling) associated with a mildly acidic pH environment was found on transmission electron microscopy. In the cell study, the EC-ME system showed a significantly greater antiproliferative effect toward A549 cells in comparison with free VP16 and the mixture of VP16 and coix seed oil. The half maximal inhibitory concentration of the EC-ME system was 3.9-fold and 10.4-fold lower relative to that of free VP16 and a mixture of VP16 and coix seed oil, respectively. Moreover, fluorescein isothiocyanate and VP16 (the green fluorescent probe and entrapped drug, respectively) were efficiently internalized into the cells by means of coix seed oil microemulsion through intuitive observation and quantitative measurement. Importantly, an EC-ME system containing 20 MUg/mL of VP16 showed a 3.3-fold and 3.5-fold improvement in induction of cell apoptosis compared with the VP-16-loaded microemulsion and free VP16, respectively. The EC-ME combination strategy holds promise as an efficient drug delivery system for induction of apoptosis and treatment of lung cancer. PMID- 25709442 TI - Factors affecting the pharmacokinetics and pharmacodynamics of PEGylated liposomal irinotecan (IHL-305) in patients with advanced solid tumors. AB - IHL-305 is a PEGylated liposomal formulation of irinotecan (CPT-11). The objective of this study was to evaluate the factors associated with interpatient variability in the pharmacokinetics and pharmacodynamics of IHL-305 in patients with advanced solid tumors. IHL-305 was administered intravenously once every 4 weeks as part of a Phase I study. Pharmacokinetic studies of the liposomal sum total CPT-11, released CPT-11, SN-38, SN-38G, 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecin, and 7-ethyl-10-[4-amino-1 piperidino]-carbonyloxycamptothecin in plasma were performed. Noncompartmental and compartmental pharmacokinetic analyses were conducted using pharmacokinetic data for sum total CPT-11. The pharmacokinetic variability of IHL-305 is associated with linear and nonlinear clearance. Patients whose age and body composition (ratio of total body weight to ideal body weight [TBW/IBW]) were greater than the median age and TBW/IBW of the study had a 1.7-fold to 2.6-fold higher ratio of released CPT-11 area under the concentration versus time curve (AUC) to sum total CPT-11 AUC. Patients aged <60 years had a 1.3-fold higher ratio of percent decrease in monocytes at nadir to percent decrease in absolute neutrophil count at nadir as compared with patients aged >=60 years. There was an inverse relationship between patient age and percent decrease in monocytes at nadir, ie, younger patients have a higher percent decrease in monocytes. Patients with a higher percent decrease in monocytes at nadir have a decreased plasma exposure of sum total CPT-11. The pharmacokinetics and pharmacodynamics of IHL 305 are consistent with those of other PEGylated liposomal carriers. Interpatient variability in the pharmacokinetics and pharmacodynamics of IHL-305 was associated with age, body composition, and monocytes. PMID- 25709443 TI - Improving intranasal delivery of neurological nanomedicine to the olfactory region using magnetophoretic guidance of microsphere carriers. AB - BACKGROUND: Although direct nose-to-brain drug delivery has multiple advantages, its application is limited by the extremely low delivery efficiency (<1%) to the olfactory region where drugs can enter the brain. It is crucial to developing new methods that can deliver drug particles more effectively to the olfactory region. MATERIALS AND METHODS: We introduced a delivery method that used magnetophoresis to improve olfactory delivery efficiency. The performance of the proposed method was assessed numerically in an image-based human nose model. Influences of the magnet layout, magnet strength, drug-release position, and particle diameter on the olfactory dosage were examined. RESULTS AND DISCUSSION: Results showed that particle diameter was a critical factor in controlling the motion of nasally inhaled ferromagnetic drug particles. The optimal particle size was found to be approximately 15 MUm for effective magnetophoretic guidance while avoiding loss of particles to the walls in the anterior nose. Olfactory delivery efficiency was shown to be sensitive to the position and strength of magnets and the release position of drug particles. The results of this study showed that clinically significant olfactory doses (up to 45%) were feasible using the optimal combination of magnet layout, selective drug release, and microsphere-carrier diameter. A 64-fold-higher delivery of dosage was predicted in the magnetized nose compared to the control case, which did not have a magnetic field. However, the sensitivity of olfactory dosage to operating conditions and the unstable nature of magnetophoresis make controlled guidance of nasally inhaled aerosols still highly challenging. PMID- 25709445 TI - Comparison of three magnetic nanoparticle tracers for sentinel lymph node biopsy in an in vivo porcine model. AB - INTRODUCTION: Breast cancer staging with sentinel lymph node biopsy relies on the use of radioisotopes, which limits the availability of the procedure worldwide. The use of a magnetic nanoparticle tracer and a handheld magnetometer provides a radiation-free alternative, which was recently evaluated in two clinical trials. The hydrodynamic particle size of the used magnetic tracer differs substantially from the radioisotope tracer and could therefore benefit from optimization. The aim of this study was to assess the performance of three different-sized magnetic nanoparticle tracers for sentinel lymph node biopsy within an in vivo porcine model. MATERIALS AND METHODS: Sentinel lymph node biopsy was performed within a validated porcine model using three magnetic nanoparticle tracers, approved for use in humans (ferumoxytol, with hydrodynamic diameter d H =32 nm; Sienna+((r)), d H =59 nm; and ferumoxide, d H =111 nm), and a handheld magnetometer. Magnetometer counts (transcutaneous and ex vivo), iron quantification (vibrating sample magnetometry), and histopathological assessments were performed on all ex vivo nodes. RESULTS: Transcutaneous "hotspots" were present in 12/12 cases within 30 minutes of injection for the 59 nm tracer, compared to 7/12 for the 32 nm tracer and 8/12 for the 111 nm tracer, at the same time point. Ex vivo magnetometer counts were significantly greater for the 59 nm tracer than for the other tracers. Significantly more nodes per basin were excised for the 32 nm tracer compared to other tracers, indicating poor retention of the 32 nm tracer. Using the 59 nm tracer resulted in a significantly higher iron accumulation compared to the 32 nm tracer. CONCLUSION: The 59 nm tracer demonstrated rapid lymphatic uptake, retention in the first nodes reached, and accumulation in high concentration, making it the most suitable tracer for intraoperative sentinel lymph node localization. PMID- 25709444 TI - Targeted lung cancer therapy: preparation and optimization of transferrin decorated nanostructured lipid carriers as novel nanomedicine for co-delivery of anticancer drugs and DNA. AB - PURPOSE: Nanostructured lipid carriers (NLC) represent an improved generation of lipid nanoparticles. They have specific nanostructures to accommodate drugs/genes, and thus achieve higher loading capacity. The aim of this study was to develop transferrin (Tf)-decorated NLC as multifunctional nanomedicine for co delivery of paclitaxel (PTX) and enhanced green fluorescence protein plasmid. METHODS: Firstly, Tf-conjugated ligands were synthesized. Secondly, PTX- and DNA loaded NLC (PTX-DNA-NLC) was prepared. Finally, Tf-containing ligands were used for the surface decoration of NLC. Their average size, zeta potential, drug, and gene loading were evaluated. Human non-small cell lung carcinoma cell line (NCl H460 cells) was used for the testing of in vitro transfection efficiency, and in vivo transfection efficiency of NLC was evaluated on mice bearing NCl-H460 cells. RESULTS: Tf-decorated PTX and DNA co-encapsulated NLC (Tf-PTX-DNA-NLC) were nano sized particles with positive zeta potential. Tf-PTX-DNA-NLC displayed low cytotoxicity, high gene transfection efficiency, and enhanced antitumor activity in vitro and in vivo. CONCLUSION: The results demonstrated that Tf-PTX-DNA-NLC can achieve impressive antitumor activity and gene transfection efficiency. Tf decoration also enhanced the active targeting ability of the carriers to NCl-H460 cells. The novel drug and gene delivery system offers a promising strategy for the treatment of lung cancer. PMID- 25709446 TI - Nanopharmaceuticals (part 2): products in the pipeline. AB - In part I of this review we assessed nanoscience-related definitions as applied to pharmaceuticals and we discussed all 43 currently approved drug formulations, which are widely publicized as nanopharmaceuticals or nanomedicines. In continuation, here we review the currently ongoing clinical trials within the broad field of nanomedicine. Confining the definition of nanopharmaceuticals to therapeutic formulations, in which the unique physicochemical properties expressed in the nanosize range, when man-made, play the pivotal therapeutic role, we found an apparently low number of trials, which reflects neither the massive investments made in the field of nanomedicine nor the general hype associated with the term "nano." Moreover, after an extensive search for information through clinical trials, we found only two clinical trials with materials that show unique nano-based properties, ie, properties that are displayed neither on the atomic nor on the bulk material level. PMID- 25709447 TI - Targeting and treatment of glioblastomas with human mesenchymal stem cells carrying ferrociphenol lipid nanocapsules. AB - Recently developed drug delivery nanosystems, such as lipid nanocapsules (LNCs), hold great promise for the treatment of glioblastomas (GBs). In this study, we used a subpopulation of human mesenchymal stem cells, "marrow-isolated adult multilineage inducible" (MIAMI) cells, which have endogenous tumor-homing activity, to deliver LNCs containing an organometallic complex (ferrociphenol or Fc-diOH), in the orthotopic U87MG GB model. We determined the optimal dose of Fc diOH-LNCs that can be carried by MIAMI cells and compared the efficacy of Fc-diOH LNC-loaded MIAMI cells with that of the free-standing Fc-diOH-LNC system. We showed that MIAMI cells entrapped an optimal dose of about 20 pg Fc-diOH per cell, with no effect on cell viability or migration capacity. The survival of U87MG-bearing mice was longer after the intratumoral injection of Fc-diOH-LNC loaded MIAMI cells than after the injection of Fc-diOH-LNCs alone. The greater effect of the Fc-diOH-LNC-loaded MIAMI cells may be accounted for by their peritumoral distribution and a longer residence time of the drug within the tumor. These results confirm the potential of combinations of stem cell therapy and nanotechnology to improve the local tissue distribution of anticancer drugs in GB. PMID- 25709448 TI - Layer-by-layer paper-stacking nanofibrous membranes to deliver adipose-derived stem cells for bone regeneration. AB - Bone tissue engineering through seeding of stem cells in three-dimensional scaffolds has greatly improved bone regeneration technology, which historically has been a constant challenge. In this study, we researched the use of adipose derived stem cell (ADSC)-laden layer-by-layer paper-stacking polycaprolactone/gelatin electrospinning nanofibrous membranes for bone regeneration. Using this novel paper-stacking method makes oxygen distribution, nutrition, and waste transportation work more efficiently. ADSCs can also secrete multiple growth factors required for osteogenesis. After the characterization of ADSC surface markers CD29, CD90, and CD49d using flow cytometry, we seeded ADSCs on the membranes and found cells differentiated, with significant expression of the osteogenic-related proteins osteopontin, osteocalcin, and osteoprotegerin. During 4 weeks in vitro, the ADSCs cultured on the paper-stacking membranes in the osteogenic medium exhibited the highest osteogenic-related gene expressions. In vivo, the paper-stacking scaffolds were implanted into the rat calvarial defects (5 mm diameter, one defect per parietal bone) for 12 weeks. Investigating with microcomputer tomography, the ADSC-laden paper-stacking membranes showed the most significant bone reconstruction, and from a morphological perspective, this group occupied 90% of the surface area of the defect, produced the highest bone regeneration volume, and showed the highest bone mineral density of 823.06 mg/cm(3). From hematoxylin and eosin and Masson staining, the new bone tissue was most evident in the ADSC-laden scaffold group. Using quantitative polymerase chain reaction analysis from collected tissues, we found that the ADSC-laden paper-stacking membrane group presented the highest osteogenic-related gene expressions of osteocalcin, osteopontin, osteoprotegerin, bone sialoprotein, runt related transcription factor 2, and osterix (two to three times higher than the control group, and 1.5 times higher than the paper-stacking membrane group in all the genes). It is proposed that ADSC-laden layer-by-layer paper-stacking scaffolds could be used as a way of promoting bone defect treatment. PMID- 25709449 TI - Enhanced antitumor activity of doxorubicin in breast cancer through the use of poly(butylcyanoacrylate) nanoparticles. AB - The use of doxorubicin (DOX), one of the most effective antitumor molecules in the treatment of metastatic breast cancer, is limited by its low tumor selectivity and its severe side effects. Colloidal carriers based on biodegradable poly(butylcyanoacrylate) nanoparticles (PBCA NPs) may enhance DOX antitumor activity against breast cancer cells, thus allowing a reduction of the effective dose required for antitumor activity and consequently the level of associated toxicity. DOX loading onto PBCA NPs was investigated in this work via both drug entrapment and surface adsorption. Cytotoxicity assays with DOX-loaded NPs were performed in vitro using breast tumor cell lines (MCF-7 human and E0771 mouse cancer cells), and in vivo evaluating antitumor activity in immunocompetent C57BL/6 mice. The entrapment method yielded greater drug loading values and a controlled drug release profile. Neither in vitro nor in vivo cytotoxicity was observed for blank NPs. The 50% inhibitory concentration (IC50) of DOX-loaded PBCA NPs was significantly lower for MCF-7 and E0771 cancer cells (4 and 15 times, respectively) compared with free DOX. Furthermore, DOX-loaded PBCA NPs produced a tumor growth inhibition that was 40% greater than that observed with free DOX, thus reducing DOX toxicity during treatment. These results suggest that DOX-loaded PBCA NPs have great potential for improving the efficacy of DOX therapy against advanced breast cancers. PMID- 25709450 TI - Interstitial diffuse radiance spectroscopy of gold nanocages and nanorods in bulk muscle tissues. AB - Radiance spectroscopy was applied to the interstitial detection of localized inclusions containing Au nanocages or nanorods with various concentrations embedded in porcine muscle phantoms. The radiance was quantified using a perturbation approach, which enabled the separation of contributions from the porcine phantom and the localized inclusion, with the inclusion serving as a perturbation probe of photon distributions in the turbid medium. Positioning the inclusion at various places in the phantom allowed for tracking of photons that originated from a light source, passed through the inclusion's location, and reached a detector. The inclusions with high extinction coefficients were able to absorb nearly all photons in the range of 650-900 nm, leading to a spectrally flat radiance signal. This signal could be converted to the relative density of photons incident on the inclusion. Finally, the experimentally measured quantities were expressed via the relative perturbation and arranged into the classical Beer-Lambert law that allowed one to extract the extinction coefficients of various types of Au nanoparticles in both the transmission and back reflection geometries. It was shown that the spatial variation of perturbation could be described as 1/r dependence, where r is the distance between the inclusion and the detector. Due to a larger absorption cross section, Au nanocages produced greater perturbations than Au nanorods of equal particle concentration, indicating a better suitability of Au nanocages as contrast agents for optical measurements in turbid media. Individual measurements from different inclusions were combined into detectability maps. PMID- 25709453 TI - The emerging role of bexarotene in the treatment of Alzheimer's disease: current evidence. AB - In 2012, a novel approach to the treatment of Alzheimer's disease was introduced, heralding a wave of excitement in the field of dementia. Bexarotene, a retinoid X receptor agonist, was shown to reverse neurodegeneration, improve cognition, and decrease levels of amyloid-beta in transgenic mice expressing familial Alzheimer disease mutations. Since then, there has been widespread discussion about bexarotene, as well as a number of follow-up studies. Bexarotene is a unique compound, as it is approved by the US Food and Drug Administration for other purposes and there are reasonable data to justify its mechanism of action in dementia. This review discusses these studies and the emerging role of bexarotene in the clinical field of Alzheimer's dementia. PMID- 25709451 TI - Synergistic effect of pH-responsive folate-functionalized poloxamer 407-TPGS mixed micelles on targeted delivery of anticancer drugs. AB - BACKGROUND: Doxorubicin (DOX), an anthracycline anticancer antibiotic, is used for treating various types of cancers. However, its use is associated with toxicity to normal cells and development of resistance due to overexpression of drug efflux pumps. Poloxamer 407 (P407) and vitamin E TPGS (D-alpha-tocopheryl polyethylene glycol succinate, TPGS) are widely used polymers as drug delivery carriers and excipients for enhancing the drug retention times and stability. TPGS reduces multidrug resistance, induces apoptosis, and shows selective anticancer activity against tumor cells. Keeping in view the problems, we designed a mixed micelle system encapsulating DOX comprising TPGS for its selective anticancer activity and P407 conjugated with folic acid (FA) for folate mediated receptor targeting to cancer cells. METHODS: FA-functionalized P407 was prepared by carbodiimide crosslinker chemistry. P407-TPGS/FA-P407-TPGS-mixed micelles were prepared by thin-film hydration method. Cytotoxicity of blank micelles, DOX, and DOX-loaded micelles was determined by alamarBlue((r)) assay. RESULTS: The size of micelles was less than 200 nm with encapsulation efficiency of 85% and 73% for P407-TPGS and FA-P407-TPGS micelles, respectively. Intracellular trafficking study using nile red-loaded micelles indicated improved drug uptake and perinuclear drug localization. The micelles show minimal toxicity to normal human cell line WRL-68, enhanced cellular uptake of DOX, reduced drug efflux, increased DOX-DNA binding in SKOV3 and DOX-resistant SKOV3 human ovarian carcinoma cell lines, and enhanced in vitro cytotoxicity as compared to free DOX. CONCLUSION: FA-P407-TPGS-DOX micelles show potential as a targeted nano-drug delivery system for DOX due to their multiple synergistic factors of selective anticancer activity, inhibition of multidrug resistance, and folate-mediated selective uptake. PMID- 25709452 TI - Neuroprotective strategies against calpain-mediated neurodegeneration. AB - Calpains are calcium-dependent proteolytic enzymes that have deleterious effects on neurons upon their pathological over-activation. According to the results of numerous studies to date, there is no doubt that abnormal calpain activation triggers activation and progression of apoptotic processes in neurodegeneration, leading to neuronal death. Thus, it is very crucial to unravel all the aspects of calpain-mediated neurodegeneration in order to protect neurons through eliminating or at least minimizing its lethal effects. Protecting neurons against calpain-activated apoptosis basically requires developing effective, reliable, and most importantly, therapeutically applicable approaches to succeed. From this aspect, the most significant studies focusing on preventing calpain-mediated neurodegeneration include blocking the N-methyl-d-aspartate (NMDA)-type glutamate receptor activities, which are closely related to calpain activation; directly inhibiting calpain itself via intrinsic or synthetic calpain inhibitors, or inhibiting its downstream processes; and utilizing the neuroprotectant steroid hormone estrogen and its receptors. In this review, the most remarkable neuroprotective strategies for calpain-mediated neurodegeneration are categorized and summarized with respect to their advantages and disadvantages over one another, in terms of their efficiency and applicability as a therapeutic regimen in the treatment of neurodegenerative diseases. PMID- 25709454 TI - Diffuse cerebral vasospasm after resection of schwannoma: a case report. AB - BACKGROUND: The etiology of vasospasm after brain tumor resection remains unclear. This is the first report of diffuse cerebral vasospasm following resection of a schwannoma located in the left portion/part of the ventral medulla oblongata. CASE PRESENTATION: A 16-year-old boy presented with dizziness and projectile vomiting without apparent cause three months before admission. Magnetic resonance imaging revealed a space-occupying lesion in the left portion of the ventral medulla oblongata. The tumor was completely resected. Pathological examination was consistent with diagnosis of schwannoma. Three days after surgery, the patient was in an unconscious state. Magnetic resonance angiography revealed the occurrence of cerebral vasospasm, with ischemic infarction and segmental cerebrovascular stenosis. Seven days after surgery, dehydration therapy was carried out and decompressive craniectomy was performed in the frontal and temporal areas. Despite treatments, the patient was in a persistent vegetative state after surgery, with normal vital signs. CONCLUSION: This was an uncommon occurrence of diffuse cerebral vasospasm following the resection of schwannoma. Appropriate management of this condition is uncertain, but aggressive treatments including expansion of blood volume and relief of spasm should be performed to treat postsurgery vasospasm. PMID- 25709455 TI - Medium-to-high prevalence of screening-detected parkinsonism in the urban area of Tehran, Iran: data from a community-based door-to-door study. AB - INTRODUCTION: Parkinsonism occurs in all ethnic groups worldwide; however, there are wide variations in the prevalence rates reported from different countries, even for neighboring regions. The huge socioeconomic burden of parkinsonism necessitates the need for prevalence studies in each country. So far, there is neither data registry nor prevalence information on parkinsonism in the Iranian population. The aim of our study was to estimate the prevalence rate of probable parkinsonism in a huge urban area in Iran, Tehran using a community-based door-to door survey. MATERIALS AND METHODS: We used a random multistage sampling of the households within the network of health centers consisting of 374 subunits in all 22 districts throughout the entire urban area of Tehran. Overall, 20,621 individuals answered the baseline checklist and screening questionnaire and data from 19,500 persons aged >=30 years were entered in the final analysis. Health care professionals used a new six-item screening questionnaire for parkinsonism, which has been previously shown to have a high validity and diagnostic value in the same population. RESULTS: A total of 157 cases were screened for parkinsonism using the validated six-item questionnaire. After age and sex adjustment based on the Tehran population, the prevalence of parkinsonism was calculated as 222.9 per 100,000. Using the World Health Organization's World Standard Population, the standardized prevalence rate of parkinsonism was 285 per 100,000 (95% confidence interval 240-329). The male:female ratio of probable parkinsonism was calculated as 1.62, and there was a significant increase in the screening rate by advancing age. CONCLUSION: The calculated rates for the prevalence of parkinsonism in our study are closer to reports from some European and Middle Eastern countries, higher than reports from Eastern Asian and African populations, and lower than Australia. The prevalence rate of >200 in 100,000 for parkinsonism in Tehran, Iran could be considered a medium-to-high rate. PMID- 25709457 TI - Remission of classic rapid cycling bipolar disorder with levothyroxine augmentation therapy in a male patient having clinical hypothyroidism. AB - The literature suggests that patients with bipolar disorder, particularly females, have greater vulnerability to rapid cycling features. Levothyroxine therapy might be potentially useful to attenuate mood instability in this patient group. In contrast, reports on male patients remain limited and controversial. Herein, we report a 32-year-old male patient who had bipolar 1 disorder for 12 years who developed a breakthrough rapid cycling course and first-onset clinical hypothyroidism at the age of 31 years during lithium therapy. After levothyroxine augmentation therapy was introduced, the patient had remission from the rapid cycling illness course along with normalization of serum levels of free T4 and thyroid stimulating hormone in the subsequent year. This observation suggested that investigation of both levothyroxine pharmacology and thyroid pathology in male patients with rapid cycling bipolar disorder might be of much value. PMID- 25709456 TI - Common psychocutaneous disorders in children. AB - The prevalence of psychosomatic disorders among dermatological patients is high but frequently unreported because of difficulties in diagnosing and treating this patient group. Psychiatric and psychological factors may play different roles in the pathogenic mechanism of some skin diseases. The mainstay of diagnosis and treatment is the differentiation between skin disorders associated with psychiatric illness and those of a purely psychiatric nature. Dermatologists and psychiatrists should be aware of this pathology and work together as a team to resolve difficult cases, especially in children. The present paper highlights the psychocutaneous diseases most frequently seen by dermatologists in pediatric population. PMID- 25709458 TI - Psychopathology, symptoms of attention-deficit/hyperactivity disorder, and risk factors in juvenile offenders. AB - BACKGROUND: The aim of this study was to assess the prevalence of potential environmental and psychopathological risk factors, with special focus on symptoms of attention-deficit/hyperactivity disorder (ADHD), in a sample of adolescent offenders in relation to the type of crime committed. METHODS: The assessment included data collection and administration of clinical standardized scales such as the Youth Self-Report and Conners' Adolescent Self-Report Scale. A total of 135 juvenile offenders participated in the study. In relation to the type of crime committed, we identified three groups matched for age and sex (crimes against people, property crimes, and alcohol-drug-related crimes). RESULTS: Fifty two percent of juvenile offenders reported educational achievement problems and 34% reported a family history of psychiatric disorders. We detected a statistically significant difference between the three groups with regard to ADHD (P=0.01) and conduct problems (P=0.034). Juvenile offenders who had committed crimes against people showed more ADHD symptoms (18%) and conduct problems (20%) than adolescents who had committed property crimes and alcohol-drug-related crimes. Sixty percent of the juvenile offenders who had committed property crimes and 54% of those who had committed alcohol-drug-related crimes showed problems in academic achievement. CONCLUSION: These findings suggest the need to implement specific interventions for prevention and treatment of specific criminal behavior. PMID- 25709459 TI - The noradrenaline metabolite MHPG is a candidate biomarker between the depressive, remission, and manic states in bipolar disorder I: two long-term naturalistic case reports. AB - BACKGROUND: Treatment of the depressive and manic states in bipolar disorder I (BDI) is a challenge for psychiatrists. Despite the recognized importance of the switch phenomenon, the precise mechanisms underlying this process are yet to be shown. We conducted a naturalistic study in two BDI patients to determine whether biological markers (monoamine metabolites and brain-derived neurotrophic factor [BDNF]) are associated with the switch between depressive and manic states. CASE PRESENTATION AND METHODS: Blood sampling and mood assessments were performed at 2 week intervals over a period of 2 (Case 1, n=72) and 6 (Case 2, n=183) years. Plasma concentrations of 3-methoxy-4-hydroxyphenylglycol (MHPG) and homovanillic acid (HVA) were analyzed by high-performance liquid chromatography with electrochemical detection. Plasma BDNF was assayed by sandwich ELISA (enzyme linked immunosorbent assay). RESULTS: MHPG had the highest standardized coefficient (beta) in the multiple regression analysis. We found a significant positive correlation between Young Mania Rating Scale scores and plasma MHPG levels (Case 1: rho=0.429; Case 2: rho=0.488), and a significant negative correlation between Montgomery-Asberg Depression Rating Scale scores and MHPG levels (Case 1: rho=-0.542; Case 2: rho=-0.465). Conversely, no significant correlation was found between the level of BDNF and the presence of a manic or depressive state, and although HVA had a slightly stronger correlation than MHPG, the levels of neither of these were found to significantly correlate with the symptoms. CONCLUSION: These data suggest that peripheral MHPG levels (which is related to noradrenaline levels in the brain) could be used as a biomarker of mood states in BDI. The noradrenaline level in the brain is likely to reflect the clinical characteristics of the switch process in BDI, and has prognostic significance for the treatment of both manic and depressive states. PMID- 25709460 TI - MRI-guided stereotactic amygdalohippocampectomy: a single center experience. AB - BACKGROUND: This paper presents our experience of stereotactic radiofrequency amygdalohippocampectomy performed for intractable mesial temporal lobe epilepsy. METHODS: The article describes the cases of 61 patients who were treated during the period from 2004 to 2010. Mean postoperative follow-up was 5.3 years. Neuropsychological results were obtained for a subset of 31 patients. RESULTS: At their last postsurgical visit, 43 (70.5%) patients were Engel class I, six (9.8%) class II, nine (14.8%) class III, and three (4.9%) class IV. The surgery was complicated by four intracranial hematomas. One of them caused acute hydrocephalus and was treated by shunting and resolved without sequelae, while another caused transitory aphasia. The remaining hematomas were asymptomatic. There were two cases of meningitis which required antibiotic treatment. One patient committed suicide due to postoperative depression. After the procedure, we performed open epilepsy surgery and rethermolesions in three and two patients, respectively (8.2%). Patients showed increases in their mean full scale, verbal, and performance intelligence quotient (IQ) scores of 4, 3, and 4 IQ points, respectively (P<0.05). Five (17.2%), four (13.8%), and four (13.3%) patients improved their full scale, verbal, and performance IQ scores, respectively. No significant changes were found in memory performance, with a mean increase of 1, 3, and 0 memory quotient points in global, verbal, and visual memory, respectively (P<0.05). Global memory improved in three (10.3%) patients, verbal memory in one (3.4%), and one patient (3.3%) showed deterioration in visual memory. CONCLUSION: Stereotactic radiofrequency amygdalohippocampectomy offers a safe, effective, and less aggressive treatment modality in cases of well-defined mesial temporal lobe epilepsy. Seizure outcome is comparable with the results of conventional epilepsy surgery and cognitive results could be even better. PMID- 25709462 TI - Current status of parenteral nutrition and enteral nutrition application: an assessment of nutritional prescriptions from 59 hospitals in the People's Republic of China. AB - PURPOSE: The aim of the study reported here was to assess the use of parenteral nutrition (PN) and enteral nutrition (EN), and the prevalence of PN and EN formulas, in the People's Republic of China. METHODS: Fifty-nine hospitals in the People's Republic of China participated in a nutrition survey. The resulting information on nutritional support was analyzed. RESULTS: We received 379,584 nutritional-support prescriptions over 40 days in 2013. PN provided approximately 63.2% and EN provided approximately 36.8% of nitrogen intake. PN provided 63.5% and EN provided 36.5% of lipid intake. There were obvious differences in nitrogen and lipid intake between PN and EN in different regions, departments, and diseases. The percentage of nourishment provided by PN in different regions was highest in Chengdu, followed by the Beijing, Guangzhou, and Hangzhou areas. The percentage of nourishment provided by PN in different departments was highest in general surgery, followed by gastroenterology and the intensive care unit. The percentage of nourishment provided by PN in different diseases/conditions was highest in acute pancreatitis, followed by cancer, and burns. The main source of nitrogen in PN was balanced amino-acid preparations, and in EN, it was protein. The main source of lipids in PN was long- and medium-chain triglyceride lipid emulsion injection. CONCLUSION: Despite recent improvements in the application of nutritional support in the People's Republic of China, a much higher percentage of nitrogen and lipids is delivered through PN than through EN. Furthermore, there are marked regional, departmental, and disease-based differences in the selection of PN versus EN. The rationale for use of nutritional support needs to be improved. PMID- 25709461 TI - Echocardiographic assessment of left ventricular function in thyrotoxicosis and implications for the therapeutics of thyrotoxic cardiac disease. AB - INTRODUCTION: Thyrotoxicosis is an endocrine disorder with prominent cardiovascular manifestations. Thyroid hormone acts through genomic and non genomic mechanisms to regulate cardiac function. Echocardiography is a useful, non-invasive, easily accessible, and affordable tool for studying the structural and physiological function of the heart. AIM: We studied thyrotoxicosis patients in a Nigerian Teaching Hospital and employed trans-thoracic echocardiography to find out if there were abnormalities in the hearts of these patients. METHODS: Fifty adult thyrotoxicosis patients diagnosed with clinical and thyroid function tests in the medical out-patient unit of the hospital were recruited and we performed transthoracic echocardiography with a Sonos 2000 HP machine. RESULTS: We documented the presence of abnormalities in the following proportion of thyrotoxicosis patients: left ventricular enhanced systolic function in 30%, enhanced diastolic function in 34%, diastolic dysfunction in 34%, heart failure with preserved ejection fraction in10%, heart failure with reduced ejection fraction in 6%, and left ventricular hypertrophy in 34%. CONCLUSION: Echocardiography was useful in the stratification of cardiac function abnormalities and is indispensable as a guide in the choice of therapeutic options in patients with thyrocardiac disease. The finding of left ventricular enhanced systolic and diastolic functions signify early echocardiographic detectable cardiac abnormalities in thyrotoxicosis, and the clinical management includes the use of anti-thyroid drugs and beta-adrenoceptor blockade. Diastolic dysfunction in thyrotoxicosis patients asymptomatic for cardiac disease should be treated with anti-thyroid drugs, and beta-adrenoceptor blockade. The judicious application of clinical therapeutics will guide the use of anti-thyroid drugs, diuretics, digoxin, angiotensin inhibitors, and beta-adrenoceptor blockade in the successful management of thyrotoxicosis patients with heart failure and reduced, preserved, or increased ejection fraction: parameters which are derived from echocardiography. PMID- 25709463 TI - Pain-to-hospital times, cardiovascular risk factors, and early intrahospital mortality in patients with acute myocardial infarction. AB - BACKGROUND: The aim of the study was to analyze the most recent trends in myocardial infarction (MI) care, the number of patients treated for MI and their outcomes, cardiovascular disease risk factors, and pain-to-hospital times in MI patients. SUBJECTS AND METHODS: For 778 patients treated for acute MI at the Coronary Care Unit (CCU) of University Hospital Split, Croatia the following data were acquired: outcome during hospitalization (survived, deceased), cardiovascular risk factors (hypertension, diabetes, dyslipidemia, previous MI, smoking), and pain-to-CCU time. RESULTS: Among 778 patients treated for acute MI, there were 291 (37%) women and 487 (63%) men. Forty-five patients (6%) died during hospitalization, mostly due to cardiogenic shock. An association was found between early intrahospital mortality and the following risk factors: age >70 years, female sex, previous MI, and smoking. Median pain-to-call time was 2 hours, and median time from the onset of pain to arrival into the CCU was 4 hours. There were 59 (7.6%) patients admitted to the CCU within recommended 90 minutes. Diabetic comorbidity was not associated with early death or with longer time from pain to emergency calls. CONCLUSION: Some of the risk factors associated with adverse outcomes in MI are modifiable. Prehospital delay of 4 hours observed in patients who suffered an MI is too long, and more effort should be devoted to investments in health care and education of the general public regarding chest pain symptoms. PMID- 25709464 TI - Travel advice for the immunocompromised traveler: prophylaxis, vaccination, and other preventive measures. AB - Immunocompromised patients are traveling at increasing rates. Physicians caring for these complex patients must be knowledgeable in pretravel consultation and recognize when referral to an infectious disease specialist is warranted. This article outlines disease prevention associated with international travel for adults with human immunodeficiency virus, asplenia, solid organ and hematopoietic transplantation, and other immunosuppressed states. While rates of infection may not differ significantly between healthy and immunocompromised travelers, the latter are at greater risk for severe disease. A thorough assessment of these risks can ensure safe and healthy travel. The travel practitioners' goal should be to provide comprehensive risk information and recommend appropriate vaccinations or prevention measures tailored to each patient's condition. In some instances, live vaccines and prophylactic medications may be contraindicated. PMID- 25709465 TI - Serum hepatitis B surface antigen titer and transient elastography in screening for insignificant fibrosis in HBeAg-positive chronic hepatitis B patients. AB - OBJECTIVE: To explore the predictive value of serum hepatitis B surface antigen (HBsAg) titer and transient elastography in screening for insignificant fibrosis in hepatitis B e antigen (HBeAg)-positive chronic hepatitis B patients. METHODS: We conducted a cross-sectional study of eligible patients treated from March 2012 to May 2013 at the West China Hospital of Sichuan University. Eligible patients underwent liver transient elastography and liver biopsy. We assessed the serum HBsAg level, serum hepatitis B virus (HBV) deoxyribonucleic acid (DNA) level, HBV genotypes, liver stiffness measurement (LSM) values by transient elastography, and histological fibrosis staging by METAVIR classification. RESULTS: A total of 129 consecutive patients were recruited. The LSM value (P<0.001, odds ratio 14.67, 95% CI 0.158-0.551) and log10HBsAg (P=0.045, odds ratio 4.03, 95% CI 0.136 0.976) correlated with a liver fibrosis score =F2 among those with an LSM value under 9.4 kPa (4.6+/-0.7 vs 4.3+/-0.5, P=0.006). The HBsAg titer achieved an area under the receiver operating characteristic curve of 0.758 (P<0.001, 95% CI 0.631-0.884) in predicting a fibrosis score T polymorphism contributes to gastric and bladder cancer risk. AB - BACKGROUND: Previous studies suggested genetic variations in PSCA (prostate stem cell antigen) may confer the susceptibility of cancer. Many case-control studies have reported the relationship between PSCA rs2294008 C > T polymorphism and cancer, especially gastric cancer and bladder cancer. However, the results are inconsistent. This meta-analysis is aimed at evaluating the association of rs2294008 polymorphism with cancer risk. METHODS: The databases of PubMed, ISI Web of Knowledge, EMBASE, and Chinese National Knowledge Infrastructure (CNKI) were searched for related publications. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to estimate the strength of the associations. Fixed models were used when heterogeneity among studies was not detected, otherwise the random model was used. RESULTS: Twenty-six studies from 24 articles with 30,050 multiple cancer cases and 51,670 controls were pooled into this meta-analysis. The results showed that the rs2294008 polymorphism was associated with increased cancer risk in any genetic model (T vs C, OR: 1.18, 95% CI: 1.08-1.28; TT vs CC, OR: 1.36, 95% CI: 1.14-1.62; TC vs CC, OR: 1.29, 95% CI: 1.17-1.44; TT + TC vs CC, OR: 1.32, 95% CI: 1.18-1.49; TT vs TC + CC, OR: 1.15, 95% CI: 1.02-1.30). In stratified analysis by cancer type, we found that the T allele had a significant high risk of gastric and bladder cancer, but not in other cancers. In subgroup analysis by ethnicity, increased cancer risk was found in both Asians and Caucasians. CONCLUSION: Our study suggested that the PSCA rs2294008 C > T polymorphism is a risk factor for cancer, especially in gastric and bladder cancer. PMID- 25709468 TI - Barriers to discharge in an acute care medical teaching unit: a qualitative analysis of health providers' perceptions. AB - BACKGROUND: The complex process of discharging patients from acute care to community care requires a multifaceted interaction between all health care providers and patients. Poor communication in a patient's discharge can result in post hospital adverse events, readmission, and mortality. Because of the gravity of these problems, discharge planning has been emphasized as a potential solution. The purpose of this paper is to identify communication barriers to effective discharge planning in an acute care unit of a tertiary care center and to suggest solutions to these barriers. METHODS: Health care providers provided comments to a single open-ended question: "What are the communication barriers between the different health care providers that limit an effective discharge of patients from Unit 36?" We conducted qualitative thematic analysis by identifying themes related to communication barriers affecting a successful discharge process. RESULTS: Three broad themes related to barriers to the discharge process were identified: communication, lack of role clarity and lack of resources. We also identified two themes for opportunities for improvement, ie, structure and function of the medical team and need for leadership. CONCLUSION: While it was evident that poor communication was an overarching barrier identified by health care providers, other themes emerged. In an effort to increase inter-team communication, "bullet rounds", a condensed form of discharge rounds, were introduced to the medical teaching unit and occurred on a daily basis between the multidisciplinary team. To help facilitate provider-patient communication, electronic transfer of care summaries were suggested as a potential solution. To help role clarity, a discharge coordinator and/or liaison was suggested. Communication can be enhanced through use of electronic discharge summaries, bullet rounds, and implementation of a discharge coordinator(s). The findings from this study can be used to aid future researchers in devising appropriate discharging strategies that are focused around the patient and inter-health care provider communication. PMID- 25709467 TI - Sitagliptin/Simvastatin: a first combination tablet to treat type 2 diabetes and hypercholesterolemia--a review of its characteristics. AB - BACKGROUND: The purpose of this study was to review the current literature and information on the combination product JuvisyncTM (sitagliptin + simvastatin), which was approved by the US Food and Drug Administration in October 2011. METHODS: PubMed (2001-2014) was searched for primary and review articles on sitagliptin, simvastatin, or the combination product. Drug manufacturing data and product labeling were also used. Studies of simvastatin, sitagliptin, or the combination were screened and analyzed to include relevant and recent papers. Selected English language trials were limited to those with human subjects and included both safety and efficacy outcomes. RESULTS: When compared with glipizide as add-on therapy to metformin, sitagliptin was noninferior but had lower rates of hypoglycemia and weight gain. In addition, when compared with insulin glargine, sitagliptin was less effective in decreasing glycosylated hemoglobin, but was associated with significantly lower rates of hypoglycemia. Further, trials have shown a beneficial effect of using statins in patients with diabetes mellitus with regard to decreasing cardiovascular risk, regardless of baseline lipid levels or the presence of a cardiac disease. Both medications have also demonstrated an acceptable side effect profile. However, caution is needed when coadministering with any drug that may increase simvastatin levels to reduce the risk of myopathy and rhabdomyolysis. CONCLUSION: Juvisync should be used in patients requiring both sitagliptin and simvastatin. Both agents have shown good efficacy and acceptable safety profiles. Sitagliptin is a good option for diabetic patients to improve glycemic control with a lower risk of hypoglycemia and weight gain. PMID- 25709469 TI - Family carers' experiences of attending a multicomponent psychosocial intervention program for carers and persons with dementia. AB - BACKGROUND: Psychosocial interventions for persons with dementia and their primary family carers are promising approaches to reducing the challenges associated with care, but, obtaining significant outcomes may be difficult. Even though carers in general are satisfied with such interventions, few studies have evaluated the interventions by means of qualitative methods. AIM: The objective of the study reported here was to investigate family carers' experiences of a multicomponent psychosocial intervention program, and also to offer advice on how to develop the intervention program. METHODS: Content analyses were taken from individual qualitative interviews conducted in 2012 with 20 carers (aged 50-82 years) who participated in a psychosocial intervention program that included education, individual and family counseling, and parallel group sessions for carers and persons with dementia. RESULTS: Two main categories emerged: 1) benefits of the intervention program, which sets out the informants' experiences for the benefits of participation, described in the subcategories "importance of content and group organization" and "importance of social support"; and 2) missing content in the intervention program, which details the informants' suggestions for future interventions, contained in the subcategories "need for extended content" and "need for new group organization". CONCLUSION: The carers found the interventions useful. The importance of even earlier and more flexible interventions for the family carers, the extended family, and the persons with dementia was underscored. PMID- 25709470 TI - XPA A23G polymorphism and risk of digestive system cancers: a meta-analysis. AB - BACKGROUND: Several studies have reported an association between the A23G polymorphism (rs 1800975) in the xeroderma pigmentosum group A (XPA) gene and risk of digestive system cancers. However, the results are inconsistent. In this study, we performed a meta-analysis to assess the association between XPA A23G polymorphism and the risk of digestive system cancers. METHODS: Relevant studies were identified using the PubMed, Web of Science, China National Knowledge Infrastructure, WanFang, and VIP databases up to August 30, 2014. The pooled odds ratio (OR) with a 95% confidence interval (CI) was calculated using the fixed or random effects model. RESULTS: A total of 18 case-control studies from 16 publications with 4,170 patients and 6,929 controls were included. Overall, no significant association was found between XPA A23G polymorphism and the risk of digestive system cancers (dominant model: GA + AA versus GG, OR 0.89, 95% CI 0.74 1.08; recessive model: AA versus GA + GG, OR 0.94, 95% CI 0.74-1.20; GA versus GG, OR 0.89, 95% CI 0.77-1.03; and AA versus GG, OR 0.87, 95% CI 0.64-1.19). When the analysis was stratified by ethnicity, similar results were observed among Asians and Caucasians in all genetic models. In stratified analysis based on tumor type, we also failed to detect any association between XPA A23G polymorphism and the risk of esophageal, gastric, or colorectal cancers. CONCLUSION: This meta-analysis indicates that the XPA A23G polymorphism is not associated with a risk of digestive system cancers. PMID- 25709471 TI - The clue of a possible etiology about spontaneous regression of hepatocellular carcinoma: a perspective on pathology. AB - Spontaneous regression of hepatocellular carcinoma (HCC) is a rare event. However, only a few of the causes of cases of HCC spontaneous regression are clear. More cases are ambiguous. We report on a patient who had a spontaneous regression of HCC as detected by histological and immunohistochemical exam, and compared this case to 20 cases of non-specific HCC. In our case, we found that the odd phenomenon is that CD163(+) macrophages are overactivated in surviving HCC, which is spontaneously regressing. Concomitantly, we cannot find a similar phenomenon in peritumoral liver tissue or non-specific HCC. According to our microscopical morphology and immunohistochemical study, we considered that a clue of a possible etiology about HCC spontaneous regression is that CD163(+) macrophages are overactivated. PMID- 25709472 TI - Use of allogeneic platelet gel in the management of chemotherapy extravasation injuries: a case report. AB - The allogeneic platelet (PLT) gel offers to be a valid supportive measure in the management of chemotherapy extravasation injuries. We report a case of a 58-year old patient with multiple myeloma enrolled for high-dose chemotherapy and autologous stem cell transplantation. As pretransplant therapy, the patient received induction therapy with bortezomib, adriblastina, and desametazone. A port was inserted in the vein on the back of the hand. After three cycles, the patient reported rapid development of redness, pain, and necrotic tissue in the left hand, and a diagnosis of extravasation was addressed. The patient presented a raw area on the back of the hand caused by cytotoxic/chemotherapeutic drug leakage because of the malposition of venous access devices. Skin ulcer was debrided, and the wound was reconstructed with a combination of local random rotational flap and abdomen skin graft. Two weeks later, a 20% skin flap necrosis was observed. In the context of wound healing, topical plasma-rich PLT gel is able to accelerate the regeneration and repair of tissue, so it was set out to assess PLT gel efficacy in this case. The PLT gel was applied topically once every 5 days, for a duration of 60 days on average. There were no adverse reactions observed during the topical therapy. Complete wound healing was observed after 12 PLT-rich plasma applications. No ulcer recurrence was noted in the patient during the follow-up period of 2-19 months. PMID- 25709473 TI - Prophylaxis and treatment of acute lymphoblastic leukemia relapse after allogeneic hematopoietic stem cell transplantation. AB - Relapse of acute lymphoblastic leukemia remains a major cause of death in patients following allogeneic hematopoietic stem cell transplantation. Several factors may affect the concurrence and outcome of relapse, which include graft versus-host disease, minimal residual disease or intrinsic factors of the disease, and transplantation characteristics. The mainstay of relapse prevention and treatment is donor leukocyte infusions, targeted therapies, second transplantation, and other novel therapies. In this review, we mainly focus on addressing the impact of graft-versus-host disease on relapse and the prophylaxis and treatment of acute lymphoblastic leukemia relapse following allogeneic hematopoietic stem cell transplantation. We also make recommendations for critical strategies to prevent relapse after transplantation and challenges that must be addressed to ensure success. PMID- 25709474 TI - High mobility group box-1 and its clinical value in breast cancer. AB - BACKGROUND: High mobility group box-1 (HMGB1) is a factor regulating malignant tumorigenesis, proliferation, and metastasis, and is associated with poor clinical pathology in various human cancers. We investigated the differential concentrations of HMGB1 in tissues and sera, and their clinical value for diagnosis in patients with breast cancer, benign breast disease, and healthy individuals. METHODS: HMGB1 levels in tumor tissues, adjacent normal tissues, and benign breast disease tissues was detected via immunohistochemistry. Serum HMGB1 was measured using an enzyme-linked immunosorbent assay in 56 patients with breast cancer, 25 patients with benign breast disease, and 30 healthy control subjects. The clinicopathological features of the patients were compared. Tissues were evaluated histopathologically by pathologists. RESULTS: HMGB1 levels in the tissues and sera of patients with breast cancer were significantly higher than those in patients with benign breast disease or normal individuals. The 56 cancer patients were classified as having high tissue HMGB1 levels (n=41) or low tissue HMGB1 levels (n=15), but the corresponsive serum HMGB1 in these two groups was not significantly different. HMGB1 levels in breast cancer tissues significantly correlated with differentiation grade, lymphatic metastasis, and tumor-node metastasis stage, but not patient age, tumor size, or HER-2/neu expression; no association between serum HMGB1 levels and these clinicopathological parameters was found. The sensitivity and specificity of tissue HMGB1 levels for the diagnosis of breast cancer were 73.21% and 84.00%, respectively, while positive and negative predictive values were 91.11% and 58.33%. CONCLUSION: HMGB1 might be involved in the development and progression of breast cancer and could be a supportive diagnostic marker for breast cancer. Serum HMGB1 could be a useful serological biomarker for diagnosis and screening of breast cancer. PMID- 25709475 TI - Single-nucleotide polymorphisms of microRNA processing machinery genes and risk of colorectal cancer. AB - OBJECTIVE: MicroRNA (miRNA)-related single-nucleotide polymorphisms (miR-SNPs) in miRNA processing machinery genes can affect cancer risk, treatment efficacy, and patient prognosis. We genotyped 6 miR-SNPs of miRNA processing machinery genes including XPO5 (rs11077), RAN (rs14035), Dicer (rs3742330), TNRC6B (rs9623117), GEMIN3 (rs197412), and GEMIN4 (rs2740348) in a case-control study to evaluate their impact on colorectal cancer (CRC) risk. MATERIALS AND METHODS: miR-SNPs were genotyped using the polymerase chain reaction- ligase detection reaction. The chi (2) test was used to analyze dichotomous values, such as the presence or absence of any individual SNP in CRC patients and healthy controls. RESULTS: Two of these SNPs were identified for their association with cancer risk in the Dicer and GEMIN3 genes. The AA allele of rs3742330 located in the Dicer gene exhibited a significantly increased risk of CRC (odds ratio, 2.11; 95% confidence interval: 1.33-3.34; P=0.001); the TT allele of rs197412 located in GEMIN3 also exhibited a significantly increased risk of CRC (odds ratio, 1.68; 95% confidence interval: 1.07-2.65; P=0.024). CONCLUSION: Our results suggest that the specific genetic variants in miRNA machinery genes may affect CRC susceptibility. PMID- 25709476 TI - Andrographolide inhibits hypoxia-inducible factor-1 through phosphatidylinositol 3-kinase/AKT pathway and suppresses breast cancer growth. AB - Hypoxia-inducible factor-1 (HIF-1) is a master regulator of the transcriptional response to hypoxia. HIF-1alpha is one of the most compelling anticancer targets. Andrographolide (Andro) was newly identified to inhibit HIF-1 in T47D cells (a half maximal effective concentration [EC50] of 1.03*10(-7) mol/L), by a dual luciferase reporter assay. It suppressed HIF-1alpha protein and gene accumulation, which was dependent on the inhibition of upstream phosphatidylinositol 3-kinase (PI3K)/AKT pathway. It also abrogated the expression of HIF-1 target vascular endothelial growth factor (VEGF) gene and protein. Further, Andro inhibited T47D and MDA-MB-231 cell proliferation and colony formation. In addition, it exhibited significant in vivo efficacy and antitumor potential against the MDA-MB-231 xenograft in nude mice. In conclusion, these results highlighted the potential effects of Andro, which inhibits HIF-1, and hence may be developed as an antitumor agent for breast cancer therapy in future. PMID- 25709477 TI - Multimodality therapy is recommended for limited-stage combined small cell esophageal carcinoma. AB - BACKGROUND AND AIM: Limited-stage combined small cell esophageal carcinoma (LS-C SCEC) is a rare, poorly understood, underdiagnosed disease, with components of both small cell esophageal cancer and non-small cell esophageal cancer. We investigated the optimal treatment strategy and prognostic factors in patients with LS-C-SCEC. PATIENTS AND METHODS: LS-C-SCEC patients included in the analysis (from our hospital and the literature) were treated between January 1966 and December 2013. Patient treatment strategies included surgery (S), chemotherapy (CT), and radiation therapy (RT). The primary end point was overall survival (OS); the secondary end points included tumor complete response rates, patterns of failure, and toxicity. Kaplan-Meier curves were compared with the log-rank test. Univariate and multivariate analyses were used to determine prognosticators for OS. RESULTS: A total of 72 patients were included in the analysis: 24 (33%) from our hospital and 48 (67%) from the literature. The median OS of all patients was 15.0 months. Patients who received CT had a significantly longer median OS than did those who did not (OS 22.8 months vs 10.0 months) (P=0.03). Patients treated with multimodality therapy (including RT+CT [18%], S+CT [40%], or S+RT+CT [17%]) vs monotherapy (typically, S [18%]) had significantly improved OS (15.5 months vs 9.3 months) (P=0.02) and complete response rates. On multivariate analysis, tumor location (upper third of the esophagus) and type of treatment (monotherapy) were the only factors predictive of poor OS. CONCLUSION: Multimodality therapy (including RT+CT, S+CT, or S+RT+CT) improves OS for patients with LS-C-SCEC compared with monotherapy (typically, S). Additional studies are necessary to personalize multimodal treatment approaches to individual patients. PMID- 25709478 TI - The imaging features of metanephric adenoma: a case report and review of literature. AB - Metanephric adenoma (MA) is a rare epithelial tumor of the kidney with a characteristic histology. To date, the imaging features of the tumor have not been clearly described. Until now, MA was considered to be benign, but the majority of MA cases underwent nephrectomy. Here, we report a case of MA confirmed by surgical pathology, and we will analyze the ultrasound and computed tomography findings. The radiological features of MA are presented along with a brief review of the pertinent literature to deepen the understanding of MA's imaging features. PMID- 25709479 TI - Stem cell technology for bone regeneration: current status and potential applications. AB - Continued improvements in the understanding and application of mesenchymal stem cells (MSC) have revolutionized tissue engineering. This is particularly true within the field of skeletal regenerative medicine. However, much remains unknown regarding the native origins of MSC, the relative advantages of different MSC populations for bone regeneration, and even the biologic safety of such unpurified, grossly characterized cells. This review will first summarize the initial discovery of MSC, as well as the current and future applications of MSC in bone tissue engineering. Next, the relative advantages and disadvantages of MSC isolated from distinct tissue origins are debated, including the MSC from adipose, bone marrow, and dental pulp, among others. The perivascular origin of MSC is next discussed. Finally, we briefly comment on pluripotent stem cell populations and their possible application in bone tissue engineering. While continually expanding, the field of MSC-based bone tissue engineering and regeneration shows potential to become a clinical reality in the not-so-distant future. PMID- 25709481 TI - Health economics, equity, and efficiency: are we almost there? AB - Health care is a highly complex, dynamic, and creative sector of the economy. While health economics has to continue its efforts to improve its methods and tools to better inform decisions, the application needs to be aligned with the insights and models of other social sciences disciplines. Decisions may be guided by four concept models based on ethical and distributive justice: libertarian, communitarian, egalitarian, and utilitarian. The societal agreement on one model or a defined mix of models is critical to avoid inequity and unfair decisions in a public and/or private insurance-based health care system. The excess use of methods and tools without fully defining the basic goals and philosophical principles of the health care system and without evaluating the fitness of these measures to reaching these goals may not contribute to an efficient improvement of population health. PMID- 25709480 TI - Cost-utility of denosumab for the treatment of postmenopausal osteoporosis in Spain. AB - BACKGROUND: The objective of this study was to estimate the cost-effectiveness of denosumab for fracture prevention compared with no treatment, generic bisphosphonates, and strontium ranelate in a cohort of osteoporotic postmenopausal women in Spain. METHODS: A Markov model represented the possible health state transitions of Spanish postmenopausal women from initiation of fracture prevention treatment until age 100 years or death. The perspective was that of the Spanish National Health System. Fracture efficacy data for denosumab were taken from a randomized controlled trial. Fracture efficacy data for alendronate, ibandronate, risedronate, and strontium ranelate were taken from an independent meta-analysis. Data on the incidence of fractures in Spain were either taken from the published literature or derived from Swedish data after applying a correction factor based on the reported incidence from each country. Resource use in each health state was obtained from the literature, or where no data had been published, conservative assumptions were made. Utility values for the various fracture health states were taken from published sources. The primary endpoints of the model were life-years gained, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios for denosumab against the comparators. RESULTS: Denosumab reduced the risk of fractures compared with either no treatment or the other active interventions, and produced the greatest gains in life-years and QALYs. With an annual acquisition cost of ?417.34 for denosumab, the incremental cost-effectiveness ratios for denosumab versus no treatment, alendronate, risedronate, and ibandronate were estimated at ?6,823, ?16,294, ?4,895, and ?2,205 per QALY gained, respectively. Denosumab dominated strontium ranelate. Sensitivity analyses confirmed the robustness of these findings. CONCLUSION: Our analyses show that denosumab is a cost-effective intervention for fracture prevention in osteoporotic postmenopausal women in Spain compared with alendronate and risedronate, and is a dominant treatment option compared with strontium ranelate. PMID- 25709482 TI - Sexual dysfunction in diabetic women: prevalence and differences in type 1 and type 2 diabetes mellitus. AB - BACKGROUND: The aim of this work was to evaluate the impact of diabetes on female sexuality and to highlight any differences between sexuality in the context of type 1 and type 2 diabetes mellitus (DM). METHODS: The subjects selected were 49 women with type 1 DM, 24 women with type 2 DM, and 45 healthy women as controls. Each participant was given the nine-item Female Sexual Function Index questionnaire to complete. The metabolic profile was evaluated by body mass index and glycosylated hemoglobin assay. RESULTS: The prevalence of sexual dysfunction (total score <=30) was significantly higher in the type 1 DM group (25/49, 51%; 95% confidence interval [CI] 18-31) than in the control group (4/45, 9%; 95% CI 3 5; P=0.00006); there were no significant variations in the type 2 DM group (4/24, 17%; 95% CI 3-4) versus the control group (P=0.630, not statistically significant). The mean total score was significantly lower in the type 1 DM group (30.2+/-6.9) versus the control group (36.5+/-4.9; P=0.0003), but there was no significant difference between the type 2 DM group and the control group (P=0.773). With regard to specific questionnaire items, the mean values for arousal, lubrication, dyspareunia, and orgasm were significantly lower only in the type 1 DM group versus the control group. The mean values for desire were reduced in type 1 and type 2 DM groups versus control group. CONCLUSION: Type 1 DM is associated with sexual dysfunction. This may be due to classic neurovascular complications or to the negative impact of the disease on psychosocial factors. Larger and ideally longitudinal studies are necessary to better understand the relationship between DM and sexual dysfunction. PMID- 25709483 TI - Angiotensin receptor blocker telmisartan suppresses renal gluconeogenesis during starvation. AB - The kidney plays an important role in gluconeogenesis during starvation. To clarify the anti-diabetic action of angiotensin receptor blockers, we examined the effects of telmisartan on the sodium-glucose co-transporters (SGLT) and the pathways of renal gluconeogenesis in streptozotocin-induced diabetes mellitus (DM) rats. At 4 weeks, the DM rats treated with/without telmisartan for 2 weeks and normal control rats were used for the study after a 24-hour fast. SGLT2 expressed on the brush border membrane of the proximal convoluted tubules increased in the DM rats, but decreased in the rats treated with telmisartan. The expression of restriction enzymes of gluconeogenesis, glucose-6-phosphatase, and phosphoenolpyruvate carboxykinase increased in the proximal tubules in the DM rats, whereas these enzymes decreased in the kidneys of the rats treated with telmisartan. The elevated cytoplasmic glucose-6-phosphate and glucose levels in the kidney of DM rats significantly decreased in those treated with telmisartan, whereas those levels in the liver did not show significant change. Meanwhile, the high plasma glucose levels in the DM rats during the intravenous insulin tolerance tests were ameliorated by telmisartan. The increased fasting plasma glucose levels after 24 hours of starvation in the DM rats thus returned to the control levels by telmisartan treatment. In conclusion, the increased renal SGLT2 expression, elevated renal gluconeogenesis enzymes and extent of insulin resistance in the DM rats were ameliorated by telmisartan therapy, thus resulting in decreased plasma glucose levels after 24 hours of fasting. PMID- 25709484 TI - Effect of different exercise intensities on the pancreas of animals with metabolic syndrome. AB - INTRODUCTION: Metabolic syndrome (MS) comprises several metabolic disorders that are risk factors for cardiovascular disease and has its source connected to the accumulation of visceral adipose tissue (VAT) and development of insulin resistance. Despite studies showing beneficial results of exercise on several risk factors for cardiovascular disease, studies evaluating the effects of different intensities of exercise training on the pancreas with experimental models are scarce. METHODS: In total, 20 Wistar rats were used, divided into four groups: control (C), metabolic syndrome (MS and without exercise), metabolic syndrome and practice of walking (MSWalk), and metabolic syndrome and practice of running (MSRun). The applied procedures were induction of MS by fructose in drinking water; experimental protocol of walking and running; weighing of body mass and VAT; sacrifice of animals with blood collection and removal of organs and processing of samples for light microscopy using the analysis of volume densities (Vv) of the studied structures. RESULTS: Running showed a reduction of VAT weight (-54%), triglyceride levels (-40%), Vv[islet] (-62%), Vv[islet.cells] (-22%), Vv[islet.insterstitial] (-44%), and Vv[acinar.insterstitial] (-24%) and an increase of Vv[acini] (+21%) and Vv[acinar.cells] (+22%). Regarding walking, we observed a decrease of VAT weight (-34%) and triglyceride levels (-27%), an increase of Vv[islet.cells] (+72%) and Vv[acinar.cells] (+7%), and a decrease of Vv[acini] (-4%) and Vv[acinar.insterstitial] (-16%) when compared with those in the MS group. CONCLUSION: Our results suggest that the experimental model with low-intensity exercise (walking) seems to be more particularly recommended for preventing morphological and metabolic disorders occurring in the MS. PMID- 25709485 TI - Complete biodegradable nature of calcium hydroxylapatite after injection for malar enhancement: an MRI study. AB - BACKGROUND: Radiesse((r)) (Calcium hydroxylapatite [CaHA]) is a biocompatible, injectable gel for facial soft tissue augmentation. It is a completely biodegradable filler and this is well documented, but objective imaging methods to confirm this property are scarce. METHODS: We present a case report in which CaHA was injected into the midface of a 50-year-old woman for volume restoration and shaping of the cheek region. On the right side of the face, 1.6 mL CaHA was injected as several (5-7) small depots (0.1-0.2 mL) using a 28G 3/4 inch needle and the vertical supraperiosteal depot technique. On the contralateral side of the face, the subject received 1.6 mL CaHA over three entry points using a 27G 1 1/2 inch blunt cannula and the fanning technique. CaHA location and degradation were assessed using magnetic resonance imaging (MRI). RESULTS: CaHA appears as low-to-intermediate signal intensity on MRI images taken immediately after injection for malar enhancement with a symmetrical distribution. On MRI images taken 2.5 years after injection, no CaHA was visible but tissue volume remained increased, indicating a collagen-stimulating effect. The treatment was well tolerated. CONCLUSION: In addition to producing long-lasting aesthetic and collagen-stimulating effects, MRI images confirm that CaHA is completely biodegradable with no product remaining 2.5 years after injection. PMID- 25709486 TI - Noninvasive skin tightening: focus on new ultrasound techniques. AB - Microfocused ultrasound (MFU) has been recently developed to meet the ever growing public demand for achieving significant, noninvasive skin lifting and tightening. MFU can be focused on subcutaneous tissue where the temperature briefly reaches greater than 60 degrees C, producing small (<1 mm(3)) thermal coagulation points to a depth of up to 5 mm within the mid-to-deep reticular layer of the dermis and subdermis. The intervening papillary dermal and epidermal layers of skin remain unaffected. The application of heat at these discrete thermal coagulation points causes collagen fibers in the facial planes such as the superficial musculoaponeurotic system and platysma, as well as the deep reticular dermis, to become denatured, contracting and stimulating de novo collagen. A commercially available device combines MFU with high-resolution ultrasound imaging (MFU-V), which enables visualization of tissue planes to a depth of 8 mm and allows the user to see where the MFU energy will be applied (Ultherapy((r)); Ulthera Inc., Mesa, AZ, USA). Using different transducers, MFU-V treatment can be customized to meet the unique physical characteristics of each patient by adjusting energy and focal depth of the emitted ultrasound. By targeting the facial superficial musculoaponeurotic system, noninvasive tightening and lifting of sagging facial and neck skin and improvements in the appearance of wrinkles can be achieved. MFU-V can also improve lines and wrinkles of the decollete. Treatment protocols for the use of MFU-V continue to be refined, and its use in combination with other rejuvenation techniques has been demonstrated. Brief discomfort that often occurs during treatment can be minimized with oral nonsteroidal anti-inflammatory drugs. Other treatment-related adverse events include transient erythema, edema, and occasional bruising. MFU-V is best suited for patients with mild-to-moderate skin and soft tissue laxity. For older patients with severe skin laxity and marked platysmal banding, surgical treatment should be considered. PMID- 25709487 TI - Drug-induced skin reactions: a 2-year study. AB - BACKGROUND: The aim of this study was to analyze the clinical characteristics of patients with adverse cutaneous drug reactions, which occur when a medicinal product results in cutaneous morbidity. METHODS: The study included 308 patients who were diagnosed as having an adverse cutaneous drug reaction during the study period (2007-2009). In 84 cases, histopathologic examination of skin biopsies were also performed. RESULTS: Patients with drug reactions were found to be more commonly female (63%) than male (37%). Beta-lactam antibiotics were found to be the most frequent cause of adverse cutaneous drug reactions (42.7%), followed by non-steroidal anti-inflammatory drugs (16.5%). Acute urticaria was the most common clinical presentation (59.2%) followed by fixed drug eruptions (18.5%), and maculopapular eruptions (14.9%). CONCLUSION: Adverse cutaneous drug reactions in our study population were mainly induced by beta-lactam antibiotics and non steroidal anti-inflammatory drugs. The most common forms of cutaneous adverse drug reactions were found to be acute urticaria, fixed drug eruptions, and maculopapular rashes. PMID- 25709488 TI - Antiaging, photoprotective, and brightening activity in biorevitalization: a new solution for aging skin. AB - BACKGROUND: Age-related changes in the dermis can be considered the result of intrinsic factors and the consequence of environmental damage, mainly due to ultraviolet (UV) radiation from the sun (responsible for skin photoaging). The great versatility of the mesotherapy "biorevitalization" lies in the synergy between different biological effects of the active injected substances, which treats the skin in a more complete way. Several studies about biorevitalization efficacy showed good results. To date, however, objective results supported by instrumental evaluation are very sparse. PURPOSE: This study evaluated the efficacy of an injectable solution (32 mg of hyaluronic acid plus an antiaging antioxidant complex consisting of vitamins, minerals, and amino acids) in the treatment of skin aging and photoaging. METHODS: A total of 64 female volunteers (37-60 years) underwent four sessions of biorevitalization at 3-week intervals, involving multiple injections in the face (external corner of the eye and cheek), neck, decolletage, and back of the hands. The esthetic result was assessed at baseline and after 6, 9, and 12 weeks, and was established through the use of clinical and instrumental evaluations, supported by photographic documentation. Additionally, a phototest was performed to assess the effect of biorevitalization treatment on UVB-induced erythema. RESULTS: Instrumental assessment showed, as early as after the second biorevitalizing treatment, the antiaging efficacy of the tested product; there was a clinical and statistically significant improvement of profilometric parameters, skin brightness, pigmentation, and deep skin hydration. The study product induced a statistically significant decrease of the visual score of the UVB-induced erythema compared with baseline, which was statistically different from placebo. CONCLUSION: The study confirmed the well known efficacy of biorevitalization in skin rejuvenation. The positive difference between deep and superficial skin hydration registered at the end of the trial suggested improved skin moisture retention of the stratum corneum. Furthermore, the obtained results suggest that the injected product could intervene at different moments of the skin pigmentation process by activating an intrinsic photoprotective mechanism and improving skin pigmentation quality. It may be that these processes employ common mechanisms in which antioxidants could play a pivotal role. This last hypothesis deserves further investigation. PMID- 25709490 TI - Solar exposure(s) and facial clinical signs of aging in Chinese women: impacts upon age perception. AB - A new reference clinical atlas of facial signs dedicated to photoaging was applied to 301 Chinese women of various ages through standardized photographs. Such approach aimed at better describing the facial changes induced by both real/chronological age and sun exposure and their respective impact on two subcohorts of different behavior with regard to sun exposure. A total of 28 various facial signs were individually graded according to their severity by a panel of experts, and a perceived apparent age of each subject was assessed. Results showed that the severity of major signs significantly increased rather linearly with age, with a higher rate in sun-exposed subjects as compared with subjects who regularly avoid sun exposure. The severity of facial signs, all impacted by sun exposure, better correlated with perceived apparent age than real/chronological age. The protocol used in the present work, similar to that previously applied to two cohorts of French women, assigned a greater impact of sun exposure in the facial aging signs of Asian women - all clinical signs are influenced by extrinsic factors - as compared with Caucasian women of comparable ages, likely related to much more intense ultraviolet (UV) radiation. PMID- 25709489 TI - New approach to the understanding of keloid: psychoneuroimmune-endocrine aspects. AB - The skin is a dynamic and complex organ that relies on the interrelation among different cell types, macromolecules, and signaling pathways. Further, the skin has interactions with its own appendages and other organs such as the sebaceous glands and hair follicles, the kidney, and adrenal glands; systems such as the central nervous system; and axes such as the hypothalamic-pituitary-adrenal axis. These continuous connections give the skin its versatility, and when an injury is caused, some triggers start a cascade of events designed to restore its integrity. Nowadays, it is known that this psychoneuroimmune-endocrine intercommunication modulates both the homeostatic condition and the healing process. In this sense, the skin conditions before a trauma, whether of endogenous (acne) or exogenous origin (injury or surgical incision), could regulate the process of tissue repair. Most skin diseases such as psoriasis and atopic dermatitis, among others, have in their pathophysiology a psychogenic component that triggers integrated actions in the nervous, immune, and endocrine systems. However, fibroproliferative disorders of wound healing, such as hypertrophic scar and keloid, are not yet included in this listing, despite showing correlation with stress, especially with the psychosocial character. This review, by understanding the "brain-skin connection", presents evidence that allows us to understand the keloid as a psychomediated disease. PMID- 25709491 TI - Value of portal venous system radiological indices in predicting esophageal varices. AB - INTRODUCTION: Portal hypertension results from increased resistance to portal blood flow and has the potential complications of variceal bleeding and ascites. The splenoportal veins increase in caliber with worsening portal hypertension, and partially decompress by opening a shunt with systemic circulation, ie, a varix. In the event of portosystemic shunting, there is a differential decompression across the portal vein and splenic vein (portal vein > splenic vein), with a resultant decrease in the ratio of portal vein diameter to that of splenic vein. Portal vein to splenic vein diameter ratio and gradient could be valuable tools in predicting the presence of portosystemic shunting. METHODS: We retrospectively reviewed patients with cirrhosis who underwent esophagogastroduodenoscopy (EGD) for variceal screening and had a computerized tomogram (CT) of the abdomen within 6 months of the index endoscopic study, between January 2009 and December 2013. Patients on nonselective beta blockers, patients with presinusoidal portal hypertension (portal vein thrombosis or extrinsic compression), and patients who had undergone portosystemic shunting procedures (transjugular intrahepatic portosystemic shunt [TIPS]) or balloon occluded retrograde transvenous obliteration (BRTO) were excluded from the study. Splenic and portal vein diameters were measured (in mm) just proximal and distal to the splenomesenteric venous confluence, respectively. RESULTS: A total of 164 patients were included in the study; of these, 60% (n=98) were male and 40% (n=66) were female. The mean age of the study population was 58.7 years. A total of 126 patients (77%) had varices, while 38 patients (33%) did not. The mean Model for End-Stage Liver Disease (MELD) score was 5.9 for those who had varices as compared with 7.03 for those who did not. The mean of ratios of portal vein to splenic vein diameters in patients with varices was 1.27 (+/-0.2), while it was 1.5 (+/-0.23) in those without varices. This difference was statistically significant (P<0.001). The mean of the gradients between the portal vein and splenic vein diameters was 2.7 (+/-2) mm for patients with varices as compared with 5 (+/-1.8) mm in those without varices. This difference was also statistically different (P<0.001). These correlations were statistically significant even after controlling for age, sex, and MELD. These radiological indices also had statistically significant correlations with the presence of gastric varices (P=0.018 for the ratio and P=0.01 for the gradient). A discriminant function analysis was performed that generated the equation: D = 2.68 (ratio of portal vein to splenic vein diameters) + 0.187 (gradient of portal vein to splenic vein diameters, in mm) - 4.152. This equation had a very high sensitivity, of 95%, but low specificity, of 26.3%, in predicting the presence of esophageal varices. CONCLUSION: Both venous diameter ratio (portal vein size/splenic vein size) and venous diameter gradient in mm (portal vein size - splenic vein size) calculated from CTs of the abdomen were good predictors of presence of esophageal varices. These parameters might be useful in stratifying patients at risk of developing esophageal varices who are poor candidates for endoscopic evaluation. PMID- 25709492 TI - Eggshell membrane hydrolyzates activate NF-kappaB in vitro: possible implications for in vivo efficacy. AB - PURPOSE: Eggshell membrane (ESM) has been shown to contain naturally occurring bioactive components, and biological activities such as reducing proinflammatory cytokines, liver fibrosis, and joint pain in osteoarthritis sufferers have also been reported for ESM matrix as a whole. Nuclear factor kappa-light-chain enhancer of activated B-cells (NF-kappaB) is a signaling protein found in the cytoplasm of nearly all human and animal cell types and is a primary regulator of immune function. The studies reported herein were designed to investigate the possible role that NF-kappaB activity might play in the reported biological activities of ESM. METHODS: Three ESM hydrolyzates produced via fermentation, enzymatic, or chemical hydrolysis were evaluated in vitro in either human peripheral blood mononuclear cell or THP-1 (human leukemic monocyte) cell cultures for NF-kappaB activity following 4-hour exposure. The hydrolyzates were compared with untreated control cells or cells incubated with lipopolysaccharide or ascorbic acid. The source of ESM activity was also evaluated. RESULTS: NF kappaB levels were increased above levels found in untreated cells at all three dilutions (1:100, 1:1,000, and 1:10,000) for the fermentation hydrolyzate of ESM (ESM-FH) (P=0.021, P=0.020, P=0.009, respectively) in peripheral blood mononuclear cells. The enzymatic hydrolyzate of ESM (ESM-EH) also produced statistically significant levels of activated NF-kappaB at the 1:100 and 1:1,000 dilutions (P=0.004, P=0.006, respectively) but fell just shy of significance at the 1:10,000 dilution (P=0.073). Similarly, ESM-FH (P=0.021, P=0.002) and ESM-EH (P=0.007, P=0.007) activated NF-kappaB in THP-1 cells at 1:1,000 and 1:10,000 dilutions, respectively. The chemical hydrolyzate of ESM (ESM-CH) showed statistically significant levels of activation at the 1:1,000 dilution (P=0.005) but failed to differ from untreated cells at the 1:10,000 dilution (P=0.193) in THP-1 cells. CONCLUSION: Results from our studies provide evidence that ESM hydrolyzates significantly activate NF-kappaB, and the source of this activity was investigated to confirm that it is inherent to ESM and not derived from bacterial contamination. Based on our findings, we propose a plausible hypothesis as to how increased NF-kappaB activity might translate into the in vivo efficacy that has been observed with ESM via an "oral tolerance" mechanism. PMID- 25709493 TI - Low-dose synthetic adrenocorticotropic hormone-analog therapy for nephrotic patients: results from a single-center pilot study. AB - INTRODUCTION: This report describes our experience using a low-dose synthetic adrenocorticotropic hormone (ACTH) analog for patients affected by nephrotic syndrome who had not responded to or had relapsed after steroid and immunosuppressive treatments. PATIENTS AND METHODS: Eighteen adult nephrotic patients with an estimated glomerular filtration rate >30 mL/min were recruited. Histological pictures included ten of membranous nephropathy, three of membranous proliferative glomerulonephritis, three of minimal change, and two of focal segmental glomerular sclerosis. All patients received the synthetic ACTH analog tetracosactide 1 mg intramuscularly once a week for 12 months. Estimated glomerular filtration rate, proteinuria, serum lipids, albumin, glucose, and potassium were determined before and during the treatment. RESULTS: One of the 18 patients discontinued the treatment after 1 month because of severe fluid retention, and two patients were lost at follow-up. Complete remission occurred in six cases, while partial remission occurred in four cases (55.5% responder rate). With respect to baseline, after 12 months proteinuria had decreased from 7.24+/-0.92 to 2.03+/-0.65 g/day (P<0.0001), and serum albumin had increased from 2.89+/-0.14 to 3.66+/-0.18 g/dL (P<0.0001). Total and low-density lipoprotein cholesterol had decreased from 255+/-17 to 193+/-10 mg/dL (P=0.01), and from 168+/-18 to 114+/-7 mg/dL (P=0.03), respectively. No cases of severe worsening of renal function, hyperglycemia, or hypokalemia were observed, and no admissions for cardiovascular or infectious events were recorded. CONCLUSION: Tetracosactide administration at the dosage of 1 mg intramuscularly per week for 12 months seems to be an acceptable alternative for nephrotic patients unresponsive or relapsing after steroid-immunosuppressive regimens. Further studies should be planned to assess the effect of this low-dose ACTH regimen also in nephrotic patients not eligible for kidney biopsy or immunosuppressive protocols. PMID- 25709494 TI - Calciphylaxis in end-stage renal disease prior to dialytic treatment: a case report and literature review. AB - INTRODUCTION: Calciphylaxis is a rare medical condition that is usually diagnosed in patients suffering from end-stage renal disease who are already receiving renal replacement therapy and in those post-transplantation. The pathogenesis still remains to be fully elucidated; hence, the treatment is not uniform. The prognosis is generally poor. The ulcerative stage exhibits a worse prognosis than the nonulcerative one. Calciphylaxis presenting in terminal kidney disease prior to dialytic treatment has only rarely been reported. CASE PRESENTATION: A 32-year old female Caucasian clerk sought medical attention for increasing tiredness and lower limb skin ulcers. Polycystic kidney disease was diagnosed in her late father and two of her siblings. At the first nephrology consultation, obesity, pallor, bilateral flank masses with ballottement, and two ulcers with a dark necrotic center on the distal left leg were noted. In addition, another indurated light bluish lesion of 5 cm just above the right knee with intact skin was observed. All lesions were very tender and warm on touch. Laboratory results yielded hypercalcemia, hyperphosphatemia, anemia, and parathyroid hormone levels that were more than ten times the normal values in the patient, and with a glomerular filtration rate of 4 mL/minute. Skin biopsy confirmed the suspicion of calciphylaxis. The patient was placed on peritoneal dialysis with low Ca concentration baths, cinacalcet, and aluminum hydroxide. The results included correction of hypercalcemia, improvement of phosphate levels, and the product of both Ca and phosphate, but only a transitory decrease in serum parathyroid hormone levels. The ulcerations were completely healed after 2 months of treatment. Cinacalcet was discontinued after 18 months, but multiple large-size, nonulcerative indurated areas appeared 3 months later in the lower limbs after discontinuation of the drug. A parathyroidectomy performed 17 months later revealed a four-gland hyperplastic disease. The patient experienced relief of skin symptoms soon after the procedure and remains in a very satisfactory condition. CONCLUSION: Calciphylaxis is a very complex clinical entity. Calciphylaxis presenting prior to dialytic treatment in end-stage renal disease is rare in the absence of a trigger. Cinacalcet and parathyroidectomy should be considered in selected patients. PMID- 25709496 TI - Reanalysis of morphine consumption from two randomized controlled trials of gabapentin using longitudinal statistical methods. AB - BACKGROUND: Postoperative pain management in total joint replacement surgery remains ineffective in up to 50% of patients and has an overwhelming impact in terms of patient well-being and health care burden. We present here an empirical analysis of two randomized controlled trials assessing whether addition of gabapentin to a multimodal perioperative analgesia regimen can reduce morphine consumption or improve analgesia for patients following total joint arthroplasty (the MOBILE trials). METHODS: Morphine consumption, measured for four time periods in patients undergoing total hip or total knee arthroplasty, was analyzed using a linear mixed-effects model to provide a longitudinal estimate of the treatment effect. Repeated-measures analysis of variance and generalized estimating equations were used in a sensitivity analysis to compare the robustness of the methods. RESULTS: There was no statistically significant difference in morphine consumption between the treatment group and a control group (mean effect size estimate 1.0, 95% confidence interval -4.7, 6.7, P=0.73). The results remained robust across different longitudinal methods. CONCLUSION: The results of the current reanalysis of morphine consumption align with those of the MOBILE trials. Gabapentin did not significantly reduce morphine consumption in patients undergoing major replacement surgeries. The results remain consistent across longitudinal methods. More work in the area of postoperative pain is required to provide adequate management for this patient population. PMID- 25709497 TI - The analgesic effect of combined treatment with intranasal S-ketamine and intranasal midazolam compared with morphine patient-controlled analgesia in spinal surgery patients: a pilot study. AB - OBJECTIVES: Ketamine is a well-known analgesic and dose-dependent anesthetic used in emergency and disaster medicine. Recently, a new formulation of S-ketamine, as an intranasal spray, was developed and tested in our institution in healthy volunteers. The authors investigated the effect of intranasal S-ketamine spray combined with midazolam intranasal spray in postoperative spinal surgery patients. MATERIALS AND METHODS: In this prospective, computer-randomized, double blinded noninferiority study in spinal surgery patients, the effects of intranasal S-ketamine and midazolam were compared with standard morphine patient controlled analgesia (PCA). The primary end point was the numeric rating scale pain score 24 hours after surgery. RESULTS: Twenty-two patients finished this study, eleven in each group. There were similar numeric rating scale scores in the morphine PCA and the S-ketamine-PCA groups at 1, 2, 4, 24, 48, and 72 hours after surgery during rest as well as in motion. There were no differences in the satisfaction scores at any time between the groups. The number of bolus demands and deliveries was not significantly different. DISCUSSION: In our study, we found that an S-ketamine intranasal spray combined with intra-nasal midazolam was similar in effectiveness, satisfaction, number of demands/deliveries of S ketamine and morphine, and number/severity of adverse events compared with standard intravenous PCA with morphine. S-ketamine can be regarded as an effective alternative for a traditional intravenous morphine PCA in the postoperative setting. PMID- 25709495 TI - Chronic pain management in the obese patient: a focused review of key challenges and potential exercise solutions. AB - In obese persons, general and specific musculoskeletal pain is common. Emerging evidence suggests that obesity modulates pain via several mechanisms such as mechanical loading, inflammation, and psychological status. Pain in obesity contributes to deterioration of physical ability, health-related quality of life, and functional dependence. We present the accumulating evidence showing the interrelationships of mechanical stress, inflammation, and psychological characteristics on pain. While acute exercise may transiently exacerbate pain symptoms, regular participation in exercise can lower pain severity or prevalence. Aerobic exercise, resistance exercise, or multimodal exercise programs (combination of the two types) can reduce joint pain in young and older obese adults in the range of 14%-71.4% depending on the study design and intervention used. While published attrition rates with regular exercise are high (~50%), adherence to exercise may be enhanced with modification to exercise including the accumulation of several exercise bouts rather than one long session, reducing joint range of motion, and replacing impact with nonimpact activity. This field would benefit from rigorous comparative efficacy studies of exercise intensity, frequency, and mode on specific and general musculoskeletal pain in young and older obese persons. PMID- 25709498 TI - Internalization: acute apoptosis of breast cancer cells using herceptin immobilized gold nanoparticles. AB - Herceptin, the monoclonal antibody, was successfully immobilized on gold nanoparticles (GNPs) to improve their precise interactions with breast cancer cells (SK-BR3). The mean size of the GNPs (29 nm), as determined by dynamic light scattering, enlarged to 82 nm after herceptin immobilization. The in vitro cell culture experiment indicated that human skin cells (FB) proliferated well in the presence of herceptin-conjugated GNP (GNP-Her), while most of the breast cancer cells (SK-BR3) had died. To elucidate the mechanism of cell death, the interaction of breast cancer cells with GNP-Her was tracked by confocal laser scanning microscopy. Consequently, GNP-Her was found to be bound precisely to the membrane of the breast cancer cell, which became almost saturated after 6 hours incubation. This shows that the progression signal of SK-BR3 cells is retarded completely by the precise binding of antibody to the human epidermal growth factor receptor 2 receptor of the breast cancer cell membrane, causing cell death. PMID- 25709499 TI - Evaluating the safety and efficacy of axitinib in the treatment of advanced renal cell carcinoma. AB - Axitinib is a tyrosine kinase inhibitor of vascular endothelial growth factor receptor, platelet-derived growth factor receptor-alpha, and c-kit. Phase I studies demonstrated 5 mg twice daily as the recommended starting dose with notable effects seen in renal cell carcinoma, an observation confirmed in Phase II trials. The trial of comparative effectivess of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS) was an international randomized Phase III study designed for registration purposes, compared axitinib to sunitinib. This trial randomized 723 patients with metastatic kidney cancer to axitinib or sunitinib in the second-line setting and demonstrated a median progression-free survival of 6.7 months for axitinib versus 4.7 months for sorafenib (P<0.0001). Clinical benefit was detected regardless of prior therapy, but no overall survival benefit has been observed. Axitinib is well tolerated without a significant effect on quality of life. The most common grade 3 toxicities are hypertension (16%), diarrhea (11%), and fatigue (11%), with other notable side effects being anorexia, nausea, hand-foot syndrome, and rash. Patients who developed diastolic blood pressure >90 mmHg were noted to have significantly longer median overall survival and overall response rates when compared to normotensive patients. Therefore, the manufacturer recommends escalating the twice-daily dose to 7 mg and 10 mg, as tolerated, if there is no significant increase in blood pressure on treatment. Currently, axitinib is approved for use in the second-line setting for patients with metastatic renal cell carcinoma. Research is ongoing in other disease settings. PMID- 25709500 TI - Gastroenteritis attributable to rotavirus in hospitalized Saudi Arabian children in the period 2007-2008. AB - PURPOSE: Rotavirus (RV) is a leading cause of severe gastroenteritis (GE) in children across the world. As there is a lack of epidemiological data for RV gastroenteritis (RVGE) in Saudi Arabia, this hospital-based study was designed to estimate the disease burden of RVGE and assess the prevalent RV types in Saudi children younger than 5 years of age. PATIENTS AND METHODS: Children hospitalized for acute GE were enrolled at four pediatric referral hospitals in Saudi Arabia. The study was conducted from February 2007 to March 2008 and used the World Health Organization's generic protocol for RVGE surveillance. The Vesikari severity scale was used to assess the severity of RVGE. Stool samples were tested for RV using an enzyme-linked immunosorbent assay. Samples were further typed by reverse transcriptase-polymerase chain reaction and hybridization assay for determining the G and P types. RESULTS: A total of 1,007 children were enrolled; the final analysis included 970 children, of whom 395 were RV positive, 568 were RV negative, and seven had unknown RV status. The proportion of RVGE among GE hospitalizations was 40.7% (95% confidence interval: 37.6-43.9). The highest percentage of RVGE hospitalizations (83.1%) was seen in children younger than 2 years of age. The highest proportion of RV among GE hospitalizations was in June 2007 with 57.1%. The most common RV types detected were G1P[8] (49.3%), G1G9P[8] (13.2%), and G9P[8] (9.6%). Before hospitalization, severe GE episodes occurred in 88.1% RV-positive and 79.6% RV-negative children. Overall, 94% children had recovered by the time they were discharged. Two children (one RV positive and one RV negative) died due to GE complications. CONCLUSION: RVGE is responsible for a high proportion of hospitalizations in Saudi children younger than 5 years of age. Routine RV vaccination has therefore been introduced into the national immunization program and may help reduce the morbidity, mortality, and disease burden associated with RVGE in Saudi Arabia. PMID- 25709502 TI - Positive predictive values of the International Classification of Diseases, 10th revision diagnoses of Gram-negative septicemia/sepsis and urosepsis for presence of Gram-negative bacteremia. AB - BACKGROUND: Health care databases are a valuable resource for infectious disease epidemiology if diagnoses are accurately coded. We examined the ability of diagnostic coding to accurately identify Gram-negative bacteremia. METHODS: We randomly selected 100 patients among 1,703 patients recorded in the Danish National Patient Register with a diagnosis of either "septicemia/sepsis due to other Gram-negative organisms" (International Classification of Diseases, 10th revision [ICD-10] code A41.5) or "urosepsis" (ICD-10 code A41.9B) who had been admitted at Aalborg University Hospital, Denmark between 1994 and 2012. We estimated the positive predictive value (PPV) of these diagnoses for presence of Gram-negative bacteremia, using microbiological results from blood cultures as standard reference. Complementary clinical information was obtained from the medical records. RESULTS: Of the 100 patients registered with Gram-negative septicemia/sepsis or urosepsis, 72 had blood culture confirmed Gram-negative bacteremia, four patients had monomicrobial Gram-positive bacteremia, 21 patients had a negative blood culture, and three had no blood culture taken. The overall PPV of a blood culture confirmed Gram-negative bacteremia diagnosis was 72% (95% confidence interval [CI]: 62%-81%); for ICD-10 code A41.5 it was 86% (95% CI: 74% 94%) and for ICD-10 code A41.9B it was 55% (95% CI: 39%-70%). The highest PPV was achieved for diagnoses registered in the most recent calendar period (2009-2012) and for secondary discharge diagnoses. CONCLUSION: Our findings indicated good agreement between ICD-10 code A41.5 "septicemia/sepsis due to other Gram-negative organisms" and Gram-negative bacteremia, whereas ICD-10 code A41.9B "urosepsis" was not suited for identification of Gram-negative bacteremia. PMID- 25709501 TI - Risk factors for amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease. It is typically fatal within 2-5 years of symptom onset. The incidence of ALS is largely uniform across most parts of the world, but an increasing ALS incidence during the last decades has been suggested. Although recent genetic studies have substantially improved our understanding of the causes of ALS, especially familial ALS, an important role of non-genetic factors in ALS is recognized and needs further study. In this review, we briefly discuss several major genetic contributors to ALS identified to date, followed by a more focused discussion on the most commonly examined non-genetic risk factors for ALS. We first review factors related to lifestyle choices, including smoking, intake of antioxidants, physical fitness, body mass index, and physical exercise, followed by factors related to occupational and environmental exposures, including electromagnetic fields, metals, pesticides, beta-methylamino-L-alanine, and viral infection. Potential links between ALS and other medical conditions, including head trauma, metabolic diseases, cancer, and inflammatory diseases, are also discussed. Finally, we outline several future directions aiming to more efficiently examine the role of non-genetic risk factors in ALS. PMID- 25709504 TI - CYFRA 21-1 in urine: a diagnostic marker for endometriosis? AB - Diagnostic workup of endometriosis usually involves laparoscopic inspection and histological examination of biopsies. Unequivocal laboratory parameters for this ailment have not been available in routine diagnostic evaluations thus far. In this study, we examined urine concentrations of cytokeratin 19 (CYFRA 21-1), a structural protein specific for epithelia. We performed immunoassays for CYFRA 21 1 in urine samples from women afflicted with endometriosis throughout their menstrual cycle. We observed a significant increase in CYFRA 21-1 concentrations, corrected by creatinine levels, in the late follicular phase as compared with the level in healthy controls. We conclude that cyclically increased CYFRA 21-1 concentrations in urine could serve as a valuable noninvasive diagnostic parameter in the workup of clinically manifesting endometriosis. PMID- 25709505 TI - Health-related quality of life in southern Iranian rural women: a multivariate multilevel study. AB - PURPOSE: The evaluation of health-related quality of life (HRQOL) is increasingly growing to be of much significance. In an attempt to improve the agricultural conditions and to prevent the rural-urban migration, analyzing HRQOL in rural communities has gained significant governmental attention. The purpose of this study was initially to investigate rural women's HRQOL, and then to assess the influence of some specific covariates on four domains of rural women's HRQOL via multivariate analysis (MA) and multivariate multilevel analysis (MMA), and finally to compare the results. METHODS: Out of 146 active health centers in villages around Shiraz, Iran, ten health centers were selected, using a multistage random sampling process. These ten health centers covered 18 villages. In this cross-sectional study, all women over the age of 15 in a sample of 1,128 rural residents were interviewed using a brief version of the World Health Organization HRQOL (the WHOQOL-BREF) questionnaire. Assessing the influence of some specific covariates on the four domains of rural women's HRQOL was conducted by MA and MMA. RESULTS: The average range for all four domain scores was between 12.53 and 14.27, which indicates that HRQOL for rural women is acceptable on the whole. The social relations domain and the environmental domain received the highest (14.3+/-2.5 SD) and the lowest (12.5+/-2.3 SD) scores respectively. Marital status did not indicate any significant effects on MA, but it presented an important influence on MMA. Furthermore, age and chronic diseases showed indifferent levels of significance in the two analytical methods. CONCLUSION: Rural women are in need of more heedfulness during their lives, especially about facilities and health. MMA is a more accurate procedure in exploring the important covariates in HRQOL. PMID- 25709503 TI - Immune reconstitution inflammatory syndrome in HIV-infected patients. AB - Access to antiretroviral therapy (ART) is improving worldwide. Immune reconstitution inflammatory syndrome (IRIS) is a common complication of ART initiation. In this review, we provide an overview of clinical and epidemiological features of HIV-associated IRIS, current understanding of pathophysiological mechanisms, available therapy, and preventive strategies. The spectrum of HIV-associated IRIS is described, with a particular focus on three important pathogen-associated forms: tuberculosis-associated IRIS, cryptococcal IRIS, and Kaposi's sarcoma IRIS. While the clinical features and epidemiology are well described, there are major gaps in our understanding of pathophysiology and as a result therapeutic and preventative strategies are suboptimal. Timing of ART initiation is critical to reduce IRIS-associated morbidity. Improved understanding of the pathophysiology of IRIS will hopefully enable improved diagnostic modalities and better targeted treatments to be developed. PMID- 25709506 TI - Random-start GnRH antagonist for emergency fertility preservation: a self controlled trial. AB - The aim of this study is to evaluate the feasibility and safety of random-start controlled ovarian hyperstimulation (COH) for emergency fertility preservation, regardless of the phase of the menstrual cycle. A self-controlled pilot clinical trial (NCT01385332) was performed in an acute-care teaching hospital and in two private reproductive centers in Barcelona, Spain. Eleven egg donors participated in the study. Two random-start gonadotropin-releasing hormone (GnRH) antagonist protocols were assessed in which ganirelix was initiated on either day 10 (protocol B) or on day 20 (protocol C) of the menstrual cycle and was continued until estradiol levels were below 60 pg/dL. These protocols were compared with a standard protocol (protocol A). The main outcome of interest was the number of metaphase 2 oocytes retrieved. Results from this study show that the number of mature oocytes retrieved was comparable across the different protocols (14.3+/ 4.6 in the standard protocol versus 13.0+/-9.1 and 13.2+/-5.2 in protocols B and C, respectively; values expressed as mean +/- standard deviation). The mean number of days needed for a GnRH antagonist to lower estradiol levels, as well as the ongoing pregnancy rates, were also similar when protocols B (stimulation in follicular phase) and C (stimulation on luteal phase) were compared with protocol A (standard stimulation). GnRH antagonists can be effectively used for random start controlled ovarian hyperstimulation with an ovarian response similar to that of standard protocols, and the antagonists appear suitable for emergency fertility preservation in cancer patients. PMID- 25709507 TI - Gunshot-like wound caused by sling shot injury - a case report. AB - We report a rare case of sling shot injury that presented with a gunshot-like wound with preseptal cellulitis, in a toddler. An 11-month-old Malay child presented with a gunshot-like wound over the forehead following sling shot injury. On examination, he had a deep circular laceration wound over the forehead, measuring 2.0 cm in diameter, with minimal bleeding. There was no obvious foreign body seen inside the wound and no palpable foreign body surrounding the wound. The gunshot-like wound was associated with left preseptal cellulitis. A skull X-ray showed a white opaque foreign body in the left frontal bone. Computed tomography (CT) scan of orbit and brain revealed a left comminuted fracture of the left orbital roof, and left frontal brain contusion with prelesional edema. Wound exploration was performed and revealed a 0.5 cm unshattered marble embedded in the left frontal bone. The marble and bone fragments were removed. The left preseptal cellulitis responded well to intravenous antibiotic and topical antibiotic. PMID- 25709508 TI - Heparin requirements for full anticoagulation are higher for patients on dabigatran than for those on warfarin - a model-based study. AB - PURPOSE: Dabigatran (D) is increasingly used for chronic anticoagulation in place of warfarin (W). These patients may present for catheter-based procedures requiring full anticoagulation with heparin. This study compares the heparin sensitivity of patients previously on dabigatran, on warfarin, or on no chronic anticoagulant during ablation of atrial fibrillation. PATIENTS AND METHODS: In a retrospective study of patients treated with D, W, or neither drug (N) undergoing atrial ablation, the timing of heparin doses and resulting activated clotting times were collected. First, the initial activated clotting time response to the first heparin bolus was compared. Then, a non-linear mixed effects modelling (NONMEM) analysis was performed, fitting a pharmacokinetic and -dynamic model to the entire anticoagulation course of each patient. Resulting model coefficients were used to compare the different patient groups. RESULTS: Data for 66 patients on dabigatran, 95 patients on warfarin, and 27 patients on no anticoagulation were retrieved. The last dose of dabigatran or warfarin had occurred 27 hours and 15 hours before the procedure. Groups D and N both responded significantly less (P<0.05) to the initial heparin bolus than Group W (approximately 50%). Likewise, the model coefficients resulting from the fit to each group reflected a significantly lower heparin sensitivity in groups D and N compared to W. Clearances of the heparin effect in the model did not differ significantly among groups. CONCLUSION: Patients on warfarin with an average INR of 1.5 or higher are more sensitive to heparin than patients not previously anticoagulated or patients who discontinued dabigatran 27 hours earlier (approximately two half-lives) warfarin. PMID- 25709509 TI - Detectability and acceptability of continuous pulse signals for the MemoPatch((r)) device, an electronic skin patch intended to deliver tactile medication reminder signals. AB - BACKGROUND: Unintended forgetfulness is the most common cause of medication nonadherence. MemoPatch((r)) is an electronic skin patch intended to deliver discreet tactile medication reminder stimuli. This study aimed 1) to evaluate, within an experimental setup, the detectability and acceptability of fifteen continuous bipolar pulse signals; 2) to identify variables, if any, associated with differential perception of the candidate reminder signals; and 3) to collect safety data as reported by subjects or observed by staff. METHODS: This was a laboratory experiment involving 147 healthy adult volunteers (55.1% female, 98.0% Caucasian, with age 41.8+/-16.0 years, body mass index [BMI] 24.7+/-4.4, upper body adiposity 28.5%+/-8.3% body fat, and skin impedance 367.6+/-140.8 Omega) and using an experimental version of the MemoPatch((r)). Following four training signals administered in fixed order, subjects were exposed to a set of fifteen randomly sequenced signals varying in rise and fall time, width, and current, to be rated in terms of detectability ("too weak", "appropriate", or "too strong") and acceptability. RESULTS: Ratings of "appropriate" were virtually independent of such variables as sex, BMI, upper body adiposity, and skin impedance at the patch location. Five signals were rated as "appropriate" by >=67% of subjects and acceptable by >=95% of subjects, virtually independently of the indicators of interest, and were retained as candidate signals for use in next stages of development and commercialization. Nine adverse events, none serious, were observed in six subjects. CONCLUSION: This study yielded five effective and safe candidate signals for potential use in the MemoPatch((r)) device, all equally considered to be of appropriate detectability and high acceptability, in an experimental context. The signals were independent from, and therefore highly robust relative to, sex, BMI, upper body adiposity, and skin impedance at the patch site, lending additional generalizability to the signals and hence their potential relevance to broad commercial application. PMID- 25709511 TI - Influences of a yoga intervention on the postural skills of the Italian short track speed skating team. AB - INTRODUCTION: In preparation for a short track speed skating season, eight men and seven women were given yoga sessions during an 8-week high volume training cycle. The sessions were planned according to the postural aspects specific to short track speed skating technical requirements. Three specific goals were selected for the intervention: 1) to observe whether the practice of yoga as postural training could improve the efficiency and the athlete's repertoire along the muscular synergies solicited in the short track speed skating specific technique; 2) to enhance and diversify the motor time-on-task of athletes without changing the prescription of other training stimulus; and 3) to lower the risk of injury during periods with high volumes of training. METHODS: A total of 36 sessions of yoga were given. Three postural tests were administered before and after the intervention with 14 angles analyzed. Non-parametric Wilcoxon test was used to compare angles' variations. RESULTS: The 36 yoga sessions totalized 986 minutes of motor time-on-task, registering a proportion of 30% of the global motor time-on-task of the training cycle. Improvements were found in eleven of the 14 angles measured when comparing pre- and post-postural tests (P-value from 0.01 to 0.005). During the 8 weeks, excepting traumatic injuries due to short track speed skating accidents, no skaters suffered injuries linked to the high volume of training. Following the intervention, coaches noticed, following their on-ice feedbacks, an adjustment in the efficiency of the skating technique, in particular regarding hip dissociation. CONCLUSION: These results suggest that yoga could be inserted into out-of-season training cycles, even in a high volume training cycle. Planned with the decision training tools, it allows athletes to diversify their motor time-on-task by integrating a new functional range of generic movements with the solicitation of neuromuscular synergies related to the specificity of their sport. PMID- 25709510 TI - Inhalation drug delivery devices: technology update. AB - The pulmonary route of administration has proven to be effective in local and systemic delivery of miscellaneous drugs and biopharmaceuticals to treat pulmonary and non-pulmonary diseases. A successful pulmonary administration requires a harmonic interaction between the drug formulation, the inhaler device, and the patient. However, the biggest single problem that accounts for the lack of desired effect or adverse outcomes is the incorrect use of the device due to lack of training in how to use the device or how to coordinate actuation and aerosol inhalation. This review summarizes the structural and mechanical features of aerosol delivery devices with respect to mechanisms of aerosol generation, their use with different formulations, and their advantages and limitations. A technological update of the current state-of-the-art designs proposed to overcome current challenges of existing devices is also provided. PMID- 25709512 TI - The relationship between sleep habits, anxiety, and depression in the elderly. AB - PURPOSE: The objective of this study is to determine which sleep-related behaviors are most often used by the elderly according to the presence or absence of anxiety and mood disorders. In particular, we are attempting to determine whether these behaviors are associated with the probability of suffering from a mental disorder. The behaviors being examined in the present study are taking naps, television watching or reading at bedtime, physical exercise at bedtime, relaxing activities at bedtime, and caffeine consumption in the evening. METHODS: The sample in this study consists of 2,759 participants aged 65 and over, with a mean age of 73.8. They were recruited through a method of random generation of telephone numbers according to a sampling strategy based on geographic location. After the goal of the study was explained to them, the participants agreed to have health professionals visit their home and to answer questions in an hour-and a-half-long structured interview (after signing a consent form). RESULTS: Taking naps is the activity most often practiced by the elderly. Watching television and reading at bedtime are also frequent practices among them. The probabilities of suffering from anxiety are greater if the person never or rarely consumes caffeine after 6 pm, if the individual takes naps during the day, or if the person practices relaxation before bedtime. Television watching, reading, and physical exercise before bedtime are activities that are not associated with the probability of suffering from a mental disorder. CONCLUSION: It would be beneficial for research to be conducted to support the findings on behavioral differences between depressive and anxious seniors so that these behaviors can become further indicators of the presence of mental disorders. PMID- 25709513 TI - Students' perceptions of educational climate in a new dental college using the DREEM tool. AB - AIM: The purpose of the study was to evaluate students' perceptions of conditions prevailing in Tagore Dental College. METHODS: Data were collected from all students enrolled in 2013, using the Dundee Ready Education Environment Measure (DREEM) forms filled in by them. For this exercise, prior approval from the Tagore Dental College Ethics Committee was obtained. RESULTS: The global score for EC was 124 (interpretation: predominantly positive). The scores obtained in the different domains were 31.03 in Learning (interpretation: a more positive perception); 26.69 in Teachers (interpretation: moving in the right direction); 21.48 in Academics (interpretation: feeling more in the positive side); 28.23 in Atmosphere (interpretation: a more positive atmosphere); and 16.52 in Social (interpretation: acceptable), all the points indicate that the institution is moving in the right direction. The DREEM score assigned by female students was significantly greater (P=0.048) than that assigned by male students. The second year students were more positive in their perception of EC than students of the other classes. CONCLUSION: Overall, Tagore Dental College students felt the EC to be acceptable. Admittedly, some areas need to be revisited to make improvements. PMID- 25709514 TI - Hospitalist workload influences faculty evaluations by internal medicine clerkship students. AB - BACKGROUND: The last decade has brought significant changes to internal medicine clerkships through resident work-hour restrictions and the widespread adoption of hospitalists as medical educators. These key medical educators face competing demands for quality teaching and clinical service intensity. OBJECTIVE: The study reported here was conducted to explore the relationship between clinical service intensity and teaching evaluations of hospitalists by internal medicine clerkship students. DESIGN: A retrospective correlation analysis of clinical service intensity and teaching evaluations of hospitalists by internal medicine clerkship students during the 2009 to 2013 academic years at Southern Illinois University School of Medicine was conducted. PARTICIPANTS: Internal medicine hospitalists who supervise the third-year inpatient experience for medical students during the 2009 to 2013 academic years participated in the study. MEASURES: Clinical service intensity data in terms of work relative value units (RVUs), patient encounters, and days of inpatient duty were collected for all members of the hospitalist service. Medical students rated hospitalists in the areas of patient rapport, enthusiasm about the profession, clinical skills, sharing knowledge and skills, encouraging the students, probing student knowledge, stimulating independent learning, providing timely feedback, providing constructive criticism, and observing patient encounters with students. RESULTS: Significant negative correlations between higher work RVU production, total patient encounters, duty days, and learner evaluation scores for enthusiasm about the profession, clinical skills, probing the student for knowledge and judgment, and observing a patient encounter with the student were identified. Higher duty days had a significant negative correlation with sharing knowledge/skills and encouraging student initiative. Higher work RVUs and total patient encounters were negatively correlated with timely feedback and constructive criticism. CONCLUSION: The results suggest that internal medicine clerkship student evaluations of hospitalist faculty are negatively influenced by high clinical service intensity measured in terms of annual work RVUs, patient encounters, and duty days. PMID- 25709515 TI - New ideas for teaching electrocardiogram interpretation and improving classroom teaching content. AB - BACKGROUND: Interpreting an electrocardiogram (ECG) is not only one of the most important parts of diagnostics but also one of the most difficult areas to teach. Owing to the abstract nature of the basic theoretical knowledge of the ECG, its scattered characteristics, and tedious and difficult-to-remember subject matter, teaching how to interpret ECGs is as difficult for teachers to teach as it is for students to learn. In order to enable medical students to master basic knowledge of ECG interpretation skills in a limited teaching time, we modified the content used for traditional ECG teaching and now propose a new ECG teaching method called the "graphics-sequence memory method." METHODS: A prospective randomized controlled study was designed to measure the actual effectiveness of ECG learning by students. Two hundred students were randomly placed under a traditional teaching group and an innovative teaching group, with 100 participants in each group. The teachers in the traditional teaching group utilized the traditional teaching outline, whereas the teachers in the innovative teaching group received training in line with the proposed teaching method and syllabus. All the students took an examination in the final semester by analyzing 20 ECGs from real clinical cases and submitted their ECG reports. RESULTS: The average ECG reading time was 32 minutes for the traditional teaching group and 18 minutes for the innovative teaching group. The average ECG accuracy results were 43% for the traditional teaching group and 77% for the innovative teaching group. CONCLUSION: Learning to accurately interpret ECGs is an important skill in the cardiac discipline, but the ECG's mechanisms are intricate and the content is scattered. Textbooks tend to make the students feel confused owing to the restrictions of the length and the format of the syllabi, apart from many other limitations. The graphics sequence memory method was found to be a useful method for ECG teaching. PMID- 25709516 TI - Impact of an emergency medicine clerkship on students' perceptions of emergency medicine. AB - PURPOSE: To determine the impact of an emergency medicine (EM) clerkship on senior (4th year) medical students' perceptions of the EM specialty. SUBJECTS AND METHODS: This was a pre/posttest observational study in a mandatory 4-week EM clerkship. Students were anonymously surveyed pre- and postclerkship regarding perceptions of EM. The survey used 24 statements grouped across four domains: 1) student EM clerkship expectations/experiences, 2) perceptions regarding EM physicians, 3) perceptions regarding patients in the emergency department (ED), and 4) EM as a desirable career. Data were analyzed using paired-sample t-tests, and comparisons made using McNemar's chi (2) test. RESULTS: A total of 385 of 407 students (94.6%) completed the pre- and postclerkship survey. There was no significant difference between mean ratings before and after related to perceptions regarding EM physicians (3.71 versus 3.71), ED patients (3.80 versus 3.76), or EM as a desirable career (3.88 versus 3.84). However, ratings regarding clerkship expectations/experiences decreased (3.88 versus 3.56, P=0.001). Of the 292 students that ranked their top three specialties in both pre- and postclerkship surveys, 46 (16%) included EM as a top choice preclerkship, with 31 of these maintaining this interest postclerkship. Conversely, 12 students (5%) became interested in EM postclerkship. Some survey-statement ratings were influenced and varied by urban versus community clerkship-rotation site. CONCLUSION: A mandatory senior EM clerkship did not significantly change overall students' perceptions regarding EM. Students with an interest in EM rated domains higher than those not interested, though there may have been an overall decline in perceptions related to clerkship expectations and experiences. Larger, multisite studies may help identify aspects of the field or EM clerkship that influence a student's ultimate career choice. PMID- 25709517 TI - Complementary and alternative medicine in US medical schools. AB - An analysis of complementary and alternative medicine (CAM) in US medical school curriculum was undertaken. Websites for 130 US medical schools were systematically analyzed for course listings and content. Half of the schools (50.8%) offered at least one CAM course or clerkship. A total of 127 different course listings were identified, embracing a range of topics and methods of instruction. The most frequently listed topics were traditional medicine, acupuncture, spirituality, and herbs, along with the general topic of CAM. Nearly 25.0% of the courses referenced personal growth or self-care through CAM practices, while only 11.0% referenced inter-professional education activities involving interaction with CAM providers. The most frequently reported instructional methods were lectures, readings, and observation of, or receiving a CAM treatment. The findings of this analysis indicated fewer medical schools offered instruction in CAM than previously reported and a wide range of approaches to the topic across the schools where CAM is taught. PMID- 25709518 TI - Parenthood and opioid dependence. AB - INTRODUCTION: Many patients in maintenance treatment programs for opioid dependence are parents to underage children. OBJECTIVE: The aim of this study was to explore how parents who are regular patients in maintenance treatment perceive their parenthood. METHODS: The study used a qualitative approach. The informants were recruited by staff at a substance abuse clinic in Sweden. Criteria for inclusion were participation in the local maintenance treatment program, having a child or children younger than 18 years, and being in contact with the child or children. Data were collected in 2012-2013 by in-depth interviews of seven fathers and five mothers and analyzed using concepts and procedures of qualitative content analysis. RESULTS: The central findings of the study were: 1) the parents' concerns about possible future discrimination against their children, ie, stigma by association; and 2) the patients' own parents' role as the most important support in parenthood. CONCLUSION: The issue of anticipated discrimination against the children of parents undergoing maintenance treatment might be an aspect to consider in the development of interventions and support. Considering the role of the patients' own parents also seems important. PMID- 25709519 TI - Description of Parvocalanusleei sp. n. (Copepoda, Calanoida, Paracalanidae) in Western Korea, with comments on the taxonomic position of Paracalanusarabiensis Kesarkar & Anil, 2010. AB - A new species of paracalanid calanoid copepod Parvocalanusleei sp. n., is described from specimens collected in shallow waters of Western Korea. The new species is closely similar to Parvocalanusarabiensis (Kesarkar & Anil, 2010), Parvocalanuscrassirostris (F. Dahl, 1894), Parvocalanuslatus Andronov, 1972, and Parvocalanusscotti (Fruchtl, 1923) in having two short terminal spines on the distal segment of the fifth leg and a similar rostrum in the female, but can be readily distinguished from its congeners by the body size, relative length of antennules, segmentation of endopod of leg 1, and pattern of ornamentation of spinules on legs 1 to 4 in the female. The taxonomic position of Parvocalanusarabiensis and the validity of the genus Parvocalanus Andronov, 1970 are also discussed. PMID- 25709520 TI - Micromyzusplatycerii sp. n. (Hemiptera, Aphididae) - a new fern-feeding aphid species from Thailand. AB - A new fern-feeding aphid species, Micromyzusplatycerii, collected in Sakaerat Research Station in Thailand, is described. PMID- 25709521 TI - Afrotropical Ophioninae (Hymenoptera, Ichneumonidae): an update of Gauld and Mitchell's revision, including two new species and an interactive matrix identification key. AB - The revision of the Afrotropical Ophioninae is updated, based on the examination of about 800-900 individuals in the South African and European museum collections. A robust interactive matrix key was built to provide quick and reliable identifications. The key is available online at http://www.waspweb.org. Two new species are described: Dicamptusmaxipol sp. n. and Enicospilusgauldetmitchellorum sp. n. Numerous new distribution and biological records are provided, and noticeable morphological intra-specific variations are detailed. Enicospilusbatus Gauld & Mitchell, syn. n. is considered as a junior synonym of Enicospilusluebberti (Enderlein). PMID- 25709522 TI - Three new species of the myrmecophilous genus Doryloxenus from China (Coleoptera, Staphylinidae, Aleocharinae). AB - Three new species of the pygostenine genus Doryloxenus Wasmann, viz., Doryloxenusaenictophilus sp. n. (from Zhejiang), Doryloxenustangliangi sp. n. (from Zhejiang), and Doryloxenussongzhigaoi sp. n. (from Yunnan), are described, illustrated and distinguished from the Asian congeners. An identification key to the Chinese species is given. PMID- 25709523 TI - Description of six new species of Lycocerus Gorham (Coleoptera, Cantharidae), with taxonomic note and new distribution data of some other species. AB - Six new species of Lycocerus Gorham are described, Lycocerusgracilicornis sp. n. (China: Sichuan), Lycoceruslongihirtus sp. n. (China: Yunnan), Lycocerussichuanus sp. n. (China: Sichuan), Lycocerushubeiensis sp. n. (China: Hubei), Lycocerusnapolovi sp. n. (Vietnam: Sa Pa) and Lycocerus quadrilineatus sp. n. (Vietnam: Sa Pa), and provided with illustrations of habitus, antennae and aedeagi of male or and antennae, abdominal sternites VIII and genitalia of female. Lycocerusrubroniger Svihla, 2011 is synonymized with Lycocerusobscurus Pic, 1916. Lycocerushickeri Pic, 1934 and Lycocerusobscurus are provided with illustrations of abdominal sternites VIII of female. Nine species are recorded from China for the first time, Lycocerusbicoloripennis (Pic, 1924), Lycoceruscaliginostus Gorham, 1889, Lycocerusjendeki Svihla, 2005, Lycocerusmalaisei (Wittmer, 1995), Lycocerusobscurus, Lycocerusolivaceus (Wittmer, 1995), Lycoceruspurpureus Kazantsev, 2007, Lycocerusruficornis (Wittmer, 1995) and Lycocerussemiextensus (Wittmer, 1995), and Lycocerusruficornis is also recorded for Myanmar for the first time. PMID- 25709524 TI - On the Domene species of China, with descriptions of four new species (Coleoptera, Staphylinidae). AB - Material of the paederine genus Domene Fauvel, 1873 from China is examined. Nine species were identified, four of them described previously, one unnamed (represented exclusively by females), and four are newly described: Domenecultrata sp. n. (Gansu, Hubei, Shaanxi); Domenecuspidata sp. n. (Gansu, Shaanxi, Sichuan); Domenechenae sp. n. (Guangxi); Domenereducta sp. n. (Sichuan). A lectotype is designated for Domenereitteri Koch, 1939; a neotype is designated for Domenechenpengi Li, 1990. Domenedersuuzalai Gusarov, 1992 is placed in synonymy with Domenechenpengi. Previous records of two Japanese species from China are most likely based on misidentifications and considered erroneous. Thus, the Domene fauna of China is currently composed of twelve described species. A key to the Domene species of China is provided. The distributions of eleven species are mapped. PMID- 25709525 TI - Italian natural history museums on the verge of collapse? AB - The Italian natural history museums are facing a critical situation, due to the progressive loss of scientific relevance, decreasing economic investments, and scarcity of personnel. This is extremely alarming, especially for ensuring the long-term preservation of the precious collections they host. Moreover, a commitment in fieldwork to increase scientific collections and concurrent taxonomic research are rarely considered priorities, while most of the activities are addressed to public events with political payoffs, such as exhibits, didactic meetings, expositions, and talks. This is possibly due to the absence of a national museum that would have better steered research activities and overall concepts for collection management. We here propose that Italian natural history museums collaborate to instate a "metamuseum", by establishing a reciprocal interaction network aimed at sharing budgetary and technical resources, which would assure better coordination of common long-term goals and scientific activities. PMID- 25709526 TI - First record of Rhoptrocentruspiceus Marshall (Hymenoptera, Braconidae, Doryctinae) as parasitoid of Psacotheahilarishilaris (Pascoe) (Coleoptera, Cerambycidae). AB - The species Rhoptrocentruspiceus Marshall (Hymenoptera: Braconidae) was reared from the larvae of the xylophagous beetle Psacotheahilarishilaris (Pascoe) (Coleoptera: Cerambycidae), an exotic pest of Ficus and Morus species native to eastern Asia. It was recorded in the north of Italy in September 2005. This discovery is the first report of this species as parasitoids of the yellow spotted longicorn beetle all over the world. PMID- 25709527 TI - Description of a new species of Apterotoxitiades Adlbauer, 2008 (Cerambycidae, Dorcasominae, Apatophyseini) and the female of A.vivesi Adlbauer, 2008, with notes on the biology of the genus. AB - Following the description of the Apatophyseini genus Apterotoxitiades Adlbauer, 2008 (Cerambycidae: Dorcasominae) from South Africa, a new species has now been discovered in the eastern Drakensberg range of the country. The holotype female is here described as Apterotoxitiadesaspinosus Bjornstad, sp. n. Also, a new small series collected at Hogsback, in the Amathole range, has allowed the description of the previously unknown female of the type species, Apterotoxitiadesvivesi Adlbauer, 2008. Both species are high altitude dwellers, occurring above 1300 m asl and their habitat consists mainly of mountain grassland interspersed with mistbelt forest pockets. All specimens were recorded in the austral winter to early spring, when these mountain ranges are occasionally covered in snow and night temperature plummet below 0 degrees C. They appear to be nocturnal and their complete lack of wings indicates a remarkable adaptation to cold conditions at high altitude. PMID- 25709528 TI - Two new species of Pseudancistrus (Siluriformes, Loricariidae) from the Amazon basin, northern Brazil. AB - Two new species of Pseudancistrus, a genus diagnosed by non-evertible cheek plates and hypertrophied odontodes along the snout margin, are described from two drainages of the Brazilian Shield: Pseudancistruskayabi from the rio Teles Pires (rio Tapajos basin) and Pseudancistrusasurini from the rio Xingu. The new species are distinguished from congeners (Pseudancistrusbarbatus, Pseudancistruscorantijniensis, Pseudancistrusdepressus, Pseudancistrusnigrescens, Pseudancistrusreus, and Pseudancistruszawadzkii) by the coloration pattern. Pseudancistruskayabi has dark bars on the dorsal and caudal fins which are similar to that of Pseudancistrusreus from the Caroni River, Venezuela. Pseudancistrusasurini is unique among Pseudancistrus in having whitish tips of the dorsal and caudal fins in juveniles to medium-sized adults. PMID- 25709529 TI - The Maghreb - one more important biodiversity hot spot for tiger beetle fauna (Coleoptera, Carabidae, Cicindelinae) in the Mediterranean region. AB - The tiger beetle fauna of the Maghreb region is one of the richest in the Palaearctic, including 22 species and 5 subspecies and 19% of all Palaearctic species of Cicindelinae. Assembled to their chorotypes, the Maghreb tiger beetles fall into eight different groups that include Maghreb endemics (26% of fauna), Mediterranean (7%), West Mediterranean (40%), North African (4%), Mediterranean Westturanian (4%), West Palaearctic (4%), Afrotropico-Indo-Mediterranean (4%), and Saharian (11%) species. The Mediterranean Sclerophyl and Atlas Steppe are the Maghreb biogeographical provinces with the highest species richness, while the Sahara Desert has the lowest Cicindelinae diversity. Twenty-five cicindelid species and subspecies (93% of Maghreb fauna) are restricted to only one or two habitat types in lowland areas. Only Calomeralittoralislittoralis and Lophyraflexuosaflexuosa are recognized as eurytopic species and occur in three types of habitat. The highest tiger beetle diversity characterizes salt marshes and river banks (in both cases 11 species and subspecies or 41% of Maghreb fauna). Approximately 85% of all Maghreb tiger beetle species and subspecies are found in habitats potentially endangered by human activity. PMID- 25709530 TI - A new species of Paracreptotrema (Digenea, Plagiorchiformes, Allocreadiidae) infecting two species of poeciliids in Rio Malila of the Rio Panuco basin, Hidalgo, Mexico, with a key to the species of the genus. AB - Paracreptotremarosenthali sp. n. was discovered in the intestine of Xiphophorusmalinche and Pseudoxiphophorusjonesii, collected from the headwaters of Rio Malila, tributary of Rio Conzintla, in the Rio Panuco basin, Hidalgo, Mexico, during 2008-2009. The new species differs from the five known species of Paracreptotrema Choudhury, Perez-Ponce de Leon, Brooks & Daverdin, 2006 by having vitelline follicles that extend from a level anterior to the pharynx to mid testes, the seminal vesicle which is more extensively folded, and a wider cirrus sac. The new species resembles Paracreptotremaheterandriae in the length of its ceca, which surpasses the posterior margin of the ovary but do not reach the testes. A key to the species of Paracreptotrema is provided. PMID- 25709531 TI - California dragonfly and damselfly (Odonata) database: temporal and spatial distribution of species records collected over the past century. AB - The recently completed Odonata database for California consists of specimen records from the major entomology collections of the state, large Odonata collections outside of the state, previous literature, historical and recent field surveys, and from enthusiast group observations. The database includes 32,025 total records and 19,000 unique records for 106 species of dragonflies and damselflies, with records spanning 1879-2013. Records have been geographically referenced using the point-radius method to assign coordinates and an uncertainty radius to specimen locations. In addition to describing techniques used in data acquisition, georeferencing, and quality control, we present assessments of the temporal, spatial, and taxonomic distribution of records. We use this information to identify biases in the data, and to determine changes in species prevalence, latitudinal ranges, and elevation ranges when comparing records before 1976 and after 1979. The average latitude of where records occurred increased by 78 km over these time periods. While average elevation did not change significantly, the average minimum elevation across species declined by 108 m. Odonata distribution may be generally shifting northwards as temperature warms and to lower minimum elevations in response to increased summer water availability in low-elevation agricultural regions. The unexpected decline in elevation may also be partially the result of bias in recent collections towards centers of human population, which tend to occur at lower elevations. This study emphasizes the need to address temporal, spatial, and taxonomic biases in museum and observational records in order to produce reliable conclusions from such data. PMID- 25709532 TI - Review of the genera Anelaphinis Kolbe, 1892 and Atrichelaphinis Kraatz, 1898 (Coleoptera, Scarabaeidae, Cetoniinae). AB - New material collected recently throughout the Afrotropical region has led to a major reassessment of taxa within the genera Anelaphinis Kolbe, 1892, Atrichelaphinis Kraatz, 1898 and other closely related genera. As a result, the name Megalleucosma Antoine, 1989 is here synonymised with Anelaphinis and a lectotype is designated for the type species, Cetoniadominula Harold, 1879. The genus Atrichelaphinis is redefined and a new subgenus, Atrichelaphinis (Eugeaphinis), is proposed for Elaphinissimillima Ancey, 1883, Elaphinisvermiculata Fairmaire, 1894, Niphetophorarhodesiana Peringuey, 1907, Atrichelaphinisdeplanata Moser, 1907 (with Anelaphiniskwangensis Burgeon, 1931 as junior synonym) and Anelaphinissternalis Moser, 1914. Additionally, three new species and one new subspecies are recognised and described in this new subgenus: Atrichelaphinis (Eugeaphinis) bomboesbergicasp. n. from South Africa; Atrichelaphinis (Eugeaphinis) bjornstadisp. n. from Tanzania; Atrichelaphinis (Eugeaphinis) garnierisp. n. from south-east Africa (Tanzania, Zimbabwe); and Atrichelaphinis (Eugeaphinis) deplanataminettiissp. n. from central Africa (Malawi, Mozambique, Congo-Kinshasa, Congo-Brazzaville, South Africa, Rwanda, Zambia, Zimbabwe). The genus Atrichelaphinis is compared to its closest relatives and two separate keys are proposed, one for Atrichelaphinis and one for the sub Saharan genera exhibiting completely or partially fused parameres. PMID- 25709533 TI - Review of the genus Apotrechus in China (Orthoptera, Gryllacrididae, Gryllacridinae). AB - In the present paper, the genus Apotrechus Brunner-Wattenwyl, 1888 is revised. Two new species from China are described and illustrated: Apotrechusquadratus sp. n. and Apotrechustruncatolobus sp. n.. A new key and the distributional data are given. PMID- 25709534 TI - A new type of ant-decapitation in the Phoridae (Insecta: Diptera). AB - The genus Dohrniphora is a hyperdiverse group of phorid flies, a family whose species are commonly characterized as generalized scavengers. The lifestyle of most species of Dohrniphora is unknown, although one cosmopolitan, synanthropic species, D.cornuta (Bigot) fits the general scavenger mold. Here we show that flies of the D.longirostrata species group exhibit highly specific "headhunting" behavior in which injured Odontomachus ants are decapitated, the heads dragged away, and females either feed on their contents or lay an egg nearby. Since most females studied lacked eggs in their ovaries, we conclude that this bizarrely specialized feeding is necessary to provide nutrients for reproduction in these flies. Our study provides further evidence that injured ants are a common, stable resource in tropical ecosystems that support a wide array of phorid flies. Such narrowly constrained lifestyles, as exemplified by exclusively feeding on and breeding in the head contents of certain ponerine worker ants, could allow the co existence of a huge community of saprophagous flies. PMID- 25709535 TI - Effects of fuels, engine load and exhaust after-treatment on diesel engine SVOC emissions and development of SVOC profiles for receptor modeling. AB - Diesel exhaust emissions contain numerous semivolatile organic compounds (SVOCs) for which emission information is limited, especially for idling conditions, new fuels and the new after-treatment systems. This study investigates exhaust emissions of particulate matter (PM), polycyclic aromatic hydrocarbons (PAHs), nitro-PAHs (NPAHs), and sterane and hopane petroleum biomarkers from a heavy-duty (6.4 L) diesel engine at various loads (idle, 600 and 900 kPa BMEP), with three types of fuel (ultra-low sulfur diesel or ULSD, Swedish low aromatic diesel, and neat soybean biodiesel), and with and without a diesel oxidation catalyst (DOC) and diesel particulate filter (DPF). Swedish diesel and biodiesel reduced emissions of PM2.5, Sigma15PAHs, Sigma11NPAHs, Sigma5Hopanes and Sigma6Steranes, and biodiesel resulted in the larger reductions. However, idling emissions increased for benzo[k]fluoranthene (Swedish diesel), 5-nitroacenaphthene (biodiesel) and PM2.5 (biodiesel), a significant result given the attention to exposures from idling vehicles and the toxicity of high-molecular-weight PAHs and NPAHs. The DOC + DPF combination reduced PM2.5 and SVOC emissions during DPF loading (>99% reduction) and DPF regeneration (83-99%). The toxicity of diesel exhaust, in terms of the estimated carcinogenic risk, was greatly reduced using Swedish diesel, biodiesel fuels and the DOC + DPF. PAH profiles showed high abundances of three and four ring compounds as well as naphthalene; NPAH profiles were dominated by nitro-naphthalenes, 1-nitropyrene and 9-nitroanthracene. Both the emission rate and the composition of diesel exhaust depended strongly on fuel type, engine load and after-treatment system. The emissions data and chemical profiles presented are relevant to the development of emission inventories and exposure and risk assessments. PMID- 25709536 TI - What makes you happy? PMID- 25709537 TI - Advances in pinhole and multi-pinhole collimators for single photon emission computed tomography imaging. AB - The collimator in single photon emission computed tomography (SPECT), is an important part of the imaging chain. One of the most important collimators that used in research, preclinical study, small animal, and organ imaging is the pinhole collimator. Pinhole collimator can improve the tradeoff between sensitivity and resolution in comparison with conventional parallel-hole collimator and facilities diagnosis. However, a major problem with pinhole collimator is a small field of view (FOV). Multi-pinhole collimator has been investigated in order to increase the sensitivity and FOV with a preserved spatial resolution. The geometry of pinhole and multi-pinhole collimators is a critical factor in the image quality and plays a key role in SPECT imaging. The issue of the material and geometry for pinhole and multi-pinhole collimators have been a controversial and much disputed subject within the field of SPECT imaging. On the other hand, recent developments in collimator optimization have heightened the need for appropriate reconstruction algorithms for pinhole SPECT imaging. Therefore, iterative reconstruction algorithms were introduced to minimize the undesirable effect on image quality. Current researches have focused on geometry and configuration of pinhole and multi-pinhole collimation rather than reconstruction algorithm. The lofthole and multi-lofthole collimator are samples of novel designs. The purpose of this paper is to provide a review on recent researches in the pinhole and multi-pinhole collimators for SPECT imaging. PMID- 25709538 TI - Radiosynovectomy in the therapeutic management of arthritis. AB - Radiosynovectomy is a well-established therapy in arthritis and involves an intra articular injection of small radioactive particles to treat a synovitis. In Europe, frequent indications are rheumatoid and poly-arthritis. Especially in Germany radiosynovectomy is the second common therapy in Nuclear Medicine with about 40,000-60,000 treated joints per year. In Spain, USA, Turkey, Argentines and Philippines the therapy is more use in hemophilic arthritis with excellent results. Especially in developing countries with low availability of clotting factors, the radiosynovectomy represent a cost effective therapeutic option for repeated bleedings in hemophilic arthropathy. The special focus in these countries is maintaining of mobility and work ability. Often only the knee and medium joints (ankle, elbow and shoulder) are treated using yttrium-90, rhenium 186 or phosphorus-32. However, in rheumatoid arthritis most common affected joints are the fingers. For the treatment in these small joints, erbium-169 is necessary. Unfortunately, erbium-169 is only available in Europe. Further indications for radiosynovectomy are osteoarthritis and the articular effusion after joint replacement. The reported response rates in rheumatoid and poly arthritis range from 60% to 80% depends from the stage of previous arthrosis. The best effectiveness of therapy was observed in hemophilic arthritis with response rate of 90% and significant reducing of bleeding frequency. The therapy is well tolerated with low rate of side effects. In respect of the specific uptake of particles in the synovia and short range of beta radiation, the radiation exposure outside the joint is very low. The radiosynovectomy has efforts in comparison to surgical synovectomy: it's a minor intervention with low costs; and simultaneous treatments of multiple joints or treatment in short intervals are possible. The presented paper summarized the published papers and reports our own experiences in >15,000 treated joints. PMID- 25709539 TI - Determination of Organ Doses in Radioiodine Therapy using Monte Carlo Simulation. AB - Radioactive iodine treatment is a type of internal radiotherapy that has been used effectively for the treatment of differentiated thyroid cancer after thyroidectomy. The limit of this method is its affects on critical organs, and hence dosimetry is necessary to consider the risk of this treatment. Scope of this work is the measurement of absorbed doses of critical organs by Monte Carlo simulation and comparing the results with other methods of dosimetry such as direct dosimetry and Medical Internal Radiation Dose (MIRD) method. To calculate absorbed doses of vital organs (thyroid, sternum and cervical vertebrae) via Monte Carlo, a mathematical phantom was used. Since iodine 131 ((131)I) emmits photon and beta particle, *F8 tallies, which give results in MeV were applied and the results were later converted to cGy by dividing by the mass within the cell and multiplying by 1.6E-8. The absorbed dose obtained by Monte Carlo simulations for 100, 150 and 175 mCi administered (131)I was found to be 388.0, 427.9 and 444.8 cGy for thyroid, 208.7, 230.1 and 239.3 cGy for sternum and 272.1, 299.9 and 312.1 cGy for cervical vertebrae. The results of Monte Carlo simulation method had no significant difference with the results obtained via direct dosimetry using thermoluminescent dosimeter-100 and MIRD method. Hence, Monte Carlo is a suitable method for dosimetry in radioiodine therapy. PMID- 25709540 TI - Impact of (18)f-fluorodeoxyglucose positron emission tomography/computed tomography scan on initial evaluation of head and neck squamous cell carcinoma: our experience at a tertiary care center in India. AB - The efficacy of the whole body (WB) (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography-computed tomography (PET-CT) as a part of conventional initial staging in all cases of head and neck squamous cell carcinoma (HNSCC) is still controversial with various studies in literature giving contradictory reports. We conducted this study at a government tertiary care oncology center in India to identify the impact of WB (18)F-FDG PET-CT scan on HNSCC staging and treatment. A prospective clinical study of patients of HNSCC who were evaluated and treated at our center was performed. The patients included in the study were HNSCC of the oral cavity, oropharynx, hypopharynx, larynx, nasopharynx, and carcinoma of unknown primary site (CUPS) with cervical metastasis. The study design was to evaluate the cases of HNSCC initially by staging with conventional investigations followed by staging with the information derived from WB (18)F-FDG PET-CT scan. At the end of the conventional investigations, a tumor, node, metastasis (TNM) staging as per AJCC 7(th) edition, and a detailed treatment plan as per NCCN 2012 guidelines was decided in consultation with the multidisciplinary oncology team of the hospital. WB (18)F-FDG PET-CT scan was carried out in all these patients. The findings of WB (18)F-FDG PET-CT were then interpreted with the staging with conventional investigations to identify the cases with change in staging and also those in whom the treatment protocol would be affected. Descriptive analysis of demographic data and analytical analysis of the sensitivity and specificity of WB (18)F-FDG PET-CT scan and also the change in staging and treatment plan after WB (18)F-FDG PET-CT scan was analyzed using SPSS version 18. A total of 131 patients met the inclusion criteria, which included 123 males and 8 females. The various sites involved among the study group are oral cavity 11 (8.3%), oropharyn * 39 (29.7%), hypopharyn * 31 (23.6%), laryn * 34 (25.9%), nasopharyn * 4 (3%), and CUPS 12 (9.1%). The majority of cases studied were of T2 and T3 stage, and changes in T staging after WB (18)F FDG PET-CT scan were minimal and not statistically significant (P > 0.5). In the nodal staging after WB (18)F-FDG PET-CT scan, there was a statistically significant change in identification of nodal metastasis in N0 group and also identification of additional multiple/bilateral nodes (N2b and N2c). 3 (2.2%) patients had a change in M status with identification of distant metastasis in lungs (2 patients) and in the liver and lung (1 patient). Of the 131 patients, 75 (57.25%) underwent surgical management with or without adjuvant treatment (Group I) and 56 (42.74%) patients underwent nonsurgical management (Group II). There was no significant statistical difference in sensitivity and specificity of (18)F FDG PET-CT scan in detecting cancer among the two groups. Considering all the patients in this study, WB (18)F-FDG PET-CT scan showed an overall sensitivity of 95.2% and specificity of 80%. In this study, change in TNM staging after WB (18)F FDG PET-CT was seen in 22 (16.8%) patients and an alteration in the treatment in 21 (16.1%) patients, which were both found to be statistically significant (P < 0.5). In our study, WB (18)F-FDG PET-CT scan has shown to have an impact on initial staging of disease affecting the change in treatment protocol in a significant number of patients. The effect of this change in staging and treatment on the eventual morbidity and mortality rates is not known. In practice, the use of (18)F-FDG PET-CT scan is limited, owing to the high cost and low availability. A realistic evaluation of cost versus benefit needs to be undertaken to identify the impact of using (18)F-FDG PET-CT scan as a mode for initial evaluation of HNSCC. PMID- 25709541 TI - Focal Colonic FDG Activity with PET/CT: Guidelines for Recommendation of Colonoscopy. AB - Focal (18)F-fluorodeoxyglucose (FDG) colonic activity can be incidentally seen in positron emission tomography/computed tomography (PET/CT) scans. Its clinical significance is still unclear. The purpose of this study was to assess the significance of focal FDG activity in PET/CT scans by correlating the imaging findings to colonoscopy results, and come up with some guidelines for recommendation of follow-up colonoscopy. A total of 133 patients who underwent both (18)F-FDG PET/CT for different oncological indications and colonoscopy within 3 months were retrospectively studied. Imaging, colonoscopy and pathology results were analyzed. Of the 133 FDG-PET/CT scans, 109/133 (82%) did not show focal colonic FDG activity, and 24/133 (18%) did. Of the 109/133 PET/CTs without focal colonic FDG activity, 109/109 (100%) did not have evidence of colon cancer after colonoscopy and histology. Of the 24/133 PET/CTs with focal colonic FDG activity, 10/24 (42%) had pathologic confirmation of colon cancer and 14/24 (58%) did not have evidence of colon cancer after colonoscopy and histological analysis. Sensitivity was 10/10 (100%), specificity 109/123 (89%), positive predictive value (PPV) 10/24 (42%) and negative predictive value (NPV) 109/109 (100%). Incidental focal (18)FDG activity in PET/CT imaging shows a high sensitivity, specificity and NPV for malignancy, with a not so high PPV of 42%. Although some people would argue that a 42% chance of malignancy justifies colonoscopy, this maybe is not possible in all cases. However, the high sensitivity of the test does not allow these studies to be overlooked. We provide our recommendations as per when to send patients with focal FDG colonic activity to have further characterization with colonoscopy. PMID- 25709542 TI - The independent functioning of the orchidopexied congenital undescended testis as assessed by positron emission tomography/computed tomography. AB - Fertility after orchidopexied undescended testes (UDT) is impaired. Although fertility parameters are known to be more favorable in unilateral cases than in bilateral cases, the exact contribution of the unilateral orchidopexied UDT to fertility is unknown. We used testicular (18)F-fluoro-2-deoxyglucose ((18)F-FDG) uptake assessed by positron emission tomography/computed tomography (PET/CT) to investigate the function of the orchidopexied unilateral congenital UDT, compared to its normally descended counterpart. We hypothesize that the contribution of the orchidopexied unilateral congenital UDT to fertility in adulthood is low. Eleven men who underwent orchidopexy for congenital UDT at the age of 1.9 +/- 1.4 (range, 4.5 months -4.0) years were seen in follow-up at the age of 24.1 +/- 2.3 (20.6-28.0) years. All underwent physical examination, testicular ultrasonography and PET/CT. Testicular (18)F-FDG-uptake was expressed as the peak Standardized Uptake Value (SUVpeak). The mean SUVpeak of the orchidopexied UDT was 2.74 +/- 0.48 (2.13-3.47), which was significantly lower than its counterpart (P = 0.021). Besides, there was no correlation between the testicular volume and the SUVpeak. The orchidopexied congenital UDT has been shown to be less metabolically active than its contralateral counterpart. Nevertheless, we suggest that the operated testes function to some degree. PMID- 25709543 TI - Clinical effectiveness of (18)f-fluorodeoxyglucose positron emission tomography/computed tomography in management of renal cell carcinoma: a single institution experience. AB - Positron emission tomography (PET) is currently the most advanced technique of metabolic imaging available for tumor diagnosis and follow-up. The aim of this study was to examine the versatility and accuracy of fluorodeoxyglucose (FDG) PET/computed tomography (CT) in the metastasis detection of renal cell carcinoma (RCC). We also compared our findings to other similar studies from the literature. This is the biggest study so far to examine the sensitivity and specificity of FDG PET/CT in the management of RCC. A retrospective review was carried out on all the FDG PET/CT studies done from January 1999 to January 2014 at our institution. Biopsy results were considered the gold standard. For our patients (n = 315) with biopsy results, FDG PET/CT studies exhibited 100% sensitivity, 100% specificity. Our results were better than results achieved by other studies. The use of FDG PET/CT in restaging and metastasis detection of RCC has many advantages, in addition to high accuracy. This imaging technique has great potential in influencing treatment decisions. We recommend the incorporation of FDG PET/CT in routine standard protocols for RCC. PMID- 25709544 TI - The Added Value of a Single-photon Emission Computed Tomography-Computed Tomography in Sentinel Lymph Node Mapping in Patients with Breast Cancer and Malignant Melanoma. AB - Single-photon emission computed tomography-computed tomography (SPECT-CT) allows for physiological and anatomical co-registration in sentinel lymph node (SLN) mapping and offers additional benefits over conventional planar imaging. However, the clinical relevance when considering added costs and radiation burden of these reported benefits remains somewhat uncertain. This study aimed to evaluate the possible added value of SPECT-CT and intra-operative gamma-probe use over planar imaging alone in the South African setting. 80 patients with breast cancer or malignant melanoma underwent both planar and SPECT-CT imaging for SLN mapping. We assessed and compared the number of nodes detected on each study, false positive and negative findings, changes in surgical approach and or patient management. In all cases where a sentinel node was identified, SPECT-CT was more accurate anatomically. There was a significant change in surgical approach in 30 cases - breast cancer (n = 13; P 0.001) and malignant melanoma (n = 17; P 0.0002). In 4 cases a node not identified on planar imaging was seen on SPECT-CT. In 16 cases additional echelon nodes were identified. False positives were excluded by SPECT CT in 12 cases. The addition of SPECT-CT and use of intra-operative gamma-probe to planar imaging offers important benefits in patients who present with breast cancer and melanoma. These benefits include increased nodal detection, elimination of false positives and negatives and improved anatomical localization that ultimately aids and expedites surgical management. This has been demonstrated in the context of industrialized country previously and has now also been confirmed in the setting of a emerging-market nation. PMID- 25709545 TI - Bone scintigraphy hot-spot in projection to rib and kidney: role of single photon emission computer tomography/computer tomography in distinguishing a urine collection in renal calyx from a metastasis to rib. AB - On planar bone scintigrams, activity enhancement foci in projection to kidney and lower ribs can arise from the kidney, or from bone lesions. A differentiation based only on the exact location and shape of the hot spot can sometimes be misleading, resulting in a false qualification of a rib metastatic lesion as urine collection in the kidney or opposite. The authors illustrate the problem with three cases: In two patients, such a hot spot appeared to be the solitary metastatic focus; in one, highly suggestive for solitary metastatic focus, it was proven to be a urine collection. PMID- 25709546 TI - Systemic Radiopharmaceutical Agents (Sm-153) may be Dangerous in Hepatacellular Carcinoma. AB - Palliation of bone metastases in hepatocellular carcinoma (HCC) is sometimes difficult. Systemic pharmaceuticals have been successfully used for the palliation of bone metastasis for many years. Safety of these agents in HCC is not known completely. We presented a male patient with decompensated liver cirrhosis with HCC. Multifocal bone metastases developed in this patient and he had refractory bone pain. We treated this patient with Sm-153 (samarium) after obtaining patient's consent. Two days after treatment, he experienced dyspnea and we detected a massive hemorrhagic pericardial effusion. He died due to this unexpected bleeding. We should use this radiopharmaceutical treatment cautiously in these cytopenic cirrhotic patients. PMID- 25709547 TI - Promising Role of Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography in Human Immunodeficiency Virus Associated Non-Hodgkin's Lymphoma. AB - This case report explores the potential role of FDG PET/CT in HIV -associated systemic non-Hodgkin's lymphoma (HIV-NHLs). In our locality, there are a cumulative total of 5523 reported HIV infections cases since 1984. We reported a case of HIV-related Burkitt's lymphoma (BL) and a case of diffuse large B-cell lymphoma (DLBCL) that underwent PET/CT examination in our PET centre. In HIV-NHLs patients, we must be reminded that not all hypermetabolic foci represent lymphomatous lesions. There is a close correlation between the pattern of lymphoid tissue activation in FDG PET/CT and HIV progression in patients without HIV-related malignancy. The unique patterns of lymphoid tissue activation observed in HIV-infected patients have great clinical implications. Secondly, HIV infected patients are prone to suffer from opportunistic infections due to immunosuppression, particularly in those with high levels of HIV viral loads. FDG PET/CT cannot reliably differentiate metabolic active lymphoma from other benign diseases such as inflammation in the context of low CD4 count and high viral loads. In those cases, benign markedly hypermetabolic foci can be erroneously interpreted as lymphoma, particularly in those normal-sized lymph nodes. Furthermore, FDG PET/CT may be useful for assessing the efficacy of HAART in suppressing HIV replication and detecting its complication such as lipodystrophy. FDG PET/CT may play a potential useful role in staging and management of HIV associated systemic non-Hodgkin's lymphoma. Plasma variables such as viral loads and CD4 count must be taken into account during image interpretation. FDG PET/CT as a potential useful tool for diagnosis, treatment response assessment and disease relapse detection in HIV -associated systemic non-Hodgkin's lymphoma worth to be further explored. PMID- 25709548 TI - (18)F-fluorodeoxyglucose positron emission tomography/computed tomography in infected polycystic kidney disease. AB - A positron emission tomography/computed tomography (PET/CT) study using (18)F fluorodeoxyglucose ((18)F-FDG) was performed in a 54-year-old female with polycystic kidney disease, fever, and abdominal discomfort. Cyst's infection was suspected, but CT and U/S findings were not specific to accurately depict pyocysts and guide surgical treatment. In PET/CT, both kidneys are enlarged with multiple cysts and little remaining parenchyma. There is intense focal or ring shaped FDG uptake in cysts in the upper and lower poles of the left kidney indicative of active infection. There is also increased FDG uptake in para-aortic lymph nodes bilaterally. Hepatic and right renal cysts do not present increased FDG uptake. As this case illustrates, FDG PET/CT can be helpful for the precise localization of cyst infections in patients with polycystic kidney disease considered for surgical treatment. PMID- 25709549 TI - Bronchobiliary fistula localized by cholescintigraphy with single-photon emission computed tomography. AB - Biliptysis is an important clinical feature to recognize as it is associated with bronchobiliary fistula, a rare entity. Bronchobiliary fistulas have been diagnosed with planar cholescintigraphy. However, cholescintigraphy with single photon emission computed tomography (SPECT) can better spatially localize a bronchobiliary fistula as compared to planar cholescintigraphy alone, and is useful for preoperative planning if surgical treatment is required. Here, we present the case of a 23-year-old male who developed a bronchobiliary fistula in the setting of posttraumatic and postsurgical infection, which was diagnosed and localized by cholescintigraphy with SPECT. PMID- 25709550 TI - Positron Emission Mammography Imaging with Low Activity Fluorodeoxyglucose and Novel Utilization in Core-needle Biopsy Sampling. AB - Positron emission mammography (PEM), a relatively novel breast imaging modality, provides certain advantages over magnetic resonance imaging, including the ability to image biopsy samples. However, the radiation activity associated with PEM has remained a concern in clinical practice. We present a case of an invasive ductal carcinoma that was adequately imaged with a much lower than the standard 185 to 370 MBq activity of (18)F-fluorodeoxyglucose. In addition, we demonstrate ultrasound-guided core-needle biopsy sample imaging with PEM to assess adequacy of sampling, a strategy that has previously only been documented with vacuum assisted biopsy samples. PMID- 25709551 TI - Unusual intense fluorodeoxyglucose uptake in the intercostal muscles due to severe shortness of breath in a patient with heart failure. AB - We present a case of unusually intense Fluorodeoxyglucose uptake in the intercostal muscles during a Fluorodeoxyglucose positron emission tomography (FDG PET). We hypothesized that severe left ventricular failure causing the patient to be short of breath during the study in association with insulin injection as part of study protocol led to the intense uptake of FDG in the respiratory muscles causing such an unusual appearance. PMID- 25709552 TI - Salivary gland scintigraphy in the evaluation of salivary gland dysfunction. PMID- 25709553 TI - Breast Metastasis Detected on Ga-68 DOTATATE Positron Emission Tomography/Computed Tomography Imaging in Malignant Pheochromocytoma. PMID- 25709554 TI - Accuracy of positron emission tomography-computed tomography in bone marrow involvement lymphoma. PMID- 25709555 TI - Fluorodeoxyglucose Uptake in Lipomatous Hypertrophy of the Interatrial Septum is Not Likely Related to Brown Adipose Tissue. PMID- 25709556 TI - Adaptation, ecology, and evolution of the halophilic stromatolite archaeon Halococcus hamelinensis inferred through genome analyses. AB - Halococcus hamelinensis was the first archaeon isolated from stromatolites. These geomicrobial ecosystems are thought to be some of the earliest known on Earth, yet, despite their evolutionary significance, the role of Archaea in these systems is still not well understood. Detailed here is the genome sequencing and analysis of an archaeon isolated from stromatolites. The genome of H. hamelinensis consisted of 3,133,046 base pairs with an average G+C content of 60.08% and contained 3,150 predicted coding sequences or ORFs, 2,196 (68.67%) of which were protein-coding genes with functional assignments and 954 (29.83%) of which were of unknown function. Codon usage of the H. hamelinensis genome was consistent with a highly acidic proteome, a major adaptive mechanism towards high salinity. Amino acid transport and metabolism, inorganic ion transport and metabolism, energy production and conversion, ribosomal structure, and unknown function COG genes were overrepresented. The genome of H. hamelinensis also revealed characteristics reflecting its survival in its extreme environment, including putative genes/pathways involved in osmoprotection, oxidative stress response, and UV damage repair. Finally, genome analyses indicated the presence of putative transposases as well as positive matches of genes of H. hamelinensis against various genomes of Bacteria, Archaea, and viruses, suggesting the potential for horizontal gene transfer. PMID- 25709557 TI - De novo sequences of Haloquadratum walsbyi from Lake Tyrrell, Australia, reveal a variable genomic landscape. AB - Hypersaline systems near salt saturation levels represent an extreme environment, in which organisms grow and survive near the limits of life. One of the abundant members of the microbial communities in hypersaline systems is the square archaeon, Haloquadratum walsbyi. Utilizing a short-read metagenome from Lake Tyrrell, a hypersaline ecosystem in Victoria, Australia, we performed a comparative genomic analysis of H. walsbyi to better understand the extent of variation between strains/subspecies. Results revealed that previously isolated strains/subspecies do not fully describe the complete repertoire of the genomic landscape present in H. walsbyi. Rearrangements, insertions, and deletions were observed for the Lake Tyrrell derived Haloquadratum genomes and were supported by environmental de novo sequences, including shifts in the dominant genomic landscape of the two most abundant strains. Analysis pertaining to halomucins indicated that homologs for this large protein are not a feature common for all species of Haloquadratum. Further, we analyzed ATP-binding cassette transporters (ABC-type transporters) for evidence of niche partitioning between different strains/subspecies. We were able to identify unique and variable transporter subunits from all five genomes analyzed and the de novo environmental sequences, suggesting that differences in nutrient and carbon source acquisition may play a role in maintaining distinct strains/subspecies. PMID- 25709558 TI - Chemosensitizing and nephroprotective effect of resveratrol in cisplatin -treated animals. AB - BACKGROUND: Cisplatin (CIS) is one of the most effective anticancer drug used in the treatment of several solid tumors .Its use is limited by its nephrotoxicity. The present study was designed to assess the role of a natural product resveratrol (RSVL) on sensitization of mammary carcinoma (Ehrlich ascites carcinoma) to the action of CIS and the possible protective effect against CIS induced nephrotoxicity in rats. METHODS: The percent survival of female tumor bearing mice was used for determination the cytotoxic activity of CIS in the presence or the absence of RSVL. Uptake and cell cycle effect, serum creatinine (CREA), blood urea nitrogen (BUN), Reduced Glutathione (GSH) and histopatholgical examination of kidney tissues after CIS and/or RSVL therapy were also investigated. RESULTS: RSVL increased the intracellular level of CIS in EAC cells and there was a strong correlation between the high cellular level of CIS and its cytotoxicity. CIS at a dose level of 5 mg/kg increased the mean survival time of female tumor bearing mice to 25 days compared with 17 days for tumor-bearing control mice. Administration of RSVL at a dose level of 25 mg/kg simultaneously with CIS increased the mean survival time to 48 days with 60% survival of the tumor-bearing animals. Cell cycle analysis of tumor cells showed that CIS treatment decreases the proliferation index of tumor cells while in presence of RSVL there was more significant inhibitions. Also, CIS treatment caused increase in level of creatinine and blood urea with significant decrease in the GSH level. While, in the presence of RSVL, level of creatinine and blood urea restored to control level. CONCLUSION: This study suggests that RSVL could increase the cytotoxic activity of CIS and protect against its nephrotoxicity. PMID- 25709559 TI - The proteome profiles of the olfactory bulb of juvenile, adult and aged rats - an ontogenetic study. AB - BACKGROUND: In this study, we searched for proteins that change their expression in the olfactory bulb (oB) of rats during ontogenesis. Up to now, protein expression differences in the developing animal are not fully understood. Our investigation focused on the question whether specific proteins exist which are only expressed during different development stages. This might lead to a better characterization of the microenvironment and to a better determination of factors and candidates that influence the differentiation of neuronal progenitor cells. RESULTS: After analyzing the samples by two-dimensional polyacrylamide gel electrophoresis (2DE) and matrix-assisted laser desorption/ionization time-of flight mass spectrometry (MALDI-TOF-MS), it could be shown that the number of expressed proteins differs depending on the developmental stages. Especially members of the functional classes, like proteins of biosynthesis, regulatory proteins and structural proteins, show the highest differential expression in the stages of development analyzed. CONCLUSION: In this study, quantitative changes in the expression of proteins in the oB at different developmental stages (postnatal days (P) 7, 90 and 637) could be observed. Furthermore, the expression of many proteins was found at specific developmental stages. It was possible to identify these proteins which are involved in processes like support of cell migration and differentiation. PMID- 25709560 TI - Effect of Otoconial Proteins Fetuin A, Osteopontin, and Otoconin 90 on the Nucleation and Growth of Calcite. AB - We investigated the roles of three proteins associated with the formation of otoconia including fetuin A, osteopontin (OPN), and otoconin 90 (OC90). In situ atomic force microscopy (AFM) studies of the effects of these proteins on the growth of atomic steps on calcite surfaces were performed to obtain insight into their effects on the growth kinetics. We also used scanning electron microscopy to examine the effects of these proteins on crystal morphology. All three proteins were found to be potent inhibitors of calcite growth, although fetuin A promoted growth at concentrations below about 40 nM and only became an inhibitor at higher concentrations. We then used in situ optical microscopy to observe calcite nucleation on films of these proteins adsorbed onto mica surfaces. By measuring the calcite nucleation rate as a function of supersaturation, the value of the interfacial energy that controls the free energy barrier to heterogeneous nucleation was determined for each protein. OPN and OC90 films led to significantly reduced interfacial energies as compared to the value for homogeneous calcite nucleation in bulk solution. The value for fetuin A was equal to that for bulk solution within experimental error. Zeta potential measurements showed all of the proteins possessed negative surface charge and varied in magnitude according to sequence fetuin A > OC90 > OPN. In addition, the interfacial energies exhibited an inverse scaling with the zeta potential. In analogy to previous measurements on polysaccharide films, this scaling indicates the differences between the proteins arise from the effect of protein surface charge on the solution-substrate interfacial energy. PMID- 25709561 TI - Oritavancin for the treatment of acute bacterial skin and skin structure infections: an evidence-based review. AB - The emergence of resistance to glycopeptide antibiotics such as vancomycin and teicoplanin among Gram-positive bacteria has spurred the search for second generation drugs of this class. Oritavancin, a promising novel, second generation, semisynthetic lipoglycopeptide, is distinguished by two mechanisms of action: inhibition of cell wall synthesis and disruption of the cell membrane. This dual mechanism of action has increased the activity of oritavancin against vancomycin-resistant Gram-positive bacteria compared to other glycopeptides. Oritavancin has a concentration-dependent and rapid bactericidal activity against Gram-positive bacteria, particularly enterococci, contrary to vancomycin and teicoplanin, which exhibit bacteriostatic activity. It has a long half-life of about 195.4 hours and is slowly eliminated by the liver and kidneys, allowing once-daily dosing. Oritavancin has demonstrated preliminary safety and efficacy in Phase I and Phase II clinical trials. It was recently shown to be noninferior to vancomycin in a large Phase III randomized, double-blind clinical trial. To date, adverse events have been mild and limited, the most common being administration site complaints, headache, and nausea. Oritavancin appears to be a promising antimicrobial alternative to vancomycin with additional activity against Staphylococcus and Enterococcus isolates resistant to vancomycin and a more convenient way of administration. PMID- 25709563 TI - Auditory working memory for objects vs. features. AB - This work considers bases for working memory for non-verbal sounds. Specifically we address whether sounds are represented as integrated objects or individual features in auditory working memory and whether the representational format influences WM capacity. The experiments used sounds in which two different stimulus features, spectral passband and temporal amplitude modulation rate, could be combined to produce different auditory objects. Participants had to memorize sequences of auditory objects of variable length (1-4 items). They either maintained sequences of whole objects or sequences of individual features until recall for one of the items was tested. Memory recall was more accurate when the objects had to be maintained as a whole compared to the individual features alone. This is due to interference between features of the same object. Additionally a feature extraction cost was associated with maintenance and recall of individual features, when extracted from bound object representations. An interpretation of our findings is that, at some stage of processing, sounds might be stored as objects in WM with features bound into coherent wholes. The results have implications for feature-integration theory in the context of WM in the auditory system. PMID- 25709562 TI - Cerebral metabolism following traumatic brain injury: new discoveries with implications for treatment. AB - Because it is the product of glycolysis and main substrate for mitochondrial respiration, lactate is the central metabolic intermediate in cerebral energy substrate delivery. Our recent studies on healthy controls and patients following traumatic brain injury (TBI) using [6,6-(2)H2]glucose and [3-(13)C]lactate, along with cerebral blood flow (CBF) and arterial-venous (jugular bulb) difference measurements for oxygen, metabolite levels, isotopic enrichments and (13)CO2 show a massive and previously unrecognized mobilization of lactate from corporeal (muscle, skin, and other) glycogen reserves in TBI patients who were studied 5.7 +/- 2.2 days after injury at which time brain oxygen consumption and glucose uptake (CMRO2 and CMRgluc, respectively) were depressed. By tracking the incorporation of the (13)C from lactate tracer we found that gluconeogenesis (GNG) from lactate accounted for 67.1 +/- 6.9%, of whole-body glucose appearance rate (Ra) in TBI, which was compared to 15.2 +/- 2.8% (mean +/- SD, respectively) in healthy, well-nourished controls. Standard of care treatment of TBI patients in state-of-the-art facilities by talented and dedicated heath care professionals reveals presence of a catabolic Body Energy State (BES). Results are interpreted to mean that additional nutritive support is required to fuel the body and brain following TBI. Use of a diagnostic to monitor BES to provide health care professionals with actionable data in providing nutritive formulations to fuel the body and brain and achieve exquisite glycemic control are discussed. In particular, the advantages of using inorganic and organic lactate salts, esters and other compounds are examined. To date, several investigations on brain injured patients with intact hepatic and renal functions show that compared to dextrose + insulin treatment, exogenous lactate infusion results in normal glycemia. PMID- 25709565 TI - Neural components of altruistic punishment. AB - Altruistic punishment, which occurs when an individual incurs a cost to punish in response to unfairness or a norm violation, may play a role in perpetuating cooperation. The neural correlates underlying costly punishment have only recently begun to be explored. Here we review the current state of research on the neural basis of altruism from the perspectives of costly punishment, emphasizing the importance of characterizing elementary neural processes underlying a decision to punish. In particular, we emphasize three cognitive processes that contribute to the decision to altruistically punish in most scenarios: inequity aversion, cost-benefit calculation, and social reference frame to distinguish self from others. Overall, we argue for the importance of understanding the neural correlates of altruistic punishment with respect to the core computations necessary to achieve a decision to punish. PMID- 25709564 TI - Methylglyoxal, the dark side of glycolysis. AB - Glucose is the main energy substrate for the brain. There is now extensive evidence indicating that the metabolic profile of neural cells with regard to glucose utilization and glycolysis rate is not homogenous, with a marked propensity for glycolytic glucose processing in astrocytes compared to neurons. Methylglyoxal, a highly reactive dicarbonyl compound, is inevitably formed as a by-product of glycolysis. Methylglyoxal is a major cell-permeant precursor of advanced glycation end-products (AGEs), which are associated with several pathologies including diabetes, aging and neurodegenerative diseases. In normal situations, cells are protected against methylglyoxal toxicity by different mechanisms and in particular the glyoxalase system, which represents the most important pathway for the detoxification of methylglyoxal. While the neurotoxic effects of methylglyoxal and AGEs are well characterized, our understanding the glyoxalase system in the brain is more scattered. Considering the high energy requirements (i.e., glucose) of the brain, one should expect that the cerebral glyoxalase system is adequately fitted to handle methylglyoxal toxicity. This review focuses on our actual knowledge on the cellular aspects of the glyoxalase system in brain cells, in particular with regard to its activity in astrocytes and neurons. A main emerging concept is that these two neural cell types have different and energetically adapted glyoxalase defense mechanisms which may serve as protective mechanism against methylglyoxal-induced cellular damage. PMID- 25709566 TI - Acetylcholine induces GABA release onto rod bipolar cells through heteromeric nicotinic receptors expressed in A17 amacrine cells. AB - Acetylcholine (ACh) is a major retinal neurotransmitter that modulates visual processing through a large repertoire of cholinergic receptors expressed on different retinal cell types. ACh is released from starburst amacrine cells (SACs) under scotopic conditions, but its effects on cells of the rod pathway have not been investigated. Using whole-cell patch clamp recordings in slices of rat retina, we found that ACh application triggers GABA release onto rod bipolar (RB) cells. GABA was released from A17 amacrine cells and activated postsynaptic GABAA and GABAC receptors in RB cells. The sensitivity of ACh-induced currents to nicotinic ACh receptor (nAChR) antagonists (TMPH ~ mecamylamine > erysodine > DhbetaE > MLA) together with the differential potency of specific agonists to mimic ACh responses (cytisine >> RJR2403 ~ choline), suggest that A17 cells express heteromeric nAChRs containing the beta4 subunit. Activation of nAChRs induced GABA release after Ca(2+) accumulation in A17 cell dendrites and varicosities mediated by L-type voltage-gated calcium channels (VGCCs) and intracellular Ca(2+) stores. Inhibition of acetylcholinesterase depolarized A17 cells and increased spontaneous inhibitory postsynaptic currents in RB cells, indicating that endogenous ACh enhances GABAergic inhibition of RB cells. Moreover, injection of neostigmine or cytisine reduced the b-wave of the scotopic flash electroretinogram (ERG), suggesting that cholinergic modulation of GABA release controls RB cell activity in vivo. These results describe a novel regulatory mechanism of RB cell inhibition and complement our understanding of the neuromodulatory control of retinal signal processing. PMID- 25709567 TI - Neurological effects of inorganic arsenic exposure: altered cysteine/glutamate transport, NMDA expression and spatial memory impairment. AB - Inorganic arsenic (iAs) is an important natural pollutant. Millions of individuals worldwide drink water with high levels of iAs. Chronic exposure to iAs has been associated with lower IQ and learning disabilities as well as memory impairment. iAs is methylated in tissues such as the brain generating mono and dimethylated species. iAs methylation requires cellular glutathione (GSH), which is the main antioxidant in the central nervous system (CNS). In humans, As species cross the placenta and are found in cord blood. A CD1 mouse model was used to investigate effects of gestational iAs exposure which can lead to oxidative damage, disrupted cysteine/glutamate transport and its putative impact in learning and memory. On postnatal days (PNDs) 1, 15 and 90, the expression of membrane transporters related to GSH synthesis and glutamate transport and toxicity, such as xCT, EAAC1, GLAST and GLT1, as well as LAT1, were analyzed. Also, the expression of the glutamate receptor N-methyl-D-aspartate (NMDAR) subunits NR2A and B as well as the presence of As species in cortex and hippocampus were investigated. On PND 90, an object location task was performed to associate exposure with memory impairment. Gestational exposure to iAs affected the expression of cysteine/glutamate transporters in cortex and hippocampus and induced a negative modulation of NMDAR NR2B subunit in the hippocampus. Behavioral tasks showed significant spatial memory impairment in males while the effect was marginal in females. PMID- 25709568 TI - Mitotic spindle asymmetry in rodents and primates: 2D vs. 3D measurement methodologies. AB - Recent data have uncovered that spindle size asymmetry (SSA) is a key component of asymmetric cell division (ACD) in the mouse cerebral cortex (Delaunay et al., 2014). In the present study we show that SSA is independent of spindle orientation and also occurs during cortical progenitor divisions in the ventricular zone (VZ) of the macaque cerebral cortex, pointing to a conserved mechanism in the mammalian lineage. Because SSA magnitude is smaller in cortical precursors than in invertebrate neuroblasts, the unambiguous demonstration of volume differences between the two half spindles is considered to require 3D reconstruction of the mitotic spindle (Delaunay et al., 2014). Although straightforward, the 3D analysis of SSA is time consuming, which is likely to hinder SSA identification and prevent further explorations of SSA related mechanisms in generating ACD. We therefore set out to develop an alternative method for accurately measuring spindle asymmetry. Based on the mathematically demonstrated linear relationship between 2D and 3D analysis, we show that 2D assessment of spindle size in metaphase cells is as accurate and reliable as 3D reconstruction provided a specific procedure is applied. We have examined the experimental accuracy of the two methods by applying them to different sets of in vivo and in vitro biological data, including mouse and primate cortical precursors. Linear regression analysis demonstrates that the results from 2D and 3D reconstructions are equally powerful. We therefore provide a reliable and efficient technique to measure SSA in mammalian cells. PMID- 25709570 TI - Activation of the mouse primary visual cortex by medial prefrontal subregion stimulation is not mediated by cholinergic basalo-cortical projections. AB - The medial prefrontal cortex (mPFC) exerts top-down control of primary visual cortex (V1) activity. As there is no direct neuronal projection from mPFC to V1, this functional connection may use an indirect route, i.e., via basalo-cortical cholinergic projections. The cholinergic projections to V1 originate from neurons in the horizontal limb of the diagonal band of Broca (HDB), which receive neuronal projections from the ventral part of the mPFC, composed of prelimbic (PrL) and infralimbic cortices (IL). Therefore, the objective of this study was to determine whether electrical stimulation of mice mPFC subregions activate (1) V1 neurons; and (2) HDB cholinergic neurons, suggesting that the HDB serves as a relay point in the mPFC-V1 interaction. Neuronal activation was quantified using c-Fos immunocytochemistry or thallium autometallography for each V1 layer using automated particle analysis tools and optical density measurement. Stimulation of IL and PrL induced significantly higher c-Fos expression or thallium labeling in layers II/III and V of V1 in the stimulated hemisphere only. A HDB cholinergic neuron-specific lesion by saporin administration reduced IL-induced c-Fos expression in layers II/III of V1 but not in layer V. However, there was no c-Fos expression or thallium labeling in the HDB neurons, suggesting that this area was not activated by IL stimulation. Stimulation of another mPFC subarea, the anterior cingulate cortex (AC), which is involved in attention and receives input from V1, activated neither V1 nor HDB. The present results indicate that IL and PrL, but not AC, stimulation activates V1 with the minor involvement of the HDB cholinergic projections. These results suggest a functional link between the ventral mPFC and V1, but this function is only marginally supported by HDB cholinergic neurons and may involve other brain regions. PMID- 25709571 TI - Metamemory ratings predict long-term changes in reactivated episodic memories. AB - Reactivation of long-term memory can render the memory item temporarily labile, offering an opportunity to modify it via behavioral or pharmacological intervention. Declarative memory reactivation is accompanied by a metamemory ability to subjectively assess the knowledge available concerning the target item (Feeling of knowing, FOK). We set out to examine whether FOK can predict the extent of change of long-term episodic memories by post-retrieval manipulations. To this end, participants watched a short movie and were immediately thereafter tested on their memory for it. A day later, they were reminded of that movie, and either immediately or 1 day later, were presented with a second movie. The reminder phase consisted of memory cues to which participants were asked to judge their FOK regarding the original movie. The memory performance of participants to whom new information was presented immediately after reactivating the original episode corresponded to the degree of FOK ratings upon reactivation such that the lower their FOK, the less their memory declined. In contrast, no relation was found between FOK and memory strength for those who learned new information 1 day after the reminder phase. Our findings suggest that the subjective accessibility of reactivated memories may determine the extent to which new information might modify those memories. PMID- 25709569 TI - The role of the serotonergic system in locomotor recovery after spinal cord injury. AB - Serotonin (5-HT), a monoamine neurotransmitter synthesized in various populations of brainstem neurons, plays an important role in modulating the activity of spinal networks involved in vertebrate locomotion. Following spinal cord injury (SCI) there is a disruption of descending serotonergic projections to spinal motor areas, which results in a subsequent depletion in 5-HT, the dysregulation of 5-HT transporters as well as the elevated expression, super-sensitivity and/or constitutive auto-activation of specific 5-HT receptors. These changes in the serotonergic system can produce varying degrees of locomotor dysfunction through to paralysis. To date, various approaches targeting the different components of the serotonergic system have been employed to restore limb coordination and improve locomotor function in experimental models of SCI. These strategies have included pharmacological modulation of serotonergic receptors, through the administration of specific 5-HT receptor agonists, or by elevating the 5-HT precursor 5-hydroxytryptophan, which produces a global activation of all classes of 5-HT receptors. Stimulation of these receptors leads to the activation of the locomotor central pattern generator (CPG) below the site of injury to facilitate or improve the quality and frequency of movements, particularly when used in concert with the activation of other monoaminergic systems or coupled with electrical stimulation. Another approach has been to employ cell therapeutics to replace the loss of descending serotonergic input to the CPG, either through transplanted fetal brainstem 5-HT neurons at the site of injury that can supply 5 HT to below the level of the lesion or by other cell types to provide a substrate at the injury site for encouraging serotonergic axon regrowth across the lesion to the caudal spinal cord for restoring locomotion. PMID- 25709572 TI - Prospects for direct social perception: a multi-theoretical integration to further the science of social cognition. AB - In this paper we suggest that differing approaches to the science of social cognition mirror the arguments between radical embodied and traditional approaches to cognition. We contrast the use in social cognition of theoretical inference and mental simulation mechanisms with approaches emphasizing a direct perception of others' mental states. We build from a recent integrative framework unifying these divergent perspectives through the use of dual-process theory and supporting social neuroscience research. Our elaboration considers two complementary notions of direct perception: one primarily stemming from ecological psychology and the other from enactive cognition theory. We use this as the foundation from which to offer an account of the informational basis for social information and assert a set of research propositions to further the science of social cognition. In doing so, we point out how perception of the minds of others can be supported in some cases by lawful information, supporting direct perception of social affordances and perhaps, mental states, and in other cases by cues that support indirect perceptual inference. Our goal is to extend accounts of social cognition by integrating advances across disciplines to provide a multi-level and multi-theoretic description that can advance this field and offer a means through which to reconcile radical embodied and traditional approaches to cognitive neuroscience. PMID- 25709574 TI - Sensorimotor control of gait: a novel approach for the study of the interplay of visual and proprioceptive feedback. AB - Sensorimotor control theories propose that the central nervous system exploits expected sensory consequences generated by motor commands for movement planning, as well as online sensory feedback for comparison with expected sensory feedback for monitoring and correcting, if needed, ongoing motor output. In our study, we tested this theoretical framework by quantifying the functional role of expected vs. actual proprioceptive feedback for planning and regulation of gait in humans. We addressed this question by using a novel methodological approach to deliver fast perturbations of the walking surface stiffness, in conjunction with a virtual reality system that provided visual feedback of upcoming changes of surface stiffness. In the "predictable" experimental condition, we asked subjects to learn associating visual feedback of changes in floor stiffness (sand patch) during locomotion to quantify kinematic and kinetic changes in gait prior to and during the gait cycle. In the "unpredictable" experimental condition, we perturbed floor stiffness at unpredictable instances during the gait to characterize the gait-phase dependent strategies in recovering the locomotor cycle. For the "unpredictable" conditions, visual feedback of changes in floor stiffness was absent or inconsistent with tactile and proprioceptive feedback. The investigation of these perturbation-induced effects on contralateral leg kinematics revealed that visual feedback of upcoming changes in floor stiffness allows for both early (preparatory) and late (post-perturbation) changes in leg kinematics. However, when proprioceptive feedback is not available, the early responses in leg kinematics do not occur while the late responses are preserved although in a, slightly attenuated form. The methods proposed in this study and the preliminary results of the kinematic response of the contralateral leg open new directions for the investigation of the relative role of visual, tactile, and proprioceptive feedback on gait control, with potential implications for designing novel robot-assisted gait rehabilitation approaches. PMID- 25709573 TI - Redefining neuromarketing as an integrated science of influence. AB - Multiple transformative forces target marketing, many of which derive from new technologies that allow us to sample thinking in real time (i.e., brain imaging), or to look at large aggregations of decisions (i.e., big data). There has been an inclination to refer to the intersection of these technologies with the general topic of marketing as "neuromarketing". There has not been a serious effort to frame neuromarketing, which is the goal of this paper. Neuromarketing can be compared to neuroeconomics, wherein neuroeconomics is generally focused on how individuals make "choices", and represent distributions of choices. Neuromarketing, in contrast, focuses on how a distribution of choices can be shifted or "influenced", which can occur at multiple "scales" of behavior (e.g., individual, group, or market/society). Given influence can affect choice through many cognitive modalities, and not just that of valuation of choice options, a science of influence also implies a need to develop a model of cognitive function integrating attention, memory, and reward/aversion function. The paper concludes with a brief description of three domains of neuromarketing application for studying influence, and their caveats. PMID- 25709575 TI - Correlations between adolescent processing speed and specific spindle frequencies. AB - Sleep spindles are waxing and waning thalamocortical oscillations with accepted frequencies of between 11 and 16 Hz and a minimum duration of 0.5 s. Our research has suggested that there is spindle activity in all of the sleep stages, and thus for the present analysis we examined the link between spindle activity (Stage 2, rapid eye movement (REM) and slow wave sleep (SWS)) and waking cognitive abilities in 32 healthy adolescents. After software was used to filter frequencies outside the desired range, slow spindles (11.00-13.50 Hz), fast spindles (13.51-16.00 Hz) and spindle-like activity (16.01-18.50 Hz) were observed in Stage 2, SWS and REM sleep. Our analysis suggests that these specific EEG frequencies were significantly related to processing speed, which is one of the subscales of the intelligence score, in adolescents. The relationship was prominent in SWS and REM sleep. Further, the spindle-like activity (16.01-18.50 Hz) that occurred during SWS was strongly related to processing speed. Results suggest that the ability of adolescents to respond to tasks in an accurate, efficient and timely manner is related to their sleep quality. These findings support earlier research reporting relationships between learning, learning potential and sleep spindle activity in adults and adolescents. PMID- 25709576 TI - Processing of unconventional stimuli requires the recruitment of the non specialized hemisphere. AB - In the present study we investigate hemispheric processing of conventional and unconventional visual stimuli in the context of visual and verbal creative ability. In Experiment 1, we studied two unconventional visual recognition tasks Mooney face and objects' silhouette recognition-and found a significant relationship between measures of verbal creativity and unconventional face recognition. In Experiment 2 we used the split visual field (SVF) paradigm to investigate hemispheric processing of conventional and unconventional faces and its relation to verbal and visual characteristics of creativity. Results showed that while conventional faces were better processed by the specialized right hemisphere (RH), unconventional faces were better processed by the non specialized left hemisphere (LH). In addition, only unconventional face processing by the non-specialized LH was related to verbal and visual measures of creative ability. Our findings demonstrate the role of the non-specialized hemisphere in processing unconventional stimuli and how it relates to creativity. PMID- 25709577 TI - Hemispheric differences in relational reasoning: novel insights based on an old technique. AB - Relational reasoning, or the ability to integrate multiple mental relations to arrive at a logical conclusion, is a critical component of higher cognition. A bilateral brain network involving lateral prefrontal and parietal cortices has been consistently implicated in relational reasoning. Some data suggest a preferential role for the left hemisphere in this form of reasoning, whereas others suggest that the two hemispheres make important contributions. To test for a hemispheric asymmetry in relational reasoning, we made use of an old technique known as visual half-field stimulus presentation to manipulate whether stimuli were presented briefly to one hemisphere or the other. Across two experiments, 54 neurologically healthy young adults performed a visuospatial transitive inference task. Pairs of colored shapes were presented rapidly in either the left or right visual hemifield as participants maintained central fixation, thereby isolating initial encoding to the contralateral hemisphere. We observed a left-hemisphere advantage for encoding a series of ordered visuospatial relations, but both hemispheres contributed equally to task performance when the relations were presented out of order. To our knowledge, this is the first study to reveal hemispheric differences in relational encoding in the intact brain. We discuss these findings in the context of a rich literature on hemispheric asymmetries in cognition. PMID- 25709578 TI - Hybrid model of the context dependent vestibulo-ocular reflex: implications for vergence-version interactions. AB - The vestibulo-ocular reflex (VOR) is an involuntary eye movement evoked by head movements. It is also influenced by viewing distance. This paper presents a hybrid nonlinear bilateral model for the horizontal angular vestibulo-ocular reflex (AVOR) in the dark. The model is based on known interconnections between saccadic burst circuits in the brainstem and ocular premotor areas in the vestibular nuclei during fast and slow phase intervals of nystagmus. We implemented a viable switching strategy for the timing of nystagmus events to allow emulation of real nystagmus data. The performance of the hybrid model is evaluated with simulations, and results are consistent with experimental observations. The hybrid model replicates realistic AVOR nystagmus patterns during sinusoidal or step head rotations in the dark and during interactions with vergence, e.g., fixation distance. By simply assigning proper nonlinear neural computations at the premotor level, the model replicates all reported experimental observations. This work sheds light on potential underlying neural mechanisms driving the context dependent AVOR and explains contradictory results in the literature. Moreover, context-dependent behaviors in more complex motor systems could also rely on local nonlinear neural computations. PMID- 25709580 TI - Optimization of the cyclotide framework to improve cell penetration properties. AB - Cell penetrating peptides have been regarded as promising vectors to deliver hydrophilic molecules inside cells. Although they are great tools for research and have high potential as drug delivery systems, their application as drugs is impaired by their low stability in serum. Cyclotides, cyclic disulfide-rich peptides from plants, are ultra-stable molecules that have inspired applications in drug design as they can be used as scaffolds to stabilize linear bioactive sequences. Recently, they have also been shown to possess cell-penetrating properties. The combination of their remarkable stability and cell-penetrating properties opens new avenues for the application of peptides to bind to and inhibit intracellular proteins. Nevertheless, for a broader application of these molecules as vectors is of utmost importance to improve their cellular internalization efficiency. In this study we successfully modified MCoTI-II, one of the most widely studied cyclotide scaffolds in drug design, and improved its internalization properties. The internalization of the newly designed MCoTI-II is as efficient as the gold standard cell-penetrating peptide (CPP) TAT and maintains all the required features as a template to graft desired bioactivities. PMID- 25709579 TI - Estimation of presynaptic calcium currents and endogenous calcium buffers at the frog neuromuscular junction with two different calcium fluorescent dyes. AB - At the frog neuromuscular junction, under physiological conditions, the direct measurement of calcium currents and of the concentration of intracellular calcium buffers-which determine the kinetics of calcium concentration and neurotransmitter release from the nerve terminal-has hitherto been technically impossible. With the aim of quantifying both Ca(2+) currents and the intracellular calcium buffers, we measured fluorescence signals from nerve terminals loaded with the low-affinity calcium dye Magnesium Green or the high affinity dye Oregon Green BAPTA-1, simultaneously with microelectrode recordings of nerve-action potentials and end-plate currents. The action-potential-induced fluorescence signals in the nerve terminals developed much more slowly than the postsynaptic response. To clarify the reasons for this observation and to define a spatiotemporal profile of intracellular calcium and of the concentration of mobile and fixed calcium buffers, mathematical modeling was employed. The best approximations of the experimental calcium transients for both calcium dyes were obtained when the calcium current had an amplitude of 1.6 +/- 0.08 pA and a half decay time of 1.2 +/- 0.06 ms, and when the concentrations of mobile and fixed calcium buffers were 250 +/- 13 MUM and 8 +/- 0.4 mM, respectively. High concentrations of endogenous buffers define the time course of calcium transients after an action potential in the axoplasm, and may modify synaptic plasticity. PMID- 25709581 TI - Renal sympathetic denervation after Symplicity HTN-3 and therapeutic drug monitoring in severe hypertension. AB - Renal sympathetic denervation (RDN) has been and is still proposed as a new treatment modality in patients with apparently treatment resistant hypertension (TRH), a condition defined as persistent blood pressure elevation despite prescription of at least 3 antihypertensive drugs including a diuretic. However, the large fall in blood pressure after RDN reported in the first randomized study, Symplicity HTN-2 and multiple observational studies has not been confirmed in five subsequent prospective randomized studies and may be largely explained by non-specific effects such as improvement of drug adherence in initially poorly adherent patients (the Hawthorne effect), placebo effect and regression to the mean. The overall blood-pressure lowering effect of RDN seems rather limited and the characteristics of true responders are largely unknown. Accordingly, RDN is not ready for clinical practice. In most patients with apparently TRH, drug monitoring and improvement of drug adherence may prove more effective and cost beneficial to achieve blood pressure control. In the meantime, research should aim at identifying characteristics of those patients with truly TRH who may respond to RDN. PMID- 25709582 TI - Carbon monoxide and mitochondria-modulation of cell metabolism, redox response and cell death. AB - Carbon monoxide (CO) is an endogenously produced gasotransmitter, which is associated with cytoprotection and cellular homeostasis in several distinct cell types and tissues. CO mainly targets mitochondria because: (i) mitochondrial heme proteins are the main potential candidates for CO to bind, (ii) many CO's biological actions are dependent on mitochondrial ROS signaling and (iii) heme is generated in the mitochondrial compartment. Mitochondria are the key cell energy factory, producing ATP through oxidative phosphorylation and regulating cell metabolism. These organelles are also implicated in many cell signaling pathways and the production of reactive oxygen species (ROS). Finally, mitochondria contain several factors activating programmed cell death pathways, which are released from the mitochondrial inter-membrane space upon mitochondrial membrane permeabilization. Therefore, disclosing CO mode of action at mitochondria opens avenues for deeper understanding CO's biological properties. Herein, it is discussed how CO affects the three main aspects of mitochondrial modulation of cell function: metabolism, redox response and cell death. PMID- 25709584 TI - Psychosocial screening and assessment in oncology and palliative care settings. AB - Psychiatric and psychosocial disorders among cancer patients have been reported as a major consequence of the disease and treatment. The problems in applying a pure psychiatric approach have determined the need for structuring more defined methods, including screening for distress and emotional symptoms and a more specific psychosocial assessment, to warrant proper care to cancer patients with psychosocial problems. This review examines some of the most significant issues related to these two steps, screening and assessment of psychosocial morbidity in cancer and palliative care. With regard to this, the many different variables, such as the factors affecting individual vulnerability (e.g., life events, chronic stress and allostatic load, well-being, and health attitudes) and the psychosocial correlates of medical disease (e.g., psychiatric disturbances, psychological symptoms, illness behavior, and quality of life) which are possibly implicated not only in "classical" psychiatric disorders but more broadly in psychosocial suffering. Multidimensional tools [e.g., and specific psychosocially oriented interview (e.g., the Diagnostic Criteria for Psychosomatic Research)] represent a way to screen for and assess emotional distress, anxiety and depression, maladaptive coping, dysfunctional attachment, as well as other significant psychosocial dimensions secondary to cancer, such as demoralization and health anxiety. Cross-cultural issues, such as language, ethnicity, race, and religion, are also discussed as possible factors influencing the patients and families perception of illness, coping mechanisms, psychological response to a cancer diagnosis. PMID- 25709583 TI - Endosome-based protein trafficking and Ca(2+) homeostasis in the heart. AB - The ability to dynamically regulate, traffic, retain, and recycle proteins within the cell membrane is fundamental to life and central to the normal function of the heart. In the cardiomyocyte, these pathways are essential for the regulation of Ca(2+), both at the level of the plasma membrane, but also in local cellular domains. One intracellular pathway often overlooked in relation to cardiovascular Ca(2+) regulation and signaling is the endosome-based trafficking pathway. Highlighting its importance, this system and its molecular components are evolutionarily conserved across all metazoans. However, remarkably little is known of how endosome-based protein trafficking and recycling functions within mammalian cells systems, especially in the heart. As the endosomal system acts to regulate the expression and localization of membrane proteins central for cardiac Ca(2+) regulation, understanding the in vivo function of this system in the heart is critical. This review will focus on endosome-based protein trafficking in the heart in both health and disease with special emphasis for the role of endocytic regulatory proteins, C-terminal Eps15 homology domain-containing proteins (EHDs). PMID- 25709585 TI - CFA with binary variables in small samples: a comparison of two methods. AB - Asymptotically optimal correlation structure methods with binary data can break down in small samples. A new correlation structure methodology based on a recently developed odds-ratio (OR) approximation to the tetrachoric correlation coefficient is proposed as an alternative to the LPB approach proposed by Lee et al. (1995). Unweighted least squares (ULS) estimation with robust standard errors and generalized least squares (GLS) estimation methods were compared. Confidence intervals and tests for individual model parameters exhibited the best performance using the OR approach with ULS estimation. The goodness-of-fit chi square test exhibited the best Type I error control using the LPB approach with ULS estimation. PMID- 25709586 TI - Combat high or traumatic stress: violent offending is associated with appetitive aggression but not with symptoms of traumatic stress. AB - Former members of armed groups in eastern DR Congo had typically witnessed, experienced, and perpetrated extreme forms of violence. Enhanced trauma-related symptoms had been shown in prior research. But also lashing out in self-defense is a familiar response to threat defined as reactive aggression. Another potential response is appetitive aggression, in which the perpetration of excessive violence is perceived as pleasurable (combat high). What roles do these forms of aggressive behavior play in modern warfare and how are they related to posttraumatic stress symptoms? To answer the question, we sought to determine predictors for appetitive aggressive and trauma-related mental illness, and investigated the frequency of psychopathological symptoms for high- and low intensity conflict demobilization settings. To this end, we interviewed 213 former members of (para)military groups in the eastern Democratic Republic of Congo in regard to their combat exposure, posttraumatic stress, appetitive aggression, depression, suicidality, and drug dependence. Random forest regression embedded in a conditional inference framework revealed that perpetrated violent acts are not necessarily stressful. In fact, the experience of violent acts that typically implicated salient cues of hunting (e.g., blood, suffering of the victim, etc.) had the strongest association with an appetite for aggression. Furthermore, the number of lifetime perpetrated violent acts was the most important predictor of appetitive aggression. However, the number of perpetrated violent acts did not significantly affect the posttraumatic stress. Greater intensity of conflict was associated with more severe posttraumatic stress symptoms and depression. Psychotherapeutic interventions that address appetitive aggression in addition to trauma-related mental illness, including drug dependence, therefore seem indispensible for a successful reintegration of those who fought in the current civil wars. PMID- 25709587 TI - Creativity and aesthetic evaluation. Two proposals to improve the model of aesthetic dis/fluency. PMID- 25709588 TI - On the efficacy of procedures to normalize Ex-Gaussian distributions. AB - Reaction time (RT) is one of the most common types of measure used in experimental psychology. Its distribution is not normal (Gaussian) but resembles a convolution of normal and exponential distributions (Ex-Gaussian). One of the major assumptions in parametric tests (such as ANOVAs) is that variables are normally distributed. Hence, it is acknowledged by many that the normality assumption is not met. This paper presents different procedures to normalize data sampled from an Ex-Gaussian distribution in such a way that they are suitable for parametric tests based on the normality assumption. Using simulation studies, various outlier elimination and transformation procedures were tested against the level of normality they provide. The results suggest that the transformation methods are better than elimination methods in normalizing positively skewed data and the more skewed the distribution then the transformation methods are more effective in normalizing such data. Specifically, transformation with parameter lambda -1 leads to the best results. PMID- 25709589 TI - The measurement of consciousness: assuming completeness of first-person report significantly restricts scope and reliability of theory-discrimination. PMID- 25709590 TI - Representational deficit or processing effect? An electrophysiological study of noun-noun compound processing by very advanced L2 speakers of English. AB - The processing of English noun-noun compounds (NNCs) was investigated to identify the extent and nature of differences between the performance of native speakers of English and advanced Spanish and German non-native speakers of English. The study sought to establish whether the word order of the equivalent structure in the non-native speakers' mothertongue (L1) had an influence on their processing of NNCs in their second language (L2), and whether this influence was due to differences in grammatical representation (i.e., incomplete acquisition of the relevant structure) or processing effects. Two mask-primed lexical decision experiments were conducted in which compounds were presented with their constituent nouns in licit vs. reversed order. The first experiment used a speeded lexical decision task with reaction time registration, and the second a delayed lexical decision task with EEG registration. There were no significant group differences in accuracy in the licit word order condition, suggesting that the grammatical representation had been fully acquired by the non-native speakers. However, the Spanish speakers made slightly more errors with the reversed order and had longer response times, suggesting an L1 interference effect (as the reverse order matches the licit word order in Spanish). The EEG data, analyzed with generalized additive mixed models, further supported this hypothesis. The EEG waveform of the non-native speakers was characterized by a slightly later onset N400 in the violation condition (reversed constituent order). Compound frequency predicted the amplitude of the EEG signal for the licit word order for native speakers, but for the reversed constituent order for Spanish speakers-the licit order in their L1-supporting the hypothesis that Spanish speakers are affected by interferences from their L1. The pattern of results for the German speakers in the violation condition suggested a strong conflict arising due to licit constituents being presented in an order that conflicts with the expected order in both their L1 and L2. PMID- 25709591 TI - Inconsistent use of gesture space during abstract pointing impairs language comprehension. AB - Pointing toward concrete objects is a well-known and efficient communicative strategy. Much less is known about the communicative effectiveness of abstract pointing where the pointing gestures are directed to "empty space." McNeill's (2003) observations suggest that abstract pointing can be used to establish referents in gesture space, without the referents being physically present. Recently, however, it has been shown that abstract pointing typically provides redundant information to the uttered speech thereby suggesting a very limited communicative value (So et al., 2009). In a first approach to tackle this issue we were interested to know whether perceivers are sensitive at all to this gesture cue or whether it is completely discarded as irrelevant add-on information. Sensitivity to for instance a gesture-speech mismatch would suggest a potential communicative function of abstract pointing. Therefore, we devised a mismatch paradigm in which participants watched a video where a female was interviewed on various topics. During her responses, she established two concepts in space using abstract pointing (e.g., pointing to the left when saying Donald, and pointing to the right when saying Mickey). In the last response to each topic, the pointing gesture accompanying a target word (e.g., Donald) was either consistent or inconsistent with the previously established location. Event related brain potentials showed an increased N400 and P600 when gesture and speech referred to different referents, indicating that inconsistent use of gesture space impairs language comprehension. Abstract pointing was found to influence comprehension even though gesture was not crucial to understanding the sentences or conducting the experimental task. These data suggest that a referent was retrieved via abstract pointing and that abstract pointing can potentially be used for referent indication in a discourse. We conclude that abstract pointing has a potential communicative function. PMID- 25709592 TI - Unaddressed participants' gaze in multi-person interaction: optimizing recipiency. AB - One of the most intriguing aspects of human communication is its turn-taking system. It requires the ability to process on-going turns at talk while planning the next, and to launch this next turn without considerable overlap or delay. Recent research has investigated the eye movements of observers of dialogs to gain insight into how we process turns at talk. More specifically, this research has focused on the extent to which we are able to anticipate the end of current and the beginning of next turns. At the same time, there has been a call for shifting experimental paradigms exploring social-cognitive processes away from passive observation toward on-line processing. Here, we present research that responds to this call by situating state-of-the-art technology for tracking interlocutors' eye movements within spontaneous, face-to-face conversation. Each conversation involved three native speakers of English. The analysis focused on question-response sequences involving just two of those participants, thus rendering the third momentarily unaddressed. Temporal analyses of the unaddressed participants' gaze shifts from current to next speaker revealed that unaddressed participants are able to anticipate next turns, and moreover, that they often shift their gaze toward the next speaker before the current turn ends. However, an analysis of the complex structure of turns at talk revealed that the planning of these gaze shifts virtually coincides with the points at which the turns first become recognizable as possibly complete. We argue that the timing of these eye movements is governed by an organizational principle whereby unaddressed participants shift their gaze at a point that appears interactionally most optimal: It provides unaddressed participants with access to much of the visual, bodily behavior that accompanies both the current speaker's and the next speaker's turn, and it allows them to display recipiency with regard to both speakers' turns. PMID- 25709593 TI - Analysis of skin conductance response during evaluation of preferences for cosmetic products. AB - We analyzed skin conductance response (SCR) as a psychophysiological index to evaluate affective aspects of consumer preferences for cosmetic products. To examine the test-retest reliability of association between preferences and SCR, we asked 33 female volunteers to complete two experimental sessions approximately 1 year apart. The participants indicated their preferences in a typical paired comparison task by choosing the better option from a combination of two products among four products. We measured anticipatory SCR prior to expressions of the preferences. We found that the mean amplitude of the SCR elicited by the preferred products was significantly larger than that elicited by the non preferred products. The participants' preferences and corresponding SCR patterns were well preserved at the second session 1 year later. Our results supported cumulating findings that SCR is a useful index of consumer preferences that has future potential, both in laboratory and marketing settings. PMID- 25709594 TI - Metacognition moderates the effects of distraction on cognition. PMID- 25709595 TI - Varying variation: the effects of within- versus across-feature differences on relational category learning. AB - Learning of feature-based categories is known to interact with feature-variation in a variety of ways, depending on the type of variation (e.g., Markman and Maddox, 2003). However, relational categories are distinct from feature-based categories in that they determine membership based on structural similarities. As a result, the way that they interact with feature variation is unclear. This paper explores both experimental and computational data and argues that, despite its reliance on structural factors, relational category-learning should still be affected by the type of feature variation present during the learning process. It specifically suggests that within-feature and across-feature variation should produce different learning trajectories due to a difference in representational cost. The paper then uses the DORA model (Doumas et al., 2008) to discuss how this account might function in a cognitive system before presenting an experiment aimed at testing this account. The experiment was a relational category-learning task and was run on human participants and then simulated in DORA. Both sets of results indicated that learning a relational category from a training set with a lower amount of variation is easier, but that learning from a training set with increased within-feature variation is significantly less challenging than learning from a set with increased across-feature variation. These results support the claim that, like feature-based category-learning, relational category learning is sensitive to the type of feature variation in the training set. PMID- 25709597 TI - Kinematic and Gait Similarities between Crawling Human Infants and Other Quadruped Mammals. AB - Crawling on hands and knees is an early pattern of human infant locomotion, which offers an interesting way of studying quadrupedalism in one of its simplest form. We investigate how crawling human infants compare to other quadruped mammals, especially primates. We present quantitative data on both the gait and kinematics of seven 10-month-old crawling infants. Body movements were measured with an optoelectronic system giving precise data on 3-dimensional limb movements. Crawling on hands and knees is very similar to the locomotion of non-human primates in terms of the quite protracted arm at touch-down, the coordination between the spine movements in the lateral plane and the limbs, the relatively extended limbs during locomotion and the strong correlation between stance duration and speed of locomotion. However, there are important differences compared to primates, such as the choice of a lateral-sequence walking gait, which is similar to most non-primate mammals and the relatively stiff elbows during stance as opposed to the quite compliant gaits of primates. These finding raise the question of the role of both the mechanical structure of the body and neural control on the determination of these characteristics. PMID- 25709596 TI - Maintenance Deep Transcranial Magnetic Stimulation Sessions are Associated with Reduced Depressive Relapses in Patients with Unipolar or Bipolar Depression. AB - INTRODUCTION: Deep transcranial magnetic stimulation (dTMS) is a new form of TMS allowing safe stimulation of deep brain regions. The objective of this preliminary study was to assess the role of dTMS maintenance sessions in protecting patients with bipolar disorder (BD) or recurrent major depressive disorder (MDD) from developing depressive or manic relapses in a 12-month follow up period. METHODS: Twenty-four drug-resistant patients with a current depressive episode and a diagnosis of MDD or BD have been enrolled in the study. All the participants underwent daily dTMS sessions for 4 weeks. One group (maintenance - M group) received additional maintenance dTMS sessions weekly or twice a week. RESULTS: After the first dTMS cycle, a significant reduction of Hamilton Depression Rating Scale (HDRS) scores was observed in all participants. Subsequently, the HDRS mean scores did not significantly change over time in the M group, while it significantly increased in the non-M-group after 6 and 12 months. DISCUSSION: This study confirms previous evidence of a positive therapeutic effect of dTMS on depressive symptoms and suggests that, after recovery from acute episodes, maintenance dTMS sessions may be helpful in maintaining euthymia in a 12-month follow-up period. PMID- 25709598 TI - Piloting a new approach to the treatment of obesity using dexamphetamine. AB - BACKGROUND AND AIMS: There is a clear need for a new approach to the treatment of obesity, which is inexpensive and is effective for establishing lifestyle change. We conducted a pilot study to evaluate whether dexamphetamine can be used safely, combined with diet and exercise, for treating obesity. Our ultimate aim is to develop a 6-month treatment program for establishing the lifestyle changes necessary for weight control, utilizing dexamphetamine for its psychotropic effect on motivation. We viewed the anorexigenic effect as an additional advantage for promoting initial weight loss. METHODS: Obese adults were treated with dexamphetamine for 6 months (maximum of 30 mg twice daily), diet, and exercise. Weight, electrocardiogram, echocardiogram, and blood pressure were monitored. RESULTS: Twelve out of 14 completed 6 months treatment. Weight loss by intention to treat was 10.6 kg (95% CI 5.8-15.5, p < 0.001). The mean weight gain in the 6 months after ceasing dexamphetamine was 4.5 kg (95% CI 1.9-7.2, p = 0.003), leaving a mean weight loss at 12 months from baseline of 7.0 kg (95% CI 13.4 to -0.6, p = 0.03). All reported favorable increases in energy and alertness. Dose-limiting symptoms were mood changes (2) and insomnia (2). None had drug craving on ceasing dexamphetamine, and there were no cardiac complications. Among the seven women, there was a significant correlation for those who lost most weight on treatment to have the least regain in the following 6 months (r = 0.88, p = 0.009). CONCLUSION: Our treatment with dexamphetamine, diet, and exercise was well tolerated and effective for initial weight loss. Future research will focus on identifying baseline predictive variables associated with long-term weight control. PMID- 25709599 TI - 30 Years Old: O-GlcNAc Reaches the Age of Reason - Regulation of Cell Signaling and Metabolism by O-GlcNAcylation. PMID- 25709600 TI - Soil bacterial and fungal communities respond differently to various isothiocyanates added for biofumigation. AB - The meals from many oilseed crops have potential for biofumigation due to their release of biocidal compounds such as isothiocyanates (ITCs). Various ITCs are known to inhibit numerous pathogens; however, much less is known about how the soil microbial community responds to the different types of ITCs released from oilseed meals (SMs). To simulate applying ITC-releasing SMs to soil, we amended soil with 1% flax SM (contains no biocidal chemicals) along with four types of ITCs (allyl, butyl, phenyl, and benzyl ITC) in order to determine their effects on soil fungal and bacterial communities in a replicated microcosm study. Microbial communities were analyzed based on the ITS region for fungi and 16S rRNA gene for bacteria using qPCR and tag-pyrosequencing with 454 GS FLX titanium technology. A dramatic decrease in fungal populations (~85% reduction) was observed after allyl ITC addition. Fungal community compositions also shifted following ITC amendments (e.g., Humicola increased in allyl and Mortierella in butyl ITC amendments). Bacterial populations were less impacted by ITCs, although there was a transient increase in the proportion of Firmicutes, related to bacteria know to be antagonistic to plant pathogens, following amendment with allyl ITC. Our results indicate that the type of ITC released from SMs can result in differential impacts on soil microorganisms. This information will aid selection and breeding of plants for biofumigation-based control of soil-borne pathogens while minimizing the impacts on non-target microorganisms. PMID- 25709601 TI - Interaction sites of DivIVA and RodA from Corynebacterium glutamicum. AB - Elongation growth in actinobacteria is localized at the cell poles. This is in contrast to many classical model organisms where insertion of new cell wall material is localized around the lateral site. We previously described a role of RodA from Corynebacterium glutamicum in apical cell growth and morphogenesis. Deletion of rodA had drastic effects on morphology and growth, likely a result from misregulation of penicillin-binding proteins and cell wall precursor delivery. We identified the interaction of RodA with the polar scaffold protein DivIVA, thus explaining subcellular localization of RodA to the cell poles. In this study, we describe this interaction in detail and map the interaction sites of DivIVA and RodA. A single amino acid residue in the N-terminal domain of DivIVA was found to be crucial for the interaction with RodA. The interaction site of RodA was mapped to its cytoplasmic, C-terminal domain, in a region encompassing the last 10 amino acids (AAs). Deletion of these 10 AAs significantly decreased the interaction efficiency with DivIVA. Our results corroborate the interaction of DivIVA and RodA, underscoring the important role of DivIVA as a spatial organizer of the elongation machinery in Corynebacterineae. PMID- 25709602 TI - Composite mobile genetic elements disseminating macrolide resistance in Streptococcus pneumoniae. AB - Macrolide resistance in Streptococcus pneumoniae emerged in the U.S. and globally during the early 1990's. The RNA methylase encoded by erm(B) and the macrolide efflux genes mef(E) and mel were identified as the resistance determining factors. These genes are disseminated in the pneumococcus on mobile, often chimeric elements consisting of multiple smaller elements. To better understand the variety of elements encoding macrolide resistance and how they have evolved in the pre- and post-conjugate vaccine eras, the genomes of 121 invasive and ten carriage isolates from Atlanta from 1994 to 2011 were analyzed for mobile elements involved in the dissemination of macrolide resistance. The isolates were selected to provide broad coverage of the genetic variability of antibiotic resistant pneumococci and included 100 invasive isolates resistant to macrolides. Tn916-like elements carrying mef(E) and mel on the Macrolide Genetic Assembly (Mega) and erm(B) on the erm(B) element and Tn917 were integrated into the pneumococcal chromosome backbone and into larger Tn5253-like composite elements. The results reported here include identification of novel insertion sites for Mega and characterization of the insertion sites of Tn916-like elements in the pneumococcal chromosome and in larger composite elements. The data indicate that integration of elements by conjugation was infrequent compared to recombination. Thus, it appears that conjugative mobile elements allow the pneumococcus to acquire DNA from distantly related bacteria, but once integrated into a pneumococcal genome, transformation and recombination is the primary mechanism for transmission of novel DNA throughout the pneumococcal population. PMID- 25709603 TI - Cellular compartmentalization of secondary metabolism. AB - Fungal secondary metabolism is often considered apart from the essential housekeeping functions of the cell. However, there are clear links between fundamental cellular metabolism and the biochemical pathways leading to secondary metabolite synthesis. Besides utilizing key biochemical precursors shared with the most essential processes of the cell (e.g., amino acids, acetyl CoA, NADPH), enzymes for secondary metabolite synthesis are compartmentalized at conserved subcellular sites that position pathway enzymes to use these common biochemical precursors. Co-compartmentalization of secondary metabolism pathway enzymes also may function to channel precursors, promote pathway efficiency and sequester pathway intermediates and products from the rest of the cell. In this review we discuss the compartmentalization of three well-studied fungal secondary metabolite biosynthetic pathways for penicillin G, aflatoxin and deoxynivalenol, and summarize evidence used to infer subcellular localization. We also discuss how these metabolites potentially are trafficked within the cell and may be exported. PMID- 25709604 TI - Environmental monitoring of waterborne Campylobacter: evaluation of the Australian standard and a hybrid extraction-free MPN-PCR method. AB - Campylobacter is the leading agent of diarrheal disease worldwide. This study evaluates a novel culture-PCR hybrid (MPN-PCR) assay for the rapid enumeration of Campylobacter spp. from estuarine and wastewater systems. To first evaluate the current, culture-based, Australian standard, an inter-laboratory study was conducted on 69 subsampled water samples. The proposed Most-Probable Number (MPN) PCR method was then evaluated, by analysing 147 estuarine samples collected over a 2 year period. Data for 14 different biological, hydrological and climatic parameters were also collated to identify pathogen-environment relationships and assess the potential for method specific bias. The results demonstrated that the intra-laboratory performance of the MPN-PCR was superior to that of AS/NZS (sigma = 0.7912, P < 0.001; kappa = 0.701, P < 0.001) with an overall diagnostic accuracy of ~94%. Furthermore, the analysis of both MPN-PCR and AS/NZS identified the potential for the introduction of method specific bias during assessment of the effects of environmental parameters on Campylobacter spp. numbers. PMID- 25709605 TI - Bioactivity of essential oils: a review on their interaction with food components. AB - Essential oils (EOs) are liquid preparations, produced from plant materials. Although EOs showed a promising bioactivity in vitro, they could interact in foods with some components (fats, proteins, carbohydrates) and pH, thus many authors have reported that a significant effect of EOs toward spoiling and pathogenic microorganisms could be achieved in vivo by using higher amounts of oils. Different methods can be used to assess the bioactivity of EOs (disk diffusion and agar or broth dilution methods); however, there is not a standardized test and researchers propose and use different protocols (evaluating the Minimal Inhibitory Concentration, studying the survival curves, analysis through the scanning electron microscopy, etc.). Thereafter, the scope of this review is a focus on interactions of EOs with proteins, carbohydrates, oils, NaCl, and pH, as well as a brief description on the different protocols to assess their bioactivity both under in vivo and in vitro conditions. PMID- 25709606 TI - Human Peripheral CD4(+) Vdelta1(+) gammadeltaT Cells Can Develop into alphabetaT Cells. AB - The lifelong generation of alphabetaT cells enables us to continuously build immunity against pathogens and malignancies despite the loss of thymic function with age. Homeostatic proliferation of post-thymic naive and memory T cells and their transition into effector and long-lived memory cells balance the decreasing output of naive T cells, and recent research suggests that also alphabetaT-cell development independent from the thymus may occur. However, the sites and mechanisms of extrathymic T-cell development are not yet understood in detail. gammadeltaT cells represent a small fraction of the overall T-cell pool, and are endowed with tremendous phenotypic and functional plasticity. gammadeltaT cells that express the Vdelta1 gene segment are a minor population in human peripheral blood but predominate in epithelial (and inflamed) tissues. Here, we characterize a CD4(+) peripheral Vdelta1(+) gammadeltaT-cell subpopulation that expresses stem cell and progenitor markers and is able to develop into functional alphabetaT cells ex vivo in a simple culture system and in vivo. The route taken by this process resembles thymic T-cell development. However, it involves the re organization of the Vdelta1(+) gammadeltaTCR into the alphabetaTCR as a consequence of TCR-gamma chain downregulation and the expression of surface Vdelta1(+)Vbeta(+) TCR components, which we believe function as surrogate pre TCR. This transdifferentiation process is readily detectable in vivo in inflamed tissue. Our study provides a conceptual framework for extrathymic T-cell development and opens up a new vista in immunology that requires adaptive immune responses in infection, autoimmunity, and cancer to be reconsidered. PMID- 25709607 TI - Combining immunotherapy with oncogene-targeted therapy: a new road for melanoma treatment. AB - Cutaneous melanoma arises from the malignant transformation of skin melanocytes; its incidence and mortality have been increasing steadily over the last 50 years, now representing 3% of total tumors. Once melanoma metastasizes, prognosis is somber and therapeutic options are limited. However, the discovery of prevalent BRAF mutations in at least 50% of melanoma tumors led to development of BRAF inhibitors, and other drugs targeting the MAPK pathway including MEK-inhibitors, are changing this reality. These recently approved treatments for metastatic melanoma have made a significant impact on patient survival; though the results are shadowed by the appearance of drug-resistance. Combination therapies provide a rational strategy to potentiate efficacy and potentially overcome resistance. Undoubtedly, the last decade has also born a renaissance of immunotherapy, and encouraging advances in metastatic melanoma treatment are illuminating the road. Immune checkpoint blockades, such as CTLA-4 antagonist-antibodies, and multiple cancer vaccines are now invaluable arms of anti-tumor therapy. Recent work has brought to light the delicate relationship between tumor biology and the immune system. Host immunity contributes to the anti-tumor activity of oncogene-targeted inhibitors within a complex network of cytokines and chemokines. Therefore, combining immunotherapy with oncogene-targeted drugs may be the key to melanoma control. Here, we review ongoing clinical studies of combination therapies using both oncogene inhibitors and immunotherapeutic strategies in melanoma patients. We will revisit the preclinical evidence that tested sequential and concurrent schemes in suitable animal models and formed the basis for the current trials. Finally, we will discuss potential future directions of the field. PMID- 25709608 TI - Signal Integration during T Lymphocyte Activation and Function: Lessons from the Wiskott-Aldrich Syndrome. AB - Over the last decades, research dedicated to the molecular and cellular mechanisms underlying primary immunodeficiencies (PID) has helped to understand the etiology of many of these diseases and to develop novel therapeutic approaches. Beyond these aspects, PID are also studied because they offer invaluable natural genetic tools to dissect the human immune system. In this review, we highlight the research that has focused over the last 20 years on T lymphocytes from Wiskott-Aldrich syndrome (WAS) patients. WAS T lymphocytes are defective for the WAS protein (WASP), a regulator of actin cytoskeleton remodeling. Therefore, study of WAS T lymphocytes has helped to grasp that many steps of T lymphocyte activation and function depend on the crosstalk between membrane receptors and the actin cytoskeleton. These steps include motility, immunological synapse assembly, and signaling, as well as the implementation of helper, regulatory, or cytotoxic effector functions. The recent concept that WASP also works as a regulator of transcription within the nucleus is an illustration of the complexity of signal integration in T lymphocytes. Finally, this review will discuss how further study of WAS may contribute to solve novel challenges of T lymphocyte biology. PMID- 25709609 TI - The bacterial rhizobiome of hyperaccumulators: future perspectives based on omics analysis and advanced microscopy. AB - Hyperaccumulators are plants that can extract heavy metal ions from the soil and translocate those ions to the shoots, where they are sequestered and detoxified. Hyperaccumulation depends not only on the availability of mobilized metal ions in the soil, but also on the enhanced activity of metal transporters and metal chelators which may be provided by the plant or its associated microbes. The rhizobiome is captured by plant root exudates from the complex microbial community in the soil, and may colonize the root surface or infiltrate the root cortex. This community can increase the root surface area by inducing hairy root proliferation. It may also increase the solubility of metals in the rhizosphere and promote the uptake of soluble metals by the plant. The bacterial rhizobiome, a subset of specialized microorganisms that colonize the plant rhizosphere and endosphere, makes an important contribution to the hyperaccumulator phenotype. In this review, we discuss classic and more recent tools that are used to study the interactions between hyperaccumulators and the bacterial rhizobiome, and consider future perspectives based on the use of omics analysis and microscopy to study plant metabolism in the context of metal accumulation. Recent data suggest that metal-resistant bacteria isolated from the hyperaccumulator rhizosphere and endosphere could be useful in applications such as phytoextraction and phytoremediation, although more research is required to determine whether such properties can be transferred successfully to non-accumulator species. PMID- 25709610 TI - Cell wall remodeling under abiotic stress. AB - Plants exposed to abiotic stress respond to unfavorable conditions on multiple levels. One challenge under drought stress is to reduce shoot growth while maintaining root growth, a process requiring differential cell wall synthesis and remodeling. Key players in this process are the formation of reactive oxygen species (ROS) and peroxidases, which initially cross-link phenolic compounds and glycoproteins of the cell walls causing stiffening. The function of ROS shifts after having converted all the peroxidase substrates in the cell wall. If ROS levels remain high during prolonged stress, OH degrees -radicals are formed which lead to polymer cleavage. In concert with xyloglucan modifying enzymes and expansins, the resulting cell wall loosening allows further growth of stressed organs. PMID- 25709611 TI - The rise of the photosynthetic rate when light intensity increases is delayed in ndh gene-defective tobacco at high but not at low CO2 concentrations. AB - The 11 plastid ndh genes have hovered frequently on the edge of dispensability, being absent in the plastid DNA of many algae and certain higher plants. We have compared the photosynthetic activity of tobacco (Nicotiana tabacum, cv. Petit Havana) with five transgenic lines (DeltandhF, pr-DeltandhF, T181D, T181A, and ndhF FC) and found that photosynthetic performance is impaired in transgenic ndhF defective tobacco plants at rapidly fluctuating light intensities and higher than ambient CO2 concentrations. In contrast to wild type and ndhF FC, which reach the maximum photosynthetic rate in less than 1 min when light intensity suddenly increases, ndh defective plants (DeltandhF and T181A) show up to a 5 min delay in reaching the maximum photosynthetic rate at CO2 concentrations higher than the ambient 360 ppm. Net photosynthesis was determined at different CO2 concentrations when sequences of 130, 870, 61, 870, and 130 MUmol m(-2) s(-1) PAR sudden light changes were applied to leaves and photosynthetic efficiency and entropy production (Sg) were determined as indicators of photosynthesis performance. The two ndh-defective plants, DeltandhF and T181A, had lower photosynthetic efficiency and higher Sg than wt, ndhF FC and T181D tobacco plants, containing full functional ndh genes, at CO2 concentrations above 400 ppm. We propose that the Ndh complex improves cyclic electron transport by adjusting the redox level of transporters during the low light intensity stage. In ndhF-defective strains, the supply of electrons through the Ndh complex fails, transporters remain over-oxidized (specially at high CO2 concentrations) and the rate of cyclic electron transport is low, impairing the ATP level required to rapidly reach high CO2 fixation rates in the following high light phase. Hence, ndh genes could be dispensable at low but not at high atmospheric concentrations of CO2. PMID- 25709612 TI - A small RNA mediated regulation of a stress-activated retrotransposon and the tissue specific transposition during the reproductive period in Arabidopsis. AB - Transposable elements (TEs) are key elements that facilitate genome evolution of the host organism. A number of studies have assessed the functions of TEs, which change gene expression in the host genome. Activation of TEs is controlled by epigenetic modifications such as DNA methylation and histone modifications. Several recent studies have reported that TEs can also be activated by biotic or abiotic stress in some plants. We focused on a Ty1/copia retrotransposon, ONSEN, that is activated by heat stress (HS) in Arabidopsis. We found that transcriptional activation of ONSEN was regulated by a small interfering RNA (siRNA)-related pathway, and the activation could also be induced by oxidative stress. Mutants deficient in siRNA biogenesis that were exposed to HS at the initial stages of vegetative growth showed transgenerational transposition. The transposition was also detected in the progeny, which originated from tissue that had differentiated after exposure to the HS. The results indicated that in some undifferentiated cells, transpositional activity could be maintained quite long after exposure to the HS. PMID- 25709613 TI - Endoglin involvement in integrin-mediated cell adhesion as a putative pathogenic mechanism in hereditary hemorrhagic telangiectasia type 1 (HHT1). AB - Mutations in the endoglin gene (ENG) are responsible for ~50% of all cases with hereditary hemorrhagic telangiectasia (HHT). Because of the absence of effective treatments for HHT symptoms, studies aimed at identifying novel biological functions of endoglin which could serve as therapeutic targets of the disease are needed. Endoglin is an endothelial membrane protein, whose most studied function has been its role as an auxiliary receptor in the TGF-beta receptor complex. However, several lines of evidence suggest the involvement of endoglin in TGF beta-independent functions. Endoglin displays, within its zona pellucida domain, an RGD motif, which is a prototypic sequence involved in integrin-based interactions with other proteins. Indeed, we have recently described a novel role for endothelial endoglin in leukocyte trafficking and extravasation via its interaction with leukocyte integrins. In addition, functional, as well as protein and gene expression analysis have shown that ectopic endoglin represses the synthesis of several members of the integrin family and modulates integrin mediated cell adhesions. This review focuses on the tight link between endoglin and integrins and how the role of endothelial endoglin in integrin-dependent cell adhesion processes can provide a better understanding of the pathogenic mechanisms leading to vascular lesions in endoglin haploinsufficient HHT1 patients. PMID- 25709614 TI - Endoplasmic reticulum stress response and transcriptional reprogramming. PMID- 25709615 TI - Genetic differentiation of Mexican Holstein cattle and its relationship with Canadian and U.S. Holsteins. AB - The Mexican Holstein (HO) industry has imported Canadian and US (CAN + USA) HO germplasm for use in two different production systems, the conventional (Conv) and the low income (Lowi) system. The objective of this work was to study the genetic composition and differentiation of the Mexican HO cattle, considering the production system in which they perform and their relationship with the Canadian and US HO populations. The analysis included information from 149, 303, and 173 unrelated or with unknown pedigree HO animals from the Conv, Lowi, and CAN + USA populations, respectively. Canadian and US Jersey (JE) and Brown Swiss (BS) genotypes (162 and 86, respectively) were used to determine if Mexican HOs were hybridized with either of these breeds. After quality control filtering, a total of 6,617 out of 6,836 single nucleotide polymorphism markers were used. To describe the genetic diversity across the populations, principal component (PC), admixture composition, and linkage disequilibrium (LD; r(2) ) analyses were performed. Through the PC analysis, HO * JE and HO * BS crossbreeding was detected in the Lowi system. The Conv system appeared to be in between Lowi and CAN + USA populations. Admixture analysis differentiated between the genetic composition of the Conv and Lowi systems, and five ancestry groups associated to sire's country of origin were identified. The minimum distance between markers to estimate a useful LD was found to be 54.5 kb for the Mexican HO populations. At this average distance, the persistence of phase across autosomes of Conv and Lowi systems was 0.94, for Conv and CAN + USA was 0.92 and for the Lowi and CAN + USA was 0.91. Results supported the flow of germplasm among populations being Conv a source for Lowi, and dependent on migration from CAN + USA. Mexican HO cattle in Conv and Lowi populations share common ancestry with CAN + USA but have different genetic signatures. PMID- 25709616 TI - SNP imputation bias reduces effect size determination. AB - Imputation is a commonly used technique that exploits linkage disequilibrium to infer missing genotypes in genetic datasets, using a well-characterized reference population. While there is agreement that the reference population has to match the ethnicity of the query dataset, it is common practice to use the same reference to impute genotypes for a wide variety of phenotypes. We hypothesized that using a reference composed of samples with a different phenotype than the query dataset would introduce imputation bias. To test this hypothesis we used GWAS datasets from Amyotrophic Lateral Sclerosis (ALS), Parkinson Disease (PD), and Crohn's Disease (CD). First, we masked and then performed imputation of 100 disease-associated markers and 100 non-associated markers from each study. Two references for imputation were used in parallel: one consisting of healthy controls and another consisting of patients with the same disease. We assessed the discordance (imprecision) and bias (inaccuracy) of imputation by comparing predicted genotypes to those assayed by SNP-chip. We also assessed the bias on the observed effect size when the predicted genotypes were used in a GWAS study. When healthy controls were used as reference for imputation, a significant bias was observed, particularly in the disease-associated markers. Using cases as reference significantly attenuated this bias. For nearly all markers, the direction of the bias favored the non-risk allele. In GWAS studies of the three diseases (with healthy reference controls from the 1000 genomes as reference), the mean OR for disease-associated markers obtained by imputation was lower than that obtained using original assayed genotypes. We found that the bias is inherent to imputation as using different methods did not alter the results. In conclusion, imputation is a powerful method to predict genotypes and estimate genetic risk for GWAS. However, a careful choice of reference population is needed to minimize biases inherent to this approach. PMID- 25709617 TI - Autophagy and apoptosis during adult adipose-derived stromal cells differentiation into neuron-like cells in vitro. AB - beta-mercaptoethanol can induce adult adipose-derived stromal cells to rapidly and efficiently differentiate into typical neuron-like cells in vitro. Immunohistochemistry showed that neuron specific enolase and neurofilament-200 expression gradually increased with the extension of induction time, and peaked at 5 hours. By contrast, glial fibrillary acidic protein was negatively expressed at all time points. Induced cells possessed a typical Nissl body, apoptosis showing condensed chromatin in the nucleus, autophagosomes with a bilayered membrane and autolysosomes in the cytoplasm at 5 hours. TUNEL assay and immunohistochemistry and immunofluorescence demonstrated that apoptosis and caspase-3 expression increased and peaked at 8 hours. Immunohistochemistry and immunofluorescence showed that microtubuleassociated protein light chain 3 gradually increased with induction and reached a peak at 5 hours. These results indicate that autophagy played an important role in protecting cells during adult adipose-derived stromal cells differentiation into neuron-like cells in vitro. PMID- 25709618 TI - Morphological properties and proliferation analysis of olfactory ensheathing cells seeded onto three-dimensional collagen-heparan sulfate biological scaffolds. AB - This study aimed to examine the differences in the morphological properties and proliferation of olfactory ensheathing cells in three-dimensional culture on collagen-heparan sulfate biological scaffolds and in two-dimensional culture on common flat culture plates. The proliferation rate of olfactory ensheathing cells in three-dimensional culture was higher than that in two-dimensional culture, as detected by an MTT assay. In addition, more than half of the olfactory ensheathing cells subcultured using the trypsinization method in three dimensional culture displayed a spindly Schwann cell-like morphology with extremely long processes, while they showed a flat astrocyte-like morphology in two-dimensional culture. Moreover, spindle-shaped olfactory ensheathing cells tended to adopt an elongated bipolar morphology under both culture conditions. Experimental findings indicate that the morphological properties and proliferation of olfactory ensheathing cells in three-dimensional culture on collagen-heparan sulfate biological scaffolds are better than those in two dimensional culture. PMID- 25709619 TI - Granulocyte-macrophage colony-stimulating factor-transfected bone marrow stromal cells for the treatment of ischemic stroke. AB - Adult, male, Sprague-Dawley rats were injected with granulocyte-macrophage colony stimulating factor-transfected bone marrow stromal cells (GM-CSF-BMSCs) into the ischemic boundary zone at 24 hours after onset of middle cerebral artery occlusion. Results showed reduced infarct volume, decreased number of apoptotic cells, improved neurological functions, increased angiogenic factor expression, and increased vascular density in the ischemic boundary zone in rats that underwent GM-CSF-BMSCs transplantation compared with the BMSCs group. Experimental findings suggested that GM-CSF-BMSCs could serve as a potential therapeutic strategy for ischemic stroke and are superior to BMSCs alone. PMID- 25709620 TI - Optical control after transfection of channelrhodopsin-2 recombinant adenovirus in visual cortical cells. AB - Channelrhodopsin-2 ectopically expressed in the retina can recover the response to blue light in genetically blind mice and rats, but is unable to restore visual function due to optic nerve or optic tract lesions. Long Evans rats at postnatal day 1 were used for primary culture of visual cortical cells, and 24 hours later, cells were transfected with recombinant adenovirus carrying channelrhodopsin-2 and green fluorescent protein genes. After 2-4 days of transfection, green fluorescence was visible in the cultured cells. Cells were stimulated with blue light (470 nm), and light-induced action potentials were recorded in patch-clamp experiments. Our findings indicate that channelrhodopsin-2-recombinant adenovirus transfection of primary cultured visual cortical cells can control the production of action potentials via blue light stimulation. PMID- 25709621 TI - Spatiotemporal alterations of presynaptic elements in the retina after high intraocular pressure. AB - A rat model of acute high intraocular pressure was established by injecting saline into the anterior chamber of the left eye. Synaptophysin expression was increased in the inner plexiform layer at 2 hours following injury, and was widely distributed in the outer plexiform layer at 3-7 days, and then decreased to the normal level at 14 days. This suggests that expression of this presynaptic functional protein experienced spatiotemporal alterations after elevation of intraocular pressure. There was no significant change in the fluorescence intensity and distribution pattern for synapse-associated protein 102 following elevated intraocular pressure. Synapse-associated protein 102 immunoreactivity was confined to the outer plexiform layer, while synaptophysin immunoreactivity spread into the outer plexiform layer and the outer nuclear layer at 3 and 7 days following injury. These alterations in presynaptic elements were not accompanied by changes in postsynaptic components. PMID- 25709622 TI - Influence of chronic intermittent hypoxia on growth associated protein 43 expression in the hippocampus of young rats. AB - This study aimed to explore the pathological change to hippocampal neurons and the expression of growth associated protein 43 in 21-day-old young rats following chronic intermittent hypoxia. Hematoxylin-eosin staining results showed varying degrees of degeneration and necrosis in hippocampal neurons depending on the modeling time. Immunohistochemistry revealed that growth associated protein 43 expression in young rats following chronic intermittent hypoxia decreased, but that levels were still higher than those of normal rats at each time point, especially 4 weeks after modeling. During 1-5 weeks after modeling, a slow growth in rat weight was observed. Experimental findings indicate that chronic intermittent hypoxia may induce growth dysfunction and necrosis of hippocampal neurons, as well as increase the expression of growth associated protein 43 in young rats. PMID- 25709623 TI - Effects of electromagnetic radiation on spatial memory and synapses in rat hippocampal CA1. AB - In this study, we investigated the effects of mobile phone radiation on spatial learning, reference memory, and morphology in related brain regions. After the near-field radiation (0.52-1.08 W/kg) was delivered to 8-week-old Wistar rats 2 hours per day for 1 month, behavioral changes were examined using the Morris water maze. Compared with the sham-irradiated rats, the irradiated rats exhibited impaired performance. Morphological changes were investigated by examining synaptic ultrastructural changes in the hippocampus. Using the physical dissector technique, the number of pyramidal neurons, the synaptic profiles, and the length of postsynaptic densities in the CA1 region were quantified stereologically. The morphological changes included mitochondrial degenerations, fewer synapses, and shorter postsynaptic densities in the radiated rats. These findings indicate that mobile phone radiation can significantly impair spatial learning and reference memory and induce morphological changes in the hippocampal CA1 region. PMID- 25709624 TI - Stem cell transplantation for treating spinal cord injury: A literature comparison between studies of stem cells obtained from various sources. AB - OBJECTIVE: To identify global research trends of stem cell transplantation for treating spinal cord injury using a bibliometric analysis of the Web of Science. DATA RETRIEVAL: We performed a bibliometric analysis of data retrievals for stem cell transplantation for treating spinal cord injury from 2002 to 2011 using the Web of Science. SELECTION CRITERIA: INCLUSION CRITERIA: (a) peer-reviewed articles on stem cell transplantation for treating spinal cord injury that were published and indexed in the Web of Science; (b) type of articles: original research articles, reviews, meeting abstracts, proceedings papers, book chapters, editorial material, and news items; and (c) year of publication: 2002-2011. EXCLUSION CRITERIA: (a) articles that required manual searching or telephone access; (b) documents that were not published in the public domain; and (c) a number of corrected papers from the total number of articles. MAIN OUTCOME MEASURES: (1) Annual publication output; (2) distribution according to country; (3) distribution according to institution; (4) distribution according to journals; (5) distribution according to funding agencies; and (6) top cited articles over the last 10 years. RESULTS: Bone marrow mesenchymal stem cells and embryonic stem cells have been widely used for treating spinal cord injury. In total, 191 studies of bone marrow mesenchymal stem cell transplantation and 236 studies of embryonic stem cell transplantation for treating spinal cord injury appeared in the Web of Science from 2002 to 2011, and almost half of which were derived from American or Japanese authors and institutes. The number of studies of stem cell transplantation for treating spinal cord injury has gradually increased over the past 10 years. Most papers on stem cell transplantation for treating spinal cord injury appeared in journals with a particular focus on stem cell research, such as Stem Cells and Cell Transplantation. Although umbilical cord blood stem cells and adipose-derived stem cells have been studied for treating spinal cord injury, the number of published papers was much smaller, with only 21 and 17 records, respectively, in the Web of Science. CONCLUSION: Based on our analysis of the literature and research trends, we found that stem cells transplantation obtained from various sources have been studied for treating spinal cord injury; however, it is difficult for researchers to reach a consensus on this theme. PMID- 25709625 TI - Application of magnetic resonance imaging for monitoring stem cell transplantation for the treatment of cerebral ischemia. AB - OBJECTIVE: To identify global research trends in the application of MRI for monitoring stem cell transplantation using a bibliometric analysis of Web of Science. DATA RETRIEVAL: We performed a bibliometric analysis of studies relating to the application of MRI for detecting stem cell transplantation for the treatment of cerebral ischemia using papers in Web of Science published from 2002 to 2011. SELECTION CRITERIA: The inclusion criteria were: (a) peer-reviewed articles on the application of MRI for detecting transplanted stem cells published and indexed in Web of Science; (b) year of publication between 2002 and 2011. Exclusion criteria were: (a) articles that required manual searching or telephone access; (b) some corrected papers. MAIN OUTCOME MEASURES: (1) Annual publication output; (2) distribution according to journals; (3) distribution according to institution; (4) distribution according to country; (5) top cited authors over the last 10 years. RESULTS: A total of 1 498 studies related to the application of MRI for monitoring stem cell transplantation appeared in Web of Science from 2002 to 2011, almost half of which were derived from American authors and institutes. The number of studies on the application of MRI for detecting stem cell transplantation has gradually increased over the past 10 years. Most papers on this topic appeared in Magnetic Resonance in Medicine. CONCLUSION: This analysis suggests that few experimental studies have been investigated the use of MRI for tracking SPIO-labeled human umbilical cord blood derived mesenchymal stem cells during the treatment of cerebral ischemia. PMID- 25709626 TI - Stem cell transplantation for treating Parkinson's disease: Literature analysis based on the Web of Science. AB - OBJECTIVE: To identify global research trends of stem cell transplantation for treating Parkinson's disease using a bibliometric analysis of the Web of Science. DATA RETRIEVAL: We performed a bibliometric analysis of data retrievals for stem cell transplantation for treating Parkinson's disease from 2002 to 2011 using the Web of Science. SELECTION CRITERIA: INCLUSION CRITERIA: (a) peer-reviewed articles on stem cell transplantation for treating Parkinson's disease which were published and indexed in the Web of Science; (b) type of articles: original research articles, reviews, meeting abstracts, proceedings papers, book chapters, editorial material and news items; (c) year of publication: 2002-2011. EXCLUSION CRITERIA: (a) articles that required manual searching or telephone access; (b) we excluded documents that were not published in the public domain; (c) we excluded a number of corrected papers from the total number of articles. MAIN OUTCOME MEASURES: (1) Type of literature; (2) annual publication output; (3) distribution according to journals; (4) distribution according to subject areas; (5) distribution according to country; (6) distribution according to institution; (7) comparison of countries that published the most papers on stem cell transplantation from different cell sources for treating Parkinson's disease; (8) comparison of institutions that published the most papers on stem cell transplantation from different cell sources for treating Parkinson's disease in the Web of Science from 2002 to 2011; (9) comparison of studies on stem cell transplantation from different cell sources for treating Parkinson's disease. RESULTS: In total, 1 062 studies on stem cell transplantation for treating Parkinson's disease appeared in the Web of Science from 2002 to 2011, almost one third of which were from American authors and institutes. The number of studies on stem cell transplantation for treating Parkinson's disease had gradually increased over the past 10 years. Papers on stem cell transplantation for treating Parkinson's disease appeared in journals such as Stem Cells and Experimental Neurology. Although the United States published more articles addressing neural stem cell and embryonic stem cell transplantation for treating Parkinson's disease, China ranked first for articles published on bone marrow mesenchymal stem cell transplantation for treating Parkinson's disease. CONCLUSION: From our analysis of the literature and research trends, we found that stem cell transplantation for treating Parkinson's disease may offer further benefits in regenerative medicine. PMID- 25709627 TI - Comparison of pregnancy outcome after letrozole versus clomiphene treatment for mild ovarian stimulation protocol in poor responders. AB - BACKGROUND: Poor ovarian response to controlled ovarian stimulation is one of the most important interest points in assisted reproduction. Mild ovarian stimulation seems to be preferable to high dose of FSH regimens in women with a history of poor ovarian response in previous protocol. Clomiphene citrate and letrozole alone or in combination with FSH have been used in mild ovarian stimulation protocol. OBJECTIVE: To compare the efficacy of letrozole and clomiphene citrate for mild ovarian stimulation on assisted reproductive technology outcomes in poor responders. MATERIALS AND METHODS: In a randomized control study, 184 women aged between 20 and 45 years with the history of poor response to ovarian stimulation who were candidate for ART were randomly subdivided into two groups: group I (n= 80), women who underwent the clomiphene/gonadotropin/antagonist protocol; and group II (n= 87), patients who underwent the letrozole/gonadotropin/antagonist protocol. Groups were compared regarding implantation, chemical and clinical pregnancy rates. RESULTS: There was a significant difference in the mean endometrial thickness between two groups (9.16+/-1.2 mm vs. 8.3+/-0.3 mm). The implantation rate was significantly higher in letrozole group compare to clomiphene group (7.2 vs. 6.6%, p=0.024 respectively). No significant differences were found in chemical and clinical pregnancy rate between two groups. CONCLUSION: In mild ovarian stimulation protocol, letrozole and clomiphene have similar value for the poor responder. The optimal treatment strategy for these patients remains debated. PMID- 25709628 TI - Single dose effect of diazinon on biochemical parameters in testis tissue of adult rats and the protective effect of vitamin E. AB - BACKGROUND: Diazinon (DZN) is an organophosphate pesticide that widely used for agricultural pest control all over the world. DZN affects target organs including reproductive system by inhibiting the activity of acetylcholinesterase and inducing oxidative stress. Vitamin E (alpha-tocopherol) is a strong antioxidant which inhibits free radicals, and probably can reduce lipid perxidation effectively in biological systems. OBJECTIVE: The present study, aimed to evaluate the effects of DZN on malondialdehyde (MDA) and glutathione (GSH) levels in testis of rats and protective effect of vitamin E. MATERIALS AND METHODS: In this experimental study, thirty adult male Wistar rats (200-250 gr) were divided into 5 groups (n= 6): control group (did not receive any material), sham group (received only pure olive oil), experimental group 1 (DZN, 60 mg/kg), experimental group 2 (Vit E, 200 mg/kg) and experimental group 3 (DZN+Vit E, with the same dose). All groups were sacrificed after 6 weeks and right testis was used to measure the MDA and GSH levels. The amount of MDA was determined by the thiobarbituric acid assay and 5, 5-Dithio-bis (2nitrobenzoic acid) DTNB-recycling protocol was used for GSH assay. RESULTS: The results showed that DZN increased MDA level (p<0.001) and reduced GSH level (p<0.001). Administration of DZN plus vitamin E decreased the MDA level (p<0.001) and increased GSH level (p=0.001). CONCLUSION: DZN induced lipid peroxidation in the testis of rats. Vitamin E by its antioxidant activity was able to improve the toxic effect of DZN. PMID- 25709629 TI - Growth changes in infants born of adolescent mothers: Results of a national cohort study in Taiwan. AB - BACKGROUND: Adolescent pregnancy and childbirth are associated with increased risk and challenges for both mothers and birth outcomes. OBJECTIVE: To investigate the associations of growth change over time with parenting factors and to compare the differences between children born to adolescent and adult mothers in Taiwan. MATERIALS AND METHODS: The dataset retrieved from Taiwan birth cohort study (TBCS) was collected by interviews using structured questionnaires, birth certificate and Passport of Well-baby Care of each child. Changes in body weight, body height and head circumference from birth to 18 months, as well as other variables were assessed by statistical analysis. RESULTS: There were 4.13% births born to adolescent mothers in 2005. Higher ratios of breastfeeding and working were found among adult mothers (p<0.001). Significantly higher percentage of adolescent mothers caregave their infants up to 18 months (p<0.001). Children born to adolescent mothers were associated with statistically significant lower body weight (p<0.001), body height (p<0.001) and head circumference (p<0.001) in spite of velocity and slop of growth patterns were similar over time. Breastfeeding did not significantly affected growth rate during the first 6 months. Generalized estimated equation models showed that gender and preterm birth were predictive factors for birth outcomes (both p<0.001) and correlated to changes over time. CONCLUSION: Adolescent childbearing was associated with preterm birth and lower body weight, body height and head circumference from birth to 18 months. The changes in growth and development among children born to adolescent mothers remain to be followed and evaluated with the TBCS. PMID- 25709630 TI - Association of fetuin A, adiponectin, interleukin 10 and total antioxidant capacity with IVF outcomes. AB - BACKGROUND: Possible roles of anti-inflammatory factors as well as total antioxidative capacity in reproductive processes of women undergoing in vitro fertilization (IVF) are still being investigated and the contributions by some of them remain controversial. OBJECTIVE: The aim of this study is to investigate the relationship between anti-inflammatory parameters and total antioxidative capacity (TAC) of the body during IVF. In this respect, adiponectin, interleukin 10 (IL-10), interleukin-1 receptor antagonist (IL-1RA), fetuin A and TAC analyses have been performed. MATERIALS AND METHODS: In this prospective, non-randomized, controlled clinical study, sera obtained from 26 fertile (Group-1), and 26 infertile women before (Group-2) and after (Group-3) IVF treatment were analyzed. IL-1RA, IL-10, fetuin A, adiponectin and insulin were determined by ELISA. TAC was determined spectrophotometrically. Mann-Whitney U test, paired sample t-test, Wilcoxon signed-rank test as well as Pearson correlation analysis by SPSS were performed for statistical analysis. RESULTS: Clinical pregnancy and live birth rates were determined as 30.8% and 23.1%, respectively, in pregnant group. For the pregnant, significant indirect correlations were detected between fetuin A and adiponectin (r=-0.843; p=0.035) as well as IL-10 (r=-0.846; p=0.034) in Group 2. The correlation between adiponectin and IL-10 doubled in pregnant compared to non-pregnant (r=0.929; p=0.007 vs. r=0.478; p=0.033). The correlations between fetuin A and TAC in pregnant were noted both in Group 2 (r=0.892; p=0.017) and Group 3 (r=0.875; p=0.022). No correlation of fetuin A with these parameters was detected in non-pregnant group. CONCLUSION: Fetuin A, TAC, IL-10, adiponectin and their associations may be important from their predictive values for IVF success point of view. Parameters with anti-inflammatory or antioxidant property appear to improve pregnancy in women undergoing IVF. PMID- 25709631 TI - High omega-3:omega-6 fatty acids ratio increases fatty acid binding protein 4 and extracellular secretory phospholipase A2IIa in human ectopic endometrial cells. AB - BACKGROUND: Endometriosis, a common chronic inflammatory disorder, is defined by the atypical growth of endometrium- like tissue outside of the uterus. Secretory phospholipase A2 group IIa (sPLA2-IIa) and fatty acid binding protein4 (FABP4) play several important roles in the inflammatory diseases. OBJECTIVE: Due to reported potential anti-inflammatory effects of omega-3 and omega-6 fatty acids, the purpose of the present study was to investigate the effects of omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) on fatty acid binding protein 4 and extracellular secretory phospholipase A2IIa in cultured endometrial cells. MATERIALS AND METHODS: Ectopic and eutopic endometrial tissues obtained from 15 women were snap frozen. After thawing and tissue digestion, primary mixed stromal and endometrial epithelial cell culture was performed for 8 days in culture mediums supplemented with normal and high ratios of omega-3 and omega-6 PUFA. sPLA2-IIa in the culture medium and FABP4 level was determined using enzyme immuno assay (EIA) technique. RESULTS: Within ectopic endometrial cells group, the level of cellular FABP4 and extracellular sPLA2-IIa were remarkably increased under high omega-3 PUFA exposure compared with control condition (p=0.014 and p=0.04 respectively). CONCLUSION: omega-3 PUFAs may increase the level of cellular FABP4 and extracellular sPLA2-IIa in ectopic endometrial cells, since sPLAIIa and FABP4 may affect endometriosis via several mechanisms, more relevant studies are encouraged to know the potential effect of increased cellular FABP4 and extracellular sPLA2-IIa on endometriosis. PMID- 25709632 TI - Molecullar and biochemical effect of alcohlic extract of Alpinia galanga on rat spermatogenesis process. AB - BACKGROUND: Alpinia galanga (A. galanga) belongs to the Zingiberaceae family has anti-oxidant effects in animals and humans body and often is used as medicament or part of medicaments in Asian folk medicine for various applications. OBJECTIVE: The objective of this study was to investigate the molecular and biochemical influence of alcoholic extract from the rhizomes of A. galangal on the spermatogenesis process in male rat. MATERIALS AND METHODS: Forty five Wistar male rats were divided into three groups, control (n=15) and two tested groups (n=30). Alcoholic extract (5%) of plant was given by oral route at doses of 100 and 300 mg/day for 56 days and spermatogenesis parameters, hormone changes and expression level of the cAMP-responsive element modulator (CREM) gene were assessed. RESULTS: Methanol extract of A. galanga increased serum testosterones level significantly in both treated groups in comparison with control group (p<0.05). Besides, the percentage of sperm viability and motility in both tested groups were significantly increased. Follicle stimulating hormone FSH hormone, morphology and weight were affected in both treated groups. With 300 mg/day an increase in sperm count was observed. Sperm motility was increased in two treated groups whereas testis weight was decreased in treated groups. Real time analysis of treated cells of testis showed increase level of mRNA related to CREM gene involved in spermatogenesis process after 56 days induction. CONCLUSION: It is concluded that application of ethanolic extract of A. galanga significantly increased sperm percentage, viability, motility and testosterone hormone. This suggested that this plant may be promising in enhancing sperm healthy parameters. PMID- 25709633 TI - Developmental competence of bovine oocytes selected based on follicle size and using the brilliant cresyl blue (BCB) test. AB - BACKGROUND: Many studies reported that follicle size has an essential role in developmental potential of oocytes. Also, the brilliant cresyl blue (BCB) test is one of the most important criteria in selection of more competent oocytes. OBJECTIVE: Selection of developmentally competent bovine oocytes. MATERIALS AND METHODS: A total of 1730 bovine cumulus oocyte complexes (COCs) were recovered from the ovaries by follicles isolation and classified into 3 categories according to the diameters of the follicles (small, <3 mm; medium 3-6 mm and large >6 mm). Oocytes were exposed to the BCB stain, diluted in Dulbecco's phosphate-buffered saline, modified with 0.4% bovine serum albumin (BSA) for 90 min. Oocytes with or without blue coloration of the cytoplasm were designated as BCB(+) and BCB(-), respectively. RESULTS: The BCB(+) and control oocytes originated from large and medium follicles exhibited a higher (p<0.0001) cleavage and blastocyst rate than BCB(-) oocytes. Furthermore, the BCB(+) oocytes from large and medium follicles had the highest (p<0.0001) proportion of blastocyst than other treatment groups. In contrast, the BCB(-) oocytes from small follicles had the lowest (p<0.0001) proportion of blastocyst than other treatment groups. Interestingly, the percentage of the BCB(+) oocytes from the large and medium ovarian follicles was significantly higher (p<0.0001), than the BCB(+) oocytes from the small follicles. CONCLUSION: Current results confirmed that each BCB(+) oocyte could not lead to perfect embryo development and the BCB test is not sufficient enough for the identification of oocytes that are competent for in vitro embryo development. PMID- 25709634 TI - Thirteen -weeks ovarian pregnancy following in vitro fertilization for primary infertility treatment: A case report. AB - BACKGROUND: Ovarian pregnancy constitutes 0.15-3% of all ectopic pregnancies. The incidence of ectopic pregnancy is on the rise owing to evolution in assisted reproductive techniques (ART). The incidence reported following In vitro fertilization (IVF) or embryo transfer (ET) is 0.27% per clinical pregnancy. CASE: We present a case of a 13-weeks ovarian pregnancy following IVF-ET and through a review of the literature, the specific symptomatology, diagnostic criteria, and treatment of this particular pathology will be described. CONCLUSION: Ovarian pregnancy is a rare condition and its diagnosis is difficult and relies on criteria based on intraoperative and histopathological findings. The management is, in spite of medical improvement, based on surgery. But the trend has shifted towards conservative surgeries in majority of cases. PMID- 25709635 TI - Evaluation of selected thrombotic factors among pregnant women with preeclampsia and normal pregnant women. AB - BACKGROUND: Preeclampsia is one of the common complications during pregnancy with considerable maternal and fetal mortality and morbidity. Hypercoagulability due to thrombophilic factors is discussed as the etiology involved in this disease. OBJECTIVE: The aim of this study was to evaluate selected thrombotic factors among pregnant women with preeclampsia and normal pregnant women. MATERIALS AND METHODS: This case-control study was performed on 200 pregnant women at third trimester of pregnancy between 2012 and 2013. 100 pregnant women admitted to Qaem and Imam Reza hospitals of Mashhad, due to preeclampsia, were selected as case group and 100 pregnant women without preeclampsia referred to OB/GYN clinic of these hospitals as control group. Blood samples were taken from two groups for evaluation of the coagulation factors including factor V Leiden, protein C, protein S, antithrombin III, anti-cardiolipin antibodies, and lupus anticoagulant antibodies. RESULTS: Two groups were not significantly different in terms of maternal age and parity (p>0.05). Levels of factor V Leiden, protein C, protein S, antithrombin III, anti-cardiolipin antibodies and lupus anticoagulant antibodies were compared between two groups. The number of patients with abnormal factor V Leiden and protein C was significantly higher in case group than in the control group (p<0.01 respectively), but other factors were not significant different between two groups. Thrombophilia disorders were significantly more in case group compared to control (p<0.001). CONCLUSION: The risk of thrombophilia disorders is higher in preeclamptic patients than normal pregnant women. PMID- 25709636 TI - Melatonin improves development of early mouse embryos impaired by actinomycin-D and TNF-alpha. AB - BACKGROUND: Melatonin, a reactive oxygen species (ROS) scavenger and an antioxidant, has been shown that can inhibit apoptosis. Administration of melatonin may improve embryo development in assisted reproductive technology (ART). OBJECTIVE: The aim of this study was to evaluate the role of melatonin in inhibition of spontaneous and induced apoptosis by Tumor Necrosis Factor Alph (TNF-alpha) and actinomycin-D during preimplantation development of mouse embryos. MATERIALS AND METHODS: Female BALB/c mice were superovulated with pregnant mare serum gonadotropin (PMSG) followed by human chorionic gonadotropin (HCG), then allowed to mate with male mice. The resultant 2-cell embryos were divided into six groups as follows: control (group I), melatonin (group II), actinomycin-D (group III), actinomycin-D + melatonin (group IV), TNF-alpha (group V), and TNF-alpha + melatonin (group VI). We recorded the numbers and developmental rates of the 4-cell, 8-cell, morula and blastocyst embryos. Blastocysts were stained with acridine orange in order to assess for the embryo quality. RESULTS: The group IV showed a significantly higher developmental rate of blastocysts compared to group III (p<0.05). The number of dead blastomers was significantly decreased in group IV in comparison to group III (p<0.05). Both V and VI groups had a lower developmental rate and lesser quality of blastocysts compared with group I. There was no significant difference in the developmental rate of blastocysts from group II compared to group I (p<0.05). CONCLUSION: Supplementation of embryo culture media with melatonin can improve the quality and developmental rate of embryos. Melatonin can prevent cell death that was induced by TNF- alpha and actinomycine-D. PMID- 25709637 TI - Immunohistochemical detection of the 1,25-dihydroxy vitamin D receptor in the human vagina. AB - BACKGROUND: Vitamin D plays a critical role in the regulation of growth and differentiation of squamous epithelium. The pleiotropic effects of 1,25 dihydroxyvitamin D3 [1,25(OH)2D3], include proliferative, pro-apoptotic, and pro differentiation effects on numerous cell types. Although 1,25-dihydroxyvitamin D3 is involved in the regulation and differentiation of epithelium, there is no data in the aspect of the distribution of 1,25-(OH)2D3 receptor (VDR), estrogen receptor-beta (ER-beta) and ezrin, and how it changes according to the menstrual phases and serum vitamin D level in the human vagina. OBJECTIVE: To detect of the 1,25-dihydroxyvitamin D3 receptor (VDR), estrogen receptor-beta (ER-beta), and ezrin in human vagina. MATERIALS AND METHODS: This cross-sectional study enrolled 15 premenopausal women who had hysterectomies. Vaginal tissues were obtained from vaginal vaults of hysterectomized uterus and processed for immunohistochemical analysis. We recorded the localization, distribution, and expression of VDR, ER beta, and ezrin in the vaginal epithelium. RESULTS: VDR was detected in all layers of vaginal epithelium regardless of the menstrual cycle stage and serum 25 hydroxyvitamin D levels. CONCLUSION: In this study, we have characterized the presence and distribution of VDR, ER-beta, and ezrin in human vaginal epithelium, including menstrual cycle-related and vitamin D-related expression. However, the VDR-related mechanisms underlying vaginal epithelial proliferation and differentiation remain to be elucidated. PMID- 25709638 TI - The relationship between clinicobiochemical markers and depression in women with polycystic ovary syndrome. AB - BACKGROUND: Previous studies have demonstrated that clinical features of Polycystic ovary syndrome (PCOS) are associated with a lower degree of health, self, and sex satisfaction. OBJECTIVE: Our study aimed to investigate possible associations between depression and different clinicobiochemical markers of PCOS. MATERIALS AND METHODS: In a cross-sectional analytic study, 120 PCOS women aged 18-45 yr, were enrolled. Beck Depression Inventory was used to assess depression. Also, all participants underwent biochemical studies. Individuals with 15 points and more in Beck test were referred to a psychiatrist to participate in a complementary interview for the diagnosis of depression based on Diagnostic and Statistical Manual of Mental Disorders IV (DSMIV-TR) criteria. RESULTS: Among the study participants, 82 women (68.3%) were non-depressed, and 38 patients (31.7%) had some degrees of depression. According to the psychiatric interview, 10 patients (8.3%) had major depression, 22 patients (18.3%) had minor depression and 6 patients (5%) had dysthymia. We failed to show any significant difference in body mass index, hirsutism, infertility, serum total testosterone, lipid profile, and the homeostasis model assessment of insulin resistance (HOMA-IR) between depressed and non-depressed subjects (p>0.05). Using Spearman correlation, we did not find a positive correlation between BDI scores and clinicobiochemical markers for all PCOS subjects (-0.139<=r<=+0.121, p>0.05). CONCLUSION: In spite of high rate of depression in women with PCOS, there was no significant association between Clinicobiochemical Markers and depression. PMID- 25709639 TI - Combination effect of Pentoxifylline and L-carnitine on idiopathic oligoasthenoteratozoospermia. AB - BACKGROUND: Pentoxifylline (PX) is a methyl xanthine derivative that influences the sperm motion characteristics and L-carnitine (L-C) is an amino acid that is naturally produced in the body. In general, separate administration of PX and L-C has been reported to be effective on preserving sperm motility in vitro, and also when is consumed orally by the Idiopathic oligoasthenoteratozoospermia (IOAT) patients. OBJECTIVE: The aim of this study was to evaluate any possible effect of a combination of L-C and PX on sperm characteristics and improving the type of assisted reproductive techniques (ART) in a group of patients with unexplained oligoasthenoteratozoospermia. MATERIALS AND METHODS: Two hundred twelve infertile men with IOAT in a double-blind, placebo-controlled, randomized clinical trial were allocated for this study. They randomized to four groups. Group I received PX/ and L-C (each one, twice daily), group II, PX and placebo, group III, L-C with the placebo, and group IV, received placebo tablets. Finally, we compared pre and post intervention sperm parameters and ART procedures between groups. RESULTS: While the use of PX and L-C are only improved sperm motility, but their combined uses improved all sperm parameters, especially the sperm count. Also the combination of PX and L-C was effective on improving the ART procedures (p<0.01). CONCLUSION: Our results demonstrate that the combination use of PX and L-C is useful in improving of sperm parameters in IOAT patients and also, improve ART procedures in this group of patients. PMID- 25709640 TI - Ovarian ectopic pregnancy: A 10 years' experience and review of literature. AB - BACKGROUND: Primary ovarian pregnancy is one of the rarest forms of ectopic pregnancy having incidence of 1/7000-1/40,000 in live births and 0.5-3% of all ectopic gestations. Intrauterine contraceptive device (IUCD), salpingitis, infertility, and assisted reproductive techniques are the important risk factors. Approximately, 75% terminate in first trimester and are often misdiagnosed as corpus luteum haemorrhage. Preoperative diagnosis by ultrasonography (USG) in early pregnancy can help in conservative medical/ surgical management. OBJECTIVE: The aim of the present study was to find the incidence, risk factors, role of USG in pre-operative diagnosis, feasibility of conservative management with medical method or minimal invasive surgery in developing countries like India. MATERIALS AND METHODS: We did a retrospective cross-sectional study of ovarian pregnancies managed at Government Medical College and Hospital Chandigarh between July 2000 to July 2010. We analyzed the incidence, risk factors, clinical presentation, management of ovarian pregnancy, and reviewed the literature. RESULTS: Incidence of ovarian pregnancy was 4.9% of all ectopic pregnancies (14/523). Thirteen (93%) patients presented in first trimester with acute pain abdomen and of these ten patients had bleeding per vaginum. One (7%) patient referred from peripheral hospital at term gestation with ultrasonographic diagnosis of breech presention with plecenta previa. Pre-operative diagnosis was made only in two cases (11%). All cases were managed by laparotomy. Excision of the sac with conservation of the ovary was done in eleven cases (78%) and oophorectomy was done in two cases (14%). CONCLUSION: Incidence of ovarian pregnancy is on the rise. Although ultrasonography can detect ovarian gestations in unruptured cases but cannot easily differentiate ovarian from other tubal gestation in ruptured state. Medical management is usually not feasible it most of the patients present in ruptured state. Conservative surgical approach is the management of choice. PMID- 25709641 TI - A rare case of a giant cystic leiomyoma presenting as a retroperitoneal mass. AB - BACKGROUND: Giant retroperitoneal uterine leiomyomas are uncommon. Degenerative changes of a leiomyoma may lead to unusual presentation resulting in misdiagnosis preoperatively. The final diagnosis can be made either intraoperatively or histologically. CASE: We report a 45-year-old multiparous women presented with abdominal distension and fatigue for six months. Abdominopelvic Sonography and computed tomography showed a large cystic mass that filled the pelvis and abdomen. With the preoperative diagnosis of a malignant tumor, a laparotomy was planned. Intraoperatively, a cystic mass originated from the uterus near the left side of the broad ligament extending to the retroperitoneal space was observed. Total hysterectomy and bilateral salphingo-oopherectomy was administered. The histology revealed a leiomyoma with cystic degeneration. CONCLUSION: Retroperitoneal leiomyomas should be kept in mind in the diferrential diagnosis of a giant cystic mass in abdomen. PMID- 25709642 TI - The cytogenetic aspect of male infertility. PMID- 25709643 TI - Re: Factors affecting recurrence and progression of high grade non invasive bladder cancer treated by intravesical BCG. PMID- 25709644 TI - Training spiking neural models using artificial bee colony. AB - Spiking neurons are models designed to simulate, in a realistic manner, the behavior of biological neurons. Recently, it has been proven that this type of neurons can be applied to solve pattern recognition problems with great efficiency. However, the lack of learning strategies for training these models do not allow to use them in several pattern recognition problems. On the other hand, several bioinspired algorithms have been proposed in the last years for solving a broad range of optimization problems, including those related to the field of artificial neural networks (ANNs). Artificial bee colony (ABC) is a novel algorithm based on the behavior of bees in the task of exploring their environment to find a food source. In this paper, we describe how the ABC algorithm can be used as a learning strategy to train a spiking neuron aiming to solve pattern recognition problems. Finally, the proposed approach is tested on several pattern recognition problems. It is important to remark that to realize the powerfulness of this type of model only one neuron will be used. In addition, we analyze how the performance of these models is improved using this kind of learning strategy. PMID- 25709645 TI - Predictors of incisional hernia after robotic assisted radical prostatectomy. AB - Introduction. To explore the long term incidence and predictors of incisional hernia in patients that had RARP. Methods. All patients who underwent RARP between 2003 and 2012 were mailed a survey reviewing hernia type, location, and repair. Results. Of 577 patients, 48 (8.3%) had a hernia at an incisional site (35 men had umbilical), diagnosed at (median) 1.2 years after RARP (mean follow up of 5.05 years). No statistically significant differences were found in preoperative diabetes, smoking, pathological stage, age, intraoperative/postoperative complications, operative time, blood loss, BMI, and drain type between patients with and without incisional hernias. Incisional hernia patients had larger median prostate weight (45 versus 38 grams; P = 0.001) and a higher proportion had prior laparoscopic cholecystectomy (12.5% (6/48) versus 4.6% (22/480); P = 0.033). Overall, 4% (23/577) of patients underwent surgical repair of 24 incisional hernias, 22 umbilical and 2 other port site hernias. Conclusion. Incisional hernia is a known complication of RARP and may be associated with a larger prostate weight and history of prior laparoscopic cholecystectomy. There is concern about the underreporting of incisional hernia after RARP, as it is a complication often requiring surgical revision and is of significance for patient counseling before surgery. PMID- 25709646 TI - A Highly Conserved GEQYQQLR Epitope Has Been Identified in the Nucleoprotein of Ebola Virus by Using an In Silico Approach. AB - Ebola virus (EBOV) is a deadly virus that has caused several fatal outbreaks. Recently it caused another outbreak and resulted in thousands afflicted cases. Effective and approved vaccine or therapeutic treatment against this virus is still absent. In this study, we aimed to predict B-cell epitopes from several EBOV encoded proteins which may aid in developing new antibody-based therapeutics or viral antigen detection method against this virus. Multiple sequence alignment (MSA) was performed for the identification of conserved region among glycoprotein (GP), nucleoprotein (NP), and viral structural proteins (VP40, VP35, and VP24) of EBOV. Next, different consensus immunogenic and conserved sites were predicted from the conserved region(s) using various computational tools which are available in Immune Epitope Database (IEDB). Among GP, NP, VP40, VP35, and VP30 protein, only NP gave a 100% conserved GEQYQQLR B-cell epitope that fulfills the ideal features of an effective B-cell epitope and could lead a way in the milieu of Ebola treatment. However, successful in vivo and in vitro studies are prerequisite to determine the actual potency of our predicted epitope and establishing it as a preventing medication against all the fatal strains of EBOV. PMID- 25709647 TI - Fertilizers and Mixed Crop Cultivation of Chromium Tolerant and Sensitive Plants under Chromium Toxicity. AB - Zea mays (maize) and Vigna radiata (green gram) are found to be the chromium (Cr) tolerant and sensitive plants, respectively. In the present paper, we investigate the reduction of the toxicity of Cr in the sensitive plants by the mixed crop cultivation in the field using various amendments. Further, the potassium dichromate was used as the source of hexavalent Cr. The results indicated that Cr adversely affects both the growth and yield of plants. The soil properties vary with Cr and different fertilizer amendments and the yield of both plants were affected by Cr. We conclude that metal accumulation of seeds of green gram was higher than corn and the application of single fertilizer either farm yard manure (FYM) or nitrogen, phosphorous, and potassium (NPK) enhances the growth and yield of both the tolerant and sensitive plants in the mixed crop cultivations. PMID- 25709649 TI - A comparison of the ultrasonographic median nerve cross-sectional area at the wrist and the wrist-to-forearm ratio in carpal tunnel syndrome. AB - BACKGROUND: Electrophysiologic (EDX) study is the most valuable method in grading the severity of carpal tunnel syndrome (CTS), but it is invasive and painful. We evaluated the efficacy of ultrasound for this purpose. MATERIALS AND METHODS: Eighty-one wrists of 52 consecutive patients with clinical evidences of CTS, confirmed and graded by EDX as mild, moderate, and severe, were examined by ultrasonography. Cross-sectional area (CSA) of the median nerve was measured at the distal wrist (CSA-D), and proximal forearm (CSA-P), and wrist-to-forearm ratio (WFR) was calculated for each hand. RESULTS: The mean CSA-D was 0.12 cm(2) +/- 0.03, 0.15 cm(2) +/- 0.03 and 0.19 cm(2) +/- 0.06 and the mean WFR was 2.77 +/- 1.14, 3.07 +/- 1.07 and 4.07 +/- 1.61 in mild, moderate and severe groups respectively. WFR showed significant differences between the severe and none severe CTS groups (P < 0.001), but there was no significant difference between mild and moderate CTS groups (P < 0.381). CSA-D showed a significant difference between all groups (P < 0.0001). In the Receiver Operating Characteristic curve analysis, the optimal cut-off value of the CSA-D and WFR for detecting severe CTS were 0.15 (area under the curve 0.784, 95% confidence interval (CI): 0.662-0.898, P < 0.001, sensitivity of 68.2% and specificity of 70.9%) and 3 (area under the curve 0.714, 95% CI: 0.585-0.84, P = 0.001, sensitivity of 68.2% and specificity of 64.8%) respectively. All values were superior in CSA-D. CONCLUSION: Ultrasonography, can be complementary but not conclusive to the classification of CTS severities. CSA-D and WFR both increased in proportion to CTS severity, but neither parameter exhibited excellent performance in grading the severities. PMID- 25709648 TI - Nelfinavir impairs glycosylation of herpes simplex virus 1 envelope proteins and blocks virus maturation. AB - Nelfinavir (NFV) is an HIV-1 aspartyl protease inhibitor that has numerous effects on human cells, which impart attractive antitumor properties. NFV has also been shown to have in vitro inhibitory activity against human herpesviruses (HHVs). Given the apparent absence of an aspartyl protease encoded by HHVs, we investigated the mechanism of action of NFV herpes simplex virus type 1 (HSV-1) in cultured cells. Selection of HSV-1 resistance to NFV was not achieved despite multiple passages under drug pressure. NFV did not significantly affect the level of expression of late HSV-1 gene products. Normal numbers of viral particles appeared to be produced in NFV-treated cells by electron microscopy but remain within the cytoplasm more often than controls. NFV did not inhibit the activity of the HSV-1 serine protease nor could its antiviral activity be attributed to inhibition of Akt phosphorylation. NFV was found to decrease glycosylation of viral glycoproteins B and C and resulted in aberrant subcellular localization, consistent with induction of endoplasmic reticulum stress and the unfolded protein response by NFV. These results demonstrate that NFV causes alterations in HSV-1 glycoprotein maturation and egress and likely acts on one or more host cell functions that are important for HHV replication. PMID- 25709650 TI - Pimpinella anisum in modifying the quality of life in patients with functional dyspepsia: A double-blind randomized clinical trial. AB - BACKGROUND: We aimed to assess the effects of anise on quality of life (QOL) of patients with functional dyspepsia (FD) in a double-blind randomized clinical trial. MATERIALS AND METHODS: Of 180 patients attending the gastroenterology clinic, 107 ones with the diagnosis of postprandial distress syndrome according to Rome III criteria were enrolled. They were randomized into two groups, anise and placebo. Anise group involved 47 patients and received anise powders, 3 g after each meal (3 times/day) for 4 weeks. Control group had 60 patients who received placebo powders (cornstarch), 3 g after each meal (3 times/day) for 4 weeks. The QOL was assessed by short-form (SF)-36 questionnaire. Mean scores of eight health domains of the two groups were compared at baseline and at the end of study. RESULTS: The age, sex, body mass index, smoking history, tea and coffee drinking patterns of the two groups were not significantly different. All domains of SF-36 were similar between the two groups at baseline but were significantly different at week 12. At baseline, mean score of physical component summary was 159 in placebo group and 167 in anise group (P = 0.1). At week 12, the score was 141 in placebo group and 251 in anise group (P = 0.0001). Mean baseline score of mental component summary was 172 and 165 in placebo and anise groups, respectively (P = 0.1). At week 12, the score was 135 in placebo group and 233 in anise group (P = 0.0001). CONCLUSION: The current study revealed the effectiveness of anise in improvement of QOL in patients with FD. PMID- 25709651 TI - Comparison of the effect of betamethasone versus dexamethasone on the amniotic fluid index in the women at risk of preterm labor. AB - BACKGROUND: The aim of this study was to compare the biophysical profile parameters (BPP), especially amniotic fluid index (AFI), before and after administration of corticosteroids (dexamethasone and betamethasone) and these two groups with each other. MATERIALS AND METHODS: This double-blind clinical trial study was done on 70 patients for 28-34 weeks women having at least one preterm labor in their previous pregnancy has been submitted in Al Zahra and Shahid Beheshti clinic in 2012-2013. 70 women were randomly allocated in two groups. The first group were received 8 mg each 12 h for 4 doses dexamethasone when the patient at risk of preterm labor admitted in clinic or hospitalized and the second group were received 12 mg betamethasone each 24 h similarly. Nonstress test (NST) and BPP and sonography AFI were done in all cases, and then NST was done in the before and 3 days after intervention. Data were analyzed by SPSS software version 20 using t-test, Chi-square, and Fisher's test. RESULTS: There was no significant difference between the range of AFI before and after the drug intervention (P > 0.05). Two groups had no significant difference in AFI before and after administration of corticosteroids. No significant difference was seen in NST acceleration tests between the two groups before and after corticosteroids administration. CONCLUSION: Biophysical profile had a significant difference in dexamethasone group respect to that of betamethasone group. Furthermore, the biophysical profile had a significant difference before and after the administration of corticosteroids in two groups. It is noted that AFI had no role in this matter. PMID- 25709652 TI - Predictive value of tissue inhibitor of metalloproteinases-1 and carcinoembryonic antigen plasma levels in response to chemotherapy in patients with metastatic colorectal cancer. AB - BACKGROUND: Colorectal cancer is one of the most important causes of morbidity and mortality in the world. It has been suggested that tissue inhibitor of metalloproteinase-1 (TIMP-1) plays a particular role in cancer promotion. The objective of the present study was to compare the effect of repeated measurement of carcinoembryonic antigen (CEA) and TIMP-1 plasma levels in a follow-up response to chemotherapy treatment in patients with unresectable metastatic colorectal cancer by surgery. MATERIALS AND METHODS: All consecutive patients between 18 and 75 years old in both genders with rectal adenocarcinoma who referred to Sayed Al-Shohada Medical Center, during 6 months of study period enrolled in the study. Level of CEA and TIMP-1 were assessed before and after two cycles of chemotherapy. Furthermore, patients underwent computed tomography scan to assess response to chemotherapy. The sensitivity, specificity, and areas under the receiver operating characteristic curves (AUC) calculated for baseline level of CEA and TIMP. RESULTS: The mean age of the studied patients was 52.7 +/- 7.5 years, 12 patients (48%) were male. Response to chemotherapy after two cycles was 80%. In patients who responded to chemotherapy level of TIMP after treatment was significantly decreased compared to before treatment (P < 0.0001). Before and after treatment in patients who responded to chemotherapy the level of TIMP was significantly lower than who did not response to chemotherapy (P < 0.05). The critical values for the prediction response to chemotherapy for CEA was >63 (AUC: 0.54) and for TIMP was <=8823 (AUC: 0.68). CONCLUSION: The present study has identified a strong significant association between high plasma TIMP-1 levels and short survival in patients with colorectal cancer. In addition, results demonstrated that the TIMP-1 provides stronger prognostic information than CEA. PMID- 25709653 TI - Comparative efficacy trial of cupping and serkangabin versus conventional therapy of migraine headaches: A randomized, open-label, comparative efficacy trial. AB - BACKGROUND: Migraine headaches are the most common acute and recurrent headaches. Current treatment of a migraine headache consists of multiple medications for control and prevention of recurrent attacks. Global emergence of alternative medicine led us to examine the efficacy of cupping therapy plus serkangabin syrup in the treatment of migraine headaches. MATERIALS AND METHODS: This study was a randomized, controlled, open-label, comparative efficacy trial. We randomly assigned patients with migraine into cupping therapy plus serkangabin group (30 patients) and conventional treatment group (30 patients). An investigator assessed the severity of headache, frequency of attacks in a week and duration of attacks per hour in 5 visits (at the end of 2 weeks, 1, 3 and 6 months). Generalized estimating equations approach was used to analyze repeated measures data to compare outcomes in both groups. RESULTS: Average age for cupping therapy group and conventional treatment group were 31.7 (+/-7.6) and 32.6 (+/-12.7) years, respectively (P = 0.45). After treatment for 2 weeks; and 1, 3 and 6 months, severity of headache (P = 0.80), frequency of migraine attacks (P = 0.63) and duration of attacks per hours (P = 0.48) were similar in conventional and cupping groups but these symptoms were decreased in each group during the study (P < 0.001). CONCLUSION: There was no significant difference between cupping plus serkangabin therapy and conventional treatment in the treatment and prophylaxis of migraine. The alternative therapy may be used in cases of drug intolerance, no medication response, and in primary care. PMID- 25709654 TI - A comparison of bladder neck preservation and bladder neck reconstruction for urinary incontinence after radical retro pubic prostatectomy. AB - BACKGROUND: Prostate cancer is the sixth most common cancer worldwide and will include about 30% of all malignancies in men. Since the initial report of the anatomic radical prostatectomy, refinements in the surgical technique have been made. Several studies show that bladder neck preservation (BNP) during radical prostatectomy makes improve early return of urinary continence, erectile function or both. However, some clinical trials have suggested little difference between the return of continence while using modifications. In this study, we compared outcomes of BNP and bladder neck reconstruction (BNR) during radical retropubic prostatectomy (RRP). MATERIALS AND METHODS: This prospective study was performed on 60 patients at a referral university hospital from March 2010 to March 2012. Study population was all patients candidate for RRP (RRP in this period. All patients divided into two groups, A and B (30 patients in each group). Group A (n = 30) who preserved bladder neck (BNP) and Group B (n = 30) who had BNR. Prostate specific antigen (PSA) before and at 2, 6, 9, 12 and18 months after surgery, anastomotic stricture symptoms, positive bladder neck margin, Gleason score and urine incontinence were compared between two groups. Also, we compared bladder neck contracture, urinary continence and positive surgical margin rates after BNP and BNR while retropubic prostatectomy in 24 months period follow-up. RESULTS: The mean age of the patients was 61.81 +/- 7.15 years (range, 50-74 years). After a follow-up period of 24 months, the PSA rising was not different between the two groups. After 2 months, 19 (63.33%) of patients in A group and the same number in B group were continent (P = 0.78). Stricture of the bladder neck at the anastomosis site requiring transurethral dilation occurred in 7 (23.33%) and 3 (10.0%) patients in groups A and B, respectively (P = 0.04). CONCLUSION: Although there was no difference in prevalence and duration of return of urinary continence after the operation between two groups, but results of our study showed that stenosis of the bladder neck was lower in BNP. Hence in the group of BNP, need for further operation and overflow incontinency due to the obstruction of urinary tract will be less likely than BNR and patients have better long time (24 months) urinary continence. PMID- 25709655 TI - The diagnostic role of cervico-vaginal fluid interleukins-1alpha in endometriosis: A case-control study. AB - BACKGROUND: Endometriosis is a chronic and progressive gynecological disorder and is manifest by dysmenorrhea and a major cause of infertility and chronic pelvic pain. The study was designed to compare the value of cervico-vaginal fluid of interleukin-1alpha (IL-1alpha) in patients with and without endometriosis. MATERIALS AND METHODS: Fifty women were assessed in this case control study. The case group included 25 patients with endometriosis. The control group included 25 women without any evidence of endometriosis or any other genital disease. Endometriosis was confirmed by laparoscopy and histopathological examination. Cervico-vaginal fluid samples were obtained from patients during the follicular phase and preup surgery to assess the levels of IL-1alpha in cervico-vaginal fluid. The level of IL-1alpha was assessed using commercially available Avi Bionhuman Enzyme-Linked Immunosorbent Assay kits (FIN-01720, Vantaa, Finland) for IL-1alpha. Receiver-operator curve analysis was used to estimate the power of IL 1alpha to distinguish subjects with endometriosis from controls. RESULTS: The cervico-vaginal fluid level of IL-1alpha in cases was 210.44 +/- 40.11 pg/mL and in controls was 54.28 +/- 25.73 pg/mL, the differences between two groups was statistically significant (P < 0.0001). The cut-off point for cervico-vaginal fluid IL-1 for endometriosis was 105 pg/mL, with a sensitivity of 100% (95% confidence interval [CI]: 86.2-100), and specificity of 100% (95% CI: 86.2-100). CONCLUSION: Results show a significant increase in the cervico-vaginal fluid levels of IL-1alpha, in women with endometriosis, that it can be a useful marker in the diagnosis of endometriosis. PMID- 25709656 TI - Magnetic resonance cholangiography compared with endoscopic retrograde cholangiography in the diagnosis of primary sclerosing cholangitis. AB - BACKGROUND: Magnetic resonance cholangiography (MRC) has gained popularity for diagnosing primary sclerosing cholangitis (PSC). We determined the accuracy of MRC compared with endoscopic retrograde cholangiography (ERC) for diagnosing PSC. MATERIALS AND METHODS: This retrospective case-control study was conducted on patients referred to an outpatient gastroenterology clinic from 2001 to 2013. Patients with established diagnosis of PSC who had undergone MRC and ERC within a 6-month interval were included. Controls were selected from patients who had undergone imaging for reasons other than PSC evaluation. Disease outcome at the study time and liver biochemistry data at diagnosis and 1-year thereafter were retrieved. Diagnostic accuracy of MRC in comparison with ERC was evaluated. RESULTS: A total of 46 definite PSC patients (age at diagnosis = 36.8 +/- 11.6 years, 33 male) were found. Diagnostic imaging for PSC was ERC alone in 12, MRC alone in 23, and ERC plus MRC in 11 patients. Controls were 89 patients mostly with bile stones. The sensitivity, specificity, and positive and negative likelihood ratios of MRC was 90.9%, 95.5%, 20.23, and 0.10, respectively. Early PSC was found more frequently by MRC compared with ERC (30.4% vs. 8.3%, P = 0.146). No significant difference was found between imaging modalities with regards to patients' outcome (P = 0.786) or liver biochemistry at diagnosis or 1 year thereafter (P >0.05). CONCLUSION: Starting diagnostic imaging for PSC with MRC seems better and may provide diagnosis of PSC at its earlier phase. Further studies with larger sample of patients and longer follow-ups are warranted. PMID- 25709657 TI - Learning styles of medical students at Taibah University: Trends and implications. AB - BACKGROUND: Understanding the learning styles of medical students can drive the institutions to adapt instructional materials to enhance students' learning of knowledge and skills. This study explored the learning styles of undergraduate medical students, comparing gender variations in terms of their significant preferences. MATERIALS AND METHODS: A cross-sectional observational study was performed in 2012-2013, incorporating 1(st)-5(th) year undergraduate medical students of Taibah University. The instrument used was a Learning Style Questionnaire, with four learning styles (activist, reflector, theorist and pragmatist) and 40 items. RESULTS: Of 450 students, 384 responded (response rate; 85%). No single learning style predominated; 96 (25%) reflectors, 78 (20%) theorists, 68 (17%) pragmatists, and 37 (9%) activists. Combined reflector and theorist was the predominant dual learning style in 27 (7%) students. Among genders, theorist style had a significant result (P = 0.071) indicating that theorists varied among genders due to their different opinions. Learning style preferences of theorists and pragmatists also showed a significant result (P = 0.000 each), depicting that both genders had unique preferences. Males had fewer variations of preferences, when compared with females who showed a significant difference of opinions (P < 0.05). CONCLUSION: The students in the study preferred diverse learning styles, which were unevenly distributed, reflectors being the most common and activists as the least common. The results reflect the need to promote self-directed learning and modifications of instructional strategies, with expectant tilt in the students' learning styles towards activists and pragmatists. PMID- 25709658 TI - The volume of fluid injected into the tissue expander and the tissue expansion. AB - BACKGROUND: Replacement of the lost tissue is the major concerns of the plastic surgeons. Expanded area should be coherent with the surrounding tissue. Tissue expansion technique is the reforming methods the skin tissue scarcities. Several methods for tissue expansion are available; including usage of silicon balloon and injecting fluid into the tissue expander. MATERIALS AND METHODS: In a clinical trial study, 35 patients, with burn scars, in the face, skull and neck area were studied. We provided a tissue expander device with capacities of 125, 250 and 350cc. Fluid was injected inside the device, 3 consecutive weeks with 1 week interval. After 3 months the device was set out and the tissue expansion was measured using a transparent board and the results were analyzed. Multiple regression was done by SPSS 20 to analyze the data. RESULTS: Regression model showed Skin expansion was positively correlated with the volume of the injected fluid. For each centimeter square of skin expansion, about 6-8 ml of fluid must be injected. CONCLUSION: Correction of skin defects resulting from burning scar is possible using tissue expanders. The tissue expansion is correlated with the amount of the injected fluid. PMID- 25709659 TI - Population-based metabolic syndrome risk score and its determinants: The Isfahan Healthy Heart Program. AB - BACKGROUND: Metabolic syndrome (MetSy), an important predisposing factor for the most of noncommunicable diseases, has become a global pandemic. Given different definitions used for the MetSy, recently using a score termed "continuous MetSy risk score (CMetSyS)" is recommended. The aim of this study was to provide a CMetSyS in a population-based sample of Iranian adults and to assess its determinants. MATERIALS AND METHODS: We used the data of the baseline survey of a community trial entitled "the Isfahan health heart program." The MetSy was defined according to the Revised National Cholesterol Education Program Third Adult Treatment Panel. All probable predictive models and their predictive performance were provided using leave-one-out cross-validated logistic regression and the receiver operation characteristic curve methods. Multiple linear regression was performed to assess factors associated with the CMetSyS. RESULTS: The study population consisted of 8313 persons (49.9% male, mean age 38.54 +/- 15.86 years). The MetSy was documented in 1539 persons (21.86%). Triglycerides and waist circumference were the best predictive components, and fasting plasma glucose had the lowest area under curve (AUC). The AUC for our best model was 95.36 (94.83-95.83%). The best predictive cutoff for this risk score was -1.151 with 89% sensitivity and 87.93% specificity. CONCLUSION: We provided four population-based leave-one-out cross-validated risk score models, with moderate to perfect predictive performance to identify the MetSy in Iranian adults. The CMetSyS had significant associations with high sensitive C-reactive protein, body mass index, leisure time, and workplace physical activity as well as age and gender. PMID- 25709660 TI - The role of information system in multiple sclerosis management. AB - Multiple sclerosis (MS) is a chronic disease of central nervous system. The multiple sclerosis information system (MSIS), such as other information system (IS), depends on identification, collection and processing of data for producing useful information. Lack of the integrated IS for collecting standard data causes undesirable effects on exchanging, comparing, and managing. The aim of this study was to recognize the role of the IS in the MS management and determine the advantages and barriers in implementing of the MSIS. The present study was a nonsystematized review that was done in order to recognize the role of the IS in the MS management. In this study, electronic scientific resources such as scientific magazines and books and published topics at conferences were used. We used key words (IS, chronic disease management, and multiple sclerosis), their combination or their synonyms in title, key words, abstracts, and text of English articles and published reports from 1980 until 2013, and by using search engines such as Google, Google Scholar and scientific databases and electronic issues such as iPubMed, sufficiently important difference, Scopus, Medlib, and Magiran for gathering information. More than 200 articles and reports were collected and assessed and 139 of them. Findings showed that the MSIS can reduce of disease expenses through continuously collecting correct, accurate, sufficient, and timely patients and disease nature information; recoding; editing; processing; exchanging, and distributing among different health care centers. Although the MSIS has many advantages; but, we cannot ignore cultural, economic, technical, organizational, and managerial barriers. Therefore, it is necessary to do studies for preventing, reducing, and controlling them. One of the ways is to recognize the advantages of the MSIS and usage information technology in optimizing disease management. PMID- 25709662 TI - Knee tuberculosis masquerading as pigmented villonodular synovitis. AB - Tuberculosis (TB), once a disease confined to undeveloped or developing nations is currently in resurgence, which is attributable to pandemic human immunodeficiency virus (HIV) infection and immigration from endemic areas. Tuberculous arthritis is difficult to diagnose early because of its atypical insidious clinical manifestations and nonspecific imaging findings. TB is also known as the 'great mimicker'. Specifically, monoarticular tuberculosis of the knee may mimic pigmented villonodular synovitis (PVNS). The present report describes a young patient with tuberculous arthritis of knee joint. Accurate diagnosis and appropriate management was delayed due to magnetic resonance imaging (MRI) findings, such as, hemosiderin deposits and a nodular mass around the knee joint, suggestive of a diffuse type of PVNS. Our findings suggest that the first step in the diagnosis of tuberculous knee arthritis is to have a high index of suspicion. PMID- 25709661 TI - Efficacy of valganciclovir and ganciclovir for cytomegalovirus disease in solid organ transplants: A meta-analysis. AB - BACKGROUND: Cytomegalovirus (CMV), a problematic virus in solid organ transplant recipients (SOTR) such as liver, can worsen overall mortality and transplant outcome, so its prevention and treatment is a key of success in such patients. This study is aimed to compare the efficacy of ganciclovir (GCV) and valganciclovir (VGC) for prevention and treatment of infection with CMV. MATERIALS AND METHODS: After sensitive and systematic search in PubMed, EMBASE, Cochrane and other available databases, both prospective and retrospective studies on effect of VGC and GCV in prevention and treatment of CMV disease among SOTR, which had our study criteria, were included. The pooled risk estimates were calculated using random-effects models. RESULTS: Among 1324 title, 19 studies were included. In 11 prophylactic studies (2368 patients), the pooled risk of CMV disease (VGC relative to GCV) was 1.16, 95% confidence interval (CI): 0.91-1.49 and in studies of liver transplant recipients, 1.53, 95% CI: 0.86-2.70. Rate of viremia eradication in VGC to GCV was 1.05, 95% CI: 0.97-1.13. In 3 treatment studies (422 patients), rate of successful treatment in VGC to GCV was 0.98, 95% CI: 0.91-1.06 and viremia eradication 0.95, CI 95% 0.77-1.16. All these values did not show statistically significantly differences between GCV and VGC. CONCLUSION: It can be concluded that VGC as an alternative to GCV can be used with equal efficacy in prevention and treatment of CMV disease in SOTR. PMID- 25709663 TI - Surgical treatment of granulomatous mastitis associated with autoimmune response. AB - Granulomatous mastitis (GM) is a rare breast disease with unknown etiology. Clinical management strategies for GM include surgery, antibiotics, and steroid treatments. As patients with GM often respond to steroids, GM is thought to be an autoimmune disease. Here we describe a case of trauma-induced GM that presented as autoimmune disease but was successfully treated by surgery without steroids. The patient showed no sign of recurrence for 11 months. This case provides useful information on both the underlying mechanisms and clinical management of GM. PMID- 25709664 TI - Primary pleomorphic rhabdomyosarcoma of breast: Report of a rare neoplasm. AB - Primary sarcoma of the breast is very rare and constitutes less than 1% of all breast cancers. Herein, we report a case of pleomorphic rhabdomyosarcoma (PRMS) of the right breast in a 49-year-old female patient presented with a mass (7 cm * 6.5 cm). Mammography and ultrasonography suspected a malignant lesion and a diagnosis of poorly differentiated carcinoma was made on fine needle aspiration cytology. Modified radical mastectomy was carried out. Histopathological examination revealed a high grade stromal sarcoma with rhabdoid morphology and multinucleated tumor giant cells. The tumor cells were strongly positive for desmin, vimentin and Myo D1 focally. The tumor cells were immunonegative for cytokeratin, epithelial membrane antigen (EMA), CD34, CD45, SMA, S100, CD68 and HMB45. A final diagnosis of PRMS was rendered. Surgical margins were free and no metastasis was seen in axillary lymph nodes. Neither post-operative radiotherapy nor adjuvant chemotherapy was given and the patient has remained disease free 12 months post-operatively. PMID- 25709665 TI - Comment on: The effects of green tea consumption on metabolic and anthropometric indices in patients with type 2 diabetes. PMID- 25709666 TI - Dose the only information on Vitamin D3 content of fish oil and fish liver oil in the Iranian scientific resource corroborate the respective international data? PMID- 25709667 TI - Global eradication of guinea worm disease: Toward a newer milestone. PMID- 25709669 TI - Evaluation of the nasopalatine canal with cone-beam computed tomography in an Iranian population. AB - BACKGROUND: Implant placement plays a vital role in oral rehabilitation following loss of the incisors. Thus, having knowledge of anatomical variations of adjacent neurovascular structures especially the nasopalatine canal (NPC) is essential. Due to the lack of basic information in Iran about the morphology of this canal and the probability of its variety in different populations, this study was designed on an Iranian population. MATERIALS AND METHODS: In this descriptive study, we selected cone-beam computed tomography images of 198 patients comprising of 98 males and 100 females in two dental groups (edentulous or dentate). The shape of the nasopalatine foramen and the form of the canal in axial views were assessed. Then, the canal height and its diameter at the palatal, middle and nasal levels in cross-sectional images were measured. The available bone in the buccal and palatal sides of the canal was assessed. Data analysis was carried out using a Chi-square test and an independent t-test (P <= 0.05). RESULTS: The majority of the samples (81.8%) presented a single foramen. Cylindrical shape (57.6%) was the most frequently detected canal form. The mean of the estimated canal height was 12.84 +/- 2.88 mm. The canal diameter at the palatal level between the sexes and dental groups showed statistically significant differences. CONCLUSION: In our investigated population, the NPC form was mainly cylindrical with a single opening foramen. The mean of the canal height was higher than that found in other populations. Furthermore, the canal diameter in the edentulous group was greater than that observed in the other group. PMID- 25709670 TI - Bleaching effect of ozone on pigmented teeth. AB - BACKGROUND: There have been numerous researches on ozone application in dentistry; yet the data regarding its whitening effect is very limited. The present study compares the bleaching effect of ozone with office bleaching. MATERIALS AND METHODS: In this experimental study, 15 maxillary premolar teeth were selected and sectioned mesio-distally and bucco-lingually. The sections were then placed in tea for 1 week according to the Sulieman method and were divided into three groups each comprised of 15 sections. The samples were bleached as followed; Group I: Bleached with 35% hydrogen peroxide in three intervals of 8 min each, Group II: Underwent ozone treatment using Ozotop unite for 4 min and Group III: Bleached with a combination of both methods. The color indices of the samples, i.e., (a) green-red pigment, (b) blue-yellow pigment, (L) brightness, (DeltaE) overall color change, were evaluated pre- and post-bleaching utilizing a digital camera, Photoshop software and CIE lab index. The color changes of specimens then were calculated and analyzed through randomized analysis of variance and Tukey tests. P < 0.001 was considered to be significant. RESULTS: The color change (DeltaE) in Group II was significantly lower than those in the two other groups (P < 0.001). There was no significant difference between the color change of Groups I and III (P = 0.639). In addition, the results of L, a and b brought forth a similar pattern to the findings obtained from DeltaE. CONCLUSION: The hydrogen peroxide gel has a more powerful whitening effect than ozone; in addition, ozone has no synergistic effect when is used simultaneously with hydrogen peroxide. PMID- 25709668 TI - Congenitally missing teeth (hypodontia): A review of the literature concerning the etiology, prevalence, risk factors, patterns and treatment. AB - Congenitally missing teeth (CMT), or as usually called hypodontia, is a highly prevalent and costly dental anomaly. Besides an unfavorable appearance, patients with missing teeth may suffer from malocclusion, periodontal damage, insufficient alveolar bone growth, reduced chewing ability, inarticulate pronunciation and other problems. Treatment might be usually expensive and multidisciplinary. This highly frequent and yet expensive anomaly is of interest to numerous clinical, basic science and public health fields such as orthodontics, pediatric dentistry, prosthodontics, periodontics, maxillofacial surgery, anatomy, anthropology and even the insurance industry. This essay reviews the findings on the etiology, prevalence, risk factors, occurrence patterns, skeletal changes and treatments of congenitally missing teeth. It seems that CMT usually appears in females and in the permanent dentition. It is not conclusive whether it tends to occur more in the maxilla or mandible and also in the anterior versus posterior segments. It can accompany various complications and should be attended by expert teams as soon as possible. PMID- 25709671 TI - Periodontal bone regeneration in intrabony defects using osteoconductive bone graft versus combination of osteoconductive and osteostimulative bone graft: A comparative study. AB - BACKGROUND: Bone loss is one of the hallmarks of periodontitis. Hence, a major focus of research into periodontal regeneration has concentrated on the initiation of Osteogenesis. Osteoinduction requires the differentiation of mesenchymal cells into osteoblasts with subsequent formation of new bone. The present study has been carried out to evaluate periodontal bone regeneration in intrabony defects using osteostimulative oleaginous calcium hydroxide suspension Osteora((r)) (Metacura, Germany) in combination with osteoconductive bone graft OssifiTM (Equinox Medical Technologies, Holland). MATERIALS AND METHODS: A total of 22 sites in patients within the age range of 25-50 years, with intrabony defects were selected and divided into two groups (Group A and Group B) by using the split-mouth design technique. All the selected sites were assessed with the clinical parameters such as - Plaque Index, Gingival Index, Sulcus Bleeding Index, Periodontal Probing Depth, Clinical Attachment Level, Gingival Recession and radiographic parameter to assess the amount of Defect Fill. Mann-Whitey U test and Wilcoxon Signed Rank Test has been used to find the significance of study parameters on continuous scale for the comparison between the mesial and distal bone levels. P < 0.05 was considered to be statistically significant. RESULTS: Osteora((r)) in combination with osteoconductive OssifiTM showed better regenerative potential and more significant amount of bone fill in periodontal intrabony defects than when OssifiTM was used alone (P = 0.039). CONCLUSION: Osteora((r)) can be used as an adjunct to osteoconductive bone grafts, as an osteo-stimulating agent in the treatment of periodontal intrabony defects. PMID- 25709672 TI - The effect of water fluoride concentration on dental caries and fluorosis in five Iran provinces: A multi-center two-phase study. AB - BACKGROUND: Water fluoride level is unknown in many regions of Iran. Besides, only few non-controlled studies world-wide have assessed the effect of water fluoride on dental fluorosis and caries. We aimed to measure the fluoride level of 76 water supplies in 54 cities and evaluate the effect of fluoride on dental caries and fluorosis in a large multi-project study. MATERIALS AND METHODS: In the first phase (cross-sectional), fluoride levels of 76 water tanks in 54 cities/villages in five provinces of Iran were randomly evaluated in five subprojects. In the second phase (retrospective cohort), 1127 middle school children (563 cohort and 564 control subjects) in the high and low ends of fluoride concentration in each subproject were visited. Their decayed, missing and filled teeth (DMFT) and fluorosis states were assessed. The data were analyzed using Chi-square, Mann-Whitney U and independent-samples t-test (alpha = 0.05). RESULTS: Mean fluoride level was 0.298 +/- 0.340 mg/L in 54 cities/villages. Only eight water tanks had fluoride levels within the normal range and only one was higher than normal and the rest (67 tanks) were all at low levels. Overall, a significant association was observed between fluoride level and fluorosis. However, this was not the case in all areas, as in 2 of 5 provinces, the effect of fluoride on fluorosis was not confirmed. In 4 of the 5 areas studied, there was a significant link between fluoride level and DMFT. CONCLUSION: Extremely low fluoride levels in Iran cities are an alarming finding and need attention. Higher fluoride is likely to reduce dental caries while increasing fluorosis. This finding was not confirmed in all the areas studied. PMID- 25709673 TI - Comparative evaluation of efficacy of EndoVac irrigation system to Max-I probe in removing smear layer in apical 1 mm and 3 mm of root canal: An in vitro scanning electron microscope study. AB - BACKGROUND: The purpose of this study was to compare the efficacy of EndoVac irrigation system and side-vented closed ended needle (Max-I probe) in removing smear layer from root canals at 1 mm and 3 mm from working length using ProTaper rotary instrumentation. MATERIALS AND METHODS: A total of 50 freshly extracted maxillary central incisors were randomly divided into two groups after complete cleaning and shaping with ProTaper rotary files. In one group, final irrigation was performed with EndoVac system while in other group, final irrigation was done with a 30 gauge Max-I probe. 3% sodium hypochlorite (NaOCl) and 17% ethylenediaminetetracetic acid were used as final irrigants in all teeth. During instrumentation, 1 ml of 3% NaOCl was used for irrigation after each rotary instrument in the similar manner as in final irrigation. After instrumentation and irrigation, teeth were sectioned longitudinally into buccal and palatal halves and viewed under scanning electron microscope for evaluation of smear layer. Statistical analysis was performed using Kruskal-Wallis and Mann-Whitney U test. (P < 0.05). RESULTS: At 3 mm level, there was no significant difference between two groups. At 1 mm level, EndoVac group showed significantly better smear layer removal compared with Max-I probe (P = 0.0001). CONCLUSION: EndoVac system results in better smear layer removal at 1 mm from working length when compared to Max-I probe irrigation. PMID- 25709674 TI - The antimicrobial sensitivity of Streptococcus mutans and Streptococcus sangius to colloidal solutions of different nanoparticles applied as mouthwashes. AB - BACKGROUND: Metal nanoparticles have been recently applied in dentistry because of their antibacterial properties. This study aimed to evaluate antibacterial effects of colloidal solutions containing zinc oxide (ZnO), copper oxide (CuO), titanium dioxide (TiO2) and silver (Ag) nanoparticles on Streptococcus mutans and Streptococcus sangius and compare the results with those of chlorhexidine and sodium fluoride mouthrinses. MATERIALS AND METHODS: After adding nanoparticles to a water-based solution, six groups were prepared. Groups I to IV included colloidal solutions containing nanoZnO, nanoCuO, nanoTiO2 and nanoAg, respectively. Groups V and VI consisted of 2.0% sodium fluoride and 0.2% chlorhexidine mouthwashes, respectively as controls. We used serial dilution method to find minimum inhibitory concentrations (MICs) and with subcultures obtained minimum bactericidal concentrations (MBCs) of the solutions against S. mutans and S. sangius. The data were analyzed by analysis of variance and Duncan test and P < 0.05 was considered as significant. RESULTS: The sodium fluoride mouthrinse did not show any antibacterial effect. The nanoTiO2-containing solution had the lowest MIC against both microorganisms and also displayed the lowest MBC against S. mutans (P < 0.05). The colloidal solutions containing nanoTiO2 and nanoZnO showed the lowest MBC against S. sangius (P < 0.05). On the other hand, chlorhexidine showed the highest MIC and MBC against both streptococci (P < 0.05). CONCLUSION: The nanoTiO2-containing mouthwash proved to be an effective antimicrobial agent and thus it can be considered as an alternative to chlorhexidine or sodium fluoride mouthrinses in the oral cavity provided the lack of cytotoxic and genotoxic effects on biologic tissues. PMID- 25709675 TI - The effect of different environmental factors on force degradation of three common systems of orthodontic space closure. AB - BACKGROUND: Different environmental conditions, such as high temperature or exposure to some chemical agents, may affect the force decay of different methods of space closure during orthodontic treatment. The aim of this in vitro study was to evaluate the force decay pattern in the presence of tea as a popular drink in some parts of the world and two mouthwashes that are usually prescribed by the orthodontist once the treatment is in progress. MATERIALS AND METHODS: Elastic chain (EC), nickel-titanium (Ni-Ti) closed coil spring and tie-back (TB) method were used as the means of space closure. The specimens were placed in five different media: Hot tea, hot water (65 degrees ), chlorhexidine mouthwash, fluoride mouthwash and the control group (water at 37 degrees ). The specimens were stretched 25 mm and the elastic force of three systems was measured at the beginning of the study, after 24 h, after 1 week and after 3 weeks. One-way ANOVA was used to compare the results between the groups and Duncan test was carried out to compare the sets of means in different groups (P <= 0.05). RESULTS: Tea increases the force decay in the EC and TB groups. Oral mouthwashes also resulted in more rapid force decay than the control group. EC and Ni-Ti groups were not much affected in the presence of oral mouthwashes. CONCLUSION: Regarding the immersion media, TB method showed the biggest variation in different media and Ni Ti coil spring was least affected by the type of media. PMID- 25709676 TI - Effect of type of luting agents on stress distribution in the bone surrounding implants supporting a three-unit fixed dental prosthesis: 3D finite element analysis. AB - BACKGROUND: Osseointegration of dental implants is influenced by many biomechanical factors that may be related to stress distribution. The aim of this study was to evaluate the effect of type of luting agent on stress distribution in the bone surrounding implants, which support a three-unit fixed dental prosthesis (FDP) using finite element (FE) analysis. MATERIALS AND METHODS: A 3D FE model of a three-unit FDP was designed replacing the maxillary first molar with maxillary second premolar and second molar as the abutments using CATIA V5R18 software and analyzed with ABAQUS/CAE 6.6 version. The model was consisted of 465108 nodes and 86296 elements and the luting agent thickness was considered 25 MUm. Three load conditions were applied on eight points in each functional cusp in horizontal (57.0 N), vertical (200.0 N) and oblique (400.0 N, theta = 120 degrees ) directions. Five different luting agents were evaluated. All materials were assumed to be linear elastic, homogeneous, time independent and isotropic. RESULTS: For all luting agent types, the stress distribution pattern in the cortical bone, connectors, implant and abutment regions was almost uniform among the three loads. Furthermore, the maximum von Mises stress of the cortical bone was at the palatal side of second premolar. Likewise, the maximum von Mises stress in the connector region was in the top and bottom of this part. CONCLUSION: Luting agents transfer the load to cortical bone and different types of luting agents do not affect the pattern of load transfer. PMID- 25709677 TI - Radiographic assessment of third molars development and it's relation to dental and chronological age in an Iranian population. AB - BACKGROUND: The aim of the present study was to estimate chronological age based on third molar development and to determine the association between dental age and third molar calcification stages. MATERIALS AND METHODS: In this cross sectional study, 505 digital panoramic radiographs of 223 males (44.2%) and 282 females (55.8%) between the age of 6 and 17 were selected from patients who were treated in Departments of Pediatrics and Orthodontics of Isfahan University of Medical Sciences between the years of 2009 and 2013. Correlation between chronological age and third molar development was analyzed with SPSS 21 using Spearman's Rank correlation coefficient, Chi-square test and multiple regression statistical tests (P < 0.05). RESULTS: All third molars demonstrated a highly significant correlation with dental age (P < 0.001). The teeth showing the highest relationship with dental age were mandibular left third molar in males and mandibular right third molar in females (r s = 0.072). When multiple regression was used to predict dental age based on molar calcification stage, the only significant correlation was between maxillary left third molar in males (P < 0.05). There was no statistically significant correlation for any of third molars in females. Relationship between chronological age and molars development stage was significant in all age subgroups and in both gender (P < 0.001). CONCLUSION: Strong correlation was observed between left third molars and dental age in males. Results showed that third molar calcification stage can be used as an age predictor and in general mandibular teeth seems to be more reliable for this purpose in both genders and in all ages. PMID- 25709678 TI - Stability of changes in mandibular intermolar and intercuspid distances following orthodontic treatment. AB - BACKGROUND: The aim of this study was to determine the pattern and amount of change exhibited in mandibular intercanine and intermolar width during treatment and assessing its stability1-3 years post-retention. MATERIALS AND METHODS: The material consisted of 70 cases of which 20 cases were treated without extraction and 30 cases were treated with extraction, which were compared with 20 untreated cases which served as a control group. A series of three measurements were made for each case of the treated group: At the beginning of treatment, end of active treatment and 1-3 years post-retention; and for the control group: At 12, 15 and 18 years of age. The Wilcoxon signed ranks test was used to evaluate treatment changes in each group. The Kruskal-Wallis H test was used to compare the treatment changes between the 3 groups (alpha = 0.05). SPSS 16 software (SPSS Inc., Chicago, IL, USA) was used to evaluate the data. RESULTS: Mean changes of intercanine width for three groups was -0.5 mm for control group, -0.26 mm for non-extraction group and +0.18 mm for extraction group. Intermolar width of the extraction group decreased significantly during treatment. In contrast to the extraction group, the control and non-extraction groups both demonstrated an increase in mean intermolar width which was 0.66 mm and 0.91 mm respectively. CONCLUSION: It was concluded that although mean changes of intercanine and intermolar width were statistically significant but they were not perceptible clinically. PMID- 25709679 TI - Association of interleukin-1 alpha (-889) gene polymorphism in patients with generalized aggressive and chronic periodontitis. AB - BACKGROUND: There is a strong evidence that genetic as well as environmental factors affect the age of onset, severity and lifetime risk of developing periodontitis. The objective of the present study was to compare and to evaluate the association between interleukin (IL)-1alpha(-889) and gene polymorphisms in patients with generalized aggressive periodontitis, chronic periodontitis and healthy controls. MATERIALS AND METHODS: A total of 60 Indian patients, with 20 aggressive periodontitis, 20 chronic periodontitis and 20 healthy controls were recruited for this study. From each patient, a volume of 2 ml of blood was collected by venipuncture in the ante-cubital fossa and was stored in sodium EDTA vacutainers and was used for genotyping assays with the polymerase chain reaction restriction fragment length polymorphism technique. Clinical parameters such as oral hygiene index, gingival index and clinical attachment loss (CAL) were evaluated for each patient. Genotype distribution between different groups were analyzed using Chi-square test. A P = 0.05 or less was set for significance. RESULTS: The mean oral hygiene index was 3.7 +/- 0.86 and 3.25 +/- 0.30 for chronic and aggressive periodontitis cases respectively. The CAL was 4.29 +/- 0.63 mm for chronic periodontitis and 6.44 +/- 0.57 mm for aggressive periodontitis. Homozygous genotype 2,2 was more predominant in cases of aggressive periodontitis whereas in chronic periodontitis, heterozygous genotype 1,2 was more predominant when compared with others (P < 0.001). Odds ratio for aggressive versus chronic periodontitis was calculated as 6.2 (95% confidence interval 6.019-7.892). CONCLUSION: The results of the present study support a positive association between aggressive periodontitis and the presence of the IL 1alpha-889, allele 2 polymorphism in Indian patients. PMID- 25709680 TI - Evaluation of exfoliative cytology in the diagnosis of oral premalignant and malignant lesions: A cytomorphometric analysis. AB - BACKGROUND: Many oral squamous cell carcinomas (OSCCs) arise within regions that previously had premalignant lesion. Early diagnosis and prompt treatment of premalignant lesions offers the best hope of improving the prognosis in patients with OSCC. Exfoliative cytology is a simple and non-invasive diagnostic technique that could be used for early detection of oral premalignant and malignant lesions. This study was undertaken to evaluate the quantitative changes in nuclear area (NA), cytoplasmic area (CA) and nuclear-to-cytoplasmic ratio (NA/CA) in cytological buccal smears of oral leukoplakia with dysplasia (OLD) and OSCC patients while comparing with normal healthy mucosa. MATERIALS AND METHODS: A quantitative study was conducted over 90 subjects including 30 cases each of OLD, OSCC and clinically normal oral mucosa. The smears obtained were stained with Papanicolaou (PAP) stain and cytomorphological assessment of the keratinocytes was carried out. The statistical tools included arithmetic mean, standard deviation, Chi-square test, analysis of variance, Tukey multiple comparison. P < 0.001 was considered as significant. RESULTS: The mean NA of keratinocytes in the normal mucosa was 65.47 +/- 4.77 MUm(2) while for OLD it was 107.97 +/- 5.44 MUm(2) and 139.02 +/- 8.10 MUm(2) for that of OSCC. The differences show a statistically significant increment in NA (P < 0.001). There was significant reduction (P < 0.001) in the CA of keratinocytes from OSCC when compared with those from smears of OLD and normal mucosa with the values of 1535.80 +/- 79.38 MUm(2), 1078.51 +/- 56.65 MUm(2) and 769.70 +/- 38.77 MUm(2) respectively. The NA/CA ratio in the smears from normal oral mucosa, OLD and OSCC showed a mean value of 0.043 +/- 0.004, 0.100 +/- 0.008, 0.181 +/- 0.015 respectively with a significant difference among the groups (P < 0.001). CONCLUSION: Evaluation of nuclear and CA of keratinocytes by cytomorphometry can serve as a useful adjunct in the diagnosis and prognosis of a dysplastic lesion which may lead to OSCC. PMID- 25709681 TI - Biodegradable nanocomposite coatings accelerate bone healing: In vivo evaluation. AB - BACKGROUND: The aim of this study was to evaluate the interaction of bioactive and biodegradable poly (lactide-co-glycolide)/bioactive glass/hydroxyapatite (PBGHA) and poly (lactide-co-glycolide)/bioactive glass (PBG) nanocomposite coatings with bone. MATERIALS AND METHODS: Sol-gel derived 58S bioactive glass nanoparticles, 50/50 wt% poly (lactic acid)/poly (glycolic acid) and hydroxyapatite nanoparticles were used to prepare the coatings. The nanocomposite coatings were characterized by scanning electron microscopy, X-ray diffraction and atomic force microscopy. Mechanical stability of the prepared nanocomposite coatings was studied during intramedullary implantation of coated Kirschner wires (K-wires) into rabbit tibia. Titanium mini-screws coated with nanocomposite coatings and without coating were implanted intramedullary in rabbit tibia. Bone tissue interaction with the prepared nanocomposite coatings was evaluated 30 and 60 days after surgery. The non-parametric paired Friedman and Kruskal-Wallis tests were used to compare the samples. For all tests, the level of significance was P < 0.05. RESULTS: The results showed that nanocomposite coatings remained stable on the K-wires with a minimum of 96% of the original coating mass. Tissue around the coated implants showed no adverse reactions to the coatings. Woven and trabecular bone formation were observed around the coated samples with a minimum inflammatory reaction. PBG nanocomposite coating induced more rapid bone healing than PBGHA nanocomposite coating and titanium without coating (P < 0.05). CONCLUSION: It was concluded that PBG nanocomposite coating provides an ideal surface for bone formation and it could be used as a candidate for coating dental and orthopedic implants. PMID- 25709682 TI - Extensive Myiasis infestation associated with Oral Squamous Cell Carcinoma: Report of two cases. AB - Myiasis is the condition of infestation of the body by fly larvae (maggots). The deposited eggs develop into larvae, which penetrate deep structures causing adjacent tissue destruction. It is an uncommon clinical condition, being more frequent in tropical countries and hot climate regions, and associated with poor hygiene, suppurative oral lesions, alcoholism and senility. The diagnosis of Myiasis is basically made by the presence of larvae. The reported cases of oral Myiasis associated with oral cancer in the literature are few. This paper reports two cases of oral and maxillofacial Myiasis involving larvae in patients with squamous cell carcinoma in adult males. The condition was managed by manual removal of the larvae, one by one, with the help of forceps and subsequent management through proper health care. PMID- 25709683 TI - Relationship between mental workload and musculoskeletal disorders among Alzahra Hospital nurses. AB - BACKGROUND: Musculoskeletal disorders (MSDs) are a serious problem among the nursing staff. Mental workload is the major cause of MSDs among nursing staff. The aim of this study was to investigate the mental workload dimensions and their association with MSDs among nurses of Alzahra Hospital, affiliated to Isfahan University of Medical Sciences. MATERIALS AND METHODS: This descriptive cross sectional study was conducted on 247 randomly selected nurses who worked in the Alzahra Hospital in Isfahan, Iran in the summer of 2013. The Persian version of National Aeronautics and Space Administration Task Load Index (NASA-TLX) (measuring mental load) specialized questionnaire and Cornell Musculoskeletal Discomfort Questionnaire (CMDQ) was used for data collection. Data were collected and analyzed by Pearson correlation coefficient and Spearman correlation coefficient tests in SPSS 20. RESULTS: Pearson and Spearman correlation tests showed a significant association between the nurses' MSDs and the dimensions of workload frustration, total workload, temporal demand, effort, and physical demand (r = 0.304, 0.277, 0.277, 0.216, and 0.211, respectively). However, there was no significant association between the nurses' MSDs and the dimensions of workload performance and mental demand (P > 0.05). CONCLUSIONS: The nurses' frustration had a direct correlation with MSDs. This shows that stress is an inseparable component in hospital workplace. Thus, reduction of stress in nursing workplace should be one of the main priorities of hospital managers. PMID- 25709684 TI - Effect of acupressure on milk volume of breastfeeding mothers referring to selected health care centers in Tehran. AB - BACKGROUND: Breast milk is the main food source for infants' growth and development. Insufficient milk is one of the obstacles to the adequate use of this substance. One of the treatments to help this issue is acupressure. Therefore, the present study was designed to determine the effect of acupressure on maternal milk volume. MATERIALS AND METHODS: This study is a randomized clinical trial in which 60 breastfeeding mothers complaining of hypogalactia and meeting the inclusion criteria were studied. In addition to providing routine education, bilateral acupressure was performed for 12 consequentia l days on the acupoints of SI1, LI4, and GB21 in the intervention group, as three sessions per week with each session conducted 2-5 times. The control group received only routine education. In both groups, breast milk volume before intervention and 2 and 4 weeks after intervention was evaluated by an electric pump. Data were analyzed by descriptive and inferential statistical analysis through SPSS. RESULTS: The t-test showed no significant difference in the mean volume of milk in the two groups (P = 0.543). Mean volumes of milk before and 2 and 4 weeks after the intervention were 10.5 (8.3), 33 (13.44), and 36.2 (12.8), respectively, in the acupressure group and 9.5 (7.7), 17.7 (9.4), 18 (9.5), respectively, in the control group. Analysis of variance (ANOVA) test showed a significant difference in the mean volume of milk at 2 and 4 weeks after the intervention (P < 0.001). CONCLUSIONS: Both acupressure and general education methods were effective on the milk volume of breastfeeding mothers. Acupressure method was more effective than the other method. Therefore, application of acupressure as a method of alternative medicine to increase breastfeeding is suggested. PMID- 25709685 TI - Efficacy of stepwise sodium profile versus individualized dialysate sodium in blood pressure control among hemodialysis patients. AB - BACKGROUND: Hypertension is very common in patients with end-stage renal disease and accelerates cardiovascular morbidity and mortality. The most important factor in achieving normal blood pressure in these patients is reaching dry weight. Sodium and extracellular fluid balance play a vital role in this regard. Considering the lack of consensus about the efficacy of stepwise sodium profile and individualized dialysate sodium, this study aimed to determine the superior method for blood pressure control in hemodialysis patients. MATERIALS AND METHODS: In a quasi-experimental study, patients satisfying the inclusion criteria were enrolled through convenience sampling. The patients were randomly assigned to two groups of stepwise sodium profile and individualized dialysate sodium. Information record form was used for data collection. Data were analyzed with paired and independent t-test and descriptive statistics using SPSS for Windows 20.0. RESULTS: Patients in the two groups were similar in qualitative and quantitative background variables. While systolic blood pressure significantly decreased following hemodialysis with individualized dialysate sodium (P < 0.001), there was no significant difference between pre- and post-dialysis systolic blood pressure values using stepwise sodium profile (P = 0.060). Individualized dialysate sodium caused greater change in the mean systolic blood pressure than stepwise sodium profile did (P = 0.040). Pre- and post-dialysis diastolic blood pressure values showed significant differences in both groups (P < 0.001 using individualized dialysate sodium and P = 0.009 using stepwise sodium profile). However, the mean changes in diastolic blood pressure of the two groups were not significantly different (P = 0.295). CONCLUSIONS: We found no significant difference in interdialytic weight gain and blood pressure control by the two methods. The change in systolic blood pressure was lower in the stepwise profile method than in the individualized dialysate sodium method, and this method did not cause interdialytic hypertension. So, by adjusting the dialysis solution with regard to plasma sodium levels, lead to more blood pressure control. Meanwhile, the two groups were not significantly different in the mean changes of diastolic blood pressure. PMID- 25709686 TI - Meaning of well-being among Iranian women: A phenomenological descriptive approach. AB - BACKGROUND: Well-being is a subjective concept and means different things to various people. Most of the research investigating the experience has concentrated on its problematic and pathological aspects. The aim of this research was to enhance the understanding of the contextual meaning of well-being based on personal life experiences of the participants. This will be of help to experts in the field of health for monitoring, diagnosis, nursing, treatment, and rehabilitation. MATERIALS AND METHODS: This research was conducted by utilizing the Husserlian approach which involves direct exploration analysis and the description of a particular phenomenon. Data were collected by conducting unstructured, in-depth interviews of 20 Iranian young and middle-aged women. Analysis was conducted using the Colaizzi's methodology. RESULTS: The general meaning of the phenomenon, well-being, is understood as having the feeling of peace in life by the participants in this study. Well-being was identified by six major themes, including enjoying and being satisfied with life, the feeling of belonging together (or relating to others), the feeling of being healthy, the feeling of a relationship with God, to be able to afford what one needs to buy, and life as a whole (interconnection between different aspects of a person's life). CONCLUSIONS: Well-being as a feeling of peace in life can originate from both hedonic and eudemonic perspectives. A person's state of satisfaction in different aspects of her life can lead to the experience of well-being. All these aspects should be taken into account when health practitioners plan to promote the state of well-being among people. PMID- 25709687 TI - Experiences of patients with cancer and their nurses on the conditions of spiritual care and spiritual interventions in oncology units. AB - BACKGROUND: Although nurses acknowledge that spiritual care is part of their role, in reality, it is performed to a lesser extent. The purpose of the present study was to explore nurses' and patients' experiences about the conditions of spiritual care and spiritual interventions in the oncology units of Tabriz. MATERIALS AND METHODS: This study was conducted with a qualitative conventional content analysis approach in the oncology units of hospitals in Tabriz. Data were collected through purposive sampling by conducting unstructured interviews with 10 patients and 7 nurses and analyzed simultaneously. Robustness of data analysis was evaluated by the participants and external control. RESULTS: Three categories emerged from the study: (1) "perceived barriers for providing spiritual care" including "lack of preparation for spiritual care," "time and space constraints," "unprofessional view," and "lack of support"; (2) "communication: A way for Strengthening spirituality despite the limitations" including "manifestation of spirituality in the appearances and communicative behaviors of nurses" and "communication: Transmission of spiritual energy"; and (3) "religion-related spiritual experiences" including "life events as divine will and divine exam," "death as reincarnation," "trust in God," "prayer/recourse to Holy Imams," and "acceptance of divine providence." Although nurses had little skills in assessing and responding to the patients' spiritual needs and did not have the organizational and clergymen's support in dealing with the spiritual distress of patients, they were the source of energy, joy, hope, and power for patients by showing empathy and compassion. The patients and nurses were using religious beliefs mentioned in Islam to strengthen the patients' spiritual dimension. CONCLUSIONS: According to the results, integration of spiritual care in the curriculum of nursing is recommended. Patients and nurses can benefit from organizational and clergymen's support to cope with spiritual distress. Researchers should provide a framework for the development of effective spiritual interventions that are sensitive to cultural differences. PMID- 25709688 TI - Exploring infertile women's experiences about sexual life: A qualitative study. AB - BACKGROUND: Infertility is a serious problem in a couple's life that affects their marriage relationships. So, dissatisfaction with sexual function resulting from interpersonal problems is common among these couples. This qualitative study aimed to explore the experiences of infertile women in their sexual life. MATERIALS AND METHODS: This is a qualitative study with a phenomenological approach. The participants were 20 infertile women referring to the health care centers and infertility clinics of Isfahan and were selected through purposive sampling. Data were collected by tape recording of deep interviews and analyzed by Colaizzi's method. RESULTS: Analysis of the participants' experiences led to five main concepts: "Disturbed in femininity-body image," "discouragement of sexual relations," "sacrifice of sexual pleasure for the sake of getting pregnant," "confusion in sexual relation during infertility treatment," and "striving to protect their marriage." CONCLUSIONS: Findings revealed that infertility affects women's different aspects of sexual life, especially disturbance in femininity-body image and sexual reluctance. With regard to women's willingness to protect their matrimonial life and prevent sexual trauma as a destroying factor for their family's mental health, it seems sexual counseling is necessary for infertile couples. PMID- 25709689 TI - Effect of role play education on primiparous women's fear of natural delivery and their decision on the mode of delivery. AB - BACKGROUND: The number of women who select cesarean section due to fear of childbirth has increased. Role play education seems to be a helpful method to remove or reduce the fear of childbirth. Therefore, this study aimed to investigate the effect of role play education on primiparous women's fear of natural delivery and their decision on the mode of delivery. MATERIALS AND METHODS: In this blind clinical trial, 67 primiparous women with natural pregnancy at 34-36 weeks of gestational age and with no indication of cesarean section were selected from the health care centers in Mashhad. They were randomly assigned to two groups who underwent pre-test and post-test with the help of delivery attitude questionnaire to investigate their fear of childbirth and a researcher-made pregnant women's decision investigation questionnaire. Education through role play was conducted in the form of three scenarios during seven stages. The findings were analyzed by Fisher's exact test and independent t-test through SPSS. RESULTS: The two groups were significantly different concerning the fear of childbirth after the intervention (P = 0.007), and the fear score showed a higher reduction in the role play group compared to the lecture group. There was a significant difference between the two groups concerning the reduction of elective cesarean section and the decision on the mode of delivery at the time of admission in the labor room (P = 0.000). About 75% in the lecture group and 100% in the role play group selected natural delivery. CONCLUSIONS: In the present study, the effect of role play was more in making a decision on natural delivery, reducing the fear of childbirth, and reducing the rate of elective cesarean section. It is suggested to use role play method to educate pregnant women to reduce the rate of cesarean sections. PMID- 25709690 TI - Comparing the effects of the second-and third-generation oral contraceptives on sexual functioning. AB - BACKGROUND: The aim of this study was to compare the effects of the second- and third-generation oral contraceptives on women's reproductive sexual function. MATERIALS AND METHODS: This randomized, double-blind, placebo-controlled clinical trial was conducted on 82 married women of reproductive age in Tehran. Samples were randomized into the groups receiving second- and third-generation oral contraceptive pills. Female Sexual Function Index (FSFI) tool was used before the intervention and 2 and 4 months after the intervention. Data analysis was carried out using analysis of variance (ANOVA) within repeated measures and P < 0.05 were considered significant. RESULTS: There was a statistically significant difference in the positive and negative moods between the experimental and control groups before the intervention in the second and fourth months. The second-generation pills caused a decrease in sexual function in the second month and an increase in sexual function in the fourth month, but the third-generation pills led to an increase in sexual function in the second and fourth months. The increase in sexual function that resulted from using the third-generation pills was significantly higher than that resulted on using the second-generation pills. CONCLUSIONS: According to the results of this study, sexual functioning decreased in the second month of using the second-generation pills and sexual performance was significantly more on using the third-generation pills compared to second generation pills. The most common type of oral contraceptive used in Iran is the second-generation oral contraceptive LDTM (low-dose estrogen), which is freely distributed in health centers. Therefore, it is necessary for women who wish to use these contraceptive methods to be educated and consulted before they start using them. The third-generation contraceptive pills can be recommended to women who wish to use oral contraceptives. PMID- 25709691 TI - Quality of work life and its association with workplace violence of the nurses in emergency departments. AB - BACKGROUND: Nurses as the major group of health service providers need to have a satisfactory quality of work life in order to give desirable care to the patients. Workplace violence is one of the most important factors that cause decline in the quality of work life. This study aimed to determine the quality of work life of nurses in selected hospitals of Isfahan University of Medical Sciences and its relationship with workplace violence. MATERIALS AND METHODS: This was a descriptive-correlational study. A sample of 186 registered nurses was enrolled in the study using quota sampling method. The research instrument used was a questionnaire consisting of three parts: Demographic information, quality of work life, and workplace violence. Collected data were analyzed using descriptive and inferential statistics by SPSS version 16. RESULTS: The subjects consisted of 26.9% men and 73.1% women, whose mean age was 33.76 (7.13) years. 29.6% were single and 70.4% were married. About 76.9% of the subjects were exposed to verbal violence and 26.9% were exposed to physical violence during past year. Mean score of QNWL was 115.88 (30.98). About 45.7% of the subjects had a low level of quality of work life. There was an inverse correlation between the quality of work and the frequency of exposures to workplace violence. CONCLUSIONS: According to the results of this study, it is suggested that the managers and decision makers in health care should plan strategies to reduce violence in the workplace and also develop a program to improve the quality of work life of nurses exposed to workplace violence. PMID- 25709692 TI - The effect of sensory stimulation provided by family on arterial blood oxygen saturation in critical care patients. AB - BACKGROUND: Stressors in the intensive care unit (ICU) impair patients' comfort, excite the stress response, and increase oxygen consumption in their body. Non medical interventions are recommended by several studies as a treatment to improve comfort in the ICU patients. Sensory stimulation is one of the most important interventions. Since arterial blood oxygen saturation is an important index of patients' clinical and respiratory condition, this study aimed to investigate the effect of sensory stimulation provided by family on arterial blood oxygen saturation in critical care patients. MATERIALS AND METHODS: This study is a clinical trial conducted on 64 patients hospitalized in the ICU wards of Al-Zahra and Kashani hospitals in Isfahan, Iran in 2012 and 2013. The patients were selected by simple sampling method and were randomly assigned to two groups (study and control). Patients' arterial blood oxygen saturations were measured 10 min before, immediately after, 10 min and 30 min after sensory stimulation in the study group, and simultaneously in the control group without any intervention. RESULTS: Repeated measures analysis of variance (ANOVA) showed a significant difference in the mean of arterial blood oxygen saturation levels 10 min before, immediately after, 10 min and 30 min after sensory stimulation in the study group (P < 0.001), but in the control group, the difference was not significant (P = 0.8). Pair wise comparison of the mean arterial blood oxygen saturation levels at different time points by Fisher's Least Significant Difference (LSD) showed that there was a significant difference in the intervention group (P < 0.022). But in the control group, there was no significant difference between pairs of time points (P > 0.18). CONCLUSIONS: Application of sensory stimulations as a nursing and non-medical intervention by the family members improves comfort and increases the level of blood oxygen saturation in critical care patients. PMID- 25709693 TI - The level of depression and its related factors among the mothers with mentally retarded girl children in exceptional primary schools. AB - BACKGROUND: Nowadays, depression is one of the most prevalent mental diseases to which some individuals like mothers of mentally retarded children are more vulnerable due to their (children's) special condition. Therefore, the present study aimed to investigate the level of depression and its related factors in these mothers. MATERIALS AND METHODS: This cross-sectional study was conducted on 120 qualified mothers with mentally retarded children who were from exceptional children girls' schools in Isfahan. The subjects filled personal characteristics and Beck depression inventory assessment, and their level of depression and its association with some baseline factors were analyzed through descriptive statistics in SPSS. RESULTS: Results showed that 75% of the mothers experienced various levels of depression, of whom 25.8% suffered from minor depression, 24.2% from moderate depression, and 25% suffered from major depression. The results obtained showed that there was a significant direct association between the intensity of depression and students' age, mothers' age, fathers' age, the number of children, and the length of parents' marriage and a reverse association between the intensity of depression and subjects', fathers', and mothers' education (P = 0.004). No association was observed between mothers' occupation and the intensity of depression. Meanwhile, there was a negative significant association between fathers' occupation and mothers' depression (P = 0.02). About 33.3% of the mothers did not believe that their spouses' and families' psychological and mental support was adequate. CONCLUSIONS: The present study showed that mothers of mentally retarded children are predisposed to depression. With regard to the important role of mothers in the family and, consequently, the risk of impaired health of the family members, especially these children's health, prevention and diagnosis of depression and treatment of these mothers seem to be essential. Adequate support to these mothers plays a key role in reduction of the risk of their depression. PMID- 25709694 TI - Effect of hope therapy on the hope of diabetic patients. AB - BACKGROUND: Hope is the most important factor in diabetic patients' life. The level of hope may be changing among these individuals as a result of chronic nature of diabetes and its complications. When the level of hope increases among these patients, they can resist against physical and psychological complications of diabetes more, accept the treatment better, enjoy life more, and adapt with their situations more efficiently. This study aimed to define the efficacy of hope therapy on hope among diabetic patients. MATERIALS AND METHODS: This was a quasi-experimental study conducted on 38 diabetic patients referring to Sedigheh Tahereh Research and Treatment Center affiliated to Isfahan University of Medical Sciences in Iran in 2012. The subjects were selected based on the goals and inclusion criteria of the study and then were randomly assigned to study and control groups. Herth Hope Index (HHI) was completed by both groups before, after, and 1 month after intervention. In the study group, 120-min sessions of hope therapy were held twice a week for 4 weeks. Descriptive and inferential statistical tests were adopted to analyze the data through SPSS version 12. RESULTS: Comparison of the results showed that hope therapy significantly increased hope in diabetic patients after intervention in the study group compared to control (P < 0.001). CONCLUSIONS: The results showed that hope therapy increased hope among diabetic patients. This method is suggested to be conducted for diabetic patients. PMID- 25709695 TI - Prediction of glucose intolerance at 24-28 weeks of gestation by glucose and insulin level measurements in the first trimester. AB - BACKGROUND: Gestational diabetes is the second common disorder in pregnancy period, which is detected in 24-28 weeks of gestational age through screening tests in low-risk women. The women with gestational diabetes are prone to prenatal mortality and development of future diabetes. Therefore, detection of these individuals in the first trimester and conducting preventive interventions is of great importance. This study aimed to define the predictive value of fasting plasma glucose (FPG) and fasting plasma insulin (FPI) test in first trimester concerning the positive result of oral glucose challenge test (OGCT). MATERIALS AND METHODS: This is a prospective and observational study conducted on 88 pregnant women in Tehran. After FPG and FPI measurements in these women in the first trimester, a screening test of GCT with 50 g oral glucose was conducted in 24-28 weeks of gestational age. Diagnostic value of FPG and in these two groups of positive and normal GCT results was evaluated through receiver operator characteristic (ROC) curve. P < 0.05 was considered significant. RESULTS: In this study, 15 subjects (17%) were detected with a positive GCT result. The sub-curve area of ROC diagram for FPG and FPI was calculated to be 0.573and 0.592, respectively, which reveals that FPG and FPI cannot have a proper predictive value for the positive result of GCT. Based on the results, the best cutoff points for FPG and FPI are 79.5 mg/dl and 7.55 MUIU/ml, with accuracy of 60-67% and specificity of 45.2-47%. CONCLUSIONS: Only higher fasting glucose levels in early pregnancy, within the normoglycemic range, would predict the development of glucose intolerance with limited sensitivity and specificity. PMID- 25709696 TI - Comparison of two educational methods (family-centered and patient-centered) on hemodialysis: Related complications. AB - BACKGROUND: Hypotension and muscular cramp are the common complications of hemodialysis. Effective control of hemodialysis complications increases the survival time and the quality of life of patients on hemodialysis. Considering that failure to follow a therapeutic plan is one of the most prevalent causes of hemodialysis complications, the present research was conducted to study the effect of two educational methods (family-centered and patient-centered) on some complications that occur during hemodialysis. MATERIALS AND METHODS: This clinical trial was performed from June to November 2012 in the hemodialysis ward of Imam Khomeini Hospital and Tehran Amir Aalam Hospital. Research samples included 60 patients in the age range of 18-65 years who were randomly included in patient-centered education (30 people in even days) and family-centered education (30 people in odd days). Blood pressure and muscle cramp were checked using researcher-made checklist in three stages (before and at the second and fourth week after intervention). Hypotension (before the start of dialysis, at the first, second, and third hour, and at the end hours) and muscle cramp (in the middle of hemodialysis and the end half an hour) were also checked. Data were analyzed using SPSS software, version 16, with Chi-square test, Fisher test, and independent t-test. RESULTS: Before intervention, the two groups did not show significant difference in terms of hypotension [with P = 0.91 and variations mean of 1.60 (1.30)] and muscle cramp [with P = 0.50 and variations mean of 1.06 (1.01)]. In the second and fourth week after intervention, there was significant difference between the two groups in terms of hypotension [with P = 0.016 and variations mean of 0.70 (0.70) and P = 0.02 and variations mean of 0.86 (0.62)] and muscle cramp [with P = 0.01 and variations mean of 0.46 (0.86) and P = 0.02 and variations mean of 1 (1.05)]. CONCLUSIONS: Considering that the study results showed that family-centered education was more effective on reduction of hemodialysis complications than patient-centered education, it is recommended that educational interventions relating to therapeutic program should be done in patients under hemodialysis, with participation of families. PMID- 25709697 TI - Comparison of parental stress among mothers and fathers of children with autistic spectrum disorder in Iran. AB - BACKGROUND: Most of the studies about parenting stress among parents of children with autistic spectrum disorder (ASD) have been conducted in western societies. The objective of this research, conducted in Iran, is to evaluate the parenting stress among fathers and mothers of children with ASD and find the correlation between severity of the disorder in children and the level of parental stress. MATERIALS AND METHODS: Participants included 42 couples having children aged between 2 and 12 diagnosed with ASD based on Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria. The diagnosis was made by two child and adolescent psychiatrists. Demographic information of the participants was collected using a questionnaire. The severity of pervasive developmental disorder in children was determined based on Childhood Autism Rating Scale (CARS); stress of parents was measured using Parenting Stress Index (PSI). Collected information was analyzed by the SPSS (version 16) software. RESULTS: Evaluation of subscales in participants' data showed a positive correlation coefficient between the PSI-parent domain and Childhood Autism Rating Scale Parent form CARS-P rating (r = 0.339, P =0 0.028) and also between the total stress index and CARS-P rating (r = 0.333, P = 0.031) for fathers. It is thus suggested that fathers of children with more severe developmental disorders experience more stress. The results showed significant differences between fathers and mothers in the three PSI subscales including PSI-child domain score (P < 0.005), PSI-parent domain score (P < 0.005), and the total stress index (P < 0.005). Mothers had significantly more stress than fathers. CONCLUSIONS: These findings show that parents with ASD children have many emotional needs which should be considered in planning the effective treatment strategies for their children. PMID- 25709698 TI - Health professionals' experiences and perceptions of challenges of interprofessional collaboration: Socio-cultural influences of IPC. AB - BACKGROUND: Literature shows that interprofessional collaboration (IPC) is a challenging phenomenon both in theory and practice, and it is affected by socio cultural contexts in which the health professionals (HPs) play their roles. Considering some evidences on the similarities and differences between eastern and western socio-cultural contexts, this study aims to explore and describe the socio-cultural factors influencing IPC in these two contexts. MATERIALS AND METHODS: This was a pilot qualitative descriptive study that was conducted in 2012-2013. Data were collected through conducting one-to-one and group interviews as face-to-face and written in terviews (narratives) with purposeful samples of HPs from various disciplines including nurses, medical doctors (MDs) from variety of specialities, social workers, and psychologists from health system in Iran and Germany. Other methods of data collection were taking field notes and reviewing related literature. The qualitative content analyses method was employed to derive the common categories and themes. RESULTS: Totally 22 participants took part in the study. Moreover, researchers had a 10-day period of field observation in Germany (health systems affiliated with Albert Ludwigs University of Freiburg). Qualitative data analysis revealed three themes and related subthemes. The themes were: (1) Interaction beyond boundaries, (2) motivation to engage in IPC, and (3) readiness to approaching toward IPC. CONCLUSIONS: The results of the study emphasized that in both eastern and western contexts, organizational, professional, and community socio-cultural textures, mainly in terms of attitudes toward other people, other professions, and IPC, play their role as important factors. We suggest future researches about each of the emerged themes. PMID- 25709699 TI - A comparative study of the effects of problem-solving skills training and relaxation on the score of self-esteem in women with postpartum depression. AB - BACKGROUND: Self-esteem is a determinant factor of mental health. Individuals with low self-esteem have depression, and low self-esteem is one of main symptoms of depression. Aim of this study is to compare the effects of problem-solving skills and relaxation on the score of self-esteem in women with postpartum depression. MATERIALS AND METHODS: This clinical trial was performed on 80 women. Sampling was done in Mashhad healthy centers from December 2009 to June 2010. Women were randomly divided and assigned to problem-solving skills (n = 26), relaxation (n = 26), and control groups (n = 28). Interventions were implemented for 6 weeks and the subjects again completed Eysenck self-esteem scale 9 weeks after delivery. Data analysis was done by descriptive statistics, Kruskal-Wallis test, and analysis of variance (ANOVA) test by SPSS software. RESULTS: The findings showed that the mean of self-esteem scale scores was 117.9 +/- 9.7 after intervention in the problem-solving group, 117.0 +/- 11.8 in the relaxation group, and 113.5 +/- 10.4 in the control group and there was significant difference between the groups of relaxation and problem solving, and also between intervention groups and control group. CONCLUSIONS: According to the results, problem-solving skills and relaxation can be used to prevent and recover from postpartum depression. PMID- 25709700 TI - Community-based maternity care from the view of Iranian midwives: A phenomenological study. AB - BACKGROUND: Midwifery cares take place in diverse communities with different ethnics groups. Therefore, midwifery cares could be planned wisely and principally based on women's and their families' changeable demands which focus on social and cultural issues. This qualitative study explored the midwives' experiences of care in the community. MATERIALS AND METHODS: This qualitative study was conducted by descriptive phenomenological approach. The subjects, selected by purposive sampling, comprised 13 midwives employed in Isfahan, Iran. Semi-structured interviews were audio-taped, transcribed, and simultaneously analyzed through Colaizzi's method. RESULTS: With descriptive analysis of participants' experiences, three main themes were explored (personal characteristics of the community midwife, social determinants of women's health, and achieving community-based midwifery skills). CONCLUSIONS: Knowledge of women's social status, gender inequality in health, and existence of social health risk factors for women in their community helps midwives to provide reproductive health care based on clients' needs and demands. Therefore, midwives should enhance the quality of their care through integrating professional skills with a full understanding of the social context. PMID- 25709701 TI - Life associated with fear and worry: A major concern among the cardiac valve replaced patients. AB - BACKGROUND: Few attempts were made for alleviating the physical/psychological problems among the cardiac valve-replaced patients and no comprehensive study was done based on the experiences of such patients. This study was undertaken to describe the stressful experiences of the heart valve-replaced patients. MATERIALS AND METHODS: In this qualitative study performed during 2012-2013 with a content analysis approach, 13 patients from Tehran and Kashan therapeutic centers participated. The study sampling was accomplished with purposeful sampling using a semi-structured interview that continued until data saturat ion. All interviews were recorded, and were immediately handwritten word by word and finally typewritten. Description and analysis of the data were done by Graneheim and Lundman content analysis. RESULTS: One hundred and seventy-five primary codes were derived among the 680 codes taken from the participants interviewed. Using abstract and deep perception of the categories, 14 subcategories and 5 themes were derived. The themes are as follows: worry of care conditions, worry of life with the ongoing condition of having prosthetic cardiac valve, worry regarding the instability in life, fear of hospital, and fear of unknown factors. Each theme consisted of special subsidiary themes with specific functions. CONCLUSIONS: The main themes of fear and worry about on losing the valve were identified and introduced in the cardiac valve-replaced patients. As the nature and function of these themes are different in different societies, recognition and discrete definition of them are necessary for care planning and promotion. PMID- 25709702 TI - Evaluation of the effects of ice massage applied to large intestine 4 (hegu) on postpartum pain during the active phase of labor. AB - BACKGROUND: The uterus continues to contract after childbirth. The pain caused by the contractions of the uterus can be as severe as labor pain. The study was aimed to evaluate the effects of ice massage applied to the large intestine 4 (LI4) on postpartum pain during the active phase of labor. MATERIALS AND METHODS: The study was designed as a randomized controlled trial with three groups and carried out in two stages. The study sample comprised of 150 pregnant women, who were referred to a maternity hospital. In the experimental group, ice massage was applied to LI4 during four contractions within the active phase of labor. In the placebo group, pressure was applied to LI4 using silicone balloons and the third group was the control group. The Visual Analog Scale (VAS) and The McGill (Melzack) Pain Questionnaire (MPQ) were compared among the experimental, placebo, and control groups. RESULTS: The mothers in the ice application group had the lowest mean VAS score. It was determined that ice massage applied to LI4 during the active phase of labor did not lead to any statistical differences in mothers in the first 24 hours postpartum in terms of the characteristics of the pain with MPQ and VAS. CONCLUSIONS: In the study, the perception of pain was tried to be minimized by applying pressure with ice balloons to LI4. However, although the application was determined to have made no difference in the pain intensity, the mothers' statements in the ice application group suggested that they felt more comfortable than did the mothers in the other groups. PMID- 25709703 TI - Addressing the sexual problems of Iranian women in a primary health care setting: A quasi-experimental study. AB - BACKGROUND: The World Health Organization emphasizes on integration of sexual health into primary health care services, educating people and health care workers about sexuality, and promoting optimal sexual health. Despite the high prevalence of sexual problems, these problems are poorly managed in primary health care services. This study was conducted to evaluate the efficacy and feasibility of the first two steps of PLISSIT (Permission, Limited Information, Specific Suggestions, Intensive Treatment) model for handling of women sexual problems in a primary health care setting. MATERIALS AND METHODS: This was a quasi-experimental study that was carried out in Zanjan, northwest of Iran. Eighty women who had got married in the past 5 years and had sexual problem were randomly assigned to control and intervention groups. The intervention group received consultation based on PLISSIT model by a trained midwife and the control group received routine services. Female Sexual Function Index (FSFI) questionnaire was used for assessing and tracking any changes in sexual function. Data were collected at three points: Before consultation and 2 and 4 weeks after consultation. Paired t-test and repeated measures analysis of variance (ANOVA) test were used for comparison of scores within groups. RESULTS: Significant improvement was found in FSFI sub-domain scores, including sexual desire (P < 0.0001), arousal (P < 0.0001), lubrication (P < 0.0001), orgasm (P = 0.005), satisfaction (P = 0.005), pain (P < 0.0001), and FSFI total score (P < 0.0001) in the intervention group compared to the control group. CONCLUSIONS: This study showed that PLISSIT model can meet the sexual health needs of clients in a primary health care setting and it can be used easily by health workers in this setting for addressing sexual complaints and dysfunctions. PMID- 25709704 TI - Ethical behavior of nurses in decision-making in Iran. AB - BACKGROUND: Ethical caring is an essential in nursing practice. Nurses are confronted with complex situations in which they are expected to autonomously make decisions in delivering good care to patients. Although a wide range of studies have examined ethical behavior of nurses, there are still many issues requiring further investigation. The aim of this article is to describe the ethical behavior of nurses in decision-making in patients' care in Iran. MATERIALS AND METHODS: This study was conducted through grounded theory method. Participants were 17 Iranian nurses, employed in Tabriz University of Medical Sciences hospitals. Unstructured, semi-structured, and in-depth interviews were used for data gathering. Interviews were transcribed and coded according to Strauss and Corbin method in open, axial, and selective coding. RESULTS: Nurses showed three major approaches in ethical behavior: Beyond the legal duty and protection of the patients, which includes dedication and full availability to nurses' job and the client, spending time for the patients and delayed exit from the workplace, and arbitrary practice; legal duty and the protection of patients and nurses, which includes caretaking for the patient, responding to the client, and implementing the physician's prescription; and below the legal duty and the protection of one's self, that is, finding evidence and having witness in case of false documentation, and shortcoming, negligence, and mistake. CONCLUSIONS: Because of the importance of the ethical behavior of nurses in decision-making, it is necessary to find ways to promote moral reasoning and moral development of nurses. Empowerment of nurses, nurse educators, and nursing students to acquire knowledge and develop ethical behavior skills is important. PMID- 25709705 TI - The effect of aromatherapy massage with lavender oil on severity of primary dysmenorrhea in Arsanjan students. AB - BACKGROUND: Presently, using complementary therapy such as lavender oil has specific application in medicine. The purpose of this study was to investigate the effect of aromatherapy massage on the severity of primary dysmenorrhea in nursing and midwifery students of Islamic Azad University of Arsanjan, Iran. MATERIALS AND METHODS: This study was performed using clinical trial method on 80 eligible students whose level of pain was measured by visual analogue scale (VAS) before the intervention. Each participant, in the first days of menstruation, randomly received two types of massage with lavender and placebo oil in two consecutive cycles of menstruation. Their level of pain was measured before and 30 min after the intervention. In this study, each group was considered as their self-control group in the next cycle. The data were analyzed by SPSS software. RESULTS: A significant decrease in VAS score after lavender massage was detected in comparison with placebo massage. There was a statistically significant difference between VAS scores after and before placebo massage. In addition, statistically the effect of lavender massage on the severity of primary dysmenorrhea was higher than that of placebo massage (P < 0.001). CONCLUSIONS: Findings of this study showed that lavender oil massage decreases primary dysmenorrhea and it can be used as an effective herbal drug. PMID- 25709706 TI - Adherence to risk evaluation and mitigation strategies (REMS) requirements for monthly testing of liver function. AB - BACKGROUND: Risk evaluation and mitigation strategies (REMS), as mandated by the US Food and Drug Administration (FDA) for medications with the potential for harm, are increasingly incorporating rigid protocols for patient evaluation, but little is known about compliance with these programs. Despite the inherent limitations, data on administrative claims may provide an opportunity to investigate adherence to these programs. METHODS: We assessed adherence to liver function test (LFT) requirements included in the REMS program for bosentan through use of administrative claims. Patients observed in the Optum Research Database who were initiators of bosentan from November 20, 2001 to March 31, 2013 were included. Adherence to LFTs was calculated using pharmacy claims for bosentan dispensation and medical claims for laboratory services, and was assessed at the time of drug initiation and within specified time intervals throughout follow-up. RESULTS: Of 742 patients, 523 (70.5%) had >=1 qualifying LFT. Among patients with >=12 dispensations, claims for LFTs at individual dispensations were 53.2-64.0%. Median proportion of dispensations with >=1 LFT was 0.8 among patients with >=6 (interquartile range, 0.7-1.0) or >=12 (0.7-0.9) dispensations. Adherence was 90-100% for 33.3% of all initiators, whereas 29.3% of initiators were non-adherent (defined as <50% of on-therapy LFTs). CONCLUSIONS: Analyses of administrative claims suggest that the REMS program for bosentan may not have adequately guaranteed adherence to the program's monthly monitoring of LFTs. Such investigations of existing REMS programs may provide insight on how to accomplish more successful evaluation of REMS. PMID- 25709707 TI - The Resin from Protium heptaphyllum Prevents High-Fat Diet-Induced Obesity in Mice: Scientific Evidence and Potential Mechanisms. AB - Herbal compounds rich in triterpenes are well known to regulate glucose and lipid metabolism and to have beneficial effects on metabolic disorders. The present study investigated the antiobesity properties of resin from Protium heptaphyllum (RPH) and the possible mechanisms in mice fed a high-fat diet (HFD) for 15 weeks. Mice treated with RPH showed decreases in body weight, net energy intake, abdominal fat accumulation, plasma glucose, amylase, lipase, triglycerides, and total cholesterol relative to their respective controls, which were RPH unfed. Additionally, RPH treatment, while significantly elevating the plasma level of ghrelin hormone, decreased the levels of insulin, leptin, and resistin. Besides, HFD-induced increases in plasma levels of proinflammatory mediators TNF-alpha, IL 6, and MCP-1 were significantly lowered by RPH. Furthermore, in vitro studies revealed that RPH could significantly inhibit the lipid accumulation in 3T3-L1 adipocytes (measured by Oil-Red O staining) at concentrations up to 50 MUg/mL. These findings suggest that the antiobese potential of RPH is largely due to its modulatory effects on various hormonal and enzymatic secretions related to fat and carbohydrate metabolism and to the regulation of obesity-associated inflammation. PMID- 25709708 TI - A Cistanches Herba Fraction/ beta -Sitosterol Causes a Redox-Sensitive Induction of Mitochondrial Uncoupling and Activation of Adenosine Monophosphate-Dependent Protein Kinase/Peroxisome Proliferator-Activated Receptor gamma Coactivator-1 in C2C12 Myotubes: A Possible Mechanism Underlying the Weight Reduction Effect. AB - Previous studies have demonstrated that HCF1, a semipurified fraction of Cistanches Herba, causes weight reduction in normal diet- and high fat diet-fed mice. The weight reduction was associated with the induction of mitochondrial uncoupling and changes in metabolic enzyme activities in mouse skeletal muscle. To further investigate the biochemical mechanism underlying the HCF1-induced weight reduction, the effect of HCF1 and its active component, beta-sitosterol (BSS), on C2C12 myotubes was examined. Incubation with HCF1/BSS caused a transient increase in mitochondrial membrane potential (MMP), possibly by fluidizing the mitochondrial inner membrane. The increase in MMP was paralleled to an increase in mitochondrial reactive oxygen species (ROS) production. Mitochondrial ROS, in turn, triggered a redox-sensitive induction of mitochondrial uncoupling by uncoupling protein 3 (UCP3). Biochemical analysis indicated that HCF1 was capable of activating an adenosine monophosphate dependent protein kinase/peroxisome proliferator-activated receptor gamma coactivator-1 pathway and thereby increased the expression of cytochrome c oxidase and UCP3. Animal studies using mitochondrial recoupler also confirmed the role of mitochondrial uncoupling in the HCF1-induced weight reduction. In conclusion, a HCF1/BSS causes the redox-sensitive induction of mitochondrial uncoupling and activation of AMPK/PGC-1 in C2C12 myotubes, with resultant reductions in body weight and adiposity by increased energy consumption. PMID- 25709709 TI - The Effects of Panax ginseng and Panax quinquefolius on Thermoregulation in Animal Models. AB - We devised a study using animal models of hyperthermia and hypothermia and also attempted to accurately assess the effects of Panax ginseng (PG) and Panax quinquefolius (PQ) on body temperature using these models. In addition, we investigated the effects of PG and PQ in our animal models in high and low temperature environments. The results of our experiments show that mice with normothermia, hyperthermia, and hypothermia maintained their body temperatures after a certain period in accordance with the condition of each animal model. In our experiments of body temperature change in models of normal, low, or high room temperature, the hyperthermic model did not show any body temperature change in either the PG- or PQ-administered group. In the normal and low room temperature models, the group administered PG maintained body temperature, while the body temperature of the PQ-administered group was lower than or similar to that of the control group. In conclusion, the fact that PG increases body temperature could not be verified until now. We also showed that the effect of maintaining body temperature in the PG-administered group was superior in a hypothermia-prone low temperature environment. PMID- 25709710 TI - Inhibition of Rat 5alpha-Reductase Activity and Testosterone-Induced Sebum Synthesis in Hamster Sebocytes by an Extract of Quercus acutissima Cortex. AB - Objective. Bokusoku (BK) is an extract from the Quercus cortex used in folk medicine for treatment of skin disorders and convergence, and is present in jumihaidokuto, a traditional Japanese medicine that is prescribed for purulent skin diseases like acne vulgaris. The excess of sebum production induced by androgen is involved in the development of acne. Our aim is to examine whether BK and its constituents inhibit testosterone metabolism and testosterone-induced sebum synthesis. Methods. Measurements of 5alpha-reductase activity and lipogenesis were performed using rat liver microsomes and hamster sebocytes, respectively. Results. BK dose-dependently reduced the conversion of testosterone to a more active androgen, dihydrotestosterone in a 5alpha-reductase enzymatic reaction. Twenty polyphenols in BK categorized as gallotannin, ellagitannin, and flavonoid were identified by LC-MS/MS. Nine polyphenols with gallate group, tetragalloyl glucose, pentagalloyl glucose, eugeniin, 1-desgalloyl eugeniin, casuarinin, castalagin, stenophyllanin C, (-)-epicatechin gallate, and (-) epigallocatechin gallate, inhibited testosterone metabolism. In particular, pentagalloyl glucose showed the strongest activity. BK and pentagalloyl glucose suppressed testosterone-induced lipogenesis, whereas they weakly inhibited the lipogenic action of insulin. Conclusions. BK inhibited androgen-related pathogenesis of acne, testosterone conversion, and sebum synthesis, partially through 5alpha-reductase inhibition, and has potential to be a useful agent in the therapeutic strategy of acne. PMID- 25709711 TI - Exploring the influence of the Global Fund and the GAVI Alliance on health systems in conflict-affected countries. AB - BACKGROUND: Global Health Initiatives (GHIs) respond to high-impact communicable diseases in resource-poor countries, including health systems support, and are major actors in global health. GHIs could play an important role in countries affected by armed conflict given these countries commonly have weak health systems and a high burden of communicable disease. The aim of this study is to explore the influence of two leading GHIs, the Global Fund and the GAVI Alliance, on the health systems of conflict-affected countries. METHODS: This study used an analytical review approach to identify evidence on the role of the Global Fund and the GAVI Alliance with regards to health systems support to 19 conflict affected countries. Primary and secondary published and grey literature were used, including country evaluations from the Global Fund and the GAVI Alliance. The WHO heath systems building blocks framework was used for the analysis. RESULTS: There is a limited evidence-base on the influence of GHIs on health systems of conflict-affected countries. The findings suggest that GHIs are increasingly investing in conflict-affected countries which has helped to rapidly scale up health services, strengthen human resources, improve procurement, and develop guidelines and protocols. Negative influences include distorting priorities within the health system, inequitable financing of disease-specific services over other health services, diverting staff away from more essential health care services, inadequate attention to capacity building, burdensome reporting requirements, and limited flexibility and responsiveness to the contextual challenges of conflict-affected countries. CONCLUSIONS: There is some evidence of increasing engagement of the Global Fund and the GAVI Alliance with health systems in conflict-affected countries, but this engagement should be supported by more context-specific policies and approaches. PMID- 25709712 TI - New steady-state microbial community compositions and process performances in biogas reactors induced by temperature disturbances. AB - BACKGROUND: The microbial community in a biogas reactor greatly influences the process performance. However, only the effects of deterministic factors (such as temperature and hydraulic retention time (HRT)) on the microbial community and performance have been investigated in biogas reactors. Little is known about the manner in which stochastic factors (for example, stochastic birth, death, colonization, and extinction) and disturbance affect the stable-state microbial community and reactor performances. RESULTS: In the present study, three replicate biogas reactors treating cattle manure were run to examine the role of stochastic factors and disturbance in shaping microbial communities. In the triplicate biogas reactors with the same inoculum and operational conditions, similar process performances and microbial community profiles were observed under steady-state conditions. This indicated that stochastic factors had a minor role in shaping the profile of the microbial community composition and activity in biogas reactors. On the contrary, temperature disturbance was found to play an important role in the microbial community composition as well as process performance for biogas reactors. Although three different temperature disturbances were applied to each biogas reactor, the increased methane yields (around 10% higher) and decreased volatile fatty acids (VFAs) concentrations at steady state were found in all three reactors after the temperature disturbances. After the temperature disturbance, the biogas reactors were brought back to the original operational conditions; however, new steady-state microbial community profiles were observed in all the biogas reactors. CONCLUSIONS: The present study demonstrated that temperature disturbance, but not stochastic factors, played an important role in shaping the profile of the microbial community composition and activity in biogas reactors. New steady-state microbial community profiles and reactor performances were observed in all the biogas reactors after the temperature disturbance. PMID- 25709713 TI - Comparative analysis of sugarcane bagasse metagenome reveals unique and conserved biomass-degrading enzymes among lignocellulolytic microbial communities. AB - BACKGROUND: As one of the most abundant agricultural wastes, sugarcane bagasse is largely under-exploited, but it possesses a great potential for the biofuel, fermentation, and cellulosic biorefinery industries. It also provides a unique ecological niche, as the microbes in this lignocellulose-rich environment thrive in relatively high temperatures (50 degrees C) with varying microenvironments of aerobic surface to anoxic interior. The microbial community in bagasse thus presents a good resource for the discovery and characterization of new biomass degrading enzymes; however, it remains largely unexplored. RESULTS: We have constructed a fosmid library of sugarcane bagasse and obtained the largest bagasse metagenome to date. A taxonomic classification of the bagasse metagenome reviews the predominance of Proteobacteria, which are also found in high abundance in other aerobic environments. Based on the functional characterization of biomass-degrading enzymes, we have demonstrated that the bagasse microbial community benefits from a large repertoire of lignocellulolytic enzymes, which allows them to digest different components of lignocelluoses into single molecule sugars. Comparative genomic analyses with other lignocellulolytic and non lignocellulolytic metagenomes show that microbial communities are taxonomically separable by their aerobic "open" or anoxic "closed" environments. Importantly, a functional analysis of lignocellulose-active genes (based on the CAZy classifications) reveals core enzymes highly conserved within the lignocellulolytic group, regardless of their taxonomic compositions. Cellulases, in particular, are markedly more pronounced compared to the non-lignocellulolytic group. In addition to the core enzymes, the bagasse fosmid library also contains some uniquely enriched glycoside hydrolases, as well as a large repertoire of the newly defined auxiliary activity proteins. CONCLUSIONS: Our study demonstrates a conservation and diversification of carbohydrate-active genes among diverse microbial species in different biomass-degrading niches, and signifies the importance of taking a global approach to functionally investigate a microbial community as a whole, as compared to focusing on individual organisms. PMID- 25709714 TI - Bioenergy and African transformation. AB - Among the world's continents, Africa has the highest incidence of food insecurity and poverty and the highest rates of population growth. Yet Africa also has the most arable land, the lowest crop yields, and by far the most plentiful land resources relative to energy demand. It is thus of interest to examine the potential of expanded modern bioenergy production in Africa. Here we consider bioenergy as an enabler for development, and provide an overview of modern bioenergy technologies with a comment on application in an Africa context. Experience with bioenergy in Africa offers evidence of social benefits and also some important lessons. In Brazil, social development, agricultural development and food security, and bioenergy development have been synergistic rather than antagonistic. Realizing similar success in African countries will require clear vision, good governance, and adaptation of technologies, knowledge, and business models to myriad local circumstances. Strategies for integrated production of food crops, livestock, and bioenergy are potentially attractive and offer an alternative to an agricultural model featuring specialized land use. If done thoughtfully, there is considerable evidence that food security and economic development in Africa can be addressed more effectively with modern bioenergy than without it. Modern bioenergy can be an agent of African transformation, with potential social benefits accruing to multiple sectors and extending well beyond energy supply per se. Potential negative impacts also cut across sectors. Thus, institutionally inclusive multi-sector legislative structures will be more effective at maximizing the social benefits of bioenergy compared to institutionally exclusive, single-sector structures. PMID- 25709715 TI - High titer and yield ethanol production from undetoxified whole slurry of Douglas fir forest residue using pH profiling in SPORL. AB - BACKGROUND: Forest residue is one of the most cost-effective feedstock for biofuel production. It has relatively high bulk density and can be harvested year round, advantageous for reducing transportation cost and eliminating onsite storage. However, forest residues, especially those from softwood species, are highly recalcitrant to biochemical conversion. A severe pretreatment for removing this recalcitrance can result in increased sugar degradation to inhibitors and hence cause difficulties in fermentation at high solid loadings. Here, we presented high titer ethanol production from Douglas-fir forest residue without detoxification. The strong recalcitrance of the Douglas-fir residue was removed by sulfite pretreatment to overcome the recalcitrance of lignocelluloses (SPORL). Sugar degradation to inhibitors was substantially reduced using a novel approach of "pH profiling" by delaying acid application in pretreatment, which facilitated the simultaneous enzymatic saccharification and fermentation of undetoxified whole slurry at a solid loading of 21%. RESULTS: "pH profiling" reduced furan production by approximately 70% in using SPORL pretreating Douglas-fir forest residue (FS-10) comparing with the control run while without sacrificing enzymatic saccharification of the resultant substrate. pH profiling also reduced carbohydrate degradation. The improved carbohydrate yield in pretreated solids and reduced fermentation inhibitors with pH profiling resulted in a terminal ethanol titer of 48.9 +/- 1.4 g/L and yield of 297 +/- 9 L/tonne FS-10, which are substantially higher, i.e., by 27% in titer and by 38% in yield, than those of a control SPORL run without pH profiling. CONCLUSIONS: Economical and large-volume production of commodity biofuels requires the utilization of feedstocks with low value (therefore low cost) and sustainably producible in large quantities, such as forest residues. However, most existing pretreatment technologies cannot remove the strong recalcitrance of forest residues to produce practically fermentable high titer sugars. Here, we demonstrated a commercially scalable and efficient technology capable of removing the strong recalcitrant nature of forest residues using "pH profiling" together with "low temperature SPORL". The resultant pretreated whole slurry of a Douglas-fir forest residue using this technology can be easily processed at high solids of 21% without detoxification to achieve a high ethanol yield of 297 L/tonne at 48.9 g/L. Graphical AbstractGraphic table of content. PMID- 25709716 TI - Needle loss in subclavian vein during central venous catheter placement: case report of a rare complication. AB - We present a case of needle separation during central venous catheter (CVC) placement in a super morbidly obese patient with subsequent surgical intervention in its retrieval. This complication, potentially lethal due to the relevant anatomy of such a procedure, alerts critical care physicians and surgeons to the possibility of equipment failure and stresses proper technique in what has become a routine procedure. It also emphasizes the routine use of ultrasound-guidance for cannulation in patients of any body habitus. While infection and arrhythmia are the generally known complications of CVC placement, clinicians must be alert to unanticipated events such as needle separation. In our case, the retrieval of this needle required multi-disciplinary intervention between radiology, critical care, vascular surgery, and thoracic surgery. Our event stresses hypervigilance to complications in a common procedure. PMID- 25709718 TI - Separating the microbiome from the hyperbolome. AB - Microbiome-based therapies are moving quickly towards the clinic, with successes including fecal microbial transplants for recurring Clostridium difficile, hints of new antibiotics to come, and possible new microbial biomarkers for common complex diseases. Can the microbiome live up to its hype? PMID- 25709717 TI - Rare variant association studies: considerations, challenges and opportunities. AB - Genome-wide association studies (GWASs) have successfully uncovered thousands of robust associations between common variants and complex traits and diseases. Despite these successes, much of the heritability of these traits remains unexplained. Because low-frequency and rare variants are not tagged by conventional genome-wide genotyping arrays, they may represent an important and understudied component of complex trait genetics. In contrast to common variant GWASs, there are many different types of study designs, assays and analytic techniques that can be utilized for rare variant association studies (RVASs). In this review, we briefly present the different technologies available to identify rare genetic variants, including novel exome arrays. We also compare the different study designs for RVASs and argue that the best design will likely be phenotype-dependent. We discuss the main analytical issues relevant to RVASs, including the different statistical methods that can be used to test genetic associations with rare variants and the various bioinformatic approaches to predicting in silico biological functions for variants. Finally, we describe recent rare variant association findings, highlighting the unexpected conclusion that most rare variants have modest-to-small effect sizes on phenotypic variation. This observation has major implications for our understanding of the genetic architecture of complex traits in the context of the unexplained heritability challenge. PMID- 25709719 TI - Clinical pharmacology of paracetamol in neonates: a review. AB - Paracetamol is commonly used to control mild-to-moderate pain or to reduce opioid exposure as part of multimodal analgesia, and is the only compound recommended to treat fever in neonates. Paracetamol clearance is lower in neonates than in children and adults. After metabolic conversion, paracetamol is subsequently eliminated by the renal route. The main metabolic conversions are conjugation with glucuronic acid and with sulphate. In the urine of neonates sulphated paracetamol concentration is higher than the glucuronidated paracetamol level, suggesting that sulfation prevails over glucuronidation in neonates. A loading dose of 20 mg/kg followed by 10 mg/kg every 6 hours of intravenous paracetamol is suggested to achieve a compartment concentration of 11 mg/L in late preterm and term neonates. Aiming for the same target concentration, oral doses are similar with rectal administration of 25 to 30 mg/kg/d in preterm neonates of 30 weeks' gestation, 45 mg/kg/d in preterm infants of 34 weeks' gestation, and 60 mg/kg/d in term neonates are suggested. The above-mentioned paracetamol doses for these indications (pain, fever) are well tolerated in neonates, but do not result in a significant increase in liver enzymes, and do not affect blood pressure and have limited effects on heart rate. In contrast, the higher doses suggested in extreme preterm neonates to induce closure of the patent ductus arteriosus have not yet been sufficiently evaluated regarding efficacy or safety. Moreover, focussed pharmacovigilance to explore the potential causal association between paracetamol exposure during perinatal life and infancy and subsequent atopy is warranted. PMID- 25709720 TI - The influence of ethnicity on warfarin dosage requirements in the chilean population. AB - BACKGROUND: Vitamin K antagonists are drugs that are widely prescribed around the world and their use has helped improve the prognosis of patients with thromboembolic disease. However, a high interindividual variability has been observed in dosage requirements to reach the desired anticoagulation range that could be due to environmental and genetic factors. Studies suggest that ethnicity influences coumarin response, supporting the observed differences in dose requirements across various populations. Studies using mitochondrial DNA (mtDNA) markers have suggested that the Chilean population has a predominantly Amerindian genetic pool. OBJECTIVE: To evaluate the influence of ethnicity, defined by the presence of Amerindian mtDNA haplogroups, on the variability in therapeutic response to warfarin in the Chilean population. METHODS: A total of 191 patients treated with warfarin were included in this study. Analysis of the mitochondrial genome for detecting the presence of Amerindian mtDNA haplogroups was performed using polymerase chain reaction and polymerase chain reaction restriction fragment length polymorphism techniques. The evaluation of warfarin requirements according to each haplogroup was performed by ANOVA with a 95% CI and assuming statistical significance at P < 0.05. RESULTS: Based on the presence of an mtDNA haplogroup, 91% of the Chilean population had an Amerindian background. There were no significant differences in warfarin dosage requirements among the different Amerindian haplogroups (P = 0.083). CONCLUSIONS: The presence of Amerindian mtDNA haplogroup does not influence warfarin dosage requirements in the Chilean population. PMID- 25709721 TI - [Very rare association: femoral shaft fracture associated with ipsilateral Hoffa fracture]. PMID- 25709722 TI - [Intestinal hemangioma: an unusual cause of unexplained gastrointestinal bleeding, a case report]. PMID- 25709723 TI - [Extensive bilateral chorioretinitis revealing human immunodeficiency virus (HIV) infection]. PMID- 25709724 TI - [Myxoid primitive liposarcoma of the middle mediastinum]. PMID- 25709725 TI - Nail dystrophy: a rare sign of sarcoidosis. PMID- 25709726 TI - [Interventricular communication following myocardial infarction: surgical repair]. PMID- 25709728 TI - [Adjuvant chemoradiotherapy in gastric adenocarcinoma: about 34 cases and review of the literature]. PMID- 25709727 TI - Genotypes and subtypes of hepatitis C virus in Burundi: a particularity in sub Saharan Africa. AB - INTRODUCTION: Hepatitis C virus (HCV) infection is a major public health issue. HCV genotype identification is clinically important to tailor the dosage and duration of treatment. Indeed, distinct therapeutic approaches are required for each genotype. Up to now, there is no study assessing HCV genotypes and subtypes in Burundi. The aim of the study was to determine HCV genotypes and subtypes in Burundi and to highlight the difficulties related to LiPA Method, widely used for African samples. METHODS: In this study, a total of 179 samples contained anti HCV antibodies were tested for HCV RNA, genotyping and subtyping. The analysis had been made in Cerba laboratory, Paris, France. RESULTS: 166 patients (92.7%) were genotype 4; 10 patients (5.6%) were genotype 1 and 3 patients (1.7%) were genotype 3. It was possible to determine subtypes for 51 HCV-4 (30.7%) patients. Among these, 25 (49.1%) had 4h subtype; 11 (21.6%) had 4e subtype; 2 (3.9%) had 4k subtype and 13 patients (25.5%) had 4a/4c/4d subtype. The LiPA method failed to subtype 115 (69.3%) HCV-4 and to separate the three subtype: 4a, 4c and 4d. CONCLUSION: Genotype 4 and subtype 4h followed by 4e are the widespread in Burundi. PMID- 25709729 TI - [Sickle cell disease in stationary phase in 6-59 months children in Lubumbashi: epidemiology and clinical features]. PMID- 25709730 TI - Postpriapism erectile dysfunction and shunt-related urethral stricture: long-term morbidity after proximal shunt for ischaemic priapism. AB - Recent guidelines have advocated for step-wise treatment of increasing invasiveness in the management of ischaemic priapism though with low-level evidences. In the past, proximal shunts were favoured as first-line treatment. We present an African man who had proximal shunt (cavernoso-spongiosal) three decades ago for ischaemic priapism and subsequently had long-term morbidity over the three decades with adverse effect on his quality of life. Recent guidelines appear to be sound despite their limitations and more invasive cavernoso spongiosal shunts may be associated with significant long-term morbidities and poor quality of life. PMID- 25709731 TI - Non traumatic cataract dislocation: when to seek an etiology? PMID- 25709732 TI - [Relapsing uterine leiomyosarcoma: report of a case]. PMID- 25709733 TI - [Rhabdomyosarcoma or inflammatory pseudotumor]. PMID- 25709734 TI - [A rare cause of non discal sciatica: rheumatoid arthritis]. PMID- 25709735 TI - [Surgical decompression of a thoracic outlet syndrome]. PMID- 25709736 TI - [Pseudotumoral AL amyloidosis of the lymph node]. PMID- 25709737 TI - [Best juvenile macular dystrophy]. PMID- 25709738 TI - [Basal cell basal cell epithelioma of the face: surgical management, about 45 cases and review of the literature]. PMID- 25709739 TI - [Unilateral polyostotic fibrous dysplasia of the upper limb]. PMID- 25709740 TI - [Black tumor of the nasal pyramid]. PMID- 25709741 TI - Symptomatic infantile Helicobacter pylori gastritis infection in indigenous African infants: a case series. AB - Helicobacter pylori gastritis infection rate increases with age. Higher rates have however been reported among young people in the developing countries of the world. The infection however has rarely been reported in infants, especially in Africa. This case series describes three cases of Helicobacter pylori gastritis infection as diagnosed in three infants. The goal is to raise the suspicion index of medical practitioners about the possibility of this this infection among infants who present with suggestive symptoms. On three separate occasions in 2012 and 2013, three ill, indigenous, black African female infants aged 4, 6 and 7 months, were brought to hospital with symptoms ranging from fever, refusal to feed, diarrhoea, restlessness, vomiting and irritability. In each case, systemic examination findings were unremarkable. After several laboratory investigations, each infant was found to have Helicobacter pylori infection following positive blood antibody (using Tell Me Fast H. Pylori antibody serum and Plasma test manufactured by Biocan Diagnostics Canada) and fecal HpSA ImmunoCardSTAT antigen tests. Repeat stool antigen test was negative in each case after completion of the recommended triple therapy. Helicobacter pylori infection has been rarely reported among infants. This case series highlights the need for health care providers to have a high index of suspicion so that infants with suggestive symptoms, especially in settings with high Helicobacter pylori colonization prevalence can be evaluated for Helicobacter pylori gastritis infection. PMID- 25709742 TI - [Methotrexate and psoriasis: about 46 cases]. PMID- 25709743 TI - Use of new technology to improve utilization and adherence to immunotherapy. AB - Technology and social media have dramatically altered the landscape in which we practice medicine. Clinicians have increasingly turned to technology and the internet to enhance patient care. Allergists have used these modalities to improve utilization and adherence to immunotherapy. Electronic medical records (EMRs) are being widely adopted by allergy practices and some offer allergy/immunology specific modules that aid in daily workflow. The development of specialized devices that reduce pain associated with immunotherapy administration may improve compliance with immunotherapy. Social media and other forms of electronic communication such as e-mail, Facebook, Twitter, short message service (SMS), and YouTube give clinicians multiple avenues to disseminate information and reach their patients, possibly improving patient adherence to therapy. Finally, tablet computers, online networks, and electronic surveys provide additional ways to connect patients and physicians. PMID- 25709744 TI - Anti-IL5 therapy for asthma and beyond. AB - Airway inflammation is considered to be the primary component contributing to the heterogeneity and severity of airway disorders. Therapeutic efficacies of diverse novel biologics targeting the inflammatory pathways are under investigation. One such target is IL-5, a type-1 cytokine that is central to the initiation and sustenance of eosinophilic airway inflammation. Over the past decade, anti-IL5 molecules have been documented to have mixed therapeutic benefits in asthmatics. Post hoc analyses of the trials reiterate the importance of identifying the IL-5 responsive patient endotypes. In fact, the currently available anti-IL5 treatments are being considered beyond asthma management; especially in clinical complications with an underlying eosinophilic pathobiology such as hypereosinophilic syndrome (HES) and eosinophilic granulomatosis and polyangitis (EGPA). In addition, closer analyses of the available data indicate alternative mechanisms of tissue eosinophilia that remain uncurbed with the current dosage and delivery platform of the anti-IL5 molecules. PMID- 25709745 TI - Oral and sublingual immunotherapy for food allergy. AB - IgE-mediated food allergy is a potentially life-threatening allergic disease with an increase in prevalence in developed countries over the past 15 years. Currently, there are no approved forms of therapy and the standard of care is dietary restriction and ready access to emergency medications, such as self injectable epinephrine and antihistamines. Allergen-specific modalities of treatment currently being studied include oral immunotherapy (OIT) and sublingual immunotherapy (SLIT). Both forms demonstrate the ability to desensitize patients to a variety of specific food allergens and show great promise. However, more research is needed to evaluate the safety and efficacy of OIT and SLIT prior to routine use in clinical practice. PMID- 25709746 TI - A novel rapid (20-minute) IL-6 release assay using blood mononuclear cells of patients with various clinical forms of drug induced skin injuries. AB - BACKGROUND: IL-6 is a pro-inflammatory cytokine which has many well-defined effects. Its synthesis and release from mononuclear cells of drug-sensitized patients was related before to in vitro drug-allergy diagnostics but has not yet been studied in detail. METHODS: The specific release of preformed IL-6 from peripheral blood mononuclear cells (PBMC) after 20 minutes incubation with 0.15 0.5 MUM of pure drugs was measured in two groups of drug-allergy suspected donors (159) and respective controls (48). IL-6, TNF-alpha, IL-2, IL-4, IFN-gamma have been measured from cell supernatants by ELISA or by cytometric bead assay. Epicutaneous, intradermal and systemic provocation tests were performed to prove or disprove culprit substances (203 in vivo against 482 in vitro tests). T-test (paired and unpaired); chi2 contingency table; Z statistics and McNemar's test were used to evaluate results. RESULTS: Concanavalin A as positive control released IL-6 from PBMC in linear concentration and exponential time dependent fashion (up to 60 minutes) pointing to the existence of a preformed pool of this cytokine. Preformed IL-6 released at any of 4 standard drug dilutions tested, above 50% over their diluents' levels significantly correlated with the patients' history on drug-induced hypersensitivity symptoms and with in vivo tests. Sensitivity of 85.4% and specificity of 82.4% of the IL-6 release assay were found. The 20' drop in release of TNF-alpha had no diagnostic importance; it has accompanied increased IL-6 release. IL-2, IL-4 and IFN-gamma were undetectable in 20 minutes supernatants. IL-6 release depended on the clinical phenotype but not on the eliciting drug(s) in the molecular mass range of 76-4000 Da. Reactivity of mononuclear cells at the lowest or at multiple drug test concentrations reflected clinical severity per diagnoses and according to area of skin involvement. CONCLUSION: This rapid test is applicable to detect a wide scale of drug hypersensitivity. PMID- 25709749 TI - Spontaneous Bone Healing after Cysts Enucleation without Bone Grafting Materials: A Randomized Clinical Study. AB - The aim of this study was to evaluate spontaneous bone regeneration after cysts enucleation of the jaws without the use of bone grafting materials. We included 18 patients at random (11 men and 7 women) with a mean age of 31.8 years, with jaw cysts treated by enucleation, without the use of grafting materials. A method of measurements to assess the percentage of reduction of the bone cavities was used to objectify the results. The patients were evaluated before and at least 6 months after surgery, with radiographic scans based on linear measures with a computerized method using Nemoceph program (Nemotec, NemoCeph Software, Madrid, Espana). The analysis of the sample shows an average of 85.59% decrease in horizontal measures, 89.53% in the vertical, and 88.98 and 89.81% in the diagonal left and right, respectively. The total average reduction was 88.47%. It showed a greater decrease in vertical and diagonal measurements with respect to horizontal. Regeneration in 12 patients was 100% and in 6 patients was higher at 50.4%. Bone density increased in the postoperative radiographs. The results suggest that in some cases, spontaneous bone regeneration can be achieved by cysts enucleation without bone grafting materials. PMID- 25709748 TI - Facial nerve trauma: evaluation and considerations in management. AB - The management of facial paralysis continues to evolve. Understanding the facial nerve anatomy and the different methods of evaluating the degree of facial nerve injury are crucial for successful management. When the facial nerve is transected, direct coaptation leads to the best outcome, followed by interpositional nerve grafting. In cases where motor end plates are still intact but a primary repair or graft is not feasible, a nerve transfer should be employed. When complete muscle atrophy has occurred, regional muscle transfer or free flap reconstruction is an option. When dynamic reanimation cannot be undertaken, static procedures offer some benefit. Adjunctive tools such as botulinum toxin injection and biofeedback can be helpful. Several new treatment modalities lie on the horizon which hold potential to alter the current treatment algorithm. PMID- 25709750 TI - Current concepts of bone tissue engineering for craniofacial bone defect repair. AB - Craniofacial fractures and bony defects are common causes of morbidity and contribute to increasing health care costs. Successful regeneration of bone requires the concomitant processes of osteogenesis and neovascularization. Current methods of repair and reconstruction include rigid fixation, grafting, and free tissue transfer. However, these methods carry innate complications, including plate extrusion, nonunion, graft/flap failure, and donor site morbidity. Recent research efforts have focused on using stem cells and synthetic scaffolds to heal critical-sized bone defects similar to those sustained from traumatic injury or ablative oncologic surgery. Growth factors can be used to augment both osteogenesis and neovascularization across these defects. Many different growth factor delivery techniques and scaffold compositions have been explored yet none have emerged as the universally accepted standard. In this review, we will discuss the recent literature regarding the use of stem cells, growth factors, and synthetic scaffolds as alternative methods of craniofacial fracture repair. PMID- 25709752 TI - Versatility of subscapular chimeric free flaps in the secondary reconstruction of composite posttraumatic defects of the upper face. AB - High energy injuries to the upper face present challenging reconstructive problems. In some cases, initial reconstructive efforts result in unfavorable outcomes that require secondary intervention. Chimeric free flaps based on the subscapular system offer the tissue components and volume needed for these complex reconstructions. This is a series of five patients who underwent secondary reconstruction of the middle and upper face following traumatic injury. Mechanism of injury, prior attempts at reconstruction, and characteristics of the tissue defects and the flaps used in their reconstruction are described. Two patients were female and three were male. Three injuries resulted from gunshot wounds, and two from motor vehicle accidents. All patients had multiple prior failed attempts at reconstruction using local/regional tissue. Defects included symptomatic oronasal or oro-orbital fistulas, enophthalmos, and forehead contour deformities. Two of the flaps used included scapular bone and latissimus muscular components, and three included scapular bone and thoracodorsal artery perforator based skin paddle components. All free tissue transfers were successful, and no patients suffered significant complications. Chimeric free flaps based on the subscapular system offer a valuable secondary strategy for reconstruction of composite defects of the upper face when other options have been exhausted through previous efforts. PMID- 25709751 TI - Traumatic optic neuropathy: a review. AB - The aim of this article is to evaluate current literature on investigation and management of traumatic optic neuropathy (TON), propose recommendations for diagnosis and management, and explore novel future treatments. TON, though uncommon, causes substantial visual loss. Without clear guidelines, there is much ambiguity regarding its diagnosis and management. Investigation and treatment (conservative, medical, surgical, and combined) vary widely between centers. Electronic databases PubMed, MEDLINE, PROSPERO, CENTRAL, and EMBASE were searched for content that matched "Traumatic optic neuropathy." Articles with abstracts and full text available, published in the past 10 years, written English and limited to human adults, were selected. All study designs were acceptable except case reports and case series with fewer 10 patients. All abstracts were then evaluated for relevance. References of these studies were evaluated and if also relevant, included. A total of 2,686 articles were retrieved and 43 examined for relevance. Of these, 23 articles were included. TON is a clinical diagnosis. Visual-evoked potential is useful in diagnosis and prognosis. Computed tomography demonstrates canal fractures and concomitant injuries. Magnetic resonance images should be reserved for select and stable patients. Conservative treatment is appropriate in mild TON. Steroids are of questionable benefit and may be harmful. Surgery should be reserved for patients with radiological evidence of compression and individualized. PMID- 25709753 TI - Updates on the epidemiology and pattern of traumatic maxillofacial injuries in a nigerian university teaching hospital: a 12-month prospective cohort in-hospital outcome study. AB - Many studies have been undertaken in Nigeria on maxillofacial trauma. However, only a few have considered both the skeletal and soft tissue injuries (in general) involving all the aspects of the maxillofacial region or considered other etiological sources of trauma apart from road traffic crashes. Fewer still have reviewed the outcome of management of facial injuries in our low-resource environment. This study sets out to examine the recent trends in both the clinical and epidemiological patterns of all facial injuries from all causes seen in a low-resource practice of a developing country. It also assessed the in hospital treatment outcomes, and the levels of the patients' satisfaction with treatment received in this setting. Over a 12-month period, the clinical records of consecutive patients who were evaluated and treated for maxillofacial injuries in our unit were prospectively acquired, entered into predesigned forms and subsequently analyzed. There were 259 patients (79.5% males) during the study period. The mean age was 32.21( +/- 16.588) years. Overall, motor bike crashes, 42.1%, were the commonest source of these traumas; and armed robbery was the commonest form (69.0%) of assault. Mandibular fractures were the commonest maxillofacial fractures (37.8%) whereas head injury had the highest frequency among the associated injuries (71.4%). Closed reduction and immobilization was deployed in 88.0% of those who had treatment and majority was satisfied with the esthetic outcome of the treatment received. Mean length of hospital stay was 12.6 ( +/- 4.423) days. Maxillofacial trauma poses a significant socioeconomic burden on affected individuals in this study population. This is made worse by the presence of associated injuries in the other body systems. More local studies on the outcome of management of maxillofacial trauma will improve the available literature in this region. PMID- 25709754 TI - Mandibular fractures in iraq: an epidemiological study. AB - The purpose of this study was to evaluate the epidemiological characteristics of the mandibular fractures relating to gender, age, the etiology of injury, and the rendered treatment modalities and complications. The data of the patients who sustained mandibular fractures were retrieved and were analyzed retrospectively, and based on these data a descriptive analysis was conducted. A total of 112 patients were included in this study; the most common cause was road traffic accidents (RTAs) followed by assaults and missile injuries. The most frequently involved age group was 11 to 20 years, treatment modalities included conservative, closed reduction and indirect fixation, and open reduction and internal fixation (ORIF) in 11.6, 79.5, and 8.9% of the cases, respectively. Most of the major complications were injury related. This study showed RTAs to be the most frequent cause followed by assaults, it also showed that a high percentage of assault victims were females mainly of low socioeconomic status. Another distinguishing feature in this study was the high incidence of missile injuries in the form of bullets and blasts. Closed reduction still has an important role in the treatment of fractures of mandible especially when the necessary equipments for ORIF are not readily available. A higher complication rate was observed in patients diagnosed with multiple and comminuted fractures as well as those caused by violence in the form of missile and assault injuries. PMID- 25709755 TI - Antibiotics and facial fractures: evidence-based recommendations compared with experience-based practice. AB - Efficacy of prophylactic antibiotics in craniofacial fracture management is controversial. The purpose of this study was to compare evidence-based literature recommendations regarding antibiotic prophylaxis in facial fracture management with expert-based practice. A systematic review of the literature was performed to identify published studies evaluating pre-, peri-, and postoperative efficacy of antibiotics in facial fracture management by facial third. Study level of evidence was assessed according to the American Society of Plastic Surgery criteria, and graded practice recommendations were made based on these assessments. Expert opinions were garnered during the Advanced Orbital Surgery Symposium in the form of surveys evaluating senior surgeon clinical antibiotic prescribing practices by time point and facial third. A total of 44 studies addressing antibiotic prophylaxis and facial fracture management were identified. Overall, studies were of poor quality, precluding formal quantitative analysis. Studies supported the use of perioperative antibiotics in all facial thirds, and preoperative antibiotics in comminuted mandible fractures. Postoperative antibiotics were not supported in any facial third. Survey respondents (n = 17) cumulatively reported their antibiotic prescribing practices over 286 practice years and 24,012 facial fracture cases. Percentages of prescribers administering pre-, intra-, and postoperative antibiotics, respectively, by facial third were as follows: upper face 47.1, 94.1, 70.6; midface 47.1, 100, 70.6%; and mandible 68.8, 94.1, 64.7%. Preoperative but not postoperative antibiotic use is recommended for comminuted mandible fractures. Frequent use of pre- and postoperative antibiotics in upper and midface fractures is not supported by literature recommendations, but with low-level evidence. Higher level studies may better guide clinical antibiotic prescribing practices. PMID- 25709756 TI - An interesting case of gunshot injury to the temporomandibular joint. AB - The head and face are relatively common sites of gunshot injury, and the temporomandibular joint is often affected. These wounds usually produce major deformity and functional impairment, particularly when the temporomandibular joint is affected or when structures such as the facial nerve are damaged. Complications may include mandibular displacement at maximum mouth opening and in protrusion, limited mouth opening, limited lateral movement of the jaw, anterior open bite, and, more rarely, temporomandibular ankylosis. Projectiles that strike the mandible usually cause comminuted fractures; maxillary wounds, in turn, are most commonly perforating. The present report describes a case of gunshot injury in which the projectile lodged within the mandibular fossa but did not cause any fractures. Oral and maxillofacial trauma surgeons must be aware of the different types of gunshot injury, as they produce distinct patterns of tissue destruction due to projectile trajectory and release of kinetic energy into surrounding tissue. PMID- 25709757 TI - A computational design approach for virtual screening of peptide interactions across K(+) channel families. AB - Ion channels represent a large family of membrane proteins with many being well established targets in pharmacotherapy. The 'druggability' of heteromeric channels comprised of different subunits remains obscure, due largely to a lack of channel-specific probes necessary to delineate their therapeutic potential in vivo. Our initial studies reported here, investigated the family of inwardly rectifying potassium (Kir) channels given the availability of high resolution crystal structures for the eukaryotic constitutively active Kir2.2 channel. We describe a 'limited' homology modeling approach that can yield chimeric Kir channels having an outer vestibule structure representing nearly any known vertebrate or invertebrate channel. These computationally-derived channel structures were tested ""in silico for 'docking' to NMR structures of tertiapin (TPN), a 21 amino acid peptide found in bee venom. TPN is a highly selective and potent blocker for the epithelial rat Kir1.1 channel, but does not block human or zebrafish Kir1.1 channel isoforms. Our Kir1.1 channel-TPN docking experiments recapitulated published in vitro ""findings for TPN-sensitive and TPN-insensitive channels. Additionally, in silico site-directed mutagenesis identified 'hot spots' within the channel outer vestibule that mediate energetically favorable docking scores and correlate with sites previously identified with in vitro thermodynamic mutant-cycle analysis. These 'proof-of-principle' results establish a framework for virtual screening of re-engineered peptide toxins for interactions with computationally derived Kir channels that currently lack channel-specific blockers. When coupled with electrophysiological validation, this virtual screening approach may accelerate the drug discovery process, and can be readily applied to other ion channels families where high resolution structures are available. PMID- 25709759 TI - Graft versus host disease: New insights into A2A receptor agonist therapy. AB - Allogeneic transplantation can cure many disorders, including sickle cell disease, chronic granulomatous disease (CGD), severe combined immunodeficiency (SCID) and many types of cancers. However, there are several associated risks that can result in severe immunological reactions and, in some cases, death. Much of this morbidity is related to graft versus host disease (GVHD) [1]. GVHD is an immune mediated reaction in which donor T cells recognize the host as antigenically foreign, causing donor T cells to expand and attack host tissues. The current method of treating recent transplant patients with immunosuppressants to prevent this reaction has met with only partial success, emphasizing a need for new methods of GVHD treatment and prevention. Recently, a novel strategy has emerged targeting adenosine A2A receptors (A2AR) through the use of adenosine agonists. These agonists have been shown in vitro to increase the TGFbeta-induced generation of FoxP3(+) regulatory T cells (Tregs) and in vivo to improve weight gain and mortality as well as inhibit the release of pro-inflammatory cytokines in GVHD murine models [2,3]. Positive results involving A2AR agonists in vitro and in vivo are promising, suggesting that A2AR agonists should be a part of the management of clinical GvHD. PMID- 25709758 TI - Tissue-nonspecific Alkaline Phosphatase Regulates Purinergic Transmission in the Central Nervous System During Development and Disease. AB - Tissue-nonspecific alkaline phosphatase (TNAP) is one of the four isozymes in humans and mice that have the capacity to hydrolyze phosphate groups from a wide spectrum of physiological substrates. Among these, TNAP degrades substrates implicated in neurotransmission. Transgenic mice lacking TNAP activity display the characteristic skeletal and dental phenotype of infantile hypophosphatasia, as well as spontaneous epileptic seizures and die around 10 days after birth. This physiopathology, linked to the expression pattern of TNAP in the central nervous system (CNS) during embryonic stages, suggests an important role for TNAP in neuronal development and synaptic function, situating it as a good target to be explored for the treatment of neurological diseases. In this review, we will focus mainly on the role that TNAP plays as an ectonucleotidase in CNS regulating the levels of extracellular ATP and consequently purinergic signaling. PMID- 25709760 TI - Purinergic control of inflammation and thrombosis: Role of P2X1 receptors. AB - Inflammation shifts the hemostatic mechanisms in favor of thrombosis. Upon tissue damage or infection, a sudden increase of extracellular ATP occurs, that might contribute to the crosstalk between inflammation and thrombosis. On platelets, P2X1 receptors act to amplify platelet activation and aggregation induced by other platelet agonists. These receptors critically contribute to thrombus stability in small arteries. Besides platelets, studies by our group indicate that these receptors are expressed by neutrophils. They promote neutrophil chemotaxis, both in vitro and in vivo. In a laser-induced injury mouse model of thrombosis, it appears that neutrophils are required to initiate thrombus formation and coagulation activation on inflamed arteriolar endothelia. In this model, by using P2X1-/ - mice, we recently showed that P2X1 receptors, expressed on platelets and neutrophils, play a key role in thrombus growth and fibrin generation. Intriguingly, in a model of endotoxemia, P2X1-/ - mice exhibited aggravated oxidative tissue damage, along with exacerbated thrombocytopenia and increased activation of coagulation, which translated into higher susceptibility to septic shock. Thus, besides its ability to recruit neutrophils and platelets on inflamed endothelia, the P2X1 receptor also contributes to limit the activation of circulating neutrophils under systemic inflammatory conditions. Taken together, these data suggest that P2X1 receptors are involved in the interplay between platelets, neutrophils and thrombosis. We propose that activation of these receptors by ATP on neutrophils and platelets represents a new mechanism that regulates thrombo-inflammation. PMID- 25709761 TI - What can we learn from molecular dynamics simulations for GPCR drug design? AB - Recent years have seen a tremendous progress in the elucidation of experimental structural information for G-protein coupled receptors (GPCRs). Although for the vast majority of pharmaceutically relevant GPCRs structural information is still accessible only by homology models the steadily increasing amount of structural information fosters the application of structure-based drug design tools for this important class of drug targets. In this article we focus on the application of molecular dynamics (MD) simulations in GPCR drug discovery programs. Typical application scenarios of MD simulations and their scope and limitations will be described on the basis of two selected case studies, namely the binding of small molecule antagonists to the human CC chemokine receptor 3 (CCR3) and a detailed investigation of the interplay between receptor dynamics and solvation for the binding of small molecules to the human muscarinic acetylcholine receptor 3 (hM3R). PMID- 25709762 TI - Choroidal Neovascularization Induces Retinal Edema and its Treatment Addresses this Problem. PMID- 25709763 TI - Transplantation of Autologous Ex Vivo Expanded Human Conjunctival Epithelial Cells for Treatment of Pterygia: A Prospective Open-label Single Arm Multicentric Clinical Trial. AB - PURPOSE: To establish the efficacy and safety of ex vivo cultured autologous human conjunctival epithelial cell (hCjEC) transplantation for treatment of pterygia. METHODS: Twenty-five patients with pterygia were recruited at different centers across the country. Autologous hCjEC grafts were prepared from conjunctival biopsy specimens excised from the healthy eye and cultured ex vivo on human amniotic membrane mounted on inserts using a unique mounting device. The hCjEC grafts were then transported in an in-house designed transport container for transplantation. Post-surgery, the patients were followed up on days 1, 7, 14, 30, 90, and 180 as per the approved study protocol. Clinical outcomes were assessed by slit lamp examination, visual acuity, imprint cytology, fluorescein/rose bengal staining, Schirmer's test, and photographic evaluation three and 6 months post-transplantation. RESULTS: Two patients were lost to follow-up and final analysis included 23 cases. No recurrence of pterygium was observed in 18 (78.3%) patients; all of these eyes showed a smooth conjunctival surface without epithelial defects. Recurrence was observed in 5 (21.7%) patients at 3 months post-treatment. No conjunctival inflammation, secondary infections or other complications were reported. Adequate goblet cells were present in 19 (82.6%) patients at the site of transplantation. CONCLUSION: We have, for the 1(st) time, standardized a protocol for preparing autologous hCjEC grafts that can be safely transported to multiple centers across the country for transplantation. The clinical outcome was satisfactory for treating pterygia. PMID- 25709764 TI - Topical cyclosporine a for treatment of dry eye due to chronic mustard gas injury. AB - PURPOSE: To evaluate the efficacy of topical cyclosporine A (tCsA) for treatment of dry eye disease in patients suffering from chronic ocular complications of mustard gas (MG) injury. METHODS: This interventional case series included patients with MG injury suffering from severe dry eye despite receiving artificial tears and punctal plugs. Patients were administered tCsA 0.05% twice daily for 3 months. Severity of the condition was evaluated by measuring tear osmolarity, ocular surface disease index (OSDI), tear break-up time (TBUT), and Schirmer's test at baseline and at the end of study. RESULTS: A total of 34 patients with chronic MG injury and mean age of 47.1 +/- 6.5 years were studied. Compared to baseline values, tear osmolarity (301.7 +/- 11.5 vs. 286.3 +/- 7.9 mOsmol/L, P < 0.001) and OSDI (47.5 +/- 7.2 vs. 42.7 +/- 7.1, P < 0.001) were significantly improved. Likewise, Schirmer's test (4.6 +/- 1.3 vs. 5 +/- 1.3 mm, P < 0.001) and TBUT (1.9 +/- 1.4 vs. 2.7 +/- 1.5 s, P < 0.001) also significantly recovered at the end of the study. CONCLUSION: TCsA 0.05% reduces tear osmolarity and improves dry eye symptoms and can serve as an efficacious treatment for ocular complications in patients with chronic MG injury. PMID- 25709765 TI - Topical interferon alpha-2b for treatment of noninvasive ocular surface squamous neoplasia with 360 degrees limbal involvement. AB - PURPOSE: To report the results of topical interferon alpha-2b (IFNalpha2b) for the treatment of ocular surface squamous neoplasia (OSSN) with 360 degrees limbal involvement. METHODS: In a prospective observational study, five patients with biopsy proven primary or recurrent OSSN with 360 degrees limbal involvement received topical IFNalpha2b (3 million IU/ml, 4 times daily) and were followed from 8 to 12 months. Outcome measures included resolution of the lesion, relief of symptoms, systemic and ocular side effects, and recurrence rate. RESULTS: Five patients including 4 primary OSSNs and one recurrent OSSN received topical interferon alpha-2b. The mean age was 60.2 (range: 52-73) years and mean follow up duration was 10.2 months. Clinical resolution of the tumor occurred in all cases 2 months after initiation of treatment and no patient developed ocular or systemic complications. No recurrence of OSSN developed during the follow up period. CONCLUSION: Topical recombinant IFNalpha2b appears to be an effective alternative treatment for OSSN with 360 degrees limbal involvement. This approach precludes the high risk of limbal stem cell deficiency which results from surgical excision or topical chemotherapeutic agents. PMID- 25709766 TI - Comparison of three phakic intraocular lenses for correction of myopia. AB - PURPOSE: To compare the visual outcomes and complications of three different types of phakic intraocular lenses (PIOLs), for correction of moderate to high myopia. METHODS: We reviewed 112 myopic eyes undergoing PIOL implantation using Artisan (40 eyes), Artiflex (36 eyes), and implantable collamer lens (ICL, 36 eyes). Best corrected visual acuity (BCVA), intraocular pressure (IOP), pachymetry, corneal endothelial cell (CEC) loss, and higher order aberrations (HOA) were compared. RESULTS: Mean follow-up period was 30 +/- 11 months. Preoperatively, spherical equivalent (SE) refractive error was -11.6 +/- 3.7, 9.59 +/- 1.97, and -12.3 +/- 4.8 D in the Artisan, Artiflex and ICL groups, respectively. SE was comparable among the study groups at final follow-up (P = 0.237). Mean astigmatic reduction was 0.31 +/- 0.72, 0.45 +/- 0.62, and 0.0 +/- 0.57 in the Artisan, Artiflex and ICL groups, respectively (P = 0.007). Emmetropia (+/-1 D) was achieved in 60%, 91.7% and 77.8% of eyes in the Artisan, Artiflex and ICL groups, respectively, the difference was significant between the Artisan and Artiflex groups (P = 0.017). BCVA improvement more than one line occurred in 25%, 19.4% and 38.9% of eyes (P = 0.158); pachymetric changes were minimal with no difference among the three groups (P = 0.754), and mean CEC loss was 10 +/- 9%, 9 +/- 6% and 9 +/- 10% in the Artisan, Artiflex and ICL groups, respectively (P = 0.694). HOAs (P = 0.039), vertical trefoil (P = 0.032) and spherical aberration (P = 0.001) were higher with Artisan group as compared to ICL. Total aberrations (P = 0.028) and spherical aberration (P = 0.001) was also higher with Artisan group as compared to Artiflex. CONCLUSION: Visual and refractive outcomes were comparable with Artisan, Artiflex and ICL. In terms of HOAs and quality of vision, ICL and Artiflex seem to be better choices in highly myopic eyes. PMID- 25709767 TI - A modified risk assessment scoring system for post laser in situ keratomileusis ectasia in topographically normal patients. AB - PURPOSE: To evaluate and modify the Randleman Ectasia Risk Score System for predicting post-laser in situ keratomileusis (LASIK) ectasia in patients with normal preoperative corneal topography. METHODS: In this retrospective study we reviewed data from 136 eyes which had undergone LASIK including 34 ectatic and 102 normal eyes between 1999 and 2009. After determining the sensitivity and specificity of the Randleman system, a modified model was designed to predict the risk of post-LASIK corneal ectasia more accurately. Next, the sensitivity and specificity of this modified scoring system was determined and compared to that of the original scoring system. RESULTS: In our sample, the sensitivity and specificity of the Randleman system was 70.1% and 50.5%, respectively. Our modified model included the following parameters: preoperative central corneal thickness, manifest refraction spherical equivalent, and maximum keratometry, as well as the number of months elapsed from surgery. Sensitivity and specificity rates of the modified system were 74.2% and 76.2%, respectively. The difference in receiver operating characteristic curves between the Randleman and modified scoring systems was statistically significant (P<0.001). The best sensitivity and specificity for our model occurred with a cumulative cutoff score of 4.00; a low risk was considered if the score was <=4.00, and high risk was defined with a score > 4.00. CONCLUSION: Our modified ectasia risk scoring system for patients with normal corneal topography can predict post LASIK ectasia risk with acceptable sensitivity and specificity. However, there are still unidentified risk factors for which further studies are required. PMID- 25709768 TI - Central corneal thickness in primary angle closure and open angle glaucoma. AB - PURPOSE: To quantitatively analyze central corneal thickness (CCT) in patients with primary angle closure glaucoma (PACG) and primary open-angle glaucoma (POAG), and to evaluate its correlation with severity of glaucoma. METHODS: In this retrospective study, records of patients with previously diagnosed POAG or PACG at a tertiary glaucoma service were reviewed. CCT was measured by ultrasound pachymetry. Mean deviation (MD) on visual field (VF) testing was recorded for glaucoma severity determination. CCT and age- and sex-adjusted CCT were compared among the study groups using Student's t-test and analysis of covariance (ANCOVA), respectively. Univariate and multivariate regression models were used for correlation of age, MD and CCT. RESULTS: A total of 115 patients with PACG, 215 with POAG, and 100 normal controls were included with mean age of 64.1 +/- 10.4, 59.9 +/- 10.5, and 62.04 +/- 10.80 years, respectively. CCT was thicker in PACG eyes (545.5 +/- 46.1 MUm) as compared to POAG eyes (531.7 +/- 37.3 MUm) and controls (531.0 +/- 38.3 MUm) even after age and gender adjustment (ANCOVA, P = 0.05). CCT was found to decrease with increasing age only in the POAG group (beta = -0.57, P = 0.01). Disease severity (MD of VF) was significantly and inversely correlated with CCT in both POAG and PACG eyes (beta = 1.89, P = 0.02; and beta = 1.38, P = 0.04, respectively) after age and sex correction. CONCLUSION: PACG eyes had thicker CCT as compared to POAG and normal healthy eyes in Iranian subjects. Severity of the disease was inversely correlated with CCT in eyes with both POAG and PACG. PMID- 25709769 TI - Long term efficacy of repeat selective laser trabeculoplasty. AB - PURPOSE: To evaluate long term intraocular pressure (IOP) control after repeat selective laser trabeculoplasty (SLT). METHODS: This single center study retrospectively reviews the electronic medical records of patients with open angle glaucoma undergoing repeat SLT. Eyes with prior argon laser trabeculoplasty, or incisional surgery before or during the study period were excluded. Demographics, laser parameters, number of glaucoma medications and IOP at baseline and after 1, 4, 8, 12, 18 and 24 months were collected. The percentage of subjects with IOP reduction >20% and >=15% from baseline was determined. RESULTS: A total of 45 eyes of 25 subjects with mean age of 73 +/- 9 years undergoing repeat SLT were included. Repeat SLT was performed at a mean interval of 28.3 +/- 12.7 months after initial treatment. Mean IOP reductions were statistically significant with repeat SLT as compared to baseline at 1, 4, 8, 12, 18 and 24 months' follow-up. Change in IOP after first and repeat SLT were comparable at most time points except at 4, 8 and 12 months when initial treatment had yielded significantly greater reductions. At 24 months, 29% and 39% of eyes achieved IOP reduction >20% and >=15% respectively after repeat SLT as compared to 36% and 54% of eyes following initial treatment (P > 0.05). CONCLUSION: Repeat SLT is effective in lowering IOP up to 24 months. Long term IOP control was achieved in 29-39% of eyes following repeat treatment in this cohort of patients. PMID- 25709770 TI - Changes in Retinal Nerve Fiber Layer Thickness after Two Intravitreal Bevacizumab Injections for Wet Type Age-related Macular Degeneration. AB - PURPOSE: To evaluate the effect of two intravitreal bevacizumab (IVB) injections on peripapillary retinal nerve fiber layer (RNFL) thickness in patients with wet type age-related macular degeneration (ARMD). METHODS: This prospective interventional case series included 18 eyes of 18 patients receiving two IVB injections within a 6 weeks interval for treatment of wet type ARMD. Peripapillary RNFL thickness was measured prior to the first injection, and 12 and 24 weeks afterwards by optical coherence tomography (3D OCT-1000, Topcon Corporation, Tokyo, Japan). Mean RNFL thickness and values in the four peripapillary quadrants were compared at baseline, and 12 and 24 weeks after initial injection. RESULTS: Mean RNFL thickness was 89 +/- 21 MUm at baseline which was significantly reduced to 82 +/- 15 MUm at 12 weeks (P = 0.021). At final follow-up (week 24), mean RNFL thickness reached 87 +/- 23 MUm and was comparable to baseline values (P = 0.356). Only the temporal quadrant showed a significant reduction in RNFL thickness at 12 weeks (P = 0.033); this quadrant followed the same pattern of change as the mean RNFL thickness, becoming comparable to pre-injection values at 24 weeks (P = 0. 298). CONCLUSION: RNFL thickness may decrease temporarily following two IVB injections in patients with wet type ARMD; however, in the long-term no significant change was detectable from baseline values. PMID- 25709771 TI - Intravitreal bevacizumab injection alone or combined with triamcinolone versus macular photocoagulation in bilateral diabetic macular edema; application of bivariate generalized linear mixed model with asymmetric random effects in a subgroup of a clinical trial. AB - PURPOSE: To compare the efficacy of intravitreal bevacizumab (IVB) injection alone or with intravitreal triamcinolone acetonide (IVB/IVT) versus macular photocoagulation (MPC) in bilateral diabetic macular edema (DME). METHODS: In this study we revisited data from a subset of subjects previously enrolled in a randomized clinical trial. The original study included 150 eyes randomized to three treatment arms: 1.25 mg IVB alone, combined injection of 1.25 mg IVB and 2 mg IVT, and focal or modified grid MPC. To eliminate the possible effects of systemic confounders, we selected fellow eyes of bilaterally treated subjects who had undergone different treatments; eventually 30 eyes of 15 patients were re evaluated at baseline, 6, 12, 18, and 24 months. Using mixed model analysis, we compared the treatment protocols regarding visual acuity (VA) and central macular thickness (CMT). RESULTS: Improvement in VA in the IVB group was significantly greater compared to MPC at months 6 and 12 (P = 0.037 and P = 0.035, respectively) but this difference did not persist thereafter up to 24 months. Other levels of VA were comparable at different follow-up intervals (all P > 0.05). The only significant difference in CMT was observed in favor of the IVB group as compared to IVB/IVT group at 24 months (P = 0.048). CONCLUSION: Overall VA was superior in IVB group as compared to MPC up to 12 months. Although the IVB group showed superiority regarding CMT reduction over 24 months as compared to IVB/IVT group, it was comparable to the MPC group through the same period of follow up. PMID- 25709772 TI - Neovascular events in eyes with central retinal vein occlusion undergoing serial bevacizumab or ranibizumab intravitreal injections: a retrospective review. AB - PURPOSE: To characterize the onset and type of neovascular events in eyes with central retinal vein occlusion (CRVO) undergoing serial anti-VEGF therapy. METHODS: Consecutive eyes undergoing serial intravitreal bevacizumab or ranibizumab injections for treatment of CME secondary to CRVO were identified. Pertinent data was retrospectively collected and included type and onset of the neovascular event, and the treatment free interval from last injection until the neovascular event. Kaplan-Meier life table analysis was performed to determine the differential effects of baseline perfusion status, early initiation of anti VEGF treatment (within 3 months of CRVO onset) versus later treatment, and continuous (1-month+/-2 weeks) versus discontinuous treatment interval (>1.5 months) on time until neovascular event. RESULTS: Of 31 eligible eyes, 12 (39%) and 19 (61%) presented with perfused and ischemic CRVO, respectively. The mean duration from CRVO until the onset of any neovascular event was 17.0+/-10.3 months. The mean treatment-free interval prior to any neovascular event was 6.2+/ 7.3 months. On average, 5.3+/-3.2 anti-VEGF injections were given prior to any neovascular event. Neovascularization of the iris or angle occurred in 18 eyes (58%), vitreous hemorrhage associated with neovascularization was observed in 9 eyes (29%) and neovascularization of the disc developed in 5 eyes (16%). Neovascular events showed a trend towards occurring later in eyes with perfused CRVO at baseline (log rank test, P=0.07). CONCLUSION: Neovascular events occur in eyes with CRVO undergoing serial anti-VEGF therapy, and these events may be delayed compared to the natural history of CRVO-associated neovascularization. Iris neovascularization occurred most frequently. PMID- 25709774 TI - Macular thickness and amblyopia. AB - PURPOSE: To compare macular thickness in children with functional amblyopia and those without amblyopia using optical coherence tomography (OCT). METHODS: This case-control study was conducted on 93 children aged 3-10 years including 44 cases with unilateral amblyopia and 49 subjects without amblyopia. Amblyopic eyes were considered as the case group and their fellow eyes as internal controls; eyes of non-amblyopic children served as the external control. Macular thickness of all eyes were measured by optical coherence tomography in the center (foveola), 1 mm ring (fovea), and 3 and 6 mm rings and compared. RESULTS: Although macular thickness was generally not different between the study groups, there was a significant difference in central macular thickness between eyes with moderate to severe amblyopia and the external controls (P = 0.037). Foveal thickness difference exceeding 10 microns between fellow eyes was detected in a larger number of amblyopic children as compared to non-amblyopic controls (P = 0.002). Mean foveal thickness was greater in boys (P = 0.037) but there was no significant difference in foveal thickness among various types of refractive errors. CONCLUSION: Although there was no significant relationship between macular thickness and amblyopia, foveolar thickness in eyes with moderate to severe amblyopia was significantly greater than the external controls. Further studies with more cases of moderate to severe amblyopia are recommended. PMID- 25709773 TI - Photodynamic Therapy and Intravitreal Bevacizumab with Versus without Triamcinolone for Neovascular Age-related Macular Degeneration; a Randomized Clinical Trial. AB - PURPOSE: To compare the outcomes of photodynamic therapy (PDT) combined with intravitreal bevacizumab (IVB) with versus without intravitreal triamcinolone (IVT) in neovascular age-related macular degeneration (AMD). METHODS: Eighty-four eyes with active CNV secondary to AMD with no prior treatment were enrolled and followed for 1-year. Eligible eyes were randomly assigned to either PDT/IVB or PDT/IVB/IVT. The main outcome measure was change in best-corrected visual acuity (BCVA). RESULTS: Mean patient age was 71 +/- 9 years. BCVA changes from baseline were statistically significant in both study arms at all follow-up intervals, however no significant difference was observed between the two groups regarding BCVA changes at week 12 (95% CI:-0.11-0.12 LogMAR) and other time points (all P > 0.6). Mixed model analysis revealed a significant effect from age (P < 0.001), pigment epithelial detachment (P = 0.009) and baseline BCVA (P < 0.001) on visual improvement. Significant central macular thickness (CMT) reduction occurred at all-time points as compared to baseline in both groups which was comparable between the study arms. There was no significant difference between the study arms in terms of retreatment rate (P = 0.1) and survival to the first repeat IVB injection (P = 0.065). CONCLUSION: Additional low-dose IVT to a PDT/IVB regimen for neovascular AMD provided no beneficial effects in terms BCVA or CMT, yet demonstrated a trend toward extending the injection-free period. PMID- 25709775 TI - Prevalence of Refractive Errors in Students with and without Color Vision Deficiency. AB - PURPOSE: To evaluate refractive errors in school age children with color vision deficiency (CVD) and those with normal color vision (NCV) in order to make a better understanding of the emmetropization process. METHODS: A total of 4,400 primary school students aged 7-12 years were screened for color vision using Ishihara pseudoisochromatic color vision plate sets. Of these, 160 (3.6%) students had CVD. A total of 400 age- and sex-matched students with NCV were selected as controls. Refractive status was evaluated using objective cyclorefraction. RESULTS: The CVD group included 136 male (85%) and 24 female (15%) subjects with mean age of 10.1 +/- 1.8 years. The NCV group comprised of 336 male (84%) and 64 female (16%) subjects with mean age of 10.5 +/- 1.2 years. The prevalence of myopia (7.7% vs. 13.9%, P < 0.001) and hyperopia (41% vs. 57.4%, P = 0.03) was significantly lower in the CVD group. Furthermore, subjects with CVD subjects demonstrated a lower magnitude of refractive errors as compared to the CVD group (mean refractive error: +0.54 +/- 0.19 D versus + 0.74 +/- 1.12 D, P < 0.001). CONCLUSION: Although the lower prevalence of myopia in subjects with CVD group supports the role of longitudinal chromatic aberration in the development of refractive errors; the lower prevalence of hyperopia in this group is an opposing finding. Myopia is a multifactorial disorder and longitudinal chromatic aberration is not the only factor influencing the emmetropization process. PMID- 25709776 TI - Nutrient Supplementation for Age-related Macular Degeneration, Cataract, and Dry Eye. AB - There have been enormous advances in the past decade for the treatment of age related macular degeneration (AMD); however, these treatments are expensive and require frequent follow-up and injections which place a tremendous burden on both the healthcare system and patients. Consequently, there remains considerable interest in preventing or slowing the progression of AMD requiring treatment. Epidemiological studies have shown that diet is a modifiable AMD risk factor, and nutrient modification is a particularly appealing treatment for AMD due to the perceived universal benefit and relatively low expense. Recently, the age-related eye disease study part two (AREDS2) was concluded and demonstrated further benefit with the addition of lutein and zeaxanthin as a replacement for the beta carotene of the previous generation formulation. The addition of omega-3 essential fatty acids did not show an added benefit. This review aims to highlight some of the evidenced based body of knowledge that has been accumulated from recent studies regarding the use of nutritional supplements and their effect on AMD, cataracts, and dry eyes. PMID- 25709778 TI - Gene therapy for retinal diseases. AB - Gene therapy has a growing research potential particularly in the field of ophthalmic and retinal diseases owing to three main characteristics of the eye; accessibility in terms of injections and surgical interventions, its immune privileged status facilitating the accommodation to the antigenicity of a viral vector, and tight blood-ocular barriers which save other organs from unwanted contamination. Gene therapy has tremendous potential for different ocular diseases. In fact, the perspective of gene therapy in the field of eye research does not confine to exclusive monogenic ophthalmic problems and it has the potential to include gene based pharmacotherapies for non-monogenic problems such as age related macular disease and diabetic retinopathy. The present article has focused on how gene transfer into the eye has been developed and used to treat retinal disorders with no available therapy at present. PMID- 25709777 TI - Visual prostheses: the enabling technology to give sight to the blind. AB - Millions of patients are either slowly losing their vision or are already blind due to retinal degenerative diseases such as retinitis pigmentosa (RP) and age related macular degeneration (AMD) or because of accidents or injuries. Employment of artificial means to treat extreme vision impairment has come closer to reality during the past few decades. Currently, many research groups work towards effective solutions to restore a rudimentary sense of vision to the blind. Aside from the efforts being put on replacing damaged parts of the retina by engineered living tissues or microfabricated photoreceptor arrays, implantable electronic microsystems, referred to as visual prostheses, are also sought as promising solutions to restore vision. From a functional point of view, visual prostheses receive image information from the outside world and deliver them to the natural visual system, enabling the subject to receive a meaningful perception of the image. This paper provides an overview of technical design aspects and clinical test results of visual prostheses, highlights past and recent progress in realizing chronic high-resolution visual implants as well as some technical challenges confronted when trying to enhance the functional quality of such devices. PMID- 25709779 TI - Sterile Keratitis following Collagen Crosslinking. AB - PURPOSE: To report a keratoconic eye that developed severe sterile keratitis and corneal scar after collagen crosslinking necessitating corneal transplantation. CASE REPORT: A 26-year-old man with progressive keratoconus underwent collagen crosslinking and presented with severe keratitis 72 hours after the procedure. The initial impression was infectious corneal ulcer and a fortified antibiotic regimen was administered. However, the clinical course and confocal microscopy results prompted a diagnosis of sterile keratitis. The eye developed severe corneal scars leading to reduced visual acuity and necessitating corneal transplantation. CONCLUSION: Sterile keratitis may develop after collagen crosslinking resulting in profound visual loss leading to corneal transplantation. PMID- 25709780 TI - Orbital oculomotor nerve schwannoma extending to the cavernous sinus: a rare cause of proptosis. AB - PURPOSE: To report a case of orbital oculomotor nerve schwannoma extending to the cavernous sinus through the superior orbital fissure presenting with proptosis, but without any neurological sign. CASE REPORT: A 32-year-old man presented with axial proptosis of his left eye. Visual acuity and other ocular examinations were normal. Orbital magnetic resonance imaging revealed a well-defined fusiform retrobulbar lesion in the left orbit extending into the superior orbital fissure and left cavernous sinus measuring 43 mm * 21 mm * 19 mm and causing superomedial displacement of the optic nerve and axial proptosis. The patient was scheduled for surgery, and gross total excision was done. Postoperatively, the patient developed total third nerve palsy. Pre and postoperative third nerve deficit confirmed the origin of the tumor from the oculomotor nerve. Histopathological examination revealed schwannoma. CONCLUSION: Orbital oculomotor nerve schwannoma, although rare, can be the cause of proptosis. Diagnosis can be confirmed histopathologically. It is a benign tumor; however, it can extend intracranially without any neurological symptoms. Therefore, neuroimaging is essential to rule out intracranial extension. Early surgical removal is mandatory. PMID- 25709781 TI - Orbital metastasis: a rare manifestation of scapular bone osteosarcoma. AB - PURPOSE: To report a case of orbital metastasis from scapular bone osteosarcoma. CASE REPORT: A 55-year-old man who was a known case of scapular bone osteosarcoma, was referred to our clinic with ocular symptoms including acute painful decreased vision, proptosis, conjunctival injection, and chemosis. He had undergone surgical excision of the original tumor and received systemic chemotherapy 4 months before. Imaging studies and incisional biopsy were performed for the orbital lesion, the histopathological examination confirmed the diagnosis of metastatic osteosarcoma. The patient was referred to the oncologist for palliative chemotherapy and further intervention; however, he deceased 2 months later due to sepsis in the context of immunosuppression. CONCLUSION: Metastatic involvement of the orbit due to osteosarcoma is a rare condition manifesting with orbital mass, pain, diplopia and ocular motility disturbance. Although there is no effective treatment, the combination of modalities such as chemotherapy, radiotherapy, and surgery may delay progression of the disease. PMID- 25709782 TI - Amblyopia associated with prominent cilioretinal artery. PMID- 25709783 TI - Modified Descemet's Stripping Automated Endothelial Keratoplasty for Congenital Hereditary Endothelial Dystrophy. AB - A 19-year-old male with congenital hereditary endothelial dystrophy (CHED) presented with severe bilateral corneal clouding precluding any view of the intraocular structures. He underwent modified Descemet's stripping automated endothelial keratoplasty (DSAEK) technique including a suture pull-through technique to prevent lens damage. Surgery resulted in progressive clearing of the cornea and decreased corneal thickness. Visual acuity increased from hand motions preoperatively to counting fingers at 4 m after 4 months. DSAEK can be successfully performed in phakic eyes with CHED as an alternative to penetrating keratoplasty. It has the advantage of less wound problems and better preservation of globe integrity especially in children. PMID- 25709784 TI - New concepts in nutraceuticals as alternative for pharmaceuticals. AB - Nutraceuticals are products, which other than nutrition are also used as medicine. A nutraceutical product may be defined as a substance, which has physiological benefit or provides protection against chronic disease. Nutraceuticals may be used to improve health, delay the aging process, prevent chronic diseases, increase life expectancy, or support the structure or function of the body. Nowadays, nutraceuticals have received considerable interest due to potential nutritional, safety and therapeutic effects. Recent studies have shown promising results for these compounds in various complications. In the present review much effort has been devoted to present new concepts about nutraceuticals based on their diseases modifying indications. Emphasis has been made to present herbal nutraceuticals effective on hard curative disorders related to oxidative stress including allergy, alzheimer, cardiovascular, cancer, diabetes, eye, immune, inflammatory and Parkinson's diseases as well as obesity. The recently published papers about different aspects of nutraceuticals as alternative for pharmaceuticals were searched using scientific sites such as Medline, PubMed, and Google Scholar. The used terms included nutraceutical and allergy, alzheimer, cardiovascular, cancer, diabetes, eye, immune, inflammatory or Parkinson. PMID- 25709785 TI - Assessment of Smartphone Addiction in Indian Adolescents: A Mixed Method Study by Systematic-review and Meta-analysis Approach. AB - There is a considerable debate on addiction and abuse to Smartphone among adolescents and its consequent impact on their health; not only in a global context, but also specifically in the Indian population; considering that Smartphone's, globally occupy more than 50% of mobile phones market and more precise quantification of the associated problems is important to facilitate understanding in this field. As per PRISMA (2009) guidelines, extensive search of various studies in any form from a global scale to the more narrow Indian context using two key search words: "Smartphone's addiction" and "Indian adolescents" was done using websites of EMBASE, MEDLINE, PubMed, Global Health, Psyc-INFO, Biomed Central, Web of Science, Cochrane Library, world library - World-Cat, Indian libraries such as National Medical Library of India from 1 January, 1995 to March 31, 2014 first for systematic-review. Finally, meta-analysis on only Indian studies was done using Med-Calc online software capable of doing meta-analysis of proportions. A total of 45 articles were considered in systematic-review from whole world; later on 6 studies out of these 45 related to Smartphone's addiction in India were extracted to perform meta-analysis, in which total 1304 participants (range: 165-335) were enrolled. The smartphone addiction magnitude in India ranged from 39% to 44% as per fixed effects calculated (P < 0.0001). Smartphone addiction among Indian teens can not only damage interpersonal skills, but also it can lead to significant negative health risks and harmful psychological effects on Indian adolescents. PMID- 25709786 TI - Barriers to and Facilitators of Long Term Weight Loss Maintenance in Adult UK People: A Thematic Analysis. AB - Adult obesity and overweight is affecting every region of the world and is described as one of today's most significant and neglected public health problems. The problem has taken the shape of an epidemic not only because the prevalence of obesity has witnessed a dramatic progress in a short period of time, but also because obesity has paved the way for increased risks for morbidity and mortality associated with it. It has been predicted that about half of the adult men and more than a quarter of adult women would be obese by 2030 in the UK and this figure could rise up to 50% in 2050 for whole of the adult UK population. Although a modest 5-10% weight loss maintained in the long term can significantly decrease health risk, few people engage in weight loss activities. Against this background, this review paper aims to investigate the reasons helping and/or hindering adults in the UK maintain weight loss in the long term; using online and organizational data sources and thematically analyzing the data. Self-body perception, enhanced self-confidence, social support, self-motivation, incentives and rewards, increased physical activity levels and healthy eating habits facilitated people in maintaining weight loss in the long term and overall quality of life. Extreme weather conditions, natural phenomena such as accidents, injuries and ill-health, work commitments, inability for time management and to resist the temptation for food constrained the successful long-term weight loss maintenance. PMID- 25709787 TI - Sono-elastography for Differentiating Benign and Malignant Cervical Lymph Nodes: A Systematic Review and Meta-Analysis. AB - We did this systematic review to determine diagnostic accuracy of sono elastography in evaluating cervical lymph nodes (LNs). A highly sensitive search for sono-elastography and LNs was performed in MEDLINE, Cochrane Library, ACP Journal Club, EMBASE, Health Technology assessment, and ISI web of knowledge for studies published prior to December 2012. SPSS version 18 (SPSS Inc., Chicago, IL, USA) used for descriptive analysis and meta-disk version 1.4 applied for meta analysis. Forest plots for pooled estimates and summery of receiver operating characteristic plots for different cut-offs were produced. The literature and manual search yielded 69 articles, of which 10 were eligible to include. A total of 578 individuals with a total number of 936 cervical LNs was evaluated (502 malignant and 434 benign). The summary sensitivity of the scoring and strain ratio (SR) measurements for the differentiation of benign and malignant LNs were 0.76 (95% CI: 0.71-0.8) and 0.83 (95% CI: 0.78-0.87). The summary specificities were 0.8 (95% confidence interval [CI]: 0.75-0.84) and 0.84 (95% CI: 0.79-0.88), respectively. Area under the curve for scoring system was 0.86 (standard error [SE] = 0.03) and 0.95 (SE = 0.02) for SR measurement. Sono-elastograohy has high accuracy in differentiating benign and malignant cervical LNs. PMID- 25709788 TI - The Effects of Consumption of Bread Fortified With Soy Bean Flour on Metabolic Profile in Type 2 Diabetic Women: A Cross-over Randomized Controlled Clinical Trial. AB - BACKGROUND: Diabetes mellitus is one of the most common chronic diseases in the world and has become a major threat for global health. Recent studies reported that the soy has beneficial effects in diabetic mellitus patients. The aim of this study was to assess the effects of soybean flour fortified bread consumption on metabolic profile in type 2 diabetic women. METHODS: This randomized, cross over, controlled clinical trial was carried out in 30 type 2 diabetic women. At first, a 2-week run-in period was applied. Then, participants were randomly assigned to either intervention or control groups. Participants in the intervention group were asked to replace 120 g of soybean flour fortified bread with the same amount of their usual bread intake or other cereal products for 6 weeks. After a 4 weeks washout period, participants were crossed over for another 6 weeks. RESULTS: Mean (+/-standard deviation) age and body mass index of subjects was 45.7 +/- 3.8 years and 29.5 +/- 3.9 kg/m(2), respectively. The results of our study showed no significant effects of soybean flour fortified bread on metabolic profile. We found a reduction in serum triglycerides (change difference: -3.7, P = 0.82), serum low-density lipoprotein-cholesterol (change difference: -11.2, P = 0.50), insulin (change difference: -3.6, P = 0.7), and homeostatic model assessment of insulin resistance (change differences: -0.57, P = 0.45) after 6 weeks but these changes were not statistically significant. No significant effects of soybean flour fortified bread on serum concentrations of fasting blood sugar, glycated hemoglobin, high-density lipoproteins and total cholesterol levels were found. CONCLUSIONS: Six weeks consumption of soybean flour fortified bread among diabetic patients had no significant effects on metabolic profile. PMID- 25709789 TI - Helicobacter pylori infection and metabolic parameters: is there an association in elderly population? AB - BACKGROUND: The association between Helicobacter pylori (HP), as one of the most prevalent infections, and serum glucose level was inconsistent with previous studies. Moreover, there are contradictory reports about the relationship between HP infection and lipid profile. The purpose of this study was to determine the relationship between HP infection with glycemic and lipid profiles in elderly people. METHODS: This cross-sectional study was conducted on 1,300 subjects over 60 years in Amirkola Health and Ageing Project. After using a standard questionnaire, the venous sampling was done to determine FBS, triglyceride (TG), cholesterol, low density lipoprotein (LDL), high-density lipoprotein (HDL) and IgG anti-HP after a 12-h overnight fast. The information about the individuals was analyzed using SPSS-17. The P < 0.05 was considered statistically significant. RESULTS: The prevalence of HP infection in diabetic and nondiabetic subjects was 77.5% and 75.7%, respectively, which had no statistically significant difference. Also, there was no significant difference between the serum lipid level including TG, LDL and HDL cholesterol with levels of anti-HP antibodies. The rate of HP infection in patients with hypertension was 75% and 78.3% in healthy patients, in which the difference was not statistically significant. In terms of body mass index (BMI), the prevalence of infection in the group with normal BMI was 77.3% and for the overweight and obese elderly population, it was 74.7%, and 77.5%, respectively (P = 0.445). CONCLUSIONS: The findings revealed that in a large population of elderly in the northern part of Iran, HP infection is not associated with BMI, serum glucose and lipid profile as well as blood pressure. PMID- 25709790 TI - Initial Treatment of Respiratory Distress Syndrome with Nasal Intermittent Mandatory Ventilation versus Nasal Continuous Positive Airway Pressure: A Randomized Controlled Trial. AB - BACKGROUND: Neonatal respiratory distress syndrome (RDS) in premature infants who survived and its complications are a common problem. Due to high morbidity and mechanical ventilation (MV) nowadays researchers in interested minimizing MV. To determine, in very low birth weight (BW) preterm neonates with RDS, if initial treatment with nasal intermittent mandatory ventilation (early NIMV) compared with early nasal continuous positive airway pressure (early NCPAP) obtains more favorable outcomes in terms of the duration of treatment, and the need for endotracheal tube ventilation. METHODS: In this single-center randomized control trial study, infants (BW <= 1500 g and/or gestational age <= 34 weeks) with respiratory distress were considered eligible. Forty-four infants were randomly assigned to receive early-NIMV and 54 comparable infants to early-NCPAP. Surfactants were given, when FIO2 requirement was of >30%. Primary outcomes were failure of noninvasive respiratory support, that is, the need for MV in the first 48 h of life and for the duration of noninvasive respiratory support in each group. RESULTS: 98 infants were enrolled (44 in the NIMV and 54 in the NCPAP group). The Preventive power of MV of NIMV usage (95.5%) was not lower than the NCPAP (98.1%) strength (hazard ratio: 0.21 (95% confidence interval: 0.02-2.66); P: 0.23). The duration of noninvasive respiratory support in the NIMV group was significantly shorter than NCPAP (the median (range) was 24 (18.00-48.00) h versus 48.00 (22.00-120.00) h in NIMV versus NCPAP groups; P < 0.001). Similarly, the duration of dependency on oxygen was less, for NIMV (the median (range) was 96.00 (41.00-504.00) h versus144.00 (70.00-1130.00) h in NIMV versus NCPAP groups; P: 0.009). Interestingly, time to full enteral feeds and length of hospital stay were more favorable in the NIMV versus the NCPAP group. CONCLUSIONS: Initial treatment of RDS with NIMV was safe, and well tolerated. Furthermore, NIMV had excellent benefits such as reduction of the duration of treatment, oxygen dependency period and length of hospital stay. Therefore, the primary mode with NIMV could be a feasible method of noninvasive ventilation in very premature infants. PMID- 25709791 TI - Development of strategies to reduce cesarean delivery rates in iran 2012-2014: a mixed methods study. AB - BACKGROUND: With the change in population policy from birth control toward encouraging birth and population growth in Iran, repeated cesarean deliveries as a main reason of cesarean section are associated with more potential adverse consequences. The aim of this research was to explore effective strategies to reduce cesarean delivery rates in Iran. METHODS: A mixed methodological study was designed and implemented. First, using a qualitative approach, concepts and influencing factors of increased cesarean delivery were explored. Based on the findings of this phase of the study, a questionnaire including the proposed strategies to reduce cesarean delivery was developed. Then in a quantitative phase, the questionnaire was assessed by key informants from across the country and evaluated to obtain more effective strategies to reduce cesarean delivery. Ten participants in the qualitative study included policy makers from the Ministry of Health, obstetricians, midwives and anthropologists. In the next step, 141 participants from private and public hospitals, insurance experts, Academic Associations of Midwifery, and policy makers in Maternity Health Affairs of Ministry of Health were invited to assess and provide feedback on the strategies that work to reduce cesarean deliveries. RESULTS: Qualitative data analysis showed four concept related to increased cesarean delivery rates including; "standardization", "education", "amending regulations", and "performance supervision". Effective strategies extracted from qualitative data were rated by participants then, using ACCEPT derived from A as attainability, C as costing, C as complication, E as effectiveness, P as popularity, and T as timing table 19 strategies were detected as priorities. CONCLUSIONS: Although developing effective strategies to reduce cesarean delivery rates is complex process because of the multi-factorial nature of increased cesarean deliveries, in this study we have achieved strategies that in the context of Iran could work. PMID- 25709793 TI - Frequency of Blood-tissue Parasitic Infections in Patients with Multiple Sclerosis, as Compared to their Family Members. AB - BACKGROUND: Multiple Sclerosis (MS) is a chronic demyelinating disease of the central nervous system which has been identifies more prevalent in economically developed countries than in the developing countries. Low prevalence of parasitic infections (which can activate immune response and prevent or modulate damage to host antigens) in these areas is among the possible responsible factors for such a difference. In this study we aimed to compare frequency of blood-tissue parasitic infections in patients with MS, as compared to their healthy family members. METHODS: This study was conducted on 50 relapsing remitting MS patients and 50 family members attending MS clinic at Alzahra Hospital. IgM and IgG anti Toxoplasma gondii were measured. Given the high prevalence of cutaneous leishmaniasis in Isfahan, all the participants were also examined for protozoan leishmania microscopically. Furthermore malaria parasite was investigated. RESULTS: Eighteen patients and 24 healthy family members had positive test in IgG Toxoplasma gondii(P = 0.09). In both groups, there was no positive IgM Toxoplasma gondii. In investigating leishmania, only 3 participants in the case group and 2 in the control tested positive (P = 0.25). No case of malaria was found among the participants. CONCLUSION: Our results showed a mismatch with hygiene hypotheses examined. However, considering that the prevalence of parasites varies with time, and depends on numerous epidemiological factors; these results do not discredit the theory investigated. PMID- 25709792 TI - Effect of conjugated linoleic Acid, vitamin e, alone or combined on immunity and inflammatory parameters in adults with active rheumatoid arthritis: a randomized controlled trial. AB - BACKGROUND: Little information about the effects of conjugated linoleic acids (CLAs) on inflammation and immune function in humans is available. This study investigated the effects of CLAs, with and without Vitamin E on immunity and inflammatory parameters in adults with active rheumatoid arthritis (RA). METHODS: In a double-blind clinical trial, 78 patients were randomly divided into four groups, each group receiving one of the following daily supplement for 3 months; group C: 2.5 g CLAs, group E: 400 mg Vitamin E, group CE: CLAs plus Vitamin E, group P: Placebo. Cytokines, matrix metalloproteinase 3 (MMP-3) and citrullinated antibody (CCP-A) were measured by ELISA method and Vitamin E by high-performance liquid chromatography. RESULTS: Consider statistical methods there were no significant differences between groups in cytokines interleukin-2 (IL-2), IL-4, tumor necrosis factor-alpha (TNF-alpha), IL-1beta, IL-2/IL-4, CCP-A white blood cells and neutrophils, lymphocyte, monocytes, and eosinophils numbers. TNF-alpha decreased in all groups, but its reduction was significant in group CE. IL-1beta increased in groups P (P = 0.004) and E (P = 0.041) but the difference between group P and CE was significant. IL-4 decreased in groups C, CE and E (P = 0.03, P = 0.03, P = 0.07 respectively). IL2 did not change significantly within groups. CCP-A increased in groups P (P = 0.035) and E (P = 0.05), while it decreased in groups CE (P = 0.034). CCP-A and MMP-3 decrease were significant between groups P and CE. MMP-3 reduction was significant in group CE. CONCLUSIONS: Co supplementation CLAs and Vitamin E may be effective in the level of inflammatory markers in RA patients. PMID- 25709794 TI - Relationship between Sleep Quality and Quality of Life in Patients with Multiple Sclerosis. AB - BACKGROUND: Impaired quality of life (QOL) is an issue considered in patients with multiple sclerosis (MS). There are limited studies evaluated poor sleep and impaired QOL in these cases. The aim of this study was to evaluate quality of sleep and poor sleep in Iranian patients with MS and the relationship between Pittsburgh Sleep Quality Index (PSQI) score and QOL subscales. METHODS: One hundred and fourteen cases with definite MS due to MC Donald criteria enrolled who referred to MS clinic of Sina and Imam Hospitals were enrolled. Patients asked to fill valid and reliable Persian versions of PSQI and MSQOL-54 questionnaires. Demographic data (sex, age), duration of the disease, education level and marital status were extracted from patients medical files. After neurological examination, Kurtzke Expanded Disability Status Scale (EDSS) was assessed. RESULTS: Ninety-one (79.8%) patients were female and 23 (20.2%) were male. Mean age and EDSS was 34.7 +/- 9.6 years and 2.3 (median: 1.5). Mean PSQI score and overall QOL score were 4.5 and 57. Sixty-seven cases were good sleepers (PSQI <= 5) and 47 were poor sleepers (PSQI > 5). Except five subscales, all others were significantly different between good and poor sleepers. There was significant positive correlation between PSQI score and EDSS (r = 0.24, P < 0.001) and negative correlation between EDSS and physical and mental health (r = 0.48, P < 0.001, r = -0.43, P < 0.001). EDSS and total PSQI score were independent predictors of physical and mental health composites. CONCLUSIONS: Sleep quality as a factor which affecting QOL should be considered and evaluated properly in MS patients. PMID- 25709795 TI - Body weight concerns and antifat attitude in Iranian children. AB - BACKGROUND: There is increasing evidence that children are showing body image issues in recent years. Body image disturbances in childhood must be taken seriously. The thin ideal is becoming more prominent in Asian countries; however, there is little research examining how this issue affects Iranian children. This study explores body weight concerns and associated factors among children in Iranian elementary schools. METHODS: This study was conducted in 500 elementary schools. An assessment of body image and antifat attitudes was undertaken using the figure rating scale. In addition, body mass index (BMI) and demographic variables were assessed. RESULTS: Nearly, 27.4% of children were underweight, and 13.3% were obese. There was a significant difference between the mean score of body dissatisfaction (BD) between boys and girls (P < 0.05). There were no differences between BD and education of parents, age, and academic grades. In girls, antifat attitudes were significantly related to BMI. CONCLUSIONS: The results of this study demonstrate the paramount importance of undertaking further research in order to identify the predictive factors of body concerns and its consequences among Iranian children. In addition, researchers must plan prevention and educational program for these children. PMID- 25709796 TI - The effect of anthocyanin supplementation on body composition, exercise performance and muscle damage indices in athletes. AB - BACKGROUND: Flavonoids consider as a large group of plant metabolites that 6,000 types of them have been identified till now. In some studies, it has been shown that they can increase aerobic performance and maximal oxygen consumption (VO2 max). The aim of this study was to evaluate the effect of anthocyanin (as one of the most important kind of flavonoids) supplementation on body composition, exercise performance and muscle damage indices in athletes. METHODS: This double blinded clinical trial involved 54 female and male athletes at Isfahan University of Medical Sciences with athletic history of at least 3 years. Body composition, exercise performance, creatine kinase, and lactate dehydrogenase were assessed. Individuals were selected by simple sampling method, they divided into two groups using permuted block randomization method. First group received 100 mg anthocyanin pills, and the second group received 100 mg placebo pills, daily for 6 weeks. Participants asked to continue their routine diet and physical activity during the study period, and they were followed through phone calls or text messages. RESULTS: Soft lean mass, total body water and percent body fat were not changed significantly in the anthocyanin group after intervention but VO2 max increased significantly in the anthocyanin group (48.65 +/- 4.73 vs. 52.62 +/- 5.04) (P <= 0.0001), also a significant difference was observed between two studied groups (52.62 +/- 5.04 for intervention group vs. 49.61 +/- 5.33 for placebo) (P = 0.003). CONCLUSIONS: Our findings suggested that the supplementation with anthocyanin in athletes may improve some indices of performance such as VO2 max. PMID- 25709797 TI - The Investigation of Construct Validity of Diagnostic and Statistical Manual of Mental Disorder-5 Personality Traits on Iranian sample with Antisocial and Borderline Personality Disorders. AB - BACKGROUND: The goal of this study was to examine the construct validity of the diagnostic and statistical manual of mental disorder-5 (DSM-5) conceptual model of antisocial and borderline personality disorders (PDs). More specifically, the aim was to determine whether the DSM-5 five-factor structure of pathological personality trait domains replicated in an independently collected sample that differs culturally from the derivation sample. METHODS: This study was on a sample of 346 individuals with antisocial (n = 122) and borderline PD (n = 130), and nonclinical subjects (n = 94). Participants randomly selected from prisoners, out-patient, and in-patient clients. Participants were recruited from Tehran prisoners, and clinical psychology and psychiatry clinics of Razi and Taleghani Hospital, Tehran, Iran. The SCID-II-PQ, SCID-II, DSM-5 Personality Trait Rating Form (Clinician's PTRF) were used to diagnosis of PD and to assessment of pathological traits. The data were analyzed by exploratory factor analysis. RESULTS: Factor analysis revealed a 5-factor solution for DSM-5 personality traits. Results showed that DSM-5 has adequate construct validity in Iranian sample with antisocial and borderline PDs. Factors similar in number with the other studies, but different in the content. CONCLUSIONS: Exploratory factor analysis revealed five homogeneous components of antisocial and borderline PDs. That may represent personality, behavioral, and affective features central to the disorder. Furthermore, the present study helps understand the adequacy of DSM-5 dimensional approach to evaluation of personality pathology, specifically on Iranian sample. PMID- 25709798 TI - Effect of honey vinegar syrup on blood sugar and lipid profile in healthy subjects. AB - BACKGROUND: The impact of honey or vinegar on several metabolic abnormalities has been studied separately, a mixture of these two ingredients known as honey vinegar syrup (HVS) has not been investigated previously so far. The aim of this study was to assess the impact of HVS consumption (Iranian's traditional syrup) on glycemic parameters and lipid profiles in healthy individuals. METHODS: We conducted a 4-week, randomized, controlled, parallel study consisting of two groups of nonobese healthy volunteers. All subjects were asked to stay on their normal diet. Intervention group (n = 36) received a cup of HVS daily in the evening snack for 4-week (250 cc syrup contains 21.66 g honey vinegar). Assessments of fasting blood sugar (FBS), insulin, homeostasis model assessment of insulin resistance (HOMA-IR), total cholesterol (TC), triglyceride (TG), high density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) were conducted at the baseline and after 4-week of study. RESULTS: We observed no significant effect of HVS on FBS, HOMA-IR, LDL-C and TG. A significant effect of HVS was found on increasing fasting insulin and HOMA-IR and reduction in TC level only in intervention group (Delta =3.39 P = 0.01, Delta =1.65 P = 0.03, Delta = -9.43 P = 0.005, respectively). Changes of FBS, TG and LDL-C were 1.83 mg/dl, -1.53 mg/dl and - 3.99 mg/dl respectively in the intervention group. These changes were not significant. An unfavorable and significant reduction in HDL-C level was also observed between two groups (Delta = -4.82 P < 0.001 in the intervention group). CONCLUSIONS: Honey vinegar syrup increased fasting insulin level and decreased TC level in the intervention group. HVS had an unfavorable effect on HDL-C level. Further prospective investigations are warranted to confirm these findings. PMID- 25709799 TI - Opportunistic Screening for Hypertension and Selected Cardiovascular Risk Factors among Adults Attending a Primary Health Center in Puducherry, India. AB - BACKGROUND: India is currently suffering from an epidemic of noncommunicable diseases; it is thus imperative to screen for cardiovascular risk factors in people visiting Primary Health Centers (PHCs). The objective of the study was to measure the amount of undiagnosed hypertension and selected cardiovascular risk factors present among the adult population through opportunistic screening at the PHC. METHODS: A facility-based opportunistic screening program was carried out in a PHC in rural Puducherry. Patients and accompanying persons aged 30 years and above, who attended the daily outpatient department (OPD) were included. The OPD provides outpatient services and medical procedures or tests without requirement of an overnight stay, and functions for 4 h a day. Known hypertensive patients and pregnant women were excluded. Information on age, gender, diabetes status, and personal history of tobacco and alcohol use were collected using an interview schedule. Height, weight and waist circumference were measured, along with blood pressure and blood sugar using standard protocols. Systolic blood pressure (SBP) >=140 and/or diastolic blood pressure (DBP) >=90 mm Hg was taken as hypertension. SBP of 120-139 mm Hg and/or DBP of 80-89 mm Hg were taken as prehypertension. RESULTS: A total of 324 participants were screened; 56.8% were females. The mean standard deviation (SD) age of the participants was 47.7 (SD 12.6) years. Hypertension and prehypertension were present in 17.9% and 37.7% of the participants respectively. 17.3% participants had diabetes. 22.2% and 21.3% of all participants were current users of tobacco and alcohol respectively. Generalized obesity was present in 31.8% of the participants; 19.1% were overweight. 45.1% participants had central obesity. CONCLUSIONS: A relatively large proportion of adults were found to have prehypertension and obesity, thus showing the need for early intervention. PMID- 25709800 TI - Pomegranate Flower Extract does not Prevent Cisplatin-Induced Nephrotoxicity in Female Rats. AB - BACKGROUND: Nephrotoxicity is the major side-effect of cisplatin (CDDP), and it is reported to be gender-related. We evaluated the effects of pomegranate flower extract (PFE) as an antioxidant on CDDP-induced nephrotoxicity in female rats. METHODS: Twenty-three adult female rats in four groups treated as following. Groups 1 and 2 received PFE at doses of 25 and 50 (mg/kg/day), respectively, for 9 days, and from day 3 on, they also received cisplatin (CDDP) (2.5 mg/kg) daily. Group 3 was treated as group 1 expects saline instead of PFE, and group 4 received PFE (25 mg/kg/day) alone. RESULTS: Cisplatin alone increased the serum levels of blood urea nitrogen, creatinine, and nitrite; and kidney tissue damage score and kidney weight. However, PFE not only did not ameliorate the induced nephrotoxicity, but also aggravated renal tissue damage. CONCLUSIONS: Pomegranate extract as an antioxidant did not ameliorate CDDP-induced nephrotoxicity in female rats. PMID- 25709801 TI - A Cross-sectional Study of Correlation of Body Image Anxiety with Social Phobia and Their Association with Depression in the Adolescents from a Rural Area of Sangli District in India. AB - BACKGROUND: Prevailing socio-cultural influences lead females to desire a thin body and males a muscular body, especially in adolescents. This results in body image anxiety which may lead to social phobia. Together they can develop depression. The aim was to study the correlation of body image anxiety with social phobia and their association with depression, among adolescents. METHODS: This was a cross-sectional study conducted in randomly selected colleges from a rural area of Sangli district Maharashtra, India. Stratified random sampling technique used with sample size 805. Pretested self-administered questionnaire used. Percentage, Chi-square test, binary logistic regression model was used to estimate odds ratio (OR) and its 95% confidence intervals. RESULTS: Of 997 study subjects body image anxiety, social phobia and depression were observed in 232 (23.3%), 193 (19.4%) and 326 (32.7%) participants, respectively. Binary logistic regression showed that body image anxiety (OR = 1.849 [1.22, 2.804]; P = 0.004) and social phobia (OR = 4.575 [2.952-7.09]; P < 0.001) were significant predictors for depression. CONCLUSIONS: Body image anxiety and social phobia are linked with the development of depression. This impresses the need for timely counseling and education among adolescents. PMID- 25709802 TI - Leech Infestation in the Vulvar Region: A Possibility to be Considered. PMID- 25709803 TI - Pericardial manifestations in autoimmune encounters: some worthy facts for consideration! PMID- 25709804 TI - The energy blocker inside the power house: Mitochondria targeted delivery of 3 bromopyruvate. AB - A key hallmark of many aggressive cancers is accelerated glucose metabolism. The enzymes that catalyze the first step of glucose metabolism are hexokinases. High levels of hexokinase 2 (HK2) are found in cancer cells, but only in a limited number of normal tissues. Metabolic reprogramming of cancer cells using the energy blocker, 3-bromopyruvate (3-BP) that inhibits HK2 has the potential to provide tumor-specific anticancer agents. However, the unique structural and functional characteristics of mitochondria prohibit selective subcellular targeting of 3-BP to modulate the function of this organelle for therapeutic gain. A mitochondria targeted gold nanoparticle (T-3-BP-AuNP) decorated with 3-BP and delocalized lipophilic triphenylphosphonium cations to target the mitochondrial membrane potential (Deltapsim) was developed for delivery of 3-BP to cancer cell mitochondria by taking advantage of higher Deltapsim in cancer cells compared to normal cells. In vitro studies demonstrated enhanced anticancer activity of T-3-BP-AuNPs compared to the non-targeted construct NT-3-BP-AuNP or free 3-BP. The anticancer activity of T-3-BP-AuNP was further enhanced upon laser irradiation by exciting the surface plasmon resonance band of AuNP and thereby utilizing a combination of 3-BP chemotherapeutic and AuNP photothermal effects. The less toxic behavior of T-3-BPNPs in normal mesenchymal stem cells indicated that these NPs preferentially kill cancer cells. T-3-BP-AuNPs showed enhanced ability to modulate cancer cell metabolism by inhibiting glycolysis as well as demolishing mitochondrial oxidative phosphorylation. Our findings demonstrated that concerted chemo-photothermal treatment of glycolytic cancer cells with a single NP capable of targeting mitochondria mediating simultaneous release of a glycolytic inhibitor and photothermal ablation may have promise as a new anticancer therapy. PMID- 25709805 TI - Chemiluminescent Probes for Imaging H2S in Living Animals. AB - Hydrogen sulphide (H2S) is an endogenous mediator of human health and disease, but precise measurement in living cells and animals remains a considerable challenge. We report the total chemical synthesis and characterization of three 1,2-dioxetane chemiluminescent reaction-based H2S probes, CHS-1, CHS-2, and CHS 3. Upon treatment with H2S at physiological pH, these probes display instantaneous light emission that is sustained for over an hour with high selectivity against other reactive sulphur, oxygen, and nitrogen species. Analysis of the phenol/phenolate equilibrium and atomic charges has provided a generally applicable predictive model to design improved chemiluminescent probes. The utility of these chemiluminescent reagents was demonstrated by applying CHS-3 to detect cellularly generated H2S using a multi-well plate reader and to image H2S in living mice using CCD camera technology. PMID- 25709806 TI - Light-induced Crosslinkable Semiconducting Polymer Dots. AB - This paper describes a synthetic approach for photocrosslinkable polyfluorene (pc PFO) semiconducting polymer dots, and demonstrates their superior ability to crosslink and form 3-D intermolecular polymer networks. The crosslinked pc-PFO Pdots are equipped with excellent encapsulating ability of functional small molecules. Optimum conditions of light irradiation on pc-PFO Pdots were investigated and clarified by using polymer thin films as a model. By employing the optimal light irradiation conditions, we successfully crosslinked pc-PFO Pdots and studied their particle sizes, photophysical, and colloidal properties. Single-particle imaging and dynamic-light-scattering measurements were conducted to understand the behaviors of photocrosslinked Pdots. Our results indicate pc PFO Pdots can be easily photocrosslinked and the crosslinked species have excellent colloidal stability, physical and chemical stability, fluorescence brightness, and specific binding properties for cellular labeling. Considering that optical stimulus can work remotely, cleanly, and non-invasively, this study should pave the way for a promising approach to further develop stimuli responsive ultrabright and versatile Pdot probes for biomedical imaging. PMID- 25709807 TI - Evaluating nurse plants for restoring native woody species to degraded subtropical woodlands. AB - Harsh habitats dominated by invasive species are difficult to restore. Invasive grasses in arid environments slow succession toward more desired composition, yet grass removal exacerbates high light and temperature, making the use of "nurse plants" an appealing strategy. In this study of degraded subtropical woodlands dominated by alien grasses in Hawai'i, we evaluated whether individuals of two native (Dodonaea viscosa, Leptocophylla tameiameia) and one non-native (Morella faya) woody species (1) act as natural nodes of recruitment for native woody species and (2) can be used to enhance survivorship of outplanted native woody species. To address these questions, we quantified the presence and persistence of seedlings naturally recruiting beneath adult nurse shrubs and compared survival and growth of experimentally outplanted seedlings of seven native woody species under the nurse species compared to intact and cleared alien-grass plots. We found that the two native nurse shrubs recruit their own offspring, but do not act as establishment nodes for other species. Morella faya recruited even fewer seedlings than native shrubs. Thus, outplanting will be necessary to increase abundance and diversity of native woody species. Outplant survival was the highest under shrubs compared to away from them with few differences between nurse species. The worst habitat for native seedling survival and growth was within the unmanaged invasive grass matrix. Although the two native nurse species did not differentially affect outplant survival, D. viscosa is the most widespread and easily propagated and is thus more likely to be useful as an initial nurse species. The outplanted species showed variable responses to nurse habitats that we attribute to resource requirements resulting from their typical successional stage and nitrogen fixation capability. PMID- 25653843 TI - UV-independent induction of beta defensin 3 in neonatal human skin explants. AB - In order to determine the effect of UV radiation on beta-defensin 3 (BD3) expression in human skin, freshly-isolated UV-naive skin was obtained from newborn male infants undergoing planned circumcision. Skin explants sustained ex vivo dermis side down on RPMI media were exposed to 0.5 kJ/m (2) UVB, and biopsies were taken from the explant through 72 hours after radiation. mRNA expression was measured by qRTPCR and normalized to TATA-binding protein. BD3 expression at each time point was compared with an untreated control taken at time 0 within each skin sample. Extensive variability in both the timing and magnitude of BD3 induction across individuals was noted and was not predicted by skin pigment phenotype, suggesting that BD3 induction was not influenced by epidermal melanization. However, a mock-irradiated time course demonstrated UV independent BD3 mRNA increases across multiple donors which was not further augmented by treatment with UV radiation, suggesting that factors other than UV damage promoted increased BD3 expression in the skin explants. We conclude that BD3 expression is induced in a UV-independent manner in human skin explants processed and maintained in standard culture conditions, and that neonatal skin explants are an inappropriate model with which to study the effects of UV on BD3 induction in whole human skin. PMID- 25709809 TI - The effect of photoinitiators on intracellular AKT signaling pathway in tissue engineering application. AB - Free-radical photopolymerization initiated by photoinitiators is an important method to make tissue engineering scaffolds. To advance understanding of photoinitiator cytocompatibility, we examined three photoinitiators including 2,2 dimethoxy-2-phenylacetophenone (DMPA), Irgacure 2959 (I-2959), and eosin Y photoinitiating system (EY) in terms of their effects on viability of HN4 cells and expression levels of intracellular AKT and its phosphorylated form p-AKT. Our results show that the photoinitiators and their UV-exposed counterparts affect intracellular AKT signaling, which can be used in conjunction with cell viability for cytocompatibility assessment of photoinitiators. PMID- 25709810 TI - Impact on bone and muscle area after spinal cord injury. AB - Spinal cord injury (SCI) causes inactivation and consequent unloading of affected skeletal muscle and bone. This cross-sectional study investigated correlations of muscle and bone in spinal cord-injured subjects compared with able-bodied subjects. Thirty-one complete SCI paraplegics were divided according to the neurological level of injury (NLoI) into group A (n=16, above thoracic 7 NLoI, age: 33+/-16 years, duration of paralysis (DoP): 6+/-6 years) and group B (n=15, thoracic 8-12, age: 39+/-14 years, DoP: 5.6+/-6 years), compared with 33 controls (group C). All were examined with peripheral quantitative computed tomography at 66% of tibia length (bone and muscle area, bone/muscle area ratio). In able bodied subjects, muscle area was correlated with bone area (P<0.001, r=0.88). Groups A and B differed significantly from the control group in terms of bone and muscle area (P<0.001). In paraplegics, less muscle per unit of bone area (bone/muscle area ratio) was found compared with controls (P<0.001). Bone area was negatively correlated with the DoP in the total paraplegic group (r=-0.66, P<0.001) and groups A and B (r=-0.77, P=0.001 vs r=-0.52, P=0.12, respectively). Muscle area and bone/muscle ratio area correlations in paraplegic groups with DoP were weak. Paraplegic subjects who performed standing and therapeutic walking had significantly higher bone area (P=0.02 and P=0.013, respectively). The relationship between bone and muscle was consistent in able-bodied subjects and it was predictably altered in those with SCI, a clinical disease affecting bone and muscle. PMID- 25709811 TI - Long-term safety of antiresorptive treatment: bone material, matrix and mineralization aspects. AB - It is well established that long-term antiresorptive use is effective in the reduction of fracture risk in high bone turnover osteoporosis. Nevertheless, during recent years, concerns emerged that longer bone turnover reduction might favor the occurrence of fatigue fractures. However, the underlying mechanisms for both beneficial and suspected adverse effects are not fully understood yet. There is some evidence that their effects on the bone material characteristics have an important role. In principle, the composition and nanostructure of bone material, for example, collagen cross-links and mineral content and crystallinity, is highly dependent on tissue age. Bone turnover determines the age distribution of the bone structural units (BSUs) present in bone, which in turn is decisive for its intrinsic material properties. It is noteworthy that the effects of bone turnover reduction on bone material were observed to be dependent on the duration of the antiresorptive therapy. During the first 2-3 years, significant decreases in the heterogeneity of material properties such as mineralization of the BSUs have been observed. In the long term (5-10 years), the mineralization pattern reverts towards normal heterogeneity and degree of mineralization, with no signs of hypermineralization in the bone matrix. Nevertheless, it has been hypothesized that the occurrence of fatigue fractures (such as atypical femoral fractures) might be linked to a reduced ability of microdamage repair under antiresorptive therapy. The present article examines results from clinical studies after antiresorptive, in particular long-term, therapy with the aforementioned potentially positive or negative effects on bone material. PMID- 25709812 TI - Big data challenges in bone research: genome-wide association studies and next generation sequencing. AB - Genome-wide association studies (GWAS) have been developed as a practical method to identify genetic loci associated with disease by scanning multiple markers across the genome. Significant advances in the genetics of complex diseases have been made owing to advances in genotyping technologies, the progress of projects such as HapMap and 1000G and the emergence of genetics as a collaborative discipline. Because of its great potential to be used in parallel by multiple collaborators, it is important to adhere to strict protocols assuring data quality and analyses. Quality control analyses must be applied to each sample and each single-nucleotide polymorphism (SNP). The software package PLINK is capable of performing the whole range of necessary quality control tests. Genotype imputation has also been developed to substantially increase the power of GWAS methodology. Imputation permits the investigation of associations at genetic markers that are not directly genotyped. Results of individual GWAS reports can be combined through meta-analysis. Finally, next-generation sequencing (NGS) has gained popularity in recent years through its capacity to analyse a much greater number of markers across the genome. Although NGS platforms are capable of examining a higher number of SNPs compared with GWA studies, the results obtained by NGS require careful interpretation, as their biological correlation is incompletely understood. In this article, we will discuss the basic features of such protocols. PMID- 25709813 TI - HIV infection and osteoporosis. AB - In the past two decades, the life expectancy of people living with HIV infection has increased significantly, and osteoporosis has emerged as a significant comorbidity. In addition to traditional risk factors for fracture, specific factors related to HIV infection are also likely to contribute, including antiretroviral therapy. The heterogeneity of the HIV-infected population in terms of age and ethnicity presents many challenges to the prevention and management of bone disease, and further studies are required to establish optimal approaches to risk assessment and treatment. PMID- 25709814 TI - A Dual Gold Nanoparticle System for Mesenchymal Stem Cell Tracking. AB - Stem cell-based therapies have demonstrated improved outcomes in preclinical and clinical trials for treating cardiovascular ischemic diseases. However, the contribution of stem cells to vascular repair is poorly understood. To elucidate these mechanisms, many have attempted to monitor stem cells following their delivery in vivo, but these studies have been limited by the fact that many contrast agents, including nanoparticles, are commonly passed on to non-stem cells in vivo. Specifically, cells of the reticuloendothelial system, such as macrophages, frequently endocytose free contrast agents, resulting in the monitoring of macrophages instead of the stem cell therapy. Here we demonstrate a dual gold nanoparticle system which is capable of monitoring both delivered stem cells and infiltrating macrophages using photoacoustic imaging. In vitro analysis confirmed preferential labeling of the two cell types with their respective nanoparticles and the maintenance of cell function following nanoparticle labeling. In addition, delivery of the system within a rat hind limb ischemia model demonstrated the ability to monitor stem cells and distinguish and quantify macrophage infiltration. These findings were confirmed by histology and mass spectrometry analysis. This work has important implications for cell tracking and monitoring cell-based therapies. PMID- 25709815 TI - A milestone for movement ecology research. PMID- 25709816 TI - Home range plus: a space-time characterization of movement over real landscapes. AB - BACKGROUND: Advances in GPS technology have created both opportunities in ecology as well as a need for analytical tools that can deal with the growing volume of data and ancillary variables associated with each location. RESULTS: We present T LoCoH, a home range construction algorithm that incorporates time into the construction and aggregation of local kernels. Time is integrated with Euclidean space using an adaptive scaling of the individual's characteristic velocity, enabling the construction of utilization distributions that capture temporal partitions of space as well as contours that differentiate internal space based on movement phase and time-use metrics. We test T-LoCoH against a simulated dataset and provide illustrative examples from a GPS dataset from springbok in Namibia. CONCLUSIONS: The incorporation of time into home range construction expands the concept of utilization distributions beyond the traditional density gradient to spatial models of movement and time, opening the door to new applications in movement ecology. PMID- 25709817 TI - The environmental-data automated track annotation (Env-DATA) system: linking animal tracks with environmental data. AB - BACKGROUND: The movement of animals is strongly influenced by external factors in their surrounding environment such as weather, habitat types, and human land use. With advances in positioning and sensor technologies, it is now possible to capture animal locations at high spatial and temporal granularities. Likewise, scientists have an increasing access to large volumes of environmental data. Environmental data are heterogeneous in source and format, and are usually obtained at different spatiotemporal scales than movement data. Indeed, there remain scientific and technical challenges in developing linkages between the growing collections of animal movement data and the large repositories of heterogeneous remote sensing observations, as well as in the developments of new statistical and computational methods for the analysis of movement in its environmental context. These challenges include retrieval, indexing, efficient storage, data integration, and analytical techniques. RESULTS: This paper contributes to movement ecology research by presenting a new publicly available system, Environmental-Data Automated Track Annotation (Env-DATA), that automates annotation of movement trajectories with ambient atmospheric observations and underlying landscape information. Env-DATA provides a free and easy-to-use platform that eliminates technical difficulties of the annotation processes and relieves end users of a ton of tedious and time-consuming tasks associated with annotation, including data acquisition, data transformation and integration, resampling, and interpolation. The system is illustrated with a case study of Galapagos Albatross (Phoebastria irrorata) tracks and their relationship to wind, ocean productivity and chlorophyll concentration. Our case study illustrates why adult albatrosses make long-range trips to preferred, productive areas and how wind assistance facilitates their return flights while their outbound flights are hampered by head winds. CONCLUSIONS: The new Env-DATA system enhances Movebank, an open portal of animal tracking data, by automating access to environmental variables from global remote sensing, weather, and ecosystem products from open web resources. The system provides several interpolation methods from the native grid resolution and structure to a global regular grid linked with the movement tracks in space and time. The aim is to facilitate new understanding and predictive capabilities of spatiotemporal patterns of animal movement in response to dynamic and changing environments from local to global scales. PMID- 25709818 TI - Flying with the wind: scale dependency of speed and direction measurements in modelling wind support in avian flight. AB - BACKGROUND: Understanding how environmental conditions, especially wind, influence birds' flight speeds is a prerequisite for understanding many important aspects of bird flight, including optimal migration strategies, navigation, and compensation for wind drift. Recent developments in tracking technology and the increased availability of data on large-scale weather patterns have made it possible to use path annotation to link the location of animals to environmental conditions such as wind speed and direction. However, there are various measures available for describing not only wind conditions but also the bird's flight direction and ground speed, and it is unclear which is best for determining the amount of wind support (the length of the wind vector in a bird's flight direction) and the influence of cross-winds (the length of the wind vector perpendicular to a bird's direction) throughout a bird's journey. RESULTS: We compared relationships between cross-wind, wind support and bird movements, using path annotation derived from two different global weather reanalysis datasets and three different measures of direction and speed calculation for 288 individuals of nine bird species. Wind was a strong predictor of bird ground speed, explaining 10-66% of the variance, depending on species. Models using data from different weather sources gave qualitatively similar results; however, determining flight direction and speed from successive locations, even at short (15 min intervals), was inferior to using instantaneous GPS-based measures of speed and direction. Use of successive location data significantly underestimated the birds' ground and airspeed, and also resulted in mistaken associations between cross-winds, wind support, and their interactive effects, in relation to the birds' onward flight. CONCLUSIONS: Wind has strong effects on bird flight, and combining GPS technology with path annotation of weather variables allows us to quantify these effects for understanding flight behaviour. The potentially strong influence of scaling effects must be considered and implemented in developing sampling regimes and data analysis. PMID- 25709819 TI - Mixed strategies of griffon vultures' (Gyps fulvus) response to food deprivation lead to a hump-shaped movement pattern. AB - BACKGROUND: The need to obtain food is a critical proximate driver of an organism's movement that shapes the foraging and survival of individual animals. Consequently, the relationship between hunger and foraging has received considerable attention, leading to the common conception that hunger primarily enhances a "food-intake maximization" (FIMax) strategy and intensive search. A complementary explanation, however, suggests a trade-off with precautions taken to reduce the risk of physiological collapse from starvation, under a strategy we denote as "energy-expenditure minimization" (EEMin). The FImax-EEmin trade-off may interact with the forager's hunger level to shape a complex (non-monotonic) response pattern to increasing hunger. Yet, this important trade-off has rarely been investigated, particularly in free-ranging wild animals. We explored how hunger affects the movements of adult griffon vultures (Gyps fulvus) in southern Israel. Transmitters combining GPS and accelerometers provided high-resolution data on vultures' movements and behavior, enabling the identification of feeding events and the estimation of food deprivation periods (FDPs, measured in days), which is used as a proxy for hunger. RESULTS: Data from 47 vultures, tracked for 339 +/- 36 days, reveal high variability in FDPs. While flight speed, flight straightness and the proportion of active flights were invariant in relation to food deprivation, a clear hump-shaped response was found for daily flight distances, maximal displacements and flight elevation. These movement characteristics increased during the first five days of the FDP sequence and decreased during the following five days. These characteristics also differed between short FDPs of up to four days, and the first four days of longer FDP sequences. These results suggest a switch from FIMax to EEMin strategies along the FDP sequence. They also indicate that vultures' response to hunger affected the eventual duration of the FDP. During winter (the vultures' incubation period characterized by unfavorable soaring meteorological conditions), the vultures' FIMax response was less intensive and resulted in longer starvation periods, while, in summer, more intensive FIMax response to hunger resulted in shorter FDPs. CONCLUSIONS: Our results show a flexible, non-monotonic response of free ranging wild animals to increasing hunger levels, reflecting a trade-off between increasing motivation to find food and the risk of starvation. The proposed trade off offers a unifying perspective to apparently contradictory or case-specific empirical findings. PMID- 25709820 TI - Integrating movement ecology with biodiversity research - exploring new avenues to address spatiotemporal biodiversity dynamics. AB - Movement of organisms is one of the key mechanisms shaping biodiversity, e.g. the distribution of genes, individuals and species in space and time. Recent technological and conceptual advances have improved our ability to assess the causes and consequences of individual movement, and led to the emergence of the new field of 'movement ecology'. Here, we outline how movement ecology can contribute to the broad field of biodiversity research, i.e. the study of processes and patterns of life among and across different scales, from genes to ecosystems, and we propose a conceptual framework linking these hitherto largely separated fields of research. Our framework builds on the concept of movement ecology for individuals, and demonstrates its importance for linking individual organismal movement with biodiversity. First, organismal movements can provide 'mobile links' between habitats or ecosystems, thereby connecting resources, genes, and processes among otherwise separate locations. Understanding these mobile links and their impact on biodiversity will be facilitated by movement ecology, because mobile links can be created by different modes of movement (i.e., foraging, dispersal, migration) that relate to different spatiotemporal scales and have differential effects on biodiversity. Second, organismal movements can also mediate coexistence in communities, through 'equalizing' and 'stabilizing' mechanisms. This novel integrated framework provides a conceptual starting point for a better understanding of biodiversity dynamics in light of individual movement and space-use behavior across spatiotemporal scales. By illustrating this framework with examples, we argue that the integration of movement ecology and biodiversity research will also enhance our ability to conserve diversity at the genetic, species, and ecosystem levels. PMID- 25709821 TI - Methods for assessment of short-term coral reef fish movements within an acoustic array. AB - BACKGROUND: Arrays of passive receivers are a widely used tool for tracking the movements of acoustically-tagged fish in marine ecosystems; however, the spatial and temporal heterogeneity of coral reef environments pose challenges for the interpretation of tag detection data. To improve this situation for reef fishes, we introduced a novel response variable method that treats signal detections as proportions (i.e., percent transmissions detected or "detection rates") and compared this against prior approaches to examine the influence of array and transmitter performance, signal distance and environmental factors on detection rates. We applied this method to tagged snappers and groupers in the Florida reef ecosystem and controlled range-tests on static targets in Bayboro Harbor, Florida, to provide methodological guidance for the planning and evaluation of passive array studies for coral reef fishes. RESULTS: Logistic regression analysis indicated detection rates were primarily a non-linear function of tag distance from receiver. A 'model-weighted' function was developed to incorporate the non-linear relationship between detection rate and distance to provide robust positioning estimates and allow for easy extension to tags with different ping rates. CONCLUSIONS: Optimal acoustic array design requires balancing the interplay between receiver spacing, detection rates, and positioning error. Spacing receivers at twice the distance of the modeled 50% detection rate may be appropriate when quantification of overall space use is a priority, and would provide a minimum of 75% detection rate. However, for research where missing detections within the array is unacceptable or time-at-arrival based fine-scale positioning is needed, tighter receiver spacing may be required to maintain signal detection probability near 100%. PMID- 25709822 TI - Movement patterns of an arboreal marsupial at the edge of its range: a case study of the koala. AB - BACKGROUND: Conservation strategies derived from research carried out in one part of the range of a widely distributed species and then uniformly applied over multiple regions risk being ineffective due to regional variations in species habitat relationships. This is particularly true at the edge of the range where information on animal movements and resource selection is often limited. Here, we investigate home range size, movement patterns and resource selection of koalas Phascolarctos cinereus in the semi-arid and arid landscapes of southwest Queensland, Australia. We placed collars with GPS units on 21 koalas in three biogeographic regions. Home range sizes, resource selection and movement patterns were examined across the three regions. RESULTS: Habitat selectivity was highest at the more arid, western edge of the koala's range with their occupancy restricted to riparian/drainage line habitats, while the more easterly koalas displayed more variability in habitat use. There was no significant difference between home range sizes of koalas at the western edge of the range compared to the more easterly koalas. Instead, variability in home range size was attributed to spatial variations in habitat quality or the availability of a key resource, with a strong influence of rainfall and the presence of freestanding water on the home range size of koalas. Within a 580 m spatial range, movement patterns of male and female paths showed a tortuous trend, consistent with foraging behavior. Beyond this spatial range, male paths showed a trend to more linear patterns, representing a transition of movement behavior from foraging to breeding and dispersal. CONCLUSIONS: The difference in home range movement patterns and resource use among the different koala populations shows that behavior changes with proximity to the arid edge of the koala's range. Changes in home range size and resource use near the range edge highlight the importance of further range edge studies for informing effective koala conservation and management actions, especially when developing species-specific adaptation responses to climate change. PMID- 25709823 TI - The Levy flight foraging hypothesis: forgetting about memory may lead to false verification of Brownian motion. AB - BACKGROUND: The Levy flight foraging hypothesis predicts a transition from scale free Levy walk (LW) to scale-specific Brownian motion (BM) as an animal moves from resource-poor towards resource-rich environment. However, the LW-BM continuum implies a premise of memory-less search, which contradicts the cognitive capacity of vertebrates. RESULTS: We describe methods to test if apparent support for LW-BM transitions may rather be a statistical artifact from movement under varying intensity of site fidelity. A higher frequency of returns to previously visited patches (stronger site fidelity) may erroneously be interpreted as a switch from LW towards BM. Simulations of scale-free, memory enhanced space use illustrate how the ratio between return events and scale-free exploratory movement translates to varying strength of site fidelity. An expanded analysis of GPS data of 18 female red deer, Cervus elaphus, strengthens previous empirical support of memory-enhanced and scale-free space use in a northern forest ecosystem. CONCLUSION: A statistical mechanical model architecture that describes foraging under environment-dependent variation of site fidelity may allow for higher realism of optimal search models and movement ecology in general, in particular for vertebrates with high cognitive capacity. PMID- 25709824 TI - Dispersal in a changing world: opportunities, insights and challenges. AB - It has been long recognised that dispersal is an important life-history trait that plays a key role in the demography and evolution of populations and species. This then suggests that dispersal play a central role in the response of populations and species to ever-increasing global change, including climate change, habitat loss and fragmentation, and biological invasions. During a symposium held at Lund University (Sweden), the causes and consequences of dispersal were discussed, and here we provide an overview of the talks. As the discussions often gravitated towards the role and our understanding of dispersal in a changing world and given the urgent challenges posed by it, we place this overview in the context of global change. We draw and discuss four conclusions: (i) methodological advances provide opportunities for improved future studies, (ii) dispersal distances can be much greater than previously thought (examples in plants and vertebrates), but also much more restricted (examples in micro organisms), (iii) dispersal is more dynamic than we often care to admit (e.g. due to individual variation, effects of parasites, variation in life history, developmental and evolutionary responses, community impacts), (iv) using results of dispersal research for detailed prediction of outcomes under global change is currently mostly out of reach - nevertheless, that should not stop us from showing the many negative consequences of global change, and how dispersal is often a limiting factor in adapting to this. PMID- 25709825 TI - Evaluating the intersection of a regional wildlife connectivity network with highways. AB - BACKGROUND: Reliable predictions of regional-scale population connectivity are needed to prioritize conservation actions. However, there have been few examples of regional connectivity models that are empirically derived and validated. The central goals of this paper were to (1) evaluate the effectiveness of factorial least cost path corridor mapping on an empirical resistance surface in reflecting the frequency of highway crossings by American black bear, (2) predict the location and predicted intensity of use of movement corridors for American black bear, and (3) identify where these corridors cross major highways and rank the intensity of these crossings. RESULTS: We used factorial least cost path modeling coupled with resistant kernel analysis to predict a network of movement corridors across a 30.2 million hectare analysis area in Montana and Idaho, USA. Factorial least cost path corridor mapping was associated with the locations of actual bear highway crossings. We identified corridor-highway intersections and ranked these based on corridor strength. We found that a major wildlife crossing overpass structure was located close to one of the most intense predicted corridors, and that the vast majority of the predicted corridor network was "protected" under federal management. However, narrow, linear corridors connecting the Greater Yellowstone Ecosystem to the rest of the analysis area had limited protection by federal ownership, making these additionally vulnerable to habitat loss and fragmentation. CONCLUSIONS: Factorial least cost path modeling coupled with resistant kernel analysis provides detailed, synoptic information about connectivity across populations that vary in distribution and density in complex landscapes. Specifically, our results could be used to quantify the structure of the connectivity network, identify critical linkage nodes and core areas, map potential barriers and fracture zones, and prioritize locations for mitigation, restoration and conservation actions. PMID- 25709826 TI - Using diel movement behavior to infer foraging strategies related to ecological and social factors in elephants. AB - BACKGROUND: Adaptive movement behaviors allow individuals to respond to fluctuations in resource quality and distribution in order to maintain fitness. Classically, studies of the interaction between ecological conditions and movement behavior have focused on such metrics as travel distance, velocity, home range size or patch occupancy time as the salient metrics of behavior. Driven by the emergence of very regular high frequency data, more recently the importance of interpreting the autocorrelation structure of movement as a behavioral metric has become apparent. Studying movement of a free ranging African savannah elephant population, we evaluated how two movement metrics, diel displacement (DD) and movement predictability (MP - the degree of autocorrelated movement activity at diel time scales), changed in response to variation in resource availability as measured by the Normalized Difference Vegetation Index. We were able to capitalize on long term (multi-year) yet high resolution (hourly) global positioning system tracking datasets, the sample size of which allows robust analysis of complex models. We use optimal foraging theory predictions as a framework to interpret our results, in particular contrasting the behaviors across changes in social rank and resource availability to infer which movement behaviors at diel time scales may be optimal in this highly social species. RESULTS: Both DD and MP increased with increasing forage availability, irrespective of rank, reflecting increased energy expenditure and movement predictability during time periods of overall high resource availability. However, significant interactions between forage availability and social rank indicated a stronger response in DD, and a weaker response in MP, with increasing social status. CONCLUSIONS: Relative to high ranking individuals, low ranking individuals expended more energy and exhibited less behavioral movement autocorrelation during lower forage availability conditions, likely reflecting sub-optimal movement behavior. Beyond situations of contest competition, rank status appears to influence the extent to which individuals can modify their movement strategies across periods with differing forage availability. Large scale spatiotemporal resource complexity not only impacts fine scale movement and optimal foraging strategies directly, but likely impacts rates of inter- and intra-specific interactions and competition resulting in socially based movement responses to ecological dynamics. PMID- 25709827 TI - Cereal aphid movement: general principles and simulation modelling. AB - Cereal aphids continue to be an important agricultural pest, with complex lifecycle and dispersal behaviours. Spatially-explicit models that are able to simulate flight initiation, movement direction, distance and timing of arrival of key aphid species can be highly valuable to area-wide pest management programmes. Here I present an overview of how knowledge about cereal aphid flight and migration can be utilized by mechanistic simulation models. This article identifies specific gaps in knowledge for researchers who may wish to further scientific understanding of aphid flight behaviour, whilst at the same time provides a synopsis of the knowledge requirements for a mechanistic approach applicable to the simulation of a wide range of insect species. Although they are one of the most comprehensively studied insect groups in entomology, it is only recently that our understanding of cereal aphid flight and migration has been translated effectively into spatially-explicit simulation models. There are now a multitude of examples available in the literature for modelling methods that address each of the four phases of the aerial transportation process (uplift, transport in the atmosphere, initial distribution, and subsequent movement). I believe it should now be possible to draw together this knowledgebase and the range of modelling methods available to simulate the entire process: integrating mechanistic simulations that estimate the initiation of migration events, with the large scale migration modelling of cereal aphids and their subsequent local movement. PMID- 25709830 TI - When to be discrete: the importance of time formulation in understanding animal movement. AB - Animal movement is essential to our understanding of population dynamics, animal behavior, and the impacts of global change. Coupled with high-resolution biotelemetry data, exciting new inferences about animal movement have been facilitated by various specifications of contemporary models. These approaches differ, but most share common themes. One key distinction is whether the underlying movement process is conceptualized in discrete or continuous time. This is perhaps the greatest source of confusion among practitioners, both in terms of implementation and biological interpretation. In general, animal movement occurs in continuous time but we observe it at fixed discrete-time intervals. Thus, continuous time is conceptually and theoretically appealing, but in practice it is perhaps more intuitive to interpret movement in discrete intervals. With an emphasis on state-space models, we explore the differences and similarities between continuous and discrete versions of mechanistic movement models, establish some common terminology, and indicate under which circumstances one form might be preferred over another. Counter to the overly simplistic view that discrete- and continuous-time conceptualizations are merely different means to the same end, we present novel mathematical results revealing hitherto unappreciated consequences of model formulation on inferences about animal movement. Notably, the speed and direction of movement are intrinsically linked in current continuous-time random walk formulations, and this can have important implications when interpreting animal behavior. We illustrate these concepts in the context of state-space models with multiple movement behavior states using northern fur seal (Callorhinus ursinus) biotelemetry data. PMID- 25709829 TI - Consequences of animal interactions on their dynamics: emergence of home ranges and territoriality. AB - Animal spacing has important implications for population abundance, species demography and the environment. Mechanisms underlying spatial segregation have their roots in the characteristics of the animals, their mutual interaction and their response, collective as well as individual, to environmental variables. This review describes how the combination of these factors shapes the patterns we observe and presents a practical, usable framework for the analysis of movement data in confined spaces. The basis of the framework is the theory of interacting random walks and the mathematical description of out-of-equilibrium systems. Although our focus is on modelling and interpreting animal home ranges and territories in vertebrates, we believe further studies on invertebrates may also help to answer questions and resolve unanswered puzzles that are still inaccessible to experimental investigation in vertebrate species. PMID- 25709828 TI - Space, time and complexity in plant dispersal ecology. AB - Dispersal of pollen and seeds are essential functions of plant species, with far reaching demographic, ecological and evolutionary consequences. Interest in plant dispersal has increased with concerns about the persistence of populations and species under global change. We argue here that advances in plant dispersal ecology research will be determined by our ability to surmount challenges of spatiotemporal scales and heterogeneities and ecosystem complexity. Based on this framework, we propose a selected set of research questions, for which we suggest some specific objectives and methodological approaches. Reviewed topics include multiple vector contributions to plant dispersal, landscape-dependent dispersal patterns, long-distance dispersal events, spatiotemporal variation in dispersal, and the consequences of dispersal for plant communities, populations under climate change, and anthropogenic landscapes. PMID- 25709831 TI - On the duality between interaction responses and mutual positions in flocking and schooling. AB - Recent research in animal behaviour has contributed to determine how alignment, turning responses, and changes of speed mediate flocking and schooling interactions in different animal species. Here, we propose a complementary approach to the analysis of flocking phenomena, based on the idea that animals occupy preferential, anysotropic positions with respect to their neighbours, and devote a large amount of their interaction responses to maintaining their mutual positions. We test our approach by deriving the apparent alignment and attraction responses from simulated trajectories of animals moving side by side, or one in front of the other. We show that the anisotropic positioning of individuals, in combination with noise, is sufficient to reproduce several aspects of the movement responses observed in real animal groups. This anisotropy at the level of interactions should be considered explicitly in future models of flocking and schooling. By making a distinction between interaction responses involved in maintaining a preferred flock configuration, and interaction responses directed at changing it, our work provides a frame to discriminate movement interactions that signal directional conflict from interactions underlying consensual group motion. PMID- 25709832 TI - Daily activity budgets reveal a quasi-flightless stage during non-breeding in Hawaiian albatrosses. AB - BACKGROUND: Animals adjust activity budgets as competing demands for limited time and energy shift across life history phases. For far-ranging migrants and especially pelagic seabirds, activity during breeding and migration are generally well studied but the "overwinter" phase of non-breeding has received less attention. Yet this is a critical time for recovery from breeding, plumage replacement and gaining energy stores for return migration and the next breeding attempt. We aimed to identify patterns in daily activity budgets (i.e. time in flight, floating on the water's surface and active foraging) and associated spatial distributions during overwinter for the laysan Phoebastria immutabilis and black-footed P. nigripes albatrosses using state-space models and generalized additive mixed-effects models (GAMMs). We applied these models to time-series of positional and immersion-state data from small light- and conductivity-based data loggers. RESULTS: During overwinter, both species exhibited a consistent 'quasi flightless' stage beginning c. 30 days after initiating migration and lasting c. 40 days, characterized by frequent long bouts of floating, very little sustained flight, and infrequent active foraging. Minimal daily movements were made within localized areas during this time; individual laysan albatross concentrated into the northwest corner of the Pacific while black-footed albatross spread widely across the North Pacific Ocean basin. Activity gradually shifted toward increased time in flight and active foraging, less time floating, and greater daily travel distances until colony return c. 155 days after initial departure. CONCLUSIONS: Our results demonstrate that these species make parallel adjustments to activity budgets at a daily time-scale within the overwinter phase of non-breeding despite different at-sea distributions and phenologies. The 'quasi-flightless' stage likely reflects compromised flight from active wing moult while the subsequent increase in activity may occur as priorities shift toward mass gain for breeding. The novel application of a GAMM-based approach used in this study offers the possibility of identifying population-level patterns in shifting activity budgets over extended periods while allowing for individual-level variation in the timing of events. The information gained can also help to elucidate the whereabouts of areas important at different times across life history phases for far-ranging migrants. PMID- 25709834 TI - Adding structure to land cover - using fractional cover to study animal habitat use. AB - BACKGROUND: Linking animal movements to landscape features is critical to identify factors that shape the spatial behaviour of animals. Habitat selection is led by behavioural decisions and is shaped by the environment, therefore the landscape is crucial for the analysis. Land cover classification based on ground survey and remote sensing data sets are an established approach to define landscapes for habitat selection analysis. We investigate an approach for analysing habitat use using continuous land cover information and spatial metrics. This approach uses a continuous representation of the landscape using percentage cover of a chosen land cover type instead of discrete classes. This approach, fractional cover, captures spatial heterogeneity within classes and is therefore capable to provide a more distinct representation of the landscape. The variation in home range sizes is analysed using fractional cover and spatial metrics in conjunction with mixed effect models on red deer position data in the Bohemian Forest, compared over multiple spatio-temporal scales. RESULTS: We analysed forest fractional cover and a texture metric within each home range showing that variance of fractional cover values and texture explain much of variation in home range sizes. The results show a hump-shaped relationship, leading to smaller home ranges when forest fractional cover is very homogeneous or highly heterogeneous, while intermediate stages lead to larger home ranges. CONCLUSION: The application of continuous land cover information in conjunction with spatial metrics proved to be valuable for the explanation of home-range sizes of red deer. PMID- 25709833 TI - Seasonal migrations of North Atlantic minke whales: novel insights from large scale passive acoustic monitoring networks. AB - BACKGROUND: Little is known about migration patterns and seasonal distribution away from coastal summer feeding habitats of many pelagic baleen whales. Recently, large-scale passive acoustic monitoring networks have become available to explore migration patterns and identify critical habitats of these species. North Atlantic minke whales (Balaenoptera acutorostrata) perform seasonal migrations between high latitude summer feeding and low latitude winter breeding grounds. While the distribution and abundance of the species has been studied across their summer range, data on migration and winter habitat are virtually missing. Acoustic recordings, from 16 different sites from across the North Atlantic, were analyzed to examine the seasonal and geographic variation in minke whale pulse train occurrence, infer information about migration routes and timing, and to identify possible winter habitats. RESULTS: Acoustic detections show that minke whales leave their winter grounds south of 30 degrees N from March through early April. On their southward migration in autumn, minke whales leave waters north of 40 degrees N from mid-October through early November. In the western North Atlantic spring migrants appear to track the warmer waters of the Gulf Stream along the continental shelf, while whales travel farther offshore in autumn. Abundant detections were found off the southeastern US and the Caribbean during winter. Minke whale pulse trains showed evidence of geographic variation, with longer pulse trains recorded south of 40 degrees N. Very few pulse trains were recorded during summer in any of the datasets. CONCLUSION: This study highlights the feasibility of using acoustic monitoring networks to explore migration patterns of pelagic marine mammals. Results confirm the presence of minke whales off the southeastern US and the Caribbean during winter months. The absence of pulse train detections during summer suggests either that minke whales switch their vocal behaviour at this time of year, are absent from available recording sites or that variation in signal structure influenced automated detection. Alternatively, if pulse trains are produced in a reproductive context by males, these data may indicate their absence from the selected recording sites. Evidence of geographic variation in pulse train duration suggests different behavioural functions or use of these calls at different latitudes. PMID- 25709835 TI - AcceleRater: a web application for supervised learning of behavioral modes from acceleration measurements. AB - BACKGROUND: The study of animal movement is experiencing rapid progress in recent years, forcefully driven by technological advancement. Biologgers with Acceleration (ACC) recordings are becoming increasingly popular in the fields of animal behavior and movement ecology, for estimating energy expenditure and identifying behavior, with prospects for other potential uses as well. Supervised learning of behavioral modes from acceleration data has shown promising results in many species, and for a diverse range of behaviors. However, broad implementation of this technique in movement ecology research has been limited due to technical difficulties and complicated analysis, deterring many practitioners from applying this approach. This highlights the need to develop a broadly applicable tool for classifying behavior from acceleration data. DESCRIPTION: Here we present a free-access python-based web application called AcceleRater, for rapidly training, visualizing and using models for supervised learning of behavioral modes from ACC measurements. We introduce AcceleRater, and illustrate its successful application for classifying vulture behavioral modes from acceleration data obtained from free-ranging vultures. The seven models offered in the AcceleRater application achieved overall accuracy of between 77.68% (Decision Tree) and 84.84% (Artificial Neural Network), with a mean overall accuracy of 81.51% and standard deviation of 3.95%. Notably, variation in performance was larger between behavioral modes than between models. CONCLUSIONS: AcceleRater provides the means to identify animal behavior, offering a user friendly tool for ACC-based behavioral annotation, which will be dynamically upgraded and maintained. PMID- 25709836 TI - Is pre-breeding prospecting behaviour affected by snow cover in the irruptive snowy owl? A test using state-space modelling and environmental data annotated via Movebank. AB - BACKGROUND: Tracking individual animals using satellite telemetry has improved our understanding of animal movements considerably. Nonetheless, thorough statistical treatment of Argos datasets is often jeopardized by their coarse temporal resolution. State-space modelling can circumvent some of the inherent limitations of Argos datasets, such as the limited temporal resolution of locations and the lack of information pertaining to the behavioural state of the tracked individuals at each location. We coupled state-space modelling with environmental characterisation of modelled locations on a 3-year Argos dataset of 9 breeding snowy owls to assess whether searching behaviour for breeding sites was affected by snow cover and depth in an arctic predator that shows a lack of breeding site fidelity. RESULTS: The state-space modelling approach allowed the discrimination of two behavioural states (searching and moving) during pre breeding movements. Tracked snowy owls constantly switched from moving to searching behaviour during pre-breeding movements from mid-March to early June. Searching events were more likely where snow cover and depth was low. This suggests that snowy owls adapt their searching effort to environmental conditions encountered along their path. CONCLUSIONS: This modelling technique increases our understanding of movement ecology and behavioural decisions of individual animals both locally and globally according to environmental variables. PMID- 25709837 TI - Movement, resting, and attack behaviors of wild pumas are revealed by tri-axial accelerometer measurements. AB - BACKGROUND: Accelerometers are useful tools for biologists seeking to gain a deeper understanding of the daily behavior of cryptic species. We describe how we used GPS and tri-axial accelerometer (sampling at 64 Hz) collars to monitor behaviors of free-ranging pumas (Puma concolor), which are difficult or impossible to observe in the wild. We attached collars to twelve pumas in the Santa Cruz Mountains, CA from 2010-2012. By implementing Random Forest models, we classified behaviors in wild pumas based on training data from observations and measurements of captive puma behavior. RESULTS: We applied these models to accelerometer data collected from wild pumas and identified mobile and non-mobile behaviors in captive animals with an accuracy rate greater than 96%. Accuracy remained above 95% even after downsampling our accelerometer data to 16 Hz. We were further able to predict low-acceleration movement behavior (e.g. walking) and high-acceleration movement behavior (e.g. running) with 93.8% and 92% accuracy, respectively. We had difficulty predicting non-movement behaviors such as feeding and grooming due to the small size of our training dataset. Lastly, we used model-predicted and field-verified predation events to quantify acceleration characteristics of puma attacks on large prey. CONCLUSION: These results demonstrate that accelerometers are useful tools for classifying the behaviors of cryptic medium and large-sized terrestrial mammals in their natural habitats and can help scientists gain deeper insight into their fine-scale behavioral patterns. We also show how accelerometer measurements can provide novel insights on the energetics and predation behavior of wild animals. Lastly we discuss the conservation implications of identifying these behavioral patterns in free ranging species as natural and anthropogenic landscape features influence animal energy allocation and habitat use. PMID- 25709838 TI - Mapping migratory flyways in Asia using dynamic Brownian bridge movement models. AB - BACKGROUND: Identifying movement routes and stopover sites is necessary for developing effective management and conservation strategies for migratory animals. In the case of migratory birds, a collection of migration routes, known as a flyway, is often hundreds to thousands of kilometers long and can extend across political boundaries. Flyways encompass the entire geographic range between the breeding and non-breeding areas of a population, species, or a group of species, and they provide spatial frameworks for management and conservation across international borders. Existing flyway maps are largely qualitative accounts based on band returns and survey data rather than observed movement routes. In this study, we use satellite and GPS telemetry data and dynamic Brownian bridge movement models to build upon existing maps and describe waterfowl space use probabilistically in the Central Asian and East Asian Australasian Flyways. RESULTS: Our approach provided new information on migratory routes that was not easily attainable with existing methods to describe flyways. Utilization distributions from dynamic Brownian bridge movement models identified key staging and stopover sites, migration corridors and general flyway outlines in the Central Asian and East Asian-Australasian Flyways. A map of space use from ruddy shelducks depicted two separate movement corridors within the Central Asian Flyway, likely representing two distinct populations that show relatively strong connectivity between breeding and wintering areas. Bar-headed geese marked at seven locations in the Central Asian Flyway showed heaviest use at several stopover sites in the same general region of high-elevation lakes along the eastern Qinghai-Tibetan Plateau. Our analysis of data from multiple Anatidae species marked at sites throughout Asia highlighted major movement corridors across species and confirmed that the Central Asian and East Asian-Australasian Flyways were spatially distinct. CONCLUSIONS: The dynamic Brownian bridge movement model improves our understanding of flyways by estimating relative use of regions in the flyway while providing detailed, quantitative information on migration timing and population connectivity including uncertainty between locations. This model effectively quantifies the relative importance of different migration corridors and stopover sites and may help prioritize specific areas in flyways for conservation of waterbird populations. PMID- 25709839 TI - Design and synthesis of novel isoxazole tethered quinone-amino Acid hybrids. AB - A new series of isoxazole tethered quinone-amino acid hybrids has been designed and synthesized involving 1,3-dipolar cycloaddition reaction followed by an oxidation reaction using cerium ammonium nitrate (CAN). Using this method, for the first time various isoxazole tethered quinone-phenyl alanine and quinone alanine hybrids were synthesized from simple commercially available 4-bromobenzyl bromide, propargyl bromide, and 2,5-dimethoxybenzaldehyde in good yield. PMID- 25709840 TI - A Meta-Analysis of Risky Sexual Behaviour among Male Youth in Developing Countries. AB - The purpose of this meta-analysis was to assess the association between risky sexual behaviour and level of education and economic status in male youth. Previous tests of the association of risky sexual behaviour with levels of education and economic status have yielded inconsistent results. Using data from 26 countries, from both within and outside Africa, we performed a meta-analysis with a specific focus on male youths' risky sexual behaviour. We applied a random effects analytic model and calculated a pooled odds ratio. Out of 19,148 males aged 15-24 years who reported having sexual intercourse in the 12 months preceding the survey, 75% engaged in higher-risk sex. The proportion of higher risk sex among male youth aged 15-19 years was nearly 90% in 21 of the 26 countries. The pooled odds ratio showed a statistically significant association of higher-risk sex with male youth younger than 20 years, living in urban centers, well educated, and of a high economic status. The overall proportion of condom use during youths' most recent higher-risk sexual encounter was 40% and 51% among 15-19-year-olds and 20-24-year-olds, respectively. Our findings suggest that male youth's socioeconomic status is directly related to the likelihood that they practice higher-risk sex. The relationship between income and sexual behaviour should be explored further. PMID- 25709841 TI - Application of two-stage cultivation for exploring the nutritional requirements for sporulation of three biocontrol fungi. AB - Fungicide was an important part in mycopesticides, which play an important role in pest management, while their mass production and commercialization faced problem. We found that the nutrition for mycelia growth and sporulation differences a lot. So, we developed "two-step method" to define the nutrition for sporulation in this paper. The results indicated that the novel method led to a great increase of spore yields for Beauveria bassiana (IBC1201), Lecanicillium lecanii (CA-1-G), and Pochonia chlamydosporia (HSY-12-14), respectively, of about 100, 2, and 16 times and, also reduced the cycle of mass production to 1/3 compared with common time for culturing. PMID- 25709842 TI - Long term anticoagulation (4-16 years) stops progression of idiopathic hip osteonecrosis associated with familial thrombophilia. AB - In 6 patients with familial thrombophilia (5 Factor V (FV) Leiden heterozygotes, 1 with resistance to activated protein C (RAPC)), we prospectively assessed whether continuous longterm (4-16 years) anticoagulation would prevent progression of idiopathic osteonecrosis (ON), ameliorate pain, and facilitate functional recovery. Four men and 2 women (9 hips, 8 Ficat stage II, 1 stage I) were anticoagulated with enoxaparin (60 mg/day) for 3 months and subsequently with Coumadin, Xarelto, or Pradaxa, warranted by >=2 prior thrombotic events. Anticoagulation was continued for 4, 4, 9, 13, 13, and 16 years, with serial clinical and X-ray follow-up. On 4-16-years anticoagulation, 9 hips in the 6 patients (8 originally Ficat II, 1 Ficat I) remained unchanged, contrasted to untreated ON Ficat stage II, where 50%-80% of hips progress to collapse (Ficat stages III-IV) within 2 years after diagnosis. Within 3, 3, 3, 9, and 16 months after starting anticoagulation, 5 patients became pain-free and remained asymptomatic throughout follow-up; the 6th patient required Percocet for pain. There were no significant bleeding episodes. Long term (4-16 years) anticoagulation initiated in Ficat stages I-II of idiopathic hip ON in patients with FV-RAPC changes the natural history of ON, stopping progression, resolving pain, and restoring function. PMID- 25709843 TI - A feasibility study into the use of three-dimensional printer modelling in acetabular fracture surgery. AB - There are a number of challenges associated with the operative treatment of acetabular fractures. The approach used is often extensive, while operative time and perioperative blood loss can also be significant. With the proliferation of 3D printer technology, we present a fast and economical way to aid the operative planning of complex fractures. We used augmented stereoscopic 3D CT reconstructions to allow for an appreciation of the normal 3D anatomy of the pelvis on the fractured side and to use the models for subsequent intraoperative contouring of pelvic reconstruction plates. This leads to a reduction in the associated soft tissue trauma, reduced intraoperative time and blood loss, minimal handling of the plate, and reduced fluoroscopic screening times. We feel that the use of this technology to customize implants, plates, and the operative procedure to a patient's unique anatomy can only lead to improved outcomes. PMID- 25709844 TI - Rehabilitation of an advanced case of adenoid cystic carcinoma. AB - Adenoid cystic carcinoma is a cancer of the salivary gland that primarily affects the parotid, submandibular, and accessory salivary glands. Its growth is slow and it has infiltrative nature. A 46-year-old female patient coming from the rural area presented a lesion on the palate and reported pain in the region for three years. After incisional biopsy, and histopathological diagnosis of adenoid cystic carcinoma of the cribriform type of minor salivary gland, superior hemimaxillectomy and adjuvant treatment with radiotherapy and maxillofacial prosthetic rehabilitation were performed. PMID- 25709845 TI - Ameloblastic fibrodentinoma presenting as a false gingival enlargement in the maxillary anterior region. AB - Ameloblastic fibrodentinoma is a rare benign mixed odontogenic neoplasm usually occurring in the first two decades of life. It is more common in males and the most common site of occurrence is in the mandibular premolar molar area. This report presents a case of ameloblastic fibrodentinoma in a 12-year-old boy in the maxillary anterior region, a less common site for the occurrence of ameloblastic fibrodentinoma. A 12-year-old boy presented with a midline diastema in 11 and 21 region and a swelling in the palatal aspect of 11 and 12. Intraoral periapical radiograph showed the presence of rarefaction of bone on the mesial aspect of the cervical and middle third of the root of 11. Excision biopsy was done. The specimen was processed and stained with hematoxylin and eosin. Microscopic examination showed islands, chords and strands of odontogenic epithelium in a primitive ectomesenchyme resembling dental papilla. The odontogenic epithelium exhibited peripheral ameloblast-like and central stellate reticulum-like cells. The presence of dentinoid material was seen adjacent to the odontogenic epithelium in some foci. The lesion was diagnosed as ameloblastic fibrodentinoma. PMID- 25709846 TI - Significantly elevated serum lipase in pregnancy with nausea and vomiting: acute pancreatitis or hyperemesis gravidarum? AB - Hyperemesis gravidarum is a severe manifestation of nausea and vomiting of pregnancy and it is associated with weight loss and metabolic abnormalities. It is known that abnormal laboratory values, including mildly elevated serum lipase level, could be associated with hyperemesis gravidarum. However, in this case report details of two women with hyperemesis gravidarum but with significantly elevated serum lipase levels were discussed. These patients presented with severe nausea and vomiting but without abdominal pain. They were found to have severely elevated lipase levels over 1,000 units/liter. In the absence of other findings of pancreatitis, they were treated with conservative measures for hyperemesis gravidarum, with eventual resolution to normal lipase levels. Although significantly elevated lipase level in pregnant patients with nausea and vomiting is a concern for acute pancreatitis, these two cases of significantly elevated serum lipase without other clinical findings of pancreatitis led to this report that serum lipase could be quite elevated in hyperemesis gravidarum and that it might not be an accurate biochemical marker for acute pancreatitis. Imaging studies are thus necessary to establish the diagnosis of acute pancreatitis. PMID- 25709847 TI - A peculiar case of the abscopal effect: radioactive iodine therapy incidentally palliating marginal zone lymphoma. AB - The abscopal effect is an extremely rare phenomenon occurring when irradiation or treatment of a primary tumor burden not only results in debulking of the targeted site but also reduces tumor size at distant sites from the intended treatment area. We present the abscopal effect occurring in a patient with low-grade marginal zone lymphoma who subsequently received radioactive iodine therapy for papillary thyroid carcinoma. She was 67 years old when a routine complete blood count at her primary care physician's office yielded a persistent leukocytosis of 14,500/MUL with lymphocytosis of 9,870/MUL. Immunophenotyping and fluorescence in situ hybridization (FISH) analysis confirmed low-grade marginal zone lymphoma. Over eight years, her peak leukocyte and lymphocyte counts were 24,100/MUL and 18,100/MUL, respectively. Subsequently, she was diagnosed with papillary thyroid carcinoma after presenting with a new complaint of dysphagia. A total thyroidectomy was performed, followed by 172.1 millicuries of oral I-131 sodium iodine radioactive ablation therapy. Following treatment, her leukocyte and lymphocyte counts were 3,100/MUL and 1,100/MUL, respectively. Over the next four years, her leukocyte and lymphocyte counts remained within normal limits and she remained symptom free. To our knowledge, there has never been a published report describing the use of radioactive iodine causing abscopal effect benefits for patients with underlying lymphoproliferative diseases. PMID- 25709848 TI - Nasal bridge intramuscular hemangioma. AB - Intramuscular haemangioma (IMH) is a benign mesenchymal tumour. It appears as a deep, nontender mass within the soft tissue, particularly in the extremities. This tumour may not be obvious on clinical examination. Head and neck IMHs represent only 13.5% of the total IMHs. The most common site for a head and neck IMH is the masseter muscle, followed by trapezius, sternocleidomastoid, and very rarely temporalis muscle. We present a patient with left nasal bridge swelling which was excised and histologically confirmed as intramuscular hemangioma. PMID- 25709849 TI - Congenital portosystemic shunt: our experience. AB - Introduction. Congenital portosystemic venous malformations are rare abnormalities in which the portal blood drains into a systemic vein and which are characterized by extreme clinical variability. Case Presentations. The authors present two case reports of a congenital extrahepatic portosystemic shunt (Type II). In the first patient, apparently nonspecific symptoms, such as headache and fatigue, proved to be secondary to hypoglycemic episodes related to the presence of a portosystemic shunt, later confirmed on imaging. During portal vein angiography, endovascular embolization of the portocaval fistula achieved occlusion of the anomalous venous tract. In the second patient, affected by Down's syndrome, the diagnosis of a portosystemic malformation was made by routine ultrasonography, performed to rule out concurrent congenital anomalies. Because of the absence of symptoms, we chose to observe this patient. Conclusions. These two case reports demonstrate the clinical heterogeneity of this malformation and the need for a multidisciplinary approach. As part of a proper workup, clinical evaluation must always be followed by radiographic diagnosis. PMID- 25709850 TI - Clear cell papillary renal cell carcinoma: a potential mimic of conventional clear cell renal carcinoma on core biopsy. AB - Clear cell papillary renal cell carcinoma (CCP-RCC) is a recently described, relatively uncommon variant of renal cell carcinoma (RCC) with a reported incidence of 4.1%. Thought to only arise in those with end stage renal disease, CCP-RCC is increasingly identified in those without renal impairment. CCP-RCCs have unique morphologic, genetic, and immunohistochemical features distinguishing them from both conventional clear cell renal cell carcinomas and papillary renal cell carcinomas. Immunohistochemically, these tumors are positive for CK7 and negative for CD10 and racemase. This is in contrast to conventional cell renal cell carcinomas (CK7 negative, CD10 positive) and papillary cell carcinomas (CK7, CD10, and racemase positive). These tumours appear to be indolent in nature, with no current documented cases of metastatic spread. We present the case of a 42 year-old female who presented with an incidental finding of a renal mass that on a core biopsy was reported as clear cell carcinoma, Fuhrman grade 1. She subsequently underwent a radical nephrectomy and further histological examination revealed the tumor to be a clear cell papillary renal cell carcinoma, Fuhrman grade 1. PMID- 25709851 TI - Life-threatening bleeding from peristomal varices after cystoprostatectomy: multimodal approach in a cirrhotic, encephalopathic patient with severe portal hypertension. AB - The bleeding of peristomal varices due to a portosystemic shunt is rare but potentially life-threatening in cirrhotic patients with portal hypertension. The scarce case reports in the literature recommend transjugular intrahepatic portosystemic shunt (TIPS) to prevent further bleeding. We report on a 72-year old man who was referred to our hospital because of life-threatening bleeding from peristomal varices, three years after radical cystoprostatectomy for invasive bladder cancer. CT imaging showed liver cirrhosis with a prominent portosystemic shunt leading to massively enlarged peristomal varices. TIPS was taken into consideration, but not possible due to hepatic encephalopathy (HE). Medical therapy with lactulose and the nonselective beta-blocker carvedilol was initiated to treat HE and portal hypertension. In a second step, the portosystemic shunt was percutaneously embolized. Here, we present a multimodal approach to treat intractable bleeding from peristomal varices in a patient with ileal conduit urinary diversion, not suitable for TIPS. PMID- 25709852 TI - Characterizing the assessment and management of vitamin d levels in patients with osteoporosis in clinical practice: a chart review initiative. AB - Though vitamin D is important for bone health, little is known about the monitoring and management of vitamin D levels in patients with osteoporosis in clinical practice-a deficit this chart review initiative aimed to remedy. A total of 52 physicians completed profiles for 983 patients being treated for osteoporosis between November 2008 and April 2009. Information collected included demographics; fracture risk factors; availability and level of serum vitamin D measurements; and information on osteoporosis medications and calcium and vitamin D supplementation. Physicians also evaluated patients' current regimens and detailed proposed changes, if applicable. Nearly 85% of patients were prescribed calcium and vitamin D supplements. Serum 25-hydroxy vitamin D levels were available for 73% of patients. Of these patients, approximately 50% had levels less than 80 nmol/L, which contrasts with the 37% thought to have "unsatisfactory" vitamin D levels based on physician perceptions. Physicians felt 26% of patients would benefit from additional vitamin D supplementation. However, no changes to the osteoporosis regimen were suggested for 48% of patients perceived to have "unsatisfactory" vitamin D levels. The results underscore the importance of considering vitamin D status when looking to optimize bone health. PMID- 25709853 TI - Superficial cortical landmarks for localization of the hippocampus: Application for temporal lobectomy and amygdalohippocampectomy. AB - BACKGROUND: Accessing the hippocampus for amygdalohippocampectomy and procedures such as depth electrode placement requires accurate knowledge regarding the location of the hippocampus. METHODS: The authors removed 10 human cadaveric brains (20 sides) from their crania, noted relationships between the lateral temporal neocortex and underlying hippocampus, and measured the distance between the hippocampus and superficial landmarks. RESULTS: Mean distances were as follows: 3.8 cm from the tip of the temporal lobe to the head of the hippocampus; 6.5 cm from the tip of the temporal lobe to the junction of the fornix and hippocampus; and 3.5 cm between the tail and head of the hippocampus. The head of the hippocampus ranged from 0 to 5 mm inferior to the inferior temporal sulcus. The tail of the hippocampus ranged from 2.2 to 7 mm superior to the inferior temporal sulcus. In two specimens, the tail was deep to the superior temporal sulcus. Generally the length of the hippocampus was along the inferior temporal sulcus and inferior aspect of the middle temporal gyrus. The hippocampus tended to be more superiorly located and shorter in females and left sides, but this was not statistically significant. CONCLUSIONS: Additional landmarks for localizing the underlying hippocampus may be helpful in temporal lobe surgery. Our study showed relatively constant anatomic landmarks between the hippocampus and overlying temporal cortex that may help localize the hippocampus during amygdalohippocampectomy and depth electrode implantation, verify the accuracy of image-guided methods, and used as adjuvant methodologies when these latter technologies are unavailable. PMID- 25709854 TI - External cortical landmarks and measurements for the temporal horn: Anatomic study with application to surgery of the temporal lobe. AB - BACKGROUND: The location of the temporal horn is important to neurosurgeons during procedures such as amygdalohippocampectomy and intraventricular electrode placement for temporal lobe seizure monitoring. However, sometimes the temporal horn is difficult to localize, especially without neuronavigation. The authors aimed to better localize this structure using superficial anatomic landmarks. METHODS: Twenty-two brain halves were dissected from the midline, and the fornix identified and followed toward the left and right temporal horns. Once the temporal horn was isolated from a mesial approach, 6-cm long needles were placed into its anterior and posterior walls of the temporal horn and passed laterally from the axial plane to the cortical surface. Pin exit sites were marked externally and measurements taken between the outer temporal lobe cortex and the underlying temporal horn. RESULTS: No statistical differences were noted between left and right sides. The temporal horn was generally directed anteroinferiorly and best marked externally by the inferior temporal sulcus. The mean length of the temporal horn was 4.4 cm. Mean distance from anterior temporal tip to anterior wall of the temporal horn was 3.3 cm. The mean distance from the anterior temporal tip to the posterior wall of the temporal horn was 7 cm. The anterior wall of the temporal horn was a mean of 3 mm superior to the inferior temporal sulcus. The posterior wall was a mean of 1.2 cm superior to the inferior temporal sulcus. CONCLUSIONS: These landmarks and measurements may help neurosurgeons better localize this part of the lateral ventricular system. PMID- 25709855 TI - The "Gemini" spinal cord fusion protocol: Reloaded. PMID- 25709856 TI - Glossopharyngeal neuralgia caused by a complex neurovascular conflict: Case report and review of the literature. AB - BACKGROUND: Glossopharyngeal neuralgia (GN) is a rare condition characterized by severe, paroxysmal episodes of pain mainly localized to the external ear canal, pharynx, and tongue, usually caused by a neurovascular conflict between postero inferior cerebellar artery (PICA) and IX cranial nerve. Sometimes there is also a compression of X c.n. CASE DESCRIPTION: We present a case of a 71-year-old female with a 3-year history of intense pain localized in the pharynx and posterior portion of the tongue. Preoperative magnetic resonance imaging (MRI) documented a neurovascular conflict between a loop of PICA and IX left c.n. Surgery was performed through a retrosigmoid craniectomy. The intraoperative findings documented a loop of PICA compressing IX, X, and XI c.n. Microvascular decompression (MVD) of IX c.n. was performed using the interposing technique. No rhizotomy and MVD of the X c.n. was performed. Postoperative course showed the regression of all symptoms. CONCLUSIONS: The surgical treatment of patients with GN caused by complex neurovascular conflicts can be safely performed with the classical MVD of IX c.n. A double MVD of both IX and X c.n. has a role only in patients presenting symptoms from both nerves. Rhizotomy, in our opinion, has to be avoided in all cases. The authors review the literature concerning GN caused by complex neurovascular conflicts. PMID- 25709857 TI - Regional interdependence of the hip and lumbo-pelvic region in divison ii collegiate level baseball pitchers: a preliminary study. AB - BACKGROUND: Pitchers may be at greater risk of injury in comparison to other overhead throwing athletes due to the repetition of the pitching motion. It has been reported that approximately 30% of all baseball injuries occur in the lower body. This may be related to limited hip mobility, which can compromise pitching biomechanics while placing excessive stress on the trunk and upper quarter. Hip motion and strength measurements have been reported in professional baseball pitchers but have not been reported in collegiate pitchers. PURPOSE: The purpose of this study was to report preliminary findings for passive hip motion and isometric hip muscle strength in collegiate pitchers and compare them to previously published values for professional level pitchers. STUDY DESIGN: Cross sectional study. METHODS: Twenty-nine collegiate baseball pitchers (age = 20.0 + 1.4 years, height = 1.88 + 0.06 m; weight = 89.3 + 10.7 kg; body mass index = 25.3 + 2.5 kg/m2) were recruited. Subjects were assessed for hip internal rotation (IR) and external rotation (ER) passive motion, hip anteversion or retroversion, gluteus maximus, gluteus medius, hip internal rotator, hip external rotator strength, and lumbo-pelvic control with the prone active hip rotation test as described by Sahrmann. Statistical analysis included calculation of subject demographics (means and SD) and use of a two-tailed t-test (p >0.05). RESULTS: Fifty-two percent of the right-handed and 50% of the left-handed pitchers demonstrated poor lumbo-pelvic motor control with an inability to stabilize during active hip IR and ER even though isolated strength deficits were not detected at a significant level. There were no significant differences in hip passive motion or gluteus medius strength between right and left-handed pitchers. Differences did exist between collegiate data and previously published values for professional pitchers for IR motion measured in prone and gluteus maximus strength. Hip retroversion was present in 55% of the pitchers primarily in both limbs with four of the pitchers presenting with retroversion singularly in either the stride or trail limb where the ER rotation motion was greater than the IR. CONCLUSION: Assessing mobility and muscle strength of the lower quarter in isolation can be misleading and may not be adequate to ensure the potential for optimal pitching performance. These findings suggest that lumbo-pelvic control in relation to the lower extremities should be assessed as one functional unit. This is the first study to explore hip motion, strength, and lumbo-pelvic control during active hip rotation in collegiate baseball pitchers. EVIDENCE LEVEL: 2. PMID- 25709858 TI - Passive hip range of motion is reduced in active subjects with chronic low back pain compared to controls. AB - BACKGROUND: Non-specific low back pain is a common condition often without a clear mechanism for its presentation. Recently more attention has been placed on the hip and its potential contributions to non-specific chronic low back pain (NSCLBP). Emphasis in research has mainly been placed on motor control, strength and endurance factors in relation to NSCLBP. Limited focus has been placed on hip mobility and its potential contribution in subjects with NSCLBP. PURPOSE/AIM: The aim of this study was to compare passive ROM in hip extension, hip internal rotation, hip external rotation and total hip rotation in active subjects with NSCLBP to healthy control subjects. The hypothesis was that active subjects with NSCLBP would present with decreased total hip ROM and greater asymmetry when compared to controls. DESIGN: Two group case controlled. SETTING: Clinical research laboratory. PARTICIPANTS: 30 healthy subjects without NSCLBP and 30 active subjects with NSCLBP. Subjects categorized as NSCLBP were experiencing pain in the low back area with or without radicular symptoms of greater than three months duration. MAIN OUTCOME MEASURE: Passive hip extension (EXT), hip internal rotation (IR), hip external rotation (ER) and total hip rotation ROM. A digital inclinometer was used for measurements. RESULTS: There was a statistically significant difference (p<0.001) in hip passive extension ROM between the control group and the NSCLBP group bilaterally. Mean hip extension for the control group was 6.88 bilaterally. For the NSCLBP group, the mean hip extension was -4.28 bilaterally. This corresponds to a difference of means between groups of 10.88. There was no statistically significant differences (p>0.05) in hip IR, ER, or total rotation ROM between groups. CONCLUSIONS: The results of this study indicate that a significant difference in hip extension exists in active subjects with NSCLBP compared to controls. It may be important to consider hip mobility restrictions and their potential impact on assessment of strength in NSLBP subjects. Future studies may be needed to investigate the relationship between measurements and intervention strategies. LEVEL OF EVIDENCE: 2b. PMID- 25709859 TI - Association between the functional movement screen and injury development in college athletes. AB - BACKGROUND: As the number of sports participants continues to rise, so does the number of sports injuries. Establishing a valid method of identifying athletes at elevated risk for injury could lead to intervention programs that lower injury rates and improve overall athlete performance. The Functional Movement Screen (FMS)TM is an efficient and reliable method to screen movement patterns during the performance of specific tasks. The purpose of this study is to explore the association between pre-season FMS TM scores and the development of injury in a population of collegiate athletes. STUDY DESIGN: Descriptive epidemiology study. METHODS: FMSTM scores were obtained for 160 collegiate athletes and injury development was tracked throughout the season. These athletes were both male and female and participated in contact and non-contact sports. Redundancies were utilized with injury data collection, including medical record reviews and interviews with team athletic trainers, to ensure that all injuries requiring medical attention were captured. At the conclusion of the season, a logistic regression analysis was performed to determine which combination of factors best predicted injury. RESULTS: Athletes with an FMSTM composite score at 14 or below combined with a self-reported past history of injury were at 15 times increased risk of injury. A positive likelihood ratio of 5.8 was calculated which improved the probability of predicting injury from 33% pretest to 74% posttest. CONCLUSIONS: This study adds to the growing body of evidence demonstrating a predictive relationship between FMSTM composite scores and past history of injury with the development of future injury. LEVEL OF EVIDENCE: 3, Non-random prospective cohort design. PMID- 25709860 TI - Normative values for the functional movement screentm in adolescent school aged children. AB - BACKGROUND: International sports programs have established pre-participation athletic screening procedures as an essential component to identify athletes that are at a high risk of becoming injured. The Functional Movement Screen (FMSTM) is a screening instrument intended to evaluate deficiencies in the mobility and stability of an athlete that might be linked to injury. To date, there are no published normative values for the FMSTM in adolescent school aged children. The purpose of this study was to establish normative values for the FMSTM in adolescent school aged children (10 to 17 years). Secondary aims were to investigate whether the performance differed between boys and girls and between those with or without previous history of injury. METHODS: 1005 adolescent school students, including both males and females between the ages of 10 and 17 years who fulfilled the inclusion and exclusion criteria, were selected for the study. The test administration procedures, instructions and scoring process associated with the standardized version of the test were followed in order to ensure accuracy in scoring. The components of the FMSTM include the deep squat, hurdle step, in-line lunge, shoulder mobility, active straight leg raise, trunk stability push up, and rotary stability. RESULTS: The mean composite FMSTM score was 14.59 (CI 14.43 - 14.74) out of a possible total of 21. There was a statistically significant difference in scores between females and males (p= .000). But no statistically significant difference in scores existed between those who reported a previous injury and those who did not report previous injury (p=.300). The variables like age (r= -.038, p=.225), height(r= .065, p= .040), weight (r=.103, p=.001) did not show a strong correlations with the mean composite score. CONCLUSION: This study provides normative values for the FMSTM in adolescent school aged children, which could assist in evaluation of functional mobility and stability in this population. LEVEL OF EVIDENCE: 2c. PMID- 25709861 TI - Reliability and accuracy of a goniometer mobile device application for video measurement of the functional movement screen deep squat test. AB - BACKGROUND/PURPOSE: The squat is a fundamental movement of many athletic and daily activities. Methods to clinically assess the squat maneuver range from simple observation to the use of sophisticated equipment. The purpose of this study was to examine the reliability of Coach's Eye (TechSmith Corp), a 2 dimensional (2D) motion analysis mobile device application (app), for assessing maximal sagittal plane hip, knee, and ankle motion during a functional movement screen deep squat, and to compare range of motion values generated by it to those from a Vicon (Vicon Motion Systems Ltd) 3-dimensional (3D) motion analysis system. METHODS: Twenty-six healthy subjects performed three functional movement screen deep squats recorded simultaneously by both the app (on an iPad [Apple Inc]) and the 3D motion analysis system. Joint angle data were calculated with Vicon Nexus software (Vicon Motion Systems Ltd). The app video was analyzed frame by frame to determine, and freeze on the screen, the deepest position of the squat. With a capacitive stylus reference lines were then drawn on the iPad screen to determine joint angles. Procedures were repeated with approximately 48 hours between sessions. RESULTS: Test-retest intrarater reliability (ICC3,1) for the app at the hip, knee, and ankle was 0.98, 0.98, and 0.79, respectively. Minimum detectable change was hip 6 degrees , knee 6 degrees , and ankle 7 degrees . Hip joint angles measured with the 2D app exceeded measurements obtained with the 3D motion analysis system by approximately 40 degrees . Differences at the knee and ankle were of lower magnitude, with mean differences of 5 degrees and 3 degrees , respectively. Bland-Altman analysis demonstrated a systematic bias in the hip range-of-motion measurement. No such bias was demonstrated at the knee or ankle. CONCLUSIONS: The 2D app demonstrated excellent reliability and appeared to be a responsive means to assess for clinical change, with minimum detectable change values ranging from 6 degrees to 7 degrees . These results also suggest that the 2D app may be used as an alternative to a sophisticated 3D motion analysis system for assessing sagittal plane knee and ankle motion; however, it does not appear to be a comparable alternative for assessing hip motion. LEVEL OF EVIDENCE: 3. PMID- 25709862 TI - Temporal efficacy of kinesiology tape vs. Traditional stretching methods on hamstring extensibility. AB - BACKGROUND: The epidemiology and aetiology of hamstring injuries in sport have been well documented. Kinesiology tape has been advocated as a means of improving muscle flexibility, with potential implications for injury prevention. PURPOSE: To compare the temporal pattern of efficacy of kinesiology tape and traditional stretching techniques on hamstring extensibility. STUDY DESIGN: Controlled laboratory study. METHODS: Thirty recreationally active male participants (Mean +/- SD: age 21.0 +/- 0.1 years; height 180 +/- 6 cm; mass 79.4 +/- 6.9 kg) completed an active knee extension assessment (of the dominant leg) as a measure of hamstring extensibility. Three experimental interventions of equal time duration were applied in randomized order: Kinesiology tape (KT), static stretch (SS), proprioceptive neuromuscular facilitation (PNF). Measures were taken at baseline, +1, +10 and +30 mins after each intervention. The temporal pattern of change in active knee extension (AKE) was modelled as a range of regression polynomials for each intervention, quantified as the regression coefficient. RESULTS: With baseline scores not statistically different between groups, and baseline AKE set at 100%, PNF showed a significant improvement immediately post intervention (PNF+1 = 107.7 +/- 8.2%, p = .01). Thereafter, only KT showed significant improvements in active knee extension (KT+10 = 106.0 +/- 7.1%, p = .05; KT+30 = 106.9 +/- 5.0%, p = .02). The temporal pattern of changes in active knee extension after intervention was best modelled as a positive quadratic for KT, with a predicted peak of 108.8% baseline score achieved at 24.2 mins. SS was best modelled as a negative linear function, and PNF as a negative logarithmic function, reflecting a rapid decrease in active knee extension after an immediate positive effect. CONCLUSION: Each intervention displayed a unique temporal pattern of changes in active knee extension. PNF was best suited to affect immediate improvements in hamstring extensibility, whereas kinesiology tape offered advantages over a longer duration. CLINICAL RELEVANCE: The logistics of the sporting or clinical context will often dictate the delay between intervention and performance. Our findings have implications for the timing and choice of intervention aimed at increasing hamstring extensibility in relation to performance. LEVEL OF EVIDENCE: 2c. PMID- 25709863 TI - The reliability and diagnostic accuracy of assessing the translation endpoint during the lachman test. AB - BACKGROUND: Interpretation of Lachman testing when evaluating the status of the anterior cruciate ligament (ACL) typically includes a numerical expression classifying the amount of translation (Grade I, II, III) in addition to a categorical modifier (Grade A [firm] or B [absent]) to describe the quality of the passive anterior tibial translation's endpoint. Most clinicians rely heavily on this tactile sensation and place value in this judgment in order to render their diagnostic decision; however, the reliability and accuracy of this endpoint assessment has not been well established in the literature. PURPOSE: The purpose of this study was to determine the intertester reliability of endpoint classification during the passive anterior tibial translation of a standard Lachman test and evaluate the classification's ability to accurately predict the presence or absence of an ACL tear. STUDY DESIGN: Prospective, blinded, diagnostic reliability and accuracy study. METHODS: Forty-five consecutive patients with a complaint of knee pain were independently evaluated for the endpoint classification during a Lachman test by two physical therapists before any other diagnostic assessment. The 21 men and 24 women ranged in age from 20 to 64 years (mean +/- SD age, 40.7 +/- 14) and in acuity of knee injury from 30 to 365 days (mean +/- SD, 238 +/-157). RESULTS: 17 of the 45 patients had a torn ACL. The agreement between examiners on A versus B endpoint classification was 91% with a kappa coefficient of 0.72. In contrast, classification agreement based on the translational amount had an agreement of 65% with a weighted kappa coefficient of 0.52. The sensitivity of the endpoint grade alone was 0.81 with perfect specificity resulting in a positive likelihood ratio of 6.2 and a negative likelihood ratio of 0.19. The overall accuracy of the Lachman test using the endpoint assessment grade alone was 93% with a number needed to diagnose of 1.2. CONCLUSIONS: Nominal endpoint classification (A or B) from a Lachman test is a reliable and accurate reflection of the status of the ACL. The true dichotomous nature of the test's interpretation (positive vs. negative) is well-served by the quality of the endpoint during passive anterior tibial translation. LEVEL OF EVIDENCE: 2. PMID- 25709864 TI - Hand-held Dynamometer Positioning Impacts Discomfort During Quadriceps Strength Testing: A Validity and Reliability Study. AB - PURPOSE/BACKGROUND: A belt-stabilized hand-held dynamometer (HHD) offers the ability to quantify quadriceps muscle strength in a clinical environment, but a limitation is participant discomfort at the interface between the HHD and the tibia. The purpose of this study was to quantify the level of discomfort associated with a modified belt-stabilized HHD configuration compared to a standard belt-stabilized configuration and an isokinetic dynamometer. The secondary purpose of this study was to determine the validity and reliability of a modified configuration used to measure quadriceps strength compared to the "gold-standard" isokinetic dynamometer. METHODS: Twenty healthy participants (5 males, 15 females; age=24.7+/-2.2 years, height=171.1+/-8.8 cm, mass=72.0+/-18.7 kg) performed maximal knee extension isometric contractions during each of three testing conditions: isokinetic dynamometer, standard configuration with HHD placement on the tibia, and an alternative configuration with the HHD interfaced with the leg of a table. Discomfort was quantified using a Visual Analog Scale (VAS). Differences in discomfort and torque (N*m) associated with the testing positions were determined using Friedman test or repeated measures analysis of variance. Validity was quantified using Pearson correlations and within-session intrarater reliability was determined using an intraclass correlation coefficient (ICC2,1) and associated confidence intervals (95% CI). RESULTS: The isokinetic dynamometer configuration resulted in the least discomfort (p< .01) and the modified configuration was more comfortable than the standard configuration (p= .003). There was a significant correlation between measures from the isokinetic dynamometer and the standard configuration (r=.87) and modified configuration (r=.93). Within-session intrarater reliability was good for both the standard configuration (ICC2,1=0.93) and modified configuration (ICC2,1=0.93) conditions. CONCLUSIONS: The use of the modified belt-stabilized HHD configuration, where the HHD was interfaced with the leg of a table, offers a more comfortable alternative compared to the standard belt-stabilized configuration to obtain isometric quadriceps strength measures in a clinical environment. This configuration is also a valid and reliable alternative to the "gold standard" isokinetic dynamometer when testing isometric quadriceps strength at 90 degrees of knee flexion. LEVEL OF EVIDENCE: Diagnostic, Level 3. PMID- 25709865 TI - Effects of wearing athletic shoes, five-toed shoes, and standing barefoot on balance performance in young adults. AB - BACKGROUND/PURPOSE: Almost all research using participants wearing barefoot-style shoes study elite runners or have participants with a history of barefoot style shoe training run on a treadmill when shod or barefoot. Wearing barefoot-style shoes is suggested as a method of transition between shod and barefoot running. Static and dynamic balance exercises also are recommended. However, little information is available on the effects five-toed barefoot style shoes have on static balance. The purpose of this study was to examine balance of subjects barefoot, wearing Vibram FiveFingersTM barefoot-style shoes, and regular athletic shoes with eyes closed when using the Biodex Balance System-SDTM. STUDY DESIGN: This was a repeated measures study. METHODS: Forty nine participants aged 18-30 years without lower extremity injury or experience wearing barefoot-style shoes were tested for static balance on the Biodex Stability SystemTM with their eyes closed while wearing Vibram FiveFingersTM, athletic shoes, or barefoot. Three trials of 10 seconds for each footwear type were completed. Repeated measures analysis of variance with Bonferroni's correction was used to analyze the degrees of sway in the anterior-posterior and medial lateral directions. An overall stability index was also calculated by the Biodex. RESULTS: For anterior posterior and overall indices, differences were found between all conditions. Participants wearing athletic shoes demonstrated the smallest anterior-posterior stability index (least sway) and spent the most time in the innermost concentric circular zone. Medial-lateral indices were not different for any condition. CONCLUSIONS: Wearing Vibram FiveFingersTM provided better overall and anterior posterior static balance than going barefoot. While differences between Vibram FiveFingersTM and barefoot are significant, results may reflect statistical significance rather than any clinical difference in young, uninjured individuals. CLINICAL RELEVANCE: It would appear that Vibram FiveFingersTM mimic going barefoot and may be a bridge for exercising in preparation for barefoot exercise. LEVEL OF EVIDENCE: 3B. PMID- 25709866 TI - Ultimate frisbee injuries in a collegiate setting. AB - PURPOSE/BACKGROUND: Ultimate Frisbee (Ultimate) is a limited-contact team sport growing in popularity, particularly as a collegiate club sport. In 2011, over 947,000 people played Ultimate. Sex, age, skill level, and physical demands of the sport place each player at risk for injury, yet there is limited information on the number of injuries with regard to clinical research. The purpose of this study is to identify injury reporting trends in Ultimate Frisbee against other collegiate club sports and examine correlation with sex, body region, and medical recommendations and to discuss associated risk of injury. METHODS: Athletes who sustained an injury related to participation in their respective club sport attended a physical therapy sports clinic, underwent screening, and were provided direction for injury management. Data was collected on various elements of each case with descriptive statistical analysis performed to catalog injury characteristics. Chi-square analyses were performed to compare proportions between sports, sex, and body region. RESULTS: Ultimate accounted for 143 (31.0%) of the 461 reported injury cases collected from all club sports. Female injuries represented 101 (70.6%) of the 143 Ultimate cases, whereas men totaled 42 (29.4%) (p<0.001). Women had significantly more foot/ankle (26) than men (4) (p<.001) and more lumbar/flank (9) injuries than men (2) (p=.022). CONCLUSIONS: Ultimate accounted for one of the highest number of reported injuries among all club sports. Women reported injuries more than twice as frequently as men. The majority of reported Ultimate injuries involved the lower extremity. Injury trends observed are similar to those previously reported in several NCAA Intercollegiate sports. LEVEL OF EVIDENCE: IV. PMID- 25709867 TI - Gait re-training to alleviate the symptoms of anterior exertional lower leg pain: a case series. AB - BACKGROUND/PURPOSE: Exercise induced lower leg pain (EILP) is a commonly diagnosed overuse injury in recreational runners and in the military with an incidence of 27-33% of all lower leg pain presentations. This condition has proven difficult to treat conservatively and patients commonly undergo surgical decompression of the compartment by fasciotomy. This case series investigates the clinical outcome of patients referred with exertional lower leg pain symptoms of the anterior compartment of the lower leg following a gait re-training intervention program. CASE DESCRIPTION: 10 patients with exercise related running pain in the anterior compartment of the lower leg underwent a gait re-training intervention over a six-week period. Coaching cues were utilized to increase hip flexion, increase cadence, to maintaining an upright torso, and to achieve a midfoot strike pattern. At initial consult and six-week follow up, two dimensional video analysis was used to measure kinematic data. Patients self reported level of function and painfree running were recorded throughout and at one-year post intervention. OUTCOMES: Running distance, subjective lower limb function scores and patient's pain improved significantly. The largest mean improvements in function were observed in 'running for 30 minutes or longer' and reported 'sports participation ability' with increases of 57.5% and 50%, respectively. 70% of patients were running painfree at follow-up. Kinematic changes affected at consultation were maintained at follow-up including angle of dorsiflexion, angle of tibia at initial contact, hip flexion angle, and stride length. A mean improvement of the EILP Questionnaire score of 40.3% and 49.2%, at six-week and one-year follow up, respectively. DISCUSSION: This case series describes a conservative treatment intervention for patients with biomechanical overload syndrome/exertional compartment syndrome of the anterior lower leg. Three of the four coaching cues affected lasting changes in gait kinematics. Significant improvements were shown in painfree running times and function. LEVEL OF EVIDENCE: 4. PMID- 25709868 TI - Return to Sport Following Surgery for a Complicated Tibia and Fibula Fracture in a Collegiate Women's Soccer Player with a Low Level of Kinesiophobia. AB - BACKGROUND & PURPOSE: Much attention has been solely paid to physical outcome measures for return to sport after injury in the past. However, current research shows that the psychological component of these injuries can be more predictive of return to sport than physical outcome measures. The purpose of this case report is to describe the successful return to sport following surgery of a complicated tibia and fibula fracture of a Division I collegiate women's soccer player with a low level of kinesiophobia. CASE DESCRIPTION: A 22-year-old female sustained a closed traumatic mid-shaft fracture of her tibia and fibula. During a high velocity play she sustained a direct blow while colliding with an opposing player's cleats. As a result of the play, her distal tibia was displaced 908 to the rest of her leg. She underwent a closed reduction and tibial internal fixation with an intramedullary rod. Outcome scores were tracked using the IKDC and TSK-11. The IKDC measures symptoms, function, and sport activity related to knee injuries. The TSK-11 measures fear of movement and re-injury, which was important to assess during this case due to the gruesome nature of the injury. OUTCOMES: At 4 months, the subject became symptomatic over the fibula and was diagnosed with a fibular nonunion fracture. This was unexpected due to the low incidence of and usual asymptomatic nature of fibular nonunion fractures, which required an additional surgery. TSK-11 scores ranged from 19-20 throughout, signifying low levels of kinesiophobia. IKDC scores improved from 8.05 to 60.92. The subject ultimately signed a professional soccer contract. DISCUSSION: The rehabilitation of this subject was complex due to her low levels of kinesiophobia, self-guided overtraining, and the potential role they may have had in her fibular nonunion fracture. This case study demonstrates a successful outcome despite a unique injury presentation, multiple surgeries, and low levels of kinesiophobia. While a low level of kinesiophobia can be detrimental to rehabilitation compliance, it may have benefited her in the long-term. LEVEL OF EVIDENCE: 5. PMID- 25709869 TI - The use of dry needling for a subject with acute onset of neck pain: a case report. AB - BACKGROUND AND PURPOSE: Neck pain is a common complaint treated by the physical therapist. Trigger points (TrPs) have been studied as a source of neuromusculoskeletal pain, though the ability of clinicians to accurately locate a TrP is not well supported. Dry needling (DN) is an intervention utilized by physical therapists where a monofilament needle is inserted into soft tissue in order to reduce pain thereby facilitating return to prior level of function. The purpose of this case report is to report the outcomes of DN as a primary treatment intervention for acute, non-specific cervical region pain. CASE DESCRIPTION: The subject was an active 64-year-old female who self- referred for cervical pain following lifting heavy boxes while moving into a new home. She had a history of multi-level cervical fusion and recurrent cervical pain that physical therapy helped to control over the past few years. Physical examination supported a diagnosis of acute cervical region strain. Objective findings included decreased cervical active range of motion (AROM) and upper extremity strength, as well as, reproduction of pain symptoms upon palpation indicating the likelihood of TrPs in the right upper trapezius, levator scapula, supraspinatus, and infraspinatus musculature. She was treated using DN to the aforementioned muscles for two sessions, and no other interventions were performed in order to determine the effectiveness of DN as a primary intervention strategy without other interventions masking the effects of DN. OUTCOMES: Clinically meaningful improvements were noted in pain and disability, as measured by the Neck Disability Index and Quadruple Visual Analog Scale. Physical examination denoted minimal to no change in cervical AROM (likely associated with multi-level fusion), except for right lateral flexion, and no change in shoulder flexion/ abduction MMT. DISCUSSION: The patient was able to return to daily and work activities without further functional limitations caused by pain. This case report shows promising outcomes for the use of DN in the treatment of non specific cervical region strain. Further research is recommended to determine if DN is clinically beneficial independent of other therapeutic interventions/ postural corrections such as general or specific exercises targeting the affected musculature, or other "manual" therapy techniques such as manipulation or non thrust mobilization. LEVEL OF EVIDENCE: Level 4. PMID- 25709871 TI - Welcome to JWS for 2015! PMID- 25709870 TI - An interval kicking progression for return to soccer following lower extremity injury. AB - BACKGROUND AND PURPOSE: The majority of all soccer injuries affect the lower extremities. Regardless of whether the injured limb is an athlete's preferred kicking or stance leg, a lower extremity injury may affect their ability to impact the ball. Sport-specific biomechanical progressions to augment loading and gradually reintroduce a player to the demands of sport have been developed for upper extremity sports such as baseball, softball, tennis, and golf. Generalized return to soccer progressions have also been published in order to assist clinicians in safely returning athletes to sport; however, there are no specific progressions for the early stages of kicking designed to introduce stance leg loading and kicking leg impact. Thus, the purpose of this clinical commentary was to review the existing literature elucidating the biomechanics of kicking a soccer ball and propose a progressive kicking program to support clinicians in safely returning their soccer athletes to the demands of sport. DESCRIPTION OF TOPIC: The interval kicking program (IKP) describes clinical guidelines for readiness to begin a kicking program as well as possible readiness to return to sport measures. The program is performed on alternate days integrating therapeutic exercise and cardiovascular fitness. The IKP gradually introduces a player to the loading and impact of kicking. The progression increases kicking distance (using the markings of a soccer field as a guide), volume, and intensity and uses proposed soreness rules, effusion guidelines, and player feedback in order to assist clinicians in determining readiness for advancement though the stages. The IKP also recommends utility of specific tests and measures to determine readiness for return to sport. DISCUSSION: Gradual reintroduction to sport specific demands is essential for a safe return to soccer. This return to sport progression provides a framework integrating injury specific therapeutic exercise, cardiovascular fitness, and the return to kicking progression, to assist clinicians in initiating an athletes' return to soccer. LEVEL OF EVIDENCE: Level 5. PMID- 25709872 TI - Open repair of the triangular fibrocartilage complex from palmar aspect. AB - Background Although foveal tears of the triangular fibrocartilage complex (TFCC) can be surgically reattached to the fovea via a dorsal approach, the foveal lesion is difficult to visualize from the dorsal side because the extensor carpi ulnaris (ECU) sheath floor and the superficial dorsal limb of the radioulnar ligament hinders the view of the fovea. Materials and Methods Twenty-one patients with foveal tears were treated by an open repair method from the palmar aspect. Pain, instability, motion, and grip strength were evaluated after a mean follow up period of 26 months, and each patient was rated according to the Mayo Modified Wrist Score (MMWS). Description of Technique A 4-cm skin incision is made on the palmar aspect of the ulnar fovea. The ulnar fovea is exposed through a transverse capsulotomy of the distal radioulnar joint. The distal aspect of the TFCC is also exposed between the ECU tendon sheath and the ulnotriquetral ligament. After curettage of the scar tissue in the fovea, the deep palmar and dorsal limbs of the TFCC are sutured back to the fovea using a suture anchor technique. Results Foveal TFCC tears could be repaired via a palmar surgical approach without violating the floor of the ECU tendon sheath and the superficial dorsal limb. Excellent results were achieved in 18 patients, and a good result was achieved in three. Conclusions Our result compared favorably with those reported for dorsal approach. The palmar surgical approach facilitates the inspection and repair of the TFCC foveal tears. Level of Evidence IV. PMID- 25709873 TI - Reconstruction of Chronic Foveal TFCC Tears with an Autologous Tendon Graft. AB - Background A triangular fibrocartilage complex (TFCC) injury can produce distal radioulnar joint (DRUJ) instability. If the foveal attachment is avulsed, it translates distally. The footprint is separated from its origin and will become covered in synovitis, preventing healing. The authors describe a surgical technique for the treatment of instability of the DRUJ due to chronic foveal detachment of the TFCC. Technique The procedure utilizes a loop of autologous palmaris longus tendon graft passed through the ulnar aspect of the TFCC and through an osseous tunnel in the distal ulna to reconstruct the fovel attachment. Patients and Methods We report on nine patients with a mean age of 42. Median follow-up was 13 months. Results The median pain scores measured were reduced from 8 to 3 postoperatively, and all had a stable DRUJ. Conclusions This technique provides stability of the distal ulna to the radius and carpus, with potential for biologic healing through osseous integration. It is a robust, anatomically based reconstruction of the TFCC to the fovea that stabilizes the DRUJ and the ulnar-carpal sag. PMID- 25709874 TI - Anatomical Reattachment of the TFCC to the Ulnar Fovea Using an ECU Half-Slip. AB - Background Since 1998, we treated 25 wrists with foveal detachment of the triangular fibrocartilage complex (TFCC) by our original reattachment technique using a half-slip of the extensor carpi ulnaris (ECU) tendon with a very small titanium interference screw. We examine the clinical outcome of this procedure with a minimum of 2 years follow-up. Patients and Methods There were 25 wrists of 24 patients (16 right, 7 left, 1 bilateral, mean age, 34.8 years) with a minimum follow-up of 2 years (range 2-7 years, average 3.1). There was a neutral ulnar variance in 19 wrists and positive in 6. In the positive-variance wrists, an ulnar shortening was performed to prevent ulnar abutment before the reattachment. The diagnosis of a TFCC injury was done by arthrogram, magnetic resonance imaging (MRI), and distal radioulnar (DRUJ) arthroscopy. The clinical outcome was evaluated using our original DRUJ evaluating system. Technique A distally based ECU half-slip was harvested, introduced into the TFCC, sutured to the remnant of the TFCC, and pulled out through a 2.5-mm bone tunnel at the center of the fovea. The ECU half-slip was subsequently anchored to the ulnar fovea with a small titanium interference screw. Results At the final follow-up, 21 wrists had no pain, 3 wrists indicated mild pain, and 1 wrist severe pain. One patient had a loss of supination by 30 degrees. The DRUJ was stable in 22 wrists, moderately unstable in 2 wrists, and severely unstable in 1 wrist. There were 21 excellent, 2 good, 1 fair, and 1 poor results. Conclusions Anatomic reattachment of the TFCC to the ulnar fovea using an ECU half-slip tendon is a promising procedure. This technique is effective for severe DRUJ instability due to chronic foveal avulsion of the TFCC. PMID- 25709875 TI - Arthroscopic foveal repair of the triangular fibrocartilage complex. AB - Background Foveal disruption of the triangular fibrocartilage complex (TFCC) is associated with distal radioulnar joint (DRUJ) instability. TFCC fixation onto the fovea is the suitable treatment, which is not achieved by conventional arthroscopic techniques. We describe an all-inside arthroscopic technique that uses a suture anchor through distal DRUJ arthroscopy for foveal repair of the TFCC. Materials and Methods Forty-eight patients with TFCC foveal tear and DRUJ instability were selected according to the Atzei-European Wrist Arthroscopy Society (EWAS) algorithm of treatment. Retrospective evaluation included pain, DRUJ instability, range of motion (ROM), grip strength, Modified Mayo Wrist Score (MMWS), and the Disabilities of the Arm, Shoulder, and Hand (DASH) Score. Description of Technique DRUJ arthroscopy was performed to debride the TFCC and the foveal area. Under arthroscopic guidance, a suture anchor was inserted via the distal foveal portal to repair the TFCC onto the fovea. Sutures were tied on the radiocarpal surface of the TFCC. Postoperative immobilization of forearm rotation was maintained for 4 weeks. Heavy tasks were allowed after 3 months. Results After a mean follow-up of 33 months, pain improved significantly but remained moderate in four patients, severe in one. DRUJ instability resolved in 44 patients. Wrist ROM increased. Grip strength, MMWS, and DASH score improved significantly. Excellent and good MMWS equaled 83.3%. Forty-one patients (85.5%) resumed previous work and sport activities. As a postoperative complication, five patients experienced neuroapraxia of the dorsal sensory branch of the ulnar nerve (DSBUN) with full spontaneous recovery. Conclusions With appropriate indications and patient selection, arthroscopic foveal repair of the TFCC may restore DRUJ stability and provide satisfactory results without significant complications. PMID- 25709876 TI - What does the transverse carpal ligament contribute to carpal stability? AB - Background The transverse carpal ligament is well known for its involvement in carpal tunnel syndrome, and sectioning of this ligament remains the definite treatment for this pathology. Some authors believe that the transverse carpal ligament is an important stabilizer of the carpal arch, whereas others do not consider it to be significant. Several studies have been performed, both in vivo and in in vitro. Sectioning of the transverse carpal ligament does not seem to have any effect on the width of the carpal arch in the unloaded condition. However, patients will load the arch during their activities of daily living. Materials and Methods A cadaveric study was done with distraction of the carpal bones before and after sectioning the transverse carpal ligament. Results With the transverse carpal ligament intact, the carpal arch is mobile, with distraction leading up to 50% widening of the arch. Sectioning of the transverse carpal ligament resulted in a significant widening of the carpal arch by a further 30%. Conclusions Loading of the carpal arch after sectioning of the transeverse carapal ligament leads to a significant increase in intracarpal mobility. This will inevitably influence carpal kinematics in the patient and might be responsible for some complications after simple carpal tunnel releases, such as pillar pain, palmar tenderness, and loss of grip strength. PMID- 25709877 TI - De Quervain Tenosynovitis Following Trapeziometacarpal Ball-and-Socket Joint Replacement. AB - Background One of the surgical treatment options for trapeziometacarpal (TMC) joint arthritis is a prosthetic ball-and-socket replacement. One of the complications in the postoperative setting is de Quervain tendinopathy. Purposes Although this complication has been reported following a resection athroplasty, we questioned whether lengthening of the thumb following the Ivory (Memometal, Stryker Corporate, Kalamazoo, MI, USA) ball-and-socket arthroplasty could be a causal factor. Methods In a prospective study regarding the overall outcome of the Ivory prosthesis, we analyzed 96 cases (83 patients; 69 female, 12 male, 8 bilateral) of primary implanted Ivory prosthesis and the incidence of de Quervain disease during the first year following surgery. We found a particularly high incidence (17%) of de Quervain tendinopathy the first year following this ball and-socket arthroplasty. We measured the lengthening of the thumb radiographically in the group presenting de Quervain and the asymptomatic group and compared this measure between the two groups. Results We did not find any measurable or statistically significant difference between the groups regarding lengthening. Discussion These findings suggest that lengthening of the thumb following ball-and-socket arthroplasty is not a causal factor in the development of de Quervain tendinopathy within one year after surgery. PMID- 25709878 TI - The Management of Kienbock Disease: A Survey of the ASSH Membership. AB - Background The purpose of this study was to determine the current trends and common practices for the treatment of Kienbock disease at different stages. Question/Purpose To determine the current trends and common practices by hand surgeons for the treatment of Kienbock disease. Methods A survey with hypothetical Kienbock disease cases stratified by the Lichtman staging system was distributed to the American Society for Surgery of the Hand (ASSH) members. Questions and responses reflected common treatment strategies. Results Of a total of 375 worldwide respondents, preferred treatments of Kienbock disease were as follows: for Stage I disease, an initial trial of splinting was favored (74%), followed by radial shortening osteotomy for continued symptoms. For Stage II disease, 63% of surgeons preferred surgical intervention, particularly radial shortening osteotomy. For Stage IIIa with negative ulnar variance, 69% chose radial shortening osteotomy. Responses were heterogeneous for Stage IIIa Kienbock with positive variance, and capitate shortening osteotomy and vascularized bone grafting were preferred. Salvage procedures predominated for Stage IIIb disease, including proximal row carpectomy (PRC; 42%), intracarpal arthrodesis (21%), and total wrist fusion (10.7%). Similarly, Stage IV disease was treated by 87% of respondents by either PRC or wrist fusion. Without regard to stage of disease, 90% of participants reported using the same Lichtman staging to guide treatment and would also alter treatment strategy based upon ulnar variance. Conclusions Most respondents used Lichtman staging and ulnar variance to guide treatment decisions. Results indicate that the most common surgical treatments were radial shortening osteotomy for early disease and PRC in later stages. Level of Evidence Level IV, Economic/Decision Analysis. PMID- 25709879 TI - Union of Scaphoid Waist Fractures Assessed by CT Scan. AB - Background Union of a scaphoid fracture is difficult to assess on a standard series of radiographs. An unnecessary and prolonged immobilization is inconvenient and may impair functional outcome. Although operative treatment permits early mobilization, its influence on time to union is still uncertain. Purpose To assess union of scaphoid waist fractures based on computed tomography (CT) scan at 6 weeks, and to compare time to union between conservative treatment and arthroscopically assisted screw fixation. Patients and methods CT scan in the longitudinal axis of the scaphoid was used to provide fracture characteristics, and to assess bone union at 6 weeks in 65 consecutive patients with scaphoid waist fractures. In a randomized subgroup from this cohort with nondisplaced fractures, we compared time to union between conservative treatment (n = 23) and arthroscopically assisted screw fixation (n = 15). Results Overall, at 6 weeks we found a 90% union rate for non- or minimally displaced fracture treated conservatively, and 82% for those who underwent surgery. In the randomized subgroup of nondisplaced fractures, no significant difference in time to union was demonstrated between those treated conservatively and those who underwent surgery. The conservatively treated fractures from this subgroup with prolonged time to union (10 to 14 weeks) were comminuted, demonstrating a radial cortical or corticospongious fragment. Conclusion The majority of non- or minimally displaced scaphoid waist fractures are sufficiently treated with 6 weeks in a cast. Screw fixation does not reduce time to fracture union compared with conservative treatment. Level of Evidence level II, Therapeutic study. PMID- 25709880 TI - Hardware-related complications following radiocarpal arthrodesis using a dorsal plate. AB - Background Hardware-related complications more than 6 months after total wrist arthrodesis are rarely reported, and controversy remains around the inclusion of the middle finger carpometacarpal joint (CMCJ) in the fusion mass. Purpose To determine the frequency of hardware-related complications including plate fractures, screw fractures, and symptomatic plate/screw loosening, and to investigate whether failure to fuse the middle finger CMCJ contributed to these hardware complications. Patients and Methods A retrospective chart review was designed to identify long-term hardware-related complications following 122 wrist arthrodeses using plate fixation. Patients with at least 6 months of follow-up were reviewed to determine the number of complications, the involvement of the middle finger CMCJ, and the procedures required to address these complications. Results At a median of 2.5 years following arthrodesis (range, 6 months-19 years), 20 (16%) hardware-related complications occurred and included screw fracture (n = 12), plate loosening (n = 5), and plate fracture (n = 3). Thirteen (65%) of the hardware complications occurred after the CMCJ was not fused during the procedure. The CMCJ did not fuse after attempted arthrodesis in 6 additional wrists. Conclusions Persistent middle finger CMCJ micromotion was likely present in 19/20 wrists (95%) that experienced symptomatic hardware complications. Given the occurrence of hardware failures centering on this joint, it is our recommendation that, unless one plans for routine plate removal within a given timeframe, the middle finger CMCJ must be included in the fusion mass. Level 4 Therapeutic Case Series. PMID- 25709881 TI - Osteoid osteoma of the hamate presenting as a midcarpal synovitis. AB - Background Osteoid osteoma is a benign bone lesion of unknown etiology uncommonly affecting the carpal bones. In the upper extremity, the clinical and imaging picture may be misleading, often mimicking other entities. We present a rare case of a patient with a subchondral osteoid osteoma mimicking a posttraumatic midcarpal synovitis. Case Description A 21-year-old woman presented with persistent pain and swelling of the right wrist. Physical examination revealed swelling and pain on direct palpation over the dorsal aspect of the wrist. Radiographs were normal. Inconclusive computed tomography (CT) and magnetic resonance imaging (MRI) scans suggesting an occult fracture versus avascular necrosis delayed the diagnosis. Scintigraphy and fine-cut CT scan provided the definitive diagnosis. Surgical excision of the nidus and synovectomy of the midcarpal joint were performed, with complete resolution of pain and rapid return to normal function. Literature Review Three different types of osteoid osteoma have been described according to radiological methods: cortical, medullar, and subperiosteal. When localized in the carpus, most lesions are intra-articular. Reactive synovitis is often present and may be the primary symptom. Radiofrequency ablation is a treatment alternative. However, if a safe distance between the electrode and a major neurovascular structures (up to 1.5 cm) cannot be guaranteed, surgical excision is recommended. Clinical Relevance A high index of suspicion and careful attention to the clinical picture are necessary for accurate diagnosis and treatment of osteoid osteoma in the hand and carpus. CT scan and scintigraphy are the most sensitive complementary investigations and enable definitive diagnosis and treatment. PMID- 25709882 TI - Extensor carpi ulnaris tenosynovitis caused by the tip of an oversized ulnar styloid: a case report. AB - Background Degenerative tendinopathy of the extensor carpi ulnaris (ECU) produced by the tip of an oversized ulnar styloid has not been formerly reported. Case Description We report an uncommon case of an injury to the ECU tendon that was related to a prominent oversized ulnar styloid. The patient's symptoms improved following resection of the styloid process. Literature Review Our case differs from previous reports in that it involves an uninjured oversized ulnar styloid that damaged the overlying ECU tendon with no apparent instability. Clinical Relevance Besides ulnar styloid impaction syndrome, the diagnosis of ECU tenosynovitis should also be considered in patients with ulnar-side pain and an oversized ulnar styloid. PMID- 25709883 TI - Bilateral symptomatic os epilunatum: a case report. AB - Background Accessory carpal ossicles may be the cause of atraumatic wrist pain or may be misinterpreted as a fracture after a trauma. Case Description We report the case of a patient suffering with chronic, bilateral wrist pain without history of trauma. Sonographic examination showed a bilateral symptomatic os epilunatum, both of which were surgically resected, resulting in pain relief. Literature Review Os epilunatum is a rare entity that has been reported only in few cadaveric specimen. Clinical Relevance Os epilunatum is a rare accessory ossicle of the carpus that can cause this aggravating pain. Sonography enabled accurate diagnosis of this anomaly. Because of possible associated tear of the scapholunate ligament, we recommend intraoperative testing of the stability of the scapholunate joint. PMID- 25709884 TI - A new technique for the treatment of midcarpal instability. AB - Extensor carpi radialis brevis (ECRB) transfer to the hamate bone is a novel procedure that offers a new surgical treatment option for select patients with midcarpal instability (MCI) who do not respond to conservative treatment. We present our early experience with this procedure. In total, 12 patients (13 wrists) were reviewed with a follow-up duration ranging from 1 to 6 years. Complications and changes in active range of motion (AROM) were noted. Patient related outcome was measured using the Patient Rated Wrist/Hand Evaluation (PRWHE) questionnaire, amongst others. Two patients failed to show a positive response to the surgery. ECRB transfer to the ulnar side of the wrist is a new procedure that offers a potential option for the surgical treatment of MCI in select patients; however, further biomechanical and clinical studies are required. The level of evidence for this study is IV (therapeutic). PMID- 25709885 TI - Robotic assisted surgeries for the treatment of spine tumors. AB - BACKGROUND: Surgery plays an important role in the treatment of patients with metastatic or primary spine tumors. In recent years, various new techniques, such as robotic assisted spine surgery have been developed which has shown some promising results by improving the accuracy of spinal instrumentation and reducing potential complications. The purpose of this study was to evaluate our early experience using robotic guidance in the treatment of spinal tumors. METHODS: Data were collected from medical records for each surgery in which the robotic system was used to assist with biopsy, pedicle screw placement and/or vertebral augmentation in the treatment of spinal tumors. Patient's age, gender, diagnosis and surgical procedure were documented. The surgical time, estimated blood loss, peri-operative and post-operative complications were obtained. The visual analog scale (VAS) for back pain and leg pain were also recorded. RESULTS: A total of 9 consecutive patients (7 female, 2 male) were included in this study, beginning with the first case experience. The mean age of the patients was 60 years (range 47-69). All patients presented with thoracic or lumbar vertebral collapse and/or myelopathy. Robotic assisted posterior instrumentation was successfully performed in all patients. Robotic assisted vertebral augmentation was performed in 4 patients. The average number of levels instrumented was 5. The average surgery time (skin to skin) was 4 hours and 24 minutes and the mean blood loss was 319 ml. There were no complications perioperatively or through the latest follow-up. Seven of the 9 patients reported improved back pain and/or leg pain at the latest follow-up and the data were not available in two patients. CONCLUSIONS: The published complication rates of spinal tumor surgeries range between 5.3% and 19%. With robotic assistance, the surgical complication rate appears improved over the historical figures. Our study shows that the robotic system was safe and performed as desired in the treatment of metastatic and primary spine tumors. These results support that further evaluation in a larger series of patients. PMID- 25709886 TI - Lumbar dorsal root Ganglia location: an anatomic and MRI assessment. AB - BACKGROUND: The dorsal root ganglion (DRG) is a key structure in the mechanism of symptomatic radicular pain, weakness and change in sensation. DRG localization can assist in the decision making process of which areas require decompression, and type of procedure that should be performed to treat radicular symptoms. In this study we determine dimensions of lumbar foramina, DRG and its relationship to the neuroforamina through anatomic and magnetic resonance imaging (MRI) evaluation Agreement between MRI and anatomic assessment of DRG location will be determined. METHODS: Sixteen embalmed cadavers, 10 females and 6 males, aged 68 to 106 years had an MRI of the thoracolumbar spine followed by dissection. Measurements made included foraminal height and width, DRG size and nerve root take off angle. The center of the DRG and its relationship to the foramina were measured and the probability of agreement between anatomic and MRI assessment were made. RESULTS: The greatest width of the DRG was 6.5mm bilaterally at L5 (range 3.2-6.5mm). The nerve root take off angle was largest at L5 on the left (range 50.5o-58.8o) and L4 on the right (range 50.5o-57.2o). The center of the DRG was found bilaterally in the medial zone of the foramen of L1-4 and lateral zone at L5. Foramina size increased from L1 to L5 in the ventral to dorsal and cephalad to caudal direction. Pedicle width increased from L1 to L5. The estimated overall probability of agreement between anatomic and MRI DRG location was 86.3% (95% confidence interval = 77.5% - 92.0%). CONCLUSIONS: The percentage of agreement between MRI and anatomic evaluation of lumbar DRG location significantly exceeded our pre-defined threshold of 70% (p = 0.0013). CLINICAL RELEVANCE: Our results aid in surgical decision-making as true anatomic position can be directly correlated to what's seen on MRI. PMID- 25709887 TI - Prospective analysis of a new bone graft in lumbar interbody fusion: results of a 2- year prospective clinical and radiological study. AB - BACKGROUND: This study examined the efficacy and safety of bone graft material ABM/P-15 (iFACTOR) for use in posterior lumbar interbody fusion. ABM/P-15 has been used safely for more than a decade in dental applications. METHODS: Forty patients underwent PLIF surgery, with each patient as control. Assessments up to 24 months included radiographs, CT scan, VAS, and ODI. Primary success criteria were fusion and safety. RESULTS: Intra-cage bridging bone occurred earlier with ABM/P-15 than autograft (97.73% vs. 59.09% at 6 months). On average pain decreased 29 points and function improved 43 points. Radio dense material outside the disk space occurred more frequently with ABM/P-15 than autograft, without clinical consequence. CONCLUSIONS: This study suggests that ABM/P-15 has equal or greater efficacy at 6 and 12 months. Pain improvements exceeded success criteria at all time points. Functional improvement exceeded success criteria at all time points. CLINICAL RELEVANCE: This study explores the safety and efficacy of an osteobiologic peptide enhanced bone graft material as a viable alternative to autograft and its attendant risks. PMID- 25709889 TI - Progressive transfusion and growth factor independence with adjuvant sertraline in low risk myelodysplastic syndrome treated with an erythropoiesis stimulating agent and granulocyte-colony stimulating factor. AB - Refractoriness to growth factor therapy is commonly associated with inferior outcome in patients with low-risk myelodysplastic syndrome (LR-MDS) who require treatment for cytopenias. However, the mechanisms leading to refractoriness are unknown. Here we describe a clinically depressed 74-year-old male with refractory cytopenia with multilineage dysplasia (RCMD) and documented growth factor refractory anemia after erythropoeisis stimulating agent (ESA) therapy, who attained transfusion and growth factor independence after the addition of sertraline to his medication regimen. Our case demonstrates hematological improvement-erythroid (HI-E) in growth factor refractory, low risk MDS and highlights a potential mechanistic link between common inflammatory diseases and LR-MDS. PMID- 25709890 TI - Emergence of a STAT3 mutated NK clone in LGL leukemia. AB - Large granular lymphocyte (LGL) leukemia is a chronic clonal lymphoproliferative disorder. Here, a T-LGL leukemia patient developed NK-LGL leukemia with residual leukemic T-LGL. TCRVbeta usage and CDR3 sequence drifts were observed with disease progression. A STAT3 S614R mutation was identified in NK but not T-cells in the mixed leukemic stage. Multiple, non-dominant T-cell clones with distinct STAT3 mutations were present throughout. Our results suggest that T and NK-LGL leukemia may share common pathogenesis mechanisms and that STAT3 mutation alone is insufficient to bring about clonal expansion. Mutational and immunological monitoring may provide diagnostic and therapeutic significance in LGL leukemia. PMID- 25709891 TI - "Preleukemic or smoldering" chronic myelogenous leukemia (CML):BCR-ABL1 positive: A brief case report. AB - Chronic myelogenous leukemia (CML), in the Chronic Phase (CP), is often suspected as a result of a complete blood count (CBC), which shows increased granulocytes, mostly mature including a peak in myelocytes, increased basophils, and rarely blasts and/or promyelocytes. Morphologic dysplasia is not present. CML is confirmed by detecting the characteristic Philadelphia chromosome (Ph)[t(9;22)(q34;q11.2)] by routine cytogenetics or fluorescent in situ hybridization (FISH) or molecular studies (RT-PCR) for the bcr-abl fusion gene. The most common feature of CML is an elevated WBC count, usually above 25*10(3)/uL, and frequently above 100*10(3)/uL. We report a case of confirmed Ph+CML with a normal CBC detected because of the presence of rare myelocytes and 2% basophils [Fig. 1]. Previous leukocyte counts for the preceding eight years were normal with the exception of one done four months prior to his presentation that showed an abnormal differential with 1% basophils, 2% metamyelocytes and 2% myelocytes. PMID- 25709892 TI - Effects of 5-azacytidine on natural killer cell activating receptor expression in patients with refractory anemia with excess of blasts. AB - Epigenetic drugs modify DNA methylation and are used in refractory anemia with excess of blasts (RAEB). These drugs may reactivate anti-oncogene expression and restore a normal phenotype instead of inducing antitumor toxicity, although they also have immunosuppressive effects on T-lymphocytes [1] In RAEB and acute myeloid leukemia, a defect in natural killer (NK) cell cytotoxicity has been shown, which relies on abnormal expression of activating receptors. Previous study has shown that 5-azacytidine impaired mRNA synthesis and induced apoptosis in NK cells [2]. In this study we investigated the effect of the demethylating drug 5-azacytidine (Vidaza((r))) on NK receptors with the hypothesis that demethylation of the promoters of activating NK receptor genes induces gene reactivation and thus may increase their expression. PMID- 25709888 TI - Friend or foe: Endoplasmic reticulum protein 29 (ERp29) in epithelial cancer. AB - The endoplasmic reticulum (ER) protein 29 (ERp29) is a molecular chaperone that plays a critical role in protein secretion from the ER in eukaryotic cells. Recent studies have also shown that ERp29 plays a role in cancer. It has been demonstrated that ERp29 is inversely associated with primary tumor development and functions as a tumor suppressor by inducing cell growth arrest in breast cancer. However, ERp29 has also been reported to promote epithelial cell morphogenesis, cell survival against genotoxic stress and distant metastasis. In this review, we summarize the current understanding on the biological and pathological functions of ERp29 in cancer and discuss the pivotal aspects of ERp29 as "friend or foe" in epithelial cancer. PMID- 25709893 TI - An intensive approach to treatment for older patients with relapsed isolated NPM1 mutated AML. AB - We present a short case series of elderly patients with NK-AML and isolated NPM1 mutation who were treated with intensive chemotherapy, achieving significant CRs multiple times on reinduction, even with a single course.We hope to highlight the NPM1 as a molecular marker in elderly for consideration of aggressive treatment, even if abridged, as this subset may achieve a durable, good quality responses at diagnosis or subsequent relapses. PMID- 25709895 TI - MTHFR (C677T) polymorphism and PR (PROGINS) mutation as genetic factors for preterm delivery, fetal death and low birth weight: A Northeast Indian population based study. AB - Preterm delivery (PTD) is one of the most significant contributors to neonatal mortality, morbidity, and long-term adverse consequences for health; with highest prevalence reported from India. The incidence of PTD is alarmingly very high in Northeast India. The objective of the present study is to evaluate the associative role of MTHFR gene polymorphism and progesterone receptor (PR) gene mutation (PROGINS) in susceptibility to PTD, negative pregnancy outcome and low birth weights (LBW) in Northeast Indian population. METHODS: A total of 209 PTD cases {extreme preterm (< 28 weeks of gestation, n = 22), very preterm (28-32 weeks of gestation, n = 43) and moderate preterm (32-37 weeks of gestation, n = 144) and 194 term delivery cases were studied for MTHFR C677T polymorphism and PR (PROGINS) gene mutation. Statistical analysis was performed using SPSS software. RESULTS: Distribution of MTHFR and PR mutation was higher in PTD cases. Presence of MTHFR C677T polymorphism was significantly associated and resulted in the increased risk of PTD (p < 0.001), negative pregnancy outcome (p < 0.001) and LBW (p = 0.001); more significantly in extreme and very preterm cases. Presence of PR mutation (PROGINS) also resulted in increased risk of PTD and negative pregnancy outcome; but importantly was found to increase the risk of LBW significantly in case of very preterm (p < 0.001) and moderately preterm (p < 0.001) delivery cases. CONCLUSIONS: Both MTHFR C677T polymorphism and PR (PROGINS) mutation are evident genetic risk factors associated with the susceptibility of PTD, negative pregnancy outcome and LBW. MTHFR C677T may be used as a prognostic marker to stratify subpopulation of pregnancy cases predisposed to PTD; thereby controlling the risks associated with PTD. PMID- 25709894 TI - Molecular Genetics and Metabolism Report Long-term follow-up of post hematopoietic stem cell transplantation for Hurler syndrome: clinical, biochemical, and pathological improvements. AB - Mucopolysaccharidosis type I (MPS I; Hurler Syndrome) is a lysosomal storage disease caused by a deficiency of the enzyme alpha-L-iduronidase which affects multiple organs such as central nervous system (CNS), skeletal system, and physical appearance. Hematopoietic stem cell transplantation (HSCT) is recommended as a primary therapeutic option at an early stage of MPS I with a severe form to ameliorate CNS involvement; however, no description of pathological improvement in skeletal dysplasia has been investigated to date. We here report a 15-year-old male case with MPS I post-HSCT. This patient received successful HSCT at the age of 2 years and 1 month, followed for over 10 years. His activity of daily living including cognitive performance has been kept normal and the present height and weight are 162 cm and 55 kg. Bone deformity has been still developed, resulting in hemiepiphysiodesis of bilateral medial proximal tibia at 12 years of age and successive arthrodesis of thoraco-lumbar spine at 13 years of age; however, skeletal histopathology from surgical remnants showed substantial improvement in bone lesion with markedly reduced occurrence and cell size of vacuolated cells. After a series of surgical procedures, he became ambulant and independent in daily activity. The levels of GAGs in blood were substantially reduced. In conclusion, this long-term post-HSCT observation should shed light on a new aspect of therapeutic effect associated with skeletal pathology and GAG levels as a biomarker, indicating that HSCT is a primary choice at an early stage for not only CNS but skeletal system in combination of appropriate surgical procedures. PMID- 25709896 TI - Investigation of molybdenum cofactor deficiency due to MOCS2 deficiency in a newborn baby. AB - BACKGROUND: Molybdenum cofactor deficiency (MOCD) is a severe autosomal recessive neonatal metabolic disease that causes seizures and death or severe brain damage. Symptoms, signs and cerebral images can resemble those attributed to intrapartum hypoxia. In humans, molybdenum cofactor (MOCO) has been found to participate in four metabolic reactions: aldehyde dehydrogenase (or oxidase), xanthine oxidoreductase (or oxidase) and sulfite oxidase, and some of the components of molybdenum cofactor synthesis participate in amidoxime reductase. A newborn girl developed refractory seizures, opisthotonus, exaggerated startle reflexes and vomiting on the second day of life. Treatment included intravenous fluid, glucose supplementation, empiric antibiotic therapy and anticonvulsant medication. Her encephalopathy progressed, and she was given palliative care and died aged 1 week. There were no dysmorphic features, including ectopia lentis but ultrasonography revealed a thin corpus callosum. OBJECTIVES: The aim of this study is to provide etiology, prognosis and genetic counseling. METHODS: Biochemical analysis of urine, blood, Sanger sequencing of leukocyte DNA, and analysis of the effect of the mutation on protein expression. RESULTS: Uric acid level was low in blood, and S-sulfo-L-cysteine and xanthine were elevated in urine. Compound Z was detected in urine. Two MOCS2 gene mutations were identified: c.501 + 2delT, which disrupts a conserved splice site sequence, and c.419C > T (pS140F). Protein expression studies confirmed that the p.S140F substitution was pathogenic. The parents were shown to be heterozygous carriers. CONCLUSIONS: Mutation analysis confirmed that the MOCD in this family could not be treated with cPMP infusion, and enabled prenatal diagnosis and termination of a subsequent affected pregnancy. PMID- 25709897 TI - A Circulating Biomarker Risk-Prediction Model Correlates with CHADS-2 Risk Score in Chronic Atrial Fibrillation. AB - BACKGROUND: Inflammation and oxidative stress have been linked to the origin and persistence of atrial fibrillation (AF). CHADS-2 scoring system is a risk stratification schema well validated in prognostication of stroke in AF. We evaluated the association of markers of oxidative stress and inflammation with CHADS-2 scores in chronic AF patients. METHODS: CHADS-2 scores were calculated for 64 subjects with chronic AF. Serum markers of inflammation [C-reactive protein (hs-CRP), interleukin-6 (IL-6), interleukin 1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha)] and of oxidative stress [Derivatives of reactive oxygen metabolites (DROMs) and isoprostanes (IsoPs)] were measured. RESULTS: Twenty subjects were categorized as 0 (no risk), 24 as 1 (intermediate risk) and 20 as 2 (severe risk) based on their CHADS-2 scores. High sensitivity CRP (CHADS-2 0=40.0%, 1=70.0%, 2=90.0%; p=0.003) and DROMs (CHADS-2 0=45%, 1=78%, 2=80%; p=0.04) were positively associated with the CHADS-2 risk score. Subjects with intermediate to severe CHADS-2 risk retained significant associations with abnormal hs-CRP (OR: 5.3, 95%CI: 1.1-25.0) and DROMs (adjusted OR: 6.7, 95%CI: 1.2-38.8) after adjusting for gender and hypertension. In a multiple logistic interaction model, there was no significant interaction between hs-CRP and DROMs in their association with CHADS-2 risk categories (p=0.64). A biomarker risk model, combining hs-CRP and DROMs, correlated well with the CHADS-2 risk categories (r= 0.49, p<0.001). CONCLUSIONS: A biomarker risk-model using a combination of hs-CRP and DROMs correlates well with CHADS-2 risk scores in chronic AF. Either or both of these markers may add predictive power to future stroke risk prediction models. PMID- 25709898 TI - Storage Conditions and Passages Alter IL-6 secretion in C26 adenocarcinoma cell lines. AB - The C26 adenocarcinoma tumor line is frequently used to establish peripheral tumors in mice for the study of cancer cachexia and cancer-related fatigue. Recently, we have noticed a progressive decline in the effects of tumor growth on our biological and behavioral measures in the tumor-bearing mice. Therefore, we compared effects of three aliquots of the C26 tumor cell line that differed in storage condition and number of passages on cytokine secretion, tumor growth, weight loss and fatigue behavior. Three aliquots of the C26 tumor line were selected as alpha (alpha), beta (beta), and gamma (gamma). Aliquot alpha was an original C26 stock line that had been stored at -80 degrees C. Aliquot beta was stored in liquid nitrogen. Aliquot gamma was taken from aliquot beta and passaged three times. The three aliquots of the C26 tumor line showed differences in IL-6 mRNA and protein secretion in vitro, with aliquot beta showing the greatest IL-6 secretion. These differences were mirrored in vivo. Plasma IL-6 levels were elevated in all tumor bearing mice but was greatest in group beta mice. Carcass weight was decreased in all three tumor groups. Brain expression of IL-1beta mRNA was greatest in group beta and group beta demonstrated the greatest decline in running activity at day 19. Storage conditions and number of passages influence C26 tumor cell secretion of cytokines.Variations in C26 aliquots may explain differences observed between laboratories using the same cell line.We recommend always storing cell lines in liquid nitrogen and limiting the number of passages before use in experiments. PMID- 25709899 TI - Semaphorin 3A controls allergic and inflammatory responses in experimental allergic conjunctivitis. AB - AIM: To assess the efficacy of topical Semaphorin-3A (SEMA3A) in the treatment of allergic conjunctivitis. METHODS: Experimental allergic conjunctivitis (EAC) mice model induced by short ragweed pollen (SRW) in 4-week-old of BALB/c mice, mice were evaluated using haematoxylin and eosin (H&E) staining, immunofluorescence and light microscope photographs. Early phase took the samples in 24h after instillation and late phase took the samples between 4 to 14d after the start of treatment. The study use of topical SEMA3A (10 U, 100 U, 1000 U) eye drops and subconjunctival injection of SEMA3A with same concentration. For comparison, five types of allergy eyedrops were quantified using clinical characteristics. RESULTS: Clinical score of composite ocular symptoms of the mice treated with SEMA3A were significantly decreased both in the immediate phase and the late phase compared to those treated with commercial ophthalmic formulations and non treatment mice. SEMA3A treatment attenuates infiltration of eosinophils entering into conjunctiva in EAC mice. The score of eosinophil infiltration in the conjunctiva of SEMA3A 1000 U-treated group were significantly lower than low concentration of SEMA3A treated groups and non-treated group. SEMA3A treatment also suppressed T-cell proliferation in vitro and decreased serum total IgE levels in EAC mice. Moreover, Treatment of SEMA3A suppressed Th2-related cytokines (IL-5, IL-13 and IL-4) and pro-inflammatory cytokines (IFN-gamma, IL-17 and TNF-alpha) release, but increased regulatory cytokine IL-10 concentration in the conjunctiva of EAC mice. CONCLUSIONS: SEMA3A as a biological agent, showed the beneficial activity in ocular allergic processes with the less damage to the intraocular tissue. It is expected that SEMA3A may be contributed in patients with a more severe spectrum of refractory ocular allergic diseases including allergic conjunctivitis in the near future. PMID- 25709900 TI - Lycium barbarum polysaccharides protected human retinal pigment epithelial cells against oxidative stress-induced apoptosis. AB - AIM: To investigate the protective effect and its mechanism of lycium barbarum polysaccharides (LBP) against oxidative stress-induced apoptosis in human retinal pigment epithelial cells. METHODS: ARPE-19 cells, a human retinal pigment epithelial cell lines, were exposed to different concentrations of H2O2 for 24h, then cell viability was measured by Cell Counting Kit-8 (CCK-8) assay to get the properly concentration of H2O2 which can induce half apoptosis of APRE-19. With different concentrations of LBP pretreatment, the ARPE-19 cells were then exposed to appropriate concentration of H2O2, cell apoptosis was detected by flow cytometric analysis. Expression levels of Bcl-2 and Bax were measured by real time quantitative polymerase chain reaction (RT-PCR) technique. RSULTS: LBP significantly reduced the H2O2-induced ARPE-19 cells' apoptosis. LBP inhibited the H2O2-induced down-regulation of Bcl-2 and up-regulation of Bax. CONCLUSION: LBP could protect ARPE-19 cells from H2O2-induced apoptosis. The Bcl-2 family had relationship with the protective effects of LBP. PMID- 25709901 TI - Activated complement classical pathway in a murine model of oxygen-induced retinopathy. AB - AIM: To investigate whether the complement system is involved in a murine model of oxygen-induced retinopathy (OIR). METHODS: Forty C57BL/6J newborn mice were divided randomly into OIR group and control group. OIR was induced by exposing mice to 75%+/-2% oxygen from postnatal 7d (P7) to P12 and then recovered in room air. For the control group, the litters were raised in room air. At the postnatal 17d (P17), gene expressions of the complement components of the classical pathway (CP), the mannose-binding lectin (MBL) pathway and the alternative pathway (AP) in the retina were determined by quantitative real-time polymerase chain reaction (RT-PCR). Retinal protein expressions of the key components in the CP were examined by Western blotting. RESULTS: Whole mounted retina in the OIR mice showed area of central hypoperfusion in both superficial and deep layers and neovascular tufts in the periphery. The expressions of C1qb and C4b genes in the OIR retina were significantly higher than those of the controls. The expression of retinal complement factor B (CFB) gene in OIR mice was significantly lower than those of the controls. However, the expressions of C3 and complement factor H (CFH) genes were higher. The protein synthesis of the key components involved in the CP (C1q, C4 and C3) were also significantly higher in OIR mouse retina. Although MBL-associated serine protease 1 (MASP1) and MASP2 were detected in both the OIR and the control groups, the expressions were weak and the difference between the two groups was not significant. CONCLUSION: Our data suggest that the complement system CP is activated during the pathogenesis of murine model of OIR. PMID- 25709902 TI - A novel mutation of sgk-1 gene in central serous chorioretinopathy. AB - AIM: To investigate the association of serum glucocorticoid kinase gene-1 (SGK-1) DNA variants with chronic central serous chorioretinopathy (CSC). METHODS: We enrolled 32 eyes of 32 patients who were diagnosed with chronic CSC and composed 32 normal eyes as a control group. Peripheral blood was used for DNA extraction and polymerase chain reaction (PCR) amplification. SGK1 gene was sequenced by using BigDye((r)) Terminator v3.1 cycle sequencing KIT (Applied Biosystems, Foster City, CA, USA). The SGK1 gene and its variants were investigated in CSC patient group and control group. RESULTS: We identified a new polymorphism M32V in two person in the patient group (Minor allele frequency (MAF)=0.009) on the region of 1-60 amino acids. The rs1057293 was located in the encoder region of the SGK 1 gene but not associated with CSC (P=0.68). An intrinsic rs1743966 is also not associated (P=0.28). CONCLUSIONS: The new polymorphism M32V is located on the region of 1-60 amino acids which is necessary for localization to the mitochondria in CSC patient. This mutation is probably important for the energy metabolism and plays an important role in the cellular response to hyperosmotic stress and other stress stimuli. Both rs1057293 and rs1743966 are not associated with CSC. PMID- 25709903 TI - Clinical outcomes of amniotic membrane loaded with 5-FU PLGA nanoparticles in experimental trabeculectomy. AB - AIM: To evaluate the effect of amniotic membrane loaded with 5-fluorouracil poly (lactic-co-glycolic acid) (PLGA) nanoparticles (5-FU-NPs) in the surgical outcomes of experimental trabeculectomy in rabbits. METHODS: Thirty-two New Zealand white rabbits were randomly categorized into four groups with 8 rabbits in each group. Group 1, the control group, performed traditional trabeculectomy without adjuvant treatment. While the experimental groups performed compound trabeculectomy with different implantations including amniotic membrane (group 2), 5-FU-NPs (group 3) and amniotic membrane loaded with 5-FU-NPs (group 4). Clinical evaluations including IOP measurement and filtration bleb analysis were performed in all groups postoperatively. RESULTS: There is no significant difference of mean IOP in all groups at first 7d after surgery. While at P14, mean IOPs of experimental group 2 (9.8+/-2.1 mm Hg), groups 3 (8.9+/-2.8 mm Hg) and group 4 (7.6+/-2.3 mm Hg) were significantly reduced compared to control group (12.4+/-2.6 mm Hg; n=8, P<0.05). At P21, mean IOPs of groups 3 (11.7+/-3.2 mm Hg) and group 4 (9.9+/-1.6 mm Hg) were significantly decreased compare to control group (17.9+/-1.6 mm Hg) and group 2 (16.6+/-2.8 mm Hg; n=8, P<0.05). At P28, mean IOPs of groups 3 (13.8+/-3.3 mm Hg) and group 4 (10.6+/-2.0 mm Hg) were also significantly reduced compare to control group (19.4+/-2.3 mm Hg) and group 2 (18.5+/-2.4 mm Hg; n=8, P<0.05). Meanwhile mean IOP of group 4 is significantly decreased compared to group 3 at P28 (n=8, P<0.05). Survival analysis of functional filtration blub in all groups revealed the longest survival time in group 4 (24.9+/-5.1d) compared to that in group 3 (20.6+/-4.3d), group 2 (15.0+/ 5.2d) and control group (10.1+/-5.7d). CONCLUSION: Amniotic membrane loaded with 5-Fu-NPs may function as an effective anti-scarring implant and provides improved long-term surgical outcomes for experimental trabeculectomy in rabbits. PMID- 25709904 TI - Early expression of mannose-binding lectin 2 during Aspergillus fumigatus infection in human corneal epithelial cells. AB - AIM: To evaluate the early expression of mannose-binding lectin 2 (MBL2) in human corneal epithelial cells (HCECs) infected by Aspergillus fumigatus (AF). METHODS: HCECs cultured in vitro with AF antigens and sampled at 0, 0.5, 1, 2, 4, 6 and 8h. The expression of MBL2 mRNA was evaluated by semiquantitative reverse transcription-polymerase chain reaction (RT-PCR). The expression of MBL2 protein in supernatant fluid was shown by enzyme linked immunosorbent assay (ELISA). MBL2 protein in HCECs was detected by immunocytochemistry at 0 and 24h. RESULTS: MBL2 mRNA and protein are expressed in normal HCECs. The expression of MBL2 mRNA and protein in supernatant fluid begin to increase after being stimulated with AF antigens. The most significantly peak of MBL2 mRNA is in 2h. The protein of MBL2 in supernatant fluid decrease gradually after 0.5h. The protein in HCECs expression increase after stimulation of 24h. CONCLUSION: MBL2 receptor expressed in normal HCECs in vitro. The stimulation by AF antigens can increase the early expression of it. PMID- 25709905 TI - Form-deprivation myopia induces decreased expression of bone morphogenetic protein-2, 5 in guinea pig sclera. AB - AIM: To identify the presence of various bone morphogenetic proteins (BMPs) and their receptors in normal sclera of human, rat and guinea pigs, and to determine whether their expression changed with form-deprivation myopia (FDM) in guinea pig sclera. METHODS: The expression of BMPs and BMP receptors were detected using reverse transcription polymerase chain reaction (RT-PCR) and immunofluorescence. Two-week-old guinea pigs were monocularly form-deprived with a translucent lens. After fourteen days induction of FDM, total RNA was isolated and subjected to RT PCR to examine the changes of BMPs and BMP receptors in tissues from the posterior sclera. Western blotting analysis was used to investigate their changes in protein levels. RESULTS: Human sclera expressed mRNAs for BMP-2, -4, -5, -7, RIA, -RIB and BMP-RII. Conversely, rat sclera only expressed mRNA for BMP-7 and BMP-RIB, while the expression of BMPs and BMP receptors in guinea pigs were similar to that of humans. Human sclera also expresses BMP-2, -4, -5,-7 in protein level. Fourteen days after the induction of myopia, significant decreased expressions for BMP-2 and BMP-5 in the posterior sclera of FDM-affected eyes (P<0.05 vs internal control eyes). CONCLUSION: Various BMPs were expressed in human and guinea pig sclera. In the posterior sclera, expressions of BMP-2 and BMP-5 significantly decreased in FDM eyes. This finding indicates that various BMPs as components of the scleral cytokines regulating tissue homeostasis and provide evidence that alterations in the expression of BMP-2 and BMP-5 are associated with sclera remodeling during myopia induction. PMID- 25709906 TI - Herpes simplex virus-1 infection or Simian virus 40-mediated immortalization of corneal cells causes permanent translocation of NLRP3 to the nuclei. AB - AIM: To investigate into the potential involvement of pyrin containing 3 gene (NLRP3), a member of the nucleotide-binding oligomerization domain-like receptors with cytosolic pattern recognition, in the host defense of corneas against viruses. METHODS: The herpes viral keratitis model was utilized in BALB/c mice with inoculation of herpes simplex virus-1 (HSV-1). Corneal tissues removed during therapy of patients with viral keratitis as well as a Simian vacuolating virus 40 (SV40)-immortalized human corneal epithelial cell line were also examined. Immunohistochemistry was used to detect NLRP3 in these subjects, focusing on their distribution in tissue or cells. Western blot was used to measure the level of NLRP3 and another two related molecules in NLPR3 inflammasome, namely caspase-1 and IL-1beta. RESULTS: The NLRP3 activation induced by HSV-1 infection in corneas was accompanied with redistribution of NLRP3 from the cytoplasm to the nucleus in both murine and human corneal epithelial cells. Furthermore, in the SV40-immortalized human corneal epithelial cells, NLRP3 was exclusively located in the nucleus, and treatment of the cells with high concentration of extracellular potassium (known as an inhibitor of NLRP3 activation) effectively drove NLRP3 back to the cytoplasm as reflected by both immunohistochemistry and Western blot. CONCLUSION: It is proposed that herpes virus infection activates and causes redistribution of NLRP3 to nuclei. Whether this NLRP3 translocation occurs with other viral infections and in other cell types merit further study. PMID- 25709907 TI - Expression of peroxisome proliferator-activated receptor gamma in rat retina during development. AB - AIM: To evaluate the spatiotemporal expression pattern of PPARgamma in embryonic and early postnatal stages of rat retina. METHODS: Fetal rats were collected at 13-18d of gestation (GD) from pregnant females and postnatal rats at 1d (P1) and 5d (P5) after birth were also used. We used RT-PCR to detect PPARgamma mRNA and immunohistochemical to observe PPARgamma protein. And at last, we chose HE staining showed the structural changes of rat retina during development. RESULTS: RT-PCR analysis showed that PPARgamma mRNA was expressed as early as GD13 and gradually decreased as maturation continued. However, the PPARgamma gene expression significantly increased after birth, especially in P5. Immunohistochemical analysis showed PPARgamma protein was expressed throughout the retinal neuroepithelium at GD13 and GD14, and then decreased during late embryogenesis but remained relatively high in the predicted ganglion cell zone. During postnatal development, PPARgamma protein was remarkably increased and the positive signals were mainly located in nerve fiber layer (NFL), ganglion cell layer (GCL) and outer layers of the retina. CONCLUSION: The spatiotemporal changes of PPARgamma expression demonstrated that PPARgamma might play a role in regulating the differentiation and maturation of retinal cells. PMID- 25709908 TI - Influence of bone morphogenetic protein type IA receptor conditional knockout in lens on expression of bone morphogenetic protein 4 in lens. AB - AIM: To investigate the influence of bone morphogenetic protein type IA receptor [BMPR-IA (ALK3)] conditional knockout in lens on expression of bone morphogenetic protein 4 (BMP4) in lens during the development of the vertebrate eye. METHODS: Cre-positive mice were mated with Cre-negative mice to generate 50% Cre-positive (conditional knockout, CKO) 4 embryos, 8 eyes and 50% Cre-negative offspring (wild type, WT) 4 embryos, 8 eyes. The embryos were fixed in 4% paraformaldehyde, embedded in paraffin, and sectioned to a thickness of 4 um. Removal of paraffin wax and dehydrating for sections, and then the procedure of in situ hybridization was processed, BMP4 MK1784-m (BOSTER) was used, and observed the expression of BMP4 in the lens in experimental group and control group. We selected SPSS11.0 software for statistical analysis, P<0.05 showed that the difference was statistically significant. RESULTS: Four embryos of each genotype were examined, totally we had 8 embryos, 16 eyes. We got the uniform outcomes in all the embryos. We found ALK3 was required during lens growing, but was not essential for the formation of lens. We observed that the expression of Bmp4 in the lens was significantly reduced in all 8 ALK3 CKO lens, BMP4 expression was normal in all the 8 WT lens, P<0.01. This phenomenon became increasingly visible in accordance with embryo development. The most apparent alteration was present at stage E15.5. CONCLUSION: ALK3 is essential for lens growth. The influence of ALK3 on the expression of BMP4 is present during the development of mice lens. PMID- 25709909 TI - QT interval dispersion in the patients with central serous chorioretinopathy. AB - AIM: To evaluate QT dispersion (QTD) in patients with central serous chorioretinopathy (CSC). METHODS: This clinical, comperative, case-control study included 30 patients with CSC at acute phase (Group 1) and 30 age- and sex matched healthy subjects (Group 2, the control group). From all subjects, a 12 lead surface electrocardiography was obtained. The heart rate (HR), QT maximum (QTmax), QT minimum (QTmin), QT corrected (QTc), QTD and Tmean were manually measured and analyzed. Student's t-test and Pearson's method of correlation were used for statistical analysis. RESULTS: The patient and control groups were matched for age, smoking status (rate and duration) and gender. There were no significant differences with regard to these among the groups (P>0.05). The participants included 19 men (63.3%) and 11 women (36.7%) in Group 1, 20 men (66.7%) and 10 women (33.3%) in Group 2. QTmax, QTD and QTc were significantly higher than those of healthy controls (P<0.001 for QTmax, P=0.01 for QTD and P=0.001 for QTc). QTmin, Tmean and HR did not differ significantly between the study groups (P=0.28 for QTmin, P=0.56 for Tmean and P>0.05 for HR). No significant correlation was found between duration of the disorder and QTD values (r=0.13, P>0.05). CONCLUSION: These findings suggest that CSC may be associated with an increase in QTD and that the patients might be at risk for ventricular arrhythmia. PMID- 25709910 TI - Optical quality of toric intraocular lens implantation in cataract surgery. AB - AIM: To analyze the optical quality after implantation of toric intraocular lens with optical quality analysis system. METHODS: Fifty-two eyes of forty-four patients with regular corneal astigmatism of at least 1.00 D underwent implantation of AcrySof toric intraocular lens, including T3 group 19 eyes, T4 group 18 eyes, T5 group 10 eyes, T6 group 5 eyes. Main outcomes evaluated at 3mo of follow-up, included uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), residual refractive cylinder and intraocular lens (IOL) axis rotation. Objective optical quality were measured using optical quality analysis system (OQAS II((r)), Visiometrics, Spain), included the cutoff frequency of modulation transfer function (MTFcutoff), objective scattering index (OSI), Strehl ratio, optical quality analysis system value (OV) 100%, OV 20% and OV 9% [the optical quality analysis system (OQAS) values at contrasts of 100%, 20%, and 9%]. RESULTS: At 3mo postoperative, the mean UDVA and CDVA was 0.18+/ 0.11 and 0.07+/-0.08 logMAR; the mean residual refractive cylinder was 0.50+/ 0.29 D; the mean toric IOL axis rotation was 3.62+/-1.76 degrees, the mean MTFcutoff, OSI, Strehl ratio, OV 100%, OV 20% and OV 9% were 22.862+/-5.584, 1.80+/-0.84, 0.155+/-0.038, 0.76+/-0.18, 0.77+/-0.19 and 0.78+/-0.21. The values of UDVA, CDVA, IOL axis rotation, MTFcutoff, OSI, Strehl ratio, OV100%, OV20% and OV9% depending on the power of the cylinder of the implantation were not significantly different (P>0.05), except the residual refractive cylinder (P<0.05). CONCLUSION: The optical quality analysis system was useful for characterizing the optical quality of AcrySof toric IOL implantation. Implantation of an AcrySof toric IOL is an effective and safe method to correct corneal astigmatism during cataract surgery. PMID- 25709911 TI - Effect of refractive error on temperament and character properties. AB - AIM: To determine the effect of refractive error on temperament and character properties using Cloninger's psychobiological model of personality. METHODS: Using the Temperament and Character Inventory (TCI), the temperament and character profiles of 41 participants with refractive errors (17 with myopia, 12 with hyperopia, and 12 with myopic astigmatism) were compared to those of 30 healthy control participants. Here, temperament comprised the traits of novelty seeking, harm-avoidance, and reward dependence, while character comprised traits of self-directedness, cooperativeness, and self-transcendence. RESULTS: Participants with refractive error showed significantly lower scores on purposefulness, cooperativeness, empathy, helpfulness, and compassion (P<0.05, P<0.01, P<0.05, P<0.05, and P<0.01, respectively). CONCLUSION: Refractive error might have a negative influence on some character traits, and different types of refractive error might have different temperament and character properties. These personality traits may be implicated in the onset and/or perpetuation of refractive errors and may be a productive focus for psychotherapy. PMID- 25709912 TI - Effects of chronic smoking on color vision in young subjects. AB - AIM: To evaluate the effects of chronic smoking on color vision in young subjects. METHODS: This study included 91 smokers and 88 non-smokers (a total of 179 volunteers) without any ophthalmologic and systemical disorders. The subjects were between 18-40 years of age with a best corrected visual acuity (BCVA) of 20/20, normal anterior and posterior segment examinations and normal intraocular pressure. The color vision of the subjects were evaluated with Farnsworth-Munsell 100 Hue test (FMHT). The total error scores and axis calculation were performed for each subject and the results correlated. RESULTS: Mean age and the standard deviation was 28+/-5y in the smokers group, and 26.7+/-5.5y in the control group (P=0.101). Sex distribution was similar in the two groups (P=0.365). There was no significant correlation between age and FMHT total error scores (P=0.069). Median of FMHT total error scores of smokers and non-smokers were 65 and 50.50, respectively. FMHT total error scores was found significantly higher in smokers than non-smokers (P=0.004). There was no statisticaly significant difference between smoker and non-smoker groups with respect to axis ratio calculation (P=0.611). There was no significant correlation with FMHT total error scores with neither smoking duration nor number of cigarettes smoked per day (P=0.405, P=0.454, respectively). CONCLUSION: This study suggested that chronic smoking affects the color vision of young smokers but this may not be sector selective. PMID- 25709913 TI - Eye rubbing-induced changes in intraocular pressure and corneal thickness measured at five locations, in subjects with ocular allergy. AB - AIM: To assess the effects of eye rubbing on corneal thickness (CT) and intraocular pressure (IOP) measurements obtained 0-30min after habitual eye rubbing in symptomatic patients. METHODS: Measurements of IOP and CT were obtained at five locations (central, temporal, superior, nasal and inferior) before, and every 5min for 30min interval after 30s of eye rubbing, for 25 randomly selected eyes of 14 subjects with ocular allergy and 11 age-matched normals. Differences in measurements were calculated in each group [Baseline measurements minus measurements recorded at each time interval after eye rubbing (for IOP), and for each corneal location (for CT)] and comparison were then made between groups (allergic versus control) for differences in any observed effects. RESULTS: Within groups, baseline mean IOPs in the allergic patient-group (14.2+/ 3.0 mm Hg) and in the control group (13.1+/-1.9 mm Hg) were similar at all times, after eye rubbing (P >0.05, for all). The maximum reduction in IOP was 0.8 mm Hg in the control subjects and the maximum increase was also 0.8 mm Hg in the allergic subjects. Between groups (allergic versus control), the changes in IOP remained under 1 mm Hg at all times (P=0.2) after 30min of eye rubbing. Between 0 and 30min of CT measurements after eye rubbing, the mean central CT (CCT), inferior CT (ICT), superior CT (SCT), temporal CT (TCT) and nasal CT (NCT) did not vary significantly from baseline values in the control and allergic-subject groups (P>0.05, for both). Between both groups, changes in CT were similar at all locations (P>0.05) except for the TC which was minimally thinner by about 4.4 um (P=0.001) in the allergic subjects than in the control subjects, 30min following 30s of eye rubbing. CONCLUSION: IOP measured in allergic subjects after 30s of habitual eye rubbing was comparable with that obtained in normal subjects at all times between 0 and 30min. Although, CT in the allergic subjects were similar to those of the control subjects at all times, it varied between +10 and -7.5 um following eye rubbing, with the temporal cornea showing consistent reductions in thickness in the subjects with allergy. However, this reduction was minimal and was considered to not be clinically relevant. PMID- 25709914 TI - Concurrent removal of intravitreal lens fragments after phacoemulsification with pars plana vitrectomy prevents development of retinal detachment. AB - AIM: To evaluate the outcomes of "concurrent vitrectomy" to retrieve dislocated lens fragment during phacoemulsification. METHODS: In a retrospective, observational case series, data of patients who underwent "concurrent" pars plana vitrectomy (PPV) for dislocated lens fragments between the period 2000 and 2008 were reviewed. Data collected included patient demographics, pre-operative visual acuity, intra-operative occurrence of retinal breaks, duration of follow up, post operative intraocular pressure, final best-corrected visual acuity (BCVA), presence of cystoid macular edema (CME) and occurrence of rhegmatogenous retinal detachment (RRD). RESULTS: A total of 58 eyes of 58 patients were included in the study. At 12mo the mean postoperative BCVA was logMAR 0.17 (20/30) with a range of logMAR 0 to 0.69 (20/20 to 20/100), with 96.6% (56/58) of patients showing post-operative improvement in visual acuity (P=0.005). None of the patients developed postoperative retinal detachment, endophthalmitis or non-resolving uveitis at 12mo. CONCLUSION: Our study results suggest concurrent PPV for retained lens fragments after cataract surgery is beneficial and may decrease the risk of glaucoma and prevent development of RRD. PMID- 25709915 TI - A short-term study of corneal collagen cross-linking with hypo-osmolar riboflavin solution in keratoconic corneas. AB - AIM: To report the 3mo outcomes of collagen cross-linking (CXL) with a hypo osmolar riboflavin in thin corneas with the thinnest thickness less than 400 um without epithelium. METHODS: Eight eyes in 6 patients with age 26.2+/-4.8y were included in the study. All patients underwent CXL using a hypo-osmolar riboflavin solution after its de-epithelization. Best corrected visual acuity, manifest refraction, the thinnest corneal thickness, and endothelial cell density were evaluated before and 3mo after the procedure. RESULTS: The mean thinnest thickness of the cornea was 408.5+/-29.0 um before treatment and reduced to 369.8+/-24.8 um after the removal of epithelium. With the application of the hypo osmolar riboflavin solution, the thickness increased to 445.0+/-26.5 um before CXL and recover to 412.5+/-22.7 um at 3mo after treatment, P=0.659). Before surgery, the mean K-value of the apex of the keratoconus corneas was 57.6+/-4.0 diopters, and slightly decreased (54.7+/-4.9 diopters) after surgery (P=0.085). Mean best-corrected visual acuity was 0.55+/-0.23 logarithm of the minimal angle of resolution, and increased to 0.53+/-0.26 logarithm after surgery (P=0.879). The endothelial cell density was 2706.4+/-201.6 cells/mm(2) before treatment, and slightly decreased (2641.2+/-218.2 cells/mm(2)) at last fellow up (P=0.002). CONCLUSION: Corneal collagen cross-linking with a hypo-osmolar riboflavin in thin corneas seems to be a promising treatment. Further study should be done to evaluate the safety and efficiency of CXL in thin corneas for the long-term. PMID- 25709916 TI - Comparison of retinal nerve fiber layer and macular thickness measurements with Stratus OCT and OPKO/OTI OCT devices in healthy subjects. AB - AIM: To compare retinal nerve fiber layer (RNFL) and macular thickness measurements obtained with the Stratus optical coherence tomography (OCT) and OPKO/OTI OCT devices. METHODS: Included in the study were 59 eyes of 30 participants. All measurements for each eye were done on the same day with both devices. Student's paired t-tests were used to compare the central macular thickness and RNFL measurements of the Stratus OCT and OPKO/OTI OCT. Pearson correlation was used to assess the relationship between the devices. Coefficient of variation (COV) was calculated to assess intersession repeatability. RESULTS: Using both the Stratus OCT and OPKO/OTI OCT, respectively, the measured mean average RNFL thicknesses were 98.9+/-11.1 um and 115.1+/-9.6 um (P=0.001), and the measured mean central retinal thicknesses (CRT) were 196.2+/-18.8 um and 204.5+/-21.1 um (P<0.001). Measured by the two devices, the RNFL thickness values were correlated in all quadrants, as were the retinal thickness values except the inferior outer sector. COV for average RNFL and CRT thickness were 2.9% and 4.6% for Stratus OCT, and 2.1% and 4.2% for OPKO/OTI OCT, respectively. CONCLUSION: We found good reproducibility of RNFL and retina thickness measurements for both Stratus OCT and OPKO/OTI OCT devices. However, even though the two OCT systems provided statistically correlated results, the values for both RNFL and macular thickness were statistically different. RNFL and macular thickness measurements with the OPKO/OTI OCT were higher than that of the Stratus OCT; therefore, the two OCT systems cannot be used interchangeably for the measurements of RNFL and macular thickness. PMID- 25709917 TI - A knotless, one-haptic fixation of posterior chamber intraocular lenses: one-year results. AB - AIM: To assess the results of a modified technique for scleral fixation of a posterior chamber intraocular lens (IOL) in eyes which had deficient of posterior capsular support. METHODS: This retrospective study was comprised of ten patients with deficient posterior capsular support who underwent one-haptic fixation of posterior chamber IOLs, between February 2010 and October 2011. IOL as implanted with one haptic supported on the capsular remnant and the other haptic drawn into the sulcus by anchoring suture without a knot. All patients were evaluated for pre- and postoperative visual acuity, lens centration, intra-and postoperative complications. RESULTS: A knotless, one-haptic fixation of posterior chamber IOLs has successfully been performed on ten eyes. All cases had inadequate capsular support (i.e. a capsular tear ranged from 5 to 7 clock hours). The average age was 74.25+/-8.87y (SD). The average postoperative uncorrected visual acuity was 0.51 logMAR. Complications included hyphema in one eye, a mild inflammatory reaction in the anterior chamber in two eyes, and a transient rise in IOP in one eye. Neither IOL tilt nor dislocation was observed and there were no later complications. CONCLUSION: In the presence of insufficient capsular support, a knotless, one-haptic fixation of posterior chamber IOLs is a safe and viable option which reduces the operation time, and minimizes postoperative suture related complications. PMID- 25709918 TI - Surgical outcomes for unilateral superior oblique palsy in Chinese population: a retrospective study. AB - AIM: To evaluate the outcome after surgery for unilateral superior oblique (SO) palsy in Chinese. METHODS: The medical records of 39 patients that underwent surgery for unilateral SO palsy between January 2003 and December 2012 at Caritas Medical Centre, Hong Kong, were retrospectively reviewed. All surgeries were performed by a single surgeon. Pre-operative assessments for vertical deviation, cyclo-deviation, and Knapp's classification were obtained to determine the nature and degree of surgical correction. Vertical deviation was measured at 1wk; 1, 6mo and on last follow-up day post-operatively. Cyclo-deviation was measured on last follow-up day post-operatively. RESULTS: During the 10y period, 39 subjects were recruited. The most common etiology was congenital (94.9%). Knapp's Type III (66.7%) and Type I (12.8%) classifications were the most common subtypes. To treat SO palsy, the most common surgical procedures were: isolated inferior oblique (IO) anteriorization (41.0%), isolated IO myectomy (10.3%), and isolated IO recession (10.3%). At 3.5+/-2.1y post-operatively, the vertical deviation was significantly reduced (15.1+/-6.2 PD versus 0.5+/-1.4 PD, P<0.0001) without significant improvement in cyclo-deviation (P=0.5). Initial vertical deviation was correlated with cyclo-torsion (r=0.4, P=0.007). Those with over-correction had greater initial vertical deviation (19.4+/-7.2 PD versus 13.2+/-4.3 PD, P=0.003). After a single operation, 84.6% of subjects achieved a vertical deviation within +/-3 PD. CONCLUSION: The majority of subjects achieved corrected vertical deviation after a single surgery although there was no improvement in cyclo-deviation. Those with over-correction of primary position deviation had greater preoperative vertical deviation and it may be related to simultaneous multiple muscle surgery. PMID- 25709919 TI - Reproducibility of peripapillary retinal nerve fiber layer thickness measurements with cirrus HD-OCT in glaucomatous eyes. AB - AIM: To assess the reproducibility of Cirrus high-definition optical coherence tomography (HD-OCT; Carl Zeiss Meditec, Dublin, CA, USA) for analysis of peripapillary retinal nerve fiber layer (RNFL) thickness in glaucomatous eyes. METHODS: Forty-five eyes (one eye from each glaucomatous patient) were imaged with Cirrus HD-OCT. Each eye was imaged three times by two separate operators. Intraclass correlation coefficient (ICC), coefficient of variation (CV), and test retest variability were evaluated for both intraobserver and interobsever measurements. RESULTS: In intraobserver measurements, the average RNFL thickness ICC was 0.983. CV and test-retest variability were 2.3% and 4.4 um respectively. In quadrants ICC ranged from 0.886 to 0.956, the lowest associated with nasal quadrant and CV ranged from 3.6% to 7.7%. In interobsever measurements, the average RNFL thickness ICC was 0.979. CV and test-retest variability were 2.4% and 4.5 um respectively. In quadrants ICC ranged from 0.886 to 0.957, the lowest associated with nasal quadrant and CV ranged from 3.8% to 8.6%. CONCLUSION: The reproducibility of Cirrus OCT for RNFL thickness is sufficiently good to be useful clinically as a measure of glaucoma progression. PMID- 25709920 TI - Effect of four different intraocular lenses on posterior capsule opacification. AB - AIM: To evaluate the impact of 4 different intraocular lenses (IOLs) on posterior capsule opacification (PCO) by comparing the neodymium: yttrium-aluminum-garnet (Nd:YAG) laser capsulotomy rates. METHODS: This retrospective study included 4970 eyes of 4013 cataract patients who underwent phacoemulsification and IOL implantation between January 2000 and January 2008 by the same surgeon at one clinic. Four different IOLs were assessed. The outcome parameter was the incidence of Nd:YAG laser posterior capsulotomies. RESULTS: An Nd:YAG laser posterior capsulotomy was performed in 153 (3.07%) of the 4970 eyes. The mean follow-up time was 84mo for all of the IOL groups. The percentage of eyes developing PCO was significantly greater for the acrylic hydrophilic IOLs than for the hydrophobic IOLs, although eyes with acrylic hydrophilic IOLs did not require Nd:YAG laser capsulotomy as soon as eyes with acrylic hydrophobic IOLs. There was no difference between the long-term PCO rates when 1- and 3-piece acrylic hydrophobic IOLs were compared or when IOLs made of the same material but with different haptic angles were compared. CONCLUSION: In this study, eyes with acrylic hydrophilic IOLs were more likely to develop PCO than those with acrylic hydrophobic IOLs. The lens design (1-piece versus 3-piece and varying haptic angles) did not affect the PCO rate. PMID- 25709921 TI - Combined 23-gauge sutureless vitrectomy and clear corneal phacoemulsification for rhegmatogenous retinal detachment repair. AB - AIM: To assess the outcomes of combined 23-gauge sutureless vitrectomy and clear corneal phacoemulsification with intraocular lens implantation for rhegmatogenous retinal detachment (RRD) repair. METHODS: This was a retrospective, consecutive, non-comparative, interventional case series of 30 eyes of 30 patients who underwent combined sutureless vitrectomy and clear corneal cataract surgery for the repair of RRD. The principal outcome measures were primary anatomical success rate, reasons for redetachment, final visual acuity, and surgical complications. RESULTS: Primary reattachment was achieved in 27 eyes (90.0%). The reasons for redetachment (3 eyes, 10%) were incomplete laser retinopexy, persistent chronic subretinal fluid, and proliferative vitreoretinopathy, respectively. The logarithm of the minimum angle of resolution visual acuity (mean+/-SD) improved from 0.76+/-0.74 preoperatively to 0.21+/-0.37 6 months' postoperatively (P<0.0001). Postoperative hypotony was not detected, but 1 eye (3.3%) had increased intraocular pressure (30mmHg) with spontaneous resolution. No endophthalmitis developed during follow-up. Macular pucker was detected in 3 eyes (10.0%). CONCLUSION: Combined 23-gauge sutureless vitrectomy and clear corneal phacoemulsification with intraocular lens implantation for RRD repair was proven safe and effective. It may provide not only the known advantages of conventional combined surgery, but also additional advantages such as less conjunctival fibrosis and the maintenance of stable intraocular pressure with low risks of postoperative hypotony and intraocular pressure elevation. PMID- 25709922 TI - Comparison of non-cycloplegic photorefraction, cycloplegic photorefraction and cycloplegic retinoscopy in children. AB - AIM: To compare the results of noncycloplegic photorefraction, cycloplegic photorefraction and cycloplegic refraction in preschool and non-verbal children. METHODS: One hundred and ninety-six eyes of 98 children (50 females, 48 males) were included in the study. Firstly, non-cycloplegic photorefraction was achieved with Plusoptix A09; secondly, cycloplegic photorefraction was carried out with Plusoptix A09 after 10 min cyclopentolate. Finally, 30min after instillation of twice cyclopentolate, cycloplegic refraction was obtained with autorefraction and/or standard retinoscopy. Spheric equivalent, spheric power, cylindric power and cylindrical axis measurements were statistically compared. RESULTS: The mean age was 28.8+/-18.5mo (range 12-72mo). The differences in spherical equivalent, spheric power and cylindrical power measured by the three methods were found statistically significant (P<0.05). The spherical equivalent and spheric power measured by cycloplegic photorefraction were statistically higher than the measurements of the other methods (P<0.05). The cylindrical power measured by cycloplegic refraction was statistically lower than the measurements of the photorefraction methods (P<0.05). There was no significant difference in cylindrical axis measurements between three methods (P>0.05). CONCLUSION: For the determination of refractive errors in children, the Plusoptix A09 measurements give incorrect results after instillation of cyclopentolate. Additionally, the cylindrical power measured by Plusoptix A09 with or without cycloplegia is higher. However, the non-cycloplegic Plusoptix A09 measures spheric equivalent and spheric power similar to cycloplegic refraction measurements in preschool and non-verbal children. PMID- 25709923 TI - Using Markov Chains to predict the natural progression of diabetic retinopathy. AB - AIM: To study the natural progression of diabetic retinopathy in patients with type 2 diabetes. METHODS: This was an observational study of 153 cases with type 2 diabetes from 2010 to 2013. The state of patient was noted at end of each year and transition matrices were developed to model movement between years. Patients who progressed to severe non-proliferative diabetic retinopathy (NPDR) were treated. Markov Chains and Chi-square test were used for statistical analysis. RESULTS: We modelled the transition of 153 patients from NPDR to blindness on an annual basis. At the end of year 3, we compared results from the Markov model versus actual data. The results from Chi-square test confirmed that there was statistically no significant difference (P=0.70) which provided assurance that the model was robust to estimate mean sojourn times. The key finding was that a patient entering the system in mild NPDR state is expected to stay in that state for 5y followed by 1.07y in moderate NPDR, be in the severe NPDR state for 1.33y before moving into PDR for roughly 8y. It is therefore expected that such a patient entering the model in a state of mild NPDR will enter blindness after 15.29y. CONCLUSION: Patients stay for long time periods in mild NPDR before transitioning into moderate NPDR. However, they move rapidly from moderate NPDR to proliferative diabetic retinopathy (PDR) and stay in that state for long periods before transitioning into blindness. PMID- 25709924 TI - Bevacizumab versus ranibizumab for neovascular age-related macular degeneration: a Meta-analysis. AB - AIM: To systematically compare the efficacy and safety of off-label bevacizumab versus licensed ranibizumab intravitreal injections as well as monthly regimen versus pro re nata [PRN (as needed)] regimen in the treatment of neovascular age related macular degeneration (nAMD). METHODS: Relevant publications were identified through automatically retrieve of database and manually retrieving. The methodological quality of studies included was assessed using the Jadad score and the risk-of-bias assessment. The efficacy estimates were measured by the weight mean difference (WMD) for the improvement of best-corrected visual acuity (BCVA) and central retinal thickness (CRT) reduction. The safety estimates were measured by odds ratios (OR) for adverse events rates. Statistical analysis was conducted by Revman 5.2.7. RESULTS: Seven studies were included in the Meta analysis. There were no statistically significant differences between bevacizumab and ranibizumab in BCVA at 1 and 2y (P=0.37, P=0.18, respectively), However, both drugs has better BCVA given monthly than given as needed at 1 and 2y (P<0.05). The results demonstrated the mean decrease in CRT was less in bevacizumab group than ranibizumab group at 1y (P<0.05), while the difference was not significant at 2y (P=0.24). Treatment monthly gained much more decrease in CRT at 1 and 2y (P<0.005). There were no differences between drugs in the rates of death, arterial thrombotic events and venous thrombotic events (P=0.41, P=0.55, P=0.10, respectively), while the rates of medical dictionary for regulatory activities (MedDAR) system organ class events and >=1 systemic serious adverse events were higher in bevacizumab group than ranibizumab group (P<0.05). But the incidences of death, arterial thrombotic events, venous thrombotic events, MedDAR system organ class events as well as >=1 systemic serious adverse events were not statistically different between both treatment regimens of monthly and as needed (P=0.14, P=0.76, P=0.73, P=0.12, P=0.11, respectively). CONCLUSION: Bevacizumab was equivalent to ranibizumab for BCVA, however bevacizumab tended to gain less decrease in CRT and had higher rates of serious adverse events. Compared with treatment as needed, treatment monthly showed superior efficacy in BCVA improvement and CRT reduction, while the rates of adverse events were similar in the two dosing regimens. PMID- 25709925 TI - The association of LOXL1 polymorphisms with exfoliation syndrome/glaucoma: Meta analysis. AB - AIM: To investigate the association of lysyl oxidase-like 1 (LOXL1) single nucleotide polymorphisms (SNPs) with exfoliation syndrome (XFS)/exfoliation glaucoma (XFG). METHODS: Published manuscripts from PubMed and EMBASE were identified until May 2014. Summary odds ratios (ORs) and 95% confidence intervals (CIs) for LOXL1 (rs1048661, rs2165241 and rs3825942) polymorphisms and the risk of XFS/XFG were estimated using random- or fixed- effect model. RESULTS: The three LOXL1 polymorphisms (rs1048661, rs3825942, and rs2165241) were associated with an increased risk for XFS/XFG among Caucasians, with OR 2.19(1.96-2.45), 8.8 (6.05-12.79) and 3.41 (3.11-3.73), respectively. On the contrast, the rs1048661 and rs2165241, but not rs3825942 polymorphism, have a potential protective effect on XFS/XFG in Asians, with OR 0.06 (0.02-0.18), 0.15 (0.09-0.25), respectively. CONCLUSION: There is strong evidence that LOXL1 polymorphisms are associated with XFS/XFG risk. The strength of risk might be ethnicity-dependent. PMID- 25709926 TI - Treatment of hydrofluoric acid exposure to the eye. AB - AIM: To review the current evidence of the treatment of hydrofluoric acid (HF) exposure to the human cornea. METHODS: A comprehensive manual search of the literature was conducted through the Ovid interface to assess the mechanism and efficacy of each irrigator through a variety of clinical cases and experimental studies. RESULTS: Ocular exposure to HF is extremely damaging to the eye and swift recognition and decontamination with an appropriate agent forms the basis of treatment. Although there are various decontamination solutions that have efficacy against the corrosive action of HF, irrigation with Hexafluorine proved to be the most safe and effective treatment for the eye. CONCLUSION: In conclusion emergency departments could benefit from the availability of Hexafluorine for the treatment of HF ocular burns in patients. PMID- 25709927 TI - Characteristics and visual outcomes of patients hospitalized for ocular trauma in central China: 2006-2011. AB - AIM: To complete the data of ocular trauma in central China, as a well-known tertiary referral center for ocular trauma, we documented the epidemiological characteristics and visual outcomes of patients hospitalized for ocular trauma in this region. METHODS: A retrospective study of patients hospitalized for ocular trauma in central China from 2006 to 2011 was performed. RESULTS: This study included 5964 eyes of 5799 patients. The average age was 35.5+/-21.8y with a male to-female ratio of 2.8:1. The most common age was 45-59y age group. Most patients were farmers and workers (51.9%). The most common injuries were firework related (24.5%), road traffic related (24.2%), and work related (15.0%). Among the most common causative agents were firecrackers (24.5%), followed by metal/knife/scissors (21.4%). Most injuries occurred in January (14.2%), February (27.0%), and August (10.0%). There were 8.5% patients with ocular injuries combined with other injuries. The incidence of open ocular injuries (4585 eyes, 76.9%) was higher than closed ocular injuries (939 eyes, 15.7%). The incidences of chemical and thermal ocular injuries were 1.2% and 0.6%. Ocular trauma score (OTS) predicted final visual acuity at non light perception (NLP), 20/200-20/50 and 20/40 with a sensitivity of 100%, and light perception (LP)/hand motion (HM) and 1/200-19/200 with a specificity of 100%. CONCLUSIONS: This study provides recent epidemiological data of patients hospitalized for ocular trauma in central China. Some factors influencing the visual outcome include time interval between injury and visit to the clinic, wound location, open or closed globe injury, initial visual acuity, and OTS. PMID- 25709928 TI - Clinical relevance of the glucocorticoid receptor gene polymorphisms in glucocorticoid-induced ocular hypertension and primary open angle glaucoma. AB - AIM: To avoid the side effects of ocular hypertension of glucocorticoid (GC) usage in eye, we must identify susceptible individuals, which exists in about one third of all population. Further, the majority of all primary open angle glaucoma (POAG) patients show this phenotype. Glucocorticoid receptor (GR) regulates C responsiveness in trabecular meshwork (TM) cells. In this study, single nucleotide polymorphism (SNP) genotyping was used to determine whether there are differences in the BclI (rs41423247) and N363S (rs6195) polymorphisms of the GR gene in healthy and POAG patients, and glucocorticoid-induced ocular hypertension (GIOH) populations. METHODS: Three hundred and twenty-seven unrelated Chinese adults, including 111 normal controls, 117 GIOH subjects and 99 POAG patients, were recruited. DNA samples were prepared and the BclI and N363S polymorphisms were screened using real-time polymerase chain reaction (RT-PCR)-restriction fragment length polymorphism (RFLP) analysis. Frequencies of the BclI and N363S polymorphisms were determined and compared using Fisher's exact test and the Chi squared test. RESULTS: Only the BclI polymorphism was identified in the Chinese Han population. The frequency of the G allele was 21.6 % in normal controls, 18.3% in GIOH patients, and 13.64% in the POAG patients. There was no significant difference in polymorphism or allele frequency in the 3 groups. Furthermore, no N363S polymorphism was found in the study subjects. CONCLUSION: The BclI polymorphisms in GR gene had no association with GIOH and POAG patients, and N363S polymorphism might not exist in the Chinese Han population. Therefore, the BclI polymorphism might not be responsible for the development of GC-induced ocular hypertension or POAG. PMID- 25709929 TI - Validity of subjective assessment as screening tool for dry eye disease and its association with clinical tests. AB - AIM: To determine the role of subjective assessment using McMonnies dry eye questionnaire in diagnosing dry eye disease and its association with clinical tests. METHODS: There were 500 patients screened for dry eye using McMonnies dry eye questionnaire between May to October 2013 at the outpatient Department of Ophthalmology of a medical college hospital. All 500 patients were subjected to clinical tests. Dry eye was defined as having one or more symptoms often or all the time. Positive signs were if one or both eyes revealed tear film breakup time (TBUT) of <=10s, a Schirmer test score of <=10 mm, a Rose Bengal staining score of >=1, a Lissamine green staining score of >=1 or existence of meibomian gland disease (>=grade 1). Statistical analysis was performed to describe the distribution of symptoms and signs, to assess the correlations between McMonnies score (MS) and variable clinical signs of dry eye, and to explore the association between dry eye symptoms and variable clinical signs. Analysis was performed using software package Epi info. A Probability (P) value using Chi-square test of <0.005 was taken as significant. RESULTS: Dry eye prevalence with symptoms (questionnaire), Schirmer test, TBUT, Rose Bengal staining and Lissamine green staining was 25.6%, 15.20%, 20.80%, 23.60%, and 22.60% respectively. Among those with severe symptoms (MS>20), 75.86% had a low TBUT (<10s), 58.62% had a low Schirmer's I test (<=10 mm), 86.20% had Rose Bengal staining score of >=1, 79.31% had Lissamine green staining score of >=1. We found statistically significant associations between positive Schirmer test and arthritis (P<0.002), dryness elsewhere (P<0.001), contact lens use (P<0.002), systemic medication (P<0.0001), sleeping with eyes partly open (P<0.002), history of dry eyes treatment (P<0.0001), environmental factors (P<0.001), swimming (P<0.001). CONCLUSION: Subjective assessment plays an important role in diagnosing dry eye disease. There is strong correlation between MS and Schirmer test, TBUT, Rose Bengal staining and Lissamine green staining in normal as well as marginal and pathological dry eye. PMID- 25709931 TI - An automated detection of glaucoma using histogram features. AB - Glaucoma is a chronic and progressive optic neurodegenerative disease leading to vision deterioration and in most cases produce increased pressure within the eye. This is due to the backup of fluid in the eye; it causes damage to the optic nerve. Hence, early detection diagnosis and treatment of an eye help to prevent the loss of vision. In this paper, a novel method is proposed for the early detection of Glaucoma using a combination of magnitude and phase features from the digital fundus images. Local binary patterns (LBP) and Daugman's algorithm are used to perform the feature set extraction. The histogram features are computed for both the magnitude and phase components. The Euclidean distance between the feature vectors are analyzed to predict glaucoma. The performance of the proposed method is compared with the higher order spectra (HOS) features in terms of sensitivity, specificity, classification accuracy and execution time. The proposed system results 95.45% output for sensitivity, specificity and classification. Also, the execution time for the proposed method takes lesser time than the existing method which is based on HOS features. Hence, the proposed system is accurate, reliable and robust than the existing approach to predict the glaucoma features. PMID- 25709932 TI - Comparing the intraoperative complication rate of femtosecond laser-assisted cataract surgery to traditional phacoemulsification. AB - AIM: To compare the complication rate of femtosecond laser-assisted cataract surgery (FLACS) and traditional phacoemulsification for the first 18mo of FLACS use at a private surgical center in Hawaii. METHODS: A retrospective chart review was conducted from January 2012 to June 2013. The first 273 consecutive eyes receiving FLACS and 553 eyes receiving traditional phacoemulsification were examined. All surgeries were performed at a single surgical center in Hawaii. The presence of intraoperative complications was used as the main outcome measure. Approval was obtained from the institutional review board of the University of Hawaii. RESULTS: The overall complication rate for FLACS was 1.8%, while that of the traditional procedure was 5.8% (P<0.05). A majority of the surgeons (80%) had a lower complication rate while using FLACS. CONCLUSION: FLACS is comparable in safety, if not safer, than traditional cataract surgery when performed by qualified cataract surgeons on carefully selected patients. PMID- 25709933 TI - When important steps for a reliable meta-analysis are missing: the bevacizumab versus ranibizumab case. PMID- 25709930 TI - Clinical correlates of common corneal neovascular diseases: a literature review. AB - A large subset of corneal pathologies involves the formation of new blood and lymph vessels (neovascularization), leading to compromised visual acuity. This article aims to review the clinical causes and presentations of corneal neovascularization (CNV) by examining the mechanisms behind common CNV-related corneal pathologies, with a particular focus on herpes simplex stromal keratitis, contact lenses-induced keratitis and CNV secondary to keratoplasty. Moreover, we reviewed CNV in the context of different types of corneal transplantation and keratoprosthesis, and summarized the most relevant treatments available so far. PMID- 25709934 TI - Night blindness due to vitamin A deficiency associated with resected adenocarcinoma of the pancreas. PMID- 25709935 TI - A rare pigmented keratitis caused by Aspergillus fumigatus. PMID- 25709936 TI - Epileptic Seizure Prediction based on Ratio and Differential Linear Univariate Features. AB - Bivariate features, obtained from multichannel electroencephalogram recordings, quantify the relation between different brain regions. Studies based on bivariate features have shown optimistic results for tackling epileptic seizure prediction problem in patients suffering from refractory epilepsy. A new bivariate approach using univariate features is proposed here. Differences and ratios of 22 linear univariate features were calculated using pairwise combination of 6 electroencephalograms channels, to create 330 differential, and 330 relative features. The feature subsets were classified using support vector machines separately, as one of the two classes of preictal and nonpreictal. Furthermore, minimum Redundancy Maximum Relevance feature reduction method is employed to improve the predictions and reduce the number of false alarms. The studies were carried out on features obtained from 10 patients. For reduced subset of 30 features and using differential approach, the seizures were on average predicted in 60.9% of the cases (28 out of 46 in 737.9 h of test data), with a low false prediction rate of 0.11 h(-1). Results of bivariate approaches were compared with those achieved from original linear univariate features, extracted from 6 channels. The advantage of proposed bivariate features is the smaller number of false predictions in comparison to the original 22 univariate features. In addition, reduction in feature dimension could provide a less complex and the more cost-effective algorithm. Results indicate that applying machine learning methods on a multidimensional feature space resulting from relative/differential pairwise combination of 22 univariate features could predict seizure onsets with high performance. PMID- 25709937 TI - Chaotic particle swarm optimization with mutation for classification. AB - In this paper, a chaotic particle swarm optimization with mutation-based classifier particle swarm optimization is proposed to classify patterns of different classes in the feature space. The introduced mutation operators and chaotic sequences allows us to overcome the problem of early convergence into a local minima associated with particle swarm optimization algorithms. That is, the mutation operator sharpens the convergence and it tunes the best possible solution. Furthermore, to remove the irrelevant data and reduce the dimensionality of medical datasets, a feature selection approach using binary version of the proposed particle swarm optimization is introduced. In order to demonstrate the effectiveness of our proposed classifier, mutation-based classifier particle swarm optimization, it is checked out with three sets of data classifications namely, Wisconsin diagnostic breast cancer, Wisconsin breast cancer and heart-statlog, with different feature vector dimensions. The proposed algorithm is compared with different classifier algorithms including k-nearest neighbor, as a conventional classifier, particle swarm-classifier, genetic algorithm, and Imperialist competitive algorithm-classifier, as more sophisticated ones. The performance of each classifier was evaluated by calculating the accuracy, sensitivity, specificity and Matthews's correlation coefficient. The experimental results show that the mutation-based classifier particle swarm optimization unequivocally performs better than all the compared algorithms. PMID- 25709938 TI - An improved method for liver diseases detection by ultrasound image analysis. AB - Ultrasound imaging is a popular and noninvasive tool frequently used in the diagnoses of liver diseases. A system to characterize normal, fatty and heterogeneous liver, using textural analysis of liver Ultrasound images, is proposed in this paper. The proposed approach is able to select the optimum regions of interest of the liver images. These optimum regions of interests are analyzed by two level wavelet packet transform to extract some statistical features, namely, median, standard deviation, and interquartile range. Discrimination between heterogeneous, fatty and normal livers is performed in a hierarchical approach in the classification stage. This stage, first, classifies focal and diffused livers and then distinguishes between fatty and normal ones. Support vector machine and k-nearest neighbor classifiers have been used to classify the images into three groups, and their performance is compared. The Support vector machine classifier outperformed the compared classifier, attaining an overall accuracy of 97.9%, with a sensitivity of 100%, 100% and 95.1% for the heterogeneous, fatty and normal class, respectively. The Acc obtained by the proposed computer-aided diagnostic system is quite promising and suggests that the proposed system can be used in a clinical environment to support radiologists and experts in liver diseases interpretation. PMID- 25709939 TI - Electrocardiogram Based Identification using a New Effective Intelligent Selection of Fused Features. AB - Over the years, the feasibility of using Electrocardiogram (ECG) signal for human identification issue has been investigated, and some methods have been suggested. In this research, a new effective intelligent feature selection method from ECG signals has been proposed. This method is developed in such a way that it is able to select important features that are necessary for identification using analysis of the ECG signals. For this purpose, after ECG signal preprocessing, its characterizing features were extracted and then compressed using the cosine transform. The more effective features in the identification, among the characterizing features, are selected using a combination of the genetic algorithm and artificial neural networks. The proposed method was tested on three public ECG databases, namely, MIT-BIH Arrhythmias Database, MITBIH Normal Sinus Rhythm Database and The European ST-T Database, in order to evaluate the proposed subject identification method on normal ECG signals as well as ECG signals with arrhythmias. Identification rates of 99.89% and 99.84% and 99.99% are obtained for these databases respectively. The proposed algorithm exhibits remarkable identification accuracies not only with normal ECG signals, but also in the presence of various arrhythmias. Simulation results showed that the proposed method despite the low number of selected features has a high performance in identification task. PMID- 25709940 TI - A comparative study on preprocessing techniques in diabetic retinopathy retinal images: illumination correction and contrast enhancement. AB - To investigate the effect of preprocessing techniques including contrast enhancement and illumination correction on retinal image quality, a comparative study was carried out. We studied and implemented a few illumination correction and contrast enhancement techniques on color retinal images to find out the best technique for optimum image enhancement. To compare and choose the best illumination correction technique we analyzed the corrected red and green components of color retinal images statistically and visually. The two contrast enhancement techniques were analyzed using a vessel segmentation algorithm by calculating the sensitivity and specificity. The statistical evaluation of the illumination correction techniques were carried out by calculating the coefficients of variation. The dividing method using the median filter to estimate background illumination showed the lowest Coefficients of variations in the red component. The quotient and homomorphic filtering methods after the dividing method presented good results based on their low Coefficients of variations. The contrast limited adaptive histogram equalization increased the sensitivity of the vessel segmentation algorithm up to 5% in the same amount of accuracy. The contrast limited adaptive histogram equalization technique has a higher sensitivity than the polynomial transformation operator as a contrast enhancement technique for vessel segmentation. Three techniques including the dividing method using the median filter to estimate background, quotient based and homomorphic filtering were found as the effective illumination correction techniques based on a statistical evaluation. Applying the local contrast enhancement technique, such as CLAHE, for fundus images presented good potentials in enhancing the vasculature segmentation. PMID- 25709941 TI - Recognition of acute lymphoblastic leukemia cells in microscopic images using k means clustering and support vector machine classifier. AB - Acute lymphoblastic leukemia is the most common form of pediatric cancer which is categorized into three L1, L2, and L3 and could be detected through screening of blood and bone marrow smears by pathologists. Due to being time-consuming and tediousness of the procedure, a computer-based system is acquired for convenient detection of Acute lymphoblastic leukemia. Microscopic images are acquired from blood and bone marrow smears of patients with Acute lymphoblastic leukemia and normal cases. After applying image preprocessing, cells nuclei are segmented by k means algorithm. Then geometric and statistical features are extracted from nuclei and finally these cells are classified to cancerous and noncancerous cells by means of support vector machine classifier with 10-fold cross validation. These cells are also classified into their sub-types by multi-Support vector machine classifier. Classifier is evaluated by these parameters: Sensitivity, specificity, and accuracy which values for cancerous and noncancerous cells 98%, 95%, and 97%, respectively. These parameters are also used for evaluation of cell sub-types which values in mean 84.3%, 97.3%, and 95.6%, respectively. The results show that proposed algorithm could achieve an acceptable performance for the diagnosis of Acute lymphoblastic leukemia and its sub-types and can be used as an assistant diagnostic tool for pathologists. PMID- 25709942 TI - Multi-scale Morphological Image Enhancement of Chest Radiographs by a Hybrid Scheme. AB - Chest radiography is a common diagnostic imaging test, which contains an enormous amount of information about a patient. However, its interpretation is highly challenging. The accuracy of the diagnostic process is greatly influenced by image processing algorithms; hence enhancement of the images is indispensable in order to improve visibility of the details. This paper aims at improving radiograph parameters such as contrast, sharpness, noise level, and brightness to enhance chest radiographs, making use of a triangulation method. Here, contrast limited adaptive histogram equalization technique and noise suppression are simultaneously performed in wavelet domain in a new scheme, followed by morphological top-hat and bottom-hat filtering. A unique implementation of morphological filters allows for adjustment of the image brightness and significant enhancement of the contrast. The proposed method is tested on chest radiographs from Japanese Society of Radiological Technology database. The results are compared with conventional enhancement techniques such as histogram equalization, contrast limited adaptive histogram equalization, Retinex, and some recently proposed methods to show its strengths. The experimental results reveal that the proposed method can remarkably improve the image contrast while keeping the sensitive chest tissue information so that radiologists might have a more precise interpretation. PMID- 25709943 TI - (99m)Tc-Phytate Lymphoscintigraphy for Detection of Sentinel Node: Preliminary Results of the First Year's Clinical Experience in Isfahan, Iran. AB - Sentinel lymph node is the first regional lymph node that drains the lymph from the primary tumor. It is potentially the first node to receive the seeding of lymph-borne metastatic cells. This study aimed to discuss lymphoscintigraphy procedural guidelines for detection of sentinel node using (99m)Tc-Phytate in Isfahan, Iran. Moreover, the preliminary results of the first year's clinical experience of lymphoscintigraphy in Isfahan, Iran are also presented. A total of 36 consecutive sentinel node procedures were performed following our protocol in March 2013 to March 2014. For all 36 patients, after intradermal injection of 0.5 1 mCi of (99m)Tc-Phytate, 5, 30 and 120 min with hands up lymphoscintigraphy was performed. All procedures were performed in a 1-day setting with (99m)Tc-Phytate injection in intradermal volume of about 0.1 cc. At 5, 30 and 120 min after injection, anterior and lateral images (4 min), were acquired using gamma-camera (energy 140 keV, window 15-20% and LEHR collimator). For all patients, at least one axillary sentinel lymph node was detected. For three patients, 2 SNs were seen. The images 5 min after injection showed at least one axillary sentinel node in 18 of 36 patients. However for the remaining patients, more delayed images (after 30 and 120 min) were needed. Although, no changes were seen in 120 min images compared to 30 min images. Considering the used protocol, from the evaluated data it can be concluded that lymphoscintigraphy after 30 min periareolar injection of about 0.5-1 mCi (99m)Tc-Phytate in an intradermal volume of about 0.1 cc yields an axillary sentinel node in all the patients. Imaging 120 min after injection is of no additional value and can be omitted. PMID- 25709944 TI - Intestinal and free living amoebae: Lesser known facts. PMID- 25709945 TI - Laboratory diagnosis of Blastocystis spp. PMID- 25709946 TI - Ethics of international collaboration. AB - Education and research together are vital components of academic institutions and globalization has improved health care education and research in numerous ways, one of which is multinational/transnational research/international collaboration. Usually academic institutions of high-income countries and institutions in low income countries participate in collaboration. These collaborative research are guided by international ethics codes proposed by the international ethics committee to avoid stringent follow/unethical practices. PMID- 25709947 TI - Entamoeba dispar: Could it be pathogenic. AB - Amebiasis is a disease caused by the protozoan parasite Entamoeba histolytica. This ameba can colonize the human intestine and persist as a commensal parasite, similar to Entamoeba dispar, an ameba considered to be non-pathogenic. The similarities between E. histolytica and E. dispar make the latter an attractive model for studies aimed at clarifying the pathogenesis of amebiasis. However, in addition to being an interesting experimental model, this relative of E. histolytica remains poorly understood. In the 1990, it was believed that E. dispar was unable to produce significant experimental lesions. This scenario began to change in 1996, when E. dispar strains were isolated from symptomatic patients in Brazil. These strains were able to produce liver and intestinal lesions that were occasionally indistinguishable from those produced by E. histolytica. These and other findings, such as the detection of E. dispar DNA sequences in samples from patients with amebic liver abscess, have revived the possibility that this species can produce lesions in humans. The present paper presents a series of studies on E. dispar that begin to reveal a new facet of this protozoan. PMID- 25709948 TI - Balamuthia mandrillaris: Morphology, biology, and virulence. AB - Balamuthia mandrillaris is a protist pathogen that can cause encephalitis with a fatality rate of >95%. This is due to our incomplete understanding of the pathogenesis and pathophysiology of B. mandrillaris encephalitis. B. mandrillaris has two stages in its life cycle, an active trophozoite stage during which it divides mitotically. However, under unfavorable conditions, the trophozoite transforms into a dormant cyst stage. A major concern during the course of therapy is that B. mandrillaris can transform into cysts. Cysts are highly resistant to physical and chemical conditions and present a problem in successful antimicrobial chemotherapy. Several lines of evidence suggest that B. mandrillaris encephalitis develops as a result of hematogenous spread, but it is unclear how circulating amoebae enter the central nervous system and cause inflammation, blood-brain barrier disruption, and neuronal injury. Recent studies have identified several parasite-host determinants for B. mandrillaris translocation of the blood-brain barrier, and host inflammatory markers that may be associated with neuronal injury. These determinants may provide important targets for the prevention and treatment of this devastating infection. Here, we present a brief overview of the current understanding of the morphology, biology, pathogenesis, and pathophysiology of B. mandrillaris encephalitis. PMID- 25709949 TI - Management of granulomatous amebic encephalitis: Laboratory diagnosis and treatment. AB - Granulomatous amebic encephalitis is a life-threatening central nervous system (CNS) infection caused by the free-living amoebae Acanthamoeba spp., Balamuthia mandrillaris and Sappinia pedata. The disease has a subacute to chronic onset affecting commonly the immunocompromised population with high mortality rate. The diagnosis of this disease entity requires high suspicion with appropriate sample collection and testing by the laboratory experts. Radiological investigations are nonspecific and commonly confused with CNS tuberculosis, neurocysticercosis, disseminated encephalomyelitis, viral encephalitis etc., delaying the accurate diagnosis of these cases. Early diagnosis plays a crucial role in the survival of these cases since appropriate management can be initiated. No single drug is effective; hence multiple antibiotics targeting various proteins or receptors are required for successful treatment. A combination of surgical and medical interventions involving multiple specialty experts is required to prevent death and morbidity in survivors. PMID- 25709950 TI - Effect of enteric parasitic infection on serum trace elements and nutritional status in upper Egyptian children. AB - INTRODUCTION: Enteric parasitic infections still the cause of major health problems among Egyptian children as they have great morbid effect on their physical and cognitive development. Malnutrition makes children more prone to micronutrient deficiency and subsequently more vulnerable to parasitic infection. The present study aimed to identify the effect of intestinal parasitism on micronutrient serum level and children nutritional status. MATERIALS AND METHODS: A case control study was carried out on children from 1 to 6 years old who were attending the Assiut University Children Hospital outpatient clinic, after parasitological stool examination they were divided into Group 1 (G1, n: 60) positive with enteric parasite and Group 2 (G2, n: 60) age and sex matched and free of parasites. Anthropometric measurements were expressed as weight for age (WFA), height for age (HFA), and weight for height (WFH) parameters. Serum zinc (Zn) and copper (Cu) were determined by atomic absorption spectrophotometer. RESULTS: Intestinal parasitic infection rate was 55.7%; more commonly detected parasites were Giardia lamblia 28%, Cryptosporidium sp. 20%, and polyparasitism 18%. All children (G1 and G2) were underweight (WFA) while 63% of G1 were malnourished, either in the form of wasting (WFH) or stunting (HFA) or both aspects. Stunting and wasting were more dominant among children infected with G. lamblia and Cryptosporidium sp. and most of them were below 2 years old. CONCLUSIONS: Coincident decrease in serum Zn level and an increase of serum Cu was more prominent among G. lamblia and Cryptosporidium sp. patients. G. lamblia and Cryptosporidium sp. were found to be more associated with nonstandard children nutritional status beside to an altered micronutrient level. PMID- 25709951 TI - Laboratory diagnosis of Blastocystis spp. in diarrheic patients. AB - BACKGROUND: Many laboratories currently diagnose Blastocystis spp. infections by looking for the presence of vacuolar forms in faeces and the amoeboid form in diarrheal stools. OBJECTIVES: To investigate the best direct method in diagnosis of Blastocystis spp. and to study different morphological forms of the parasite. MATERIALS AND METHODS: The study was carried out on one thousand and two hundred diarrheic stool samples. All samples were examined using direct smear, iodine stained smear, formalin-ether concentration techniques, trichrome stained smear and in vitro cultivation using Jones' medium. RESULTS: Using direct smear, Blastocystis spp was detected in 42 cases (3.5%) with a sensitivity (28.4%) and specificity (100%). Iodine stained smear detected 72 positive cases (6%) with a sensitivity (48.7%), specificity (100%). Formol ether concentration technique detected 120 positive cases (10%) with a sensitivity (81.1%) and specificity (100%). Trichrome stained smear detected 148 positive cases (12.3%). In vitro cultivation using Joni's medium detected 274 positive cases (22.8%) which was the highest number among all different diagnostic methods with a sensitivity (100%) ,specificity (88%), PPV (54.1%) and NPV (100%). It was found that, 49 blastocystosis cases had mixed infection with other intestinal parasites. Giardia lamblia was the most frequently associated parasite with Blastocystis spp. CONCLUSION: In vitro cultivation is more sensitive in detection of B. hominis than simple smear and concentration technique. Blastocystis spp. vacuolar form was the most common form that was found by all methods used in this study G. lamblia was the most frequent parasite associated with Blastocystis spp . PMID- 25709952 TI - Is the coverage of mass-drug-administration adequate for elimination of Bancroftian filariasis? An experience from West Bengal, India. AB - BACKGROUND: Bancroftian filariasis is the second most common mosquito-borne disease in India. Government of India adopted mass-drug-administration (MDA) since 2004 for its elimination by 2015 AD. OBJECTIVE: The aim was to assess the coverage, compliance, factors-related to noncompliance to MDA. MATERIALS AND METHODS: A cross-sectional survey of 1 week was conducted within 2 weeks after completion of MDA for 2012 in three villages and two municipal wards of North 24 Parganas district of West Bengal, India selected as clusters by multistage random sampling. Information was collected via interview of inhabitants of the clusters selected by systematic random sampling and drug administrators of the selected clusters along with verifying left over medicines, if any. RESULTS: Both appropriate medicine distribution (83.4%) and 61.28% of people who received drug reported consumption and effective consumption rate (48.01%) fell short of the target. The lowest consumption (38.15%) was noted in one of the rural cluster (villages), followed by municipal wards (43.14%). Consumption was significantly higher among rural residents and Hindu community. Fear of the adverse reaction was the commonest (63.02%) cause of noncompliance. Contrary to the requirement, almost all consumptions were unsupervised by drug administrators. Only 10.71% of the respondents reportedly were paid house to house campaign of forthcoming MDA. About 64% participants had heard about filariasis out of which 71% & 47% mentioned swelling of legs as symptoms and mosquito bite as mode of spread, respectively. About one-third opined mosquito control and MDA each as means of prevention. Approximately, 60% participants had heard about MDA. Information education and communication related to MDA program was conspicuously inadequate in the last round. CONCLUSION: Mass mobilization as in intensive pulse polio immunization with effective monitoring and supervision is the need of the hour for universal coverage of MDA with supervised on the spot consumption of tablets. PMID- 25709953 TI - Identification of Leishmania species by kinetoplast DNA-polymerase chain reaction for the first time in Khaf district, Khorasan-e-Razavi province, Iran. AB - CONTEXT: Cutaneous leishmaniasis (CL) is an endemic parasitic skin disease in many parts of Iran including Khorasan province. Both clinical forms of the disease, anthroponotic cutaneous leishmaniasis (ACL) and zoonotic cutaneous leishmaniasis (ZCL) are present in this province. However, leishmaniasis molecular map is determined in four cities of Khorasan, but several foci still are remained unknown. AIM: The aim was to identify the species of Leishmania causing CL in Khaf, a District in Khorasan-e-Razavi province. MATERIALS AND METHODS: Slide smears obtained from skin lesions of 120 patients suspected to leishmaniasis. Direct microscopy and polymerase chain reaction (PCR) performed using specific kinetoplast DNA primers. Data were analyzed with the use of SPSS. RESULTS: Among 120 persons with skin ulcers suspected to CL, the results of direct smear of 54 (45%) samples were positive. PCR band were observed in 66 (55%) of examined samples in which 46 bands identified for Leishmania tropica and 20 for Leishmania major. CONCLUSION: Both ACL and ZCL are present in Khaf. L. tropica is the dominant causative species for ACL. Further study is recommended to discover probable reservoir and vector for L. major in Khaf. PMID- 25709954 TI - Pancreatic ascariasis with periampullary carcinoma. AB - Ascarias lumbricoides infestation is endemic in tropical countries. Most infections are asymptomatic, but it can produce a wide spectrum of manifestations including hepatobiliary and pancreatic complications. There are reports of association of biliary ascariasis with bilary malignancies in the past, but same is not known for pancreatic ascariasis. We report a case of association of periampullary malignancy with pancreatic ascariasis. PMID- 25709955 TI - Vulval myiasis: An unusual presentation of a rare entity in an adolescent female. AB - Human myiasis refers to parasitic infestation of body tissues by larvae of several fly species. The entity has a simple management. Human myiasis is well documented in the literature however genital myiasis in females is scarcely reported in the literature. We hereby report this entity in an adolescent female who presented with urinary retention and concomitant urinary tract infection. PMID- 25709956 TI - Uncommon neurological manifestations of a common tropical vector borne disease. AB - Malaria poses a major public health problem in India, where it is endemic, especially severe malaria caused by Plasmodium falciparum infestation. There have been great changes in the clinical manifestation of severe falciparum malaria over the past couple of decades, with a shift from cerebral malaria to fever with jaundice, renal failure, bleeding diathesis, and multi-organ dysfunction syndrome. Here, we discuss two cases of severe falciparum malaria which presented with extremely uncommon neurological manifestations. PMID- 25709957 TI - Ocular sparganosis from Assam. AB - Sparganosis is caused by plerocercoid larvae of the Pseudophyllidea tapeworms of the genus Spirometra. Though prevalent in East Asian and south east Asian countries like China, Japan, Korea, Taiwan, Vietnam, Thailand; yet very few cases are reported from India. We report a case of migrating sub-conjunctival ocular sparganosis mimicking scleritis which later on developed into orbital cellulitis from Dibrugarh, Assam, North-eastern part of India. This case is reported for its rarity. PMID- 25709958 TI - Finding of an unusual ova - Schistosoma mansoni. PMID- 25709959 TI - Hypothesis: The potential application of doxorubicin against cutaneous leishmaniasis. PMID- 25709960 TI - An E-mail interview with Prof. John Horton. PMID- 25709961 TI - Theranostic nanomedicine: Potential therapeutic epitome. PMID- 25709962 TI - Production and estimation of alkaline protease by immobilized Bacillus licheniformis isolated from poultry farm soil of 24 Parganas and its reusability. AB - Microbial alkaline protease has become an important industrial and commercial biotech product in the recent years and exerts major applications in food, textile, detergent, and pharmaceutical industries. By immobilization of microbes in different entrapment matrices, the enzyme produced can be more stable, pure, continuous, and can be reused which in turn modulates the enzyme production in an economical manner. There have been reports in support of calcium alginate and corn cab as excellent matrices for immobilization of Bacillus subtilis and Bacillus licheniformis, respectively. This study has been carried out using calcium alginate, kappa-carrageenan, agar-agar, polyacrylamide gel, and gelatin which emphasizes not only on enzyme activity of immobilized whole cells by different entrapment matrices but also on their efficiency with respect to their reusability as first attempt. Gelatin was found to be the best matrix among all with highest enzyme activity (517 U/ml) at 24 h incubation point and also showed efficiency when reused. PMID- 25709963 TI - Inhibition of lipase and inflammatory mediators by Chlorella lipid extracts for antiacne treatment. AB - Acne vulgaris is a chronic inflammatory disease, and its treatment is challenging due to the multifactorial etiology and emergence of antibiotic-resistant Propionibacterium acnes strains. This study was focused to reduce antibiotics usage and find an alternate therapeutic source for treating acne. Lipid extracts of six Chlorella species were tested for inhibition of lipase, reactive oxygen species (ROS) production, cytokine production using P. acnes (Microbial Type Culture Collection 1951). Lipase inhibitory assay was determined by dimercaprol Tributyrate - 5, 5'- dithiobis 2-nitrobenzoic acid method and ROS production assay was performed using nitro-blue tetrazolium test. The anti-inflammatory activity of algal lipid extracts was determined by in vitro screening method based on inhibition of pro-inflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha) produced by human peripheral blood mononuclear cells. Minimum inhibitory concentration (MIC) values of lipid extracts were determined by microdilution method, and the fatty acid methyl esters (FAME) were analyzed by gas chromatography-mass spectroscopy. Chlorella ellipsoidea has the highest lipase inhibitory activity with 61.73% inhibition, followed by Chlorella vulgaris (60.31%) and Chlorella protothecoides (58.9%). Lipid extracts from C. protothecoides and C. ellipsoidea has significantly reduced the ROS production by 61.27% and 58.34% respectively. Inhibition of pro-inflammatory cytokines TNF alpha showed the inhibition ranging from 58.39% to 78.67%. C. vulgaris has exhibited the MICvalue of 10 MUg/ml followed by C. ellipsoidea, C. protothecoides and Chlorella pyrenoidosa (20 MUg/ml). FAME analysis detected 19 fatty acids of which 5 were saturated fatty acids, and 14 were unsaturated fatty acids ranging from C14 to C24. The results suggest that lipid extracts of Chlorella species has significant inhibitory activity on P. acnes by inhibiting lipase activity. Further, anti-inflammatory reaction caused by the pathogen could be reduced by the inhibiting the production of ROS and inflammatory mediators TNF-alpha and exposes new frontiers on the antiacne activities of Chlorella lipid extracts. PMID- 25709964 TI - Three-dimensional quantitative structure-activity relationships and docking studies of some structurally diverse flavonoids and design of new aldose reductase inhibitors. AB - Aldose reductase (AR) plays an important role in the development of several long term diabetic complications. Inhibition of AR activities is a strategy for controlling complications arising from chronic diabetes. Several AR inhibitors have been reported in the literature. Flavonoid type compounds are shown to have significant AR inhibition. The objective of this study was to perform a computational work to get an idea about structural insight of flavonoid type compounds for developing as well as for searching new flavonoid based AR inhibitors. The data-set comprising 68 flavones along with their pIC50 values ranging from 0.44 to 4.59 have been collected from literature. Structure of all the flavonoids were drawn in Chembiodraw Ultra 11.0, converted into corresponding three-dimensional structure, saved as mole file and then imported to maestro project table. Imported ligands were prepared using LigPrep option of maestro 9.6 version. Three-dimensional quantitative structure-activity relationships and docking studies were performed with appropriate options of maestro 9.6 version installed in HP Z820 workstation with CentOS 6.3 (Linux). A model with partial least squares factor 5, standard deviation 0.2482, R(2) = 0.9502 and variance ratio of regression 122 has been found as the best statistical model. PMID- 25709965 TI - Estrogenic activity of a hydro-alcoholic extract of Bambusa arundinaceae leaves on female wistar rats. AB - To study the estrogenic activity of the hydro-alcoholic extract of Bambusa arundinaceae leaves (HEBA) in female Wistar rats. The dried powdered leaves were extracted with hydroalcoholic mixture (60%), and the resultant extract was subjected for phytochemical analyses to identify different phytoconstituents. HEBA were administered to ovariectomized rats for 7 days at three different doses (viz., 200, 300, 400 mg/kg body weight, p.o.) and their estrogenic activity were compared with each of daily treatment with 0.2 mg/kg body weight, i.p. conjugated equine estrogen as a positive control or olive oil as a negative control. Estrogenic activity was evaluated by doing uterotropic assay, vaginal cytology and measurement of vaginal opening in female Wistar rats. Oral administration of HEBA in ovariectomized immature and mature female Wistar rats in a dose of 400 mg/kg b.w. resulted in significant increase in the uterine wet weight (in mg) (224.82 +/- 7.01) and (912.25 +/- 27.22) when compared with ovariectomized control rats (111.52 +/- 3.17) and (506.67 +/- 21.39). HEBA (400 mg/kg b.w., p.o.) treated rats, showing only cornified epithelial cells which was an indication of the presence of the estrogen and also showed 100% vaginal opening. It was observed that HEBA possess significant estrogenic activity at 400 mg/kg b.w., p.o. which was evident by uterotropic assay, measurement of vaginal opening, and histopathological changes. PMID- 25709966 TI - Simultaneous determination of linagliptin and metformin by reverse phase-high performance liquid chromatography method: An application in quantitative analysis of pharmaceutical dosage forms. AB - To enhance patient compliance toward treatment in diseases like diabetes, usually a combination of drugs is prescribed. Therefore, an anti-diabetic fixed-dose combination of 2.5 mg of linagliptin 500 mg of metformin was taken for simultaneous estimation of both the drugs by reverse phase-high performance liquid chromatography (RP-HPLC) method. The present study aimed to develop a simple and sensitive RP-HPLC method for the simultaneous determination of linagliptin and metformin in pharmaceutical dosage forms. The chromatographic separation was designed and evaluated by using linagliptin and metformin working standard and sample solutions in the linearity range. Chromatographic separation was performed on a C18 column using a mobile phase of 70:30 (v/v) mixture of methanol and 0.05 M potassium dihydrogen orthophosphate (pH adjusted to 4.6 with orthophosphoric acid) delivered at a flow rate of 0.6 mL/min and UV detection at 267 nm. Linagliptin and metformin shown linearity in the range of 2-12 MUg/mL and 400-2400 MUg/mL respectively with correlation co-efficient of 0.9996 and 0.9989. The resultant findings analyzed for standard deviation (SD) and relative standard deviation to validate the developed method. The retention time of linagliptin and metformin was found to be 6.3 and 4.6 min and separation was complete in <10 min. The method was validated for linearity, accuracy and precision were found to be acceptable over the linearity range of the linagliptin and metformin. The method was found suitable for the routine quantitative analysis of linagliptin and metformin in pharmaceutical dosage forms. PMID- 25709967 TI - Knowledge, attitude and practices toward pharmacovigilance and adverse drug reactions in postgraduate students of Tertiary Care Hospital in Gujarat. AB - Being key health care professional, physicians, pharmacist and nurses have immense responsibility in reporting adverse drug reaction (ADR). Therefore, the study objective was to evaluate the knowledge, attitude and practices (KAP) toward pharmacovigilance and ADRs of postgraduate students of our institute. A cross-sectional questionnaires based study was carried out in postgraduate students of the clinical department at tertiary care hospital attached with Govt. Medical College, Vadodara, Gujarat (India). A total of 22 questionnaires about KAP toward ADRs and pharmacovigilance were developed and peer viewed of all questionnaires by expert faculties from our institute. We were contacted directly to postgraduate students of respective clinical department; questionnaires were distributed and taken back after 30 min. The filled KAP questionnaires were analyzed in question wise and their percentage value was calculated by using Microsoft Excel spreadsheet. Postgraduate residents (n = 101) from different clinical departments were enrolled in the study. Average 34.83% correct and 64.08% incorrect knowledge about ADRs and pharmacovigilance and an average 90.76% students were agreed to reporting ADRs is necessary, mandatory and increased patient's safety. Only 7.92% of postgraduate doctors were reported ADR at institute or ADR reporting center. We concluded that postgraduate students have a better attitude toward reporting ADRs, but have lack of knowledge and poor practices of ADRs. The majority of postgraduate students were felt ADR reporting and monitoring is very important, but few had ever reported ADRs because of lack of sensitization and knowledge of pharmacovigilance and ADR. PMID- 25709968 TI - Recurrent seizures after lidocaine ingestion. AB - Lidocaine has a concentration-dependent effect on seizures. Concentrations above 15 MUg/mL frequently result in seizures in laboratory animals and human. We report a case of central nervous system (CNS) lidocaine toxicity and recurrent seizure after erroneous ingestion of lidocaine solution. A 4-year-old boy presented to the Emergency Department of Imam Hospital of Sari in December 2013 due to tonic-clonic generalized seizures approximately 30 min ago. 3 h before seizure, his mother gave him 2 spoons (amount 20-25 cc) lidocaine hydrochloride 2% solution instead of pediatric gripe by mistake. Seizure with generalized tonic clonic occurred 3 times in home. Neurological examination was essentially unremarkable except for the depressed level of consciousness. Personal and medical history was unremarkable. There was no evidence of intracranial ischemic or hemorrhagic lesions in computed tomography scan. There were no further seizures, the condition of the patient remained stable, and he was discharged 2 days after admission. The use of viscous lidocaine may result in cardiovascular and CNS toxicity, particularly in children. Conservative management is the best option for treatment of lidocaine induced seizure. PMID- 25709969 TI - Cell-cycle protein expression in a population-based study of ovarian and endometrial cancers. AB - Aberrant expression of cyclin-dependent kinase (CDK) inhibitors is implicated in the carcinogenesis of many cancers, including ovarian and endometrial cancers. We examined associations between CDK inhibitor expression, cancer risk factors, tumor characteristics, and survival outcomes among ovarian and endometrial cancer patients enrolled in a population-based case-control study. Expression (negative vs. positive) of three CDK inhibitors (p16, p21, and p27) and ki67 was examined with immunohistochemical staining of tissue microarrays. Logistic regression was used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for associations between biomarkers, risk factors, and tumor characteristics. Survival outcomes were only available for ovarian cancer patients and examined using Kaplan-Meier plots and Cox proportional hazards regression. Among ovarian cancer patients (n = 175), positive p21 expression was associated with endometrioid tumors (OR = 12.22, 95% CI = 1.45-102.78) and higher overall survival (log-rank p = 0.002). In Cox models adjusted for stage, grade, and histology, the association between p21 expression and overall survival was borderline significant (hazard ratio = 0.65, 95% CI = 0.42-1.05). Among endometrial cancer patients (n = 289), positive p21 expression was inversely associated with age (OR >= 65 years of age = 0.25, 95% CI = 0.07-0.84) and current smoking status (OR: 0.33, 95% CI 0.15, 0.72) compared to negative expression. Our study showed heterogeneity in expression of cell-cycle proteins associated with risk factors and tumor characteristics of gynecologic cancers. Future studies to assess these markers of etiological classification and behavior may be warranted. PMID- 25709970 TI - Use of Helical TomoTherapy for the Focal Hypofractionated Treatment of Limited Brain Metastases in the Initial and Recurrent Setting. AB - BACKGROUND: Whole-brain radiation therapy (WBRT), stereotactic radiosurgery (SRS), or both are commonly employed in the treatment of limited brain metastases in the initial or recurrent setting. Hypofractionated partial volume irradiation is also employed, however, published experience using helical TomoTherapy (HT) for this purposes is limited. We reviewed our institutional experience to assess patient selection factors, fractionation scheme, and outcomes associated with this technique. METHODS: A retrospective chart review was performed to evaluate patients treated with partial volume hypofractionated HT-based IMRT for brain metastases at our institution. RESULTS: Thirteen patients (7M/6F, median age 62, median KPS 90) with a limited (1-9) number of brain metastases in the primary or recurrent setting were identified. Primary malignancies included colorectal (3), NSCLC (5), RCC (1), breast (1), melanoma (1), uterine (1), and ovarian (1). The median time from initial diagnosis to brain metastases was 20.7 months (range 0 61.3). Treatment was delivered to intact metastases in six patients, to a single resection cavity in six patients, and to both in one patient. A total of 27 lesions were treated. The median number of intact metastases treated was two (range 1-9). Previous treatments included WBRT (5), WBRT + SRS (3), SRS alone (1), and none (4). The most common fractionation schemes were 25 Gy in five fractions and 27.5 Gy in five fractions to each lesion. At a median of 6 months follow up (range 1.26-20.13) after TomoTherapy, 10 patients were deceased, 2 were alive, and 1 was lost to follow up. Systemic progression occurred in seven patients and intracranial progression occurred in five. The median intracranial progression free survival and overall survival after TomoTherapy was 6.3 months. Freedom from local failure for treated lesions was 71% and 59% at 6 and 12 months. CONCLUSION: TomoTherapy-based hypofractionated radiotherapy to a limited number of metastatic lesions is associated with acceptable intracranial disease control and survival outcomes and represents a viable treatment option in the primary and recurrent setting for select patients. PMID- 25709971 TI - Chronic Plantar Fasciitis is Mediated by Local Hemodynamics: Implications for Emerging Therapies. AB - Plantar fasciitis (PF) is a common, disabling condition affecting millions of patients each year. With early diagnosis and timely application of traditional nonsurgical treatments, symptoms generally resolve over time. However, despite adequate treatment, 20% of patients will experience persistent symptoms. In these patients, minimally invasive therapies that augment local hemodynamics to initiate a regenerative tissue-healing cascade have the greatest potential to resolve long-standing symptoms. We performed a narrative review based on a best evidence evaluation of manuscripts published in Medline-indexed journals to determine the mechanisms involved in soft tissue injury and healing. This evaluation also highlights emerging minimally invasive therapies that exploit these mechanisms in recalcitrant PF. PMID- 25709972 TI - Use of oral anti-diabetic agents in pregnancy: a pragmatic approach. AB - Insulin is the gold standard for treatment of hyperglycemia during pregnancy, when lifestyle measures do not maintain glycemic control during pregnancy. However, recent studies have suggested that certain oral hypoglycemic agents (metformin and glyburide) may be safe and be acceptable alternatives. There are no serious safety concerns with metformin, despite it crossing the placenta. Neonatal outcomes are also comparable, with benefit of reductions in neonatal hypoglycemia, maternal hypoglycemia and weight gain, and improved treatment satisfaction. Glibenclamide is more effective in lowering blood glucose in women with gestational diabetes, and with a lower treatment failure rate than metformin. Although generally well-tolerated, some studies have reported higher rates of pre-eclampsia, neonatal jaundice, longer stay in the neonatal care unit, macrosomia, and neonatal hypoglycaemia. There is also paucity of long-term follow up data on children exposed to oral agents in utero. This review aims to provide an evidence-based approach, concordant with basic and clinical pharmacological knowledge, which will help medical practitioners use oral anti-diabetic agents in a rational and pragmatic manner. Pubmed search was made using Medical Subject Headings (MESH) terms "Diabetes" and "Pregnancy" and "Glyburide"; "Diabetes" and "Pregnancy" and "Metformin". Limits were randomized controlled trials (RCTs) and meta-analysis. The expert reviews on the topic were also used for discussion. Additional information (studies/review) pertaining to discussion under sub headings like safety during breastfeeding; placental transport; long-term safety data were searched (pubmed/cross-references/expert reviews). PMID- 25709973 TI - Dental anxiety among adults: an epidemiological study in South India. AB - BACKGROUND: Dental anxiety is a major barrier for dental care utilization. Hence, identifying anxious individuals and their appropriate management becomes crucial in clinical practice. AIM: The study aims to assess dental anxiety, factors influencing dental anxiety, and anxiety towards tooth extraction procedure among patients attending a dental hospital in India. MATERIALS AND METHODS: The study sample consisted of 1,148 consecutive patients aged 18-70 years. The assessment tools consisted of a consent form, history form, a questionnaire form containing the Modified Dental Anxiety Scale (MDAS) which was used to assess the level of dental anxiety, and an additional question on anxiety towards dental extraction procedure. RESULTS: Among the study group, 63.7% were men and 36.3% were women. Based on the MDAS score, 45.2% of the participants were identified to be less anxious, 51.8% were moderately or extremely anxious, and 3% were suffering from dental phobia. Mean MDAS total score was 10.4 (standard deviation (SD) = 3.91). Female participants and younger subjects were more anxious (P < 0.001). Subjects who were anxious had postponed their dental visit (P < 0.001). Participants who had negative dental experience were more anxious (P < 0.05). Notably, 82.6% reported anxiety towards extraction procedure. Significant association was seen between anxiety towards extraction procedure and the respondents gender (P < 0.05), age (P < 0.001), education level (P < 0.05), employment status (P < 0.001), income (P < 0.001), self-perceived oral health status (P < 0.05), and their history of visit to dentist (P < 0.05). CONCLUSION: Significant percentage of population was suffering from dental anxiety in this study population. A plethora of factors like age, gender, education level, occupation, financial stability, and previous bad dental experience influences dental anxiety to various levels. Extraction followed by drilling of tooth and receiving local anesthetic injection provoked more anxiety. PMID- 25709974 TI - Dentinogenic ghost cell tumor - a neoplastic variety of calcifying odontogenic cyst: case presentation and review. AB - CONTEXT: The calcifying odontogenic cyst (COC), also referred to as calcifying ghost cell odontogenic cyst (CGCOC) is a heterogeneous lesion existing either as cystic or solid variant. Due to the fact that all CGCOC lesions are not cystic, and the biological behavior is often not consistent with a cyst, there has always been a controversy as to whether COC is a cyst or a tumor. The dentinogenic ghost cell tumor (DGCT), a solid variant of the COC, is an uncommon odontogenic neoplasm occurring predominantly in later life. Case report is followed by a concise review and disambiguation of controversial terminologies regarding nomenclature of COC. CASE REPORT: We report a case of 33-year-old female patient who presented with an insidious, steadily increasing swelling on the left side of her face since 8 months. Patient reported slight difficulty in eating because of reduced intraoral space and an obvious concern with facial disfigurement. There was no contributory dental or medical history. Intraorally, a hard, well defined, bicortical swelling was noted in left maxillary region with slight mobility of the associated teeth and normal appearing overlying mucosa. A provisional diagnosis of adenomatoid odontogenic tumor was made, and orthopantomogram, paranasal sinus radiograph and computed tomograpy scan of the face were acquired. A radiographic diagnosis of COC was made, which was subsequently confirmed on histopathology postenucleation of the tumor mass. COC has been seen to be of extensive diversity in its clinical and histopathological features as well as in its biological behavior. CONCLUSION: The present case of 33-year-old female was diagnosed as DGCT, a tumorous form of COC, due to its characteristic histological features; numerous ghost cells and dentinoid material. PMID- 25709975 TI - Cutaneous metastasis from squamous carcinoma of the base of tongue. AB - CONTEXT: Cutaneous metastasis from head and neck cancer is uncommon and it is seen from laryngeal cancer. Cutaneous metastasis from the base of tongue is relatively rare. CASE REPORT: A 55-year-old male, who was a treated case of squamous carcinoma of the base of tongue presented with metastatic nodule on the skin of face and thigh. But, there was complete resolution of the tumor at the primary site. In the present case, clinically obvious cutaneous nodules with metastasis appeared soon after the completion of treatment with concurrent chemo radiotherapy. The metastasis to the skin of face clinically appeared like an inflammatory lesion. Fine needle aspiration cytology confirmed the diagnosis of metastasis to skin at both the sites. CONCLUSION: Our case has highlighted that there could be associated occult skin metastasis at the time of diagnosis in squamous carcinoma of the base of tongue. PMID- 25709976 TI - An adolescent with tingling and numbness of hand: gitelman syndrome. AB - CONTEXT: Gitelman syndrome is an inherited autosomal recessive disorder. It is usually diagnosed incidentally during adolescence or early adulthood based on clinical and biochemical findings. CASE REPORT: We present a case of 16 years old adolescent female presenting with recurrent chest pain, tingling, and numbness of bilateral hands. Diagnosis was established by the typical biochemical abnormalities with hypokalemia, hypomagnesemia, hypocalciuria, metabolic alkalosis, and hyperreninemic hyperaldosteronism. Genetic diagnosis was confirmed by sequence analysis of the SLC12A3 gene showing the compound heterozygous mutation encoding the thiazide-sensitive sodium chloride co-transporter. The patient was treated with oral potassium, magnesium, and amiloride with complete improvement of symptoms and biochemical profile. CONCLUSION: Gitelman syndrome should be considered as a differential diagnosis in work up of hypokalemia, especially in adolescent age group. The presence of hypokalemia, metabolic alkalosis, hypomagnesaemia, hypocalciuria, and mutation analysis provides the final diagnosis. PMID- 25709977 TI - Evolutionary paradox of immunity. PMID- 25709978 TI - Regional pericardits: a mischievous masquerader. PMID- 25709979 TI - Regional pericarditis status post cardiac ablation: a case report. PMID- 25709980 TI - Effect of Education through Support -Group on Early Symptoms of Menopause: a Randomized Controlled Trial. AB - INTRODUCTION: Menopause is one of the most important crises in the life of women. The control of menopause symptoms is a main challenge in providing care to this population. So, the aim of present study was to investigate the effect of education through support -group on early symptoms of menopause. METHODS: In this randomized controlled clinical trial 124 postmenopausal women who had a health records in Valiasr participatory health center of Eslamshahr city were participated. These women were allocated by block randomization method into support group (62 women) and control group (62 women).Women in support group was assigned into 6 groups. Three 60-minutes educational sessions were conducted in 3 sequential weekly sessions. Early menopausal symptoms were measured before and 4 weeks after the intervention by using Greene scale (score ranged from 0 to 63). Data analysis was performed by ANCOVA statistical test. RESULTS: There were no statistical differences between two groups in demographic characteristics and the total score of the Greene scale before intervention. The mean score of the Greene scale in support group was statistically less than control group 4 weeks after intervention. The number of hot flashes in the support group was significantly lower than control group, 4 weeks after intervention. CONCLUSION: Education through support group was effective in reducing the early symptoms of menopause. Thus, this educational method can be used as an appropriate strategy for enhancing women' health and their dealing with annoying symptoms of menopause. PMID- 25709981 TI - Perceived Social Support and Stress among Pregnant Women at Health Centers of Iran- Tabriz. AB - INTRODUCTION: Social support is considered the interaction between the person and environment, which reduces stressors, covers the effects of stress and consequently protects individuals from the harmful effects of stressful situations. This study aimed to determine social support in pregnant women and its relationship with the rate of pregnant women's perceived stress at health centers of Tabriz in 2012-13. METHODS: This cross-sectional study was carried out on 450 pregnant women selected through cluster sampling. Data collection tools consisted of a demographic questionnaire, interpersonal support evaluation list (ISEL) and perceived stress questionnaire (PSS) that were completed in an interview. The range of obtainable score for social support and perceived stress was 0-90 and 0-30, respectively. Descriptive and analytical statistics including Pearson and Independent t-test were used for analyzing the data. RESULTS: The mean score of social support and perceived stress in pregnant women was 96.6 (14.6), and 11.5 (5.5), respectively .The women with favorable social support had significantly less stress than the women with unfavorable social support. CONCLUSION: The study finding showed that the rate of social support in highly stressful women is significantly less than low-stress mothers. Therefore, considering adverse effects of the stress on pregnancy outcomes, some strategies should be designed and implemented in order to strengthen and improve the social support for pregnant women so that it can reduce the rate of pregnant women's stress. PMID- 25709982 TI - The prevalence of isolated hepatitis B core antibody and its related risk factors among male injected drug users in Isfahan prisons. AB - BACKGROUND: The prevalence of isolated hepatitis B core antibody (anti-HBc) varies between 1% and 30% in different populations. Isolated anti-HBc-positive patients who suffer from occult hepatitis B virus (HBV) infection have the potential to transmit HBV infection. So isolated anti-HBc screening is a valuable tool to prevent HBV transmission. Considering the importance of isolated anti-HBc screening and high prevalence of HBV among injected drug users (IDU) prisoners, we designed this study to evaluate the isolated anti-HBc positivity among inmates with the history of IDU in our area. MATERIALS AND METHODS: We did this cross sectional study from September 2009 to March 2010 among volunteer male IDU prisoners in Isfahan. Blood samples were taken from all of subjects and tested for HBV markers. Then a questionnaire containing socio-demographic, drug histories and high risk behaviors information was completed for all participants. Data analysis was done utilizing univariate analysis and multiple logistic regressions. A P < 0.05 was considered significant. RESULTS: Totally 970 male IDU prisoners (mean age 32.6 +/- 8.1) were included in our study. The prevalence of isolated HBc Ab was 4.5%. Isolated anti-HBc significantly was related to tooth filling (OR: 2.62, CI: 1.20-7.14) and imprisonment (OR: 3.95, CI: 1.39-11.18). We couldn't find any relationship between isolated anti-HBc positivity and addiction duration, incarceration frequency, recent incarceration duration or number of injection per month. CONCLUSION: For screening high risk groups in parallel with hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (HBsAb) and other viral markers, maybe it is better to check HBcAb too, because isolated HBcAb-positive patients may have occult hepatitis B infection which could transfer the infection to others. PMID- 25709983 TI - Distribution of mediastinal ectopic thymic tissue in patients without thymic disease. AB - BACKGROUND: Different approaches to treat myasthenia gravis showed variable outcomes probably because of remained ectopic thymic tissue. The aim of this study is to determine incidence of thymic tissue in cases without any thymic disease. MATERIALS AND METHODS: Seventy-two patients scheduled for open heart surgery during 2000 and 2007 without thymic disease that were enrolled in the study at Chamran Hospital. Intraoperative biopsies were taken form aortopulmonary window, aortocaval groove and left and right pericardiophrenic regions. Finally, the distribution of ectopic thymic tissue was evaluated in above regions. RESULTS: Thymic tissue was found overall in 70.85% of patients. The most common sites for thymic tissue were left pericardiophrenic (50%) and right pericardiophrenic (31.9%) regions. Frequencies of ectopic thymus in aortopulmonary window and aortocaval groove were 19.4% and 12.5%, respectively. CONCLUSION: Because of high incidence of ectopic thymic tissue in mediastinum in patients without thymic disease, we recommend wide excision of thymus gland and all of adipose tissue in patients with myasthenia gravis. PMID- 25709984 TI - The evaluation and comparison of kidney length obtained from axial cuts in spiral CT scan with its true length. AB - BACKGROUND: Increased size of kidney is the main symptom of pyelonephritis and renal ischemia in children. Ultrasound and computed tomography (CT) scan methods are the imaging methods for evaluating the urogenital system. The aim of this study is to compare the kidney length obtained from spiral CT scan with the true length obtained from multi-slice CT. MATERIALS AND METHODS: From 100 patients 200 kidneys were examined in Alzahra Hospital in 2012. Multi-slice CT was used to obtain coronal and sagittal cuts to find the length of kidneys. RESULTS: The mean values of true size of axial sections of the right and left kidneys were 108.37 +/- 12.3 mm and 109.74 +/- 13.6 mm, respectively. The mean difference of axial sections' lengths in the right and left kidneys was 1.37 +/- 1.22 mm. The mean values of length in the spiral CT scan of the right and left kidneys were 98.61 +/- 15.8 mm and 103.11 +/- 15.9 mm, respectively. The difference in the estimated size by multi-slice CT scan in oblique and axial images was significant (9.77 +/- 1.19 mm and 6.63 +/- 0.8 mm for the right and left kidneys, respectively (P < 0.001). CONCLUSION: The average size of both kidneys determined in axial images was smaller than the actual size. The estimation of kidney size in axial images is not reliable, and to obtain the actual size, it is required to have the coronal and sagittal cuts with proper quality, which could be achieved by multi slice method. PMID- 25709985 TI - The effect of Kisspeptin-10 on mesenchymal stem cells migration in vitro and in vivo. AB - BACKGROUND: Kisspeptins (kp) activate a receptor coupled to a Galphaq subunit (GPR54 or KiSS-1R) receptor to perform a variety of functions, including inhibition of cell motility, chemotaxis, and metastasis. In this study we have investigated whether kp-10, the most potent member of the kisspeptin family, can modulate CXCR4 (C-X-C chemokine receptor type 4) expression and mesenchymal stem cells (MSCs) migration that may influence the development of tumors. MATERIALS AND METHODS: We compared the directional migration of MSCs treated with 10-100 or 500 nM kp-10 for 24 hours and no treated cells using an in vitro transmembrane migration assay. In addition, Chloromethylbenzamido Dialkylacarbocyanine (CM-Dil) labeled adipose-derived mesenchymal stem cells treated with 10-100 or 500 nM kp 10 and no treated cells were transfused via the tail vein to the melanoma tumor bearing C57BL/6 mice. After 24 hours, the mice were scarified, the tumors were dissected, and the tumor cell suspensions were analyzed by flow cytometry for detection of CM-Dil(+) MSCs. RESULTS: We have found that kp-10 increased the MSCs migration at 100 nM, while it decreased the MSCs migration at 500 nM, both in vitro and in vivo, with a significant increase of CXCR4 expression at 100 nM kp 10 compared to the no treated cells, but it had no significant difference between the various concentrations of kp-10. CONCLUSION: Thus, our data showed that kp-10 can differently affect MSCs migration in various concentrations, probably through different effects on CXCR4 expression in various concentrations. PMID- 25709986 TI - Clinical utility of residual latency in ulnar neuropathy at elbow: Is there any correlation? AB - BACKGROUND: Residual latency is the time difference between measured and predicted distal conduction time. We investigated ulnar nerve residual latency in patients with ulnar neuropathy at elbow for the possibility of its clinical utility. MATERIALS AND METHODS: In a cross-sectional study and based on the inclusion and exclusion criteria, ulnar nerve residual latency was calculated by using standard settings in 63 hands of patients who had signs and symptoms suggesting ulnar neuropathy at elbow and 94 healthy hands as the control group. RESULTS: Mean ulnar nerve residual latency for case and control groups were 1.82 +/- 0.45 and 1.59 +/- 0.54 ms, respectively, which showed a statistically significant difference (P = 0.01). There was no significant difference in mean ulnar nerve residual latency between males and females and also between right and left hands (P > 0.05). By considering different cut-off points, the sensitivity and specificity of a residual latency of 2.86 ms were 70% and 56%, respectively. CONCLUSION: Ulnar nerve residual latency may reflect the effects of an axonal injury at elbow on distal ulnar motor fibers. So, its measurement may help in the diagnosis of ulnar neuropathy at elbow. PMID- 25709987 TI - Geranisetron versus gabapentin in preventing postoperative nausea and vomiting after middle ear surgery in adults: A double-blinded randomized clinical trial study. AB - BACKGROUND: The incidence of postoperative nausea and vomiting (PONV) after middle ear surgery is high. In this study we want to compare the effects of intravenous granisetron and oral gabapentin as a premedication before surgery on the incidence and severity of PONV after middle ear surgery in adult patents. MATERIALS AND METHODS: We enrolled 90 patients that were randomly divided into the three groups of 30 in each. Group I received granisetron 3 mg iv 2 minutes before induction of anesthesia; Group II received oral gabapentin 300 mg 1 hour before anesthesia and Group III received placebo. The incidence and severity of PONV were recorded each 15 minutes in the post-anesthesia care unit (PACU) and each 8 hours until 24 hours after discharge from the PACU. RESULT: The incidence and severity of nausea and vomiting at different time intervals in Groups I and Group II was significantly lower compared with Group III (P < 0.05). There was no significant difference in the incidence of side effects of study drug administration including respiratory depression, apnea, extra pyramidal disorders, drowsiness, dizziness, vertigo and headache in three groups. CONCLUSION: The study was shown that using gabapentin and granisetron have equal anti-emetic effects, but significant differences were seen between these two groups compared to the control group. These submit the efficiency of these drugs in preventing PONV. PMID- 25709988 TI - Prevalence of different hip sonographic types: A cross-sectional study. AB - BACKGROUND: Developmental dysplasia of the hip (DDH) is an anatomical abnormality, which needs early detection and treatment. Ultrasound (US) is a sensitive method to study neonatal hip joint and detection of different types of sonographic hip. This study was aimed to determine relative frequency of different types of DDH ultrasonographically. MATERIALS AND METHODS: Ultrasound examination was performed on 380 newborns to determine hip joint status according to the Graf ultrasound classification system for infant hips. In addition, hip joint status was compared based on the hip side, gender, and method of delivery. RESULTS: In this study, we observed three sonographic types: Ia (74%), type Ib (20%), and IIa (6%). No significant difference was found in relative frequency of different types of DDH regarding the side of the hip (P = 0.18). Type IIa was found significantly more in the female newborns (P < 0.0001) and in newborns who were born by cesarean section (P < 0.0001). CONCLUSION: This study supports the role of US detection of different types of DDH; however, the frequency of pathologic types of hip sonography is 6%. PMID- 25709989 TI - Mismanagement of a hypochondriacal patient. AB - Hypochondriasis is a persistent preoccupation that despite appropriate medical evaluations and assurance of patient's physical health, the patient insists on having a serious disease. The case which is discussed in this article is a 39 years-old woman that hospitalized for half of her life and no one can perceive her disorder according to her assertions. The mentioned case is a "difficult patient" with fear of oxygen shortage and being choked (Pnigophobia) which leads to continuous tendency to wear oxygen device even during sleep. There is no benefit in exaggerating her condition for herself so there is no fictitious disorder considered. During the therapy she has been assured that she does not have a serious disease and she has learnt to decrease oxygen intake and breath with his mouth. The point that makes this study different from the others is that most of hypochondriacal patients have a fear of getting HIV, cancers, hepatitis and MS but our patient has phobia of pulmonary embolism. PMID- 25709990 TI - Persistence of endothelial cell damage late after Kawasaki disease in patients without coronary artery complications. AB - BACKGROUND: Recent studies proposed an increased risk of atherosclerosis in patients with a history of Kawasaki disease. This study aimed to investigate the persistence of vascular injury after an acute phase of the Kawasaki disease. MATERIALS AND METHODS: We determined the number of circulating endothelial cells (CEC) in the peripheral blood of 13 patients with a history of Kawasaki disease within four to ten years, in comparison with 13 healthy relative controls. The CECs were counted as CD146+/CD34 + cells by the standard flow cytometry technique, and the independent t-test was employed to compare the mean number of CECs in the two groups. RESULTS: The mean number of CECs was significantly higher in patients than in controls (12 +/- 3.03 vs. 2.38 +/- 0.87, respectively, P < 0.001). CONCLUSION: This study elucidates the persistence of vascular injury late after Kawasaki disease. This finding suggests that prolonged administration of vascular anti-inflammatory agents might be beneficial for preventing atherosclerosis in the subsequent years, in these patients. PMID- 25709991 TI - Correlation of serological markers and platelet count in the diagnosis of Dengue virus infection. AB - BACKGROUND: The dengue virus causes one of the most important mosquito-borne viral diseases. Annually, it affects up to 100 million people. Detection of the secreted NS1 protein represents a new approach to the diagnosis of acute dengue infection. Platelet count is the only non-dengue parameter that can support the diagnosis of the dengue shock syndrome (DSS) and dengue hemorrhagic fever (DHF). This study was done to correlate the platelet count and dengue parameters detected by the immunochromatographic test (ICT). MATERIALS AND METHODS: Serum samples collected from patients presenting with dengue-like illness and for whom an anti-dengue antibody test was requested between August 2010 and August 2012, were included in this study. A total of 520 serum samples were collected from the suspected dengue fever patients. The samples were tested for NS1 antigen, IgM, and IgG antibodies, using the ICT kit. The platelet count was recorded in dengue parameter-positive and -negative cases. RESULTS: A total of 520 serum samples were collected from the suspected dengue fever patients. Sixty-two samples tested positive for one or more dengue-specific parameters. Out of the 62 samples, 39 (62.9%) were positive for the NS1 antigen, only seven (11.3%) were positive for IgM, and only three (4.9%) were positive for IgG. A platelet count < 1,00,000/ml was observed in 32 cases (51.6%). When the platelet count was done in 100 dengue parameter-negative fever patients (controls), thrombocytopenia was observed in 30% of the cases. CONCLUSION: Association of thrombocytopenia in dengue parameter positive cases was highly significant (Z = 2.76, P = 0.006) when compared to thrombocytopenia in dengue parameter-negative patients. PMID- 25709992 TI - The profile of hypertension and dyslipidemia in prediabetic subjects; results of the Isfahan Diabetes Prevention program: A large population-based study. AB - BACKGROUND: The present study was designed to evaluate hypertension and dyslipidemia in prediabetic subjects with a family history of type 2 diabetes (first-degree relatives), and they were compared with the normal glucose tolerance subjects. MATERIALS AND METHODS: Three thousand and eighty-six (788 men and 2298 women) subjects were selected from a consecutive sample of patients with Impaired Glucose Tolerance (IGT), Impaired Fasting Glucose (IFG), and Combined (IFG and IGT), and their first-degree relatives formed the control group. Potential risk factors for diabetes including age, gender, body size, HbA1c, cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides, blood pressure (BP), urine microalbumin, and family and personal medical history were assessed. RESULTS: The studied participants included 300 IGT patients (9.7%), 625 IFG patients (44.9%), 411 combined patients (13.3%), and 1750 (56.7%) normal subjects. Aging led to increase in hypertension. Increase in body mass index (BMI) led to an increase in the prevalence of hypertension significantly in all groups. The mean triglyceride in the normal group was different in comparison with that of the IGT (P < 0.05) and combined (P < 0.001) groups. Differences in total cholesterol were observed in the normal group when compared with the IGT (P < 0.05) and combined (P < 0.001) groups, and of the combined group in comparison with the IGT (P < 0.05) group. The difference in LDL level was related to the combined group in comparison with IGT, marginally (P < 0.1), and normal in comparison with the combined group (P < 0.05). CONCLUSION: Prevalence of hypertension was not significantly different between the groups, however, in prediabetic patients it was higher than in the normal group, and prevalence of dyslipidemia in prediabetic subjects was significantly higher than in the normal group. PMID- 25709993 TI - A comparative study of one minute versus five seconds endoscopic biliary balloon dilation after small sphincterotomy in choleducolithiasis. AB - BACKGROUND: Limited sphincterotomy and endoscopic papillary balloon dilation (EPBD) is a low-risk method for the treatment of choleducolithiasis. Traditionally one minute ballooning time (BT) is applied; however, the effective BT is not clear. In this study, we compare five seconds and one minute ballooning time. MATERIALS AND METHODS: In this single-blind, randomized, clinical trial 60 patients with common bile duct (CBD) stones documented in ultrasonography or magnetic resonance cholangiopancreatography (MRCP), with no severe hepatic, biliary or systemic diseases, enrolled in the study. The patients were randomly assigned to receive EPBD with either five seconds (n = 31) or one minute (n = 29) ballooning time (BT) after endoscopic retrograde cholangiopancreatography (ERCP) and small sphincterotomy. Then stones were retrieved with an extractor balloon. The patients were followed for 48 hours to check the possible complications. RESULTS: Successful CBD stone removal was the same in the five-second and one minute BT groups (93.5% vs. 96.6%; P = 0.594). Pancreatitis occurred in three (9.7%) patients in the five-second BT group and in six (20.7%) patients in the one-minute BT group (P = 0.233). No hemorrhage or perforation was noted. CONCLUSIONS: After a small sphincterotomy, EPBD in the five-second and one-minute BT groups had a similar efficacy. Small sphincterotomy combined with very short BT is a safe and effective method for CBD stone removal. PMID- 25709994 TI - Histomorphometric effects of gemcitabine on Swiss albino mice spermatogenesis. AB - BACKGROUND: Spermatogenesis is a highly conserved and regulated process and it is sensitive to fluctuations in the physical and chemical environment. Gemcitabine is a novel antimetabolic anticancer drug used frequently in the treatment of many cancers. This study aimed to investigate the histomorphometric effects of gemcitabine on spermatogenesis in Swiss albino mice. MATERIALS AND METHODS: Gemcitabine in high and low doses (80 and 40 mg/kg) injected intraperitoneally to inbred Swiss albino mice. Gross testicular features and seminiferous tubular histomorphometry was studies at the end of 7(th), 14(th) day and at 2 months sperm shape abnormalities were studied. RESULTS: Seminiferous tubular morphology was altered significantly, showing a reduction in height, perimeter and area in a dose dependent manner. Sertoli cell number decreased. Basement membrane thickness was reduced and it appeared to be permanent, with statistically insignificant changes even after 2 months. There was a reduction of intertubular spaces. Sperms have shown banana heading, decapitation and loss of normal hook of head. The effects were partially reversible at the end of 2 months. CONCLUSION: It was concluded that gemcitabine affects the process of spermatogenesis adversely in a dose and time dependent manner and the effects are partially reversible. PMID- 25709995 TI - Case report of the bronchioloalveolar carcinoma. AB - Bronchioloalveolar carcinoma is a form of adenocarcinoma. Its clinical presentation spans the entire spectrum from asymptomatic solitary pulmonary nodule to full presentation with cough, hemoptysis and dyspnea. Clinical symptoms usually are in correlation with the extent of disease. The case we present here is a patient in late stage of disease with few symptoms regarding to the extent of disease involvement. PMID- 25709996 TI - A comparison of cell-free placental messenger ribonucleic acid and color Doppler ultrasound for the prediction of placental invasion in patients with placenta accreta. AB - BACKGROUND: The aim of the present study was to comparison between cell-free placental messenger ribonucleic acid (mRNA) and Doppler ultrasound for the prediction of placental invasion in women with placenta accreta. MATERIALS AND METHODS: In this cross-sectional study, 50 pregnant women at risk for placenta accreta underwent color Doppler and assessment of cell-free placental mRNA. Real time reverse-transcription polymerase chain reaction was used for measurement of cell-free placental mRNA in maternal plasma. Based on the findings at cesarean delivery and histological examination, patients were divided into two groups of women with and without placenta accrete. To compare of the mean of mRNA levels between the two groups we used independent t-test and to compare of the mean of age and gestational age at sonography we used Mann-Whitney test. For determination of sensitivity and specificity and the cut-off point of mRNA levels we used the receiver operating characteristic curve. RESULTS: A total of 50 women with a mean age of 30.24 +/- 4.905 years entered the study and 12 (24%) patients were diagnosed with placenta accreta. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of Doppler ultrasound were 83.3%, 78.9%, 56% and 94%, respectively. Results of our study showed if we consider a cut-off point equal to 3.325, with sensitivity and specificity of 0.917 and 0.789, respectively and the sensitivity, specificity, PPV and NPV of mRNA with were cut-off point of 3.325 were 91.7%, 78.9%, 57.9% and 96.8%, respectively. CONCLUSIONS: Cell-free mRNA is an acceptable, easy made, functional test with sensitivity, specificity, PPV and NPV more than Doppler ultrasound for diagnosis and prediction of incidence of placenta accrete and we recommend the use of cell-free mRNA test for diagnosis of placenta accreta. PMID- 25709997 TI - Design and development of intraocular polymeric implant systems for long-term controlled-release of clindamycin phosphate for toxoplasmic retinochoroiditis. AB - BACKGROUND: The release of the anti-toxoplasmosis drug, clindamycin phosphate, from intraocular implants of the biodegradable polymers poly (D, L-lactic acid) (PLA) and poly (D, L-lactide-co-glycolide) (PLGA) has been studied in vitro. MATERIALS AND METHODS: The preparation of the implants was performed by a melt extrusion method. The developed extrudates were characterized and compared in in vitro release profiles for elucidating the drug release mechanism. The formulations containing up to 40% w/w of drug were prepared. Release data in phosphate buffer (pH 7.4) were analyzed by high performance liquid chromatography. The release kinetics were fitted to the zero-order, Higuchi's square-root, first order and the Korsmeyer-Peppas empirical equations for the estimation of various parameters of the drug release curves. Degradation of implants was also investigated morphologically with time (Scanning Electron Microscopy). RESULTS: It was observed that, the release profiles for the formulations exhibit a typical biphasic profile for bulk-eroding systems, characterized by a first phase of burst release (in first 24 hrs), followed by a phase of slower release. The duration of the secondary phase was found to be proportional to the molecular weight and monomer ratio of copolymers and also polymer-to-drug ratios. It was confirmed that Higuchi and first-order kinetics were the predominant release mechanisms than zero order kinetic. The Korsmeyer Peppas exponent (n) ranged between 0.10 and 0.96. This value, confirmed fickian as the dominant mechanism for PLA formulations (n <= 0.45) and the anomalous mechanism, for PLGAs (0.45 < n < 0.90). CONCLUSION: The implant of PLA (I.V. 0.2) containing 20% w/w of clindamycin, was identified as the optimum formulation in providing continuous efficient in-vitro release of clindamycin for about 5 weeks. PMID- 25709998 TI - Antihyperglycemic and antihyperlipidemic effects of hydroalcoholic extract of Securigera securidaca seeds in streptozotocin-induced diabetic rats. AB - BACKGROUND: Hyperlipidemia is an associated complication of diabetes mellitus. Lowering of serum lipid levels seems to be associated with a decrease in the risk of vascular disease and related complications. The purpose of the current study was to evaluate the antihyperglycemic and antihyperlipidemic effects of the hydroalcoholic extract of Securigera securidaca seeds in streptozotocin-induced diabetic rats. MATERIALS AND METHODS: Female Wistar rats were randomly divided into four groups as follows: Control, diabetic, and diabetic rats treated with the Securigera extract at doses of 100 and 200 mg/kg. The animals were rendered diabetic by a single intraperitoneal injection of 55 mg/kg streptozotocin. Diabetic rats received the Securigera extract daily in drinking water from the day on which diabetes was confirmed for 4 weeks. The levels of serum glucose and lipids were spectrophotometrically measured in all groups at weeks 0 (before diabetes induction), 2, and 4. RESULTS: The results showed that there was a significant increase in serum glucose, triglycerides, total cholesterol, and low density lipoprotein (LDL)-cholesterol in streptozotocin-induced diabetic rats, accompanied by a decrease in high density lipoprotein (HDL)-cholesterol. Treatment of diabetic rats with S. securidaca seed extract at a dose of 200 mg/kg over a 4-week period significantly reduced the levels of serum glucose, total cholesterol, and LDL-cholesterol and increased the level of HDL-cholesterol, compared to diabetic untreated rats. CONCLUSIONS: Securigera extract at a dose of 200 mg/kg exhibited hypoglycemic and hypolipidemic activities in streptozotocin diabetic rats during the 4-week treatment period. This provides a valid scientific basis for using it in the treatment of diabetes in Iranian folk medicine. PMID- 25709999 TI - Anthropometric predictive equations for estimating body composition. AB - BACKGROUND: Precise and accurate measurements of body composition are useful in achieving a greater understanding of human energy metabolism in physiology and in different clinical conditions, such as, cardiovascular disease and overall mortality. Dual-energy x-ray absorptiometry (DXA) can be used to measure body composition, but the easiest method to assess body composition is the use of anthropometric indices. This study has been designed to evaluate the accuracy and precision of body composition prediction equations by various anthropometric measures instead of a whole body DXA scan. MATERIALS AND METHODS: We identified 143 adult patients underwent DXA evaluation of the whole body. The anthropometric indices were also measured. Datasets were split randomly into two parts. Multiple regression analysis with a backward stepwise elimination procedure was used as the derivation set and then the estimates were compared with the actual measurements from the whole-body scans for a validation set. The SPSS version 20 for Windows software was used in multiple regression and data analysis. RESULTS: Using multiple linear regression analyses, the best equation for predicting the whole-body fat mass (R(2) = 0.808) included the body mass index (BMI) and gender; the best equation for predicting whole-body lean mass (R(2) = 0.780) included BMI, WC, gender, and age; and the best equation for predicting trunk fat mass (R(2) = 0.759) included BMI, WC, and gender. CONCLUSIONS: Combinations of anthropometric measurements predict whole-body lean mass and trunk fat mass better than any of these single anthropometric indices. Therefore, the findings of the present study may be used to verify the results in patients with various diseases or diets. PMID- 25710000 TI - Wireless magnetoelastic sensors for tracking degradation profiles of nitrodopamine-modified poly(ethylene glycol). AB - A critical property for tissue adhesives is a controllable degradation rate so that these adhesives do not act as barriers to wound healing. Typical degradation tests require large amount of samples, which can be tedious and expensive to perform. Additionally, current degradation tests are carried out in vitro under simulated physiological conditions and may not accurately reflect the complex environment that an adhesive would experience in vivo. As a means to develop a simple technique for testing tissue adhesive, a rapidly degrading adhesive hydrogel that mimics mussel adhesive proteins was coated onto magnetoelastic (ME) sensor strips to track the degradation of the adhesive remotely and in real time. Adhesive-coated ME sensors were submerged in phosphate buffer saline solution (pH 7.4) at body temperature (37 degrees C). Based on the change in the resonant amplitude, the degradation time was determined to be 22 min, which was in agreement with qualitative monitoring of the bulk adhesive hydrogel. Additionally, when the adhesive-coated ME sensor was incubated in a slightly acidic medium (pH 5.7), the degradation rate was drastically lengthened (3 hrs) as the hydrolysis of ester bonds is faster under basic conditions. Oscillatory rheological testing confirmed the formation and degradation of the adhesive. However, rheological test results did not accurately reflect the degradation rate of the adhesive hydrogel, potentially due to a slow exchange of acidic degradation products with the surrounding medium. ME sensor was demonstrated as a potential useful tool for evaluating the degradation rate of bioadhesives. PMID- 25710001 TI - Searching and Indexing Genomic Databases via Kernelization. AB - The rapid advance of DNA sequencing technologies has yielded databases of thousands of genomes. To search and index these databases effectively, it is important that we take advantage of the similarity between those genomes. Several authors have recently suggested searching or indexing only one reference genome and the parts of the other genomes where they differ. In this paper, we survey the 20-year history of this idea and discuss its relation to kernelization in parameterized complexity. PMID- 25710003 TI - Immunodiagnosis of canine visceral leishmaniasis using mimotope peptides selected from phage displayed combinatorial libraries. AB - ELISA and RIFI are currently used for serodiagnosis of canine visceral leishmaniasis (CVL). The accuracy of these tests is controversial in endemic areas where canine infections by Trypanosoma cruzi may occur. We evaluated the usefulness of synthetic peptides that were selected through phage display technique in the serodiagnosis of CVL. Peptides were chosen based on their ability to bind to IgGs purified from infected dogs pooled sera. We selected three phage clones that reacted only with those IgGs. Peptides were synthesized, polymerized with glutaraldehyde, and used as antigens in ELISA assays. Each individual peptide or a mix of them was reactive with infected dogs serum. The assay was highly sensitive and specific when compared to soluble Leishmania antigen that showed cross-reactivity with anti-T. cruzi IgGs. Our results demonstrate that phage display technique is useful for selection of peptides that may represent valuable synthetic antigens for an improved serodiagnosis of CVL. PMID- 25710002 TI - Body composition indices and predicted cardiovascular disease risk profile among urban dwellers in Malaysia. AB - OBJECTIVES: This study aims to compare various body composition indices and their association with a predicted cardiovascular disease (CVD) risk profile in an urban population in Kuala Lumpur, Malaysia. METHODS: A cross-sectional survey was conducted in metropolitan Kuala Lumpur, Malaysia, in 2012. Households were selected using a simple random-sampling method, and adult members were invited for medical screening. The Framingham Risk Scoring algorithm was used to predict CVD risk, which was then analyzed in association with body composition measurements, including waist circumference, waist-hip ratio, waist-height ratio, body fat percentage, and body mass index. RESULTS: Altogether, 882 individuals were included in our analyses. Indices that included waist-related measurements had the strongest association with CVD risk in both genders. After adjusting for demographic and socioeconomic variables, waist-related measurements retained the strongest correlations with predicted CVD risk in males. However, body mass index, waist-height ratio, and waist circumference had the strongest correlation with CVD risk in females. CONCLUSIONS: The waist-related indicators of abdominal obesity are important components of CVD risk profiles. As waist-related parameters can quickly and easily be measured, they should be routinely obtained in primary care settings and population health screens in order to assess future CVD risk profiles and design appropriate interventions. PMID- 25710004 TI - Impairment of neutrophil migration to remote inflammatory site during lung histoplasmosis. AB - Histoplasma capsulatum (Hc) induces a pulmonary disease in which leukotrienes promote activation and recruitment of effectors cells. It is also well-recognized that leukotriene B4 (LTB4) and platelet-activating factor (PAF) induce leukocyte recruitment to inflammatory sites. We investigated the impact of pulmonary Hc infection on PMN migration to a remote inflammatory site. Our results show that pulmonary Hc infection impairs LTB4- or PAF-stimulated PMN recruitment to air pouch. Yet, remote inflammation did not modify PMN numbers in the bronchoalveolar lavage fluid (BALF) of Hc-infected mice. Interestingly, the concomitant administration of PAF and LTB4 receptor antagonists inhibited PMN recruitment to both BALF and the remote site, demonstrating cooperation between both mediators. Along that line, our results show that PAF-elicited PMN chemotaxis was abrogated in 5-lipoxygenase-deficient animals. These results suggest caution in the indiscriminate use of anti-inflammatory drugs during infectious diseases. PMID- 25710005 TI - Association of polymorphisms in X-ray repair cross complementing 1 gene and risk of esophageal squamous cell carcinoma in a Chinese population. AB - OBJECTIVES: To investigate the association between three single nucleotide polymorphisms (SNPs) in the X-ray repair cross complementing 1 gene (XRCC1) and the risk of esophageal squamous cell carcinoma (ESCC) in Chinese population. METHODS: A case-control study including 381 primary ESCC patients recruited from hospital and 432 normal controls matched with patients by age and gender from Chinese Han population was conducted. The genotypes of three XRCC1 polymorphisms at -77T>C (T-77C), codon 194 (Arg194Trp), and codon 399 (Arg399Gln) were studied by means of polymerase chain reaction-restriction fragment length polymorphism techniques (PCR-RFLP). Unconditional logistic regression model and haplotype analysis were used to estimate associations of these three SNPs in XRCC1 gene with ESCC risk. RESULTS: Polymorphisms at these three sites in XRCC1 gene were not found to be associated with risk for developing ESCC; however the haplotype C(codon 194)G(codon 399)C(-77T>C) was significantly associated with reduced risk of ESCC (OR: 0.62, 95% CI: 0.40-0.96) upon haplotype analysis. CONCLUSION: These results suggested that the gene-gene interactions might play vital roles in the progression on esophageal cancer in Chinese Han population and it would be necessary to confirm these findings in a large and multiethnic population. PMID- 25710006 TI - Locus of enterocyte effacement: a pathogenicity island involved in the virulence of enteropathogenic and enterohemorragic Escherichia coli subjected to a complex network of gene regulation. AB - The locus of enterocyte effacement (LEE) is a 35.6 kb pathogenicity island inserted in the genome of some bacteria such as enteropathogenic Escherichia coli, enterohemorrhagic E.coli, Citrobacter rodentium, and Escherichia albertii. LEE comprises the genes responsible for causing attaching and effacing lesions, a characteristic lesion that involves intimate adherence of bacteria to enterocytes, a signaling cascade leading to brush border and microvilli destruction, and loss of ions, causing severe diarrhea. It is composed of 41 open reading frames and five major operons encoding a type three system apparatus, secreted proteins, an adhesin, called intimin, and its receptor called translocated intimin receptor (Tir). LEE is subjected to various levels of regulation, including transcriptional and posttranscriptional regulators located both inside and outside of the pathogenicity island. Several molecules were described being related to feedback inhibition, transcriptional activation, and transcriptional repression. These molecules are involved in a complex network of regulation, including mechanisms such as quorum sensing and temporal control of LEE genes transcription and translation. In this mini review we have detailed the complex network that regulates transcription and expression of genes involved in this kind of lesion. PMID- 25710007 TI - Calcium channel expression and applicability as targeted therapies in melanoma. AB - The remodeling of Ca(2+) signaling is a common finding in cancer pathophysiology serving the purpose of facilitating proliferation, migration, or survival of cancer cells subjected to stressful conditions. One particular facet of these adaptive changes is the alteration of Ca(2+) fluxes through the plasma membrane, as described in several studies. In this review, we summarize the current knowledge about the expression of different Ca(2+) channels in the plasma membrane of melanoma cells and its impact on oncogenic Ca(2+) signaling. In the last few years, new molecular components of Ca(2+) influx pathways have been identified in melanoma cells. In addition, new links between Ca(2+) homeostasis and specific cell processes important in melanoma tumor progression have been unveiled. Thus, not only do Ca(2+) channels appear to have a potential as prognostic markers, but their pharmacological blockade or gene silencing is hinted as interesting therapeutic approaches. PMID- 25710008 TI - Differential regulation of microRNAs in end-stage failing hearts is associated with left ventricular assist device unloading. AB - Mechanical unloading by left ventricular assist devices (LVADs) in advanced heart failure (HF), in addition to improving symptoms and end-organ perfusion, is supposed to stimulate cellular and molecular responses which can reverse maladaptive cardiac remodeling. As microRNAs (miRNAs) are key regulators in remodeling processes, a comparative miRNA profiling in transplanted hearts of HF patients with/without LVAD assistance could aid to comprehend underlying molecular mechanisms. Next generation sequencing (NGS) was used to analyze miRNA differential expression in left ventricles of HF patients who underwent heart transplantation directly (n = 9) or following a period of LVAD support (n = 8). After data validation by quantitative real-time PCR, association with functional clinical parameters was investigated. Bioinformatics' tools were then used for prediction of putative targets of modulated miRNAs and relative pathway enrichment. The analysis revealed 13 upregulated and 10 downregulated miRNAs in failing hearts subjected to LVAD assistance. In particular, the expression level of some of them (miR-338-3p, miR-142-5p and -3p, miR-216a-5p, miR-223-3p, miR-27a 5p, and miR-378g) showed correlation with off-pump cardiac index values. Predicted targets of these miRNAs were involved in focal adhesion/integrin pathway and in actin cytoskeleton regulation. The identified miRNAs might contribute to molecular regulation of reverse remodeling and heart recovery mechanisms. PMID- 25710009 TI - High pressure air jet in the endoscopic preparation room: risk of noise exposure on occupational health. AB - After high-level disinfection of gastrointestinal endoscopes, they are hung to dry in order to prevent residual water droplets impact on patient health. To allow for quick drying and clinical reuse, some endoscopic units use a high pressure air jet (HPAJ) to remove the water droplets on the endoscopes. The purpose of this study was to evaluate the excessive noise exposure with the use of HPAJ in endoscopic preparation room and to investigate the risk to occupational health. Noise assessment was taken during 7 automatic endoscopic reprocessors (AERs) and combined with/without HPAJ use over an 8-hour time weighted average (TWA). Analytical procedures of the NIOSH and the ISO for noise induced hearing loss were estimated to develop analytic models. The peak of the noise spectrum of combined HPAJ and 7 AERs was significantly higher than that of the 7 AERs alone (108.3 +/- 1.36 versus 69.3 +/- 3.93 dBA, P < 0.0001). The risk of hearing loss (HL > 2.5 dB) was 2.15% at 90 dBA, 11.6% at 95 dBA, and 51.3% at 100 dBA. The odds ratio was 49.1 (95% CI: 11.9 to 203.6). The noise generated by the HPAJ to work over TWA seriously affected the occupational health and safety of those working in an endoscopic preparation room. PMID- 25710011 TI - Flail chest in polytraumatized patients: surgical fixation using Stracos reduces ventilator time and hospital stay. AB - OBJECTIVES: Conservative management of patients with flail chest is the treatment of choice. Rib fracture repair is technically challenging; however, with the advent of specially designed molding titanium clips, surgical management has been simplified. Surgical stabilization has been used with good outcomes. We are reporting on our institutional matched-case-control study. METHODS: Between April 2010 and April 2011, ten polytraumatized patients undergoing rib stabilization for flail chest were matched 1 : 1 to 10 control patients by age +/-10 years, sex, neurological or vertebral trauma, abdominal injury, and arm and leg fractures. Surgery was realized in the first 48 hours. RESULTS: There were no significant differences between groups for matched data and prognostic scores: injury severity score, revised trauma score, and trauma injury severity score. Ventilator time (142 +/- 224 versus 74 +/- 125 hours, P = 0.026) and overall hospital stay (142 +/- 224 versus 74 +/- 125 hours, P = 0.026) were significantly lower for the surgical group after adjustment on prognostic scores. There was a trend towards shorter ICU stay for operative patients (12.3 +/- 8.5 versus 9.0 +/ 4.3 days, P = 0.076). CONCLUSIONS: Rib fixation with Stracos is feasible and decreases the length of ventilation and hospital stay. A multicenter randomized study is warranted so as to confirm these results and to evaluate impact on pulmonary function status, pain, and quality of life. PMID- 25710010 TI - The intergenerational effects on birth weight and its relations to maternal conditions, Sao Paulo, Brazil. AB - BACKGROUND AND OBJECTIVES: Parents' birth weight acts as a predictor for the descendant birth weight, with the correlation more strongly transmitted through maternal line. The present research aims to study the correlation between the child's low or increased birth weight, the mother's birth weight, and maternal conditions. METHODS: 773 mother-infant binomials were identified with information on both the baby's and the mother's birth weight recorded. Group studies were constituted, dividing the sample according to birth weight (<2,500 grams (g) and >=3,500 grams (g)). The length at birth was also studied in children <=47.5 cm (lower quartile). Chi(2) test or Fisher's exact test, Spearman's Rho, and odds ratio were performed in order to investigate the relation between the children's weight and length at birth and the mothers' and children's variables. RESULTS: The girls were heavier at birth than their mothers, with an average increase at birth weight between the generations of 79 g. The child's birth weight <2,500 g did not show any correlation with maternal birth weight <2,500 g (Fisher 0.264; Spearman's Rho 0.048; OR 2.1 and OR lower 0.7) or with maternal stature below the lower quartile (<157 cm) (Chi (2) sig 0.323; with Spearman's Rho 0.036; OR 1.5 and OR lower 0.7). The child's low birth weight (<2,500 g) was lightly correlated with drug use by the mother during pregnancy (Fisher 0.083; Spearman's Rho 0.080; OR 4.9 and OR lower 1.0). The child's birth weight <2,500 g showed increased correlation with gestational age lower than 38 weeks and 3 days (Chi (2) sig 0.002; Spearman's Rho 0.113; OR 3.2 and OR lower 1.5). The child's weight at birth >=3,500 g showed strong correlation with maternal weight at birth >=3,500 g (Chi (2) sig 0; Spearman's Rho +0.142; OR 0.5 and OR upper 0.7). It was also revealed that the higher the maternal prepregnancy BMI, the stronger the correlation with child's birth weight >=3,500 g ((maternal prepregnancy BMI > 25.0 with Chi (2) sig 0.013; Spearman's Rho 0.09; OR 1.54 and OR upper 2.17) and (maternal prepregnancy BMI > 30.0 with Chi (2) sig 0 Spearman's Rho 0.137; OR 2.58 and OR upper 4.26)). The child's length at birth in the lower quartile (<=47.5 cm) showed strong correlation with drug use by the mother during pregnancy (Chi (2) sig 0.004; Spearman's Rho 0.105; OR 4.3 and OR lower 1.5). CONCLUSIONS: The mother's increased weight at birth and the prenatal overweight or obesity were correlated with increased weight and length at birth of the newborn, coupled with the tendency of increasing birth weight between generations of mothers and daughters. Also, descendants with smaller length at birth are the children of women with the lowest statures. PMID- 25710012 TI - Detection of human cytomegalovirus in different histopathological types of glioma in Iraqi patients. AB - Human Cytomegalovirus (HCMV) is an endemic herpes virus that reemerges in cancer patients enhancing oncogenic potential. HCMV infection is associated with certain types of cancer morbidity such as glioblastomas. HCMV, like all other herpes viruses, has the ability to remain latent within the body of the host and can contribute in chronic inflammation. To determine the role of HCMV in glioma pathogenesis, paraffin-embedded blocks from glioma patients (n = 50) and from benign meningioma patients (n = 30) were obtained and evaluated by immunohistochemistry and polymerase chain reaction for the evidence of HCMV antigen expression and the presence of viral DNA. We detected HCMV antigen and DNA for IEI-72, pp65, and late antigen in 33/36, 28/36, and 26/36 in glioblastoma multiforme patients whereas 12/14, 10/14, and 9/14 in anaplastic astrocytoma patients, respectively. Furthermore, 84% of glioma patients were positive for immunoglobulin G (IgG) compared to 72.5% among control samples (P = 0.04). These data indicate the presence of the HCMV virus in a high percentage of glioma samples demonstrating distinct histopathological grades and support previous reports showing the presence of HCMV infection in glioma tissue. These studies demonstrate that detection of low-levels of latent viral infections may play an active role in glioma development and pathogenesis. PMID- 25710013 TI - Predictive value of interim PET/CT in DLBCL treated with R-CHOP: meta-analysis. AB - OBJECTIVE: We conducted a meta-analysis to evaluate the predictive value of interim (18)F-FDG PET/CT in patients with DLBCL treated with R-CHOP chemotherapy. METHODS: We searched for articles published in PubMed, ScienceDirect, Wiley, Scopus, and Ovid database from inception to March 2014. Articles related to interim PET/CT in patients with DLBCL treated with R-CHOP chemotherapy were selected. PFS with or without OS was chosen as the endpoint to evaluate the prognostic significance of interim PET/CT. RESULTS: Six studies with a total of 605 cases were included. The sensitivity of interim PET/CT ranged from 21.2% to 89.7%, and the pooled sensitivity was 52.4%. The specificity of interim PET/CT ranged from 37.4% to 90.7%, and the pooled specificity was 67.8%. The pooled positive likelihood ratio and negative likelihood ratio were 1.780 and 0.706, respectively. The explained AUC was 0.6978 and the Q* was 0.6519. CONCLUSIONS: The sensitivity and specificity of interim PET/CT in predicting the outcome of DLBCL patients treated with R-CHOP chemotherapy were not satisfactory (52.4% and 67.8%, resp.). To improve this, some more work should be done to unify the response criteria and some more research to assess the prognostic value of interim PET/CT with semiquantitative analysis. PMID- 25710014 TI - Multiple sclerosis increases fracture risk: a meta-analysis. AB - PURPOSE: The association between multiple sclerosis (MS) and fracture risk has been reported, but results of previous studies remain controversial and ambiguous. To assess the association between MS and fracture risk, a meta analysis was performed. METHOD: Based on comprehensive searches of the PubMed, Embase, and Web of Science, we identified outcome data from all articles estimating the association between MS and fracture risk. The pooled risk ratios (RRs) with 95% confidence intervals (CIs) were calculated. RESULTS: A significant association between MS and fracture risk was found. This result remained statistically significant when the adjusted RRs were combined. Subgroup analysis stratified by the site of fracture suggested significant associations between MS and tibia fracture risk, femur fracture risk, hip fracture risk, pelvis fracture risk, vertebrae fracture risk, and humerus fracture risk. In the subgroup analysis by gender, female MS patients had increased fracture risk. When stratified by history of drug use, use of antidepressants, hypnotics/anxiolytics, anticonvulsants, and glucocorticoids increased the risk of fracture risk in MS patients. CONCLUSIONS: This meta-analysis demonstrated that MS was significantly associated with fracture risk. PMID- 25710015 TI - The osteogenic properties of multipotent mesenchymal stromal cells in cultures on TiO2 sol-gel-derived biomaterial. AB - The biocompatibility of the bone implants is a crucial factor determining the successful tissue regeneration. The aim of this work was to compare cellular behavior and osteogenic properties of rat adipose-derived multipotent stromal cells (ASCs) and bone marrow multipotent stromal cells (BMSCs) cultured on metallic substrate covered with TiO2 sol-gel-derived nanolayer. The morphology, proliferation rate, and osteogenic differentiation potential of both ASCs and BMSCs propagated on the biomaterials were examined. The potential for osteogenic differentiation of ASCs and BMSCs was determined based on the presence of specific markers of osteogenesis, that is, alkaline phosphatase (ALP), osteopontin (OPN), and osteocalcin (OCL). Additionally, the concentration of calcium and phosphorus in extracellular matrix was determined using energy dispersive X-ray spectroscopy (SEM-EDX). Obtained results showed that TiO2 layer influenced proliferation activity of ASCs, which manifested by shortening of population doubling time and increase of OPN secretion. However, characteristic features of cells morphology and growth pattern of cultures prompted us to conclude that ultrathin TiO2 layer might also enhance osteodifferentiation of BMSCs. Therefore in our opinion, both populations of MSCs should be used for biological evaluation of biomaterials compatibility, such results may enhance the area of investigations related to regenerative medicine. PMID- 25710016 TI - Studies on molecular characterizations of the outer membrane proteins, lipids profile, and exopolysaccharides of antibiotic resistant strain Pseudomonas aeruginosa. AB - Susceptibility of the tested Pseudomonas aeruginosa strain to two different antibiotics, tetracycline (TE) and ciprofloxacin (CIP), was carried out using liquid dilution method. Minimum inhibitory concentrations of TE and CIP were 9.0 and 6.0 mg/100 mL, respectively. Some metabolic changes due to both, the mode of action of TE and CIP on P. aeruginosa and its resistance to high concentrations of antibiotics (sub-MIC) were detected. The total cellular protein contents decreased after antibiotic treatment, while outer membrane protein (OMP) contents were approximately constant for both treated and untreated cells. Sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) analysis of the OMPs for untreated and TE and CIP treated cells indicated that the molecular changes were achieved as; lost in, induction and stability of some protein bands as a result of antibiotics treatment. Five bands (with mol. wt. 71.75, 54.8, 31.72, 28.63, and 20.33 KDa) were stable in both treated and untreated tested strains, while two bands (with mol. wt. 194.8 and 118.3 KDa) were induced and the lost of only one band (with mol. wt. 142.5 KDa) after antibiotics treatment. On the other hand, total lipids and phospholipids increased in antibiotic treated cells, while neutral lipids decreased. Also, there was observable stability in the number of fatty acids in untreated and treated cells (11 fatty acids). The unsaturation index was decreased to 56% and 17.6% in both TE and CIP treatments, respectively. The produced amount of EPSs in untreated cultures of P. aeruginosa was relatively higher than in treated cultures with sub-MICs of TE and CIP antibiotics. It was also observed that the amounts of exopolysaccharides (EPSs) increased by increasing the incubation period up to five days of incubation in case of untreated and antibiotic treated cultures. PMID- 25710017 TI - Ring-oxidative biotransformation and drug interactions of propofol in the livers of rats. AB - Propofol, an intravenous anesthetic agent, is widely used for inducing and maintaining anesthesia during surgical procedures and for sedating intensive care unit patients. In the clinic, rapid elimination is one of the major advantages of propofol. Meanwhile, the biotransformation and drug interactions of propofol in rat livers are still little known. In this study, we evaluated the ring-oxidative metabolism of propofol in phenobarbital-treated rat livers and possible drug interactions. Administration of phenobarbital to male Wistar rats significantly increased levels of hepatic cytochrome P450 (CYP) 2B1/2 and microsomal pentoxyresorufin O-dealkylase (PROD) activity. Analyses by high-performance liquid chromatography and liquid chromatography mass spectroscopy revealed that propofol was metabolized by phenobarbital-treated rat liver microsomes into 4 hydroxypropofol. In comparison, PROD activity and 4-hydroxy-propofol production from propofol metabolism were suppressed by orphenodrine, an inhibitor of CYP2B1/2, and a polyclonal antibody against rat CYP2B1/2 protein. Furthermore, exposure of rats to propofol did not affect the basal or phenobarbital-enhanced levels of hepatic CYP2B1/2 protein. Meanwhile, propofol decreased the dealkylation of pentoxyresorufin by phenobarbital-treated rat liver microsomes in a concentration-dependent manner. Taken together, this study shows that rat hepatic CYP2B1/2 plays a critical role in the ring-oxidative metabolism of propofol into 4-hydroxypropofol, and this anesthetic agent can inhibit CYP2B1/2 activity without affecting protein synthesis. PMID- 25710018 TI - A new mechanism of vitamin C effects on A/FM/1/47(H1N1) virus-induced pneumonia in restraint-stressed mice. AB - It is well known that vitamin C could protect against influenza infection, but little is known about the mechanisms. This study aimed to investigate the influence and possible mechanisms of vitamin C on pneumonia induced by influenza virus in stressed mice. Results showed that restraint stress significantly increased the mortality and the severity of pneumonia in mice caused by A/FM/1/47(H1N1) virus infection, which was attenuated by oral administration of vitamin C (125 and 250 mg/kg). Moreover, vitamin C administration significantly decreased expression of susceptibility genes, including mitochondrial antiviral signaling (MAVS) and interferon regulatory factor 3 (IRF3), and increased expression of NF-kappaB. These work in conjunction to induce type I interferons (IFNs) and elicit innate antiviral response as key factors in RIG-I-mediated signal transduction pathway. The above effects of vitamin C were further found to relate with inhibition of excess CORT synthesis by regulating steroid hydroxylating enzymes in adrenal gland. In conclusion, the protective effects of vitamin C on influenza virus-caused pneumonia might be related to its inhibition of CORT synthesis, which reduces the susceptibility to influenza viral infection in restraint-stressed mice. These findings provide a new mechanism for the effects of vitamin C on influenza virus-induced pneumonia in restraint-stressed mice. PMID- 25710019 TI - Mechanisms linking red blood cell disorders and cardiovascular diseases. AB - The present paper aims to review the main pathophysiological links between red blood cell disorders and cardiovascular diseases, provides a brief description of the latest studies in this area, and considers implications for clinical practice and therapy. Anemia is associated with a special risk in proatherosclerotic conditions and heart disease and became a new therapeutic target. Guidelines must be updated for the management of patients with red blood cell disorders and cardiovascular diseases, and targets for hemoglobin level should be established. Risk scores in several cardiovascular diseases should include red blood cell count and RDW. Complete blood count and hemorheological parameters represent useful, inexpensive, widely available tools for the management and prognosis of patients with coronary heart disease, heart failure, hypertension, arrhythmias, and stroke. Hypoxia and iron accumulation cause the most important cardiovascular effects of sickle cell disease and thalassemia. Patients with congenital chronic hemolytic anemia undergoing splenectomy should be monitored, considering thromboembolic and cardiovascular risk. PMID- 25710021 TI - Advanced glycation end products induce endothelial-to-mesenchymal transition via downregulating Sirt 1 and upregulating TGF-beta in human endothelial cells. AB - In the present study, we examined the advanced glycation end products- (AGEs-) induced endothelial-to-mesenchymal transition (EndMT) in human umbilical vein endothelial cells (HUVECs). Results demonstrated that AGE-BSAs significantly reduced the cluster of differentiation 31 (CD 31) expression, whereas they promoted the expression of fibroblast-specific protein-1 (FSP-1), alpha-smooth muscle antibody (alpha-SMA), and collagen I at both mRNA and protein levels in HUVECs. And the AGE-BSAs also promoted the receptors for AGEs (RAGEs) and receptor I for TGF-beta (TGFR I) markedly with a dose dependence, whereas the Sirt 1 was significantly downregulated by the AGE-BSA at both mRNA and protein levels. Moreover, the Sirt 1 activity manipulation with its activator, resveratrol (RSV), or its inhibitor, EX527, markedly inhibited or ameliorated the AGE-mediated TGF-beta upregulation. And the manipulated Sirt 1 activity positively regulated the AGE-induced CD31, whereas it negatively regulated the AGE-induced FSP-1. Thus, Sirt 1 was confirmed to regulate the AGE-induced EndMT via TGF-beta. In summary, we found that AGE-BSA induced EndMT in HUVECs via upregulating TGF-beta and downregulating Sirt 1, which also negatively regulated TGF-beta in the cell. This study implied the EndMT probably as an important mechanism of AGE-induced cardiovascular injury. PMID- 25710020 TI - MicroRNAs and cardiovascular diseases. AB - Coronary artery diseases (CAD) and heart failure have high mortality rate in the world, although much progress has been made in this field in last two decades. There is still a clinical need for a novel diagnostic approach and a therapeutic strategy to decrease the incidence of CAD. MicroRNAs (miRNAs) are highly conserved noncoding small RNA molecules that regulate a large fraction of the genome by binding to complementary messenger RNA sequences, resulting in posttranscriptional gene silencing. Recent studies have shown that specific miRNAs are involved in whole stage of atherosclerosis, from endothelium dysfunction to plaque rupture. These findings suggest that miRNAs are potential biomarkers in early diagnosis and therapeutic targets in CAD. In the present review, we highlight the role of miRNAs in every stage of atherosclerosis, and discuss the prospects of miRNAs in the near future. PMID- 25710022 TI - Athletic differences in the characteristics of the photoplethysmographic pulse shape: effect of maximal oxygen uptake and maximal muscular voluntary contraction. AB - This study aimed to investigate the athletic differences in the characteristics of the photoplethysmographic (PPG) pulse shape. 304 athletes were enrolled and divided into three subgroups according to a typical sport classification in terms of the maximal oxygen uptake (MaxO2_low, MaxO2_middle and MaxO2_high groups) or the maximal muscular voluntary contraction (MMVC_low, MMVC_middle, and MMVC_high groups). Finger PPG pulses were digitally recorded and then normalized to derive the pulse area, pulse peak time T p , dicrotic notch time T n , and pulse reflection index (RI). The four parameters were finally compared between the three subgroups categorized by MaxO2 or by MMVC. In conclusion, it has been demonstrated by quantifying the characteristics of the PPG pulses in different athletes that MaxO2, but not MMVC, had significant effect on the arterial properties. PMID- 25710023 TI - Characterization of LpGPAT gene in Lilium pensylvanicum and response to cold stress. AB - LpGPAT was obtained from L. pensylvanicum using RT-PCR and rapid amplification of cDNA ends. The cloned full-length cDNA was 1544 bp; it encoded 410 amino acids and had a molecular size of 46 KDa. The nucleic acid sequence analysis showed that it shared high homology with other known GPATs. SMAT result suggests that there is a PlsC that exists in 176-322 amino acid sequence of LpGAPT; it means LpGPAT protein is a member of the family of acyltransferase and has acyltransferase enzymatic activity. Result of real-time quantitative PCR and semiquantitative PCR support LpGPAT gene is definitely induced by low temperature stress. PMID- 25710024 TI - Nitrate promotes capsaicin accumulation in Capsicum chinense immobilized placentas. AB - In chili pepper's pods, placental tissue is responsible for the synthesis of capsaicinoids (CAPs), the compounds behind their typical hot flavor or pungency, which are synthesized from phenylalanine and branched amino acids. Placental tissue sections from Habanero peppers (Capsicum chinense Jacq.) were immobilized in a calcium alginate matrix and cultured in vitro, either continuously for 28 days or during two 14-day subculture periods. Immobilized placental tissue remained viable and metabolically active for up to 21 days, indicating its ability to interact with media components. CAPs contents abruptly decreased during the first 7 days in culture, probably due to structural damage to the placenta as revealed by scanning electron microcopy. CAPs levels remained low throughout the entire culture period, even though a slight recovery was noted in subcultured placentas. However, doubling the medium's nitrate content (from 40 to 80 mM) resulted in an important increment, reaching values similar to those of intact pod's placentas. These data suggest that isolated pepper placentas cultured in vitro remain metabolically active and are capable of metabolizing inorganic nitrogen sources, first into amino acids and, then, channeling them to CAP synthesis. PMID- 25710025 TI - Hepatocyte-specific ablation of PP2A catalytic subunit alpha attenuates liver fibrosis progression via TGF-beta1/Smad signaling. AB - Protein phosphatase 2A (PP2A), a family of the major serine/threonine phosphatases in cells, regulates many aspects of physiological processes. However, isoform-specific substrates and the biological role of each specific member of the PP2A family remain largely unknown. In this study, we investigated whether PP2A catalytic subunit Calpha (PP2Acalpha) is involved in chronic hepatic injury and fibrosis. A hepatocyte-specific PP2Acalpha ablation mice model was established to examine the effect of PP2Acalpha on carbon tetrachloride- (CCl4-) induced chronic hepatic injury and fibrosis. Our results showed that PP2Acalpha knockout mice were less susceptible to chronic CCl4-induced liver injury as evidenced by lower levels of serum alanine aminotransferase and aspartate aminotransferase, decreased hepatocyte proliferation, and increased rate of apoptotic removal of the injured hepatocytes. PP2Acalpha knockout mice also displayed a lesser extent of liver fibrosis as a significant decrease in the proportion of alpha-smooth muscle actin-expressing cells and collagen deposition was observed in their liver tissues. Furthermore, the levels of serum TGF-beta1 and hepatocytic Smad phosphorylation were reduced in the PP2Acalpha knockout mice. These data suggest that hepatocyte-specific ablation of PP2Acalpha protects against CCl4-induced chronic hepatic injury and fibrogenesis and the protective effect is mediated at least partially through the impaired TGF-beta1/Smad signaling. PMID- 25710026 TI - Musculotendinous stiffness of triceps surae, maximal rate of force development, and vertical jump performance. AB - The relationships between ankle plantar flexor musculotendinous stiffness (MTS) and performance in a countermovement vertical jump (CMJ) and maximal rate of torque development (MRTD) were studied in 27 active men. MTS was studied by means of quick releases at 20 (S0.2), 40 (S0.4), 60 (S0.6), and 80% (S0.8) of maximal voluntary torque (T(MVC)). CMJ was not correlated with strength indices but was positively correlated with MRTD/BM, S 0.4/BM. The slope alpha 2 and intercept beta 2 of the torque-stiffness relationships from 40 to 80% T(MVC) were correlated negatively (alpha 2) and positively (beta 2) with CMJ. The different stiffness indices were not correlated with MRTD. The prediction of CMJ was improved by the introduction of MRTD in multiple regressions between CMJ and stiffness. CMJ was also negatively correlated with indices of curvature of the torque-stiffness relationship. The subjects were subdivided in 3 groups in function of CMJ (groups H, M, and L for high, medium, and low performers, resp.). There was a downward curvature of the torque-stiffness relationship at high torques in group H or M and the torque-stiffness regression was linear in group L only. These results suggested that torque-stiffness relationships with a plateau at high torques are more frequent in the best jumpers. PMID- 25710027 TI - Effects of surgical and dietary weight loss therapy for obesity on gut microbiota composition and nutrient absorption. AB - Evidence suggests a correlation between the gut microbiota composition and weight loss caused by caloric restriction. Laparoscopic sleeve gastrectomy (LSG), a surgical intervention for obesity, is classified as predominantly restrictive procedure. In this study we investigated functional weight loss mechanisms with regard to gut microbial changes and energy harvest induced by LSG and a very low calorie diet in ten obese subjects (n = 5 per group) demonstrating identical weight loss during a follow-up period of six months. For gut microbiome analysis next generation sequencing was performed and faeces were analyzed for targeted metabolomics. The energy-reabsorbing potential of the gut microbiota decreased following LSG, indicated by the Bacteroidetes/Firmicutes ratio, but increased during diet. Changes in butyrate-producing bacterial species were responsible for the Firmicutes changes in both groups. No alteration of faecal butyrate was observed, but the microbial capacity for butyrate fermentation decreased following LSG and increased following dietetic intervention. LSG resulted in enhanced faecal excretion of nonesterified fatty acids and bile acids. LSG, but not dietetic restriction, improved the obesity-associated gut microbiota composition towards a lean microbiome phenotype. Moreover, LSG increased malabsorption due to loss in energy-rich faecal substrates and impairment of bile acid circulation. This trial is registered with ClinicalTrials.gov NCT01344525. PMID- 25710028 TI - Antibiotic therapies in maxillofacial surgery in the context of prophylaxis. AB - OBJECTIVES: There is no single pattern for preventive action as to the duration and type of antibiotic therapy in maxillofacial surgery. In these circumstances, it appears reasonable to set relevant standards for prophylactic procedures after such surgeries. METHODS: Retrospective analysis of bacteriological tests has been carried out as well as a susceptibility evaluation of cultured bacterial and fungal strains to antibiotics over a five-year period in subjects treated at the Cranio-Maxillo-Facial Clinic in Katowice. A total of 726 bacterial and fungal strains were cultured in 484 patients (200 women and 284 males). The age of the patients was 40.2 on average. RESULTS: The most frequent bacteria isolated from the patients were Gram-positive 541 (74.5%). Gram-negative bacteria were present in 177 (24.4%) cases. Fungi of the Candida genus were isolated in eight cases (1.1%). CONCLUSIONS: The most often isolated bacteria were Streptococcus mitis and Streptococcus oralis, whose number has grown over the last two years. Empiric therapies should be based on ciprofloxacin and gentamicin. It has been observed that all the Gram-positive bacteria are becoming more resistant to all antibiotics. Ampicillin and imipenem were antibiotics with the steepest resistance reduction while vancomycin showed the lowest resistance drop. PMID- 25710029 TI - Utility of circulating microRNAs as clinical biomarkers for cardiovascular diseases. AB - MicroRNAs (miRNAs) are small noncoding RNA molecules that regulate gene and protein expression by translational repression and/or mRNA degradation. miRNAs are implicated in the pathogenesis of various cardiovascular diseases and have become potential targets for therapeutic intervention. Their stability and presence in variety of readily accessible cell types including whole blood, serum, plasma, and other body fluids render them as potential source of a clinical biomarker. This review provides a brief overview of miRNA biogenesis and function, the diagnostic potential of circulating extracellular miRNA and their specific role in vivo in various cardiovascular settings, and their future perspective as clinical biomarkers. It is clearly evident from experimental studies that miRNAs are responsible for the regulation of several biological functions and alterations in cardiovascular diseases. Current data supports the concept of using circulating miRNAs as a biomarker in cardiovascular disease. It remains to be seen, however, whether circulating miRNAs can fulfil this role to improve risk and severity prediction. PMID- 25710031 TI - MIC as an appropriate method to construct the brain functional network. AB - Using an effective method to measure the brain functional connectivity is an important step to study the brain functional network. The main methods for constructing an undirected brain functional network include correlation coefficient (CF), partial correlation coefficient (PCF), mutual information (MI), wavelet correlation coefficient (WCF), and coherence (CH). In this paper we demonstrate that the maximal information coefficient (MIC) proposed by Reshef et al. is relevant to constructing a brain functional network because it performs best in the comprehensive comparisons in consistency and robustness. Our work can be used to validate the possible new functional connection measures. PMID- 25710030 TI - In vitro inhibitory and cytotoxic activity of MFM 501, a novel codonopsinine derivative, against Methicillin-Resistant Staphylococcus aureus clinical isolates. AB - 28 new pyrrolidine types of compounds as analogues for natural polyhydroxy alkaloids of codonopsinine were evaluated for their anti-MRSA activity using MIC and MBC value determination assay against a panel of S. aureus isolates. One pyrrolidine compound, MFM 501, exhibited good inhibitory activity with MIC value of 15.6 to 31.3 MUg/mL against 55 S. aureus isolates (43 MRSA and 12 MSSA isolates). The active compound also displayed MBC values between 250 and 500 MUg/mL against 58 S. aureus isolates (45 MRSA and 13 MSSA isolates) implying that MFM 501 has a bacteriostatic rather than bactericidal effect against both MRSA and MSSA isolates. In addition, MFM 501 showed no apparent cytotoxicity activity towards three normal cell lines (WRL-68, Vero, and 3T3) with IC50 values of >625 ug/mL. Selectivity index (SI) of MFM 501 gave a value of >10 suggesting that MFM 501 is significant and suitable for further in vivo investigations. These results suggested that synthetically derived intermediate compounds based on natural products may play an important role in the discovery of new anti-infective agents against MRSA. PMID- 25710032 TI - Exercise-induced neuroprotection in the spastic Han Wistar rat: the possible role of brain-derived neurotrophic factor. AB - Moderate aerobic exercise has been shown to enhance motor skills and protect the nervous system from neurodegenerative diseases, like ataxia. Our lab uses the spastic Han Wistar rat as a model of ataxia. Mutant rats develop forelimb tremor and hind limb rigidity and have a decreased lifespan. Our lab has shown that exercise reduced Purkinje cell degeneration and delayed motor dysfunction, significantly increasing lifespan. Our study investigated how moderate exercise may mediate neuroprotection by analyzing brain-derived neurotrophic factor (BDNF) and its receptor TrkB. To link BDNF to exercise-induced neuroprotection, mutant and normal rats were infused with the TrkB antagonist K252a or vehicle into the third ventricle. During infusion, rats were subjected to moderate exercise regimens on a treadmill. Exercised mutants receiving K252a exhibited a 21.4% loss in Purkinje cells compared to their controls. Cerebellar TrkB expression was evaluated using non-drug-treated mutants subjected to various treadmill running regimens. Running animals expressed three times more TrkB than sedentary animals. BDNF was quantified via Sandwich ELISA, and cerebellar expression was found to be 26.6% greater in mutant rats on 7-day treadmill exercise regimen compared to 30 days of treadmill exercise. These results suggest that BDNF is involved in mediating exercise-induced neuroprotection. PMID- 25710033 TI - Three-dimensional modeling of the pelvic floor support systems of subjects with and without pelvic organ prolapse. AB - The purpose of this study was to develop three-dimensional finite element models of the whole pelvic support systems of subjects with and without pelvic organ prolapse (POP) that can be used to simulate anterior and posterior wall prolapses. Magnetic resonance imaging was performed in one healthy female volunteer (55 years old, para 2) and one patient (56 years old, para 1) with anterior vaginal wall prolapse. Contours of the pelvic structures were traced by a trained gynecologist. Smoothing of the models was conducted and attachments among structures were established. Finite element models of the pelvic support system with anatomic details were established for both the healthy subject and the POP patient. The models include the uterus, vagina with cavity, cardinal and uterosacral ligaments, levator ani muscle, rectum, bladder, perineal body, pelvis, obturator internus, and coccygeal muscle. Major improvements were provided in the modeling of the supporting ligaments and the vagina with high anatomic precision. These anatomically accurate models can be expected to allow study of the mechanism of POP in more realistic physiological conditions. The resulting knowledge may provide theoretical help for clinical prevention and treatment of POP. PMID- 25710034 TI - The value of cerebral CT angiography with low tube voltage in detection of intracranial aneurysms. AB - OBJECTIVE: The aim of this study is to investigate the value of cerebral CT angiography (CTA) with low tube voltage in detection of intracranial aneurysms. MATERIALS AND METHODS: A total of 294 consecutive patients with spontaneous subarachnoid hemorrhage (SAH) were enrolled in this study and randomly assigned into conventional voltage CTA (C-CTA) group and low voltage CTA (L-CTA) group. The objective and subjective image qualities were analyzed and compared between C CTA and L-CTA groups. With the results of 3D-DSA as "gold standard," the sensitivity, specificity, and accuracy of C-CTA and L-CTA in diagnosis of aneurysms were calculated and compared with each other. RESULTS: Compared with group C-CTA, the CT dose index volume (CTDIvol) of group L-CTA reduced by 35.65%. There were no significant differences between C-CTA and L-CTA groups regarding objective and subjective image qualities. The sensitivity, specificity, and accuracy of L-CTA in diagnosis of aneurysms were 95.16%, 99.72%, and 99.42%, respectively. There were no significant differences in sensitivity, specificity, and accuracy between the C-CTA and L-CTA groups. CONCLUSION: The value of cerebral CTA with 100 kV low tube voltage in detection of intracranial aneurysms is significant, and it should be recommended as a routine scan method. PMID- 25710035 TI - High in vitro antibacterial activity of Pac-525 against Porphyromonas gingivalis biofilms cultured on titanium. AB - In order to investigate the potential of short antimicrobial peptides (AMPs) as alternative antibacterial agents during the treatment of peri-implantitis, the cytotoxic activity of three short AMPs, that is, Pac-525, KSL-W, and KSL, was determined using the MTT assay. The antimicrobial activity of these AMPs, ranging in concentration from 0.0039 mg/mL to 0.5 mg/mL, against the predominant planktonic pathogens, including Streptococcus sanguis, Fusobacterium nucleatum, and Porphyromonas gingivalis, involved in peri-implantitis was investigated. Furthermore, 2-day-old P. gingivalis biofilms cultured on titanium surfaces were treated with Pac-525 and subsequently observed and analysed using confocal laser scanning microscopy (CLSM). The average cell proliferation curve indicated that there was no cytotoxicity due to the three short AMPs. The minimum inhibitory concentration and minimum bactericidal concentration values of Pac-525 were 0.0625 mg/mL and 0.125 mg/mL, respectively, for P. gingivalis and 0.0078 mg/mL and 0.0156 mg/mL, respectively, for F. nucleatum. Using CLSM, we confirmed that compared to 0.1% chlorhexidine, 0.5 mg/mL of Pac-525 caused a significant decrease in biofilm thickness and a decline in the percentage of live bacteria. These data indicate that Pac-525 has unique properties that might make it suitable for the inhibition the growth of pathogenic bacteria around dental implants. PMID- 25710037 TI - An expedient synthesis, acetylcholinesterase inhibitory activity, and molecular modeling study of highly functionalized hexahydro-1,6-naphthyridines. AB - A series of hexahydro-1,6-naphthyridines were synthesized in good yields by the reaction of 3,5-bis[(E)-arylmethylidene]tetrahydro-4(1H)-pyridinones with cyanoacetamide in the presence of sodium ethoxide under simple mixing at ambient temperature for 6-10 minutes and were assayed for their acetylcholinesterase (AChE) inhibitory activity using colorimetric Ellman's method. Compound 4e with methoxy substituent at ortho-position of the phenyl rings displayed the maximum inhibitory activity with IC50 value of 2.12 MUM. Molecular modeling simulation of 4e was performed using three-dimensional structure of Torpedo californica AChE (TcAChE) enzyme to disclose binding interaction and orientation of this molecule into the active site gorge of the receptor. PMID- 25710036 TI - Elevated plasma levels of interleukin-12p40 and interleukin-16 in overweight adolescents. AB - INTRODUCTION: Obesity during adolescence is an increasing problem for both the individual and health care systems alike. In Western world countries, childhood adiposity has reached epidemic proportions. It is known that elevated levels of proinflammatory cytokines can be found in the plasma of obese patients. In this study, we sought to determine the relation between IL-12p40, IL-12p70, and Interleukin-16 (IL-16) in overweight adolescents. MATERIALS AND METHODS: Seventy nine male Caucasian adolescents aged 13-17 years were included in this study. Thirty-seven of them had a body mass index (BMI) above the 90th age-specific percentile. Il-12p40, IL-12p70, and IL-16 were measured from plasma using Luminex multiplex technology. RESULTS: Both IL-12p40 and IL-16 concentrations were significantly increased in overweight subjects compared to normal weight controls (IL-12p40: 1086.6 pg/mL +/- 31.7 pg/mL SEM versus 1228.6 pg/mL +/- 43.5 pg/mL SEM; IL-16 494.0 pg/mL +/- 29.4 pg/mL SEM versus 686.6 pg/mL +/- 52.5 pg/mL SEM, P < 0.05 and P < 0.01, resp.). No differences were found for IL-12p70. CONCLUSIONS: Based on these results, we believe that the increased levels of IL 12p40 and IL-16 are associated with an ongoing inflammatory response in obese individuals and could lead to the development of disease conditions related to obesity. PMID- 25710038 TI - Biochemical storage lesions occurring in nonirradiated and irradiated red blood cells: a brief review. AB - Red blood cells undergo a series of biochemical fluctuations during 35-42-day storage period at 1 degrees C to 6 degrees C. The sodium/potassium pump is immobilised causing a decrease in intracellular potassium with an increase in cytoplasmic sodium levels, glucose levels decline, and acidosis occurs as a result of low pH levels. The frailty of stored erythrocytes triggers the formation of haemoglobin-containing microparticles and the release of cell-free haemoglobin which may add to transfusion difficulties. Lipid peroxidation, oxidative stress to band 3 structures, and other morphological and structural molecular changes also occur leading to spheroechinocytes and osmotic fragility. These changes that transpire in the red cells during the storage period are referred to as "storage lesions." It is well documented that gamma irradiation exacerbates storage lesions and the reports of increased potassium levels leading to adverse reactions observed in neonates and infants have been of particular concern. There are, however, remarkably few systematic studies comparing the in vitro storage lesions of irradiated and nonirradiated red cell concentrates and it has been suggested that the impact of storage lesions on leucocyte reduced red blood cell concentrate (RBCC) is incomplete. The review examines storage lesions in red blood cells and their adverse effects in reference to blood transfusion. PMID- 25710039 TI - Predictors of mortality and prehospital monitoring limitations in blunt trauma patients. AB - This study aimed at determining predictors of in-hospital mortality and prehospital monitoring limitations in severely injured intubated blunt trauma patients. We retrospectively reviewed patients' charts. Prehospital vital signs, Injury Severity Score (ISS), initial Glasgow Coma Scale (GCS), Revised Trauma Score (RTS), arterial blood gases, and lactate were compared in two study groups: survivors (n = 40) and nonsurvivors (n = 30). There were no significant differences in prehospital vital signs between compared groups. Nonsurvivors were older (P = 0.006), with lower initial GCS (P < 0.001) and higher ISS (P < 0.001), along with higher lactate (P < 0.001) and larger base deficit (BD; P = 0.006), whereas RTS (P = 0.001) was lower in nonsurvivors. For predicting mortality, area under the curve (AUC) was calculated: for lactate 0.82 (P < 0.001), for ISS 0.82 (P < 0.001), and for BD 0.69 (P = 0.006). Lactate level of 3.4 mmol/L or more was 82% sensitive and 75% specific for predicting in-hospital death. In a multivariate logistic regression model, ISS (P = 0.037), GCS (P = 0.033), and age (P = 0.002) were found to be independent predictors of in-hospital mortality. The AUC for regression model was 0.93 (P < 0.001). Increased levels of lactate and BD on admission indicate more severe occult hypoperfusion in nonsurvivors whereas vital signs did not differ between the groups. PMID- 25710040 TI - Automatic epileptic seizure detection using scalp EEG and advanced artificial intelligence techniques. AB - The epilepsies are a heterogeneous group of neurological disorders and syndromes characterised by recurrent, involuntary, paroxysmal seizure activity, which is often associated with a clinicoelectrical correlate on the electroencephalogram. The diagnosis of epilepsy is usually made by a neurologist but can be difficult to be made in the early stages. Supporting paraclinical evidence obtained from magnetic resonance imaging and electroencephalography may enable clinicians to make a diagnosis of epilepsy and investigate treatment earlier. However, electroencephalogram capture and interpretation are time consuming and can be expensive due to the need for trained specialists to perform the interpretation. Automated detection of correlates of seizure activity may be a solution. In this paper, we present a supervised machine learning approach that classifies seizure and nonseizure records using an open dataset containing 342 records. Our results show an improvement on existing studies by as much as 10% in most cases with a sensitivity of 93%, specificity of 94%, and area under the curve of 98% with a 6% global error using a k-class nearest neighbour classifier. We propose that such an approach could have clinical applications in the investigation of patients with suspected seizure disorders. PMID- 25710042 TI - Sex-differences in renal expression of selected transporters and transcription factors in lean and obese Zucker spontaneously hypertensive fatty rats. AB - The aim of this study was to identify sex-dependent expression of renal transporter mRNA in lean and obese Zucker spontaneously hypertensive fatty (ZSF1) rats and to investigate the interaction of the most altered transporter, organic anion transporter 2 (Oat2), with diabetes-relevant metabolites and drugs. Higher incidence of glomerulosclerosis, tubulointerstitial fibrosis, and protein casts in Bowman's space and tubular lumen was detected by PAS staining in obese male compared to female ZSF1 rats. Real-time PCR on RNA isolated from kidney cortex revealed that Sglt1-2, Oat1-3, and Oct1 were higher expressed in kidneys of lean females. Oct2 and Mrp2 were higher expressed in obese males. Renal mRNA levels of transporters were reduced with diabetic nephropathy in females and the expression of transcription factors Hnf1beta and Hnf4alpha in both sexes. The highest difference between lean and obese ZSF1 rats was found for Oat2. Therefore, we have tested the interaction of human OAT2 with various substances using tritium labeled cGMP. Human OAT2 showed no interaction with diabetes-related metabolites, diabetic drugs, and ACE-inhibitors. However, OAT2-dependent uptake of cGMP was inhibited by furosemide. The strongly decreased expression of Oat2 and other transporters in female diabetic ZSF1 rats could possibly impair renal drug excretion, for example, of furosemide. PMID- 25710041 TI - Dairy consumption and insulin resistance: the role of body fat, physical activity, and energy intake. AB - The relationship between dairy consumption and insulin resistance was ascertained in 272 middle-aged, nondiabetic women using a cross-sectional design. Participants kept 7-day, weighed food records to report their diets, including dairy intake. Insulin resistance was assessed using the homeostatic model assessment (HOMA). The Bod Pod was used to measure body fat percentage, and accelerometry for 7 days was used to objectively index physical activity. Regression analysis was used to determine the extent to which mean HOMA levels differed across low, moderate, and high dairy intake categories. Results showed that women in the highest quartile of dairy consumption had significantly greater log-transformed HOMA values (0.41 +/- 0.53) than those in the middle-two quartiles (0.22 +/- 0.55) or the lowest quartile (0.19 +/- 0.58) (F = 6.90, P = 0.0091). The association remained significant after controlling for each potential confounder individually and all covariates simultaneously. Adjusting for differences in energy intake weakened the relationship most, but the association remained significant. Of the 11 potential confounders, only protein intake differed significantly across the dairy categories, with those consuming high dairy also consuming more total protein than their counterparts. Apparently, high dairy intake is a significant predictor of insulin resistance in middle aged, nondiabetic women. PMID- 25710043 TI - Drug pricing policies in one of the largest drug manufacturing nations in the world: Are affordability and access a cause for concern? PMID- 25710044 TI - Magnesium sulfate versus Lidocaine pretreatment for prevention of pain on etomidate injection: A randomized, double-blinded placebo controlled trial. AB - OBJECTIVE: Etomidate is an imidazole derivative and formulated in 35% propylene glycol. When given without a rapid lidocaine injection, etomidate is associated with pain after injection. Magnesium (Mg) is a calcium channel blocker and influences the N-methyl-D-aspartate receptor ion channel. The aim of the study is to evaluate the efficiency of preemptive injection of magnesium sulfate and lidocaine on pain alleviation on etomidate intravenous injection. METHODS: In a randomized, double-blinded trial study, 135 adult patients scheduled for elective outpatient or inpatient surgery were divided into three groups. Group M received 620 mg magnesium sulfate, Group L received 3 ml lidocaine 1% and Group S received normal saline, all in a volume of 5 mL followed by a maximal dose of 0.3 mg/kg of 1% etomidate. Pain was assessed on a four-point scale: 0 = no pain, 1 = mild pain, 2 = moderate pain and 3 = severe pain at the time of pretreatment and etomidate injection. FINDINGS: About 60% of patients in the control group had pain during etomidate injection as compared to 22.2% and 40% in the lidocaine and magnesium sulfate groups, respectively. There was difference in induction pain score between three treatment groups, significantly (P = 0.01) and observed differences in pain scores between "normal saline and lidocaine group" (P < 0.001) and "normal saline and magnesium sulfate groups" were statistically meaningful (P = 0.044). CONCLUSION: Intravenous magnesium sulfate and lidocaine injection are comparably effective in reducing etomidate-induced pain. PMID- 25710045 TI - Resource allocation and purchasing arrangements to improve accessibility of medicines: Evidence from Iran. AB - OBJECTIVE: The aim of this study was to review the current methods of pharmaceutical purchasing by Iranian insurance organizations within the World Bank conceptual framework model so as to provide applicable pharmaceutical resource allocation and purchasing (RAP) arrangements in Iran. METHODS: This qualitative study was conducted through a qualitative document analysis (QDA), applying the four-step Scott method in document selection, and conducting 20 semi structured interviews using a triangulation method. Furthermore, the data were analyzed applying five steps framework analysis using Atlas-ti software. FINDINGS: The QDA showed that the purchasers face many structural, financing, payment, delivery and service procurement and purchasing challenges. Moreover, the findings of interviews are provided in three sections including demand-side, supply-side and price and incentive regime. CONCLUSION: Localizing RAP arrangements as a World Bank Framework in a developing country like Iran considers the following as the prerequisite for implementing strategic purchasing in pharmaceutical sector: The improvement of accessibility, subsidiary mechanisms, reimbursement of new drugs, rational use, uniform pharmacopeia, best supplier selection, reduction of induced demand and moral hazard, payment reform. It is obvious that for Iran, these customized aspects are more various and detailed than those proposed in a World Bank model for developing countries. PMID- 25710046 TI - Risk factors and the outcome of therapy in patients with seizure after Carbamazepine poisoning: A two-year cross-sectional study. AB - OBJECTIVE: We aimed to investigate the frequency of seizure after acute carbamazepine poisoning and the important risk factors related to the outcomes of therapy. METHODS: In this two-year cross-sectional study conducted in a University Hospital in Iran, 114 patients with acute carbamazepine poisoning were divided into two groups of with seizure (n = 8) and without seizure (n = 106) after intoxication. Demographic data, average amount of drug ingestion, time elapsed from ingestion to hospital admission, history of seizure before poisoning, mental status, visual disturbances and nystagmus, duration of hospitalization, the outcomes of therapy, arterial blood gas values and serum biochemical indices were compared between the two groups. FINDINGS: Patients with seizure had an estimated (Mean +/- SD) ingestion of 14,300 +/- 570 mg carbamazepine, which was significantly higher (P < 0.0001) than the seizure-free group (4600 +/- 420 mg). The estimated average time between drug ingestion and hospital admission in patients with seizure and the seizure-free group were 515 +/- 275 and 370 +/- 46 minutes, respectively (P < 0.0001). In this study, 104 out of the total number of patients had recovered without any complication. Need for respiratory support, including airway support or intubation were the most recorded complication. One patient died after status epilepticus and aspiration pneumonia. CONCLUSION: The ingested amount of carbamazepine and the time elapsed from the ingestion of drug to hospital admission may influence the occurrence of seizure after acute carbamazepine poisoning; however, the outcome of supportive care in these patients seems to be positive. PMID- 25710047 TI - Emergence agitation prevention in paediatric ambulatory surgery: A comparison between intranasal Dexmedetomidine and Clonidine. AB - OBJECTIVE: Emergence agitation (EA), a short-lived, self-limiting phenomenon, arises frequently after the use of inhalational agents and hampers the implementation of pediatric ambulatory surgery in spite of using so many drugs with variable efficacy. METHODS: In this prospective, double-blinded, parallel group study (2008-2009), 80 children of both sex aged 3-7 years, with American Society of Anesthesiologists (ASA) physical status grade I-II, undergoing sevoflurane-based general anesthesia for elective day care surgery were randomly assigned into groups C or D. Group C received 4 MUg/kg intranasal clonidine, whereas group D received 1 MUg/kg intranasal dexmedetomidine, 45 min before induction of anesthesia. In postanesthesia care unit (PACU), the incidence of EA was assessed with Aonos four-point scale and the severity of EA was assessed with pediatric anesthesia emergence delirium scale upon admission (T0), after 5 min (T5), 15 min (T15), and 25 min (T25). Extubation time, emergence time, duration of PACU stay, dose and incidence of fentanyl use for pain control were noted. FINDINGS: Based on comparable demographic profiles, the incidence and severity of EA were significantly lower in group D as compared to group C at T0, T5, T15, and T25. But time of regular breathing, awakening, extubation, and emergence were significantly delayed in group D than C. The number and dose of fentanyl used in group C were significantly higher than group D. PACU and hospital stay were quite comparable between groups. CONCLUSION: Intranasal dexmedetomidine 1 MUg/kg was more effective than clonidine 4 MUg/kg in decreasing the incidence and severity of EA, when administered 45 min before the induction of anesthesia with sevoflurane for pediatric day care surgery. Dexmedetomidine also significantly reduced fentanyl consumption in PACU. PMID- 25710048 TI - Early administration of surfactant via a thin intratracheal catheter in preterm infants with respiratory distress syndrome: Feasibility and outcome. AB - OBJECTIVE: Currently, the method of early nasal continuous positive airway pressure (nCPAP) and selective administration of surfactant via an endotracheal tube is widely used in the treatment of respiratory distress syndrome (RDS) in premature infants. To prevent complications related to endotracheal intubation and even a brief period of mechanical ventilation, in this study, we compared the effectiveness of surfactant administration via a thin intratracheal catheter versus the current method using an endotracheal tube. METHODS: Thirty eight preterm infants <=34 weeks' gestation with birth weight of 1000-1800 g who were putted on nCPAP for RDS within the first hour of life, were randomly assigned to receive surfactant either via endotracheal tube (ET group) or via thin intratracheal catheter (CATH group). The primary outcomes were the need for mechanical ventilation and duration of oxygen therapy. Data were analyzed by independent t-test, Mann-Whitney U-test, and Chi-square test, using SPSS v. 21. FINDINGS: There was no significant difference between groups regarding to need for mechanical ventilation during the first 72 h of birth (3 [15.8%] in ET group vs. 2 [10.5%] in CATH group; P = 0.99). Duration of oxygen therapy in CATH group was significantly lower than ET group (243.7 +/- 74.3 h vs. 476.8 +/- 106.8 h, respectively; P = 0.018). The incidence of adverse events during all times of surfactant administration was not statistically significant between groups (P = 0.14), but the number of infants who experienced adverse events during surfactant administration was significantly lower in CATH group than ET group (6 [31.6%] vs. 12 [63.2%], respectively; P = 0.049). All other outcomes, including duration of treatment with CPAP and mechanical ventilation, times of surfactant administration and the need for more than one dose of the drug, the rate of intraventricular hemorrhage, mortality and combined outcome of chronic lung disease or mortality were statistically similar between the groups. CONCLUSION: Surfactant administration via thin intratracheal catheter in preterm infants receiving nCPAP for treatment of RDS has similar efficacy, feasibility and safety to its administration via endotracheal tube. PMID- 25710049 TI - Knowledge, attitude and practice of B.Sc. Pharmacy students about antibiotics in Trinidad and Tobago. AB - OBJECTIVE: The aim of this study was to assess the knowledge, attitude and practice of B.Sc. Pharmacy students about usage and resistance of antibiotics in Trinidad and Tobago. METHODS: This was a cross-sectional questionnaire-based study involving B.Sc. Pharmacy students. The questionnaire was divided into five components including Demographics data, knowledge about antibiotic use, attitude toward antibiotic use and resistance, self-antibiotic usage and possible causes of antibiotic resistance. Data were analyzed by employing Mann-Whitney and Chi square tests using SPSS version 20. FINDINGS: The response rate was 83.07%. The results showed good knowledge of antibiotic use among students. The overall attitude of pharmacy students was poor. About 75% of participants rarely use antibiotics, whereas self-decision was the major reason of antibiotic use (40.7%) and main source of information was retail pharmacist (42.6%). Common cold and flu is a major problem for which antibiotics were mainly utilized by pharmacy students (35.2%). CONCLUSION: The study showed good knowledge of pharmacy students regarding antibiotic usage. However, students' attitude towards antibiotic use was poor. The study recommends future studies to be conducted with interventional design to improve knowledge and attitude of pharmacy students about antibiotic use and resistance. PMID- 25710050 TI - Complementary and alternative medicine: A buzz for medical and health care systems. PMID- 25710051 TI - Int-soft (generalized) bi-ideals of semigroups. AB - The notions of int-soft semigroups and int-soft left (resp., right) ideals in semigroups are studied in the paper by Song et al. (2014). In this paper, further properties and characterizations of int-soft left (right) ideals are studied, and the notion of int-soft (generalized) bi-ideals is introduced. Relations between int-soft generalized bi-ideals and int-soft semigroups are discussed, and characterizations of (int-soft) generalized bi-ideals and int-soft bi-ideals are considered. Given a soft set (alpha;S) over U, int-soft (generalized) bi-ideals generated by (alpha;S) are established. PMID- 25710052 TI - Recent developments on sequence spaces and compact operators with applications. PMID- 25710054 TI - Assessment of the frequency of the transforming growth factor beta-1 sequence polymorphisms in patients with alcohol dependence syndrome. AB - Alcohol abuse is one of the most significant factors in the development of liver fibrosis. The pathomechanism of liver fibrosis is the same regardless of its etiology. Fibrosis is a sign of an imbalance between the synthesis of the extracellular matrix components and their degradation. Among the many cytokines that affect hepatic stellate cell activation it seems that transforming growth factor beta (TGF-beta) is the most significant, either as the direct factor stimulating polymerase chain reaction (HSC) proliferation and transformation into myofibroblasts, or as the direct factor causing an increase in the activity of genes responsible for the synthesis of extracellular matrix components. The aim of the study was to reveal possible dependencies and differences between the presence of certain alleles of the TGF-beta1 gene and its blood level in the study and control group. Blood samples were obtained from 39 patients, the control group consisted of 21 patients. The results obtained in the course of this study showed no statistically significant differences between the frequencies of particular polymorphisms. In the case of haplotype frequencies, insignificant differences were found for the algorithm Excoffier-Laval-Balding predicted haplotypes while one significant difference between the study and control groups was detected in case of the TC haplotype frequency predicted using the Expectation-Maximization algorithm. However, the difference in frequency of TC haplotype predicted by both algorithms was not significant. Genetic analysis of two single nucleotide polymorphisms (SNPs) in exon I of the TGF-beta1 gene did not show significant differences between the occurrence of particular polymorphisms and haplotypes in the populations under study. PMID- 25710053 TI - Measurement properties and implementation of a checklist to assess leadership skills during interdisciplinary rounds in the intensive care unit. AB - The implementation of interdisciplinary teams in the intensive care unit (ICU) has focused attention on leadership behavior. A daily recurrent situation in ICUs in which both leadership behavior and interdisciplinary teamwork are integrated concerns the interdisciplinary rounds (IDRs). Although IDRs are recommended to provide optimal interdisciplinary and patient-centered care, there are no checklists available for leading physicians. We tested the measurement properties and implementation of a checklist to assess the quality of leadership skills in interdisciplinary rounds. The measurement properties of the checklist, which included 10 essential quality indicators, were tested for interrater reliability and internal consistency and by factor analysis. The interrater reliability among 3 raters was good (kappa, 0.85) and the internal consistency was acceptable (alpha, 0.74). Factor analysis showed all factor loadings on 1 domain (>0.65). The checklist was further implemented during videotaped IDRs which were led by senior physicians and in which 99 patients were discussed. Implementation of the checklist showed a wide range of "no" and "yes" scores among the senior physicians. These results may underline the need for such a checklist to ensure tasks are synchronized within the team. PMID- 25710055 TI - Real-time PCR approach in dermatophyte detection and Trichophyton rubrum identification. AB - Dermatophytes are keratinophilic molds that infect human hair, nails and skin. Diagnosis of dermatophytosis is based on morphological, serological and biochemical features. However, identification is difficult and laborious due to similarities between microorganisms. Thus, there is considerable interest to develop mycological diagnostic procedures based on molecular biology methods. In this study, fast, two-step DNA extraction method and real-time PCR was used for detection of dermatophytes DNA using pan-dermatophyte primers and identification of Trichophyton rubrum from pure cultures. The applied method allowed correct detection of all dermatophytes and correct identification of Trichophyton rubrum in less than 2 hours. PMID- 25710056 TI - Biotechnological conversion of glycerol from biofuels to 1,3-propanediol using Escherichia coli. AB - In the face of shortage of fossil fuel supplies and climate warming triggered by excessive carbon dioxide emission, alternative resources for chemical industry have gained considerable attention. Renewable resources and their derivatives are of particular interest. Glycerol, which constitutes one of the by-products during biodiesel production, is such a substrate. Thus, generated excess glycerol may become an environmental problem, since it cannot be disposed of in the environment. The most promising products obtained from glycerol are polyols, including 1,3-propanediol, an important substrate in the production of synthetic materials, e.g. polyurethanes, unsaturated polyesters, and epoxy resins. Glycerol can be used as a carbon and energy source for microbial growth in industrial microbiology to produce 1,3-propanediol. This paper is a review of metabolic pathways of native producers and E. coli with the acquired ability to produce the diol via genetic manipulations. Culture conditions during 1,3-PDO production and genetic modifications of E. coli used in order to increase efficiency of glycerol bioconversion are also described in this paper. PMID- 25710057 TI - A Tribute to Leon F. Burmeister, PhD (1941-2014). PMID- 25710058 TI - Preface. Site-specific protein labeling. PMID- 25710061 TI - Retractions. PMID- 25710059 TI - Reply to Martinez-Gonzalez et al. PMID- 25710062 TI - "What's past is prologue": views from Dr. Lawrence Green. AB - A discussion with visionary Larry Green, a professor, prolific author and co creator of a health promotion planning framework that has been a core component of public health education academic training for 35 years. PMID- 25710063 TI - Purpose, core values, and vision for health promotion. AB - Responses from leading experts on the direction and priorities for the field of health promotion. PMID- 25710064 TI - When visionary influences and professional tenets are inseparable. AB - A discussion of how our professional behaviors have mitigated our effectiveness in changing public policies. PMID- 25710065 TI - A statistical modeling approach to computer-aided quantification of dental biofilm. AB - Biofilm is a formation of microbial material on tooth substrata. Several methods to quantify dental biofilm coverage have recently been reported in the literature, but at best they provide a semiautomated approach to quantification with significant input from a human grader that comes with the grader's bias of what is foreground, background, biofilm, and tooth. Additionally,human assessment indices limit the resolution of the quantification scale; most commercial scales use five levels of quantification for biofilm coverage (0%, 25%, 50%, 75%, and 100%). On the other hand, current state-of-the-art techniques in automatic plaque quantification fail to make their way into practical applications owing to their inability to incorporate human input to handle misclassifications. This paper proposes a new interactive method for biofilm quantification in Quantitative light-induced fluorescence(QLF) images of canine teeth that is independent of the perceptual bias of the grader. The method partitions a QLF image into segments of uniform texture and intensity called superpixels; every superpixel is statistically modeled as a realization of a single 2-D Gaussian Markov random field (GMRF) whose parameters are estimated; the superpixel is then assigned to one of three classes (background, biofilm, tooth substratum) based on the training set of data. The quantification results show a high degree of consistency and precision. At the same time, the proposed method gives pathologists full control to postprocess the automatic quantification by flipping misclassified superpixels to a different state (background,tooth, biofilm) with a single click, providing greater usability than simply marking the boundaries of biofilm and tooth as done by current state-of-the-art methods. PMID- 25710066 TI - [Experience of the first "whisker-dependent" task influenced c-Fos induction in rat barrel cortex neurons during acquisition of the second "whisker-independent" task]. AB - In this work we aimed to create a controlled history of two sequential trainings in order to find out activation patterns of "the first task" neurons during the second task learning. Rats were first trained to perform instrumental water rewarded behavior that required using left or right whiskers (a conditioned "whisking" task), and then to perform food-acquisition task of pedal pressing (not a conditioned "whisking" task). We found that food-acquisition task learning is accompanied by c-Fos induction in the barrel cortex neurons in animals that learned previously a conditioned "whisking" task. These data suggest that c-Fos induction during the second training took place in neurons that were specialized in relation to the first, "whisking" task. PMID- 25710067 TI - [The mechanisms of interdependent influence of prefrontal cortex, hippocampus and amygdala on the basal ganglia functioning and selection of behaviour]. AB - The hypothetical mechanism of functioning of neural networks that include limbic structures, neocortex and basal ganglia is proposed. A hypothesis is based on known data that the hippocampus, amygdala and prefrontal cortex interreact with each other, that their efferents converge on spiny cells of nucleus accumbens, that these inputs are topically organised and could be modified. Since GABAergic spiny cells of nucleus accumbens innervate neurons in the output basal ganglia nuclei which inhibit excitatory transmission through the thalamic nuclei into limbic structures and neocortex, the degree of activation of neurones in mentioned structures and, hence, a behaviour selection essentially depends on the character of responses of spiny cells. A summation of excitation of spiny cells and amplification of their responses during simultaneous firing of neurons of a limbic structure and neocortex, ultimately will lead to rising in neocortical activity and increase of its influence on a behaviour selection. If two structures are excited with temporary shift, activation of neurons of that structure which has firstly been strongly excited can be additionally increased due to a disinhibition of thalamic nuclei through the basal ganglia, whereas activity of neurons in other structure can be depressed if responses of spiny cells evoked by excitation arriving from this structure are decreased. Such suppression can be a consequence of heterosynaptic depression which is based on potentiation of efficacy of excitatory inputs from the different structures converging on inhibitory interneurons in the nucleus accumbens and basolateral amygdala. As a result, the behaviour choice will be determined by that structure which has been involved in activity firstly. A damage of different inputs into the nucleus accumbens from limbic structures must result in various behaviour disorders owing to the topical organisation of these inputs. PMID- 25710068 TI - [Quality of neuronal signal registered in the monkey motor cortex with chronically implanted multiple microwires]. AB - Disconnection of central and peripheral parts of motor system leads to severe forms of disability. However, current research of brain-computer interfaces will solve the problem of rehabilitation of patients with motor disorders in future. Chronic recordings of single-unit activity in specialized areas of cerebral cortex could provide appropriate control signal for effectors with multiple degrees of freedom. In present article we evaluated the quality of chronic single unit recordings in the primary motor cortex of awake behaving monkeys obtained with bundles of multiple microwires. Action potentials of proper quality were recorded from single units during three months. In some cases up to 7 single units could be extracted on a channel. Recording quality stabilized after 40 days since electrodes were implanted. Ultimately, functionality of multiple electrodes bundle makes it highly usable and reliable instrument for obtaining of control neurophysiologic signal from populations of neurons for brain-computer interfaces. PMID- 25710069 TI - [The influence of movement's observation on recuperation after physical fatigue]. AB - The study aim was to investigate effects of mental activity, accompanied by mu rhythm depression, on recuperation after physical fatigue. In a study participants performed 11 one minute bouts of static hand grip intermitted by 2 minutes restpauses. During pauses participants watched video with either dynamic hand grips (biological movements) or deformation of geometric figure (control). Obtained data showed there was a significant depression of mu-rhythm during biological movement's observation. There was significant fatigue of subjects in an exercise with physical activity, but there was no reliable influence of performed mental activity on recovery after fatigue. PMID- 25710070 TI - [EEG and fMRI reactions of a healthy brain at active and passive movements by a leading hand]. AB - Bioelectrical (EEG) and hemodynamic (fMRI) responses of cerebral reactions to active and passive movements by the right hand were analyzed in 17 right-handed healthy persons. Individual and averaged fMRI and EEG data was analyzed. The main cortex fMRI responses (sensorimotor cortex of the contralateral, left hemisphere) were topographically similar during both active and passive movements. This fact allows us to recommend the usage of the passive movement paradigm for the mapping of the motor areas in patients with movement disorders. Including in reactive process of cerebellum and subcortical structures at passive movements was more variability than active ones. FMRI-reactions at passive movements were characterized more individual variability than during active ones at the expense of diversity of cerebellum and subcortical structures answers. The EEG analysis revealed that at both passive and active movements there is a coherence increase in the high-frequency alpha-ban in left central-frontal area of the left, activated hemisphere. The power-frequency changes of the EEG parameters during active and passive movements were primarily shown in a frequency increase and the desynchronization of the beta-band. Consistency with the topography of the fMRI response was not found. PMID- 25710071 TI - [Analysis of independent components for event-related potentials from patients with an established diagnosis of schizophrenia, obsessive-compulsive and depressive disorders]. AB - We investigated the possibility to classify data from patients with different psychiatric disorders on the base of physiological measures of the brain activity. Event-related potentials during the execution of GO/NOGO task were recorded from age matched groups of patients with schizophrenia, major depression and obsessive-compulsive disorder. Separation of independent components for event related potentials was performed by applying Independent Component Analysis method. Picked out components were used in the method of discriminant analysis to classify the data according to clinical diagnosis. Discriminant analysis of components for event-related potentials allows classifying the data of patients with a suitable amount of matches with an established diagnosis. PMID- 25710072 TI - [The role of 5-HT3, 5-HT(1A) receptors and its coaction in the regulation behavior in mice]. AB - Here we investigated whether the 5-HT3 receptor and the 5-HT3/5-HT(1A) receptors coaction play essential role in the regulation of locomotion, depressive-like and social behavior. It was found that central administration of selective agonist of 5-HT3 receptor m-CPBG (2.5, 5.0, 10.0 nmol) produced significant decrease of horizontal and vertical locomotor activity in the open field (OF) test. Selective antagonist of 5-HT(1A) receptor WAY-100635 (2.0 mg/kg (3.7 MUmol/kg), i.p.) attenuated the effect of m-CPBG on behavior in the OF test. Selective 5-HT(1A) receptor agonist 8-OH-DPAT (0.25, 0.5, 1.0 mg/kg (0.76, 1.5 and 3.0 MUmol/kg correspondingly), i.p.) significantly decreased horizontal and vertical locomotor activity in the OF test as well. The activation of 5-HT3 receptors failed to affect immobility time in the tail suspension test, whereas the activation 5 HT(1A) receptors significantly decreased the immobility time. Administration of m CPBG also did not produced considerable effect on social behavior. At the same time, 8-OH-DPAT significantly decreased time and number of social contacts. Thus it was shown for the first time that 5-HT3 receptor-induced behavioral response observed in the OF realized mainly via 5-MHT(1A) receptor. Obtained results provide new evidence on the role of 5-HT3 receptors and 5-HT3/5-HT(1A) receptors coaction in the regulation of locomotor activity but not in the depressive-like and social behavior. PMID- 25710073 TI - [Does the selection of fox for tame and aggressive behavior changes their ability to focus attention, and training the motor skills?]. AB - Foxes long time selected for tame and aggressive behavior were compared on ability to focus attention on the object of food reinforcement. Attenuation of this behavior and rate of training for motor skills also has been examined. Maximal duration of eye focusing was significantly higher in aggressive foxes, in comparison with tame ones. Our experiments allowed divide the group of tame foxes into two subgroups "calm" and "emotional", on the base of emotionality and motor activity during tests. Features of behavior of these two subgroups steadily differed in all tests. "Calm" tame foxes at the extinction test continued the trained skill longer than "emotional" and aggressive ones. Tame foxes were more successful than aggressive in the training for motor skills. The possible reasons of the data obtained are discussed. PMID- 25710074 TI - [Sound affects the discrimination of weak intensities of light in the visual cortex of the rabbit depending on time intervals between sound and light]. AB - In this paper, we researched an influence of sound (2000 Hz, 70 dB, 40 ms) to the discrimination of low-light intensities (0.3 and 1 cd/m2) in the visual cortex of the rabbit. We used a recording of evoked potentials from the visual cortex of awaked rabbits in chronic experiments. The sound was switched on with different time slots before and after the replacement of the light intensities at each other (range from -750 to +150 ms). Sound itself caused no response. In 42 experiments on 3 rabbits we revealed that' he sound has a significant modulating effect on the discrimination of low-light intensities in the range of time shifts from -300 to +50 ms. Maximum sound effect was manifested in the transition of light from a high-intensity (1 cd/m2) to lower (0.3 cd/m2). Analyses of the phases of visual evoked potentials revealed that significant influence of sound to the light occurs in the intervals -300, -100, -60, -40, -20, 0, -20 and + 50 ms. We found that phase P2 (120-150 ms from the moment of replacement of the light stimuli) is most affected by sound in response to the replacement of low light intensities both in the number of significant (p < 0.05) time slots (7) and the impact of sound on the light response. In phase P2 the impact of sound was almost exclusively facilitating (by 19-36%) compared with the responses to the light, whereas in phases N1 80-110 ms) and N2 (180-250 ms) were only 2-3 intervals with the significant influence of the sound. And the degree of response facilitation to light was ranged by 8-12%. We assumed that the effect of sound on the light response in visual cortex is delayed that caused by the passage of auditory signal through the auditory,parietal cortex, superior colliculus. PMID- 25710075 TI - [Long-term potentiation and oscillation synchrony in the-ventral hippocampal prefrontal pathways]. AB - The results of the present study show the augmentation of hippocampal-cortical coherence and phase synchronization in theta-frequency and wider (1-15 Hz) low frequency range, during the time-period of LTP of monosynaptic prefrontal cortex focal potentials. The augmentation was detectable only in that activity segments with low to near-zero hippocampal theta frequency power. No definite changes in amplitude correlation of theta-rhytm envelops has been established. PMID- 25710076 TI - [Inhibition of histone deacetylases in the chick brain modulates expression of c Fos and ZENK transcription factors and facilitates establishment of long-term memory]. AB - The aim of the work was to examine the role of histone acetylation in memory consolidation in newborn chicks. We studied the effects of histone deacetylase inhibitor trichostatin A (TSA) on a "weak" memory for passive avoidance and on expression of two transcription factors c-Fos and ZENK known to play a role in neuronal plasticity in the chick brain. Intraventricular administration of trichostatin A prior to training produced a dose-dependent enhancement of memory when tested 24 hours after the training. It also increased neuronal expression of c-Fos and ZENK proteins: the density of ZENK immunopositive cells increased in the hippocampus and intermediate medial mesopallium and the density of c-Fos immunopositive cells increased in intermediate arcopallium and dorsocaudal nidopallium. Weak passive avoidance training did not produce further enhancement of c-Fos and ZENK expression in any of these brain areas. These data demonstrate possibility of facilitating long-term memory in day-old chicks by a histone deacetylases inhibitor, thus supporting the hypothesis on the role of histone acetylation in long-term memory formation. They also suggest that these effects might be mediated through modulation of transcriptional response in brain areas involved in consolidation of this form of memory. PMID- 25710077 TI - [Concentrations of monoamines in the brain structures and features of behavior in the two-month old WAG/Rij rats]. AB - The first spike-wave discharges (SWDs) in WAG/Rij rats begin to appear at age of 2-3 months and are fully manifested by 5-6 months. Occurrence of SWDs in the EEG is the main indicator of absence epilepsy. Extensive absence epilepsy in 5-6 months-old WAG/Rij rats is accompanied by decreases in dopamine and its metabolites concentrations in the meso-cortico-limbic and nigro-striatal dopaminergic brain systems, resulting in the expression of depression-like behavioral symptoms. In 36 day-old WAG/Rij rats, SWDs are not manifested, deficiency of dopamine is not revealed, and symptoms of depression-like behavior are not expressed. In this study, behavior and monoamines and their metabolites concentrations were investigated in 5 brain structures (prefrontal cortex, nucleus accumbens, hypothalamus, striatum, hippocampus) in 2 month-old WAG/Rij rats in comparison with Wistar rats of the same age. Reduction of the dopamine and its metabolites concentration in 2 month-old WAG/Rij rats was found only in the prefrontal cortex, indicating rapid response of the prefrontal cortex or its high sensitivity. Rapid response of the prefrontal cortex is supposed to be a.fundamental property of this brain structure. Decreases in the dopamine and its metabolites concentration in the prefrontal cortex in 2 month-old WAG/Rij rats were associated with features of behavior which can be regarded as a state of so called pre-pathology (increased anxiety and stress reactivity) preceding the development of depression-like behavior typical for 5-6-months old rats of this strain. PMID- 25710078 TI - Effect of Custom Foot Insoles on Postural Stability in Figure Skaters While on Ice. AB - CONTEXT: Improvements in postural stability in figure skaters can play a significant role in performance, as well as reducing fall risk. OBJECTIVE: To explore the effect of custom foot insoles on postural stability in advanced figure skaters. DESIGN: Exploratory study. SETTING: Out of laboratory. PARTICIPANTS: Nine advanced figure skaters were recruited and 7 completed the study (age 38 +/- 18.5 y, body-mass index 25 +/- 3.6 kg/m2). INTERVENTION: Custom foot insoles. MAIN OUTCOME MEASURES: Primary outcome of changes in postural stability (PS) quantified by center-of-mass sway with secondary outcomes of ankle and hip-joint sway and joint range of motion. Sway measurements were assessed using body-worn sensors while participants wore skates on ice. PS was assessed in single-leg stance, as well as during gliding on the dominant foot. RESULTS: A significant improvement in static PS was observed after 6-wk use of custom insoles. Center-of-mass sway reduced significantly on average by 48.44% (P = .023), and ankle-joint sway reduced by 45.7% (P = .05) during single-leg-stance balance measurements. During the gliding maneuver nonsignificant changes were observed for both ankle- and knee-joint range of motion. CONCLUSION: The results of this study suggest proof of concept toward benefits of custom insoles in improving postural stability in advanced figure skaters. To generalize the findings, randomized controlled trials with larger sample sizes are warranted. PMID- 25710079 TI - On-chip picosecond pulse detection and generation using graphene photoconductive switches. AB - We report on the use of graphene for room temperature on-chip detection and generation of pulsed terahertz (THz) frequency radiation, exploiting the fast carrier dynamics of light-generated hot carriers, and compare our results with conventional low-temperature-grown gallium arsenide (LT-GaAs) photoconductive (PC) switches. Coupling of picosecond-duration pulses from a biased graphene PC switch into Goubau line waveguides is also demonstrated. A Drude transport model based on the transient photoconductance of graphene is used to describe the mechanism for both detection and generation of THz radiation. PMID- 25710080 TI - Individuals with hematological malignancies before undergoing chemotherapy present oxidative stress parameters and acute phase proteins correlated with nutritional status. AB - Hematological malignancies present abnormal blood cells that may have altered functions. This study aimed to evaluate nutritional status, acute phase proteins, parameters of cell's functionality, and oxidative stress of patients with hematological malignancies, providing a representation of these variables at diagnosis, comparisons between leukemias and lymphomas and establishing correlations. Nutritional status, C-reactive protein (CRP), albumin, phagocytic capacity and superoxide anion production of mononuclear cells, lipid peroxidation and catalase activity in plasma were evaluated in 16 untreated subjects. Main diagnosis was acute leukemia (n = 9) and median body mass index (BMI) indicated overweight (25.6 kg/m(2)). Median albumin was below (3.2 g/dL) and CRP above (37.45 mg/L) the reference values. Albumin was inversely correlated with BMI (r = -0.53). Most patients were overweight before the beginning of treatment and had a high CRP/albumin ratio, which may indicate a nutrition inflammatory risk. BMI values correlated positively with lipid peroxidation and catalase activity. A strong correlation between catalase activity and lipid peroxidation was found (r = 0.75). Besides the elevated BMI, these patients also have elevated CRP values and unexpected relations between nutritional status and albumin, reinforcing the need for nutritional counseling during the course of chemotherapy, especially considering the correlations between oxidative stress parameters and nutritional status evidenced here. PMID- 25710081 TI - Bioactive Metabolites from the Fruits of Psoralea corylifolia. AB - Twenty-four metabolites, including seven new compounds (1-7), were isolated from the dried fruits of Psoralea corylifolia. On the basis of combined spectroscopic and chemical analysis, the new compounds were determined to be six flavonoids (1 6) and a meroterpenoid (7). The absolute configurations of the natural products obtained, including the previously undetermined 16 and 17, were assigned by several methods, such as NOE spectroscopy, optical rotation, and CD spectroscopy. Several of these compounds exhibited moderate inhibitory activity toward Staphylococcus mutans-derived SrtA (2, 6, and 16) and significant stimulation of SIRT1 activity (2, 3, and 15). PMID- 25710082 TI - Optimal chest compression rate in cardiopulmonary resuscitation: a prospective, randomized crossover study using a manikin model. AB - OBJECTIVES: When performing cardiopulmonary resuscitation (CPR), the 2010 American Heart Association guidelines recommend a chest compression rate of at least 100 min, whereas the 2010 European Resuscitation Council guidelines recommend a rate of between 100 and 120 min. The aim of this study was to examine the rate of chest compression that fulfilled various quality indicators, thereby determining the optimal rate of compression. METHODS: Thirty-two trainee emergency medical technicians and six paramedics were enrolled in this study. All participants had been trained in basic life support. Each participant performed 2 min of continuous compressions on a skill reporter manikin, while listening to a metronome sound at rates of 100, 120, 140, and 160 beats/min, in a random order. Mean compression depth, incomplete chest recoil, and the proportion of correctly performed chest compressions during the 2 min were measured and recorded. RESULTS: The rate of incomplete chest recoil was lower at compression rates of 100 and 120 min compared with that at 160 min (P=0.001). The numbers of compressions that fulfilled the criteria for high-quality CPR at a rate of 120 min were significantly higher than those at 100 min (P=0.016). CONCLUSION: The number of high-quality CPR compressions was the highest at a compression rate of 120 min, and increased incomplete recoil occurred with increasing compression rate. However, further studies are needed to confirm the results. PMID- 25710083 TI - The neonatal resuscitation algorithm organized cart is more efficient than the airway-breathing-circulation organized drawer: a crossover randomized control trial. AB - INTRODUCTION: Although there is consensus on the resuscitation of newborns, there is no standardization on how resuscitation equipment should be organized. This might lead to difficulty and inefficiency in retrieval of the right equipment during resuscitation. The neonatal resuscitation carts organized in accordance with the American Academy of Pediatrics (AAP) Neonatal Resuscitation Program (NRP) algorithm might result in more efficient retrieval of resuscitation equipment. OBJECTIVES: To compare user preference and lengths of time required to retrieve standard resuscitation equipment from an NRP Cart versus a generic storage drawer. STUDY DESIGN: A prospective, randomized, controlled, and crossover trial was conducted during simulation-based NRP provider courses in the Accident & Emergency Training Centre from September to October 2013. The mean time of accurate equipment retrieval and ease of use, which was rated by the participants using a five-point Likert scale (1=most difficult, 5=easiest to use), were compared using the Wilcoxon signed-rank test because of right skew. RESULTS: A total of 55 individuals participated in this study. The mean length of time required for equipment retrieval from the NRP Cart was significantly less than that from the drawer (Z=-3.90, P<0.01, median=36.23 s, interquartile range=97 s). In general, the NRP Cart was 32% faster than the drawer when extensive resuscitation equipment was required. All the participants rated the NRP Cart as easier to use than the drawer, with a median score of 4 for NRP Cart and 3 for the drawer (Z=-4.10, P<0.01, interquartile range=2). CONCLUSION: The NRP Cart was superior to the generic drawer in terms of the speed of equipment retrieval and user acceptability. PMID- 25710084 TI - Mortality and prognostic factors of patients who have blood cultures performed in the emergency department: a cohort study. AB - BACKGROUND: Early identification and treatment of patients with severe infection improve their prognosis. The aims of this study were to describe the 30-day mortality and to identify prognostic factors among blood-cultured patients in a medical emergency department (MED). PATIENTS AND METHODS: This was a hospital based cohort study including all adult (>=15 years old) blood-cultured patients at the MED at Odense University Hospital between 1 August 2009 and 31 August 2011. RESULTS: During the study period, 5499/11 988 (45.9%) patients had blood cultures performed within 72 h of arrival and were included in the study. Of those included, 2631 (47.8%) were men, median age 69 years (range 15-103), and 418 (7.6%) were diagnosed with bacteraemia. The overall 30-day mortality among blood-cultured patients was 11.0% (10.2-11.9). In a multivariate Cox regression model, age of more than 80 years [hazard ratio (HR) 4.6 (95% CI 3.6-6.0)], at least two organ failure [HR 3.6 (2.9-4.5)], bacteraemia [HR 1.4 (1.1-1.8)], Charlson Comorbidity Index of at least 2 h [HR 1.7 (1.3-2.0)], SIRS [HR 1.5 (1.2 1.7)], a history of alcohol dependency [HR 1.7 (1.3-2.3)] and late drawing of blood cultures 24-48 h after arrival [HR 1.7 (1.3-2.2)] were found to be prognostic factors of mortality among blood-cultured patients in the MED. CONCLUSION: Among blood-cultured patients in the MED, we found an 11.0% overall 30-day mortality. Factors associated with 30-day mortality were age more than 80 years, at least two organ failure, bacteraemia, Charlson Comorbidity Index of at least 2, SIRS, a history of alcohol dependency and late drawing of blood cultures. PMID- 25710085 TI - Elevated TGF-beta1/IL-31 Pathway Is Associated with the Disease Severity of Hepatitis B Virus-Related Liver Cirrhosis. AB - The proinflammatory cytokines transforming growth factor beta 1 (TGF-beta1) and interleukin (IL)-31 have been implicated in tissue injury. However, whether TGF beta1/IL-31 are stimulated and elevated in response to liver injury that leads to fibrogenesis in hepatitis B virus-related liver cirrhosis (HBV-LC) remains unclear. To investigate the association between TGF-beta1/IL-31 and stages of chronic HBV infection, serum TGF-beta1, IL-9, IL-10,IL-17, IL-22, IL-23, IL-31, IL-33, and IL-35 were determined among patients with chronic hepatitis B (CHB; n=19), HBV-LC (n=20), and a normal control population (NC; n=18). Disease severity in patients with HBV-LC was assessed using model for end-stage liver disease (MELD) scores. Serum TGF-beta1 and IL-31 levels were strongly positively linked in all subjects, and both correlated positively with IL-22, IL-33, and IL 17. TGF-beta1 and IL-31 levels in the blood were both significantly higher in CHB and HBV-LC patients than in NC subjects. Elevated serum TGF-beta1 and IL-31 levels were positively associated with albumin, alpha-fetoprotein, creatinine, white blood cell count, and platelet levels. Serum TGF-beta1 and IL-31 were markedly higher in HBV-LC patients who did not have esophageal varices, and IL-31 had the highest sensitivity and specificity (90.9% and 66.7%, respectively) for indicating the absence of this complication. In summary, TGF-beta1 and IL-31 were linked to progression from CHB to LC, and correlated well with the severity of HBV-LC. These findings suggest possible roles of the TGF-beta1/IL-31 pathway in the pathogenesis of liver fibrosis during chronic HBV infection. PMID- 25710086 TI - Superior cell penetration by a rigid and anisotropic synthetic protein. AB - Molecules with structural anisotropy and rigidity, such as asbestos, demonstrate high cell-penetrating activity but also high toxicity. Here we synthesize a biodegradable, rigid, and fibrous artificial protein, CCPC 140, as a potential vehicle for cellular delivery. CCPC 140 penetrated 100% of cells tested in vitro, even at a concentration of 3.1 nM-superior to previously reported cell penetrating peptides. The effects of cell-strain-dependency and aspect ratio on the cell-penetrating activity of CCPC 140 were also investigated. PMID- 25710087 TI - Visual tracking using neuromorphic asynchronous event-based cameras. AB - This letter presents a novel computationally efficient and robust pattern tracking method based on a time-encoded, frame-free visual data. Recent interdisciplinary developments, combining inputs from engineering and biology, have yielded a novel type of camera that encodes visual information into a continuous stream of asynchronous, temporal events. These events encode temporal contrast and intensity locally in space and time. We show that the sparse yet accurately timed information is well suited as a computational input for object tracking. In this letter, visual data processing is performed for each incoming event at the time it arrives. The method provides a continuous and iterative estimation of the geometric transformation between the model and the events representing the tracked object. It can handle isometry, similarities, and affine distortions and allows for unprecedented real-time performance at equivalent frame rates in the kilohertz range on a standard PC. Furthermore, by using the dimension of time that is currently underexploited by most artificial vision systems, the method we present is able to solve ambiguous cases of object occlusions that classical frame-based techniques handle poorly. PMID- 25710088 TI - Self-organization of control circuits for invariant fiber projections. AB - Assuming that patterns in memory are represented as two-dimensional arrays of local features, just as they are in primary visual cortices, pattern recognition can take the form of elastic graph matching (Lades et al., 1993 ). Neural implementation of this may be based on preorganized fiber projections that can be activated rapidly with the help of control units (Wolfrum, Wolff, Lucke, & von der Malsburg, 2008 ). Each control unit governs a set of projection fibers that form part of a coherent mapping. We describe a mathematical model for the ontogenesis of the underlying connectivity based on a principle of network self organization as described by the Haussler system (Haussler & von der Malsburg, 1983 ), modified to be sensitive to pattern similarity and to support formation of multiple mappings, each under the command of a control unit. The process takes the form of a soft-winner-take-all, where units compete for the representation of maps. We show simulations for invariant point-to-point and feature-to-feature mappings. PMID- 25710089 TI - Accurate connection strength estimation based on variational bayes for detecting synaptic plasticity. AB - Connection strength estimation is widely used in detecting the topology of neuronal networks and assessing their synaptic plasticity. A recently proposed model-based method using the leaky integrate-and-fire model neuron estimates membrane potential from spike trains by calculating the maximum a posteriori (MAP) path. We further enhance the MAP path method using variational Bayes and dynamic causal modeling. Several simulations demonstrate that the proposed method can accurately estimate connection strengths with an error ratio of less than 20%. The results suggest that the proposed method can be an effective tool for detecting network structure and synaptic plasticity. PMID- 25710090 TI - Solving stereo transparency with an extended coarse-to-fine disparity energy model. AB - Modeling stereo transparency with physiologically plausible mechanisms is challenging because in such frameworks, large receptive fields mix up overlapping disparities, whereas small receptive fields can reliably compute only small disparities. It seems necessary to combine information across scales. A coarse-to fine disparity energy model, with both position- and phase-shift receptive fields, has already been proposed. However, because each scale decodes only one disparity for each location and uses the decoded disparity to select cells at the next scale, this model cannot represent overlapping surfaces at different depths. We have extended the model to solve stereo transparency. First, we introduce multiplicative connections from cells at one scale to the next to implement coarse-to-fine computation. The connection is the strongest when the presynaptic cell's preferred disparity matches the postsynaptic cell's position-shift parameter, encouraging the next scale to encode residual disparities with the more reliable phase-shift mechanism. This modification not only eliminates the artificial decoding and selection steps of the original model but also enables maintenance of complete population responses throughout the coarse-to-fine process. Second, because of this modification, explicit decoding is no longer necessary but rather is for visualization only. We use a simple threshold criterion to decode multiple disparities from population energy responses instead of a single disparity in the original model. We demonstrate our model using simulations on a variety of transparent and nontransparent stereograms. The model also reproduces psychophysically observed disparity interactions (averaging, thickening, attraction, and repulsion) as the depth separation between two overlapping planes varies. PMID- 25710091 TI - Online EM with weight-based forgetting. AB - In the online version of the EM algorithm introduced by Sato and Ishii ( 2000 ), a time-dependent discount factor is introduced for forgetting the effect of the old estimated values obtained with an earlier, inaccurate estimator. In their approach, forgetting is uniformly applied to the estimators of each mixture component depending exclusively on time, irrespective of the weight attributed to each unit for the observed sample. This causes an excessive forgetting in the less frequently sampled regions. To address this problem, we propose a modification of the algorithm that involves a weight-dependent forgetting, different for each mixture component, in which old observations are forgotten according to the actual weight of the new samples used to replace older values. A comparison of the time-dependent versus the weight-dependent approach shows that the latter improves the accuracy of the approximation and exhibits much greater stability. PMID- 25710092 TI - Coding accuracy is not fully determined by the neuronal model. AB - It is automatically assumed that the accuracy with which a stimulus can be decoded is entirely determined by the properties of the neuronal system. We challenge this perspective by showing that the identification of pure tone intensities in an auditory nerve fiber depends on both the stochastic response model and the arbitrarily chosen stimulus units. We expose an apparently paradoxical situation in which it is impossible to decide whether loud or quiet tones are encoded more precisely. Our conclusion reaches beyond the topic of auditory neuroscience, however, as we show that the choice of stimulus scale is an integral part of the neural coding problem and not just a matter of convenience. PMID- 25710093 TI - Factors influencing decisions to enroll in the health informatics educational programs. AB - The aim of this study was to identify the most important factors associated with undergraduate students' decisions to enroll in the health informatics program at Hail University in Saudi Arabia. A cross-sectional survey was conducted among the population of 73 students (second to fourth year; 52 females, 21 males; age range 19-25 years). A hierarchy of perceived sources of influence was identified. Counselors, teachers and other professionals, and promotional materials, including information in the media, as well as the high quality characteristics of the institution, had the strongest influence. Other students, friends and family, the academic reputation of the University and the health informatics department faculty, together with interactions in the academic environment (e.g. segregation by gender) and financial, job, career, and postgraduate opportunities, were perceived to be weaker sources of influence. The strengths of the sources of influence varied significantly with respect to the socio demographic characteristics of the students, as well as the categories associated with the decision-making process. Strong sources of influence were particularly important for the increasing number of female students who often made the final decision to enroll. These findings will support policy and decision makers to make better plans for health informatics education by understanding the influential sources that attract students into the health informatics profession, and will also assist the health care sector's attempts to avoid a deficiency in this rapidly expanding professional field. PMID- 25710094 TI - Yoga interventions in pregnancy: a qualitative review. AB - OBJECTIVES: Every second 4.3 births occur in the world, signifying the magnitude and importance of pregnancy. This study looked at yoga interventions done from 2008 to December 2013 and examined whether yoga can be an efficacious approach for influencing maternal and birth outcomes in pregnancy. DESIGN: A systematic search of MEDLINE (PubMed), CINAHL, Alt HealthWatch, Cochrane Database of Systematic Reviews, and ACP Journal Club databases was conducted for quantitative articles of pregnancy involving all schools of yoga. RESULTS: A total of 15 articles met the inclusion criteria: 6 from the United States, 6 from India, 2 from Taiwan, and 1 each from Korea and Thailand. Of the 15 studies, 10 showed positive changes in maternal psychological or birth outcomes. CONCLUSIONS: The included studies have some limitations. Nonetheless, yoga appears to be a promising intervention for pregnancy. PMID- 25710095 TI - Cognitive and emotional biomarkers of melancholic depression: An iSPOT-D report. AB - BACKGROUND: Depressed patients with melancholic features have distinct impairments in cognition and anhedonia, but it remains unknown whether these impairments can be quantified on neurocognitive biomarker tests of behavioral performance. We compared melancholic major depressive disorder (MDD) patients to non-melancholic MDD patients and controls on a neurocognitive test battery that assesses eight general and emotional cognitive domains including the hypothesized decision-making and reward-threat perception. METHODS: MDD outpatients (n=1008) were assessed using a computerized battery of tests. MDD participants met DSM-IV criteria for MDD and had a score >=16 on the 17-item Hamilton Rating Scale for Depression. Melancholic MDD was defined using the Mini-International Neuropsychiatric Interview and a psychomotor disturbance observer-rated CORE measure score >7. Controls were age- and gender-matched with no previous DSM-IV or significant medical history. RESULTS: Melancholic participants (33.7% of the MDD sample) exhibited significantly poorer performance than controls across each domain of cognitive function and for speed of emotion identification and implicit emotion priming. Compared to the non-melancholic group, specific disturbances were seen on tests of information speed, decision speed, and reward-relevant emotional processing of happy expressions, even after co-varying for symptom severity. LIMITATIONS: Assessments were taken at only one medication-free time point. Reward was investigated using an emotional faces task. CONCLUSIONS: Melancholic MDD is distinguished by a specific neurocognitive marker profile consistent with reduced decision-making capacity under time demands and loss of reward sensitivity. This profile suggests an underlying deficit in mesolimbic cortical circuitry for motivationally-directed behavior. PMID- 25710096 TI - Performance study and influence of radiation emission energy and soil contamination level on gamma-radiation shielding of stabilised/solidified radionuclide-polluted soils. AB - This work focuses on the stabilisation/solidification (S/S) of radionuclide polluted soils at different (232)Th levels using Portland cement alone and with barite aggregates. The potential of S/S was assessed applying a full testing protocol and calculating gamma-radiation shielding (gammaRS) index, that included the measurement of soil radioactivity before and after the S/S as a function of the emission energy and soil contamination level. The results indicate that setting processes are strongly dependent on the contaminant concentration, and for contamination level higher than 5%, setting time values longer than 72 h. The addition of barite aggregates to the cement gout leads to a slight improvement of the S/S performance in terms of durability and contaminant leaching but reduces the mechanical resistance of the treated soils samples. Barite addition also causes an increase in the gamma-rays shielding properties of the S/S treatment up to about 20%. Gamma-ray measurements show that gammaRS strongly depends on the energy, and that the radioactivity with the contamination level was governed by a linear trend, while, gammaRS index does not depend on the radionuclide concentration. Results allow the calculated gammaRS values and those available from other experiments to be applied to hazard radioactive soil contaminations. PMID- 25710097 TI - Pheromones: a new ergogenic aid in sport? AB - Nowadays, antidoping laboratories are improving detection methods to confirm the use of forbidden substances. These tests are based both on direct identification of new substances or their metabolites and on indirect evaluation of changes in gene, protein, or metabolite patterns (genomics, proteomics, or metabolomics). The World Anti-Doping Agency (WADA) officially monitors anabolic steroids, hormones, growth factors, beta-agonists, hormone and metabolic modulators, masking agents, street drugs, manipulation of blood and blood components, chemical and physical manipulation, gene doping, stimulants, narcotics, glucocorticosteroids, and beta-blockers. However, several other substances are under review by WADA. Pheromones accomplish the structure and function of life from its first step, while they have an impact on the body's performance. Both testosterone and pheromones have an ergogenic effect that could potentially affect an athlete's performance. The authors share their questions concerning the potential impact of pheromones in sports. PMID- 25710099 TI - Polymers under confinement: single polymers, how they interact, and as model chromosomes. AB - How confinement or a physical constraint modifies polymer chains is not only a classical problem in polymer physics but also relevant in a variety of contexts such as single-molecule manipulations, nanofabrication in narrow pores, and modelling of chromosome organization. Here, we review recent progress in our understanding of polymers in a confined (and crowded) space. To this end, we highlight converging views of these systems from computational, experimental, and theoretical approaches, and then clarify what remains to be clarified. In particular, we focus on exploring how cylindrical confinement reshapes individual chains and induces segregation forces between them - by pointing to the relationships between intra-chain organization and chain segregation. In the presence of crowders, chain molecules can be entropically phase-separated into a condensed state. We include a kernel of discussions on the nature of chain compaction by crowders, especially in a confined space. Finally, we discuss the relevance of confined polymers for the nucleoid, an intracellular space in which the bacterial chromosome is tightly packed, in part by cytoplasmic crowders. PMID- 25710100 TI - Conversion of aminodeoxychorismate synthase into anthranilate synthase with Janus mutations: mechanism of pyruvate elimination catalyzed by chorismate enzymes. AB - The central importance of chorismate enzymes in bacteria, fungi, parasites, and plants combined with their absence in mammals makes them attractive targets for antimicrobials and herbicides. Two of these enzymes, anthranilate synthase (AS) and aminodeoxychorismate synthase (ADCS), are structurally and mechanistically similar. The first catalytic step, amination at C2, is common between them, but AS additionally catalyzes pyruvate elimination, aromatizing the aminated intermediate to anthranilate. Despite prior attempts, the conversion of a pyruvate elimination-deficient enzyme into an elimination-proficient one has not been reported. Janus, a bioinformatics method for predicting mutations required to functionally interconvert homologous enzymes, was employed to predict mutations to convert ADCS into AS. A genetic selection on a library of Janus predicted mutations was performed. Complementation of an AS-deficient strain of Escherichia coli grown on minimal medium led to several ADCS mutants that allow growth in 6 days compared to 2 days for wild-type AS. The purified mutant enzymes catalyze the conversion of chorismate to anthranilate at rates that are ~50% of the rate of wild-type ADCS-catalyzed conversion of chorismate to aminodeoxychorismate. The residues mutated do not contact the substrate. Molecular dynamics studies suggest that pyruvate elimination is controlled by the conformation of the C2-aminated intermediate. Enzymes that catalyze elimination favor the equatorial conformation, which presents the C2-H to a conserved active site lysine (Lys424) for deprotonation and maximizes stereoelectronic activation. Acid/base catalysis of pyruvate elimination was confirmed in AS and salicylate synthase by showing incorporation of a solvent-derived proton into the pyruvate methyl group and by solvent kinetic isotope effects on pyruvate elimination catalyzed by AS. PMID- 25710101 TI - Efficacy of transabdominal sonoelastography in the diagnosis of caesarean section scar endometrioma: A pilot study. AB - Transabdominal sonoelastography (TASE) is a new imaging technique that maps the elastic properties of soft tissue. We evaluated 34, consecutive women with suspected scar endometrioma using standard B-mode ultrasound and elastography. Twenty-three women (23/34) underwent surgical excision and had the diagnosis confirmed by histopathology. All endometriomas (23 patients) in B-mode imaging appeared as hypoechoic masses along the line of a previous caesarean section incision and the outer borders were difficult to define precisely. By TASE, the endometrioma presented a typical blue-green-red appearance and the outer borders were clearly defined. (red and green area corresponds with the central hypoechoic soft areas). Strain ratios varied from 0.02 to 0.75. Real-time TASE is a simple, useful technique in confirming a clinical diagnosis of endometrioma in a caesarean section scar. Compared with B-mode ultrasound, it provides additional, preoperative information about the extent of the lesion that may be helpful to the surgeon. PMID- 25710102 TI - Fast and direct Na and K determination in table, marine, and low-sodium salts by X-ray fluorescence and chemometrics. AB - X-ray fluorescence (XRF) is a fast, low-cost, nondestructive, and truly multielement analytical technique. The objectives of this study are to quantify the amount of Na(+) and K(+) in samples of table salt (refined, marine, and light) and to compare three different methodologies of quantification using XRF. A fundamental parameter method revealed difficulties in quantifying accurately lighter elements (Z < 22). A univariate methodology based on peak area calibration is an attractive alternative, even though additional steps of data manipulation might consume some time. Quantifications were performed with good correlations for both Na (r = 0.974) and K (r = 0.992). A partial least-squares (PLS) regression method with five latent variables was very fast. Na(+) quantifications provided calibration errors lower than 16% and a correlation of 0.995. Of great concern was the observation of high Na(+) levels in low-sodium salts. The presented application may be performed in a fast and multielement fashion, in accordance with Green Chemistry specifications. PMID- 25710104 TI - Quantitative analysis of dual-purpose, patient-specific craniofacial implants for correction of temporal deformity. AB - BACKGROUND: The development of computer-assisted design, virtual modeling, and computed tomography has allowed precise customization of implants for patients who undergo neurosurgical or craniofacial surgery procedures. However, such techniques and implant designs have not adequately addressed temporal asymmetry due to postoperative bone resorption, temporalis muscle malposition/foreshortening, and/or temporal fat pad atrophy. OBJECTIVE: We hypothesized that an alteration in customized craniofacial implant (CCI) design with a strategic extension inferolaterally and excessive material bulking would provide simultaneous reconstruction of coexisting temporal skull defects and therefore reduce the effect of soft tissue deformities. METHODS: A single surgeon, single-institution retrospective cohort study was performed to include 10 consecutive subjects who underwent cranioplasty reconstruction with modified implants during a 3-year period. Implants were placed with the use of our previously described pericranial-onlay technique. With the use of a computed tomography-based, computer-assisted design/manufacturing methodology, novel dual purpose implants were designed to prevent and/or correct persistent temporal hollowing. The efficacy of the new CCI shape and design for cranial restoration of temporal symmetry was analyzed in both 2 and 3 dimensions. RESULTS: In 2 dimensional analyses, the modified implant provided enhanced lateral projection (21%; 1.06 cm(3)) in areas closest to the temporal arch. Three-dimensional volumetric analyses demonstrated that additional bulking totaled 24 +/- 11 cm(3) (range, 9-43 cm), which essentially replaced 40 +/- 13.7% (range, 26%-60%) of the absent temporal volume contributing to persistent temporal hollowing. CONCLUSION: Computer-designed, dual-purpose CCIs can be safely created with unprecedented shape to prevent and/or eradicate postoperative temporal deformity. PMID- 25710103 TI - Remnants and recurrences after the use of the WEB intrasaccular device in large neck bifurcation aneurysms. AB - BACKGROUND: Flow disruption with the WEB technique has been developed to treat large-neck bifurcation aneurysms. OBJECTIVE: To report our anatomic angiographic results at first (3-6 months) and second (18 +/- 3 months) angiographic follow-up in a series of 15 patients. METHODS: Fifteen patients (15 aneurysms) were consecutively treated in our center by 2 operators for a large-neck bifurcation aneurysm between March 2012 and February 2014. Results were evaluated by assessing WEB cage position at the aneurysm neck on angiography and high resolution contrast-enhanced flat-panel detector computed tomography, contrast medium stagnation within the WEB and aneurysm on intraprocedural angiography, and 1-day time-of-flight magnetic resonance angiography. All aneurysms were followed up by angiography. Results at follow-up were graded as complete occlusion, neck remnant, or residual aneurysm. The 2 operators compared postprocedural and follow up images and classified them as better, same, or worse. Subtracted images were compared in different projections to assess any WEB device compression or shape changes. RESULTS: A worsening was observed between the postprocedural and first follow-up angiography in 10 of 14 (71.5%) and in 4 of 7 (57.2%) between the first and second control angiography. Compression of the WEB cage was observed at first follow-up in 8 of 14 (57.2%) and in an additional 3 of 7 cases (42.8%) at second control. Last angiography showed complete occlusion in 1 of 14 (7.2%), neck remnant in 8 of 14 (57.2%), and residual aneurysm in 5 of 14 (35.7%) cases. CONCLUSION: This article draws attention to the risk of WEB compression and aneurysm recanalization. Future prospective studies should evaluate delayed WEB shape changes with different types of WEB devices (dual layer, single layer, single layer spherical). ABBREVIATIONS: CO, complete occlusionNR, neck remnantRA, residual aneurysm. PMID- 25710105 TI - Temporal trends in surgical intervention for severe traumatic brain injury caused by extra-axial hemorrhage, 1995 to 2012. AB - BACKGROUND: Surgical intervention for severe traumatic brain injury (TBI) caused by extra-axial hemorrhage has declined in recent decades. The effect of this change on patient outcomes is unknown. OBJECTIVE: To determine the change over time in surgical intervention in this population and to assess changes in patient outcomes. METHODS: In this retrospective cohort study, the Washington State Trauma Registry was queried from 1995 to 2012 for patients with extra-axial hemorrhage and head Abbreviated Injury Scale score of 3 to 5. Data were linked to the state-wide death registry to analyze long-term mortality. The primary outcome was inpatient mortality. Secondary outcomes included 6- and 12-month mortality and modified Functional Independence Measure at discharge. Multivariable analyses were completed for all outcomes. RESULTS: A total of 22974 patients met inclusion criteria. Over the study period, surgical intervention for severe TBI declined from 36% to 7%. There was a decline in case fatality from 22% to 12%. In 2012, the relative risk of inpatient mortality was 23% lower compared with 1995 (adjusted mortality risk ratio, 0.77; 95% confidence interval, 0.63-0.94). Changes in 6- and 12-month adjusted mortality and modified Functional Independence Measure were not statistically significant. CONCLUSION: The decline in surgical intervention for severe TBI caused by extra-axial hemorrhage in Washington State was ubiquitous across regional, demographic, and injury characteristic strata. There was concurrently a reduction in inpatient mortality in this population. Functional status and long-term mortality, however, have remained the same. Future studies are needed to better identify modifiable risk factors for improvement in functional status and long-term mortality in this population. PMID- 25710106 TI - Endoscopy-assisted interhemispheric transcallosal hemispherotomy: preliminary description of a novel technique. AB - BACKGROUND: Various hemispherotomy techniques have been developed to reduce complication rates and achieve the best possible seizure control. OBJECTIVE: To present a novel and minimally invasive endoscopy-assisted approach to perform this procedure. METHODS: Endoscopy-assisted interhemispheric transcallosal hemispherotomy was performed in 5 children (April 2013-June 2014). The procedure consisted of performing a small craniotomy (4 * 3 cm) just lateral to midline using a transverse skin incision. After dural opening, the surgery was performed with the assistance of a rigid high-definition endoscope, and bayoneted self irrigating bipolar forceps and other standard endoscopic instruments. Steps included a complete corpus callosotomy followed by the disconnection of the hemisphere at the level of the basal nuclei and thalamus. The surgeries were performed in a dedicated operating room with intraoperative magnetic resonance imaging and neuronavigation. Intraoperative magnetic resonance imaging confirmed a total disconnection. RESULTS: The pathologies for which surgeries were performed included sequelae of middle a cerebral artery infarct (n = 2), Rasmussen syndrome (n = 1), and hemimegalencephaly (2). Four patients had an Engel class I and 1 patient had a class II outcome at a mean follow-up of 10.2 months (range, 3-14 months). The mean blood loss was 80 mL, and mean operating time was 220 minutes. There were no complications in this study. CONCLUSION: This study describes a pilot novel technique and the feasibility of performing a minimally invasive, endoscopy-assisted hemispherotomy. PMID- 25710107 TI - Integration of indocyanine green videoangiography with operative microscope: augmented reality for interactive assessment of vascular structures and blood flow. AB - BACKGROUND: Preservation of adequate blood flow and exclusion of flow from lesions are key concepts of vascular neurosurgery. Indocyanine green (ICG) fluorescence videoangiography is now widely used for the intraoperative assessment of vessel patency. OBJECTIVE: Here, we present a proof-of-concept investigation of fluorescence angiography with augmented microscopy enhancement: real-time overlay of fluorescence videoangiography within the white light field of view of conventional operative microscopy. METHODS: The femoral artery was exposed in 7 anesthetized rats. The dissection microscope was augmented to integrate real-time electronically processed near-infrared filtered images with conventional white light images seen through the standard oculars. This was accomplished by using an integrated organic light-emitting diode display to yield superimposition of white light and processed near-infrared images. ICG solution was injected into the jugular vein, and fluorescent femoral artery flow was observed. RESULTS: Fluorescence angiography with augmented microscopy enhancement was able to detect ICG fluorescence in a small artery of interest. Fluorescence appeared as a bright-green signal in the ocular overlaid with the anatomic image and limited to the anatomic borders of the femoral artery and its branches. Surrounding anatomic structures were clearly visualized. Observation of ICG within the vessel lumens permitted visualization of the blood flow. Recorded video loops could be reviewed in an offline mode for more detailed assessment of the vasculature. CONCLUSION: The overlay of fluorescence videoangiography within the field of view of the white light operative microscope allows real-time assessment of the blood flow within vessels during simultaneous surgical manipulation. This technique could improve intraoperative decision making during complex neurovascular procedures. PMID- 25710108 TI - Unruptured intracranial aneurysms in children with sickle cell disease: analysis of 18 aneurysms in 5 patients. AB - BACKGROUND: Intracranial aneurysms (IAs) are rare in the general pediatric population and account for <2% of all cerebral aneurysms. Only 7 children with sickle hemoglobinopathy and IAs have been reported, the majority of which were discovered after rupture. OBJECTIVE: To report the prevalence of unruptured IAs in a selected population of children with sickle cell disease (SCD) and to describe the aneurysm morphology, hematologic characteristics, and management in this patient population. METHODS: A retrospective review of the electronic database for all children with SCD who underwent brain magnetic resonance imaging or angiography from January 2002 to August 2013 at a single institution was performed. Records were reviewed for IA, age, sex, sickle cell genotype, neurological symptoms, hematologic indexes, transcranial Doppler findings, and management. RESULTS: Five of 179 children (2.8%) with SCD imaged by brain magnetic resonance imaging or angiography were diagnosed with IAs. None presented with subarachnoid hemorrhage. Four patients (80%) had HbSS disease, and 1 patient had hemoglobin sickle cell HbSC disease. A total of 18 aneurysms were detected; the majority of patients had multiple aneurysms (80%) and bilateral involvement (60%). CONCLUSION: Children with SCD are at risk for developing multiple intracranial aneurysms, and a high index of suspicion must be maintained during the interpretation of routine magnetic resonance imaging or angiography of the brain. PMID- 25710109 TI - Viability of anastomoses with coupler in extra-intracranial bypass: cadaveric study. AB - BACKGROUND: The time required to perform an anastomosis in extra-intracranial bypass is approximately 20 to 60 minutes. The search for alternative methods to reduce the ischemic time remains vital. OBJECTIVE: To evaluate Coupler anastomosis for extra-intracranial bypass in cadavers. METHODS: In 8 fresh adult cadavers, the saphenous vein and radial artery were used as donor vessels. The superficial temporal and the extracranial internal and external carotid arteries were dissected. A wide craniotomy with a sylvian fissure opening was performed, exposing the middle cerebral and supraclinoid internal carotid arteries. The Coupler devices were tested in all 8 cadavers. The diameter of the donor and recipient vessels as well as the time required to perform the anastomosis were measured. Bypass permeability was evaluated by injecting saline solution under pressure, checking for leaks. RESULTS: The anastomoses were successfully performed in all specimens. The size of the head of the fitting Coupler required the performance of a wide craniotomy (6 * 6 cm) and a wide opening of the sylvian fissure. The time required to perform each anastomosis ranged from 4 to 7 minutes, being easier with the radial artery than with the saphenous vein. CONCLUSION: Coupler devices are helpful to perform the anastomoses, because they significantly reduce ischemia time. Their use is easier at the M1 segment, just before the bifurcation and after takeoff of the lenticulostriate arteries, and in the M2 segment. It would be advisable to have a smaller coupling system, allowing maneuverability in the deeper areas where space is limited. PMID- 25710110 TI - Ionic Liquid Hybrid Electrolytes for Lithium-Ion Batteries: A Key Role of the Separator-Electrolyte Interface in Battery Electrochemistry. AB - Batteries are multicomponent systems where the theoretical voltage and stoichiometric electron transfer are defined by the electrochemically active anode and cathode materials. While the electrolyte may not be considered in stoichiometric electron-transfer calculations, it can be a critical factor determining the deliverable energy content of a battery, depending also on the use conditions. The development of ionic liquid (IL)-based electrolytes has been a research area of recent reports by other researchers, due, in part, to opportunities for an expanded high-voltage operating window and improved safety through the reduction of flammable solvent content. The study reported here encompasses a systematic investigation of the physical properties of IL-based hybrid electrolytes including quantitative characterization of the electrolyte separator interface via contact-angle measurements. An inverse trend in the conductivity and wetting properties was observed for a series of IL-based electrolyte candidates. Test-cell measurements were undertaken to evaluate the electrolyte performance in the presence of functioning anode and cathode materials, where several promising IL-based hybrid electrolytes with performance comparable to that of conventional carbonate electrolytes were identified. The study revealed that the contact angle influenced the performance more significantly than the conductivity because the cells containing IL tetrafluoroborate-based electrolytes with higher conductivity but poorer wetting showed significantly decreased performance relative to the cells containing IL bis(trifluoromethanesulfonyl)imide electrolytes with lower conductivity but improved wetting properties. This work contributes to the development of new IL battery-based electrolyte systems with the potential to improve the deliverable energy content as well as safety of lithium-ion battery systems. PMID- 25710111 TI - Density functional theory study of new azo dyes with different pi-spacers for dye sensitized solar cells. AB - Some of new azo-based metal-free dyes with different pi-conjugation spacers, such as carbazole, fluorene, pyrrole, thiophene, furan and thiazole, have been investigated with density functional theory (DFT) and time-dependent DFT (TDDFT) calculations. Theoretical calculations allow us to quantify factors such as light harvesting efficiency (LHE), electron injection driving force (DeltaG(inject)) and the weight of the LUMO orbital on the carboxylic group (QLUMO) related to the short-circuit photocurrent density (Jsc), and to evaluate both charge recombination between the semiconductor conduction band electrons and the oxidized dyes and/or electrolyte, and also the shift of the conduction band of the semiconductor as a result of the adsorption of the dyes onto the semiconductor surface, associated with the open-circuit photovoltage (Voc). According to the results, we could predict that how the pi-conjugation spacers influence the Jsc as well as the Voc of DSSCs. Among these dyes, the carbazole and fluorene-based dyes (dyes 1 and 2) show the highest LHE, DeltaG(inject), QLUMO, and the slowest recombination rate. Consequently, the obtained results show that the carbazole and fluorene-based dyes could have the better Jsc and Voc compared to the other dyes. PMID- 25710113 TI - Structure and nonlinear optical property analysis of L-Methioninium oxalate: a DFT approach. AB - Infrared and FT-Raman spectra of the nonlinear optical material l-Methioninium Oxalate were recorded and analyzed. The optimized geometry, first-order hyperpolarizability and harmonic vibrational wavenumbers were calculated with the help of density functional theory method. The detailed interpretation of the vibrational spectra was carried out with the aid of normal coordinate analysis followed by scaled quantum mechanical force field methodology. Stability of the molecule arising from hyperconjugative interactions leading to its nonlinear optical activity and charge delocalization were analyzed using natural bond orbital technique. Mulliken atomic charge and molecular electrostatic potential are also predicted. HOMO-LUMO energy gap value suggests the possibility of charge transfer within the molecule. The thermodynamic properties at different temperatures are also calculated. PMID- 25710112 TI - Different behaviors in the transformation of PATP adsorbed on Ag or Au nanoparticles investigated by surface-enhanced Raman spectroscopy - a study of the effects from laser energy and annealing. AB - In order to explore the key role of surface plasmon resonance (SPR) and active (3)O2 for the chemical transformation to 4,4-dimercaptoazobenzene (DMAB) from p aminothiophenol (PATP) adsorbed on Ag or Au NPs, we systematically investigated the laser wavelength and temperature dependent surface-enhanced Raman spectra of PATP capped Ag and Au NPs. DMAB can be easily observed at the 514.5nm laser for Ag NPs but at the 632.8nm laser for Au NPs, indicating that a suitable energy level is necessary for the formation of DMAB. The tendency is consistent with the wavelength dependent SPR properties of Ag or Au NPs accordingly. With the energy provided by annealing, the transformation of PATP to DMAB is much easier on Ag NPs at a lower temperature, and more DMAB can be observed at the same temperature, compared to the case of Au NPs under the same condition. It is mainly due to the active (3)O2 on Ag surfaces could be more easily formed than that on Au surfaces. PMID- 25710114 TI - Synthesis, characterization, biological evaluation and docking studies of macrocyclic binuclear manganese(II) complexes containing 3,5-dinitrobenzoyl pendant arms. AB - A series of bis(phenoxo) bridged binuclear manganese(II) complexes of the type [Mn2L(1-3)](ClO4)2 (1-3) containing 3,5-dinitrobenzoyl pendant-arms have been synthesized by cyclocondensation of 2,6-diformyl-4-R-phenols (where R=CH3, C(CH3)3 or Br) with 2,2'-3,5-dinitrobenzoyliminodi(ethylamine) trihydrochloride in the presence of manganese(II) perchlorate. The IR spectra of complexes indicate the presence of uncoordinated perchlorate anions. The UV-Vis spectra of complexes suggest the distorted octahedral geometry around manganese(II) nuclei. The EPR spectra of Mn(II) complexes show a broad signal with g value 2.03-2.04, which is characteristic for octahedral high spin Mn(2+) complex. The observed room temperature magnetic moment values of the Mn(II) complexes (5.60-5.62B.M.) are less than the normal value (5.92B.M.), indicating weak antiferromagnetic coupling interaction between the two metal ions. Electrochemical studies of the complexes show two distinct quasi-reversible one electron transfer processes in the cathodic (E(1)pc=-0.73 to -0.76V, E(2)pc=-1.30 to -1.36V), and anodic (E(1)pa=1.02-1.11V, E(2)pa=1.32-1.79V) potential regions. Antibacterial efficacy of complexes have been screened against four Gram (-ve) and two Gram (+ve) bacterial strains. The DNA interaction studies suggest that these complexes bind with CT-DNA by intercalation, giving the binding affinity in the order 1>2>3. All the complexes display significant cleavage activity against circular plasmid pBR322 DNA. Docking simulation was performed to insert complexes into the crystal structure of EGFR tyrosine kinase and B-DNA at active site to determine the probable binding mode. PMID- 25710115 TI - Intra- and intermolecular hydrogen bonding and conformation in 1-acyl thioureas: an experimental and theoretical approach on 1-(2-chlorobenzoyl)thiourea. AB - The vibrational analysis (FT-IR and FT-Raman) for the new 1-(2 chlorobenzoyl)thiourea species suggests that strong intramolecular interactions affect the conformational properties. The X-ray structure determination corroborates that an intramolecular N-H?OC hydrogen bond occurs between the carbonyl (-CO) and thioamide (-NH2) groups. Moreover, periodic system electron density and topological analysis have been applied to characterize the intermolecular interactions in the crystal. Extended N-H?SC hydrogen-bonding networks between both the thioamide (N-H) and carbamide (NH2) groups and the thiocarbonyl bond (CS) determine the crystal packing. The Natural Bond Orbital (NBO) population analysis demonstrates that strong hyperconjugative remote interactions are responsible for both, intra and intermolecular interactions. The Atom in Molecule (AIM) results also show that the N-H?Cl intramolecular hydrogen bond between the 2-Cl-phenyl ring and the amide group characterized in the free molecule changes to an N?Cl interaction as a consequence of crystal packing. PMID- 25710116 TI - Raman and infrared spectroscopic study of kamphaugite-(Y). AB - We have studied the carbonate mineral kamphaugite-(Y)(CaY(CO3)2(OH).H2O), a mineral which contains yttrium and specific rare earth elements. Chemical analysis shows the presence of Ca, Y and C. Back scattering SEM appears to indicate a single pure phase. The vibrational spectroscopy of kamphaugite-(Y) was obtained using a combination of Raman and infrared spectroscopy. Two distinct Raman bands observed at 1078 and 1088cm(-1) provide evidence for the non equivalence of the carbonate anion in the kamphaugite-(Y) structure. Such a concept is supported by the number of bands assigned to the carbonate antisymmetric stretching mode. Multiple bands in the nu4 region offers further support for the non-equivalence of carbonate anions in the structure. Vibrational spectroscopy enables aspects of the structure of the mineral kamphaugite-(Y) to be assessed. PMID- 25710117 TI - A family of tri- and dimetallic pyridine dicarboxamide cryptates: unusual O,N,O coordination and facile access to secondary coordination sphere hydrogen bonding interactions. AB - A series of tri- and dimetallic metal complexes of pyridine dicarboxamide cryptates are reported in which changes to the base and metal source result in diverse structure types. Addition of strong bases, such as KH or KN(SiMe3)2, followed by divalent metal halides allows direct access to trinuclear complexes in which each metal center is coordinated by a dianionic N,N,N-chelate of each arm. These complexes bind a guest K(+) cation within the central cavity in a trigonal planar coordination environment. Minor changes to the solvent and equivalents of base used in the syntheses of the triiron(II) and tricobalt(II) complexes affords two trinuclear clusters with atypical O,N,O-coordination by each pyridine dicarboxamide arm; the amide carbonyl O atoms are oriented toward the interior of the cavity to coordinate to each metal center. Finally, varying the base enables the selective synthesis of dinuclear nickel(II) and copper(II) complexes in which one pyridine dicarboxamide arm remains protonated. These amide protons are at one end of a hydrogen bonding network that extends throughout the internal cavity and terminates at a metal bound hydroxide, carbonate, or bicarbonate donor. In the dinickel complex, the bicarbonate cannot be liberated as CO2 either thermally or upon sparging with N2, which differs from previously reported monometallic complexes. The carbonate or bicarbonate ligands likely arise from sequestration of atmospheric CO2 based on the observed reaction of the di(hydroxonickel) analog. PMID- 25710118 TI - Justification and good practice in using handheld portable dental X-ray equipment: a position paper prepared by the European Academy of DentoMaxilloFacial Radiology (EADMFR). AB - Handheld portable X-ray devices are increasingly used for intraoral radiography. This development introduces new challenges to staff and patient safety, for which new or revised risk assessments must be made and acted upon prior to use. Major issues might be: difficulties in using rectangular collimation with beam aiming devices, more complex matching of exposure settings to the X-ray receptor used (e.g. longer exposure times), movements owing to the units' weight, protection of the operator and third persons, and the use in uncontrolled environments. These problems may result in violation of the "as low as reasonably achievable'', that is, ALARA principle by an increase in (re)exposures compared with the other available intraoral X-ray devices. Hence, the use of handheld portable X-ray devices should be considered only after careful and documented evaluation (which might be performed based on medical physics support), when there is evidence that handheld operation has benefits over traditional modalities and when no new risks to the operators and/or third parties are caused. It is expected that the use of handheld portable X-ray devices will be very exceptional, and for justified situations only. Special attention should be drawn to beam-aiming devices, rectangular collimation, the section of the X-ray receptor, focus-skin distance, and backscatter shielding, and that the unit delivers reproducible dose over the full set of environmental conditions (e.g. battery status and temperature). PMID- 25710119 TI - Genetic variants in combination with early partial improvement as a clinical utility predictor of treatment outcome in major depressive disorder: the result of two pooled RCTs. AB - Pharmacogenetics may allow for a personalized treatment, but a combination with clinical variables may further enhance prediction. In particular, in the present paper, we investigated early partial improvement (EPI) defined as 20% or more improvement by rating scales 2 weeks after treatment, in combination with selected gene variants as a predictor of treatment outcome in patients with major depressive disorder. Two randomized controlled trials with 168 Japanese depressed patients were used. A stepwise multiple linear regression model with HAM-D score change at week 6 as the dependent variable and genotypes, EPI, baseline HAM-D score, age and sex as independent variables was performed in paroxetine, fluvoxamine and milnacipran, respectively, to estimate the prediction of HAM-D change at week 6. In the paroxetine sample, only EPI (P<0.001) was significantly associated with HAM-D change (n=81, R(2)=0.25, P<0.001). In the fluvoxamine sample, 5-HTTLPR La/Lg, S (P=0.029), FGF2 rs1449683C/T (P=0.013) and EPI (P=0.003) were associated with HAM-D change (n=42, R(2)=0.43, P<0.001). In the milnacipran sample, HTR-1A-1019C/G (P=0.001), ADRA2A-1297C/G (P=0.028) and EPI (P<0.001) were associated with outcome (n=45, R(2)=0.71, P<0.001). EPI in combination with genetic variants could be a useful predictor of treatment outcome and could strengthen the practical use of pharmacogenetic data in clinical practice. PMID- 25710120 TI - Searching for a minimal set of behaviors for autism detection through feature selection-based machine learning. AB - Although the prevalence of autism spectrum disorder (ASD) has risen sharply in the last few years reaching 1 in 68, the average age of diagnosis in the United States remains close to 4--well past the developmental window when early intervention has the largest gains. This emphasizes the importance of developing accurate methods to detect risk faster than the current standards of care. In the present study, we used machine learning to evaluate one of the best and most widely used instruments for clinical assessment of ASD, the Autism Diagnostic Observation Schedule (ADOS) to test whether only a subset of behaviors can differentiate between children on and off the autism spectrum. ADOS relies on behavioral observation in a clinical setting and consists of four modules, with module 2 reserved for individuals with some vocabulary and module 3 for higher levels of cognitive functioning. We ran eight machine learning algorithms using stepwise backward feature selection on score sheets from modules 2 and 3 from 4540 individuals. We found that 9 of the 28 behaviors captured by items from module 2, and 12 of the 28 behaviors captured by module 3 are sufficient to detect ASD risk with 98.27% and 97.66% accuracy, respectively. A greater than 55% reduction in the number of behaviorals with negligible loss of accuracy across both modules suggests a role for computational and statistical methods to streamline ASD risk detection and screening. These results may help enable development of mobile and parent-directed methods for preliminary risk evaluation and/or clinical triage that reach a larger percentage of the population and help to lower the average age of detection and diagnosis. PMID- 25710121 TI - Pregnant women's cognitive appraisal of a natural disaster affects DNA methylation in their children 13 years later: Project Ice Storm. AB - Prenatal maternal stress (PNMS) can impact a variety of outcomes in the offspring throughout childhood and persisting into adulthood as shown in human and animal studies. Many of the effects of PNMS on offspring outcomes likely reflect the effects of epigenetic changes, such as DNA methylation, to the fetal genome. However, no animal or human research can determine the extent to which the effects of PNMS on DNA methylation in human offspring is the result of the objective severity of the stressor to the pregnant mother, or her negative appraisal of the stressor or her resulting degree of negative stress. We examined the genome-wide DNA methylation profile in T cells from 34 adolescents whose mothers had rated the 1998 Quebec ice storm's consequences as positive or negative (that is, cognitive appraisal). The methylation levels of 2872 CGs differed significantly between adolescents in the positive and negative maternal cognitive appraisal groups. These CGs are affiliated with 1564 different genes and with 408 different biological pathways, which are prominently featured in immune function. Importantly, there was a significant overlap in the differentially methylated CGs or genes and biological pathways that are associated with cognitive appraisal and those associated with objective PNMS as we reported previously. Our study suggests that pregnant women's cognitive appraisals of an independent stressor may have widespread effects on DNA methylation across the entire genome of their unborn children, detectable during adolescence. Therefore, cognitive appraisals could be an important predictor variable to explore in PNMS research. PMID- 25710123 TI - A methodological framework for linking bioreactor function to microbial communities and environmental conditions. AB - In the continuing quest to relate microbial communities in bioreactors to function and environmental and operational conditions, engineers and biotechnologists have adopted the latest molecular and 'omic methods. Despite the large amounts of data generated, gaining mechanistic insights and using the data for predictive and practical purposes is still a huge challenge. We present a methodological framework that can guide experimental design, and discuss specific issues that can affect how researchers generate and use data to elucidate the relationships. We also identify, in general terms, bioreactor research opportunities that appear promising. PMID- 25710122 TI - Prefrontal cortex markers of suicidal vulnerability in mood disorders: a model based structural neuroimaging study with a translational perspective. AB - The vulnerability to suicidal behavior has been modeled in deficits in both valuation and cognitive control processes, mediated by ventral and dorsal prefrontal cortices. To uncover potential markers of suicidality based on this model, we measured several brain morphometric parameters using 1.5T magnetic resonance imaging in a large sample and in a specifically designed study. We then tested their classificatory properties. Three groups were compared: euthymic suicide attempters with a past history of mood disorders and suicidal behavior (N=67); patient controls with a past history of mood disorders but not suicidal behavior (N=82); healthy controls without any history of mental disorder (N=82). A hypothesis-driven region-of-interest approach was applied targeting the orbitofrontal cortex (OFC), ventrolateral (VLPFC), dorsal (DPFC) and medial (including anterior cingulate cortex; MPFC) prefrontal cortices. Both voxel-based (SPM8) and surface-based morphometry (Freesurfer) analyses were used to comprehensively evaluate cortical gray matter measure, volume, surface area and thickness. Reduced left VLPFC volume in attempters vs both patient groups was found (P=0.001, surviving multiple comparison correction, Cohen's d=0.65 95% (0.33-0.99) between attempters and healthy controls). In addition, reduced measures in OFC and DPFC, but not MPFC, were found with moderate effect sizes in suicide attempters vs healthy controls (Cohen's d between 0.34 and 0.52). Several of these measures were correlated with suicidal variables. When added to mood disorder history, left VLPFC volume increased within-sample specificity in identifying attempters in a significant but limited way. Our study, therefore, confirms structural prefrontal alterations in individuals with histories of suicide attempts. A future clinical application of these markers will, however, necessitate further research. PMID- 25710124 TI - Gradual release of strongly bound nitric oxide from Fe2(NO)2(dobdc). AB - An iron(II)-based metal-organic framework featuring coordinatively unsaturated redox-active metal cation sites, Fe2(dobdc) (dobdc(4-) = 2,5-dioxido-1,4 benzenedicarboxylate), is shown to strongly bind nitric oxide at 298 K. Adsorption isotherms indicate an adsorption capacity greater than 16 wt %, corresponding to the adsorption of one NO molecule per iron center. Infrared, UV vis, and Mossbauer spectroscopies, together with magnetic susceptibility data, confirm the strong binding is a result of electron transfer from the Fe(II) sites to form Fe(III)-NO(-) adducts. Consistent with these results, powder neutron diffraction experiments indicate that NO is bound to the iron centers of the framework with an Fe-NO separation of 1.77(1) A and an Fe-N-O angle of 150.9(5) degrees . The nitric oxide-containing material, Fe2(NO)2(dobdc), steadily releases bound NO under humid conditions over the course of more than 10 days, suggesting it, and potential future iron(II)-based metal-organic frameworks, are good candidates for certain biomedical applications. PMID- 25710125 TI - Peak match speed and maximal sprinting speed in young soccer players: effect of age and playing position. AB - This study assessed the relationship between peak match speed (PMS) and maximal sprinting speed (MSS) in regard to age and playing positions. MSS and absolute PMS (PMSAbs) were collected from 180 male youth soccer players (U13-U17, 15.0 +/- 1.2 y, 161.5 +/- 9.2 cm, and 48.3 +/- 8.7 kg). The fastest 10-m split over a 40-m sprint was used to determine MSS. PMSAbs was recorded using a global positioning system and was also expressed as a percentage of MSS (PMSRel). Sprint data were compared between age groups and between playing positions. Results showed that regardless of age and playing positions, faster players were likely to reach higher PMSAbs and possibly lower PMSRel. Despite a lower PMSAbs than in older groups (eg, 23.4 +/- 1.8 vs 26.8 +/- 1.9 km/h for U13 and U17, respectively, ES = 1.9 90%, confidence limits [1.6;2.1]), younger players reached a greater PMSRel (92.0% +/- 6.3% vs. 87.2% +/- 5.7% for U13 and U17, respectively, ES = -0.8 90% CL [-1.0;-0.5]). Playing position also affected PMSAbs and PMSRel, as strikers were likely to reach higher PMSAbs (eg, 27.0 +/- 2.7 vs 23.6 +/- 2.2 km/h for strikers and central midfielders, respectively, ES = 2.0 [1.7;2.2]) and PMSRel (eg, 93.6% +/- 5.2% vs 85.3% +/- 6.5% for strikers and central midfielders, respectively, ES = 1.0 [0.7;1.3]) than all other positions. The findings confirm that age and playing position affect the absolute and relative intensity of speed related actions during matches. PMID- 25710126 TI - Dietary exposure to non-dioxin-like PCBs of different population groups in Austria. AB - The dietary exposure to the sum of the six indicator PCBs (Sigma6 PCBs; PCB 28, 52, 101, 138, 153, and 180) across different Austrian population groups was assessed in this study by combining data on occurrence from food of the Austrian market (n=157) analysed during 2006-2011 with national food consumption data. The most contaminated food group was meat, poultry, game and offal with average levels of ndl-PCBs of 5.20 ng g(-1) fat. In fish and fish products and eggs, mean concentrations of 3.89 ng g(-1) fresh weight (fw) and 4.00 ng g(-1) fat, respectively, were found. In milk and dairy products average concentrations ranged from 3.07 to 4.44 ng g(-1) fat. The mean dietary intake of Sigma6 PCBs was estimated to be 3.37 ng kg(-1) bw d(-1) for children (6-15 years old), 3.19 ng kg(-1) bw d(-1) for women (19-65 years) and 2.64 ng kg(-1) bw d(-1) for men (19 65 years). In all three population groups, milk and dairy products was the major contributing food group to the total dietary intake (50-55%) followed by fish and fish products (23-27%). The exposure of all Austrian population groups is well below the tolerable daily intake (TDI) of 10 ng kg(-1) bw d(-1) proposed by WHO, accounting for 34% in children, 32% in women and 26% in men. PMID- 25710127 TI - Phase transitions and interrelated instabilities in PbHfO3 single crystals. AB - PbHfO(3) is investigated theoretically and experimentally with respect to possible precursor effects starting in the paraelectric phase far above the cubic to tetragonal phase transition temperature. The theoretical modeling within the polarizability model predicts a giant softness of the system with spatially large polar and antiferrodistortive domain formation which compete with each other. These predictions are substantiated by the experiments, where the softness and the precursor effects are confirmed by birefringence, dielectric permittivity measurements and elastic properties by Brillouin scattering. The intermediate phase is found to have the polar nature confirmed by P-E hysteresis loop measurements, which is another manifestation of the competition between interrelated instabilities, namely a polar one and an antiferroelectric one. PMID- 25710128 TI - Iminoborylene complexes: evaluation of synthetic routes towards BN-allenylidenes and unexpected reactivity towards carbodiimides. AB - The synthetic and reaction chemistries of cationic iminoborylene complexes [LnM=B=N=CR2](+), which feature a unique heterocumulene structure, have been systematically investigated. Precursors of the type CpFe(CO)2B(Cl)NCAr2 (Ar = p Tol/Mes, 5c/d) have been generated by B-centred substitution chemistry using CpFe(CO)2BCl2 and suitable lithiated ketimines - a reaction which is found to be highly sensitive to the steric bulk at both the metal fragment and the ketimino group. Carbonyl/phosphine exchange (using PCy3 or PPh3), followed by halide abstraction allows for the generation of the cationic iminoborylenes [CpFe(PR3)(CO)(BNCAr2)](+)[BAr(X)4](-) (R = Cy, Ar = p-Tol/Mes, 12c/d; R = Ph, Ar = Mes, 13d; Ar(X) = 3,5-X2C6H3 where X = Cl, CF3) which have been characterized spectroscopically and by X-ray crystallography. The reactivity of these iminoborylene systems towards a range of nucleophiles and unsaturated substrates has been investigated. The latter includes the first examples of M=B metathesis reactivity with a carbodiimide, and results in Fe=B cleavage and formation of the isonitrile complexes [CpFe(PCy3)(CO)(CNR)](+)[BAr(Cl)4](-) (R = (i)Pr/Cy, 16/17). PMID- 25710129 TI - Post-infectious bronchiolitis obliterans in children: CT features that predict responsiveness to pulse methylprednisolone. AB - OBJECTIVE: Intravenous pulse methylprednisolone therapy (IPMT) is an important treatment option for post-infectious obliterative bronchiolitis (OB), although it must be used carefully and only in selected patients because of its drawbacks. This study evaluated whether CT and clinical features of children with post infectious OB can predict their responsiveness to IPMT. METHODS: We searched the medical records for patients (less than 18 years of age) who were diagnosed with post-infectious OB between January 2000 and December 2011. 17 children who received IPMT were included in this study. All underwent chest CT before and after IPMT. The radiological features seen on pre-treatment CT were recorded. The air-trapping area percentages on pre- and post-treatment CT images were determined. The nine patients who exhibited decreased air trapping on post treatment CT scans relative to pre-treatment scans were classed as responders. The patient ages and time from initial pneumonia to IPMT were recorded. RESULTS: All responders and only four non-responders had thickened bronchial walls before treatment (p = 0.029). The two groups did not differ significantly in terms of bronchiolitis, bronchiectasis or the extent of air trapping, although the responders had a significantly shorter median interval between initial pneumonia and IPMT (4 vs 50 months; p = 0.005) and were significantly younger (median, 2.0 vs 7.5 years; p = 0.048). CONCLUSION: Immediate IPMT may improve the degree of air trapping in children with post-infectious OB if they show a thickened bronchial wall on CT. ADVANCES IN KNOWLEDGE: Children with post-infectious OB may respond favourably to IPMT when pre-treatment CT indicates bronchial-wall thickening. PMID- 25710130 TI - Raman response of network modifier cations in alumino-silicate glasses. AB - Raman scattering is performed in three sets of aluminosilicate glasses with light cations and concentrations varying from peralcaline to peraluminate domain. The depolarized spectra highlight two cation modes below ~400 cm(-1). Comparison with infrared data reveals very stringent selection rules providing as much additional information for a vibrational analysis. The latter suggests in-phase (network coupled) and out-of-phase (network-decoupled) displacements of the cations relative to their adjacent negatively charged structures. The low frequency vibration involves all cations whatever their role in the glass, network modifiers or charge compensators. Very interestingly, the second mode originates mostly from cations at modifier's places, providing thereby a new support for structural and chemical analysis of silicate glasses using Raman scattering. PMID- 25710131 TI - Cerebral Amyloid Angiopathy-related Inflammation Presenting With Rapidly Progressive Dementia, Responsive to IVIg. PMID- 25710132 TI - Cancer and Dementia: It's Complicated. AB - The relationship between dementia and cancer is complex. A wealth of observational data suggest (1) reduced risk of certain cancers in Alzheimer and Parkinson diseases; and (2) increased risk of other cancers in Parkinson disease. These relationships persist despite correcting for reporting artifacts and survival bias. Several potential mechanisms have been proposed and warrant further investigation. Aging is a risk factor for both. Common environmental exposures, such as smoking, may play roles. Common mechanisms such as chronic inflammation and immunosenescence, and common risk factors such as diabetes and obesity, have been implicated. Shared genetic pathways are a major focus, particularly those favoring apoptosis and cell proliferation at opposite ends of the spectrum. To complicate the picture further, certain cancer chemotherapy and adjuvant therapy agents have neurotoxic effects, whereas animal studies show other cancer drugs reducing neurodegeneration, raising the possibility of repurposing those agents for use in Alzheimer disease. These multiple potential lines of evidence must be disentangled to investigate underlying mechanisms, the end-game being to develop and to test potential prevention and treatment strategies. PMID- 25710133 TI - Quantitating membrane bleb stiffness using AFM force spectroscopy and an optical sideview setup. AB - AFM-based force spectroscopy in combination with optical microscopy is a powerful tool for investigating cell mechanics and adhesion on the single cell level. However, standard setups featuring an AFM mounted on an inverted light microscope only provide a bottom view of cell and AFM cantilever but cannot visualize vertical cell shape changes, for instance occurring during motile membrane blebbing. Here, we have integrated a mirror-based sideview system to monitor cell shape changes resulting from motile bleb behavior of Xenopus cranial neural crest (CNC) cells during AFM elasticity and adhesion measurements. Using the sideview setup, we quantitatively investigate mechanical changes associated with bleb formation and compared cell elasticity values recorded during membrane bleb and non-bleb events. Bleb protrusions displayed significantly lower stiffness compared to the non-blebbing membrane in the same cell. Bleb stiffness values were comparable to values obtained from blebbistatin-treated cells, consistent with the absence of a functional actomyosin network in bleb protrusions. Furthermore, we show that membrane blebs forming within the cell-cell contact zone have a detrimental effect on cell-cell adhesion forces, suggesting that mechanical changes associated with bleb protrusions promote cell-cell detachment or prevent adhesion reinforcement. Incorporating a sideview setup into an AFM platform therefore provides a new tool to correlate changes in cell morphology with results from force spectroscopy experiments. PMID- 25710134 TI - Medical interventions for acanthamoeba keratitis. AB - BACKGROUND: Acanthamoeba are microscopic, free-living, single-celled organisms which can infect the eye and lead to Acanthamoeba keratitis (AK). AK can result in loss of vision in the infected eye or loss of eye itself; however, there are no formal guidelines or standards of care for the treatment of AK. OBJECTIVES: To evaluate the relative effectiveness and safety of medical therapy for the treatment of AK. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (2015, Issue 1), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to January 2015), EMBASE (January 1980 to January 2015), PubMed (1948 to January 2015), Latin American and Caribbean Health Sciences Literature Database (LILACS) (1982 to January 2015), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic search for trials. We last searched the electronic databases on 9 January 2015. SELECTION CRITERIA: We included randomized controlled trials (RCTs) of medical therapy for AK, regardless of the participants' age, sex, or etiology of disease. We included studies that compared either anti-amoeba therapy (drugs used alone or in combination with other medical therapies) with no anti-amoeba therapy or one anti amoeba therapy with another anti-amoeba therapy. DATA COLLECTION AND ANALYSIS: Two authors independently screened search results and full-text reports, assessed risk of bias, and abstracted data. We used standard methodological procedures as set forth by the Cochrane Collaboration. MAIN RESULTS: We included one RCT (56 eyes of 55 participants) in this review. The study compared two types of topical biguanides for the treatment of AK: chlorhexidine 0.02% and polyhexamethylene biguanide (PHMB) 0.02%. All participants were contact lens wearers with a median age of 31 years. Treatment duration ranged from 51 to 145 days. The study, conducted in the UK, was well-designed and had low risk of bias overall.Outcome data were available for 51 (91%) of 56 eyes. Follow-up times for outcome measurements in the study were not reported. Resolution of infection, defined as control of ocular inflammation, relief of pain and photosensitivity, and recovery of vision, was 86% in the chlorhexidine group compared with 78% in the PHMB group (relative risk (RR) 1.10, 95% confidence intervals (CI) 0.84 to 1.42). In the chlorhexidine group, 20 of 28 eyes (71%) had better visual acuity compared with 13 of 23 eyes (57%) in the PHMB group at final follow-up (RR 1.26, 95% CI 0.82 to 1.94). Five participants required therapeutic keratoplasty: 2 in the chlorhexidine group compared with 3 in the PHMB group (RR 0.55, 95% CI 0.10 to 3.00). No serious adverse event related to drug toxicity was observed in the study. AUTHORS' CONCLUSIONS: There is insufficient evidence to evaluate the relative effectiveness and safety of medical therapy for the treatment of AK. Results from the one included study yielded no difference with respect to outcomes reported between chlorhexidine and PHMB. However, the sample size was inadequate to detect clinically meaningful differences between the two groups as indicated by the wide confidence intervals of effect estimates. PMID- 25710135 TI - Application of a three-dimensional computational wrist model to proximal row carpectomy. AB - A three-dimensional (3D) computational model of the wrist examined the biomechanical effects of the proximal row carpectomy (PRC), a surgical treatment of certain wrist degenerative conditions but with functional consequences. Model simulations, replicating the 3D bony anatomy, soft tissue restraints, muscle loading, and applied perturbations, demonstrated quantitatively accurate responses for the decreased motions subsequent to the surgical procedure. It also yielded some knowledge of alterations in radiocarpal contact force which likely increase contact pressure as well as additional insight into the importance of the triangular fibrocartilage complex and retinacular/capsular structures for stabilizing the deficient wrist. As better understanding of the wrist joint is achieved, this model could serve as a useful clinical tool. PMID- 25710137 TI - Transfer of Escherichia coli O157:H7 from simulated wildlife scat onto romaine lettuce during foliar irrigation. AB - A field trial in Salinas Valley, California, was conducted during July 2011 to quantify the microbial load that transfers from wildlife feces onto nearby lettuce during foliar irrigation. Romaine lettuce was grown using standard commercial practices and irrigated using an impact sprinkler design. Five grams of rabbit feces was spiked with 1.29 * 10(8) CFU of Escherichia coli O157:H7 and placed - 3, - 2, and - 1 days and immediately before a 2-h irrigation event. Immediately after irrigation, 168 heads of lettuce ranging from ca. 23 to 69 cm (from 9 to 27 in.) from the fecal deposits were collected, and the concentration of E. coli O157:H7 was determined. Thirty-eight percent of the collected lettuce heads had detectable E. coli O157:H7, ranging from 1 MPN to 2.30 * 10(5) MPN per head and a mean concentration of 7.37 * 10(3) MPN per head. Based on this weighted arithmetic mean concentration of 7.37 * 10(3) MPN of bacteria per positive head, only 0.00573% of the original 5 g of scat with its mean load of 1.29 * 10(8) CFU was transferred to the positive heads of lettuce. Bacterial contamination was limited to the outer leaves of lettuce. In addition, factors associated with the transfer of E. coli O157:H7 from scat to lettuce were distance between the scat and lettuce, age of scat before irrigation, and mean distance between scat and the irrigation sprinkler heads. This study quantified the transfer coefficient between scat and adjacent heads of lettuce as a function of irrigation. The data can be used to populate a quantitative produce risk assessment model for E. coli O157:H7 in romaine lettuce to inform risk management and food safety policies. PMID- 25710138 TI - Survival of Salmonella or Escherichia coli O157:H7 during holding of manure-based compost mixtures at sublethal temperatures as influenced by the carbon amendment. AB - During the early phases of aerobic composting of animal manures, pathogens are inactivated primarily from the accumulation of heat produced by indigenous microbial activity. When compost materials are not exposed to these lethal temperatures, the required holding time needed to obtain a pathogen-free product that may be applied to fields is unknown. Consequently, a series of studies examined whether the carbon amendment (wheat straw, peanut hulls, rice hulls, and pine needles) added to animal manures affected survival of either Salmonella or E. coli O157:H7 during storage of compost mixtures at sublethal temperatures (20 to 40 degrees C). Pathogens consistently survived for longer periods of time in compost mixtures prepared with pine needles than compost mixtures prepared with either of the other three carbon amendments. Pathogen inactivation in wheat straw or peanut hull-amended compost mixtures was dependent on the target pathogen, moisture level, and storage temperature. Moisture levels in wheat straw-amended compost mixtures stored at 40 degrees C had no effect on inactivation of E. coli O157:H7. In contrast, wheat straw-amended mixtures stored at 30 to 35 degrees C and equilibrated to suboptimal moisture contents (30 to 40%) were less effective for inactivating pathogens compared with drier (25% moisture) or moister (60% moisture) mixtures. In peanut hull-amended compost mixtures, inactivation of E. coli O157:H7 was affected minimally by moisture levels, whereas Salmonella survival increased as the moisture level was decreased. The different inactivation responses of Salmonella and E. coli O157:H7 in compost mixtures prepared with wheat straw or peanut hulls and equilibrated to different moisture levels suggest that there are different mechanisms for inactivation. Hence, developing reliable guidelines relying on time-temperature for holding of compost mixtures at sublethal temperatures will be challenging and, perhaps, not possible. PMID- 25710139 TI - Microbiological effects of a routine treatment for decontaminating hide-on carcasses at a large beef packing plant. AB - To investigate the microbiological effects of a hide-on carcass decontaminating treatment recently implemented at a beef packing plant, carcasses undergoing routine processing at the plant were sampled during successive periods in January/February, April/May, and September/October. During each period, samples were collected from carcasses before and after the decontamination of hide-on carcasses, after skinning, before decontamination of the skinned carcasses, and at the end of the carcass dressing process. At each stage of processing during each period, samples were obtained by swabbing an area of 1,000 cm(2) on each of 25 carcasses. Aerobes, coliforms, and Escherichia coli were enumerated. In most samples, coliforms were predominantly E. coli. In all three periods, the log mean numbers of aerobes and E. coli recovered from hides before decontamination were between 6.6 and 6.8 and between 5.3 and 5.9 log CFU/1,000 cm(2), respectively. The log mean numbers of aerobes recovered from decontaminated hides were 6.6 log CFU/1,000 cm(2) in January/February and April/May but 5.4 log CFU/1,000 cm(2) in September/October. The log total numbers of E. coli recovered from decontaminated hides in January/February and April/May were 2.4 and 3.8 log CFU/25,000 cm(2), respectively, but no E. coli was recovered from such carcasses in September/October. Log total numbers of aerobes and E. coli recovered from skinned or dressed carcasses were mostly >4 and between 1 and 2 log CFU/25,000 cm(2), respectively. Typing of 480 E. coli isolates by multiple-locus variable number tandem repeat analysis (MLVA) identified 218 MLVA types. Most isolates recovered from carcasses in different periods or at different stages of processing were of different MLVA types. However, small numbers of MLVA types were recovered in more than one period or from both hides before and after decontamination and skinned or dressed carcasses. The findings show that the hide decontaminating treatment disrupted the usual transfer of E. coli from hides to meat surfaces during carcass skinning. PMID- 25710140 TI - Virulence characterization and molecular subtyping of typical and atypical Escherichia coli O157:H7 and O157:H(-) isolated from fecal samples and beef carcasses in Mexico. AB - The objective of the study was to characterize virulence genes and subtype Escherichia coli O157:H7 and O157:H( 2 ) isolates obtained from a vertically integrated feedlot slaughter plant in Mexico. A total of 1,695 samples were collected from feedlots, holding pens, colon contents, hides, and carcasses. E. coli O157:H7 detection and confirmation was carried out using conventional microbiology techniques, immunomagnetic separation, latex agglutination, and the BAX system. A total of 97 E. coli O157 strains were recovered and screened for key virulence and metabolic genes using multiplex and conventional PCR. Eighty eight (91.72%) of the strains carried stx2, eae, and ehxA genes. Ten isolates (8.25%) were atypical sorbitol-fermenting strains, and nine were negative for the flicH7 gene and lacked eae, stx1, stx2, and ehxA. One sorbitol-positive strain carried stx2, eae, tir, toxB, and iha genes but was negative for stx1 and ehxA. Pulsed-field gel electrophoresis (PFGE) analysis yielded 49 different PFGE subtypes, showing a high genetic diversity; however, the majority of the typical isolates were closely related (80 to 90% cutoff). Atypical O157 isolates were not closely related within them or to typical E. coli O157:H7 isolates. Identical PFGE subtypes were found in samples obtained from colon contents, feedlots, holding pens, and carcasses. Isolation of a sorbitolfermenting E. coli O157 positive for a number of virulence genes is a novel finding in Mexico. These data showed that genetically similar strains of E. coli O157:H7 can be found at various stages of beef production and highlights the importance of preventing cross-contamination at the pre- and postharvest stages of processing. PMID- 25710141 TI - Distribution of Escherichia coli passaged through processing equipment during ground beef production using inoculated trimmings. AB - The contamination of raw ground beef by Escherichia coli O157:H7 is not only a public health issue but also an economic concern to meat processors. When E. coli O157:H7 is detected in a ground beef sample, the product lots made immediately before and after the lot represented by the positive sample are discarded or diverted to lethality treatment. However, there is little data to base decisions on how much product must be diverted. Therefore, five 2,000-lb (907-kg) combo bins of beef trimmings were processed into 10-lb (4.54-kg) chubs of raw ground beef, wherein the second combo of meat was contaminated with a green fluorescent protein (GFP)-expressing strain of E. coli. This was performed at two different commercial ground beef processing facilities, and at a third establishment where ground beef chubs from the second grinding establishment were mechanically split and repackaged into 3-lb (1.36-kg) loaves in trays. The GFP E. coli was tracked through the production of 10-lb (4.54-kg) chubs and the strain could not be detected after 26.5% more material (500 lb or 227 kg) and 87.8% more material (1,840 lb or 835 kg) followed the contaminated combo at each establishment, respectively. Three-pound (1.36-kg) loaves were no longer positive after just 8.6% more initially noncontaminated material (72 lb or 33 kg) was processed. The GFP strain could not be detected postprocessing in any residual meat or fat collected from the equipment used in the three trials. These results indicate that diversion to a safe end point (lethality or rendering) of the positive lot of ground beef, plus the lot before and lot after should remove contaminated ground beef, and as such provides support for the current industry practice. Further, the distribution and flow of E. coli on beef trimmings through various commercial equipment was different; thus, each establishment needs to consider this data when segregating lots of ground beef and establishing sampling protocols to monitor production. PMID- 25710142 TI - Effect of rapid product desiccation or hydration on thermal resistance of Salmonella enterica serovar enteritidis PT 30 in wheat flour. AB - Salmonella is able to survive in low-moisture environments and is known to be more heat resistant as product water activity (aw) decreases. However, it is unknown how rapidly the resistance changes if product aw is altered rapidly, as can occur in certain processes. Therefore, the objective was to determine the effect of rapid product desiccation or hydration on Salmonella thermal resistance. Two dynamic moisture treatments were compared with two static moisture treatments to determine the effect of time-at-moisture on the thermal resistance of Salmonella enterica serovar Enteritidis phage type 30 (PT 30) in wheat flour. After inoculation, two static moisture groups were equilibrated to 0.3 and 0.6 aw over 4 to 7 days, and two dynamic moisture groups then were rapidly (<4 min) desiccated from 0.6 to 0.3 aw or hydrated from 0.3 to 0.6 aw. Samples then were subjected to isothermal (80 degrees C) heat treatments, and Salmonella thermal resistance was compared via decimal reduction times (i.e., D80 degrees C-values). The D80 degrees C-value in flour that was rapidly desiccated from 0.6 to 0.3 aw was statistically equivalent (P > 0.05) to the D80 degrees C value in flour previously equilibrated to 0.3 aw, but both were greater (P < 0.05) than the D80 degrees C-value in flour previously equilibrated to 0.6 aw. Similarly, the D80 degrees C-value in flour rapidly hydrated from 0.3 to 0.6 aw was statistically equivalent (P > 0.05) to the D80 degrees C-value in flour previously equilibrated to 0.6 aw, and both were less than the D80 degrees C value in flour previously equilibrated to 0.3 aw. Therefore, Salmonella in the rapidly desiccated flour (0.3 aw) was as thermally resistant as that which previously had been equilibrated to 0.3 aw, and Salmonella in the rapidly hydrated flour (0.6 aw) responded similarly to that in the flour previously equilibrated to 0.6 aw. These results suggest that the response period to new aw is negligible, which is critically important in applying thermal resistance data or parameters to industrial pasteurization validations. PMID- 25710143 TI - Survival of Salmonella enterica serovar infantis on and within stored table eggs. AB - Contaminated table eggs are considered a primary source of foodborne salmonellosis globally. Recently, a single clone of Salmonella enterica serovar Infantis emerged in Israel and became the predominant serovar isolated in poultry. This clone is currently the most prevalent strain in poultry and is the leading cause of salmonellosis in humans. Because little is known regarding the potential transmission of this strain from contaminated eggs to humans, the objective of this study was to evaluate the ability of Salmonella Infantis to survive on the eggshell or within the egg during cold storage or at room temperature. Salmonella cells (5.7 log CFU per egg) were inoculated on the surface of 120 intact eggs or injected into the egg yolk (3.7 log CFU per egg) of another 120 eggs. Half of the eggs were stored at 5.5 +/- 0.3 degrees C and half at room temperature (25.5 +/- 0.1 degrees C) for up to 10 weeks. At both temperatures, the number of Salmonella cells on the shell declined by 2 log up to 4 weeks and remained constant thereafter. Yolk-inoculated Salmonella counts at cold storage declined by 1 log up to 4 weeks and remained constant, while room temperature storage supported the growth of the pathogen to a level of 8 log CFU/ml of total egg content, as early as 4 weeks postinoculation. Examination of egg content following surface inoculation revealed the presence of Salmonella in a portion of the eggs at both temperatures up to 10 weeks, suggesting that this strain can also penetrate through the shell and survive within the egg. These findings imply that Salmonella enterica serovar Infantis is capable of survival both on the exterior and interior of table eggs and even multiply inside the egg at room temperature. Our findings support the need for prompt refrigeration to prevent Salmonella multiplication during storage of eggs at room temperature. PMID- 25710144 TI - Modeling the impact of vapor thymol concentration, temperature, and modified atmosphere condition on growth behavior of Salmonella on raw shrimp. AB - Salmonella is a microorganism of concern on a global basis for raw shrimp. This research modeled the impact of vapor thymol concentration (0, 0.8, and 1.6 mg/liter), storage temperature (8, 12, and 16 degrees C), and modified atmosphere condition (0.04 as in the natural atmosphere and 59.5% CO2) against the growth behavior of a Salmonella cocktail (six strains) on raw shrimp. Lag time (hour) and maximum growth rate (log CFU per gram per hour), chosen as two growth indicators, were obtained through DMFit software and then developed into polynomial as well as nonlinear modified secondary models (dimensional and/or dimensionless), consisting of two or even three impact factors in the equations. The models were validated, and results showed that the predictive values from both models demonstrated good matches to the observed experimental values, yet the prediction based on lag time was more accurate than maximum growth rate. The information will provide the food industry with insight into the potential safety risk of Salmonella growth on raw shrimp under stressed conditions. PMID- 25710145 TI - Manure source and age affect survival of zoonotic pathogens during aerobic composting at sublethal temperatures. AB - Heat is the primary mechanism by which aerobic composting inactivates zoonotic bacterial pathogens residing within animal manures, but at sublethal temperatures, the time necessary to hold the compost materials to ensure pathogen inactivation is uncertain. To determine the influence of the type of nitrogen amendment on inactivation of Salmonella, Listeria monocytogenes, and Escherichia coli O157:H7 in compost mixtures stored at sublethal temperatures, specific variables investigated in these studies included the animal source of the manure, the initial carbon/nitrogen (C:N) ratio of the compost mixture, and the age of the manure. Salmonella and L. monocytogenes were both inactivated more rapidly in chicken and swine compost mixtures stored at 20 degrees C when formulated to an initial C:N ratio of 20:1 compared with 40:1, whereas a C:N ratio did not have an effect on inactivation of these pathogens in cow compost mixtures. Pathogen inactivation was related to the elevated pH of the samples that likely arises from ammonia produced by the indigenous microflora in the compost mixtures. Indigenous microbial activity was reduced when compost mixtures were stored at 30 degrees C and drier conditions (<10% moisture level) were prevalent. Furthermore, under these drier conditions, Salmonella persisted to a greater extent than L. monocytogenes, and the desiccation resistance of Salmonella appeared to convey cross-protection to ammonia. Salmonella persisted longer in compost mixtures prepared with aged chicken litter compared with fresh chicken litter, whereas E. coli O157:H7 survived to similar extents in compost mixtures prepared with either fresh or aged cow manure. The different responses observed when different sources of manure were used in compost mixtures reveal that guidelines with times required for pathogen inactivation in compost mixtures stored at sublethal temperatures should be dependent on the source of nitrogen, i.e., type of animal manure, present. PMID- 25710146 TI - Estimation of Listeria monocytogenes and Escherichia coli O157:H7 prevalence and levels in naturally contaminated rocket and cucumber samples by deterministic and stochastic approaches. AB - The aims of the present study were to determine the prevalence and levels of Listeria monocytogenes and Escherichia coli O157:H7 in rocket and cucumber samples by deterministic (estimation of a single value) and stochastic (estimation of a range of values) approaches. In parallel, the chromogenic media commonly used for the recovery of these microorganisms were evaluated and compared, and the efficiency of an enzyme-linked immunosorbent assay (ELISA) based protocol was validated. L. monocytogenes and E. coli O157:H7 were detected and enumerated using agar Listeria according to Ottaviani and Agosti plus RAPID' L. mono medium and Fluorocult plus sorbitol MacConkey medium with cefixime and tellurite in parallel, respectively. Identity was confirmed with biochemical and molecular tests and the ELISA. Performance indices of the media and the prevalence of both pathogens were estimated using Bayesian inference. In rocket, prevalence of both L. monocytogenes and E. coli O157:H7 was estimated at 7% (7 of 100 samples). In cucumber, prevalence was 6% (6 of 100 samples) and 3% (3 of 100 samples) for L. monocytogenes and E. coli O157:H7, respectively. The levels derived from the presence-absence data using Bayesian modeling were estimated at 0.12 CFU/25 g (0.06 to 0.20) and 0.09 CFU/25 g (0.04 to 0.170) for L. monocytogenes in rocket and cucumber samples, respectively. The corresponding values for E. coli O157:H7 were 0.59 CFU/25 g (0.43 to 0.78) and 1.78 CFU/25 g (1.38 to 2.24), respectively. The sensitivity and specificity of the culture media differed for rocket and cucumber samples. The ELISA technique had a high level of cross-reactivity. Parallel testing with at least two culture media was required to achieve a reliable result for L. monocytogenes or E. coli O157:H7 prevalence in rocket and cucumber samples. PMID- 25710147 TI - Survival of Salmonella, Escherichia coli O157:H7, and Listeria monocytogenes on raw peanut and pecan kernels stored at -24, 4, and 22 degrees C. AB - Cocktails of lawn-collected cells were used to determine the survival of Salmonella, Escherichia coli O157:H7, and Listeria monocytogenes on the surface of raw peanut and pecan kernels. Kernels were inoculated with mixtures of four to five strains at 3 or 6 log CFU/g, dried at room temperature, and then stored at 24 +/- 1, 4 +/- 2, and 22 +/- 1 degrees C for 28 or 365 days. In most cases, rates of decline of the pathogens did not differ significantly between the two inoculum concentrations in the 28-day study. At 6 log CFU/g, populations of all pathogens were reduced by 0.5 to 1.6 log CFU/g during an initial 3-day drying period on both peanuts and pecans. The moisture content of peanuts and pecans remained stable at -24 +/- 1 and 22 +/- 1 degrees C; at 4 +/- 2 degrees C, the moisture content increased from 3.8 to 5.6% on peanuts and from 2.6 to 3% on pecans over 365 days. Pathogen populations were stable on pecans stored under frozen and refrigerated conditions, except for L. monocytogenes, which declined at a rate of 0.03 log CFU/g/30 days at 4 +/- 2 degrees C. Salmonella populations were stable on peanuts stored at -24 +/- 1 and 4 +/- 2 degrees C, but E. coli O157:H7 and L. monocytogenes declined at rates of 0.03 to 0.12 log CFU/g/30 days. At 22 +/- 1 degrees C, Salmonella, E. coli O157:H7, and L. monocytogenes declined at a rate of 0.22, 0.37, and 0.59 log CFU/g/30 days, respectively, on peanuts, and at 0.15, 0.34, and 1.17 log CFU/g/30 days, respectively, on pecans. Salmonella counts were above the limit of detection (0.30 log CFU/g) throughout the study. In most cases during storage, counts obtained from pecans were higher than from peanuts. PMID- 25710148 TI - Microbial quality of popular locally processed meats sold in retail outlets in Trinidad, West Indies. AB - A total of 480 samples of locally produced processed meats, including chicken franks, chicken bologna, and bacon from brands A and B, was collected from 8 supermarkets across the island of Trinidad over a 1-year period and subjected to a range of microbiological analyses. The results showed that 54.2, 0.4, and 1.7% of the samples exceeded recommended limits for aerobic bacteria, Escherichia coli and Staphylococcus aureus, respectively. Listeria spp. were detected in 19.4% of samples, whereas L. monocytogenes was present at a prevalence rate of 7.5%. Brand A products had lower microbiological quality, accounting for 100% of samples positive for L. monocytogenes, E. coli, and S. aureus; and 75% for Listeria spp. and coliforms. Bacon was the product that most frequently exceeded microbiological limits, and accounted for 100% of samples positive for E. coli, 83.3% for L. monocytogenes, 72% for Listeria spp., 62.5% for S. aureus, and 61.9% for coliforms. PMID- 25710149 TI - Pulsed light decontamination of endive salad and mung bean sprouts and impact on color and respiration activity. AB - The objective of this study was the determination of the efficiency of pulsed light (PL) treatments for the decontamination of endive salad and mung bean sprouts, as well as the assessment of quality changes in relation to discoloration and alteration of respiration activity. Produce samples were artificially inoculated with two bacterial test strains Escherichia coli (DSM 498) and Listeria innocua (DSM 20649) and exposed to PL at different energy doses. The inactivation efficiency with regard to the naturally occurring microbiota was also investigated. Besides microbiological investigations, color changes were determined as well as the produce respiration during chilled storage. The results indicated that inactivation of more than 2 log was possible with one flash in the case of fresh-cut salad, while the reduction on mung bean sprouts was limited to approximately 1.6 log with one flash, irrespective if the natural flora or inoculated E. coli or L. innocua were considered. The UV part of the PL proved to be exclusively responsible for the inactivation of microorganisms. Significant lower levels of microbial counts of treated compared with untreated samples were maintained for up to 6 days. In the case of endive salad, a dose-dependent progressive discoloration and increase in respiration was diminished by applying optical bandpass filters, which only slightly affected the inactivation efficiency. In contrast, PL treatments showed a positive effect on color and general appearance of mung bean sprouts, while the respiration was almost unaffected. However, care must be taken with regard to efficiency-limiting matrix effects and impact on food quality. These aspects have to be assessed for each treated product. The integration of PL in industrial food processing plants could be an alternative way to improve the microbial quality of fresh produce, and therefore have a positive impact on public health by reducing the risk of contaminations with pathogenic bacteria. PMID- 25710150 TI - Assessing the survival of Listeria monocytogenes in a domestic freezer by analyzing subsequent growth at 30 degrees C using a novel reference method. AB - Listeria monocytogenes is a serious pathogen capable of extensive survival under frozen storage. Using optical density and multiple initial inocula in multiple identically prepared microtiter plates, the effect of storage time at -22 degrees C on the subsequent growth at 30 degrees C of the organism when defrosted was studied using a technique that compared the growth (through time to detection) of a test plate (previously frozen) with that of an identically prepared control plate, analyzed at the start of the experiment. Experiments were carried out using tryptic soy broth (TSB) or TSB supplemented with 3% salt. Plates were stored and frozen for up to 6 months (10 days, 20 days, 2 months, and 6 months). As storage time increased, there was only a small relative increase in the lag and the variance in the time to detection observed. When compared with storage in 3% salt TSB, which reduced the specific growth rate relative to growth in standard TSB, there were only marginally greater increases in lag and data variance. After 6 months storage in 3% salt TSB, there were some indications of inactivation (observed as small reductions of the initial optical density (equal to 1 * 10(9) CFU/ml) equivalent to a 50% inactivation. The method and the analyses suggest that this technique could allow easy examination of the effect of frozen storage on given cultures, with respect to the effects of pH, water activity, and also the effect of preservatives commonly used as extra hurdles in foods. PMID- 25710151 TI - Rapid detection method for Bacillus anthracis using a combination of multiplexed real-time PCR and pyrosequencing and its application for food biodefense. AB - Bacillus anthracis, the causative agent of anthrax, has the capacity to form highly resilient spores as part of its life cycle. The potential for the dissemination of these spores using food as a vehicle is a huge public health concern and, hence, requires the development of a foodborne bioterrorism response approach. In this work, we address a critical gap in food biodefense by presenting a novel, combined, sequential method involving the use of real-time PCR and pyrosequencing for the rapid, specific detection of B. anthracis spores in three food matrices: milk, apple juice, and bottled water. The food samples were experimentally inoculated with 40 CFU ml(-1), and DNA was extracted from the spores and analyzed after immunomagnetic separation. Applying the combination of multiplex real-time PCR and pyrosequencing, we successfully detected the presence of targets on both of the virulence plasmids and the chromosome. The results showed that DNA amplicons generated from a five-target multiplexed real-time PCR detection using biotin-labeled primers can be used for single-plex pyrosequencing detection. The combined use of multiplexed real-time PCR and pyrosequencing is a novel, rapid detection method for B. anthracis from food and provides a tool for accurate, quantitative identification with potential biodefense applications. PMID- 25710152 TI - Development of an indirect competitive enzyme-linked immunosorbent assay based on the multiepitope peptide for the synchronous detection of staphylococcal enterotoxin A and G proteins in milk. AB - Staphylococcal food poisoning (SFP), one of the most common foodborne diseases, results from ingestion of staphylococcal enterotoxins (SEs) in foods. In our previous studies, we found that SEA and SEG were two predominant SE proteins produced by milkacquired S. aureus isolates. Here, a tandemly arranged multiepitope peptide (named SEAGepis) was designed with six linear B-cell epitopes derived from SEA or SEG and was heterologously expressed. The SEAGepis specific antibody was prepared by immunizing rabbit with rSEAGepis. Then, an indirect competitive enzyme-linked immunosorbent assay (ic-ELISA) based on rSEAGepis and the corresponding antibody was developed to simultaneously detect SEA and SEG. Under the optimized conditions, the ic-ELISA standard curve for rSEAGepis was constructed in the concentration range of 0.5 to 512 ng/ml, and the average coefficients of variation of intra- and interassay were 4.28 and 5.61% during six standard concentrations. The average half-maximal inhibitory concentration was 5.07 ng/ml, and the limit of detection at a signal-to-noise ratio of 3 was 0.52 ng/ml. The anti-rSEAGepis antibody displayed over 90% cross reactivity with SEA and SEG but less than 0.5% cross-reactivity with other enterotoxins. Artificially contaminated milk with different concentrations of rSEAGepis, SEA, and SEG was detected by the established ic-ELISA; the recoveries of rSEAGepis, SEA, and SEG were 91.1 to 157.5%, 90.3 to 134.5%, and 89.1 to 117.5%, respectively, with a coefficient of variation below 12%. These results demonstrated that the newly established ic-ELISA possessed high sensitivity, specificity, stability, and accuracy and could potentially be a useful analytical method for synchronous detection of SEA and SEG in milk. PMID- 25710153 TI - First two domains at the lp_1643 protein N terminus inhibit pathogen adhesion to porcine mucus in vitro. AB - Gastrointestinal probiotics are important members of intestinal microflora in both healthy animals and human beings, and these bacteria may reduce the risk of infection caused by certain opportunistic pathogens through exclusive inhibition, competition, and displacement. The lp_1643 protein on the cell surface of Lactobacillus plantarum WCFSI was assumed to possess a mucus-binding capability. This study aimed to determine if purified His-N2 protein exclusively inhibits pathogen adhesion to porcine mucus. The interaction of the His-N2 protein with porcine mucus was determined by indirect enzyme-linked immunosorbent assay (ELISA), and the adhesion was assessed by a traditional plating method to count the bacteria adhered to the porcine mucus. Indirect ELISA showed that His-N2 protein adhered to porcine mucus, and its interacting molecules existed. The His N2 protein effectively inhibited the adhesion of Escherichia coli DH5alpha, Listeria monocytogenes CMCC54004, Salmonella Typhimurium ATCC 14028, and Shigella flexneri CMCC(B)51572 to porcine mucus. Results showed that inhibition of pathogen adhesion to porcine mucus depended on dose and strain. The adhesion of L. monocytogenes CMCC54004, Salmonella Typhimurium ATCC 14028, and S. flexneri CMCC(B)51572 was reduced by 95.7, 97.0, and 95.7%, respectively, by pre-adding 100 MUl of 3.92 mg/ml of His-N2 protein, whereas that of E. coli DH5alpha was only 50.4%. The inhibition of adhesion of some pathogens by His-N2 was different at pH 6.6 and 7.5. The inhibition of E. coli DH5alpha, L. monocytogenes CMCC54004, and Salmonella Typhimurium ATCC 14028 at pH 6.6 was significantly higher than that at pH 7.5, whereas no statistically significant difference was observed in S. flexneri CMCC(B)51572. These results suggest that various types of inhibition mechanisms of His-N2 were involved in different pathogens. PMID- 25710154 TI - Effect of water activity, temperature, and mixed fungal spore interactions on ochratoxin A production by Aspergillus carbonarius. AB - The purpose of this work was to investigate the potential of two nontoxigenic Aspergillus section Nigri species (Aspergillus tubingensis and Aspergillus japonicus) to influence the in vitro ochratoxin A (OTA) production of three toxigenic Aspergillus carbonarius isolates (Ac-28, Ac-29, and Ac-33) from Greek vineyards of different geographical areas. OTA accumulation was evaluated by inoculation of 0:100, 25:75, 50:50, 75:25, and 100:0 ratios of mixed spore suspensions on a synthetic grape juice medium for up to 28 days at different temperatures (15, 20, and 25 degrees C), water activity (aw) levels (0.95 and 0.98 aw) and incubation time (7, 14, 21, and 28 days). Results confirmed that environmental factors and fungal species had a significant effect on OTA production. Specifically, maximum OTA concentration for Ac-28 (3.21 MUg g(-1)) and Ac-29 (7.69 MUg g(-1)) was observed at 20 degrees C/0.98 aw and for Ac-33 (9.13 MUg g(-1)) at 15 degrees C/0.95 aw, regardless of incubation time. Moreover, A. tubingensis had no significant influence on OTA concentration of all toxigenic isolates assayed, regardless of temperature, aw, and incubation time. On the other hand, the presence of A. japonicus slightly inhibited OTA production of Ac-29 and Ac-33, while for Ac-28, stimulation of OTA was observed in some cases. Overall, lower aw levels reduced OTA accumulation for Ac-28 and Ac-29, regardless of temperature, inoculum ratio, and time. On the contrary, for Ac-33, low aw increased OTA production, regardless of the investigated parameters. The importance of this study concerns the understanding of interspecific interactions on OTA diffusion by A. carbonarius in an attempt to find ways to prevent the presence of toxins in grapes and their derivatives. PMID- 25710155 TI - Identification and inhibition of histamine-forming bacteria in blue scad (Decapterus maruadsi) and chub mackerel (Scomber japonicus). AB - In this study, we investigated the differences in histamine accumulation between blue scad and chub mackerel and methods of inhibiting histamine-forming bacteria and controlling histamine accumulation in fish. The free histidine contents in blue scad and chub mackerel were 1.45 and 2.75 mg/g, respectively. The histamine forming bacteria isolated from them were identified as Citrobacter freundii, Citrobacter braakii, and Enterobacter aerogenes using 16S rDNA sequence analysis, the VITEK 2 Compact system, and MALDI-TOF MS. The histamine-producing capacities of C. freundii, C. braakii, and E. aerogenes were 470, 1,057, and 4,213 mg/liter, respectively, after culture at 37 degrees C for 48 h. Among the different antimicrobials and preservatives tested, potassium sorbate and sodium diacetate effectively inhibited the histamine-forming bacteria and their histamine production. After chub mackerel was dipped into 0.5% potassium sorbate or sodium diacetate, its histamine content increased more slowly at room temperature. Therefore, a potassium sorbate or sodium diacetate dipping treatment could effectively control histamine accumulation in fish. PMID- 25710156 TI - Bioconcentration factors and potential human health risks of heavy metals in cultivated Lentinus edodes in Chengdu, People's Republic of China. AB - Lentinus edodes is one of the most popular edible mushrooms in the market. However, it contains heavy metals that are poisonous to humans even at trace concentrations. The concentrations and bioconcentration factors of five heavy metals in cultivated L. edodes in Chengdu were studied, and the potential health risks to local residents associated with the cultivated L. edodes consumption were evaluated. Total concentrations of cadmium (Cd), lead (Pb), chromium (Cr), arsenic (As), and mercury were determined in the fruiting bodies and the substrate from three agricultural areas. Fruiting bodies samples were collected at different growing times (2, 4, 6, and 8 days). The bioconcentration factors of heavy metals from the substrate to the fruiting bodies were estimated, and the potential health risks of local L. edodes were assessed. Because antioxidant enzymes can resist the creation of reactive oxygen species and defend against heavy metals, the activities of three antioxidant enzymes (superoxide dismutase, catalase, and peroxidase) in the fruiting bodies were also determined. A gradual change in heavy metal concentrations occurred across the growing time of the fruiting bodies. Cd transferred from the substrate to the fruiting bodies in larger concentrations than did Pb, Cr, and As. However, Chengdu residents were not exposed to significant health risks associated with consumption of local L. edodes. Nevertheless, more attention should be focused on children because of their higher sensitivity to metal pollutants. PMID- 25710157 TI - Postharvest correlation between swordfish (Xiphius gladius) size and mercury concentration in edible tissues. AB - Total mercury was measured via thermal decomposition amalgamation atomic absorption spectroscopy in the muscle tissue of 82 swordfish originating in the Pacific Ocean and was found to range from 228 to 2,090 ppb. The relationships between total mercury concentration and the size of the fish (i.e., length and weight) were analyzed. It was found that dressed weight (DW) was a better predictor of mercury concentration than cleithrum-to-caudal keel length in a single variable model, and DW was the only significant predictor of mercury concentration in a multivariable model. Based on these relationships, swordfish with a DW greater than 96.4 kg (213 lb; 95% confidence interval, 88 to 107 kg [195 to 235 lb]) will exceed 1,000 ppb of mercury-the action level in the United States, Canada, and Europe-and should not be sold in commercial markets. Additionally, a logistic regression model was created to illustrate the probability of a swordfish at any DW being unsafe to consume (i.e., containing more than 1,000 ppb of mercury). In this model, the probability of a swordfish being unsafe exceeds the probability of being safe at 94.6 kg (209 lb). Taken together, the models presented in this report give regulators valuable postharvest tools to use for rapid determination of the safety of swordfish intended for sale in commercial markets. PMID- 25710158 TI - Survival of Salmonella on basil plants and in pesto. AB - Leafy greens, including fresh herbs, have repeatedly been involved in outbreaks of foodborne disease. Although much effort has been put into studying leafy greens and products such as head lettuce and baby leaves, less is known about fresh leafy herbs, such as basil. The goal of this study was to investigate the survival of Salmonella on basil plants and in pesto. A mix of three Salmonella strains (Reading, Newport, and Typhimurium) was inoculated onto basil leaves and pesto and survived during the experimental period. Whereas the mix of Salmonella survived in pesto stored at 4 degrees C for 4 days, Salmonella was recovered from inoculated leaves for up to 18 days at 20 to 22 degrees C. Although the steady decline of Salmonella on leaves and in pesto suggests a lack of growth, it appears that pesto is a hostile environment for Salmonella because the rate of decline in pesto was faster (0.29 log CFU/g/day) than on leaves (0.11 log CFU/g/day). These findings suggest that the dilution of contaminated ingredients and the bactericidal effect of the pesto environment helped to further reduce the level of enteric organisms during storage, which may have applications for food safety. PMID- 25710159 TI - Resistance phenotypes and genotypes of Salmonella enterica subsp. enterica isolates from feed, pigs, and carcasses in Brazil. AB - Salmonella enterica subsp. enterica plays a role as a foodborne pathogen worldwide. The consumption of contaminated pork has been associated with human salmonellosis and the increase in antimicrobial resistance among Salmonella from pigs and pork products is a concern. A total of 225 Salmonella isolates from feed mills, the lairage environment, and the intestinal contents of pigs and carcasses were investigated for their antimicrobial susceptibility. A MIC for ciprofloxacin was screened by agar dilution, and antimicrobial resistance genes were investigated by PCR assays. Among the tested isolates, 171 (76%) showed resistance to at least one antimicrobial agent, and 91 (40.4%) were multiresistant. Resistance occurred most frequently to tetracycline (54.5%), sulfonamides (39.6%), and streptomycin (33.7%). Thirty-two (94.1%) nalidixic acid resistant isolates exhibited decreased susceptibility to ciprofloxacin. The resistance genes found were blaTEM (ampicillin), tet(A) (tetracycline), tet(B) (tetracycline/minocycline), sul1, sul2, and sul3 (sulfonamides), catA1 (chloramphenicol), floR (florfenicol/chloramphenicol), strA and strB (streptomycin), aph(3')-Ia (kanamycin), aac(3)-IIa and aac(3)-IVa (apramycin/gentamicin), aadA variant (streptomycin/spectinomycin), and dfrA1 (trimethoprim). Salmonella isolates from pig feces and carcasses displayed a higher frequency of resistance to most antimicrobials tested than isolates from feed mills. Common resistance gene profiles were found in isolates from the lairage and the intestinal content of pigs and carcasses, demonstrating that resistance genes selected on farms may be found in pork. PMID- 25710160 TI - Chlorine inactivation of Salmonella Kentucky isolated from chicken carcasses: evaluation of strain variation. AB - The current study was undertaken to evaluate chlorine resistance among strains of Salmonella Kentucky isolated from chicken carcasses. Selected strains (n = 8) were exposed to 30 ppm of chlorine in 10% buffered peptone water (pH 7.4) for 0 to 10 min at 4 degrees C and 150 rpm. The initial level (mean +/- SD) of Salmonella Kentucky was 6.18 +/- 0.09 log CFU/ml and did not differ (P > 0.05) among strains. A two-way analysis of variance indicated that the level of Salmonella Kentucky in chlorinated water was affected (P < 0.05) by a time by strain interaction. Differences among strains increased as a function of chlorine exposure time. After 10 min of chlorine exposure, the most resistant strain (SK145) was 5.63 +/- 0.54 log CFU/ml, whereas the least resistant strain (SK275) was 3.07 +/- 0.29 log CFU/ml. Significant differences in chlorine resistance were observed for most strain comparisons. Death of Salmonella Kentucky was nonlinear over time and fitted well to a power law model with a shape parameter of 0.34 (concave upward). Time (minutes) for a 1-log reduction of Salmonella Kentucky differed (P < 0.05) among strains: >10 min for SK145, 6.0 min for SK254, 1.5 min for SK179, and 0.3 to 0.65 min for other strains. Results of this study indicate that strain is an important variable to include in models that predict changes in levels of Salmonella Kentucky in chlorinated water. PMID- 25710161 TI - Survival after cryogenic freezing of Campylobacter species in ground Turkey patties treated with polyphosphates. AB - The use of polyphosphate-based marinades in the processing of poultry has been previously shown to increase the survival of Campylobacter species present in the exudates derived from these products. This study investigates the effects that some of the same polyphosphates have on the survival of Campylobacter species within a ground turkey product subjected to cryogenic freezing. Ground turkey patties with two different polyphosphate formulations added in two different concentrations were artificially contaminated with known concentrations of Campylobacter jejuni or Campylobacter coli. The patties were cryogenically frozen at -80 degrees F (-62.2 degrees C) with liquid nitrogen vapor and held at -20 degrees C for 7 or 33 days, after which the number of Campylobacter surviving in the patties was determined. On average the cryogenic freezing resulted in a 2.5 log decrease in the survival of C. jejuni cells and a 2.9-log decrease in C. coli cells present in the turkey patties. Additionally, the presence of polyphosphates in the turkey patties had no effect on Campylobacter survival up to the maximum allowed concentration (0.5%) for polyphosphates in poultry marinades. Finally, it was determined that the added polyphosphates had little effect on the pH of the ground turkey meat; an effect which previously had been implicated in the enhancement of Campylobacter survival due to the presence of polyphosphates. PMID- 25710162 TI - Influence of carvacrol and 1,8-cineole on cell viability, membrane integrity, and morphology of Aeromonas hydrophila cultivated in a vegetable-based broth. AB - This study investigated the effects of carvacrol (CAR) and 1,8-cineole (CIN) alone (at the MIC) or in combination at subinhibitory amounts (both at 1/8 MIC) on the cell viability, membrane permeability, and morphology of Aeromonas hydrophila INCQS 7966 (A. hydrophila) cultivated in a vegetable-based broth. CAR and CIN alone or in combination severely affected the viability of the bacteria and caused dramatic changes in the cell membrane permeability, leading to cell death, as observed by confocal laser microscopy. Scanning and transmission electron microscopy images of bacterial cells exposed to CAR or CIN or the mixture of both compounds revealed severe changes in cell wall structure, rupture of the plasma membrane, shrinking of cells, condensation of cytoplasmic content, leakage of intracellular material, and cell collapse. These findings suggest that CAR and CIN alone or in combination at subinhibitory amounts could be applied to inhibit the growth of A. hydrophila in foods, particularly as sanitizing agents in vegetables. PMID- 25710163 TI - Combined steam-ultrasound treatment of 2 seconds achieves significant high aerobic count and Enterobacteriaceae reduction on naturally contaminated food boxes, crates, conveyor belts, and meat knives. AB - Food contact surfaces require rigorous sanitation procedures for decontamination, although these methods very often fail to efficiently clean and disinfect surfaces that are visibly contaminated with food residues and possible biofilms. In this study, the results of a short treatment (1 to 2 s) of combined steam (95 degrees C) and ultrasound (SonoSteam) of industrial fish and meat transportation boxes and live-chicken transportation crates naturally contaminated with food and fecal residues were investigated. Aerobic counts of 5.0 to 6.0 log CFU/24 cm(2) and an Enterobacteriaceae spp. level of 2.0 CFU/24 cm(2) were found on the surfaces prior to the treatment. After 1 s of treatment, the aerobic counts were significantly (P < 0.0001) reduced, and within 2 s, reductions below the detection limit (<10 CFU) were reached. Enterobacteriaceae spp. were reduced to a level below the detection limit with only 1 s of treatment. Two seconds of steam ultrasound treatment was also applied on two different types of plastic modular conveyor belts with hinge pins and one type of flat flexible rubber belt, all visibly contaminated with food residues. The aerobic counts of 3.0 to 5.0 CFU/50 cm(2) were significantly (P < 0.05) reduced, while Enterobacteriaceae spp. were reduced to a level below the detection limit. Industrial meat knives were contaminated with aerobic counts of 6.0 log CFU/5 cm(2) on the handle and 5.2 log CFU/14 cm(2) on the steel. The level of Enterobacteriaceae spp. contamination was approximately 2.5 log CFU on the handle and steel. Two seconds of steam ultrasound treatment reduced the aerobic counts and Enterobacteriaceae spp. to levels below the detection limit on both handle and steel. This study shows that the steam-ultrasound treatment may be an effective replacement for disinfection processes and that it can be used for continuous disinfection at fast process lines. However, the treatment may not be able to replace efficient cleaning processes used to remove high loads of debris. PMID- 25710164 TI - Seek and destroy process: Listeria monocytogenes process controls in the ready-to eat meat and poultry industry. AB - The majority of human listeriosis cases appear to be caused by consumption of ready-to-eat (RTE) foods contaminated at the time of consumption with high levels of Listeria monocytogenes. Although strategies to prevent growth of L. monocytogenes in RTE products are critical for reducing the incidence of human listeriosis, control of postprocessing environmental contamination of RTE meat and poultry products is an essential component of a comprehensive L. monocytogenes intervention and control program. Complete elimination of postprocessing L. monocytogenes contamination is challenging because this pathogen is common in various environments outside processing plants and can persist in food processing environments for years. Persistent L. monocytogenes strains in processing plants have been identified as the most common postprocessing contaminants of RTE foods and the cause of multiple listeriosis outbreaks. Identification and elimination of L. monocytogenes strains persisting in processing plants is thus critical for (i) compliance with zero-tolerance regulations for L. monocytogenes in U.S. RTE meat and poultry products and (ii) reduction of the incidence of human listeriosis. The seek-and-destroy process is a systematic approach to finding sites of persistent strains (niches) in food processing plants, with the goal of either eradicating or mitigating effects of these strains. This process has been used effectively to address persistent L. monocytogenes contamination in food processing plants, as supported by peer reviewed evidence detailed here. Thus, a regulatory environment that encourages aggressive environmental Listeria testing is required to facilitate continued use of this science-based strategy for controlling L. monocytogenes in RTE foods. PMID- 25710165 TI - Preventing and controlling foodborne disease in commercial and institutional food service settings: a systematic review of published intervention studies. AB - This study reviews the current literature on behavioral and environmental food safety interventions conducted in commercial and institutional food service settings. A systematic search of the published literature yielded 268 candidate articles, from which a set of 23 articles reporting intervention outcomes was retained for evaluation. A categorization of measured outcomes is reported; studies addressed multiple outcomes ranging from knowledge, attitudes, and behavior of personal hygiene and food safety to management practices and disease rates and outbreaks. This study also investigates the quality of reported research methods used to evaluate the effectiveness of the interventions, using a nine-point quality index adapted by the authors. The observed scores suggest that there are opportunities to improve the design and reporting of research in the field of foodborne disease prevention as it applies to food safety interventions that target the food service industry. The aim is to aid researchers in this area to design higher quality studies and to produce clearer and more useful reports of their research. In turn, this can help to create a more complete evidence base that can be used to continually improve interventions in this domain. PMID- 25710166 TI - Prevalence and risk factors for Toxoplasma gondii infection in meat animals and meat products destined for human consumption. AB - Toxoplasma gondii is a protozoan parasite that is responsible for approximately 24% of all estimated deaths attributed to foodborne pathogens in the United States. Human infection results from accidental ingestion of oocysts from the environment, in water, or on insufficiently washed produce or from consumption of raw or undercooked meat products that contain T. gondii tissue cysts. This review focused on studies of T. gondii in meat because many human T. gondii infections are acquired through consumption of raw or undercooked meat. Prevalence of T. gondii is higher in conventionally reared pigs, sheep, and poultry than in cattle and is greater in meat products from organic than from conventionally reared meat animals because of outdoor access, which poses substantially greater opportunities for exposure to infected rodents, wildlife, and oocyst-contaminated feed, water, or environmental surfaces. Risk factors related to T. gondii exposure for livestock include farm type, feed source, presence of cats, methods of rodent and bird control, methods of carcass handling, and water quality. This review serves as a useful resource and information repository for informing quantitative risk assessment studies for T. gondii infection in humans through meat consumption. PMID- 25710167 TI - Algorithm evolution for drug resistance prediction: comparison of systems for HIV 1 genotyping. AB - BACKGROUND: Different genotypic HIV resistance algorithms are based on different rules. They may therefore result in different drug-resistance interpretations for the same patient sample. In particular, for early periods of new retroviral inhibitors or classes, sequence interpretation is expected to vary. One would, however, assume that those differences between systems wane with growing experience and that different algorithms yield similar results for well established drugs. METHODS: To assess the concordance of the Agence Nationale de Recherche sur le SIDA (ANRS), Rega and Stanford-HIVdb algorithms and their evolution over time, we analysed 284 routine samples with the current versions of each algorithm in 2004 and 2013. For 446 recent clinical sequences the differences for actual drugs were analysed. Scoring as 'susceptible' by one algorithm and 'resistant' by a second one defined a discordance. RESULTS: The longitudinal analysis showed similar overall discordances for both time points as well as an evolution over time. The actual analysis demonstrated a higher overall discordance rate, mainly for certain drugs. Most deviations reflected differences between the ANRS and the other two algorithms. CONCLUSIONS: This study demonstrates discordances between three most commonly used interpretation tools even for long-available drugs. It thereby reveals a need for further adjustment and improvement of current interpretation tools and may point at a possibly crucial role of subtype-specific information. PMID- 25710168 TI - acal is a long non-coding RNA in JNK signaling in epithelial shape changes during drosophila dorsal closure. AB - Dorsal closure is an epithelial remodeling process taking place during Drosophila embryogenesis. JNK signaling coordinates dorsal closure. We identify and characterize acal as a novel negative dorsal closure regulator. acal represents a new level of JNK regulation. The acal locus codes for a conserved, long, non coding, nuclear RNA. Long non-coding RNAs are an abundant and diverse class of gene regulators. Mutations in acal are lethal. acal mRNA expression is dynamic and is processed into a collection of 50 to 120 bp fragments. We show that acal lies downstream of raw, a pioneer protein, helping explain part of raw functions, and interacts genetically with Polycomb. acal functions in trans regulating mRNA expression of two genes involved in JNK signaling and dorsal closure: Connector of kinase to AP1 (Cka) and anterior open (aop). Cka is a conserved scaffold protein that brings together JNK and Jun, and aop is a transcription factor. Misregulation of Cka and aop can account for dorsal closure phenotypes in acal mutants. PMID- 25710169 TI - HITS-CLIP analysis uncovers a link between the Kaposi's sarcoma-associated herpesvirus ORF57 protein and host pre-mRNA metabolism. AB - The Kaposi's sarcoma associated herpesvirus (KSHV) is an oncogenic virus that causes Kaposi's sarcoma, primary effusion lymphoma (PEL), and some forms of multicentric Castleman's disease. The KSHV ORF57 protein is a conserved posttranscriptional regulator of gene expression that is essential for virus replication. ORF57 is multifunctional, but most of its activities are directly linked to its ability to bind RNA. We globally identified virus and host RNAs bound by ORF57 during lytic reactivation in PEL cells using high-throughput sequencing of RNA isolated by cross-linking immunoprecipitation (HITS-CLIP). As expected, ORF57-bound RNA fragments mapped throughout the KSHV genome, including the known ORF57 ligand PAN RNA. In agreement with previously published ChIP results, we observed that ORF57 bound RNAs near the oriLyt regions of the genome. Examination of the host RNA fragments revealed that a subset of the ORF57-bound RNAs was derived from transcript 5' ends. The position of these 5'-bound fragments correlated closely with the 5'-most exon-intron junction of the pre mRNA. We selected four candidates (BTG1, EGR1, ZFP36, and TNFSF9) and analyzed their pre-mRNA and mRNA levels during lytic phase. Analysis of both steady-state and newly made RNAs revealed that these candidate ORF57-bound pre-mRNAs persisted for longer periods of time throughout infection than control RNAs, consistent with a role for ORF57 in pre-mRNA metabolism. In addition, exogenous expression of ORF57 was sufficient to increase the pre-mRNA levels and, in one case, the mRNA levels of the putative ORF57 targets. These results demonstrate that ORF57 interacts with specific host pre-mRNAs during lytic reactivation and alters their processing, likely by stabilizing pre-mRNAs. These data suggest that ORF57 is involved in modulating host gene expression in addition to KSHV gene expression during lytic reactivation. PMID- 25710170 TI - Genome wide nucleosome mapping for HSV-1 shows nucleosomes are deposited at preferred positions during lytic infection. AB - HSV is a large double stranded DNA virus, capable of causing a variety of diseases from the common cold sore to devastating encephalitis. Although DNA within the HSV virion does not contain any histone protein, within 1 h of infecting a cell and entering its nucleus the viral genome acquires some histone protein (nucleosomes). During lytic infection, partial micrococcal nuclease (MNase) digestion does not give the classic ladder band pattern, seen on digestion of cell DNA or latent viral DNA. However, complete digestion does give a mono-nucleosome band, strongly suggesting that there are some nucleosomes present on the viral genome during the lytic infection, but that they are not evenly positioned, with a 200 bp repeat pattern, like cell DNA. Where then are the nucleosomes positioned? Here we perform HSV-1 genome wide nucleosome mapping, at a time when viral replication is in full swing (6 hr PI), using a microarray consisting of 50mer oligonucleotides, covering the whole viral genome (152 kb). Arrays were probed with MNase-protected fragments of DNA from infected cells. Cells were not treated with crosslinking agents, thus we are only mapping tightly bound nucleosomes. The data show that nucleosome deposition is not random. The distribution of signal on the arrays suggest that nucleosomes are located at preferred positions on the genome, and that there are some positions that are not occupied (nucleosome free regions -NFR or Nucleosome depleted regions -NDR), or occupied at frequency below our limit of detection in the population of genomes. Occupancy of only a fraction of the possible sites may explain the lack of a typical MNase partial digestion band ladder pattern for HSV DNA during lytic infection. On average, DNA encoding Immediate Early (IE), Early (E) and Late (L) genes appear to have a similar density of nucleosomes. PMID- 25710171 TI - Recalibration of the limiting antigen avidity EIA to determine mean duration of recent infection in divergent HIV-1 subtypes. AB - BACKGROUND: Mean duration of recent infection (MDRI) and misclassification of long-term HIV-1 infections, as proportion false recent (PFR), are critical parameters for laboratory-based assays for estimating HIV-1 incidence. Recent review of the data by us and others indicated that MDRI of LAg-Avidity EIA estimated previously required recalibration. We present here results of recalibration efforts using >250 seroconversion panels and multiple statistical methods to ensure accuracy and consensus. METHODS: A total of 2737 longitudinal specimens collected from 259 seroconverting individuals infected with diverse HIV 1 subtypes were tested with the LAg-Avidity EIA as previously described. Data were analyzed for determination of MDRI at ODn cutoffs of 1.0 to 2.0 using 7 statistical approaches and sub-analyzed by HIV-1 subtypes. In addition, 3740 specimens from individuals with infection >1 year, including 488 from patients with AIDS, were tested for PFR at varying cutoffs. RESULTS: Using different statistical methods, MDRI values ranged from 88-94 days at cutoff ODn = 1.0 to 177-183 days at ODn = 2.0. The MDRI values were similar by different methods suggesting coherence of different approaches. Testing for misclassification among long-term infections indicated that overall PFRs were 0.6% to 2.5% at increasing cutoffs of 1.0 to 2.0, respectively. Balancing the need for a longer MDRI and smaller PFR (<2.0%) suggests that a cutoff ODn = 1.5, corresponding to an MDRI of 130 days should be used for cross-sectional application. The MDRI varied among subtypes from 109 days (subtype A&D) to 152 days (subtype C). CONCLUSIONS: Based on the new data and revised analysis, we recommend an ODn cutoff = 1.5 to classify recent and long-term infections, corresponding to an MDRI of 130 days (118-142). Determination of revised parameters for estimation of HIV-1 incidence should facilitate application of the LAg-Avidity EIA for worldwide use. PMID- 25710172 TI - Exposure to diesel exhaust particle extracts (DEPe) impairs some polarization markers and functions of human macrophages through activation of AhR and Nrf2. AB - Macrophages (MPhi), well-known to play an important role in immune response, also respond to environmental toxic chemicals such as diesel exhaust particles (DEP). Potential effects of DEPs towards MPhi polarization, a key hall-mark of MPhi physiology, remain however poorly documented. This study was therefore designed to evaluate the effects of a reference DEP extract (DEPe) on human MPhi polarization. Human blood monocytes-derived MPhi were incubated with IFNgamma+LPS or IL-4 to obtain M1 and M2 subtypes, respectively; a 24 h exposure of polarizing MPhi to 10 MUg/ml DEPe was found to impair expression of some macrophagic M1 and M2 markers, without however overall inhibition of M1 and M2 polarization processes. Notably, DEPe treatment increased the secretion of the M1 marker IL-8 and the M2 marker IL-10 in both MPhi subtypes, whereas it reduced lipopolysaccharide-induced IL-6 and IL-12p40 secretion in M1 MPhi. In M2 MPhi, DEPe exposure led to a reduction of CD200R expression and of CCL17, CCL18 and CCL22 secretion, associated with a lower chemotaxis of CCR4-positive cells. DEPe activated the Nrf2 and AhR pathways and induced expression of their reference target genes such as Hmox-1 and cytochrome P-4501B1 in M1 and M2 MPhi. Nrf2 or AhR silencing through RNA interference prevented DEPe-related down-regulation of IL-6. AhR silencing also inhibited the down-secretion of IL-12p40 and CCL18 in M1 and M2-DEPe-exposed MPhi, respectively. DEPs are therefore likely to alter expression of some M1 and M2 markers in an AhR- and Nrf2-dependent manner; such regulations may contribute to deleterious immune effects of atmospheric DEP. PMID- 25710173 TI - Effects of exogenous gibberellic acid3 on iron and manganese plaque amounts and iron and manganese uptake in rice. AB - Gibberellins (GA) regulate various components of plant development. Iron and Mn plaque result from oxiding and hydroxiding Fe and Mn, respectively, on the roots of aquatic plant species such as rice (Oryza sativa L.). In this study, we found that exogenous gibberellic acid3 (GA3) spray decreased Fe plaque, but increased Mn plaque, with applications of Kimura B nutrient solution. Similar effects from GA3, leading to reduced Fe plaque and increased Mn plaque, were also found by scanning electron microscopy and energy dispersive X-ray spectrometric microanalysis. Reduced Fe plaque was observed after applying GA3 to the groups containing added Fe2+ (17 and 42 mg*L(-1)) and an increasing trend was detected in Mn plaques of the Mn2+ (34 and 84 mg*L(-1)) added treatments. In contrast, an inhibitor of GA3, uniconazole, reversed the effects of GA3. The uptake of Fe or Mn in rice plants was enhanced after GA3 application and Fe or Mn plaque production. Strong synergetic effects of GA3 application on Fe plaque production were detected. However, no synergetic effects on Mn plaque production were detected. PMID- 25710174 TI - Genetic analysis of membrane cofactor protein (CD46) of the complement system in women with and without preeclamptic pregnancies. AB - Preeclampsia is a common disorder of pregnancy characterized by endothelial dysfunction. It may be life-threatening for the mother and fetus in severe cases. Dysregulation of the complement system has been suggested to predispose women to preeclampsia. Complement is part of the innate and adaptive immune systems and potentially capable of causing inflammation and tissue damage. Membrane cofactor protein MCP (CD46) is among the potent complement regulators that have recently been linked to a severe form of preeclampsia with or without an underlying autoimmune phenotype. Mutations in CD46 predispose to thrombotic microangiopathy with endothelial cell dysfunction. The exome of CD46 were sequenced in 95 Finnish women with severe preeclampsia. Genetic variations discovered in the full exome were compared to those observed in 95 control women who did not develop preeclampsia. Because A304V (rs35366573) was associated with preeclampsia in one previous study, we sequenced the transmembrane region including the A304V variant and part of the cytoplasmic tail in 95 additional controls. We did not discover any association between A304V or other CD46 SNPs and preeclampsia. This study describes a carefully characterized cohort of severely preeclamptic Finnish women and found no potentially predisposing variants in CD46. However, it is possible that other genetic components of the complement system may affect the pathogenesis of severe preeclampsia and related diseases. PMID- 25710175 TI - Gene expression in obliterative bronchiolitis-like lesions in 2,3-pentanedione exposed rats. AB - Obliterative bronchiolitis (OB) is an irreversible lung disease characterized by progressive fibrosis in the small airways with eventual occlusion of the airway lumens. OB is most commonly associated with lung transplant rejection; however, OB has also been diagnosed in workers exposed to artificial butter flavoring (ABF) vapors. Research has been limited by the lack of an adequate animal model of OB, and as a result the mechanism(s) is unclear and there are no effective treatments for this condition. Exposure of rats to the ABF component, 2,3 pentanedione (PD) results in airway lesions that are histopathologically similar to those in human OB. We used this animal model to evaluate changes in gene expression in the distal bronchi of rats with PD-induced OB. Male Wistar Han rats were exposed to 200 ppm PD or air 6 h/d, 5 d/wk for 2-wks. Bronchial tissues were laser microdissected from serial sections of frozen lung. In exposed lungs, both fibrotic and non-fibrotic airways were collected. Following RNA extraction and microarray analysis, differential gene expression was evaluated. In non-fibrotic bronchi of exposed rats, 4683 genes were significantly altered relative to air exposed controls with notable down-regulation of many inflammatory cytokines and chemokines. In contrast, in fibrotic bronchi, 3807 genes were significantly altered with a majority of genes being up-regulated in affected pathways. Tgf beta2 and downstream genes implicated in fibrosis were significantly up-regulated in fibrotic lesions. Genes for collagens and extracellular matrix proteins were highly up-regulated. In addition, expression of genes for peptidases and peptidase inhibitors were significantly altered, indicative of the tissue remodeling that occurs during airway fibrosis. Our data provide new insights into the molecular mechanisms of OB. This new information is of potential significance with regard to future therapeutic targets for treatment. PMID- 25710176 TI - Synergistic and antagonistic interplay between myostatin gene expression and physical activity levels on gene expression patterns in triceps Brachii muscles of C57/BL6 mice. AB - Levels of myostatin expression and physical activity have both been associated with transcriptome dysregulation and skeletal muscle hypertrophy. The transcriptome of triceps brachii muscles from male C57/BL6 mice corresponding to two genotypes (wild-type and myostatin-reduced) under two conditions (high and low physical activity) was characterized using RNA-Seq. Synergistic and antagonistic interaction and ortholog modes of action of myostatin genotype and activity level on genes and gene pathways in this skeletal muscle were uncovered; 1,836, 238, and 399 genes exhibited significant (FDR-adjusted P-value < 0.005) activity-by-genotype interaction, genotype and activity effects, respectively. The most common differentially expressed profiles were (i) inactive myostatin reduced relative to active and inactive wild-type, (ii) inactive myostatin reduced and active wild-type, and (iii) inactive myostatin-reduced and inactive wild-type. Several remarkable genes and gene pathways were identified. The expression profile of nascent polypeptide-associated complex alpha subunit (Naca) supports a synergistic interaction between activity level and myostatin genotype, while Gremlin 2 (Grem2) displayed an antagonistic interaction. Comparison between activity levels revealed expression changes in genes encoding for structural proteins important for muscle function (including troponin, tropomyosin and myoglobin) and for fatty acid metabolism (some linked to diabetes and obesity, DNA-repair, stem cell renewal, and various forms of cancer). Conversely, comparison between genotype groups revealed changes in genes associated with G1 to-S-phase transition of the cell cycle of myoblasts and the expression of Grem2 proteins that modulate the cleavage of the myostatin propeptide. A number of myostatin-feedback regulated gene products that are primarily regulatory were uncovered, including microRNA impacting central functions and Piezo proteins that make cationic current-controlling mechanosensitive ion channels. These important findings extend hypotheses of myostatin and physical activity master regulation of genes and gene pathways, impacting medical practices and therapies associated with muscle atrophy in humans and companion animal species and genome-enabled selection practices applied to food-production animal species. PMID- 25710177 TI - Metabolic and chaperone gene loss marks the origin of animals: evidence for Hsp104 and Hsp78 chaperones sharing mitochondrial enzymes as clients. AB - The evolution of animals involved acquisition of an emergent gene repertoire for gastrulation. Whether loss of genes also co-evolved with this developmental reprogramming has not yet been addressed. Here, we identify twenty-four genetic functions that are retained in fungi and choanoflagellates but undetectable in animals. These lost genes encode: (i) sixteen distinct biosynthetic functions; (ii) the two ancestral eukaryotic ClpB disaggregases, Hsp78 and Hsp104, which function in the mitochondria and cytosol, respectively; and (iii) six other assorted functions. We present computational and experimental data that are consistent with a joint function for the differentially localized ClpB disaggregases, and with the possibility of a shared client/chaperone relationship between the mitochondrial Fe/S homoaconitase encoded by the lost LYS4 gene and the two ClpBs. Our analyses lead to the hypothesis that the evolution of gastrulation-based multicellularity in animals led to efficient extraction of nutrients from dietary sources, loss of natural selection for maintenance of energetically expensive biosynthetic pathways, and subsequent loss of their attendant ClpB chaperones. PMID- 25710178 TI - Neurorehabilitation after neonatal intensive care: evidence and challenges. AB - Neonatologists and paediatric providers of developmental care have documented poor neurodevelopmental outcomes of infants who have received neonatal intensive care due to prematurity, perinatal neurological insults such as asphyxia or congenital anomalies such as congenital heart disease. In parallel, developmental specialists have researched treatment options in these high-risk children. The goal of this review is connect the main categories of poor outcomes (sensory and motor function, cognition, communication, behaviour) studied by neonatal intensive care follow-up specialists to the research focused on improving these outcomes. We summarise challenges in designing diagnostic and interventional approaches in infants <2 years of age and review the evidence for existing therapies and future treatments aimed at improving functionality. PMID- 25710180 TI - Electronic health records and patient safety: should we be discouraged? PMID- 25710179 TI - Inguinal hernia repair in premature infants: more questions than answers. AB - This review shows that there are many single institution studies reviewing outcomes of premature infants with IH. However, the numbers of patients in these studies are often small and most studies were retrospective, therefore, these studies were subject to the limitations inherent to observational studies for identifying best treatment methods. Nevertheless, the studies show that risks are high in this population and that outcomes may vary with the timing of repair. There have been calls for multicentre randomised trials comparing early versus later IH repair from all over the world and for a very long time. Yet, despite the frequency of IH repair in premature infants, this issue remains unstudied in a high-quality manner. A large, multicentre randomised trial is currently underway to address the effect of timing on the short-term and long-term safety and efficacy of IH repair in this population so that we may be able to deliver safe surgical care to this vulnerable population. PMID- 25710181 TI - Response to: 'Driven to distraction and driving for excellence in ward round practice' by Pucher and Aggarwal. PMID- 25710182 TI - Effects of manipulating volume and intensity training in masters swimmers. AB - PURPOSE: Recently, some studies have suggested that overall training intensity may be more important than training volume for improving swimming performance. However, those studies focused on very young subjects, and/or the difference between high-volume and high-intensity training was blurred. The aim of this study was to investigate in masters swimmers the effects of manipulation of training volume and intensity on performance and physiological variables. METHODS: A group of 10 male masters swimmers (age 32.3 +/- 5.1 y) performed 2 different 6-wk training periods followed by 1 wk of tapering. The first period was characterized by high training volume performed at low intensity (HvLi), whereas the second period was characterized by low training volume performed at high intensity (LvHi). Peak oxygen consumption (VO2peak) during incremental arm exercise, individual anaerobic threshold (IAT), and 100-m, 400-m, and 2000-m freestyle time were evaluated before and at the end of both training periods. RESULTS: HvLi training significant increased VO2peak (11.9% +/- 4.9% [mean change +/- 90%CL], P = .002) and performance in the 400-m (-2.8% +/- 1.8%, P = .002) and 2000-m (-3.4% +/- 2.9%, P = .025), with a likely change in IAT (4.9% +/- 4.7%, P > .05). After LvHi training, speed at IAT (12.4% +/- 5.3%, P = .004) and 100-m performance (-1.2% +/- 0.8%, P = .001) also improved, without any significant changes in VO2peak, 2000-m, and 400-m. CONCLUSIONS: These findings indicate that in masters swimmers an increase of training volume may lead to an improvement of VO2peak and middle- to long-distance performance. However, a subsequent period of LvHi training maintains previous adjustments and positively affects anaerobic threshold and short-distance performance. PMID- 25710184 TI - Standardization of the Dmax method for calculating the second lactate threshold. AB - PURPOSE: The purpose of this study was to test the reliability and validity of 2 standardized methods for calculating speed at the second lactate-threshold point (LT2) based on the preexisting Dmax (LTD) and modified Dmax (LTMOD) procedures. METHODS: 13 trained male road runners and triathletes completed 2 incremental laboratory running tests to determine LT2, followed by separate time trials (5, 10, 15 km) on an outdoor running track. Two new methods were proposed for calculating the speed at LT2: (1) the single standardized lactate threshold (LTSDs) and (2) the paired standardized lactate threshold (LTSDp) for quantifying changes over time. RESULTS: The LTSDs and LTSDp methods had high relative (ICC >= .98) and absolute (CV <= 1.9%) reliability in identifying the speed at LT2. The speed at LT2 according to the LTSDs and LTSDp methods had a strong correlation and was not different to the performance speed during the 10- and 15-km time trials (<=2.3%; rhoc > 0.8; P > .05). The following natural log-based formula was created to estimate the percentage of LT2 speed (using the LTSDs method) that could be sustained for events ~15-75 min: y = -7.256(ln x) + 157.64, where y = %LT2 speed, x = time-trial performance (s), and ln = natural log. CONCLUSIONS: The standardized methods are reliable for determining LT2. The LTSDs and LTSDp methods for calculating the speed at LT2 from a near-maximal incremental test calculated speeds similar to those exhibited in 10- and 15-km running time trials. A prediction equation for estimating the percentage of LT2 that can be sustained for events of ~15-75 min was generated. PMID- 25710183 TI - No evidence of inhibition of horizontal gene transfer by CRISPR-Cas on evolutionary timescales. AB - The CRISPR (clustered, regularly, interspaced, short, palindromic repeats)-Cas (CRISPR-associated genes) systems of archaea and bacteria provide adaptive immunity against viruses and other selfish elements and are believed to curtail horizontal gene transfer (HGT). Limiting acquisition of new genetic material could be one of the sources of the fitness cost of CRISPR-Cas maintenance and one of the causes of the patchy distribution of CRISPR-Cas among bacteria, and across environments. We sought to test the hypothesis that the activity of CRISPR-Cas in microbes is negatively correlated with the extent of recent HGT. Using three independent measures of HGT, we found no significant dependence between the length of CRISPR arrays, which reflects the activity of the immune system, and the estimated number of recent HGT events. In contrast, we observed a significant negative dependence between the estimated extent of HGT and growth temperature of microbes, which could be explained by the lower genetic diversity in hotter environments. We hypothesize that the relevant events in the evolution of resistance to mobile elements and proclivity for HGT, to which CRISPR-Cas systems seem to substantially contribute, occur on the population scale rather than on the timescale of species evolution. PMID- 25710186 TI - Spin splitting anisotropy in single diluted magnetic nanowire heterostructures. AB - We study the impact of the nanowire shape anisotropy on the spin splitting of excitonic photoluminescence. The experiments are performed on individual ZnMnTe/ZnMgTe core/shell nanowires as well as on ZnTe/ZnMgTe core/shell nanowires containing optically active magnetic CdMnTe insertions. When the magnetic field is oriented parallel to the nanowire axis, the spin splitting is several times larger than for the perpendicular field. We interpret this pronounced anisotropy as an effect of mixing of valence band states arising from the strain present in the core/shell geometry. This interpretation is further supported by theoretical calculations which allow to reproduce experimental results. PMID- 25710185 TI - EGR1 regulates radiation-induced apoptosis in head and neck squamous cell carcinoma. AB - The transcription factor, early growth response 1 (EGR1) belongs to the early growth response family. EGR1 regulates the transactivation of genes involved in growth inhibition and apoptosis by ionizing radiation. The aims of the present study were to evaluate the expression of EGR1, and its relationship to prognosis, in patients with advanced laryngeal and hypopharyngeal squamous cell carcinoma (LHSCC) receiving chemoradiation therapy, and to observe the effect of EGR1 on the apoptosis of head and neck squamous cell carcinoma (HNSCC) cells treated with ionizing radiation. Expression of the EGR1 protein in tissue samples from patients with LHSCC was detected by immunohistochemistry. A high expression of the EGR1 protein was observed in 37 (67.3%) of the 55 LHSCC tissue samples examined. A high EGR1 protein expression in patients with LHSCC who were treated with chemoradiation was significantly associated with improved larynx preservation survival (p=0.04). The 5-year disease-specific survival rate with larynx preservation was 59% in patients with a high EGR1 protein expression vs. 30% in those with a low EGR1 protein expression. In the human HNSCC cell line, PCI50, EGR1 mRNA expression was induced at 30-60 min, and EGR1 protein expression was induced at 60-120 min, after exposure to a 5 Gy dose of ionizing radiation. To evaluate the impact of EGR1 on radiation-induced apoptosis, we used small interfering RNA to knock down endogenous EGR1 gene expression. Cleaved caspase 3, cleaved caspase 7, and cleaved PARP were decreased, while XIAP was increased, in EGR1-knockdown PCI50 cells compared to negative control PCI50 cells, at all observed post-irradiation time points. These findings suggested that EGR1 knockdown inhibits radiation-induced apoptosis. In conclusion, EGR1 may be associated with larynx-preservation survival, through the regulation of radiation induced apoptosis in patients with LHSCC treated with chemoradiation. Although further investigations are required to support the present study, EGR1 serves as a favorable biomarker of radiosensitivity in the treatment of LHSCC. PMID- 25710187 TI - Computer-aided diagnosis of Parkinson's disease based on [(123)I]FP-CIT SPECT binding potential images, using the voxels-as-features approach and support vector machines. AB - OBJECTIVE: The aim of the present study was to develop a fully-automated computational solution for computer-aided diagnosis in Parkinson syndrome based on [(123)I]FP-CIT single photon emission computed tomography (SPECT) images. APPROACH: A dataset of 654 [(123)I]FP-CIT SPECT brain images from the Parkinson's Progression Markers Initiative were used. Of these, 445 images were of patients with Parkinson's disease at an early stage and the remainder formed a control group. The images were pre-processed using automated template-based registration followed by the computation of the binding potential at a voxel level. Then, the binding potential images were used for classification, based on the voxel-as feature approach and using the support vector machines paradigm. MAIN RESULTS: The obtained estimated classification accuracy was 97.86%, the sensitivity was 97.75% and the specificity 98.09%. SIGNIFICANCE: The achieved classification accuracy was very high and, in fact, higher than accuracies found in previous studies reported in the literature. In addition, results were obtained on a large dataset of early Parkinson's disease subjects. In summation, the information provided by the developed computational solution potentially supports clinical decision-making in nuclear medicine, using important additional information beyond the commonly used uptake ratios and respective statistical comparisons. (ClinicalTrials.gov Identifier: NCT01141023). PMID- 25710188 TI - Electrospun amplified fiber optics. AB - All-optical signal processing is the focus of much research aiming to obtain effective alternatives to existing data transmission platforms. Amplification of light in fiber optics, such as in Erbium-doped fiber amplifiers, is especially important for efficient signal transmission. However, the complex fabrication methods involving high-temperature processes performed in a highly pure environment slow the fabrication process and make amplified components expensive with respect to an ideal, high-throughput, room temperature production. Here, we report on near-infrared polymer fiber amplifiers working over a band of ~20 nm. The fibers are cheap, spun with a process entirely carried out at room temperature, and shown to have amplified spontaneous emission with good gain coefficients and low levels of optical losses (a few cm(-1)). The amplification process is favored by high fiber quality and low self-absorption. The found performance metrics appear to be suitable for short-distance operations, and the large variety of commercially available doping dyes might allow for effective multiwavelength operations by electrospun amplified fiber optics. PMID- 25710189 TI - Analysis of the Relative Age Effect in Elite Youth Judo Athletes. AB - The purpose of this investigation was to evaluate relative age effects (RAEs) in elite youth judo athletes from different chronological age groups, between sexes, and across weight categories. Data from 1542 place winners of the cadet (under 17 y, 2009-2013) and junior judo world championships (under 20/21 y, 1990-2013) were separated by birth month into quarters (Q1, Q2, Q3, and Q4). The observed values were compared with expected annual age distributions using chi2 analyses, and odd ratios (OR) were used to evaluate effect sizes between quarters. The observed frequency of place winners was significantly different from the expected frequency for the age-group and sex comparisons and all body-mass groups (P < .05) with the exception of the extra-light categories (P = .572). When comparing Q1 with Q4 (OR, 95% confidence interval), small effect sizes were observed for cadets (1.72, 1.12-2.66), juniors (1.54, 1.23-1.94), males (1.75, 1.32-2.33), females (1.39, 1.03-1.87), and the light- (1.79, 1.21-2.64) and middle-weight (1.80, 1.20-2.70) categories. RAEs are apparent in cadet and junior judo athletes. Thus, coaches and administrators should consider the potential for physical and/or competitive advantages while adopting strategies that encourage long-term participation in youth judo athletes. PMID- 25710190 TI - The effects of Red Bull energy drink compared with caffeine on cycling time-trial performance. AB - This study investigated the ergogenic effects of a commercial energy drink (Red Bull) or an equivalent dose of anhydrous caffeine in comparison with a noncaffeinated control beverage on cycling performance. Eleven trained male cyclists (31.7 +/- 5.9 y 82.3 +/- 6.1 kg, VO2max = 60.3 +/- 7.8 mL . kg-1 . min 1) participated in a double-blind, placebo-controlled, crossover-design study involving 3 experimental conditions. Participants were randomly administered Red Bull (9.4 mL/kg body mass [BM] containing 3 mg/kg BM caffeine), anhydrous caffeine (3 mg/kg BM given in capsule form), or a placebo 90 min before commencing a time trial equivalent to 1 h cycling at 75% peak power output. Carbohydrate and fluid volumes were matched across all trials. Performance improved by 109 +/- 153 s (2.8%, P = .039) after Red Bull compared with placebo and by 120 +/- 172 s (3.1%, P = .043) after caffeine compared with placebo. No significant difference (P > .05) in performance time was detected between Red Bull and caffeine treatments. There was no significant difference (P > .05) in mean heart rate or rating of perceived exertion among the 3 treatments. This study demonstrated that a moderate dose of caffeine consumed as either Red Bull or in anhydrous form enhanced cycling time-trial performance. The ergogenic benefits of Red Bull energy drink are therefore most likely due to the effects of caffeine, with the other ingredients not likely to offer additional benefit. PMID- 25710191 TI - Direct ion imaging approach for investigation of ion dynamics in multipole ion guides. AB - A key requirement of electrospray ionization (ESI) and other techniques facilitating ionization at elevated pressures is the efficient transport of free gas-phase ions into the high vacuum region of the mass spectrometer. Radio frequency (RF) multipole ion guides that allow for collisional cooling are one of the most popular means of achieving this. However, their performance is highly dependent on several experimental factors, including pressure and various electrode potentials along the ion path. To experimentally visualize these effects, we have employed a position-sensitive detector at the exit of a quadrupole mass spectrometer (QMS) instrument operated in RF only mode that employs an RF only octopole as a collisional cooling ion guide. This allows the spatial distribution of the ions, and its dependence on experimentally determined conditions, to be directly visualized at the exit of the quadrupole. This investigation provides a detailed insight into the ion dynamics occurring inside multipole ion guides. This knowledge can directly be applied to instrument development and to improve the ion transmission efficiency and, thus, sensitivity. Numerical simulations using custom-developed trajectory simulation software are compared and contrasted with the experimental observations. PMID- 25710194 TI - Efficient light-emitting diodes based on nanocrystalline perovskite in a dielectric polymer matrix. AB - Electroluminescence in light-emitting devices relies on the encounter and radiative recombination of electrons and holes in the emissive layer. In organometal halide perovskite light-emitting diodes, poor film formation creates electrical shunting paths, where injected charge carriers bypass the perovskite emitter, leading to a loss in electroluminescence yield. Here, we report a solution-processing method to block electrical shunts and thereby enhance electroluminescence quantum efficiency in perovskite devices. In this method, a blend of perovskite and a polyimide precursor dielectric (PIP) is solution deposited to form perovskite nanocrystals in a thin-film matrix of PIP. The PIP forms a pinhole-free charge-blocking layer, while still allowing the embedded perovskite crystals to form electrical contact with the electron- and hole injection layers. This modified structure reduces nonradiative current losses and improves quantum efficiency by 2 orders of magnitude, giving an external quantum efficiency of 1.2%. This simple technique provides an alternative route to circumvent film formation problems in perovskite optoelectronics and offers the possibility of flexible and high-performance light-emitting displays. PMID- 25710192 TI - Structural basis of activity against aztreonam and extended spectrum cephalosporins for two carbapenem-hydrolyzing class D beta-lactamases from Acinetobacter baumannii. AB - The carbapenem-hydrolyzing class D beta-lactamases OXA-23 and OXA-24/40 have emerged worldwide as causative agents for beta-lactam antibiotic resistance in Acinetobacter species. Many variants of these enzymes have appeared clinically, including OXA-160 and OXA-225, which both contain a P -> S substitution at homologous positions in the OXA-24/40 and OXA-23 backgrounds, respectively. We purified OXA-160 and OXA-225 and used steady-state kinetic analysis to compare the substrate profiles of these variants to their parental enzymes, OXA-24/40 and OXA-23. OXA-160 and OXA-225 possess greatly enhanced hydrolytic activities against aztreonam, ceftazidime, cefotaxime, and ceftriaxone when compared to OXA 24/40 and OXA-23. These enhanced activities are the result of much lower Km values, suggesting that the P -> S substitution enhances the binding affinity of these drugs. We have determined the structures of the acylated forms of OXA-160 (with ceftazidime and aztreonam) and OXA-225 (ceftazidime). These structures show that the R1 oxyimino side-chain of these drugs occupies a space near the beta5 beta6 loop and the omega loop of the enzymes. The P -> S substitution found in OXA-160 and OXA-225 results in a deviation of the beta5-beta6 loop, relieving the steric clash with the R1 side-chain carboxypropyl group of aztreonam and ceftazidime. These results reveal worrying trends in the enhancement of substrate spectrum of class D beta-lactamases but may also provide a map for beta-lactam improvement. PMID- 25710196 TI - Picosecond fluorescence dynamics of tryptophan and 5-fluorotryptophan in monellin: slow water-protein relaxation unmasked. AB - Time dependent fluorescence Stokes (emission wavelength) shifts (TDFSS) from tryptophan (Trp) following sub-picosecond excitation are increasingly used to investigate protein dynamics, most recently enabling active research interest into water dynamics near the surface of proteins. Unlike many fluorescence probes, both the efficiency and the wavelength of Trp fluorescence in proteins are highly sensitive to microenvironment, and Stokes shifts can be dominated by the well-known heterogeneous nature of protein structure, leading to what we call pseudo-TDFSS: shifts that arise from differential decay rates of subpopulations. Here we emphasize a novel, general method that obviates pseudo-TDFSS by replacing Trp by 5-fluorotryptophan (5Ftrp), a fluorescent analogue with higher ionization potential and greatly suppressed electron-transfer quenching. 5FTrp slows and suppresses pseudo-TDFSS, thereby providing a clearer view of genuine relaxation caused by solvent and protein response. This procedure is applied to the sweet tasting protein monellin which has uniquely been the subject of ultrafast studies in two different laboratories (Peon, J.; et al. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 10964; Xu, J.; et al. J. Am. Chem. Soc. 2006, 128, 1214) that led to disparate interpretations of a 20 ps transient. They differed because of the pseudo-TDFSS present. The current study exploiting special properties of 5FTrp strongly supports the conclusion that both lifetime heterogeneity-based TDFSS and environment relaxation-based TDFSS are present in monellin and 5FTrp-monellin. The original experiments on monellin were most likely dominated by pseudo-TDFSS, whereas, in the present investigation of 5FTrp-monellin, the TDFSS is dominated by relaxation and any residual pseudo-TDFSS is overwhelmed and/or slowed to irrelevance. PMID- 25710195 TI - Effect of aging on phosphorus speciation in surface deposit of a vertical flow constructed wetland. AB - This study was conducted to determine phosphorus (P) species captured in a vertical-flow constructed wetland (VFCW) system combining a trickling filter followed by FeCl3 injection for phosphate coagulation. Suspended solids (SS) thus formed accumulated over time at the VFCW surface and transformed into a sludge deposit layer, which was shown to concentrate most of the P captured in the system. In order to investigate the effect of aging on P species, representative SS and sludge samples were taken from a wastewater treatment plant that had been in operation for 8 years and analyzed using P fractionation, solution (31)P NMR spectroscopy, and P and Fe K-edge XANES spectroscopy. A partial mineralization of organic matter was shown by comparing organic carbon contents of SS and sludge materials. Chemical fractionations combined with P and Fe K-edge XANES spectroscopy showed that P was predominantly bound to iron within both samples in the form of ferric phosphate, rather than adsorbed onto ferric oxyhydroxide. Calcium-bound P was more significantly observed in sludge than in SS, suggesting that aging induced the recombination of part of the organic and iron-bound P species into calcium-bound forms, as a possible consequence of the partial mineralization of organic matter. PMID- 25710197 TI - alpha-Conotoxin dendrimers have enhanced potency and selectivity for homomeric nicotinic acetylcholine receptors. AB - Covalently attached peptide dendrimers can enhance binding affinity and functional activity. Homogenous di- and tetravalent dendrimers incorporating the alpha7-nicotinic receptor blocker alpha-conotoxin ImI (alpha-ImI) with polyethylene glycol spacers were designed and synthesized via a copper-catalyzed azide-alkyne cycloaddition of azide-modified alpha-ImI to an alkyne-modified polylysine dendron. NMR and CD structural analysis confirmed that each alpha-ImI moiety in the dendrimers had the same 3D structure as native alpha-ImI. The binding of the alpha-ImI dendrimers to binding protein Ac-AChBP was measured by surface plasmon resonance and revealed enhanced affinity. Quantitative electrophysiology showed that alpha-ImI dendrimers had ~100-fold enhanced potency at halpha7 nAChRs (IC50 = 4 nM) compared to native alpha-ImI (IC50 = 440 nM). In contrast, no significant potency enhancement was observed at heteromeric halpha3beta2 and halpha9alpha10 nAChRs. These findings indicate that multimeric ligands can significantly enhance conotoxin potency and selectivity at homomeric nicotinic ion channels. PMID- 25710198 TI - Comparison of three magnetic bead surface functionalities for RNA extraction and detection. AB - Magnetic beads are convenient for extracting nucleic acid biomarkers from biological samples prior to molecular detection. These beads are available with a variety of surface functionalities designed to capture particular subsets of RNA. We hypothesized that bead surface functionality affects binding kinetics, processing simplicity, and compatibility with molecular detection strategies. In this report, three magnetic bead surface chemistries designed to bind nucleic acids, silica, oligo (dT), and a specific oligonucleotide sequence were evaluated. Commercially available silica-coated and oligo (dT) beads, as well as beads functionalized with oligonucleotides complementary to respiratory syncytial virus (RSV) nucleocapsid gene, respectively recovered ~75, ~71, and ~7% target RSV mRNA after a 1 min of incubation time in a surrogate patient sample spiked with the target. RSV-specific beads required much longer incubation times to recover amounts of the target comparable to the other beads (~77% at 180 min). As expected, silica-coated beads extracted total RNA, oligo (dT) beads selectively extracted total mRNA, and RSV-specific beads selectively extracted RSV N gene mRNA. The choice of bead functionality is generally dependent on the target detection strategy. The silica-coated beads are most suitable for applications that require nucleic acids other than mRNA, especially with detection strategies that are tolerant of a high concentration of nontarget background nucleic acids, such as RT-PCR. On the other hand, oligo (dT) beads are best-suited for mRNA targets, as they bind biomarkers rapidly, have relatively high recovery, and enable detection strategies to be performed directly on the bead surface. Sequence-specific beads may be best for applications that are not tolerant of a high concentration of nontarget nucleic acids that require short RNA sequences without poly(A) tails, such as microRNAs, or that perform RNA detection directly on the bead surface. PMID- 25710199 TI - A ligand field series for the 4f-block from experimental and DFT computed Ce(IV/III) electrochemical potentials. AB - Understanding of the sensitivity of the reduction potential of cerium(IV) cations to ligand field strength has yet to benefit from systematic variation of the ligand environment. Detailed analyses for a series of seven cerium(IV) tetrakis(pyridyl-nitroxide) compounds and their cerium(III) analogues in varying ligand field strengths are presented. Electrochemical, spectroscopic, and computational results reveal a close correlation of electronic properties with ligand substituents. Together with electrochemical data for reported eight coordinate compounds, DFT calculations reveal a broad range of the cerium(IV/III) redox potentials correlated to ligand field strengths, establishing a semiempirical, predictive model for the modulation of cerium redox thermodynamics and ligand field strengths. Applications over a variety of scientific disciplines make use of the fundamental redox thermodynamics of cerium. Such applications will benefit from a combined experimental and theoretical approach for assessing redox cycling of cerium compounds. PMID- 25710200 TI - One-carbon metabolism and epigenetic regulation of embryo development. AB - One-carbon (1C) metabolism consists of an integrated series of metabolic pathways that include the folate cycle and methionine remethylation and trans-sulfuration pathways. Most, but not all, 1C metabolic enzymes are expressed in somatic cells of the ovary, mammalian oocytes and in preimplantation embryos. The metabolic implications of this, with regard to the provision of methyl donors (e.g. betaine) and 1C cofactors (e.g. vitamin B12), together with consequences of polymorphic variances in genes encoding 1C enzymes, are not fully understood but are the subject of ongoing investigations at the authors' laboratory. However, deficiencies in 1C-related substrates and/or cofactors during the periconception period are known to lead to epigenetic alterations in DNA and histone methylation in genes that regulate key developmental processes in the embryo. Such epigenetic modifications have been demonstrated to negatively impact on the subsequent health and metabolism of offspring. For this reason, parental nutrition around the time of conception has become a focal point of investigation in many laboratories with the aim of providing improved nutritional advice to couples. These issues are considered in detail in this article, which offers a contemporary overview of the effects of 1C metabolism on epigenetic programming in mammalian gametes and the early embryo. PMID- 25710201 TI - Comparing two classifications of cancer cachexia and their association with survival in patients with unresected pancreatic cancer. AB - There is no universally accepted definition of cancer cachexia. Two classifications have been proposed; the 3-factor classification requiring >= 2 of 3 factors; weight loss >= 10%, food intake <= 1500 kcal/day, and C-reactive protein >= 10 mg/l, and the consensus classification requiring weight loss >5% the past 6 mo, or body mass index <20 kg/m(2) or sarcopenia, both with ongoing weight loss >2%. Precachexia is the initial stage of the cachexia trajectory, identified by weight loss <= 5%, anorexia and metabolic change. We examined the consistency between the 2 classifications, and their association with survival in a palliative cohort of 45 (25 men, median age of 72 yr, range 35-89) unresected pancreatic cancer patients. Computed tomography images were used to determine sarcopenia. Height/weight/C-reactive protein and survival were extracted from medical records. Food intake was self-reported. The agreement for cachexia and noncachexia was 78% across classifications. Survival was poorer in cachexia compared to noncachexia (3-factor classification, P = 0.0052; consensus classification, P = 0.056; when precachexia was included in the consensus classification, P = 0.027). Both classifications showed a trend toward lower median survival (P < 0.05) with the presence of cachexia. In conclusion, the two classifications showed good overall agreement in defining cachectic pancreatic cancer patients, and cachexia was associated with poorer survival according to both. PMID- 25710202 TI - Framing the implementation process of video conferencing in discharge planning According to staff experience. AB - Challenges of improving discharge planning have been an area of concern for many years, including problems related to the lack of time for professionals to participate. In a county in South East Sweden, video conferencing was implemented in discharge planning sessions to enable distance participation of the professionals. To examine the implementation process, interviews were conducted with the implementers, who were project leaders, discharge planning coordinators in the hospital, and in home-care. The interviews were analyzed qualitatively, using directed content analysis with a deductive approach to a theoretical framework that was composed from theories about implementation processes to be suitable for the healthcare sector, consisting of the factors: implementation objects; implementation actions; actors; users; inner context and outer context. The results of this study are consistent with the framework but with the addition of a new dimension-time, i.e. time to prepare; time to understand; time to run through and time to reflect. It is suggested that implementation frameworks are useful when IT is introduced in healthcare. Framing the implementation process supports the exposure of factors and highlights relationships and states of dependence between those factors which may affect implementation. PMID- 25710203 TI - New Insights into the Life Cycle of the Wheat Powdery Mildew: Direct Observation of Ascosporic Infection in Blumeria graminis f. sp. tritici. AB - Although Blumeria graminis is an intensively studied pathogen, an important part of its life cycle (namely, the way ascospores initiate primary infections on cereal leaves) has not yet been explored in detail. This study reports, for the first time, the direct observation of this process in B. graminis f. sp. tritici using light and confocal laser-scanning microscopy. All the germinated ascospores produced a single germ tube type both in vitro and on host plant surfaces; therefore, the ascosporic and conidial germination patterns are markedly different in this fungus, in contrast to other powdery mildews. Germinated ascospores penetrated the epidermal cells of wheat leaves and produced haustoria as known in the case of conidial infections. This work confirmed earlier studies reporting that B. graminis chasmothecia collected from the field do not contain mature ascospores, only asci filled with protoplasm; ascospore development is induced by moist conditions and is a fast process compared with other powdery mildews. Although ascosporic infections are frequent in B. graminis f. sp. tritici in the field, as shown by this study and other works as well, a recent analysis of the genomes of four isolates revealed the signs of clonal or near clonal reproduction. Therefore, chasmothecia and ascospores are probably more important as oversummering structures than genetic recombination factors in the life cycle of this pathogen. PMID- 25710204 TI - Genome-Enabled Phylogeographic Investigation of the Quarantine Pathogen Ralstonia solanacearum Race 3 Biovar 2 and Screening for Sources of Resistance Against Its Core Effectors. AB - Phylogeographic studies inform about routes of pathogen dissemination and are instrumental for improving import/export controls. Genomes of 17 isolates of the bacterial wilt and potato brown rot pathogen Ralstonia solanacearum race 3 biovar 2 (R3bv2), a Select Agent in the United States, were thus analyzed to get insight into the phylogeography of this pathogen. Thirteen of fourteen isolates from Europe, Africa, and Asia were found to belong to a single clonal lineage while isolates from South America were genetically diverse and tended to carry ancestral alleles at the analyzed genomic loci consistent with a South American origin of R3bv2. The R3bv2 isolates share a core repertoire of 31 type III secreted effector genes representing excellent candidates to be targeted with resistance genes in breeding programs to develop durable disease resistance. Toward this goal, 27 R3bv2 effectors were tested in eggplant, tomato, pepper, tobacco, and lettuce for induction of a hypersensitive-like response indicative of recognition by cognate resistance receptors. Fifteen effectors, eight of them core effectors, triggered a response in one or more plant species. These genotypes may harbor resistance genes that could be identified and mapped, cloned, and expressed in tomato or potato, for which sources of genetic resistance to R3bv2 are extremely limited. PMID- 25710205 TI - Genetic Diversity and Population Structure of Cucurbit Gummy Stem Blight Fungi Based on Microsatellite Markers. AB - Combining population genetics with epidemiology provides insight into the population biology of pathogens, which could lead to improved management of plant diseases. Gummy stem blight, caused by three closely related species of Stagonosporopsis-Stagonosporopsis cucurbitacearum (syn. Didymella bryoniae), S. citrulli, and S. caricae-is a devastating disease of cucurbits worldwide. Sources of inoculum for epidemics, mechanisms of dispersal, and the mating system of these species are not well understood. To improve our knowledge of gummy stem blight epidemiology, we developed 18 polymorphic microsatellite markers by combining microsatellite motif enrichment with next-generation sequencing. When tested on 46 isolates from diverse cucurbit hosts and regions, the markers were robust for the dominant and widely distributed S. citrulli. Within this species, we found no population structure based on broad-scale geographic region or host of origin. Using the microsatellites, a rapid polymerase chain reaction-based method was developed to distinguish the three morphologically similar species causing gummy stem blight. To better understand dispersal, reproduction, and fine scale genetic diversity of S. citrulli within and among watermelon fields, 155 isolates from two field populations in Georgia, United States were genotyped with the 18 microsatellite loci. Although dominant and widespread clones were detected, we found relatively high genotypic diversity and recombinant genotypes consistent with outcrossing. Significant population genetic structure between the two field populations demonstrated that there is regional geographic structure and limited dispersal among fields. This study provides insight into the fine scale genetic diversity and reproductive biology of the gummy stem blight pathogen S. citrulli in the field. PMID- 25710207 TI - Topical administration of isoflavones for treatment of vaginal symptoms in postmenopausal women: A systematic review of randomised controlled trials. AB - Current systematic review evaluated the efficacy of topical isoflavones to relieve vaginal symptoms in menopausal women. MEDLINE (1966 to January 2014), Scopus (1990 to January 2014), and the Cochrane Central Register of Controlled Trials (The Cochrane Library issue 1, 2013) were searched using keywords 'isoflavone and vagina'. Relevant studies were reviewed by two independent reviewers. Only randomised controlled trials (RCTs) were included in the systematic review. Out of 115 potentially relevant publications, four studies met the inclusion criteria. Topical isoflavones showed beneficial effects on dyspareunia, vaginal dryness and maturation value. Based on only one trial, the result of conjugated equine oestrogen cream (0.3 mg/day) was similar to use of isoflavone vaginal gel and superior to that of placebo gel. However, drawing any definite conclusion was difficult because of the limited number of RCTs, the small sample sizes, weak methodology and considerable heterogeneity of the included studies. PMID- 25710206 TI - Manual and electrical needle stimulation in acupuncture research: pitfalls and challenges of heterogeneity. AB - In the field of acupuncture research there is an implicit yet unexplored assumption that the evidence on manual and electrical stimulation techniques, derived from basic science studies, clinical trials, systematic reviews, and meta analyses, is generally interchangeable. Such interchangeability would justify a bidirectional approach to acupuncture research, where basic science studies and clinical trials each inform the other. This article examines the validity of this fundamental assumption by critically reviewing the literature and comparing manual to electrical acupuncture in basic science studies, clinical trials, and meta-analyses. The evidence from this study does not support the assumption that these techniques are interchangeable. This article also identifies endemic methodologic limitations that have impaired progress in the field. For example, basic science studies have not matched the frequency and duration of manual needle stimulation to the frequency and duration of electrical stimulation. Further, most clinical trials purporting to compare the two types of stimulation have instead tested electroacupuncture as an adjunct to manual acupuncture. The current findings reveal fundamental gaps in the understanding of the mechanisms and relative effectiveness of manual versus electrical acupuncture. Finally, future research directions are suggested to better differentiate electrical from manual simulation, and implications for clinical practice are discussed. PMID- 25710208 TI - Adenosine receptor transcriptomic profile in cardiac tissue of a Zucker rat model. AB - To evaluate the possible variations of adenosine receptor (AR) profile together with TNF-alpha and IL-6 mRNA in cardiac tissue of obese Zucker rats (OZR) during fasting conditions (fc) and during the induction of acute hyperglycemia (AH). OZR (O, n=21) and age-matched lean control rats (CO, n=18) were studied during fc (COfc, n=8; Ofc, n=13) and during the induction of AH (COAH, n=10; OAH, n=8). The histopathologic analysis performed on O and CO heart samples did not show abnormalities of myocardial structure. The AR transcriptomic profile was analyzed in O and CO by real-time polymerase chain reaction (PCR) and a significantly lower mRNA expression was observed for A2AR in O with respect to CO (p=0.047), while a significant upregulation was observed for A3R in O with respect to CO (p=0.002). No significant differences between O and CO were observed for TNF alpha or IL-6. Correlations were found between glycemia and A1R (p=0.03) and A2BR (p=0.002); total cholesterol and A2BR (p=0.02) and A3R (p=0.0002), as well as between IL-6 and A1R (p=0.05) and TNF-alpha and A2AR (p<0.0001). The modulation of ARs in these settings could represent a promising approach to pharmacological treatment, which must be supported by diet restrictions and physical exercise. PMID- 25710209 TI - Isovaleric acid in stool correlates with human depression. AB - OBJECTIVE: Human depression is a major burden, both on the individuals who suffer from the disease and on society at large. Traditionally, depression has been linked to psychological and biological causes, but there has been increasing interest in the gut-brain axis. In this regard, we have recently shown that specific bacteria are correlated with human depression, and we hypothesize that volatile fatty acids (VFAs) are mediators. METHODS: Here, we analyzed the direct correlation between VFAs, depression and cortisol in a cohort consisting of 34 depressed patients and 17 controls. RESULTS: We found statistically significant correlations between depression and the VFA isovaleric acid, as well as between isovaleric acid and cortisol. Furthermore, bacteria that previously have been identified as being correlated with depression were also correlated with isovaleric acid. Isovaleric acid showed a bimodal distribution in which the depressed patients were overrepresented in the high level group (P < 0.00005, binominal test). DISCUSSION: It has recently been shown that gut-derived VFAs can cross the blood-brain barrier, where isovaleric acid interferes with synaptic neurotransmitter release. The multiple correlation patterns, in addition to a potential mechanistic model, point towards a potential causal relationship between depression and isovaleric acid. PMID- 25710210 TI - Ultra-low-dose dual-source CT coronary angiography with high pitch: diagnostic yield of a volumetric planning scan and effects on dose reduction and imaging strategy. AB - OBJECTIVE: To evaluate the role of an ultra-low-dose dual-source CT coronary angiography (CTCA) scan with high pitch for delimiting the range of the subsequent standard CTCA scan. METHODS: 30 patients with an indication for CTCA were prospectively examined using a two-scan dual-source CTCA protocol (2.0 * 64.0 * 0.6 mm; pitch, 3.4; rotation time of 280 ms; 100 kV): Scan 1 was acquired with one-fifth of the tube current suggested by the automatic exposure control software [CareDose 4DTM (Siemens Healthcare, Erlangen, Germany) using 100 kV and 370 mAs as a reference] with the scan length from the tracheal bifurcation to the diaphragmatic border. Scan 2 was acquired with standard tube current extending with reduced scan length based on Scan 1. Nine central coronary artery segments were analysed qualitatively on both scans. RESULTS: Scan 2 (105.1 +/- 10.1 mm) was significantly shorter than Scan 1 (127.0 +/- 8.7 mm). Image quality scores were significantly better for Scan 2. However, in 5 of 6 (83%) patients with stenotic coronary artery disease, a stenosis was already detected in Scan 1 and in 13 of 24 (54%) patients with non-stenotic coronary arteries, a stenosis was already excluded by Scan 1. Using Scan 2 as reference, the positive- and negative predictive value of Scan 1 was 83% (5 of 6 patients) and 100% (13 of 13 patients), respectively. CONCLUSION: An ultra-low-dose CTCA planning scan enables a reliable scan length reduction of the following standard CTCA scan and allows for correct diagnosis in a substantial proportion of patients. ADVANCES IN KNOWLEDGE: Further dose reductions are possible owing to a change in the individual patient's imaging strategy as a prior ultra-low-dose CTCA scan may already rule out the presence of a stenosis or may lead to a direct transferal to an invasive catheter procedure. PMID- 25710211 TI - When we don't want to stop. PMID- 25710212 TI - Training physician assistants to be physicians. PMID- 25710213 TI - In reply to brock and scott. PMID- 25710214 TI - Mentoring mentors in scientific communication for trainees. PMID- 25710215 TI - In Reply to Chang and colleagues. PMID- 25710216 TI - In Reply to Chang and colleagues. PMID- 25710217 TI - Medical student membership on a hospital-based institutional review board: a unique educational opportunity. PMID- 25710218 TI - A Vienna reflection. PMID- 25710219 TI - Artist's statement: Touch the Lives. PMID- 25710221 TI - Medicine and the arts. By Small and Small: Midnight to Four A.M. by Jack Gilbert. Commentary. PMID- 25710222 TI - Palliative care: my first rotation and the other side of healing. PMID- 25710223 TI - Interwoven three-dimensional architecture of cobalt oxide nanobrush graphene@Ni(x)Co(2x)(OH)(6x) for high-performance supercapacitors. AB - Development of pseudocapacitor electrode materials with high comprehensive electrochemical performance, such as high capacitance, superior reversibility, excellent stability, and good rate capability at the high mass loading level, still is a tremendous challenge. To our knowledge, few works could successfully achieve the above comprehensive electrochemical performance simultaneously. Here we design and synthesize one interwoven three-dimensional (3D) architecture of cobalt oxide nanobrush-graphene@Ni(x)Co(2x)(OH)(6x) (CNG@NCH) electrode with high comprehensive electrochemical performance: high specific capacitance (2550 F g( 1) and 5.1 F cm(-2)), good rate capability (82.98% capacitance retention at 20 A g(-1) vs 1 A g(-1)), superior reversibility, and cycling stability (92.70% capacitance retention after 5000 cycles at 20 A g(-1)), which successfully overcomes the tremendous challenge for pseudocapacitor electrode materials. The asymmetric supercapacitor of CNG@NCH//reduced-graphene-oxide-film exhibits good rate capability (74.85% capacitance retention at 10 A g(-1) vs 0.5 A g(-1)) and high energy density (78.75 Wh kg(-1) at a power density of 473 W kg(-1)). The design of this interwoven 3D frame architecture can offer a new and appropriate idea for obtaining high comprehensive performance electrode materials in the energy storage field. PMID- 25710224 TI - Destabilisation of the hexatic phase in systems of hard disks by quenched disorder due to pinning on a lattice. AB - We investigate the effect of quenched disorder on the melting mechanism of two dimensional hard disks using large-scale event-driven molecular dynamics simulations. The two-stage melting scenario of a continuous solid-hexatic and a first-order hexatic-liquid transition for a 2D system of hard disks does not persist in the case of quenched disorder, which arises by pinning less than one percent of the particles on a triangular lattice. Based on the Halperin-Nelson Young (HNY) renormalization group equation, we observe that a first-order solid liquid transition preempts the Kosterlitz-Thouless-type solid-hexatic transition in a 2D system of hard disks with quenched disorder as the stiffness of the crystal is increased by the presence of pinned particles. PMID- 25710225 TI - [Ethical review of research in the grey area. The Ethical Review Act should be widened and case management more efficient]. AB - The present legal definition of the term research creates problems with what can be considered for ethical vetting by the Research Ethical Review Board. The Ethical Review Act should be revised in order for student projects involving patients or quality assurance in healthcare to be accepted for ethical vetting by the Board. PMID- 25710226 TI - [Dizziness in the emergency room]. AB - The majority of patients who present to the Emergency Department with vertigo suffer from benign conditions. However, a few percent of these patients have life threatening conditions, such as a cerebellar stroke. The HINTS clinical decision rule (Head-Impulse test, Nystagmus, Test-of-Skew) allows the physician to identify patients with an acute vestibular syndrome of central origin. HINTS is more sensitive than early magnetic resonance imaging. There is no role for computed tomography in the evaluation of patients with isolated acute vestibular syndrome in the Emergency Department. For patients with benign paroxysmal positional vertigo, simple reposition maneuvers are effective for symptom relief. PMID- 25710227 TI - [Up in the blue]. PMID- 25710228 TI - [E-cigarettes should be considered for therapy-resistant smoke-induced COPD]. PMID- 25710229 TI - [Can we trust the Swedish Hip Arthroplasty Register?]. PMID- 25710230 TI - [The silent film era was a golden age for obese actors]. PMID- 25710231 TI - [You can rely on the registry--if the clinics register correctly]. PMID- 25710232 TI - [The medical students association are hopeful about a new opportunity for the medical education report]. PMID- 25710234 TI - [Physicians against racism]. PMID- 25710233 TI - [An extraordinary situation. Reflection over Swedish health care]. PMID- 25710235 TI - [Internship in an ever changing health care]. PMID- 25710236 TI - [Lack of information can make the patient a felon]. PMID- 25710237 TI - [The Swedish Society of Medicine: Two organizations is a strength]. PMID- 25710238 TI - [Reconsider the diagnosis and treatment approach for ADHD]. PMID- 25710239 TI - [High latitudes--an internship-adventure]. PMID- 25710240 TI - [Correction: Language assessments at child health services develops positively. More common with evidence-based methods]. PMID- 25710241 TI - Schizophrenia: a critical psychiatry perspective. AB - PURPOSE OF REVIEW: The term 'schizophrenia' has been hotly contested over recent years. The current review explores the meanings of the term, whether it is valid and helpful and how alternative conceptions of severe mental disturbance would shape clinical practice. RECENT FINDINGS: Schizophrenia is a label that implies the presence of a biological disease, but no specific bodily disorder has been demonstrated, and the language of 'illness' and 'disease' is ill-suited to the complexities of mental health problems. Neither does the concept of schizophrenia delineate a group of people with similar patterns of behaviour and outcome trajectories. This is not to deny that some people show disordered speech and behaviour and associated mental suffering, but more generic terms, such as 'psychosis' or just 'madness', would be preferable because they are less strongly associated with the disease model, and enable the uniqueness of each individual's situation to be recognized. SUMMARY: The disease model implicit in current conceptions of schizophrenia obscures the underlying functions of the mental health system: the care and containment of people who behave in distressing and disturbing ways. A new social framework is required that makes mental health services transparent, fair and open to democratic scrutiny. PMID- 25710242 TI - Drug development in schizophrenia: are glutamatergic targets still worth aiming at? AB - PURPOSE OF REVIEW: The ketamine model has dominated drug discovery in schizophrenia over the past decade, supported by genetic and postmortem evidence implicating glutamatergic transmission. This review assesses recent successes and disappointments of glutamatergic agents and identifies promising new directions. RECENT FINDINGS: Strategies focused on enhancing activity of the N-methyl D aspartate (NMDA) receptor via direct agonists at the glycine site or by inhibition of glycine reuptake have produced modest and often inconsistent evidence of efficacy, as have approaches to reduce excessive glutamate release by lamotrigine or by mGluR2/3 agonists. Strategies targeting alpha-amino-3-hydroxy-5 methyl-4-isoxazole propionic acid (AMPA) receptors have also met with only limited success. Newer approaches include selective allosteric modulation of NMDA receptor subunits and of mGluR5 receptors. In addition, intracellular pathways downstream of NMDA receptors may also provide new treatment targets, as exemplified by phosphodiesterase (PDE) inhibitors. SUMMARY: Targeting glutamatergic transmission remains one of the most promising strategies in schizophrenia, particularly early in the course of illness, but therapeutic approaches may require greater specificity for receptor subtype type, illness phase, and individual biology in order to enhance efficacy and overcome problems with reproducibility of clinical results. PMID- 25710243 TI - Non-target adjacent stimuli classification improves performance of classical ERP based brain computer interface. AB - OBJECTIVE: The classical ERP-based speller, or P300 Speller, is one of the most commonly used paradigms in the field of Brain Computer Interfaces (BCI). Several alterations to the visual stimuli presentation system have been developed to avoid unfavorable effects elicited by adjacent stimuli. However, there has been little, if any, regard to useful information contained in responses to adjacent stimuli about spatial location of target symbols. This paper aims to demonstrate that combining the classification of non-target adjacent stimuli with standard classification (target versus non-target) significantly improves classical ERP based speller efficiency. APPROACH: Four SWLDA classifiers were trained and combined with the standard classifier: the lower row, upper row, right column and left column classifiers. This new feature extraction procedure and the classification method were carried out on three open databases: the UAM P300 database (Universidad Autonoma Metropolitana, Mexico), BCI competition II (dataset IIb) and BCI competition III (dataset II). MAIN RESULTS: The inclusion of the classification of non-target adjacent stimuli improves target classification in the classical row/column paradigm. A gain in mean single trial classification of 9.6% and an overall improvement of 25% in simulated spelling speed was achieved. SIGNIFICANCE: We have provided further evidence that the ERPs produced by adjacent stimuli present discriminable features, which could provide additional information about the spatial location of intended symbols. This work promotes the searching of information on the peripheral stimulation responses to improve the performance of emerging visual ERP-based spellers. PMID- 25710244 TI - A practitioner's guide to necrotizing fasciitis. AB - Necrotizing fasciitis (NF) is a severe bacterial infection that attacks subcutaneous fat tissues, superficial fascia, deep fascia, and muscle. NF is a rare condition with a mortality that requires nurse practitioners to be adept at identifying signs and symptoms to prompt a quick diagnosis and treatment. PMID- 25710245 TI - Management of patients with psoriatic arthritis. AB - Psoriatic arthritis is a chronic inflammatory arthritis condition. If left untreated, patients with psoriatic arthritis may suffer pain, reduced quality of life, joint damage, and disability. Understanding clinical presentation and comorbidities of the disease, as well as current guidelines for treatment, allows the nurse practitioner to provide comprehensive care for patients. PMID- 25710247 TI - Anti-Mullerian hormone and lifestyle, reproductive, and environmental factors among women in rural South Africa. AB - BACKGROUND: Few data exist regarding anti-Mullerian hormone, a marker of ovarian reserve, in relation to environmental factors with potential ovarian toxicity. METHODS: This analysis included 420 women from Limpopo, South Africa studied in 2010-2011. Women were administered comprehensive questionnaires, and plasma concentrations of anti-Mullerian hormone and dichlorodiphenyltrichloroethane were determined. We used separate multivariable models to examine the associations between natural log-transformed anti-Mullerian hormone concentration (ng/ml) and each of the lifestyle, reproductive, and environmental factors of interest, adjusted for age, body mass index, education, and parity. RESULTS: The median age of women was 24 years (interquartile range [IQR] = 22 to 26); the median anti Mullerian hormone concentration was 3.1 ng/ml (IQR = 2.0 to 6.0). Women who reported indoor residual spraying in homes with painted walls (indicative of exposure to pyrethroids) had 25% lower (95% confidence interval [CI] = -39%, -8%) anti-Mullerian hormone concentrations compared with women who reported no spraying. Little evidence of decreased anti-Mullerian hormone concentrations was observed among women with the highest dichlorodiphenyltrichloroethane levels. Compared with women who used an electric stove, no association was observed among women who cooked indoors over open wood fires. The findings also suggested lower anti-Mullerian hormone concentrations among women who drank coffee (-19% [95% CI = -31%, -5%]) or alcohol (-21% [95% CI = -36%, -3%]). CONCLUSIONS: These are among the first data regarding anti-Mullerian hormone concentrations relative to pesticides and indoor air pollution. Our results are suggestive of decreased ovarian reserve associated with exposure to pyrethroid pesticides, which is consistent with laboratory animal data. PMID- 25710248 TI - Angiogenin mutants as novel effector molecules for the generation of fusion proteins with increased cytotoxic potential. AB - Human cytolytic fusion proteins (hCFPs) are therapeutically efficacious recombinant polypeptides comprising a target cell-specific binding component and a human effector domain that induces apoptosis. Compared with former generations of immunotoxins, which contain immunogenic cytotoxic domains derived from bacteria or plants, hCFPs contain solely human proteins that do not induce an immune response, thus avoiding the development of neutralizing antibodies. Here, we investigated the suitability of human angiogenin (Ang) mutants as effector domains. We engineered 3 different Ang variants that outperformed the wild-type enzyme by replacing amino acid residues with key roles in the protein's catalytic activity and its interaction with the ribonuclease inhibitor RNH1. The cytotoxic potential of these mutants was compared with wild-type Ang by fusing each to the CD64-specific single-chain variable fragment H22. All hCFPs were successfully expressed in HEK293T cells and purified from the cell culture supernatant by immobilized metal ion affinity chromatography. The Ang mutant-based hCFPs showed normal binding activity towards human interferon-gamma-stimulated CD64 HL-60 cells and activated human macrophages isolated from peripheral blood mononuclear cells, but increased cytotoxicity based on reduced affinity towards RNH1 and higher ribonucleolytic activity. PMID- 25710246 TI - Long-term exposure to air pollution and markers of inflammation, coagulation, and endothelial activation: a repeat-measures analysis in the Multi-Ethnic Study of Atherosclerosis (MESA). AB - BACKGROUND: Air pollution is associated with cardiovascular disease, and systemic inflammation may mediate this effect. We assessed associations between long- and short-term concentrations of air pollution and markers of inflammation, coagulation, and endothelial activation. METHODS: We studied participants from the Multi-Ethnic Study of Atherosclerosis from 2000 to 2012 with repeat measures of serum C-reactive protein (CRP), interleukin-6 (IL-6), fibrinogen, D-dimer, soluble E-selectin, and soluble Intercellular Adhesion Molecule-1. Annual average concentrations of ambient fine particulate matter (PM2.5), individual-level ambient PM2.5 (integrating indoor concentrations and time-location data), oxides of nitrogen (NOx), nitrogen dioxide (NO2), and black carbon were evaluated. Short term concentrations of PM2.5 reflected the day of blood draw, day prior, and averages of prior 2-, 3-, 4-, and 5-day periods. Random-effects models were used for long-term exposures and fixed effects for short-term exposures. The sample size was between 9,000 and 10,000 observations for CRP, IL-6, fibrinogen, and D dimer; approximately 2,100 for E-selectin; and 3,300 for soluble Intercellular Adhesion Molecule-1. RESULTS: After controlling for confounders, 5 ug/m increase in long-term ambient PM2.5 was associated with 6% higher IL-6 (95% confidence interval = 2%, 9%), and 40 parts per billion increase in long-term NOx was associated with 7% (95% confidence interval = 2%, 13%) higher level of D-dimer. PM2.5 measured at day of blood draw was associated with CRP, fibrinogen, and E selectin. There were no other positive associations between blood markers and short- or long-term air pollution. CONCLUSIONS: These data are consistent with the hypothesis that long-term exposure to air pollution is related to some markers of inflammation and fibrinolysis. PMID- 25710249 TI - Caregiver Burden: Looking Beyond the Unidimensional Total Score. AB - The Zarit Burden Interview allows caregiver burden to be interpreted from a total score. However, recent studies propose a multidimensional Zarit Burden Interview model. This study aims to determine the agreement between unidimensional (UD) and multidimensional (MD) classification of burden, and differences in predictors among identified groups. We studied 165 dyads of dementia patients and primary caregivers. Caregivers were dichotomized into low-burden and high-burden groups based upon: (1) UD score using quartile cutoffs; and (2) MD model via exploratory cluster analysis. We compared UD versus MD 2*2 classification of burden using kappa statistics. Caregivers not showing agreement by either definition were classified as "intermediate" burden. We performed binary logistic regression to ascertain differences in predictive factors. The 2 models showed moderate agreement (kappa=0.72, P<0.01), yielding 104 low, 20 intermediate (UD "low burden"/MD "high burden"), and 41 high-burden caregivers. Neuropsychiatric symptoms [odds ratio (OR)=1.27, P=0.003], coresidence (OR=6.32, P=0.040), and decreased caregiving hours (OR=0.99, P=0.018) were associated with intermediate burden, whereas neuropsychiatric symptoms (OR=1.21, P=0.001) and adult children caregivers (OR=2.80, P=0.055) were associated with high burden. Our results highlight the differences between UD and MD classification of caregiver burden. Future studies should explore the significance of the noncongruent intermediate group and its predictors. PMID- 25710251 TI - Computational and experimental investigation of the optical properties of the chromene dyes. AB - Absorption and fluorescence spectra of the chromene 3 and chromene 13 dyes are studied experimentally and by density functional theory (DFT) including vibronic structure analysis. Vertical electronic absorption spectra are also calculated with the ab initio multiconfiguration method XMC-QDTP2. The vibronic progression for the S0 -> S1 electronic transition is calculated within the Franck-Condon approximation including Dushinsky effect and promoting modes are analyzed. The laser-active solid-state media with high efficiency and long operation time are created implementing the studied dyes. The results of investigation indicate that the studied compounds can be used as effective laser dyes in the red range of visible light. PMID- 25710250 TI - Lifestyle Factors and Dementia in the Oldest-old: The 90+ Study. AB - Dementia incidence increases exponentially with age even in people aged 90 years and above. Because therapeutic regimens are limited, modification of lifestyle behaviors may offer the best means for disease control. To test the hypotheses that lifestyle factors are related to lower risk of dementia in the oldest-old, we analyzed data from The 90+ Study, a population-based longitudinal cohort study initiated in 2003. This analysis included 587 participants (mean age=93 y) seen in-person and determined not to have dementia at enrollment. Information on lifestyle factors (smoking, alcohol, caffeine, vitamin supplements, exercise, and other activities) was obtained at enrollment and was available from data collected 20 years previously. After an average follow-up of 36 months, 268 participants were identified with incident dementia. No variable measured 20 years previously was associated with risk. Engagement in specific social/mental activities and intakes of antioxidant vitamin supplements and caffeine at time of enrollment were, associated with significantly reduced risks. When these variables were analyzed together, the HRs changed little and remained significant for reading (0.54, P=0.01) and going to church/synagogue (HR=0.66, P<0.05) but not for caffeine (HR=0.61, P=0.15) and vitamin C (HR=0.68, P=0.07). While lifestyle behaviors around age 70 did not modify risk of late-life dementia, participation in activities and caffeine and supplemental vitamin intake around age 90 warrant further investigation. PMID- 25710252 TI - Roles of hydroxyapatite allocation and microgroove dimension in promoting preosteoblastic cell functions on photocured polymer nanocomposites through nuclear distribution and alignment. AB - This study clarifies how hydroxyapatite (HA) allocation and microgroove dimension affect mouse preosteoblastic MC3T3-E1 cell functions on microgrooved substrates of polymer nanocomposites. Using replica molding from micromachined silicon wafer templates, we fabricated photocured poly(epsilon-caprolactone) triacrylate (PCLTA)/HA nanocomposite substrates with parallel microgrooves (two groove widths of 5 and 15 MUm and one groove depth of 5 MUm). Four types of microgrooved substrates were made: "homogeneous" ones of PCLTA and PCLTA/HA with uniform distribution and two "heterogeneous" laminated microgrooved substrates with HA only in the PCLTA matrix in the ridges or bottom. These substrates were used to regulate MC3T3-E1 cell attachment, proliferation, alignment, nuclear circularity and distribution, and mineralization. MC3T3-E1 cell attachment and proliferation were much higher on the microgrooved substrates of PCLTA/HA than on those of PCLTA, in particular, on the 5 MUm wide microgrooved substrate with PCLTA/HA ridges and PCLTA bottom. The shape and distribution of MC3T3-E1 cytoskeleton and nuclei were altered by the substrate topography and HA allocation. For 5 MUm wide heterogeneous microgrooved substrates with HA only in the ridges, MC3T3-E1 cells exhibited better spreading perpendicular to the microgrooves but tended to extend along the microgrooves containing HA in the bottom. The widest cells and the roundest/largest cell nuclei were observed on the heterogeneous substrate with PCLTA/HA ridges, while the narrowest cells with the best elongation were found on the homogeneous PCLTA/HA substrate. The trend in MC3T3-E1 cell mineralization on the substrates was consistent with that in cell/nuclear elongation. Osteocalcin mRNA expression was significantly higher on the PCLTA/HA substrates than on the PCLTA ones and also on the microgrooved substrates of PCLTA/HA than on the flat ones, regardless of the groove width of 5 or 15 MUm. PMID- 25710253 TI - Bifunctional glass membrane designed to interface SDS-PAGE separations of proteins with the detection of peptides by mass spectrometry. AB - We describe the construction and characterization of a novel membrane designed to allow proteins separated by gel electrophoresis (SDS-PAGE) to be detected as peptides by mass spectrometry in an efficient and comprehensive manner. The key attribute of the membrane is a bifunctional design that allows for the digestion of protein(s) and retention of the resulting peptides with minimal lateral diffusion. Silane chemistries are used to differentially treat the opposing surfaces of a glass filter paper to enable this unique capability. PMID- 25710255 TI - Fabrication of 3D high aspect ratio PDMS microfluidic networks with a hybrid stamp. AB - We report a novel methodology for fabricating large-area, multilayer, thin-film, high aspect ratio, 3D microfluidic structures with through-layer vias and open channels that can be bonded between hard substrates. It is realized by utilizing a hybrid stamp with a thin plastic sheet embedded underneath a PDMS surface. This hybrid stamp solves an important edge protrusion issue during PDMS molding while maintaining necessary stamp elasticity to ensure the removal of PDMS residues at through-layer regions. Removing edge protrusion is a significant progress toward fabricating 3D structures since high aspect ratio PDMS structures with flat interfaces can be realized to facilitate multilayer stacking and bonding to hard substrates. Our method also allows for the fabrication of 3D deformable channels, which can lead to profound applications in electrokinetics, optofluidics, inertial microfluidics, and other fields where the shape of the channel cross section plays a key role in device physics. To demonstrate, as an example, we have fabricated a microfluidic channel by sandwiching two 20 MUm wide, 80 MUm tall PDMS membranes between two featureless ITO glass substrates. By applying electrical bias to the two ITO substrates and pressure to deform the thin membrane sidewalls, strong electric field enhancement can be generated in the center of a channel to enable 3D sheathless dielectrophoretic focusing of biological objects including mammalian cells and bacteria at a flow speed up to 14 cm s(-1). PMID- 25710256 TI - Synthesis of 1,2-borazaronaphthalenes from imines by base-promoted borylation of C-H bond. AB - A new route from benzylic imines permits the synthesis of 1,2 borazaronaphthalenes in good yields. The reaction involves formation of the enamidyl dibromoborane, which undergoes base-promoted borylation of the nearby aromatic C-H bond. Electrophilic attack of the boron species onto the benzylic arene is supported by the slow borylation of arenes substituted with electron withdrawing groups. The resultant boron bromides can be easily substituted with lithium reagents to provide a range of products. The electronic properties of these 1,2-borazaronaphthalene derivatives have been investigated by UV-vis and fluorescence spectroscopy. PMID- 25710257 TI - Monitoring Fatigue During the In-Season Competitive Phase in Elite Soccer Players. AB - PURPOSE: To quantify the relationship between daily training load and a range of potential measures of fatigue in elite soccer players during an in-season competitive phase (17 d). METHODS: Total high-intensity-running (THIR) distance, perceived ratings of wellness (fatigue, muscle soreness, sleep quality), countermovement-jump height (CMJ), postexercise heart-rate recovery (HRR), and heart-rate variability (Ln rMSSD) were analyzed during an in-season competitive period (17 d). General linear models were used to evaluate the influence of daily fluctuation in THIR distance on potential fatigue variables. RESULTS: Fluctuations in fatigue (r = -.51, large, P < .001), Ln rMSSD (r = -.24, small, P = .04), and CMJ (r = .23, small, P = .04) were significantly correlated with fluctuations in THIR distance. Correlations between variability in muscle soreness, sleep quality, and HRR and THIR distance were negligible and not statistically significant. CONCLUSIONS: Perceived ratings of fatigue and Ln rMSSD were sensitive to daily fluctuations in THIR distance in a sample of elite soccer players. Therefore, these particular markers show promise as simple, noninvasive assessments of fatigue status in elite soccer players during a short in-season competitive phase. PMID- 25710258 TI - Analysis of the radiation-damage-free X-ray structure of photosystem II in light of EXAFS and QM/MM data. AB - A recent femtosecond X-ray diffraction study produced the first high-resolution structural model of the oxygen-evolving complex of photosystem II that is free of radiation-induced manganese reduction (Protein Data Bank entries 4UB6 and 4UB8 ). We find, however, that the model does not match extended X-ray absorption fine structure and QM/MM data for the S1 state. This is attributed to uncertainty about the positions of oxygen atoms that remain partially unresolved, even at 1.95 A resolution, next to the heavy manganese centers. In addition, the photosystem II crystals may contain significant amounts of the S0 state, because of extensive dark adaptation prior to data collection. PMID- 25710259 TI - Consecutive days of prolonged tennis match play: performance, physical, and perceptual responses in trained players. AB - PURPOSE: To determine how consecutive days of prolonged tennis match play affect performance, physiological, and perceptual responses. METHODS: Seven well-trained male tennis players completed 4-h tennis matches on 4 consecutive days. Pre- and postmatch measures involved tennis-specific (serve speed and accuracy), physical (20-m sprint, countermovement jump [CMJ], shoulder-rotation maximal voluntary contraction, isometric midthigh pull), perceptual (Training Distress Scale, soreness), and physiological (creatine kinase [CK]) responses. Activity profile was assessed by heart rate, 3D load (accumulated accelerations measured by triaxial accelerometers), and rating of perceived exertion (RPE). Statistical analysis compared within- and between-days values. Changes (+/- 90% confidence interval [CI]) >=75% likely to exceed the smallest important effect size (0.2) were considered practically important. RESULTS: 3D load reduced on days 2 to 4 (mean effect size +/- 90% CI -1.46 +/- 0.40) and effective playing time reduced on days 3 to 4 (-0.37 +/- 0.51) compared with day 1. RPE did not differ and total points played only declined on day 3 (-0.38 +/- 1.02). Postmatch 20-m sprint (0.79 +/- 0.77) and prematch CMJ (-0.43 +/- 0.27) performance declined on days 2 to 4 compared with prematch day 1. Although serve velocity was maintained, compromised postmatch serve accuracy was evident compared with prematch day 1 (0.52 +/- 0.58). CK increased each day, as did ratings of muscle soreness and fatigue. CONCLUSIONS: Players reduced external physical loads, through declines in movement, over 4 consecutive days of prolonged competitive tennis. This may be affected by tactical changes and pacing strategies. Alongside this, impairments in sprinting and jumping ability, perceptual and biochemical markers of muscle damage, and reduced mood states may be a function of neuromuscular and perceptual fatigue. PMID- 25710260 TI - Quality of nursing home environments. PMID- 25710261 TI - FDA approves new drug to treat dementia. PMID- 25710262 TI - Improving quality of life for older adults with arthritis and muscle/joint pain. PMID- 25710263 TI - Trigeminal neuralgia: pain, pricks, and anxiety. AB - Trigeminal neuralgia (TN) is one of the most common forms of neuralgia experienced by older adults. Early in the course of the illness, individuals may be misdiagnosed, with associated delays in treatment. The current article uses an individual example to provide a framework for assessment and clinical management. Because pain associated with TN may be chronic, specific quality of life issues and related management approaches are presented, as well as guidelines for monitoring response to treatment. Targeted strategies to prevent pain triggers and suggestions for supportive coaching provide direction for health providers caring for older adults with TN. PMID- 25710264 TI - An audit of a diverse community for safe routes to age in place: environmental policy implications. AB - Physical and cognitive limitations often accompany aging, increasing the importance of a safe and supportive environment to help older adults maintain mobility. Neighborhood design and maintenance must be evaluated to promote physical activity, mobility, and safety. Audit tools, geographic information system data, and resident interviews are used for this purpose, but often fail to provide information that can be translated to practice. The current project is part of a larger Miami-Dade Age-Friendly Initiative to create a metropolitan area that fosters a healthy environment for diverse adults of all ages and abilities. Safe Routes uses a toolkit based on the 5-E model providing practical resources to guide stakeholders in meeting the needs of the community. Findings include the Centers for Disease Control Healthy Aging Research Network Audit Tool assessment for environmental walkability factors. Results from street segment audits along with input from residents can be used to inform sound environmental policies. PMID- 25710266 TI - New CPT codes for advance care planning: communicating future health choices. PMID- 25710267 TI - Label-free and highly sensitive electrochemiluminescence biosensing using quantum dots/carbon nanotubes in ionic liquid. AB - Combining with the synergic effect of carbon nanotubes and ionic liquids for enhancing electrochemiluminescence (ECL) response of CdSe QDs, a universal strategy for highly sensitive biosensing was designed. Using alpha-fetoprotein as a model and monitoring the variation of ECL intensity before and after immunoreaction, a label-free ECL biosensor was developed. PMID- 25710268 TI - Nanowire perovskite solar cell. AB - Organolead iodide perovskite, CH3NH3PbI3, was prepared in the form of nanowire by means of a small quantity of aprotic solvent in two-step spin-coating procedure. One-dimensional nanowire perovskite with the mean diameter of 100 nm showed faster carrier separation in the presence of hole transporting layer and higher lateral conductivity than the three-dimensional nanocuboid crystal. Reduction in dimensionality resulted in the hypsochromic shift of both absorption and fluorescence spectra, indicative of more localized exciton states in nanowires. The best performing device employing nanowire CH3NH3PbI3 delivered photocurrent density of 19.12 mA/cm(2), voltage of 1.052 V, and fill factor of 0.721, leading to a power conversion efficiency (PCE) of 14.71% at standard AM 1.5G solar illumination. A small I-V hysteresis was observed, where a PCE at forward scan was measured to be 85% of the PCE at reverse scan. PMID- 25710269 TI - Differential effects of particulate matter upwind and downwind of an urban freeway in an allergic mouse model. AB - Near-road exposure to air pollutants has been associated with decreased lung function and other adverse health effects in susceptible populations. This study was designed to investigate whether different types of near-road particulate matter (PM) contribute to exacerbation of allergic asthma. Samples of upwind and downwind coarse, fine, and ultrafine PM were collected using a wind direction actuated ChemVol sampler at a single site 100 m from Interstate-96 in Detroit, MI during winter 2010/2011. Upwind PM was enriched in crustal and wood combustion sources while downwind PM was dominated by traffic sources. Control and ovalbumin (OVA)-sensitized BALB/cJ mice were exposed via oropharyngeal (OP) aspiration to 20 or 100 MUg of each PM sample 2 h prior to OP challenge with OVA. In OVA allergic mice, 100 MUg of downwind coarse PM caused greater increases than downwind fine/ultrafine PM in bronchoalveolar lavage neutrophils, eosinophils, and lactate dehydrogenase. Upwind fine PM (100 MUg) produced greater increases in neutrophils and eosinophils compared to other upwind size fractions. Cytokine (IL 5) levels in BAL fluid also increased markedly following 100 MUg downwind coarse and downwind ultrafine PM exposures. These findings indicate coarse PM downwind and fine PM upwind of an interstate highway promote inflammation in allergic mice. PMID- 25710270 TI - Solvation structure of Zn(2+) and Cu(2+) ions in acetonitrile: a combined EXAFS and XANES study. AB - The solvation structure of Zn(2+) and Cu(2+) in acetonitrile has been determined by a combined approach using both X-ray absorption near edge structure (XANES) and the extended X-ray absorption fine structure (EXAFS) spectroscopy. For the former cation, an octahedral geometry of the acetonitrile solvate complex has been found with a Zn-N distance of 2.12(1) A. For the Cu(2+) solvates the EXAFS technique has been found to be not able to provide a conclusive determination of the coordination numbers and polyhedral environment, while the analysis of the XANES spectra unambiguously shows the existence of an axially elongated square pyramidal coordination, ruling out the previously proposed octahedral Jahn-Teller (JT) distorted geometry. The Cu-N distances obtained are 2.00(1) and 2.28(2) A for the equatorial and axial ligands, respectively, and the EXAFS and XANES techniques find values of the bond distances in good agreement. The XANES technique has proven to be extremely powerful in providing a reliable resolution of solution structure for dynamic ion complexes. PMID- 25710271 TI - Chemical structure and properties of interstrand cross-links formed by reaction of guanine residues with abasic sites in duplex DNA. AB - A new type of interstrand cross-link resulting from the reaction of a DNA abasic site with a guanine residue on the opposing strand of the double helix was recently identified, but the chemical connectivity of the cross-link was not rigorously established. The work described here was designed to characterize the chemical structure and properties of dG-AP cross-links generated in duplex DNA. The approach involved characterization of the nucleoside cross-link "remnant" released by enzymatic digestion of DNA duplexes containing the dG-AP cross-link. We first carried out a chemical synthesis and complete spectroscopic structure determination of the putative cross-link remnant 9b composed of a 2-deoxyribose adduct attached to the exocyclic N(2)-amino group of dG. A reduced analogue of the cross-link remnant was also prepared (11b). Liquid chromatography-tandem mass spectrometric (LC-MS/MS) analysis revealed that the retention times and mass spectral properties of synthetic standards 9b and 11b matched those of the authentic cross-link remnants released by enzymatic digestion of duplexes containing the native and reduced dG-AP cross-link, respectively. These results establish the chemical connectivity of the dG-AP cross-link released from duplex DNA and provide a foundation for detection of this lesion in biological samples. The dG-AP cross-link in duplex DNA was remarkably stable, decomposing with a half life of 22 days at pH 7 and 23 degrees C. The intrinsic chemical stability of the dG-AP cross-link suggests that this lesion in duplex DNA may have the power to block DNA-processing enzymes involved in transcription and replication. PMID- 25710272 TI - Nutrient and nonnutrient components of legumes, and its chemopreventive activity: a review. AB - Legumes in combination with other products are the staple food for a large part of the world population, especially the low-income fragment, because their seeds provide valuable amounts of carbohydrates, fiber, and proteins, and have an important composition of essential amino acids, the sulphured amino acids being the limiting ones. Furthermore, legumes also have nonnutritional compounds that may decrease the absorption of nutrients or produce toxic effects; however, it has been reported that depending on the dose, these nonnutritional compounds also have different bioactivities as antioxidant, hypolipidemic, hypoglycemic, and anticarcinogenic agents, which have been proven in scientific studies. It has been observed that in countries with a high consumption of legumes, the incidence of colorectal cancer is lower. Some studies have shown that legume seeds are an alternative chemopreventive therapy against various cancers especially colon; this was verified in various animal models of induced by azoxymethane, a colon specific carcinogenic compound, in which a diet was supplemented with different concentrations of beans, lentils, chickpeas, or soybeans, mostly. These studies have proven the anticancer activity of legumes in early stages of carcinogenesis. Therefore, it is important to review the information available to elucidate the chemopreventive mechanisms of action of legume compounds. PMID- 25710275 TI - Attitudes towards schizophrenia on YouTube: A content analysis of Finnish and Greek videos. AB - OBJECTIVE: To investigate attitudes towards schizophrenia and people with schizophrenia presented in YouTube videos. METHODS: We searched YouTube using the search terms "schizophrenia" and "psychosis" in Finnish and Greek language on April 3rd, 2013. The first 20 videos from each search (N = 80) were retrieved. Deductive content analysis was first applied for coding and data interpretation and it was followed by descriptive statistical analysis. RESULTS: A total of 52 videos were analyzed (65%). The majority of the videos were in the "Music" category (50%, n = 26). Most of the videos (83%, n = 43) tended to present schizophrenia in a negative way, while less than a fifth (17%, n = 9) presented schizophrenia in a positive or neutral way. Specifically, the most common negative attitude towards schizophrenia was dangerousness (29%, n = 15), while the most often identified positive attitude was objective, medically appropriate beliefs (21%, n = 11). All attitudes identified were similarly present in the Finnish and Greek videos, without any statistically significant difference. CONCLUSIONS: Negative presentations of schizophrenia are most likely to be accessed when searching YouTube for schizophrenia in Finnish and Greek language. More research is needed to investigate to what extent, if any, YouTube viewers' attitudes are affected by the videos they watch. PMID- 25710274 TI - Synaptotagmin 1 directs repetitive release by coupling vesicle exocytosis to the Rab3 cycle. AB - In response to Ca(2+) influx, a synapse needs to release neurotransmitters quickly while immediately preparing for repeat firing. How this harmonization is achieved is not known. In this study, we found that the Ca(2+) sensor synaptotagmin 1 orchestrates the membrane association/disassociation cycle of Rab3, which functions in activity-dependent recruitment of synaptic vesicles. In the absence of Ca(2+), synaptotagmin 1 binds to Rab3 GTPase activating protein (GAP) and inhibits the GTP hydrolysis of Rab3 protein. Rab3 GAP resides on synaptic vesicles, and synaptotagmin 1 is essential for the synaptic localization of Rab3 GAP. In the presence of Ca(2+), synaptotagmin 1 releases Rab3 GAP and promotes membrane disassociation of Rab3. Without synaptotagmin 1, the tight coupling between vesicle exocytosis and Rab3 membrane disassociation is disrupted. We uncovered the long-sought molecular apparatus linking vesicle exocytosis to Rab3 cycling and we also revealed the important function of synaptotagmin 1 in repetitive synaptic vesicle release. PMID- 25710276 TI - Comparison of the toxicity profile of benzalkonium chloride-preserved tafluprost and SofZia-preserved travoprost applied to the ocular surface. AB - PURPOSE: To evaluate some clinically important features of benzalkonium chloride (BAK) toxicity by comparing tafluprost with 0.001% BAK and travoprost preserved with SofZia applied to the ocular surface of the eyes with glaucoma. METHODS: This was a prospective, randomized, observer unmasked, multicenter crossover trial. A total of 195 patients were randomized and 174 patients completed the study at 19 clinics between November 2011 and August 2012. Topical BAK-preserved tafluprost or SofZia-preserved travoprost was newly administered or continued. Superficial punctate keratopathy (SPK), tear break-up time (BUT), the conjunctival hyperemia score, and intraocular pressure (IOP) were compared at the baseline visit, 4, and 12 weeks after the start of therapy. The eye drops were switched to another eye drop after 12 weeks of observation. RESULTS: The total SPK and conjunctival hyperemia scores were significantly lower in the tafluprost compared with those in the travoprost phase (both P=0.038). There were no significant differences in the SPK scores of the superior area (P=0.679), central area (P=0.089), inferior area (P=0.090), and tear BUT (P=0.271). The IOP-lowering effects were similar (P=0.155). CONCLUSIONS: SPK, hyperemia score, and tear BUT while using tafluprost with 0.001% BAK were not inferior compared with those caused by travoprost with SofZia. PMID- 25710277 TI - Solid-state structure of a degradation product frequently observed on historic metal objects. AB - In the course of the investigation of glass-induced metal corrosion processes, a microcrystalline sodium copper formate hydroxide oxide hydrate, Cu4Na4O(HCOO)8(H2O)4(OH)2, was detected on a series of antique works of art, and its crystal structure was determined ab initio from high-resolution laboratory X ray powder diffraction data using the method of charge flipping, simulated annealing, and difference-Fourier analysis (P42/n, a = 8.425 109(97) A, c = 17.479 62(29) A, V = 1240.747(35) A(3), Z = 8). In the crystal structure, the metal cations are interconnected in a two-dimensional metal-organic framework via the oxygen atoms of the formate, hydroxide, and oxide anions. Doublets of face sharing square pyramidal Cu(2+) polyhedra are linked via a single, central oxide oxygen atom to give a paddle-wheel arrangement, while the Na(+) cations are organized in Na2O11 moieties with highly disordered, edge-sharing octahedral coordination. In addition, hydrogen bonding plays an important role in stabilizing the crystal structure. PMID- 25710278 TI - The ASLA Score: A CT Angiographic Index to Predict Functionally Significant Coronary Stenoses in Lesions with Intermediate Severity-Diagnostic Accuracy. AB - PURPOSE: To identify computed tomographic (CT) coronary indexes independently associated with a fractional flow reserve (FFR) of 0.8 or less, to derive a score that combines CT indexes most predictive of an FFR of 0.8 or less, and to evaluate the diagnostic accuracy of the score in predicting an FFR of 0.8 or less. MATERIALS AND METHODS: This retrospective study had institutional review board approval and waiver of the need to obtain informed consent. Consecutive patients who underwent CT coronary angiography and FFR assessment with one or more discrete lesion(s) of intermediate (30%-70%) severity at CT were included. Quantitative CT measurements were performed by using dedicated software. The CT indexes evaluated included the following: plaque burden, minimal luminal area and diameter, stenosis diameter, area of stenosis, lesion length, remodeling index, plaque morphology, calcification severity, and the Alberta Provincial Project for Outcome Assessment in Coronary Heart Disease (APPROACH) score, which approximates the size of the myocardium subtended by a lesion. By using covariates independently associated with an FFR of 0.8 or less, a score was determined on the basis of modified Akaike information criteria, and the C statistics of individual and combined indexes were compared. RESULTS: Eighty-five patients (mean age, 64.2 years; range, 48-88 years; 65.9% men; 124 lesions; 38 lesions with an FFR <= 0.8) were included. Area of stenosis, lesion length, and APPROACH score were the strongest predictors of an FFR of 0.8 or less and were used to derive the ASLA score. The optimism-adjusted Harrell C statistic for the combined score was 0.82, which was superior to that for area of stenosis (0.74), lesion length (0.75), and the APPROACH score (0.71) (P < .001 for trend). The corresponding incremental discrimination improvement indexes were 0.17, 0.11, and 0.19, respectively (P < .001 for all), suggesting that the score improves reclassification compared with any one angiographic index. The average time required for score derivation was 102.6 seconds. CONCLUSION: The ASLA score, which accounts for CT-derived area of stenosis, lesion length, and APPROACH score, may conveniently improve the prediction, beyond individual indexes, of functionally significant intermediate coronary lesions. PMID- 25710279 TI - Overcoming obstacles in the implementation of factorial design for assay optimization. AB - Factorial experimental design (FED) is a powerful approach for efficient optimization of robust in vitro assays-it enables cost and time savings while also improving the quality of assays. Although it is a well-known technique, there can be considerable barriers to overcome to fully exploit it within an industrial or academic organization. The article describes a tactical roll out of FED to a scientist group through: training which demystifies the technical components and concentrates on principles and examples; a user-friendly Excel based tool for deconvoluting plate data; output which focuses on graphical display of data over complex statistics. The use of FED historically has generally been in conjunction with automated technology; however we have demonstrated a much broader impact of FED on the assay development process. The standardized approaches we have rolled out have helped to integrate FED as a fundamental part of assay development best practice because it can be used independently of the automation and vendor-supplied software. The techniques are applicable to different types of assay, both enzyme and cell, and can be used flexibly in manual and automated processes. This article describes the application of FED for a cellular assay. The challenges of selling FED concepts and rolling out to a wide bioscience community together with recommendations for good working practices and effective implementation are discussed. The accessible nature of these approaches means FED can be used by industrial as well as academic users. PMID- 25710280 TI - Vitamin B12-responsive neuropathies: A case series. AB - OBJECTIVES: Neuropathies often accompany vitamin B12 deficiency. Since many neuropathies are linked to oxidative stress and since B12 has both antioxidant and neurotrophic properties, B12 may also be effective treatment in non-deficient subjects. Thus, the characteristics and predictors of B12-responsive neuropathies and their relationship to disorders associated with increased oxidative stress (oxidant risks) were examined. METHODS: Retrospective review of 78 subjects with neurological abnormalities treated with B12 and evaluated by the measurement of B12 and the B12-dependent metabolites, methylmalonic acid (MMA), and homocysteine. RESULTS: Sixty-five subjects had neurological improvement (83%), including 35 with other known causes of neuropathy. Only two responders had B12 responsive macrocytosis. Pretherapy B12, MMA, and homocysteine values were normal in 72, 33 and 54% of responders, with all three normal in 23%. Moreover, B12 therapy did not significantly decrease elevated MMA and homocysteine levels in 20 and 37%, respectively, of responders tested but did decrease both metabolites in 75% of evaluable non-responders. At least one oxidant risk was present in 41 of the 46 responders with normal B12 levels (89%). Oral therapy was effective, but parenteral B12 improved responses in four subjects. DISCUSSION: B12-responsive neuropathies are thus (1) common even when confounding disorders are present; (2) dissociated from the presence of hematological abnormalities; (3) dissociated from the presence of B12-responsive metabolical abnormalities; and (4) associated with the presence of oxidant risks when B12 levels are normal. Since no predictors of responses to B12 therapy were identified, empiric trials with parenteral B12 should be considered in appropriate subjects. PMID- 25710281 TI - TNF-alpha-induced NF-kappaB activation stimulates skeletal muscle glycolytic metabolism through activation of HIF-1alpha. AB - A shift in quadriceps muscle metabolic profile toward decreased oxidative metabolism and increased glycolysis is a consistent finding in chronic obstructive pulmonary disease (COPD). Chronic inflammation has been proposed as a trigger of this pathological metabolic adaptation. Indeed, the proinflammatory cytokine TNF-alpha impairs muscle oxidative metabolism through activation of the nuclear factor-kappaB (NF-kappaB) pathway. Putative effects on muscle glycolysis, however, are unclear. We hypothesized that TNF-alpha-induced NF-kappaB signaling stimulates muscle glycolytic metabolism through activation of the glycolytic regulator hypoxia-inducible factor-1alpha (HIF-1alpha). Wild-type C2C12 and C2C12 IkappaBalpha-SR (blocked NF-kappaB signaling) myotubes were stimulated with TNF alpha, and its effects on glycolytic metabolism and involvement of the HIF pathway herein were investigated. As proof of principle, expression of HIF signaling constituents was investigated in quadriceps muscle biopsies of a previously well-characterized cohort of clinically stable patients with severe COPD and healthy matched controls. TNF-alpha increased myotube glucose uptake and lactate production and enhanced the activity and expression levels of multiple effectors of muscle glycolytic metabolism in a NF-kappaB-dependent manner. In addition, TNF-alpha activated HIF signaling, which required classical NF-kappaB activation. Moreover, the knockdown of HIF-1alpha largely attenuated TNF-alpha induced increases in glycolytic metabolism. Accordingly, the mRNA levels of HIF 1alpha and the HIF-1alpha target gene, vascular endothelial growth factor (VEGF), were increased in muscle biopsies of COPD patients compared with controls, which was most pronounced in the patients with high levels of muscle TNF-alpha. In conclusion, these data show that TNF-alpha-induced classical NF-kappaB activation enhances muscle glycolytic metabolism in a HIF-1alpha-dependent manner. PMID- 25710282 TI - Kisspeptin is a component of the pulse generator for GnRH secretion in female sheep but not the pulse generator. AB - We tested the hypothesis that kisspeptin cells constitute the "pulse generator" for GnRH secretion. In ewes, we determined whether iv administered kisspeptin elicits a secretory pulse of LH in anaesthetized, sex-steroid suppressed ovariectomized ewes. A response was seen in both anaesthetized and conscious animals, which was not associated with induction of c-Fos labeling in GnRH cells, supporting the notion that kisspeptin acts on the neurosecretory GnRH terminals. Response was lower in the anaesthetized animals, suggesting that some nonkisspeptin elements may be involved in GnRH responses. Microinjection of kisspeptin (100 nmol) into the median eminence of conscious ewes elicited a pulse of LH, indicating that kisspeptin acts at this level to cause GnRH secretion. To determine which cells are activated at the time of GnRH secretion, we blood sampled 18 ewes during the luteal phase of the estrous cycle and harvested brains after 3 hours. Three of these ewes displayed a pulse of LH within 30 minutes of euthanasia. An increase in c-Fos labeling was seen in kisspeptin and glutamate cells of the arcuate nucleus but not in GnRH neurons, preoptic kisspeptin neurons, or preoptic glutamate neurons. Immunohistochemistry in 4 hypothalami showed that 72% of arcuate kisspeptin cells receive glutamatergic input. These data support the concept that the kisspeptin cells of the arcuate nucleus drive pulsatile secretion of GnRH at the level of the median eminence, but this may involve "upstream" input from glutamate cells. We conclude that the pulse generator for GnRH secretion involves more than 1 element. PMID- 25710284 TI - In situ synthesis of metal-organic frameworks in a porous polymer monolith as the stationary phase for capillary liquid chromatography. AB - In this study, HKUST-1 was synthesized in situ on the porous polymer monolith as the stationary phase for capillary liquid chromatography (cLC). The unique carboxyl functionalized poly(methacrylic acid-co-ethylene dimethacrylate) (poly(MAA-co-EDMA)) monolith was used as a support to directly grow HKUST-1 by a controlled layer-by-layer self-assembly strategy. X-ray diffraction, scanning electron microscopy, energy dispersive X-ray spectrometry, and Fourier transform infrared spectroscopy of the resulting HKUST-1-poly(MAA-co-EDMA) monoliths indicated that HKUST-1 was successfully grafted onto the pore surface of the poly(MAA-co-EDMA) monolith. The column performance of HKUST-1-poly(MAA-co-EDMA) monoliths for the separation of various small molecules, such as benzenediols, xylenes, ethylbenzenes, and styrenes, was evaluated. The chromatographic performance was found to improve with increasing HKUST-1 density, and the column efficiencies and resolutions of HKUST-1-poly(MAA-co-EDMA) monoliths were 18 320 19 890 plates m(-1) and 1.62-6.42, respectively, for benzenediols. The HKUST-1 poly(MAA-co-EDMA) monolith displayed enhanced resolution for the separation of positional isomers when compared to the traditional C18 and HKUST-1 incorporated polymer monoliths. Hydrophobic, pi-pi, and hydrogen bonding interactions within the HKUST-1-poly(MAA-co-EDMA) monolith were observed in the separation of small molecules. The results showed that the HKUST-1-poly(MAA-co-EDMA) monoliths are promising stationary phases for cLC. PMID- 25710283 TI - Multimodality imaging and clinical features in Castleman disease: single institute experience in 30 patients. AB - OBJECTIVE: To analyse imaging features of subtypes of Castleman disease (CD), emphasizing differentiating features from lymphoma. METHODS: Institutional review board-approved, Health Insurance Portability and Accountability Act compliant, retrospective study examined 30 patients with CD. 30 patients (females, 20; mean age, 46 years; range, 22-87 years) with histopathologically confirmed CD and pre treatment imaging formed the analytic cohort. Imaging at presentation in all patients [CT, 30; positron emission tomography (PET)/CT, 5; MR, 4; ultrasound, 3] and subsequent imaging in three cases that developed lymphoma was reviewed by two radiologists in consensus. RESULTS: Subtypes: hyaline-vascular (n = 18); multicentric not otherwise specified (NOS) (n = 6); human herpesvirus 8 associated (n = 2); mixed unicentric (n = 2); pure plasma-cell variant (n = 1); and unicentric NOS (n = 1). Distribution: unicentric (n = 17); and multicentric (n = 13). Nodal sites-unicentric: 13 thoracic, 3 abdominal and 1 cervical; multicentric: 9 abdominal, 8 thoracic, 6 cervical, 5 inguinal, 4 axillary and 4 supraclavicular. On CT, differentiating features from lymphoma were calcification (n = 8; 26.7%) and heterogeneous enhancement (n = 5; 19.2%). No association between CD subtype, degree or enhancement pattern, or calcification was noted. On PET/CT (n = 5), nodes were typically fluorine-18 fludeoxyglucose avid (n = 4). On ultrasound (n = 3), nodes were hypoechoic, homogeneous with posterior acoustic enhancement. On MR (n = 4), nodes were hypointense (n = 2) to isointense (n = 2) on T1 weighted images and isointense (n = 1) to hyperintense (n = 3) on T2 weighted images. All (n = 4) demonstrated homogeneous enhancement. Three cases developed non-Hodgkin's lymphoma, two of the three had larger spleens, and these cases had effusions/ascites. CONCLUSION: CD can be unicentric or multicentric and involve nodes above and below the diaphragm. Patients with CD can develop lymphoma. ADVANCES IN KNOWLEDGE: Assessing individual risk of developing lymphoma in patients with CD is difficult, although the findings of splenomegaly, pleural effusion and ascites may be suggestive. PMID- 25710285 TI - Access to biaryl sulfonamides by palladium-catalyzed intramolecular oxidative coupling and subsequent nucleophilic ring opening of heterobiaryl sultams with amines. AB - The installation of sulfonamide pharmacophores on heterobiaryls has successfully been executed by a previously unknown palladium-catalyzed intramolecular oxidative coupling in N-arylsulfonyl heterocycles followed by novel ring opening of heterobiaryl sultams with amine nucleophiles. The protocol has a wide scope of substrates warranting broad applications in the synthesis of heterobiaryls containing an o-sulfonyl or carboxyl functional group. PMID- 25710286 TI - Electrophysiological biomarkers of diagnosis and outcome in neurodevelopmental disorders. AB - PURPOSE OF REVIEW: The heterogeneity in clinical presentation and outcome in neurodevelopmental disorders such as attention deficit hyperactivity disorder (ADHD) autism spectrum disorder (ASD) necessitates the identification and validation of biomarkers that can guide diagnosis, predict developmental outcomes, and monitor treatment response. Electrophysiology holds both practical and theoretical advantages as a clinical biomarker in neurodevelopmental disorders, and considerable effort has been invested in the search for electroencephalography (EEG) biomarkers in ADHD and ASD. RECENT FINDINGS: Here, we discuss the major themes in the evaluation of biomarkers and then review studies that have applied EEG to better inform diagnosis, focusing on the controversy surrounding the theta:beta ratio in ADHD; prediction of risk, highlighting recent studies of infants at high risk for ASD; and treatment monitoring, presenting new efforts in the redefinition of outcome measures in clinical trials of ASD treatment. SUMMARY: We conclude that insights gained from EEG studies will contribute significantly to a more mechanistic understanding of these disorders and to the development of biomarkers that can assist with diagnosis, prognosis, and intervention. There is a need, however, to utilize approaches that accommodate, rather than ignore, diagnostic heterogeneity and individual differences. PMID- 25710287 TI - Faldaprevir and pegylated interferon alpha-2a/ribavirin in individuals co infected with hepatitis C virus genotype-1 and HIV. AB - OBJECTIVE: Faldaprevir is a potent, once-daily hepatitis C virus (HCV) NS3/4A protease inhibitor. STARTVerso4 assessed the efficacy and safety of faldaprevir and response-guided pegylated interferon alpha-2a/ribavirin (PegIFN/RBV) in individuals with HCV/HIV co-infection. DESIGN: A phase 3 open-label study (NCT01399619). METHODS: Individuals (N = 308) co-infected with HCV genotype 1 (treatment-naive or prior interferon relapsers) and HIV [96% on antiretroviral therapy (ART)] received faldaprevir 120 mg (N = 123) or 240 mg (N = 185) and PegIFN/RBV. Those receiving a protease inhibitor or efavirenz ART were assigned to faldaprevir 120 or 240 mg, respectively. Individuals achieving early treatment success (ETS; HCV RNA <25 IU/ml at week 4 and undetectable at week 8) were randomized to 24 or 48 weeks of PegIFN/RBV. The primary endpoint was sustained virologic response 12 weeks after treatment (SVR12). RESULTS: SVR12 was achieved in 221 (72%) individuals, and the rates were comparable across faldaprevir doses. ETS was achieved in 80%, and of these 86% achieved SVR12, with comparable rates with 24 and 48 weeks of PegIFN/RBV (87 and 94%, respectively). In multivariate analysis, age below 40 years, IL28B CC genotype, and baseline HCV RNA below 800 000 IU/ml were associated with SVR12 (P = 0.027, P < 0.0001, and P = 0.0002, respectively), whereas treatment (ART regimen and faldaprevir dose), liver cirrhosis, and genotype 1 subtype were not. The safety profile was comparable to that of faldaprevir in HCV-monoinfected individuals. CONCLUSIONS: High SVR12 rates were achieved with faldaprevir and PegIFN/RBV in HIV/HCV co-infected individuals, regardless of faldaprevir dose and background ART, HCV genotype 1 subtype, or cirrhosis status. SVR rates mirrored those obtained with similar regimens in HCV monoinfected individuals. PMID- 25710289 TI - The evolving HIV epidemic among people who inject drugs in India and the need for a heightened response. PMID- 25710290 TI - Sexual networks, HIV, race and bacterial vaginosis. PMID- 25710288 TI - Pubertal development in HIV-infected African children on first-line antiretroviral therapy. AB - OBJECTIVES: To estimate age at attaining Tanner stages in Ugandan/Zimbabwean HIV infected children initiating antiretroviral therapy (ART) in older childhood and investigate predictors of delayed puberty, particularly age at ART initiation. DESIGN: Observational analysis within a randomized trial. METHODS: Tanner staging was assessed every 24 weeks from 10 years of age, menarche every 12 weeks and height every 4-6 weeks. Age at attaining different Tanner stages was estimated using normal interval regression, considering predictors using multivariable regression. Growth was estimated using multilevel models with child-specific intercepts and trajectories. RESULTS: Median age at ART initiation was 9.4 years (inter-quartile range 7.8, 11.3) (n = 582). At the first assessment, the majority (80.2%) were in Tanner stage 1; median follow-up with staging was 2.8 years. There was a strong delaying effect of older age at ART initiation on age at attaining all Tanner stages (P < 0.05) and menarche (P = 0.02); in boys the delaying effect generally weakened with older age. There were additional significant delays associated with greater impairments in pre-ART height-for-age Z-score (P < 0.05) in both sexes and pre-ART BMI-for-age in girls (P < 0.05). There was no evidence that pre-ART immuno-suppression independently delayed puberty or menarche. However, older children/adolescents had significant growth spurts in intermediate Tanner stages, and were still significantly increasing their height when in Tanner stage 5 (P < 0.01). CONCLUSION: Delaying ART initiation until older childhood substantially delays pubertal development and menarche, independently of immuno-suppression. This highlights that factors other than CD4, such as pubertal development, need consideration when making decisions about timing of ART initiation in older children. PMID- 25710291 TI - Reply to 'sexual networks, HIV, race and bacterial vaginosis'. PMID- 25710292 TI - How does weight influence tenofovir disoproxil-fumarate induced renal function decline? PMID- 25710293 TI - Reply to 'how does weight influence tenofovir disoproxil-fumarate induced renal function decline?'. PMID- 25710294 TI - Elevated baseline plasma phospholipid protein (PLTP) levels are an independent predictor of long-term all-cause mortality in patients with diabetes mellitus and known or suspected coronary artery disease. AB - OBJECTIVES: To investigate the long-term prognostic significance of baseline plasma PLTP levels in a group of well-characterized male patients with diabetes mellitus and known or suspected coronary artery disease referred for coronary angiography. BACKGROUND: PLTP is a plasma protein that mediates the net transfer and exchange of phospholipids between lipoproteins. It has been implicated in the pathogenesis of atherosclerosis and elevated plasma levels have been reported in patients with diabetes mellitus. METHODS: Baseline plasma PLTP levels were measured in 154 male patients with diabetes mellitus who were referred for coronary angiography and followed prospectively for 5 years for the development of all-cause mortality. RESULTS: After adjustment for a variety of baseline clinical, angiographic and laboratory parameters, plasma PLTP levels (analyzed as a continuous variable) were an independent predictor of all-cause mortality at 5 years (HR, 1.55; 95% CI, 1.22-2.00; P = 0.0009). Furthermore, in 3 additional multivariate models that also included a wide variety of contemporary biomarkers with established prognostic efficacy (i.e., ST2, GDF-15, Cystatin C, Fibrinogen, and NT-proBNP), PLTP remained an independent predictor of all-cause mortality at 5 years. CONCLUSIONS: Elevated baseline plasma levels of PLTP are associated with an increased risk of long-term all-cause mortality in patients with diabetes and known or suspected coronary disease. Furthermore, this association is independent of a variety of clinical, angiographic, and laboratory variables, including a whole host of contemporary biomarkers with established prognostic efficacy. PMID- 25710296 TI - The independent use of self-instructions for the acquisition of untrained multi step tasks for individuals with an intellectual disability: A review of the literature. AB - Systematic instruction on multi-step tasks (e.g., cooking, vocational skills, personal hygiene) is common for individuals with an intellectual disability. Unfortunately, when individuals with disabilities turn 22-years-old, they no longer receive services in the public school system in most states and systematic instruction often ends (Bouck, 2012). Rather than focusing instructional time on teacher-delivered training on the acquisition of specific multi-step tasks, teaching individuals with disabilities a pivotal skill, such as using self instructional strategies, may be a more meaningful use of time. By learning self instruction strategies that focus on generalization, individuals with disabilities can continue acquiring novel multi-step tasks in post-secondary settings and remediate skills that are lost over time. This review synthesizes the past 30 years of research related to generalized self-instruction to learn multi-step tasks, provides information about the types of self-instructional materials used, the ways in which participants received training to use them, and concludes with implications for practitioners and recommendations for future research. PMID- 25710295 TI - Diverging trajectory patterns of systemic versus vascular inflammation over age in healthy Caucasians and African-Americans. AB - OBJECTIVE: Age and inflammation are risk factors for cardiovascular disease but the impact of inflammation on cardiovascular risk across the lifespan is not understood. We investigated whether an inflammatory burden is modulated by age in healthy subjects. METHODS: Caucasian and African-American families were recruited from the general population (age range: 6-74 years, n = 267). Systemic inflammation was assessed by C-reactive protein (CRP), serum amyloid A (SAA), fibrinogen, haptoglobin and alpha-acid glycoprotein, and vascular inflammation was assessed by pentraxin-3 (PTX-3), soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM). To collectively assess systemic or vascular factors across the age spectrum, a composite z-score for each marker category was calculated. RESULTS: There was a contrasting pattern in systemic versus vascular inflammatory burden over age with an increase in systemic but a decrease in vascular markers in both ethnic groups. The results remained unchanged after adjustments for the covariates and covariance. When looking at individual markers to examine which markers are most contributing factors to the composite scores, CRP and SAA were significantly and positively associated with age, while PTX-3 and sVCAM were significantly and negatively associated with age in both ethnic groups. CONCLUSIONS: The composite z-score for systemic inflammation increased with age, while the composite z-score for vascular inflammation declined with age, irrespective of ethnicity. The findings illustrate a regulatory relationship between age and inflammation, and suggest that a perceived elevation of vascular markers among the very young may be an indication of physiological changes rather than reflecting a disease process. PMID- 25710297 TI - Infrared matrix isolation study of the thermal and photochemical reactions of ozone with trimethylgallium. AB - The thermal and photochemical reactions of (CH3)3Ga and O3 have been explored using a combination of matrix isolation, infrared spectroscopy, and theoretical calculations. Experimental data using twin jet deposition and theoretical calculations demonstrate the formation of multiple product species after deposition, annealing to 35 K, and UV irradiation of the matrices. The products were identified as (CH3)2GaOCH3, (CH3)2GaCH2OH, (CH3)(CH3O)Ga(OCH3), (CH3)2GaCHO, and (CH3)Ga(OCH3)(CH2OH). Product identifications were confirmed by annealing and irradiation behavior, (18)O substitution experiments, and high level theoretical calculations. Merged jet deposition led to a number of stable late reaction products, including C2H6, CH3OH, and H2CO. A white solid film was also noted on the walls of the merged (flow reactor) region of the deposition system, likely due to the formation of Ga2O3. PMID- 25710298 TI - Aberrant Readout of a Gas Analyzer: Clinical Importance of Interpretation. PMID- 25710299 TI - Is Sevoflurane Responsible for Postoperative Myoclonic Seizure? PMID- 25710300 TI - Changes in Energy Levels by Dexamethasone in Ischemic Hearts and Brains in Male Mice. AB - BACKGROUND: Glucocorticoids have been shown to alleviate ischemia-induced myocardial injury, while aggravating neuronal damage caused by ischemia. As energy failure is a predominant factor in cellular viability, we examined the effects of glucocorticoids on energy utilization in the mouse heart and brain. METHODS: Seventy-two male ddY mice were assigned to 1 of 3 groups: saline (S), dexamethasone (a glucocorticoid without mineralocorticoid activity, 5 mg/kg) (D), and metyrapone (a potent inhibitor of the synthesis of glucocorticoids, 100 mg/kg) (M) groups (n=24 in each). Three hours after intraperitoneal administration, all animals were decapitated, and the heads were frozen in liquid nitrogen after 0, 0.5, 1, or 2 minutes (n=6 in each). The hearts were immediately removed and frozen in liquid nitrogen after 0, 5, 10, or 20 minutes of incubation at 37 degrees C (n=6 in each). The concentrations of adenylates and monoamines were determined by high-performance liquid chromatography. RESULTS: In the heart, the adenosine 5'-triphosphate (ATP) concentration did not differ among the 3 groups at 0 minute of ischemia (3 h of S, D, or M treatment). Ischemia for 5 minutes decreased the ATP content to 21% of the basal level in the S group. The ATP decrease was suppressed by either the D or M treatment, such that after 5 minutes ATP levels were 63% and 64% of each basal level, respectively. In the brain, the ATP level in the M group was 62% of that in the S group at 0 minute of ischemia, and the 5'-monophosphate (AMP) level was 276% of that in the S group. Brain dopamine metabolism was facilitated by dexamethasone, and suppressed by metyrapone. CONCLUSIONS: The relationship between effects of glucocorticoids on ischemia-induced changes in energy levels and cellular viability was not clearly elucidated. PMID- 25710301 TI - [Sports Activity Following Joint Arthroplasty: Experiences and Expectations of Elderly Patients--Findings from a Qualitative Content Analysis of Guided Interviews]. AB - OBJECTIVE: The study investigated specific motives and barriers of sports activities in elderly patients with hip or knee arthroplasty. METHODS: We conducted guided interviews and analysed them by content analysis. RESULTS: 7 women and 8 men were interviewed. In total, we coded 520 passages; on average 34.7 (SD=11.1) per interview. Our findings document severe preoperative handicaps and identified a variety of sports activities which were practiced before treatment. The most emphasized motive was the social function of sports. The main barriers were the self-definition as a sick and elderly person and insecurity and concerns over the course of illness and healing. Very constraining advises on sports activities without consideration of the individual experience in sports were not perceived as helpful. CONCLUSION: Counselling on sports activities following joint replacement needs to consider individual motives, barriers and previous sports experience in order to be perceived as supportive. PMID- 25710302 TI - [Parkinson syndromes: aspects of social medical care]. AB - Parkinson syndromes (PS) represent frequent neurodegenerative disorders. The demographic change suggests an increasing prevalence of PS in the near future. Treatment expenses, early retirement and need of long-term care result in rising public health care expenditures. Standardised concepts of care do not only improve the quality of patient-centered care, but also help to minimize its consequential costs. Their implementation requires profound knowledge of therapeutic strategies and sociomedical regulations. Medical treatment and sociomedical care have to be regularly reevaluated and adapted to the patient's needs and disease severity. An optimal therapy concept guarantees the patient's long term social integration and improves the compliance. PMID- 25710303 TI - [Different Health Impairments at the Beginning of Medical Rehab: Possibilities of more Flexibility using the Example of Rehab Aftercare]. AB - BACKGROUND: The aftercare-program new credo was developed interdisciplinary and with practical orientation for rehabilitation patients with chronic back pain. The concept focuses on rehabilitation aftercare from the beginning of rehabilitation treatment and includes a long-term support of rehabilitation patients after inpatient rehabilitation. A multi-center, controlled longitudinal study demonstrated that participants in the intervention group (IG) implemented significantly better rehabilitation contents and objectives in everyday life and had significant better long-term effects. Anyway, there are participants who don't benefit from the new credo as they begin rehabilitation treatment with low impairments. Assuming that rehabilitation patients with lower impairments need a less comprehensive rehabilitation aftercare compared to those with higher impairments, a follow-up study including a flexible aftercare strategy was conducted. Thereby it is investigated whether the IG achieves more sustainable effects despite of less aftercare compared to the control group (CG) without the aftercare program. METHOD: A prospective controlled longitudinal study in 2 rehabilitation clinics with 3 points of measurement was conducted. The flexibilization of the aftercare program was based on the level of impairment in the main outcome variable functional limitation in activities of daily living (FFbH-R) and restriction in participation (IMET) at the beginning of rehabilitation. Both questionnaires have been used in numerous studies successfully. Rehabilitation patients with low impairments received only the elements of the new credo during inpatient rehabilitation, rehabilitation patients with relevant impairments received the entire new credo over a period of 12 month after inpatient rehabilitation. The effects were evaluated with data from the CG of the primary study [Deck et al., 2012]. This sample was also divided according to their impairments. Rehabilitation patients with no relevant impairments were included in the analysis (IG N=81, KG N=157). RESULT: Regarding the long-term effects for the primary outcome variable FFbH-R a significant positive intragroup-effect was detected for the IG, the CG reached the initial value 12 month after inpatient rehabilitation. For the IMET a significant intragroup-effect is also visible in the IG, the CG does not change over the period of time. For both primary outcomes, there are no significant interaction effects to be observed. With respect to the secondary outcomes, in the IG significant small to moderate intragroup-effects were determined in all outcomes, the CG achieved for half of those outcomes significant small intragroup-effects. CONCLUSION: Rehabilitation patients, who begin rehabilitation with rather low impairments perpetuate their rehabilitation effects with an even reduced aftercare. Aftercare-programs should therefore be adapted to the individual needs. Rehabilitation patient, who start the rehabilitation with relative good health, seem not to have an added value from an intensive aftercare-program. PMID- 25710304 TI - Hearing in Drosophila. AB - The dissection of the Drosophila auditory system has revealed multiple parallels between fly and vertebrate hearing. Recent studies have analyzed the operation of auditory sensory cells and the processing of sound in the fly's brain. Neuronal responses to sound have been characterized, and novel classes of auditory neurons have been defined; transient receptor potential (TRP) channels were implicated in auditory transduction, and genetic and environmental causes of auditory dysfunctions have been identified. This review discusses the implications of these recent advances on our understanding of how hearing happens in the fly. PMID- 25710305 TI - Probing the adsorption of weak acids on graphite using amplitude modulation frequency modulation atomic force microscopy. AB - Recent thermodynamics calculations and adsorption isotherms showed that the adsorption of a self-assembled layer (SAL) of ionized weak acids to carbon was attributed to the negatively charged hydrogen bonding (-CAHB), yet the direct visualization and characterization of this adsorption behavior have not been reported. Here, an amplitude modulation-frequency modulation atomic force microscopy (AM-FM AFM) technique was applied to discriminate the adsorption of decanoic acids (DA) on highly ordered pyrolytic graphite (HOPG). Thermodynamics calculations revealed that the adsorption of SAL was driven by the formation of CAHB with negatively charged functional groups of HOPG. Multilayer adsorption could occur over the adsorbed ionized SAL, leading to the development of aggregates. AM-FM AFM imaging showed that the adsorption of the DA molecules forming aggregates occurred only for the HOPG-functionalized steps, while DA molecules were found to adsorb over the entire functionalized HOPG surface after water-plasma treatment, as evident from the frequency shifts identified in AFM images. PMID- 25710306 TI - Boundary discretization in the numerical simulation of light propagation in skin tissue: problem and strategy. AB - To adapt the complex tissue structure, laser propagation in a two-layered skin model is simulated to compare voxel-based Monte Carlo (VMC) and tetrahedron-based MC (TMC) methods with a geometry-based MC (GMC) method. In GMC, the interface is mathematically defined without any discretization. GMC is the most accurate but is not applicable to complicated domains. The implementation of VMC is simple because of its structured voxels. However, unavoidable errors are expected because of the zigzag polygonal interface. Compared with GMC and VMC, TMC provides a balance between accuracy and flexibility by the tetrahedron cells. In the present TMC, the body-fitted tetrahedra are generated in different tissues. No interface tetrahedral cells exist, thereby avoiding the photon reflection error in the interface cells in VMC. By introducing a distance threshold, the error caused by confused optical parameters between neighboring cells when photons are incident along the cell boundary can be avoided. The results show that the energy deposition error by TMC in the interfacial region is one-tenth to one-fourth of that by VMC, yielding more accurate computations of photon reflection, refraction, and energy deposition. The results of multilayered and n shaped vessels indicate that a laser with a 1064-nm wavelength should be introduced to clean deep-buried vessels. PMID- 25710307 TI - Application of nanoimprinting technique for fabrication of trifocal diffractive lens with sine-like radial profile. AB - The fabrication of submicron-height sine-like relief of a trifocal diffractive zone plate using a nanoimprinting technique is studied. The zone plate is intended for use in combined trifocal diffractive-refractive lenses and provides the possibility to form trifocal intraocular lenses with predetermined light intensity distribution between foci. The optical properties of the designed zone plate having the optical powers 3 D, 0, -3D in the three main diffraction orders are theoretically and experimentally investigated. The results of the theoretical investigations are in good agreement with experimental measurements. The effects of the pupil size (lens diameter) as well as the wavelength-dependent behavior of the zone plate are also discussed. PMID- 25710308 TI - Intravital live cell triggered imaging system reveals monocyte patrolling and macrophage migration in atherosclerotic arteries. AB - Intravital multiphoton imaging of arteries is technically challenging because the artery expands with every heartbeat, causing severe motion artifacts. To study leukocyte activity in atherosclerosis, we developed the intravital live cell triggered imaging system (ILTIS). This system implements cardiac triggered acquisition as well as frame selection and image registration algorithms to produce stable movies of myeloid cell movement in atherosclerotic arteries in live mice. To minimize tissue damage, no mechanical stabilization is used and the artery is allowed to expand freely. ILTIS performs multicolor high frame-rate two dimensional imaging and full-thickness three-dimensional imaging of beating arteries in live mice. The external carotid artery and its branches (superior thyroid and ascending pharyngeal arteries) were developed as a surgically accessible and reliable model of atherosclerosis. We use ILTIS to demonstrate Cx3cr1GFP monocytes patrolling the lumen of atherosclerotic arteries. Additionally, we developed a new reporter mouse (Apoe-/-Cx3cr1GFP/+Cd11cYFP) to image GFP+ and GFP+YFP + macrophages "dancing on the spot" and YFP+ macrophages migrating within intimal plaque. ILTIS will be helpful to answer pertinent open questions in the field, including monocyte recruitment and transmigration, macrophage and dendritic cell activity, and motion of other immune cells. PMID- 25710309 TI - Electron transfer and catalysis with high-valent metal-oxo complexes. AB - High-valent metal-oxo complexes are produced by reductive activation of dioxygen via reduction of metal complexes with reductants and dioxygen. Photoinduced electron transfer from substrates to metal complexes with dioxygen also leads to the generation of high-valent metal-oxo complexes that can oxygenate substrates. In such a case metal complexes act as a photocatalyst to oxygenate substrates with dioxygen. High-valent metal-oxo complexes are also produced by proton coupled electron-transfer oxidation of metal complexes by one-electron oxidants with water, oxygenating substrates to regenerate metal complexes. In such a case metal complexes act as a catalyst for electron-transfer oxygenation of substrates by one-electron oxidants with water that acts as an oxygen source. The one electron oxidants which can oxidize metal complexes can be replaced by much weaker oxidants by a combination of redox photocatalysts and metal complexes. Thus, photocatalytic oxygenation of substrates proceeds via photoinduced electron transfer from a photocatalyst to reductants followed by proton-coupled electron transfer oxidation of metal complexes with the oxidized photocatalyst to produce high-valent metal-oxo complexes that oxygenate substrates. Thermal and photoinduced electron-transfer catalytic reactions of high-valent metal-oxo complexes for oxygenation of substrates using water or dioxygen as an oxygen source are summarized in this perspective. PMID- 25710312 TI - Promoting Excellence and Reflective Learning in Simulation (PEARLS): development and rationale for a blended approach to health care simulation debriefing. AB - STATEMENT: We describe an integrated conceptual framework for a blended approach to debriefing called PEARLS [Promoting Excellence And Reflective Learning in Simulation]. We provide a rationale for scripted debriefing and introduce a PEARLS debriefing tool designed to facilitate implementation of the new framework. The PEARLS framework integrates 3 common educational strategies used during debriefing, namely, (1) learner self-assessment, (2) facilitating focused discussion, and (3) providing information in the form of directive feedback and/or teaching. The PEARLS debriefing tool incorporates scripted language to guide the debriefing, depending on the strategy chosen. The PEARLS framework and debriefing script fill a need for many health care educators learning to facilitate debriefings in simulation-based education. The PEARLS offers a structured framework adaptable for debriefing simulations with a variety in goals, including clinical decision making, improving technical skills, teamwork training, and interprofessional collaboration. PMID- 25710311 TI - The lifetime medical cost savings from preventing HIV in the United States. AB - OBJECTIVE: Enhanced HIV prevention interventions, such as preexposure prophylaxis for high-risk individuals, require substantial investments. We sought to estimate the medical cost saved by averting 1 HIV infection in the United States. METHODS: We estimated lifetime medical costs in persons with and without HIV to determine the cost saved by preventing 1 HIV infection. We used a computer simulation model of HIV disease and treatment (CEPAC) to project CD4 cell count, antiretroviral treatment status, and mortality after HIV infection. Annual medical cost estimates for HIV-infected persons, adjusted for age, sex, race/ethnicity, and transmission risk group, were from the HIV Research Network (range, $1854 $4545/mo) and for HIV-uninfected persons were from the Medical Expenditure Panel Survey (range, $73-$628/mo). Results are reported as lifetime medical costs from the US health system perspective discounted at 3% (2012 USD). RESULTS: The estimated discounted lifetime cost for persons who become HIV infected at age 35 is $326,500 (60% for antiretroviral medications, 15% for other medications, 25% nondrug costs). For individuals who remain uninfected but at high risk for infection, the discounted lifetime cost estimate is $96,700. The medical cost saved by avoiding 1 HIV infection is $229,800. The cost saved would reach $338,400 if all HIV-infected individuals presented early and remained in care. Cost savings are higher taking into account secondary infections avoided and lower if HIV infections are temporarily delayed rather than permanently avoided. CONCLUSIONS: The economic value of HIV prevention in the United States is substantial given the high cost of HIV disease treatment. PMID- 25710310 TI - Neutralization of (NK-cell-derived) B-cell activating factor by Belimumab restores sensitivity of chronic lymphoid leukemia cells to direct and Rituximab induced NK lysis. AB - Natural killer (NK) cells are cytotoxic lymphocytes that substantially contribute to the therapeutic benefit of antitumor antibodies like Rituximab, a crucial component in the treatment of B-cell malignancies. In chronic lymphocytic leukemia (CLL), the ability of NK cells to lyse the malignant cells and to mediate antibody-dependent cellular cytotoxicity upon Fc receptor stimulation is compromised, but the underlying mechanisms are largely unclear. We report here that NK-cells activation-dependently produce the tumor necrosis factor family member 'B-cell activating factor' (BAFF) in soluble form with no detectable surface expression, also in response to Fc receptor triggering by therapeutic CD20-antibodies. BAFF in turn enhanced the metabolic activity of primary CLL cells and impaired direct and Rituximab-induced lysis of CLL cells without affecting NK reactivity per se. The neutralizing BAFF antibody Belimumab, which is approved for treatment of systemic lupus erythematosus, prevented the effects of BAFF on the metabolism of CLL cells and restored their susceptibility to direct and Rituximab-induced NK-cell killing in allogeneic and autologous experimental systems. Our findings unravel the involvement of BAFF in the resistance of CLL cells to NK-cell antitumor immunity and Rituximab treatment and point to a benefit of combinatory approaches employing BAFF-neutralizing drugs in B-cell malignancies. PMID- 25710313 TI - Testing of a Complete Training Model for Chest Tube Insertion in Traumatic Pneumothorax. AB - INTRODUCTION: Chest tube insertion is a frequent procedure in cases of traumatic pneumothorax, but severe complications can occur if not well performed. Although simulation-based training in chest tube insertion has improved performance, an affordable and realistic model for surgical insertion of a chest tube is lacking. OBJECTIVE: The objective was to design a model for surgical chest tube insertion that would be realistic, affordable, and transportable and that would reflect all extrathoracic and intrathoracic steps of the procedure. METHODS: The model was a task trainer designed by 4 experts in our simulation laboratory combining plastic, electronic, and biologic material. The cost of supplies needed for construction was evaluated. The model was used and tested over 30 months on 56 participants, of whom 44 were surveyed regarding the realism of the model. RESULTS: The model involved a half chest wall (lamb) on a plastic box, connected to a webcam facilitating assessment of the extrathoracic and intrathoracic steps of the procedure, for a cost of ?60. Chest tubes, water seal package, and sterile instruments costed ?200. All anatomic structures were represented during surgical insertion of chest tube. The demonstration contributed to teaching small groups of up to 8 participants and was reproducible over 30 months of diversely located courses. Anatomic correlation, realism, and learning experience were highly rated by users. CONCLUSIONS: This model for surgical chest tube insertion in traumatic pneumothorax was found to be realistic, affordable, and transportable. Furthermore, it allowed comprehensive assessment of the extrathoracic and intrathoracic procedural steps. PMID- 25710314 TI - The training value of a low-fidelity cervical biopsy workshop. AB - INTRODUCTION: Cervical biopsy increases diagnostic yield compared with cytology and reduces time between presentation with and diagnosis of cervical cancer. Procedural training however needs to evolve in line with legislated working time restrictions and patient safety concerns. This makes gynecologic procedures ideal for simulation training. To date, no studies have looked at the use of low fidelity simulation models to teach cervical punch biopsy. METHODS: A cervical punch biopsy model was created using home and departmental waste products. The simulation model was tested by expert colposcopists and used during a gynecology trainee cervical study day. Twenty-one trainees attended a lecture that showed photographs of normal and abnormal cervices and a workshop where colposcopists demonstrated the technique before direct hands-on training with the simulator. Participants were asked to complete a survey, using a 5-point Likert scale, outlining the educational value of the workshop. RESULTS: Five low-fidelity cervical biopsy simulation models were created, these cost nothing, took an hour to make, and were easily transported. Of the different "cervix" materials tested, sponge provided the most realistic traction and the least fragmented biopsies (3 5 mm). Eighteen trainees completed the survey of whom all strongly agreed that learning was enhanced compared with didactics alone. The mean score for the value of the simulation in preparing trainees to perform future cervical biopsies was 4.7 (SD = 0.42) (95% confidence interval, 4.49-4.90). CONCLUSIONS: Our low fidelity cervical biopsy models are easy to make, portable, and low cost. Trainees have reported the significant educational value of this simulation model in teaching an outpatient gynecologic/colposcopy procedure in a nonclinical environment. PMID- 25710316 TI - An evaluation of the use of deliberate practice and simulation to train interns in requesting blood products. AB - INTRODUCTION: Technical or practical skills deficits upon graduation from medical school are prevalent and contribute to increasing medical error. The current study sought to evaluate the efficacy of a simulation- and deliberate practice based learning program for requesting blood products, delivered to newly graduated interns. METHODS: The requesting of blood products by a group of 27 "trained" interns was prospectively compared with that of a group of 30 "untrained" interns throughout the first 13 weeks of internship at an Irish teaching hospital. RESULTS: Our analysis showed that the training intervention reduced the risk of a rejected sample by 65% as compared with interns who did not receive the training. Moreover, the risk of a rejected sample for trained interns was 45% lower than for much more experienced doctors. The untrained interns required more than 2 months of clinical experience to reach an error rate that was not significantly different from that of the trained interns. CONCLUSIONS: These findings indicate that skills acquired through deliberate practice generalized to the clinical setting led to a significant reduction in blood product prescribing errors. PMID- 25710315 TI - Decision making in trauma settings: simulation to improve diagnostic skills. AB - INTRODUCTION: In the setting of acute injury, a wrong, missed, or delayed diagnosis can impact survival. Clinicians rely on pattern recognition and heuristics to rapidly assess injuries, but an overreliance on these approaches can result in a diagnostic error. Simulation has been advocated as a method for practitioners to learn how to recognize the limitations of heuristics and develop better diagnostic skills. The objective of this study was to determine whether simulation could be used to provide teams the experiences in managing scenarios that require the use of heuristic as well as analytic diagnostic skills to effectively recognize and treat potentially life-threatening injuries. METHODS: Ten scenarios were developed to assess the ability of trauma teams to provide initial care to a severely injured patient. Seven standard scenarios simulated severe injuries that once diagnosed could be effectively treated using standard Advanced Trauma Life Support algorithms. Because diagnostic error occurs more commonly in complex clinical settings, 3 complex scenarios required teams to use more advanced diagnostic skills to uncover a coexisting condition and treat the patient. Teams composed of 3 to 5 practitioners were evaluated in the performance of 7 (of 10) randomly selected scenarios (5 standard, 2 complex). Expert rates scored teams using standardized checklists and global scores. RESULTS: Eighty three surgery, emergency medicine, and anesthesia residents constituted 21 teams. Expert raters were able to reliably score the scenarios. Teams accomplished fewer checklist actions and received lower global scores on the 3 analytic scenarios (73.8% [12.3%] and 5.9 [1.6], respectively) compared with the 7 heuristic scenarios (83.2% [11.7%] and 6.6 [1.3], respectively; P < 0.05 for both). Teams led by more junior residents received higher global scores on the analytic scenarios (6.4 [1.3]) than the more senior team leaders (5.3 [1.7]). CONCLUSIONS: This preliminary study indicates that teams led by more senior residents received higher scores when managing heuristic scenarios but were less effective when managing the scenarios that require a more analytic approach. Simulation can be used to provide teams with decision-making experiences in trauma settings and could be used to improve diagnostic skills as well as study the decision-making process. PMID- 25710317 TI - Queen's simulation assessment tool: development and validation of an assessment tool for resuscitation objective structured clinical examination stations in emergency medicine. AB - INTRODUCTION: The use of high-fidelity simulation is emerging as an effective approach to competency-based assessment in medical education. We aimed to develop and validate a modifiable anchored global assessment scoring tool for simulation based Objective Structured Clinical Examinations (OSCEs) of resuscitation competence in postgraduate emergency medicine (EM) trainees. METHODS: The Queen's Simulation Assessment Tool was developed using a modified Delphi technique with a panel of EM physicians. Ten standardized resuscitation OSCE scenarios were administered to EM trainees, and their video-recorded performances were scored by 3 independent and blinded EM attending physicians using the Queen's Simulation Assessment Tool. Correlational analyses and analysis of variance were applied to measure the discriminatory capabilities and interrater reliability of each scenario. A fully crossed generalizability study was conducted for each examination. RESULTS: Emergency medicine postgraduate trainees at Queen's University (n = 19-25 per station) participated in the study over 3 years. Interrater reliability showed acceptable levels of agreement for each scenario (mean Spearman rho = 0.75 [0.63-0.87]; mean interclass correlation coefficient, 0.69 [0.58-0.87]). Discriminatory validity was strong, with senior residents outperforming junior residents in all but 1 of the 10 scenarios. Generalizability studies found the trainee and trainee by scenario interactions as the largest contributors to variance, with G coefficients ranging from 0.67 to 0.84. Resident trainees reported comfort being assessed in the simulation environment (3.8/5) and found the simulation-based examination valuable to their learning (4.6/5). CONCLUSIONS: This study describes the development and validation of a novel modifiable anchored global assessment scoring tool for simulation-based OSCE assessment of resuscitation competence in postgraduate EM trainees. PMID- 25710318 TI - Co-debriefing for simulation-based education: a primer for facilitators. AB - STATEMENT: As part of simulation-based education, postevent debriefing provides an opportunity for learners to critically reflect on the simulated experience, with the goal of identifying areas in need of reinforcement and correcting areas in need of improvement. The art of debriefing is made more challenging when 2 or more educators must facilitate a debriefing together (ie, co-debriefing) in an organized and coordinated fashion that ultimately enhances learning. As the momentum for incorporating simulation-based health care education continues to grow, the need for faculty development in the area of co-debriefing has become essential. In this article, we provide a practical toolbox for co-facilitators by discussing the advantages of co-debriefing, describing some of the challenges associated with co-debriefing, and offering practical approaches and strategies to overcome the most common challenges associated with co-debriefing in the context of simulation-based health care education. PMID- 25710319 TI - Debriefing and feedback: two sides of the same coin? PMID- 25710320 TI - Short-term effects of TiO2, CeO2, and ZnO nanoparticles on metabolic activities and gene expression of Nitrosomonas europaea. AB - Nanosized TiO2 (n-TiO2), CeO2 (n-CeO2), and ZnO (n-ZnO) and bulk ZnO were chosen for a 4-h exposure study on a model ammonia oxidizing bacterium, Nitrosomonas europaea. n-ZnO displayed the most serious cytotoxicity while n-TiO2 was the least toxic one. The change of cell morphologies, the retardance of specific oxygen uptake rates and ammonia oxidation rates, and the depression of amoA gene expressions under NP stresses were generally observed when the cell densities and membrane integrities were not significantly impaired yet. The TEM imaging and the synchrotron X-ray fluorescence microscopy of the NPs impacted cells revealed the increase of the corresponding intracellular Ti, Ce or Zn contents and suggested the intracellular NP accumulation. The elevation of intracellular S contents accompanied with higher K contents implied the possible activation of thiol containing glutathione and thioredoxin production for NP stress alleviation. The NP cytotoxicity was not always a function of NP concentration. The 200 mg L(-1) n TiO2 or n-CeO2 impacted cells displayed the similar ammonia oxidation activities but higher amoA gene expression levels than the 20 mg L(-1) NPs impacted ones. Such phenomenon further indicated the possible establishment of an anti-toxicity mechanism in N. europaea at the genetic level to redeem the weakened AMO activities along with the NP aggregation effects. PMID- 25710321 TI - Development of a multi-compartment pharmacokinetic model to characterize the exposure to Hexamoll(r) DINCH(r). AB - We developed and calibrated a multi compartment pharmacokinetic (PK) model to predict urinary concentrations after oral exposure of four specific DINCH metabolites: MINCH, OH-MINCH, cx-MINCH, and oxo-MINCH. This descriptive model has 4 compartments: a "stomach" (SC) compartment, a "holding" (HC) compartment, a "blood" (BC) compartment and a "bladder" (BLC) compartment. DINCH is assumed to first deposit into the SC, with transfer split between the HC and the BC. Unmetabolized DINCH from the HC then transfers to the BC. The DINCH metabolism is assumed to occur in the BC before excretion via the BLC. At each urination event, all the metabolite mass in the BLC is excreted. The model was calibrated using published urine metabolite data from 3 different male volunteers, each orally dosed with 50mg DINCH. Full urine voids were taken for 48 h after dosage. The predicted values showed a good agreement with the observed urinary DINCH metabolite concentrations, with a Spearman correlation coefficient exceeding 0.7 for all oxidized metabolites. We showed the importance of a holding reservoir. Without it, a good agreement could not be found. We applied the model to a set of 24-h general population samples measured for DINCH metabolites. The model was unable to duplicate the ratio of metabolites seen in the 24-h samples. Two possibilities were offered to explain the difference: the exposure pattern in the general population did not match the oral exposure in the dosing experiments, or the long-term toxicokinetics of DINCH was not captured in the 48-h controlled dosing experiments. PMID- 25710323 TI - Stereoselective synthesis of 3-methyleneisoindolin-1-ones via base-catalyzed intermolecular reactions of electron-deficient alkynes with N hydroxyphthalimides. AB - Highly stereoselective intermolecular reactions of electron-deficient alkynes with N-hydroxyphthalimides for efficient construction of N-unprotected 3 methyleneisoindolin-1-ones have been developed through base catalytic strategies. The reaction of alkynoates with N-hydroxyphthalimides catalyzed by Bu3P in DMF at 150 degrees C gave the corresponding 3-methyleneisoindolin-1-ones with a (Z) configuration, while the reaction of alkynoates with N-hydroxyphthalimides catalyzed by K2CO3 in DMF at 60 degrees C gave the corresponding 3 methyleneisoindolin-1-ones with an (E)-configuration, and (Z)-3 methyleneisoindolin-1-ones were obtained when alkyne ketones reacted with N hydroxyphthalimide. PMID- 25710324 TI - Technical bias of microcultivation environments on single-cell physiology. AB - Microscale cultivation systems are important tools to elucidate cellular dynamics beyond the population average and understand the functional architecture of single cells. However, there is scant knowledge about the bias of different microcultivation technologies on cellular functions. We therefore performed a systematic cross-platform comparison of three different microscale cultivation systems commonly harnessed in single-cell analysis: microfluidic non-contact cell traps driven by negative dielectrophoresis, microfluidic monolayer growth chambers, and semi-solid agarose pads. We assessed the specific single-cell growth rates, division rates and morphological characteristics of single Corynebacterium glutamicum cells and microcolonies as a bacterial model organism with medical and biotechnological relevance under standardized growth conditions. Strikingly, the specific single-cell and microcolony growth rates, MUmax, were robust and conserved for several cell generations with all three microcultivation technologies, whereas the division rates of cells grown on agarose pads deviated by up to 50% from those of cells cultivated in negative dielectrophoresis traps and monolayer growth chambers. Furthermore, morphological characteristics like cell lengths and division symmetries of individual cells were affected when the cells were grown on agarose pads. This indicated a significant impact of solid cultivation supports on cellular traits. The results demonstrate the impact of microcultivation technology on microbial physiology for the first time and show the need for a careful selection and design of the microcultivation technology in order to allow unbiased analysis of cellular behavior. PMID- 25710325 TI - Objective vs. Self-report Sedentary Behavior in Overweight and Obese Young Adults. AB - BACKGROUND: Sedentary behavior (SED) has been measured almost exclusively by self reported total SED or television time in longitudinal studies. This manuscript aimed to compare self-reported vs. objectively measured SED. METHODS: Among overweight and obese young adults enrolled in a weight loss trial, baseline SED was assessed by 3 methods: 1) a questionnaire assessing 8 common SEDs (SEDQ), 2) 1 question assessing SED from the Global Physical Activity Questionnaire (SEDGPAQ), and 3) a monitor worn on the arm (SEDOBJ). In addition, television time (SEDTV) was isolated from the SEDQ. SED measures were compared using Spearman's correlations, signed-rank tests, and Bland-Altman plots. RESULTS: In 448 participants, SEDQ and SEDGPAQ were only weakly associated with SEDOBJ (rs = 0.21; P < .001, rs = 0.32; P < .001, respectively). Compared with SEDOBJ, SEDQ more often overestimated SEDOBJ (median difference: 1.1 hours/day; P < .001), while SEDGPAQ more often underestimated SEDOBJ (median difference: -0.7 hours/day; P < .001). The correlation between SEDTV and SEDOBJ was not significantly different from 0 (rs = 0.08; P = .08). CONCLUSIONS: SEDQ and SEDGPAQ were weakly correlated with, and significantly different from, SEDOBJ in overweight and obese young adults. SEDTV was not related to SEDOBJ. The poor associations of self-reported and objectively measured SED could affect interpretation and comparison across studies relating SED to adverse health outcomes. PMID- 25710326 TI - Substrate pathways in the nitrogenase MoFe protein by experimental identification of small molecule binding sites. AB - In the nitrogenase molybdenum-iron (MoFe) protein, we have identified five potential substrate access pathways from the protein surface to the FeMo-cofactor (the active site) or the P-cluster using experimental structures of Xe pressurized into MoFe protein crystals from Azotobacter vinelandii and Clostridium pasteurianum. Additionally, all published structures of the MoFe protein, including those from Klebsiella pneumoniae, were analyzed for the presence of nonwater, small molecules bound to the protein interior. Each pathway is based on identification of plausible routes from buried small molecule binding sites to both the protein surface and a metallocluster. Of these five pathways, two have been previously suggested as substrate access pathways. While the small molecule binding sites are not conserved among the three species of MoFe protein, residues lining the pathways are generally conserved, indicating that the proposed pathways may be accessible in all three species. These observations imply that there is unlikely a unique pathway utilized for substrate access from the protein surface to the active site; however, there may be preferred pathways such as those described here. PMID- 25710327 TI - Paralympic Sprint Performance Between 1992 and 2012. AB - The Paralympic Games have undergone many changes since their inception in 1960, one being the advances made in running-specific prostheses (RSPs) for track athletes with lower-limb amputations. PURPOSE: To investigate the sprinting performance changes in athletes with lower-limb amputations since 1992 to assess whether the influence of developments in RSP technology is evident. METHODS: The results of the Olympic and Paralympic Games ranging between 1992 and 2012 for the 100-m and 200-m were collected, and performance trends, percentage change in performance, and competition density (CD) were calculated. RESULTS: The results indicate that the greatest performance increases were seen in athletes with lower limb amputations (T42 = 26%, T44 = 14%). These performance improvements were greater than for Olympic athletes (<3%), as well as Paralympic athletes from other selected classes (<10%). The T42 and T44 classes also showed the lowest CD values. DISCUSSION: These results suggest that although there is an overall trend for improved Paralympic sprint performances, RSP technology has played a noteworthy role in the progression of performances of athletes with amputations. It is also hypothesized that the difference in the performance improvements between the T42 and T44 classes is due to the level of disability and therefore the extent to which technology is required to enable locomotion. CONCLUSION: It is evident that RSP technology has played a significant role in the progression of performances in athletes with lower-limb amputations. PMID- 25710329 TI - Robust gapless surface state and Rashba-splitting bands upon surface deposition of magnetic Cr on Bi2Se3. AB - The interaction between magnetic impurities and the gapless surface state is of critical importance for realizing novel quantum phenomena and new functionalities in topological insulators. By combining angle-resolved photoemission spectroscopic experiments with density functional theory calculations, we show that surface deposition of Cr atoms on Bi2Se3 does not lead to gap opening of the surface state at the Dirac point, indicating the absence of long-range out-of plane ferromagnetism down to our measurement temperature of 15 K. This is in sharp contrast to bulk Cr doping, and the origin is attributed to different Cr occupation sites. These results highlight the importance of nanoscale configuration of doped magnetic impurities in determining the electronic and magnetic properties of topological insulators. PMID- 25710330 TI - Nickel complexes for catalytic C-H bond functionalization. AB - The direct catalytic functionalization of traditionally unreactive C-H bonds is an atom-economic transformation that has become increasingly important and commonplace in synthetic applications. In general, 2(nd) and 3(rd) row transition metal complexes are used as catalysts in these reactions, whereas the less costly and more abundant 1(st) row metal complexes have limited utility. This Perspective article summarizes progress from our laboratory towards understanding the fundamental issues that complicate the use of Ni complexes for catalytic C-H bond functionalization, as well as approaches to overcoming these limitations. In practice it is found that Ni complexes can functionalize C-H bonds by processes that, to date, have not been observed with the heavier metals. An example is provided by the catalytic stannylation of C-H bonds with tributylvinyltin, Bu3SnCH=CH2, which produces ethylene as a by-product. PMID- 25710328 TI - Cortical hierarchies perform Bayesian causal inference in multisensory perception. AB - To form a veridical percept of the environment, the brain needs to integrate sensory signals from a common source but segregate those from independent sources. Thus, perception inherently relies on solving the "causal inference problem." Behaviorally, humans solve this problem optimally as predicted by Bayesian Causal Inference; yet, the underlying neural mechanisms are unexplored. Combining psychophysics, Bayesian modeling, functional magnetic resonance imaging (fMRI), and multivariate decoding in an audiovisual spatial localization task, we demonstrate that Bayesian Causal Inference is performed by a hierarchy of multisensory processes in the human brain. At the bottom of the hierarchy, in auditory and visual areas, location is represented on the basis that the two signals are generated by independent sources (= segregation). At the next stage, in posterior intraparietal sulcus, location is estimated under the assumption that the two signals are from a common source (= forced fusion). Only at the top of the hierarchy, in anterior intraparietal sulcus, the uncertainty about the causal structure of the world is taken into account and sensory signals are combined as predicted by Bayesian Causal Inference. Characterizing the computational operations of signal interactions reveals the hierarchical nature of multisensory perception in human neocortex. It unravels how the brain accomplishes Bayesian Causal Inference, a statistical computation fundamental for perception and cognition. Our results demonstrate how the brain combines information in the face of uncertainty about the underlying causal structure of the world. PMID- 25710332 TI - Evidence of catalase mimetic activity in Ce(3+)/Ce(4+) doped bioactive glasses. AB - The ability of Ce-containing bioactive glasses to inhibit oxidative stress in terms of reduction of hydrogen peroxide, by mimicking the catalase enzyme activity is demonstrated here for the first time. The antioxidant properties of three bioactive glasses containing an increasing amount of CeO2 have been evaluated by following the degradation of hydrogen peroxide with time after immersion in H2O2 aqueous solutions with different concentration. XPS and UV-vis measurements allowed us to determine the Ce(3+)/Ce(4+) ratio in the bulk and on the glass surface, and to correlate it with the ability of the samples to show catalase mimetic activity. Interestingly, we have found that the bioactive glass with composition 23.2Na2O-25.7CaO-43.4SiO2-2.4P2O5-5.3CeO2 immersed in 0.1 M H2O2 aqueous solution is able to degrade 90% of it in 1 week. The reduction in bioactivity of the glasses with increasing CeO2 content is here rationalized in terms of a lower amount of phosphate groups available for the hydroxyapatite layer formation, after binding with cerium ions. In fact, classical molecular dynamics simulations revealed that the addition of CeO2 leads to the formation of cerium phosphate rich regions. The formation of an insoluble CePO4 crystalline phase is also observed by XRD analysis after thermal treatment of the glass samples. PMID- 25710331 TI - Unique toxicological behavior from single-wall carbon nanotubes separated via selective adsorption on hydrogels. AB - Over the past decade, extensive research has been completed on the potential threats of single-wall carbon nanotubes (SWCNTs) to living organisms upon release to aquatic systems. However, these studies have focused primarily on the link between adverse biological effects in exposed test organisms on the length, diameter, and metallic impurity content of SWCNTs. In contrast, few studies have focused on the bioeffects of the different SWCNTs in the as-produced mixture, which contain both metallic (m-SWCNT) and semiconducting (s-SWCNT) species. Using selective adsorption onto hydrogels, high purity m-SWCNT and s-SWCNT fractions were produced and their biological impacts determined in dose-response studies with Pseudokirchneriella subcapitata as test organism. The results show significant differences in the biological responses of P. subcapitata exposed to high purity m- and s-SWCNT fractions. Contrary to the biological response observed using SWCNTs separated by density gradient ultracentrifugation, it is found that the high-pressure CO conversion (HiPco) s-SWCNT fraction separated by selective adsorption causes increased biological impact. These findings suggest that s-SWCNTs are the primary factor driving the adverse biological responses observed from P. subcapitata cells exposed to our as-produced suspensions. Finally, the toxicity of the s-SWCNT fraction is mitigated by increasing the concentration of biocompatible surfactant in the suspensions, likely altering the nature of surfactant coverage along SWCNT sidewalls, thereby reducing potential physical interaction with algal cells. These findings highlight the need to couple sample processing and toxicity response studies. PMID- 25710334 TI - The normativity of the concept of heteronormativity. AB - The aim of the article is to analyze and to critically examine use of the concept of heteronormativity. We find it important to adjust the concept to some extent in order to analyze, for example, changes occurring in homosexual families, contemporary gender-equal families, or the progressive youth culture. We find two approaches when using the concept. One minimizes the importance of how sexual practices are embedded in social institutions. The first approach becomes too idealistic, whereas the second approach often is based on a structural view of society. This approach makes it hard to imagine a transformation of the family that could lead to more equal and democratic relations in contemporary families. We suggest a third approach, and the possibility of finding creative ways of analyzing actual change and contestations of heteronormativity. An approach containing a space of reflexivity and aiming at political change both involving subjects as well as structures. PMID- 25710335 TI - Biochemical Assay Development for Histone Methyltransferases Using a Transcreener Based Assay for S-Adenosylhomocysteine. AB - Epigenetic regulation has been implicated in diverse diseases including cancer, diabetes, and inflammation, and high-throughput screening for histone methyltransferase (HMT) inhibitors is an area of intense drug discovery effort. HMTs catalyze the transfer of methyl group from S-adenosylmethionine (SAM) to lysine or arginine on histone tails forming the methylated products and S adenosylhomocysteine (SAH). HMTs are challenging to incorporate into biochemical assays for a number of reasons. They have slow turnovers and low Km values for SAM, which leads to low levels of product formation, and thus requires very sensitive detection methods and/or high levels of enzyme. They also have diverse acceptor substrate requirements, ranging from peptides to intact nucleosomes. Additionally, some HMTs function as complexes of three or more proteins. Developing assays for individual HMTs, including sourcing and acquiring high quality enzymes and acceptor substrates, therefore can be laborious and expensive. We recently developed the Transcreener((r)) EPIGEN Methyltransferase assay, a sensitive SAH detection method with a fluorescence polarization readout, to enable universal HMT detection independent of acceptor substrate. To facilitate screening and profiling of HMTs, we describe the development of turnkey assay systems for thirteen HMTs including identification of optimal acceptor substrates and their concentrations, optimization of detection reagents, determination of initial velocity enzyme concentrations, and measurement of inhibitor potencies. PMID- 25710336 TI - Science to Practice: can MR relaxation and diffusion measurements be used to detect in vivo differentiation of transplanted muscle precursor cells? AB - Tissue magnetic resonance (MR) relaxometry and diffusion measurements were successfully used to detect the differentiation of implanted human muscle precursor cells (MPCs) into mature skeletal muscle. As no contrast agents are required, this label-free imaging approach may be immediately used in patients to evaluate the outcome of stem cell- and progenitor cell-based therapies aimed to restore defunct muscle. PMID- 25710338 TI - Bill Cook. PMID- 25710339 TI - The developing asymmetry: revisiting a perceptual and diagnostic challenge. AB - Developing asymmetry is a subtype of asymmetry that has changed in appearance over time. This change implies a higher level of suspicion than other types of asymmetry. This article aims to clarify and review (a) the defining features of a developing asymmetry, (b) tools to facilitate its appropriate identification and evaluation at mammography and sonography, (c) relevant percutaneous biopsy considerations, and (d) benign and malignant pathologies that may present as developing asymmetries. PMID- 25710343 TI - Case 215: voriconazole-induced periostitis. AB - History A 74-year-old woman presented with multifocal bone pain, including pain in multiple ribs, bilateral shoulders, and bilateral hips. The pain began several months before presentation and was quite severe, ultimately necessitating control with narcotics. At examination, strength in both lower extremities was slightly reduced, sensation and reflexes were intact, and range of motion was full, though painful. There were no notable constitutional symptoms of fever or weight loss. Laboratory work-up was remarkable for elevated alkaline phosphatase level (277 U/L [4.6 mkat/L]). The patient had undergone left lung transplantation 8 years prior for pulmonary fibrosis. A thorough pulmonary work-up for the cause of fibrosis, which included gathering an exposure, occupational, allergy, and previous infectious history, and a rheumatoid work-up were negative. The patient's posttransplantation course was complicated by bronchiolitis obliterans from chronic rejection and by recent pulmonary embolism, for which she was undergoing anticoagulation therapy at the time of presentation. Additionally, the patient experienced repeated pulmonary infections with Aspergillus, leading to multiple hospitalizations and long-term antifungal prophylaxis with voriconazole. A bone scan from an outside hospital was reviewed, and further imaging was performed. PMID- 25710344 TI - Usefulness of diffusion-weighted MR imaging in predicting Masaoka-Koga clinical staging of thymic epithelial tumors by using the apparent diffusion coefficient. PMID- 25710345 TI - Imaging-based evaluation of retroperitoneal fibrosis: a challenge for radiologists. PMID- 25710346 TI - Incidental pancreatic cyst is a significant predictor of mortality? What determines life expectancy? PMID- 25710347 TI - Shared decision making in interventional radiology: tools and limitations. PMID- 25710348 TI - William J. Tuddenham, MD. PMID- 25710351 TI - Pathways to the polymerization of boron monoxide dimer to give low-density porous materials containing six-membered boroxine rings. AB - Density functional theory has been used to examine the key mechanistic details of the polymerization of boron monoxide (BO) via its O=B-B=O dimer to give ultimately low-density porous polymeric (BO)n materials. The structures of such materials consist of planar layers of six-membered boroxine (B3O3) rings linked by boron-boron bonds. Initial cyclooligomerization of B2O2 leads to a B4O4 dimer with a four-membered B2O2 ring, a B6O6 trimer containing a six-membered B3O3 (boroxine) ring, a B8O8 tetramer containing an eight-membered B4O4 ring, and even a B10O10 pentamer containing a ten-membered B5O5 ring. However, an isomeric B10O10 structure containing two boroxine rings linked by a B-B bond is a much lower energy structure by ~31 kcal/mol owing to the special stability of the aromatic boroxine rings. Rotation of the boroxine rings around the central B-B bond in this B10O10 structure has a low rotation barrier suggesting that further oligomerization to give products containing either perpendicular or planar orientations of the B3O3 rings is possible. However, the planar oligomers are energetically more favorable since they have fewer high-energy external BO groups bonded to the network of boroxine rings. The pendant boronyl groups are reactive sites that can be used for further polymerization. Mechanistic aspects of the further oligomerization of (BO)x systems to give a B24O24 oligomer with a naphthalene-like arrangement of boroxine rings and a B84O84 structure with a coronene-like arrangement of boroxine rings have been examined. Further polymerization of these intermediates by similar processes is predicted to lead ultimately to polymers consisting of planar networks of boroxine rings. The holes between the boroxine rings in such polymers suggests that they will be porous low density materials. Applications of such materials as absorbents for small molecules are anticipated. PMID- 25710352 TI - Psychenet.de: Development and process evaluation of an e-mental health portal. AB - BACKGROUND: E-mental health interventions can have a positive impact on patient reported and clinical outcomes. The purpose of this project was to develop a user centered e-mental health portal. METHODS: The development of the portal www.psychenet.de included mixed-methods techniques for needs assessment to identify user-relevant content. Furthermore, user-centered design techniques were applied by utilizing individual usability testing with cognitive task analysis. First, a basic version of the portal was created and introduced to the public by means of a media campaign. After the development of module-specific content, exposure and use of the portal was investigated as part of a process evaluation. RESULTS: Relevant content identified by needs assessment covered both, overarching and diagnosis-specific topics. Results of the process evaluation showed a highly accessed website. During the first 18 months, 119,423 visits were tracked. The portal was predominantly accessed by Google searches (73.9%), while 17.6% of visits were related to direct traffic. DISCUSSION: Serving as a complement to face-to-face consultations, www.psychenet.de attempts to inform about mental disorders, and engage patients in the course of their treatment. Results of the process evaluation confirm the high relevance and potential of the portal and can be used for further improvements and extensions in the future. PMID- 25710353 TI - Facile and rapid deprotection conditions for the cleavage of synthetic oligonucleotides from 1,4-anhydroerythritol-based universal polymer support. AB - In our previous report [Kumar, P.; Dhawan, G.; Chandra, R.; Gupta, K.C. Polyamine assisted rapid and clean cleavage of oligonucleotides from cis-diol bearing universal support. Nucl. Acids Res. 2002, 30, e130 (1-8)], we demonstrated polyamine-mediated deprotection of oligonucleotides from cis-diol group bearing universal polymer support (I). However, vulnerability of the conventional dC(bz) to modifications under these conditions compelled us to employ dC(ac) during synthesis of oligonucleotide using conventional synthons. Here, a new set of simple and rapid deprotection conditions has been developed for the complete cleavage of oligonucleotides from the 1,4-anhydroerythritol-based universal polymer support employing conventional dC(bz) synthon. Using manganese-imidazole complex in aqueous ammonium hydroxide (~ 30%), fully deprotected oligonucleotide sequences were obtained in 40 min, which were analyzed on reverse phase-HPLC and compared with the standard oligomers in terms of their retention time. Finally, their biological compatibility was established by analyzing PCR amplified products of npsA gene of N. meningitidis. PMID- 25710354 TI - The first synthesis of 4'-branched 5'-deoxycarbocyclic 9-deazaadenosine and phosphonic acids as antiviral agents. AB - The first synthetic route to 4'-trifluoromethylated 5'-deoxycarbocyclic-9 deazaadenosine analog and its phosphonic acid derivatives was described from alpha-trifluoromethyl-alpha,beta-unsaturated ester. The C-C bond connection between cyclopentane and base moiety was accomplished using Knoevenagel type condensation from ketone derivative 11. Synthesized nucleoside and phosphonic acid analogs were tested for anti-HIV activity as well as cytotoxicity. PMID- 25710355 TI - Practical synthesis of cytidine-5-carboxamide-modified nucleotide reagents. AB - Chemically-modified derivatives of cytidine, bearing a 5-(N-substituted carboxamide) functional group, are new reagents for use in aptamer discovery via the SELEX process (Systematic Evolution of Ligands by EXponential enrichment). Herein, we disclose a practical synthesis of 5-(N-benzylcarboxamide)-2' deoxycytidine, and the corresponding 5-(N-1-naphthylmethylcarboxamide)- and 5-(N 3-phenylpropylcarboxamide)-2'-deoxycytidine analogs, as both the suitably protected 3'-O-cyanoethylphosphoramidite reagents (CEP; gram scale) and the 5'-O triphosphate reagents (TPP; milligram-scale). The key step in the syntheses is a mild, palladium(0)-catalyzed carboxyamidation of an unprotected 5-iodo-cytidine. Use of the CEP reagents for solid-phase oligonucleotide synthesis was demonstrated and incorporation of the TPP reagents by KOD polymerase in a primer extension assay confirmed the utility of these reagents for SELEX. Finally, the carboxyamidation reaction was also used to prepare the nuclease-resistant sugar variants: 5-(N-benzylcarboxamide)-2'-O-methyl-cytidine and 5-(N-3 phenylpropylcarboxamide)-2'-deoxy-2'-fluoro-cytidine. PMID- 25710357 TI - A new efficient stereoselective method for the synthesis of (E)-5-aminoallyl pyrimidine-5'-triphosphates using palladium-catalyzed Heck reaction. AB - An efficient overall two-step strategy for the synthesis of (E)-5-aminoallyl pyrimidine-5'-triphoshate, starting from commercially available pyrimidine-5' triphosphate is described. The method involves regioselective iodination of pyrimidine-5'-triphosphate, followed by the palladium-catalyzed Heck coupling with allylamine. The catalytic reaction is highly stereoselective and compatible with many functional groups present in the reactants. PMID- 25710356 TI - Design, synthesis and evaluation of Fe-S targeted adenosine 5'-phosphosulfate reductase inhibitors. AB - Adenosine 5'-phosphosulfate reductase (APR) is an iron-sulfur enzyme that is vital for survival of Mycobacterium tuberculosis during dormancy and is an attractive target for the treatment of latent tuberculosis (TB) infection. The 4Fe-4S cluster is coordinated to APR by sulfur atoms of four cysteine residues, is proximal to substrate, adenosine 5'-phopsphosulfate (APS), and is essential for catalytic activity. Herein, we present an approach for the development of a new class of APR inhibitors. As an initial step, we have employed an improved solid-phase chemistry method to prepare a series of N(6)-substituted adenosine analogues and their 5'-phosphates as well as adenosine 5'-phosphate diesters bearing different Fe and S binding groups, such as thiols or carboxylic and hydroxamic acid moieties. Evaluation of the resulting compounds indicates a clearly defined spacing requirement between the Fe-S targeting group and adenosine scaffold and that smaller Fe-S targeting groups are better tolerated. Molecular docking analysis suggests that the S atom of the most potent inhibitor may establish a favorable interaction with an S atom in the cluster. In summary, this study showcases an improved solid-phase method that expedites the preparation of adenosine and related 5'-phosphate derivatives and presents a unique Fe-S targeting strategy for the development of APR inhibitors. PMID- 25710358 TI - AMP-deaminase from thymus of patients with myasthenia gravis. AB - Myasthenia gravis (MG) is characterized clinically by skeletal muscle fatigue following the excessive exercise. Interestingly most of MG patients manifest parallely also some abnormalities of the thymus.AMP-deaminase (AMPD) from human thymus was not a subject of studies up to now. In this paper, mRNA expression and some physico-chemical and immunological properties of AMPD purified from the thymus of MG patients were described. Experiments performed identified the liver isozyme (AMPD2) as the main isoform of AMPD expressed in this organ. The activity of AMPD found in this organ was higher than in other human non-(skeletal) muscle tissues indicating on role the enzyme may play in supplying of guanylates required for the intensive multiplication of thymocytes. PMID- 25710359 TI - Highly specific detection of thrombin using an aptamer-based suspension array and the interaction analysis via microscale thermophoresis. AB - A novel aptamer-based suspension array detection platform was designed for the sensitive, specific and rapid detection of human alpha-thrombin as a model. Thrombin was first recognized by a 29-mer biotinylated thrombin-binding aptamer (TBA) in solution. Then 15-mer TBA modified magnetic beads (MBs) captured the former TBA-thrombin to form an aptamer-thrombin-aptamer sandwich complex. The median fluorescence intensity obtained via suspension array technology was positively correlated with the thrombin concentration. The interactions between TBAs and thrombin were analyzed using microscale thermophoresis (MST). The dissociation constants could be respectively achieved to be 44.2 +/- 1.36 nM (TBA1-thrombin) and 15.5 +/- 0.637 nM (TBA2-thrombin), which demonstrated the high affinities of TBA-thrombin and greatly coincided with previous reports. Interaction conditions such as temperature, reaction time, and coupling protocol were optimized. The dynamic quantitative working range of the aptamer-based suspension array was 18.37-554.31 nM, and the coefficients of determination R(2) were greater than 0.9975. The lowest detection limit of thrombin was 5.4 nM. This method was highly specific for thrombin without being affected by other analogs and interfering proteins. The recoveries of thrombin spiked in diluted human serum were in the range 82.6-114.2%. This innovative aptamer-based suspension array detection platform not only exhibits good sensitivity based on MBs facilitating highly efficient separation and amplification, but also suggests high specificity by the selective aptamer binding, thereby suggesting the expansive application prospects in research and clinical fields. PMID- 25710360 TI - Health Information Seeking and Implications for the Operative Dentist. AB - The steady increase in online health information seeking by patients is ingrained in central notions of patient-centered care and shared decision-making models reflected in operative dentistry and the healthcare industry at large. More patients today seek health information prior to an appointment, communicate their findings with their providers, and expect two-way communication exchanges. This e consumer trend has many implications for operative dentistry, for which surgery, by its very nature, lends to a confluence of questioning and informational needs. Operative dentists must acknowledge patient information and be prepared to address the breadth of information brought to them. The purpose of this literature review is threefold: 1) to provide the operative dentist with information about the demographics, psychology, and behavior of today's e-health patient; 2) to provide a review of the benefits and challenges of communicating with e-health patients; and 3) to provide recommendations for communicating with e-patients interpersonally and through Internet communication. In so doing, it is hoped that discussion can provide insight useful for improving provider/patient relationships in the progressive communication era. PMID- 25710361 TI - Variability in cardiac MR measurement of left ventricular ejection fraction, volumes and mass in healthy adults: defining a significant change at 1 year. AB - OBJECTIVE: Variability in the measurement of left ventricular (LV) parameters in cardiovascular imaging has typically been assessed over a short time interval, but clinicians most commonly compare results from studies performed a year apart. To account for variation in technical, procedural and biological factors over this time frame, we quantified the within-subject changes in LV volumes, LV mass (LVM) and LV ejection fraction (EF) in a well-defined cohort of healthy adults at 12 months. METHODS: Cardiac MR (CMR) was performed in 42 healthy control subjects at baseline and at 1 year (1.5 T Magnetom(r) Avanto; Siemens Healthcare, Erlangen, Germany). Analysis of steady-state free precession images was performed manually offline (Argus software; Siemens Healthcare) for assessment of LV volumes, LVM and EF by a single blinded observer. A random subset of 10 participants also underwent repeat imaging within 7 days to determine short-term interstudy reproducibility. RESULTS: There were no significant changes in any LV parameter on repeat CMR at 12 months. The short-term interstudy biases were not significantly different from the long-term changes observed at 1 year. The smallest detectable change (SDC) for LVEF, end-diastolic volume, end-systolic volume and LVM that could be recognized with 95% confidence were 6%, 13 ml, 7 ml and 6 g, respectively. CONCLUSION: The variability in CMR-derived LV measures arising from technical, procedural and biological factors remains minimal at 12 months. Thus, for patients undergoing repeat annual assessment by CMR, even small differences in LV function, size and LVM (which are greater than the SDC) may be attributed to disease-related factors. ADVANCES IN KNOWLEDGE: The reproducibility and reliability of CMR data at 12 months is excellent allowing clinicians to be confident that even small changes in LV structure and function over this time frame are real. PMID- 25710362 TI - Bioactivity and chemical composition of the essential oil from the leaves of Guatteria australis A.St.-Hil. AB - Essential oil from the leaves of Guatteria australis was obtained by hydrodistillation, analyzed by Gas Chromatography coupled to Mass Spectromery (GC MS) and their antiproliferative, antileishmanial, antibacterial, antifungal and antioxidant activities were also evaluated. Twenty-three compounds were identified among which germacrene B (50.66%), germacrene D (22.22%) and (E) caryophyllene (8.99%) were the main compounds. The highest antiproliferative activity was observed against NCI-ADR/RES (TGI = 31.08 MUg/ml) and HT-29 (TGI = 32.81 MUg/ml) cell lines. It also showed good antileishmanial activity against Leishmania infantum (IC50 = 30.71 MUg/ml). On the other hand, the oil exhibited a small effect against Staphylococcus aureus ATCC 6538, S. aureus ATCC 14458 and Escherichia coli ATCC 10799 (MIC = 250 MUg/ml), as well as small antioxidant activity (457 MUmol TE/g) assessed through ORACFL assay. These results represent the first report regarding chemical composition and bioactivity of G. australis essential oil. PMID- 25710363 TI - phoU inactivation in Pseudomonas aeruginosa enhances accumulation of ppGpp and polyphosphate. AB - Inorganic polyphosphate (polyP) is a linear polymer composed of several molecules of orthophosphate (Pi) linked by energy-rich phosphoanhydride bonds. In Pseudomonas aeruginosa, Pi is taken up by the ABC transporter Pst, encoded by an operon consisting of five genes. The first four genes encode proteins involved in the transport of Pi and the last gene of the operon, phoU, codes for a protein which exact function is unknown. We show here that the inactivation of phoU in P. aeruginosa enhanced Pi removal from the medium and polyP accumulation. The phoU mutant also accumulated high levels of the alarmone guanosine tetraphosphate (ppGpp), which in turn increased the buildup of polyP. In addition, phoU inactivation had several pleiotropic effects, such as reduced growth rate and yield and increased sensitivity to antibiotics and stresses. However, biofilm formation was not affected by the phoU mutation. PMID- 25710364 TI - Oxidative stress correlates with Wolbachia-mediated antiviral protection in Wolbachia-Drosophila associations. AB - Wolbachia mediates antiviral protection in insect hosts and is being developed as a potential biocontrol agent to reduce the spread of insect-vectored viruses. Definition of the molecular mechanism that generates protection is important for understanding the tripartite interaction between host insect, Wolbachia, and virus. Elevated oxidative stress was previously reported for a mosquito line experimentally infected with Wolbachia, suggesting that oxidative stress is important for Wolbachia-mediated antiviral protection. However, Wolbachia experimentally introduced into mosquitoes impacts a range of host fitness traits, some of which are unrelated to antiviral protection. To explore whether elevated oxidative stress is associated with antiviral protection in Wolbachia-infected insects, we analyzed oxidative stress of five Wolbachia-infected Drosophila lines. In flies infected with protective Wolbachia strains, hydrogen peroxide concentrations were 1.25- to 2-fold higher than those in paired fly lines cured of Wolbachia infection. In contrast, there was no difference in the hydrogen peroxide concentrations in flies infected with nonprotective Wolbachia strains compared to flies cured of Wolbachia infection. Using a Drosophila mutant that produces increased levels of hydrogen peroxide, we investigated whether flies with high levels of endogenous reactive oxygen species had altered responses to virus infection and found that flies with high levels of endogenous hydrogen peroxide were less susceptible to virus-induced mortality. Taken together, these results suggest that elevated oxidative stress correlates with Wolbachia-mediated antiviral protection in natural Drosophila hosts. PMID- 25710365 TI - In-feed supplementation of trans-cinnamaldehyde reduces layer-chicken egg-borne transmission of Salmonella enterica serovar enteritidis. AB - Salmonella enterica serovar Enteritidis is a major foodborne pathogen in the United States, causing gastroenteritis in humans, primarily through consumption of contaminated eggs. Chickens are the reservoir host of S. Enteritidis. In layer hens, S. Enteritidis colonizes the intestine and migrates to various organs, including the oviduct, leading to egg contamination. This study investigated the efficacy of in-feed supplementation with trans-cinnamaldehyde (TC), a generally recognized as safe (GRAS) plant compound obtained from cinnamon, in reducing S. Enteritidis cecal colonization and systemic spread in layers. Additionally, the effect of TC on S. Enteritidis virulence factors critical for macrophage survival and oviduct colonization was investigated in vitro. The consumer acceptability of eggs was also determined by a triangle test. Supplementation of TC in feed for 66 days at 1 or 1.5% (vol/wt) for 40- or 25-week-old layer chickens decreased the amounts of S. Enteritidis on eggshell and in yolk (P<0.001). Additionally, S. Enteritidis persistence in the cecum, liver, and oviduct in TC-supplemented birds was decreased compared to that in controls (P<0.001). No significant differences in feed intake, body weight, or egg production in birds or in consumer acceptability of eggs were observed (P>0.05). In vitro cell culture assays revealed that TC reduced S. Enteritidis adhesion to and invasion of primary chicken oviduct epithelial cells and reduced S. Enteritidis survival in chicken macrophages (P<0.001). Follow-up gene expression analysis using real-time quantitative PCR (qPCR) showed that TC downregulated the expression of S. Enteritidis virulence genes critical for chicken oviduct colonization (P<0.001). The results suggest that TC may potentially be used as a feed additive to reduce egg-borne transmission of S. Enteritidis. PMID- 25710366 TI - Simple and portable magnetic immunoassay for rapid detection and sensitive quantification of plant viruses. AB - Plant pathogens cause major economic losses in the agricultural industry because late detection delays the implementation of measures that can prevent their dissemination. Sensitive and robust procedures for the rapid detection of plant pathogens are therefore required to reduce yield losses and the use of expensive, environmentally damaging chemicals. Here we describe a simple and portable system for the rapid detection of viral pathogens in infected plants based on immunofiltration, subsequent magnetic detection, and the quantification of magnetically labeled virus particles. Grapevine fanleaf virus (GFLV) was chosen as a model pathogen. Monoclonal antibodies recognizing the GFLV capsid protein were immobilized onto immunofiltration columns, and the same antibodies were linked to magnetic nanoparticles. GFLV was quantified by immunofiltration with magnetic labeling in a double-antibody sandwich configuration. A magnetic frequency mixing technique, in which a two-frequency magnetic excitation field was used to induce a sum frequency signal in the resonant detection coil, corresponding to the virus concentration within the immunofiltration column, was used for high-sensitivity quantification. We were able to measure GFLV concentrations in the range of 6 ng/ml to 20 MUg/ml in less than 30 min. The magnetic immunoassay could also be adapted to detect other plant viruses, including Potato virus X and Tobacco mosaic virus, with detection limits of 2 to 60 ng/ml. PMID- 25710367 TI - C/N ratio drives soil actinobacterial cellobiohydrolase gene diversity. AB - Cellulose accounts for approximately half of photosynthesis-fixed carbon; however, the ecology of its degradation in soil is still relatively poorly understood. The role of actinobacteria in cellulose degradation has not been extensively investigated despite their abundance in soil and known cellulose degradation capability. Here, the diversity and abundance of the actinobacterial glycoside hydrolase family 48 (cellobiohydrolase) gene in soils from three paired pasture-woodland sites were determined by using terminal restriction fragment length polymorphism (T-RFLP) analysis and clone libraries with gene-specific primers. For comparison, the diversity and abundance of general bacteria and fungi were also assessed. Phylogenetic analysis of the nucleotide sequences of 80 clones revealed significant new diversity of actinobacterial GH48 genes, and analysis of translated protein sequences showed that these enzymes are likely to represent functional cellobiohydrolases. The soil C/N ratio was the primary environmental driver of GH48 community compositions across sites and land uses, demonstrating the importance of substrate quality in their ecology. Furthermore, mid-infrared (MIR) spectrometry-predicted humic organic carbon was distinctly more important to GH48 diversity than to total bacterial and fungal diversity. This suggests a link between the actinobacterial GH48 community and soil organic carbon dynamics and highlights the potential importance of actinobacteria in the terrestrial carbon cycle. PMID- 25710368 TI - Responses of yeast biocontrol agents to environmental stress. AB - Biological control of postharvest diseases, utilizing wild species and strains of antagonistic yeast species, is a research topic that has received considerable attention in the literature over the past 30 years. In principle, it represents a promising alternative to chemical fungicides for the management of postharvest decay of fruits, vegetables, and grains. A yeast-based biocontrol system is composed of a tritrophic interaction between a host (commodity), a pathogen, and a yeast species, all of which are affected by environmental factors such as temperature, pH, and UV light as well as osmotic and oxidative stresses. Additionally, during the production process, biocontrol agents encounter various severe abiotic stresses that also impact their viability. Therefore, understanding the ecological fitness of the potential yeast biocontrol agents and developing strategies to enhance their stress tolerance are essential to their efficacy and commercial application. The current review provides an overview of the responses of antagonistic yeast species to various environmental stresses, the methods that can be used to improve stress tolerance and efficacy, and the related mechanisms associated with improved stress tolerance. PMID- 25710369 TI - An inexpensive, accurate, and precise wet-mount method for enumerating aquatic viruses. AB - Viruses affect biogeochemical cycling, microbial mortality, gene flow, and metabolic functions in diverse environments through infection and lysis of microorganisms. Fundamental to quantitatively investigating these roles is the determination of viral abundance in both field and laboratory samples. One current, widely used method to accomplish this with aquatic samples is the "filter mount" method, in which samples are filtered onto costly 0.02-MUm-pore size ceramic filters for enumeration of viruses by epifluorescence microscopy. Here we describe a cost-effective (ca. 500-fold-lower materials cost) alternative virus enumeration method in which fluorescently stained samples are wet mounted directly onto slides, after optional chemical flocculation of viruses in samples with viral concentrations of <5*10(7) viruses ml(-1). The concentration of viruses in the sample is then determined from the ratio of viruses to a known concentration of added microsphere beads via epifluorescence microscopy. Virus concentrations obtained by using this wet-mount method, with and without chemical flocculation, were significantly correlated with, and had precision equivalent to, those obtained by the filter mount method across concentrations ranging from 2.17*10(6) to 1.37*10(8) viruses ml(-1) when tested by using cultivated viral isolates and natural samples from marine and freshwater environments. In summary, the wet-mount method is significantly less expensive than the filter mount method and is appropriate for rapid, precise, and accurate enumeration of aquatic viruses over a wide range of viral concentrations (>=1*10(6) viruses ml(-1)) encountered in field and laboratory samples. PMID- 25710370 TI - A patatin-like protein associated with the polyhydroxyalkanoate (PHA) granules of Haloferax mediterranei acts as an efficient depolymerase in the degradation of native PHA. AB - The key enzymes and pathways involved in polyhydroxyalkanoate (PHA) biosynthesis in haloarchaea have been identified in recent years, but the haloarchaeal enzymes for PHA degradation remain unknown. In this study, a patatin-like PHA depolymerase, PhaZh1, was determined to be located on the PHA granules in the haloarchaeon Haloferax mediterranei. PhaZh1 hydrolyzed the native PHA (nPHA) [including native polyhydroxybutyrate (nPHB) and native poly(3-hydroxybutyrate-co 3-hydroxyvalerate) (nPHBV) in this study] granules in vitro with 3 hydroxybutyrate (3HB) monomer as the primary product. The site-directed mutagenesis of PhaZh1 indicated that Gly16, Ser47 (in a classical lipase box, G-X S47-X-G), and Asp195 of this depolymerase were essential for its activity in nPHA granule hydrolysis. Notably, phaZh1 and bdhA (encoding putative 3HB dehydrogenase) form a gene cluster (HFX_6463 to _6464) in H. mediterranei. The 3HB monomer generated from nPHA degradation by PhaZh1 could be further converted into acetoacetate by BdhA, indicating that PhaZh1-BdhA may constitute the first part of a PHA degradation pathway in vivo. Interestingly, although PhaZh1 showed efficient activity and was most likely the key enzyme in nPHA granule hydrolysis in vitro, the knockout of phaZh1 had no significant effect on the intracellular PHA mobilization, implying the existence of an alternative PHA mobilization pathway(s) that functions effectively within the cells of H. mediterranei. Therefore, identification of this patatin-like depolymerase of haloarchaea may provide a new strategy for producing the high-value-added chiral compound (R)-3HB and may also shed light on the PHA mobilization in haloarchaea. PMID- 25710371 TI - Preferential association of endophytic bradyrhizobia with different rice cultivars and its implications for rice endophyte evolution. AB - Plant colonization by bradyrhizobia is found not only in leguminous plants but also in nonleguminous species such as rice. To understand the evolution of the endophytic symbiosis of bradyrhizobia, the effect of the ecosystems of rice plantations on their associations was investigated. Samples were collected from various rice (Oryza sativa) tissues and crop rotational systems. The rice endophytic bradyrhizobia were isolated on the basis of oligotrophic properties, selective medium, and nodulation on siratro (Macroptilium atropurpureum). Six bradyrhizobial strains were obtained exclusively from rice grown in a crop rotational system. The isolates were separated into photosynthetic bradyrhizobia (PB) and nonphotosynthetic bradyrhizobia (non-PB). Thai bradyrhizobial strains promoted rice growth of Thai rice cultivars better than the Japanese bradyrhizobial strains. This implies that the rice cultivars possess characteristics that govern rice-bacterium associations. To examine whether leguminous plants in a rice plantation system support the persistence of rice endophytic bradyrhizobia, isolates were tested for legume nodulation. All PB strains formed symbioses with Aeschynomene indica and Aeschynomene evenia. On the other hand, non-PB strains were able to nodulate Aeschynomene americana, Vigna radiata, and M. atropurpureum but unable to nodulate either A. indica or A. evenia. Interestingly, the nodABC genes of all of these bradyrhizobial strains seem to exhibit low levels of similarity to those of Bradyrhizobium diazoefficiens USDA110 and Bradyrhizobium sp. strain ORS285. From these results, we discuss the evolution of the plant-bradyrhizobium association, including nonlegumes, in terms of photosynthetic lifestyle and nod-independent interactions. PMID- 25710372 TI - A new fungal isolate, Penidiella sp. strain T9, accumulates the rare earth element dysprosium. AB - With an aim to develop a highly efficient method for the recovery of rare earth elements (REEs) by using microorganisms, we attempted to isolate dysprosium (Dy) accumulating microorganisms that grow under acidic conditions from environmental samples containing high concentrations of heavy metals. One acidophilic strain, T9, which was isolated from an abandoned mine, decreased the concentration of Dy in medium that contained 100 mg/liter Dy to 53 mg/liter Dy after 3 days of cultivation at pH 2.5. The Dy content in the cell pellet of the T9 strain was 910 MUg/mg of dry cells. The T9 strain also accumulated other REEs. Based on the results of 28S-D1/D2 rRNA gene sequencing and morphological characterization, we designated this fungal strain Penidiella sp. T9. Bioaccumulation of Dy was observed on the cell surface of the T9 strain by elemental mapping using scanning electron microscopy-energy dispersive X-ray spectroscopy. Our results indicate that Penidiella sp. T9 has the potential to recover REEs such as Dy from mine drainage and industrial liquid waste under acidic conditions. PMID- 25710373 TI - Spatial and temporal heterogeneity in high-grade serous ovarian cancer: a phylogenetic analysis. AB - BACKGROUND: The major clinical challenge in the treatment of high-grade serous ovarian cancer (HGSOC) is the development of progressive resistance to platinum based chemotherapy. The objective of this study was to determine whether intra tumour genetic heterogeneity resulting from clonal evolution and the emergence of subclonal tumour populations in HGSOC was associated with the development of resistant disease. METHODS AND FINDINGS: Evolutionary inference and phylogenetic quantification of heterogeneity was performed using the MEDICC algorithm on high resolution whole genome copy number profiles and selected genome-wide sequencing of 135 spatially and temporally separated samples from 14 patients with HGSOC who received platinum-based chemotherapy. Samples were obtained from the clinical CTCR-OV03/04 studies, and patients were enrolled between 20 July 2007 and 22 October 2009. Median follow-up of the cohort was 31 mo (interquartile range 22-46 mo), censored after 26 October 2013. Outcome measures were overall survival (OS) and progression-free survival (PFS). There were marked differences in the degree of clonal expansion (CE) between patients (median 0.74, interquartile range 0.66 1.15), and dichotimization by median CE showed worse survival in CE-high cases (PFS 12.7 versus 10.1 mo, p = 0.009; OS 42.6 versus 23.5 mo, p = 0.003). Bootstrap analysis with resampling showed that the 95% confidence intervals for the hazard ratios for PFS and OS in the CE-high group were greater than 1.0. These data support a relationship between heterogeneity and survival but do not precisely determine its effect size. Relapsed tissue was available for two patients in the CE-high group, and phylogenetic analysis showed that the prevalent clonal population at clinical recurrence arose from early divergence events. A subclonal population marked by a NF1 deletion showed a progressive increase in tumour allele fraction during chemotherapy. CONCLUSIONS: This study demonstrates that quantitative measures of intra-tumour heterogeneity may have predictive value for survival after chemotherapy treatment in HGSOC. Subclonal tumour populations are present in pre-treatment biopsies in HGSOC and can undergo expansion during chemotherapy, causing clinical relapse. PMID- 25710375 TI - Antipyretic therapy in critically ill patients with established sepsis: a trial sequential analysis. AB - BACKGROUND AND OBJECTIVE: antipyretic therapy for patients with sepsis has long been debated. The present study aimed to explore the beneficial effect of antipyretic therapy for ICU patients with sepsis. DESIGN: systematic review and trial sequential analysis of randomized controlled trials. DATABASE: Pubmed, Scopus, EBSCO and EMBASE were searched from inception to August 5, 2014. METHODS: Mortality was dichotomized as binary outcome variable and odds ratio (OR) was chosen to be the summary statistic. Pooled OR was calculated by using DerSimonian and Laird method. Statistical heterogeneity was assessed by using the statistic I2. Trial sequential analysis was performed to account for the small number of trials and patients. MAIN RESULTS: A total of 6 randomized controlled trials including 819 patients were included into final analysis. Overall, there was no beneficial effect of antipyretic therapy on mortality risk in patients with established sepsis (OR: 1.02, 95% CI: 0.50-2.05). The required information size (IS) was 2582 and our analysis has not yet reached half of the IS. The Z-curve did not cross the O'Brien-Fleming alpha-spending boundary or reach the futility, indicating that the non-significant result was probably due to lack of statistical power. CONCLUSION: our study fails to identify any beneficial effect of antipyretic therapy on ICU patients with established diagnosis of sepsis. Due to limited number of total participants, more studies are needed to make a conclusive and reliable analysis. PMID- 25710374 TI - Prion infections and anti-PrP antibodies trigger converging neurotoxic pathways. AB - Prions induce lethal neurodegeneration and consist of PrPSc, an aggregated conformer of the cellular prion protein PrPC. Antibody-derived ligands to the globular domain of PrPC (collectively termed GDL) are also neurotoxic. Here we show that GDL and prion infections activate the same pathways. Firstly, both GDL and prion infection of cerebellar organotypic cultured slices (COCS) induced the production of reactive oxygen species (ROS). Accordingly, ROS scavenging, which counteracts GDL toxicity in vitro and in vivo, prolonged the lifespan of prion infected mice and protected prion-infected COCS from neurodegeneration. Instead, neither glutamate receptor antagonists nor inhibitors of endoplasmic reticulum calcium channels abolished neurotoxicity in either model. Secondly, antibodies against the flexible tail (FT) of PrPC reduced neurotoxicity in both GDL-exposed and prion-infected COCS, suggesting that the FT executes toxicity in both paradigms. Thirdly, the PERK pathway of the unfolded protein response was activated in both models. Finally, 80% of transcriptionally downregulated genes overlapped between prion-infected and GDL-treated COCS. We conclude that GDL mimic the interaction of PrPSc with PrPC, thereby triggering the downstream events characteristic of prion infection. PMID- 25710376 TI - Active immunization with an octa-valent Staphylococcus aureus antigen mixture in models of S. aureus bacteremia and skin infection in mice. AB - Proteomic studies with different Staphylococcus aureus isolates have shown that the cell surface-exposed and secreted proteins IsaA, LytM, Nuc, the propeptide of Atl (pro-Atl) and four phenol-soluble modulins alpha (PSMalpha) are invariantly produced by this pathogen. Therefore the present study was aimed at investigating whether these proteins can be used for active immunization against S. aureus infection in mouse models of bacteremia and skin infection. To this end, recombinant His-tagged fusions of IsaA, LytM, Nuc and pro-Atl were isolated from Lactococcus lactis or Escherichia coli, while the PSMalpha1-4 peptides were chemically synthesized. Importantly, patients colonized by S. aureus showed significant immunoglobulin G (IgG) responses against all eight antigens. BALB/cBYJ mice were immunized subcutaneously with a mixture of the antigens at day one (5 MUg each), and boosted twice (25 MUg of each antigen) with 28 days interval. This resulted in high IgG responses against all antigens although the response against pro-Atl was around one log lower compared to the other antigens. Compared to placebo-immunized mice, immunization with the octa-valent antigen mixture did not reduce the S. aureus isolate P load in blood, lungs, spleen, liver, and kidneys in a bacteremia model in which the animals were challenged for 14 days with a primary load of 3 * 10(5) CFU. Discomfort scores and animal survival rates over 14 days did not differ between immunized mice and placebo immunized mice upon bacteremia with S. aureus USA300 (6 * 10(5) CFU). In addition, this immunization did not reduce the S. aureus isolate P load in mice with skin infection. These results show that the target antigens are immunogenic in both humans and mice, but in the used animal models do not result in protection against S. aureus infection. PMID- 25710377 TI - Determining plant-leaf miner-parasitoid interactions: a DNA barcoding approach. AB - A major challenge in network ecology is to describe the full-range of species interactions in a community to create highly-resolved food-webs. We developed a molecular approach based on DNA full barcoding and mini-barcoding to describe difficult to observe plant-leaf miner-parasitoid interactions, consisting of animals commonly regarded as agricultural pests and their natural enemies. We tested the ability of universal primers to amplify the remaining DNA inside leaf miner mines after the emergence of the insect. We compared the results of a) morphological identification of adult specimens; b) identification based on the shape of the mines; c) the COI Mini-barcode (130 bp) and d) the COI full barcode (658 bp) fragments to accurately identify the leaf-miner species. We used the molecular approach to build and analyse a tri-partite ecological network of plant leaf miner-parasitoid interactions. We were able to detect the DNA of leaf-mining insects within their feeding mines on a range of host plants using mini-barcoding primers: 6% for the leaves collected empty and 33% success after we observed the emergence of the leaf miner. We suggest that the low amplification success of leaf mines collected empty was mainly due to the time since the adult emerged and discuss methodological improvements. Nevertheless our approach provided new species-interaction data for the ecological network. We found that the 130 bp fragment is variable enough to identify all the species included in this study. Both COI fragments reveal that some leaf miner species could be composed of cryptic species. The network built using the molecular approach was more accurate in describing tri-partite interactions compared with traditional approaches based on morphological criteria. PMID- 25710378 TI - Transcriptome analysis of resistant and susceptible alfalfa cultivars infected with root-knot nematode Meloidogyne incognita. AB - Nematodes are one of the major limiting factors in alfalfa production. Root-knot nematodes (RKN, Meloidogyne spp.) are widely distributed and economically important sedentary endoparasites of agricultural crops and they may inflict significant damage to alfalfa fields. As of today, no studies have been published on global gene expression profiling in alfalfa infected with RKN or any other plant parasitic nematode. Very little information is available about molecular mechanisms that contribute to pathogenesis and defense responses in alfalfa against these pests and specifically against RKN. In this work, we performed root transcriptome analysis of resistant (cv. Moapa 69) and susceptible (cv. Lahontan) alfalfa cultivars infected with RKN Meloidogyne incognita, widespread root-knot nematode species and a major pest worldwide. A total of 1,701,622,580 pair-end reads were generated on an Illumina Hi-Seq 2000 platform from the roots of both cultivars and assembled into 45,595 and 47,590 transcripts in cvs Moapa 69 and Lahontan, respectively. Bioinformatic analysis revealed a number of common and unique genes that were differentially expressed in susceptible and resistant lines as a result of nematode infection. Although the susceptible cultivar showed a more pronounced defense response to the infection, feeding sites were successfully established in its roots. Characteristically, basal gene expression levels under normal conditions differed between the two cultivars as well, which may confer advantage to one of the genotypes toward resistance to nematodes. Differentially expressed genes were subsequently assigned to known Gene Ontology categories to predict their functional roles and associated biological processes. Real-time PCR validated expression changes in genes arbitrarily selected for experimental confirmation. Candidate genes that contribute to protection against M. incognita in alfalfa were proposed and alfalfa-nematode interactions with respect to resistance are discussed. PMID- 25710379 TI - Roux-en Y gastric bypass surgery induces genome-wide promoter-specific changes in DNA methylation in whole blood of obese patients. AB - CONTEXT: DNA methylation has been proposed to play a critical role in many cellular and biological processes. OBJECTIVE: To examine the influence of Roux-en Y gastric bypass (RYGB) surgery on genome-wide promoter-specific DNA methylation in obese patients. Promoters are involved in the initiation and regulation of gene transcription. METHODS: Promoter-specific DNA methylation in whole blood was measured in 11 obese patients (presurgery BMI >35 kg/m(2), 4 females), both before and 6 months after RYGB surgery, as well as once only in a control group of 16 normal-weight men. In addition, body weight and fasting plasma glucose were measured after an overnight fast. RESULTS: The mean genome-wide distance between promoter-specific DNA methylation of obese patients at six months after RYGB surgery and controls was shorter, as compared to that at baseline (p<0.001). Moreover, postsurgically, the DNA methylation of 51 promoters was significantly different from corresponding values that had been measured at baseline (28 upregulated and 23 downregulated, P<0.05 for all promoters, Bonferroni corrected). Among these promoters, an enrichment for genes involved in metabolic processes was found (n = 36, P<0.05). In addition, the mean DNA methylation of these 51 promoters was more similar after surgery to that of controls, than it had been at baseline (P<0.0001). When controlling for the RYGB surgery-induced drop in weight (-24% of respective baseline value) and fasting plasma glucose concentration (-16% of respective baseline value), the DNA methylation of only one out of 51 promoters (~2%) remained significantly different between the pre and postsurgery time points. CONCLUSIONS: Epigenetic modifications are proposed to play an important role in the development of and predisposition to metabolic diseases, including type II diabetes and obesity. Thus, our findings may form the basis for further investigations to unravel the molecular effects of gastric bypass surgery. CLINICAL TRIAL: ClinicalTrials.gov NCT01730742. PMID- 25710380 TI - Pseudohypoparathyroidism type Ib associated with novel duplications in the GNAS locus. AB - CONTEXT: Pseudohypoparathyroidism type 1b (PHP-Ib) is characterized by renal resistance to PTH (and, sometimes, a mild resistance to TSH) and absence of any features of Albright's hereditary osteodystrophy. Patients with PHP-Ib suffer of defects in the methylation pattern of the complex GNAS locus. PHP-Ib can be either sporadic or inherited in an autosomal dominant pattern. Whereas familial PHP-Ib is well characterized at the molecular level, the genetic cause of sporadic PHP-Ib cases remains elusive, although some molecular mechanisms have been associated with this subtype. OBJECTIVE: The aim of the study was to investigate the molecular and imprinting defects in the GNAS locus in two unrelated patients with PHP-Ib. DESIGN: We have analyzed the GNAS locus by direct sequencing, Methylation-Specific Multiplex Ligation-dependent Probe Amplification, microsatellites, Quantitative Multiplex PCR of Short Fluorescent fragments and array-Comparative Genomic Hybridization studies in order to characterize two unrelated families with clinical features of PHP-Ib. RESULTS: We identified two duplications in the GNAS region in two patients with PHP-Ib: one of them, comprising ~ 320 kb, occurred 'de novo' in the patient, whereas the other one, of ~ 179 kb in length, was inherited from the maternal allele. In both cases, no other known genetic cause was observed. CONCLUSION: In this article, we describe the to-our-knowledge biggest duplications reported so far in the GNAS region. Both are associated to PHP-Ib, one of them occurring 'de novo' and the other one being maternally inherited. PMID- 25710381 TI - Tyrosine hydroxylase is short-term regulated by the ubiquitin-proteasome system in PC12 cells and hypothalamic and brainstem neurons from spontaneously hypertensive rats: possible implications in hypertension. AB - Aberrations in the ubiquitin-proteasome system (UPS) are implicated in the pathogenesis of various diseases. Tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamines biosynthesis, is involved in hypertension development. In this study we investigated whether UPS regulated TH turnover in PC12 cells and hypothalamic and brainstem neurons from spontaneously hypertensive rats (SHR) and whether this system was impaired in hypertension. PC12 cells were exposed to proteasome or lysosome inhibitors and TH protein level evaluated by Western blot. Lactacystin, a proteasome inhibitor, induced an increase of 86 +/- 15% in TH levels after 30 min of incubation, then it started to decrease up to 6 h to reach control levels and finally it rose up to 35.2 +/- 8.5% after 24 h. Bafilomycin, a lysosome inhibitor, did not alter TH protein levels during short times, but it increased TH by 92 +/- 22% above basal after 6 h treatment. Before degradation proteasome substrates are labeled by conjugation with ubiquitin. Efficacy of proteasome inhibition on TH turnover was evidenced by accumulation of ubiquitinylated TH after 30 min. Further, the inhibition of proteasome increased the quantity of TH phosphorylated at Ser40, which is essential for TH activity, by 2.7 +/- 0.3 fold above basal. TH protein level was upregulated in neurons from hypothalami and brainstem of SHR when the proteasome was inhibited during 30 min, supporting that neuronal TH is also short-term regulated by the proteasome. Since the increased TH levels reported in hypertension may result from proteasome dysfunction, we evaluate proteasome activity. Proteasome activity was significantly reduced by 67 +/- 4% in hypothalamic and brainstem neurons from SHR while its protein levels did not change. Present findings show that TH is regulated by the UPS. The impairment in proteasome activity observed in SHR neurons may be one of the causes of the increased TH protein levels reported in hypertension. PMID- 25710383 TI - Stiffness and toughness prediction of Co-Fe-Ta-B metallic glasses, alloyed with Y, Zr, Nb, Mo, Hf, W, C, N and O by ab initio molecular dynamics. AB - Ab initio molecular dynamics simulations are used to systematically explore the influence of alloying on the stiffness and plasticity of Co-Fe-Ta-B metallic glasses. The Co(43.5)Ta(6.1)B(50.4) metallic glass studied in this work, with a Young's modulus of 295 GPa, is the stiffest metallic glass known in literature. From the analysis of the density of the states it is suggested that the very large stiffness is due to strong covalent metal to boron bonding. Furthermore it has been observed that by alloying with Y, Zr, Nb, Mo, Hf, W, C, N and O the bulk to shear modulus ratio can be varied from 2.08 to 2.82. As noted by Lewandowski et al (2005 Phil. Mag. Lett.85 77) a brittle to plastic transition for metallic glasses can be identified in the range of 2.33 to 2.44. Hence, it is evident that the whole range from brittle to plastic behaviour can be covered,with the systems studied in this work. This evolution from brittle to plastic behaviour can be attributed to a change from predominately covalent to predominately metallic bond character. PMID- 25710382 TI - The TORC2 component, Sin1, controls migration of anterior mesendoderm during zebrafish gastrulation. AB - TORC2 is a serine-threonine kinase complex conserved through evolution that recently emerged as a new regulator of actin dynamics and cell migration. However, knockout in mice of its core components Sin1 and Rictor is embryonic lethal, which has limited in vivo analyses. Here, we analysed TORC2 function during early zebrafish development, using a morpholino-mediated loss of function of sin1. Sin1 appears required during gastrulation for migration of the prechordal plate, the anterior most mesoderm. In absence of Sin1, cells migrate both slower and less persistently, which can be correlated to a reduction in actin-rich protrusions and a randomisation of the remaining protrusions. These results demonstrate that, as established in vitro, the TORC2 component Sin1 controls actin dynamics and cell migration in vivo. We furthermore establish that Sin1 is required for protrusion formation downstream of PI3K, and is acting upstream of the GTPase Rac1, since expression of an activated form of Rac1 is sufficient to rescue sin1 loss of function. PMID- 25710384 TI - Organocatalytic enantioselective 1,3-dipolar cycloadditions between Seyferth Gilbert reagent and isatylidene malononitriles: synthesis of chiral spiro phosphonylpyrazoline-oxindoles. AB - A new method has been developed for the catalytic enantioselective 1,3-dipolar cycloaddition of the Seyferth-Gilbert reagent (SGR) to isatylidene malononitriles using a cinchona alkaloid derivative as a catalyst. This method allowed for the synthesis of a series of chiral spiro-phosphonylpyrazoline-oxindoles in good yields with excellent enantioselectivities. The synthetic utility of this method was further demonstrated by its use in a three-component domino reaction involving isatin, malononitrile, and SGR based on sequential Knoevenagel condensation and 1,3-dipolar cycloaddition reactions. PMID- 25710385 TI - Microscopic structure and properties of discrete water layer in Na-exchanged montmorillonite. AB - In this work, we focus on the atomic structure of the water interlayer of Na exchanged montmorillonite. For two different surface charge densities, namely 0.086 and -0.172 C/m(2), the adsorption process in the presence of water is described by first principles calculations. We describe the interactions and forces for every water molecule entering the interlayer during the swelling process. In particular, the dielectric permittivity of the water interlayer is calculated. Finally, we confirm our results performing ab initio thermodynamics calculations leading to a wide range of realistic experimental scenarios. PMID- 25710386 TI - Removal of fluoxetine from water by adsorbent materials produced from paper mill sludge. AB - In this work, three adsorbents were produced by using as precursor primary paper mill sludge and applying KOH, NaOH or ZnCl2 as chemical activating agents (PS800 10KOH, PS800-10NaOH and PS800-10ZnCl2) and subjected to pyrolysis. The produced materials were tested for removal of fluoxetine from water, reported as one of the most persistent pharmaceuticals in the aquatic environment. Also, primary sludge pyrolysed under the same conditions but without activation (PS800-10) and a commercial activated carbon (PBFG4) were studied for comparison. Physical and chemical properties of the materials were determined and adsorption kinetic and equilibrium studies were performed in batch experiments. Equilibrium studies allowed testing the capacity of the produced materials for adsorb fluoxetine-HCl, showing no apparent correlation between the S(BET) areas and the adsorption capacities of the materials. The maximum adsorption capacity (mg g(-1)) was of 191.6+/-4.8 for PS800-10KOH; 136.6+/-9.6 for PS800-10NaOH; 28.4+/-0.3 for PS800 10ZnCl2; 120.4+/-2.5 for PS800-10 and 96.2+/-1.0 for PBFG4. It was demonstrated that many factors influence the removal of fluoxetine from solution and that the surface area is not the main factor in the process. Also the activation process did not enhance the properties of the produced materials. PMID- 25710387 TI - Carbon-supported ionic liquids as innovative adsorbents for CO2 separation from synthetic flue-gas. AB - Fixed-bed thermodynamic CO2 adsorption tests were performed in model flue-gas onto Filtrasorb 400 and Nuchar RGC30 activated carbons (AC) functionalized with [Hmim][BF4] and [Emim][Gly] ionic liquids (IL). A comparative analysis of the CO2 capture results and N2 porosity characterization data evidenced that the use of [Hmim][BF4], a physical solvent for carbon dioxide, ended up into a worsening of the parent AC capture performance, due to a dominating pore blocking effect at all the operating temperatures. Conversely, the less sterically-hindered and amino acid-based [Emim][Gly] IL was effective in increasing the AC capture capacity at 353 K under milder impregnation conditions, the beneficial effect being attributed to both its chemical affinity towards CO2 and low pore volume reduction. The findings derived in this work outline interesting perspectives for the application of amino acid-based IL supported onto activated carbons for CO2 separation under post-combustion conditions, and future research efforts should be focused on the search for AC characterized by optimal pore size distribution and surface properties for IL functionalization. PMID- 25710388 TI - Formation of furan along with HO2 during the OH-initiated oxidation of 2,5-DHF and 2,3-DHF: an experimental and computational study. AB - Experimental characterization of products during OH-initiated oxidation of dihydrofurans (DHF) confirms the formation of furan accompanied by the formation of HO2 to be a significant channel in 2,5-DHF (21 +/- 3%), whereas it is absent in 2,3-DHF. Theoretical investigations on the reaction of OH with these molecules are carried out to understand this difference. All possible channels of reaction are studied at M06-2X level with 6-311G* basis set, and the stationary points on the potential energy surface are optimized. The overall rate coefficients calculated using conventional TST with Wigner tunneling correction for 2,5-DHF and 2,3-DHF are 2.25 * 10(-11) and 4.13 * 10(-10) cm(3) molecule(-1) s(-1), respectively, in the same range as the previously determined experimental values. The branching ratios of different channels were estimated using the computed rate coefficients. The abstraction of H atom, leading to dihydrofuranyl radical, is found to be a significant probability, equally important as the addition of OH to the double bond in the case of 2,5-DHF. However, this probability is very small in the case of 2,3-DHF because the rate coefficient of the addition reaction is more than 10 times that of the abstraction reaction. This explains the conspicuous absence of furan among the products of the reaction of OH with 2,3 DHF. The calculations also indicate that the abstraction reaction, and hence furan formation, may become significant for OH-initiated oxidation of 2,3-DHF at temperatures relevant to combustion. PMID- 25710389 TI - The use of aromatase inhibitors for ovulation induction. AB - PURPOSE OF REVIEW: Approximately 15% of the infertile population faces an ovulatory disorder; most of them classified as WHO class two anovulation [polycystic ovarian syndrome (PCOS) prototype]. Worldwide, this translates into millions of patients and emphasizes the need of a simple, effective and well tolerated method of ovulation induction. In this review, we will revisit letrozole use in the subset of WHO class two ovulatory problems and evaluate the contribution of the last year's literature to its practice. RECENT FINDINGS: In a multicentre, randomized controlled trial comparing letrozole with clomiphene in 750 PCOS patients having regular intercourse, live birth rates were significantly higher for the letrozole group [rate ratio 1.44, 95% confidence interval (95% CI) 1.10-1.87]. In a meta-analysis summarizing clinical trials testing aromatase inhibitors used alone or with other medical therapies for ovulation induction in PCOS patients, live birth rates were again significantly higher when letrozole was compared with clomiphene citrate [odds ratio (OR) 1.64, 95% CI 1.32-2.04]. A retrospective analysis of children born to infertile women assessed the congenital malformation rate after exposure to letrozole in comparison to clomiphene citrate and to natural conceptions. No significant differences in malformation rates were detected between the groups (2.9, 2.5 and 3.9%, respectively). SUMMARY: High-level evidence supports letrozole as the first drug of choice for ovulation induction in the PCOS population. The increasing use of letrozole with pregnancy follow-up provides additional reassurance for foetal safety. PMID- 25710391 TI - [Symptomatic os trigonum with irritation of the flexor hallucis longus tendon - arthroscopic management via a dorsal approach]. AB - Therapy-resistant pain in the region of the medial mallelous in the presence of an os trigonum is suggestive for irritation of the flexor hallucis longus tendon. Two patients were treated by arthroscopy in the prone position via a dorsal approach; the os trigonum was removed and the tendon released. Under the conditions of blunt dissection, dorsal arthroscopy of the os trigonum is a safe and expedient operation in our toolbox. After two weeks of partial load-bearing with 2 crutches, pain-free full load-bearing is already possible and after 3 weeks the patients can return to work. PMID- 25710392 TI - [Loosening of a Calcaneo-Stop Screw after Trampolining]. AB - Flexible flatfoot is a common malalignment in the paediatric population. Arthroereisis with a calcaneo-stop screw is an effective surgical procedure for treating juvenile flexible flatfoot after conservative measures have been fully exploited. In the present report, we describe the case of a loosening of a calcaneo-stop screw in a 12-year-old youth after excessive trampolining. PMID- 25710393 TI - [Safety in physical education - a teacher's perspective]. AB - BACKGROUND: A high percentage of all sports injuries occur during school sports. The aim of this study was to collect statements and opinions of sports teachers for safety in physical education. METHODS: In a cross-sectional study, 296 teachers (202 with, 94 without a teaching qualification in "exercise and sports") at 77 Tyrolean "New Middle Schools" (former secondary schools) were interviewed. They judged various statements on school sports safety using a 5-point verbal rating scale. RESULTS: Irrespective of gender, teachers with a teaching qualification stated significantly more frequently (p = 0.015) that they have participated in continuing education on accident prevention than had their colleagues without qualification. The same applies to the checking of gymnastic and sports equipment before use (p < 0.001) and warming up at the beginning of the lesson (p < 0.001). Female sports teachers allowed their pupils more often (p = 0.002) to participate without adequate sportswear in physical education than did their male counterparts. Of all respondents, 57 % knew about technical faults in sports halls, which have also been reported to the school administration. In more than half (58 %) of these, reported defects were repaired completely and in one-third (36 %), a partial repair was reported. Participants estimated that the major risk for school sports injuries was due to the low motor skills of the pupils, inhomogeneous groups, large numbers of pupils, outdated sports equipment, and ball games. CONCLUSION: Since about a third of all surveyed teachers had no teaching qualification in exercise and sports, this group should come into the focus of regular continuing education in accident prevention. PMID- 25710390 TI - Force-induced remodelling of proteins and their complexes. AB - Force can drive conformational changes in proteins, as well as modulate their stability and the affinity of their complexes, allowing a mechanical input to be converted into a biochemical output. These properties have been utilised by nature and force is now recognised to be widely used at the cellular level. The effects of force on the biophysical properties of biological systems can be large and varied. As these effects are only apparent in the presence of force, studies on the same proteins using traditional ensemble biophysical methods can yield apparently conflicting results. Where appropriate, therefore, force measurements should be integrated with other experimental approaches to understand the physiological context of the system under study. PMID- 25710394 TI - [Reliability of Selected Parameters of Cycling Ergospirometry from the PowerCube Ergo Respiratory Gas Analyser]. AB - This study aimed to investigate the reliability of 1) the key parameters of cycling ergospirometry (maximum power output [Pmax] and oxygen uptake [VO2peak], ventilatory thresholds 1 [VT 1] and 2 [VT 2], and cycling efficiency [CE] and gross efficiency [GE]), 2) the commonly used parameters to quantify exhaustion (maximum heart rate [HFmax], respiratory quotient [RQmax], blood lactate concentration [BLAmax], and ratings of perceived exhaustion [RPEmax]), and 3) the kinetics of exercise induced gas exchange measurements (oxygen uptake [VO2], carbon dioxide output [VCO2], and minute ventilation [VE]) using the PowerCube Ergo metabolic system in consideration of international statistical recommendations. 12 women and 12 men (28 +/- 4 years; 23.2 +/- 2.4 kg/m(2)) performed two cycling tests (20 watt/min) separated by one week. The reliability was calculated based on differences in means (t test and effect sizes), retest correlation (intraclass correlation coefficient [ICC]), and within-subject variation (standard error of measurement [SEM]). Of the key parameters of cycling ergospirometry, an excellent reliability (ICC >= 0.969; p = 0.000) and high accuracy (%SEM <= 4.6) were found for Pmax, VO2peak, and VT 1. Of the most commonly used parameters to quantify exhaustion, an excellent reliability (ICC = 0.922; p = 0.000) and high accuracy (%SEM = 1.0) existed only for HFmax. The gas exchange measurements (VO2, VCO2 und VE) of the PowerCube-Ergo were all excellently reliable (ICC >= 0,991; p = 0.000) and the accuracy of VO2 (SEM = 0.10 l/min) and VE (SEM = 3.13 l/min) fulfilled the quality guidance of exercise physiology laboratories. For future studies and practical purposes, the results are vital for the decision as to whether a difference between two tests represents a true intervention effect or just a measurement error and for the estimation of required sample sizes. PMID- 25710395 TI - [The assessment of biological maturation for talent selection - which method can be used?]. AB - BACKGROUND: The biological maturity status plays an important role in sports, since it influences the performance level and the talent selection in various types of sport. More mature athletes are favorably selected for regional and national squads. Therefore, the biological maturity status should be considered during the talent selection process. In this context, the relative age effect (RAE), which exists when the relative age quarter distribution of selected sports groups shows a biased distribution with an over-representation of athletes born in the first months after the specific cut-off-date for the competition categories, represents another problem in the talent development. From an ethical point of view, discrimination of young talented kids does exist: the relatively younger athletes have little to no chance of reaching the elite level, despite their talents and efforts. The causal mechanisms behind the RAE are still unclear and have to be assessed. In this context, the biological maturation seems to be a possible influential factor for the existence of a RAE in sport, which has to be examined. Several methods for estimating the biological maturity status exist; however, they are often expensive and not practicable. Consequently, the aim of the present study was to assess the concordance of a simple, yet accurate method of estimating biological maturation (prediction equation of age at peak height velocity, APHV) of Mirwald and co-workers, and the gold standard method of estimating skeletal age (SA, the x-ray of the left wrist). METHODS: In total, 75 Austrian students (40?, 35?) aged 10 - 13 years, were examined. Thirty of the participants (17?, 13?) were students of a well-known Austrian ski boarding school, and 45 (23?, 22?) of a non-sportive secondary modern school of the same region. The participants included in the study had not experienced a rupture of the carpal bones of the left wrist. Parents and participants were informed of the study aims, requirements and risks before providing written informed consent. The study was performed according to the Declaration of Helsinki. The study was approved by the Board for Ethical Questions in Science (Nr.: 2/2014) and the Institutional Ethics Review Boards for Human Research. For the prediction equations, the body height, the body mass and the sitting height were examined 8. The actual CA at time of measurement, and the leg length as the difference between body height and sitting height were calculated. These parameters were used to predict MO as time before or after PHV for boys and girls using the prediction equations of Mirwald et al. 19. According to Malina and Koziel 8, the participants were classified as late, on time (average) or early maturing on the basis of their APHV relative to the sample mean and standard deviation separated by sex. Participants within plus/minus the standard deviation of the mean were considered on time; participants with APHV > mean + standard deviation were classified late, while those with APHV < mean - standard deviation were classified early. An expert in pediatric endocrinology evaluated the x-rays of the left-hand wrist with the Greulich-Pyle-Method for assessing SA, the most widely used method of determining SA 24. The difference between SA and CA were calculated (= difference SA-CA). Consistent with other studies, the participants were divided into three groups according to their maturity status: on time or average maturity status was a SA within +/-1 year of CA, late maturating was a SA behind CA of more than 1 year, and early maturating was a SA in advance of CA of more than 1 year 5 19 25. The most accurate method used to compare two methods of measurement is the Bland-Altman plot and the 95 % limits of agreement 26 27 28. Bland-Altman plots of the difference between difference in APHV (from the literature mean) and difference SA-CA (y-axis) and the mean of difference in APHV and difference SA-CA (x-axis) were performed. Approximately 95 % of the points in the plot should lie within the limits; then the concordance between the two methods of measurement is given 28. Additionally, intraclass correlation coefficients (ICC(3,1); two-way-mixed, total agreement) were calculated between difference in APHV and difference SA-CA. Chi2-tests were used to assess the difference in the percentage of pupils classified as on time, early or late maturing between the classifications based on the SA and on APHV, respectively. The level of significance was set at p < 0.05 and for highly significant at p < 0.01. All of the calculations were performed using PASW Statistics V.21.0. RESULTS: Chi2-tests did not show any significant differences (p = 0.404) in the percentage of participants classified as on time, early or late maturing between the two classifications based on SA and on APHV, respectively, neither for the total sample, nor for the two groups ski racers and non-athletes. The Bland Altman analysis showed that more than 95 % of the points in the plot lie within the limits; consequently, there is concordance between the two methods with regard to estimating biological maturation. The ICC(3,1) statistics showed a highly significant correlation: p = 0.002, ICC (95 % CI) = 0.48 (0.13 - 0.69). CONCLUSIONS: The prediction equations to determine APHV seem to be a valid method of assessing the biological maturity status of youths aged 10 - 13 years. The percentage of pupils classified as on time, early or late maturing did not differ significantly between the classifications based on the two methods. Also the Bland-Altman analysis proved the concordance between the two methods. The RAE could be influenced and strengthened by the biological age in sports in which advantages in maturity parameters are important. Athletes born early in the selection year, who are also at the same time advanced in maturity, might be advantaged in the selection process. However, since the prediction equations seem to be valid, this method can be used in the future in the talent selection process in order to not disadvantage late-maturing athletes, which in turn could result in the reduction of the occurrence of the RAE in various types of sports in the future. In talent selection processes the growth spurt and the implemented changes in proportions between core and the extremities are often not considered; although it was shown that during this period, athletes showed poor performances in physical fitness. Since physical fitness is an important criterion in talent selection processes, athletes who go through their individual peak growth spurt at the time of selection have disadvantages due to the diverse proportions. As a consequence, it seems important to know the athlete's APHV in order to consider the variations in physical performance caused by developmental changes. The prediction equations to determine APHV include the leg length and sitting height in order to consider the diverse proportions between core and extremities; hence, this method seems to be accurate and should be implemented in the talent selection process. PMID- 25710397 TI - Physician assistants in Taiwan. PMID- 25710398 TI - In Themba's eyes: visualizing clinical associates in South Africa. PMID- 25710399 TI - On physician assistant autonomy. PMID- 25710400 TI - A painful elbow after a fall. PMID- 25710402 TI - An unusual cause of stridor after thoracotomy. AB - Acute airway obstruction after endotracheal intubation is uncommon. Treatment focuses on protecting the patient's airway and preventing long-term complication of tracheal stenosis. This article describes the successful treatment of a patient with acute subglottic stenosis via mechanical debridement of granulation tissue. PMID- 25710403 TI - Hyperkalemia and potential pitfalls of sodium polystyrene sulfonate. AB - Sodium polystyrene sulfonate (SPS), FDA-approved more than 60 years ago for treating hyperkalemia, is an ion exchange resin that works by exchanging sodium for potassium in the colon. Though widely used in clinical practice, SPS use is not supported by well-designed clinical trials. In 2009, the FDA issued a warning that SPS was associated with colonic necrosis and other serious gastrointestinal adverse reactions. This article reviews the pros and cons of SPS therapy. PMID- 25710404 TI - Payment source and provider type in the US healthcare system. AB - Greater use of physician assistants (PAs) and nurse practitioners (NPs) to meet growing demand for healthcare in the United States is an increasingly common strategy to improve access to care and control costs. Evidence suggests that payment for services differs depending on the type of provider. This study sought to determine if the source of payment for a medical visit varies based on whether care is provided by a physician, PA, or NP. Data from the National Hospital Ambulatory Medical Care Survey (2006 through 2010) were analyzed. Physicians were proportionally more likely than NPs or PAs to provide care for medical visits compensated by private insurance or Medicare. Conversely, PAs and NPs were more likely to serve as providers of care for services with other payment sources such as Medicaid and out-of-pocket. PMID- 25710405 TI - Lower extremity peripheral arterial disease. PMID- 25710406 TI - What is causing this girl's abdominal pain? PMID- 25710407 TI - Kindred. PMID- 25710408 TI - Evaluation of carcass composition of intact boars using linear measurements from performance testing, dissection, dual energy X-ray absorptiometry (DXA) and magnetic resonance imaging (MRI). AB - The objective of this study was to investigate non-invasive imaging methods to update the used regression equation for stationary tested boars. A total of 94 boars were examined. 20 boars were dissected to provide the reference LMP. Performance data (PD) from right carcasses were available from all groups. The left carcasses were studied by MRI & DXA. Based on the reference LMP and the MRI & DXA data, regression equations for LMP were developed. The estimates for LMP based on MRI & DXA data were used to calculate new regression equations for entire male carcass halves based on linear PD. Further 33 PD sets served as independent sample, which was included in a Monte Carlo simulation for imputing the missing reference LMPs (n=74) and discussing the accuracy of the results. The LMP regression equation based on the combined MRI & DXA data is as accurate as the former regression equation, but needs only three instead of seven variables. PMID- 25710410 TI - Quantum dot surface chemistry and functionalization for cell targeting and imaging. AB - Quantum dots (QDs) are highly fluorescent nanoscale crystals with size-dependent emission spectra. Due to their excellent photophysical properties, QDs are a promising alternative to organic fluorescent dyes and fluorescent proteins for cell targeting, imaging, and drug delivery. For biomedical applications, QDs should be chemically modified to be stable in aqueous solutions and tagged with the recognition molecules or drugs. Here, we review surface modification approaches to, and strategies for, conjugation of bioactive molecules with QDs. There are a variety of methods of QD surface modification and QD incorporation into larger delivery systems that yield fluorescent nanocarriers from 10 nm to several micrometers. Conjugates of QDs with peptides, proteins, antibodies, oligonucleotides, and small molecules have been used for fluorescent targeting, tracking, and imaging both in vitro and in vivo. Due to an extremely high stability to photobleaching, QDs were used for long-term visualization. QD applications pave the way for new generations of ultrasensitive detection, diagnostic systems, as well as drug delivery approaches, combining accurate targeting, delivery, and imaging in a single assay. PMID- 25710411 TI - Enhancing nurses' participation in implementing evidence-based practice. AB - The article gives an overview of a multidimensional project to enhance nurses' participation in implementing evidence-based practice (EBP) in one university hospital in Finland. The project provided an opportunity for many nurses to be an active part of the EBP process. Moreover, it provided an interesting opportunity to increase all nurses' awareness of EBP. PMID- 25710409 TI - Adenosine Monophosphate-activated Protein Kinase Regulates Interleukin-1beta Expression and Glial Glutamate Transporter Function in Rodents with Neuropathic Pain. AB - BACKGROUND: Neuroinflammation and dysfunctional glial glutamate transporters (GTs) in the spinal dorsal horn are implicated in the genesis of neuropathic pain. The authors determined whether adenosine monophosphate-activated protein kinase (AMPK) in the spinal dorsal horn regulates these processes in rodents with neuropathic pain. METHODS: Hind paw withdrawal responses to radiant heat and mechanical stimuli were used to assess nociceptive behaviors. Spinal markers related to neuroinflammation and glial GTs were determined by Western blotting. AMPK activities were manipulated pharmacologically and genetically. Regulation of glial GTs was determined by measuring protein expression and activities of glial GTs. RESULTS: AMPK activities were reduced in the spinal dorsal horn of rats (n = 5) with thermal hyperalgesia induced by nerve injury, which were accompanied with the activation of astrocytes, increased production of interleukin-1beta and activities of glycogen synthase kinase 3beta, and suppressed protein expression of glial glutamate transporter-1. Thermal hyperalgesia was reversed by spinal activation of AMPK in neuropathic rats (n = 10) and induced by inhibiting spinal AMPK in naive rats (n = 7 to 8). Spinal AMPKalpha knockdown (n = 6) and AMPKalpha1 conditional knockout (n = 6) induced thermal hyperalgesia and mechanical allodynia. These genetic alterations mimicked the changes of molecular markers induced by nerve injury. Pharmacological activation of AMPK enhanced glial GT activity in mice with neuropathic pain (n = 8) and attenuated glial glutamate transporter-1 internalization induced by interleukin-1beta (n = 4). CONCLUSIONS: These findings suggest that enhancing spinal AMPK activities could be an effective approach for the treatment of neuropathic pain. PMID- 25710413 TI - The early evolving sex hormone environment is associated with significant outcome and inflammatory response differences after injury. AB - BACKGROUND: Clinical research characterizing the mechanisms responsible for sex based outcome differences after injury remains conflicting. Currently lacking is an understanding of the early sex hormone milieu of the injured patient and the effects these early hormone differences have on clinical outcomes and the innate immune response following injury. METHODS: A prospective cohort study was performed over a 20-month period. Blunt injury patients requiring intensive care unit admission were enrolled. Samples were collected within 6 hours and at 24 hours after injury and were analyzed for total testosterone (TT) and estradiol concentrations. Outcomes of interest included multiple-organ failure (MOF; Marshall Multiple Organ Dysfunction Score [MODScore] > 5), nosocomial infection (NI), mortality, and serial cytokine/chemokine measurements. Multivariate logistic regression was used to determine the independent risks associated with early sex hormone measurements. RESULTS: In 288 prospectively enrolled patients, 69% were male, with a median Injury Severity Score (ISS) of 16 (interquartile range 10-21). Elevated TT levels at 6 hours were associated with elevated interleukin 6 levels and cytokine/chemokine measurements (18 of 24 measured). Rising TT levels were significantly associated with more than a fivefold and twofold higher independent risk of MOF and NI, respectively (odds ratio [OR], 5.2; p = 0.02; 95% confidence interval [CI], 1.2-22.3; and OR, 2.1; p = 0.03; 95% CI, 1.02-4.2). At 24 hours, TT levels were no longer associated with poor outcome, while estradiol levels were significantly associated with nearly a fourfold higher independent risk of MOF (OR, 3.9; p = 0.04, 95% CI, 1.05-13). CONCLUSION: Early elevations and increasing testosterone levels over initial 24 hours after injury are associated with an exaggerated inflammatory response and a significantly greater risk of MOF and NI. High estrogen levels at 24 hours are independently associated with an increased risk of MOF. The current analysis suggests that an early evolving testosterone to estrogen hormonal environment is associated with a significantly higher independent risk of poor outcome following traumatic injury. LEVEL OF EVIDENCE: Prognostic/epidemiologic study, level II. PMID- 25710412 TI - Pregnancy is associated with elevation of liver enzymes in HIV-positive women on antiretroviral therapy. AB - OBJECTIVE: The objective of this study is to assess whether pregnancy is associated with an increased risk of liver enzyme elevation (LEE) and severe LEE in HIV-positive women on antiretroviral therapy (ART). DESIGN: Two observational studies: the UK Collaborative HIV Cohort (UK CHIC) study and the UK and Ireland National Study of HIV in Pregnancy and Childhood (NSHPC). METHODS: Combined data from UK CHIC and NSHPC were used to identify factors associated with LEE (grade 1 4) and severe LEE (grade 3-4). Women starting ART in 2000-2012 were included irrespective of pregnancy status. Cox proportional hazards were used to assess fixed and time-dependent covariates including pregnancy status, CD4 cell count, drug regimen and hepatitis B virus/hepatitis C virus (HBV/HCV) coinfection. RESULTS: One-quarter (25.7%, 982/3815) of women were pregnant during follow-up, 14.2% (n = 541) when starting ART. The rate of LEE was 14.5/100 person-years in and 6.0/100 person-years outside of pregnancy. The rate of severe LEE was 3.9/100 person-years in and 0.6/100 person-years outside of pregnancy. The risk of LEE and severe LEE was increased during pregnancy [LEE: adjusted hazard ratio (aHR) 1.66 (1.31-2.09); severe LEE: aHR 3.57 (2.30-5.54)], including in secondary analyses excluding 541 women pregnant when starting ART. Other factors associated with LEE and severe LEE included lower CD4 cell count (<250 cells/MUl), HBV/HCV coinfection and calendar year. CONCLUSION: Although few women developed severe LEE, this study provides further evidence that pregnancy is associated with an increased risk of LEE and severe LEE, reinforcing the need for regular monitoring of liver biomarkers during pregnancy. PMID- 25710414 TI - Prospective derivation of a clinical decision rule for thoracolumbar spine evaluation after blunt trauma: An American Association for the Surgery of Trauma Multi-Institutional Trials Group Study. AB - BACKGROUND: Unlike the cervical spine (C-spine), where National Emergency X Radiography Utilization Study (NEXUS) and the Canadian C-spine Rules can be used, evidence-based thoracolumbar spine (TL-spine) clearance guidelines do not exist. The aim of this study was to develop a clinical decision rule for evaluating the TL-spine after injury. METHODS: Adult (>=15 years) blunt trauma patients were prospectively enrolled at 13 US trauma centers (January 2012 to January 2014). Exclusion criteria included the following: C-spine injury with neurologic deficit, preexisting paraplegia/tetraplegia, and unevaluable examination. Remaining evaluable patients underwent TL-spine imaging and were followed up to discharge. The primary end point was a clinically significant TL-spine injury requiring TL-spine orthoses or surgical stabilization. Regression techniques were used to develop a clinical decision rule. Decision rule performance in identifying clinically significant fractures was tested. RESULTS: Of 12,479 patients screened, 3,065 (24.6%) met inclusion criteria (mean [SD] age, 43.5 [19.8] years [range, 15-103 years]; male sex, 66.3%; mean [SD] Injury Severity Score [ISS], 8.8 [7.5]). The majority underwent computed tomography (93.3%), 6.3% only plain films, and 0.2% magnetic resonance imaging exclusively. TL-spine injury was identified in 499 patients (16.3%), of which 264 (8.6%) were clinically significant (29.2% surgery, 70.8% TL-spine orthosis). The majority was AO Type A1 282 (56.5%), followed by 67 (13.4%) A3, 43 (8.6%) B2, and 32 (6.4%) A4 injuries. The predictive ability of clinical examination (pain, midline tenderness, deformity, neurologic deficit), age, and mechanism was examined; positive clinical examination finding resulted in a sensitivity of 78.4% and a specificity of 72.9%. Addition of age of 60 years or older and high-risk mechanism (fall, crush, motor vehicle crash with ejection/rollover, unenclosed vehicle crash, auto vs. pedestrian) increased sensitivity to 98.9% with specificity of 29.0% for clinically significant injuries and 100.0% sensitivity and 27.3% specificity for injuries requiring surgery. CONCLUSION: Clinical examination alone is insufficient for determining the need for imaging in evaluable patients at risk of TL-spine injury. Addition of age and high-risk mechanism results in a clinical decision-making rule with a sensitivity of 98.9% for clinically significant injuries. LEVEL OF EVIDENCE: Diagnostic test, level III. PMID- 25710415 TI - Adherence to an established diagnostic threshold for ventilator-associated pneumonia contributes to low false-negative rates in trauma patients. AB - BACKGROUND: The diagnosis of ventilator-associated pneumonia (VAP) in our institution has followed an established diagnostic threshold (DT) of equal to or greater than 10 colony-forming units (CFU) per milliliter on bronchoalveolar lavage (BAL) based on our previous study (PS). Because mortality from VAP is related to treatment delay, some have advocated a lower DT. The purpose of the current study (CS) was to evaluate the impact of adherence to this DT for VAP on false-negative (FN) rates and mortality in trauma patients. METHODS: Consecutive patients over 9 years with VAP (defined as >=10 CFU/mL in the BAL effluent) subsequent to the PS were identified. Data regarding each BAL performed and the colony counts of each organism identified were recorded. An FN BAL result was defined as any patient who had less than 10 CFU/mL and developed VAP with the same organism up to 7 days after the previous culture. The CS was then compared with the PS. RESULTS: Over 9 years, 1,679 patients underwent 3,202 BALs. Of these, 79% were male, 88% experienced blunt injury, mean age and Injury Severity Score (ISS) were 44 years and 31, respectively. Overall, there were 73 FN BAL results (2.3%) in the CS compared with 3% in the PS (p = 0.092). In those patients with 10 organisms, the FN rate was reduced (7.5% vs. 11%, p = 0.045), and mortality was unchanged (5.4% vs. 8.3%, p = 0.361) in the CS compared with the PS. The use of the threshold equal to or greater than 10 resulted in a cumulative reduction in antibiotic charges of $1.57 million. CONCLUSION: Continued adherence to the diagnostic threshold of equal to or greater than 10 for quantitative BAL in trauma patients has maintained a low incidence of FN BALs and reduced patient charges without impacting mortality. The purported benefit of a lower threshold is not supported. In addition, the potential sequelae of increased resistant organisms, antibiotic-related complications, and costs associated with prolonged unnecessary antibiotic exposure are minimized. LEVEL OF EVIDENCE: Prognostic study, level III. PMID- 25710416 TI - Can we ever stop worrying about venous thromboembolism after trauma? AB - BACKGROUND: Trauma patients are known to be at increased risk for venous thromboembolism (VTE); this risk may change over time following injury. Determining the period in which patients are at increased risk of developing VTE may have an impact on prophylaxis, cost, and quality of care. METHODS: The California Office of Statewide Health Planning and Development hospital discharge database was searched between 1995 and 2010 for patients admitted with traumatic pelvic fractures, vertebral fractures, and spinal cord injuries. Those patients were then searched for VTE any time after injury. Cox proportional hazards analyses were used to assess the timing and risk of VTE events after injury. RESULTS: A total of 267,743 trauma patients met the injury criteria; of those, 10,633 or 3.97% developed VTE. The occurrence of VTE was a significant predictor of mortality (hazard ratio [HR], 1.18; p < 0.001). Compared with patients with pelvic fractures, patients with vertebral fractures were less likely to develop VTE (HR, 0.85; p = 0.002). However, patients with spinal cord injury were more likely to develop VTE (HR, 3.17; p < 0.001); this remained true when in combination with a pelvic fracture (HR, 2.17; p = 0.001). Patients with cervical or thoracic spinal cord injuries were significantly more likely to develop VTE (HR of 1.49 [p = 0.037] and 1.87 [p = 0.001], respectively), compared with those with lumbar injury.In the first 3 months after injury, the incidence of VTE is 10.3%. This rate dropped to 0.5% by 6 months after injury, subsequently falling to 0.2% at 1 year and 0.14% at 18 months and remaining low at 0.12% at 2 years. CONCLUSION: The highest risk of VTE is during the first 3 months after injury; between 12 months and 15 months, the rate returns to that of the general population at 0.1% to 0.2%. These results may guide management strategies such as duration of VTE prophylaxis and removal of inferior vena cava filters, which may have an impact on quality of care. LEVEL OF EVIDENCE: Epidemiologic study, level IV. PMID- 25710417 TI - National estimates of predictors of outcomes for emergency general surgery. AB - BACKGROUND: Identifying predictors of mortality and surgical complications has led to outcome improvements for a variety of surgical conditions. However, similar work has yet to be done for factors affecting outcomes of emergency general surgery (EGS). The objective of this study was to determine the predictors of in-hospital complications and mortality among EGS patients. METHODS: The Nationwide Inpatient Sample (2003-2011) was queried for patients with conditions encompassing EGS as determined by the American Association for Surgery of Trauma, categorizing them into predefined EGS groups using DRG International Classification of Diseases-9th Rev.-Clinical Modification codes. Primary outcomes considered included incidence of a major complication (pneumonia, pulmonary emboli, urinary tract infections, myocardial infarctions, sepsis, or septic shock) and in-hospital mortality. Separate multivariate logistic regression analyses for complications and mortality were performed to identify risk factors of either outcome from the following domains: patient demographics (age, sex, insurance type, race, and income quartile), comorbidities, and hospital characteristics (location, teaching status, and bed size). RESULTS: This study included 6,712,151 discharge records, weighted to represent 32,910,446 visits for EGS conditions. Mean age was 58.50 (19.74) years; slightly more than half (54.66%) were female. Uninsured patients were more likely to die (odds ratio,1.25; 95% confidence interval, 1.20-1.30), whereas patients in the highest income quartile had the least likelihood of mortality (odds ratio, 0.86; 95% confidence interval, 0.84-0.87). Old age was an independent predictor of mortality for all EGS subdiagnoses. The overall mortality rate was 1.76%; the overall complication rate was 10.03%. Of the patients who died, 62% experienced at least one major complication. Patients requiring resuscitation had the highest likelihood of mortality followed by patients with vascular disease and hepatic disease. CONCLUSION: Death patterns of EGS patients were discerned using an administrative data set. Understanding patterns of mortality and complications derived from studies such as this could improve hospital benchmarking for EGS, akin to trauma surgery's previous success. LEVEL OF EVIDENCE: Prognostic and epidemiologic study, level III. PMID- 25710418 TI - Intracranial pressure monitoring and inpatient mortality in severe traumatic brain injury: A propensity score-matched analysis. AB - BACKGROUND: Although intracranial pressure (ICP) monitoring in severe traumatic brain injury (TBI) is recommended by the Brain Trauma Foundation, the benefits remain controversial. We sought to determine the impact of ICP monitor placement on inpatient mortality within a regional trauma system after correcting for selection bias through propensity score matching. METHODS: Data were collected on all severe TBI cases presenting to 14 trauma centers during the 2-year study period (2009-2010). Inclusion criteria were as follows: blunt injury, Glasgow Coma Scale (GCS) score of 8 or lower in the emergency department, and abnormal intracranial findings on head computed tomography (CT). Two separate multivariate logistic regression models were used to predict ICP monitor placement and inpatient mortality after controlling for demographics, severity of injury, comorbidities, and TBI-specific variables (GCS score, pupil reactivity, international normalized ratio, and nine specific head CT findings). To account for selection bias, we developed a propensity score-matched model to estimate the "true" effect of ICP monitoring on in-hospital mortality. RESULT: A total of 844 patients met inclusion criteria; 22 died on arrival to the emergency department. Inpatient mortality was 38.8%; 46.0% of the patients underwent ICP monitor placement. Unadjusted mortality rates were significantly lower in the ICP monitoring group (30.7% vs. 45.7%, p < 0.001). ICP monitor placement was positively associated with CT findings of subdural hematoma, intraparenchymal contusion, and mass effect and negatively associated with age, alcoholism, and elevated international normalized ratio. After adjusting for selection bias via propensity score matching, ICP monitor placement was associated with an 8.3 percentage point reduction in the risk-adjusted mortality rate. CONCLUSION: ICP monitor placement occurred in only 46% of eligible patients but was associated with significantly decreased mortality after adjusting for baseline risk profile and the propensity to undergo monitoring. As the individual impact of ICP monitoring may vary, future efforts must determine who stands to benefit from invasive monitoring techniques. LEVEL OF EVIDENCE: Therapeutic/care management study, level III. PMID- 25710419 TI - Same-day combined endoscopic retrograde cholangiopancreatography and cholecystectomy: Achievable and minimizes costs. AB - BACKGROUND: It is estimated that choledocholithiasis is present in 5% to 20% of patients at the time of laparoscopic cholecystectomy (LC). Several European studies have found decreased length of stay (LOS) when performing LC and intraoperative endoscopic retrograde cholangiopancreatography (ERCP) on the same day for choledocholithiasis. In the United States, common bile duct stones are usually managed preoperatively and typically on a day separate from the day LC was performed. Our aim was to evaluate LOS and total hospital cost for separate day versus same-day ERCP/cholecystectomy. METHODS: This was a retrospective study of patients undergoing ERCP and cholecystectomy during the same admission for the management of choledocholithiasis from 2010 to 2014 at Geisinger Medical Center. The separate-day group underwent ERCP at least 1 day before cholecystectomy and often underwent two separate anesthesia events, while the same-day group had ERCP and cholecystectomy performed on the same day under one general anesthesia event. The primary outcome measured was LOS. RESULTS: The study population included 240 patients. There were 175 patients in the separate-day group and 65 patients in the same-day group. Median age was similar between the two groups. The separate day group had a median of one minor comorbidity compared with zero within the same-day group using the Charlson Comorbidity Index. Overall, LOS for the separate-day group was 5 days compared with 3 days in the same-day group (p < 0.0001). There was no difference in conversion rates to open cholecystectomy between the two groups (14% in the separate-day vs. 12% in the same-day group). Total median hospital cost for the separate-day group was $102,537 compared with $90,269 in the same-day group (p < 0.0001). CONCLUSION: Same-day ERCP and cholecystectomy is feasible and minimizes costs. Same-day procedures decreased hospital LOS by 2 days and had approximately $12,000 in cost savings. Future goals include a multidisciplinary protocol to study outcomes in larger numbers. LEVEL OF EVIDENCE: Therapeutic study, level IV. Economic study, level III. PMID- 25710420 TI - Overuse of helicopter transport in the minimally injured: A health care system problem that should be corrected. AB - BACKGROUND: Mortality benefit has been demonstrated for trauma patients transported via helicopter but at great cost. This study identified patients who did not benefit from helicopter transport to our facility and demonstrates potential cost savings when transported instead by ground. METHODS: We performed a 6-year (2007-2013) retrospective analysis of all trauma patients presenting to our center. Patients with a known mode of transfer were included in the study. Patients with missing data and those who were dead on arrival were excluded from the study. Patients were then dichotomized into helicopter transfer and ground transfer groups. A subanalysis was performed between minimally injured patients (ISS < 5) in both the groups after propensity score matching for demographics, injury severity parameters, and admission vital parameters. Groups were then compared for hospital and emergency department length of stay, early discharge, and mortality. RESULTS: Of 5,202 transferred patients, 18.9% (981) were transferred via helicopter and 76.7% (3,992) were transferred via ground transport. Helicopter-transferred patients had longer hospital (p = 0.001) and intensive care unit (p = 0.001) stays. There was no difference in mortality between the groups (p = 0.6).On subanalysis of minimally injured patients there was no difference in hospital length of stay (p = 0.1) and early discharge (p = 0.6) between the helicopter transfer and ground transfer group. Average helicopter transfer cost at our center was $18,000, totaling $4,860,000 for 270 minimally injured helicopter-transferred patients. CONCLUSION: Nearly one third of patients transported by helicopter were minimally injured. Policies to identify patients who do not benefit from helicopter transport should be developed. Significant reduction in transport cost can be made by judicious selection of patients. Education to physicians calling for transport and identification of alternate means of transportation would be both safe and financially beneficial to our system. LEVEL OF EVIDENCE: Epidemiologic study, level III. Therapeutic study, level IV. PMID- 25710421 TI - Evolving beyond the vicious triad: Differential mediation of traumatic coagulopathy by injury, shock, and resuscitation. AB - BACKGROUND: A subset of trauma patients with critical injury present with coagulopathy, portending markedly worse outcomes. Clinical practice is evolving to treat the classical risk factors of hypothermia, hemodilution, and acidosis; however, coagulopathy persists even in the absence of these factors. We sought to determine the relative importance of injury- and shock-specific factors compared with resuscitation-associated factors in coagulopathy after trauma. METHODS: Comprehensive demographic data, laboratory data, and outcomes data were prospectively collected from seven trauma centers over 8 years (November 2003 to August 2011) as part of the Inflammation and the Host Response to Injury Large Scale Collaborative Program. A total of 1,537 critically injured patients with blunt trauma and hemorrhagic shock were analyzed to evaluate predictors of admission coagulopathy (international normalized ratio [INR] >= 1.3), multiorgan failure, and mortality. RESULTS: Of 1,537 patients, 578 (37.6%) had admission INR of 1.3 or greater. Coagulopathic patients had more severe injury, more severe base deficit and lactate levels, as well as lower admission temperature, lower pH, and higher prehospital crystalloid volume (all p < 0.001). Coagulopathic patients required more blood products and mechanical ventilation and had higher rates of nosocomial infection, multiorgan failure, and mortality (all p < 0.02). Injury severity, temperature, and acidosis (all p < 0.02) independently predicted coagulopathy in multivariate analysis, with a significant interaction between lactate and prehospital crystalloid. In Cox regression models, however, coagulopathy itself remained an independent predictor of both multiorgan failure and mortality (p < 0.02) even when adjusted for injury severity, shock, and elements of the vicious triad. CONCLUSION: Most patients with coagulopathy after trauma have mixed risk factors; however, coagulopathy has deleterious effects independent of injury severity, shock, and the vicious triad. Better understanding of the biochemical mechanisms of acute traumatic coagulopathy may facilitate biochemically targeted resuscitation strategies and improve outcomes. LEVEL OF EVIDENCE: Prognostic and epidemiologic study, level II. PMID- 25710422 TI - Use of pelvic hemostasis belt to control lethal pelvic arterial hemorrhage in a swine model. AB - BACKGROUND: Hemorrhage is the leading cause of death for both civilian and battlefield injuries. Hemorrhage from pelvic vascular wounds is of concern since it is difficult to control before surgical intervention. This has resulted in renewed interest in developing presurgical endovascular approaches to hemorrhage control. However, it is likely that other short-term techniques may be needed as a bridge to such approaches. We tested a prototype device called the pelvic hemostasis belt (PHB) for its ability to reduce or halt blood flow in a lethal model of pelvic arterial injury. METHODS: Seventeen male swine, 42 (5.2)kg were anesthetized, instrumented, and then randomized into three groups (control, military antishock trousers [MAST], and PHB). Animals underwent laparotomy with placement of a 4-0 stainless steel monofilament suture through the right iliac artery. The laparotomy was closed, and the iliac suture was exteriorized. Hemorrhage was produced by pulling the suture through the iliac artery. In both PHB and MAST groups, the devices were applied over the pelvis and lower abdomen for 60 minutes, followed by release and monitoring for 30 minutes or until the animal expired. Hetastarch (500 mL) was infused immediately after commencement of hemorrhage. RESULTS: All PHB group animals and only two from the MAST group survived for 60 minutes. Mean (SD) survival time for the control group was 13 (12.3) minutes. Log-rank (Mantel-Cox) survival analysis demonstrated a significant difference in survival time when comparing all groups (p < 0.0001) as well as when comparing PHB and MAST groups (p = 0.018). Significant differences were noted between groups in mean arterial pressure, lactate, and central venous hemoglobin oxygen saturation levels. CONCLUSION: The PHB was successful in improving survival for 60 minutes after a lethal vascular injury. Such a device may be helpful to bridge endovascular methods of hemorrhage control. PMID- 25710423 TI - Utility of three-dimensional computed tomography for the surgical management of rib fractures. AB - BACKGROUND: Surgical stabilization of flail chest is increasingly recognized as a valid approach to improve pulmonary mechanics in selected trauma patients. The use of two-dimensional (2D) computed tomography (CT) has become almost universal in the assessment of blunt chest trauma and multiple rib fractures. We hypothesized that three-dimensional (3D) CT adds valuable information to the preoperative plan for fixation of rib fractures. METHODS: Using a retrospective cohort of 35 consecutive adult patients with flail chest requiring surgery, we evaluated the intraobserver and interobserver reliability of plain radiographs, 2D CT and 3D CT, for the identification of rib fractures and identified how often the surgical plan changed with the addition of the information provided by the 3D CT. Two fellowship-trained orthopedic trauma surgeons who regularly operate on rib fractures in their clinical practice and were not involved in the treatment of the study population evaluated the radiographic data. RESULTS: Intraobserver and interobserver reliability was excellent for both 2D CT and 3D CT and was the highest for 2D CT. Overall, 2D CT had the highest diagnostic accuracy for detecting rib fractures as compared with plain radiographs and 3D CT. However, 3D CT changed the surgical tactic in 65.7% of the cases. CONCLUSION: We conclude that 3D CT is not as accurate as 2D CT for rib fracture diagnostic purposes; it seems to be an important tool for the preoperative planning of rib fracture fixation. LEVEL OF EVIDENCE: Diagnostic study, level II. PMID- 25710424 TI - Changes in gene expression following trauma are related to the age of transfused packed red blood cells. AB - BACKGROUND: Transfusion of packed red blood cells (PRBCs) is associated with an increased incidence of nosocomial infections and an increased risk of death. The duration of storage before transfusion may influence these outcomes. Here, we explore the association between the age of transfused PRBCs and specific patterns of inflammatory gene expression in severely injured trauma patients. METHODS: Severely injured trauma patients requiring intensive care unit treatment and receiving transfusion of PRBCs within 24 hours of the injury were recruited. Blood samples were obtained within 2 hours of the trauma, at 24 hours, and at 72 hours. Messenger RNA was extracted from whole blood, and gene expression was quantified using quantitative polymerase chain reaction. The median age of the units of PRBCs transfused to each patient was recorded. The primary outcome measure was the change in candidate gene expression over the initial 72 hours. RESULTS: Sixty-four patients were studied. Fifty-three patients (83%) were male, and the median age was 40.5 years (interquartile range [IQR], 31-59). Median Injury Severity Score (ISS) was 31.5 (IQR, 23-43), and 55 patients (86%) experienced a blunt injury. Forty-one patients (64%) developed a nosocomial infection, and 15 patients (23%) died before hospital discharge. Each patient received a median of 5 U of PRBCs (IQR, 4-9.8 U) during the first 24 hours of hospital admission. The median age of the units of PRBCs transfused in each patient was 20 days (IQR, 17-22 days). Older blood was associated with greater decreases in interleukin 12 (IL-12), IL-23, and RORgammat (all p's < 0.05) gene expression over the initial 24 hours, greater decreases in IL-12 gene expression over 72 hours, and a rise in transforming growth factor beta gene expression over the first 72 hours. A multivariate analysis confirmed the independence of these associations. CONCLUSION: Increasing the duration of storage of PRBCs before transfusion is associated with a pattern of gene expression consistent with more severe immunosuppression. LEVEL OF EVIDENCE: Epidemiologic study, level III. PMID- 25710425 TI - Staging of acute diverticulitis based on clinical, radiologic, and physiologic parameters. AB - BACKGROUND: Acute diverticulitis is a broad spectrum of diseases with highly varying mortality and need for surgery. The aim of this study was to create an accurate staging of diverticulitis, which could be used both preoperatively and intraoperatively to predict outcome and guide treatment. METHODS: This was a retrospective study of patients treated for diverticulitis in a secondary and tertiary referral center. Multivariate analysis was performed on several clinical, radiologic, and physiologic parameters to find predictors of mortality, need for surgery, need for intensive care, and length of stay. RESULTS: A total of 631 patients were analyzed. Organ dysfunction, peritonitis, and abscess size greater than 6 cm were identified as independent predictors of poor outcome. Pericolic air or no extraluminal air predicted better outcome. Based on these factors, a five-grade staging was created as follows: Stage 1, uncomplicated diverticulitis; Stage 2, complicated diverticulitis with small abscess (<6 cm); Stage 3, complicated diverticulitis with large abscess (>=6 cm) or distant intraperitoneal or retroperitoneal air; Stage 4, Generalized peritonitis without organ dysfunction; Stage 5, generalized peritonitis with organ dysfunction. Mortality was 0, 1%, 3%, 4%, and 32%; need for surgery was 1%, 5%, 46%, 98%, and 100%; and need for intensive care was 0%, 0%, 8%, 11%, and 50%, in Stages 1 to 5, respectively. New staging showed better predictive ability of outcomes compared with earlier classifications in receiver operating characteristic curve analyses. CONCLUSION: The proposed staging can be used on all patients both preoperatively and intraoperatively. It takes into account organ dysfunction, which has major influence on survival. The new staging may be easily implemented in daily clinical practice and incorporated in clinical trials. LEVEL OF EVIDENCE: Diagnostic study, level II. PMID- 25710426 TI - Fat embolism sensitizes rats to a "second hit" with lipopolysaccharide: An animal model of pulmonary fibrosis. AB - BACKGROUND: Pulmonary fat embolism (FE) in patients after major bone fracture and other trauma may lead to acute respiratory distress, but few clinical evidence of lung injury remains, and there is a dearth of histopathologic information after the initial recovery. We recently reported histologic changes in the lungs of a patient who died after cesarian delivery, which were similar to a rat model of FE. In this model, we found that despite an apparent full recovery, modest fibrotic damage persisted up to 6 weeks. We tested whether at that time, an additional insult could exacerbate the effects. METHODS: Triolein (0.2 mL intravenously administered) was given to 18 rats and saline to 18 controls. Six weeks later, each group received (intraperitoneal) lipopolysaccharide (LPS, 3 mg/kg; n = 9) or saline (n = 9). At necropsy 48 hours later, lungs and organs were harvested for study. Lung parenchymal, vascular, and bronchial damage was scored by two pathologists and by Image J analysis. RESULTS: Animals given LPS after triolein showed reduced pulmonary arterial medial diameters compared with those that received LPS alone (p < 0.04). Lung small arterial patency (lumen) was reduced after triolein and even more after combined LPS and triolein (p = 0.018). Triolein increased fibrotic markers (trichrome and smooth muscle actin staining), and this was more severe after LPS. At 6 weeks, fat droplets remained in the lungs, localizing to the subpleural septa. These were smaller and more widespread after LPS. CONCLUSION: This report describes an animal model to study exacerbation of lung histopathology induced by FE using a known pulmonary toxicant, LPS (a "second hit"). Vascular and fibrotic lung damage was more severe when LPS was given to rats 6 weeks after triolein compared with LPS alone. FE rendered the lungs extra sensitive to a second hit long after apparent clinical recovery. This experimental model of fat embolism provides useful informations for the treatment of patients suffering for similar conditions. PMID- 25710427 TI - Ultrastructural lung pathology following brain injury combined with femur shaft fracture in a rat model. AB - BACKGROUND: This study aimed to explore the early pathologic changes in the lung ultrastructure in rat models of isolated or multiple traumatic injuries. METHODS: Ninety-six rats were divided into a control group, a unilateral femur fracture group, a brain injury group, and a unilateral femur fracture combined with brain injury group. At 1, 6, 12, and 24 hours following model creation, the rat lungs were isolated and examined under a transmission electron microscope. A lung injury scoring model was used to evaluate the ultrastructural changes in the organelles of Type II alveolar epithelial cells (AEC-II). The ultrastructural changes and lung injury scores were compared among the four groups. RESULTS: Mild ultrastructural damage was seen in the single-trauma groups. In the unilateral femur fracture group, the organelle morphology alleviated within 24 hours. The brain injury group showed more obvious ultrastructural changes, and some organelles were irreversibly damaged. This ultrastructural damage to the AEC-II was significantly augmented in the combined injury group; in this group, the damage was most obvious, occurred the earliest, involved the widest area, continued to progress throughout the study, and apparently worsened in 24 hours. The lung injury scores increased at all the time points in the three experimental groups compared with the control group and were significantly higher in the combined injury group than in the other groups. CONCLUSION: Ultrastructural AEC II damage was significantly augmented in the combined injury model compared with the single-injury models. The pulmonary condition should be considered when treating this type of injury. PMID- 25710428 TI - Smoke inhalation injury repaired by a bone marrow-derived mesenchymal stem cell paracrine mechanism: Angiogenesis involving the Notch signaling pathway. AB - BACKGROUND: Smoke inhalation injury is an acute lung injury induced by smoke exposure characterized by vascular endothelial injury and increased permeability. Cell therapy is an attractive new therapeutic approach, although its underlying mechanism and signaling pathway remain poorly understood. We investigated the effect of systemic transplantation of preconditioned bone marrow-derived mesenchymal stem cells (BMSCs) on angiogenesis in rat model of smoke inhalation injury and explored the underlying mechanism and possible signaling pathway. METHODS: After the establishment of a smoke inhalation injury rat model, the animals were further randomized into subgroups that received either a tail vein injection of 2 * 10(6) preconditioned or nonpreconditioned BMSCs in 5-mL phosphate-buffered saline to explore the characteristics of preconditioned BMSCs, pulmonary microvessel quantities in smoke inhalation injury, and its Notch1 expression. RESULTS: BMSCs preconditioned by 60Co gamma-ray radiation at an appropriate dose were inhibited differentiation potential in vitro without significantly affecting the paracrine activity, the ability of cell proliferation, viability, and homing. Systemic preconditioned BMSC transplantation significantly increased the quantities of microvessels in rat with smoke inhalation injury, improved the lung wet-dry weight ratio, and alleviated lung injury simply through paracrine activity. Immunofluorescence staining and Western blot analysis confirmed that the expression level of Notch microvessel and Notch1 protein increased significantly after systemic transplantation. CONCLUSION: Our findings indicate that systemic transplantation of preconditioned BMSCs promotes angiogenesis through paracrine activity after smoke inhalation injury and that the Notch signaling pathway is involved in the angiogenesis process. PMID- 25710430 TI - Risk of pulmonary embolism with repair or ligation of major venous injury following penetrating trauma. AB - BACKGROUND: There are many benefits of repair over ligation of major venous injuries (MVIs) following penetrating trauma, but the risk of pulmonary embolism (PE) is not well defined. We hypothesized that rates of PE are comparable between repair and ligation of MVI. METHODS: All penetrating trauma patients with MVI requiring an operation from 2003 to 2012 (n = 158) were retrospectively reviewed. Propensity scores were based on a logistic regression model using patient and injury characteristics. A 1:1 fixed ratio nearest neighbor matching was performed to compare outcomes of the repair and ligation cohorts. Data are reported as mean +/- SD if parametric, or median (interquartile range) if not, and compared using a t test, Mann-Whitney U-test, chi2, or Fisher's exact test, as appropriate. RESULTS: The population was 89% male, age 32 +/- 12 years, 74% gunshot wound, Injury Severity Score of 19 +/- 13, length of stay of 9 (18) days, 3.8% PE, and a mortality of 21.5%. Repair was performed in 37% (n = 59), ligation was performed in 60% (n = 94), and 3% required both. With ligation versus repair, ligation patients were generally more critically injured; 48-hour survival was 78% versus 93% (p = 0.0083), initial Glasgow Coma Scale (GCS) score was 12 +/- 5 versus 14 +/- 3 (p = 0.003), initial base excess was -9 +/- 8 versus -5 +/- 5 mEq/L (p = 0.003), more packed red blood cells were transfused (12 (14) U vs. 9 (12) U; p = 0.032), and major arterial injury was more likely (86% vs. 42%, p < 0.001), but the PE rate was identical (5.9%) in propensity-matched cohorts. In those who developed a PE, all were receiving standard thromboprophylaxis. CONCLUSION: Following penetrating trauma, the risk of PE between repair and ligation of MVI is comparable. LEVEL OF EVIDENCE: Epidemiologic study, level III. PMID- 25710429 TI - MitoQ modulates oxidative stress and decreases inflammation following hemorrhage. AB - BACKGROUND: Oxidative stress associated with hemorrhagic shock and reperfusion (HSR) results in the production of superoxide radicals and other reactive oxygen species, leading to cell damage and multiple-organ dysfunction. We sought to determine if MitoQ, a mitochondria-targeted antioxidant, reduces morbidity in a rat model of HSR by limiting oxidative stress. METHODS: HSR was achieved in male rats by arterial blood withdrawal to a mean arterial pressure of 25 +/- 2 mm Hg for 1 hour before resuscitation. MitoQ (5 mg/kg), TPP (triphenylphosphonium, 5 mg/kg) or saline (0.9% vol./vol.) was administered intravenously 30 minutes before resuscitation, followed by an intraperitoneal administration (MitoQ, 20 mg/kg) immediately after resuscitation (n = 5 per group). Morbidity was assessed based on cumulative markers of animal distress (0-10 scale). Rats were sacrificed 2 hours after procedure completion, and liver tissue was collected and processed for histology or assayed for lipid peroxidation (thiobarbituric acid reactive substance [TBARS]) or endogenous antioxidant (catalase, glutathione peroxidase [GPx], and superoxide dismutase) activity. RESULTS: HSR significantly increased morbidity as well as TBARS and catalase activities versus sham. Conversely, no difference in GPx or superoxide dismutase activity was measured between sham, HSR, and TPP, MitoQ administration reduced morbidity versus HSR (5.8 +/- 0.3 vs. 7.6 +/- 0.3; p < 0.05), while TPP administration significantly reduced hepatic necrosis versus both HSR and HSR-MitoQ (1.2 +/- 0.1 vs. 2.0 +/- 0.2 vs. 1.9 +/- 0.2; p < 0.05, n = 5). Analysis of oxidative stress demonstrated increased TBARS and GPx in HSR-MitoQ versus sham (12.0 +/- 1.1 MUM vs. 6.2 +/- 0.5 MUM and 37.9 +/- 3.0 MUmol/min/mL vs. 22.9 +/- 2.7 MUmol/min/mL, TBARS and GPx, respectively, n = 5; p < 0.05). Conversely, catalase activity in HSR-MitoQ was reduced versus HSR (1.96 +/- 1.17 mol/min/mL vs. 2.58 +/- 1.81 mol/min/mL; n = 5; p < 0.05). Finally, MitoQ treatment decreased tumor necrosis factor alpha (0.66 +/- 0.07 pg/mL vs. 0.92 +/- 0.08 pg/mL) and interleukin 6 (7.3 +/- 0.8 pg/mL vs. 11 +/- 0.9 pg/mL) versus HSR as did TPP alone (0.58 +/- 0.05 pg/mL vs. 0.92 +/- 0.08 pg/mL; 6.7 +/- 0.6 pg/mL vs. 11 +/- 0.9 pg/mL; n = 5; p < 0.05). CONCLUSION: Our data demonstrate that MitoQ treatment following hemorrhage significantly limits morbidity and decreases hepatic tumor necrosis factor alpha and interleukin 6. In addition, MitoQ differentially modulates oxidative stress and hepatic antioxidant activity. PMID- 25710431 TI - Complete major amputation of the upper extremity: Early results and initial treatment algorithm. AB - BACKGROUND: Traumatic major amputations of the upper extremity are devastating injuries. These injuries have a profound impact on patient's quality of life and pose a burden on social economy. The aims of the current study were to report about the initial management of isolated traumatic major upper limb amputation from the time of admission to definitive soft tissue closure and to establish a distinct initial management algorithm. METHODS: We recorded data concerning the initial management of the patient and the amputated body part in the emergency department (ED) (time from admission to the operation, Injury Severity Score [ISS], cold ischemia time from injury to ED, and total cold ischemia time). The duration, amount of surgical procedures, the time to definitive soft tissue coverage, and the choice of flap were part of the documentation. All intraoperative and postoperative complications were recorded. RESULTS: All patients were successfully replanted (time from injury to ED, 59 +/- 4 minutes; ISS16; time from admission to operating room 57 +/- 10 minutes; total cold ischemia time 203 +/- 20 minutes; total number of procedures 7.3 +/- 2.5); definitive soft tissue coverage could be achieved 23 +/- 14 days after injury. Two thromboembolic complications occurred, which could be treated by embolectomy during revision surgery, and we saw one early infection, which could be successfully managed by serial debridements in our series. CONCLUSION: The management of complete major amputations of the upper extremity should be reserved for large trauma centers with enough resources concerning technical, structural, and personnel infrastructure to meet the demands of surgical reconstruction as well as the postoperative care. Following a distinct treatment algorithm is mandatory to increase the rate of successful major replantations, thus laying the foundation for promising secondary functional reconstructive efforts. LEVEL OF EVIDENCE: Therapeutic study, level V. PMID- 25710432 TI - Tourniquet use at the Boston Marathon bombing: Lost in translation. AB - BACKGROUND: The Boston Marathon bombing was the first major, modern US terrorist event with multiple, severe lower extremity injuries. First responders, including trained professionals and civilian bystanders, rushed to aid the injured. The purpose of this review was to determine how severely bleeding extremity injuries were treated in the prehospital setting in the aftermath of the Boston Marathon bombing. METHODS: A database was created and populated by all the Boston Level I trauma centers following the Boston Marathon bombing. Data regarding specific injuries, extremities affected, demographics, prehospital interventions (including tourniquet types), and outcomes were extracted. RESULTS: Of 243 injured, 152 patients presented to the emergency department within 24 hours. Of these 152 patients, there were 66 (63.6% female) experiencing at least one extremity injury, with age ranging from younger than 15 years to 71 years, and with a median Injury Severity Score (ISS) of 10 (range, 1-38). Of the 66 injured patients, 4 had upper limbs affected, 56 had injuries on the lower limbs only, and 6 had combined upper and lower limbs affected. The extremity Abbreviated Injury Scale (AIS) scores had a median of 3 (range, 1-4). There were 17 lower extremity traumatic amputations in 15 patients. In addition, there were 10 patients with 12 lower extremities experiencing major vascular injuries. Of 66 injured patients, 29 patients had recognized extremity exsanguination at the scene. In total, 27 tourniquets were applied: 16 of 17 traumatic amputations, 5 of 12 lower extremities with major vascular injuries, and 6 additional limbs with major soft tissue injury. All tourniquets were improvised, and no commercial, purpose-designed tourniquets were identified. Among all 243 patients, mortality was 0%. CONCLUSION: After the Boston Marathon bombings, extremity exsanguination at the point of injury was either left untreated or treated with an improvised tourniquet in the prehospital environment. An effective, prehospital extremity hemorrhage control posture should be translated to all civilian first responders in the United States and should mirror the military's posture toward extremity bleeding control. The prehospital response to extremity exsanguination after the Boston Marathon bombing demonstrates that our current practice is an approach, lost in translation, from the battlefield to the homeland. LEVEL OF EVIDENCE: Epidemiologic study, level V. PMID- 25710433 TI - A comparison of prehospital lactate and systolic blood pressure for predicting the need for resuscitative care in trauma transported by ground. AB - BACKGROUND: Reliance on prehospital trauma triage guidelines misses patients with serious injury. Lactate is a biomarker capable of identifying high-risk trauma patients. Our objective was to compare prehospital point-of-care lactate (P-LAC) with systolic blood pressure (SBP) for predicting the need for resuscitative care (RC) in trauma patients transported by ground emergency medical services. METHODS: This is a prospective observational study at nine sites within the Resuscitation Outcomes Consortium conducted from March 2011 to August 2012. Lactate was measured on patients with a prehospital SBP of 100 mm Hg or less who were transported by emergency medical services to a Level I or II trauma center. Patients were followed up for the need for RC, defined as any of the following within 6 hours of emergency department arrival: blood transfusion of 5 U or greater; intervention for hemorrhage including thoracotomy, laparotomy, pelvic fixation, or interventional radiology embolization; or death. RESULTS: A total of 387 patients had a lactate value and presented with SBP between 71 mm Hg and 100 mm Hg, and 70 (18%) required RC. With the use of a P-LAC decision rule (>=2.5 mmol/L) that yielded the same specificity as that of SBP of 90 mm Hg or less (48%), the observed sensitivities for RC were 93% (95% confidence interval [CI], 84-98%) for P-LAC of 2.5 mmol/L or greater and 67% (95% CI, 55-78%) for SBP of 90 mm Hg or less (McNemar's test, p < 0.001). P-LAC has an estimated area under the curve of 0.78 (95% CI, 0.73-0.83), which is statistically superior to that of SBP (0.59; 95% CI, 0.53-0.66) and shock index (heart rate / SBP) (0.66; 95% CI, 0.60 0.74). CONCLUSION: P-LAC obtained at the scene is associated with the need for RC. P-LAC is superior to other early surrogates for hypoperfusion (SBP and shock index) in predicting the need for RC in trauma patients with 70 mm Hg < SBP <= 100 mm Hg. LEVEL OF EVIDENCE: Prognostic study, level II. PMID- 25710434 TI - Diagnosis and deployment of a self-expanding foam for abdominal exsanguination: Translational questions for human use. AB - BACKGROUND: We have previously described the hemostatic efficacy of a self expanding polyurethane foam in lethal venous and arterial hemorrhage models. A number of critical translational questions remain, including prehospital diagnosis of hemorrhage, use with diaphragmatic injury, effects on spontaneous respiration, the role of omentum, and presence of a laparotomy on foam properties. METHODS: In Experiment 1, diagnostic blood aspiration was attempted through a Veress needle before foam deployment during exsanguination (n = 53). In Experiment 2: a lethal hepatoportal injury/diaphragmatic laceration was created followed by foam (n = 6) or resuscitation (n = 10). In Experiment 3, the foam was deployed in naive, spontaneously breathing animals (n = 7), and respiration was monitored. In Experiments 4 and 5, the foam was deployed above (n = 6) and below the omentum (n = 6) and in naive animals (n = 6). Intra-abdominal pressure and organ contact were assessed. RESULTS: In Experiment 1, blood was successfully aspirated from a Veress needle in 70% of lethal iliac artery injuries and 100% of lethal hepatoportal injuries. In Experiment 2, in the presence of a diaphragm injury, between 0 cc and 110 cc of foam was found within the pleural space. Foam treatment resulted in a survival benefit relative to the control group at 1 hour (p = 0.03). In Experiment 3, hypercarbia was observed: mean (SD) Pco2 was 48 (9.4) mm Hg at baseline and 65 (14) mm Hg at 60 minutes. In Experiment 4, abdominal omentum seemed to influence organ contact and transport in two foam deployments. In Experiment 5, there was no difference in intra-abdominal pressure following foam deployment in the absence of a midline laparotomy. CONCLUSION: In a series of large animal studies, we addressed key translational issues surrounding safe use of foam treatment. These additional data, from diagnosis to deployment, will guide human experiences with foam treatment for massive abdominal exsanguination where no other treatments are available. PMID- 25710435 TI - Preinjury warfarin, but not antiplatelet medications, increases mortality in elderly traumatic brain injury patients. AB - BACKGROUND: Previous studies of traumatic brain injury (TBI) outcomes in elderly patients on oral antithrombotic (OAT) therapies have yielded conflicting results. Our objective was to examine the effect of premorbid OAT medications on outcomes among elderly TBI patients with intracranial hemorrhage. METHODS: We performed a retrospective analysis of elderly TBI patients (>=65 years) with closed head injury and evidence of brain hemorrhage on computed tomography scan from 2006 to 2010. Patient demographics, injury severity, clinical course, hospital and intensive care unit length of stay, and disposition were collected. Comparison of patients stratified by premorbid OAT use was performed using nonparametric Kruskal-Wallis and Fisher's exact tests. Multivariable logistic regression was used to compare groups and identify predictors of primary outcomes, including mortality, neurosurgical intervention, hemorrhage progression, complications, and infection. RESULTS: A total of 1,552 patients were identified: 543 on aspirin only, 97 on clopidogrel only, 218 on warfarin only, 193 on clopidogrel and aspirin, and 501 on no antithrombotic agent. Blood products were administered to reverse coagulopathy in 77.3% of patients on antithrombotic medications. After adjusting for covariates, including medication reversal, OAT use was associated with increased mortality (p = 0.04). Warfarin use was identified as a key predictor (odds ratio, 2.27; p = 0.05), in contrast to the preinjury use of antiplatelet medications, which was not associated with increased risk of in hospital death. Rates of neurosurgical intervention differed between groups, with patients on warfarin undergoing intervention more frequently. Survivor subset analysis demonstrated that hemorrhage progression was not associated with preinjury antithrombotic therapy, nor were rates of complication or infection, hospital and intensive care unit lengths of stay, or ventilator days. CONCLUSION: Preinjury use of warfarin, but not antiplatelet medications, influences survival and need for neurosurgical intervention in elderly TBI patients with intracranial hemorrhage; hemorrhage progression and morbidity are not affected. The importance of antithrombotic therapy may lie in its impact on initial injury severity. LEVEL OF EVIDENCE: Epidemiologic study, level III. PMID- 25710436 TI - Load index model: An advanced tool to support decision making during mass casualty incidents. AB - BACKGROUND: In mass-casualty events, accessing information concerning hospital congestion levels is crucial to improving patient distribution and optimizing care. The study aimed to develop a decision support tool for distributing casualties to hospitals in an emergency scenario involving multiple casualties. METHODS: A comprehensive literature review and structured interviews with 20 content experts produced a shortlist of relevant criteria for inclusion in the model. A "load index model" was prepared, incorporating results of a modified Delphi survey of 100 emergency response experts. The model was tested in three simulation exercises in which an emergency scenario was presented to six groups of senior emergency managers. Information was provided regarding capacities of 11 simulated admitting hospitals in the region, and evacuation destinations were requested for 600 simulated casualties. Of the three simulation rounds, two were performed without the model and one after its presentation. Following simulation experiments and implementation during a real-life security threat, the efficacy of the model was assessed. RESULTS: Variability between experts concerning casualties' evacuation destinations decreased significantly following the model's introduction. Most responders (92%) supported the need for standardized data, and 85% found that the model improved policy setting regarding casualty evacuation in an emergency situation. These findings were reaffirmed in a real-life emergency scenario. CONCLUSION: The proposed model improved capacity to ensure evacuation of patients to less congested medical facilities in emergency situations, thereby enhancing lifesaving medical services. The model supported decision-making processes in both simulation exercises and an actual emergency situation. PMID- 25710437 TI - Physical and mental health 10 years after multiple trauma: A prospective cohort study. AB - BACKGROUND: People who have sustained severe multiple injuries have reduced health and functioning years after the injury. For people who have sustained severe injuries, an optimal degree of predictability in future functioning and health-related quality of life is important. The main aim was to study the impacts of demographic- and injury-related factors as well as functioning at 1 year and 2 years after injury on physical and mental health 10 years after injury. METHODS: Fifty-eight participants completed a 10-year follow-up (55.2% of all included patients). Demographic and injury severity characteristics were collected, and assessments at 1, 2, 5, and 10 years after injury were performed. Patient-reported outcome measures were the Short Form 36 (SF-36), the Brief Approach/Avoidance Coping Questionnaire, and the cognitive function scale (COG). The SF-36 Physical and Mental Component Summaries (PCS and MCS, respectively) were the main outcome variables. We performed hierarchical multiple regression analyses to assess functioning on the PCS and MCS. RESULTS: Mean (SD) age at injury was 37.8 (14.7) years, 74% were male. Mean (SD) New Injury Severity Score (NISS) was 33.7 (13.0). Mean (SD) PCS score was 41.8 (11.7). Mean (SD) MCS was 48.8 (10.7). Predictors of the PCS were change in coping from 2 years to 10 years (p = 0.032), physical functioning (p < 0.001) and cognitive functioning at 1 year (p = 0.011), as well as bodily pain at 2 years (p = 0.005). Adjusted R was 0.57. Predictors of the MCS were change in coping (p = 0.031), vitality (p = 0.008) at 1 year, as well as social functioning (p = 0.034) and mental health (p = 0.043) at 2 years. Adjusted R was 0.64. CONCLUSION: Physical health was reduced compared with the adjusted general population at 10 years after injury. The mental health did not differ from that of the general population. In addition to physical functioning, coping strategies, vitality, social functioning, and mental health should be considered in the long-term rehabilitation perspective. A more comprehensive approach should be used for rehabilitation after multiple injuries. PMID- 25710438 TI - A consensus-based criterion standard definition for pediatric patients who needed the highest-level trauma team activation. PMID- 25710439 TI - Advocating policy with patient safety in the balance: The case of cervical spine clearance. PMID- 25710440 TI - The current concepts in management of animal (dog, cat, snake, scorpion) and human bite wounds. AB - Animal and human bite wounds represent a significant global health issue. In the United States, animal and human bites are a very common health issue, causing significant morbidity and even, in rare scenarios, mortality. Most animal bite wounds in the United States are caused by dogs, with cat bites being a distant second. Human bite wounds constitute a dominant subset of all bite wounds. Several studies of bite wounds have reported improved outcomes with early diagnosis and immediate treatment. However, the available literature on the initial treatment provides a plethora of conflicting opinions and results. In this review, our aim was to identify and assess the current evidence on the management of animal (dog, cat, insects, scorpions, and snakes) and human bite wounds. LEVEL OF EVIDENCE: Review article, level III. PMID- 25710441 TI - Duodenum preserving pancreatic head resection (Beger procedure) for pancreatic trauma. PMID- 25710442 TI - A case of internal jugular injury with delayed symptom onset after a stab wound to Zone 1 of the neck. PMID- 25710445 TI - Hippos stem from the longest sequence of terrestrial cetartiodactyl evolution in Africa. AB - According to molecular data, hippopotamuses and cetaceans form a clade excluding other extant cetartiodactyls. Despite a wealth of spectacular specimens documenting cetacean evolution, this relationship remains poorly substantiated by the fossil record. Indeed, the evolutionary path leading from the hippo-cetacean ancestor to Hippopotamidae is plagued by missing fossil data and phylogenetic uncertainties. Only an origination within the extinct anthracotheres is compatible with molecular results, substantial filling of phyletic gaps and recent discoveries of early Miocene hippopotamids. Yet, the anthracothere stock that gave rise to Hippopotamidae has not been identified. Consequently, recent phylogenetic accounts do not properly integrate the anthracotheriid hypothesis, and relate Hippopotamidae to a stretched ghost lineage and/or close to Suina. Here we describe a new anthracothere from Lokone (Kenya) that unambiguously roots the Hippopotamidae into a well-identified group of bothriodontines, the first large mammals to invade Africa. The hippos are deeply anchored into the African Paleogene. PMID- 25710446 TI - Bulky metallocavitands with a chiral cavity constructed by aluminum and magnesium atrane-likes: enantioselective recognition and separation of racemic alcohols. AB - Seven new type metallocavitand complexes 1-7 were synthesized via the self assembly of aluminum and magnesium atrane-likes. The recognition of R-2-butanol from racemic 2-butanol can be achieved in the chiral cavity of metallocavitand complex 5. The crystal structure of complex 5 showed that the enantioselectivity of the center cavity for the inclusion of two 2-butanol molecules is higher than that of the groups at the outer rim, which indicates that the size-limited cavity is more sensitive to the chirality of 2-butanol. Furthermore, desorption of R-2 butanol is successful through vacuumization which afforded complex 6 and gives R 2-butanol with an enantiomeric excess (ee) value of 53(+/-1)%. The reaction of enantiopure H3L2, MgnBu2, and racemic 1-phenylethanol afforded complex 7. The structure of complex 7 showed that the center cavity was occupied by three H2O molecules and one molecular R-1-phenylethanol suspended in the outer rim of the metallocavitand via a hydrogen bond, which indicated that 1-phenylethanol is too bulky for the size-limited cavity. Because a certain amount of racemic 1 phenylethanol is also co-crystallized in the unit cell, the final separated 1 phenylethanol has an ee value of 33(+/-1)%. The host-guest mechanism for the separation is clearly determined through X-ray crystal structural analysis. PMID- 25710447 TI - Development of a comet-FISH assay for the detection of DNA damage in hemocytes of Crassostrea gigas. AB - In this work, the DNA-damaging effect of hydrogen peroxide on the structural integrity of nucleolar organizer regions (NORs) was studied for the first time by comet-FISH in the Pacific oyster Crassostrea gigas. Global DNA damage was assessed in hemocytes using an alkaline version of the comet assay. Next, NOR sensitivity was analyzed by mapping major rDNA repeat unit by fluorescence in situ hybridization (FISH) on the same comet slides. Exposure of hemocytes to 100 MUM of hydrogen peroxide induced a significant increase in both DNA damage and number of FISH-signals of major ribosomal genes versus the control. Moreover, a significant positive correlation was shown between DNA damage as measured by the comet assay (percentage of DNA in comet tail) and the number of signals present in comet tails. This study demonstrates the potential value of the comet-FISH assay for the study of DNA damage induced by genotoxicant exposure of target genes. It offers a perspective for better understanding the impact of genotoxicity on animal physiology and fitness. PMID- 25710448 TI - Bioaccumulation of arsenic and silver by the caddisfly larvae Hydropsyche siltalai and H. pellucidula: a biodynamic modeling approach. AB - Biodynamic modeling was used to investigate the uptake and bioaccumulation of arsenic and silver from water and food by two Hydropsychid caddisfly larvae: Hydropsyche siltalai and Hydropsyche pellucidula. Radiotracer techniques determined the uptake rate constants of arsenic and silver from water, and assimilation efficiencies from food, and their subsequent loss rate constants after accumulation from either route. The uptake rate constants (+/-SE) of As and Ag from solution were 0.021+/-0.005 and 0.350+/-0.049Lg(-1)day(-1), respectively, for H. siltalai, and 0.435+/-0.054 and 0.277+/-0.021Lg(-1)day(-1), respectively, for H. pellucidula in moderately hard synthetic water at 10 degrees C. The assimilation efficiencies (+/-SE) of As and Ag from radiolabeled ingested food were 46.0+/-7.7% and 75.7+/-3.6%, respectively, for H. siltalai, and 61.0+/-4.2% and 52.6+/-8.6%, respectively, for H. pellucidula. Ag, but not As, AEs were significantly different between species. The AE of Ag differed from the AE of As in H. siltalai, but not in H. pellucidula. Mean efflux rate constants after accumulation of metals from solution or food ranged from 0.039 to 0.190day(-1). The efflux rate constants of As and Ag accumulated from solution were significantly lower than those of As and Ag assimilated from ingested food in both species. Experimentally derived ku and ke values were then used to predict As and Ag tissue concentrations in hydropsychids collected from 13 UK sites, including metal-contaminated streams in Cornwall. Arsenic and silver concentrations in environmental water and food (suspended particles) samples were measured. Biodynamic models successfully predicted accumulated As and Ag concentrations in resident H. siltalai and H. pellucidula at each site. The models also showed that more than 95% of accumulated As and almost 100% of accumulated Ag in H. siltalai and H. pellucidula are derived from ingested food rather than from water. PMID- 25710449 TI - Errata: Diffusion characteristics of ethylene glycol in skeletal muscle. PMID- 25710450 TI - Walk on the wild side: estimating the global magnitude of visits to protected areas. AB - How often do people visit the world's protected areas (PAs)? Despite PAs covering one-eighth of the land and being a major focus of nature-based recreation and tourism, we don't know. To address this, we compiled a globally-representative database of visits to PAs and built region-specific models predicting visit rates from PA size, local population size, remoteness, natural attractiveness, and national income. Applying these models to all but the very smallest of the world's terrestrial PAs suggests that together they receive roughly 8 billion (8 x 109) visits/y-of which more than 80% are in Europe and North America. Linking our region-specific visit estimates to valuation studies indicates that these visits generate approximately US $600 billion/y in direct in-country expenditure and US $250 billion/y in consumer surplus. These figures dwarf current, typically inadequate spending on conserving PAs. Thus, even without considering the many other ecosystem services that PAs provide to people, our findings underscore calls for greatly increased investment in their conservation. PMID- 25710451 TI - DiiodoBodipy-perylenebisimide dyad/triad: preparation and study of the intramolecular and intermolecular electron/energy transfer. AB - 2,6-diiodoBodipy-perylenebisimide (PBI) dyad and triad were prepared, with the iodoBodipy moiety as the singlet/triplet energy donor and the PBI moiety as the singlet/triplet energy acceptor. IodoBodipy undergoes intersystem crossing (ISC), but PBI is devoid of ISC, and a competition of intramolecular resonance energy transfer (RET) with ISC of the diiodoBodipy moiety is established. The photophysical properties of the compounds were studied with steady-state and femtosecond/nanosecond transient absorption and emission spectroscopy. RET and photoinduced electron transfer (PET) were confirmed. The production of the triplet state is high for the iodinated dyad and the triad (singlet oxygen quantum yield PhiDelta = 80%). The Gibbs free energy changes of the electron transfer (DeltaGCS) and the energy level of the charge transfer state (CTS) were analyzed. With nanosecond transient absorption spectroscopy, we confirmed that the triplet state is localized on the PBI moiety in the iodinated dyad and the triad. An exceptionally long lived triplet excited state was observed (tauT = 150 MUs) for PBI. With the uniodinated reference dyad and triad, we demonstrated that the triplet state localized on the PBI moiety in the iodinated dyad and triad is not produced by charge recombination. These information are useful for the design and study of the fundamental photochemistry of multichromophore organic triplet photosensitizers. PMID- 25710452 TI - Hospital readmission of skilled nursing facility residents: a systematic review. AB - Hospital readmission of patients discharged to skilled nursing facilities (SNFs) is common and costly with increasing public attention over the past decade, particularly in light of the new health care environment surrounding the advent of the Affordable Care Act. The purpose of the current systematic review is to critically examine prevalence, predictors, and costs of hospital readmission of SNF residents found in the medical literature. Individual resident, facility, and intervention factors predicting hospital readmission of SNF residents were studied. Despite the heterogeneity of the reviewed articles' data sources and study designs, the existing literature asserts that hospital readmission of SNF residents is associated with individual resident and facility characteristics. Implementation of promising intervention programs can promote quality of care and reduce hospital readmission of SNF residents. PMID- 25710453 TI - Carboranes in the chemist's toolbox. AB - Once seldom encountered outside of a few laboratories, carboranes are now everywhere, playing a role in the development of a broad range of technologies encompassing organic synthesis, radionuclide handling, drug design, heat resistant polymers, cancer therapy, nanomaterials, catalysis, metal-organic frameworks, molecular machines, batteries, electronic devices, and more. This perspective highlights selected examples in which the special attributes of carboranes and metallacarboranes are being exploited for targeted purposes in the laboratory and in the wider world. PMID- 25710454 TI - Circulating endothelial cell enumeration demonstrates prolonged endothelial damage in recipients of myeloablative allogeneic stem cell transplantation. PMID- 25710455 TI - CD127+ innate lymphoid cells are dysregulated in treatment naive acute myeloid leukemia patients at diagnosis. PMID- 25710456 TI - Phase I/II study of the combination of panobinostat and carfilzomib in patients with relapsed/refractory multiple myeloma. AB - The purpose of this study was to assess the safety and efficacy of the combination of panobinostat and carfilzomib in patients with relapsed/refractory multiple myeloma. Patients with multiple myeloma who had relapsed after at least one prior treatment were eligible to participate. In the dose escalation part of the study a standard 3+3 design was used to determine the maximum tolerated dose of four planned dose levels of the combination of carfilzomib and panobinostat. Panobinostat was administered on days 1, 3, 5, 15, 17, and 19. Carfilzomib was administered on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. Treatment was continued until progression or intolerable toxicity. Forty-four patients were accrued into the trial, 13 in the phase I part and 31 in the phase II part of the study. The median age of the patients was 66 years and the median number of prior therapies was five. The expansion dose was established as 30 mg panobinostat, 20/45 mg/m(2) carfilzomib. The overall response rate was 67% for all patients, 67% for patients refractory to prior proteasome inhibitor treatment and 75% for patients refractory to prior immune modulating drug treatment. At a median follow up of 17 months, median progression-free survival was 7.7 months, median time to progression was 7.7 months, and median overall survival had not been reached. The regimen was well tolerated, although there were several panobinostat dose reductions. In conclusion, the combination of panobinostat and carfilzomib is feasible and effective in patients with relapsed/refractory multiple myeloma. (Trial registered at ClinicalTrials.gov: NCT01496118). PMID- 25710457 TI - Low frequency mutations independently predict poor treatment-free survival in early stage chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis. PMID- 25710458 TI - The texture, sensory properties and stability of cookies prepared with wax oleogels. AB - Shortening is the essential component of high quality baked foods. Its effects on dough structure formation and the desired final product attributes depend mostly on its solid fat content and beta' crystalline polymorphs. Saturated and trans fatty acids present in shortening pose some important negative health considerations. Hence, alternative plastic fats with lower or zero quantity of saturated and trans fatty acids are in high demand. Oleogels are gel networks of liquid edible oils with no trans and very low saturated fatty acids. In this study, sunflower wax (SW) and beeswax (BW) oleogels of hazelnut oil were used in cookie preparation against commercial bakery shortening (CBS) as the control, to compare the textural, sensory and stability properties of the cookies. The basic chemical composition, textural properties, and some physical attributes of the cookies were compared. Sensory texture/flavor profile analysis (T/FPA) and consumer hedonic tests were also accomplished. Furthermore, the changes in cookie texture and stability were monitored during 30 day storage at room temperature. It was found out that in almost all properties, the oleogel cookies resembled CBS cookies. T/FPA results present detailed data for literature. Consumer hedonic scores indicated that oleogel cookies were better than CBS cookies and were also well accepted by consumers. Wax oleogels can be used as cookie shortening successfully. PMID- 25710460 TI - Significance of serum 24,25-dihydroxyvitamin D in the assessment of vitamin D status: a double-edged sword? AB - BACKGROUND: 24,25-Dihydroxyvitamin D [24,25(OH)2D] in serum may be both a nuisance and nutritionally valuable. METHODS: We investigated the impact of 24,25(OH)2D3 on the performance of commercially available immunoassays for serum total 25-hydroxyvitamin D [25(OH)D] using (a) serum from a nationally representative sample of adults, (b) serum from a spiking experiment, and (c) data from the UK Vitamin D External Quality Assurance Scheme (DEQAS). We also investigated the utility of the serum ratio of 24,25(OH)2D3 to 25(OH)D as an index of inactivation and of response to vitamin D supplementation using randomized controlled trial (RCT) data. Measurement of 24,25(OH)2D in sera by a LC-MS/MS method allowed for an investigation of its impact on immunoassay-derived serum 25(OH)D values as well as its clinical utility. We report data from a nationally representative sample of adults, a recent vitamin D RCT in older adults, and DEQAS. RESULTS: 24,25(OH)2D3 contributed to the positive bias observed in some immunoassays relative to LC-MS/MS-derived estimates for total 25(OH)D. A spiking experiment showed that the degree of cross-reactivity with 24,25(OH)2D was high and may underpin this positive bias. Adjustment for 24,25(OH)2D3 concentration brought estimates closer to true values. Data from the vitamin D RCT showed that the ratio of 24,25(OH)2D3 to 25(OH)D was associated with serum 25(OH)D3 and with response of serum 25(OH)D to vitamin D supplementation. CONCLUSIONS: Our findings highlight that the effect of 24,25(OH)2D3 in serum is a double-edged sword-an interferent for some immunoassays, yet potentially informative of nutritional status. PMID- 25710461 TI - Detection of fetal subchromosomal abnormalities by sequencing circulating cell free DNA from maternal plasma. AB - BACKGROUND: The development of sequencing-based noninvasive prenatal testing (NIPT) has been largely focused on whole-chromosome aneuploidies (chromosomes 13, 18, 21, X, and Y). Collectively, they account for only 30% of all live births with a chromosome abnormality. Various structural chromosome changes, such as microdeletion/microduplication (MD) syndromes are more common but more challenging to detect. Recently, several publications have shown results on noninvasive detection of MDs by deep sequencing. These approaches demonstrated the proof of concept but are not economically feasible for large-scale clinical applications. METHODS: We present a novel approach that uses low-coverage whole genome sequencing (approximately 0.2*) to detect MDs genome wide without requiring prior knowledge of the event's location. We developed a normalization method to reduce sequencing noise. We then applied a statistical method to search for consistently increased or decreased regions. A decision tree was used to differentiate whole-chromosome events from MDs. RESULTS: We demonstrated via a simulation study that the sensitivity difference between our method and the theoretical limit was <5% for MDs >=9 Mb. We tested the performance in a blinded study in which the MDs ranged from 3 to 40 Mb. In this study, our algorithm correctly identified 17 of 18 cases with MDs and 156 of 157 unaffected cases. CONCLUSIONS: The limit of detection for any given MD syndrome is constrained by 4 factors: fetal fraction, MD size, coverage, and biological and technical variability of the event region. Our algorithm takes these factors into account and achieved 94.4% sensitivity and 99.4% specificity. PMID- 25710459 TI - Duchenne muscular dystrophy gene therapy in the canine model. AB - Duchenne muscular dystrophy (DMD) is an X-linked lethal muscle disease caused by dystrophin deficiency. Gene therapy has significantly improved the outcome of dystrophin-deficient mice. Yet, clinical translation has not resulted in the expected benefits in human patients. This translational gap is largely because of the insufficient modeling of DMD in mice. Specifically, mice lacking dystrophin show minimum dystrophic symptoms, and they do not respond to the gene therapy vector in the same way as human patients do. Further, the size of a mouse is hundredfolds smaller than a boy, making it impossible to scale-up gene therapy in a mouse model. None of these limitations exist in the canine DMD (cDMD) model. For this reason, cDMD dogs have been considered a highly valuable platform to test experimental DMD gene therapy. Over the last three decades, a variety of gene therapy approaches have been evaluated in cDMD dogs using a number of nonviral and viral vectors. These studies have provided critical insight for the development of an effective gene therapy protocol in human patients. This review discusses the history, current status, and future directions of the DMD gene therapy in the canine model. PMID- 25710462 TI - Super-resolution imaging of ESCRT-proteins at HIV-1 assembly sites. AB - The cellular endosomal sorting complex required for transport (ESCRT) machinery is involved in membrane budding processes, such as multivesicular biogenesis and cytokinesis. In HIV-infected cells, HIV-1 hijacks the ESCRT machinery to drive HIV release. Early in the HIV-1 assembly process, the ESCRT-I protein Tsg101 and the ESCRT-related protein ALIX are recruited to the assembly site. Further downstream, components such as the ESCRT-III proteins CHMP4 and CHMP2 form transient membrane associated lattices, which are involved in virus-host membrane fission. Although various geometries of ESCRT-III assemblies could be observed, the actual membrane constriction and fission mechanism is not fully understood. Fission might be driven from inside the HIV-1 budding neck by narrowing the membranes from the outside by larger lattices surrounding the neck, or from within the bud. Here, we use super-resolution fluorescence microscopy to elucidate the size and structure of the ESCRT components Tsg101, ALIX, CHMP4B and CHMP2A during HIV-1 budding below the diffraction limit. To avoid the deleterious effects of using fusion proteins attached to ESCRT components, we performed measurements on the endogenous protein or, in the case of CHMP4B, constructs modified with the small HA tag. Due to the transient nature of the ESCRT interactions, the fraction of HIV-1 assembly sites with colocalizing ESCRT complexes was low (1.5%-3.4%). All colocalizing ESCRT clusters exhibited closed, circular structures with an average size (full-width at half-maximum) between 45 and 60 nm or a diameter (determined using a Ripley's L-function analysis) of roughly 60 to 100 nm. The size distributions for colocalizing clusters were narrower than for non-colocalizing clusters, and significantly smaller than the HIV-1 bud. Hence, our results support a membrane scission process driven by ESCRT protein assemblies inside a confined structure, such as the bud neck, rather than by large lattices around the neck or in the bud lumen. In the case of ALIX, a cloud of individual molecules surrounding the central clusters was often observed, which we attribute to ALIX molecules incorporated into the nascent HIV 1 Gag shell. Experiments performed using YFP-tagged Tsg101 led to an over 10-fold increase in ESCRT structures colocalizing with HIV-1 budding sites indicating an influence of the fusion protein tag on the function of the ESCRT protein. PMID- 25710463 TI - Fluorescence-guided surgery of retroperitoneal-implanted human fibrosarcoma in nude mice delays or eliminates tumor recurrence and increases survival compared to bright-light surgery. AB - The aim of this study is to determine if fluorescence-guided surgery (FGS) can eradicate human fibrosarcoma growing in the retroperitoneum of nude mice. One week after retroperitoneal implantation of human HT1080 fibrosarcoma cells, expressing green fluorescent protein (GFP) (HT-1080-GFP), in nude mice, bright light surgery (BLS) was performed on all tumor-bearing mice (n = 22). After BLS, mice were randomized into 2 treatment groups; BLS-only (n = 11) or the combination of BLS + FGS (n = 11). The residual tumors remaining after BLS were resected with FGS using a hand-held portable imaging system under fluorescence navigation. The average residual tumor area after BLS + FGS was significantly smaller than after BLS-only (0.4 +/- 0.4 mm(2) and 10.5 +/- 2.4 mm(2), respectively; p = 0.006). Five weeks after surgery, the fluorescent-tumor areas of BLS- and BLS + FGS-treated mice were 379 +/- 147 mm(2) and 11.7 +/- 6.9 mm(2), respectively, indicating that FGS greatly inhibited tumor recurrence compared to BLS. The combination of BLS + FGS significantly decreased fibrosarcoma recurrence compared to BLS-only treated mice (p < 0.001). Mice treated with BLS+FGS had a significantly higher disease-free survival rate than mice treated with BLS-only at five weeks after surgery. These results suggest that combination of BLS + FGS significantly reduced the residual fibrosarcoma volume after BLS and improved disease-free survival. PMID- 25710464 TI - Health-related lifestyle behaviors among male and female rural-to-urban migrant workers in Shanghai, China. AB - BACKGROUND: Lifestyle behaviors significantly impact health, yet remain poorly defined in Chinese rural-to-urban migrants. METHODS: In a cross-sectional study of health-related behaviors of 5484 rural-to-urban migrants who had worked in Shanghai for at least six months, we assessed the contribution of demographics and physical and mental health to lifestyle behaviors in male and female participants by multiple stepwise cumulative odds logistic regression. RESULTS: Respondents were 51.3% male. 9.9% exhibited abnormal blood pressure; 27.0% were overweight or obese; 11.2% reported abnormal mental health; 36.9% reported healthy lifestyle. Multiple stepwise cumulative odds logistic regression indicated that men working in manufacturing reported less unhealthy lifestyle than those in hospitality (cumulative odds ratio (COR) = 1.806, 95%CI 1.275 2.559) or recreation/leisure (COR = 3.248, 95%CI 2.379-4.435); and women working in manufacturing and construction reported less unhealthy lifestyle than those in all other sectors. Unhealthy lifestyle was associated with small workplaces for men (COR = 1.422, 95%CI 1.154-1.752), working more than 8 or 11 hours per day for women and men, respectively, and earning over 3500 RMB in women (COR = 1.618, 95%CI 1.137-2.303). Single women and women who had previously resided in three or more cities were more likely to report unhealthy lifestyle (COR = 2.023, 95%CI 1.664-2.461, and COR = 1.311, 95%CI 1.072-1.602, respectively). Abnormal mental status was also correlated with unhealthy lifestyle in men (COR = 3.105, 95%CI 2.454-3.930) and women (COR = 2.566, 95%CI 2.024-3.252). CONCLUSIONS: There were different risk factors of unhealthy lifestyle score in male and female rural-to urban migrants, especially in number of cities experienced, salary, marital status, work place scale. Several demographic groups: employment sectors (e.g. hospitality and recreation/leisure), working conditions (e.g. long hours) and abnormal mental status were associated with unhealthy lifestyle behaviors in Chinese rural-to-urban migrants, and health interventions should be targeted to these groups. PMID- 25710465 TI - A systematic review of interventions addressing adherence to anti-diabetic medications in patients with type 2 diabetes--impact on adherence. AB - BACKGROUND: The global prevalence of diabetes is increasing. Medications are a recommended strategy to control hyperglycaemia. However, patient adherence can be variable, impacting health outcomes. A range of interventions for patients with type 2 diabetes have focused on improving treatment adherence. This review evaluates the impact of these interventions on adherence to anti-diabetic medications and focuses on the methods and tools used to measure adherence. METHOD: Medline, Embase, CINAHL, IPA, PUBmed, and PsychINFO were searched for relevant articles published in 2000-2013, using appropriate search terms. RESULTS: Fifty two studies addressing adherence to anti-diabetic medications in patients with type 2 diabetes met the inclusion criteria and were reviewed. Each study was assessed for research design, method(s) used for measuring medication adherence, and impact of intervention on medication adherence and glycaemic control. Fourteen studies were published in 2000-2009 and 38 in 2010-2013. Twenty two interventions led to improvements in adherence to anti-diabetic medications, while only nine improved both medication adherence and glycaemic control. A single strategy could not be identified which would be guaranteed to improve anti diabetic medication adherence consistently. Nonetheless, most interventions were successful in influencing one or more of the outcomes assessed, indicating the usefulness of these interventions under certain circumstances. Self-report, particularly the Summary of Diabetes Self-Care Activities questionnaire was the most commonly used tool to assess medication adherence, although other self report tools were used in more recent studies. Overall, there was a slight increase in the number of studies that employed multiple methods to assess medication adherence in studies conducted after 2008. CONCLUSION: The diversity of interventions and adherence measurements prevented a meta-analysis of the impact of interventions on adherence to therapy, highlighting the need for more consistency in methods in the area of adherence research. Whilst effective interventions were identified, it is not possible to conclude on an effective intervention that can be generalised to all patients with type 2 diabetes. PMID- 25710466 TI - Environment and colonisation sequence are key parameters driving cooperation and competition between Pseudomonas aeruginosa cystic fibrosis strains and oral commensal streptococci. AB - Cystic fibrosis (CF) patient airways harbour diverse microbial consortia that, in addition to the recognized principal pathogen Pseudomonas aeruginosa, include other bacteria commonly regarded as commensals. The latter include the oral (viridans) streptococci, which recent evidence indicates play an active role during infection of this environmentally diverse niche. As the interactions between inhabitants of the CF airway can potentially alter disease progression, it is important to identify key cooperators/competitors and environmental influences if therapeutic intervention is to be improved and pulmonary decline arrested. Importantly, we recently showed that virulence of the P. aeruginosa Liverpool Epidemic Strain (LES) could be potentiated by the Anginosus-group of streptococci (AGS). In the present study we explored the relationships between other viridans streptococci (Streptococcus oralis, Streptococcus mitis, Streptococcus gordonii and Streptococcus sanguinis) and the LES and observed that co-culture outcome was dependent upon inoculation sequence and environment. All four streptococcal species were shown to potentiate LES virulence factor production in co-culture biofilms. However, in the case of S. oralis interactions were environmentally determined; in air cooperation within a high cell density co culture biofilm occurred together with stimulation of LES virulence factor production, while in an atmosphere containing added CO2 this species became a competitor antagonising LES growth through hydrogen peroxide (H2O2) production, significantly altering biofilm population dynamics and appearance. Streptococcus mitis, S. gordonii and S. sanguinis were also capable of H2O2 mediated inhibition of P. aeruginosa growth, but this was only visible when inoculated as a primary coloniser prior to introduction of the LES. Therefore, these observations, which are made in conditions relevant to the biology of CF disease pathogenesis, show that the pathogenic and colonisation potential of P. aeruginosa isolates can be modulated positively and negatively by the presence of oral commensal streptococci. PMID- 25710467 TI - Engrailed 1 mediates correct formation of limb innervation through two distinct mechanisms. AB - Engrailed-1 (En1) is expressed in the ventral ectoderm of the developing limb where it plays an instructive role in the dorsal-ventral patterning of the forelimb. Besides its well-described role as a transcription factor in regulating gene expression through its DNA-binding domain, En1 may also be secreted to form an extracellular gradient, and directly impact on the formation of the retinotectal map. We show here that absence of En1 causes mispatterning of the forelimb and thus defects in the dorsal-ventral pathfinding choice of motor axons in vivo. In addition, En1 but not En2 also has a direct and specific repulsive effect on motor axons of the lateral aspect of the lateral motor column (LMC) but not on medial LMC projections. Moreover, an ectopic dorsal source of En1 pushes lateral LMC axons to the ventral limb in vivo. Thus, En1 controls the establishment of limb innervation through two distinct molecular mechanisms. PMID- 25710468 TI - Genetic diversity and host specificity varies across three genera of blood parasites in ducks of the Pacific Americas Flyway. AB - Birds of the order Anseriformes, commonly referred to as waterfowl, are frequently infected by Haemosporidia of the genera Haemoproteus, Plasmodium, and Leucocytozoon via dipteran vectors. We analyzed nucleotide sequences of the Cytochrome b (Cytb) gene from parasites of these genera detected in six species of ducks from Alaska and California, USA to characterize the genetic diversity of Haemosporidia infecting waterfowl at two ends of the Pacific Americas Flyway. In addition, parasite Cytb sequences were compared to those available on a public database to investigate specificity of genetic lineages to hosts of the order Anseriformes. Haplotype and nucleotide diversity of Haemoproteus Cytb sequences was lower than was detected for Plasmodium and Leucocytozoon parasites. Although waterfowl are presumed to be infected by only a single species of Leucocytozoon, L. simondi, diversity indices were highest for haplotypes from this genus and sequences formed five distinct clades separated by genetic distances of 4.9% 7.6%, suggesting potential cryptic speciation. All Haemoproteus and Leucocytozoon haplotypes derived from waterfowl samples formed monophyletic clades in phylogenetic analyses and were unique to the order Anseriformes with few exceptions. In contrast, waterfowl-origin Plasmodium haplotypes were identical or closely related to lineages found in other avian orders. Our results suggest a more generalist strategy for Plasmodium parasites infecting North American waterfowl as compared to those of the genera Haemoproteus and Leucocytozoon. PMID- 25710469 TI - Graphene oxide-phosphor hybrid nanoscrolls with high luminescent quantum yield: synthesis, structural, and X-ray absorption studies. AB - Highly luminescent graphene oxide (GO)-phosphor hybrid thin films with a maximum quantum yield of 9.6% were synthesized via a simple chemical method. An intense luminescence emission peak at 537 nm and a broad emission peak at 400 nm were observed from the GO-phosphor hybrid films. The maximum quantum yield of the emissions from the hybrid films was found to be 9.6%, which is 48 times higher than that of pristine GO films. The GO-phosphor hybrids were prepared via spin coating and subsequent postannealing of the films, resulting in scrolling of the GO sheets. The resulting GO nanoscrolls exhibited a length of ~2 MUm with nanoscale interior cavities. Transmission electron microscopy and selected-area electron diffraction analyses revealed that the lattice structure of the tubular scrolls is similar to that of carbon nanotubes. While pristine GO films are p type, in the GO-phosphor hybrids, the Fermi level shifted upward and fell between the HOMO-LUMO gap due to phosphor attachment via C-N bonding. The highly luminescent GO-phosphor hybrids will find important applications in graphene based optoelectronic devices. PMID- 25710470 TI - The proteasome inhibitior bortezomib depletes plasma cells and ameliorates clinical manifestations of refractory systemic lupus erythematosus. AB - OBJECTIVES: To investigate whether bortezomib, a proteasome inhibitor approved for treatment of multiple myeloma, induces clinically relevant plasma cell (PC) depletion in patients with active, refractory systemic lupus erythematosus (SLE). METHODS: Twelve patients received a median of two (range 1-4) 21-day cycles of intravenous bortezomib (1.3 mg/m(2)) with the coadministration of dexamethasone (20 mg) for active SLE. Disease activity was assessed using the SLEDAI-2K score. Serum concentrations of anti-double-stranded DNA (anti-dsDNA) and vaccine-induced protective antibodies were monitored. Flow cytometry was performed to analyse peripheral blood B-cells, PCs and Siglec-1 expression on monocytes as surrogate marker for type-I interferon (IFN) activity. RESULTS: Upon proteasome inhibition, disease activity significantly declined and remained stable for 6 months on maintenance therapies. Nineteen treatment-emergent adverse events occurred and, although mostly mild to moderate, resulted in treatment discontinuation in seven patients. Serum antibody levels significantly declined, with greater reductions in anti-dsDNA (~60%) than vaccine-induced protective antibody titres (~30%). Bortezomib significantly reduced the numbers of peripheral blood and bone marrow PCs (~50%), but their numbers increased between cycles. Siglec-1 expression on monocytes significantly declined. CONCLUSIONS: These findings identify proteasome inhibitors as a putative therapeutic option for patients with refractory SLE by targeting PCs and type-I IFN activity, but our results must be confirmed in controlled trials. PMID- 25710471 TI - The effect of comedication with conventional synthetic disease modifying antirheumatic drugs on TNF inhibitor drug survival in patients with ankylosing spondylitis and undifferentiated spondyloarthritis: results from a nationwide prospective study. AB - OBJECTIVE: To assess the effect of comedication with conventional synthetic disease modifying antirheumatic drugs (csDMARDs) on retention to tumour necrosis factor inhibitor (TNFi) therapy in patients with ankylosing spondylitis (AS) and undifferentiated spondyloarthritis (uSpA). METHODS: Data on patients with a clinical diagnosis of AS or uSpA starting treatment with adalimumab, etanercept or infliximab as their first TNFi during 2003-2010 were retrieved from the Swedish national biologics register and linked to national population based registers. Five-year drug survival was analysed by Cox regression with age, sex, baseline csDMARD comedication, TNFi type, prescription year and covariates representing frailty and socioeconomic status. AS and uSpA were analysed separately. Sensitivity analyses included models with csDMARD as a time-dependent covariate and adjustments for additional potential confounders. RESULTS: 1365 patients with AS and 1155 patients with uSpA were included, of whom 40.8% versus 50.3% used csDMARD comedication at baseline. In the unadjusted analyses superior drug survival was observed for patients using versus not using csDMARD comedication among patients with AS (p<0.001) but not among patients with uSpA (p=0.175). In the multivariable Cox regression analyses comedication with csDMARD was associated with better retention to TNFi therapy both in AS (HR 0.71, p<0.001) and uSpA (HR 0.82, p=0.020). The results were similar with csDMARD comedication as a time-dependent covariate, and the associations were retained when adjusting for erythrocyte sedimentation rate, C-reactive protein, patient global, swollen joints, uveitis, psoriasis and inflammatory bowel disease. CONCLUSIONS: In this large register study of patients with AS and uSpA, use of csDMARD comedication was associated with better 5-year retention to the first TNFi. PMID- 25710472 TI - The movement of multidrug-resistant tuberculosis across borders in East Africa needs a regional and global solution. AB - Kevin Cain and colleagues reflect on the cross border movement of people from Somalia with MDR-TB and the implications for MDR-TB programs in East Africa. PMID- 25710473 TI - Serum interleukin (IL)-15 as a biomarker of Alzheimer's disease. AB - Interleukin (IL-15), a pro-inflammatory cytokine has been studied as a possible marker of Alzheimer's disease (AD); however its exact role in neuro-inflammation or the pathogenesis AD is not well understood yet. A Multiple Indicators Multiple Causes (MIMIC) approach was used to examine the relationship between serum IL-15 levels and AD in a well characterized AD cohort, the Texas Alzheimer's Research and Care Consortium (TARCC). Instead of categorical diagnoses, we used two latent construct d (for dementia) and g' (for cognitive impairments not contributing to functional impairments) in our analysis. The results showed that the serum IL-15 level has significant effects on cognition, exclusively mediated by latent construct d and g'. Contrasting directions of association lead us to speculate that IL-15's effects in AD are mediated through functional networks as d scores have been previously found to be specifically related to default mode network (DMN). Our finding warrants the need for further research to determine the changes in structural and functional networks corresponding to serum based biomarkers levels. PMID- 25710474 TI - Polymorphic regions in the interleukin-1 gene and susceptibility to chronic periodontitis: a genetic association study. AB - OBJECTIVE: The objectives of this study were to determine the association between single nucleotide polymorphisms (SNPs) in IL1B (-511, +3954), IL1A (-889, +4845), and the variable number of tandem repeats (VNTRs) polymorphism in the IL-1RN gene with chronic periodontitis susceptibility and to analyze gene-gene interactions in a hospital-based sample population from South India. SUBJECTS AND METHODS: A total of 400 individuals were recruited for this study; 200 individuals with healthy gingiva and 200 chronic periodontitis patients. Genomic DNA was isolated from peripheral blood samples and genotyping was performed for the above mentioned single nucleotide and VNTR polymorphisms by polymerase chain reaction, DNA sequencing, and agarose gel electrophoresis. RESULTS: A higher proportion of the variant alleles were observed in the chronic periodontitis group for all the SNPs examined. The SNP at +3954 (C>T) in the IL1B gene was found to be significantly associated with chronic periodontitis (p=0.007). VNTR genotypes (chi(2) value: 5.163, df=1, p=0.023) and alleles (chi(2) value: 6.818, df=1, p=0.009) were found to have a significant association with chronic periodontitis susceptibility. CONCLUSION: In the study population examined, the SNP in the IL1B gene (+3954) and VNTR polymorphisms in the IL1RN gene were found to have a significant association with chronic periodontitis susceptibility. PMID- 25710475 TI - Effects of magnolol and honokiol on adhesion, yeast-hyphal transition, and formation of biofilm by Candida albicans. AB - BACKGROUND: The first step in infection by Candida albicans is adhesion to host cells or implanted medical devices and this followed by hyphal growth and biofilm formation. Yeast-to-hyphal transition has long been identified as a key factor in fungal virulence. Following biofilm formation, C. albicans is usually less sensitive or insensitive to antifungals. Therefore, development of new antifungals with inhibitory action on adhesion, yeast-hyphal transition and biofilm formation by C. albicans is very necessary. METHODS: The effects of magnolol and honokiol on hypha growth were investigated using different induction media. Their inhibitory effects were determined using the 2,3-bis(2-methoxy-4 nitro-5-sulfophenyl)-2H-tetrazolium-5- carboxanilide assay, and biofilm thickness and viability were observed by a confocal scanning laser microscope. Mammalian cells were used in adhesion assays. Genes related to hyphae development and cell adhesions were analyzed by real-time reverse transcription-polymerase chain reaction. The exogenous cyclic adenosine monophosphate was used to determine the mechanisms of action of magnolol and honokiol. Caenorhabditis elegans was used as an in vivo model to estimate the antifungal activities of magnolol and honokiol. RESULTS AND CONCLUSIONS: Magnolol and honokiol inhibited adhesion, the transition from yeast to hypha, and biofilm formation by C. albicans through the Ras1-cAMP Efg1 pathway. Moreover, magnolol and honokiol prolonged the survival of nematodes infected by C. albicans. Magnolol and honokiol have potential inhibitory effects against biofilm formation by C. albicans. GENERAL SIGNIFICANCE: This study provides useful information towards the development of new strategies to reduce the incidence of C. albicans biofilm-associated infection. PMID- 25710476 TI - Multisensory causal inference in the brain. AB - At any given moment, our brain processes multiple inputs from its different sensory modalities (vision, hearing, touch, etc.). In deciphering this array of sensory information, the brain has to solve two problems: (1) which of the inputs originate from the same object and should be integrated and (2) for the sensations originating from the same object, how best to integrate them. Recent behavioural studies suggest that the human brain solves these problems using optimal probabilistic inference, known as Bayesian causal inference. However, how and where the underlying computations are carried out in the brain have remained unknown. By combining neuroimaging-based decoding techniques and computational modelling of behavioural data, a new study now sheds light on how multisensory causal inference maps onto specific brain areas. The results suggest that the complexity of neural computations increases along the visual hierarchy and link specific components of the causal inference process with specific visual and parietal regions. PMID- 25710477 TI - Studies on residue-free decontaminants for chemical warfare agents. AB - Residue-free decontaminants based on hydrogen peroxide, which decomposes to water and oxygen in the environment, are examined as decontaminants for chemical warfare agents (CWA). For the apparent special case of CWA on concrete, H2O2 alone, without any additives, effectively decontaminates S-2 (diisopropylamino)ethyl O-ethyl methylphosphonothioate (VX), pinacolyl methylphosphorofluoridate (GD), and bis(2-choroethyl) sulfide (HD) in a process thought to involve H2O2 activation by surface-bound carbonates/bicarbonates (known H2O2 activators for CWA decontamination). A plethora of products are formed during the H2O2 decontamination of HD on concrete, and these are characterized by comparison to synthesized authentic compounds. As a potential residue-free decontaminant for surfaces other than concrete (or those lacking adsorbed carbonate/bicarbonate) H2O2 activation for CWA decontamination is feasible using residue-free NH3 and CO2 as demonstrated by reaction studies for VX, GD, and HD in homogeneous solution. Although H2O2/NH3/CO2 ("HPAC") decontaminants are active for CWA decontamination in solution, they require testing on actual surfaces of interest to assess their true efficacy for surface decontamination. PMID- 25710478 TI - On the transgressiveness of ambiguity: Richard Bruce Nugent and the flow of sexuality and race. AB - The study focuses on the slender corpus of literary work by Harlem Renaissance poet, author and visual artist Richard Bruce Nugent (1906-1987), arguably America's foremost Black aesthete. As an individualist in the footsteps of post Hegelian and pre-Nietzschean philosopher Max Stirner (1806-1856), Nugent sought to re-think sexuality and race beyond fixed schemes of categorial distribution. To this end, Nugent deployed a strategy of sexual and racial ambiguity that aimed at situating the uniquely sexed and raced individual within the continuities of ever-diversifying Nature. Nugent's deconstructive approach of sexuality and race proves to be convergent with (but not genealogically dependent on) the universalization of sexual intermediariness and racial miscegenation postulated by German-Jewish sexologist Magnus Hirschfeld during the first third of the twentieth century. Nugent's non-identitarian conception of sex acts anticipated by more than a decade comparable insights propounded by Alfred Kinsey. PMID- 25710479 TI - Non-equilibrium electrokinetic micromixer with 3D nanochannel networks. AB - We report an active micromixer which utilizes vortex generation due to non equilibrium electrokinetics near the interface between a microchannnel and a nanochannel networks membrane (NCNM), constructed from geometrically controlled in situ self-assembled nanoparticles. A large interfacing area where it is possible to generate vortices can be realized, because nano-interstices between the assembled nanoparticles are intrinsically collective three-dimensional nanochannel networks, which may be compared to typical silicon-based 2D nanochannels. The proposed mixer shows a 2-fold shorter mixing time (~0.78 ms) and a 34-fold shorter mixing length (~7.86 MUm) compared to conventional 2D nanochannels. PMID- 25710480 TI - Expression of CD150 in tumors of the central nervous system: identification of a novel isoform. AB - CD150 (IPO3/SLAM) belongs to the SLAM family of receptors and serves as a major entry receptor for measles virus. CD150 is expressed on normal and malignant cells of the immune system. However, little is known about its expression outside the hematopoietic system, especially tumors of the central nervous system (CNS). Although CD150 was not found in different regions of normal brain tissues, our immunohistochemical study revealed its expression in 77.6% of human CNS tumors, including glioblastoma, anaplastic astrocytoma, diffuse astrocytoma, ependymoma, and others. CD150 was detected in the cytoplasm, but not on the cell surface of glioma cell lines, and it was colocalized with the endoplasmic reticulum and Golgi complex markers. In addition to the full length mRNA of the mCD150 splice isoform, in glioma cells we found a highly expressed novel CD150 transcript (nCD150), containing an 83 bp insert. The insert is derived from a previously unrecognized exon designated Cyt-new, which is located 510 bp downstream of the transmembrane region exon, and is a specific feature of primate SLAMF1. Both mCD150 and nCD150 cDNA variants did not contain any mutations and had the leader sequence. The nCD150 transcript was also detected in normal and malignant B lymphocytes, primary T cells, dendritic cells and macrophages; however, in glioma cells nCD150 was found to be the predominant CD150 isoform. Similarly to mCD150, cell surface expression of nCD150 allows wild type measles virus entry to the cell. Our data indicate that CD150 expression in CNS tumors can be considered a new diagnostic marker and potential target for novel therapeutic approaches. PMID- 25710481 TI - One-seeded fruits in the core Caryophyllales: their origin and structural diversity. AB - The core Caryophyllales consist of approximately 30 families (12,000 species) distributed worldwide. Many members evolved one-seeded or conjoined fruits, but their origin and structural diversity have not been investigated. A comparative anatomical investigation of the one-seeded fruits within the core Caryophyllales was conducted. The origin of the one-seeded fruits and the evolutionary reconstructions of some carpological characters were traced using a tree based on rbcl and matK data in order to understand the ancestral characters and their changes. The one-seeded fruit type is inferred to be an ancestral character state in core Caryophyllales, with a subsequent increase in the seed number seen in all major clades. Most representatives of the 'Earlier Diverging' clade are distinguished in various carpological traits. The organization of the pericarp is diverse in many groups, although fruits with a dry, many-layered pericarp, consisting of sclerenchyma as outer layers and a thin-walled parenchyma below, with seeds occupying a vertical embryo position, are likely ancestral character states in the core Caryophyllales clade. Several carpological peculiarities in fruit and seed structure were discovered in obligate one-seeded Achatocarpaceae, Chenopodiaceae, Nyctaginaceae, Seguieriaceae and Sarcobataceae. The horizontal embryo evolved in only certain groups of Chenopodiaceae. The bar-thickening of endotegmen cells appears to be an additional character typical of core Caryophyllales. The syncarpy-to-lysicarpy paradigm in Caryophyllaceae needs to be reinterpreted. PMID- 25710483 TI - Effects of altitude on performance of elite track-and-field athletes. AB - PURPOSE: Lower barometric air pressure at altitude can affect competitive performance of athletes in some sports. Reported here are the effects of various altitudes on elite track-and-field athletes' performance. METHODS: Lifetime track and-field performances of athletes placed in the top 16 in at least 1 major international competition between 2000 and 2009 were downloaded from the database at tilastopaja.org. There were 132,104 performances of 1889 athletes at 794 venues. Performances were log-transformed and analyzed using a mixed linear model with fixed effects for 6 levels of altitude and random quadratic effects to adjust for athlete age. RESULTS: Men's and women's sprint events (100-400 m) showed marginal improvements of ~0.2% at altitudes of 500-999 m, and above 1500 m all but the 100- and 110-m hurdles showed substantial improvements of 0.3-0.7%. Some middle- and long-distance events (800-10,000 m) showed marginal impairments at altitudes above 150 m, but above 1000 m the impairments increased dramatically to ~2-4% for events >800 m. There was no consistent trend in the effects of altitude on field events up to 1000 m; above 1000 m, hammer throw showed a marginal improvement of ~1% and discus was impaired by 1-2%. Above 1500 m, triple jump and long jump showed marginal improvements of ~1%. CONCLUSIONS: In middle and long-distance runners, altitudes as low as 150 to 299 m can impair performance. Higher altitudes (>=1000 m) are generally required before decreases in discus performance or enhancements in sprinting, triple and long jump, or hammer throw are seen. PMID- 25710482 TI - Identification of STAT1 and STAT3 specific inhibitors using comparative virtual screening and docking validation. AB - Signal transducers and activators of transcription (STATs) facilitate action of cytokines, growth factors and pathogens. STAT activation is mediated by a highly conserved SH2 domain, which interacts with phosphotyrosine motifs for specific STAT-receptor contacts and STAT dimerization. The active dimers induce gene transcription in the nucleus by binding to a specific DNA-response element in the promoter of target genes. Abnormal activation of STAT signaling pathways is implicated in many human diseases, like cancer, inflammation and auto-immunity. Searches for STAT-targeting compounds, exploring the phosphotyrosine (pTyr)-SH2 interaction site, yielded many small molecules for STAT3 but sparsely for other STATs. However, many of these inhibitors seem not STAT3-specific, thereby questioning the present modeling and selection strategies of SH2 domain-based STAT inhibitors. We generated new 3D structure models for all human (h)STATs and developed a comparative in silico docking strategy to obtain further insight into STAT-SH2 cross-binding specificity of a selection of previously identified STAT3 inhibitors. Indeed, by primarily targeting the highly conserved pTyr-SH2 binding pocket the majority of these compounds exhibited similar binding affinity and tendency scores for all STATs. By comparative screening of a natural product library we provided initial proof for the possibility to identify STAT1 as well as STAT3-specific inhibitors, introducing the 'STAT-comparative binding affinity value' and 'ligand binding pose variation' as selection criteria. In silico screening of a multi-million clean leads (CL) compound library for binding of all STATs, likewise identified potential specific inhibitors for STAT1 and STAT3 after docking validation. Based on comparative virtual screening and docking validation, we developed a novel STAT inhibitor screening tool that allows identification of specific STAT1 and STAT3 inhibitory compounds. This could increase our understanding of the functional role of these STATs in different diseases and benefit the clinical need for more drugable STAT inhibitors with high specificity, potency and excellent bioavailability. PMID- 25710484 TI - Variation in the Antimicrobial Susceptibility of Actinobacillus pleuropneumoniae Isolates in a Pig, Within a Batch of Pigs, and Among Batches of Pigs from One Farm. AB - Antimicrobial resistance in bacterial porcine respiratory pathogens has been shown to exist in many countries. However, little is known about the variability in antimicrobial susceptibility within a population of a single bacterial respiratory pathogen on a pig farm. This study examined the antimicrobial susceptibility of Actinobacillus pleuropneumoniae using multiple isolates within a pig and across the pigs in three different slaughter batches. Initially, the isolates from the three batches were identified, serotyped, and subsample genotyped. All the 367 isolates were identified as A. pleuropneumoniae serovar 1, and only a single genetic profile was detected in the 74 examined isolates. The susceptibility of the 367 isolates of A. pleuropneumoniae to ampicillin, tetracycline and tilmicosin was determined by a disc diffusion technique. For tilmicosin, the three batches were found to consist of a mix of susceptible and resistant isolates. The zone diameters of the three antimicrobials varied considerably among isolates in the second sampling. In addition, the second sampling provided statistically significant evidence of bimodal populations in terms of zone diameters for both tilmicosin and ampicillin. The results support the hypothesis that the antimicrobial susceptibility of one population of a porcine respiratory pathogen can vary within a batch of pigs on a farm. PMID- 25710486 TI - Learning from PAINful lessons. AB - Chemical probes are important both as tools to understand biology and as starting points for drug leads, but not every active molecule makes a good probe; many react nonspecifically with thiols. These promiscuous inhibitors are worse than useless because they can mislead researchers and muddy the literature. Understanding the mechanisms of such compounds can prevent scientists from following false hits down blind alleys. PMID- 25710485 TI - Liquid-solid phase-inversion PLGA implant for the treatment of residual tumor tissue after HIFU ablation. AB - BACKGROUND: HIFU has been shown to be a more suitable alternative for the treatment of primary solid tumors and metastatic diseases than other focal heat ablation techniques due to its noninvasive and extracorporeal nature. However, similar to other focal heat ablation techniques, HIFU is still in need of refinements due to tumor recurrence. METHODS: In this work, we investigated the effectiveness of an adjunct treatment regimen using doxorubicin (DOX)-loaded, injectable, in situ-forming, and phase-inverting PLGA as the second line of defense after HIFU ablation to destroy detrimental residual tumors and to prevent tumor recurrence. All of the statistical analyses were performed using the Statistical Package for the Social Sciences 18.0 (SPSS, Inc., Chicago, IL, USA), and p<0.05 was considered statistically significant. All of the results are presented as the means +/- STDEV (standard deviation). For multiple comparisons, ANOVA (differences in tumor volumes, growth rates, apoptosis, proliferation indexes, and Bcl-2 and Bax protein levels) was used when the data were normally distributed with homogenous variance, and rank sum tests were used otherwise. Once significant differences were detected, Student-t tests were used for comparisons between two groups. RESULTS: Our results revealed that DOX diffused beyond the ablated tissue regions and entered tumor cells that were not affected by the HIFU ablation. Our results also show that HIFU in concert with DOX-loaded PLGA led to a significantly higher rate of tumor cell apoptosis and a lower rate of tumor cell proliferation in the areas beyond the HIFU-ablated tissues and consequently caused significant tumor volume shrinkage (tumor volumes:0.26+/ 0.1,1.09+/-0.76, and 1.42+/-0.9 cm3 for treatment, sham, and no treatment control, respectively). CONCLUSIONS: From these results, we concluded that the intralesional injection of DOX-loaded PLGA after HIFU ablation is significantly more effective than HIFU alone for the treatment of solid tumors. PMID- 25710487 TI - It takes two to tango: a new partner in amylose synthesis. AB - The mechanism by which plants make starch-a vital foodstuff for billions of humans-is poorly understood, with a clear role for just one enzyme, granular binding starch synthase. A new study identifies a protein needed to recruit this enzyme to the starch granule. Read the Research Article. PMID- 25710488 TI - Promotion of ovarian follicle growth following mTOR activation: synergistic effects of AKT stimulators. AB - Mammalian target of rapamycin (mTOR) is a serine/threonine kinase and mTOR signaling is important in regulating cell growth and proliferation. Recent studies using oocyte- and granulosa cell-specific deletion of mTOR inhibitor genes TSC1 or TSC2 demonstrated the important role of mTOR signaling in the promotion of ovarian follicle development. We now report that treatment of ovaries from juvenile mice with an mTOR activator MHY1485 stimulated mTOR, S6K1 and rpS6 phosphorylation. Culturing ovaries for 4 days with MHY1485 increased ovarian explant weights and follicle development. In vivo studies further demonstrated that pre-incubation of these ovaries with MHY1485 for 2 days, followed by allo-grafting into kidney capsules of adult ovariectomized hosts for 5 days, led to marked increases in graft weights and promotion of follicle development. Mature oocytes derived from MHY1485-activated ovarian grafts could be successfully fertilized, leading the delivery of healthy pups. We further treated ovaries with the mTOR activator together with AKT activators (PTEN inhibitor and phosphoinositol-3-kinase stimulator) before grafting and found additive enhancement of follicle growth. Our studies demonstrate the ability of an mTOR activator in promoting follicle growth, leading to a potential strategy to stimulate preantral follicle growth in infertile patients. PMID- 25710489 TI - Negative regulation of DSS-induced experimental colitis by PILRalpha. AB - Inflammatory bowel disease is thought to be a complex multifactorial disease, in which an increased inflammatory response plays an important role. Paired immunoglobulin-like type 2 receptor alpha (PILRalpha), well conserved in almost all mammals, is an inhibitory receptor containing immunoreceptor tyrosine-based inhibitory motifs in the cytoplasmic domain. PILRalpha is mainly expressed on myeloid cells and plays an important role in the regulation of inflammation. In the present study, we investigated the function of PILRalpha in inflammatory bowel disease using PILRalpha-deficient mice. When mice were orally administered dextran sulfate sodium (DSS), colonic mucosal injury and inflammation were significantly exacerbated in DSS-treated PILRalpha-deficient mice compared with wild-type (WT) mice. Flow cytometric analysis revealed that neutrophil and macrophage cell numbers were higher in the colons of DSS-treated PILRalpha deficient mice than in those of WT mice. Blockade of CXCR2 expressed on neutrophils using a CXCR2 inhibitor decreased the severity of colitis observed in PILRalpha-deficient mice. These results suggest that PILRalpha negatively regulates inflammatory colitis by regulating the infiltration of inflammatory cells such as neutrophils and macrophages. PMID- 25710490 TI - CD1d-dependent expansion of NKT follicular helper cells in vivo and in vitro is a product of cellular proliferation and differentiation. AB - NKT follicular helper cells (NKTfh cells) are a recently discovered functional subset of CD1d-restricted NKT cells. Given the potential for NKTfh cells to promote specific antibody responses and germinal center reactions, there is much interest in determining the conditions under which NKTfh cells proliferate and/or differentiate in vivo and in vitro. We confirm that NKTfh cells expressing the canonical semi-invariant Valpha14 TCR were CXCR5(+)/ICOS(+)/PD-1(+)/Bcl6(+) and increased in number following administration of the CD1d-binding glycolipid alpha galactosylceramide (alpha-GC) to C57Bl/6 mice. We show that the alpha-GC stimulated increase in NKTfh cells was CD1d-dependent since the effect was diminished by reduced CD1d expression. In vivo and in vitro treatment with alpha GC, singly or in combination with IL-2, showed that NKTfh cells increased in number to a greater extent than total NKT cells, but proliferation was near identical in both populations. Acquisition of the NKTfh phenotype from an adoptively transferred PD-1-depleted cell population was also evident, showing that peripheral NKT cells differentiated into NKTfh cells. Therefore, the alpha GC-stimulated, CD1d-dependent increase in peripheral NKTfh cells is a result of cellular proliferation and differentiation. These findings advance our understanding of the immune response following immunization with CD1d-binding glycolipids. PMID- 25710491 TI - Hybridization-sensitive fluorescent oligonucleotide probe conjugated with a bulky module for compartment-specific mRNA monitoring in a living cell. AB - Live-cell RNA imaging at specific intracellular locations is technically limited because of the diffusive nature of small oligonucleotide probes. The bulky fluorescent light-up probes that possess streptavidin or gold nanoparticles at the end of oligonucleotides were designed and synthesized. The bulky probes allowed nucleus- and cytoplasm-selective monitoring of endogenous mRNAs through nuclear and cytoplasmic microinjection, respectively. Simultaneous use of bulky and unbulky probes conjugated with different fluorescent dyes enabled dual color imaging of mRNAs present in nucleus and cytoplasm. Furthermore, we observed that the fluorescence near the cell edge in a living HeLa cell traveled over time in coordination with the dynamic formation and deformation of the pseudopodial protrusions after lipofection of the bulky probes. PMID- 25710493 TI - Overexpression of cotton RAV1 gene in Arabidopsis confers transgenic plants high salinity and drought sensitivity. AB - RAV (related to ABI3/VP1) protein containing an AP2 domain in the N-terminal region and a B3 domain in the C-terminal region, which belongs to AP2 transcription factor family, is unique in higher plants. In this study, a gene (GhRAV1) encoding a RAV protein of 357 amino acids was identified in cotton (Gossypium hirsutum). Transient expression analysis of the eGFP:GhRAV1 fusion genes in tobacco (Nicotiana tabacum) epidermal cells revealed that GhRAV1 protein was localized in the cell nucleus. Quantitative RT-PCR analysis indicated that expression of GhRAV1 in cotton is induced by abscisic acid (ABA), NaCl and polyethylene glycol (PEG). Overexpression of GhRAV1 in Arabidopsis resulted in plant sensitive to ABA, NaCl and PEG. With abscisic acid (ABA) treatment, seed germination and green seedling rates of the GhRAV1 transgenic plants were remarkably lower than those of wild type. In the presence of NaCl, the seed germination and seedling growth of the GhRAV1 transgenic lines were inhibited greater than those of wild type. And chlorophyll content and maximum photochemical efficiency of the transgenic plants were significantly lower than those of wild type. Under drought stress, the GhRAV1 transgenic plants displayed more severe wilting than wild type. Furthermore, expressions of the stress related genes were altered in the GhRAV1 transgenic Arabidopsis plants under high salinity and drought stresses. Collectively, our data suggested that GhRAV1 may be involved in response to high salinity and drought stresses through regulating expressions of the stress-related genes during cotton development. PMID- 25710492 TI - A gamma-secretase inhibitor, but not a gamma-secretase modulator, induced defects in BDNF axonal trafficking and signaling: evidence for a role for APP. AB - Clues to Alzheimer disease (AD) pathogenesis come from a variety of different sources including studies of clinical and neuropathological features, biomarkers, genomics and animal and cellular models. An important role for amyloid precursor protein (APP) and its processing has emerged and considerable interest has been directed at the hypothesis that Abeta peptides induce changes central to pathogenesis. Accordingly, molecules that reduce the levels of Abeta peptides have been discovered such as gamma-secretase inhibitors (GSIs) and modulators (GSMs). GSIs and GSMs reduce Abeta levels through very different mechanisms. However, GSIs, but not GSMs, markedly increase the levels of APP CTFs that are increasingly viewed as disrupting neuronal function. Here, we evaluated the effects of GSIs and GSMs on a number of neuronal phenotypes possibly relevant to their use in treatment of AD. We report that GSI disrupted retrograde axonal trafficking of brain-derived neurotrophic factor (BDNF), suppressed BDNF-induced downstream signaling pathways and induced changes in the distribution within neuronal processes of mitochondria and synaptic vesicles. In contrast, treatment with a novel class of GSMs had no significant effect on these measures. Since knockdown of APP by specific siRNA prevented GSI-induced changes in BDNF axonal trafficking and signaling, we concluded that GSI effects on APP processing were responsible, at least in part, for BDNF trafficking and signaling deficits. Our findings argue that with respect to anti-amyloid treatments, even an APP-specific GSI may have deleterious effects and GSMs may serve as a better alternative. PMID- 25710494 TI - Proteomic profiling of the outer membrane fraction of the obligate intracellular bacterial pathogen Ehrlichia ruminantium. AB - The outer membrane proteins (OMPs) of Gram-negative bacteria play a crucial role in virulence and pathogenesis. Identification of these proteins represents an important goal for bacterial proteomics, because it aids in vaccine development. Here, we have developed such an approach for Ehrlichia ruminantium, the obligate intracellular bacterium that causes heartwater. A preliminary whole proteome analysis of elementary bodies, the extracellular infectious form of the bacterium, had been performed previously, but information is limited about OMPs in this organism and about their role in the protective immune response. Identification of OMPs is also essential for understanding Ehrlichia's OM architecture, and how the bacterium interacts with the host cell environment. First, we developed an OMP extraction method using the ionic detergent sarkosyl, which enriched the OM fraction. Second, proteins were separated via one dimensional electrophoresis, and digested peptides were analyzed via nano-liquid chromatographic separation coupled with mass spectrometry (LC-MALDI-TOF/TOF). Of 46 unique proteins identified in the OM fraction, 18 (39%) were OMPs, including 8 proteins involved in cell structure and biogenesis, 4 in transport/virulence, 1 porin, and 5 proteins of unknown function. These experimental data were compared to the predicted subcellular localization of the entire E. ruminantium proteome, using three different algorithms. This work represents the most complete proteome characterization of the OM fraction in Ehrlichia spp. The study indicates that suitable subcellular fractionation experiments combined with straightforward computational analysis approaches are powerful for determining the predominant subcellular localization of the experimentally observed proteins. We identified proteins potentially involved in E. ruminantium pathogenesis, which are good novel targets for candidate vaccines. Thus, combining bioinformatics and proteomics, we discovered new OMPs for E. ruminantium that are valuable data for those investigating new vaccines against this organism. In summary, we provide both pioneering data and novel insights into the pathogenesis of this obligate intracellular bacterium. PMID- 25710495 TI - Sleep-wake evaluation from whole-night non-contact audio recordings of breathing sounds. AB - STUDY OBJECTIVES: To develop and validate a novel non-contact system for whole night sleep evaluation using breathing sounds analysis (BSA). DESIGN: Whole-night breathing sounds (using ambient microphone) and polysomnography (PSG) were simultaneously collected at a sleep laboratory (mean recording time 7.1 hours). A set of acoustic features quantifying breathing pattern were developed to distinguish between sleep and wake epochs (30 sec segments). Epochs (n = 59,108 design study and n = 68,560 validation study) were classified using AdaBoost classifier and validated epoch-by-epoch for sensitivity, specificity, positive and negative predictive values, accuracy, and Cohen's kappa. Sleep quality parameters were calculated based on the sleep/wake classifications and compared with PSG for validity. SETTING: University affiliated sleep-wake disorder center and biomedical signal processing laboratory. PATIENTS: One hundred and fifty patients (age 54.0+/-14.8 years, BMI 31.6+/-5.5 kg/m2, m/f 97/53) referred for PSG were prospectively and consecutively recruited. The system was trained (design study) on 80 subjects; validation study was blindly performed on the additional 70 subjects. MEASUREMENTS AND RESULTS: Epoch-by-epoch accuracy rate for the validation study was 83.3% with sensitivity of 92.2% (sleep as sleep), specificity of 56.6% (awake as awake), and Cohen's kappa of 0.508. Comparing sleep quality parameters of BSA and PSG demonstrate average error of sleep latency, total sleep time, wake after sleep onset, and sleep efficiency of 16.6 min, 35.8 min, and 29.6 min, and 8%, respectively. CONCLUSIONS: This study provides evidence that sleep-wake activity and sleep quality parameters can be reliably estimated solely using breathing sound analysis. This study highlights the potential of this innovative approach to measure sleep in research and clinical circumstances. PMID- 25710497 TI - Physical and economic impacts of sea-level rise and low probability flooding events on coastal communities. AB - Conventionally flood mapping typically includes only a static water level (e.g. peak of a storm tide) in coastal flood inundation events. Additional factors become increasingly important when increased water-level thresholds are met during the combination of a storm tide and increased mean sea level. This research incorporates factors such as wave overtopping and river flow in a range of flood inundation scenarios of future sea-level projections for a UK case study of Fleetwood, northwest England. With increasing mean sea level it is shown that wave overtopping and river forcing have an important bearing on the cost of coastal flood events. The method presented converts inundation maps into monetary cost. This research demonstrates that under scenarios of joint extreme surge-wave river events the cost of flooding can be increased by up to a factor of 8 compared with an increase in extent of up to a factor of 3 relative to "surge alone" event. This is due to different areas being exposed to different flood hazards and areas with common hazard where flood waters combine non-linearly. This shows that relying simply on flood extent and volume can under-predict the actual economic impact felt by a coastal community. Additionally, the scenario inundation depths have been presented as "brick course" maps, which represent a new way of interpreting flood maps. This is primarily aimed at stakeholders to increase levels of engagement within the coastal community. PMID- 25710496 TI - The neurotrophic receptor Ntrk2 directs lymphoid tissue neovascularization during Leishmania donovani infection. AB - The neurotrophic tyrosine kinase receptor type 2 (Ntrk2, also known as TrkB) and its ligands brain derived neurotrophic factor (Bdnf), neurotrophin-4 (NT-4/5), and neurotrophin-3 (NT-3) are known primarily for their multiple effects on neuronal differentiation and survival. Here, we provide evidence that Ntrk2 plays a role in the pathologic remodeling of the spleen that accompanies chronic infection. We show that in Leishmania donovani-infected mice, Ntrk2 is aberrantly expressed on splenic endothelial cells and that new maturing blood vessels within the white pulp are intimately associated with F4/80(hi)CD11b(lo)CD11c(+) macrophages that express Bdnf and NT-4/5 and have pro-angiogenic potential in vitro. Furthermore, administration of the small molecule Ntrk2 antagonist ANA-12 to infected mice significantly inhibited white pulp neovascularization but had no effect on red pulp vascular remodeling. We believe this to be the first evidence of the Ntrk2/neurotrophin pathway driving pathogen-induced vascular remodeling in lymphoid tissue. These studies highlight the therapeutic potential of modulating this pathway to inhibit pathological angiogenesis. PMID- 25710498 TI - Dual-sensor fluorescent probes of surfactant-induced unfolding of human serum albumin. AB - Two extrinsic fluorescent probes, 3-(dimethylamino)-8,9,10,11-tetrahydro-7H cyclohepta[a]naphthalen-7-one (1) and 7-(dimethylamino)-2,3-dihydrophenanthren 4(1H)-one (2), are used to probe the unfolding of human serum albumin by sodium dodecyl sulfate (SDS). These probes respond separately to the polarity and H-bond donating ability of their surroundings. Competitive binding experiments show that fluorophore 1 binds to site I (domain IIA) and 2 binds to site II (domain IIIA). The local acidity of 1 in site I is out of the sensing range of 1, whereas the local acidity of 2 in site II is calculated to be nearly zero on Catalan's solvent acidity index. Both probes show that the first two equivalents of bound SDS result in a decrease in the local polarity of the binding sites. Each subsequent equivalent of SDS gives rise to a dramatic increase in polarity until HSA is saturated with seven molecules of SDS at the end of the specific binding domain. Compound 2 experiences an increase of acidity of 0.10 on Catalan's solvent acidity index through seven equivalents of SDS, but the local acidity for 1 is still out of range. The increase in acidity experienced by 2 is greater than the increase in polarity. This result is consistent with greater exposure of the carbonyl group in 2, but not the bulk of 2, to the aqueous solvent in site II of the SDS-saturated HSA complex. PMID- 25710499 TI - Robust volume assessment of brain tissues for 3-dimensional fourier transformation MRI via a novel multispectral technique. AB - A new TRIO algorithm method integrating three different algorithms is proposed to perform brain MRI segmentation in the native coordinate space, with no need of transformation to a standard coordinate space or the probability maps for segmentation. The method is a simple voxel-based algorithm, derived from multispectral remote sensing techniques, and only requires minimal operator input to depict GM, WM, and CSF tissue clusters to complete classification of a 3D high resolution multislice-multispectral MRI data. Results showed very high accuracy and reproducibility in classification of GM, WM, and CSF in multislice multispectral synthetic MRI data. The similarity indexes, expressing overlap between classification results and the ground truth, were 0.951, 0.962, and 0.956 for GM, WM, and CSF classifications in the image data with 3% noise level and 0% non-uniformity intensity. The method particularly allows for classification of CSF with 0.994, 0.961 and 0.996 of accuracy, sensitivity and specificity in images data with 3% noise level and 0% non-uniformity intensity, which had seldom performed well in previous studies. As for clinical MRI data, the quantitative data of brain tissue volumes aligned closely with the brain morphometrics in three different study groups of young adults, elderly volunteers, and dementia patients. The results also showed very low rates of the intra- and extra-operator variability in measurements of the absolute volumes and volume fractions of cerebral GM, WM, and CSF in three different study groups. The mean coefficients of variation of GM, WM, and CSF volume measurements were in the range of 0.03% to 0.30% of intra-operator measurements and 0.06% to 0.45% of inter-operator measurements. In conclusion, the TRIO algorithm exhibits a remarkable ability in robust classification of multislice-multispectral brain MR images, which would be potentially applicable for clinical brain volumetric analysis and explicitly promising in cross-sectional and longitudinal studies of different subject groups. PMID- 25710500 TI - Negligible "negative space-charge layer effects" at oxide-electrolyte/electrode interfaces of thin-film batteries. AB - In this paper, we report the surprisingly low electrolyte/electrode interface resistance of 8.6 Omega cm(2) observed in thin-film batteries. This value is an order of magnitude smaller than that presented in previous reports on all-solid state lithium batteries. The value is also smaller than that found in a liquid electrolyte-based batteries. The low interface resistance indicates that the negative space-charge layer effects at the Li3PO(4-x)N(x)/LiCoO2 interface are negligible and demonstrates that it is possible to fabricate all-solid state batteries with faster charging/discharging properties. PMID- 25710501 TI - PROTEIN TARGETING TO STARCH is required for localising GRANULE-BOUND STARCH SYNTHASE to starch granules and for normal amylose synthesis in Arabidopsis. AB - The domestication of starch crops underpinned the development of human civilisation, yet we still do not fully understand how plants make starch. Starch is composed of glucose polymers that are branched (amylopectin) or linear (amylose). The amount of amylose strongly influences the physico-chemical behaviour of starchy foods during cooking and of starch mixtures in non-food manufacturing processes. The GRANULE-BOUND STARCH SYNTHASE (GBSS) is the glucosyltransferase specifically responsible for elongating amylose polymers and was the only protein known to be required for its biosynthesis. Here, we demonstrate that PROTEIN TARGETING TO STARCH (PTST) is also specifically required for amylose synthesis in Arabidopsis. PTST is a plastidial protein possessing an N-terminal coiled coil domain and a C-terminal carbohydrate binding module (CBM). We discovered that Arabidopsis ptst mutants synthesise amylose-free starch and are phenotypically similar to mutants lacking GBSS. Analysis of granule-bound proteins showed a dramatic reduction of GBSS protein in ptst mutant starch granules. Pull-down assays with recombinant proteins in vitro, as well as immunoprecipitation assays in planta, revealed that GBSS physically interacts with PTST via a coiled coil. Furthermore, we show that the CBM domain of PTST, which mediates its interaction with starch granules, is also required for correct GBSS localisation. Fluorescently tagged Arabidopsis GBSS, expressed either in tobacco or Arabidopsis leaves, required the presence of Arabidopsis PTST to localise to starch granules. Mutation of the CBM of PTST caused GBSS to remain in the plastid stroma. PTST fulfils a previously unknown function in targeting GBSS to starch. This sheds new light on the importance of targeting biosynthetic enzymes to sub-cellular sites where their action is required. Importantly, PTST represents a promising new gene target for the biotechnological modification of starch composition, as it is exclusively involved in amylose synthesis. PMID- 25710502 TI - A retrospective observational study of the relationship between single nucleotide polymorphisms associated with the risk of developing colorectal cancer and survival. AB - BACKGROUND: There is variability in clinical outcome for patients with apparently the same stage colorectal cancer (CRC). Single nucleotide polymorphisms (SNPs) mapping to chromosomes 1q41, 3q26.2, 6p21, 8q23.3, 8q24.21, 10p14, 11q13, 11q23.1, 12q13.13, 14q22, 14q22.2, 15q13.3, 16q22.1, 18q21.1, 19q13.11, 20p12, 20p12.3, 20q13.33 and Xp22 have robustly been shown to be associated with the risk of developing CRC. Since germline variation can also influence patient outcome the relationship between these SNPs and patient survivorship from CRC was examined. METHODS: All enrolled into the National Study of Colorectal Cancer Genetics (NSCCG) were genotyped for 1q41, 3q26.2, 6p21, 8q23.3, 8q24.21, 10p14, 11q13, 11q23.1, 12q13.13, 14q22, 14q22.2, 15q13.3, 16q22.1, 18q21.1, 19q13.11, 20p12, 20p12.3, 20q13.33 and xp22 SNPs. Linking this information to the National Cancer Data Repository allowed patient genotype to be related to survival. RESULTS: The linked dataset consisted of 4,327 individuals. 14q22.22 genotype defined by the SNP rs4444235 showed a significant association with overall survival. Specifically, the C allele was associated with poorer observed survival (per allele hazard ratio 1.13, 95% confidence interval 1.05-1.22, P = 0.0015). CONCLUSION: The CRC susceptibility SNP rs4444235 also appears to exert an influence in modulating patient survival and warrants further evaluation as a potential prognostic marker. PMID- 25710503 TI - Using extreme value theory approaches to forecast the probability of outbreak of highly pathogenic influenza in Zhejiang, China. AB - BACKGROUND: Influenza is a contagious disease with high transmissibility to spread around the world with considerable morbidity and mortality and presents an enormous burden on worldwide public health. Few mathematical models can be used because influenza incidence data are generally not normally distributed. We developed a mathematical model using Extreme Value Theory (EVT) to forecast the probability of outbreak of highly pathogenic influenza. METHODS: The incidence data of highly pathogenic influenza in Zhejiang province from April 2009 to November 2013 were retrieved from the website of Health and Family Planning Commission of Zhejiang Province. MATLAB "VIEM" toolbox was used to analyze data and modelling. In the present work, we used the Peak Over Threshold (POT) model, assuming the frequency as a Poisson process and the intensity to be Pareto distributed, to characterize the temporal variability of the long-term extreme incidence of highly pathogenic influenza in Zhejiang, China. RESULTS: The skewness and kurtosis of the incidence of highly pathogenic influenza in Zhejiang between April 2009 and November 2013 were 4.49 and 21.12, which indicated a "fat tail" distribution. A QQ plot and a mean excess plot were used to further validate the features of the distribution. After determining the threshold, we modeled the extremes and estimated the shape parameter and scale parameter by the maximum likelihood method. The results showed that months in which the incidence of highly pathogenic influenza is about 4462/2286/1311/487 are predicted to occur once every five/three/two/one year, respectively. CONCLUSIONS: Despite the simplicity, the present study successfully offers the sound modeling strategy and a methodological avenue to implement forecasting of an epidemic in the midst of its course. PMID- 25710504 TI - Humanitarian access to unapproved interventions in public health emergencies of international concern. AB - Jerome Singh considers how regulatory mechanisms can allow access to experimental interventions in humanitarian emergencies such as the Ebola epidemic. PMID- 25710506 TI - Peptide receptor radionuclide therapy: an overview. AB - Peptide receptor radionuclide therapy (PRRT) is a site-directed targeted therapeutic strategy that specifically uses radiolabeled peptides as biological targeting vectors designed to deliver cytotoxic levels of radiation dose to cancer cells, which overexpress specific receptors. Interest in PRRT has steadily grown because of the advantages of targeting cellular receptors in vivo with high sensitivity as well as specificity and treatment at the molecular level. Recent advances in molecular biology have not only stimulated advances in PRRT in a sustainable manner but have also pushed the field significantly forward to several unexplored possibilities. Recent decades have witnessed unprecedented endeavors for developing radiolabeled receptor-binding somatostatin analogs for the treatment of neuroendocrine tumors, which have played an important role in the evolution of PRRT and paved the way for the development of other receptor targeting peptides. Several peptides targeting a variety of receptors have been identified, demonstrating their potential to catalyze breakthroughs in PRRT. In this review, the authors discuss several of these peptides and their analogs with regard to their applications and potential in radionuclide therapy. The advancement in the availability of combinatorial peptide libraries for peptide designing and screening provides the capability of regulating immunogenicity and chemical manipulability. Moreover, the availability of a wide range of bifunctional chelating agents opens up the scope of convenient radiolabeling. For these reasons, it would be possible to envision a future where the scope of PRRT can be tailored for patient-specific application. While PRRT lies at the interface between many disciplines, this technology is inextricably linked to the availability of the therapeutic radionuclides of required quality and activity levels and hence their production is also reviewed. PMID- 25710508 TI - Cone-beam computed tomography for planning and assessing surgical outcomes of osteo-odonto-keratoprosthesis. AB - PURPOSE: The aim of this study was to investigate the feasibility and effectiveness of cone-beam computed tomography (CBCT) in the planning, assessment, and follow-up for osteo-odonto-keratoprosthesis (OOKP). METHODS: Six OOKP patients received a CBCT scan. CBCT scans were performed before and/or between ~5 and 504 months after the primary OOKP intervention. Preoperative and postoperative results of the CBCT were assessed, regarding the available teeth and to assess the loss of bone in 1 patient, respectively. Resorption of the osteo-odonto-lamina was measured and graded. Five different measurements (I-V) were performed in the coronal and transversal views of CBCT. RESULTS: Four CBCT scans were performed preoperatively and 4 postoperatively. The follow-up time of the patients is between ~1 to 528 months. Visualization of the potential donor teeth resulted in accurate 3-dimensional visualization of the tooth-lamina-bone complex. CBCT was found to help in the preoperative decision-making process (diameter of optical implant) and in enabling accurate postoperative evaluation of the bone volume and resorption zones of the OOKP. Loss of bone could be measured in a precise range and showed in the completed cases an average loss of 20.2%. CONCLUSIONS: The use of CBCT simplifies the preoperative decision making and ordering process. It also helps in determining the postoperative structure and resorption of the prosthesis. PMID- 25710507 TI - Ultraviolet A/riboflavin collagen cross-linking for treatment of moderate bacterial corneal ulcers. AB - PURPOSE: To evaluate the therapeutic effect of UV-A/riboflavin collagen cross linking (CXL) on moderate bacterial corneal ulcers. METHODS: Thirty-two patients with moderate bacterial keratitis were selected. All patients were treated according to the standard medical treatment protocol. The patients were randomly allocated to 2 groups: case and control groups of 16 patients each using a numerical randomization table. The case group received CXL treatment. In the CLX group, corneal epithelium was removed and 0.1% riboflavin drops were applied. Then the corneas were irradiated with UV-A (365 nm) with an irradiance of 3 mW/cm for 30 minutes. The grade of ulcers, size of epithelial defects, and area of infiltrates were recorded on days 1, 7, and 14 of treatment. RESULTS: There was no statistically significant difference between the groups 1 day after the treatment. The mean treatment duration was 17.2 +/- 4.1 days in the CXL group and 24.7 +/- 5.5 days in the control group. The epithelial defects were smaller in the CXL group at 7 days (P = 0.001) and 14 days (P = 0.001) after the beginning of treatment. The area of infiltrates in CXL group was smaller than the control group at both 7 days (P = 0.001) and 14 days (P < 0.001) after the start of treatment. CONCLUSIONS: Our results support the beneficial effect of CXL in patients with moderate bacterial keratitis. In addition to accelerating epithelialization, this method shortens the course of treatment and may minimize or remove the need for surgery or other serious sequelae, such as corneal perforation. PMID- 25710509 TI - Factors associated with age of onset of herpes zoster ophthalmicus. AB - PURPOSE: The aim of this study was to evaluate factors associated with the age of onset of herpes zoster ophthalmicus (HZO) in the era of varicella vaccination. METHODS: A retrospective series of 400 subjects with a diagnosis of HZO, and an analysis of public health databases. Variables studied included the age at onset, period of disease onset (1996-2004 and 2005-2012), sex, smoking habits, diabetes status, autoimmunity, and immunosuppressed status. Community data were gathered from the Oklahoma Outpatient Surgery Discharge Public Use Data File and the United States Census' American Community Survey data set. RESULTS: The mean onset age was significantly lower for 2005 to 2012 as compared with 1996 to 2004 among females (mean decrease, 9.3 years; 95% confidence interval, 4.6-13.9 years; P < 0.0001), but the mean onset age was similar between the 2 periods among males (P = 0.640). Whereas 32.3% of the patients with zoster were <60 years old in 1996 to 2004, compared with 44.8% in the 2005 to 2012 period (chi test: P = 0.017). In the multivariate model, smokers were found to have disease onset 11.5 (95% confidence interval, 6.9-16.1) years younger than nonsmokers. CONCLUSIONS: The proportion of younger patients with HZO increased, whereas the institutional and community data sets demonstrate a downward shift of the average age of onset of HZO among females. This may be an effect of widespread childhood varicella vaccination. Immunosuppression and smoking were also associated with a younger age of onset of HZO. This has implications for clinical care of patients at risk for developing HZO, as well as public health and vaccination policies. PMID- 25710511 TI - Association between diabetes and keratoconus: a case-control study. PMID- 25710512 TI - Reply: To PMID 25343697. PMID- 25710510 TI - Corneal nerve structure and function after long-term wear of fluid-filled scleral lens. AB - PURPOSE: The aim of this study was to determine whether long-term wear of a fluid filled scleral lens alters basal tear production, corneal sensation, corneal nerve density, and corneal nerve morphology in 2 disease categories. METHODS: Patients recruited from the Prosthetic Replacement of the Ocular Surface Ecosystem (PROSE) treatment program at the Weill Cornell Medical College were categorized into 2 groups: distorted corneas (DC) or ocular surface disease (OSD). We measured tear production, central corneal sensation, subbasal nerve density and tortuosity, and stromal nerve thickness before and after long-term wear of the prosthetic device used in PROSE treatment, defined as at least 60 days of wear for a minimum of 8 hours a day. RESULTS: Twenty patients were included in the study. After long-term wear of the prosthetic device, tear production decreased in patients with DC (21.2 +/- 8.5 to 10.4 +/- 4.6 mm; P < 0.0001) but did not change in patients with OSD (7.5 +/- 5.2 to 8.7 +/- 7.2 mm; P = 0.71). Corneal sensation increased in the DC group (45.6 +/- 9.2 to 55.0 +/- 5.6 mm; P < 0.05). There was no significant change in sensation in patients with OSD (45.0 +/- 8.7 to 49.1 +/- 14.8 mm; P = 0.37). Subbasal nerve density, subbasal nerve tortuosity, and stromal nerve thickness remained unchanged in both DC and OSD groups after long-term wear (P > 0.05). CONCLUSIONS: Patients with DC had significantly reduced basal tear production and increased corneal sensation after long-term wear of the scleral lens, but patients with OSD did not show any changes in tear production or corneal sensation. PMID- 25710513 TI - Commentary: Migrant study designs for epigenetic studies of disease risk. PMID- 25710515 TI - Gold(I)-catalyzed dearomative Rautenstrauch rearrangement: enantioselective access to cyclopenta[b]indoles. AB - A highly enantioselective dearomative Rautenstrauch rearrangement catalyzed by cationic (S)-DTBM-Segphosgold(I) is reported. This reaction provides a straightforward method to prepare enantioenriched cyclopenta[b]indoles. These studies show vast difference in enantioselectivity in the reactions of propargyl acetates and propargyl acetals in the chiral ligand-controlled Rautenstrauch reaction. PMID- 25710516 TI - Quantitative drug-susceptibility in patients treated for multidrug-resistant tuberculosis in Bangladesh: implications for regimen choice. AB - BACKGROUND: Multidrug-resistant tuberculosis (MDR-TB) treatment in Bangladesh is empiric or based on qualitative drug-susceptibility testing (DST) by comparative growth in culture media with and without a single drug concentration. METHODS: Adult patients were enrolled throughout Bangladesh during the period of 2011-2013 at MDR-TB treatment initiation. Quantitative DST by minimum inhibitory concentration (MIC) testing for 12 first and second-line anti-TB drugs was compared to pretreatment clinical characteristics and treatment outcomes. MIC values at or one dilution lower than the resistance breakpoint used for qualitative DST were categorized as borderline susceptible, and MIC values one or two dilutions greater as borderline resistant. RESULTS: Seventy-four patients were enrolled with a mean age of 35 +/- 15 years, and 51 (69%) were men. Of the rifampin isolates with MIC >1.0 MUg/ml, 12 (19%) were fully susceptible or borderline susceptible to rifabutin (MIC <= 0.5 MUg/ml). Amikacin was fully susceptible in 73 isolates (99%), but kanamycin in only 54 (75%) (p<0.001). Ofloxacin was borderline susceptible in 64%, and fully susceptible in only 14 (19%) compared to 60 (81%) of isolates fully susceptible for moxifloxacin (p<0.001). Kanamycin non-susceptibility and receipt of the WHO Category IV regimen trended with interim treatment failure: adjusted odd ratios respectively of 5.4 [95% CI 0.82-36.2] (p = 0.08) and 7.2 [0.64-80.7] (p = 0.11). CONCLUSIONS: Quantitative MIC testing could impact MDR-TB regimen choice in Bangladesh. Comparative trials of higher dose or later generation fluoroquinolone, within class change from kanamycin to amikacin, and inclusion of rifabutin appear warranted. PMID- 25710517 TI - Modification of an Internet-based patient education program for adults with schizophrenia spectrum disorder to suit adolescents with psychosis. AB - INTRODUCTION: The overall goal of this study was to produce a user-friendly and high quality Internet-based patient education program for adolescents with psychosis. To achieve this, we ascertained the adolescents' and health care professionals' needs and expectations of patient education using Internet and the improvement proposals for an existing MentalNet program originally developed for adults with schizophrenia. METHODS: The research process was conducted in two phases. First, adolescents' and healthcare professionals' needs for patient education and Internet were ascertained by interviewing adolescents and in two educational sessions with staff members (Phase I). Second, the preliminary evaluation of the Internet-based patient education program MentalNet was gathered from adolescents by an iterative process (see cyclic, recurring, repeating method), in one educational session with staff members and a questionnaire via email from other health care professionals (Phase II). RESULTS: The needs and expectations of adolescents and health care professionals were related to the content, usability, design and realization of Internet-based patient education. Based on the information obtained the MentalNet program was modified to satisfy adolescents' needs. DISCUSSION: The usefulness and effectiveness of the program will require scrutiny in future studies. PMID- 25710518 TI - Per-oral immunization with antigen-conjugated nanoparticles followed by sub cutaneous boosting immunization induces long-lasting mucosal and systemic antibody responses in mice. AB - Food or water-borne enteric pathogens invade their hosts via intestinal mucosal surfaces, thus developing effective oral vaccines would greatly reduce the burden of infectious diseases. The nature of the antigen, as well as the mode of its internalization in the intestinal mucosa affects the ensuing immune response. We show that model protein antigen ovalbumin (Ova) given per-orally (p.o.) induces oral tolerance (OT), characterized by systemic IgG1-dominated antibody response, which cannot be boosted by sub-cutaneous (s.c.) immunization with Ova in complete Freund's adjuvant (CFA). Intestinal IgA generated in response to Ova feeding diminished over time and was abrogated by s.c. immunization with Ova+CFA. Humoral response to Ova was altered by administering Ova conjugated to 20 nm nanoparticles (NP-Ova). P.o. administration of NP-Ova induced systemic IgG1/IgG2c, and primed the intestinal mucosa for secretion of IgA. These responses were boosted by secondary s.c. immunization with Ova+CFA or p.o. immunization with NP-Ova. However, only in s.c.-boosted mice serum and mucosal antibody titers remained elevated for 6 months after priming. In contrast, s.c. priming with NP-Ova induced IgG1-dominated serum antibodies, but did not prime the intestinal mucosa for secretion of IgA, even after secondary p.o. immunization with NP-Ova. These results indicate that Ova conjugated to NPs reaches the internal milieu in an immunogenic form and that mucosal immunization with NP-Ova is necessary for induction of a polarized Th1/Th2 immune response, as well as intestinal IgA response. In addition, mucosal priming with NP-Ova, followed by s.c. boosting induces superior systemic and mucosal memory responses. These findings are important for the development of efficacious mucosal vaccines. PMID- 25710519 TI - Phenotype shift from atypical scrapie to CH1641 following experimental transmission in sheep. AB - The interactions of host and infecting strain in ovine transmissible spongiform encephalopathies are known to be complex, and have a profound effect on the resulting phenotype of disease. In contrast to classical scrapie, the pathology in naturally-occurring cases of atypical scrapie appears more consistent, regardless of genotype, and is preserved on transmission within sheep homologous for the prion protein (PRNP) gene. However, the stability of transmissible spongiform encephalopathy phenotypes on passage across and within species is not absolute, and there are reports in the literature where experimental transmissions of particular isolates have resulted in a phenotype consistent with a different strain. In this study, intracerebral inoculation of atypical scrapie between two genotypes both associated with susceptibility to atypical forms of disease resulted in one sheep displaying an altered phenotype with clinical, pathological, biochemical and murine bioassay characteristics all consistent with the classical scrapie strain CH1641, and distinct from the atypical scrapie donor, while the second sheep did not succumb to challenge. One of two sheep orally challenged with the same inoculum developed atypical scrapie indistinguishable from the donor. This study adds to the range of transmissible spongiform encephalopathy phenotype changes that have been reported following various different experimental donor-recipient combinations. While these circumstances may not arise through natural exposure to disease in the field, there is the potential for iatrogenic exposure should current disease surveillance and feed controls be relaxed. Future sheep to sheep transmission of atypical scrapie might lead to instances of disease with an alternative phenotype and onward transmission potential which may have adverse implications for both public health and animal disease control policies. PMID- 25710521 TI - The relationship between start performance and race outcome in elite 500-m short track speed skating. AB - Initial short-track speed-skating 14-m start performance has substantial influence on 500-m race outcome at the international level, yet the relationship has not been systematically quantified. The purpose of this investigation was to examine the relationship between rank position entering first corner (RPEFC) and race outcome and to understand how this relationship changes with competition round and absolute race intensity. Data were compiled from 2011-2014 World Cup seasons and 2010 and 2014 Olympic Winter Games. Association between RPEFC and race outcome was determined through Kendall tau-rank correlations. A visual comparison was made of how the relationship changes with relative competition level (race tau correlations were sorted by competition round) and with race intensity (race tau correlations were sorted by within-event winning time). A very large relationship between RPEFC and race outcome was observed (correlations for cohort, tau = .60; men, tau = .53; women, tau = .67). When examined by competition round (quarter- to A-finals), no substantial change in relationship was observed (men, tau = .57-.46; women, tau = .73-.53). However, when the start performance relationship was considered by within-event winning time, the relationship strength increased with decreasing time (men, tau = .61 to .46; women, tau = .76 to .57; fastest to 7th- and 8th-fastest combined, respectively). These results establish and quantify RPEFC as an important aspect of elite short track 500-m race outcome. RPEFC as an indicator of race outcome becomes increasingly important with absolute race intensity, suggesting that RPEFC capability is a discriminating factor for competitors of similar top speed and speed endurance. PMID- 25710520 TI - The DEAH-box helicase Dhr1 dissociates U3 from the pre-rRNA to promote formation of the central pseudoknot. AB - In eukaryotes, the highly conserved U3 small nucleolar RNA (snoRNA) base-pairs to multiple sites in the pre-ribosomal RNA (pre-rRNA) to promote early cleavage and folding events. Binding of the U3 box A region to the pre-rRNA is mutually exclusive with folding of the central pseudoknot (CPK), a universally conserved rRNA structure of the small ribosomal subunit essential for protein synthesis. Here, we report that the DEAH-box helicase Dhr1 (Ecm16) is responsible for displacing U3. An active site mutant of Dhr1 blocked release of U3 from the pre ribosome, thereby trapping a pre-40S particle. This particle had not yet achieved its mature structure because it contained U3, pre-rRNA, and a number of early acting ribosome synthesis factors but noticeably lacked ribosomal proteins (r proteins) that surround the CPK. Dhr1 was cross-linked in vivo to the pre-rRNA and to U3 sequences flanking regions that base-pair to the pre-rRNA including those that form the CPK. Point mutations in the box A region of U3 suppressed a cold-sensitive mutation of Dhr1, strongly indicating that U3 is an in vivo substrate of Dhr1. To support the conclusions derived from in vivo analysis we showed that Dhr1 unwinds U3-18S duplexes in vitro by using a mechanism reminiscent of DEAD box proteins. PMID- 25710522 TI - Sleep Disorders, Physical Activity, and Sedentary Behavior Among U.S. Adults: National Health and Nutrition Examination Survey. AB - BACKGROUND: Disruptive sleeping patterns have been linked to serious medical conditions. Regular physical activity (PA) has a positive impact on health; however, few research have investigated the relationships between PA, body mass index (BMI), sedentary behaviors (SB), and sleep disorders (SD). METHODS: Data from the 2005-2006 NHANES were analyzed for this study. Participants (N = 2989; mean age = 50.44 years) were grouped based upon responses to SD questions. Accelerometers were used to measure the average time spent in moderate or vigorous physical activity (MVPA) and SB. Multinomial logistic regression analyses were used to examine the associations between PA, SB, and SD after controlling for covariates and to explore potential moderation effects among common risk factors and the main study variables. RESULTS: Among middle-aged adults, PA was significantly associated with SD [Wald chi2 (8) = 22.21; P < .001]. Furthermore, among adults in the highest tertile of SB, PA was significantly associated with SD [Wald chi2 (8) = 32.29; P < .001]. CONCLUSIONS: These results indicate that middle-aged adults who are less active may have increased likelihoods of SD. It is important for health care professionals to continue developing methods for increasing PA to decrease the risk of SD. PMID- 25710523 TI - Optimization and technological development strategies of an antimicrobial extract from Achyrocline alata assisted by statistical design. AB - Achyrocline alata, known as Jatei-ka-ha, is traditionally used to treat several health problems, including inflammations and infections. This study aimed to optimize an active extract against Streptococcus mutans, the main bacteria that causes caries. The extract was developed using an accelerated solvent extraction and chemometric calculations. Factorial design and response surface methodologies were used to determine the most important variables, such as active compound selectivity. The standardized extraction recovered 99% of the four main compounds, gnaphaliin, helipyrone, obtusifolin and lepidissipyrone, which represent 44% of the extract. The optimized extract of A. alata has a MIC of 62.5 MUg/mL against S. mutans and could be used in mouth care products. PMID- 25710524 TI - Impact of Diagnostic Delay and Other Risk Factors on Eosinophilic Esophagitis Phenotype and Esophageal Diameter. AB - GOALS: Endoscopic features of eosinophilic esophagitis (EoE) are variable with at least 2 phenotypes. The goal of this study was to classify adult EoE patients based on esophageal phenotype and diameter, and assess an association between demographical and clinical histories to define EoE phenotypes and overall disease progression. METHODS: All consecutive patients with a confirmed diagnosis of EoE from 1988 to 2013 treated at University of South Florida were included. Patients were grouped into inflammatory or fibrostenotic phenotype, and further characterized by esophageal diameter: group 1 (6 to 9.9 mm), group 2 (10 to 16.9 mm), and group 3 (>17 mm-control). Significance level was set at 5%. RESULTS: Sixty-four adult patients met inclusion criteria. Sixty-one percent of patients (39/64) were defined as fibrostenotic and 39% (25/64) as inflammatory phenotype. There was a significant difference in mean time of delayed diagnosis in patients with <10 mm esophageal diameter (14.8 y) and patients with a diameter of 10 to 16.9 mm (11.1 y) compared with patients with an esophageal diameter of >=17 mm (5 y); P=0.002 and 0.006, respectively. Patients on aspirin with delayed diagnosis (>7 y) were significantly more likely to present with strictures (<10 mm) compared with nonaspirin users [odds ratio (OR=7.0; 95% confidence interval (CI), 7.2-31.3; P=0.008]. Similar results were found with non-steroid anti-inflammatory drugs, smoking, and alcohol (OR=6.4; 95% CI, 1.6-26.4; P=0.01, OR=5.2; 95% CI, 1.4-20.1; P=0.02, and OR=6.4; 95% CI, 1.6-26.0; P=0.009), respectively. CONCLUSIONS: In our US population, a delay in diagnosis was shown to be associated with stricture formation in EoE confirming the Swiss experience. The results show the importance of reducing the diagnostic delay in EoE as there appears to be progression to fibrosis over time, aggravated by common medications and social habits. PMID- 25710525 TI - Active Treatments Prolong the Survival in Patients With Hepatocellular Carcinoma and Performance Status 3 or 4: A Propensity Score Analysis. AB - GOALS AND BACKGROUNDS: Best supportive care is suggested as the standard treatment for hepatocellular carcinoma (HCC) patients with performance status (PS) 3-4 by the Barcelona Clinic Liver Cancer (BCLC) system. To investigate the rationale of treatment allocation. STUDY: A total of 2660 HCC patients were reviewed. One-to-one matched pairs between PS 3 and 4 patients receiving supportive care and anti-HCC treatments were generated by using the propensity score with matching model. The survival analysis was performed with the Kaplan Meier method and log-rank test. The hazard ratio was calculated with the Cox proportional hazards model. RESULTS: Among 328 patients with PS 3-4, 38% of patients received active anti-HCC treatments against the BCLC system. Compared with patients undergoing supportive care, patients receiving anti-HCC treatments more often had milder cirrhosis, smaller tumor burden, and lower serum alpha fetoprotein levels (all P<0.05). Patients undergoing supportive care had significantly decreased survival (P<0.0001). With propensity scores, 101 pairs of similar HCC patients with PS 3-4 were selected from different treatment groups. They were comparable in age, sex, etiologies of liver disease, severity of cirrhosis, tumor burden, and prevalence of diabetes mellitus (all P>0.05) at baseline. In the matching model, patients with PS 3-4 undergoing supportive care had significantly shortened survival with an adjusted hazard ratio of 4.711 (confidence interval: 3.041-7.297, P<0.0001). CONCLUSIONS: Over one-third of patients with PS 3-4 receive active anti-HCC treatments against the BCLC allocation algorithm in this study. Active anticancer therapies rather than best supportive care should be performed if there is no apparent contraindication. PMID- 25710526 TI - Puzzling out neurodevelopment. PMID- 25710527 TI - The evolution of early neurogenesis. AB - The foundation of the diverse metazoan nervous systems is laid by embryonic patterning mechanisms, involving the generation and movement of neural progenitors and their progeny. Here we divide early neurogenesis into discrete elements, including origin, pattern, proliferation, and movement of neuronal progenitors, which are controlled by conserved gene cassettes. We review these neurogenetic mechanisms in representatives of the different metazoan clades, with the goal to build a conceptual framework in which one can ask specific questions, such as which of these mechanisms potentially formed part of the developmental "toolkit" of the bilaterian ancestor and which evolved later. PMID- 25710528 TI - Evolution of patterning systems and circuit elements for locomotion. AB - Evolutionary modifications in nervous systems enabled organisms to adapt to their specific environments and underlie the remarkable diversity of behaviors expressed by animals. Resolving the pathways that shaped and modified neural circuits during evolution remains a significant challenge. Comparative studies have revealed a surprising conservation in the intrinsic signaling systems involved in early patterning of bilaterian nervous systems but also raise the question of how neural circuit compositions and architectures evolved within specific animal lineages. In this review, we discuss the mechanisms that contributed to the emergence and diversity of animal nervous systems, focusing on the circuits governing vertebrate locomotion. PMID- 25710529 TI - Genetic changes shaping the human brain. AB - The development and function of our brain are governed by a genetic blueprint, which reflects dynamic changes over the history of evolution. Recent progress in genetics and genomics, facilitated by next-generation sequencing and single-cell sorting, has identified numerous genomic loci that are associated with a neuroanatomical or neurobehavioral phenotype. Here, we review some of the genetic changes in both protein-coding and noncoding regions that affect brain development and evolution, as well as recent progress in brain transcriptomics. Understanding these genetic changes may provide novel insights into neurological and neuropsychiatric disorders, such as autism and schizophrenia. PMID- 25710531 TI - Dynamics and mechanisms of CNS myelination. AB - Vertebrate myelination is an evolutionary advancement essential for motor, sensory, and higher-order cognitive function. CNS myelin, a multilamellar differentiation of the oligodendrocyte plasma membrane, ensheaths axons to facilitate electrical conduction. Myelination is one of the most pivotal cell cell interactions for normal brain development, involving extensive information exchange between differentiating oligodendrocytes and axons. The molecular mechanisms of myelination are discussed, along with new perspectives on oligodendrocyte plasticity and myelin remodeling of the developing and adult CNS. PMID- 25710530 TI - It takes a village: constructing the neurogenic niche. AB - Although many features of neurogenesis during development and in the adult are intrinsic to the neurogenic cells themselves, the role of the microenvironment is irrefutable. The neurogenic niche is a melting pot of cells and factors that influence CNS development. How do the diverse elements assemble and when? How does the niche change structurally and functionally during embryogenesis and in adulthood? In this review, we focus on the impact of non-neural cells that participate in the neurogenic niche, highlighting how cells of different embryonic origins influence this critical germinal space. PMID- 25710533 TI - Microglia: multitasking specialists of the brain. AB - Microglia are macrophages that colonize the brain during development to establish a resident population of professional phagocytes that protect against invading pathogens and contribute to brain development and homeostasis. As such, these cells sit at the interface between immunology and neurobiology. In addition to their key roles in brain physiology, microglia offer a great opportunity to address central questions in biology relating to how migrating cells find their positions in the embryo, adopt a behavior that is appropriate for that position, and interact with their local environment. We aim, in this review, to survey key recent advances in microglial research. PMID- 25710534 TI - Programmed cell death in neurodevelopment. AB - Programmed cell death (PCD) is an evolutionarily conserved contributor to nervous system development. In the vertebrate peripheral nervous system, PCD is the basis of the neurotrophic theory, whereby cell death results from a surplus of neurons relative to target and competition for neurotrophic factors. In addition to stochastic cell death, PCD can be intrinsically determined by cell lineage or position and timing in both invertebrate and vertebrate central nervous systems. The underlying PCD molecular mechanisms include intrinsic transcription factor cascades and regulators of competence/susceptibility to cell death. Here, we provide a framework for understanding neural PCD from its regulation to its functions. PMID- 25710532 TI - Subcellular patterning: axonal domains with specialized structure and function. AB - Myelinated axons are patterned into discrete and often-repeating domains responsible for the efficient and rapid transmission of electrical signals. These domains include nodes of Ranvier and axon initial segments. Disruption of axonal patterning leads to nervous system dysfunction. In this review, we introduce the concept of subcellular patterning as applied to axons and discuss how these patterning events depend on both intrinsic, cytoskeletal mechanisms and extrinsic, myelinating glia-dependent mechanisms. PMID- 25710536 TI - Cellular functions of the amyloid precursor protein from development to dementia. AB - Amyloid precursor protein (APP) is a key player in Alzheimer's disease (AD). The Abeta fragments of APP are the major constituent of AD-associated amyloid plaques, and mutations or duplications of the gene coding for APP can cause familial AD. Here we review the roles of APP in neuronal development, signaling, intracellular transport, and other aspects of neuronal homeostasis. We suggest that APP acts as a signaling nexus that transduces information about a range of extracellular conditions, including neuronal damage, to induction of intracellular signaling events. Subtle disruptions of APP signaling functions may be major contributors to AD-causing neuronal dysfunction. PMID- 25710537 TI - Neuronal regeneration from ependymo-radial glial cells: cook, little pot, cook! AB - Adult fish and salamanders regenerate specific neurons as well as entire CNS areas after injury. Recent studies shed light on how these anamniotes activate progenitor cells, generate the required cell types, and functionally integrate these into a complex environment. Some developmental signals and mechanisms are recapitulated during neuronal regeneration, whereas others are unique to the regeneration process. The use of genetic techniques, such as cell ablation and lineage-tracing, in combination with cell-type-specific expression profiling reveal factors that initiate, fine-tune, and terminate the regenerative response in anamniotes, with a view to translating findings to non-regenerating species. PMID- 25710535 TI - Neuronal aggregates: formation, clearance, and spreading. AB - Proteostasis is maintained by multiple cellular pathways, including protein synthesis, quality control, and degradation. An imbalance of neuronal proteostasis, associated with protein misfolding and aggregation, leads to proteinopathies or neurodegeneration. While genetic variations and protein modifications contribute to aggregate formation, components of the proteostasis network dictate the fate of protein aggregates. Here we provide an overview of proteostasis pathways and their interplay (particularly autophagy) with the metabolism of disease-related proteins. We review recent studies on neuronal activity-mediated regulation of proteostasis and transcellular propagation of protein aggregates in the nervous system. Targeting proteostasis pathways therapeutically remains an attractive but challenging task. PMID- 25710538 TI - Open access to large scale datasets is needed to translate knowledge of cancer heterogeneity into better patient outcomes. AB - In this guest editorial, Andrew Beck discusses the importance of open access to big data for translating knowledge of cancer heterogeneity into better outcomes for cancer patients. PMID- 25710539 TI - Changes in disability, physical/mental health states and quality of life during an 8-week multimodal physiotherapy programme in patients with chronic non specific neck pain: a prospective cohort study. AB - AIM: The aim of this study was to analyse the effect of an 8-week multimodal physiotherapy programme (MPP), integrating physical land-based therapeutic exercise (TE), adapted swimming and health education, as a treatment for patients with chronic non-specific neck pain (CNSNP), on disability, general health/mental states and quality of life. METHODS: 175 CNSNP patients from a community-based centre were recruited to participate in this prospective study. INTERVENTION: 60 minute session (30 minutes of land-based exercise dedicated to improving mobility, motor control, resistance and strengthening of the neck muscles, and 30 minutes of adapted swimming with aerobic exercise keeping a neutral neck position using a snorkel). Health education was provided using a decalogue on CNSNP and constant repetition of brief advice by the physiotherapist during the supervision of the exercises in each session. STUDY OUTCOMES: primary: disability (Neck Disability Index); secondary: physical and mental health states and quality of life of patients (SF-12 and EuroQoL-5D respectively). Differences between baseline data and that at the 8-week follow-up were calculated for all outcome variables. RESULTS: Disability showed a significant improvement of 24.6% from a mean (SD) of 28.2 (13.08) at baseline to 16.88 (11.62) at the end of the 8-week intervention. All secondary outcome variables were observed to show significant, clinically relevant improvements with increase ranges between 13.0% and 16.3% from a mean of 0.70 (0.2) at baseline to 0.83 (0.2), for EuroQoL-5D, and from a mean of 40.6 (12.7) at baseline to 56.9 (9.5), for mental health state, at the end of the 8-week intervention. CONCLUSION: After 8 weeks of a MPP that integrated land-based physical TE, health education and adapted swimming, clinically-relevant and statistically-significant improvements were observed for disability, physical and mental health states and quality of life in patients who suffer CNSNP. The clinical efficacy requires verification using a randomised controlled study design. TRIAL REGISTRATION: ClinicalTrials.gov NCT02046876. PMID- 25710540 TI - Genome analysis of a novel Bradyrhizobium sp. DOA9 carrying a symbiotic plasmid. AB - Bradyrhizobium sp. DOA9 isolated from the legume Aeschynomene americana exhibited a broad host range and divergent nodulation (nod) genes compared with other members of the Bradyrhizobiaceae. Genome analysis of DOA9 revealed that its genome comprised a single chromosome of 7.1 Mbp and a plasmid of 0.7 Mbp. The chromosome showed highest similarity with that of the nod gene-harboring soybean symbiont B. japonicum USDA110, whereas the plasmid showed highest similarity with pBBta01 of the nod gene-lacking photosynthetic strain BTAi1, which nodulates Aeschynomene species. Unlike in other bradyrhizobia, the plasmid of DOA9 encodes genes related to symbiotic functions including nodulation, nitrogen fixation, and type III/IV protein secretion systems. The plasmid has also a lower GC content (60.1%) than the chromosome (64.4%). These features suggest that the plasmid could be the origin of the symbiosis island that is found in the genome of other bradyrhizobia. The nod genes of DOA9 exhibited low similarity with those of other strains. The nif gene cluster of DOA9 showed greatest similarity to those of photosynthetic bradyrhizobia. The type III/IV protein secretion systems of DOA9 are similar to those of nod gene-harboring B. elkanii and photosynthetic BTAi1. The DOA9 genome exhibited intermediate characteristics between nod gene-harboring bradyrhizobia and nod gene-lacking photosynthetic bradyrhizobia, thus providing the evidence for the evolution of the Bradyrhizobiaceae during ecological adaptation. Bradyrhizobium sp. DOA9 isolated from the legume Aeschynomene americana exhibited a broad host range and divergent nodulation (nod) genes compared with other members of the Bradyrhizobiaceae. Genome analysis of DOA9 revealed that its genome comprised a single chromosome of 7.1 Mbp and a plasmid of 0.7 Mbp. The chromosome showed highest similarity with that of the nod gene harboring soybean symbiont B. japonicum USDA110, whereas the plasmid showed highest similarity with pBBta01 of the nod gene-lacking photosynthetic strain BTAi1, which nodulates Aeschynomene species. Unlike in other bradyrhizobia, the plasmid of DOA9 encodes genes related to symbiotic functions including nodulation, nitrogen fixation, and type III/IV protein secretion systems. The plasmid has also a lower GC content (60.1%) than the chromosome (64.4%). These features suggest that the plasmid could be the origin of the symbiosis island that is found in the genome of other bradyrhizobia. The nod genes of DOA9 exhibited low similarity with those of other strains. The nif gene cluster of DOA9 showed greatest similarity to those of photosynthetic bradyrhizobia. The type III/IV protein secretion systems of DOA9 are similar to those of nod gene harboring B. elkanii and photosynthetic BTAi1. The DOA9 genome exhibited intermediate characteristics between nod gene-harboring bradyrhizobia and nod gene-lacking photosynthetic bradyrhizobia, thus providing the evidence for the evolution of the Bradyrhizobiaceae during ecological adaptation. PMID- 25710541 TI - A new chapter for ASSAY and drug development technologies. PMID- 25710542 TI - Interview with Mel Reichman, PhD. PMID- 25710543 TI - Development of a phenotypic high-content assay to identify pharmacoperone drugs for the treatment of primary hyperoxaluria type 1 by high-throughput screening. AB - Primary hyperoxaluria is a severe disease for which the best current therapy is dialysis or organ transplantation. These are risky, inconvenient, and costly procedures. In some patients, pyridoxine treatment can delay the need for these surgical procedures. The underlying cause of particular forms of this disease is the misrouting of a specific enzyme, alanine:glyoxylate aminotransferase (AGT), to the mitochondria instead of the peroxisomes. Pharmacoperones are small molecules that can rescue misfolded proteins and redirect them to their correct location, thereby restoring their function and potentially curing disease. In the present study, we miniaturized a cell-based assay to identify pharmacoperone drugs present in large chemical libraries to selectively correct AGT misrouting. This assay employs AGT-170, a mutant form of AGT that predominantly resides in the mitochondria, which we monitor for its relocation to the peroxisomes through automated image acquisition and analysis. Over the course of a pilot screen of 1,280 test compounds, we achieved an average Z'-factor of 0.72+/-0.02, demonstrating the suitability of this assay for HTS. PMID- 25710544 TI - Integrated in vitro-in silico screening strategy for the discovery of antibacterial compounds. AB - Multidrug-resistant bacterial infections are an increasing source of healthcare problems, and the research for new antibiotics is currently unable to respond to this challenge. In this work, we present a screening strategy that integrates cell-based high-throughput screening (HTS) with in silico analogue search for antimicrobial small-molecule drug discovery. We performed an HTS on a diverse chemical library by using an assay based on a bioluminescent Escherichia coli K 12 (pTetLux1) strain. The HTS yielded eight hit compounds with >50% inhibition. These hits were then used for structural similarity-based virtual screening, and of the 29 analogues selected for in vitro testing, four compounds displayed potential activity in the pTetLux1 assay. The 11 most active compounds from combined HTS and analogue search were further assessed for antimicrobial activity against clinically important strains of E. coli and Staphylococcus aureus and for in vitro cytotoxicity against human cells. Three of the compounds displayed antibacterial activity and low human cell cytotoxicity. Additionally, two compounds of the set fully inhibited S. aureus growth after 24 h, but also exhibited human cell cytotoxicity in vitro. PMID- 25710546 TI - Recent advances in paediatric gastroenterology. AB - Over the last few years, many changes have been introduced in the diagnosis and management of paediatric gastrointestinal problems. This review highlights the recent developments in Helicobacter pylori infection, eosinophilic oesophagitis, coeliac disease and inflammatory bowel disease. PMID- 25710547 TI - PAWS for thought. PMID- 25710545 TI - Adapting high-throughput screening methods and assays for biocontainment laboratories. AB - High-throughput screening (HTS) has been integrated into the drug discovery process, and multiple assay formats have been widely used in many different disease areas but with limited focus on infectious agents. In recent years, there has been an increase in the number of HTS campaigns using infectious wild-type pathogens rather than surrogates or biochemical pathogen-derived targets. Concurrently, enhanced emerging pathogen surveillance and increased human mobility have resulted in an increase in the emergence and dissemination of infectious human pathogens with serious public health, economic, and social implications at global levels. Adapting the HTS drug discovery process to biocontainment laboratories to develop new drugs for these previously uncharacterized and highly pathogenic agents is now feasible, but HTS at higher biosafety levels (BSL) presents a number of unique challenges. HTS has been conducted with multiple bacterial and viral pathogens at both BSL-2 and BSL-3, and pilot screens have recently been extended to BSL-4 environments for both Nipah and Ebola viruses. These recent successful efforts demonstrate that HTS can be safely conducted at the highest levels of biological containment. This review outlines the specific issues that must be considered in the execution of an HTS drug discovery program for high-containment pathogens. We present an overview of the requirements for HTS in high-level biocontainment laboratories. PMID- 25710548 TI - Management of intestinal failure in children. AB - The management of children with intestinal failure is a rewarding but resource intensive process. There is however variability in practice and outcome for patients, despite the basic principles of care and measures of success being well defined. The importance of multidisciplinary working is paramount and there is an urgent need to obtain collaboration between paediatric surgical and medical gastroenterological colleagues and an obligation of commissioners to see that there is recognition and implementation of ideal practice as an essential element in improving the outlook for children with intestinal failure in the United Kingdom. PMID- 25710550 TI - Posttraumatic Midface Pain: Clinical Significance of the Anterior Superior Alveolar Nerve and Canalis Sinuosus. AB - BACKGROUND: Posttraumatic midface pain secondary to injury of the anterior superior alveolar nerve (ASAN) is characterized as pain localized to the central and lateral incisors, canines, and maxilla. This nerve is susceptible to injury and subsequent formation of neuromas after midface trauma. Surgical intervention requires an accurate and precise understanding of the course of the ASAN. METHODS: Dissections of 12 human cadaver heads were conducted to identify the course of the ASAN through the canalis sinuosus (CS). Fifty 1-mm slice face computed tomographic scans were evaluated to document the dimensions and course of the CS. RESULTS: The ASAN branched laterally from the infraorbital nerve before reaching the infraorbital rim in all cadavers. The bifurcation occurred 18 mm posterior to the infraorbital rim (range, 10-30 mm). At a point 25 mm inferior to the infraorbital rim, the ASAN is found 3.4 mm lateral to the piriform aperture (range, 3-4 mm). Radiographic analysis demonstrated a 12.9-mm horizontal length of the CS across the anterior maxilla (SD, 2.2 mm), a distance of 4.8 mm between the piriform aperture and the CS (SD, 1.2 mm), and 11.7 mm vertical length of the CS along the piriform aperture (SD, 3.0 mm). CONCLUSIONS: The ASAN maintains consistent coordinates at specific points along its course through the midface. An improved understanding of the course of the ASAN will guide future diagnosis of injury to this nerve and surgical intervention for patients with posttraumatic midface pain secondary to ASAN injury. PMID- 25710553 TI - Immediate Great Toe Transfer for Thumb Reconstruction After Tumor Resection: Report of 3 Cases. AB - BACKGROUND: Modern oncologic surgery aims not only to obtain tumor-free margins but also to spare or reconstruct limb function and preserve quality of life. A negative tumor margin in the digit generally requires amputation; therefore, function is preserved with reconstruction. We report results of simultaneous ablative tumor resection and reconstruction with a great toe transfer in patients requiring surgery for aggressive benign and malignant thumb tumors. METHODS: Between 2000 and 2009, three patients with extensive soft tissue tumors of the distal thumb underwent amputation to obtain wide negative surgical margins. In each case, an immediate trimmed toe-to-thumb transfer was performed. Results, evaluated retrospectively, included a review of perioperative complications, donor-site morbidity, oncologic status, objective functional outcomes, and subjective patient satisfaction. RESULTS: Three patients were found with either locally aggressive benign (n = 1) or malignant (n = 2) tumors of the thumb. All patients underwent immediate reconstruction after amputation through the base of the proximal phalanx for tumor eradication. No perioperative complications were encountered, and all toes survived. Full thumb opposition and protective sensation were achieved in all patients. All patients returned to their previous occupation without functional limitations. There is no local or distant tumor recurrence. Delayed wound healing at the ipsilateral foot donor site occurred in all 3 patients. Wet-to-dry dressing changes were successful in 2 patients, whereas the third patient required full-thickness skin grafting. All patients were satisfied with their reconstruction. CONCLUSIONS: An immediate great toe-to thumb transfer should be considered when thumb amputation is required to satisfy adequate oncologic margins. Such a transfer provides simultaneous restoration of digit length, position, sensation, and acceptable esthetics. This procedure is technically demanding and requires an experienced microsurgical team as well as appropriate patient counseling and consent before surgery. PMID- 25710554 TI - The effect of combined use of platelet-rich plasma and adipose-derived stem cells on fat graft survival. AB - BACKGROUND: Free fat grafts have an unpredictable survival rate that limits their successful use. To increase the viability of fat grafts, it is important to minimize the reabsorption rate. OBJECTIVE: Our aim was to investigate whether the combined use of platelet-rich plasma (PRP) and adipose derived stem cells (ADSCs) would contribute an improvement in lower resorption rates of fat grafts. METHODS: Inbred Fischer 344 rats were randomized into 4 groups (n = 10). Fat grafts were mixed with Dulbecco modified Eagle medium in group A, with PRP in group B, with ADSC in group C, and with PRP + ADSC in group D and were injected to the scalp.In vitro growth factor (vascular endothelial growth factor, transforming growth factor-beta, and fibroblast growth factor) levels were compared using enzyme linked immunoassay method. After 12 weeks weight, volume and histology of the transplants were evaluated. RESULTS: The mean weight and volume of the fat grafts were highest in group D. Histopathological investigations revealed that the number of viable adipocytes and blood vessels were highest in group D. The level of growth factors was significantly higher in stem cell plus PRP group. CONCLUSION: Adipose-derived stem cells combined with PRP can enhance the survival of transplanted fat tissue. PMID- 25710555 TI - Treatment of elbow osteomyelitis with an interposition arthroplasty using a rectus abdominis free flap. AB - INTRODUCTION: Osteomyelitis of the elbow may be a complex clinical problem. Treatment goals include the eradication of infection and preservation of maximal joint function. Bony debridement may be necessary in addition to elbow joint arthroplasty. The use of synthetic material or allograft as the arthroplasty material may be contraindicated in the setting of infection. The use of free muscle transfer as an arthroplasty medium has not been well described. METHODS: A 22-year-old paraplegic man developed recurrent osteomyelitis of the right elbow, necessitating extensive bony debridement by the orthopedic surgery team. Reconstruction arthroplasty was performed using a free rectus abdominis muscle flap as the arthroplasty material to serve as a source of biologically active, well-vascularized arthroplasty medium in the presence of ongoing infection. RESULTS: A successful free muscle flap arthroplasty was performed. External fixation and physical therapy were implemented postoperatively. The patient had resolution of osteomyelitis and excellent functional use of the elbow for activities of daily living and wheelchair motion. CONCLUSIONS: Elbow arthroplasty in the setting of active infection may be accomplished by means of free tissue muscle transfer. Elimination of infection and acceptable joint function may be possible with this form of reconstruction. PMID- 25710556 TI - Secondary Genioplasties for the Treatment of Chin Deformities After Orthognathic Surgery in Asian Women: Defining the Aesthetic Importance of Managing the Chin Shape in Orthognathic Surgery. AB - BACKGROUND: Achieving aesthetically favorable results in orthognathic surgery is equally as important as good postoperative occlusion and jaw function. Orthognathic surgery that only changes profile or proportion in the vertical dimension can often lead to patient's dissatisfaction and additional surgical revision. To achieve maximal aesthetic improvement and postoperative patient's satisfaction, the chin shape should be considered as important a component of orthognathic surgery as dental occlusion or jaw function. METHODS: From April 2010 to January 2014, 82 female patients with aesthetic complaints after previous orthognathic surgery visited our clinic for reevaluation and management. Among those 82 patients, 54 patients who were dissatisfied with their lower facial shape from the frontal view underwent revision surgery with narrowing genioplasty and contouring of the lower border of the mandible. RESULTS: Facial shapes, when viewed from the front in all patients, became more slender and balanced postoperatively, and there was no need for additional surgical revisions in this series. There were no significant complications caused by our surgical revisions. CONCLUSIONS: Good aesthetic results were obtained after 54 secondary genioplasties for chin deformities after orthognathic surgery. These results suggest that surgeons should give more attention to managing chin shape when performing orthognathic surgery to meet the high aesthetic demands of patients and to avoid surgical revisions. PMID- 25710557 TI - Water oxidation catalysis by birnessite@iron oxide core-shell nanocomposites. AB - In this work, magnetic nanocomposite particles were prepared for water oxidation reactions. The studied catalysts consist of maghemite (gamma-Fe2O3), magnetite (Fe3O4), and manganese ferrite (MnFe2O4) nanoparticles as cores coated in situ with birnessite-type manganese oxide shells and were characterized by X-ray diffraction, transmission electron microscopy, scanning electron microscopy, thermal, chemical, and surface analyses, and magnetic measurements. The particles were found to be of nearly spherical core-shell architectures with average diameter of 150 nm. Water oxidation catalysis was examined using Ce(4+) as the sacrificial oxidant. All core-shell particles were found to be active water oxidation catalysts. However, the activity was found to depend on a variety of factors like the type of iron oxide core, the structure and composition of the shell, the coating characteristics, and the surface properties. Catalysts containing magnetite and manganese ferrite as core materials displayed higher catalytic activities per manganese ion (2650 or 3150 mmolO2 molMn(-1) h(-1)) or per mass than nanoiron oxides (no activity) or birnessite alone (1850 mmolO2 molMn(-1) h(-1)). This indicates synergistic effects between the MnOx shell and the FeOx core of the composites and proves the potential of the presented core shell approach for further catalyst optimization. Additionally, the FeOx cores of the particles allow magnetic recovery of the catalyst and might also be beneficial for applications in water-oxidizing anodes because the incorporation of iron might enhance the overall conductivity of the material. PMID- 25710558 TI - Visualizing collaborative electronic health record usage for hospitalized patients with heart failure. AB - OBJECTIVE: To visualize and describe collaborative electronic health record (EHR) usage for hospitalized patients with heart failure. MATERIALS AND METHODS: We identified records of patients with heart failure and all associated healthcare provider record usage through queries of the Northwestern Medicine Enterprise Data Warehouse. We constructed a network by equating access and updates of a patient's EHR to a provider-patient interaction. We then considered shared patient record access as the basis for a second network that we termed the provider collaboration network. We calculated network statistics, the modularity of provider interactions, and provider cliques. RESULTS: We identified 548 patient records accessed by 5113 healthcare providers in 2012. The provider collaboration network had 1504 nodes and 83 998 edges. We identified 7 major provider collaboration modules. Average clique size was 87.9 providers. We used a graph database to demonstrate an ad hoc query of our provider-patient network. DISCUSSION: Our analysis suggests a large number of healthcare providers across a wide variety of professions access records of patients with heart failure during their hospital stay. This shared record access tends to take place not only in a pairwise manner but also among large groups of providers. CONCLUSION: EHRs encode valuable interactions, implicitly or explicitly, between patients and providers. Network analysis provided strong evidence of multidisciplinary record access of patients with heart failure across teams of 100+ providers. Further investigation may lead to clearer understanding of how record access information can be used to strategically guide care coordination for patients hospitalized for heart failure. PMID- 25710559 TI - Differential impact of acute high-intensity exercise on circulating endothelial microparticles and insulin resistance between overweight/obese males and females. AB - BACKGROUND: An acute bout of exercise can improve endothelial function and insulin sensitivity when measured on the day following exercise. Our aim was to compare acute high-intensity continuous exercise (HICE) to high-intensity interval exercise (HIIE) on circulating endothelial microparticles (EMPs) and insulin sensitivity in overweight/obese men and women. METHODS: Inactive males (BMI = 30 +/- 3, 25 +/- 6 yr, n = 6) and females (BMI = 28 +/- 2, 21 +/- 3 yr, n = 7) participated in three experimental trials in a randomized counterbalanced crossover design: 1) No exercise control (Control); 2) HICE (20 min cycling @ just above ventilatory threshold); 3) HIIE (10 X 1-min @ ~ 90% peak aerobic power). Exercise conditions were matched for external work and diet was controlled post-exercise. Fasting blood samples were obtained ~ 18 hr after each condition. CD62E(+) and CD31(+)/CD42b- EMPs were assessed by flow cytometry and insulin resistance (IR) was estimated by homeostasis model assessment (HOMA-IR). RESULTS: There was a significant sex X exercise interaction for CD62E(+) EMPs, CD31(+)/CD42b- EMPs, and HOMA-IR (all P < 0.05). In males, both HICE and HIIE reduced EMPs compared to Control (P <= 0.05). In females, HICE increased CD62E(+) EMPs (P < 0.05 vs. Control) whereas CD31(+)/CD42b- EMPs were unaltered by either exercise type. There was a significant increase in HOMA-IR in males but a decrease in females following HIIE compared to Control (P<0.05). CONCLUSIONS: Overweight/obese males and females appear to respond differently to acute bouts of high-intensity exercise. A single session of HICE and HIIE reduced circulating EMPs measured on the morning following exercise in males but in females CD62E(+) EMPs were increased following HICE. Next day HOMA-IR paradoxically increased in males but was reduced in females following HIIE. Future research is needed to investigate mechanisms responsible for potential differential responses between males and females. PMID- 25710560 TI - Neonicotinoid insecticide residues in surface water and soil associated with commercial maize (corn) fields in southwestern Ontario. AB - Neonicotinoid insecticides have come under scrutiny for their potential unintended effects on non-target organisms, particularly pollinators in agro ecosystems. As part of a larger study of neonicotinoid residues associated with maize (corn) production, 76 water samples within or around the perimeter of 18 commercial maize fields and neighbouring apiaries were collected in 5 maize producing counties of southwestern Ontario. Residues of clothianidin (mean = 2.28, max. = 43.60 ng/mL) and thiamethoxam (mean = 1.12, max. = 16.50 ng/mL) were detected in 100 and 98.7% of the water samples tested, respectively. The concentration of total neonicotinoid residues in water within maize fields increased six-fold during the first five weeks after planting, and returned to pre-plant levels seven weeks after planting. However, concentrations in water sampled from outside the fields were similar throughout the sampling period. Soil samples from the top 5 cm of the soil profile were also collected in these fields before and immediately following planting. The mean total neonicotinoid residue was 4.02 (range 0.07 to 20.30) ng/g, for samples taken before planting, and 9.94 (range 0.53 to 38.98) ng/g, for those taken immediately after planting. Two soil samples collected from within an conservation area contained detectable (0.03 and 0.11 ng/g) concentrations of clothianidin. Of three drifted snow samples taken, the drift stratum containing the most wind-scoured soil had 0.16 and 0.20 ng/mL mainly clothianidin in the melted snow. The concentration was at the limit of detection (0.02 ng/mL) taken across the entire vertical profile. With the exception of one sample, water samples tested had concentrations below those reported to have acute, chronic or sublethal effects to honey bees. Our results suggest that neonicotinoids may move off-target by wind erosion of contaminated soil. These results are informative to risk assessment models for other non target species in maize agro-ecosytems. PMID- 25710561 TI - mRNA profiling reveals determinants of trastuzumab efficiency in HER2-positive breast cancer. AB - Intrinsic and acquired resistance to the monoclonal antibody drug trastuzumab is a major problem in the treatment of HER2-positive breast cancer. A deeper understanding of the underlying mechanisms could help to develop new agents. Our intention was to detect genes and single nucleotide polymorphisms (SNPs) affecting trastuzumab efficiency in cell culture. Three HER2-positive breast cancer cell lines with different resistance phenotypes were analyzed. We chose BT474 as model of trastuzumab sensitivity, HCC1954 as model of intrinsic resistance, and BTR50, derived from BT474, as model of acquired resistance. Based on RNA-Seq data, we performed differential expression analyses on these cell lines with and without trastuzumab treatment. Differentially expressed genes between the resistant cell lines and BT474 are expected to contribute to resistance. Differentially expressed genes between untreated and trastuzumab treated BT474 are expected to contribute to drug efficacy. To exclude false positives from the candidate gene set, we removed genes that were also differentially expressed between untreated and trastuzumab treated BTR50. We further searched for SNPs in the untreated cell lines which could contribute to trastuzumab resistance. The analysis resulted in 54 differentially expressed candidate genes that might be connected to trastuzumab efficiency. 90% of 40 selected candidates were validated by RT-qPCR. ALPP, CALCOCO1, CAV1, CYP1A2 and IGFBP3 were significantly higher expressed in the trastuzumab treated than in the untreated BT474 cell line. GDF15, IL8, LCN2, PTGS2 and 20 other genes were significantly higher expressed in HCC1954 than in BT474, while NCAM2, COLEC12, AFF3, TFF3, NRCAM, GREB1 and TFF1 were significantly lower expressed. Additionally, we inferred SNPs in HCC1954 for CAV1, PTGS2, IL8 and IGFBP3. The latter also had a variation in BTR50. 20% of the validated subset have already been mentioned in literature. For half of them we called and analyzed SNPs. These results contribute to a better understanding of trastuzumab action and resistance mechanisms. PMID- 25710562 TI - A novel dual AMPK activator/mTOR inhibitor inhibits thyroid cancer cell growth. AB - CONTEXT: Activated AMP protein kinase (AMPK) is a key regulator of intracellular energy homeostasis and may also function as a tumor suppressor by inhibiting cell growth through suppression of mammalian target of rapamycin (mTOR)/p70S6K signaling. AMPK activating agents, such as metformin and 5-aminoimidazole-4 carboxamide-ribonucleoside, have been demonstrated to inhibit thyroid cancer cell growth in in vitro and in vivo models. OSU-53, a recently developed AMPK activator, was previously shown to exhibit both in vitro and in vivo antitumor activity against aggressive breast cancer cell lines and their xenografts in nude mice. OBJECTIVE: The objective of the study was to assess the in vitro effects of OSU-53 treatment in a panel of thyroid cancer cells. DESIGN: Experiments were performed to determine the effects of OSU-53 on cell growth, oncogenic signaling, apoptosis, autophagy, and cell rescue after selective knockdown of AMPK. RESULTS: OSU-53 inhibited in vitro cell growth of all seven thyroid cancer cells tested and induced activation of AMPK. Cell lines with activating mutations in RAS or BRAF, compared with cells with phosphatase and tensin homolog deleted from chromosome 10 null and RET/papillary thyroid carcinoma mutations, were more sensitive to drug treatment and demonstrated a more robust AMPK activation, inhibition of mTOR signaling, and autophagy stimulation. After selective knockdown of AMPK, cell rescue from OSU-53 treatment was not observed. We demonstrated an off-target effect of direct mTOR inhibition by OSU-53. Increased autophagy was observed in cells with activation RAS or BRAF mutations. CONCLUSIONS: OSU-53, a novel dual-AMPK activator/mTOR inhibitor, effectively inhibits growth in a variety of thyroid cancer cell lines and is most potent in cells with activating mutations in RAS or BRAF. PMID- 25710563 TI - Dapagliflozin lowers plasma glucose concentration and improves beta-cell function. AB - BACKGROUND: beta-Cell dysfunction is a core defect in T2DM, and chronic, sustained hyperglycemia has been implicated in progressive beta-cell failure, ie, glucotoxicity. The aim of the present study was to examine the effect of lowering the plasma glucose concentration with dapagliflozin, a glucosuric agent, on beta cell function in T2DM individuals. RESEARCH DESIGN AND METHODS: Twenty-four subjects with T2DM received dapagliflozin (n = 16) or placebo (n = 8) for 2 weeks, and a 75-g oral glucose tolerance test (OGTT) and insulin clamp were performed before and after treatment. Plasma glucose, insulin, and C-peptide concentrations were measured during the OGTT. RESULTS: Dapagliflozin significantly lowered both the fasting and 2-hour plasma glucose concentrations and the incremental area under the plasma glucose concentration curve (DeltaG0 120) during OGTT by -33 +/- 5 mg/dL, -73 +/- 9 mg/dL, and -60 +/- 12 mg/dL . min, respectively, compared to -13 +/- 9, -33 +/- 13, and -18 +/- 9 reductions in placebo-treated subjects (both P < .01). The incremental area under the plasma C peptide concentration curve tended to increase in dapagliflozin-treated subjects, whereas it did not change in placebo-treated subjects. Thus, DeltaC-Pep0 120/DeltaG0-120 increased significantly in dapagliflozin-treated subjects, whereas it did not change in placebo-treated subjects (0.019 +/- 0.005 vs 0.002 +/- 0.006; P < .01). Dapagliflozin significantly improved whole-body insulin sensitivity (insulin clamp). Thus, beta-cell function, measured as DeltaC-Pep0 120/ DeltaG0-120 / insulin resistance, increased by 2-fold (P < .01) in dapagliflozin-treated vs placebo-treated subjects. CONCLUSION: Lowering the plasma glucose concentration with dapagliflozin markedly improves beta-cell function, providing strong support in man for the glucotoxic effect of hyperglycemia on beta-cell function. PMID- 25710564 TI - Serum thyroid hormone autoantibodies in type 1 diabetes mellitus. AB - CONTEXT: Autoimmune thyroid diseases (AITDs) can be associated with type 1 diabetes (DM1). The prevalence of serum antibodies against thyroid hormones (THAb) in subjects with autoimmune diseases other than DM1 is increasing. No data are available for DM1. OBJECTIVE: The objectives were evaluate the rate of associated AITD; the rate of positiveness for serum THAb; the panel of THAb based on thyroid hormone interaction and on Ig class; and the association of AITD alone, THAb alone, or AITD plus THAb with diabetes-related complications. DESIGN: This was an observational, prospective study with 6-year (2005-2011) follow-up. SETTING: The setting was an outpatient diabetes clinic. PATIENTS: Fifty-two consecutive subjects (53.8% males; mean age, 37.4 +/- 7.4 y; diabetes duration, 19.9 +/- 8.2 y) with DM1. All participants completed the study. MAIN OUTCOME MEASURES: Main outcome measures were AITD rate; THAb positivity according to hormone interaction and Ig class; association of AITD and THAb with diabetes related complications. RESULTS: AITD rate increased from baseline (34.6%) to follow-up (38.5%). Subjects with DM1 had a high prevalence of THAb (92.3%). The presence of AITD at baseline was associated with subsequent development of macroangiopathy (0 vs 33% at baseline and follow-up, respectively; P = .029). Some THAb patterns, the majority having T3 binding in common, were associated with the progression and development of diabetes-related complications. CONCLUSIONS: THAb synthesis in DM1 might be driven by increased glycosylation of thyroglobulin. Anti T3-THAb may cause a relative "tissue hypothyroidism" by sequestering thyroid hormone, this at least partially contributing to worsening diabetes-related vascular complications. In a clinical setting THAb positivity could identify subjects more likely to develop diabetes complications. PMID- 25710565 TI - Preconception low dose aspirin and time to pregnancy: findings from the effects of aspirin in gestation and reproduction randomized trial. AB - OBJECTIVE: The objective was to determine the effect of preconception-initiated daily low-dose aspirin (LDA; 81 mg/day) treatment on time to pregnancy in women with a history of pregnancy loss. DESIGN: This was a multicenter, block randomized, double-blind, placebo-controlled trial. Participants were block randomized by center and eligibility stratum. SETTING: The study was conducted at four U.S.A. medical centers (2007-2012). PARTICIPANTS: Participants women aged 18 40 years actively attempting pregnancy, stratified by eligibility criteria: the "original" stratum, women with one loss <20 weeks' gestation during the previous year; and the "expanded" stratum, women with one or two previous losses of any gestational age regardless of time since loss. INTERVENTION: Daily LDA was compared with matching placebo for up to six menstrual cycles of attempting pregnancy. MAIN OUTCOME MEASURE: Time to hCG detected pregnancy and clinically confirmed pregnancy, analyzed by intention-to-treat, was measured. RESULTS: Of the 1228 women randomly assigned to LDA (n = 615) or placebo (n = 613), 410 (67%) women receiving LDA achieved pregnancy compared to 382 (63%) receiving placebo, corresponding to a fecundability odds ratio (FOR) of 1.14 (95% CI: 0.97, 1.33). Among women in the original stratum (n = 541), LDA was associated with increased fecundability compared to placebo (FOR: 1.28; 95%CI: 1.02, 1.62). CONCLUSIONS: Preconception-initiated LDA treatment resulted in a nonsignificant increase in fecundability of 14% in women with a history of 1-2 pregnancy losses, and a significant increase of 28% in women with a history of only one pregnancy loss of <20 weeks' gestation in the preceding year. Preconception-initiated LDA may increase fecundability in certain women with a recent early pregnancy loss. PMID- 25710566 TI - Aromatase inhibitors for ovulation induction. AB - Normogonadotropic anovulation, including polycystic ovary syndrome (PCOS), is one of the main causes of infertility. Recent meta-analysis and randomized controlled trial suggest the use of aromatase inhibitors (ie, letrozole) as effective drug and first-line treatment to restore fertility in these patients. The current manuscript will give a critical, provocative, and personal point of view on the topic. PMID- 25710567 TI - A Reverse J-Shaped Association Between Serum 25-Hydroxyvitamin D and Cardiovascular Disease Mortality: The CopD Study. AB - CONTEXT: Cardiovascular disease is the major cause of death in the Western world, but the association between 25-hydroxyvitamin D [25(OH)D] levels and the risk of cardiovascular disease mortality remains unclear. OBJECTIVE: The objective of the study was to determine the association between cardiovascular, stroke, and acute myocardial infarct mortality and serum levels of 25(OH)D. DESIGN: This was an observational cohort study, the Copenhagen vitamin D study, data from a single laboratory center in Copenhagen, Denmark. Follow-up was from 2004 to 2011. SETTING: Serum 25(OH)D was analyzed from 247 574 subjects from the Copenhagen general practice sector. PARTICIPANTS: Examination of the association 25(OH)D levels and mortality from cardiovascular disease, stroke, and acute myocardial infarct was performed among 161 428 women and 86 146 men. MAIN OUTCOME MEASURES: A multivariate Cox regression analysis was used to compute hazard ratios for cardiovascular, stroke, and acute myocardial infarct mortality. RESULTS: Of 247 574 subjects, a total of 16 645 subjects died in the ensuing 0-7 years. A total of 5454 died from cardiovascular disease including 1574 from stroke and 702 from acute myocardial infarct. The 25(OH)D level of 70 nmol/L was associated with the lowest cardiovascular disease mortality risk. Compared with that level, the hazard ratio for cardiovascular disease mortality was 2.0 [95% confidence interval (CI) 1.8-2.1] at the lower extreme (~ 12.5 nmol/L) with a higher risk for men [2.5 (95% CI 2.2-2.9)] than for women [1.7 (95% CI 1.5-1.9)]. At the higher extreme (~ 125 nmol/L), the hazard ratio of cardiovascular disease mortality was 1.3 (95% CI 1.2-1.4), with a similar risk among men and women. Results were similar for stroke and acute myocardial subgroups. CONCLUSIONS: In this large observational study, low and high levels of 25(OH)D were associated with cardiovascular disease, stroke, and acute myocardial mortality in a nonlinear, reverse J-shaped manner, with the highest risk at lower levels. Whether this was a causal or associational finding cannot be determined from our data. There is a need for randomized clinical trials that include information on the effects of 25(OH)D levels greater than 100 nmol/L. PMID- 25710568 TI - Long-term echocardiographic and cardioscintigraphic effects of growth hormone treatment in adults with Prader-Willi syndrome. AB - CONTEXT: In Prader-Willi syndrome (PWS), an altered GH secretion has been related to reduced cardiac mass and systolic function compared to controls. OBJECTIVE: The objective was to evaluate the cardiovascular response to a 4-year GH therapy in adult PWS patients. STUDY PARTICIPANTS: Study participants were nine severely obese PWS adults (three females, six males) and 13 age-, gender-, and body mass index-matched obese controls. METHODS: In an open-label prospective study, assessment of endocrine parameters and metabolic outcome, whole-body and abdominal fat scans, echocardiography, and radionuclide angiography in unstimulated and dobutamine-stimulated conditions were conducted at baseline and after 1 and 4 years of GH treatment. RESULTS: GH treatment increased IGF-1 (P < .0001), decreased C-reactive protein levels (P < .05), improved visceral fat mass (P < .05), and achieved near-significant changes of fat and fat-free body mass in PWS patients. Left ventricle mass indexed by fat mass increased significantly after 1 and 4 years of GH therapy (P < .05) without evident abnormalities of diastolic function, while a trend toward a reduction of the ejection fraction was documented by echocardiography (P = .054). Radionuclide angiography revealed stable values throughout the study of both the left and right ventricle ejection fractions, although this was accompanied by a statistically nonsignificant reduction of the left ventricle filling rate. A positive association between lean body mass and left ventricle ejection fraction was evident during the study (P < .05). CONCLUSIONS: GH therapy increased the cardiac mass of PWS adults without causing overt abnormalities of systolic and diastolic function. Although the association between lean mass and left ventricle ejection fraction during GH therapy corroborates a favorable systemic outcome of long-term GH treatment in adults with PWS, subtle longitudinal modifications of functional parameters advocate appropriate cardiac monitoring in the long-term therapeutic strategy for PWS. PMID- 25710569 TI - Scale effect of anaerobic digestion tests in fed-batch and semi-continuous mode for the technical and economic feasibility of a full scale digester. AB - Methane production capacity in mesophilic conditions of waste from two food industry plants was assessed in a semi-pilot (6L, fed-batch) and pilot (300 L, semi-continuous) scale. This was carried out in order to evaluate the convenience of producing heat and electricity in a full scale anaerobic digester. The pilot test was performed in order to obtain more reliable results for the design of the digester. Methane yield, returned from the pilot scale test, was approximately 80% of that from the smaller scale test. This outcome was in line with those from other studies performed in different scales and modes and indicates the success of the pilot scale test. The net electricity produced from the digester accounted for 30-50% of the food industry plants' consumption. The available thermal energy could cover from 10% to 100% of the plant requirements, depending on the energy demand of the processes performed. PMID- 25710570 TI - Tolerance to organic loading rate by aerobic granular sludge in a cyclic aerobic granular reactor. AB - Sodium acetate as carbon source, tolerance to organic loading rate (OLR) by aerobic granular sludge in a cyclic aerobic granular reactor (CAGR) was investigated by gradually increasing the influent COD. AGS could maintain stability in the continuous flow reactor under OLR?15kg/m(3)d in the former 65 days, and SVI, granulation rate, average particle size and water content was 21 ml/g, 98%, 1.8mm and 97.2% on the 65th day. However, AGS gradually disintegrated after the 66 th day when OLR increased to 18 kg/m(3)d, and granules' properties deteriorated rapidly in a short time. High removal rates to pollutants were achieved by CAGR in the former 65 days, but the removal rates of pollutants dropped sharply from the 66 th day. With the increase of OLR and particle size, anaerobic cores inside the granules were formed by massive dead cells, while instability of anaerobic core eventually led to the collapse of the system. PMID- 25710571 TI - Distribution and mass transfer of dissolved oxygen in a multi-habitat membrane bioreactor. AB - This work investigated the DO distribution and the factors influencing the mass transfer of DO in a multi-habitat membrane bioreactor. Through the continuous measurements of an on-line automatic system, the timely DO values at different zones in the bioreactor were obtained, which gave a detailed description to the distribution of oxygen within the bioreactor. The results indicated that the growth of biomass had an important influence on the distribution of oxygen. As the extension of operational time, the volumetric oxygen mass transfer coefficient (kLa) was generally decreased. With the difference in DO values, a complex environment combining anoxic and oxic state was produced within a single bioreactor, which provided a fundamental guarantee for the total removal of TN. Aeration rate, the concentration and apparent viscosity of MLSS have different influences on kLa, but adjusting the viscosity is a feasible method to improve the mass transfer of oxygen in the bioreactor. PMID- 25710572 TI - Biogas production from ensiled meadow grass; effect of mechanical pretreatments and rapid determination of substrate biodegradability via physicochemical methods. AB - As the biogas sector is rapidly expanding, there is an increasing need in finding new alternative feedstock to biogas plants. Meadow grass can be a suitable co substrate and if ensiled it can be supplied to biogas plants continuously throughout the year. Nevertheless, this substrate is quite recalcitrant and therefore efficient pretreatment is needed to permit easy access of microbes to the degradable components. In this study, different mechanical pretreatment methods were applied on ensiled meadow grass to investigate their effect on biomass biodegradability. All the tested pretreatments increased the methane productivity and the increase ranged from 8% to 25%. The best mechanical pretreatment was the usage of two coarse mesh grating plates. Additionally, simple analytical methods were conducted to investigate the possibility of rapidly determining the methane yield of meadow grass. Among the methods, electrical conductivity test showed the most promising calibration statistics (R(2)=0.68). PMID- 25710573 TI - Hydrothermal carbonization (HTC) of wheat straw: influence of feedwater pH prepared by acetic acid and potassium hydroxide. AB - In this study, influence of feedwater pH (2-12) was studied for hydrothermal carbonization (HTC) of wheat straw at 200 and 260 degrees C. Acetic acid and KOH were used as acidic and basic medium, respectively. Hydrochars were characterized by elemental and fiber analyses, SEM, surface area, pore volume and size, and ATR FTIR, while HTC process liquids were analyzed by HPLC and GC. Both hydrochar and HTC process liquid qualities vary with feedwater pH. At acidic pH, cellulose and elemental carbon increase in hydrochar, while hemicellulose and pseudo-lignin decrease. Hydrochars produced at pH 2 feedwater has 2.7 times larger surface area than that produced at pH 12. It also has the largest pore volume (1.1 * 10(-1) ml g(-1)) and pore size (20.2 nm). Organic acids were increasing, while sugars were decreasing in case of basic feedwater, however, phenolic compounds were present only at 260 degrees C and their concentrations were increasing in basic feedwater. PMID- 25710574 TI - Effects of occasional reinforced trials during extinction on the reacquisition of conditioned responses to food cues. AB - BACKGROUND AND OBJECTIVES: Successful long-term dieting appears to be difficult, and part of its difficulty might be explained by processes related to classical appetitive conditioning. Increasing the speed of extinction of appetitive responses to food cues and decreasing the magnitude of returns of these responses could help increase the long-term effectiveness of weight loss attempts. Two extinction techniques hypothesized to slow down rapid reacquisition of conditioned appetitive responses were investigated: the provision of 1) occasional reinforced extinction trials (OR) and 2) unpaired unconditioned stimuli (USs) during extinction (UNP). METHODS: After acquisition, participants (N = 90) received one of three extinction trainings: OR, UNP, or normal extinction (control), followed by a reacquisition phase. Their desire to eat, US expectancy, and salivation were measured. Effects of impulsivity on different phases of appetitive conditioning were also assessed. RESULTS: It was found that both extinction techniques were successful in reducing the rate of reacquisition of US expectancies. Participants in the OR condition also demonstrated a slower extinction of US expectancies and desires to eat. However, the reacquisition of conditioned desires was not affected by either extinction technique. Impulsivity did not moderate responses during acquisition or extinction, but appeared to slow down the reacquisition of conditioned desires. LIMITATIONS: US expectancies and eating desires were not completely extinguished, and a few differences in baseline responses caused difficulty in interpreting some of the findings. CONCLUSIONS: It is concluded that the provision of occasional reinforced extinction trials and unpaired USs seem promising techniques to slow down reacquisition, but that additional studies are needed. PMID- 25710575 TI - An observed effect of ultraviolet radiation emitted from beta-irradiated HaCaT cells upon non-beta-irradiated bystander cells. AB - Previous research has shown that beta radiation can induce ultraviolet (UV) photon emission in human keratinocyte cells. Spectral analysis using a filter based method in the ultraviolet range demonstrated that the strongest externally measureable photon emission was induced by beta radiation in the UVA range. In the current study, the potential biological implications of this UV photon emission from beta-irradiated cells were investigated. HaCaT human keratinocyte cells were irradiated with tritium ((3)H) and the photon emission induced was concurrently measured at the strongest externally measurable wavelength, 340 +/- 5 nm, using a combination filter-photomultiplier tube system. Unirradiated reporter HaCaT cell cultures were also placed directly above (3)H-irradiated cells so that they would receive the induced secondary photons emitted from beta irradiated cells, and the clonogenic survival in reporter cells was then assessed. Maximum photon emission (1207.04 +/- 107.65 counts per second) was observed during irradiation of 2,000 cells/cm(2) with (3)H and the maximum reporter cell death (23.2 +/- 0.9% reduction in survival) was observed under the same conditions. The measured photon emission from beta-irradiated cells and reporter cell death were strongly correlated (r = 0.977, P < 0.01). Placement of a polyethylene terephthalate filter, designed to eliminate >90% of UV wavelengths below 390 nm, between the directly irradiated and reporter cell layers was effective in nearly abolishing both 340 nm photon detection and reporter cell death in treated groups. Concurrent treatment of reporter cells with lomefloxacin during exposure to the secondary photons resulted in significantly increased cell killing, indicating a potential synergistic effect, while melanin treatment resulted in decreased reporter cell killing regardless of irradiation. These results suggest that secondary photons in the UV spectral range induced by beta irradiation play a role in inducing a response in neighboring non-beta-irradiated reporter cells. PMID- 25710577 TI - Reactive DESI-MS imaging of biological tissues with dicationic ion-pairing compounds. AB - This work illustrates reactive desorption electrospray ionization mass spectrometry (DESI-MS) with a stable dication on biological tissues. Rat brain and zebra fish tissues were investigated with reactive DESI-MS in which the dictation forms a stable bond with biological tissue fatty acids and lipids. Tandem mass spectrometry (MS/MS) was used to characterize the dication (DC9) and to identify linked lipid-dication compounds formed. The fragment m/z 85 common to both DC9 fragmentation and DC9-lipid fragmentation was used to confirm that DC9 is indeed bonded with the lipids. Lipid signals in the range of m/z 250-350 and phosphoethanolamines (PE) m/z 700-800 observed in negative ion mode were also detected in positive ion mode with reactive DESI-MS with enhanced signal intensity. Reactive DESI-MS imaging in positive ion mode of rat brain and zebra fish tissues allowed enhanced detection of compounds commonly observed in the negative ion mode. PMID- 25710576 TI - A tocotrienol-enriched formulation protects against radiation-induced changes in cardiac mitochondria without modifying late cardiac function or structure. AB - Radiation-induced heart disease (RIHD) is a common and sometimes severe late side effect of radiation therapy for intrathoracic and chest wall tumors. We have previously shown that local heart irradiation in a rat model caused prolonged changes in mitochondrial respiration and increased susceptibility to mitochondrial permeability transition pore (mPTP) opening. Because tocotrienols are known to protect against oxidative stress-induced mitochondrial dysfunction, in this study, we examined the effects of tocotrienols on radiation-induced alterations in mitochondria, and structural and functional manifestations of RIHD. Male Sprague-Dawley rats received image-guided localized X irradiation to the heart to a total dose of 21 Gy. Twenty-four hours before irradiation, rats received a tocotrienol-enriched formulation or vehicle by oral gavage. Mitochondrial function and mitochondrial membrane parameters were studied at 2 weeks and 28 weeks after irradiation. In addition, cardiac function and histology were examined at 28 weeks. A single oral dose of the tocotrienol-enriched formulation preserved Bax/Bcl2 ratios and prevented mPTP opening and radiation induced alterations in succinate-driven mitochondrial respiration. Nevertheless, the late effects of local heart irradiation pertaining to myocardial function and structure were not modified. Our studies suggest that a single dose of tocotrienols protects against radiation-induced mitochondrial changes, but these effects are not sufficient against long-term alterations in cardiac function or remodeling. PMID- 25710578 TI - Effect of Sarcosine (a Glycine Transport 1 Inhibitor) and Risperidone (an Atypical antipsychotic Drug) on MK-801 Induced Learning and Memory Deficits in Rats. AB - The present study was carried out to evaluate whether the combined administration of sarcosine with risperidone possess any advantageous effects on dopaminergic and NMDA receptor-mediated glutamatergic neurotransmissions as compared to single drug administration in rats. The Wistar rats were divided into 7 groups each with different treatments. MK-801 (0.1 mg/kg, i.p.) was injected as single dose on 14th day for inducing learning and memory deficits in animals. Sarcosine (300 and 600 mg/kg, i.p.) and risperidone (0.2 mg/kg, i.p.) were administered daily for 14 days. Spatial habituation learning and hole board tests were performed on 14th day followed by measurement of GABA and 5-HT levels in brain tissues of rats. Pretreatment of sarcosine (600 mg/kg, i.p.) non-significantly improved learning and memory deficits induced by non-competitive NMDA receptor antagonist MK-801, significantly increased the GABA and decreased the 5-HT levels (p<0.05). Combined administration of sarcosine (300 mg/kg, i.p.) with risperidone (0.1 mg/kg, i.p.) synergistically improved cognitive deficits significantly, decreased % errors in hole board learning test, and increased centre time, corner time in spatial habituation learning test (p<0.05). The combined administration also potentiated the GABA and decreased 5-HT levels, indicating that the increased synaptic glycine concentrations may enhance NMDA receptor function which is directly linked with increased GABAergic transmission in striatum region and decreased 5 HT levels showed antagonistic action hence, enhancing the cognition. Our results suggest that combined administration of sarcosine with risperidone may strengthen glutamatergic tone in striatum. Thus, it may be a novel regime to improve psychotic symptoms and cognitive deficit in schizophrenia. PMID- 25710579 TI - Prognostic Significance of CD44v6, CD133, CD166, and ALDH1 Expression in Small Intestinal Adenocarcinoma. AB - BACKGROUND: Small intestinal adenocarcinoma (SIAC) is a rare human malignant tumor. According to the cancer stem cell (CSC) hypothesis, only a small subpopulation of tumor cells has the ability to initiate and increase tumor growth. CD44v6, CD133, CD166, and ALDH1 have been proposed to be putative CSC markers in gastrointestinal malignancies. However, their implications in SIAC still remain unclear. We aimed to investigate the expressions of CD44v6, CD133, CD166, and ALDH1 and evaluate their relationships with clinicopathologic parameters including the survival data in SIACs. MATERIALS AND METHODS: Immunohistochemical analysis for CD44, CD133, CD166, and ALDH1 was performed using tissue microarrays for 191 surgically resected SIACs. RESULTS: CD44v6, CD133, CD166, and ALDH1 expression was found in 25 (13.5%), 58 (30.7%), 82 (44.1%), and 63 (33.3%) cases, respectively. CD44v6(+) was correlated with vascular tumor invasion (P=0.023). CD133(+) was marginally correlated with the histologic subtype of the tumors (P=0.085). Combined CD44v6(+)/CD133(+) was observed in 11 (5.9%) and was associated with a significantly worse survival rate by univariate (P=0.016) and multivariate (P=0.048; Cox hazard ratio, 2.403) analyses. . CONCLUSIONS: Evaluation of the combined CD133 and CD44v6 expression could be a useful tool for predicting a poor outcome in patients with SIAC. PMID- 25710580 TI - De Novo Acute Myeloid Leukemia in Adults: Suppression of MicroRNA-223 is Independent of LMO2 Protein Expression BUT Associate With Adverse Cytogenetic Profile and Undifferentiated Blast Morphology. AB - MicroRNA (MIR) signatures are critical to pathobiology and prognosis of acute myeloid leukemia (AML). MIR223 is expressed at low levels in progenitor cells, whereas high expression is induced by granulocytic differentiation. Novel targeted therapies through epigenetic manipulation of MIR223 regulators are being explored in AML but correlative data between established clinical prognostic markers and MIR223 expression in AML is lacking. MIR223 has inverse relationship with LMO2 protein expression and our group has recently reported a close association between LMO2 protein expression and chromosomal findings in AML patients. In this study, we examined the expression of MIR223 in a large cohort of AML patients and correlated it with LMO2 protein expression, cytogenetic data, degree of differentiation [French-American and British (FAB)/World Health Organization classifications], and overall survival. MIR223 expression was upregulated in only a subset of patients (37%). Suppression of MIR223 was more frequent among patients with aneuploid karyotype compared with diploid karyotype (P=0.005). In AML, not otherwise specified category, AML with maturation (FAB-M2) showed higher levels of MIR223 when compared with either AML without maturation (FAB M0/M1) (P=0.001); AML with monoblastic differentiation (FAB M4/M5) (P=0.004) or AML with myelodysplasia-related changes (P=0.011). Among cytogenetic risk groups, suppression of MIR223 was universal (>95%) in high-risk group when compared with intermediate-risk group (P=0.004). No correlation between MIR223 and LMO2 protein expression was identified. In conclusion, we have shown that suppression of MIR223 expression, as compared with controls, is associated with lack of differentiation and adverse cytogenetic profile, but unrelated with LMO2 protein expression or overall survival. PMID- 25710581 TI - The Diagnostic Utility of PAX8 for Neuroendocrine Tumors: An Immunohistochemical Reappraisal. AB - PAX8 is a transcription factor crucial for the development of the kidneys, thyroid glands, and Mullerian system. It is commonly expressed by epithelial tumors from these organs. Recently, the diagnostic utility of PAX8 has been expanded to pancreatic neuroendocrine tumors (NETs). However, PAX8 is not expressed by pancreatic islets during organogenesis. The potential cross reactivity of polyclonal PAX8 antibody to other PAX family members makes it essential that related findings need to be validated. In this study, we used 4 antibodies (1 polyclonal and 3 monoclonal) on 115 NETs from various organs (pancreas, n=20; thymus, n=16; cervix, n=27; parathyroid, n=7; and thyroid, lung, ileum, stomach, duodenum, appendix, rectum, ovary, and skin, each n=5) to test the utility of PAX8 as a differential diagnosis marker of NETs. Our results showed that NETs from a large variety of organs except for lung and ileum could be immunoreactive to the 2 less specific antibodies that have been observed to cross-react with other PAX proteins (Proteintech polyclonal and Cell Marque MRQ50). However, all NETs were immunonegative for the other 2 monoclonal antibodies specific for the less conserved C-terminal portion of PAX8 (Abcam PAX8R1 and Biocare BC12). We concluded that PAX8 may provide help in the differential diagnosis of NETs in certain specific contexts but the antibody used and the clinical information must be considered. PMID- 25710583 TI - The Differential Immunohistochemical Expression of p53, c-Jun, c-Myc, and p21 Between HCV-related Hepatocellular Carcinoma With and Without Cirrhosis. AB - Hepatocellular carcinoma (HCC) constitutes 70.48% of all liver tumors among Egyptians with multifactorial etiology and complex pathogenesis. HCV infection is the most common risk factor of HCC in Egypt, which commonly develops on top of cirrhosis (HCC-C); however, 15% to 20% of HCC are reported to arise in noncirrhotic livers (HCC-NC). This study aimed to explore the differences in the immunohistochemical expression of p53, c-Jun, c-Myc, and p21 between HCC-C and HCC-NC to verify the underlying molecular pathways and to study their role in hepatocarcinogenesis. This study investigated 103 cases of HCC (86 cases of HCC-C and 17 cases HCC-NC including tumorous and nontumorous tissues) together with 10 cases of chronic hepatitis and 10 cases of pure cirrhosis as control groups. Zero, 100%, 100%, and 50% of chronic hepatitis cases were positive for p53, c Jun, c-Myc, and p21, respectively. All cirrhotic cases were negative for p53 and c-Jun, whereas they were all positive for c-Myc and p21. A total of 41%, 11.65%, 86.4%, and 57.3% of HCC cases showed p53, c-Jun, c-Myc, and p21 expression, respectively. The only difference between HCC-C and HCC-NC was the H-score values of p21 expression, which were higher in HCC-C compared with HCC-NC (P=0.03). HCV related HCC commonly develops on top of cirrhosis with a minority develops on top of noncirrhotic liver. Only p21 pathway appears to be upregulated in favor of HCC C than HCC-NC. p53 is considered as a late-event molecular carcinogen, whereas p21 and c-Myc may serve as early-event molecular carcinogen in HCC. The oncogenic role of p21 may be related to its cytoplasmic localization and its promotion of c Myc expression. Progressive increase in the intensity of c-Myc expression from chronic hepatitis to cirrhosis to HCC may refer to its role as a multistep regulator of hepatocarcinogenesis. The marked reduction of c-Jun in HCC may refer to its tumor suppressor activity. PMID- 25710582 TI - Immunohistochemical Expression of CD105 and TGF-beta1 in Oral Squamous Cell Carcinoma and Adjacent Apparently Normal Oral Mucosa and its Correlation With Clinicopathologic Features. AB - Angiogenesis in oral squamous cell carcinomas (OSCC) is essential for its growth, invasion, and metastasis. This entails a shift in the balance between proangiogenic and antiangiogenic factors. CD105 and TGF-beta1 are 2 such proangiogenic factors wherein CD105 exerts its angiogenic effect by binding to and modulating the TGF-beta1 pathway. A total of 50 resected specimens of OSCC were considered. One tissue specimen was taken from tumor proper and another specimen from adjacent apparently normal mucosa (AANM). Both tissues were immunohistochemically stained using CD105 and TGF-beta1 antibodies. The expression of each antibody was individually assessed and then compared. Pearson chi test was used for statistical comparison of expression. CD105 was significantly expressed in OSCC as compared with AANM and also correlated with increasing TNM stage. The mean microvessel density was higher in OSCC. TGF-beta1 was significantly expressed in epithelium of OSCC as compared with AANM. On comparing expression of TGF-beta1 and CD105, 79.54% of endothelial cells expressed positivity for both molecules. Both CD105 and TGF-beta1 were increased in OSCC, although based on our results CD105 alone can be used as a prognostic marker. On the basis of immunohistochemical expression of CD105 and TGF-beta1 in endothelial cells, our results demonstrate that CD105 acts as one of the receptors of TGF-beta1 on endothelial cells and induces the angiogenic pathway in OSCC. PMID- 25710584 TI - The Predictive and Prognostic Role of Topoisomerase IIalpha and Tissue Inhibitor of Metalloproteinases 1 Expression in Locally Advanced Breast Carcinoma of Egyptian Patients Treated With Anthracycline-based Neoadjuvant Chemotherapy. AB - PURPOSE: Locally advanced breast cancer (LABC) is a heterogeneous entity that remains a clinical challenge. Anthracycline-based neoadjuvant chemotherapy has emerged as the standard of care for those patients. However, it is associated with serious side effects including cardiotoxicity. This study aimed to evaluate the prognostic and predictive role of topoisomerase IIalpha (TOP2alpha) and tissue inhibitor of metalloproteinases 1 (TIMP-1) in Egyptian LABC patients after anthracycline-based neoadjuvant chemotherapy. MATERIALS AND METHODS: This retrospective study was conducted on 84 LABC cases. Immunohistochemical expression of TOP2alpha and TIMP-1 was evaluated in pretreatment needle core biopsies. Results were correlated with clinicopathlogic parameters, response to neoadjuvant chemotherapy in postoperative specimens, disease-free survival and overall survival (OS). RESULTS: Positive TOP2alpha expression was detected in 57/84 (67.9%) cases. It was significantly associated with good response to chemotherapy in breast (P=0.048) and lymph node (P=0.06) as well as prolonged OS (P=0.04). It tended to be the most independent prognostic factor for OS (P=0.06). Positive TIMP-1 expression was detected in 48/84 (57.1%) cases. It was significantly associated with poor response to chemotherapy in breast (P=0.02). The 2T profile (TOP2alpha+ and TIMP-1-) was significantly associated with good response to chemotherapy in breast (P=0.006). CONCLUSION: TOP2alpha and TIMP-1 are important predictive and prognostic factors in LABC patients who received anthracycline-based chemotherapy. PMID- 25710585 TI - BRAFV600E Gene Mutation in Colonic Adenocarcinomas. Immunohistochemical Detection Using Tissue Microarray and Clinicopathologic Characteristics: An 86 Case Series. AB - The detection of BRAF mutation in colorectal cancer has several clinical applications: enabling the discrimination between sporadic and Lynch syndrome related colorectal carcinoma, and providing warning of a poorer prognosis. Few immunohistochemical studies using whole-tissue tumor section staining have recently been performed on colorectal cancer. The aim of this study was to evaluate the detection of BRAF mutation by immunohistochemistry (IHC) on tissue microarray (TMA). IHC was performed with the BRAF-specific antibody using TMA on a retrospective series of 86 colonic adenocarcinomas with known BRAF status. IHC using BRAF-specific antibody allowed to detect 20/21 BRAF mutated colonic adenocarcinomas and 60/65 BRAF wild-type cases. The staining was equivocal because of equivocal staining in 4 cases and heterogeneity in 3 cases. When compared with TaqMan real-time PCR, the sensitivity and specificity were 95.2% and 92.3%, respectively. Comparison with the whole section immunostaining improved sensitivity to 100% and specificity to 95.4%. Furthermore, in this study we found that BRAF mutated colonic adenocarcinoma were significantly more frequent in women, older patients, and right-sided. Moreover, morphologic features significantly associated with BRAF mutation were: serrated adenocarcinoma subtype, adenocarcinomas with a mucinous component, high histologic grade, pushing margins, stromal inflammation. BRAF-specific antibody can be used on TMA to screen BRAF-mutated colorectal carcinomas. Cases with equivocal or heterogenous staining must be compared with whole section staining. Moreover, BRAF mutated colonic carcinomas have distinct clinical and histopathologic features. PMID- 25710586 TI - Oligonucleotide Array-based Comparative Genomic Hybridization Approach in Hematologic Malignancies With Normal/Failed Conventional Cytogenetics and Fluorescent In Situ Hybridization. AB - Oligonucleotide array-based comparative genomic hybridization (oaCGH) was used to investigate 60 cases of hematologic malignancies, mainly acute myeloid leukemias and myelodysplastic syndromes, in order to evaluate its sensitivity and specificity and to search for genomic alterations undetected by previous investigation with conventional cytogenetics (CC) and fluorescent in situ hybridization (FISH). On the basis of CC and FISH results, we subdivided the series into group A (36 cases with a normal karyotype after CC and/or FISH testing) and group B (24 cases with anomalies detected by CC and/or FISH). oaCGH did not show alterations in 21 cases of the group A (58.3%); in the remaining 15 cases (41.7%), it detected 19 new abnormalities (14 amplifications and 5 deletions). In the group B, oaCGH confirmed 32/55 aneuploidies detected by FISH (58.1%). The sensitivity increased at 27/33 confirmed aneuploidies (81.8%) by placing as a cutoff a mosaic of 50%. Moreover, in the cases of this group oaCGH revealed 36 new alterations (15 amplifications and 21 deletions). From these results it is possible to assess a strong overlap between results obtained by FISH and oaCGH. However, oaCGH is a reliable alternative where CC and FISH are not feasible and is able to identify new alterations unexplored by FISH. PMID- 25710587 TI - Primary Cutaneous Extranodal Natural Killer/T-Cell Lymphoma Misdiagnosed as Peripheral T-Cell Lymphoma: The Importance of Consultation/Referral and Inclusion of EBV In Situ Hybridization for Diagnosis. AB - BACKGROUND: Primary cutaneous T-cell lymphomas (CTCL) are heterogenous extranodal non-Hodgkin lymphomas including a few distinct and provisional entities. Compared with the West, Asian populations have a relatively higher frequency of nonmycosis fungoides CTCL. Primary cutaneous extranodal natural killer/T-cell lymphoma (PC ENKTL) is distinct from other CTCL by the presence of EBV association. METHOD: In our recent retrospective Asian study of PC-ENKTL, we identified 5 cases initially misdiagnosed as various CTCL. We fully characterized these cases with immunohistochemistry, EBV in situ hybridization, and clonality study for T-cell receptor (TCR) gamma-chain gene (TRG). RESULTS: The 5 patients included 3 males and 2 females with a median age of 45. All tumors were positive for EBER. Two cases were clonal for TRG gene rearrangement but without expression of betaF1 or TCR-gamma (TCR-silent T-cell origin), 1 tumor expressed TCR-gamma (gammadelta T cell origin), and the remaining 2 were polyclonal for TRG and negative for TCR expression (NK-cell origin). On the basis of the initial diagnoses (2 as peripheral T-cell lymphoma, unspecified, 2 as primary cutaneous anaplastic large cell lymphoma, and 1 as subcutaneous panniculitis-like T-cell lymphoma), all patients received CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) chemotherapy with additional radiotherapy in 3. All patients experienced persistent disease or relapse despite treatment in a mean duration of 8.8 months (range, 1 to 12 mo). CONCLUSIONS: PC-ENKTL is rare and aggressive. These cases strongly demonstrate the importance of consultation/referral to experienced hematopathologists and the inclusion of EBER in the initial diagnostic work-up for patients with nonmycosis fungoides CTCL to avoid erroneous diagnosis and subsequent inadequate treatment of the patients. PMID- 25710588 TI - The Immunophenotype of Nodular Variant of Medullary Carcinoma of the Breast. AB - The histologic and immunohistochemical profile of typical medullary carcinomas (TMC) of the breast are well established. Among the strict histologic criteria for the diagnosis of TMC is complete circumscription of tumor with pushing borders. Those tumors that do not fulfill all morphologic requirements of TMC are designated as atypical medullary carcinomas (AMC). We herewith describe the histology and immunophenotype of a heretofore undescribed variant of TMC composed of multiple distinctly separate nodules that otherwise meet all other histologic and immunohistochemical phenotypes of TMC. Among 2952 cases of infiltrating mammary carcinomas, 111 (3.8%) met the strict criteria for TMC, including positivity for HLA-DR. Nine of these tumors were composed of multiple separate noncoalescing nodules. Immunohistochemical stains for ER, PR, HER2, and HLA-DR, as well as for p53 and Ki-67 were repeated on these nodular forms. Staining for p63 was used to identify possible intraductal components of these tumors. The age of patients ranged from 34 to 53 years. All 9 patients had negative sentinel lymph nodes. Tumors ranged in the overall size from 2.2 to 3.9 cm and were composed of 3 to 6 distinct nodules ranging in size from 0.2 to 1.1 cm surrounding a larger main tumor nodule. The nodules were composed of syncytial groups of large cells with atypical nuclei and prominent nucleoli. A lymphoplasmacytic infiltrate was present within and around each satellite nodule. Serial sections did not show coalescing of the nodules into a single tumor mass. Similarly, staining for p63 failed to support the possibility of nodules representing intraductal components of main tumor. All tumors were negative for ER, PR, and HER2, but positive for HLA-DR. Eight of 9 tumors were diffusely positive for p53 and all 9 showed a high proliferation index in >70% of tumor cells with Ki-67. We conclude that the nodular variants of medullary carcinomas (nTMC) of the breast are uncommon forms of TMC. They occur in relatively younger women and share the same immunophenotype with TMCs; they are triple negative, express HLA-DR and p53, and show a high proliferative index. As the diagnosis of TMC carries major clinical and prognostic implications, the recognition of its nodular variant becomes equally important. PMID- 25710589 TI - Solvatochromic Nile Red probes with FRET quencher reveal lipid order heterogeneity in living and apoptotic cells. AB - Detecting and imaging lipid microdomains (rafts) in cell membranes remain a challenge despite intensive research in the field. Two types of fluorescent probes are used for this purpose: one specifically labels a given phase (liquid ordered, Lo, or liquid disordered, Ld), while the other, being environment sensitive (solvatochromic), stains the two phases in different emission colors. Here, we combined the two approaches by designing a phase-sensitive probe of the Ld phase and a quencher of the Ld phase. The former is an analogue of the recently developed Nile Red-based probe NR12S, bearing a bulky hydrophobic chain (bNR10S), while the latter is based on Black Hole Quencher-2 designed as bNR10S (bQ10S). Fluorescence spectroscopy of large unilamellar vesicles and microscopy of giant vesicles showed that the bNR10S probe can partition specifically into the Ld phase, while bQ10S can specifically quench the NR12S probe in the Ld phase so that only its fraction in the Lo phase remains fluorescent. Thus, the toolkit of two probes with quencher can specifically target Ld and Lo phases and identify their lipid order from the emission color. Application of this toolkit in living cells (HeLa, CHO, and 293T cell lines) revealed heterogeneity in the cell plasma membranes, observed as distinct probe environments close to the Lo and Ld phases of model membranes. In HeLa cells undergoing apoptosis, our toolkit showed the formation of separate domains of the Ld-like phase in the form of blebs. The developed tools open new possibilities in lipid raft research. PMID- 25710590 TI - Bacillus-shape design of polymer based drug delivery systems with janus-faced function for synergistic targeted drug delivery and more effective cancer therapy. AB - The particle shape of the drug delivery systems had a strong impact on their in vitro and in vivo performance, but there was limited availability of techniques to produce the specific shaped drug carriers. In this article, the novel methotrexate (MTX) decorated MPEG-PLA nanobacillus (MPEG-PLA-MTX NB) was prepared by the self-assembly technique followed by the extrusion through SPG membrane with high N2 pressure for targeted drug delivery, in which Janus-like MTX was not only used as a specific anticancer drug but could also be served as a tumor targeting ligand. The MPEG-PLA-MTX NBs demonstrated much higher in vitro and in vivo targeting efficiency compared to the MPEG-PLA-MTX nanospheres (MPEG-PLA-MTX NSs) and MPEG-PLA nanospheres (MPEG-PLA NSs). In addition, the MPEG-PLA-MTX NBs also displayed much more excellent in vitro and in vivo antitumor activity than the MPEG-PLA-MTX NSs and free MTX injection. To our knowledge, this work provided the first example of the integration of the shape design (which mediated an early phase tumor accumulation and a late-phase cell internalization) and Janus-faced function (which mediated an early phase active targeting effect and a late-phase anticancer effect) on the basis of nanoscaled drug delivery systems. The highly convergent and cooperative drug delivery strategy opens the door to more drug delivery systems with new shapes and functions for cancer therapy. PMID- 25710591 TI - Microfluidic paper-based analytical devices fabricated by low-cost photolithography and embossing of Parafilm(r). AB - Microfluidic paper-based analytical devices (MUPADs) attract tremendous attention as an economical tool for in-field diagnosis, food safety and environmental monitoring. We innovatively fabricated 2D and 3D MUPADs by photolithography patterning microchannels on a Parafilm(r) and subsequently embossing them to paper. This truly low-cost, wax printer and cutter plotter independent approach offers the opportunity for researchers from resource-limited laboratories to work on paper-based analytical devices. PMID- 25710592 TI - Synthetic studies of 7-oxygenated aporphine alkaloids: preparation of (-) oliveroline, (-)-nornuciferidine, and derivatives. AB - 7-Oxygenated aporphines 1-6 possessing anti-configurations have previously been reported. In order to explore their bioactivities, a synthesis was established by utilizing a diastereoselective reductive acid-mediated cyclization followed by palladium-catalyzed ortho-arylations. Moderate XPhos precatalyst loading (10 mol %) and short reaction times (30 min) were sufficient to mediate the arylations. Alkaloids 1-5 were successfully prepared, while (-)-artabonatine A was revised to syn-isomer 30. Consequently, (-)-artabonatine E likely also has a syn configuration (31). PMID- 25710593 TI - Structural and bonding patterns in gold clusters. AB - The study of gold cluster compounds originated from Malatesta's syntheses of tertiaryphosphine derivatives in the 1960s and was greatly extended between 1970 and 2000. Single crystal X-ray studies defined the major structural classes and led to the development of a theoretical model which accounted for their closed shell requirements in terms of their topological features and proved to be sufficiently flexible to be extended to related heteronuclear cluster compounds. Since the turn of the century the range of gold cluster compounds has been greatly extended by the study of organothiolato-gold cluster compounds. The structures of these compounds have revealed that the gold atoms combine with the organothiolato-ligands to generate a novel class of metallo-organothiolato ligands which protect and stabilise the inner core of gold atoms. These developments originally suggested that the phosphine and organothiolato-clusters defined quite distinct classes of gold clusters, but recent structural and theoretical developments have reconciled many of these differences. This review summarises the structures of all the clusters of gold and suggests a theoretical model which effectively unites the broad structural properties of the two classes of compound. This model is based on the united atom model for diatomics developed by Mulliken and the compression co-ordinate is related to the interpenetration of icosahedral and cuboctahedral pseudo-spherical clusters. The predicted closed shell requirements agree well with the results of structural determinations. PMID- 25710595 TI - Chemical Kinetic Influences of Alkyl Chain Structure on the High Pressure and Temperature Oxidation of a Representative Unsaturated Biodiesel: Methyl Nonenoate. AB - The high pressure and temperature oxidation of methyl trans-2-nonenoate, methyl trans-3-nonenoate, 1-octene, and trans-2-octene are investigated experimentally to probe the influence of the double bond position on the chemical kinetics of long esters and alkenes. Single pulse shock tube experiments are performed in the ranges p = 3.8-6.2 MPa and T = 850-1500 K, with an average reaction time of 2 ms. Gas chromatographic measurements indicate increased reactivity for trans-2-octene compared to 1-octene, whereas both methyl nonenoate isomers have reactivities similar to that of 1-octene. A difference in the yield of stable intermediates is observed for the octenes when compared to the methyl nonenoates. Chemical kinetic models are developed with the aid of the Reaction Mechanism Generator to interpret the experimental results. The models are created using two different base chemistry submodels to investigate the influence of the foundational chemistry (i.e., C0-C4), whereas Monte Carlo simulations are performed to examine the quality of agreement with the experimental results. Significant uncertainties are found in the chemistry of unsaturated esters with the double bonds located close to the ester groups. This work highlights the importance of the foundational chemistry in predictive chemical kinetics of biodiesel combustion at engine relevant conditions. PMID- 25710594 TI - Research resource: the dynamic transcriptional profile of sertoli cells during the progression of spermatogenesis. AB - Sertoli cells (SCs), the only somatic cells within seminiferous tubules, associate intimately with developing germ cells. They not only provide physical and nutritional support but also secrete factors essential to the complex developmental processes of germ cell proliferation and differentiation. The SC transcriptome must therefore adapt rapidly during the different stages of spermatogenesis. We report comprehensive genome-wide expression profiles of pure populations of SCs isolated at 5 distinct stages of the first wave of mouse spermatogenesis, using RNA sequencing technology. We were able to reconstruct about 13 901 high-confidence, nonredundant coding and noncoding transcripts, characterized by complex alternative splicing patterns with more than 45% comprising novel isoforms of known genes. Interestingly, roughly one-fifth (2939) of these genes exhibited a dynamic expression profile reflecting the evolving role of SCs during the progression of spermatogenesis, with stage-specific expression of genes involved in biological processes such as cell cycle regulation, metabolism and energy production, retinoic acid synthesis, and blood testis barrier biogenesis. Finally, regulatory network analysis identified the transcription factors endothelial PAS domain-containing protein 1 (EPAS1/Hif2alpha), aryl hydrocarbon receptor nuclear translocator (ARNT/Hif1beta), and signal transducer and activator of transcription 1 (STAT1) as potential master regulators driving the SC transcriptional program. Our results highlight the plastic transcriptional landscape of SCs during the progression of spermatogenesis and provide valuable resources to better understand SC function and spermatogenesis and its related disorders, such as male infertility. PMID- 25710596 TI - Cerebrospinal fluid beta-amyloid1-42 levels in the differential diagnosis of Alzheimer's disease--systematic review and meta-analysis. AB - OBJECTIVES: The purpose of this study was to carry out systematic review of the literature and meta-analysis to evaluate the diagnostic utility of cerebrospinal fluid (CSF) levels of the 42 amino acid form of amyloid-beta (Abeta1-42) as a biomarker for differentiating Alzheimer's disease (AD) from non-AD dementia. METHODS: Design. Systematic literature review was used to evaluate the effectiveness of the Abeta for the diagnosis of AD. The Scottish Intercollegiate Guidelines Network (SIGN) tool was used to evaluate independently the quality of the studies. Data sources. The literature review covered from January 1, 2004, to October 22, 2013, and searched eight domestic databases including Korea Med and international databases including Ovid-MEDLINE, EMBASE, and Cochrane Library. Data Extraction and Synthesis. Primary criteria for inclusion were valid studies on (i) patients with mild cognitive impairment with confirmed or suspected AD and non-AD dementia, and (ii) assessment of Abeta1-42 levels using appropriate comparative tests. RESULTS: A total of 17 diagnostic evaluation studies were identified in which levels of CSF Abeta1-42 were assessed. Meta-analysis was performed on 11 robust studies that compared confirmed AD (n = 2211) with healthy individuals (n = 1030), 10 studies that compared AD with non-AD dementias (n = 627), and 5 studies that compared amnestic mild cognitive impairment (n = 1133) with non-amnestic type subjects (n = 1276). Overall, the CSF Abeta1-42 levels were reduced in AD compared to controls or non-AD dementia. The effectiveness of test was evaluated for diagnostic accuracy (pooled sensitivity, 0.80 (95% CI 0.78 0.82); pooled specificity, 0.76 (95% CI 0.74-0.78). CONCLUSIONS: Reduced CSF Abeta1-42 levels are of potential utility in the differential diagnosis of AD versus non-AD dementias and controls. Diagnostic accuracy was high in AD versus healthy controls. However, differential diagnosis for MCI or non-AD might be evaluated by other biomarkers. PMID- 25710597 TI - Chemical profiling and quantification of Gua-Lou-Gui-Zhi decoction by high performance liquid chromatography/quadrupole-time-of-flight mass spectrometry and ultra-performance liquid chromatography/triple quadrupole mass spectrometry. AB - Gua-Lou-Gui-Zhi decoction (GLGZD) is a classical formula of traditional Chinese medicine, which has been commonly used to treat dysfunction after stroke, epilepsy and spinal cord injury. In this study, a systematic method was established for chemical profiling and quantification analysis of the major constituents in GLGZD. For qualitative analysis, a method of high performance liquid chromatography/quadrupole time-of-flight mass spectrometry (Q-TOF MS) was developed. 106 compounds, including monoterpene glycosides, galloyl glucoses, phenolic acids, flavonoids, gingerols and triterpene saponins were identified or tentatively presumed by comparison with reference standards or literature data. According to the qualitative results, a new quantitative analysis method of ultra performance liquid chromatography/triple quadrupole mass spectrometry (QqQ-MS) was established. 24 representative compounds were simultaneously detected in 10 batches of GLGZD samples in 7.5 min. The calibration curves for all analytes showed good linearity (r>0.9959) within the test ranges. The LODs and the LOQs were less than 30.6 and 70.9 ng/mL, respectively. The RSDs of intra- and inter day precision, repeatability and stability were below 3.64%, 4.85%, 4.84% and 3.87%, respectively. The overall recoveries ranged from 94.94% to 103.66%, with the RSDs within 5.12%. This study established a high sensitive and efficient method for the integrating quality control, including identification and quantification of Chinese medicinal preparation. PMID- 25710598 TI - Pd-catalyzed regioselective arylation on the C-5 position of N-aryl 1,2,3 triazoles. AB - We herein report a highly efficient method for the arylation at the C-5 position of N-aryl 1,2,3-triazoles via a direct palladium catalyzed arylation reaction. The optimal reaction conditions required a combination of Pd(OAc)2 and tris(o tolyl)phosphine as catalyst, and Cs2CO3 as the base under inert atmosphere. A variety of C-5 substituted N-aryl 1,2,3-triazoles were prepared using these conditions with yields in the 70-88% range. Regioselective C-5 arylations were also performed on 1,4-disubstituted 1,2,3-triazoles. The regioselectivity in triazole substitution at the C-5 position was confirmed by single crystal XRD. In addition, computational investigations of key steps of the catalytic cycle using the density functional theory have provided a rationalization to the selective C 5 arylation of N-aryl 1,2,3-triazoles. PMID- 25710599 TI - Cadmium telluride (CdTe) and cadmium selenide (CdSe) leaching behavior and surface chemistry in response to pH and O2. AB - Cadmium telluride (CdTe) and cadmium selenide (CdSe) are increasingly being applied in photovoltaic solar cells and electronic components. A major concern is the public health and ecological risks associated with the potential release of toxic cadmium, tellurium, and/or selenium species. In this study, different tests were applied to investigate the leaching behavior of CdTe and CdSe in solutions simulating landfill leachate. CdTe showed a comparatively high leaching potential. In the Toxicity Characteristic Leaching Procedure (TCLP) and Waste Extraction Test (WET), the concentrations of cadmium released from CdTe were about 1500 and 260 times higher than the regulatory limit (1 mg/L). In contrast, CdSe was relatively stable and dissolved selenium in both leaching tests was below the regulatory limit (1 mg/L). Nonetheless, the regulatory limit for cadmium was exceeded by 5- to 6- fold in both tests. Experiments performed under different pH and redox conditions confirmed a marked enhancement in CdTe and CdSe dissolution both at acidic pH and under aerobic conditions. These findings are in agreement with thermodynamic predictions. Taken as a whole, the results indicate that recycling of decommissioned CdTe-containing devices is desirable to prevent the potential environmental release of toxic cadmium and tellurium in municipal landfills. PMID- 25710600 TI - Statistical analysis and ANN modeling for predicting hydrological extremes under climate change scenarios: the example of a small Mediterranean agro-watershed. AB - The purpose of this study was to create a modeling management tool for the simulation of extreme flow events under current and future climatic conditions. This tool is a combination of different components and can be applied in complex hydrogeological river basins, where frequent flood and drought phenomena occur. The first component is the statistical analysis of the available hydro meteorological data. Specifically, principal components analysis was performed in order to quantify the importance of the hydro-meteorological parameters that affect the generation of extreme events. The second component is a prediction forecasting artificial neural network (ANN) model that simulates, accurately and efficiently, river flow on an hourly basis. This model is based on a methodology that attempts to resolve a very difficult problem related to the accurate estimation of extreme flows. For this purpose, the available measurements (5 years of hourly data) were divided in two subsets: one for the dry and one for the wet periods of the hydrological year. This way, two ANNs were created, trained, tested and validated for a complex Mediterranean river basin in Crete, Greece. As part of the second management component a statistical downscaling tool was used for the creation of meteorological data according to the higher and lower emission climate change scenarios A2 and B1. These data are used as input in the ANN for the forecasting of river flow for the next two decades. The final component is the application of a meteorological index on the measured and forecasted precipitation and flow data, in order to assess the severity and duration of extreme events. PMID- 25710601 TI - Increased frequency of dietitian visits is associated with improved body mass index outcomes in obese youth participating in a comprehensive pediatric weight management program. AB - BACKGROUND: Comprehensive weight management (CWM) interventions are most effective for obese youth when they include multiple components, such as nutrition, physical activity, and behavioral strategies. However, effectiveness of different approaches to delivering the nutrition component is unknown. Our aim was to evaluate two dietary approaches and extent of registered dietitian (RD) involvement on outcomes of obese youth participating in a CWM program. METHODS: A retrospective review of CWM patients was conducted before and after redesign of the nutrition component. The earlier clinical model (CM1) introduced a portion controlled diet at an RD visit after the initial medical visit, whereas the later clinical model (CM2) introduced a reduced glycemic load diet at the initial medical visit. CWM patients were included if they had at least one RD visit and an initial and 3- to 6-month medical follow-up visit during CM1 or CM2. Differences between CM1 and CM2 groups regarding changes in BMI and programmatic success (BMI change <=0) were evaluated. RESULTS: Median BMI change during follow up did not differ between CM1 (n=41) and CM2 (n=51) groups (p=0.41). In a multiple logistic regression model combining study groups, each additional RD visit was associated with a 28% increased odds of success (odds ratio [95% confidence interval]: 1.28 [1.00, 1.64]; p=0.05). The probability of success exceeded 78% with >=1 RD visit/month versus 43% with minimal RD exposure. CONCLUSIONS: Increased frequency of RD visits is associated with improved BMI outcomes in obese youth participating in a CWM program regardless of dietary intervention implemented. PMID- 25710603 TI - Digital microfluidics for time-resolved cytotoxicity studies on single non adherent yeast cells. AB - Single cell analysis (SCA) has gained increased popularity for elucidating cellular heterogeneity at genomic, proteomic and cellular levels. Flow cytometry is considered as one of the most widely used techniques to characterize single cell responses; however, its inability to analyse cells with spatio-temporal resolution poses a major drawback. Here, we introduce a digital microfluidic (DMF) platform as a useful tool for conducting studies on isolated yeast cells in a high-throughput fashion. The reported system exhibits (i) a microwell array for trapping single non-adherent cells by shuttling a cell-containing droplet over the array, and allows (ii) implementation of high-throughput cytotoxicity assays with enhanced spatio-temporal resolution. The system was tested for five different concentrations of the antifungal drug Amphotericin B, and the cell responses were monitored over time by time lapse fluorescence microscopy. The DMF platform was validated by bulk experiments, which mimicked the DMF experimental design. A correlation analysis revealed that the results obtained on the DMF platform are not significantly different from those obtained in bulk; hence, the DMF platform can be used as a tool to perform SCA on non-adherent cells, with spatio-temporal resolution. In addition, no external forces, other than the physical forces generated by moving the droplet, were used to capture single cells, thereby avoiding cell damage. As such, the information on cellular behaviour during treatment could be obtained for every single cell over time making this platform noteworthy in the field of SCA. PMID- 25710602 TI - Membrane-mediated interaction between strongly anisotropic protein scaffolds. AB - Specialized proteins serve as scaffolds sculpting strongly curved membranes of intracellular organelles. Effective membrane shaping requires segregation of these proteins into domains and is, therefore, critically dependent on the protein-protein interaction. Interactions mediated by membrane elastic deformations have been extensively analyzed within approximations of large inter protein distances, small extents of the protein-mediated membrane bending and small deviations of the protein shapes from isotropic spherical segments. At the same time, important classes of the realistic membrane-shaping proteins have strongly elongated shapes with large and highly anisotropic curvature. Here we investigated, computationally, the membrane mediated interaction between proteins or protein oligomers representing membrane scaffolds with strongly anisotropic curvature, and addressed, quantitatively, a specific case of the scaffold geometrical parameters characterizing BAR domains, which are crucial for membrane shaping in endocytosis. In addition to the previously analyzed contributions to the interaction, we considered a repulsive force stemming from the entropy of the scaffold orientation. We computed this interaction to be of the same order of magnitude as the well-known attractive force related to the entropy of membrane undulations. We demonstrated the scaffold shape anisotropy to cause a mutual aligning of the scaffolds and to generate a strong attractive interaction bringing the scaffolds close to each other to equilibrium distances much smaller than the scaffold size. We computed the energy of interaction between scaffolds of a realistic geometry to constitute tens of kBT, which guarantees a robust segregation of the scaffolds into domains. PMID- 25710604 TI - Staff Reactions Toward Lesbian, Gay, or Bisexual (LGB) People Living in Residential Aged Care Facilities (RACFs) Who Actively Disclose Their Sexual Orientation. AB - Fifty-three staff members currently working in residential aged care facilities located in Barcelona, Spain, were asked about the way they would react if a resident told them that he or she felt sexually attracted and had maintained sexual relationships with another resident of the same gender. Acceptance of non heterosexual sexual orientation was a frequent answer, and around one in four professionals stated that they would try helping the resident in question, by offering a private space or giving some emotional support. However, some reactions were not consistent with a respectful approach toward sexual diversity, as, for instance, informing the resident's family or advising the resident to keep his or her sexual orientation hidden. We highlight the importance of developing formal policies and offering formal training to staff in order to address the specific needs of older LGB people living in RACFs. PMID- 25710605 TI - Integration of non-fuel coproducts into the GREET model. AB - The life-cycle greenhouse gas (GHG) emissions of alternative fuels that are capable of replacing conventional, petroleum-derived gasoline and diesel continue to be scrutinized for policy implementation. These alternative fuel technologies can also produce a number of value-adding nonfuel coproducts that require thorough and rigorous assessment in order to achieve an accurate life-cycle GHG emissions value. By using the gas to liquids (GTL) diesel pathway as a proxy for other alternative fuel pathways with coproducts, this paper examines how integration of coproduct analysis using the substitution method is possible within the existing framework and functionality of the GREET model. Using this approach, a GREET-compatible external tool was developed to calculate the life cycle inventory of GTL coproducts to determine the life-cycle GHG emissions of GTL diesel using the substitution method. In addition to having built-in regional scenarios, this tool allows the user the flexibility to configure a given GTL product slate and to calculate the life-cycle GHG emissions of GTL diesel based on a given product composition. Using this protocol, the life-cycle GHG emissions of GTL diesel can range from 71.7 to 95.7 gCO2e/MJ on a well to wheel basis, with the range in carbon intensity being dependent on the mix of coproducts. These results highlight a weakly understood relationship between fuel and chemical products in LCA models. The coproduct integration approach described herein could potentially be incorporated into fuel LCA models, such as GREET, to allow users to further understand the potential environmental benefits of alternative fuel pathways, such as GTL. PMID- 25710606 TI - ProstateAnalyzer: Web-based medical application for the management of prostate cancer using multiparametric MR imaging. AB - OBJECTIVES: In this paper, we present ProstateAnalyzer, a new web-based medical tool for prostate cancer diagnosis. ProstateAnalyzer allows the visualization and analysis of magnetic resonance images (MRI) in a single framework. METHODS: ProstateAnalyzer recovers the data from a PACS server and displays all the associated MRI images in the same framework, usually consisting of 3D T2-weighted imaging for anatomy, dynamic contrast-enhanced MRI for perfusion, diffusion weighted imaging in the form of an apparent diffusion coefficient (ADC) map and MR Spectroscopy. ProstateAnalyzer allows annotating regions of interest in a sequence and propagates them to the others. RESULTS: From a representative case, the results using the four visualization platforms are fully detailed, showing the interaction among them. The tool has been implemented as a Java-based applet application to facilitate the portability of the tool to the different computer architectures and software and allowing the possibility to work remotely via the web. CONCLUSION: ProstateAnalyzer enables experts to manage prostate cancer patient data set more efficiently. The tool allows delineating annotations by experts and displays all the required information for use in diagnosis. According to the current European Society of Urogenital Radiology guidelines, it also includes the PI-RADS structured reporting scheme. PMID- 25710607 TI - Commercial Driver Medical Examinations: Prevalence of Obesity, Comorbidities, and Certification Outcomes. AB - OBJECTIVE: The objective of this study was to assess relationships between body mass index (BMI) and comorbid conditions within a large sample of truck drivers. METHODS: Commercial driver medical examination data from 88,246 commercial drivers between 2005 and 2012 were analyzed for associations between BMI, medical disorders, and driver certification. RESULTS: Most drivers were obese (53.3%, BMI >30.0 kg/m) and morbidly obese (26.6%, BMI >35.0 kg/m), higher than prior reports. Obese drivers were less likely to be certified for 2 years and more likely to report heart disease, hypertension, diabetes mellitus, nervous disorders, sleep disorders, and chronic low back pain (all P < 0.0001). There are relationships between multiple potentially disqualifying conditions and increasing obesity (P < 0.0001). Morbid obesity prevalence increased 8.9% and prevalence of three or more multiple conditions increased fourfold between 2005 and 2012. CONCLUSIONS: Obesity is related to multiple medical factors as well as increasing numbers of conditions that limit driving certification. PMID- 25710608 TI - Bronchoalveolar Lavage Fluid (1,3)beta-D-Glucan for the Diagnosis of Invasive Fungal Infections in Solid Organ Transplantation: A Prospective Multicenter Study. AB - BACKGROUND: Prompt diagnosis of invasive fungal infections (IFI) remains a challenge. (1,3)beta-D-glucan detection in bronchoalveolar lavage (BAL) fluid by Fungitell assay aims to further improve upon the test's utility by directly applying it to specimens from the target organ. METHODS: A prospective multicenter analysis of the Fungitell assay was performed on BAL and serum samples obtained from nonselected solid-organ transplantation patients suffering from probable, proven or no IFI according to the revised criteria of the European Organisation for Research and Treatment of Cancer / Mycosis Study Group. RESULTS: Two hundred thirty-three BAL and 109 serum specimens from 135 patients with proven, probable, or no IFI were tested. Based on a 100 pg/mL: cutoff per test sensitivity, specificity, positive and negative predictive values were 79.2%, 38.5%, 27.6%, and 86.3% in BALs and 79.2%, 81.8%, 69.2%, and 83.1% in sera investigated. CONCLUSIONS: The accuracy of the (1,3)beta-D-glucan test is marginal so that its utility as a clinical test for early diagnosis of IFI is questionable in the lung transplant population. Although the high negative predictive value of the Fungitell assay in both, BALs and sera, may support exclusion of pulmonary IFI in solid-organ transplantation patients, the low positive predictive value limits its utility as a screening tool for early diagnosis of IFI. PMID- 25710610 TI - The roles of T helper type 17/regulatory T cells in acute rejection after liver transplantation in rats. AB - BACKGROUND: Liver transplantation is a widely accepted treatment for end-stage liver disease. The aim of our study was to investigate the imbalance between T helper type 17 (Th17) and CD4(+) CD25(+) Foxp3(+) regulatory T (Treg) cells during hepatic allograft rejection in a rodent grafts model because their roles in liver transplantation is not fully understood. METHODS: We compared median survival time (MST) survivals, Th17/Treg cells and related cytokines levels (interleukin [IL]-17, IL-6, IL-10, and transforming growth factor-beta1), as well as serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin (T-Bili) after liver transplantation. In addition, the allograft groups were injected with IL-17 neutralizing antibody to evaluate the role of IL-17 in acute rejection. RESULTS: Th17 cells and related cytokines (IL 17 and IL-6) were obviously increased in the allograft group (all P < 0.01), whereas Treg cells and related cytokines (IL-10 and transforming growth factor beta1) were markedly lower than those of isograft and control groups (all P < 0.01). In addition, liver grafts in allograft groups rejected acutely (MST, 8.0 +/- 1.2 days) accompanied by impaired liver function (AST, ALT, and T-Bili), while isograft groups survived long term (MST, 50.0 +/- 3.8 days, all P < 0.01 vs. allograft group). Finally, neutralization of IL-17 in allograft groups significantly prolonged the survival (MST, 32.0 +/- 4.8 days, P < 0.01), improved the liver function (AST, ALT, and T-Bili), and increased Treg cells in the liver (all P < 0.01). CONCLUSIONS: Th17 cells and secreted IL-17 play critical roles in acute rejection after liver grafts. The reduction of IL-17 may be 1 mechanism of immune tolerance after liver transplantation. PMID- 25710609 TI - Assessment of Cotinine Reveals a Dose-Dependent Effect of Smoking Exposure on Long-term Outcomes After Renal Transplantation. AB - BACKGROUND: Smoking is a risk factor for poor late outcomes in renal transplant recipients (RTR). Smoking exposure can be assessed by self-report and cotinine measurements. We investigated whether use of cotinine as a biomarker for smoking exposure can serve as an alternative for self-report and to compare associations of smoking exposure by self-report and cotinine with outcomes in RTR and assess dose dependency. METHODS: Renal transplant recipients were classified as never, former, light (<=10 cigarettes/day), and heavy smokers (>10 cigarettes/day) according to self-report and analogous categories for urine and plasma cotinine. First, we assessed agreement of self-reported smoking exposure with smoking exposure according urine and plasma cotinine. Second, we compared the associations with graft failure and mortality. RESULTS: Of 603 RTR (age 51.5 +/- 12.1 years, 55% men), 36.0% RTR were never, 42.3% former, 10.6% light, and 11.1% heavy smokers according to self-report. The majority (98.6%) of never smokers had nondetectable cotinine. However, 14 and 13 RTR reporting no active smoking had respective urine or plasma cotinine consistent with active smoking. Cotinine based measurements were dose-dependently associated with mortality and graft failure. CONCLUSIONS: Plasma and urine cotinine can serve as an alternative to self-report and were dose-dependently associated with poor late outcomes in RTR. PMID- 25710611 TI - Follow-up Imaging After Liver Transplantation Should Take Into Consideration Primary Hepatocellular Carcinoma Characteristics. AB - BACKGROUND: Tumor recurrence occurs in almost 10% after liver transplantation (LT) for early stage hepatocellular carcinoma (HCC). Evidence-based recommendation regarding these techniques and their schedule remains unclear. The aim was to analyze the imaging characteristics of HCC recurrence after LT according to the initial primary tumor characteristics to provide relevant evidence regarding their role. METHODS: Among 336 cirrhotic patients undergoing LT between 2000 and 2011, 25 (7.4%) experienced HCC recurrence. Their pre-LT characteristics, long-term outcome and imaging characteristics of recurrences were retrospectively analyzed. RESULTS: All patients were men and median age at the time of recurrence was 54 (41-64) years. Before LT, 13 (52%) patients had HCC outside the Milan criteria. Median time to HCC recurrence was 13.8 months (1-75) after LT and 8 patients (32%) experienced recurrence longer than 24 months after LT. The most frequently involved organs were the lungs (n = 13, 52%) and the bones (n = 9, 36%). Recurrent HCC involved more than 1 organ in 11 patients (44%). Recurrences were limited to the liver in 1 patient (4%), exclusively extrahepatic in 18 patients (72%), and were both intra and extrahepatic in 6 patients (24%). Delay of recurrence was shorter in the presence of microvascular invasion (17 vs 28 months), but this was not significant (P = 0.208). Poorly differentiated tumors showed a trend toward decreased recurrence-free survival (8 vs 28 months, P = 0.075). CONCLUSIONS: Both pattern and delay of HCC recurrence support performing regular whole-body imaging initially every 6 to 12 months and continuing beyond 2 years after LT for HCC, especially in patients with pejorative pathological features of the primary tumor that could influence HCC recurrence pattern. PMID- 25710612 TI - Treatment With Dimethyl Fumarate Attenuates Calcineurin Inhibitor-induced Nephrotoxicity. AB - BACKGROUND: Cyclosporine A (CsA) is an immunosuppressive drug which has been widely used to prevent rejection after organ transplantation. However, its therapeutic use is limited by nephrotoxicity, in part mediated by oxidative stress. The present study aims to investigate the protective effects of dimethyl fumarate (DMF) on CsA-induced nephrotoxicity by enhancing the antioxidant defense system. METHODS: Male Sprague-Dawley rats were treated with CsA (n = 8, 20 mg/kg per day intraperitoneally) or CsA + DMF (n = 7, 50 mg/kg per day orally) for 28 days. Renal function, histopathology, malondialdehyde (MDA), myeloperoxidase levels, and antioxidant enzyme expression were determined. RESULTS: The DMF cotreatment ameliorated CsA-induced renal dysfunction as evidenced by significant decrease in serum creatinine (CsA 0.79 +/- 0.02 mg/dL vs CsA + DMF 0.62 +/- 0.04 mg/dL, P = 0.001) and urea (CsA 66.9 +/- 0.4 mg/dL vs CsA + DMF 53.3 +/- 2.6 mg/dl, P < 0.0001) levels, as well as improvement of creatinine clearance. Dimethyl fumarate also significantly decreased serum MDA and renal tissue MDA and myeloperoxidase contents. The protein expression of NAD(P)H quinone oxidoreductase-1, a major cellular antioxidant and detoxifying enzyme, was significantly enhanced by DMF administration in kidney. CONCLUSIONS: Administration of DMF has a protective potential against CsA nephrotoxicity. The protection afforded by DMF is mediated in part through inhibiting oxidative stress and inflammation and enhancing the antioxidant capacity. PMID- 25710615 TI - Maternal-fetal transfer of anti-N-methyl-D-aspartate receptor antibodies. AB - BACKGROUND: Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is a neuroautoimmune disease commonly associated with ovarian teratomas. It is characterized by neuropsychiatric symptoms, seizures, and autonomic instability. Few cases are described in pregnancy, and little is known about potential fetal effects. CASE: Anti-NMDA receptor encephalitis was diagnosed at 24 weeks of gestation. No improvement occurred with intravenous immunoglobulin, methylprednisolone, and plasmapheresis. Imaging was unremarkable. Cesarean delivery with concurrent bilateral oophorectomy resulted in prompt maternal improvement. Antibody titers were positive in cord blood. CONCLUSION: Anti-N methyl-D-aspartate receptor encephalitis in pregnancy can lead to NMDA receptor antibodies in the fetal circulation. Pregnancy interruption through early delivery with or without oophorectomy may accelerate maternal recovery. PMID- 25710614 TI - Genome-wide association study identifies peanut allergy-specific loci and evidence of epigenetic mediation in US children. AB - Food allergy (FA) affects 2%-10% of US children and is a growing clinical and public health problem. Here we conduct the first genome-wide association study of well-defined FA, including specific subtypes (peanut, milk and egg) in 2,759 US participants (1,315 children and 1,444 parents) from the Chicago Food Allergy Study, and identify peanut allergy (PA)-specific loci in the HLA-DR and -DQ gene region at 6p21.32, tagged by rs7192 (P=5.5 * 10(-8)) and rs9275596 (P=6.8 * 10( 10)), in 2,197 participants of European ancestry. We replicate these associations in an independent sample of European ancestry. These associations are further supported by meta-analyses across the discovery and replication samples. Both single-nucleotide polymorphisms (SNPs) are associated with differential DNA methylation levels at multiple CpG sites (P<5 * 10(-8)), and differential DNA methylation of the HLA-DQB1 and HLA-DRB1 genes partially mediate the identified SNP-PA associations. This study suggests that the HLA-DR and -DQ gene region probably poses significant genetic risk for PA. PMID- 25710616 TI - Early severe fetal Graves disease in a mother after thyroid ablation and thyroidectomy. AB - BACKGROUND: Fetal Graves disease rarely presents before 26 weeks of gestation. We report a case of severe fetal Graves disease at 18 weeks of gestation in a mother who had very elevated Graves disease antibodies despite being several years post thyroid ablative therapy and thyroidectomy. CASE: A 36-year-old woman, gravida 1 para 0, with severe Graves disease post-radioiodine ablation followed by thyroidectomy on levothyroxine presented at 18 weeks of gestation for ultrasound examination. Her fetus was found to be severely tachycardic with a goiter. Propylthiouracil was initiated for fetal therapy. Delivery at 34 weeks of gestation was undertaken as a result of preterm premature rupture of membranes. The neonate experienced heart failure and pulmonary hypertension at birth but recovered with appropriate medical therapy. CONCLUSION: It is possible for fetal Graves disease to develop as early as 18 weeks of gestation, and women who have had thyroid ablation and postsurgical hypothyroidism remain at risk for this serious pregnancy complication. PMID- 25710617 TI - Gonadotropin-releasing hormone agonist use to guide diagnosis and treatment of autoimmune progesterone dermatitis. AB - BACKGROUND: Autoimmune progesterone dermatitis is a catamenial disorder traditionally diagnosed by subcutaneous or intramuscular progesterone challenge. Little has been reported regarding the use of a gonadotropin-releasing hormone (GnRH) agonist with a progestin add-back challenge to diagnose and guide management of this condition. CASE: A 50-year-old premenopausal woman presented with cyclic facial rash minimally responsive to standard treatment. Symptoms improved with depot leuprolide acetate and worsened with add-back progesterone therapy. Hysterectomy and oophorectomy were performed with resolution of symptoms. This surgery eliminated endogenous progesterone and permitted estrogen replacement to treat vasomotor symptoms experienced with GnRH agonist therapy. CONCLUSION: This case of autoimmune progesterone dermatitis exemplifies the utility of GnRH agonists with a steroid add-back challenge for diagnosing catamenial disorders and guiding treatment. PMID- 25710618 TI - Cosensitization of D-A-pi-A quinoxaline organic dye: efficiently filling the absorption valley with high photovoltaic efficiency. AB - In the efficient cosensitization, the pure organic sensitizers with high molecular extinction coefficients and long wavelength response are highly preferable since the dye loading amount for each dye in cosensitization is decreased with respect to single dye sensitization. A D-A-pi-A featured quinoxaline organic sensitizer IQ21 is specifically designed. The high conjugation building block of 4H-cyclopenta[2,1-b:3,4-b']dithiophene (CPDT) is introduced as the pi bridge, instead of the traditional thiophene unit, especially in realizing high molecular extinction coefficients (up to 66 600 M( 1) cm(-1)) and extending the light response wavelength. With respect to the reference dye IQ4, the slightly lower efficiency of IQ21 (9.03%) arises from the decrease of VOC, which offsets the gain in JSC. While cosensitized with a smaller D-pi-A dye S2, the efficiency in IQ21 is further improved to 10.41% (JSC = 19.8 mA cm(-2), VOC = 731 mV, FF = 0.72). The large improvement in efficiency is attributed to the well-matched molecular structures and loading amounts of both dyes in the cosensitization system. We also demonstrated that coabsorbent dye S2 can distinctly compensate the inherent drawbacks of IQ21, not only enhancing the response intensity of IPCE, making up the absorption defects around low wavelength region of IPCE, but also repressing the charge recombination rate to some extent. PMID- 25710619 TI - Novel 18F labeling strategy for polyester-based NPs for in vivo PET-CT imaging. AB - Drug-loaded nanocarriers and nanoparticulate systems used for drug release require a careful in vivo evaluation in terms of physicochemical and pharmacokinetic properties. Nuclear imaging techniques such as positron emission tomography (PET) are ideal and noninvasive tools to investigate the biodistribution and biological fate of the nanostructures, but the incorporation of a positron emitter is required. Here we describe a novel approach for the (18)F-radiolabeling of polyester-based nanoparticles. Our approach relies on the preparation of the radiolabeled active agent 4-[(18)F]fluorobenzyl-2 bromoacetamide ([(18)F]FBBA), which is subsequently coupled to block copolymers under mild conditions. The labeled block copolymers are ultimately incorporated as constituent elements of the NPs by using a modified nano coprecipitation method. This strategy has been applied in the current work to the preparation of peptide-functionalized NPs with potential applications in drug delivery. According to the measurements of particle size and zeta potential, the radiolabeling process did not result in a statistically significant alteration of the physicochemical properties of the NPs. Moreover, radiochemical stability studies showed no detachment of the radioactivity from NPs even at 12 h after preparation. The radiolabeled NPs enabled the in vivo quantification of the biodistribution data in rats using a combination of imaging techniques, namely, PET and computerized tomography (CT). Low accumulation of the nanoparticles in the liver and their elimination mainly via urine was found. The different biodistribution pattern obtained for the "free" radiolabeled polymer suggests chemical and radiochemical integrity of the NPs under investigation. The strategy reported here may be applied to any polymeric NPs containing polymers bearing a nucleophile, and hence our novel strategy may find application for the in vivo and noninvasive investigation of a wide range of NPs. PMID- 25710620 TI - Blunting of exercise-induced salivary testosterone in elite-level triathletes with a 10-day training camp. AB - PURPOSE: This study examined the influence of 10 days of intensified training on salivary cortisol and testosterone responses to 30-min, high-intensity cycling (55/80) in a group of male elite triathletes. METHODS: Seven elite male triathletes (age 19 +/- 1 y, VO2max 67.6 +/- 4.5 mL . kg-1 . min-1) completed the study. Swim distances increased by 45%. Running and cycling training hours increased by 25% and 229%, respectively. REST-Q questionnaires assessed mood status before, during, and after the training period. Unstimulated saliva samples were collected before, after, and 30 min after a continuous, high-intensity exercise test. Salivary cortisol and testosterone concentrations were assessed. RESULTS: Compared with pretraining, blunted exercise-induced salivary testosterone responses to the posttraining 55/80 were found (P = .004). The absolute response of salivary testosterone concentrations to the 55/80 decreased pretraining to posttraining from 114% to 85%. No changes were found in exercise induced salivary cortisol concentration responses to the 55/80. REST-Q scores indicated no changes in the participants' psychological stress-recovery levels over the training camp. CONCLUSIONS: The blunted exercise-induced salivary testosterone is likely due to decreased testicular testosterone production and/or secretion, possibly attributable to hypothalamic dysfunction or reduced testicular blood flow. REST-Q scores suggest that the triathletes coped well with training-load elevations, which could account for the finding of no change in the exercise-induced salivary cortisol concentration. Overall, these findings suggest that the 55/80 can detect altered exercise-induced salivary testosterone concentrations in an elite athletic population due to increased training stress. However, this alteration occurs independently of a perceived elevation of training stress. PMID- 25710621 TI - Effects of predicted climatic changes on distribution of organic contaminants in brackish water mesocosms. AB - Predicted consequences of future climate change in the northern Baltic Sea include increases in sea surface temperatures and terrestrial dissolved organic carbon (DOC) runoff. These changes are expected to alter environmental distribution of anthropogenic organic contaminants (OCs). To assess likely shifts in their distributions, outdoor mesocosms were employed to mimic pelagic ecosystems at two temperatures and two DOC concentrations, current: 15 degrees C and 4 mg DOCL(-1) and, within ranges of predicted increases, 18 degrees C and 6 mg DOCL(-1), respectively. Selected organic contaminants were added to the mesocosms to monitor changes in their distribution induced by the treatments. OC partitioning to particulate matter and sedimentation were enhanced at the higher DOC concentration, at both temperatures, while higher losses and lower partitioning of OCs to DOC were observed at the higher temperature. No combined effects of higher temperature and DOC on partitioning were observed, possibly because of the balancing nature of these processes. Therefore, changes in OCs' fates may largely depend on whether they are most sensitive to temperature or DOC concentration rises. Bromoanilines, phenanthrene, biphenyl and naphthalene were sensitive to the rise in DOC concentration, whereas organophosphates, chlorobenzenes (PCBz) and polychlorinated biphenyls (PCBs) were more sensitive to temperature. Mitotane and diflufenican were sensitive to both temperature and DOC concentration rises individually, but not in combination. PMID- 25710622 TI - Detrital phosphorus as a proxy of flooding events in the Changjiang River Basin. AB - In this study, sediment grain size (MGS), specific surface area (SSA), total organic carbon (TOC) contents, C/N molar ratios, stable carbon isotope, and P species in a sediment core, collected from the East China Sea (ECS) inner-shelf were measured to explore the applicability of detrital phosphorus (De-P) as a potential indicator of past flooding events in the Changjiang River Basin (CRB). In particular, we examined the linkages between the evolution of floods with regional climate changes and anthropogenic activities in the CRB. Peaks of De-P concentrations in sediments corresponded well with the worst flooding events of the CRB over the past two centuries (e.g., 1850s, 1860s, 1900s, 1920s, 1950s, 1980s, and 2000s). Moreover, De-P also corresponded well with the extreme hypoxic events in 1981 and 1998 in the Changjiang Estuary as indicated by Mo/Al ratios, indicating potential linkages between De-P as a flooding proxy to flood-induced hypoxia events in this region. In addition, a robust relationship was found among De-P, the floods in 1950s, 1980s, and 2000s of the CRB, the intensive El Nino Southern Oscillation (ENSO), the abnormally weak East Asian Summer Monsoon (EASM) and the warm phase of Pacific Decadal Oscillation (PDO), suggesting that De-P also provided insights to linkages between regional climate change and flooding events in this region. PMID- 25710623 TI - The temporal structure of pollution levels in developed cities. AB - Currently, the need for mobility can cause significant pollution levels in cities, with important effects on health and quality of life. Any approach to the study of urban pollution and its effects requires an analysis of spatial distribution and temporal variability. It is a crucial dilemma to obtain proven methodologies that allow an increase in the quality of the prediction and the saving of resources in the spatial and temporal sampling. This work proposes a new analytical methodology in the study of temporal structure. As a result, a model for estimating annual levels of urban traffic noise was proposed. The average errors are less than one decibel in all acoustics indicators. A new working methodology of urban noise has begun. Additionally, a general application can be found for the study of the impacts of pollution associated with traffic, with implications for urban design and possibly in economic and sociological aspects. PMID- 25710624 TI - Determinants of aerosol lung-deposited surface area variation in an urban environment. AB - Ultrafine particles are characterized by a high surface area per mass. Particle surface has been reported to play a significant role in determining the toxicological activity of ultrafine particles. In light of this potential role, the time variation of lung deposited surface area (LDSA) concentrations in the alveolar region was studied at the urban background environment of Barcelona (Spain), aiming to asses which processes and sources govern this parameter. Simultaneous data on Black Carbon (BC), total particle number (N) and particle number size distribution were correlated with LDSA. Average LDSA concentrations in Barcelona were 37 +/- 26 MUm(2)cm(-3), levels which seem to be characteristic for urban environments under traffic influence across Europe. Results confirm the comparability between LDSA data provided by the online monitor and those calculated based on particle size distributions (by SMPS), and reveal that LDSA concentrations are mainly influenced by particles in the size range 50-200 nm. A set of representative daily cycles for LDSA concentrations was obtained by means of a k-means cluster technique. The contribution of traffic emissions to daily patterns was evidenced in all the clusters, but was quantitatively different. Traffic events under stable atmospheric conditions increased mean hourly background LDSA concentrations up to 6 times, attaining levels higher than 200 MUm(2)cm(-3). However, under warm and relatively clean atmospheric conditions, the traffic rush hour contribution to the daily LDSA mean appeared to be lower and the contribution of new urban particle formation events (by photochemically induced nucleation) was detected. These nucleation events were calculated to increase average background LDSA concentrations by 15-35% (maximum LDSA levels=45 50 MUm(2)cm(-3)). Thereby, it may be concluded that in the urban background of Barcelona road traffic is the main source increasing the aerosol surface area which can deposit on critical regions of the human lung, followed by nucleation episodes. PMID- 25710626 TI - Need for Increased Promotion of Physical Activity Among Adults at Risk for Alzheimer's Disease: A Brief Report. AB - BACKGROUND: We have a limited understanding of the physical activity (PA) and sedentary levels among individuals at risk and not at risk for developing Alzheimer's disease (AD), which was the purpose of this study. METHODS: Data from the 2003-2004 NHANES were used, from which 3015 participants were evaluated with 416 indicating a family history of AD. Physical activity and sedentary behavior were assessed via accelerometry with individuals at risk for AD self-reporting a family history of AD. RESULTS: For the entire sample, those at risk for AD engaged in more sedentary behavior than those not at risk (494.9 vs. 477.9 min/day, P = .03, respectively). Similarly, those at risk for AD engaged in less total MVPA than those not at risk (22.4 vs. 24.3 min/day, P = .05, respectively). Results were also significant for various subgroups at risk for AD. CONCLUSION: Despite the beneficial effects of PA in preventing AD and prolonging the survival of AD, adults at risk for AD tend to engage in more sedentary behavior and less PA than those not at risk for AD. This finding even persisted among minorities (Hispanics and non-Hispanic blacks) who are already at an increased risk of developing AD. PMID- 25710625 TI - Positive influence of being overweight/obese on long term survival in patients hospitalised due to acute heart failure. AB - BACKGROUND: Obesity is clearly associated with increased morbidity and mortality rates. However, in patients with acute heart failure (AHF), an increased BMI could represent a protective marker. Studies evaluating the "obesity paradox" on a large cohort with long-term follow-up are lacking. METHODS: Using the AHEAD database (a Czech multi-centre database of patients hospitalised due to AHF), 5057 patients were evaluated; patients with a BMI <18.5 kg/m2 were excluded. All cause mortality was compared between groups with a BMI of 18.5-25 kg/m2 and with BMI >25 kg/m2. Data were adjusted by a propensity score for 11 parameters. RESULTS: In the balanced groups, the difference in 30-day mortality was not significant. The long-term mortality of patients with normal weight was higher than for those who were overweight/obese (HR, 1.36; 95% CI, 1.26-1.48; p<0.001)). In the balanced dataset, the pattern was similar (1.22; 1.09-1.39; p<0.001). A similar result was found in the balanced dataset of a subgroup of patients with de novo AHF (1.30; 1.11-1.52; p = 0.001), but only a trend in a balanced dataset of patients with acute decompensated heart failure. CONCLUSION: These data suggest significantly lower long-term mortality in overweight/obese patients with AHF. The results suggest that at present there is no evidence for weight reduction in overweight/obese patients with heart failure, and emphasize the importance of prevention of cardiac cachexia. PMID- 25710627 TI - Effects of rare-earth size on the electronic structure of La1-xLuxVO3. AB - The electronic structure of La(1-x)Lu(x)VO(3)(x = 0, 0.2, 0.6 and 1) single crystals has been investigated using soft x-ray absorption spectroscopy, soft x ray emission spectroscopy, and resonant soft x-ray inelastic scattering to study the effects of rare-earth size. The x-ray absorption and emission spectra at the O K-edge present a progressive evolution with R-site cation, in agreement with local spin density approximation calculations. This evolution with R, together with the temperature dependence of the O K-edge spectra, is attributed to changes in the crystal structure of La(1-x)Lu(x)VO(3). The crystal-field dd. excitations probed by resonant inelastic x-ray scattering at the V L(3)-edge exhibit an increase in energy and enhanced intensity with the decrease of R-site ionic radius, which is mainly attributed to the increased tilting magnitude of the VO(6) octahedra. Upon cooling to ~95 K, the dd* excitations are prominently enhanced in relative Intensity, in agreement with the formation of the Jahn.Teller distortion int he orbital ordering phase. Additionally, the dd* transitions of the mixed compounds are noticeably suppressed with respect to those of the pure compounds, possibly owing to the formation of C-type orbital ordering induced by large R-site size variances. PMID- 25710629 TI - The role of weak hydrogen and halogen bonding interactions in the assembly of a series of Hg(II) coordination polymers. AB - A series of eight new Hg(II) complexes based on the L4-X ligands, where L is (E) 4-halo-N-(pyridin-4-ylmethylene)aniline, were synthesized and characterized and their supramolecular crystal structures were studied by different geometrical and theoretical methods. Our study reveals the role of weak intermolecular interactions involving halogens, such as C-H???X hydrogen bonds (in the cases of 1, 2, 3, 5, 6 and 7) and C-X???X'-M halogen bonds (in the cases of 4 and 8), in the structural changes of supramolecular assemblies of coordination compounds. Complexes 1-8 were also synthesized by sonochemical irradiation and the morphology of the prepared complexes was investigated using FE-SEM. The BFDH analysis helps us to compare the predicted morphology to that obtained under ultrasonication. This study may provide further insight into discovering the role of weak intermolecular interactions in the context of metallosupramolecular assembly. PMID- 25710628 TI - A Comparison of Antiserum and Protein A as Secondary Reagents to Assess Toxoplasma gondii Antibody Titers in Cats and Spotted Hyenas. AB - Toxoplasma gondii is a protozoal parasite with worldwide distribution that is able to infect a wide variety of mammals and birds. Our main goal was to screen for T. gondii antibody titers in a previously untested species, the spotted hyena ( Crocuta crocuta); however, this goal first required us to investigate serological procedures that could be suitable for hyenas. Cats are the closest domestic relations of hyenas, so T. gondii antibody titers were first compared in 26 feral cats with specific or nonspecific fluorophore-labeled secondary reagents, i.e., anti-cat IgG or protein A. Substitution of anti-cat IgG with protein A caused a statistically significant drop in titer measurements in cats (P = 0.01) with a reduction of the geometric mean titer equivalent to 1 doubling dilution. The same procedures were then applied to captive spotted hyenas. Titers measured in 9 of 10 hyenas were identical whether anti-cat IgG or protein A was used as the secondary reagent: 5 had titers <1:16, 2 had titers of 1:16, and 2 had titers of 1:32. One hyena had maximum titers of 1:64 or 1:32 when anti-cat IgG or protein A was used, respectively. The use of protein A as the secondary reagent in serologic assays can be applied to a range of mammalian species and seems unlikely to affect test specificity; however, the use of protein A may reduce test sensitivity, as suggested in the present study using cats. Despite a control program, some exposure to T. gondii had occurred in the Zoo's spotted hyenas. PMID- 25710630 TI - DNA-encoded chemical libraries of macrocycles. PMID- 25710631 TI - Discovery of Intestinal Targeted TGR5 Agonists for the Treatment of Type 2 Diabetes. AB - Activation of TGR5 stimulates intestinal glucagon-like peptide-1 (GLP-1) release, but activation of the receptors in gallbladder and heart has been shown to cause severe on-target side effects. A series of low-absorbed TGR5 agonists was prepared by modifying compound 2 with polar functional groups to limit systemic exposure and specifically activate TGR5 in the intestine. Compound 15c, with a molecular weight of 1401, a PSA value of 223 A(2), and low permeability on Caco-2 cells, exhibited satisfactory potency both in vitro and in vivo. Low levels of 15c were detected in blood, bile, and gallbladder tissue, and gallbladder-related side effects were substantially decreased compared to the absorbed small-molecule TGR5 agonist 2. PMID- 25710632 TI - Periodic Lateralized Epileptiform Discharges and Afterdischarges: Common Dynamic Mechanisms. AB - PURPOSE: No neurophysiological hypothesis currently exists addressing how and why periodic lateralized epileptiform discharges (PLEDs) arise in certain types of brain disease. Based on spectral analysis of clinical scalp EEG traces, the authors formulated a general mechanism for the emergence of PLEDs. METHODS: The authors retrospectively analyzed spectra of PLED time series and control EEG segments from the opposite hemisphere in 25 hospitalized neurological patients. The observations led to the development of a phenomenological model for PLED emergence. RESULTS: Similar to that observed in our previous work with afterdischarges, an analytic relationship is found between the spectrum of the baseline EEG and the PLED EEG, characterized by "condensation" of the main baseline spectral cluster, with variable inclusion of higher harmonics of the condensate. CONCLUSIONS: Periodic lateralized epileptiform discharges may arise by synchronization of preexisting local field potentials, through a variable combination of enhancement of excitatory neurotransmission and inactivation of inhibitory neurotransmission provoked by the PLED-associated disease process. Higher harmonics in the PLED spectrum may arise by recurrent feedback, possibly from entrained single units. A mechanism is suggested for PLED emergence in certain diseased brain states and the association of PLEDs with EEG seizures. The framework is a spatially extended version of that, which the authors proposed, underlies afterdischarge and analogous to the cooperative behavior seen in a variety of natural multi-oscillator systems. PMID- 25710633 TI - Preparation of multi-functionalized Fe3O4/Au nanoparticles for medical purposes. AB - In this work, we investigate a route towards the synthesis of multi functionalized nanoparticles for medical purposes. The aim is to produce magnetite/gold (Fe3O4/Au) nanoparticles combining several complementary properties, specifically, being able to carry simultaneously an antitumor drug and a selected antibody chosen so as to improve specificity of the drug vehicle. The procedure included, firstly, the preparation of Fe3O4 cores coated with Au nanoparticles: this was achieved by using initially the layer-by-layer technique in order to coat the magnetite particles with a three polyelectrolyte (cationic anionic-cationic) layer. With this, the particles became a good substrate for the growth of the gold layer in a well-defined core-shell structure. The resulting nanoparticles benefit from the magnetic properties of the magnetite and the robust chemistry and the biostability of gold surfaces. Subsequently, the Fe3O4/Au nanoparticles were functionalized with a humanized monoclonal antibody, bevacizumab, and a chemotherapy drug, doxorubicin. Taken together, bevacizumab enhances the therapeutic effect of chemotherapy agents on some kinds of tumors. In this work we first discuss the morphology of the particles and the electrical characteristics of their surface in the successive synthesis stages. Special attention is paid to the chemical stability of the final coating, and the physical stability of the suspensions of the nanoparticles in aqueous solutions and phosphate buffer. We describe how optical absorbance and electrokinetic data provide a follow up of the progress of the nanostructure formation. Additionally, the same techniques are employed to demonstrate that the composite nanoparticles are capable of loading/releasing doxorubicin and/or bevacizumab. PMID- 25710635 TI - Photoactivation of cryptochromes from Drosophila melanogaster and Sylvia borin: insight into the chemical compass mechanism by computational investigation. AB - Although behavioral studies demonstrated light-induced magnetoreception in the insect Drosophila melanogaster, gaining insight into the possibility that a radical-pair mechanism accounts for the magnetic response of the cryptochrome (DmCry1) is complicated by a number of factors. In addition, the mechanism of magnetoreception for the cryptochrome from the garden warbler bird Sylvia borin (gwCry1a), which demonstrated a long-lived radical pair by transient optical absorption measurements, has also not been rationalized. To assess potential feasibility of a radical-pair mechanism in DmCry1 and gwCry1a, formed by excitation and electron transfer between a Trp-triad and flavin adenine dinucleotide (FAD), further separated by electron transfer within the triad, we applied a combination of theoretical methods, including homology modeling and molecular dynamics (MD) for structure refinement, high-level ab initio theory, and MD simulations using a polarizable force-field for prediction of pKa and the electron transfer rate. Calculated excitation energies, followed by electron transfer in model compounds of DmCry1 that assume proton transfer in conjunction with electron transfer from Trp (W420) to FAD and the predicted pKa for the proximate residue to FAD (Cys416), support a radical-pair mechanism. Furthermore, free-energy and reorganization energies for the Trp-triad in DmCry1 demonstrate facile electron transfer, explained by the local protein environment and exposure to solvent, which in turn enables a large enough distance separation for the radical-pair partners. Results for gwCry1a demonstrated the importance of accounting for relaxed excited-state geometries in validating the first stage of a radical-pair mechanism. This work provides insight into the so-called chemical compass mechanism to explain magnetic-field sensing in DmCry1 and gwCry1a, expanding on previous work on the cyrptochrome from the plant Arabidopsis thaliana (Solov'yov et al. J. Am. Chem. Soc. 2012, 134, 18046-18052. Solov'yov et al., Sci. Rep. 2014, 4, 1-8.). PMID- 25710634 TI - Toward a biorelevant structure of protein kinase C bound modulators: design, synthesis, and evaluation of labeled bryostatin analogues for analysis with rotational echo double resonance NMR spectroscopy. AB - Protein kinase C (PKC) modulators are currently of great importance in preclinical and clinical studies directed at cancer, immunotherapy, HIV eradication, and Alzheimer's disease. However, the bound conformation of PKC modulators in a membrane environment is not known. Rotational echo double resonance (REDOR) NMR spectroscopy could uniquely address this challenge. However, REDOR NMR requires strategically labeled, high affinity ligands to determine interlabel distances from which the conformation of the bound ligand in the PKC-ligand complex could be identified. Here we report the first computer guided design and syntheses of three bryostatin analogues strategically labeled for REDOR NMR analysis. Extensive computer analyses of energetically accessible analogue conformations suggested preferred labeling sites for the identification of the PKC-bound conformers. Significantly, three labeled analogues were synthesized, and, as required for REDOR analysis, all proved highly potent with PKC affinities (~1 nM) on par with bryostatin. These potent and strategically labeled bryostatin analogues are new structural leads and provide the necessary starting point for projected efforts to determine the PKC-bound conformation of such analogues in a membrane environment, as needed to design new PKC modulators and understand PKC-ligand-membrane structure and dynamics. PMID- 25710636 TI - The effects of exercise on right ventricular contractility and right ventricular arterial coupling in pulmonary hypertension. AB - RATIONALE: Exercise tolerance is decreased in patients with pulmonary hypertension (PH). It is unknown whether exercise intolerance in PH coincides with an impaired rest-to-exercise response in right ventricular (RV) contractility. OBJECTIVES: To investigate in patients with PH the RV exertional contractile reserve, defined as the rest-to-exercise response in end-systolic elastance (DeltaEes), and the effects of exercise on the matching of Ees and RV afterload (Ea) (i.e., RV-arterial coupling; Ees/Ea). In addition, we compared DeltaEes with a recently proposed surrogate, the rest-to-exercise change in pulmonary artery pressure (DeltaPAP). METHODS: We prospectively included 17 patients with precapillary PH and 7 control subjects without PH who performed a submaximal invasive cardiopulmonary exercise test between January 2013 and July 2014. Ees and Ees/Ea were assessed using single-beat pressure-volume loop analysis. MEASUREMENTS AND MAIN RESULTS: Exercise data in 16 patients with PH and 5 control subjects were of sufficient quality for analysis. Ees significantly increased from rest to exercise in control subjects but not in patients with PH. Ea significantly increased in both groups. As a result, exercise led to a decrease in Ees/Ea in patients with PH, whereas Ees/Ea was unaffected in control subjects (Pinteraction = 0.009). In patients with PH, DeltaPAP was not related to DeltaEes but significantly correlated to the rest-to-exercise change in heart rate. CONCLUSIONS: In contrast to control subjects, patients with PH were unable to increase Ees during submaximal exercise. Failure to compensate for the further increase in Ea during exercise led to deterioration in Ees/Ea. Furthermore, DeltaPAP did not reflect DeltaEes but rather the change in heart rate. PMID- 25710637 TI - Stridulatory sound-production and its function in females of the cicada Subpsaltria yangi. AB - Acoustic behavior plays a crucial role in many aspects of cicada biology, such as reproduction and intrasexual competition. Although female sound production has been reported in some cicada species, acoustic behavior of female cicadas has received little attention. In cicada Subpsaltria yangi, the females possess a pair of unusually well-developed stridulatory organs. Here, sound production and its function in females of this remarkable cicada species were investigated. We revealed that the females could produce sounds by stridulatory mechanism during pair formation, and the sounds were able to elicit both acoustic and phonotactic responses from males. In addition, the forewings would strike the body during performing stridulatory sound-producing movements, which generated impact sounds. Acoustic playback experiments indicated that the impact sounds played no role in the behavioral context of pair formation. This study provides the first experimental evidence that females of a cicada species can generate sounds by stridulatory mechanism. We anticipate that our results will promote acoustic studies on females of other cicada species which also possess stridulatory system. PMID- 25710638 TI - A tree-structured crash surrogate measure for freeways. AB - In this paper, we propose a novel methodology to define and estimate a surrogate measure. By imposing a hypothetical disturbance to the leading vehicle, the following vehicle's action is represented as a probabilistic causal model. After that, a tree is built to describe the eight possible conflict types under the model. The surrogate measure, named Aggregated Crash Index (ACI), is thus proposed to measure the crash risk. This index reflects the accommodability of freeway traffic state to a traffic disturbance. We further apply this measure to evaluate the crash risks in a freeway section of Pacific Motorway, Australia. The results show that the proposed indicator outperforms the three traditional crash surrogate measures (i.e., Time to Collision, Proportion of Stopping Distance, and Crash Potential Index) in representing rear-end crash risks. The applications of this measure are also discussed. PMID- 25710641 TI - By the river: Edward W. Redfield. PMID- 25710642 TI - Efforts seek to develop systematic ways to objectively assess surgeons' skills. PMID- 25710643 TI - On fear, distrust, and Ebola. PMID- 25710652 TI - Genomic engineering and the future of medicine. PMID- 25710653 TI - Medicare and care coordination: expanding the clinician's toolbox. PMID- 25710654 TI - A piece of my mind. For what it's worth. PMID- 25710655 TI - Potential hazards of adding nonsteroidal anti-inflammatory drugs to antithrombotic therapy after myocardial infarction: time for more than a gut check. PMID- 25710656 TI - Precision medicine to improve the risk and benefit of cancer care: genetic factors in vincristine-related neuropathy. PMID- 25710657 TI - Association of NSAID use with risk of bleeding and cardiovascular events in patients receiving antithrombotic therapy after myocardial infarction. AB - IMPORTANCE: Antithrombotic treatment is indicated for use in patients after myocardial infarction (MI); however, concomitant use of nonsteroidal anti inflammatory drugs (NSAIDs) could pose safety concerns. OBJECTIVE: To examine the risk of bleeding and cardiovascular events among patients with prior MI taking antithrombotic drugs and for whom NSAID therapy was then prescribed. DESIGN, SETTING, AND PARTICIPANTS: Using nationwide administrative registries in Denmark (2002-2011), we studied patients 30 years or older admitted with first-time MI and alive 30 days after discharge. Subsequent treatment with aspirin, clopidogrel, or oral anticoagulants and their combinations, as well as ongoing concomitant NSAID use, was determined. EXPOSURES: Use of NSAIDs with ongoing antithrombotic treatment after first-time MI. MAIN OUTCOMES AND MEASURES: Risk of bleeding (requiring hospitalization) or a composite cardiovascular outcome (cardiovascular death, nonfatal recurrent MI, and stroke) according to ongoing NSAID and antithrombotic therapy, calculated using adjusted time-dependent Cox regression models. RESULTS: We included 61,971 patients (mean age, 67.7 [SD, 13.6] years; 63% men); of these, 34% filled at least 1 NSAID prescription. The number of deaths during a median follow-up of 3.5 years was 18,105 (29.2%). A total of 5288 bleeding events (8.5%) and 18,568 cardiovascular events (30.0%) occurred. The crude incidence rates of bleeding (events per 100 person-years) were 4.2 (95% CI, 3.8-4.6) with concomitant NSAID treatment and 2.2 (95% CI, 2.1 2.3) without NSAID treatment, whereas the rates of cardiovascular events were 11.2 (95% CI, 10.5-11.9) and 8.3 (95% CI, 8.2-8.4). The multivariate-adjusted Cox regression analysis found increased risk of bleeding with NSAID treatment compared with no NSAID treatment (hazard ratio, 2.02 [95% CI, 1.81-2.26]), and the cardiovascular risk was also increased (hazard ratio, 1.40 [95% CI, 1.30 1.49]). An increased risk of bleeding and cardiovascular events was evident with concomitant use of NSAIDs, regardless of antithrombotic treatment, types of NSAIDs, or duration of use. CONCLUSIONS AND RELEVANCE: Among patients receiving antithrombotic therapy after MI, the use of NSAIDs was associated with increased risk of bleeding and excess thrombotic events, even after short-term treatment. More research is needed to confirm these findings; however, physicians should exercise appropriate caution when prescribing NSAIDs for patients who have recently experienced MI. PMID- 25710658 TI - Association of an inherited genetic variant with vincristine-related peripheral neuropathy in children with acute lymphoblastic leukemia. AB - IMPORTANCE: With cure rates of childhood acute lymphoblastic leukemia (ALL) exceeding 85%, there is a need to mitigate treatment toxicities that can compromise quality of life, including peripheral neuropathy from vincristine treatment. OBJECTIVE: To identify genetic germline variants associated with the occurrence or severity of vincristine-induced peripheral neuropathy in children with ALL. DESIGN, SETTING, AND PARTICIPANTS: Genome-wide association study of patients in 1 of 2 prospective clinical trials for childhood ALL that included treatment with 36 to 39 doses of vincristine. Genome-wide single-nucleotide polymorphism (SNP) analysis and vincristine-induced peripheral neuropathy were assessed in 321 patients from whom DNA was available: 222 patients (median age, 6.0 years; range, 0.1-18.8 years) enrolled in 1994-1998 in the St Jude Children's Research Hospital protocol Total XIIIB with toxic effects follow-up through January 2001, and 99 patients (median age, 11.4 years; range, 3.0-23.8 years) enrolled in 2007-2010 in the Children's Oncology Group (COG) protocol AALL0433 with toxic effects follow-up through May 2011. Human leukemia cells and induced pluripotent stem cell neurons were used to assess the effects of lower CEP72 expression on vincristine sensitivity. EXPOSURE: Treatment with vincristine at a dose of 1.5 or 2.0 mg/m2. MAIN OUTCOMES AND MEASURES: Vincristine-induced peripheral neuropathy was assessed at clinic visits using National Cancer Institute criteria and prospectively graded as mild (grade 1), moderate (grade 2), serious/disabling (grade 3), or life threatening (grade 4). RESULTS: Grade 2 to 4 vincristine-induced neuropathy during continuation therapy occurred in 28.8% of patients (64/222) in the St Jude cohort and in 22.2% (22/99) in the COG cohort. A SNP in the promoter region of the CEP72 gene, which encodes a centrosomal protein involved in microtubule formation, had a significant association with vincristine neuropathy (meta-analysis P = 6.3*10(-9)). This SNP had a minor allele frequency of 37% (235/642), with 50 of 321 patients (16%; 95% CI, 11.6%-19.5%) homozygous for the risk allele (TT at rs924607). Among patients with the high-risk CEP72 genotype (TT at rs924607), 28 of 50 (56%; 95% CI, 41.2% 70.0%) developed at least 1 episode of grade 2 to 4 neuropathy, a higher rate than in patients with the CEP72 CC or CT genotypes (58/271 patients [21.4%; 95% CI, 16.9%-26.7%]; P = 2.4*10(-6)). The severity of neuropathy was greater in patients homozygous for the TT genotype compared with patients with the CC or CT genotype (2.4-fold by Poisson regression [P<.0001] and 2.7-fold based on mean grade of neuropathy: 1.23 [95% CI, 0.74-1.72] vs 0.45 [95% CI, 0.3-0.6]; P = .004 by t test). Reducing CEP72 expression in human neurons and leukemia cells increased their sensitivity to vincristine. CONCLUSIONS AND RELEVANCE: In this preliminary study of children with ALL, an inherited polymorphism in the promoter region of CEP72 was associated with increased risk and severity of vincristine related peripheral neuropathy. If replicated in additional populations, this finding may provide a basis for safer dosing of this widely prescribed anticancer agent. PMID- 25710659 TI - Anticoagulant reversal, blood pressure levels, and anticoagulant resumption in patients with anticoagulation-related intracerebral hemorrhage. AB - IMPORTANCE: Although use of oral anticoagulants (OACs) is increasing, there is a substantial lack of data on how to treat OAC-associated intracerebral hemorrhage (ICH). OBJECTIVE: To assess the association of anticoagulation reversal and blood pressure (BP) with hematoma enlargement and the effects of OAC resumption. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study at 19 German tertiary care centers (2006-2012) including 1176 individuals for analysis of long term functional outcome, 853 for analysis of hematoma enlargement, and 719 for analysis of OAC resumption. EXPOSURES: Reversal of anticoagulation during acute phase, systolic BP at 4 hours, and reinitiation of OAC for long-term treatment. MAIN OUTCOMES AND MEASURES: Frequency of hematoma enlargement in relation to international normalized ratio (INR) and BP. Incidence analysis of ischemic and hemorrhagic events with or without OAC resumption. Factors associated with favorable (modified Rankin Scale score, 0-3) vs unfavorable functional outcome. RESULTS: Hemorrhage enlargement occurred in 307 of 853 patients (36.0%). Reduced rates of hematoma enlargement were associated with reversal of INR levels <1.3 within 4 hours after admission (43/217 [19.8%]) vs INR of >=1.3 (264/636 [41.5%]; P < .001) and systolic BP <160 mm Hg at 4 hours (167/504 [33.1%]) vs >=160 mm Hg (98/187 [52.4%]; P < .001). The combination of INR reversal <1.3 within 4 hours and systolic BP of <160 mm Hg at 4 hours was associated with lower rates of hematoma enlargement (35/193 [18.1%] vs 220/498 [44.2%] not achieving these values; OR, 0.28; 95% CI, 0.19-0.42; P < .001) and lower rates of in-hospital mortality (26/193 [13.5%] vs 103/498 [20.7%]; OR, 0.60; 95% CI, 0.37-0.95; P = .03). OAC was resumed in 172 of 719 survivors (23.9%). OAC resumption showed fewer ischemic complications (OAC: 9/172 [5.2%] vs no OAC: 82/547 [15.0%]; P < .001) and not significantly different hemorrhagic complications (OAC: 14/172 [8.1%] vs no OAC: 36/547 [6.6%]; P = .48). Propensity-matched survival analysis in patients with atrial fibrillation who restarted OAC showed a decreased HR of 0.258 (95% CI, 0.125-0.534; P < .001) for long-term mortality. Functional long term outcome was unfavorable in 786 of 1083 patients (72.6%). CONCLUSIONS AND RELEVANCE: Among patients with OAC-associated ICH, reversal of INR <1.3 within 4 hours and systolic BP <160 mm Hg at 4 hours were associated with lower rates of hematoma enlargement, and resumption of OAC therapy was associated with lower risk of ischemic events. These findings require replication and assessment in prospective studies. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01829581. PMID- 25710661 TI - Hydroxychloroquine and the retina. PMID- 25710660 TI - Glomerular filtration rate and albuminuria for detection and staging of acute and chronic kidney disease in adults: a systematic review. AB - IMPORTANCE: Because early-stage kidney disease is asymptomatic and is associated with both morbidity and mortality, laboratory measurements are required for its detection. OBJECTIVE: To summarize evidence supporting the use of laboratory tests for glomerular filtration rate (GFR) and albuminuria to detect and stage acute kidney injury, acute kidney diseases and disorders, and chronic kidney disease in adults. EVIDENCE REVIEW: We reviewed recent guidelines from various professional groups identified via the National Guideline Clearing House and author knowledge, and systematically searched MEDLINE for other sources of evidence for selected topics. FINDINGS: The KDIGO (Kidney Disease Improving Global Outcomes) guidelines define and stage acute and chronic kidney diseases by GFR and albuminuria. For initial assessment of GFR, measuring serum creatinine and reporting estimated GFR based on serum creatinine (eGFRcr) using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 2009 equation is recommended. If confirmation of GFR is required because of conditions that affect serum creatinine independent of GFR (eg, extremes of muscle mass or diet), or interference with the assay, cystatin C should be measured and estimated GFR should be calculated and reported using cystatin C (eGFRcys) and serum creatinine (eGFRcr-cys) or GFR should be measured directly using a clearance procedure. Initial assessment of albuminuria includes measuring urine albumin and creatinine in an untimed spot urine collection and reporting albumin-to-creatinine ratio. If confirmation of albuminuria is required because of diurnal variation or conditions affecting creatinine excretion, such as extremes of muscle mass or diet, the albumin excretion rate should be measured from a timed urine collection. CONCLUSIONS AND RELEVANCE: Detection and staging of acute and chronic kidney diseases can be relatively simple. Because of the morbidity and mortality associated with kidney disease, early diagnosis is important and should be pursued in at-risk populations. PMID- 25710662 TI - Elevated lactate levels in a non-critically ill patient. PMID- 25710663 TI - Trends in the proportion of patients with lung cancer meeting screening criteria. PMID- 25710664 TI - Assessing the benefit of vascular closure devices after femoral artery puncture. PMID- 25710665 TI - Assessing the benefit of vascular closure devices after femoral artery puncture- reply. PMID- 25710666 TI - Male body image and weight-related disorders. PMID- 25710667 TI - Male body image and weight-related disorders--reply. PMID- 25710668 TI - Alternative pricing strategies for cancer drugs. PMID- 25710670 TI - Alternative pricing strategies for cancer drugs--reply. PMID- 25710672 TI - The effects of weather on pain, comfort and efficiency. PMID- 25710673 TI - JAMA patient page. Advance directives. PMID- 25710674 TI - New nanocrystalline materials: a previously unknown simple cubic phase in the SnS binary system. AB - We report a new phase in the binary SnS system, obtained as highly symmetric nanotetrahedra. Due to the nanoscale size and minute amounts of these particles in the synthesis yield, the structure was exclusively solved using electron diffraction methods. The atomic model of the new phase (a = 11.7 A, P2(1)3) was deduced and found to be associated with the rocksalt-type structure. Kramers Kronig analysis predicted different optical and electronic properties for the new phase, as compared to alpha-SnS. PMID- 25710675 TI - The effects of levetiracetam, sumatriptan, and caffeine in a rat model of trigeminal pain: interactions in 2-component combinations. AB - BACKGROUND: Levetiracetam is an antiepileptic drug with analgesic efficacy shown in pain models and small clinical trials. Sumatriptan is used in acute migraine treatment. Caffeine is widely consumed in some beverages/foods and is also an adjuvant in analgesic formulations. We examined the effects of systemic levetiracetam, sumatriptan, and caffeine and their interactions in 2-component combinations in the rat orofacial formalin test, a model of trigeminal pain. METHODS: Rats received a subcutaneous injection of formalin solution into the perinasal area, and the total time spent in nociceptive behavior (face rubbing) was quantified. The antinociceptive effect of drugs/drug combinations was assessed 1 hour after per os administration. The type of interaction between levetiracetam/sumatriptan and caffeine was examined by comparing the effects of a fixed, effective dose of levetiracetam/sumatriptan alone with the effects of the same dose applied with increasing, subeffective doses of caffeine. The type of interaction between levetiracetam and sumatriptan was determined by isobolographic analysis. RESULTS: Levetiracetam (1-50 mg/kg) and sumatriptan (0.5 5 mg/kg) produced significant and dose-dependent antinociceptive effects in both phases of the orofacial formalin test (P <= 0.001). Caffeine (7.5-100 mg/kg) produced significant antinociception in the second phase of the test (P = 0.04). Caffeine (1-7.5 mg/kg) significantly reduced the antinociceptive effects of levetiracetam (25 mg/kg) (first phase P = 0.002, second phase P < 0.001) and sumatriptan (2.5 mg/kg) (first phase P = 0.014, second phase P = 0.027); dose dependent inhibition was observed in the second phase. Levetiracetam and sumatriptan exerted an additive interaction in the second phase of the orofacial formalin test. CONCLUSIONS: Results indicate that levetiracetam may be useful for treatment of pain in the trigeminal region. Dietary caffeine might decrease the effects of levetiracetam and sumatriptan; this needs to be considered in clinical settings. A levetiracetam-sumatriptan combination could also be useful in trigeminal pain treatment. Its efficacy and adverse effects should be examined clinically. PMID- 25710676 TI - Uranyl and uranyl-3d block cation complexes with 1,3-adamantanedicarboxylate: crystal structures, luminescence, and magnetic properties. AB - The reaction of 1,3-adamantanedicarboxylic acid (LH2) with uranyl nitrate under solvo-hydrothermal conditions, either alone or in the presence of additional metal cations (Co(2+), Ni(2+), or Cu(2+)) gives a series of nine complexes displaying a wide range of architectures. While [UO2(L)(H2O)].1.25CH3CN (1) and [UO2(L)(DMF)] (2) are one-dimensional (1D) species analogous to that previously known, [H2NMe2]2[(UO2)2(L)3].1.5H2O (3), which includes dimethylammonium counterions generated in situ, is a three-dimensional (3D) framework, and [UO2(L)(NMP)] (4) (NMP = N-methyl-2-pyrrolidone) is a braid-shaped 1D polymer. When 3d block metal ions are present and bound to 2,2'-bipyridine (bipy) coligands, their role is reduced to that of decorating species attached to uranyl containing 1D polymers, as in [UO2M(L)2(bipy)2].0.5H2O with M = Co (5) or Ni (6), and [(UO2)2Cu2(L)3(NO3)2(bipy)2].0.5H2O (9), or of counterions, as in [Ni(bipy)3][(UO2)4(O)2(L)3].3H2O (7), in which a two-dimensional (2D) assembly is built from tetranuclear uranyl-containing building units. In contrast, the heterometallic 3D framework [UO2Cu(L)2] (8) can be isolated in the absence of bipy. The emission spectra measured in the solid state display the usual uranyl vibronic fine structure, with various degrees of resolution and quenching, except for that of complex 7, which shows emission from the nickel(II) centers. The magnetic properties of complexes 5, 6, 8, and 9 were investigated, showing, in particular, the presence of zero-field splitting effects in 6 and weak antiferromagnetic interactions in 9. PMID- 25710677 TI - Biomass logistics analysis for large scale biofuel production: case study of loblolly pine and switchgrass. AB - The objective of this study was to assess the costs, energy consumption and greenhouse gas (GHG) emissions throughout the biomass supply chain for large scale biofuel production. Two types of energy crop were considered, switchgrass and loblolly pine, as representative of herbaceous and woody biomass. A biomass logistics model has been developed to estimate the feedstock supply system from biomass production through transportation. Biomass in the form of woodchip, bale and pellet was investigated with road, railway and waterway transportation options. Our analysis indicated that the farm or forest gate cost is lowest for loblolly pine whole tree woodchip at $39.7/dry tonne and highest for switchgrass round bale at $72.3/dry tonne. Switchgrass farm gate GHG emissions is approximately 146kgCO2e/dry tonne, about 4 times higher than loblolly pine. The optimum biomass transportation mode and delivered form are determined by the tradeoff between fixed and variable costs for feedstock shipment. PMID- 25710678 TI - From lignin to cycloparaffins and aromatics: directional synthesis of jet and diesel fuel range biofuels using biomass. AB - The continual growth in commercial aviation fuels and more strict environmental legislations have led to immense interest in developing green aviation fuels from biomass. This paper demonstrated a controllable transformation of lignin into jet and diesel fuel range hydrocarbons, involving directional production of C8-C15 aromatics by the catalytic depolymerization of lignin into C6-C8 low carbon aromatic monomers coupled with the alkylation of aromatics, and the directional production of C8-C15 cycloparaffins by the hydrogenation of aromatics. The key step, the production of the desired C8-C15 aromatics with the selectivity up to 94.3%, was achieved by the low temperature alkylation reactions of the lignin derived monomers using ionic liquid. The synthetic biofuels basically met the main technical requirements of conventional jet fuels. The transformation potentially provides a useful way for the development of cycloparaffinic and aromatic components in jet fuels using renewable lignocellulose biomass. PMID- 25710679 TI - Effects of inhibitory compounds in lignocellulosic hydrolysates on Mortierella isabellina growth and carbon utilization. AB - Oleaginous fungus Mortierella isabellina showed excellent lipid conversion on non detoxified lignocellulosic hydrolysate. This study investigated the effects of inhibitory compounds (furfural, hydroxymethylfurfural, and ferulic and coumaric acids) in lignocellulosic hydrolysate on M. isabellina growth and lipid production. M. isabellina can tolerate furfural (~1 g/L), hydroxymethylfurfural (~2.5 g/L), ferulic (~0.5 g/L) and coumaric acid (~0.5 g/L) with normal growth rates. Synergistic effect of these inhibitors (2 g/L furfural, 0.4 g/L hydroxymethylfurfural, 0.02 g/L ferulic acid and 0.02 g/L coumaric acid) moderately reduces total fungal growth (by 28%), while the presence of these inhibitors has minor impact on cell lipid contents and lipid profiles. In the presence of inhibitory compounds, (13)C-tracing has revealed that M. isabellina can simultaneously utilize glucose and acetate, and acetate is mainly assimilated for synthesis of lipid and TCA cycle amino acids. The results also demonstrate that glucose has strong catabolite repression for xylose utilization for biomass and lipid production in the presence of inhibitors. PMID- 25710680 TI - Bioaugmentation treatment of municipal wastewater with heterotrophic-aerobic nitrogen removal bacteria in a pilot-scale SBR. AB - PCN bacteria capable of heterotrophic-aerobic nitrogen removal was successfully applied for bioaugmented treatment of municipal wastewater in a pilot-scale SBR. At an appropriate COD/N ratio of 8, the bioaugmentation system exhibited stable and excellent carbon and nutrients removal, the averaged effluent concentrations of COD, NH4(+)-N, TN and TP were 20.6, 0.69, 14.1 and 0.40 mg/L, respectively, which could meet the first class requirement of the National Municipal Wastewater Discharge Standards of China (COD<50 mg/L, TN<15 mg/L, TP<0.5 mg/L). Clone library and real-time PCR analysis revealed that the introduced bacteria greatly improved the structure of original microbial community and facilitated their aerobic nutrients removal capacities. The proposed emerging technology was shown to be an alternative technology to establish new wastewater treatment systems and upgrade or retrofit conventional systems from secondary-level to tertiary-level. PMID- 25710681 TI - A submerged membrane bioreactor with pendulum type oscillation (PTO) for oily wastewater treatment: membrane permeability and fouling control. AB - In this study, a novel submerged membrane bioreactor (SMBR) with pendulum type oscillation (PTO) hollow fiber membrane modules was developed to treat oily wastewater and control the problem of membrane fouling. To assess the potential of PTO membrane modules, the effect of oscillation orientation and frequency on membrane permeability was investigated in detail. The forces exerted on sludge flocs in the oscillating SMBR were analyzed to evaluate the impact of membrane oscillating on the cake layer resistance reduction. Results showed that the optimized PTO SMBR system exhibited 11 times higher membrane permeability and better fouling controllability than the conventional MBR system. By hydrodynamic analysis, it was found that the cooperative effect of bubble-induced turbulence and membrane oscillation in PTO SMBR system generated strong shear stress at liquid-membrane interface in vertical and horizontal direction and effectively hindered the particles from depositing on membrane surface. PMID- 25710682 TI - Cationic polyacrylamide enhancing cellulase treatment efficiency of hardwood kraft-based dissolving pulp. AB - Cellulase treatment for decreasing viscosity and increasing Fock reactivity of dissolving pulp is a promising approach to reduce the use of toxic chemicals, such as hypochlorite in the dissolving pulp manufacturing process in the industry. Improving the cellulase treatment efficiency during the process is of practical interest. In the present study, the concept of using cationic polyacrylamide (CPAM) to enhance the cellulase treatment efficiency was demonstrated. This was mainly attributed to the increased cellulase adsorption onto cellulose fibers based on the patching/bridging mechanism. Results showed that the cellulase adsorption was increased by about 20% with the addition of 250 ppm of CPAM under the same conditions as those of the control. It was found that the viscosity decrease and Fock reactivity increase for the cellulase treatment was enhanced from using CPAM. The CPAM-assisted cellulase treatment concept may provide a practical alternative to the present hypochlorite-based technology for viscosity control in the industry. PMID- 25710683 TI - Predictors of sexual function during pregnancy. AB - The aim of the study was to evaluate sexual functions of pregnant women and to determine the factors affecting their sexual function. The cross-sectional study recruited 286 pregnant women from a hospital. To collect data, 'Patient Information Form', 'State Anxiety Inventory' and 'Female Sexual Function Index' were used. The mean age of women was 29.15 +/- 4.85 and 77.6% of them presented with sexual dysfunction. Having partner at advanced age, a history of miscarriage, a history of health problem during previous pregnancy and a high level of anxiety were found to be factors negatively affecting sexual function. Health professionals should be aware of a number of risk factors that may contribute to sexual dysfunction in pregnant women. PMID- 25710684 TI - Rapid diagnostic tests for dengue virus infection in febrile Cambodian children: diagnostic accuracy and incorporation into diagnostic algorithms. AB - BACKGROUND: Dengue virus (DENV) infection is prevalent across tropical regions and may cause severe disease. Early diagnosis may improve supportive care. We prospectively assessed the Standard Diagnostics (Korea) BIOLINE Dengue Duo DENV rapid diagnostic test (RDT) to NS1 antigen and anti-DENV IgM (NS1 and IgM) in children in Cambodia, with the aim of improving the diagnosis of DENV infection. METHODOLOGY AND PRINCIPAL FINDINGS: We enrolled children admitted to hospital with non-localised febrile illnesses during the 5-month DENV transmission season. Clinical and laboratory variables, and DENV RDT results were recorded at admission. Children had blood culture and serological and molecular tests for common local pathogens, including reference laboratory DENV NS1 antigen and IgM assays. 337 children were admitted with non-localised febrile illness over 5 months. 71 (21%) had DENV infection (reference assay positive). Sensitivity was 58%, and specificity 85% for RDT NS1 and IgM combined. Conditional inference framework analysis showed the additional value of platelet and white cell counts for diagnosis of DENV infection. Variables associated with diagnosis of DENV infection were not associated with critical care admission (70 children, 21%) or mortality (19 children, 6%). Known causes of mortality were melioidosis (4), other sepsis (5), and malignancy (1). 22 (27%) children with a positive DENV RDT had a treatable other infection. CONCLUSIONS: The DENV RDT had low sensitivity for the diagnosis of DENV infection. The high co-prevalence of infections in our cohort indicates the need for a broad microbiological assessment of non-localised febrile illness in these children. PMID- 25710685 TI - Topicality and impact in social media: diverse messages, focused messengers. AB - We have a limited understanding of the factors that make people influential and topics popular in social media. Are users who comment on a variety of matters more likely to achieve high influence than those who stay focused? Do general subjects tend to be more popular than specific ones? Questions like these demand a way to detect the topics hidden behind messages associated with an individual or a keyword, and a gauge of similarity among these topics. Here we develop such an approach to identify clusters of similar hashtags in Twitter by detecting communities in the hashtag co-occurrence network. Then the topical diversity of a user's interests is quantified by the entropy of her hashtags across different topic clusters. A similar measure is applied to hashtags, based on co-occurring tags. We find that high topical diversity of early adopters or co-occurring tags implies high future popularity of hashtags. In contrast, low diversity helps an individual accumulate social influence. In short, diverse messages and focused messengers are more likely to gain impact. PMID- 25710687 TI - Taking up the cyanine challenge with quantum tools. AB - Cyanine derivatives, named from the Greek word kyanos meaning dark-blue, were discovered more than 150 years ago and remain one of the most widely used classes of organic dyes with contemporary applications in photography (panchromatic emulsions), information storage (CD-R and DVD-R media) and biochemistry (DNA and protein labeling) fields. Cyanine chromogens consist of a charged pi-conjugated segment containing an odd number of sp(2) carbon atoms with the chain capped at the extremities by two electronegative centers, typically nitrogen or oxygen atoms. Cyanines are characterized by a vanishing bond length alternation indicating nearly equal carbon-carbon bond lengths, as well as a very intense and sharp absorption band presenting a shoulder. This hallmark band undergoes a strong red shift when the chain is extended. This so-called vinyl shift is extremely large (ca. 100 nm for each pair of carbon atoms added in the pi conjugated path), making cyanines ideal building blocks for the design of devices with near-infrared applications. Numerous cyanines also exhibit emission bands with large quantum yields. These exceptional optical properties explain why both canonical cyanines and the corresponding fluoroborates (e.g., boron dipyrromethene, BODIPY) remain the focus of an ever-growing body of experimental work. In turn, this popularity has stimulated quantum mechanical investigations aiming, on the one hand, at probing the specific electronic nature of cyanine dyes and, on the other hand, at helping to design new dyes. However, the adiabatic approximation to time-dependent density functional theory, the most widespread ab initio model for electronically excited states, fails to accurately reproduce the absorption spectra of cyanine derivatives: it yields a systematic and large underestimation of the experimental wavelengths irrespective of the details of the computational protocol. In contrast, highly correlated wave function approaches provide accurate transition energies for model systems but are hardly applicable to real-life cyanines and BODIPY. This indicates that setting up a computationally tractable theoretical protocol that provides both robust and accurate optical spectra for cyanine-based dyes is a major challenge that has only been taken up lately. In this Account, we compile the most recent advances in the field by considering both compact streptocyanines and large fluoroborates. For the former, we summarize the key results obtained with a large panel of theoretical approaches, allowing us not only to understand the origin of the cyanine challenge but also to pinpoint the schemes presenting the most promising accuracy/effort ratio. For the latter, we show via selected examples how theoretical models can be used to reproduce simultaneously experimental band shapes and transition energies, thus paving the way to an efficient in silico design of new compounds. PMID- 25710686 TI - The impairment of osteogenesis in bone sialoprotein (BSP) knockout calvaria cell cultures is cell density dependent. AB - Bone sialoprotein (BSP) belongs to the "small integrin-binding ligand N-linked glycoprotein" (SIBLING) family, whose members interact with bone cells and bone mineral. BSP is strongly expressed in bone and we previously showed that BSP knockout (BSP-/-) mice have a higher bone mass than wild type (BSP+/+) littermates, with lower bone remodelling. Because baseline bone formation activity is constitutively lower in BSP-/- mice, we studied the impact of the absence of BSP on in vitro osteogenesis in mouse calvaria cell (MCC) cultures. MCC BSP-/- cultures exhibit fewer fibroblast (CFU-F), preosteoblast (CFU-ALP) and osteoblast colonies (bone nodules) than wild type, indicative of a lower number of osteoprogenitors. No mineralized colonies were observed in BSP-/- cultures, along with little/no expression of either osteogenic markers or SIBLING proteins MEPE or DMP1. Osteopontin (OPN) is the only SIBLING expressed in standard density BSP-/- culture, at higher levels than in wild type in early culture times. At higher plating density, the effects of the absence of BSP were partly rescued, with resumed expression of osteoblast markers and cognate SIBLING proteins, and mineralization of the mutant cultures. OPN expression and amount are further increased in high density BSP-/- cultures, while PHEX and CatB expression are differentiatlly regulated in a manner that may favor mineralization. Altogether, we found that BSP regulates mouse calvaria osteoblast cell clonogenicity, differentiation and activity in vitro in a cell density dependent manner, consistent with the effective skeletogenesis but the low levels of bone formation observed in vivo. The BSP knockout bone microenvironment may alter the proliferation/cell fate of early osteoprogenitors. PMID- 25710688 TI - [Neurological health care activity in a recently created district hospital: model of high efficiency]. AB - AIM: To analyze the neurological attention of a county hospital of recent creation, with a special emphasis in the health care indicators, both in hospital out-patients consultations and in patients admitted to the hospital. PATIENTS AND METHODS: We have made a descriptive analysis of the neurological attention developed by our Neurology Section between the years 2008 and 2013. We also made a comparative analysis of health care indicators corresponding to the years 2012 and 2013 (5th and 6th years of clinical activity) of our hospital with those of two other hospitals with similar features, other three hospitals of secondary level, and four of tertiary level. RESULTS: The Neurology Section of our hospital was the best in the number of first visits divided by number of physicians, in the follow-up/first visit index, in the percentage of high-resolution visits, and was the best in the mean stay in hospital for the two most frequent diagnostic related groups (DRG) in our speciality, the second in number of hospital admissions divided by number of physicians for the DRG 'stroke with infarction' and the third in number of hospital admissions divided by number of physicians for the DRG 'other nervous system disorders'. CONCLUSIONS: The health care indicators of the Neurology Section of our hospital showed a very high efficiency model of medical assistance, which was only followed by other two hospitals with similar features to ours. The gradual implementation of assistance models similar to that used in these hospitals in other of secondary or tertiary levels could be useful in the improvement of their health care efficiency. PMID- 25710689 TI - [Assessment of the effectiveness and safety of Sativex(r) in compassionate use]. AB - INTRODUCTION: Sativex(r) is a drug approved for use in the treatment of spasticity in multiple sclerosis. We sought to study the tolerability and effectiveness of this drug product in pathologies beyond the scope of the indications of the product data sheet, by means of its compassionate use. AIM: To evaluate the effectiveness and safety of Sativex in pathologies that are not included on the product data sheet, using a compassionate use protocol. PATIENTS AND METHODS: A six-month observational study was conducted to evaluate the effectiveness and safety of Sativex in neuropathic pain and in spasticity from causes other than multiple sclerosis. RESULTS: A total of 10 patients were included: six females and four males. Side effects appeared in only two of them and the drug product was withdrawn in one case. After starting treatment with Sativex by means of a compassionate use protocol, the consumption of concomitant drugs was reduced by 34.2% (p=0.004), and administration of botulinum toxin was suspended in seven patients (70%). The improvement on the Ashworth spasticity scale was 65.6% (p=0.004) and the score on the analogical visual scale dropped by 49.2% (p=0.026). CONCLUSIONS: Sativex may be an interesting therapeutic alternative in patients with spasticity and pain when the treatments that are usually available have been employed but patients' quality of life continues to be significantly compromised. PMID- 25710690 TI - [Language comprehension disorders in non-verbal children with autism spectrum disorders and their implications in the family quality of life]. AB - INTRODUCTION: Language widely varies in children with autism spectrum disorders (ASD). Evidence, however, suggests that these children understand language worse than their peers with typical development, showing a delay in acquisition of receptive vocabulary. Research relating quality of life (QOL) and language is limited. AIMS: To increase our knowledge about structural aspects of language in children with ASD, and to determine the effects of deficits in understanding in children with ASD in their families' QOL. SUBJECTS AND METHODS: We analyzed language comprehension in 26 non-verbal children with ASD (mean: 9.8 years) and 26 children with typical development (mean: 3.9 years) matched for age vocabulary, using standardized measures of receptive language. RESULTS: We found that levels of receptive vocabulary, auditory comprehension, and grammar comprehension in children with ASD are lower than typical levels for their age, and significantly differ from those in children with typical development. Parents of children with ASD also report severe communication problems in their children and lack of social support. Family QOL is influenced by language problems of children with ASD. CONCLUSIONS: There is a significant relationship between receptive language skills in children with ASD and perceptions of QOL in their families. These results can have important implications for designing clinical interventions. PMID- 25710691 TI - [Intragenic deletions of NRXN1: three new case reports and a review of the phenotype]. AB - AIM: To offer data on the phenotype determined by microdeletions of alpha exons in the NRXN1 gene. CASE REPORTS: Three neuropaediatric cases of intragenic microdeletions of NRXN1 alpha are studied. The phenotype of these three cases is unspecific, with mild-moderate mental retardation, behavioural disorders and slight dysmorphic traits or malformations. CONCLUSIONS: The phenotype found in the microdeletions of alpha exons of the NRXN1 gene is clearly distinguishable from the one found in the microdeletions of beta exons, with macrocephaly, epilepsy and mental retardation. PMID- 25710692 TI - [Neuronal communication and synaptic metabolism in childhood epilepsy]. AB - INTRODUCTION: Basic neuroscience and neurometabolism are providing a rapidly increasing amount of knowledge on paediatric epilepsy and, more specifically, on the mechanisms involved in synaptic communication. There is, however, a mismatch between these advances and a vision that integrates them in a global way, in clinical and therapeutic practice. AIMS: To offer an integrative view of the different molecular and metabolic mechanisms that are known and postulated in paediatric epilepsy, and to suggest concepts such as 'synaptic metabolism' and 'synaptic phenotypes' as useful tools for developing this approach. DEVELOPMENT: We also review the most notable studies that attempt to explain the essential characteristics of synaptic communication in the developing brain by means of different molecules, essentially synaptic proteins, ion channels (chlorine, sodium and potassium co-transporters), and pre- and post-synaptic compartmentalisation, as well as the main players in metabolism (neurotransmitters, energy metabolism, growth factors and lipids). This combination of biological mechanisms has led to examples of 'synaptic phenotypes' being suggested in two specific cases of genetic (SCN1A) and metabolic epilepsy (epilepsy with response to pyridoxine). CONCLUSIONS: A holistic perspective, which takes into account the diversity of elements that are related and which take place at certain times in neurodevelopment, can help to define phenotypes, channels for synaptic metabolism and brain connectivity, which facilitate not only the understanding of the pathophysiology, but also new therapeutic approaches in paediatric epilepsy. PMID- 25710693 TI - [Cinema and neurology: early educational applications]. AB - INTRODUCTION: Since its earliest days, cinema has been used in the teaching of neurology both to illustrate the professor's explanations and to make learning easier for students. AIM: To analyse some of the first applications of cinema to the teaching and learning of neurology. DEVELOPMENT: Shortly after the birth of the film projector it became apparent that it could be a valuable aid in teaching medicine, and especially neurology. Initially, actual recordings made by doctors themselves were used, and later documentaries, short films and feature films were employed as means of showing diagnostic and therapeutic methods, as well as different pathological signs, such as movement disorders. The intention was not to replace other methodologies but instead to complement them and to make the process of acquiring knowledge easier. CONCLUSIONS: Applying cinema in teaching is a useful way to portray the contents of different subjects, especially in the field of neurology, and to favour the acquisition of both specific and cross disciplinary competences, with very positive results being obtained among students. PMID- 25710694 TI - [Post-traumatic vertex epidural haematoma treated with conservative therapy]. PMID- 25710695 TI - [Complex partial seizures and cerebellar structural damage]. PMID- 25710696 TI - [Enlarged Virchow-Robin spaces mimicking cystic brainstem tumor]. PMID- 25710697 TI - ['Ice Bucket Challenge': impact of a mass media campaign for amyotrophic lateral sclerosis]. PMID- 25710698 TI - Research highlights: aptamers on a chip. AB - Aptamers, oligonucleic acid or peptide molecules with binding affinity to a specific molecule, have gained broad scientific attention due to their stability, ease of production and modification, and durability, and therefore have been employed in a wide range of applications both in basic research and clinical science. Recent advances in high-throughput sequencing are poised to revolutionize the selection of aptamers, while microfluidic and microarray approaches have helped automate these processes of selection. Here we highlight work addressing several challenges in using aptamers more widely. We discuss array-based discovery of multivalent aptamers which is used to develop high affinity or paired aptamers by cleverly selecting new aptamers that bind to previously aptamer-bound proteins. Other highlighted work is addressing problems in analyzing local cell secretions, as well as refreshable sensors that detect signals over hundreds of cycles and can be refreshed with DI water scavenged from the air, leading to less reagent storage towards wearable sensors. PMID- 25710699 TI - Role of the nurse in returning birth to the North. AB - With the colonization of the Americas came the eventual stigmatization of Aboriginal women and their traditional birthing methods. Gradual introduction of Western ideology and medicine led to government pressure to medicalize birth. Women were eventually flown to southern hospitals with immediate medical and surgical services available to ensure 'safer' deliveries and thereby improve serious maternal and infant morbidity and mortality statistics that were becoming too obvious to ignore. This process led to devastating consequences for women and families, which are still being felt today. The history of colonization of birth for Aboriginal families is discussed, with current strategies to alleviate this suffering in the north. Proposals for change from the Society of Obstetricians and Gynecologists of Canada (SOGC) are discussed. The role of the nurse is described, including being culturally competent, fostering an environment of respect, dispelling myths and stereotypes, ensuring research involving Aboriginal peoples is done ethically, and promoting pursuing a career in health care. PMID- 25710701 TI - Chirality detection of two enantiomorphic 3D lanthanide coordination polymers by vibrational circular dichroism spectra. AB - Two enantiomorphic 3D lanthanide coordination polymers of {[Dy5(L)4(H2O)10][Dy(H2O)7][Na(H2O)5]}.(ClO4)7.(H2O)15 (1a for R and 1b for S) with chiral helical chains were synthesized based on an achiral ligand N-(2 hydroxyethyl)ethylenediamine-N,N',N'-triacetic acid (H3L) and Dy(ClO4)3. Crystal analysis revealed that 1a and 1b were crystallized in chiral space groups P4132 and P4332, respectively. The absolute configurations of the two structures were evidenced by vibrational circular dichroism (VCD) spectra with one single crystal sample. PMID- 25710700 TI - Retrotransposition of long interspersed nucleotide element-1 is associated with colitis but not tumors in a murine colitic cancer model. AB - Long interspersed element-1 (L1) is a transposable element that can move within the genome, potentially leading to genome diversity and modified gene function. Although L1 activity in somatic cells is normally suppressed through DNA methylation, some L1s are activated in tumors including colorectal carcinoma. However, how L1-retrotransposition (L1-RTP) is involved in gastrointestinal disorders remains to be elucidated. We hypothesized that L1-RTP in somatic cells might contribute to colitis-associated cancer (CAC). To address this, we employed an experimental model of CAC using transgenic L1-reporter mice carrying a human L1-EGFP reporter gene. Mice were subjected to repeated cycles of colitis induced by administration of dextran sodium sulfate (DSS) in drinking water with injection of carcinogen azoxymethane (AOM). L1-RTP levels were measured by a quantitative polymerase chain reaction targeting the newly inserted reporter EGFP in various tissues and cell types, including samples obtained by laser microdissection and cell sorting with flow cytometry. DNA methylation levels of the human L1 promoter were analyzed by bisulfite pyrosequencing. AOM+DSS-treated mice exhibited significantly higher levels of L1-RTP in whole colon tissue during the acute phase of colitis when compared with control naive mice. L1-RTP levels in whole colon tissue were positively correlated with the histological severity of colitis and degree of neutrophil infiltration into the lamina propria (LP), but not with tumor development in the colon. L1-RTP was enriched in LP mesenchymal cells rather than epithelial cells (ECs), myeloid, or lymphoid cells. DNA methylation levels of the human L1 promoter region showed a negative correlation with L1-RTP levels. L1-RTP was absent from most tumors found in 22 week-old mice. In conclusion, we demonstrated that L1-RTP was induced in the mouse CAC mucosa in accordance with the acute inflammatory response; however, retrotransposition appears not to have direct relevance to colitis-induced cancer initiation. PMID- 25710702 TI - A perspective on sirtuins in the metabolic syndrome. AB - The metabolic syndrome is a cluster of risk factor for diabetes and cardiovascular diseases. The metabolic syndrome pandemic reflects poor cardiometabolic health due to sedentary lifestyles and excess caloric intake over the background of an aging population. Sirtuins are protein deacetylases that represent master regulators of senescence, metabolism, and substrate utilization. In this perspective, we underline the pervasive role of sirtuins in the development of the typical features of metabolic syndrome and describe how sirtuins are becoming an attractive target of therapy. PMID- 25710703 TI - Multivariate analyses of rotator cuff pathologies in shoulder disability. AB - BACKGROUND: Disability of the shoulder joint is often caused by a tear in the rotator cuff (RC) muscles. Four RC muscles coordinate shoulder movement and stability, among them the supraspinatus and infraspinatus muscle which are predominantly torn. The contribution of each RC muscle to tear pathology is not fully understood. We hypothesized that muscle atrophy and fatty infiltration, features of RC muscle degeneration, are predictive of superior humeral head translation and shoulder functional disability. METHODS: Shoulder features, including RC muscle surface area and fatty infiltration, superior humeral translation and RC tear size were obtained from a consecutive series of Magnetic Resonance Imaging with arthrography (MRA). We investigated patients with superior (supraspinatus, n = 39) and posterosuperior (supraspinatus and infraspinatus, n = 30) RC tears, and patients with an intact RC (n = 52) as controls. The individual or combinatorial contribution of RC measures to superior humeral translation, as a sign of RC dysfunction, was investigated with univariate or multivariate models, respectively. RESULTS: Using the univariate model the infraspinatus surface area and fatty infiltration in both the supraspinatus and infraspinatus had a significant contribution to RC dysfunction. With the multivariate model, however, the infraspinatus surface area only affected superior humeral translation (p<0.001) and discriminated between superior and posterosuperior tears. In contrast neither tear size nor fatty infiltration of the supraspinatus or infraspinatus contributed to superior humeral translation. CONCLUSION: Our study reveals that infraspinatus atrophy has the strongest contribution to RC tear pathologies. This suggests a pivotal role for the infraspinatus in preventing shoulder disability. PMID- 25710705 TI - Cytokeratin 7 negative invasive breast carcinoma: clinicopathological and immunohistochemical analysis of 14 cases with clinical follow-up. AB - Cytokeratin 7 (CK 7) negative breast tumours are reported to occur rarely. We studied 14 CK 7 negative cases of primary invasive ductal carcinoma (IDC) detected during sentinel lymph node metastases work-up and immunohistochemistry panel in the work-up of metastatic carcinoma of unknown origin. Axillary lymph node metastases were present in seven patients (50%). Oestrogen receptor (ER) was strongly positive in all cases: progesterone receptor in 78%, Her-2/neu in 7% and high proliferation index with Ki-67 >20% was seen in 71% of the cases. Metastatic and/or recurrence were found in 8 of 14 patients (57%) with the mean clinical follow-up of 55 months. Metastatic sites include multiple bones, brain, spinal cord, liver, pancreas, ovary, lung, lymph node other than ipsilateral axillary and skin. 12 of 14 patients received adjuvant chemotherapy. All 14 patients received hormonal therapy and radiation therapy. Morphologically, IDC with neuroendocrine features was noted in 57%. Synaptophysin stain was positive in 57% and chromogranin was positive in 21% of the cases. In conclusion, these CK 7 negative breast carcinomas were ER positive, mostly Her-2/neu negative, had high Ki-67 and frequently showed neuroendocrine differentiation. More than half of these cases had a poor outcome. PMID- 25710706 TI - Socio-economic inequalities in diet and body weight: evidence, causes and intervention options. PMID- 25710704 TI - Longitudinal association between serum leptin concentration and glomerular filtration rate in humans. AB - BACKGROUND: Obesity is a risk factor for decline in glomerular filtration rate (GFR). One proposed mechanism leading to glomerulopathy is an increase in leptin levels. However, the association between leptin and GFR has never been demonstrated. The aim of this study is to verify whether higher levels of leptin are associated with longitudinal changes of estimated GFR (eGFR). METHODS AND FINDINGS: We selected 744 participants in the InCHIANTI study (416 women). The association between eGFR and leptin changes over a 6-years follow-up was assessed using random effect models including leptin as a time-varying covariate and adjusted for potential confounders. We also compared the proportion of patients with rapid decline of renal function across tertiles of change in serum leptin between baseline and 6-years follow-up. Mean baseline eGFR was 82.2 ml/min/1.73 m, 78.7 ml/min/1.73 m, and 75.4 ml/min/1.73 m in the first, second and third tertile of baseline serum leptin concentration, respectively. After adjustment for potential confounders, leptin concentration was inversely associated with changes of eGFR over time (beta for log-leptin: -1.288, 95% CI: -2.079 - -0.497). Relative to baseline levels, the estimated change in eGFR for unit-increase in log-leptin was -1.9% (95% CI: -2.977 - -0.761). After stratification by sex, the results were confirmed in women only. In women we also found an association between increasing leptin concentration over time and rapid decline of renal function. CONCLUSIONS: In women, serum leptin may contribute to eGFR decline independently from obesity and diabetes mellitus, although a cause-effect relationship cannot be established due to the observational nature of our study. A better characterization of adipokine profile of obese individuals may shed light on the accelerated renal function decline reported in a proportion of high risk obese individuals. PMID- 25710707 TI - Incidence, prevalence, and trend analysis of the use of insulin delivery systems in the United States (2005 to 2011). AB - OBJECTIVE: Estimate the incidence and prevalence rates and assess overall trends among patients with diabetes using insulin vial/syringe and pens over time. METHODS: A retrospective study was conducted using the Truven MarketScan database from 1 July 2004 to 31 December 2011. The database contained medical and pharmacy claims of >20 million US residents insured by commercial health plans. Patients with diabetes who utilized vial/syringe and pens were included. Incidence rate was defined as the proportion of patients initiating a new insulin type for the first time with vial/syringe and pens within each year from 2005 to 2011 among the total number of patients initiating that particular insulin type for the first time. Prevalence rate was defined as the proportion of patients using vial/syringe or pens among patients with diabetes using that insulin type within each year from 2005 to 2011. A linear trend over time was assessed by Cochran Armitage Trend tests and Generalized Estimating Equations. RESULTS: Incidence of patients initiating vial/syringe decreased from 2005 to 2011 (basal analog [90.5% to 31.3%]; mealtime analog [67.6% to 37.1%]), while patients initiating pens increased (basal analog [9.5% to 68.7%]; mealtime analog [32.4% to 62.9%]). There was a significant trend over time indicating increased usage of pens relative to vial/syringe; the number of pen users increased (all p < 0.0001 except mealtime human). Prevalence of patients using vial/syringe decreased from 2005 to 2011 (basal analog [93.8% to 41.2%]; mealtime analog [71.0% to 50.6%]), while patients using pens increased (basal analog [6.2% to 58.8%]; mealtime analog [29.0% to 49.4%]). From 2005 to 2011, patients were more likely to use pens than vial/syringe (all p < 0.0001 except for human mixtures and mealtime human). CONCLUSIONS: The incidence and prevalence of patients using the traditional vial/syringe decreased over time, while the use of pens increased. Some patient populations may be under-represented, limiting generalizability of results. PMID- 25710708 TI - Functional outcome after recanalization for acute pure M1 occlusion of the middle cerebral artery as assessed by collateral CTA flow. AB - OBJECTIVE: Collateral flow is important for ischemic brain tissue after an acute occlusion of the cerebral artery. The purpose of this study was to evaluate baseline collateral flow, on CT angiography (CTA), as a predictor of functional outcome in patients who had endovascular recanalization, after acute pure first segment (M1) occlusion of the middle cerebral artery (MCA). METHODS: Thirty patients with acute pure M1 occlusion treated by endovascular recanalization, who were ineligible for intravenous thrombolysis or resistant to intravenous thrombolysis, were reviewed. The relationship between baseline collateral flow, on CTA, and functional outcome, was analyzed. In addition, other factors affecting clinical outcome were assessed. RESULTS: The mean NIHSS score on admission was 16.87+/-4.86 (7-24). The mean time interval between onset of stroke symptoms and recanalization was 324.37+/-68.38 (210-463) min. Successful recanalization (TICI 2b-3) was achieved in 18 patients (60%). Twenty-seven of 30 patients improved their NIHSS score (mean 8.4); NIHSS score 8.9+/-5.4 (median 10, range 0-16) at seven days. Two patients had aggravated symptoms and one patient had no change on the NIHSS score. At 90 days after recanalization, a modified Rankin Scale (mRS) of <=3 was achieved in 15 patients (50%) and a mRS of <=2 was achieved in nine patients (30%). Symptomatic intra-cerebral hemorrhage occurred in two patients (6.7%). Multivariate regression analysis showed an initial NIHSS score (p=0.004), grade of baseline collateral flow on CTA (p=0.025), presence of diabetes mellitus (p=0.037), and TICI scale (p=0.049) were factors associated with an improved NIHSS. For the mRS at 90 days, only the grade of the baseline collateral flow on CTA was associated with a good functional outcome (p=0.013). CONCLUSIONS: The results of this study suggest that the grade of baseline collateral flow, on CTA, is an independent predictor of functional outcome for endovascular recanalization of acute pure M1 occlusion of the middle cerebral artery. PMID- 25710709 TI - Attitudes toward homosexuality among young adults: connections to gender role identity, gender-typed activities, and religiosity. AB - Individual differences in attitudes toward homosexuality have been linked to numerous personality and demographic variables. This study investigated the influence that gender role identity, involvement in gender-typed activities, and religiosity plays in this relationship. The sample included 194 undergraduate students from a Northeastern university. Analyses revealed that both males and females who held a more masculine gender role identity and individual commitment to religion scored higher on measures of homophobia and heteronormativity, whereas there was no association between spiritual meaning in life and attitudes toward homosexuality. Among males, but not females, more masculine gender identity and less spiritual meaning in life was associated with greater homophobia. The importance of the findings for research on the origins of attitudes toward individuals with a homosexual orientation are discussed, as well as the potential directions for future research on connections between gender role identity, religious affiliation, and attitudes toward gays and lesbians. PMID- 25710711 TI - Comparative binding mechanism of lupeol compounds with plasma proteins and its pharmacological importance. AB - Lupeol, a triterpene, possesses beneficial effects like anti-inflammatory and anti-cancer properties. Binding of lupeol and its derivative (phytochemicals) to plasma proteins such as human serum albumin (HSA) and alpha-1-acid glycoprotein (AGP) is a major determinant in the disposition of drugs. Cytotoxic studies with mouse macrophages (RAW 246.7) and HeLa cell lines revealed anti-inflammatory and anti-cancer properties for both lupeol and lupeol derivative. Both molecules reduced the expression of pro-inflammatory cytokines in LPS induced macrophages. Further, apoptosis was observed in HeLa cell lines when they were incubated with these molecules for 24 h. The fluorescence quenching of HSA was observed upon titration with different concentrations of lupeol and lupeol derivative; their binding constants were found to be 3 +/- 0.01 * 10(4) M(-1) and 6.2 +/- 0.02 * 10(4) M(-1), with binding free energies of -6.59 kcal M(-1) and -7.2 kcal M(-1). With AGP, however, the lupeol and lupeol derivative showed binding constants of 0.9 +/- 0.02 * 10(3) M(-1) and 2.7 +/- 0.01 * 10(3) M(-1), with free energies of 4.6 kcal M(-1) and -5.1 kcal M(-1) respectively. Molecular displacement studies based on competition with site I-binding phenylbutazone (which binds site I of HSA) and ibuprofen (which binds site II) suggest that lupeol binds site II and the lupeol derivative site I. Molecular docking studies also confirmed that lupeol binds to the IIIA and the lupeol derivative to the IIA domain of HSA. Secondary structure changes were observed upon formation of HSA-lupeol/lupeol derivative complexes by circular dichroism spectroscopy. Molecular dynamics simulations support greater stability of HSA-lupeol and HSA-lupeol derivative complexes compared to that of HSA alone. PMID- 25710712 TI - CopC protein from Pseudomonas fluorescens SBW25 features a conserved novel high affinity Cu(II) binding site. AB - Copper homeostasis in the bacterium Pseudomonas fluorescens SBW25 appears to be mediated mainly via chromosomal cue and cop systems. Under elevated copper levels that induce stress, the cue system is activated for expression of a P1B-type ATPase to remove excess copper from the cytosol. Under copper-limiting conditions, the cop system is activated to express two copper uptake proteins, Pf CopCD, to import this essential nutrient. Pf-CopC is a periplasmic copper chaperone that may donate copper to the inner membrane transporter Pf-CopD for active copper importation. A database search revealed that Pf-CopC belongs to a new family of CopC proteins (designated Type B in this work) that differs significantly from the known CopC proteins of Type A that possess two separated binding sites specific for Cu(I) and Cu(II). This article reports the isolation and characterization of Pf-CopC and demonstrates that it lacks a Cu(I) binding site and possesses a novel Cu(II) site that binds Cu(II) with 100 times stronger affinity than do the Type A proteins. Presumably, this is a requirement for a copper uptake role under copper-limiting conditions. The Cu(II) site incorporates a highly conserved amino terminal copper and nickel (ATCUN) binding motif, NH2 Xxx-Xxx-His, but the anticipated ATCUN binding mode is prevented by a thermodynamically more favorable binding mode comprising His1 as a key bidentate ligand and His3 and His85 as co-ligands. However, upon His1 mutation, the ATCUN binding mode is adopted. This work demonstrates how a copper chaperone may fine tune its copper binding site to meet new challenges to its function. PMID- 25710710 TI - New insights into iron regulation and erythropoiesis. AB - PURPOSE OF REVIEW: Iron homeostasis and erythropoiesis regulate each other to ensure optimal delivery of oxygen and iron to cells and tissues. Defining the mechanisms of this crosstalk is important for understanding the pathogenesis of common conditions associated with disordered iron metabolism and erythropoiesis. RECENT FINDINGS: Stress erythropoiesis causes suppression of hepcidin to increase iron availability for hemoglobin synthesis. The erythroid hormone erythroferrone (ERFE) was identified as the mediator of this process. ERFE and additional candidates (TWSG1 and GDF15) may also mediate hepcidin suppression in ineffective erythropoiesis. Several mechanisms by which iron regulates erythropoiesis were also recently identified. Iron deficiency suppresses erythropoietin production via the IRP1-HIF2alpha axis to prevent excessive iron usage by erythropoiesis during systemic iron restriction. Iron restriction also directly impairs erythroid maturation by inhibiting aconitase, and this can be reversed by the administration of the aconitase product isocitrate. Another novel target is GDF11, which is thought to autoinhibit erythroid maturation. GDF11 traps show promising pharmacologic activity in models of both ineffective erythropoiesis and iron-restricted anemia. SUMMARY: This review summarizes exciting advances in understanding the mechanisms of iron and erythropoietic regulation, and development of novel therapeutic tools for disorders resulting from dysregulation of iron metabolism or erythropoiesis. PMID- 25710713 TI - Chemoenzymatic synthesis of vitamin B5-intermediate (R)-pantolactone via combined asymmetric organo- and biocatalysis. AB - The combination of an asymmetric organocatalytic aldol reaction with a subsequent biotransformation toward a "one-pot-like" process for the synthesis of (R) pantolactone, which to date is industrially produced by a resolution process, is demonstrated. This process consists of an initial aldol reaction catalyzed by readily available l-histidine followed by biotransformation of the aldol adduct by an alcohol dehydrogenase without the need for intermediate isolation. Employing the industrially attractive starting material isobutanal, a chemoenzymatic three-step process without intermediate purification is established allowing the synthesis of (R)-pantolactone in an overall yield of 55% (three steps) and high enantiomeric excess of 95%. PMID- 25710714 TI - Co-creation of information leaflets to meet the support needs of people living with complex regional pain syndrome (CRPS) through innovative use of wiki technology. AB - OBJECTIVE: People living with complex regional pain syndrome (CRPS) experience frustration with the lack of knowledge and understanding of CRPS as a pain condition. We report on our attempt to address this issue. METHODS: People living with CRPS taking part in a larger study were invited to co-construct a CRPS wiki page that addressed the areas in which they had experienced the most difficulty. A blank wiki page was set up for participants to populate with issues they felt needed to be raised and addressed. RESULTS: Participants failed to engage with the wiki technology. We modified our procedure and completed an inductive analysis of a sister-forum which participants were using as part of the larger study. Six issues of importance were identified. We used the discussion forum threads to populate the themes. Due to a continued lack of engagement with the wiki technology, the team decided to create a suite of leaflets which were piloted with delegates at a CRPS patient conference. CONCLUSIONS: Future work should be mindful of the extent to which patients are able and willing to share their experiences through such technology. Striking the balance between patient endorsed and researcher-driven co-creation of such material is imperative. PMID- 25710715 TI - Independently controlled wing stroke patterns in the fruit fly Drosophila melanogaster. AB - Flies achieve supreme flight maneuverability through a small set of miniscule steering muscles attached to the wing base. The fast flight maneuvers arise from precisely timed activation of the steering muscles and the resulting subtle modulation of the wing stroke. In addition, slower modulation of wing kinematics arises from changes in the activity of indirect flight muscles in the thorax. We investigated if these modulations can be described as a superposition of a limited number of elementary deformations of the wing stroke that are under independent physiological control. Using a high-speed computer vision system, we recorded the wing motion of tethered flying fruit flies for up to 12,000 consecutive wing strokes at a sampling rate of 6250 Hz. We then decomposed the joint motion pattern of both wings into components that had the minimal mutual information (a measure of statistical dependence). In 100 flight segments measured from 10 individual flies, we identified 7 distinct types of frequently occurring least-dependent components, each defining a kinematic pattern (a specific deformation of the wing stroke and the sequence of its activation from cycle to cycle). Two of these stroke deformations can be associated with the control of yaw torque and total flight force, respectively. A third deformation involves a change in the downstroke-to-upstroke duration ratio, which is expected to alter the pitch torque. A fourth kinematic pattern consists in the alteration of stroke amplitude with a period of 2 wingbeat cycles, extending for dozens of cycles. Our analysis indicates that these four elementary kinematic patterns can be activated mutually independently, and occur both in isolation and in linear superposition. The results strengthen the available evidence for independent control of yaw torque, pitch torque, and total flight force. Our computational method facilitates systematic identification of novel patterns in large kinematic datasets. PMID- 25710717 TI - Authors' response. PMID- 25710716 TI - Relation between vitamin D status and nonalcoholic fatty liver disease in children. AB - OBJECTIVES: In adults, vitamin D deficiency is common in patients with nonalcoholic fatty liver disease (NAFLD) and has been associated with the severity of histology. There are known differences between adult and pediatric NAFLD, with little data regarding the relation between vitamin D and pediatric NAFLD. The aim of the present study was to examine the relation between vitamin D levels and NAFLD in children. METHODS: Clinical and histological data were used from children ages 2 to 18 years with biopsy-proven NAFLD enrolled in the Nonalcoholic Steatohepatitis Clinical Research Network studies. 25(OH) vitamin D levels were measured from serum. Data examined included demographics, anthropometrics, laboratory markers, and liver histology. Data were analyzed using 3 categories of vitamin D level: deficient (<= 20 ng/mL), insufficient (21 29 ng/mL), and sufficient (>= 30 ng/mL). RESULTS: A total of 102 children were studied. There was a high prevalence (80/102, 78%) of vitamin D deficiency or insufficiency; however, there were no significant associations between vitamin D level and the histological characteristics or severity of NAFLD. Significantly higher levels of triglycerides were found in those with vitamin D deficiency (P = 0.004), but there was no association with other features of the metabolic syndrome. CONCLUSIONS: There is a high prevalence of vitamin D deficiency and insufficiency in children with biopsy-proven NAFLD; however, no association was found between vitamin D deficiency and the severity of disease on biopsies. This differs from adult NAFLD studies in which vitamin D deficiency correlates with histological severity, suggesting differences in the risk factors for or consequences of pediatric NAFLD. PMID- 25710718 TI - Perianastomotic ulceration: an important but underrecognised condition. PMID- 25710719 TI - Author's response. PMID- 25710720 TI - An extreme event of sea-level rise along the Northeast Coast of North America in 2009-2010. AB - The coastal sea levels along the Northeast Coast of North America show significant year-to-year fluctuations in a general upward trend. The analysis of long-term tide gauge records identified an extreme sea-level rise (SLR) event during 2009-10. Within this 2-year period, the coastal sea level north of New York City jumped by 128 mm. This magnitude of interannual SLR is unprecedented (a 1-in-850 year event) during the entire history of the tide gauge records. Here we show that this extreme SLR event is a combined effect of two factors: an observed 30% downturn of the Atlantic meridional overturning circulation during 2009-10, and a significant negative North Atlantic Oscillation index. The extreme nature of the 2009-10 SLR event suggests that such a significant downturn of the Atlantic overturning circulation is very unusual. During the twenty-first century, climate models project an increase in magnitude and frequency of extreme interannual SLR events along this densely populated coast. PMID- 25710722 TI - Pharmacogenetics informed decision making in adolescent psychiatric treatment: a clinical case report. AB - Advances made in genetic testing and tools applied to pharmacogenetics are increasingly being used to inform clinicians in fields such as oncology, hematology, diabetes (endocrinology), cardiology and expanding into psychiatry by examining the influences of genetics on drug efficacy and metabolism. We present a clinical case example of an adolescent male with anxiety, attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder who did not tolerate numerous medications and dosages over several years in attempts to manage his symptoms. Pharmacogenetics testing was performed and DNA results on this individual elucidated the potential pitfalls in medication use because of specific pharmacodynamic and pharmacokinetic differences specifically involving polymorphisms of genes in the cytochrome p450 enzyme system. Future studies and reports are needed to further illustrate and determine the type of individualized medicine approach required to treat individuals based on their specific gene patterns. Growing evidence supports this biological approach for standard of care in psychiatry. PMID- 25710723 TI - Mammalian introns: when the junk generates molecular diversity. AB - Introns represent almost half of the human genome, yet their vast majority is eliminated from eukaryotic transcripts through RNA splicing. Nevertheless, they feature key elements and functions that deserve further interest. At the level of DNA, introns are genomic segments that can shelter independent transcription units for coding and non-coding RNAs which transcription may interfere with that of the host gene, and regulatory elements that can influence gene expression and splicing itself. From the RNA perspective, some introns can be subjected to alternative splicing. Intron retention appear to provide some plasticity to the nature of the protein produced, its distribution in a given cell type and timing of its translation. Intron retention may also serve as a switch to produce coding or non-coding RNAs from the same transcription unit. Conversely, splicing of introns has been directly implicated in the production of small regulatory RNAs. Hence, splicing of introns also appears to provide plasticity to the type of RNA produced from a genetic locus (coding, non-coding, short or long). We addressed these aspects to add to our understanding of mechanisms that control the fate of introns and could be instrumental in regulating genomic output and hence cell fate. PMID- 25710725 TI - Changes in choroidal thickness during pregnancy detected by enhanced depth imaging optical coherence tomography. AB - AIM: To compare the choroidal thickness measurements of healthy pregnant women obtained in the first trimester with measurements obtained in the third trimester using enhanced depth imaging optical coherence tomography (OCT). METHODS: 54 eyes of 27 healthy pregnant women and 50 eyes of 25 age matched healthy women were enrolled in this observational, cross-sectional study. The pregnant women underwent two OCT scans, one in the first trimester at gestational weeks 6-8, and the other during the third trimester at gestational weeks 32-37; the control group had OCT scanning during the follicular phase of the menstrual cycle, using the enhanced depth imaging mode. Choroidal thicknesses were measured at the fovea, at three locations nasal, and at three locations temporal to the fovea at 500 MUm intervals. RESULTS: The choroidal thickness measurements obtained in the third trimester were significantly decreased in all measured points in both eyes compared to the measurements obtained in the first trimester (p<0.05). At the fovea, the mean (+/-SD) choroidal thickness measured in the first trimester was 349.22+/-82.11 MUm in the right eyes and 341.30+/-85.22 MUm in the left eyes, which decreased to 333.56+/-76.61 MUm in the right eyes (p=0.014) and 326.93+/ 75.84 MUm in the left eyes (p=0.024) in the third trimester. Although not statistically significant, choroidal thicknesses of the control group were less than the choroidal thicknesses of the pregnant women (p>0.05). CONCLUSIONS: Choroidal thickness was found to be significantly decreased in healthy pregnant women during the third trimester compared to the first trimester. This finding can provide valuable information when interpreting pregnancy related ocular disorders. PMID- 25710724 TI - Licochalcone A, a polyphenol present in licorice, suppresses UV-induced COX-2 expression by targeting PI3K, MEK1, and B-Raf. AB - Licorice is a traditional botanical medicine, and has historically been commonly prescribed in Asia to treat various diseases. Glycyrrhizin (Gc), a triterpene compound, is the most abundant phytochemical constituent of licorice. However, high intake or long-term consumption of Gc has been associated with a number of side effects, including hypertension. However, the presence of alternative bioactive compounds in licorice with anti-carcinogenic effects has long been suspected. Licochalcone A (LicoA) is a prominent member of the chalcone family and can be isolated from licorice root. To date, there have been no reported studies on the suppressive effect of LicoA against solar ultraviolet (sUV) induced cyclooxygenase (COX)-2 expression and the potential molecular mechanisms involved. Here, we show that LicoA, a major chalcone compound of licorice, effectively inhibits sUV-induced COX-2 expression and prostaglandin E2 PGE2 generation through the inhibition of activator protein 1 AP-1 transcriptional activity, with an effect that is notably more potent than Gc. Western blotting analysis shows that LicoA suppresses sUV-induced phosphorylation of Akt/ mammalian target of rapamycin (mTOR) and extracellular signal-regulated kinases (ERK)1/2/p90 ribosomal protein S6 kinase (RSK) in HaCaT cells. Moreover, LicoA directly suppresses the activity of phosphoinositide 3-kinase (PI3K), mitogen activated protein kinase kinase (MEK)1, and B-Raf, but not Raf-1 in cell-free assays, indicating that PI3K, MEK1, and B-Raf are direct molecular targets of LicoA. We also found that LicoA binds to PI3K and B-Raf in an ATP-competitive manner, although LicoA does not appear to compete with ATP for binding with MEK1. Collectively, these results provide insight into the biological action of LicoA, which may have potential for development as a skin cancer chemopreventive agent. PMID- 25710726 TI - Dry eye symptoms align more closely to non-ocular conditions than to tear film parameters. AB - OBJECTIVE: To evaluate the relationship between dry eye symptoms, non-ocular conditions and tear film parameters. METHODS: DESIGN: Cross-sectional study. PARTICIPANTS/SETTING: The study population consisted of patients who were seen in the Miami Veterans Affairs eye clinic. Patients filled out standardised questionnaires assessing dry eye symptoms (dry eye questionnaire 5 (DEQ5) and ocular surface disease index (OSDI)), non-ocular pain, depression and post traumatic stress disorder (PTSD), and also underwent measurement of tear film parameters. MAIN OUTCOME MEASURES: Correlations between dry eye symptoms and non ocular conditions as compared with tear film parameters. RESULTS: 136 patients with a mean age of 65 (SD 11) years participated in the study. All correlations between the dry eye questionnaire scores (DEQ5 and OSDI) and (A) self-reported non-ocular pain measures (numerical rating scale and pain history), (B) depression and (C) PTSD were significant and moderate in strength (Pearson's coefficient 0.24 to 0.60, p<0.01 for all). All correlations between the dry eye questionnaires and tear film measures were weak (Pearson's coefficient -0.10 to 0.18) and most were not significant. Multivariable linear regression analyses revealed that PTSD and non-ocular pain more closely associated with dry eye symptoms than did tear film parameters. Specifically, non-ocular pain and PTSD accounted for approximately 36% of the variability in DEQ5 scores (R=0.60) and approximately 40% of variability in OSDI scores (R=0.64). Of note, none of the tear parameters remained significantly associated with dry eye symptoms in either model. CONCLUSIONS: Dry eye symptoms more closely align to non-ocular pain, depression and PTSD than to tear film parameters. PMID- 25710727 TI - Atomic scale surface structure and morphology of InAs nanowire crystal superlattices: the effect of epitaxial overgrowth. AB - While shell growth engineering to the atomic scale is important for tailoring semiconductor nanowires with superior properties, a precise knowledge of the surface structure and morphology at different stages of this type of overgrowth has been lacking. We present a systematic scanning tunneling microscopy (STM) study of homoepitaxial shell growth of twinned superlattices in zinc blende InAs nanowires that transforms {111}A/B-type facets to the nonpolar {110}-type. STM imaging along the nanowires provides information on different stages of the shell growth revealing distinct differences in growth dynamics of the crystal facets and surface structures not found in the bulk. While growth of a new surface layer is initiated simultaneously (at the twin plane interface) on the {111}A and {111}B nanofacets, the step flow growth proceeds much faster on {111}A compared to {111}B leading to significant differences in roughness. Further, we observe that the atomic scale structures on the {111}B facet is different from its bulk counterpart and that shell growth on this facet occurs via steps perpendicular to the ?112?B-type directions. PMID- 25710728 TI - The form and origin of orbital ordering in the electronic nematic phase of iron based superconductors. AB - We investigated the form of orbital ordering in the electronic nematic phase of iron-based superconductors by applying a group theoretical analysis on a realistic five-band model. We find the orbital order can be either of the inter orbital s-wave form or intra-orbital d-waveform. From the comparison with existing ARPES measurements of band splitting, we find the orbital ordering in the 122 system is dominated by an intra-orbital d-wave component, while that of the 111 system is dominated by an inter-orbital s-wave component. We find both forms of orbital order are strongly entangled with the nematicity in the spin correlation of the system.The condensation energy of the magnetic ordered phase is found to be significantly improved (by more than 20%) when the degeneracy between the (pi, 0) and (0, pi) ordering pattern is lifted by the orbital order. We argue there should be a large difference in both the scattering rate and the size of the possible pseudogap on the electron pocket around the X = (pi, 0) and Y = (0, pi) point in the electronic nematic phase. We propose this as a possible origin for the observed nematicity in resistivity measurements. PMID- 25710730 TI - A Head-to-Head Comparison of the Personality Inventory for DSM-5 (PID-5) With the Personality Diagnostic Questionnaire-4 (PDQ-4) in Predicting the General Level of Personality Pathology Among Community Dwelling Subjects. AB - In order to evaluate if measures of DSM-5 Alternative PD Model domains predicted interview-based scores of general personality pathology when compared to self report measures of DSM-IV Axis II/DSM-5 Section II PD criteria, 300 Italian community adults were administered the Iowa Personality Disorder Screen (IPDS) interview, the Personality Inventory for DSM-5 (PID-5), and the Personality Diagnostic Questionnaire-4+ (PDQ-4+). Multiple regression analyses showed that the five PID-5 domain scales collectively explained an adequate rate of the variance of the IPDS interview total score. This result was slightly lower than the amount of variance in the IPDS total score explained by the 10 PDQ-4+ scales. The PID-5 traits scales performed better than the PDQ-4+, although the difference was marginal. Hierarchical regression analyses revealed that the PID-5 domain and trait scales provided a moderate, but significant increase in the prediction of the general level of personality pathology above and beyond the PDQ-4+ scales. PMID- 25710729 TI - Accumulation of Domain-Specific Physical Inactivity and Presence of Hypertension in Brazilian Public Healthcare System. AB - BACKGROUND: Hypertension is one of the most common noncommunicable diseases worldwide, and physical inactivity is a risk factor predisposing to its occurrence and complications. However, it is still unclear the association between physical inactivity domains and hypertension, especially in public healthcare systems. Thus, this study aimed to investigate the association between physical inactivity aggregation in different domains and prevalence of hypertension among users of Brazilian public health system. METHODS: 963 participants composed the sample. Subjects were divided into quartiles groups according to 3 different domains of physical activity (occupational; physical exercises; and leisure-time and transportation). Hypertension was based on physician diagnosis. RESULTS: Physical inactivity in occupational domain was significantly associated with higher prevalence of hypertension (OR = 1.52 [1.05 to 2.21]). The same pattern occurred for physical inactivity in leisure-time (OR = 1.63 [1.11 to 2.39]) and aggregation of physical inactivity in 3 domains (OR = 2.46 [1.14 to 5.32]). However, the multivariate-adjusted model showed significant association between hypertension and physical inactivity in 3 domains (OR = 2.57 [1.14 to 5.79]). CONCLUSIONS: The results suggest an unequal prevalence of hypertension according to physical inactivity across different domains and increasing the promotion of physical activity in the healthcare system is needed. PMID- 25710731 TI - Using Negative Emotions to Trace the Experience of Borderline Personality Pathology: Interconnected Relationships Revealed in an Experience Sampling Study. AB - While emotional difficulties are highly implicated in borderline personality disorder (BPD), the dynamic relationships between emotions and BPD symptoms that occur in everyday life are unknown. The current paper examined the function of negative emotions as they relate to BPD symptoms in real time. Experience sampling methodology with 281 participants measured negative emotions and borderline symptoms, expressed as a spectrum of experiences, five times daily for two weeks. Overall, having a BDP diagnosis was associated with experiencing more negative emotions. Multilevel modeling supported positive concurrent relationships between negative emotions and BPD symptoms. Lagged models showed that even after 3 hours negative emotions and several symptoms continued to influence each other. Therefore, results indicated that negative emotions and BPD symptoms are intricately related; some evidenced long-lasting relationships. This research supports emotion-symptom contingencies within BPD and provides insight regarding the reactivity and functionality of negative emotions in borderline pathology. PMID- 25710732 TI - Impairments in Object Relations and Chronicity of Suicidal Behavior in Individuals With Borderline Personality Disorder. AB - While studies have demonstrated connections between impairments in object relations and self-destructive behaviors in individuals with borderline personality disorder (BPD), few have investigated whether these impairments relate to actual suicidal behaviors. The current study utilized the Social Cognition and Object Relations Scale-Global Method to investigate object relational functioning and suicidal behaviors in 131 residential treatment patients. Cognitive but not affective aspects of internalized representations predicted past suicidal behavior in BPD subjects; no relationships were found between quality of object representations and suicide in other-PD subjects. Implications of these findings for research, theory, and treatment of suicidal individuals are discussed. PMID- 25710733 TI - Attributional "Tunnel Vision" in Patients With Borderline Personality Disorder. AB - We aimed to examine the profile of interpersonal attributions in BPD. We hypothesized that patients show more mono-causal and internal attributions than healthy controls. A revised version of the Internal, Personal, Situational and Attributions Questionnaire was assessed in 30 BPD patients and 30 healthy controls. BPD patients and controls differed significantly in their attributional pattern. Patients displayed more mono-causal inferences, that is, they had difficulties considering alternative explanatory factors. For negative events, patients made more internal attributions compared to healthy controls. We concluded that mono-causal "trapped" thinking might contribute to (interpersonal) problems in BPD patients by fostering impulsive consequential behaviors, for example, harming one's self or others. A self-blaming tendency likely promotes depressive symptoms and low self-esteem. PMID- 25710734 TI - Thinking Structurally About Narcissism: An Examination of the Five-Factor Narcissism Inventory and Its Components. AB - The Five-Factor Narcissism Inventory (FFNI) is a self-report measure of the traits linked to grandiose and vulnerable narcissism, as well as narcissistic personality disorder (NPD), from a five-factor model perspective (FFM). In the current studies, the factor structure of the FFNI was explored and the results supported the extraction of three factors: Antagonism (e.g., Arrogance), Neuroticism (e.g., Need for Admiration), and Agentic Extraversion (e.g., Authoritativeness). In Study 2, the FFNI factors manifested convergent validity with their corresponding Big Five domains and diverging relations with measures of grandiose and vulnerable narcissism, NPD, and self-esteem. Ultimately, the FFNI factors help explicate the differences between various expressions of narcissism such that all are related to Antagonism but differ with regard to Neuroticism (relevant to vulnerable narcissism and NPD) and Agentic Extraversion (relevant to grandiose narcissism and NPD). The results also highlight the complex relation between self-esteem and the traits that comprise narcissism measures. PMID- 25710735 TI - Acoustic Emotional Processing in Patients With Borderline Personality Disorder: Hyper- or Hyporeactivity? AB - Earlier studies have demonstrated emotional overreactions to affective visual stimuli in patients with borderline personality disorder (BPD). However, contradictory findings regarding hyper- versus hyporeactivity have been reported for peripheral physiological measures. In order to extend previous results, the authors investigated emotional reactivity and long-term habituation in the acoustic modality. Twenty-two female BPD patients and 19 female nonclinical controls listened to emotionally negative, neutral, and positive sounds in two identical sessions. Heart rate, skin conductance, zygomaticus/corrugator muscle, and self-reported valence/arousal responses were measured. BPD patients showed weaker skin conductance responses to negative sounds than controls. The elevated zygomaticus activity in response to positive sounds observed in controls was absent in BPD patients, and BPD patients assigned lower valence ratings to positive sounds than controls. In Session 2, patients recognized fewer positive sounds than controls. Across both groups, physiological measures habituated between sessions. These findings add to growing evidence toward partial affective hyporeactivity in BPD. PMID- 25710736 TI - Triarchic Psychopathy Measure: Validity in Relation to Normal-Range Traits, Personality Pathology, and Psychological Adjustment. AB - The triarchic model of psychopathy replaces a syndromal view of this pathological personality condition with a tripartite trait-based conception, positing three distinct phenotypic dispositions as building blocks for what theorists have traditionally termed psychopathy. The Triarchic Psychopathy Measure (TriPM) offers an efficient means for measuring the three dimensions to facilitate research on the model's validity. We tested the reliability of the TriPM as well as its convergent and discriminant validity with respect to differing models of personality and other criterion variables reflecting social-emotional adjustment and mental health in an undergraduate participant sample (n = 120). The TriPM evidenced excellent internal consistencies, good test-retest reliability, and strong validity consistent with the triarchic model. We discuss the results with respect to prior research and offer suggestions for future research on the validity of the TriPM and the triarchic model. PMID- 25710737 TI - Transdiagnostic Treatment of Borderline Personality Disorder and Comorbid Disorders: A Clinical Replication Series. AB - Borderline personality disorder (BPD) is a severe, difficult-to-treat psychiatric condition that represents a large proportion of treatment-seeking individuals. BPD is characterized by high rates of co-occurrence with depressive and anxiety disorders, and recently articulated conceptualizations of this comorbidity suggest that these disorders may result from common temperamental vulnerabilities and functional maintenance factors. The Unified Protocol for the Transdiagnostic Treatment of Emotional Disorders (UP) was developed to address these shared features relevant across frequently co-occurring disorders. The purpose of the present study was to explore the preliminary efficacy of the UP for treatment of BPD with comorbid depressive and/or anxiety disorders in a clinical replication series consisting of five cases. For the majority of cases, the UP resulted in clinically significantly decreases in BPD, anxiety, and depressive symptoms, as well as increases in emotion regulation skills. PMID- 25710738 TI - Controlling the self-assembly of homochiral coordination architectures of Cu(II) by substitution in amino acid based ligands: synthesis, crystal structures and physicochemical properties. AB - Through the strategic design of ligands based on amino acids, structural diversity in chiral coordination architectures of CuII is demonstrated with six new examples: {[Cu(L-HTyrbenz)2].CH3OH.H2O}n (1), {[Cu(L-HSerbenz)2].3H2O}n (2), {[Cu(L-HTyrthio)2].H2O}n (3), [Cu(L-HTyr4-pyr)2(H2O)].2H2O (4), [Cu(L HSerthio)2(H2O)] (5), and [Cu(L-Phethio)2(H2O)].3H2O (6) [where L-H2Tyrbenz = L-N (benzyl)-tyrosine, L-H2Serbenz = L-N-(benzyl)-serine, L-H2Tyrthio = L-N-(methyl-2 thiophenyl)-tyrosine, L-H2Tyr4-pyr = L-N-(methyl-4-pyridyl)-tyrosine, L-H2Serthio = L-N-(methyl-2-thiophenyl)-serine and L-HPhethio = L-N-(methyl-2-thiophenyl) phenylalanine]. For these 1:2 metal-ligand complexes, the availability of a donor atom (either from the phenolic OH group or the carboxylate group of one of the ligands) for bridging between the CuII centers results in the formation of coordination polymers (1-3), while no such availability allows a water molecule to occupy the fifth site around the CuII center to generate hydrogen bonded supramolecular assemblies (4-6). In 1, a coordination polymer is formed via a syn anti bridging carboxylate, and the phenolic group has no role in its formation. To further emphasize this point, L-tyrosine in 1 is replaced with L-serine to form 2, in which an anti-anti bridging by the carboxylate group is observed. On the other hand, the formation of {[Cu(L-HTyrthio)2].H2O}n (3) results from the growth of a spiral polymer via the unique phenolic bridging with a distance of 10.806(9) A between two CuII centers. On changing from the L-H2Tyrbenz ligand to the L-H2Tyr4-pyr ligand (1vs.4), the strong hydrogen bonding of the pyridyl nitrogen with the phenolic group does not allow the latter to bind to CuII. Similarly, on changing from L-H2Tyrthio to L-H2Serthio (3vs.5), the length of the -CH2OH group in the latter is much less than the distance between the two CuII centers, therefore this group cannot occupy the fifth site and thus a water molecule is coordinated. This is further confirmed by reacting 5 with 2 eq. of L H2Tyrthio in methanol to form 3, while the reverse is not possible. All these compounds are characterized by a number of analytical methods, such as elemental analysis, FTIR, UV-Vis and circular dichroism spectroscopy, polarimetry, powder and single crystal X-ray diffraction and thermogravimetric analysis. Photoluminescence properties of all ligands containing the L-tyrosine group and their metal complexes (1, 3 and 4) are compared in solution at room temperature. PMID- 25710740 TI - Greater than the sum of their parts: characterizing plant microbiomes at the community-level. AB - Specific subsets of microbes are capable of assembly into plant-associated communities that influence the fitness of both the host and the microbes. While there is a large spectrum of plant phenotypes cause by microbes, the microbial community members benefit from living in protected and nutrient rich plant associated environments. Recent advances in '-omics' technologies have provided researchers with the ability to identify and assign functions to even unculturable microbes inhabiting both above-ground and below-ground plant tissues. Thus, we are beginning to unravel the molecular mechanisms of microbiome assembly and activities that contribute to overall plant health, not only for individuals, but also at the community-level. PMID- 25710739 TI - Discovery of imidazo[2,1-b]thiazole HCV NS4B inhibitors exhibiting synergistic effect with other direct-acting antiviral agents. AB - The design, synthesis, and SAR studies of novel inhibitors of HCV NS4B based on the imidazo[2,1-b]thiazole scaffold were described. Optimization of potency with respect to genotype 1b resulted in the discovery of two potent leads 26f (EC50 = 16 nM) and 28g (EC50 = 31 nM). The resistance profile studies revealed that 26f and 28g targeted HCV NS4B, more precisely the second amphipathic alpha helix of NS4B (4BAH2). Cross-resistance between our 4BAH2 inhibitors and other direct acting antiviral agents targeting NS3/4A, NS5A, and NS5B was not observed. For the first time, the synergism of a series of combinations based on 4BAH2 inhibitors was evaluated. The results demonstrated that our 4BAH2 inhibitor 26f was synergistic with NS3/4A inhibitor simeprevir, NS5A inhibitor daclatasvir, and NS5B inhibitor sofosbuvir, and it could also reduce the dose of these drugs at almost all effect levels. Our study suggested that favorable effects could be achieved by combining 4BAH2 inhibitors such as 26f with these approved drugs and that new all-oral antiviral combinations based on 4BAH2 inhibitors were worth developing to supplement or even replace current treatment regimens for curing HCV infection. PMID- 25710741 TI - Endoscopic-assisted navigation-guided removal of long-standing metallic foreign body near to the sphenoid. AB - PURPOSE: It is unusual to see a metallic foreign body having stayed at the temporal surface of the sphenoid greater wing for 2 decades. Because of the change of proximity anatomy and the difficult access to delicate structure, removal of this foreign body seemed challenging. The application of surgical navigation system combined with endoscopy from other directions could reduce damage to the surrounding tissues during the removal and lower the risk. RESULTS: Computed tomographic scan on the head indicated that finalposition was the temporal surface of the sphenoid greater wing posterior to the lateral orbital wall. To relieve the patient from sustaining pain caused by the metallic foreign body, surgical navigation system combined with endoscopy was adopted to remove the foreign body. Two different incisions were made to place the probe of the navigation and the endoscope respectively, in which way we could get a better view of the anatomic structures when reaching the metallic foreign body. The patient's problem was solved safely and efficiently. No sequela was observed. CONCLUSIONS: In case of complicated anatomic structure, surgical navigation system combined with endoscopy from another direction proved to be a practical and safe method to remove foreign bodies. PMID- 25710742 TI - Cholesterol granuloma of the orbit. AB - PURPOSE: The aim of this study was to present image findings, clinical and histopathologic features, and surgical management of orbital cholesterol granuloma (CG), a rare orbital entity. METHODS: Findings from 2 patients with orbitofrontal CG are presented along with a review of the literature on CG of the orbit. RESULTS: Both patients were 40-year-old men. The common symptoms of this condition in the present cases were proptosis and inferomedial displacement of the globe. Computed tomography scan in patient 1 revealed the presence of a cystic lesion without bone erosion in the superolateral orbital roof. Magnetic resonance imaging in patient 2 revealed a non-contrast-enhancing lesion with moderate signal intensity on T1-weighted images and high signal intensity on T2 weighted images. For both cases, anterior orbitotomy through subbrow incision by drainage and curettage resulted in a curative outcome. No lesion recurrence was observed by 5 years after surgery in 1 case and 3 years in the other. Histopathologic evaluation revealed numerous inflammatory cells, blood degradation products, and cholesterol clefts. The absence of epithelial elements led to the diagnosis of CG. CONCLUSIONS: Orbital CG is a rare expansive cystic condition and nearly always occurs in the lateral region of the superior orbital ridge within the frontal diploic space. This condition shows a marked preponderance in middle-aged males. The findings that computed tomography scan did not reveal bone erosion in patient 1, and magnetic resonance imaging examination showed moderate signal intensity, rather than high signal intensity, on T1-weighted images in patient 2 indicated that these represented unusual presentations. Surgical excision has a high success rate with a low incidence of recurrence. PMID- 25710743 TI - Application of a computer-aided navigation technique in surgery for recurrent malignant infratemporal fossa tumors. AB - BACKGROUND: Because of the complexity of the local anatomy, tumors in the infratemporal fossa present a great challenge to oral and maxillofacial surgeons. Recurrent malignant tumors in this area are particularly difficult and precarious to resect because scars from previous operations may dislocate some important structures. METHODS: From August 2010 to December 2013, all recurrent cases of malignant infratemporal fossa tumors at Peking University Stomatological Hospital were enrolled in this study. The patients were divided into 2 groups: the navigation group and the nonnavigation group, with different managements. The following factors were evaluated: operation time, bleeding volume, tumor size, surgical approach and complications, follow-up survey, and outcomes.In addition, survival analyses were performed for all patients. RESULTS: In total, 42 patients were investigated. The mean operation time for the navigation group was not significantly longer than that of the nonnavigation group (283.64 versus 252.10 min, respectively; P = 0.393); the group's mean intraoperative bleeding volumes were similar (536.36 versus 503.87 mL, respectively; P = 0.814). The surgical approach was determined and categorized as an inferior approach (transmandibular approach, with or without splitting of the mandible), anterior approach (transmaxillary approach), lateral approach (subtemporal-preauricular approach), or combined approach. The inferior approach was most frequently used in both groups (ie, 63.6% for the navigation group and 80.6% for the nonnavigation group). The tumors were completely resected in 4 patients from the navigation group and 24 patients from the nonnavigation group. Regarding complications in the navigation and nonnavigation groups, the incidence was not significantly different (27.2% versus 41.9%, respectively; P = 0.485). The 3-year survival for patients in the navigation group was 71.6% compared with 52.9% in the nonnavigation group, with no significant difference. In the survival analysis, no significant factor was determined. CONCLUSIONS: A computer-aided navigation technique has been successfully introduced to resect infratemporal fossa tumors and was successfully applied to the resection of recurrent malignant tumors. This new technique alone does not determine the outcome of patients with recurrent malignant infratemporal fossa tumors. Although some improvements are necessary, the visible navigation during surgery could increase the accuracy and safety of the operations and enhance surgeon confidence. PMID- 25710744 TI - Acupuncture: a potential modality for the treatment of auricular pruritus in Ramsay Hunt Syndrome with multiple cranial nerve lesions. AB - Auricular pruritus coexisted with multiple cranial nerve lesions in Ramsay Hunt syndrome has been rarely reported in the literature especially its treatment. However, auricular pruritus cannot be better improved along with the improvement of multiple cranial nerve lesions. We tried to solve the problem with acupuncture and got experience from it. The following 2 cases of Ramsay Hunt syndrome show a potential modality for the treatment of auricular pruritus with acupuncture. PMID- 25710745 TI - Immunoglobulin G4-related disease in the skull base mimicking nasopharyngeal carcinoma. AB - Immunoglobulin G4-related disease (IgG4-RD) is a rare clinical condition. Although it has been described in the head and neck region, skull base involvement is exceedingly uncommon. We present a clinical report of a patient with IgG4-RD of the skull base that mimicked nasopharyngeal cancer. This case highlights challenges in the clinical diagnosis of this rare condition. The diagnosis could be made only on histopathologic evaluation, which showed dense fibrosis with lymphoplasmacytic infiltration by IgG4-positive plasma cells. Serum IgG4 level was also elevated. Once IgG4-RD was confirmed, treatment with glucocorticoid yielded a good clinical outcome. PMID- 25710746 TI - Intracranial hemorrhage due to rupture of an anterior communicating artery aneurysm in a patient with pituitary adenoma. AB - The coexistence of pituitary adenoma (PA) and anterior communicating artery aneurysm is extremely rare, making the diagnosis difficult and the treatment challenging. Herein, we present a PA patient with intracranial hemorrhage due to rupture of an anterior communicating artery aneurysm. For the best diagnosis of intracranial aneurysm among PA patients, cranial magnetic resonance together with three-dimensional time-of-flight magnetic resonance angiography are strongly recommended. Previous treatment of the intracranial aneurysm is advisable and essential to avoid possible catastrophic bleeding during the transsphenoidal or microsurgical removal of PA. PMID- 25710747 TI - Treatment of severe hemifacial atrophy with dorsal thoracic adipofascial free flap and concurrent lipoinjection. AB - BACKGROUND: Parry-Romberg syndrome is an infrequent, acquired disorder characterized by progressive facial atrophy of the skin and soft tissue of the face and, in some cases, results in atrophy of muscles, cartilage, and the underlying bony structures. We investigated dorsal thoracic adipofascial free flap and concurrent lipoinjection as a reconstructive option for Parry-Romberg syndrome. METHODS: Thirteen patients with hemifacial atrophy caused by Parry Romberg syndrome underwent surgical correction after their deformitiesreached a stable stage. All patients were classified as having severe atrophy; they had either atrophy of the skin and subcutaneous tissues observable in all 3 sensory branches of the trigeminal nerve or bone involvement. In all cases, we applied dorsal thoracic adipofascial free flap and concurrent lipoinjection followed by secondary revision with debulking or lipoinjection. RESULTS: The adipofascial flaps survived after the initial operation in all 13 patients. After the second stage operation, 11 of 13 patients had achieved a natural appearance without any sagging or insufficient filling in the upper face. CONCLUSIONS: For patients with severe hemifacial atrophy with little or no bone involvement, dorsal thoracic adipofascial free flap and concurrent lipoinjection was a feasible and reliable reconstructive option. PMID- 25710748 TI - Surgical management of osteoradionecrosis of the jaws. AB - OBJECTIVE: The objective of this study is to evaluate our 10-year clinical experience in surgical management of patients with osteoradionecrosis (ORN) unresolved with conservative nonoperative treatment. PATIENTS AND METHODS: The medical records of 120 patients who had been surgically treated for ORN during a 10-year period (January 2003 to January 2013) were retrospectively reviewed. RESULTS: The most predilection ORN site was mandible (82.5%), followed by the maxilla (11.7%). ORN developed within initial 12 months in 39.2% and within the first 3 years in 68.3%. The median radiation dose was 68.1 Gy (range, 35-148 Gy), but 51 patients (42.5%) experienced ORN even though radiation doses were controlled under 60 Gy. Surgical trauma, as we believed, was the most important factor leading to this result. Among all the patients, 12 (10.0%) patients were found ineligible for operative treatment due to comorbid systematic diseases whereas none healed or improved. In terms of surgical management of the rest of the 108 patients, 90 (75.0%) patients underwent radical resection (4 patients unhealed), and 18 (15.0%) patients underwent mild surgical procedures such as sequestrectomy or debridement (1 patient unhealed). Of the 90 radical resection patients, 58 patients underwent radical resections and immediate microvascular flap reconstruction (19 bone flaps and 39 soft flaps), and 32 patients only experience radical resection (5 patients received second-stage reconstruction). According to follow-up information, 55 patients were free of disease. CONCLUSION: Though priority should be given to surgical treatment for the patient whose ORN does not respond to conservative nonoperative treatment, we may as well take into account more individualized regimens based on ORN severity. A hard lesson learned from our article is that the oral maxillofacial surgeon should minimize the trauma for jaws as possible as he can, especially to patients who need to receive postoperative radiotherapy. PMID- 25710749 TI - Nonaneurysmal subarachnoid hemorrhage secondary to transsphenoidal surgery for pituitary adenomas. AB - Nonaneurysmal subarachnoid hemorrhage (SAH) is a rare and severe complication of transsphenoidal surgery for pituitary adenoma(PA). To improve recognition of this complication, we reviewed and examined 4 patients with nonaneurysmal SAH secondary to transsphenoidal surgery for PAs. Furthermore, possible causes contributed to the SAH, and the attention on preventing the occurrence of SAH is reviewed and stressed. PMID- 25710750 TI - Clinical studies of the relationship between the complication of cervicofacial rhytidectomy postoperative nausea and vomiting and different rhytidectomy sites. AB - BACKGROUND: It was demonstrated that there are many complications following cervicofacial rhytidectomy, such as hematoma, edema, seromas, ecchymosis, nerve injury, hypertrophic scarring, contour irregularities, infection, nausea, vomiting, and so on. Accordingly, there is a lot of reports about the treatment of complications following rhytidectomy; nonetheless, we find that there is a trifle of research about the complication of postoperative nausea and vomiting. Thus, this study analyzes the cause of postoperative nausea and vomiting and the relationship between it and different sites. METHODS: From 2004 to 2008, 108 patients with a mean age of 52 years (range, 30-74 years) underwent cervicofacial rhytidectomy.The approach of operation is local subcutaneous undermining and superficial musculoaponeurotic system double-plication or suture. All data were recorded such as the time when postoperative nausea and vomiting occurred, the duration of the symptom, the frequency of nausea and vomiting, and the antiemetic medicine taken. All cases were grouped according to the different sites of operation. We divided the patients into group A1 and group A2 based on whether forehead rhytidectomy was performed. Meanwhile, we divided the patients into group B1 and group B2 based on whether cervical rhytidectomy was performed. The data of each group were recorded and statistically analyzed. RESULT: Among 108 patients, postoperative nausea and vomiting occurred in 55 patients. The duration of symptom was about 24 hours. The frequency of vomiting was 1 to 5 times. Besides, nausea and vomiting was characteristic of time limit and the tendency of termination. The ratios of vomiting between groups A1 and A2 were significantly different (P < 0.000 l). The ratios between groups B1 and B2 are of no significant difference (P > 0.05). CONCLUSIONS: The occurrence of postoperative nausea and vomiting is significantly related with forehead rhytidectomy; nonetheless, postoperative nausea and vomiting almost do not occur in the mid inferior face and cervical rhytidectomy. PMID- 25710751 TI - Solid-state dynamics in the closo-carboranes: a (11)B MAS NMR and molecular dynamics study. AB - This work explores the dynamic behavior of the three closo-carborane isomers (formula C2B10H12) using modern solid-state magic angle spinning (MAS) NMR techniques and relates the experimental measurements to theoretical results obtained using molecular dynamics simulations. At high temperatures and at B0 = 9.4 T, the (11)B MAS line widths are narrow (40-90 Hz) for the three isomers. The rotational correlation times (tauc) calculated by molecular dynamics are on the picosecond time scale, showing a quasi-isotropic rotation at these temperatures, typical for liquid systems. For all three isomers, the values of the (11)B spin lattice relaxation times (T1) show discontinuities as the temperature is decreased, confirming the phase changes reported in the literature. At low temperatures, the (11)B MAS spectra of all three isomers exhibit much broader lines. The simulations showed that the molecular reorientation was anisotropic around different symmetry axes for each isomer, and this was supported by the values of the reduced quadrupolar parameter PQ(eff) derived from "dynamic shift" measurements using (11)B MQMAS NMR spectroscopy. The behavior of PQ(eff) as a function of temperature for p-carborane suggests that molecular reorientation is about the C5 symmetry axis of the molecule at low temperatures, and this was supported by the molecular dynamics simulations. PMID- 25710752 TI - Enantioenrichment of a tungsten dearomatization agent utilizing chiral acids. AB - A method is described for the resolution of the versatile dearomatization reagent TpW(NO)(PMe3)(eta(2)-benzene), in which the 1,3-dimethoxybenzene (DMB) analogue of this complex is synthesized. In turn, the coordinated arene of TpW(NO)(PMe3)(DMB) is protonated with either D or L dibenzoyl tartaric acid (DBTH2) in a butanone/water or 2-pentanone/water solution. Sustained stirring of this mixture results in the selective precipitation of a single form of the diastereomeric salt [TpW(NO)(PMe3)(DMBH)](DBTH). After isolation, the salt can be redissolved, and the DMB ligand can be deprotonated and exchanged for benzene to produce the desired product TpW(NO)(PMe3)(eta(2)-benzene) in either its R or S form. The absolute configuration of the tungsten stereocenter in TpW(NO)(PMe3)(eta(2)-benzene) can be determined in either case by substituting the naturally occurring terpene (S)-beta-pinene for benzene and evaluating the 2D NMR spectrum of the corresponding beta-pinene complex. PMID- 25710755 TI - Desflurane and sevoflurane elimination kinetics and recovery quality in horses. AB - OBJECTIVE: To evaluate pharmacokinetics, recovery times, and recovery quality in horses anesthetized with 1.2 times the minimum alveolar concentration of sevoflurane or desflurane. ANIMALS: 6 healthy adult horses. PROCEDURES: Anesthesia was maintained with sevoflurane or desflurane for 2 hours at 1.2 times the minimum alveolar concentration. Horses recovered without assistance. During recovery, end-tidal gas samples were collected until horses spontaneously moved. Anesthetic concentrations were measured by use of gas chromatography. After a 1 week washout period, horses were anesthetized with the other inhalation agent. Video recordings of anesthetic recovery were evaluated for recovery quality on the basis of a visual analogue scale by investigators who were unaware of the anesthetic administered. Anesthetic washout curves were fit to a 2-compartment kinetic model with multivariate nonlinear regression. Normally distributed interval data were analyzed by means of paired Student t tests; ordinal or nonnormally distributed data were analyzed by means of Wilcoxon signed rank tests. RESULTS: Horses recovered from both anesthetics without major injuries. Results for subjective recovery evaluations did not differ between anesthetics. Area under the elimination curve was significantly smaller and time to standing recovery was significantly less for desflurane than for sevoflurane, although distribution and elimination constants did not differ significantly between anesthetics. CONCLUSIONS AND CLINICAL RELEVANCE: Differences in area under elimination the curve between anesthetics indicated more rapid clearance for desflurane than for sevoflurane in horses, as predicted by anesthetic blood solubility differences in this species. More rapid elimination kinetics was associated with faster recovery times, but no association with improved subjective recovery quality was detected. PMID- 25710756 TI - Effect of flunixin meglumine and firocoxib on ex vivo cyclooxygenase activity in horses undergoing elective surgery. AB - OBJECTIVE: To evaluate ex vivo cyclooxygenase (COX) inhibition and compare in vitro and ex vivo COX-1 inhibition by flunixin meglumine and firocoxib in horses. ANIMALS: 4 healthy horses for in vitro experiments and 12 healthy horses (6 males and 6 females; 5 Thoroughbreds, 5 Warmbloods, and 2 ponies) undergoing elective surgery for ex vivo experiments. PROCEDURES: 12 horses received flunixin meglumine (1.1 mg/kg, IV, q 12 h) or firocoxib (0.09 mg/kg, IV, q 24 h). Blood samples were collected before (baseline) and 2 and 24 hours after NSAID administration. Prostanoids (thromboxane B2, prostaglandin E2, and prostaglandin E metabolites) served as indicators of COX activity, and serum drug concentrations were measured by use of high-performance liquid chromatography. An in vitro coagulation-induced thromboxane B2 assay was used to calculate drug concentration-COX-1 inhibition curves. Effect of time and treatment on COX activity was determined. Agreement between in vitro and ex vivo measurement of COX activity was assessed with Bland-Altman analysis. RESULTS: At 2 and 24 hours after NSAID administration, COX-1 activity was reduced, compared with baseline activity, for the flunixin meglumine group only and relative COX-1 activity was significantly greater for the firocoxib group, compared with that for the flunixin meglumine group. There was no significant change in COX-2 activity after surgery for either group. Bland-Altman analysis revealed poor agreement between in vitro and ex vivo measurement of COX-1 activity. CONCLUSIONS AND CLINICAL RELEVANCE: Compared with flunixin meglumine, firocoxib had COX-1-sparing effects ex vivo in equine patients that underwent elective surgery. PMID- 25710757 TI - Effect of gantacurium on evoked laryngospasm and duration of apnea in anesthetized healthy cats. AB - OBJECTIVE: To evaluate whether the ultrashort-acting neuromuscular blocking agent gantacurium can be used to blunt evoked laryngospasm in anesthetized cats and to determine the duration of apnea without hemoglobin desaturation. ANIMALS: 8 healthy adult domestic shorthair cats. PROCEDURES: Each cat was anesthetized with dexmedetomidine and propofol, instrumented with a laryngeal mask, and allowed to breathe spontaneously (fraction of inspired oxygen, 1.0). The larynx was stimulated by spraying sterile water (0.3 mL) at the rima glottidis; a fiberscope placed in the laryngeal mask airway was used to detect evoked laryngospasm. Laryngeal stimulation was performed at baseline; after IV administration of gantacurium at doses of 0.1, 0.3, and 0.5 mg/kg; and after the effects of the last dose of gantacurium had terminated. Duration of apnea and hemoglobin oxygen saturation (measured by means of pulse oximetry) after each laryngeal stimulation were recorded. Neuromuscular block was monitored throughout the experiment by means of acceleromyography on a pelvic limb. RESULTS: Laryngospasm was elicited in all cats at baseline, after administration of 0.1mg of gantacurium/kg, and after the effects of the last dose of gantacurium had terminated. The 0.3 and 0.5 mg/kg doses of gantacurium abolished laryngospasm in 3 and 8 cats, respectively, and induced complete neuromuscular block measured at the pelvic limb; the mean +/ SE duration of apnea was 2 +/- 1 minutes and 3 +/- 1.5 minutes, respectively. Hemoglobin oxygen saturation did not decrease significantly after administration of any dose of gantacurium. CONCLUSIONS AND CLINICAL RELEVANCE: Gantacurium may reduce tracheal intubation-associated morbidity in cats breathing oxygen. PMID- 25710758 TI - Evaluation of hepatic contrast enhancement with a hepatocyte-specific magnetic resonance imaging contrast agent (gadoxetic acid) in healthy dogs. AB - OBJECTIVE: To determine, by means of MRI, the time to maximal contrast enhancement in T1-weighted images following IV administration of gadoxetic acid in healthy dogs and assess the impact of gadoxetic acid on the signal intensity of T2-weighted images. ANIMALS: 7 healthy dogs. PROCEDURES: No hepatic abnormalities were detected during ultrasonographic examination. Each dog was anesthetized and positioned in dorsal recumbency for MRI. Transverse T1- and T2 weighted images of the liver were acquired prior to and following (at 5-minute intervals) IV injection of 0.1 mL of gadoxetic acid/kg. Signal intensity of the liver parenchyma was measured in 3 regions of interest in the T1- and T2-weighted images before and at various times point after contrast agent administration. Time versus signal-to-noise ratio curves were plotted to determine time to maximal contrast enhancement and contrast agent-related changes in signal intensity in T2-weighted images. RESULTS: Analysis of T1-weighted images revealed that mean +/- SD time to maximal enhancement after gadoxetic acid injection was 10.5 +/- 3.99 minutes. Signal intensity of T2-weighted images was not significantly affected by gadoxetic acid administration. No injection-related adverse effects were observed in any dog. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that gadoxetic acid can be used for hepatic MRI in healthy dogs and the resultant hepatic enhancement patterns are similar to those described for humans. Maximal contrast enhancement occurred between 10 and 15 minutes after contrast agent injection; thus, T2-weighted images may be obtained in the interval between injection and maximal enhancement for a more time-efficient clinical protocol. PMID- 25710759 TI - Efficacy of polyethylene glycol-conjugated bovine granulocyte colony-stimulating factor for reducing the incidence of naturally occurring clinical mastitis in periparturient dairy cows and heifers. AB - OBJECTIVE: To evaluate effects of various doses of polyethylene glycol (PEG) conjugated bovine granulocyte colony-stimulating factor (bG-CSF) on the incidence of naturally occurring clinical mastitis in periparturient dairy cattle. ANIMALS: 211 periparturient Holstein cows and heifers. PROCEDURES: Approximately 7 days before the anticipated date of parturition (day of parturition = day 0), healthy cattle received SC injections of sterile saline (0.9% NaCl) solution (control treatment) or PEG-bG-CSF at 5, 10, or 20 MUg/kg. Cattle were commingled and housed in a pen with dirt flooring, which was kept wet to maximize the incidence of naturally occurring clinical mastitis. Within 24 hours after parturition, each animal again received the assigned treatment. Mammary glands and milk were visually scored for abnormalities twice daily for 28 days after parturition. Milk samples were aseptically collected from mammary glands with an abnormal appearance or abnormal milk and submitted for microbial culture. Daily milk production was recorded, and milk composition was assessed on days 3, 5, 7, and 10. RESULTS: Cattle treated with PEG-bG-CSF at 10 and 20 MUg/kg had significantly fewer cases of clinical mastitis (9/54 and 5/53, respectively), compared with control cattle (18/53). Administration of PEG -bG-CSF did not significantly affect daily milk production or milk composition. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that PEG-bG-CSF was effective for reducing the incidence of naturally occurring clinical mastitis in periparturient dairy cattle. Further investigations of the use of PEG-bG-CSF as a potential preventative intervention should be conducted. PMID- 25710760 TI - Association of bovine respiratory disease or vaccination with serologic response in dairy heifer calves up to three months of age. AB - OBJECTIVE: To investigate the association of bovine respiratory disease (BRD) or vaccination with serologic response in calves. ANIMALS: 94 Holstein calves. PROCEDURES: To assess the association between BRD and antibody titers, 38 calves < 3 months old that were treated for BRD were matched with 38 untreated calves. To investigate the effect of vaccination on antibody titers, 24 calves were randomly assigned to be vaccinated against bovine respiratory syncytial virus (BRSV), bovine viral diarrhea virus types 1 and 2, bovine herpesvirus type 1 (BHV1), and parainfluenza virus type 3 at 2 weeks of age (n = 6), 5 weeks of age (6), and both 2 and 5 weeks of age (6) or were assigned to be unvaccinated controls (6). Blood samples were obtained at I, 2, 5, and 12 weeks for determination of serum neutralization antibody titers against the vaccine viruses, bovine coronavirus, and Mannheimia haemolytica. Antibody rates of decay were calculated. RESULTS: Calves with initial antibody titers against BRSV < 1:64 that were treated for BRD had a slower rate of anti-BRSV antibody decay than did similar calves that were not treated for BRD. Calves with high initial antibody titers against BRSV and BHV1 had lower odds of BRD than did calves with low initial antibody titers against those 2 pathogens. Vaccination at 2 or 5 weeks of age had no effect on the rate of antibody decay. CONCLUSIONS AND CLINICAL RELEVANCE: Clinical BRD and the serologic response of dairy calves were associated with initial antibody titers against BRSV and BHV1. Serologic or clinical responses to viral exposure may differ in calves with low passive immunity. PMID- 25710761 TI - Effect of exercise and environmental terrain on development of the digital cushion and bony structures of the bovine foot. AB - OBJECTIVE: To determine whether exercise on alternative terrain affects the development of the digital cushion and bony structures of the bovine foot. ANIMALS: 20 weaned bull calves. PROCEDURES: Two-month-old calves were randomly allocated to an exercise or control group. For 4 months, the control group was maintained in grass paddocks, and the exercise group was maintained in a 0.8-km lane with a mixed terrain of dirt, stones (0.32- to 0.95-cm pea gravel and 5-cm crusher run), and grass. Water and food for the exercise group were located at opposite ends of the lane; calves were fed twice daily, which ensured they walked 3.2 km/d. Pedometers were applied to all calves to measure distance traveled. All calves were slaughtered at 6 months of age. The right forefeet and hind feet were harvested for MRI and CT evaluation. RESULTS: Control calves walked a mean of 1.1 km daily, whereas the exercised calves walked a mean of 3.2 km daily. Mean digital cushion volume and surface area were 25,335 mm(3) and 15,647 mm(2), respectively, for the exercised calves and 17,026 mm(3) and 12,745 mm(2), respectively, for the control calves. When weight was controlled, mean digital cushion volume and surface area for the exercise group were increased by 37.10% and 18.25%, respectively, from those for the control group. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that exercise on alternative terrain increased the volume and surface area of the digital cushion of the feet of dairy calves, which should make them less susceptible to lameness. PMID- 25710762 TI - Systemic absorption and adverse ocular and systemic effects after topical ophthalmic administration of 0.1% diclofenac to healthy cats. AB - OBJECTIVE: To quantify plasma concentrations and determine adverse ocular, renal, or hepatic effects associated with repeated topical ophthalmic application of 0.1% diclofenac to healthy cats. ANIMALS: 8 healthy sexually intact male cats. PROCEDURES: A randomized, placebo-controlled crossover study was conducted. A topical formulation of 0.1% diclofenac was administered 4 times/d for 7 days to 4 cats, and artificial tear (control) solution was administered to the other 4 cats. After a 12-day washout period, cats received the other treatment. Ophthalmic examinations were performed daily. Plasma samples were obtained on days 1 and 7 for pharmacokinetic analysis. A CBC, serum biochemical analysis, urinalysis, determination of urine protein-to-creatinine ratio, and determination of glomerular filtration rate were performed before the start of the study and after each 7-day treatment period. RESULTS: Mild conjunctival hyperemia was the only adverse ocular effect detected. Maximal drug concentration and area under the curve were significantly higher on day 7 than on day 1. Diclofenac-treated cats had a significantly lower glomerular filtration rate than did control treated cats after the second but not after the first treatment period, presumably associated with iatrogenic hypovolemia. CONCLUSIONS AND CLINICAL RELEVANCE: Topical ophthalmic administration of 0.1% diclofenac was well tolerated in healthy cats, with only mild signs of ocular irritation. Detectable systemic concentrations of diclofenac were achieved with accumulation over 7 days. Systemic absorption of diclofenac may be associated with reduced glomerular filtration rate, particularly in volume-contracted animals. Topical ophthalmic 0.1% diclofenac should be used with caution in volume-contracted or systemically ill cats. PMID- 25710763 TI - Comparison of directly measured arterial blood pressure at various anatomic locations in anesthetized dogs. AB - OBJECTIVE: To determine whether directly measured arterial blood pressure differs among anatomic locations and whether arterial blood pressure is influenced by body position. ANIMALS: 33 client-owned dogs undergoing anesthesia. PROCEDURES: Dogs undergoing anesthetic procedures had 20-gauge catheters placed in both the superficial palmar arch and the contralateral dorsal pedal artery (group 1 [n = 20]) or the superficial palmar arch and median sacral artery (group 2 [13]). Dogs were positioned in dorsal recumbency, and mean arterial blood pressure (MAP), systolic arterial blood pressure (SAP), and diastolic arterial blood pressure (DAP) were recorded for both arteries 4 times (2-minute interval between successive measurements). Dogs were positioned in right lateral recumbency, and blood pressure measurements were repeated. RESULTS: Differences were detected between pressures measured at the 2 arterial sites in both groups. This was especially true for SAP measurements in group 1, in which hind limb measurements were a mean of 16.12 mm Hg higher than carpus measurements when dogs were in dorsal recumbency and 14.70 mm Hg higher than carpus measurements when dogs were in lateral recumbency. Also, there was significant dispersion about the mean for all SAP, DAP, and MAP measurements. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that arterial blood pressures may be dependent on anatomic location and body position. Because this may affect outcomes of studies conducted to validate indirect blood pressure measurement systems, care must be used when developing future studies or interpreting previous results. PMID- 25710764 TI - Comparison of the protective effect of a commercially available western diamondback rattlesnake toxoid vaccine for dogs against envenomation of mice with western diamondback rattlesnake (Crotalus atrox), northern Pacific rattlesnake (Crotalus oreganus oreganus), and southern Pacific rattlesnake (Crotalus oreganus helleri) venom. AB - OBJECTIVE: To evaluate effectiveness of a commercially available toxoid manufactured from western diamondback (WD) rattlesnake (Crotalus atrox) venom against envenomation of mice with WD, northern Pacific (NP) rattlesnake (Crotalus oreganus oreganus), and southern Pacific (SP) rattlesnake (Crotalus oreganus helleri) venom. ANIMALS: 90 specific pathogen-free female mice. PROCEDURES: Mice were allocated into 3 cohorts (30 mice/cohort). Mice received SC injections of C atrox toxoid (CAT) vaccine (n = 15/group) or adjuvant (15/group) at day 0 and again at 4 weeks. At 8 weeks, mice were challenge-exposed with 1 of 3 venoms. Survival until 48 hours was evaluated by use of log-rank analysis of survival curves and the z test for proportions. RESULTS: 6 of 15 WD-challenged CAT vaccinated mice, 3 of 15 NP-challenged CAT-vaccinated mice, and 0 of 15 SP challenged CAT-vaccinated mice survived until 48 hours. All adjuvant-only vaccinates survived <= 21 hours. Mean survival time of CAT vaccinates was longer than that of adjuvant-only vaccinates for all venoms (1,311 vs 368 minutes for WD, 842 vs 284 minutes for NP, and 697 vs 585 minutes for SP). Results of the z test indicated a significantly increased survival rate for vaccinates exposed to WD rattlesnake venom but not for vaccinates exposed to NP or SP rattlesnake venom. Log-rank analysis revealed a significant difference between survival curves of vaccinated versus unvaccinated mice exposed to NP but not WD or SP venom. CONCLUSIONS AND CLINICAL RELEVANCE: CAT vaccination improved survival rate and survival time after challenge exposure with WD rattlesnake venom and may offer limited protection against NP rattlesnake venom but did not provide significant cross-protection against SP rattlesnake venom. PMID- 25710766 TI - Confining crack propagation in defective graphene. AB - Crack propagation in graphene is essential to understand mechanical failure in 2D materials. We report a systematic study of crack propagation in graphene as a function of defect content. Nanoindentations and subsequent images of graphene membranes with controlled induced defects show that while tears in pristine graphene span microns length, crack propagation is strongly reduced in the presence of defects. Accordingly, graphene oxide exhibits minor crack propagation. Our work suggests controlled defect creation as an approach to avoid catastrophic failure in graphene. PMID- 25710765 TI - Traditional Chinese medicine for neck pain and low back pain: a systematic review and meta-analysis. AB - BACKGROUND: Neck pain (NP) and low back pain (LBP) are common symptoms bothering people in daily life. Traditional Chinese medicine (TCM) has been used to treat various symptoms and diseases in China and has been demonstrated to be effective. The objective of the present study was to review and analyze the existing data about pain and disability in TCM treatments for NP and LBP. METHODS: Studies were identified by a comprehensive search of databases, such as MEDLINE, EMBASE, and Cochrane Library, up to September 1, 2013. A meta-analysis was performed to evaluate the efficacy and safety of TCM in managing NP and LBP. RESULTS: Seventy five randomized controlled trials (n = 11077) were included. Almost all of the studies investigated individuals experiencing chronic NP (CNP) or chronic LBP (CLBP). We found moderate evidence that acupuncture was more effective than sham acupuncture in reducing pain immediately post-treatment for CNP (visual analogue scale (VAS) 10 cm, mean difference (MD) = -0.58 (-0.94, -0.22), 95% confidence interval, p = 0.01), CLBP (standardized mean difference = -0.47 (-0.77, -0.17), p = 0.003), and acute LBP (VAS 10 cm, MD = -0.99 (-1.24, -0.73), p< 0.001). Cupping could be more effective than waitlist in VAS (100 mm) (MD = -19.10 (-27.61, 10.58), p < 0. 001) for CNP or medications (e.g. NSAID) for CLBP (MD = -5.4 ( 8.9, -0.19), p = 0.003). No serious or life-threatening adverse effects were found. CONCLUSIONS: Acupuncture, acupressure, and cupping could be efficacious in treating the pain and disability associated with CNP or CLBP in the immediate term. Gua sha, tai chi, qigong, and Chinese manipulation showed fair effects, but we were unable to draw any definite conclusions, and further research is still needed. The efficacy of tuina and moxibustion is unknown because no direct evidence was obtained. These TCM modalities are relatively safe. PMID- 25710767 TI - Electrospun poly (3-hydroxybutyrate-co-3-hydroxyvalerate)/hydroxyapatite scaffold with unrestricted somatic stem cells for bone regeneration. AB - The combination of scaffolds and cells can be useful in tissue reconstruction. In this study, nanofibrous poly (3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV)/nanohydroxyapatite (nano-HAp) scaffolds, filled with unrestricted somatic stem cells (USSCs), were used for healing calvarial bone in rat model. The healing effects of these scaffolds, with and without stem cells, in bone regeneration were investigated by computed tomography (CT) analysis and pathology assays after 28 days of grafting. The results of CT analysis showed that bone regeneration on the scaffolds, and the amounts of regenerated new bone for polymer/nano-HAp scaffold with USSC, was significantly greater than the scaffold without cell and untreated control samples. Therefore, the combination of scaffold especially with USSC could be considered as a useful method for bone regeneration. PMID- 25710768 TI - Anti-xa directed protocol for anticoagulation management in children supported with extracorporeal membrane oxygenation. AB - The optimum heparin monitoring method during extracorporeal membrane oxygenation (ECMO) is unknown. We report a protocol utilizing only anti-factor Xa (anti-Xa) to manage anticoagulation in 22 consecutive ECMO patients. Anti-Xa was monitored with heparin titration every hour until goal 0.4-0.8 IU/ml. Once therapeutic, monitoring was progressively spaced up to every 6 hours. Patients received frequent antithrombin III (ATIII). Extracorporeal membrane oxygenation indications were as follows: 13 cardiorespiratory failures, eight extracorporeal cardiopulmonary resuscitations (ECPRs), and one pulmonary hypertension. Median weight was 4 kg, age 12.5 days, and ECMO duration 88 hours. Survival was 50%. Mean heparin dose was 38 +/- 11 unit/kg/hr. Eight patients received no heparin for median 9 hours because of postoperative bleeding. Compared with prior activated clotting time (ACT) protocol, there were 20 fewer blood draws per day to manage anticoagulation, p < 0.001. Only 9% of the anti-Xa levels were outside therapeutic range versus 22% using ACT, p < 0.01. Six patients had bleeding complications, and seven had oxygenator change-out. Change-out was associated with blood product administration and bleeding but not with heparin-free period (p = 0.39). Survival to discharge was higher among those who did not require circuit/oxygenator change-outs, 4/7 versus 7/7 (p < 0.01). Anti-factor Xa-based ECMO heparin management protocol is feasible, decreases blood sampling and heparin infusion adjustments, and does not appear to increase complications. PMID- 25710769 TI - False-positive hepatitis C testing in long-term LVAD support. PMID- 25710770 TI - Kinetics of plasma refilling during hemodialysis sessions with different initial fluid status. AB - Removal of fluid excess from the plasma volume by ultrafiltration during hemodialysis (HD) is balanced by plasma refilling from the interstitium, driven mainly by the increase in plasma oncotic pressure. We calculated the plasma refilling coefficient (Kr, a parameter expressing the ratio of refilling rate to the increase in oncotic pressure) for nine patients, each undergoing two HD sessions differing by pretreatment fluid status and session time (shorter session, SH, 3.5 h, and longer session, LH, 4.5h). Relative blood volume change was measured online, and solute concentrations were measured regularly during the sessions. The volume of body compartments was measured by bioimpedance. The patients were more volume expanded before LH session (higher initial body mass and total body water). Oncotic pressure was similar for both sessions. The refilling rate, despite higher fluid overload in the LH sessions, was similar for both sessions. The final Kr values stabilized on similar levels (SH: 136.6 +/- 55.6 ml/mm Hg/h and LH: 150.7 +/- 73.6 ml/mm Hg/h) at similar times, notwithstanding the difference in initial fluid overload between the two groups, suggesting that Kr at dry weight is relatively insensitive to the initial fluid status of the patient. PMID- 25710771 TI - Inhaled Nitric Oxide Augments Left Ventricular Assist Device Capacity by Ameliorating Secondary Right Ventricular Failure. AB - Clinical right ventricular (RV) impairment can occur with left ventricular assist device (LVAD) use, thereby compromising the therapeutic effectiveness. The underlying mechanism of this RV failure may be related to induced abnormalities of septal wall motion, RV distension and ischemia, decreased LV filling, and aberrations of LVAD flow. Inhaled nitric oxide (NO), a potent pulmonary vasodilator, may reduce RV afterload, and thereby increase LV filling, LVAD flow, and cardiac output (CO). To investigate the mechanisms associated with LVAD induced RV dysfunction and its treatment, we created a swine model of hypoxia induced pulmonary hypertension and acute LVAD-induced RV failure and assessed the physiological effects of NO. Increased LVAD speed resulted in linear increases in LVAD flow until pulse pressure narrowed. Higher speeds induced flow instability, LV collapse, a precipitous fall of both LVAD flow and CO. Nitric oxide (20 ppm) treatment significantly increased the maximal achievable LVAD speed, LVAD flow, CO, and LV diameter. Nitric oxide resulted in decreased pulmonary vascular resistance and RV distension, increased RV ejection, promoted LV filling and improved LVAD performance. Inhaled NO may thus have broad utility for the management of biventricular disease managed by LVAD implantation through the effects of NO on LV and RV wall dynamics. PMID- 25710772 TI - A new Bayesian network-based risk stratification model for prediction of short term and long-term LVAD mortality. AB - Existing risk assessment tools for patient selection for left ventricular assist devices (LVADs) such as the Destination Therapy Risk Score and HeartMate II Risk Score (HMRS) have limited predictive ability. This study aims to overcome the limitations of traditional statistical methods by performing the first application of Bayesian analysis to the comprehensive Interagency Registry for Mechanically Assisted Circulatory Support dataset and comparing it to HMRS. We retrospectively analyzed 8,050 continuous flow LVAD patients and 226 preimplant variables. We then derived Bayesian models for mortality at each of five time end points postimplant (30 days, 90 days, 6 month, 1 year, and 2 years), achieving accuracies of 95%, 90%, 90%, 83%, and 78%, Kappa values of 0.43, 0.37, 0.37, 0.45, and 0.43, and area under the receiver operator characteristic (ROC) of 91%, 82%, 82%, 80%, and 81%, respectively. This was in comparison to the HMRS with an ROC of 57% and 60% at 90 days and 1 year, respectively. Preimplant interventions, such as dialysis, ECMO, and ventilators were major contributing risk markers. Bayesian models have the ability to reliably represent the complex causal relations of multiple variables on clinical outcomes. Their potential to develop a reliable risk stratification tool for use in clinical decision making on LVAD patients encourages further investigation. PMID- 25710773 TI - Inflammatory Response to Sorbent Hemodialysis. AB - Inflammation is common and associated with morbidity and mortality in hemodialysis (HD) patients. Exposure to endotoxin contained in the dialysate may trigger inflammation. Dialysate volume is substantially reduced in sorbent HD compared with standard single-pass dialysis. In this prospective study (Clinicaltrials.gov, number: NCT00788905), we compared the inflammatory response to single-pass and sorbent HD. Patients receiving single-pass HD were studied during 1 week of sorbent HD (Allient system; Renal Solutions, Warrendale, PA) and 1 week of single-pass HD. Patients were dialyzed using high-flux polysulfone dialyzers. Midweek pre- and post-HD serum levels of high-sensitivity C-reactive protein, interleukin (IL)-1beta, IL-6, IL-10, interferon gamma, tumor necrosis factor alpha (TNF-alpha), and eotaxin were determined and their intradialytic change corrected for hemoconcentration during single-pass HD and sorbent HD compared by paired t-test. We enrolled 18 patients, nine completed the study. Although TNF-alpha decreased during both single-pass and sorbent HD (p < 0.001), none of the other biomarkers changed significantly during HD. We observed no difference between single-pass and sorbent HD. For the markers investigated in this study, there was no difference in the acute intradialytic inflammatory response to single-pass or sorbent HD. PMID- 25710774 TI - Left Ventricular Assist Device-Associated Carbon Monoxide and Iron-Enhanced Hypercoagulation: Impact of Concurrent Disease. AB - Left ventricular assist device (LVAD) therapy is associated with thrombophilia despite anticoagulation. Of interest, LVAD patients have increased carboxyhemoglobin, a measure of upregulated heme oxygenase (Hmox) activity that releases carbon monoxide (CO) and iron. Given that CO and iron enhance plasmatic coagulation, we determined if LVAD patients had hypercoagulability and decreased fibrinolytic vulnerability with measurable CO and iron-mediated effects. Blood samples were obtained a month or more after implantation of the LVAD. Thrombelastographic methods to assess coagulation kinetics, fibrinolytic kinetics, formation of carboxyhemefibrinogen, and iron-mediated enhancement of clot growth were utilized. Coagulation and fibrinolytic parameter normal individual (n = 30) plasma values were determined. Sixteen LVAD patients were studied. CO and iron enhancement of coagulation were observed in the majority of LVAD patients, contributing to hypercoagulation. However, most patients demonstrated abnormally increased rates of clot lysis. Critically, hemolysis as assessed by circulating lactate dehydrogenase activity was small in this cohort, and only four patients without comorbid states (e.g., obesity, diabetes, sleep apnea) were hypercoagulable with evidence of Hmox upregulation. However, seven patients with comorbidities were hypercoagulable with Hmox upregulation. Future investigation of CO and iron-related thrombophilia and comorbid disease is warranted to define its role in LVAD-related thrombosis. PMID- 25710775 TI - Transhepatic Cannulation for Venovenous Extracorporeal Membrane Oxygenation. AB - Limited vascular access because of vessel injury or thrombosis may complicate care of children with congenital heart disease. Although transhepatic venous access for cardiac catheterization and central venous catheter placement has been used in children, its use for extracorporeal membrane oxygenation (ECMO) has not been described. We report successful use of transhepatic cannulation for venovenous ECMO to support a 15 month-old child with bidirectional Glenn anatomy and intractable hypoxemia. PMID- 25710776 TI - Assessment of Topographical Disorientation: First Application of New Tests and Case Report. AB - A right posterior cerebral lesion can lead to an inability to orient and can consequently interfere with daily-life autonomy. Despite the wide literature about navigation abilities, it is still difficult to assess topographical disorientation (TD) because of the interindividual specificity of spatial knowledge and the diversity of symptoms. We describe here a set of new tests evaluating spatial cognition in a patient with TD presenting difficulties in navigating inside the hospital and in his hometown more than 3 years after his diffuse ischemic right Sylvian stroke. These tests assess mental imagery (global and specifically spatial imagery), perspective change, and the ability to recall spatial relations in familiar environments. The evaluation revealed difficulties with all the tests (but not in global mental imagery) in this patient when compared with matched controls. Hence, these new tests seem specific and affected by a right hemispheric lesion. The observed deficits can explain, at least partially, the spatial orientation difficulties experienced by this patient in the hospital and familiar environments. In conclusion, these tests could be appropriate tools for the assessment of visuospatial and spatial processes. PMID- 25710778 TI - Psychophysical Map Stability in Bilateral Sequential Cochlear Implantation: Comparing Current Audiology Methods to a New Statistical Definition. AB - OBJECTIVES: The purpose of this study was to establish a statistical definition for stability in cochlear implant maps. Once defined, this study aimed to compare the duration taken to achieve a stable map in first and second implants in patients who underwent sequential bilateral cochlear implantation. This article also sought to evaluate a number of factors that potentially affect map stability. DESIGN: A retrospective cohort study of 33 patients with sensorineural hearing loss who received sequential bilateral cochlear implantation (Cochlear, Sydney, Australia), performed by the senior author. Psychophysical parameters of hearing threshold scores, comfort scores, and the dynamic range were measured for the apical, medial, and basal portions of the cochlear implant electrode at a range of intervals postimplantation. Stability was defined statistically as a less than 10% difference in threshold, comfort, and dynamic range scores over three consecutive mapping sessions. A senior cochlear implant audiologist, blinded to implant order and the statistical results, separately analyzed these psychophysical map parameters using current assessment methods. First and second implants were compared for duration to achieve stability, age, gender, the duration of deafness, etiology of deafness, time between the insertion of the first and second implant, and the presence or absence of preoperative hearing aids were evaluated and its relationship to stability. Statistical analysis included performing a two-tailed Student's t tests and least squares regression analysis, with a statistical significance set at p <= 0.05. RESULTS: There was a significant positive correlation between the devised statistical definition and the current audiology methods for assessing stability, with a Pearson correlation coefficient r = 0.36 and a least squares regression slope (b) of 0.41, df(58), 95% confidence interval 0.07 to 0.55 (p = 0.004). The average duration from device switch on to stability in the first implant was 87 days using current audiology methods and 81 days using the statistical definition, with no statistically significant difference between assessment methods (p = 0.2). The duration to achieve stability in the second implant was 51 days using current audiology methods and 60 days using the statistical method, and again no difference between the two assessment methods (p = 0.13). There was a significant reduction in the time to achieve stability in second implants for both audiology and statistical methods (p < 0.001 and p = 0.02, respectively). There was a difference in duration to achieve stability based on electrode array region, with basal portions taking longer to stabilize than apical in the first implant (p = 0.02) and both apical and medial segments in second implants (p = 0.004 and p = 0.01, respectively). No factors that were evaluated in this study, including gender, age, etiology of deafness, duration of deafness, time between implant insertion, and the preoperative hearing aid status, were correlated with stability duration in either stability assessment method. CONCLUSIONS: Our statistical definition can accurately predict cochlear implant map stability when compared with current audiology practices. Cochlear implants that are implanted second tend to stabilize sooner than the first, which has a significant impact on counseling before a second implant. No factors evaluated affected the duration required to achieve stability in this study. PMID- 25710777 TI - Molecular evolution and phylogenetic analysis of eight COL superfamily genes in group I related to photoperiodic regulation of flowering time in wild and domesticated cotton (Gossypium) species. AB - Flowering time is an important ecological trait that determines the transition from vegetative to reproductive growth. Flowering time in cotton is controlled by short-day photoperiods, with strict photoperiod sensitivity. As the CO-FT (CONSTANS-FLOWER LOCUS T) module regulates photoperiodic flowering in several plants, we selected eight CONSTANS genes (COL) in group I to detect their expression patterns in long-day and short-day conditions. Further, we individually cloned and sequenced their homologs from 25 different cotton accessions and one outgroup. Finally, we studied their structures, phylogenetic relationship, and molecular evolution in both coding region and three characteristic domains. All the eight COLs in group I show diurnal expression. In the orthologous and homeologous loci, each gene structure in different cotton species is highly conserved, while length variation has occurred due to insertions/deletions in intron and/or exon regions. Six genes, COL2 to COL5, COL7 and COL8, exhibit higher nucleotide diversity in the D-subgenome than in the A subgenome. The Ks values of 98.37% in all allotetraploid cotton species examined were higher in the A-D and At-Dt comparison than in the A-At and D-Dt comparisons, and the Pearson's correlation coefficient (r) of Ks between A vs. D and At vs. Dt also showed positive, high correlations, with a correlation coefficient of at least 0.797. The nucleotide polymorphism in wild species is significantly higher compared to G. hirsutum and G. barbadense, indicating a genetic bottleneck associated with the domesticated cotton species. Three characteristic domains in eight COLs exhibit different evolutionary rates, with the CCT domain highly conserved, while the B-box and Var domain much more variable in allotetraploid species. Taken together, COL1, COL2 and COL8 endured greater selective pressures during the domestication process. The study improves our understanding of the domestication-related genes/traits during cotton evolutionary process. PMID- 25710780 TI - Secular trend of earlier onset and decelerated development of third molars: evidence from Croatia. AB - The purpose of this study was to evaluate the influence of the secular trend on development of third molars in 30 years period in Littoral region of Croatia. A total of 1103 panoramic radiographs of subjects aged from 6 to 18 years were analysed. First group comprised 531 panoramic radiographs (258 girls) taken from year period 1977 till 1979 and second group 572 radiographs (325 girls) taken from year period 2007 till 2009. Demirjian's method was used to determine the developmental stage of third molars. A secular trend in 30 years period was observed as earlier onset of third molars development in boys (6 months on average maxillary and 11 months mandibular) and girls (6 months for maxillary and 4 months for mandibular). Now-a-days, an increase in mineralisation for one Demirjian stage occurs at a slower pace of 5.2 months in boys and 3.4 in girls in maxilla and 2.3 or 2 months in mandible for boys and girls, respectively. The study showed a secular trend present as earlier onset but decelerated development of third molars in both genders and both jaws. PMID- 25710779 TI - Salvinorin A content in legal high products of Salvia divinorum sold in Mexico. AB - Salvia divinorum (Lamiaceae) is a herb native to Mexico where it is used by Mazatec shamans for spiritual and divination purposes. S. divinorum products are easily available to consumers and are used worldwide as legal highs because of the hallucinogenic effects caused mainly by salvinorin A. Highly popular videos and websites on the internet depicting the use of S. divinorum products have contributed to an increase in their consumption. Recent reports have highlighted the potential of these products to induce psychosis in consumers. In Mexico, dried leaf extracts of S. divinorum are sold in different strengths, claiming to correlate with increasing amounts of salvinorin A. In order to determine the variability of salvinorin A content between brands and to investigate possible correlation between brand strengths, this study sought to quantify salvinorin A in commercial products available in Mexico using an HPLC method. The HPLC analytical method showed a correlation coefficient R(2)>0.99, with LOD of 0.44 MUg/mL and LOQ of 1.34 MUg/mL. The retention time for salvinorin A was 23.09+/ 0.95 min and the measured concentrations ranged between 8.32+/-0.65 and 56.52+/ 3.77 mg/g dried leaf. The results for brand c did not show an agreement between the declared and the calculated amount of salvinorin A. Additionally, the emergence in Mexico of high strength salvia products (100*), the lack of regulation and the observed variability of salvinorin A content between brands of commercial legal highs products of S. divinorum could result in a health problem for consumers. PMID- 25710781 TI - The harmful chemistry behind krokodil (desomorphine) synthesis and mechanisms of toxicity. AB - "Krokodil" is the street name for the homemade injectable mixture that has been used as a cheap substitute for heroin. Its use begun in Russia and Ukraine and nowadays is being spread over several other countries. Desomorphine is the semi synthetic opioid claimed to be the main component of krokodil and considered to be responsible for its psychoactive characteristics. The starting materials for desomorphine synthesis are codeine tablets, alkali solutions, organic solvent, acidified water, iodine and red phosphorus, all of which are easily available in retail outlets, such as supermarkets, drugstores, etc. The resulting product is a light brown liquid that is called krokodil. People who inject krokodil present a great variety of serious signs and symptoms, including thrombophlebitis, ulcerations, gangrene, and necrosis, quickly evolving to limb amputation and death. These effects are thought to result from the toxic components produced as byproducts during the homemade drug synthesis. In this work, we reviewed several aspects of krokodil use, including its epidemiology, pharmacology and the chemical properties of the main active ingredient (desomorphine). To enhance our understanding of the clinical and toxic effects and to support the implementation of harm reduction measures, we also describe the "bathtub chemistry" of krokodil and the content of the final solution. PMID- 25710782 TI - The interaction of fingermark deposits on metal surfaces and potential ways for visualisation. AB - The interaction of fingermark deposits on metals has been examined by a variety of techniques. Visualisation by film growth has been the main area of investigation through: thermal oxidation, anodising, peroxide solution, and the interaction with vapour of iodine and ammonium sulphide. Corrosion of the underlying metal has also been examined as an alternative means of visualisation. Confocal microscopy was used to look at the film thickness and corrosion products around the prints. Scanning electron microscopy and energy dispersion of X-rays (SEM-EDX) examined a number of metal samples to investigate film growth and the elemental distribution. The observations suggest that differential oxidation was occurring as well as corrosion into the metal. Fingermark deposits on metals can corrode into the metal depending on the reactivity of the metal and leave a recoverable mark. However, fingermark deposits can also alter the rate of chemical reaction of the substrate metal by oxidation. In some cases organic matter can inhibit reaction, both when forming an oxide layer and when corroding the metal. However, signs of third level detail from pore contact may also be visible and the monovalent ions from salts could also influence film growth. Whilst further work would need to be carried out to decide whether any of these techniques may have application in fingermark recovery, this study does suggest that fingermarks on metals may be recoverable after incidents such as fires or immersion in water. PMID- 25710783 TI - Physical activity, mammographic density, and age-related lobular involution among premenopausal and postmenopausal women. AB - OBJECTIVE: Physical activity may protect against breast cancer by modulating breast tissue composition. We evaluated the association of physical activity with two visual assessments of breast tissue composition-percentage of mammographic density (a radiologic observation) and age-related lobular involution (a histologic assessment). METHODS: Among 164 premenopausal and postmenopausal women with breast cancer, physical activity (household, occupational, and recreational) performed during the year preceding the diagnosis was evaluated using a validated questionnaire. Percentage of mammographic density was assessed in the contralateral breast by a computer-assisted method. Age-related lobular involution was assessed in normal breast tissue on H&E-stained slides. Multivariate generalized linear models were used to assess associations by quartiles of physical activity. RESULTS: Overall, we observed no significant association between total physical activity and percentage of mammographic density or degree of lobular involution. However, occupational physical activity was significantly positively associated with the predominant type I/no type III lobules among premenopausal women (last quartile: prevalence ratio [PR], 5.92; P(trend )= 0.04). Although total physical activity was positively associated with the predominant type I/no type III lobules among premenopausal women (last quartile: PR, 2.61; P(trend) = 0.08), an inverse association was observed among postmenopausal women (last quartile: PR, 0.44; P(trend) = 0.01). Higher levels of household physical activity were significantly associated with higher prevalence of lower mammographic density and complete involution among postmenopausal women (last quartile: PR, 1.21; P(trend) = 0.01). CONCLUSIONS: Physical activity may be associated with less dense and more involuted breasts. Physical activity's effect on mammographic density or age-related lobular involution may mediate, in part, its protective effect against breast cancer. PMID- 25710784 TI - Accelerated diagnostic protocol using high-sensitivity cardiac troponin T in acute chest pain patients. AB - BACKGROUND: We aimed to evaluate the efficacy and safety of using high sensitivity cardiac troponin T (hs-cTnT) within an accelerated diagnostic protocol (ADP) in patients presenting with symptoms suggestive of acute myocardial infarction (AMI) for rapid rule-out of AMI. METHODS: In two independent large multicenter studies, levels of hs-cTnT at presentation and at 2 h were combined with the Thrombolysis In Myocardial Infarction (TIMI) risk score and ECG findings. The ADP defined patients with normal levels of hs-cTnT at presentation and 2 h, a TIMI score <=1, and normal ECG findings as candidates for rapid rule-out of AMI and rapid discharge. Major adverse cardiac events (MACEs) occurring within 30-days were centrally adjudicated by two independent cardiologists. RESULTS: In the derivation cohort, among 1085 consecutive patients 198 patients (18.2%) had a MACE. The ADP classified 374 patients (34.5%) as low risk. None of these patients had a MACE at 30 days, resulting in a negative predictive value (NPV) of 100% (95% CI, 99.0-100%) and a sensitivity of 100% (95% CI, 98.2%-100%). In the validation cohort, among 1590 consecutive patients 231 patients (14.5%) had a MACE. The ADP classified 641 patients (40.3%) as low-risk. 6 of these patients had a MACE at 30 days, resulting in a NPV of 99.1% (95% CI, 98.0-99.6%) and a sensitivity of 97.4% (95% CI, 94.5-98.8%). CONCLUSIONS: The ADP including hs-cTnT allows early identification 35 to 40% of patients to be at extremely low risk of MACE and therefore ideal candidates for outpatient management. PMID- 25710785 TI - Reverse epidemiology in different stages of heart failure. AB - BACKGROUND: In heart failure (HF), traditional cardiovascular risk factors (RF) as body mass index (BMI), total cholesterol (TC) and systolic blood pressure (SBP) are associated with better survival. It is unknown at which time point along the disease continuum the adverse impact of these RF ceases and may 'start to reverse'. We analyzed the distribution of RF and their association with survival across HF stages. METHODS: We pooled data from four cohort studies from the German Competence Network HF. Employing ACC/AHA-criteria, patients were allocated to stage A (n=218), B (n=1324), C1 (i.e., New York Heart Association [NYHA] classes I & II; n=1134), and C2+D (NYHA III & IV; n=639). RESULTS: With increasing HF severity median age increased (63/67/67/70 years), whereas the proportion of females (56/52/37/35%), median BMI (26.1/28.8/27.7/26.6 kg/m(2)), TC (212/204/191/172 mg/dl), and SBP (140/148/130/120 mmHg) decreased (P<0.001 for trend for all). In the total cohort, higher levels of all RF were associated with better survival, even after extensive adjustment for multiple confounders. If analyses were stratified, however, a higher RF burden predicted better survival only in clinically symptomatic patients: hazard ratio (HR) per +2 kg/m(2) BMI 0.91 (95% confidence interval 0.88; 0.95); per +10 mg/dl TC 0.93 (0.92; 0.95); per +5 mmHg SBP 0.94 (0.92; 0.95). CONCLUSION: In this well-characterized sample of patients representing the entire HF continuum, reverse associations were only consistently observed in symptomatic HF stages. Our data indicate that the phenomenon of a "reverse epidemiology" in HF is subject to significant selection bias in less advanced disease. PMID- 25710786 TI - Quantitative imaging of electrospun fibers by PeakForce Quantitative NanoMechanics atomic force microscopy using etched scanning probes. AB - Electrospun polymeric submicron and nanofibers can be used as tissue engineering scaffolds in regenerative medicine. In physiological conditions fibers are subjected to stresses and strains from the surrounding biological environment. Such stresses can cause permanent deformation or even failure to their structure. Therefore, there is a growing necessity to characterize their mechanical properties, especially at the nanoscale. Atomic force microscopy is a powerful tool for the visualization and probing of selected mechanical properties of materials in biomedical sciences. Image resolution of atomic force microscopy techniques depends on the equipment quality and shape of the scanning probe. The probe radius and aspect ratio has huge impact on the quality of measurement. In the presented work the nanomechanical properties of four different polymer based electrospun fibers were tested using PeakForce Quantitative NanoMechanics atomic force microscopy, with standard and modified scanning probes. Standard, commercially available probes have been modified by etching using focused ion beam (FIB). Results have shown that modified probes can be used for mechanical properties mapping of biomaterial in the nanoscale, and generate nanomechanical information where conventional tips fail. PMID- 25710787 TI - Hemimegalencephaly associated with fetal cardiac failure and hydrops. PMID- 25710788 TI - Road traffic noise and markers of obesity - a population-based study. AB - BACKGROUND: Noise has been found to be associated with endocrine changes and cardiovascular disease. Increased cortisol levels and chronic sleep problems due to noise may increase the risk of obesity. OBJECTIVES: We investigated the relationship between road traffic noise and obesity markers. Furthermore, we explored the modifying role of noise sensitivity, noise annoyance, and sleep disturbances. METHODS: We used data from a population-based study, HUBRO (N=15,085), and its follow-up study HELMILO (N=8410) conducted in Oslo, Norway. Measurements were used to define body mass index (BMI), waist circumference (WC), waist-hip ratio (WHR), and these binary outcomes: BMI>=30kg/m(2), WC>=102cm (men)/88cm (women), and WHR>=0.90 (men)/0.85 (women). Modelled levels of road traffic noise (Lden) were assigned to each participant's home address. Linear and logistic regression models were used to examine the associations. RESULTS: The results indicated no significant associations between road traffic noise and obesity markers in the total populations. However, in highly noise sensitive women (n=1106) a 10dB increase in noise level was associated with a slope (=beta) of 1.02 (95% confidence interval (CI): 1.01, 1.03) for BMI, 1.01 (CI: 1.00, 1.02) for WC, and an odds ratio (OR) of 1.24 (CI: 1.01, 1.53) for WHR >=0.85. The associations appeared weaker in highly noise sensitive men. We found no effect modification of noise annoyance or sleep disturbances. In a sub-population with bedroom facing a road, the associations increased in men (e.g. an OR of 1.25 (CI: 0.88, 1.78) for BMI >=30kg/m(2)), but not in women. Among long-term residents the associations increased for BMI >=30kg/m(2) (OR of 1.07 (CI: 0.93, 1.24) in men and 1.10 (CI: 0.97, 1.26) in women), but not for the other outcomes. CONCLUSION: In an adult urban Scandinavian population, road traffic noise was positively associated with obesity markers among highly noise sensitive women. The associations appeared stronger among men with bedroom facing a street, representing a population with more accurately assigned exposure. PMID- 25710791 TI - Biomechanical diversity despite mechanobiological stability in tissue engineered vascular grafts two years post-implantation. AB - Recent advances in vascular tissue engineering have enabled a paradigm shift from ensuring short-term graft survival to focusing on long-term stability and growth potential. We present the first experimental-computational study of a tissue engineered vascular graft (TEVG) effectively over the full lifespan of the recipient. We show that grafts implanted within the venous circulation of mice remained patent over 2 years without thrombus, stenosis, or aneurysmal dilatation. Moreover, the gross appearance and mechanical properties of the grafts evolved to be similar to the host vein within 24 weeks, with mean neovessel geometry and properties remaining unchanged thereafter despite a continued turnover of extracellular matrix. Biomechanical diversity manifested after 24 weeks, however, via two subsets of grafts despite all procedures being the same. Computational modeling and associated immunohistological analyses suggested that this diversity likely resulted from a differential ratio of collagen types I and III, with lower I to III ratios promoting grafts having a compliance similar to the native vein. We submit that TEVGs can exhibit the desired long-term mechanobiological stability; hence, we must now focus on evaluating growth potential and optimizing scaffold properties to achieve compliance matching throughout neovessel development. PMID- 25710790 TI - Association between appendectomy and subsequent colorectal cancer development: an Asian population study. AB - OBJECTIVES: The appendix may modulate colon microbiota and bowel inflammation. We investigated whether appendectomy alters colorectal cancer risk. METHODS: We identified a cohort of 75,979 patients who underwent appendectomy between 1997 and 1999 based on the insurance claims of Taiwan. A comparison cohort of 303,640 persons without appendectomy was selected randomly, frequency matched by age, sex, comorbidity and entry year was also selected. We monitored subsequent colorectal cancer development in both cohorts. RESULTS: The overall colorectal cancer incidence was 14% higher in the appendectomy patients than in the comparison cohort (p <0.05): the highest incidence was observed for rectal cancer, and the lowest incidence was observed for cancer of the cecum-ascending colon for both cohorts. Men were at higher risk than women. Subjects >= 60 years had an HR of 12.8 compared to those <60 years. The incidence of colorectal cancer was much higher in 1.5-3.5 years post appendectomy follow-up than for the comparisons (HR of 2.13). Patients who received an incidental appendectomy had an HR of 2.90 when compared to the comparisons. CONCLUSIONS: Results of our study suggest that appendectomy in patients with appendicitis is likely associated with the development of colorectal cancer in the post-surgery period. PMID- 25710789 TI - Leishmania infantum amastigotes trigger a subpopulation of human B cells with an immunoregulatory phenotype. AB - Visceral leishmaniasis is caused by the protozoan parasites Leishmania infantum and Leishmania donovani. This infection is characterized by an uncontrolled parasitization of internal organs which, when left untreated, leads to death. Disease progression is linked with the type of immune response generated and a strong correlation was found between disease progression and serum levels of the immunosuppressive cytokine IL-10. Other studies have suggested a role for B cells in the pathology of this parasitic infection and the recent identification of a B cell population in humans with regulatory functions, which secretes large amounts of IL-10 following activation, have sparked our interest in the context of visceral leishmaniasis. We report here that incubation of human B cells with Leishmania infantum amastigotes resulted in upregulation of multiple cell surface activation markers and a dose-dependent secretion of IL-10. Conditioned media from B cells incubated with Leishmania infantum amastigotes were shown to strongly inhibit CD4(+) T-cell activation, proliferation and function (i.e. as monitored by TNF and IFNgamma secretion). Blockade of IL-10 activity using a soluble IL-10 receptor restored only partially TNF and IFNgamma production to control levels. The parasite-mediated IL-10 secretion was shown to rely on the activity of Syk, phosphatidylinositol-3 kinase and p38, as well as to require intracellular calcium mobilization. Cell sorting experiments allowed us to identify the IL-10-secreting B-cell subset (i.e. CD19(+)CD24(+)CD27(-)). In summary, exposure of human B cells to Leishmania infantum amastigotes triggers B cells with regulatory activities mediated in part by IL-10, which could favor parasite dissemination in the organism. PMID- 25710792 TI - Photonic nanosensor for colorimetric detection of metal ions. AB - The real-time sensing of metal ions at point of care requires integrated sensors with low energy and sample consumption, reversibility, and rapid recovery. Here, we report a photonic nanosensor that reversibly and quantitatively reports on variation in the concentrations of Pb(2+) and Cu(2+) ions in aqueous solutions (<500 MUL) in the visible region of the spectrum (lambda(max) ~ 400-700 nm). A single 6 ns laser pulse (lambda = 532 nm) was used to pattern an ~10 MUm thick photosensitive recording medium. This formed periodic AgBr nanocrystal (o ~ 5-20 nm) concentrated regions, which produced Bragg diffraction upon illumination with a white light source. The sensor functionalized with 8-hydroxyquinoline allowed sensing through inducing Donnan osmotic pressure and tuning its lattice spacing. The sensor quantitatively measured Pb(2+) and Cu(2+) ion concentrations within the dynamic range of 0.1-10.0 mM with limits of detection of 11.4 and 18.6 MUM in under 10 min. The sensor could be reset in 3 min and was reused at least 100 times without compromising its accuracy. The plasmonic nanosensor represents a simple and label-free analytical platform with potential scalability for applications in medical diagnostics and environmental monitoring. PMID- 25710793 TI - Analysis of the link between the redox state and enzymatic activity of the HtrA (DegP) protein from Escherichia coli. AB - Bacterial HtrAs are proteases engaged in extracytoplasmic activities during stressful conditions and pathogenesis. A model prokaryotic HtrA (HtrA/DegP from Escherichia coli) requires activation to cleave its substrates efficiently. In the inactive state of the enzyme, one of the regulatory loops, termed LA, forms inhibitory contacts in the area of the active center. Reduction of the disulfide bond located in the middle of LA stimulates HtrA activity in vivo suggesting that this S-S bond may play a regulatory role, although the mechanism of this stimulation is not known. Here, we show that HtrA lacking an S-S bridge cleaved a model peptide substrate more efficiently and exhibited a higher affinity for a protein substrate. An LA loop lacking the disulfide was more exposed to the solvent; hence, at least some of the interactions involving this loop must have been disturbed. The protein without S-S bonds demonstrated lower thermal stability and was more easily converted to a dodecameric active oligomeric form. Thus, the lack of the disulfide within LA affected the stability and the overall structure of the HtrA molecule. In this study, we have also demonstrated that in vitro human thioredoxin 1 is able to reduce HtrA; thus, reduction of HtrA can be performed enzymatically. PMID- 25710794 TI - Interventions for vitiligo. AB - BACKGROUND: Vitiligo is a chronic skin disorder characterised by patchy loss of skin colour. Some people experience itching before the appearance of a new patch. It affects people of any age or ethnicity, more than half of whom develop it before the age of 20 years. There are two main types: generalised vitiligo, the common symmetrical form, and segmental, affecting only one side of the body. Around 1% of the world's population has vitiligo, a disease causing white patches on the skin. Several treatments are available. Some can restore pigment but none can cure the disease. OBJECTIVES: To assess the effects of all therapeutic interventions used in the management of vitiligo. SEARCH METHODS: We updated our searches of the following databases to October 2013: the Cochrane Skin Group Specialised Register, CENTRAL in The Cochrane Library (2013, Issue 10), MEDLINE, Embase, AMED, PsycINFO, CINAHL and LILACS. We also searched five trials databases, and checked the reference lists of included studies for further references to relevant randomised controlled trials (RCTs). SELECTION CRITERIA: Randomised controlled trials (RCTs) assessing the effects of treatments for vitiligo. DATA COLLECTION AND ANALYSIS: At least two review authors independently assessed study eligibility and methodological quality, and extracted data. MAIN RESULTS: This update of the 2010 review includes 96 studies, 57 from the previous update and 39 new studies, totalling 4512 participants. Most of the studies, covering a wide range of interventions, had fewer than 50 participants. All of the studies assessed repigmentation, however only five reported on all of our three primary outcomes which were quality of life, > 75% repigmentation and adverse effects. Of our secondary outcomes, six studies measured cessation of spread but none assessed long-term permanence of repigmentation resulting from treatment at two years follow-up.Most of the studies assessed combination therapies which generally reported better results. New interventions include seven new surgical interventions.We analysed the data from 25 studies which assessed our primary outcomes. We used the effect measures risk ratio (RR), and odds ratio (OR) with their 95% confidence intervals (CI) and where N is the number of participants in the study.We were only able to analyse one of nine studies assessing quality of life and this showed no statistically significant improvement between the comparators.Nine analyses from eight studies reported >75% repigmentation. In the following studies the repigmentation was better in the combination therapy group: calcipotriol plus PUVA (psoralen with UVA light) versus PUVA (paired OR 4.25, 95% CI 1.43 to 12.64, one study, N = 27); hydrocortisone-17-butyrate plus excimer laser versus excimer laser alone (RR 2.57, 95% CI 1.20 to 5.50, one study, N = 84); oral minipulse of prednisolone (OMP) plus NB-UVB (narrowband UVB) versus OMP alone (RR 7.41, 95% CI 1.03 to 53.26, one study, N = 47); azathioprine with PUVA versus PUVA alone (RR 17.77, 95% CI 1.08 to 291.82, one study, N = 58) and 8-Methoxypsoralen (8-MOP ) plus sunlight versus psoralen (RR 2.50, 95% CI 1.06 to 5.91, one study, N = 168). In these three studies ginkgo biloba was better than placebo (RR 4.40, 95% CI 1.08 to 17.95, one study, N = 47); clobetasol propionate was better than PUVAsol (PUVA with sunlight) (RR 4.70, 95% CI 1.14 to 19.39, one study, N = 45); split skin grafts with PUVAsol was better than minipunch grafts with PUVAsol (RR 1.89, 95% CI 1.25 to 2.85, one study, N = 64).We performed one meta-analysis of three studies, in which we found a non-significant 60% increase in the proportion of participants achieving >75% repigmentation in favour of NB-UVB compared to PUVA (RR 1.60, 95% CI 0.74 to 3.45; I2 = 0%).Studies assessing topical preparations, in particular topical corticosteroids, reported most adverse effects. However, in combination studies it was difficult to ascertain which treatment caused these effects. We performed two analyses from a pooled analysis of three studies on adverse effects. Where NB-UVB was compared to PUVA, the NB-UVB group reported less observations of nausea in three studies (RR 0.13, 95% CI 0.02 to 0.69; I2 = 0% three studies, N = 156) and erythema in two studies (RR 0.73, 95% CI 0.55 to 0.98; I2 = 0%, two studies, N = 106), but not itching in two studies (RR 0.57, 95% CI 0.20 to 1.60; I2 = 0%, two studies, N = 106).Very few studies only assessed children or included segmental vitiligo. We found one study of psychological interventions but we could not include the outcomes in our statistical analyses. We found no studies evaluating micropigmentation, depigmentation, or cosmetic camouflage. AUTHORS' CONCLUSIONS: This review has found some evidence from individual studies to support existing therapies for vitiligo, but the usefulness of the findings is limited by the different designs and outcome measurements and lack of quality of life measures. There is a need for follow-up studies to assess permanence of repigmentation as well as high- quality randomised trials using standardised measures and which also address quality of life. PMID- 25710796 TI - Left ventricular myxoma causing sudden death. AB - Sudden cardiac death due to a myxoma is rarely reported in the literature. Cardiac myxomas are benign tumors of the heart, most frequently located in the left atrium. Left ventricular myxomas are rare. Left ventricular myxomas attached to the anterior papillary muscle are especially rare, with only 1 case being reported in the literature. Myxomas have the potential to cause embolization, obstruction, or arrhythmia. We report a case of a 32-year-old man who sustained sudden death and was found to have a left ventricular myxoma attached to the anterior papillary muscle at autopsy. Although the subject also had evidence of a distant myocardial infarction and dilated cardiomyopathy, the myxoma was apparently clinically silent. Cardiac myxomas may be treated by surgical excision with excellent prognosis. However, they can remain silent and undiagnosed and, hence, have the potential for causing sudden cardiac death. In addition to the case report, we present a literature review of these issues involving cardiac myxomas. PMID- 25710795 TI - Electromuscular incapacitating devices discharge and risk of severe bradycardia. AB - Electromuscular incapacitating devices (EMDs) are high-voltage, low-current stimulators causing involuntary muscle contractions and sensory response. Existing evidence about cardiac effects of EMD remains inconclusive. The aim of our study was to analyze electrocardiographic, echocardiographic, and microvolt T wave alternans (MTWA) changes induced by EMD discharge.We examined 26 volunteers (22 men; median age 30 years) who underwent single standard 5-second duration exposure to TASER X26 under continuous echocardiographic and electrocardiographic monitoring. Microvolt T-wave alternans testing was performed at baseline (MTWA 1), as well as immediately and 60 minutes after EMD exposure (MTWA-2 and MTWA-3, respectively).Mean heart rate (HR) increased significantly from 88 +/- 17 beats per minute before to 129 +/- 17 beats per minute after exposure (P < 0.001). However, in 2 individuals, an abrupt decrease in HR was observed. In one of them, interval between two consecutive beats increased up to 1.7 seconds during the discharge. New onset of supraventricular premature beats was observed after discharge in 1 patient. Results of MTWA-1, MTWA-2, and MTWA-3 tests were positive in one of the subjects, each time in a different case.Standard EMD exposure can be associated with a nonuniform reaction of HR and followed by heart rhythm disturbances. New MTWA positivity can reflect either the effect of EMD exposure or a potential false positivity of MTWA assessments. PMID- 25710797 TI - Introduction by the guest editors. PMID- 25710798 TI - Mindfulness-based interventions for the treatment of smoking: a systematic literature review. AB - OBJECTIVES: Smoking is a chronic process in which craving and negative affect are considered the main barriers to maintaining abstinence in patients who have gone through treatment. Mindfulness-based interventions have presented encouraging preliminary results in follow-up lasting up to 6 months. The aim of this study was to perform a systematic literature review on the effects of mindfulness-based interventions for the treatment of smoking. METHODS: Of 198 articles on mindfulness and smoking, 13 controlled empirical studies were selected for the analysis. The search included papers published through April 14, 2014. The databases used were Cochrane Central Register of Controlled Trials, PsycINFO, PubMed, and Scopus. RESULTS: Scientific interest on mindfulness-based interventions for the treatment of smoking has increased over the past decade. All articles reported promising results, especially for smoking cessation, relapse prevention, number of cigarettes smoked, the moderation of mindfulness on the strength of relationship between craving and smoking, and the development of coping strategies to deal with triggers to smoke. Most of the articles corresponded to pilot or feasibility randomized controlled trials with low risk of bias regarding random sequence generation, attrition, and reporting. However, few articles reported sufficient data on selection, performance, and detection bias. CONCLUSIONS: Mindfulness appears to induce positive effects on mental health, which might contribute to the maintenance of tobacco abstinence. Despite the promising results regarding the responses of tobacco smokers to mindfulness based interventions, additional well-designed clinical studies are needed. PMID- 25710799 TI - Predicting death without dialysis in elderly patients with CKD. PMID- 25710800 TI - Pain, analgesics, and safety in patients with CKD. PMID- 25710801 TI - Effects of sevelamer carbonate on advanced glycation end products and antioxidant/pro-oxidant status in patients with diabetic kidney disease. AB - BACKGROUND AND OBJECTIVES: The primary goals were to re-examine whether sevelamer carbonate (SC) reduces advanced glycation end products (AGEs) (methylglyoxal and carboxymethyllysine [CML]), increases antioxidant defenses, reduces pro-oxidants, and improves hemoglobin A1c (HbA1c) in patients with type 2 diabetes mellitus (T2DM) and diabetic kidney disease (DKD). Secondary goals examined albuminuria, age, race, sex, and metformin prescription. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This two-center, randomized, intention-to-treat, open-label study evaluated 117 patients with T2DM (HbA1c >6.5%) and stages 2-4 DKD (urinary albumin/creatinine ratio >=200 mg/g) treated with SC (1600 mg) or calcium carbonate (1200 mg), three times a day, without changing medications or diet. Statistical analyses used linear mixed models adjusted for randomization levels. Preselected subgroup analyses of sex, race, age, and metformin were conducted. RESULTS: SC lowered serum methylglyoxal (95% confidence interval [CI], -0.72 to 0.29; P<0.001), serum CML (95% CI, -5.08 to -1.35; P<=0.001), and intracellular CML (95% CI, -1.63 to -0.28; P=0.01). SC increased anti-inflammatory defenses, including nuclear factor like-2 (95% CI, 0.58 to 1.29; P=0.001), AGE receptor 1 (95% CI, 0.23 to 0.96; P=0.001), NAD-dependent deacetylase sirtuin-1 (95% CI, 0.20 to 0.86; P=0.002), and estrogen receptor alpha (95% CI, 1.38 to 2.73; P <=0.001). SC also decreased proinflammatory factors such as TNF receptor 1 (95% CI, -1.56 to -0.72; P<=0.001) and the receptor for AGEs (95% CI, -0.58 to 1.53; P<=0.001). There were no differences in HbA1c, GFR, or albuminuria in the overall group. Subanalyses showed that SC lowered HbA1c in women (95% CI, -1.71 to -0.27; P=0.01, interaction P=0.002), and reduced albuminuria in those aged <65 years (95% CI, -1.15 to -0.07; P=0.03, interaction P=0.02) and non-Caucasians (95% CI, 1.11 to -0.22; P=0.003, interaction P<=0.001), whereas albuminuria increased after SC and calcium carbonate in Caucasians. CONCLUSIONS: SC reduced circulating and cellular AGEs, increased antioxidants, and decreased pro-oxidants, but did not change HbA1c or the albumin/creatinine ratio overall in patients with T2DM and DKD. Because subanalyses revealed that SC may reduce HbA1c and albuminuria in some patients with T2DM with DKD, further studies may be warranted. PMID- 25710803 TI - Infection prevention and the medical director: uncharted territory. AB - Infections continue to be a major cause of disease and contributor to death in patients on dialysis. Despite our knowledge and acceptance that hemodialysis catheters should be avoided and eliminated, most patients who begin dialysis initiate treatment through a central vein hemodialysis catheter. Dialysis Medical Directors must be the instrument through which our industry changes. We must lead the charge to educate our dialysis staff and our dialysis patients. We must also educate ourselves so that we not only know that our facility policies are consistent with the best evidence available, but we must also know where local and federal regulations differ. When these differences impact on patient care, we must speak out and have these regulations changed. But it is not enough to know the rules and write them. We must lead by example and show our patients, our nephrology colleagues and our dialysis staff that we always follow these same policies. We need to practice what we preach and be willing and available to redirect those individuals who have difficulty following the rules. In order to effectively change process meaningful data must be collected, analyzed and acted upon. Dialysis Medical Directors must direct and lead the quality improvement process. We hope this review provides Dialysis Medical Directors with the necessary tools to effectively drive this process and improve care. PMID- 25710804 TI - Development and validation of a model to predict 5-year risk of death without ESRD among older adults with CKD. AB - BACKGROUND AND OBJECTIVES: CKD is associated with mortality. Accurate prediction tools for mortality may guide clinical decision-making, particularly among elderly persons with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A prediction equation was developed for 5-year risk of mortality among participants with CKD in the Cardiovascular Health Study. Sixteen candidate predictor variables were explored, which included demographics, physical examination measures, comorbidity, medication use, and kidney function measures (eGFR calculated from serum creatinine and the CKD Epidemiology Collaboration equation and the urine albumin-to-creatinine ratio). Models were developed using Cox regression and evaluated using c statistics. A final parsimonious model was externally validated in an independent cohort of community-living elders with CKD in the Health, Aging, and Body Composition Study. RESULTS: The development cohort included 828 participants who had a mean age of 80 (+/-5.6) years and an eGFR of 47 (+/-11) ml/min per 1.73 m(2), and median albumin-to-creatinine ratio of 13 (interquartile range 6-51) mg/g. The validation cohort included 789 participants who had a mean age of 74 (+/-2.8) years and an eGFR of 50 (+/-9) ml/min per 1.73 m(2), and median albumin-to-creatinine ratio of 13 (interquartile range 6-42) mg/g. The final model for 5-year mortality risk included age, sex, race, eGFR, urine albumin-to-creatinine ratio, smoking, diabetes mellitus, and history of heart failure and stroke (c statistic=0.72; 95% confidence interval, 0.68 to 0.74). When a point-based system was assigned for each of nine variables in the equation, the estimated risk of death within 5 years ranged from 3.8% among participants with the lowest scores to 83.6% among participants with nine points. The model performed fair in external validation (c statistic=0.69; 95% confidence interval, 0.64 to 0.74). CONCLUSIONS: A simple prediction tool using nine readily available clinical variables can assist in predicting 5-year mortality risk in elderly patients with CKD, which may be useful in counseling patients and guiding clinical decision making. PMID- 25710807 TI - Dalton Discussion 15 - Metal ions in medical imaging: optical, radiopharmaceutical and MRI contrast, 8th-10th September 2014, York. PMID- 25710806 TI - Chronic pain and analgesic use in CKD: implications for patient safety. AB - BACKGROUND AND OBJECTIVES: Chronic pain in predialysis CKD is not fully understood. This study examined chronic pain in CKD and its relationship with analgesic usage. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Data include baseline visits from 308 patients with CKD enrolled between 2011 and 2013 in the Safe Kidney Care cohort study in Baltimore, Maryland. The Wong-Baker FACES Pain Rating Scale measured chronic pain severity. Analgesic prescriptions and over-the counter purchases were recorded up to 30 days before visits, and were classified as a drug-related problem (DRP) based on an analgesic's nephrotoxicity and dose appropriateness at participants' eGFR. Participants were sorted by pain frequency and severity and categorized into ordinal groups. Analgesic use and the rate of analgesics with a DRP were reported across pain groups. Multivariate regression determined the factors associated with chronic pain and assessed the relationship between chronic pain and analgesic usage. RESULTS: There were 187 (60.7%) participants who reported chronic pain. Factors associated with pain severity included arthritis, taking >=12 medications, and lower physical function. Use of nonsteroidal anti-inflammatory drugs was reported by seven participants (5.8%) with no chronic pain. Mild and severe chronic pain were associated with analgesics with a DRP, with odds ratios of 3.04 (95% confidence interval [95% CI], 1.12 to 8.29) and 5.46 (95% CI, 1.85 to 16.10), respectively. The adjusted rate of analgesics with a DRP per participant increased from the group with none to severe chronic pain, with rates of 0.07 (95% CI, 0.04 to 0.13), 0.12 (95% CI, 0.07 to 0.20) and 0.16 (95% CI, 0.09 to 0.27), respectively. CONCLUSIONS: Chronic pain is common in CKD with a significant relationship between the severity of pain and both proper and improper analgesic usage. Screening for chronic pain may help in understanding the role of DRPs in the delivery of safe CKD care. PMID- 25710808 TI - Navigating the digital divide: A systematic review of eHealth literacy in underserved populations in the United States. AB - eHealth provides an important mechanism to connect medically underserved populations with health information, but little is known about gaps in eHealth literacy research in underserved adult populations within the U.S. Between June and July 2013, three systematic literature reviews of five databases were conducted and a subsequent hand search was completed. Identified literature was screened and studies meeting exclusion and inclusion criteria were synthesized and analyzed for common themes. Of the 221 articles critically appraised, 15 met these criteria. Thirty-five of these studies were excluded due to international origin. Of the articles meeting the inclusion criteria, underserved populations assessed included immigrant women, the elderly, low-income, the un- and underemployed, and African-American and Hispanic populations. eHealth literacy assessments utilized included one or two item screeners, the eHEALS scale, health information competence and cognitive task analysis. Factors examined in relation to eHealth literacy included age, experience, overall health literacy, education, income and culture. The majority did not assess the impact of locality and those that did were predominately urban. These data suggest that there is a gap in the literature regarding eHealth literacy knowledge for underserved populations, and specifically those in rural locations, within the U.S. PMID- 25710805 TI - Mineral metabolism in European children living with a renal transplant: a European society for paediatric nephrology/european renal association-European dialysis and transplant association registry study. AB - BACKGROUND AND OBJECTIVES: Data on mineral metabolism in pediatric renal transplant recipients largely arise from small single-center studies. In adult patients, abnormal mineral levels are related to a higher risk of graft failure. This study used data from the European Society for Paediatric Nephrology/European Renal Association-European Dialysis and Transplant Association Registry to study the prevalence and potential determinants of mineral abnormalities, as well as the predictive value of a disturbed mineral level on graft survival in a large cohort of European pediatric renal transplant recipients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This study included 1237 children (0-17 years) from 10 European countries, who had serum calcium, phosphorus, and parathyroid hormone measurements from 2000 onward. Abnormalities of mineral metabolism were defined according to European guidelines on prevention and treatment of renal osteodystrophy in children on chronic renal failure. RESULTS: Abnormal serum phosphorus levels were observed in 25% (14% hypophosphatemia and 11% hyperphosphatemia), altered serum calcium in 30% (19% hypocalcemia, 11% hypercalcemia), and hyperparathyroidism in 41% of the patients. A longer time since transplantation was associated with a lower risk of having mineral levels above target range. Serum phosphorus levels were inversely associated with eGFR, and levels above the recommended targets were associated with a higher risk of graft failure independently of eGFR. CONCLUSIONS: Abnormalities in mineral metabolism are common after pediatric renal transplantation in Europe and are associated with graft dysfunction. PMID- 25710809 TI - Covalent attachment of 1-alkenes to oxidized platinum surfaces. AB - We report the formation of covalently bound alkyl layers onto oxidized Pt (PtOx) substrates by reaction with 1-alkenes as a novel way to bind organic molecules to metal surfaces. The organic layers were characterized by static contact angle, infrared reflection absorption spectroscopy (IRRAS), X-ray photoelectron spectroscopy (XPS), and atomic force microscopy (AFM). The grafted alkyl layers display a hydrolytic stability that is comparable to that of alkyl thiols on Au. PtOx-alkene attachment is compatible with terminal ester moieties enabling further anchoring of functional groups, such as redox-active ferrocene, and thus has great potential to extend monolayer chemistry on noble metals. PMID- 25710810 TI - Effect of the particle size of cellulose from sweet potato residues on lipid metabolism and cecal conditions in ovariectomized rats. AB - This study aims to examine the effect of the particle size of cellulose from sweet potato residues on lipid metabolism and cecal conditions in ovariectomized rats. Forty mature female Wistar rats were divided into five groups. The sham operated group was used as the sham control. The other four groups were double ovariectomized and assigned to the model, ordinary cellulose (100 g kg(-1) diet), microcrystalline cellulose (100 g kg(-1) diet), and cellulose nanocrystal (100 g kg(-1) diet) groups. As the cellulose particle size decreased, the body weight gain and food intake were decreased. The plasma lipids and hepatic lipids were decreased. In addition, the mRNA levels of cholesterol 7alpha-hydroxylase, farnesoid X receptor, and 3-hydroxy-3-methylglutaryl coenzyme A reductase were decreased, whereas those of ileal apical sodium-dependent bile acid transporter and intestinal bile acid binding protein were increased. The cecum weight, cecum content, and short-chain fatty acid concentration and the amount of total bile acids in the small intestinal content, as well as the bile acids and neutral steroids in fecal excretion, were increased. These results indicate that as the particle size decreased, cellulose was more effective in preventing ovarian hormone deficiency-induced hyperlipidemia and in improving intestinal health. PMID- 25710811 TI - Importance of tissue preparation methods in FTIR micro-spectroscopical analysis of biological tissues: 'traps for new users'. AB - Fourier Transform Infrared (FTIR) micro-spectroscopy is an emerging technique for the biochemical analysis of tissues and cellular materials. It provides objective information on the holistic biochemistry of a cell or tissue sample and has been applied in many areas of medical research. However, it has become apparent that how the tissue is handled prior to FTIR micro-spectroscopic imaging requires special consideration, particularly with regards to methods for preservation of the samples. We have performed FTIR micro-spectroscopy on rodent heart and liver tissue sections (two spectroscopically very different biological tissues) that were prepared by desiccation drying, ethanol substitution and formalin fixation and have compared the resulting spectra with that of fully hydrated freshly excised tissues. We have systematically examined the spectra for any biochemical changes to the native state of the tissue caused by the three methods of preparation and have detected changes in infrared (IR) absorption band intensities and peak positions. In particular, the position and profile of the amide I, key in assigning protein secondary structure, changes depending on preparation method and the lipid absorptions lose intensity drastically when these tissues are hydrated with ethanol. Indeed, we demonstrate that preserving samples through desiccation drying, ethanol substitution or formalin fixation significantly alters the biochemical information detected using spectroscopic methods when compared to spectra of fresh hydrated tissue. It is therefore imperative to consider tissue preparative effects when preparing, measuring, and analyzing samples using FTIR spectroscopy. PMID- 25710812 TI - A pilot study to compare meal-triggered gastric electrical stimulation and insulin treatment in Chinese obese type 2 diabetes. AB - BACKGROUND: Gastrointestinal electromodulation therapy is a novel alternative for achieving diabetes control without traditional bariatric surgery. We compared the efficacy of a meal-initiated implantable gastric contractility modulation (GCM) device with that of insulin therapy in obese Chinese type 2 diabetes (T2D) patients, for whom oral antidiabetes drugs (OADs) had failed. PATIENTS AND METHODS: Sixteen obese (body mass index, 27.5-40.0 kg/m(2)) T2D patients with a glycated hemoglobin (HbA1c) level of >7.5% on maximal doses of two or more OADs were offered either insulin therapy (n=8) or laparoscopic implantation of a GCM (n=8). We compared changes in body weight, waist circumference (WC), and HbA1c level 1 year after surgery. RESULTS: The GCM and insulin groups had similar baseline body weight and HbA1c. At 12 months, body weight (-3.2+/-5.2 kg, P=0.043) and WC (-3.8+/-4.5 cm, P=0.021) fell in the GCM group but not in the insulin group (P<0.05 for between-group difference). At 6 and 12 months, the HbA1c level fell by 1.6+/-1.1% and 0.9+/-1.6% (P=0.011), compared with 0.6+/-0.3% and 0.6+/-0.3% (P=0.08) for the insulin group (P=0.15 for between-group difference). The mean 24-h systolic blood pressure (BP) fell by 4.5+/-1.0 mm Hg in the GCM group (P=0.017) but not in the insulin group. The GCM group required fewer antidiabetes medications (P<0.05) and BP-lowering drugs (P<0.05) than the insulin group. A subgroup analysis showed that patients with a triglyceride level of <1.7 mmol/L had a tendency toward a lower HbA1c level (P=0.090) compared with the controls. CONCLUSIONS: In obese T2D patients for whom OADs had failed, GCM implantation was a well-tolerated alternative to insulin therapy, with a low triglyceride level as a possible predictor for glycemic response. PMID- 25710813 TI - Forensic and population genetic analyses of Danes, Greenlanders and Somalis typed with the Yfiler(r) Plus PCR amplification kit. AB - Recently, the Yfiler(r) Plus PCR Amplification Kit (Yfiler(r) Plus, Thermo Fisher Scientific, Waltham, MA, USA) was introduced. Yfiler(r) Plus amplifies 27 Y chromosomal short tandem repeat loci (Y-STRs) and adds ten new Y-STRs to those analysed with the commonly used AmpFlSTR(r) Yfiler(r) PCR Amplification Kit (Yfiler(r), Thermo Fisher Scientific, Waltham, MA, USA). Seven of the new Y-STRs are rapidly mutating Y-STRs (RM Y-STRs). In this study, 551 male individuals from Denmark, Greenland and Somalia were typed with Yfiler(r) Plus. The results were compared to those obtained with Yfiler(r) in the same individuals. Forensic and population genetic parameters were estimated for Yfiler(r) Plus. Yfiler(r) Plus had a higher power of discrimination than Yfiler(r) in all three populations. Compared to Yfiler(r), Yfiler(r) Plus offers increased power of discrimination, which is obviously an advantage in crime case investigations. However, the inclusion of seven RM Y-STRs in Yfiler(r) Plus makes it less attractive for relationship testing because of the relatively high combined mutation rate, approximately 15%. PMID- 25710814 TI - Population data for 15 autosomal STR loci in the Dong ethnic minority from Guizhou Province, Southwest China. PMID- 25710815 TI - Towards an HIV cure based on targeted killing of infected cells: different approaches against acute versus chronic infection. AB - PURPOSE OF REVIEW: Current regimens of combination antiretroviral therapy (cART) offer effective control of HIV infection, with maintenance of immune health and near-normal life expectancy. What will it take to progress beyond the status quo, whereby infectious virus can be eradicated (a 'sterilizing cure') or fully controlled without the need for ongoing cART (a 'functional cure')? RECENT FINDINGS: On the basis of therapeutic advances in the cancer field, we propose that targeted cytotoxic therapy to kill HIV-infected cells represents a logical complement to cART for achieving an HIV cure. This concept is based on the fact that cART effectively blocks replication of the virus, but does not eliminate cells that are already infected; targeted cytotoxic therapy would contribute precisely this missing component. We suggest that different modalities are suited for curing primary acute versus established chronic infection. For acute infection, relatively short-acting potent agents such as recombinant immunotoxins might prove sufficient for HIV eradication, whereas for chronic infection, a long lasting (lifelong?) modality is required to maintain full virus control, as might be achieved with genetically modified autologous T cells. SUMMARY: We present perspectives for complementing cART with targeted cytotoxic therapy, whereby HIV infection is either eradicated or fully controlled, thereby eliminating the need for lifelong cART. PMID- 25710817 TI - Identification of antimycotic drugs transformation products upon UV exposure. AB - The reactivity of three imidazolic, environmental persistent antimycotic drugs (clotrimazole, CTZ; ketoconazole, KTZ; and miconazole, MCZ) upon exposure to ultraviolet (UV) radiation is discussed. First, precursor compounds were immobilized in a silicone support which was further exposed to UV light at two different wavelengths: 254 and 365 nm. After solvent desorption, degradation kinetics of the precursor pharmaceuticals, identification of the arising transformation products (TPs) and evaluation of their time-course were investigated by liquid chromatography (LC) with quadrupole time-of-flight (QTOF) mass spectrometry (MS) detection. The three antimycotics displayed similar stabilities when exposed to 254 nm light; however, CTZ was significantly more stable than MCZ and KTZ when irradiated with the 365 nm lamp. TPs identified in silicone supports resulted from de-chlorination, cleavage, intra-molecular cyclization and hydroxylation reactions. Many of these species were also detected when exposing other solid matrices, such as sand and agricultural soil, previously spiked with target compounds, to UV light. The 50% estimated lethal concentration, calculated using the 48-h Daphnia magna test, for the two main TPs of CTZ and MCZ, at both wavelengths, were lower than those corresponding to the precursor drugs. PMID- 25710816 TI - Quantitative T2 combined with texture analysis of nuclear magnetic resonance images identify different degrees of muscle involvement in three mouse models of muscle dystrophy: mdx, Largemyd and mdx/Largemyd. AB - Quantitative nuclear magnetic resonance imaging (MRI) has been considered a promising non-invasive tool for monitoring therapeutic essays in small size mouse models of muscular dystrophies. Here, we combined MRI (anatomical images and transverse relaxation time constant-T2-measurements) to texture analyses in the study of four mouse strains covering a wide range of dystrophic phenotypes. Two still unexplored mouse models of muscular dystrophies were analyzed: The severely affected Largemyd mouse and the recently generated and worst double mutant mdx/Largemyd mouse, as compared to the mildly affected mdx and normal mice. The results were compared to histopathological findings. MRI showed increased intermuscular fat and higher muscle T2 in the three dystrophic mouse models when compared to the wild-type mice (T2: mdx/Largemyd: 37.6+/-2.8 ms; mdx: 35.2+/-4.5 ms; Largemyd: 36.6+/-4.0 ms; wild-type: 29.1+/-1.8 ms, p<0.05), in addition to higher muscle T2 in the mdx/Largemyd mice when compared to mdx (p<0.05). The areas with increased muscle T2 in the MRI correlated spatially with the identified histopathological alterations such as necrosis, inflammation, degeneration and regeneration foci. Nevertheless, muscle T2 values were not correlated with the severity of the phenotype in the 3 dystrophic mouse strains, since the severely affected Largemyd showed similar values than both the mild mdx and worst mdx/Largemyd lineages. On the other hand, all studied mouse strains could be unambiguously identified with texture analysis, which reflected the observed differences in the distribution of signals in muscle MRI. Thus, combined T2 intensity maps and texture analysis is a powerful approach for the characterization and differentiation of dystrophic muscles with diverse genotypes and phenotypes. These new findings provide important noninvasive tools in the evaluation of the efficacy of new therapies, and most importantly, can be directly applied in human translational research. PMID- 25710802 TI - The Effects of Cinacalcet in Older and Younger Patients on Hemodialysis: The Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) Trial. AB - BACKGROUND AND OBJECTIVES: The calcimimetic cinacalcet reduced the risk of death or cardiovascular (CV) events in older, but not younger, patients with moderate to severe secondary hyperparathyroidism (HPT) who were receiving hemodialysis. To determine whether the lower risk in younger patients might be due to lower baseline CV risk and more frequent use of cointerventions that reduce parathyroid hormone (kidney transplantation, parathyroidectomy, and commercial cinacalcet use), this study examined the effects of cinacalcet in older (>=65 years, n=1005) and younger (<65 years, n=2878) patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) was a global, multicenter, randomized placebo-controlled trial in 3883 prevalent patients on hemodialysis, whose outcomes included death, major CV events, and development of severe unremitting HPT. The age subgroup analysis was prespecified. RESULTS: Older patients had higher baseline prevalence of diabetes mellitus and CV comorbidity. Annualized rates of kidney transplantation and parathyroidectomy were >3-fold higher in younger relative to older patients and were more frequent in patients randomized to placebo. In older patients, the adjusted relative hazard (95% confidence interval) for the primary composite (CV) end point (cinacalcet versus placebo) was 0.70 (0.60 to 0.81); in younger patients, the relative hazard was 0.97 (0.86 to 1.09). Corresponding adjusted relative hazards for mortality were 0.68 (0.51 to 0.81) and 0.99 (0.86 to 1.13). Reduction in the risk of severe unremitting HPT was similar in both groups. CONCLUSIONS: In the EVOLVE trial, cinacalcet decreased the risk of death and of major CV events in older, but not younger, patients with moderate to severe HPT who were receiving hemodialysis. Effect modification by age may be partly explained by differences in underlying CV risk and differential application of cointerventions that reduce parathyroid hormone. PMID- 25710818 TI - The comparative study of a laccase-natural clinoptilolite-based catalyst activity and free laccase activity on model compounds. AB - For the first time a laccase from Trametes versicolor was immobilized on a natural clinoptilolite with Si/Al=5 to obtain a biocatalyst for environmental applications. Immobilization procedures exploiting adsorption and covalent binding were both tested, and only the last provided enough activity for practical applications. The optimal conditions for the immobilization of the enzyme on the support and the kinetic parameters for the free and covalent bonded laccase were determined. The laccase bonded to the zeolitic support showed a lower activity than the free laccase, but the pH and thermal stability were greater. 20 mg of dry biocatalyst containing 1 U of laccase were able to remove in 50h 73-78% of 2-chlorophenol and 2,4-dichlorophenol in relatively concentrated aqueous solutions (100 MUmol L(-1)). PMID- 25710819 TI - Facile preparation of electroactive amorphous alpha-ZrP/PANI hybrid film for potential-triggered adsorption of Pb(2+) ions. AB - An electroactive hybrid film composed of amorphous alpha-zirconium phosphate and polyaniline (alpha-ZrP/PANI) is controllably synthesized on carbon nanotubes (CNTs) modified Au electrodes in aqueous solution by cyclic voltammetry method. Electrochemical quartz crystal microbalance (EQCM), scanning electron microscopy (SEM) and X-ray power diffraction (XRD) analysis are applied for the evaluation of the synthesis process. It is found that the exfoliated amorphous alpha-ZrP nanosheets are well dispersed in PANI and the hydrolysis of alpha-ZrP is successfully suppressed by controlling the exfoliation temperature and adding appropriate supporting electrolyte. The insertion/release of heavy metals into/from the film is reversibly controlled by a potential-triggered mechanism. Herein, alpha-ZrP, a weak solid acid, can provide an acidic micro-environment for PANI to promote the electroactivity in neutral aqueous solutions. Especially, the hybrid film shows excellent potential-triggered adsorption of Pb(2+) ion due to the selective complexation of Pb(2+) ion with oxygen derived from P-O-H of alpha ZrP. Also, it shows long-term cycle stability and rapid potential-responsive adsorption/desorption rate. This kind of novel hybrid film is expected to be a promising potential-triggered ESIX material for separation and recovery of heavy metal ions from wastewater. PMID- 25710820 TI - Toxicity assessment of 4-chlorophenol to aerobic granular sludge and its interaction with extracellular polymeric substances. AB - The main objective of this study was to evaluate the toxicity of 4-chlorophenol (4-CP) to aerobic granular sludge in the process of treating ammonia rich wastewater. In the short-term exposure of 4-CP of 5 and 10 mg/L, ammonia nitrogen removal efficiencies in the batch reactors decreased to 87.18+/-2.81 and 41.16+/ 3.55%, which were remarkably lower than that of control experiment (99.83+/ 0.54%). Correspondingly, the respirometric activities of heterotrophic and autotrophic bacteria of aerobic granular sludge were significantly inhibited in the presence of 4-CP. Moreover, the main components of extracellular polymeric substances (EPS) including polysaccharides and proteins increased from 18.74+/ 0.29 and 22.57+/-0.34 mg/g SS to 27.79+/-0.51 and 24.69+/-0.38 mg/g SS, respectively, indicating that the presence of 4-CP played an important role on the EPS production. Three-dimensional excitation-emission matrix (3D-EEM) fluorescence spectroscopy further showed that the intensities of EPS samples were obviously quenched with the increased of 4-CP concentrations. To be more detailed, synchronous fluorescence spectra indicated that the interaction between EPS and 4-CP was mainly caused by tryptophan residues. The mechanism of fluorescence quenching belongs to static quenching with a formation constant (KA) of 0.07*10(4) L/mol, implying the strong formation of EPS and 4-CP complex. The results could provide reliable and accurate information to determine the potential toxicity of 4-CP on the performance of aerobic granular sludge system. PMID- 25710821 TI - Tomato SOBIR1/EVR Homologs Are Involved in Elicitin Perception and Plant Defense Against the Oomycete Pathogen Phytophthora parasitica. AB - During host-pathogen interactions, pattern recognition receptors form complexes with proteins, such as receptor-like kinases, to elicit pathogen-associated molecular pattern-triggered immunity (PTI), an evolutionarily conserved plant defense program. However, little is known about the components of the receptor complex, as are the molecular events leading to PTI induced by the oomycete Phytophthora pathogen. Here, we demonstrate that tomato (Solanum lycopersicum) SlSOBIR1 and SlSOBIR1-like genes are involved in defense responses to Phytophthora parasitica. Silencing of SlSOBIR1 and SlSOBIR1-like enhanced susceptibility to P. parasitica in tomato. Callose deposition, reactive oxygen species production, and PTI marker gene expression were compromised in SlSOBIR1- and SlSOBIR1-like-silenced plants. Interestingly, P. parasitica infection and elicitin (ParA1) treatment induced the relocalization of SlSOBIR1 from the plasma membrane to endosomal compartments and silencing of NbSOBIR1 compromised ParA1 mediated cell death on Nicotiana benthamiana. Moreover, the SlSOBIR1 kinase domain is indispensable for ParA1 to trigger SlSOBIR1 internalization and plant cell death. Taken together, these results support the idea of participation of solanaceous SOBIR1/EVR homologs in the perception of elicitins and indicate their important roles in plant basal defense against oomycete pathogens. PMID- 25710822 TI - Outstanding laser damage threshold in Li2MnGeS4 and tunable optical nonlinearity in diamond-like semiconductors. AB - The new Li2MnGeS4 and Li2CoSnS4 compounds result from employing a rational and simple design strategy that guides the discovery of diamond-like semiconductors (DLSs) with wide regions of optical transparency, high laser damage threshold, and efficient second-order optical nonlinearity. Single-crystal X-ray diffraction was used to solve and refine the crystal structures of Li2MnGeS4 and Li2CoSnS4, which crystallize in the noncentrosymmetric space groups Pna21 and Pn, respectively. Synchrotron X-ray powder diffraction (SXRPD) was used to assess the phase purity, and diffuse reflectance UV-vis-NIR spectroscopy was used to estimate the bandgaps of Li2MnGeS4 (Eg = 3.069(3) eV) and Li2CoSnS4 (Eg = 2.421(3) eV). In comparison with Li2FeGeS4, Li2FeSnS4, and Li2CoSnS4 DLSs, Li2MnGeS4 exhibits the widest region of optical transparency (0.60-25 MUm) and phase matchability (>=1.6 MUm). All four of the DLSs exhibit second-harmonic generation and are compared with the benchmark NLO material, AgGaSe2. Most remarkably, Li2MnGeS4 does not undergo two- or three-photon absorption upon exposure to a fundamental Nd:YAG beam (lambda = 1.064 MUm) and exhibits a laser damage threshold > 16 GW/cm(2). PMID- 25710823 TI - Growth of Indonesian Infants Compared With World Health Organization Growth Standards. AB - OBJECTIVES: The ability of the World Health Organization (WHO) growth standards to represent the growth of South East Asian infants has been questioned. The aim of this study was to provide contemporary data on the growth of Indonesian breast fed and formula-fed infants, compared with the WHO growth standards. METHODS: A prospective cohort study of 160 normal healthy infants was undertaken in a suburban area of South Jakarta, Indonesia. Infants from 2 to 6 weeks of age were recruited, and they consumed exclusively either breast milk or infant formula for at least 6 months, with follow-up until 12 months of age. RESULTS: Overall, the infants in the present study were lighter (weight-for-age), were shorter (length for-age), and had smaller head circumferences (head circumference-for-age) than the average WHO Growth Reference Study population but were of similar proportion (weight-for-length). Compared with the WHO Growth Reference Study, the z scores for weight-for-age, length-for-age, and head circumference-for-age in the Indonesian children fell from birth to 6 weeks of age and then increased until 3 months of age in both the breast-fed and the formula-fed infants. At 6 weeks of age, the weight-for-age z scores fell below -2 standard deviations for 16 (20.5%) breast-fed and 40 (51.3%) formula-fed infants, and the length-for-age z scores fell below -2 standard deviations for 31 (39.7%) breast-fed and 41 (52.6%) formula-fed infants. CONCLUSION: The WHO growth standards do not reflect the growth of the present cohort of Indonesian infants and may overestimate the levels of underweight and stunted children. PMID- 25710824 TI - Palytoxin induces dissociation of HSP 27 oligomers through a p38 protein kinase pathway. AB - Palytoxin (PlTX) induces a stress response in MCF-7 cells that involves the phosphorylation of HSP 27 at serines 15, 78, and 82 by an as yet undetermined mechanism. We have studied the involvement of major groups of the mitogen activated protein kinase (MAPK) family in this molecular response and focused our analyses on the ERK1/2, JNK, p38 protein kinase (p38K), and ERK5 pathways. The results show that PlTX induces the activation of JNK and p38 kinase but not ERK1/2 and 5 in MCF-7 cells. Through the use of protein kinase inhibitors, we established that blocking p38K, but not JNK, prevents the phosphorylation of HSP 27 induced by PlTX and that MAPKAPK2 participates in the response induced by the toxin under our experimental conditions. The cell death response induced by PlTX was inhibited by preventing JNK phosphorylation but not by blocking p38K/MAPKAPK2 and HSP 27 phosphorylation. Sucrose density gradient centrifugation revealed that MCF-7 cell extracts contain a heterodisperse population of HSP 27, including oligomers and smaller forms. Treating MCF-7 cells with PlTX caused the dissociation of HSP 27 oligomers, and using inhibitors of the JNK and p38K pathways showed that the dissociation of HSP 27 oligomers induced by PlTX involves a p38K-dependent process. We conclude that the changes induced by PlTX in the HSP 27 stress response protein system proceed through a molecular mechanism involving the activation of the p38 kinase pathway and its substrate, MAPKAK2, leading to dissociation of HSP 27 oligomers and the stabilization of a cellular pool of monomers phosphorylated at serines 15, 78 and 82, which could play a protective role against the death response induced by PlTX. PMID- 25710825 TI - Let there be light .... PMID- 25710826 TI - Pathways in gut-brain communication: evidence for distinct gut-to-brain and brain to-gut syndromes. AB - OBJECTIVE: The rich interconnectedness between gut and brain is increasingly being identified. This article reviews the evidence for brain-gut and gut-brain syndromes, particularly recent epidemiological evidence, and animal studies demonstrating bi-directionality at the formative stage of development. METHOD: Narrative literature review with selection for relevance and quality. RESULTS: Population surveys show a strong correlation between anxiety, depression, and functional gastrointestinal disorders, contradicting early suspicions that the high prevalence of anxiety and depression in the clinic was mainly due to neurotic health seeking behaviour. Five and 12 year follow-up shows that psychological distress can predict later onset of a functional gastrointestinal disorder and vice versa. Brain-gut pathways include the autonomic nervous system, hypothalamic-pituitary-adrenal axis including corticotrophin releasing factor directly acting on the gut. Gut-brain pathways include ascending pain pathways, cytokines including tumour necrosis factor alpha in response to bacterial translocation and inflammation, 5-hydroxytryptamine secretion by entero-endocrine cells and psychoactive chemicals of bacterial origin which may enter the blood stream, such as gamma-aminobutyric acid, fatty acids and 5-hydroxytryptamine precursors. The ability to control rodent temperament and HPA responsiveness with early modification of gastrointestinal flora, and the effects of early stress on the barrier function of the gastrointestinal tract and flora, suggests an ability of both systems to prime each other in early life for later problems. This hypothesis seems to be supported by a possible protective effect of a probiotic strain of bacteria in a model of early rat psychological trauma. CONCLUSION: Psychological treatments are known to improve functional gastrointestinal disorders, the next wave of research may involve preventative microbiological gut based treatments for primary psychological presentations, both to treat the presenting complaint and inoculate against later functional gastrointestinal disorders. PMID- 25710827 TI - Focus on epilepsy. PMID- 25710828 TI - GDNF is not required for catecholaminergic neuron survival in vivo. PMID- 25710829 TI - Reply to "GDNF is not required for catecholaminergic neuron survival in vivo". PMID- 25710830 TI - The amygdala accountant: new tricks for an old structure. PMID- 25710831 TI - Neighborly synapses help each other out. PMID- 25710832 TI - Attention: feedback focuses a wandering mind. PMID- 25710833 TI - Tread softly and carry a clock's tick. PMID- 25710834 TI - Beyond the hammer and the scalpel: selective circuit control for the epilepsies. AB - Current treatment options for epilepsy are inadequate, as too many patients suffer from uncontrolled seizures and from negative side effects of treatment. In addition to these clinical challenges, our scientific understanding of epilepsy is incomplete. Optogenetic and designer receptor technologies provide unprecedented and much needed specificity, allowing for spatial, temporal and cell type-selective modulation of neuronal circuits. Using such tools, it is now possible to begin to address some of the fundamental unanswered questions in epilepsy, to dissect epileptic neuronal circuits and to develop new intervention strategies. Such specificity of intervention also has the potential for direct therapeutic benefits, allowing healthy tissue and network functions to continue unaffected. In this Perspective, we discuss promising uses of these technologies for the study of seizures and epilepsy, as well as potential use of these strategies for clinical therapies. PMID- 25710835 TI - Animal models in epilepsy research: legacies and new directions. AB - Human epilepsies encompass a wide variety of clinical, behavioral and electrical manifestations. Correspondingly, studies of this disease in nonhuman animals have brought forward an equally wide array of animal models; that is, species and acute or chronic seizure induction protocols. Epilepsy research has a long history of comparative anatomical and physiological studies on a range of mostly mammalian species. Nonetheless, a relatively limited number of rodent models have emerged as the primary choices for most investigations. In many cases, these animal models are selected on the basis of convenience or tradition, although technical or experimental rationale does, and should, factor into these decisions. More complex mammalian brains and genetic model organisms including zebrafish have been studied less, but offer substantial advantages that are becoming widely recognized. PMID- 25710836 TI - Pathway-driven discovery of epilepsy genes. AB - Epilepsy genes deliver critical insights into the molecular control of brain synchronization and are revolutionizing our understanding and treatment of the disease. The epilepsy-associated genome is rapidly expanding, and two powerful complementary approaches, isolation of de novo exome variants in patients and targeted mutagenesis in model systems, account for the steep increase. In sheer number, the tally of genes linked to seizures will likely match that of cancer and exceed it in biological diversity. The proteins act within most intracellular compartments and span the molecular determinants of firing and wiring in the developing brain. Every facet of neurotransmission, from dendritic spine to exocytotic machinery, is in play, and defects of synaptic inhibition are over represented. The contributions of somatic mutations and noncoding microRNAs are also being explored. The functional spectrum of established epilepsy genes and the arrival of rapid, precise technologies for genome editing now provide a robust scaffold to prioritize hypothesis-driven discovery and further populate this genetic proto-map. Although each gene identified offers translational potential to stratify patient care, the complexity of individual variation and covert actions of genetic modifiers may confound single-gene solutions for the clinical disorder. In vivo genetic deconstruction of epileptic networks, ex vivo validation of variant profiles in patient-derived induced pluripotent stem cells, in silico variant modeling and modifier gene discovery, now in their earliest stages, will help clarify individual patterns. Because seizures stand at the crossroads of all neuronal synchronization disorders in the developing and aging brain, the neurobiological analysis of epilepsy-associated genes provides an extraordinary gateway to new insights into higher cortical function. PMID- 25710837 TI - Microcircuits and their interactions in epilepsy: is the focus out of focus? AB - Epileptic seizures represent dysfunctional neural networks dominated by excessive and/or hypersynchronous activity. Recent progress in the field has outlined two concepts regarding mechanisms of seizure generation, or ictogenesis. First, all seizures, even those associated with what have historically been thought of as 'primary generalized' epilepsies, appear to originate in local microcircuits and then propagate from that initial ictogenic zone. Second, seizures propagate through cerebral networks and engage microcircuits in distal nodes, a process that can be weakened or even interrupted by suppressing activity in such nodes. We describe various microcircuit motifs, with a special emphasis on one that has been broadly implicated in several epilepsies: feed-forward inhibition. Furthermore, we discuss how, in the dynamic network in which seizures propagate, focusing on circuit 'choke points' remote from the initiation site might be as important as that of the initial dysfunction, the seizure 'focus'. PMID- 25710838 TI - Reprogramming patient-derived cells to study the epilepsies. AB - The epilepsies and related disorders of brain circuitry present significant challenges associated with the use of human cells to study disease mechanisms and develop new therapies. Some of these obstacles are being overcome through the use of induced pluripotent stem cells to obtain patient-derived neural cells for in vitro studies and as a source of cell-based treatments. The field is evolving rapidly with the addition of genome-editing approaches and expanding protocols for generating different neural cell types and three-dimensional tissues, but the application of these techniques to neurological disorders, and particularly to the epilepsies, is in its infancy. We discuss the progress made and the distinct advantages and limitations of using patient-derived cells to study or treat epilepsy, as well as critical future directions for the field. PMID- 25710839 TI - Molecular mechanisms of epilepsy. AB - Decades of experimental work have established an imbalance of excitation and inhibition as the leading mechanism of the transition from normal brain function to seizure. In epilepsy, these transitions are rare and abrupt. Transition processes incorporating positive feedback, such as activity-dependent disinhibition, could provide these uncommon timing features. A rapidly expanding array of genetic etiologies will help delineate the molecular mechanism(s). This delineation will entail quite a bit of cell biology. The genes discovered so far are more remarkable for their diversity than their similarities. PMID- 25710842 TI - Antibacterial barbituric acid analogues inspired from natural 3-acyltetramic acids; synthesis, tautomerism and structure and physicochemical property antibacterial activity relationships. AB - The synthesis, tautomerism and antibacterial activity of novel barbiturates is reported. In particular, 3-acyl and 3-carboxamidobarbiturates exhibited antibacterial activity, against susceptible and some resistant Gram-positive strains of particular interest is that these systems possess amenable molecular weight, rotatable bonds and number of proton-donors/acceptors for drug design as well as less lipophilic character, with physicochemical properties and ionic states that are similar to current antibiotic agents for oral and injectable use. Unfortunately, the reduction of plasma protein affinity by the barbituric core is not sufficient to achieve activity in vivo. Further optimization to reduce plasma protein affinity and/or elevate antibiotic potency is therefore required, but we believe that these systems offer unusual opportunities for antibiotic drug discovery. PMID- 25710843 TI - Eliminating aluminum toxicity in an acid sulfate soil for rice cultivation using plant growth promoting bacteria. AB - Aluminum toxicity is widely considered as the most important limiting factor for plants growing in acid sulfate soils. A study was conducted in laboratory and in field to ameliorate Al toxicity using plant growth promoting bacteria (PGPB), ground magnesium limestone (GML) and ground basalt. Five-day-old rice seedlings were inoculated by Bacillus sp., Stenotrophomonas maltophila, Burkholderia thailandensis and Burkholderia seminalis and grown for 21 days in Hoagland solution (pH 4.0) at various Al concentrations (0, 50 and 100 MUM). Toxicity symptoms in root and leaf were studied using scanning electron microscope. In the field, biofertilizer (PGPB), GML and basalt were applied (4 t.ha-1 each). Results showed that Al severely affected the growth of rice. At high concentrations, the root surface was ruptured, leading to cell collapse; however, no damages were observed in the PGPB inoculated seedlings. After 21 days of inoculation, solution pH increased to >6.0, while the control treatment remained same. Field study showed that the highest rice growth and yield were obtained in the bio-fertilizer and GML treatments. This study showed that Al toxicity was reduced by PGPB via production of organic acids that were able to chelate the Al and the production of polysaccharides that increased solution pH. The release of phytohormones further enhanced rice growth that resulted in yield increase. PMID- 25710844 TI - A meta-analysis of the associations between the SLC6A4 promoter polymorphism (5HTTLPR) and the risk for alcohol dependence. AB - Serotonin reuptake variation is linked to a functional polymorphism in the promoter region of the SLC6A4 gene on chromosome 17. It is plausible that variations in genetically determined SLC6A4 activity may modify the risk for alcohol dependence. To determine whether this allele is associated with alcohol dependence, the authors conducted a systematic review and meta-analysis. Twenty five studies including 8885 participants were reviewed and analyzed. The meta analysis was carried out using a random-effects model. Overall, the results did not support an association between alcohol dependence and the SLC6A4 promoter polymorphism for the dominant, recessive, and additive genetic risk models, respectively [odds ratio (OR)=0.99 (95% confidence interval (CI): 0.83, 1.18), OR=0.86 (95% CI: 0.71, 1.03), and OR=0.88 (95% CI: 0.69, 1.13)]. When effect modification was tested for sex, race/ethnicity, presence/absence of a psychiatric disorder, year of publication, and diagnostic criteria, none of the factors were found to be significantly associated with alcohol dependence. The findings in this meta-analysis suggest that the SLC6A4 promoter polymorphism is not associated with alcohol dependence. PMID- 25710845 TI - Active ribosomal genes, translational homeostasis and oxidative stress in the pathogenesis of schizophrenia and autism. AB - BACKGROUND: Infantile autism and schizophrenia are severe multifactorial disorders with a pronounced genetic predisposition. Their pathogeneses are often associated with oxidative stress in the brain. Previously, we established that a cell's resistance to oxidative stress depended on the copy number of transcriptionally active genes for rRNA (ribosomal genes) in the cell's genome. The feature is measured cytogenetically in cultured lymphocytes derived from patients. It varies from 120 up to 190 copies per diploid genome, with an arithmetic mean of 150+/-4 (SE) copies in a healthy population (n=239), being considerably lower, according to our previous results, in a sample of patients with rheumatoid arthritis (n=49), another multifactorial disease with a proven significant role of oxidative stress in its pathogenesis: from 115 to 165 copies, with a mean of 140+/-4 (SE). Conversely, a sample of schizophrenic patients (n=42) previously showed a higher value of copy number of active rRNA genes compared with a healthy population: from 145 to 190 copies, with a mean of 170+/ 4. This fact is of special interest in the context of the well-known, but still unexplained phenomenon of the reduced comorbidity rate of schizophrenia and rheumatoid arthritis. RESULTS: The copy number of active ribosomal genes was estimated in a sample of autistic children (n=51). In contrast with the schizophrenic patients studied previously, we found that the values were significantly lower than those in the healthy population: from 125 to 160 copies, with a mean of 142+/-5. In this work, we suggest a mathematical model of the oxidative stress dynamics on the basis of Lotka-Volterra's approach to predator prey interactions. In our model, the 'prey' represents reactive oxygen species, whereas the 'predator' simulates molecules of the antioxidant enzymes. The rate of biosynthesis of the latter is limited by the number of ribosomes available, which, in turn, is determined by the copy number of active rRNA genes. Analysis of the model showed the existence of a unique equilibrium point that makes biological sense. The reactive oxygen species level oscillatory approaches this equilibrium value, which inversely depends on the copy number of active rRNA genes. DISCUSSION: Our findings confirm the hypothesis of disturbance of the 'translational homeostasis' in the pathogeneses of autism and schizophrenia, and would help explain why oxidative stress markers are discovered in most autism studies, whereas similar reports related to schizophrenia are far less consistent. PMID- 25710846 TI - Meta-analysis and association of brain-derived neurotrophic factor (BDNF) gene with obsessive-compulsive disorder. AB - Obsessive-compulsive disorder (OCD) is a severe psychiatric condition with a clear genetic component (Nicolini et al., 2009) in which neurodevelopmental mechanisms may be etiologically important. Brain-derived neurotrophic factor (BDNF) is an interesting candidate for molecular analysis in OCD on the basis of potential functional relevance, positive association studies, and reported interaction between this gene and other neurotransmitters implicated in this disorder. PMID- 25710847 TI - Lack of genetic association between the MYO9B locus and schizophrenia in a Chinese population. AB - Jungerius et al. (2008) have reported that the myosin IXB (MYO9B) gene is strongly associated with susceptibility to schizophrenia in a Dutch population. However, this initial work failed to be replicated in a British population (Law et al., 2011). The present study was then undertaken to examine whether the association of MYO9B with schizophrenia could be replicated in a Chinese population. PMID- 25710848 TI - Nanopatterned graphene on a polymer substrate by a direct peel-off technique. AB - A graphene (Gr) on a polyimide (PI) polymer film (Gr-PI film), obtained by a direct peel-off technique, is proposed and investigated. Thanks to its high transparency, electrical conductivity, mechanical strength, and chemical durability, the Gr-PI film is an ideal substrate for flexible electronic and optoelectronic devices, including transistors, light-emitting diodes, and plasmonic antennas. It is obtained using a straightforward method. After spin coating and curing a PI film on Gr previously grown on Cu, one can separate the Gr-PI film from the Cu foil thanks to the difference in the adhesive energy between the Gr-Cu and Gr-PI interfaces. The resulting Gr-PI film shows an average electrical sheet resistance ranging from 520 to 860 Omega/sq and a very high optical transmission (>90%), which have allowed the demonstration of a transparent heater. The surface morphology of the Gr-PI film follows that of the Cu foil, with the latter maintaining its surface properties and allowing in this way its reuse in subsequent chemical vapor deposition growth. The method can also be applied to patterned Gr, as is demonstrated for nanosize ribbons with a width of a few tens of nanometers. PMID- 25710841 TI - Visualizing transient dark states by NMR spectroscopy. AB - Myriad biological processes proceed through states that defy characterization by conventional atomic-resolution structural biological methods. The invisibility of these 'dark' states can arise from their transient nature, low equilibrium population, large molecular weight, and/or heterogeneity. Although they are invisible, these dark states underlie a range of processes, acting as encounter complexes between proteins and as intermediates in protein folding and aggregation. New methods have made these states accessible to high-resolution analysis by nuclear magnetic resonance (NMR) spectroscopy, as long as the dark state is in dynamic equilibrium with an NMR-visible species. These methods - paramagnetic NMR, relaxation dispersion, saturation transfer, lifetime line broadening, and hydrogen exchange - allow the exploration of otherwise invisible states in exchange with a visible species over a range of timescales, each taking advantage of some unique property of the dark state to amplify its effect on a particular NMR observable. In this review, we introduce these methods and explore two specific techniques - paramagnetic relaxation enhancement and dark state exchange saturation transfer - in greater detail. PMID- 25710849 TI - The toxicological effects of thiamethoxam on Gammarus kischineffensis (Schellenberg 1937) (Crustacea: Amphipoda). AB - Neonicotinoids are a new group of insecticides, and little is known about their toxicity to nontarget freshwater organisms an potential effects on freshwater ecosystems. The aim of this study is to establish the acute toxicity and histopathological effects of thiamethoxam-based pesticide on the gill tissue of Gammarus kischineffensis. In this study G. kischineffensis samples were exposed to 2.5, 5, 7.5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90 and 100mg/l of commercial grade thiamethoxam for 96 h. The 24, 48, 72 and 96 h LC50 values were determined as 75.619, 23.505, 8.048 and 3.751 mg/l respectively. In histopathological study the individuals were exposed to 0.004, 0.04 and 0.4 mg/l thiamethoxam concentrations for 14 days. The results showed that the most common changes at all doses of thiamethoxam were vacuolization and hemostatic infiltration in the gill tissue of G. kischineffensis. PMID- 25710850 TI - Effort of controlling the outbreak. PMID- 25710851 TI - A new moment for facing dengue? PMID- 25710852 TI - New insights into tumor immunity revealed by the unique genetic and genomic aspects of ovarian cancer. AB - Ovarian cancer is a challenging disease that nonetheless provokes brisk, prognostically favorable immune responses in many patients. The biology of ovarian cancer offers unique insights into the factors that engender protective tumor immunity. Tumor-infiltrating lymphocyte (TIL) patterns range from CD8+ TIL alone to complex aggregates that additionally include CD4+ and CD20+ TIL. Patient survival rates increase in step with TIL complexity, suggesting cooperative interactions between these lymphocyte subsets. TIL are associated with high-grade serous histology and BRCA1 disruption; the latter may promote immunity through altered cytokine signaling, oxidative stress responses, or antigen expression. The ovarian tumor genome demonstrates extensive spatial and temporal heterogeneity, yet TIL exhibit relatively homogeneous spatial distributions that may reflect core properties of the tumor. In summary, ovarian cancer attracts the attention of the immune system in ways that create unique challenges and opportunities for immunotherapy. PMID- 25710853 TI - Staphylococcus aureus and community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) in and around therapeutic whirlpools in college athletic training rooms. AB - CONTEXT: Community-associated methicillin-resistant Staphylococcus aureus (CA MRSA) has become a leading cause of skin and soft tissue infection in the nonhospitalized community. Care of the athletes in athletic training rooms is specifically designed with equipment tailored to the health care needs of the athletes, yet recent studies indicate that CA-MRSA is still prevalent in athletic facilities and that cleaning methods may not be optimal. OBJECTIVE: To investigate the prevalence of Staphylococcus aureus and CA-MRSA in and around whirlpools in the athletic training room. DESIGN: Cross-sectional study. SETTING: National Collegiate Athletic Association Division I university. PATIENTS OR OTHER PARTICIPANTS: Student-athletes (n = 109) consisting of 46 men (42%) and 63 women (58%) representing 6 sports. MAIN OUTCOME MEASURE(S): Presence of MRSA and Staphylococcus aureus in and around the whirlpool structures relative to sport and number of athletes using the whirlpools. RESULTS: We identified Staphylococcus aureus in 22% (n = 52/240) of the samples and MRSA in 0.8% (n = 2/240). A statistically significant difference existed between the number of athletes using the whirlpool and the presence of Staphylococcus aureus in and around the whirlpools (F(2,238) = 2.445, P = .007). However, Staphylococcus aureus was identified regardless of whether multiple athletes used a whirlpool or no athletes used a whirlpool. We did not identify a relationship between the number of athletes who used a whirlpool and Staphylococcus aureus or MRSA density (P = .134). CONCLUSIONS: Staphylococcus aureus and MRSA were identified in and around the whirlpools. Transmission of the bacteria can be reduced by following the cleaning and disinfecting protocols recommended by the Centers for Disease Control and Prevention. Athletic trainers should use disinfectants registered by the Environmental Protection Agency to sanitize all whirlpools between uses. PMID- 25710854 TI - Sequence-specific, nanomolar peptide binding via cucurbit[8]uril-induced folding and inclusion of neighboring side chains. AB - This paper describes the molecular recognition of the tripeptide Tyr-Leu-Ala by the synthetic receptor cucurbit[8]uril (Q8) in aqueous buffer with nanomolar affinity and exceptional specificity. This combination of characteristics, which also applies to antibodies, is desirable for applications in biochemistry and biotechnology but has eluded supramolecular chemists for decades. Building on prior knowledge that Q8 binds to peptides with N-terminal aromatic residues, a library screen of 105 peptides was designed to test the effects of residues adjacent to N-terminal Trp, Phe, or Tyr. The screen used tetramethylbenzobis(imidazolium) (MBBI) as a fluorescent indicator and resulted in the unexpected discovery that MBBI can serve not only as a turn-off sensor via the simultaneous inclusion of a Trp residue but also as a turn-on sensor via the competitive displacement of MBBI upon binding of Phe- or Tyr-terminated peptides. The unusual fluorescence response of the Tyr series prompted further investigation by (1)H NMR spectroscopy, electrospray ionization mass spectrometry, and isothermal titration calorimetry. From these studies, a novel binding motif was discovered in which only 1 equiv of peptide binds to Q8, and the side chains of both the N-terminal Tyr residue and its immediate neighbor bind within the Q8 cavity. For the peptide Tyr-Leu-Ala, the equilibrium dissociation constant value is 7.2 nM, whereas that of its sequence isomer Tyr Ala-Leu is 34 MUM. The high stability, recyclability, and low cost of Q8 combined with the straightforward incorporation of Tyr-Leu-Ala into recombinant proteins should make this system attractive for the development of biological applications. PMID- 25710855 TI - Association of regional and cultural factors with the prevalence of rheumatoid arthritis in the Mexican population: a multilevel analysis. AB - BACKGROUND: The overall estimated prevalence of rheumatoid arthritis (RA) in Mexico is 1.6%, but there are major variations in different geographic areas of the country. OBJECTIVE: This study aimed to determine the impact of individual and regional variables on the geographic distribution of RA in Mexico. METHODS: This multilevel analysis used data from a cross-sectional study that investigated the prevalence of RA among 19,213 individuals older than 18 years throughout 5 geographic regions in Mexico. Logistic regression models were used to determine predictors of RA, including individual and regional variables as well as cultural factors. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were determined. RESULTS: The prevalence of RA varied from 0.77% to 2.8% across the 5 regions. Individual factors associated with RA were sex (OR, 2.32; 95% CI, 1.74 3.07), previous medical diagnosis of RA ( OR 3.3, 95%CI: 2919-5.1 [corrected]), disability (OR, 2.07; 95% CI, 1.48-2.93), and the 56- to 65-year age group (OR, 1.95; 95% CI, 1.08-3.74). The regional factor of speaking an indigenous language had an OR of 2.27 (95% CI, 1.13-4.55). CONCLUSIONS: Various individual and regional factors were associated with variations in the prevalence of RA in the Mexican population. PMID- 25710857 TI - Pneumocystis jirovecii pneumonia in patients with autoimmune disease on high-dose glucocorticoid. AB - OBJECTIVE: Indications for Pneumocystis jirovecii pneumonia (PCP) prophylaxis in patients with autoimmune disease remain unclear. We aimed to determine (1) the incidence of PCP in patients with autoimmune disease in general, in a clinical setting where prophylaxis is not routine, and (2) whether high-dose glucocorticoid (>=30 mg oral prednisolone or equivalent per day) is a risk factor for PCP infection. METHODS: A retrospective review of the medical records of patients with autoimmune diseases hospitalized to a tertiary center over a 5-year study period was carried out. Patient demographics, mean glucocorticoid dose (in the last 1 month), and the outcomes of patients who developed PCP were analyzed. RESULTS: The incidence rate of PCP infection was 75 per 100,000 patients per year. The in-hospital mortality was 50%, and all those who died were on high-dose glucocorticoid at the time of PCP diagnosis. There was a significant difference between the occurrence of PCP in patients who were on high-dose vs non-high-dose glucocorticoid (df = 1, P = 0.009), with a relative risk of 19 (P = 0.010; 95% confidence interval, 2.0-182.8). The mean oral prednisolone dose of patients who developed PCP and those who did not were 55.5 versus 10.7 mg, respectively, P = 0.002. CONCLUSION: High-dose glucocorticoid may be associated with an increased risk of PCP infection in patients with autoimmune diseases. PMID- 25710856 TI - Presence of gout is associated with increased prevalence and severity of knee osteoarthritis among older men: results of a pilot study. AB - BACKGROUND: Gout and osteoarthritis (OA) are the most prevalent arthritides, but their relationship is neither well established nor well understood. OBJECTIVES: We assessed whether a diagnosis of gout or asymptomatic hyperuricemia (AH) is associated with increased prevalence/severity of knee OA. METHODS: One hundred nineteen male patients aged 55 to 85 years were sequentially enrolled from the primary care clinics of an urban Veterans Affairs hospital, assessed and categorized into 3 groups: gout (American College of Rheumatology Classification Criteria), AH (serum urate >=6.8 mg/dL, no gout), and control (serum urate <6.8 mg/dL, no gout). Twenty-five patients from each group subsequently underwent formal assessment of knee OA presence and severity (American College of Rheumatology Clinical/Radiographic Criteria, Kellgren-Lawrence grade). Musculoskeletal ultrasound was used to detect monosodium urate deposition at the knees and first metatarsophalangeal joints. RESULTS: The study showed 68.0% of gout, 52.0% of AH, and 28.0% of age-matched control subjects had knee OA (gout vs control, P = 0.017). Odds ratio for knee OA in gout versus control subjects was 5.46 prior to and 3.80 after adjusting for body mass index. Gout subjects also had higher Kellgren-Lawrence grades than did the control subjects (P = 0.001). Subjects with sonographically detected monosodium urate crystal deposition on cartilage were more likely to have OA than those without (60.0 vs 27.5%, P = 0.037), with crystal deposition at the first metatarsophalangeal joints correlating most closely with OA knee involvement. CONCLUSIONS: Knee OA was more prevalent in gout patients versus control subjects and intermediate in AH. Knee OA was more severe in gout patients versus control subjects. PMID- 25710858 TI - Risk of falls in patients with ankylosing spondylitis. AB - BACKGROUND: Risk of vertebral fractures is increased in patients with ankylosing spondylitis (AS). The underlying mechanisms for the elevated fracture risk might be associated with bone and fall-related risks. The aims of this study were to evaluate the risk of falls and to determine the factors that increase the risk of falls in AS patients. METHODS: Eighty-nine women, 217 men, a total of 306 AS patients with a mean age of 40.1 +/- 11.5 years from 9 different centers in Turkey were included in the study. Patients were questioned regarding history of falls within the last 1 year. Their demographics, disease characteristics including Bath AS Disease Activity Index, Bath AS Metrology Index (BASMI), Bath AS Functional Index (BASFI), and risk factors for falls were recorded. The Short Physical Performance Battery (SPPB) test was used for evaluation of static and dynamic balance. Erythrocyte sedimentation rate, C-reactive protein, and 25 hydroxyvitamin D levels were measured. RESULTS: Forty of 306 patients reported at least 1 fall in the recent 1 year. The patients with history of falls had higher mean age and longer disease duration than did nonfallers (P = 0.001). In addition, these patients' BASMI and BASFI values were higher than those of nonfallers (P = 0.002; P = 0.000, respectively). We found that the patients with history of falls had lower SPPB scores (P = 0.000). We also found that the number of falls increased with longer disease duration and older age (R = 0.117 [P = 0.041] and R = 0.160 [P = 0.005]). Our results show that decreased SPPB scores were associated with increased number of falls (R = 0.183, P = 0.006). Statistically significant correlations were found between number of falls and AS related lost job (R = 0.140, P = 0.014), fear of falling (R = 0.316, P = 0.000), hip involvement (R = 0.112, P = 0.05), BASMI (R =0.234, P = 0.000), and BASFI (R = 0.244, P = 0.000). CONCLUSIONS: Assessment of pain, stiffness, fatigue, and lower-extremity involvement as well as asking for a history of falls will highlight those at high risk for further falls. In addition to the general exercise program adopted for all patients, we suggest that a balance rehabilitation program should be valuable for the patients with risk factors for fall. Exercise may improve fear of falling and BASFI and BASMI scores. However, further study is needed to investigate these hypotheses. We believe that clinicians should train and support the patients via reducing fear of falls and maintaining good posture and functional capacity. PMID- 25710859 TI - Cross-sectional neurocognitive data do not support a transition from fibrofog to Alzheimer disease in fibromyalgia patients. AB - BACKGROUND: Cognitive dysfunction is a signature feature of fibromyalgia. Many who develop cognitive problems in their middle years are concerned that it is prodromal to Alzheimer's disease. OBJECTIVE: To determine if deficits in episodic memory and progressive cognitive decline, hallmarks of Alzheimer's disease, are prominent in the cognitive makeup of fibromyalgia patients. METHODS: In a cross sectional study, performance on 15 neurocognitive (NC) measures was evaluated in 2 cohorts of fibromyalgia subjects. The first cohort contained 94 subjects with a short duration of cognitive problems (<=12 months). The second cohort contained 55 subjects with a long duration of cognitive problems (>=84 months). RESULTS: The 2 groups were similar in education (14.9 +/- 2.3 vs 14.9 +/- 2.4), vocabulary scale score (11.2 +/- 2.3 vs 11.6 +/- 2.7), and depression (17.9 +/- 9.8 vs 17.7 +/- 9.4). The mean durations of cognitive problems in the short- and long-term group were 7.3 +/- 3.9 months and 13.3 +/- 7.1 years, respectively. There was no evidence of decline on 14 of 15 measures in the fibromyalgia group with an additional 12.6 years of cognitive dysfunction. Normality of function was in evidence on 4 measures of episodic memory in both cohorts. CONCLUSIONS: Fibromyalgia patients' fear of developing Alzheimer's disease was not borne out by the data. The cognitive pattern of fibromyalgia appears distinct from that of Alzheimer's disease. Fibrofog is not associated with either episodic memory loss on standard tests of episodic memory or progressive cognitive decline. Patients with fibrofog remember personally experienced events termed episodic memory at a normal rate in quiet, distraction-free conditions. Patients with Alzheimer's disease do not. They forget the essential elements of short stories just read to them in environments free of distractions. In Alzheimer's disease, the brain mechanisms responsible for encoding personally experienced events into memory are irreversibly impaired. In fibrofog, the encoding mechanisms are intact. At the heart of memory loss in fibromyalgia is the inability to appropriately filter out relevant distractions. Encoding mechanisms that otherwise operate normally in forming episodic memories for everyday events in fibromyalgia appear to malfunction when 2 streams of information operate concurrently (relevant information and a source of distraction overlap). The findings should allay the worries of many with fibromyalgia who fear that fibrofog is the start of a dementing process. PMID- 25710860 TI - Chronic graft-versus-host disease presenting as eosinophilic fasciitis: therapeutic challenges and an additional case. AB - Chronic graft-versus-host disease (cGVHD) is one of the main late complications of allogeneic hematopoietic stem cell transplant and a major contributor to the mortality and morbidity in surviving recipients. Skin is the most common involved organ in cGVHD and may mimic a wide spectrum of dermatological conditions in its clinical and histopathologic manifestations. Some of the commonly simulated diseases are scleroderma, morphea, and lichen sclerosus. Chronic GVHD simulating eosinophilic fasciitis (EF) is relatively rare, frequently presenting with skin induration, a typical "peau d'orange" appearance, peripheral blood eosinophilia, myalgia, arthralgia, and arthritis leading to joint contractures in severe cases.Diagnosis is based on clinical manifestations and histopathology. Treatment is challenging because most cases are refractory to first-line therapy of glucocorticoids and calcineurin inhibitors (CNIs), and there is no standard second-line therapy.We report a comprehensive review of literature on all reported cases of CGVHD presenting as EF. We also describe an additional interesting case of cGVHD presenting as EF that was resistant to traditional therapy of high-dose glucocorticoids and cyclosporin A, but showed complete resolution of skin manifestations after addition of imatinib.Chronic GVHD presenting as EF is a rare variant of sclerodermatous cGVHD. Diagnosis is difficult, and treatment of cGVHD mimicking EF remains a therapeutic challenge because of obscure pathogenesis and poor response to traditional immunosuppressive medications. Emerging insights into the pathogenesis of cGVHD have resulted in the development of novel targeted therapies, which may improve outcomes and should be attempted in this subset of the disease. Larger studies are warranted to substantiate these preliminary findings. PMID- 25710861 TI - Arthritis, eosinophilia, and autoimmune liver disease: a diagnostic challenge. AB - Autoimmune hepatitis (AIH) is a chronic liver disease of unknown etiology. It is composed of immune-mediated liver injury and significant immunological aspects. Arthritis can be observed in patients with AIH before recognition of the disease, which can lead to a diagnostic challenge. Although there are few reported cases in literature, peripheral blood eosinophilia might also play a part in such diagnosis. We report an intriguing case of a 41-year-old man who presented to our service with arthritis and eosinophilia as initial manifestations and was eventually diagnosed with overlap syndrome: AIH and primary sclerosing cholangitis. The present report aims to include eosinophilia among the clinical features of AIH, highlighting the possibility of its detection before the onset of either articular or hepatic disturbances. PMID- 25710862 TI - Ultrasound evaluation of the greater trochanter pain syndrome: bursitis or tendinopathy? PMID- 25710863 TI - Trifid median nerve associated with persistent median artery. PMID- 25710864 TI - Bullhead sign. PMID- 25710865 TI - More than meets the eye. PMID- 25710866 TI - Characteristic dysphagia as a manifestation of dermatomyositis on oropharyngeal muscle imaging. PMID- 25710868 TI - Crystal-induced delirium. PMID- 25710869 TI - Gestational gigantomastia in autoimmune diseases. PMID- 25710870 TI - Recurrent posterior reversible encephalopathy syndrome in a child with microscopic polyangiitis. PMID- 25710871 TI - Correction to "integrative analysis of transcriptomics, proteomics, and metabolomics data of white adipose and liver tissue of high-fat diet and rosiglitazone-treated insulin-resistant mice identified pathway alterations and molecular hubs". PMID- 25710872 TI - Experimental demonstration of a second-order memristor and its ability to biorealistically implement synaptic plasticity. AB - Memristors have been extensively studied for data storage and low-power computation applications. In this study, we show that memristors offer more than simple resistance change. Specifically, the dynamic evolutions of internal state variables allow an oxide-based memristor to exhibit Ca(2+)-like dynamics that natively encode timing information and regulate synaptic weights. Such a device can be modeled as a second-order memristor and allow the implementation of critical synaptic functions realistically using simple spike forms based solely on spike activity. PMID- 25710874 TI - A Population- and Hospital-based Cross-sectional Study of Renal Function in Hidradenitis Suppurativa. AB - The chronic inflammatory skin diseases hidradenitis suppurativa (HS) and psoriasis have been linked to cardiovascular risk factors and the latter has also been linked to possible renal dysfunction. Since basement membrane thinning in the skin of HS patients has been described, we speculated whether similar basement membrane defects might occur in renal tissue. Our objective was to investigate a possible association between HS and renal dysfunction. We performed a hospital and population-based cross-sectional study using estimated Glomerular Filtration-Rate (eGFR) to assess renal function. Thirty-two hospital individuals with HS, 430 population individuals with HS, and 20,780 population individuals without HS were (controls) identified. The age-, sex-, smoking-, BMI-, hypertension- and diabetes-adjusted analysis revealed a statistically significant higher eGFR for the hospital group with HS and a mean difference in eGFR of 6.81 (1.27-12.35) ml/min/1.73 m2 between the hospital group with HS and the population group without HS. The observed higher eGFR in the hospital group with HS indicates a possible association of HS and renal dysfunction. PMID- 25710875 TI - Integrating dimension reduction and out-of-sample extension in automated classification of ex vivo human patellar cartilage on phase contrast X-ray computed tomography. AB - Phase contrast X-ray computed tomography (PCI-CT) has been demonstrated as a novel imaging technique that can visualize human cartilage with high spatial resolution and soft tissue contrast. Different textural approaches have been previously investigated for characterizing chondrocyte organization on PCI-CT to enable classification of healthy and osteoarthritic cartilage. However, the large size of feature sets extracted in such studies motivates an investigation into algorithmic feature reduction for computing efficient feature representations without compromising their discriminatory power. For this purpose, geometrical feature sets derived from the scaling index method (SIM) were extracted from 1392 volumes of interest (VOI) annotated on PCI-CT images of ex vivo human patellar cartilage specimens. The extracted feature sets were subject to linear and non linear dimension reduction techniques as well as feature selection based on evaluation of mutual information criteria. The reduced feature set was subsequently used in a machine learning task with support vector regression to classify VOIs as healthy or osteoarthritic; classification performance was evaluated using the area under the receiver-operating characteristic (ROC) curve (AUC). Our results show that the classification performance achieved by 9-D SIM derived geometric feature sets (AUC: 0.96 +/- 0.02) can be maintained with 2-D representations computed from both dimension reduction and feature selection (AUC values as high as 0.97 +/- 0.02). Thus, such feature reduction techniques can offer a high degree of compaction to large feature sets extracted from PCI-CT images while maintaining their ability to characterize the underlying chondrocyte patterns. PMID- 25710876 TI - Self-reported Symptoms after Induced and Inhibited Bronchoconstriction in Athletes. AB - PURPOSE: A change in the perception of respiratory symptoms after treatment with inhaled beta2 agonists is often used to aid diagnosis of exercise-induced bronchoconstriction (EIB). Our aim was to test the association between subjective ratings of respiratory symptoms and changes in airway caliber after induced and inhibited bronchoconstriction in athletes with EIB. METHODS: Eighty-five athletes with diagnosed or suspected EIB performed a eucapnic voluntary hyperpnea (EVH) challenge with dry air. Of the 45 athletes with hyperpnea-induced bronchoconstriction [i.e., post-EVH fall in forced expiratory volume in 1 s (FEV1) >=10%, EVH], 36 were randomized in a double-blind, placebo-controlled, crossover study. Terbutaline (0.5 mg) or placebo was administered by inhalation 15 min before EVH. Spirometry (for FEV1) was performed before and after EVH, and respiratory symptoms were recorded 15 min after EVH on visual analog scales. RESULTS: Terbutaline inhibited bronchoconstriction (i.e., maximal fall in FEV1 <10% after EVH) in 83% of the EVH-positive athletes, with an average degree of bronchoprotection of 53% (95% confidence interval [CI], 45% to 62%). Terbutaline reduced group mean symptom scores (P < 0.01), but the degree of bronchoprotection did not correlate with individual differences in symptom scores between terbutaline and placebo. Of the 29 athletes who had less than 10% FEV1 fall after EVH in the terbutaline condition, almost half (48%) rated at least one respiratory symptom higher under terbutaline, and more than one quarter (28%) had a higher total symptom score under terbutaline. CONCLUSION: Self-reports of respiratory symptoms in conditions of induced and inhibited bronchoconstriction do not correlate with changes in airway caliber in athletes with EIB. Therefore, subjective ratings of respiratory symptoms after treatment with inhaled beta2 agonists should not be used as the sole diagnostic tool for EIB in athletes. PMID- 25710877 TI - Two cathepsins B are responsible for the yolk protein hydrolysis in Culex quinquefasciatus. AB - Despite the established role of Culex quinquefasciatus as a vector of various neurotropic viruses, such as the Rift Valley and West Nile viruses, as well as lymphatic filariasis, little is known regarding the organism's reproductive physiology. As in other oviparous animals, vitellogenin, the most important source of nutrients for the embryo development, is digested by intracellular proteases. Using mass spectrometry, we have identified two cathepsin B homologues partially purified by self-proteolysis of Cx. quinquefasciatus total egg extract. The transcriptional profile of these two cathepsin B homologues was determined by quantitative RT-PCR, and the enzymatic activity associated with the peptidase was determined in ovaries after female engorgement. According to the VectorBase (vectorbase.org) annotation, both cathepsin B homologues shared approximately 66% identity in their amino acid sequences. The two cathepsin B genes are expressed simultaneously in the fat body of the vitellogenic females, and enzymatic activity was detected within the ovaries, suggesting an extra-ovarian origin. Similar to the transcriptional profile of vitellogenin, cathepsin B transcripts were shown to accumulate post-blood meal and reached their highest expression at 36 h PBM. However, while vitellogenin expression decreased drastically at 48 h PBM, the expression of the cathepsins increased until 84 h PBM, at which time the females of our colony were ready for oviposition. The similarity between their transcriptional profiles strongly suggests a role for the cathepsin B homologues in vitellin degradation. PMID- 25710878 TI - Genetic variation of COLEC10 and COLEC11 and association with serum levels of collectin liver 1 (CL-L1) and collectin kidney 1 (CL-K1). AB - Collectin liver 1 (CL-L1, alias CL-10) and collectin kidney 1 (CL-K1, alias CL 11), encoded by the COLEC10 and COLEC11 genes, respectively, are highly homologous soluble pattern recognition molecules in the lectin pathway of complement. These proteins may be involved in anti-microbial activity and in tissue development as mutations in COLEC11 are one of the causes of the developmental defect syndrome 3MC. We studied variations in COLEC10 and COLEC11, the impact on serum concentration and to what extent CL-L1 and CL-K1 serum concentrations are correlated. We sequenced the promoter regions, exons and exon intron boundaries of COLEC10 and COLEC11 in samples from Danish Caucasians and measured the corresponding serum levels of CL-L1 and CL-K1. The median concentration of CL-L1 and CL-K1 was 1.87 MUg/ml (1.00-4.14 MUg/ml) and 0.32 MUg/ml (0.11-0.69 MUg/ml), respectively. The level of CL-L1 strongly correlated with CL-K1 (rho = 0.7405, P <0.0001). Both genes were highly conserved with the majority of variations in the non-coding regions. Three non-synonymous variations were tested: COLEC10 Glu78Asp (rs150828850, minor allele frequency (MAF): 0.003), COLEC10 Arg125Trp (rs149331285, MAF: 0.007) and COLEC11 His219Arg (rs7567833, MAF: 0.033). Carriers of COLEC10 Arg125Trp had increased CL-L1 serum levels (P = 0.0478), whereas promoter polymorphism COLEC11-9570C>T (rs3820897) was associated with decreased levels of CL-K1 (P = 0.044). In conclusion, COLEC10 and COLEC11 are highly conserved, which may reflect biological importance of CL-L1 and CL-K1. Moreover, the strong inter individual correlation between the two proteins suggests that a major proportion are found as heterooligomers or subjected to the same regulatory mechanisms. PMID- 25710879 TI - Oxidized LDL activates blood platelets through CD36/NOX2-mediated inhibition of the cGMP/protein kinase G signaling cascade. AB - Oxidized low-density lipoprotein (oxLDL) promotes unregulated platelet activation in dyslipidemic disorders. Although oxLDL stimulates activatory signaling, it is unclear how these events drive accelerated thrombosis. Here, we describe a mechanism for oxLDL-mediated platelet hyperactivity that requires generation of reactive oxygen species (ROS). Under arterial flow, oxLDL triggered sustained generation of platelet intracellular ROS, which was blocked by CD36 inhibitors, mimicked by CD36-specific oxidized phospholipids, and ablated in CD36(-/-) murine platelets. oxLDL-induced ROS generation was blocked by the reduced NAD phosphate oxidase 2 (NOX2) inhibitor, gp91ds-tat, and absent in NOX2(-/-) mice. The synthesis of ROS by oxLDL/CD36 required Src-family kinases and protein kinase C (PKC)-dependent phosphorylation and activation of NOX2. In functional assays, oxLDL abolished guanosine 3',5'-cyclic monophosphate (cGMP)-mediated signaling and inhibited platelet aggregation and arrest under flow. This was prevented by either pharmacologic inhibition of NOX2 in human platelets or genetic ablation of NOX2 in murine platelets. Platelets from hyperlipidemic mice were also found to have a diminished sensitivity to cGMP when tested ex vivo, a phenotype that was corrected by infusion of gp91ds-tat into the mice. This study demonstrates that oxLDL and hyperlipidemia stimulate the generation of NOX2-derived ROS through a CD36-PKC pathway and may promote platelet hyperactivity through modulation of cGMP signaling. PMID- 25710881 TI - p53 mediates loss of hematopoietic stem cell function and lymphopenia in Mysm1 deficiency. AB - MYSM1 is a chromatin-binding transcriptional cofactor that deubiquitinates histone H2A. Studies of Mysm1-deficient mice have shown that it is essential for hematopoietic stem cell (HSC) function and lymphopoiesis. Human carriers of a rare MYSM1-inactivating mutation display similar lymphopoietic deficiencies. However, the mechanism by which MYSM1 regulates hematopoietic homeostasis remains unclear. Here, we show that Mysm1-deficiency results in p53 protein elevation in many hematopoietic cell types. p53 is a central regulator of cellular stress responses and HSC homeostasis. We thus generated double-knockout mice to assess a potential genetic interaction between Mysm1 and p53 in hematopoiesis. Mysm1(-/ )p53(-/-) mouse characterization showed a full rescue of Mysm1(-/-) developmental and hematopoietic defects. This included restoration of lymphopoiesis, and HSC numbers and functions. These results establish p53 activation as the driving mechanism for hematopoietic abnormalities in Mysm1 deficiency. Our findings may advance the understanding of p53 regulation in hematopoiesis and implicate MYSM1 as a potential p53 cofactor. PMID- 25710880 TI - Arginine dependence of acute myeloid leukemia blast proliferation: a novel therapeutic target. AB - Acute myeloid leukemia (AML) is one of the most common acute leukemias in adults and children, yet significant numbers of patients relapse and die of disease. In this study, we identify the dependence of AML blasts on arginine for proliferation. We show that AML blasts constitutively express the arginine transporters CAT-1 and CAT-2B, and that the majority of newly diagnosed patients' blasts have deficiencies in the arginine-recycling pathway enzymes argininosuccinate synthase and ornithine transcarbamylase, making them arginine auxotrophic. BCT-100, a pegylated human recombinant arginase, leads to a rapid depletion in extracellular and intracellular arginine concentrations, resulting in arrest of AML blast proliferation and a reduction in AML engraftment in vivo. BCT-100 as a single agent causes significant death of AML blasts from adults and children, and acts synergistically in combination with cytarabine. Using RNA sequencing, 20 further candidate genes which correlated with resistance have been identified. Thus, AML blasts are dependent on arginine for survival and proliferation, as well as depletion of arginine with BCT-100 of clinical value in the treatment of AML. PMID- 25710882 TI - Deformation twinning of ferrocene crystals assisted by the rotational mobility of cyclopentadienyl rings. AB - Deformation twinning, which is a type of plastic deformation, has been particularly investigated in metal materials. However, only a few examples are found in organic solids. We observed mechanical twinning deformation on a simple ferrocene crystal, which is considered the most representative organometallic compound, and evaluated the crystal structures under the twinning state and the shear deformation characteristics by single-crystal X-ray diffraction analysis and uniaxial compression tests. The structural analyses showed the molecular rearrangement during twinning deformation. The shear deformation properties depend on the rotational mobility of the cyclopentadienyl rings in comparison with crystals of nickelocene, ruthenocene, and mixed crystals of ferrocene/ruthenocene. PMID- 25710883 TI - Smectic block copolymer thin films on corrugated substrates. AB - In this work we study equilibrium and non-equilibrium structures of smectic block copolymer thin films deposited on a topographically patterned substrate. A Brazovskii free energy model is employed to analyze the coupling between the smectic texture and the local mean curvature of the substrate. The substrate's curvature produces out-of-plane deformations of the block copolymer such that equilibrium textures are modified and dictated by the underlying geometry. For weak curvatures it is shown that the free energy of the block copolymer film follows a Helfrich form, scaling with the square of the mean curvature, with a bending constant dependent on the local pattern orientation. On substrates of varying mean curvature simulations show that topological defects are rapidly expelled from regions with large curvature. These results compare well with available experimental data of poly(styrene)-co-poly(ethylene-alt-propylene) smectic thin films. PMID- 25710885 TI - Ebola: The Ethics of Thinking Ahead. PMID- 25710887 TI - A novel role of angiopoietin-like-3 associated with podocyte injury. AB - BACKGROUND: Angiopoietin-like-3 (ANGPTL3) expression is increased in glomerular podocytes of nephrotic syndrome. We hypothesize whether ANGPTL3 plays an important role in podocyte injury and promoting proteinuria. METHODS: Angptl3(+/+) and Angptl3(-/-) female mice on B6;129S5 gene background were injected with adriamycin by tail vein at the dose of 25 mg/Kg to produce nephropathy. Proteinuira was measured and podocytes ultrastructure was observed by electron microscopy. The interaction between ANGPTL3 and intergrin beta3 was analyzed by CO-IP and confocal immunofluorescence. The relative gene and protein expression were analyzed by RT-PCR and western blot. RESULTS: The deletion of ANGPTL3 tremendously attenuates proteinuria (more than a fivefold decrease in albuminuria) and protects podocytes from injury in a mouse model of adriamycin induced nephropathy. We further demonstrate that ANGPTL3 interacts with and activates podocyte-expressed integrin beta3 and regulate expression of alpha actinin-4, which may result in the cytoskeletal rearrangement of podocytes. Additionally, we identify the activation of the ANGPTL3-integrin beta3 signaling pathway in patients with nephrotic syndrome. CONCLUSION: ANGPTL3 might play a crucial role in podocyte injury. Either decreasing ANGPTL3 expression or interfering with the ANGPTL3-integrin beta3 interaction might be benefit for podocyte protection and decrease proteinuira. PMID- 25710884 TI - Clinicopathological and prognostic significance of survivin expression in patients with oral squamous cell carcinoma: evidence from a meta-analysis. AB - BACKGROUND: Survivin has been proposed as a promising prognostic marker in oral squamous cell carcinoma (OSCC), but the published data on survivin expression in patients with this condition are controversial. To address this we performed a meta-analysis systematically to assess the clinicopathological and prognostic significance of survivin expression in OSCC. METHODS: We searched PubMed, Embase, Web of Science and Ovid databases for papers investigating the clinicopathological and prognostic significance of survivin expression in OSCC. The pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were used to determine the relevance of survivin. RESULTS: A total of 15 papers, including 1040 cases in which survivin expression was detected by immunohistochemistry (IHC) or reverse transcription polymerase chain reaction (RT PCR), were included. A meta-analysis of clinicopathological variables revealed a correlation between survivin expression and lymph node metastasis (OR = 0.62, 95% CI = 0.44-0.88, p < 0.05) and clinical stage (OR = 0.63, 95% CI = 0.41-0.96, p < 0.05). However, no significant associations were found between survivin expression and tumor differentiation grade (OR = 0.72, 95%CI = 0.26-1.11, p > 0.05), depth of invasion (OR = 0.76, 95% CI = 0.50-1.14, p > 0.05), age (OR = 0.78, 95% CI = 0.48-1.29, p > 0.05) or gender (OR = 1.31, 95% CI = 0.86-2.01, p > 0.05). Subgroup analysis using stratified detection methods showed no significant associations between the expression of survivin protein and clinicopathological variables in OSCC. A correlation between survivin expression and poor prognosis of patients with OSCC (HR = 1.62, 95% CI = 1.23-2.01, p < 0.05) was demonstrated. CONCLUSION: Survivin is a potential prognostic marker of OSCC. Future studies with larger sample sizes and well-designed inclusion criteria will be needed to dissect the role of survivin expression in determining the clinicopathological features and/or prognosis of OSCC. PMID- 25710888 TI - Mechanical analysis of rat trabecular meshwork. AB - Stiffness of trabecular meshwork (TM) may play an important role in regulating outflow resistance in healthy and glaucomatous eyes. However, the current techniques for stiffness measurement can only be applied to TM dissected from human donor or large animal eyes. It is a challenge to measure TM stiffness in mouse/rat eyes because of their smaller sizes and the delicate nature of TM dissection. To this end, a new technique was developed to determine the stiffness of rat TM using atomic force microscopy (AFM). In the study, rat eyes were enucleated immediately after death and perfused with a tracer (Evans blue) for 40 min. Then, the anterior segment was dissected and flat-mounted on a Petri dish with TM facing upwards. An AFM probe with a gold-coated colloid tip was used to sequentially indent the corneal, TM, and uveoscleral tissues. Assuming these tissues to be neo-Hookean materials, the indentation data were analyzed with a newly developed mathematical model to calculate the apparent initial Young's moduli (E0)(app). The geometric mean & SE of (E0)(app) were 162 Pa & 1.2 (n = 13) for TM and 6189 Pa & 1.4 (n = 11) for cornea; and the difference was statistically significant (p < 0.01). The technique established in this study allows the use of rat eye as a potential model for investigation of TM stiffness and its influences on outflow resistance. Future studies may also utilize this technique to evaluate mechanisms of TM stiffness change caused by aging, outflow dysfunction, pathogenesis of glaucoma, and drug treatment. PMID- 25710889 TI - Evaluation of ViroCyt(r) Virus Counter for rapid filovirus quantitation. AB - Development and evaluation of medical countermeasures for diagnostics, vaccines, and therapeutics requires production of standardized, reproducible, and well characterized virus preparations. For filoviruses this includes plaque assay for quantitation of infectious virus, transmission electron microscopy (TEM) for morphology and quantitation of virus particles, and real-time reverse transcription PCR for quantitation of viral RNA (qRT-PCR). The ViroCyt(r) Virus Counter (VC) 2100 (ViroCyt, Boulder, CO, USA) is a flow-based instrument capable of quantifying virus particles in solution. Using a proprietary combination of fluorescent dyes that stain both nucleic acid and protein in a single 30 min step, rapid, reproducible, and cost-effective quantification of filovirus particles was demonstrated. Using a seed stock of Ebola virus variant Kikwit, the linear range of the instrument was determined to be 2.8E+06 to 1.0E+09 virus particles per mL with coefficient of variation ranging from 9.4% to 31.5% for samples tested in triplicate. VC particle counts for various filovirus stocks were within one log of TEM particle counts. A linear relationship was established between the plaque assay, qRT-PCR, and the VC. VC results significantly correlated with both plaque assay and qRT-PCR. These results demonstrated that the VC is an easy, fast, and consistent method to quantify filoviruses in stock preparations. PMID- 25710892 TI - L-Methioninium picrate. AB - Single crystals of l-methioninium picrate were obtained by evaporation of aqueous solution containing equimolar quantities of each component. l-Methioninium picrate crystallizes in the monoclinic system (space group P21, Z=2). The asymmetric unit contains one l-methioninium cation and one picrate anion. The carboxyl group of the cation forms an O-H?O hydrogen bond with the phenoxy oxygen atom and has an O?O distance of 2.669(3)A. The protonated amino group of the l methioninium cation forms N-H?O hydrogen bonds with the phenoxy oxygen atom of the picrate anion and the carbonyl oxygen atom of the symmetry related cation. The infrared and Raman spectra are recorded and discussed. PMID- 25710891 TI - Plant mediated green synthesis and antibacterial activity of silver nanoparticles using Emblica officinalis fruit extract. AB - A green straight forward method of synthesizing silver nanoparticles (AgNPs) in an aqueous medium was designed using Emblica officinalis (EO) fruit extract as stabilizer and reducer. The formation of AgNPs depends on the effect of extract concentration and pH were studied. The AgNPs was synthesized using E.officinalis (fruit extract) and nanoparticles were characterized using UV-Vis spectrophotometer, the presence of biomolecules of E.officinalis capped in AgNPs was found by FT-IR analysis, shape and size were examined by SEM and XRD. The XRD analysis respects the Bragg's law and confirmed the crystalline nature of silver nanoparticles. From XRD the average size of AgNPs was found to be around 15nm. AFM has proved to be very helpful in the determination and verification of various morphological features and parameters. EO fruit extract mediated AgNPs was synthesized and confirmed through kinetic behavior of nanoparticles. The shape of the bio-synthesized AgNPs was spherical. Potent biomolecules of E.officinalis such as polyphenols, glucose, and fructose was capped with AgNPs which reduces the toxicity. The synthesized AgNPs were tested for its antibacterial activity against the isolates by disc diffusion method. The obtained results confirmed that the E.officinalis fruit extract is a very good bioreductant for the synthesis of AgNPs. It was investigated that the synthesized AgNPs showed inhibition and had significant antibacterial against both gram positive and gram-negative bacterial strains. PMID- 25710893 TI - HOMO-LUMO, UV, NLO, NMR and vibrational analysis of 3-methyl-1-phenylpyrazole using FT-IR, FT-RAMAN FT-NMR spectra and HF-DFT computational methods. AB - In this paper, the spectral analysis of 3-methyl-1-phenylpyrazole is carried out using the FT-IR, FT Raman, FT NMR and UV-Vis spectra with the help of quantum mechanical computations using HF and density functional theories. The different conformers of the compound and their minimum energies are studied using B3LYP functional with 6-311+G (d,p) basis set and the most stable conformer with minimum energy was identified and the same conformer was used for further computations. The computed wave numbers from different methods are scaled so as to agree with the experimental values and the scaling factors are reported. All the modes of vibrations are assigned and the structure the molecule is analyzed in terms of parameters like bond length, bond angle and dihedral angle predicted by both HF and B3LYP methods with 6-311+G (d,p) and 6-311++G (d,p) basis sets. The values of dipole moment (MU), polarizability (alpha) and hyperpolarizability (beta) of the molecule are reported, using which the non-linear property of the molecule is discussed. The HOMO-LUMO mappings are reported which reveals the different charge transfer possibilities within the molecule. The isotropic chemical shifts predicted for (1)H and (13)C atoms using gauge invariant atomic orbital (GIAO) theory show good agreement with experimental shifts. NBO analysis is carried out to picture the charge transfer between the localized bonds and lone pairs. The thermodynamic properties (heat capacity, entropy and enthalpy) at different temperatures are also calculated. PMID- 25710894 TI - A label-free electrochemical DNA biosensor based on covalent immobilization of salmonella DNA sequences on the nanoporous glassy carbon electrode. AB - Herein, an easy and cost-effective approach to the immobilization of probe was performed. The amino modified salmonella ssDNA probe sequence was covalently linked with carboxylic group on the surface of nanoporous glassy carbon electrode to prepare the DNA biosensor. The differential pulse voltammetry (DPV) and electrochemical impedance spectroscopy (EIS) techniques were used for the determination of salmonella DNA in the concentration ranges of 10-400pM and 1 400pM with limits of detection of 2.1pM and 0.15pM, respectively. PMID- 25710895 TI - Transition from the Lactational Amenorrhea Method to other modern family planning methods in rural Bangladesh: barrier analysis and implications for behavior change communication program intervention design. AB - The timely transition from Lactational Amenorrhea Method (LAM)(2) to another modern family planning method contributes to healthy spacing of pregnancies by increasing the adoption of family planning during the first year postpartum. Yet, literature suggests challenges in completing a timely LAM transition. To guide program implementation in Bangladesh, this study identified factors influencing women's transition decisions. Eighty postpartum women, comprising 40 who transitioned from LAM(3) and 40 who did not,(4) participated. Half of each group participated in in-depth interviews to explore the decision-making process. All participants responded to a "Barrier Analysis" questionnaire to identify differences in eight behavioral determinants. More than half of transitioners switched to another modern method before or within the same month that LAM ended. Of the 18 transitioners who delayed,(5) 15 waited for menses to return. For non transitioners, key barriers included waiting for menses to return, misconceptions on return to fertility, and perceived lack of familial support. The LAM transition can help women prevent unintended pregnancy during the first year postpartum. Increased emphasis on counseling women about the risk of pregnancy, and misconceptions about personal fertility patterns are critical for facilitating the transition. Strategies should also include interventions that train health workers and improve social support. PMID- 25710897 TI - Universal health coverage: a unique policy opportunity for oral health. PMID- 25710896 TI - Development of an intervention to improve mental health for obstetric fistula patients in Tanzania. AB - Obstetric fistula is a debilitating childbirth injury that has been associated with high rates of psychological distress. Global efforts have helped to link women to surgical repair, but thus far no evidence-based interventions exist to address the psychological needs of these women during the hospital stay. In this paper, we describe the development of a psychological intervention for women in Tanzania who are receiving surgical care for an obstetric fistula. The intervention was developed based on theories of cognitive behavioral therapy and coping models. Content and delivery were informed by qualitative data collection with a range of stakeholders including women with fistula, and input from a study advisory board. The resulting intervention was six individual sessions, delivered by a trained community health nurse. The session topics were (1) recounting the fistula story; (2) creating a new story about the fistula; (3) loss, grief and shame; (4) specific strategies for coping; (5) social relationships; and (6) planning for the future. A trial run of the intervention revealed that the intervention could be delivered with fidelity and was acceptable to patients. A future randomized control trial will evaluate the efficacy of this intervention to address the mental health symptoms of this population. PMID- 25710898 TI - Improving clinical trials in dentistry. PMID- 25710899 TI - Ichthyosis Linearis Circumflexa as the Only Clinical Manifestation of Netherton Syndrome. AB - Ichthyosis linearis circumflexa (ILC) presents as serpiginous and migratory erythematous patches with double-edged scales. ILC is rarely an isolated skin manifestation, but most commonly a part of Netherton syndrome (NS). NS is caused by SPINK5 mutations, which lead to absent or sometimes reduced expression of the serine protease inhibitor LEKTI. NS is characterised by congenital ichthyosiform erytroderma, trichorrhexis invaginata (TI) and atopy. We report 2 children who presented since the first months of life cheek erythema followed by the appearance of sparse ILC lesions on the face, trunk and proximal extremities. Erythroderma at birth, TI and atopy were absent. LEKTI immunoreactivity was reduced in patient epidermis, and serine protease activity was modestly increased, while desmoglein-1 expression remained unaffected. SPINK5 mutation and expression analysis in patient keratinocytes revealed compound heterozygous splicing variants, which allowed residual LEKTI secretion. Our results show that ILC can be the only clinical manifestation of NS. PMID- 25710900 TI - Metallacyclic yttrium alkyl and hydrido complexes: synthesis, structures and catalytic activity in intermolecular olefin hydrophosphination and hydroamination. AB - Metallacyclic neutral and ionic yttrium alkyl complexes coordinated by a dianionic ene-diamido ligand ([2,6-iPr2C6H3NC(Me)=C(Me)NC6H3iPr2-2,6] = L(1)) [L(1)]Y(CH2SiMe3)(THF)2 (2), {[L(1)]Y(CH2SiMe3)2}(-){Li(THF)4}(+) (3), [L(1)]Y(OEt2)(MU-Me)2Li(TMEDA) (4) were synthesized using a salt-metathesis approach starting from the related chloro complex [L(1)]Y(THF)2(MU-Cl)2Li(THF)2 (1) in 70, 85 and 72% yields respectively. The reactions of 2 with H2 or PhSiH3 afford the dimeric hydride {[L(1)]Y(THF)(MU-H)}2(MU-THF) (5) containing two MU bridging hydrido and one MU-bridging THF ligands (91 and 85% yields). The X-ray studies of complexes 2, 3 and 5 revealed eta(2)-coordination of the C=C fragment of an ene-diamido ligand to a Y cation. DFT calculations were carried out to give an insight into the metal-ligand bonding and especially the interaction between the metal and the ene-diamido ligand. The observed bonding of the ene-diamido fragment is found to reflect the acidity of the metal center in the complex that is partially overcome by a better donation from the double bond (better overlap with an empty d orbital at the yttrium center). The treatment of complex 4 with DME resulted in the C-O bond cleavage of DME and afforded a three nuclear methoxide oxide complex [{[L(1)]Y}3(MU(2)-OMe)3(MU(3)-O)](2-)[Li(DME)3](+)2 (6). Complexes 2, 3, 5 and 7 proved to be efficient precatalysts for the intermolecular hydrophosphination of styrene, 4-vinylpyridine, and 1-nonene with PhPH2 and Ph2PH as well as hydroamination of styrene and pyrrolidine. PMID- 25710901 TI - Long-term characterization of residential runoff and assessing potential surrogates of fecal indicator organisms. AB - Investigations into the microbiological impacts of urban runoff on receiving water bodies, especially during storm conditions, have yielded general paradigms that influence runoff abatement and control management strategies. To determine whether these trends are present in other runoff sources, the physical, chemical, and microbiological components of residential runoff from eight neighborhoods in Northern and Southern California were characterized over the course of five years. Sampling occurred regularly and during storm events, resulting in 833 data sets. Analysis of runoff data assisted in characterizing residential runoff, elucidating differences between dry and storm conditions, and identifying surrogates capable of assessing microbiological quality. Results indicate that although microbial loading increases during storm events similar to urban runoff, annual microbial loading in these study sites principally occurs during dry conditions (24% storm, 76% dry). Generated artificial neural network and multiple linear regression models assessed surrogate performance by accurately predicting Escherichia coli concentrations from validation data sets (R(2) = 0.74 and 0.77, respectively), but required input from other fecal indicator organism (FIO) variables to maintain performance (R(2) = 0.27 and 0.18, respectively, without FIO). This long-term analysis of residential runoff highlights characteristics distinct from urban runoff and establishes necessary variables for determining microbiological quality, thus better informing future management strategies. PMID- 25710902 TI - Micro Computer Tomography for medical device and pharmaceutical packaging analysis. AB - Biomedical device and medicine product manufacturing are long processes facing global competition. As technology evolves with time, the level of quality, safety and reliability increases simultaneously. Micro Computer Tomography (Micro CT) is a tool allowing a deep investigation of products: it can contribute to quality improvement. This article presents the numerous applications of Micro CT for medical device and pharmaceutical packaging analysis. The samples investigated confirmed CT suitability for verification of integrity, measurements and defect detections in a non-destructive manner. PMID- 25710903 TI - Development and validation of LC-MS/MS method for quantification of pseudolaric acid B from the root bark of Pseudolarix kaempferi in rat plasma: application to a pharmacokinetic study. AB - Pseudolaric acid B (PAB), which is the main biologically active diterpene acid of Pseudolarix kaempferi, has presented anti-fungal, anti-tumor, anti-fertility, and anti-tubulin activities. In this study, a sensitive and selective liquid chromatography tandem mass spectrometry (LC-MS/MS) method with multiple-reaction monitoring mode was employed for quantification of PAB in rat plasma. The calibration curve was linear over the range of 0.86-288 ng/mL with correlation coefficient (r) greater than 0.995 for PAB, and the lower limit of quantification was 0.86 ng/mL in rat plasma. The accuracy of PAB was between -9.1% and 7.0% relative error, and precision ranged from 1.2 to 10.6% relative standard deviation. This method was successfully applied to the pharmacokinetic studies of PAB in Sprague-Dawley rats. After single intravenous administration of 2.0, 4.0, and 8.0mg/kg PAB to rats, the t1/2 were (16.1 +/- 5.6), (30.0 +/- 13.7), and (27.4 +/- 5.3)min, respectively. The pharmacokinetics (C(2min), AUC) of PAB within the used dosage range were in accordance with linear pharmacokinetic characteristics. PMID- 25710904 TI - Quantitative bioanalysis of paracetamol in rats using volumetric absorptive microsampling (VAMS). AB - Volumetric absorptive microsampling (VAMS) is a simple intuitive technique for collecting and quantitative analysis of dried blood samples. It enables the collection of an accurate blood volume (approximately 10MUL) regardless of blood hematocrit. A bioanalytical method for the determination of paracetamol in dried blood supported on VAMS samplers has been validated and used to support a toxicokinetic (TK) study in rat. The calculated TK parameters were comparable to those obtained from blood-water (1:1, v/v) samples. VAMS is demonstrated to be a robust method that simplifies both the blood sample collection and bioanalytical laboratory procedures and generates high quality quantitative data. However, problems were encountered with controlling the bleed rate during sample collection, resulting in the VAMS tips being flooded and highlighting the need for bleeding methods to be compatible with microsampling techniques to avoid wasting blood. Alternative sample collection procedures are discussed that minimize these issues. PMID- 25710905 TI - Screening and profiling stilbene-type natural products with angiotensin converting enzyme inhibitory activity from Ampelopsis brevipedunculata var. hancei (Planch.) Rehder. AB - In this study, we screened 10 resveratrol derivatives isolated from Ampelopsis brevipedunculata var. hancei (Planch.) Rehder (ABH) for angiotensin I converting enzyme (ACE) inhibitory (ACEI) activity. Among these compounds, (+)-hopeaphenol and (+)-vitisin A showed the lowest IC50 values (~ 1.5 MUM) toward ACE. In addition, the compounds' abundances and distributions in ABH were profiled using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Interestingly, trimers and tetramers of resveratrol were mainly obtained from the bark of ABH when 90% ethanol was used for extraction. This result implies that the antihypertension effect of ABH extract may be mainly contributed by (+)-hopeaphenol (F1) and (+) vitisin A (F2) in the ABH bark due to their remarkable ACE inhibitions. Moreover, the sizes and structures of these compounds were further correlated to their affinities toward ACE using molecular docking calculations. The results showed that resveratrol tetramers interact with ACE more favorably than other smaller oligomers. PMID- 25710906 TI - Microencapsulation of bioactives for food applications. AB - Health issues are an emerging concern to the world population, and therefore the food industry is searching for novel food products containing health-promoting bioactive compounds, with little or no synthetic ingredients. However, there are some challenges in the development of functional foods, particularly in which the direct use of some bioactives is involved. They can show problems of instability, react with other food matrix ingredients or present strong odour and/or flavours. In this context, microencapsulation emerges as a potential approach to overcome these problems and, additionally, to provide controlled or targeted delivery or release. This work intends to contribute to the field of functional food development by performing a comprehensive review on the microencapsulation methods and materials, the bioactives used (extracts and isolated compounds) and the final application development. Although several studies dealing with microencapsulation of bioactives exist, they are mainly focused on the process development and the majority lack proof of concept for final applications. These factors, together with the lack of regulation, in Europe and in the United States, delay the development of new functional foods and, consequently, their market entry. In conclusion, the potential of microencapsulation to protect bioactive compounds ensuring their bioavailability is shown, but further studies are required, considering both its applicability and incentives by regulatory agencies. PMID- 25710907 TI - From data to optimal decision making: a data-driven, probabilistic machine learning approach to decision support for patients with sepsis. AB - BACKGROUND: A tantalizing question in medical informatics is how to construct knowledge from heterogeneous datasets, and as an extension, inform clinical decisions. The emergence of large-scale data integration in electronic health records (EHR) presents tremendous opportunities. However, our ability to efficiently extract informed decision support is limited due to the complexity of the clinical states and decision process, missing data and lack of analytical tools to advice based on statistical relationships. OBJECTIVE: Development and assessment of a data-driven method that infers the probability distribution of the current state of patients with sepsis, likely trajectories, optimal actions related to antibiotic administration, prediction of mortality and length-of-stay. METHODS: We present a data-driven, probabilistic framework for clinical decision support in sepsis-related cases. We first define states, actions, observations and rewards based on clinical practice, expert knowledge and data representations in an EHR dataset of 1492 patients. We then use Partially Observable Markov Decision Process (POMDP) model to derive the optimal policy based on individual patient trajectories and we evaluate the performance of the model-derived policies in a separate test set. Policy decisions were focused on the type of antibiotic combinations to administer. Multi-class and discriminative classifiers were used to predict mortality and length of stay. RESULTS: Data-derived antibiotic administration policies led to a favorable patient outcome in 49% of the cases, versus 37% when the alternative policies were followed (P=1.3e-13). Sensitivity analysis on the model parameters and missing data argue for a highly robust decision support tool that withstands parameter variation and data uncertainty. When the optimal policy was followed, 387 patients (25.9%) have 90% of their transitions to better states and 503 patients (33.7%) patients had 90% of their transitions to worse states (P=4.0e-06), while in the non-policy cases, these numbers are 192 (12.9%) and 764 (51.2%) patients (P=4.6e-117), respectively. Furthermore, the percentage of transitions within a trajectory that lead to a better or better/same state are significantly higher by following the policy than for non-policy cases (605 vs 344 patients, P=8.6e-25). Mortality was predicted with an AUC of 0.7 and 0.82 accuracy in the general case and similar performance was obtained for the inference of the length-of-stay (AUC of 0.69 to 0.73 with accuracies from 0.69 to 0.82). CONCLUSIONS: A data-driven model was able to suggest favorable actions, predict mortality and length of stay with high accuracy. This work provides a solid basis for a scalable probabilistic clinical decision support framework for sepsis treatment that can be expanded to other clinically relevant states and actions, as well as a data-driven model that can be adopted in other clinical areas with sufficient training data. PMID- 25710908 TI - Ly6C(high) monocytes control cerebral toxoplasmosis. AB - Cerebral infection with the parasite Toxoplasma gondii is followed by activation of resident cells and recruitment of immune cells from the periphery to the CNS. In this study, we show that a subset of myeloid cells, namely Ly6C(high)CCR2(+) inflammatory monocytes that infiltrate the brain upon chronic T. gondii infection, plays a decisive role in host defense. Depletion of this monocyte subset resulted in elevated parasite load and decreased survival of infected mice, suggesting their crucial role. Notably, Ly6C(high)CCR2(+) monocytes governed parasite control due to production of proinflammatory mediators, such as IL-1alpha, IL-1beta, IL-6, inducible NO synthase, TNF, and reactive oxygen intermediate. Interestingly, Ly6C(high)CCR2(+) monocytes were also able to produce the regulatory cytokine IL-10, revealing their dual feature. Moreover, we confirmed by adoptive transfer that the recruited monocytes further develop into two distinct subpopulations contributing to parasite control and profound host defense. The differentiated Ly6C(int)CCR2(+)F4/80(int) subset upregulated MHC I and MHC II molecules, suggesting dendritic cell properties such as interaction with T cells, whereas the Ly6C(neg)F4/80(high) cell subset displayed elevated phagocytic capacity while upregulating triggering receptor expressed on myeloid cells-2. Finally, we have shown that the recruitment of Ly6C(high) monocytes to the CNS is regulated by P-selectin glycoprotein ligand-1. These results indicate the critical importance of recruited Ly6C(high) monocytes upon cerebral toxoplasmosis and reveal the behavior of further differentiated myeloid-derived mononuclear cell subsets in parasite control and immune regulation of the CNS. PMID- 25710909 TI - Blimp-1, an intrinsic factor that represses HIV-1 proviral transcription in memory CD4+ T cells. AB - CD4(+) T cell subsets differentially support HIV-1 replication. For example, quiescent CD4(+) memory T cells are susceptible to HIV-1 infection but do not support robust HIV-1 transcription and have been implicated as the primary reservoir of latent HIV-1. T cell transcription factors that regulate maturation potentially limit HIV-1 transcription and mediate the establishment and maintenance of HIV-1 latency. We report that B lymphocyte-induced maturation protein-1 (Blimp-1), a critical regulator of B and T cell differentiation, is highly expressed in memory CD4(+) T cells compared with naive CD4(+) T cells and represses basal and Tat-mediated HIV-1 transcription. Blimp-1 binds an IFN stimulated response element within HIV-1 provirus, and it is displaced following T cell activation. Reduction of Blimp-1 in infected primary T cells including CD4(+) memory T cells increases RNA polymerase II processivity, histone acetylation, and baseline HIV-1 transcription. Therefore, the transcriptional repressor, Blimp-1, is an intrinsic factor that predisposes CD4(+) memory T cells to latent HIV-1 infection. PMID- 25710910 TI - CIKS/DDX3X interaction controls the stability of the Zc3h12a mRNA induced by IL 17. AB - IL-17 is a proinflammatory cytokine that promotes the expression of different cytokines and chemokines via the induction of gene transcription and the posttranscriptional stabilization of mRNAs. In this study, we show that IL-17 increases the half-life of the Zc3h12a mRNA via interaction of the adaptor protein CIKS with the DEAD box protein DDX3X. IL-17 stimulation promotes the formation of a complex between CIKS and DDX3X, and this interaction requires the helicase domain of DDX3X but not its ATPase activity. DDX3X knockdown decreases the IL-17-induced stability of Zc3h12a without affecting the stability of other mRNAs. IKKepsilon, TNFR-associated factor 2, and TNFR-associated factor 5 were also required to mediate the IL-17-induced Zc3h12a stabilization. DDX3X directly binds the Zc3h12a mRNA after IL-17 stimulation. Collectively, our findings define a novel, IL-17-dependent mechanism regulating the stabilization of a selected mRNA. PMID- 25710911 TI - Canonical wnt signaling in dendritic cells regulates Th1/Th17 responses and suppresses autoimmune neuroinflammation. AB - Breakdown in immunological tolerance to self-Ags or uncontrolled inflammation results in autoimmune disorders. Dendritic cells (DCs) play an important role in regulating the balance between inflammatory and regulatory responses in the periphery. However, factors in the tissue microenvironment and the signaling networks critical for programming DCs to control chronic inflammation and promote tolerance are unknown. In this study, we show that wnt ligand-mediated activation of beta-catenin signaling in DCs is critical for promoting tolerance and limiting neuroinflammation. DC-specific deletion of key upstream (lipoprotein receptor related protein [LRP]5/6) or downstream (beta-catenin) mediators of canonical wnt signaling in mice exacerbated experimental autoimmune encephalomyelitis pathology. Mechanistically, loss of LRP5/6-beta-catenin-mediated signaling in DCs led to an increased Th1/Th17 cell differentiation but reduced regulatory T cell response. This was due to increased production of proinflammatory cytokines and decreased production of anti-inflammatory cytokines such as IL-10 and IL-27 by DCs lacking LRP5/6-beta-catenin signaling. Consistent with these findings, pharmacological activation of canonical wnt/beta-catenin signaling delayed experimental autoimmune encephalomyelitis onset and diminished CNS pathology. Thus, the activation of canonical wnt signaling in DCs limits effector T cell responses and represents a potential therapeutic approach to control autoimmune neuroinflammation. PMID- 25710912 TI - Repression of Ccr9 transcription in mouse T lymphocyte progenitors by the Notch signaling pathway. AB - The chemokine receptor CCR9 controls the immigration of multipotent hematopoietic progenitor cells into the thymus to sustain T cell development. Postimmigration, thymocytes downregulate CCR9 and migrate toward the subcapsular zone where they recombine their TCR beta-chain and gamma-chain gene loci. CCR9 is subsequently upregulated and participates in the localization of thymocytes during their selection for self-tolerant receptor specificities. Although the dynamic regulation of CCR9 is essential for early T cell development, the mechanisms controlling CCR9 expression have not been determined. In this article, we show that key regulators of T cell development, Notch1 and the E protein transcription factors E2A and HEB, coordinately control the expression of Ccr9. E2A and HEB bind at two putative enhancers upstream of Ccr9 and positively regulate CCR9 expression at multiple stages of T cell development. In contrast, the canonical Notch signaling pathway prevents the recruitment of p300 to the putative Ccr9 enhancers, resulting in decreased acetylation of histone H3 and a failure to recruit RNA polymerase II to the Ccr9 promoter. Although Notch signaling modestly modulates the binding of E proteins to one of the two Ccr9 enhancers, we found that Notch signaling represses Ccr9 in T cell lymphoma lines in which Ccr9 transcription is independent of E protein function. Our data support the hypothesis that activation of Notch1 has a dominant-negative effect on Ccr9 transcription and that Notch1 and E proteins control the dynamic expression of Ccr9 during T cell development. PMID- 25710913 TI - Specific roles of each TCR hemichain in generating functional chain-centric TCR. AB - TCRalpha- and beta-chains cooperatively recognize peptide-MHC complexes. It has been shown that a "chain-centric" TCR hemichain can, by itself, dictate MHC restricted Ag specificity without requiring major contributions from the paired TCR counterchain. Little is known, however, regarding the relative contributions and roles of chain-centric and its counter, non-chain-centric, hemichains in determining T cell avidity. We comprehensively analyzed a thymically unselected T cell repertoire generated by transducing the alpha-chain-centric HLA A*02:01(A2)/MART127-35 TCRalpha, clone SIG35alpha, into A2-matched and unmatched postthymic T cells. Regardless of their HLA-A2 positivity, a substantial subset of peripheral T cells transduced with SIG35alpha gained reactivity for A2/MART127 35. Although the generated A2/MART127-35-specific T cells used various TRBV genes, TRBV27 predominated with >10(2) highly diverse and unique clonotypic CDR3beta sequences. T cells individually reconstituted with various A2/MART127-35 TRBV27 TCRbeta genes along with SIG35alpha possessed a wide range (>2 log orders) of avidity. Approximately half possessed avidity higher than T cells expressing clone DMF5, a naturally occurring A2/MART127-35 TCR with one of the highest affinities. Importantly, similar findings were recapitulated with other self-Ags. Our results indicate that, although a chain-centric TCR hemichain determines Ag specificity, the paired counterchain can regulate avidity over a broad range (>2 log orders) without compromising Ag specificity. TCR chain centricity can be exploited to generate a thymically unselected Ag-specific T cell repertoire, which can be used to isolate high-avidity antitumor T cells and their uniquely encoded TCRs rarely found in the periphery because of tolerance. PMID- 25710914 TI - cGAS and Ifi204 cooperate to produce type I IFNs in response to Francisella infection. AB - Type I IFN production is an important host immune response against viral and bacterial infections. However, little is known about the ligands and corresponding host receptors that trigger type I IFN production during bacterial infections. We used a model intracellular pathogen, Francisella novicida, to begin characterizing the type I IFN response to bacterial pathogens. F. novicida replicates in the cytosol of host cells and elicits a robust type I IFN response that is largely TLR independent, but is dependent on the adapter molecule STING, suggesting that the type I IFN stimulus during F. novicida infection is cytosolic. In this study, we report that the cytosolic DNA sensors, cyclic GMP AMP synthase (cGAS) and Ifi204, are both required for the STING-dependent type I IFN response to F. novicida infection in both primary and immortalized murine macrophages. We created cGAS, Ifi204, and Sting functional knockouts in RAW264.7 macrophages and demonstrated that cGAS and Ifi204 cooperate to sense dsDNA and activate the STING-dependent type I IFN pathway. In addition, we show that dsDNA from F. novicida is an important type I IFN stimulating ligand. One outcome of cGAS-STING signaling is the activation of the absent in melanoma 2 inflammasome in response to F. novicida infection. Whereas the absent in melanoma 2 inflammasome is beneficial to the host during F. novicida infection, type I IFN signaling by STING and IFN regulatory factor 3 is detrimental to the host during F. novicida infection. Collectively, our studies indicate that cGAS and Ifi204 cooperate to sense cytosolic dsDNA and F. novicida infection to produce a strong type I IFN response. PMID- 25710915 TI - Myeloid HIF-1 is protective in Helicobacter pylori-mediated gastritis. AB - Helicobacter pylori infection triggers chronic inflammation of the gastric mucosa that may progress to gastric cancer. The hypoxia-inducible factors (HIFs) are the central mediators of cellular adaptation to low oxygen levels (hypoxia), but they have emerged recently as major transcriptional regulators of immunity and inflammation. No studies have investigated whether H. pylori affects HIF signaling in immune cells and a potential role for HIF in H. pylori-mediated gastritis. HIF-1 and HIF-2 expression was examined in human H. pylori-positive gastritis biopsies. Subsequent experiments were performed in naive and polarized bone marrow-derived macrophages from wild-type (WT) and myeloid HIF-1alpha-null mice (HIF-1(Deltamyel)). WT and HIF-1(Deltamyel) mice were inoculated with H. pylori by oral gavage and sacrificed 6 mo postinfection. HIF-1 was specifically expressed in macrophages of human H. pylori-positive gastritis biopsies. Macrophage HIF-1 strongly contributed to the induction of proinflammatory genes (IL-6, IL-1beta) and inducible NO synthase in response to H. pylori. HIF-2 expression and markers of M2 macrophage differentiation were decreased in response to H. pylori. HIF-1(Deltamyel) mice inoculated with H. pylori for 6 mo presented with a similar bacterial colonization than WT mice but, surprisingly, a global increase of inflammation, leading to a worsening of the gastritis, measured by an increased epithelial cell proliferation. In conclusion, myeloid HIF-1 is protective in H. pylori-mediated gastritis, pointing to the complex counterbalancing roles of innate immune and inflammatory phenotypes in driving this pathology. PMID- 25710917 TI - MicroRNA-223 regulates inflammation and brain injury via feedback to NLRP3 inflammasome after intracerebral hemorrhage. AB - NLRP3 inflammasome, the multimeric protein complexes involved in the processing of IL-1beta through Caspase-1 cleavage, facilitates the inflammatory response. The control and activation of NLRP3 after intracerebral hemorrhage have not been fully studied. In the current study, we explore the specific microRNA which could regulate the NLRP3 inflammasome and inflammation after intracerebral hemorrhage. We detected the inverse relationship between the expression of miR-223 and NLRP3. We found that NLRP3 mRNA contains conserved miR-223 binding sites in its 3' UTR, and miR-223 could directly regulate NLRP3 expression through these 3' UTR sites. Our results indicate that miR-223 could downregulate NLRP3 to inhibit inflammation through caspase-1 and IL-1beta, reduce brain edema and improve neurological functions. Together, miR-223 may be a vital regulator of NLRP3 inflammasome activation. The results suggest that miR-223 represents a novel target reducing the inflammatory response, and offers a new therapeutical strategy following ICH. PMID- 25710918 TI - Bilateral Sporotrichoid Cutaneous Infection by Mycobacterium haemophilum in a Chinese Patient with Systemic Lupus Erythematosus. PMID- 25710916 TI - 'Do Well B.': Design Of WELL Being monitoring systems. A study protocol for the application in autism. AB - INTRODUCTION: Individuals with autism spectrum disorder (ASD) have difficulties in communication and social interaction resulting from atypical perceptual and cognitive information processing, leading to an accumulation of anxiety. Extreme overloading experienced internally may not be externally visible. Identifying stressful situations at an early stage may avoid socially problematic behaviour from occurring, such as self-injurious behaviour. Activation of the autonomous nervous system (ANS) is involved in the response to anxiety, which can be measured through heart rate variability and skin conductance with the use of portable devices, non-intrusively and pain-free. Thus, developing innovative analysis of signal perception and reaction is necessary, mainly for non communicative individuals with autism. METHODS AND ANALYSIS: The protocol will take place in real life (home and social environments). We aim to associate modifications of the ANS with external events that will be recorded in a synchronous manner through a specific design (spy glasses with video/audio recording). Four phases will be carried out on ASD participants and aged-matched controls: (1) 24-hour baseline pre-experiment (physical activity, sleep), (2) 2 h in a real life situation, (3) 30 min in a quiet environment, interrupted by a few seconds of stressful sound, (4) an interview to record feelings about events triggering anxiety. ASD and control participants will be together for phases 2 and 3, revealing different physiological responses to the same situations, and thus identifying potentially problematic events. The novelty will be to apply time-series analyses (which led to several Nobel Prizes in quantitative finance) on ANS series (heart rate, heart rate variability, skin conductance) and wrist motion. ETHICS AND DISSEMINATION: Ethical approval has been obtained from Ethics Committee of Clermont-Ferrand (South-East I), France (2014-A00611-46). Trial findings will be disseminated via open-access peer-reviewed publications, conferences, clinical networks, public lectures and our websites. TRIAL REGISTRATION NUMBER: ClinicalTrials identifier NCT02275455. PMID- 25710919 TI - Next steps for cancer immune therapy. PMID- 25710920 TI - Multisystem Morbidity and Mortality in Offspring of Women With Type 1 Diabetes (the EPICOM Study): A Register-Based Prospective Cohort Study. AB - OBJECTIVE: This study examined the long-term consequences for offspring born to mothers with pregestational type 1 diabetes regarding mortality, hospital admissions, and medication. We also examined the association between HbA1c levels during pregnancy and mortality and incidence of hospital admissions. RESEARCH DESIGN AND METHODS: We performed a prospective combined clinical and register based cohort study comparing mortality, hospital admissions, and use of medication in offspring (n = 1,326) of women with pregestational type 1 diabetes (index children) with matched control subjects (n = 131,884). We also examined the association between HbA1c levels during pregnancy and mortality and the incidence of hospital admissions. Participants were monitored from birth to the age of 13-21 years. RESULTS: Overall mortality was significantly increased for index children (hazard ratio 2.10, 95% CI 1.33-3.30, P = 0.001). The incidence of hospital admissions for index children was significantly increased (incidence rate ratio [IRR] 1.45, 95% CI 1.38-1.53, P < 0.001), and this was the case for all age groups until the age of 15 years. The incidence of hospital admissions among index children was positively associated with maternal HbA1c before pregnancy and in the first trimester. In addition, the overall use of medication was increased in index children (IRR 1.13, 95% CI 1.07-1.19, P < 0.001). CONCLUSIONS: Type 1 diabetes during pregnancy has long-term implications on the health of offspring, with increased mortality, incidence of hospital admissions, and use of medication. Among mothers with type 1 diabetes, glycemic regulation is positively associated with incidence of hospital admissions in offspring. PMID- 25710921 TI - Post-Glucose Load Plasma alpha-Dicarbonyl Concentrations Are Increased in Individuals With Impaired Glucose Metabolism and Type 2 Diabetes: The CODAM Study. AB - OBJECTIVE: There is increasing evidence that postprandial glucose excursions play an important role in the development of vascular complications. The underlying mechanism is unknown, but glucose-derived formation of reactive alpha-dicarbonyl compounds may explain why acute hyperglycemia leads to increased risk for diabetes complications. In the current study, we investigated whether alpha dicarbonyls are increased after a glucose load in individuals without or with impaired glucose metabolism (IGM) and type 2 diabetes. RESEARCH DESIGN AND METHODS: Cross-sectional, linear analyses were performed in the Cohort on Diabetes and Atherosclerosis Maastricht (CODAM [n = 574, 61% men, 60 years old]) study. Individuals with normal glucose metabolism (n = 279), IGM (n = 120), and type 2 diabetes (n = 92) who had complete data on an oral glucose tolerance test (OGTT) and were not on insulin treatment were included in the study population. Plasma alpha-dicarbonyl (methylglyoxal [MGO], glyoxal [GO], and 3-deoxyglucosone [3-DG]) levels were measured in the fasting state and in samples of the OGTT by ultra-performance liquid chromatography-tandem mass spectrometry. RESULTS: The presence of both IGM and type 2 diabetes was significantly associated with higher alpha-dicarbonyl incremental areas under the curve (iAUCs), as calculated from the OGTT (for IGM, MGO beta = 0.190 [95% CI 0.106-0.274], GO beta = 0.287 [95% CI 0.172-0.401], and 3-DG beta = 0.285 [95% CI 0.221-0.349]; for type 2 diabetes, MGO beta = 0.293 [95% CI 0.180-0.405], GO beta = 0.536 [95% CI 0.382-0.689], and 3-DG beta = 0.542 [95% CI 0.456-0.628]). Adjustment for glucose iAUC attenuated these associations. iAUCs of the alpha-dicarbonyls correlated highly with glucose iAUC but not with fasting glucose levels or HbA1c. CONCLUSIONS: The increased levels of alpha-dicarbonyls during an OGTT in individuals with IGM and type 2 diabetes underline the potential importance of alpha-dicarbonyl stress as a candidate to explain the increased risk of diabetes complications in individuals with postprandial hyperglycemia. PMID- 25710923 TI - Efficacy of a web-based intervention with mobile phone support in treating depressive symptoms in adults with type 1 and type 2 diabetes: a randomized controlled trial. AB - OBJECTIVE: Depression is common in diabetes and linked to adverse health outcomes. This study evaluated the efficacy of a guided web-based intervention in reducing depression in adults with type 1 and type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 260 participants with diabetes and elevated depressive symptoms (Center for Epidemiologic Studies Depression Scale [CES-D >=23]) were randomly assigned to the GET.ON Mood Enhancer Diabetes (a guided self-help intervention, n = 130) or a brief online unguided psychoeducation program for depression (n = 130). The primary outcome was depressive symptoms severity (CES D). The secondary outcomes included diabetes-specific emotional distress (Problem Areas in Diabetes [PAID] scale) and participant satisfaction (adaption CSQ-8). Data were collected at baseline and 2 months after randomization. To identify differences in outcome between the groups, we used analyses of covariance with the baseline CES-D score as covariate on both intent-to-treat (ITT) and per protocol (PP) basis. RESULTS: Compared with the control group, the intervention group showed significantly less depressive symptom severity at posttreatment based on ITT (d = 0.89) and PP analyses (d = 1.00). The intervention participants displayed a significantly larger reduction in diabetes-specific emotional distress (d = 0.58, ITT). The intervention appeared to be acceptable to the participants; 95% (n = 121) would recommend the training to a friend with diabetes in need of psychological help. CONCLUSIONS: A guided, web-based intervention to reduce depression in adults with type 1 and type 2 diabetes is effective in reducing both depressive symptoms and diabetes-specific emotional distress. PMID- 25710922 TI - Preventable major cardiovascular events associated with uncontrolled glucose, blood pressure, and lipids and active smoking in adults with diabetes with and without cardiovascular disease: a contemporary analysis. AB - OBJECTIVE: The objective of this study was to assess the incidence of major cardiovascular (CV) hospitalization events and all-cause deaths among adults with diabetes with or without CV disease (CVD) associated with inadequately controlled glycated hemoglobin (A1C), high LDL cholesterol (LDL-C), high blood pressure (BP), and current smoking. RESEARCH DESIGN AND METHODS: Study subjects included 859,617 adults with diabetes enrolled for more than 6 months during 2005-2011 in a network of 11 U.S. integrated health care organizations. Inadequate risk factor control was classified as LDL-C >=100 mg/dL, A1C >=7% (53 mmol/mol), BP >=140/90 mm Hg, or smoking. Major CV events were based on primary hospital discharge diagnoses for myocardial infarction (MI) and acute coronary syndrome (ACS), stroke, or heart failure (HF). Five-year incidence rates, rate ratios, and average attributable fractions were estimated using multivariable Poisson regression models. RESULTS: Mean (SD) age at baseline was 59 (14) years; 48% of subjects were female, 45% were white, and 31% had CVD. Mean follow-up was 59 months. Event rates per 100 person-years for adults with diabetes and CVD versus those without CVD were 6.0 vs. 1.7 for MI/ACS, 5.3 vs. 1.5 for stroke, 8.4 vs. 1.2 for HF, 18.1 vs. 40 for all CV events, and 23.5 vs. 5.0 for all-cause mortality. The percentages of CV events and deaths associated with inadequate risk factor control were 11% and 3%, respectively, for those with CVD and 34% and 7%, respectively, for those without CVD. CONCLUSIONS: Additional attention to traditional CV risk factors could yield further substantive reductions in CV events and mortality in adults with diabetes. PMID- 25710924 TI - Impact of parental socioeconomic status on excess mortality in a population-based cohort of subjects with childhood-onset type 1 diabetes. AB - OBJECTIVE: The aim of this study was to analyze the possible impact of parental and individual socioeconomic status (SES) on all-cause mortality in a population based cohort of patients with childhood-onset type 1 diabetes. RESEARCH DESIGN AND METHODS: Subjects recorded in the Swedish Childhood Diabetes Registry (SCDR) from 1 January 1978 to 31 December 2008 were included (n = 14,647). The SCDR was linked to the Swedish Cause of Death Registry (CDR) and the Longitudinal Integration Database for Health Insurance and Labour Market Studies (LISA). RESULTS: At a mean follow-up of 23.9 years (maximum 46.5 years), 238 deaths occurred in a total of 349,762 person-years at risk. In crude analyses, low maternal education predicted mortality for male patients only (P = 0.046), whereas parental income support predicted mortality in both sexes (P < 0.001 for both). In Cox models stratified by age-at-death group and adjusted for age at onset and sex, parental income support predicted mortality among young adults (>=18 years of age) but not for children. Including the adult patient's own SES in a Cox model showed that individual income support to the patient predicted mortality occurring at >=24 years of age when adjusting for age at onset, sex, and parental SES. CONCLUSIONS: Exposure to low SES, mirrored by the need for income support, increases mortality risk in patients with childhood-onset type 1 diabetes who died after the age of 18 years. PMID- 25710925 TI - Use of coronary artery calcium scanning beyond coronary computed tomographic angiography in the emergency department evaluation for acute chest pain: the ROMICAT II trial. AB - BACKGROUND: Whether a coronary artery calcium (CAC) scan provides added value to coronary computed tomographic angiography (CCTA) in emergency department patients with acute chest pain remains unsettled. We sought to determine the value of CAC scan in patients with acute chest pain undergoing CCTA. METHODS AND RESULTS: In the multicenter Rule Out Myocardial Infarction using Computer-Assisted Tomography (ROMICAT) II trial, we enrolled low-intermediate risk emergency department patients with symptoms suggesting acute coronary syndrome (ACS). In this prespecified subanalysis of 473 patients (54+/-8 years, 53% men) who underwent both CAC scanning and CCTA, the ACS rate was 8%. Overall, 53% of patients had CAC=0 of whom 2 (0.8%) developed ACS, whereas 7% had CAC>400 with 49% whom developed ACS. C-statistic of CAC>0 was 0.76, whereas that using the optimal cut point of CAC>=22 was 0.81. Continuous CAC score had lower discriminatory capacity than CCTA (c-statistic, 0.86 versus 0.92; P=0.03). Compared with CCTA alone, there was no benefit combining CAC score with CCTA (c-statistic, 0.93; P=0.88) or with selective CCTA strategies after initial CAC>0 or optimal cut point CAC>=22 (P>=0.09). Mean radiation dose from CAC acquisition was 1.4+/-0.7 mSv. Higher CAC scores resulted in more nondiagnostic CCTA studies although the majority remained interpretable. CONCLUSIONS: In emergency department patients with acute chest pain, CAC score does not provide incremental value beyond CCTA for ACS diagnosis. CAC=0 does not exclude ACS, nor a high CAC score preclude interpretation of CCTA in most patients. Thus, CAC results should not influence the decision to proceed with CCTA, and the decision to perform a CAC scan should be balanced with the additional radiation exposure required. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01084239. PMID- 25710926 TI - Liraglutide prevents fast weight gain and beta-cell dysfunction in male catch-up growth rats. AB - We reported recently that after a nutritional growth retardation, rats showed significant weight gain, central fat accumulation, dyslipidemia, and beta-cell dysfunction during a catch-up growth (CUG) phase. Here, we investigated whether glucagon-like peptide-1 (GLP-1) ameliorated the rapid weight gain, central fat deposition, and beta-cell dysfunction during the CUG in rats. Sixty-four male Sprague Dawley rats were stratified into four groups including normal control group, CUG group, catch-up growth with liraglutide treatment group, and catch-up growth with liraglutide and exendin 9-39 treatment group. Energy intake, body weight, and body length were monitored. Fat mass percentage was analyzed by dual energy X-ray absorptiometry scan. Plasma triglyceride and non-esterified fatty acid were measured. The beta-cell mass was analyzed by morphometric analysis and signaling molecules were examined by Western blot and real-time PCR. Insulin secretion capability was evaluated by hyperglycemic clamp test. Liraglutide prevented weight gain and improved lipid and glucose metabolism in rats under CUG conditions, which were associated with reduced fasting insulin levels and improved glucose-stimulated insulin secretion. Improved beta-cell function is found to be associated with increased beta-cell replication as determined by beta cell density and insulin-Ki67 dual staining. Furthermore, liraglutide increased islet pancreatic duodenal homeobox-1 (Pdx-1) and B-cell lymphoma-2 transcript and protein expression, and reduced Procaspase-3 transcript and Caspase-3 p11 subunit protein expression, suggesting that expression of Pdx-1 and reduction of apoptosis may be the mechanisms involved. The therapeutic effects were attenuated in rats co-administered with exendin 9-39, suggesting a GLP-1 receptor-dependent mechanism. These studies revealed that incretin therapy effectively prevented fast weight gain and beta-cell dysfunction in rats under conditions of nutrition restriction followed by nutrition excess, which is in part due to enhanced functional beta-cell mass and insulin secretory capacity. PMID- 25710927 TI - Losartan reduces oxidative damage to renal DNA and conserves plasma antioxidant capacity in diabetic rats. AB - Increased reactive oxygen species (ROS) levels produced by hyperglycemia and angiotensin-II (AT-II) are considered among the pathogenic factors in the malignant transformation of diabetic renal cells. We aimed to investigate the potential role of AT-II in the increased cancer risk seen in diabetes; measuring oxidative damage to renal DNA and protective antioxidant defenses, including adiponectin (Adp) and plasma antioxidant capacity by the Ferric Reducing Ability of Plasma (FRAP) method. In the kidney of streptozotocin (STZ)-induced (55 mg/kg) diabetic rats either treated or not treated for 3 weeks with losartan, an AT-II type 1 receptor antagonist (20 mg/kg/day); we measured 8-oxo-7,8-dihydro-2' deoxyguanosine (8-oxodGuo) levels, as an index of oxidative DNA damage, circulating Adp and FRAP. Diabetic rats showed significantly higher 8-oxodGuo levels in renal DNA (8.48 +/- 0.98 * 10(-6) dG, mean +/- SEM n = 11) than normoglycemic ones (1.18 +/- 0.04 * 10(-6) dG, mean +/- SEM, n=7) and lower plasma Adp and FRAP levels in comparison to normoglycemics. The treatment of diabetic rats with losartan significantly (P < 0.01) reduced 8-oxodGuo levels (5.4 +/- 0.58 * 10(-6) dG, mean +/- SEM n=9) in renal DNA and conserved FRAP values. Moreover, an inverse correlation was found between 8-oxodGuo in kidney DNA and circulating Adp levels in normoglycemic and diabetic rats. Losartan treatment preserves FRAP levels, reduces DNA oxidative injury and thus the carcinogenesis risk. Furthermore, our results indicate that Adp plasma levels are a further marker of oxidative injury to the kidney and confirm that it is an important part of the plasma antioxidant defense. PMID- 25710928 TI - Atoh7 promotes the differentiation of Muller cells-derived retinal stem cells into retinal ganglion cells in a rat model of glaucoma. AB - Glaucoma is one of the leading eye diseases resulting in blindness due to the death of retinal ganglion cells. This study aimed to develop novel protocol to promote the differentiation of retinal Muller cells into ganglion cells in vivo in a rat model of glaucoma. The stem cells dedifferentiated from rat retinal Muller cells were randomized to receive transfection with empty lentivirus PGC-FU GFP or lentivirus PGC-FU-Atoh7-GFP, or no transfection. The stem cells were induced further to differentiate. Ocular hypertension was induced using laser photocoagulation. The eyes were injected with Atoh7 expression vector lentivirus PGC-FU-Atoh7-GFP. Eyeball frozen sections, immunohistochemistry, RT-PCR, Western bolt, and apoptosis assay were performed. We found that the proportion of ganglion cells differentiated from Atoh7-tranfected stem cells was significantly higher than that of the other two groups. The mean intraocular pressure of glaucomatous eyes was elevated significantly compared with those of contralateral eyes. Some retinal Muller cells in the inner nuclear layer entered the mitotic cell cycle in rat chronic ocular hypertension glaucoma model. Atoh7 contributes to the differentiation of retinal Muller cells into retinal ganglion cells in rat model of glaucoma. In conclusion, Atoh7 promotes the differentiation of Muller cells-derived retinal stem cells into retinal ganglion cells in a rat model of glaucoma, thus opening up a new avenue for gene therapy and optic nerve regeneration in glaucoma. PMID- 25710929 TI - SIRT1 attenuates high glucose-induced insulin resistance via reducing mitochondrial dysfunction in skeletal muscle cells. AB - Insulin resistance is often characterized as the most critical factor contributing to the development of type 2 diabetes mellitus (T2DM). Sustained high glucose is an important extracellular environment that induces insulin resistance. Acquired insulin resistance is associated with reduced insulin stimulated mitochondrial activity as a result of increased mitochondrial dysfunction. Silent information regulator 1 (SIRT1) is one member of the SIRT2 (Sir2)-like family of proteins involved in glucose homeostasis and insulin secretion in mammals. Although SIRT1 has a therapeutic effect on metabolic deterioration in insulin resistance, it is still not clear how SIRT1 is involved in the development of insulin resistance. Here, we demonstrate that pcDNA3.1 vector-mediated overexpression of SIRT1 attenuates insulin resistance in the high glucose-induced insulin-resistant skeleton muscle cells. These beneficial effects were associated with ameliorated mitochondrial dysfunction. Further studies have demonstrated that SIRT1 restores mitochondrial complex I activity leading to decreased oxidative stress and mitochondrial dysfunction. Furthermore, SIRT1 significantly elevated the level of another SIRT which is named SIRT3, and SIRT3 siRNA-suppressed SIRT1-induced mitochondria complex activity increments. Taken together, these results showed that SIRT1 improves insulin sensitivity via the amelioration of mitochondrial dysfunction, and this is achieved through the SIRT1 SIRT3-mitochondrial complex I pathway. PMID- 25710930 TI - Effects of Rosmarinus officinalis extract on human primary omental preadipocytes and adipocytes. AB - The prevalence of obesity is increasing all over the world. Although it has been shown that natural substances influence fat metabolism, little is known about the effect on cellular and molecular mechanisms in human. In this in vitro study, the activity of Rosmarinus officinalis (RO) standardized extract in modulating human primary visceral preadipocytes differentiation, lipolysis, and apoptosis was investigated. Moreover, gene expression of key adipogenesis modulators and microRNAs-seq were evaluated. Preadipocytes treated with RO extract significantly reduced triglyceride incorporation during maturation in a dose-dependent manner without affecting cell viability. In addition, RO extract stimulated lipolytic activity in differentiating preadipocytes and mature adipocytes in treated cells compared to controls. Differentiating preadipocytes incubated in the presence of RO extract showed a decreased expression of cell cycle genes such as cyclin D1, cyclin-dependent kinase 4, cyclin-dependent kinase inhibitor 1A (p21, Cip1) and an increased expression of GATA binding protein 3, wingless-type MMTV integration site family, member 3A mRNA levels. Recent studies have demonstrated that some phytochemicals alter the expression of specific genes and microRNAs that play a fundamental role in the pathogenesis of obesity and related diseases. Interestingly, genes modulated in RO-treated cells were found to be validated miRNAs targets, such as let-7f-1, miR-17, and miR-143. The results indicated that RO extract modulates human adipocyte differentiation and significantly interferes with adipogenesis and lipid metabolism, supporting its interest as dietary supplement. PMID- 25710932 TI - Effective bony mallet reduction using the principles of Elson's test. PMID- 25710931 TI - Versatile communication strategies among tandem WW domain repeats. AB - Interactions mediated by short linear motifs in proteins play major roles in regulation of cellular homeostasis since their transient nature allows for easy modulation. We are still far from a full understanding and appreciation of the complex regulation patterns that can be, and are, achieved by this type of interaction. The fact that many linear-motif-binding domains occur in tandem repeats in proteins indicates that their mutual communication is used extensively to obtain complex integration of information toward regulatory decisions. This review is an attempt to overview, and classify, different ways by which two and more tandem repeats cooperate in binding to their targets, in the well characterized family of WW domains and their corresponding polyproline ligands. PMID- 25710933 TI - Combined tendon avulsion and fracture in a mallet finger injury in a juvenile. PMID- 25710934 TI - Compressive neuropathy of the palmar cutaneous branch of the median nerve after a malunited fracture of the distal radius. PMID- 25710935 TI - Pyogenic flexor tenosynovitis after intralesional injection of triamcinolone acetonide by jet injector (Dermojet(r)). PMID- 25710936 TI - Proximal supination osteotomy of the first metatarsal for hallux valgus. AB - BACKGROUND: Risk factors for hallux valgus recurrence include postoperative round shaped lateral edge of the first metatarsal head and postoperative incomplete reduction of the sesamoids. To prevent the occurrence of such conditions, we developed a proximal supination osteotomy of the first metatarsal. Our aim was to describe this novel technique and report the outcomes in this report. METHODS: Sixty-six patients (83 feet) underwent a distal soft tissue procedure combined with a proximal supination osteotomy. After the proximal crescentic osteotomy, the proximal fragment was pushed medially, and the distal fragment was abducted, and then the distal fragment of the first metatarsal was manually supinated. Outcomes were assessed using the American Orthopaedic Foot & Ankle Society (AOFAS) score and radiographic examinations. The average follow-up duration was 34 (range, 25 to 52) months. RESULTS: The mean AOFAS score improved significantly from 58.0 points preoperatively to 93.8 points postoperatively (P < .0001). The mean hallux valgus and intermetatarsal angle decreased significantly from 38.6 and 18.0 degrees preoperatively to 11.0 and 7.9 degrees postoperatively, respectively (both, P < .0001). Sixty-nine feet (69/83, 83%) had a positive round sign preoperatively, and 66 feet (66/83, 80%) had a negative round sign postoperatively. According to the Hardy's classification of position of the sesamoids, all feet were classified as grade V or greater preoperatively, and 49 feet (49/83, 59%) were classified as grade IV or less postoperatively. Three feet (3/83, 4%) had recurrence of hallux valgus, defined as a hallux valgus angle >= 25 degrees. CONCLUSION: The rates of occurrence of a positive round sign and incomplete reduction of the sesamoids significantly decreased postoperatively, which may have contributed to the low hallux valgus recurrence rates. We conclude that a proximal supination osteotomy was an effective procedure for correction of hallux valgus and can achieve a low rate of hallux valgus recurrence. LEVEL OF EVIDENCE: Level IV, retrospective case series. PMID- 25710937 TI - Significance of trophoblastic infiltration into the tubal wall in ampullary pregnancy. AB - A total of 81 patients with an ampullary ectopic pregnancy undergoing salpingectomy were enrolled in the study. The ampullary pregnancies were classified according to the depth of trophoblastic infiltration into tubal wall as follows: Stage I, limited to mucosa; Stage II, extension to the tubal muscularis; Stage III, complete tubal wall infiltration up to the serosa. An association was observed between serum beta-human chorionic gonadotropin (beta hCG) levels and the depth of trophoblastic infiltration. Significantly higher severe ischemic changes and rupture of tubal wall were observed in patients with stage III infiltration compared with the other groups. A significant association was found between the absolute depth of trophoblastic invasion and severe ischemic changes, and also rupture of serosa. In conclusion, serum beta-hCG levels are associated with depth of trophoblastic invasion into the tubal wall, severe ischemic changes, and rupture of the tubal wall. PMID- 25710938 TI - Renal tubular secretion of tanshinol: molecular mechanisms, impact on its systemic exposure, and propensity for dose-related nephrotoxicity and for renal herb-drug interactions. AB - Tanshinol has desirable antianginal and pharmacokinetic properties and is a key compound of Salvia miltiorrhiza roots (Danshen). It is extensively cleared by renal excretion. This study was designed to elucidate the mechanism underlying renal tubular secretion of tanshinol and to compare different ways to manipulate systemic exposure to the compound. Cellular uptake of tanshinol was mediated by human organic anion transporter 1 (OAT1) (Km, 121 MUM), OAT2 (859 MUM), OAT3 (1888 MUM), and OAT4 (1880 MUM) and rat Oat1 (117 uM), Oat2 (1207 MUM), and Oat3 (1498 MUM). Other renal transporters (human organic anion-transporting polypeptide 4C1 [OATP4C1], organic cation transporter 2 [OCT2], carnitine/organic cation transporter 1 [OCTN1], multidrug and toxin extrusion protein 1 [MATE1], MATE2-K, multidrug resistance-associated protein 2 [MRP2], MRP4, and breast cancer resistance protein [BCRP], and rat Oct1, Oct2, Octn1, Octn2, Mate1, Mrp2, Mrp4, and Bcrp) showed either ambiguous ability to transport tanshinol or no transport activity. Rats may be a useful model, to investigate the contribution of the renal transporters on the systemic and renal exposure to tanshinol. Probenecid-induced impairment of tubular secretion resulted in a 3- to 5-fold increase in the rat plasma area under the plasma concentration-time curve from 0 to infinity (AUC0-infinity) of tanshinol. Tanshinol exhibited linear plasma pharmacokinetic properties over a large intravenous dose range (2-200 mg/kg) in rats. The dosage adjustment could result in increases in the plasma AUC0-infinity of tanshinol of about 100-fold. Tanshinol exhibited very little dose-related nephrotoxicity. In summary, renal tubular secretion of tanshinol consists of uptake from blood, primarily by OAT1/Oat1, and the subsequent luminal efflux into urine mainly by passive diffusion. Dosage adjustment appears to be an efficient and safe way to manipulate systemic exposure to tanshinol. Tanshinol shows low propensity to cause renal transporter-mediated herb-drug interactions. PMID- 25710939 TI - CYP2A7 pseudogene transcript affects CYP2A6 expression in human liver by acting as a decoy for miR-126. AB - Human cytochrome P450 (CYP)2A6 is responsible for the metabolic activation of tobacco-related nitrosamines, as well as the metabolism of nicotine and some pharmaceutical drugs. There are large interindividual differences in CYP2A6 activity and expression, largely attributed to genetic polymorphisms. However, the variability was observed within homozygotes of the wild-type CYP2A6 gene. In this study, we investigated the possibility that CYP2A6 might be regulated by microRNA. A luciferase assay revealed that a microRNA recognition element (MRE) of miR-126* found in the 3'-untranslated region (UTR) of CYP2A6 mRNA is functional. We established two HEK293 cell lines stably expressing CYP2A6, with one including and the other excluding the full-length 3'-UTR (HEK/2A6+UTR and HEK/2A6 cells, respectively). Overexpression of miR-126* markedly decreased CYP2A6 protein levels, enzyme activity, and mRNA level in HEK/2A6+UTR cells, whereas it marginally decreased those in HEK/2A6 cells, indicating that the 3' UTR including the MRE is functional for the downregulation of CYP2A6 by miR-126*. The inhibition of miR-126* increased CYP2A6 protein levels in primary human hepatocytes, suggesting that miR-126* downregulates endogenous CYP2A6 expression. In 20 human liver samples, the expression ratios of CYP2A6 and a pseudogene transcript CYP2A7 mRNA were highly variable (CYP2A7/CYP2A6: 0.1 to 12). Interestingly, we found that CYP2A7 was another target of miR-126* and restored the miR-126*-dependent downregulation of CYP2A6 by acting as a decoy for miR 126*. In conclusion, this study demonstrates that human CYP2A6 is post transcriptionally regulated by miR-126* and that CYP2A7 affects CYP2A6 expression by competing for miR-126* binding. PMID- 25710940 TI - Metabolism of MRX-I, a novel antibacterial oxazolidinone, in humans: the oxidative ring opening of 2,3-Dihydropyridin-4-one catalyzed by non-P450 enzymes. AB - MRX-I is an analog of linezolid containing a 2,3-dihydropyridin-4-one (DHPO) ring rather than a morpholine ring. Our objectives were to characterize the major metabolic pathways of MRX-I in humans and clarify the mechanism underlying the oxidative ring opening of DHPO. After an oral dose of MRX-I (600 mg), nine metabolites were identified in humans. The principal metabolic pathway proposed involved the DHPO ring opening, generating the main metabolites in the plasma and urine: the hydroxyethyl amino propionic acid metabolite MRX445-1 and the carboxymethyl amino propionic acid metabolite MRX459. An in vitro phenotyping study demonstrated that multiple non-cytochrome P450 enzymes are involved in the formation of MRX445-1 and MRX459, including flavin-containing monooxygenase 5, short-chain dehydrogenase/reductase, aldehyde ketone reductase, and aldehyde dehydrogenase (ALDH). H2 (18)O experiments revealed that two (18)O atoms are incorporated into MRX445-1, one in the carboxyethyl group and the other in the hydroxyl group, and three (18)O atoms are incorporated into MRX459, two in the carboxymethyl group and one in the hydroxyl group. Based on these results, the mechanism proposed for the DHPO ring opening involves the metabolism of MRX-I via FMO5-mediated Baeyer-Villiger oxidation to an enol lactone, hydrolysis to an enol, and enol-aldehyde tautomerism to an aldehyde. The aldehyde is reduced by short-chain dehydrogenase/reductase, aldehyde ketone reductase, ALDH to MRX445-1, or oxidized by ALDH to MRX459. Our study suggests that few clinical adverse drug drug interactions should be anticipated between MRX-I and cytochrome P450 inhibitors or inducers. PMID- 25710941 TI - Suppression of pulmonary CYP2A13 expression by carcinogen-induced lung tumorigenesis in a CYP2A13-humanized mouse model. AB - CYP2A13 is a human cytochrome P450 (P450) enzyme important in the bioactivation of the tobacco-specific lung procarcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1 butanone (NNK). CYP2A13 expression levels vary dramatically among lung biopsy samples from patients, presumably owing in part to a suppression of CYP2A13 expression by disease-associated inflammation. Here, we determined whether CYP2A13 expression in the lungs of CYP2A13-humanized mice is suppressed by the presence of lung tumors. Tissues from an NNK lung tumor bioassay were examined. CYP2A13-humanized mice (95-100%) had multiple lung tumors at 16 weeks after NNK (30 or 50 mg/kg) treatment; whereas only ~9% of saline-treated CYP2A13-humanized mice had lung tumor (~1/lung). Mice with lung tumors, from the NNK-treated groups, were used for dissecting adjacent tumor-free lung tissues; whereas mice without visible lung tumors, from the saline-treated group, were used as controls. Compared with the controls, the levels of CYP2A13 protein and mRNA were both reduced significantly (by >=50%) in the NNK-treated groups. The levels of mouse CYP2B10 and CYP2F2 mRNAs were also significantly lower in the dissected normal lung tissues from tumor-bearing mice than in lungs from the control mice. Pulmonary tissue levels of three proinflammatory cytokines, tumor necrosis factor alpha, interferon gamma, and interleukin-6, were significantly higher in the tumor-bearing mice than in the controls, indicating occurrence of low-grade lung inflammation at the time of necropsy. Taken together, these findings support the hypothesis that CYP2A13 levels in human lungs can be suppressed by disease associated inflammation in tissue donors, a scenario causing underestimation of CYP2A13 levels in healthy lungs. PMID- 25710942 TI - Survey on the need for menopause education in Londonderry, Northern Ireland. AB - Menopause is part of the ageing process for all women. However, the experience of menopause is different for each person. To recognize and manage the menopause properly, healthcare professionals need to be well informed and should have access to the necessary resources. The purpose of this survey was to ascertain whether an educational need and a resource need exist among healthcare professionals in Londonderry, Northern Ireland. One hundred and eight surveys were completed by healthcare professionals. From the responses, it is clearly evident that the desire for more education and the establishment of a local specialist clinic exists. PMID- 25710943 TI - A randomized controlled study examining the effect of exercise on inflammatory cytokine levels in post-menopausal women. AB - BACKGROUND: Elevated plasma levels of inflammatory cytokine are associated with body mass index, percent body fat and increased morbidity. Evidence suggests that higher levels of physical activity result in beneficial anti-inflammatory effects compared to a more sedentary lifestyle. Further, reproductive hormones are associated with inflammaotry cytokines. This study examined the effect of a 16 week low-moderate intensity exercise (EX) programme on reproductive hormones and inflammatory cytokines. METHODS: Twenty-eight healthy, sedentary post-menopausal women were randomly assigned to EX (n = 14) or control (Con, n = 14) groups. The EX group completed low-moderate intensity treadmill training 25-30 min/day, up to 55% of HRmax, 3-4 days/week, for 16-weeks. Con maintained current physical activity level. Baseline and week-16 serum samples evaluated interleukin-1 beta, interleukin-6, tumor necrosis factor-alpha, C-reactive protein, estradiol, luteinizing hormone and follicular stimulating hormone. RESULTS: Post intervention, the EX group showed a significant decrease in interleukin-1 beta, interleukin-6, tumor necrosis factor-alpha, estradiol, follicular stimulating hormone and luteinizing hormone levels compared to baseline values. No significant changes were observed in Con. Significant correlations were observed between IL-1beta, IL-6, TNF-alpha, and reproductive hormones, both before and after the exercise intervention. CONCLUSION: Findings suggest that a low-moderate intensity EX programme decreases cytokines in relation to reproductive hormones in post-menopausal women. These findings support the role of EX in reducing inflammatory markers and improved reproductive hormones in post-menopausal women. PMID- 25710944 TI - Does temporary socket removal affect residual limb fluid volume of trans-tibial amputees? AB - BACKGROUND: Lower-limb prosthesis users typically experience residual limb volume losses over the course of the day that can detrimentally affect socket fit. OBJECTIVES: To determine whether temporarily doffing the prosthesis encouraged residual limb fluid volume recovery and whether the recovered fluid was maintained. STUDY DESIGN: Experimental design. METHODS: Residual limb fluid volume was monitored on 16 participants in three test sessions each. Participants conducted six cycles of resting/standing/walking. Between the third and fourth cycles, participants sat for 30 min with the prosthesis and liner: donned (ON), the prosthesis doffed but the liner donned (LINER), or the prosthesis and liner doffed (OFF). RESULTS: Percentage fluid volume gain and retention were greatest for the OFF condition followed by the LINER condition. Participants experienced fluid volume losses for the ON condition. CONCLUSION: Doffing the prosthesis or both the prosthesis and liner during rest improved residual limb fluid volume retention compared with leaving the prosthesis and liner donned. CLINICAL RELEVANCE: Practitioners should advise patients who undergo high daily limb volume losses to consider temporarily doffing their prosthesis. Fluid volume retention during subsequent activity will be highest if both the prosthesis and liner are doffed. PMID- 25710945 TI - Prevalence of hepatitis E virus in Chinese blood donors. AB - OBJECTIVE: To investigate the prevalence of hepatitis E virus (HEV) antibodies and RNA in voluntary blood donors, in China. METHODS: Serum samples from blood donors were collected sequentially at six blood donation centres in five geographical regions of China. Donors were stratified between two groups according to their serum alanine aminotransferase (ALT) concentration (<= 40 U/l and >40 U/l. Enzyme-linked immunosorbent assay and reverse transcription polymerase chain reaction were used to quantify anti-HEV antibodies and RNA, respectively. RESULTS: In total, 21.1% (172/816) of donors were positive for anti HEV immunoglobulin (Ig) G (elevated ALT samples group 18.9% [85/450]; normal ALT group 23.8% [87/366]), and 0.5% (four of 816) donors were positive for anti-HEV IgM (elevated ALT group 0.9% [four of 450]; normal ALT group 0% [none of 366]). The rate of anti-HEV IgG seropositivity was significantly higher in male than in female donors. No serum sample tested positive for HEV RNA. CONCLUSION: The prevalence of anti-HEV antibodies in blood donors in China is high, regardless of ALT concentration. PMID- 25710946 TI - Adipose Tissue-Derived Regenerative Cell-Enhanced Lipofilling for Treatment of Cryptoglandular Fistulae-in-Ano: The ALFA Technique. AB - BACKGROUND: The treatment of complex fistulae-in-ano is challenging and often includes a number of operations due to high rates of recurrence. Recently, techniques using in vitro expanded adipose tissue-derived stem cells have been described. We describe a novel treatment for cryptoglandular fistulae used in 7 patients, using a combination of surgical closure of the internal opening and real-time autologous adipose tissue-derived regenerative cells (ADRC)-enhanced lipofilling, without need for in vitro expansion. METHODS: Following exclusion of active perianal sepsis, patients underwent a standard tumescent liposuction procedure, harvesting ~300 to 400 mL of raw lipoaspirate. The lipoaspirate was prepared in real time, using the Celution 800/CRS system to obtain the stromal vascular fraction containing ADRCs. After excision of the fistula tract and closure of the internal orifice, fresh ADRC-enhanced lipoaspirate was injected into and around the fistula tract. RESULTS: At 6-months' follow-up, 5 of 7 (71.4%) patients showed clinical signs of fistula closure; one of these patients had a recurrence at 10 months due to sepsis. The remaining 4 patients (57.1%) all had complete fistula closure at a median of 46 months' follow-up. There were no adverse events associated with the technique, and no new incontinence. CONCLUSION: Treatment of cryptoglandular fistulae-in-ano with ADRC-enhanced lipofilling appears feasible and safe, and may add to the range of procedures that can be used to treat this difficult problem. PMID- 25710947 TI - Student-Perceived School Climate Is Associated With ADHD Medication Treatment Among Adolescents in Medicaid. AB - OBJECTIVE: The objective of this study was to evaluate the relationship between school climate and ADHD medication treatment among adolescents in Medicaid in Georgia. METHOD: School climate and Medicaid claims data were aggregated for 159 GA counties. County-level school climate percentile and medicated ADHD prevalence were calculated. The t tests and regression models evaluated the relationship between school climate, medicated ADHD, and demographics, weighted by county population. Poorer 2008 school climate (<25th percentile) was regressed on 2011 medicated ADHD prevalence, controlling for potential confounders. RESULTS: The prevalence of medicated ADHD was 7.8% among Medicaid-enrolled GA adolescents. The average county-level prevalence of medicated ADHD was 10.0% (SD = 2.9%). Poorer school climate was associated with lower rates of medicated ADHD (p < .0001); along with demographics, these factors accounted for 50% of the county variation in medicated ADHD. CONCLUSION: School climate is associated with medicated ADHD among adolescents in Medicaid. Additional research may reveal whether high medicated ADHD may reflect a lack of access to non-pharmacological therapies in some communities. PMID- 25710948 TI - Practitioner characteristics and organizational contexts as essential elements in the evidence-based practice versus cultural competence debate. AB - The different pathways chosen to efficiently and effectively provide relief to those struggling with mental health challenges reflect different assumptions about the human condition and have led to disagreements over which intervention strategies are best suited to particular individuals or populations. Evidence based practice and culturally competent services, as discussed within the United States, have been characterized as opposites. However, neither approach captures all of the elements that embody the full treatment experience. This article offers a framework that includes the personal identity of the practitioner and the organizational context as two elements that serve as active agents in the helping relationship, although they have rarely been included in the discourse about evidence-based practice or cultural competence. Suggestions for practice, education, and research are included based on this analysis. PMID- 25710949 TI - Emphysematous Eosinophilic Lymphangitis in the Ruminal Submucosa of Cattle. AB - Twenty cattle (14 Holstein-Friesian, 3 Japanese Black, 3 Aberdeen Angus) ranging in age from 3 months to 8 years exhibited, at slaughter, emphysematous thickening of the ruminal submucosa owing to the appearance of numerous, contiguous, small gas bubbles. Microscopic changes in the ruminal submucosa consisted of (1) multiple cystic (emphysematous) lymphangiectasis that was frequently lined or occluded by granulomatous inflammatory infiltrates including macrophages, multinucleate giant cells, and eosinophils; (2) intralymphatic phagocytosis by macrophages and giant cells of eosinophils that showed positive labeling with the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling assay; and (3) an inflammatory infiltrate extending from the area of lymphangitis into surrounding tissue, as well as edema, hemorrhage, fibrin exudation, fibroplasia, or capillary proliferation throughout the lesional submucosa. In addition, 15 (75%) of the cattle had globular leukocyte infiltrates in the mucosal epithelia of the rumen. PMID- 25710950 TI - Infection and medication-related osteonecrosis of the jaw. AB - Medication-related osteonecrosis of the jaw (MRONJ), although initially believed to be exclusively associated with bisphosphonates, has been implicated in recent reports with additional drugs, especially the bone antiresorptive denosumab. The pathophysiology has not been fully elucidated, and no causal association between bone antiresorptive regimens and MRONJ has yet been established. However, reduced bone turnover and infection, an almost universal finding, are thought to be central to the pathogenesis of MRONJ. Both bisphosphonates and denosumab, through different pathways of action, significantly reduce the rate of bone turnover and potentially reduce the efficacy of the host defense against infection. Recent evidence questions the simplified etiology of low bone turnover causing MRONJ and offers evidence on the prominent role of infection instead. The management of MRONJ remains a significant clinical challenge, with little progress having been made on treatment. The aim of this article is to explore the current theories on the etiology of MRONJ and to emphasize the importance of infection in the development of this devastating pathology. PMID- 25710951 TI - Treating pit-and-fissure caries: a systematic review and network meta-analysis. AB - For shallow or moderately deep pit-and-fissure lesions, various treatment options are available: (1) noninvasive treatments (e.g., fluoride application, antibacterial treatments, oral hygiene advice) avoid any dental hard tissue removal; (2) microinvasive treatments (e.g., sealing) remove only a few micrometers of hard tissues by etching; and minimally invasive methods (e.g., "preventive" resin/sealant restoration) remove carious dentin but avoid sacrificing sound tissues. We aimed at systematically reviewing and comparing these strategies for treating pit-and-fissure lesions in permanent teeth using network meta-analysis. Randomized or nonrandomized clinical trials investigating shallow or moderately deep primary caries lesions in fissured or pitted surfaces were included. We compared the risk of requiring invasive treatments or any retreatments in noninvasive, microinvasive, and minimally invasive treated lesions; untreated lesions were used as controls. Five electronic databases were systematically screened up to September 2013 and cross-referencing performed. Pairwise and network meta-analyses were performed and odds ratios and 95% confidence intervals (CI) calculated. Certainty of estimates was evaluated via GRADE criteria. From a total of 2,214 identified records, 14 studies representing 1,440 patients with 3,551 treated lesions were included. Pairwise meta-analysis found microinvasive and minimally invasive treated lesions to require less invasive retreatments than control lesions (odds ratios [95% confidence intervals]: 0.13 [0.07 to 0.26], 0.13 [0.03 to 0.50], respectively), whereas the estimate for noninvasively treated lesions remained nonsignificant (0.64 [0.39 to 1.06]). These findings were reflected in the strategy ranking stemming from network meta-analysis (first, minimally invasive; second, microinvasive; third, noninvasive). However, microinvasive treatment required significantly more total retreatments (including resealing) than minimally or noninvasive treatments. Due to limited study quality, the evidence was graded as low or very low. Clinical treatment decisions should consider the long-term sequelae and costs stemming from different therapies as well as their subjective impact on the patient. Available treatment options seem suitable for treating shallow or moderately deep pit-and-fissure lesions in permanent teeth; further conclusions are not possible. PMID- 25710952 TI - Mechanobiological bone reaction quantified by positron emission tomography. AB - While nuclear medicine has been proven clinically effective for examination of the change in bone turnover as a result of stress injury, quantitative correlation between tracer uptake and mechanical stimulation in the human jawbone remains unclear. This study aimed to investigate the relationship between bone metabolism observed by 18F-fluoride positron emission tomography (PET) images and mechanical stimuli obtained by finite element analysis (FEA) in the residual ridge induced by the insertion of a removable partial denture (RPD). An 18F fluoride PET/CT (computerized tomography) scan was performed to assess the change of bone metabolism in the residual ridge under the denture before and after RPD treatment. Corresponding patient-specific 3D finite element (FE) models were created from CT images. Boundary conditions were prescribed by the modeling of condylar contacts, and muscular forces were derived from the occlusal forces measured in vivo to generate mechanobiological reactions. Different mechanobiological stimuli, e.g., equivalent von Mises stress (VMS), equivalent strain (EQV), and strain energy density (SED), determined from nonlinear FEA, were quantified and compared with the standardized uptake values (SUVs) of PET. Application of increased occlusal force after RPD insertion induced higher mechanical stimuli in the residual bone. Accordingly, SUV increased in the region of residual ridge with higher mechanical stimuli. Thus, with SUV, a clear correlation was observed with VMS and SED in the cancellous bone, especially after RPD insertion (R(2) > 0.8, P < 0.001). This study revealed a good correlation between bone metabolism and mechanical stimuli induced by RPD insertion. From this patient-specific study, it was shown that metabolic change detected by PET in the loaded bone, in a much shorter duration than conventional x-ray assessment, is associated with mechanical stimuli. The nondestructive nature of PET/CT scans and FEA could potentially provide a new method for clinical examination and monitoring of prosthetically driven bone remodeling. PMID- 25710953 TI - Clinical and radiographic assessment of the efficacy of calcium silicate indirect pulp capping: a randomized controlled clinical trial. AB - The aims of this study were to assess the effectiveness of calcium silicate cement (Biodentine) versus glass ionomer cement (GIC; control group) as indirect pulp capping materials in patients with reversible pulpitis and to compare the effectiveness of cone beam computed tomography (CBCT) versus periapical (PA) radiographs in detecting PA changes at baseline (T0) and at 12 mo (T12) postoperatively. Seventy-two restorations (36 Biodentine, 36 Fuji IX) were placed randomly in 53 patients. CBCT/PA radiographs were taken at T0 and T12. Two calibrated examiners assessed the presence/absence and increase/decrease in the size of existing PA radiolucencies under standardized conditions. The Kappa coefficient evaluated statistically the effectiveness of CBCT versus PA radiographs in detecting PA changes. Chi-square/Mann-Whitney tests were used to evaluate the association between PA changes in CBCT with various clinical measures. Significance was predetermined at alpha = 0.05. Clinical success rates for Biodentine and Fuji IX GIC were 83.3%. CBCT was significantly more effective in detecting PA radiolucencies compared with radiographs (P = 0.0069). Of the teeth, 65.4% and 90.4% were deemed healthy using CBCT and PA radiographs, respectively, at T12. Healing/healed rates were 17.3%/0%, while new/progressed radiolucency were 30.8%/9.6% with CBCT/PA radiographs, respectively. Seventy-one percent of healed lesions had received Biodentine; 88% of new/progressed lesions received Fuji IX GIC. Teeth presenting with an initial CBCT PA lesion had a failure rate of 63%, whereas teeth with no initial lesion had a failure rate of 16%. Although no statistically significant difference was detected in the clinical efficacy of Biodentine/Fuji IX when used as indirect pulp capping materials in patients with reversible pulpitis, CBCT showed a significant difference in that most healed CBCT lesions had received Biodentine while most that did not heal received Fuji IX. Longer-term follow-up is needed to establish their effect on the healing dynamics of PA tissues (ClinicalTrials.gov NCT02201641). PMID- 25710954 TI - Comment on "IgH chain class switch recombination: mechanism and regulation". PMID- 25710955 TI - Response to comment on "IgH chain class switch recombination: mechanism and regulation". PMID- 25710956 TI - The DNA deamination model of somatic antibody diversification. PMID- 25710957 TI - Pillars article: AID mutates E. coli suggesting a DNA deamination mechanism for antibody diversification. Nature. 2002. 418: 99-103. PMID- 25710958 TI - Tapping CD4 T cells for cancer immunotherapy: the choice of personalized genomics. AB - Cellular immune responses that protect against tumors typically have been attributed to CD8 T cells. However, CD4 T cells also play a central role. It was shown recently that, in a patient with metastatic cholangiocarcinoma, CD4 T cells specific for a peptide from a mutated region of ERBB2IP could arrest tumor progression. This and other recent findings highlight new opportunities for CD4 T cells in cancer immunotherapy. In this article, I discuss the role and regulation of CD4 T cells in response to tumor Ags. Emphasis is placed on the types of Ags and mechanisms that elicit tumor-protective responses. I discuss the advantages and drawbacks of cancer immunotherapy through personalized genomics. These considerations should help to guide the design of next-generation therapeutic cancer vaccines. PMID- 25710959 TI - Correction: novel insights on human NK cells' immunological modalities revealed by gene expression profiling. PMID- 25710960 TI - A statistical evaluation of dose expansion cohorts in phase I clinical trials. AB - BACKGROUND: Phase I trials often include a dose expansion cohort (DEC), in which additional patients are treated at the estimated maximum tolerated dose (MTD) after dose escalation, with the goal of ensuring that data are available from more than six patients at a single dose level. However, protocols do not always detail how, or even if, the additional toxicity data will be used to reanalyze the MTD or whether observed toxicity in the DEC will warrant changing the assigned dose. A DEC strategy has not been statistically justified. METHODS: We conducted a simulation study of two phase I designs: the "3+3" and the Continual Reassessment Method (CRM). We quantified how many patients are assigned the true MTD using a 10 to 20 patient DEC and how a sensible reanalysis using the DEC changes the probability of selecting the true MTD. We compared these results with those from an equivalently sized larger CRM that does not include a DEC. RESULTS: With either the 3+3 or CRM, reanalysis with the DEC increased the probability of identifying the true MTD. However, a large CRM without a DEC was more likely to identify the true MTD while still treating 10 or 15 patients at this dose level. CONCLUSIONS: Where feasible, a CRM design with no explicit DEC is preferred to designs that fix a dose for all patients in a DEC. PMID- 25710961 TI - Building firm foundations for therapy development. PMID- 25710963 TI - An interesting case of ptosis in an infant. PMID- 25710962 TI - Blockade of MMP14 activity in murine breast carcinomas: implications for macrophages, vessels, and radiotherapy. AB - BACKGROUND: Matrix metalloproteinase (MMP) 14 may mediate tumor progression through vascular and immune-modulatory effects. METHODS: Orthotopic murine breast tumors (4T1 and E0771 with high and low MMP14 expression, respectively; n = 5-10 per group) were treated with an anti-MMP14 inhibitory antibody (DX-2400), IgG control, fractionated radiation therapy, or their combination. We assessed primary tumor growth, transforming growth factor beta (TGFbeta) and inducible nitric oxide synthase (iNOS) expression, macrophage phenotype, and vascular parameters. A linear mixed model with repeated observations, with Mann-Whitney or analysis of variance with Bonferroni post hoc adjustment, was used to determine statistical significance. All statistical tests were two-sided. RESULTS: DX-2400 inhibited tumor growth compared with IgG control treatment, increased macrophage numbers, and shifted the macrophage phenotype towards antitumor M1-like. These effects were associated with a reduction in active TGFbeta and SMAD2/3 signaling. DX-2400 also transiently increased iNOS expression and tumor perfusion, reduced tissue hypoxia (median % area: control, 20.2%, interquartile range (IQR) = 6.4% 38.9%; DX-2400: 1.2%, IQR = 0.2%-3.2%, P = .044), and synergistically enhanced radiation therapy (days to grow to 800mm(3): control, 12 days, IQR = 9-13 days; DX-2400 plus radiation, 29 days, IQR = 26-30 days, P < .001) in the 4T1 model. The selective iNOS inhibitor, 1400W, abolished the effects of DX-2400 on vessel perfusion and radiotherapy. On the other hand, DX-2400 was not capable of inducing iNOS expression or synergizing with radiation in E0771 tumors. CONCLUSION: MMP14 blockade decreased immunosuppressive TGFbeta, polarized macrophages to an antitumor phenotype, increased iNOS, and improved tumor perfusion, resulting in reduced primary tumor growth and enhanced response to radiation therapy, especially in high MMP14-expressing tumors. PMID- 25710964 TI - MrSkn7 controls sporulation, cell wall integrity, autolysis, and virulence in Metarhizium robertsii. AB - Two-component signaling pathways generally include sensor histidine kinases and response regulators. We identified an ortholog of the response regulator protein Skn7 in the insect-pathogenic fungus Metarhizium robertsii, which we named MrSkn7. Gene deletion assays and functional characterizations indicated that MrSkn7 functions as a transcription factor. The MrSkn7 null mutant of M. robertsii lost the ability to sporulate and had defects in cell wall biosynthesis but was not sensitive to oxidative and osmotic stresses compared to the wild type. However, the mutant was able to produce spores under salt stress. Insect bioassays using these spores showed that the virulence of the mutant was significantly impaired compared to that of the wild type due to the failures to form the infection structure appressorium and evade host immunity. In particular, deletion of MrSkn7 triggered cell autolysis with typical features such as cell vacuolization, downregulation of repressor genes, and upregulation of autolysis related genes such as extracellular chitinases and proteases. Promoter binding assays confirmed that MrSkn7 could directly or indirectly control different putative target genes. Taken together, the results of this study help us understand the functional divergence of Skn7 orthologs as well as the mechanisms underlying the development and control of virulence in insect-pathogenic fungi. PMID- 25710965 TI - Yeast beta-1,6-glucan is a primary target for the Saccharomyces cerevisiae K2 toxin. AB - Certain Saccharomyces cerevisiae strains secrete different killer proteins of double-stranded-RNA origin. These proteins confer a growth advantage to their host by increasing its survival. K2 toxin affects the target cell by binding to the cell surface, disrupting the plasma membrane integrity, and inducing ion leakage. In this study, we determined that K2 toxin saturates the yeast cell surface receptors in 10 min. The apparent amount of K2 toxin, bound to a single cell of wild type yeast under saturating conditions, was estimated to be 435 to 460 molecules. It was found that an increased level of beta-1,6-glucan directly correlates with the number of toxin molecules bound, thereby impacting the morphology and determining the fate of the yeast cell. We observed that the binding of K2 toxin to the yeast surface receptors proceeds in a similar manner as in case of the related K1 killer protein. It was demonstrated that the externally supplied pustulan, a poly-beta-1,6-glucan, but not the glucans bearing other linkage types (such as laminarin, chitin, and pullulan) efficiently inhibits the K2 toxin killing activity. In addition, the analysis of toxin binding to the intact cells and spheroplasts confirmed that majority of K2 protein molecules attach to the beta-1,6-glucan, rather than the plasma membrane localized receptors. Taken together, our results reveal that beta-1,6-glucan is a primary target of K2 toxin and is important for the execution of its killing property. PMID- 25710966 TI - Infant male circumcision and the autonomy of the child: two ethical questions. AB - Routine neonatal circumcision--the non-therapeutic circumcision of infant males- has generated considerable ethical controversy. In this article, I suggest that much of the disagreement results from conflicting ideas about the autonomy of the child. I examine two questions about autonomy. First, I ask whether we should be realists or idealists about the future autonomous choices of the child-that is, whether we should account for the fact that the child may not make the best choices in future, or whether we should assume that his future choices will reflect his best interests. Second, I ask whether the child has a right to autonomy with respect to circumcision, an interest in autonomy or neither--that is, whether respect for autonomy overrides considerations of interests, whether it counts as one interest among many or whether it counts for nothing. In response to the first question, I argue that we should be idealists when evaluating the child's own interests, but realists when evaluating public health justifications for circumcision. In response to the second question, I argue that the child has an interest in deciding whether or not to be circumcised, insofar as the decision is more likely to reflect his actual interests and his own values. Finally, I show how these findings may help to resolve some particular disputes over the ethics of infant male circumcision. PMID- 25710969 TI - [Keypoints in reconstruction using artificial chordae tendineae in mitral valvoplasty]. PMID- 25710968 TI - A structural equation modelling approach examining the pathways between safety climate, behaviour performance and workplace slipping. AB - OBJECTIVE: Safety climate has previously been associated with increasing safe workplace behaviours and decreasing occupational injuries. This study seeks to understand the structural relationship between employees' perceptions of safety climate, performing a safety behaviour (ie, wearing slip-resistant shoes) and risk of slipping in the setting of limited-service restaurants. METHODS: At baseline, we surveyed 349 employees at 30 restaurants for their perceptions of their safety training and management commitment to safety as well as demographic data. Safety performance was identified as wearing slip-resistant shoes, as measured by direct observation by the study team. We then prospectively collected participants' hours worked and number of slips weekly for the next 12 weeks. Using a confirmatory factor analysis, we modelled safety climate as a higher order factor composed of previously identified training and management commitment factors. RESULTS: The 349 study participants experienced 1075 slips during the 12 week follow-up. Confirmatory factor analysis supported modelling safety climate as a higher order factor composed of safety training and management commitment. In a structural equation model, safety climate indirectly affected prospective risk of slipping through safety performance, but no direct relationship between safety climate and slips was evident. CONCLUSIONS: Results suggest that safety climate can reduce workplace slips through performance of a safety behaviour as well as suggesting a potential causal mechanism through which safety climate can reduce workplace injuries. Safety climate can be modelled as a higher order factor composed of safety training and management commitment. PMID- 25710970 TI - [Latest pathological diagnosis that is important in thoracic surgery (2): epidermoid carcinoma of the lung]. PMID- 25710967 TI - Synthetic metallochaperone ZMC1 rescues mutant p53 conformation by transporting zinc into cells as an ionophore. AB - p53 is a Zn(2+)-dependent tumor suppressor inactivated in >50% of human cancers. The most common mutation, R175H, inactivates p53 by reducing its affinity for the essential zinc ion, leaving the mutant protein unable to bind the metal in the low [Zn(2+)]free environment of the cell. The exploratory cancer drug zinc metallochaperone-1 (ZMC1) was previously demonstrated to reactivate this and other Zn(2+)-binding mutants by binding Zn(2+) and buffering it to a level such that Zn(2+) can repopulate the defective binding site, but how it accomplishes this in the context of living cells and organisms is unclear. In this study, we demonstrated that ZMC1 increases intracellular [Zn(2+)]free by functioning as a Zn(2+) ionophore, binding Zn(2+) in the extracellular environment, diffusing across the plasma membrane, and releasing it intracellularly. It raises intracellular [Zn(2+)]free in cancer (TOV112D) and noncancer human embryonic kidney cell line 293 to 15.8 and 18.1 nM, respectively, with half-times of 2-3 minutes. These [Zn(2+)]free levels are predicted to result in ~90% saturation of p53-R175H, thus accounting for its observed reactivation. This mechanism is supported by the X-ray crystal structure of the [Zn(ZMC1)2] complex, which demonstrates structural and chemical features consistent with those of known metal ionophores. These findings provide a physical mechanism linking zinc metallochaperone-1 in both in vitro and in vivo activities and define the remaining critical parameter necessary for developing synthetic metallochaperones for clinical use. PMID- 25710971 TI - [Functional imaging--static & more dynamic]. PMID- 25710972 TI - Authors' response. PMID- 25710973 TI - Osseoseparation and peri-implantitis: what's in a name? PMID- 25710974 TI - In memoriam: Per-Ingvar Branemark. PMID- 25710975 TI - Introduction. PMID- 25710976 TI - [Undergraduate nursing education and nursing staff]. PMID- 25710977 TI - [The next health care policy unveiled in congress]. PMID- 25710978 TI - [Report on tap water quality in France ]. PMID- 25710979 TI - [Breast cancer: a real Life databank]. PMID- 25710980 TI - [Kiss & Love...never give up in the battle against HIV]. PMID- 25710981 TI - [Alzheimer, better screening and management of apathy]. PMID- 25710982 TI - [France mobilizes health care professionals against ebola]. PMID- 25710983 TI - [The health legislation for nursing education is modified again]. PMID- 25710985 TI - [Three public health agencies are fusing together]. PMID- 25710984 TI - [Choosing a contraception method with a health care professional]. PMID- 25710986 TI - [The 55-85 years old behaviors analyzed by Inpes]. PMID- 25710987 TI - [Designing tomorrow's pharmacy]. PMID- 25710988 TI - [Evaluation of the national program for nosocomial infections prevention]. PMID- 25710989 TI - [First symposia on general aspects of Arthritis]. PMID- 25710990 TI - [An additional degree for better equivalency in Europe]. PMID- 25710991 TI - [Lung cancer: major step forward in early diagnosis]. PMID- 25710993 TI - [Emergency departments and deliberate medicinal self-poisoning]. AB - Deliberate medicinal self-poisonings are a frequent cause of admission to emergency departments. These patients are almost always brought to hospital by paramedics rather than by family or private ambulances. PMID- 25710992 TI - [Emergency departments and psychiatry]. AB - Psychiatric care is becoming an increasingly important part of general emergency departments. Historically incorporated into the psychiatric hospital, emergency mental health care has since been moved to the general hospital. This move was intended to boost the accessibility and deinstitutionalisation of psychiatry. The end of the "asylum" opened up new dialogue with the somatic care network. PMID- 25710994 TI - [Emergency departments and demand for psychiatric care]. AB - New organisations have been established in the general hospital to respond to care increasing needs linked to the psychiatrics pathologies. In France, there are different types of organisation within emergency departments, in order to host these patients in the best way. In the context of psychiatric emergency departments, the role of the nurse is critical. This article presents the example of the case of a patient needing psychiatric care admitted to the emergency department. PMID- 25710995 TI - [Psychotic decompensation of a patient in the emergency department]. AB - The care of a patient experiencing a psychotic decompensation episode in an emergency department is complex. At the centre is a patient who is suffering and who requires care. This article presents the example of the treatment of a delirious and aggressive patient and its review of ways to improve practices. PMID- 25710996 TI - [Specific training in psychiatry for nurses in general emergency departments]. AB - Specific training in psychiatric emergencies is provided in hospitals which receive such cases. What is the situation for the somatic teams? This article presents the experience of Toulouse Purpan Emergency Department with the role of the triage nurse, who constitutes the first contact with the care universe for patients arriving in the emergency department. PMID- 25710997 TI - [Practice of hypnosis in the nurse care]. AB - Hypnosis is practicing in hospital, especially in palliative care and in pain consultation. This technique is used in a well-defined field by doctors, psychologists and caregivers, all specificially trained. PMID- 25710998 TI - [In-service training, a tool which favours wellbeing at work]. AB - Designed to offer health professionals opportunities to exchange around the meaning of their practices, in-service training contributes to the process of professionalisation. The reflexive approach boosts the feeling of belonging to a team, around shared values and objectives. In turn, this helps to develop professional assertiveness, a source of well-being at work. PMID- 25710999 TI - [The motivational interview in the educational approach]. AB - The motivational interview helps nurses trained in this technique to optimise the motivational approach with the patient. This communication tool also gives them greater understanding of the resistance of people confronted with a chronic disease and to support them more effectively towards change. PMID- 25711000 TI - [Proper acknowledgement of the global care provided by nurses in patients' homes]. AB - The richness of nursing practice is expressed notably by the holistic character of the care provided. In their practice in patients' homes, nurses sometimes come up against regulatory constraints which determine the refunding of patients' treatment and take insufficient account of the global nature of the treatment carried out. PMID- 25711001 TI - [Screening for melanoma, an advanced practice nurse consultation]. AB - In the dermatology consultation, at Cochin hospital, Paris, a nurse cooperates with a dermatologist in order to insure the clinical follow-up for high-risk melanoma patients. To adopt this innovative public health approach, the nurse has received theoretical, clinical and educational knowledge. PMID- 25711002 TI - [Gathering advance directives in geriatrics]. AB - Advance directives have existed since 2005 but are still relatively unknown by the public. Many nurses find it difficult to explain and gather advance directives from elderly hospitalised patients. A survey was carried out within the geriatric department of Allauch general hospital to gain a clearer understanding of the difficulties encountered by the teams. PMID- 25711003 TI - [Nurse's role facing an infected wound]. PMID- 25711004 TI - [Management of abdominal trauma in a pregnant woman]. PMID- 25711005 TI - [Communication strategies in a crisis situation]. PMID- 25711006 TI - [Central catheterization using peripheral insertion method]. PMID- 25711007 TI - [Control levels of Sin3 histone deacetylase for spontaneous and UV-induced mutagenesis in yeasts Saccharomyces cerevisiae]. AB - SIN3 gene product operates as a repressor for a huge amount of genes in Saccharomyces cerevisiae. Sin3 protein with a mass of about 175 kDa is a member of the RPD3 protein complex with an assessed mass of greater than 2 million Da. It was previously shownthat RPD3 gene mutations influence recombination and repair processes in S. cerevisiae yeasts. We studied the impacts of the sin3 mutation on UV-light sensitivity and UV-induced mutagenesis in budding yeast cells. The deletion ofthe SIN3 gene causes weak UV-sensitivity of mutant budding cells as compared to the wild-type strain. These results show that the sin3 mutation decreases both spontaneous and UV-induced levels of levels. This fact is hypothetically related to themalfunction of ribonucleotide reductase activity regulation, which leads to a decrease in the dNTP pool and the inaccurate error prone damage bypass postreplication repair pathway, which in turn provokes a reduction in the incidence of mutations. PMID- 25711008 TI - [Molecular phylogenetic analysis of the genus Abies (Pinaceae) based on the nucleotide sequence of chloroplast DNA]. AB - A phylogenetic study of firs (Abies Mill.) was conducted using nucleotide sequences of several chloroplast DNA regions with a total length of 5580 bp. The analysis included 37 taxa, which represented the main evolutionary lineages of the genus, and Keteleeria daviana. According to phylogenetic reconstruction the Abies species were subdivided into six main groups, generally corresponding to their geographic distribution. The phylogenetic tree had three basal clades. All of these clades contained American species, and only one of them contained Eurasian species. The divergence time calibrations, based on paleobotanical data and the chloroplast DNA mutation rate estimates in Pinaceae, produced similar results..The age of diversification among the clades of the present-day Abies was estimated as the end of the Oligocene-beginning of Miocene. The age of the separation of Mediterranean firs from the Asian-North American branch corresponds to the Miocene. The age of diversification within the young groups of Mediterranean, Asian, and boreal American firs (A. lasiocarpa, A. balsamea, A. fraseri) was estimated as the Pliocene-Pleistocene. Based on the phylogenetic reconstruction obtained, the most plausible biogeographic scenarios were suggested. It is noted that the existing systematic classification of the genus Abies strongly contradicts with phylogenetic reconstruction and requires revision. PMID- 25711009 TI - [Cellulose synthase genes that control the fiber formation of flax (Linum usitatissimum L.)]. AB - Four cellulose synthase genes were identified by analysis of their class-specific regions (CSRII) in plants of fiber flax during the "rapid growth" stage. These genes were designated as LusCesA1, LusCesA4, LusCesA7 and LusCesA9. LusCesA4, LusCesA7, and LusCesA9 genes were expressed in the stem; LusCesA1 and LusCesA4 genes were expressed in the apex part of plants, and the LusCesA4 gene was expressed in the leaves of fiber flax. The expression of the LusCesA7 and LusCesA9 genes was specific to the stems of fiber flax. These genes may influence the quality of the flax fiber. PMID- 25711010 TI - [Genetic potential of local endemic forms of the pea (Pisum sativum L.) on the basis of nitrogen fixation and productivity]. AB - Morphological and symbiotic traits were studied in local endemic forms of the pea originating from Egypt, Syria, Afghanistan, and Palestine. A number of endemic forms exceeded the zoned Druzhnaya variety of the fodder pea in productivity of the seeds in field and greenhouse experiments. In order to improve nodulation and nitrogen fixation, endemic forms were crossed with the supernodulating K301 mutant marked by the nod4 gene. Recurrent selection of lines up to F5,6 generations was conducted with an estimation of productivity, nodulation, and nitrogen fixation. The most promising recurrent lines with a high productivity, active nodulation, and high nitrogen fixation were obtained during the crossing of endemic forms with the recurrent line marked by the nod4 gene. The line was previously created during the crossing between the Druzhnaya variety and the supernodulating K301 mutant marked by the nod4 gene. PMID- 25711011 TI - [The creation of transgenic tobacco plants expressing fragments of the ARGOS and NtEXPA4 genes in antisense orientation]. AB - Transgenic tobacco plants expressing the fragments of the ARGOS and NtEXPA4 genes in antisense orientation have been created. Eleven lines of transgenic plants were investigated and five of them were characterized by a decrease in the sizes of the leaves and flowers as compared to control. Stalk sizes decreased when only the NtEXPA4 gene fragment was used. The organ size of the experimental plants decreased because of a reduction in the level of both cell division and cell expansion. Two lines of transgenic tobacco plants expressing the part of the ARGOS gene in antisense orientation were characterized by a reduction in the level of the NtEXPA1 and NtEXPA4 gene expression. PMID- 25711012 TI - [Population genetic differentiation of white-spotted char Salvelinus leucomaenis (Pallas) of Russian Far East]. AB - The genetic structure of the populations in white-spotted char Salvelinus leucomaenis (family Salmonidae) was determined based on variations in ten microsatellite DNA loci in samples from different parts of the species range in the Russian Far East. In a number of samples, variations in 21 allozyme loci were examined, of which five loci were found to be polymorphic. The overall diversity level in the examined markers was comparable to that observed in a closely related char species, Dolly Varden. The estimates of interpopulation genetic differentiation were highly statistically significant in most of the pairwise comparisons amongthe samples. The overall evaluation of the spatial genetic differentiation in white-spotted char constituted F(ST) = 0.203 and R(ST) = 0.202. Cluster analysis and multidimensional scaling based on microsatellite allele frequencies indicated the possible subdivision of the examined samples into two main groups, i.e., northern (represented by the regions of the north of Khabarovsk krai, Kamchatka, Yama Bay) and southern (with regions including Sakhalin, Primorye, and the Kuril Islands). The allozome data demonstrated a similar pattern of differentiation. The level of intra- and interpopulation genetic diversity in the southern group was higher than in the northern group. The isolation-by-distance test did not identify a significant correlation between genetic and geographic distances among the samples. The data obtained enabled the suggestion that the genetic structure of the population of white-spotted char was shaped by the influence of historical geological climatic rearrangements of its range and the genetic drift, because of determined by relatively low population number and limited in the extent of the migration activity of its anadromous form. PMID- 25711013 TI - [Chemosignals from isolated females have antimutagenic effect in dividing the cells of bone marrow from male mice of the CBA line]. AB - A level of X-ray induced mitotic disturbances in the cells of the bone marrow of male mice was studied under the modifying influence ofchemosignals from isolated adult female mice of the CBA line. It has been shown that the frequency of chromosomal aberrations in irradiated (4 Gr) males after exposing them for 24 hours on bedding soiled with female chemosignals is lower than in irradiated males in cages with clean bedding. The mechanisms and importance of the antimutagenic effect of female house mouse chemosignals are discussed. PMID- 25711014 TI - [Genetic components and the uncertainty of the phenotypic realization of the mass of newborns in domestic pigs Sus scrofa L]. AB - In this article, we discuss the features of the genetic determination of a continuous quantitative trait, the mass of newborn offspring in populations of the domestic pig. We defined several components that determine the phenotypic trait, such as the maternal effect, complete dominance, interaction of the parental alleles in the genotype of the offspring, and the uncertainty of phenotypic realization of genotype. We found that a phenotypic trait of high genetic determinacy can also have a maximum range in phenotypic realization, in which case each genotype encountered in the population can realize within the entire range of possible phenotypes. PMID- 25711015 TI - [Natural selection associated with color vision defects in some population groups of Eurasia]. AB - Fitness coefficients and other quantitative parameters of selection associated with the generalized color blindness gene CB+ were obtained for three ethnogeographic population groups, including Belarusians from Belarus, ethnic populations of the Volga-Ural region, and ethnic populations of Siberia and the Far East of Russia. All abnormalities encoded by the OPN1LW and OPN1MW loci were treated as deviations from normal color perception. Coefficients were estimated from an approximation of the observed CB+ frequency distributions to the theoretical stationary distribution for the Wright island model. This model takes into account the pressure of migrations, selection, and random genetic drift, while the selection parameters are represented in the form of the distribution parameters. In the populations of Siberia and Far East, directional selection in favor of normal color vision and the corresponding allele CB- was observed. In the Belarusian and ethnic populations of the Volga-Ural region, stabilizing selection was observed. The selection intensity constituted 0.03 in the Belarusian; 0.22 in the ethnic populations of the Volga-Ural region; and 0.24 in ethnic populations of Siberia and Far East. PMID- 25711016 TI - [The load and diversity of hereditary diseases in four raions of Rostov oblast]. AB - The results of a medical genetic survey of the population of four raions (176 535 individuals) of Rostov oblast (Dubovsky, Zimovnikovsky, Myasnikovsky, and Krasnosulinsky raions) are presented. The load of autosomal dominant (AD), autosomal recessive (AR), and X-linked hereditary diseases for urban and rural population was calculated, and the diversity of monogenic hereditary diseases (MHD) was reviewed. The nosological spectrum of MHD constituted 117 diseases (63 diseases with AD inheritance; 38 with AR inheritance; and 16 with X-linked inheritance). The analysis showed that the incidence of MHD among the population of Rostov oblast was 1 : 336. Considerable differentiation in the prevalence rates of MHD (AD, AR, and X-linked pathologies) among certain raions was revealed. PMID- 25711017 TI - [Risk of genetic transformation of multipotent mesenchymal stromal cells in vitro]. AB - Proof of the efficacy of cell therapy by numerous studies and clinical trials inevitably has raised the question of improving the regulatory framework that governs its use. Particular attention should be paid to the genetic safety of cell preparations. The immune, genetic, and pharmacological modification and expansion of cells in vitro can lead to an undesired effect, which not only has reduced the healing, recovery, and regulatory potential of cell therapy, but also increased the risk of accumulating genetically aberrant cells and the oncogenic transformation of cell preparations. The article has presented the estimation of the parameters of the genetic stability of cultured multipotent mesenchymal stromal cells (MSCs) derived from bone marrow and adipose tissue. The study was conducted using classic methods of genotoxicology, i.e., the individual cells gel electrophoresis (DNA comets) and the micronucleus test. We described a basic level of DNA damage and the frequency of micronucleus, identified genetically instable cultures, and conducted the comparison of genetic variability of MSCs isolated from different tissues. PMID- 25711018 TI - [Comparative transcriptome pairwise analysis of spontaneously transformed multipotent stromal cells from human adipose tissue]. AB - Potential markers and the mechanism of the spontaneous transformation of multipotent stromal cells (MSC) with perivascular immunophenotype have been determined. A transcriptome comparative study was performed involving six paired specimens of normal and spontaneously transformed MSC with perivascular immunophenotype, obtained in the first passages following the isolation of adipose tissue of six healthy donors. According to the results obtained using the microarray Illumina HT-12 v4 with the Significance Analysis of Microarrays software, differentially expressed transcripts were revealed and a statistical analysis using Gene Ontology and Molecular Signatures Databases was conducted. The association of the spontaneous transformation of isolated MSC with perivascular immunophenotype with previously identified oncogenic cell transformation pathways (E2F, ATR/ATM, RAS, and RHOA) is suggested and further aims for more detailed study are set. Potential transformation markers, including largely unknown genes and those previously not associated with cancer genes (HSPB6, PLAC9, FEZ1, DTWD1, APH1A, and ATP5L) are described. PMID- 25711019 TI - Isolation and characterization of eighteen polymorphic microsatellite loci in Schizopygopsis younghusbandi Regan and cross-amplification in three other Schizothoracinae species. AB - Eighteen polymorphic microsatellite loci were isolated from Schizopygopsis younghusbandi Regan and the characterization of these loci was assessed in 46 individuals collected from the Yarlung Tsangpo River in Tibet, China. The numberof alleles per locus ranged from 2 to 14. The expected heterozygosity and Shannon-Wiener diversity index ranged from 0.022 to 0.879 and from 0.059 to 2.313, respectively. The cross-species amplification and applicability of these loci were tested in three other Schizothoracinae species belonging to Schizothorax and Oxygymnocypris. These loci will be useful for the evaluation of genetic diversity and population genetic structure in S. younghusbandi and other related species. PMID- 25711020 TI - [Molecular and genetic aspects of interactions of the circadian clock and the energy-producing substrate metabolism in mammals]. AB - The circadian clock system coordinates al the processes occurring in the body and controls the rhythmic pattern in metabolic system functioning. The reciprocal relationship between molecular and genetic systems of the circadian clock and the systems responsible for carbohydrate and lipid turnover provide fine tuning both of metabolic processes and the circadian clock regulation system, permitting the body to adapt to a variable environment. NAD-dependent enzymes, protein-kinases, and transcription regulators could serve as presumable molecular components, which are responsible for such a type of relationship. Genetic models and epidemiological studies demonstrate an association between mutations in the circadian clock genes with the risk of a disturbance of metabolic processes regulation, obesity development, and other maniifestations of metabolic syndrome. PMID- 25711021 TI - [DNA divergence as a criterion for the choice of the initial material of the sweet pepper (Capsicum annum L.) in selection for heterosis]. AB - The identification of perspective parental forms for the creation of high-yield hybrids is the most labor-consuming stage of selection, because it needs extensive crossings and trials of combinative ability. Based on eval- uation of the genetic divergence of the parental forms, the efficiency of the prediction of the yield potential of F1 hybrids of the sweet pepper (Capsicum annuum L.) was investigated in this study. The value of the divergence was calculated using biometric and molecular analyses, such as inter simple sequence repeats (ISSR) and random amplified polymorphic DNA (RAPD). As a result of molecular-genetic study on the selective collection, 10 lines were selected for cyclic cross (scheme I) and testcross (scheme II). In most combinations, the F1 hybrids were significantly superior to the parents in the main economically valuable traits. The level of heterosis was significantly higher among hybrids of scheme I. Analysis of the relationship between parental divergence and F1 performance showed that the hybrid productivity of scheme I was predetermined by ISSR divergence in 86%, and productivity was caused by RAPD divergence in 69%, whereas the F1 yield of scheme II was not related to the value of genetic distances. Since the values of DNA divergence were closely associated both with mid-parent level and F1 performance, we assumed that some part of the polymorphic DNA fragments of the constituents of scheme I is related to heterotic loci (HTL), which may be considered potential markers for the choice of the initial material in selection for heterosis. PMID- 25711022 TI - [The effectiveness of molecular markers for the identification of Lr28, Lr35, and Lr47 genes in common wheat]. AB - The effectiveness of molecular markers for the identification of leaf rust resistance genes Lr28, Lr35, Lr47 transferred to common wheat was assessed the using samplesof Triticum spp. and Aegilops spp. from Ae. speltoides. Markers Sr39F2/R3, BCD260F1/35R2 of gene Lr35 and PS10 of Lr47 gene were characterized by high efficiency and were revealed in a line of common wheat containing these genes, and samples of Ae. speltoides (their donor). Marker SCS421 of Lr28gene and markers Sr39#22r, Sr39#50s, BE500705 of Lr35/Sr39 genes turned out to be less specific. Marker SCS421 was amplified in the samples of the T. timopheevii species, and markers Sr39#22r, Sr39#50s--in the Ae. speltoides, Ae. tauschii, T. timopheevii, line KS90WRC010 (Lr41), the sort of common wheat In Memory of Maistrenko, obtained using synthetic hexaploid T. timopheevii x Ae. tauschii and introgressive lines obtained using Ae. speltoides. Marker BE500705, which indicates the absence of Lr35/Sr39 genes, was not revealed in lines TcLr35 and MqSr39, in Ae. speltoides, Ae. tauschii and T. boeoticum (kk-61034, 61038). Analysis of the nucleotide sequences of amplification products obtained with the markers SCS421 and Sr39#22r indicated their low homology with TcLr28 and TcLr35. Using molecular markers, we showed a different distribution of Lr28 (77%), Lr35 (100%) and Lr47 (15%) genes in 13 studied samples ofAe. speltoides. In introgressive lines derived from Ae. speltoides, contemporary Russian sorts of common wheat and triticale variants Lr28, Lr35, Lr47 genes were not revealed. PMID- 25711023 TI - [The role of peptidyl-prolyl-Cis/trans-isomerase Genes of Arabidopsis thaliana in plant defense during the course of Xanthomonas campestris infection]. AB - Experimental data obtained in this study showed the involvement of A. thaliana immunophilin genes At2g16600, At4g33060, and At5g48570 in plant defense responses to the Xanthomonas campestris invasion. We found not only that the expression levels of these genes changed upon bacterial infection, but also that the plant's resistance to the pathogen was increased if the expression levels of the immunophilin genes were elevated in the host cells. PMID- 25711024 TI - [Comparative sequence analysis of the LEA gene fragment in Pinus sibirica du tour and Pinus pumila (Pallas) regel]. AB - A comparative sequence analysis of the LEA (Late Embryogenesis Abundant (LEA) like gene) intron fragment was performed in Pinus sibirica and P. pumila differing in geographic origin. It was demonstrated that in P. sibirica this fragment was represented by two types of PCR products, 224 and 202 bp in size. Similarly, in accessions of P. pumila, two PCR products of 224 and 159 bp in size were identified. Comparison of 224 bp fragments in P. sibirica and P. pumila showed that they differed in single nucleotide substitutions. Analysis of the intron fragment in a plant, which was characterized as an interspecific hybrid based on morphological characters, showed that it had fragments of 224 and 159 bp in size. The sequence of 224 bp fragment was similar to that of the corresponding fragment in P. sibirica. The structure of the short fragment was the same as the structure of the corresponding fragment in P. pumila. The data obtained are discussed in terms of the use of the sequences examined for species taxonomic classification and of an analysis of species hybridization. PMID- 25711025 TI - [Genetic analysis of leaf pubescence in isogenic lines of conmmon wheat Novosibirsk 67]. AB - In this study, genetic and monosomic analyses of the leaf pubescence of ANK 7A, ANK 7B, and ANK 7C wheat isogenic lines were carried out based on the Novosibirsk 67 wheat variety. According to visual analysis, the variety-recipient has a soft, uniform pubescence, and lines have trichomes on the surfaces of their leaves inherited from the two. Chinese varieties and one Soviet variety. Using the high throughput phenotyping method LHDetect2, which allows one to allocate the phenotypic classes of offspring in crosses based on the quantitative characteristics of leaf pubescence, it was found that chromosome 7B of the isogenic lines has a gene that determines the presence of long trichomes, and chromosome 7D of the Novosibirsk 67 variety has a gene that increases the density of pubescence. The obtained data allowed for the formulation of a hypothesis for the existence of a homoallelic series of genes that control leaf pubescence in the chromosomes of the seventh homeologous group of common wheat. PMID- 25711026 TI - [Radiation doses and allozyme variability in the population of the northern red backed vole (Clethrionomys rutilus) from the east urals radioactive trace zone]. AB - The paper estimates the external (due to radionuclides accumulated in the soil) and internal (due to incorporated radionuclides) exposure of rodents that live in the head of the East Urals Radioactive Trace (EURT). It is shown that in the last decades the dose rates were lower than the values that lead to doubling the number of mutations in the allozyme loci in mammals. The variability ofthe eight allozyme loci in populations of northern red-backed voles from the EURT zone and their neighboring plots, as well as the territories of the Urals and Trans-Urals with background levels of radioactive contamination, are analyzed. No differences in the pattern and frequency of allozymes that would distinguish the EURT samples from a number of other populations of the Urals, were found. In the control sample "Sysert", "unique" for the Ural populations of northern red-backed voles, alleles of the loci Got and Sod were marked, conspecific to a closely related species--the bank vole. This fact can be regarded as evidence of recent cross species hybridization. PMID- 25711027 TI - [Episodes of adaptive evolution of mitochondrial genome in Asiatic salamanders (Amphibia, Caudata, Hynobiidae)]. AB - To elucidate the effect of natural selection on the evolution of mitochondrial DNA (mtDNA) in Asiatic salamanders of the family Hynobiidae, nucleotide sequences of 12 protein-coding genes were analyzed. Using a mixed effects model of evolution, it was found that, in spite of the pronounced effect of negative selection on the mtDNA evolution in Hynobiidae (which is typical for the animals in general), two phylogenetic clusters, the West Asian one, represented by the genera Ranodon and Paradactylodon, and North Eurasian one, represented by the genus Salamandrella, were formed under the influence of episodic positive selection. Analysis of protein sequences encoded by the mitochondrial genome also supported the influence of positive selection on the evolution of Hynobiidae at some stages of their cladogenesis. It is suggested that the signatures of adaptive evolution detected in the mtDNA of Hynobiidae were determined by the complex and long-lasting history of their formation, accompanied by adaptation to the changing environment. PMID- 25711028 TI - [Genetic variations in Clupea pallasii herring from okhotsk sea based on microsatellite markers]. AB - The genetic variations among spawning groups of herrings from different spawning grounds of the northwestern part of the Okhotsk Sea was assessed using ten microsatellite loci. All loci were polymorphic with the ex- pected heterozygosity estimates varying at different loci in the range of 0.7-95.0% (with a mean of 68.5%). The degree of genetic differentiation displayed by the herrings from the Okhotsk Sea was not statistically sig nificant (0 = 0.74%). The level of pairwise genetic differentiation F(ST) varied in the range of 0.002-0.014, no was it statistically significant in all comparison pairs between the herring samples. PMID- 25711029 TI - [Gene pool of Buryats: clinal variability and territorial subdivision based on data of Y-chromosome markers]. AB - The structure of the Buryat gene pool has been studied based on the composition and frequency of Y-chromosome haplogroups in eight geographically distant populations. Eleven haplotypes have been found in the Buryat gene pool, two of which are the most frequent (N1cl and C3d). The greatest difference in haplogroup frequencies was fixed between the western and eastern Buryat samples. The evaluation of genetic diversity based on haplotype frequencies revealed that it has low values in most of the samples. The evaluation of the genetic differentiation of the examined samples using an analysis of molecular variance (AMOVA) shows that the Buryat gene pool is highly differentiated by haplotype frequencies. Phylogenetic analysis within haplo-groups N1cl and C3d revealed a strong founder effect, i.e., reduced diversity and starlike phylogeny of the median network of haplotypes that form specific subclusters. The results of a phylogenetic analysis of the haplogroups identified common genetic components for Buryats and Mongols. PMID- 25711030 TI - [The mutation spectrum of the GJB2 gene in Belarussian patients with hearing loss. Results of pilot genetic screening of hearing impairment in newborns]. AB - A total of 111 unrelated probands and their 8 sibs from Grodno oblast (Belarus) with bilateral isolated sensorineural hearing impairment were studied for the presence of mutations in the connexin 26--GJB2gene. Mutations were detected in 51 probands (46% of the sample). A significantly higher frequency of the GJB2gene mutations was observed in familial cases of the disease with the autosomal recessive type of inheritance (in 78% of families). Detected peculiarities of the GJB2 gene mutation spectrum demonstrated that use of the algorithm, which was developed for Russian patients, is optimal for the molecular study of patients from Be- larus. In the sample of patients with hearing loss, the highest (among other similar samples studied in the world) allele frequency of c.313_326de114 mutation (7% out of all pathological GJB2 alleles) was registered; Polish origin of this deletion was suggested. It was demonstrated that detection of the GJB2 gene mutation on only one patient's chromosome is insufficient to confirm a molecular genetic diagnosis of hearing loss of the DFNB1 genetic type (autosomal recessive hearing loss caused by the GJB2 gene mutations). Pilot screening in the presence of GJB2 gene mutations in newborns from Grodno oblast was conducted. The material from 235 children was studied during the screening; nine heterozygous carriers of the mutation were found. The c.35delG mutation was detected in a homozygous state in a single newborn (hearing loss of moderate severity was subsequently audiologically confirmed in this child). PMID- 25711031 TI - [TOMM40 gene polymorphism association with lipid profile]. AB - The distribution of the allele and genotype frequency for the TOMM40 gene polymorphic variants rs741780, rs157580, rs1160985, rs2075650, and rs8106922 was analyzed in a sampling of ethnic Russians from the city of Kemerovo. The study of the structure of linkage disequilibrium in terms of five studied polymorphic variants showed the presence ofa haplotype block 2 Kb in length, which includes three polymorphic variants, i.e., rs741780, rs1160985, and rs8106922. The differences in the frequencies of alleles and genotypes in terms of the polymorphic rs2075650 and rs157580 variants between ethnic Russians from the city of Kemerovo and other European populations were detected. It was discovered that polymorphic variants of TOMM40 rs741780, rs1160985, and rs8106922 are associated with serum triglyceride concentrations. In men, the polymorphic variant rs2075650 is associated with low-density lipoprotein cholesterol levels. In women, the polymorphic variant rs741780 is associated with diastolic blood pressure levels. PMID- 25711032 TI - [Association of matrix metalloproteinases' polymorphisms of MMP3 and MMP9 with development of genital endometriosis]. AB - We present a comparative analysis of the allelic polymorphism of the matrix metalloproteinase (MMP) gene family, including MMP3 (rs3025058), MMP7 (rs11568818), MMP9 (rs17576, rs2250889), MMP12 (rs2276109), and MMP13 (rs2252070), in patients with external genital endometriosis (EGE) and in a control group of healthy women proven to be free of disease by laparoscopic inspection. We found significant differences in the incidence of particular MMP3 and MMP9 alleles, which substantiate the role of matrix metalloproteinases in EGE pathogenesis. We used the Multifactor Dimensionality Reduction (MDR) analysis to show that 14 allelic combinations of the MMP containing MMP3 (rs3025058) x MMP7 (rs11568818) x MMP9 (rs17576) alleles showed a statistically significant association with an increased risk of EGE, while 10 other combinations correlated with a reduced risk of the disease. MDR analysis produced two statistically significant models for MMP allelic combinations involved in EGE progression, both with 100% penetrance and 83% and 78% accuracy. PMID- 25711033 TI - [Association between inflanummatory gene polymorphisms and the risk of myocardial infarction]. AB - Allele and genotype frequency distributions of polymorphism rs2076059 (3832T>C) within the SELE gene rs6131 (S290N), within the SELP gene, rs1131498 (F206L), within the SELL gene, rs5498 (K469E) within the ICAM1 gene, rs35569394 ( 2549(18)I/D) within the VEGFA gene, and rs1024611 (-2518A>G) within the CCL2 gene were examined in a group of patients after myocardial infarction (MI)(280 individuals) and in a control group (312 individuals). An implementation of the Markov chain and Monte-Carlo method (AP- Sampler) revealed the allele combinations associated with decreased and increased risk of MI. Among these the most important allele combinations were SELE*C + SELP*S + CCL2*A (FDR = 0.0005; OR = 0.42) SELP*S + CCL2*A (FDR = 0.0009; OR= 0.36}, SELL*F + VEGFA*I+ CCL2*G/G(FDR = 0.0009; OR = 4.17) VEGFA*I+ CCL2*G/G (FDR = 0.0009; OR = 3.76), SELE*C + CCL2*A (FDR = 0.0023; OR = 0.47), and SELL*I+ CCL2*G/G (FDR = 0.003; OR = 3.15). PMID- 25711034 TI - [Spontaneous mutation rate changes in saccharomyces cerevisiae at combinations of hsm3 and hsm6 mutations with rad52 mutation]. AB - Long-term storage at +4 degrees C and cultivation at +30 degrees C changes the spontaneous mutation rate of the yeast Saccharomyces cerevisiae double mutants rad52hsm3delta and rad52hsm6-1. Combinations of hsm3 and hsm6 mutations with the rad52 mutation lead to a decrease of the spontaneous mutation rate mediated by DNA repair synthesis in multiply replanted strains in comparison with the same strains investigated right after RAD52 gene decay. Combinations of hsm3 and hsm6 mutations with mutations in other genes of the RAD52 epistatic group did not provide a spontaneous mutation rate decrease. PMID- 25711035 TI - Three new di-O-glycosyl-C-glucosyl flavones from the leaves of Caesalpinia ferrea Mart.. AB - Three hitherto unknown di-O-xylosyl-C-glycosyl flavones were isolated from the leaves of Caesalpinia ferrea. The structures of all isolated compounds were elucidated by conventional methods and spectroscopic analysis, including 1D and 2D NMR, as well as by HRESIMS. PMID- 25711036 TI - Amino phenolics from the fruit of the argan tree Argania spinosa (Skeels L.). AB - A new phenolic-type compound containing a nitrogenous, heterocyclic-fused ring from the fruit of the argan tree, Argania spinosa (Skeels L.), is described. This and another already known compound also isolated in the course of the work belong to an obscure and rare class of natural products, the amino phenolics. PMID- 25711037 TI - Synthesis and antimicrobial evaluation of 2-(p-substituted phenyl)-5-[(4 substituted piperazin-l-yl)acetamido]-benzoxazoles. AB - A series of 2-(p-substituted phenyl)-5-(2-{4-[(p-chloro-fluorophenyl)/phenyl] piperazin-1-yl}acetamido)-benzoxazoles were synthesized and tested for their antimicrobial activities. The structures of the new derivatives were elucidated by spectral techniques. The minimum inhibitory concentrations (MIC) of the new benzoxazoles, along with those of previously synthesized analogues, were determined against standard bacterial and fungal strains and drug-resistant isolates, and compared with those of several reference drugs. The new benzoxazole derivatives were found to possess a broad spectrum of antimicrobial activity with MIC values of 32-1024 MUg/ml. Although the standard drugs were more active against the tested pathogens, the activities of the new benzoxazoles and the reference drugs were largely similar against the drug-resistant isolates. PMID- 25711038 TI - Antibacterial flavanones and dihydrochalcones from Macaranga trichocarpa. AB - Previously we had isolated two prenylated flavanones and two prenylated dihydrochalcones, macatrichocarpins A-D (1-4), from the acetone extract of the leaves of Macaranga trichocarpa. Re-examination of the fractions containing minor components resulted in the isolation of four more flavonoid derivatives, including two new prenylated dihydrochalcones, oxymacatrichocarpin C (5) and isomacatrichocarpin C (6). The structures of these compounds were determined by the analysis of UV, NMR, and mass spectral data. The eight isolated flavonoids were tested on eight pathogenic bacteria and found to be mostly moderate antibacterial agents, with the lowest MIC value of 26.5 MUM achieved by the flavanone macatrichocarpin A (1) against Bacillus subtilis. PMID- 25711039 TI - Chemical constituents and biological activities of Cirsium leucopsis, C. sipyleum, and C. eriophorum. AB - Two endemic Cirsium species, C. leucopsis DC. and C. sipyleum O. Schwarz, and C. eriophorum (L.) Scop. growing in Turkey were investigated to establish their secondary metabolites, fatty acid compositions, and antioxidant and anticholinesterase potentials. Spectroscopic methods were used to elucidate the structures of thirteen known compounds (p-hydroxy-benzoic acid, vanillic acid, cis-epoxyconiferyl alcohol, syringin, balanophonin, 1'-O-methyl-balanophonin, apigenin, kaempferol-3- O-beta-D-glucopyranoside, kaempferol-3-O-alpha-L rhamnopyranoside, taraxasterol, taraxasterol acetate, beta-sitosterol, beta sitosterol-3-O-beta-D-glucopyranoside). cis-Epoxyconiferyl alcohol and 1'-O methyl- balanophonin were isolated for the first time from Cirsium species. Palmitic acid (47.1%) was found to be the main fatty acid of C. leucopsis, linoleic acid in both C. sipyleum (42.1%) and C. eriophorum (37.8 %). Assays of beta-carotene bleaching, scavenging of 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radicals, 2,2-azinobis (3-ethylbenzothiazoline-6-sulfonic acid) diammonium (ABTS) cation radicals, and superoxide anion radicals, as well as cupric reducing antioxidant capacity (CUPRAC) were used to determine the antioxidant activities of the extracts and isolated compounds. Vanillic acid, balanohonin, and kaempferol-3-O-aalphaL-rhamnopyranoside exhibited strong antioxidant activity. Taraxa-terol was a potent inhibitor of acetyl- and butyrylcholinesterase activity, respectively. PMID- 25711040 TI - Antihyperglycemic activities of extracts of the mistletoes Plicosepalus acaciae and P. curviflorus in comparison to their solid lipid nanoparticle suspension formulations. AB - The antihyperglycemic activity of the extracts and preparations of solid lipid nanoparticle suspensions of two mistletoes growing in Saudi Arabia, Plicosepalus acaciae and P. curviflorus, as well as their possible antioxidant effect were investigated in a type 2 diabetic animal model. Type 2 diabetes was induced in adult male Wistar rats by a high-fat diet followed by injection of streptozotocin (STZ). The diabetic rats were treated in parallel with pioglitazone hydrochloride (PIO), non-toxic extracts of P. acaciae and P. curviflorus, as well as three different solid lipid nanoparticle (SLN) suspension formulations prepared from each of the two extracts. Blood glucose level, insulin resistance, oxidative stress parameters, and antioxidant markers were determined. The total extracts of P. acaciae and P. curviflorus as well as the SLN formulations exhibited a significant blood glucose-lowering effect associated with antioxidant effects in the diabetic rats. The SLN preparation with the highest lipid content gave the best result. Reduction of hyperglycemia and insulin resistance in the diabetic rats was, at least partly, due to the antioxidant activities of the extracts and their SLN formulations. PMID- 25711041 TI - Effect of copper toxicity on root morphology, ultrastructure, and copper accumulation in Moso bamboo (Phyllostachys pubescens). AB - A hydroponic culture experiment was conducted to study the effect of copper toxicity on root morphology, ultrastructure, and copper accumulation in Moso bamboo (Phyllostachys pubescens). Root ultrastructure of Moso bamboo was studied by transmission electron microscopy and scanning electron microscopy. Application of 200 MUM Cu resulted in an accumulation of 810 mg kg(-1) dry weight and 91 mg kg(-1) dry weight Cu in roots and shoots, respectively. The majority of the plants did not survive the application of 400 MUM Cu. Biomass production declined consistently with application of each additional increment of Cu. Root growth was more severely inhibited than shoot growth. Cu adversely affected the root morphology of the plants, however, root surface area and number of root tips increased slightly at low levels of Cu. Root cell ultrastructure and organelles changed significantly under Cu stress, in particular, cell walls, mitochondria, and xylem parenchyma were affected. PMID- 25711042 TI - Evaluation of Cucurbita maxima extract against scopolamine-induced amnesia in rats: implication of tumour necrosis factor alpha. AB - Cucurbita maxima (CM) seed oil is commonly used in Indian folk medicine to treat various ailments. We have investigated the effect of CM seed oil on memory impairment induced by scopolamine in rats. Male adult Wistar rats were administered scopolamine 1 mg/kg body weight, i.p. or 1.25 mg/kg body weight, s.c. to induce memory impairment. The nootropic agent piracetam 100 mg/kg body weight, i.p. and CM seed oil 100 and 200 mg/kg body weight, p.o. were administered daily for five consecutive days. The memory function was evaluated in the Morris water maze (MWM) test, the social recognition test (SRT), the elevated plus maze (EPM) test, and the pole climbing test (PCT). Acetylcholinesterase (AChE) activity and oxidative stress parameters were estimated in the cortex, hippocampus, and cerebellum of the brains after completion of the behavioural studies. The effects of scopolamine on the levels of the tumour necrosis factor alpha (TNF-alpha) transcript were also investigated. Scopolamine caused memory impairment in all the behavioural paradigms along with a significant increase in the AChE activity and oxidative stress in the brain. Scopolamine also caused a significant increase in the expression of TNF-alpha in the hippocampus. CM seed oil exhibited antiamnesic activity as indicated by a significant reduction in the latency time in the MWM test and decreased social interaction during trial 2 in the SRT. Further, treatment with CM seed oil significantly decreased the AChE activity and malondialdehyde levels and increased the glutathione level in brain regions. CM seed oil also significantly decreased the expression of TNF-alpha in the hippocampus. The effect of CM seed oil on behavioural and biochemical parameters was comparable to that observed in rats treated with piracetam. These results indicate that CM seed oil may exert antiamnesic activity which may be attributed to the inhibition of AChE and inflammation as well as its antioxidant activity in the brain. PMID- 25711043 TI - Effect of debarking water from Norway spruce (Picea abies) on the growth of five species of wood-decaying fungi. AB - Norway spruce (Picea abies) debarking water is an aqueous extract obtained as waste from the debarking of logs at paper mills. The debarking water contains a mixture of natural compounds that can exhibit diverse biological activities, potentially including fungicidal activity on some species of wood-decaying fungi. Thus, we investigated the growth rates of such fungi on agar plates to which debarking water extracts had been added. The experiment included five wood decaying fungi, viz. Gloeophyllum sepiarium, Oligoporus lateritius, Ischnoderma benzoinum, Junghuhnia luteoalba, and Phlebia sp. Growth reduction was observed for all species at the highest tested concentrations of freeze-dried and ethanol extracted debarking water, the ethyl acetate-soluble fraction and the diethyl ether-soluble fraction. However, the magnitude of the effect varied between different species and strains of individual species. The brown-rot fungi G. sepiarium and O. lateritius were generally the most sensitive species, with the growth of all tested strains being completely inhibited by the ethyl acetate soluble fraction. These results indicate that development of antifungal wood protecting agents from debarking water could potentially be a way to make use of a low-value industrial waste. PMID- 25711044 TI - Where do we go from here? Envisioning physician version 3.0. PMID- 25711045 TI - Future tense. PMID- 25711046 TI - Physician autonomy in the future--an introspective analysis. PMID- 25711047 TI - The era of big data. PMID- 25711049 TI - Teamwork and integrated care programs: a way forward. PMID- 25711048 TI - Comparative effectiveness and value-based purchasing: can we improve quality and cost? PMID- 25711050 TI - The autonomous automaton: a physician's role in the patient's decision. PMID- 25711051 TI - How healthcare will change: envisioning our world 30 years from now. PMID- 25711052 TI - Navigating the telefuture. PMID- 25711053 TI - A message from the editorial board of Maryland Medicine. PMID- 25711054 TI - The metamorphosis of words. PMID- 25711055 TI - [Ocular surface acidity and buffering system (by studying the conjunctival sac)]. AB - As any mucous membrane the conjunctiva is characterized by a definite pH value which guarantees-physiological functioning of the ocular surface. The most commonly used method of assessment is potentiometric pH measurement with ion specific glass microelectrodes. The results, however, can be affected by such factors, as conjunctival sac zoning, tissue acidity, epithelial trauma, and reflex tear secretion. Few data and hypotheses are available on mechanisms of maintaining the acid-base balance of the conjunctival sac (bicarbonate buffering system in particular). OBJECTIVE: to study spatial variability of conjunctival tear fluid pH and possible mechanisms of its maintenance using original methods of acidity measurement and mineral content assessment. MATERIAL AND METHODS: Tear pH was determined in 42 healthy participants (84 eyes) by means of litmus test strips and computer- aided colorimetry. Electron probe microanalysis in combination with energy dispersive spectrometry was performed in 8 healthy participants (8 eyes, 8 samples). RESULTS: In the group of 42 healthy participants (84 eyes) the pH value of conjunctival tear fluid varied from 6.30 to 7.23 with the average of 6.76 and pH mode 6.74. The pH value of conjunctival mucous discharge was measured in 25 healthy participants (28 eyes) and varied from 7.00 to 8.00 with the average of 7.26 and pH mode 7.30. The main mineral components of tear fluid are chlorine, sodium, potassium, and boron. Borate buffer is regarded as a mechanism of maintaining the acid-base balance of the ocular surface. CONCLUSIONS: The developed method of pH measurement ensuresreliable determination of conjunctival sac acidity in accordance with zoning and heterogeneity of its media as well as the complex structure of the tear film. In a healthy population, the acidity of tear significantly differs from that of conjunctival mucous discharge. Soluble chlorine, sodium, potassium, and boron compounds are the prevailing mineral components of tear fluid. Borate buffer appears to be the most stable of all mechanisms of maintaining the acid base status of tear fluid. PMID- 25711056 TI - [Pre- and postoperative ocular blood flow in transconjunctival orbital surgery]. AB - OBJECTIVE: to evaluate the pre- and postoperative ocular blood flow in patients with post-traumatic orbital deformities who underwent transconjunctival orbital reconstruction. MATERIAL AND METHODS: A total of 40 patients with post-traumatic deformities of the inferior and medial orbital walls were examined before and after transconjunctival "Alloplant" implantation to the orbit. RESULTS: Before the surgery, blood flow deficiency in a. ophthalmica and elevation in peripheral vascular resistance were found in all patients. Postoperatively, orbital hemodynamic parameters were restored and remained stable over the whole follow-up period. CONCLUSION: Post-traumatic disturbances of regional blood flow are revealed and postoperative changes of the relevant parameters are assessed. PMID- 25711057 TI - [Intraocular pressure and ocular blood flow features intravitreal infection of anti-vascular endothelial growth factor agents]. AB - OBJECTIVE: to investigate intraocular pressure (IOP) and ocular blood flow (OBF) changes as well as the individual normal range of IOP in patients with age related macular degeneration (AMD) with or without concomitant glaucoma after intravitreal anti-vascular endothelial growth factor (VEGF) therapy. MATERIAL AND METHODS: Group 1 included 34 patients (34 eyes) with AMD and no glaucoma, group 2 34 patients (34 eyes) with both AMD and glaucoma. In all patients the IOP and OBF were measured (with Ocular Blood Flow Analyzer) and the individual normal range of lOP calculated before the treatment, on the third day after the injection and at the 1-month follow-up visit. Statistical analysis was performed by STATISTICA 10. RESULTS: In group 1 there were no significant changes in ocular blood flow at different times after ranibizumab injection. In group 2 a considerable decrease in OBF was detected 1 month after the injection (p<0.001). In group 1 the intraocular pressure was at the same level before and after the treatment. In group 2 the IOP significantly decreased on the third day after the anti-VEGF injection (p=0.03) but was back to the initial level in 1 month. The individual normal range of lOP, when calculated on the third day after the injection, appeared to be much lower than before due to a moderate decrease in both IOP and OBF. At the 1-month follow-up the individual normal range of IOP was back to initial values in non-glaucoma patients but remained low in the glaucoma group due to reduced OBF. CONCLUSION: The established decrease in the individual normal range of IOP in the late period after an anti-VEGF injection should be taken into account when managing patients with both AMD and glaucoma. PMID- 25711058 TI - [Evoked retinal and cortical potentials in children with advanced and resistant retinoblastoma after neoadjuvant polychemotherapy and superselective intra arterial chemotherapy]. AB - Electrophysiological examinations (in accordance with the ISCEV Standards and original protocols) were performed after neoadjuvant chemotherapy or before and after superselective intra-arterial chemotherapy (SIACT) in 18 children aged 1-3 years with either newly diagnosed advanced retinoblastoma (8 eyes) or resistant retinoblastoma (14 eyes). The most considerable decrease in amplitude was demonstrated by the cone response b-wave, photopic 24 Hz flicker electroretinogram (ERG), photopic negative response, and the P1-component of multifocal ERG, indicating a significant dysfunction of bipolar and ganglion cells, more pronounced in the macular zone. After the SIACT, central retinal functions improved. In eyes with retinoblastoma there is a moderate peak latency shortening of the flash visual evoked potential (VEP) P2-component, which reflects functional changes in the central retina rather than those in the visual pathways, and therefore, flash VEP analysis is a useful tool of chemotherapy patient monitoring, especially when electroretinography cannot be performed. PMID- 25711059 TI - [Oxidative stress in uveitis and its correction with superoxide dismutase antioxidative enzyme (experimental study)]. AB - OBJECTIVE: to study the influence of experimental uveitis on those biochemical parameters of aqueous humor that reflect inflammation acuity as well as local antioxidant and local antiproteolytic activity; to study the effect of topical superoxide dismutase (SOD) on the clinical course of uveitis and ocular metabolism. MATERIAL AND METHODS: Acute uveitis was induced in rabbits by a double injection (subcutaneous and intravitreal) of normal horse serum. The following parameters of aqueous humor were measured: protein concentration, antioxidant activity, SOD activity, alpha2-macroglobulin level, total nitrates and nitrites, and leukocyte number. Clinical assessment and histopathological study were performed. RESULTS: It was found that uveitis is associated with a statistically significant increase in protein concentration, leukocyte number, SOD activity, and alpha2-macroglobulin level in aqueous humor as well as a decrease in anti-hydroxyl radical activity. SOD instillations contributed to the reduction of the listed parameters and improvement of the antioxidant activity. Clinical presentations of uveitis also became less pronounced. CONCLUSION: SOD instillations for oxidative stress correction help reduce clinical presentations of uveitis, which is confirmed by biochemical examination. PMID- 25711060 TI - [Application fluorescein angiography for assessment of anterior eye segment hemomicrocirculation in patients with cataract and pseudoexfoliation syndrome]. AB - OBJECTIVE: to study the state of anterior eye segment (AES) hemomicrocirculation by means of application fluorescein angiography (FAG) in patients with cataract of different maturity solely or in combination with pseudoexfoliation syndrome (PES). MATERIAL AND METHODS: A total of 58 patients (98 eyes) with cataract or cataract and PES aged from 45 to 82 years (68.4 +/- 5.2 years on average) were assessed (study group). These patients were divided into 2 subgroups: I--patients with cataract and no PES, II--patients with both cataract and PES. The control group included 15 individuals (21 eyes) without ophthalmic pathology aged from 47 to 72 years (57.7 +/- 4.7 years on average). Conjunctival microcirculation was assessed by the proposed FAG method, in which the dye is introduced directly to the bulbar conjunctival capillary bed through application. RESULTS: The following parameters of application FAG that characterize hemomicrocirculation of the AES were analyzed: venular appearance time, venous phase duration, beginning of extravasal hyperfluorescence, microvessels functionality regarding their number and caliber. All patients demonstrated hypoperfusion, the intensity of which correlated with cataract maturation and the presence of PES. CONCLUSION: Application FAG adequately reflects the state of hemomicrocirculation of the AES in cataracts and PES. PMID- 25711061 TI - [Results of intraocular lens implantation on top of the anterior capsule in cases of phaco complications]. AB - Posterior capsule rupture during cataract extraction requires that the intraocular lens (IOL) implanted on top of the capsular bag was stable and well centered. The objective of this study was to evaluate the results of Rayner C flex aspheric and M-flex aspheric (United Kingdom) IOLs implantation on top of the capsular bag and their stability in patients with phaco complications. MATERIAL AND METHODS: A total of 2556 phacoemulsification cases were analyzed. Posterior capsule rupture as a complication occurred in 7 cases, that is 0.27%. In all patients Rayner C-flex (5) and M-flex (6) IOLs were implanted on top of the capsular bag according to the initial calculations and with no modifications in the procedure. The 2nd-year follow-up included measurement of the corneal compensated intraocular pressure (IOP) and B-mode and 3D grey-scale ultrasound in order to assess the structures of the anterior segment and to check the position of the IOL. RESULTS: All surgeries yielded positive clinical results. In 2 years after the intervention uncorrected visual acuity averaged 0.7-0.13, corrected-- 0.91+0.07; clinical refraction: sphera-- +0.46 +/- 0.26 diopters, cylinder-- 0.71 +/- 0.29 diopters. The shape and other parameters of Rayner IOLs contribute to their long-term stability. Postoperative lOP in the treated eye was higher than in the fellow nonoperated eye (13.9 +/- 0.76 and 11.8 +/- 0.59 mmHg correspondingly) but the difference lied within the range of normal asymmetry. CONCLUSION: The 3D ultrasound technology is an informative mean of monitoring the position of the IOL in case of its extracapsular implantation; a comparatively higher IOP in the operated eye does not exceed the range of normal asymmetry between the two eyes; Rayner C-flex and M-flex IOLs remain stable and well centered after being implanted on top of the capsular bag. PMID- 25711062 TI - [Laser speckle-based method for binocular vision recovery in diploptic treatment of concomitant strabismus]. AB - OBJECTIVE: to investigate the effectiveness of the method of "dissociation" for concomitant strabismus treatment, which involves laser speckles and polaroid separation of visual fields. MATERIAL AND METHODS: A total of 40 patients with different types of concomitant strabismus and the average age of 9.8 years were enrolled. The treatment method implies the use of the Forbis device with polaroid separation of visual fields and low-energy helium-neon laser speckle patterns (green and red, 0.53 pm and 0.65 pm correspondingly). Binocular vision recovery was performed in the conditions of alternating exertion and relaxation of accommodation obtained through plus and minus spherical lenses. CONCLUSIONS: The method ensures an increase in the number of individuals capable of stereopsis from 31.2-44.4% (conventional treatment) to 54.4% as well as widening of the range of tolerated plus/minus spherical lenses, in which the binocular fusion is retained at the same degree of convergence. PMID- 25711063 TI - [Comprehensive assessment of risk factors for retinal vein occlusion and derivation of classification criteria for retinal ischemia]. AB - OBJECTIVE: to perform a complex ophthalmological and general examination of patients with retinal vein occlusion (RVO) and to derive classification criteria for retinal ischemia. MATERIALS AND METHODS: A total of 44 patients with RVO and macular edema and 20 controls were enrolled. All patients underwent a thorough ophthalmological and general examination and clinical laboratory testing. RESULTS: Cardinal risk factors of RVO development were derived from among somatic illnesses and laboratory results. Regional hemodynamics assessment helped identify the most significant systolic and diastolic blood flow disturbances in the central retinal vein and central retinal artery circulation systems. Profound changes in electrophysiological parameters were found. Statistical analysis of the collected data allowed to identify 3 stages of retinal ischemia. CONCLUSION: The established risk factors of RVO development, regional blood flow impairment and original classification criteria for retinal ischemia make it possible to predict the course of the disease and treatment effect. PMID- 25711064 TI - [Lamellar minikeratoplasty for recurrent herpes keratitis in the late post-LASIK period]. AB - The article presents a case report of sutureless lamellar minikeratoplasty for progressive corneal ulceration associated with herpes simplex infection in the late period after LASIK. PMID- 25711066 TI - [Options for correction of endothelial dysfunction and oxidative stress in patients with primary open-angle glaucoma]. AB - OBJECTIVE: To evaluate the efficacy of Tanakan in patients with primary open angle glaucoma (POAG) with respect to its influence on vascular endothelial function and oxidative stress. MATERIAL AND METHODS: Oxidative stress severity and antioxidant status were investigated in 52 patients with POAG divided into two groups. The effect of different treatment schemes on flow-dependent vasodilation and dynamic level of endotelin-1 (ET-1), which is a marker of endothelial dysfunction, was studied. RESULTS: In the main group glaucomatous optic neuropathy progressed significantly as compared to the baseline (p<0.05). A trend for a decrease in malondialdehyde-modified low-density lipoproteins (MDA LDL) and plasma malondialdehyde (MDA) levels (p<0.1) was also found, which indicates the activation of antioxidant response and resolution of oxidative stress. Due to endothelial dysfunction, plasma ET-1 levels in glaucoma patients are on average 5 times higher than the corresponding median physiological concentration. After the treatment started plasma ET-1 levels reduced and 3 months later approached the normal range. Reactive hyperemia testing and assessment of flow-dependent vasodilation revealed a poor initial endothelial response in 64.6% of patients. During the treatment paradoxical vasoconstriction was noted in 12.4% of patients. After the treatment patients from the main group demonstrated a statistically significant increase in brachial artery diameter. CONCLUSION: Tanakan is showed to produce a positive effect on vascular remodeling in patients with POAG, which indicates its high antioxidant and antihypoxic activity. A significantly increased flow-dependent vasodilation found in the main group (especially 1-3 months after the beginning of the therapy) is thought to be due to an improved vasodilating ability of the vascular endothelium as the result of Tanakan use. PMID- 25711065 TI - [Evaluating the effectiveness and safety of diode laser trans-scleral thermotherapy of the ciliary body as a treatment for refractory glaucoma]. AB - OBJECTIVE: To evaluate the effectiveness and safety of diode laser trans-scleral thermotherapy (TSTT) in cyclodestruction for refractory glaucoma (RG). MATERIAL AND METHODS: The proposed cyclodestructive procedure was performed on 87 patients with severe and terminal RG (stages III and IV) at power levels of 0.4-0.5 W with exposure times of 15-25 seconds. RESULTS: The incidence of severe inflammatory response was less than that after well-known cyclodestructive procedures. The average reduction of intraocular pressure at the first day after surgery (considering all observations) was 10.45 +/- 7.23 mmHg. In all cases after TSTT of the ciliary body the pain resolved within the first day. CONCLUSION: The effectiveness of the new method is comparable to that of other methods of cyclodestruction, however, the proposed TSTT technique is much safer than the conventional trans-scleral cyclophotocoagulation. PMID- 25711067 TI - [Current therapeutic possibilities for uveal ocular hypertension]. AB - OBJECTIVE: to evaluate the efficacy of combination therapy with three antiglaucoma agents (dorzolamide + brimonidine/timolol) for uveal ocular hypertension. MATERIAL AND METHODS: The study enrolled 20 patients with anterior uveitis complicated by intraocular pressure (IOP) elevation. Besides standard anti-inflammatory agents, the treatment included IOP-lowering instillations, namely dorzolamide 2% 3 times daily and timolol 0.5% 2 times daily. Those patients whose IOP remained uncompensated were then switched to a three-drug regimen: dorzolamide 2% 3 times daily and a fixed combination of brimonidine 0.2%, an aLPHA2-receptor agonist, and timolol 0.5%, a 3-blocker, 2 times daily (Combigan, Allergan). IOP was measured with Maklakov tonometer three times during the day before the treatment and then three times daily while performing the two- or three-drug combination therapy. RESULTS: The mean initial IOP was 34.57 +/- 0.09 mmHg with daily fluctuations of 5.2 +/- 0.08 mmHg. After starting the unfixed combination therapy (dorzolamide + timolol) the mean IOP decreased by 7.86 +/- 0.07 mmHg. Switching to the three-drug therapy (dorzolamide+ brimonidine/timolol) enabled an additional decrease in IOP by 5.43 +/- 0.06 mmHg. Thus, with the new regimen the total decrease in IOP averaged 13.29 +/- 0.09 mmHg with daily fluctuations of 2.5?0.06 mmHg, which ensured that the target IOP was achieved in all patients. All the drugs were well-tolerated. CONCLUSION: Combination therapy with three antiglaucoma agents in the form of two medications -dorzolamide 2% and brimonidine/timolol fixed combination (Combigan)--is shown to be effective in uveal ocular hypertension patients. PMID- 25711068 TI - [Treatment of chronic allergic blepharoconjunctivitis]. AB - OBJECTIVE: to evaluate the effectiveness of therapeutic eyelid hygiene in the treatment of chronic, or perennial, allergic blepharoconjunctivitis (ABC). MATERIAL AND METHODS: A total of 30 patients with chronic ABC (11 men, 19 women aged 25-41 years; disease duration 2-4 years) were examined before and after a treatment course which included instillations of olopatodine hydrochloride instillations (1 mg/ml, 2 times daily) and hyaluronic acid (2 mg/ml, 3-4 times daily). Patients from the main group (18 patients, 36 eyes) additionally practiced therapeutic eyelid hygiene using Blepharoshampoo, Blepharolotion or Blepharosalfetka, and Blepharogel-1 (2 times daily). The control group was given only anti-allergic therapy and tear substitutes. Conventional ophthalmological examination, allergy testing, ABC signs and symptoms evaluation, Schirmer's 1 and Norn's tests, tear film break-up time evaluation, assessment of meibomian gland function, optical coherence tomography (OCT) for tear meniscus, xerosis index evaluation and lissamine green staining for lid wiper epitheliopathy, and anterior segment photography with further computer morphometry were performed in all patients. RESULTS: Dry eye signs and symptoms, including combined lipid, water, and mucus tear deficiency, were found in all patients with chronic ABC. Patients from the main group demonstrated a significantly greater decrease of integral indices of subjective ocular discomfort, reduction of chronic ABC signs as well as more pronounced improvement of the meibomian gland function, appearance of the lid wiper region, tear film break-up time, results of the OCT meniscometry, and xerosis index. CONCLUSION: Introduction of therapeutic eyelid hygiene to the complex treatment of chronic allergic blepharoconjunctivitis with the aim of resolving secondary dry eye symptoms enhances the effectiveness of the treatment. PMID- 25711069 TI - [Tafluprost--a novel prostaglandin F2alpha analogue]. AB - The review provides a brief history of the evolution of ophthalmic containers: from glass vials to plastic bottles with obligatory preservatives and, finally, to preservative-free polypropylene single-use single-dose tubes. A brief characteristic of benzalkonium chloride, the most commonly used preservative, including mechanisms of its antiseptic activity and ocular toxicity is given. The problem of ocular surface damage, especially in glaucoma patients, due to the long-term use of preserved eye drops, is discussed. Pharmacodynamics of tafluprost, the first commercially available preservative-free single-dose prostaglandin analogue, is described. Operating characteristics of experimental preclinical studies and the first three phases of clinical trials of tafluprost are provided. Post-approval studies of the comparative efficacy and tolerability of the new drug are analyzed and its prospects for clinical use are assessed. PMID- 25711070 TI - [Genetic studies of primary open-angle glaucoma]. AB - The present review is devoted to genetic studies of primary open-angle glaucoma (POAG). Today, POAG is considered a multifactorial disease with threshold effect, which is associated with single or multiple genes mutation as well as external influences. According to molecular genetic studies, three causative genes (MYOC, optinevrin, WDR 36) and several dosens of candidate genes are involved in the development of POAG. PMID- 25711071 TI - [Methods of ocular microcirculation assessment in experimental animals]. AB - The review discusses some of the most common methods of ocular microcirculation assessment in animals: fluorescent and indocyanine green angiography, scanning laser ophthalmoscopy with various dyes, laser Doppler flowmetry and velocimetry, color and power Doppler imaging, and pulsed-wave spectral Doppler ultrasonography. Each method possesses certain advantages and disadvantages, thus, the choice between them depends on the purposes and objectives of the given experimental study. PMID- 25711072 TI - Three questions every team member must ask your patients to "Connect the Dots". PMID- 25711073 TI - ODA Cares series: Good Shepherd Ministries. PMID- 25711074 TI - Patient's page. How to get a bright white smile. PMID- 25711075 TI - Member spotlight: Dr. Jana Winfree. PMID- 25711076 TI - Afghanistan Dental Relief Project. PMID- 25711077 TI - As dentists leave "horse and buggy" training behind, new questions emerge. PMID- 25711078 TI - [The problem of genomic instability of cultivated human stem cells]. AB - The wide application of human stem cells in biomedical technologies leads to the necessity to analyze the genomic stability of cultivated stem cells of different origin. The review presents data on genetically stable and unstable continuous lines of human embryonic stem cells (hESC), their differentiated derivatives and adult stem cells. Causes of genomic instability occurrence are considered and analysis of the methods used to study the genome of cell lines has been carried out. The results presented in this review demonstrate the need for periodic control of genomic instability of all types of stem cells. Molecular-genetic analysis in order to avoid contamination of adult stem cell lines by tumor cells is also needed. This aspect is particularly important in connection with the active use of the adult stem cells for regenerative medicine. PMID- 25711079 TI - [Actin cytoskeleton organization and spreading of bone marrow stromal cells and cartilage cells during their combined and independent cultivation on different extracellular matrix proteins]. AB - To clarify the mutual influence of bone marrow stromal cells (BMSCs) and cartilage cells we studied the organization of their actin cytoskeleton and cell spreading on different extracellular matrix proteins--laminin 2/4, collagen type I or fibronectin. It has been shown that the most pronounced difference in morphological characteristics of the cells such as their form, size and actin cytoskeleton organization occur in the case of interaction with fibronectin. So, after separate brief incubation of both cell types on fibronectin, the average area of BMSCs spreading was about 4 times greater than the area of the cartilage cell spreading. However, in the co-culture of these cells in a ratio of 1:1, the average jointed spreading area on fibronctin was nearly 1.5 times less than the theoretically calculated. To determine the nature of exposure of the cells to each other we have studied spreading of these cells in the media conditioned by another cell type. We have found that the area of BMSC's spreading in the medium conditioned by cartilage cells is markedly smaller than the area of spreading of the same cells in the control medium. These data suggest that the cartilage cells secrete factors that reduce BMSC's spreading. PMID- 25711080 TI - [Activity of matrix metalloproteinases of transformed fibroblasts under the antioxidant action]. AB - We have shown that antioxidant N-acetylcysteine (NAC, 2-10 mM) quickly (for 2 hours) and completely inactivates the activity of matrix metalloproteinases (gelatinases MMP-2 and MMP-9, and collagenases MMP-1 and MMP-8) secreted by transformed mouse fibroblasts 3T3-SV40 into the medium. The same MMP inhibition took place in the cell-free conditioned medium of HT-1080 fibroblasts, which suggests a direct chemical interaction between NAC and MMP resulting in the loss of MMP activity. Besides inhibitory effect, NAC decreased MMP-1 and MMP-9 (but not MMP-2) production in the cell medium. However, the level of MMP-1 and MMP-9 inhibitor (TIMP-1) remained normal, indicating a shift in the balance between the enzyme and inhibitor. The correlation between MMP-2 level and tissue enzyme inhibitor TIMP-2 was similar in control and NAC treated cells. At the same time, reorganization of type I collagen at the cell surface occurred. All together permits the conclusion that NAC action results in the extracellular matrix remodeling and changing in cellular functions. PMID- 25711081 TI - [Changes of right atrial myoendocrine cells during hypertension and after arterial pressure decrease]. AB - It is well known now that atrial cardiomyocytes carry out both contractile and endocrine activities--they synthesize, accumulate in specific secretory granules and release the natriuretic peptides. The main physiological effects of natriuretic peptides are antagonistic to the renin-angiotensin-aldostrol system, but their role in the development of hypertension is still disputable. The aim of this investigation is to estimate using electron microscopy the secretory activities of atrial myoendocrine cells in rats with inherited stress-induced arterial hypertension (ISIAH stain). It has been shown that myoendocrine cells in the ISIAH rats with arterial pressure about 180 mm Hg reveal morphological features of increased synthesis, extra accumulation and release of natriuretic peptides compared with normotensive control rats. In the ISIAH rats treated with losartan (angiotensin II receptor blocker) and therefore having a sustained decrease in arterial pressure to 140 mm Hg, changes in granular pool composition, reduction of the number and diameter of the secretory granules, reduction of Golgi complexes, and increased intracellular degradation of secretory stores were found in the myoendocrine cells. At the same time the marked capillary hyperemia and interstitial edema in the myocardium were observed. Thus, in rats with severe inherited hypertension, the secretory activity of heart myoendocrine cells is sharply increased and directly depends on the arterial blood pressure level. This proves that natriuretic peptides actively participate in the regulation of hemodynamics during with cardiovascular pathology. PMID- 25711082 TI - [Rat heat structural and functional characteristics and gas exchange parameters after experimental myocardial infarction]. AB - Rat heart structural and functional changes and gas exchange parameters were investigated in six months after experimental myocardial infarction. Left ventricular end-systolic and end-diastolic dimensions in rats with chronic heart failure were 78 and 30% higher than in control respectively. Left ventricle cavity volume in systole and diastole were 5 and 2 times increased respectively. Left ventricular cavity stretching was accompanied by thinning of the interventricular septum. Left ventricular structural changes leads to its functional deterioration. Left ventricular contraction fraction was reduced by 60%, and the ejection fraction--by 52% in comparison with control. Gas exchange investigation revealed that in six month after myocardial infarction oxygen consumption of operated rats was increased by 30% and production of carbon dioxide by more than 40%. Respiratory quotient, which reflects the nature of oxidized substrates, in rats with myocardial infarction was amounted to 0.85, indicating significant increase in the contribution of carbohydrates as an energy substrate for myocardial metabolism. PMID- 25711083 TI - [Analysis of vesicle subpopulations carrying early endosomal autoantigen EEA1]. AB - Confocal immunofluorescent analysis of interphase HeLa cells has demonstrated that involved in regulation of homotypic fusions early endosomal autoantigene EEA1 is associated with vesicles represented by two populations differing in apparent size, localization and the level of bound EEA1. Before analysis the cells have been preincubated in serum-deprived medium for 12 h to minimize ligand dependent endocytosis of serum growth factors. The first subpopulation is mainly represented by large vesicles strongly decorated with EEA1. These vesicles are localized presumably in juxtanuclear region. Microtubule depolimerization experiments have shown that this localization is maintained by tubulin cytoskeleton. The second subpopulation consists of numerous small vesicles slightly stained by EEA1 antibody and localized more peripherally. Double indirect immunofluorescent ananlysis of fixed cell images has revealed that juxtanuclear vesicles enriched in EEA1 are fully colocalized with key protein of early endosomes small GTPase Rab5, whereas about 50% of slightly decorated peripheral vesicles are Rab5-negative. It is found that the number of Rab5 positive vesicles per cell is higher than that of EEA1-positive vesicles. Thus, in serum-deprivated HeLa cells with low endocytic activity two subpopulations of EEA1-vesicles are revealed: the first one carries the both EEA1 at high level and Rab5 (EEA1+++/Rab5+), and the second subpopulation oconsists of weakly decorated EEA1-vesicles, that can be both Rab5-positive and -negative (EEA1+/Rab5- and EEA1+/Rab5+). Besides, there are vesicles carrying Rab5 only (EEA1-/Rab5+). The data obtained favor different functional role of all these subpopulations, which are associated with proteins widely considered as equivalent markers of early endosomes. PMID- 25711084 TI - [The interaction between SGLT1 or GLUT2 glucose transporter and the cytoskeleton in the enterocyte as well as Caco2 cell during hexose absorption]. AB - The distribution of cytoskeleton elements (microtubules and actin filaments) and SGLT1 or GLUT2 glucose transporter in enterocyte of rat intestine and Caco2 cell during hexose absorption has been considered. The alteration of SGLT1 and GLUT2 transporter distribution in absorptive cell of intestine villus depending on maltose concentration has been determined using the confocal microscope. The colocalization of the transporters and actin has been revealed. The increase of vesicles number close to microtubules in the apical part of cell during absorption of high hexoze concentration has been found by electron microscope. The fact together with the transporter and actin as well as actin and alpha tubulin colocalizations can prove the participation of cytoskeleton elements in glucose transporter movement to apical membrane of the cells studied. PMID- 25711085 TI - [Influence of modeling of gravitational unloading on the postsynaptic acetylcholine receptor organization and acetylcholinesterase activity in neuromuscular synapses of rat fast and slow muscles]. AB - Using immunofluorescent techniques, we have revealed that, after 35 days of rats hindlimb unloading, neuromuscular synapses of fast and slow muscles show enhanced fluorescence intensity and decreased area of fluorescent staining of acetylcholine receptors; increased fluorescent intensity and area of fluorescent staining for acetylcholinesterase. The ratio of the number of postsynaptic acetylcholine receptors and the amount of acetylcholinesterase changed as well as their spatial position in relation to each other. These rearrangements correspond to electrophysiological data on the reduction of the amplitude of the miniature endplate currents in both muscles. Identified synapses restructuring accompanied by a decrease in the volume of muscle fibers. Hindlimb unloading (simulation of hypogravity) leads to an increase in functional activity of acetylcholinesterase on the background of reduced postsynaptic membrane area occupied by acetylcholine receptors. This leads to a decrease in the amplitude of excitatory postsynaptic potentials thereby reducing the nerve-muscle excitation transmission safety factor. PMID- 25711086 TI - [Modulation of S-1 conformation and inhibition of the skeletal muscle S-1-ATPase by calponin of the mussel]. AB - A novel 40 kDa protein has been detected in native thin filaments from catch muscles of the mussel Crenomytilus grayanus. In this study, using skeletal muscle actin and S-1, we investigated the effects of the mussel 40-kDa actin-binding protein on the acto . S-1 ATPase activity. On increasing the 40-kDa actin-binding protein (CaP-40) concentration, the actin-activated ATPase activity decreased, and was inhibited 80% at a CaP-40 to actin ratio of 0.5. Polarized fluorimetry technique and glycerinated muscle fibers were used to study effects of CaP-40 on the orientation and mobility of fluorescent label 1.5-IAEDANS specifically bound to CyS-707 of myosin subfragment-1 in the absence of nucleotide, and in the presence of MgADP or MgATP. We have concluded that CaP-40 binding to actin affects the strong binding of myosin to actin but has no effect on the weak binding. Thus, the influence of the CaP-40 on the formation of strong actomyosin binding forms A . M and A . M . ADP manifests itself by a decrease in the relative content of myosin cross-bridges strongly bound with actin, which probably results in a decrease in the relative content of "switch on" actin monomers in thin filaments. This suggests that, as calponin CaP-40 selects its target the phase of strong actomyosin binding binding which preceded by a phase generating power stroke. PMID- 25711087 TI - [Reisolation and redescription of pelobiont Pelomyxa paradoxa Penard, 1902 (Archamoebae, Pelobiontida)]. AB - Morphology of a pelobiont Pelomyxa paradoxa Penard, 1902 was investigated at light- and electron-microscopical levels. Locomoting cells are cigar-shaped. The cells produce many hyaline pseudopodia of digital and conical form at lateral sides of the body. The organism has a pronounced hyaline bulbous uroid with broad peripheral zone of hyaloplasm and many conical hyaline villi. There is a thin layer of amorphous glycocalix at the cell surface. "Structure" and food vacuoles of different size are very abundant in the endoplasm. Two different species of prokaryote endocytobionts are peculiar for P. paradoxa. Uninucleate stage dominates in the life cycle of P. paradoxa. Usually there are no more than 10-12 nuclei in multinucleate forms of P. paradoxa. Pelomyxae nuclei are closely surrounded by thick multilaminar layer and additionally by one more layer, which is formed by small vesicles with electron-dense content. Several irregular-shaped nucleoli are situated at the nucleus periphery. Inside the nucleoli, and sometimes directly in nucleoplasm the small round bodies are revealed, these bodies being formed by tightly packed electron-dense fibrils. Many non-motile flagellae are located mainly in the uroidal zone of the cell. Pronounced lateral root and 50-60 radial microtubules originate from the electrone-dense muft around the kinetosome. All elements of the rootlet system of flagella are limited by peripheral layers of cytoplasm. P. paradoxa occupy an intermediate position between two groups of species of Pelomyxa genus--P. gruberi + P. prima and P. palustris + P. stagnalis + P. belewski, which differ greatly by the organization of their flagella basal apparatus. PMID- 25711088 TI - [Classifier of domestic pig (Sus scrofa domesticus) automatic chromosome identification]. AB - Automated chromosome classification is an essential task in cytogenetics of animals and plants. Until now the automatic karyotyping systems were obtained only for human chromosomes. The main aim of this study was to develop the automatic pig chromosome classifier using image processing software "VideoTest Karyo 3.1". To solve this problem 1578 chromosomes from 47 metaphases were used. The constructed classifier was checked with the use of additional sample of metaphases classified in fully automatic regime: error rate was 8.2%, this corresponds to 3.12 +/- 0.26 errors per metaphase plate (these values are within acceptable limits for such kind of studies). In further studies the extra sample of pig acrocentric chromosomes was added to classifier up to 1807 chromosomes. This addition reduced the error rate up to 6.1%, which correspondes to 2.78 +/- 0.18 errors per metaphase plate. It should be underlined that the revealed errors can immediately be corrected by an operator on every stage of analysis. The classifier was also verified using the chromosomes of boar with rcp(1p-; 11p+) in fully automatic regime and routine stained metaphases of Siberian minipigs with rob(16;17) in semi automatic regime. In both cases the chromosomes were identified correctly. The area of application of obtained pig automatic chromosome classifier is discussed. PMID- 25711089 TI - [Movement of crab axon during action potential--little known discovery of the 1980th. To memory of Solomon Veniaminovich Levin (1929-2014)]. PMID- 25711090 TI - [Functional organization of the cerebral cortex during preparation to recognition of incomplete linedrawings in 7-8 years-old children and adults]. AB - Functional interaction between prefrontal, temporal and tempo-parieto-occipital zones during preparation to recognition of incomplete linedrawings were analyzed in adults (n = 26) and children of 7-8 years old (n = 20). The strength of cortico-cortical interactions was estimated with the imaginary part of the complex-valued coherence at the frequency of alpha-rhythm (Jalpha). The Jalpha value was analyzed in the following three experimental conditions which corresponded to different stages of preparation to visual recognition: nonspecific sustained attention in the period preceding the cue (C1); focused attention in the period preceding a not-yet-recognized target stimulus (C2) and focused attention prior the successfully recognized stimulus (C3). When sustained attention changed to focused attention toward a target stimulus Jalpha increased in adults but decreased in children. Comparing Jalpha in the subgroups of both adults and children that showed highest recognition scores helped to uncover the age-related pattern of rearrangement of the cortico-cortical functional interactions in alpha-rhythm. That pattern was found to be hemisphere-specific and different at different stages of preparation to recognition of incomplete linedrawings. In adults, the maximal Jalpha were found in the left hemisphere during the period preceding the recognition of a target stimulus. At this stage of the functional preparatory tuning, in adults, Jalpha in the left hemisphere was significantly greater than in children. In adults, Jalpha related to the right hemisphere attained the highest values when attention was directed to not yet-recognized stimuli. These values were significantly higher than similar values measured in children. In children, Jalpha reached its highest value during sustained attention. The characteristic pattern of functional interactions among prefrontal, temporal and temporo-parieto-occipital cortices that observed in children of 7-8 years old during preparatory functional tuning for the recognition of incomplete linedrawings is considered to be an indication of relative immaturity of mechanisms of directed voluntary attention and working memory. PMID- 25711091 TI - [Features of brain biopotentials' spatial organization in adolescents]. AB - Adolescence is characterized by an intensive formation of inter-regional cortical fields interaction, in this period significantly reorganized the activities of deep brain structures and cortical-subcortical interaction are enhanced. Our objectives were to evaluate the nature of changes in the spatial organization of brain bioelectric potentials with age and characteristics of such an organization in adolescents. For this purpose, EEG studies have been conducted in 230 subjects of both sexes aged 4 to 35 years. We estimated interdependent changes of biopotentials correlations fluctuations in 20-lead EEG, using the integral index Vol. Analyzed age-related changes of EEG correlations in rest condition and during verbal activity (Russian and English texts audition). Verbal tasks were sued in subjects over 8 years. It was found that the spatial synchronization of the EEG both in background and verbal activity increases with age, but after 20 years the rate of change is significantly reduced. In adolescence (12-17 years old), sex differences appear between the degree of EEG coherence processes occurring in the left and right hemispheres in subjects performing verbal tasks. In males 12 to 14 years nonlinear changes in overall correlation (indicators VOL) was observed, whereas in females of this age systemic reorganization of the brain interrelations occurs more smoothly, ahead of 1.5-2 years. PMID- 25711092 TI - [Features of detection of the general direction of movement of visual objects at children of preschool age with typical and atypical development]. AB - It is investigated the specificity of functioning of the two pathways for visual processing--magno- and parvocellular, in solving the problem of recognition of moving objects preschool children in the norm and in case of violation of development normal and impaired development. It is shown that in children with disorder autistic spectrum, complicated by mental retardation and learning disabilities, there is a lack of functioning of the higher levels of magno- and parvocellular pathways of visual processing, related to the violation of the direction of the evaluation mechanisms for the temporal and spatial characteristics of objects. Thus the severity of the deficiency is correlated with both severity of neurological disorders, as the speech level and child development. PMID- 25711093 TI - [Local EEG characteristics of the children with psychic abnormalities, examined by independent components analysis (ICA)]. AB - The method of independent components within the range of 3-13 Hz was used for the analysis of EEG of the children with psychic abnormalities of perinatal origin. The research was undertaken while children were keeping awake with open eyes. In cases of harder developmental delay it was revealed a significant rise of theta range power spectrum in frontal-temporal cortex areas of left hemisphere and temporal areas of right hemisphere. This fact make it possible to regard these areas as hypothetic sources of slow activity and a damage/immaturity marker of frontal-thalamic area and the temporal areas, responsible for auditory analysis and verbal synthesis, audio & visual data integration. PMID- 25711094 TI - [EEG-parameters dynamic during relaxation (frequencies analysis)]. AB - The aim of this study was to analyze the wide frequency range of EEG-parameters to estimate a possible functional importance of different EEG-components to reach the relaxation state. Sixty five subjects 17 to 20 years old were involved in the investigation. The relaxation session with monopolar EEG-registration and autonomic parameters recording was conducted to each subject. Significant changes in all analyzed EEG-bands were observed during relaxation. Two types of changes of EEG-coherence were distinguished by wakefulness-relaxation shift of state, and correlation of the type of dynamic with LF/HF ratio were discovered. PMID- 25711095 TI - [Factor structure of functional state of 5-6 year-old children's]. AB - The factors determining functional state (FS) of 5-6 year-old children's organisms (n = 155) were identified during the research: parasympathetic regulation FS (factor I); haemodynamic ensuring cognitive activity (factor II); efficiency of cognitive activity (factor III); nonspecific-stability of an organism (factor IV); sympathetic regulation FS (factor V); general working capacity (factor VI). The realized systematic approach during the work allowed considering psycho-physiological contents of these facts. In whole, the research work results show that rather stable, qualitatively peculiar groups of variables characterizing different aspects of preschool children's FS exist. The set of stable relations between the varieties of different FS elements, supplying its complete integrative character was discovered. The presence of actual connection of physical capability with such FS aspects as productivity and efficiency of cognitive activity, sympathetic and parasympathetic regulation of physiological functions, nonspecific stability of an organism to cold-related diseases, gives us the base to consider that with the help of adequate programs knowledge of PE it is possible to make purposeful influence on children's FS under a tense activity. PMID- 25711096 TI - [Eye movement parameters in reading the sentences with syntactic ambiguity in Russian language]. AB - We studied the eye movement parameters during reading of syntactically ambiguous sentences with feminine relative clause in Russian language. A priori difficulties of sentence structural analysis results in increase of time spent on reading as opposed to reading control sentences (unambiguous). Such a delay is caused by an increase of frequency of regressions (backward saccades) which are executed for rereading an ambiguous fragment ofsentence. This fact in turn leads to an increase in number of fixations and their duration. The total reading time for particular words composing the ambiguous fragment of sentence depended on disambiguation result (relative clause attachment, early/late closure). In case of early closure (when the subject attached relative clause to first noun) the total reading time for this noun exceeded one for second noun. In case of late closure (when the subject attached relative clause to second noun) the total reading time for both nouns didn't differ. Our results indicate that early closure domination in Russian language determines the greater total reading time for first noun of nominal group associated with relative clause. PMID- 25711097 TI - [On possibility of partial restore integrative brain activity in patients with vegetative state]. AB - A combined approach to neuroreconstructive effects on pathogenesis mechanisms of vegetative state that develops as a result of severe traumatic brain injury (TBI). It is shown that under the influence of chemical transtimpanal vestibular dereception and transcranial micropolarization (TDCS) accelerated and more pronounced therapeutic effect than conventional therapy. Neurophysiological in depth examination of the dynamics shows that over time in patients in a vegetative state, picking up the intensity, "tension" and "rigidity" of inter regional cortical interactions in the organization that are beginning to dominate the area TPO cortex of both hemispheres. It is suggested that in the dislocation of the brain stem in severe TBI is vestibulotalamic tract, thanks to its anatomical location, is the least vulnerable. As a result, the prevailing afferentation forming inter-regional cortical interactions is vestibular afferent impulses. On its basis the pathological functional system, blocking the work of other functional systems of the damaged brain. Suggested treatments significantly reduce the amount of vestibular afferent flow and open up the possibility of recovery of more effective interafferential interactions. This greatly facilitates the work of the brain as a multimodal analyzer. PMID- 25711099 TI - [Spatiotemporal characteristics, of the heart electrical field at the period of ventricular depolarization in athletes training endurance and strength]. AB - As a result of haemodynamic and structural changes occurring in athletes' heart under the influence of systematic physical loads, myocardial electrical activity changes that is reflected on the electric field being formed on the body surface. The heart electrical activity during ventricular depolarization at rest has been investigated in the highly skilled athletes who train to develop physical characteristics--endurance and strength by a method of electrocardiotopography. In the investigated sportsmen under uniformity of the character of the movement of positive and negative cardioelectric potential zones and localization of extrema, and general depolarization duration, the significant distinctions of: 1) amplitude of the maximum negative extremum, 2) the time of the beginning and end of the first inversion, 3) duration of the second inversion, the initial stage and the stability period between inversions, 4) the relative location of the zones of positive and negative cardiopotentials were revealed. PMID- 25711098 TI - [Rates of breathing values and kinetics of respiration response in critical patterns of muscular activity in middle and long distance running]. AB - Parameters of ventilation influx, ventilation debt and ventilation demand of exercise were calculated on the basis of heart rate dynamics and parameters of external breathing during the testing procedure and recovery of elite runners during of the maximum workout. It was established that all of external breathing values closely reproduce changes of basic parameters of oxygen demand during the exercises at high intensity and duration and can be used for quantification and valuation of exercise loads in sport. During the conducted at the research it was experimentally proved that high level of sporting achievements in middle and long distance running is defined by three major factors of an aerobic exchange in an organism: 1. General ratio of increase in level of pulmonary ventilation (VE), consumption of oxygen (VO2) and allocation of carbon dioxide (CO2); 2. During the expiration--rate and of supply speed of oxygen (O2) from lungs to working muscles; 3. Rate of oxygenation (StO2) and total speed of the blood-groove. PMID- 25711100 TI - [The study of hemodynamic parameters of human internal carotid arteries depending on the age considering the sex and the localization of the artery]. AB - The research of the ultrasound diameter, linear velocity and the resistance of internal carotid arteries of 647 people of both sexes aged from one to 74 years was conducted. Additionally, shear stress and the Reynolds number were calculated. During the period from early childhood to adolescence and from the first mature to old age there is an increase in the diameter of the internal carotid arteries. The phases of increased vascular resistance by the first period of childhood, adolescence and old age are observed. Volumetric flow rate has relatively stable parameters till adolescence, then it declines by old age. The average linear velocity, shear stress, and the Reynolds number diminish progressively twice with age. Laminar blood flow with local twists in the early stages of postnatal ontogenesis is characteristic of internal carotid arteries. The diameter of internal carotid arteries, vascular resistance index, blood flow velocity are higher in males than in females during most age periods. Shear stress in both internal carotid arteries during the age periods studied is symmetrical and has no sex differences. PMID- 25711101 TI - [Energetics of child's organisim: qualitative and quantitative specifics]. AB - The review summarizes data on the age transformations of energy metabolism observed in the human ontogeny from birth to maturity. Shown that elevated basal energy in child is not associated with the activity of the growth processes. As maturing body structures qualitative changes of metabolic processes appear, which generally lead to economizing and expand functional range. At the same time, even in the adult organism there are some specialized structures (a.e. brown adipose tissue), providing energy dissipation and thereby participate in maintaining energy and substrate homeostasis. Suggested that the increased metabolic rate in childhood forms the body's resistance thanks to the "gyroscopic effect" and thus allows safely overcome the most intense and important stages of ontogenesis. PMID- 25711102 TI - [On the age-related trends in using sensory information in movement organization]. AB - In the present paper, two apparently contradictory developmental trends routinely found in developmental experimental studies are discussed. One of them is the reduction in relative usage of sensory information in movement control; the other (reverse) trend is that, along the course of development, the sensory information plays increasing role in movement organization. An analysis of experimental data suggests that these two trends can be considered as two mutually related overt consequences of the growing ability to build internal models of the processes in the external world and those within the motor system. PMID- 25711103 TI - [The role of mTOR in the regulation of skeletal muscle metabolism]. AB - mTOR enzyme belongs to a family of specific serine/threonine protein kinases. mTOR plays an important role in the transmission of extracellular signals by phosphorylation of various substrates in many metabolic reactions in humans. Protein mTOR, having protein kinase activity, is encoded by a gene FRAP1, which is localized on chromosome 1 (1p36.2) in skeletal muscle. It exists in two mTOR protein complexes mTORC1 and mTORC2 with various sensitivity to the inhibitory effect of rapamycin. mTOR regulates metabolism in skeletal muscle by phosphorylation of various of protein metabolizing enzymes as well as transcription and translation factors. mTOR expression occurs in response to metabolic requests of muscles and leads to increased metabolism of proteins. The data of recent studies suggest an important role of mTOR in the regulation of intracellular metabolism and point to the need of studying the molecular mechanisms involved in physiological function of skeletal muscles. PMID- 25711104 TI - [Target function of human adaptation: developing the ideas by Vsevolod Ivanovich Medvedev]. AB - The article is aimed at further development of the ideas by V.I. Medvedev regarding the specific of human adaptational processes described in his monograph Human Adaptation (Adaptatsiya cheloveka, St. Petersburg: Institute of the Human Brain, Russian Academy of Sciences, 2003, 584 p.). The key point is the statement that "human adaptation is a process that ensures the achievement of a particular objective". The article specifies and develops this statement drawing upon a cross-disciplinary approach to the issue of adaptation (including biological, psychological, and social adaptation) and basing on the results of a number of empirical researches. PMID- 25711105 TI - [Individual adaptation strategies]. AB - The article looks at the relation between adaptation strategy and individual style of activity based on the doctrine of human adaptation of V.I. Medvedev that enables opening up characteristics of professional activity in diverse environments. It illustrates a role and the relation between physiological and psychological mechanisms, which can vary, depending on individual adaptation strategies of a person. Theoretical and practical studies based on activity paradigm allow us to look at the basic principles of human interaction with the environment from a new perspective. Based on the law on the conceptual model of adaptation proposed by V.I. Medvedev, the article illustrates that humans are active figures in adaptation situations, modeling their own adaption strategies, using different individual styles manifested in the programs of adaptive behaviour. PMID- 25711106 TI - [Age and gender characteristics of the content of macro- and trace elements in the organisms of the children from the European North]. AB - By means of the nuclear-emission spectral analysis with inductively connected argon plasma were studied the contents of 28 macro- and trace elements (Al, Ag, Li, Ba, Bi, Ca, Cd, Co, Cr, Cu, Fe, Ga, In, K, Mg, Mn, Na, Ni, Mo, P, Zn, Se, Tl, Pb, Sr, S, Si) in the hair of children and teenagers living in the European North of the Russian Federation (Arkhangelsk region). There were revealed both: decrease and increase of some elements' contents. Also were revealed the dynamics of mentioned elements contents in the hair of the same children in different years. Significant individual variability of the macro and trace elements' status of children-northerners and some gender dependence were revealed. PMID- 25711107 TI - [Age, gender and individually-typological characteristics of reaction to acute hypoxic exposure]. AB - Individual pequliarities of hypoxic resistance, assessed by the response of cardiorespiratory system to acute normobaric hypoxia (10% O2), were studied in healthy subjects. Age changes in dynamics of blood oxygen saturation after the acute hypoxia are shown at level of separate sites curve SpO2 (phases of a delay, decrease and lifting). It is established, that at children sensitivity to acute hypoxia above, than at teenagers, and at teenagers above, than at adults. Higher lability of mental processes, sympathetic activity, and personal anxiety are associated with choleric temperament. Cholerics are characterized by slower restoration of blood oxygen saturation after the acute hypoxia compared with sanguine persons that we consider an indication of less hypoxic tolerance of the first group. We have developed the complex algorithm, dynamics describing dependence oxygen saturation in various phases of the hypoxic test, which can be used as a universal method of an estimation hypoxic stability at different groups of the population. PMID- 25711108 TI - [The study of the somnological aspects of the human acute adaptation to the high altitude]. AB - The primary reason of neocortex electrogenesis alteration in high-altitude adaptation at the altitude 3000-5600 m above sea level according to the EEG parameters of the night sleep and wakefulness is brain noncompensated superficial hypoxia. The situation becomes worse at the night by reason of apnoe/hypopnoe effects which occur because of muscular atony during slow sleep fall. The compensation these disorders at the expense of hypertensive and cardiorespiratory responses are identified by general mechanisms and individual strategy. PMID- 25711109 TI - [Functional indices of the participants of the satellite experiments of the "Mars 500" project in the north of Russia in different seasons of a year]. AB - 17 male northerners participating in the satellite experiments of the '"Mars-500" project passed through the morphological, physiometric, psychological and biochemical studies. The prenosological health indices in different seasons were calculated using the hardware-software complex "Ecosan-2007". Seasonal sinusoidal fluctuations were detected for the thermoregulation (body and skin temperature), lipids metabolism (cholesterol, HDL and LDL levels in the blood), circulation regulation under physical exercise (the increase of "double product" and its recovery time). In the majority of the participants the unfavorable deviations of body mass index, "power" and "life" indices, simple visual-motor reaction time, Kerdo vegetative index, physical health levels and regulatory systems activity index (in comparison with the mid-latitude standards) were found. PMID- 25711111 TI - [Auditory event-related evoked potentials in dynamics of treatment of affective delusional conditions]. AB - With the aim to study neurophysiologic correlates and to search for some possible predictors of therapeutic response correlation analysis has been carried out of links between temporal parameters of components of auditory event-related potentials (AERPs) and dynamics of quantitative clinical assessments of mental state conditions in two groups of patients--with depressive-delusional conditions (group 1) and with manic-delusional conditions (group 2) in the frames of attack like schizophrenia. Statistically significant correlations have been revealed between values of peak latencies of main AERPs components and severity of psychopathologic symptoms before beginning of treatment course, as well as between initial (before treatment course) AERPs temporal parameters and quantitative clinical assessments at the stage of remission establishment. Larger severity of residual positive, negative and common psychopathologic symptoms of schizophrenia (and also of depression and anxiety in group 1) after course of treatment was associated with smaller initial (before treatment course) values of peak latencies of "early" (P1 and N1) and with larger initial values of "late" (P2, N2 and P3) AERPs components in both groups of patients. The data obtained allow to justify basic views on brain mechanisms of affective-delusional disorders, and to reveal possible neurophysiologic predictors of treatment efficacy in such disorders. PMID- 25711110 TI - [The spatial synchronization and power of the alpha and theta rhythm after action of signals Go/NoGo]. AB - At adult healthy subjects (n = 35) in pause between the target (facial expression) and triggering stimuli showed the conditioning signals of Go/NoGo defining significants of triggering stimulus. The low-frequency alpha rhythm reacts to stimuli Go/NoGo in the left hemisphere more strongly. The coherence of low-frequency alpha potentials on 5-7 second after positive and negative conditioning (Go/NoGo) stimuli increases. Just before the triggering stimulus irrespective of their sign, confirms situation that development of a differentiation demands not less functional activity, than positive conditional reaction. Modulation of cortical activity is connected generally with the talamo cortical system of selective attention. The coherence a theta rhythm increases after action of positive conditioning signal in the medial cortical areas. It is linked with the function of emotional memory. PMID- 25711112 TI - [Mechanisms of human orientation sensitivity of the vision system. Part I. Behavioral characteristics of human orientation sensitivity. Influence of task type, experimental conditions and gender]. AB - Orientation sensitivity in human visual system was investigated in three experiments. In the first experiment 134 subjects were to determine the orientation of the segments of short lines, by "selecting" it from a set of reference orientations (Benton's test). In the second experiment 41 subject, which was chosen from participants of the first experiment, were to estimate the proximity of oblique lines to the vertical, horizontal, and 45 degrees axis. In the third experiment participants were to identify the orientation of cardinal (0 degrees and 90 degrees ) and oblique (45 degrees and 135 degrees ) lines. It was shown that the cardinal orientations were defined more accurately and faster than the oblique ones. Error type depended on experimental conditions: participant answers tilted to horizontal under normal illumination in the presence of peripheral visual information, but they tilted to vertical under low illumination (3 lux.). Women performed worse only those tasks which require precise determination of the line orientation. It was assumed that the metric spatial characteristics determined better by males then females. The oblique effect was more pronounced in females, presumably due to gender differences in brain organization of the multimodal reference frame. PMID- 25711113 TI - [The physiological analysis of cross adaptation to regular cold exposure and physical activities]. AB - Research is devoted to the comparative analysis of results of cold adaptation and physical training. The adaptive shifts occurring in an organism under the influence of a hardening (douche by a cold shower 2 times a day 2 minutes long within 6 weeks) and running training on the treadmill (30 minutes at 70-80% of individual VO2max, 3 times a week, within 6 weeks) were compared at 6 the same subjects. The interval between the two cycles of training was no less than 3 months. The indicators registered during ramp test and standard cold exposure test before and after each cycle of trainings were compared. It is shown that patterns of adaptive shifts at adaptation to factors of various modality strongly differ. Shifts at adaptation to physical activities were as a whole more expressed, than at adaptation to regular cold exposition. An individual variety of adaptive reactions suggests the feasibility of developing new approaches to the theory of the adaptation, connected with studying of physiological individuality. PMID- 25711114 TI - [Inspiratory muscle resistance to fatigue during exercise and simulated airway obstruction]. AB - Respiratory muscle fatigue can develop during simulated airway obstruction. The aim of this study was to characterize the pattern of inspiratory muscle fatigue and to assess the resistance to fatigue of diaphragm (D), parasternal (PS), sternocleidomastoid (SM) and scalene (SC). 8 healthy untrained subjects participated in this study. To identify signs of inspiratory muscles fatigue development electromyographic activity of D, PS, SCM and SC was recorded during 5 min exercise with loaded breathing (40 cm H2O/L . s(-1)). The before-to-after exercise measurements of maximal inspiratory pressure (MIP) and EMG power spectrum changes were performed. Maximal inspiratory pressure declined about 12% after exercise test compared with control, whereas the peak magnitude of integrated electrical activity of D, PS, SCM and SC during post-exercise Muller's maneuver was significantly greater than in pre-exercise test in all subjects. The extent ofinspiratory muscles fatigue was evaluated by analysis of shift in centroid frequency (fc) of EMG power spectrum. All subjects demonstrated a significant reduction in fc of PS, SCM and SC.fc of D was not changed. Diaphragm is more resistantto fatigue during obstructive breathing compared with PS, SCM and SC. The data suggest that the reduction of maximum inspiratory pressure in chronic obstructive pulmonary disease also caused primarily by the weakening of the accessory muscles, while the weakness of the diaphragm may occur in the later stages of the disease. The functional failure of accessory muscles is an additional factor, which, along with the additional breathing resistance increases the load on the diaphragm, promoting its fatigue and reduced respiratory reserve. PMID- 25711115 TI - [Peak frequency of tracheal forced expiratory wheezes during bronhodilatation test]. AB - The response of peak frequencies of the most powerful tracheal forced expiratory wheezes (FEWs) and volumetric flow rates was experimentally evaluated under influence of bronhodilatation test in representative samples of 71 healthy volunteers and 69 patients with reversible bronchial obstruction. Lack of response of FEWs peak frequency in the middle of forced expiratory maneuver was found in patients, while significant reduction of FEWs peak frequency was characteristic for healthy volunteers. The response of peak value of mid frequency (400-600 Hz) and early high-frequency (>600 Hz) FEWs observed in the middle of forced expiratory maneuver can be interpreted in favor of forced flow mechanism production of these respiratory sounds. The behaviour is consistent with the predictions of the vortex shedding model. Response of peak frequency of late high-frequency (>600 Hz) FEWs indicates the possibility of auto-oscillatory mechanism (independent on flow) involvement in formation of these respiratory sounds. PMID- 25711116 TI - [Adverse drug reactions of psychotropic agents: adverse drug reactions and safety monitoring of psychotropic agents]. AB - Pharmacological treatments of psychiatric illness have been developed and many psychotropic drugs are now on the market. The body of safety information regarding psychotropic agents is so large that it is difficult for clinicians to consider all the details of possible adverse drug reactions(ADRs) in daily clinical practice. Although it is impossible to predict and prevent all occurrences of ADRs, many of them may be preventable. In this context, there is a strong need for compact manuals of diagnosis and treatment for ADRs arising from psychotropic agents that are likely to be used in daily practice. Under the auspices of the Japanese Society of Psychiatry and Neurology, a task force was convened to answer this need. This review focuses on the general considerations of ADRs with psychotropic agents, based on discussions of the task force. We also discuss the guidelines for drug safety monitoring, targeted towards specific psychiatric disorders or patients taking specific classes of drugs. Finally, we introduce the Adverse Drug Reactions Relief System in Japan. PMID- 25711117 TI - [Effects of ramelteon on a patient with circadian rhythm sleep disorder and mood disorder]. AB - Ramelteon is a novel hypnotic characterized by its action as a melatonin receptor (MT1/MT2) agonist. It has been reported that ramelteon can alter the phase of the sleep period. We report a patient with circadian rhythm sleep disorder and mood disorder who improved with ramelteon. A 25-year-old man had a 5-year history of emotional instability, excessive daytime sleepiness, and difficulty awakening. He had been diagnosed with mood disorder and narcolepsy by a psychiatrist. Sertraline, milnacipran, valproate, and methylphenidate were ineffective, and so he presented to our hospital. Interview data and a sleep log demonstrated a delayed sleep phase. As other examinations such as actigraphy and video polysomnography indicated no other diseases, the patient was diagnosed with circadian rhythm sleep disorder, delayed sleep phase type (ICSD-2). In addition, his mental symptoms were consistent with the criteria for cyclothymia (ICD-10). After the administration of ramelteon, the phase of his sleep period gradually advanced and his emotional instability improved. Because of the high rate of comorbidity between these two diseases, we should be aware of circadian rhythm sleep disorders that are masked by mood disorders. PMID- 25711118 TI - [Patient anxiety and expectations surrounding the use of medication]. AB - Patients who take prescription drugs are thought to feel both "anxiety" and "expectations" surrounding medication use. Anxiety is felt regarding medication effectiveness, side effects, and potential dependency, and is believed to impact medication adherence, which declines to less than 50% after six months. A good therapeutic relationship between patients and physicians, which allows discussion of such topics as side effects, or the duration of ongoing medication use, is required to relieve patient anxiety, but doctor-patient communication usually does not meet patients' expectations: A discrepancy exists between what clinicians report they communicate to patients, and patients' perceptions of what they were told. At the same time, patients also maintain positive expectations for change induced by pharmacotherapy. These expectations can be inferred to be closely related to the placebo effect, which is reported to account for 30% of overall therapeutic effect. However, at the beginning of treatment, few patients are seeking pharmacotherapy; rather, they hope to share their worries with physicians, or talk about the difficulties of their illness with therapists. Physicians must therefore work to understand patients' treatment preferences, and should make initial treatment decisions only after sharing information and thoroughly consulting with patients. PMID- 25711119 TI - [The importance of the wisdom of not knowing in clinical practice]. AB - The theme of this Special issue is to investigate the relationship between pharmacotherapy and therapeutic relationships. In my paper, I first examine therapeutic relationships from a number of psychoanalytic perspectives. Specifically, I use concepts such as the building of therapeutic alliances, ego support, as well as autogenous and iatrogenous illnesses. A therapeutic relationship is a process in which a patient and his/her therapist build a relationship as collaborative therapists in the context of repeated interactions with each other. In this sense, a therapeutic relationship is not the premise for treatment, but its result. From the perspective of adherence and therapeutic effects, pharmacotherapy becomes a yardstick for measuring the quality of the therapeutic relationship. At the same time, pharmacotherapy is also a medium for building a therapeutic relationship. Lastly, I note that psychiatric knowledge and experience are factors that may impede these interactions. It is the wisdom of not knowing that helps a therapist avoid this pitfall and make therapeutic practice fruitful. PMID- 25711120 TI - [Psychotherapeutic considerations regarding medication treatment for refractory cases]. AB - The aim of this paper is to consider the psychotherapeutic approach to refractory cases in a psychiatric clinic. Although standardized, formulated psychotherapies, i. e., CBT and IPT, have a limited efficacy against antidepressant-resistant or chronic depression, psychotherapy and medication treatment may complement each other in combination. However, the first step in the psychotherapeutic consideration of refractory depression is to give up seeking "a specific medicine" which does not exist. On the other hand, a doctor should give his/her patient new hope for recovery and stimulate their motivation for treatment. In the dialogue between a doctor and patient, the following points are to be focused on : 1) The essential part of treatment is not medicine but the patient him /herself. 2) Recommendation of medication should not further reduce the patient's pride. 3) It should be clear that medication treatment is a collaborative activity between patients and doctors. It is preferable for topics of an interview to extend from a reconsideration of the prescription contents to reconstruction of the daily life. It may be helpful for patients to obtain detailed advice on basic lifestyle aspects, such as sleep, meals, and daily activities. PMID- 25711121 TI - Development and psychometric evaluation of a new team effectiveness scale for all types of community adult mental health teams: a mixed-methods approach. AB - Defining 'effectiveness' in the context of community mental health teams (CMHTs) has become increasingly difficult under the current pattern of provision required in National Health Service mental health services in England. The aim of this study was to establish the characteristics of multi-professional team working effectiveness in adult CMHTs to develop a new measure of CMHT effectiveness. The study was conducted between May and November 2010 and comprised two stages. Stage 1 used a formative evaluative approach based on the Productivity Measurement and Enhancement System to develop the scale with multiple stakeholder groups over a series of qualitative workshops held in various locations across England. Stage 2 analysed responses from a cross-sectional survey of 1500 members in 135 CMHTs from 11 Mental Health Trusts in England to determine the scale's psychometric properties. Based on an analysis of its structural validity and reliability, the resultant 20-item scale demonstrated good psychometric properties and captured one overall latent factor of CMHT effectiveness comprising seven dimensions: improved service user well-being, creative problem-solving, continuous care, inter-team working, respect between professionals, engagement with carers and therapeutic relationships with service users. The scale will be of significant value to CMHTs and healthcare commissioners both nationally and internationally for monitoring, evaluating and improving team functioning in practice. PMID- 25711122 TI - Lifestyle changes or metformin reduce type 2 diabetes risk in women with gestational diabetes, US study shows. PMID- 25711123 TI - The body electric: a long view of electrical therapy for functional neurological disorders. AB - The use of electricity in medical treatment has always been technology-driven, rather than aetiology-driven; as new techniques have appeared, clinicians have quickly looked to try them in the treatment of all sorts of conditions where existing treatment options are limited. Functional disorders--as identified anachronistically in our analysis--have been key contenders for emerging electrical treatments: with Leyden jars, with galvanic and electromagnetic machines, and more recently with TMS and TENS. Parallels can be drawn with the history of electrical treatments for migraine and headache (Koehler and Boes, 2010). Regardless of the mode of delivery of electricity, stimulating a limb to produce movement has repeatedly been found to aid and assist recovery in functional motor disorders. This may also be true of non-electrical methods: we have found benefits using both therapeutic sedation and explanatory demonstration of a positive Hoover's sign as therapeutic methods of demonstrating normal movement in functionally weak limbs (Stone et al., 2014). Each surge in enthusiasm for new electrical treatments has been followed by questions about the nature of the disorder and validity of the treatment response. Physicians have tended to attribute therapeutic success initially to powerful biological or even metaphysical effects, but with time and experience these explanations have been replaced by views that the treatment works through suggestion and placebo. Discomfort with these conclusions has in the past discouraged ongoing development of electrical treatments, even if the end result for patients has been encouraging. In Edwards's Bayesian model, functional motor and sensory symptoms are hypothesized to arise when 'pathologically precise prior beliefs' mediated by attentional processes cause experience of symptoms via a hierarchy of false inferences (Edwards, 2012). It can be argued that use of TMS or peripheral stimulation to produce movement of a functionally weak limb has the specific potential to modulate pathological expectations. To reject these treatments as no more than placebo may mean missing an unusual opportunity to manipulate key elements in the mechanism of the disorder. However, changes to these 'priors' may also be dependent upon patient expectations, and as we see through history, this may only happen if the patient believes there is an actual neuromodulatory effect. This may give rise to significant ethical issues in that the treatment may well directly benefit patients but only if they are (mis)informed that there is an underlying biological rationale. We conclude that modern trials of TMS in functional disorders are part of a repeating cycle of experimentation recurring since the mid-18th century. We suspect that emerging technology, including transcranial direct current stimulation, will follow a similar pattern of experimentation, speculation and marginalization. We suggest that considering our modern efforts in a historical context could aid our ability to further expand and maintain our use of electrical therapies that have proven helpful in the past for patients with functional disorders. PMID- 25711124 TI - Stable silicon-ionic liquid interface for next-generation lithium-ion batteries. AB - We are currently in the midst of a race to discover and develop new battery materials capable of providing high energy-density at low cost. By combining a high-performance Si electrode architecture with a room temperature ionic liquid electrolyte, here we demonstrate a highly energy-dense lithium-ion cell with an impressively long cycling life, maintaining over 75% capacity after 500 cycles. Such high performance is enabled by a stable half-cell coulombic efficiency of 99.97%, averaged over the first 200 cycles. Equally as significant, our detailed characterization elucidates the previously convoluted mechanisms of the solid electrolyte interphase on Si electrodes. We provide a theoretical simulation to model the interface and microstructural-compositional analyses that confirm our theoretical predictions and allow us to visualize the precise location and constitution of various interfacial components. This work provides new science related to the interfacial stability of Si-based materials while granting positive exposure to ionic liquid electrochemistry. PMID- 25711125 TI - Parental presence on neonatal intensive care unit clinical bedside rounds: randomised trial and focus group discussion. AB - BACKGROUND: There are limited data to inform the choice between parental presence at clinical bedside rounds (PPCBR) and non-PPCBR in neonatal intensive care units (NICUs). METHODS: We performed a single-centre, survey-based, crossed-over randomised trial involving parents of all infants who were admitted to NICU and anticipated to stay >11 days. Parents were randomly assigned using a computer generated stratified block randomisation protocol to start with PPCBR or non PPCBR and then crossed over to the other arm after a wash-out period. At the conclusion of each arm, parents completed the 'NICU Parental Stressor Scale' (a validated tool) and a satisfaction survey. After completion of the trial, we surveyed all healthcare providers who participated at least in one PPCBR rounding episode. We also offered all participating parents and healthcare providers the opportunity to partake in a focus group discussion regarding PPCBR. RESULTS: A total of 72 parents were enrolled in this study, with 63 parents (87%) partially or fully completing the trial. Of the parents who completed the trial, 95% agreed that parents should be allowed to attend clinical bedside rounds. A total of 39 healthcare providers' surveys were returned and 35 (90%) agreed that parents should be allowed to attend rounds. Nine healthcare providers and 8 parents participated in an interview or focus group, augmenting our understanding of the ways in which PPCBR was beneficial. CONCLUSIONS: Parents and healthcare providers strongly support PPCBR. NICUs should develop policies allowing PPCBR while mitigating the downsides and concerns of parents and healthcare providers such as decreased education opportunity and confidentiality concerns. TRIAL REGISTRATION NUMBER: Australia and New Zealand Clinical Trials Register number, ACTRN12612000506897. PMID- 25711126 TI - Kidney Function Alters the Relationship between Postoperative Troponin T Level and Death. AB - Cardiac troponin T (cTnT), even at low concentrations, is a risk factor for 30 day mortality in patients undergoing noncardiac surgery, but it is uncertain whether that risk is generalizable to patients with poor kidney function. We, therefore, evaluated the relationship between cTnT concentration and kidney function on the outcome of 30-day mortality in a post hoc analysis of a prospective cohort study of patients undergoing noncardiac surgery. cTnT was measured for 3 days after surgery and considered abnormal if the peak was >=0.02 ng/ml. Of the included 14,037 patients, 267 (1.9%) patients died within 30 days of surgery. The adjusted hazard ratios for death with an abnormal cTnT concentration were 4.37 (95% confidence intervals [95% CI], 3.21 to 6.22), 6.15 (95% CI, 2.95 to 140.9), 6.30 (95% CI, 3.12 to 21.23), 1.33 (95% CI, 0.56 to 4.85), and 1.46 (95% CI, 0.46 to 9.21) for eGFR>=60, 45 to <60, 30 to <45, 15 to <30, and <15 ml/min per 1.73 m(2) or on dialysis, respectively. Compared with patients with eGFR>=60 ml/min per 1.73 m(2), the adjusted hazard ratio was significantly lower for patients with eGFR=15 to <30 ml/min per 1.73 m(2) (interaction P value=0.02). Redefining abnormal cTnT concentration as >=0.03 ng/ml or a change of >=0.02 ng/ml did not alter results. Because the risk associated with postoperative cTnT levels may be different for patients with eGFR<30 ml/min per 1.73 m(2), additional research is required to determine how to interpret perioperative cTnT values for patients with low kidney function. PMID- 25711128 TI - Infertility and preterm delivery: what do we know and where do we go from here? PMID- 25711127 TI - Improved Plasmids for Fluorescent Protein Tagging of Microtubules in Saccharomyces cerevisiae. AB - The ability to fluorescently label microtubules in live cells has enabled numerous studies of motile and mitotic processes. Such studies are particularly useful in budding yeast owing to the ease with which they can be genetically manipulated and imaged by live cell fluorescence microscopy. Because of problems associated with fusing genes encoding fluorescent proteins (FPs) to the native alpha-tubulin (TUB1) gene, the FP-Tub1 fusion is generally integrated into the genome such that the endogenous TUB1 locus is left intact. Although such modifications have no apparent consequences on cell viability, it is unknown if these genome-integrated FP-tubulin fusions negatively affect microtubule functions. Thus, a simple, economical and highly sensitive assay of microtubule function is required. Furthermore, the current plasmids available for generation of FP-Tub1 fusions have not kept pace with the development of improved FPs. Here, we have developed a simple and sensitive assay of microtubule function that is sufficient to identify microtubule defects that were not apparent by fluorescence microscopy or cell growth assays. Using results obtained from this assay, we have engineered a new family of 30 FP-Tub1 plasmids that use various improved FPs and numerous selectable markers that upon genome integration have no apparent defect on microtubule function. PMID- 25711129 TI - The importance of early life studies of telomere attrition. PMID- 25711130 TI - Chinese kindergartners learn to read characters analytically. AB - Do Chinese children implicitly extract information from Chinese print before they are formally taught to read? We examined Chinese kindergartners' sensitivity to regularities in Chinese characters and the relationship between such sensitivity and later literacy ability. Eighty-five kindergartners from Beijing were given a character-learning task and assessed on word reading and word writing twice within a 1-year interval. Sensitivity to the structural and phonetic regularities in Chinese appeared in 4-year-olds, and sensitivity to the positions of radicals in Chinese characters emerged in 5-year-olds. Such sensitivities explained unique variance in Chinese word reading and writing 1 year later, with age and nonverbal IQ statistically controlled. Young children detected regularities in written Chinese before they received formal instruction in it, which underscores both the importance of early statistical learning for literacy development and the analytic properties of Chinese print. PMID- 25711133 TI - Gestational weight gain and offspring asthma: a novel opportunity for primary prevention research. PMID- 25711134 TI - BSACI guideline for the management of chronic urticaria and angioedema. AB - This guidance for the management of patients with chronic urticaria and angioedema has been prepared by the Standards of Care Committee of the British Society for Allergy and Clinical Immunology (BSACI). The guideline is based on evidence as well as on expert opinion and is aimed at both adult physicians and paediatricians practising in allergy. The recommendations are evidence graded. During the development of these guidelines, all BSACI members were included in the consultation process using a Web-based system. Their comments and suggestions were carefully considered by the Standards of Care Committee. Where evidence was lacking, a consensus was reached by the experts on the committee. Included in this management guideline are clinical classification, aetiology, diagnosis, investigations, treatment guidance with special sections on children with urticaria and the use of antihistamines in women who are pregnant or breastfeeding. Finally, we have made recommendations for potential areas of future research. PMID- 25711136 TI - Deep grey matter growth predicts neurodevelopmental outcomes in very preterm children. AB - We evaluated whether the volume and growth rate of critical brain structures measured by MRI in the first weeks of life following very preterm (<32/40 weeks) birth could predict subsequent neurodevelopmental outcomes at 4 years of age. A significant proportion of children born very prematurely have cognitive deficits, but these problems are often only detected at early school age. Structural T2 weighted magnetic resonance images were acquired in 96 very preterm neonates scanned within 2 weeks of birth and 70 of these at term-equivalent age. An automated 3D image analysis procedure was used to measure the volume of selected brain structures across all scans and time points. At 4 years of age, 53 children returned for neuropsychological assessments evaluating IQ, language and visual motor integration. Associations with maternal education and perinatal measures were also explored. Multiple regression analyses revealed that growth of the caudate and globus pallidus between preterm birth and term-equivalent age predicted visual motor integration scores after controlling for sex and gestational age. Further associations were found between caudate and putamen growth with IQ and language scores. Analyses at either preterm or term-equivalent age only found associations between normalized deep grey matter growth and visual motor integration scores at term-equivalent age. Maternal education levels were associated with measures of IQ and language, but not visual motor integration. Thalamic growth was additionally linked with perinatal measures and presence of white matter lesions. These results highlight deep grey matter growth rates as promising biomarkers of long-term outcomes following very preterm birth, and contribute to our understanding of the brain-behaviour relations in these children. PMID- 25711138 TI - Technical decision-making with higher order structure data: starting a new dialogue. AB - Characterization of the higher order structure (HOS) of biological products has been growing in importance in recent years. Scientists in the biopharmaceutical industry, academic researchers, and regulators are all increasingly aware of the critical role that HOS plays in maintaining the stability and intended biological function of biopharmaceutical products. We organized a consortium of scientists and researchers from industry and academic institutions to address how HOS data can be used most effectively to drive decisions during product development. In this commentary, we introduce the purpose, objectives, and scope of the consortium and then provide some brief points to consider in the context of characterizing HOS of biopharmaceutical products. Scientific advances in HOS analysis, as well as continued dialogue among academia, industry, and regulatory agencies will ensure that appropriate methodologies are used to inform technical decision-making during biopharmaceutical development. PMID- 25711137 TI - A human homologue of monkey F5c. AB - Area F5c is a monkey premotor area housing mirror neurons which responds more strongly to grasping observation when the actor is visible than when only the actor's hand is visible. Here we used this characteristic fMRI signature of F5c in seven imaging experiments - one in macaque monkeys and six in humans - to identify the human homologue of monkey F5c. By presenting the two grasping actions (actor, hand) and varying the low level visual characteristics, we localized a putative human homologue of area F5c (phF5c) in the inferior part of precentral sulcus, bilaterally. In contrast to monkey F5c, phF5c is asymmetric, with a right-sided bias, and is activated more strongly during the observation of the later stages of grasping when the hand is close to the object. The latter characteristic might be related to the emergence, in humans, of the capacity to precisely copy motor acts performed by others, and thus imitation. PMID- 25711139 TI - Ischemia preconditioning protects astrocytes from ischemic injury through 14-3 3gamma. AB - Stroke is a leading cause of death and disability, and new strategies are required to reduce neuronal injury and improve prognosis. Ischemia preconditioning (IPC) is an intrinsic phenomenon that protects cells from subsequent ischemic injury and might provide promising mechanisms for clinical treatment. In this study, primary astrocytes exhibited significantly less cell death than control when exposed to different durations of IPC (15, 30, 60, or 120 min). A 15-min duration was the most effective IPC to protect astrocytes from 8 hr-ischemia injury. The protective mechanisms of IPC involve the upregulation of protective proteins, including 14-3-3gamma, and attenuation of malondialdehyde (MDA) content and ATP depletion. 14-3-3gamma is an antiapoptotic intracellular protein that was significantly upregulated for up to 84 hr after IPC. In addition, IPC promoted activation of the c-Jun N-terminal kinase (JNK), extracellular signal-related kinase (ERK)-1/2, p38, and protein kinase B (Akt) signaling pathways. When JNK was specifically inhibited with SP600125, the upregulation of 14-3-3gamma induced by IPC was almost completely abolished; however, there was no effect on ATP or MDA levels. This suggests that, even though both energy preservation and 14-3-3gamma up-regulation were turned on by IPC, they were controlled by different pathways. The ERK1/2, p38, and Akt signaling pathways were not involved in the 14-3-3gamma upregulation and energy preservation. These results indicate that IPC could protect astrocytes from ischemia injury by inducing 14-3-3gamma and by alleviating energy depletion through different pathways, suggesting multiple protection of IPC and providing new insights into potential stroke therapies. PMID- 25711140 TI - Factors Affecting the Absorption, Metabolism, and Excretion of Cocoa Flavanols in Humans. AB - Cocoa is rich in a subclass of flavonoids known as flavanols, the cardiovascular health benefits of which have been extensively reported. The appearance of flavanol metabolites in the systemic circulation after flavanol-rich food consumption is likely to mediate the physiological effects on the vascular system, and these levels are influenced by numerous factors, including food matrix, processing, intake, age, gender, or genetic polymorphisms, among others. This review will focus on our current understanding of factors affecting the absorption, metabolism, and excretion of cocoa flavanols in humans. Second, it will identify gaps in these contributing factors that need to be addressed to conclusively translate our collective knowledge into the context of public health, dietary guidelines, and evidence-based dietary recommendations. PMID- 25711141 TI - Dynamic pressure mapping of personalized handwriting by a flexible sensor matrix based on the mechanoluminescence process. AB - A self-powered pressure-sensor matrix based on ZnS:Mn particles for more-secure signature collection is presented, by recording both handwritten signatures and the pressure applied by the signees. This large-area, flexible sensor matrix can map 2D pressure distributions in situ, either statically or dynamically, and the piezophotonic effect is proposed to initiate the mechanoluminescence process once a dynamic mechanical strain is applied. PMID- 25711142 TI - Lighten the Olympia of the Flatland: Probing and Manipulating the Photonic Properties of 2D Transition-Metal Dichalcogenides. AB - Following the adventures of graphene, 2D transition metal dichalcogenides (TMDs) have recently seized part of the territory in the flatland. Branched by different components of metals and chalcogenides, the families of 2D TMDs have grown rapidly, in which the semiconductive ones have shown colorful photonic properties. By tuning the atomic components and reducing the thickness or planar size of the layers, one can manipulate the optical performance of 2D TMDs, e.g., the intensity, angular momentum, and frequency of the emitted light, or toward ultrafast nonlinear absorption. As a powerful optical method, the Raman characteristics of 2D TMDs have been successfully used to explore their lattices and electronic structures. Along with the maturing of 2D TMDs, their hybrids play an important role. The unique photonic properties of 2D van der Waals heterostructures and 2D alloys are introduced here. Apart from the group VI TMDs, future prospects are identified to harness the optical properties of other 2D TMDs and the related investigations of their hybrids are underway. PMID- 25711143 TI - [Imaging in syndrome complex diabetes mellitus: Current standards and future perspectives]. AB - CLINICAL/METHODICAL ISSUE: Diabetes mellitus is a highly prevalent multisystemic disorder with numerous potential complications and substantial socioeconomic consequences. In many cases, the patient history, physical examination and laboratory tests are not sufficient for a comprehensive evaluation of complicating disorders. STANDARD RADIOLOGICAL METHODS: Imaging modalities, such as sonography, computed tomography (CT) and magnetic resonance imaging (MRI) are of major significance in the evaluation of complicating disorders of diabetes according to current guidelines. Examples include assessment of coronary artery disease, peripheral artery disease, stroke and diabetic foot syndrome. METHODICAL INNOVATIONS: Technical developments allow a substantial reduction in radiation dose and scan time in CT and MRI, respectively and could therefore justify a broader application in this patient population. PERFORMANCE: In the future CT and MRI could also be used for the early detection of diabetic complications. Furthermore, they could also be used for risk stratification, e.g. measurement of hepatic fat content and evaluation of atherosclerosis in whole body MRI. ACHIEVEMENTS: Prior to widespread application of advanced imaging techniques in this patient population, improved outcomes with respect to survival, quality of life and cost-effectiveness need to be demonstrated. PRACTICAL RECOMMENDATIONS: Diagnostic imaging modalities for the evaluation of the syndrome complex of diabetic disorders should be used according to the current guidelines but the use is predicted to increase given the high potential in this population. PMID- 25711144 TI - [Prognostic value of cardiovascular MRI in diabetics]. AB - CLINICAL/METHODICAL ISSUE: Despite an increased cardiovascular risk in patients with diabetes mellitus they are a heterogeneous population with very different individual manifestation of diseases; therefore, a profound stratification is recommended. STANDARD METHODS: Clinical examinations and blood biomarkers are typically used in diabetic patients to determine the risk for developing cardio cerebrovascular events. METHODICAL INNOVATIONS: Cardiac as well as whole-body magnetic resonance imaging (MRI) including cardiovascular sequences are established methods for clinical diagnostics. Their significance in predicting the outcome and the corresponding risk stratification for patients with diabetes is becoming increasingly more important based on recent study results. PERFORMANCE: Late gadolinium enhancement (LGE) in cardiac MRI detects silent myocardial ischemia in up to 30% of diabetic patients, which is associated with a hazard ratio of 3-6 for cardiovascular events. Regional left ventricular wall motion abnormalities and decreased ejection fraction also have a prognostic value in diabetics. Based on whole-body MRI, the vessel score as well as carotid artery stenosis have been evaluated as additional predictors for cardio-cerebrovascular events. ACHIEVEMENTS: The MRI-based predictors have independent and incremental prognostic value beyond traditional risk stratification for cardio cerebrovascular events; however, only the comprehensive assessment of whole-body MRI including angiography allows the identification of patients who remain free of cardio-cerebrovascular events over a period of 6 years. PRACTICAL RECOMMENDATIONS: Cardiac MRI, particularly the detection of LGE, can be recommended for risk stratification of patients with diabetes mellitus. The clinical relevance of the added prognostic value of whole-body MRI needs to be clarified in further studies. PMID- 25711145 TI - [Clinical or radiological diagnosis of impingement]. AB - CLINICAL/METHODICAL ISSUE: Shoulder impingement syndrome is a clinically common entity involving trapping of tendons or bursa with typical clinical findings. STANDARD RADIOLOGICAL METHODS: Important radiological procedures are ultrasound, magnetic resonance imaging (MRI) and MR arthrography. Projection radiography and computed tomography (CT) are ideal to identify bony changes and CT arthrography also serves as an alternative method in cases of contraindications for MRI. These modalities support the clinically suspected diagnosis of impingement syndrome and may identify its cause in primary diagnosis. In addition, effects of impingement are determined by imaging. Therapy decisions are based on a synopsis of radiological and clinical findings. PERFORMANCE: The sensitivity and specificity of these imaging modalities with regard to the diagnostics of a clinically evident impingement syndrome are given in this review article. PRACTICAL RECOMMENDATIONS: Orthopedic and trauma surgeons express the suspicion of an impingement syndrome based on patient history and physical examination and radiologists confirm structural changes and damage of intra-articular structures using dedicated imaging techniques. PMID- 25711147 TI - Mast cells in the colon of Trypanosoma cruzi-infected patients: are they involved in the recruitment, survival and/or activation of eosinophils? AB - Megacolon is frequently observed in patients who develop the digestive form of Chagas disease. It is characterized by dilation of the rectum-sigmoid portion and thickening of the colon wall. Microscopically, the affected organ presents denervation, which has been considered as consequence of an inflammatory process that begins at the acute phase and persists in the chronic phase of infection. Inflammatory infiltrates are composed of lymphocytes, macrophages, natural killer cells, mast cells, and eosinophils. In this study, we hypothesized that mast cells producing tryptase could influence the migration and the activation of eosinophils at the site, thereby contributing to the immunopathology of the chronic phase. We seek evidence of interactions between mast cells and eosinophils through (1) evaluation of eosinophils, regarding the expression of PAR2, a tryptase receptor; (2) correlation analysis between densities of mast cells and eosinophils; and (3) ultrastructural studies. The electron microscopy studies revealed signs of activation of mast cells and eosinophils, as well as physical interaction between these cells. Immunohistochemistry and correlation analyses point to the participation of tryptase immunoreactive mast cells in the migration and/or survival of eosinophils at the affected organ. PMID- 25711149 TI - Characterization of Norwegian women eating wholegrain bread. AB - OBJECTIVE: To investigate dietary and non-dietary characteristics of wholegrain bread eaters in the Norwegian Women and Cancer study. DESIGN: Cross-sectional study using an FFQ. SETTING: Women were divided into two groups according to wholegrain bread consumption. SUBJECTS: Adult women (n 69 471). RESULTS: Median daily consumption of standardized slices of wholegrain bread was 2.5 in the low intake group and 4.5 in the high intake group. The OR for high wholegrain bread consumption was 0.28, 2.19 and 4.63 for the first, third and fourth quartile of energy intake, respectively, compared with the second quartile. Living outside Oslo or in East Norway and having a high level of physical activity were associated with high wholegrain bread consumption. BMI and smoking were inversely associated with wholegrain bread consumption. Intake of many food items was positively associated with wholegrain bread consumption (P trend <0.01). After adjustment for energy intake, consumption of most food items was inversely associated with wholegrain bread consumption (P trend <0.001). The mean intakes of thiamin and Fe were higher in those with high wholegrain bread consumption, even after taking energy intake into account. CONCLUSIONS: Energy intake was strongly positively associated with wholegrain bread consumption. Geographical differences in wholegrain bread consumption were observed. Our study suggests that women with high wholegrain bread consumption do not generally have a healthier diet than those who eat less wholegrain bread, but that they tend to be healthier in regard to other lifestyle factors. PMID- 25711148 TI - The WHO ultrasonography protocol for assessing morbidity due to Schistosoma haematobium. Acceptance and evolution over 14 years. Systematic review. AB - In 2000, the World Health Organization (WHO) published an ultrasound field protocol for assessing morbidity due to schistosomiasis. The present study aims to review the acceptance of the WHO protocol for Schistosoma haematobium. A PubMed literature research using the keywords "ultrasound OR ultrasonography (US) AND schistosomiasis," "US AND S. haematobium," "US AND urinary schistosomiasis" from 2001 through 2014 was performed. Thirty-eight eligible publications reporting on 17,861 patients from 13 endemic and 2 non-endemic countries were analysed. Of these, 33 referred to field studies on 17,317 patients. The Niamey protocol was applied to 15,367/17,317 (88.74%) patients in 23/33 (69.70%) of field studies (all studies: 15,649/17,861 [87.61%] patients (25/38 [68.42%] studies). The acceptance of the protocol by single country in field studies varied from 0 to 100%. It varied over time between 55.56% (5/9) in the period from 2001 to 2004, to 87.50% (7/8) from 2005 to 2008, to 62.50% (5/8) from 2009 to 2011 and 75.00% (6/8) from 2012 through 2014 (all studies: 50% [5/10], 88.89% [8/9], 62.50% [5/8], 63.64% [7/11], respectively). The Niamey protocol was applied also in 2/5 hospital studies in 282/544 (51.84%) patients.The usefulness of the WHO protocol for S. haematobium infections is confirmed by its worldwide acceptance. Some simplifications might facilitate its use also for focused ultrasound examinations performed by less skilled examiners. Organ abnormalities due to schistosomiasis detectable by ultrasonography not yet covered by the WHO protocol should be added to the additional investigations section. PMID- 25711151 TI - Tissue engineered constructs: perspectives on clinical translation. AB - In this article, a "bedside to bench and back" approach for developing tissue engineered medical products (TEMPs) for clinical applications is reviewed. The driving force behind this approach is unmet clinical needs. Preclinical research, both in vitro and in vivo using small and large animal models, will help find solutions to key research questions. In clinical research, ethical issues regarding the use of cells and tissues, their sources, donor consent, as well as clinical trials are important considerations. Regulatory issues, at both institutional and government levels, must be addressed prior to the translation of TEMPs to clinical practice. TEMPs are regulated as drugs, biologics, devices, or combination products by the U.S. Food and Drug Administration (FDA). Depending on the mode of regulation, applications for TEMP introduction must be filed with the FDA to demonstrate safety and effectiveness in premarket clinical studies, followed by 510(k) premarket clearance or premarket approval (for medical devices), biologics license application approval (for biologics), or new drug application approval (for drugs). A case study on nerve cuffs is presented to illustrate the regulatory process. Finally, perspectives on commercialization such as finding a company partner and funding issues, as well as physician culture change, are presented. PMID- 25711152 TI - VEGF-Loaded Nanoparticle-Modified BAMAs Enhance Angiogenesis and Inhibit Graft Shrinkage in Tissue-Engineered Bladder. AB - Insufficient angiogenesis is a common problem in bladder tissue engineering and is believed to be a major factor responsible for graft shrinkage. In this study, we investigated the use of bladder acellular matrix allografts (BAMAs) modified with vascular endothelial growth factor (VEGF)-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) for the long-term sustained release of VEGF to enhance blood supply and inhibit graft shrinkage in a rabbit model of bladder reconstruction. Rabbits underwent partial bladder cystectomy using a 2 * 3 cm BAMA modified with VEGF-loaded PLGA NPs in the experimental group, while no modification was used in the control. Histology and immunohistochemical analyses showed that urothelium, smooth muscle fibers and blood vessels were formed in both groups at 4 and 12 weeks postoperatively. The microvessel density in the experiment group was significantly higher than that in control and the contracture rate declined to 27%. In vitro functional experiments indicated that the characteristics of regenerated bladders were similar to native bladders. The VEGF release from BAMA in vivo was almost 83% within 3 months. Our data demonstrated the effectiveness of VEGF-loaded PLGA NPs-modified BAMAs to enhance neovascularization and solve the problems of insufficient angiogenesis and graft shrinkage associated with bladder tissue engineering. PMID- 25711150 TI - A novel Mitosomal beta-barrel Outer Membrane Protein in Entamoeba. AB - Entamoeba possesses a highly divergent mitochondrion-related organelle known as the mitosome. Here, we report the discovery of a novel protein in Entamoeba, which we name Mitosomal beta-barrel Outer Membrane Protein of 30 kDa (MBOMP30). Initially identified through in silico analysis, we experimentally confirmed that MBOMP30 is indeed a beta-barrel protein. Circular dichroism analysis showed MBOMP30 has a predominant beta-sheet structure. Localization to Entamoeba histolytica mitosomes was observed through Percoll-gradient fractionation and immunofluorescence assay. Mitosomal membrane integration was demonstrated by carbonate fractionation, proteinase K digestion, and immunoelectron microscopy. Interestingly, the deletion of the putative beta-signal, a sequence believed to guide beta-barrel outer membrane protein (BOMP) assembly, did not affect membrane integration, but abolished the formation of a ~240 kDa complex. MBOMP30 represents only the seventh subclass of eukaryotic BOMPs discovered to date and lacks detectable homologs outside Entamoeba, suggesting that it may be unique to Entamoeba mitosomes. PMID- 25711153 TI - Oral penicillin-associated acute kidney injury in an infant with acute pyelonephritis. AB - Beta-lactam-associated acute tubulointerstitial nephritis (ATIN) is a rare condition in childhood. We report the case of an infant with penicillin associated ATIN and concomitant acute pyelonephritis resulting in the development of severe acute kidney injury (AKI). The treatment consisted of penicillin suspension and appropriate AKI management, which required a short period of dialysis. Finally, full recovery and normalization of laboratory parameters occurred. We present here the first case of oral penicillin-associated ATIN in childhood. PMID- 25711154 TI - High-resolution MRI analysis of breast cancer xenograft on the chick chorioallantoic membrane. AB - The chick chorioallantoic membrane (CAM) model has been successfully used to study angiogenesis, cancer progression and its pharmacological treatment, tumor pharmacokinetics, and properties of novel nanomaterials. MRI is an attractive technique for non-invasive and longitudinal monitoring of physiological processes and tumor growth. This study proposes an age-adapted cooling regime for immobilization of the chick embryo, enabling high-resolution MRI of the embryo and the CAM tumor xenograft. 64 chick embryos were enrolled in this study. The novel immobilization and imaging protocol was optimized in 29 embryos. From d7 to d18 immobilization of the embryo up to 90 min was achieved by cooling at 4 degrees C pre-imaging, with cooling times adapted to age. Its application to tumor growth monitoring was evaluated in 15 embryos after xenotransplantation of human MDA-MB-231 breast cancer cells on CAM. Tumor volumes were monitored from d4 to d9 after grafting (d11 to d16 after incubation) applying a T2 -weighted multislice RARE sequence. At d9 after grafting, the tumors were collected and compared with the MRI-derived data by histology and weight measurements. Additional imaging methods comprising DWI, T2 mapping, and the bio-distribution of contrast agents were tested at d9 after grafting in 20 further embryos. With the adaptive cooling regime, motion artifacts could be completely avoided for up to 90 min scan time, enabling high-resolution in ovo imaging. Excellent anatomical details could be obtained in the embryo and tumors. Tumor volumes could be quantified over time. The results prove the feasibility of high resolution MRI for longitudinal tumor and organ growth monitoring. The suggested method is promising for future applications such as testing tailored and/or targeted treatment strategies, longitudinal monitoring of tumor development, analysis of therapeutic efficacies of drugs, or assessment of tumor pharmacokinetics. The method provides an alternative to animal experimentation. PMID- 25711155 TI - A child with ictal vocalizations and generalized epilepsy. AB - Ictal vocalizations in the form of both articulate speech and non-speech vocalizations have been described in focal epilepsies, with seizures originating mainly from the frontal and temporal lobe, however, this phenomenon has not been described in generalized epilepsies. We report the case of an adolescent boy with juvenile-onset generalized epilepsy who presented with ictal "ovine vocalizations" (resembling the bleating of sheep). The ictal EEG revealed a clear correlate of vocalizations with time-locked generalized spikes and polyspike discharges. The 3T cerebral MRI ruled out any focal lesion. The boy is currently seizure-free under valproic acid, after twelve months of follow-up. We conclude that ictal non-speech vocalizations may be observed not only in focal or structural epilepsies, but also in generalized epilepsies; the exact underlying mechanism of this phenomenon needs to be further delineated. [Published with video sequence]. PMID- 25711156 TI - A systematic review and meta-analysis of circumcision with Shang Ring vs conventional circumcision. AB - Herein, we conduct a systematic review and meta-analysis of the current evidence to compare the safety and efficacy of Shang Ring circumcision (SRC) with conventional circumcision (CC) for male patients. Articles were searched by 2 independent reviewers. Overall, 8 randomized controlled trials involving 3314 patients were included. Compared with the CC group, SRC is associated with shorter operative time, lower intraoperative pain score, higher satisfaction with penile appearances, less intraoperative blood loss, lower adverse event rate, and lower wound bleeding rate. SRC appears to be a safer and more effective choice in comparison with CC for male patients. PMID- 25711157 TI - Prospective Randomized Trial Comparing 2 Flexible Digital Ureteroscopes: ACMI/Olympus Invisio DUR-D and Olympus URF-V. AB - OBJECTIVE: To compare 2 digital flexible ureteroscopes in a randomized, prospective, clinical trial; the complementary metal oxide semiconductor-based Gyrus ACMI/Olympus Invisio DUR-D and the charged coupled device-based Olympus URF V. METHODS: Patients scheduled for ureteroscopy were prospectively enrolled and randomized between the DUR-D and URF-V. Patient demographics, laser and total procedure time, laser energy, lower pole time, and difficulties encountered were recorded. The visibility and maneuverability were rated on a scale of 0-10. RESULTS: A total of 101 patients (58 women) with a mean age of 49.5 years (20-80 years) were enrolled. Laser lithotripsy (mean stone size, 11.8 mm) was performed in 88 patients, 10 underwent stone basketing, and 3 had diagnostic ureteroscopy. For the DUR-D and URF-V, the mean total operative time (26.5 vs 25 minutes), laser time (12.5 vs 13 minutes), lower pole time (9 vs 11 minutes), and basket time (14.5 vs 13 minutes) were comparable. In 3 of 45 (6.6%) and 6 of 56 (10.7%) cases, the stone could not be reached with the DUR-D and URF-V, respectively. A fiberoptic scope (URF-P5) reached the stone in all cases. On a scale of 0-10, the mean visibility was 6.86 and 8.73 (P <.01) and the maneuverability was 7.18 and 8.17 (P <.01) for DUR-D and URF-V, respectively. There were 8 repairs, 4 for each scope. The DUR-D averaged 11.25 cases per repair and the URF-V averaged 14. CONCLUSION: The URF-V offered better visibility and maneuverability compared with the DUR-D. Both had similar failure rates compared with the previous study with fiberoptic scopes. PMID- 25711158 TI - Bioequivalence of n-3 fatty acids from microencapsulated fish oil formulations in human subjects. AB - Fish oil n-3 fatty acids (FA) have known health benefits. Microencapsulation stabilises and protects fish oil from oxidation, enabling its incorporation into foods. The aim of the present study was to compare the bioavailability of n-3 FA delivered as two microencapsulated fish oil-formulated powders or fish oil gel capsules (FOGC) taken with a flavoured milk in healthy participants. Formulation 1 (F1) composed of a heated mixture of milk protein-sugar as an encapsulant, and formulation 2 (F2) comprised a heated mixture of milk protein-sugar-resistant starch as an encapsulant. Participants consumed 4 g fish oil (approximately 1.0 g EPA and DHA equivalent per dose). Bioavailability was assessed acutely after ingestion of a single dose by measuring total plasma FA composition over a period of 48 h (n 14) using a randomised cross-over design, and over the short term for a period of 4 weeks using an unblinded parallel design (after daily supplementation) by measuring total plasma and erythrocyte FA composition at baseline and at 2 and 4 weeks (n 47). In the acute study, F1 greatly increased (% Delta) plasma EPA and total n-3 FA levels at 2 and 4 h and DHA levels at 4 h compared with FOGC. The time to reach maximal plasma values (T(max)) was shorter for F1 than for FOGC or F2. In the short-term study, increases in plasma and erythrocyte n-3 FA values were similar for all treatments and achieved an omega-3 index in the range of 5.8-6.3 % after 4 weeks. Overall, the results demonstrated human bioequivalence for microencapsulated fish oil powder compared with FOGC. PMID- 25711159 TI - Focal adhesion kinase and Src expression in premalignant and malignant skin lesions. AB - Focal adhesion kinase (FAK) and Src are non-receptor tyrosine kinases. FAK and Src play a critical role in inducing malignant transformation in tumor cells. We performed immunohistochemical staining for total and phosphorylated forms of FAK and Src, to evaluate the role of FAK and Src in the development of premalignant and malignant skin lesions. A total of 59 facial skin samples (30 actinic keratoses, 10 Bowen's diseases, 13 squamous cell carcinomas and six perilesional skins) were immunohistochemically stained for Ki-67, total (t) and phosphorylated (p) form of FAK and Src. Cells positive for t-Src, p-Src-y530, t-FAK and pFAK s722 were detected in premalignant intra-epithelial lesions (PELs) and squamous cell carcinomas (SCCs), but not in the perilesional skin. There was a tendency towards high correlation between Ki-67 and t-FAK or pFAK-s722, suggestive of the active role of FAK in cell proliferation. However, our findings of higher t-Src and p-Src-y530 positive cells in PELs, as compared to SCCs (with higher Ki-67 level), are suggestive of the other role of Src in tumor formation and progression, which requires further investigation. PMID- 25711160 TI - Solving the mystery of the internal structure of casein micelles. AB - The interpretation of milk X-ray and neutron scattering data in relation to the internal structure of the casein micelle is an ongoing debate. We performed resonant X-ray scattering measurements on liquid milk and conclusively identified key scattering features, namely those corresponding to the size of and the distance between colloidal calcium phosphate particles. An X-ray scattering feature commonly assigned to the particle size is instead due to protein inhomogeneities. PMID- 25711161 TI - Erratum. AB - [This corrects the article on p. 176 in vol. 2, PMID: 24570940.]. PMID- 25711162 TI - Concomitant reactivity to methylisothiazolinone, benzisothiazolinone, and octylisothiazolinone. International Network of Departments of Dermatology data, 2009-2013. PMID- 25711163 TI - Nickel-catalyzed amination of aryl chlorides with ammonia or ammonium salts. AB - The nickel-catalyzed amination of aryl chlorides to form primary arylamines occurs with ammonia or ammonium sulfate and a well-defined single-component nickel(0) precatalyst containing a Josiphos ligand and an eta(2)-bound benzonitrile ligand. This system also catalyzes the coupling of aryl chlorides with gaseous amines in the form of their hydrochloride salts. PMID- 25711164 TI - T cell subsets in human airways prior to and following endobronchial administration of endotoxin. AB - BACKGROUND AND OBJECTIVES: Bronchial instillation of lipopolysaccharide (LPS) provides a reversible model of lung inflammation that may resemble early stages of acute respiratory distress syndrome (ARDS). We investigated the distributions of T-cell subsets in the human airways and sought to determine whether pro- and anti-inflammatory T cells are involved in the local immune response to lung inflammation. METHODS: Bronchoalveolar lavage (BAL) was performed in 15 healthy volunteers, after which Escherichia coli LPS (4 ng/kg) was administered. BAL was repeated at 2, 4, 6, 8 or 24 h after instillation of LPS. RESULTS: BALF CD4+ and CD8+ T cells were characterized by expression of activation markers (HLA DR+CD38+), the proportion of cells expressing naive markers (CD45RA+CD27+CCR7+) was lower, and that of cells expressing effector memory markers (CD45RA-CD27+CCR7 ) was higher, compared with peripheral blood. Bronchial LPS induced a local inflammatory response with recruitment of CD4+ (P=0.014), CD8+ T cells (P=0.034), an increase in the proportion of CD4+CD25+CD127lowFoxp3+ regulatory T cells (Tregs) (P=0.045) and a tendency towards an increase in CD4+CD161+ cells (P=0.071) were observed. CONCLUSIONS: A unique distribution of T cells with little day-to-day variation was found in human airways. An increase in Tregs after endobronchial LPS suggests a role for Tregs during early stages of pulmonary inflammation. PMID- 25711165 TI - Successful living donor liver transplantation for acute liver failure after acetylsalicylic acid overdose. AB - A 20-year-old woman was admitted to an emergency hospital after ingesting 66 g of acetylsalicylic acid in a suicide attempt. Although she was treated with gastric lavage, oral activated charcoal, and intravenous hydration with sodium bicarbonate, her hepatic and renal function gradually deteriorated and serum amylase levels increased. Steroid pulse therapy, plasma exchange, and continuous hemodiafiltration did not yield any improvement in her hepatic or renal function, and she was transferred to our hospital for living donor liver transplantation. Nine days after drug ingestion, she developed hepatic encephalopathy: thus, we diagnosed the patient with acute liver failure with hepatic coma accompanied by acute pancreatitis due to the overdose of acetylsalicylic acid. Living donor liver transplantation was immediately performed using a left lobe graft from the patient's mother. Following transplantation, the patient's renal and hepatic function and consciousness improved, and she was discharged. In this report, we describe a rare case of acetylsalicylic acid-induced acute liver failure with acute hepatic coma and concomitant acute pancreatitis and acute renal failure, which were treated successfully with emergency living donor liver transplantation. PMID- 25711166 TI - Na2B10O17.H2en: a three-dimensional open-framework layered borate co-templated by inorganic cations and organic amines. AB - A layered borate Na2B10O17.H2en (1, en = ethylenediamine) with three-dimensional microporosity within the layers has been synthesized under solvothermal conditions by using organic amines and inorganic cations as the templates. Its framework displays a unique 5-connected net constructed by B5O11 cluster and emits blue luminescence. PMID- 25711167 TI - A critical review of the mean measure of divergence and Mahalanobis distances using artificial data and new approaches to the estimation of biodistances employing nonmetric traits. AB - This article reviews the two most common distance measures employed for the calculation of biodistances based on nonmetric traits, the mean measure of divergence (MMD) and the tetrachoric Mahalanobis D(2) distance (TMD). In addition, two new approaches for the estimation of biodistances from nonmetric traits are proposed and assessed. The first (OMD) is based on the direct application of the Mahalanobis distance to ordinally recorded data before their transformation to binary dichotomies. The second (RMD) approximates the covariances of the Mahalanobis distance by the Pearson correlation coefficients calculated in the binary dataset. The application of all four methods to artificial datasets demonstrates that they overall provide a satisfactory estimation of the biodistance among samples especially when the number of statistically non significant distances is very limited. However, the best performance is observed by the OMD, whereas special attention should be paid to the TMD since its values might come out of an ill-conditioned system. The influence of the number of traits, the effect of missing values, as well as the validity of the test statistics used to assess biodistance significance are also examined and discussed. PMID- 25711169 TI - Biofilm and saliva affect the biomechanical behavior of dental implants. AB - Friction coefficient (FC) was quantified between titanium-titanium (Ti-Ti) and titanium-zirconia (Ti-Zr), materials commonly used as abutment and implants, in the presence of a multispecies biofilm (Bf) or salivary pellicle (Pel). Furthermore, FC was used as a parameter to evaluate the biomechanical behavior of a single implant-supported restoration. Interface between Ti-Ti and Ti-Zr without Pel or Bf was used as control (Ctrl). FC was recorded using tribometer and analyzed by two-way Anova and Tukey test (p<0.05). Data were transposed to a finite element model of a dental implant-supported restoration. Models were obtained varying abutment material (Ti and Zr) and FCs recorded (Bf, Pel, and Ctrl). Maximum and shear stress were calculated for bone and equivalent von Misses for prosthetic components. Data were analyzed using two-way ANOVA (p<0.05) and percentage of contribution for each condition (material and FC) was calculated. FC significant differences were observed between Ti-Ti and Ti-Zr for Ctrl and Bf groups, with lower values for Ti-Zr (p<0.05). Within each material group, Ti-Ti differed between all treatments (p<0.05) and for Ti-Zr, only Pel showed higher values compared with Ctrl and Bf (p<0.05). FC contributed to 89.83% (p<0.05) of the stress in the screw, decreasing the stress when the FC was lower. FC resulted in an increase of 59.78% of maximum stress in cortical bone (p=0.05). It can be concluded that the shift of the FC due to the presence of Pel or Bf is able to jeopardize the biomechanical behavior of a single implant-supported restoration. PMID- 25711170 TI - Ligand- and Bronsted acid/base-switchable reaction pathways in gold(I)-catalyzed cycloisomerizations of allenoic acids. AB - Gold-promoted cyclizations of 2,2-diaryl substituted gamma-allenoic acids were found to give three isomeric lactone products, each of which could be obtained selectively by exploiting Bronsted acid/base and ligand effects. Simple 5-exo trig cyclization products were favored by strong donor ligands or base additives, whereas weak donor ligands and a Bronsted acid additive gave isomeric enelactones resulting from double bond migration. Further optimization afforded a class of medicinally relevant bridged tricyclic lactones via a tandem hydroacyloxylation/hydroarylation process. Kinetic studies and control experiments indicated that the initial 5-exo-trig cyclization product serves as a branch point for further isomerization to the other lactone products via cooperative gold(I)/Bronsted acid catalysis. PMID- 25711168 TI - Multiple cis elements and GATA factors regulate a cuticle collagen gene in Caenorhabditis elegans. AB - The cuticle of the nematode Caenorhabditis elegans is a specialized extracellular matrix whose major component is collagen. Cuticle collagens are encoded by a large multigene family consisting of more than 150 members. Cuticle collagen genes are expressed in epidermis (hypodermis) and may be stage-specific or cyclically expressed. We identified cuticle collagen genes as transcriptional targets of the DBL-1 TGF-beta-related signaling pathway. These studies prompted us to investigate the cis-regulatory sequences required for transcription of one of the target genes, col-41. We generated reporter constructs that reproduce stage- and tissue-specific expression of fluorescent markers. We identify four conserved sequence elements that are required for transcription of reporters. Finally, we provide evidence that col-41 expression is controlled by a sequence element containing two GATA sites and by the epidermal GATA transcription factors ELT-1 and ELT-3. PMID- 25711171 TI - Human rights and conservation of biodiversity considerations associated with roads in the Serengeti: response to Hopcraft et al. PMID- 25711172 TI - Presence of hypertension modifies the impact of insulin resistance on incident cardiovascular disease in a Middle Eastern population: the Tehran Lipid and Glucose Study. AB - AIMS: To examine the independent impacts of the homeostasis model assessment of insulin resistance (HOMA-IR) and the updated model (HOMA2-IR) on incident cardiovascular /coronary heart disease in a Middle Eastern population with a high prevalence of cardiovascular disease risk factors. METHODS: We examined 3777 Iranian people, aged >= 30 years, without history of cardiovascular disease and without use of antidiabetic medication at baseline. Both HOMA-IR and HOMA2-IR were log-transformed and categorized into quartiles. The multivariable Cox proportional hazard regression model, adjusted for traditional cardiovascular disease risk factors, was applied to examine the association between HOMA IR/HOMA2-IR with incident cardiovascular/coronary heart disease, considering the lowest quartile as reference. RESULTS: During a median follow-up of > 10 years, 197 cardiovascular disease and 181 coronary heart disease events occurred. Among the covariates, we found a significant interaction between hypertension and HOMA IR/HOMA2-IR for incident coronary heart/cardiovascular disease (all P <= 0.01). Among the population without hypertension, the risk of cardiovascular disease significantly increased in the second [hazard ratio 1.96 (95% CI 1.04-3.68)], third [hazard ratio 1.93 (95% CI 1.00-3.75)] and fourth [hazard ratio 2.34 (95% CI 1.15-4.75)] quartiles of HOMA-IR, and the risk of coronary heart disease increased significantly in the fourth quartile of HOMA-IR [hazard ratio 2.30 (95% CI 1.12-4.73)], but no significant association was detected between HOMA-IR and cardiovascular/coronary heart disease in the population with hypertension. Among the populations both with and without hypertension, no risk was found to be associated with HOMA2-IR quartiles however, a 1-unit increase in HOMA2-IR was associated with a significant risk of cardiovascular disease among the non hypertensive group [hazard ratio 1.60 (95% CI 1.03-2.48); P = 0.03]. CONCLUSIONS: The presence of hypertension modified the impact of HOMA-IR/HOMA2-IR on incident cardiovascular/coronary heart disease. The presence of insulin resistance highlighted a significant and independent risk for cardiovascular disease/coronary heart disease only in the population without hypertension. PMID- 25711173 TI - Comparison of the soft and hard tissue effects of two different protraction mechanisms in class III patients: a randomized clinical trial. AB - OBJECTIVE: The objective of the present study is to test the null hypotheses that there were no significant differences for hard and soft tissue changes induced by mini maxillary protractor (MMP) and face mask and rapid maxillary expansion (FM/RME). MATERIALS AND METHODS: Thirty-two patients who met the criteria were randomly divided into two groups: 16 patients (males/females 7/9) in the MMP group and 16 patients (males/females 6/10) in the FM/RME group. The patients in both groups were instructed to wear the appliances for at least 20 h per day until a 2-mm positive overjet was achieved. Hard and soft tissue profile changes observed by MMP and FM/RME were compared using paired and Student's t tests. RESULTS: Class III malocclusion and negative overjet were improved by means of skeletal changes in conjunction with upper incisor proclination and lower incisor retroclination in both groups. Maxilla and surrounding soft tissues (SNA, Ls-E, and Ls-PMV) were significantly moved anteriorly with less rotation of the palatal plane in the MMP group. Mandibular incisors were found to be more retrusive in the FM/RME group (p = 0.024). CONCLUSION: Both groups showed similar effects except more anterior movement of the maxilla and surrounding soft tissues with less rotation of the palatal plane and retrusion of lower incisors in the MMP group. CLINICAL RELEVANCE: This is the first study to compare the soft and hard tissue changes induced by MMP appliance with a conventional FM /RME. PMID- 25711174 TI - Common genetic factors among sexual orientation, gender nonconformity, and number of sex partners in female twins: implications for the evolution of homosexuality. AB - INTRODUCTION: Homosexuality is a stable population-level trait in humans that lowers direct fitness and yet is substantially heritable, resulting in a so called Darwinian "paradox." Evolutionary models have proposed that polymorphic genes influencing homosexuality confer a reproductive benefit to heterosexual carriers, thus offsetting the fitness costs associated with persistent homosexuality. This benefit may consist of a "sex typicality" intermediate phenotype. However, there are few empirical tests of this hypothesis using genetically informative data in humans. AIM: This study aimed to test the hypothesis that common genetic factors can explain the association between measures of sex typicality, mating success, and homosexuality in a Western (British) sample of female twins. METHODS: Here, we used data from 996 female twins (498 twin pairs) comprising 242 full dizygotic pairs and 256 full monozygotic pairs (mean age 56.8) and 1,555 individuals whose co-twin did not participate. Measures of sexual orientation, sex typicality (recalled childhood gender nonconformity), and mating success (number of lifetime sexual partners) were completed. MAIN OUTCOME MEASURE: Variables were subject to multivariate variance component analysis. RESULTS: We found that masculine women are more likely to be nonheterosexual, report more sexual partners, and, when heterosexual, also report more sexual partners. Multivariate twin modeling showed that common genetic factors explained the relationship between sexual orientation, sex typicality, and mating success through a shared latent factor. CONCLUSIONS: Our findings suggest that genetic factors responsible for nonheterosexuality are shared with genetic factors responsible for the number of lifetime sexual partners via a latent sex typicality phenotype in human females. These results may have implications for evolutionary models of homosexuality but are limited by potential mediating variables (such as personality traits) and measurement issues. PMID- 25711176 TI - Retrospective quality control review of FDG scans in the imaging sub-study of PALETTE EORTC 62072/VEG110727: a randomized, double-blind, placebo-controlled phase III trial. AB - PURPOSE: (18)F-Labelled fluorodeoxyglucose (FDG) can detect early changes in tumour metabolism and may be a useful quantitative imaging biomarker (QIB) for prediction of disease stabilization, response and duration of progression-free survival (PFS). Standardization of imaging procedures is a prerequisite, especially in multicentre clinical trials. In this study we reviewed the quality of FDG scans and compliance with the imaging guideline (IG) in a phase III clinical trial. METHODS: Forty-four cancer patients were enroled in an imaging sub-study of a randomized international multicentre trial. FDG scan had to be performed at baseline and 10-14 days after treatment start. The image transmittal forms (ITFs) and Digital Imaging and Communications in Medicine (DICOM) [1] standard headers were analysed for compliance with the IG. Mean liver standardized uptake values (LSUVmean) were measured as recommended by positron emission tomography (PET) Response Criteria in Solid Tumors 1.0 (PERCIST) [2]. RESULTS: Of 88 scans, 81 were received (44 patients); 36 were properly anonymized; 77/81 serum glucose values submitted, all but one within the IG. In 35/44 patients both scans were of sufficient visual quality. In 22/70 ITFs the reported UT differed by >1 min from the DICOM headers (max. difference 1 h 4 min). Based on the DICOM, UT compliance for both scans was 31.4%. LSUVmean was fairly constant for the 11 patients with UT compliance: 2.30 +/- 0.33 at baseline and 2.27 +/- 0.48 at follow-up (FU). Variability substantially increased for the subjects with unacceptable UT (11 patients): 2.27 +/- 1.04 at baseline and 2.18 +/- 0.83 at FU. CONCLUSION: The high attrition number of patients due to low compliance with the IG compromised the quantitative assessment of the predictive value for early response monitoring. This emphasizes the need for better regulated procedures in imaging departments, which may be achieved by education of involved personnel or efforts towards regulations. LSUVmean could be monitored to assess quality and compliance in an FDG PET/CT study. PMID- 25711175 TI - Volume changes and brain-behavior relationships in white matter and subcortical gray matter in children with prenatal alcohol exposure. AB - Children with prenatal alcohol exposure (PAE) may have cognitive, behavioral and brain abnormalities. Here, we compare rates of white matter and subcortical gray matter volume change in PAE and control children, and examine relationships between annual volume change and arithmetic ability, behavior, and executive function. Participants (n = 75 PAE/64 control; age: 7.1-15.9 years) each received two structural magnetic resonance scans, ~2 years apart. Assessments included Wechsler Intelligence Scale for Children (WISC-IV), the Child Behavior Checklist and the Behavior Rating Inventory of Executive Function. Subcortical white and gray volumes were extracted for each hemisphere. Group volume differences were tested using false discovery rate (q < 0.05). Analyses examined group-by-age interactions and group-score interactions for correlations between change in volume and raw behavioral scores. Results showed that subjects with PAE had smaller volumes than control subjects across the brain. Significant group-score interactions were found in temporal and parietal regions for WISC arithmetic scores and in frontal and parietal regions for behavioral measures. Poorer cognitive/ behavioral outcomes were associated with larger volume increases in PAE, while control subjects generally showed no significant correlations. In contrast with previous results demonstrating different trajectories of cortical volume change in PAE, our results show similar rates of subcortical volume growth in subjects with PAE and control subjects. We also demonstrate abnormal brain behavior relationships in subjects with PAE, suggesting different use of brain resources. Our results are encouraging in that, due to the stable volume differences, there may be an extended window of opportunity for intervention in children with PAE. PMID- 25711177 TI - Stress-first protocol for myocardial perfusion SPECT imaging with semiconductor cameras: high diagnostic performances with significant reduction in patient radiation doses. AB - PURPOSE: Effective doses of 14 mSv or higher are currently being attained in patients having stress and rest myocardial perfusion imaging (MPI) single photon emission computed tomography (SPECT) performed on the same day with conventional protocols. This study aimed to assess the actual reduction in effective doses as well as diagnostic performances for MPI routinely planned with: (1) high sensitivity cadmium zinc telluride (CZT) cameras, (2) very low injected activities and (3) a stress-first protocol where the normality of stress images may lead to avoiding rest imaging. METHODS: During a 1-year period, 2,845 patients had MPI on a CZT camera, a single-day stress-first protocol and low injected activities (120 MBq of (99m)Tc-sestamibi at stress for 75 kg body weight and threefold higher at rest). The ability to detect > 50% coronary stenosis was assessed in a subgroup of 149 patients who also had coronary angiography, while the normalcy rate was assessed in a subgroup of 128 patients with a low pretest likelihood of coronary artery disease (<10%). RESULTS: Overall, 33% of patients had abnormal MPI of which 34% were women and 34% were obese. The mean effective doses and the percentage of exams involving only stress images were: (1) 3.53 +/- 2.10 mSv and 37% in the overall population, (2) 4.83 +/- 1.56 mSv and 5% in the subgroup with angiography and (3) 1.96 +/- 1.52 mSv and 71 % in the low probability subgroup. Sensitivity and global accuracy for identifying the 106 patients with coronary stenosis were 88 and 80%, respectively, while the normalcy rate was 97 %. CONCLUSION: When planned with a low-dose stress-first protocol on a CZT camera, MPI provides high diagnostic performances and a dramatic reduction in patient radiation doses. This reduction is even greater in low-risk subgroups with high rates of normal stress images, thus allowing the mean radiation dose to be balanced against cardiac risk in targeted populations. PMID- 25711178 TI - Complexation of alkyl glycosides with alpha-cyclodextrin can have drastically different effects on their conversion by glycoside hydrolases. AB - Substrates present in aggregated forms, such as micelles, are often poorly converted by enzymes. Alkyl glycosides constitute typical examples and the critical micelle concentration (CMC) decreases with increasing length of the alkyl group. In this study, possibilities to hydrolyse alkyl glycosides by glycoside hydrolases were explored, and alpha-cyclodextrin was used as an agent to form inclusion complexes with the alkyl glycosides, thereby preventing micelle formation. The cyclodextrin complexes were accepted as substrates by the enzymes to variable extent. The beta-glucosidases originating from Thermotoga neapolitana (Tn Bgl3B) and from almond were not at all able to hydrolyse alkyl beta glucosides in the presence of 100mM alpha-cyclodextrin. However, Aspergillus niger amyloglucosidase readily accepted the complexes as substrates. In reactions involving decyl and dodecyl maltosides, the presence of 100mM alpha-cyclodextrin caused an increase in reaction rate in most cases, especially at high substrate concentrations. Surprisingly, the amyloglucosidase-catalyzed hydrolysis of octyl beta-maltoside to glucose and beta-octylglucoside was faster in the presence of alpha-cyclodextrin than without, even at substrate concentrations below CMC. A possible explanation of the observed rate enhancement is that binding sites on the carbohydrate binding domain of amyloglucosidase, known to bind cyclodextrins, help to guide the alkyl glycoside-cyclodextrin complex to the active site, and thereby promote its conversion. PMID- 25711179 TI - Increasing international efforts to understand and conquer testicular germ cell cancer. PMID- 25711180 TI - Contralateral biopsy in the management of testicular cancer: what we have learned and what we need to improve. PMID- 25711182 TI - Now you Bayes, now you don't: effects of set-problem and frequency-format mental representations on statistical reasoning. AB - People appear to be Bayesian when statistical information is presented in terms of natural frequencies and non-Bayesian when presented in terms of single-event probabilities, unless the probabilities resemble natural frequencies, for example, as chances. The isomorphic format of chances, however, does not always facilitate performance to the extent that the format of natural frequencies does. Prior research has not addressed the underlying mechanism that accounts for this gap despite its theoretical significance. The mechanism explaining this external format gap could lie in the interpretation of the problem as a set-problem, which cues relevant problem model and arithmetic operations (the problem interpretation hypothesis) and/or in the interpretation of the format as frequencies, which may be easier to process (the format interpretation hypothesis). In two parallel experiments, we found support for the problem interpretation hypothesis only: set representations mediated solely the isomorphic format gap (Experiment 1: part A) and accounted for the transfer effect to natural frequencies (Experiment 1: part B); priming set representations improved performance with chances (Experiment 2). We discuss how the supported explanation corroborates the nested-sets rather than the ecological rationality account of statistical reasoning and how it helps explain individual differences in Bayesian reasoning. PMID- 25711183 TI - Piecewise power laws in individual learning curves. AB - The notion that human learning follows a smooth power law (PL) of diminishing gains is well-established in psychology. This characteristic is observed when multiple curves are averaged, potentially masking more complex dynamics underpinning the curves of individual learners. Here, we analyzed 25,280 individual learning curves, each comprising 500 measurements of cognitive performance taken from four cognitive tasks. A piecewise PL (PPL) model explained the individual learning curves significantly better than a single PL, controlling for model complexity. The PPL model allows for multiple PLs connected at different points in the learning process. We also explored the transition dynamics between PL curve component pieces. Performance in later pieces typically surpassed that in earlier pieces, after a brief drop in performance at the transition point. The transition rate was negatively associated with age, even after controlling for overall performance. Our results suggest at least two processes at work in individual learning curves: locally, a gradual, smooth improvement, with diminishing gains within a specific strategy, which is modeled well as a PL; and globally, a discrete sequence of strategy shifts, in which each strategy is better in the long term than the ones preceding it. The piecewise extension of the classic PL of practice has implications for both individual skill acquisition and theories of learning. PMID- 25711184 TI - Social comparison modulates reward-driven attentional capture. AB - It is well established that attention can be captured by task irrelevant and non salient objects associated with value through reward learning. However, it is unknown whether social comparison influences reward-driven attentional capture. The present study created four social contexts to examine whether different social comparisons modulate the reward-driven capture of attention. The results showed that reward-driven attentional capture varied with different social comparison conditions. Most prominently, reward-driven attentional capture is dramatically reduced in the disadvantageous social comparison context, in which an individual is informed that the other participant is earning more monetary reward for performing the same task. These findings suggest that social comparison can affect the reward-driven capture of attention. PMID- 25711186 TI - Epidemiological Perspectives of Diabetes. AB - The global statistics of diabetes mellitus in year 2013 indicated, about 382 million people had this disease worldwide, with type 2 diabetes making up about 90 % of the cases. This is equal to 8.3 % of the adult population with equal rates in both women and men. In year 2012 and 2013 diabetes resulted in mortality of 1.5-5.1 million people per year, making it the 8th leading cause of death in the world. It is predicted that by year 2035 about 592 million people will die of diabetes. The economic cost of diabetes seems to have increased worldwide. An average age of onset of diabetes is 42.5 years and could be due to consumption of high sugar and high-calorie diet, low physical activity, genetic susceptibility, and lifestyle. Approximately 8 % children and about 26 % young adults have diabetes mellitus in the world. The results of epidemiological study of type 1 diabetes mellitus (T1D) are presented by demographic, geographic, biologic, cultural, and other factors in human populations. The prevalence of T1D has been increased by 2-5 % worldwide and its prevalence is approximately one in 300 in US by 18 years of age. The epidemiological studies are important to study the role, causes, clinical care, prevention, and treatment of type1 diabetes in pregnant women and their children before and after birth. In this article, causes, diagnosis, symptoms, treatment and medications, and epidemiology of diabetes will be described. PMID- 25711185 TI - Can hospitals compete on quality? Hospital competition. AB - In this paper, we consider two hospitals with different perceived quality of care competing to capture a fraction of the total market demand. Patients select the hospital that provides the highest utility, which is a function of price and the patient's perceived quality of life during their life expectancy. We consider a market with a single class of patients and show that depending on the market demand and perceived quality of care of the hospitals, patients may enjoy a positive utility. Moreover, hospitals share the market demand based on their perceived quality of care and capacity. We also show that in a monopoly market (a market with a single hospital) the optimal demand captured by the hospital is independent of the perceived quality of care. We investigate the effects of different parameters including the market demand, hospitals' capacities, and perceived quality of care on the fraction of the demand that each hospital captures using some numerical examples. PMID- 25711187 TI - Predisposition to Schizophrenia: An Update of Current Understanding. AB - Within the field of mental health, the concept of predisposition or that of being "at risk" has been properly addressed by Mrazek and Haggarty. This period prior to clear diagnosis of psychosis has been referred by several names like 'premorbid' phase, at-risk individuals, predisposed individuals, prodromal phase, etc. The premorbid phase is perhaps the most debated term in this list because this term suggests that the morbidity arises only in the overt illness phase. However, evidences arising from several different lines of observations suggest that this may not be the case. In spite of the fact that it has been generally accepted that the prodromal phase precedes the clinical phase, identification of this phase remains a challenge. The real challenge in identifying the onset of the prepsychotic phase is the differentiation of 'normal' experiences from these 'abnormal' experiences. Much fewer studies have been conducted for the assessment of cognitive functions in prodromal phase or predisposed phases of schizophrenia. Cognitive deficits, particularly in memory and attentional functions, are among the most extensively documented aspects of psychosis. Regarding the somatosensory abnormalities in the high-risk individuals, so far there has been only one study conducted which involved somatosensory evoked potentials in these patients. PMID- 25711188 TI - Translaminar Screw Fixation in the Upper Thoracic Spine: Computed Tomography Based Quantitative Laminar Analysis and Feasibility Study of Translaminar Virtual Screw Placement. AB - Translaminar screws (TLS) offer an alternative to pedicle screw fixation in the upper thoracic spine. Although some studies have described the anatomy of the laminae at the upper thoracic spine, computed tomography (CT) imaging is the modality of choice for presurgical planning. The characteristics of upper thoracic lamina in healthy Han adults have not been ascertained for the safe placement of TLSs. To determine the measurements (the diameter, maximal screw length, and optimal screw trajectory) required for safe TLSs placement in the T1 3 by CT scan evaluation, forty patients (20 men, 20 women), age (48.2 +/- 13.9) years (range 19-78 years), were involved in the study from December 2008 to June 2012. Patients received a standardized axial bone-window CT imaging at T1-3, and had no evidence of spinal trauma, bone defect, or deformity. For each lamina, the height, thickness (outer cortical and inner cancellous), maximal screw length, and the crossing angle of the lamina were measured using Syngo 3D software and statistically analyzed. There were no significant differences between the left and right sides for each of the measurements (P > 0.05), but significant differences were determined between males and females for some measurements. The thickness of the laminar outer cortical diameter for the axial reconstruction was higher than that for the sagittal reconstruction (P < 0.01). The T1 lamina was estimated to accommodate, on average, a 4.2-mm longer screw than the T2 lamina, and a 5.7-mm longer screw than the T3 lamina. Most laminae could accept a 4.0-mm screw with a 1.0-mm clearance. Thus, it is more reasonable and accurate to select screw sizes according to the measurement of laminar thickness in the parasagittal reconstruction of the CT scan. T1 crossing laminar screws were successfully placed, without impingement to the spinal canal. Based on the CT evaluation, there are no anatomical limitations to the placement of TLSs at T1-3 in Chinese patients. Gender differences were noted in the superior thoracic vertebrae for dimensions of the laminae, which must be considered when placing TLSs at these levels. The TLSs add to the surgeon's armamentarium for instrumented fixation of the upper thoracic vertebrae. PMID- 25711189 TI - Clinical Application of Confocal Laser Scanning Microscopy for Atypical Dermatoses. AB - Confocal laser scanning microscopy (CLSM) is a novel non-invasive imaging technique for in vivo evaluation of cutaneous lesions at near-histologic resolution. The applicability of CLSM for various neoplastic and inflammatory skin diseases has been shown. The objective of the study is to utilize the CLSM for the differential diagnosis of atypical dermatoses. Six patients with atypical clinical manifestation were detected by CLSM. In spite of non-typical clinical manifestations, CLSM can still detect their characteristic pathological changes and help differentiate them from other diseases that are liable to be confused in clinical practice. CLSM deserves wide application in clinical practice as it boasts of easy and convenient operation, broad application, no pains or traumas for patients, rapid examination reports, as well as it can relieve patient's distress by avoiding the traumas resulting from histopathological biopsy. PMID- 25711190 TI - Curcumin Mediates a Protective Effect Via TLR-4/NF-kappaB Signaling Pathway in Rat Model of Severe Acute Pancreatitis. AB - Severe acute pancreatitis (SAP) is a common acute abdominal disease. This study was designed to investigate the preventive effects of curcumin on SAP and its possible mechanism of action. We observed increased volume of ascites, serum AMY, IL-6, and TNF-alpha levels, and expression of TLR-4 and NF-kappaB mRNA and protein in a rat model of SAP. Application of curcumin resulted in lower ascites volume and serum AMY. The levels of serum cytokines IL-10 and TNF-alpha were also significantly reduced after curcumin treatment, as evident from ELISA analysis. RT-PCR analysis showed down-regulation of TLR4 and NF-kappaB expressions as a function of curcumin treatment. Our results demonstrate the protective effect of curcumin in a rat model of SAP via the involvement of TLR-4/NF-kappaB signaling pathway. PMID- 25711191 TI - Commercialized biomarkers: new horizons in prostate cancer diagnostics. AB - Limitations with current clinical tools available for diagnosis and prognosis of prostate cancer (PCa) have resulted in overdiagnosis and costly overtreatment, which is affecting the outcomes and quality of life of men. The biotech industry is investing significant resources into developing more specific biomarkers for PCa detection and patient stratification that would greatly advance the decision making processes behind PCa management and treatment. In this review, we focus on those biomarkers that have been translated into commercial tests available to clinicians. Since these tests aim to fill specific gaps during the decision making process of PCa management, we have grouped them based on the clinical question they claim to address, that is, improved PCa screening, false-negative biopsy dilemma, prognostic tests following a positive biopsy and tests predicting relapse/metastases after surgery. We evaluate each test with respect to its development, platform, clinical validation, biomatrix, regulatory approval status and cost. PMID- 25711192 TI - Targetoid haemosiderotic haemangioma in a 3-year-old girl. PMID- 25711193 TI - Smad1/5 and Smad4 expression are important for osteoclast differentiation. AB - To investigate the necessity of the canonical BMP pathway during osteoclast differentiation, we created osteoclasts with a conditional gene deletion for Smad1 and Smad5 (SMAD1/5), or Smad4 using adenovirus expressing CRE recombinase (Ad-CRE). Reduction of either Smad4 or Smad1/5 expression resulted in fewer and smaller multinuclear cells compared to control cells. We also detected changes in osteoclast enriched genes, demonstrated by decreased Dc-stamp and cathepsin K expression in both Smad4 and Smad1/5 Ad-CRE osteoclasts, and changes in c-fos and Nfatc1 expression in only Smad4 Ad-CRE cells. Lastly we also detected a significant decrease in resorption pits and area resorbed in both the Smad4 and Smad1/5 Ad-CRE osteoclasts. Because we inhibited osteoclast differentiation with loss of either Smad4 or Smad1/5 expression, we assessed whether BMPs affected osteoclast activity in addition to BMP's effects on differentiation. Therefore, we treated mature osteoclasts with BMP2 or with dorsomorphin, a chemical inhibitor that selectively suppresses canonical BMP signaling. We demonstrated that BMP2 stimulated resorption in mature osteoclasts whereas treatment with dorsomorphin blocks osteoclast resorption. These results indicate that the BMP canonical signaling pathway is important for osteoclast differentiation and activity. PMID- 25711195 TI - Preventing Urethral Trauma from Inadvertent Inflation of Catheter Balloon in the Urethra during Catheterization: Evaluation of a Novel Safety Syringe after Correlating Trauma with Urethral Distension and Catheter Balloon Pressure. AB - PURPOSE: We investigated urethral diametric strain and threshold maximum inflation pressure for rupture during inadvertent inflation of a catheter anchoring balloon in the urethra. In addition, we evaluated a novel safety device to prevent trauma based on these parameters. MATERIALS AND METHODS: Inflation of a urethral catheter anchoring balloon was performed in the bulbar urethra of 21 ex vivo porcine models using 16Fr catheters. Urethral trauma was assessed with retrograde urethrography. Urethral rupture was correlated with internal urethral diametric strain and maximal urethral pressure threshold values in kPa. Urethral catheters were then inflated in the bulbar urethras of 7 fresh male cadavers using a standard syringe and a prototype syringe. The plunger of the standard syringe was depressed until opposing resistance pressure generated by the urethra prevented further inflation of the anchoring balloon. The plunger of the prototype safety syringe was depressed until sterile water in the syringe decanted through an activated safety threshold pressure valve. RESULTS: Retrograde urethrography demonstrated that porcine urethral rupture consistently occurred at an internal urethral diametric strain greater than 40% and a maximum inflation pressure greater than 150 kPa. The mean +/- SD maximum human urethral threshold inflation pressure required to activate the safety prototype syringe pressure valve was 153 +/- 3 kPa. In comparison, maximum inflation pressure was significantly greater using the standard syringe than the activated prototype syringe (mean 452 +/- 188 kPa, p <0.001). CONCLUSIONS: Internal urethral diametric strain and threshold maximum inflation pressures are important parameters for designing a safer urethral catheter system with lower intrinsic threshold inflation pressures. PMID- 25711194 TI - Radical Prostatectomy or External Beam Radiation Therapy vs No Local Therapy for Survival Benefit in Metastatic Prostate Cancer: A SEER-Medicare Analysis. AB - PURPOSE: We assessed survival after radical prostatectomy, intensity modulated radiation therapy or conformal radiation therapy vs no local therapy for metastatic prostate cancer adjusting for patient comorbidity, androgen deprivation therapy and other factors. MATERIALS AND METHODS: We identified men 66 years old or older with metastatic prostate cancer treated with radical prostatectomy, intensity modulated radiation therapy, conformal radiation therapy or no local therapy in the SEER-Medicare linked database from 2004 to 2009. Multivariable Cox proportional hazards models before and after inverse propensity score weighting were used to assess all cause and prostate cancer specific mortality. Competing risk regression analysis was done to assess prostate cancer specific mortality. RESULTS: Of 4,069 men with metastatic prostate cancer radical prostatectomy in 47, intensity modulated radiation therapy in 88 and conformal radiation therapy in 107 were selected as local therapy vs no local therapy in 3,827. Radical prostatectomy was associated with a 52% decrease (HR 0.48, 95% CI 0.27-0.85) in the risk of prostate cancer specific mortality after adjusting for sociodemographics, primary tumor characteristics, comorbidity, androgen deprivation therapy and bone radiation within 6 months of diagnosis. Intensity modulated radiation therapy was associated with a 62% decrease (HR 0.38, 95% CI 0.24-0.61) in the risk of prostate specific cancer specific mortality. Conformal radiation therapy was not associated with improved survival compared to no local therapy. Propensity score weighting yielded comparable results. Competing risk analysis revealed a 42% and 57% decrease (SHR 0.58, 95% CI 0.35-0.95 and SHR 0.43, 95% CI 0.27-0.68, respectively) in the risk of prostate cancer specific mortality for radical prostatectomy and intensity modulated radiation therapy. CONCLUSIONS: Local therapy with radical prostatectomy and intensity modulated radiation therapy but not with conformal radiation therapy was associated with a survival benefit in men with metastatic prostate cancer. This finding warrants prospective evaluation in clinical trials. PMID- 25711196 TI - Does Pressure Regulating Balloon Location Make a Difference in Functional Outcomes of Artificial Urinary Sphincter? AB - PURPOSE: We compared functional outcomes in patients who received an artificial urinary sphincter in the space of Retzius vs the same device placed at a high submuscular location. MATERIALS AND METHODS: We reviewed a prospectively maintained database of patients who received an artificial urinary sphincter between July 2007 and December 2014. After cuff placement was completed via a perineal incision, a 61 to 70 cm H2O pressure regulating balloon was placed through a separate high scrotal incision in the space of Retzius or in a high submuscular tunnel. Demographics, perioperative comorbidities and functional outcomes were compared between the groups. RESULTS: A total of 294 consecutive patients underwent artificial urinary sphincter placement. Mean followup was 23 months. Space of Retzius and high submuscular placement was performed in 140 (48%) and 154 patients (52%), respectively. Functional outcomes were similar between the groups, including the continence rate (defined as 0 or 1 pad daily) in 81% vs 88% (p = 0.11), the erosion rate in 9% vs 8% (p = 0.66) and the explantation rate in 10% vs 11% (p = 0.62). Artificial urinary sphincter revision for persistent incontinence was required in a similar proportion of the 2 groups (13% vs 8%, p = 0.16) with a comparable mean followup (24 vs 23 months, p = 0.30). Kaplan-Meier analysis revealed no difference between the groups in the rate of explantation (p = 0.70) or revision (p = 0.06). CONCLUSIONS: High submuscular placement of a pressure regulating balloon at artificial urinary sphincter surgery is a safe, effective alternative with functional outcomes equivalent to those of traditional placement in the space of Retzius. PMID- 25711197 TI - Lynch Syndrome: A Primer for Urologists and Panel Recommendations. AB - PURPOSE: Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer, is a common genetic disease. The predisposition of patients with Lynch syndrome to urological cancer, particularly upper tract urothelial carcinoma, is underappreciated. Urologists may be involved in several aspects of care involving Lynch syndrome, including identifying undiagnosed patients, surveillance of those with established Lynch syndrome or screening family members, in addition to treating patients with Lynch syndrome in whom upper tract urothelial carcinoma develops. We sought to increase awareness in the urological community about Lynch syndrome and provide some guidance where little currently exists. MATERIALS AND METHODS: Using the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement we reviewed the available published literature and guidelines from 1998 to 2014 on Lynch syndrome and its association with upper tract urothelial carcinoma. Recommendations based on the literature and the consensus of expert opinion are provided. RESULTS: No randomized or prospective study has been done to evaluate Lynch syndrome in the setting of urological cancer. All data were based on retrospective studies. Lynch syndrome is an autosomal dominant genetic disease caused by germline mutations in 4 mismatch repair genes, leading to the accumulation of DNA errors in microsatellite regions. Upper tract urothelial carcinoma develops in up to 28% of patients with known Lynch syndrome. The diagnosis of Lynch syndrome is established by clinical criteria, tumor tissue testing and genetic evaluation. Urologists should suspect Lynch syndrome when a patient with upper tract urothelial carcinoma presents before age 60 years or meets the 3-2-1 rule. Screening patients with Lynch syndrome for upper tract urothelial carcinoma presents a particular challenge. While no ideal screening test exists, at a minimum routine urinalysis is recommended using the American Urological Association guideline of 3 or more red blood cells per high power field as a trigger for further assessment. Upper tract urothelial carcinoma associated with Lynch syndrome presents at a younger age than sporadic upper tract urothelial carcinoma. It shows a higher proportion of ureteral cancer with a female preponderance and a possible predisposition to bilaterality. CONCLUSIONS: Lynch syndrome is a common genetic disease that is an underappreciated cause of upper tract urothelial carcinoma and possibly other urological cancers. Optimal screening for upper tract urothelial carcinoma in this population is unclear. Further study is needed to identify the best screening test and interval of testing. Urologists should consider routine tissue testing of de novo upper tract urothelial carcinoma tissue in individuals at risk. PMID- 25711198 TI - Reducing readmissions and mortality after radical cystectomy. PMID- 25711199 TI - Image Guided Focal Therapy for Magnetic Resonance Imaging Visible Prostate Cancer: Defining a 3-Dimensional Treatment Margin Based on Magnetic Resonance Imaging Histology Co-Registration Analysis. AB - PURPOSE: We compared prostate tumor boundaries on magnetic resonance imaging and radical prostatectomy histological assessment using detailed software assisted co registration to define an optimal treatment margin for achieving complete tumor destruction during image guided focal ablation. MATERIALS AND METHODS: Included in study were 33 patients who underwent 3 Tesla magnetic resonance imaging before radical prostatectomy. A radiologist traced lesion borders on magnetic resonance imaging and assigned a suspicion score of 2 to 5. Three-dimensional reconstructions were created from high resolution digitalized slides of radical prostatectomy specimens and co-registered to imaging using advanced software. Tumors were compared between histology and imaging by the Hausdorff distance and stratified by the magnetic resonance imaging suspicion score, Gleason score and lesion diameter. Cylindrical volume estimates of treatment effects were used to define the optimal treatment margin. RESULTS: Three-dimensional software based registration with magnetic resonance imaging was done in 46 histologically confirmed cancers. Imaging underestimated tumor size with a maximal discrepancy between imaging and histological boundaries for a given tumor of an average +/- SD of 1.99 +/- 3.1 mm, representing 18.5% of the diameter on imaging. Boundary underestimation was larger for lesions with an imaging suspicion score 4 or greater (mean 3.49 +/- 2.1 mm, p <0.001) and a Gleason score of 7 or greater (mean 2.48 +/- 2.8 mm, p = 0.035). A simulated cylindrical treatment volume based on the imaging boundary missed an average 14.8% of tumor volume compared to that based on the histological boundary. A simulated treatment volume based on a 9 mm treatment margin achieved complete histological tumor destruction in 100% of patients. CONCLUSIONS: Magnetic resonance imaging underestimates histologically determined tumor boundaries, especially for lesions with a high imaging suspicion score and a high Gleason score. A 9 mm treatment margin around a lesion visible on magnetic resonance imaging would consistently ensure treatment of the entire histological tumor volume during focal ablative therapy. PMID- 25711201 TI - Comparison of the efficacies of entecavir 0.5 and 1.0 mg combined with adefovir in patients with chronic hepatitis B who had failed on prior nucleos(t)ide analogue treatments. AB - Entecavir (ETV) plus adefovir (ADV) combination therapy is one of the useful treatment option for the patients with chronic hepatitis B (CHB) who had failed on prior nucleos(t) ide analogue (NA) treatments. This study compared the efficacies of the combinations of ETV 0.5 mg plus ADV and ETV 1.0 mg plus ADV in patients who had failed on prior multiple NA treatments. This retrospective analysis included 148 consecutive patients with CHB infection in Korea (n = 37 with ETV 0.5 mg plus ADV and n = 111 with ETV 1.0 mg plus ADV). The virological and biochemical responses were compared between the two groups. The cumulative probability of viral suppression of ETV 0.5 mg plus ADV was not inferior to that of ETV 1.0 mg plus ADV (hazard ratio [HR], 0.64; 95% confidence interval [CI], 0.38-1.08; P = 0.094). The changes in serum HBV DNA level in the ETV 0.5 mg plus ADV group were not different between the two groups over 12 months. Moreover, no significant difference was observed in acquiring ETV-resistant variants between the two groups during the treatment (HR, 0.95; P = 0.953). This study suggests the proof-of-concept that the lower dose of NA in combination with other NA might be the theoretical option for rescue combination therapy in patients with CHB who had failed on prior multiple NA treatments in order to reduce systemic exposure and possible side effects of NA. PMID- 25711200 TI - Brain White Matter Abnormalities in Female Interstitial Cystitis/Bladder Pain Syndrome: A MAPP Network Neuroimaging Study. AB - PURPOSE: Several chronic pain conditions may be distinguished by condition specific brain anatomical and functional abnormalities on imaging, which are suggestive of underlying disease processes. We present what is to our knowledge the first characterization of interstitial cystitis/bladder pain syndrome associated white matter (axonal) abnormalities based on multicenter neuroimaging from the MAPP Research Network. MATERIALS AND METHODS: We assessed 34 women with interstitial cystitis/bladder pain syndrome and 32 healthy controls using questionnaires on pain, mood and daily function. White matter microstructure was evaluated by diffusion tensor imaging to model directional water flow along axons or fractional anisotropy. Regions correlating with clinical parameters were further examined for gender and syndrome dependence. RESULTS: Women with interstitial cystitis/bladder pain syndrome showed numerous white matter abnormalities that correlated with pain severity, urinary symptoms and impaired quality of life. Interstitial cystitis/bladder pain syndrome was characterized by decreased fractional anisotropy in aspects of the right anterior thalamic radiation, the left forceps major and the right longitudinal fasciculus. Increased fractional anisotropy was detected in the right superior and bilateral inferior longitudinal fasciculi. CONCLUSIONS: To our knowledge we report the first characterization of brain white matter abnormalities in women with interstitial cystitis/bladder pain syndrome. Regional decreases and increases in white matter integrity across multiple axonal tracts were associated with symptom severity. Given that white matter abnormalities closely correlated with hallmark symptoms of interstitial cystitis/bladder pain syndrome, including bladder pain and urinary symptoms, brain anatomical alterations suggest that there are neuropathological contributions to chronic urological pelvic pain. PMID- 25711202 TI - Structure-property relationships: asymmetric alkylphenyl-substituted anthracene molecules for use in small-molecule solar cells. AB - Two asymmetric anthracene-based organic molecules, NDHPEA and TNDHPEA, were prepared without or with a thiophene spacer between the anthracene and naphthalene units. These asymmetric oligomers displayed different degrees of coplanarity, as evidenced by differences in the dihedral angles calculated by using DFT. Differential scanning calorimetry and XRD studies were used to probe the crystallization characteristics and molecular packing structures in the active layers. The coplanarity of the molecules in the asymmetric structure significantly affected the crystallization behavior and the formation of crystalline domains in the solid state. The small-molecule crystalline properties were correlated with the device physics by determining the J-V characteristics and hole mobilities of the devices. PMID- 25711203 TI - Alexithymia, emotion perception, and social assertiveness in adult women with Noonan and Turner syndromes. AB - Noonan syndrome (NS) and Turner syndrome (TS) are associated with cognitive problems and difficulties in affective information processing. While both phenotypes include short stature, facial dysmorphisms, and a webbed neck, genetic etiology and neuropsychological phenotype differ significantly. The present study examines putative differences in affective information processing and social assertiveness between adult women with NS and TS. Twenty-six women with NS, 40 women with TS, and 40 female controls were matched on age and intelligence, and subsequently compared on (1) alexithymia, measured by the Bermond-Vorst Alexithymia Questionnaire, (2) emotion perception, evaluated by the Emotion Recognition Task, and (3) social assertiveness and social discomfort, assessed by the Scale for Interpersonal Behavior. Women with TS showed higher levels of alexithymia than women with NS and controls (P-values < 0.001), whereas women with NS had more trouble recognizing angry facial expressions in comparison with controls (P = 0.01). No significant group differences were found for the frequency of social assertiveness and the level of social discomfort. Women with NS and TS demonstrated different patterns of impairment in affective information processing, in terms of alexithymia and emotion perception. The present findings suggest neuropsychological phenotyping to be helpful for the diagnosis of specific cognitive-affective deficits in genetic syndromes, for the enhancement of genetic counseling, and for the development of personalized treatment plans. PMID- 25711204 TI - HIPK2 expression in progression of cutaneous epithelial neoplasm. AB - BACKGROUND: Homeodomain-interacting protein kinase 2 (HIPK2) is responsible for a DNA damage response, centrally regulating p53. The aberrant HIPK2 expression is known to be involved in carcinogenesis in several malignancies. However, the correlation of HIPK2 expression along with progression of cutaneous epithelial neoplasm has not been investigated. METHODS: Using immunohistochemistry and real time reverse transcription-polymerase chain reaction, we examined the correlation between HIPK2 and HIPK2-related protein expressions and the progression of some cutaneous epithelial neoplasms (i.e., actinic keratosis, Bowen's disease, keratoacanthoma, squamous cell carcinoma, and basal cell carcinoma). RESULTS: HIPK2 expression was distinct between preinvasive and invasive lesions: the expression decreased in keratoacanthoma (none of eight) and squamous cell carcinoma (five of 35) compared to actinic keratosis (12 of 19) and Bowen's disease (10 of 23) (P < 0.001). HIPK2 expression was also negatively correlated with aggressiveness of basal cell carcinoma; high-risk subtypes showed lower HIPK2 expression than did low-risk subtypes (P < 0.001). HIPK2 mRNA expression of each tumor group was significantly higher than that of normal skin. HIPK2 mRNA expression of each tumor group was not correlated with the relevant HIPK2 protein expression, which was consistent with previous studies. CONCLUSIONS: HIPK2 expression tends to be decreased along tumor progression and may be involved with the invasive potential, suggesting a possible tumor suppressor role for HIPK2. PMID- 25711205 TI - Beliefs, perceptions, and treatment modalities of acne among schoolchildren in Lithuania: a cross-sectional study. AB - BACKGROUND: Acne vulgaris is a chronic inflammatory disease that affects the majority of adolescents. OBJECTIVES: We sought to evaluate children's and adolescents' beliefs, perceptions, sources of information, and modalities of treatment of acne. METHODS: A cross-sectional study was conducted in 1277 pupils aged 7-19 years. Children and adolescents were surveyed using a self-administered questionnaire and were subsequently examined by one specially trained dermatologist. Children and adolescents with specialist-confirmed acne were additionally interviewed about their help-seeking behavior and acne treatment. RESULTS: The rate of response to the study was 51.4%. The overall prevalence of acne among responders was 82.9%. According to the Leeds Revised Acne Grading System, 44.6% of responders had no acne, 49.3% had mild acne, 5.9% had moderate acne, and 0.2% had severe acne. Responders with moderate or severe acne more often knew what acne was than responders with mild acne (odds ratio [OR] 5.6, 95% confidence interval [CI] 1.3-24.3; OR 1.9, 95% CI 1.3-2.8, respectively). The three main sources of information about acne were parents (76.3%), magazines (35.5%), and friends (29.3%). The three main causal or exacerbating factors of acne pointed out by responders were poor hygiene (69.0%), hormones (65.3%), and diet (64.5%). Only 7.2% of pupils had been provided with treatment for acne by a dermatologist. The majority of pupils (84.9%) with acne had been using cosmetic remedies to control it. CONCLUSIONS: Many children and adolescents consider acne to be a skin problem that is caused by lack of hygiene and misuse acne treatment modalities. PMID- 25711206 TI - Angioma serpiginosum: report of two cases suggesting type 1 mosaicism and proposal of adding it to the list of mosaic skin conditions. PMID- 25711207 TI - Improved photoelectrochemical water oxidation kinetics using a TiO2 nanorod array photoanode decorated with graphene oxide in a neutral pH solution. AB - We prepared TiO2 nanorod (NR) arrays on a fluorine-doped tin oxide substrate and decorated with graphene oxide (GO) to study their photoelectrochemical (PEC) water oxidation activities in two different electrolytes. The PEC performances of GO-decorated TiO2 NR photoanodes were characterized by optical and electrochemical impedance spectroscopy measurements. In 1 M KOH, the photocurrent density of the TiO2 NR film decreased after deposition of GO, while in the neutral pH electrolyte (phosphate buffered 0.5 M Na2SO4), the TiO2 NR photoanode showed enhanced performance after deposition with the 2 wt% GO solution. This was a consequence of the decrease in charge transfer resistance between the electrode surface and the electrolyte. The improvement of photocurrents by GO decoration was obvious near the onset potential of the photocurrents in the neutral pH electrolyte. These opposite contributions of GO on the TiO2 NR photoanodes suggest that GO can promote water oxidation effectively in a neutral electrolyte because depending on the pH of the electrolyte, different chemical species interact with the surface of the photoanode in the water oxidation reaction. PMID- 25711208 TI - In-house plagiarism and editorial unaccountability. PMID- 25711209 TI - Intergenerational global heath. PMID- 25711210 TI - Essay: my own feet. AB - A medical student reflection on humbling compassion through giving and receiving care in the context of global health. PMID- 25711211 TI - Missed Opportunity: Spirituality as a Bridge to Resilience in Latinos with Cancer. AB - Going through adverse life events can help a person learn how to cope with life's challenges, overcome them, learn from the adverse experiences, grow, and be positively transformed by them. Spirituality is a resource that supports adaptation and resilience to improve quality of life in patients with cancer or other chronic illnesses. For Latinos, spirituality is an important core cultural value. As such, it is crucial to pay close attention to how cultural values play a role in health-related concerns when caring for Latino cancer patients, and to how spirituality, being an important aspect of Latino culture, influences how Latinos adjust and cope with cancer. Understanding how to facilitate resilience in the face of potentially negative life events, such as cancer, can not only help Latino cancer patients in active treatment, but can also impact effectiveness of managing and coping with the consequences of cancer during survivorship. PMID- 25711213 TI - CD160 is essential for NK-mediated IFN-gamma production. AB - NK-derived cytokines play important roles for natural killer (NK) function, but how the cytokines are regulated is poorly understood. CD160 is expressed on activated NK or T cells in humans but its function is unknown. We generated CD160 deficient mice to probe its function. Although CD160(-/-) mice showed no abnormalities in lymphocyte development, the control of NK-sensitive tumors was severely compromised in CD160(-/-) mice. Surprisingly, the cytotoxicity of NK cells was not impaired, but interferon-gamma (IFN-gamma) secretion by NK cells was markedly reduced in CD160(-/-) mice. Functionally targeting CD160 signaling with a soluble CD160-Ig also impaired tumor control and IFN-gamma production, suggesting an active role of CD160 signaling. Using reciprocal bone marrow transfer and cell culture, we have identified the intrinsic role of CD160 on NK cells, as well as its receptor on non-NK cells, for regulating cytokine production. To demonstrate sufficiency of the CD160(+) NK cell subset in controlling NK-dependent tumor growth, intratumoral transfer of the CD160(+) NK fraction led to tumor regression in CD160(-/-) tumor-bearing mice, indicating demonstrable therapeutic potential for controlling early tumors. Therefore, CD160 is not only an important biomarker but also functionally controls cytokine production by NK cells. PMID- 25711212 TI - Restored glial glutamate transporter EAAT2 function as a potential therapeutic approach for Alzheimer's disease. AB - Glutamatergic systems play a critical role in cognitive functions and are known to be defective in Alzheimer's disease (AD) patients. Previous literature has indicated that glial glutamate transporter EAAT2 plays an essential role in cognitive functions and that loss of EAAT2 protein is a common phenomenon observed in AD patients and animal models. In the current study, we investigated whether restored EAAT2 protein and function could benefit cognitive functions and pathology in APPSw,Ind mice, an animal model of AD. A transgenic mouse approach via crossing EAAT2 transgenic mice with APPSw,Ind. mice and a pharmacological approach using a novel EAAT2 translational activator, LDN/OSU-0212320, were conducted. Findings from both approaches demonstrated that restored EAAT2 protein function significantly improved cognitive functions, restored synaptic integrity, and reduced amyloid plaques. Importantly, the observed benefits were sustained one month after compound treatment cessation, suggesting that EAAT2 is a potential disease modifier with therapeutic potential for AD. PMID- 25711214 TI - Monitoring and management of patients with chronic atrial fibrillation: Is there added value in the identification of clinical phenotypes? PMID- 25711215 TI - A core curriculum for the continuing professional development of nurses: Developed by the Education Committee on behalf of the Council on Cardiovascular Nursing and Allied Professions of the ESC. AB - BACKGROUND: The European Society of Cardiology and the Council on Cardiovascular Nursing and Allied Professions share a vision; to decrease the burden of cardiovascular disease in Europe. Nurses represent the largest sector of the health professional workforce and have a significant contribution to make, which has not yet been fully realised. Recent evidence highlights an association between the level of nurse education and inpatient mortality making this an important topic, particularly as the provision of nurse education in Europe is variable. AIM: To develop a core curriculum to inform the education of nurses following initial qualification for work in cardiovascular settings. METHOD: A syllabus was developed using published literature, policy documents and existing curricula with expert input from service users, specialist nurses, cardiologists, educationalists and academics. The syllabus formed the framework for the development of the core curriculum. RESULTS: Eight key themes characterise the core curriculum which are presented together with an account of the development process. While the curriculum is not intended to cover all aspects of the highly complex role of the cardiovascular nurse, the themes do exemplify the science and art of nursing and are transferable across different levels of clinical practice and settings. The curriculum functions both as a 'map', which identifies key themes to include in nurse education, and as a 'tool' to inform educational provision that bridges' the gap between initial nurse education and advanced specialist practice. Content can be adapted for use to fit the national context and reflects the specific needs, health priorities, legislative and regulatory standards that govern safe nursing practice across different countries. CONCLUSION: The core curriculum can be used as a learning framework to guide nurse education, in particular the continuing professional education of post qualifying nurses working in cardiovascular settings. This represents a significant step towards streamlining cardiovascular nurse education in Europe. PMID- 25711216 TI - Publishing integrity and good practices in editing in biomedicine. AB - The Macedonian Academy of Sciences and Arts (MASA), held a scientific workshop for journal editors in biomedicine: "Publishing integrity and good practices in editing in biomedicine" on April 25, 2014 in MASA, Skopje. The meeting looked into old problems and new situations in editing and publishing, with emphasis on the situation in developing countries. This global knowledge-based society is founded on the results obtained from scientific research. The data from basic research in developed countries contribute in a quite substantial manner to the newly added economic value. One of the main reasons for underdevelopment in South Eastern Europe (SEE) is certainly a low or non-existent contribution of scientific research in the newly added economic value. This has largely to do with the perception of the political elites which simply lack the insight on the crucial importance of science in development. In the long term this leads to societies in which there are distortions in the understanding of the most basic values. Academic publishing has experienced tremendous growth: so far there are at least 50 million scientific articles. Interestingly, publishing in developing countries has experienced a rate of growth higher than in developed countries. However, this is not the case with the Balkan countries. The meeting looked at some old and some newly emerging problems in editing and publishing. First, the high cost for universities and researchers to purchase journals adversely affects both publishing and editing. In developing countries the high cost of purchasing scientific literature is an almost insurmountable problem in spite of the fact that some publishing companies offer discounted fees. Open access journals in South Eastern European (SEE) countries are hardly achievable as this also incurs costs that have to be covered in some way or other. The peer review process has the fundamental difficulty that reviewers are in the situation of a Procrustean bed, tending to accept reports which support the reviewer's concepts of thinking and, like Procrustes, cutting everything else out. Authorship is often a contentious issue, as undeserved authors appear on the list of authors. Some principles are now a norm in academic publishing. This applies to the declaration of a conflict of interest, the consent of the patient and the approval of the Ethical Board of the institution. This global informational technological revolution has, unfortunately, led to largely widespread and increasingly sophisticated deviations: plagiarism, data fabrication and data falsification as forms of scientific misconduct. Those events are now more widespread than in the past. Luckily new tools to track them are much better than previously. The race for perfect publishing integrity and for the best good practices in editing in biomedicine is on. New and old challenges will be met. The benevolent and caring society, educated professionals and an enlightened public remain essential preconditions. The wealth of nations depends on R&D and consequently on academic publishing. PMID- 25711217 TI - Publishing scientific journals in the digital age: opportunities for small scholarly journals. AB - Scientific publishing is rapidly developing from print-only to digital journals and extensive use of social media. This essay presents our experience in developing a small and scholarly journal from the so-called scientific semi periphery and using the advantages of digital publishing to increase the visibility of the journal in international indexing and citation databases, and ensure greater visibility in the global scientific community. An editor of a scientific journal does not need to master all details of different digital publishing tools, but needs to follow the developments so that they can be best implemented in the journal. PMID- 25711218 TI - Publication ethics: whose problem is it? AB - Discussions about publication ethics often focus on misconduct by authors such as data fabrication and plagiarism. However, the roles of editors, publishers, academic societies, and research institutions should not be ignored. All these players have ethical responsibilities and should carefully consider the effects of their policies and actions. If people believe that publication ethics is 'somebody else's problem', little progress will be made and problems will persist. PMID- 25711219 TI - Responsible research publication: international standards for authors. AB - The research being reported should have been conducted in an ethical and responsible manner and should comply with all relevant legislation. Researchers should present their results clearly, honestly, and without fabrication, falsification or inappropriate data manipulation. Researchers should strive to describe their methods clearly and unambiguously so that their findings can be confirmed by others. Researchers should adhere to publication requirements that submitted work is original, is not plagiarized, and has not been published elsewhere. Authors should take collective responsibility for submitted and published work. The authorship of research publications should accurately reflect individuals' contributions to the work and its reporting. Funding sources and relevant conflicts of interest should be disclosed. PMID- 25711220 TI - Responsible research publication: international standards for editors. AB - Editors are accountable and should take responsibility for everything they publish. Editors should make fair and unbiased decisions independent from commercial consideration and ensure a fair and appropriate peer review process. Editors should adopt editorial policies that encourage maximum transparency and complete, honest reporting. Editors should guard the integrity of the published record by issuing corrections and retractions when needed and pursuing suspected or alleged research and publication misconduct. Editors should pursue reviewer and editorial misconduct. Editors should critically assess the ethical conduct of studies in humans and animals. Peer reviewers and authors should be told what is expected of them. Editors should have appropriate policies in place for handling editorial conflicts of interest. PMID- 25711221 TI - Biomedical journals in Republic of Macedonia: the current state. AB - Several biomedical journals in the Republic of Macedonia have succeeded in maintaining regular publication over the years, but only a few have a long standing tradition. In this paper we present the basic characteristics of 18 biomedical journals that have been published without a break in the Republic of Macedonia. Of these, more details are given for 14 journals, a particular emphasis being on the journal Prilozi/Contributions of the Macedonian Academy of Sciences and Arts, Section of Medical Sciences as one of the journals with a long term publishing tradition and one of the journals included in the Medline/PubMed database. A brief or broad description is given for the following journals: Macedonian Medical Review, Acta Morphologica, Physioacta, MJMS-Macedonian Journal of Medical Sciences, International Medical Journal Medicus, Archives of Public Health, Epilepsy, Macedonian Orthopaedics and Traumatology Journal, BANTAO Journal, Macedonian Dental Review, Macedonian Pharmaceutical Bulletin, Macedonian Veterinary Review, Journal of Special Education and Rehabilitation, Balkan Journal of Medical Genetics, Contributions of the Macedonian Scientific Society of Bitola, Vox Medici, Social Medicine: Professional Journal for Public Health, and Prilozi/Contributions of the Macedonian Academy of Sciences and Arts. Journals from Macedonia should aim to be published regularly, should comply with the Uniform requirements for manuscripts submitted to biomedical journals, and with the recommendations of reliable organizations working in the field of publishing and research. These are the key prerequisites which Macedonian journals have to accomplish in order to be included in renowned international bibliographic databases. Thus the results of biomedical science from the Republic of Macedonia will be presented to the international scientific arena. PMID- 25711222 TI - Macedonian journal of chemistry and chemical engineering: open journal systems- editor's perspective. AB - The development and availability of personal computers and software as well as printing techniques in the last twenty years have made a profound change in the publication of scientific journals. Additionally, the Internet in the last decade has revolutionized the publication process to the point of changing the basic paradigm of printed journals. The Macedonian Journal of Chemistry and Chemical Engineering in its 40-year history has adopted and adapted to all these transformations. In order to keep up with the inevitable changes, as editor-in chief I felt my responsibility was to introduce an electronic editorial managing of the journal. The choice was between commercial and open source platforms, and because of the limited funding of the journal we chose the latter. We decided on Open Journal Systems, which provided online submission and management of all content, had flexible configuration--requirements, sections, review process, etc., had options for comprehensive indexing, offered various reading tools, had email notification and commenting ability for readers, had an option for thesis abstracts and was installed locally. However, since there is limited support it requires a moderate computer knowledge/skills and effort in order to set up. Overall, it is an excellent editorial platform and a convenient solution for journals with a low budget or journals that do not want to spend their resources on commercial platforms or simply support the idea of open source software. PMID- 25711223 TI - New developments in publishing related to authorship. AB - AIM: To present the inappropriate types of authorship and practice, and the most recent developments related to basic principles and criteria to a fair system for allocating authorship in scientific publications. METHODS: An analysis of relevant materials and documents, sources from the internet and published literature and personal experience and observations of the author. RESULTS: Working in multidisciplinary teams is a common feature of modern research processes. The most sensitive question is how to decide on who to acknowledge as author of a multi-authored publication. The pertinence of this question is growing with the increasing importance of individual scientists' publication records for professional status and career. However, discussions about authorship allocation might lead to serious conflicts and disputes among coworkers which could even endanger cooperation and successful completion of a research project. It seems that discussion and education about ethical standards and practical guidelines for fairly allocating authorship are insufficient and the question of ethical practices related to authorship in multi-authored publications remains generally unresolved. CONCLUSION: It is necessary to work for raising awareness about the importance and need for education about principles of scientific communication and fair allocation of authorship, ethics of research and publication of results. The use of various forms of education in the scientific community, especially young researchers and students, in order to create an ethical environment, is one of the most effective ways to prevent the emergence of scientific and publication dishonesty and fraud, including pathology of authorship. PMID- 25711224 TI - Current biomedical scientific impact (2013) of institutions, academic journals and researchers in the Republic of Macedonia. AB - AIM: To analyse current ranking (2013) of institutions, journals and researchers in the Republic of Macedonia. MATERIAL AND METHODS: the country rankings of R. Macedonia were analyzed with SCImago Country & Journal Rank (SJR) for subject area Medicine in the years 1996-2013, and ordered by H-index. SCImago Institutions Rankings for 2013 was used for the scientific impact of biomedical institutions in the Republic of Macedonia. Journal metrics from Elsevier for the Macedonian scholarly journals for the period 2009-2013 were performed. Source Normalized Impact per Paper (SNIP), the Impact per Publication (IPP), and SCImago Journal Rank (SJR) were analysed. Macedonian scholarly biomedical journals included in Google Scholar metrics (2013, 2012) were analysed with h5-index and h5-median (June 2014). A semantic analysis of the PubMed database was performed with GoPubMed on November 2, 2014 in order to identify published papers from the field of biomedical sciences affiliated with the country of Macedonia. Harzing's Publish or Perish software was used for author impact analysis and the calculation of the Hirsh-index based on Google Scholar query. RESULTS: The rank of subject area Medicine of R. Macedonia according to the SCImago Journal & Country Rank (SJR) is 110th in the world and 17th in Eastern Europe. Of 20 universities in Macedonia, only Ss Cyril and Methodius University, Skopje, and the University St Clement of Ohrid, Bitola, are listed in the SCImago Institutions Rankings (SIR) for 2013. A very small number of Macedonian scholarly journals is included in Web of Sciences (2), PubMed (1), PubMed Central (1), SCOPUS (6), SCImago (6), and Google Scholar metrics (6). The rank of Hirsh index (h-index) was different from the rank of number of abstracts indexed in PubMed for the top 20 authors from R. Macedonia. CONCLUSION: The current biomedical scientific impact (2013) of institutions, academic journals and researchers in R. Macedonia is very low. There is an urgent need for organized measures to improve the quality and output of institutions, scholarly journals, and researchers in R. Macedonia in order to achieve higher international standards. PMID- 25711225 TI - Editorial policies and background in editing Macedonian Medical Review and BANTAO journal. AB - Even in as small a country as R. Macedonia with limited resources allocated for science, there are many journals trying to establish good editorial practices and policies in publishing the scientific work achieved. Among the currently existing medical journals Macedonian Medical Review (MMR), ISSN 0025-1097, deserves to be elaborated as the oldest journal with continuous publication since its first appearance as the journal of the Macedonian Medical Association (MMA). Since its first issue, published in 1946, there has been an opus of some 4500 peer-reviewed published papers in more than 210 issues and some 80 supplements from various congresses and meetings. In this regard, great respect should be paid not only to the editorial boards, but also to the collaborators who have contributed to its successful continuity in all previous years. In line with the needs for further development of the journal and possibilities for access to world databases, the Editorial Board of MMR has made every effort to improve and modernize its work as well as the technical quality of the journal. Hence, MMA has signed a contract with De Gruyter Open as leading publisher of Open Access academic content for further improvement and promotion of the journal and facilitation of the Medline application, so we do hope for the further success of the journal. BANTAO Journal is published on behalf of the Balkan Cities Association of Nephrology, Dialysis, Transplantation and Artificial Organs (BANTAO), ISSN 1312-2517. The first issue was published in 2003, ten years after BANTAO was born. Its appearance was an extremely important event in the existence of BANTAO. The first official editor of the journal was Dimitar Nenov, Varna (2003-2005), followed by Ali Basci (Izmir, Turkey) and Goce Spasovski (Skopje, Macedonia) as editor-in-chief since 2009. Over the years, the Journal has been included in the EBSCO, DOAJ and SCOPUS/SCIMAGO databases. The journal is published biannually. Until now, 345 papers have been published in the past 11 years, in 21 regular issues and 3 supplements. It may be said that the journal is the "glue" between the nephrologists from the Balkan cities, reflecting the high quality research and scientific potential of Balkan nephrologists. The entire process of submitting and reviewing the manuscripts is electronically done and after their acceptance they are freely available (open access journal) on the website of the association and the journal: www.bantao.org. In this regard, the current President of BANTAO has already signed a contract with De Gruyter Open as leading publisher of Open Access academic content for further improvement and promotion of the journal and Medline application for the further success of the journal. PMID- 25711226 TI - Editorial policies and good practices in editing the journal 'International Medical Journal--Medicus'. AB - Ten years ago the Association of Albanian Physicians in Macedonia undertook the very brave step of publishing a scientific medical journal, Medicus, as a platform for publishing biomedical research papers. Medical journal MEDICUS is an international peer-review journal of biomedical science. The first issue was published in 2004, starting with publishing two issues per year. From 2013, the journal delivered three issues per year, namely in January, May and September. Editor-in-Chief of the journal is Prof. Dr. Aziz Pollozhani. This year marks the tenth anniversary since publication of the first issue of Medicus, a fact that makes us proud and happy. The journal has its own official website (www.imjm.mk), where papers can be submitted and published in electronic form. In addition, the journal also comes out in print form to be distributed mainly in the region. Taking into account the specific socio-cultural characteristics of the region, the journal attempts to promote research activities in the region, while seeking to serve as an educational tool to promote scientific work in such a setting. As a result, Medicus accepts manuscripts for publication in English, Albanian and Macedonian, with a mandatory abstract in English for all papers. The journal Medicus represents a solid platform of biomedical sciences that will serve to advance scientific research and promote professional achievements in medicine. PMID- 25711227 TI - "Balkan journal of medical genetics"--facts, editorial policies, practices and challenges. AB - The Balkan Journal of Medical Genetics (BJMG) is an international, open access journal that publishes scientific papers covering different aspects of medical genetics. It is published by the Macedonian Academy of Sciences and Arts twice a year in both printed and electronic versions. BJMG is covered by many abstracting and indexing databases, including PubMed Central and Thomson Reuters. Although there are many journals in the field of medical genetics, only a few come from regions outside Western Europe and North America. Being one of these few journals, BJMG aims to promote genetics and research on this topic in the Balkan countries and beyond. BJMG's ultimate goal is to raise the scientific quality and metrics of the journal and provide a better place for BJMG in the community of scientific journals. PMID- 25711228 TI - How should journal editors respond to cases of suspected misconduct? AB - Journals and institutions have important complementary roles to play in cases of suspected research and publication misconduct. Journals should take responsibility for everything they publish and should alert institutions to cases of possible serious misconduct but should not attempt to investigate such cases. Institutions should take responsibility for their researchers and for investigating cases of possible misconduct and for ensuring journals are informed if they have published unreliable or misleading articles so that these can be retracted or corrected. Journals and institutions should have policies in place for handling such cases and these policies should respect their different roles. PMID- 25711229 TI - Co-Expression of p16, Ki67 and COX-2 Is Associated with Basal Phenotype in High Grade Ductal Carcinoma In Situ of the Breast. AB - We assessed the co-expression of cell cycle-related biomarkers in a series of 121 consecutive cases of high-grade ductal carcinoma in situ (DCIS), pure or associated with invasive carcinoma, and their associations with the different immunoprofiles of DCIS. Cases were identified from the histopathology files of the Breast Pathology Laboratory, Federal University of Minas Gerais, Brazil, from 2003 to 2008. The expression of estrogen receptor, progesterone receptor, HER2 overexpression, cytokeratin 5, epidermal growth factor receptor 1, cyclooxygenase 2, p16 and Ki67 were assessed. Tumors were placed into five subgroups according to their immunohistochemical profile: luminal A, luminal B, HER2, basal-like and "not classified". We found that the basal phenotype was associated with a higher frequency of p16-positive cases (83%) and the luminal A phenotype showed a higher frequency of p16-negative cases (93%; p=0.000). The association of biomarkers p16(+)/Ki67(+)/COX2(+) was expressed in 02/06 cases (33.3%) of the basal phenotype but in only 01/70 cases (1.4%) of the luminal A phenotype (p=0.01). The co-expression of p16(+)/Ki67(+)/COX2(-) was associated with a basal phenotype (p=0.004). P16 expression, p16(+)/Ki67(+)/COX2(+) and p16(+)/Ki67(+)/COX2(-) co expression showed significant associations with the basal phenotype and these profiles could be used to guide more aggressive treatment strategies in patients with high-grade DCIS. PMID- 25711230 TI - High phosphohistone H3 expression correlates with adverse clinical, biological, and pathological factors in neuroblastomas. AB - Phosphohistone H3 (pHH3), a biomarker of the late G2- and M-phase of the cell cycle, provides a powerful indication of the proliferative state of many cancers. We investigated the prognostic significance of pHH3 by immunostaining 80 neuroblastomas and counting the average number of strongly stained nuclei and mitotic figures. The median and 75th percentile pHH3 proliferation indices (PIs) were 0.54% and 1.06% (range, 0.01% to 2.23%) respectively. pHH3 expression was significantly higher in neuroblastomas from patients with adverse clinical characteristics, all unfavorable pathological factors including high mitosis karyorrhexis index (MKI), and adverse biological factors including MYCN oncogene amplification. High pHH3-PIs, at 1% threshold, were significantly associated with a shorter overall survival (OS) and event-free survival (EFS) in the univariable Cox regression analyses. In the multivariable models, high pHH3 counts were significantly associated with worse OS after adjustment for age but were not independent of either high MKI or MYCN amplification. In children less than 18 months of age, high MKIs and high PHH3-PIs were associated with significantly worse OS and EFS. In conclusion, high pHH3 expression correlates strongly with high MKI and MYCN amplification and indicates poor prognosis in neuroblastomas. PMID- 25711231 TI - Magnetic resonance elastography (MRE) for measurement of muscle stiffness of the shoulder: feasibility with a 3 T MRI system. AB - BACKGROUND: Magnetic resonance elastography (MRE) at 3 T MR has the potential to improve the objective detection of skeletal muscle stiffness. PURPOSE: To determine the feasibility of MRE using 3 T MR for measurement of the stiffness of shoulder muscles in subjects. MATERIAL AND METHODS: This study prospectively evaluated 16 healthy subjects (mean age, 29.8 years; range, 25-51 years). MRE was acquired with 3 T MR through the use of a 2D-gradient-echo-based MRE sequence at two different excitation frequencies (90 and 120 Hz). The mean stiffness values (MSV) of the trapezius and infraspinatus muscles were measured by two radiologists. Differences between the MSV in the x, y, and z motion-sensitization directions were assessed. Inter-observer agreement was also measured. RESULTS: The MSV of the trapezius muscle were 2.72 kPa +/- 0.6 (SD) at 90 Hz and 4.66 kPa +/- 1.2 at 120 Hz, while the MSV for the infraspinatus muscle were 3.2 kPa +/- 0.52 at 90 Hz and 4.38 kPa +/- 0.92 at 120 Hz. The MSV for both muscles were significantly higher at 120 Hz than at 90 Hz (P < 0.05). The MSV in the three different directions were significantly different from each other in the infraspinatus muscle (P < 0.05). Levels of inter-observer agreement regarding MSV were good to excellent for both the trapezius (intraclass correlation coefficient [ICC] = 0.979-0.996) and infraspinatus muscles (ICC = 0.614-0.943). CONCLUSION: MRE at 3 T is a feasible technique for the evaluation of shoulder muscle stiffness. Extended application of skeletal muscle MRE at 3 T will contribute to the evaluation and treatment of skeletal muscle disorders. PMID- 25711232 TI - Pulmonary metastases from angiosarcoma: a spectrum of CT findings. AB - BACKGROUND: Though a few reports have summarized the computed tomography (CT) findings of pulmonary metastases from angiosarcoma, the detailed CT findings of cysts are not well known, except for their characteristic thin walls. PURPOSE: To retrospectively summarize the CT findings of pulmonary metastases from angiosarcoma, focusing mainly on the CT findings of cysts. MATERIAL AND METHODS: Thirty-three patients with pulmonary metastases from angiosarcoma were selected retrospectively. Two radiologists reviewed and assessed patients' chest CT images on a consensus basis for nodules, cysts, the CT halo sign, pneumothorax, pleural effusion, and enlarged lymph nodes. Cysts were also evaluated by wall thickness and smoothness, air-fluid levels, and vessels or bronchi penetrating the cysts. The relationship between cysts and pneumothorax was assessed using the Chi-square test. RESULTS: Nodules were found in 28 (85%) patients. Cysts were found in 19 (58%) patients; 17 had thin and smooth walls, 10 had thin and irregular walls, and four had thick and irregular walls. In addition, 12 patients showed vessels or bronchi penetrating the cysts, and six showed air-fluid levels. The CT halo sign, pneumothorax, pleural effusion, and mediastinal lymphadenopathy were seen in 19 (58%), 16 (48%), 26 (78.8%), and five (15.2%) patients, respectively. Pneumothorax occurred significantly more frequently in patients with cysts (P = 0.002). CONCLUSION: Cysts showed variability in their walls, and air-fluid levels and vessels or bronchi penetrating the cysts appeared to be characteristic findings, which may be useful for detection and accurate diagnosis in patients with pulmonary metastases from angiosarcoma. PMID- 25711233 TI - Influence of different reconstruction parameters in the visualization of intracranial stents using C-arm flat panel CT angiography: experience in an animal model. AB - BACKGROUND: C-arm flat panel computed tomography angiography (CA-CTA) is a relatively new imaging modality. Consequently, knowledge about postprocessing parameters and their influence on image quality is still limited, especially for the visualization of implanted microstents. PURPOSE: To optimize reconstruction parameters by evaluating the influence of these different parameters for CA-CTA visualization of microstents in an animal model. MATERIAL AND METHODS: Eleven microstents were implanted within the left common carotid artery of 11 New Zealand white rabbits. Both CA-CTA, using intra-venous delivery of contrast material, and conventional digital subtraction angiography (DSA) was performed. CA-CTA datasets were reconstructed using three different image characteristics (normal, sharp, smooth). Two experienced neuroradiologists evaluated the image quality and performed measurements of inner and outer stent diameters as well as measurements of the lumen area. RESULTS: Stent deployment was performed successfully in all animals. Inter-observer correlation coefficient for all measurements was high (r = 0.87-0.92). Lumen area and inner stent diameter were significantly smaller in image characteristic "smooth" (P < 0.01) than in "sharp" and "normal". Outer stent diameter was larger in "smooth" than in "sharp" and "normal" (P < 0.01). Stent strut size was significantly wider using image characteristic "smooth". "Sharp" and "normal" compared best to DSA, with "sharp" providing the closest match to DSA measurements, with the trade-off of significantly more noise than in the "normal" reconstructions. CONCLUSION: The use of different image characteristics in the postprocessing of CA-CTA datasets has an influence on the visualization of implanted stents. Image characteristic "sharp" and "normal" compared best to DSA. PMID- 25711234 TI - Determination of Hepatotoxicity and Its Underlying Metabolic Basis of 1,2 Dichloropropane in Male Syrian Hamsters and B6C3F1 Mice. AB - 1,2-Dichloropropane (1,2-DCP) has recently been reclassified from not classifiable as to its carcinogenicity to humans (Group 3) to carcinogenic to humans (Group 1) by the International Agency for Research on Cancer. This was based on the findings of epidemiological studies in Japan that occupational exposure to paint stripers containing 1,2-DCP was associated with increased cholangiocarcinomas. It is known that 1,2-DCP is negative for cholangiocarcinogenicity in rats and mice. However, its toxicity and carcinogenicity has not been examined in hamsters and little is known about the regulation of its metabolism in hamsters. The purpose of this study was to determine the hepatobiliary toxicity of 1,2-DCP in hamsters and to characterize and compare the altered patterns of hepatic xenometabolic enzymes in hamsters and mice. Male Syrian hamsters and male B6C3F1 mice were treated with various doses of 1,2-DCP for 4 h or 3 days or 4 weeks. These experiments demonstrated that a high dose of 1,2-DCP induced centrilobular hepatocellular necrosis in hamsters. CYP2E1 is possibly the key enzyme responsible for bioactivation and the consequent hepatocytotoxicity of 1,2-DCP, and GSH conjugation catalyzed by GST-T1 may exert a cytoprotective role in hamsters and mice. Notably, the expression pattern of GST-T1 in bile duct epithelial cells differed between hamsters and mice: GST-T1 was expressed in bile duct epithelial cells of mice but not hamsters. This indicates that responses to 1,2-DCP in the bile duct of hamsters might differ from that of mice, and suggests that long-term studies are necessary to clarify the chalangiocarcinogenicity of 1,2-DCP in hamsters, though no biliary toxicity was observed in the present short-term experiments. PMID- 25711235 TI - Re-evaluation of the Mutagenic Response to Phosphorothioate Nucleotides in Human Lymphoblastoid TK6 Cells. AB - The degradation of phosphorothioate oligonucleotides (PS-ONDs) and the release of potentially genotoxic modified mononucleotides raise a safety concern for OND based therapeutics. Deoxyadenosine monophosphorothioate (dAMPalphaS), a PS nucleotide analog, has been reported to be a potent in vitro mutagen at the thymidine kinase (TK) locus in human TK6 lymphoblastoid cells. This led us to explore the mechanism behind the apparent positive response induced by dAMPalphaS in the TK gene-mutation assay in TK6 cells. In this work, treatment of TK6 cells with dAMPalphaS produced a dose-dependent increase in cytotoxicity and mutant frequency at the TK locus. Surprisingly, when the colonies from dAMPalphaS were re-challenged with the selective agent trifluorothymidine (TFT), the TFT resistant phenotype was lost. Moreover, dAMPalphaS-induced colonies displayed distinct growth kinetics and required longer incubation time than 4 nitroquinoline-1-oxide-induced colonies to start growing. Treatment of TK6 cells with dAMPalphaS induced cell cycle arrest at the G1 phase, enabling cells to grow, and form a colony after the efficacy of TFT in the culture medium was lost. Our findings suggest that a fraction of parental "nonmutant" TK6 cells escaped the toxicity of TFT, possibly via G1 arrest, and resumed growth after the degradation of TFT. We conclude that dAMPalphaS did not induce real TFT-resistant mutants and caution should be taken with interpretation of mutation data from TK gene-mutation assay in TK6 cells when assessing modified nucleotides. PMID- 25711237 TI - Insulation Failure of the Linox Defibrillator Lead: A Case Report and Retrospective Review of a Single Center Experience. AB - Implantable cardioverter defibrillator (ICD) lead insulation failure and conductor externalization have been increasingly reported. The 7.8F silicon insulated Linox SD and Linox S ICD leads (Biotronik, Berlin, Germany) were released in 2006 and 2007, respectively, with an estimated 85,000 implantations worldwide. A 39-year-old female suffered an out-of-hospital ventricular fibrillation (VF) arrest with successful resuscitation. An ICD was implanted utilizing a single coil active fixation Linox(Smart) S lead (Biotronik, Berlin, Germany). A device-triggered alert approximately 3 years after implantation confirmed nonphysiological high rate sensing leading to VF detection. A chest X ray showed an abnormality of the ICD lead and fluoroscopic screening confirmed conductor externalization proximal to the defibrillator coil. In view of the combined electrical and fluoroscopic abnormalities, urgent lead extraction and replacement were performed. A review of Linox (Biotronik) and Vigila (Sorin Group, Milan, Italy) lead implantations within our center (n = 98) identified 3 additional patients presenting with premature lead failure, 2 associated with nonphysiological sensed events and one associated with a significant decrease in lead impedance. All leads were subsequently removed and replaced. This case provides a striking example of insulation failure affecting the Linox ICD lead and, we believe, is the first to demonstrate conductor externalization manifesting both electrical and fluoroscopic abnormalities. PMID- 25711238 TI - The Authors' Reply: Statins and thyroid-stimulating hormone. PMID- 25711239 TI - Heterologous expression of mitochondria-targeted microbial nitrilase enzymes increases cyanide tolerance in Arabidopsis. AB - Anthropogenic activities have resulted in cyanide (CN) contamination of both soil and water in many areas of the globe. While plants possess a detoxification pathway that serves to degrade endogenously generated CN, this system is readily overwhelmed, limiting the use of plants in bioremediation. Genetic engineering of additional CN degradation pathways in plants is one potential strategy to increase their tolerance to CN. Here we show that heterologous expression of microbial nitrilase enzymes targeted to the mitochondria increases CN tolerance in Arabidopsis. Root length in seedlings expressing either a CN dihydratase from Bacillus pumilis or a CN hydratase from Neurospora crassa was increased by 45% relative in wild-type plants in the presence of 50 MUm KCN. We also demonstrate that in contrast to its strong inhibitory effects on seedling establishment, seed germination of the Col-0 ecotype of Arabidopsis is unaffected by CN. PMID- 25711236 TI - Advanced morphological - behavioral test platform reveals neurodevelopmental defects in embryonic zebrafish exposed to comprehensive suite of halogenated and organophosphate flame retardants. AB - The increased use of flammable plastics and electronic devices along with stricter fire safety standards has led to the heavy use of flame retardant chemicals in many consumer, commercial, and industrial products. Although flame retardant use has increased, a great deal of uncertainty surrounds their safety with some evidence showing toxicity and risk to human and environmental health. Recent efforts have focused on designing high-throughput biological platforms with nonmammalian models to evaluate and prioritize chemicals with limited hazard information. To complement these efforts, this study used a new morphological and behavioral testing platform with embryonic zebrafish to characterize the developmental toxicity of 44 halogenated and organophosphate flame retardants, including several of their known metabolites. Zebrafish were exposed to flame retardants from 6 to 120 h post fertilization (hpf) across concentrations spanning 4 orders of magnitude (eg, 6.4 nM to 64 uM). Flame retardant effects on survival and development were evaluated at 24 and 120 hpf, and neurobehavioral changes were measured using 2 photomotor response (PMR) assays. Compared to controls, 93% (41/44) of flame retardants studied elicited adverse effects among one or more of the bioassays and concentrations tested with the aryl phosphate ester (APE)-based mono-isopropylated triaryl phosphate and the brominated bisphenol-A analog tetrabromobisphenol-A producing the greatest array of malformations. Hierarchical clustering showed that APE flame retardants with isopropyl, butyl, and cresyl substituents on phenyl rings clustered tightly and were particularly potent. Both PMR assays were highly predictive of morphological defects supporting their use as nonlethal means of evaluating teratogenicity that could allow for additional evaluations of long-term or delayed effects in older animals. Taken together, evidence presented here indicates that zebrafish neurodevelopment is highly sensitive to many flame retardants currently in use and can be used to understand potential vulnerabilities to human health. PMID- 25711240 TI - Cardiovascular safety of sulphonylureas: over 40 years of continuous controversy without an answer. AB - More than 40 years after publication of the University Group Diabetes Program trial, the cardiovascular safety of sulphonylureas is still contentious. Although several hypotheses linking sulphonylureas to adverse cardiovascular effects exist, none provide conclusive evidence. Adding to the controversy, current clinical trials and observational studies provide inconsistent, and sometimes conflicting, evidence for the cardiovascular effects of sulphonylureas. Overall, observational evidence suggests that an increased risk of adverse cardiovascular outcomes is associated with sulphonylureas; however, these data may be subject to residual confounding and bias. Although evidence from randomized controlled trials has suggested a neutral effect, the majority of these studies were not specifically designed to assess the effect of sulphonylureas on adverse cardiovascular event risk. Current ongoing large clinical trials may provide some clarity on the cardiovascular safety of sulphonylureas, but the results are not expected for several years. With the continued uncertainties concerning the cardiovascular safety of all antidiabetic drugs, a clear answer with regard to sulphonylureas is warranted. The objectives of the present article were to provide an overview of the controversy surrounding sulphonylurea-related cardiovascular effects, to discuss the limitations of the current literature, and to provide recommendations for future studies aiming to elucidate the true relationship between sulphonylureas and adverse cardiovascular effects in people with type 2 diabetes. PMID- 25711241 TI - Anaphylaxis and cardiovascular disease: therapeutic dilemmas. AB - Cardiovascular disease (CVD) increases the risk of severe or fatal anaphylaxis, and some medications for CVD treatment can exacerbate anaphylaxis. The aim of this article is to review the effect of anaphylaxis on the heart, the potential impact of medications for CVD on anaphylaxis and anaphylaxis treatment, and the cardiovascular effects of epinephrine. The therapeutic dilemmas arising from these issues are also discussed and management strategies proposed. PubMed searches were performed for the years 1990-2014 inclusive, using terms such as angiotensin-converting enzyme (ACE) inhibitors, adrenaline, allergic myocardial infarction, anaphylaxis, angiotensin-receptor blockers (ARBs), beta-adrenergic blockers, epinephrine, and Kounis syndrome. Literature analysis indicated that: cardiac mast cells are key constituents of atherosclerotic plaques; mast cell mediators play an important role in acute coronary syndrome (ACS); patients with CVD are at increased risk of developing severe or fatal anaphylaxis; and medications for CVD treatment, including beta-adrenergic blockers and ACE inhibitors, potentially exacerbate anaphylaxis or make it more difficult to treat. Epinephrine increases myocardial contractility, decreases the duration of systole relative to diastole, and enhances coronary blood flow. Its transient adverse effects include pallor, tremor, anxiety, and palpitations. Serious adverse effects (including ventricular arrhythmias and hypertension) are rare, and are significantly more likely after intravenous injection than after intramuscular injection. Epinephrine is life-saving in anaphylaxis; second-line medications (including antihistamines and glucocorticoids) are not. In CVD patients (especially those with ACS), the decision to administer epinephrine for anaphylaxis can be difficult, and its benefits and potential harms need to be carefully considered. Concerns about potential adverse effects need to be weighed against concerns about possible death from untreated anaphylaxis, but there is no absolute contraindication to epinephrine injection in anaphylaxis. PMID- 25711242 TI - Membranous nephropathy presenting with nephrotic syndrome in a child with thalassemia major. AB - Few data on the renal effects of thalassemia syndrome are available in the literature. Recent clinical studies identified proximal tubular damage and glomerular filtration abnormalities in thalassemia. Iron-chelating agents might be nephrotoxic as well, but proven glomerular injury, either due to anemia or chelating therapy, has not previously been demonstrated in thalassemia patients. Here, we report the first thalassemia patient presenting with nephrotic syndrome to be diagnosed with membranous nephropathy in the literature. PMID- 25711243 TI - Peeking into the black box: a trait-based approach to predicting plant-soil feedback. PMID- 25711244 TI - From pond slime to rain forest: the evolution of ABA signalling and the acquisition of dehydration tolerance. PMID- 25711245 TI - When two is a crowd: mitochondrial genome merger and its aftermath. PMID- 25711246 TI - Trickery flowers: the extraordinary chemical mimicry of Aristolochia to accomplish deception to its pollinators. PMID- 25711247 TI - Training doctors in basic EEG: analysis of a learning tool relevant to resource limited settings. AB - AIM: Clinicians trained to interpret EEG in Africa are scarce. The region is challenged by inadequate access to healthcare professionals and a significant burden of disease, with the result that trained neurophysiologists and epileptologists may not be viewed as an immediate priority. However, approaches, specific to the African context, could be adopted to enable safe practice of basic EEG interpretation. Educational guidelines for the interpretation of paediatric studies, relevant to the region, are lacking. As a result, a handbook targeting this training need was developed and a pilot study undertaken to assess the efficacy of this tool to improve EEG-reporting skills for clinicians at a basic level. METHODS: Eleven health practitioners, who manage children with epilepsy, from various African countries, were recruited. The group analysed selected EEGs before and after reading a training manual (the handbook). A survey was conducted on how useful the participants found the handbook. RESULTS: There was a trend (p<0.06) supporting improvement in the ability to analyse EEGs following reading of the handbook. The doctors who had one-on-one tutoring, in addition to access to the handbook, did significantly better in most EEG reporting variables (p<0.01). CONCLUSIONS: The handbook was found to be a viable tool to promote EEG interpretation in the African setting, where foundation skills are needed. However, optimal outcomes were evident with additional individual tutoring, as well as on-going support to maintain skills. This curriculum will be adapted into a post-graduate qualification intended to generate clinicians with key basic EEG skills, but not fully trained electrophysiologists. Currently, in the African setting, for maximum impact on patient care, this approach is considered the most likely to have the furthest reach. PMID- 25711248 TI - Commentary on "Meta-analysis of the independent and cumulative effects of multiple genetic modifications on pig lung xenograft performance during ex vivo perfusion with human blood" (by Harris et al.): tailoring donor pigs for xenotransplantation-how to find the right combination of genetic modifications? PMID- 25711249 TI - A comparative study of laparoscopic and open Nissen fundoplication for GERD in Georgia. AB - AIM: The study compares and analyzes the effectiveness and outcomes of open A. Chernousov modified Nissen fundoplication (CMNF) and laparoscopic total fundoplication in Georgia for gastroesophageal reflux disease (GERD) concerning perioperative course, postoperative complications, symptomatic relief, recurrent disease and the need for reinterventional surgery. MATERIALS AND METHODS: A prospective randomized trial was performed. Twohundred fortythree patients with GERD were randomized, 123 patients underwent open CMNF procedure and 120 patients of laparoscopic total fundoplication. Pre- and postoperative tests included endoscopy, X-Ray, patient questionnaire (GERD - HQRL scale) and clinical assessment. Patients were followed for 10 years. RESULTS: This prospective randomized trial showed good and excellent long-term results after open and laparoscopic total fundoplication for GERD (92,7% vs 88,5% respectively) (p=0,03). After open CMNF procedure there were 3 cases of postoperative ventral hernia, 9 cases of mild dysphagia. There was no recurrence. After laparoscopic approach there were 7 cases of solid and transient dysphagia, 3 cases of hard stenosis of cardiacs caused by wrap. There were 2 cases of recurrence, 3 cases of reflux and 1 case of epigastral trocar hernia. CONCLUSION: In Georgia as well as throughout the world laparoscopic total fundoplication at the present time is the preferred method of choice for the treatment of GERD. It has best cosmetic effect, less pain and wound problems, shorter hospital stay, early return to work. Open CMNF is safe and effective procedure too. It prevents slippage syndrome and is characterized by better control of reflux and less frequency of recurrence and guarantees slightly better long-term functional results. KEY WORDS: Antireflux surgery, GERD, Modified Nissen fundoplication, Prospective randomized trial. PMID- 25711251 TI - Corrigendum to "Asymptomatic Liver Abscesses Mimicking Metastases in Patients after Whipple Surgery: Infectious Complications following Percutaneous Biopsy-A Report of Two Cases". AB - [This corrects the article DOI: 10.1155/2012/817314.]. PMID- 25711252 TI - Guidelines for fetal echocardiography. PMID- 25711250 TI - UK rates of occupational skin disease attributed to rubber accelerators, 1996 2012. AB - BACKGROUND: Natural and synthetic rubbers containing rubber accelerators are well known causes of allergic contact dermatitis (ACD). Latex contact urticaria (CU) has been widely reported, especially when powdered latex glove use was commonplace. Consequently, interventions to reduce latex exposure by altering glove manufacture were introduced. OBJECTIVE: This study aimed to analyse trends in UK-reported incidence of occupational skin disease associated with rubber accelerators. METHOD: We analysed cases reported to EPIDERM (part of The Health and Occupation Research network) of occupational ACD caused by natural and synthetic rubber products, between 1996 and 2012. RESULTS: For the studied period, a decreasing incidence of ACD associated with rubber products was found, with an average annual change of -1.2% [95% confidence interval (CI) -3.1 to 0.7]. The number of cases of latex CU (n = 580) significantly declined. The number of cases of ACD caused by mercapto mix and mercaptobenzothiazole (n = 177) and thiuram mix (n = 603) also declined. Reports of ACD associated with carba mix and its constituents (n = 219) increased significantly, by an average annual percentage of 10.1% (95%CI: 6.1-14.2). Twenty-six cases of ACD caused by rarer rubber compounds were identified, highlighting skin disease attributable to less widely recognized chemicals. CONCLUSIONS: These data show a falling reported incidence of occupational ACD attributed to rubber chemicals, but within this a significant rise attributable to the constituents of the carba mix. Clinicians should recognize the changing diversity of chemicals used in rubber manufacturing, and consider including carba mix in their baseline series and testing beyond this in suspect cases to avoid false-negative results. PMID- 25711253 TI - Cutaneous leukocytoclastic vasculitis associated with anti-tuberculosis drugs. AB - Leukocytoclastic vasculitis (LCV), a disease characterized by inflammation of the small vessels, presents with palpable purpura, especially in the lower extremities. Its etiology is known to include drugs, infection, collagen tissue disease, and malignancy, but LCV caused by anti-tuberculosis drugs is very rarely seen. This report describes the case of a 12-year-old girl who developed LCV with rifampicin and ethambutol while undergoing anti-tuberculosis treatment due to extensive pulmonary involvement. PMID- 25711255 TI - Mesenteric hernia causing bowel obstruction in very low-birthweight infants. AB - Internal hernia through a mesenteric defect, called mesenteric hernia, is an uncommon cause of acute intestinal obstruction in newborns. Strangulated mesenteric hernia results in intestinal necrosis or perforation and progressive deterioration with fatal outcome, especially when it occurs in low-birthweight infants. We report two very low-birthweight (VLBW) infants, who presented with acute intestinal obstruction related to mesenteric defect. The initial diagnosis was meconium obstruction in those cases, which is a common cause of bowel obstruction occurring in VLBW infants. Correct diagnosis of mesenteric hernia was difficult in these cases because of rapid deterioration and non-specific radiological findings. Awareness of the possibility of rare mesenteric hernia causing acute intestinal obstruction and surgical intervention in an appropriate timeframe are important for rescuing VLBW infants with such organic abnormalities. PMID- 25711254 TI - Rotavirus gastroenteritis-associated urinary ammonium acid urate crystals. AB - Although ammonium acid urate (AAU) calculi are extremely rare renal stone components, it was recently found that many urinary tract calculi that cause post renal renal failure in rotavirus (RV) gastroenteritis are AAU calculi. The mechanism of AAU calculi development in RV gastroenteritis has not been fully elucidated. We analyzed data from eight RV gastroenteritis patients who transiently had AAU crystals in their urinary sediment. In these patients, formation of AAU crystals occurred earlier than the formation of AAU calculi. No difference was observed in serum and urine uric acid levels between RV gastroenteritis patients with or without AAU crystals. Interestingly, fractional excretion of sodium was extremely low among patients with AAU crystals. These results suggest that the formation of AAU crystals might not be due to excretion of uric acid, but excretion of sodium. PMID- 25711256 TI - Pott's puffy tumor in a 12-year-old boy. AB - Pott's puffy tumor (PPT) is a rare complication of sinusitis characterized by subperiosteal abscess and osteomyelitis of the frontal bone. Early diagnosis and treatment is vital before it causes intracranial complications such as subdural empyema or brain abscess. Herein we describe the case of a 12-year-old patient who developed preseptal cellulitis and PPT, and was successfully treated with abscess drainage, sinus surgery and long-term antibiotic therapy. PMID- 25711257 TI - Severe primary pulmonary lymphangiectasis in a premature infant: management and follow up to early childhood. AB - Primary pulmonary lymphangiectasis (PPL) is a rare congenital developmental abnormality of the lung with a generally poor prognosis. Only a limited number of patients with neonatal-onset PPL have been reported to survive. We present the case of a male preterm infant (gestational age 34 weeks 6 days) with histologically confirmed PPL, complicated by hydrops fetalis, bilateral hydrothorax (treated in utero with pleuro-amniotic shunts), and immediate respiratory distress at birth. He survived after extensive neonatal intensive care therapy and was discharged home at the age of 7 months. At last follow up he was 3 years 7 months old, still requiring assisted ventilation via tracheostomy, having recurrent episodes of wheezing and had mild global developmental delay. This case demonstrates that survival beyond the neonatal period is possible even with severe PPL but long-term morbidity may be relevant, and multidisciplinary management and close follow up are essential. PMID- 25711258 TI - Long-term efficacy of bevacizumab and irinotecan in recurrent pediatric glioblastoma. AB - A 5-year-old boy with glioblastoma relapsed soon after postoperative irradiation in combination with temozolomide. Second-line chemotherapy was also ineffective; therefore, the bevacizumab and irinotecan were given after a third gross-total resection of the tumor. Treatment was interrupted for 1 month due to development of posterior reversible encephalopathy syndrome, but was re-initiated at a lower dose of bevacizumab with prolonged intervals between treatments. The patient was alive and disease free 2 years after initial diagnosis. Bevacizumab and irinotecan are a promising regimen for pediatric cases of recurrent glioblastoma after gross-total resection, although the optimal treatment schedule must be determined on a patient-by-patient basis. PMID- 25711259 TI - Concomitant percutaneous aortic embolectomy and excision of left atrial myxoma in a child. AB - Cardiac myxoma is rare in children and often associated with cerebrovascular events. Reported herein is the case of a 9-year-old boy who presented with acute obstruction of the aortic bifurcation associated with a huge left atrial (LA) myxoma, thereby leading to acute ischemia of the lower extremities. Immediate surgical removal of the LA myxoma with concomitant percutaneous embolectomy using a Forgathy catheter was done, with relief of ischemic symptoms. Cardiac myxoma should always be considered in the case of acute embolic events in children, given that it needs immediate intervention to prevent further complications. PMID- 25711260 TI - Cochlear implantation in children with sickle cell disease. AB - Sickle cell disease (SCD) is associated with sensorineural hearing loss (SNHL). Although the hearing loss is usually mild, some develop severe-to-profound hearing loss, in whom cochlear implants (CI) may be an option. We present the cases of two children with SCD who developed bilateral severe-to-profound SNHL and underwent cochlear implantation. One patient became profoundly deaf after an acute episode of dizziness. Imaging indicated bilateral cochlear ossification, making subsequent cochlear implant surgery challenging. The second patient developed bilateral severe-to-profound SNHL following acute vaso-occlusive crises. She went on to have uncomplicated cochlear implant surgery. These cases illustrate the variable manner in which children with SCD may develop SNHL, and the difficulties associated with managing such cases. We recommend that children with SCD should undergo regular audiological assessment. Furthermore, clinicians should be aware of the risk of cochlear fibrosis and ossification and ensure prompt assessment following an acute vaso-occlusive crisis or unexplained vestibulocochlear event. PMID- 25711261 TI - Congenital nephrotic syndrome of NPHS1 associated with cardiac malformation. AB - Congenital nephrotic syndrome (CNS) is a rare disease inherited as an autosomally recessive trait and defined as proteinuria manifesting at birth or in the first 3 months of life. The classical form is the Finnish type of CNS (CNF), which is caused by mutations in the nephrin gene (NPHS1). The classical findings include prematurity, large placenta and massive proteinuria. Minor cardiac findings have been reported as a minor functional disorder but CNS with major cardiac malformation is rare. Here we report the case of a Turkish child with CNS with small indel mutation (c.614_621delCACCCCGGinsTT) in exon 6 of NPHS1 and also major cardiac malformation who did not develop end-stage renal disease until the age of 5 years. PMID- 25711262 TI - Simulation analysis of three intubating supraglottic devices during infant chest compression. AB - Current guidelines for pediatric cardiopulmonary resuscitation suggest that supraglottic devices are alternatives for tracheal intubation with minimal interruption of chest compression. We examined the utility of three intubating supraglottic devices, air-Q(r) (air-Q), Ambu(r) aura-i (aura-i), and i-gel(r) (i gel), utilizing manikin simulation. Twenty-two novice physicians performed securing of airway on an infant manikin with the three devices. We measured the rate of success on ventilation and the insertion time with or without chest compression. Successful ventilation rate did not significantly decrease with chest compression in the three devices (without chest compression: air-Q, 21/22; aura-i, 20/22; i-gel, 20/22, during chest compression: air-Q, 20/22; aura-i, 20/22; i-gel, 18/22). The insertion time with air-Q and aura-i did not extend significantly for chest compression. In contrast, the insertion time with i-gel was significantly extended in chest compression (P < 0.05). Air-Q and aura-i are more useful for airway management during chest compression than i-gel. PMID- 25711263 TI - Tolvaptan in a pediatric patient with diuretic-resistant heart and kidney failure. AB - Despite conventional diuretic therapy, volume overload persists in many patients with decompensated heart failure. Adverse effects of diuretics are common, including worsening kidney function and electrolyte disturbance. Furthermore, decreased kidney function also affects the response to diuretics and is associated with an increased risk of mortality. A 10-year-old boy with congestive heart failure (CHF) complicated by advanced chronic kidney disease (CKD) presented with oliguria and generalized edema. He was being treated with furosemide and spironolactone, and these doses were increased to 3 mg/kg/day after admission. Although edema decreased temporarily, the symptoms worsened and furosemide resistance developed 2 months later. Tolvaptan (0.1 mg/kg/day) was started, resulting in a gradual increase in the plasma sodium level and adequate decongestion of the volume overload state. Cardiac function also improved. The use of tolvaptan should be considered in pediatric cases of conventional diuretic resistant CHF, even when complicated by advanced CKD. PMID- 25711264 TI - Expiratory CO2 as the first sign of successful ventilation during neonatal resuscitation. AB - Three-lead electrocardiography and expired CO2 monitoring were used during positive pressure ventilation of seven non-intubated newborns (gestational age, 31-37 weeks; birthweight, 1503-2885 g). In all cases, adequate CO2 (>15 mmHg) was detected prior to the achievement of stable heart rate (>100 beats/min). The delay between detection of adequate CO2 and improvement of bradycardia ranged from 8 to 73 s (median, 15 s). Inadequate expired CO2 during positive pressure ventilation indicates airway obstruction or poor aeration of the newborn lungs. Thus, positive expiratory CO2 can be the first recognizable sign of successful ventilation during neonatal resuscitation. PMID- 25711265 TI - Drug treatment for bronchopulmonary dysplasia in Japan: questionnaire survey. AB - Bronchopulmonary dysplasia (BPD) is one of the most common complications in premature infants. Although several different drugs have been developed for BPD, there is a wide variation in the choice of drug used among facilities. The aim of this study was to carry out a survey of the current drugs used to treat BPD in Japan. Questionnaires regarding the current use of drugs for BPD were sent to tertiary neonatal units. The response rate was 80% (77/96). Most units used antenatal steroids and oral diuretics for the prevention and treatment of BPD, respectively. Only 4% used caffeine for prevention, whereas 88% used systemic corticosteroids for treatment. Few units used inhaled anticholinergics and i.v. vitamins for the prevention and treatment of BPD, respectively. It was found that the drugs used to treat BPD vary greatly among institutions. Further research is required to develop evidence-based clinical guidelines for BPD in premature infants. PMID- 25711266 TI - Racial differences of the tricuspid annular plane systolic excursion. PMID- 25711267 TI - Early intervention for late-onset ornithine transcarbamylase deficiency. AB - We report the case of a family with late-onset ornithine transcarbamylase deficiency (OTCD). Several family members had died from OTCD, and the c.221G>A, p.Lys221Lys mutation was detected at the 3' end of exon 6 of OTC in the X chromosome of some members. We provided genetic counseling on pregnancy, delivery, and neonate management to a 4th-generation female carrier and decided on metabolic management of her child from birth. Two male patients were diagnosed with late-onset OTCD on the basis of blood amino acid and genetic analysis, and they received arginine supplementation from the asymptomatic, early neonatal period. These children grew and developed normally, without decompensation. Patients with late-onset OTCD can and should be diagnosed and treated in the early neonatal period, especially those from families already diagnosed with late onset OTCD, and family members must be provided with genetic counseling. PMID- 25711268 TI - Japanese neonate with congenital chloride diarrhea caused by SLC26A3 mutation. AB - Congenital chloride diarrhea (CCD) beginning in utero is a rare autosomal recessive inherited disorder characterized by impairment of Cl(-) /HCO3 (-) exchange in an otherwise normal distal ileum and colon. Life-long secretory diarrhea is caused by mutations in solute carrier family 26, member 3, (SLC26A3), which disrupt epithelial Cl(-) /HCO3 (-) transport in the ileum and colon. Although 55 mutations in SLC26A3 have been identified throughout the world, few Japanese cases have been confirmed on genetic analysis. We report the successful treatment of a Japanese neonate with CCD caused by SLC26A3 mutation. PMID- 25711269 TI - Transient abnormal myelopoiesis in non-Down syndrome neonate. AB - We encountered a case of neonatal acute megakaryoblastic leukemia not associated with Down syndrome (DS). Molecular cytogenetic analysis of leukemic blast cells indicated that increased blast cell status was caused by transient abnormal myelopoiesis with trisomy 21 and GATA1 mutation. Based on these molecular cytogenetic data, intensive chemotherapy was avoided, and the patient was successfully cured with low-dose cytarabine. Morphologically, leukemic blast cells of acute megakaryoblastic leukemia in a non-DS neonate are indistinguishable from a blast cell of transient abnormal myelopoiesis. The possibility of transient abnormal myelopoiesis should be carefully considered before intensive chemotherapy is adopted. PMID- 25711270 TI - Collagenous sprue in a 3-month-old infant. AB - Collagenous sprue (CS) is a severe malabsorption disorder, the etiology of which has not been well defined. Herein, we report the case of a 3-month-old infant with CS who responded to steroid and immunomodulator treatment and presented a thick subepithelial collagen band. A 3-month-old Japanese girl presented with severe watery diarrhea that lasted for 2 weeks. She was admitted to the referring hospital, but symptomatic improvement was not achieved with fasting and rehydration. Gastroduodenal endoscopy showed an edematous duodenal mucosal surface. Duodenal biopsy indicated severe villous atrophy with infiltration of mostly CD8-positive T cells; and deposition of subepithelial collagen was confirmed. The subepithelial collagen deposits, however, had disappeared after treatment. Historically, child-onset CS is extremely rare and this case is likely to be the youngest case of infantile CS. The present case suggests that CS should be considered as a differential diagnosis for intractable diarrhea, even in infants. PMID- 25711272 TI - Tsukamurella inchonensis infection in a child with Hodgkin's lymphoma. AB - Tsukamurella spp. infection is a rare but important cause of bacteremia in immunocompromised patients. The organism is an aerobic, Gram-positive, weakly acid-fast bacillus that is difficult to differentiate from other aerobic Actinomycetales by standard laboratory methods. Here, we report on the case of a 14-year-old patient with Hodgkin's lymphoma who, after intensive chemotherapy, developed Tsukamurella inchonensis bacteremia, which was identified on the peripherally inserted central venous catheter (PICC) using 16S rRNA sequencing analysis. The bacteremia was successfully controlled with antimicrobial therapy and subsequent removal of the PICC. This is the first report of bacteremia by Tsukamurella inchonensis in immunocompromised children. Careful observation and prompt analysis of opportunistic infection, including Tsukamurella spp., is very important in immunocompromised children. PMID- 25711271 TI - Fusarium falciforme infection in a patient with chronic granulomatous disease: Unique long-term course of epidural abscess. AB - Chronic granulomatous disease (CGD) is a primary immunodeficiency disease characterized by recurrent life-threatening bacterial and fungal infections with granuloma formation. Species of the genus Fusarium are opportunistic environmental microorganisms that are rarely pathogenic in humans. We report here the first case of X-linked CGD complicated with epidural abscess caused by Fusarium falciforme infection. The abscesses extended along the dura mater for >7 years and finally resulted in fatal meningitis and cervical myelitis. Early intervention with hematopoietic stem cell transplantation should be considered, especially in patients with severe CGD, before the development of serious infectious complication. PMID- 25711273 TI - Pharyngeal pouch: which technique? AB - BACKGROUND: Pharyngeal pouches have been recognised as a cause of dysphagia for centuries and have been treated in a variety of ways over that time. OBJECTIVE: This article aimed to analyse the results of surgery by a variety of techniques, as performed by one surgeon. METHOD: A retrospective analysis of a case series was conducted, analysing the variables of patient age, sex, type of surgery, length of hospital stay, leak, recurrence and other complications. RESULTS: A total of 121 patients were treated by 135 operations. There were no leaks in the group treated by endoscopic stapling and this group also had a significantly shorter hospital stay. As for recurrence, the lowest rate appeared to be in the group treated by excision of the pouch. CONCLUSION: The techniques used by the author all still seem to have a role in the management of pharyngeal pouch, with the endoscopic stapling approach associated with a low rate of complications and short hospital stay. PMID- 25711275 TI - Assessment of perioperative cardiac risk of patients undergoing noncardiac surgery using coronary computed tomographic angiography. AB - BACKGROUND: The appropriate indication for coronary computed tomographic angiography (CTA) as a part of preoperative evaluation has not been defined yet. We investigated the value of coronary CTA in patients undergoing noncardiac surgery. METHODS AND RESULTS: We included 844 patients (median age, 67 years; male sex, 62%) who underwent coronary CTA for screening of coronary artery disease before noncardiac surgery. Clinically determined revised cardiac risk index were compared with the extent and severity of coronary artery disease assessed by coronary CTA. Perioperative major cardiac event (PMCE), defined as cardiac death, myocardial infarction, or pulmonary edema within postoperative 30 days, developed in 25 patients (3.0%). Significant coronary CTA finding was defined as >3 any lesions with >=1 (diameter stenosis >=70%) stenosis based on the relationship between the severity of coronary artery disease and PMCE risk. The risk of PMCE was 14.0% in patients with significant CTA findings, whereas 2.2% of patients without significant CTA findings regardless of revised cardiac risk index score. The predictive performance of revised cardiac risk index could be improved significantly after addition of significant coronary CTA findings (c statistics=0.631 versus 0.757; net reclassification improvement=0.923; integrated discrimination improvement=0.051). On the basis of revised cardiac risk index and coronary CTA, the risk of PMCE could be estimated with sensitivity, specificity, positive predictive value, and negative predictive value of 76%, 73%, 8%, and 99%, respectively. CONCLUSIONS: Addition of coronary CTA to clinical risk improved perioperative risk stratification. Absence of significant coronary CTA findings conferred low PMCE risk with high specificity and negative predictive value regardless of clinical risk. Coronary CTA may improve perioperative risk stratification in patients undergoing noncardiac surgery. PMID- 25711276 TI - Diagnostic accuracy of noninvasive testing: necessary but insufficient. PMID- 25711274 TI - Detection of significant coronary artery disease by noninvasive anatomical and functional imaging. AB - BACKGROUND: The choice of imaging techniques in patients with suspected coronary artery disease (CAD) varies between countries, regions, and hospitals. This prospective, multicenter, comparative effectiveness study was designed to assess the relative accuracy of commonly used imaging techniques for identifying patients with significant CAD. METHODS AND RESULTS: A total of 475 patients with stable chest pain and intermediate likelihood of CAD underwent coronary computed tomographic angiography and stress myocardial perfusion imaging by single photon emission computed tomography or positron emission tomography, and ventricular wall motion imaging by stress echocardiography or cardiac magnetic resonance. If >=1 test was abnormal, patients underwent invasive coronary angiography. Significant CAD was defined by invasive coronary angiography as >50% stenosis of the left main stem, >70% stenosis in a major coronary vessel, or 30% to 70% stenosis with fractional flow reserve <=0.8. Significant CAD was present in 29% of patients. In a patient-based analysis, coronary computed tomographic angiography had the highest diagnostic accuracy, the area under the receiver operating characteristics curve being 0.91 (95% confidence interval, 0.88-0.94), sensitivity being 91%, and specificity being 92%. Myocardial perfusion imaging had good diagnostic accuracy (area under the curve, 0.74; confidence interval, 0.69-0.78), sensitivity 74%, and specificity 73%. Wall motion imaging had similar accuracy (area under the curve, 0.70; confidence interval, 0.65-0.75) but lower sensitivity (49%, P<0.001) and higher specificity (92%, P<0.001). The diagnostic accuracy of myocardial perfusion imaging and wall motion imaging were lower than that of coronary computed tomographic angiography (P<0.001). CONCLUSIONS: In a multicenter European population of patients with stable chest pain and low prevalence of CAD, coronary computed tomographic angiography is more accurate than noninvasive functional testing for detecting significant CAD defined invasively. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00979199. PMID- 25711277 TI - Coronary computed tomographic angiography for preoperative risk: improved area under curve is not enough. PMID- 25711278 TI - A 45 year old patient with headache, fever, and hyponatraemia. PMID- 25711279 TI - Traffic lines: new tools for genetic analysis in Arabidopsis thaliana. AB - Genetic analysis requires the ability to identify the genotypes of individuals in a segregating population. This task is straightforward if each genotype has a distinctive phenotype, but is difficult if these genotypes are phenotypically similar or identical. We show that Arabidopsis seeds homozygous or heterozygous for a mutation of interest can be identified in a segregating family by placing the mutation in trans to a chromosome carrying a pair of seed-expressed green and red fluorescent transgenes (a "traffic line") that flank the mutation. Nonfluorescent seeds in the self-pollinated progeny of such a heterozygous plant are usually homozygous for the mutation, whereas seeds with intermediate green and red fluorescence are typically heterozygous for the mutation. This makes it possible to identify seedlings homozygous for mutations that lack an obvious seedling phenotype, and also facilitates the analysis of lethal or sterile mutations, which must be propagated in heterozygous condition. Traffic lines can also be used to identify progeny that have undergone recombination within a defined region of the genome, facilitating genetic mapping and the production of near-isogenic lines. We produced 488 transgenic lines containing single genome mapped insertions of NAP:dsRED and NAP:eGFP in Columbia (330 lines) and Landsberg erecta (158 lines) and generated sets of traffic lines that span most regions of the Arabidopsis genome. We demonstrated the utility of these lines for identifying seeds of a specific genotype and for generating near-isogenic lines using mutations of WUSCHEL and SHOOTMERISTEMLESS. This new resource significantly decreases the effort and cost of genotyping segregating families and increases the efficiency of experiments that rely on the ability to detect recombination in a defined chromosomal segment. PMID- 25711280 TI - First CDK 4/6 Inhibitor Heads to Market. AB - The FDA granted accelerated approval to palbociclib for the treatment of estrogen receptor-positive, HER2-negative metastatic breast cancer in postmenopausal women who have not yet received endocrine-based therapy. Palbociclib is the first cell cycle-targeting CDK 4/6 inhibitor to reach the market. PMID- 25711281 TI - Illusory feature slowing: evidence for perceptual models of global facial change. AB - Upright static faces are widely thought to recruit holistic representations, whereby individual features are integrated into nondecomposable wholes for recognition and interpretation. In contrast, little is known about the perceptual integration of dynamic features when viewing moving faces. People are frequently exposed to correlated eye and mouth movements, such as the characteristic changes that accompany facial emotion, yawning, sneezing, and laughter. However, it is unclear whether the visual system is sensitive to these dynamic regularities, encoding facial behavior relative to a set of dynamic global prototypes, or whether it simply forms piecemeal descriptions of feature states over time. To address this question, we sought evidence of perceptual interactions between dynamic facial features. Crucially, we found illusory slowing of feature motion in the presence of another moving feature, but it was limited to upright faces and particular relative-phase relationships. Perceptual interactions between dynamic features suggest that local changes are integrated into models of global facial change. PMID- 25711282 TI - Combined Molecular Docking, 3D-QSAR, and Pharmacophore Model: Design of Novel Tubulin Polymerization Inhibitors by Binding to Colchicine-binding Site. AB - Interference with dynamic equilibrium of microtubule-tubulin has proven to be a useful tactics in the clinic. Based on investigation into the structure-activity relationship (SAR) studies of tubulin polymerization inhibitors obtained from several worldwide groups, we attempted to design 691 compounds covering several main heterocyclic scaffolds as novel colchicine-site inhibitors (CSIs). Evaluated by a series of combination of commonly used computer methods such as molecular docking, 3D-QSAR, and pharmacophore model, we can obtain the ultimate 16 target compounds derived from five important basic scaffolds in the field of medicinal chemistry. Among these compounds, compound A-132 with in silico moderate activity was synthesized, and subsequently validated for preliminary inhibition of tubulin polymerization by immunofluorescence assay. In additional, the work of synthesis and validation of biological activity for other 15 various structure compounds will be completed in our laboratory. This study not only developed a hierarchical strategy to screen novel tubulin inhibitors effectively, but also widened the spectrum of chemical structures of canonical CSIs. PMID- 25711283 TI - Conservation and economic benefits of a road around the Serengeti. PMID- 25711284 TI - Characterizing the genetic risk for Type 2 diabetes in a Malaysian multi-ethnic cohort. AB - AIMS: To characterize the association with Type 2 diabetes of known Type 2 diabetes risk variants in people in Malaysia of Malay, Chinese and Indian ancestry who participated in the Malaysian Cohort project. METHODS: We genotyped 1604 people of Malay ancestry (722 cases, 882 controls), 1654 of Chinese ancestry (819 cases, 835 controls) and 1728 of Indian ancestry (851 cases, 877 controls). First, 62 candidate single-nucleotide polymorphisms previously associated with Type 2 diabetes were assessed for association via logistic regression within ancestral groups and then across ancestral groups using a meta-analysis. Second, estimated odds ratios were assessed for excess directional concordance with previously studied populations. Third, a genetic risk score aggregating allele dosage across the candidate single-nucleotide polymorphisms was tested for association within and across ancestral groups. RESULTS: After Bonferroni correction, seven individual single-nucleotide polymorphisms were associated with Type 2 diabetes in the combined Malaysian sample. We observed a highly significant excess in concordance of effect directions between Malaysian and previously studied populations. The genetic risk score was strongly associated with Type 2 diabetes in all Malaysian groups, explaining from 1.0 to 1.7% of total Type 2 diabetes risk variance. CONCLUSION: This study suggests there is substantial overlap of the genetic risk alleles underlying Type 2 diabetes in Malaysian and other populations. PMID- 25711286 TI - Cardiac PET/MR: Big footprint-small step? PMID- 25711288 TI - Mechanisms of change in psychotherapy for children and adolescents: current state, clinical implications, and methodological and conceptual recommendations for mediation analysis. PMID- 25711287 TI - Interpersonal sensitivity and functioning impairment in youth at ultra-high risk for psychosis. AB - A personality trait that often elicits poor and uneasy interpersonal relationships is interpersonal sensitivity. The aim of the present study was to explore the relationship between interpersonal sensitivity and psychosocial functioning in individuals at ultra-high risk for psychosis as compared to help seeking individuals who screened negative for an ultra-high risk of psychosis. A total sample of 147 adolescents and young adult who were help seeking for emerging mental health problems participated in the study. The sample was divided into two groups: 39 individuals who met criteria for an ultra-high-risk mental state (UHR), and 108 (NS). The whole sample completed the Interpersonal Sensitivity Measure (IPSM) and the Global Functioning: Social and Role Scale (GF:SS; GF:RS). Mediation analysis was used to explore whether attenuated negative symptoms mediated the relationship between interpersonal sensitivity and social functioning. Individuals with UHR state showed higher IPSM scores and lower GF:SS and GF:RS scores than NS participants. A statistically negative significant correlation between two IPSM subscales (Interpersonal Awareness and Timidity) and GF:SS was found in both groups. Our results also suggest that the relationship between the aforementioned aspects of interpersonal sensitivity and social functioning was not mediated by negative prodromal symptoms. This study suggests that some aspects of interpersonal sensitivity were associated with low level of social functioning. Assessing and treating interpersonal sensitivity may be a promising therapeutic target to improve social functioning in young help seeking individuals. PMID- 25711289 TI - Exposure to non-steroid anti-inflammatory drugs (NSAIDs) and suppressing hydrogen sulfide synthesis leads to altered structure and impaired function of the oesophagus and oesophagogastric junction. AB - INTRODUCTION: The non-steroid anti-inflammatory drugs (NSAIDs) are among the drugs that can commonly cause injury in the esophagus, such as non-reflux oesophagitis, with important clinical consequences. This injury may be 'silent' and therefore often overlooked. Recently, we established that hydrogen sulfide (H2S) is a critical mediator of esophageal mucosal protection and repair. The aim of the study was to determine the effect of naproxen, the most commonly used NSAIDs, on the oesophagus and oesophagogastric junction and its relation with suppression or stimulation of endogenous H2S synthesis during naproxen-induced oesophageal injury. METHODS: Rats were treated with vehicle (control) or naproxen, with or without being subjected to water immersion restricted stress (Takagi et al. Chem Pharm Bul 12:465-472, 1964). Subgroups of rats were pre treated with an inhibitor of H2S synthesis cystathionine gamma-lyase (CSE) or cystathionine beta-synthase (CBS), or with the Sodium sulphide (NaHS), which spontaneously generates H2S in solution. Damage of the oesophageal mucosa and oesophagogastric junction was estimated and scored using a histological damage index. RESULTS: Treatment with naproxen increased the thickness of the corneal and epithelial layers of the oesophagus, as well as producing disorganization of the muscle plate and irregular submucosal oedema. Both injury factors, stress and suppression of H2S synthesis resulted in the development of severe esophagitis and damage to the oesophagogastric junction. The damage was exacerbated by inhibitors of H2S biosynthesis, and attenuated by treatment with NaHS. CONCLUSIONS: Inhibition of endogenous H2S synthesis provides a novel experimental model that can be useful in preclinical studies NSAID-related non-reflux oesophagitis. H2S contributes significantly to mucosal defence in the oesophagus. PMID- 25711290 TI - The use of computed tomography in determining development, anomalies, and trauma of the hyoid bone. AB - PURPOSE: Recognition of injury to the hyoid bone is intrinsic to post-mortem examination. Given its superficial location in the neck hyoid fractures are generally associated with some form of compressive neck force although they are well recognized in the peri-mortem period, in the context of manual handling and resuscitation. Hyoid fractures are variably reported to occur in manual strangulation and during hanging. METHODS: In this study Computer Tomography (CT) scans of the head and neck of 431 deceased persons (235 males and 196 females) between the ages of 1 day and 100 years of age (mean age 35.93 +/- 24.15) and including 25 victims of hangings were examined to reveal the pattern of age related change and the types of injury that occurred. Hyoid variants were also documented. RESULTS: The synchondroses between greater cornua and body were found to progressively fuse with age although in the current sample 20% non-fusion was observed beyond 65 years of age. Sex differences were evident in adult hyoid bones and discriminant function analysis correctly confirmed sex in 74.7% of cases. CONCLUSIONS: The greatest age-related changes occurred from puberty to post-adolescence and a linear regression equation successfully assessed age into three general categories in 87.7% of cases. Hyoid fractures were documented in 24% of victims of hangings and while previous reports indicate these are more likely in older age, when synchondroses are fused, in this study the average age of victims with fracture was 27 +/- 10 years. In the majority of cases the site of ligature was below the hyoid bone and in only one on the hyoid body. PMID- 25711291 TI - The correlation of epicardial adipose tissue on postmortem CT with coronary artery stenosis as determined by autopsy. AB - The goal of this study was to assess whether epicardial and paracardial adipose tissue volumes, as determined by computed tomography (CT), correlate with coronary artery stenosis as determined by autopsy. The postmortem CT data and autopsy findings of 116 adult human decedents were retrospectively compared. Subjects were classified into three groups according to their degree of coronary artery stenosis: >=50, <50%, and no stenosis. Epicardial and paracardial adipose tissue volumes were calculated based on manual segmentation after threshold based masking. In addition, epicardial adipose tissue thickness was measured using a caliper. All three parameters (thickness of epicardial fat and volumes of both epicardial and paracardial fat) were compared among the three groups and correlated with the degree of coronary artery stenosis. The group with no coronary artery stenosis showed the lowest mean values of epicardial adipose tissue volume, while the coronary artery stenosis >=50 % group showed the highest volume. All measured variables (thickness of epicardial fat and volumes of both epicardial and paracardial fat) correlated significantly with the grade of coronary artery stenosis, even after controlling for BMI, however, epicardial adipose tissue volume exhibited the strongest correlation. This study reveals that there is an association between the degree of coronary artery stenosis and the amount of epicardial fat tissue: The larger the volume of epicardial fat, the higher the degree of coronary artery stenosis. PMID- 25711293 TI - Disialoganglioside-specific human natural killer cells are effective against drug resistant neuroblastoma. AB - The disialoganglioside GD2 is a well-established target antigen for passive immunotherapy in neuroblastoma (NB). Despite the recent success of passive immunotherapy with the anti-GD2 antibody ch14.18 and cytokines, treatment of high risk NB remains challenging. We expanded the approach of GD2-specific, antibody based immunotherapy to an application of a GD2-specific natural killer (NK) cell line, NK-92-scFv(ch14.18)-zeta. NK-92-scFv(ch14.18)-zeta is genetically engineered to express a GD2-specific chimeric antigen receptor generated from ch14.18. Here, we show that chimeric receptor expression enables NK-92 scFv(ch14.18)-zeta to effectively lyse GD2(+) NB cells also including partially or multidrug-resistant lines. Our data suggest that recognition of GD2 by the chimeric receptor is the primary mechanism involved in NK-92-scFv(ch14.18)-zeta mediated lysis and is independent of activating NK cell receptor/ligand interactions. Furthermore, we demonstrate that NK-92-scFv(ch14.18)-zeta is able to mediate a significant anti-tumor response in vivo in a drug-resistant GD2(+) NB xenograft mouse model. NK-92-scFv(ch14.18)-zeta is an NB-specific NK cell line that has potential for future clinical development due to its high stability and activity toward GD2(+) NB cell lines. PMID- 25711294 TI - Promiscuous hydroxylases for the functionalization of polycyclic tetramate macrolactams--conversion of ikarugamycin to butremycin. AB - Polycyclic tetramate macrolactams (PTMs) are a structurally, biomedically and biosynthetically intriguing class of bacterial metabolites. By combining parts of the machineries of different PTM biosynthetic pathways, we demonstrate for the first time the substrate promiscuity of a class of PTM tailoring enzymes, thereby facilitating the (bio)synthesis of butremycin. PMID- 25711295 TI - A Systematic Review of HIV and STI Behavior Change Interventions for Female Sex Workers in the United States. AB - The lives of female sex workers (FSW) in the US are typically marked by substance abuse, violence, trauma, and poverty. These factors place FSW at risk for acquiring and transmitting HIV and other sexually transmitted infections (STIs). The purpose of this systematic review is to examine HIV/STI interventions conducted in the US that aim to reduce sexual- or drug-related risk behavior among FSW. Eighteen studies describing 19 unique interventions met our selection criteria: five exclusively targeted FSW, two reported stratified data for FSW, and 12 included at least 50 % FSW. Results indicate that 15 interventions provided HIV/STI information, 13 provided substance abuse prevention information, and few included content tailored to specific needs of FSW. Our findings suggest that current HIV/STI prevention efforts in the US do not adequately address the needs of FSW. Interventions are needed to address issues facing FSW in order to reduce HIV/STI transmission in this high-risk group. PMID- 25711296 TI - A preliminary evaluation of a community-based campaign to increase awareness of concurrency and HIV transmission in African American and African-Born communities. AB - We evaluate an innovative grassroots community-based campaign in Seattle, WA focused on educating African American and African-born communities about concurrent partnerships and HIV transmission. Respondents completed a short self administered questionnaire on a handheld personal digital assistant to evaluate the reach, acceptability and preliminary efficacy of the campaign. Of those who remembered seeing the campaign materials (82 %), social networks were the most common source of exposure (80 %). Respondents rated campaign materials very visually attractive (86 %), very interesting (91 %), and very important for themselves (90 %) and their community (93 %). Respondents reported that the campaign increased their knowledge about concurrency (84 %), changed their attitudes about it (77 %), and 65 % said it was likely or very likely that they would change their behavior as a result. This inexpensive grassroots campaign demonstrated extensive reach in the local black community and was able to move beyond individual exposure and into social networks. PMID- 25711297 TI - Recall of Nadir CD4 Cell Count and Most Recent HIV Viral Load Among HIV-Infected, Socially Marginalized Adults. AB - Lower nadir CD4 cell counts and higher HIV viral loads are associated with increased risks of adverse events in the progression of HIV disease. In cases where medical records are inaccessible or incomplete, little evidence is available regarding whether nadir CDR cell count or HIV viral load is reliably reported in any patient population. We compare survey data collected from 207 HIV infected individuals detained in San Francisco jails to data collected from electronic medical records (EMR) kept by the jails and community health providers. The sensitivity of self-reported nadir CD4 cell count less than 200 was 82 % [95 % confidence interval (CI) 68, 88], and the sensitivity of reporting an undetectable most recent HIV viral load was 93 % (95 % CI 84, 97). This suggests that in a highly socially marginalized population, nadir CD4 cell count and most recent HIV viral load are recalled accurately when compared to EMR. PMID- 25711298 TI - The 'Fears' of Disclosing HIV Status to Sexual Partners: A Mixed Methods Study in a Counseling Setting in Ghana. AB - Encouraging disclosure within a trusting and supportive environment is imperative in dealing with HIV/AIDS related stigma. However, disclosure rates and the factors that influence it are vaguely understood in African societies. This study aimed at determining the disclosure rate and factors that influence disclosure in Cape Coast, Ghana. In-depth interviews of 15 peer educators and a survey of 510 PLHIV were used in a mixed methods study design. Majority of the study participants (78.6 %) had disclosed their HIV positive status to their sexual partners. Although peer educators in this study portrayed the overall outcome of disclosure to be negative, 84.0 % of disclosers were accepted by their partners without negative consequences after disclosure. This study suggests that the existing support services ill prepares newly diagnosed HIV positive clients and hampers disclosure initiatives. Providing comprehensive support services and re training peer educators may be crucial in creating a safe disclosure environment in Ghana. PMID- 25711301 TI - Understanding Gay Community Subcultures: Implications for HIV Prevention. AB - Gay and bisexual men (GBM) who participate in gay community subcultures have different profiles, including differing risk behaviors. We examined men's participation in gay community subcultures, and its association with risk behavior. In a cross-sectional survey, 849 GBM provided information about men in their personal networks. We devised measures of their participation in five subcultural groupings and explored their associations with sexual behavior. We identified five subcultural groupings: sexually adventurous; bear tribes; alternative queer; party scene; and sexually conservative. Higher scores on the sexually adventurous measure was associated with being older, having more gay friends, being HIV-positive, and being more sexually active. It was also independently associated with unprotected anal intercourse with casual partners (AOR 1.82; 95 % CI 1.20-2.76; p = 0.005). HIV prevention strategies need to account for the different subcultural groupings in which GBM participate. Measures of engagement with gay subcultures are useful indicators of differential rates of risk behavior and modes of participation in gay community life. Men in more sexually adventurous subcultures are more likely to engage in sexual risk behavior. PMID- 25711300 TI - "If I don't use a condom ... I would be stressed in my heart that I've done something wrong": Routine Prevention Messages Preclude Safer Conception Counseling for HIV-Infected Men and Women in South Africa. AB - Intended conception likely contributes to a significant proportion of new HIV infections in South Africa. Safer conception strategies require healthcare provider-client communication about fertility intentions, periconception risks, and options to modify those risks. We conducted in-depth interviews with 35 HIV infected men and women accessing care in South Africa to explore barriers and promoters to patient-provider communication around fertility desires and intentions. Few participants had discussed personal fertility goals with providers. Discussions about pregnancy focused on maternal and child health, not sexual HIV transmission; no participants had received tailored safer conception advice. Although participants welcomed safer conception counseling, barriers to client-initiated discussions included narrowly focused prevention messages and perceptions that periconception transmission risk is not modifiable. Supporting providers to assess clients' fertility intentions and offer appropriate advice, and public health campaigns that address sexual HIV transmission in the context of conception may improve awareness of and access to safer conception strategies. PMID- 25711299 TI - Alcohol-Related Diagnoses and All-Cause Hospitalization Among HIV-Infected and Uninfected Patients: A Longitudinal Analysis of United States Veterans from 1997 to 2011. AB - Individuals with HIV infection are living substantially longer on antiretroviral therapy, but hospitalization rates continue to be relatively high. We do not know how overall or diagnosis-specific hospitalization rates compare between HIV infected and uninfected individuals or what conditions may drive hospitalization trends. Hospitalization rates among United States Veterans were calculated and stratified by HIV serostatus and principal diagnosis disease category. Because alcohol-related diagnoses (ARD) appeared to have a disproportional effect, we further stratified our calculations by ARD history. A multivariable Cox proportional hazards model was fitted to assess the relative risk of hospitalization controlling for demographic and other comorbidity variables. From 1997 to 2011, 46,428 HIV-infected and 93,997 uninfected patients were followed for 1,497,536 person-years. Overall hospitalization rates decreased among HIV infected and uninfected patients. However, cardiovascular and renal insufficiency admissions increased for all groups while gastrointestinal and liver, endocrine, neurologic, and non-AIDS cancer admissions increased among those with an alcohol related diagnosis. After multivariable adjustment, HIV-infected individuals with an ARD had the highest risk of hospitalization (hazard ratio 3.24, 95 % CI 3.00, 3.49) compared to those free of HIV infection and without an ARD. Still, HIV alone also conferred increased risk (HR 2.08, 95 % CI 2.04, 2.13). While decreasing overall, risk of all-cause hospitalization remains higher among HIV infected than uninfected individuals and is strongly influenced by the presence of an ARD. PMID- 25711302 TI - Categories, continua and the growth of psychiatric knowledge. PMID- 25711303 TI - Letter to the editor. PMID- 25711304 TI - Establishment and characterization of human lingual squamous cell carcinoma cell lines designated Nialym derived from metastatic foci of lymph node, and Nialymx derived from transplanted tumor of Nialym cells. AB - The squamous cell carcinoma cell lines Nialym was successfully established from metastatic foci of lymph nodes from a 48-year-old male Japanese patient with squamous cell carcinoma of the tongue. In addition, the Nialymx cell line was established from a transplanted tumor of Nialym cells in SCID mice. Nialym cells were angular, with neoplastic and pleomorphic features. Two types of Nialym cell were observed by electron microscopy; light cells and dark cells. The dark cells had a number of waved tonofilaments in the cytoplasm, while light cells showed poorly developed organelles. The population doubling times for Nialym and Nialymx cells were approximately, 46 and 42 h at the 10th passage. Nialym cells secreted 4.8 ng/ml VEGF and 5.9 ng/ml HGF, Nialymx cells also secreted 6.7 ng/ml VEGF and 4.3 ng/ml HGF at the 10th passage for 3 days of culture. Histopathological aspects of Nialym and Nialymx cell lines were similar. We believe that these cell lines are valuable tools for elucidating the mechanisms of cancer metastasis and developing immunotherapy and chemotherapy regimens. PMID- 25711305 TI - Stapling monomeric GCN4 peptides allows for DNA binding and enhanced cellular uptake. AB - The basic DNA recognition region of the GCN4 protein comprising 23 amino acids has been modified to contain two optimally positioned cysteines which have been linked and stapled using cross-linkers of suitable lengths. This results in stapled peptides with a stabilized alpha-helical conformation which allows for DNA binding and concurrent enhancement of cellular uptake. PMID- 25711306 TI - A polymorphic pseudoautosomal boundary in the Carica papaya sex chromosomes. AB - Sex chromosomes are defined by a non-recombining sex-determining region (SDR) flanked by one or two pseudoautosomal regions (PARs). The genetic composition and evolutionary dynamics of the PAR is also influenced by its linkage to the differentiated non-recombining SDR; however, understanding the effects of this linkage requires a precise definition of the PAR boundary. Here, we took a molecular population genetic approach to further refine the location of the PAR boundary of the evolutionary young sex chromosomes of the tropical plant, Carica papaya. We were able to map the position of the papaya PAR boundary A to a 100-kb region between two genetic loci approximately 2 Mb upstream of the previously genetically identified PAR boundary. Furthermore, this boundary is polymorphic within natural populations of papaya, with an approximately 100-130 kb expansion of the non-recombining SDR found in 16 % of individuals surveyed. The expansion of the PAR boundary in one Y haplotype includes at least one additional gene. Homologs of this gene are involved in male gametophyte and pollen development in other plant species. PMID- 25711307 TI - Association of the LINGO2-related SNP rs10968576 with body mass in a cohort of elderly Swedes. AB - Genome-wide association studies (GWAS) have identified common genetic factors influencing body mass as well as body adiposity. The functional implications of these loci are currently under investigation. Intense scrutiny of the body mass associated FTO locus revealed age-specific effects, or a weakened effect in elderly populations. In this study, we aimed to determine the effects of single nucleotide polymorphisms (SNPs) representing 35 GWAS-identified body mass- and adiposity-associated genetic loci. In our analysis, 949 participants of the Prospective Investigation of the Vasculature in Uppsala Seniors cohort were included. All participants were born between 1920 and 1924. Data were available for 474 male and 475 female participants at age 70 and 380 male and 390 female participants at age 75. Genetic associations with BMI and change in BMI from age 70 to 75 were analyzed. In our analysis, rs10968576, an intronic SNP within the LINGO2 (LERN3, LRRN6C) gene, was associated with body mass in a cross section of elderly Swedes at age 70. This is the first study to replicate the association of a LINGO2-related genetic variant with body mass in an independent cohort of elderly citizens. PMID- 25711308 TI - terMITEs: miniature inverted-repeat transposable elements (MITEs) in the termite genome (Blattodea: Termitoidae). AB - Transposable elements (TEs) are discrete DNA sequences which are able to replicate and jump into different genomic locations. Miniature inverted-repeats TEs (MITEs) are non-autonomous DNA elements whose origin is still poorly understood. Recently, some MITEs were found to contain core repeats that can be arranged in tandem arrays; in some instances, these arrays have even given rise to satellite DNAs in the (peri)centromeric region of the host chromosomes. I report the discovery and analysis of three new MITEs found in the genome of several termite species (hence the name terMITEs) in two different families. For two of the MITEs (terMITE1-Tc1/mariner superfamily; terMITE2-piggyBac superfamily), evidence of past mobility was retrieved. Moreover, these two MITEs contained core repeats, 16 bp and 114 bp long respectively, exhibiting copy number variation. In terMITE2, the tandem duplication appeared associated with element degeneration, in line with a recently proposed evolutionary model on MITEs and the origin of tandem arrays. Concerning their genomic distribution, terMITE1 and terMITE3 appeared more frequently inserted close to coding regions while terMITE2 was mostly associated with TEs. Although MITEs are commonly distributed in coding regions, terMITE2 distribution is in line with that of other insects' piggyBac-related elements and of other small TEs found in termite genomes. This has been explained through insertional preference rather than through selective processes. Data presented here add to the knowledge on the poorly exploited polyneopteran genomes and will provide an interesting framework in which to study TEs' evolution and host's life history traits. PMID- 25711309 TI - Changes of Osvaldo expression patterns in germline of male hybrids between the species Drosophila buzzatii and Drosophila koepferae. AB - Hybridization between different genomes is a source of genomic instability, sometimes associated with transposable element (TE) mobilization. Previous work showed that hybridization between the species Drosophila buzzatii and Drosophila koepferae induced mobilization of different (TEs), the Osvaldo retrotransposon being the most unstable. However, we ignore the mechanisms involved in this transposition release in interspecific hybrids. In order to disentangle the mechanisms involved in this process, we performed Osvaldo expression studies in somatic and germinal tissues from hybrids and parental species. There was a trend towards increased Osvaldo expression in the somatic tissues of hybrid females and males, which was always significant in males compared to the parental species D. buzzatii but, not in females compared to maternal species D. koepferae. There were massive changes of Osvaldo expression in the testes, which varied depending on the hybrid generation and family. Moreover, Osvaldo hybridization signals, restricted to the apical and primary spermatocyte regions in parents, occupied broader region in the hybrids. In ovaries, there were no significant differences in Osvaldo expression rates between hybrids and the maternal species D. koepferae. The transcript location was restricted to ovarian nurse cells in both parents and hybrids, undetectable in some hybrids. This research highlights first, the existence of putative complex deregulation mechanisms different between sexes and cell types and second, disruption of Osvaldo activity particularly evident in testes from sterile hybrid males. Deeper studies of the total transcriptome in hybrids and parental species are necessary to gain a better knowledge of the TE deregulation pathways in hybrids. PMID- 25711310 TI - Four genetic variants interact to confer susceptibility to atopic dermatitis in Chinese Han population. AB - Atopic dermatitis is a chronic inflammatory skin disease and is affected by environmental and genetic factors. Gene-gene/environment interactions are strongly believed to contribute to the genetic risk of common diseases. A number of gene-environment interactions of atopic dermatitis were performed. However, there are few comprehensive investigations on the gene-gene (or genetic variants) interactions for atopic dermatitis. We explored the association model of 6 single nucleotide polymorphisms (SNPs) which were most significant (P < 10E-05) in our previous genome wide association study (GWAS) for atopic dermatitis, and search for the possible genetic variant interactions based on the previous GWAS data using Generalized Multifactor Dimensionality Reduction and Plink 1.07 in the combined sample of 4,636 cases and 13,559 controls. The most significant associated evidence was observed under dominant model for SNPs rs3126085, rs12085366, and rs7701890, recessive model for SNP rs17173197, and additive model for SNPs rs2393903 and rs6010620. Three significant pair-way interactions were observed, including PRKAG2 and FLG SNPs (rs17173197 * rs3126085, P combined = 1.11E-15), PRKAG2 and TMEM232-SLC25A46 SNPs (rs17173197 * rs7701890, P combined = 2.22E-15), PRKAG2 and TNFRSF6B-ZGPAT SNPs (rs17173197 * rs6010620, P combined = 6.66E-16). Besides, a three-way significant interaction among PRKAG2, TMEM232 SLC25A46 and TNFRSF6B-ZGPAT SNPs (rs17173197 * rs7701890 * rs6010620, P combined = 5.99E-15) was observed in this study. These four genetic variant interactions confer susceptibility to atopic dermatitis, and highlight the genetic variant interactions in the etiology of atopic dermatitis in Chinese Han population. PMID- 25711311 TI - Resuming anticoagulation after brain hemorrhage while on warfarin treatment: INR at the time of bleeding should be taken into consideration. PMID- 25711312 TI - Use of administrative data in healthcare research. AB - Health research based on administrative data and the availability of regional or national administrative databases has been increasing in recent years. We will discuss the general characteristics of administrative data and specific aspects of their use for health research purposes, indicating their advantages and disadvantages. Some fields of application will be discussed and described through examples. PMID- 25711313 TI - Prevalence and significance of two major inherited thrombophilias in infective endocarditis. AB - The pathogenesis of infective endocarditis (IE) involves activation of the haemostasis system at the site of endocardial defects. Whether prothrombotic conditions are associated with IE by enhancing early vegetation formation is unknown. In this study, we assess the prevalence and clinical significance of two major conditions associated with thrombophilia in patients with IE. Mutations G20210A of the prothrombin (PTH) gene and G1691A of factor V (FV Leiden) gene were studied by means of allele-specific polymerase chain reaction in 203 IE patients, 175 valvular heart disease (VHD) patients and 200 blood donors (BD). IE patients show higher cumulative frequencies of mutated alleles of PTH and FV Leiden [6.4 vs 3.25 %; OR 2.03 (95 % CI 0.97-3.66); p = 0.047] compared to BD, but not VHD. Device-related IE is enriched with FV Leiden, and prosthetic valve IE with PTH mutations (allele frequency 8.3 vs 2.2 % in native valve IE; p = 0.021). Vegetation size and embolic complications are not influenced by the examined thrombophilias. A trend for a higher mortality was observed in IE patients with any of the two thrombophilias studied. Our data do not support a role for factor V Leiden and G20210A prothrombin gene mutations in the susceptibility to IE. Whether any of these genetic polymorphisms play a role in a specific subtype of IE needs to be re-examined in larger studies. PMID- 25711314 TI - The infarct-sparing effect of IB-MECA against myocardial ischemia/reperfusion injury in mice is mediated by sequential activation of adenosine A3 and A 2A receptors. AB - Conflicting results exist regarding the role of A3 adenosine receptors (A3ARs) in mediating cardioprotection during reperfusion following myocardial infarction. We hypothesized that the effects of the A3AR agonist IB-MECA to produce cardioprotection might involve activation of other adenosine receptor subtypes. C57Bl/6 (B6), A3AR KO, A2AAR KO, and A2AAR KO/WT bone marrow chimeric mice were assigned to 12 groups undergoing either hemodynamic studies or 45 min of LAD occlusion and 60 min of reperfusion. IB-MECA (100 MUg/kg) or vehicle was administered by iv bolus 5 min before reperfusion. Radioligand binding assays showed that IB-MECA has high affinity for the mouse A3AR (K i = 0.17 +/- 0.05 nM), but also can bind with lower affinity to the A1AR (9.0 +/- 2.4 nM) or the A2AAR (56.5 +/- 10.2 nM). IB-MECA caused bi-phasic hemodynamic changes, which were completely absent in A3AR KO mice and were modified by A2AAR blockade or deletion. IB-MECA stimulated histamine release, increased heart rate, and significantly reduced IF size in B6 mice from 61.5 +/- 1.4 to 48.6 +/- 2.4% of risk region (RR; 21% reduction, p < 0.05) but not in A3AR KO mice. Compared to B6, A3AR KO mice had significantly reduced IF size (p < 0.05). In B6/B6 bone marrow chimeras, IB-MECA caused a 47% reduction of IF size (from 47.3 +/- 3.9 to 24.7 +/- 4.5, p < 0.05). However, no significant cardioprotective effect of IB MECA was observed in A2AARKO/B6 mice, which lacked A2AARs only on their bone marrow-derived cells. Activation of A3ARs induces a bi-phasic hemodynamic response, which is partially mediated by activation of A2AARs. The cardioprotective effect of IB-MECA is due to the initial activation of A3AR followed by activation of A2AARs in bone marrow-derived cells. PMID- 25711318 TI - Community perspective on the INSIGHT Strategic Timing of AntiRetroviral Treatment (START) trial. AB - Determining when to start antiretroviral treatment (ART) is vitally important for people living with HIV. Yet the optimal point at which to start to maximize clinical benefit remains unknown. In the absence of randomized studies, current guidelines rely on conflicting observational data and expert opinion, and consequently diverge on this point. In the USA, ART is recommended irrespective of CD4 cell count. The World Health Organization now recommends starting ART at a CD4 cell count of 500 cells/MUL, while the threshold for the UK and South Africa remains at 350 cells/MUL. The Strategic Timing of AntiRetroviral Treatment (START) study, one of the largest clinical trials on the treatment of HIV infection, will answer this question. START compares two treatment strategies: immediate treatment at a CD4 cell count of 500 cells/MUL or higher versus deferring treatment until the CD4 cell count decreases to 350 cells/MUL or until AIDS develops. START includes seven substudies, five of which will clarify the relative contributions of HIV and ART in common comorbidities. START is fully enrolled and expected to be completed in 2016. HIV advocates support the study's design and have been involved from inception to enrolment. The trial will produce rigorous data on the benefits and risks of earlier treatment. It will inform policy and treatment advocacy globally, benefitting the health of HIV-positive people. PMID- 25711319 TI - Challenges, successes and patterns of enrolment in the INSIGHT Strategic Timing of AntiRetroviral Treatment (START) trial. AB - OBJECTIVES: The aim of this report is to describe the challenges, successes and patterns of enrolment in the Strategic Timing of AntiRetroviral Treatment (START) study. METHODS: START is a collaboration of many partners with central coordination provided by the protocol team, the statistical and data management centre (SDMC), the International Network for Strategic Initiatives in Global HIV Trials (INSIGHT) network leadership, international coordinating centres and site coordinating centres. The SDMC prepared reports on study accrual, baseline characteristics and site performance that allowed monitoring of enrolment and data quality and helped to ensure the successful enrolment of this large international trial. We describe the pattern of enrolment and challenges faced during the enrolment period of the trial. RESULTS: An initial pilot phase began in April 2009 and established feasibility of accrual at 101 sites. In August 2010, funding approval for an expanded definitive phase led to the successful accrual of 4688 participants from 215 sites in 35 countries by December 2013. Challenges to accrual included regulatory delays (e.g. national/local ethics approval and drug importation approval) and logistical obstacles (e.g. execution of contracts with pharmaceutical companies, setting up of a central drug repository and translation of participant materials). The personal engagement of investigators, strong central study coordination, and frequent and transparent communication with site investigators, community members and participants were key contributing factors to this success. CONCLUSIONS: Accrual into START was completed in a timely fashion despite multiple challenges. This success was attributable to the efforts of site investigators committed to maintaining study equipoise, transparent and responsive study coordination, and community involvement in problem-solving. PMID- 25711320 TI - Reported consent processes and demographics: a substudy of the INSIGHT Strategic Timing of AntiRetroviral Treatment (START) trial. AB - OBJECTIVES: Efforts are needed to improve informed consent of participants in research. The Strategic Timing of AntiRetroviral Therapy (START) study provides a unique opportunity to study the effect of length and complexity of informed consent documents on understanding and satisfaction among geographically diverse participants. METHODS: Interested START sites were randomized to use either the standard consent form or the concise consent form for all of the site's participants. RESULTS: A total of 4473 HIV-positive participants at 154 sites world-wide took part in the Informed Consent Substudy, with consent given in 11 primary languages. Most sites sent written information to potential participants in advance of clinic visits, usually including the consent form. At about half the sites, staff reported spending less than an hour per participant in the consent process. The vast majority of sites assessed participant understanding using informal nonspecific questions or clinical judgment. CONCLUSIONS: These data reflect the interest of START research staff in evaluating the consent process and improving informed consent. The START Informed Consent Substudy is by far the largest study of informed consent intervention ever conducted. Its results have the potential to impact how consent forms are written around the world. PMID- 25711321 TI - Demographic and HIV-specific characteristics of participants enrolled in the INSIGHT Strategic Timing of AntiRetroviral Treatment (START) trial. AB - OBJECTIVES: The risks and benefits of initiating antiretroviral treatment (ART) at high CD4 cell counts have not been reliably quantified. The Strategic Timing of AntiRetroviral Treatment (START) study is a randomized international clinical trial that compares immediate with deferred initiation of ART for HIV-positive individuals with CD4 cell counts above 500 cells/MUL. We describe the demographics, HIV-specific characteristics and medical history of this cohort. METHODS: Data collected at baseline include demographics, HIV-specific laboratory values, prior medical diagnoses and concomitant medications. Baseline characteristics were compared by geographical region, gender and age. RESULTS: START enrolled 4685 HIV-positive participants from 215 sites in 35 countries. The median age is 36 years [interquartile range (IQR) 29-44 years], 27% are female, and 45% self-identify as white, 30% as black, 14% as Latino/Hispanic, 8% as Asian and 3% as other. The route of HIV acquisition is reported as men who have sex with men in 55% of participants, heterosexual sex in 38%, injecting drug use in 1% and other/unknown in 5%. Median time since HIV diagnosis is 1.0 year (IQR 0.4 3.0 years) and the median CD4 cell count and HIV RNA values at study entry are 651 cells/MUL (IQR 584-765 cells/MUL) and 12,754 HIV RNA copies/mL (IQR 3014 43,607 copies/mL), respectively. CONCLUSIONS: START has enrolled a diverse group of ART-naive individuals with high CD4 cell counts who are comparable to the HIV positive population from the regions in which they were enrolled. The information collected with this robust study design will provide a database with which to evaluate the risks and benefits of early ART use for many important outcomes. PMID- 25711322 TI - Clinical and demographic factors associated with low viral load in early untreated HIV infection in the INSIGHT Strategic Timing of AntiRetroviral Treatment (START) trial. AB - OBJECTIVES: A small subset of HIV-positive adults have low HIV RNA in the absence of therapy, sometimes for years. Clinical factors associated with low HIV RNA in early infection have not been well defined. METHODS: We assessed factors associated with low plasma HIV RNA level at study entry in the Strategic Timing of AntiRetroviral Treatment (START) trial. All START participants had a baseline HIV RNA assessment within 60 days prior to randomization. The key covariables considered for this analysis were race, and hepatitis B virus (HBV) and hepatitis C virus (HCV) status. We assessed factors associated with HIV RNA <= 50 and <= 400 HIV-1 RNA copies/mL using logistic regression. Because of the strong association between region of randomization and baseline low HIV RNA, analyses were stratified by region. RESULTS: We found that, of 4676 eligible participants randomized in START with a baseline HIV RNA assessment, 113 (2.4%) had HIV RNA <= 50 copies/mL at baseline, and a further 257 (5.5%) between 51 and 400 copies/mL. We found that HIV exposure routes other than male homosexual contact, higher high density lipoprotein (HDL) cholesterol levels, higher CD4 cell counts, and higher CD4:CD8 ratio were associated with increased odds of low HIV RNA. HCV antibody positivity was borderline statistically significantly associated with low HIV RNA. Race and HBV surface antigen positivity were not significantly associated with low HIV RNA. CONCLUSIONS: In a modern cohort of individuals with early untreated HIV infection, we found that HIV exposure routes other than male homosexual contact and higher HDL cholesterol were associated with increased odds of low HIV RNA. PMID- 25711323 TI - Baseline cardiovascular risk in the INSIGHT Strategic Timing of AntiRetroviral Treatment (START) trial. AB - OBJECTIVES: The Strategic Timing of AntiRetroviral Treatment (START) trial has recruited antiretroviral-naive individuals with high CD4 cell counts from all regions of the world. We describe the distribution of cardiovascular disease (CVD) risk factors, overall and by geographical region, at study baseline. METHODS: The distribution of CVD risk factors was assessed and compared by geographical region among START participants who had a baseline electrocardiogram (n = 4019; North America, 11%; Europe/Australia/Israel, 36%; South America, 26%; Asia, 4%; Africa, 23%; median age 36 years; 26% female). RESULTS: About 58.3% (n = 2344) of the participants had at least one CVD risk factor and 18.9% (n = 761) had two or more. The most common CVD risk factors were current smoking (32%), hypertension (19.3%) and obesity (16.5%). There were significant differences in the prevalence of CVD risk factors among geographical regions. The prevalence of at least one risk factor across regions was as follows: North America, 70.0%; Europe/Australia/Israel, 65.1%; South America, 49.4%; Asia, 37.0%; Africa, 55.8% (P-value < 0.001). Significant regional differences were also observed when risk factors were used as part of the Framingham and Data Collection on Adverse events of Anti-HIV Drugs (D:A:D) risk scores or used to define a favourable risk profile. CONCLUSIONS: CVD risk factors are common among START participants, and their distribution varies by geographical region. Better understanding of how and why CVD risk factors develop in people with HIV infection and their geographical distributions could shed light on appropriate strategies for CVD prevention and may inform the interpretation of the results of START, as CVD is expected to be a major fraction of the primary endpoints observed. PMID- 25711324 TI - Kidney disease in antiretroviral-naive HIV-positive adults with high CD4 counts: prevalence and predictors of kidney disease at enrolment in the INSIGHT Strategic Timing of AntiRetroviral Treatment (START) trial. AB - OBJECTIVES: HIV infection has been associated with an increased risk of chronic kidney disease (CKD). Little is known about the prevalence of CKD in individuals with high CD4 cell counts prior to initiation of antiretroviral therapy (ART). We sought to address this knowledge gap. METHODS: We describe the prevalence of CKD among 4637 ART-naive adults (mean age 36.8 years) with CD4 cell counts > 500 cells/MUL at enrolment in the Strategic Timing of AntiRetroviral Treatment (START) study. CKD was defined by estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m(2) and/or dipstick urine protein >= 1+. Logistic regression was used to identify baseline characteristics associated with CKD. RESULTS: Among 286 [6.2%; 95% confidence interval (CI) 5.5%, 6.9%] participants with CKD, the majority had isolated proteinuria. A total of 268 participants had urine protein >= 1+, including 41 with urine protein >= 2+. Only 22 participants (0.5%) had an estimated glomerular filtration rate < 60 mL/min/1.73 m(2) , including four who also had proteinuria. Baseline characteristics independently associated with CKD included diabetes [adjusted odds ratio (aOR) 1.73; 95% CI 1.05, 2.85], hypertension (aOR 1.82; 95% CI 1.38, 2.38), and race/ethnicity (aOR 0.59; 95% CI 0.37, 0.93 for Hispanic vs. white). CONCLUSIONS: We observed a low prevalence of CKD associated with traditional CKD risk factors among ART-naive clinical trial participants with CD4 cell counts > 500 cells/MUL. PMID- 25711325 TI - Transmission risk behaviour at enrolment in participants in the INSIGHT Strategic Timing of AntiRetroviral Treatment (START) trial. AB - OBJECTIVES: A proportion of HIV-positive people have condomless sex. Antiretroviral treatment (ART) reduces infectiousness, but a substantial proportion of HIV-diagnosed people are not yet on ART. We describe baseline self reported risk behaviours in ART-naive Strategic Timing of AntiRetroviral Treatment (START) trial participants. METHODS: All START participants completed a risk behaviour questionnaire. Data were collected on sociodemographics, lifestyle factors, health and wellbeing status and clinical status. Recent sexual behaviour and HIV transmission beliefs in the context of ART were also assessed. The primary interest was in condomless sex with serodifferent partners (CLS-D) in the past two months. RESULTS: A total of 4601 of 4685 HIV-positive participants (98%) completed the questionnaire [2559 men who have sex with men (MSM), 803 heterosexual men and 1239 women]. Region of recruitment was Europe/Israel, 33%; South America/Mexico, 25%; Africa, 22%; other, 21%. Median age was 36 years [interquartile range (IQR) 29, 44 years]. Forty-five per cent reported white ethnicity and 31% black ethnicity. Two per cent had HIV viral load < 50 HIV-1 RNA copies/mL. Seventeen per cent (767 of 4601) reported CLS-D; 20% of MSM compared with 10% of heterosexual men and 14% of women. MSM were also more likely to report multiple CLS-D partners. Possible risk limitation measures (reported by more than half of those who had CLS-D) were seropositioning (receptive anal CLS-D only) or withdrawal (insertive anal CLS-D always without ejaculation). CLS-D was more commonly reported by participants from South America/Mexico and North America compared with Europe; among heterosexual men and women CLS-D was also more commonly reported among participants from Africa compared with Europe. Knowledge of ART impact on transmission risk was low. CONCLUSIONS: A substantial minority recruited to the START study reported CLS-D at baseline. CLS-D reporting was higher in MSM than heterosexuals and varied significantly according to region of recruitment. A substantial proportion of MSM reporting CLS-D appear to take transmission risk limitation measures. PMID- 25711326 TI - Global HIV-1 transmitted drug resistance in the INSIGHT Strategic Timing of AntiRetroviral Treatment (START) trial. AB - OBJECTIVES: HIV-1 transmitted drug resistance (TDR) in treatment-naive individuals is a well-described phenomenon. Baseline genotypic resistance testing is considered standard of care in most developed areas of the world. The aim of this analysis was to characterize HIV-1 TDR and the use of resistance testing in START trial participants. METHODS: In the Strategic Timing of AntiRetroviral Treatment (START) trial, baseline genotypic resistance testing results were collected at study entry and analysed centrally to determine the prevalence of TDR in the study population. Resistance was based on a modified 2009 World Health Organization definition to reflect newer resistance mutations. RESULTS: Baseline resistance testing was available in 1946 study participants. Higher rates of testing occurred in Europe (86.7%), the USA (81.3%) and Australia (89.9%) as compared with Asia (22.2%), South America (1.8%) and Africa (0.1%). The overall prevalence of TDR was 10.1%, more commonly to nonnucleoside reverse transcriptase inhibitors (4.5%) and nucleoside reverse transcriptase inhibitors (4%) compared with protease inhibitors (2.8%). The most frequent TDR mutations observed were M41L, D67N/G/E, T215F/Y/I/S/C/D/E/V/N, 219Q/E/N/R, K103N/S, and G190A/S/E in reverse transcriptase, and M46I/L and L90M in protease. By country, the prevalence of TDR was highest in Australia (17.5%), France (16.7%), the USA (12.6%) and Spain (12.6%). No participant characteristics were identified as predictors of the presence of TDR. CONCLUSIONS: START participants enrolled in resource-rich areas of the world were more likely to have baseline resistance testing. In Europe, the USA and Australia, TDR prevalence rates varied by country. PMID- 25711327 TI - Quality of life assessment among HIV-positive persons entering the INSIGHT Strategic Timing of AntiRetroviral Treatment (START) trial. AB - OBJECTIVES: With HIV treatment prolonging survival and HIV infection now managed as a chronic illness, quality of life (QOL) is important to evaluate in persons living with HIV (PLWH). We assessed at study entry the QOL of antiretroviral naive PLWH with CD4 counts > 500 cells/MUL in the Strategic Timing of AntiRetroviral Treatment (START) clinical trial. METHODS: QOL was assessed with: (1) a visual analogue scale (VAS) for self-assessment of overall current health; (2) the Short-Form 12-Item Version 2 Health Survey((r)) (SF-12V2), for which responses are summarized into eight individual QOL domains plus component summary scores for physical health [the Physical Health Component Summary (PCS)] and mental health [the Mental Health Component Summary (MCS)]. The VAS and eight domain scores were scaled from 0 to 100. Mean QOL measures were calculated overall and by demographic, clinical and behavioural factors. RESULTS: A total of 4631 participants completed the VAS and 4119 the SF-12. The mean VAS score (with standard deviation) was 80.9 +/- 15.7. Mean SF-12 domain scores were lowest for vitality (66.3 +/- 26.4) and mental health (68.6 +/- 21.4), and highest for physical functioning (89.3 +/- 23.0) and bodily pain (88.0 +/- 21.4). Using multiple linear regression, PCS scores were lower (P < 0.001) for Asians, North Americans, female participants, older participants, and those with less education, longer duration of known HIV infection, alcoholism/substance dependence and body mass index >= 30 kg/m(2) . MCS scores were highest (P < 0.001) for Africans, South Americans and older participants, and lowest for female participants, current smokers and those with alcoholism/substance dependence. CONCLUSIONS: In this primarily healthy population, QOL was mostly favourable, emphasizing that it is important that HIV treatments do not negatively impact QOL. Self-assessed physical health summary scores were higher than mental health scores. Factors such as older age and geographical region had different effects on perceived physical and mental health. PMID- 25711328 TI - Factors associated with neurocognitive test performance at baseline: a substudy of the INSIGHT Strategic Timing of AntiRetroviral Treatment (START) trial. AB - OBJECTIVES: We describe neuropsychological test performance (NP) in antiretroviral treatment (ART)-naive HIV-positive individuals with CD4 cell counts above 500 cells/MUL. METHODS: In a neurology substudy of the International Network for Strategic Initiatives in Global HIV Trials (INSIGHT) Strategic Timing of AntiRetroviral Treatment (START) study, eight neurocognitive tests were administered. The primary measure of NP was the quantitative NP z-score (QNPZ-8), the average of the z-scores for the eight tests. Associations of baseline factors with QNPZ-8 scores were assessed by multiple regression. Mild neurocognitive impairment (NCI) was defined as z-scores < -1 in at least two of six cognitive domains. RESULTS: A total of 608 participants had a median age of 34 years; 11% were women and 15% were black; the median time since HIV diagnosis was 0.9 years; the median CD4 cell count was 633 cells/MUL; 19.9% had mild NCI. Better NP was independently associated with younger age, being white, higher body mass index (0.10 per 10 kg/m(2) higher), and higher haematocrit percentage (0.19 per 10% higher). Worse NP was associated with longer time since HIV diagnosis (-0.17 per 10 years), diabetes (-0.29) and higher Framingham risk score (-0.15 per 10 points higher). QNPZ-8 scores differed significantly between geographical locations, with the lowest scores in Brazil and Argentina/Chile. CONCLUSIONS: This is the largest study of NP in ART-naive HIV-positive adults with CD4 counts > 500 cells/MUL. Demographic factors and diabetes were most strongly associated with NP. Unmeasured educational/sociocultural factors may explain geographical differences. Poorer NP was independently associated with longer time since HIV diagnosis, suggesting that untreated HIV infection might deleteriously affect NP, but the effect was small. PMID- 25711329 TI - Assessment of arterial elasticity among HIV-positive participants with high CD4 cell counts: a substudy of the INSIGHT Strategic Timing of AntiRetroviral Treatment (START) trial. AB - OBJECTIVES: Both HIV infection and antiretroviral therapy (ART) may increase cardiovascular disease (CVD) risk. Assessments of vascular function and structure can be used to study the pathogenesis and progression of CVD, including the effects of ART and other interventions. The objective of this report is to understand methods to assess vascular (dys)function and report our experience in the Arterial Elasticity Substudy in the Strategic Timing of AntiRetroviral Treatment (START) trial. METHODS: We review literature and analyze baseline data from the Arterial Elasticity Substudy, which estimated vascular (dys)function through analysis of the diastolic blood pressure (BP) waveform. Linear regression was used to study cross-sectional associations between baseline clinical factors and small or large arterial elasticity. RESULTS: Arterial elasticity measurement was chosen for its improved measurement reproducibility over other methodologies and the potential of small arterial elasticity to predict clinical risk. Analysis of baseline data demonstrates that small artery elasticity is impaired (lower) with older age and differs by race and between geographical regions. No HIV specific factors studied remained significantly associated with arterial elasticity in multivariate models. CONCLUSIONS: Longitudinal analyses in this substudy will provide essential randomized data with which to study the effects of early ART initiation on the progression of vascular disease among a diverse global population. When combined with future biomarker analyses and clinical outcomes in START, these findings will expand our understanding of the pathogenesis of HIV-related CVD. PMID- 25711330 TI - Pulmonary function in an international sample of HIV-positive, treatment-naive adults with CD4 counts > 500 cells/MUL: a substudy of the INSIGHT Strategic Timing of AntiRetroviral Treatment (START) trial. AB - OBJECTIVES: The aim of the study was to describe the prevalence and correlates of chronic obstructive pulmonary disease (COPD) in a multicentre international cohort of persons living with HIV (PLWH). METHODS: We performed a cross-sectional analysis of adult PLWH, naive to HIV treatment, with baseline CD4 cell count > 500 cells/MUL enrolled in the Pulmonary Substudy of the Strategic Timing of AntiRetroviral Treatment (START) trial. We collected standardized, quality controlled spirometry. COPD was defined as forced expiratory volume in 1 s:forced vital capacity (FEV1 :FVC) ratio less than the lower limit of normal. RESULTS: Among 1026 participants from 80 sites and 20 countries, the median age was 36 [interquartile range (IQR) 30, 44] years, 29% were female, and the median time since HIV diagnosis was 1.2 (IQR 0.4, 3.5) years. Baseline median CD4 cell count was 648 (IQR 583, 767) cells/MUL, median viral load was 4.2 (IQR 3.5, 4.7) log10 HIV-1 RNA copies/mL, and 10% had a viral load <= 400 copies/mL despite lack of HIV treatment. Current/former/never smokers comprised 28%/11%/61% of the cohort, respectively. COPD was present in 6.8% of participants, and varied by age, smoking status and region. Forty-eight per cent of those with COPD reported lifelong nonsmoking. In multivariable regression, age and pack-years of smoking had the strongest associations with FEV1 :FVC ratio (P < 0.0001). There was a significant effect of region on FEV1 :FVC ratio (P = 0.010). CONCLUSIONS: Our data suggest that, among PLWH who were naive to HIV treatment and had CD4 cell counts > 500 cells/MUL, smoking and age were important factors related to COPD. Smoking cessation should remain a high global priority for clinical care and research in PLWH. PMID- 25711331 TI - Baseline prevalence and predictors of liver fibrosis among HIV-positive individuals: a substudy of the INSIGHT Strategic Timing of AntiRetroviral Treatment (START) trial. AB - OBJECTIVES: Liver disease is increasingly recognized in HIV-positive individuals, even among those without viral hepatitis, partly as a result of the recent availability of noninvasive methods of liver fibrosis assessment. The objective of this substudy is to compare the effects of early versus deferred antiretroviral therapy (ART) on liver fibrosis progression. METHODS: Sites in the Strategic Timing of AntiRetroviral Treatment (START) study with access to FibroScan(r) were invited to participate in the Liver Fibrosis Progression Substudy. All substudy participants underwent FibroScan(r) at baseline, and two noninvasive serum algorithms, APRI and FIB-4, were calculated. Demographic and liver-related information was collected for all START participants at baseline. RESULTS: A total of 230 participants were enrolled in the substudy (11.5% with hepatitis B or C virus coinfection), of whom 221 had a valid transient elastography (TE) result. The median TE score was 4.9 kPa [interquartile range (IQR) 4.3-6.0 kPa]. Seventeen patients (7.8%) [95% confidence interval (CI) 5.1 12.1%] had a TE score of > 7.2 kPa, indicating significant liver fibrosis. Baseline factors associated with higher TE scores in multivariate analysis were higher alanine aminotransferase (ALT) per 10 U/L (P = 0.045), higher log10 HIV RNA (P < 0.001) and Hispanic/Latino ethnicity (P = 0.01). TE correlated weakly with noninvasive markers. CONCLUSIONS: At baseline, significant liver fibrosis was observed in approximately 8% of participants, with higher ALT and HIV RNA the only clinical factors associated with increasing TE score. TE will be used annually to monitor fibrosis and evaluate the role of ART in further fibrosis progression. PMID- 25711317 TI - Why START? Reflections that led to the conduct of this large long-term strategic HIV trial. PMID- 25711332 TI - Prevalence of and risk factors for low bone mineral density in untreated HIV infection: a substudy of the INSIGHT Strategic Timing of AntiRetroviral Treatment (START) trial. AB - OBJECTIVES: HIV infection is associated with a higher prevalence of low bone mineral density (BMD) and fractures than that found in the general population. There are limited data in HIV-positive adults, naive to antiretroviral therapy (ART), with which to estimate the relative contribution of untreated HIV infection to bone loss. METHODS: The primary objective of the Strategic Timing of AntiRetroviral Treatment (START) Bone Mineral Density Substudy is to compare the effect of immediate versus deferred initial ART on bone. We evaluated traditional, demographic, HIV-related and immunological factors for their associations with baseline hip and lumbar spine BMD, measured by dual-energy X ray absorptiometry, using multiple regression. RESULTS: A total of 424 ART-naive participants were enrolled at 33 sites on six continents; the mean age was 34 years [standard deviation (SD) 10.1 years], 79.0% were nonwhite, 26.0% were women, and 12.5% had a body mass index (BMI) < 20 kg/m(2) . Mean (SD) Z-scores were -0.41 (0.94) at the spine and -0.36 (0.88) for total hip; 1.9% had osteoporosis and 35.1% had low BMD (hip or spine T-score < -1.0). Factors independently associated with lower BMD at the hip and spine were female sex, Latino/Hispanic ethnicity, lower BMI and higher estimated glomerular filtration rate. Longer time since HIV diagnosis was associated with lower hip BMD. Current or nadir CD4 cell count and HIV viral load were not associated with BMD. CONCLUSIONS: In this geographically and racially diverse population of ART-naive adults with normal CD4 cell counts, low BMD was common, but osteoporosis was rare. Lower BMD was significantly associated with traditional risk factors but not with CD4 cell count or viral load. PMID- 25711333 TI - Causes of the failure and the revision methods for congenital scoliosis due to hemivertebra. AB - The purpose of this study was to retrospectively investigate the causes of failure in the first operation and the revision procedure for patients with congenital scoliosis due to hemivertebra. Nineteen patients who underwent the revision operations because of failure in the first operation were included in this study. All the malformations were identified as fully segmented hemivertebra, including 16 cases in thoracolumbar vertebra (T10: three patients; T12: seven patients; L1: six patients), and three cases in thoracic vertebra (T8). The causes of failure in the first operation and the outcome of revision procedure for patients were retrospectively analyzed. All patients were successfully performed the personalized revision surgeries. The failure reasons of the first operation included limitations of the first operation procedure, no or incomplete resection of the malformed hemivertebra, improper operation during surgery, improper internal fixation material, and improper internal fixation scope. The average postoperative scoliosis Cobb's angle and kyphosis Cobb's angle were corrected from 54.1 degrees preoperatively to 23.1 degrees postoperatively, and 59.3 degrees preoperatively to 25.8 degrees postoperatively, respectively. The average postoperative distance between the C7 plumb line and the center sacral vertical line was decreased from 2.5 cm preoperatively to 1.5 cm postoperatively. The average follow-up period was 2.2 years. No serious complication was observed. The cause of the failure of the first operations for the congenital scoliosis due to hemivertebra is verified. Our study may provide a basis for the treatment of congenital scoliosis due to hemivertebra. PMID- 25711335 TI - Telehealth-based cardiac rehabilitation: A solution to the problem of access? PMID- 25711334 TI - Surface characterization of dialyzer polymer membranes by imaging ToF-SIMS and quantitative XPS line scans. AB - The surfaces of polymeric dialyzer membranes consisting of polysulfone and polyvinylpyrrolidone were investigated regarding the lateral distribution and quantitative surface composition using time-of-flight secondary-ion-mass spectrometry and x-ray photoelectron spectroscopy. Knowledge of the distribution and composition on the outer surface region is of utmost importance for understanding the biocompatibility of such dialyzer membranes. Both flat membranes and hollow fiber membranes were studied. PMID- 25711336 TI - Emerging energy and environmental applications of vertically-oriented graphenes. AB - Graphene nanosheets arranged perpendicularly to the substrate surface, i.e., vertically-oriented graphenes (VGs), have many unique morphological and structural features that can lead to exciting properties. Plasma-enhanced chemical vapor deposition enables the growth of VGs on various substrates using gas, liquid, or solid precursors. Compared with conventional randomly-oriented graphenes, VGs' vertical orientation on the substrate, non-agglomerated morphology, controlled inter-sheet connectivity, as well as sharp and exposed edges make them very promising for a variety of applications. The focus of this tutorial review is on plasma-enabled simple yet efficient synthesis of VGs and their properties that lead to emerging energy and environmental applications, ranging from energy storage, energy conversion, sensing, to green corona discharges for pollution control. PMID- 25711337 TI - Neuroimaging in neonatal seizures. AB - Seizures are the most common sign of neurological dysfunction in full-term neonates, with an incidence estimated at 0.15-3.5/1,000 live births. Neonatal seizures often reflect severe underlying brain injury and are associated with high rates of mortality and morbidity. Prognosis is primarily determined by the nature, site and extent of the underlying aetiology, making accurate diagnosis and identification of associated brain lesions essential. Data on neuroimaging in newborns presenting with seizures is limited and most studies report on MRI findings in infants with a specific underlying problem, such as hypoxic-ischaemic encephalopathy, stroke or metabolic disorders. The aim of this review is to discuss the spectrum of neuroimaging findings in full-term newborns presenting with seizures, divided into subgroups with different underlying aetiologies. A standard neonatal MRI protocol is presented. PMID- 25711338 TI - Simultaneous inhibition of fatty acid amide hydrolase and monoacylglycerol lipase shares discriminative stimulus effects with Delta9-tetrahydrocannabinol in mice. AB - Monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH) inhibitors exert preclinical effects indicative of therapeutic potential (i.e., analgesia). However, the extent to which MAGL and FAAH inhibitors produce unwanted effects remains unclear. Here, FAAH and MAGL inhibition was examined separately and together in a Delta(9)-tetrahydrocannabinol (Delta(9)-THC; 5.6 mg/kg i.p.) discrimination assay predictive of subjective effects associated with cannabis use, and the relative contribution of N-arachidonoyl ethanolamine (AEA) and 2 arachidonoylglycerol (2-AG) in the prefrontal cortex, hippocampus, and caudate putamen to those effects was examined. Delta(9)-THC dose-dependently increased Delta(9)-THC appropriate responses (ED50 value = 2.8 mg/kg), whereas the FAAH inhibitors PF-3845 [N-3-pyridinyl-4-[[3-[[5-(trifluoromethyl)-2 pyridinyl]oxy]phenyl]methyl]-1-piperidinecarboxamide] and URB597 [(3' (aminocarbonyl)[1,1'-biphenyl]-3-yl)-cyclohexylcarbamate] or a MAGL inhibitor JZL184 [4-nitrophenyl-4-(dibenzo[d][1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1 carboxylate] alone did not substitute for the Delta(9)-THC discriminative stimulus. The nonselective FAAH/MAGL inhibitors SA-57 [4-[2-(4 chlorophenyl)ethyl]-1-piperidinecarboxylic acid 2-(methylamino)-2-oxoethyl ester] and JZL195 [4-nitrophenyl 4-(3-phenoxybenzyl)piperazine-1-carboxylate] fully substituted for Delta(9)-THC with ED50 values equal to 2.4 and 17 mg/kg, respectively. Full substitution for Delta(9)-THC was also produced by a combination of JZL184 and PF-3845, but not by a combination of JZL184 and URB597 (i.e., 52% maximum). Cannabinoid receptor type 1 antagonist rimonabant attenuated the discriminative stimulus effects of Delta(9)-THC, SA-57, JZL195, and the combined effects of JZL184 and PF-3845. Full substitution for the Delta(9)-THC discriminative stimulus occurred only when both 2-AG and AEA were significantly elevated, and the patterns of increased endocannabinoid content were similar among brain regions. Overall, these results suggest that increasing both endogenous 2-AG and AEA produces qualitatively unique effects (i.e., the subjective effects of cannabis) that are not obtained from increasing either 2-AG or AEA separately. PMID- 25711339 TI - Species differences in hepatobiliary disposition of taurocholic acid in human and rat sandwich-cultured hepatocytes: implications for drug-induced liver injury. AB - The bile salt export pump (BSEP) plays an important role in bile acid excretion. Impaired BSEP function may result in liver injury. Bile acids also undergo basolateral efflux, but the relative contributions of biliary (CLBile) versus basolateral efflux (CLBL) clearance to hepatocellular bile acid excretion have not been determined. In the present study, taurocholic acid (TCA; a model bile acid) disposition was characterized in human and rat sandwich-cultured hepatocytes (SCH) combined with pharmacokinetic modeling. In human SCH, biliary excretion of TCA predominated (CLBile = 0.14 +/- 0.04 ml/min per g liver; CLBL = 0.042 +/- 0.019 ml/min per g liver), whereas CLBile and CLBL contributed approximately equally to TCA hepatocellular excretion in rat SCH (CLBile = 0.34 +/- 0.07 ml/min per g liver; CLBL = 0.26 +/- 0.07 ml/min per g liver). Troglitazone decreased TCA uptake, CLBile, and CLBL; membrane vesicle assays revealed for the first time that the major metabolite, troglitazone sulfate, was a noncompetitive inhibitor of multidrug resistance-associated protein 4, a basolateral bile acid efflux transporter. Simulations revealed that decreased CLBile led to a greater increase in hepatic TCA exposure in human than in rat SCH. A decrease in both excretory pathways (CLBile and CLBL) exponentially increased hepatic TCA in both species, suggesting that 1) drugs that inhibit both pathways may have a greater risk for hepatotoxicity, and 2) impaired function of an alternate excretory pathway may predispose patients to hepatotoxicity when drugs that inhibit one pathway are administered. Simulations confirmed the protective role of uptake inhibition, suggesting that a drug's inhibitory effects on bile acid uptake also should be considered when evaluating hepatotoxic potential. Overall, the current study precisely characterized basolateral efflux of TCA, revealed species differences in hepatocellular TCA efflux pathways, and provided insights about altered hepatic bile acid exposure when multiple transport pathways are impaired. PMID- 25711342 TI - Erratum: the palatability of cereal based nutritional supplements in cancer patients. AB - [This corrects the article on p. 48 in vol. 3, PMID: 24527420.]. PMID- 25711340 TI - A South African mixed race lip/philtrum guide for diagnosis of fetal alcohol spectrum disorders. AB - The adverse effects of maternal alcohol use during pregnancy represent a spectrum of growth restriction, facial dysmorphology, and neurocognitive challenges in the offspring. The continuum of diagnoses is referred to as fetal alcohol spectrum disorders (FASD). Short palpebral fissures, a smooth philtrum, and a thin vermilion border of the upper lip comprise the three cardinal facial features of FASD. Early attempts to define a smooth philtrum and thin vermilion border of the upper lip were subjective. Astley and colleagues introduced a 5-point Likert scaled lip/philtrum guide based on Caucasian North American subjects as an objective tool for the evaluation of the facial dysmorphology in FASD. This Caucasian guide has been incorporated into all current diagnostic schemes for FASD. However, broad international clinical experience with FASD indicates racial and ethnic differences with respect to the facial morphology. Because of the substantial number of children with FASD in South Africa among the Cape Coloured (mixed race) population in the Western Cape Province, we developed a specific lip/philtrum guide for that population. The guide incorporates a 45-degree view of the philtrum that enables an enhanced 3-dimensional evaluation of philtral height not possible with a frontal view alone. The guide has proven to be a more specific and sensitive tool for evaluation of the facial dysmorphology of FASD in the Cape Coloured population than the use of the previous North American Caucasian guide and points to the utility of racial and ethnic-specific dysmorphology tools in the evaluation of children with suspected FASD. PMID- 25711341 TI - Percutaneous fetal cardiac catheterization technique for stenting the foramen ovale in a midgestation lamb model. AB - BACKGROUND: Intact or highly restricted intra-atrial septum can be reliably diagnosed in the human fetus as early as 22 to 24 weeks of gestation. Fetal interventions targeting the atrial septum have used a direct approach through the atrial wall. Here, we report stenting of the foramen ovale with a large, open cell stent via percutaneous access through the fetal hepatic vein in a sheep model. METHODS AND RESULTS: In 5 fetal sheep of 109 to 111 days of gestation (term, 147 days), the fetal hepatic vein was punctured percutaneously under ultrasound guidance and a 13.3-cm 14-gauge intravenous catheter was inserted. After catheterization of the inferior vena cava, right atrium, foramen ovale, and left atrium with a guidewire and 1.8F to 2.6F tapered catheter, a self expandable, 8*12-mm flexible open-cell stent was positioned in an unrestricted foramen ovale. Flow and fetal well-being were documented for 45 minutes after the procedure. Access to the left atrium was achieved in all 5 animals and all survived. In 4 animals, the stent was successfully positioned in the foramen ovale. One fetus was born at term and euthanized on day 3: postmortem examination confirmed the patency of the stent. The other 3 fetuses were well after being monitored by ultrasound for 45 minutes. In 1 animal, the stent dislodged immediately after release obstructing the mitral valve. This fetus developed ascites and was euthanized after 4 days. CONCLUSIONS: It is feasible to safely advance a large diameter, self-expandable, open-cell design stent into the fetal atrial septum via a percutaneous access route through the fetal hepatic vein. PMID- 25711343 TI - Sub-wavelength terahertz beam profiling of a THz source via an all-optical knife edge technique. AB - Terahertz technologies recently emerged as outstanding candidates for a variety of applications in such sectors as security, biomedical, pharmaceutical, aero spatial, etc. Imaging the terahertz field, however, still remains a challenge, particularly when sub-wavelength resolutions are involved. Here we demonstrate an all-optical technique for the terahertz near-field imaging directly at the source plane. A thin layer (<100 nm-thickness) of photo carriers is induced on the surface of the terahertz generation crystal, which acts as an all-optical, virtual blade for terahertz near-field imaging via a knife-edge technique. Remarkably, and in spite of the fact that the proposed approach does not require any mechanical probe, such as tips or apertures, we are able to demonstrate the imaging of a terahertz source with deeply sub-wavelength features (<30 MUm) directly in its emission plane. PMID- 25711344 TI - Geoecohydrological mechanisms couple soil and leaf water dynamics and facilitate species coexistence in shallow soils of a tropical semiarid mixed forest. AB - Trees growing on shallow rocky soils must have exceptional adaptations when underlying weathered bedrock has no deep fractures for water storage. Under semiarid conditions, hydrology of shallow soils is expected to decouple from plant hydrology, as soils dry out as a result of rapid evaporation and competition for water increases between coexisting tree species. Gas exchange and plant-water relations were monitored for 15 months for Pinus cembroides and Quercus potosina tree species in a tropical semiarid forest growing on c. 20-cm deep soils over impermeable volcanic bedrock. Soil and leaf water potential maintained a relatively constant offset throughout the year in spite of high intra-annual fluctuations reaching up to 5 MPa. Thus, hydrology of shallow soils did not decouple from hydrology of trees even in the driest period. A combination of redistribution mechanisms of water stored in weathered bedrock and hypodermic flow accessible to oak provided the source of water supply to shallow soils, where most of the actively growing roots occurred. This study demonstrates a unique geoecohydrological mechanism that maintains a tightly coupled hydrology between shallow rocky soils and trees, as well as species coexistence in this mixed forest, where oak facilitates water access to pine. PMID- 25711345 TI - Vogt-Koyanagi-Harada disease in 3-year-old boy. PMID- 25711347 TI - Buffering effect of parental engagement on the relationship between corporal punishment and children's emotional/behavioral problems. AB - BACKGROUND: Previous research has established links between corporal punishment and children's developmental problems, but few studies have investigated the moderating effect of positive parenting between corporal punishment and children's developmental difficulties in detail. This study investigated the buffering effect of parental engagement on the association between corporal punishment and children's emotional/behavioral problems. METHODS: The main caregivers completed the Evaluation of Environmental Stimulation Scale (EES), which is an evaluation of daily parenting behaviors, and the Strengths and Difficulties Questionnaire (SDQ), which evaluates children's developmental problems. RESULTS: Corporal punishment was associated with worse emotional and behavioral problems in children, whereas parental engagement in games or sports was associated with fewer emotional symptoms. Similarly, parental engagement in homework or housework significantly moderated the association between corporal punishment and children's behavioral problems. CONCLUSIONS: Parental engagement positively moderated the association between parental corporal punishment and children's developmental difficulties. This association varied with child gender. PMID- 25711346 TI - Quantitative relationship between liver fat content and metabolic syndrome in obese children and adolescents. AB - OBJECTIVE: Previous studies have shown a significant association between quantified liver fat content (LFC) and metabolic syndrome (MetS) in adults, but the nature of this association in obese paediatric populations is unclear. The aim of this study was to investigate the quantitative relationship of LFC to MetS and its individual components in obese children and adolescents. DESIGN: A population-based cross-sectional study. PATIENTS AND MEASUREMENTS: One hundred and eighty-nine Chinese obese paediatric subjects aged 5-16 years were enrolled. Measurements included MetS components, as defined by the Chinese-specific version of the International Diabetes Foundation MetS criteria (MetS-CHN2012), and LFC using proton magnetic resonance spectroscopy. RESULTS: LFC was significantly higher in subjects with MetS [median 9.7% (interquartile range 4.5-19.9%)] than without MetS [5.7% (2.0-12.8%)] (P < 0.01). LFC was also positively associated with the total number of MetS components (P for trend <0.01). In analyses adjusted for traditional risk factors, increasing levels of LFC were associated with a greater risk of MetS, hypertriglyceridaemia and low high-density lipoprotein cholesterol (P < 0.05 for all associations), but were not associated with risk of hyperglycaemia or hypertension. CONCLUSIONS: In obese Chinese paediatric patients, quantitative measures of LFC are positively associated with the risk of MetS, hypertriglyceridaemia and low high-density lipoprotein cholesterol, independent of traditional risk factors. These findings suggest that quantitatively measured LFC may be a clinically useful marker for identifying obese paediatric who are at increased risk of developing MetS and its components. PMID- 25711348 TI - Efficacy and cost-effectiveness: A study of different treatment approaches in a tertiary pain centre. AB - BACKGROUND: Chronic pain is considered to be a complex phenomenon, involving an interrelation of biological, psychosocial and sociocultural factors. Currently, no single treatment or therapy can address all aspects of this pathology. In our expert tertiary pain centre, we decide to assess the effectiveness of four treatments for chronic pain classically proposed in our daily clinical work: physiotherapy; psycho-education; physiotherapy combined with psycho-education; and self-hypnosis/self-care learning. METHODS: This study included 527 chronic pain patients, with a mean duration of pain of 10 years. Patients were allocated either to one of the four pre-cited treatment groups or to the control group. Pain intensity, quality of life, pain interference, anxiety and depression were assessed before and after treatment. RESULTS: This study revealed a significant positive effect on pain interference and anxiety in patients included in the physiotherapy combined with psycho-education group, after 20 sessions spread over 9 months of treatment. The most prominent results were obtained for patients allocated to the self-hypnosis/self-care group, although they received only six sessions over a 9-month period. These patients showed significant benefits in the areas of pain intensity, pain interference, anxiety, depression and quality of life. CONCLUSIONS: This clinical report demonstrates the relevance of biopsychosocial approaches in the improvement of pain and psychological factors in chronic pain patients. The study further reveals the larger impact of self hypnosis/self-care learning treatment, in addition to a cost-effectiveness benefit of this treatment comparative to other interventions. PMID- 25711349 TI - Right ventricular myocardial deformation patterns in children with congenital heart disease associated with right ventricular pressure overload. AB - AIMS: Longitudinal wall motion of the right ventricle (RV) has been thoroughly studied in patients with RV dysfunction. However, circumferential strain of the RV free wall has yet to be investigated. Therefore, this study was conducted to assess the utility of RV free wall circumferential strain. METHODS AND RESULTS: Strain profile curves were obtained using speckle tracking echocardiography from the subcostal left ventricular (LV) short-axis view in 30 normal children (normal group) and 25 patients with RV pressure overload (RVO group). The time-strain curves of three individual segmental (anterior, lateral, and inferior segments) and global circumferential deformations were evaluated. RV ejection fraction (RVEF), RV systolic pressure (RVSP), and RV fractional area change obtained in the four-chamber view and LV short-axis view [RVFAC (4CH) and RVFAC (SAX), respectively] were measured, and their relationships with RV free wall deformation were assessed. In the normal group, circumferential strain was significantly lower in the anterior segment than in the other segments. The inferior segment had a significantly larger strain than the other segments in the RVO group. Circumferential strain was predominant over longitudinal RV free wall strain in the RVO group (-18.4 +/- 3.9 vs. -14.2 +/- 3.8%, respectively; P < 0.005), whereas no significant difference between them was observed in the normal group (-23.0 +/- 3.9 vs. -22.4 +/- 4.7%, respectively). Global circumferential strain had a significantly higher correlation with RVFAC (4CH), RVFAC (SAX), RVEF, and RVSP than global longitudinal strain (P < 0.05 for all). CONCLUSION: RV free wall circumferential strain provides better information about RV function than longitudinal strain in children with RVO. PMID- 25711350 TI - Sympathetic denervation is associated with microvascular dysfunction in non infarcted myocardium in patients with cardiomyopathy. AB - AIMS: Sympathetic denervation typically occurs in the infarcted myocardium and is associated with sudden cardiac death. Impaired innervation was also demonstrated in non-infarcted myocardium in ischaemic and dilated cardiomyopathy (ICMP and DCMP). Factors affecting sympathetic nerve integrity in remote myocardium are unknown. Perfusion abnormalities, even in the absence of epicardial coronary artery disease, may relate to sympathetic dysfunction. This study was aimed to assess the interrelations of myocardial blood flow (MBF), contractile function, and sympathetic innervation in non-infarcted remote myocardium. METHODS AND RESULTS: Seventy patients with ICMP or DCMP and LVEF <=35% were included. [(15)O]H2O- and [(11)C]hydroxyephedrine (HED) PET was performed to quantify resting MBF, hyperaemic MBF, and sympathetic innervation. Cardiovascular magnetic resonance (CMR) imaging was performed to assess left ventricular function, mass, wall thickening, and scar size. Wall thickening, [(11)C]HED retention index (RI), and MBF were assessed in remote segments without scar, selected on CMR. [(11)C]HED RI was correlated with resting MBF (r = 0.41, P < 0.001) and hyperaemic MBF (r = 0.55, P < 0.001) in remote myocardium in both ICMP and DCMP. In addition, LV volumes (r = -0.40, P = 0.001), LV mass (r = -0.31, P = 0.008), and wall thickening (r = 0.45, P < 0.001) correlated with remote [(11)C]HED RI. Multivariable analysis revealed that hyperaemic MBF (B = 0.79, P < 0.001), wall thickening (B = 0.01, P = 0.03), and LVEDV (B = -0.03, P = 0.02) were independent predictors for remote [(11)C]HED RI. CONCLUSION: Hyperaemic MBF is independently associated with sympathetic innervation in non-infarcted remote myocardium in patients with ICMP and DCMP. This suggests that microvascular dysfunction might be an important factor related to sympathetic nerve integrity. Whether impaired hyperaemic MBF is the primary cause of this relation remains unclear. PMID- 25711352 TI - Delayed longitudinal myocardial function recovery after dobutamine challenge as a novel presentation of myocardial dysfunction in type 2 diabetic patients without angiographic coronary artery disease. AB - AIMS: Since myocardial dysfunction in diabetic patients without coronary artery disease (CAD) is subtle at rest, the assessment during dobutamine stress echocardiography (DSE) may be more sensitive for detection of myocardial involvement. We assessed systolic function of the left ventricle during all stages of DSE in 3 diabetic patients free of significant CAD using state-of-the art speckle-tracking quantification. METHODS AND RESULTS: We performed DSE in 250 patients with angina recording views during baseline (0), peak (1), and recovery phase (2). All patients had coronary anatomy verified with >= 50% stenosis in left main and >= 70% in other arteries considered as significant. In this analysis, we included 25 subjects with diabetes mellitus (DM) but without CAD (mean age 62 +/- 8) and compared them with an age- and sex-matched group of 85 controls without DM and CAD (mean age 60 +/- 9). Global peak systolic longitudinal strain (PSLS) of the left ventricle was obtained by automated function imaging (AFI) at rest, peak, and recovery phase of DSE. The global PSLS was similar in both groups at baseline (-17.3 +/- 4.0% in diabetics vs. -18.7 +/- 3.3% in controls, P = ns) and at peak stage of DSE (-16.4 +/- 4.5% in diabetics vs. -17.9 +/- 4.2% in controls, P = ns), whereas at recovery absolute value was lower in patients with DM (-15.3 +/- 3.2% vs. -17.2 +/- 3.3%, P = 0.01). CONCLUSION: Peak systolic longitudinal strain measured by AFI during recovery of DSE was impaired in diabetic patients. It may reflect longer time needed for full restoration of myocardial systolic function in this group of subjects. PMID- 25711351 TI - Myocardial inflammation on cardiovascular magnetic resonance predicts left ventricular function recovery in children with recent dilated cardiomyopathy. AB - AIMS: To analyse the predictive role of myocardial inflammation assessed by cardiac magnetic resonance (CMR) on the outcome of recently diagnosed dilated cardiomyopathy in children. METHODS AND RESULTS: Over a period of 4 years, 66 children underwent CMR within 2 weeks after the diagnosis of dilated cardiomyopathy. CMR sequences sensitive for oedema, hyperaemia, and irreversible injury were applied: unenhanced cine steady-state free precession (SSFP), black blood-prepared T1-weighted images, T2-weighted images, gadolinium-enhanced T1 weighted images (EGE), and late gadolinium-enhanced (LGE) images. Inflammatory cardiomyopathy defined as the presence of at least two CMR criteria was diagnosed in 31/66 children (CMR positive) while no criterion was present in the remaining 33 (CMR-negative). Only two patients had one positive criterion and were excluded from subsequent analysis. After a mean follow-up of 24 months, LV function recovery (LV ejection fraction >55%) was more frequent in the CMR-positive group (24 vs. 11, P < 0.05). The presence of myocardial inflammation and elevated troponin levels at baseline were the two predictors of LV function recovery with an odds ratio of 3.76 (P = 0.02) and 2.76 (P = 0.03), respectively, in a logistic regression model. Persisting LGE was rare in patients of the CMR-positive group at control CMR (6/22) and was never observed in the CMR-negative group (0/16). CONCLUSION: The presence of myocardial inflammation on CMR at time of diagnosis of a dilated cardiomyopathy in children is a strong predictor of LV recovery. PMID- 25711353 TI - Myocardial strain measurement with feature-tracking cardiovascular magnetic resonance: normal values. AB - AIMS: Myocardial deformation is a key to clinical decision-making. Feature tracking cardiovascular magnetic resonance (FT-CMR) provides quantification of motion and strain using standard steady-state in free-precession (SSFP) imaging, which is part of a routine CMR left ventricular (LV) study protocol. An accepted definition of a normal range is essential if this technique is to enter the clinical arena. METHODS AND RESULTS: One hundred healthy individuals, with 10 men and women in each of 5 age deciles from 20 to 70 years, without a history of cardiovascular disease, diabetes, renal impairment, or family history of cardiovascular disease, and with a normal stress echocardiogram, underwent FT-CMR assessment of LV myocardial strain and strain rate using SSFP cines.Peak systolic longitudinal strain (Ell) was -21.3 +/- 4.8%, peak systolic circumferential strain (Ecc) was -26.1 +/- 3.8%, and peak systolic radial strain (Err) was 39.8 +/- 8.3%. On Bland-Altman analyses, peak systolic Ecc had the best inter-observer agreement (bias 0.63 +/- 1.29% and 95% CI -1.90 to 3.16) and peak systolic Err the least inter-observer agreement (bias 0.13 +/- 6.41 and 95% CI -12.44 to 12.71). There was an increase in the magnitude of peak systolic Ecc with advancing age, which was greatest in subjects over the age of 50 years (R(2) = 0.11, P = 0.003). There were significant gender differences (P < 0.001) in peak systolic Ell, with a greater magnitude of deformation in females (-22.7%) than in males (-19.3%). CONCLUSION: Normal values for myocardial strain measurements using FT-CMR are provided. All circumferential and longitudinal based variables had excellent intra- and inter-observer variability. PMID- 25711354 TI - Three-dimensional echocardiography guidance in case of papillary fibroelastoma complicating transaortic valve implantation. PMID- 25711355 TI - Benign primary cardiac neoplasm with intense FDG uptake. PMID- 25711356 TI - Moderate activity and fitness, not sedentary time, are independently associated with cardio-metabolic risk in U.S. adults aged 18-49. AB - This cross-sectional study is one of the first to examine and compare the independent associations of objectively measured sedentary time, moderate to vigorous physical activity (MVPA) and fitness with cardio-metabolic risk factors. We studied 543 men and women (aged 18-49 years) from the NHANES 2003-2004 survey. Sedentary time and MVPA were measured by accelerometry. Fitness was assessed with a submaximal treadmill test. Cardio-metabolic risk factors included: waist circumference (WC), BMI, blood pressure, fasting glucose, HDL- and non HDL cholesterol, triglycerides (TG), and C-reactive protein (CRP). Sedentary time, MVPA and fitness were used as predictors for the cardio-metabolic outcomes in a multiple regression analysis. Standardized regression coefficients were computed. Results show that sedentary time was associated with HDL-cholesterol (beta= 0.080, p=0.05) and TG (beta=0.080, p=0.03). These results became non-significant after adjustment for MVPA and fitness. MVPA was associated with WC (beta=-0.226), BMI (beta=-0.239), TG (beta=-0.108) and HDL-cholesterol (beta=0.144) (all p<0.05). These results remained significant after adjustment for sedentary time and fitness. Fitness was associated with WC (beta=-0.287), BMI (beta=-0.266), systolic blood pressure (beta=-0.159), TG (beta=-0.092), and CRP (beta=-0.130) (all p<0.05). After adjustment for sedentary time and MVPA these results remained significant. These differences in relative importance of sedentary time, MVPA and fitness on cardio-metabolic-risk are important in the design of prevention programs. In this population, the strength of the associations between MVPA and fitness with cardio-metabolic markers appeared to be similar; both MVPA and fitness showed independent associations with cardio-metabolic risk factors. In contrast, sedentary time showed no independent associations with cardio-metabolic risk after correction for fitness and MVPA. PMID- 25711357 TI - Impact of a risk management plan on Legionella contamination of dental unit water. AB - The study aimed to assess the prevalence of Legionella spp. in dental unit waterlines of a dental clinic and to verify whether the microbiological parameters used as indicators of water quality were correlated with Legionella contamination. A risk management plan was subsequently implemented in the dental health care setting, in order to verify whether the adopted disinfection protocols were effective in preventing Legionella colonization. The water delivered from syringes and turbines of 63 dental units operating in a dental clinic, was monitored for counts of the heterotrophic bacteria P. aeruginosa and Legionella spp. (22 degrees C and 37 degrees C). At baseline, output water from dental units continuously treated with disinfection products was more compliant with the recommended standards than untreated and periodically treated water. However, continuous disinfection was still not able to prevent contamination by Legionella and P. aeruginosa. Legionella was isolated from 36.4%, 24.3% and 53.3% of samples from untreated, periodically and continuously treated waterlines, respectively. The standard microbiological parameters used as indicators of water quality proved to be unreliable as predictors of the presence of Legionella, whose source was identified as the tap water used to supply the dental units. The adoption of control measures, including the use of deionized water in supplying the dental unit waterlines and the application of a combined protocol of continuous and periodic disinfection, with different active products for the different devices, resulted in good control of Legionella contamination. The efficacy of the measures adopted was mainly linked to the strict adherence to the planned protocols, which placed particular stress on staff training and ongoing environmental monitoring. PMID- 25711358 TI - Gender differences in suicide prevention responses: implications for adolescents based on an illustrative review of the literature. AB - BACKGROUND: There are well-documented gender differences in adolescent suicidal behavior; death by suicide is more common in males, while nonfatal suicide attempts are more common among females. Over the past three decades, researchers have documented the effectiveness of a myriad of suicide prevention initiatives. However, there has been insufficient attention to which types of suicide prevention interventions are effective in changing attitudes and behaviors for young males and females. In this review of the literature, we consider common examples of primarily universal suicide prevention programs from three implementation settings: school-based, community-based, and healthcare-based. Our purpose is to delineate how the potential gender bias in such strategies may translate into youth suicide prevention efforts. METHODS: Research in which gender was found to moderate program success was retrieved through online databases. RESULTS: The results that feature programming effects for both males and females are provocative, suggesting that when gender differences are evident, in almost all cases, females seem to be more likely than males to benefit from existing prevention programming. CONCLUSIONS: We conclude by considering recommendations that may benefit males more directly. Implications for adolescent suicide prevention in particular are discussed. Personalization of suicide intervention is presented as a promising solution to reduce suicide rates. PMID- 25711359 TI - The Internet as a new tool in the rehabilitation process of patients--education in focus. AB - In the article we deal with the rehabilitation of patients using information technology, especially Internet support. We concentrate on two main areas in the IT support of rehabilitation: one of them is the support for individual therapy, the other one is providing patients with information, which is the basic step in emphasising individual responsibility. In the development of rehabilitation programmes, the knowledge of the IT professional and the therapist, in the IT support of web guidance, medical expertise plays the primary role. The degree of assistance involved in the rehabilitation process depends on the IT knowledge of medical (general practitioner, nursing staff) professionals as well. The necessary knowledge required in healing and development processes is imparted to professionals by a special (full-time) university training. It was a huge challenge for us to teach web-based information organisation skills to doctors and nurses, and it is also a complex task to put forward such an IT viewpoint to information specialists in order to create the foundations of the cooperation between IT and healthcare professionals. PMID- 25711360 TI - Environmental factors and WASH practices in the perinatal period in Cambodia: implications for newborn health. AB - Infection contributes to a significant proportion of neonatal death and disability worldwide, with the major burden occurring in the first week of life. Environmental conditions and gaps in water, sanitation and hygiene (WASH) practices may contribute to the risk of infection, particularly in settings where health centers are expanding to meet the growing demand for skilled care at birth and homes do not have adequate access to water and sanitation. A qualitative approach was used to understand the environmental context for infection prevention and control (IPC) and WASH associated behaviors in health centers where women give birth, and in homes of newborns, in a rural Cambodian province. Structured observations and focus group discussions revealed important gaps in optimal practices, and both structural and social barriers to maintaining IPC during delivery and post-partum. Solutions are available to address the issues identified, and tackling these could result in marked environmental improvement for quality of care and neonatal outcomes. Water, sanitation and hygiene in home and health center environments are likely to be important contributors to health and should be addressed in strategies to improve neonatal survival. PMID- 25711361 TI - Cigarette smoking and alcohol consumption among Chinese older adults: do living arrangements matter? AB - This study used five waves of the Chinese Longitudinal Healthy Longevity Survey to examine the relationship between living arrangements, smoking, and drinking among older adults in China from 1998-2008. We found that living arrangements had strong implications for cigarette smoking and alcohol consumption among the elderly. First, the likelihood of smoking was lower among older men living with children, and older women living either with a spouse, or with both a spouse and children; and the likelihood of drinking was lower among both older men, and women living with both a spouse and children, compared with those living alone. Second, among dual consumers (i.e., being a drinker and a smoker), the amount of alcohol consumption was lower among male dual consumers living with children, while the number of cigarettes smoked was higher among female dual consumers living with others, compared with those living alone. Third, among non-smoking drinkers, the alcohol consumption was lower among non-smoking male drinkers in all types of co-residential arrangements (i.e., living with a spouse, living with children, living with both a spouse and children, or living with others), and non smoking female drinkers living with others, compared with those living alone. Results highlighted the importance of living arrangements to cigarette smoking and alcohol consumption among Chinese elderly. Co-residential arrangements provided constraints on Chinese older adults' health-risk behaviors, and had differential effects for men and women. PMID- 25711362 TI - Impact of an educational hands-on project on the antimicrobial, antitumor and anti-inflammatory properties of plants on Portuguese students' awareness, knowledge, and competences. AB - Promoting environmental and health education is crucial to allow students to make conscious decisions based on scientific criteria. The study is based on the outcomes of an Educational Project implemented with Portuguese students and consisted of several activities, exploring pre-existent Scientific Gardens at the School, aiming to investigate the antibacterial, antitumor and anti-inflammatory properties of plant extracts, with posterior incorporation in soaps and creams. A logo and a webpage were also created. The effectiveness of the project was assessed via the application of a questionnaire (pre- and post-test) and observations of the participants in terms of engagement and interaction with all individuals involved in the project. This project increased the knowledge about autochthonous plants and the potential medical properties of the corresponding plant extracts and increased the awareness about the correct design of scientific experiments and the importance of the use of experimental models of disease. The students regarded their experiences as exciting and valuable and believed that the project helped to improve their understanding and increase their interest in these subjects and in science in general. This study emphasizes the importance of raising students' awareness on the valorization of autochthonous plants and exploitation of their medicinal properties. PMID- 25711363 TI - Recent advances in proteomic profiling of human blood: clinical scope. AB - A chromosome-centric approach in combination with targeted selected reaction monitoring-mass spectrometry analysis is one of the main approaches to study the human proteome. Measuring the size of the human plasma proteome includes both definition of all forms of proteins and quantitative measuring of the content of each protein form. The algorithm for measuring the proteome of canonical (master) proteins of chromosome 18 was created by combining a chromosome-centric approach and selected reaction monitoring-mass spectrometry. It can be scaled for all chromosomes to measure master proteins in the human blood plasma. Establishment of selected reaction monitoring-mass spectrometry diagnostic assays for quantitative measuring of the proteins associated with the development of diseases is a practical result. PMID- 25711364 TI - Sudden bilateral hearing loss after spinal anaesthesia. AB - BACKGROUND: Spinal anaesthesia is one of the most widely used regional anaesthesia techniques. Sudden bilateral hearing loss following spinal anaesthesia has only been reported in a few cases. CASE REPORT: This paper reports the case of a 50-year-old woman who developed sudden bilateral hearing loss following spinal anaesthesia for hallux valgus orthopaedic surgery. This is followed by a literature review. RESULTS: The patient's hearing improved almost completely on the morning of the 3rd day following surgery. No recurrence of hearing loss, tinnitus or vertigo was reported during the six-month follow-up period. CONCLUSION: Some complications regarding hearing may emerge after spinal anaesthesia. The possibility of hearing loss after spinal anaesthesia should be taken into consideration. Complaints such as hearing loss, tinnitus or vertigo should be taken seriously when reported, and the patient should be referred to an ENT clinic. This will ensure early diagnosis and treatment. PMID- 25711365 TI - Rising trends of obesity and abdominal obesity in 10 years of follow-up among Tehranian adults: Tehran Lipid and Glucose Study (TLGS). AB - OBJECTIVE: Some recent studies have shown stablity or declining trends in obesity while others still report increasing trends. The present study aimed to investigate the trends of obesity and abdominal obesity in Tehranian adults during a median follow-up of 10 years. DESIGN: Prospective cohort study. SETTING: Community-based data collection from the Tehran Lipid and Glucose Study (TLGS). SUBJECTS: Participants from four phases of the TLGS from 1999 to 2011 (n 10,368), aged >=20 years. RESULTS: The crude prevalence of obesity and abdominal obesity increased from 23.1% and 47.9% at baseline to 34.1% and 71.1% at the end of follow-up, respectively. Generalized estimating equation (GEE) models were used to analyse the correlated data and calculate the relative risks (RR). Risks of obesity and abdominal obesity increased over the whole study period for men (RR=1.62; 95% CI 1.49, 1.76 and RR=1.46; 95% CI 1.41, 1.52, respectively) and women (RR=1.24; 95% CI 1.19, 1.29 and RR=1.22; 95% CI 1.18, 1.27, respectively). These rising trends were observed in all subgroups regardless of age, marital status and educational level. CONCLUSIONS: Trends of obesity and abdominal obesity are increasing in Tehranian adults during a decade of follow-up in both genders and in all study subgroups. These results underscore the still growing obesity epidemic in the capital of Iran, calling for urgent action to educate people in lifestyle modifications and the need for effective preventive and educational strategies on obesity. PMID- 25711366 TI - Genetic factors in susceptibility to contact sensitivity. AB - There are clear differences in individual susceptibility to the development of contact allergies; some individuals readily become allergic to many chemicals, and others remain clinically tolerant of everything that they come into contact with. A great number of molecules and pathways can contribute to the perturbation by xenobiotics and the subsequent possible immune response. It is necessary to consider susceptibility in two ways: as allergen-specific and as non-allergen specific. It is likely that different receptor pathways and processes will be involved in the different forms of susceptibility. As investigations of the genetic control of such susceptibility have failed to identify major genetic control, it is likely that small contributions will be made by many components. Whereas genome-wide associations and transcriptome analyses may reveal genetic clues in the future, explanation of how/why the expression of multiple molecular components can be controlled in a coordinated fashion may follow from investigation of microRNAs. It is becoming clear that microRNAs can regulate the expression of multiple genes and even multiple components of biochemical pathways. PMID- 25711367 TI - Colonic stenting in acutely obstructed left-sided colon cancer Clinical evaluation and cost analysis. AB - AIM: This retrospective study aims to evaluate clinical and cost effectiveness of colonic stenting as a bridge to surgery and as a palliative treatment in acutely obstructed left-sided colon cancer. MATERIAL AND METHODS: Onehundred fortyfour patients were collected between 2006 and 2012, with acute left-sided malignant colonic obstruction with no evidence of peritonitis: 96 patients underwent surgical treatment, 48 underwent decompressive stenting. For the stenting we used self-expandable metallic stent in nitinol. RESULTS: Patients who had successful colonic stenting were 40, 8 underwent elective surgery within 10 days, 32 decompression stenting had only palliative intent. in 8/48 patients subjected to stenting decompression there was a technical failure (16%) and underwent emergency surgery. 40 patients had follow-up. at the time of observation 36 patients had a functioning stent, within 10 days 8 underwent elective definitive colonic resection with primary anastomosis trought videolaparoscopic thecnical, 4 (10%) had major complications and underwent emergency surgery. no patient of 40 in the stenting group required defunctioning stomas compared to 38 of 96 in emergency surgery group. we also compared the cost of decompressive stenting and emergency surgery treatment in acutely obstructed left-sided colon cancer referring to average cost of drg (1 and 2 code t-student test). the comparison of the average costs between decompressive stenting and emergency surgery was performed in the group of patients underwent palliative treatment separately from ones underwent radical treatment. CONCLUSION: Colonic stenting followed by elective surgery may be safer and cost-effective, comparing to emergency surgery for left-sided malignant colonic obstruction. KEY WORDS: Bowel obstruction, Colonic cancer, Colonic stenting. PMID- 25711368 TI - Gene silencing by CRISPR interference in mycobacteria. AB - Recombination-based tools for introducing targeted genomic mutations in Mycobacterium tuberculosis are not efficient due to higher rate of illegitimate recombination compared with homologous DNA exchange. Moreover, involvement of multiple steps and specialized reagents make these tools cost ineffective. Here we introduce a novel clustered regularly interspaced short palindromic repeat (CRISPR) interference (CRISPRi) approach that efficiently represses expression of target genes in mycobacteria. CRISPRi system involves co-expression of the catalytically dead form of RNA-guided DNA endonuclease from the type II CRISPR system known as dCas9 and the small guide RNA specific to a target sequence, resulting in the DNA recognition complex that interferes with the transcription of corresponding DNA sequence. We show that co-expression of the codon-optimized dCas9 of S. pyogenes with sequence-specific guide RNA results in complete repression of individual or multiple targets in mycobacteria. CRISPRi thus offers a simple, rapid and cost-effective tool for selective control of gene expression in mycobacteria. PMID- 25711370 TI - Social functioning using direct and indirect measures with children with High Functioning Autism, nonverbal learning disability, and typically developing children. AB - Social perception is an important underlying foundation for emotional development and overall adaptation. The majority of studies with children with High Functioning Autism (HFA) or nonverbal learning disabilities (NLD) evaluating social functioning have used measures of parent and/or teacher ratings. The present study utilized parent and teacher ratings of behavior as well as executive functioning in addition to direct measures of social perception. Three groups participated in this study (control [n = 38] HFA [n = 36], NLD [n = 31]). Results indicated that the HFA group experienced the most difficulty understanding emotional cues on the direct measure while both the HFA and NLD groups experienced difficulty with nonverbal cues. Significant difficulties were reported on the parent rating scale for sadness and social withdrawal for both clinical groups. Executive functioning was found to be particularly problematic for the clinical groups. The direct social perception measure was highly correlated with the measures of executive functioning and reflects the contribution that executive functions have on social functioning. These findings suggest that the clinical presentation on behavior rating scales may be very similar for children with HFA and NLD. Moreover, it appears that measures of executive functioning are sensitive to the clinical difficulties these groups experience. The findings also suggest there is a commonality in these disorders that warrants further investigation. PMID- 25711369 TI - Molecular Mechanisms Underlying the Regulation of the MFG-E8 Gene Promoter Activity in Physiological and Inflammatory Conditions. AB - Milk fat globule-EGF factor 8 (MFG-E8) is expressed by macrophages and plays an important role in attenuating inflammation and maintaining tissue homeostasis. Previously, we and others found that lipopolysaccharide (LPS) inhibits MFG-E8 gene expression in macrophages. Here, we characterized the 5'-flanking region of the mouse MFG-E8 gene. To functionally analyze the upstream regulatory region of the MFG-E8 gene, a series of luciferase reporter gene constructs containing deleted or mutated regulatory elements were prepared. Using the luciferase assay, we revealed that Sp1 binding motifs within the proximal promoter region were necessary for full activity of the MFG-E8 promoter, whereas AP-1 like binding sequence at -372 played a role in governing the promoter activity at a homeostatic level. With chromatin immunoprecipitation assay, we showed that Sp1 and c-Jun physically interact with the MFG-E8 promoter region in vivo. In addition, Sp1 was found to regulate the MFG-E8 promoter activity positively and c Jun negatively. Furthermore, we demonstrated that LPS inhibited MFG-E8 promoter activity via targeting Sp1 and AP-1-like motifs in the 5'-flanking region. Collectively, our data indicate that Sp1 and AP-1-related factors are involved in the regulation of MFG-E8 gene transcription by targeting their binding sites in the 5'-flanking region under physiological and inflammatory states. PMID- 25711371 TI - High-order non-linear optical effects in organic luminogens with aggregation induced emission. AB - 2,3-bis(4-(phenyl(4-(1,2,2-triphenylvinyl)phenyl)amino)phenyl)fumaronitrile (TTF) shows unique aggregation-induced emission (AIE) characteristics. Under the excitation of a 1560 nm femtosecond laser, simultaneous three-photon-excited luminescence (3PL) and third-harmonic-generation signals can be observed from its nanoaggregate and the solid state. TTF is further encapsulated with DSPE-mPEG (a type of amphiphilic polymer) to form AIE-active nanoparticles. 3PL brain imaging of mice is achieved based on the nanoparticles. PMID- 25711372 TI - Surface ECG f Wave Analysis of Dofetilide Drug Effect in the Atrium. AB - INTRODUCTION: The electrocardiogram (ECG) fibrillatory (f) wave characteristics in atrial fibrillation (AF) could provide important information regarding the efficacy of antiarrhythmic drug therapy. METHODS AND RESULTS: To measure the effects of dofetilide on the surface ECG f wave characteristics in patients with persistent AF, baseline and post-drug (2 hours after first dose and after multiple doses) ECGs in 31 patients with persistent AF admitted for dofetilide loading were evaluated. A QRST template subtraction algorithm was used to yield an atrial ECG. Fast Fourier transform analysis was performed to evaluate the maximum organizational index (OI), the dominant frequency (DF) in the lead with max OI, the median DF for all leads, and the vector magnitude f wave amplitude. Dofetilide reduced DF in the lead with the max OI (6.32 +/- 0.98 Hz at baseline vs. 4.83 +/- 0.63 Hz after final dose, P < 0.0001) and median DF (6.46 +/- 0.87 Hz vs. 4.92 +/- 0.62 Hz, P < 0.0001). Dofetilide also increased the maximum OI from 0.52 +/- 0.11 at baseline to 0.59 +/- 0.11 after final dose (P = 0.02). Of the 29 patients with long-term follow-up, the 22 (76%) with recurrent AF on dofetilide had a lower baseline DF in the lead with the max OI (6.01 +/- 1.08 vs. 6.89 +/- 0.46; P = 0.05). The change in DF after dofetilide did not correlate with the change in QTc interval. CONCLUSIONS: The standard ECG can be used to assess atrial rate in AF. This may be useful to assess antiarrhythmic drug effects for treatment of AF. PMID- 25711373 TI - Implications of In-Use Photostability: Proposed Guidance for Photostability Testing and Labeling to Support the Administration of Photosensitive Pharmaceutical Products, Part 2: Topical Drug Product. AB - Although essential guidance to cover the photostability testing of pharmaceuticals for manufacturing and storage is well-established, there continues to be a significant gap in guidance regarding testing to support the effective administration of photosensitive drug products. Continuing from Part 1, (Baertschi SW, Clapham D, Foti C, Jansen PJ, Kristensen S, Reed RA, Templeton AC, Tonnesen HH. 2013. J Pharm Sci 102:3888-3899) where the focus was drug products administered by injection, this commentary proposes guidance for testing topical drug products in order to support administration. As with the previous commentary, the approach taken is to examine "worst case" photoexposure scenarios in comparison with ICH testing conditions to provide practical guidance for the safe and effective administration of photosensitive topical drug products. PMID- 25711375 TI - An unconventional route to monodisperse and intimately contacted semiconducting organic-inorganic nanocomposites. AB - We developed an unconventional route to produce uniform and intimately contacted semiconducting organic-inorganic nanocomposites for potential applications in thermoelectrics. By utilizing amphiphilic star-like PAA-b-PEDOT diblock copolymer as template, monodisperse PEDOT-functionalized lead telluride (PbTe) nanoparticles were crafted via the strong coordination interaction between PAA blocks of star-like PAA-b-PEDOT and the metal moieties of precursors (i.e., forming PEDOT-PbTe nanocomposites). As the inner PAA blocks are covalently connected to the outer PEDOT blocks, the PEDOT chains are intimately and permanently tethered on the PbTe nanoparticle surface, thereby affording a well defined PEDOT/PbTe interface, which prevents the PbTe nanoparticles from aggregation, and more importantly promotes the long-term stability of PEDOT-PbTe nanocomposites. We envision that the template strategy is general and robust, and offers easy access to other conjugated polymer-inorganic semiconductor nanocomposites for use in a variety of applications. PMID- 25711376 TI - Central retinal vein occlusion caused by hyperviscosity syndrome in a young patient with Sjogren's syndrome and MALT lymphoma. AB - We report in this article central retinal vein occlusion (CRVO) caused by hyperviscosity syndrome (HVS) in a young patient with mucosa-associated lymphoid tissue (MALT) lymphoma and Sjogren's syndrome (SjS). A 32-year-old female was referred to our hospital from a local ophthalmologist. Fundoscopic examination and fluorescein angiogram revealed she had a serous retinal detachment in the right eye, together with CRVO (nonischemic type) in both eyes. Systemic examinations revealed hyperglobulinemia, increased blood viscosity, increased antinuclear antibody, increased rheumatoid arthritis particle aggregation, and increased anti-SS-A antibody. Together with a decreased salivary gland secretory function, she was eventually diagnosed as suffering from SjS. Moreover, a large cystic mass was found in the anterior mediastinum on the chest X-ray. Fine needle biopsy soon revealed she had MALT lymphoma. After eight courses of the administration of rituximab, cyclophosphamide, vincristine, and prednisolone (R CVP), most laboratory values were normalized, including blood viscosity. Cystic mass in the anterior mediastinum decreased, and the conditions of CRVO in both eyes had much improved. Decreased best-corrected visual acuity (BCVA) in the right eye was fully restored by sixth month. Not only MALT lymphoma, but also SjS can cause secondary hyperglobulinemia. Indeed, immunoelectrophoresis-serum test showed a polyclonal pattern of hyperglobulinemia. Therefore, SjS was thought to be the primary reason of hyperglobulinemia in this patient, which induced HVS, eventually causing CRVO. R-CVP therapy was effective for not only MALT lymphoma but also SjS accompanied with HVS. Consequently, R-CVP therapy led to the improvement of CRVO. PMID- 25711374 TI - Effect of chronic administration of phenobarbital, or bromide, on pharmacokinetics of levetiracetam in dogs with epilepsy. AB - BACKGROUND: Levetiracetam (LEV) is a common add-on antiepileptic drug (AED) in dogs with refractory seizures. Concurrent phenobarbital administration alters the disposition of LEV in healthy dogs. HYPOTHESIS/OBJECTIVES: To evaluate the pharmacokinetics of LEV in dogs with epilepsy when administered concurrently with conventional AEDs. ANIMALS: Eighteen client-owned dogs on maintenance treatment with LEV and phenobarbital (PB group, n = 6), LEV and bromide (BR group, n = 6) or LEV, phenobarbital and bromide (PB-BR group, n = 6). METHODS: Prospective pharmacokinetic study. Blood samples were collected at 0, 1, 2, 4, and 6 hours after LEV administration. Plasma LEV concentrations were determined by high pressure liquid chromatography. To account for dose differences among dogs, LEV concentrations were normalized to the mean study dose (26.4 mg/kg). Pharmacokinetic analysis was performed on adjusted concentrations, using a noncompartmental method, and area-under-the-curve (AUC) calculated to the last measured time point. RESULTS: Compared to the PB and PB-BR groups, the BR group had significantly higher peak concentration (Cmax ) (73.4 +/- 24.0 versus 37.5 +/ 13.7 and 26.5 +/- 8.96 MUg/mL, respectively, P < .001) and AUC (329 +/- 114 versus 140 +/- 64.7 and 98.7 +/- 42.2 h*MUg/mL, respectively, P < .001), and significantly lower clearance (CL/F) (71.8 +/- 22.1 versus 187 +/- 81.9 and 269 +/- 127 mL/h/kg, respectively, P = .028). CONCLUSIONS AND CLINICAL IMPORTANCE: Concurrent administration of PB alone or in combination with bromide increases LEV clearance in epileptic dogs compared to concurrent administration of bromide alone. Dosage increases might be indicated when utilizing LEV as add-on treatment with phenobarbital in dogs. PMID- 25711377 TI - Evaluation of the charge transfer efficiency of organic thin-film photovoltaic devices fabricated using a photoprecursor approach. AB - Recently, a unique 'photoprecursor approach' was reported as a new option to fabricate a p-i-n triple-layer organic photovoltaic device (OPV) through solution processes. By fabricating the p-i-n architecture using two kinds of photoprecursors and a [6,6]-phenyl C71 butyric acid methyl ester (PC71BM) as the donor and the acceptor, the p-i-n OPVs afforded a higher photovoltaic efficiency than the corresponding p-n devices and i-devices, while the photovoltaic efficiency of p-i-n OPVs depended on the photoprecursors. In this work, the charge transfer efficiency of the i-devices composed of the photoprecursors and PC71BM was investigated using high-sensitivity fluorescence microspectroscopy combined with a time-correlated single photon counting technique to elucidate the photovoltaic efficiency depending on the photoprecursors and the effects of the p i-n architecture. The spatially resolved fluorescence images and fluorescence lifetime measurements clearly indicated that the compatibility of the photoprecursors with PC71BM influences the charge transfer and the photovoltaic efficiencies. Although the charge transfer efficiency of the i-device was quite high, the photovoltaic efficiency of the i-device was much lower than that of the p-i-n device. These results imply that the carrier generation and carrier transportation efficiencies can be increased by fabricating the p-i-n architecture. PMID- 25711378 TI - Diketopyrrolopyrrole (DPP)-Based Donor-Acceptor Polymers for Selective Dispersion of Large-Diameter Semiconducting Carbon Nanotubes. AB - Low-bandgap diketopyrrolopyrrole (DPP)-based polymers are used for the selective dispersion of semiconducting single-walled carbon nanotubes (s-SWCNTs). Through rational molecular design to tune the polymer-SWCNT interactions, highly selective dispersions of s-SWCNTs with diameters mainly around 1.5 nm are achieved. The influences of the polymer alkyl side-chain substitution (i.e., branched vs linear side chains) on the dispersing yield and selectivity of s SWCNTs are investigated. Introducing linear alkyl side chains allows increased polymer-SWCNT interactions through close pi-pi stacking and improved C-H-pi interactions. This work demonstrates that polymer side-chain engineering is an effective method to modulate the polymer-SWCNT interactions and thereby affecting both critical parameters in dispersing yield and selectivity. Using these sorted s-SWCNTs, high-performance SWCNT network thin-film transistors are fabricated. The solution-deposited s-SWCNT transistors yield simultaneously high mobilities of 41.2 cm(2) V(-1) s(-1) and high on/off ratios of greater than 10(4) . In summary, low-bandgap DPP donor-acceptor polymers are a promising class of polymers for selective dispersion of large-diameter s-SWCNTs. PMID- 25711379 TI - Dynamic hydrogen bonding and DNA flexibility in minor groove binders: molecular dynamics simulation of the polyamide f-ImPyIm bound to the Mlu1 (MCB) sequence 5' ACGCGT-3' in 2:1 motif. AB - Molecular dynamics simulations of the DNA 10-mer 5'-CCACGCGTGG-3' alone and complexed with the formamido-imidazole-pyrrole-imidazole (f-ImPyIm) polyamide minor groove binder in a 2:1 fashion were conducted for 50 ns using the pbsc0 parameters within the AMBER 12 software package. The change in DNA structure upon binding of f-ImPyIm was evaluated via minor groove width and depth, base pair parameters of Slide, Twist, Roll, Stretch, Stagger, Opening, Propeller, and x displacement, dihedral angle distributions of zeta, epsilon, alpha, and gamma determined using the Curves+ software program, and hydrogen bond formation. The dynamic hydrogen bonding between the f-ImPyIm and its cognate DNA sequence was compared to the static image used to predict sequence recognition by polyamide minor groove binders. Many of the predicted hydrogen bonds were present in less than 50% of the simulation; however, persistent hydrogen bonds between G5/15 and the formamido group of f-ImPyIm were observed. It was determined that the DNA is wider in the Complex than without the polyamide binder; however, there is flexibility in this particular sequence, even in the presence of the f-ImPyIm as evidenced by the range of minor groove widths the DNA exhibits and the dynamics of the hydrogen bonding that binds the two f-ImPyIm ions to the minor groove. The Complex consisting of the DNA and the 2 f-ImPyIm binders shows slight fraying of the 5' end of the 10-mer at the end of the simulation, but the portion of the oligomer responsible for recognition and binding is stable throughout the simulation. Several structural changes in the Complex indicate that minor groove binders may have a more active role in inhibiting transcription than just preventing binding of important transcription factors. PMID- 25711380 TI - Growth velocity and weaning delta(15)N "Dips" during ontogeny in Macaca mulatta. AB - OBJECTIVES: A "dip" in the stable nitrogen isotope ratios (delta(15)N) of subadults in the late weaning/early post-weaning phase of growth and development has been observed. Speculatively, this is the mechanism of positive nitrogen balance operating among rapidly growing subadults. An alternate hypothesis for delta(15)N dips is that during weaning, subadults eat lower-(15)N foods than adults. METHODS: This study explores the role of positive nitrogen balance in affecting delta(15) N variation of growing subadults by comparing growth velocity with stable carbon isotope (delta(13)C) and delta(15)N ratios of blood serum from captive rhesus macaques (Macaca mulatta) (n = 14) with controlled diets during the first 10 months of life. RESULTS: During the first six months, delta(15)N values are inversely correlated with growth in some of the anthropometrics (weight and sagittal circumference). Dips in some infants' delta(15)N values below their mothers' values are observed at the end of the weaning period. However, during this time frame, delta(15)N values of the infants are not correlated with anthropometric indices. Serum stable isotope ratios of lactating and non-lactating adult females differ significantly. CONCLUSIONS: Growth in body mass and size explains some of the variation in infant delta(15)N values, but are not responsible for dips in the late weaning/early post-weaning phase. It is advised that future research evaluate the extent to which growth in other body systems affects nitrogen balance and delta(15)N dips during ontogeny, and expand on isotopic differences between lactating and non-lactating females. PMID- 25711384 TI - Synthesis and Evaluation of 3-(furo[2,3-b]pyridin-3-yl)-4-(1H-indol-3-yl) maleimides as Novel GSK-3beta Inhibitors and Anti-Ischemic Agents. AB - A series of novel 3-(furo[2,3-b]pyridin-3-yl)-4-(1H-indol-3-yl)-maleimides were designed, synthesized, and biologically evaluated for their GSK-3beta inhibitory activities. Most compounds showed favorable inhibitory activities against GSK 3beta protein. Among them, compounds 5n, 5o, and 5p significantly reduced GSK 3beta substrate tau phosphorylation at Ser396 in primary neurons, indicating inhibition of cellular GSK-3beta activity. In the in vitro neuronal injury models, compounds 5n, 5o, and 5p prevented neuronal death against glutamate, oxygen-glucose deprivation, and nutrient serum deprivation which are closely associated with cerebral ischemic stroke. In the in vivo cerebral ischemia animal model, compound 5o reduced infarct size by 10% and improved the neurological deficit. The results may provide new insights into the development of novel GSK 3beta inhibitors with potential neuroprotective activity against brain ischemic stroke. PMID- 25711386 TI - Langerhans cell histiocytosis in children with congenital anomalies: a population based record linkage study. AB - BACKGROUND: The etiology of Langerhans cell histiocytosis (LCH), a rare cancer like disorder of the immune system, is largely unknown although a genetic component has been suggested based on familial cases, and reports of chromosome instability and genetic mutation. Associations between various cancers and congenital anomalies have been reported and although congenital anomalies have been noted in children with LCH only one study to date has reported their frequency. An association between congenital anomalies and LCH may suggest a common etiological pathway, in particular, a genetic pathway. METHODS: Data from two coterminous registries in the same geographic region were used. All cases of LCH on the Northern Region Young Persons Malignant Disease Register diagnosed between 1985 and 2010 were cross-matched with live-born cases of congenital anomaly registered by the Northern Congenital Abnormality Survey. RESULTS: A total of 819,890 children and young people were born during 1985 to 2008. Of these, 13,799 (1.7%) had a congenital anomaly and 39 (0.005%) were diagnosed with LCH. Three LCH cases were identified among those with congenital anomalies, all three of whom had congenital heart disease. The relative risk of LCH for those with a congenital anomaly, compared with those without, was 4.87 (95% confidence interval, 1.50-15.81; p = 0.03). CONCLUSION: LCH was associated with congenital anomaly in a small but statistically significant number of patients, raising the possibility of a common genetic pathway in some cases. PMID- 25711387 TI - [Osteoarthritis patients often have cardiovascular diseases]. PMID- 25711385 TI - Cyclin-Dependent kinase 5 targeting prevents beta-Amyloid aggregation involving glycogen synthase kinase 3beta and phosphatases. AB - Inappropriate activation of cyclin-dependent kinase 5 (CDK5) resulting from proteolytic release of the activator fragment p25 from the membrane contributes to the formation of neurofibrillary tangles, beta-amyloid (betaA) aggregation, and chronic neurodegeneration. At 18 months of age, 3* Tg-AD mice were sacrificed after either 3 weeks (short term) or 1 year (long term) of CDK5 knockdown. In short-term-treated animals, CDK5 knockdown reversed betaA aggregation in the hippocampi via inhibitory phosphorylation of glycogen synthase kinase 3beta Ser9 and activation of phosphatase PP2A. In long-term-treated animals, CDK5 knockdown induced a persistent reduction in CDK5 and prevented betaA aggregation, but the effect on amyloid precursor protein processing was reduced, suggesting that yearly booster therapy would be required. These findings further validate CDK5 as a target for preventing or blocking amyloidosis in older transgenic mice. PMID- 25711388 TI - Iodine-catalyzed ammoxidation of methyl arenes. AB - The development of organic transformation using cheap and readily available substrates under mild conditions will be pivotal for green and sustainable synthetic organic chemistry. Concerning our continued interest in the cyanation reaction, a metal-free direct ammoxidation of readily available methyl arenes leading to nitriles was established under mild conditions. A series of aryl methanes especially heteroaryl methanes (30 examples) were applicable in moderate to good yields with good functionality tolerance. PMID- 25711389 TI - Methods for Preparation of MS2 Phage-Like Particles and Their Utilization as Process Control Viruses in RT-PCR and qRT-PCR Detection of RNA Viruses From Food Matrices and Clinical Specimens. AB - RNA viruses are pathogenic agents of many serious infectious diseases affecting humans and animals. The detection of pathogenic RNA viruses is based on modern molecular methods, of which the most widely used methods are the reverse transcription polymerase chain reaction (RT-PCR) and the real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR). All steps of RT-PCR and qRT-PCR should be strictly controlled to ensure the validity of obtained results. False-negative results may be caused not only by inhibition of RT or/and PCR steps but also by failure of the nucleic acid extraction step, particularly in the case of viral RNA extraction. The control of nucleic acid extraction generally involves the utilization of a non-pathogenic virus (process control virus) of similar structural properties to those of the target virus. Although in clinical samples the use of such process control virus is only recommended, in other kinds of settings such as food matrices its use is necessary. Currently, several different process control viruses are used for these purposes. Process control viruses can also be constructed artificially using technology for production of MS2 phage-like particles, which have many advantages in comparison with other used controls and are especially suited for controlling the detection and quantification of certain types of RNA viruses. The technology for production of MS2 phage-like particles is theoretically well established, uses the knowledge gained from the study of the familiar bacteriophage MS2 and utilizes many different approaches for the construction of the various process control viruses. Nevertheless, the practical use of MS2 phage-like particles in routine diagnostics is relatively uncommon. The current situation with regard to the use of MS2 phage-like particles as process control viruses in detection of RNA viruses and different methods of their construction, purification and use are summarized and discussed in this review. PMID- 25711390 TI - Photoelectrochemical water oxidation efficiency of a core/shell array photoanode enhanced by a dual suppression strategy. AB - The development of earth-abundant semiconductor photoelectrodes is of great importance to high-efficiency and sustainable photoelectrochemical water splitting. Herein, a one-dimensional TiO2 array photoanode was sheathed with an ultrathin overlayer of phosphated nickel-chromium double-metal hydroxide by a photoassisted modification and deposition strategy. The core/shell array photoanode resulted in a large cathodic shift of photocurrent onset potential (~200 mV). Nearly 100 % oxidative efficiency for PEC water oxidation was achieved over a wide range of potential. Mechanism studies show that the modification of phosphate leads to significantly improved charge separation. The amorphous hydroxide sheath could efficiently inhibit oxygen reduction reactions. Therefore, this strategy enables the simultaneous suppression of surface carrier recombination and back reactions, which is promising to improve the water oxidation efficiency of currently prevailing photoanodes. PMID- 25711392 TI - Evidence Use in Mental Health Policy Making for Children in Foster Care. AB - Considerable attention is being given to the use of research evidence to inform public policy making. Building upon Weiss's model of research utilization, we examined the types and uses of evidence that child welfare administrators used in response to federal policy reforms requiring psychotropic medications oversight for children in foster care. Participants relied on a range of "global" and "local" evidence types throughout the policy development phase. Global research evidence was used to raise awareness about problems associated with psychotropic medication use. Local evidence helped to contextualize concerns and had problem solving and political uses. In most states, policy actions were informed by a combination of evidence types. PMID- 25711391 TI - Placental transfer of antidepressant medications: implications for postnatal adaptation syndrome. AB - Seven to thirteen percent of women are either prescribed or taking (depending on the study) an antidepressant during pregnancy. Because antidepressants freely cross into the intrauterine environment, we aim to summarize the current findings on placental transfer of antidepressants. Although generally low risk, antidepressants have been associated with postnatal adaptation syndrome (PNAS). Specifically, we explore whether the antidepressants most closely associated with PNAS (paroxetine, fluoxetine, venlafaxine) cross the placenta to a greater extent than other antidepressants. We review research on antidepressants in the context of placental anatomy, placental transport mechanisms, placental metabolism, pharmacokinetics, as well as non-placental maternal and fetal factors. This provides insight into the complexity involved in understanding how placental transfer of antidepressants may relate to adverse perinatal outcomes. Ultimately, from this data there is no pattern in which PNAS is related to placental transfer of antidepressant medications. In general, there is large interindividual variability for each type of antidepressant. To make the most clinically informed decisions about the use of antidepressants in pregnancy, studies that link maternal, placental and fetal genetic polymorphisms, placental transfer rates and infant outcomes are needed. PMID- 25711393 TI - Heterologous expression, purification, and phylogenetic analysis of oil-degrading biosurfactant biosynthesis genes from the marine sponge-associated Bacillus licheniformis NIOT-06. AB - Surfactin is a lipopeptide, composed of one beta-hydroxy fatty acid, a long fatty acid moiety, and seven amino acids. In this study, the biosurfactant biosynthesis genes; 4'-pantetheinyl transferase (sfp), phosphopantetheinyl transferase (sfpO), and surfactin synthetase (srfA) have been characterized from the marine sponge associated Bacillus licheniformis NIOT-06 from the Andaman and Nicobar Islands. The purified recombinant biosurfactant revealed excellent emulsification activity with crude oil and kerosene. Reverse-phase high-performance liquid chromatography resolved the purified recombinant biosurfactant into several fractions and one of which had significant surface tension reducing property. Fourier transform infrared spectroscopy spectrum also revealed the presence of C-N-N, alkenes, and N-H as the functional groups, and a similar overlapping pattern was observed with that of standard lipopeptide surfactin. The diversity and phylogeny of sfp, sfpO, and srfA gene sequences were compared with other eubacteria. The sfp, sfpO, and srfA gene sequences obtained from Bacillus licheniformis NIOT-06 were diverse and appeared to be partially conserved when compared with the GenBank reported sequences of several eubacteria. PMID- 25711395 TI - Inpatient mortality after orthopaedic surgery. AB - PURPOSE: Adequate comorbidity risk adjustment is central for reliable outcome prediction and provider performance evaluation. The two most commonly employed risk-adjustment methods in orthopaedic surgery were not originally validated in this patient population. We sought (1) to develop a single numeric comorbidity score for predicting inpatient mortality in patients undergoing orthopaedic surgery by combining and reweighting the conditions included in the Charlson and Elixhauser measures, and to compare its predictive performance to each of the separate component scores. We also (2) evaluated the new score separately for spine surgery, adult reconstruction, hip fracture, and musculoskeletal oncology admissions. METHODS: Data from the National Hospital Discharge Survey for the years 1990 through 2007 were obtained. A comorbidity score for predicting inpatient mortality was developed by combining conditions from the Charlson and Elixhauser measures. Weights were derived from a random sample of 80% of the cohort (n = 26,454,972), and the predictive ability of the new score was internally validated on the remaining 20% (n = 6,739,169). Performance of scores was assessed and compared using the area under the receiver operating characteristic curve (AUC) derived from multivariable logistic regression models. RESULTS: The new combined comorbidity score (AUC = 0.858, 95% CI 0.856-0.859) performed 58% better than the Charlson score (AUC = 0.794, 95% CI 0.792-0.796) and 12% better than the Elixhauser score (AUC = 0.845, 95% CI 0.844-0.847). Of the seven conditions that received the highest weights in the new combined score, only three of them were included in both the Charlson and the Elixhauser indices. The new combined score achieved higher discriminatory power for all orthopaedic admission subgroups. CONCLUSION: A single numeric comorbidity score combining conditions from the Charlson and Elixhauser models provided better discrimination of inpatient mortality than either of its constituent scores. Future research should test this score in other populations and data settings. PMID- 25711396 TI - Olecranon tension plating or olecranon tension band wiring? A comparative biomechanical study. AB - PURPOSE: The complication rate of a tension band wiring (TBW) used for the internal fixation of olecranon fractures remains high. The aim of this study was to compare the stability of a novel olecranon tension plate (OTP) with TBW in a simulated fracture model. METHODS: We tested 12 fresh frozen-pairs of cadaver proximal ulnae treated with OTP and TBW under cyclic loading. The elbow motion ranged from full extension to 90 degrees of flexion, and the pulling force of the triceps tendon ranged from 50 to 350 N. The displacement of the fracture fragments was measured continuously. Data were assessed statistically using the Wilcoxon test with significance level of p < 0.05. RESULTS: The cyclic loading tests showed median displacements of the fracture fragments of 0.25 mm using OTP and 1.12 mm for TBW. Statistical analysis showed the difference to be substantial (p = 0.086) but not statistically significant. No plate breakage or screw loosening occurred. CONCLUSIONS: The concept of replacing prominent K-wires at the proximal end of the ulna using an low-profile plate with classical lag and multidirectional angle-stable screws demonstrated biomechanical advantages over TBW. PMID- 25711397 TI - Management and prognostic significance of pathological fractures through chondrosarcoma of the femur. AB - PURPOSE: The aim of the study was to report overall survival, local recurrence and development of metastasis in a group of patients with femur chondrosarcoma that presented with or without a pathological fracture. METHODS: A retrospective review was performed, and 182 patients (39 pathological fractures) that had been treated by oncologic surgery for femoral chondrosarcoma were included. The mean age of the series was 50 years (range, eight to 90) and 114 patients were male (63%). Mean follow-up was 113 months (range, three to 216). Cancer-specific overall survival, development of metastasis and local recurrence were analysed, grouping patients by grade (grade I / grade 2-3 / dedifferentiated). RESULTS: Disease-specific survival in the entire group of chondrosarcoma of the femur was 69% (CI95% 63-76) at 5 years. Five-year disease-specific survival in the fracture group was 49% lower than in the control group 75% (p = 0.0001). Survival of patients with grade 1 chondrosarcoma with fracture was significantly less than those without fracture (p = 0.02) but there was no difference in those with grade 2-3 (p = 0.49) and dedifferentiated tumours (p = 0.09). The local recurrence rate of the entire series was 27%. Only dedifferentiated chondrosarcomas with an associated pathological fracture had a significantly higher rate of local recurrence. There was no relationship between development of metastases and fracture. CONCLUSION: A pathological fracture of the femur has a negative prognostic influence in grade 1 chondrosarcoma and increases the risk of local recurrence in dedifferentiated femur chondrosarcomas. PMID- 25711398 TI - Predictive value of single photon emission computerized tomography and computerized tomography in osteonecrosis after femoral neck fracture: a prospective study. AB - PURPOSE: Osteonecrosis of the femoral head (ONFH) is a very common complication after femoral neck fracture. The purpose of this study was to assess the femoral head vascularity after femoral neck fracture using single photon emission computerized tomography and computerized tomography (SPECT/CT), and to evaluate its value in predicting ONFH. METHODS: Between January 2008 and March 2011, 120 patients diagnosed with femoral neck fracture underwent SPECT-CT before the internal fixation. The fracture was classified according to the Garden classification. The ratios of the radionuclide uptake of the fractured femoral head to that of the contralateral femoral head (F/N) were calculated to assess the femoral head vascularity. After a minimum of two years' follow-up, magnetic resonance imaging (MRI) was used as the "gold standard" for the diagnosis of possible ONFH. RESULTS: A total of 114 patients completed the study. The SPECT/CT examination showed that the F/N ratios of Garden I, II, III and IV were 2.6, 1.8, 0.8, and 0.6, respectively. At the time of the most recent follow-up, osteonecrosis developed in two of the 27 patients who had a Garden Stage-II fracture, in eight of the 34 patients who had a Garden Stage-III fracture, and nine of the 27 patients who had a Garden Stage-VI fracture. With a cutoff of 0.55 from the receiver operating characteristic (ROC) curve, F/N ratio showed a sensitivity of 97%, a specificity of 79%, a positive predictive value of 95%, and a negative predictive value of 19%. CONCLUSION: SPECT-CT proved to be reliable and valid for predicting ONFH after femoral neck fracture. PMID- 25711399 TI - Thermoelastic and structural properties of ionically conducting cerate perovskites: (II) SrCeO3 between 1273 K and 1723 K. AB - The temperature dependence of the crystal structure and the thermoelastic properties of SrCeO(3) have been determined from Rietveld refinement of high resolution, neutron time-of-flight powder diffraction data collected in 5 K intervals between 1273 K and 1723 K. No evidence was found for critical behaviour in the amplitudes of the modes that soften in zone boundary phase transitions in perovskite-structured phases suggesting SrCeO(3) may remain orthorhombic, space group Pbnm from 1.2 K up to the 1 atm melting point of 2266 K. The temperature variation of the crystal structure has been determined from mode decomposition techniques and the structural evolution has been inferred from the temperature dependences of the spontaneous shear strain and the order parameter associated with the anti-phase tilt. Thermoelastic properties have been derived from the temperature variation of the unit cell, isobaric heat capacity, and atomic displacement parameters and shows good agreement with earlier work carried out on the lightly doped system SrCe(0.95)Yb(0.05)O(xi) (xi~ 3). Temperature-dependent corrections for the bond valence parameters for strontium and cerium are reported. PMID- 25711400 TI - Clinical efficacy of collagenase Clostridium histolyticum in the treatment of Peyronie's disease by subgroup: results from two large, double-blind, randomized, placebo-controlled, phase III studies. AB - OBJECTIVES: To examine the efficacy of intralesional collagenase Clostridium histolyticum (CCH) in defined subgroups of patients with Peyronie's disease (PD). PATIENTS AND METHODS: The efficacy of CCH compared with placebo, assessed from baseline to week 52, was examined in subgroups of participants from the Investigation for Maximal Peyronie's Reduction Efficacy and Safety Studies (IMPRESS) I and II. The subgroups were defined according to: severity of penile curvature deformity at baseline (30-60 degrees [n = 492] and 61-90 degrees [n = 120]); PD duration (1 to <=2 [n = 201], >2 to <=4 [n = 212] and >4 years [n = 199]); degree of plaque calcification (no calcification [n = 447], non-contiguous stippling [n = 103] and contiguous calcification that did not interfere with injection of CCH [n = 62]); and baseline erectile function (International Index of Erectile Function [IIEF] scores 1-5 [n = 22], 6-16 [n = 106] and >=17 [n = 480]). RESULTS: Reductions in penile curvature deformity and PD symptom bother were observed in all subgroups. Penile curvature deformity reductions were significantly greater with CCH than with placebo for the following subgroups: baseline penile curvature 30-60 degrees and 61-90 degrees ; disease duration >2 to <=4 years and >4 years; no calcification; and IIEF score >=17 (high IIEF erectile function score; P < 0.05 for all). PD symptom bother reductions were significantly greater in the CCH group for: penile curvature 30-60 degrees ; disease duration >4 years; no calcification; and IIEF score 1-5 (no sexual activity) and >=17 (P < 0.05 for all). CONCLUSIONS: In this analysis, clinical efficacy of CCH treatment for reducing penile curvature deformity and PD symptom bother was found across subgroups. In the IMPRESS I and II overall, adverse events (AEs) were typically mild or moderate, although treatment-related serious AEs, including corporal rupture or penile haematoma, occurred. Future studies could be considered to directly assess the efficacy and safety of CCH treatment in defined subgroups of PD patients, with the goal of identifying predictors of optimum treatment success. PMID- 25711401 TI - High sugar-induced repression of antioxidant and anti-apoptotic genes in lens: reversal by pyruvate. AB - Impairment of vision in diabetes has been suggested to be due to an acceleration of the polyol pathway in the lens as well as in the retina. This acceleration is attributed largely to the rate-limiting steps of glycolysis and consequent diversion of glucose in the polyol pathway with its consequent effects on diverse tissue transport and redox activities. In addition, high sugar also induces a generalized oxidative stress via generating superoxide and its derivatization to other reactive oxygen species (ROS). While the immediate toxicity of hyperglycemia could be linked to the acceleration of this pathway, we hypothesize that in the long term, the toxic effects of the high sugar level are due to an upregulation of certain microRNAs (as we have shown before) and consequent repression of the transcription and translation of many antioxidant and anti apoptotic genes. Therefore, in the present study, we measured the expression levels of certain major antioxidant and pro- and anti-apoptotic mRNAs in the lenses of mice made hyperglycemic by feeding a high galactose diet, without or with fortification with 1% sodium pyruvate-a potent ROS scavenger. As speculated, the expression of several antioxidant and anti-apoptotic mRNAs has been found to be significantly repressed in the lenses of animals fed a high galactose diet. Such repression was significantly prevented by pyruvate. Thus, the findings also strongly suggest that visual impairment induced by the diabetic hyperglycemia could be treatable by administration of certain anti-microRNAs. PMID- 25711403 TI - AMP-regulated protein kinase activity in the hearts of mice treated with low- or high-fat diet measured using novel LC-MS method. AB - AMP-regulated protein kinase (AMPK) is involved in regulation of energy generating pathways in response to the metabolic needs in different organs including the heart. The activity of AMPK is mainly controlled by AMP concentration that in turn could be affected by nucleotide metabolic pathways. This study aimed to develop a procedure for measurement of AMPK activity together with nucleotide metabolic enzymes and its application for studies of mice treated with high-fat diet. The method developed was based on analysis of conversion of AMARA peptide to pAMARA by partially purified heart homogenate by liquid chromatography/mass spectrometry (LC/MS). Activities of the enzymes of nucleotide metabolism were evaluated by analysis of conversion of substrates into products by HPLC. The method was applied for analysis of hearts of mice fed 12 weeks with low- (LFD) or high-fat diet (HFD). The optimized method for AMPK activity analysis (measured in presence of AMP) revealed change of activity from 0.089 +/- 0.035 pmol/min/mg protein in LFD to 0.024 +/- 0.002 in HFD. This coincided with increase of adenosine deaminase (ADA) activity from 0.11 +/- 0.02 to 0.19 +/- 0.06 nmol/mg tissue/min and decrease of AMP-deaminase (AMPD) activity from 1.26 +/- 0.35 to 0.56 +/- 0.15 nmol/mg tissue/min for LFD and HFD, respectively. We have proven quality of our LC/MS method for analysis of AMPK activity. We observed decrease in AMPK activity in the heart of mice treated with high-fat diet. However, physiological consequences of this change could be modulated by decrease in AMPD activity. PMID- 25711402 TI - Inhibiting (pro)renin receptor-mediated p38 MAPK signaling decreases hypoxia/reoxygenation-induced apoptosis in H9c2 cells. AB - The (pro)renin receptor is a new molecular member of the renin-angiotensin system and participates in regulating many physiological and pathological processes. However, the role of (pro)renin receptor-mediated signaling pathways in myocardial ischemic/reperfusion injury remains unclear. In this study, we hypothesized that p38 mitogen-activated protein kinase (MAPK) signaling pathway activation by the (pro)renin receptor had effects on myocardial apoptosis induced by ischemia/reperfusion. This analysis was performed using a hypoxia/reoxygenation model in H9c2 cells to mimic ischemia/reperfusion injury. The H9c2 rat cardiomyocyte cell line was subjected to 2 h of hypoxia followed by 6 h of reoxygenation. The (pro)renin receptor, caspase 3, and phosphorylated p38 MAPK protein expression levels were analyzed by Western blot. After 2 h of hypoxia followed by 6 h of reoxygenation, apoptosis increased in H9c2 cells; the (pro)renin receptor, caspase 3, and phosphorylated p38 MAPK protein expressions were upregulated. siRNA silencing of the (pro)renin receptor significantly decreased p38 MAPK phosphorylation. siRNA silencing of the (pro)renin receptor and treatment with the p38MAPK inhibitor SB203580 significantly decreased the hypoxia/reoxygenation-induced apoptosis and caspase 3 protein expression in H9c2 cells. Furthermore, we found that the role of the (pro)renin receptor was independent of angiotensin II (Ang II). Thus, we concluded that (pro)renin receptor activation could trigger hypoxia/reoxygenation-induced apoptosis in H9c2 cells, partially through the p38 MAPK/caspase 3 signaling pathway, independent of Ang II. Therefore, this study may provide new therapeutic targets for myocardial ischemic/reperfusion injury prevention, and further in vivo studies are needed. PMID- 25711404 TI - Tadalafil 5 mg once daily for the treatment of Asian men with lower urinary tract symptoms secondary to benign prostatic hyperplasia: analyses of data pooled from three randomized, double-blind, placebo-controlled studies. AB - OBJECTIVES: Assess the efficacy and safety of tadalafil 5 mg once-daily in Asian men with lower urinary tract symptoms by pooling data from three clinical studies. METHODS: Data on 1199 Japanese, Korean, and Taiwanese men given tadalafil 5 mg (n = 601) or placebo (n = 598) were pooled from three double blind, placebo-controlled, 12-week studies. Efficacy measures included International Prostate Symptom Score, and Patient and Clinician Global Impressions of Improvement. These measures were also assessed for patient subgroups (age categories, baseline disease severity and/or prostate volume, prior alpha-blocker treatment). Safety measures included adverse events, including those in selected body systems. Efficacy measure changes throughout treatment were assessed by mixed-effect model repeated-measures analysis; baseline to end-point changes for the total population and subgroups were evaluated by analysis of covariance. RESULTS: Tadalafil 5 mg led to significant improvement (vs placebo) in all International Prostate Symptom Scores at all time points (week 4 P <= 0.013 for all measures; week 8 P <= 0.005, week 12 P < 0.001). End-point results for both global impressions scales also favored tadalafil (both P < 0.001 vs placebo). Tadalafil efficacy was similar between patient subgroups of varied disease severity (interaction P = 0.097), prior alpha blocker use (P = 0.580), and prostate volume (P = 0.921). The drug was slightly less effective in older men (interaction P = 0.042). No unexpected adverse events were reported, and no meaningful adverse effects were observed in visual, auditory, or cardiovascular systems. CONCLUSIONS: Tadalafil 5 mg once-daily for 12 weeks is efficacious and safe in Asian men with lower urinary tract symptoms. Tadalafil is also effective in men of different ages, disease severity, prior alpha-blocker exposure, and prostate volumes. PMID- 25711405 TI - Exploration of Aboriginal and Torres Strait Islander perspectives of Home Medicines Review. AB - INTRODUCTION: In Australia, Home Medicines Review (HMR) has been found to be an important tool to raise awareness of medication safety, reduce adverse events and improve medication adherence. Aboriginal and Torres Strait Islander people are 'underserviced' by the HMR program and are the most likely of all Australians to miss out on HMRs despite their high burden of chronic disease and high rates of hospitalisation due to medication misadventure. The goal of this study was to explore Aboriginal and Torres Strait Islander perspectives of the Home Medicines Review program and their suggestions for an 'improved' or more readily accessible model of service. METHODS: Eighteen semi-structured focus groups were conducted with 102 Aboriginal and Torres Strait Islander patients at 11 Aboriginal Health Services (AHSs). Participants who were multiple medication users and understood English were recruited to the study by AHS staff. Seven focus groups were conducted for people who had already used the HMR program (User, n=23) and 11 focus groups were conducted for people who had not had an HMR (Non User, n=79). Focus groups were recorded, de-identified and transcribed. Transcripts were coded and analysed for themes. Focus groups continued and concepts were explored until no new findings were being generated and thus saturation of data occurred. RESULTS: Focus group participants who had not had an HMR had little or no awareness of the HMR program. All the participants felt that lack of awareness and promotion of the HMR program were contributing factors to the low uptake of the HMR program by Aboriginal and Torres Strait Islander people. Most participants felt that an HMR would assist them to better understand their medicines, would empower them to seek information about medicines, would improve relationships with health professionals and would increase the likelihood of medication adherence. Most of the User participants reported that the HMR interview had been very useful for learning more about their medicines. However, many reported that they found the process confusing and confronting. The majority of participants felt HMRs for Aboriginal and Torres Strait Islander patients should be organised by AHS staff, with patients being offered a choice of location for the HMR interview. Participants identified that Aboriginal Health Workers should play a key role in communication, knowledge translation, referral and follow-up. CONCLUSIONS: Current HMR rules impede rather than facilitate HMRs for Aboriginal and Torres Strait Islander people. Tailoring and remodelling of the HMR program is needed to increase the awareness, accessibility, acceptability and effectiveness of the HMR program for Aboriginal and Torres Strait Islander people. PMID- 25711406 TI - Guideline: vulvovaginal candidosis (AWMF 015/072), S2k (excluding chronic mucocutaneous candidosis). AB - The oestrogenised vagina is colonised by Candida species in at least 20% of women; in late pregnancy and in immunosuppressed patients, this increases to at least 30%. In most cases, Candida albicans is involved. Host factors, particularly local defence mechanisms, gene polymorphisms, allergies, serum glucose levels, antibiotics, psycho-social stress and oestrogens influence the risk of candidal vulvovaginitis. Non-albicans species, particularly Candida glabrata, and in rare cases also Saccharomyces cerevisiae, cause less than 10% of all cases of vulvovaginitis with some regional variation; these are generally associated with milder signs and symptoms than normally seen with a C. albicans associated vaginitis. Typical symptoms include premenstrual itching, burning, redness and odourless discharge. Although itching and redness of the introitus and vagina are typical symptoms, only 35-40% of women reporting genital itching in fact suffer from vulvovaginal candidosis. Medical history, clinical examination and microscopic examination of vaginal content using 400* optical magnification, or preferably phase contrast microscopy, are essential for diagnosis. In clinically and microscopically unclear cases and in chronically recurring cases, a fungal culture for pathogen determination should be performed. In the event of non-C. albicans species, the minimum inhibitory concentration (MIC) should also be determined. Chronic mucocutaneous candidosis, a rarer disorder which can occur in both sexes, has other causes and requires different diagnostic and treatment measures. Treatment with all antimycotic agents on the market (polyenes such as nystatin; imidazoles such as clotrimazole; and many others including ciclopirox olamine) is easy to administer in acute cases and is successful in more than 80% of cases. All vaginal preparations of polyenes, imidazoles and ciclopirox olamine and oral triazoles (fluconazole, itraconazole) are equally effective (Table ); however, oral triazoles should not be administered during pregnancy according to the manufacturers. C. glabrata is not sufficiently sensitive to the usual dosages of antimycotic agents approved for gynaecological use. In other countries, vaginal suppositories of boric acid (600 mg, 1-2 times daily for 14 days) or flucytosine are recommended. Boric acid treatment is not allowed in Germany and flucytosine is not available. Eight hundred-milligram oral fluconazole per day for 2-3 weeks is therefore recommended in Germany. Due to the clinical persistence of C. glabrata despite treatment with high-dose fluconazole, oral posaconazole and, more recently, echinocandins such as micafungin are under discussion; echinocandins are very expensive, are not approved for this indication and are not supported by clinical evidence of their efficacy. In cases of vulvovaginal candidosis, resistance to C. albicans does not play a significant role in the use of polyenes or azoles. Candida krusei is resistant to the triazoles, fluconazole and itraconazole. For this reason, local imidazole, ciclopirox olamine or nystatin should be used. There are no studies to support this recommendation, however. Side effects, toxicity, embryotoxicity and allergies are not clinically significant. Vaginal treatment with clotrimazole in the first trimester of a pregnancy reduces the rate of premature births. Although it is not necessary to treat a vaginal colonisation of Candida in healthy women, vaginal administration of antimycotics is often recommended in the third trimester of pregnancy in Germany to reduce the rate of oral thrush and napkin dermatitis in healthy full-term newborns. Chronic recurrent vulvovaginal candidosis continues to be treated in intervals using suppressive therapy as long as immunological treatments are not available. The relapse rate associated with weekly or monthly oral fluconazole treatment over 6 months is approximately 50% after the conclusion of suppressive therapy according to current studies. Good results have been achieved with a fluconazole regimen using an initial 200 mg fluconazole per day on 3 days in the first week and a dosage-reduced maintenance therapy with 200 mg once a month for 1 year when the patient is free of symptoms and fungal infection (Table ). Future studies should include Candida autovaccination, antibodies to Candida virulence factors and other immunological experiments. Probiotics with appropriate lactobacillus strains should also be examined in future studies on the basis of encouraging initial results. Because of the high rate of false indications, OTC treatment (self-treatment by the patient) should be discouraged. PMID- 25711407 TI - No association between prenatal exposure to psychotropics and intelligence at age five. AB - OBJECTIVE: To examine associations between prenatal exposure to selective serotonin reuptake inhibitors (SSRIs)/anxiolytics and intelligence assessed with a standard clinical intelligence test at age 5 years. DESIGN: Longitudinal follow up study. SETTING: Denmark, 2003-2008. POPULATION/SAMPLE: A total of 1780 women and their children sampled from the Danish National Birth Cohort. METHODS: Self reported information on use of SSRI and anxiolytics was obtained from the Danish National Birth Cohort at the time of consent and from two prenatal interviews. Intelligence was assessed at age 5 years, and parental education, maternal intelligence quotient (IQ), maternal smoking and alcohol consumption in pregnancy, the child's age at testing, sex, and tester were included in the full model. The IQ of 13 medication-exposed children was compared with the IQ of 19 children whose mothers had untreated depression and 1748 control children. MAIN OUTCOME MEASURE: Wechsler Preschool and Primary Scale of Intelligence - Revised. RESULTS: In unadjusted analyses, children of mothers who used antidepressants or anxiolytics during pregnancy had higher verbal IQ; this association, however, was insignificant after adjustment for potentially confounding maternal and child factors. CONCLUSION: No consistent associations between IQ and fetal exposure to antidepressants and anxiolytics were observed, but the study had low statistical power, and there is an obvious need to conduct long-term follow-up studies with comprehensive cognitive assessment and sufficiently large samples of adolescent or adult offspring. PMID- 25711408 TI - Critical design issues in the targeted molecular imaging of cell surface receptors. AB - The imaging of cell-surface receptors can be achieved using several methods, including single photon emission tomography (SPECT) positron emission tomography (PET), optical imaging and magnetic resonance imaging (MRI). The application of targeted MRI contrast agents is particularly well-suited to this task, provided that the agents reach the desired site efficiently and selectively. In addition, they should bind reversibly to the cell-surface receptor and give rise to a large change in cellular relaxation rate, in competition with binding to the natural substrate. Such approaches offer promise in the molecular imaging of neurotransmission in the brain, using conjugates that selectively target dopamine or glutamate receptor sub-types. Strategies based on the use of competitive antagonist vectors offer particular scope, as such conjugates are generally not taken into the target cell following cell surface receptor binding, in contrast to the use of MRI contrast agents based on agonists that tend to be internalised quickly or are designed to target intracellular sites. PMID- 25711409 TI - Reduction of Lactobacillus in the milks of cows with subclinical mastitis. AB - Clinical and subclinical bovine mastitis are the most frequent diseases encountered on dairy farms worldwide, which cause significant economic loss and veterinary cost. The mastitic disease status is associated with increases in both milk bacterial pathogens and somatic cell count (SCC). Although it is well established that the mastitic pathogens generally correlate with the milk SCC, to our knowledge, the correlation between the probiotic genus, Lactobacillus, and the mastitic causative bacteria and SCC have not been determined previously. Thus, in this study, milk samples from 12 mild and 28 severe subclinical mastitic dairy cows were collected from the same farm. The overall milk bacterial load was quantified with the total plate count method. The Lactobacillus genus and 4 common clinical and subclinical mastitic pathogens (Escherichia coli, Staphylococcus aureus, Streptococcus agalactiae, and Trueperella pyogenes) in the sampled milk were enumerated by quantitative PCR. Mild and severe subclinical mastitic samples were distinctly separated on the principal component analysis score plot generated based on the quantities of these 5 target bacteria, suggesting that clear differences existed in the microbiological composition between the two sample groups. Based on comparison with the pairwise Mann-Whitney test, the mild subclinical mastitic dairy cows had a significantly higher amounts of lactobacilli (P=0.0175), but lower E. coli (P=0.0002), S. aureus (P<0.0001), S. agalactiae (P=0.0001) and T. pyogenes (P=0.0044) quantities, while an opposite trend occurred in the severe subclinical mastitic group. The negative correlation between Lactobacillus and the pathogenic bacteria, as well as the SCC, was confirmed with Spearman correlation analysis. Data generated from the current study may hint to a close relationship between Lactobacillus and the health of bovine udder. PMID- 25711410 TI - How effective is melatonin as a preventive treatment for hemicrania continua? A clinic-based study. AB - OBJECTIVE: To assess the efficacy of melatonin as a preventive therapy for hemicrania continua in a larger population of patients than has previously been studied. BACKGROUND: Hemicrania continua is defined by its sensitivity to indomethacin. Rarely can patients be fully tapered off indomethacin without headache recurrence; thus, the risks associated with chronic indomethacin usage are substantial for these individuals. Melatonin, a pineal hormone with a similar chemical structure to indomethacin, has shown efficacy as a preventive agent for hemicrania continua in isolated case reports. Melatonin would be a preferential alternative prophylactic treatment to indomethacin because of its minimal side effect profile. How truly effective melatonin is as a preventive for hemicrania continua is unknown at present and needs further study. METHODS: Retrospective analysis of all International Classification of Headache Disorders-3 beta diagnosed hemicrania continua patients treated with both indomethacin and melatonin at the Geisinger Headache Center from July 2011 to January 2014. RESULTS: Eleven patients were treated (9 women, 2 men). Two patients became pain free on melatonin, while partial relief was noted in 3 other patients; thus, they were able to lower their dose of indomethacin but could not achieve pain freedom with melatonin alone. Six patients had no response. Melatonin dosing needed for response ranged from 3 to 30 mg. In the partial relief responders, indomethacin dosing decreased by 50% to 75%. CONCLUSION: From this single clinic investigation, only a small percent of subjects with hemicrania continua (less than 20%) will achieve pain freedom on melatonin, thus clearly not matching the effectiveness of indomethacin. However, the addition of melatonin to indomethacin may allow around 45% of patients to have complete or partial relief of their headache with the subsequent ability to reduce or eliminate their indomethacin dosage, which may lead to a decrease in medical morbidity over time secondary to less exposure to indomethacin. PMID- 25711411 TI - The receptor-like cytoplasmic kinase PCRK1 contributes to pattern-triggered immunity against Pseudomonas syringae in Arabidopsis thaliana. AB - In this paper we describe PATTERN-TRIGGERED IMMUNITY (PTI) COMPROMISED RECEPTOR LIKE CYTOPLASMIC KINASE 1 (PCRK1) of Arabidopsis thaliana, an RLCK that is important for defense against the pathogen Pseudomonas syringae pv. maculicola ES4326 (Pma ES4326). We examined defense responses such as bacterial growth, production of reactive oxygen species (ROS) and callose deposition in pcrk1 mutant plants to determine the role of PCRK1 during pathogen infection. Expression of PCRK1 was induced following pathogen infection. Pathogen growth was significantly higher in pcrk1 mutant lines than in wild-type Col-0. Mutant pcrk1 plants showed reduced pattern-triggered immunity (PTI) against Pma ES4326 after pretreatment with peptides derived from flagellin (flg22), elongation factor-Tu (elf18), or an endogenous protein (pep1). Deposition of callose was reduced in pcrk1 plants, indicating a role of PCRK1 in activation of early immune responses. A PCRK1 transgene containing a mutation in a conserved lysine residue important for phosphorylation activity of kinases (K118E) failed to complement a pcrk1 mutant for the Pma ES4326 growth phenotype. Our study shows that PCRK1 plays an important role during PTI and that a conserved lysine residue in the putative kinase domain is important for PCRK1 function. PMID- 25711413 TI - Biofuel cell based self-powered sensing platform for L-cysteine detection. AB - L-cysteine (L-Cys) detection is of great importance because of its crucial roles in physiological and clinical diagnoses. In this study, a glucose/O2 biofuel cell (BFC) was assembled by using flavin adenine dinucleotide-dependent glucose dehydrogenase (FAD-GDH)-based bioanode and laccase-based biocathode. Interestingly, the open circuit potential (OCP) of the BFC could be inhibited by Cu(2+) and subsequently activated by L-Cys, by which a BFC-based self-powered sensing platform for the detection of L-Cys was proposed. The FAD-GDH activity can be inhibited by Cu(2+) and, in turn, subsequent reversible activation by L Cys because of the binding preference of L-Cys toward Cu(2+) by forming the Cu-S bond. The preferential interaction between L-Cys and Cu(2+) facilitated Cu(2+) to remove from the surface of the bioanode, and thus, the OCP of the system could be turned on. Under optimized conditions, the OCP of the BFC was systematically increased upon the addition of the L-Cys. The OCP increment (DeltaOCP) was linear with the concentration of L-Cys within 20 nM to 3 MUM. The proposed sensor exhibited lower detection limit of 10 nM L-Cys (S/N = 3), which is significantly lower than those values for other methods reported so far. Other amino acids and glutathione did not affect L-Cys detection. Therefore, this developed approach is sensitive, facile, cost-effective, and environmental-friendly, and could be very promising for the reliable clinically detecting of L-Cys. This work would trigger the interest of developing BFCs based self-powered sensors for practical applications. PMID- 25711414 TI - Molecular phylogeny revealed distinct origin of the Y and St genome in Elymus longearistatus (Triticeae: Poaceae). AB - Cytogenetic data has indicated the presence of St and Y genome in Elymus longearistatus (Boiss.) Tzvelev. However, a random amplified polymorphic DNA (RAPD) based sequence tagged site (STS) study suggested one accession of Pseudoroegneria spicata (Pursh) A Love (St genome) as a potential Y genome donor candidate in tetraploid E. longearistatus. To examine the origin of Y genome in and the phylogeny of tetraploid E. longearistatus, sequences of cpDNA (RPS16 and TrnD/T intergenic spacer) and single copy nuclear genes (EF-G and HTL) from eight accessions of E. longearistatus, six StY genomic Elymus species and 62 accessions of diploid in Triticeae were analyzed. The cpDNA data suggested that P. stipifolia (St) is the most likely maternal donor of these six Iranian accessions of E. longearistatus, although P. strigosa could not be excluded. Two nuclear gene data convincingly showed that tetraploid E. longearistatus contains two distinct genomes, St and Y genome. The phylogenetic analyses from both the EF-G and HTL rejected the previous suggestion that accession PI232134 of Pseudoroegneria spicata (Pursh) A Love (St genome) was potential Y genome donor to E. longearistatus. Phylogenetic analyses revealed a separation of the Y genome sequences in Iranian accessions of E. longearistatus from the sequences in the Pakistan accession, indicating that geographic isolation might influence the evolution of the Y genome in E. longearistatus. PMID- 25711412 TI - A novel mechanism of post-translational modulation of HMGA functions by the histone chaperone nucleophosmin. AB - High Mobility Group A are non-histone nuclear proteins that regulate chromatin plasticity and accessibility, playing an important role both in physiology and pathology. Their activity is controlled by transcriptional, post-transcriptional, and post-translational mechanisms. In this study we provide evidence for a novel modulatory mechanism for HMGA functions. We show that HMGAs are complexed in vivo with the histone chaperone nucleophosmin (NPM1), that this interaction requires the histone-binding domain of NPM1, and that NPM1 modulates both DNA-binding affinity and specificity of HMGAs. By focusing on two human genes whose expression is directly regulated by HMGA1, the Insulin receptor (INSR) and the Insulin-like growth factor-binding protein 1 (IGFBP1) genes, we demonstrated that occupancy of their promoters by HMGA1 was NPM1-dependent, reflecting a mechanism in which the activity of these cis-regulatory elements is directly modulated by NPM1 leading to changes in gene expression. HMGAs need short stretches of AT-rich nucleosome-free regions to bind to DNA. Therefore, many putative HMGA binding sites are present within the genome. Our findings indicate that NPM1, by exerting a chaperoning activity towards HMGAs, may act as a master regulator in the control of DNA occupancy by these proteins and hence in HMGA-mediated gene expression. PMID- 25711415 TI - SUICIDAL THOUGHTS AND BEHAVIORS IN CHILDREN AND ADOLESCENTS WITH CHRONIC TIC DISORDERS. AB - OBJECTIVE: Despite evidence of elevated risk factors for suicidal thoughts and behavior in youth with Tourette syndrome and chronic tic disorders (CTD), few studies have actually examined that relationship. This study documented the frequency and clinical correlates of suicidal thoughts and behaviors in a sample of children and adolescents with CTD (N = 196, range 6-18 years old). The content is solely the responsibility of the authors and does not necessarily represent the official views of the Centers for Disease Control. METHOD: Youth and parents completed a battery of measures that assessed co-occurring psychiatric diagnoses, child emotional and behavioral symptoms, and impairment due to tics or co occurring conditions. RESULTS: A structured diagnostic interview identified that 19 youths with CTD (9.7%) experienced suicidal thoughts and/or behaviors, which was elevated compared to 3 youths (3%) who experienced these thoughts in a community control sample (N = 100, range 6-18 years old, P = .03). For youth with CTD, suicidal thoughts and behaviors were frequently endorsed in the context of anger and frustration. The Child Behavior Checklist (CBCL) anxious/depressed, withdrawn, social problems, thought problems, and aggressive behavior subscales, as well as the total internalizing problems scale, were associated with the presence of suicidal thoughts and/or behaviors. Suicidal thoughts and/or behaviors were significantly associated with tic symptom severity; tic-related impairment; and obsessive-compulsive, depressive, anxiety, and attention deficit/hyperactivity disorders' symptom severity. CBCL anxiety/depression scores mediated the relationship between tic severity and suicidal thoughts and behaviors. CONCLUSIONS: Findings suggest that about 1 in 10 youth with CTD experience suicidal thoughts and/or behaviors, which are associated with a more complex clinical presentation and often occur in the presence of anger and frustration. PMID- 25711417 TI - Human leukocyte antigen-E alleles and expression in patients with serous ovarian cancer. AB - Human leukocyte antigen-E (HLA-E) is one of the most extensively studied non classical MHC class I molecules that is almost non-polymorphic. Only two alleles (HLA-E*0101 and HLA-E*0103) are found in worldwide populations, and suggested to be functional differences between these variants. The HLA-E molecule can contribute to the escape of cancer cells from host immune surveillance. However, it is still unknown whether HLA-E gene polymorphisms might play a role in cancer immune escape. To explore the association between HLA-E alleles and the susceptibility to serous ovarian cancer (SOC), 85 primary SOC patients and 100 healthy women were enrolled. Here, we indicated that high frequency of HLA-E*0103 allele existed in SOC patients by the allele-specific quantitative real-time PCR method. The levels of HLA-E protein expression in SOC patients with the HLA E*0103 allele were higher than those with the HLA-E*0101 allele using immunohistochemistry analysis. The cell surface expression and functional differences between the two alleles were verified by K562 cells transfected with HLA-E*0101 or HLA-E*0103 allelic heavy chains. The HLA-E*0103 allele made the transfer of the HLA-E molecule to the cell surface easier, and HLA-E/peptides complex more stable. These differences ultimately influenced the function of natural killer cells, showing that the cells transfected with HLA-E*0103 allele inhibited natural killer cells to lysis. This study reveals a novel mechanism regarding the susceptibility to SOC, which is correlated with the HLA-E*0103 allele. PMID- 25711416 TI - Hydrogen/deuterium exchange mass spectrometry applied to IL-23 interaction characteristics: potential impact for therapeutics. AB - IL-23 is an important therapeutic target for the treatment of inflammatory diseases. Adnectins are targeted protein therapeutics that are derived from domain III of human fibronectin and have a similar protein scaffold to antibodies. Adnectin 2 was found to bind to IL-23 and compete with the IL-23/IL 23R interaction, posing a potential protein therapeutic. Hydrogen/deuterium exchange mass spectrometry and computational methods were applied to probe the binding interactions between IL-23 and Adnectin 2 and to determine the correlation between the two orthogonal methods. This review summarizes the current structural knowledge about IL-23 and focuses on the applicability of hydrogen/deuterium exchange mass spectrometry to investigate the higher order structure of proteins, which plays an important role in the discovery of new and improved biotherapeutics. PMID- 25711418 TI - Phylogenies support out-of-equilibrium models of biodiversity. AB - There is a long tradition in ecology of studying models of biodiversity at equilibrium. These models, including the influential Neutral Theory of Biodiversity, have been successful at predicting major macroecological patterns, such as species abundance distributions. But they have failed to predict macroevolutionary patterns, such as those captured in phylogenetic trees. Here, we develop a model of biodiversity in which all individuals have identical demographic rates, metacommunity size is allowed to vary stochastically according to population dynamics, and speciation arises naturally from the accumulation of point mutations. We show that this model generates phylogenies matching those observed in nature if the metacommunity is out of equilibrium. We develop a likelihood inference framework that allows fitting our model to empirical phylogenies, and apply this framework to various mammalian families. Our results corroborate the hypothesis that biodiversity dynamics are out of equilibrium. PMID- 25711419 TI - Protective effects of moderate alcohol consumption on fatty liver: a spurious association? PMID- 25711420 TI - Reply to: "To target or not to target viral antigens in HBV related HCC?". PMID- 25711421 TI - Reply to: "protective effects of moderate alcohol consumption on fatty liver: a spurious association?". PMID- 25711422 TI - To target or not to target viral antigens in HBV related HCC? PMID- 25711423 TI - An efficient Agrobacterium-mediated transformation of strawberry cv. Camarosa by a dual plasmid system. AB - An Agrobacterium-mediated transformation method was applied to introduce the luciferase reporter gene under the control of the CaMV35S promoter in the pGreen0049 binary vector into strawberry cv. Camarosa. The in vitro regeneration system of strawberry leaves to be used in the transformation was optimized using different TDZ concentrations in MS medium. TDZ at 16 uM showed the highest percentage (100%) of shoot formation and the highest mean number of shoots (24) produced per explant. Studies on the effects of different antibiotics, namely timentin, cefotaxime, carbenicillin and ampicillin, on shoot regeneration of strawberry leaf explants showed the best shoot regeneration in the presence of 300 mg/L timentin and 150 mg/L cefotaxime. Assessment of the different factors affecting Agrobacterium mediated-transformation of strawberry with the luciferase gene showed the highest efficiency of putative transformant production (86%) in the treatment with no preculture, bacterial OD600 of 0.6 and the addition of 150 mg/L cefotaxime in the pre-selection and selection media. The presence of the luciferase gene in the plant genome was verified by the luciferase reporter gene assay, nested PCR amplification and dot blot of genomic DNA isolated from the young leaves of each putatively transformed plantlet. PMID- 25711424 TI - Comparative study of two table grape varieties with contrasting texture during cold storage. AB - Postharvest softening of grape berries is one of the main problems affecting grape quality during export. Cell wall disassembly, especially of pectin polysaccharides, has been commonly related to fruit softening, but its influence has been poorly studied in grapes during postharvest life. In order to better understand this process, the Thompson seedless (TS) variety, which has significantly decreased berry texture after prolonged cold storage, was compared to NN107, a new table grape variety with higher berry firmness. Biochemical analysis revealed a greater amount of calcium in the cell wall of the NN107 variety and less reduction of uronic acids than TS during cold storage. In addition, the activity of polygalacturonase was higher in TS than NN107 berries; meanwhile pectin methylesterase activity was similar in both varieties. Polysaccharide analysis using carbohydrate gel electrophoresis (PACE) suggests a differential pectin metabolism during prolonged cold storage. Results revealed lower pectin fragments in TS after 60 days of cold storage and shelf life (SL) compared to 30 days of cold storage and 30 + SL, while NN107 maintained the same fragment profile across all time points evaluated. Our results suggest that these important differences in cell wall metabolism during cold storage could be related to the differential berry firmness observed between these contrasting table grape varieties. PMID- 25711425 TI - A reliable liquid chromatography-tandem mass spectrometry method for simultaneous determination of multiple mycotoxins in fresh fish and dried seafoods. AB - A reliable liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for simultaneous determination of nine mycotoxins, i.e., aflatoxin B1 (AFB1), aflatoxin B2 (AFB2), aflatoxin G1 (AFG1), aflatoxin G2 (AFG2), ochratoxin A (OTA), zearalenone (ZEN), T-2 toxin, HT2 toxin and deoxynivalenol (DON), in fresh fish (muscle and entrails) as well as dried seafoods. Special focus was given to sample pretreatment which is crucial for an accurate and reliable analytical method. With regards to the high complexity of the matrices, extraction solvent, time, and temperature as well as clean-up cartridges were optimized to improve extraction efficiency and reduce matrix effects. The optimum procedure included ultrasound-assisted extraction with acetonitrile/water/acetic acid (79/20/1, v/v/v) at 40 degrees C for 30 min, defatting with n-hexane and purification by Oasis HLB cartridges. The method was further validated by determining the linearity (R(2) >= 0.9989), sensitivity (limit of detection <= 2 MUg/kg, limit of quantitation <= 3 MUg/kg), recovery (72.2-119.9%) and precision (<= 18.3%) in muscle and entrails of fresh crucian carp (Carassius carassius) as well as dried fish products. The method was proven to be suitable for its intended purposes. Mycotoxins of OTA, ZEN and AFB2 have been found in fresh fish and dried seafoods for the first time. PMID- 25711426 TI - Cultural variation in implicit independence: An extension of Kitayama et al. (). AB - Previous research shows that European Americans are consistently more independent (or less interdependent) than Japanese when implicit indices are used to assess independence (vs. interdependence). The present work extended this evidence by including a novel implicit association test (IAT), as an index of implicit attitude towards independence and interdependence. Consistent with the previous findings, as compared to Japanese, Americans were significantly higher in multiple indices of implicit independence (vs. interdependence) including personal (vs. social) self-definition, experience of disengaging (vs. engaging) emotions and personal (vs. social) form of happiness. Furthermore, as compared to Japanese, Americans had a significantly more positive implicit attitude towards independence assessed with the IAT. As also observed in the previous research, explicit measures showed inconsistent cross-cultural patterns. Lastly, we observed little statistical within-culture coherence among the implicit measures of independence (vs. interdependence), consistent with a view that the implicit indices capture alternative ways for individuals to achieve the cultural mandate of independence or interdependence. PMID- 25711427 TI - A short review of adipokines, smooth muscle and uterine contractility. AB - Obesity is a major health problem worldwide. The prevalence of obesity is increasing in both developed and developing countries. In the UK, for example, 60% of adults are overweight and 25% are obese. Obesity is associated with many pathological complications including respiratory, cardiovascular and endocrine, but it also affects fertility and is associated with many reproductive complications. This has led us and others to investigate links between women with high BMI, pregnancy outcome and uterine function. These studies in turn have led investigators to ask how obesity can have such an impact on reproduction and, as part of this, to consider the role of the adipokines released from adipose tissues. Our focus in this short review is on adipokines and myometrial activity, and for completeness we overview their effects on other smooth muscles. To date four adipokines (leptin, visfatin, apelin and ghrelin) have been investigated and all affect myometrial contractility, but some more potently than others. We consider the possible mechanisms involved in how adipokines may modify uterine contractility, and discuss the potential impact on labor and delivery. PMID- 25711428 TI - Characterization of the anti-inflammatory properties of NCX 429, a dual-acting compound releasing nitric oxide and naproxen. AB - AIMS: Cyclooxygenase (COX)-inhibiting nitric oxide donors (CINODs) are a new class of drugs that structurally combine a COX inhibitor with a nitric oxide (NO) donating moiety. This combination reduces potential toxicity of the non-steroidal anti-inflammatory drugs (NSAIDs) whilst maintaining the analgesic and anti inflammatory effects. The present study was undertaken to investigate the anti inflammatory effects of NCX 429, a naproxen-based CINOD, and to assess the additional properties of NO donation beyond those related to naproxen. MAIN METHODS: We evaluated the in vitro effects of NCX 429 on oxy-radical production, phagocytosis, cytokine release, MMP-9, PPARgamma expression and NF-kappaB activation in human monocytes/MDM and compared to naproxen. Moreover, we compared the in vivo efficacy of NCX 429 and naproxen in a murine model of peritonitis. KEY FINDINGS: In all the experiments performed in vitro, NCX 429 reduced the inflammatory responses with equal or higher efficacy compared to naproxen. Moreover, in in vivo experiments, NCX 429, at the lowest dose tested, was able to significantly inhibit cell influx in response to IL-1beta administration although naproxen was found to be more potent than NCX 429 at reducing PGE2 in inflammatory exudates. SIGNIFICANCE: These results demonstrate that both in vitro and in vivo--in a murine model of peritonitis--NCX 429 elicits significant anti inflammatory activity, beyond the simple COX inhibition or pure NO release. Therefore, NO donation along with COX inhibition may represent a strategy for investigating inflammatory diseases in which pain and function are not fully resolved by analgesics/anti-inflammatory drugs. PMID- 25711429 TI - Inflammatory profiling of early experimental necrotizing pancreatitis. AB - AIMS: Inflammatory mediators play a pivotal role in severe necrotizing pancreatitis (SNP). Therapeutic approaches aim at the early inflammatory liberation of cytokines to avoid systemic complications. The present study evaluates the kinetics of inflammatory mediator release in SNP. MAIN METHODS: Experimental SNP was induced in male Wistar rats using the GDOC model. The animals were allocated into seven groups (n = 6/group). In group 1, sample harvesting was performed after sham operation while in groups 2-7 this was performed 1 h, 2 h, 4 h, 6 h, 9 h, and 12 h after initiation of SNP, respectively. Inflammatory mediator release,morphologic injury, and tissue MPO concentrations were evaluated between 1 and 12 h after induction. KEY FINDINGS: Pancreatic injury showed a continuous increase over the observation period (p b 0.05, respectively). MPO levels in the pancreas and lungs increased until 12 h after induction (p b 0.05, respectively). Antiinflammatory IL-10 showed an early peak and the pro-inflammatory mediators TNFalpha and IL-1beta peaked after 6 and 9 h, respectively (p b 0.05, respectively). HMGB1 levels constantly increased over time (p b 0.05, respectively). SIGNIFICANCE: The present study shows the release of relevant pro- and anti-inflammatory mediators in SNP for the first time in one single experimental setup. Inflammatory mediators peak within the first few hours after SNP induction. Consequently, the effect of therapeutic approaches on early changes in cytokine release should be evaluated later than 2 h after initiation. PMID- 25711430 TI - Carcinostatic effects of platinum nanocolloid combined with gamma irradiation on human esophageal squamous cell carcinoma. AB - AIMS: To explore the carcinostatic effects of platinum nanocolloid (Pt-nc) combined with gamma rays on human esophageal squamous cell carcinoma (ESCC). MAIN METHODS: ESCC-derived KYSE-70 cells were treated with various concentrations of Pt-nc and/or gamma irradiation, and subsequently cultured in phenol red free DMEM with 10% FBS for 48 h. The proliferative status of the KYSE-70 cells was evaluated using trypan blue dye exclusion and WST-8 assays. Cellular and nucleic morphological aspects were evaluated using crystal violet and Hoechst 33342 stainings, respectively. Radiosensitivity was quantified by a cell viability assay, and the activated form of caspase-3, a characteristic apoptosis-related protein, was detected by Western blotting. KEY FINDINGS: Although single treatment with either Pt-nc or gamma irradiation could slightly inhibit the growth of the KYSE-70 cells, their combination exerted remarkable carcinostatic effects in a manner dependent on either Pt-nc concentrations or gamma ray doses, compared with the effect of each treatment alone (p<0.05). By fluorescence micrographic observation, the KYSE-70 cells that were treated with Pt-nc and subsequently irradiated with gamma rays, were shown to undergo distinct apoptotic morphological changes. The carcinostatic effect of gamma rays at 7 Gy without Pt nc was approximately equal to that when 3-Gy irradiation was combined with 100 ppm Pt-nc or that 5-Gy irradiation was combined with 50 ppm Pt-nc. SIGNIFICANCE: Pt-nc in combination with gamma rays may exert a cooperative effect through platinum- or gamma ray-induced apoptosis resulting in the inhibition of growth of cancer cells, while concurrently enabling the lowering of the radiative dose. PMID- 25711431 TI - Infomarkers for transition to goals consistent with palliative care in dying patients. AB - OBJECTIVE: Electronic health records (EHRs) may contain infomarkers that identify patients near the end of life for whom it would be appropriate to shift care goals to palliative care. Discovery and use of such infomarkers could be used to conduct effectiveness research that ultimately could help to reduce the monumental cost of caring for the dying. The aim of our study was to identify changes in the plans of care that represent infomarkers, which signal a transition of care goals from nonpalliative care ones to those consistent with palliative care. METHOD: Using an existing electronic health record database generated during a two-year longitudinal study of nine diverse medical-surgical units from four Midwest hospitals and a known group approach, we evaluated patient care episodes for 901 patients who died (mean age = 74.5 +/- 14.6 years). We used ANOVA and Tukey's post-hoc tests to compare patient groups. RESULTS: We identified 11 diagnoses, including Death Anxiety and Anticipatory Grieving, whose addition to the care plan, some of which also occurred with removal of nonpalliative care diagnoses, represent infomarkers of transition to palliative care goals. There were four categories of patients, those who had: no infomarkers on plans (n = 507), infomarkers added on the admission plan (n = 194), infomarkers added on a post-admission plan (minor transitions, n = 109), and infomarkers added and nonpalliative care diagnoses removed on a post-admission plan (major transition, n = 91). Age, length of stay, and pain outcomes differed significantly for these four categories of patients. SIGNIFICANCE OF RESULTS: EHRs contain pertinent infomarkers that if confirmed in future studies could be used for timely referral to palliative care for improved focus on comfort outcomes and to identify palliative care subjects from data repositories in order to conduct big-data research, comparative effectiveness studies, and health services research. PMID- 25711433 TI - Characteristics of a silicon nanowires/PEDOT:PSS heterojunction and its effect on the solar cell performance. AB - The interfacial energy-level alignment of a silicon nanowires (SiNWs)/PEDOT:PSS heterojunction is investigated using Kelvin probe force microscopy. The potential difference and electrical distribution in the junction are systematically revealed. When the PEDOT:PSS layer is covered at the bottom of the SiNW array, an abrupt junction is formed at the interface whose characteristics are mainly determined by the uniformly doped Si bulk. When the PEDOT:PSS layer is covered on the top, a hyperabrupt junction localized at the top of the SiNWs forms, and this characteristic depends on the surface properties of the SiNWs. Because the calculation shows that the absorption of light from the SiNWs and the Si bulk are equally important, the bottom-coverage structure leads to better position matching between the depletion and absorption area and therefore shows better photovoltaic performance. The dependence of JSC and VOC on the junction characteristic is discussed. PMID- 25711432 TI - Herbal medicine as a cause of recurrent facial oedema. PMID- 25711434 TI - Relation between cancer and atrial fibrillation (from the REasons for Geographic And Racial Differences in Stroke Study). AB - Atrial fibrillation (AF) is common in patients with life-threatening cancer and those undergoing active cancer treatment. However, data from subjects with a history of non-life-threatening cancer and those who do not require active cancer treatment are lacking. A total of 15,428 (mean age 66 +/- 8.9 years; 47% women; 45% blacks) participants from the REasons for Geographic And Racial Differences in Stroke (REGARDS) study with baseline data on previous cancer diagnosis and AF were included. Participants with life-threatening cancer and active cancer treatment within 2 years of study enrollment were excluded. History of cancer was identified using computer-assisted telephone interviews. AF cases were identified from baseline electrocardiogram data and by a self-reported history of a previous diagnosis. Logistic regression was used to examine the cross-sectional association between cancer diagnosis and AF. A total of 2,248 (15%) participants had a diagnosis of cancer and 1,295 (8.4%) had AF. In a multivariable logistic regression model adjusted for sociodemographic characteristics (age, gender, race, education, income, and region of residence) and cardiovascular risk factors (systolic blood pressure, high-density lipoprotein cholesterol, total cholesterol, C-reactive protein, body mass index, smoking, diabetes, antihypertensive and lipid-lowering agents, left ventricular hypertrophy, and cardiovascular disease), those with cancer were more likely to have prevalent AF than those without cancer (odds ratio 1.19, 95% confidence interval 1.02 to 1.38). Subgroup analyses by age, sex, race, cardiovascular disease, and C reactive protein yielded similar results. In conclusion, AF was more prevalent in participants with a history of non-life-threatening cancer and those who did not require active cancer treatment in REGARDS. PMID- 25711435 TI - Efficacy and safety of a routine early invasive strategy in relation to time from symptom onset to fibrinolysis (a subgroup analysis of TRANSFER-AMI). AB - The aim of this study was to assess the efficacy and safety of an early invasive strategy post-fibrinolysis in relation to time from symptom onset to fibrinolysis in patients with ST-elevation myocardial infarction (STEMI). The Trial of Routine Angioplasty and Stenting after Fibrinolysis to Enhance Reperfusion in Acute Myocardial Infarction (TRANSFER-AMI) randomized 1,059 patients receiving fibrinolysis for STEMI to an early invasive strategy versus standard therapy. The primary end point was the composite of death, reinfarction, recurrent ischemia, new or worsening heart failure, or cardiogenic shock at 30 days. In this post hoc subgroup analysis, we examined the effect of an early invasive strategy on efficacy and safety outcomes after stratification by time from symptom onset to fibrinolysis (<2 or >=2 hours). Of 1,059 patients in TRANSFER-AMI, 557 (53%) received fibrinolysis <2 hours and 502 (47%) >=2 hours after symptom onset. Compared to patients who received fibrinolysis within 2 hours of symptoms, patients who received fibrinolysis >=2 hours after symptom onset had higher Global Registry of Acute Coronary Events risk scores (median 127 vs 122, p = 0.004). The effect of an early invasive strategy did not differ between symptom to-fibrinolysis time strata for the primary efficacy end point (p-heterogeneity = 0.67), 30-day mortality, the composite of death or reinfarction at 30 days, 6 months, or 1 year, or bleeding (all p-heterogeneity >0.40). In conclusion, the efficacy and safety of an early invasive strategy in patients undergoing fibrinolysis for STEMI do not vary in relation to time (<2 or >=2 hours) from symptom onset to fibrinolysis. PMID- 25711436 TI - Current and future status of adult congenital training in North America. AB - Adult congenital heart disease (ACHD) presents a unique and growing patient population, but there are no data to suggest there are sufficient training programs available to train specialists to meet the needs of this population. The objective of this national survey was to determine the current status of ACHD fellowship curricula and training. An online questionnaire was provided to adult and pediatric cardiology fellowship programs to determine program demographics, status, duration, faculty teaching responsibilities, volume or patient exposure, and institutional obstacles. Of the 225 programs surveyed, 81 responded (36%). Nearly all were university affiliated (93%) with <1/3 (29%) reporting an ACHD fellowship program. Most offered either a 1- (42%) or a 2-year (47%) fellowship. ACHD fellowship funding was provided by hospital budget (68%). Half reported an increase in applicants to their fellowship. Applicants were more likely to have had previous training in adult cardiovascular medicine (56%). Respondents ranked "Volume of Outpatients/Year" and "Lack of Institutional Support" as the most important aspect of an ACHD program to applicants and greatest obstacle to ACHD training, respectively. After training, ACHD fellows obtained adult cardiology/ACHD positions (47%) and were within an academic center (88%). In conclusion, the results demonstrate a deficiency in the number of currently available ACHD fellowship programs. Measures should be taken to strengthen and standardize ACHD training to meet the increasing workforce requirements of this population. PMID- 25711437 TI - Large-scale insertional mutagenesis of Chlamydomonas supports phylogenomic functional prediction of photosynthetic genes and analysis of classical acetate requiring mutants. AB - Chlamydomonas reinhardtii is a unicellular green alga that is a key model organism in the study of photosynthesis and oxidative stress. Here we describe the large-scale generation of a population of insertional mutants that have been screened for phenotypes related to photosynthesis and the isolation of 459 flanking sequence tags from 439 mutants. Recent phylogenomic analysis has identified a core set of genes, named GreenCut2, that are conserved in green algae and plants. Many of these genes are likely to be central to the process of photosynthesis, and they are over-represented by sixfold among the screened insertional mutants, with insertion events isolated in or adjacent to 68 of 597 GreenCut2 genes. This enrichment thus provides experimental support for functional assignments based on previous bioinformatic analysis. To illustrate one of the uses of the population, a candidate gene approach based on genome position of the flanking sequence of the insertional mutant CAL027_01_20 was used to identify the molecular basis of the classical C. reinhardtii mutation ac17. These mutations were shown to affect the gene PDH2, which encodes a subunit of the plastid pyruvate dehydrogenase complex. The mutants and associated flanking sequence data described here are publicly available to the research community, and they represent one of the largest phenotyped collections of algal insertional mutants to date. PMID- 25711438 TI - Vascular smooth muscle cell calcification is mediated by regulated exosome secretion. AB - RATIONALE: Matrix vesicles (MVs), secreted by vascular smooth muscle cells (VSMCs), form the first nidus for mineralization and fetuin-A, a potent circulating inhibitor of calcification, is specifically loaded into MVs. However, the processes of fetuin-A intracellular trafficking and MV biogenesis are poorly understood. OBJECTIVE: The objective of this study is to investigate the regulation, and role, of MV biogenesis in VSMC calcification. METHODS AND RESULTS: Alexa488-labeled fetuin-A was internalized by human VSMCs, trafficked via the endosomal system, and exocytosed from multivesicular bodies via exosome release. VSMC-derived exosomes were enriched with the tetraspanins CD9, CD63, and CD81, and their release was regulated by sphingomyelin phosphodiesterase 3. Comparative proteomics showed that VSMC-derived exosomes were compositionally similar to exosomes from other cell sources but also shared components with osteoblast-derived MVs including calcium-binding and extracellular matrix proteins. Elevated extracellular calcium was found to induce sphingomyelin phosphodiesterase 3 expression and the secretion of calcifying exosomes from VSMCs in vitro, and chemical inhibition of sphingomyelin phosphodiesterase 3 prevented VSMC calcification. In vivo, multivesicular bodies containing exosomes were observed in vessels from chronic kidney disease patients on dialysis, and CD63 was found to colocalize with calcification. Importantly, factors such as tumor necrosis factor-alpha and platelet derived growth factor-BB were also found to increase exosome production, leading to increased calcification of VSMCs in response to calcifying conditions. CONCLUSIONS: This study identifies MVs as exosomes and shows that factors that can increase exosome release can promote vascular calcification in response to environmental calcium stress. Modulation of the exosome release pathway may be as a novel therapeutic target for prevention. PMID- 25711439 TI - Our experience in the management of obstructing colorectal cancer. AB - AIM: Comparing the different possible surgical procedures and the results in urgent/emergency and in elective surgery for obstructing colorectal cancer. MATERIAL OF STUDY: From 2008 we operated on 238 patients affected by colorectal cancer, 136 complicated tumours, 115 obstructing and 19 perforated. 23 patients had right-sided and 92 left-sided obstructing colonic tumour, divided retrospectively in 4 groups. 18 decompressive colostomy; 32 two-stages procedures: 25 Hartmann's operations and 7 total colectomies with terminal ileostomy; 7 one-stage procedures, with defunctioning ileostomy: 4 total colectomies and 3 colonic resections with wash-out; 35 one-stage procedures with primary anastomosis+wash-out or milking. RESULTS: Operative mortality is 7% in urgent/emergency versus 1% in elective surgery and anastomotic leakage affected 6 /58 cases, 5 requiring additional surgery. Overall, about 2/3 of the perioperative deaths were related to general complications and 1/3 to anastomotic failure. The local recurrence rate was 7% in elective and 11% in urgent/emergency surgery. DISCUSSION AND CONCLUSIONS: Obstructing colorectal cancer is associated with a high operative mortality and a worse prognosis, in terms of recurrence and survival. Actually, immediate resection with primary anastomosis represents the goldstandard in selected patients with a low anaesthetic risk, performing either as a typical resection with wash-out, or a subtotal colectomy; a temporary defunctioning colostomy or ileostomy could be proposed for patients with an intermediate risk; in high-risk cases, advanced obstruction, simultaneous colonic perforation, metastatic or locally advanced disease, Hartmann's operation should be used, as a safer procedure. Colon stenting can be an useful palliative or bridge-to-surgery option. KEY WORDS: Bowel obstruction, Colorectal cancer, Primary anastomosis. PMID- 25711440 TI - The challenge: "bridging the gap" with fish: advances in assessing exposure and effects across biological scales. PMID- 25711441 TI - In response: scaling polycyclic aromatic hydrocarbon toxicity to fish early life stages: a governmental perspective. PMID- 25711442 TI - In Response: environmental and biological considerations for active pharmaceutical ingredients in the environment and their effects across multiple biological scales: an academic perspective. PMID- 25711443 TI - In response: conservation versus functional diversification of nuclear receptors: an academic perspective. PMID- 25711444 TI - In summary. PMID- 25711446 TI - An analytical framework for optimizing variant discovery from personal genomes. AB - The standardization and performance testing of analysis tools is a prerequisite to widespread adoption of genome-wide sequencing, particularly in the clinic. However, performance testing is currently complicated by the paucity of standards and comparison metrics, as well as by the heterogeneity in sequencing platforms, applications and protocols. Here we present the genome comparison and analytic testing (GCAT) platform to facilitate development of performance metrics and comparisons of analysis tools across these metrics. Performance is reported through interactive visualizations of benchmark and performance testing data, with support for data slicing and filtering. The platform is freely accessible at http://www.bioplanet.com/gcat. PMID- 25711447 TI - Working memory and memory loss in neurodegenerative disease. PMID- 25711449 TI - NICE approval of dimethyl fumarate could benefit thousands living with relapsing remitting multiple sclerosis. PMID- 25711450 TI - Mild cognitive impairment definitions: more evolution than revolution. AB - Early identification of those at higher risk of dementia may play a part in secondary prevention and has received great clinical and research interest. Mild cognitive impairment (MCI) is a construct originally proposed to identify those who fall between normal cognitive aging and dementia. Clinical and research utility and validity of MCI are hotly debated. New MCI criteria proposed include the recent construct of mild neurocognitive disorder in the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders, MCI criteria proposed by the National Institute on Aging-Alzheimer's Society and criteria elaborated by the International Working Group. This article aims to discuss whether these definitions provide clearer conceptualization of MCI and to highlight implications for research. PMID- 25711451 TI - What role does tobacco smoking play in multiple sclerosis disability and mortality? A review of the evidence. AB - There is increasing evidence of tobacco smoking as an associative factor in multiple sclerosis (MS). Numerous studies have been conducted investigating the effects of smoking before the onset of MS as well as its impact on disease course. This special report reviews the available evidence and summarizes the contribution of smoking to increased mortality in patients with MS. It also explores some putative mechanisms for the involvement of tobacco constituents in the pathology of MS and the effects of smoking on disease-modifying treatments. PMID- 25711452 TI - Pharmacogenetic considerations in the treatment of Parkinson's disease. AB - Recently, a lot of progress has been made in the identification of genetic biomarkers of drug response. Efforts to define the role of genetic polymorphisms in optimizing pharmacotherapy of Parkinson's disease were also undertaken. This report presents the current state of knowledge on pharmacogenetics of PD, including genes encoding enzymes involved in drug metabolism, drug transporters and direct targets of antiparkinsonian drugs. In most of cases, available data on pharmacogenetic factors that could turn out to be significant modifiers of therapy with anti-PD drugs is still very incomplete and makes it impossible to reach final conclusion about their usefulness in the clinic. More extensive studies, in more uniform, large patient groups, including genome-wide association studies, should be undertaken to finally confirm or deny the value of genetic tests in PD therapy individualization. PMID- 25711453 TI - Are the effects of APOE epsilon4 on cognitive function in nonclinical populations age- and gender-dependent? AB - APOE epsilon4 - one of three possible allelic variants (epsilon2, epsilon3 and epsilon4) of the polymorphic protein APOE - is well characterized in its role as the strongest risk factor (after old age) for sporadic Alzheimer's disease (AD). Perhaps less well known, and certainly less well characterized, is that this epsilon4 variant of the APOE gene also is a significant risk factor for age related cognitive decline in nonclinical populations. This article considers APOE epsilon4 effects on cognition in people without dementia, the extent to which such effects may depend on age and on gender and other interactive biological systems that change across the lifespan. PMID- 25711454 TI - Remyelination in multiple sclerosis: what do we know and where are we going? AB - Multiple sclerosis (MS) patients today have more hope of a good disease outcome with an ever-increasing choice of immunomodulatory therapies to reduce disease relapses, thought to be caused by inflammation within the CNS, leading to axonal demyelination. However, although there has been much progress in this disease phase, there has been little impact on the progressive phase of MS, when neurodegeneration dominates and patients accumulate disability over years. This failure of prevention of progressive disease has led to a frame-shift in research thinking, focusing on neuroprotective strategies such as promotion of remyelination, to be used alongside immunomodulatory therapies. This review discusses this unmet need in MS, in terms of pathology and current knowledge of remyelination and proremyelinating therapies. PMID- 25711455 TI - The biomarker and therapeutic potential of miRNA in Alzheimer's disease. AB - Alzheimer's disease (AD) is the most common cause of dementia. Currently, a clinical diagnosis of AD is based on evidence of both cognitive and functional decline. Progression is monitored by detailed clinical evaluations over many months to years. It is increasingly clear that to advance disease-modifying therapies for AD, patients must be identified and treated early, before obvious cognitive and functional changes. In addition, better methods are needed to sensitively monitor progression of disease and therapeutic efficacy. Therefore, considerable research has focused on characterizing biomarkers that can identify the disease early as well as accurately monitor disease progression. miRNA offer a unique opportunity for biomarker development. Here, we review research focused on characterizing miRNA as potential biomarkers and as a treatment for disease. PMID- 25711456 TI - Agitation and aggression in Alzheimer's disease: an update on pharmacological and psychosocial approaches to care. AB - Agitation and aggression are prevalent in Alzheimer's disease and have significant consequences for the patient, caregiver and care system more generally. We briefly discuss the epidemiology and etiology of agitation and aggression in Alzheimer's disease and provide an overview of assessment and approaches to care. We then review the evidence for and against a number of pharmacological and psychosocial approaches to care. There has been a growth in the evidence base for psychosocial interventions and nonpharmacological approaches to care should ordinarily be the first option. Antipsychotics remain the pharmacological agents with most evidence to support their use while there is more limited evidence for other agents such as carbamazepine and selective serotonin reuptake inhibitors such as citalopram. PMID- 25711457 TI - Pure and palladium-loaded Co3O4 hollow hierarchical nanostructures with giant and ultraselective chemiresistivity to xylene and toluene. AB - Pure and palladium-loaded Co3O4 hollow hierarchical nanostructures consisting of nanosheets have been prepared by solvothermal self-assembly. The nanostructures exhibited an ultrahigh response and selectivity towards p-xylene and toluene. The responses (resistance ratio) of the palladium-loaded Co3O4 hollow hierarchical nanostructures to 5 ppm of p-xylene and toluene were as high as 361 and 305, respectively, whereas the selectivity values (response ratios) towards p-xylene and toluene over interference from ethanol were 18.1 and 16.1, respectively. We attributed the giant response and unprecedented high selectivity towards methylbenzenes to the abundant adsorption of oxygen by Co3O4, the high chemiresistive variation in the Co3O4 nanosheets (thickness~11 nm), and the catalytic promotion of the specific gas-sensing reaction. The morphological design of the p-type Co3O4 nanostructures and loading of the palladium catalyst have paved a new way to monitoring the most representative indoor air pollutants in a highly selective, sensitive, and reliable manner. PMID- 25711458 TI - Cavitary effusion associated with Anaplasma phagocytophilum infection in 2 equids. PMID- 25711459 TI - Respiratory Sinus Arrhythmia Moderates the Relation between Parent-Adolescent Relationship Quality and Adolescents' Social Adjustment. AB - This 2-wave longitudinal study aimed (1) to investigate whether high resting RSA predicted adolescents' lower externalizing behavior and higher empathic concern, and (2) to address the potential moderating role of resting RSA in the association between parent-adolescent relationship quality and adolescents' externalizing behavior and empathic concern. In a sample of 379 adolescents (212 boys, 167 girls), resting RSA was assessed during a laboratory session, and adolescents reported on parental support, negative interaction with parents, empathic concern and externalizing behavior during a home visit. We found no support for high resting RSA predicting low externalizing behavior or high empathic concern. However, in line with our hypotheses, we did find several instances of RSA functioning as a moderator, although the interaction patterns varied. First, negative interaction with parents was a negative predictor of externalizing behavior for girls low in resting RSA, whereas the association was non-significant for girls with high RSA. Second, higher negative interaction with parents predicted lower empathic concern for boys high in resting RSA, whereas the association was reversed for boys with low resting RSA. Third, parental support was a positive predictor of empathic concern for girls high in resting RSA, whereas the association was non-significant for girls low in resting RSA. The findings suggest that adolescents with different levels of resting RSA respond differentially to relationship quality with parents. PMID- 25711460 TI - Discovery of a small-molecule pBcl-2 inhibitor that overcomes pBcl-2-mediated resistance to apoptosis. AB - Although the role of Bcl-2 phosphorylation is still under debate, it has been identified in a resistance mechanism to BH3 mimetics, for example ABT-737 and S1. We identified an S1 analogue, S1-16, as a small-molecule inhibitor of pBcl-2. S1 16 efficiently kills EEE-Bcl-2 (a T69E, S70E, and S87E mutant mimicking phosphorylation)-expressing HL-60 cells and high endogenously expressing pBcl-2 cells, by disrupting EEE-Bcl-2 or native pBcl-2 interactions with Bax and Bak, followed by apoptosis. In vitro binding assays showed that S1-16 binds to the BH3 binding groove of EEE-Bcl-2 (Kd =0.38 MUM by ITC; IC50 =0.16 MUM by ELISA), as well as nonphosphorylated Bcl-2 (npBcl-2; Kd =0.38 MUM; IC50 =0.12 MUM). However, ABT-737 and S1 had much weaker affinities to EEE-Bcl-2 (IC50 =1.43 and >10 MUM, respectively), compared with npBcl-2 (IC50 =0.011 and 0.74 MUM, respectively). The allosteric effect on BH3 binding groove by Bcl-2 phosphorylation in the loop region was illustrated for the first time. PMID- 25711461 TI - Development of an ionic-liquid-based dispersive liquid-liquid microextraction method for the determination of antichagasic drugs in human breast milk: Optimization by central composite design. AB - Chagas disease constitutes a major public health problem in Latin America. Human breast milk is a biological sample of great importance for the analysis of therapeutic drugs, as unwanted exposure through breast milk could result in pharmacological effects in the nursing infant. Thus, the goal of breast milk drug analysis is to inquire to which extent a neonate may be exposed to a drug during lactation. In this work, we developed an analytical technique to quantify benznidazole and nifurtimox (the two antichagasic drugs currently available for medical treatment) in human breast milk, with a simple sample pretreatment followed by an ionic-liquid-based dispersive liquid-liquid microextraction combined with high-performance liquid chromatography and UV detection. For this technique, the ionic liquid 1-octyl-3-methylimidazolium hexafluorophosphate has been used as the "extraction solvent." A central composite design was used to find the optimum values for the significant variables affecting the extraction process: volume of ionic liquid, volume of dispersant solvent, ionic strength, and pH. At the optimum working conditions, the average recoveries were 77.5 and 89.7%, the limits of detection were 0.06 and 0.09 MUg/mL and the interday reproducibilities were 6.25 and 5.77% for benznidazole and nifurtimox, respectively. The proposed methodology can be considered sensitive, simple, robust, accurate, and green. PMID- 25711462 TI - Computational challenges of structure-based approaches applied to HIV. AB - Here, we review some of the opportunities and challenges that we face in computational modeling of HIV therapeutic targets and structural biology, both in terms of methodology development and structure-based drug design (SBDD). Computational methods have provided fundamental support to HIV research since the initial structural studies, helping to unravel details of HIV biology. Computational models have proved to be a powerful tool to analyze and understand the impact of mutations and to overcome their structural and functional influence in drug resistance. With the availability of structural data, in silico experiments have been instrumental in exploiting and improving interactions between drugs and viral targets, such as HIV protease, reverse transcriptase, and integrase. Issues such as viral target dynamics and mutational variability, as well as the role of water and estimates of binding free energy in characterizing ligand interactions, are areas of active computational research. Ever-increasing computational resources and theoretical and algorithmic advances have played a significant role in progress to date, and we envision a continually expanding role for computational methods in our understanding of HIV biology and SBDD in the future. PMID- 25711463 TI - Do nuclear DNA and dental nonmetric data produce similar reconstructions of regional population history? An example from modern coastal Kenya. AB - This study investigates whether variants in dental morphology and nuclear DNA provide similar patterns of intergroup affinity among regional populations using biological distance (biodistance) estimates. Many biodistance studies of archaeological populations use skeletal variants in lieu of ancient DNA, based on the widely accepted assumption of a strong correlation between phenetic- and genetic-based affinities. Within studies of dental morphology, this assumption has been well supported by research on a global scale but remains unconfirmed at a more geographically restricted scale. Paired genetic (42 microsatellite loci) and dental (nine crown morphology traits) data were collected from 295 individuals among four contemporary Kenyan populations, two of which are known ethnically as "Swahili" and two as "Taita;" all have well-documented population histories. The results indicate that biodistances based on genetic data are correlated with those obtained from dental morphology. Specifically, both distance matrices indicate that the closest affinities are between population samples within each ethnic group. Both also identify greater divergence among samples from the different ethnic groups. However, for this particular study the genetic data may provide finer resolution at detecting overall among-population relationships. PMID- 25711464 TI - Iron overload in adults with sickle cell disease who have received intermittent red blood cell transfusions. AB - OBJECTIVE: To assess the prevalence of iron overload in adults with sickle cell disease (SCD) not on a chronic transfusion protocol. DESIGN: Retrospective chart review. DATA SOURCE: University of South Alabama Comprehensive Sickle Cell Center adult outpatient clinic. RESULTS: There was no significant difference in units transfused across the four genotypes (HbSS, HbSC, HbSbeta(0)-thalassemia, and HbSbeta(+)-thalassemia). Only individuals with HbSS (n = 63) met criteria for iron overload with ferritins of >=1500 ng/mL. Forty-eight had ferritins <1500 ng/mL, eight (13%) had ferritins >=3000 ng/mL, and seven (11%) had ferritins >=1500 and <3000 ng/mL. The overall prevalence of iron overload was 9.74% in SCD cohort and 23.8% in the HbSS genotype. CONCLUSIONS: Our data support that patients with HbSS are at a particularly high risk for inadvertent iron overload as compared to HbSC, HbSbeta(0)-thalassemia, and HbSbeta(+)-thalassemia. IMPLICATIONS FOR PRACTICE: This study supports the need for healthcare providers to closely monitor the number of red blood cell (RBC) transfusions, RBC units transfused, and serial baseline, steady-state ferritin levels. With closer monitoring, the clinical significance of iron overload in SCD can be established and guide the healthcare provider's management in the prevention of iron overload. PMID- 25711465 TI - Melatonin-mediated Bim up-regulation and cyclooxygenase-2 (COX-2) down-regulation enhances tunicamycin-induced apoptosis in MDA-MB-231 cells. AB - Melatonin is involved in many physiological functions, and it has differential effects on apoptosis in normal and cancer cells. However, the mechanism of its antitumor roles is not well understood. In this study, we show that melatonin enhances tunicamycin-induced apoptosis in human breast carcinoma MDA-MB-231 cells. Melatonin up-regulates pro-apoptotic protein Bim expression at the transcriptional levels in the presence of tunicamycin. Melatonin inhibits tunicamycin-induced COX-2 expression in MDA-MB-231 cells. Furthermore, inhibition of COX-2 activity using the COX-2 inhibitor, NS398, increases tunicamycin-induced apoptosis. Interestingly, these effects were not associated with melatonin receptor signal pathways. Pertussis toxin (a general Gi protein inhibitor) or luzindole (a nonspecific melatonin receptor antagonist) did not reverse the effect of melatonin. In addition, melatonin blocked tunicamycin-induced NF-kappaB transcriptional activity, p65 nuclear translocation, and p38 MAPK activation. Melatonin-mediated p38 MAPK inhibition contributed to decreased COX-2 mRNA stability. Taken together, our results suggest that melatonin enhances antitumor function through up-regulation of Bim expression and down-regulation of COX-2 expression in tunicamycin-treated MDA-MB-231 cells. PMID- 25711466 TI - Different protein of Echinococcus granulosus stimulates dendritic induced immune response. AB - Cystic echinococcosis is a chronic infectious disease that results from a host/parasite interaction. Vaccination with ferritin derived from Echinococcus granulosus is a potential preventative treatment. To understand whether ferritin is capable of inducing a host immune response, we investigated the response of dendritic cells (DCs) to both recombinant ferritin protein and the hydatid fluid (HF) of E. granulosus. We evaluated the immunomodulatory potential of these antigens by performing, immunocytochemistry, electron microscopy and in vivo imaging of monocyte-derived murine DCs. During antigen stimulation of DCs, ferritin cause DCs maturation and induced higher levels of surface marker expression and activated T-cell proliferation and migration. On contrary, HF failed to induce surface marker expression and to stimulate T-cell proliferation. In response to HF, DCs produced interleukin-6 (IL-6), but no IL-12 and IL-10. DCs stimulated with ferritin produced high levels of cytokines. Overall, HF appears to induce host immunosuppression in order to ensure parasite survival via inhibits DC maturation and promotes Th2-dependent secretion of cytokines. Although ferritin also promoted DC maturation and cytokine release, it also activates CD4+T-cell proliferation, but regard of the mechanism of the Eg.ferritin induce host to eradicate E. granulosus were not clear. PMID- 25711467 TI - A review of standard pharmacological therapy for adult asthma - Steps 1 to 5. AB - The aim of pharmacological therapy for asthma is to improve symptoms and lung function and minimize the risk of asthma attacks. The intensity of treatment is based on the level of asthma control and the potential risk of future deterioration. In the British asthma guidelines, treatments are divided into steps 1 to 5, with each step signifying a need for an increase in therapy in response to symptoms or to prevent exacerbations. Treatments comprise of inhaled or systemic medications. Inhaled therapy includes short-acting and long-acting medication to improve symptoms and inhaled corticosteroids that reduce airway inflammation. Systemic treatments include medications that act on specific biological pathways, such as the leukotriene or immunoglobulin E pathways, or systemic corticosteroids. In choosing a particular therapy, treatment benefits are balanced by the potential risks of medication-related adverse effects. This review will provide a practical guide to the key pharmacological therapies for adult asthma at steps 1 to 5 based on British guidelines and consider future options for new treatments. PMID- 25711468 TI - GOLD B-C-D groups or GOLD II-III-IV grades: Which one better reflects the functionality of patients with chronic obstructive pulmonary disease? AB - The aim of this article is to investigate which global initiative for chronic obstructive lung disease (GOLD) classification (B-C-D or II-III-IV) better reflects the functionality of patients with moderate to very severe chronic obstructive pulmonary disease (COPD). Ninety patients with COPD were classified according to the GOLD B-C-D and II-III-IV classifications. Functionality was assessed by different outcomes: 6-min walk test (6MWT), activities of daily living (ADL) (London Chest ADL Scale), and daily life activity/inactivity variables assessed by activity monitoring (SenseWear armband, Pittsburgh, Pennsylvania, USA). The 6MWT was the only outcome significantly associated with both the GOLD classifications. Good functionality as assessed by the 6MWT was observed in 80%, 69%, and 43.5% (GOLD B, C, and D, respectively) and 81%, 59%, and 29% (GOLD II, III, and IV, respectively) of the patients. Association (V Cramer's) and correlation (Spearman) coefficients of 6MWT with GOLD B-C-D and II III-IV were V = 0.30, r = -0.35, and V = 0.37, r = -0.25, respectively. Neither GOLD classification showed V or r >= 0.30 with any other functionality outcome. Both the GOLD B-C-D and II-III-IV classifications do not reflect well COPD patients' functionality. Despite low association and correlation coefficients in general, both GOLD classifications were better associated with functional exercise capacity (6MWT) than with subjectively assessed ADL and objectively assessed outcomes of physical activity/inactivity. PMID- 25711469 TI - Hydrogen sulphide induces vasoconstriction of rat coronary artery via activation of Ca(2+) influx. AB - AIM: Hydrogen sulphide (H2S) exhibits a dual modulation of isolated artery tension. This study investigated the vasoconstrictive effect of sulphur sodium hydride (NaHS), a donor of gaseous H2S, on rat coronary artery. METHODS: The contractile response of isolated arteries was recorded using a wire myograph. Fluo-3/AM was used to load vascular smooth muscle, and intracellular calcium was determined using confocal laser microscopy. The protein expression of Rho kinase was examined using Western blot. RESULTS: NaHS induced concentration-dependent contractions of rat coronary artery, and the contraction reached approx. 65% of 60 mm KCl-induced contraction. The NaHS-induced contraction was elevated following the removal of endothelium or the use of the nitric oxide synthase inhibitor L-NAME. The cyclooxygenase inhibitor indomethacin reduced NaHS-induced contraction. The Rho kinase inhibitor Y-27632 significantly attenuated NaHS induced vasoconstriction. Furthermore, NaHS elevated the protein expression of Rho kinase. NaHS-induced contraction was completely abolished in a Ca(2+)-free solution and suppressed by the Ca(2+) influx blocker nifedipine (100 nm). NaHS also significantly increased the change rate of Ca(2+) fluorescence intensity. However, treatment with a Cl(-)/HCO(3-) exchanger blocker, K(+) channel blockers, the mitogen-activated protein kinase inhibitor U-0126 or cyclic adenosine monophosphate did not affect contraction. Species-dependent differences in NaHS induced vasoconstriction were observed because these effects were only modest in dog coronary artery and absent in rabbit coronary artery. CONCLUSIONS: NaHS induces the contraction of rat coronary artery, which is dependent on the activation of Ca(2+) influx. Rho kinase likely participates in the vasoconstriction. PMID- 25711471 TI - Extracorporeal life support, ethics, and questions at the bedside: how does the end of the pathway look? PMID- 25711470 TI - 1-[2-(4-Benzyloxyphenoxy)Ethyl]Imidazole inhibits monoamine oxidase B and protects against neuronal loss and behavioral impairment in rodent models of Parkinson's disease. AB - Monoamine oxidase B (MAO-B) is well known as a therapeutic target for Parkinson's disease (PD). MAO-B inhibitors retain antiparkinsonism abilities to improve motor function and prevent neuronal loss by decreasing dopamine metabolism and oxidative stress in the brain. From the study to find novel antiparkinsonism drugs that can inhibit MAO-B activity, neuronal loss, and behavioral deficits in the mouse model of PD, we identified that 1-[2-(4 benzyloxyphenoxy)ethyl]imidazole (BPEI) or safinamide strongly and selectively inhibited MAO-B activities in a dose-dependent manner (IC50 of BPEI and safinamide for MAO-B were 0.016 and 0.0021 uM and for MAO-A were 70.0 and 370 uM, respectively). In ex vivo studies after an administration (30 mg/kg, i.p.) of BPEI or safinamide to normal mice, the MAO-B activity in the brain was reduced by up to 90.6% or 82.4% at 1.0 hr. BPEI (20 mg/kg, i.p.) or safinamide (20 mg/kg, i.p.) significantly reversed the behavioral impairments, dopamine levels in the striatum, and neuronal loss in the substantia nigra of 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP)-treated mice compared with the MPTP-alone-treated group. In the 6-hydroxydopamine-induced PD rat model, behavioral improvement by levodopa sparing activity was observed in the BPEI- or safinamide-treated (20 mg/kg, i.p.) rats. Moreover, BPEI revealed additional curative activities for nonmotor symptoms of PD such as pain, anxiety, epilepsy, and depression in rodent disease models. Therefore, BPEI has broad therapeutic potential for treating motor symptoms via strong and selective inhibitory effects on MAO-B, with additional benefits for comorbid symptoms in PD. PMID- 25711472 TI - Where was I when I was in a coma? PMID- 25711473 TI - Ten old antibiotics that will never disappear. PMID- 25711475 TI - Another pressurization system for invasive monitoring. PMID- 25711476 TI - In reply: another pressurization system for invasive monitoring. PMID- 25711477 TI - Vasoactive Intestinal Peptide in Early Spondyloarthritis: Low Serum Levels as a Potential Biomarker for Disease Severity. AB - Spondyloarthritis (SpA) is a family of inflammatory diseases sharing clinical, genetic, and radiological features. While crucial for tailoring early interventions, validated prognostic biomarkers are scarce in SpA. We analyze the correlation between serum levels of vasoactive intestinal peptide (VIP) and disease activity/severity in patients with early chronic inflammatory back pain. The study population comprised 54 patients enrolled in our early chronic inflammatory back pain register. We collected demographic information, clinical data, laboratory data, and imaging findings. VIP levels were measured by enzyme immunoassay in serum samples from 162 visits. The association between independent variables and VIP levels was analyzed using longitudinal multivariate analysis nested by patient and visit. No significant differences were observed in VIP levels between these two groups. Lower levels of VIP were significantly associated with a higher Bath Ankylosing Spondylitis Disease Activity Index (BASFI) score, presence of bone edema in magnetic resonance imaging (MRI) scan, and lower hemoglobin levels. Coexistence of cutaneous psoriasis was independently associated with lower VIP levels, and similar trend was observed for enthesitis. We conclude that SpA patients with low serum VIP levels had worse 2-year disease outcome, suggesting that serum VIP levels could be a valid prognostic biomarker. PMID- 25711478 TI - Association of GWAS-Supported Variants rs2200733 and rs6843082 on Chromosome 4q25 with Ischemic Stroke in the Southern Chinese Han Population. AB - Genome-wide association studies (GWAS) have revealed two single-nucleotide polymorphisms (SNPs) on chromosome 4q25, rs2200733, and rs6843082, associated with ischemic stroke (IS) in Caucasians. However, subsequent validation studies have remained controversial. The current study aims to evaluate the associations between rs2200733, rs6843082, and IS in the southern Chinese Han population. A total of 1632 subjects were recruited in this case-control study. Genotyping for rs2200733 and rs6843082 was conducted in the Sequenom MassARRAY iPLEX platform. The genetic association of the rs2200733 and rs6843082 polymorphisms with IS was estimated using the PLINK program. Our results show that the SNP rs2200733 and rs6843082 have no significant associations with IS in additive, dominant, recessive, and allelic models (all p > 0.050). However, the results also indicate that the rs2200733 polymorphism is associated with systolic blood pressure (SBP) in IS patients in both the additive model (p adj = 0.002) and the recessive model (p adj = 0.002) after correcting for age. Meanwhile, the rs6843082 polymorphism showed a significant association with serum total cholesterol (TC) in IS individuals in the additive model (p adj = 0.017) and the dominant model (p adj = 0.023). These findings suggest that the SNP rs2200733 and rs6843082 on chromosome 4q25 may be not associated with IS susceptibility in southern Han Chinese. As for IS-related quantitative traits, the rs2200733 and rs6843082 polymorphisms might influence SBP and TC in IS patients, respectively. PMID- 25711479 TI - Is extinction forever? AB - Mistrust of science has seeped into public perception of the most fundamental aspect of conservation-extinction. The term ought to be straightforward, and yet, there is a disconnect between scientific discussion and public views. This is not a mere semantic issue, rather one of communication. Within a population dynamics context, we say that a species went locally extinct, later to document its return. Conveying our findings matters, for when we use local extinction, an essentially nonsensical phrase, rather than extirpation, which is what is meant, then we contribute to, if not create outright, a problem for public understanding of conservation, particularly as local extinction is often shortened to extinction in media sources. The public that receives the message of our research void of context and modifiers comes away with the idea that extinction is not forever or, worse for conservation as a whole, that an extinction crisis has been invented. PMID- 25711480 TI - Seasonal and Ontogenetic Variation in Subcutaneous Adipose Of the Bowhead Whale (Balaena mysticetus). AB - Cetacean evolution was shaped by an extraordinary land-to-sea transition in which the ancestors of whales became fully aquatic. As part of this transition, these mammals evolved unusually thick blubber which acts as a metabolic reservoir as well as an insulator and provides buoyancy and streamlining. This study describes blubber stratification and correlates it to seasonal variation, feeding patterns, and ontogeny in an arctic-adapted mysticete, the bowhead whale (Balaena mysticetus). Bowheads are unique among mammals for possessing the largest known blubber stores. We found that adipocyte numbers in bowheads, like other mammals, do not vary with season or feeding pattern but that adipocyte size and structural fiber densities do vary with blubber depth. PMID- 25711481 TI - Catalytic total hydrodeoxygenation of biomass-derived polyfunctionalized substrates to alkanes. AB - The total hydrodeoxygenation of carbohydrate-derived molecules to alkanes, a key reaction in the production of biofuel, was reviewed from the aspect of catalysis. Noble metals (or Ni) and acid are the main components of the catalysts, and group 6 or 7 metals such as Re are sometimes added as modifiers of the noble metal. The main reaction route is acid-catalyzed dehydration plus metal-catalyzed hydrogenation, and in some systems metal-catalyzed direct C?O dissociation is involved. The appropriate active metal, acid strength, and reaction conditions depend strongly on the reactivity of the substrate. Reactions that use Pt or Pd catalysts supported on Nb-based acids or relatively weak acids are suitable for furanic substrates. Carbohydrates themselves and sugar alcohols undergo C?C dissociation easily. The systems that use metal-catalyzed direct C?O dissociations can give a higher yield of the corresponding alkane from carbohydrates and sugar alcohols. PMID- 25711483 TI - Pharmacotherapy of acute mania: monotherapy or combination therapy with mood stabilizers and antipsychotics? AB - The use of combination therapy with mood stabilizers and antipsychotics in acute mania in bipolar disorder (BD) is widespread, although most treatment guidelines recommend monotherapy as the first option, and reserve combination therapy, which is associated with more frequent and more severe side effects, for when patients do not respond to the former treatment option. Reasons to prescribe combination therapy include the lack of efficacy of the current treatment (either real or due to undisclosed poor adherence), psychiatric comorbidities, severe previous course of illness, slow cross-tapering during treatment switching, and potential benefits from particular combinations. The decision to start with monotherapy or combination therapy may depend on the patient characteristics, and is still under debate. Clinical trials designed to ascertain whether combination therapy or monotherapy is more advantageous for patients in acute mania and beyond, according to illness severity, are urgently needed. Adding a third monotherapy arm to the conventional two-arm, adjunctive-design trials or initiating combination therapy from the beginning may help to shed some light on the issue. PMID- 25711484 TI - A systematic evaluation of the lagged effects of spatiotemporally relative surface weather types on wintertime cardiovascular-related mortality across 19 US cities. AB - Previous research using varying methods has shown that the day-to-day variability in cardiovascular (CV)-related mortality is correlated with a number of different meteorological variables, though these relationships can vary geographically. This research systematically examines the relationship between anomalous winter CV-related mortality and geographically and seasonally relative multivariate surface weather types derived from a recently developed gridded weather typing classification (GWTC) for cities in varying climate regions of the United States of America (USA). Results indicate that for all locations examined, during winter, a dry and cool (DC) weather type is significantly related to increased CV related mortality, especially in the 2 weeks immediately after it occurs, with no apparent mortality displacement. Across the USA as a whole, the peak of this relationship is a 4.1% increase in CV-related mortality at a lag of 3 days. Spike days in CV-related mortality show similar trends, being over 50% more likely 2 to 4 days after the DC type occurs. A humid and warm (HW) weather type exhibited a significant and opposite relationship to that of DC. While these results for DC and HW were statistically significant at every location examined, the magnitudes were larger in the warmer locations. Among other weather types, Warm Front Passages (WFP) were also related to significant increases in CV-related mortality, especially 1 day after they occurred. Though this link was much more varied geographically than results found with DC or HW, it suggests that sequences of multiple DC days followed by WFP may result in increased CV-related mortality. PMID- 25711485 TI - Complications After Laparoscopic Cholecystectomy: A Video Evaluation Study of Whether the Critical View of Safety was Reached. AB - BACKGROUND: Achieving the critical view of safety (CVS) before transection of the cystic artery and duct is important to reduce biliary duct injury in laparoscopic cholecystectomy. To gain more insight into complications after laparoscopic cholecystectomy, we investigated whether the criteria for CVS were met during surgery by analyzing videos of operations performed at our institution. METHODS: All consecutive patients who underwent a completed laparoscopic cholecystectomy between 2009 and 2011 were included. The videos of the operations of patients with complications were independently reviewed and rated by two investigators with a third consulted in the event of a disagreement. The reviewers answered consecutive questions about whether the CVS criteria were met. Patients who underwent an elective laparoscopic cholecystectomy and had no complications were used as a control group for comparison. RESULTS: Of the 1108 consecutive patients who had undergone a laparoscopic cholecystectomy during the study period, 8.8 % developed complications (average age 51 years) and 1.7 % had bile duct injuries [six patients (0.6 %) had a major bile duct injury, type B, D, or E injury]. In the 65 surgical videos available for analysis, CVS was reached in 80 % of cases according to the operative notes. However, the reviewers found that CVS was reached in only 10.8 % of the cases. Only in 18.7 % of the cases the operative notes and video agreed about CVS being reached. CVS was not reached in any of the patients who had biliary injuries. In the control group, CVS was reached significantly more often in 72 %. CONCLUSIONS: In our institutional series of laparoscopic cholecystectomies with postoperative complications, CVS was reached in only a few cases. Evaluating surgical videos of laparoscopic cholecystectomy cases are important and we recommend its use to improve surgical technique and decrease the number of biliary injuries. PMID- 25711486 TI - Overexpression of Ku80 suggests poor prognosis of locally advanced esophageal squamous cell carcinoma patients. AB - BACKGROUND: Recent studies have shown that Ku80 expression was implicated in development and progression of malignant tumors. In the present study, we analyzed for the first time the expression of Ku80 in locally advanced esophageal squamous cell carcinoma (ESCC) and its correlation with clinicopathologic features and patient survival. METHODS: The expression profile of Ku80 was analyzed in 126 cases of locally advanced ESCC and 79 cases of normal subjects as control using immunohistochemistry and Western blot. The associations of Ku80 expression with clinicopathological features were estimated by chi (2) test. We further performed univariate and multivariate analyses to identify prognostic factors for overall survival (OS) of patients. RESULTS: Immunohistochemistry and Western blot analyses both showed the Ku80 protein expression was significantly higher in ESCC than normal esophageal mucosa and corresponding healthy esophageal mucosa. Statistical analysis suggested a significant correlation of Ku80 overexpression with the tumor size (p = 0.037), differentiation degree (p = 0.018), depth of invasion (p = 0.020), lymph node metastasis (p = 0.045), clinicopathological staging (p = 0.001), and tumor recurrence (p = 0.011) in locally advanced ESCC patients. Moreover, overexpression of Ku80 was associated with reduced OS of patients after surgery (p = 0.001). Multivariate analysis with a Cox proportional hazards model further suggested that Ku80 expression was an independent prognostic indicator for patients' OS (p = 0.029). CONCLUSIONS: Ku80 was a predictor of tumor's progression and prognosis of locally advanced ESCC patients. All of these results indicate that assessment of Ku80 level could improve stratification of locally advanced ESCC patients. PMID- 25711487 TI - p21-activated kinase 1 predicts recurrence and survival in patients with non metastatic clear cell renal cell carcinoma. AB - OBJECTIVES: To estimate the impact of p21-activated kinase 1 expression on recurrence and survival of patients with non-metastatic clear cell renal cell carcinoma after surgical resection. METHODS: We retrospectively enrolled 254 patients (187 in the training cohort and 67 in the validation cohort) with non metastatic clear cell renal cell carcinoma undergoing nephrectomy at a single institution. Clinicopathological features, overall survival and recurrence-free survival were recorded. p21-activated kinase 1 intensities were assessed by immunohistochemistry of patients' specimens. The Kaplan-Meier method was applied to compare survival curves. Cox regression models were used to analyze the impact of prognostic factors on overall survival and recurrence-free survival. The concordance index was calculated to assess predictive accuracy. RESULTS: In both cohorts, elevated p21-activated kinase 1 expression in tumor tissues positively correlated with advanced T stage and Fuhrman grade. High p21-activated kinase 1 expression indicated poor survival and early recurrence of patients with non metastatic clear cell renal cell carcinoma, especially with early T1-2 stage disease. After backward elimination, p21-activated kinase 1 expression was identified as an independent adverse prognostic factor for survival and recurrence. The predictive accuracy of the traditional University of California Integrated Staging System and Mayo Clinic stage, size, grade and necrosis prognostic models was improved when p21-activated kinase 1 expression was added. CONCLUSIONS: Elevated expression of p21-activated kinase 1 seems to be an independent adverse prognostic biomarker for recurrence and survival in patients with non-metastatic clear cell renal cell carcinoma after nephrectomy. PMID- 25711489 TI - Multiresolution quantum chemistry in multiwavelet bases: excited states from time dependent Hartree-Fock and density functional theory via linear response. AB - A fully numerical method for the time-dependent Hartree-Fock and density functional theory (TD-HF/DFT) with the Tamm-Dancoff (TD) approximation is presented in a multiresolution analysis (MRA) approach. From a reformulation with effective use of the density matrix operator, we obtain a general form of the HF/DFT linear response equation in the first quantization formalism. It can be readily rewritten as an integral equation with the bound-state Helmholtz (BSH) kernel for the Green's function. The MRA implementation of the resultant equation permits excited state calculations without virtual orbitals. The integral equation is efficiently and adaptively solved using a numerical multiresolution solver with multiwavelet bases. Our implementation of the TD-HF/DFT methods is applied for calculating the excitation energies of H2, Be, N2, H2O, and C2H4 molecules. The numerical errors of the calculated excitation energies converge in proportion to the residuals of the equation in the molecular orbitals and response functions. The energies of the excited states at a variety of length scales ranging from short-range valence excitations to long-range Rydberg-type ones are consistently accurate. It is shown that the multiresolution calculations yield the correct exponential asymptotic tails for the response functions, whereas those computed with Gaussian basis functions are too diffuse or decay too rapidly. We introduce a simple asymptotic correction to the local spin-density approximation (LSDA) so that in the TDDFT calculations, the excited states are correctly bound. PMID- 25711488 TI - Diagnosis and treatment of chronic bacterial prostatitis and chronic prostatitis/chronic pelvic pain syndrome: a consensus guideline. AB - OBJECTIVES: To improve awareness and recognition of chronic bacterial prostatitis (CBP) and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) among non specialists and patients. To provide guidance to healthcare professionals treating patients with CBP and CP/CPPS, in both non-specialist and specialist settings. To promote efficient referral of care between non-specialists and specialists and the involvement of the multidisciplinary team (MDT). PATIENTS AND METHODS: The guideline population were men with CBP or CP/CPPS (persistent or recurrent symptoms and no other urogenital pathology for >=3 of the previous 6 months). Consensus recommendations for the guidelines were based on a search to identify literature on the diagnosis and management of CBP and CP/CPPS (published between 1999 and February 2014). A Delphi panel process was used where high quality, published evidence was lacking. RESULTS: CBP and CP/CPPS can present with a wide range of clinical manifestations. The four main symptom domains are urogenital pain, lower urinary tract symptoms (LUTS - voiding or storage symptoms), psychological issues and sexual dysfunction. Patients should be managed according to their individual symptom pattern. Options for first-line treatment include antibiotics, alpha-adrenergic antagonists (if voiding LUTS are present) and simple analgesics. Repeated use of antibiotics, such as quinolones, should be avoided if there is no obvious symptomatic benefit from infection control or cultures do not support an infectious cause. Early use of treatments targeting neuropathic pain and/or referral to specialist services should be considered for patients who do not respond to initial measures. An MDT approach (urologists, pain specialists, nurse specialists, specialist physiotherapists, general practitioners, cognitive behavioural therapists/psychologists, and sexual health specialists) is recommended. Patients should be fully informed about the possible underlying causes and treatment options, including an explanation of the chronic pain cycle. CONCLUSION: Chronic prostatitis can present with a wide variety of signs and symptoms. Identification of individual symptom patterns and a symptom-based treatment approach are recommended. Further research is required to evaluate management options for CBP and CP/CPPS. PMID- 25711490 TI - Publications and rejections. PMID- 25711491 TI - Fixation of atmospheric carbon dioxide by ruthenium complexes bearing an NHC based pincer ligand: formation of a methylcarbonato complex and its methylation. AB - A methylcarbonato ruthenium complex was prepared by capture of CO2 from air using the (CNC)(bpy)Ru scaffold. The methylcarbonato complex was relatively inert to decarboxylation. Treatments with methylating reagents released dimethylcarbonate. PMID- 25711492 TI - Liver transplant and kidney disease: the scope of the problem. PMID- 25711493 TI - Role of microemuslsions in advanced drug delivery. AB - Microemulsions have gained significant attention from formulation scientists since the time they have been discovered, because of their excellent properties related to their stability, solubility, simplicity, and formulation aspects. The application of microemulsions is not limited to drug delivery via the oral, topical or ocular routes, but may also be seen in cosmetics, immunology, sensor devices, coating, textiles, analytical chemistry, and spermicide. Finally, the objective of this review is to discuss briefly the applications of microemulsions in advanced drug delivery. PMID- 25711494 TI - Characteristics and contributions of hyperandrogenism to insulin resistance and other metabolic profiles in polycystic ovary syndrome. AB - OBJECTIVE: To investigate the different characteristics in Chinese Han women with polycystic ovary syndrome, and to analyze the significance of hyperandrogenism in insulin resistance and other metabolic profiles. DESIGN: A cross-sectional study. SETTING: Medical university hospital. POPULATION: A total of 229 women with polycystic ovary syndrome aged 18-45 years. METHODS: Women with polycystic ovary syndrome, diagnosed by Rotterdam criteria, were divided into four groups according to the quartile intervals of free androgen index levels. MAIN OUTCOME MEASURES: Comparisons between groups were performed using one-way analysis of variance. Stepwise logistic regression analysis was performed to investigate the association between homeostasis model assessment-insulin resistance and independent variables. RESULTS: Within the four phenotypes, women with phenotype 1 (hyperandrogenism, oligo/anovulation, and polycystic ovaries) exhibited higher total testosterone, free androgen index, androstenedione, low-density lipoprotein, and lower quantitative insulin sensitivity check index (p < 0.05); women with phenotype 4 (oligo/anovulation and polycystic ovaries) showed lower total cholesterol, low-density lipoprotein, and homeostasis model assessment insulin resistance, but higher high-density lipoprotein (p < 0.05). The levels of triglycerides, total cholesterol, low-density lipoprotein, and homeostasis model assessment-insulin resistance significantly increased, but high-density lipoprotein and quantitative insulin sensitivity check index decreased with the elevation of free androgen index intervals. After adjustment for lipid profiles, free androgen index was significantly associated with homeostasis model assessment-insulin resistance in both lean and overweight/obese women (odds ratio 1.302, p = 0.039 in lean vs. odds ratio 1.132, p = 0.036 in overweight/obese). CONCLUSIONS: Phenotypes 1 and 4 represent groups with the most and least severe metabolic profiles, respectively. Hyperandrogenism, particularly with elevated free androgen index, is likely a key contributing factor for insulin resistance and for the aggravation of other metabolic profiles. PMID- 25711495 TI - Synthesis of sulfonamide conjugates of Cu(II), Ga(III), In(III), Re(V) and Zn(II) complexes: carbonic anhydrase inhibition studies and cellular imaging investigations. AB - Carbonic anhydrase IX (CA IX) is currently generating great interest as a marker of tumour hypoxia and a potential chemotherapeutic target. In order to test the principle that a CA IX inhibitor could be used for targeting PET or SPECT metallic radioisotopes to tumours we have prepared a number of conjugates involving aryl-sulfonamides or an acetazolamide derivative linked to a range of copper, indium, rhenium, 99m-technetium and zinc complexes. Radiolabelled (64)Cu and (99m)Tc analogues of the 'cold' Cu and some of the Re complexes were prepared in good radiochemical incorporation. Inhibition of various human carbonic anhydrase isoforms (I, II, IX and XII) was tested with the 'cold', non radiolabelled complexes, and compared with an acetazolamide standard (AZA). The molecular structure of a new, tri-sulfonated porphyrin-labeled sulfonamide was determined using synchrotron X-ray crystallography. PMID- 25711497 TI - DNA damage in cells exhibiting radiation-induced genomic instability. AB - Cells exhibiting radiation-induced genomic instability exhibit varied spectra of genetic and chromosomal aberrations. Even so, oxidative stress remains a common theme in the initiation and/or perpetuation of this phenomenon. Isolated oxidatively modified bases, abasic sites, DNA single strand breaks and clustered DNA damage are induced in normal mammalian cultured cells and tissues due to endogenous reactive oxygen species generated during normal cellular metabolism in an aerobic environment. While sparse DNA damage may be easily repaired, clustered DNA damage may lead to persistent cytotoxic or mutagenic events that can lead to genomic instability. In this study, we tested the hypothesis that DNA damage signatures characterised by altered levels of endogenous, potentially mutagenic, types of DNA damage and chromosomal breakage are related to radiation-induced genomic instability and persistent oxidative stress phenotypes observed in the chromosomally unstable progeny of irradiated cells. The measurement of oxypurine, oxypyrimidine and abasic site endogenous DNA damage showed differences in non double-strand breaks (DSB) clusters among the three of the four unstable clones evaluated as compared to genomically stable clones and the parental cell line. These three unstable clones also had increased levels of DSB clusters. The results of this study demonstrate that each unstable cell line has a unique spectrum of persistent damage and lead us to speculate that alterations in DNA damage signaling and repair may be related to the perpetuation of genomic instability. PMID- 25711496 TI - Increased levels of chromosomal aberrations and DNA damage in a group of workers exposed to formaldehyde. AB - Formaldehyde (FA) is a commonly used chemical in anatomy and pathology laboratories as a tissue preservative and fixative. Because of its sensitising properties, irritating effects and cancer implication, FA accounts probably for the most important chemical-exposure hazard concerning this professional group. Evidence for genotoxic effects and carcinogenic properties in humans is insufficient and conflicting, particularly in regard to the ability of inhaled FA to induce toxicity on other cells besides first contact tissues, such as buccal and nasal cells. To evaluate the effects of exposure to FA in human peripheral blood lymphocytes, a group of 84 anatomy pathology laboratory workers exposed occupationally to FA and 87 control subjects were tested for chromosomal aberrations (CAs) and DNA damage (comet assay). The level of exposure to FA in the workplace air was evaluated. The association between genotoxicity biomarkers and polymorphic genes of xenobiotic-metabolising and DNA repair enzymes were also assessed. The estimated mean level of FA exposure was 0.38+/-0.03 ppm. All cytogenetic endpoints assessed by CAs test and comet assay % tail DNA (%TDNA) were significantly higher in FA-exposed workers compared with controls. Regarding the effect of susceptibility biomarkers, results suggest that polymorphisms in CYP2E1 and GSTP1 metabolic genes, as well as, XRCC1 and PARP1 polymorphic genes involved in DNA repair pathways are associated with higher genetic damage in FA exposed subjects. Data obtained in this study show a potential health risk situation of anatomy pathology laboratory workers exposed to FA (0.38 ppm). Implementation of security and hygiene measures may be crucial to decrease risk. The obtained information may also provide new important data to be used by health care programs and by governmental agencies responsible for occupational health and safety. PMID- 25711498 TI - The exposome concept in a human nutrigenomics study: evaluating the impact of exposure to a complex mixture of phytochemicals using transcriptomics signatures. AB - The application of transcriptome analyses in molecular epidemiology studies has become a promising tool in order to evaluate the impact of environmental exposures. These analyses have a great value in establishing the exposome, the totality of human exposures, both by identifying the chemical nature of the exposures and the induced molecular responses. Transcriptomic signatures can be regarded as biomarker of exposure as well as markers of effect which reflect the interaction between individual genetic background and exposure levels. However, the biological interpretation of modulated gene expression profiles is a challenging task and translating affected molecular pathways into risk assessment, for instance in terms of cancer promoting or disease preventing responses, is a far from standardised process. Here, we describe the in-depth analyses of the gene expression responses in a human dietary intervention in which the interaction between genotype and exposure to a blueberry-apple juice containing a complex mixture of phytochemicals is investigated. We also describe how data on differences in genetic background combined with different effect markers can provide a better understanding of gene-environment interactions. Pathway analyses of differentially expressed genes in combination with gene were used to identify complex but strong changes in several biological processes like immune response, cell adhesion, lipid metabolism and apoptosis. These observed changes may lead to upgraded growth control, induced immunity, reduced platelet aggregation and activation, diminished production of reactive oxidative species by platelets, blood glucose homeostasis, regulation of blood lipid levels and increased apoptosis. Our findings demonstrate that applying transcriptomics to well-controlled human dietary intervention studies can provide insight into mechanistic pathways involved in disease prevention by dietary factors. PMID- 25711500 TI - A vantage from space can detect earlier drought onset: an approach using relative humidity. AB - Each year, droughts cause significant economic and agricultural losses across the world. The early warning and onset detection of drought is of particular importance for effective agriculture and water resource management. Previous studies show that the Standard Precipitation Index (SPI), a measure of precipitation deficit, detects drought onset earlier than other indicators. Here we show that satellite-based near surface air relative humidity data can further improve drought onset detection and early warning. This paper introduces the Standardized Relative Humidity Index (SRHI) based on the NASA Atmospheric Infrared Sounder (AIRS) observations. The results indicate that the SRHI typically detects the drought onset earlier than the SPI. While the AIRS mission was not originally designed for drought monitoring, we show that its relative humidity data offers a new and unique avenue for drought monitoring and early warning. We conclude that the early warning aspects of SRHI may have merit for integration into current drought monitoring systems. PMID- 25711499 TI - Wood dust exposure induces cell transformation through EGFR-mediated OGG1 inhibition. AB - A high risk of neoplastic transformation of nasal and paranasal sinuses mucosa is related to the occupational exposure to wood dust. However, the role of occupational exposures in the aetiology of the airway cancers remains largely unknown. Here, an in vitro model was performed to investigate the carcinogenic effect of wood dusts. Human bronchial epithelial cells were incubated with hard and soft wood dusts and the DNA damage and response to DNA damage evaluated. Wood dust exposure induced accumulation of oxidised DNA bases, which was associated with a delay in DNA repair activity. By exposing cells to wood dust at a prolonged time, wood dust-initiated cells were obtained. Initiated-cells were able to form colonies in soft agar, and to induce blood vessel formation. These cells showed extensive autophagy, reduced DNA repair, which was associated with reduced OGG1 expression and oxidised DNA base accumulation. These events were found related to the activation of EGFR/AKT/mTOR pathway, through phosphorylation and subsequent inactivation of tuberin. The persistence in the tissue of wood dusts, their repetitious binding with EGFR may continually trigger the activation switch, leading to chronic down-regulation of genes involved in DNA repair, leading to cell transformation and proliferation. PMID- 25711501 TI - Hijab (headscarf) headache. AB - Hijab (headscarf) headache is well known among wearers and is a common topic of discussion. It has never previously been reported in the medical literature. Five women described bilateral headache either prompted by or worsened by donning the hijab, or headscarf. The headache always resolved soon after removal of the headscarf. Hijab headache may also be alleviated by minimal modifications in style while allowing women to maintain their moral conviction. It likely represents an extracranial etiology of headache, and recognition may prevent unnecessary evaluation and suffering in hijab wearers. PMID- 25711502 TI - The effect of ANK3 bipolar-risk polymorphisms on the working memory circuitry differs between loci and according to risk-status for bipolar disorder. AB - Polymorphisms at the rs10994336 and rs9804190 loci of the Ankyrin 3 (ANK3) gene have been strongly associated with increased risk for bipolar disorder (BD). However, their potential pathogenetic effect on BD-relevant neural circuits remains unknown. We examined the effect of BD-risk polymorphisms at rs10994336 and rs9804190 on the working memory (WM) circuit using functional magnetic resonance imaging (fMRI) data obtained from euthymic patients with BD (n = 41), their psychiatrically healthy first-degree relatives (n = 25) and unrelated individuals without personal or family history of psychiatric disorders (n = 46) while performing the N-back task. In unrelated healthy individuals, the rs10994336-risk-allele was associated with reduced activation of the ventral visual cortical components of the WM circuit while the rs9804190-risk-allele was associated with inefficient hyperactivation of the prefrontal cortical components of the WM. In patients and their healthy relatives, risk alleles at either loci were associated with hyperactivation in the ventral anterior cingulate cortex. Additionally, Rs9804190-risk-allele carriers with BD evidenced abnormal hyperactivation within the posterior cingulate cortex. This study provides new insights on the neurogenetic correlates of allelic variation at different genome wide supported BD-risk associated ANK3 loci that support their involvement in BD and highlight the modulatory influence of increased background genetic risk for BD. PMID- 25711503 TI - RNAseq reveals weed-induced PIF3-like as a candidate target to manipulate weed stress response in soybean. AB - Weeds reduce yield in soybeans (Glycine max) through incompletely defined mechanisms. The effects of weeds on the soybean transcriptome were evaluated in field conditions during four separate growing seasons. RNASeq data were collected from six biological samples of soybeans growing with or without weeds. Weed species and the methods to maintain weed-free controls varied between years to mitigate treatment effects, and to allow detection of general soybean weed responses. Soybean plants were not visibly nutrient- or water-stressed. We identified 55 consistently downregulated genes in weedy plots. Many of the downregulated genes were heat shock genes. Fourteen genes were consistently upregulated. Several transcription factors including a PHYTOCHROME INTERACTING FACTOR 3-like gene (PIF3) were included among the upregulated genes. Gene set enrichment analysis indicated roles for increased oxidative stress and jasmonic acid signaling responses during weed stress. The relationship of this weed induced PIF3 gene to genes involved in shade avoidance responses in Arabidopsis provide evidence that this gene may be important in the response of soybean to weeds. These results suggest that the weed-induced PIF3 gene will be a target for manipulating weed tolerance in soybean. PMID- 25711504 TI - Anthropogenic nitrogen deposition enhances carbon sequestration in boreal soils. AB - It is proposed that carbon (C) sequestration in response to reactive nitrogen (Nr ) deposition in boreal forests accounts for a large portion of the terrestrial sink for anthropogenic CO2 emissions. While studies have helped clarify the magnitude by which Nr deposition enhances C sequestration by forest vegetation, there remains a paucity of long-term experimental studies evaluating how soil C pools respond. We conducted a long-term experiment, maintained since 1996, consisting of three N addition levels (0, 12.5, and 50 kg N ha(-1) yr(-1) ) in the boreal zone of northern Sweden to understand how atmospheric Nr deposition affects soil C accumulation, soil microbial communities, and soil respiration. We hypothesized that soil C sequestration will increase, and soil microbial biomass and soil respiration will decrease, with disproportionately large changes expected compared to low levels of N addition. Our data showed that the low N addition treatment caused a non-significant increase in the organic horizon C pool of ~15% and a significant increase of ~30% in response to the high N treatment relative to the control. The relationship between C sequestration and N addition in the organic horizon was linear, with a slope of 10 kg C kg(-1) N. We also found a concomitant decrease in total microbial and fungal biomasses and a ~11% reduction in soil respiration in response to the high N treatment. Our data complement previous data from the same study system describing aboveground C sequestration, indicating a total ecosystem sequestration rate of 26 kg C kg(-1) N. These estimates are far lower than suggested by some previous modeling studies, and thus will help improve and validate current modeling efforts aimed at separating the effect of multiple global change factors on the C balance of the boreal region. PMID- 25711505 TI - Acute Bilateral Compartment Syndrome Secondary to Polydipsia-Induced Severe Hyponatremia. PMID- 25711506 TI - Psychosocial Approaches in the Treatment of Psychosis: Cognitive Behavior Therapy for Psychosis (CBTp) and Metacognitive Training (MCT). AB - Although antipsychotic medication has been the most widely used and efficacious treatment in ameliorating the symptoms of psychosis, there has been a growing realization that pharmacological treatment has limitations. A significant minority of individuals continue to show "treatment-resistant" symptoms and significant relapse risk, while others show symptom reduction without the corresponding improvement in social and role functioning. Psychotherapy, in combination with medication, can help with symptom reduction, as well as improve functioning and quality of life. In this paper, we focus on two modalities of psychotherapy which have been shown to improve symptomatology and functioning in individuals with psychosis: Cognitive Behavior Therapy for psychosis (CBTp) and Metacognitive Training (MCT). Both treatment approaches focus on increasing the individuals' understanding of the psychological mechanisms associated with delusions and hallucinations, and helping them develop strategies to improve reality testing and belief evaluation. We aim to provide an overview of both treatments, examining not only the theoretical mechanisms and efficacy of each approach, but also the common therapeutic components they share. PMID- 25711507 TI - Psychosis in a Patient with Davidoff-Dyke-Masson Syndrome. AB - OBJECTIVES: To report the finding of psychosis in a patient with Davidoff-Dyke Masson Syndrome. METHOD: Case report. CONCLUSIONS: Right-sided hemiatrophy may be an addition to the list of neuro-developmental and structural cerebral anomalies associated with psychotic disorders including schizophrenia. PMID- 25711508 TI - Disorganized Symptoms Predicted Worse Functioning Outcome in Schizophrenia Patients with Established Illness. AB - : Most patients with schizophrenia will have subsequent relapses of the disorder, with continuous impairments in functioning. However, evidence is lacking on how symptoms influence functioning at different phases of the disease. This study aims to investigate the relationship between symptom dimensions and functioning at different phases: acute exacerbation, nonremission and remission. METHODS: Patients with schizophrenia were grouped into acutely ill (n=89), not remitted (n=89), and remitted (n=69). Three exploratory stepwise linear regression analyses were performed for each phase of schizophrenia, in which the five PANSS factors and demographic variables were entered as the independent variables and the total Global Assessment of Functioning Scale (GAF) score was entered as the dependent variable. An additional exploratory stepwise logistic regression analysis was performed to predict subsequent remission at discharge in the inpatient population. RESULTS: The Disorganized factor was the most significant predictor for acutely ill patients (p<0.001), while the Hostility factor was the most significant for not-remitted patients and the Negative factor was the most significant for remitted patients (p=0.001 and p<0.001, respectively). In the logistic regression, the Disorganized factor score presented a significant negative association with remission (p=0.007). CONCLUSIONS: Higher disorganization symptoms showed the greatest impact in functioning at acute phase, and prevented patients from achieving remission, suggesting it may be a marker of symptom severity and worse outcome in schizophrenia. PMID- 25711509 TI - Patient-Centered Outcomes with Aripiprazole Once-Monthly for Maintenance Treatment in Patients with Schizophrenia: Results From Two Multicenter, Randomized, Double-Blind Studies. AB - OBJECTIVES: To further characterize the clinical profile of long-term treatment with aripiprazole once-monthly 400 mg (AOM 400) by examining patient-centered outcomes in adults with schizophrenia. METHODS: Data are from 2 separate studies: a 52-week, multicenter, randomized, double-blind, placebo-controlled study and a 38-week, multicenter, randomized, double-blind, active-controlled study that evaluated the clinical profile of AOM 400 as maintenance treatment in patients with schizophrenia. The studies were conducted from July 2008 through February 2011 and from September 2008 through August 2012, respectively. Both studies included the Drug Attitude Inventory (DAI), the Medication Adherence Questionnaire (MAQ), the Patient Satisfaction with Medication Questionnaire, and a resource utilization and hospitalization form as prespecified patient-centered endpoints. RESULTS: A total of 710 patients entered the oral stabilization phase in the 52-week study, and 403 patients were randomized to double-blind treatment. The corresponding sample sizes in the 38-week study were 842 and 662, respectively. In both studies, mean DAI and MAQ scores remained stable across all treatment phases; mean changes from baseline during the double-blind phase were not significantly different between treatment arms. Treatment satisfaction remained high throughout both studies, and most patients reported no or fewer side effects with AOM 400 relative to their prior medication. Most patients did not have unscheduled outpatient visits or hospitalizations throughout the studies. CONCLUSIONS: Data from 2 randomized, double-blind studies indicated that patient perceptions about treatment satisfaction, side effects, and medication adherence were maintained in patients with schizophrenia receiving maintenance treatment with AOM 400. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00705783, NCT00706654. PMID- 25711510 TI - Aripiprazole-Induced Hypoprolactinemia in an Adult Male with First-Episode Psychosis. AB - Aripiprazole is an atypical antipsychotic that acts as a partial agonist at dopamine D2 receptors. Compared to other atypical antipsychotics, aripiprazole has less metabolic side effects and is less likely to increase prolactin. Moreover, it has been shown to have a unique prolactin lowering effect. While aripiprazole has been associated with subnormal prolactin levels in children, no documented cases of hypoprolactinemia in adults exist thus far. Here we report a case of aripiprazole-induced hypoprolactinemia in an adult male with first episode psychosis, and the possible effects of abnormally low prolactin are discussed. PMID- 25711511 TI - Phase I study of tivantinib in Japanese patients with advanced hepatocellular carcinoma: Distinctive pharmacokinetic profiles from other solid tumors. AB - A c-Met inhibitor tivantinib is a candidate anticancer agent for patients with hepatocellular carcinoma (HCC), and CYP2C19 is the key metabolic enzyme for tivantinib. Previous Japanese phase I studies in patients with solid tumors (except HCC) recommend 360 mg twice daily (BID) and 240 mg BID for CYP2C19 extensive metabolizers (EM) and poor metabolizers (PM), respectively. In this study, Japanese patients with HCC in whom sorafenib treatment has failed were enrolled to evaluate the safety, tolerability and pharmacokinetics of oral tivantinib as a single agent. The dose was escalated separately in EM and PM, from 120 mg BID to 240 mg BID, in both capsule and tablet formulations. A total of 28 patients (EM: 21, PM: 7) received tivantinib. At a dose of 120 mg BID, dose limiting toxicities (DLT) did not develop in 12 EM (capsule: 6, tablet: 6) and 7 PM (capsule: 4, tablet: 3) during the DLT-observation period (for 29 days after first dosing). At this dose, the pharmacokinetic profiles of tivantinib (AUC0-12 and Cmax ) did not remarkably differ between EM and PM. When treated with 240 mg BID, 5 of 9 EM (capsule: 4 of 6, tablet: 1 of 3) developed neutropenia-related DLT accompanying plasma tivantinib concentration higher than expected from the previous studies. Consequently, PM did not receive 240 mg BID. In conclusion, 120 mg BID of tivantinib is recommended among Japanese patients with HCC regardless of CYP2C19 phenotype. PMID- 25711512 TI - Carbon nanopipette electrodes for dopamine detection in Drosophila. AB - Small, robust, sensitive electrodes are desired for in vivo neurotransmitter measurements. Carbon nanopipettes have been previously manufactured and used for single-cell drug delivery and electrophysiological measurements. Here, a modified fabrication procedure was developed to produce batches of solid carbon nanopipette electrodes (CNPEs) with ~250 nm diameter tips, and controllable lengths of exposed carbon, ranging from 5 to 175 MUm. The electrochemical properties of CNPEs were characterized with fast-scan cyclic voltammetry (FSCV) for the first time. CNPEs were used to detect the electroactive neurotransmitters dopamine, serotonin, and octopamine. CNPEs were significantly more sensitive for serotonin detection than traditional carbon-fiber microelectrodes (CFMEs). Similar to CFMEs, CNPEs have a linear response for dopamine concentrations ranging from 0.1 to 10 MUM and a limit of detection of 25 +/- 5 nM. Recordings with CNPEs were stable for over 3 h when the applied triangle waveform was scanned between -0.4 and +1.3 V vs Ag/AgCl/Cl(-) at 400 V/s. CNPEs were used to detect endogenous dopamine release in Drosophila larvae using optogenetics, which verified the utility of CNPEs for in vivo neuroscience studies. CNPEs are advantageous because they are 1 order of magnitude smaller in diameter than typical CFMEs and have a sharp, tunable geometry that facilitates penetration and implantation for localized measurements in distinct regions of small organisms, such as the Drosophila brain. PMID- 25711513 TI - Minor ABO Incompatibility Does Not Impact Nonrelapse Mortality in T Cell-Depleted Human Leukocyte Antigen-Matched Sibling Transplantation. PMID- 25711514 TI - Dabrafenib in the treatment of metastatic or unresectable melanoma. AB - Dabrafenib is a potent inhibitor of mutant BRAF. Trials to date have shown it to be well tolerated, with significant activity in unresectable stage III or IV metastatic melanoma. Overall response rates of approximately 50% were seen in addition to improved progression-free and overall survival of 6 and 18 months, respectively. Preclinical studies suggested that combining BRAF and MEK inhibition would increase response rates and decrease toxicity. Clinical trials with the combination of dabrafenib and trametinib have improved progression-free and overall survival in interim analyses. Future improvements in responses and outcomes will depend on additional combination strategies, possibly employing immunotherapy. PMID- 25711515 TI - Climate-dependent costs of reproduction: survival and fecundity costs decline with length of the growing season and summer temperature. AB - Costs of reproduction are expected to vary with environmental conditions thus influencing selection on life-history traits. Yet, the effects of habitat conditions and climate on trade-offs among fitness components remain poorly understood. For 2-5 years, we quantified costs of experimentally increased reproduction in two populations (coastal long-season vs. inland short-season) of two long-lived orchids that differ in natural reproductive effort (RE; 30 vs. 75% fruit set). In both species, survival costs were found only at the short-season site, whereas growth and fecundity costs were evident at both sites, and both survival and fecundity costs declined with increasing growing season length and/or summer temperature. The results suggest that the expression of costs of reproduction depend on the local climate, and that climate warming could result in selection favouring increased RE in both study species. PMID- 25711516 TI - Novel pyridyl substituted 4,5-dihydro-[1,2,4]triazolo[4,3-a]quinolines as potent and selective aldosterone synthase inhibitors with improved in vitro metabolic stability. AB - CYP11B2 inhibition is a promising treatment for diseases caused by excessive aldosterone. To improve the metabolic stability in human liver miscrosomes of previously reported CYP11B2 inhibitors, modifications were performed via a combination of ligand- and structure-based drug design approaches, leading to pyridyl 4,5-dihydro-[1,2,4]triazolo[4,3-a]quinolones. Compound 26 not only exhibited a much longer half-life (t1/2 ? 120 min), but also sustained inhibitory potency (IC50 = 4.2 nM) and selectivity over CYP11B1 (SF = 422), CYP17, CYP19, and a panel of hepatic CYP enzymes. PMID- 25711517 TI - Ultrasonography for confirmation of endotracheal tube placement: a systematic review and meta-analysis. AB - OBJECTIVE: This study aimed to undertake a systematic review and meta-analysis to summarize evidence on the diagnostic value of ultrasonography for the assessment of endotracheal tube placement in adult patients. METHODS: The major databases, PubMed, EMBASE, and the Cochrane Library, were searched for studies published from inception to June 2014. We selected studies that used ultrasonography to confirm endotracheal tube placement. The search was limited to human studies, and had no publication date or country restrictions. Exclusion criteria included case reports, comments, reviews, guidelines and animal studies. Two reviewers extracted and verified the data independently. We summarized test performance characteristics with the use of forest plots, hierarchical summary receiver operating characteristic (HSROC) curves, and bivariate random effect models. Meta regression analysis was performed to explore the source of heterogeneity. The methodological quality of individual studies was evaluated using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) tool. RESULTS: A total of 12 eligible studies involving adult patients and cadaveric models were identified from 1488 references. For detection of esophageal intubation, the pooled sensitivity was 0.93 (95% CI: 0.86-0.96) and the specificity was 0.97 (95% CI: 0.95-0.98). The area under the summary ROC curve was 0.97 (95% CI: 0.95-0.98). The positive and negative likelihood ratios were 26.98 (95% CI: 19.32-37.66) and 0.08 (95% CI: 0.04-0.15), respectively. CONCLUSIONS: Current evidence supports that ultrasonography has high diagnostic value for identifying esophageal intubation. With optimal sensitivity and specificity, ultrasonography can be a valuable adjunct in this aspect of airway assessment, especially in situations where capnography may be unreliable. PMID- 25711518 TI - What CPR means to surrogate decision makers of ICU patients. AB - AIM OF THE STUDY: The decision to accept or decline cardiopulmonary resuscitation (CPR) by surrogate decision makers on behalf of a family member is a common and important component of end-of-life decision-making in the ICU. While many determinants influence this decision, surrogates' understanding of CPR may be a major guiding factor. However, little is known about surrogates' knowledge and perceptions of CPR during the periods of time when their family member is critically ill. We conducted this study to explore surrogates' understanding of some basic concepts of CPR. METHODS: This is a descriptive, survey-based exploratory study of understanding of CPR concepts and outcomes conducted in a single-center medical ICU at a tertiary academic hospital in the United States. Study subjects were surrogate decision-makers of critically ill ICU patients who participated in an interview-format survey within 24h of the patient's ICU admission. RESULTS: Of 97 eligible subjects (surrogates), 50 were enrolled in this study and represented a wide spectrum of demographics. All subjects had heard of CPR. The main source of information about CPR was a course. While 46% identified cardiac arrest as a main indication for CPR, only 8% identified at least 2 of the 3 main components of CPR. The majority (72%) believed survival after CPR was >=75%. Forty-two percent of surrogates had spoken to the patient about CPR prior to coming to the hospital, and 57% had spoken to the physician during this hospitalization. Twenty-six percent changed their decision on CPR during the ICU stay. CONCLUSION: There is a wide variation in surrogates' understanding and knowledge of CPR concepts and outcomes. PMID- 25711519 TI - Oral mixing ability and cognition in elderly persons with dementia: a cross sectional study. AB - Masticatory performance has been positively associated with cognitive ability in both animals and healthy humans. We hypothesised that there would also be a positive correlation between masticatory performance and cognition in older persons suffering from dementia. Older persons suffering from dementia (n = 114) and receiving institutionalised care were studied in a cross-sectional design. The assessments included masticatory performance, which was measured objectively with a two-colour gum mixing ability test, and cognition, which was assessed with a multidomain neuropsychological test battery. Significant relationships were observed between masticatory performance and general cognition and between masticatory performance and verbal fluency. Hierarchical regression analysis revealed that the correlation with general cognition was influenced by the scores for dependency in activities of daily living. The association between verbal fluency and masticatory performance was not significantly affected by secondary variables. An unexpected limitation of this study was the high dropout rate for the mixing ability test. The clinical implications of these findings are profound; care professionals should endeavour to maintain and stimulate mastication in older persons with dementia in an attempt to preserve cognition. PMID- 25711520 TI - The first Polish liver transplantation after Roux-en-Y gastric bypass surgery for morbid obesity: a case report and literature review. AB - BACKGROUND: Morbid obesity is associated with liver pathology, most commonly non alcoholic steatohepatitis (NASH) leading to cirrhosis. However, the morbid obesity impedes qualification for organ transplantation. CASE REPORT: We present a case report of a 56-year-old woman who underwent bariatric procedure followed by liver transplantation (LTx). Her initial weight was 130.2 kg (BMI 50.9 kg/m2). The patient had a history of arterial hypertension, diabetes, gonarthrosis, and obstructive sleep apnea syndrome and no history of alcohol abuse. She underwent Roux-en-Y gastric bypass (RYGB) procedure. The routine intraoperative liver biopsy revealed fibrosis (III degrees ), steatosis (II degrees ), and intra acinar inflammation. The operation led to a substantial loss of weight. Two years after the surgery the patient was referred to the Transplantation Clinic of Department of General Surgery and Transplantology with suspicion of liver failure due to advanced cirrhosis, which could be a result of previously diagnosed NASH and, probably, excessive alcohol use after bariatric surgery. The patient was qualified for elective LTx, which was performed 3 years after the RYGB. Immediately before LTx, the patient's weight was 65 kg (BMI 25.4 kg/m2). The postoperative period was complicated by bleeding into the peritoneal cavity, which required reoperation. She also had renal failure, requiring renal replacement therapy. One year after LTx, she showed stable liver function with normal transaminases activity and bilirubin concentration, remission of diabetes, and good renal function. CONCLUSIONS: Steatohepatitis in morbidly obese patients may lead to cirrhosis. Bariatric procedure can be a bridge to liver transplantation for morbidly obese patients with advanced liver fibrosis. PMID- 25711521 TI - Towards the Dynamic Assessment of the Lesion Generation Process in an Experimental Model of Cardiac Ablation. PMID- 25711522 TI - Spontaneous and experimental conversion of a regressing subordinate follicle of wave 1 to the dominant follicle of wave 2 in heifers. AB - Examination of daily ultrasound records from a previous study indicated that spontaneous conversion of a regressing largest subordinate follicle (SF) of wave 1 (SF1) to the dominant follicle (DF) of wave 2 (DF2) occurred on Day 6 or 7 (Day 0 = ovulation) in two of 28 heifers (7%). A conversion was considered definitive on the basis of no other SFs in the same ovary as SF1, thereby avoiding error in maintaining follicle identity. Spontaneous conversion appeared to involve an FSH fluctuation. In a separate study, experimental conversion of SF1 to DF2 was studied by ultrasonic imaging every 6 hours after ablating follicles other than SF1 when DF of wave 1 was close to 11.0 mm (hour 0). Diameter of SF1 decreased (P < 0.01) between hours -6 (7.8 +/- 0.3 mm) and 0 (7.6 +/- 0.3 mm). A decrease of 0.1 to 0.8 mm occurred in each heifer, indicating that SF1 was in early regression at hour 0. Conversion occurred in four of 12 (33%) heifers. A diameter increase (P < 0.05) in DF2 after conversion from SF1 occurred between hours 6 and 12. An increase (P < 0.05) in FSH occurred by hour 12 with and without conversion of SF1. Concentration of FSH at each of hours 30 to 48 was greater (P < 0.05) for nonconversion than that for conversion of SF1 to DF2 and greater (P < 0.05) for conversion than that for the basal concentration in controls (n = 7). The hypothesis that a regressing SF1 can be converted to DF2 by ablating other follicles was supported. PMID- 25711523 TI - Fhit Nuclear Import Following EGF Stimulation Sustains Proliferation of Breast Cancer Cells. AB - The tumor-suppressor protein fragile histidine triad (Fhit) exerts its functions in the cytoplasm, although some reports suggest that it may also act in the nucleus. We previously showed that cytosolic Fhit protein levels in cancer cell lines stimulated to proliferate were reduced by proteasomal degradation. Here, we demonstrate that Fhit is physiologically present in the nucleus of breast cancer cell lines and tissues at a low level and that proliferative stimulation increases nuclear levels. Breast cancer cells expressing the FhitY114F mutant, which do not undergo proteasomal degradation, contained mutated Fhit in the nucleus, while cells treated with a proteasome inhibitor accumulated nuclear Fhit during proliferation. Thus, Fhit nuclear shuttling and proteasome degradation phenomena occur independently. When Fhit was coupled to a nuclear localization sequence, the proliferation rate of the transfected cells increased together with levels of proliferation pathway mediators cyclin D1, phospho-MAPK, and phospho STAT3. Fhit nuclear translocation upon mitogenic stimulation may represent a new regulatory mechanism that allows rapid restoration of Fhit cytoplasmic levels and promotes the proliferation cascade activated by mitogenic stimulation. PMID- 25711524 TI - Surface design and engineering of hierarchical hybrid nanostructures for asymmetric supercapacitors with improved electrochemical performance. AB - With the current rising world demand for energy sufficiency, there is an increased necessity for the development of efficient energy storage devices. To address these needs, the scientific community has focused on the improvement of the electrochemical properties of the most well known energy storage devices; the Li-ion batteries and electrochemical capacitors, also called supercapacitors. Despite the fact that supercapacitors exhibit high power densities, good reversibility and long cycle life, they still exhibit lower energy densities than batteries, which limit their practical application. Various strategies have been employed to circumvent this problem, specifically targetting an increase in the specific capacitance and the broadening of the potential window of operation of these systems. In recent years, sophisticated surface design and engineering of hierarchical hybrid nanostructures has facilitated significant improvements in the specific and volumetric storage capabilities of supercapacitors. These nanostructured electrodes exhibit higher surface areas for ion adsorption and reduced ion diffusion lengths for the electrolyte ions. Significant advances have also been achieved in broadening the electrochemical window of operation of these systems, as realized via the development of asymmetric two-electrode cells consisting of nanocomposite positive and negative electrodes with complementary electrochemical windows, which operate in environmentally benign aqueous media. We provide an overview of the diverse approaches, in terms of chemistry and nanoscale architecture, employed recently for the development of asymmetric supercapacitors of improved electrochemical performance. PMID- 25711525 TI - Multifractal dimension and lacunarity of yolk sac vasculature after exposure to magnetic field. AB - Several studies have reported about the effects of magnetic fields (MFs) on vascular tissue. Extremely low frequency magnetic fields (ELF-MFs) can promote either inhibition or stimulation of vasculogenesis and angiogenesis, depending upon the intensity and time of exposure to the MF. To investigate the possible effects of ELF-MF on vascular processes, it is necessary to employ methods that allow parameterization of the vascular network. Vascular network is a structure with fractal geometry; therefore, fractal methods have been used to evaluate its morphometric complexity. Here, we used the lacunarity parameter (complementary method of fractal analysis) and multifractal analyses to investigate angiogenesis and vasculogenesis in the embryonic yolk sac membrane (YSM) of Japanese quails (Coturnix japonica) with and without exposure to an external MF of 1 mT and 60 Hz. Lacunarity results showed that the vascular density was lower for the group exposed to the magnetic field for 9 h/day. In addition, multifractal analysis showed reduced vascularization in the experimental groups (6 h/day and 9 h/day of exposure to MF). Furthermore, multifractal analysis showed difference between the groups exposed for 12 and 24 h/day. Using multifractal methods (generalized dimensions and singularity spectrum), it was possible to characterize the vascular network of the quail embryo YSM as a multifractal object, therefore proving this method to be a more appropriate application than the traditional monofractal methods. PMID- 25711526 TI - Mechanisms of tubulogenesis and endothelial phenotype expression by MSCs. AB - Stem cell-based therapies are a promising new avenue for treating ischemic disease and chronic wounds. Mesenchymal stem cells (MSCs) have a proven ability to augment the neovascularization processes necessary for wound healing and are widely popular as an autologous source of progenitor cells. Our lab has previously reported on PEGylated fibrin as a unique hydrogel that promotes spontaneous tubulogenesis of encapsulated MSCs without exogenous factors. However, the mechanisms underlying this process have remained unknown. To better understand the therapeutic value of PEGylated fibrin delivery of MSCs, we sought to clarify the relationship between biomaterial properties and cell behavior. Here we find that fibrin PEGylation does not dramatically alter the macroscopic mechanical properties of the fibrin-based matrix (less than 10% difference). It does, however, dramatically reduce the rate of diffusion through the gel matrix. PEGylated fibrin enhances the tubulogenic growth of encapsulated MSCs demonstrating fluid-filled lumens by interconnected MSCs. Image analysis gave a value of 4320 +/- 1770 MUm total network length versus 618 +/- 443 MUm for unmodified fibrin. PEGylation promotes the endothelial phenotype of encapsulated MSCs--compared to unmodified fibrin--as evidenced by higher levels of endothelial markers (von Willebrand factor, 2.2-fold; vascular endothelial cadherin, 1.8 fold) and vascular endothelial growth factor (VEGF, up to 1.8-fold). Prospective analysis of underlying molecular pathways demonstrated that this endothelial-like MSC behavior is sensitively modulated by hypoxic stress, but not VEGF supplementation as evidenced by a significant increase in VEGF and MMP-2 secretion per cell under hypoxia. Further gain-of-function studies under hypoxic stress demonstrated that hypoxia culture of MSCs in unmodified fibrin could increase both vWF and VE-cadherin levels to values that were not significantly different than cells cultured in PEGylated fibrin. This result corroborated our hypothesis that the diffusion-limited environment of PEGylated fibrin is augmenting endothelial differentiation cues provided by unmodified fibrin. However, MSC networks lack platelet endothelial cell adhesion molecule-1 (PECAM 1) expression, which indicates incomplete differentiation towards an endothelial cell type. Collectively, the data here supports a revised understanding of MSC derived neovascularization that contextualizes their behavior and utility as a hybrid endothelial-stromal cell type, with mixed characteristics of both populations. PMID- 25711527 TI - Physiological status of broiler chicks at pulling time and the relationship to duration of holding period. AB - Newly hatched chicks may be held longer than 48 h and experience long periods of fasting in commercial hatcheries. Limited information is known about the physiological status of chicks in such situations, due to the difficulty of precisely recording time of hatch. This study investigated the effect of the time from hatch to pulling (holding period) on physiological measures/parameters in 109 broiler chicks. Fertile Ross 308 eggs were incubated in a custom built small scale incubator. The individual hatching time of each focal chick was determined using eggshell temperature monitoring. At 'pulling' (512 h of incubation time), the quality of focal chicks was assessed using the chick scoring method and physiological parameters were measured including BW, organ (heart, liver and stomach) weights, blood values and plasma corticosterone level. The time from hatch to pulling varied from 7.58 to 44.97 h. Egg weight at setting was significantly correlated with chick BW and weight of organs at pulling, but had no effect on chick quality, blood values and plasma corticosterone. Relative BW at pulling was negatively associated with the duration of holding period (P=0.002). However, there was a positive correlation between relative stomach weight and the duration of the holding period (P<0.001). As the holding period duration increased, there was a trend that blood partial pressure of oxygen, haematocrit and haemoglobin also increased, and blood partial pressure of carbon dioxide, total carbon dioxide and bicarbonate decreased (P<0.05). A wide range of plasma corticosterone was observed from chicks that had experienced different durations of holding period. We conclude that shortening the hatch window and minimising the number of chicks that experience a long holding period before pulling may improve chick quality and physiological status, which may be due to unfavourable environmental conditions that include feed and water deprivation. PMID- 25711528 TI - Android Adiposity and Lack of Moderate and Vigorous Physical Activity Are Associated With Insulin Resistance and Diabetes in Aging Adults. AB - BACKGROUND: Physical inactivity and excess adiposity are thought to be interdependent "lifestyle" factors and thus, many older adults are at exaggerated risk for preventable diseases. The purposes of this study were to determine the degree of discordance between body mass index (BMI) and adiposity among adults older than 50 years, and to determine the extent to which direct measures of adiposity, and objectively measured sedentary behavior (SB) and physical activity (PA) are associated with insulin resistance (IR) or diabetes. METHODS: A population representative sample of 2,816 individuals, aged 50-85 years, was included from the combined 2003-2006 National Health and Nutrition Examination Survey (NHANES) datasets. BMI, percent body fat (%BF) and android adiposity as determined by dual energy x-ray absorptiometry, objectively measured SB and PA, established markers of cardiometabolic risk, IR, and type 2 diabetes were analyzed. RESULTS: Approximately 50% of the men and 64% of the women who were normal weight according to BMI had excessive %BF. Adults with the least SB and greatest moderate and vigorous PA exhibited the healthiest cardiometabolic profiles, whereas adults with the greatest SB and lowest activity had highest risk. Greater android adiposity stores were robustly associated with IR or diabetes in all adults, independent of SB and activity. Among men, less moderate to-vigorous PA was associated with IR or diabetes; whereas among women, less lifestyle moderate activity was associated with IR or diabetes. CONCLUSIONS: Android adiposity and low moderate and vigorous PA are the strongest predictors of IR or diabetes among aging adults. PMID- 25711529 TI - Inflammatory and Glutamatergic Homeostasis Are Involved in Successful Aging. AB - Whole body studies using long-lived growth hormone receptor gene disrupted or knock out (GHR-KO) mice report global GH resistance, increased insulin sensitivity, reduced insulin-like growth factor 1 (IGF-1), and cognitive retention in old-age, however, little is known about the neurobiological status of these mice. The aim of this study was to determine if glutamatergic and inflammatory markers that are altered in aging and/or age-related diseases and disorders, are preserved in mice that experience increased healthspan. We examined messenger ribonucleic acid (mRNA) expression levels in the brain of 4- to 6-, 8- to 10-, and 20- to 22-month GHR-KO and normal aging control mice. In the hippocampus, glutamate transporter 1 (GLT-1) and anti-inflammatory nuclear factor kappa-light-chain-enhancer of activated B cells (NFkappaB)-p50 were elevated in 8- to 10-month GHR-KO mice compared with age-matched controls. In the hypothalamus, NFkappaB-p50, NFkappaB-p65, IGF-1 receptor (IGF-1R), glutamate/aspartate transporter (GLAST), and 2-amino-3-(5-methyl-3-oxo 2,3 dihydro-1,2 oxazol-4-yl) propanoic acid receptor subunit 1 (GluA1) were elevated in 8- to 10- and/or 20- to 22-month GHR-KO mice when comparing genotypes. Finally, interleukin 1-beta (IL-1beta) mRNA was reduced in 4- to 6- and/or 8- to 10-month GHR-KO mice compared with normal littermates in all brain areas examined. These data support the importance of decreased brain inflammation in early adulthood and maintained homeostasis of the glutamatergic and inflammatory systems in extended longevity. PMID- 25711530 TI - Impact of Longevity Interventions on a Validated Mouse Clinical Frailty Index. AB - This article investigates the effect on the mouse frailty index (FI), of factors known to influence lifespan and healthspan in mice: strain (short-lived DBA/2J mice vs long-lived C57BL/6J mice), calorie restriction (CR), and resveratrol treatment. The mouse FI, based on deficit accumulation, was recently validated in C57BL/6J mice by Whitehead JC, Hildebrand BA, Sun M, et al. (A clinical frailty index in aging mice: comparisons with frailty index data in humans. J Gerontol A Biol Sci Med Sci. 2014;69:621-632) and shares many characteristics of the human FI. FI scores were measured in male and female aged (18 months) ad-libitum fed and CR DBA/2J and C57BL/6J mice, as well as male aged (24 months) C57BL/6J mice ad-libitum fed with or without resveratrol (100 mg/kg/day) in the diet for 6 months. Mean scores of two raters were used, and the raters had excellent inter rater reliability (ICC = 0.88, 95% CI [0.80, 0.92]). Furthermore, the interventions of CR and resveratrol were associated with a significant reduction in FI scores in C57BL/6J mice, compared to age-matched controls. The short-lived DBA/2J mice also had slightly higher FI scores than the C57BL/6J mice, for the male calorie-restricted groups (DBA/2J FI = 0.16+/-0.03, C57BL/6J FI = 0.11+/ 0.03, p = .01). This study uses the mouse FI developed by Whitehead JC, Hildebrand BA, Sun M, et al. (A clinical frailty index in aging mice: comparisons with frailty index data in humans. J Gerontol A Biol Sci Med Sci. 2014;69:621 632) in a different mouse colony and shows that this tool can be applied to quantify the effect of dietary and pharmaceutical interventions on frailty. PMID- 25711531 TI - Assays for the determination of the activity of DNA nucleases based on the fluorometric properties of the YOYO dye. AB - Here we characterize the fluorescence of the YOYO dye as a tool for studying DNA protein interactions in real time and present two continuous YOYO-based assays for sensitively monitoring the kinetics of DNA digestion by lambda-exonuclease and the endonuclease EcoRV. The described assays rely on the different fluorescence intensities between single- and double-stranded DNA-YOYO complexes, allowing straightforward determination of nuclease activity and quantitative determination of reaction products. The assays were also employed to assess the effect of single-stranded DNA-binding proteins on the lambda-exonuclease reaction kinetics, showing that the extreme thermostable single-stranded DNA-binding protein (ET-SSB) significantly reduced the reaction rate, while the recombination protein A (RecA) displayed no effect. PMID- 25711532 TI - HemQ: An iron-coproporphyrin oxidative decarboxylase for protoheme synthesis in Firmicutes and Actinobacteria. AB - Genes for chlorite dismutase-like proteins are found widely among heme synthesizing bacteria and some Archaea. It is now known that among the Firmicutes and Actinobacteria these proteins do not possess chlorite dismutase activity but instead are essential for heme synthesis. These proteins, named HemQ, are iron coproporphyrin (coproheme) decarboxylases that catalyze the oxidative decarboxylation of coproheme III into protoheme IX. As purified, HemQs do not contain bound heme, but readily bind exogeneously supplied heme with low micromolar affinity. The heme-bound form of HemQ has low peroxidase activity and in the presence of peroxide the bound heme may be destroyed. Thus, it is possible that HemQ may serve a dual role as a decarboxylase in heme biosynthesis and a regulatory protein in heme homeostasis. PMID- 25711533 TI - The anti-cancer effects of carotenoids and other phytonutrients resides in their combined activity. AB - Epidemiological studies have consistently shown that regular consumption of fruits and vegetables is strongly associated with reduced risk of developing chronic diseases, such as cancer. It is now accepted that the actions of any specific phytonutrient alone do not explain the observed health benefits of diets rich in fruits and vegetables as nutrients that were taken alone in clinical trials did not show consistent preventive effects. The considerable cost and complexity of such clinical trials requires prudent selection of combinations of ingredients rather than single compounds. Indeed, synergistic inhibition of prostate and mammary cancer cell growth was evident when using combinations of low concentrations of various carotenoids or carotenoids with retinoic acid and the active metabolite of vitamin-D. In this study we aimed to develop simple and sensitive in vitro methods which provide information on potent combinations suitable for inclusion in clinical studies for cancer prevention. We, thus, used reporter gene assays of the transcriptional activity of the androgen receptor in hormone-dependent prostate cancer cells and of the electrophile/antioxidant response element (EpRE/ARE) transcription system. We found that combinations of several carotenoids (e.g., lycopene, phytoene and phytofluene), or carotenoids and polyphenols (e.g., carnosic acid and curcumin) and/or other compounds (e.g., vitamin E) synergistically inhibit the androgen receptor activity and activate the EpRE/ARE system. The activation of EpRE/ARE was up to four fold higher than the sum of the activities of the single ingredients, a robust hallmark of synergy. Such combinations can further be tested in the more complex in vivo models and human studies. PMID- 25711534 TI - Contact allergy to reactive diluents and related aliphatic epoxy resins. AB - BACKGROUND: Diglycidyl ether of bisphenol A resin (DGEBA-R) is the most common sensitizer in epoxy systems, but a minority of patients also develop contact allergy to reactive diluents. OBJECTIVES: To analyse the frequency and clinical relevance of allergic reactions to different epoxy reactive diluents and related aliphatic epoxy resins. METHODS: Test files (January 1991 to June 2014) were screened, and the clinical records of patients with allergic reactions were analysed for occupation, concomitant allergic reactions, and exposure. RESULTS: A total of 67 patients reacted to at least one of the compounds. The largest numbers of allergic reactions were to phenyl glycidyl ether (PGE; n = 41), 1,4 butanediol diglycidyl ether (BDDGE; n = 34), and p-tert-butylphenyl glycidyl ether (PTBPGE; n = 19). Ten of the patients did not have contact allergy to DGEBA R. The reactions of 5 of these were related to the use of BDDGE-containing products. We found no significant exposure to PGE or PTBPGE in patients sensitized to them, but some of the patients had used cresyl glycidyl ether containing products. CONCLUSIONS: Allergic reactions to reactive diluents and related aliphatic epoxy resins usually occurred together with reactions to DGEBA R. BDDGE was the clinically most significant compound, and was the sole cause of occupational allergic contact dermatitis in 3 patients. PMID- 25711535 TI - Induction of HER2 Immunity in Outbred Domestic Cats by DNA Electrovaccination. AB - Domestic cats share human living environments and genetic traits. They develop spontaneous feline mammary carcinoma (FMC) with similar histopathology to human breast cancer. HER2 and AKT phosphorylation was demonstrated in primary FMC by immunoblot analysis, indicating HER2 as a therapeutic target. FMC lines K12 and K248 expressing HER1, HER2, and HER3 were sensitive to receptor tyrosine kinase (RTK) inhibitors gefitinib and lapatinib. To test HER2 vaccine response in cats, purpose-bred, healthy cats were electrovaccinated with heterologous (xenogeneic) or point-mutated feline HER2 DNA. T-cell reactivity to feline self-HER2 was detected in 4 of 10 cats that received bear HER2, human-rat fusion HER2 (E2Neu) or mutant feline HER2 (feHER2-K), which contains a single amino acid substitution. The variable T-cell responses may resemble that in the genetically heterogeneous human population. All immune sera to heterologous HER2 recognized feline HER2 expressed in 3T3 cells (3T3/HER2), but not that in FMC K12 or K248. Immune sera to mutant pfeHER2-K bound 3T3/HER2 cells weakly, but they showed better recognition of K12 and K248 cells that also express HER1 and HER3, suggesting distinct HER2 epitopes displayed by FMC that may be simulated by feHER2-K. In summary, HER2 DNA electroporation overcomes T-cell immune tolerance in approximately 40% of healthy cats and induces antibodies with distinct specificity. Vaccination studies in domestic cats can expedite vaccine iteration to guide human vaccine design and better predict outcome, with the added benefit of helping feline mammary tumor patients. PMID- 25711536 TI - CAR-T Cells Inflict Sequential Killing of Multiple Tumor Target Cells. AB - Adoptive therapy with chimeric antigen receptor (CAR) T cells shows great promise clinically. However, there are important aspects of CAR-T-cell biology that have not been explored, particularly with respect to the kinetics of activation, immune synapse formation, and tumor cell killing. Moreover, the effects of signaling via the endogenous T-cell receptor (TCR) or CAR on killing kinetics are unclear. To address these issues, we developed a novel transgenic mouse (designated CAR.OT-I), in which CD8(+) T cells coexpressed the clonogenic OT-I TCR, recognizing the H-2K(b)-presented ovalbumin peptide SIINFEKL, and an scFv specific for human HER2. Primed CAR.OT-I T cells were mixed with SIINFEKL-pulsed or HER2-expressing tumor cells and visualized in real-time using time-lapse microscopy. We found that engagement via CAR or TCR did not affect cell death kinetics, except that the time from degranulation to CAR-T-cell detachment was faster when CAR was engaged. We showed, for the first time, that individual CAR.OT-I cells can kill multiple tumor cells ("serial killing"), irrespective of the mode of recognition. At low effector:target ratios, the tumor cell killing rate was similar via TCR or CAR ligation over the first 20 hours of coincubation. However, from 20 to 50 hours, tumor cell death mediated through CAR became attenuated due to CAR downregulation throughout the time course. Our study provides important insights into CAR-T-tumor cell interactions, with implications for single- or dual receptor-focused T-cell therapy. PMID- 25711539 TI - Nonvolatile organic field-effect transistors memory devices using supramolecular block copolymer/functional small molecule nanocomposite electret. AB - Organic field-effect transistors (OFETs) memory devices based on hybrid nanocomposite electret were fabricated by cooperative supramolecular polystyrene block-poly(4-vinylpyridine) (PS-b-P4VP) with two different block compositions (asymmetric L1 and symmetric L2) that contain hydroxyl-functionalized ferrocene small molecules (FMs). Because of the selective hydrogen interaction between the hydroxyl groups of FM and pyridine groups in P4VP block, the small FMs can preferentially disperse in the P4VP nanodomain, which can be used as nanostructured charge-trapping nanocomposite electret (L1-FMX and L2-FMX) under solvent-annealing process. The charge-storage functionalities can be easily tailored by morphologies of the hybrid nanocomposite thin film and spatial distribution of the FM molecules in which the relative molecular mass of block copolymers and the FM loading ratio can further control both of them. These block copolymer nanocomposite thin film electrets with charge-controlling guest FM for OFETs memory devices exhibit significant features including the ternary bits storage, high-density trapping sites, charge-carrier trapping of both polarities (ambipolar trapping), and solution processing that can make important progress for future advanced storage and memory technology. PMID- 25711537 TI - Human Leukocyte Antigen (HLA) A*1101-Restricted Epstein-Barr Virus-Specific T cell Receptor Gene Transfer to Target Nasopharyngeal Carcinoma. AB - Infusing virus-specific T cells is effective treatment for rare Epstein-Barr virus (EBV)-associated posttransplant lymphomas, and more limited success has been reported using this approach to treat a far more common EBV-associated malignancy, nasopharyngeal carcinoma (NPC). However, current approaches using EBV transformed lymphoblastoid cell lines to reactivate EBV-specific T cells for infusion take 2 to 3 months of in vitro culture and favor outgrowth of T cells targeting viral antigens expressed within EBV(+) lymphomas, but not in NPC. Here, we explore T-cell receptor (TCR) gene transfer to rapidly and reliably generate T cells specific for the NPC-associated viral protein LMP2. We cloned a human leukocyte antigen (HLA) A*1101-restricted TCR, which would be widely applicable because 40% of NPC patients carry this HLA allele. Studying both the wild-type and modified forms, we have optimized expression of the TCR and demonstrated high avidity antigen-specific function (proliferation, cytotoxicity, and cytokine release) in both CD8(+) and CD4(+) T cells. The engineered T cells also inhibited LMP2(+) epithelial tumor growth in a mouse model. Furthermore, transduced T cells from patients with advanced NPC lysed LMP2-expressing NPC cell lines. Using this approach, within a few days large numbers of high-avidity LMP2-specific T cells can be generated reliably to treat NPC, thus providing an ideal clinical setting to test TCR gene transfer without the risk of autoimmunity through targeting self antigens. PMID- 25711538 TI - Individual Motile CD4(+) T Cells Can Participate in Efficient Multikilling through Conjugation to Multiple Tumor Cells. AB - T cells genetically modified to express a CD19-specific chimeric antigen receptor (CAR) for the investigational treatment of B-cell malignancies comprise a heterogeneous population, and their ability to persist and participate in serial killing of tumor cells is a predictor of therapeutic success. We implemented Timelapse Imaging Microscopy in Nanowell Grids (TIMING) to provide direct evidence that CD4(+)CAR(+) T cells (CAR4 cells) can engage in multikilling via simultaneous conjugation to multiple tumor cells. Comparisons of the CAR4 cells and CD8(+)CAR(+) T cells (CAR8 cells) demonstrate that, although CAR4 cells can participate in killing and multikilling, they do so at slower rates, likely due to the lower granzyme B content. Significantly, in both sets of T cells, a minor subpopulation of individual T cells identified by their high motility demonstrated efficient killing of single tumor cells. A comparison of the multikiller and single-killer CAR(+) T cells revealed that the propensity and kinetics of T-cell apoptosis were modulated by the number of functional conjugations. T cells underwent rapid apoptosis, and at higher frequencies, when conjugated to single tumor cells in isolation, and this effect was more pronounced on CAR8 cells. Our results suggest that the ability of CAR(+) T cells to participate in multikilling should be evaluated in the context of their ability to resist activation-induced cell death. We anticipate that TIMING may be used to rapidly determine the potency of T-cell populations and may facilitate the design and manufacture of next-generation CAR(+) T cells with improved efficacy. PMID- 25711540 TI - Endorectal ultrasonography performance in staging rectal cancer before and after neoadjuvant chemoradiotherapy. AB - AIM: To evaluate accuracy of endorectal ultrasonography (ERUS) both in staging and restaging rectal cancer after neoadjuvant chemoradiotherapy treatment. METHODS: In a group of 80 patients with rectal cancer, we retrospectively selected 67 patients and divided in two groups: 41 patients affected by a stage I were investigated with a single preoperative endorectal sonography; 26 patients with locally advanced rectal cancer (stage II or more) were restaged after neoadjuvant treatment, which consisted of 5,040 cGy in 28 daily fractions associated with continuous infusion of 5-Fluorouracil. All patients underwent surgery and ERUS findings were subsequently compared with histological findings. RESULTS: Diagnostic accuracy of ERUS in the first group of patients was high: in fact T-staging was accurate in 85% of cases. Results in the second group were significantly less accurate, with a correct T-staging just for 47% of cases. Nodes involvement was correctly evaluated in 86% of cases for the first group and in 63% of cases for the second one. CONCLUSIONS: Endorectal sonography is a valid staging modality for early rectal malignancy. Advanced cancer is treated with neoadjuvant preoperative chemoradiotherapy which is associated with better outcome than postoperative treatment. We found endorectal sonography, based on the layer model of rectal wall, often fails restaging and we think we have to develop new criteria for a correct preoperative assessment after neoadjuvant chemoradiation. KEY WORDS: Endorectal ultrasonography, Neoadjuvant chemoradiotherapy, Rectal cancer, Staging. PMID- 25711541 TI - Integration of geriatric oncology in daily multidisciplinary cancer care: the time is now. PMID- 25711543 TI - Prostate cancer survivorship and psychosexual care. PMID- 25711542 TI - Dissociation of event-based prospective memory and time-based prospective memory in patients with prostate cancer receiving androgen-deprivation therapy: a neuropsychological study. AB - The primary purpose of this study was to evaluate the event-based prospective memory (EBPM) and time-based prospective memory (TBPM) in androgen-deprivation therapy (ADT)-induced cognitive impairment in patients with prostate cancer (PC). Participants included PC patients who had undergone ADT (ADT group, n = 43) or patients who did not undergo ADT (non-ADT group, n = 35), as well as age and education-matched healthy controls (HC group, n = 40). All participants were administered with a battery of neuropsychological tests including EBPM and TBPM tasks. Our results indicated that during the EBPM task, the ADT group obtained significantly lower scores than the non-ADT and HC group did, while no significant differences in the TBPM task scores were found among these three groups. Additionally, the ADT group demonstrated significantly lower scores in several cognitive tasks, including attention, memory, and information processing, when compared with the other two groups. This study demonstrated that PC patients receiving ADT may have selective reductions in EBPM performance but unimpaired TBPM performance and that these deficits may result from the changes of function and structure of the pre-frontal cortex induced by ADT. PMID- 25711544 TI - Erratum: Single-photon sensitive light-in-flight imaging. PMID- 25711545 TI - Defining an exposure-response relationship for suspended kaolin clay particulates and aquatic organisms: work toward defining a water quality guideline for suspended solids. AB - Water quality guidelines for suspended solids generally rely on the percentage departure from reference condition, an approach that has been criticized. Attempts to develop a biological effects-base guideline have, however, been confounded by low data availability. Furthermore, the high biological response variability to suspended solids exposure suggests that organisms are responding not only to exposure concentration and duration but also to other mechanisms of effect associated with suspended particles (e.g., size, shape, and geochemical composition). An alternative option is to develop more situation and site specific guidelines by generating biological effects data to suspended particles of a particular geochemistry and restricted size range. With this in mind, aquatic organism responses to kaolin clay particle exposure were collated from the literature and incorporated into 2 exposure-response relationship approaches. The species sensitivity distribution approach produced a hazardous concentration affecting 5% of species estimate of 58 mg/L for mortality responses, and 36 mg/L for sublethal data. The severity-of-ill-effect approach produced similar estimates for lethal and sublethal data. These results suggest that aquatic organisms are slightly more tolerant of kaolin clay particles than particles from barite or bentonite clays, based on results from previous studies on these clay types. This type of information can enable better estimates of the risk faced by aquatic organisms exposed to suspended solids. For example, when the sediments of a particular water body are dominated by a particular type of clay particle, then the most appropriate exposure-response relationship can be applied. PMID- 25711546 TI - Maladaptive Behavior in Autism Spectrum Disorder: The Role of Emotion Experience and Emotion Regulation. AB - Maladaptive behavior is common in Autism Spectrum Disorder (ASD). However, the factors that give rise to maladaptive behavior in this context are not well understood. The present study examined the role of emotion experience and emotion regulation in maladaptive behavior in individuals with ASD and typically developing (TD) participants. Thirty-one individuals with ASD and 28 TD participants and their parents completed questionnaires assessing emotion experience, regulation, and maladaptive behavior. Compared to TD participants, individuals with ASD used cognitive reappraisal less frequently, which was associated with increased negative emotion experience, which in turn was related to greater levels of maladaptive behavior. By decreasing negative emotions, treatments targeting adaptive emotion regulation may therefore reduce maladaptive behaviors in individuals with ASD. PMID- 25711548 TI - Transforming care is everyone's business. PMID- 25711549 TI - 'Caring' nurse goes on trial for murder. PMID- 25711550 TI - Visiting hours extended on wards at more than half of NHS trusts. PMID- 25711547 TI - Traumatic Childhood Events and Autism Spectrum Disorder. AB - Traumatic childhood events are associated with a wide range of negative physical, psychological and adaptive outcomes over the life course and are one of the few identifiable causes of psychiatric illness. Children with autism spectrum disorder (ASD) may be at increased risk for both encountering traumatic events and developing traumatic sequelae; however, this topic has been understudied. This review considers the rationale for examining traumatic events and related symptomology in individuals with ASD and summarizes the limited research on this topic. A conceptual framework for understanding the interplay of ASD, trauma and traumatic sequelae is proposed and recommendations for future research presented. PMID- 25711551 TI - Family wins support of RCN in call for better community mental health care. PMID- 25711552 TI - Wearable CCTV kit initiative aims to quell A&E violence. PMID- 25711553 TI - Ebola nurse Cafferkey subject of NMC investigation. PMID- 25711554 TI - Staff face conflicting pressures as they deal with discharge delays. PMID- 25711555 TI - Staff just keep calm and carry on. PMID- 25711560 TI - Student 'role play' masks prompt mental health stigma complaint. PMID- 25711559 TI - Nurses overlooked in new cancer task force to improve survival rates. PMID- 25711566 TI - Tobacco. PMID- 25711567 TI - 'Care is improved when we listen to patients'. PMID- 25711568 TI - When the patient takes the lead. AB - The Five Year Forward View for the NHS recommends a raft of changes to put patients in charge of their own care. Nurses may need training to work in this new way, but there is evidence that those who make the shift find it satisfying and 'professionally empowering'. PMID- 25711569 TI - Turning feedback into action. PMID- 25711570 TI - Customer care. PMID- 25711571 TI - Voices - gathering feedback in the community can be challenging, says Crystal Oldman. PMID- 25711572 TI - Implementing change. PMID- 25711573 TI - Starting out - a patient with Parkinson's taught me the importance of listening. PMID- 25711574 TI - Crossing the divide. PMID- 25711575 TI - Feedback is an opportunity, not a threat. PMID- 25711576 TI - Readers panel - playing the name game with patients. PMID- 25711577 TI - At the heart of care. PMID- 25711578 TI - Taking control of anorexia together. AB - Many people with anorexia receive inadequate treatment for what is a debilitating, relentless and life-threatening illness. In Lincolnshire an innovative nurse-led day programme is helping people stay out of hospital and take back control from the illness. Peer support is crucial to the programme's success. PMID- 25711584 TI - More resources are needed to address poor end of life care. PMID- 25711585 TI - Some residents refuse to drink despite all efforts to tempt them. PMID- 25711586 TI - Stark contrast between the pay offer for nurses and 10% for MPs. PMID- 25711587 TI - A 'named nurse' is important, but teamwork is essential. PMID- 25711588 TI - Use a hoist to lift patients and rise from the hips - not knees. PMID- 25711589 TI - Care home residents need to be protected from eviction. PMID- 25711592 TI - Response to the Ebola crisis in Sierra Leone. AB - The Ebola outbreak in 2014 marked the first time that an epidemic of this viral haemorrhagic fever had occurred in West Africa. From its origin in Guinea, the outbreak rapidly increased to become a humanitarian crisis affecting all aspects of life in the three countries worst affected: Guinea, Sierra Leone and Liberia. Improving understanding of Ebola virus disease among the general population and instigating the behavioural changes required to help break the epidemic were central to the public health response. This article explores some of the misconceptions about Ebola as it spread into Sierra Leonean communities, and the social mobilisation response of the government of Sierra Leone. It is a reflective account of conversations with Sierra Leonean nationals during a military deployment at the International Security Advisory Team headquarters medical treatment facility in Freetown. PMID- 25711593 TI - Nursing care of patients with a temporary tracheostomy. AB - Safety considerations are important when caring for a patient with a temporary tracheostomy. Early detection and resolution of problems in tracheostomy management are important to prevent serious incidents arising. Nurses working outside critical care areas need to be competent and confident in the management or detection of potential problems with tracheostomies. This article summarises the essential care of a patient with a temporary tracheostomy with reference to best practice guidelines, emphasising the importance of prompt intervention and response, if a potential problem is identified. PMID- 25711594 TI - Fever in children. AB - Fever is a naturally occurring adaptive mechanism and part of the immune system's inflammatory response. It is often caused by self-limiting viral illnesses. Fever in children causes concern for parents and it is a common reason for attendance at GP surgeries and for children being admitted to hospital in the UK. PMID- 25711595 TI - Preventing pressure ulcers in patients in intensive care. AB - This article discusses the prevention and management of pressure ulcers in intensive care. It outlines a service improvement project conducted in the intensive care units at Imperial College Healthcare NHS Trust with the aim of reducing the incidence of hospital-acquired pressure ulcers. The project introduced a set of 'essential standards' and an audit tool to monitor compliance. Implementation of the essential standards resulted in a reduction in the total number of pressure ulcers acquired in the four intensive care units, with an absence of any category 3 or 4 pressure ulcers (the most severe categories of pressure ulcer). The article describes the measures taken to ensure the sustainability and spread of the initiative within the NHS trust. PMID- 25711596 TI - Reducing avoidable pressure ulcers in the community. AB - The elimination of avoidable pressure ulcers remains a challenge in healthcare provision, represents an increasing financial burden on resources and continues to affect patients' quality of life. Many pressure ulcers are deemed to be avoidable and there are several factors that can influence this, including the development of a care delivery system and a service delivery strategy that incorporate a comprehensive structure, a meticulous process and measurable outcomes. Nottingham CityCare developed a strategy to reduce avoidable pressure ulcers. The implementation of the strategy in an inner city community setting is discussed. The importance of eliminating pressure ulcers is explored, and the barriers to care delivery are reviewed, demonstrating how a new culture in clinical practice can ensure the elimination of avoidable pressure ulcers. The challenges within the implementation process are reflected on and the implementation of the SSKIN (Surface, Skin inspection, Keep your patient moving, Incontinence and moisture, Nutrition and hydration) phenomenon is reviewed in relation to care delivery, record-keeping and evaluation. PMID- 25711597 TI - Out and on the way up. PMID- 25711598 TI - Potential beneath the surface. PMID- 25711600 TI - Second job, big responsibility. PMID- 25711601 TI - Student life - getting reflection right. PMID- 25711604 TI - Dynamic combinatorial enrichment of polyconformational D-/L-peptide dimers. AB - D-/L-peptides such as gramicidin A (gA) adopt unique dimeric beta-helical structures of different topologies. To overcome their conformational promiscuity and enrich individual components, a dynamic combinatorial approach assisted by thiol tags was developed. This method led to identification of the preferential formation of antiparallel dimers under a broad range of conditions, which was independent of peptide side-chain polarity. Exclusive formation of an antiparallel cyclic dimer was achieved in the presence of cesium ions. PMID- 25711603 TI - A Photorhabdus natural product inhibits insect juvenile hormone epoxide hydrolase. AB - Simple urea compounds ("phurealipids") have been identified from the entomopathogenic bacterium Photorhabdus luminescens, and their biosynthesis was elucidated. Very similar analogues of these compounds have been previously developed as inhibitors of juvenile hormone epoxide hydrolase (JHEH), a key enzyme in insect development and growth. Phurealipids also inhibit JHEH, and therefore phurealipids might contribute to bacterial virulence. PMID- 25711602 TI - Histiocytic sarcoma with central nervous system involvement in dogs: 19 cases (2006-2012). AB - BACKGROUND: Reports of histiocytic sarcoma (HS) involving the central nervous system (CNS) are sparse and consist mainly of case reports describing 1-3 animals. OBJECTIVE: The objective of this study was to report the signalments, clinical signs, clinicopathologic and diagnostic imaging findings, treatment, and outcome of a series of dogs with HS and CNS involvement. ANIMALS: Nineteen dogs with HS examined at veterinary referral hospitals. METHODS: Retrospective case series. Medical records were reviewed and cases with a histopathological diagnosis of CNS HS were included in the study. Diagnostic imaging studies of the CNS were evaluated and histopathologic samples were reviewed to confirm the diagnosis. RESULTS: Retrievers and Pembroke Welsh Corgis were overrepresented in this cohort of dogs. Tumors involved the brain in 14 dogs and the spinal cord in 5. In 4 dogs, HS was part of a disseminated, multiorgan process whereas it appeared confined to the CNS in 15 dogs. Diagnostic imaging had variable appearances although extraaxial masses predominated in the brain. There was meningeal enhancement in all dogs that was often profound and remote from the primary mass lesion. Pleocytosis was present in all dogs with CSF evaluation. Median survival was 3 days. CONCLUSIONS AND CLINICAL IMPORTANCE: Breed predispositions appear to vary from reports of HS in other organ systems. Some unique imaging and clinicopathologic characteristics, particularly brain herniation, profound meningeal enhancement, and pleocytosis in combination with 1 or more mass lesions, might help to differentiate this neoplasm from others involving the CNS, although this requires further study. PMID- 25711605 TI - Opportunities in theoretical and computational polymeric materials and soft matter. AB - Soft materials are abundant in nature and ubiquitous in living systems. Elucidating their multi-faceted properties and underlying mechanisms is not only theoretically challenging and important in its own right, but also serves as the foundation for new materials and applications that will have wide-ranging impact on technology and the national economy. Recent initiatives in computation and data-driven materials discovery, such as the Materials Genome Initiative and the National Science Foundation Designing Materials to Revolutionize and Engineer our Future (NSF-DMREF) program, recognize and highlight the many future opportunities in the field. Building upon similar past efforts, a workshop was held at the University of California, Santa Barbara in October 2013 to specifically identify the central challenges and opportunities in theoretical and computational studies of polymeric as well as non-polymeric soft materials. This article presents a summary of the main findings of the workshop. PMID- 25711606 TI - Effects of land use on plague (Yersinia pestis) activity in rodents in Tanzania. AB - Understanding the effects of land-use change on zoonotic disease risk is a pressing global health concern. Here, we compare prevalence of Yersinia pestis, the etiologic agent of plague, in rodents across two land-use types-agricultural and conserved-in northern Tanzania. Estimated abundance of seropositive rodents nearly doubled in agricultural sites compared with conserved sites. This relationship between land-use type and abundance of seropositive rodents is likely mediated by changes in rodent and flea community composition, particularly via an increase in the abundance of the commensal species, Mastomys natalensis, in agricultural habitats. There was mixed support for rodent species diversity negatively impacting Y. pestis seroprevalence. Together, these results suggest that land-use change could affect the risk of local transmission of plague, and raise critical questions about transmission dynamics at the interface of conserved and agricultural habitats. These findings emphasize the importance of understanding disease ecology in the context of rapidly proceeding landscape change. PMID- 25711607 TI - The "Performance of Rotavirus and Oral Polio Vaccines in Developing Countries" (PROVIDE) study: description of methods of an interventional study designed to explore complex biologic problems. AB - Oral vaccines appear less effective in children in the developing world. Proposed biologic reasons include concurrent enteric infections, malnutrition, breast milk interference, and environmental enteropathy (EE). Rigorous study design and careful data management are essential to begin to understand this complex problem while assuring research subject safety. Herein, we describe the methodology and lessons learned in the PROVIDE study (Dhaka, Bangladesh). A randomized clinical trial platform evaluated the efficacy of delayed-dose oral rotavirus vaccine as well as the benefit of an injectable polio vaccine replacing one dose of oral polio vaccine. This rigorous infrastructure supported the additional examination of hypotheses of vaccine underperformance. Primary and secondary efficacy and immunogenicity measures for rotavirus and polio vaccines were measured, as well as the impact of EE and additional exploratory variables. Methods for the enrollment and 2-year follow-up of a 700 child birth cohort are described, including core laboratory, safety, regulatory, and data management practices. Intense efforts to standardize clinical, laboratory, and data management procedures in a developing world setting provide clinical trials rigor to all outcomes. Although this study infrastructure requires extensive time and effort, it allows optimized safety and confidence in the validity of data gathered in complex, developing country settings. PMID- 25711608 TI - Performance of an HRP-2 rapid diagnostic test in Nigerian children less than 5 years of age. AB - The diagnostic performance of histidine-rich protein 2 (HRP-2)-based malaria rapid diagnostic test (RDT) was evaluated in a mesoendemic area for malaria, Kaduna, Nigeria. We compared RDT results with expert microscopy results of blood samples from 295 febrile children under 5 years. Overall, 11.9% (35/295) tested positive with RDT compared with 10.5% (31/295) by microscopy: sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were 100%, 98.5%, 88.6%, and 100%, respectively. The RDT sensitivity was not affected by transmission season, parasite density, and age. Specificity and positive PV decreased slightly during the high-transmission season (97.5% and 83.3%). The RDT test positivity rates in the low- and high-transmission seasons were 9.4% and 13.5%, respectively. Overall, the test performance of this RDT was satisfactory. The findings of a low proportion of RDT false positives, no invalid and no false-negative results should validate the performance of RDTs in this context. PMID- 25711609 TI - Dramatic decrease in prevalence of soil-transmitted helminths and new insights into intestinal protozoa in children living in the Chaco region, Bolivia. AB - We assessed the prevalence of intestinal parasites among 268 2-12-year-old children living in rural areas, small villages, and semi-urban areas of the Chaco region, south-eastern Bolivia. The overall parasitism was 69%. Only protozoa, helminths, or co-infections were observed in 89.2%, 5.9%, or 4.9% of the positive children, respectively. A significant progressive increase in overall parasite prevalence was found when passing from rural areas to small villages and semi urban areas. The most commonly found species were Entamoeba coli (38.4%), Giardia intestinalis (37.7%), and Blastocystis spp. (16%). Hymenolepis nana was the most prevalent helminth (5.6%), followed by Ascaris lumbricoides and hookworms (1.5% and 0.4%) evidenced only in rural areas and in villages. Molecular diagnostics identified Blastocystis subtypes 9 and 2, and 5 infections by Entamoeba histolytica and 4 by Entamoeba dispar. The dramatic decrease in prevalence of soil-transmitted helminths with respect to that observed about 20 years ago (> 40%) evidences the success of the preventive chemotherapy intervention implemented in 1986. Health education and improved sanitation should be intensified to control protozoan infections. PMID- 25711611 TI - SFTS virus in ticks in an endemic area of China. AB - In total, 3,145 ticks of the species Haemaphysalis longicornis (3,048; 96.9%), R. microplus (82; 2.6%), H. campanulata (9; 0.3%), and Dermacentor sinicus (5; 0.2%) were collected from animals and vegetation at Yantai in Shandong Province. Both adult and immature ticks were obtained, and all ticks collected from vegetation were unfed. Eggs were obtained from 22 blood-fed female ticks through maintenance at room temperature after collection. Severe fever with thrombocytopenia syndrome virus (SFTSV) viral RNA was identified in H. longicornis and R. microplus, with a prevalence of 4.75 per 100 ticks (95% confidence interval [95% CI] = 3.87-5.63) for ticks collected from animals and 2.24 per 100 ticks (95% CI = 1.27-3.21) for ticks collected from vegetation. The possibility that SFTSV transmission may occur by both the transstadial and transovarial routes was suggested by the fact that viral RNA was detected in H. longicornis at all developmental stages. Tick derived sequences shared over 95.6% identity with human- and animal-derived isolates. This study provides evidence that implicates ticks as not only vectors but also, reservoirs of SFTSV. PMID- 25711610 TI - Potential animal reservoirs of Toscana virus and coinfections with Leishmania infantum in Turkey. AB - Toscana virus (TOSV), a sandfly-borne phlebovirus, is an important agent of human meningoencephalitis in the Mediterranean region, for which vertebrates acting as reservoirs have not yet been determined. This study investigates TOSV and Leishmania infections in dogs, cats, sheep, and goats from Adana and Mersin provinces in southeastern Turkey. TOSV neutralizing antibodies were demonstrated in 40.4% of the dog and 4% of the goat samples. TOSV RNA was detected in 9.9% of the 252 samples that mainly comprise dogs (96%). Thus, canine species can be suggested as the candidate reservoirs of TOSV. Partial sequences revealed the activity of TOSV genotypes A and B. In two dogs presenting with symptoms of canine leishmaniasis, infections of TOSV genotype B and Leishmania infantum have been documented, describing the first report of coinfections with these agents. PMID- 25711612 TI - Interleukin-10 limits intense acute swimming-induced muscle mechanical hyperalgesia in mice. AB - NEW FINDINGS: What is the central question of this study? This study investigated the role of the endogenous anti-inflammatory cytokine interleukin-10 in intense acute swimming-induced muscle mechanical hyperalgesia in mice. What is the main finding and its importance? Endogenous interleukin-10 has a key role in limiting exercise-induced muscle pain in a model presenting similarities to delayed-onset muscle soreness in mice. Interleukin-10 reduced muscle pain by diminishing leucocyte recruitment, hyperalgesic cytokine production, oxidative stress and myocyte damage. Interleukin-10 (IL-10) is an antihyperalgesic cytokine. In this study, IL-10-deficient (IL-10(-/-) ) mice were used to investigate the role of endogenous IL-10 in intense acute swimming-induced muscle mechanical hyperalgesia, which presents similarities with delayed-onset muscle soreness. An intense acute swimming session of 1 or 2 h induced significant muscle mechanical hyperalgesia in a time-dependent manner in wild-type mice compared with the sham group 24 h after the session, which was further increased in IL-10(-/-) mice (P ? 0.05). Intraperitoneal treatment of wild-type mice with IL-10 (1-10 ng) reduced muscle mechanical hyperalgesia in a dose-dependent manner and reversed the enhanced muscle hyperalgesia in IL-10(-/-) mice (P ? 0.05). The 2 h swimming session induced increases in tumour necrosis factor-alpha, interleukin-1beta and IL-10 production in the soleus muscle. However, tumour necrosis factor-alpha and interleukin-1beta production in the soleus muscle were even higher in IL-10(-/-) mice between 2 and 6 h after the stimulus (P ? 0.05). There was no statistical difference in the levels of the antihyperalgesic cytokines interleukin-4, interleukin-5, interleukin-13 and transforming growth factor-beta between wild type and IL-10(-/-) mice (P ? 0.05). Interleukin-10 deficiency also resulted in increased myeloperoxidase activity, greater depletion of reduced glutathione levels, increased superoxide anion production and the maintenance of high plasma concentrations of creatine kinase (until 24 h after the swimming session) in soleus muscle (P ? 0.05). These results demonstrate that endogenous IL-10 controls intense acute swimming-induced muscle mechanical hyperalgesia by limiting oxidative stress and cytokine production. PMID- 25711613 TI - Serious, Violent Young Offenders in South Africa: Are They Life-Course Persistent Offenders? AB - Life-course persistent offending contributes greatly to violent offending in any country. South Africa has high rates of violence; this study investigated what proportion of young South African offenders might be identified as life-course persistent, and what risk factors identified this group. Offenders aged 12 to 25 years (N = 395) were selected from eight different correctional facilities in four provinces of South Africa. Latent class analysis identified 164 offenders (41.5%) with distinctly earlier starts and more serious offending. These (probably life-course persistent) offenders were distinguished from others by male gender, violence at home, other victimization, familial crime, school performance, violence at school, and alcohol abuse and gang membership. Correctional services should be specifically targeted at this large subgroup of offenders to prevent recidivism. Primary prevention efforts should be targeted at preventing violence at home and school, at promoting school attachment, at substance abuse treatment, and at gang membership. PMID- 25711614 TI - The Role of Parent Communication and Connectedness in Dating Violence Victimization among Latino Adolescents. AB - Dating violence among U.S. adolescents is a substantial concern. Previous research indicates that Latino youth are at increased risk of dating violence victimization. This secondary data analysis examined the prevalence of physical and sexual dating violence victimization among subgroups of Latino adolescents and associations of parent communication, parent caring, and dating violence victimization using data from the 2010 Minnesota Student Survey (N = 4,814). Parallel analyses were conducted for Latino-only and multiple-race Latino adolescents, stratified by gender. Multivariate logistic regression models tested associations between race/ethnicity, parent communication, perceived parent caring, and adolescent dating violence experiences. Overall, 7.2% to 16.2% of Latinos reported physical or sexual dating violence. Both types of dating violence were more prevalent among multiple-race Latinos than among Latino-only adolescents, with prevalence rates highest among multiple-race Latino females (19.8% and 19.7% for physical and sexual dating violence victimization, respectively). In multivariate models, perceived parent caring was the most important protective factor against physical and sexual dating violence among males and females. High levels of mother and father communication were associated with less physical violence victimization among males and females and with less sexual violence victimization among females. Results highlight the importance of parent communication and parent caring as buffers against dating violence victimization for Latino youth. These findings indicate potential for preventive interventions with Latino adolescents targeting family connectedness to address dating violence victimization. PMID- 25711615 TI - Adverse Childhood Experiences and Arrest Patterns in a Sample of Sexual Offenders. AB - Developmental psychopathology theories suggest that childhood adversity can contribute to antisocial conduct and delinquent activities. The purpose of this study was to explore the influence of adverse childhood experiences (ACE) on arrest patterns in a sample of sexual offenders (N = 740). Higher ACE scores were associated with a variety of arrest outcomes, indicating that the accumulation of early trauma increased the likelihood of versatility and persistence of criminal behavior. Rapists of adults had higher ACE scores, lower levels of specialization, and higher levels of persistence than sex offenders with minor victims only. Child sexual abuse, emotional neglect, and domestic violence in the childhood home were significant predictors of a higher number of sex crime arrests. For measures of nonsexual arrests and criminal versatility, it was the household dysfunction factors-substance abuse, unmarried parents, and incarceration of a family member-that were predictive, suggesting that family dysfunction and a chaotic home environment contributed significantly to increased risk of general criminal behavior. Sex offenders inspire little sympathy in our society but may be among those most in need of trauma-informed models of treatment that recognize the influence of early adversity on maladaptive schema and self-regulation deficits related to criminal behavior. PMID- 25711616 TI - Low Self-Control and the Victim-Offender Overlap: A Gendered Analysis. AB - The overlap between victimization and offending is well documented. Yet, there have been fewer investigations of the reasons underlying this relationship. One possible, but understudied, explanation lies with Gottfredson and Hirschi's arguments regarding self-control. The current study adds to this line of inquiry by assessing whether low self-control accounts for the victim-offender overlap in a sample of young adults and whether self-control accounts for the observed overlap similarly across gender. Results from a series of bivariate probit regression models indicate that low self-control is positively related to both victimization and offending. However, only among males does low self-control account for a substantive portion of the victim-offender overlap. Limitations of the study and implications and directions for future research are discussed. PMID- 25711617 TI - More Polygraph Futility: A Comment on Jensen, Shafer, Roby, and Roby (2015). AB - This article takes a critical look at the recent Jensen, Shafer, Roby, and Roby study that found that juveniles and adults have no statistically significant different rates of passing sexual history polygraph examinations. Numerous research and statistical issues are identified, including lack of independence, no adjustment for differing rates of opportunity across ages, poor construct validity of deceit, failure to adjust for base rates of deceit in subsequent analyses, and failure to include recidivism as an outcome. In addition, three arguments made by Jensen et al. against using recidivism as an outcome to judge post-conviction polygraph are discussed along with critical assessments of two recent studies examining the relationship between recidivism and sexual history polygraph examinations. It ends with a discussion of the current state of post conviction polygraph testing research and way forward to find solid, replicable evidence that assesses its utility as a correctional intervention. PMID- 25711618 TI - Bullying and Peer Victimization: An Examination of Cognitive and Psychosocial Constructs. AB - Research has demonstrated a link between internalizing factors and bullying perpetration and peer victimization; however, few studies have examined predictors of cognitive and psychosocial factors, such as locus of control and hopelessness. The current study examined cognitive and psychosocial factors in bullying perpetration and peer victimization in a sample of 469 middle school students. A mediator model of hopelessness was also investigated. Students involved in bullying reported a greater external locus of control compared with peers who were not involved in bullying. Bully-victims endorsed the highest externality. Results showed that hopelessness fully mediated the relationship between verbal/relational victimization and external locus of control for the victim group, but not the bully-victim group. Implications for bullying prevention and intervention efforts are discussed. PMID- 25711619 TI - Association of Domestic Violence From Husband and Women Empowerment in Slum Community, Mumbai. AB - Prevalence of violence by husband against wife is an indicator of women's status at household level. The objective of the study is to understand the relationship between domestic violence and women's empowerment in a slum community in Mumbai, India. Data were collected from a sample of 1,136 married women aged 18 to 39 years having at least one child and reporting of unmet need for family planning. Domestic violence by husband against wife was measured in terms of either physical, sexual, or emotional violence. Three logit regression analyses were carried out using decision-making power, freedom of movement, and justified wife beating as dependent variables separately and socio-demographic and economic variables as independent variables. Furthermore, the relationship between domestic violence and women's decision-making power, freedom of movement, and justified wife-beating index has been explored. About 21% of women had ever experienced violence, and 38% of women had decision-making power with respect to own health care, household purchase, or visiting family and relatives. A little more than one fifth of the women reported freedom of movement to market, health facilities, or places outside the community. Women who justified wife beating were 2.29 (95% CI [1.59, 3.29]) times at risk of experiencing violence than women who disagreed with the wife-beating statements. Women not empowered in decision making were 1.15 (95% CI [0.91, 1.46]) times at risk of experiencing domestic violence than women who were empowered in decision making. Women who are empowered are less likely to be at risk of domestic violence. Programs aimed at empowering women must address socio-cultural norms relating to justification of violence in marriage. PMID- 25711620 TI - Effect of partial atomic charges on the calculated free energy of solvation of poly(vinyl alcohol) in selected solvents. AB - It is well-known that properties of poly(vinyl alcohol) (PVA) in the pure and solution states depend largely on the hydrogen bonding networks formed. In the context of molecular simulation, such networks are handled through the Coulombic interactions. Therefore, a good set of partial atom charges (PACs) for simulations involving PVA is highly desirable. In this work, we calculated the PACs for PVA using a few commonly used population analysis schemes with a hope to identify an accurate set of PACs for PVA monomers. To evaluate the quality of the calculated parameters, we have benchmarked their predictions for free energy of solvation (FES) in selected solvents by molecular dynamics simulations against the ab initio calculated values. Selected solvents were water, ethanol and benzene as they covered a range of size and polarity. Also, PVA with different tacticities were used to capture their effect on the calculated FESs. Based on our results, neither PACs nor FESs are affected by the chain tacticity. While PACs predicted by the Merz-Singh-Kollman scheme were close to original values in the OPLS-AA force field in way that no significant difference in properties of pure PVA was observed, free energy of solvation calculated using such PACs showed greater agreement with ab initio calculated values than those calculated by OPLS AA (and all other schemes used in this work) in all three solvents considered. PMID- 25711621 TI - A polar nature of benzoic acids extrusion from nitroalkyl benzoates: DFT mechanistic study. AB - Using DFT calculations at various theory levels, quantum-chemical simulations of decomposition paths were performed for a series of nitroalkyl benzoates. It was discovered, that these reactions proceed via polar, but one-step mechanism. It turned out that depending on the nature of the substituent in the ester molecule and on medium polarity, the studied reactions may take place via transition states with varied synchronicity-from E1-like structures, to E1cb-like structures. A purely ionic, two-stage mechanism was not identified in any of the cases. PMID- 25711622 TI - A comparative study of the chalcogen bond, halogen bond and hydrogen bond S?O/Cl/H formed between SHX and HOCl. AB - Ab initio quantum chemistry methods were used to analyze the noncovalent interactions between HOCl and SHX (X = F, CN, NC, Cl, Br, NO2, CCH, CH3, H). Three energetic minimal configurations were characterized for each case, where the S center acts as a Lewis acid interacting with O to form a chalcogen bond, as well as a Lewis base interacting with Cl or H of HOCl to form halogen bond and hydrogen bond, respectively. An electronegative substituent such as F, CN, NC and NO2 tends to form a stronger chalcogen bond, while an electropositive substituent such as CCH, CH3 and H is inclined to form a more stable H-bonded complex. The chalcogen-bonded, halogen-bonded and H-bonded complexes are stabilized by charge transfers from Lp(O) to sigma*(SX), from Lp(S) to sigma*(ClO), and from Lp(S) to sigma*(HO), respectively. As a result, the SHX unit becomes positively charged in halogen-bonded and hydrogen-bonded complexes but negatively charged in chalcogen bonded complexes. Theory of atoms in molecules, natural bond orbital analysis, molecular electrostatic potential and localized molecular orbital energy decomposition analysis were applied to investigate these noncovalent bonds. PMID- 25711623 TI - Exploring sigma-hole bonding in XH3Si...HMY (X=H, F, CN; M=Be, Mg; Y=H, F, CH3) complexes: a "tetrel-hydride" interaction. AB - In this work, a sigma-hole interaction is predicted theoretically in XH3Si...HMY complexes, where X=H, F, CN; M=Be, Mg and Y=H, F, CH3. The properties of this interaction, termed "tetrel-hydride" interaction, are investigated in terms of geometric, interaction energies, and electronic features of the complexes. The geometry of these complexes is obtained using the second-order Moller-Plesset perturbation theory (MP2) with aug-cc-pVTZ basis set. For each XH3Si...HMY complex, a tetrel-hydride bond is formed between the negatively charged H atom of HMY molecule and the positively charged Si atom of XH3Si molecule. The CCSD(T)/aug-cc-pVTZ interaction energies of this type of sigma-hole bonding range from -0.6 to -3.8 kcal mol(-1). The stability of XH3Si...HMY complexes is attributed mainly to electrostatic and correlation effects. The nature of tetrel hydride interaction is analyzed with atoms in molecules (AIM) and natural bond orbital (NBO) theories. PMID- 25711624 TI - Melatonin induces class A1 heat-shock factors (HSFA1s) and their possible involvement of thermotolerance in Arabidopsis. AB - Melatonin (N-acetyl-5-methoxytryptamine) serves as an important signal molecule during plant developmental processes and multiple abiotic stress responses. However, the involvement of melatonin in thermotolerance and the underlying molecular mechanism in Arabidopsis were largely unknown. In this study, we found that the endogenous melatonin level in Arabidopsis leaves was significantly induced by heat stress treatment, and exogenous melatonin treatment conferred improved thermotolerance in Arabidopsis. The transcript levels of class A1 heat shock factors (HSFA1s), which serve as the master regulators of heat stress responses, were significantly upregulated by heat stress and exogenous melatonin treatment in Arabidopsis. Notably, exogenous melatonin-enhanced thermotolerance was largely alleviated in HSFA1s quadruple knockout (QK) mutants, and HSFA1s activated transcripts of heat-responsive genes (HSFA2, heat stress-associated 32 (HSA32), heat-shock protein 90 (HSP90), and 101 (HSP101)) might be contributed to melatonin-mediated thermotolerance. Taken together, this study provided direct link between melatonin and thermotolerance and indicated the involvement of HSFA1s-activated heat-responsive genes in melatonin-mediated thermotolerance in Arabidopsis. PMID- 25711625 TI - You are not what you eat during physiological stress: Isotopic evaluation of human hair. AB - Variation in delta(13) C and delta(15) N values can be assessed to understand not only diet, but also the influence of physiological factors on an individual. The metabolic balance of an individual can impact isotopic signals in tissues that are forming during the periods of metabolic stress. Fluctuating delta(15) N values are associated with physiological stressors that alter an individual's metabolism such as infection, injury, or pregnancy. This study examines variation in delta(13) C and delta(15) N values along sequentially segmented hair in both modern and archaeological individuals. Subjects with an observable skeletal pathology, known chronic illness, or evidence of pregnancy were compared with controls exhibiting no evidence of physiological stress. The results on hair samples from individuals from 19(th) century Belleville, Ontario, four modern cadavers (two with cancer and two sudden deaths), and two living pregnant women indicate that delta(15) N values are approximately 10/00 higher in individuals with a pathological condition (e.g., infection, fracture, or cancer) and are 10/00 lower during pregnancy, whereas delta(13) C values show less variability. Higher nitrogen values may represent the recycling of nitrogen derived from the breakdown of existing proteins in the body (catabolism), whereas lower delta(15) N values are related to increased utilization of dietary and urea nitrogen for tissue synthesis during pregnancy. These findings suggest that short-term fluctuations of delta(15) N values may be the result of changes in an individual's metabolic balance, and that metabolic imbalance poses a confounding factor to ancient dietary studies when using rapidly growing tissues such as hair. PMID- 25711626 TI - Procedures of limited clinical value in ENT: what effect has there been on operating numbers? PMID- 25711627 TI - Plasticity, not genetic variation, drives infection success of a fungal parasite. AB - Hosts strongly influence parasite fitness. However, it is challenging to disentangle host effects on genetic vs plasticity-driven traits of parasites, since parasites can evolve quickly. It remains especially difficult to determine the causes and magnitude of parasite plasticity. In successive generations, parasites may respond plastically to better infect their current type of host, or hosts may produce generally 'good' or 'bad' quality parasites. Here, we characterized parasite plasticity by taking advantage of a system in which the parasite (the yeast Metschnikowia bicuspidata, which infects Daphnia) has no detectable heritable variation, preventing rapid evolution. In experimental infection assays, we found an effect of rearing host genotype on parasite infectivity, where host genotypes produced overall high or low quality parasite spores. Additionally, these plastically induced differences were gained or lost in just a single host generation. Together, these results demonstrate phenotypic plasticity in infectivity driven by the within-host rearing environment. Such plasticity is rarely investigated in parasites, but could shape epidemiologically important traits. PMID- 25711628 TI - Randomized controlled trial of arthroscopic electrothermal capsulorrhaphy with Bankart repair and isolated arthroscopic Bankart repair. AB - PURPOSE: Electrothermal arthroscopic capsulorrhaphy (ETAC) was introduced as an adjunct to shoulder stabilization surgery to address capsular laxity in the treatment of traumatic anterior dislocation. No previous RCT has compared arthroscopic Bankart repair with ETAC of the medial glenohumeral ligament and anterior band of the inferior glenohumeral ligament versus undergoing arthroscopic Bankart repair alone. Our hypothesis was that there would be no difference in quality of life between these two groups. Complication/failure rates were also compared. METHODS: Eighty-eight patients were randomly assigned to receive arthroscopic Bankart repair with (n = 44) or without ETAC (n = 44). Post-operative visits occurred at 3, 6, 12, and 24 months with WOSI, ASES, and Constant scores completed, and rates of dislocation/subluxation were determined. RESULTS: Data on 74 patients were analysed, with the rest lost to follow-up. There were no differences between groups at any post-surgery time points for WOSI, ASES, or Constant scores (n.s.). Eight patients in the no-ETAC group and 7 in the ETAC group were considered failures (n.s.). CONCLUSIONS: No benefits in patient-reported outcome or recurrence rates using ETAC were found. Mean WOSI scores 2 years post-surgery were virtually identical for the two groups. ETAC could not be shown to provide benefit or detriment when combined with arthroscopic labral repair for traumatic anterior instability of the shoulder. LEVEL OF EVIDENCE: II. PMID- 25711629 TI - Chronic salsolinol administration prevents the behavioral and neurochemical effects of L-DOPA in rats. AB - 1-Methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (salsolinol) is a well known endogenous compound that has been proposed as a factor involved in the pathogenesis of Parkinson's disease. In the present study, we investigated the impact of acute and chronic salsolinol (100 mg.kg i.p.) administration on L-DOPA induced locomotor hyperactivity and neurochemical changes (the dopamine level and its metabolism in rat brain structures). Moreover, using the in vivo microdialysis technique, we measured the effect of acute and chronic salsolinol injection on L-DOPA-induced dopamine release in the rat striatum. The behavioral data demonstrated that both acute and chronic salsolinol administration antagonized L-DOPA-mediated hyperactivity. An ex vivo neurochemical experiment indicated that chronic but not acute salsolinol administration partially inhibited the L-DOPA-induced increases in the concentration of dopamine and all of its metabolites in dopaminergic structures. Additionally, the in vivo dopamine release data obtained from the microdialysis experiments clearly indicated that the differences in the effect of salsolinol on the activities of L-DOPA depended on the mode of salsolinol treatment. Acute injection of salsolinol enhanced the L DOPA-induced elevation of dopamine release (by ~1200 %; P < 0.01), whereas chronic administration of salsolinol completely blocked the L-DOPA-induced elevation of dopamine release in the rat striatum. These data demonstrated that chronic administration of salsolinol significantly impaired the response of dopaminergic neurons to L-DOPA administration. In conclusion, we propose that an elevated salsolinol level in parkinsonian patients may represent a serious risk factor of the clinical efficacy of L-DOPA therapy. PMID- 25711630 TI - High efficacy of cisplatin neoadjuvant therapy in a prospective series of patients carrying BRCA1 germ-line mutation. AB - Development of malignancies in BRCA1 germ-line mutation carriers usually involves somatic inactivation of the remaining BRCA1 allele. This feature leads to a tumor specific deficiency of double-strand DNA break repair and underlies pronounced sensitivity of BRCA1-driven cancers to cisplatin. BRCA1-specific activity of cisplatin has been repeatedly demonstrated in cell culture and animal experiments; however, corresponding clinical evidence remains limited. We applied neoadjuvant monotherapy by cisplatin (75-100 mg/m(2), 4-6 cycles) to six breast cancer patients carrying BRCA1 5382insC mutation. Pronounced reduction in tumor size was observed in all treated women. Three patients (T2N0M0, T4N2M0 and T4N2M0) showed pathologic complete response, two women (T4N0M0 and T2N1M0) had partial pathologic response, and one woman (T3N2M0) declined surgery. This study and available literature data suggest that cisplatin is a preferable option for systemic treatment of BRCA1-related hereditary breast cancer. PMID- 25711631 TI - Cancer Stem Cell Markers in Eyelid Sebaceous Gland Carcinoma: High Expression of ALDH1, CD133, and ABCG2 Correlates With Poor Prognosis. AB - PURPOSE: To investigate the expression of cancer stem cell (CSC) marker proteins in eyelid sebaceous gland carcinoma and evaluate the clinical significance. METHODS: Archival tissue blocks from 50 cases of eyelid sebaceous gland carcinoma were tested via immunohistochemistry for 16 putative CSC markers. Levels of protein expression were analyzed alongside various clinicopathologic parameters such as metastasis-free survival time. RESULTS: Ten patients (20%) showed nodal or distant metastasis during the follow-up period (median, 35.2 months; range, 1 128 months) without any mortality in our series. Among the 16 markers, ALDH1, CD44, CD133, ABCG2, Sox4, Sox9, and slug were selected for candidates of CSC markers because they were frequently and predominantly found in the tumor cells compared with control tarsus cells, which showed negative or very low expression. Univariate analysis revealed that ALDH1, CD133, and ABCG2 were significantly associated with metastasis; patients with ALDH1- or CD133-positive tumors developed metastasis more frequently than patients with tumors that were negative for these markers (log-rank test, P = 0.014, P = 0.013, respectively), and diffuse expression of ABCG2 was associated with significantly shorter metastasis free survival (log-rank test, P = 0.010). Multivariate Cox proportional hazard model revealed that ALDH1 (hazard ratio [HR] = 5.682, P = 0.038) was significantly associated with metastasis. CONCLUSIONS: Development of metastasis in eyelid sebaceous gland carcinoma might be attributed to increased number of CSCs or acquisition of dedifferentiated phenotype. Our findings suggest that CSCs are involved in the disease progression of eyelid sebaceous gland carcinoma, and in particular, expression of ALDH1 is a predictor of a poor outcome. PMID- 25711632 TI - Identification of miRNAs in a Model of Retinal Degenerations. AB - PURPOSE: We investigated the expression profile of and identify all microRNAs (miRNAs) that potentially regulate inflammation in a light-induced model of focal retinal degeneration. METHODS: Sprague Dawley (SD) rats aged 90 to 140 postnatal days were exposed to 1000 lux white fluorescent light for 24 hours. At 24 hours, and 3 and 7 days after exposure, the animals were euthanized and retinas processed for RNA. Expression of 750 miRNAs at 24 hours of exposure was assessed using low density array analysis. Significantly modulated miRNAs and their target mRNAs were used to assess the potential biological effects. Expression of seven miRNAs, potentially modulating inflammation, was investigated across a protracted time course after light exposure using quantitative PCR. Photoreceptor cell death was analyzed using TUNEL. RESULTS: Intense light exposure for 24 hours led to differential expression of a number of miRNAs, 37 of which were significantly modulated by 2-fold or more. Of those, 19 may potentially regulate the inflammatory immune response observed in the model. MicroRNAs -125-3p, -155, 207, -347, -449a, -351, and -542-3p are all upregulated at 24 hours of exposure along with peak photoreceptor cell death. The MiRNAs -542-3p and -351 reached maximum expression at 7 days after exposure, while -125-3p, -155, -207, -347, and -449 reached a peak expression at 3 days. CONCLUSIONS: The results of the study show that miRNAs are modulated in response to light damage (LD). These miRNAs potentially regulate the inflammatory immune response, triggered as a result of the acute retinal damage, which is a key mediator of retinal degeneration in this model and age-related macular degeneration. PMID- 25711633 TI - Genetic Variants Associated With Different Risks for High Tension Glaucoma and Normal Tension Glaucoma in a Chinese Population. AB - PURPOSE: We investigated the association of genetic factors with primary open angle glaucoma (POAG), including high tension glaucoma (HTG) and normal tension glaucoma (NTG), in a Han Chinese population. METHODS: We recruited 1157 POAG cases, including 860 HTG and 297 NTG, and 934 normal controls. A total of 13 previously reported single nucleotide polymorphisms (SNPs) located at four gene regions (TMCO1, CDKN2B-AS1, ATOH7, and SIX1/SIX6) was genotyped. Distributions of allele frequencies were compared between cases and controls as well as in the HTG and NTG subgroups. The IOP, vertical cup-to-disc ratio (VCDR), central corneal thickness (CCT), axial length (AL), and age at diagnosis also were investigated as quantitative phenotypes with genotypes of these SNPs. RESULTS: The SNPs rs4656461 and rs7555523 at TMCO1, rs523096 and rs2157719 at CDKN2B-AS1, as well as rs33912345 and rs10483727 at SIX1/SIX6 showed statistically significant association with POAG. The SNPs at ATOH7 did not show statistically significant association with POAG in our dataset. In the subgroup analysis of HTG and NTG, multiple variants at CDKN2B-AS1 and SIX1/SIX6 showed stronger association with NTG than HTG. The SNPs rs523096 and rs2157719 at CDKN2B-AS1 as well as rs33912345 and rs10483727 at SIX1/SIX6 were found to be associated with IOP where the minor alleles were associated with an increase in IOP. In contrast, SNPs at TMCO1 showed significant association with HTG only. CONCLUSIONS: Genetic variants in CDKN2B-AS1, SIX1/SIX6, and TMCO1 were associated with POAG in a Han Chinese population. Genes CDKN2B-AS1 and SIX1/SIX6 seem to harbor a tendency toward POAG with lower IOP, while carriers of risk alleles at TMCO1 seem to be predisposed to developing POAG with higher IOP. PMID- 25711634 TI - Serum leptin and age-related macular degeneration. AB - PURPOSE: Leptin, a 167-amino acid protein secreted by adipocytes, has been shown to reduce beta-amyloid deposition and intracellular lipid concentration in animal models, two key pathogenic mechanisms underlying aging. We examined the association between serum leptin levels and AMD. METHODS: We conducted a population-based case-control study including Chinese and Indian adults aged 40 to 80 years who participated in the Singapore Epidemiology of Eye Diseases Study (2007-2011). Age-related macular degeneration was assessed from retinal photographs graded using a modified Wisconsin Age-Related Maculopathy Grading System (n = 426; early = 389, late = 37). Controls (n = 927) without AMD were frequency matched for age, sex, and ethnicity. Serum leptin levels were measured using direct sandwich ELISA. RESULTS: Participants with AMD had lower levels of leptin compared with those without (mean [SD] = 10.0 [11.5] ng/mL versus 12.9 [16.4] ng/mL; P = 0.001). Mean levels of leptin among those with late, early, and without AMD were 8.8, 10.1, and 12.9 ng/mL (P trend = 0.005). In multivariable models adjusting for potential confounders, including smoking, body mass index, blood pressure, and high-density lipoprotein cholesterol, increasing quartiles of leptin were associated with lower odds of AMD, odds ratio (95% confidence interval) of AMD was 0.56 (0.34-0.92) comparing highest to lowest quartile of serum leptin. In subgroup analyses, the inverse association between leptin and AMD was significant in women, Indian ethnicity, and ex-smokers. CONCLUSIONS: Higher serum leptin levels were inversely associated with AMD. These findings, if confirmed in prospective studies, may provide insights into new pathogenic pathways and possibly therapeutic targets in AMD. PMID- 25711635 TI - Poly(ADP-Ribose) Polymerase Inhibition Improves Corneal Epithelial Innervation and Wound Healing in Diabetic Rats. AB - PURPOSE: We evaluated the effect of poly(ADP-ribose) polymerase (PARP) inhibition by using 1,5-isoquinolinediol (ISO) on corneal epithelial innervation in diabetic rats. METHODS: ISO (3 mg/kg, intraperitoneal) or vehicle was administered to rats with diabetes induced by streptozotocin for 4 weeks. Epithelial innervation, epithelial wound healing, and corneal sensation were evaluated in diabetic rats (DM rats), diabetic rats treated with ISO (DM-ISO rats), and nondiabetic (non-DM) rats. The density of epithelial innervation was calculated separately as nerve terminals and sub-basal nerve plexus by analyzing the images of whole-mount corneas. Healed areas of epithelial defect were measured at 0, 18, and 36 hours after creating a 4-mm wound on the cornea. Corneal sensitivity test was conducted using a Cochet-Bonnet handheld esthesiometer. Additionally, PARP1 and poly(ADP ribosyl)ated polymers (pADPr) as its products, were identified in trigeminal ganglions (TGs) by Western blot analysis and immunofluorescence staining. RESULTS: In DM rats, the density of nerve terminals (5.57% +/- 0.94%) and sub basal nerve plexus (22.08 +/- 1.78 mm/mm(2)) was significantly reduced in comparison with that in DM-ISO rats (8.64% +/- 1.42%, 30.82 +/- 2.01 mm/mm(2), respectively) and non-DM rats (9.02 +/- 1.14%, 34.77 +/- 4.45 mm/mm(2), respectively). The percentages of healed area of the epithelial defects at 18 and 36 hours were significantly smaller in DM rats (23.8 +/- 5.2%, 53.2 +/- 4.6%, respectively) than in DM-ISO rats (43.2 +/- 1.4%, 75.8 +/- 2.2%, respectively) and non-DM rats (48.1 +/- 8.6%, 86.1 +/- 3.3%, respectively). Corneal sensitivity decreased in DM rats (51.1 +/- 0.3 mm) but not in DM-ISO rats (57.8 +/- 0.2 mm). There were no differences between parameters in DM-ISO rats and those in non-DM rats. CONCLUSIONS: Diabetic corneas showed loss of epithelial innervation, resulting in delayed epithelial healing and decreased corneal sensitivity. Inhibition of poly(ADP-ribose) polymerase (PARP) with 1,5-isoquinolinediol alleviated these diabetes-induced alterations in the corneal epithelium in the diabetic rats. PMID- 25711637 TI - Normative distribution of visual acuity in 3- to 6-year-old Chinese preschoolers: the Shenzhen kindergarten eye study. AB - PURPOSE: To document the distribution of uncorrected visual acuity (UCVA) in a defined population of Chinese preschoolers and to discuss its implications for vision referral. METHODS: Preschoolers aged 3 to 6 years old were recruited from kindergartens in Shenzen. Uncorrected visual acuity was estimated by using Early Treatment Diabetic Retinopathy Study Tumbling E charts, followed by cycloplegic refraction and ocular examination. The reference population was defined as children without clinically significant ocular abnormalities, with spherical equivalent refraction greater than -0.50 to less than +2.00 diopters (D), astigmatism less than 0.75 D, and anisometropia less than 2.00 D. The age specific UCVA cutoffs were defined by the line where the single-sided 95th percentile of the reference population fell. RESULTS: A total of 483 of the 1255 children enrolled were considered the reference population. The monocular UCVA cutoff fell on the line of 20/63 at age 3, 20/50 at age 4, and 20/40 at ages 5 and 6. Using no better than these lines as criteria generated referral rates of 9.4% to 27.8% in the general population at different ages, and detected 83.3% and more than 90.0% of those with myopia and amblyopia, respectively. Using uncorrected interocular difference of two or more lines referred 3.6% to 4.3% of the population but identified only approximately 20.0% of those with amblyopia. CONCLUSIONS: Visual acuity is still developing in preschoolers even at age 6. Most children with myopia and amblyopia can be identified with age-specific, monocular UCVA cutoffs in vision screening using Tumbling E charts, with tolerable false-positive rates. Further studies are needed to define the age at which children without significant refractive errors reach 20/20 UCVA. PMID- 25711636 TI - The Chemokine Platelet Factor-4 Variant (PF-4var)/CXCL4L1 Inhibits Diabetes Induced Blood-Retinal Barrier Breakdown. AB - PURPOSE: To investigate the expression of platelet factor-4 variant (PF 4var/CXCL4L1) in epiretinal membranes from patients with proliferative diabetic retinopathy (PDR) and the role of PF-4var/CXCL4L1 in the regulation of blood retinal barrier (BRB) breakdown in diabetic rat retinas and human retinal microvascular endothelial cells (HRMEC). METHODS: Rats were treated intravitreally with PF-4var/CXCL4L1 or the anti-vascular endothelial growth factor (VEGF) agent bevacizumab on the first day after diabetes induction. Blood retinal barrier breakdown was assessed in vivo with fluorescein isothiocyanate (FITC)-conjugated dextran and in vitro in HRMEC by transendothelial electrical resistance and FITC-conjugated dextran cell permeability assay. Occludin, vascular endothelial (VE)-cadherin, hypoxia-inducible factor (HIF)-1alpha, VEGF, tumor necrosis factor (TNF)-alpha, receptor for advanced glycation end products (RAGE), caspase-3 levels, and generation of reactive oxygen species (ROS) were assessed by Western blot, enzyme-linked immunosorbent assays, or spectrophotometry. RESULTS: In epiretinal membranes, vascular endothelial cells and stromal cells expressed PF-4var/CXCL4L1. In vitro, HRMEC produced PF 4var/CXCL4L1 after stimulation with a combination of interleukin (IL)-1beta and TNF-alpha, and PF-4var/CXCL4L1 inhibited VEGF-mediated hyperpermeability in HRMEC. In rats, PF-4var/CXCL4L1 was as potent as bevacizumab in attenuating diabetes-induced BRB breakdown. This effect was associated with upregulation of occludin and VE-cadherin and downregulation of HIF-1alpha, VEGF, TNF-alpha, RAGE, and caspase-3, whereas ROS generation was not altered. CONCLUSIONS: Our findings suggest that increasing the intraocular PF-4var/CXCL4L1 levels early after the onset of diabetes protects against diabetes-induced BRB breakdown. PMID- 25711638 TI - Next-generation sequencing and novel variant determination in a cohort of 92 familial exudative vitreoretinopathy patients. AB - PURPOSE: Familial exudative vitreoretinopathy (FEVR) is a developmental disease that can cause visual impairment and retinal detachment at a young age. Four genes involved in the Wnt signaling pathway were previously linked to this disease: NDP, FDZ4, LRP5, and TSPAN12. Identification of novel disease-causing alleles allows for a deeper understanding of the disease, better molecular diagnosis, and improved treatment. METHODS: Sequencing libraries from 92 FEVR patients were generated using a custom capture panel to enrich for 163 known retinal disease-causing genes in humans. Samples were processed using next generation sequencing (NGS) techniques followed by data analysis to identify and classify single nucleotide variants and small insertions and deletions. Sanger validation and segregation testing were used to verify suspected variants. RESULTS: Of the cohort of 92, 45 patients were potentially solved (48.9%). Solved cases resulted from the determination of 49 unique mutations, 41 of which are novel. Of the novel variants discovered, 13 were highly likely to cause FEVR due to the nature of these variants (frameshifting indels, splicing mutations, and nonsense variants types). To our knowledge, this is the largest study of a FEVR cohort using NGS. CONCLUSIONS: We were able to determine probable disease-causing variants in a large number of FEVR patients, the majority of which were novel. Knowledge of these variants will help to further characterize and diagnose FEVR. PMID- 25711639 TI - A Novel Mgp-Cre Knock-In Mouse Reveals an Anticalcification/Antistiffness Candidate Gene in the Trabecular Meshwork and Peripapillary Scleral Region. AB - PURPOSE: Soft tissue calcification is a pathological condition. Matrix Gla (MGP) is a potent mineralization inhibitor secreted by cartilage chondrocytes and arteries' vascular smooth muscle cells. Mgp knock-out mice die at 6 weeks due to massive arterial calcification. Arterial calcification results in arterial stiffness and higher systolic blood pressure. Intriguingly, MGP was highly abundant in trabecular meshwork (TM). Because tissue stiffness is relevant to glaucoma, we investigated which additional eye tissues use Mgp's function using knock-in mice. METHODS: An Mgp-Cre-recombinase coding sequence (Cre) knock-in mouse, containing Mgp DNA plus an internal ribosomal entry site (IRES)-Cre cassette was generated by homologous recombination. Founders were crossed with Cre-mediated reporter mouse R26R-lacZ. Their offspring expresses lacZ where Mgp is transcribed. Eyes from MgpCre/+;R26RlacZ/+ (Mgp-lacZ knock-in) and controls, 1 to 8 months were assayed for beta-gal enzyme histochemistry. RESULTS: As expected, Mgp-lacZ knock-in's TM was intensely blue. In addition, this mouse revealed high specific expression in the sclera, particularly in the peripapillary scleral region (ppSC). Ciliary muscle and sclera above the TM were also positive. Scleral staining was located immediately underneath the choroid (chondrocyte layer), began midsclera and was remarkably high in the ppSC. Cornea, iris, lens, ciliary body, and retina were negative. All mice exhibited similar staining patterns. All controls were negative. CONCLUSIONS: Matrix Gla's restricted expression to glaucoma-associated tissues from anterior and posterior segments suggests its involvement in the development of the disease. Matrix Gla's anticalcification/antistiffness properties in the vascular tissue, together with its high TM and ppCS expression, place this gene as a strong candidate for TM's softness and sclera's stiffness regulation in glaucoma. PMID- 25711641 TI - Scleral thinning after repeated intravitreal injections of antivascular endothelial growth factor agents in the same quadrant. AB - PURPOSE: We assessed the effects of intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy on scleral architecture using spectral domain anterior segment optical coherence tomography (OCT). METHODS: A total of 35 eyes of 35 patients treated with at least 30 intravitreal injections in one eye in the inferotemporal quadrant with ranibizumab or aflibercept and 10 or less intravitreal injections in the fellow eye attending the intravitreal injection clinic were included. Enhanced depth imaging anterior segment OCT was used to measure scleral thickness. For each eye the sclera was measured in four quadrants at 3 mm from the limbus. In addition axial eye length was measured in all subjects using partial coherence interferometry. RESULTS: The mean number of intravitreal injections was 42 (range, 30-73) and 1.6 (range, 0-9) in the fellow eyes. In the study eyes with more than 30 injections the average scleral thickness in the inferotemporal quadrant was 568.4 MUm (SD +/- 66 MUm) and 590.6 MUm (SD +/- 75 MUm) in the fellow eyes with 10 or less injections (P = 0.003). The mean average scleral thickness in the other three quadrants (inferonasal, superotemporal, and superonasal) was 536.6 MUm in the study eyes (SD +/- 100 MUm) and 545.2 MUm (SD +/- 109 MUm) in the fellow eyes (P = 0.22). There was a borderline association of the total number of injections with scleral thickness change in the inferotemporal quadrant (r = 0.3, P = 0.052). CONCLUSIONS: Intravitreal injections may lead to scleral changes when applied repeatedly in the same quadrant. Thus, alternating the injection site should be considered in patients requiring multiple intravitreal injections. PMID- 25711642 TI - aaaa. AB - Purpose:a Methods: Results: Conclusions: PMID- 25711640 TI - Peripapillary choroidal thickness variation with age and race in normal eyes. AB - PURPOSE: This study examined the association between peripapillary choroidal thickness (PCT) with age and race in a group of African descent (AD) and European descent (ED) subjects with normal eyes. METHODS: Optic nerve head images from enhanced depth imaging spectral-domain optical coherence tomography of 166 normal eyes from 84 subjects of AD and ED were manually delineated to identify the principal surfaces of Bruch's membrane (BM), Bruch's membrane opening (BMO), and anterior sclera (AS). Peripapillary choroidal thickness was measured between BM and AS at increasing distance away from BMO. The mean PCT was compared between AD and ED subjects and generalized estimating equation (GEE) regression analysis was used to examine the association between race and PCT overall, in each quadrant, and by distance from BMO. Models were adjusted for age, BMO area, and axial length in the regression analysis. RESULTS: Overall, the mean PCT increased from 63.9 MUm +/- 18.1 at 0 to 250 MUm to 170.3 MUm +/- 56.7 at 1500 to 2000 MUm from BMO. Individuals of AD had a greater mean PCT than those of ED at all distances from BMO (P < 0.05 at each distance) and in each quadrant (P < 0.05 in each quadrant). Results from multivariate regression indicate that ED subjects had significantly lower PCT compared to AD overall and in all quadrants and distances from BMO. Increasing age was also significantly associated with a lower PCT in both ED and AD participants. CONCLUSIONS: Peripapillary choroidal thickness varies with race and age, as individuals of AD have a thicker peripapillary choroid than those of ED. (ClinicalTrials.gov number, NCT00221923.). PMID- 25711643 TI - Unknown Title. PMID- 25711645 TI - The consequential outcomes of personality dysfunction. PMID- 25711644 TI - Reply: To PMID 25130427. PMID- 25711646 TI - Comment on Tyrer: Personality dysfunction is the cause of recurrent non-cognitive mental disorder: a testable hypothesis. PMID- 25711647 TI - The clinical implications of personality-generated mental illness. PMID- 25711648 TI - Emotional processing in a ten-session general psychiatric treatment for borderline personality disorder: a case study. AB - This study examines the effects of a borderline-specific treatment, called general psychiatric management, on emotional change, outcome and therapeutic alliance of an outpatient presenting with borderline personality disorder. Based on the sequential model of emotional processing, emotional states were assessed in a 10-session setting. The case showed an increase in expressions of distress and no change in therapeutic alliance and tended towards general deterioration. Results suggest emotional processing may play a lesser role in general psychiatric management in early phase treatment than previously hypothezised. PMID- 25711649 TI - Soluble CD44 concentration in the serum and peritoneal fluid samples of patients with different stages of endometriosis. AB - PURPOSE: Endometriosis is a gynecological disease defined by the histological presence of endometrial glands and stroma outside the uterine cavity, most commonly implanted over visceral and peritoneal surface within the female pelvis. CD44 is a membrane protein expressed by human endometrial cells, and it has been shown to promote the adhesion of endometrial cells. The aim of this study was to determine the levels of soluble CD44 (sCD44) in the serum and peritoneal fluid (PF) samples of patients with different stages of endometriosis. METHODS: 39 PF and serum samples from normal healthy and 130 samples from different stages of patients with endometriosis (33 cases of stage I, 38 stage II, 30 stage III and 29 stage IV) were included in this study. Total protein concentration (TPC) and the level of s-cMet in the serum were determined by Bio-Rad protein assay based on the Bradford dye procedure and enzyme-linked immunosorbent assay, respectively. RESULTS: No significant change in the TPC was seen in the serum of patients with endometriosis when compared to normal controls. Results obtained demonstrated that all serum and peritoneal fluid samples, presented sCD44 expression, whereas, starting from stages I to IV endometriosis, a significant increase of sCD44 expression was observed as compared to control group. CONCLUSIONS: The results of this study show that a high expression of sCD44 is correlated with advanced stages of endometriosis. It is also concluded that the detection of serum and/or peritoneal fluid sCD44 may be useful in classifying endometriosis. PMID- 25711650 TI - Erratum to: Is ursodeoxycholic acid crucial for ischemia/reperfusion-induced ovarian injury in rat ovary? PMID- 25711651 TI - Surfactant Effects on the Morphology and Pseudocapacitive Behavior of V2 O5 ?H2 O. AB - To overcome the drawback of low electrical conductivity within supercapacitor applications, several surfactants are used for nanoscale V2 O5 to enhance the specific surface area. Polyethylene glycol 6000 (PEG-6000), sodium dodecylbenzene sulfonate (SDBS), and Pluronic P-123 (P123) controllers, if used as soft templates, easily form large specific surface area crystals. However, the specific mechanism through which this occurs and the influence of these surfactants is not clear for V2 O5 ?H2 O. In the present study, we aimed to investigate the mechanism of crystal growth through hydrothermal processes and the pseudocapacitive behavior of these crystals formed by using diverse surfactants, including PEG-6000, SDBS, and P123. Our results show that different surfactants can dramatically influence the morphology and capacitive behavior of V2 O5 ?H2 O powders. Linear nanowires, flower-like flakes, and curly bundled nanowires can be obtained because of electrostatic interactions in the presence of PEG-6000, SDBS, and P123, respectively. Furthermore, the electrochemical performance of these powders shows that the nanowires, which are electrodes mediated by PEG-6000, exhibit the highest capacitance of 349 F g(-1) at a scan rate of 5 mV s(-1) of all the surfactants studied. However, a symmetric P123 electrode comprising curly bundled nanowires with numerous nanopores showed an excellent and stable specific capacitance of 127 F g(-1) after 200 cycles. This work is beneficial to understanding the fundamental role of the surfactant in the assisted growth of V2 O5 ?H2 O and the resulting electrochemical properties of the pseudocapacitors, which could be useful for the future design of appropriate materials. PMID- 25711653 TI - Management of the extravasation of anti-neoplastic agents. AB - BACKGROUND: Extravasation is a potentially severe complication that can occur during the administration of chemotherapy. The scarcity of evidence available makes it difficult to develop an optimal management scheme. The purpose of this guideline is to review the relevant scientific literature on the prevention, management, and treatment of extravasation occurring during the administration of chemotherapy to cancer patients. METHOD: A scientific literature review was conducted using the PubMed search tool. The period covered was from database inception to April 2014, inclusively. Since the literature on extravasation treatment is often empirical, anecdotal, and controversial, the review also identified clinical practice guidelines and expert consensuses published by relevant international organizations and cancer agencies. RESULTS: Identification of potential risk factors and preventive measures can reduce the risk of extravasation. Recognition and management of symptoms are crucial in patients with this complication. Provision of adequate instruction to personnel responsible for administering chemotherapy and to patients on recognizing symptoms, preventing, and managing extravasation is essential. Extravasation can be treated with dry warm or cold compresses and various antidotes such as dimethyl sulfoxide, dexrazoxane, hyaluronidase, or sodium thiosulfate, depending on the agent that has caused extravasation. Patient monitoring to assess the progression or regression of symptoms and to thus take the appropriate measures is necessary. CONCLUSION: Several strategies must be established to ensure that extravasation is recognized and properly managed. Given the evidence available at this time, the Comite de l'evolution des pratiques en oncologie (CEPO) has made recommendations for clinical practice in Quebec. PMID- 25711654 TI - Integrating mindfulness in supportive cancer care: a cohort study on a mindfulness-based day care clinic for cancer survivors. AB - PURPOSE: The aim of this study was to investigate the effects of a mindfulness based day care clinic group program for cancer survivors on health-related quality of life and mental health; and to investigate which psychological variables are associated with changes in health variables. METHODS: One hundred seventeen cancer survivors (91.0 % female; mean age 53.9 +/- 10.7 years; 65.0 % breast cancer; mean time since diagnosis 27.2 +/- 46.5 months) participated in an 11-week mindfulness-based day care clinic group program, 6 h per week. The intervention incorporated mindfulness-based meditation, yoga, cognitive behavioral techniques, and lifestyle modification. Outcome measures including health-related quality of life (EORTC QLQ-C30), depression and anxiety (HADS); and psychological variables including life satisfaction (BMLSS), mindfulness (FMI), adaptive coping styles (AKU), spiritual/religious attitudes in dealing with illness (SpREUK), and interpretation of illness (IIQ) were assessed before, after, and 3 months after the intervention. RESULTS: Using mixed linear models, significant improvements in global health status, physical functioning, role functioning, emotional functioning, cognitive functioning, and social functioning were found. Cancer-related symptoms, including fatigue, pain, insomnia, constipation, anxiety, and depression, also improved significantly. Mindfulness, life satisfaction, health satisfaction, all coping styles, all spiritual/religious attitudes, and interpretation of illness as something of value increased; interpretation of illness as punishment decreased significantly (all p < 0.05). Improved outcomes were associated with increases in psychological variables, mainly life satisfaction, health satisfaction, and trust in medical help (R (2) = 7.3-43.6 %). CONCLUSION: Supportive mindfulness-based interventions can be considered as an effective means to improve cancer survivors' physical and mental health. Functional improvements are associated with improved satisfaction and coping styles. PMID- 25711655 TI - The financial burden of cancer patients: time to stop averting our eyes. PMID- 25711658 TI - Neuronal activity in the nucleus accumbens and hippocampus in rats during formation of seeking behavior in a radial maze. AB - Seeking behavior of rats in a radial maze with asymmetric reward was studied by means of synchronous recording of cell activity in the hippocampus and ventral striatum. The synchrony of cell activity in the hippocampus and nucleus accumbens was modulated by spatial position and reward; the important role in this synchronization can be played by theta rhythm. This is in line with the anatomical and physiological data on the convergence of hippocampal spatially organized positional and reward value information inputs from the amygdala and ventral segmental area to n. accumbens. PMID- 25711656 TI - The influence of life stage on supportive care and information needs in cancer patients: does older age matter? AB - PURPOSE: The purpose of this study is to clarify the effect of older age, on supportive care needs, information satisfaction and service needs in the year following a cancer diagnosis. METHODS: Primary or recurrent prostate, breast, lung or colorectal cancer patients (n = 394) were prospectively surveyed 3 and 9 months post-diagnosis using the Support Care Needs Survey (SCNS-LF59) and Information Satisfaction (ISQ) and Service Needs (SNQ) questionnaires. Two age groups were compared: >=65 years (senior) versus <=64 years (junior). RESULTS: Few differences emerged between age groups (SCNS) with the exception of psychological (p < 0.001) and sexuality (p < 0.001) domains where these were greater in the younger patients 3 months post-diagnosis. Sexuality (p < 0.001) and patient care and support (p = 0.023) needs were predicted by age (continuous); younger patients had more needs at 3 months post-diagnosis. For information satisfaction, the older group preferred doctors to make decisions (3 months p < 0.001; 9 months p = 0.008) and preferred positive information (3 months p = 0.006). For the whole group fears about cancer spreading (51 %) and returning (45 %) predominate, alongside patients' concerns about worries of those closest to them (51 %) and uncertainty about their future (42 %) at 3 months. CONCLUSIONS: Older patients differ on information satisfaction showing a preference for doctors to make treatment decisions. For supportive care, there were few age differences; however, the SCNS sexuality and patient care and support domains indicate greater need in younger patients around the 3-month period following diagnosis. With a few exceptions, individual rather than age specific needs determine supportive and informational care requirements. PMID- 25711659 TI - Effect of selective blockade of alpha2-adrenoceptor subtypes on cardiovascular system in rats. AB - Selective blockade of various alpha2-adrenoceptors exerts various effects on the cardiovascular system in rats. Blockade of alpha2A/D-adrenoceptors in experimental animals decelerates and then accelerates HR. Blockade of alpha2B adrenoceptors produces a negative chronotropic effect; blockade of alpha2C adrenoceptors has a positive chronotropic effect. Administration of selective blockers of alpha2A/D- and alpha2B-adrenoceptors causes hypotension, while selective blockade of alpha2C-adrenoceptors increases BP. PMID- 25711657 TI - Does routine symptom screening with ESAS decrease ED visits in breast cancer patients undergoing adjuvant chemotherapy? AB - BACKGROUND: In 2007, the provincial cancer agency in Ontario, Canada initiated a wide-scale program to screen for symptoms in the cancer population using the Edmonton Symptom Assessment Scale (ESAS). The purpose of this study is to evaluate the impact of screening with ESAS on emergency department (ED) visit rates in women with breast cancer receiving adjuvant chemotherapy. PATIENTS AND METHODS: This retrospective cohort study used linked administrative health care data from across the province of Ontario, Canada. The cohort included all women aged >=18 who were diagnosed with stage I-III breast cancer between January 2007 and December 2009 and received adjuvant chemotherapy within 6 months of diagnosis. Using an adjusted recurrent event model, we examined the association of screening with ESAS at a clinic visit on the ED visit rate. RESULTS: The relative rate of ED visits was 0.57 when prior ESAS screening occurred compared to when it did not. The relative rate of ED visits was 0.83 when the prior number of ESAS screens was modeled as a continuous variable. Alternatively stated, the rate of ED visits was 43 % lower among patients previously screened with ESAS compared to those not previously screened. For each additional prior ESAS assessment, there was a 17 % decreased rate of ED visits. CONCLUSIONS: Our results demonstrate that screening with ESAS is associated with decreased ED visits. To our knowledge, this is the first report on the effectiveness of routinely documenting a patient reported outcome on ED visits, in a real-world setting. PMID- 25711660 TI - Role of PI3K, MAPK/ERK1/2, and p38 in implementation of the proliferative and differentiation potential of erythroid progenitors after blood loss. AB - The involvement of PI3K, ERK and p38-dependent signaling system in the regulation of functional activity of erythroid precursors after blood loss (30% of circulating volume) was studied. We demonstrated the important role of PI3K and p38 in the suppression of differentiation of erythroid precursors the contribution of p38 to stimulation of mitotic activity of erythroid CFU, which maintains the growth potential of the precursors at the optimal physiological level. The classical MAPK/ERK-kinase pathway does not determine the proliferative and differentiation status of erythroid CFU. PMID- 25711661 TI - Markers of myocardial damage in children of the first year of life with congenital heart disease in the early period after surgery with cardioplegic anoxia. AB - We measured the level of cardiac markers (high-sensitivity troponin T and MB fraction of creatine kinase) in children of the first year of life with congenital heart disease in the perioperative period. After cardiac surgery, plasma levels of the above markers exceed the reference limits in the examined children. The diagnosis of myocardial ischemia using biochemical markers in the postoperative period is possible only by dynamic monitoring of the cardiac marker level. The preoperative concentration of high-sensitivity troponin T in children of the first year of life with congenital heart disease can be regarded as a predictor of postoperative complications. PMID- 25711662 TI - Effect of zinc on the content of chemical elements in the lung tissue during obesity in the experiment. AB - We found no deviations from normalcy in the content of chemical elements (K, Ca, Mn, Fe, Cu, Zn, Se, Br, Rb, and Sr) in the lungs of rats with mild alimentary obesity, but revealed redistribution of correlations between the elements indicating impaired metabolism in this organ. Zinc supplementation had no effect on the body weight and content of chemical elements (including zinc) in the lung tissue in rats fed high fat diet, but led to significant changes in the correlations between the elements. Bromine, rubidium, and strontium are actively involved in interelement interactions in the lung tissue. These elements should be given more attention in considering biological processes including alimentary obesity. PMID- 25711663 TI - Parameters of proliferation and apoptosis of epithelial cells in the gastric mucosa in indigenous and non-indigenous residents of Khakassia with Helicobacter pylori positive duodenal ulcer disease. AB - We evaluated parameters of apoptosis in the mucosa of the gastric antrum and body of indigenous and non-indigenous residents of Khakassia with duodenal ulcer disease associated with Helicobacter pylori infection. In the gastric antrum, apoptotic index was significantly increased in patients with ulcer disease in comparison with healthy individuals in both populations. The ratio of proliferation index to apoptotic index was lower in patients with ulcer disease in comparison with healthy individuals in both populations. Similar, but less pronounced processes were recorded in the body of the stomach. Significant changes in the parameters of proliferation and apoptosis were noted in the gastric antrum and body of the stomach in both populations, but they were more pronounced in Caucasians in comparison with Khakasses. PMID- 25711664 TI - Biochemical changes in rats with different behavioral characteristics under conditions of metabolic stress. AB - Food deprivation is an extreme state of the functional feeding system, which is reflected in the character of changes in the activity of central and peripheral components selectively included in the system. We studied the dynamics of coenzyme Q10 levels and spectrum of omega-3 and omega-6 polyunsaturated fatty acids in the blood serum, liver, and brain as well as LPO intensity in the serum and liver in behaviorally passive and active rats under conditions of food deprivation. Our results indicate that adaptive and compensatory processes during acute metabolic stress depend on the initial behavioral characteristics of the animals. PMID- 25711665 TI - Effect of sunlight transformed by luminophore-containing materials on cell functions in vitro and in vivo. AB - Effect of sunlight transformed by luminophore-containing materials on cell viability and functional state of the retina was assessed using the photodamage model. Exposure to the luminescent component of light improved viability of NIH 3T3 cells and promoted recovery of electric activity in rabbit retina after photodamage. PMID- 25711666 TI - Analysis of toxicity biomarkers of fullerene C60 nanoparticles by confocal fluorescent microscopy. AB - The methods of laser confocal microscopy were employed to study the changes in rat target organs (iliac mucosa and liver) provoked by peroral administration of dispersion of nanosized (31 nm) multimolecular fullerene C60 particles in doses of 0.1, 1.0, and 10 mg/kg body weight over 92 days. The micropreparations were selectively stained with fluorescent dyes to mark the cell nuclei (DAPI), actin microfilaments (fluorescently labeled phalloidin), and the membrane proteins CD106, CD31, and claudins in tight junctions (fluorescently labeled monoclonal antibodies). In rats treated with fullerene in the examined doses, the iliac mucosa demonstrated normal morphology of the villi. There were no signs of inflammation and no alterations in the actin fi laments of cytoskeleton and in enterocytic tight junctions. The count of CD106(+) and CD31(+) cells did not change. The highest examined doses of fullerene (1 and 10 mg/kg body weight) increased population and modified distribution of hepatic CD106(+) cells. They also resulted in accumulation of cytoplasmic granules presumably identified as Kupffer macrophages without any signs of visible inflammation or necrotic areas. This phenomenon can reflect the early stages of toxic reaction being a sensitive bioindicator of the damage produced by administered fullerene C60 in the hepatic tissue. PMID- 25711669 TI - User-driven development of a web-based tool for patient reporting of drug-related harm. AB - Commissioned by the Monitoring Medicines project, the Uppsala Monitoring Centre (UMC) led the design and development of a web-based ADR (adverse drug reaction) reporting tool intended for use by patients. The software design was undertaken in close collaboration with representatives of national pharmacovigilance centres (NPCs) and with patient and consumer organizations. The web-based tool was developed by these participants through several telephone conferences, a workshop and site testing. The tool is directly compatible with the UMC's Individual Case Safety Report (ICSR) data management system VigiFlow((r)) and is also compliant with the ICH-E2B(R2) format. The UMC team benefited by working closely with the end-users during the development process. A major challenge was to balance the need for detailed information required by the NPCs to be able to assess reports with the amount of detail patients are able and willing to provide. Needs, ideas and suggestions from the end users were valuable and were taken into account throughout the process of designing the tool. PMID- 25711667 TI - Exercise training intensity prescription in breast cancer survivors: validity of current practice and specific recommendations. AB - PURPOSE: Cancer survivors are recommended to perform 150 min/week of moderate or 75 min/week of vigorous aerobic exercise, but it remains unclear how moderate and vigorous intensities can be prescribed. Therefore, it was investigated whether and how intensity prescriptions for healthy adults by the American College of Sports Medicine (ACSM) need to be adapted for breast cancer survivors. METHODS: Fifty-two breast cancer survivors (stage 0-III, age 52 +/- 9 years, BMI 25.4 +/- 3.5 kg/m2) performed cardiopulmonary exercise tests at the end of primary therapy. Intensity classes defined as percentages of maximal heart rate (HRmax), heart rate reserve (HRR), and maximal oxygen uptake (VO2max) were compared to the ACSM's intensity classes using oxygen uptake reserve as reference. RESULTS: The prescriptions for moderate and vigorous exercise intensities were significantly different between breast cancer survivors and healthy adults when using VO2max (moderate 50-66 vs. 46-63 and vigorous 67-91 vs. 64-90% VO2max) or HRR (moderate 26-50 vs. 40-59 and vigorous 51-88 vs. 60-89 % HRR), but not when using HRmax (moderate 65-76 vs. 64-76 and vigorous 77-94 vs. 77-95% HRmax). CONCLUSIONS: In breast cancer survivors, intensity prescriptions for healthy adults result in considerably too intense training if HRR is used as guiding factor. Prescriptions using VO2max result in a slightly too low exercise intensity, whereas recommendations in percentages of HRmax appear valid. IMPLICATIONS FOR CANCER SURVIVORS: Cancer survivors should not uncritically adopt exercise intensity prescriptions for healthy adults. Specific prescriptions for the studied population are provided. PMID- 25711668 TI - Evaluation of an automated surveillance system using trigger alerts to prevent adverse drug events in the intensive care unit and general ward. AB - INTRODUCTION: Adverse events in the intensive care unit (ICU) may be associated with several possible causes, so determining a drug-related causal assessment is more challenging than in general ward patients. Therefore, the hypothesis was that automated trigger alerts may perform differently in various patient care settings. The purpose of this study was to compare the frequency and type of clinically significant automated trigger alerts in critically ill and general ward patients as well as evaluate the performance of alerts for drug-related hazardous conditions (DRHCs). METHODS: A retrospective cohort study was conducted in adult ICU and general ward patients at three institutions (academic, community, and rural hospital) in a health system. Automated trigger alerts generated during two nonconsecutive months were obtained from a centralized database. Pharmacist responses to alerts and prescriber response to recommendations were evaluated for all alerts. A clinical significant event was defined as an actionable intervention requiring drug therapy changes that the pharmacist determined to be appropriate for patient safety and where the physician accepted the pharmacist's recommendation. The positive predictive value (PPV) was calculated for each trigger alert considered a DRHC (i.e., abnormal laboratory values and suspected drug causes). RESULTS: A total of 751 alerts were generated in 623 patients during the study period. Pharmacists intervened on 39.8 and 44.8 % alerts generated in the ICU and general ward, respectively. Overall, the physician acceptance rate of approximately 90 % was comparable irrespective of patient care setting. Therefore, the number of clinically significant alerts was 88.9 and 83.4 % for the ICU and non-ICU, respectively. The types of drug therapy changes were similar between settings. The PPV of alerts identifying a DRHC was 0.66 in the ICU and 0.76 in general ward patients. CONCLUSIONS: The number and type of clinically significant alerts were similar irrespective of patient population, suggesting that the alerts may be equally as beneficial in the ICU population, despite the challenges in drug-related event adjudication. An opportunity exists to improve the performance of alerts in both settings, so quality improvement programs for measuring alert performance and making refinements is needed. PMID- 25711670 TI - Long-term outcomes of autologous hematopoietic stem cell transplantation with reduced-intensity conditioning in multiple sclerosis: physician's and patient's perspectives. AB - High-dose immunosuppressive therapy (HDIT) with autologous hematopoietic stem cell transplantation (AHSCT) is a promising approach to treatment of multiple sclerosis (MS) patients. In this paper, we present the long-term outcomes of a prospective single-center study with the analysis of the safety and efficacy of HDIT + AHSCT with reduced-intensity BEAM-like conditioning regimen in 99 MS patients: mean age-35 years old; male/female-39/60; median Expanded Disability Status Scale (EDSS) = 3.5; 43 relapsing/remitting MS, 56 progressive MS. No transplant-related deaths were observed. The mobilization and transplantation procedures were well tolerated. At 6 months post-transplant, neurological improvement or stabilization was observed in all the patients except one. Cumulative incidence of disease progression was 16.7 % at 8 years after HDIT + AHSCT. Estimated event-free survival at median follow-up of 48.9 months was 80 %: 83.3 % in relapsing/remitting MS vs 75.5 % in progressive MS. Sixty-four patients who did not progress during the first 3 years post-transplant and were monitored for more than 3 years were included in long-term outcome analysis. At the median long-term follow-up of 62 months, 47 % of patients improved by at least 0.5 points on the EDSS scale as compared to baseline and exhibited improvement during the entire period of follow-up; 45 % of patients were stable. No active, new, or enlarging lesions on magnetic resonance imaging were registered in patients without disease progression. AHSCT was accompanied by a significant improvement in patient's quality of life. Due to the fact that patient selection was quite different to the other studies and that the information about disease activity prior in the disease course and its treatment was inhomogeneous, comparison with the results in the literature should be done with caution. Thus, the risk/benefit ratio of HDIT + AHSCT with reduced-intensity BEAM-like conditioning regimen in our population of MS patients is very favorable. The consistency of our long-term clinical and quality of life results, together with the persistence of improvement, is in favor of the efficacy and safety of this treatment approach in MS patients. PMID- 25711671 TI - Differentiation of lower urinary tract dysfunctions: The role of ambulatory urodynamic monitoring. AB - OBJECTIVES: To determine the value of ambulatory urodynamic monitoring in the assessment of patients with lower urinary tract symptoms. METHODS: This was a cross-sectional study including patients who underwent both conventional urodynamic and ambulatory urodynamic assessment at our Center between December 2002 and February 2013. The ambulatory urodynamic studies were interpreted in a standardized way by a resident experienced with urodynamic measurements, and one staff member who specialized in incontinence and urodynamics. RESULTS: A total of 239 patients (71 male and 168 female) were included in the present study. The largest subgroup of patients, 79 (33%), underwent ambulatory urodynamic monitoring based on suspicion of an acontractile bladder. However, 66 of these patients (83.5%) still showed contractions on ambulatory urodynamics. Other groups that were analyzed were patients with suspected storage dysfunction (47 patients), inconclusive conventional urodynamic studies (68 patients) and incontinence of unclear origin (45 patients). Particularly in this last group, ambulatory urodynamics appeared to be useful for discrimination between different causes of incontinence. CONCLUSIONS: Ambulatory urodynamic monitoring is a valuable discriminating diagnostic tool in patients with lower urinary tract symptoms who have already undergone conventional urodynamics, particularly in the case of patients with suspected bladder acontractility and incontinence of unclear origin during ambulatory urodynamics. Further study is required to determine the clinical implications of the findings and their relationship with treatment outcome. PMID- 25711672 TI - Salvage radical prostatectomy for recurrent prostate cancer: verification of European Association of Urology guideline criteria. AB - OBJECTIVE: To analyse oncological and functional outcomes of salvage radical prostatectomy (SRP) in patients with recurrent prostate cancer and to compare outcomes of patients within and outside the European Association of Urology (EAU) guideline criteria (organ-confined prostate cancer <=T2b, Gleason score <=7 and preoperative PSA level <10 ng/mL) for SRP. PATIENTS AND METHODS: In all, 55 patients who underwent SRP from January 2007 to December 2012 were retrospectively analysed. Kaplan-Meier curves assessed time to biochemical recurrence (BCR), metastasis-free survival (MFS) and cancer-specific survival. Cox regressions addressed factors influencing BCR and MFS. BCR was defined as a PSA level of >0.2 ng/mL and rising, continence as the use of 0-1 safety pad/day, and potency as a five-item version of the International Index of Erectile Function score of >=18. RESULTS: The median follow-up was 36 months. After SRP, 42.0% of the patients experienced BCR, 15.9% developed metastasis, and 5.5% died from prostate cancer. Patients fulfilling the EAU guideline criteria were less likely to have positive lymph nodes (LNs) and had significantly better BCR-free survival (5-year BCR-free survival 73.9% vs 11.6%; P = 0.001). In multivariate analysis, low-dose-rate brachytherapy as primary treatment (P = 0.03) and presence of positive LNs at SRP (P = 0.02) were significantly associated with worse BCR-free survival. The presence of positive LNs or Gleason score >7 at SRP were independently associated with metastasis. The urinary continence rate at 1 year after SRP was 74%. Seven patients (12.7%) had complications >=III (Clavien grade). CONCLUSION: SRP is a safe procedure providing good cancer control and reasonable urinary continence. Oncological outcomes are significantly better in patients who met the EAU guideline recommendations. PMID- 25711674 TI - Falsely decreased ionized calcium levels in kidney transplant recipients with polyomavirus-associated nephropathy treated with leflunomide. PMID- 25711673 TI - Prolonged treatment with bevacizumab is associated with brain atrophy: a pilot study in patients with high-grade gliomas. AB - Bevacizumab is widely used for treatment of high-grade gliomas and other malignancies. Because bevacizumab has been shown to be associated with neurocognitive decline, this study is designed to investigate whether prolonged treatment with bevacizumab is also associated with brain atrophy. We identified 12 high-grade glioma patients who received bevacizumab for 12 months at the first recurrence and 13 matched controls and blindly compared the volumes of the contralateral hemispheres and contralateral ventricle in these two groups at baseline and after 12 +/- 2 months of the baseline scan by two independent analyses. The volumes of the contralateral hemispheres and ventricles did not differ significantly between the two groups at baseline. Whereas, in the control group the volumes of the contralateral hemisphere changed subtly from baseline to follow-up (p = 0.23), in the bevacizumab-treated group the volumes significantly decreased from baseline to follow-up (p = 0.03). There was significant increase in the contralateral ventricle volume from base line to follow-up scans in both the control group (p = 0.01) and in the bevacizumab group (p = 0.005). Both the absolute and the percentage changes of contralateral hemisphere volumes and contralateral ventricular volumes between the two patient groups were statistically significant (p < 0.05). Results of this study demonstrate prolonged treatment with bevacizumab is associated with atrophy of the contralateral brain hemisphere. PMID- 25711675 TI - Plug-n-play microfluidic systems from flexible assembly of glass-based flow control modules. AB - In this study, we report on a simple and versatile plug-n-play microfluidic system that is fabricated from flexible assembly of glass-based flow-control modules for flexibly manipulating flows for versatile emulsion generation. The microfluidic system consists of three basic functional units: a flow-control module, a positioning groove, and a connection fastener. The flow-control module that is based on simple assembly of low-cost glass slides, coverslips, and glass capillaries provides excellent chemical resistance and optical properties, and easy wettability modification for flow manipulation. The flexible combination of the flow-control modules with 3D-printed positioning grooves and connection fasteners enables creation of versatile microfluidic systems for generating various higher-order multiple emulsions. The simple and reversible connection of the flow-control modules also allows easy disassembly of the microfluidic systems for further scale-up and functionalization. We demonstrate the scalability and controllability of flow manipulation by creating microfluidic systems from flexible assembly of flow-control modules for controllable generation of multiple emulsions from double emulsions to quadruple emulsions. Meanwhile, the flexible flow manipulation in the flow-control module provides advanced functions for improved control of the drop size, and for controllable generation of drops containing distinct components within multiple emulsions to extend the emulsion structure. Such modular microfluidic systems provide flexibility and versatility to flexibly manipulate micro-flows for enhanced and extended applications. PMID- 25711676 TI - The Interplay Between Respiratory Supercomplexes and ROS in Aging. AB - SIGNIFICANCE: The molecular mechanism of aging is still vigorously debated, although a general consensus exists that mitochondria are significantly involved in this process. However, the previously postulated role of mitochondrial-derived reactive oxygen species (ROS) as the damaging agents inducing functional loss in aging has fallen out of favor in the recent past. In this review, we critically examine the role of ROS in aging in the light of recent advances on the relationship between mitochondrial structure and function. RECENT ADVANCES: The functional mitochondrial respiratory chain is now recognized as a reflection of the dynamic association of respiratory complexes in the form of supercomplexes (SCs). Besides providing kinetic advantage (channeling), SCs control ROS generation by the respiratory chain, thus providing a means to regulate ROS levels in the cell. Depending on their concentration, these ROS are either physiological signals essential for the life of the cell or toxic species that damage cell structure and functions. CRITICAL ISSUES: We propose that under physiological conditions the dynamic nature of SCs reversibly controls the generation of ROS as signals involved in mitochondrial-nuclear communication. During aging, there is a progressive loss of control of ROS generation so that their production is irreversibly enhanced, inducing a vicious circle in which signaling is altered and structural damage takes place. FUTURE DIRECTIONS: A better understanding on the forces affecting SC association would allow the manipulation of ROS generation, directing these species to their physiological signaling role. PMID- 25711677 TI - Hysterectomy types in Estonia are still different from the Nordic countries. AB - OBJECTIVE: To describe hysterectomy rates in different age groups, indications and proportion of surgery types over time. DESIGN: Nationwide register-based study. SETTING: Estonia. POPULATION: Women who had hysterectomies for benign indications from 2004 to 2011. METHODS: For each case, diagnosis according to ICD 10, type of surgery according to Nordic Medico-Statistical Committee, age, and time of operation were retrieved from the Estonian Health Insurance Fund database. Mid-year female population statistics were obtained from Statistics Estonia. MAIN OUTCOME MEASURES: Rate of hysterectomies per 100 000 women, proportions of different operation types, and main indications for hysterectomies. RESULTS: The total number of hysterectomies was 12 336, with a yearly mean of 1542. The rate of hysterectomies per 100 000 women/year decreased between 2004 and 2011 from 239.1 to 204.9. The proportion of abdominal hysterectomies decreased from 86.0 to 56.1% and the proportion of laparoscopic hysterectomies increased from 6.3 to 34.7%, while the proportion of vaginal hysterectomies remained more or less stable (7.8-9.1%). Most hysterectomies (74.4%) occurred in the age group 35-54 years. The main indications for hysterectomies were leiomyoma (61.5%), female genital prolapse (9.0%) and endometriosis (8.8%). CONCLUSIONS: Population rates and indications for hysterectomies in Estonia were similar to those in most Nordic countries, but the proportion of abdominal hysterectomies was higher and that of vaginal hysterectomy lower. The rates of laparoscopic and vaginal hysterectomies should be increased. PMID- 25711678 TI - Organometallic chemistry of ethynyl boronic acid MIDA ester, HC=CB(O2CCH2)2NMe. AB - The reactions of HC=CBMIDA (BMIDA = B(O2CCH2)2NMe) with a range of ruthenium complexes afford the first isolated examples of sigma-alkynyl, sigma-alkenyl and vinylidene complexes bearing 4-coordinate boron substituents. Specifically, the reactions of HC=CBMIDA with [RuH(S2CNR2)(CO)(PPh3)2] (R = Me, Et) and [Ru(CO)2(PPh3)3] afford the alkynyl complexes [Ru(C=CBMIDA)(S2CNR2)(CO)(PPh3)2] and [RuH(C=CBMIDA)(CO)2(PPh3)2], the latter being converted to [Ru(C=CBMIDA)Cl(CO)2(PPh3)2] on treatment with chloroform. With [RuCl(dppe)2]PF6 the vinylidene salt [RuCl(=C=CHBMIDA)(dppe)2]PF6 is obtained, which reacts with Et3N to afford the neutral alkynyl derivative [Ru(C=CBMIDA)Cl(dppe)2]. Hydrometallation of HC=CBMIDA by [RuHCl(CO)(PPh3)3] affords the coordinatively unsaturated sigma-alkenyl complex [RuCl(CH=CHBMIDA)(CO)(PPh3)2] which in turn reacts with CO, CNC6H2Me3-2,4,6, [Et2NH2][S2CNEt2] or K[HB(pz)3] (pz = pyrazol-1 yl) to afford the coordinatively saturated complexes [Ru(CH=CHBMIDA)Cl(CO)2(PPh3)2], [Ru(CH=CHBMIDA)Cl(CO)(CNC6H2Me3)(PPh3)2], [Ru(CH=CHBMIDA)(S2CNEt2)(CO)-(PPh3)2] and [Ru(CH=CHBMIDA)(CO)(PPh3){HB(pz)3}]. In all cases, the transannular N->B dative bond is retained in the BMIDA substituent. PMID- 25711679 TI - Families of nuclear receptors in vertebrate models: characteristic and comparative toxicological perspective. AB - Various synthetic chemicals are ligands for nuclear receptors (NRs) and can cause adverse effects in vertebrates mediated by NRs. While several model vertebrates, such as mouse, chicken, western clawed frog and zebrafish, are widely used in toxicity testing, few NRs have been well described for most of these classes. In this report, NRs in genomes of 12 vertebrates are characterized via bioinformatics approaches. Although numbers of NRs varied among species, with 40 42 genes in birds to 66-74 genes in teleost fishes, all NRs had clear homologs in human and could be categorized into seven subfamilies defined as NR0B-NR6A. Phylogenetic analysis revealed conservative evolutionary relationships for most NRs, which were consistent with traditional morphology-based systematics, except for some exceptions in Dolphin (Tursiops truncatus). Evolution of PXR and CAR exhibited unexpected multiple patterns and the existence of CAR possibly being traced back to ancient lobe-finned fishes and tetrapods (Sarcopterygii). Compared to the more conservative DBD of NRs, sequences of LBD were less conserved: Sequences of THRs, RARs and RXRs were >=90% similar to those of the human, ERs, AR, GR, ERRs and PPARs were more variable with similarities of 60%-100% and PXR, CAR, DAX1 and SHP were least conserved among species. PMID- 25711680 TI - Gut immune deficits in LEW.1AR1-iddm rats partially overcome by feeding a diabetes-protective diet. AB - The gut immune system and its modification by diet have been implicated in the pathogenesis of type 1 diabetes (T1D). Therefore, we investigated gut immune status in non-diabetes-prone LEW.1AR1 and diabetes-prone LEW.1AR1-iddm rats and evaluated the effect of a low antigen, hydrolysed casein (HC)-based diet on gut immunity and T1D. Rats were weaned onto a cereal-based or HC-based diet and monitored for T1D. Strain and dietary effects on immune homeostasis were assessed in non-diabetic rats (50-60 days old) and rats with recent-onset diabetes using flow cytometry and immunohistochemistry. Immune gene expression was analysed in mesenteric lymph nodes (MLN) and jejunum using quantitative RT-PCR and PCR arrays. T1D was prevented in LEW.1AR1-iddm rats by feeding an HC diet. Diabetic LEW.1AR1-iddm rats had fewer lymphoid tissue T cells compared with LEW.1AR1 rats. The percentage of CD4(+) Foxp3(+) regulatory T (Treg) cells was decreased in pancreatic lymph nodes (PLN) of diabetic rats. The jejunum of 50-day LEW.1AR1 iddm rats contained fewer CD3(+) T cells, CD163(+) M2 macrophages and Foxp3(+) Treg cells. Ifng expression was increased in MLN and Foxp3 expression was decreased in the jejunum of LEW.1AR1-iddm rats; Ifng/Il4 was decreased in jejunum of LEW.1AR1-iddm rats fed HC. PCR arrays revealed decreased expression of M2 associated macrophage factors in 50-day LEW.1AR1-iddm rats. Wheat peptides stimulated T-cell proliferation and activation in MLN and PLN cells from diabetic LEW.1AR1-iddm rats. LEW.1AR1-iddm rats displayed gut immune cell deficits and decreased immunoregulatory capacity, which were partially corrected in animals fed a low antigen, protective HC diet consistent with other models of T1D. PMID- 25711682 TI - Genetic and environmental contributions to the association between attention deficit hyperactivity disorder and alcohol dependence in adulthood: A large population-based twin study. AB - Previous research indicates that attention deficit hyperactivity disorder (ADHD) frequently co-occurs with alcohol dependence; however, the extent to which shared genetic risk factors underpin this association remains unclear. The aim of this study is to investigate the relative importance of genetic, shared, and nonshared environmental factors for the overlap between ADHD and alcohol dependence in adults. Almost 18,000 adult twins aged 20-45 years, from more than 12,000 twin pairs (5,420 complete pairs), from the population-representative Swedish Twin Registry, were included. Self-ratings were used to assess symptoms of ADHD and alcohol dependence. Twin analysis was used to determine the role of additive genetic (A), shared (C), and nonshared environmental (E) factors. As a result, we found a significant association between ADHD and alcohol dependence (odds ratio 3.58; 95% confidence interval, 2.85-4.49). Twin analysis suggested that shared genetic risk factors explained 64% of the overlap between ADHD and alcohol dependence. Nonshared environmental factors accounted for the remaining 36%, whereas the contribution of shared environmental factors was minimal. We found no support for statistically significant sex differences in the overlap between ADHD and alcohol dependence. In conclusion the overlap between ADHD and alcohol dependence in adulthood was largely explained by shared genetic risk factors. This is an important step toward understanding the underlying nature of the risk of alcohol dependence in patients with ADHD and suggests that individuals with ADHD and their family members are important targets for alcohol prevention and treatment. (c) 2015 Wiley Periodicals, Inc. PMID- 25711681 TI - Enhanced antitumor effect of anti-tissue factor antibody-conjugated epirubicin incorporating micelles in xenograft models. AB - For the creation of a successful antibody-drug conjugate (ADC), both scientific and clinical evidence has indicated that highly toxic anticancer agents (ACA) should be conjugated to a monoclonal antibody (mAb) to administer a reasonable amount of ADC to patients without compromising the affinity of the mAb. For ordinary ACA, the conjugation of a mAb to ACA-loaded micellar nanoparticles is clinically applicable. Tissue factor (TF) is often overexpressed in various cancer cells and tumor vascular endothelium. Accordingly, anti-TF-NC-6300, consisting of epirubicin-incorporating micelles (NC-6300) conjugated with the F(ab')2 of anti-TF mAb was developed. The in vitro and in vivo efficacy and pharmacokinetics of anti-TF-NC-6300 were compared to NC-6300 using two human pancreatic cancer cell lines, BxPC3 (high TF expression) and SUIT2 (low TF expression), and a gastric cancer cell line, 44As3 (high TF expression). The intracellular uptake of epirubicin was faster and greater in BxPC3 cells treated with anti-TF-NC-6300, compared with NC-6300. Anti-TF-NC-6300 showed a superior antitumor activity in BxPC3 and 44As3 xenografts, compared with NC-6300, while the activities of both micelles were similar in the SUIT2 xenograft. A higher tumor accumulation of anti-TF-NC-6300 compared to NC-6300 was seen, regardless of the TF expression levels. However, anti-TF-NC-6300 appeared to be localized to the tumor cells with high TF expression. These results indicated that the enhanced antitumor effect of anti-TF-NC6300 may be independent of the tumor accumulation but may depend on the selective intratumor localization and the preferential internalization of anti-TF-NC-6300 into high TF tumor cells. PMID- 25711683 TI - Incidental Detection of Hb Disorders During HbA1c Analysis. PMID- 25711684 TI - Electronic health records and the evolution of diabetes care: a narrative review. AB - Adoption of electronic health records (EHRs) has increased dramatically since the 2009 implementation of the Health Information Technology for Economic and Clinical Health (HITECH) Act. The latest data from the Centers for Disease Control and Prevention (CDC) indicate that the majority of U.S. hospitals and nearly half of U.S. health care professionals have implemented an EHR with advanced functionality.(1) The goals of the HITECH act were not only to incentivize the adoption of EHRs, but also to increase the quality, safety, and efficiency of health care by promoting the concept of "meaningful use."(2,3) The stepwise implementation of "meaningful use" is now entering the latter stages with a focus on improving patient outcomes.(4). PMID- 25711685 TI - Interference of Hemoglobin N-Baltimore on Measurement of HbA1c Using the HA-8160 and HA-8180 HPLC Methods. PMID- 25711686 TI - Candida albicans autophagy, no longer a bystander: Its role in tolerance to ER stress-related antifungal drugs. AB - Autophagy is a degradation process involved in pathogenicity of many pathogenic fungi. However, its roles in Candida albicans, the leading fungal pathogen in human beings, remain to be detailed. Most recently, we found that endoplasmic reticulum (ER) stress-inducing conditions led to transcriptional up-regulation of C. albicans autophagy-related (ATG) genes, implying a possible link between autophagy and ER stress response in this pathogen. Using a series of C. albicans ATG mutants and autophagy reporting systems, we found that both treatment of ER stress-related drugs and loss of the ER calcium pump Spf1 promoted autophagic flux of Atg8 and Lap41 (a homologue of Saccharomyces cerevisiae Ape1), indicating that these conditions induce autophagy. Moreover, deletion of ATG genes in the spf1Delta/Delta mutant rendered cells hypersensitive to these drugs and caused activation of UPR, revealing a role of autophagy in alleviating ER stress. In addition, only treatment of tunicamycin and loss of Spf1 in combination increased autophagic flux of the ER component Sec63, suggesting that most of the ER stress related conditions cause non-selective autophagy rather than selective ER phagy. This study uncovers the important role of C. albicans autophagy in ER stress response and tolerance to antifungal drugs. PMID- 25711687 TI - Health disparities in cardiovascular disease risk in obese youth. PMID- 25711688 TI - Partial Verification--A Common Source of Bias in Diagnostic Accuracy Studies. PMID- 25711689 TI - Unpleasant odors increase aversion to monetary losses. AB - Loss aversion is the tendency to prefer avoiding losses over acquiring gains of equal nominal values. Unpleasant odors not only influence affective state but have also been shown to activate brain regions similar to those mediating loss aversion. Therefore, we hypothesized a stronger loss aversion in a monetary gamble task if gambles were associated with an unpleasant as opposed to pleasant odor. In thirty human subjects, unpleasant (methylmercaptan), pleasant (jasmine), and neutral (clean air) odors were presented for 4 s. At the same time, uncertain gambles offering an equal chance of gain or loss of a variable amount of money, or a prospect of an assured win were displayed. One hundred different gambles were presented three times, each time paired with a different odor. Loss aversion, risk aversion, and logit sensitivity were evaluated using non-linear fitting of individual gamble decisions. Loss aversion was larger when prospects were displayed in the presence of methylmercaptan compared to jasmine or clean air. Moreover, individual differences in changes in loss aversion to the unpleasant as compared to pleasant odor correlated with odor pleasantness but not with odor intensity. Skin conductance responses to losses during the outcome period were larger when gambles were associated with methylmercaptan compared to jasmine. Increased loss aversion while perceiving an unpleasant odor suggests a dynamic adjustment of loss aversion toward greater sensitivity to losses. Given that odors are biological signals of hazards, such adjustment of loss aversion may have adaptive value in situations entailing threat or danger. PMID- 25711690 TI - Is combination therapy for carbapenem-resistant Klebsiella pneumoniae the new standard of care? AB - Carbapenem-resistant Klebsiella pneumoniae causes serious nosocomial infections and therapeutic options are limited. There is increasing evidence suggesting that combination antibiotic therapy is more effective than monotherapy and leads to better outcomes. However, questions remain about which regimen is optimal and how to balance the potential benefits of combination therapy versus the risks and possible complications (e.g., toxicity, increased costs, Clostridium difficile infection). Well-designed randomized clinical trials are needed to clarify these issues. PMID- 25711691 TI - Lignin decomposition is sustained under fluctuating redox conditions in humid tropical forest soils. AB - Lignin mineralization represents a critical flux in the terrestrial carbon (C) cycle, yet little is known about mechanisms and environmental factors controlling lignin breakdown in mineral soils. Hypoxia is thought to suppress lignin decomposition, yet potential effects of oxygen (O2 ) variability in surface soils have not been explored. Here, we tested the impact of redox fluctuations on lignin breakdown in humid tropical forest soils during ten-week laboratory incubations. We used synthetic lignins labeled with 13 C in either of two positions (aromatic methoxyl or propyl side chain Cbeta ) to provide highly sensitive and specific measures of lignin mineralization seldom employed in soils. Four-day redox fluctuations increased the percent contribution of methoxyl C to soil respiration relative to static aerobic conditions, and cumulative methoxyl-C mineralization was statistically equivalent under static aerobic and fluctuating redox conditions despite lower soil respiration in the latter treatment. Contributions of the less labile lignin Cbeta to soil respiration were equivalent in the static aerobic and fluctuating redox treatments during periods of O2 exposure, and tended to decline during periods of O2 limitation, resulting in lower cumulative Cbeta mineralization in the fluctuating treatment relative to the static aerobic treatment. However, cumulative mineralization of both the Cbeta - and methoxyl-labeled lignins nearly doubled in the fluctuating treatment relative to the static aerobic treatment when total lignin mineralization was normalized to total O2 exposure. Oxygen fluctuations are thought to be suboptimal for canonical lignin-degrading microorganisms. However, O2 fluctuations drove substantial Fe reduction and oxidation, and reactive oxygen species generated during abiotic Fe oxidation might explain the elevated contribution of lignin to C mineralization. Iron redox cycling provides a potential mechanism for lignin depletion in soil organic matter. Couplings between soil moisture, redox fluctuations, and lignin breakdown provide a potential link between climate variability and the biochemical composition of soil organic matter. PMID- 25711692 TI - Letter to the Editor. PMID- 25711693 TI - 5-Aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside alleviated carbon tetrachloride-induced acute hepatitis in mice. AB - AMP-activated protein kinase (AMPK) is one of the principal cellular energy sensors participating in maintenance of energy balance but recent evidences also suggested that AMPK might be involved in the regulation of inflammation. In the present study, the AMPK activator 5-aminoimidazole-4-carboxamide-1-beta-d ribofuranoside (AICAR) was used to investigate the potential roles of AMPK in carbon tetrachloride (CCl4)-induced acute hepatitis. The experimental data indicated that treatment with AICAR significantly decreased the elevation of plasma aminotransferases and alleviated hepatic histological abnormalities in CCl4-exposed mice. Treatment with AICAR also inhibited the increase of myeloperoxidase (MPO), the induction of TNF-alpha, IL-6, inducible nitric oxide synthase (iNOS), nitric oxide and the upregulation of matrix metalloproteinase 2 (MMP-2), MMP-3 and MMP-9 in mice exposed to CCl4. These effects were associated with suppressed nuclear accumulation of NF-kappaB p65. These results indicated that the AMPK activator AICAR effectively suppressed the inflammatory responses and alleviated liver damage induced by CCl4, implying that AMPK activation might be beneficial for ameliorating inflammation-based liver damage. PMID- 25711695 TI - An uncontrolled trial of a present-focused cognitive-behavioral conjoint therapy for posttraumatic stress disorder. AB - OBJECTIVE: The efficacy of a present-focused version of cognitive-behavioral conjoint therapy for posttraumatic stress disorder (CBCT for PTSD) was examined in a community sample. METHOD: Seven couples completed pretreatment assessments, including measures of clinician-, self- and partner-rated PTSD symptoms and relationship satisfaction. Six couples completed present-focused CBCT for PTSD and all posttreatment assessments. A seventh couple terminated their relationship prior to completing treatment; therefore, they completed posttreatment symptom measures, but not ratings of relationship satisfaction. RESULTS: Results revealed significant decreases in PTSD symptoms that were associated with medium-to-large effect sizes. Medium effect sizes for changes in relationship satisfaction were found, though were only significant for partners. CONCLUSION: Results from this pilot study suggest that present-focused CBCT for PTSD may be a promising alternative for individuals who are unwilling to engage in a trauma-focused treatment. PMID- 25711694 TI - The Crc/CrcZ-CrcY global regulatory system helps the integration of gluconeogenic and glycolytic metabolism in Pseudomonas putida. AB - In metabolically versatile bacteria, carbon catabolite repression (CCR) facilitates the preferential assimilation of the most efficient carbon sources, improving growth rates and fitness. In Pseudomonas putida, the Crc and Hfq proteins and the CrcZ and CrcY small RNAs, which are believed to antagonize Crc/Hfq, are key players in CCR. Unlike that seen in other bacterial species, succinate and glucose elicit weak CCR in this bacterium. In the present work, metabolic, transcriptomic and constraint-based metabolic flux analyses were combined to clarify whether P. putida prefers succinate or glucose, and to identify the role of the Crc protein in the metabolism of these compounds. When provided simultaneously, succinate was consumed faster than glucose, although both compounds were metabolized. CrcZ and CrcY levels were lower when both substrates were present than when only one was provided, suggesting a role for Crc in coordinating metabolism of these compounds. Flux distribution analysis suggested that, when both substrates are present, Crc works to organize a metabolism in which carbon compounds flow in opposite directions: from glucose to pyruvate, and from succinate to pyruvate. Thus, our results support that Crc not only favours the assimilation of preferred compounds, but balances carbon fluxes, optimizing metabolism and growth. PMID- 25711696 TI - Lab on paper: iodometric titration on a printed card. AB - A paper test card has been engineered to perform an iodometric titration, an application that requires storage and mixing on demand of several mutually incompatible reagents. The titration is activated when a user applies a test solution to the test card: the dried reagents are reconstituted and combined through a surface-tension-enabled mixing (STEM) mechanism. The device quantifies 0.8-15 ppm of iodine atoms from iodate in aqueous solutions. This is useful, for example, to quantify iodine levels in fortified salt. A blinded internal laboratory validation established the accuracy as 1.4 ppm I and the precision as 0.9 ppm I when the test card was read by newly trained users. Using computer software to process images, the accuracy and precision both improved to 0.9 ppm I. The paper card can also detect substandard beta lactam antibiotics using an iodometric back-titration. When used to quantify amoxicillin, good distinction is achieved between solutions that differ by 0.15 mg/mL over a working range of 0 0.9 mg/mL. The test card was designed to meet the World Health Organization ASSURED criteria for use in low resource settings, where laboratory-based analytical procedures are often not available. PMID- 25711697 TI - Th2-M2 immunity in lesions of muscular sarcoidosis and macrophagic myofasciitis. AB - OBJECTIVE: To analyse the paradox of a lack of giant cell formation and fibrosis in chronic lesions of macrophagic myofasciitis (MMF) in comparison with muscular sarcoidosis (MuS). METHODS: Inflammatory lesions and contiguous muscle regions from biopsy samples of 10 patients with MuS and 10 patients with MMF were cut out by laser microdissection. Mediators of the T helper cell (Th)1 inducing classical macrophage activation (e.g. STAT1, IFNgamma and CXCR3), and Th2 inducing alternative activation of macrophages (e.g. CD206/MRC1, STAT6, SOCS1), molecules involved in development of fibrosis (e.g. TGFbeta) and giant cells (e.g. TYROBP), were assessed by immunohistochemistry and real-time polymerase chain reaction (PCR). RESULTS: STAT6-induced Th2 immunity was associated with up-regulated gene expression of MRC1, SOCS1 and TGFB in inflammatory foci, in comparison with adjacent tissue. TYROBP and TREM2, genes regulating giant cell formation, were more strongly expressed in lesions of MuS patients than in those of MMF. TGFbeta co-localized with CD206(+) macrophages in MuS but not in MMF. Conversely, Th1 immunity was illustrated by STAT1 staining both in macrophages and myofibres in MuS, but not in MMF. Also, STAT1-induced IFNG and CXCR3 expression in lesions and the surrounding tissue was elevated compared with normal controls, but without statistically significant differences. CONCLUSION: Giant cell and typical granuloma formations, including fibrogenesis, is dependent on two main mechanisms, both involving specific macrophage activation: a strong Th2-M2 polarization and a significant expression of TYROBP and TGFbeta in macrophages. The low-grade alternative activation of macrophages in MMF lesions and poor TYROBP and TGFbetaco-expression are obviously insufficient to produce giant cells. PMID- 25711698 TI - Assessment of welfare of finishing beef cattle kept on different types of floor after short- or long-term housing. AB - This study aimed at evaluating short- and long-term effects of housing beef cattle on deep litter (DL) or concrete fully slatted floor (FS) on their welfare. Animal-based measures of the Welfare Quality(r) assessment protocol for cattle were used to assess health status and behaviour of bulls. The assessment was carried out in a large commercial farm on 15 batches of bulls (4 DL and 11 FS) 1 month after their receiving day (short-term) and on 12 batches (three DL and nine FS) the week before slaughter (long-term). Signs of better comfort on deep litter in terms of shorter lying down durations (5.1 +/- 0.5 v. 6.5 +/- 0.4 s; P<0.05) and lower risk of hairless patches (odds ratio=0.09; 95% confidence interval=0.01 to 0.68; P<0.05) were already observed after 1 month. Heavy bulls after a long term housing on FS showed a higher prevalence of bursitis, hairless patches and lesions/swellings than animals on DL. Bulls on fully slatted floor were at higher risk of early culling (odds ratio=6.44; 95% confidence interval=1.57 to 26.37; P<0.01), mainly due to musculoskeletal system pathologies/lameness. Deep litter proved to be a valid alternative to slatted floor, making animals more confident to interact with powerful movements such as mounting at the end of the finishing period. A negative aspect of the deep litter was the poor cleanliness of the bulls. Compared with the fully slatted floor, there were higher odds ratios for dirty bulls at both, the short- (odds ratio=25.09; 95% confidence interval=8.96 to 70.22; P<0.001) and the long-term housing (odds ratio=276.13; 95% confidence interval=98.21 to 776.38; P<0.001). In order to improve health and welfare of beef cattle finished at a heavy weight, deep litter systems are a promising alternative to fully slatted floors. However, proper management of deep litter is necessary to maintain satisfactory cleanliness of the bulls. PMID- 25711699 TI - Bond strength tests of dental adhesive systems and their correlation with clinical results - A meta-analysis. AB - OBJECTIVE: To evaluate the variability of bond strength test results of adhesive systems (AS) and to correlate the results with clinical parameters of clinical studies investigating cervical restorations. MATERIALS AND METHODS: Regarding the clinical studies, the internal database which had previously been used for a meta analysis on cervical restorations was updated with clinical studies published between 2008 and 2012 by searching the PubMed and SCOPUS databases. PubMed and the International Association for Dental Research abstracts online were searched for laboratory studies on microtensile, macrotensile and macroshear bond strength tests. The inclusion criteria were (1) dentin, (2) testing of at least four adhesive systems, (3) same diameter of composite and (4) 24h of water storage prior to testing. The clinical outcome variables were retention loss, marginal discoloration, detectable margins, and a clinical index comprising the three parameters by weighing them. Linear mixed models which included a random study effect were calculated for both, the laboratory and the clinical studies. The variability was assessed by calculating a ratio of variances, dividing the variance among the estimated bonding effects obtained in the linear mixed models by the sum of all variance components estimated in these models. RESULTS: Thirty two laboratory studies fulfilled the inclusion criteria comprising 183 experiments. Of those, 86 used the microtensile test evaluating 22 adhesive systems (AS). Twenty-seven used the macrotensile test with 17 AS, and 70 used the macroshear test with 24 AS. For 28 AS the results from clinical studies were available. Microtensile and macrotensile (Spearman rho=0.66, p=0.007) were moderately correlated and also microtensile and macroshear (Spearman rho=0.51, p=0.03) but not macroshear and macrotensile (Spearman rho=0.34, p=0.22). The effect of the adhesive system was significant for microtensile and macroshear (p < 0.001) but not for macrotensile. The effect of the adhesive system could explain 36% of the variability of the microtensile test, 27% of the macrotensile and 33% of the macroshear test. For the clinical trials, about 49% of the variability of retained restorations could be explained by the adhesive system. With respect to the correlation between bond strength tests and clinical parameters, only a moderate correlation between micro- and macrotensile test results and marginal discoloration was demonstrated. However, no correlation between these tests and a retention loss or marginal integrity was shown. The correlation improved when more studies were included compared to assessing only one study. SIGNIFICANCE: The high variability of bond strength test results highlights the need to establish individual acceptance levels for a given test institute. The weak correlation of bond-strength test results with clinical parameters leads to the conclusion that one should not rely solely on bond strength tests to predict the clinical performance of an adhesive system but one should conduct other laboratory tests like tests on the marginal adaptation of fillings in extracted teeth and the retention loss of restorations in non retentive cavities after artificial aging. PMID- 25711700 TI - In vivo temperature rise in anesthetized human pulp during exposure to a polywave LED light curing unit. AB - OBJECTIVES: This in vivo study evaluated pulp temperature (PT) rise in human premolars during exposure to a light curing unit (LCU) using selected exposure modes (EMs). METHODS: After local Ethics Committee approval, intact first upper premolars, requiring extraction for orthodontic reasons, from 8 volunteers, received infiltrative and intraligamental anesthesia. The teeth (n=15) were isolated using rubber dam and a minute pulp exposure was attained. A sterile probe from a wireless, NIST-traceable, temperature acquisition system was inserted directly into the coronal pulp chamber, and real time PT ( degrees C) was continuously monitored while the buccal surface was exposed to polywave light from a LED LCU (Bluephase 20i, Ivoclar Vivadent) using selected EMs allowing a 7 min span between each exposure: 10-s either in low (10-s/L) or high (10-s/H); 5-s turbo (5-s/T); and 60-s-high (60-s/H) intensities. Peak PT values and PT increases from baseline (DeltaT) after exposure were subjected to one-way, repeated measures ANOVAs, and Bonferroni's post hoc tests (alpha=0.05). Linear regression analysis was performed to establish the relationship between applied radiant exposure and DeltaT. RESULTS: All EMs produced higher peak PT than the baseline temperature (p<0.001). The 60-s/H mode generated the highest peak PT and DeltaT (p<0.001), with some teeth exhibiting DeltaT higher than 5.5 degrees C. A significant, positive relationship between applied radiant exposure and DeltaT (r(2)=0.916; p<0.001) was noted. SIGNIFICANCE: Exposing intact, in vivo anesthetized human upper premolars to a polywave LED LCU increases PT, and depending on EM and the tooth, PT increase can be higher than the critical DeltaT, thought to be associated with pulpal necrosis. PMID- 25711701 TI - Novel MtCEP1 peptides produced in vivo differentially regulate root development in Medicago truncatula. AB - Small, post-translationally modified and secreted peptides regulate diverse plant developmental processes. Due to low natural abundance, it is difficult to isolate and identify these peptides. Using an improved peptide isolation protocol and Orbitrap mass spectrometry, nine 15-amino-acid CEP peptides were identified that corresponded to the two domains encoded by Medicago truncatula CEP1 (MtCEP1). Novel arabinosylated and hydroxylated peptides were identified in root cultures overexpressing MtCEP1. The five most abundant CEP peptides were hydroxylated and these species were detected also in low amounts in vector control samples. Synthetic peptides with different hydroxylation patterns differentially affected root development. Notably, the domain 1 peptide hydroxylated at Pro4 and Pro11 (D1:HyP4,11) imparted the strongest inhibition of lateral root emergence when grown with 5mM KNO3 and stimulated the highest increase in nodule number when grown with 0mM KNO3. Inhibition of lateral root emergence by D1:HyP4,11 was not alleviated by removing peptide exposure. In contrast, the domain 2 peptide hydroxylated at Pro11 (D2:HyP11) increased stage III-IV lateral root primordium numbers by 6-fold (P < 0.001) which failed to emerge. Auxin addition at levels which stimulated lateral root formation in wild-type plants had little or no ameliorating effect on CEP peptide-mediated inhibition of lateral root formation or emergence. Both peptides increased and altered the root staining pattern of the auxin-responsive reporter GH3:GUS suggesting CEPs alter auxin sensitivity or distribution. The results showed that CEP primary sequence and post-translational modifications influence peptide activities and the improved isolation procedure effectively and reproducibly identifies and characterises CEPs. PMID- 25711702 TI - Cross-talk between environmental stresses and plant metabolism during reproductive organ abscission. AB - In plants, flowering is a crucial process for reproductive success and continuity of the species through time. Fruit production requires the perfect development of reproductive structures. Abscission, a natural process, can occur to facilitate shedding of no longer needed, infected, or damaged organs. If stress occurs during flower development, abscission can intervene at flower level, leading to reduced yield. Flower abscission is a highly regulated developmental process simultaneously influenced and activated in response to exogenous (changing environmental conditions, interactions with microorganisms) and endogenous (physiological modifications) stimuli. During climate change, plant communities will be more susceptible to environmental stresses, leading to increased flower and fruit abscission, and consequently a decrease in fruit yield. Understanding the impacts of stress on the reproductive phase is therefore critical for managing future agricultural productivity. Here, current knowledge on flower/fruit abscission is summarized by focusing specifically on effects of environmental stresses leading to this process in woody plants. Many of these stresses impair hormonal balance and/or carbohydrate metabolism, but the exact mechanisms are far from completely known. Hormones are the abscission effectors and the auxin/ethylene balance is of particular importance. The carbohydrate pathway is the result of complex regulatory processes involving the balance between photosynthesis and mobilization of reserves. Hormones and carbohydrates together participate in complex signal transduction systems, especially in response to stress. The available data are discussed in relation to reproductive organ development and the process of abscission. PMID- 25711703 TI - Ethylene is critical to the maintenance of primary root growth and Fe homeostasis under Fe stress in Arabidopsis. AB - Iron (Fe) is an essential microelement but is highly toxic when in excess. The response of plant roots to Fe toxicity and the nature of the regulatory pathways engaged are poorly understood. Here, we examined the response to excess Fe exposure in Arabidopsis wild type and ethylene mutants with a focus on primary root growth and the role of ethylene. We showed that excess Fe arrested primary root growth by decreasing both cell elongation and division, and principally resulteds from direct external Fe contact at the root tip. Pronounced ethylene, but not abscisic acid, evolution was associated with excess Fe exposure. Ethylene antagonists intensified root growth inhibition in the wild type, while the inhibition was significantly reduced in ethylene-overproduction mutants. We showed that ethylene plays a positive role in tissue Fe homeostasis, even in the absence of iron-plaque formation. Ethylene reduced Fe concentrations in the stele, xylem, and shoot. Furthermore, ethylene increased the expression of genes encoding Fe-sequestering ferritins. Additionally, ethylene significantly enhanced root K(+) status and upregulated K(+)-transporter (HAK5) expression. Our findings highlight the important role of ethylene in tissue Fe and K homeostasis and primary root growth under Fe stress in Arabidopsis. PMID- 25711704 TI - Growth-defence balance in grass biomass production: the role of jasmonates. AB - Growth-defence balance is the selective partitioning of resources between biomass accumulation and defence responses. Although it is generally postulated that reallocation of limited carbon pools drives the antagonism between growth and defence, little is known about the mechanisms underlying this regulation. Jasmonates (JAs) are a group of oxylipins that are required for a broad range of responses from defence against insects to reproductive growth. Application of JAs to seedlings also leads to inhibited growth and repression of photosynthesis, suggesting a role for JAs in regulating growth-defence balance. The majority of JA research uses dicot models such as Arabidopsis and tomato, while understanding of JA biology in monocot grasses, which comprise most bioenergy feedstocks, food for human consumption, and animal feed, is limited. Interestingly, JA mutants of grasses exhibit unique phenotypes compared with well-studied dicot models. Gene expression analyses in bioenergy grasses also suggest roles for JA in rhizome development, which has not been demonstrated in Arabidopsis. In this review we summarize current knowledge of JA biology in panicoid grasses-the group that consists of the world's emerging bioenergy grasses such as switchgrass, sugarcane, Miscanthus, and sorghum. We discuss outstanding questions regarding the role of JAs in panicoid grasses, and highlight the importance of utilizing emerging grass models for molecular studies to provide a basis for engineering bioenergy grasses that can maximize biomass accumulation while efficiently defending against stress. PMID- 25711705 TI - Metabolite fingerprinting of pennycress (Thlaspi arvense L.) embryos to assess active pathways during oil synthesis. AB - Pennycress (Thlaspi arvense L.), a plant naturalized to North America, accumulates high levels of erucic acid in its seeds, which makes it a promising biodiesel and industrial crop. The main carbon sinks in pennycress embryos were found to be proteins, fatty acids, and cell wall, which respectively represented 38.5, 33.2, and 27.0% of the biomass at 21 days after pollination. Erucic acid reached a maximum of 36% of the total fatty acids. Together these results indicate that total oil and erucic acid contents could be increased to boost the economic competitiveness of this crop. Understanding the biochemical basis of oil synthesis in pennycress embryos is therefore timely and relevant to guide future breeding and/or metabolic engineering efforts. For this purpose, a combination of metabolomics approaches was conducted to assess the active biochemical pathways during oil synthesis. First, gas chromatography-mass spectrometry (GC-MS) profiling of intracellular metabolites highlighted three main families of compounds: organic acids, amino acids, and sugars/sugar alcohols. Secondly, these intermediates were quantified in developing pennycress embryos by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in multiple reaction monitoring mode. Finally, partitional clustering analysis grouped the intracellular metabolites that shared a similar pattern of accumulation over time into eight clusters. This study underlined that: (i) sucrose might be stored rather than cleaved into hexoses; (ii) glucose and glutamine would be the main sources of carbon and nitrogen, respectively; and (iii) glycolysis, the oxidative pentose phosphate pathway, the tricarboxylic acid cycle, and the Calvin cycle were active in developing pennycress embryos. PMID- 25711706 TI - Recent advances in understanding plant nuclear envelope proteins involved in nuclear morphology. AB - The nuclear envelope (NE) is a fundamental structure of the nucleus and plays an important role in nuclear morphology through the strict regulation of NE protein function. Beyond its physical barrier function between nucleoplasm and cytoplasm, recent studies of the plant NE have provided novel insights into basic aspects of nuclear morphology as well as cellular organization. In this review, we focus on plant NE proteins that have emerged from recent studies in nuclear morphology, and we discuss their physiological functions in cellular activities. A better understanding of the NE protein functions should provide key insights into the physiological significance of proper nuclear structure in plants. PMID- 25711707 TI - Analysis of plant leaf metabolites reveals no common response to insect herbivory by Pieris rapae in three related host-plant species. AB - Studying the biochemical responses of different plant species to insect herbivory may help improve our understanding of the evolution of defensive metabolites found in host plants and their role in plant-herbivore interactions. Untargeted metabolic fingerprints measured as individual mass features were used to compare metabolite reactions in three Brassicales host-plant species (Cleome spinosa, Brassica oleracea, and Lunaria annua) to larval herbivore attack (Pieris rapae; Lepidoptera). Principal component analyses of metabolic fingerprints were able to distinguish among the three plant species and between uneaten control plants and plants that had been eaten. A large number of mass features (1186, 13% of mass features measured in control plants) were common to the three plant species. However, there were few similarities in the mass features that were induced (i.e. changed in abundance) following herbivory. Of the 87 and 68 induced mass features in B. oleracea and C. spinosa, respectively, there were only three that were induced in both plant species. By contrast, L. annua only had one mass feature induced by herbivory, and this was not induced in the other two plant species. The growth of the P. rapae larvae was poorer on the host plant L. annua than on B. oleracea and C. spinosa. The absence of common metabolites among the plants meant these induced responses could not be related to the performance of the herbivore. Thus, the response to herbivory by the same herbivore in these three host plants has evolved to be idiosyncratic in terms of the specific metabolites induced. PMID- 25711709 TI - Should we treat the ionome as a combination of individual elements, or should we be deriving novel combined traits? AB - It has been more than 10 years since the concept of the ionome, all of the mineral nutrients in a cell tissue or organism, was introduced. In the intervening years, ionomics, high throughput elemental profiling, has been used to analyse over 400,000 samples from at least 10 different organisms. There are now multiple published examples where an ionomics approach has been used to find genes of novel function, find lines or environments that produce foods with altered nutritional profiles, or define gene by environmental effects on elemental accumulation. In almost all of these studies, the ionome has been treated as a collection of independent elements, with the analysis repeated on each measured element. However, many elements share chemical properties, are known to interact with each other, or have been shown to have similar interactions with biological molecules. Accordingly, there is strong evidence from ionomic studies that the elements of the ionome do not behave independently and that combinations of elements should be treated as the phenotypes of interest. In this review, I will consider the evidence that we have for the interdependence of the ionome, some of its causes, methods for incorporating this interdependence into analyses and the benefits, drawbacks, and challenges of taking these approaches. PMID- 25711708 TI - The tarani mutation alters surface curvature in Arabidopsis leaves by perturbing the patterns of surface expansion and cell division. AB - The leaf surface usually stays flat, maintained by coordinated growth. Growth perturbation can introduce overall surface curvature, which can be negative, giving a saddle-shaped leaf, or positive, giving a cup-like leaf. Little is known about the molecular mechanisms that underlie leaf flatness, primarily because only a few mutants with altered surface curvature have been isolated and studied. Characterization of mutants of the CINCINNATA-like TCP genes in Antirrhinum and Arabidopsis have revealed that their products help maintain flatness by balancing the pattern of cell proliferation and surface expansion between the margin and the central zone during leaf morphogenesis. On the other hand, deletion of two homologous PEAPOD genes causes cup-shaped leaves in Arabidopsis due to excess division of dispersed meristemoid cells. Here, we report the isolation and characterization of an Arabidopsis mutant, tarani (tni), with enlarged, cup shaped leaves. Morphometric analyses showed that the positive curvature of the tni leaf is linked to excess growth at the centre compared to the margin. By monitoring the dynamic pattern of CYCLIN D3;2 expression, we show that the shape of the primary arrest front is strongly convex in growing tni leaves, leading to excess mitotic expansion synchronized with excess cell proliferation at the centre. Reduction of cell proliferation and of endogenous gibberellic acid levels rescued the tni phenotype. Genetic interactions demonstrated that TNI maintains leaf flatness independent of TCPs and PEAPODs. PMID- 25711710 TI - Protein lipid modifications and the regulation of ROP GTPase function. AB - In eukaryotes, the RHO superfamily of small G-proteins is implicated in the regulation of cell polarity and growth. Rho of Plants (ROPs)/RACs are plant specific Rho family proteins that have been shown to regulate cell polarity, auxin transport and responses, ABA signalling, and response to pathogens. A hallmark of ROP/RAC function is their localization in specific plasma membrane domains. This short review focuses on the mechanisms responsible for membrane interactions of ROPs/RACs and how they affect ROP/RAC function. PMID- 25711711 TI - Differential expression of GS5 regulates grain size in rice. AB - Grain weight is a major determinant of grain yield. GS5 is a positive regulator of grain size such that grain width, filling, and weight are correlated with its expression level. Previous work suggested that polymorphisms of GS5 in the promoter region might be responsible for the variation in grain size. In this study, two single nucleotide polymorphisms (SNPs) between the wide-grain allele GS5-1 and the narrow-grain allele GS5-2 in the upstream region of the gene that were responsible for the differential expression in developing young panicles were identified. These two polymorphs altered the responses of the GS5 alleles to abscisic acid (ABA) treatments, resulting in higher expression of GS5-1 than of GS5-2 in developing young panicles. It was also shown that SNPs in light responsive elements of the promoter altered the response to light induction, leading to higher expression of GS5-2 than GS5-1 in leaves. Enhanced expression of GS5 competitively inhibits the interaction between OsBAK1-7 and OsMSBP1 by occupying the extracellular leucine-rich repeat (LRR) domain of OsBAK1-7, thus preventing OsBAK1-7 from endocytosis caused by interacting with OsMSBP1, providing an explanation for the positive association between grain size and GS5 expression. These results advanced our understanding of the molecular mechanism by which GS5 controls grain size. PMID- 25711712 TI - Tailored near-infrared contrast agents for image guided surgery. AB - The success of near-infrared (NIR) fluorescence to be employed for intraoperative imaging relies on the ability to develop a highly stable, NIR fluorescent, nontoxic, biocompatible, and highly excreted compound that retains a reactive functionality for conjugation to a cancer-recognizing peptide. Herein, systematic modifications to previously detailed fluorophore ZW800-1 are explored. Specific modifications, including the isosteric replacement of the O atom of ZW800-1, include nucleophilic amine and sulfur species attached to the heptamethine core. These novel compounds have shown similar satisfactory results in biodistribution and clearance while also expressing increased stability in serum. Most importantly, all of the synthesized and evaluated compounds display a reactive functionality (either a free amino group or carboxylic acid moiety) for further bioconjugation. The results obtained from the newly prepared derivatives demonstrate that the central substitution with the studied linking agents retains the ultralow background in vivo performance of the fluorophores regardless of the total net charge. PMID- 25711713 TI - Management of toxoplasmic retinochoroiditis during pregnancy, postpartum period and lactation: clinical observations. AB - BACKGROUND: During pregnancy and labor, the immune response is physiologically impaired and women are more susceptible to infections. Since many drugs may have potentially adverse effects on the fetus and newborn, less aggressive treatment regimens should be considered in pregnant and lactating patients. The aim of our study was to present the management of toxoplasmic retinochoroiditis during pregnancy, postpartum period, and lactation. MATERIAL AND METHODS: A retrospective study was undertaken of the clinical records of 24 women during pregnancy, postpartum period, and lactation who were referred in the years 1994 2014 to the Department of Zoonoses and Tropical Diseases or the Department of Ophthalmology, Medical University of Warsaw for toxoplasmic retinochoroiditis. The diagnosis was based on the typical ophthalmoscopic picture, confirmed by serological testing using an ELISA method. RESULTS: A total of 28 attacks of toxoplasmic retinochoroiditis were observed in 24 patients during pregnancy, postpartum period, and lactation. The choice of treatment was guided by the character and location of the inflammatory lesion and the gestational age. Topical (steroidal/nonsteroidal eye drops) and systemic treatments with spiramycin or azithromycin, Fansidar (pyrimethamine 25 mg/sulfadoxine 500 mg), and prednisone were used. CONCLUSIONS: Management of toxoplasmic retinochoroiditis during pregnancy, postpartum period, or lactation must be individualized and guided by the gestational age and location of the active lesion. Women of childbearing age with toxoplasma ocular lesions should be informed by their doctors about possible active recurrences during pregnancy and followed carefully by an ophthalmologist when pregnant. PMID- 25711714 TI - Improving osteointegration and osteogenesis of three-dimensional porous Ti6Al4V scaffolds by polydopamine-assisted biomimetic hydroxyapatite coating. AB - Titanium alloys with various porous structures can be fabricated by advanced additive manufacturing techniques, which are attractive for use as scaffolds for bone defect repair. However, modification of the scaffold surfaces, particularly inner surfaces, is critical to improve the osteointegration of these scaffolds. In this study, a biomimetic approach was employed to construct polydopamine assisted hydroxyapatite coating (HA/pDA) onto porous Ti6Al4V scaffolds fabricated by the electron beam melting method. The surface modification was characterized with the field emission scanning electron microscopy, energy dispersive spectroscopy, water contact angle measurement, and confocal laser scanning microscopy. Attachment and proliferation of MC3T3-E1 cells on the scaffold surface were significantly enhanced by the HA/pDA coating compared to the unmodified surfaces. Additionally, MC3T3-E1 cells grown on the HA/pDA-coated Ti6Al4V scaffolds displayed significantly higher expression of runt-related transcription factor-2, alkaline phosphatase, osteocalcin, osteopontin, and collagen type-1 compared with bare Ti6Al4V scaffolds after culture for 14 days. Moreover, microcomputed tomography analysis and Van-Gieson staining of histological sections showed that HA/pDA coating on surfaces of porous Ti6Al4V scaffolds enhanced osteointegration and significantly promoted bone regeneration after implantation in rabbit femoral condylar defects for 4 and 12 weeks. Therefore, this study provides an alternative to biofunctionalized porous Ti6Al4V scaffolds with improved osteointegration and osteogenesis functions for orthopedic applications. PMID- 25711715 TI - Restoration of Firearm Rights in New York. AB - The National Instant Criminal Background Check System (NICS) Improvement Amendments Act of 2007 encouraged states to create processes by which individuals who have lost their rights to firearm possession for mental-illness-related reasons could receive relief from restrictions. Over 20 states have created relief processes for this sub-group, but there still exists considerable state-by state heterogeneity. The spectrum ranges from states that require a physician's opinion regarding appropriateness for restoration to those that rely solely on judicial proceedings without input from psychiatrists or other mental health professionals. This article reviews the restoration process in New York State, a model in which psychiatrists participate in the process of assessing whether an individual's firearm rights can be restored. It discusses the legislative background of these regulations, the specific policies and procedures governing the restoration process, and clinical considerations for the forensic evaluation. PMID- 25711716 TI - Is gentamicin-impregnated collagen sponge to be recommended in pilonidal sinus patient treated with marsupialization? A prospective randomized study. AB - BACKGROUND: The ideal treatment method for pilonidal sinus has always been a matter of debate. Although primary closure or various flap applications offer shorter wound healing times, their infection rates are very high. Secondary recovery involves long recovery period. The aim of this study is to investigate the effects of gentamicin-impregnated collagen sponge on wound healing and infection in patients undergoing marsupialization. PATIENTS AND METHODS: Fifty patients were included in the study. Twenty-five patients in control group (Group 1) underwent excision and marsupialization. Gentamicin-impregnated collagen sponge was used postoperatively in twentyfive patients in group 2. Three dimensional wound measurements were made on the 0.7 and 15th days and recorded. RESULTS: No significant difference was observed between the groups in terms of development of hemorrhage and infection. Excessive granulation was detected in five patients (two in group 1 and three in group 2). There was no significant difference between the groups with respect to this criterion. Full recovery times were 29.6 and 28.2 days respectively. No statistically significant difference was observed between the groups (p = 0.571). None of the patients developed recurrence at the end of the follow-up period of 6-30 months. CONCLUSION: In accordance with the results obtained in this randomized and controlled study, no significant difference was observed between gentamicin-impregnated collagen sponge group and control group with respect to development of infection, hemorrhage and wound healing times. Therefore, we do not recommend the use of gentamicin-impregnated collagen sponge after marsupialization. KEY WORDS: Gentamicin-impregnated collagen sponge, Marsupialization, Pilonidal sinus. PMID- 25711717 TI - Efficacy of intravenous administration of combined acid suppressants in healthy dogs. AB - BACKGROUND: Short-term intravenous co-administration of famotidine and pantoprazole is used by some veterinarians to treat gastrointestinal bleeding in critically ill dogs. However, clinical studies have not evaluated the efficacy of combination acid suppressant treatment in dogs. HYPOTHESIS/OBJECTIVES: To compare the effect of intravenous co-administration of famotidine and pantoprazole to monotherapy with pantoprazole on intragastric pH in dogs. We hypothesized that single agent pantoprazole would be more effective than combination with famotidine. ANIMALS: Twelve healthy adult colony dogs. METHODS: Randomized, 2-way crossover design. All dogs received placebo (0.9% saline) for 24 hours followed by 1.0 mg/kg i.v. q12h pantoprazole or combination treatment with famotidine and pantoprazole for 3 consecutive days. Intragastric pH monitoring was used to continuously record intragastric pH for 96 hours beginning on day 0 of treatment. Mean percentage time (MPT) that intragastric pH was >=3 and >=4 were compared between groups using ANOVA with a posthoc Tukey-Kramer test (alpha = 0.017). RESULTS: The MPT +/- standard deviation intragastric pH was greater than >=3 and 4 were 79 +/- 17% and 68 +/- 17% for pantoprazole and 74 +/- 19% and 64 +/- 23% for combination treatment, respectively. There were no significant differences in MPT intragastric pH was >=3 and 4 between groups. Pantoprazole administered alone achieved pH goals established for humans with acid-related disorders. CONCLUSIONS AND CLINICAL IMPORTANCE: These results suggest that short-term combination treatment with famotidine and pantoprazole is not superior to pantoprazole alone for increasing intragastric pH in dogs. PMID- 25711720 TI - Erratum: Synthetic retinal analogs modify the spectral and kinetic characteristics of microbial rhodopsin optogenetic tools. PMID- 25711719 TI - Simultaneous use of in silico design and a correlated mutation network as a tool to efficiently guide enzyme engineering. AB - In order to improve the efficiency of directed evolution experiments, in silico multiple-substrate clustering was combined with an analysis of the variability of natural enzymes within a protein superfamily. This was applied to a Pseudomonas fluorescens esterase (PFE I) targeting the enantioselective hydrolysis of 3 phenylbutyric acid esters. Data reported in the literature for nine substrates were used for the clustering meta-analysis of the docking conformations in wild type PFE I, and this highlighted a tryptophan residue (W28) as an interesting target. Exploration of the most frequently, naturally occurring amino acids at this position suggested that the reduced flexibility observed in the case of the W28F variant leads to enhancement of the enantioselectivity. This mutant was subsequently combined with mutations identified in a library based on analysis of a correlated mutation network. By interrogation of <80 variants a mutant with 15 fold improved enantioselectivity was found. PMID- 25711718 TI - Metabolic consequences of chronic intermittent mild stress exposure. AB - Chronic stress in humans has divergent effects on food intake, with some individuals reporting increased vs. decreased food intake during stress. This divergence may depend in part on stress intensity, with higher-intensity stressors preferentially promoting anorexia. Consistent with this idea, rodents given a high-intensity chronic variable stress paradigm have robustly decreased food intake and body weight gain. However, the metabolic effects of a less intense chronic stress paradigm are not clear. Thus in the present study, adult male rats were given chronic intermittent mild stress (CIMS) exposure (3 cycles, in which each cycle consists of once daily mild stress for 5 days/week for 2 weeks, followed by 2 weeks of no stress) vs. non-stress controls, combined with ongoing access to a palatable diet (PD; choice of chow, high-fat diet, 30% sucrose drink, and water) vs. control diet (chow and water). As expected, access to PD increased caloric intake, body weight gain, and adiposity, and impaired glucose tolerance. CIMS decreased body weight gain only during the first cycle of stress and did not affect body weight gain thereafter, regardless of diet. Moreover, CIMS did not alter total food intake, adiposity or glucose tolerance regardless of diet. Lastly, CIMS transiently increased high-fat diet preference in PD-fed rats during the first stress cycle. Collectively, these results suggest that CIMS has relatively modest metabolic effects that occur primarily during initial stress exposure. These results support the hypothesis that the metabolic consequences of chronic stress vary with stress intensity and/or frequency. PMID- 25711721 TI - Intestinal neuronal dysplasia-like histopathology in infancy. AB - The present patient was delivered at a gestational age of 27 weeks. She had abdominal bloating with symptoms of respiratory distress. We suspected Hirschsprung disease (HD) or small intestinal stricture, but examinations were not definitive. Exploratory laparotomy was performed at 97 days of age. Intraoperative findings showed no evidence of small intestinal stricture or changes in intestinal caliber. A transanal drainage tube was inserted, and decompression therapy and intestinal lavage were started. Rectal mucosal biopsy was performed at 184 days of age, and HE and acetylcholinesterase staining showed intestinal neuronal dysplasia (IND)-like pathological findings. At 15 months, giant ganglia were no longer present on follow-up rectal mucosal biopsy, and the pathological diagnosis was normoganglionosis. It should be recognized that while the enteric nervous system is developing, IND-like pathological findings may be seen as a pathological condition during the maturation process. PMID- 25711722 TI - Life coaching following haematopoietic stem cell transplantation: a mixed-method investigation of feasibility and acceptability. AB - Haematopoietic stem cell transplantation (HSCT) cures many haematological cancers. Recovery post-HSCT is physically and psychologically challenging, lasting several months. Beyond the first post-transplant year, a fifth report difficulties encompassing practical, social and emotional domains, including finance and employment. We investigated the feasibility, acceptability and impact of a life coaching intervention designed to address psychosocial 'survivor' concerns of HSCT recipients and facilitate transition to life post-treatment. A concurrent embedded experimental mixed-method design was employed. Pre- and post intervention data collection comprised qualitative semi-structured telephone interviews and quantitative postal questionnaires. Seven purposively sampled HSCT recipients (<18 months) participated, reporting on one-to-one life coaching delivered by a professional life coach fortnightly over 8 weeks. Participants reported less anxiety, depression and fewer survivor concerns post-intervention, with a trend for lower social difficulties and increased functional well-being. Perceived self-efficacy was unchanged. Life coaching was feasible to deliver and acceptable to the participants who indicated it was a positive experience, with benefits described in diverse areas including work, lifestyle and hobbies. Life coaching within cancer services potentially offers the means to address psychosocial concerns and support transition to life after treatment, enabling patients to reach their potential, e.g. returning to employment and financial independence. Further investigation of this intervention in cancer survivors is warranted. PMID- 25711723 TI - Accentuated lines in the enamel of primary incisors from skeletal remains: A contribution to the explanation of early childhood mortality in a medieval population from Poland. AB - Physiological disruptions resulting from an impoverished environment during the first years of life are of key importance for the health and biological status of individuals and populations. Studies of growth processes in archaeological populations point to the fact that the main causes of childhood mortality in the past are to be sought among extrinsic factors. Based on this assumption, one would expect random mortality of children, with the deceased individuals representing the entire subadult population. The purpose of this study is to explore whether differences in early childhood survival are reflected in differences in deciduous tooth enamel, which can provide an insight into the development of an individual during prenatal and perinatal ontogeny. Deciduous incisors were taken from 83 individuals aged 2.0-6.5 years from a medieval inhumation cemetery dated AD 1300-1600. Prenatal and postnatal enamel formation time, neonatal line width, and the number of accentuated lines were measured using an optical microscope. The significantly wider neonatal line and the higher frequency of accentuated lines in the enamel of the incisors of children who died at the age of 2-3 years suggest the occurrence of stronger or more frequent stress events in this group. These results indicate that in skeletal populations mortality was not exclusively determined by random external factors. Individuals predisposed by an unfavorable course of prenatal and perinatal growth were more likely to die in early childhood. PMID- 25711724 TI - Downregulation of natriuretic peptide clearance receptor mRNA in vascular smooth muscle cells by angiotensin II. AB - Angiotensin II can downregulate atrial natriuretic peptide binding to rat vascular smooth muscle cells (VSMCs), but the mechanism is not known. Because protein kinase C (PKC) mimetic phorbol myristate acetate (PMA) can destabilize natriuretic peptide clearance receptor (NPR-C) mRNA and angiotensin II activates several PKC isoforms in VSMCs, we hypothesized that angiotensin II treatment decreases NPR-C mRNA stability and exerts this effect through PKC. This study demonstrated that angiotensin II induced time- and concentration-dependent downregulation of NPR-C, which was completely inhibited by an angiotensin II type I receptor blocker losartan. NPR-C mRNA disappearance rate over 6 h was nearly doubled by exposure of VSMCs to 100 nm angiotensin II, compared with that observed after inhibition of RNA synthesis alone. However, this response to angiotensin II was undiminished by the PKC inhibitor chelerythrine, or by depletion of PKC by prior exposure of cells to PMA for 48 h. Inhibitors of tyrosine kinases, phospholipase C, or mitogen-activated protein kinase kinase also failed to reverse the angiotensin II effect. We conclude that at least two distinct proximal signaling pathways, one involved and one independent of phorbol ester-sensitive protein kinase C, lead to downregulation of NPR-C gene expression by destabilizing its mRNA. PMID- 25711725 TI - Oral bacteria adherence to suture threads: an in vitro study. AB - PURPOSE: This study investigated the adherence of oral microorganisms to different types of suture threads. METHODS: Pieces of thread were distributed on 24-well plates, according to the following groups: (G1) nylon, (G2) silk, (G3) polyglactin 910, (G4) polyglactin 910 with triclosan. Blank control (G5) consisted of one thread from each group. Adherence to thread tests was performed to observe adhesion of total microorganisms from saliva or two isolates of Prevotella intermedia (ATCC49046) and Fusobacterium nucleatum (ATCC51190). Brain heart infusion (BHI) medium with or without bacterial inoculum (1.8 * 10(7) CFU/mL) was added to each well of microplates. The microplates were incubated in an anaerobic chamber at 37 degrees C, for 5 days for biofilm formation. RESULTS: There was no difference between the groups as regard to adhesion of F. nucleatum (p > 0.05). For P. intermedia, the threads in G1 and G4 showed a lower level of adhesion (p < 0.05), with no difference between them. Against total microorganisms, G1 presented a lower level of adherence (p < 0.05), followed by G4; and no difference was observed between G2 and G3. CONCLUSIONS: Total microorganisms and P. intermedia have different affinities to the tested suture threads, whereas F. nucleatum presented a similar adherence level. Among the threads, nylon (G1), followed by polyglactin 910 with triclosan (G4) presented the lowest microbial adherence level. PMID- 25711726 TI - Comparative study of hemodynamic changes caused by diazepam and midazolam during third molar surgery: a randomized controlled trial. AB - The aim of the present study was to compare hemodynamic changes using midazolam 7.5 mg and diazepam 10.0 mg during the surgical removal of symmetrically positioned third molars. A prospective, randomized, double-blind, clinical trial was carried out involving 120 patients divided into three groups: Group 1 (diazepam and placebo), Group 2 (midazolam and placebo), and Group 3 (diazepam and midazolam). Each subject underwent two surgeries on separate occasions under local anesthesia. The following parameters were assessed at five different times (T0, T1, T2, T3, and T4): systolic, diastolic, and mean blood pressure (SBP, DBP, and MBP, respectively); heart rate (HR); oxygen saturation (SpO(2)); rate pressure product (RPP); and pressure rate quotient (PRQ). Statistically significant differences were found regarding heart rate at T2 and T3 (p < 0.005) in Group 2, with a higher rate occurring during midazolam administration. Moreover, significant differences in rate pressure product were found at T2, T3, and T4 in this group, with higher values also occurring during midazolam administration. In Group 3, significant differences in diastolic blood pressure were found at T3 and T4, with higher values occurring during diazepam administration, whereas a higher heart rate occurred at T3 with midazolam. Midazolam 7.5 mg and diazepam 10.0 mg exert an influence on some hemodynamic parameters without perceptible clinical changes in healthy patients undergoing lower third molar surgery. PMID- 25711727 TI - The European eel may tolerate multiple infections at a low biological cost. AB - Most animals are concurrently infected with multiple parasites, and interactions among them may influence both disease dynamics and host fitness. However, the sublethal costs of parasite infections are difficult to measure and the effects of concomitant infections with multiple parasite species on individual physiology and fitness are poorly described for wild hosts. To understand the costs of co infection, we investigated the relationships among 189 European eel (Anguilla anguilla) from Mar Menor, parasites (richness and intensity) and eel's 'health status' (fluctuant asymmetry, splenic somatic index and the scaled mass index) by partial least squares regression. We found a positive relationship with 44% of the health status variance explained by parasites. Contracaecum sp. (Nematoda: Anisakidae) was the strongest predictor variable (44.72%) followed by Bucephalus anguillae (Platyhelminthes: Bucephalidae), (29.26%), considered the two most relevant parasites in the analysis. Subsequently, 15.67 and 12.01% of the response variables block were explained by parasite richness and Deropristis inflata (Platyhelminthes: Deropristiidae), respectively. Thus, the presence of multiple parasitic exposures with little effect on condition, strongly suggests that eels from Mar Menor tolerate multiparasitism. PMID- 25711728 TI - The effect of antenatal pelvic floor muscle training on labor and delivery outcomes: a systematic review with meta-analysis. AB - INTRODUCTION AND HYPOTHESIS: Pelvic floor muscle training (PFMT) has been widely used to prevent and treat urinary incontinence; however, the possible effect of antenatal PFMT on labor and delivery is still not clear. The purpose of the study was to investigate the possible effect of antenatal PFMT on labor and delivery. METHODS: A systematic review of the scientific literature was conducted in accordance with the preferred reporting items for systematic reviews and meta analyses (PRISMA) statement. Randomized or quasi-randomized controlled studies of an obstetric population who had done antenatal PFMT met the inclusion criteria. Data about labor and delivery outcomes included the first stage of labor, the second stage of labor, episiotomy, instrumental delivery, and perineal laceration. The nine English and four Chinese databases were searched from their inception through November 6, 2014. Fixed or random effects models were selected based on study heterogeneity. The weighted mean differences (WMDs) and odds ratios (ORs) with the corresponding 95 % confidence intervals (CIs) were calculated to assess the association between PFMT and the labor and delivery outcomes. RESULTS: Twelve studies were identified, involving a total of 2,243 women, in which 1,108 were PFMT and 1,135 controls. They indicated that PFMT during pregnancy significantly shortened the first and second stage of labor in the primigravida (WMD = -28.33, 95 % CI: -42.43 to -14.23, I(2) = 0.0 % , and WMD = -10.41, 95 % CI: -18.38 to -2.44, I(2) = 64.0 % respectively). In the subgroup analysis on the second stage of labor, heterogeneity decreased for subgroups of China and European countries (I(2) = 0.0 %, P = 0.768 and I(2) = 0.0 %, P = 0.750 respectively), but statistically significant association only existed in the subgroup of China (WMD = -17.42, 95 % CI: -23.41 to -11.43). When evaluating the effect on the rates of episiotomy, instrumental delivery and perineal laceration, the meta-analysis showed that the results were not significant (OR = 0.75, 95 % CI: 0.54 to 1.02; OR = 0.84, 95 % CI: 0.61 to 1.17 and OR = 0.96, 95 % CI: 0.66 to 1.40 respectively). CONCLUSIONS: Antenatal PFMT might be effective at shortening the first and second stage of labor in the primigravida. The moderate heterogeneity for the second stage of labor data need further study. Antenatal PFMT may not increase the risk of episiotomy, instrumental delivery, and perineal laceration in the primigravida. PMID- 25711729 TI - Contradictions in client-centred discharge planning: through the lens of relational autonomy. AB - BACKGROUND: While client-centred practice has received wide support, it remains difficult to apply in many practice settings. Identified barriers include constraints on time, resources, and services imposed by healthcare policies. Healthcare professionals' prioritizing of client safety over (other) interests that clients may name may further restrict the application of client-centred practice. Discharge planning is one area where such considerations can conflict. AIM: This paper presents a secondary analysis of data examining the process of discharge in one Canadian rehabilitation setting. It examines how discourses of client-centred practice and of prioritizing safety were reflected in discharge planning with older adults and considers the implications of potential conflicts between these discourses. METHOD: Taking a critical bioethics perspective informed by relational autonomy theory, microethnographic case studies were used to examine discharge planning from the perspectives of older adult clients and healthcare professionals. RESULTS: Healthcare professionals interpreted client centred practice to require abiding by client wishes, as long as this was safe; furthermore prioritizing safety took precedence over other considerations in discharge planning. CONCLUSION AND SIGNIFICANCE: Client-centred practice was not promoted in discharge planning processes in the research setting. Applying a relational autonomy lens to practice could promote approaches that better facilitate client-centred practice. PMID- 25711730 TI - Experiences among undocumented migrants accessing primary care in the United Kingdom: a qualitative study. AB - Immigration is a key political issue in the United Kingdom. The 2014 Immigration Act includes a number of measures intended to reduce net immigration, including removing the right of non-European Economic Area migrants to access free health care. This change risks widening existing health and social inequalities. This study explored the experiences of undocumented migrants trying to access primary care in the United Kingdom, their perspectives on proposed access restrictions, and suggestions for policymakers. Semi-structured interviews were conducted with 16 undocumented migrants and four volunteer staff at a charity clinic in London. Inductive thematic analysis drew out major themes. Many undocumented migrants already faced challenges accessing primary care. None of the migrants interviewed said that they would be able to afford charges to access primary care and most said they would have to wait until they were much more unwell and access care through Accident & Emergency (A&E) services. The consequences of limiting access to primary care, including threats to individual and public health consequences and the additional burden on the National Health Service, need to be fully considered by policymakers. The authors argue that an evidence-based approach would avoid legislation that targets vulnerable groups and provides no obvious economic or societal benefit. PMID- 25711731 TI - Coronary thrombus aspiration revealed tumorous embolism of myxofibrosarcoma from the left atrium. AB - Thrombus aspiration is currently the standard strategy for primary PCI. Thrombus can be aspirated via aspiration catheters, restoring coronary blood flow. However, there are a limited number of reports regarding thrombus aspiration toward tumor embolized occlusion. We present a case of 90-year-old male with AMI caused by the metastatic tumor embolism. Emergent coronary angiography revealed total occlusion in three epicardial vessels. Histopathological examination of the aspirated specimen revealed the mixture of thrombus and metastatic tumor cells. Thrombus aspiration was partially effective for restoring coronary blood flow; however, it was very helpful for the final diagnosis of tumor embolism. PMID- 25711732 TI - Descending aortic dissection injured by tip of the sheath during transcatheter aortic valve implantation. AB - An 86-year-old woman was referred for transcatheter aortic valve implantation (TAVI) because of recurrent severe aortic stenosis after balloon aortic valvuloplasty in May 2014. We planned to implant a 23-mm Sapien XT valve by transfemoral approach. During procedure, aortic dissection was detected by transesophageal echocardiography (TEE). The dissection limited to the descending aorta and did not include the ascending aorta. Therefore, our team decided to implant the 23-mm Sapien valve as planned. After the procedure, the dissection was treated conservatively without surgical repair. Three weeks later, she was discharged without any complications. PMID- 25711733 TI - Primary human papillomavirus testing. PMID- 25711734 TI - Increased expression of transcription factor Bcl-6 in chronic rhinosinusitis with nasal polyps. AB - B cell activation and excessive immunoglobulin (Ig) production were suggested as the key molecular events of chronic rhinosinusitis with nasal polyp (CRSwNP). However, whether T follicular cells (Tfh cells) were involved in this process has not been documented. In this study, 22 CRSwNP patients and 12 normal controls were enrolled, Bcl-6 (the key transcription factor for Tfh cell differentiation) immunoreactivity was examined by immunohistochemical staining, and the mRNA and protein expression of Bcl-6 and IL-21 was examined using qPCR, ELISA and Western blot, respectively. Moreover, the frequencies of Bcl-6(+)CD4(+) cells (Tfh cells) in polyp tissues and normal controls were measured by flow cytometry. We found that Bcl-6 mRNA and protein levels, as well as the frequencies of Bcl-6(+)CD4(+) cells were significantly increased in polyp tissues compared with normal controls. The frequencies of Bcl-6(+)CD4(+) cells were found to be significantly associated with B cell cluster formation, tissue eosinophilia, asthma comorbidity and polyp recurrence. These findings thus added a new insight into the molecular mechanisms underlying CRSwNP and raise the possibility that Tfh cells could be a novel therapeutic target for difficult-to-treat CRSwNP. PMID- 25711737 TI - Cisplatin versus cetuximab given concomitantly with radiotherapy in non resectable head and neck squamous cell carcinoma: an open question. PMID- 25711735 TI - Application of the European Test of Olfactory Capabilities in patients with olfactory impairment. AB - A central issue in olfaction concerns the characterization of loss of olfactory function: partial (hyposmia) or total (anosmia). This paper reports the application in a clinical setting of the European Test of Olfactory Capabilities (ETOC), combining odor detection and identification. The study included three phases. In phase 1, anosmics, hyposmics and controls were tested with the 16 items version of the ETOC. In phase 2, a short version of the ETOC was developed: patients with and controls without olfactory impairment were tested on a 6-items ETOC. In phase 3, to predict olfactory impairments in new individuals, the 16 items ETOC was administered on samples of young and older adults, and the 6-items version was applied in samples of young, elderly participants and Alzheimer patients. In phase 1, linear discriminant analysis (LDA) of ETOC scores classified patients and controls with 87.5 % accuracy. In phase 2, LDA provided 84 % correct classification. Results of phase 3 revealed: (1) 16-items ETOC: whereas in young adults, 10 % were classified as hyposmic and 90 % as normosmic, in elderly, 1 % were classified as anosmic, 39 % hyposmic and 60 % normosmic; (2) 6-items ETOC: 15 % of the young adults were classified as having olfactory impairment, compared to 28 % in the older group and 83 % in Alzheimer patients. In conclusion, the ETOC enables characterizing the prevalence of olfactory impairment in young subjects and in normal and pathological aging. Whereas the 16 items ETOC is more discriminant, the short ETOC may provide a fast (5-10 min) tool to assess olfaction in clinical settings. PMID- 25711736 TI - Stapes surgery: a National Survey of British Otologists. AB - To investigate individual stapes surgery practice in the UK, a retrospective study was conducted by postal questionnaire to all 'assumed' stapes-performing otologists. 225 questionnaires were sent out to practicing otologists in the UK. 184 replies (81.8 %) indicated that 134 (72.9 %) otologists perform stapes surgery [stapedectomy (8.2 %), stapedotomy (91.0 %) or other (0.8 %)]. The '6-10 stapes operation per year' category is the most common, with most using general anaesthetic (GA) (78.3 %). Unilateral surgery is advised in 89.6 %, and 96.3 % perform second-side surgery, with all advising the option of a hearing aid prior to surgery. The majority (88.1 %) would fit the prosthesis after removing the stapes, with the top three prostheses being Causse, Smart and Teflon (as described by respondents). 42.5 % always use a vein graft or fat to cover the fenestration, 9.3 % use a laser and 48.5 % carry out the surgery as a day case. For an overhanging facial nerve (less than 50 % of the footplate obscured), the majority stated that it would depend whether they would abandon surgery. 25.4 % have encountered a 'gusher' and 83.6 % would recommend revision surgery. 82.8 % have a registrar present when carrying out stapes operations, but 69.4 % only offer training to trainees with an otological interest. In the UK, stapedotomy is the preferred technique. Most prefer the Causse prosthesis, general anaesthesia and an inpatient stay. Hearing aids are advised prior to surgery. Day-case and inpatient practice is about equal. 'Gushers' are encountered rarely. Revision surgery is advised if a conductive loss returns. Flying is recommended from 6 weeks. Most otologists are willing to teach trainees with an otological interest. PMID- 25711738 TI - Teaching laryngeal electromyography. AB - To achieve consensus in the methodology, interpretation, validity, and clinical application of laryngeal electromyography (LEMG), a working group on neurolaryngology from the European Laryngological Society (ELS) was founded in 2010. The main task of the working group was to teach key techniques like LEMG procedures. The objective of this study was to collect information on the teaching techniques used and describe them. A multicenter registry was created to analyze the data collected from LEMGs in 14 departments. We screened how often different departments participated in teaching events. Teaching events were classified retrospectively: presentations at conferences and meetings; workshops with hands-on training on patients; workshops with hands-on training on animal models; workshops with hands-on training on anatomic specimens; and supervision by experts to perform LEMG together. Both, supervision to perform LEMG together and the total number of PCA-LEMGs (r = 0.713), as well as supervision to perform LEMG together and the PCA/total-number-of-LEMG ratio (r = 0.814) were correlated significantly (p < 0.05). Similarly, the sum of teaching events was correlated significantly with the total number of PCA-LEMGs (r = 0.605), and so did the sum of teaching events with the PCA/total-number-of-LEMG ratio (r = 0.704). Participation in hands-on training in humans was correlated significantly with the PCA/total-number-of-LEMG ratio (r = 0.640). The data presented herein suggest that multimodal teaching techniques are most effective. To promote multimodal learning an interactive webpage ( http://www.lemg.org) providing videos and animations, and the possibility to discuss cases with other experts was established. PMID- 25711739 TI - Predicting outcome in tracheal and cricotracheal segmental resection. AB - The aim of this study was to analyze prognostic factors of successful tracheal and cricotracheal segmental resection (TR/CTR), the type of revisions performed in cases of failure, and the outcome of revisions. The study is designed as case series with chart review. Between 1995 and 2011, 122 adult patients underwent TR/CTR. Forty-six patients (38 %) had concomitant airway pathologies and 59 patients (48 %) failed previous interventions. Forty-six patients (38 %) were aphonic with a complete obstruction. Cricotracheal, tracheotracheal, and thyrotracheal anastomosis was performed in 78 (64 %), 24 (20 %) and 20 (16 %) patients, respectively. Subglottic involvement, higher grade of obstruction, preoperative tracheostomy, presence of any concomitant airway pathology and impaired vocal cord movement were all associated with poorer outcome. Initially, 85 patients (68 %) achieved primary goal with no need for further intervention. Thirty-six patients underwent one or more revision surgeries (laser, dilatation, tracheostomy, stent or T-tube, laryngoplasty, segmental resection, posterior cordotomy) with a success rate of 69 %. Overall success rate, after revisions, was 88.5 %. Segmental tracheal resection for tracheal stenosis is highly successful in non-tracheotomized, cricoid sparing incomplete tracheal stenosis patients, without secondary airway pathologies. Initial failures of TR/CTR can be managed with revision surgery. PMID- 25711740 TI - Adenovirus Dodecahedron, a VLP, Can be Purified by Size Exclusion Chromatography Instead of Time-Consuming Sucrose Density Gradient Centrifugation. AB - Adenoviral dodecahedron (Dd) is a virus-like particle composed of twelve pentameric penton base (Pb) proteins, responsible for adenovirus cell penetration. It is generated spontaneously in the baculovirus system upon expression of the Pb gene of adenovirus serotype 3. This particle shows remarkable cell penetration ability with 2,00,000-3,00,000 Dd internalized into one cell in culture, conceivably delivering several millions of foreign cargo molecules to the target cell. We have used it in the past for delivery of small drugs as well as a vaccination platform, in which Dd serves as a particulate vaccine delivery system. Since development of new biomedicals depends strongly on the cost of their expression and purification, we attempted, albeit unsuccessfully, to obtain Dd expression in bacteria. We therefore retained its expression in the baculovirus/insect cells system but introduced significant improvements in the protocols for Dd expression and purification, leading to considerable savings in time and improved yield. PMID- 25711741 TI - Functional Characterization and Low-Resolution Structure of an Endoglucanase Cel45A from the Filamentous Fungus Neurospora crassa OR74A: Thermostable Enzyme with High Activity Toward Lichenan and beta-Glucan. AB - Biomass is the most abundant and short-term renewable natural resource on Earth whose recalcitrance toward enzymatic degradation represents significant challenge for a number of biotechnological applications. The not so abundant but critically necessary class of GH45 endoglucanases constitutes an essential component of tailored industrial enzyme cocktails because they randomly and internally cleave cellulose molecules. Moreover, GH45 glucanases are core constituents of major brand detergent formulations as well as enzymatic aid components in the cotton processing industry, clipping unwanted cellulosic fibers from cotton (cellulosic) based tissues. Here we report on a recombinant high-yield Neurospora crassa OR74A NcCel45A production system, a single-band GH45 endoglucanase purification, and a complete enzyme functional characterization. NcCel45A is a bimodular endoglucanase showing maximum activity at pH 6.0 and 60 degrees C, while most active against lichenan and beta-glucans and lesser active toward filter paper, carboxymethylcellulose, and phosphoric acid-swollen cellulose. Gluco oligosaccharide degradation fingerprinting experiments suggest cellopentaose as the minimal length substrate and ThermalFluor studies indicate that NcCel45A displays excellent stability at elevated temperatures up to 70 degrees C and pHs ranging from 5 to 9. Remarkably, we show that NcCel45A is uniquely resistant to a wide-range of organic solvents and small-angle X-ray scattering show a monkey wrench molecular shape structure in solution, which indicates, unlike to other known cellulases, a non-fully extended conformation, thus conferring solvent protection. These NcCel45A unique enzymatic properties maybe key for specific industrial applications such as cotton fiber processing and detergent formulations. PMID- 25711742 TI - A novel vascular pattern promotes metastasis of hepatocellular carcinoma in an epithelial-mesenchymal transition-independent manner. AB - Early metastasis is responsible for frequent relapse and high mortality of hepatocellular carcinoma (HCC), but its underlying mechanisms remain unclear. Epithelial-mesenchymal transition (EMT) has been considered a key event in metastasis. Based on histological examination of serial HCC sections and three dimensional reconstruction, we found a novel and prevalent vascular pattern, vessels that encapsulated tumor clusters (VETC) and formed cobweb-like networks. The presence of VETC (VETC(+) ) predicted higher metastasis and recurrence rates of HCC. Using clinical samples and mouse xenograft models, we further showed that VETC was composed of functional vessels with blood perfusion and induced by tumor cells at the early stage of HCC. Subsequent investigations revealed that HCC cell derived angiopoietin-2 was a prerequisite for VETC formation and that the VETC pattern was a critical factor promoting HCC metastasis as knockdown of angiopoietin-2 abolished this vascular pattern and consequently attenuated in vivo tumor metastasis. Interestingly, abrogation of EMT by knockdown of Snail or Slug significantly diminished in vivo metastasis of VETC(-) xenografts but did not affect that of VETC(+) ones, although silencing of Snail or Slug substantially reduced the in vitro migration of both VETC(+) and VETC(-) HCC cells. In contrast to human VETC(-) cases, EMT signatures were rarely observed in VETC(+) cases with metastatic potential. Further analysis revealed that VETC provided an efficient metastasis mode by facilitating the release of whole tumor clusters into the bloodstream. CONCLUSION: Our findings identify a novel metastasis mechanism that relies on vascular pattern but is independent of EMT, which may provide new targets for antimetastasis therapy and offer a basis for selecting patients who may benefit from certain molecularly targeted drugs. PMID- 25711743 TI - Wound-healing effect of electrospun gelatin nanofibres containing Centella asiatica extract in a rat model. AB - Centella asiatica (CA) is a traditional herbal medicine that has been shown to exert pharmacological effects on wound healing. This study demonstrated that CA extract facilitates the wound-repair process by promoting fibroblast proliferation and collagen synthesis and exhibits antibacterial activity. Gelatin nanofibres containing C. asiatica extract were fabricated via electrospinning and were shown to exhibit dermal wound-healing activity in a rat model. The wound areas of rat skin treated with electrospun gelatin membranes containing C. asiatica (EGC) presented the highest recovery rate compared with those treated with gauze, neat gelatin membranes and commercial wound dressings. The results of the histopathological examination support the outcome of the wound models. Contact-angle and water-retention measurements confirmed that the addition of C. asiatica extract did not significantly affect the hydrophilicity of the EGC membranes. The measured weight loss revealed that the EGC membranes are biodegradable. The findings suggest that EGC membranes are a promising material for the treatment of skin wounds. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 25711744 TI - Ectomycorrhizal fungal communities of Coccoloba uvifera (L.) L. mature trees and seedlings in the neotropical coastal forests of Guadeloupe (Lesser Antilles). AB - We studied belowground and aboveground diversity and distribution of ectomycorrhizal (EM) fungal species colonizing Coccoloba uvifera (L.) L. (seagrape) mature trees and seedlings naturally regenerating in four littoral forests of the Guadeloupe island (Lesser Antilles). We collected 546 sporocarps, 49 sclerotia, and morphotyped 26,722 root tips from mature trees and seedlings. Seven EM fungal species only were recovered among sporocarps (Cantharellus cinnabarinus, Amanita arenicola, Russula cremeolilacina, Inocybe littoralis, Inocybe xerophytica, Melanogaster sp., and Scleroderma bermudense) and one EM fungal species from sclerotia (Cenococcum geophilum). After internal transcribed spacer (ITS) sequencing, the EM root tips fell into 15 EM fungal taxa including 14 basidiomycetes and 1 ascomycete identified. Sporocarp survey only weakly reflected belowground assessment of the EM fungal community, although 5 fruiting species were found on roots. Seagrape seedlings and mature trees had very similar communities of EM fungi, dominated by S. bermudense, R. cremeolilacina, and two Thelephoraceae: shared species represented 93 % of the taxonomic EM fungal diversity and 74 % of the sampled EM root tips. Furthermore, some significant differences were observed between the frequencies of EM fungal taxa on mature trees and seedlings. The EM fungal community composition also varied between the four investigated sites. We discuss the reasons for such a species-poor community and the possible role of common mycorrhizal networks linking seagrape seedlings and mature trees in regeneration of coastal forests. PMID- 25711745 TI - [Survey on avoidable blindness and visual impairment in Panama]. AB - OBJECTIVE: Determine prevalence of blindness and visual impairment in adults aged >= 50 years in Panama, identify their main causes, and characterize eye health services. METHODS: Cross-sectional population study using standard Rapid Assessment of Avoidable Blindness methodology. Fifty people aged >= 50 years were selected from each of 84 clusters chosen through representative random sampling of the entire country. Visual acuity was assessed using a Snellen chart; lens and posterior pole status were assessed by direct ophthalmoscopy. Cataract surgery coverage was calculated and its quality assessed, along with causes of visual acuity < 20/60 and barriers to access to surgical treatment. RESULTS: A total of 4 125 people were examined (98.2% of the calculated sample). Age- and sex adjusted prevalence of blindness was 3.0% (95% CI: 2.3-3.6). The main cause of blindness was cataract (66.4%), followed by glaucoma (10.2%). Cataract (69.2%) was the main cause of severe visual impairment and uncorrected refractive errors were the main cause of moderate visual impairment (60.7%). Surgical cataract coverage in individuals was 76.3%. Of all eyes operated for cataract, 58.0% achieved visual acuity <= 20/60 with available correction. CONCLUSIONS: Prevalence of blindness in Panama is in line with average prevalence found in other countries of the Region. This problem can be reduced, since 76.2% of cases of blindness and 85.0% of cases of severe visual impairment result from avoidable causes. PMID- 25711746 TI - [Priority research agendas: a strategic resource for health in Latin America]. AB - OBJECTIVE: Understand and analyze procedures used to create national integrated research agendas from 2007 to 2011 in Argentina, Guatemala, Mexico, Panama, and Paraguay. METHODS: Descriptive, cross-sectional study using an online survey of agenda preparation processes; specifically, development, integration, implementation, and use and dissemination of the agenda. RESULTS: The 45 respondents reported following specific methodologies for agenda construction and had a good opinion of organizational aspects with regard to prior information provided and balance among disciplines and stakeholders. Some 60% considered the coordinators impartial, although 25% mentioned biases favoring some subject; 42% received technical support from consultants, reading matter, and methodological guidelines; 40% engaged in subject-matter priority-setting; and 55% confirmed dissemination and communication of the agenda. However, only 22% reported inclusion of agenda topics in national calls for research proposals. CONCLUSIONS: In the countries studied, development of the health research agenda was characterized by prior planning and appropriate organization to achieve - consensus-based outcomes. Nevertheless, the agendas were not used in national calls for research proposals, reflecting lack of coordination in national health research systems and lack of connection between funders and researchers. It is recommended that stakeholders strengthen integration and advocacy efforts to modify processes and structures of agenda-based calls for research proposals. PMID- 25711747 TI - The 2008 Global Burden of Disease study in Brazil: a new methodological approach for estimation of injury morbidity. AB - OBJECTIVE: To present the methodological approach used to estimate injury morbidity (Years Lived with Disability, YLD) in the 2008 Global Burden of Disease study in Brazil (GBD-Br). METHODS: YLD was based on the admission rate for injuries from both public and private sector facilities. Morbidity arising from emergency room (ER) visits was estimated using logistic regression models of the likelihood of hospitalization for different types of injuries, controlling for sex, age and geographic region. Data was obtained from the Mortality Information System, the Hospitalization Information System of the Unified Health System and the 2009 survey for the Surveillance System for Violence and Accidents (VIVA). RESULTS: Injuries accounted for 10.0% of the total burden of disease in Brazil in 2008, corresponding to 19 years of life lost per 100 000 inhabitants. YLD accounted for 10% of total years of life lost. CONCLUSIONS: This approach represents a methodological advance, particularly due to the inclusion of the VIVA survey, which provides a more reliable measurement of the burden of injury in Brazil than other sources. PMID- 25711748 TI - Chronic kidney disease among children in Guatemala. AB - OBJECTIVE: To describe the distribution of pediatric chronic kidney disease (CKD) in Guatemala, estimate incidence and prevalence of pediatric end-stage renal disease (ESRD), and estimate time to progress to ESRD. METHODS: This study analyzed the registry of the only pediatric nephrology center in Guatemala, from 2004-2013. Incidence and prevalence were calculated for annual periods. Moran's index for spatial autocorrelation was used to determine significance of geographic distribution of incidence. Time to progress to ESRD and associated risk factors were calculated with multivariate Cox regression. RESULTS: Of 1 545 patients from birth to less than 20 years of age, 432 had chronic renal failure (CRF). Prevalence and incidence of ESRD were 4.9 and 4.6 per million age-related population, respectively. Incidence was higher for the Pacific coast and Guatemala City. The cause of CRF was undetermined in 43% of patients. Average time to progress to ESRD was 21.9 months; factors associated with progression were: older age, diagnosis of glomerulopathies, and advanced-stage CKD at consultation. CONCLUSIONS: Prevalence and incidence of ESRD in Guatemala are lower than in other countries. This may reflect poor access to diagnosis. Areas with higher incidence and large proportion of CKD of undetermined cause are compatible with other studies from the geographic subregion. Findings on progression to ESRD may reflect delayed referral. PMID- 25711749 TI - Lessons learned in evaluating the Familias Fuertes program in three countries in Latin America. AB - This report describes 1) the evaluation of the Familias Fuertes primary prevention program in three countries (Bolivia, Colombia, and Ecuador) and 2) the effect of program participation on parenting practices. Familias Fuertes was implemented in Bolivia (10 groups, 96 parents), Colombia (12 groups, 173 parents), and Ecuador (five groups, 42 parents) to prevent the initiation and reduce the prevalence of health-compromising behaviors among adolescents by strengthening family relationships and enhancing parenting skills. The program consists of seven group sessions (for 6-12 families) designed for parents/caregivers and their 10-14-year-old child. Parents/caregivers answered a survey before the first session and at the completion of the program. The survey measured two important mediating constructs: "positive parenting" and "parental hostility." The Pan American Health Organization provided training for facilitators. After the program, parents/caregivers from all three countries reported significantly higher mean scores for "positive parenting" and significantly lower mean scores for "parental hostility" than at the pre-test. "Positive parenting" practices paired with low "parental hostility" are fundamental to strengthening the relationship between parents/caregivers and the children and reducing adolescents' health-compromising behaviors. More research is needed to examine the long-term impact of the program on adolescent behaviors. PMID- 25711750 TI - Diabetes among Latinos in the Southwestern United States: border health and binational cooperation. AB - This analysis reviews cooperation between the four border states of the United States of America (Arizona, California, New Mexico, and Texas) and international partners in Mexico with regard to type 2 diabetes among Latinos. Binational cooperation, academic collaboration, preventative health initiatives, and efforts to improve health care access for the border population are highlighted. This meta-analysis of the literature points out causative factors of the increased type 2 diabetes prevalence among Latinos in the United States; an inverse correlation between diabetes and education and socioeconomic level; contributing factors, including barriers with language, health care payment, transportation, and underestimating diabetes implications; and a lack of social and environmental support for disease management. Medical and indirect costs in socioeconomic terms are also included. Cooperation between the United States and Mexico may be beneficial to promoting further collaborative efforts between these nations, and serve as a template for greater cooperative efforts to mitigate the substantial public health and socioeconomic implications of type 2 diabetes globally. PMID- 25711751 TI - Adverse drug reactions associated with the use of disease-modifying anti rheumatic drugs in patients with rheumatoid arthritis. AB - This study describes the adverse drug reactions (ADRs) and their incidence in patients with rheumatoid arthritis who were treated in the Colombian health system. A retrospective cohort study was conducted using information from all patients who were diagnosed with rheumatoid arthritis and attended specialized health care centers in the cities of Bogota, Cali, Manizales, Medellin, and Pereira between 1 December 2009 and 30 August 2013. The ADRs were obtained from medical records and the pharmacovigilance system registry and sorted by frequency and affected tissue according to World Health Organization Adverse Reaction Terminology (WHO-ART). A total of 949 reports of ADRs were obtained from 419 patients (32.8 ADRs per 100 patient-years); these patients were from a cohort of 1,364 patients being treated for rheumatoid arthritis and followed up for an average of 23.8 months (+/- 12.9). The cohort was mostly female (366, 87.4%) and had a mean age of 52.7 years (+/- 13.1). The highest numbers of ADRs were reported following the use of tocilizumab, rituximab, and infliximab (28.8, 23.1, and 13.3 reports per 100 patient-years respectively). The most frequently reported ADRs were elevated transaminase levels and dyspepsia. Overall, 87.7% of ADRs were classified as type A, 36.6% as mild, 40.7% as moderate, and 22.7% as severe. As a result, 73.2% of patients who experienced an ADR stopped taking their drugs. The occurrence of ADRs in patients treated for rheumatoid arthritis is common, especially in those associated with the use of biotechnologically produced anti-rheumatic drugs. This outcome should be studied in future research and monitoring is needed to reduce the risks in these patients. PMID- 25711753 TI - EPOS 34th Annual Meeting. PMID- 25711754 TI - IFPOS 34th Annual Meeting. PMID- 25711752 TI - [Preparedness for natural disasters among older US adults: a nationwide survery]. AB - OBJECTIVES: We sought to determine natural disaster preparedness levels among older US adults and assess factors that may adversely affect health and safety during such incidents. METHODS: We sampled adults aged 50 years or older (n = 1 304) from the 2010 interview survey of the Health and Retirement Study. The survey gathered data on general demographic characteristics, disability status or functional limitations, and preparedness-related factors and behaviors. We calculated a general disaster preparedness score by using individual indicators to assess overall preparedness. RESULTS: Participant (n = 1 304) mean age was 70 years (SD = 9.3). Only 34.3% reported participating in an educational program or reading materials about disaster preparation. Nearly 15% reported using electrically powered medical devices that might be at risk in a power outage. The preparedness score indicated that increasing age, physical disability, and lower educational attainment and income were independently and significantly associated with worse overall preparedness. CONCLUSIONS: Despite both greater vulnerability to disasters and continuous growth in the number of older US adults, many of the substantial problems discovered are remediable and require attention in the clinical, public health, and emergency management sectors of society. PMID- 25711755 TI - IFPOS 34th Annual Meeting. PMID- 25711757 TI - Childhood ODD and ADHD Behavior: The Effect of Classroom Sharing, Gender, Teacher Gender and Their Interactions. AB - One criterion for a diagnostic and statistical manual of mental disorders (DSM IV) diagnosis of attention deficit hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD) is that symptoms are present in at least two settings, and often teacher ratings are taken into account. The short Conners' Teacher Rating Scales-Revised (CTRS-R) is a widely used standardized instrument measuring ODD and ADHD behavior in a school setting. In the current study CTRS-R data were available for 7, 9 and 12-year-old twins from the Netherlands Twin Register. Measurement invariance (MI) across student gender and teacher gender was established for three of the four scales (Oppositional Behavior, Hyperactivity and ADHD Index) of the CTRS-R. The fourth scale (ATT) showed an unacceptable model fit even without constraints on the data and revision of this scale is recommended. Gene-environment (GxE) interaction models revealed that heritability was larger for children sharing a classroom. There were some gender differences in the heritability of ODD and ADHD behavior and there was a moderating effect of teacher's gender at some of the ages. Taken together, this indicates that there was evidence for GxE interaction for classroom sharing, gender of the student and gender of the teacher. PMID- 25711758 TI - Mass cytometry analysis shows that a novel memory phenotype B cell is expanded in multiple myeloma. AB - It would be very beneficial if the status of cancers could be determined from a blood specimen. However, peripheral blood leukocytes are very heterogeneous between individuals, and thus high-resolution technologies are likely required. We used cytometry by time-of-flight and next-generation sequencing to ask whether a plasma cell cancer (multiple myeloma) and related precancerous states had any consistent effect on the peripheral blood mononuclear cell phenotypes of patients. Analysis of peripheral blood samples from 13 cancer patients, 9 precancer patients, and 9 healthy individuals revealed significant differences in the frequencies of the T-cell, B-cell, and natural killer-cell compartments. Most strikingly, we identified a novel B-cell population that normally accounts for 4.0% +/- 0.7% (mean +/- SD) of total B cells and is up to 13-fold expanded in multiple myeloma patients with active disease. This population expressed markers previously associated with both memory (CD27(+)) and naive (CD24(lo)CD38(+)) phenotypes. Single-cell immunoglobulin gene sequencing showed polyclonality, indicating that these cells are not precursors to the myeloma, and somatic mutations, a characteristic of memory cells. SYK, ERK, and p38 phosphorylation responses, and the fact that most of these cells expressed isotypes other than IgM or IgD, confirmed the memory character of this population, defining it as a novel type of memory B cells. PMID- 25711759 TI - Robust Antitumor Effects of Combined Anti-CD4-Depleting Antibody and Anti-PD-1/PD L1 Immune Checkpoint Antibody Treatment in Mice. AB - Depletion of CD4(+) cells in tumor-bearing mice has strong antitumor effects. However, the mechanisms underlying these effects and the therapeutic benefits of CD4(+) cell depletion relative to other immunotherapies have not been fully evaluated. Here, we investigated the antitumor effects of an anti-CD4-depleting mAb as a monotherapy or in combination with immune checkpoint mAbs. In B16F10, Colon 26, or Lewis lung carcinoma subcutaneous tumor models, administration of the anti-CD4 mAb alone had strong antitumor effects that were superior to those elicited by CD25(+) Treg depletion or other immune checkpoint mAbs, and which were completely reversed by CD8(+) cell depletion. CD4(+) cell depletion led to the proliferation of tumor-specific CD8(+) T cells in the draining lymph node and increased infiltration of PD-1(+)CD8(+) T cells into the tumor, with a shift toward type I immunity within the tumor. Combination treatment with the anti-CD4 mAb and immune checkpoint mAbs, particularly anti-PD-1 or anti-PD-L1 mAbs, synergistically suppressed tumor growth and greatly prolonged survival. To our knowledge, this work represents the first report of robust synergy between anti CD4 and anti-PD-1 or anti-PD-L1 mAb therapies. PMID- 25711765 TI - Enzalutamide: a review of its use in chemotherapy-naive metastatic castration resistant prostate cancer. AB - Enzalutamide (Xtandi((r))) is an androgen receptor inhibitor that blocks several steps in the androgen receptor signalling pathway. This article reviews the clinical efficacy and tolerability of oral enzalutamide in chemotherapy-naive men with metastatic castration-resistant prostate cancer (CRPC), as well as summarizing its pharmacological properties. In the randomized, double-blind, multinational PREVAIL trial, enzalutamide significantly improved both radiographic progression-free survival and overall survival versus placebo in chemotherapy-naive men with metastatic CRPC who were asymptomatic or mildly symptomatic. In addition, enzalutamide significantly delayed the need for chemotherapy and the decline in health-related quality of life versus placebo. Enzalutamide was generally well tolerated in chemotherapy-naive men with metastatic CRPC. In conclusion, enzalutamide is a convenient, effective and well tolerated treatment for chemotherapy-naive men with metastatic CRPC who are asymptomatic or mildly symptomatic. PMID- 25711766 TI - Response to: comment on "Delayed methotrexate excretion in infants and young children with primary central nervous system tumors and postoperative fluid collections". PMID- 25711767 TI - Editorial Comment to Prognostic significance of visceral obesity in patients with advanced renal cell carcinoma undergoing nephrectomy. PMID- 25711768 TI - A tadpole-shaped gene carrier with distinct phase segregation in a ternary polymeric micelle. AB - A distinct tadpole-shaped nanostructure characterized by a spherical head and an extended shaft was identified in a single plasmid DNA (pDNA)-based polymeric micelle. The tadpole-shaped structure was constructed by adding anionic chondroitin sulfate (CS) to the rod-shaped polyplex micelle containing a single pDNA molecule packaged by the PEG-polycation block copolymer through their electrostatic self-assembly. The complex consequently developed a novel structure composed of segregated domains of the CS-rich inflated head and CS-poor folded DNA tail. Hence, this tadpole structure can be regarded as evidence that distinct phase segregation occurred in a single polymeric micelle containing pDNA. PMID- 25711769 TI - Alfaxalone anesthesia by immersion in oriental fire-bellied toads (Bombina orientalis). AB - OBJECTIVES: To establish an effective alfaxalone concentration to be used for bath immersion of fire-bellied toads (Bombina orientalis) and to describe its effects. STUDY DESIGN: Prospective experimental study. ANIMALS: Thirteen oriental fire-bellied toads. METHODS: The study was carried out in two phases. The pilot phase involved five animals and aimed to identify an alfaxalone concentration capable of producing induction of anesthesia, defined as immobility with a head down position and loss of responsiveness to stimulation with a stick. The following trial in an additional eight toads used the effective alfaxalone concentration established during the pilot phase. Data from 11 animals (three toads in the pilot study and the eight additional toads) were analyzed. Twenty minutes after immersion in the anesthetic solution, the toads were removed from the bath, and heart rate, respiratory rate, the righting, myotactic and the nociceptive withdrawal reflexes were evaluated every 5 minutes. The loss of both righting and nociceptive withdrawal reflexes was considered indicative of a surgical depth of anesthesia. The time elapsed from anesthetic induction to return of righting reflex, the quality of recovery and the occurrence of undesired effects were observed and recorded. RESULTS: Immersion was found to be a suitable anesthetic technique for oriental fire-bellied toads and 200 mg L(-1) alfaxalone concentration produced anesthetic induction in 10 out of 11 toads. Side effects, such as skin irritation, erythema and changes in cutaneous pigmentation, were not observed in any animal. The duration of anesthesia ranged from 10 to 30 minutes after removal of the toads from the alfaxalone bath, and surgical depth of anesthesia was never achieved. CONCLUSIONS AND CLINICAL RELEVANCE: It was concluded that alfaxalone anesthesia induced by immersion in a concentration of 200 mg L(-1) is only suitable for toads undergoing non-invasive short procedures. PMID- 25711770 TI - The biological effect of the nitroimidazole derivative of a polypyridyl ruthenium complex on cancer and endothelial cells. AB - The ruthenium polypyridyl complexes [Ru(dip)2(bpy/bpy-2-nitroIm)](2+) (dip = 4,7 diphenyl-1,10-phenanthroline, bpy = 2,2'-bipyridine, bpy-2-nitroIm = 4-[3-(2 nitro-1H-imidazol-1-yl)propyl]) were found to be ca. ten times more cytotoxic against breast cancer (4T1) and human lung adenocarcinoma epithelial cells (A549) than a well-known anticancer drug, cisplatin. Even though the Ru complexes were quite cytotoxic towards FVB mouse lung microvascular endothelial cells (MLuMEC FVB) their efflux from these non transformed cells was much more efficient than from cancer ones. Both Ru complexes accumulated in cells. The cellular uptake of both Ru complexes occurs through passive diffusion while the nitroimidazole derivative is also endocytosed. They arrest cell growth in the S-phase and induce apoptosis. Such cell response can result from activation of oxidative stress by Ru complexes. The modulation of the mRNA expression profile for genes which might be involved in metastasis and angiogenesis processes by Ru complexes was analyzed for both cancer (4T1) and endothelial (MLuMEC FVB) cells. Ru complexes appeared to have a distinct impact on cell adhesion and migration as well as they affect endothelial cell vasculature. They are not only cytotoxic but are also potentially invasive and anti-metastatic agents. This work illustrates the putative future development of polypyridyl ruthenium. PMID- 25711771 TI - Combined heart-liver transplantation: a single-center experience. AB - Combined orthotopic heart and liver transplantation (CHLT) is a lifesaving procedure for patients with end-stage heart-liver disease. We reviewed the long term outcome of patients who have undergone CHLT at the University of Bologna, Italy. Fifteen patients with heart and liver failure were placed on the transplant list between November 1999 and March 2012. The pretransplant cardiac diagnoses were familial amyloidosis in 14 patients and chronic heart failure due to chemotherapy with liver failure due to chronic hepatitis in one patient. CHLT was performed as a single combined procedure in 14 hemodynamically stable patients; there was no peri-operative mortality. The survival rates for the CHLT recipients were 93%, 93%, and 82% at 1 month and 1 and 5 years, respectively. Freedom from graft rejection was 100%, 90%, and 36% at 1, 5, and 10 years, respectively, for the heart graft and 100%, 91%, and 86% for the liver graft. The livers of eight recipients were transplanted as a "domino" with mean overall 1 year survival of 93%. Simultaneous heart and liver transplantation is feasible and was achieved in this extremely sick cohort of patients. By adopting the domino technique, we were able to enlarge the donor cohort and include high-risk patients. PMID- 25711772 TI - Unsettled weather and the end for thiopental? Obstetric general anaesthesia after the NAP5 and MBRRACE-UK reports. PMID- 25711773 TI - Combined radiological and surgical management of spinal dural fistulas. AB - INTRODUCTION: Spinal Dural Fistulas (SDAVF) are the most common Spinal Vascular Malformation. The management of SDAVFs involves diagnosis and localisation with MRI and spinal angiography and subsequent embolisation or surgical interruption. We report our experience in treating these fistulas in which we undertake endovascular treatment, if technically feasible, with recourse to surgery only if occlusion is not possible. METHOD: This retrospective study reviews the management of 38 patients treated for SDAVFs over a 13-year period (1997-2010). Patient demographics, procedure and follow-up over a 6-12-month period (mean of approximately 10 months) were analysed and a qualitative assessment of patient outcome was made. RESULTS: Patient ages ranged from 20 to 86 (mean 63.5), with 27 male and 11 female patients. A total of 28 patients managed with a combination of embolisation and surgery report either with improved symptoms or a return to normal. The presence of bladder and bowel symptoms indicated more severe disability and their presence at presentation was associated with lack of improvement following treatment. CONCLUSIONS: We report a treatment strategy for SDAVF involving primary endovascular intervention and reserving surgery for those patients in whom endovascular treatment is not possible. PMID- 25711774 TI - Quantum computation under micromotion in a planar ion crystal. AB - We propose a scheme to realize scalable quantum computation in a planar ion crystal confined by a Paul trap. We show that the inevitable in-plane micromotion affects the gate design via three separate effects: renormalization of the equilibrium positions, coupling to the transverse motional modes, and amplitude modulation in the addressing beam. We demonstrate that all of these effects can be taken into account and high-fidelity gates are possible in the presence of micromotion. This proposal opens the prospect to realize large-scale fault tolerant quantum computation within a single Paul trap. PMID- 25711775 TI - A Case Study on Promoting Neuroplasticity in a Patient With Schizophrenia. AB - PURPOSE: The purpose of this study is to introduce the concept of neuroplasticity, explore strategies that psychiatric nurse practitioners can use to improve cognitive functioning, and apply these strategies to a case study of a patient diagnosed with schizophrenia. DESIGN AND METHODS: This study used an explanatory descriptive approach with a single-case study to describe cognitive functioning in people with schizophrenia and to illustrate practical implications. FINDINGS: Schizophrenia is a severe mental illness with typical onset in late adolescence and young adulthood. Cognitive impairment often accompanies schizophrenia and may lead to significant functional impairment. Research demonstrates that the brain is able to change (neuroplasticity) in response to environmental stimuli either negatively or positively. Evidence suggests intervention, including cognitive remediation, physical activity, and sleep, can positively modify neuroplasticity in schizophrenia and improve cognitive function, which may lead to improved quality of life. PRACTICE IMPLICATIONS: Psychiatric mental health nurses need to offer cognitive enhancing strategies to take advantage of neuroplasticity. Ongoing nursing education regarding therapeutic neurocognitive approaches from basic research should be emphasized. PMID- 25711776 TI - New NIR-emissive tetranuclear Er(III) complexes with 4-hydroxo-2,1,3 benzothiadiazolate and dibenzoylmethanide ligands: synthesis and characterization. AB - New tetranuclear heteroleptic complexes [Er4(dbm)6(O-btd)4(OH)2] (1) and [Er4(dbm)4(O-btd)6(OH)2] (2) (O-btd = 4-hydroxo-2,1,3-benzothiadiazolate and dbm = dibenzoylmethanide) and their solvates with toluene, THF and CH2Cl2 were prepared using two synthetic approaches. The structures of the products were confirmed by single-crystal X-ray diffraction. Magnetic properties of 1 and 2 are in good agreement with X-ray data. The effective magnetic moment (MUeff) values at 300 K for 1 and 2 corresponds to a system of 4 non-interacting Er(III) ions in the ground state 4J15/2 with g = 6/5. At ambient temperature and upon excitation with lambdaexc = 450 nm, complexes 1 and 2 exhibit luminescence at 1530 nm, i.e. in the near infra-red (NIR) region. The luminescence intensity grows with increasing the number of the (O-btd)- ligands in the complexes. This observation suggests (O-btd)- as a new efficient antenna ligand for the lanthanide-based NIR luminescence. PMID- 25711777 TI - Prognosis of Japanese patients with previously untreated metastatic renal cell carcinoma in the era of molecular-targeted therapy. AB - A multicenter cooperative study was conducted to clarify the prognosis of Japanese patients with metastatic renal cell carcinoma in the era of molecular targeted therapy and the clinical usefulness of the Japanese metastatic renal cancer (JMRC) prognostic classification. Of 389 consecutive patients for whom treatment was started between 2008 and 2010 at 23 hospitals in Japan, 357 patients who received vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFR-TKI) or cytokine as initial systemic therapy were the subject of the present study. Patients were classified into three prognostic groups according to the JMRC prognostic classification. The endpoints were progression free survival (PFS) and overall survival (OS) after the start of the initial treatment. The median PFS and OS for the entire cohort of 357 patients were 9.1 and 27.2 months, respectively. VEGFR-TKI were selected for patients with multiple organ metastases, those with liver metastasis, and those with bone metastasis. The median PFS and OS were 11.0 and 23.2 months and 5.4 and 38.2 months in the VEGFR-TKI group and the cytokines group, respectively. The JMRC prognostic classification was useful as a prognostic model for PFS and OS (c-indexes: 0.613 and 0.630 in patients who initially received VEGFR-TKI and 0.647 and 0.642 in patients who received cytokines, respectively). The present study showed for the first time the prognosis of Japanese patients with metastatic renal cell carcinoma in the era of molecular-targeted therapy. The JMRC prognostic classification may be clinically useful as a prognostic model. PMID- 25711778 TI - Nurse-led educational interventions on cancer pain outcomes for oncology outpatients: a systematic review. AB - BACKGROUND: Cancer pain management is still unsatisfactory, although some effective guidelines exist. Educational interventions are reported to be useful in pain relief for oncology outpatients. AIM: The aims of this systematic review were to evaluate the effects of nurse-led educational interventions on improving cancer pain outcomes for oncology patients, and to establish an effective cancer pain protocol for clinical nursing practice in China. METHODS: A three-step search strategy was utilized. Eight databases were searched using the standards provided by the Joanna Briggs Institute that guided article selection, critical appraisal, data collection and data synthesis. RESULTS: A total of 1093 studies were identified through a literature search. Only six studies complied with the inclusion criteria and were found to be methodologically sound. In general, the included studies indicated positive results pertaining to patient's knowledge and attitudes towards analgesics and cancer pain management and decreased pain intensity. Studies reported minimal effects of intervention on anxiety, depression, satisfaction regarding cancer pain management and patient's quality of life. CONCLUSIONS: Educational interventions were reported as effective methods to improve cancer pain outcomes. Analysis of the six included studies demonstrated the overall positive effects of nurse-led educational interventions for improving cancer pain management. IMPLICATIONS FOR NURSING AND HEALTH POLICY: The results suggest that an effective cancer pain protocol for improving cancer pain management can be established in China. PMID- 25711779 TI - Response to "DRD2 Ser311Cys polymorphism and risk of schizophrenia". PMID- 25711781 TI - The expression of leptin, hypothalamic neuropeptides and UCP1 before, during and after fattening in the Daurian ground squirrel (Spermophilus dauricus). AB - The Daurian ground squirrel (Spermophilus dauricus) accumulates large amounts of body fat during pre-hibernation fattening. Leptin, an adipose-derived hormone, plays important roles in energy balance and thermogenesis. We predicted that body fat accumulation would lead to the elevation of leptin concentration while its effect on satiety would be suppressed in hypothalamus during fattening. In addition, the uncoupling protein 1 (UCP1) in brown adipose tissue (BAT) would increase and correlated positively with leptin concentration before hibernation. Here, we measured serum leptin concentration and leptin mRNA in white adipose tissue (WAT), hypothalamic neuropeptides involved in energy regulation and UCP1 in BAT before, during and after fattening in squirrels. The fat mass gradually increased during fattening but serum leptin increased mainly in the late phase of fattening, which was consistent with leptin mRNA expression in WAT. During fattening, the mRNA of hypothalamic leptin receptor was up-regulated and correlated positively with serum leptin. Orexigenic neuropeptide Y mRNA increased by 67%; however agouti-related peptide remained unchanged before hibernation. There was no significant change in anorexigenic neuropeptide mRNA. No change in suppressor of cytokine signaling-3 and protein tyrosine phosphatase-1B was detected. UCP1 mRNA expression and protein content in BAT increased significantly after fattening. These changes were independent of environmental conditions and serum leptin concentration. Our results suggest that the dissociation of leptin production and adiposity during fattening may facilitate fat accumulation. No evidence of suppressed leptin signal was found in fattening squirrels. The UCP1 recruitment in post-fattening squirrels could occur without winter-like acclimation and increased leptin. PMID- 25711782 TI - [Palliative care by the family physician]. PMID- 25711783 TI - [CME]. PMID- 25711780 TI - Challenges and opportunities in developmental integrative physiology. AB - This review explores challenges and opportunities in developmental physiology outlined by a symposium at the 2014 American Physiological Society Intersociety Meeting: Comparative Approaches to Grand Challenges in Physiology. Across animal taxa, adverse embryonic/fetal environmental conditions can alter morphological and physiological phenotypes in juveniles or adults, and capacities for developmental plasticity are common phenomena. Human neonates with body sizes at the extremes of perinatal growth are at an increased risk of adult disease, particularly hypertension and cardiovascular disease. There are many rewarding areas of current and future research in comparative developmental physiology. We present key mechanisms, models, and experimental designs that can be used across taxa to investigate patterns in, and implications of, the development of animal phenotypes. Intraspecific variation in the timing of developmental events can be increased through developmental plasticity (heterokairy), and could provide the raw material for selection to produce heterochrony--an evolutionary change in the timing of developmental events. Epigenetics and critical windows research recognizes that in ovo or fetal development represent a vulnerable period in the life history of an animal, when the developing organism may be unable to actively mitigate environmental perturbations. 'Critical windows' are periods of susceptibility or vulnerability to environmental or maternal challenges, periods when recovery from challenge is possible, and periods when the phenotype or epigenome has been altered. Developmental plasticity may allow survival in an altered environment, but it also has possible long-term consequences for the animal. "Catch-up growth" in humans after the critical perinatal window has closed elicits adult obesity and exacerbates a programmed hypertensive phenotype (one of many examples of "fetal programing"). Grand challenges for developmental physiology include integrating variation in developmental timing within and across generations, applying multiple stressor dosages and stressor exposure at different developmental timepoints, assessment of epigenetic and parental influences, developing new animal models and techniques, and assessing and implementing these designs and models in human health and development. PMID- 25711785 TI - [Specifics of Analgesia in Palliative Care Patients at Home]. AB - Pain management at home for a patient, suffering from one or more advanced progressive diseases, goes beyond the prescription of an opioid. Apart from the importance of finding the most suitable analgesic drug (controlled pain with least possible adverse effects), three important dimensions will be addressed: interprofessionnal care (shared care goals, evaluation, monitoring of pain and other symptoms; physiotherapy, etc.) information, education and support for patients and relatives in particular on the use of opioids, and finally the importance of anticipation. This includes for example the requirement of breakthrough pain treatment in case of pain exacerbation or the definition of the place of hospitalization in case of worsening general condition or of death. PMID- 25711786 TI - [Issues and Challenges of End of Life at Home for the Treating Physician]. AB - Palliative care and end of life at home remains a challenge for the general practitioner. The success is related to many factors, including the situation of the patient, his social and family environment, the presence of the various health professionals and the physician's engagement. Beyond the medical-technical skills, he plays a central coordinating role in an interdisciplinary team regularly adjusted according to the patient's evolution. The positive emotional impact on bereaved relatives after the end of life at home is often underestimated by the physician. PMID- 25711787 TI - [Exploring and Responding to a Wish to Hasten Death of a patient with Advanced Illness]. AB - It is not uncommon for patients with an advanced disease to express a desire to their physician to hasten their death. Recent studies show that the motivation of such a desire is multifactorial and multidimensional, including depression, physical, psycho-social and spiritual suffering, fears about the process of dying and/or misunderstandings about the options for end-of-life care. The objective of this paper is to propose to the physician how to explore the dimensions of this request and some elements to answer it. PMID- 25711788 TI - [Palliative Care in Nursing Homes: Characteristics and Specificities]. AB - Elderly patients in palliative situations residing in a nursing home present characteristics and specificities that clearly distinguish them from patients with advanced cancer. Besides the difficulty to define a precise prognosis, their many comorbidities, their communication difficulties because of cognitive disorders, their high sensitivity to primary and secondary effects of drugs render their management a real challenge for physician and caregivers. Accompanying these patients at the end of their life also raises many ethical problems, especially when they are no longer able to express their wishes and have not previously expressed advance directives. PMID- 25711789 TI - [Consequences of Serious Illness in Family or Informal Caregivers]. AB - This article is the result of 700 interviews that have taken place during the past three years in the "Espace Proches" in Lausanne, a place devoted to home caregivers. It attempts to describe the reality of relatives and highlight the specific difficulties they encounter in the different roles they adopt or are given by their surroundings in the face of a progressive disease. It offers suggestions to the physicians of this population at risk on how to better support them in their physical and psychological burden. PMID- 25711790 TI - [Telomere length and Mediterranean diet - a clear association]. PMID- 25711791 TI - [High prevalence of masked uncontrolled arterial hypertension in patients under therapy]. PMID- 25711793 TI - [CME - EKG 48]. PMID- 25711796 TI - Activation of mu-opioid receptors in the ventrolateral orbital cortex inhibits the GABAergic miniature inhibitory postsynaptic currents in rats. AB - Previous studies have indicated that mu-opioid receptors in the ventrolateral orbital cortex (VLO) are involved in antinociception in tail flick tests and GABAergic neurons or terminals express mu-opioid receptors in the VLO. The current study examined the effect of selective mu-opioid receptor agonist DAMGO on the GABAergic miniature inhibitory postsynaptic currents (mIPSCs) in the VLO in rats using the whole-cell patch clamp. The results demonstrated that 5 MUM DAMGO application into the rat VLO slices significantly reduced the GABAergic mIPSCs frequency, without any effect on its amplitude, and this effect of DAMGO was reversed by pretreatment with selective mu-opioid receptor antagonist 1 MUM CTOP. Importantly, application of CTOP alone into the VLO slices did not produce any effect on the frequency and amplitude of GABAergic mIPSCs. These results indicate a presynaptic effect of mu-opioid receptor activation on the GABAergic neurons in the VLO. The current data suggests that a presynaptic inhibition of the GABA release may contribute to the mu-opioid receptor mediated effects in the VLO and provides novel electrophysiological evidence for the underlying mechanisms of mu-opioid receptors in the VLO. PMID- 25711797 TI - Selective weighting of cutaneous receptor feedback and associated balance impairments following short duration space flight. AB - The present study investigated the perception of low frequency (3 Hz) vibration on the foot sole and its relationship to standing balance following short duration space flight in nine astronauts. Both 3 Hz vibration perception threshold (VPT) and standing balance measures increased on landing day compared to pre-flight. Contrary to our hypothesis, a positive linear relationship between these measures was not observed; however astronauts with the most sensitive skin (lowest 3 Hz VPT) were found to have the largest sway on landing day. While the change in foot sole sensitivity does not appear to directly relate to standing balance control, an exploratory strategy may be employed by astronauts whose threshold to pressure information is lower. Understanding sensory adaptations and balance control has implications to improve balance control strategies following space flight and in sensory impaired populations on earth. PMID- 25711798 TI - Decrease of phosphorylated CREB and ERK in nucleus accumbens is associated with the incubation of heroin seeking induced by cues after withdrawal. AB - cAMP response element binding protein (CREB) signaling is involved in the heroin reward, but whether the CREB signaling is involved in the incubation of heroin seeking remains unknown. Here we aim to explore the expression of p-CREB and the p-ERK, an upstream molecular of CREB, in the nucleus accumbens (NAc) in the incubation of heroin-seeking induced by cue after withdrawal. First, rats were trained to self-administer heroin for 14 days, and then assessed heroin-seeking induced by context cue (CC)or by conditioned cues (CS)after 1 or 14 d withdrawal. We found that the active responses induced by CC or CS was higher after 14 d withdrawal than that after 1 d withdrawal, and the extent increased was more significant by CS than that by CC. Meanwhile, the expression of p-ERK decreased significantly when rats exposed to the CS, and decreased more after 14 d withdrawal. In contrast, reduction of the expression of p-CREB was more obvious with exposure to CS after 14 d withdrawal. Furthermore, microinjection of rolipram into the NAc decreased the heroin-seeking behavior induced by CS after 14 d withdrawal, which was correlated to an enhancement in the expression of p CREB in the NAc. These findings suggest that the inactivation of CREB and ERK may be involved in the incubation of heroin-seeking induced by cues after prolonged withdrawal. PMID- 25711799 TI - The spino-bulbar-cerebellar pathway: Activation of neurons projecting to the lateral reticular nucleus in the rat in response to noxious mechanical stimuli. AB - It is now well established that the cerebellum receives input from nociceptors which may serve to adjust motor programmes in response to pain and injury. In this study, we investigated the possibility that spinoreticular neurons (SRT) which project to a pre-cerebellar nucleus, the lateral reticular nucleus (LRt), respond to noxious mechanical stimulation. Seven adult male rats received stereotaxic injections of the b subunit of cholera toxin in the LRt. Following a 5 day interval, animals were anesthetised with urethane and a noxious mechanical stimulus was applied to the right hind paw. Animals were fixed by perfusion 5min following application of the stimulus. Retrogradely labelled SRT neurons of the lumbar spinal cord were examined for immunoreactivity for phosphorylated ERK (pERK) and the neurokinin-1 (NK-1) receptor. Approximately 15% of SRT cells in deep laminae (IV-VII and X) expressed pERK ipsilateral to the site of the stimulus. Around 60% of SRT cells with the NK-1 receptor expressed pERK but 5% of pERK expressing cells were negatively labelled for NK-1. It is concluded that a significant proportion of SRT cells projecting to the LRt respond to noxious mechanical stimuli and that one of the functions of this pathway may be to provide the cerebellum with nociceptive information. PMID- 25711800 TI - Anticipatory and compensatory postural adjustments in individuals with multiple sclerosis in response to external perturbations. AB - Deficit in balance control is a common and often an initial disabling symptom of multiple sclerosis (MS). The aim of the study was to investigate the organization of anticipatory and compensatory postural adjustments in individuals with MS dealing with external perturbations. Ten individuals with MS and ten age-and gender matched healthy controls were exposed to external perturbations applied at the shoulder level. The perturbations were either predictable or unpredictable as subjects stood with eyes open or closed. Electrical activity of six leg and trunk muscles as well as displacements of the center of pressure (COP) were recorded and quantified within the time intervals typical of anticipatory (APAs) and compensatory (CPAs) postural adjustments. Individuals with MS demonstrated delayed anticipatory onsets of muscle activity and smaller anticipatory COP displacements as compared to healthy control subjects. The deficiency of the APAs was associated with increased displacements of the COP during the balance restoration phase. The results demonstrate the underlying impairment in anticipatory postural control of individuals with MS. The study outcome provides a background for development of rehabilitation strategies focused on balance restoration in people with MS. PMID- 25711801 TI - 3D-printed biological organs: medical potential and patenting opportunity. AB - Three-dimensional (3D) bioprinting has emerged as a new disruptive technology that may address the ever-increasing demand for organ transplants. 3D bioprinting offers many technical features that allow for building functional biological tissue constructs by dispensing the individual or group of cells into specific locations along with various types of bio-scaffold materials and extracellular matrices, and thus, may provide flexibility needed for on-demand individualized construction of biological organs. Several key classes of 3D bioprinting techniques are reviewed, including potential medical and industrial applications. Several unanswered engineering components for the ultimate creation of printed biological organs are also discussed. The complicated nature of the human organs, in addition to the legal and ethical requirements for safe implantation into the human body, would require significant research and development to produce marketable bioprinted organs. This also suggests the possibility for further patenting and licensing opportunities from different sectors of the economy. PMID- 25711802 TI - Twenty-five years of change in southern African passerine diversity: nonclimatic factors of change. AB - We analysed more than 25 years of change in passerine bird distribution in South Africa, Swaziland and Lesotho, to show that species distributions can be influenced by processes that are at least in part independent of the local strength and direction of climate change: land use and ecological succession. We used occupancy models that separate species' detection from species' occupancy probability, fitted to citizen science data from both phases of the Southern African Bird Atlas Project (1987-1996 and 2007-2013). Temporal trends in species' occupancy probability were interpreted in terms of local extinction/colonization, and temporal trends in detection probability were interpreted in terms of change in abundance. We found for the first time at this scale that, as predicted in the context of bush encroachment, closed-savannah specialists increased where open savannah specialists decreased. In addition, the trend in the abundance of species a priori thought to be favoured by agricultural conversion was negatively correlated with human population density, which is in line with hypotheses explaining the decline in farmland birds in the Northern Hemisphere. In addition to climate, vegetation cover and the intensity and time since agricultural conversion constitute important predictors of biodiversity changes in the region. Their inclusion will improve the reliability of predictive models of species distribution. PMID- 25711803 TI - Characterization of pleural effusion after left atrial appendage exclusion using the Lariat procedure. AB - BACKGROUND: The Lariat procedure is increasingly used for the exclusion of the left atrial appendage (LAA) in atrial fibrillation (AF) patients. There are anecdotal reports of pleural effusions after the Lariat procedure. However, the incidence, demographics, and pathophysiology of these effusions are largely unknown. OBJECTIVE: Characterization of pleural effusions in patients who underwent LAA exclusion using the Lariat procedure. METHODS: We report the incidence, demographics, and clinical and laboratory characteristics of patients from a multicenter prospective registry who underwent the Lariat procedure and subsequently developed pleural effusions. RESULTS: A total of 10 out of 310 (3.2%) patients developed significant pleural effusions after the Lariat procedure. The mean age of these patients was 67 +/- 9, ranging from 52 to 78 years and included 5 (50%) males. Nine patients had persistent AF with median CHADS2 score of 2.7 +/- 1.2. The LAA was successfully ligated in all these patients. Post-Lariat procedure, 6 patients developed bilateral and 4 patients developed left-sided pleural effusions. Pleural tap revealed transudative in 2 and exudative in 6 patients. The remaining 2 patients responded to active diuresis and behaved clinically like transudative effusions. There is a statistically significant difference between the onset of pleural effusion after the Lariat procedure between tPLE versus ePLE groups (14 +/- 1.2 vs. 6 +/- 6, P = 0.05). CONCLUSION: Incidence of clinically significant pleural effusion is uncommon after the Lariat procedure and can be either exudative or transudative in nature depending on the underlying mechanisms. More prospective studies are needed to study the pathophysiologic basis of development of pleural effusions after the Lariat procedure. PMID- 25711804 TI - Evidence for synergistic control of glutamate biosynthesis by glutamate dehydrogenases and glutamate in Bacillus subtilis. AB - In the Gram-positive bacterium, Bacillus subtilis glutamate is synthesized by the glutamine synthetase and the glutamate synthase (GOGAT). During growth with carbon sources that exert carbon catabolite repression, the rocG glutamate dehydrogenase (GDH) gene is repressed and the transcription factor GltC activates the expression of the GOGAT encoding gltAB genes. In the presence of amino acids of the glutamate family, the GDH RocG is synthesized and the enzyme prevents GltC from binding to DNA. The dual control of glutamate biosynthesis allows the efficient utilization of the available nutrients. Here we provide genetic and biochemical evidence that, like RocG, also the paralogous GDH GudB can inhibit the transcription factor GltC, thereby controlling glutamate biosynthesis. Contradictory previous observations show that high level of GDH activity does not result in permanent inhibition of GltC. By controlling the intracellular levels of glutamate through feeding with exogenous arginine, we observed that the GDH dependent control of GltC and thus expression of the gltAB genes inversely correlates with the glutamate pool. These results suggest that the B. subtilis GDHs RocG and GudB in fact act as glutamate sensors. In conclusion, the GDH mediated control of glutamate biosynthesis seems to depend on the intracellular glutamate concentration. PMID- 25711805 TI - Characterization and changes in neurotrophin receptor p75-Expressing motor neurons in SOD1(G93A) G1H mice [corrected]. AB - Mice with high numbers of the Cu/Zn superoxide dismutase-1 G93A transgene (SOD1(G93A) G1H) have become the most commonly used animal model to study amyotrophic lateral sclerosis. This study investigated changes in size, numbers, and cell stress/death markers of motor neuron numbers in G1H mice that re-express the common p75 neurotrophin receptor (p75NTR). SOD1(G93A) G1H mice and age matched C57BL/6J controls at 60, 80, 100, 120 days and end stage/140 days were analyzed for p75NTR, choline acetyltransferase (ChAT), activating transcription factor 3 (ATF3), and cleaved caspase-3. In addition, motor neuron counts and soma sizes were recorded. Motor neurons re-expressing p75NTR in SOD1(G93A) G1H mice were first observed at 80 days, and this continued to 140 days, peaking at 100 120 days at ~5%. The soma area of motor neurons re-expressing p75NTR was always 600-800 um(2) , suggesting that these are alpha motor neurons, which was confirmed after examination of somas post injection of a retrogradely transported antibody to p75NTR in 110-day-old SOD1(G93A) G1H mice. In motor neurons not re expressing p75NTR, the frequency of small soma 200-400 um2 motor neurons increased, whereas the larger 600-900 um2 motor neurons decreased with progression, indicating that large motor neurons were dying off and shrinking in the process. There was minimal coexpression of p75NTR with ATF3, a marker for cell stress, but 85% coexpressed the apoptotic marker cleaved caspase-3. These findings indicate that in SOD1(G93A) G1H mice, p75NTR re-expression is detectable from 80 days in a small population of large motor neurons that represent 5% of the total motor neurons. Furthermore, p75NTR re-expression occurs in larger alpha motor neurons that express cleaved caspsase-3 and are destined to die. PMID- 25711806 TI - Bioinspired polydopamine sheathed nanofibers for high-efficient in vivo solid phase microextraction of pharmaceuticals in fish muscle. AB - In this study, electrospun nanofibers were used as solid-phase microextraction (SPME) fiber coatings after substituting the water-soluble sheath of the emulsion electrospun polystyrene (PS)@Plurinic F-127 core-sheath nanofibers with biocompatible and water-stable polydopamine (PDA) and subsequently being appropriately cross-linked with glutaraldehyde (GA) to enhance the strength of the electrospun architecture. The novel custom-made PS@PDA-GA coating was wettable in aqueous solutions and thus exhibited much higher extraction efficiency than the nonsheathed PS nanofiber coating and the thicker polydimethylsiloxane (PDMS) coating. The novel coating also possessed excellent stability (relative standard deviations (RSDs) less than 7.3% for six sampling desorption cycles), interfiber reproducibility (RSDs less than 14.3%), and antibiofouling ability, which were beneficial for in vivo sampling. The PS@PDA-GA fiber was used to monitor pharmaceuticals in dorsal-epaxial muscle of living fish, and satisfactory sensitivities with the limits of detection in the range of 1.1 (mefenamic acid) to 8.9 (fluoxetine) ng.g(-1) and comparable accuracies to liquid extraction were achieved. In general, this study explored a convenient and effective method to sheath nanofibers for high-efficient in vivo SPME of analytes of interest in semisolid tissues. PMID- 25711807 TI - Does light attract piglets to the creep area? AB - Hypothermia, experienced by piglets, has been related to piglet deaths and high and early use of a heated creep area is considered important to prevent hypothermia. The aims of the present study were to investigate how a newly invented radiant heat source, eHeat, would affect piglets' use of the creep area and whether light in the creep area works as an attractant on piglets. A total of 39 sows, divided between two batches, were randomly distributed to three heat source treatments: (1) standard infrared heat lamp (CONT, n=19), (2) eHeat with light (EL, n=10) and (3) eHeat without light (ENL, n=10). Recordings of piglets' use of the creep area were made as scan sampling every 10 min for 3 h during two periods, one in daylight (0900 to 1200 h) and one in darkness (2100 to 2400 h), on day 1, 2, 3, 7, 14 and 21 postpartum. On the same days, piglets were weighted. Results showed an interaction between treatment and observation period (P<0.05) with a lower use of the creep area during darkness compared with daylight for CONT and EL litters, but not for ENL litters. Piglets average daily weight gain was not affected by treatment, but was positively correlated with piglets' birth weight and was lower in batch 1 compared with batch 2. Seen from the present results, neither eHeat nor light worked as an attractant on piglets; in contrast, piglets preferred to sleep in the dark and it would therefore be recommended to turn off the light in the creep area during darkness. Heating up the creep area without light can be accomplished by using a radiant heat source such as eHeat in contrast to the normally used light-emitting infrared heat lamp. PMID- 25711808 TI - Evolution of root-specific carotenoid precursor pathways for apocarotenoid signal biogenesis. AB - Various cleavage products of C40 carotenoid substrates are formed preferentially or exclusively in roots. Such apocarotenoid signaling or regulatory compounds differentially induced in roots during environmental stress responses including root colonization by arbuscular mycorrhizal fungi include ABA, strigolactones and C13 alpha-ionol/C14 mycorradicin derivatives. The low carotenoid levels in roots raise the question of whether there is a regulated precursor supply channeled into apocarotenoid formation distinct from default carotenoid pathways. This review describes root-specific isogene components of carotenoid pathways toward apocarotenoid formation, highlighting a new PSY3 class of phytoene synthase genes in dicots. It is clearly distinct from the monocot PSY3 class co-regulated with ABA formation. At least two members of the exclusive dicot PSY3s are regulated by nutrient stress and mycorrhization. This newly recognized dicot PSY3 (dPSY3 vs. mPSY3 from monocots) class probably represents an ancestral branch in the evolution of the plant phytoene synthase family. The evolutionary history of PSY genes is compared with the evolution of MEP pathway isogenes encoding 1-deoxy-d xylulose 5-phosphate synthases (DXS), particularly DXS2, which is co-regulated with dPSY3s in mycorrhizal roots. Such stress-inducible isoforms for rate limiting steps in root carotenogenesis might be components of multi-enzyme complexes committed to apocarotenoid rather than to carotenoid formation. PMID- 25711809 TI - Functional plasticity of miR165/166 in plant development revealed by small tandem target mimic. AB - MicroRNA 165 and 166 (miR165/166) is composed of nine members and targets five members (PHB, PHV, REV, ATHB8 and ATHB15) of the HD-ZIP III transcription factor family. Mutants generated by traditional methods could hardly reveal the overall functions of miR165/166 in plant development. In this study, the expressions of all miR165/166 members were simultaneously blocked by over-expressing STTM165/166 31 in Arabidopsis and tomato for functional dissection of miR165/166 family. Following a down-regulation of over 90% endogenous miR165/166, the target HD-ZIP III genes were correspondingly up-regulated in the STTM transgenic Arabidopsis and tomato plants. Notably, the STTM165/166-31 over-expressed Arabidopsis and tomato displayed pleiotropic effects on development which were not frequently observed in previously identified genetic mutants of either individual miR165/166 gene or any of the five target genes. Furthermore, the transgenic Arabidopsis showed increased IAA content and decreased IAA sensitivity accompanied by enhanced expressions of genes responsible for auxin biosynthesis and signaling, suggesting possible roles of auxin in mediation of miR165/166-regulated processes. Importantly, the transgenic Arabidopsis exhibited the improved behavior under salt stress. Overall, such diverse variations in plant development and physiological process revealed by STTM165/166 demonstrate a key role of miR165/166-mediated network in regulating plant development and responses to abiotic stresses. PMID- 25711810 TI - Identification and analysis of the mechanism underlying heat-inducible expression of rice aconitase 1. AB - Respiratory metabolism is an important though poorly understood facet of plant adaptation to stress. Posttranslational modification of aconitase, a component of the tricarboxylic acid cycle (TCA), may be involved in stress tolerance. However, such stress-related transcriptional regulation and its mechanism remain unknown. In this study, we found that expression of the rice Aconitase gene OsACO1 is induced in a time-dependent manner by heat but not other typical abiotic stresses. To analyze the transcriptional regulation mechanism underlying the response to heat, the OsACO1 promoter (POsACO1) was isolated and characterized in transgenic rice. Using qualitative and quantitative analyses, we found that the expression of the GUS reporter gene responded to heat in different tissues and at different stages of development when driven by POsACO1. A series of 5' distal deletions of POsACO1 was generated to delineate the region responsible for heat induced gene expression. Transient expression analyses in tobacco leaves identified a 322-bp minimal region between -1386 and -1065 as being essential and sufficient for heat-induced expression by POsACO1. We screened for known heat response-related cis-elements in this 322-bp region; however, sequences correlating with heat-induced gene expression were not identified in POsACO1. Therefore, truncations and successive mutagenesis analyses were performed in this 322-bp region. By comparing the activities of promoter fragments and their derivatives, our results indicated that the heat response element resided in a 9 bp region between -1132 and -1124, a sequence that contains a W-box motif. Additional site-directed mutagenesis analyses eliminated the heat response activity of POsACO1 via the W-box element, and an electrophoretic mobility shift assay (EMSA) indicated the binding of POsACO1 by factors in the nuclear extracts of heat-stressed rice seedlings in a W-box-dependent manner. Our results illustrate the expression pattern of a key component of the TCA response to abiotic stress and establish a putative regulatory pathway in the transcriptional modulation of rice respiratory metabolism genes in response to heat. PMID- 25711811 TI - AIR12, a b-type cytochrome of the plasma membrane of Arabidopsis thaliana is a negative regulator of resistance against Botrytis cinerea. AB - AIR12 (Auxin Induced in Root culture) is a single gene of Arabidopsis that codes for a mono-heme cytochrome b. Recombinant AIR12 from Arabidopsis accepted electrons from ascorbate or superoxide, and donated electrons to either monodehydroascorbate or oxygen. AIR12 was found associated in vivo to the plasma membrane. Though linked to the membrane by a glycophosphatidylinositol anchor, AIR12 is a hydrophilic and glycosylated protein predicted to be fully exposed to the apoplast. The expression pattern of AIR12 in Arabidopsis is developmentally regulated and correlated to sites of controlled cell separation (e.g. micropilar endosperm during germination, epidermal cells surrounding the emerging lateral root) and cells around wounds. Arabidopsis (Landsberg erecta-0) mutants with altered levels of AIR12 did not show any obvious phenotype. However, AIR12 overexpressing plants accumulated ROS (superoxide, hydrogen peroxide) and lipid peroxides in leaves, indicating that AIR12 may alter the redox state of the apoplast under particular conditions. On the other hand, AIR12-knock out plants displayed a strongly decreased susceptibility to Botrytis cinerea infection, which in turn induced AIR12 expression in susceptible wild type plants. Altogether, the results suggest that AIR12 plays a role in the regulation of the apoplastic redox state and in the response to necrotrophic pathogens. Possible relationships between these functions are discussed. PMID- 25711812 TI - Three novel alleles of FLOURY ENDOSPERM2 (FLO2) confer dull grains with low amylose content in rice. AB - Rice is a major food source for much of the world, and expanding our knowledge of genes conferring specific rice grain attributes will benefit both farmer and consumer. Here we present novel dull grain mutants with a low amylose content (AC) derived from mutagenesis of Oryza sativa, ssp. japonica cv. Taikeng 8 (TK8). Positional cloning of the gene conferring the dull grain phenotype revealed a point mutation located at the acceptor splice site of intron 11 of FLOURY ENDOSPERM2 (FLO2), encoding a tetratricopeptide repeat domain (TPR)-containing protein. Three novel flo2 alleles were identified herein, which surprisingly conferred dull rather than floury grains. The allelic diversity of flo2 perturbed the expression of starch synthesis-related genes including OsAGPL2, OsAGPS2b, OsGBSSI, OsBEI, OsBEIIb, OsISA1, and OsPUL. The effect of the flo2 mutations on the physicochemical properties of the grain included a low breakdown, setback, and consistency of rice, indicating a good elasticity and soft texture of cooked rice grains. The effects of FLO2, combined with the genetic background of the germplasm and environmental effects, resulted in a variety of different amylose content levels, grain appearance, and physicochemical properties of rice, providing a host of useful information to future grain-quality research and breeding. PMID- 25711813 TI - Pathogenic attributes of Sclerotinia sclerotiorum: switching from a biotrophic to necrotrophic lifestyle. AB - Plants and fungi have had many years of friendly and not-so friendly competition for resources and quality of life. As a result, diverse pathosystems evolved numerous strategies, coupled with the emergence of multifaceted pathogenic and saprophytic lifestyles. We discuss fungal lifestyle classifications and how the views associated with certain fungal pathogens, particularly necrotophs, are changing as we learn more about the complexities of their interactions with a given host plant. We discuss the physiological events leading to the transition from biotrophy to necrotrophy in hemi-biotrophs, and conclude that both the control of plant immune responses and the need for a more efficient mode of nutrient acquisition are possible triggers for the transition to necrotrophy. Based on recent findings, we focus on the polyphagous plant pathogen Sclerotinia sclerotiorum. Rather than overwhelming plant foes, S. sclerotiorum has evolved clever means to compromise host recognition and establish disease, resulting in a broad and immensely successful pathogenic lifestyle. The tactics used by this fungus to achieve pathogenic success are being clarified. We propose that the hemi-biotrophic lifestyle may be more temporally and spatially complex than currently depicted, and that combining lifestyle attributes with damage response curves that consider the contribution of both the fungus and the host to pathogenesis, may provide a more holistic manner to view plant pathogens. PMID- 25711814 TI - OsSEC24, a functional SEC24-like protein in rice, improves tolerance to iron deficiency and high pH by enhancing H(+) secretion mediated by PM-H(+)-ATPase. AB - Iron is abundant in the soil, but its low solubility in neutral or alkaline soils limits its uptake. Plants can rely on rhizosphere acidification to increase iron solubility. OsSEC27p was previously found to be a highly up-regulated gene in iron-deficient rice roots. Here, pH-dependent complementation assays using yeast mutants sec24Delta/SEC24 and sec27Delta/SEC27 showed that OsSEC27 could functionally complement SEC24 but not SEC27 in yeast; thus, it was renamed as OsSEC24. We found that OsSEC24-transgenic tobacco plants increased the length and number of roots under iron deficiency at pH 8.0. To explore how OsSEC24 confers tolerance to iron deficiency, we utilized transgenic tobacco, rice and rice protoplasts. H(+) flux measurements using Non-invasive Micro-test Technology (NMT) indicated that the transgenic OsSEC24 tobacco and rice enhanced H(+) efflux under iron deficiency. Conversely, the application of plasma membrane PM-H(+) ATPase inhibitor vanadate elucidated that H(+) secretion increased by OsSEC24 was mediated by PM-H(+)-ATPase. OsPMA2 was used as a representative of iron deficiency-responsive PM-H(+)-ATPases in rice root via RT-PCR analysis. In transgenic rice protoplasts OsPMA2 was packaged into OsSEC24 vesicles after export from the ER through confocal-microscopy observation. Together, OsSEC24 vesicles, along with PM-H(+)-ATPases stimulate roots formation under iron deficiency by enhancing rhizosphere acidification. PMID- 25711815 TI - The role of nitrogen in leaf senescence of summer maize and analysis of underlying mechanisms using comparative proteomics. AB - Leaf senescence is associated with fundamental changes on the level of the proteome and it can be modulated by nitrogen. To determine the precise regulatory mechanisms underlying these effects, we conducted a comparative proteomics study using 2-dimensional gel electrophoresis and MALDI-TOF/TOF MS. Based on our study of the maize leaf proteome, leaf senescence induces complex responses including the degradation of 32 senescence-associated proteins that are involved in many biological processes, especially energy, metabolism and cell rescue, defense and virulence pathways. Although similar conclusions have been highlighted in other crops, this study filled the knowledge gap in maize leaf senescence. Moreover, we discovered, for the first time, 29 "nitrogen-regulated senescence proteins" had significant (P<=0.05) interaction term for nitrogen*stage. Although further study of nitrogen-related senescence proteins, such as 30S ribosomal protein, will be required to fully elucidate their complex functions, the surprising results in our study provide a new vision to research the relationship between nitrogen and senescence. PMID- 25711816 TI - Differential response of cell-cycle and cell-expansion regulators to heat stress in apple (Malus domestica) fruitlets. AB - Temperature is one of the most significant factors affecting physiological and biochemical aspects of fruit development. Current and progressing global warming is expected to change climate in the traditional deciduous fruit tree cultivation regions. In this study, 'Golden Delicious' trees, grown in a controlled environment or commercial orchard, were exposed to different periods of heat treatment. Early fruitlet development was documented by evaluating cell number, cell size and fruit diameter for 5-70 days after full bloom. Normal activities of molecular developmental and growth processes in apple fruitlets were disrupted under daytime air temperatures of 29 degrees C and higher as a result of significant temporary declines in cell-production and cell-expansion rates, respectively. Expression screening of selected cell cycle and cell expansion genes revealed the influence of high temperature on genetic regulation of apple fruitlet development. Several core cell-cycle and cell-expansion genes were differentially expressed under high temperatures. While expression levels of B type cyclin-dependent kinases and A- and B-type cyclins declined moderately in response to elevated temperatures, expression of several cell-cycle inhibitors, such as Mdwee1, Mdrbr and Mdkrps was sharply enhanced as the temperature rose, blocking the cell-cycle cascade at the G1/S and G2/M transition points. Moreover, expression of several expansin genes was associated with high temperatures, making them potentially useful as molecular platforms to enhance cell-expansion processes under high-temperature regimes. Understanding the molecular mechanisms of heat tolerance associated with genes controlling cell cycle and cell expansion may lead to the development of novel strategies for improving apple fruit productivity under global warming. PMID- 25711817 TI - Protein-protein interactions among enzymes of starch biosynthesis in high-amylose barley genotypes reveal differential roles of heteromeric enzyme complexes in the synthesis of A and B granules. AB - The present study investigated the role of protein phosphorylation, and protein complex formation between key enzymes of amylopectin synthesis, in barley genotypes exhibiting "high amylose" phenotypes. Starch branching enzyme (SBE) down-regulated lines (DeltaSBEIIa and DeltaSBEIIb), starch synthase (SS)IIa (ssiia(-), sex6) and SSIII (ssiii(-), amo1) mutants were compared to a reference genotype, OAC Baxter. Down-regulation of either SBEIIa or IIb caused pleiotropic effects on SSI and starch phosphorylase (SP) and resulted in formation of novel protein complexes in which the missing SBEII isoform was substituted by SBEI and SP. In the DeltaSBEIIb down-regulated line, soluble SP activity was undetectable. Nonetheless, SP was incorporated into a heteromeric protein complex with SBEI and SBEIIa and was readily detected in starch granules. In amo1, unlike other mutants, the data suggest that both SBEIIa and SBEIIb are in a protein complex with SSI and SSIIa. In the sex6 mutant no protein complexes involving SBEIIa or SBEIIb were detected in amyloplasts. Studies with Pro-Q Diamond revealed that GBSS, SSI, SSIIa, SBEIIb and SP are phosphorylated in their granule bound state. Alteration in the granule proteome in DeltaSBEIIa and DeltaSBEIIb lines, suggests that different protein complexes are involved in the synthesis of A and B granules. PMID- 25711818 TI - Metabolic contribution to salt stress in two maize hybrids with contrasting resistance. AB - Salt stress reduces the growth of salt-sensitive plants such as maize. The cultivation of salt-resistant maize varieties might therefore help to reduce yield losses. For the elucidation of the underlying physiological and biochemical processes of a resistant hybrid, we used a gas chromatography mass spectrometry approach and analyzed five different salt stress levels. By comparing a salt sensitive and a salt-resistant maize hybrid, we were able to identify an accumulation of sugars such as glucose, fructose, and sucrose in leaves as a salt resistance adaption of the salt-sensitive hybrid. Although, both hybrids showed a strong decrease of the metabolite concentration in the tricarboxylic acid cycle. These decreases resulted in the same reduced catabolism for the salt-sensitive and even the salt-resistant maize hybrid. Surprisingly, the change of root metabolism was negligible under salt stress. Moreover, the salt-resistance mechanisms were the most effective at low salt-stress levels in the leaves of the salt-sensitive maize. PMID- 25711819 TI - Rootin, a compound that inhibits root development through modulating PIN-mediated auxin distribution. AB - Plant roots anchor the plant to the soil and absorb water and nutrients for growth. Understanding the molecular mechanisms regulating root development is essential for improving plant survival and agricultural productivity. Extensive molecular genetic studies have provided important information on crucial components for the root development control over the last few decades. However, it is becoming difficult to identify new regulatory components in root development due to the functional redundancy and lethality of genes involved in root development. In this study, we performed a chemical genetic screen to identify novel synthetic compounds that regulate root development in Arabidopsis seedlings. The screen yielded a root growth inhibitor designated as 'rootin', which inhibited Arabidopsis root development by modulating cell division and elongation, but did not significantly affect shoot development. Transcript analysis of phytohormone marker genes revealed that rootin preferentially altered the expression of auxin-regulated genes. Furthermore, rootin reduced the accumulation of PIN1, PIN3, and PIN7 proteins, and affected the auxin distribution in roots, which consequently may lead to the observed defects in root development. Our results suggest that rootin could be utilized to unravel the mechanisms underlying root development and to investigate dynamic changes in PIN-mediated auxin distribution. PMID- 25711820 TI - TILLING mutants of durum wheat result in a high amylose phenotype and provide information on alternative splicing mechanisms. AB - The amylose/amylopectin ratio has a major influence over the properties of starch and determines its optimal end use. Here, high amylose durum wheat has been bred by combining knock down alleles at the two homoelogous genes encoding starch branching enzyme IIa (SBEIIa-A and SBEIIa-B). The complete silencing of these genes had a number of pleiotropic effects on starch synthesis: it affected the transcriptional activity of SBEIIb, ISA1 (starch debranching enzyme) and all of the genes encoding starch synthases (SSI, SSIIa, SSIII and GBSSI). The starch produced by grain of the double SBEIIa mutants was high in amylose (up to ~1.95 fold that of the wild type) and contained up to about eight fold more resistant starch. A single nucleotide polymorphism adjacent to the splice site at the end of exon 10 of the G364E mutant copies of both SBEIIa-A and SBEIIa-B resulted in the loss of a conserved exonic splicing silencer element. Its starch was similar to that of the SBEIIa double mutant. G364E SBEIIa pre-mRNA was incorrectly processed, resulting in the formation of alternative, but non-functional splicing products. PMID- 25711822 TI - Detection of QTL for metabolic and agronomic traits in wheat with adjustments for variation at genetic loci that affect plant phenology. AB - Mapping of quantitative trait loci associated with levels of individual metabolites (mQTL) was combined with the mapping of agronomic traits to investigate the genetic basis of variation and co-variation in metabolites, agronomic traits, and plant phenology in a field-grown bread wheat population. Metabolome analysis was performed using liquid chromatography-mass spectrometry resulting in identification of mainly polar compounds, including secondary metabolites. A total of 558 metabolic features were obtained from the flag leaves of 179 doubled haploid lines, of which 197 features were putatively identified, mostly as alkaloids, flavonoids and phenylpropanoids. Coordinated genetic control was observed for several groups of metabolites, such as organic acids influenced by two loci on chromosome 7A. Five major phenology-related loci, which were introduced as cofactors in the analyses, differed in their impact upon metabolic and agronomic traits with QZad-aww-7A having more impact on the expression of both metabolite and agronomic QTL than Ppd-B1, Vrn-A1, Eps, and QZad-aww-7D. This QTL study validates the utility of combining agronomic and metabolomic traits as an approach to identify potential trait enhancement targets for breeding selection and reinforces previous results that demonstrate the importance of including plant phenology in the assessment of useful traits in this wheat mapping population. PMID- 25711821 TI - Regulation of ascorbic acid metabolism by blue LED light irradiation in citrus juice sacs. AB - In the present study, the effects of red and blue LED lights on the accumulation of ascorbic acid (AsA) were investigated in the juice sacs of three citrus varieties, Satsuma mandarin, Valencia orange, and Lisbon lemon. The results showed that the blue LED light treatment effectively increased the AsA content in the juice sacs of the three citrus varieties, whereas the red LED light treatment did not. By increasing the blue LED light intensity, the juice sacs of the three citrus varieties accumulated more AsA. Moreover, continuous irradiation with blue LED light was more effective than pulsed irradiation for increasing the AsA content in the juice sacs of the three citrus varieties. Gene expression results showed that the modulation of AsA accumulation by blue LED light was highly regulated at the transcription level. The up-regulation of AsA biosynthetic genes (CitVTC1, CitVTC2, CitVTC4, and CitGLDH), AsA regeneration genes (CitMDAR1, CitMDAR2, and CitDHAR) and two GSH-producing genes (CitGR and CitchGR) contributed to these increases in the AsA content in the three citrus varieties. PMID- 25711824 TI - Specific mechanisms of tolerance to copper and cadmium are compromised by a limited concentration of glutathione in alfalfa plants. AB - The induction of oxidative stress is a characteristic symptom of metal phytotoxicity and is counteracted by antioxidants such as glutathione (GSH) or homoglutathione (hGSH). The depletion of GSH?hGSH in fifteen-day-old alfalfa (Medicago sativa) plants pre-incubated with 1mM buthionine sulfoximine (BSO) affected antioxidant responses in a metal-specific manner under exposure to copper (Cu; 0, 6, 30 and 100MUM) or cadmium (Cd; 0, 6 and 30MUM) for 7 days. The phytotoxic symptoms observed with excess Cu were accompanied by an inhibition of root glutathione reductase (GR) activity, a response that was augmented in Cd treated plants but reverted when combined with BSO. The synthesis of phytochelatins (PCs) was induced by Cd, whereas the biothiol concentration decreased in Cu-treated plants, which did not accumulate PCs. The depletion of GSH?hGSH by BSO also produced a strong induction of oxidative stress under excess Cu stress, primarily due to impaired GSH?hGSH-dependent redox homeostasis. In addition, the synthesis of PCs was required for Cd detoxification, apparently also determining the distribution of Cd in plants, as less metal was translocated to the shoots in BSO-incubated plants. Therefore, specific GSH?hGSH-associated mechanisms of tolerance were triggered by stress due to each metal. PMID- 25711825 TI - Transcriptomic analysis of nitrogen starvation- and cultivar-specific leaf senescence in winter oilseed rape (Brassica napus L.). AB - High nitrogen (N) efficiency, characterized by high grain yield under N limitation, is an important agricultural trait in Brassica napus L. cultivars related to delayed senescence of older leaves during reproductive growth (a syndrome called stay-green). The aim of this study was thus to identify genes whose expression is specifically altered during N starvation-induced leaf senescence and that can be used as markers to distinguish cultivars at early stages of senescence prior to chlorophyll loss. To this end, the transcriptomes of leaves of two B. napus cultivars differing in stay-green characteristics and N efficiency were analyzed 4 days after the induction of senescence by either N starvation, leaf shading or detaching. In addition to N metabolism genes, N starvation mostly (and specifically) repressed genes related to photosynthesis, photorespiration and cell-wall structure, while genes related to mitochondrial electron transport and flavonoid biosynthesis were predominately up-regulated. A kinetic study over a period of 12 days with four B. napus cultivars differing in their stay-green characteristics confirmed the cultivar-specific regulation of six genes in agreement with their senescence behavior: the senescence regulator ANAC029, the anthocyanin synthesis-related genes ANS and DFR-like1, the ammonium transporter AMT1;4, the ureide transporter UPS5, and SPS1 involved in sucrose biosynthesis. The identified genes represent markers for the detection of cultivar-specific differences in N starvation-induced leaf senescence and can thus be employed as valuable tools in B. napus breeding. PMID- 25711823 TI - Suppression of soil nitrification by plants. AB - Nitrification, the biological oxidation of ammonium to nitrate, weakens the soil's ability to retain N and facilitates N-losses from production agriculture through nitrate-leaching and denitrification. This process has a profound influence on what form of mineral-N is absorbed, used by plants, and retained in the soil, or lost to the environment, which in turn affects N-cycling, N-use efficiency (NUE) and ecosystem health and services. As reactive-N is often the most limiting in natural ecosystems, plants have acquired a range of mechanisms that suppress soil-nitrifier activity to limit N-losses via N-leaching and denitrification. Plants' ability to produce and release nitrification inhibitors from roots and suppress soil-nitrifier activity is termed 'biological nitrification inhibition' (BNI). With recent developments in methodology for in situ measurement of nitrification inhibition, it is now possible to characterize BNI function in plants. This review assesses the current status of our understanding of the production and release of biological nitrification inhibitors (BNIs) and their potential in improving NUE in agriculture. A suite of genetic, soil and environmental factors regulate BNI activity in plants. BNI function can be genetically exploited to improve the BNI-capacity of major food- and feed-crops to develop next-generation production systems with reduced nitrification and N2O emission rates to benefit both agriculture and the environment. The feasibility of such an approach is discussed based on the progresses made. PMID- 25711826 TI - Transcriptomic basis of functional difference and coordination between seeds and the silique wall of Brassica napus during the seed-filling stage. AB - The silique of oilseed rape (Brassica napus) is a composite organ including seeds and the silique wall (SW) that possesses distinctly physiological, biochemical and functional differentiations. Yet, the molecular events controlling such differences between the SW and seeds, as well as their coordination during silique development at transcriptional level are largely unknown. Here, we identified large sets of differentially expressed genes in the SW and seeds of siliques at 21-22 days after flowering with a Brassica 95K EST microarray. At this particular stage, there were 3278 SW preferentially expressed genes and 2425 seed preferentially expressed genes. Using the MapMan visualization software, genes differentially regulated in various metabolic pathways and sub-pathways between the SW and seeds were revealed. Photosynthesis and transport-related genes were more actively transcripted in the SW, while those involved in lipid metabolism were more active in seeds during the seed filling stage. On the other hand, genes involved in secondary metabolisms were selectively regulated in the SW and seeds. Large numbers of transcription factors were identified to be differentially expressed between the SW and seeds, suggesting a complex pattern of transcriptional control in these two organs. Furthermore, most genes discussed in categories or pathways showed a similar expression pattern through 21 DAF to 42 DAF. Our results thus provide insights into the coordination of seeds and the SW in the developing silique at the transcriptional levels, which will facilitate the functional studies of important genes for improving B. napus seed productivity and quality. PMID- 25711828 TI - Effects of cannabidiol on contractions and calcium signaling in rat ventricular myocytes. AB - Cannabidiol (CBD), a major nonpsychotropic cannabinoid found in Cannabis plant, has been shown to influence cardiovascular functions under various physiological and pathological conditions. In the present study, the effects of CBD on contractility and electrophysiological properties of rat ventricular myocytes were investigated. Video edge detection was used to measure myocyte shortening. Intracellular Ca(2+) was measured in cells loaded with the Ca(2+) sensitive fluorescent indicator fura-2 AM. Whole-cell patch clamp was used to measure action potential and Ca(2+) currents. Radioligand binding was employed to study pharmacological characteristics of CBD binding. CBD (1MUM) caused a significant decrease in the amplitudes of electrically evoked myocyte shortening and Ca(2+) transients. However, the amplitudes of caffeine-evoked Ca(2+) transients and the rate of recovery of electrically evoked Ca(2+) transients following caffeine application were not altered. CBD (1MUM) significantly decreased the duration of APs. Further studies on L-type Ca(2+) channels indicated that CBD inhibits these channels with IC50 of 0.1MUM in a voltage-independent manner. Radioligand studies indicated that the specific binding of [(3)H]Isradipine, was not altered significantly by CBD. The results suggest that CBD depresses myocyte contractility by suppressing L-type Ca(2+) channels at a site different than dihydropyridine binding site and inhibits excitation-contraction coupling in cardiomyocytes. PMID- 25711827 TI - New insights into the wheat chromosome 4D structure and virtual gene order, revealed by survey pyrosequencing. AB - Survey sequencing of the bread wheat (Triticum aestivum L.) genome (AABBDD) has been approached through different strategies delivering important information. However, the current wheat sequence knowledge is not complete. The aim of our study is to provide different and complementary set of data for chromosome 4D. A survey sequence was obtained by pyrosequencing of flow-sorted 4DS (7.2*) and 4DL (4.1*) arms. Single ends (SE) and long mate pairs (LMP) reads were assembled into contigs (223Mb) and scaffolds (65Mb) that were aligned to Aegilops tauschii draft genome (DD), anchoring 34Mb to chromosome 4. Scaffolds annotation rendered 822 gene models. A virtual gene order comprising 1973 wheat orthologous gene loci and 381 wheat gene models was built. This order was largely consistent with the scaffold order determined based on a published high density map from the Ae. tauschii chromosome 4, using bin-mapped 4D ESTs as a common reference. The virtual order showed a higher collinearity with homeologous 4B compared to 4A. Additionally, a virtual map was constructed and ~5700 genes (~2200 on 4DS and ~3500 on 4DL) predicted. The sequence and virtual order obtained here using the 454 platform were compared with the Illumina one used by the IWGSC, giving complementary information. PMID- 25711829 TI - Blood glucose levels during the initial 72 h and 3-month functional outcomes in acute intracerebral hemorrhage: the SAMURAI-ICH study. AB - PURPOSE: Prognostic values of blood glucose levels following admission remain unclear. We investigated associations between blood glucose levels during the initial 72 h and outcomes of acute ICH. METHODS: Participants comprised hyperacute ICH patients who received intravenous antihypertensive treatment. Blood glucose levels were measured on admission and at 24 and 72 h after starting treatment, along with hemoglobin (Hb)A1c level on admission. Associations with clinical outcomes of hematoma expansion (>33% increase), none to minimal disability (3-month modified Rankin Scale [mRS] 0-1) and bedridden or death (3 month mRS 5-6) were analyzed. RESULTS: Of the 176 patients (70 women; 65 +/- 12 years), 30 (18%) showed hematoma expansion, and 33 (19%) had none to minimal disability and 15 (10%) were bedridden or died. On multivariate regression analysis, blood glucose at 24h (per 10mg/dl odds ratio [OR], 0.84; 95% confidence interval [CI], 0.69-0.98) and blood glucose at 72 h (OR, 0.75; 95%CI, 0.59-0.92) were inversely associated with none to minimal disability, and blood glucose at 24h (OR, 1.14; 95%CI, 1.00-1.30) was positively associated with bedridden or death. No parameters were associated with hematoma expansion. CONCLUSIONS: High blood glucose levels at 24 and 72 h were independently associated with poor functional outcomes 3 months after ICH. We need to investigate whether blood glucose control during the acute period ameliorates clinical outcomes. PMID- 25711830 TI - Differential regulation of antagonistic pleiotropy in synthetic and natural populations suggests its role in adaptation. AB - Antagonistic pleiotropy (AP), the ability of a gene to show opposing effects in different phenotypes, has been identified in various life history traits and complex disorders, indicating its fundamental role in balancing fitness over the course of evolution. It is intuitive that natural selection might maintain AP to allow organisms phenotypic flexibility in different environments. However, despite several attempts, little evidence exists for its role in adaptation. We performed a meta-analysis in yeast to identify the genetic basis of AP in bi parental segregants, natural isolates, and a laboratory strain genome-wide deletion collection, by comparing growth in favorable and stress conditions. We found that whereas AP was abundant in the synthetic populations, it was absent in the natural isolates. This finding indicated resolution of trade-offs, i.e., mitigation of trade-offs over evolutionary history, probably through accumulation of compensatory mutations. In the deletion collection, organizational genes showed AP, suggesting ancient resolutions of trade-offs in the basic cellular pathways. We find abundant AP in the segregants, greater than estimated in the deletion collection or observed in previous studies, with IRA2, a negative regulator of the Ras/PKA signaling pathway, showing trade-offs across diverse environments. Additionally, IRA2 and several other Ras/PKA pathway genes showed balancing selection in isolates of S. cerevisiae and S. paradoxus, indicating that multiple alleles maintain AP in this pathway in natural populations. We propose that during AP resolution, retaining the ability to vary signaling pathways such as Ras/PKA, may provide organisms with phenotypic flexibility. However, with increasing organismal complexity AP resolution may become difficult. A partial resolution of AP could manifest as complex human diseases, and the inability to resolve AP may play a role in speciation. Our findings suggest that testing a universal phenomenon like AP across multiple experimental systems may elucidate mechanisms underlying its regulation and evolution. PMID- 25711831 TI - A systematic mutational analysis of a histone H3 residue in budding yeast provides insights into chromatin dynamics. AB - In previous work using the Saccharomyces cerevisiae model system, a mutant version of histone H3-H3-L61W-was found to confer a variety of abnormal growth phenotypes and defects in specific aspects of the transcription process, including a pronounced alteration in the distribution pattern of the transcription elongation factor Spt16 across transcribed genes and promotion of cryptic transcription initiation within the FLO8 gene. To gain insights into the contribution of the H3-L61 residue to chromatin function, we have generated yeast strains expressing versions of histone H3 harboring all possible natural amino acid substitutions at position 61 (H3-L61X mutants) and tested them in a series of assays. We found that whereas 16 of the 19 H3-L61X mutants support viability when expressed as the sole source of histone H3 in cells, all 19 confer abnormal phenotypes ranging from very mild to severe, a finding that might in part explain the high degree of conservation of the H3-L61 residue among eukaryotes. An examination of the strength of the defects conferred by each H3-L61X mutant and the nature of the corresponding substituted residue provides insights into structural features of the nucleosome required for proper Spt16-gene interactions and for prevention of cryptic transcription initiation events. Finally, we provide evidence that the defects imparted by H3-L61X mutants on Spt16-gene interactions and on repression of intragenic transcription initiation are mechanistically related to each other. PMID- 25711832 TI - A survey of imprinted gene expression in mouse trophoblast stem cells. AB - Several hundred mammalian genes are expressed preferentially from one parental allele as the result of a process called genomic imprinting. Genomic imprinting is prevalent in extra-embryonic tissue, where it plays an essential role during development. Here, we profiled imprinted gene expression via RNA-Seq in a panel of six mouse trophoblast stem lines, which are ex vivo derivatives of a progenitor population that gives rise to the placental tissue of the mouse. We found evidence of imprinted expression for 48 genes, 31 of which had been described previously as imprinted and 17 of which we suggest as candidate imprinted genes. An equal number of maternally and paternally biased genes were detected. On average, candidate imprinted genes were more lowly expressed and had weaker parent-of-origin biases than known imprinted genes. Several known and candidate imprinted genes showed variability in parent-of-origin expression bias between the six trophoblast stem cell lines. Sixteen of the 48 known and candidate imprinted genes were previously or newly annotated noncoding RNAs and six encoded for a total of 60 annotated microRNAs. Pyrosequencing across our panel of trophoblast stem cell lines returned levels of imprinted expression that were concordant with RNA-Seq measurements for all eight genes examined. Our results solidify trophoblast stem cells as a cell culture-based experimental model to study genomic imprinting, and provide a quantitative foundation upon which to delineate mechanisms by which the process is maintained in the mouse. PMID- 25711833 TI - Rock, paper, scissors: harnessing complementarity in ortholog detection methods improves comparative genomic inference. AB - Ortholog detection (OD) is a lynchpin of most statistical methods in comparative genomics. This task involves accurately identifying genes across species that descend from a common ancestral sequence. OD methods comprise a wide variety of approaches, each with their own benefits and costs under a variety of evolutionary and practical scenarios. In this article, we examine the proteomes of ten mammals by using four methodologically distinct, rigorously filtered OD methods. In head-to-head comparisons, we find that these algorithms significantly outperform one another for 38-45% of the genes analyzed. We leverage this high complementarity through the development MOSAIC, or Multiple Orthologous Sequence Analysis and Integration by Cluster optimization, the first tool for integrating methodologically diverse OD methods. Relative to the four methods examined, MOSAIC more than quintuples the number of alignments for which all species are present while simultaneously maintaining or improving functional-, phylogenetic-, and sequence identity-based measures of ortholog quality. Further, this improvement in alignment quality yields more confidently aligned sites and higher levels of overall conservation, while simultaneously detecting of up to 180% more positively selected sites. We close by highlighting a MOSAIC-specific positively selected sites near the active site of TPSAB1, an enzyme linked to asthma, heart disease, and irritable bowel disease. MOSAIC alignments, source code, and full documentation are available at http://pythonhosted.org/bio-MOSAIC. PMID- 25711834 TI - Engaging nonaromatic, heterocyclic tosylates in reductive cross-coupling with aryl and heteroaryl bromides. AB - A method has been developed for the introduction of nonaromatic heterocyclic structures onto aryl and heteroaryl bromides using alkyl tosylates in a reductive cross-coupling manifold. This protocol offers an improvement over previous methods by utilizing alkyl tosylate coupling partners that are bench-stable, crystalline solids that can be prepared from inexpensive, commercially available alcohols. PMID- 25711835 TI - Genetic aspects of monomorphic teratozoospermia: a review. AB - Teratozoospermia is characterized by the presence of spermatozoa with abnormal morphology over 85 % in sperm. When all the spermatozoa display a unique abnormality, teratozoospermia is said to be monomorphic. Two forms of monomorphic teratozoospermia, representing less than 1 % of male infertility, are recognized: macrozoospermia (also called macrocephalic sperm head syndrome) and globozoospermia (also called round-headed sperm syndrome). Macrozoospermia is defined as the presence of a very high percentage of spermatozoa with enlarged head and multiple flagella. Meiotic segregation studies in 30 males revealed that over 90 % of spermatozoa were aneuploid, mainly diploid. Sperm DNA fragmentation studies performed in a few patients showed an increase in DNA fragmentation index compared to fertile men. Four mutations in the AURKC gene, a key player in meiosis and more particularly in spermatogenesis, have been found to be responsible for macrozoospermia. Globozoospermia is characterized by round-headed spermatozoa with an absent acrosome, an aberrant nuclear membrane and midpiece defects. The rate of aneuploidy of various chromosomes in spermatozoa from 26 globozoospermic men was slightly increased compared to fertile men. However, this increase was of the same order as that commonly found in infertile men with altered sperm parameters. The majority of the studies found that globozoospermic males had a sperm DNA fragmentation index higher than in fertile men. Mutations or deletions in three genes, SPATA16, PICK1 and DPY19L2, have been shown to be responsible for globozoospermia. Identification of the genetic causes of macrozoospermia and globozoospermia should help refine diagnosis and treatment of these patients, avoiding long and painful treatments. Elucidating the molecular causes of these defects is of utmost importance as intracytoplasmic sperm injection (ICSI) is very disappointing in these two pathologies. PMID- 25711836 TI - Restoring microvascular efficiency with mesoglycan in women affected by moderate chronic venous disease. AB - AIM: Chronic venous disorders (CVDs) subtend a spectrum of vascular abnormalities, including microcirculation and skin damages (as ulcers) in the lower limb. Mesoglycan has been established as an effective agent to improve microcirculation associated with CVDs. The aim of this study was to determine the beneficial function of mesoglycan on cutaneous blood flow measured by laser Doppler fluometry (LDF) before and after iontophoresis analysis using methacholine chloride (MCh) injection in a group of female patients in different stages of CVDs, according to the CEAP classification. METHODS: Female patients with chronic venous disorders (CVD) were referred from primary care practices and vascular clinics. The study selected 75 women aged 45.5 +/- 9.6 years (range, 30 to 60 years). And grading in CEAP classification. Eligible patients were allocated consecutively, according to entrance order, in an active treatment group and in a control group for 90 days. The active group (N. = 37) received mesoglycan 50 mg twice daily in adjunct to standard care. The primary outcome variable for the study was the measurement of skin microcirculation blood flow by LDF. Data obtained was transferred to a database (Excel) and analysed using statistical software (SPSS version 12, SPSS, USA). RESULTS: After 90 days of treatment, mesoglycan obtained a significative increase in peak flow at LDF of about 13% respect of baseline and standard care in the entire group of CVD treated women. In upper CEAP classes there was a trend for a more intense vasodilating activity of mesoglycan. CONCLUSION: The study shows improving in microvascular function induced by a 3-month mesoglycan treatment in patients classified by CEAP stages C1 and C4. PMID- 25711837 TI - Selective pacing sites. AB - he right ventricular apex (RVA) has always been the most used pacing site, because it is easily accessible and provides a stable lead position with a low dislodgment rate. However, it is well-known that long-term right ventricular apical pacing may have deleterious effects on left ventricular function by inducing a iatrogenic left bundle branch block, which can have strong influences on the left ventricle hemodynamic performances. More specifically, RVA pacing causes abnormal contraction patterns and the consequent dyssynchrony may cause myocardial perfusion defects, histopathological alterations, left ventricular dilation and both systolic and diastolic left ventricular dysfunction. All these long-term changes could account for the higher morbidity and mortality rates observe in patients with chronic RVA pacing compared with atrial pacing. This observation led to the reassessment of traditional approaches and to the research of alternative pacing sites, in order to get to more physiological pattern of ventricular activation and to avoid deleterious effects. Then, attempts were made with: right ventricular outflow tract (RVOT) pacing, direct His bundle pacing (DHBP), parahisian pacing (PHP) and bifocal (RVA + RVOT) pacing. For example, RVOT pacing, especially in its septal portion, is superior to the RVA pacing and it would determine a contraction pattern very similar to the spontaneous one, not only because the septal portions are the first parts to became depolarized, but also for the proximity to the normal conduction system. RVOT is preferable in terms of safety too. DHBP is an attractive alternative to RVA pacing because it leads to a synchronous depolarization of myocardial cells and, therefore, to an efficient ventricular contraction. So it would be the best technique, however the procedure requires longer average implant times and dedicated instruments and it cannot be carried out in patients affected by His bundle pathologies; furthermore, due to the His bundle fibrous area, higher pacing thresholds are required, causing accelerated battery depletion. For all these reasons, PHP could be considered an important alternative to DHBP, to be used on a large scale. Finally, bifocal pacing in CRT candidates, provides better acute hemodynamic performance than RVA pacing, derived from a minor intra- and interventricular dyssynchrony, expressed also by the QRS shortening. Then, bifocal pacing could be taken into account when RVA pacing is likely to be the origin of serious mechanical and electrical dyssynchrony or when CRT is contraindicated or technically impossible. So, whatever chosen as selective pacing site, you must look also at safety, effectiveness and necessary equipment for an optimal pacing site. PMID- 25711838 TI - Very late drug-eluting stent thrombosis with bare-metal stent simultaneously after excessive alcohol intake despite dual antiplatelet therapy after 2737 days. PMID- 25711839 TI - Coumadin Ridge: usefulness of 3D-transesophageal echocardiography. PMID- 25711840 TI - Sindrome X, Tako-Tsubo cardiomyopathy and variant angina in mother and daughter. A striking coincidence? PMID- 25711841 TI - Chronic Obstructive Pulmonary Disease Patients' Experiences of an Enhanced Self Management Model of Care. AB - Chronic obstructive pulmonary disease (COPD) is debilitating and costly. Self management is championed to empower individuals to better manage their condition and also to efficiently utilize health resources. As a multi-disciplinary team, we conducted focus group research with individuals living with COPD who were participating in a longitudinal study to use an electronic "diary" to monitor, record, and transmit their own health status, plus receiving regular nurse visits. The main aims of the focus groups were to investigate how far individuals embraced the electronic diary and experienced it as an aid to the self-management of their condition. We also looked at the importance of the nurse visits to the process. Thematic analysis revealed that patients responded positively to the use of technology (the electronic diary), including psychological benefits of perceived support offered by the remote symptom surveillance. Findings also showed patients' increased awareness and monitoring of personal symptoms together with an improved understanding of disease self-management. Nurse support emerged as an important "human" factor in the process. In addition, a reduction in hospital admission was observed, thus reducing costs to the health service. PMID- 25711842 TI - Parents' Experiences of Health Care for Their Children With Cerebral Palsy. AB - Although current health care service delivery approaches for children with cerebral palsy recognize the importance of including parents in the health care of their child, we do not yet understand how parents experience this phenomenon. In this study, we used grounded theory methodology to explore parents' experiences of health care for their children with cerebral palsy living in a regional area of Australia. Our findings indicate that parents experience health care for their child as a cyclical process of "making the most of their body and their life." Important aspects of care include "learning as you go," "navigating the systems," "meeting needs through partnership," "being empowered or disempowered," and "finding a balance." We suggest modifications to health care service delivery practices that might contribute to improved experiences of health care for this population. PMID- 25711843 TI - How Men Manage Bulbar Urethral Stricture by Concealing Urinary Symptoms. AB - In this article, we present findings from research conducted as part of a multi center surgical trial. Bulbar urethral stricture, a narrowing of the middle urethra, is a common cause of urinary problems in men that can have a profound impact on their lives. Semi-structured interviews were conducted with a sample of 19 men seeking treatment for urethral stricture. The findings reveal how men tend to develop routines and tactics to adapt to their symptoms and hide them from others rather than seek help. We argue that this concealment becomes an inseparable part of how the disease is managed and is an additional hidden practical and emotional burden for these men. In addition, we suggest that the patients only sought curative treatments once practices of social concealment are no longer viable. PMID- 25711844 TI - The "Conflicted Dying": The Active Search for Life Extension in Advanced Cancer Through Biomedical Treatment. AB - Using a poststructural perspective, we examine the subjectivities that are produced when advanced cancer patients seek life extension through biomedical treatments. Seven case studies were developed that included 20 interviews with patients, family, nurses, and physicians recruited from a tertiary hospital in Canada, 30 documents, and 5 hours of participant observation. We identify seven types of subjectivity: (a) the Desperate Subject, (b) the Cancer Expert Subject, (c) the Proactive Subject, (d) the Productive Subject, (e) the Mistrusting Subject, (f) the Model Patient Subject, and (g) the Suffering Subject. We characterize the "conflicted dying," a contemporary figure who holds multiple perspectives about seeking curative treatment despite the acknowledgment of death. Using active strategies to gain access to treatment, this figure resists traditional arrangements of power/knowledge established by health care providers. We suggest that the search for life extension is a process of shaping the self to fit certain aesthetical traits associated with surviving cancer. PMID- 25711845 TI - Lived Observations: Linking the Researcher's Personal Experiences to Knowledge Development. AB - As researchers in palliative care, we recognize how involvement with seriously ill and dying persons has an impact on us. Using one's own senses, emotional and bodily responses in observations might open intersubjective dimensions of the research topic. The aim of the article is to highlight how phenomenological theories on intersubjectivity can be useful to develop rich and transparent data generation and analysis. We present three field note examples from observation in a hospice ward, which illuminate how researcher awareness of aspects of intersubjectivity can add valuable insights to data and analysis. Out of the examples, we elaborate on three arguments: (a) how the researcher's lived experience of time and space during fieldwork triggers new research questions, (b) how observations as an embodied activity can bring new insights and open new layers of meaning, and (c) the value of observations in gaining insight into relational aspects in a hospice. PMID- 25711846 TI - Portuguese War Veterans: Moral Injury and Factors Related to Recovery From PTSD. AB - This study explored the factors to which a sample of Portuguese war veterans attributed their recovery from posttraumatic stress disorder (PTSD). Participants were a sample of veterans (N = 60) with mental sequelae of the Portuguese Colonial War: 30 suffered from chronic PTSD (unrecovered) and 30 veterans with remission from PTSD (recovered). Two semistructured interviews were conducted. Analysis of the interviews was conducted using the Thematic and Categorical Analysis. Results showed that unrecovered participants reported higher postwar betrayal, appraisal of hostile societal homecoming, social stigmatization, lack of personal resources (mental fatigue and restriction of coping strategies), and reduced perceived social support. Recovered participants verbalized some capability for self-awareness of their own mental states and/or awareness of others' mental states (mentalization ability), a wider repertoire of coping strategies, and higher perceived social support. The authors discussed that recovery from PTSD among veterans can be related to the assimilation of moral injury by developing higher mentalization abilities. PMID- 25711847 TI - "Nature Does Things Well, Why Should We Interfere?": Vaccine Hesitancy Among Mothers. AB - Parents' decision to use vaccination services is complex and multi-factorial. Of particular interest are "vaccine-hesitant" parents who are in the middle of the continuum between vaccine acceptance and refusal. The objective of this qualitative longitudinal study was to better understand why mothers choose to vaccinate-or not-their newborns. Fifty-six pregnant mothers living in different areas of Quebec (Canada) were interviewed. These interviews gathered information on mothers' views about health and vaccination. Almost half of the mothers were categorized as vaccine-hesitant. A second interview was conducted with these mothers 3 to 11 months after birth to look at their actual decision and behavior concerning vaccination. Our results show the heterogeneity of factors influencing vaccine decision making. Although the majority of vaccine-hesitant mothers finally chose to follow the recommended vaccine schedule for their child, they were still ambivalent and they continued to question their decision. PMID- 25711848 TI - Endoscopic forehead surgery for migraine therapy Personal technique. AB - AIM: The aim of this study is to prove the therapeutic effectiveness of nerve decompression, performed endoscopically for frontal migraine and by open surgery for occipital migraine. MATERIALS AND METHODS: Twenty patients were enrolled and underwent surgery for endoscopic resection of the glabellar muscle group, including the corrugator supercilii, depressor supercilii, and procerus muscles, while the occipital decompression was performed in open surgery through decompression of occipital nerves from occipital, semispinalis capitis, trapezius and sternocleidomastoid muscles. Every patient was diagnosed with: migraine without aura, chronic tensiontype headache and new daily persistent headache, refractory to medical management. RESULTS: Analyzing the answers given by the patients to validated questionnaires, 9 referred alleviation of migraine symptoms (45%), 8 described elimination of their migraine headaches (40%) while 3 didn't report any improvement. DISCUSSION: Our data confirmed the results of previous studies, pointing out the effectiveness of trigeminal branches and occipital nerves (trigger points) decompression from the surrounding muscles. Moreover, our technique has the same results but it's less invasive and has less collateral effects. CONCLUSIONS: Our results highlight migraine surgery as an effective treatment for patients with migraine headaches who do not tolerate or do not wish to continue medical interventions. KEY WORDS: Endoscopic surgery, Headache migraine. PMID- 25711849 TI - Comparison of alemtuzumab vs. antithymocyte globulin induction therapy in primary non-sensitized renal transplant patients treated with rapid steroid withdrawal. AB - Alemtuzumab and rabbit antithymocyte globulin (rATG) are commonly used for induction therapy in renal transplantation. This retrospective, single-center, cohort study evaluated cumulative incidence of one-yr biopsy-proven acute rejection (BPAR) among 200 consecutive primary non-sensitized kidney transplant recipients who received either alemtuzumab (n = 100) or rATG (n = 100) induction followed by rapid steroid taper, tacrolimus, and mycophenolate mofetil. Protocol biopsies, plasma and urine BK virus PCR, serum creatinine and iothalamate glomerular filtration rate (iGFR), were obtained at 1, 4, and 12 months from transplantation. The one-yr BPAR rates were similar between the alemtuzumab and rATG groups; however, rejection Banff IA and higher was more common in the alemtuzumab arm (18% vs. 5%, p = 0.047). After adjusting for confounding variables, alemtuzumab was still associated with Banff IA and higher rejection (adjusted OR: 3.7, CI: 1.2-10.5, p = 0.02). Despite similar rates of BK viremia, more patients in the alemtuzumab arm developed BK nephropathy (16% vs. 3%, p = 0.046). One-year iGFR (53.4 +/- 20.2 vs. 71.9 +/- 27.2 mL/min/1.73 m(2), p = 0.002) and three-yr graft survival (89.5% vs. 95%, p = 0.05) were lower in the alemtuzumab group. In low immunological risk kidney transplant recipients on steroid-free immunosuppression, alemtuzumab was associated with more severe rejection and BK nephropathy compared to rATG. PMID- 25711850 TI - Soft tissue sarcoma of the head & neck: nomogram validation and analysis of staging systems. AB - BACKGROUND AND OBJECTIVES: Soft tissue sarcomas of the head and neck (STSHN) comprise a rare group of malignancies. Our objective is to determine the utility of soft tissue sarcoma staging systems within the head and neck, and to validate an individualized soft tissue sarcoma nomogram within head and neck primary sites. METHODS: Previously-untreated patients with STSHN diagnosed and treated between 1982 and 2012 were eligible (n = 319, median follow-up 46 months). Clinical variables were extracted from a prospectively-maintained database. The performance of AJCC/UICC and MSK staging systems and a soft tissue sarcoma specific nomogram were assessed. RESULTS: Four-year overall survival (OS), disease specific survival (DSS), and recurrence-free survival (RFS) were 72%, 76%, and 71%, respectively. AJCC/UICC and MSK staging systems accurately stratified outcomes (OS, DSS, and RFS; P < 0.001 for all comparisons). The nomogram stratified outcomes by quartile (P < 0.001), and predicted risk of death at 4, 8 and 12 years (P < 0.001). Concordance indices for overall survival for the AJCC/UICC system, MSK system, and the nomogram were 0.71, 0.70, and 0.78, respectively. CONCLUSIONS: Oncologic outcomes among groups of patients with STSHN can be accurately predicted using both the AJCC/UICC and MSK staging systems. A soft tissue sarcoma-specific nomogram provides reliable, individualized prognostic information for patients with STSHN. PMID- 25711851 TI - The relationship between meaning discrepancy and emotional distress among patients with cancer: the role of posttraumatic growth in a collectivistic culture. AB - The aim of this study was to examine the relationship between meaning discrepancy and emotional distress (i.e. anxiety and depression) among patients with cancer in a collectivistic culture, and to explore the stress-buffering effect of posttraumatic growth on this relationship. We collected data from 198 patients with cancer who completed questionnaires measuring meaning discrepancy, posttraumatic growth, anxiety and depression. Correlation analyses indicated that meaning discrepancy positively correlated with anxiety (r = 0.477, P < 0.01) and depression (r = 0.452, P < 0.01). Three structural equation models were built to compare competing hypotheses. Results showed that the moderation model fits the data better than the mediation and independence models (chi(2) /df = 1.31, RMSEA = 0.040, CFI = 0.98, GFI = 0.92). The present study demonstrated a positive association between meaning discrepancy and anxiety/depression, and a protective effect of posttraumatic growth on mental health by buffering traumatic stress. The study has clinical implications for the medical practice of oncology; doctors, nurses, relatives and counsellors should attend to the psychological care of patients with cancer by exploring their meaning discrepancy, and promoting the use of posttraumatic growth as a psychological resource to buffer the anxiety and depression of patients with cancer. PMID- 25711852 TI - Potential drug-drug interactions in hospitalized patients undergoing systemic chemotherapy: a prospective cohort study. AB - BACKGROUND: Adverse drug-drug interactions (DDI) are a major cause of morbidity and mortality in susceptible populations. Cancer patients are a population at high risk for DDI especially because they commonly receive several drugs concomitantly. The knowledge about the most common interactions between drugs used in oncology inpatients is essential to reduce drug-related problems and increase the safety and efficacy of the therapy. OBJECTIVE: To assess the frequency of potential DDI throughout the hospital stay of cancer patients undergoing systemic chemotherapy, describe their epidemiology, and identify risk factors for major DDI. Setting An oncology-hematology inpatient unit of a public hospital in southern Brazil. METHOD: Drug prescriptions were prospectively reviewed throughout the hospital stay of patients admitted for systemic chemotherapy. Descriptive statistics and Poisson regression were used for data analysis. MAIN OUTCOME MEASURE: Potential DDI and their characteristics. RESULTS: The cohort consisted of 113 patients, who used a mean of 8.9 +/- 2.7 drugs/day. All patients had at least one potential DDI (median, 7.0/patient; 25th-75th percentile, 3.5-12.0), and 46 % of the patients had at least one DDI classified as major, i.e. that it may result in death, hospitalization, permanent injury, or therapeutic failure. Only 13.7 % of all interactions involved antineoplastic agents, identified in 62.8 % of patients. Most interactions were of moderate severity, 6.4 % were major, and 8.5 % had a recommendation for therapy modification. Multivariate analysis revealed mean number of drugs prescribed [relative risk (RR) for each additional drug: 1.12; 95 % confidence interval (CI) 1.07-1.17; P < 0.01] and age >=60 years (RR 1.48; 95 % CI 1.03-2.14; P < 0.01) as independent risk factors for major DDI. CONCLUSION: Potential DDI were highly frequent in this cohort. Older age and number of drugs prescribed were more likely to lead to major interactions. Prospective surveillance is required to detect adverse DDI, aiming primarily at reducing the risk of toxicity or treatment failure. PMID- 25711853 TI - 5-HT3 receptors antagonists reduce serotonin-induced scratching in mice. AB - Serotonin (5-hydroxytryptamine, 5-HT) acts as a pruritogen in humans and animals, but the mechanisms of action through that serotonin induces itch response have not been extensively discovered. In our study, we attempted to investigate the role of 5-HT3 receptors in scratching behavior due to intradermal serotonin injection. Intradermal injection of serotonin (14.1-235 nmol/site) into the nape of the neck of mice was performed to elicit itch. Scratching behavior was evaluated by measuring the number of bouts during 60 min after injection. We evaluated the effect of intraperitoneal pretreatment with ondansetron and tropisetron (0.1, 0.3, and 1 mg/kg) on itch induced by serotonin. Also, intradermal ondansetron and tropisetron at doses 50, 100, and 200 nmol/site were concurrently administrated with serotonin. Serotonin produced a significant enhancement in scratching at dose 141 nmol/site. Concurrent administration of ondansetron (50, 100, and 200 nmol/site) and tropisetron (100 and 200 nmol/site) with serotonin reduced scratching activity compared to the animals that only received serotonin. Also, pretreatment with intraperitoneal ondansetron and tropisetron (0.3 and 1 mg/kg) 30 min before serotonin attenuated the itch response. We showed that the scratching induced by intradermal serotonin is mediated by 5-HT3 receptors subtype. It can be concluded that 5-HT3 may play a role in mediating serotonin-associated itch responses, and we introduce 5-HT3 receptors as possible targets for antipruritic agents. PMID- 25711854 TI - Effect of chain topology of polyethylenimine on physisorption and chemisorption of carbon dioxide. AB - Polyethylenimine (PEI) is a promising candidate for CO2 capture. In this work, the physisorption and chemisorption of CO2 on various low-molecular-weight PEIs are investigated to identify the effect of chain architecture on sorption. The reliability of theoretical calculations are partially supported by our experimental measurements. Physisorption is calculated independently by the reference interaction-site model integral equation theory; chemisorption is distinguished from the total sorption given by the quantum density functional theory. It is shown that, as the chain length increases, both chemisorption and physisorption drop off nonlinearly, but the decay amplitude of chemisorption is more apparent. Conversely, as the amine group approaches the central triamine unit of each oligomer, the sorption capacity decreases, affecting the sorption equilibrium in a complex way. This arises from the cooperative contribution of an increased steric effect and renormalized electronic distribution. PMID- 25711855 TI - Hospital teaching status and volume related to mortality after pancreatic cancer surgery in a national cohort. AB - BACKGROUND: The association between hospital teaching status and mortality after pancreatic resection is not well explored. Although hospital volume is related to short-term mortality, the effect on long-term survival needs investigation, taking into account hospital teaching status and selective referral patterns. METHODS: This was a nationwide retrospective register-based cohort study of patients undergoing pancreatic resection between 1990 and 2010. Follow-up for survival was carried out until 31 December 2011. The associations between hospital teaching status and annual hospital volume and short-, intermediate- and long-term mortality were determined by use of multivariable Cox regression models, which provided hazard ratios (HRs) with 95 per cent c.i. The analyses were mutually adjusted for hospital teaching status and volume, as well as for patients' sex, age, education, co-morbidity, type of resection, tumour site and histology, time interval, referral and hospital clustering. RESULTS: A total of 3298 patients were identified during the study interval. Hospital teaching status was associated with a decrease in overall mortality during the latest interval (years 2005-2010) (university versus non-university hospitals: HR 0.72, 95 per cent c.i. 0.56 to 0.91; P = 0.007). During all time periods, hospital teaching status was associated with decreased mortality more than 2 years after surgery (university versus non-university hospitals: HR 0.86, 0.75 to 0.98; P = 0.026). Lower annual hospital volume increased the risk of short-term mortality (HR for 3 or fewer compared with 4-6 pancreatic cancer resections annually: 1.60, 1.04 to 2.48; P = 0.034), but not long-term mortality. Sensitivity analyses with adjustment for tumour stage did not change the results. CONCLUSION: Hospital teaching status was strongly related to decreased mortality in both the short and long term. This may relate to processes of care rather than volume per se. Very low-volume hospitals had the highest short-term mortality risk. PMID- 25711856 TI - Paradoxically, iron overload does not potentiate doxorubicin-induced cardiotoxicity in vitro in cardiomyocytes and in vivo in mice. AB - Doxorubicin (DOX) is known to induce serious cardiotoxicity, which is believed to be mediated by oxidative stress and complex interactions with iron. However, the relationship between iron and DOX-induced cardiotoxicity remains controversial and the role of iron chelation therapy to prevent cardiotoxicity is called into question. Firstly, we evaluated in vitro the effects of DOX in combination with dextran-iron on cell viability in cultured H9c2 cardiomyocytes and EMT-6 cancer cells. Secondly, we used an in vivo murine model of iron overloading (IO) in which male C57BL/6 mice received a daily intra-peritoneal injection of dextran iron (15mg/kg) for 3weeks (D0-D20) and then (D21) a single sub-lethal intra peritoneal injection of 6mg/kg of DOX. While DOX significantly decreased cell viability in EMT-6 and H9c2, pretreatment with dextran-iron (125-1000MUg/mL) in combination with DOX, paradoxically limited cytotoxicity in H9c2 and increased it in EMT-6. In mice, IO alone resulted in cardiac hypertrophy (+22%) and up regulation of brain natriuretic peptide and beta-myosin heavy-chain (beta-MHC) expression, as well as an increase in cardiac nitro-oxidative stress revealed by electron spin resonance spectroscopy. In DOX-treated mice, there was a significant decrease in left-ventricular ejection fraction (LVEF) and an up regulation of cardiac beta-MHC and atrial natriuretic peptide (ANP) expression. However, prior IO did not exacerbate the DOX-induced fall in LVEF and there was no increase in ANP expression. IO did not impair the capacity of DOX to decrease cancer cell viability and could even prevent some aspects of DOX cardiotoxicity in cardiomyocytes and in mice. PMID- 25711858 TI - Announcement: double-blind peer review. PMID- 25711857 TI - Combination effects of AHR agonists and Wnt/beta-catenin modulators in zebrafish embryos: Implications for physiological and toxicological AHR functions. AB - Wnt/beta-catenin signaling regulates essential biological functions and acts in developmental toxicity of some chemicals. The aryl hydrocarbon receptor (AHR) is well-known to mediate developmental toxicity of persistent dioxin-like compounds (DLCs). Recent studies indicate a crosstalk between beta-catenin and the AHR in some tissues. However the nature of this crosstalk in embryos is poorly known. We observed that zebrafish embryos exposed to the beta-catenin inhibitor XAV939 display effects phenocopying those of the dioxin-like 3,3',4,4',5 pentachlorobiphenyl (PCB126). This led us to investigate the AHR interaction with beta-catenin during development and ask whether developmental toxicity of DLCs involves antagonism of beta-catenin signaling. We examined phenotypes and transcriptional responses in zebrafish embryos exposed to XAV939 or to a beta catenin activator, 1-azakenpaullone, alone or with AHR agonists, either PCB126 or 6-formylindolo[3,2-b]carbazole (FICZ). Alone 1-azakenpaullone and XAV939 both were embryo-toxic, and we found that in the presence of FICZ, the toxicity of 1 azakenpaullone decreased while the toxicity of XAV939 increased. This rescue of 1 azakenpaullone effects occurred in the time window of Ahr2-mediated toxicity and was reversed by morpholino-oligonucleotide knockdown of Ahr2. Regarding PCB126, addition of either 1-azakenpaullone or XAV939 led to lower mortality than with PCB126 alone but surviving embryos showed severe edemas. 1-Azakenpaullone induced transcription of beta-catenin-associated genes, while PCB126 and FICZ blocked this induction. The data indicate a stage-dependent antagonism of beta-catenin by Ahr2 in zebrafish embryos. We propose that the AHR has a physiological role in regulating beta-catenin during development, and that this is one point of intersection linking toxicological and physiological AHR-governed processes. PMID- 25711859 TI - Evolution of Tibetan wild boars. PMID- 25711860 TI - Reply to 'Evolution of Tibetan wild boars'. PMID- 25711861 TI - On genetic differentiation between domestic pigs and Tibetan wild boars. PMID- 25711862 TI - Reply to 'On genetic differentiation between domestic pigs and Tibetan wild boars'. PMID- 25711863 TI - YAP and the drug resistance highway. AB - Deciphering mechanisms of drug resistance is crucial to winning the battle against cancer. A new study points to an unexpected function of YAP in drug resistance and illuminates its potential role as a therapeutic target. PMID- 25711864 TI - Avalanching mutations in biallelic mismatch repair deficiency syndrome. AB - Tumors from pediatric patients generally contain relatively few somatic mutations. A new study reports a striking exception in individuals in whom biallelic germline deficiency for mismatch repair is compounded by somatic loss of function in DNA proofreading polymerases, resulting in 'ultra-hypermutated' malignant brain tumors. PMID- 25711865 TI - Big Bang and context-driven collapse. AB - Heterogeneity is the single most important factor driving cancer progression and treatment failure, yet little is understood about how and when this heterogeneity arises. A new study shows that colorectal cancers acquire their dominant mutations early in development and that subsequent mutations, even if they confer greater fitness, are unlikely to sweep through the tumor. PMID- 25711871 TI - Corrigendum: The genome sequence of the orchid Phalaenopsis equestris. PMID- 25711872 TI - Corrigendum: Mutations in the voltage-gated potassium channel gene KCNH1 cause Temple-Baraitser syndrome and epilepsy. PMID- 25711873 TI - Influenza seasonality in Madagascar: the mysterious African free-runner. AB - BACKGROUND: The seasonal drivers of influenza activity remain debated in tropical settings where epidemics are not clearly phased. Antananarivo is a particularly interesting case study because it is in Madagascar, an island situated in the tropics and with quantifiable connectivity levels to other countries. OBJECTIVES: We aimed at disentangling the role of environmental forcing and population fluxes on influenza seasonality in Madagascar. METHODS: We compiled weekly counts of laboratory-confirmed influenza-positive specimens for the period 2002 to 2012 collected in Antananarivo, with data available from sub-Saharan countries and countries contributing most foreign travelers to Madagascar. Daily climate indicators were compiled for the study period. RESULTS: Overall, influenza activity detected in Antananarivo predated that identified in temperate Northern Hemisphere locations. This activity presented poor temporal matching with viral activity in other countries from the African continent or countries highly connected to Madagascar excepted for A(H1N1)pdm09. Influenza detection in Antananarivo was not associated with travel activity and, although it was positively correlated with all climatic variables studied, such association was weak. CONCLUSIONS: The timing of influenza activity in Antananarivo is irregular, is not driven by climate, and does not align with that of countries in geographic proximity or highly connected to Madagascar. This work opens fresh questions regarding the drivers of influenza seasonality globally particularly in mid latitude and less-connected regions to tailor vaccine strategies locally. PMID- 25711874 TI - A maximum difference scaling survey of barriers to intensive combination treatment strategies with glucocorticoids in early rheumatoid arthritis. AB - The objectives of the study were to determine the relative importance of barriers related to the provision of intensive combination treatment strategies with glucocorticoids (ICTS-GCs) in early rheumatoid arthritis (ERA) from the rheumatologists' perspective and to explore the relation between rheumatologists' characteristics and importance scores. A maximum difference scaling (MDS) survey was administered to 66 rheumatologists in Flanders and the Brussels-Capital Region. The survey included 25 barriers, previously being discovered in a qualitative study. The survey included 25 choice sets, each of which contained a different set of four barriers. In each choice situation, respondents were asked to choose the most important barrier. The mean relative importance score (RIS) for each barrier was calculated using hierarchical Bayes modeling. The potential relation between rheumatologists' characteristics and the RIS was examined using Spearman's correlation coefficient, Mann-Whitney U test, and Kruskal-Wallis H test. The three highest ranked barriers included "contraindicated for some patients (e.g., patients with comorbidities, older patients)," "an increased risk of side effects and related complications," and "patients' resistance" with a mean +/- SD RIS of 9.76 +/- 0.82, 8.50 +/- 1.17, and 7.45 +/- 1.22, respectively. Comparing the RISs based on rheumatologists' characteristics, a different ranking was found for three barriers depending on the age, university location, and/or frequency of prescribing ICTS-GCs. The dominant barriers hindering ICTS-GCs prescription from a rheumatologists' perspective are patient-related barriers and barriers related to the complexity of prescribing a combination therapy including GCs. A tailored improvement intervention is needed to overcome these barriers and should focus on the familiarity of rheumatologists with ICTS-GC and patient education. PMID- 25711875 TI - 18F-FDG PET/CT in patients with adult-onset Still's disease. AB - (18)F-fluorodeoxyglucose positron emission tomography/computed tomography ((18)F FDG PET/CT) has become useful for the detection and diagnosis of inflammatory conditions, including rheumatic diseases, immunoglobulin (Ig) G4-related disease and giant cell arteritis. However, few articles based on small sample sizes (n = 7) diagnosed as adult-onset Still's disease (AOSD) have been published. The study aim was to observe the reliable characteristics and usefulness of (18)F-FDG PET/CT for the evaluation of consecutive patients with AOSD. Eligible patients were selected from among those who had undergone (18)F-FDG PET/CT between May 2007 and June 2014. Twenty-six consecutive AOSD patients were recruited retrospectively according to criteria set by Yamaguchi et al. All patients underwent evaluation by (18)F-FDG PET/CT. The characteristics and usefulness of (18)F-FDG PET/CT for evaluation of consecutive patients with AOSD were evaluated. All 26 patients had (18)F-FDG-avid lesion(s) related to their particular disease. Diffuse and homogeneous accumulation of (18)F-FDG was seen in the bone marrow (26/26; 100 %; maximum standardized uptake (SUVmax), 2.10-6.73) and spleen (25/26; 96.15 %). The SUVmax of affected lymph nodes was 1.3-9.53 (mean +/- SD, 4.12 +/- 2.24). The SUVmax and size factors (maximum diameter and areas) of affected lymph nodes were significantly different (P = 0.033 and P = 0.012, respectively). (18)F-FDG PET/CT showed the general distribution of (18)F-FDG accumulation. This factor helped to exclude malignant disease and aided the diagnosis of AOSD (42.3 %) in 11 cases when combined with clinical features and aided decisions regarding appropriate biopsy sites, such as the lymph nodes (n = 9) and bone marrow (n = 13). (18)F-FDG PET/CT is a unique imaging method for the assessment of metabolic activity throughout the body in subjects with AOSD. Characteristics or patterns of AOSD observed on (18)F-FDG PET/CT can be used for the indication and diagnosis or to guide the clinical management of ASOD. PMID- 25711876 TI - Early systemic sclerosis-opportunities for treatment. AB - Systemic sclerosis (SSc) is characterized by microvasculopathy (Raynaud's phenomenon and fibrointimal proliferation), presence of autoantibodies and collagen deposition in skin (scleroderma) and internal organs. Microvasculopathy, detected by nailfold capillaroscopy, and disease-specific autoantibodies (anti topoisomerase I, anti-centromere, anti-RNA polymerase III antibodies) usually appear earlier, even years before scleroderma. At that stage of the disease, immune activation with T cells and B cells promote fibrosis. Diagnosis of SSc has been relied on scleroderma, and by this time, internal organs may have developed fibrosis, a lethal feature with no available treatment. The new EULAR/ACR 2013 criteria for the classification of SSc will help identify SSc patients before fibrosis of internal organs. The early diagnosis of SSc, before the development of fibrosis in internal organs, will allow the introduction of immunosuppressive medications in these patients in a controlled setting (randomized trials). It is anticipated that this approach will change the hitherto grim prognosis of SSc for the better. PMID- 25711877 TI - Procoagulant microparticles are increased in patients with Behcet's disease but do not define a specific subset of clinical manifestations. AB - Microparticles (MP) are considered a key component in the haemostatic response. Beyond their in vitro procoagulant properties, a number of pieces of evidence points to procoagulant MP as efficient effectors in the haemostatic response and as pathogenic markers of thrombotic disorders and vascular damage. The aim of the present study was to analyze the procoagulant activity of MP and its correlation with clinical manifestations focusing on vascular involvement in patients with Behcet's disease (BD). We analyzed 55 BD patients in inactive phase of the disease (26 men; mean age, 35 +/- 15 years) of which 19 had previously suffered from thrombosis (deep venous thrombosis in 17 and ischemic stroke in 2), and 73 healthy controls matched for age and sex. Procoagulant MP were assessed by a functional assay. BD patients showed higher procoagulant MP values than controls (22.89 +/- 15.74 nM versus 14.47 +/- 7.34 nM; p < 0.0001). Conversely, we did not find differences in the levels of procoagulant MP according to the gender of patients (22.22 +/- 16.23 nM for men versus 21.46 +/- 16.47 for women; p = 0.846) or to previous and current treatments. Moreover, the plasmatic concentration of MP does not define any clinical phenotype and it was not related to the time of evolution of the disease. Although inactive BD patients had high values of procoagulant MP, they did not differentiate between BD patients with or without thrombosis. PMID- 25711878 TI - Effect of three different bariatric obesity surgery procedures on nutrient and energy digestibility using a swine experimental model. AB - Morbid obesity is a worldwide health concern that compromises life quality and health status of obese human subjects. Bariatric surgery for treating morbid obesity remains as one of the best alternatives to promote excess weight loss and to reduce co-morbidities. We have not found studies reporting nutrients and energy balance considering digestibility trials in humans following surgery. The purpose of this study was to determine protein, lipid, fiber, energy, calcium, and phosphorous digestibility in a swine model that underwent ileal transposition (IT), sleeve gastrectomy with ileal transposition (SGIT), Roux-en-Y gastric bypass (RYGBP), and with sham operated animals (SHAM). Thirty-two pigs were randomly assigned to four laparoscopic procedures: IT (n = 8), RYGBP (n = 8), SGIT (n = 8), and Sham-operated pigs (n = 8). From day 0 postsurgery to 130, pigs were weighed monthly to determine live weight and weight gain was calculated for each month postsurgery until day 130. Food intake in a metabolic weight basis was calculated by measuring ad libitum food intake at day 130. Swine were fitted into metabolic crates to determine digestibility coefficients of dry matter, protein, fat, fiber, ash, energy, calcium, and phosphorous from day 130. A one-way ANOVA and Student-Newman-Keuls were used to detect differences in weight, food intake, and digestibility coefficients. Digestibility values for dry matter, fiber, phosphorus, and energy showed no differences among groups (P > 0.05). However, significant differences (P <= 0.05) were encountered among groups for fat, protein, ash, and calcium digestibilities. The RYGBP procedure, when applied to the pig model, significantly reduced calcium, fat, and ash digestibility, which did not occur with SGIT or IT procedure, when compared with Sham-operated animals. PMID- 25711879 TI - Germanium in ginseng is low and causes no sodium and water retention or renal toxicity in the diuretic-resistant rats. AB - Ginseng preparations contain high concentrations of germanium (Ge), which was reported to contribute to diuretic resistance or renal failure. However, Ge content in ginseng and the influence on renal functions remain unclear. Forty rats were randomly divided into control group, low, moderate, and high Ge ginseng treated group and observed for 25 days. Daily urine, renal functions, and serum and urine electrolytics were measured. Ge retention in the organs and renal histological changes were also evaluated. Ge content ranged from 0.007 to 0.450 ug/g in various ginseng samples. Four groups showed no difference in the daily urine output, glomerular filtration rate, urinary electrolytes excretions, 24 h urine protein, as well as plasma and urine urea nitrogen, creatinine, osmotic pressure, and pH values. Ge did not cause any renal pathological effects in this study. No Na and water retention was detected in the ginseng-treated groups. Ge retention in various organs was found highest in spleen, followed by the kidney, liver, lung, stomach, heart, and pancreas. The total Ge contents in various ginsengs were low, and ginseng treatment did not affect renal functions or cause renal histological changes. PMID- 25711880 TI - Gastrointestinal ischemia monitoring through impedance spectroscopy as a tool for the management of the critically ill. AB - Impedance spectroscopy (IS) has been proposed as a tool for monitoring mucosal tissue ischemia and damage in the gut of critically ill patients resulting from shock and hypoperfusion. A specific device and system have been developed and tested for this specific application over the past 12 years by our research group. This paper reviews previously published studies as well as unpublished experimental results, and puts the whole in context and perspective to help understand this technology. Results presented include summaries of gastric reactance measurement understanding, in vivo measurements in animal models, clinical significance of the measurement, and future perspectives of clinical use of this technology. All of the experimental work done to date has been designed to determine the evolving device prototypes' performance and limitations from an instrumentation point of view. Although there are still questions to be answered with regard to the IS measurement, we conclude that we have reached enough confidence in the measurement and the device's performance and safety to begin clinically oriented research to learn how this technology may be useful in the diagnosis and management of different populations of the critically ill. PMID- 25711881 TI - 4-Nitrobenzaldehyde thiosemicarbazone: a new compound derived from S-(-)-limonene that induces mitochondrial alterations in epimastigotes and trypomastigotes of Trypanosoma cruzi. AB - Trypanosoma cruzi is the causative agent of Chagas' disease, a parasitic disease that remains a serious health concern with unsatisfactory treatment. Drugs that are currently used to treat Chagas' disease are partially effective in the acute phase but ineffective in the chronic phase of the disease. The aim of the present study was to evaluate the antitrypanosomal activity and morphological, ultrastructural and biochemical alterations induced by a new molecule, 4 nitrobenzaldehyde thiosemicarbazone (BZTS), derived from S-(-)-limonene against epimastigote, trypomastigote and intracellular amastigote forms of T. cruzi. BZTS inhibited the growth of epimastigotes (IC50 = 9.2 MU m), intracellular amastigotes (IC50 = 3.23 MU m) and inhibited the viability of trypomastigotes (EC50 = 1.43 MU m). BZTS had a CC50 of 37.45 MU m in LLCMK2 cells. BZTS induced rounding and distortion of the cell body and severely damaged parasite mitochondria, reflected by extensive swelling and disorganization in the inner mitochondrial membrane and the presence of concentric membrane structures inside the organelle. Cytoplasmic vacuolization, endoplasmic reticulum that surrounded organelles, the loss of mitochondrial membrane potential, and increased mitochondrial O2 *- production were also observed. Our results suggest that BZTS alters the ultrastructure and physiology of mitochondria, which could be closely related to parasite death. PMID- 25711882 TI - Control of the intermolecular coupling of dibromotetracene on Cu(110) by the sequential activation of C-Br and C-H bonds. AB - Dibromotetracene molecules are deposited on the Cu(110) surface at room temperature. The complex evolution of this system has been monitored at different temperatures (i.e., 298, 523, 673, and 723 K) by means of a variety of complementary techniques that range from STM and temperature-programmed desorption (TPD) to high-resolution X-ray spectroscopy (XPS) and near-edge X-ray absorption fine structure spectroscopy (NEXAFS). State-of-the-art density functional calculations were used to determine the chemical processes that take place on the surface. After deposition at room temperature, the organic molecules are transformed into organometallic monomers through debromination and carbon radical binding to copper adatoms. Organometallic dimers, trimers, or small oligomers, which present copper-bridged molecules, are formed by increasing the temperature. Surprisingly, further heating to 673 K causes the formation of elongated chains along the Cu(110) close-packed rows as a consequence of radical site migration to the thermodynamically more stable molecule heads. Finally, massive dehydrogenation occurs at the highest temperature followed by ring condensation to nanographenic patches. This study is a paradigmatic example of how intermolecular coupling can be modulated by the stepwise control of a simple parameter, such as temperature, through a sequence of domino reactions. PMID- 25711883 TI - Mitigated reactive oxygen species generation leads to an improvement of cell proliferation on poly[glycidyl methacrylate-co-poly(ethylene glycol) methacrylate] functionalized polydimethylsiloxane surfaces. AB - In vitro cell-based analysis is strongly affected by material's surface chemical properties. The cell spreading, migration, and proliferation on a substrate surface are initiated and controlled by successful adhesion, particularly for anchor-dependent cells. Unfortunately, polydimethylsiloxane (PDMS), one of the most used polymeric materials for construction of microfluidic and miniaturized biomedical analytic devices, is not a cell-friendly surface because of its inherent hydrophobic property. Herein, a poly[glycidyl methacrylate-co poly(ethylene glycol) methacrylate] (poly(GMA-co-pEGMA)) polymer brush was synthesized on a PDMS surface through a surface-initiated atom-transfer radical polymerization method. Contact angle and Fourier transform infrared characterization show that the poly (GMA-co-pEGMA) polymer brush functionalization can increase wettability of PDMS and introduce epoxy, hydroxyl, and ether groups into PDMS surface. In vitro cell growth assay demonstrates that cell adhesion and proliferation on poly(GMA-co-pEGMA) polymer brush functionalized PDMS (poly(GMA-co-pEGMA)@PDMS) are better than on pristine PDMS. Additionally, immobilization of collagen type I (CI) and fibronectin (FN) on poly(GMA-co-pEGMA)@PDMS is better than direct coating of CI and FN on pristine PDMS to promote cell adhesion. Furthermore, increased intracellular reactive oxygen species and cell mitochondrial membrane depolarization, two indicators of cell oxidative stress, are observed from cells growing on pristine PDMS, but not from those on poly(GMA-co-pEGMA)@PDMS. Collectively, we demonstrate that poly(GMA co-pEGMA) functionalization can enhance cell adhesion and proliferation on PDMS, and thus can be potentially used for microfluidic cell assay devices for cellular physiology study or drug screening. PMID- 25711886 TI - Intervening to alleviate word-finding difficulties in children: case series data and a computational modelling foundation. AB - We evaluated a simple computational model of productive vocabulary acquisition, applied to simulating two case studies of 7-year-old children with developmental word-finding difficulties across four core behavioural tasks. Developmental models were created, which captured the deficits of each child. In order to predict the effects of intervention, we exposed the computational models to simulated behavioural interventions of two types, targeting the improvement of either phonological or semantic knowledge. The model was then evaluated by testing the predictions from the simulations against the actual results from an intervention study carried out with the two children. For one child it was predicted that the phonological intervention would be effective, and the semantic intervention would not. This was borne out in the behavioural study. For the second child, the predictions were less clear and depended on the nature of simulated damage to the model. The behavioural study found an effect of semantic but not phonological intervention. Through an explicit computational simulation, we therefore employed intervention data to evaluate our theoretical understanding of the processes underlying acquisition of lexical items for production and how they may vary in children with developmental language difficulties. PMID- 25711887 TI - Authors' reply to Foster and colleagues. PMID- 25711888 TI - Medical Innovation Bill is fundamentally unworkable. PMID- 25711889 TI - NHS health checks are a waste of resources. PMID- 25711890 TI - Support for doctors working in immigration detention centres. PMID- 25711891 TI - Improving access to specialist palliative care. PMID- 25711892 TI - Early diagnosis and treatment: the goal of hepatitis C screening. PMID- 25711893 TI - NICE's recommendation on sofosbuvir for hepatitis C. PMID- 25711894 TI - Hepatitis C screening of men who have sex with men. PMID- 25711895 TI - Screening and treatment for hepatitis C: a balanced perspective. PMID- 25711896 TI - Authors' reply to Selvapatt and colleagues, Matthews and colleagues, Badrinath, and Ward and Lee. PMID- 25711897 TI - NHS health checks are totally unscientific. PMID- 25711898 TI - Doctors are free to innovate without fear of litigation. PMID- 25711899 TI - The FAST tool is effective but not for posterior fossa stroke. PMID- 25711900 TI - Response from Hepatitis C Trust, BASL, BIA, BVHG, BSG, and BHIVA to article asking whether widespread screening for hepatitis C is justified. PMID- 25711901 TI - FNA, core biopsy, or both for the diagnosis of lung carcinoma: Obtaining sufficient tissue for a specific diagnosis and molecular testing. AB - BACKGROUND: Increasingly, minimally invasive procedures are performed to assess lung lesions and stage lung carcinomas. In cases of advanced-stage lung cancer, the biopsy may provide the only diagnostic tissue. The aim of this study was to determine which method-fine-needle aspiration (FNA), core biopsy (CBx), or both (B)--is optimal for providing sufficient tissue for rendering a specific diagnosis and pursuing molecular studies for guiding tumor-specific treatment. METHODS: A search was performed for computed tomography-guided lung FNA, CBx, or B cases with rapid onsite evaluation. Carcinomas were assessed for the adequacy to render a specific diagnosis; this was defined as enough refinement to subtype a primary carcinoma or to assess a metastatic origin morphologically and/or immunohistochemically. In cases of primary lung adenocarcinoma, the capability of each modality to yield sufficient tissue for molecular studies (epidermal growth factor receptor, KRAS, or anaplastic lymphoma kinase) was also assessed. RESULTS: There were 210 cases, and 134 represented neoplasms, including 115 carcinomas. For carcinomas, a specific diagnosis was reached in 89% of FNA cases (33 of 37), 98% of CBx cases (43 of 44), and 100% of B cases (34 of 34). For primary lung adenocarcinomas, adequate tissue remained to perform molecular studies in 94% of FNA cases (16 of 17), 100% of CBx cases (19 of 19), and 86% of B cases (19 of 22). No statistical difference was found among the modalities for either reaching a specific diagnosis (p = .07, Fisher exact test) or providing sufficient tissue for molecular studies (p = .30, Fisher exact test). CONCLUSIONS: The results suggest that FNA, CBx, and B are comparable for arriving at a specific diagnosis and having sufficient tissue for molecular studies: they specifically attained the diagnostic and prognostic goals of minimally invasive procedures for lung carcinoma. PMID- 25711902 TI - Orosomucoid, an acute response protein with multiple modulating activities. AB - Orosomucoid (ORM), or alpha-1-acid glycoprotein (AGP), is one of the acute-phase proteins. It has a molecular weight of 37-54 kDa, low pI of 2.8-3.8, and is heavily glycosylated (45 %). It is mainly synthesized by the liver, but many extrahepatic tissues have also been reported to produce ORM under myriad physiological and pathological conditions. Expression of the ORM gene is mainly controlled by a combination of the major regulatory mediators, such as glucocorticoids, interleukin (IL)-1, TNF-alpha, and IL-6. ORM has many activities including, but not limited to, acting as an acute-phase reactant and disease marker, modulating immunity, binding and carrying drugs, maintaining the barrier function of capillary, and mediating the sphingolipid metabolism. Its related receptor has been preliminarily explored in macrophages, neutrophils, and liver parenchymal cells, involving the membrane receptor CCR5, Siglect-5, and HBB, respectively. Additional activities of ORM such as regulating metabolism are currently being explored. Because of its regulation in liver diseases, cancer, and HIV, future ORM research is warranted. PMID- 25711904 TI - "Knock once for yes, twice for no". AB - Previous studies have indicated that the expression of CCN3, a member of the CCN family of proteins, was tightly regulated during central nervous development and was associated with acquisition of cognitive functions in rats (Perbal, Mol Pathol 54(2):57-79, 2001; Su et al. Sheng Li Xue Bao 52(4):290-294, 2000) therefore suggesting that CCN3 might be involved in higher levels of physiological communication in the brain. In spite of the considerable amount of progress made into the understanding of neuronal organization and communication, reducing the knowledge gap between brain cellular biology and behavioral studies remains a huge challenge. Mind-to-mind communication has been the subject of numerous science fiction writings, intense research and emotional debates for many years. Scientists have tried for a long time to achieve transmission of messages between living subjects via non intrusive protocols. Thanks to the great progress made in imagery and neurosciences, another dimension of neuronal function in communication has now been documented. Two recent experimental demonstrations of direct brain to brain communication without physical contact (Grau et al. (2014) Conscious brain-to-brain communication in humans using non invasive technologies. PLoS One. Aug 19;9(8)- - Rao et al. (2014) A direct brain to-brain interface in humans. PLoS One. Nov 5;9(11)) pave the road to more sophisticated applications that could profoundly affect communications of humans with other humans, animals and machines. Although the wide use of such applications might seem a long way off, they raise quite a number of ethical, legal and societal issues. PMID- 25711903 TI - The NOTCH signaling pathway in normal and malignant blood cell production. AB - The NOTCH pathway is an evolutionarily conserved signalling network, which is fundamental in regulating developmental processes in invertebrates and vertebrates (Gazave et al. in BMC Evol Biol 9:249, 2009). It regulates self renewal (Butler et al. in Cell Stem Cell 6:251-264, 2010), differentiation (Auderset et al. in Curr Top Microbiol Immunol 360:115-134, 2012), proliferation (VanDussen et al. in Development 139:488-497, 2012) and apoptosis (Cao et al. in APMIS 120:441-450, 2012) of diverse cell types at various stages of their development. NOTCH signalling governs cell-cell interactions and the outcome of such responses is highly context specific. This makes it impossible to generalize about NOTCH functions as it stimulates survival and differentiation of certain cell types, whereas inhibiting these processes in others (Meier-Stiegen et al. in PLoS One 5:e11481, 2010). NOTCH was first identified in 1914 in Drosophila and was named after the indentations (notches) present in the wings of the mutant flies (Bigas et al. in Int J Dev Biol 54:1175-1188, 2010). Homologs of NOTCH in vertebrates were initially identified in Xenopus (Coffman et al. in Science 249:1438-1441, 1990) and in humans NOTCH was first identified in T-Acute Lymphoblastic Leukaemia (T-ALL) (Ellisen et al. in Cell 66:649-61, 1991). NOTCH signalling is integral in neurogenesis (Mead and Yutzey in Dev Dyn 241:376-389, 2012), myogenesis (Schuster-Gossler et al. in Proc Natl Acad Sci U S A 104:537 542, 2007), haematopoiesis (Bigas et al. in Int J Dev Biol 54:1175-1188, 2010), oogenesis (Xu and Gridley in Genet Res Int 2012:648207, 2012), differentiation of intestinal cells (Okamoto et al. in Am J Physiol Gastrointest Liver Physiol 296:G23-35, 2009) and pancreatic cells (Apelqvist et al. in Nature 400:877-881, 1999). The current review will focus on NOTCH signalling in normal and malignant blood cell production or haematopoiesis. PMID- 25711905 TI - How IGF-1 activates its receptor. AB - This study presents a new model for IGF-I receptor activation in which the transmembrane domains are held apart until ligand binding brings them together in an activated state. PMID- 25711906 TI - Heparan sulfate provides a mechanism to respond to FGFR2b and control regenerative expansion. AB - Fast varying 3-O-sulfated groups in epithelial KIT+ progenitors provides a cellular mechanism to respond to FGFR2b-mediated signaling and expansion of fetal and adult progenitors. This is allowed by the synthesis of 3-O-sulfated heparan sulfate that up-regulate KIT and 3-O-sulfotransferase enzymes, augmenting 3-O sulfated heparan sulfate. PMID- 25711907 TI - The evolution of human communication. PMID- 25711908 TI - Liver fibrosis occurs through dysregulation of MyD88-dependent innate B-cell activity. AB - Chronic liver disease mediated by activation of hepatic stellate cells (HSCs) leads to liver fibrosis. Here, we postulated that the immune regulatory properties of HSCs might promote the profibrogenic activity of B cells. Fibrosis is completely attenuated in carbon tetrachloride-treated, B cell-deficient uMT mice, showing that B cells are required. The retinoic acid produced by HSCs augmented B-cell survival, plasma cell marker CD138 expression, and immunoglobulin G production. These activities were reversed following addition of the retinoic acid inhibitor LE540. Transcriptional profiling of fibrotic liver B cells revealed increased expression of genes related to activation of nuclear factor kappa light chain enhancer of activated B cells, proinflammatory cytokine production, and CD40 signaling, suggesting that these B cells are activated and may be acting as inflammatory cells. Biological validation experiments also revealed increased activation (CD44 and CD86 expression), constitutive immunoglobulin G production, and secretion of the proinflammatory cytokines tumor necrosis factor-alpha, monocyte chemoattractant protein-1, and macrophage inflammatory protein-1alpha. Likewise, targeted deletion of B-cell-intrinsic myeloid differentiation primary response gene 88 signaling, an innate adaptor with involvement in retinoic acid signaling, resulted in reduced infiltration of migratory CD11c(+) dendritic cells and Ly6C(++) monocytes and, hence, reduced liver pathology. CONCLUSION: Liver fibrosis occurs through a mechanism of HSC mediated augmentation of innate B-cell activity. These findings highlight B cells as important "first responders" of the intrahepatic immune environment. PMID- 25711909 TI - A novel therapy strategy for bile duct repair using tissue engineering technique: PCL/PLGA bilayered scaffold with hMSCs. AB - The current clinical treatments for complications caused by hepatobiliary surgery still have some inevitable weakness. The aim of the study was to fabricate a tissue-engineered bile duct that utilized a novel bilayered polymer scaffold combined with human bone marrow-derived mesenchymal stem cells (hMSCs) for new treatment of biliary disease. The biocompatibility of polycaprolactone (PCL) (PCL)/poly(lactide-co-glycolide) (PLGA) scaffold with hMSCs was first examined, and the hMSC-PCL/PLGA constructs (MPPCs) prepared. The MPPCs and blank scaffolds were then transplanted into 18 pigs for evaluation its efficacy on bile duct repairing, respectively. In vitro, the PCL/PLGA scaffold was verified to support the adhesion, proliferation and matrix deposition of hMSCs. There was no sign of bile duct narrowing and cholestasis in all experimental animals. At 6 months, the MPPCs had a superior repairing effect on the bile duct injury, compared with the blank PCL/PLGA scaffolds. Therefore, the implanted scaffolds could not only support the biliary tract and allow free bile flow but also had direct or indirect positive effects on repair of injured bile duct. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 25711910 TI - ICAM1 depletion reduces spinal metastasis formation in vivo and improves neurological outcome. AB - INTRODUCTION: Clinical treatment of spinal metastasis is gaining in complexity while the underlying biology remains unknown. Insufficient biological understanding is due to a lack of suitable experimental animal models. Intercellular adhesion molecule-1 (ICAM1) has been implicated in metastasis formation. Its role in spinal metastasis remains unclear. It was the aim to generate a reliable spinal metastasis model in mice and to investigate metastasis formation under ICAM1 depletion. MATERIAL AND METHODS: B16 melanoma cells were infected with a lentivirus containing firefly luciferase (B16-luc). Stable cell clones (B16-luc) were injected retrogradely into the distal aortic arch. Spinal metastasis formation was monitored using in vivo bioluminescence imaging/MRI. Neurological deficits were monitored daily. In vivo selected, metastasized tumor cells were isolated (mB16-luc) and reinjected intraarterially. mB16-luc cells were injected intraarterially in ICAM1 KO mice. Metastasis distribution was analyzed using organ-specific fluorescence analysis. RESULTS: Intraarterial injection of B16-luc and metastatic mB16-luc reliably induced spinal metastasis formation with neurological deficits (B16-luc:26.5, mB16-luc:21 days, p<0.05). In vivo selection increased the metastatic aggressiveness and led to a bone specific homing phenotype. Thus, mB16-luc cells demonstrated higher number (B16-luc: 1.2+/ 0.447, mB16-luc:3.2+/-1.643) and increased total metastasis volume (B16 luc:2.87+/-2.453 mm3, mB16-luc:11.19+/-3.898 mm3, p<0.05) in the spine. ICAM1 depletion leads to a significantly reduced number of spinal metastasis (mB16 luc:1.2+/-0.84) with improved neurological outcome (29 days). General metastatic burden was significantly reduced under ICAM1 depletion (control: 3.47*10(7)+/ 1.66*10(7); ICAM-1-/-: 5.20*10(4)+/-4.44*10(4), p<0.05 vs. control) CONCLUSION: Applying a reliable animal model for spinal metastasis, ICAM1 depletion reduces spinal metastasis formation due to an organ-unspecific reduction of metastasis development. PMID- 25711912 TI - Erratum to: Patient-specific spinal stiffness in AIS: a preoperative and noninvasive method. PMID- 25711911 TI - The risks of aorta impingement from pedicle screw may increase due to aorta movement during posterior instrumentation in Lenke 5C curve: a computed tomography study. AB - PURPOSE: To investigate the aorta movement following correction surgery for patients with thoracolumbar/lumbar scoliosis and to determine the subsequent risk of the aorta impingement for pedicle screw (PS) misplacement. METHODS: Thirty-six AIS patients with a main thoracolumbar or lumbar curve were included in this study. According to the direction of the main curve, the patients were divided into Group R and Group L, with Group R comprising 16 patients with a right-sided curve and Group L comprising 20 patients with a left-sided curve. All patients underwent CT scans of the lower thoracic and lumbar spine before and after surgery. To identify the relative positions of the aorta to vertebral body, several parameters were measured from the CT images of the middle transverse planes of vertebrae from T11 to L4, including aorta-vertebra angle (alpha), vertebral rotation angle (beta), left safety distance (LSD) and right safety distance (RSD). The risk of the aorta impingement from T11 to L4 was calculated. An intragroup comparison regarding the position of the aorta relative to the vertebral body before and after correction surgery was performed accordingly. RESULTS: After surgery, the aorta moved toward the vertebral body among all levels in both groups. Compared with that in Group L, the aorta in Group R was significantly closer to the entry point at all levels, especially at T11. Before surgery, the aorta in Group R was at a high risk of impingement from left PS placement regardless of the diameters of the simulated screws. While in Group L, the risk of aorta impingement was mainly caused by the right placement of 45 mm PS. After surgery, both groups had an increased risk of aorta impingement from PS insertion, especially at T11. The risk of aorta impingement from PS placement was significantly higher in Group R than in Group L. CONCLUSION: The risk of aorta impingement increased as the aorta shifted leftward after correction surgery, especially in right-sided Lenke 5C curve. Thus, preoperative risk evaluation could be insufficient for clinical practice due to aorta movement following correction surgery. Surgeons should be aware of the potential risk of aorta impingement, especially when placing PS in patients with right-sided curves. PMID- 25711913 TI - Erratum to: Minimally invasive PLIF with divergent, cortical trajectory pedicle screws. PMID- 25711914 TI - Incidence and treatment of delayed symptoms of CSF leak following lumbar spinal surgery. AB - PURPOSE: Dural tear (DT) resulting in cerebrospinal fluid (CSF) leak is a common complication of spinal surgery. Most cases of DT are recognised and addressed intraoperatively; however, a small percentage of cases may present at a later stage with delayed symptoms of CSF leak, either due to an unrecognised intraoperative DT or as a result of a de novo delayed DT. Apart from few reports describing delayed symptomatic CSF leaks, most studies tend not to separate intraoperatively recognised DTs from delayed symptomatic CSF leaks. To our knowledge, there are no long-term studies describing specifically the incidence and management of this complication. The aim of this study is to determine the incidence of late presentation of dural tear (LPDT) following lumbar spinal surgery, its treatment, associated complications and clinical outcomes from long term follow-up in a consecutive series of patients. METHODS: A retrospective review was conducted on 2052 consecutive patients who underwent spinal surgery by two spinal surgeons from 2000 to 2005 and 2007 to 2013 at two institutions. RESULTS: A total of 2052 patient records were reviewed. Seventeen patients (0.83%) were found to have LPDT, unrecognised intraoperatively. Fifteen patients required surgical intervention, one patient was treated with insertion of a subarachnoid drain and only one patient settled with conservative measures. Out of the 15 patients who underwent surgery, two patients required another operation and 2 patients were treated with a subarachnoid drain. At 9 months mean follow up, there was no significant difference in outcome in cases with LPDT compared to those without. CONCLUSION: A delayed symptomatic presentation of DT unrecognised intraoperatively is a specific complication that needs to be recognised and treated appropriately. A high suspicion and vigilance can help discover and address delayed CSF leaks with no long-term sequelae. PMID- 25711915 TI - Mitochondria in health, aging and diseases: the epigenetic perspective. AB - The rate/quality of human aging and the development/progression of diseases depend on a complex interplay among genetics, epigenetics and environment. In this scenario, mitochondrial function (or dysfunction) and mitochondrial DNA have emerged as major players. This is mainly due to their crucial role in energetic balance, in modulating epigenetic programs and in influencing cell stress response. Moreover, it is also emerging the existence of epigenetic changes in mitochondrial DNA and of non coding mitochondrial RNAs which, together with the nuclear ones, play regulatory roles in numerous human phenotypes. In this review we will provide an overview on "mitochondrial epigenetics" state of the art, by summarizing the involvement of mitochondrial function and of mitochondria-nucleus communication in regulating nuclear epigenome, as well as the key aspects of the epigenetic marks related to mitochondrial DNA. Despite the limited data available in the literature to date, mainly due to the novelty of the topic, the intriguing interplay of the mitochondrial epigenetic changes in both physiological and pathological conditions will also be presented. PMID- 25711917 TI - Editorial Comment to p21-activated kinase 1 predicts recurrence and survival in patients with non-metastatic clear cell renal cell carcinoma. PMID- 25711916 TI - A guide to the use of anticoagulant drugs in children. AB - Increasing thrombotic complications in children with complex medication conditions have led to more widespread use of anticoagulants [Raffini et al. in Pediatrics 124(4):1001-8, 2009]. While current guidelines for the management of antithrombotic therapy in neonates and children exist, they are based on low- and very low-quality evidence [Monagle et al. in Chest 141(2 Suppl):e737-801S, 2012]. Despite numerous differences, current anticoagulation practice is largely extrapolated from adult studies. This is sub-optimal, particularly in neonates who have a rapidly evolving hemostatic system. The majority of pediatric patients have underlying medical conditions that may significantly influence drug choice and bleeding risk. This article reviews the use of anticoagulants in children with thrombosis, focusing on practical aspects such as dosing, monitoring, and complications. Low molecular weight heparin has become the preferred anticoagulant in children, although unfractionated heparin and warfarin remain frequently used. Other anticoagulants, including fondaparinux, direct thrombin inhibitors, and the newer target-specific oral anticoagulants are also discussed. Given the many unique challenges surrounding the use of anticoagulants in children, pediatric hospitals should have written practice guidelines as well as experienced providers to care for children with thrombosis. This is an evolving field, and further studies of the use of anticoagulants in neonates and children are greatly needed to help optimize care. PMID- 25711918 TI - Risk Factors of Epstein-Barr Virus Infection Among United States Children: Data From the National Health and Nutrition Examination Survey (NHANES), 2009-2010. AB - BACKGROUND: Epstein-Barr virus (EBV) has become a common medical condition in adolescents and young children. The objective of this study was to examine the association of low dietary intake and food insecurity with EBV infection. METHODS: Cross-sectional data were analyzed using the National Health and Nutrition Examination Survey 2009-2010 sample population (n = 1550) aged 6 to 15 years. Self-report data on dietary intake and food security were abstracted from data files. The outcome variable was measured using EBV index from the laboratory data. Multivariable logistic regression analysis was used to determine the association between exposure and outcome variables. RESULTS: The prevalence of EBV in this population was 56.4%. In the unadjusted analyses, adolescents who consumed 100% fruit juice (OR = 1.49, 95% CI = 1.09-2.05), beans (OR = 2.35, 95% CI = 1.12-4.94), and red meat (OR = 1.57, 95% CI = 1.09-2.24) daily had statistically significant elevated odds of EBV as compared to adolescents who consumed them monthly. Furthermore, adolescents who sometimes did not get fed a balanced meal and had to rely on low-cost food had statistically significant increased odds of EBV. However, after adjusting for potential confounders the results for both dietary factors and food insecurity were no longer statistically significant. CONCLUSIONS: Certain dietary factors and food insecurity may predispose children to EBV infection. PMID- 25711919 TI - C-terminal heat shock protein 90 modulators produce desirable oncogenic properties. AB - The cellular protection mechanism, the heat shock response, is only activated by classical heat shock 90 inhibitors (Hsp90) that "target" the N-terminus of the protein, but not by those that modulate the C-terminus. Significant differences in cytotoxicity (nanomolar) for classical inhibitors versus their ability to modulate Hsp90 (low micromolar) are discussed. In contrast, molecules that modulate Hsp90's C-terminus show similar IC50 values for cytotoxicity and Hsp90 inhibition. A comparison between the two types of Hsp90 inhibitors suggests that classical inhibitors may be modulating an alternative biological target that stresses the cell rather directly inhibiting Hsp90, whereas C-terminal modulators are most likely acting by directly inhibiting Hsp90. PMID- 25711920 TI - In vitro caloric restriction induces protective genes and functional rejuvenation in senescent SAMP8 astrocytes. AB - Astrocytes are key cells in brain aging, helping neurons to undertake healthy aging or otherwise letting them enter into a spiral of neurodegeneration. We aimed to characterize astrocytes cultured from senescence-accelerated prone 8 (SAMP8) mice, a mouse model of brain pathological aging, along with the effects of caloric restriction, the most effective rejuvenating treatment known so far. Analysis of the transcriptomic profiles of SAMP8 astrocytes cultured in control conditions and treated with caloric restriction serum was performed using mRNA microarrays. A decrease in mitochondrial and ribosome mRNA, which was restored by caloric restriction, confirmed the age-related profile of SAMP8 astrocytes and the benefits of caloric restriction. An amelioration of antioxidant and neurodegeneration-related pathways confirmed the brain benefits of caloric restriction. Studies of oxidative stress and mitochondrial function demonstrated a reduction of oxidative damage and partial improvement of mitochondria after caloric restriction. In summary, caloric restriction showed a significant tendency to normalize pathologically aged astrocytes through the activation of pathways that are protective against the age-related deterioration of brain physiology. PMID- 25711921 TI - Sustained linear growth and preserved renal function in 10-year survivors of pediatric liver transplantation. AB - The aim of this study was to characterize the clinical outcomes of children and adolescents who achieved survival of more than 10 years following liver transplantation (LT) in a single center in Korea. From June 1996 to October 2003, 57 pediatric LTs were performed. The medical records of 44 patients who had survived more than 10 years were reviewed retrospectively. Median age of patients at LT was 0.8 years. Forty-one patients received living donor LT, and three patients received deceased donor LT. Biliary atresia was the most common indication (65.9%). Thirty-five patients were on tacrolimus monotherapy at 10 years post-LT with a mean trough level of 2.73 ng/ml, and five patients were maintaining stable graft function without any immunosuppression. There were no patients receiving antihypertensive medication and one case of diabetes mellitus. Renal dysfunction was seen in two patients (4.5%), while none required renal replacement therapy. Mean height z-score prior to LT was -1.35 and at 10 years post-transplant was 0.05. Good linear growth was sustained in this cohort throughout the 10 years, approaching the 50th percentile. Also, there were remarkably low incidences of renal dysfunction and patients requiring medications for glycemic or hypertensive control, all hallmarks of continued use of immunosuppressive agents. PMID- 25711922 TI - Giant Pontine Capillary Telangiectasia. PMID- 25711923 TI - Percolating plasmonic networks for light emission control. AB - Optical nanoantennas have revolutionised the way we manipulate single photons emitted by individual light sources in a nanostructured photonic environment. Complex plasmonic architectures allow for multiscale light control by shortening or stretching the light wavelength for a fixed operating frequency, meeting the size of the emitter and that of propagating modes. Here, we study self-assembled semi-continuous gold films and lithographic gold networks characterised by large local density of optical state (LDOS) fluctuations around the electrical percolation threshold, a regime where the surface is characterised by large metal clusters with fractal topology. We study the formation of plasmonic networks and their effect on light emission from embedded fluorescent probes in these systems. Through fluorescence dynamics experiments we discuss the role of global long range interactions linked to the degree of percolation and to the network fractality, as well as the local near-field contributions coming from the local electro-magnetic fields and the topology. Our experiments indicate that local properties dominate the fluorescence modification. PMID- 25711924 TI - Catechol-O-methyltransferase, a new target for pancreatic cancer therapy. AB - Catechol-O-methyltransferase (COMT) is an important molecule in different types of cancers. Its biological effect and therapeutic significance, however, rarely been investigated fully in pancreatic cancer. Immunohistologically, high COMT expression was significantly correlated with the longer overall survival of patients (P < 0.05), indicating its protective nature. The effects of COMT on cell growth, apoptosis, and invasion were evaluated using overexpression and silencing methods. In detail, we carried out experiments using one stably transduced and two transiently transfected pancreatic cancer cell lines in vitro, and one stably transduced cell line in vivo mice xenograft models. In vitro experiments showed that COMT inhibited cell proliferation, enhanced gemcitabine induced apoptosis, and inhibited cell invasion in stably transduced and transiently transfected cell lines by regulating the PI3K/Akt pathway, p53, and E cadherin. The COMT overexpressed and silenced cell lines showed significantly inhibited and enhanced growth capacities in in vivo xenograft models, respectively. In conclusion, COMT suppressed pancreatic cancer and its high expression predicted longer survival time. The interaction of COMT with the PI3K/Akt pathway makes it a potential target for therapy. PMID- 25711925 TI - Ongoing challenges responding to behavioural and psychological symptoms of dementia. AB - BACKGROUND: Mid- to late-stage dementia is often characterized by behavioural and psychological symptoms, including, but not limited to physical and verbal aggression. INTRODUCTION: Although there is a considerable research about the prevalence, aetiology, and management of behavioural and psychological symptoms of dementia, there is limited research about the experience of caring for people with such symptoms in long-term aged care facilities. AIM: The aims of the study were to describe: (i) nurses' experiences of caring for people with behavioural and psychological symptoms of dementia in long-term aged care facilities, and (ii) strategies nurses used to deal with these symptoms. METHODS: A qualitative exploratory and descriptive design, involving focus group interviews with 30 nurses from three long-term aged care units in Australia. The transcripts were analysed using inductive content analysis. RESULTS: The findings revealed five interrelated themes: (i) working under difficult conditions, (ii) behavioural and psychological symptoms of dementia: an everyday encounter, (iii) making sense of behavioural and psychological symptoms of dementia, (iv) attempting to manage behavioural and psychological symptoms of dementia, and (v) feeling undervalued. CONCLUSION: This study highlighted the difficult conditions under which nurses worked and the complexity of caring for individuals who have behavioural and psychological symptoms of dementia. IMPLICATIONS FOR NURSING AND HEALTH POLICY: Organizational efforts to enhance the quality of care for individuals with behavioural and psychological symptoms of dementia in long-term aged care facilities should extend beyond staff education to heed nurses' concerns about organizational barriers to interpersonal care. PMID- 25711926 TI - Whole-mount single molecule FISH method for zebrafish embryo. AB - Noise in gene expression renders cells more adaptable to changing environment by imposing phenotypic and functional heterogeneity on genetically identical individual cells. Hence, quantitative measurement of noise in gene expression is essential for the study of biological processes in cells. Currently, there are two complementary methods for quantitatively measuring noise in gene expression at the single cell level: single molecule FISH (smFISH) and single cell qRT-PCR (or single cell RNA-seq). While smFISH has been developed for culture cells, tissue sections and whole-mount invertebrate organisms, the method has not been reported for whole-mount vertebrate organisms. Here, we report an smFISH method that is suitable for whole-mount zebrafish embryo, a popular vertebrate model organism for the studies of development, physiology and disease. We show the detection of individual transcripts for several cell-type specific and ubiquitously expressed genes at the single cell level in whole-mount zebrafish embryo. We also demonstrate that the method can be adapted to detect two different genes in individual cells simultaneously. The whole-mount smFISH method described in this report is expected to facilitate the study of noise in gene expression and its role in zebrafish, a vertebrate animal model relevant to human biology. PMID- 25711928 TI - Among the Dying. PMID- 25711927 TI - DRD2 Ser311Cys polymorphism and risk of schizophrenia. PMID- 25711929 TI - MicroRNA-122 targets genes related to liver metabolism in chickens. AB - MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression by targeting mRNAs. MicroRNA-122 (miR-122) has important functions in mammalian and fish livers, but its functions in the poultry liver are largely unknown. In this study, we determined the expression patterns of miR-122 in the chicken and identified its target genes in the chicken liver. We found that chicken miR-122 was highly expressed in the liver and that its expression in the liver was up regulated during the early posthatch life. By bioinformatics and reporter gene analyses, we identified PKM2, TGFB3, FABP5 and ARCN1 as miR-122 target genes in the chicken liver. miR-122 knockdown in primary chicken hepatocytes and expression analysis of miR-122 and predicted target mRNAs in the chicken liver suggested that the expression of PKM2 and FABP5 in the chicken liver is regulated by miR-122. Knockdown of miR-122 affected the expression of 123 genes in cultured chicken hepatocytes. Among these genes, the largest cluster, which consisted of 21 genes, was involved in liver metabolism. These findings suggest that miR-122 plays a role in liver metabolism in the chicken by directly or indirectly regulating the expression of genes involved in liver metabolism. PMID- 25711930 TI - Care for Postpartum Depression: What Do Women and Their Partners Prefer? AB - PURPOSE: To compare the preferences of those who accept a mental health assessment and those who do not. DESIGN AND METHODS: Thirty couples participated in a qualitative study. Nineteen couples accepted a mental health assessment and 11 declined. FINDINGS: Acceptors wanted more contact with professionals. Decliners preferred support from their informal network, parental leave, and exercise. However, acceptors also cited these preferences. PRACTICE IMPLICATIONS: Nurses should tailor care to couples' preferences, helping them identify and utilize preferred resources. Mental health care might be more acceptable to decliners if provided in obstetrical care. PMID- 25711931 TI - Molecular Phylogeny of Mobilid and Sessilid Ciliates Symbiotic in Eastern Pacific Limpets (Mollusca: Patellogastropoda). AB - The phylogenetic relationships of the ciliate subclass Peritrichia, composed of the orders Mobilida and Sessilida, have recently come under debate as morphological and molecular analyses have struck contrasting conclusions as to the monophyly of the group. We provide additional molecular data to assess the monophyly of the Peritrichia by sequencing the small subunit ribosomal RNA genes of two symbiotic peritrichs, Urceolaria korschelti and Scyphidia ubiquita, found inhabiting the mantle cavity of limpets. Although phylogenetic analyses indicated a nonmonophyletic Peritrichia, approximately unbiased tests revealed that the monophyletic hypothesis could not be rejected. With regard to the Mobilida, our analysis showed divergence within the family Trichodinidae related to host taxa-a molluscan clade and a fish clade. For the Sessilida, the family Scyphidiidae was sister to the Astylozoidae. In our sampling of U. korschelti and S. ubiquita, both species showed significant genetic divergence among geographically isolated, yet morphologically indistinguishable populations. We hypothesize that cryptic speciation has produced these morphologically identical species and argue that more extensive genomic analyses are required to fully assess the monophyly, biogeography, and ultimately biodiversity of the peritrichs. PMID- 25711933 TI - The medusa-headed myoma. PMID- 25711932 TI - Fatty acid-releasing activities in Sinorhizobium meliloti include unusual diacylglycerol lipase. AB - Phospholipids are well known for their membrane-forming properties and thereby delimit any cell from the exterior world. In addition, membrane phospholipids can act as precursors for signals and other biomolecules during their turnover. Little is known about phospholipid signalling, turnover and remodelling in bacteria. Recently, we showed that a FadD-deficient mutant of Sinorhizobium meliloti, unable to convert free fatty acids to their coenzyme A derivatives, accumulates free fatty acids during the stationary phase of growth. Enzymatic activities responsible for the generation of these free fatty acids were unknown in rhizobia. Searching the genome of S. meliloti, we identified a potential lysophospholipase (SMc04041) and two predicted patatin-like phospholipases A (SMc00930, SMc01003). Although SMc00930 as well as SMc01003 contribute to the release of free fatty acids in S. meliloti, neither one can use phospholipids as substrates. Here we show that SMc01003 converts diacylglycerol to monoacylglycerol and a fatty acid, and that monoacylglycerol can be further degraded by SMc01003 to another fatty acid and glycerol. A SMc01003-deficient mutant of S. meliloti transiently accumulates diacylglycerol, suggesting that SMc01003 also acts as diacylglycerol lipase (DglA) in its native background. Expression of the DglA lipase in Escherichia coli causes lysis of cells in stationary phase of growth. PMID- 25711934 TI - Molecular dynamics investigation of the substrate binding mechanism in carboxylesterase. AB - A recombinant carboxylesterase, cloned from Pseudomonas putida and designated as rPPE, is capable of catalyzing the bioresolution of racemic 2-acetoxy-2-(2' chlorophenyl)acetate (rac-AcO-CPA) with excellent (S)-enantioselectivity. Semirational design of the enzyme showed that the W187H variant could increase the activity by ~100-fold compared to the wild type (WT) enzyme. In this study, we performed all-atom molecular dynamics (MD) simulations of both apo-rPPE and rPPE in complex with (S)-AcO-CPA to gain insights into the origin of the increased catalysis in the W187H mutant. Our results show differential binding of (S)-AcO-CPA in the WT and W187H enzymes, especially the interactions of the substrate with the two active site residues Ser159 and His286. The replacement of Trp187 by His leads to considerable structural rearrangement in the active site of W187H. Unlike in the WT rPPE, the cap domain in the W187 mutant shows an open conformation in the simulations of both apo and substrate-bound enzymes. This open conformation exposes the catalytic triad to the solvent through a water accessible channel, which may facilitate the entry of the substrate and/or the exit of the product. Binding free energy calculations confirmed that the substrate binds more strongly in W187H than in WT. On the basis of these computational results, we further predicted that the mutations W187Y and D287G might also be able to increase the substrate binding and thus improve the enzyme's catalytic efficiency. Experimental binding and kinetic assays on W187Y and D287G show improved catalytic efficiency over WT, but not W187H. Contrary to our prediction, W187Y shows slightly decreased substrate binding coupled with a 100-fold increase in turnover rate, while in D287G the substrate binding is 8 times stronger but with a slightly reduced turnover rate. Our work provides important molecular-level insights into the binding of the (S)-AcO-CPA substrate to carboxylesterase rPPEs, which will help guide future development of more efficient rPPE variants. PMID- 25711935 TI - Antecedent moisture and temperature conditions modulate the response of ecosystem respiration to elevated CO2 and warming. AB - Terrestrial plant and soil respiration, or ecosystem respiration (Reco ), represents a major CO2 flux in the global carbon cycle. However, there is disagreement in how Reco will respond to future global changes, such as elevated atmosphere CO2 and warming. To address this, we synthesized six years (2007-2012) of Reco data from the Prairie Heating And CO2 Enrichment (PHACE) experiment. We applied a semi-mechanistic temperature-response model to simultaneously evaluate the response of Reco to three treatment factors (elevated CO2 , warming, and soil water manipulation) and their interactions with antecedent soil conditions [e.g., past soil water content (SWC) and temperature (SoilT)] and aboveground factors (e.g., vapor pressure deficit, photosynthetically active radiation, vegetation greenness). The model fits the observed Reco well (R2 = 0.77). We applied the model to estimate annual (March-October) Reco , which was stimulated under elevated CO2 in most years, likely due to the indirect effect of elevated CO2 on SWC. When aggregated from 2007 to 2012, total six-year Reco was stimulated by elevated CO2 singly (24%) or in combination with warming (28%). Warming had little effect on annual Reco under ambient CO2 , but stimulated it under elevated CO2 (32% across all years) when precipitation was high (e.g., 44% in 2009, a 'wet' year). Treatment-level differences in Reco can be partly attributed to the effects of antecedent SoilT and vegetation greenness on the apparent temperature sensitivity of Reco and to the effects of antecedent and current SWC and vegetation activity (greenness modulated by VPD) on Reco base rates. Thus, this study indicates that the incorporation of both antecedent environmental conditions and aboveground vegetation activity are critical to predicting Reco at multiple timescales (subdaily to annual) and under a future climate of elevated CO2 and warming. PMID- 25711936 TI - Fluoxetine and S-citalopram inhibit M1 activation and promote M2 activation of microglia in vitro. AB - Increasing evidence has suggested that microglia dysfunction plays an important role in the pathogenesis of depression. Both classical activation (M1 activation) and alternative activation (M2 activation) may be involved in the process. M1 activated microglia secrete various pro-inflammatory cytokines and neurotoxic mediators, which may contribute to the development of depression, while M2 activated microglia promote tissue reconstruction by releasing anti-inflammatory cytokines involved in the process of depression. Selective serotonin reuptake inhibitors (SSRIs) are first-line treatments for depression, and their effects on immune system modulation have recently gained attention. Several studies have suggested that SSRIs affect the M1 activation of microglia, but results have varied. In addition, little is known about the effect of SSRIs on M2 activation in depression. The aim of this study was to investigate the effects of fluoxetine and S-citalopram, two widely used SSRIs in clinical, on both the M1 and M2 activation of microglia (the murine BV2 cell line and mouse primary microglia cell). The indexes of activation were measured by real-time polymerase chain reaction (PCR), enzyme-linked immunosorbent assay (ELISA) and Western blot. The present results showed that both fluoxetine and S-citalopram significantly down regulated the indexes of M1 activation and up-regulated the M2 activation indexes on mRNA and protein levels either in cell line or primary cells. Taken together, the results suggested that fluoxetine and S-citalopram modulated the immune system by inhibiting M1 activation and by improving M2 activation of microglia and that the immune system modulation may partially mediate the therapeutic effects of antidepressant drugs-SSRIs. PMID- 25711937 TI - Increased gain of vestibulospinal potentials evoked in neck and leg muscles when standing under height-induced postural threat. AB - OBJECTIVE: To measure changes in amplitudes of vestibular evoked myogenic potentials (VEMPs) elicited from neck, upper and lower limb muscles during a quiet standing task with increased postural threat achieved by manipulating surface height. METHODS: Twenty eight subjects were tested while standing on a platform raised to 0.8 m and 3.2 m from the ground. Surface electromyography was recorded from the ipsilateral sternocleidomastoid (SCM), biceps brachii (BB), flexor carpi radialis (FCR), soleus (SOL) and medial gastrocnemius (MG) muscles. Stimulation was with air-conducted short tone bursts (4 ms). After controlling for background muscle activity, VEMP amplitudes were compared between heights and correlated with changes in state anxiety, fear and arousal. RESULTS: VEMP amplitude significantly increased in SCM (9%) and SOL (12.7%) with increased surface height (p<0.05). These modest increases in SCM VEMP amplitude were significantly correlated with anxiety (Rho=0.57, p=0.004) and confidence (Rho= 0.38, p=0.047) and those for SOL were significantly correlated with anxiety (Rho=0.33, p=0.049) and fear (Rho=0.36, p=0.037). CONCLUSION: Postural threat significantly increased vestibulospinal reflex (VSR) gains. Results demonstrate that VEMPs can be used to test different VSR pathways simultaneously during stance. Since fear and anxiety are prevalent with vestibular disorders, they should be considered as potential contributing factors for clinical vestibular outcome measures. PMID- 25711938 TI - The role of connexin43-Src interaction in astrocytomas: A molecular puzzle. AB - Connexin43 (Cx43) as a building block of gap junction channels and hemichannels exerts important functions in astrocytes. When these cells acquire a malignant phenotype Cx43 protein but not mRNA levels are downregulated, being negligible in high-grade astrocytoma or glioblastoma multiforme, the most common and deadliest of malignant primary brain tumors in adults. Some microRNAs associated to glioma target Cx43 and could explain the lack of correlation between mRNA and protein levels of Cx43 found in some high-grade astrocytomas. More importantly, these microRNAs could be a promising therapeutic target. A great number of studies have confirmed the relationship between cancer and connexins that was proposed by Loewenstein more than 40years ago, but these studies have also revealed that this is a very complex relationship. Indeed, restoring Cx43 to glioma cells reduces their rate of proliferation and their tumorigenicity but this tumor suppressor effect could be counterbalanced by its effects on invasiveness, adhesion and migration. The mechanisms underlying these effects suggest the participation of a great variety of proteins that bind to different regions of Cx43. The present review focuses on an intrinsically disordered region of the C-terminal domain of Cx43 in which converges the interaction of several proteins, including the proto oncogene Src. We summarize data that indicate that Cx43-Src interaction inhibits the oncogenic activity of Src and promotes a conformational change in the structure of Cx43 that allosterically modifies the binding to other important signaling proteins. As a consequence, crucial cell functions, such as proliferation or migration, could be strongly affected. We propose that the knowledge of the structural basis of the antitumorigenic effect of Cx43 on astrocytomas could help to design new therapies against this incurable disease. PMID- 25711939 TI - Metaplastic up-regulation of LTP in the rat visual cortex by monocular visual training: requirement of task mastery, hemispheric specificity, and NMDA-GluN2B involvement. AB - "Metaplasticity" is defined as an alteration of synaptic plasticity properties or mechanisms by a priming event without actual changes in synaptic strength. For example, visual discrimination training of rats leads to a facilitation of the subsequent induction of long-term potentiation (LTP) between the lateral geniculate nucleus (LGN) and the primary visual cortex (V1). Here, rats received visual discrimination training in a modified water maze, with one eye occluded during training to create monocular viewing conditions; 63% of rats acquired the task under these conditions. Following training, in vivo electrophysiology was used to examine LTP of field postsynaptic potentials (fPSPs) in V1 elicited by LGN stimulation. Rats that had successfully learned the task showed significantly greater LTP in the "trained V1" (contralateral to the open, trained eye) relative to the "untrained" hemisphere. Rats that underwent training but failed to acquire the task did not show this lateralized plasticity enhancement and had similar levels of LTP in both cerebral hemispheres. Cortical application of the NMDA receptor-GluN2B subunit antagonist Ro 25-6981 (2 mM) reversed the training induced LTP facilitation without affecting LTP in the untrained V1. Whole-cell patch clamp recordings of V1 (layers II/III) pyramidal cells in vitro demonstrated that pharmacologically isolated NMDA currents exhibit a greater sensitivity to GluN2B blockade in the trained relative to the untrained V1. Together, these experiments reveal a surprising degree of anatomical (only in the hemisphere contralateral to the trained eye) and behavioral specificity (only in rats that mastered the task) for the effect of visual training to enhance LTP in V1. Further, cortical GluN2B subunits appear to be directly involved in this metaplastic facilitation of thalamocortical plasticity, suggesting that NMDA subunit composition or functioning is, at least in part, regulated by the exposure to behaviorally significant stimuli in an animal's sensory environment. PMID- 25711940 TI - Src controls neuronal migration by regulating the activity of FAK and cofilin. AB - Migration of postmitotic neurons in the developing cortex along radial glial fiber is essential for the formation of cortical layers. Several neurological diseases are caused by defects in neuronal migration, underlining the importance of this process for brain function. Multiple molecules are involved in this process. However, the precise mechanisms are largely unknown. In the present study, we examined the expression of Src in the developing cortex and investigated the role of Src in neuronal migration and its cellular and molecular mechanisms. Our results showed that Src was strongly expressed in the cerebral cortex during corticogenesis and mainly targeted to the leading processes of migrating neurons. Overexpression of wildtype Src (Src-WT) and its mutants, constitutively active Src (Src-CA) and dominant negative Src (Src-DN) in the mouse brain by in utero electroporation perturbed neuronal migration through affecting the adhesion properties and cytoskeletal dynamics of migrating neurons. Overexpression of Src-WT and Src-CA induced aggregation and branching of migrating neurons, whereas overexpression of Src-DN led to abnormal elongation of the leading processes of migrating neurons. Furthermore, we showed that Src activates the focal adhesion kinase (FAK) and cofilin by regulating their phosphorylation levels. We conclude that Src controls neuronal migration by regulating adhesion properties and F-actin dynamics of migrating neurons. PMID- 25711941 TI - Serotonin transporter polymorphism modulates neural correlates of real-life joint action. An investigation with functional near-infrared spectroscopy (fNIRS). AB - A functional polymorphism (5-HTTLPR) within the serotonin transporter gene (SERT) has been associated with personality dimensions such as neuroticism, with emotional reactivity to negative events, and with an increased risk of affective disorders. More specifically, the short (S) allele of 5-HTTLPR has been linked to increased amygdala activity and has been identified as a risk allele for depressive disorders. Recently, Homberg and Lesch (2011) urged for a conceptual change in the current deficit-oriented connotation of the 5-HTTLPR S-allele and argued that the S-allele could be considered adaptive in certain contexts. They postulated that S-allele carriers show hypervigilant behavior in social situations and should thus show increased social conformity. Therefore, we tested whether 5-HTTLPR modulates the neural correlates of real-life social joint action through functional near-infrared spectroscopy (fNIRS). Thirty participants, homozygote for 5-HTTLPR, were measured and analyzed while they were involved in a previously published joint-action paradigm, which reliably leads to an activation of the left parietal cortex. We found that homozygote S-allele carriers showed increased inferior parietal lobe activation, compared to the LL-allele carriers for the contrast "joint action greater solo action". Therefore, our results provide evidence for beneficial effects of the S-allele on the neural correlates of social interactions. PMID- 25711942 TI - Longitudinal changes in maternal and neonatal anthropometrics: a case study of the Helsinki Birth Cohort, 1934-1944. AB - Changes in anthropometrics often reflect changes in living conditions, and one's characteristics at birth may be associated with future health. The aim of this study was to investigate the secular trends in maternal and neonatal anthropometrics in the Helsinki Birth Cohort Study. The study participants, thus, comprised all 13,345 live births recorded in Helsinki, Finland, between 1934 and 1944. Adult characteristics of the clinical subsample comprised of 2003 individuals, alive during 2003, were also analyzed. Linear Regression analysis with seasonal terms was applied to see whether clinically and statistically significant trends can be found in maternal age, height and body mass index (BMI) at pregnancy; gestational age, birth weight, ponderal index and sex ratio; and adult height, BMI and fat percentage. Statistically significant trends were found in maternal age and maternal BMI with abrupt changes between 1941 and 1944. Gestational age increased by an average of 0.11% per year (P<0.0001), and the proportion of premature births dropped from 7.9% in 1934 to 4.5% in 1944 (P<0.0001). In the clinical sample, a statistically significant, although small, average annual increase of 0.1% in adult heights was detected (P=0.0012 for men and P=0.0035 for women). In conclusion, although no significant changes were found in either neonatal or adult anthropometrics of babies born in Helsinki between 1934 and 1944, there were abrupt changes in the characteristics of their mothers. PMID- 25711943 TI - Lymphoproliferative disease and cancer among patients with common variable immunodeficiency. AB - Innate immune deficiencies are a heterogeneous group of genetically inherited diseases affecting the innate and adaptive immune systems that confer susceptibility to infection, autoimmunity, and cancer. This review discusses the latest insights into the links between common variable immunodeficiency (CVI) and malignancies. Although Ig therapy greatly reduces the number of infections and enhances survival, it does not appear to address the development of cancer, especially lymphoma. The reasons for the increased susceptibility to lymphoid malignancies are unclear. These include genetics, immune dysregulation, radiosensitivity and chronic infections such as Helicobacter pylori, EBV, human herpes virus type 8 and cytomegalovirus. Further studies will allow us to better stratify the risk for cancer in these patients, and teach us to better prevent these complications and to better treat them. PMID- 25711945 TI - Intrinsic and extrinsic innervation of the heart in zebrafish (Danio rerio). AB - In the vertebrate heart the intracardiac nervous system is the final common pathway for autonomic control of cardiac output, but the neuroanatomy of this system is not well understood. In this study we investigated the innervation of the heart in a model vertebrate, the zebrafish. We used antibodies against acetylated tubulin, human neuronal protein C/D, choline acetyltransferase, tyrosine hydroxylase, neuronal nitric oxide synthase, and vasoactive intestinal polypeptide to visualize neural elements and their neurotransmitter content. Most neurons were located at the venous pole in a plexus around the sinoatrial valve; mean total number of cells was 197 +/- 23, and 92% were choline acetyltransferase positive, implying a cholinergic role. The plexus contained cholinergic, adrenergic, and nitrergic axons and vasoactive intestinal polypeptide-positive terminals, some innervating somata. Putative pacemaker cells near the plexus showed immunoreactivity for hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4) and the transcription factor Islet-1 (Isl1). The neurotracer neurobiotin showed that extrinsic axons from the left and right vagosympathetic trunks innervated the sinoatrial plexus proximal to their entry into the heart; some extrinsic axons from each trunk also projected into the medial dorsal plexus region. Extrinsic axons also innervated the atrial and ventricular walls. An extracardiac nerve trunk innervated the bulbus arteriosus and entered the arterial pole of the heart to innervate the proximal ventricle. We have shown that the intracardiac nervous system in the zebrafish is anatomically and neurochemically complex, providing a substrate for autonomic control of cardiac effectors in all chambers. PMID- 25711944 TI - Use of ED and hospital services for patients with acute leukemia after induction therapy: one year follow-up. AB - Previous studies have documented use of health care services by oncology patients in the Emergency Department (ED), but little is known about the utilization of health services of patients with acute leukemia after induction therapy. The aim of this study was to examine chief reasons for ED and hospital use by patients newly diagnosed with acute leukemia patients after induction therapy up to one year after discharge. A retrospective, longitudinal study of all visits to the ED or unplanned hospital admissions at a single institution for patients with acute leukemia was conducted. Inclusion criteria were patients >=18 years of age at time of diagnosis, a confirmed diagnosis of AML or ALL, and received and discharged from induction treatment between 2007 and 2010. Donabedian's structure process-outcome framework guided this study examining health services utilization and assessing patient outcomes. 80 patients met the inclusion criteria; 52 had AML and 28 had ALL; median age was 48 (range: 18-76) and 29% (n=23) were non Caucasian. 70% (n=56) were discharged from induction in remission. 81% (n=65) had at least 1 ED or hospitalization event, and 44% (n=35) had 2 or more events. Of 137 events in 65 patients, the most common reason was neutropenic fever/infection (55%), bleeding (12%), and GI problems (11%). Mean number of events for ALL was 2.43 compared to 1.33 for AML patients (p=0.02), and 2.23 for <50 years of age compared to 1.20 for those older (p=0.002). 20 patients died within one year of diagnosis. Findings from this study can help inform health services delivery and utilization among patients with acute leukemia after induction therapy. Oncology providers can anticipate discharge needs and enhance follow-up care for those at higher risk for problems needing hospitalization. PMID- 25711947 TI - Appreciation--Professor Godfrey Paul Bolwell MA DSc: 13 December 1946-13 April 2012. PMID- 25711946 TI - Extracorporeal membrane oxygenation: a radiologists' guide to who, what and where. AB - Extracorporeal membrane oxygenation (ECMO) is the short-term (days to weeks) support of patients with severe respiratory and/or cardiac failure. The use of these devices has been well established in paediatric and post-heart and lung transplantation patients; however, its use in patients with severe acute respiratory distress syndrome (ARDS) has gained acceptance as standard clinical practice over the past decade. The results of the CESAR trial (Conventional ventilation or ECMO for Severe Adult Respiratory failure) showed significant survival benefit for patients with ARDS undergoing ECMO. Substantial numbers of radiological examinations are performed in this patient group, prompting the need for general radiologists to understand the radiological appearances of these devices and associated complications. In this review, we highlight the uses, subtypes, physiology, normal appearances, and complications of ECMO. An example of the chronological radiographic images in the perioperative period demonstrates the importance of discriminating normal appearances associated with EMCO. PMID- 25711948 TI - Editorial for Phytochemistry issue 'In memory of G. Paul Bolwell: Plant cell wall dynamics'. PMID- 25711949 TI - The return of the prodigal son and the extraordinary development route of antibody TGN1412 - lessons for drug development and clinical pharmacology. PMID- 25711950 TI - The Australian Work Exposures Study: prevalence of occupational exposure to diesel engine exhaust. AB - BACKGROUND: Diesel engines are widely used in occupational settings. Diesel exhaust has been classified as a lung carcinogen, but data on number of workers exposed to different levels of diesel exhaust are not available in Australia. The aim of this study was to estimate the current prevalence of exposure to diesel engine exhaust in Australian workplaces. METHODS: A cross-sectional survey of Australian males and females (18-65 years old) in current paid employment was undertaken. Information about the respondents' current job and various demographic factors was collected in a telephone interview using the web-based tool OccIDEAS. Semi-quantitative occupational exposure levels to diesel exhaust were assigned using programmed decision rules and numbers of workers exposed in Australia in 2011 were estimated. We defined substantial exposure as exposed at a medium or high level, for at least 5h per week. RESULTS: Substantial occupational exposure to diesel exhaust was experienced by 13.4% of the respondents in their current job. Exposure prevalence varied across states, ranging from 6.4% in the Australian Capital Territory to 17.0% in Western Australia. Exposures occurred mainly in the agricultural, mining, transport and construction industries, and among mechanics. Men (20.4%) were more often exposed than women (4.7%). Extrapolation to the total working population indicated that 13.8% (95% confidence interval 10.0-20.4) of the 2011 Australian workforce were estimated to be substantially exposed to diesel exhaust, and 1.8% of the workers were estimated to experience high levels of exposures in their current job. CONCLUSION: About 1.2 million Australian workers were estimated to have been exposed to diesel exhaust in their workplace in 2011. This is the first study to describe the prevalence of occupational diesel exhaust exposure in Australia and will enable estimation of the number of lung cancers attributable to diesel exhaust exposure in the workplace. PMID- 25711951 TI - Incidence of Chronic and Other Knee Pain in Relation to Occupational Risk Factors in a Large Working Population. AB - OBJECTIVES: The aim of this study was to estimate the incidence of chronic and other knee pain (KP) in relation to occupational and personal risk factors among workers representative of a general working population. METHODS: Of 3710 workers in a French region included in a surveillance network for musculoskeletal disorders (2002-2005), 2332 completed a follow-up questionnaire in 2007-2009 (Cosali cohort). The questionnaires included questions on musculoskeletal symptoms, and personal and occupational exposure. Incident cases of KP in 2007 2009 (i.e. with KP at follow-up but not at baseline) were dichotomized into chronic KP (>30 days in the previous year) and other KP. Associations between incident KP and personal and occupational factors at baseline were studied separately according to sex using multinomial logistic regression. RESULTS: Of the 1616 respondents without KP at baseline, 122 (7.5%) reported chronic KP and 243 (15.0%) reported other KP. The incidence rate of chronic KP was estimated at 19.6 per 1000 worker-years (95% CI: 16.3-23.5). After adjustment for age and body mass index, significant associations were found between incident chronic KP and handling loads >4kg [odds ratio (OR) 2.1 (1.2-3.6) for men, OR 2.3 (1.1-5.0) for women] and kneeling >2h a day for men [OR 1.8 (1.0-3.0)]. CONCLUSIONS: This study highlights the high frequency of chronic KP in the working population and the role of occupational factors in its incidence, in particular those kneeling and handling loads. PMID- 25711952 TI - The effect of C-reactive protein reduction with a highly specific antisense oligonucleotide on atrial fibrillation assessed using beat-to-beat pacemaker Holter follow-up. AB - PURPOSE: C-reactive protein (CRP) is known to be strongly associated with atrial fibrillation (AF). However, it is not clear if CRP is a causal factor for AF. ISIS-CRPRx is a novel antisense oligonucleotide that reduces CRP production by specifically inhibiting mRNA translation. The effect of ISIS-CRPRx on AF was evaluated. METHODS: A double-blind phase II trial of ISIS-CRPRx in patients with paroxysmal AF and DDDRP permanent pacemakers (PPMs) with advanced atrial and ventricular Holters allowing beat-to-beat arrhythmia follow-up. RESULTS: Twenty six patients were screened and seven patients dosed with ISIS-CRPRx. After 4 weeks of baseline assessment, patients were randomly assigned to two treatment periods of either placebo then ISIS-CRPRx or ISIS-CRPRx then placebo. All patients were followed up for 8 weeks after the active treatment period. There was a 63.7 % (95 % CI 38.4 to 78.6 %, p = 0.003) relative reduction in CRP on treatment with ISIS-CRPRx versus baseline. Sensitivity analyses demonstrated a consistent treatment effect. The primary end-point was change in AF burden assessed by PPM. There was no significant difference in AF burden on treatment with ISIS-CRPRx versus baseline (OR 1.6, 95 % CI -2.42 to 5.62, p = 0.37). ISIS CRPRx was safe and well tolerated and there were no serious adverse events. CONCLUSIONS: Treatment with ISIS-CRPRx did not reduce AF burden in patients with paroxysmal AF and PPMs, despite a large relative reduction in CRP. In this population, highly specific CRP reduction had no clinically discernable effect upon paroxysmal AF. However, average levels of CRP at baseline were relatively low, so it remains possible that AF patients with higher levels of CRP may benefit from CRP-directed therapy. PMID- 25711953 TI - Left atrial appendage occlusion for prevention of stroke in nonvalvular atrial fibrillation: a meta-analysis. AB - PURPOSE: When anticoagulation for stroke prevention is contraindicated, left atrial appendage occlusion (LAAO) may be performed. Studies of LAAO have been limited by their small size, disparate patient populations, and lack of control group. Our purpose was to perform a meta-analysis of the safety and efficacy of LAAO in comparison with standard therapy for stroke prevention in nonvalvular AF. METHODS: Due to the lack of a control group in studies of LAAO, data on stroke prevention from multiple large outcomes studies were used to produce a hypothetical control group based on clinical variables in the individual studies. Results were stratified according to LAAO device type. RESULTS: We identified 16 studies with a total of 1759 patients receiving LAAO. Summary estimates demonstrate LAAO reduced risk of stroke in comparison with no therapy or aspirin therapy [relative risk (RR), 0.34; 95 % CI, 0.25-0.46] and in comparison with warfarin therapy (RR, 0.65; 95 % CI, 0.46-0.91). Summary estimates differed based on the study used to derive the hypothetical control group. Device deployment was unsuccessful in 6.1 % of patients, and overall complication rate was 7.1 %. Efficacy and safety were similar across LAAO device type although a majority of patients in the meta-analysis received a Watchman device. CONCLUSION: Our data suggest that LAAO is a reasonable option for stroke prophylaxis in AF when anticoagulation is not an option, and the risk for stroke outweighs the risk of procedural complications. Data were limited with the use of most available devices. To better establish the risk and benefit of LAAO in comparison with standard therapy, more randomized controlled trials are necessary. PMID- 25711955 TI - The effect of breakfast type and frequency of consumption on glycemic response in overweight/obese late adolescent girls. AB - BACKGROUND/OBJECTIVES: The primary aim was to examine the daily glycemic response to normal-protein (NP) vs higher-protein (HP) breakfasts in overweight adolescents who habitually skip breakfast (H-BS). The secondary aim examined whether the glycemic response to these meals differed in H-BS vs habitual breakfast consumers (H-BC). SUBJECTS/METHODS: Thirty-five girls (age: 19 +/- 1 year; body mass index: 28.4 +/- 0.7 kg/m(2)) participated in the semi-randomized crossover-design study. The participants were grouped according to habitual breakfast frequency. H-BS (n = 20) continued to skip breakfast (BS) or consumed a NP (12 g protein) or HP (32 g protein) breakfast for 3 days, whereas the H-BC (n = 15) completed the NP and HP breakfast conditions for 3 days. On day 4 of each pattern, an 8 h testing day was completed. The respective breakfast and a standard lunch meal were provided, and plasma was collected to assess morning, afternoon, and total glucose and insulin area under the curves (AUC). RESULTS: In H-BS, the addition of a HP breakfast increased total glucose AUC vs BS (P < 0.05), whereas NP breakfast increased total insulin AUC vs BS (P < 0.05). In H BC, the HP breakfast reduced morning, afternoon and total glucose AUCs vs NP (all, P < 0.05). No differences in insulin were detected. When comparing the HP NP differential glycemic responses between groups, H-BS experienced greater afternoon and total glucose AUCs following HP vs NP breakfasts (both, P<0.05). No differences in insulin responses were observed between groups. CONCLUSIONS: Novel differences in the glucose response to HP vs NP breakfasts were observed and were influenced by the frequency of habitual breakfast consumption in overweight adolescents. PMID- 25711956 TI - Differential serodiagnostics of Toxocara canis and Toxocara cati--is it possible? AB - One of the most common zoonotic helminth infections is caused by species in the genus Toxocara, particularly Toxocara canis and T. cati (Syn. T. mystax). However, their relative contribution to toxocarosis in humans remains largely unknown because causative larvae are seldom recovered and uncertainties regarding the validity of existing serological assays. In this study, we used sera from a pig model experimentally infected with T. canis and T. cati to evaluate whether a Western blot could discriminate between the two species. No proteins were observed that could be used as a diagnostic tool. In addition, a heterogenic protein pattern between individual hosts was found, which was most pronounced in the T. cati-infected pigs. There is therefore an urgent need to optimize and validate current methods or develop new species-specific serological methods in order to implement appropriate control measures. PMID- 25711954 TI - A systematic review of brief dietary questionnaires suitable for clinical use in the prevention and management of obesity, cardiovascular disease and type 2 diabetes. AB - The aim of this systematic review was to identify and describe brief dietary assessment tools suitable for use in clinical practice in the management of obesity, cardiovascular disease and type 2 diabetes. Papers describing development of brief (<35 items) dietary assessment questionnaires, that were accessible, simple to score and assessed aspects of the diet of relevance to the conditions of interest were identified from electronic databases. The development of 35 tools was described in 47 papers. Ten tools assessed healthy eating or healthy dietary patterns, 2 assessed adherence to the Mediterranean diet, 18 assessed dietary fat intake, and 5 assessed vegetable and/or fruit intake. Twenty tools were developed in North America. Test-retest reliability was conducted on 18 tools; correlation coefficients for total scores ranged from 0.59 to 0.95. Relative validation was conducted on 34 tools. The most common reference variable was percentage energy from fat (15 tools) and correlation coefficients ranged from 0.24, P<0.001 to 0.79, P<0.002. Tools that have been evaluated for reliability and/or relative validity are suitable for guiding clinicians when providing dietary advice. Variation in study design, settings and populations makes it difficult to recommend one tool over another, although future developers can enhance the understanding and use of tools by giving clear guidance as to the strengths and limitations of the study design. When selecting a tool, clinicians should consider whether their patient population is similar in characteristics to the evaluation sample. PMID- 25711957 TI - Lipomatous tumours of the hand and wrist A series of 25 cases and review of the literature. AB - consequently reports in the international literature are mainly of individual cases and small series. MATERIAL OF STUDY: This is a retrospective review of a series of 25 patients with lipomatous tumours of the hand and wrist treated between 2001 and 2009. All patients underwent clinical and radiological assessment and a marginal excisional biopsy. 23 lipomas, 1 fibrolipomatous hamartoma (FLH) and 1 well differentiated lipoma-like liposarcoma/atypical lipomatous tumour (WDLLL/ALT) were identified. CONCLUSION: Choosing the most appropriate investigations is mandatory for a correct diagnosis and planning. Ultrasound should always be considered as the first line investigation. MRI helps delineating the anatomy of the lesions and their relationships with the surrounding structures in the hand and wrist, enabling more accurate surgical planning. Histological examination of the excised specimen remains the gold standard for the formulation of the definitive diagnosis and should be performed in every case. KEY WORDS: Digits tumours, Fibrolipomatous hamartoma, Hand tumours, Lipoma, Lipoma-like liposarcoma, Wrist tumours. PMID- 25711958 TI - The influence of socioeconomic deprivation on outcomes in pancreas transplantation. AB - Socioeconomic deprivation is an important factor in determining poor health and is associated with a higher prevalence of many chronic diseases including diabetes and renal failure, with poorer outcomes of their treatments. The influence of deprivation on outcomes following pancreas transplantation has not previously been reported. The Welsh Index of Multiple Deprivation was used to assess the influence of socioeconomic deprivation on outcomes for 119 consecutive pancreas transplant recipients from a single center in the United Kingdom, transplanted between 2004 and 2013. Outcomes measured were rate of acute rejection and graft survival. Thirty-five (29.4%) patients experienced at least one episode of acute rejection following their transplant. Rejection rates in least deprived were 37% and most deprived 24% (p = 0.29). Within the individual domains, rejection rate was higher for the "physical environment" domain (least deprived 40% vs. most deprived 17% (p = 0.053). Five-year graft survival for least and most deprived groups was 75% and 88%, respectively (log-rank test p value 0.24). This study has not demonstrated any significant differences in outcomes following pancreas transplantation in Wales in relation to socioeconomic deprivation with the exception possibly of the "physical environment" domain. Further studies with larger patient population or concentrating on physical environment deprivation would be of interest. PMID- 25711959 TI - Racial disparity in survival from early breast cancer in the department of defense healthcare system. AB - BACKGROUND: Racial disparity is often identified as a factor in survival from breast cancer in the United States. Current data regarding survival in patients treated in the Department of Defense Military Healthcare System is lacking. METHODS: The Department of Defense Automated Central Tumor Registry (ACTUR) was queried for all women diagnosed with Stage I or II breast cancer from January 1, 1996 through December 31, 2008. Statistical analyses evaluated demographics, surgical treatment, tumor stage, and survival rates. RESULTS: There were 8,890 patients meeting inclusion criteria. Patients who were younger, Asian American (versus white or black), lower T and/or N stage had significantly improved survival rates. Interestingly, white and black patients demonstrated similar survival in this study. Patients with a longer period of time between diagnosis and treatment had no decrement in survival. As would be expected, patients with a longer recurrence free period enjoyed longer survival. CONCLUSIONS: Survival from early stage breast cancer is equivalent between white and black patients in the Department of Defense Healthcare System. This finding is contrary to reports from our civilian counterparts and may be indicative of improved access to care and overall improved cancer surveillance. PMID- 25711960 TI - Atrial fibrillation and stroke after atrial septal defect closure. Is earlier closure warranted? PMID- 25711961 TI - Editorial: protein stabilization - crossroad for protein-based processes and products. PMID- 25711962 TI - Evolutionary diversification of type 2 porcine reproductive and respiratory syndrome virus. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the leading swine pathogens causing tremendous economic loss to the global swine industry due to its virulence, pathogenesis, infectivity and transmissibility. Although formally recognized only two and half decades ago, molecular dating estimation indicates a more ancient evolutionary history, which involved divergence into two genotypes (type 1 and type 2) prior to the 'initial' outbreaks of the late 1980s. Type 2 PRRSV circulates primarily in North America and Asia. The relatively greater availability of sequence data for this genotype from widespread geographical territories has enabled a better understanding of the evolving genotype. However, there are a number of challenges in terms of the vastness of data available and what this indicates in the context of viral diversity. Accordingly, here we revisit the mechanisms by which PRRSV generates variability, describe a means of organizing type 2 diversity captured in voluminous ORF5 sequences in a phylogenetic framework and provide a holistic view of known global type 2 diversity in the same setting. The consequences of the expanding diversity for control measures such as vaccination are discussed, as well as the contribution of modified live vaccines to the circulation of field isolates. We end by highlighting some limitations of current molecular epidemiology studies in relation to inferring PRRSV diversity, and what steps can be taken to overcome these and additionally enable PRRSV sequence data to be informative about viral phenotypic traits such as virulence. PMID- 25711963 TI - Post-translational regulation and modifications of flavivirus structural proteins. AB - Flaviviruses are a group of single-stranded, positive-sense RNA viruses that generally circulate between arthropod vectors and susceptible vertebrate hosts, producing significant human and veterinary disease burdens. Intensive research efforts have broadened our scientific understanding of the replication cycles of these viruses and have revealed several elegant and tightly co-ordinated post translational modifications that regulate the activity of viral proteins. The three structural proteins in particular - capsid (C), pre-membrane (prM) and envelope (E) - are subjected to strict regulatory modifications as they progress from translation through virus particle assembly and egress. The timing of proteolytic cleavage events at the C-prM junction directly influences the degree of genomic RNA packaging into nascent virions. Proteolytic maturation of prM by host furin during Golgi transit facilitates rearrangement of the E proteins at the virion surface, exposing the fusion loop and thus increasing particle infectivity. Specific interactions between the prM and E proteins are also important for particle assembly, as prM acts as a chaperone, facilitating correct conformational folding of E. It is only once prM/E heterodimers form that these proteins can be secreted efficiently. The addition of branched glycans to the prM and E proteins during virion transit also plays a key role in modulating the rate of secretion, pH sensitivity and infectivity of flavivirus particles. The insights gained from research into post-translational regulation of structural proteins are beginning to be applied in the rational design of improved flavivirus vaccine candidates and make attractive targets for the development of novel therapeutics. PMID- 25711964 TI - Progress in clinical oncolytic virus-based therapy for hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) carries a dismal prognosis, with advanced disease being resistant to both radiotherapy and conventional cytotoxic drugs, whilst anti-angiogenic drugs are marginally efficacious. Oncolytic viruses (OVs) offer the promise of selective cancer therapy through direct and immune-mediated mechanisms. The premise of OVs lies in their preferential genomic replication, protein expression and productive infection of malignant cells. Numerous OVs are being tested in preclinical models of HCC, with good evidence of direct and immune-mediated anti-tumour efficacy. Efforts to enhance the performance of these agents have concentrated on engineering OV cellular specificity, immune evasion, enhancing anti-tumour potency and improving delivery. The lead agent in HCC clinical trials, JX-594, a recombinant Wyeth strain vaccinia virus, has demonstrated evidence for significant benefit and earned orphan drug status. Thus, JX-594 appears to be transcending the barrier between novel laboratory science and credible clinical therapy. Relatively few other OVs have entered clinical testing, a hurdle that must be overcome if significant progress is to be made in this field. This review summarizes the preclinical and clinical experience of OV therapy in the difficult-to-treat area of HCC. PMID- 25711965 TI - Global molecular genetic analysis of porcine circovirus type 2 (PCV2) sequences confirms the presence of four main PCV2 genotypes and reveals a rapid increase of PCV2d. AB - The oldest porcine circovirus type 2 (PCV2) sequence dates back to 1962 and is among several hundreds of publicly available PCV2 sequences. Despite this resource, few studies have investigated the global genetic diversity of PCV2. To evaluate the phylogenetic relationship of PCV2 strains, 1680 PCV2 open reading frame 2 (ORF2) sequences were compared and analysed by methods of neighbour joining, maximum-likelihood, Bayesian inference and network analysis. Four distinct clades were consistently identified and included PCV2a, PCV2b, PCV2c and PCV2d; the p-distance between PCV2d and PCV2b was 0.055+/-0.008, larger than the PCV2 genotype-definition cut-off of 0.035, supporting PCV2d as an independent genotype. Among the 1680 sequences, 278-285 (16.5-17 %) were classified as PCV2a, 1007-1058 (59.9-63 %) as PCV2b, three (0.2 %) as PCV2c and 322-323 (19.2 %) as PCV2d, with the remaining 12-78 sequences (0.7-4.6 %) classified as intermediate clades or strains by the various methods. Classification of strains to genotypes differed based on the number of sequences used for the analysis, indicating that sample size is important when determining classification and assessing PCV2 trends and shifts. PCV2d was initially identified in 1999 in samples collected in Switzerland, now appears to be widespread in China and has been present in North America since 2012. During 2012-2013, 37 % of all investigated PCV2 sequences from US pigs were classified as PCV2d and overall data analysis suggests an ongoing genotype shift from PCV2b towards PCV2d. The present analyses indicate that PCV2d emerged approximately 20 years ago. PMID- 25711966 TI - Differential permissivity of human cerebrovascular endothelial cells to enterovirus infection and specificities of serotype EV-A71 in crossing an in vitro model of the human blood-brain barrier. AB - Human cerebral microvascular endothelial cells (hCMEC/D3 cell line) form a steady polarized barrier when cultured in vitro on a permeable membrane. Their susceptibility to enterovirus (EV) strains was analysed to investigate how these viruses may cross the blood-brain barrier. A sample of 88 virus strains was selected on phylogenetic features amongst 43 epidemiologically relevant types of the four EV species A-D. The EV-A71 genome was replicated at substantial rates, whilst the infectious virus was released at extremely low but sustained rates at both barrier sides for at least 4 days. EV-A71 antigens were detected in a limited number of cells. The properties of the endothelial barrier (structure and permeability) remained intact throughout infection. The chronic EV-A71 infection was in sharp contrast to the productive infection of cytolytic EVs (e.g. echoviruses E-6 and E-30). The hCMEC/D3 barriers infected with the latter EVs exhibited elevated proportions of apoptotic and necrotic cells, which resulted in major injuries to the endothelial barriers with a dramatic increase of paracellular permeability and virus crossing to the abluminal side. The following intracellular rearrangements were also seen: early destruction of the actin cytoskeleton, remodelling of intracellular membranes and reorganization of the mitochondrion network in a small cluster near the perinuclear space. PMID- 25711967 TI - Stimulatory effects of human cytomegalovirus tegument protein pp71 lead to increased expression of CCL2 (monocyte chemotactic protein-1) during infection. AB - Human cytomegalovirus (CMV) is the most common infectious cause of congenital birth defects in developed countries. Studies of infected amniotic fluid and placentae show CMV infection leads to a pro-inflammatory shift in cytokine profiles with implications for pathogenesis of foetal disease. ELISA, immunofluorescence and real-time-PCR assays were used to investigate CCL2 (monocyte chemotactic protein-1) and TNF-alpha changes following CMV infection of human fibroblasts, as well as following transient expression of CMV gene products in HeLa cells. Infection of human fibroblasts with CMV AD169 resulted in increased cytoplasmic and extracellular expression of CCL2 during early stages of infection, followed by marked downregulation of the chemokine at late times. Induction of CCL2 was not observed with CMV clinical strain Merlin, consistent with the postulated immune-evasion potential of this genetically intact WT strain. Comparison between live and UV-irradiated virus infections showed that changes in CCL2 levels were a direct response to active CMV replication. There were no significant changes in TNF-alpha expression during a parallel time-course of CMV infection. In transient transfection assays, overexpression of CMV tegument protein pp71 resulted in intracellular and extracellular upregulation of CCL2 protein. mRNA analysis showed that pp71-induced elevation in CCL2 was mediated through transcriptional upregulation. The data showed that CMV-induced upregulation of CCL2 during early stages of infection was mediated, at least in part, by stimulation of viral pp71, which may contribute to viral pathogenesis through enhanced virus dissemination. PMID- 25711968 TI - Defects in RNA polyadenylation impair both lysogenization by and lytic development of Shiga toxin-converting bacteriophages. AB - In Escherichia coli, the major poly(A) polymerase (PAP I) is encoded by the pcnB gene. In this report, a significant impairment of lysogenization by Shiga toxin converting (Stx) bacteriophages (Phi24B, 933W, P22, P27 and P32) is demonstrated in host cells with a mutant pcnB gene. Moreover, lytic development of these phages after both infection and prophage induction was significantly less efficient in the pcnB mutant than in the WT host. The increase in DNA accumulation of the Stx phages was lower under conditions of defective RNA polyadenylation. Although shortly after prophage induction, the levels of mRNAs of most phage-borne early genes were higher in the pcnB mutant, at subsequent phases of the lytic development, a drastically decreased abundance of certain mRNAs, including those derived from the N, O and Q genes, was observed in PAP I deficient cells. All of these effects observed in the pcnB cells were significantly more strongly pronounced in the Stx phages than in bacteriophage lambda. Abundance of mRNA derived from the pcnB gene was drastically increased shortly (20 min) after prophage induction by mitomycin C and decreased after the next 20 min, while no such changes were observed in non-lysogenic cells treated with this antibiotic. This prophage induction-dependent transient increase in pcnB transcript may explain the polyadenylation-driven regulation of phage gene expression. PMID- 25711969 TI - More action, less resistance: report of the 2014 summit of the Global Respiratory Infection Partnership. AB - 'Antimicrobial resistance is a global health security threat that requires concerted cross-sectional action by governments and society as a whole,' according to a report published by the WHO in April 2014([1]) . On 24-25 June 2014, the Global Respiratory Infection Partnership (GRIP) met in London, UK, together with delegates from 18 different countries to discuss practical steps that can be taken at a local level to address this global problem in an aligned approach. This was the second annual summit of GRIP. The group, formed in 2012, includes primary care and hospital physicians, microbiologists, researchers, and pharmacists from nine core countries. GRIP aims to unite healthcare professionals (HCPs) around the world to take action against inappropriate antibiotic use, focussing on one of the most prevalent therapy areas where antibiotics are inappropriately prescribed - upper respiratory tract infections (URTIs). Chaired by GRIP member, Professor John Oxford (UK), the 2014 summit included engaging presentations by guest speakers examining the latest science regarding the impact of inappropriate antibiotic use. PMID- 25711970 TI - Hepatic angiosarcoma mimicking congenital cytomegalovirus infection in an infant with thrombocytopenia. AB - Hepatic angiosarcomas are uncommon, highly aggressive tumors, rarely seen in children. A 3-month-old female infant was admitted to hospital for evaluation of multiple petechiae on her body. She had hepatosplenomegaly and scattered petechiae over her entire body. Laboratory tests indicated thrombocytopenia and positive cytomegalovirus (CMV) polymerase chain reaction. Ganciclovir was started, and the platelet count increased. After 4 months the patient was readmitted to hospital for drowsy mental status and eventually died from severe bleeding. Needle biopsy of the liver was performed after receiving written consent from the parents. Pathological findings of the liver lesion included features consistent with hepatic angiosarcoma. There have been no previous reports of hepatic angiosarcoma in Korean infants. Here, we report an infant with hepatosplenomegaly and thrombocytopenia who was diagnosed with hepatic angiosarcoma mimicking congenital CMV infection. PMID- 25711971 TI - Identification of tapetum-specific genes by comparing global gene expression of four different male sterile lines in Brassica oleracea. AB - The tapetum plays an important role in anther development by providing necessary enzymes and nutrients for pollen development. However, it is difficult to identify tapetum-specific genes on a large-scale because of the difficulty of separating tapetum cells from other anther tissues. Here, we reported the identification of tapetum-specific genes by comparing the gene expression patterns of four male sterile (MS) lines of Brassica oleracea. The abortive phenotypes of the four MS lines revealed different defects in tapetum and pollen development but normal anther wall development when observed by transmission electron microscopy. These tapetum displayed continuous defective characteristics throughout the anther developmental stages. The transcriptome from flower buds, covering all anther developmental stages, was analyzed and bioinformatics analyses exploring tapetum development-related genes were performed. We identified 1,005 genes differentially expressed in at least one of the MS lines and 104 were non-pollen expressed genes (NPGs). Most of the identified NPGs were tapetum-specific genes considering that anther walls were normally developed in all four MS lines. Among the 104 NPGs, 22 genes were previously reported as being involved in tapetum development. We further separated the expressed NPGs into different developmental stages based on the MS defects. The data obtained in this study are not only informative for research on tapetum development in B. oleracea, but are also useful for genetic pathway research in other related species. PMID- 25711972 TI - Gut dysbiosis in acute-on-chronic liver failure and its predictive value for mortality. AB - BACKGROUND: Bacterial translocation from the gut plays an important role in the pathophysiology of acute-on-chronic liver failure (ACLF). However, gut dysbiosis in ACLF was not widely documented in previous studies. AIM: This research characterized the fecal microbiota in patients with ACLF and analyzed the temporal stability of gut microbiota during illness. METHODS: Fecal microbiota of 79 ACLF patients (42 patients were followed in the next 4 weeks after the first visit for longitudinal study) and 50 healthy controls was analyzed by 16S ribosomal DNA pyrosequencing. RESULTS: There was a marked difference between the ACLF group and the control group. The overall microbial diversity and richness were significantly lower in ACLF than in controls. ACLF patients had lower abundance of Bacteroidaceae, Ruminococcaceae, and Lanchnospiraceae, but higher abundance of Pasteurellaceae, Streptococcaceae, and Enterecoccaceae. The relative abundance of Lachnospiraceae was obviously decreased in ACLF patients with hepatic encephalopathy. The gut microbiota kept relatively stable in a short term after the onset of ACLF. The use of antibiotics only showed moderate impacts on the gut microbiota. The relative abundance of Pasteurellaceae and Model of End Stage Liver Disease score were independent factors predicting mortality rate. Network analysis comparison showed robust correlations between specific bacterial families (Ruminococcaceae and Lachnospiraceae) and inflammatory cytokines (interleukin [IL]-6, tumor necrosis factor alpha, IL-2) in ACLF patients. CONCLUSIONS: These data suggest gut dysbiosis in ACLF and its predictive value for mortality. The results thus open up the possibility of designing diagnostic biomarkers and targeted probiotics aimed at decreasing mortality in ACLF. PMID- 25711973 TI - pi-Hole Bonds: Boron and Aluminum Lewis Acid Centers. AB - MP2/aug-cc-pVTZ calculations were performed on complexes of boron and aluminum trihydrides and trihalides with hydrogen cyanide (ZH3 -NCH and ZX3 -NCH; Z=B, Al; X=F, Cl). The complexes are linked through the B???N and Al???N interactions, which are named as triel bonds and which are classified as pi-hole bonds. It was found that they possess numerous characteristics of typical covalent bonds, since they are ruled mainly by processes of the electron charge shift from the Lewis base to the Lewis acid unit. Other configurations of the ZH3 -NCH and ZX3 -NCH complexes linked by the dihydrogen, hydrogen, and halogen bonds were found. However, these interactions are much weaker than the corresponding pi-hole bonds. The quantum theory of atoms in molecules and the natural bond orbital approaches were applied to characterize the complexes and interactions analyzed. The crystal structures of triel trihydrides and triel trihalides were also analyzed for comparison with the results of calculations. PMID- 25711975 TI - Epigenetics for anthropologists: An introduction to methods. AB - The study of epigenetics, or chemical modifications to the genome that may alter gene expression, is a growing area of interest for social scientists. Anthropologists and human biologists are interested in epigenetics specifically, as it provides a potential link between the environment and the genome, as well as a new layer of complexity for the study of human biological variation. In pace with the rapid increase in interest in epigenetic research, the range of methods has greatly expanded over the past decade. The primary objective of this article is to provide an overview of the current methods for assaying DNA methylation, the most commonly studied epigenetic modification. We will address considerations for all steps required to plan and conduct an analysis of DNA methylation, from appropriate sample collection, to the most commonly used methods for laboratory analyses of locus-specific and genome-wide approaches, and recommendations for statistical analyses. Key challenges in the study of DNA methylation are also discussed, including tissue specificity, the stability of measures, timing of sample collection, statistical considerations, batch effects, and challenges related to analysis and interpretation of data. Our hope is that this review serves as a primer for anthropologists and human biologists interested in incorporating epigenetic data into their research programs. PMID- 25711974 TI - Automated pain intervention for underserved minority women with breast cancer. AB - BACKGROUND: Minority patients with breast cancer are at risk for undertreatment of cancer-related pain. The authors evaluated the feasibility and efficacy of an automated pain intervention for improving pain and symptom management of underserved African American and Latina women with breast cancer. METHODS: Sixty low-income African American and Latina women with breast cancer and cancer related pain were enrolled in a pilot study of an automated, telephone-based, interactive voice response (IVR) intervention. Women in the intervention group were called twice weekly by the IVR system and asked to rate the intensity of their pain and other symptoms. The patients' oncologists received e-mail alerts if the reported symptoms were moderate to severe. The patients also reported barriers to pain management and received education regarding any reported obstacles. RESULTS: The proportion of women in both groups reporting moderate to severe pain decreased during the study, but the decrease was significantly greater for the intervention group. The IVR intervention also was associated with improvements in other cancer-related symptoms, including sleep disturbance and drowsiness. Although patient adherence to the IVR call schedule was good, the oncologists who were treating the patients rated the intervention as only somewhat useful for improving symptom management. CONCLUSIONS: The IVR intervention reduced pain and symptom severity for underserved minority women with breast cancer. Additional research on technological approaches to symptom management is needed. PMID- 25711976 TI - A comparison of haptic material perception in blind and sighted individuals. AB - We investigated material perception in blind participants to explore the influence of visual experience on material representations and the relationship between visual and haptic material perception. In a previous study with sighted participants, we had found participants' visual and haptic judgments of material properties to be very similar (Baumgartner, Wiebel, & Gegenfurtner, 2013). In a categorization task, however, visual exploration had led to higher categorization accuracy than haptic exploration. Here, we asked congenitally blind participants to explore different materials haptically and rate several material properties in order to assess the role of the visual sense for the emergence of haptic material perception. Principal components analyses combined with a procrustes superimposition showed that the material representations of blind and blindfolded sighted participants were highly similar. We also measured haptic categorization performance, which was equal for the two groups. We conclude that haptic material representations can emerge independently of visual experience, and that there are no advantages for either group of observers in haptic categorization. PMID- 25711977 TI - The impact of unilateral brain damage on weight perception, sensorimotor anticipation, and fingertip force adaptation. AB - Damage to the left parietal cortex can lead to apraxia - a selective deficit in tool use and action planning. There is conflicting evidence as to whether this disorder affects more fundamental motor parameters, such as applying the appropriate forces to lift objects based upon how heavy they look. Here we examined how individuals with left and right-lateralized brain damage lift and perceive the weight of objects of the same mass which vary in their size and material properties. No clear differences emerged between the groups in terms of how visual material properties affected their perceptions of object weight or their initial application of grip and load forces. There was, however, some evidence that unilateral brain injury impaired the use of size cues for the parameterization of grip forces. PMID- 25711978 TI - Results of a pilot study using self-collected mid-turbinate nasal swabs for detection of influenza virus infection among pregnant women. AB - BACKGROUND: We evaluated the feasibility of asking pregnant women to self-collect and ship respiratory specimens. METHODS: In a preliminary laboratory study, we compared the RT-PCR cycle threshold (CT) values of influenza A and B viruses incubated at 4 storage temperatures (from 4 to 35 degrees C) for 6 time periods (8, 24, 48, 72, and 168 hours and 30 days), resulting in 24 conditions that were compared to an aliquot tested after standard freezing (-20 degrees C) (baseline condition). In a subsequent pilot study, during January-February, 2014, we delivered respiratory specimen collection kits to 53 pregnant women with a medically attended acute respiratory illness using three delivery methods. RESULTS: CT values were stable after storage at temperatures <27 degrees C for up to 72 hours for influenza A viruses and 48 hours for influenza B viruses. Of 53 women who received kits during the pilot, 89% collected and shipped nasal swabs as requested. However, 30% (14/47) of the women took over 2 days to collect and ship their specimen. The human control gene, ribonuclease P (RNase P), was detected in 100% of nasal swab specimens. However, the mean CT values for RNase P (26.5, 95% confidence interval [CI] = 26.0-27.1) and for the 8 influenza A virus positives in our pilot (32.2, 95% CI = 28.9-35.5) were significantly higher than the CTs observed in our 2010-2012 study using staff-collected nasal pharyngeal swabs (P-values < 0.01). DISCUSSION: Self-collection of respiratory specimens is a promising research method, but further research is needed to quantify the sensitivity and specificity of the approach. PMID- 25711979 TI - Learning curve for gastric cancer surgery based on actual survival. AB - BACKGROUND: The aim of this study was to investigate learning curves for surgeons performing D2 lymph node dissection based on actual patient survival. METHODS: A total of 3,284 patients with gastric cancer who underwent curative intent gastric cancer surgery by nine surgeons in eight Korean hospitals between 2001 and 2006 were included. Each surgeon's experience was coded as the number of D1 + beta or more gastrectomies performed before that for each patient, which indicates the surgeon's total number of prior surgical experiences. Surgeon experience was grouped into two sets of categories. The set of categories included four groups of experience: <=50, 51-100, 101-200, and >200 applicable operations. Multivariate survival time regression models were used to evaluate the association between surgeon experience and overall survival. RESULTS: The learning curve for gastric cancer survival after open gastric cancer surgery was steep and did not reach a plateau until a surgeon completed 100 operations. Overall survival rate was the lowest among patients treated by a surgeon with an experience of 50-100 cases. The overall survival of patients at 5 years when the surgeon had a history of more than 100 experiences was higher in each stage than that when the surgeon had a history of fewer than 100 experiences. CONCLUSION: As a surgeon's experience increases, survival after gastric cancer surgery improves. Special attention needs to be paid to the second period of surgeon experience because survival of patients in this period was the lowest. PMID- 25711981 TI - Enantioselective halogenative semi-pinacol rearrangement: extension of substrate scope and mechanistic investigations. AB - The present Full Paper article discloses a survey of our recent results obtained in the context of the enantioselective halogenation-initiated semi-pinacol rearrangement. Commencing with the fluorination/semi-pinacol reaction first and moving to the heavier halogens (bromine and iodine) second, the scope and limitations of the halogenative phase-transfer methodology will be discussed and compared. An extension of the fluorination/semi-pinacol reaction to the ring expansion of five-membered allylic cyclopentanols will be also described, as well as some preliminary results on substrates prone to desymmetrization will be given. Finally, the present manuscript will culminate with a detailed mechanistic investigation of the canonical fluorination/semi-pinacol reaction. Our mechanistic discussion will be based on in situ reaction progress monitoring, complemented with substituent effect, kinetic isotopic effect and non-linear behaviour studies. PMID- 25711980 TI - TSPAN8, identified by Escherichia coli ampicillin secretion trap, is associated with cell growth and invasion in gastric cancer. AB - BACKGROUND: Gastric cancer (GC) is one of the most common human cancers. Genes expressed only in cancer tissue, especially on the cell membrane, will be useful biomarkers for cancer diagnosis and therapeutics. METHODS: To identify novel genes encoding transmembrane protein specifically expressed in GC, we generated an Escherichia coli ampicillin secretion trap (CAST) library from diffuse-type GC cell line MKN-45. CAST is a survival-based signal sequence trap method that exploits the ability of mammalian signal sequences to confer ampicillin resistance to a mutant beta-lactamase lacking the endogenous signal sequence. RESULTS: By sequencing 1,536 colonies, we identified 23 genes encoding the transmembrane protein present in GC. Among these genes, TSPAN8 (also known as CO 029 and TM4SF3) gene, which encodes transmembrane protein tetraspanin 8, was emphasized as a candidate. Immunohistochemical analysis of tetraspanin 8 in human GC tissues revealed that 72 (34 %) of 210 GC cases were positive for tetraspanin 8, and microvessel density was significantly higher in tetraspanin 8-positive GC than in tetraspanin 8-negative GC. Furthermore, univariate and multivariate analyses revealed that tetraspanin 8 expression is an independent prognostic classifier of patients with GC. TSPAN8 knockdown by siRNA reduced the invasion of GC cell line. The reduction of invasiveness was retrieved by the tetraspanin 8 containing exosome. CONCLUSION: These results suggest that tetraspanin 8 is involved in tumor progression and is an independent prognostic classifier in patients with GC. PMID- 25711982 TI - Sex ratios among infants with birth defects, National Birth Defects Prevention Study, 1997-2009. AB - A small number of population-based studies have examined sex differences among infants with birth defects. This study presents estimates of sex ratio for both isolated cases and those with multiple congenital anomalies, as well as by race/ethnicity. Male-female sex ratios and their 95% confidence intervals were calculated for 25,952 clinically reviewed case infants included in the National Birth Defects Prevention Study (1997-2009), a large population-based case-control study of birth defects. The highest elevations in sex ratios (i.e., male preponderance) among isolated non-cardiac defects were for craniosynostosis (2.12), cleft lip with cleft palate (2.01), and cleft lip without cleft palate (1.78); the lowest sex ratios (female preponderance) were for choanal atresia (0.45), cloacal exstrophy (0.46), and holoprosencephaly (0.64). Among isolated cardiac defects, the highest sex ratios were for aortic stenosis (2.88), coarctation of the aorta (2.51), and d-transposition of the great arteries (2.34); the lowest were multiple ventricular septal defects (0.52), truncus arteriosus (0.63), and heterotaxia with congenital heart defect (0.64). Differences were observed by race/ethnicity for some but not for most types of birth defects. The sex differences we observed for specific defects, between those with isolated versus multiple defects, as well as by race/ethnicity, demonstrate patterns that may suggest etiology and improve classification. PMID- 25711983 TI - Concepts and methods when considering negative symptom course. PMID- 25711984 TI - Comparative outcomes of different endovenous thermal ablation systems on great and small saphenous vein insufficiency: Long-term results. AB - BACKGROUND AND OBJECTIVE: This study examined the outcomes of over a decade of endovenous thermal ablation (EVTA) treatments for great and small saphenous vein (GSV and SSV) insufficiency, utilizing three different endovenous thermal ablation systems. MATERIALS AND METHODS: This retrospective study reviewed EVTA treatments performed at an outpatient clinic (MDLSVI) from April 1999 to February 2013. Systems included 810 nm diode (hemoglobin targeting), 1,320 nm laser (water targeting) and a radiofrequency (direct thermal transfer) (RF) device. Clinical and ultrasonographic evaluation were performed before treatment and at each follow-up visit. Patients were examined yearly by Duplex ultrasonography. Success was defined as complete absence of reflux. RESULTS: Analysis of 934 treatments demonstrated that although recanalization could occur over time, endovenous ablation has a very high success rate. Ablation rates were 92.5%, 85.9%, and 71.9% at 6-months, 1-year, and 5-years after procedures. Recanalization occurred in 156 out of 934 treatments (16.7%) during the follow-up period. Among three difference systems, the total ablation success rate was significantly different (P < 0.001). The 1,320 nm Nd:YAG laser (n = 502) provided the highest ablation rate compared to the radiofrequency (n = 398) and 810 nm diode (n = 34) throughout their follow-up period, which were 8, 13, and 9 years, respectively. At 1-year follow-up, successful ablation rates of RF, 810 nm, and 1,320 nm were 78.2%, 80.8%, and 93.7%, respectively. At 5-year follow-up, successful ablation rates of RF, 810 nm, and 1,320 nm were 61.7%, 65.7%, and 84.7%, respectively. CONCLUSION: EVTA is very effective for ablation of the GSV and SSV. Complete ablation varied significantly among different systems with water targeting 1,320 nm providing the highest incidence saphenous vein ablation. This remained durable at 8-year follow-up by Duplex ultrasound. PMID- 25711985 TI - "All proteins all the time"--a comment on visions, claims, and wording in mass spectrometry-based proteomics. PMID- 25711986 TI - New methods based on capillary electrophoresis for in vitro evaluation of protein tau phosphorylation by glycogen synthase kinase 3-beta. AB - The hyperphosphorylation of tau protein is associated with the development of the neuronal pathology of Alzheimer's disease. As most conventional methods study only particular phosphorylation sites of tau, it is necessary to develop a simple and reliable assay to determine the phosphorylation of tau at multiple sites. Capillary electrophoresis (CE)-based enzymatic assays are not yet used to monitor tau phosphorylation. The present work aims to develop CE-based assays to evaluate tau phosphorylation by the glycogen synthase kinase 3-beta (GSK3beta). A novel pre-capillary CE assay was first developed. An in-capillary CE-based enzymatic assay was also used since this approach is known to be time- and cost- effective. The enzymatic reaction was monitored by quantifying the product adenosine 5'- diphosphate (ADP). The influence of two classes of glycosaminoglycan (GAG), namely heparin and heparan sulfate, on the phosphorylation reaction was also assessed. Results obtained by both CE approaches were comparable and in excellent agreement with those reported in the literature using conventional radiometric and immunoblotting methods. In fact, CE results confirmed the inductory effect of the sulfated sugars heparin and heparan sulfate on tau hyperphosphorylation, probably because of the exposition of new sites phosphorylatable by GSK3beta. This study shows that simple (no-labeling), rapid (less than 30 min per assay), and eco-friendly (no-radioactivity) CE-based kinase assays can give insight into the abnormal phosphorylation of tau. They can be extended to screen different modulators of tau phosphorylation to highlight their function and to develop effective drugs for neurodegenerative disease treatments. PMID- 25711987 TI - Long-term stability and temporal trends of organic contaminants in four collections of mussel tissue frozen standard reference materials. AB - The stability of polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), and chlorinated pesticides in frozen mussel tissue Standard Reference Materials (SRMs) stored at -80 degrees C was assessed by analyzing samples of SRM 1974, SRM 1974a, and SRM 1974b Organics in Mussel Tissue (Mytilus edulis) periodically over 25 y, 20 y, and 12 y, respectively. The most recent analyses were performed during the certification of the fourth release of this material, SRM 1974c. Results indicate the concentrations of these persistent organic pollutants have not changed during storage at -80 degrees C. In addition, brominated diphenyl ethers (BDEs) were quantified in each of the materials during this study. The stability information is important for on-going monitoring studies collecting large quantities of samples for future analyses (i.e., formally established specimen banking programs). Since all four mussel tissue SRMs were prepared from mussels collected at the same site in Dorchester Bay, MA, USA, the results provide a temporal trend study for these contaminants over a 17 year period (1987 to 2004). PMID- 25711988 TI - Bright or dark immune complexes of anti-TAMRA antibodies for adapted fluorescence based bioanalysis. AB - Fluorescence labels, for example fluorescein or rhodamin derivatives, are widely used in bioanalysis applications including lateral-flow assays, PCR, and fluorescence microscopy. Depending on the layout of the particular application, fluorescence quenching or enhancement may be desired as the detection principle. Especially for multiplexed applications or high-brightness requirements, a tunable fluorescence probe can be beneficial. The alterations in the photophysics of rhodamine derivatives upon binding to two different anti-TAMRA antibodies were investigated by absorption and fluorescence-spectroscopy techniques, especially determining the fluorescence decay time and steady-state and time-resolved fluorescence anisotropy. Two monoclonal anti-TAMRA antibodies were generated by the hybridoma technique. Although surface-plasmon-resonance measurements clearly proved the high affinity of both antibodies towards 5-TAMRA, the observed effects on the fluorescence of rhodamine derivatives were very different. Depending on the anti-TAMRA antibody either a strong fluorescence quenching (G71-DC7) or a distinct fluorescence enhancement (G71-BE11) upon formation of the immune complex was observed. Additional rhodamine derivatives were used to gain further information on the binding interaction. The data reveal that such haptens as 5 TAMRA could generate different paratopes with equal binding affinities but different binding interactions, which provide the opportunity to adapt bioanalysis methods including immunoassays for optimized detection principles for the same hapten depending on the specific requirements. PMID- 25711989 TI - Online determination of polycyclic aromatic hydrocarbon formation from a flame soot generator. AB - In this study, we produced a class of diffusion flame soot particles with varying chemical and physical properties by using the mini-Combustion Aerosol STandard (CAST) and applying varying oxidant gas flow rates under constant propane, quenching, and dilution gas supply. We varied the soot properties by using the following fuel-to-air equivalence ratios (Phi): 1.13, 1.09, 1.04, 1.00, 0.96, and 0.89. Within this Phi range, we observed drastic changes in the physical and chemical properties of the soot. Oxidant-rich flames (Phi < 1) were characterized by larger particle size, lower particle number concentration, higher black carbon (BC) concentration, lower brown carbon BrC.[BC](-1) than fuel-rich flames (Phi > 1). To investigate the polycyclic aromatic hydrocarbons (PAH) formation online, we developed a new method for quantification by using the one (13)C-containing doubly charged PAH ion in a high-resolution time-of-flight aerosol mass spectrometry (HR-ToF-AMS). The time-resolved concentration showed that the larger PAHs prevailed in the fuel-rich flames and diminished in the oxidant-rich flames. By comparison with the offline in situ derivatization-thermal-desorption gas chromatography time-of-flight mass spectrometry (IDTD-GC-ToF-MS), we found that the concentration by using the HR-ToF-AMS was underestimated, especially for lower mass PAHs (C14-C18) in the fuel-rich flames possibly due to size limitation and degradation of semi-volatile species under high vacuum and desorption temperature in the latter. For oxidant-rich flames, the large PAHs (C20 and C22) were detected in the HR-ToF-AMS while it was not possible in IDTD-GC-ToF-MS due to matrix effect. The PAH formation was discussed based on the combination of our results and with respect to Phi settings. PMID- 25711990 TI - Metabolic fate, mass spectral fragmentation, detectability, and differentiation in urine of the benzofuran designer drugs 6-APB and 6-MAPB in comparison to their 5-isomers using GC-MS and LC-(HR)-MS(n) techniques. AB - The number of so-called new psychoactive substances (NPS) is still increasing by modification of the chemical structure of known (scheduled) drugs. As analogues of amphetamines, 2-aminopropyl-benzofurans were sold. They were consumed because of their euphoric and empathogenic effects. After the 5-(2 aminopropyl)benzofurans, the 6-(2-aminopropyl)benzofuran isomers appeared. Thus, the question arose whether the metabolic fate, the mass spectral fragmentation, and the detectability in urine are comparable or different and how an intake can be differentiated. In the present study, 6-(2-aminopropyl)benzofuran (6-APB) and its N-methyl derivative 6-MAPB (N-methyl-6-(2-aminopropyl)benzofuran) were investigated to answer these questions. The metabolites of both drugs were identified in rat urine and human liver preparations using GC-MS and/or liquid chromatography-high resolution-mass spectrometry (LC-HR-MS(n)). Besides the parent drug, the main metabolite of 6-APB was 4-carboxymethyl-3-hydroxy amphetamine and the main metabolites of 6-MAPB were 6-APB (N-demethyl metabolite) and 4-carboxymethyl-3-hydroxy methamphetamine. The cytochrome P450 (CYP) isoenzymes involved in the 6-MAPB N-demethylation were CYP1A2, CYP2D6, and CYP3A4. An intake of a common users' dose of 6-APB or 6-MAPB could be confirmed in rat urine using the authors' GC-MS and the LC-MS(n) standard urine screening approaches with the corresponding parent drugs as major target allowing their differentiation. Furthermore, a differentiation of 6-APB and 6-MAPB in urine from their positional isomers 5-APB and 5-MAPB was successfully performed after solid phase extraction and heptafluorobutyrylation by GC-MS via their retention times. PMID- 25711991 TI - Hairpin-based DNA electrochemical sensor for selective detection of a repetitive and structured target codifying a gliadin fragment. AB - High selectivity of genosensors is crucial for certain applications such as those involving species with high genetic variability. This is an unresolved problem when dealing with long target sequences that is further complicated when the target contains repetitive sequence domains. As a model for this situation, the problem of detecting gluten in food with identification of the source is studied. In order to discriminate the specific DNA sequence that encodes the wheat prolamin (gliadin) from rye and barley prolamins, the exquisite selectivity of a rationally designed hairpin capture probe is proposed and compared to a nonstructured capture probe. An electrochemical sandwich assay is proposed, involving capture probes chemisorbed on Au surfaces and biotinylated-signaling probes in combination with streptavidin-peroxidase labeling conjugates. As a result, a genosensor with similar sensitivity to that observed with linear probes but with complete specificity against closely related species was achieved. The surface-attached DNA stem-loop yields a device capable of accurately discriminating wheat DNA from rye and barley with a limit of detection of 1 nM. PMID- 25711992 TI - Excited-state intramolecular proton transfer to carbon atoms: nonadiabatic surface-hopping dynamics simulations. AB - Excited-state intramolecular proton transfer (ESIPT) between two highly electronegative atoms, for example, oxygen and nitrogen, has been intensely studied experimentally and computationally, whereas there has been much less theoretical work on ESIPT to other atoms such as carbon. We have employed CASSCF, MS-CASPT2, RI-ADC(2), OM2/MRCI, DFT, and TDDFT methods to study the mechanistic photochemistry of 2-phenylphenol, for which such an ESIPT has been observed experimentally. According to static electronic structure calculations, irradiation of 2-phenylphenol populates the bright S1 state, which has a rather flat potential in the Franck-Condon region (with a shallow enol minimum at the CASSCF level) and may undergo an essentially barrierless ESIPT to the more stable S1 keto species. There are two S1/S0 conical intersections that mediate relaxation to the ground state, one in the enol region and one in the keto region, with the latter one substantially lower in energy. After S1 -> S0 internal conversion, the transient keto species can return back to the S0 enol structure via reverse ground-state hydrogen transfer in a facile tautomerization. This mechanistic scenario is verified by OM2/MRCI-based fewest-switches surface hopping simulations that provide detailed dynamic information. In these trajectories, ESIPT is complete within 118 fs; the corresponding S1 excited-state lifetime is computed to be 373 fs in vacuum. Most of the trajectories decay to the ground state via the S1/S0 conical intersection in the keto region (67%), and the remaining ones via the enol region (33%). The combination of static electronic structure computations and nonadiabatic dynamics simulations is expected to be generally useful for understanding the mechanistic photophysics and photochemistry of molecules with intramolecular hydrogen bonds. PMID- 25711993 TI - Microphthalmia transcription factor immunohistochemistry for FNA biopsy of ocular malignant melanoma. AB - BACKGROUND: Microphthalmia transcription factor (MiTF) is a sensitive and specific immunohistochemistry (IHC) marker for malignant melanoma (MM) in surgical resections, but its utility in cytology specimens has not been extensively studied. METHODS: A search of the pathology database identified fine needle aspiration biopsies signed out as MM or suspicious for MM (1998-2012). The final diagnosis and the IHC results were recorded, and all slides were re reviewed. MiTF IHC (C5/D5 cocktail) was performed on alcohol-fixed, Papanicolaou stained direct smears. Any amount of nuclear staining was considered positive. Staining was scored on a scale of 1 to 4 (1, 1%-24%; 2, 25%-49%; 3, 50%-74%; 4, 75%-100%). RESULTS: Two hundred seventy-four cases were diagnosed as MM, and 24 were diagnosed as suspicious for MM. IHC staining was performed for 25% (69 of 274) of the MM cases and for 33% (8 of 24) of the cases suspicious for MM. MiTF IHC of Papanicolaou slides was performed for 37% (101 of 274) of the MM cases (positive, 82% [83 of 101]; negative, 4% [4 of 101]; noncontributory, 14% [14 of 101]) and for 33% (8 of 24) of the cases suspicious for MM (positive, 38% [3 of 8]; noncontributory, 62% [5 of 8]). The majority of positive staining was scored as 3 or 4. The sensitivity of MiTF on Papanicolaou-stained slides was 95%. CONCLUSIONS: MiTF is a useful IHC stain for the evaluation of ocular MM, and it is effective when it is performed on alcohol-fixed, Papanicolaou-stained aspirate smears. PMID- 25711994 TI - Acta Radiologica Short Reports changes name to Acta Radiologica Open. PMID- 25711999 TI - Antidote shortages in the USA: impact and response. PMID- 25712001 TI - Why would a consultant think of going into management? PMID- 25712002 TI - Variation of 210Po daily urinary excretion for male subjects at environmental level. AB - (210)Po was determined in 24-h urine of seven healthy males from Prague, Czech Republic, for ten consecutive days. The results show that for each volunteer, the urinary excretion of (210)Po changed only little from day to day in the studied time period. For two volunteers, the difference in the daily excreted (210)Po activity for two consecutive days was not significant, given the 95% confidence interval (two sigma) of the activity measurements. The same is valid for the excretion data of the other volunteers, except for some days where the differences were slightly higher. The range of daily urinary excretion of (210)Po of each volunteer in the studied time period was quite narrow. Among the volunteers, the maximum daily urinary excretion value of (210)Po was at most about a factor of 2.5 higher than the lowest excretion value. An attempt to explain the observed small inter-individual variability of (210)Po excretion in daily urine is made. PMID- 25712003 TI - Synthesis, characterization and biological activity of Cu(II), Zn(II) and Re(I) complexes derived from S-benzyldithiocarbazate and 3-acetylcoumarin. AB - Cu(II), Zn(II) and Re(I) complexes have been synthesized with the Schiff base, N' [1-(2-oxo-2H-chromen-3-yl)-ethylidene]-hydrazinecarbodithioic acid benzyl ester (SBCM-H) which was prepared by condensation of S-benzyldithiocarbazate and 3 acetylcoumarin. The metal complexes were characterized on the basis of various physico-chemical and spectroscopic techniques including elemental analysis and electrochemical studies, and FT-IR, UV-Vis, NMR, EPR and mass spectroscopy. The Schiff base was found to behave as a bidentate ligand coordinating with Cu(II) and Zn(II) in the thiolate form with 1:2 metal to ligand stoichiometry. Crystals suitable for X-ray diffractometry (XRD) were obtained from the reaction of ReCl(CO)5 with SBCM-H forming a centrosymmetric dimeric complex Re2L2(CO)6 linked by Re-S-Re bridges, where S is the thiolate sulfur of the N,S-bidentate ligand. This Re(I) complex is the first metal carbonyl complex with a bidentate dithiocarbazate ligand to have been characterized by XRD. Cytotoxicity assays revealed enhancement of the bioactivity of SBCM-H upon complexation. Both Cu(II) and Re(I) complexes are found to be active against human breast adenocarcinoma cancer cell lines MDA-MB-231 and MCF-7. TOC diagram. PMID- 25712004 TI - Should patients with cirrhosis and variceal hemorrhage receive glucocorticoid therapy? PMID- 25712006 TI - Erratum to: The Pediatrix BabySteps(r) Data Warehouse - A Unique National Resource for Improving Outcomes for Neonates. PMID- 25712005 TI - Health Related Quality of Life and its Predictors among Bengali Thalassemic Children Admitted to a Tertiary Care Hospital. AB - OBJECTIVE: To assess the quality of life among thalassemic children and to find out association of quality of life (QOL) with the socio-demographic factors, and clinico-therapeutic profile. METHODS: This cross sectional descriptive epidemiological study was conducted from July 2011 through June 2012 on 365 admitted thalassemic patients of 5 to 12 y of age in the Burdwan Medical College and Hospital. Parents of the children were interviewed using Paediatric Quality of Life Inventory 4.0 Generic Core Scale. Statistically significant variables in bivariate analysis were considered for correlation matrix where independent variables were found inter related. So, partial correlation was done and statistically significant variables in partial correlation were considered for linear regression. RESULTS: The mean age of 365 thalassemic children was 8.3 +/- 2.4 y. Multiple linear regressions predicted that only 70.5 % variation of total summary score depended on duration since splenectomy (31.2 % variation), last pre transfusion Hb level (20.7 %), family history of thalassemia (17.3 %) and frequency of blood transfusions (1.3 %). After splenectomy, thalassemic children could lead a better quality of life upto 5 y only. The betterment of the quality of life needs maintaining pre transfusion Hb level above 7 g/dl. Previous experience of the disease among the family members enriches the awareness among them and helps them to take correct decisions timely about the child and that leads to better QOL. CONCLUSIONS: More awareness regarding the maintenance of pre transfusion Hb level should be built up among parents and families where such disease has occurred for the first time. PMID- 25712007 TI - Predictors of Altered Sensorium at Admission in Children with Diabetic Ketoacidosis: Correspondence. PMID- 25712008 TI - Predictors of Altered Sensorium at Admission in Children with Diabetic Ketoacidosis: Authors' Reply. PMID- 25712009 TI - CRHR1 Gene SNPs and Response to Systemic Corticosteroids in Indian Asthmatic Children During Acute Exacerbation. AB - OBJECTIVE: To determine association of corticotrophin releasing hormone receptor 1 (CRHR1) gene single nucleotide polymorphisms (SNPs), rs242939 (A>G) and rs242941 (G>T) with response to systemic corticosteroids in North Indian asthmatic children during acute exacerbation. METHODS: This was a hospital based cross-sectional study. Sixty-eight children aged 1 to 12 y with acute exacerbation of asthma were included in the study. The study was approved by the institutional ethics committee and written informed consent was obtained from parents/guardians of recruited children. GINA guidelines 2008, were used for classification and treatment of acute exacerbation of asthma. As per the GINA guidelines 2008, children who had good response to injectable corticosteroid were classified as "Corticosteroid Responders" (CR). Rest of the children with incomplete or poor response to injectable corticosteroid were classified as "Corticosteroid Non Responders" (CNR). RESULTS: Among 68 hospitalized children, 45 (66.17 %) children were CR whereas 23 (33.83 %) children were CNR. On analyzing as dominant model, children with one or two copies of mutant allele of SNP rs242941 had statistically significant better response to systemic corticosteroid (OR = 5.00; 95 %CI = 1.32-19.64; p 0.013) as compared to children with no mutant allele. CONCLUSIONS: Thus, CRHR1 gene SNP rs242941 polymorphism is associated with better response to systemic corticosteroid during acute exacerbation of asthma. PMID- 25712012 TI - Sustained-release of naproxen sodium from electrospun-aligned PLLA-PCL scaffolds. AB - Spontaneous tendon healing may result in reduced tissue functionality. In view of this, tissue engineering (TE) emerges as a promising approach in promoting proper tendon regeneration. However, unfavourable post-surgical adhesion formations restrict adequate tendon healing through the TE approach. Naproxen sodium (NPS), a non-steroidal anti-inflammatory drug (NSAID), has been demonstrated to prevent adhesions by inhibiting the inflammatory response. Therefore, in this study, various factors, such as polymer composition, i.e. different poly-l-lactic acid (PLLA):polycaprolactone (PCL) ratios, and percentage of water:hexafluoroisopropanol (HFIP; as co-solvent) ratios, were investigated to understand how these can influence the release of NPS from electrospun scaffolds. By adjusting the amount of water as the co-solvent, NPS could be released sustainably for as long as 2 weeks. Scaffold breaking strength was also enhanced with the addition of water as the co-solvent. This NPS-loaded scaffold showed no significant cytotoxicity, and L929 murine fibroblasts cultured on the scaffolds were able to proliferate and align along the fibre orientation. These scaffolds with desirable tendon TE characteristics would be promising candidates in achieving better tendon regeneration in vivo. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 25712010 TI - The asthma COPD overlap syndrome (ACOS). AB - Asthma and chronic obstructive pulmonary disease (COPD) have traditionally been viewed as distinct clinical entities. Recently, however, much attention has been focused on patients with overlapping features of both asthma and COPD: those with asthma COPD overlap syndrome (ACOS). Although no universal definition criteria exist, recent publications attempted to define patients with ACOS based on differences in clinical features, radiographic findings, and diagnostic tests. Patients with ACOS make up a large percentage of those with obstructive lung disease and have a higher overall health-care burden. Identifying patients with ACOS has significant therapeutic implications particularly with the need for early use of inhaled corticosteroids and the avoidance of use of long-acting bronchodilators alone in such patients. However, unlike asthma and COPD, no evidence-based guidelines for the management of ACOS currently exist. Future research is needed to improve our understanding of ACOS and to achieve the best management strategies. PMID- 25712014 TI - Of capturing fish, mobilizing enzymes, and a surprising source for serotonin. PMID- 25712013 TI - Overexpression of CuZnSOD from Arachis hypogaea alleviates salinity and drought stress in tobacco. AB - KEY MESSAGE: Overexpression of CuZnSOD gene from Arachis hypogaea demonstrating its involvement in abiotic stress tolerance. Abiotic stress is accompanied by the formation of reactive oxygen species (ROS) such as superoxide, hydrogen peroxide, and hydroxyl radicals, causing extensive cellular damage and inhibition of photosynthesis that limit the plant productivity. The level of ROS in cells needs to be tightly regulated and the toxic effects of ROS are countered by enzymatic as well as non-enzymatic antioxidant systems. The superoxide dismutase is the first enzyme involved in the detoxification of ROS and converts superoxide (O2(. )) radicals to H2O2. A full-length cDNA clone encoding a CuZnSOD, named AhCuZnSOD, was isolated from the salt tolerant cell lines of Arachis hypogaea, stably thriving at 200 mM NaCl. The cell line showed higher transcript accumulation under multiple abiotic stresses, including drought, salinity, cold and oxidative stress treatment. The functional role of AhCuZnSOD in alleviation of abiotic stress was assessed by its overexpression in transgenic tobacco plants. The T1 transgenic plants showed improved tolerance to salinity and dehydration stress as indicated by higher seed germination and better chlorophyll content. The transgenic plants survived under longer periods of water deficiency and salinity stress and displayed improved recovery after rehydration compared to the wild type (WT) plants. The enhanced level of the transgene correlated with higher relative water content, less electrolyte damage, less malondialdehyde, higher antioxidant enzyme activity, H2O2 and O2(.-) accumulation under stress conditions compared to WT plants. Our results substantiate that increased levels of SOD activity brought about by overexpression of AhCuZnSOD gene may play an important role in ameliorating oxidative injury induced by various environmental stresses. PMID- 25712015 TI - A better method to measure total calcium in biological samples yields immediate payoffs. PMID- 25712016 TI - Identification of a key residue in Kv7.1 potassium channel essential for sensing external potassium ions. AB - Kv7.1 voltage-gated K(+) (Kv) channels are present in the apical membranes of marginal cells of the stria vascularis of the inner ear, where they mediate K(+) efflux into the scala media (cochlear duct) of the cochlea. As such, they are exposed to the K(+)-rich (~ 150 mM of external K(+) (K(+) e)) environment of the endolymph. Previous studies have shown that Kv7.1 currents are substantially suppressed by high K(+) e (independent of the effects of altering the electrochemical gradient). However, the molecular basis for this inhibition, which is believed to involve stabilization of an inactivated state, remains unclear. Using sequence alignment of S5-pore linkers of several Kv channels, we identified a key residue, E290, found in only a few Kv channels including Kv7.1. We used substituted cysteine accessibility methods and patch-clamp analysis to provide evidence that the ability of Kv7.1 to sense K(+) e depends on E290, and that the charge at this position is essential for Kv7.1's K(+) e sensitivity. We propose that Kv7.1 may use this feedback mechanism to maintain the magnitude of the endocochlear potential, which boosts the driving force to generate the receptor potential of hair cells. The implications of our findings transcend the auditory system; mutations at this position also result in long QT syndrome in the heart. PMID- 25712018 TI - Structural and functional properties of ryanodine receptor type 3 in zebrafish tail muscle. PMID- 25712017 TI - Nonexocytotic serotonin release tonically suppresses serotonergic neuron activity. AB - The firing activity of serotonergic neurons in raphe nuclei is regulated by negative feedback exerted by extracellular serotonin (5-HT)o acting through somatodendritic 5-HT1A autoreceptors. The steady-state [5-HT]o, sensed by 5-HT1A autoreceptors, is determined by the balance between the rates of 5-HT release and reuptake. Although it is well established that reuptake of 5-HTo is mediated by 5 HT transporters (SERT), the release mechanism has remained unclear. It is also unclear how selective 5-HT reuptake inhibitor (SSRI) antidepressants increase the [5-HT]o in raphe nuclei and suppress serotonergic neuron activity, thereby potentially diminishing their own therapeutic effect. Using an electrophysiological approach in a slice preparation, we show that, in the dorsal raphe nucleus (DRN), continuous nonexocytotic 5-HT release is responsible for suppression of phenylephrine-facilitated serotonergic neuron firing under basal conditions as well as for autoinhibition induced by SSRI application. By using 5 HT1A autoreceptor-activated G protein-gated inwardly rectifying potassium channels of patched serotonergic neurons as 5-HTo sensors, we show substantial nonexocytotic 5-HT release under conditions of abolished firing activity, Ca(2+) influx, vesicular monoamine transporter 2-mediated vesicular accumulation of 5 HT, and SERT-mediated 5-HT transport. Our results reveal a cytosolic origin of 5 HTo in the DRN and suggest that 5-HTo may be supplied by simple diffusion across the plasma membrane, primarily from the dense network of neurites of serotonergic neurons surrounding the cell bodies. These findings indicate that the serotonergic system does not function as a sum of independently acting neurons but as a highly interdependent neuronal network, characterized by a shared neurotransmitter pool and the regulation of firing activity by an interneuronal, yet activity-independent, nonexocytotic mechanism. PMID- 25712019 TI - Richard M. Krause, M.D. Jan. 4. 1925-Jan. 6. 2015. PMID- 25712020 TI - Targeting PI3K/AKT/mTOR network for treatment of leukemia. AB - OBJECTIVE: Increased activity of PI3K/AKT/mTOR pathway has been observed in a huge number of malignancies. This pathway can function as a prosurvival factor in leukemia stem cells and early committed leukemic precursors and its inhibition is regarded as a therapeutic approach. Accordingly, the aim of this review is to evaluate the PI3K/Akt/mTOR inhibitors used in leukemia models. DISCUSSION: Inhibition of the PI3K/AKT/mTOR pathway has been reported to have beneficial therapeutic effects in leukemias, both in vitro in leukemia cell lines and in vivo in animal models. Overall, the use of dual PI3K/mTOR inhibitor, dual Akt/RTK inhibitor, Akt inhibitor, selective inhibitor of PI3K, mTOR inhibitor and dual PI3K/PDK1 inhibitor in CML, AML, APL, CLL, B-ALL and T-ALL has a better therapeutic effect than conventional treatments. CONCLUSIONS: Targeting the PI3K/Akt/mTOR pathway may have pro-apoptotic and antiproliferative effects on hematological malignancies. Furthermore, modulation of miRNA can be used as a novel therapeutic approach to regulate the PI3K/Akt/mTOR pathway. However, both aspects require further clinical studies. PMID- 25712021 TI - High-definition optical coherence tomography algorithm for discrimination of basal cell carcinoma from clinical BCC imitators and differentiation between common subtypes. AB - BACKGROUND: Preliminary studies have described morphological features of basal cell carcinoma (BCC) imaged by high-definition optical coherence tomography (HD OCT) and suggested that this technique may aid in its diagnosis and management. However, systematic studies evaluating the accuracy of HD-OCT for the diagnosis of BCC are lacking. OBJECTIVE: The aim of this study was to identify three dimensional (3-D) HD-OCT features able i) to distinguish BCC from clinical BCC imitators and ii) to discriminate between the most common BCC subtypes. Based on these particular features, a diagnostic algorithm will be suggested. METHOD: A total of 50 histopathologically confirmed BCCs (18 superficial, 19 nodular, 13 infiltrative) were imaged by HD-OCT at the centre of the lesion prior to standard surgical excision and subsequent histopathological analysis. Fifty images of clinical BCC imitators were also retrieved as a 'pitfalls' group. RESULTS: The simultaneous presence of grey/dark subepidermal (hemi-spherical) or intradermal lobulated structure(s) presenting a typical cockade feature in both HD-OCT modes was a significant feature for BCC diagnosis. Features discriminating between BCC subtypes were location of the roof of BCC lobules, vascular pattern of the papillary plexus and stretching effect on the stroma. Clinical BCC imitators such as actinic keratosis, compound and intradermal naevi, amelanotic melanoma, sebaceous hyperplasia and small haemangioma could be differentiated from BCC by means of HD-OCT. CONCLUSION: This study provides a thorough description of 3-D HD OCT features that can permit discrimination of BCC from clinical BCC imitators and differentiation of BCC subtypes. Based on these features, a diagnostic algorithm is proposed which requires additional validation, but enhances current understanding of the morphological correlates of HD-OCT images in skin. PMID- 25712022 TI - One-Year Multicenter Prospective Evaluation of Survival Rates and Bone Resorption in One-Piece Implants. AB - BACKGROUND: Several studies have reported the efficiency of immediate loading techniques. PURPOSE: The aim of this multicenter prospective study was to evaluate the clinical efficiency of the one-piece screw (OPS) implants used by general dentists. MATERIALS AND METHODS: A total of 272 patients were treated with 533 implants at five dental clinics by five general dentists. Some implants were provided with provisional restoration. Implants in partially edentulous spaces were splinted with acryl, composite, and intraoral welding. The implant survival rates, bone resorption, plaque accumulation, and soft tissue health were evaluated after 3, 6, and 12 months. The final restorations were cemented in the maxilla after 6 months and in the mandible after 3 months. RESULTS: Twelve implants failed (98% survival rate) after 12 months. None of the splinted implants failed during the follow-ups. There were five failures in unsplinted partial cases. The average amounts of bone loss around the implants were 0.40 +/- 0.35 mm, 0.56 +/- 0.41 mm, and 0.59 +/- 0.41 mm after 3, 6, and 12 months, respectively. Visible plaque was registered in 18% of the implants, and bleeding on probing was observed in 17% of the implants after 12 months. CONCLUSIONS: High survival rates and favorable host tissue responses support the clinical performance of OPS implants. This study demonstrated that one-piece implants can be efficiently used by well-trained general dentists. PMID- 25712023 TI - A polyimide anode with high capacity and superior cyclability for aqueous Na-ion batteries. AB - A redox-active and water-insoluble polyimide, poly-(naphthalene four formyl ethylenediamine), demonstrates a high capacity of 130 mA h g(-1), a strong rate capability at 10 C rate and an excellent capacity retention of 91.2% over 1000 cycles, offering a low cost and environmentally benign anode for aqueous Na-ion batteries. PMID- 25712024 TI - An efficient synthesis of quinolines via copper-catalyzed C-N cleavage. AB - An efficient method to synthesize substituted quinolines from ketones and 2-amino benzylamines is described. Copper-catalyzed C-N cleavage of amines followed by condensation with ketones deliver quinolines in moderate to high yields. The broad scope of substrates and the use of air as the sole oxidant make this transformation very attractive. PMID- 25712026 TI - Fluorescence axial nanotomography with plasmonics. AB - We present a novel imaging technique with super-resolution axial sensitivity, exploiting the changes in fluorescence lifetime above a plasmonic substrate. Using conventional confocal fluorescence lifetime imaging, we show that it is possible to deliver down to 6 nm axial position sensitivity of fluorophores in whole biological cell imaging. We employ this technique to map the topography of the cellular membrane, and demonstrate its application in an investigation of receptor-mediated endocytosis in carcinoma cells. PMID- 25712025 TI - Resting-State Functional Connectivity in Individuals with Down Syndrome and Williams Syndrome Compared with Typically Developing Controls. AB - The emergence of resting-state functional connectivity (rsFC) analysis, which examines temporal correlations of low-frequency (<0.1 Hz) blood oxygen level dependent signal fluctuations between brain regions, has dramatically improved our understanding of the functional architecture of the typically developing (TD) human brain. This study examined rsFC in Down syndrome (DS) compared with another neurodevelopmental disorder, Williams syndrome (WS), and TD. Ten subjects with DS, 18 subjects with WS, and 40 subjects with TD each participated in a 3-Tesla MRI scan. We tested for group differences (DS vs. TD, DS vs. WS, and WS vs. TD) in between- and within-network rsFC connectivity for seven functional networks. For the DS group, we also examined associations between rsFC and other cognitive and genetic risk factors. In DS compared with TD, we observed higher levels of between-network connectivity in 6 out 21 network pairs but no differences in within-network connectivity. Participants with WS showed lower levels of within network connectivity and no significant differences in between-network connectivity relative to DS. Finally, our comparison between WS and TD controls revealed lower within-network connectivity in multiple networks and higher between-network connectivity in one network pair relative to TD controls. While preliminary due to modest sample sizes, our findings suggest a global difference in between-network connectivity in individuals with neurodevelopmental disorders compared with controls and that such a difference is exacerbated across many brain regions in DS. However, this alteration in DS does not appear to extend to within-network connections, and therefore, the altered between-network connectivity must be interpreted within the framework of an intact intra-network pattern of activity. In contrast, WS shows markedly lower levels of within network connectivity in the default mode network and somatomotor network relative to controls. These findings warrant further investigation using a task-based procedure that may help disentangle the relationship between brain function and cognitive performance across the spectrum of neurodevelopmental disorders. PMID- 25712027 TI - Knowledge and understanding of antibiotic resistance and the risk of becoming a carrier when travelling abroad: a qualitative study of Swedish travellers. AB - BACKGROUND: Increasing globalisation, with the migration of people, animals and food across national borders increases the risk of the spread of antibiotic resistant bacteria. To avoid becoming a carrier of antibiotic-resistant bacteria when travelling, knowledge about antibiotic resistance is important. MATERIALS AND METHODS: We aimed to describe the knowledge and understanding of antibiotic resistant bacteria, and of the risk for becoming a carrier of such bacteria, among Swedish travellers before their travel to high-risk areas. A questionnaire with three open-ended questions was distributed to 100 individuals before departure. RESULTS: The travellers' answers were analysed using content analysis, resulting in the theme 'To be an insecure traveller who takes control over one's own journey'. Our results showed that the travellers were aware of what the term 'antimicrobial resistance' meant, but did not understand its real significance, nor the consequences for the individual nor for society. They also distanced themselves from the problem. Few thought that their travel would entail a risk of becoming a carrier of resistant bacteria. The lack of knowledge caused an uncertainty among the travellers, whom tried to master the situation by using coping strategies. They proposed a number of measures to prevent carriership. The measures were general and primarily aimed at avoiding illness abroad, particularly acute gastro-intestinal infection. CONCLUSIONS: In health care and vaccination clinics, there is a need for improved information for persons intending to travel to high-risk areas, both about the risks of contracting antibiotic-resistant bacteria and about effective preventive measures. PMID- 25712028 TI - Improvement in health expectancy at ages 50 and 65 in Denmark during the period 2004-2011. AB - AIMS: In Denmark life expectancy (LE) has increased since 1995 after a long period of stagnation. Healthy life expectancy (HLE) at age 65 increased more than LE during the period 1987-2005. The aim of the study was to determine the trend in HLE in Denmark at ages 50 and 65 during the period 2004-2011. METHODS: The study was based on nationwide register data on mortality and data on health status from the SHARE surveys carried out in 2004/2005, 2006/2007 and 2010/2011. Expected lifetime in various health states was estimated by Sullivan's method. Changes from 2004 to 2011 were decomposed into contributions from changes in mortality and prevalence of activity limitations. RESULTS: During the period 2004 2011 LE increased by about 1 year at both age 50 and age 65. However, the increase in expected lifetime in self-rated good health, without long-term health problems and without activity limitations was even longer in both genders and it increased by 1.5-4.0 years depending on age, gender and health indicator. Consequently, expected lifetime in an unhealthy state decreased and the proportions of lifetime in a healthy state increased. The disability effect of the health gain was stronger than the mortality effect. CONCLUSIONS: In Denmark HLE increased substantially more than LE during the period 2004-2011 for all three health indicators at both age 50 and age 65, and for both genders. Thus, the improvement in health expectancy continued in Denmark in recent years. PMID- 25712029 TI - Neighborhood environment and physical activity among young children: a cross sectional study from Sweden. AB - AIMS: The aims of this study were to investigate the association between the neighbourhood environment and physical activity among young children in a Scandinavian setting, and to assess the influences of seasonal variations, age, sex and parental education. METHODS: Physical activity was assessed with an accelerometer and neighbourhood resources were estimated using geographic information systems for 205 Swedish children aged 4-11 years. Neighbourhood resources were generated as the sum of three neighbourhood attributes: (a) foot and bike paths, (b) non-restricted destinations and (c) recreational area, all within 300 m of each child's home. Physical activity was assessed as: (a) total volume of physical activity (i.e. counts per minute), (b) sedentary time and (c) moderate to vigorous physical activity (MVPA). The association between neighbourhood resources and physical activity was analysed using mixed linear models weighted by measurement time and adjusted for sex, age, season of activity measurement, type of housing and parental education. RESULTS: Children were more physically active in areas with intermediate access to neighbourhood resources for physical activity compared to areas with worst access, while the difference between intermediate and best neighbourhood resource areas was less clear. The association between physical activity and neighbourhood resources was weaker than with seasonal variations but compatible in magnitude with sex, age, type of housing and parental education. Among specific neighbourhood attributes, the amount of foot and bike paths was associated with less sedentary time and more MVPA. CONCLUSIONS: This study provides some, not entirely consistent, evidence overall for an association between the neighbourhood environment and physical activity among young children in Scandinavia. PMID- 25712030 TI - Gender differences in development of mental well-being from adolescence to young adulthood: an eight-year follow-up study. AB - BACKGROUND: The transition from adolescence to young adulthood is marked by many changes. Mental well-being plays an important role in how individuals deal with these changes and how they develop their lifestyle. The goal of this study was to examine gender differences in the long-term development of self-esteem and other mental well-being variables from the age of 15 to the age of 23. METHODS: A baseline measurement was performed in a nationwide sample of 385 Icelandic adolescents aged 15, and a follow-up measurement was conducted eight years later, when participants had reached the age of 23. Standardized questionnaires were used to measure self-reports of self-esteem, life satisfaction, body image, anxiety, depression and somatic complaints. RESULTS: Women improved their self esteem significantly more than men from the age of 15 to 23 (p=0.004). Women were more satisfied with their life than men at the age of 23 (p=0.009). Men had a better body image, less anxiety, less depression and fewer somatic complaints than women, independent of age. Across gender, anxiety declined and somatic complaints became fewer (p<0.05). CONCLUSIONS These findings suggest that gender differences in mental well-being factors, favouring men, found in adolescents, are not as long-lasting as previously thought. Women improve their mental well being from adolescence to young adulthood while men's mental well-being does not change. PMID- 25712032 TI - An integrated superhydrophobic-plasmonic biosensor for mid-infrared protein detection at the femtomole level. AB - In this work we present an integrated biosensor that enables FTIR (Fourier Transform-Infrared) detection of analytes contained in diluted solutions. The fabricated nanosensor allows for the detection of proteins through the identification of the fine structure of their amide I and II bands, up to the nanomolar concentration range. We exploited two distinct effects to enhance the sensitivity: (i) the concentration effect due to the presence of the superhydrophobic surface that conveys molecules dispersed in solution directly inside the focus of a FTIR spectromicroscope; (ii) the plasmonic resonance of the nanoantenna array that provides electromagnetic field enhancement in the amide I and II spectral region (1500-1700 cm(-1)). We demonstrate the detection of ferritin in the nanomolar concentration range, a blood protein that is usually available in small amounts in typical blood samples. PMID- 25712031 TI - Mechanical stretch promotes matrix metalloproteinase-2 and prolyl-4-hydroxylase alpha1 production in human aortic smooth muscle cells via Akt-p38 MAPK-JNK signaling. AB - Hypertension can increase mechanical stretch on the vessel wall, an important stimulus that induces collagen remodeling. Prolyl-4-hydroxylasealpha1 (P4Halpha1) and matrix metalloproteinases (MMPs) are essential for collagen synthesis and degradation. However, the effect of mechanical strain and collagen synthesis remains largely unknown. This study aimed to identify the effect of stretch on MMPs and P4Halpha1 and the involved signaling pathways. Human aortic smooth muscle cells (HASMCs) were stimulated with mechanical stretch (0, 10% and 18% strain), and production of P4Halpha1 as well as production and gelatinolytic activity of MMP-2 was force-dependently increased. Mechanical stretch at 18% also increased the expression of type I and III collagen and the phosphorylation of Akt, p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK). MMP-2 production and activity enhanced by 18% stretch were inhibited by the PI3K/Akt inhibitor LY294002. Blockade of p38 MAPK or JNK inhibited the promoting effect of stretch on P4Halpha1. The in vivo model of aortic banding showed increased protein levels of MMP-2, P4Halpha1 and collagen I and III in the aorta. Thus, mechanical stretch increased MMP-2 and P4Halpha1 expression in HASMCs via AKT-P38 MAPK-JNK signaling, thereby inducing vascular remodeling. PMID- 25712033 TI - Site-specific integration in CHO cells mediated by CRISPR/Cas9 and homology directed DNA repair pathway. AB - Chinese hamster ovary (CHO) cells are the most widely used mammalian hosts for production of therapeutic proteins. However, development of recombinant CHO cell lines has been hampered by unstable and variable transgene expression caused by random integration. Here we demonstrate efficient targeted gene integration into site-specific loci in CHO cells using CRISPR/Cas9 genome editing system and compatible donor plasmid harboring a gene of interest (GOI) and short homology arms. This strategy has enabled precise insertion of a 3.7-kb gene expression cassette at defined loci in CHO cells following a simple drug-selection, resulting in homogeneous transgene expression. Taken together, the results displayed here can help pave the way for the targeting of GOI to specific loci in CHO cells, increasing the likelihood of generating isogenic cell lines with consistent protein production. PMID- 25712034 TI - Contrasting models of parity-mode evolution in squamate reptiles. AB - Recent analyses using large-scale phylogenies suggest a radically different history for the evolution of live birth and egg laying in squamate reptiles (lizards and snakes) than traditionally understood. What is the ancestral condition for lizards and snakes? How frequently does live bearing evolve in egg laying lineages? Can the eggshell ever re-evolve in live-bearing lineages? Answering these fundamental questions about the evolution of key physiological processes will require additional data from genomic, developmental, and fossil data. PMID- 25712035 TI - Microbial community dynamics during the early stages of plant polymer breakdown in paddy soil. AB - We used paddy soil slurries amended with rice straw to identify the microbial populations involved in the methanogenic breakdown of plant polymers. Rice straw greatly stimulated microbial activity over the 28-day incubation period. On day 7, the transient peak concentration of acetate (24 mM) coincided with the onset of increased methane production. Microbial 16S rRNA transcript numbers increased by one to two orders of magnitude, but not the 16S rRNA gene copy numbers. Using metatranscriptomic rRNA, Clostridiaceae, Lachnospiraceae, Ruminococcaceae, Veillonellaceae and Pseudomonadaceae were identified to be the most abundant and the most dynamic bacterial groups. Changes in methanogen rRNA and mRNA abundances corresponded well with methanogenic activity. Acetate determined the abundance ratio between Methanosarcinaceae and Methanosaetaceae. Methanocellaceae dominated hydrogenotrophic methanogenesis. Transcript levels of mRNA families involved in plant polymer breakdown increased slightly with time. Glycosyl hydrolase (GH) transcripts involved in cellulose and chitin breakdown were predominantly expressed by the Firmicutes, whereas those involved in hemicellulose breakdown exhibited more diverse taxonomic sources, including Acidobacteria, Bacteriodetes and Chloroflexi. Taken together, we observed strong population dynamics and the expression of taxonomically diverse GH families, suggesting that not only Firmicutes, but also less abundant groups play a major functional role in the decomposition of rice straw. PMID- 25712037 TI - Characterization of Two Species of Trypanosomatidae from the Honey Bee Apis mellifera: Crithidia mellificae Langridge and McGhee, and Lotmaria passim n. gen., n. sp. AB - Trypanosomatids are increasingly recognized as prevalent in European honey bees (Apis mellifera) and by default are attributed to one recognized species, Crithidia mellificae Langridge and McGhee, 1967. We provide reference genetic and ultrastructural data for type isolates of C. mellificae (ATCC 30254 and 30862) in comparison with two recent isolates from A. mellifera (BRL and SF). Phylogenetics unambiguously identify strains BRL/SF as a novel taxonomic unit distinct from C. mellificae strains 30254/30862 and assign all four strains as lineages of a novel clade within the subfamily Leishmaniinae. In vivo analyses show strains BRL/SF preferably colonize the hindgut, lining the lumen as adherent spheroids in a manner identical to previous descriptions from C. mellificae. Microscopy images show motile forms of C. mellificae are distinct from strains BRL/SF. We propose the binomial Lotmaria passim n. gen., n. sp. for this previously undescribed taxon. Analyses of new and previously accessioned genetic data show C. mellificae is still extant in bee populations, however, L. passim n. gen., n. sp. is currently the predominant trypanosomatid in A. mellifera globally. Our findings require that previous reports of C. mellificae be reconsidered and that subsequent trypanosomatid species designations from Hymenoptera provide genetic support. PMID- 25712038 TI - Adapting to alcohol: Dwarf hamster (Phodopus campbelli) ethanol consumption, sensitivity, and hoard fermentation. AB - Ethanol consumption and sensitivity in many species are influenced by the frequency with which ethanol is encountered in their niches. In Experiment 1, dwarf hamsters (Phodopus campbelli) with ad libitum access to food and water consumed high amounts of unsweetened alcohol solutions. Their consumption of 15%, but not 30%, ethanol was reduced when they were fed a high-fat diet; a high carbohydrate diet did not affect ethanol consumption. In Experiment 2, intraperitoneal injections of ethanol caused significant dose-related motor impairment. Much larger doses administered orally, however, had no effect. In Experiment 3, ryegrass seeds, a common food source for wild dwarf hamsters, supported ethanol fermentation. Results of these experiments suggest that dwarf hamsters may have adapted to consume foods in which ethanol production naturally occurs. PMID- 25712036 TI - Childhood adversity and subsequent mental health status in adulthood: screening for associations using two linked surveys. AB - AIMS: Accumulating evidence links childhood adversity to negative health outcomes in adulthood. However, most of the available evidence is retrospective and subject to recall bias. Published reports have sometimes focused on specific childhood exposures (e.g. abuse) and/or specific outcomes (e.g. major depression). Other studies have linked childhood adversity to a large and diverse number of adult risk factors and health outcomes such as cardiovascular disease. To advance this literature, we undertook a broad examination of data from two linked surveys. The goal was to avoid retrospective distortion and to provide a descriptive overview of patterns of association. METHODS: A baseline interview for the Canadian National Longitudinal Study of Children and Youth collected information about childhood adversities affecting children aged 0-11 in 1994. The sampling procedures employed in a subsequent study called the National Population Health Survey (NPHS) made it possible to link n = 1977 of these respondents to follow-up data collected later when respondents were between the ages of 14 and 27. Outcomes included major depressive episodes (MDE), some risk factors and educational attainment. Cross-tabulations were used to examine these associations and adjusted estimates were made using the regression models. As the NPHS was a longitudinal study with multiple interviews, for most analyses generalized estimating equations (GEE) were used. As there were multiple exposures and outcomes, a statistical procedure to control the false discovery rate (Benjamini Hochberg) was employed. RESULTS: Childhood adversities were consistently associated with a cluster of potentially related outcomes: MDE, psychotropic medication use and smoking. These outcomes may be related to one another since psychotropic medications are used in the treatment of major depression, and smoking is strongly associated with major depression. However, no consistent associations were observed for other outcomes examined: physical inactivity, excessive alcohol consumption, binge drinking or educational attainment. CONCLUSIONS: The conditions found to be the most strongly associated with childhood adversities were a cluster of outcomes that potentially share pathophysiological connections. Although prior literature has suggested that a very large number of adult outcomes, including physical inactivity and alcohol related outcomes follow childhood adversity, this analysis suggests a degree of specificity with outcomes potentially related to depression. Some of the other reported adverse outcomes (e.g. those related to alcohol use, physical inactivity or more distal outcomes such as obesity and cardiovascular disease) may emerge later in life and in some cases may be secondary to depression, psychotropic medication use and smoking. PMID- 25712039 TI - Further evidence of close correspondence for alcohol demand decision making for hypothetical and incentivized rewards. AB - Alcohol purchase tasks (APTs) are increasingly being used to assess behavioral economic demand for alcohol. Prior studies utilizing APTs have typically assessed demand for hypothetical outcomes, making the extent to which these hypothetical measures reflect preferences when actual rewards are at stake an important empirical question. This study examined alcohol demand across hypothetical and incentivized APTs. Nineteen male heavy drinkers completed two APTs - one for hypothetical alcohol and another in which one randomly-selected outcome was provided. Participants were given an opportunity to consume the alcohol associated with their choice on the incentivized APT during a self-administration period in a simulated bar environment. Results indicated generally close correspondence between APT versions, though participants were more sensitive to increases in price and tended to consume more at low prices on the incentivized version. Estimated consumption on the incentivized APT was highly correlated with the amount of alcohol consumed in the laboratory (r=.87, p<.001), suggesting that APT responses are valid indicators of actual drinking behavior. These results provide further evidence of congruence of demand-based decision-making when rewards are hypothetical vs. actually available. Implications for behavioral economic approaches to addictive behavior and directions for future research are discussed. PMID- 25712040 TI - Super-resurgence: ABA renewal increases resurgence. AB - Previously extinguished operant responding recurs under both resurgence and renewal procedures, but the effects of combining these procedures on recurrence has not been studied. Because renewal and resurgence are known to independently produce response recurrence, we examined whether greater resurgence would occur if the resurgence procedure was combined with an ABA renewal procedure, relative to a resurgence procedure without contextual changes. Three pigeons were exposed to a concurrent resurgence procedure in which key colors served as contextual stimuli. In the Training phase, reinforcement for pecking two keys was scheduled on concurrent variable-interval (VI) 120-s VI 120-s schedules, each correlated with different key colors. In the Alternative Reinforcement phase, reinforcement occurred when neither key was pecked for 20-s (a differential-reinforcement-of other-behavior [DRO] 20-s schedule). During this phase, one of the key colors was changed (ABA key), while the other key color remained as in the Training phase (AAA key). In the third phase, reinforcement was not provided and the color of the ABA key was changed back to the color in effect during the Training phase while the same color remained in effect on the other key. Greater resurgence occurred on the ABA renewal key with each pigeon, demonstrating that a superimposed ABA renewal procedure increases resurgence. PMID- 25712041 TI - Preparation of ready-to-use small unilamellar phospholipid vesicles by ultrasonication with a beaker resonator. AB - Lipid vesicles are widely used as models to investigate the interactions of proteins, peptides, and small molecules with lipid bilayers. We present a sonication procedure for the preparation of well-defined and ready-to-use small unilamellar vesicles composed of phospholipids with the aid of a beaker resonator. This indirect but efficient sonication method does not require subsequent centrifugation or other purification steps, which distinguishes it from established sonication procedures. Vesicles produced by this method reveal a unimodal size distribution and are unilamellar, as demonstrated by dynamic light scattering and (31)P nuclear magnetic resonance spectroscopy, respectively. PMID- 25712042 TI - A high-throughput mass spectrometric assay for discovery of human lipoxygenase inhibitors and allosteric effectors. AB - Lipoxygenases (LOXs) regulate inflammation through the production of a variety of molecules whose specific downstream effects are not entirely understood due to the complexity of the inflammation pathway. The generation of these biomolecules can potentially be inhibited and/or allosterically regulated by small synthetic molecules. The current work describes the first mass spectrometric high throughput method for identifying small molecule LOX inhibitors and LOX allosteric effectors that change the substrate preference of human lipoxygenase enzymes. Using a volatile buffer and an acid-labile detergent, enzymatic products can be directly detected using high-performance liquid chromatography-mass spectrometry (HPLC-MS) without the need for organic extraction. The method also reduces the required enzyme concentration compared with traditional ultraviolet (UV) absorbance methods by approximately 30-fold, allowing accurate binding affinity measurements for inhibitors with nanomolar affinity. The procedure was validated using known LOX inhibitors and the allosteric effector 13(S)-hydroxy 9Z,11E-octadecadienoic acid (13-HODE). PMID- 25712043 TI - Assessing pyloric sphincter pathophysiology using EndoFLIP in patients with gastroparesis. AB - BACKGROUND: Pyloric dysfunction has been associated with gastroparesis, particularly diabetic gastroparesis. Endoscopic functional luminal imaging probe (EndoFLIP) uses 16 sensors inside a balloon that is inflated inside a sphincter to assess physiologic characteristics. The aim of this study was to measure the pressure, diameter, cross-sectional area (CSA), and distensibility of the pylorus using EndoFLIP in patients with gastroparesis. In addition, the relationship between pyloric pathophysiology with gastroparesis etiology, symptoms, and gastric emptying was assessed. METHODS: EndoFLIP was performed in 54 patients (39 idiopathic gastroparesis, 15 diabetic gastroparesis). The EndoFLIP catheter was passed endoscopically so that the balloon straddled the pylorus. Pressure, diameter, CSA, and distensibility of the pylorus were measured at 20, 30, 40, and 50 cc balloon volume. KEY RESULTS: Pyloric sphincter contour was seen best at 40 cc balloon distension (diameter 12.2 +/- 0.44 mm, CSA 125.2 +/- 9.15 mm(2), pressure 18.0 +/- 1.23 mmHg, length 1.59 +/- 0.34 cm, distensibility 10.7 +/- 2.57 mm(2)/mmHg). There was a wide range seen in diameter (5.6-22.1 mm) and distensibility (1-55 mm(2)/mmHg) of the pylorus. Symptoms of early satiety and postprandial fullness were inversely correlated with pyloric sphincter diameter and CSA. No significant difference was seen between diabetic and idiopathic gastroparetics. CONCLUSIONS & INFERENCES: EndoFLIP is a novel technique that can be used to assess pyloric physiologic characteristics. Early satiety and postprandial fullness were inversely correlated with diameter and CSA of the pyloric sphincter. No significant differences were seen comparing diabetic and idiopathic gastroparetics. This technology may be of benefit to help select patients with pyloric sphincter abnormalities. PMID- 25712044 TI - Neurological heterotopic ossification following spinal cord injury is triggered by macrophage-mediated inflammation in muscle. AB - Neurological heterotopic ossification (NHO) is the abnormal formation of bone in soft tissues as a consequence of spinal cord or traumatic brain injury. NHO causes pain, ankyloses, vascular and nerve compression and delays rehabilitation in this high-morbidity patient group. The pathological mechanisms leading to NHO remain unknown and consequently there are no therapeutic options to prevent or reduce NHO. Genetically modified mouse models of rare genetic forms of heterotopic ossification (HO) exist, but their relevance to NHO is questionable. Consequently, we developed the first model of spinal cord injury (SCI)-induced NHO in genetically unmodified mice. Formation of NHO, measured by micro-computed tomography, required the combination of both SCI and localized muscular inflammation. Our NHO model faithfully reproduced many clinical features of NHO in SCI patients and both human and mouse NHO tissues contained macrophages. Muscle-derived mesenchymal progenitors underwent osteoblast differentiation in vitro in response to serum from NHO mice without additional exogenous osteogenic stimuli. Substance P was identified as a candidate NHO systemic neuropeptide, as it was significantly elevated in the serum of NHO patients. However, antagonism of substance P receptor in our NHO model only modestly reduced the volume of NHO. In contrast, ablation of phagocytic macrophages with clodronate-loaded liposomes reduced the size of NHO by 90%, supporting the conclusion that NHO is highly dependent on inflammation and phagocytic macrophages in soft tissues. Overall, we have developed the first clinically relevant model of NHO and demonstrated that a combined insult of neurological injury and soft tissue inflammation drives NHO pathophysiology. PMID- 25712045 TI - Intermolecular interaction and the extended wormlike chain conformation of chitin in NaOH/urea aqueous solution. AB - The intra- and intermolecular interactions of chitin in NaOH/urea aqueous system were studied by a combination of NMR measurements (including (13)C NMR, (23)Na NMR, and (15)N NMR) and differential scanning calorimetry. The results revealed that the NaOH and chitin formed a hydrogen-bonded complex that was surrounded by the urea hydrates to form a sheath-like structure, leading to the good dissolution. The optimal concentration range, in which chitin was molecularly dispersed in NaOH/urea aqueous, was found to investigate the chain conformation in the dilute solution with a combination of static and dynamic light scattering. The weight-average molecular weight (Mw), radii of gyration (?Rg?z), and hydrodynamic radii (?Rh?z) values of chitin were determined, and the structure sensitive parameter (rho) and persistent length (Lp) were calculated to be >2.0 and ~30 nm, respectively, suggesting an extended wormlike chain conformation. The visualized images from TEM, cryo-TEM, and AFM indicated that, chitin nanofibers were fabricated from the parallel aggregation of chitin chains in NaOH/urea system. This work would provide a theoretical guidance for constructing novel chitin-based nanomaterials via "bottom-up" method at the molecular level. PMID- 25712046 TI - Emotion regulation as a mediator of the relation between sexual abuse and behavior problems in preschoolers. AB - Maltreated children show poor emotion regulation competencies compared to non maltreated children. Emotion regulation has been found to mediate the association between maltreatment and behavior problems in children. The aim of the present study was to examine the relationships among child sexual abuse (CSA), emotion regulation (ER), and internalized and externalized behavior problems in preschoolers using conditional process analyses. ER competencies were assessed in 127 children aged 41-79 months (62 abused, 65 non-abused) by their parents (N=124) and early childhood educators (N=88) using the Emotion Regulation Checklist (Shields & Cicchetti, 1995, 1997). Behavior problems were evaluated by parents using the Child Behavior Checklist (Achenbach & Rescorla, 2000, 2001). ER was found to completely mediate the relation between CSA and internalized behavior problems and partially mediate the relation between CSA and externalized behavior problems. Parents' and educators' evaluations of ER were also found to differ as a function of child gender. The discussion focuses on the relationships among CSA, ER, behavior problems, and child gender. The clinical implications of these findings are also examined. Promoting the optimal development of ER could prevent the emergence and exacerbation of behavior problems in these at-risk children and, in turn, foster resilience. PMID- 25712047 TI - Life after the pan and the fire: Depression, order, attachment, and the legacy of abuse among North Korean refugee youth and adolescent children of North Korean refugees. AB - Given previous research on depression, history of physical abuse, family order, attachment, and parenting, we hypothesized that the physical abuse-depression relationship would be moderated by (a) family order and (b) attachment, and that (c) attachment and family order would interact significantly in predicting depression. Hypotheses were tested in South Korea in a random cluster sample of 82 youth aged 15-25 who were either themselves North Korean refugees (n=39) or who were born to North Korean refugee mothers in China (n=43). A qualitative interview was used to shed further light on the findings. Family order appears to be a protective factor against depression in that more order is associated with a weakened past abuse-depression relationship. PMID- 25712048 TI - Regional-scale directional changes in abundance of tree species along a temperature gradient in Japan. AB - Climate changes are assumed to shift the ranges of tree species and forest biomes. Such range shifts result from changes in abundances of tree species or functional types. Owing to global warming, the abundance of a tree species or functional type is expected to increase near the colder edge of its range and decrease near the warmer edge. This study examined directional changes in abundance and demographic parameters of forest trees along a temperature gradient, as well as a successional gradient, in Japan. Changes in the relative abundance of each of four functional types (evergreen broad-leaved, deciduous broad-leaved, evergreen temperate conifer, and evergreen boreal conifer) and the demography of each species (recruitment rate, mortality, and population growth rate) were analyzed in 39 permanent forest plots across the Japanese archipelago. Directional changes in the relative abundance of functional types were detected along the temperature gradient. Relative abundance of evergreen broad-leaved trees increased near their colder range boundaries, especially in secondary forests, coinciding with the decrease in deciduous broad-leaved trees. Similarly, relative abundance of deciduous broad-leaved trees increased near their colder range boundaries, coinciding with the decrease in boreal conifers. These functional-type-level changes were mainly due to higher recruitment rates and partly to the lower mortality of individual species at colder sites. This is the first report to show that tree species abundances in temperate forests are changing directionally along a temperature gradient, which might be due to current or past climate changes as well as recovery from past disturbances. PMID- 25712049 TI - NOTCH mutations: multiple faces in human malignancies. AB - NOTCH proteins have been implicated in multiple cellular functions, such as stem cell maintenance and cell fate determination. Initially identified as proto oncogenes because they promote the development of certain types of leukemia, inactivating mutations of NOTCH were later reported. Together with the potential distinct functions of NOTCH family members, their ligands and associated niches, the precise roles of NOTCH in human cancers, particularly solid tumors, remain unsettled. In oral squamous cell carcinoma (OSCC), mutations of NOTCH1 are found in 10% to 15% tumors from Caucasian patients, mostly inactivating mutations. Recent studies of OSCC from Chinese patients, however, showed mutation rates of NOTCH1 about 50% with a considerable portion of potential activating mutations. These findings add another twist into the already complex picture of NOTCH alterations in human cancers, calling for further investigation to uncover what role exactly these molecules play in cancer initiation and progression to develop strategies targeting NOTCH signaling for cancer prevention and treatment. PMID- 25712050 TI - Hepatitis B Virus X Protein Stabilizes Cyclin D1 and Increases Cyclin D1 Nuclear Accumulation through ERK-Mediated Inactivation of GSK-3beta. AB - The Hepatitis B virus X protein (HBx) contributes centrally to the pathogenesis of hepatocellular carcinoma (HCC). It has been suggested that the transcriptional activation of cyclin D1 by HBx is implicated in the development of HCC. However, numerous studies have shown that overexpression of cyclin D1 alone is not sufficient to drive oncogenic transformation. Herein, we investigated whether HBx can stabilize cyclin D1 and induce cyclin D1 protein nuclear accumulation, and thereby accelerate hepatocarcinogenesis. The effects of HBx on cyclin D1 stabilization were assessed in cell-based transfection, Western blot, immunoprecipitation, immunocytofluorescence staining, and flow-cytometric assays. The results demonstrated that ectopic expression of HBx in HCC cells could extend the half-life of cyclin D1 protein from 40-60 minutes to 80-110 minutes. HBx stabilized cyclin D1 primarily in the S phase of the cell cycle, in a manner dependent on the inactivation of GSK-3beta, which was mediated by ERK activation. HBx also prompted the nuclear accumulation of cyclin D1, and cotransfection of the constitutively active mutant of GSK-3beta along with HBx could reverse the nuclear accumulation and subsequent cell proliferation induced by HBx. Further, a positive correlation between HBx and nuclear cyclin D1 level was established in HCC specimens detected by an immunohistochemical assay. Taken together, our results indicated that HBx could stabilize and increase cyclin D1 nuclear accumulation through ERK-mediated inactivation of GSK-3beta. This HBx-induced cyclin D1 upregulation might play an important role in HCC development and progression. PMID- 25712052 TI - A novel target for oral cancer chemoprevention? Notch quite, yet.... AB - The two major goals of oral cancer chemoprevention efforts are the ability to segregate the high-risk patients and the identification of an effective pharmacologic agent that halts progression to invasive cancer. Considerable progress has recently been achieved in profiling invasive head and neck squamous cell carcinomas, particularly with the use of high-throughput technologies. A similar molecular characterization of potentially malignant oral epithelial lesions (OPML; leukoplakia and erythroplakia) is yet to be accomplished. It is postulated, though, that molecular profiling could lead to the discovery of novel markers of cancer risk that could also serve as potential targets for chemoprevention. In this perspective, we comment on the work by Izumchenko and colleagues that reports a high prevalence of NOTCH1 gain-of-function mutations in Chinese patients with OPMLs. Although additional studies are needed to validate the findings, the study is the first to link alterations in this gene in oral premalignancy. These findings could serve as a first prototype of a single gene mutation as a potential target in clinical chemoprevention setting. PMID- 25712051 TI - Fenretinide Perturbs Focal Adhesion Kinase in Premalignant and Malignant Human Oral Keratinocytes. Fenretinide's Chemopreventive Mechanisms Include ECM Interactions. AB - The membrane-associated protein, focal adhesion kinase (FAK), modulates cell extracellular matrix interactions and also conveys prosurvival and proliferative signals. Notably, increased intraepithelial FAK levels accompany transformation of premalignant oral intraepithelial neoplasia (OIN) to oral squamous cell carcinoma (OSCC). OIN chemoprevention is a patient-centric, optimal strategy to prevent OSCC's comorbidities and mortality. The cancer chemopreventive and synthetic vitamin A derivative, fenretinide, has demonstrated protein-binding capacities, for example, mTOR- and retinol-binding protein interactions. These studies used a continuum of human oral keratinocytes (normal-HPV E6/E7-transduced OSCC) to assess potential fenretinide-FAK drug protein interactions and functional consequences on cellular growth regulation and motility. Molecular modeling studies demonstrated that fenretinide has approximately 200-fold greater binding affinity relative to the natural ligand (ATP) at FAK's kinase domain. Fenretinide also shows intermediate binding at FAK's FERM domain and interacts at the ATP-binding site of the closest FAK analogue, PYK2. Fenretinide significantly suppressed proliferation via induction of apoptosis and G2-M cell-cycle blockade. Fenretinide-treated cells also demonstrated F-actin disruption, significant inhibition of both directed migration and invasion of a synthetic basement membrane, and decreased phosphorylation of growth-promoting kinases. A commercially available FAK inhibitor did not suppress cell invasion. Notably, although FAK's FERM domain directs cell invasion, FAK inhibitors target the kinase domain. In addition, FAK-specific siRNA-treated cells showed an intermediate cell migration capacity; data which suggest cocontribution of the established migrating-enhancing PYK2. Our data imply that fenretinide is uniquely capable of disrupting FAK's and PYK2's prosurvival and mobility-enhancing effects and further extend fenretinide's chemopreventive contributions beyond induction of apoptosis and differentiation. PMID- 25712053 TI - Omega-3 and omega-6 Fatty acids in blood and breast tissue of high-risk women and association with atypical cytomorphology. AB - The ratio of omega-3 to omega-6 fatty acids, especially the long-chain eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) to arachidonic acid (AA) ratio, is inversely associated with breast cancer risk. We measured the association between cytologic atypia, a biomarker for short-term risk of breast cancer development, and omega-3 and omega-6 fatty acid intake and levels in blood and breast tissue. Blood and benign breast tissue, sampled by random periareolar fine-needle aspiration (RPFNA), was obtained from 70 women at elevated risk for breast cancer. Self-reported dietary intake was assessed by the NCI's Food Frequency Questionnaire. The fatty acid composition of five lipid compartments, red blood cell, plasma and breast phospholipids, and plasma and breast triaclyglycerides (TAG), was analyzed by gas chromatography as weight percent. Median daily intakes of EPA+DHA and total omega-3 fatty acids were 80 mg and 1.1 g, respectively. The median total omega-3:6 intake ratio was 1:10. Compared with women without atypia, those with cytologic atypia had lower total omega-3 fatty acids in red blood cell and plasma phospholipids and lower omega-3:6 ratios in plasma TAGs and breast TAGs (P < 0.05). The EPA+DHA:AA ratio in plasma TAGs was also lower among women with atypia. This is the first report of associations between tissue levels of omega-3 and omega-6 fatty acids and a reversible tissue biomarker of breast cancer risk. RPFNA cytomorphology could serve as a surrogate endpoint for breast cancer prevention trials of omega-3 fatty acid supplementation. PMID- 25712054 TI - CXCR4 is a novel target of cancer chemopreventative isothiocyanates in prostate cancer cells. AB - Isothiocyanates (ITCs) derived from cruciferous vegetables, including phenethyl isothiocyanate (PEITC) and sulforaphane (SFN), exhibit in vivo activity against prostate cancer in a xenograft and transgenic mouse model, and thus are appealing for chemoprevention of this disease. Watercress constituent PEITC and SFN-rich broccoli sprout extract are under clinical investigations but the molecular mechanisms underlying their cancer chemopreventive effects are not fully understood. The present study demonstrates that chemokine receptor CXCR4 is a novel target of ITCs in prostate cancer cells. Exposure of prostate cancer cells (LNCaP, 22Rv1, C4-2, and PC-3) to pharmacologically applicable concentrations of PEITC, benzyl isothiocyanate (BITC), and SFN (2.5 and 5 MUmol/L) resulted in downregulation of CXCR4 expression. None of the ITCs affected secretion of CXCR4 ligand (stromal-derived factor-1). In vivo inhibition of PC-3 xenograft growth upon PEITC treatment was associated with a significant decrease in CXCR4 protein level. A similar trend was discernible in the tumors from SFN-treated TRAMP mice compared with those of control mice, but the difference was not significant. Stable overexpression of CXCR4 in PC-3 cells conferred significant protection against wound healing, cell migration, and cell viability inhibition by ITCs. Inhibition of cell migration resulting from PEITC and BITC exposure was significantly augmented by RNAi of CXCR4. This study demonstrates, for the first time, that cancer chemopreventive ITCs suppress CXCR4 expression in prostate cancer cells in vitro as well as in vivo. These results suggest that CXCR4 downregulation may be an important pharmacodynamic biomarker of cancer chemopreventative ITCs in prostate adenocarcinoma. PMID- 25712055 TI - Novel Evidence for Curcumin and Boswellic Acid-Induced Chemoprevention through Regulation of miR-34a and miR-27a in Colorectal Cancer. AB - Colorectal cancer is one of the most common causes of cancer-associated mortality worldwide, but it is truly a preventable disease. Both curcumin and boswellic acids are well-established dietary botanicals with potent antitumorigenic properties that have been shown to modulate multiple oncogenic pathways. Recent data suggest that the chemopreventive effects of these botanicals may, in part, be mediated through regulation of key cancer-related microRNAs (miRNA) and their downstream gene targets. Here, we investigated the antitumorigenic effects of curcumin and 3 acetyl-11-keto-beta-boswellic acid (AKBA) on modulation of specific cancer-related miRNAs in colorectal cancer cells and validated their protective effects in vivo using a xenograft mouse model. Both curcumin and AKBA inhibited cellular proliferation, induced apoptosis and cell-cycle arrest in colorectal cancer cell lines, and these effects were significantly enhanced with combined treatment. Gene-expression arrays revealed that curcumin and AKBA regulated distinct cancer signaling pathways, including key cell-cycle regulatory genes. Combined bioinformatics and in silico analysis identified apoptosis, proliferation, and cell-cycle regulatory signaling pathways as key modulators of curcumin and AKBA-induced anticancer effects. We discovered that curcumin and AKBA induced upregulation of tumor-suppressive miR-34a and downregulation of miR 27a in colorectal cancer cells. Furthermore, we demonstrated in a mouse xenograft model that both curcumin and AKBA treatments suppressed tumor growth, which corresponded with alterations in the expression of miR-34a and miR-27a, consistent with our in vitro findings. Herein, we provide novel mechanistic evidence for the chemopreventive effects of curcumin and AKBA through regulation of specific miRNAs in colorectal cancer. PMID- 25712056 TI - Nrf2-dependent suppression of azoxymethane/dextran sulfate sodium-induced colon carcinogenesis by the cinnamon-derived dietary factor cinnamaldehyde. AB - The progressive nature of colorectal cancer and poor prognosis associated with the metastatic phase of the disease create an urgent need for the development of more efficacious strategies targeting colorectal carcinogenesis. Cumulative evidence suggests that the redox-sensitive transcription factor Nrf2 (nuclear factor-E2-related factor 2), a master regulator of the cellular antioxidant defence, represents a promising molecular target for colorectal cancer chemoprevention. Recently, we have identified cinnamon, the ground bark of Cinnamomum aromaticum (cassia cinnamon) and Cinnamomum verum (Ceylon cinnamon), as a rich dietary source of the Nrf2 inducer cinnamaldehyde (CA) eliciting the Nrf2-regulated antioxidant response in human epithelial colon cells, conferring cytoprotection against electrophilic and genotoxic insult. Here, we have explored the molecular mechanism underlying CA-induced Nrf2 activation in colorectal epithelial cells and have examined the chemopreventive potential of CA in a murine colorectal cancer model comparing Nrf2(+/+) with Nrf2(-/-) mice. In HCT116 cells, CA caused a Keap1-C151-dependent increase in Nrf2 protein half-life via blockage of ubiquitination with upregulation of cytoprotective Nrf2 target genes and elevation of cellular glutathione. After optimizing colorectal Nrf2 activation and target gene expression by dietary CA-supplementation regimens, we demonstrated that CA suppresses AOM/DSS-induced inflammatory colon carcinogenesis with modulation of molecular markers of colorectal carcinogenesis. Dietary suppression of colorectal cancer using CA supplementation was achieved in Nrf2(+/+) but not in Nrf2(-/-) mice confirming the Nrf2 dependence of CA-induced chemopreventive effects. Taken together, our data suggest feasibility of colorectal cancer suppression by dietary CA, an FDA-approved food additive derived from the third most consumed spice in the world. PMID- 25712057 TI - Living with mild to moderate Alzheimer patients increases the caregiver's burden at 6 months. AB - The objective of our study was to demonstrate that living with a person affected by mild to moderate Alzheimer's disease can lead to an increased perception of the caregiver's burden using the Caregiver Burden Inventory (CBI). The sample consisted of 153 dyads, caregiver-patient. At baseline, a greater perception of the caregiver's burden was observed in the live-in caregivers. A further increase in the total burden of the live-in caregivers was noticed at the 6-month follow up. More specifically, with the inclusion of correction factors such as the caregiver's age and the CBI subscales at baseline, the social and emotional burden becomes statistically significant (P < .001). The present paper confirms our hypothesis that live-in caregivers perceive a greater burden than nonlive-in, and this difference increases further after 6 months. The difference in involvement between live-in and nonlive-in caregivers could be the foundation to tailor more specific interventions. PMID- 25712058 TI - Left atrial appendage occlusion debate revisited. PMID- 25712059 TI - ECG response: February 24, 2015. PMID- 25712060 TI - Development and receding of a coronary artery aneurysm after implantation of a fully bioresorbable scaffold. PMID- 25712061 TI - Biopsy-proven Loeffler endocarditis successfully treated with steroids. PMID- 25712062 TI - Letter by Heidrich et al regarding article, "A word of caution: risk of device erosion after percutaneous treatment of atrial septal defect in patients with dilated aortic root". PMID- 25712063 TI - Response to letter regarding article, "A word of caution: risk of device erosion after percutaneous treatment of atrial septal defect in patients with dilated aortic root". PMID- 25712064 TI - Letter by Azzalini and Ly regarding article, "The learning curve for transradial percutaneous coronary intervention among operators in the United States: a study from the National Cardiovascular Data Registry". PMID- 25712065 TI - Response to letter regarding article, "The learning curve for transradial percutaneous coronary intervention among operators in the United States: a study from the National Cardiovascular Data Registry". PMID- 25712066 TI - Correction. The postthrombotic syndrome: evidence-based prevention, diagnosis, and treatment strategies: a scientific statement from the American Heart Association. PMID- 25712067 TI - Health literacy: towards system level solutions. PMID- 25712068 TI - Another piece of the puzzle--optimal TKI selection before treatment discontinuation in CML. PMID- 25712069 TI - Are we improving the outcome for patients with T-cell prolymphocytic leukemia by allogeneic stem cell transplantation? PMID- 25712070 TI - The Hawke's Bay Condom Card Scheme: a qualitative study of the views of service providers on increased, discreet access for youth to free condoms. AB - OBJECTIVES: The incidence of sexually transmitted infections and unplanned pregnancies in adolescence is of concern. The Hawke's Bay District Health Board, New Zealand, set up a pilot condom card scheme ('the Scheme') to allow 13- to 24 year-olds, deemed suitable for the Scheme, to access free condoms from pharmacies on presentation of a Condom Card. Our study explored the views of service providers of a pilot Condom Card Scheme. METHODS: Qualitative interviews were conducted with 17 service providers (nurses, pharmacists, pharmacy staff) between February and April 2013. KEY FINDINGS: Our findings showed that the Scheme was viewed positively by service providers, who indicated almost universal support for the Scheme to continue. However, participants noted a perceived lack of advertising, low number of sites for collection of condoms, lack of flexibility of the Scheme's criteria relating to who could access the scheme and issues with some pharmacy service providers, all of which led to a number of recommendations for improving the Scheme. CONCLUSIONS: The views of service providers indicate broad support for the continuation of the Scheme. Canvassing young people's suggestions for improving the Scheme is also essential. PMID- 25712071 TI - Assessing diagnostic complexity: An image feature-based strategy to reduce annotation costs. AB - Computer-aided diagnosis systems can play an important role in lowering the workload of clinical radiologists and reducing costs by automatically analyzing vast amounts of image data and providing meaningful and timely insights during the decision making process. In this paper, we present strategies on how to better manage the limited time of clinical radiologists in conjunction with predictive model diagnosis. We first introduce a metric for discriminating between the different categories of diagnostic complexity (such as easy versus hard) encountered when interpreting CT scans. Second, we propose to learn the diagnostic complexity using a classification approach based on low-level image features automatically extracted from pixel data. We then show how this classification can be used to decide how to best allocate additional radiologists to interpret a case based on its diagnosis category. Using a lung nodule image dataset, we determined that, by a simple division of cases into hard and easy to diagnose, the number of interpretations can be distributed to significantly lower the cost with limited loss in prediction accuracy. Furthermore, we show that with just a few low-level image features (18% of the original set) we are able to determine the easy from hard cases for a significant subset (66%) of the lung nodule image data. PMID- 25712072 TI - New feature selection for gene expression classification based on degree of class overlap in principal dimensions. AB - Micro-array data are typically characterized by high dimensional features with a small number of samples. Several problems in identifying genes causing diseases from micro-array data can be transformed into the problem of classifying the features extracted from gene expression in micro-array data. However, too many features can cause low prediction accuracy as well as high computational complexity. Dimensional reduction is a method to eliminate irrelevant features to improve the prediction accuracy. Typically, the eigenvalues or dimensional data variance from principal component analysis are used as criteria to select relevant features. This approach is simple but not efficient since it does not concern the degree of data overlap in each dimension in the feature space. A new method to select relevant features based on degree of dimensional data overlap with proper feature selection was introduced. Furthermore, our study concentrated on small sized data sets which usually occur in reality. The experimental results signified that this new approach can achieve substantially higher prediction accuracy when compared with other methods. PMID- 25712073 TI - External beam radiation therapy for orthopaedic pathology. AB - External beam radiation therapy is essential in the management of a wide spectrum of musculoskeletal conditions, both benign and malignant, including bony and soft tissue sarcomas, metastatic tumors, pigmented villonodular synovitis, and heterotopic ossification. Radiation therapy, in combination with surgery, helps reduce the functional loss from cancer resections. Although the field of radiation therapy is firmly rooted in physics and radiation biology, its indications and delivery methods are rapidly evolving. External beam radiation therapy mainly comes in the form of four sources of radiotherapy: protons, photons, electrons, and neutrons. Each type of energy has a unique role in treating various pathologies; however, these energy types also have their own distinctive limitations and morbidities. PMID- 25712074 TI - In vivo wear particles of remelted highly crosslinked polyethylene after total hip arthroplasty: report of four cases. AB - This is the first report of in vivo wear particles from four total hip arthroplasties using remelted highly crosslinked polyethylene. The number of particles was (1.51 +/- 0.45) * 10(7) g(-1) (mean +/- standard error); particle size (equivalent circle diameter), 0.72 +/- 0.15 um; and roundness, 1.45 +/- 0.05. Remelted highly crosslinked polyethylene generates fewer, rounder, equivalently sized particles compared with corresponding reported values for particles generated from conventional polyethylene. PMID- 25712075 TI - Reply to Wilms tumor and breast cancer. PMID- 25712076 TI - Monoclonal antibody-functionalized multilayered particles: targeting cancer cells in the presence of protein coronas. AB - Engineered particles adsorb biomolecules (e.g., proteins) when introduced in a biological medium to form a layer called a "corona". Coronas, in particular the protein corona, play an important role in determining the surface properties of particles and their targeting abilities. This study examines the influence of protein coronas on the targeting ability of layer-by-layer (LbL)-assembled polymer capsules and core-shell particles functionalized with monoclonal antibodies. Upon exposure of humanized A33 monoclonal antibody (huA33 mAb) functionalized poly(methacrylic acid) (PMA) capsules or huA33 mAb-PMA particles to human serum, a total of 83 or 65 proteins were identified in the protein coronas, respectively. Human serum of varying concentrations altered the composition of the protein corona. The antibody-driven specific cell membrane binding was qualitatively and quantitatively assessed by flow cytometry and fluorescence microscopy in both the absence and presence of a protein corona. The findings show that although different protein coronas formed in human serum (at different concentrations), the targeting ability of both the huA33 mAb functionalized PMA capsules and particles toward human colon cancer cells was retained, demonstrating no significant difference compared with capsules and particles in the absence of protein coronas: ~70% and ~90% A33-expressing cells were targeted by the huA33 mAb-PMA capsules and particles, respectively, in a mixed cell population. This result demonstrates that the formation of protein coronas did not significantly influence the targeting ability of antibody functionalized LbL-polymer carriers, indicating that the surface functionality of engineered particles in the presence of protein coronas can be preserved. PMID- 25712077 TI - Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. AB - The rapid technological developments of the past decade and the changes in echocardiographic practice brought about by these developments have resulted in the need for updated recommendations to the previously published guidelines for cardiac chamber quantification, which was the goal of the joint writing group assembled by the American Society of Echocardiography and the European Association of Cardiovascular Imaging. This document provides updated normal values for all four cardiac chambers, including three-dimensional echocardiography and myocardial deformation, when possible, on the basis of considerably larger numbers of normal subjects, compiled from multiple databases. In addition, this document attempts to eliminate several minor discrepancies that existed between previously published guidelines. PMID- 25712078 TI - Indications for cardiovascular magnetic resonance in children with congenital and acquired heart disease: an expert consensus paper of the Imaging Working Group of the AEPC and the Cardiovascular Magnetic Resonance Section of the EACVI. AB - This article provides expert opinion on the use of cardiovascular magnetic resonance (CMR) in young patients with congenital heart disease (CHD) and in specific clinical situations. As peculiar challenges apply to imaging children, paediatric aspects are repeatedly discussed. The first section of the paper addresses settings and techniques, including the basic sequences used in paediatric CMR, safety, and sedation. In the second section, the indication, application, and clinical relevance of CMR in the most frequent CHD are discussed in detail. In the current era of multimodality imaging, the strengths of CMR are compared with other imaging modalities. At the end of each chapter, a brief summary with expert consensus key points is provided. The recommendations provided are strongly clinically oriented. The paper addresses not only imagers performing CMR, but also clinical cardiologists who want to know which information can be obtained by CMR and how to integrate it in clinical decision making. PMID- 25712079 TI - Clinical utility gene card for: Nemaline myopathy - update 2015. PMID- 25712080 TI - Novel de novo heterozygous loss-of-function variants in MED13L and further delineation of the MED13L haploinsufficiency syndrome. AB - MED13L haploinsufficiency has recently been described as responsible for syndromic intellectual disability. We planned a search for causative gene variants in seven subjects with intellectual disability and overlapping dysmorphic facial features such as bulbous nasal tip, short mouth and straight eyebrows. We found two de novo frameshift variants in MED13L, consisting in single-nucleotide deletion (c.3765delC) and duplication (c.607dupT). A de novo nonsense variant (c.4420A>T) in MED13L was detected in a further subject in the course of routine whole-exome sequencing. By analyzing the clinical data of our patients along with those recently described in the literature, we confirm that there is a common, recognizable phenotype associated with MED13L haploinsufficiency, which includes intellectual disability and a distinctive facial appearance. Congenital heart diseases are found in some subjects with various degree of severity. Our observation of cleft palate, ataxia, epilepsy and childhood leukemia observed in single cases broadens the known clinical spectrum. Haploinsufficiency for MED13L should be considered in the differential diagnosis of the 1p36 microdeletion syndrome, due to overlapping dysmorphic facial features in some patients. The introduction of massive parallel-sequencing techniques into clinical practice is expected to allow for detection of other causative point variants in MED13L. Analysis of genomic data in connection with deep clinical evaluation of patients could elucidate genetic heterogeneity of the MED13L haploinsufficiency phenotype. PMID- 25712081 TI - GWAS with longitudinal phenotypes: performance of approximate procedures. AB - Analysis of genome-wide association studies with longitudinal data using standard procedures, such as linear mixed model (LMM) fitting, leads to discouragingly long computation times. There is a need to speed up the computations significantly. In our previous work (Sikorska et al: Fast linear mixed model computations for genome-wide association studies with longitudinal data. Stat Med 2012; 32.1: 165-180), we proposed the conditional two-step (CTS) approach as a fast method providing an approximation to the P-value for the longitudinal single nucleotide polymorphism (SNP) effect. In the first step a reduced conditional LMM is fit, omitting all the SNP terms. In the second step, the estimated random slopes are regressed on SNPs. The CTS has been applied to the bone mineral density data from the Rotterdam Study and proved to work very well even in unbalanced situations. In another article (Sikorska et al: GWAS on your notebook: fast semi-parallel linear and logistic regression for genome-wide association studies. BMC Bioinformatics 2013; 14: 166), we suggested semi-parallel computations, greatly speeding up fitting many linear regressions. Combining CTS with fast linear regression reduces the computation time from several weeks to a few minutes on a single computer. Here, we explore further the properties of the CTS both analytically and by simulations. We investigate the performance of our proposal in comparison with a related but different approach, the two-step procedure. It is analytically shown that for the balanced case, under mild assumptions, the P-value provided by the CTS is the same as from the LMM. For unbalanced data and in realistic situations, simulations show that the CTS method does not inflate the type I error rate and implies only a minimal loss of power. PMID- 25712082 TI - Differential allelic expression of SOS1 and hyperexpression of the activating SOS1 c.755C variant in a Noonan syndrome family. AB - Noonan syndrome (NS) is a genetic condition characterized by congenital heart defects, short stature and characteristic facial features. We here present the case of a girl with moderate learning disabilities, delayed language development, craniofacial features and skin anomalies reminiscent of NS. After a mutation screening of the known NS genes PTPN11, SOS1, RAF1, KRAS, GRB2, BRAF and SHOC2 we found the heterozygous c.755T>C variant in SOS1 causing the p.I252T amino-acid substitution, which was considered possibly pathogenetic by bioinformatic predictions. The same variant was present in the proband's mother, displaying some NS features, and maternal grandfather showing no NS traits, but also by a healthy subject in 1000 genomes project database without phenotype informations. The functional analysis revealed that SOS1 c.755C activated the RAS-ERK intracellular pathway, whereas no effects on RAC-JNK cascade have been detected. After a comparison between the sequence of SOS1 cDNA from peripheral blood and SOS1 genomic DNA, we showed for the first time a differential allelic expression of the SOS1 gene in healthy individuals, thus occurring as a physiologic condition. Interestingly, we found that the mutated allele C was 50% more expressed than the wild-type allele T in all familial carriers. The comparable amount of SOS1 mRNA between mutated individuals and the controls indicates that the variant does not affect SOS1 expression. The present study provides a first evidence of allelic imbalance of SOS1 and pinpoints this condition as a possible mechanism underlying a different penetrance of some SOS1-mutated alleles in unrelated carriers. PMID- 25712083 TI - Intelligence: shared genetic basis between Mendelian disorders and a polygenic trait. AB - Multiple inquiries into the genetic etiology of human traits indicated an overlap between genes underlying monogenic disorders (eg, skeletal growth defects) and those affecting continuous variability of related quantitative traits (eg, height). Extending the idea of a shared genetic basis between a Mendelian disorder and a classic polygenic trait, we performed an association study to examine the effect of 43 genes implicated in autosomal recessive cognitive disorders on intelligence in an unselected Dutch population (N=1316). Using both single-nucleotide polymorphism (SNP)- and gene-based association testing, we detected an association between intelligence and the genes of interest, with genes ELP2, TMEM135, PRMT10, and RGS7 showing the strongest associations. This is a demonstration of the relevance of genes implicated in monogenic disorders of intelligence to normal-range intelligence, and a corroboration of the utility of employing knowledge on monogenic disorders in identifying the genetic variability underlying complex traits. PMID- 25712085 TI - GPs battling in "David versus Goliath" over out-of-hours tenders, says RCGP. PMID- 25712084 TI - Next generation sequencing in sporadic retinoblastoma patients reveals somatic mosaicism. AB - In about 50% of sporadic cases of retinoblastoma, no constitutive RB1 mutations are detected by conventional methods. However, recent research suggests that, at least in some of these cases, there is somatic mosaicism with respect to RB1 normal and mutant alleles. The increased availability of next generation sequencing improves our ability to detect the exact percentage of patients with mosaicism. Using this technology, we re-tested a series of 40 patients with sporadic retinoblastoma: 10 of them had been previously classified as constitutional heterozygotes, whereas in 30 no RB1 mutations had been found in lymphocytes. In 3 of these 30 patients, we have now identified low-level mosaic variants, varying in frequency between 8 and 24%. In 7 out of the 10 cases previously classified as heterozygous from testing blood cells, we were able to test additional tissues (ocular tissues, urine and/or oral mucosa): in three of them, next generation sequencing has revealed mosaicism. Present results thus confirm that a significant fraction (6/40; 15%) of sporadic retinoblastoma cases are due to postzygotic events and that deep sequencing is an efficient method to unambiguously distinguish mosaics. Re-testing of retinoblastoma patients through next generation sequencing can thus provide new information that may have important implications with respect to genetic counseling and family care. PMID- 25712086 TI - A Randomized Controlled Study to Evaluate the Impact of Instrument and Laparoscope Length on Performance and Learning Curve in Single-Incision Laparoscopic Surgery. AB - INTRODUCTION: The proximity of instrumentation in single-incision laparoscopic surgery (SILS) creates ergonomic challenges. An innovative method to reduce external collisions between instruments and handles is to use instruments of different lengths. This study evaluated the impact of instrument and laparoscope length on simulated SILS performance. METHODS: Performance was assessed using peg transfer (PEG) and pattern cutting (CUT) tasks from the Fundamentals of Laparoscopic Surgery (FLS) curriculum. Following baseline testing, surgeons were randomized into 3 trial arms: Control--standard length instruments and standard length laparoscope; group 1--one long instrument, one standard length instrument and standard length laparoscope; and group 2--standard length instruments and long laparoscope. Two phases were undertaken using a validated SILS-modified FLS box trainer: phase 1--25 repetitions of PEG and phase 2--5 repetitions of CUT. FLS scoring parameters measured performance and the Imperial College Surgical Assessment Device (ICSAD) captured motion analysis of hands. RESULTS: Twenty three surgeons were recruited--control (n = 7), group 1 (n = 9), and group 2 (n = 7). No significant differences were observed in operative experience or baseline skills performance. Phase 1: Peak FLS score was significantly higher in group 1 compared with control (P = .009). Comparison of learning curves revealed learning plateau was significantly higher in group 1 compared with control (P = .010). Phase 2: Group 1 revealed a trend toward higher peak FLS scores over the control (P = .067). No significant differences in motion analysis of hands were demonstrated using ICSAD. CONCLUSIONS: This study demonstrates that using instruments of different lengths can improve simulated SILS performance. PMID- 25712087 TI - Three-Dimensional Eye Tracking in a Surgical Scenario. AB - INTRODUCTION: Eye tracking has been widely used in studying the eye behavior of surgeons in the past decade. Most eye-tracking data are reported in a 2 dimensional (2D) fashion, and data for describing surgeons' behaviors on stereoperception are often missed. With the introduction of stereoscopes in laparoscopic procedures, there is an increasing need for studying the depth perception of surgeons under 3D image-guided surgery. METHODS: We developed a new algorithm for the computation of convergence points in stereovision by measuring surgeons' interpupillary distance, the distance to the view target, and the difference between gaze locations of the 2 eyes. To test the feasibility of our new algorithm, we recruited 10 individuals to watch stereograms using binocular disparity and asked them to develop stereoperception using a cross-eyed viewing technique. Participants' eye motions were recorded by the Tobii eye tracker while they performed the trials. Convergence points between normal and stereo-viewing conditions were computed using the developed algorithm. RESULTS: All 10 participants were able to develop stereovision after a short period of training. During stereovision, participants' eye convergence points were 14 +/- 1 cm in front of their eyes, which was significantly closer than the convergence points under the normal viewing condition (77 +/- 20 cm). CONCLUSION: By applying our method of calculating convergence points using eye tracking, we were able to elicit the eye movement patterns of human operators between the normal and stereovision conditions. Knowledge from this study can be applied to the design of surgical visual systems, with the goal of improving surgical performance and patient safety. PMID- 25712088 TI - Blindsight is sensitive to stimulus numerosity and configuration: evidence from the redundant signal effect. AB - One important, yet relatively unexplored question is whether blindsight, i.e., unconscious visually guided behavior in hemianopic patients, is endowed with basic perceptual properties such as detecting stimulus numerosity and overall configuration. Rather than a forced-choice procedure in which patients are supposed to guess about stimuli presented to the blind hemifield, we used a redundant signal effect paradigm, i.e., the speeding of simple reaction time (RT) when presenting multiple versus single similar stimuli. The presence of an effect of numerosity for the (unseen) stimuli presented to the blind field was indirectly assessed by measuring RT to bilateral versus unilateral stimuli presented to the intact hemifield. Chronic hemianopic patients were tested with unilateral or bilateral black dots, both of which could be either single or quadruple. The latter could either have a fixed spatial configuration representing a diamond or be randomly spatially assembled on every trial. Both configurations covered the same extent of visual field and had the overall same luminance. We found that a numerosity effect as a result of increasing the number of stimuli in the blind field was indeed present but only with the diamond configuration. This is a convincing evidence that this form of blindsight does not depend upon stimulus numerosity per se but is likely to be related to the presence of structured and memorized rather than meaningless changing stimuli. PMID- 25712089 TI - The beta hairpin structure within ribosomal protein S5 mediates interplay between domains II and IV and regulates HCV IRES function. AB - Translation initiation in Hepatitis C Virus (HCV) is mediated by Internal Ribosome Entry Site (IRES), which is independent of cap-structure and uses a limited number of canonical initiation factors. During translation initiation IRES-40S complex formation depends on high affinity interaction of IRES with ribosomal proteins. Earlier, it has been shown that ribosomal protein S5 (RPS5) interacts with HCV IRES. Here, we have extensively characterized the HCV IRES RPS5 interaction and demonstrated its role in IRES function. Computational modelling and RNA-protein interaction studies demonstrated that the beta hairpin structure within RPS5 is critically required for the binding with domains II and IV. Mutations disrupting IRES-RPS5 interaction drastically reduced the 80S complex formation and the corresponding IRES activity. Computational analysis and UV cross-linking experiments using various IRES-mutants revealed interplay between domains II and IV mediated by RPS5. In addition, present study demonstrated that RPS5 interaction is unique to HCV IRES and is not involved in 40S-3' UTR interaction. Further, partial silencing of RPS5 resulted in preferential inhibition of HCV RNA translation. However, global translation was marginally affected by partial silencing of RPS5. Taken together, results provide novel molecular insights into IRES-RPS5 interaction and unravel its functional significance in mediating internal initiation of translation. PMID- 25712090 TI - Roles of Rad51 paralogs for promoting homologous recombination in Leishmania infantum. AB - To achieve drug resistance Leishmania parasite alters gene copy number by using its repeated sequences widely distributed through the genome. Even though homologous recombination (HR) is ascribed to maintain genome stability, this eukaryote exploits this potent mechanism driven by the Rad51 recombinase to form beneficial extrachromosomal circular amplicons. Here, we provide insights on the formation of these circular amplicons by analyzing the functions of the Rad51 paralogs. We purified three Leishmania infantum Rad51 paralogs homologs (LiRad51 3, LiRad51-4 and LiRad51-6) all of which directly interact with LiRad51. LiRad51 3, LiRad51-4 and LiRad51-6 show differences in DNA binding and annealing capacities. Moreover, it is also noteworthy that LiRad51-3 and LiRad51-4 are able to stimulate Rad51-mediated D-loop formation. In addition, we succeed to inactivate the LiRad51-4 gene and report a decrease of circular amplicons in this mutant. The LiRad51-3 gene was found to be essential for cell viability. Thus, we propose that the LiRad51 paralogs play crucial functions in extrachromosomal circular DNA amplification to circumvent drug actions and preserve survival. PMID- 25712091 TI - 3dRNAscore: a distance and torsion angle dependent evaluation function of 3D RNA structures. AB - Model evaluation is a necessary step for better prediction and design of 3D RNA structures. For proteins, this has been widely studied and the knowledge-based statistical potential has been proved to be one of effective ways to solve this problem. Currently, a few knowledge-based statistical potentials have also been proposed to evaluate predicted models of RNA tertiary structures. The benchmark tests showed that they can identify the native structures effectively but further improvements are needed to identify near-native structures and those with non canonical base pairs. Here, we present a novel knowledge-based potential, 3dRNAscore, which combines distance-dependent and dihedral-dependent energies. The benchmarks on different testing datasets all show that 3dRNAscore are more efficient than existing evaluation methods in recognizing native state from a pool of near-native states of RNAs as well as in ranking near-native states of RNA models. PMID- 25712092 TI - Assessing the prevalence of mycoplasma contamination in cell culture via a survey of NCBI's RNA-seq archive. AB - Mycoplasmas are notorious contaminants of cell culture and can have profound effects on host cell biology by depriving cells of nutrients and inducing global changes in gene expression. Over the last two decades, sentinel testing has revealed wide-ranging contamination rates in mammalian culture. To obtain an unbiased assessment from hundreds of labs, we analyzed sequence data from 9395 rodent and primate samples from 884 series in the NCBI Sequence Read Archive. We found 11% of these series were contaminated (defined as >=100 reads/million mapping to mycoplasma in one or more samples). Ninety percent of mycoplasma mapped reads aligned to ribosomal RNA. This was unexpected given 37% of contaminated series used poly(A)-selection for mRNA enrichment. Lastly, we examined the relationship between mycoplasma contamination and host gene expression in a single cell RNA-seq dataset and found 61 host genes (P < 0.001) were significantly associated with mycoplasma-mapped read counts. In all, this study suggests mycoplasma contamination is still prevalent today and poses substantial risk to research quality. PMID- 25712093 TI - Lesion search and recognition by thymine DNA glycosylase revealed by single molecule imaging. AB - The ability of DNA glycosylases to rapidly and efficiently detect lesions among a vast excess of nondamaged DNA bases is vitally important in base excision repair (BER). Here, we use single molecule imaging by atomic force microscopy (AFM) supported by a 2-aminopurine fluorescence base flipping assay to study damage search by human thymine DNA glycosylase (hTDG), which initiates BER of mutagenic and cytotoxic G:T and G:U mispairs in DNA. Our data reveal an equilibrium between two conformational states of hTDG-DNA complexes, assigned as search complex (SC) and interrogation complex (IC), both at target lesions and undamaged DNA sites. Notably, for both hTDG and a second glycosylase, hOGG1, which recognizes structurally different 8-oxoguanine lesions, the conformation of the DNA in the SC mirrors innate structural properties of their respective target sites. In the IC, the DNA is sharply bent, as seen in crystal structures of hTDG lesion recognition complexes, which likely supports the base flipping required for lesion identification. Our results support a potentially general concept of sculpting of glycosylases to their targets, allowing them to exploit the energetic cost of DNA bending for initial lesion sensing, coupled with continuous (extrahelical) base interrogation during lesion search by DNA glycosylases. PMID- 25712094 TI - Identification and characterization of intracellular proteins that bind oligonucleotides with phosphorothioate linkages. AB - Although the RNase H-dependent mechanism of inhibition of gene expression by chemically modified antisense oligonucleotides (ASOs) has been well characterized, little is known about the interactions between ASOs and intracellular proteins that may alter cellular localization and/or potency of ASOs. Here, we report the identification of 56 intracellular ASO-binding proteins using multi-step affinity selection approaches. Many of the tested proteins had no significant effect on ASO activity; however, some proteins, including La/SSB, NPM1, ANXA2, VARS and PC4, appeared to enhance ASO activities, likely through mechanisms related to subcellular distribution. VARS and ANXA2 co-localized with ASOs in endocytic organelles, and reduction in the level of VARS altered lysosome/ASO localization patterns, implying that these proteins may facilitate ASO release from the endocytic pathway. Depletion of La and NPM1 reduced nuclear ASO levels, suggesting potential roles in ASO nuclear accumulation. On the other hand, Ku70 and Ku80 proteins inhibited ASO activity, most likely by competition with RNase H1 for ASO/RNA duplex binding. Our results demonstrate that phosphorothioate-modified ASOs bind a set of cellular proteins that affect ASO activity via different mechanisms. PMID- 25712095 TI - Inhibition of HCV translation by disrupting the structure and interactions of the viral CRE and 3' X-tail. AB - A phylogenetically conserved RNA structure within the NS5B coding region of hepatitis C virus functions as a cis-replicating element (CRE). Integrity of this CRE, designated SL9266 (alternatively 5BSL3.2), is critical for genome replication. SL9266 forms the core of an extended pseudoknot, designated SL9266/PK, involving long distance RNA-RNA interactions between unpaired loops of SL9266 and distal regions of the genome. Previous studies demonstrated that SL9266/PK is dynamic, with 'open' and 'closed' conformations predicted to have distinct functions during virus replication. Using a combination of site-directed mutagenesis and locked nucleic acids (LNA) complementary to defined domains of SL9266 and its interacting regions, we have explored the influence of this structure on genome translation and replication. We demonstrate that LNAs which block formation of the closed conformation inhibit genome translation. Inhibition was at least partly independent of the initiation mechanism, whether driven by homologous or heterologous internal ribosome entry sites or from a capped message. Provision of SL9266/PK in trans relieved translational inhibition, and mutational analysis implied a mechanism in which the closed conformation recruits a cellular factor that would otherwise suppresses translation. We propose that SL9266/PK functions as a temporal switch, modulating the mutually incompatible processes of translation and replication. PMID- 25712096 TI - Structural plasticity of Cid1 provides a basis for its distributive RNA terminal uridylyl transferase activity. AB - Terminal uridylyl transferases (TUTs) are responsible for the post transcriptional addition of uridyl residues to RNA 3' ends, leading in some cases to altered stability. The Schizosaccharomyces pombe TUT Cid1 is a model enzyme that has been characterized structurally at moderate resolution and provides insights into the larger and more complex mammalian TUTs, ZCCHC6 and ZCCHC11. Here, we report a higher resolution (1.74 A) crystal structure of Cid1 that provides detailed evidence for uracil selection via the dynamic flipping of a single histidine residue. We also describe a novel closed conformation of the enzyme that may represent an intermediate stage in a proposed product ejection mechanism. The structural insights gained, combined with normal mode analysis and biochemical studies, demonstrate that the plasticity of Cid1, particularly about a hinge region (N164-N165), is essential for catalytic activity, and provide an explanation for its distributive uridylyl transferase activity. We propose a model clarifying observed differences between the in vitro apparently processive activity and in vivo distributive monouridylylation activity of Cid1. We suggest that modulating the flexibility of such enzymes-for example by the binding of protein co-factors-may allow them alternatively to add single or multiple uridyl residues to the 3' termini of RNA molecules. PMID- 25712097 TI - Generation of a conditionally self-eliminating HAC gene delivery vector through incorporation of a tTAVP64 expression cassette. AB - Human artificial chromosome (HAC)-based vectors represent an alternative technology for gene delivery and expression with a potential to overcome the problems caused by virus-based vectors. The recently developed alphoid(tetO)-HAC has an advantage over other HAC vectors because it can be easily eliminated from cells by inactivation of the HAC kinetochore via binding of chromatin modifiers, tTA or tTS, to its centromeric tetO sequences. This provides a unique control for phenotypes induced by genes loaded into the HAC. The alphoid(tetO)-HAC elimination is highly efficient when a high level of chromatin modifiers as tetR fusion proteins is achieved following transfection of cells by a retrovirus vector. However, such vectors are potentially mutagenic and might want to be avoided under some circumstances. Here, we describe a novel system that allows verification of phenotypic changes attributed to expression of genes from the HAC without a transfection step. We demonstrated that a single copy of tTA(VP64) carrying four tandem repeats of the VP16 domain constitutively expressed from the HAC is capable to generate chromatin changes in the HAC kinetochore that are not compatible with its function. To adopt the alphoid(tetO)-HAC for routine gene function studies, we constructed a new TAR-BRV- tTA(VP64) cloning vector that allows a selective isolation of a gene of interest from genomic DNA in yeast followed by its direct transfer to bacterial cells and subsequent loading into the loxP site of the alphoid(tetO)-HAC in hamster CHO cells from where the HAC may be MMCT-transferred to the recipient human cells. PMID- 25712098 TI - EWS-FLI1 employs an E2F switch to drive target gene expression. AB - Cell cycle progression is orchestrated by E2F factors. We previously reported that in ETS-driven cancers of the bone and prostate, activating E2F3 cooperates with ETS on target promoters. The mechanism of target co-regulation remained unknown. Using RNAi and time-resolved chromatin-immunoprecipitation in Ewing sarcoma we report replacement of E2F3/pRB by constitutively expressed repressive E2F4/p130 complexes on target genes upon EWS-FLI1 modulation. Using mathematical modeling we interrogated four alternative explanatory models for the observed EWS FLI1/E2F3 cooperation based on longitudinal E2F target and regulating transcription factor expression analysis. Bayesian model selection revealed the formation of a synergistic complex between EWS-FLI1 and E2F3 as the by far most likely mechanism explaining the observed kinetics of E2F target induction. Consequently we propose that aberrant cell cycle activation in Ewing sarcoma is due to the de-repression of E2F targets as a consequence of transcriptional induction and physical recruitment of E2F3 by EWS-FLI1 replacing E2F4 on their target promoters. PMID- 25712099 TI - Ovarian carcinoma CDK12 mutations misregulate expression of DNA repair genes via deficient formation and function of the Cdk12/CycK complex. AB - The Cdk12/CycK complex promotes expression of a subset of RNA polymerase II genes, including those of the DNA damage response. CDK12 is among only nine genes with recurrent somatic mutations in high-grade serous ovarian carcinoma. However, the influence of these mutations on the Cdk12/CycK complex and their link to cancerogenesis remain ill-defined. Here, we show that most mutations prevent formation of the Cdk12/CycK complex, rendering the kinase inactive. By examining the mutations within the Cdk12/CycK structure, we find that they likely provoke structural rearrangements detrimental to Cdk12 activation. Our mRNA expression analysis of the patient samples containing the CDK12 mutations reveals coordinated downregulation of genes critical to the homologous recombination DNA repair pathway. Moreover, we establish that the Cdk12/CycK complex occupies these genes and promotes phosphorylation of RNA polymerase II at Ser2. Accordingly, we demonstrate that the mutant Cdk12 proteins fail to stimulate the faithful DNA double strand break repair via homologous recombination. Together, we provide the molecular basis of how mutated CDK12 ceases to function in ovarian carcinoma. We propose that CDK12 is a tumor suppressor of which the loss-of-function mutations may elicit defects in multiple DNA repair pathways, leading to genomic instability underlying the genesis of the cancer. PMID- 25712100 TI - A genome-wide analysis of Cas9 binding specificity using ChIP-seq and targeted sequence capture. AB - Clustered regularly interspaced short palindromic repeat (CRISPR) RNA-guided nucleases have gathered considerable excitement as a tool for genome engineering. However, questions remain about the specificity of target site recognition. Cleavage specificity is typically evaluated by low throughput assays (T7 endonuclease I assay, target amplification followed by high-throughput sequencing), which are limited to a subset of potential off-target sites. Here, we used ChIP-seq to examine genome-wide CRISPR binding specificity at gRNA specific and gRNA-independent sites for two guide RNAs. RNA-guided Cas9 binding was highly specific to the target site while off-target binding occurred at much lower intensities. Cas9-bound regions were highly enriched in NGG sites, a sequence required for target site recognition by Streptococcus pyogenes Cas9. To determine the relationship between Cas9 binding and endonuclease activity, we applied targeted sequence capture, which allowed us to survey 1200 genomic loci simultaneously including potential off-target sites identified by ChIP-seq and by computational prediction. A high frequency of indels was observed at both target sites and one off-target site, while no cleavage activity could be detected at other ChIP-bound regions. Our results confirm the high-specificity of CRISPR endonucleases and demonstrate that sequence capture can be used as a high throughput genome-wide approach to identify off-target activity. PMID- 25712101 TI - Gene-specific cell labeling using MiMIC transposons. AB - Binary expression systems such as GAL4/UAS, LexA/LexAop and QF/QUAS have greatly enhanced the power of Drosophila as a model organism by allowing spatio-temporal manipulation of gene function as well as cell and neural circuit function. Tissue specific expression of these heterologous transcription factors relies on random transposon integration near enhancers or promoters that drive the binary transcription factor embedded in the transposon. Alternatively, gene-specific promoter elements are directly fused to the binary factor within the transposon followed by random or site-specific integration. However, such insertions do not consistently recapitulate endogenous expression. We used Minos-Mediated Integration Cassette (MiMIC) transposons to convert host loci into reliable gene specific binary effectors. MiMIC transposons allow recombinase-mediated cassette exchange to modify the transposon content. We developed novel exchange cassettes to convert coding intronic MiMIC insertions into gene-specific binary factor protein-traps. In addition, we expanded the set of binary factor exchange cassettes available for non-coding intronic MiMIC insertions. We show that binary factor conversions of different insertions in the same locus have indistinguishable expression patterns, suggesting that they reliably reflect endogenous gene expression. We show the efficacy and broad applicability of these new tools by dissecting the cellular expression patterns of the Drosophila serotonin receptor gene family. PMID- 25712102 TI - Multiple facets of histone variant H2AX: a DNA double-strand-break marker with several biological functions. AB - In the last decade, many papers highlighted that the histone variant H2AX and its phosphorylation on Ser 139 (gammaH2AX) cannot be simply considered a specific DNA double-strand-break (DSB) marker with a role restricted to the DNA damage response, but rather as a 'protagonist' in different scenarios. This review will present and discuss an up-to-date view regarding the 'non-canonical' H2AX roles, focusing in particular on possible functional and structural parts in contexts different from the canonical DNA DSB response. We will present aspects concerning sex chromosome inactivation in male germ cells, X inactivation in female somatic cells and mitosis, but will also focus on the more recent studies regarding embryonic and neural stem cell development, asymmetric sister chromosome segregation in stem cells and cellular senescence maintenance. We will discuss whether in these new contexts there might be a relation with the canonical DNA DSB signalling function that could justify gammaH2AX formation. The authors will emphasize that, just as H2AX phosphorylation signals chromatin alteration and serves the canonical function of recruiting DSB repair factors, so the modification of H2AX in contexts other than the DNA damage response may contribute towards creating a specific chromatin structure frame allowing 'non canonical' functions to be carried out in different cell types. PMID- 25712103 TI - Structure and regulatory role of the C-terminal winged helix domain of the archaeal minichromosome maintenance complex. AB - The minichromosome maintenance complex (MCM) represents the replicative DNA helicase both in eukaryotes and archaea. Here, we describe the solution structure of the C-terminal domains of the archaeal MCMs of Sulfolobus solfataricus (Sso) and Methanothermobacter thermautotrophicus (Mth). Those domains consist of a structurally conserved truncated winged helix (WH) domain lacking the two typical 'wings' of canonical WH domains. A less conserved N-terminal extension links this WH module to the MCM AAA+ domain forming the ATPase center. In the Sso MCM this linker contains a short alpha-helical element. Using Sso MCM mutants, including chimeric constructs containing Mth C-terminal domain elements, we show that the ATPase and helicase activity of the Sso MCM is significantly modulated by the short alpha-helical linker element and by N-terminal residues of the first alpha helix of the truncated WH module. Finally, based on our structural and functional data, we present a docking-derived model of the Sso MCM, which implies an allosteric control of the ATPase center by the C-terminal domain. PMID- 25712106 TI - Anticipatory Grief: A Mere Concept? AB - Anticipatory grief (AG) has been studied, debated, and written about for several decades. This type of grief is also recognized in hospice and palliative care (HPC). The question, however, is whether the reality of AG is sufficiently upheld by professionals at the point of concrete service delivery. In other words, is AG a mere concept or is everyday practice of HPC duly informed of AG as evidenced by the resulting care delivery? PMID- 25712105 TI - Medical Manuscript: Serum Total Testosterone as a Prognostic Indicator in Male Patients With Terminal Cancer. AB - The role of total serum testosterone in the prognosis of terminal cancer is unclear. We retrospectively investigated the total serum testosterone level in 69 male patients with terminal cancer in a palliative care unit. The association between the serum testosterone level and survival was assessed using Cox proportional hazard model. The median value of serum total testosterone was 44.5 ng/dL, far lower than previously reported in patients with advanced cancer. Multivariate analysis revealed thrombocytopenia (adjusted hazard ratio [aHR], 2.68), hypoalbuminemia (aHR, 2.02), azotemia (aHR, 2.67), and lower serum testosterone level (aHR, 2.03) were significantly negatively prognostic of survival. Lower serum testosterone level was an independent unfavorable prognostic factor for life expectancy in male patients with terminal cancer. PMID- 25712104 TI - H3K4me3 demethylation by the histone demethylase KDM5C/JARID1C promotes DNA replication origin firing. AB - DNA replication is a tightly regulated process that initiates from multiple replication origins and leads to the faithful transmission of the genetic material. For proper DNA replication, the chromatin surrounding origins needs to be remodeled. However, remarkably little is known on which epigenetic changes are required to allow the firing of replication origins. Here, we show that the histone demethylase KDM5C/JARID1C is required for proper DNA replication at early origins. JARID1C dictates the assembly of the pre-initiation complex, driving the binding to chromatin of the pre-initiation proteins CDC45 and PCNA, through the demethylation of the histone mark H3K4me3. Fork activation and histone H4 acetylation, additional early events involved in DNA replication, are not affected by JARID1C downregulation. All together, these data point to a prominent role for JARID1C in a specific phase of DNA replication in mammalian cells, through its demethylase activity on H3K4me3. PMID- 25712107 TI - Urethral condylomas in men: experience in 123 patients without previous treatment. AB - The most common sexually transmitted infection (STI) is infection by human papillomavirus. There are more than 100 types of human papillomavirus, and over 30 of them involve the genital area. Urethral involvement is uncommon and usually limited to the distal 3 cm of the meatus. There are various treatments for urethral condylomas; as a rule, they are limited by a difficult approach, by recurrences, and by potential complications, the most significant of which is urethral stenosis. The purpose of the treatments is to remove the warts and induce lesion-free periods. Such treatments do not eliminate the infection nor do they prevent continued transmission of the virus. We retrospectively evaluated 123 patients diagnosed and treated for condylomas in the genital area at our Institution between April 2009 and April 2012. The patients' mean age was 28.7 years (range 19-51). Of the 123 patients included, 48 (39%) had a history of previous STIs, most frequently gonococcal urethritis. Three of them had a urethral malformation in the form of hypospadias, and another three reported a previous urologic manipulation (catheterisation). Meatal/urethral condylomas are rare, cryotherapy is simple, easy to apply, and has a very low risk of complications in patients with externally accessible warts. PMID- 25712108 TI - Internal e-consultations in an integrated multispecialty practice: a retrospective review of use, content, and outcomes. AB - E-consultations are being offered within clinic walls as an option for specialist advice without a face-to-face consultation appointment. In a six month time frame, nearly 100% of primary care internists and family medicine providers in a multispecialty practice had used an e-consultation at least once. Specialists also used e-consultations for advice from other specialists. E-consultations were often questions about interpreting images or laboratory tests, or questions about management of chronic conditions such as osteoporosis, hypertension, or headaches. Although e-consultations were offered as an alternative to face-to face specialty consultations, 1,111 of 5,334 e-consultations eventually did receive face-to-face appointments in the same specialty. Within 30 days of the e consultation 11.5% had a specialty face-to-face visit and 17.7% had seen a specialist face-to-face within 90 days of the e-consultation. The conversions of e-consultations to face-to-face consultations depended on the specialty providing the e-consultation (fewer for gastroenterology and infectious disease), patient distance from the clinic (fewer for international patients and those living greater than 800 kilometers from the clinic), and experience of specialist responding to the e-consultation (lower conversions for specialists providing 15 or more e-consultations). PMID- 25712109 TI - Telerehabilitation and recovery of motor function: a systematic review and meta analysis. AB - Recent advances in telecommunication technologies have boosted the possibility to deliver rehabilitation via the internet (i.e. telerehabilitation). Several studies have shown that telerehabilitation is effective to improve clinical outcomes in disabling conditions. The aim of this review was to determine whether telerehabilitation was more effective than other modes of delivering rehabilitation to regain motor function, in different populations of patients.We searched PubMed, Embase and the Cochrane library retrieving 2360 records. Twelve studies were included involving different populations (i.e. neurological, total knee arthroplasty (TKA), cardiac) of patients. Inconclusive finding were found on the effect of telerehabilitation for neurological patients (SMD = 0.08, CI 95% = 0.13, 0.29), while both for cardiac (SMD = 0.24, CI 95% = 0.04, 0.43) and TKA patients (Timed Up and Go test: MD = -5.17, CI 95% = -9.79, -0.55) the results were in favour of telerehabilitation.Conclusive evidence on the efficacy of telerehabilitation for treatment of motor function, regardless of pathology, was not reached. Nevertheless, a strong positive effect was found for patients following orthopaedic surgery, suggesting that the increased intensity provided by telerehabilitation is a promising option to be offered to patients. More and higher quality research is needed in this field especially with neurological patients. PMID- 25712110 TI - Telemedical diabetic retinopathy screening in Hungary: a pilot programme. AB - Our aim was to introduce the Hungarian pilot telemedical screening program for diabetic retinopathy (DRP) and also to evaluate the efficacy of non-mydriatic fundus photographs. A total of 502 eyes of 251 diabetic patients were photographed with a non-mydriatic digital fundus camera in a tertiary diabetology care center. These three 45 degrees -field images were transmitted to the reading center via Internet, where they were graded by two independent ophthalmologists. After non-mydriatic photography (NM method), 28 patients were also examined in mydriasis by an ophthalmologist (O method) and were also photographed in mydriasis (M method). For the comparison of the three methods the kappa statistic was used. With non-mydriatic imaging of 502 eyes no retinopathy was found in 74.5%, DRP was detected in 15.5%, while 10.1% of the photos were ungradable. The rates of DRP severity levels were: 13.55% mild/moderate non-proliferative, 0.59% severe and 1.39% proliferative DRP. Comparing the results of the gradable non mydriatic photos by the two independent graders, perfect intergrader agreement was found (k = 1.00). The measure of intermethod agreement between NM and M method was also perfect, with a kappa value of 1.00 (grader A and grader B). Based on the results of the O method, there were no misdiagnosed cases nor with the NM-, neither with the M method. Non-mydriatic cameras could be ideal tools of an extended countrywide retinopathy screening program which may serve to reduce the high prevalence of diabetes-related blindness in Hungary. PMID- 25712111 TI - Web-based interventions for comorbid depression and chronic illness: a systematic review. AB - Web-based interventions offer potential benefits for managing and treating depression in the context of chronic physical illness, however their use with this population has yet to be quantitatively assessed. The present systematic review examined the biopsychosocial data from 11 independent studies (N = 1348 participants), including randomised controlled and quasi-experimental designs most commonly performed with diabetes and multiple sclerosis. Study quality was evaluated using the Downs and Black (1998) index, with most studies being statistically underpowered although internal validity was demonstrated. Treatment outcomes were quantified using Cohen's d effect sizes. Results indicated significant short-term improvements in depression severity (d w = 0.36, CI = 0.20 0.52, p < 0.01), in addition to quality of life, problem-solving skills, functional ability, anxiety and pain-related cognitions (d range = 0.23 to 1.10). Longer-term outcomes could not be determined based on the limited data. Further robust studies are required before wider adoption of web techniques takes place. PMID- 25712112 TI - Development and current status of an advanced telehealth consultation system in Japan. PMID- 25712113 TI - Telepsychology for Posttraumatic Stress Disorder: A systematic review. AB - The effectiveness of psychological services provided remotely, telepsychology, for the management of Posttraumatic Stress Disorder (PTSD) was evaluated. Eleven studies (n = 472 participants) were identified from electronic database searches. Study quality was assessed, with studies characterised by small and underpowered samples. Effect sizes and associated confidence intervals (CIs) were calculated to determine the direction and magnitude of treatment change. Short-term treatment gains were reported for internet and video-based interventions. This included significant medium to large improvements (d range = 0.66-3.22) in cognitive and behavioural symptoms of depression, generalised anxiety and posttraumatic stress. However, the equivalence of telepsychology and face-to-face psychotherapy could not be determined, with few comparative studies available. Both treatment gains and deterioration were noted 1 to 6 months following treatment cessation, although this was based on limited follow-up data. Further larger scale and longitudinal research will help to ascertain the minimum requirements for the management and treatment of PTSD in a technology-supported environment. PMID- 25712114 TI - Fluorescence Properties of Diphenylthiazolo[4,5-b]pyrazines Tuned by Donor Acceptor Substituent Effects. AB - Fluorescence properties of 2,6- and 2,5-diphenylthiazolo[4,5-b]pyrazine (TPy) derivatives having an electron-donating substituent (methoxy and dimethylamino) on the 6- and 5-phenyl groups were studied. It was found that 2,6-diphenyl derivatives fluoresce more efficiently than 2,5-diphenyl derivatives. Furthermore, a 2,6-diphenyl derivative having an additional cyano group on the 2 phenyl ring was an excellent fluorophore showing a wide solvatochromism with great fluorescence yields. Based on the obtained spectroscopic data and mechanistic explanations concerning the substituent effects on the fluorescence properties, useful information on designing new TPy fluorophores is provided. PMID- 25712115 TI - Low incidence of symptomatic thromboembolic events after total ankle arthroplasty without routine use of chemoprophylaxis. AB - BACKGROUND: There is little evidence regarding the incidence of symptomatic venous thromboembolism (VTE) following total ankle arthroplasty (TAA) to allow formulation of treatment recommendations. The purpose of this study was to determine the incidence of symptomatic VTE events after TAA without use of chemoprophylaxis and to identify risk factors contributing to the occurrence of VTEs. METHODS: We conducted a retrospective chart review of 637 patients (664 ankles) who received a TAA between May 2007 and January 2014 and had a minimum follow-up of 3 months. Chemoprophylaxis was prescribed only in the setting of a history of VTE or active coagulopathy. Patients were continued on chemoprophylactic agents if they were taking these medications preoperatively. A VTE event was defined when clinical signs and symptoms of deep venous thrombosis (DVT) were confirmed with use of Doppler ultrasonography or pulmonary embolism was confirmed with the use of a computed tomography scan. Routine screening for VTE was not performed. RESULTS: The overall incidence of clinically detected VTE events was 0.60% (4/664), with 0.45% (3 patients) developing a DVT and 0.15% (1 patient) developing a nonfatal pulmonary embolism. Moreover, we identified a subset of 434 patients without identifiable preoperative risk factors who were not taking chemoprophylaxis preoperatively and were not prescribed chemoprophylaxis postoperatively. Two of these patients developed a DVT postoperatively (0.46%). Given the low incidence of clinically detected VTE, no significant correlation could be identified between the occurrence of VTE events and risk factors. CONCLUSIONS: Our results suggest that clinically detectable VTE after TAA is uncommon. Patients without identifiable risk factors do not appear to require chemoprophylaxis following TAA. We recommend continuation of antiplatelet or anticoagulation therapy in patients who are taking these medications preoperatively and the initiation of chemoprophylaxis postoperatively in patients with known risk factors for VTE. LEVEL OF EVIDENCE: Level IV, case series. PMID- 25712116 TI - Radiographic Outcomes of Postoperative Taping Following Hallux Valgus Correction. AB - BACKGROUND: Traditionally, hallux valgus operative correction has been accompanied by serial spica taping of the great toe during the postoperative period. METHODS: We retrospectively reviewed 187 adult patients who underwent proximal first metatarsal osteotomy with a modified McBride procedure in 2008 2009 (n = 83) and 2011-2012 (n = 104). Postoperatively, to maintain the corrected position of the hallux, patients from 2008 through 2009 underwent weekly spica taping, while patients from 2011 through 2012 utilized a toe separator. The hallux valgus angle (HVA) and intermetatarsal angle (IMA) were measured using anteroposterior weight-bearing preoperative, 2-week postoperative non-weight bearing, and 3-month weight-bearing final follow-up radiographs. A mixed-effects linear regression model identified differences between the treatment groups over time, and a t test compared actual radiographic differences at final follow-up. RESULTS: The mixed-effects model revealed no significant difference in the HVA over time when comparing patients taped to those not taped at the preoperative (33 +/- 6 vs 33 +/- 6), 2-week postoperative (10 +/- 7 vs 9 +/- 6), and 3-month follow-up (14 +/- 6 vs 11 +/- 7) visits (P = .08). At final follow-up, the HVA was lower for the group that was not taped, but the difference (2.5 degrees) was below the minimal clinically important difference (MCID) (P = .015, 95% CI 0.5 4.5). For IMA, there was improved maintenance of correction over time in the patients that were not taped compared to those taped at the preoperative (15 +/- 3 vs 15 +/- 3), 2-week postoperative (2 +/- 2 vs 3 +/- 3), and 3-month follow-up (5 +/- 4 vs 7 +/- 4) visits (P = .002). At final follow-up, the IMA was lower for the group that was not taped, but the difference (1.7 degrees) was below the MCID (P = .004, 95% CI 0.7-2.9). CONCLUSIONS: We report no radiographic benefit of postoperative taping after hallux valgus correction. The present study challenges the previous dogma of postoperative spica taping as the protocol is cost and time intensive for the patient and surgeon. LEVEL OF EVIDENCE: Level III, comparative series. PMID- 25712117 TI - Operative versus nonoperative treatment of geriatric ankle fractures: a Medicare Part A claims database analysis. AB - BACKGROUND: The incidence of ankle fractures is increasing in the geriatric population, and several studies suggest them to be the third most common extremity fracture in this age group. Previous work has reflected relatively low complication rates during operative treatment. Little is known, however, about the association between these injuries and overall mortality, nor whether operative intervention has any effect on mortality. We hypothesized that geriatric ankle fractures would be correlated with an elevated mortality rate and that operative intervention would be associated with a reduced mortality when compared to nonoperative management. METHODS: Following Institutional Review Board approval we retrospectively assessed all relevant 2008 part A inpatient claims from the Medicare database. We queried diagnosis codes for ankle fractures, and then excluded any patients whose age was less then 65 or had an admission related to an ankle fracture during the previous year. Operative patients were then identified by their ICD-9 procedure codes occurring within 30 days of their initial diagnosis code; all other patients were presumed to be treated without operative intervention, thereby creating 2 groups for comparison. We then analyzed this database for specific variables including overall mortality, length of stay, age distribution, and other demographical characteristics. Groups were compared with Elixhauser and Deyo-Charlson scores to determine the level of comorbidities in each group. Multivariate logistic regression analysis was used to determine if operative intervention had a protective effect. RESULTS: In all, 19 648 patients with an ankle fracture were identified. Of those, 15 193 underwent operative intervention (77.3% ) and 4455 were treated nonoperatively (22.7% ). The mean ages for nonoperative and operative intervention were 80.9 and 76.5, respectively (P < .0001). The average length of stay for nonoperative management was 4.5 days, while operative intervention resulted in a length of stay of 4.6 days (P = .43). One-year mortality was 21.5% for the nonoperative group and 9.1% for the operative group (P < .0001). The mean Elixhauser score for the nonoperative group was 2.5 and 2.2 for the operative group (P < .0001). The mean Deyo-Charlson score was 1.3 and 1.0 for the nonoperative and operative groups, respectively (P < .0001). Multivariate logistic regression analysis demonstrated an odds ratio of 0.534 of death within 1 year for patients undergoing operative intervention as compared to nonoperative intervention (95% CI 0.483-0.591, P < .0001). CONCLUSION: The incidence of geriatric ankle fractures continue to increase as our population continues to grow older. A significantly larger number of those patients were treated with operative intervention, at a ratio of approximately 3:1 versus nonoperative management. Despite a relatively low overall reported complication rate with treatment of these injuries, they are associated with substantially increased 1 year mortality in both patient groups. Compared to the operative group, the nonoperative cohort demonstrated a 2-fold elevated mortality rate, although this may be related to them being an arguably more frail population as suggested by both comorbidity indexes. In spite of the difference in comorbidities, logistic regression analysis demonstrated operative intervention to have a protective effect. LEVEL OF EVIDENCE: Level III, comparative series. PMID- 25712118 TI - Comparison of the outcomes between two 3-component total ankle implants. AB - BACKGROUND: Total ankle arthroplasty (TAA) with the use of third generation implants has demonstrated favorable clinical results and improved survival. However, few studies have compared the different types of implants. The purpose of this study was to perform a retrospective evaluation of patient outcomes and complications by comparing TAA procedures performed with HINTEGRA versus MOBILITY systems. METHODS: Fifty-two consecutively enrolled patients (28 men and 24 women; mean age 64.8 years) underwent TAA using HINTEGRA (21 ankles) or MOBILITY (33 ankles) between September 2004 and July 2012. Visual analog scale (VAS) pain scores and the American Orthopaedic Foot & Ankle Society (AOFAS) ankle-hindfoot scores were determined at each follow-up visit. The radiographs were reviewed to assess component positioning, radiolucency, heterotopic ossification, and other factors. The mean follow-up period was 28.3 months in the HINTEGRA group and 32.5 months in the MOBILITY group. RESULTS: VAS decreased from 8.3 to 2.0 for the HINTEGRA group and from 7.9 to 2.7 for the MOBILITY group. The AOFAS score increased from 43.8 to 87.3 for the HINTEGRA group and from 46.6 to 83.7 for the MOBILITY group. Intra- and postoperative malleolar fractures were not noted in the HINTEGRA group, whereas 5 ankles (15.2%) in the MOBILITY group sustained this injury (P = .144). Ankle impingement syndrome was noted in 8 ankles (38.1%) in the HINTEGRA group and 3 (9.1%) in the MOBILITY group (P = .015). However, no significant differences in postoperative osteolysis and neuralgia were noted between the groups. CONCLUSIONS: Both implants exhibited favorable clinical outcome without significant differences. However, in terms of complications, ankle impingement syndrome was significantly more common in the HINTEGRA group, while intraoperative malleolar fracture was observed only in the MOBILITY group. LEVEL OF EVIDENCE: Level III, comparative series. PMID- 25712119 TI - Why do lesser toes deviate laterally in hallux valgus? A radiographic study. AB - BACKGROUND: Hallux valgus foot with laterally deviated lesser toes is a complex condition to treat. Ignoring the laterally deviated lesser toes in hallux valgus might result in unsatisfactory foot shape. Without lateral support of the lesser toes, it might increase the risk of recurrence of hallux valgus. We sought to identify associated radiographic findings in patients where lesser toes follow the great toe in hallux valgus and deviate laterally. METHODS: The weight bearing, anteroposterior foot radiographs of 24 female hallux valgus feet with laterally deviated lesser toes (group L), 34 female hallux valgus feet with normal lesser toes (group H), and 43 normal female feet (group N) were selected for the study. A 2-dimensional coordinated system was used to analyze the shapes and angles of these feet by converting each dot made on the radiographs onto X and Y coordinates. Diagrams of the feet in each group were drawn for comparison. The hallux valgus angle, lateral deviation angle of the second toe, intermetatarsal angles, toe length, metatarsal length, and metatarsus adductus were calculated according to the coordinates of the corresponding points. RESULTS: The mapping showed the bases of the second, third, and fourth toe in group L shifted laterally away from their corresponding metatarsal head (P < .001). The mean 2-3 intermetatarsal angles were: group L, H, N = 7.7 +/- 2.6, 4.3 +/- 1.9, 4.3 +/- 1.3 degrees, respectively (P < .001); mean 3-4 intermetatarsal angles were, for groups L, H, N = 7.3 +/- 2.3, 6.1 +/- 2.1, 6.3 +/- 1.4 degrees, respectively (P < .05). Larger hallux valgus angles (P < .001), more adducted first metatarsal (P < .05), and divergent lateral splaying of the lesser metatarsals (P < .001) were found in group L. CONCLUSION: Larger 2-3 and 3-4 intermetatarsal angles, larger hallux valgus angle, more adducted first metatarsal, and divergent lateral splaying of the lesser metatarsals were associated with lateral deviation of the lesser toes in hallux valgus. LEVEL OF EVIDENCE: Level III, comparative study. PMID- 25712120 TI - Single-photon-emission computed tomography in painful total ankle replacements. AB - BACKGROUND: The use of single-photon-emission computed tomography (SPECT) in identifying unexplained pain in the foot and ankle has been described, where other imaging modalities have failed. The investigation of a painful total ankle replacement (TAR) is difficult, often not delineating a definitive cause. Our aim in this study was to investigate the use of SPECT-CT imaging in painful TARs. METHODS: We performed a retrospective analysis of SPECT imaging performed for painful TARs in our department between October 2010 and December 2014. There were 14 patients identified who had undergone SPECT-CT imaging for a painful TAR. The mean age was 63.1 years, with a male/female sex ratio of 2:3 and a minimum time from surgery to imaging of 18 months. RESULTS: Of the 14 patients, 13 were positive for increased osteoblastic activity in relation to the periprosthetic area consistent with implant loosening. The most common finding was tracer activity in relation to the talar component in 13 cases. There was additional tracer activity localized to the tibial component in 5 of these cases. In 10 of the 13 cases with prosthetic loosening/failure of bony ongrowth, there was no evidence of loosening on the plain radiographs. Infection was ruled out by using joint aspiration as clinically indicated. CONCLUSION: In our series, SPECT-CT imaging revealed a high incidence of medial sided talar prosthesis activity consistent with loosening. The finding of a high incidence of talar nonintegration illustrates the limitations of conventional radiology in follow-up of total ankle replacements, as this was not apparent on plain radiographs. We therefore conclude that there should be a high index of suspicion for talar prosthesis nonintegration in patients with otherwise unexplained ongoing medial pain in total ankle replacements. LEVEL OF EVIDENCE: Level IV, retrospective case series. PMID- 25712121 TI - An attachment-based description of the medial collateral and spring ligament complexes. AB - BACKGROUND: Anatomy of the medial collateral and spring ligament complexes has been the cause of confusion. The anatomic description is highly dependent on the source studied and little agreement exists between texts. In addition, inconsistent nomenclature has been used to describe the components. This study attempted to clarify confusion through the creation of a 3D ligament map using attachment-based dissection. METHODS: Nine fresh foot and ankle specimens were observed. The medial collateral ligament and spring ligament complexes were dissected using their attachment sites as a guide to define individual components. Each component's perimeter and thickness was measured and each bony attachment was mapped using a microscribe 3D digitizer. RESULTS: Five components were identified contributing to the ligament complexes of interest: the tibiocalcaneonavicular, superficial posterior tibiotalar, deep posterior tibiotalar, deep anterior tibiotalar, and inferoplantar longitudinal ligaments. The largest component by total attachment area was the tibiocalcaneonavicular ligament followed by the deep posterior tibiotalar ligament. The largest ligament surface area of attachment to the tibia and talus was the deep posterior tibiotalar ligament. The largest attachment to the navicular and calcaneus was the tibiocalcaneonavicular ligament, which appeared to function in holding these bones in proximity while supporting the head of the talus. CONCLUSION: By defining complex components by their attachment sites, a novel, more functional and reproducible description of the medial collateral and spring ligament complexes was created. CLINICAL RELEVANCE: The linear measurements and 3D maps may prove useful when attempting more anatomically accurate reconstructions. PMID- 25712122 TI - Plantar loading forces while walking in a below-knee cast with an attached loadbearing frame. AB - BACKGROUND: We measured loading forces across different points of the plantar foot surface to examine how different types of casts affect load distribution through the foot and ankle. The patella tendon-bearing (PTB) or Sarmiento cast is the current "gold-standard" casting method for offloading force through the foot and ankle. We aimed to determine if a rocker bottom frame attached to a below knee cast (Beagle Bohler Walker) would be as effective or better at reducing load distribution during full weightbearing. METHOD: We applied TekScan FlexiForce A201 force sensors to the first and fifth metatarsal heads and the plantar surface of the calcaneus of 14 healthy volunteers. All volunteers had force measurements taken without a cast applied and then with a traditional Sarmiento cast, a standard below-knee cast, and a below-knee cast with the Bohler Walker frame fitted. RESULTS: Compared with a standard below-knee cast, the Bohler Walker frame reduced the mean peak force through the head of the first metatarsal by 58.9% (P < .0001), 73.1% through the head of the fifth metatarsal (P < .0001), and 32.2% (P < .0001) through the calcaneus. The Sarmiento cast demonstrated a mean percentage reduction in peak force of 8.6% (P = .39) and 4.4% (P = .87) through the first and fifth metatarsal heads, respectively, but increased the mean peak force by 5.9% (P = .54) through the calcaneus. CONCLUSION: Using a Bohler Walker frame applied to a below-knee cast significantly reduced weight transfer through the foot compared with a Sarmiento cast or standard below-knee cast. CLINICAL RELEVANCE: This reduction in force through the foot could mean early weightbearing would be safer in patients with a wide variety of foot and ankle pathologies such as ankle fractures or operative fixations. This may reduce the incidence of immobility-dependent morbidity. PMID- 25712123 TI - Replication of Standardized ADOS Domain Scores in the Simons Simplex Collection. AB - Raw totals from diagnostic and screening measures for autism spectrum disorder (ASD) are frequently used as dimensional measures of autism symptom severity without appropriate correction for confounding factors, such as developmental level or non-ASD-specific behavior problems. Although these associated features are important to consider when diagnosing ASD and developing intervention plans, both researchers and clinicians sometimes need metrics of ASD severity that are not influenced by these factors. The Autism Diagnostic Observation Schedule (ADOS) domain calibrated severity scores (CSS) were created to provide separate estimates of social affect (SA-CSS) and restricted, repetitive behaviors (RRB CSS) that are relatively independent of child characteristics (Hus et al., 2014). Using a sample of 2,509 probands with ASD from the Simons Simplex Collection (SSC), this study provides the first replication of the ADOS domain CSS in an independent sample. Consistent with the original standardization study, when applied to existing SSC data, the ADOS domain CSS were less influenced by age and cognitive ability compared to raw domain totals. Domain CSS were also relatively independent of behavior problems. Use of the ADOS domain CSS to assess relationships between ASD symptoms and genetic risk factors will increase confidence that associations reflect domain-specific relationships. Scores also offer less developmentally-influenced estimates of ASD severity for future phenotypic explorations in the SSC. This independent replication provides support for the application of the ADOS domain CSS in other samples, though further replication in population-based samples will be an important next step. PMID- 25712124 TI - Small-Molecule ONC201/TIC10 Targets Chemotherapy-Resistant Colorectal Cancer Stem like Cells in an Akt/Foxo3a/TRAIL-Dependent Manner. AB - Self-renewing colorectal cancer stem/progenitor cells (CSC) contribute to tumor maintenance and resistance to therapy. Therapeutic targeting of CSCs could improve treatment response and prolong patient survival. ONC201/TIC10 is a first in-class antitumor agent that induces TRAIL pathway-mediated cell death in cancer cells without observed toxicity. We have previously described that ONC201/TIC10 exposure leads to transcriptional induction of the TRAIL gene via transcription factor Foxo3a, which is activated by dual inactivation of Akt and ERK. The Akt and ERK pathways serve as important targets in CSCs. Foxo3a is a key mediator of Akt and ERK-mediated CSC regulation. We hypothesized that the potent antitumor effect of ONC201/TIC10 in colorectal cancer involves targeting CSCs and bulk tumor cells. ONC201/TIC10 depletes CD133(+), CD44(+), and Aldefluor(+) cells in vitro and in vivo. TIC10 significantly inhibits colonosphere formation of unsorted and sorted 5-fluorouracil-resistant CSCs. ONC201/TIC10 significantly reduces CSC-initiated xenograft tumor growth in mice and prevents the passage of these tumors. ONC201/TIC10 treatment also decreased xenograft tumor initiation and was superior to 5-fluorouracil treatment. Thus, ONC201/TIC10 inhibits CSC self-renewal in vitro and in vivo. ONC201/TIC10 inhibits Akt and ERK, consequently activating Foxo3a and significantly induces cell surface TRAIL and DR5 expression in both CSCs and non-CSCs. ONC201/TIC10-mediated anti-CSC effect is significantly blocked by the TRAIL sequestering antibody RIK-2. Overexpression of Akt, DR5 knockdown, and Foxo3a knockdown rescues ONC201/TIC10-mediated depletion of CD44(+) cells and colonosphere inhibition. In conclusion, ONC201/TIC10 is a promising agent for colorectal cancer therapy that targets both non-CSCs and CSCs in an Akt-Foxo3a-TRAIL-dependent manner. PMID- 25712125 TI - Hyperthermia Sensitizes Glioma Stem-like Cells to Radiation by Inhibiting AKT Signaling. AB - Glioma stem-like cells (GSC) are a subpopulation of cells in tumors that are believed to mediate self-renewal and relapse in glioblastoma (GBM), the most deadly form of primary brain cancer. In radiation oncology, hyperthermia is known to radiosensitize cells, and it is reemerging as a treatment option for patients with GBM. In this study, we investigated the mechanisms of hyperthermic radiosensitization in GSCs by a phospho-kinase array that revealed the survival kinase AKT as a critical sensitization determinant. GSCs treated with radiation alone exhibited increased AKT activation, but the addition of hyperthermia before radiotherapy reduced AKT activation and impaired GSC proliferation. Introduction of constitutively active AKT in GSCs compromised hyperthermic radiosensitization. Pharmacologic inhibition of PI3K further enhanced the radiosensitizing effects of hyperthermia. In a preclinical orthotopic transplant model of human GBM, thermoradiotherapy reduced pS6 levels, delayed tumor growth, and extended animal survival. Together, our results offer a preclinical proof-of-concept for further evaluation of combined hyperthermia and radiation for GBM treatment. PMID- 25712127 TI - Breastfeeding and use of social media among first-time African American mothers. AB - OBJECTIVE: To describe the use of social media during the antepartum and postpartum periods among first-time African American mothers and their support persons. DESIGN: A qualitative critical ethnographic research design within the contexts of family life course development theory and Black feminist theory. SETTING: Participants were recruited from community-based, public health, and home visiting programs. PARTICIPANTS: A purposive sample was recruited, consisting of 14 pregnant African American women and eight support persons. METHODS: Pregnant and postpartum African American women and their support persons were interviewed separately during the antepartum and postpartum periods. Data were analyzed thematically. RESULTS: Participants frequently used social media for education and social support and searched the Internet for perinatal and parenting information. Most participants reported using at least one mobile application during their pregnancies and after giving birth. Social media were typically accessed through smartphones and/or computers using different websites and applications. Although participants gleaned considerable information about infant development from these applications, they had difficulty finding and recalling information about infant feeding. CONCLUSION: Social media are an important vehicle to disseminate infant feeding information; however, they are not currently being used to full potential. Our findings suggest that future interventions geared toward African American mothers and their support persons should include social media approaches. The way individuals gather, receive, and interpret information is dynamic. The increasing popularity and use of social media platforms offers the opportunity to create more innovative, targeted mobile health interventions for infant feeding and breastfeeding promotion. PMID- 25712126 TI - MyD88-Dependent Signaling Decreases the Antitumor Efficacy of Epidermal Growth Factor Receptor Inhibition in Head and Neck Cancer Cells. AB - EGFR is upregulated in the majority of head and neck squamous cell carcinomas (HNSCC). However, many patients with HNSCC respond poorly to the EGFR inhibitors (EGFRI) cetuximab and erlotinib, despite tumor expression of EGFR. Gene expression analysis of erlotinib-treated HNSCC cells revealed an upregulation of genes involved in MyD88-dependent signaling compared with their respective vehicle-treated cell lines. We therefore investigated whether MyD88-dependent signaling may reduce the antitumor efficacy of EGFRIs in HNSCC. Erlotinib significantly upregulated IL6 secretion in HNSCC cell lines, which our laboratory previously reported to result in reduced drug efficacy. Suppression of MyD88 expression blocked erlotinib-induced IL6 secretion in vitro and increased the antitumor activity of erlotinib in vivo. There was little evidence of Toll-like receptor or IL18 receptor involvement in erlotinib-induced IL6 secretion. However, suppression of IL1R signaling significantly reduced erlotinib-induced IL6 production. A time-dependent increase of IL1alpha but not IL1beta was observed in response to erlotinib treatment, and IL1alpha blockade significantly increased the antitumor activity of erlotinib and cetuximab in vivo. A pan caspase inhibitor reduced erlotinib-induced IL1alpha secretion, suggesting that IL1alpha was released because of cell death. Human HNSCC tumors showed higher IL1alpha mRNA levels compared with matched normal tissue, and IL1alpha was found to be negatively correlated with survival in patients with HNSCC. Overall, the IL1alpha/IL1R/MYD88/IL6 pathway may be responsible for the reduced antitumor efficacy of erlotinib and other EGFRIs, and blockade of IL1 signaling may improve the efficacy of EGFRIs in the treatment of HNSCC. PMID- 25712128 TI - Malignant transformation of germinoma 14 years after onset: Favorable efficacy of oral etoposide. AB - We report the case of a 19-year-old woman with a highly malignant intracranial germ cell tumor (GCT) that developed 14 years after treatment for neurohypophyseal germinoma. Magnetic resonance imaging (MRI) showed a large neurohypophyseal mass and a synchronous lesion in the pineal region. Plasma alpha fetoprotein was elevated to 3038 ng/mL. Although the tumor shrank and tumor marker levels normalized after chemotherapy and craniospinal irradiation, treatment was switched to oral etoposide for the residual tumor because of adverse events. MRI after oral etoposide introduction showed additional tumor shrinkage for 27 months after the onset of the second tumor. To the best of our knowledge, this is the longest interval between germinoma onset and the development of highly malignant recurrent GCT to be reported in the English language literature. Oral etoposide prevented regrowth of the GCT, which has a poor prognosis, and decreased the size of the residual tumor. PMID- 25712129 TI - Loss of the scavenger mRNA decapping enzyme DCPS causes syndromic intellectual disability with neuromuscular defects. AB - mRNA decay is an essential and active process that allows cells to continuously adapt gene expression to internal and environmental cues. There are two mRNA degradation pathways: 3' to 5' and 5' to 3'. The DCPS protein is the scavenger mRNA decapping enzyme which functions in the last step of the 3' end mRNA decay pathway. We have identified a DCPS pathogenic mutation in a large family with three affected individuals presenting with a novel recessive syndrome consisting of craniofacial anomalies, intellectual disability and neuromuscular defects. Using patient's primary cells, we show that this homozygous splice mutation results in a DCPS loss-of-function allele. Diagnostic biochemical analyses using various m7G cap derivatives as substrates reveal no DCPS enzymatic activity in patient's cells. Our results implicate DCPS and more generally RNA catabolism, as a critical cellular process for neurological development, normal cognition and organismal homeostasis in humans. PMID- 25712130 TI - Mutation in exon 1a of PLEC, leading to disruption of plectin isoform 1a, causes autosomal-recessive skin-only epidermolysis bullosa simplex. AB - PLEC, the gene encoding the cytolinker protein plectin, has eight tissue-specific isoforms in humans, arising by alternate splicing of the first exon. To date, all PLEC mutations that cause epidermolysis bullosa simplex (EBS) were found in exons common to all isoforms. Due to the ubiquitous presence of plectin in mammalian tissues, EBS from recessive plectin mutations is always associated with extracutaneous involvement including muscular dystrophy, pyloric atresia and cardiomyopathy. We studied a consanguineous family with sisters having isolated blistering suggesting EBS. Skin disease started with foot blisters at walking age and became generalized at puberty while sparing mucous membranes. DNA sequencing revealed a homozygous nonsense mutation (c.46C>T; p.Arg16X) in the first exon of the plectin variant encoding plectin isoform 1a (P1a). Immunofluorescence antigen mapping, transmission electron microscopy, western blot analysis and qRT-PCR were performed on patient skin and cultured keratinocytes, control myocardium and striated muscle samples. We found hypoplastic hemidesmosomes and intra-epidermal 'pseudo-junctional' cleavage fitting EBS. Screening for cardiomyopathy and muscle dystrophy showed no abnormalities. We report the first cases of autosomal recessive EBS from P1a deficiency affecting skin, while mucous membranes, heart and muscle are spared. The dominant expression of the P1a isoform in epidermal basal cell layer and cultured keratinocytes suggests that mutations in the first exon of isoform 1a cause skin-only EBS without extracutaneous involvement. Our study characterizes yet another of the eight isoforms of plectin and adds a tissue-specific phenotype to the spectrum of 'plectinopathies' produced by mutations of unique first exons of this gene. PMID- 25712131 TI - Protein misfolding and the pathogenesis of ABCA4-associated retinal degenerations. AB - Mutations in the ABCA4 gene are a common cause of autosomal recessive retinal degeneration. All mouse models to date are based on knockouts of Abca4, even though the disease is often caused by missense mutations such as the complex allele L541P;A1038V (PV). We now show that the PV mutation causes severe human disease whereas the V mutation alone causes mild disease. Mutant ABCA4 proteins expressed heterologously in mammalian cells retained normal cellular localization. However, basal and all-trans-retinal-stimulated ATPase activities were reduced substantially for P and PV but only mildly for V. Electron microscopy revealed marked structural changes and misfolding for the P and PV mutants but few changes for the V mutant, consistent with the disease severity difference in patients. We generated Abca4(PV/PV) knock-in mice homozygous for the complex PV allele to investigate the effects of this misfolding mutation in vivo. Mutant ABCA4 RNA levels approximated WT ABCA4 RNA levels but, surprisingly, only trace amounts of mutant ABCA4 protein were noted in the retina. RNA sequencing of WT, Abca4(-/-) and Abca4(PV/PV) mice revealed mild gene expression alterations in the retina and RPE. Similar to Abca4(-/-) mice, Abca4(PV/PV) mice showed substantial A2E and lipofuscin accumulation in their RPE cells but no retinal degeneration up to 12 months of age. Thus, rapid degradation of this large misfolded mutant protein in mouse retina caused little detectable photoreceptor degeneration. These findings suggest likely differences in the unfolded protein response between murine and human photoreceptors and support development of therapies directed at increasing this capability in patients. PMID- 25712133 TI - Extensive size variability of the GGGGCC expansion in C9orf72 in both neuronal and non-neuronal tissues in 18 patients with ALS or FTD. AB - A GGGGCC-repeat expansion in C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) among Caucasians. However, little is known about the variability of the GGGGCC expansion in different tissues and whether this correlates with the observed phenotype. Here, we used Southern blotting to estimate the size of hexanucleotide expansions in C9orf72 in neural and non-neural tissues from 18 autopsied ALS and FTD patients with repeat expansion in blood. Digitalization of the Southern blot images allowed comparison of repeat number, smear distribution and expansion band intensity between tissues and between patients. We found marked intra-individual variation of repeat number between tissues, whereas there was less variation within each tissue group. In two patients, the size variation between tissues was extreme, with repeat numbers below 100 in all studied non-neural tissues, whereas expansions in neural tissues were 20-40 times greater and in the same size range observed in neural tissues of the other 16 patients. The expansion pattern in different tissues could not distinguish between diagnostic groups and no correlation was found between expansion size in frontal lobe and occurrence of cognitive impairment. In ALS patients, a less number of repeats in the cerebellum and parietal lobe correlated with earlier age of onset and a larger number of repeats in the parietal lobe correlated with a more rapid progression. In 43 other individuals without repeat expansion in blood, we find that repeat sizes up to 15 are stable, as no size variation between blood, brain and spinal cord was found. PMID- 25712132 TI - Molecular mechanism of CHRDL1-mediated X-linked megalocornea in humans and in Xenopus model. AB - Chordin-Like 1 (CHRDL1) mutations cause non-syndromic X-linked megalocornea (XMC) characterized by enlarged anterior eye segments. Mosaic corneal degeneration, presenile cataract and secondary glaucoma are associated with XMC. Beside that CHRDL1 encodes Ventroptin, a secreted bone morphogenetic protein (BMP) antagonist, the molecular mechanism of XMC is not well understood yet. In a family with broad phenotypic variability of XMC, we identified the novel CHRDL1 frameshift mutation c.807_808delTC [p.H270Wfs*22] presumably causing CHRDL1 loss of function. Using Xenopus laevis as model organism, we demonstrate that chrdl1 is specifically expressed in the ocular tissue at late developmental stages. The chrdl1 knockdown directly resembles the human XMC phenotype and confirms CHRDL1 deficiency to cause XMC. Interestingly, secondary to this bmp4 is down-regulated in the Xenopus eyes. Moreover, phospho-SMAD1/5 is altered and BMP receptor 1A is reduced in a XMC patient. Together, we classify these observations as negative feedback regulation due to the deficient BMP antagonism in XMC. As CHRDL1 is preferentially expressed in the limbal stem cell niche of adult human cornea, we assume that CHRDL1 plays a key role in cornea homeostasis. In conclusion, we provide novel insights into the molecular mechanism of XMC as well as into the specific role of CHRDL1 during cornea organogenesis, among others by the establishment of the first XMC in vivo model. We show that unravelling monogenic cornea disorders like XMC-with presumably disturbed cornea growth and differentiation-contribute to the identification of potential limbal stem cell niche factors that are promising targets for regenerative therapies of corneal injuries. PMID- 25712134 TI - The Meaningful Use of Electronic Health Records and Health Care Utilization. AB - This study sought to determine the effects on health care utilization of meaningful use (MU) of electronic health records (EHRs) compared to typical use of EHRs without MU. This was a cohort study of primary care physicians in New York State (2010-2011). A total of 7 outcomes (primary care visits, specialist visits, laboratory tests, radiology tests, emergency department visits, admissions and readmissions) and 11 potential confounders were considered. The study sample included 213 physicians (50% of whom had achieved MU) and 127 353 patients. There were 17 fewer primary care visits and 61 fewer laboratory tests for every 100 patients whose physicians achieved MU, compared with patients whose physicians did not achieve MU (P < .05 for each). There were no differences for other outcomes. Achieving stage 1 MU was associated with fewer primary care visits and laboratory tests, suggesting that effects of MU are distinct from effects of typical EHR use. PMID- 25712135 TI - Analysis of invdupdel(8p) rearrangement: Clinical, cytogenetic and molecular characterization. AB - Inverted duplication 8p associated with deletion of the short arms of chromosome 8 (invdupdel[8p]) is a relatively uncommon complex chromosomal rearrangement, with an estimated incidence of 1 in 10,000-30,000 live borns. The chromosomal rearrangement consists of a deletion of the telomeric region (8p23-pter) and an inverted duplication of the 8p11.2-p22 region. Clinical manifestations of this disorder include severe to moderate intellectual disability and characteristic facial features. In most cases, there are also CNS associated malformations and congenital heart defects. In this work, we present the cytogenetic and molecular characterization of seven children with invdupdel(8p) rearrangements. Subsequently, we have carried out genotype-phenotype correlations in these seven patients. The majority of our patients carry a similar deletion but different size of duplications; the latter probably explaining the phenotypic variability among them. We recommend that complete clinical evaluation and detailed chromosomal microarray studies should be undertaken, enabling appropriate genetic counseling. PMID- 25712136 TI - Genetics of familial hypercholesterolemia. AB - Familial hypercholesterolemia (FH) is a genetic disorder characterized by elevated low-density lipoprotein (LDL) cholesterol and premature cardiovascular disease, with a prevalence of approximately 1 in 200-500 for heterozygotes in North America and Europe. Monogenic FH is largely attributed to mutations in the LDLR, APOB, and PCSK9 genes. Differential diagnosis is critical to distinguish FH from conditions with phenotypically similar presentations to ensure appropriate therapeutic management and genetic counseling. Accurate diagnosis requires careful phenotyping based on clinical and biochemical presentation, validated by genetic testing. Recent investigations to discover additional genetic loci associated with extreme hypercholesterolemia using known FH families and population studies have met with limited success. Here, we provide a brief overview of the genetic determinants, differential diagnosis, genetic testing, and counseling of FH genetics. PMID- 25712139 TI - Are IPL home devices really foolproof? PMID- 25712138 TI - Bacterial cytoplasmic display platform Retained Display (ReD) identifies stable human germline antibody frameworks. AB - Conventional antibody surface display requires fusion protein export through at least one cellular membrane, constraining the yield and occasioning difficulties in achieving scaled production. To circumvent this limitation, we developed a novel cytoplasmic display platform, Retained Display (ReD), and used it to screen for human scFv frameworks that are highly soluble and stable in the bacterial cytoplasm. ReD, based on the retention of high-molecular weight complexes within detergent-permeabilized Escherichia coli, enabled presentation of exogenous targets to antibodies that were expressed and folded in the cytoplasm. All human lambda and kappa light chain family genes were expressed as IGHV3-23 fusions. Members of the lambda subfamilies 1, 3 and 6 were soluble cytoplasmic partners of IGHV3-23. Contrary to previous in vivo screens for soluble reduced scFvs, the pairings identified by ReD were identical to the human germline sequences for the framework, CDR1 and CDR2 regions. Using the most soluble scFv scaffold identified, we demonstrated tolerance to CDR3 diversification and isolated a binding scFv to an exogenous protein target. This screening system has the potential to rapidly produce antibodies to target threats such as emerging infectious diseases and bioterror agents. PMID- 25712137 TI - Targeting PCSK9 for therapeutic gains. AB - Even though it is only a little over a decade from the discovery of proprotein convertase subtilisin/kexin type 9 (PCSK9) as a plasma protein that associates with both hypercholesterolemia and low cholesterol syndromes, a rich literature has developed describing its unique physiology and the impact of antagonism of this molecule on cholesterol metabolism for therapeutic purposes. Indeed, the PCSK9 story is unfolding rapidly, with many answers and more questions. This review summarizes the most recent data from phase II/III clinical trials of PCSK9 inhibition with the three leading antibodies, highlights the clinical significance of the ongoing studies, and suggests future areas of investigation based on recent basic science discoveries on the physiology of PCSK9. PMID- 25712140 TI - A case of thrombotic micro-angiopathy after heart transplantation successfully treated with eculizumab. PMID- 25712142 TI - Interaction of PiB-derivative metal complexes with beta-amyloid peptides: selective recognition of the aggregated forms. AB - Metal complexes are increasingly explored as imaging probes in amyloid peptide related pathologies. We report the first detailed study on the mechanism of interaction between a metal complex and both the monomer and the aggregated form of Abeta1-40 peptide. We have studied lanthanide(III) chelates of two PiB derivative ligands (PiB=Pittsburgh compound B), L(1) and L(2), differing in the length of the spacer between the metal-complexing DO3A macrocycle (DO3A=1,4,7,10 tetraazacyclododecane-1,4,7-triacetic acid) and the peptide-recognition PiB moiety. Surface plasmon resonance (SPR) and saturation transfer difference (STD) NMR spectroscopy revealed that they both bind to aggregated Abeta1-40 (KD =67-160 MUM), primarily through the benzothiazole unit. HSQC NMR spectroscopy on the (15) N-labeled, monomer Abeta1-40 peptide indicates nonsignificant interaction with monomeric Abeta. Time-dependent circular dichroism (CD), dynamic light scattering (DLS), and TEM investigations of the secondary structure and of the aggregation of Abeta1-40 in the presence of increasing amounts of the metal complexes provide coherent data showing that, despite their structural similarity, the two complexes affect Abeta fibril formation distinctly. Whereas GdL(1), at higher concentrations, stabilizes beta-sheets, GdL(2) prevents aggregation by promoting alpha-helical structures. These results give insight into the behavior of amyloid targeted metal complexes in general and contribute to a more rational design of metal-based diagnostic and therapeutic agents for amyloid- associated pathologies. PMID- 25712141 TI - Generation of a CRISPR database for Yersinia pseudotuberculosis complex and role of CRISPR-based immunity in conjugation. AB - The clustered regularly interspaced short palindromic repeat - CRISPR-associated genes (CRISPR-Cas) system is used by bacteria and archaea against invading conjugative plasmids or bacteriophages. Central to this immunity system are genomic CRISPR loci that contain fragments of invading DNA. These are maintained as spacers in the CRISPR loci between direct repeats and the spacer composition in any bacterium reflects its evolutionary history. We analysed the CRISPR locus sequences of 335 Yersinia pseudotuberculosis complex strains. Altogether 1902 different spacer sequences were identified and these were used to generate a database for the spacer sequences. Only ~10% of the spacer sequences found matching sequences. In addition, surprisingly few spacers were shared by Yersinia pestis and Y. pseudotuberculosis strains. Interestingly, 32 different protospacers were present in the conjugative plasmid pYptb32953. The corresponding spacers were identified from 35 different Y. pseudotuberculosis strains indicating that these strains had encountered pYptb32953 earlier. In conjugation experiments, pYptb32953-specific spacers generally prevented conjugation with spacer-positive and spacer-free strains. However, some strains with one to four spacers were invaded by pYptb32953 and some spacer-free strains were fully resistant. Also some spacer-positive strains were intermediate resistant to conjugation. This suggests that one or more other defence systems are determining conjugation efficiency independent of the CRISPR-Cas system. PMID- 25712143 TI - An abnormality in glucocorticoid receptor expression differentiates steroid responders from nonresponders in keloid disease. AB - BACKGROUND: Glucocorticoids (GCs) are first-line treatment for keloid disease (KD) but are limited by high incidence of resistance, recurrence and undesirable side-effects. Identifying patient responsiveness early could guide therapy. METHODS: Nineteen patients with KD were recruited at week 0 (before treatment) and received intralesional steroids. At weeks 0, 2 and 4, noninvasive imaging and biopsies were performed. Responsiveness was determined by clinical response and a significant reduction in vascular perfusion following steroid treatment, using full-field laser perfusion imaging (FLPI). Responsiveness was also evaluated using (i) spectrophotometric intracutaneous analysis to quantify changes in collagen and melanin and (ii) histology to identify changes in epidermal thickness and glycosaminoglycan (GAG) expression. Biopsies were used to quantify changes in glucocorticoid receptor (GR) expression using quantitative reverse transcriptase polymerase chain reaction, immunoblotting and immunohistochemistry. RESULTS: At week 2, the FLPI was used to separate patients into steroid responsive (n = 12) and nonresponsive groups (n = 7). All patients demonstrated a significant decrease in GAG at week 2 (P < 0.05). At week 4, responsive patients exhibited significant reduction in melanin, GAG, epidermal thickness (all P < 0.05) and a continued reduction in perfusion (P < 0.001) compared with nonresponders. Steroid-responsive patients had increased GR expression at baseline and showed autoregulation of GR compared with nonresponders, who showed no change in GR transcription or protein. CONCLUSIONS: This is the first demonstration that keloid response to steroids can be measured objectively using noninvasive imaging. FLPI is a potentially reliable tool to stratify KD responsiveness. Altered GR expression may be the mechanism gating therapeutic response. PMID- 25712144 TI - Diffusion-weighted MRI for uveal melanoma liver metastasis detection. AB - OBJECTIVES: We aimed to assess the sensitivity of diffusion-weighted (DW) magnetic resonance (MR) imaging for the detection of pathologically confirmed uveal melanoma liver metastases (UMLM). METHODS: Twenty patients who underwent complete surgical resection of their UMLM (N = 83) were included. Pre-surgery liver MR imaging included T2-weighted, T1-weighted, DW and dynamic-gadolinium enhanced MR sequences. Two radiologists independently reviewed three sets of images (DW / morphologic-dynamic / combined) for each patient using intraoperative and pathological findings as a standard of reference. RESULTS: The sensitivities of the morphologic-dynamic and DW images for UMLM detection were 63 % and 59 %, respectively, for reader #1 (R1) and 64 % and 53 %, for reader #2 (R2). Sensitivity of the combined set was higher than sensitivity in the two other sets (R1:69 %, R2:67 %), but was only significantly different than the sensitivity of the DW images (McNemar test). For the three sets and the two readers, the sensitivity for UMLM smaller than 5 mm (37-46 %) was significantly lower than that for UMLM larger than 5 mm (67-90 %). The sensitivity for UMLM located in the subcapsular area (41-54 %) was significantly lower than that for intraparenchymal UMLM (68-86 %) (Chi-square test). CONCLUSION: Our study shows that the addition of DW imaging to morphologic-dynamic images does not significantly increase MR sensitivities for UMLM detection. KEY POINTS: * The MR imaging sensitivity for uveal melanoma liver metastases (UMLM) was 69 %. * Addition of DW imaging to morphologic-dynamic images does not increase sensitivity significantly. * Sensitivity for subcapsular UMLM was significantly lower than sensitivity for intraparenchymal UMLM. * The T2 shortening effect does not appear to influence lesion detection in DWI. PMID- 25712145 TI - Interim anatase coating layer stabilizes rutile@Crx Oy photoanode for visible light-driven water oxidation. AB - Ternary core-shell heterostructured rutile@anatase@Crx Oy nanorod arrays were elaborately designed as photoanodes for efficient photoelectrochemical water splitting under visible-light illumination. The four-fold enhanced and stabilized visible-light photocurrent highlights the unique role of the interim anatase layer in accelerating the interfacial charge transfer from the Crx Oy chromophore to rutile nanorods. PMID- 25712147 TI - P-glycoprotein in autoimmune rheumatic diseases. AB - P-glycoprotein (Pgp) is a transmembrane protein of 170 kD encoded by the multidrug resistance 1 (MDR-1) gene, localized on chromosome 7. More than 50 polymorphisms of the MDR-1 gene have been described; a subset of these has been shown to play a pathophysiological role in the development of inflammatory bowel disease, femoral head osteonecrosis induced by steroids, lung cancer and renal epithelial tumors. Polymorphisms that have a protective effect on the development of conditions such as Parkinson disease have also been identified. P-glycoprotein belongs to the adenosine triphosphate binding cassette transporter superfamily and its structure comprises a chain of approximately 1280 aminoacid residues with an N-C terminal structure, arranged as 2 homologous halves, each of which has 6 transmembrane segments, with a total of 12 segments with 2 cytoplasmic nucleotide binding domains. Many cytokines like interleukin 2 and tumor necrosis factor alpha increase Pgp expression and activity. Pgp functions as an efflux pump for a variety of toxins in order to protect particular organs and tissues as the central nervous system. Pgp transports a variety of substrates including glucocorticoids while other drugs such as tacrolimus and cyclosporine A act as modulators of this protein. The most widely used method to measure Pgp activity is flow cytometry using naturally fluorescent substrates such as anthracyclines or rhodamine 123. The study of drug resistance and its association to Pgp began with the study of resistance to chemotherapy in the treatment of cancer and antiretroviral therapy for human immunodeficiency virus; however, the role of Pgp in the treatment of systemic lupus erythematosus, rheumatoid arthritis and psoriatic arthritis has been a focus of study lately and has emerged as an important mechanism by which treatment failure occurs. The present review analyzes the role of Pgp in these autoimmune diseases. PMID- 25712148 TI - Beyond Strain: Personal Strengths and Mental Health of Mexican and Argentinean Dementia Caregivers. AB - INTRODUCTION: Life expectancy is increasing in Latin America resulting in the need for more family caregivers for older adults with dementia. The purpose of the current study was to examine the relationships between personal strengths (optimism, sense of coherence [SOC], and resilience) and the mental health of dementia caregivers from Latin America. METHOD: Primary family dementia caregivers (n = 127) were identified via convenience sampling at the Instituto de Neurociencias de San Lucas, Argentina, and CETYS University, in Baja California, Mexico and completed measures of these constructs. FINDINGS: Personal strengths explained between 32% and 50% of the variance in caregiver mental health. In a series of hierarchical multiple regressions, more manageability (beta = -.38, p = .001), general resilience (beta = -.24, p = .012), and social competence (beta = .21, p = .034) were uniquely associated with lower depression. Greater comprehensibility (beta = -.28, p = .008) was uniquely associated with decreased burden, and manageability was marginally related (beta = -.21, p< .10). Greater optimism (beta = .37, p< .001) and manageability (beta = .27, p = .004) were uniquely associated with increased life satisfaction. DISCUSSION: The personal strengths of caregivers in Latin America may be particularly important for their mental health because of the culturally imbedded sense of duty toward older family members. IMPLICATIONS: Incorporating strengths-based approaches into research on caregiver interventions in regions where caregiving is a highly culturally valued role such as Latin America may have the potential to improve the mental health of dementia caregivers. PMID- 25712149 TI - Nurses leading the fight against Ebola virus disease. AB - The current Ebola crisis has sparked worldwide reaction of panic and disbelief in its wake as it decimated communities in West Africa, particularly in Guinea, Liberia, and Sierra Leone, including its health care workers. This article affirms the crucial role nurses play in maintaining health and preventing diseases, connects the devastating havoc of the Ebola virus disease to another issue of nursing shortage in underdeveloped countries, and asserts the key leadership nurses play in protecting the communities they serve while maintaining their safety and those of other health care workers. Nurses must actively seek a place at the table, as echoed by the American Academy of Nursing and American Nurses Association and the American Nurses Association, when decisions are being made regarding Ebola virus disease: at care settings, in the board room, and at federal, state, and local levels. PMID- 25712150 TI - Identification of two structural elements important for ribosome-dependent GTPase activity of elongation factor 4 (EF4/LepA). AB - The bacterial translational GTPase EF4/LepA is structurally similar to the canonical elongation factor EF-G. While sharing core structural features with other translational GTPases, the function of EF4 remains unknown. Recent structural data locates the unique C-terminal domain (CTD) of EF4 in proximity to the ribosomal peptidyl transferase center (PTC). To investigate the functional role of EF4's CTD we have constructed three C-terminal truncation variants. These variants are fully functional with respect to binding mant-GTP and mant-GDP as determined by rapid kinetics, as well as their intrinsic multiple turnover GTPase activity. Furthermore, they are able to form stable complexes with the 70S ribosome and 50S/30S ribosomal subunits. However, successive removal of the C terminus impairs ribosome-dependent multiple turnover GTPase activity of EF4, which for the full-length protein is very similar to EF-G. Our findings suggest that the last 44 C-terminal amino acids of EF4 form a sub-domain within the C terminal domain that is important for GTP-dependent function on the ribosome. Additionally, we show that efficient nucleotide hydrolysis by EF4 on the ribosome depends on a conserved histidine (His 81), similar to EF-G and EF-Tu. PMID- 25712151 TI - Does low coping efficacy mediate the association between negative life events and incident psychopathology? A prospective-longitudinal community study among adolescents and young adults. AB - AIMS: To prospectively examine whether negative life events (NLE) and low perceived coping efficacy (CE) increase the risk for the onset of various forms of psychopathology and low CE mediates the associations between NLE and incident mental disorders. METHODS: A representative community sample of adolescents and young adults (N = 3017, aged 14-24 at baseline) was prospectively followed up in up to three assessment waves over 10 years. Anxiety, depressive and substance use disorders were assessed at each wave using the DSM-IV/M-CIDI. NLE and CE were assessed at baseline with the Munich Event List and the Scale for Self-Control and Coping Skills. Associations (odds ratios, OR) of NLE and CE at baseline with incident mental disorders at follow-up were estimated using logistic regressions adjusted for sex and age. RESULTS: NLE at baseline predicted the onset of any disorder, any anxiety disorder, panic disorder, agoraphobia, generalised anxiety disorder, any depression, major depressive episodes, dysthymia, any substance use disorder, nicotine dependence and abuse/dependence of illicit drugs at follow-up (OR 1.02-1.09 per one NLE more). When adjusting for any other lifetime disorder prior to baseline, merely the associations of NLE with any anxiety disorder, any depression, major depressive episodes, dysthymia and any substance use disorder remained significant (OR 1.02-1.07). Low CE at baseline predicted the onset of any disorder, any anxiety disorder, agoraphobia, generalised anxiety disorder, any depression, major depressive episodes, dysthymia, any substance use disorder, alcohol abuse/dependence, nicotine dependence and abuse/dependence of illicit drugs at follow-up (OR 1.16-1.72 per standard deviation). When adjusting for any other lifetime disorder prior to baseline, only the associations of low CE with any depression, major depressive episodes, dysthymia, any substance use disorder, alcohol abuse/dependence, nicotine dependence and abuse/dependence of illicit drugs remained significant (OR 1.15-1.64). Low CE explained 9.46, 13.39, 12.65 and 17.31% of the associations between NLE and any disorder, any depression, major depressive episodes and dysthymia, respectively. When adjusting for any other lifetime disorder prior to baseline, the reductions in associations for any depression (9.77%) and major depressive episodes (9.40%) remained significant, while the reduction in association for dysthymia was attenuated to non significance (p-value > 0.05). CONCLUSIONS: Our findings suggest that NLE and low perceived CE elevate the risk for various incident mental disorders and that low CE partially mediates the association between NLE and incident depression. Subjects with NLE might thus profit from targeted early interventions strengthening CE to prevent the onset of depression. PMID- 25712153 TI - High-level expression of a novel alpha-galactosidase gene from Rhizomucor miehei in Pichia pastoris and characterization of the recombinant enyzme. AB - The second alpha-galactosidase gene (designated as RmgalB) was cloned from the thermophilic fungus Rhizomucor miehei and expressed in Pichia pastoris. The gene belonging to glycoside hydrolase (GH) family 36 has an open reading frame (ORF) of 2241bp encoding 746 amino acids with two introns. The recombinant alpha galactosidase (RmgalB) was secreted at high levels of 1953.9Uml(-1) in high cell density fermentor, which is the highest yield obtained for a alpha-galactosidase. The purified enzyme as a tetramer gave a single band corresponding to a molecular mass of 83.1kDa in SDS-PAGE. The enzyme exhibited a very high specific activity of 505.5Umg(-1). The optimum temperature and pH of RmgalB were determined to be 55 degrees C and pH 5.5, respectively. It was stable within pH 5.5-9.5 and up to 55 degrees C. RmgalB displayed specificity toward raffinose and stachyose, and completely hydrolyzed the anti-nutritive raffinose family oligosaccharides (RFOs). These properties make RmgalB useful in the food and feed industries. PMID- 25712154 TI - Exosome-transported microRNAs of helminth origin: new tools for allergic and autoimmune diseases therapy? AB - Chronic diseases associated with inflammation show fast annual increase in their incidence. This has been associated with excessive hygiene habits that limit contacts between the immune system and helminth parasites. Helminthic infections induce regulation and expansion of regulatory T cells (Treg) leading to atypical Th2 type immune responses, with downregulation of the inflammatory component usually associated with these type of responses. Many cells, including those of the immune system, produce extracellular vesicles called exosomes which mediate either immune stimulation (DCs) or immune modulation (T cells). The transfer of miRNAs contained in T-cell exosomes has been shown to contribute to downregulate the production of inflammatory mediators. It has been recently described the delivery to the host-parasite interface of exosomes containing miRNAs by helminths and its internalization by host cells. In this sense, helminth microRNAs transported in exosomes and internalized by immune host cells exert an important role in the expansion of Treg cells, resulting in the control of inflammation. We here provide relevant information obtained in the field of exosomes, cell-cell communication and miRNAs, showing the high potential of helminth miRNAs delivered in exosomes to host cells as new therapeutic tools against diseases associated with exacerbated inflammatory responses. PMID- 25712152 TI - Germinal centres and B cell lymphomagenesis. AB - Germinal centres (GCs) are involved in the selection of B cells secreting high affinity antibodies and are also the origin of most human B cell lymphomas. Recent progress has been made in identifying the functionally relevant stages of the GC and the complex trafficking mechanisms of B cells within the GC. These studies have identified transcription factors and signalling pathways that regulate distinct phases of GC development. Notably, these factors and pathways are hijacked during tumorigenesis, as revealed by analyses of the genetic lesions associated with various types of B cell lymphomas. This Review focuses on recent insights into the mechanisms that regulate GC development and that are relevant for human B cell lymphomagenesis. PMID- 25712155 TI - Effect of xantham gum, steviosides, clove, and cinnamon essential oils on the sensory and microbiological quality of a low sugar tomato jam. AB - The partial or total decrease of sugar content in the formulation of jams affects their physical, chemical and microbiological stability. In order to minimize these technological problems, we studied the effect of xanthan gum (XG), steviosides, cinnamon (CO), and clove (CLO) essential oils on the sensory and microbiological quality of a low sugar tomato jam. Levels of 0.250 g/100 g steviosides and 0.450 g/100 g XG showed maximum score of overall acceptability of jam. The combination of essential oils produced synergistic and additive effects in vitro on growth of Z. bailii and Z. rouxii, respectively. However, in the jam, CO was more effective and CLO did not modify the CO action. Cell surface was one of the sites of action of CO since a decrease in yeast cell surface hydrophobicity was observed. From the microbiological and sensory points of view, 0.0060 g/100 g CO showed the maximum score of jam overall acceptability and did not cause yeast inactivation but it could be useful as an additional stress factor against yeast post--process contamination. The adequate levels of XG, steviosides, and CO can improve the quality of a low sugar jam formulation. PMID- 25712156 TI - Reducing margins of wide local excision in head and neck melanoma for function and cosmesis: 5-year local recurrence-free survival. AB - BACKGROUND: The proximity of head and neck (H&N) melanomas to critical anatomical structures requires that surgeons achieve a balance between adequate margins of excision and the functional and cosmetic needs of patients. This study sought to determine the risk associated with reducing margins of wide local excision (WLE) in H&N melanoma and to identify risk factors of recurrence. METHODS: Seventy-nine cases of primary, invasive H&N melanoma were treated by WLE and followed prospectively for local recurrence. Forty-two WLEs were performed according to current practice guidelines (1cm for lesions<1.0 mm thick, 1-2 cm for lesions 1.01-2.0 mm thick, and 2 cm for lesions >2.0 mm thick). Reduced margins (0.5 cm for lesions <=1.0 mm thick, 0.5-1.0 cm for lesions 1.01-2.0 mm thick, and 1.0 cm for lesion >2.0 mm thick) were utilized in 37 cases to preserve critical anatomical structures such as the eyelid, nose, mouth and auricle. RESULTS: Overall local recurrence rate was 8.9% over a mean follow-up period of 71.3 months and a minimum of 60 months. Reducing margins of WLE did not increase local recurrence rates as demonstrated by local recurrence-free survival (90.4% vs. 91.9%, P = 0.806). CONCLUSION: Margins of WLE may be safely reduced in melanomas in close proximity to structures of the H&N without affecting local recurrence rates. PMID- 25712157 TI - Aortic valve replacement in a patient with ostegenesis imperfecta A case report. AB - AIM: Osteogenesis imperfecta (OI) is an inherited connective tissue disorder in which fragile bones readily cause fractures. Aortic root dilatation, aortic valve regurgitation and mitral valve prolapse are uncommon cardiovascular manifestations of OI. Cardiac surgery in these patients carries a high risk of complications due to increased tissue and capillary fragility. We describe an open heart surgery in a woman with isolated aortic valve regurgitation secondary to OI. MATERIAL OF STUDY: A 58-year-old woman was referred to our hospital for surgical correction of aortic valve regurgitation. She had a past history of recurrent long bone fractures, and OI was diagnosed in the childhood. A standard median sternotomy was performed; the sternum was found to be thin and brittle. The native aortic valve was replaced with a size 23 mm stented aortic bioprosthesis. The sternum was closed with stainless steel wires. RESULTS: The postoperative course was uneventful, and the patient was discharged home on the eighth postoperative day. We used thoracic band to avoid sternal diastasis. One year postoperatively, the echocardiogram showed a normal aortic bioprosthesis function without paravalvular leakage. The sternum was stable without dehiscence. DISCUSSION: The mortality rate in cardiac surgery patients with heritable generalized connective tissue disorders, such as osteogenesis imperfecta, is high. Although tissue friability had no impact on surgical outcome, it should be kept in mind when operating on patients with OI. CONCLUSIONS: We highlight the importance of a meticulous surgical technique, together with a strategy for management of anticipated perioperative complications to ensure a successful outcome. KEY WORDS: Aortic valve, Endocardirtis, Mitral valve, Replacement. PMID- 25712158 TI - First-line gemcitabine and oxaliplatin (GEMOX) plus sorafenib, followed by sorafenib as maintenance therapy, for patients with advanced hepatocellular carcinoma: a preliminary study. AB - BACKGROUND: Because of the poor prognosis of unresectable or metastatic hepatocellular carcinoma there is a need for effective systemic therapy. The purpose of this study was to assess the efficacy and safety of gemcitabine and oxaliplatin (GEMOX) combined with sorafenib, as first-line therapy, followed by sorafenib as maintenance therapy for patients with advanced hepatocellular carcinoma (HCC). METHODS: In this open-label, multicenter, single-group, prospective study, eligible patients with advanced HCC received oral sorafenib 400 mg twice daily, gemcitabine 1,000 mg/m(2) intravenously (i.v.) on day 1 and oxaliplatin 85 mg/m(2) i.v. on day 2 every 14 days for up to six cycles. Patients without disease progression were then treated further with sorafenib as maintenance therapy until disease progression. RESULTS: All forty-nine patients completed six cycles of combined GEMOX and sorafenib therapy. The objective response was 26.5 %. The median time to progression was 10.3 months (95 % CI: 8.7 11.9 months) and median overall survival was 15.7 months (95 % CI: 13.0-18.4 months). During the combination therapy, the most common grade 3/4 hematologic toxicity was neutropenia (22.4 %, 11/49 patients) and thrombocytopenia (14.3 %, 7/49 patients); grade 3/4 non-hematologic toxicity was fatigue (22.4 %, 11/49 patients) and appetite loss (18.4 %, 9/49 patients). During the maintenance therapy, grade 3/4 adverse events were nonhematologic toxicity, for example fatigue (16.0 %, 4/25 patients) and appetite loss (16.0 %, 4/25 patients). CONCLUSIONS: GEMOX combined with sorafenib as first-line therapy followed by sorafenib as maintenance therapy was effective with manageable toxicity for patients with advanced hepatocellular carcinoma. However, the results should be further validated in controlled phase II trials. PMID- 25712160 TI - Putative role of cationic amino acid transporter-3 in murine liver metabolism. PMID- 25712159 TI - Oncogenic human papillomavirus is not helpful for cytology screening of the precursor lesions of anal cancers in Taiwanese men who are infected with human immunodeficiency virus. AB - BACKGROUND: Homosexual men infected with human immunodeficiency virus (HIV) are at increased risk of developing anal cancer. The aim of this study was to assess the clinical sensitivity of anal cytology analysis and oncogenic human papillomavirus (HPV) detection for predicting histological anal intraepithelial neoplasia. METHODS: Between March 2011 and December 2013, we enrolled 196 HIV positive men in Taoyuan General Hospital, Taiwan. We analyzed the results of thin preparation anal Pap smears, HPV genotyping, and histology of anoscopic biopsy samples. RESULTS: The mean age (+/-standard deviation) was 31.43 (+/-8.74) years. The proportion (95 % confidence interval) with abnormal thin-preparation anal cytology was 36.2 % (29.8-43.2 %): 16.8 % (12.2-22.7 %) atypical squamous cells of undetermined significance, 14.8 % (10.5-20.4 %) low-grade squamous intraepithelial lesions, and 4.6 % (2.4-8.5 %) high-grade squamous intraepithelial lesions. At least one HPV genotype was detected in 90.8 % of subjects, and the mean number of HPV infection types was 4.41 (+/-3.24).The frequency of histological high-grade anal intraepithelial lesions was 7.14 % (95 % confidence interval 4.3-11.6 %). Anal cytology yielding atypical squamous cells of undetermined significance or higher grades resulted in a sensitivity of 64.3 %, specificity of 65.9 %, positive predictive value of 12.7 %, and negative predictive value of 96 %. Using both oncogenic HPV and cytology did not provide better performance. CONCLUSIONS: Anal cytology yielding atypical squamous cells of undetermined significance or higher grades could detect two-thirds of high grade anal intraepithelial neoplasias in HIV-infected men and should be promoted for anal cancer prevention. PMID- 25712162 TI - MRI for neurodevelopmental prognostication in the high-risk term infant. AB - MRI performed in the neonatal period has become a tool widely used by clinicians and researchers to evaluate the developing brain. MRI can provide detailed anatomical resolution, enabling identification of brain injuries due to various perinatal insults. This review will focus on the link between neonatal MRI findings and later neurodevelopmental outcomes in high-risk term infants. In particular, the role of conventional and advanced MR imaging in prognosticating outcomes in neonates with hypoxic-ischemic encephalopathy, ischemic perinatal stroke, need for extracorporeal membrane oxygenation life support, congenital heart disease, and other neonatal neurological conditions will be discussed. PMID- 25712161 TI - Design, synthesis, and kinetic analysis of potent protein N-terminal methyltransferase 1 inhibitors. AB - The protein N-terminal methyltransferase 1 (NTMT1) methylates the alpha-N terminal amines of proteins. NTMT1 is upregulated in a variety of cancers and knockdown of NTMT1 results in cell mitotic defects. Therefore, NTMT1 inhibitors could be potential anticancer therapeutics. This study describes the design and synthesis of the first inhibitor targeting NTMT1. A novel bisubstrate analogue (NAM-TZ-SPKRIA) was shown to be a potent inhibitor (Ki = 0.20 MUM) for NTMT1 and was selective versus protein lysine methyltransferase G9a and arginine methyltransferase 1. NAM-TZ-SPKRIA was found to exhibit a competitive inhibition pattern for both substrates, and mass spectrometry experiments revealed that the inhibitor substantially suppressed the methylation progression. Our results demonstrate the feasibility of using a triazole group to link an S-adenosyl-L methionine analog with a peptide substrate to construct bisubstrate analogues as NTMT1 potent and selective inhibitors. This study lays a foundation to further discover small molecule NTMT1 inhibitors to interrogate its biological functions, and suggests a general strategy for the development of selective protein methyltransferase inhibitors. PMID- 25712163 TI - Coordinated assembly of a new 3D mesoporous Fe3O4@Cu2O-graphene oxide framework as a highly efficient and reusable catalyst for the synthesis of quinoxalines. AB - A new three-dimensional (3D) mesoporous hybrid framework was synthesized by coordinated layer-by-layer assembly between nanosheets of reduced graphene oxide and Fe3O4@Cu2O. This 3D mesoporous framework shows an excellent catalytic performance with a remarkable activity, selectivity (>99%), and strong durability in the synthesis of quinoxalines. PMID- 25712164 TI - Single-walled carbon nanotubes functionalized with aptamer and piperazine polyethylenimine derivative for targeted siRNA delivery into breast cancer cells. AB - Epithelial cell adhesion molecule (EpCAM) is a glycosylated type 1 membrane protein which is frequently over expressed in most solid tumors and it has recently been identified as a cancer stem cell (CSC) marker. Specific targeting of CSCs using nano-carriers would enhance treatment efficacy of cancer. In this study, we used a RNA aptamer against EpCAM (EpDT3) attached physically to our newly synthesized non-viral vector, based on single-walled carbon nanotube (SWNT) conjugated to piperazine-polyethylenimine derivative. The DNA transfection efficiency and siRNA delivery activity of the synthesized vector was investigated against upregulated BCL9l, which has been associated with breast and colorectal cancers. The complexes of the vector-aptamer/siRNA could specifically induce apoptosis by more than 20% in MCF-7 cell line as a positive EpCAM than MDA-MB-231 cells which are EpCAM negative. The decrease of BCL9l protein level was observed with western blot analysis in MCF-7 cells indicating the targeted silencing activity of the complex. PMID- 25712165 TI - Low-temperature (77 K) phosphorescence of triplet chlorophyll in isolated reaction centers of photosystem II. AB - Phosphorescence characterized by the main emission band at 952 +/- 1 nm (1.30 eV), the lifetime of 1.5 +/- 0.1 ms and the quantum yield nearly equal to that for monomeric chlorophyll a in aqueous detergent dispersions, has been detected in isolated reaction centers (RCs) of spinach photosystem II at 77 K. The excitation spectrum shows maxima corresponding to absorption bands of chlorophyll a, pheophytin a, and beta-carotene. The phosphorescence intensity strongly depends upon the redox state of RCs. The data suggest that the phosphorescence signal originates from the chlorophyll triplet state populated via charge recombination in the radical pair [Formula: see text]. PMID- 25712166 TI - Integrated SnO2 nanorod array with polypyrrole coverage for high-rate and long life lithium batteries. AB - Conversion/alloying reactions, in which more lithium ions are involved, are severely handicapped by the dramatic volume changes. A facile and versatile strategy has been developed for integrating the SnO2 nanorod array in the PPy nanofilm for providing a flexible confinement for anchoring each nanorod and maintaining the entire structural integrity and providing sustainable contact; therefore, exhibiting much more stable cycling stability (701 mA h g(-1) after 300 cycles) and better high-rate capability (512 mA h g(-1) at 3 A g(-1)) when compared with the core-shell SnO2-PPy NA. PMID- 25712167 TI - Vegetation plop. PMID- 25712168 TI - Coronary microcirculation changes in non-ischemic dilated cardiomyopathy identified by novel perfusion CT. AB - Intramyocardial microvessels demonstrate functional changes in cardiomyopathies. However, clinical computed tomography (CT) does not have adequate spatial resolution to assess the microvessels. Our hypothesis is that these functional changes manifest as altered heterogeneity of the spatial distribution of arteriolar perfusion territories. Our goal was to determine whether the spatial analysis of perfusion CT could clinically detect changes in the function and structure of the intramyocardial microcirculation in a non-ischemic dilated cardiomyopathy (DCM). Two groups were studied: (1) a Control group (12 male plus 12 female) with no risk factors nor evidence of coronary artery disease, and (2) a DCM group (12 male plus 12 female) with left ventricular ejection fraction <=40% and no evidence of coronary artery disease. Using the CT scan, the LV free wall thickness and its radius of curvature were measured. The DCM group was sub divided into those with LV free wall thickness <11.5 mm and those with thickness >=11.5 mm. In the myocardial opacification phase of the CT scan sequence, myocardial perfusion (F) and intramyocardial blood volume (Bv) for multiple intramyocardial regions were computed. No significant differences between the groups were demonstrable in overall myocardial F or Bv. However, the myocardial regional data showed significantly increased spatial heterogeneity in the DCM group when compared to the Control group. The findings demonstrate that altered function of the subresolution intramyocardial microcirculation can be quantified with myocardial perfusion CT and that significant changes in these parameters occur in the DCM subjects with LV wall thickness greater than 11.5 mm. PMID- 25712169 TI - Composite Pain Index: Reliability, Validity, and Sensitivity of a Patient Reported Outcome for Research. AB - OBJECTIVE: A single score that represents the multidimensionality of pain would be an innovation for patient-reported outcomes. Our aim was to determine the reliability, validity, and sensitivity of the Composite Pain Index (CPI). DESIGN: Methodological analysis of data from a randomized controlled, pretest/post-test education-based intervention study. SETTING: The study was conducted in outpatient oncology clinics. SUBJECTS: The 176 subjects had pain, were 52 +/- 12.5 years on average, 63% were female, and 46% had stage IV cancers. METHODS: We generated the CPI from pain location, intensity, quality, and pattern scores measured with an electronic version of Melzack's McGill Pain Questionnaire. RESULTS: The internal consistency values for the individual scores comprising the CPI were adequate (0.71 baseline, 0.69 post-test). Principal components analysis extracted one factor with an eigenvalue of 2.17 with explained variance of 54% at baseline and replicated the one factor with an eigenvalue of 2.11 at post-test. The factor loadings for location, intensity, quality, and pattern were 0.65, 0.71, 0.85, and 0.71, respectively (baseline), and 0.59, 0.81, 0.84, and 0.63, respectively (post-test). The CPI was sensitive to an education intervention effect. CONCLUSIONS: Findings support the CPI as a score that integrates the multidimensional pain experience in people with cancer. It could be used as a patient-reported outcome measure to quantify the complexity of pain in clinical research and population studies of cancer pain and studied for relevance in other pain populations. PMID- 25712170 TI - Axonal myelin increase in the callosal genu in depression but not schizophrenia. AB - BACKGROUND: Abnormalities in the anterior inter-hemispheric connectivity have previously been implicated in major depressive disorder. Disruptions in fractional anisotropy in the callosum and fornix have been reported in schizophrenia and major depressive disorder. Oligodendrocyte density and overall size of the callosum and fornix show no alteration in either illness, suggesting that gross morphology is unchanged but more subtle organizational disruption may exist within these brain regions in mood and affective disorders. METHOD: Using high-resolution oil-immersion microscopy we examined the cross-sectional area of the nerve fibre and the axonal myelin sheath, and using standard high-resolution light microscopy we measured the density of myelinated axons. These measurements were made in the genu of the corpus callosum and the medial body of the fornix at its most dorsal point. Measures were taken in the sagittal plane in the callosal genu and in the coronal plane at the most dorsal part of the fornix body. RESULTS: Cases of major depressive disorder had significantly greater mean myelin cross-sectional area (p = 0.017) and myelin thickness (p = 0.004) per axon in the genu than in control or schizophrenia groups. There was no significant change in the density of myelinated axons, and no changes observed in the fornix. CONCLUSION: The results suggest a clear increase of myelin in the axons of the callosal genu in MDD, although this type of neuropathological study is unable to clarify whether this is caused by changes during life or has a developmental origin. PMID- 25712171 TI - New ischaemic brain lesions in cervical artery dissection stratified to antiplatelets or anticoagulants. AB - BACKGROUND AND PURPOSE: To determine the frequency of new ischaemic or hemorrhagic brain lesions on early follow-up magnetic resonance imaging (MRI) in patients with cervical artery dissection (CAD) and to investigate the relationship with antithrombotic treatment. METHODS: This prospective observational study included consecutive CAD patients with ischaemic or non ischaemic symptoms within the preceding 4 weeks. All patients had baseline brain MRI scans at the time of CAD diagnosis and follow-up MRI scans within 30 days thereafter. Ischaemic lesions were detected by diffusion-weighted imaging (DWI), intracerebral bleeds (ICBs) by paramagnetic-susceptible sequences. Outcome measures were any new DWI lesions or ICBs on follow-up MRI scans. Kaplan-Meier statistics and calculated odds ratios with 95% confidence intervals were used for lesion occurrence, baseline characteristics and type of antithrombotic treatment (antiplatelet versus anticoagulant). RESULTS: Sixty-eight of 74 (92%) CAD patients were eligible for analysis. Median (interquartile range) time interval between baseline and follow-up MRI scans was 5 (3-10) days. New DWI lesions occurred in 17 (25%) patients with a cumulative 30-day incidence of 41.3% (standard error 8.6%). Occurrence of new DWI lesions was associated with stroke or transient ischaemic attack at presentation [7.86 (2.01-30.93)], occlusion of the dissected vessel [4.09 (1.24-13.55)] and presence of DWI lesions on baseline MRI [6.67 (1.70-26.13)]. The type of antithrombotic treatment had no impact either on occurrence of new DWI lesions [1.00 (0.32-3.15)] or on functional 6 month outcome [1.27 (0.41-3.94)]. No new ICBs were observed. CONCLUSION: New ischaemic brain lesions occurred in a quarter of CAD patients, independently of the type of antithrombotic treatment. MRI findings could potentially serve as surrogate outcomes in pilot treatment trials. PMID- 25712174 TI - Type 4 phosphodiesterase enzyme inhibitor, rolipram rescues behavioral deficits in olfactory bulbectomy models of depression: Involvement of hypothalamic pituitary-adrenal axis, cAMP signaling aspects and antioxidant defense system. AB - Olfactory bulbectomy (OBX) model has been proposed as a well documented model of depression. Accumulated evidences suggest that cAMP selective PDE4 enzyme plays an important role in the pathophysiology of depression disorder. Moreover, PDE4 inhibitors have shown antidepressant-like effect in behavioral despair models. However, the potential of PDE4 inhibitors to produce antidepressant-like effect in OBX model and their underlying mechanism(s) has not been adequately addressed. The present study was designed to investigate the possible antidepressant-like effects and underlying mechanism of rolipram in OBX model. The effects of rolipram were measured in a battery of behavioral paradigms, including hyperactivity in open field test (OFT), anhedonia behavior in sucrose consumption test, open arm activity in elevated plus maze test (EPM) and emotional scores in hyperemotionality test. The underlying signaling mechanisms were also investigated by measuring serum corticosterone (CORT), brain-derived neurotrophic factor (BDNF) and brain oxidant/antioxidant levels. Treatment with rolipram (0.5 and 1mg/kg, p.o., 14days) significantly improved the behavioral anomalies (decreased the hyperactivity, open arm activity and hyperemotionality scores, whereas, increased sucrose consumption). Further, rolipram significantly decreased the CORT level and increased cAMP, pCREB and BDNF levels. Additionally, rolipram reduced oxidative-nitrosative stress markers (lipid peroxidation and nitrite levels) and restored the antioxidant enzyme level, including reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT), indicating attenuation of oxidative-nitrosative stress. Our results revealed that antidepressant-like effects of rolipram in OBX model may be mediated by modulating the hypothalamic-pituitary-adrenal (HPA) axis activity, increasing the cAMP signaling aspects and restoring the antioxidant mechanisms. PMID- 25712173 TI - Alcohol preferring (P) rats as a model for examining sex differences in alcohol use disorder and its treatment. AB - RATIONALE: Despite epidemiological and clinical data indicating marked gender differences in alcohol use disorders (AUDs), few preclinical studies have examined sex differences in animal models of AUDs. OBJECTIVE: The purpose of this study was to first characterize sex differences in ethanol consumption and reinforcement in an alcohol preferring (P) rat model of alcoholism, then use this model to screen pharmacological treatments for sex-specific effects. METHODS: Ethanol consumption was first assessed in male and female P rats under a three bottle free-choice procedure. Next, ethanol's reinforcing effects were assessed under a fixed-ratio 1 (FR1) schedule followed by a progressive-ratio (PR) schedule. Finally, the effects of two pharmacological treatments for AUDs, naltrexone (1mg/kg) and topiramate (10 or 20mg/kg), alone and in combination, were tested for sex-specific differences in their efficacy at reducing ethanol's reinforcing effects. RESULTS: Although females initially had higher consumption of and preference for ethanol, male rats increased their consumption and preference over time and rapidly became equal to females. Following prolonged 24 hour/day access, males and females self-administered similar levels of ethanol under FR1 and PR schedules. In response to pharmacological treatment, we observed some sex differences and similarities, most notably, a more robust effect of the combination of naltrexone and topiramate in males as compared to females. CONCLUSIONS: This model of selectively bred P rats may be useful for understanding sex differences in AUDs and related behavior and their underlying neurobiological mechanisms and treatment. PMID- 25712175 TI - Pharmacological mechanism underlying the antinociceptive activity of vanillic acid. AB - Vanillic acid is found at high concentrations in many plants used in traditional medicine. It has been associated with a variety of pharmacologic activities such as carcinogenesis inhibition, apoptosis and inflammation; however, it has become most popular for its pleasant creamy odor. Since there are few reports concerning the antinociceptive activity of this phenolic compound, the aim of this work was to study this activity in in vivo animal models. Vanillic acid was administered by the intraperitoneal route producing a dose-dependent inhibition of the acetic acid-induced writhing response (ED50: 9.3mg/kg). The antinociceptive activity was inhibited by the pretreatment with ondansetron and yohimbine, indicating that the serotoninergic and adrenergic systems could participate in the mechanism underlying the analgesic activity of vanillic acid. This compound was also demonstrated to interact with ASICs (Acid-sensing Ion Channels) as well as with TPRV1, TRPA1, and TRPM8 receptors in vivo. Furthermore, vanillic acid did not interfere with the locomotor function or motor coordination. The plasmatic phenolic content, analyzed by HPLC, showed that its t1/2 and AUC were 0.123h and 1.38MUg.h/mL; respectively. In conclusion, vanillic acid might represent a potential therapeutic option for the treatment of pain. PMID- 25712176 TI - The origin of turtles: a paleontological perspective. AB - The origin of turtles and their unusual body plan has fascinated scientists for the last two centuries. Over the course of the last decades, a broad sample of molecular analyses have favored a sister group relationship of turtles with archosaurs, but recent studies reveal that this signal may be the result of systematic biases affecting molecular approaches, in particular sampling, non randomly distributed rate heterogeneity among taxa, and the use of concatenated data sets. Morphological studies, by contrast, disfavor archosaurian relationships for turtles, but the proposed alternative topologies are poorly supported as well. The recently revived paleontological hypothesis that the Middle Permian Eunotosaurus africanus is an intermediate stem turtle is now robustly supported by numerous characters that were previously thought to be unique to turtles and that are now shown to have originated over the course of tens of millions of years unrelated to the origin of the turtle shell. Although E. africanus does not solve the placement of turtles within Amniota, it successfully extends the stem lineage of turtles to the Permian and helps resolve some questions associated with the origin of turtles, in particular the non composite origin of the shell, the slow origin of the shell, and the terrestrial setting for the origin of turtles. PMID- 25712177 TI - Private healthcare providers in India are above the law, leaving patients without protection. PMID- 25712178 TI - Whistleblowing in India: what protections can doctors who raise concerns expect? PMID- 25712179 TI - India's private healthcare sector treats patients as revenue generators. PMID- 25712180 TI - Semilobar Holoprosencephaly Associated with Multiple Malformations in a Foal. AB - A full-term male foal born in a farm holidays in Maremma (Tuscany, Italy) was euthanized shortly after birth due to the presence of several malformations. The rostral maxilla and the nasal septum were deviated to the right (wry nose), and a severe cervico-thoracic scoliosis and anus atresia were evident. Necropsy revealed ileum atresia and agenesis of the right kidney. The brain showed an incomplete separation of the hemispheres of the rostral third of the forebrain and the olfactory bulbs and tracts were absent (olfactory aplasia). A diagnosis of semilobar holoprosencephaly (HPE) was achieved. This is the first case of semilobar HPE associated with other organ anomalies in horses. PMID- 25712181 TI - Expansion of pharmacogenomics into the community pharmacy: billing considerations. PMID- 25712182 TI - Effect of clinical factors and gene polymorphism of CYP2C19*2, *17 and CYP4F2*3 on early stent thrombosis. AB - AIM: To determine the main clinical and genetic factors having impact on early coronary stent thrombosis. MATERIALS & METHODS: Genotyping of CYP2C19*2, *17 and CYP4F2*3 in patients with (n = 31) and without stent thrombosis (n = 456) was performed. Clinical and genetic data were analyzed by binary logistic regression. RESULTS: Smoking (OR: 0.317; 95% CI: 0.131-0.767), high-density lipoprotein level in mmol/l (OR: 0.142; 95% CI: 0.040-0.506), CYP2C19*2*2 versus *1*1 and *1*2 genotype (OR: 11.625; 95% CI: 3.498-38.633), CYP4F2 AA versus GA and GG genotype (OR: 3.532; 95% CI: 1.153-10.822) were associated with early stent thrombosis. CONCLUSION: For the first time we have identified a clinically important polymorphism (CYP4F2 G1347A) that was independently associated with early stent thrombosis. Original submitted 18 August 2014; Revision submitted 10 November 2014. PMID- 25712183 TI - Genetic polymorphism in ATG16L1 gene influences the response to adalimumab in Crohn's disease patients. AB - AIM: To see if SNPs could help predict response to biological therapy using adalimumab (ADA) in Crohn's disease (CD). MATERIALS & METHODS: IBDQ index and CRP levels were used to monitor therapy response. We genotyped 31 CD-associated genes in 102 Slovenian CD patients. RESULTS: The strongest association for treatment response defined as decrease in CRP levels was found for ATG16L1 SNP rs10210302. Additional SNPs in 7 out of 31 tested CD-associated genes (PTGER4, CASP9, IL27, C11orf30, CCNY, IL13, NR1I2) showed suggestive association with ADA response. CONCLUSION: Our results suggest ADA response in CD patients is genetically predisposed by SNPs in CD risk genes and suggest ATG16L1 as most promising candidate gene for drug response in ADA treatment. Original submitted 24 September 2014; Revision submitted 1 December 2014. PMID- 25712184 TI - Genetic variations in NADPH-CYP450 oxidoreductase in a Czech Slavic cohort. AB - AIM: Estimating polymorphic allele frequencies of the NADPH-CYP450 oxidoreductase (POR) gene in a Czech Slavic population. METHODS: The POR gene was analyzed in 322 individuals from a control cohort by sequencing and high resolution melting analysis. RESULTS: We identified seven unreported SNP genetic variations, including two SNPs in the 5' flanking region (g.4965C>T and g.4994G>T), one intronic variant (c.1899-20C>T), one synonymous SNP (p.20Ala=) and three nonsynonymous SNPs (p.Thr29Ser, p.Pro384Leu and p.Thr529Met). The p.Pro384Leu variant exhibited reduced enzymatic activities compared with wild-type. CONCLUSION: New POR variant identification indicates the number of uncommon variants might be specific for each subpopulation being investigated, particularly germane to the singular role that POR plays in providing reducing equivalents to all CYP450s in the endoplasmic reticulum. Original submitted 15 September 2014; Revision submitted 17 November 2014. PMID- 25712185 TI - Factors influencing pharmacokinetics of warfarin in African-Americans: implications for pharmacogenetic dosing algorithms. AB - AIM: This study attempted to identify predictors of S-warfarin clearance (CL[S]) and to make a pharmacokinetic evaluation of genotype-based dosing algorithms in African-Americans. METHODS: Using plasma S-warfarin concentration (Cp[S]) at a steady state and eight SNPs previously shown to influence warfarin dose in African-Americans, CL(S) and its predictors were estimated by population pharmacokinetic analysis in 60 African-Americans. The time courses of Cp(S) following either the loading dose or maintenance dose were simulated using the population pharmacokinetic estimates. RESULTS: CYP2C9*8 and body surface area or body weight were predictors of CL(S) (-30 and -5% per -0.1 m(2)/-10 kg reduction in CL[S], respectively) in African-Americans. Simulations of Cp(S) showed that Cp(S) at steady state was 1.4-times higher in patients with CYP2C9*8 than in those with CYP2C9*1/*1, irrespective of the algorithm for loading dose or maintenance dose. CONCLUSION: African-Americans possess independent predictors of CL(S), possibly leading to a prediction error of any dosing algorithm that excludes African-specific variant(s). Original submitted 3 September 2014; Revision submitted 3 November 2014. PMID- 25712186 TI - Pharmacogenomics in diverse practice settings: implementation beyond major metropolitan areas. AB - AIM: The limited formal study of the clinical feasibility of implementing pharmacogenomic tests has thus far focused on providers at large medical centers in urban areas. Our research focuses on small metropolitan, rural and tribal practice settings. MATERIALS & METHODS: We interviewed 17 healthcare providers in western Montana regarding pharmacogenomic testing. RESULTS: Participants were optimistic about the potential of pharmacogenomic tests, but noted unique barriers in small and rural settings including cost, adherence, patient acceptability and testing timeframe. Participants in tribal settings identified heightened sensitivity to genetics and need for community leadership approval as additional considerations. CONCLUSION: Implementation differences in small metropolitan, rural and tribal communities may affect pharmacogenomic test adoption and utilization, potentially impacting many patients. Original submitted 3 September 2014; Revision submitted 3 December 2014. PMID- 25712187 TI - Donor IL-18 rs5744247 polymorphism as a new biomarker of tacrolimus elimination in Chinese liver transplant patients during the early post-transplantation period: results from two cohort studies. AB - AIM: This study evaluated the relationships between IL-18 polymorphisms and tacrolimus elimination in Chinese liver transplant patients. PATIENTS & METHODS: Eighty-four liver transplant patients from Shanghai (training set) and 50 patients from Shandong (validating set) were inculded. IL-18 polymorphisms (rs5744247, rs7106524, rs549908, rs187238 and rs1946518) and CYP3A5 rs776746 were genotyped. RESULTS: In training set, daily drug dose, total bilirubin, donor CYP3A5 rs776746 and IL-18 rs5744247 genotypes were screened to construct prediction model for tacrolimus elimination. This model was confirmed in validating set (p < 0.001). Donor IL-18 rs5744247 polymorphism was an independent predictor of tacrolimus elimination in the first week after transplantation in both training (p = 0.008) and validating cohorts (p = 0.033). CONCLUSION: Donor IL-18 rs5744247 polymorphism may influence on tacrolimus elimination. Original submitted 16 July 2014; Revision submitted 12 November 2014. PMID- 25712188 TI - Nurses' communication of pharmacogenetic test results as part of discharge care. AB - As pharmacogenetic (PGx) testing is becoming integrated into routine clinical procedures for admitted hospital patients, consideration is needed as to when test results will be communicated to patients and by whom. Given the implications of PGx test results for current and future care, we propose that if results are not promptly discussed with patients when testing is completed, results should be discussed with patients during discharge care when possible, included in the printed or electronic discharge summary and a copy of the results sent to their primary provider. Nurses play an important role in discharge planning and care by providing patients with the necessary information and support to transfer from the hospital setting to an outpatient setting or to return to home and work. To promote nurses' ability to fulfill the role of communicating PGx test results, revised curricula and interprofessional and clinical decision support are needed. PMID- 25712189 TI - Targeting HER family in HER2-positive metastatic breast cancer: potential biomarkers and novel targeted therapies. AB - HER2-targeted therapies have radically changed the prognosis of HER2-positive breast cancer over the last few years. However, resistance to these therapies has been a constant, leading to treatment-failure and new tumor progression. Recently, the kinase-impaired HER3 emerged as a pivotal player in oncogenic signaling, with an important role in both non-treated progression and treatment response. HER2/HER3 dimerization is required for full signaling potential and constitutes the key oncogenic unit. Also, when inhibiting PI3K/AKT pathway (as with anti-HER2 drugs) feedback mechanisms lead to a rebound in HER3 activity, which is one of the main roads to resistance. As current strategies to treat HER2 positive breast cancer are unable to inhibit this feedback response, two great promises emerged: the combination of targeted-therapies and drugs targeting HER3. In this article HER2 and HER3-targeted drugs and possible combinations between them, as well as the biomarkers to predict and monitor these drugs effect, are reviewed. PMID- 25712192 TI - Designing responsive pattern generators: stable heteroclinic channel cycles for modeling and control. AB - A striking feature of biological pattern generators is their ability to respond immediately to multisensory perturbations by modulating the dwell time at a particular phase of oscillation, which can vary force output, range of motion, or other characteristics of a physical system. Stable heteroclinic channels (SHCs) are a dynamical architecture that can provide such responsiveness to artificial devices such as robots. SHCs are composed of sequences of saddle equilibrium points, which yields exquisite sensitivity. The strength of the vector fields in the neighborhood of these equilibria determines the responsiveness to perturbations and how long trajectories dwell in the vicinity of a saddle. For SHC cycles, the addition of stochastic noise results in oscillation with a regular mean period. In this paper, we parameterize noise-driven Lotka-Volterra SHC cycles such that each saddle can be independently designed to have a desired mean sub-period. The first step in the design process is an analytic approximation, which results in mean sub-periods that are within 2% of the specified sub-period for a typical parameter set. Further, after measuring the resultant sub-periods over sufficient numbers of cycles, the magnitude of the noise can be adjusted to control the mean period with accuracy close to that of the integration step size. With these relationships, SHCs can be more easily employed in engineering and modeling applications. For applications that require smooth state transitions, this parameterization permits each state's distribution of periods to be independently specified. Moreover, for modeling context dependent behaviors, continuously varying inputs in each state dimension can rapidly precipitate transitions to alter frequency and phase. PMID- 25712191 TI - Pharmacogenomics toward personalized tamoxifen therapy for breast cancer. AB - Tamoxifen has been used not only for the treatment or prevention of recurrence in patients with estrogen receptor positive breast cancers but also for recurrent breast cancer. Because CYP2D6 is known to be an important enzyme responsible for the generation of the potent tamoxifen metabolite, 'endoxifen', lots of studies reported that genetic variation which reduced its enzyme activity were associated with poor clinical outcome of breast cancer patients treated with tamoxifen. However, there are some discrepant reports questioning the association between CYP2D6 genotype and clinical outcome after tamoxifen therapy. Dose-adjustment study of tamoxifen based on CYP2D6 genotypes provides the evidence that dose adjustment is useful for the patients carrying reduced or null allele of CYP2D6 to maintain the effective endoxifen level. This review describes critical issues in pharmacogenomic studies as well as summarizes the results of the association of CYP2D6 genotype with tamoxifen efficacy. PMID- 25712190 TI - In vitro human cell line models to predict clinical response to anticancer drugs. AB - In vitro human cell line models have been widely used for cancer pharmacogenomic studies to predict clinical response, to help generate pharmacogenomic hypothesis for further testing, and to help identify novel mechanisms associated with variation in drug response. Among cell line model systems, immortalized cell lines such as Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines (LCLs) have been used most often to test the effect of germline genetic variation on drug efficacy and toxicity. Another model, especially in cancer research, uses cancer cell lines such as the NCI-60 panel. These models have been used mainly to determine the effect of somatic alterations on response to anticancer therapy. Even though these cell line model systems are very useful for initial screening, results from integrated analyses of multiple omics data and drug response phenotypes using cell line model systems still need to be confirmed by functional validation and mechanistic studies, as well as validation studies using clinical samples. Future models might include the use of patient-specific inducible pluripotent stem cells and the incorporation of 3D culture which could further optimize in vitro cell line models to improve their predictive validity. PMID- 25712193 TI - Cell culture on microfabricated one-dimensional polymeric structures for bio actuator and bio-bot applications. AB - Here, we present the development, characterization and quantification of a novel 1D/2D like polymeric platform for cell culture. The platform consists of a 2D surface anchoring a long (few millimeters) narrow filament (1D) with a single cell scale (micro scale) cross section. We plate C2C12 cells on the platform and characterize their migration, proliferation, and differentiation patterns in contrast to 2D culture. We find that the cells land on the 2D surface, and then migrate to the filament only when the 2D surface has become nearly confluent. Individual and isolated cells randomly approaching the filament always retract away towards the 2D surface. Once on the filament, their differentiation to myotubes is expedited compared to that on 2D substrate. The myotubes generate periodic twitching forces that deform the filament producing more than 17 MUm displacement at the tip. Such flagellar motion can be used to develop autonomous micro scale bio-bots. PMID- 25712195 TI - Enterocytozoon bieneusi in Dairy Cattle in the Northeast of China: Genetic Diversity of ITS Gene and Evaluation of Zoonotic Transmission Potential. AB - Enterocytozoon bieneusi is the most frequently diagnosed microsporidian species in humans. It has been found in a wide range of animals and is considered an important zoonotic pathogen. To date, little information is available on the role that cattle play in the epidemiology of human microsporidiosis caused by E. bieneusi in China. In this study, 133 fecal specimens from dairy cattle were collected in Heilongjiang Province, China. Enterocytozoon bieneusi was identified and genotyped by nested PCR analysis of the internal transcribed spacer (ITS) region of the rRNA gene, with 30.1% positive. Nine ITS genotypes were identified: six known genotypes-O (n = 26), EbpA (n = 2), I (n = 2), J (n = 2), D (n = 1) and BEB4 (n = 1)-and three novel genotypes named as CC-I to CC-III (two each). Genotype O was identified in cattle for the first time. The observation of all the six known genotypes here reported previously in humans, and also the fact of all the three novel genotypes (CHN-DC1 to CHN-DC3) falling into zoonotic group 1, indicate the possibility of cattle in the transmission of E. bieneusi to humans. PMID- 25712194 TI - Dynamic variation of the microbial community structure during the long-time mono fermentation of maize and sugar beet silage. AB - This study investigated the development of the microbial community during a long term (337 days) anaerobic digestion of maize and sugar beet silage, two feedstocks that significantly differ in their chemical composition. For the characterization of the microbial dynamics, the community profiling method terminal restriction fragment length polymorphism (TRFLP) in combination with a cloning-sequencing approach was applied. Our results revealed a specific adaptation of the microbial community to the supplied feedstocks. Based on the high amount of complex compounds, the anaerobic conversion rate of maize silage was slightly lower compared with the sugar beet silage. It was demonstrated that members from the phylum Bacteroidetes are mainly involved in the degradation of low molecular weight substances such as sugar, ethanol and acetate, the main compounds of the sugar beet silage. It was further shown that species of the genus Methanosaeta are highly sensitive against sudden stress situations such as a strong decrease in the ammonium nitrogen (NH4(+)-N) concentration or a drop of the pH value. In both cases, a functional compensation by members of the genera Methanoculleus and/or Methanosarcina was detected. However, the overall biomass conversion of both feedstocks proceeded efficiently as a steady state between acid production and consumption was recorded, which further resulted in an equal biogas yield. PMID- 25712197 TI - Fast imaging strategies for mouse kidney perfusion measurement with pseudocontinuous arterial spin labeling (pCASL) at ultra high magnetic field (11.75 tesla). AB - BACKGROUND: To derive an adapted protocol at ultra high magnetic field for mouse kidney perfusion measurements using pCASL in combination with three widely available fast imaging readouts: segmented SE EPI (sSE EPI), RARE, and TrueFISP. METHODS: pCASL sSE EPI, pCASL RARE, and pCASL TrueFISP were used for the acquisition of mouse kidney perfusion images in the axial and coronal planes at 11.75T. Results were compared in terms of perfusion sensitivity, signal-to-noise ratio (SNR), blood flow values, intrasession and intersession repeatability, and image quality (subjectively classified into three grades: good, satisfactory, and unacceptable). RESULTS: Renal cortex perfusion measurements were performed within 2 min with pCASL RARE/pCASL TrueFISP and 4 min with pCASL sSE EPI. In an axial direction, SNR values of 6.6/5.6/2.8, perfusion sensitivity values of 16.1 +/- 3.7/13.6 +/- 2.4/13.4 +/- 1.0 %, blood flow values of 679 +/- 149/466 +/- 111/572 +/- 46 mL/100 g/min and in-ROI variations values of 192/161/181 mL/100 g/min were obtained with pCASL sSE EPI/pCASL RARE/pCASL TrueFISP. Highest SNR per unit of time (1.8) and highest intra/intersession reliability (92.9% and 95.1%) were obtained with pCASL RARE, which additionally presented highly reproducible satisfactory image quality. In coronal plane, significantly lower SNR, perfusion sensitivity and perfusion values were obtained for all techniques compared with that in the axial plane (P < 0.05) due to magnetization saturation effects. CONCLUSION: pCASL RARE demonstrated more advantages for longitudinal preclinical kidney perfusion studies at ultra high magnetic field. PMID- 25712196 TI - Germline deletions in the tumour suppressor gene FOCAD are associated with polyposis and colorectal cancer development. AB - Heritable genetic variants can significantly affect the lifetime risk of developing cancer, including polyposis and colorectal cancer (CRC). Variants in genes currently known to be associated with a high risk for polyposis or CRC, however, explain only a limited number of hereditary cases. The identification of additional genetic causes is, therefore, crucial to improve CRC prevention, detection and treatment. We have performed genome-wide and targeted DNA copy number profiling and resequencing in early-onset and familial polyposis/CRC patients, and show that deletions affecting the open reading frame of the tumour suppressor gene FOCAD are recurrent and significantly enriched in CRC patients compared with unaffected controls. All patients carrying FOCAD deletions exhibited a personal or family history of polyposis. RNA in situ hybridization revealed FOCAD expression in epithelial cells in the colonic crypt, the site of tumour initiation, as well as in colonic tumours and organoids. Our data suggest that monoallelic germline deletions in the tumour suppressor gene FOCAD underlie moderate genetic predisposition to the development of polyposis and CRC. PMID- 25712198 TI - Reversible modification of the structural and electronic properties of a boron nitride monolayer by CO intercalation. AB - We demonstrate the reversible intercalation of CO between a hexagonal boron nitride (h-BN) monolayer and a Rh(111) substrate above a threshold CO pressure of 0.01 mbar at room temperature. The intercalation of CO results in the flattening of the originally corrugated h-BN nanomesh and an electronic decoupling of the BN layer from the Rh substrate. The intercalated CO molecules assume a coverage and adsorption site distribution comparable to that on the free Rh(111) surface at similar conditions. The pristine h-BN nanomesh is reinstated upon heating to above 625 K. These observations may open up opportunities for a reversible tuning of the electronic and structural properties of monolayer BN films. PMID- 25712199 TI - Monosegment ALPPS hepatectomy: extending resectability by rapid hypertrophy. AB - BACKGROUND: Liver remnant function limits major liver resections to generally leave patients with >=2 Couinaud segments. Associating Liver Partition and Portal vein ligation for Staged hepatectomy (ALPPS) induces extensive hypertrophy and allows surgeons to perform extreme liver resections. METHODS: The international ALPPS registry (NCT01924741; 2011-2014) was screened for novel resection type with only 1 segment remnant. The anatomy of lesions and indications for ALPPS, operative technique, complications, survival, and recurrence were evaluated. RESULTS: Among 333 patients, 12 underwent monosegment ALPPS hepatectomies in 6 centers, all for extensive bilobar colorectal liver metastases. All patients were considered unresectable by conventional means, and all had a response to or no progression after chemotherapy before surgery. In 2 patients, the liver remnant consisted of segment 2, in 2 of segment 3, in 6 of segment 4, and in 2 of segment 6. Median time to proceed to stage 2 was 13 days and median hypertrophy of the liver remnant was 160%. There was no mortality. Four patients experienced liver failure, but all recovered. Complications higher than Dindo-Clavien IIIa occurred in 4 patients with no long-term sequelae. At a median follow-up of 14 months, 6 patients are tumor free and 6 patients have developed recurrent metastatic disease. CONCLUSION: ALPPS allows systematic liver resections with monosegment remnants, a novelty in liver surgery. Because such resections are difficult to conceive without rapid hypertrophy, we propose to name such resections after the segments constituting the liver remnant rather than the segments removed. PMID- 25712200 TI - Validation and improvement of a proposed scoring system to detect retained common bile duct stones in gallstone pancreatitis. AB - BACKGROUND: In 2009, a study from our institution used retrospective data and multivariate analysis to identify 5 quantitative variables and their cutoffs that have a positive predictive value (PPV) for common bile duct (CBD) stones in gallstone pancreatitis. They also proposed a management protocol based on the scoring system. This prospective study sought to validate that scoring system. METHODS: From October 2009 to August 2013, patients with gallstone pancreatitis were enrolled in the study. Scores of 0-5 were determined at admission, with 1 point for each criterion met: CBD >= 9 mm, gamma glutamyltransferase >= 350 U/L, alkaline phosphatase >= 250 U/L, total bilirubin >= 3 mg/dL, and direct bilirubin >= 2 mg/dL. All CBDs were assessed using intraoperative cholangiogram, MR cholangiopancreatography (MRCP), or endoscopic retrograde cholangiopancreatography (ERCP). RESULTS: Of 84 patients, 16 had CBD stones. A score of 0 had negative predictive value (NPV) of 100% for CBD stones (P < .001). Scores of 1 and 2 had NPV of 81% and 83%, respectively. A score of 3 had NPV of 60%. A score of 4 had PPV of 67% (P = .002). A score of 5 had PPV of 100% (P < .001). The overall accuracy of the scoring system was 88%. CONCLUSION: The scoring system is accurate in prediction of CBD stones in patients with gallstone pancreatitis. We propose that patients with 0 points undergo laparoscopic cholecystectomy, 1 and 2 points undergo laparoscopic cholecystectomy with intraoperative cholangiogram, 3 and 4 points undergo MRCP, and 5 points undergo ERCP as the first step in management for gallstone pancreatitis. The proposed protocol eliminated negative ERCPs. PMID- 25712201 TI - Ex vivo resection of giant epidermoid cyst and vascularized partial splenic autotransplantation: 3.5-year follow-up. PMID- 25712202 TI - Cancer-Related Information Seeking Among Cancer Survivors: Trends Over a Decade (2003-2013). AB - The demonstrated benefits of information seeking for cancer patients, coupled with increases in information availability, underscore the importance of monitoring patient information seeking experiences over time. We compared information seeking among cancer survivors to those with a family history of cancer and those with no history of cancer. We identified characteristics associated with greater information seeking among cancer survivors, key sources of cancer-related information, and changes in information source use over time. Data from five iterations of the Health Information National Trends Survey (HINTS) spanning 2003 to 2013 were merged and analyzed. Frequencies, cross tabulations, multivariate logistic regression, and multinomial regression analyses were conducted. All data were weighted to provide representative estimates of the adult US population. Cancer information seeking was reported most frequently by cancer survivors (69.8 %). The percentage of cancer survivors who reported information seeking increased from 66.8 % in 2003 to 80.8 % in 2013. Cancer information seeking was independently associated with age, education, and income; seeking was less likely among older adults, those with less education, and those with lower incomes. Compared to respondents in 2003, those in 2005 (odds ratio (OR) = 0.40, 95 % confidence interval (CI) = 0.24-0.65) and 2008 (OR = .43, 95 % CI = 0.26-0.70) were about half as likely to use the Internet as the first source of cancer information compared to a healthcare provider. Despite overall increases in cancer information seeking and access to health information from a variety of sources, healthcare providers remain a key source of health information for cancer survivors. PMID- 25712203 TI - Spread of an Enterococcus faecalis sequence type 6 (CC2) clone in patients undergoing selective decontamination of the digestive tract. AB - Enterococcus faecalis (E. faecalis) is a common cause of nosocomial infection in immunocompromised patients. The presence and dissemination of high-risk clonal complexes, such as CC2, is an ongoing problem in hospitals. The aim of this work was to characterize 24 E. faecalis isolates from ICU patients undergoing selective decontamination of the digestive tract (SDD) by phenotypical (antimicrobial susceptibility) and genotypical (presence of virulence genes, RAPD PCR and MLST) methods. Our results showed high prevalence of the ST6 E. faecalis clone (91.6%), especially adapted to the hospital environment, with a multidrug resistance pattern and a multitude of putative virulence genes. In addition, ST179 (4.2%) and ST191 (4.2%) were detected. By RAPD-PCR analysis, the 22 isolates identified as ST6 showed six different DNA patterns, while the two remaining isolates, ST179 and ST191, showed two additional profiles. CC2 is a known clonal complex with high adaptability to hospital environment and worldwide distribution. The high prevalence of the ST6 clone in the studied population could be related to the presence of gentamicin in the SDD mixture since most strains were gentamicin resistant. Consequently, strict surveillance should be applied for rapid detection and control of this clone to prevent future spread outside the ICU. PMID- 25712204 TI - Multiple causes for ischemia without obstructive coronary artery disease: not a short list. PMID- 25712205 TI - Invasive evaluation of patients with angina in the absence of obstructive coronary artery disease. AB - BACKGROUND: More than 20% of patients presenting to the cardiac catheterization laboratory with angina have no angiographic evidence of coronary artery disease. Despite a "normal" angiogram, these patients often have persistent symptoms, recurrent hospitalizations, a poor functional status, and adverse cardiovascular outcomes, without a clear diagnosis. METHODS AND RESULTS: In 139 patients with angina in the absence of obstructive coronary artery disease (no diameter stenosis >50%), endothelial function was assessed; the index of microcirculatory resistance, coronary flow reserve, and fractional flow reserve were measured; and intravascular ultrasound was performed. There were no complications. The average age was 54.0+/-11.4 years, and 107 (77%) were women. All patients had at least some evidence of atherosclerosis based on an intravascular ultrasound examination of the left anterior descending artery. Endothelial dysfunction (a decrease in luminal diameter of >20% after intracoronary acetylcholine) was present in 61 patients (44%). Microvascular impairment (an index of microcirculatory resistance >=25) was present in 29 patients (21%). Seven patients (5%) had a fractional flow reserve <=0.80. A myocardial bridge was present in 70 patients (58%). Overall, only 32 patients (23%) had no coronary explanation for their angina, with normal endothelial function, normal coronary physiological assessment, and no myocardial bridging. CONCLUSIONS: The majority of patients with angina in the absence of obstructive coronary artery disease have occult coronary abnormalities. A comprehensive invasive assessment of these patients at the time of coronary angiography can be performed safely and provides important diagnostic information that may affect treatment and outcomes. PMID- 25712207 TI - ADAMTS7 in cardiovascular disease: from bedside to bench and back again? PMID- 25712206 TI - Knockout of Adamts7, a novel coronary artery disease locus in humans, reduces atherosclerosis in mice. AB - BACKGROUND: Genome-wide association studies have established ADAMTS7 as a locus for coronary artery disease in humans. However, these studies fail to provide directionality for the association between ADAMTS7 and coronary artery disease. Previous reports have implicated ADAMTS7 in the regulation of vascular smooth muscle cell migration, but a role for and the direction of impact of this gene in atherogenesis have not been shown in relevant model systems. METHODS AND RESULTS: We bred an Adamts7 whole-body knockout mouse onto both the Ldlr and Apoe knockout hyperlipidemic mouse models. Adamts7(-/-)/Ldlr(-/-) and Adamts7(-/-)/Apoe(-/-) mice displayed significant reductions in lesion formation in aortas and aortic roots compared with controls. Adamts7 knockout mice also showed reduced neointimal formation after femoral wire injury. Adamts7 expression was induced in response to injury and hyperlipidemia but was absent at later time points, and primary Adamts7 knockout vascular smooth muscle cells showed reduced migration in the setting of tumor necrosis factor-alpha stimulation. ADAMTS7 localized to cells positive for smooth muscle cell markers in human coronary artery disease lesions, and subcellular localization studies in cultured vascular smooth muscle cells placed ADAMTS7 at the cytoplasm and cell membrane, where it colocalized with markers of podosomes. CONCLUSIONS: These data represent the first in vivo experimental validation of the association of Adamts7 with atherogenesis, likely through modulation of vascular cell migration and matrix in atherosclerotic lesions. These results demonstrate that Adamts7 is proatherogenic, lending directionality to the original genetic association and supporting the concept that pharmacological inhibition of ADAMTS7 should be atheroprotective in humans, making it an attractive target for novel therapeutic interventions. PMID- 25712208 TI - ADAMTS-7 inhibits re-endothelialization of injured arteries and promotes vascular remodeling through cleavage of thrombospondin-1. AB - BACKGROUND: ADAMTS-7, a member of the disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) family, was recently identified to be significantly associated genomewide with coronary artery disease. However, the mechanisms that link ADAMTS-7 and coronary artery disease risk remain elusive. We have previously demonstrated that ADAMTS-7 promotes vascular smooth muscle cell migration and postinjury neointima formation via degradation of a matrix protein cartilage oligomeric matrix protein. Because delayed endothelium repair renders neointima and atherosclerosis plaque formation after vessel injury, we examined whether ADAMTS-7 also inhibits re-endothelialization. METHODS AND RESULTS: Wire injury of the carotid artery and Evans blue staining were performed in Adamts7(-/ ) and wild-type mice. Adamts-7 deficiency greatly promoted re-endothelialization at 3, 5, and 7 days after injury. Consequently, Adamts-7 deficiency substantially ameliorated neointima formation in mice at days 14 and 28 after injury in comparison with the wild type. In vitro studies further indicated that ADAMTS-7 inhibited both endothelial cell proliferation and migration. Surprisingly, cartilage oligomeric matrix protein deficiency did not affect endothelial cell proliferation/migration and re-endothelialization in mice. In a further examination of other potential vascular substrates of ADAMTS-7, a label-free liquid chromatography-tandem mass spectrometry secretome analysis revealed thrombospondin-1 as a potential ADAMTS-7 target. The subsequent studies showed that ADAMTS-7 was directly associated with thrombospondin-1 by its C terminus and degraded thrombospondin-1 in vivo and in vitro. The inhibitory effect of ADAMTS-7 on postinjury endothelium recovery was circumvented in Tsp1(-/-) mice. CONCLUSIONS: Our study revealed a novel mechanism by which ADAMTS-7 affects neointima formation. Thus, ADAMTS-7 is a promising treatment target for postinjury vascular intima hyperplasia. PMID- 25712210 TI - The BAFFling function of Syk in B-cell homeostasis. AB - The TNF receptor family member BAFFR is essential for providing mature B cells with pro-survival signals and has recently been claimed to transduce these, though not exclusively, via a Syk-dependent signaling hub that feeds into ERK/AKT activation. In this issue of The EMBO Journal, Hobeika et al (2015) describe a synergistic prosurvival scenario involving BAFFR and CD19, which remains functional under Syk null conditions and is able to maintain mature B-cell survival. The authors hence propose a BAFFR-/CD19-driven mechanism to act in parallel with homeostatic NF-kappaB/AKT activation in non-stimulated B cells. PMID- 25712209 TI - Transcription factor-mediated reprogramming toward hematopoietic stem cells. AB - De novo generation of human hematopoietic stem cells (HSCs) from renewable cell types has been a long sought-after but elusive goal in regenerative medicine. Paralleling efforts to guide pluripotent stem cell differentiation by manipulating developmental cues, substantial progress has been made recently toward HSC generation via combinatorial transcription factor (TF)-mediated fate conversion, a paradigm established by Yamanaka's induction of pluripotency in somatic cells by mere four TFs. This review will integrate the recently reported strategies to directly convert a variety of starting cell types toward HSCs in the context of hematopoietic transcriptional regulation and discuss how these findings could be further developed toward the ultimate generation of therapeutic human HSCs. PMID- 25712212 TI - Reprogramming of human cancer cells to pluripotency for models of cancer progression. AB - The ability to study live cells as they progress through the stages of cancer provides the opportunity to discover dynamic networks underlying pathology, markers of early stages, and ways to assess therapeutics. Genetically engineered animal models of cancer, where it is possible to study the consequences of temporal-specific induction of oncogenes or deletion of tumor suppressors, have yielded major insights into cancer progression. Yet differences exist between animal and human cancers, such as in markers of progression and response to therapeutics. Thus, there is a need for human cell models of cancer progression. Most human cell models of cancer are based on tumor cell lines and xenografts of primary tumor cells that resemble the advanced tumor state, from which the cells were derived, and thus do not recapitulate disease progression. Yet a subset of cancer types have been reprogrammed to pluripotency or near-pluripotency by blastocyst injection, by somatic cell nuclear transfer and by induced pluripotent stem cell (iPS) technology. The reprogrammed cancer cells show that pluripotency can transiently dominate over the cancer phenotype. Diverse studies show that reprogrammed cancer cells can, in some cases, exhibit early-stage phenotypes reflective of only partial expression of the cancer genome. In one case, reprogrammed human pancreatic cancer cells have been shown to recapitulate stages of cancer progression, from early to late stages, thus providing a model for studying pancreatic cancer development in human cells where previously such could only be discerned from mouse models. We discuss these findings, the challenges in developing such models and their current limitations, and ways that iPS reprogramming may be enhanced to develop human cell models of cancer progression. PMID- 25712213 TI - Macrophage migration inhibitory factor-CXCR4 is the dominant chemotactic axis in human mesenchymal stem cell recruitment to tumors. AB - Mesenchymal stromal cells (MSCs) are inherently tumor homing and can be isolated, expanded, and transduced, making them viable candidates for cell therapy. This tumor tropism has been used to deliver anticancer therapies to various tumor models. In this study, we sought to discover which molecules are the key effectors of human MSC tumor homing in vitro and using an in vivo murine model. In this study, we discover a novel role for macrophage migration inhibitory factor (MIF) as the key director of MSC migration and infiltration toward tumor cells. We have shown this major role for MIF using in vitro migration and invasion assays, in presence of different receptor inhibitors and achieving a drastic decrease in both processes using MIF inhibitor. Additionally, we demonstrate physical interaction between MIF and three receptors: CXCR2, CXCR4, and CD74. CXCR4 is the dominant receptor used by MIF in the homing tumor context, although some signaling is observed through CXCR2. We demonstrate downstream activation of the MAPK pathway necessary for tumor homing. Importantly, we show that knockdown of either CXCR4 or MIF abrogates MSC homing to tumors in an in vivo pulmonary metastasis model, confirming the in vitro two-dimensional and three-dimensional assays. This improved understanding of MSC tumor tropism will further enable development of novel cellular therapies for cancers. PMID- 25712214 TI - Liver-resident CD103+ dendritic cells prime antiviral CD8+ T cells in situ. AB - The liver maintains a tolerogenic environment to avoid unwarranted activation of its resident immune cells upon continuous exposure to food and bacterially derived Ags. However, in response to hepatotropic viral infection, the liver's ability to switch from a hyporesponsive to a proinflammatory environment is mediated by select sentinels within the parenchyma. To determine the contribution of hepatic dendritic cells (DCs) in the activation of naive CD8(+) T cells, we first characterized resident DC subsets in the murine liver. Liver DCs exhibit unique properties, including the expression of CD8alpha (traditionally lymphoid tissue specific), CD11b, and CD103 markers. In both the steady-state and following viral infection, liver CD103(+) DCs express high levels of MHC class II, CD80, and CD86 and contribute to the high number of activated CD8(+) T cells. Importantly, viral infection in the Batf3(-/-) mouse, which lacks CD8alpha(+) and CD103(+) DCs in the liver, results in a 3-fold reduction in the proliferative response of Ag-specific CD8(+) T cells. Limiting DC migration out of the liver does not significantly alter CD8(+) T cell responsiveness, indicating that CD103(+) DCs initiate the induction of CD8(+) T cell responses in situ. Collectively, these data suggest that liver-resident CD103(+) DCs are highly immunogenic in response to hepatotropic viral infection and serve as a major APC to support the local CD8(+) T cell response. It also implies that CD103(+) DCs present a promising cellular target for vaccination strategies to resolve chronic liver infections. PMID- 25712215 TI - Predominant development of mature and functional human NK cells in a novel human IL-2-producing transgenic NOG mouse. AB - We generated a severe immunodeficient NOD/Shi-scid-IL-2Rgamma(null) (NOG) mouse substrain expressing the transgenic human IL-2 gene (NOG-IL-2 Tg). Upon transfer of human cord blood-derived hematopoietic stem cells (HSCs), CD3( )CD56(high)CD16(+/-) cells developed unexpectedly, predominantly in the NOG-IL-2 Tg (hu-HSC NOG-IL-2 Tg). These cells expressed various NK receptors, including NKp30, NKp44, NKp46, NKG2D, and CD94, as well as a diverse set of killer cell Ig like receptor molecules at levels comparable to normal human NK cells from the peripheral blood, which is evidence of their maturity. They produced levels of granzyme A as high as in human peripheral blood-derived NK cells, and a considerable amount of perforin protein was detected in the plasma. Human NK cells in hu-HSC NOG-IL-2 Tg produced IFN-gamma upon stimulation, and IL-2, IL-15, or IL-12 treatment augmented the in vitro cytotoxicity. Inoculation of K562 leukemia cells into hu-HSC NOG-IL-2 Tg caused complete rejection of the tumor cells, whereas inoculation into hu-HSC NOG fully reconstituted with human B, T, and some NK cells did not. Moreover, when a CCR4(+) Hodgkin's lymphoma cell line was inoculated s.c. into hu-HSC NOG-IL-2 Tg, the tumor growth was significantly suppressed by treatment with a therapeutic humanized anti-CCR4 Ab (mogamulizumab), suggesting that the human NK cells in the mice exerted active Ab dependent cellular cytotoxicity in vivo. Taken together, these data suggest that the new NOG-IL-2 Tg strain is a unique model that can be used to investigate the biological and pathological functions of human NK cells in vivo. PMID- 25712211 TI - Programming and reprogramming a human heart cell. AB - The latest discoveries and advanced knowledge in the fields of stem cell biology and developmental cardiology hold great promise for cardiac regenerative medicine, enabling researchers to design novel therapeutic tools and approaches to regenerate cardiac muscle for diseased hearts. However, progress in this arena has been hampered by a lack of reproducible and convincing evidence, which at best has yielded modest outcomes and is still far from clinical practice. To address current controversies and move cardiac regenerative therapeutics forward, it is crucial to gain a deeper understanding of the key cellular and molecular programs involved in human cardiogenesis and cardiac regeneration. In this review, we consider the fundamental principles that govern the "programming" and "reprogramming" of a human heart cell and discuss updated therapeutic strategies to regenerate a damaged heart. PMID- 25712217 TI - HSV-2 immediate-early protein US1 inhibits IFN-beta production by suppressing association of IRF-3 with IFN-beta promoter. AB - HSV-2 is the major cause of genital herpes, and its infection increases the risk of HIV-1 acquisition and transmission. After initial infection, HSV-2 can establish latency within the nervous system and thus maintains lifelong infection in humans. It has been suggested that HSV-2 can inhibit type I IFN signaling, but the underlying mechanism has yet to be determined. In this study, we demonstrate that productive HSV-2 infection suppresses Sendai virus (SeV) or polyinosinic polycytidylic acid-induced IFN-beta production. We further reveal that US1, an immediate-early protein of HSV-2, contributes to such suppression, showing that US1 inhibits IFN-beta promoter activity and IFN-beta production at both mRNA and protein levels, whereas US1 knockout significantly impairs such capability in the context of HSV-2 infection. US1 directly interacts with DNA binding domain of IRF 3, and such interaction suppresses the association of nuclear IRF-3 with the IRF 3 responsive domain of IFN-beta promoter, resulting in the suppression of IFN beta promoter activation. Additional studies demonstrate that the 217-414 aa domain of US1 is critical for the suppression of IFN-beta production. Our results indicate that HSV-2 US1 downmodulates IFN-beta production by suppressing the association of IRF-3 with the IRF-3 responsive domain of IFN-beta promoter. Our findings highlight the significance of HSV-2 US1 in inhibiting IFN-beta production and provide insights into the molecular mechanism by which HSV-2 evades the host innate immunity, representing an unconventional strategy exploited by a dsDNA virus to interrupt type I IFN signaling pathway. PMID- 25712216 TI - IL-4-secreting secondary T follicular helper (Tfh) cells arise from memory T cells, not persisting Tfh cells, through a B cell-dependent mechanism. AB - Humoral immunity requires cross-talk between T follicular helper (Tfh) cells and B cells. Nevertheless, a detailed understanding of this intercellular interaction during secondary immune responses is lacking. We examined this by focusing on the response to a soluble, unadjuvanted, pathogen-derived Ag (soluble extract of Schistosoma mansoni egg [SEA]) that induces type 2 immunity. We found that activated Tfh cells persisted for long periods within germinal centers following primary immunization. However, the magnitude of the secondary response did not appear to depend on pre-existing Tfh cells. Instead, Tfh cell populations expanded through a process that was dependent on memory T cells recruited into the reactive LN, as well as the participation of B cells. We found that, during the secondary response, IL-4 was critical for the expansion of a population of plasmablasts that correlated with increased SEA-specific IgG1 titers. Additionally, following immunization with SEA (but not with an Ag that induced type 1 immunity), IL-4 and IL-21 were coproduced by individual Tfh cells, revealing a potential mechanism through which appropriate class-switching can be coupled to plasmablast proliferation to enforce type 2 immunity. Our findings demonstrate a pivotal role for IL-4 in the interplay between T and B cells during a secondary Th2 response and have significant implications for vaccine design. PMID- 25712218 TI - Basal cells contribute to innate immunity of the airway epithelium through production of the antimicrobial protein RNase 7. AB - Basal cells play a critical role in the response of the airway epithelium to injury and are recently recognized to also contribute to epithelial immunity. Antimicrobial proteins and peptides are essential effector molecules in this airway epithelial innate immunity. However, little is known about the specific role of basal cells in antimicrobial protein and peptide production and about the regulation of the ubiquitous antimicrobial protein RNase 7. In this study, we report that basal cells are the principal cell type producing RNase 7 in cultured primary bronchial epithelial cells (PBEC). Exposure of submerged cultured PBEC (primarily consisting of basal cells) to the respiratory pathogen nontypeable Haemophilus influenzae resulted in a marked increase in expression of RNase 7, although this was not observed in differentiated air-liquid interface cultured PBEC. However, transient epithelial injury in air-liquid interface-cultured PBEC induced by cigarette smoke exposure led to epidermal growth factor receptor mediated expression of RNase 7 in remaining basal cells. The selective induction of RNase 7 in basal cells by cigarette smoke was demonstrated using confocal microscopy and by examining isolated luminal and basal cell fractions. Taken together, these findings demonstrate a phenotype-specific innate immune activity of airway epithelial basal cells, which serves as a second line of airway epithelial defense that is induced by airway epithelial injury. PMID- 25712219 TI - Rare loss-of-function mutation in complement component C3 provides insight into molecular and pathophysiological determinants of complement activity. AB - The plasma protein C3 is a central element in the activation and effector functions of the complement system. A hereditary dysfunction of C3 that prevents complement activation via the alternative pathway (AP) was described previously in a Swedish family, but its genetic cause and molecular consequences have remained elusive. In this study, we provide these missing links by pinpointing the dysfunction to a point mutation in the beta-chain of C3 (c.1180T > C; p.Met(373)Thr). In the patient's plasma, AP activity was completely abolished and could only be reconstituted with the addition of normal C3. The M373T mutation was localized to the macroglobulin domain 4 of C3, which contains a binding site for the complement inhibitor compstatin and is considered critical for the interaction of C3 with the AP C3 convertase. Structural analyses suggested that the mutation disturbs the integrity of macroglobulin domain 4 and induces conformational changes that propagate into adjacent regions. Indeed, C3 M373T showed an altered binding pattern for compstatin and surface-bound C3b, and the presence of Thr(373) in either the C3 substrate or convertase-affiliated C3b impaired C3 activation and opsonization. In contrast to known gain-of-function mutations in C3, patients affected by this loss-of-function mutation did not develop familial disease, but rather showed diverse and mostly episodic symptoms. Our study therefore reveals the molecular mechanism of a relevant loss-of function mutation in C3 and provides insight into the function of the C3 convertase, the differential involvement of C3 activity in clinical conditions, and some potential implications of therapeutic complement inhibition. PMID- 25712220 TI - Effects of osmolytes on protein-solvent interactions in crowded environment: Analyzing the effect of TMAO on proteins in crowded solutions. AB - We analyzed the effect of a natural osmolyte, trimethylamine N-oxide (TMAO), on structural properties and conformational stabilities of several proteins under macromolecular crowding conditions by a set of biophysical techniques. We also used the solvent interaction analysis method to look at the peculiarities of the TMAO-protein interactions under crowded conditions. To this end, we analyzed the partitioning of these proteins in TMAO-free and TMAO-containing aqueous two-phase systems (ATPSs). These ATPSs had the same polymer composition of 6.0 wt.% PEG 8000 and 12.0 wt.% dextran-75, and same ionic composition of 0.01 M K/NaPB, pH 7.4. These analyses revealed that there is no direct interaction of TMAO with proteins, suggesting that the TMAO effects on the protein structure in crowded solutions occur via the effects of this osmolyte on solvent properties of aqueous media. The effects of TMAO on protein structure in the presence of polymers were rather complex and protein-specific. Curiously, our study revealed that in highly concentrated polymer solutions, TMAO does not always act to promote further protein folding. PMID- 25712221 TI - Catalytic activity of human indoleamine 2,3-dioxygenase (hIDO1) at low oxygen. AB - A cytokine-inducible extrahepatic human indoleamine 2,3-dioxygenase (hIDO1) catalyzes the first step of the kynurenine pathway. Immunosuppressive activity of hIDO1 in tumor cells weakens host T-cell immunity, contributing to the progression of cancer. Here we report on enzyme kinetics and catalytic mechanism of hIDO1, studied at varied levels of dioxygen (O2) and L-tryptophan (L-Trp). Using a cytochrome b5-based activating system, we measured the initial rates of O2 decay with a Clark-type oxygen electrode at physiologically-relevant levels of both substrates. Kinetics was also studied in the presence of two substrate analogs: 1-methyl-L-tryptophan and norharmane. Quantitative analysis supports a steady-state rather than a rapid equilibrium kinetic mechanism, where the rates of individual pathways, leading to a ternary complex, are significantly different, and the overall rate of catalysis depends on contributions of both routes. One path, where O2 binds to ferrous hIDO1 first, is faster than the second route, which starts with the binding of L-Trp. However, L-Trp complexation with free ferrous hIDO1 is more rapid than that of O2. As the level of L-Trp increases, the slower route becomes a significant contributor to the overall rate, resulting in observed substrate inhibition. PMID- 25712222 TI - AVE 3085, a novel endothelial nitric oxide synthase enhancer, attenuates cardiac remodeling in mice through the Smad signaling pathway. AB - AVE 3085 is a novel endothelial nitric oxide synthase enhancer. Although AVE 3085 treatment has been shown to be effective in spontaneously restoring endothelial function in hypertensive rats, little is known about the effects and mechanisms of AVE 3085 with respect to cardiac remodeling. The present study was designed to examine the effects of AVE 3085 on cardiac remodeling and the mechanisms underlying the effects of this compound. Mice were subjected to aortic banding to induce cardiac remodeling and were then administered AVE 3085 (10 mg kg day(-1), orally) for 4 weeks. At the end of the treatment, the aortic banding-treated mice exhibited significant elevations in cardiac remodeling, characterized by an increase in left ventricular weight relative to body weight, an increase in the area of collagen deposition, an increase in the mean myocyte diameter, and increases in the gene expressions of the hypertrophic markers atrial natriuretic peptide (ANP) and beta-MHC. These indexes were significantly decreased in the AVE 3085-treated mice. Furthermore, AVE 3085 treatment reduced the expression and activation of the Smad signaling pathway in the aortic banding-treated mice. Our data showed that AVE 3085 attenuated cardiac remodeling, and this effect was possibly mediated through the inhibition of Smad signaling. PMID- 25712223 TI - Preoperative chemoradiotherapy for clinically diagnosed T3N0 rectal cancer. AB - PURPOSE: This retrospective study compared the recurrence-free survival (RFS) and local recurrence rates of patients who received preoperative chemoradiotherapy (PCRT) for cT3N0 vs. those who did not. METHODS: We analyzed the records of 593 patients with transrectal ultrasound (TUS) or magnetic resonance image (MRI) staged cT3N0 mid and low locally advanced rectal cancer, including 255 who received PCRT and 338 who did not. The RFS and cumulative local recurrence rates were compared in the two groups. We also investigated the rates of pathologic complete response (pCR) and mesorectal lymph node (LN) involvement in the PCRT group. RESULTS: The overall pCR rate was 13.3 %. Of the 338 non-PCRT patients, 125 (37.0 %) had pathologically positive mesorectal LNs. Sphincter-preserving surgery was performed in 431 (72.7 %) of the 593 patients, with similar rates in the two groups. However, the sphincter preservation rate in patients with low rectal cancer was higher among those who received PCRT than among those who did not (64.8 vs. 47 %, P = 0.002). The 5-year RFS (76.4 vs. 75.5 %, P = 0.92) and local recurrence (3.9 vs. 3.0 %, P = 0.97) rates were similar in the PCRT and non PCRT groups. CONCLUSION: Although PCRT did not improve the RFS or local recurrence rates, it increased the chance of sphincter preservation in patients with low rectal cancer. The advantages of PCRT for patients with cT3N0 should be re-evaluated considering the limitation of pretreatment staging, oncologic benefits, and improved sphincter preservation. PMID- 25712225 TI - Human neural stem cell-derived cultures in three-dimensional substrates form spontaneously functional neuronal networks. AB - Differentiated human neural stem cells were cultured in an inert three dimensional (3D) scaffold and, unlike two-dimensional (2D) but otherwise comparable monolayer cultures, formed spontaneously active, functional neuronal networks that responded reproducibly and predictably to conventional pharmacological treatments to reveal functional, glutamatergic synapses. Immunocytochemical and electron microscopy analysis revealed a neuronal and glial population, where markers of neuronal maturity were observed in the former. Oligonucleotide microarray analysis revealed substantial differences in gene expression conferred by culturing in a 3D vs a 2D environment. Notable and numerous differences were seen in genes coding for neuronal function, the extracellular matrix and cytoskeleton. In addition to producing functional networks, differentiated human neural stem cells grown in inert scaffolds offer several significant advantages over conventional 2D monolayers. These advantages include cost savings and improved physiological relevance, which make them better suited for use in the pharmacological and toxicological assays required for development of stem cell-based treatments and the reduction of animal use in medical research. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 25712224 TI - Circulating cell-free microRNAs as biomarkers for colorectal cancer. AB - MicroRNAs (miRNAs) are a class of small, endogenous, non-coding, single-stranded RNAs that act as post-transcriptional regulators. Their discovery has provided new avenues for the diagnosis and treatment of cancer. The expression of both oncogenic and tumor suppressor miRNAs can be aberrantly either up- or down regulated in cancer cells. These miRNAs target mRNAs of genes that either promote or inhibit tumor growth, and are one of several epigenetic factors that control the initiation and progression of colorectal cancer (CRC) and other cancers. Investigations of miRNAs as CRC biomarkers have employed the expression profiling of traditional tissue samples and, more recently, non-invasive samples, such as feces and body fluids, have been analyzed. MiRNAs may also be able to predict responses to chemo- and radiotherapy, and may be manipulated to modify CRC characteristics. We herein discuss the use of circulating miRNAs as possible non invasive biomarkers of early CRC onset, relapse, or response to treatment. We also discuss the obstacles that currently limit the routine use of epigenetic biomarkers in clinical settings. PMID- 25712226 TI - Meaning of illness and self-care in patients with type 2 diabetes. AB - PURPOSE: The purpose of this study was to assess the relationship between meaning of illness, diabetes knowledge, self-care understanding, and behaviors in a group of individuals with type 2 diabetes. METHODS: Patients diagnosed with type 2 diabetes completed questionnaires with measures for diabetes knowledge, self-care understanding, diet adherence, and control problems based on the validated Diabetes Care Profile, as well as a 5-factor Meaning of Illness Questionnaire (MIQ) measure. Linear regression investigated the associations between self-care outcomes and the 5 MIQ factors. RESULTS: After adjustment for possible confounders, both diabetes self-care understanding and diet adherence were negatively and significantly associated with little effect of illness. Control problems were negatively associated with degree of stress/change in commitments. Diabetes knowledge was not significantly associated with meaning of illness. CONCLUSION: Aspects of the meaning attributed to illness were significantly associated with self-care in patients with type 2 diabetes. Therefore, cognitive appraisals may explain variances observed in self-care understanding and behaviors. Based on these results, it is important to understand the negative effect that diabetes could have when promoting self-care understanding and diet adherence. In addition, it shows that helping patients address the stress and changing commitments that result from diabetes may help decrease the amount of diabetes control problems, even if there is little effect on diabetes understanding. Taking these differences into account may help in creating more personalized and effective self-care education plans. PMID- 25712227 TI - A molecular perspective on a complex polymorphic inversion system with cytological evidence of multiply reused breakpoints. AB - Genome sequence comparison across the Drosophila genus revealed that some fixed inversion breakpoints had been multiply reused at this long timescale. Cytological studies of Drosophila inversion polymorphism had previously shown that, also at this shorter timescale, some breakpoints had been multiply reused. The paucity of molecularly characterized polymorphic inversion breakpoints has so far precluded contrasting whether cytologically shared breakpoints of these relatively young inversions are actually reused at the molecular level. The E chromosome of Drosophila subobscura stands out because it presents several inversion complexes. This is the case of the E1+2+9+3 arrangement that originated from the ancestral Est arrangement through the sequential accumulation of four inversions (E1, E2, E9 and E3) sharing some breakpoints. We recently identified the breakpoints of inversions E1 and E2, which allowed establishing reuse at the molecular level of the cytologically shared breakpoint of these inversions. Here, we identified and sequenced the breakpoints of inversions E9 and E3, because they share breakpoints at sections 58D and 64C with those of inversions E1 and E2. This has allowed establishing that E9 and E3 originated through the staggered break mechanism. Most importantly, sequence comparison has revealed the multiple reuse at the molecular level of the proximal breakpoint (section 58D), which would have been used at least by inversions E2, E9 and E3. In contrast, the distal breakpoint (section 64C) might have been only reused once by inversions E1 and E2, because the distal E3 breakpoint is displaced >70 kb from the other breakpoint limits. PMID- 25712228 TI - Per-oral endoscopic myotomy for achalasia. Are results comparable to laparoscopic Heller myotomy? AB - OBJECTIVE: Per-oral endoscopic myotomy (POEM) has recently been introduced as a minimal invasive alternative to conventional treatment for achalasia. This study aimed to clarify the feasibility and the short-term clinical efficacy of POEM as compared to laparoscopic Heller myotomy (LHM). METHODS: Treatment outcomes were prospectively recorded and compared between the procedures in a nonrandomized fashion. Reduction rate (RR) in timed barium esophagogram (TBE) was calculated at 1, 2 and 5 min after barium ingestion as: RR = 1- postoperative barium height/preoperative barium height. Risk factors for treatment failure defined as the proportion of patients with RR <0.5 (1 min) and gastroesophageal reflux (GER) after POEM were analyzed. RESULTS: Forty-two consecutive patients who underwent POEM were compared to 41 patients who had a LHM during the immediate time period prior to the introduction of POEM. Ninety percent of the cases reported complete symptom relief after POEM. The percentage of esophageal emptying and RR in TBE improved dramatically by both procedures without significant difference. A longer operation time (odds ratio [OR] 32.80, 95%CI 2.99-359.82, p = 0.004) and younger age (OR 26.81, 95%CI 2.09-344.03, p = 0.012) were the independent predictors of treatment failure after POEM. GER was observed in seven patients where previous dilatation (OR 8.59, 95%CI 1.16-63.45, p = 0.035) and higher body mass index (OR 8.69, 95%CI 1.13-66.63, p = 0.037) were the independent predictors for symptomatic GER after POEM. CONCLUSION: POEM seems to be a safe and effective treatment option for achalasia in the short-term perspective; an effect well comparable to LHM. PMID- 25712229 TI - Cation-cation pairing by N-C-H???O hydrogen bonds. AB - The pairing of ions of opposite charge is a fundamental principle in chemistry, and is widely applied in synthesis and catalysis. In contrast, cation-cation association remains an elusive concept, lacking in supporting experimental evidence. While studying the structure and properties of 4-oxopiperidinium salts [OC5 H8 NH2 ]X for a series of anions X(-) of decreasing basicity, we observed a gradual self-association of the cations, concluding in the formation of an isolated dicationic pair. In 4-oxopiperidinium bis(trifluoromethylsulfonyl)amide, the cations are linked by N?H???O?C hydrogen bonds to form chains, flanked by hydrogen bonds to the anions. In the tetra(perfluoro-tert-butoxy)aluminate salt, the anions are fully separated from the cations, and the cations associate pairwise by N?C?H???O?C hydrogen bonds. The compounds represent the first genuine examples of self-association of simple organic cations based merely on hydrogen bonding as evidenced by X-ray structure analysis, and provide a paradigm for an extension of this class of compounds. PMID- 25712230 TI - The prevalence and phenotypic characteristics of spontaneous premature ovarian failure: a general population registry-based study. AB - STUDY QUESTION: What is the measured prevalence and phenotype of spontaneous premature ovarian failure (POF) in the general population? SUMMARY ANSWER: Spontaneous POF occurs in ~1% of the general population with unique phenotype of post-menopausal ageing distinct from surgically induced premature menopause. WHAT IS KNOWN ALREADY: POF is multifactorial ovarian quiescence before the age of 40. The clinical features of POF are diverse and the population prevalence of POF is still not known. STUDY DESIGN, SIZE, DURATION: This population-depictive registry based case-cohort study included 34 041 women from the Estonian Genome Center registered between 2003 and 2013. PARTICIPANTS/MATERIALS, SETTING, METHODS: Spontaneous POF was selected retrospectively by excluding other causes for premature menopause under the age of 40 (N = 310) and women with surgically induced premature menopause participated as a reference group (N = 242). MAIN RESULTS AND THE ROLE OF CHANCE: The prevalence of spontaneous POF was 0.91% (0.81 1.02%) among women of the general population in Estonia. In women with POF, menarche occurred a few months later than in the reference group and a significantly higher number of live births during their reproductive life was recorded. Women with POF also consumed less alcohol and had smaller waist-to-hip ratios than those in the reference group, although both groups of women were similar in body mass index a decade after menopause. The prevalence of concomitant diseases was similar between two groups of women by their fifties, but the pattern of onset of these diseases was different. Surgically induced premature menopause associated with faster development of osteoporosis, hypertension, and connective tissue diseases, but slower development of allergies, compared with spontaneous POF. The age of menopause was determined by irregular menstrual cycles, but not by the length of regular menstrual cycles, the age of menarche, the number of pregnancies or live births, smoking or alcohol consumption, or the use of oral contraceptives for some time during the reproductive period. LIMITATIONS, REASONS FOR CAUTION: POF is rarely stated in medical records and cannot be diagnosed retrospectively by standard procedures. Therefore the data on all cases of women with primary amenorrhea or premature menopause before the age of 40 were requested from the registry and spontaneous POF was predicted retrospectively by excluding other extraovarian causes for premature menopause. Since the current study is retrospective registry-based data analysis, no genetic evaluation concerning possible candidate genes and no blood analysis concerning immunologic disorders could be performed to describe etiopathogenesis of POF. WIDER IMPLICATION OF THE FINDINGS: Spontaneous POF most likely comprises several diseases with different etiopathologies and there may be a unique phenotype of post-menopausal ageing distinct from that in surgically induced premature menopause. Irregular menstrual cycles may be a prospective risk for developing spontaneous POF. Compared with spontaneous POF, surgically induced premature menopause associates with faster development of age-related diseases. The data point to new ideas and hypotheses for further studies on etiopathologies and treatment options for spontaneous POF. STUDY FUNDING/COMPETING INTERESTS: The study was funded by grant SF0180044s09, SF0180027s10 and IUT20-43 from the Estonian Ministry of Education and Research, Enterprise Estonia, grant no EU30020, Eureka's EUROSTARS programme grant (NOTED, EU41564). No competing interests are declared. PMID- 25712231 TI - Follicle activation and 'burn-out' contribute to post-transplantation follicle loss in ovarian tissue grafts: the effect of graft thickness. PMID- 25712232 TI - Metal nanoparticle dispersion, alignment, and assembly in nematic liquid crystals for applications in switchable plasmonic color filters and E-polarizers. AB - Viewing angle characteristics of displays and performance of electro-optic devices are often compromised by the quality of dichroic thin-film polarizers, while dichroic optical filters usually lack tunability and cannot work beyond the visible part of optical spectrum. We demonstrate that molecular-colloidal organic inorganic composites formed by liquid crystals and relatively dilute dispersions of orientationally ordered anisotropic gold nanoparticles, such as rods and platelets, can be used in engineering of switchable plasmonic polarizers and color filters. The use of metal nanoparticles instead of dichroic dyes allows for obtaining desired polarizing or scattering and absorption properties not only within the visible but also in the infrared parts of an optical spectrum. We explore spontaneous surface-anchoring-mediated alignment of surface functionalized anisotropic gold nanoparticles and its control by low-voltage electric fields, elastic colloidal interactions and self-assembly, as well as the uses of these effects in defining tunable properties of the ensuing organic inorganic nanostructured composites. Electrically tunable interaction of the composites may allow for engineering of practical electro-optic devices, such as a new breed of color filters and plasmonic polarizers. PMID- 25712233 TI - Eculizumab in pregnancy-associated atypical hemolytic uremic syndrome: insights for optimizing management. AB - Pregnancy-associated atypical hemolytic uremic syndrome is a systemic disease associated with high morbidity and mortality rates, caused by dysregulation of the alternative complement pathway, leading to uncontrolled complement activation resulting in thrombotic microangiopathy. This condition can be effectively treated by anti-C5 therapy, which controls complement activation. Treatment can be safely discontinued after complete remission and resolution of the precipitating cause, especially in patients with a low-risk genetic profile. PMID- 25712234 TI - Liver steatosis and the risk of albuminuria: the multi-ethnic study of atherosclerosis. AB - OBJECTIVE: To measure association between hepatic fat and albuminuria (an early marker of renal injury) in individuals without diabetes or hypertension. METHODS: 2,281 individuals in the Multi-Ethnic Study of Atherosclerosis without diabetes or hypertension, renal disease, or excess alcohol consumption underwent computed tomography (CT) for assessment of liver attenuation (marker of hepatic lipid content) and urinalysis (for albuminuria) at initial study visit, with assessment of incident and prevalent albuminuria by logistic regression in follow-up. RESULTS: After adjustment for age, gender, race, smoking, blood pressure, insulin resistance, and body mass index, individuals with less liver fat (higher liver CT attenuation) had a lower probability of having albuminuria at Exam 1 (OR per 10 unit increase in attenuation 0.77, 95 % CI 0.61-0.97, P = 0.02). At median 9.3 years follow-up, albuminuria was identified in 129 individuals were (5.8 %). In fully adjusted models (with age, smoking, body mass index, blood pressure, diabetes and hypertension as time-dependent covariates), lower liver attenuation (greater liver fat) was associated with higher risk of incident albuminuria (OR 0.79, 95 % CI 0.66-0.94, P = 0.008). CONCLUSIONS: Hepatic attenuation is associated with prevalent and incident albuminuria, an early, potent risk factor for renal risk in a population not clearly at risk for future renal failure. PMID- 25712235 TI - Renal diseases in adults with cystic fibrosis: a 40 year single centre experience. AB - BACKGROUND: There is a sizable literature describing renal disease in patients with cystic fibrosis. Previous studies have focused on single disease processes alone, most commonly renal stone disease or acute kidney injury. In this study we report for the first time on the prevalence of all forms of renal disease in a cystic fibrosis population. METHODS: A retrospective review of adult patients with cystic fibrosis attending the Adult Cystic Fibrosis Department at the Royal Brompton Hospital was carried out by searching the department's database to identify patients with renal problems and subsequently retrieving clinical information from medical notes. RESULTS: The prevalence of all renal diseases in our population was 5.1 %. The most commonly identified problem was renal stones. At 2.0 % the prevalence of renal stones in adult patients with cystic fibrosis was comparable to the general population. A range of other renal diseases were identified, the next most common being drug-induced acute kidney injury. CONCLUSIONS: A range of cystic fibrosis independent and attributable diseases has been identified but no cystic fibrosis specific disease. In contrast to other cystic fibrosis centres no increased prevalence of renal stones was found. PMID- 25712236 TI - Diagnostic value of quantitative contrast-enhanced ultrasound (CEUS) for early detection of renal hyperperfusion in diabetic kidney disease. AB - PURPOSE: To investigate the diagnostic value of quantitative contrast-enhanced ultrasound (CEUS) for early detection of renal hyperperfusion in diabetic kidney disease (DKD). MATERIALS AND METHODS: 55 DKD patients with estimated glomerular filtration rate (eGFR) >30 ml/min/1.73 m(2) and 26 normal controls (NCs) were enrolled. Clinical data was well documented. Blood samples were drawn for evaluation of renal function including blood urea nitrogen (BUN), serum creatinine (SCr) and serum uric acid (SUA), and urine samples were assayed for total protein quantification, and various microprotein markers. According to eGFR level, DKD patients were divided into early-stage DKD (eGFR >=90 ml/min/1.73 m(2), n = 18) and middle-stage DKD (eGFR 30-90 ml/min/1.73 m(2), n = 37). Based on urinary microalbumin/creatinine ratio (MALB/UCR), early-stage DKD patients were further classified into two groups: MALB/UCR <10 g/mol (n = 11) and MALB/UCR >=10 g/mol (n = 7). Then, CEUS was performed to observe the real-time renal perfusion, and low acoustic power contrast-specific imaging was used for quantitative analysis. RESULTS: The renal perfusion images of CEUS were well developed successively. The corresponding perfusion curves based on echo-power signals in time series were constructed. Quantitative analysis showed that area under the descending curve (AUC2) was significantly increased in early-stage DKD compared to middle-stage DKD (p < 0.05), but AUC showed no significant difference. Further comparison between different MALB/UCR levels of early-stage DKD showed that patients with MALB/UCR >=10 g/mol had significantly increased levels of AUC, AUC2 and proteinuria than patients with low MALB/UCR (p < 0.05). Also, high MALB/UCR DKD patients had increased proteinuria but similar eGFR compared to low MALB/UCR patients. CONCLUSION: Renal microvascular hyperperfusion may be responsible for overt proteinuria until decline of renal filtration in DKD. AUC2 could be an early and sensitive marker for early renal injury and renal microvascular hyperperfusion in DKD. PMID- 25712238 TI - Can managers empower nurse-midwives to improve maternal health care? A comparison of two resource-poor hospitals in Tanzania. AB - Maternal mortality is very high in Tanzania. Competent hospital care is key to improving maternal outcomes, but there is a crisis of availability and performance of health workers in maternal care. This article uses interviews with managers, nurse-midwives, and women who had given birth in two hospitals providing virtually all the emergency maternal care in one Tanzania city. It contrasts women's experience in the two hospitals, and analyses interconnections with nurse-midwives' and managers' experiences of working conditions. The conceptual literature on nurse empowerment identifies some key explanatory variables for these contrasts. Staff experienced less frustration and constraint in one of the hospitals; had more access to structurally empowering resources; and experienced greater congruence between job commitment and working culture, resulting in better work engagement. Conversely, nurse-midwives in the other hospital were constrained by supply shortages and recurrent lack of support. Contrasting management styles and their impacts demonstrate that even in severely resource-constrained environments, there is room for management to empower staff to improve maternal care. Empowering management practices include participatory management, supportive supervision, better incentives, and clear leadership concerning ward culture. Structural constraints beyond the capacity of health facility managers must however also be addressed. (c) 2015 The Authors. International Journal of Health Planning and Management published by John Wiley & Sons, Ltd. PMID- 25712237 TI - How to balance risks and benefits in the management of CKD patients with coronary artery disease. AB - Chronic kidney disease (CKD) is associated with a high burden of coronary artery disease (CAD), which remains the most common cause of morbidity and mortality in CKD patients. Although the management of CAD is more challenging in patients with CKD than in the general population, and coupled with concerns about further deterioration of renal function and therapy-related toxic effects, CKD patients and those receiving dialysis have not traditionally been included in randomized trials evaluating either medical or revascularization therapies. Thus, only scant data from small prospective studies or retrospective analyses of controlled trials and registries are available, and to date no optimal treatment approach has been defined for this subgroup of patients. However, they potentially have much to gain from the pharmacological, interventional, and surgical strategies used in the general population. Thus, the objective of this review is to summarize the current evidence regarding the management of CAD in CKD patients, in particular with respect to uncertainties regarding coronary revascularization options, and their risk-benefit relationship in such a high-risk population. PMID- 25712239 TI - MAS solid state NMR of proteins: simultaneous 15N- 13CA and 15N- 13CO dipolar recoupling via low-power symmetry-based RF pulse schemes. AB - The generation of efficient RN n (nu)s,(nu)k symmetry-based low-power RF pulse schemes for simultaneous (15)N-(13)CA and (15)N-(13)CO dipolar recoupling is demonstrated. The method involves mixing schemes employing phase and amplitude modulated dual band-selective 180 degrees pulses as basic "R" element and tailoring of the RF field-modulation profile of the 180 degrees pulses so as to obtain efficient magnetisation transfer characteristics over the resonance offset range of the nuclei involved. Mixing schemes leading to simultaneous (15)N-(13)CA and (15)N-(13)CO dipolar recoupling would permit the one-shot acquisition of different chemical shift correlation spectra that are typically utilized for protein backbone resonance assignments and thereby save data acquisition time. At representative MAS frequencies the efficacies of the mixing schemes presented here have been experimentally demonstrated via the simultaneous acquisition of {3D CONH and 3D CANH}, {3D CONH and 3D CO(CA)NH} and {3D CONH, 3D CANH, 3D CO(CA)NH and 3D CA(CO)NH} spectra generated via the magnetisation transfer pathways (1)H -> (13)CO -> (15)N -> (1)H (CONH), (1)H -> (13)CA -> (15)N -> (1)H (CANH) and (1)H -> (13)CO -> (13)CA -> (15)N -> (1)H (CO(CA)NH) and (1)H -> (13)CA -> (13)CO -> (15)N -> (1)H (CA(CO)NH). PMID- 25712241 TI - Increased circulating follicular helper T cells and activated B cells correlate with disease severity in patients with psoriasis. AB - BACKGROUND: Follicular Helper T (TFH) Cells are a population of recently discovered CD4(+) T cells involved in autoimmune diseases. However, the contribution of TFH cells in patients with psoriasis remains unknown. OBJECTIVE: We aimed to investigate the levels of TFH cells, B cells and their clinical relevance in patients with psoriasis. METHODS: Using multi-colour flow cytometry, we detected different subsets of TFH cells and B cells in the peripheral blood of 27 patients with psoriasis and 13 healthy donors. Serum IL-21 levels were measured by ELISA. The relationship between the levels of TFH cells, IL-21, B cells and disease severity were analysed. RESULTS: Compared with healthy donors, higher levels of circulating CD3(+) CD4(+) CXCR5(+) cells, CD3(+) CD4(+) CXCR5(+) ICOS(+), CD3(+) CD4(+) CXCR5(+) PD-1(+), CD3(+) CD4(+) CXCR5(+) ICOS(+) PD-1(+) TFH cells and CD19(+) IgD(+) CD27(-) naive B, CD19(+) CD86(+) activated B, but lower levels of CD19(+) IgD(+) CD27(+) preswitch and CD19(+) IgD(-) CD27(+) postswitch memory B cells, were observed in patients with psoriasis. In addition, serum IL-21 levels in patients with psoriasis were significantly higher than those in healthy donors, and showed to be positively correlated with the levels of different subsets of TFH cells, and the level of CD19(+) CD86(+) B cells was also correlated with TFH cells and IL-21 levels. Furthermore, a significant correlation was found between the levels of CD3(+) CD4(+) CXCR5(+) ICOS(+) TFH cells, CD3(+) CD4(+) CXCR5(+) ICOS(+) PD-1(+) TFH cells, CD19(+) CD86(+) B cells and IL-21 with Psoriasis Area and Severity Index scores. CONCLUSION: The levels of TFH cells and activated B cells were increased in the peripheral blood of patients with psoriasis, and positively correlated with disease severity. These results suggest that TFH cells and activated B cells may play a role in the pathogenesis of psoriasis. PMID- 25712242 TI - A novel rhodium-catalyzed domino-hydroformylation-reaction for the synthesis of sulphonamides. AB - An efficient and highly selective method for the synthesis of sulphonamides by a domino hydroformylation-reductive sulphonamidation reaction has been developed. Various olefins and sulphonamides are converted into the desired products in good yields and with excellent selectivities in the presence of a rhodium/Naphos catalyst. PMID- 25712240 TI - Using the Theory of Planned Behavior to Understand Cervical Cancer Screening Among Latinas. AB - To reduce the high incidence of cervical cancer among Latinas in the United States it is important to understand factors that predict screening behavior. The aim of this study was to test the utility of theory of planned behavior in predicting cervical cancer screening among a group of Latinas. A sample of Latinas (N = 614) completed a baseline survey about Pap test attitudes subjective norms, perceived behavioral control, and intention to be screened for cervical cancer. At 6 months postbaseline, cervical cancer screening behavior was assessed. Structural equation modeling was used to test the theory. Model fit statistics indicated good model fit: chi(2)(48) = 54.32, p = .246; comparative fit index = .992; root mean square error of approximation = .015; weighted root mean square residual = .687. Subjective norms (p = .005) and perceived behavioral control (p < .0001) were positively associated with intention to be screened for cervical cancer, and the intention to be screened predicted actual cervical cancer screening (p < .0001). The proportion of variance (R2) in intention accounted for by the predictors was .276 and the R2 in cervical cancer screening accounted for was .130. This study provides support for the use of the theory of planned behavior in predicting cervical cancer screening among Latinas. This knowledge can be used to inform the development of a theory of planned behavior based intervention to increase cervical cancer screening among Latinas and reduce the high incidence of cervical cancer in this group of women. PMID- 25712243 TI - Valve-in-valve-in-valve: Treating endocarditis of a transcatheter heart valve. AB - Transcatheter heart valve endocarditis is a rare, but life threatening complication. We describe the case of a patient who was successfully treated by transcatheter aortic valve-in-valve-in-valve replacement with a favorable 1-year outcome, despite severe early complications. PMID- 25712244 TI - Interventions to reach underscreened populations: a narrative review for planning cancer screening initiatives. AB - OBJECTIVES: This review was conducted to support knowledge translation (KT) and implementation of interventions to increase participation in organized cancer screening programs in the province of Ontario, Canada. METHODS: A rigorously designed literature search yielded over 900 references which were then subjected to exclusion criteria. The remainder was organized according to type of intervention, based on the categories applied in two authoritative systematic reviews and an analysis of the level of evidence. Emerging themes in the literature were then identified to provide a bridge between high-level evidence and on-the-ground practice. RESULTS: We identify three promising types of KT interventions: community-based health education; lay or peer health education; and targeted or tailored interventions. Each is summarized with illustrative examples and a summary of key themes and considerations. CONCLUSIONS: The authors conclude with a summary the types and a decision tool designed to help KT and implementation teams select interventions which could be adapted to their own context. PMID- 25712245 TI - A qualitative case study of poststroke sexuality in a woman of childbearing age. AB - OBJECTIVE: To explore perceptions of poststroke sexuality in a woman of childbearing age. DESIGN: Qualitative case study. SETTING: Community. PARTICIPANT: A 36-year-old married mother of two children with a history of acute ischemic stroke 7 months prior to interview. METHODS: A semistructured interview guide was used to gather data during a single face-to-face interview. Data consisted of an audio-recorded interview and verbatim transcription, field notes, and demographic information. The inductive approach of qualitative content analysis was used to analyze the data. RESULTS: Four main categories, Slow to Get Back to the Sexual Life, The Vulnerable Body, Crushed by the Stroke and The Inadequate Self, were used to describe how the emotional trauma of having a stroke at a young age affected the participant's sense of self. Issues with sexuality were related to her perception of her poststroke body as vulnerable. Stage of life informed the participant's perceptions of pre- and poststroke sexuality. CONCLUSION: A stroke during childbearing years may affect a woman's perception of herself as a sexual being and her ability to carry out gender roles. PMID- 25712246 TI - An expanded family of dysprosium-scandium mixed-metal nitride clusterfullerenes: the role of the lanthanide metal on the carbon cage size distribution. AB - A large family of dysprosium-scandium (Dy-Sc) mixed-metal nitride clusterfullerenes (MMNCFs), Dy(x)Sc(3-x)N@C2n (x = 1, 2, 2n = 68, 70, 76-86) have been successfully synthesized and isolated. Among these, the C70 and C82-based MMNCFs are two new cages that have never been isolated for MMNCFs. Synthesis of Dy(x)Sc(3-x)N@C2n was accomplished by the "selective organic solid" route using guanidinium thiocyanate as the nitrogen source, and their isolation was fulfilled by recycling HPLC. UV/Vis-NIR spectroscopic study indicates that almost all Dy(x)Sc(3-x)N@C2n MMNCFs are kinetically stable fullerenes with optical band gaps beyond 1 eV. This feature is distinctly different to their counterparts Dy3N@C2n (78<=2n<=88), whose for optical band-gaps are below 1 eV for relatively large cages such as C84 and C86. An FTIR spectroscopic study in combination with DFT calculations enables reasonable assignments of the cage isomeric structures of all isolated Dy(x)Sc(3-x)N@C2n (x = 1, 2, 2n = 68, 70, 76-86) MMNCFs. The carbon cage size distribution of Dy(x)Sc(3-x)N@C2n (2n = 68, 70, 76-86) is compared to the reported Dy3N@C2n (78<=2n<=8) homogeneous NCF and Dy(x)Sc(3-x)N@C2n (78<=2n<=88) MMNCF families, revealing that the medium-sized Dy metal plays a crucial role on the expanded cage size distribution of MMNCFs. As a result, Dy(x)Sc(3-x)N@C2n MMNCFs are the largest MMNCF family reported to date. PMID- 25712247 TI - Drug-induced allergic hepatitis develops in mice when myeloid-derived suppressor cells are depleted prior to halothane treatment. AB - Clinical evidence suggests that many cases of serious idiosyncratic drug-induced liver injury are mediated by the adaptive immune system in response to hepatic drug-protein adducts, also referred to as "drug-induced allergic hepatitis"; but detailed mechanistic proof has remained elusive due to the lack of animal models. We have hypothesized that drug-induced allergic hepatitis is as rare in animals as it is in humans due at least in part to the tolerogenic nature of the liver. We provide evidence that immune tolerance can be overcome in a murine model of halothane-induced liver injury initiated by trifluoroacetylated protein adducts of halothane formed in the liver. Twenty-four hours after female Balb/cJ mice were initially treated with halothane, perivenous necrosis and an infiltration of CD11b(+) Gr-1(high) cells were observed in the liver. Further study revealed a subpopulation of myeloid-derived suppressor cells within the CD11b(+) Gr-1(high) cell fraction that inhibited the proliferation of both CD4(+) and CD8(+) T cells. When CD11b(+) Gr-1(high) cells were depleted from the liver with Gr-1 antibody treatment, enhanced liver injury was observed at 9 days after halothane rechallenge. Toxicity was associated with increased serum levels of interleukin-4 and immunoglobulins G1 and E directed against hepatic trifluoroacetylated protein adducts, as well as increased hepatic infiltration of eosinophils and CD4(+) T cells, all features of an allergic reaction. When hepatic CD4(+) T cells were depleted 5 days after halothane rechallenge, trifluoroacetylated protein adduct specific serum immunoglobulin and hepatotoxicity were reduced. CONCLUSION: Our data provide a rational approach for developing animal models of drug-induced allergic hepatitis mediated by the adaptive immune system and suggest that impaired liver tolerance may predispose patients to this disease. PMID- 25712248 TI - Association of PELI1 polymorphisms in systemic lupus erythematosus susceptibility in a Chinese population. AB - OBJECTIVE: Studies in animal models have indicated that Pellino 1 is involved in inflammatory and autoimmune diseases, such as systemic lupus erythematosus (SLE). The current study was designed to determine whether PELI1 confers genetic susceptibility to SLE in humans, as assessed in a Chinese Han population. METHODS: Blood samples were drawn from patients diagnosed with SLE and healthy volunteers. Three single nucleotide polymorphism (SNP) loci with a minor allele frequency of at least 0.05 were chosen to evaluate the correlation between PELI1 genotype and the incidence of SLE. RESULTS: There was a significant difference in the frequency distribution of the rs329497 allele between the SLE patients and the healthy controls (A vs. G; Bonferroni corrected p = 0.036, odds ratio = 0.75, 95% confidence interval = 0.60-0.94). No differences in the genotype and allele frequencies of other SNP loci were observed between the two groups. Furthermore, the alleles and genotypes of the three SNPs were not associated with lupus nephritis. CONCLUSION: In the Chinese Han population, PELI1 SNPs may be associated with SLE susceptibility. PMID- 25712249 TI - Childhood lupus nephritis in a developing country-24 years' single-center experience from North India. AB - OBJECTIVE: Data on outcome of childhood lupus nephritis from developing countries are sparse. This study looks at outcome in children with lupus nephritis from a federal government-funded teaching hospital in North India. METHODS: This study included children less than 14 years of age with lupus nephritis who presented to a single center during a period of 24 years (1991 to 2013). Data on clinical characteristics and outcome were extracted from medical records. The primary outcome was actuarial survival (time-to-death) and secondary outcome was actuarial renal survival using Kaplan-Meier analysis. A worst-case scenario that assumed children who were lost to follow-up as having either died or gone into end-stage renal disease was also calculated. Log-rank test and Cox-regression were used to assess difference in survival by histological class and predictors of poor outcome, respectively. RESULTS: This study included 72 children, with a female:male ratio of 3:1, mean (+/-SD) age at onset of lupus 9.3 (+/-2.4) years and mean (+/-SD) time from onset-to-nephritis being 9.4 (+/-12.6) months. Renal biopsy was conducted in 53 children. The most common histological class was class IV (35 children). Mortality occurred in 22 children (30%), with half of these occurring at presentation. The two important causes of death were infection and end-stage renal disease. Actuarial survival was 81%, 67% and 59% at one, five and 10 years, respectively. In the worst-case scenario, actuarial survival was 72%, 53% and 38%, respectively. Renal survival was 96%, 89% and 78% (worst-case scenario 86%, 73% and 52%) at one, five and 10 years, respectively. There was no difference in survival by histological class. On univariate analysis, serum creatinine at presentation (hazard ratio = 2.2 (95% CI 1.3-3.9)) and serious infection (hazard ratio 7.9 (95% CI 2.6-23.5)) were statistically significant predictors of time-to-death. CONCLUSION: Outcome of children with lupus nephritis from India is worse than developed countries. Nearly one-third of the children died, half at presentation, with common causes being infection and end-stage renal disease. PMID- 25712250 TI - Pregnancy and patients with preexisting lupus nephritis: 15 years of experience at a single center in Korea. AB - We investigated obstetric outcomes and comorbidities during pregnancy in females with preexisting lupus nephritis (LN) and identified predictors for renal flare. In cases of renal flare during pregnancy, we assessed the long-term post-delivery renal outcome. We performed a retrospective analysis of 183 systemic lupus erythematosus (SLE) pregnancies including blood chemistry, urinalysis, urinary protein, and disease activity recorded at prepregnancy, during pregnancy, and at one month, six months, and one year post-delivery. Pregnancies with preexisting LN had a greater frequency of adverse obstetric outcomes and maternal comorbidity. Renal flares occurred in 50.7% of pregnancies with preexisting LN, 89.2% of which were reactivations. Renal flare among pregnancies with SLE was predicted based on preexisting lupus nephritis (OR 17.73; 95% CI, 5.770-54.484), an active disease prior to pregnancy (OR 2.743; 95% CI, 1.074-7.004), and prepregnancy eGFR < 90 ml/min/1.73 m(2) (OR 11.151; 95% CI, 3.292-37.768). Persistent LN one year after delivery was observed in 33.3% of pregnancies. The median follow-up time after delivery was 5.9 (3.1-9.7) years and chronic kidney disease (CKD) occurred in 21.4% of pregnancies with renal flare. In patients with renal flare, failing to achieve a >= 50% reduction in urine protein levels within six months, longer total duration of renal flare, and acute kidney injury at renal flare was associated with CKD development. Females with preexisting LN should achieve remission before pregnancy. When patients experience renal flares during pregnancy, it is important to reduce the proteinuria level by >50% within six months and to achieve early remission for excellent long-term renal outcomes. PMID- 25712251 TI - Wilms tumor and breast cancer. PMID- 25712252 TI - Bioanalysis of acetylcarnitine in cerebrospinal fluid by HILIC-mass spectrometry. AB - Acetyl-L-carnitine (ALCAR) is a potential biomarker for the modulation of brain neurotransmitter activity, but is also present in cerebrospinal fluid (CSF). Recent studies have utilized hydrophilic interaction liquid chromatography-tandem mass spectrometry (HILIC-MS/MS) based assays to detect and quantify ALCAR within biofluids such as urine, plasma and serum, using various sample pretreatment procedures. In order to address the need to quantify ALCAR in CSF on a high throughput scale, a new and simple HILIC-MS/MS assay has been successfully developed and validated. For rapid analysis, CSF sample pretreatment was performed via 'dilute and shoot' directly onto an advanced HILIC column prior to MS/MS detection. This newly developed HILIC-MS/MS assay shows good recoveries of ALCAR without the need for chemical derivatization and multistep sample extraction procedures. The employment of this assay is suitable for the high throughput bioanalysis and quantification of ALCAR within the CSF of various animal models and human clinical studies. PMID- 25712253 TI - Community pharmacists' experience and perceptions of the New Medicines Service (NMS). AB - OBJECTIVES: The New Medicines Service (NMS) is provided by community pharmacists in England to support patient adherence after the initiation of a new treatment. It is provided as part of the National Health Service (NHS) pharmacy contractual framework and involves a three-stage process: patient engagement, intervention and follow-up. The study aims to explore community pharmacists' experiences and perceptions of NMS within one area of the United Kingdom. METHODS: In-depth semi structured telephone interviews were conducted with 14 community pharmacists. Interviews were audio-recorded, independently transcribed and thematically analysed. KEY FINDINGS: Pharmacists gave a mixed response to the operationalisation, ranging from positive opportunities for improving adherence and enhancement of practice to difficulties in terms of its administration. Pharmacists generally welcomed opportunities to utilise their professional expertise to achieve better patient engagement and for pharmacy practice to develop as a patient resource. There was a perceived need for better publicity about the service. Different levels of collaborative working were reported. Some pharmacists were working closely with local general practices most were not. Collaboration with nurses in the management of long-term conditions was rarely reported but desired by pharmacists. Where relationships with general practitioners (GPs) and nurses were established, NMS was an opportunity for further collaboration; however, others reported a lack of feedback and recognition of their role. CONCLUSIONS: Community pharmacists perceived the NMS service as beneficial to patients by providing additional advice and reassurance, but perceptions of its operationalisation were mixed. Overall, our findings indicate that NMS provides an opportunity for patient benefit and the development of contemporary pharmacy practice, but better collaboration with GPs and practice nurses could enhance the service. PMID- 25712255 TI - Effect of Vitamin B12 and Folic Acid Supplementation on Bone Mineral Density and Quantitative Ultrasound Parameters in Older People with an Elevated Plasma Homocysteine Level: B-PROOF, a Randomized Controlled Trial. AB - High plasma homocysteine (Hcy) levels are associated with increased osteoporotic fracture incidence. However, the mechanism remains unclear. We investigated the effect of Hcy-lowering vitamin B12 and folic acid treatment on bone mineral density (BMD) and calcaneal quantitative ultrasound (QUS) parameters. This randomized, double-blind, placebo-controlled trial included participants aged >=65 years with plasma Hcy levels between 12 and 50 umol/L. The intervention comprised 2-year supplementation with either a combination of 500 ug B12, 400 ug folic acid, and 600 IU vitamin D or placebo with 600 IU vitamin D only. In total, 1111 participants underwent repeated dual-energy X-ray assessment and 1165 participants underwent QUS. Femoral neck (FN) BMD, lumbar spine (LS) BMD, calcaneal broadband ultrasound attenuation (BUA), and calcaneal speed of sound (SOS) were assessed. After 2 years, FN-BMD and BUA had significantly decreased, while LS-BMD significantly increased (all p < 0.01) and SOS did not change in either treatment arm. No statistically significant differences between the intervention and placebo group were present for FN-BMD (p = 0.24), LS-BMD (p = 0.16), SOS (p = 0.67), and BUA (p = 0.96). However, exploratory subgroup analyses revealed a small positive effect of the intervention on BUA at follow-up among compliant persons >80 years (estimated marginal mean 64.4 dB/MHz for the intervention group and 61.0 dB/MHz for the placebo group, p = 0.04 for difference). In conclusion, this study showed no overall effect of treatment with vitamin B12 and folic acid on BMD or QUS parameters in elderly, mildly hyperhomocysteinemic persons, but suggests a small beneficial effect on BUA in persons >80 years who were compliant in taking the supplement. PMID- 25712254 TI - Ubiquitin E3 Ligase LNX2 is Critical for Osteoclastogenesis In Vitro by Regulating M-CSF/RANKL Signaling and Notch2. AB - The Notch signaling pathway plays a crucial role in skeletal development and homeostasis by regulating the proliferation and differentiation of osteoblasts and osteoclasts. However, the molecular mechanisms modulating the level and activity of Notch receptors in bone cells remain unknown. In this study, we uncovered that LNX2, an E3 ubiquitin ligase and Notch inhibitor Numb binding protein, was up-regulated during osteoclast differentiation. Knocking-down LNX2 expression in bone marrow macrophages by lentivirus-mediated short hairpin RNAs markedly inhibited osteoclast formation. Decreased LNX2 expression attenuated macrophage colony-stimulating factor (M-CSF)-induced ERK and AKT activation and RANKL-stimulated activation of NF-kappaB and JNK pathways; therefore, accelerated osteoclast apoptosis. Additionally, loss of LNX2 led to an increased accumulation of Numb, which promoted the degradation of Notch and caused a reduction of the expression of the Notch downstream target gene, Hes1. We conclude that LNX2 regulates M-CSF/RANKL and the Notch signaling pathways during osteoclastogenesis. PMID- 25712256 TI - Bone's Material Constituents and their Contribution to Bone Strength in Health, Disease, and Treatment. AB - Type 1 collagen matrix volume, its degree of completeness of its mineralization, the extent of collagen crosslinking and water content, and the non-collagenous proteins like osteopontin and osteocalcin comprise the main constituents of bone's material composition. Each influences material strength and change in different ways during advancing age, health, disease, and drug therapy. These traits are not quantifiable using bone densitometry and their plurality is better captured by the term bone 'qualities' than 'quality'. These qualities are the subject of this manuscript. PMID- 25712257 TI - The generation of C-3alpha epimer of 25-hydroxyvitamin D and its biological effects on bone mineral density in adult rodents. AB - The source and function of C-3alpha epimer of 25(OH)D (C-3 epimer) is unknown. The objectives were to (1) establish if increasing doses of vitamin D (VD) results in a proportionate dose-response in C-3 epimer; and (2) determine the biological response of bone to C-3 epimer treatment. Sprague Dawley rats (12 weeks, n = 36 female, n = 36 male) were randomized to control AIN93-M diet (1 IU VD3/g diet) or an experimental diet for 8 weeks containing VD3 at 2 or 4 IU/g diet, C-3 epimer at 0.5 or 1 IU/g diet or 25(OH)D (0.5 IU/g diet). BW and food consumption were measured weekly. Blood was sampled at week 0, 4, and 8 for assessment of VD metabolites and bone metabolism biomarkers. DXA (week 0, 4, and 8) and in vivo micro CT (MUCT) (week 0 and 8) were performed in vivo plus ex vivo MUCT imaging and bone biomechanics. Dietary intake and anthropometry did not differ among diet groups. The dose-response of VD generated significantly elevated C-3 epimer only in females with concentrations of 4 IU VD diet group [mean 84.6 (62.5) nmol/L] exceeding control [mean 21.4 (18.5) nmol/L, p = 0.005]. Both sexes in the 25(OH)D group did not show significant increases in C-3 epimer, whereas 0.5 and 1 IU epimer groups exceeded 100 nmol/L of C-3 epimer by 8 weeks. These data suggest C-3 epimer is endogenously generated with higher intakes of VD. Endogenous and exogenous C-3 epimer accumulates in serum without impact upon bone health outcomes in a healthy young adult model over 8 weeks. PMID- 25712258 TI - Hospital readmission of patients with diabetes. AB - Hospital readmission is a high-priority health care quality measure and target for cost reduction. Despite broad interest in readmission, relatively little research has focused on patients with diabetes. The burden of diabetes among hospitalized patients, however, is substantial, growing, and costly, and readmissions contribute a significant portion of this burden. Reducing readmission rates of diabetic patients has the potential to greatly reduce health care costs while simultaneously improving care. Risk factors for readmission in this population include lower socioeconomic status, racial/ethnic minority, comorbidity burden, public insurance, emergent or urgent admission, and a history of recent prior hospitalization. Hospitalized patients with diabetes may be at higher risk of readmission than those without diabetes. Potential ways to reduce readmission risk are inpatient education, specialty care, better discharge instructions, coordination of care, and post-discharge support. More studies are needed to test the effect of these interventions on the readmission rates of patients with diabetes. PMID- 25712259 TI - Emotions, immunity and sport: Winner and loser athlete's profile of fighting sport. AB - Several studies have focused on the relationship between hormonal changes and affective states in sporting contexts relating to an agonistic outcome. More recently, pro-inflammatory cytokines have also been successfully associated with affective state modulation. The aim of this study was to investigate whether athletes who won or lost show different levels of steroid hormones (testosterone and cortisol), pro-inflammatory cytokine IL-1beta, or expressions of anger and anxiety during six training fights in seasonal competitions down to the main seasonal competition. In 25 male kick-boxing athletes (age+/-SD, 28.68+/-5.34), anger states (RS score) and anxiety states (AS score) were assessed by STAXI-2 and STAI-Y, respectively. Cortisol (C), testosterone (T) and IL-1beta salivary levels were measured by the ELISA method. The saliva samples were taken in the afternoon, 30min prior to the start and 30min from the end of both simulated and official competitions. The results showed that the RS score, T, T/C ratio salivary levels increased during the season, whereas the AS score, C and IL-1beta suggested an opposite trend. Close to an official competition, the RS score, T, T/C ratio and IL-1beta salivary concentrations were significantly higher, and then decreased during competition. By contrast, the AS score and C levels significantly increased throughout the official competition. In addition, significant differences were found for hormones and IL-1beta concentrations as well as psychometric assessment close to the outcome of an official match. Athletes who lost showed an higher AS score and C level, while those who won were characterized by an higher level during the pre-competition RS score, T, T/C ratio, and IL-1beta. Note that these factors were positively and significantly correlated at the pre-official competition time, while in a linear regression analysis, IL-1beta, T and T/C ratio concentrations explained 43% of the variance in the RS score observed at the same time (adjusted R(2)=0.43, ANOVA P<.05). Our data suggest that the beginning of an agonistic event could trigger emotional responses which correspond to different biological processes instead that of a simulated fight. In particular, IL-1beta could be a potential new biological marker of anger and the combined measurement of these factors may be a useful way of understanding athletes' change in relation to their performance. PMID- 25712260 TI - Tlr4 upregulation in the brain accompanies depression- and anxiety-like behaviors induced by a high-cholesterol diet. AB - An association between metabolic abnormalities, hypercholesterolemia and affective disorders is now well recognized. Less well understood are the molecular mechanisms, both in brain and in the periphery, that underpin this phenomenon. In addition to hepatic lipid accumulation and inflammation, C57BL/6J mice fed a high-cholesterol diet (0.2%) to induce non-alcoholic fatty liver disease (NAFLD), exhibited behavioral despair, anxiogenic changes, and hyperlocomotion under bright light. These abnormalities were accompanied by increased expression of transcript and protein for Toll-like receptor 4, a pathogen-associated molecular pattern (PAMP) receptor, in the prefrontal cortex and the liver. The behavioral changes and Tlr4 expression were reversed ten days after discontinuation of the high-cholesterol diet. Remarkably, the dietary fat content and body mass of experimental mice were unchanged, suggesting a specific role for cholesterol in the molecular and behavioral changes. Expression of Sert and Cox1 were unaltered. Together, our study has demonstrated for the first time that high consumption of cholesterol results in depression- and anxiety-like changes in C57BL/6J mice and that these changes are unexpectedly associated with the increased expression of TLR4, which suggests that TLR4 may have a distinct role in the CNS unrelated to pathogen recognition. PMID- 25712261 TI - Biological databases for human research. AB - The completion of the Human Genome Project lays a foundation for systematically studying the human genome from evolutionary history to precision medicine against diseases. With the explosive growth of biological data, there is an increasing number of biological databases that have been developed in aid of human-related research. Here we present a collection of human-related biological databases and provide a mini-review by classifying them into different categories according to their data types. As human-related databases continue to grow not only in count but also in volume, challenges are ahead in big data storage, processing, exchange and curation. PMID- 25712262 TI - YPED: an integrated bioinformatics suite and database for mass spectrometry-based proteomics research. AB - We report a significantly-enhanced bioinformatics suite and database for proteomics research called Yale Protein Expression Database (YPED) that is used by investigators at more than 300 institutions worldwide. YPED meets the data management, archival, and analysis needs of a high-throughput mass spectrometry based proteomics research ranging from a single laboratory, group of laboratories within and beyond an institution, to the entire proteomics community. The current version is a significant improvement over the first version in that it contains new modules for liquid chromatography-tandem mass spectrometry (LC-MS/MS) database search results, label and label-free quantitative proteomic analysis, and several scoring outputs for phosphopeptide site localization. In addition, we have added both peptide and protein comparative analysis tools to enable pairwise analysis of distinct peptides/proteins in each sample and of overlapping peptides/proteins between all samples in multiple datasets. We have also implemented a targeted proteomics module for automated multiple reaction monitoring (MRM)/selective reaction monitoring (SRM) assay development. We have linked YPED's database search results and both label-based and label-free fold change analysis to the Skyline Panorama repository for online spectra visualization. In addition, we have built enhanced functionality to curate peptide identifications into an MS/MS peptide spectral library for all of our protein database search identification results. PMID- 25712264 TI - Neonatal necrotizing fasciitis of the scrotum caused by Streptococcus agalactiae. AB - We herein describe the case of a 27-day-old male infant who was brought to the emergency room for intermittent crying, and swelling of the left scrotum. Based on the clinical findings, necrotizing fasciitis was suspected, and surgical intervention was successfully completed within a few hours of admission. Streptococcus agalactiae type Ia was cultured from the drained abscess, and was considered the causative pathogen. To our knowledge, this is the first report of neonatal necrotizing fasciitis caused by S. agalactiae. Prompt diagnosis and immediate surgical debridement are crucial in the initial management of this disease. PMID- 25712265 TI - Marcel Storr: a new case of clandestine outsider art. PMID- 25712263 TI - Entinostat, a novel histone deacetylase inhibitor is active in B-cell lymphoma and enhances the anti-tumour activity of rituximab and chemotherapy agents. AB - Histone deacetylases (HDACs) inhibitors are active in T-cell lymphoma and are undergoing pre-clinical and clinical testing in other neoplasms. Entinostat is an orally bioavailable class I HDAC inhibitor with a long half-life, which is under evaluation in haematological and solid tumour malignancies. To define the activity and biological effects of entinostat in B-cell lymphoma we studied its anti-tumour activity in several rituximab-sensitive or -resistant pre-clinical models. We demonstrated that entinostat is active in rituximab-sensitive cell lines (RSCL), rituximab-resistant cell lines (RRCL) and primary tumour cells isolated from lymphoma patients (n = 36). Entinostat exposure decreased Bcl-XL (BCL2L1) levels and induced apoptosis in cells. In RSCL and RRCL, entinostat induced p21 (CDKN1A) expression leading to G1 cell cycle arrest and exhibited additive effects when combined with bortezomib or cytarabine. Caspase inhibition diminished entinostat activity in some primary tumour cells suggesting that entinostat has dual mechanisms-of-action. In addition, entinostat increased the expression of CD20 and adhesion molecules. Perhaps related to these effects, we observed a synergistic activity between entinostat and rituximab in a lymphoma bearing severe combined immunodeficiency (SCID) mouse model. Our data suggests that entinostat is an active HDAC inhibitor that potentiates rituximab activity in vivo and supports its further clinical development in B-cell lymphoma. PMID- 25712268 TI - Length of hospital stay after hip fracture: how low can we go before patients are at risk? PMID- 25712267 TI - Anemia in young patients with ischaemic stroke. AB - BACKGROUND AND PURPOSE: To investigate the association of anemia on admission with ischaemic stroke (IS), stroke severity and early functional outcome in patients with cervical artery dissection (CeAD) or with IS of other causes (non CeAD-IS patients). METHODS: The study sample comprised all patients from the Cervical Artery Dissection and Ischaemic Stroke Patients (CADISP) study without pre-existing disability and with documentation of stroke severity and hemoglobin (Hb) concentration on admission. Anemia was classified as mild (Hb < 12 g/dl in women and Hb < 13 g/dl in men) or moderate to severe (Hb < 10 g/dl in women and Hb < 11 g/dl in men). Stroke severity on admission was assessed with the National Institutes of Health Stroke Scale (NIHSS). Outcome after 3 months was assessed with the modified Rankin Scale (mRS-3mo). Unfavorable outcome was defined as mRS 3mo >= 3. RESULTS: Amongst 1206 study patients (691 CeAD and 515 non-CeAD), 87 (7.2%) had anemia, which was moderate to severe in 18 (1.5%) patients. Anemia was associated with female sex in both study samples, but no further associations with risk factors or comorbidities were observed. In CeAD patients, anemia was associated with occurrence of stroke (P = 0.042). In both study samples, anemic patients had more severe strokes (CeAD, P = 0.023; non-CeAD, P = 0.005). Functional outcome was not associated with anemia in general, but moderate to severe anemia was significantly associated with unfavorable outcome (P = 0.004). CONCLUSION: Anemia on admission was associated with stroke in CeAD patients and with more severe strokes in both study samples. Moderate to severe anemia may predict unfavorable outcome. PMID- 25712266 TI - KdmA, a histone H3 demethylase with bipartite function, differentially regulates primary and secondary metabolism in Aspergillus nidulans. AB - Aspergillus nidulans kdmA encodes a member of the KDM4 family of jumonji histone demethylase proteins, highly similar to metazoan orthologues both within functional domains and in domain architecture. This family of proteins exhibits demethylase activity towards lysines 9 and 36 of histone H3 and plays a prominent role in gene expression and chromosome structure in many species. Mass spectrometry mapping of A. nidulans histones revealed that around 3% of bulk histone H3 carried trimethylated H3K9 (H3K9me3) but more than 90% of histones carried either H3K36me2 or H3K36me3. KdmA functions as H3K36me3 demethylase and has roles in transcriptional regulation. Genetic manipulation of KdmA levels is tolerated without obvious effect in most conditions, but strong phenotypes are evident under various conditions of stress. Transcriptome analysis revealed that in submerged early and late cultures - between 25% and 30% of the genome is under KdmA influence respectively. Transcriptional imbalance in the kdmA deletion mutant may contribute to the lethal phenotype observed upon exposure of mutant cells to low-density visible light on solid medium. Although KdmA acts as transcriptional co-repressor of primary metabolism genes, it is required for full expression of several genes involved in biosynthesis of secondary metabolites. PMID- 25712269 TI - Pharmacotherapy in chronic kidney disease patients presenting with acute coronary syndrome: a scientific statement from the American Heart Association. PMID- 25712270 TI - Afadin regulates RhoA/Rho-associated protein kinase signaling to control formation of actin stress fibers in kidney podocytes. AB - The function of kidney podocytes is closely associated with actin cytoskeleton. Rho family small GTPase RhoA promotes stress fiber assembly through Rho associated protein kinase (ROCK)-dependent myosin II phosphorylation and plays an important role in maintenance of actin stress fibers of podocytes. However, little is known how stress fiber assembly is regulated in podocytes. Here, we found that afadin, an actin filament-binding protein, is required for RhoA/ROCK dependent formation of actin stress fibers in rat podocyte C7 cells. We show that depletion of afadin in C7 cells induced loss of actin stress fibers. Conversely, forced expression of afadin increased the formation of actin stress fibers. Depletion of afadin inactivated RhoA and reduced the phosphorylation of myosin II. Moreover, the DIL domain of afadin appears to be responsible for actin stress fiber formation. Thus, afadin mediates RhoA/ROCK signaling and contributes to the formation of actin stress fibers in podocyte cells. PMID- 25712271 TI - Diversity trends in bread wheat in Italy during the 20th century assessed by traditional and multivariate approaches. AB - A collection of 157 Triticum aestivum accessions, representative of wheat breeding in Italy during the 20(th) century, was assembled to describe the evolutionary trends of cultivated varieties throughout this period. The lines were cultivated in Italy, in two locations, over two growing seasons, and evaluated for several agronomical, morphological and qualitative traits. Analyses were conducted using the most common univariate approach on individual plant traits coupled with a correspondance multivariate approach. ANOVA showed a clear trend from old to new varieties, leading towards earliness, plant height reduction and denser spikes with smaller seeds. The average protein content gradually decreased over time; however this trend did not affect bread-making quality, because it was counterbalanced by a gradual increase of SDS sedimentation volume, achieved by the incorporation of favourable alleles into recent cultivars. Correspondence analysis allowed an overall view of the breeding activity. A clear-cut separation was observed between ancient lines and all the others, matched with a two-step gradient, the first, corresponding roughly to the period 1920-1940, which can be ascribed mostly to genetics, the second, from the 40s onward, which can be ascribed also to the farming practice innovations, such as improvement of mechanical devices and optimised use of fertilizers. PMID- 25712272 TI - Ice cover extent drives phytoplankton and bacterial community structure in a large north-temperate lake: implications for a warming climate. AB - Mid-winter limnological surveys of Lake Erie captured extremes in ice extent ranging from expansive ice cover in 2010 and 2011 to nearly ice-free waters in 2012. Consistent with a warming climate, ice cover on the Great Lakes is in decline, thus the ice-free condition encountered may foreshadow the lakes future winter state. Here, we show that pronounced changes in annual ice cover are accompanied by equally important shifts in phytoplankton and bacterial community structure. Expansive ice cover supported phytoplankton blooms of filamentous diatoms. By comparison, ice free conditions promoted the growth of smaller sized cells that attained lower total biomass. We propose that isothermal mixing and elevated turbidity in the absence of ice cover resulted in light limitation of the phytoplankton during winter. Additional insights into microbial community dynamics were gleaned from short 16S rRNA tag (Itag) Illumina sequencing. UniFrac analysis of Itag sequences showed clear separation of microbial communities related to presence or absence of ice cover. Whereas the ecological implications of the changing bacterial community are unclear at this time, it is likely that the observed shift from a phytoplankton community dominated by filamentous diatoms to smaller cells will have far reaching ecosystem effects including food web disruptions. PMID- 25712274 TI - The 60th Anniversary of the American College of Nurse-Midwives: honoring our past, celebrating our present, forging the future. PMID- 25712273 TI - Utility of sentinel lymph node biopsy for solitary dermal melanomas. AB - BACKGROUND AND OBJECTIVES: Solitary dermal melanoma (SDM) is melanoma confined to subcutaneous and/or dermal layers in the absence of a known primary cutaneous lesion. We hypothesized that sentinel node biopsy is an effective staging strategy for this rare disease. METHODS: A Markov decision model was constructed to represent two management strategies for SDM: wide local excision followed by observation, and wide local excision followed by sentinel node biopsy. Utilities, likelihood of positive sentinel node biopsy, and cancer progression rates during a five year time horizon were assigned based on institutional data and a review of existing literature. Estimated costs were derived using Medicare reimbursements. RESULTS: Excision followed by sentinel node biopsy provides greater utility, yielding 3.85 discounted quality-adjusted life years (dQALY) compared to 3.66 for excision alone. The incremental cost-effectiveness ratio for sentinel node biopsy is $19,102 per dQALY. Sensitivity analyzes demonstrated that observation is more cost-effective if greater than 23% of sentinel node biopsies are positive (16% reported), or if 5-year survival for observed patients is greater than 76% (69% reported). CONCLUSIONS: Based on existing clinical evidence, sentinel node biopsy yields greater utility than excision alone and is cost-effective for patients presenting with solitary dermal melanoma. PMID- 25712275 TI - The Journal of Midwifery & Women's Health 2005-2015: a decade of transformation and success. PMID- 25712276 TI - Midwife-attended births in the United States, 1990-2012: results from revised birth certificate data. AB - INTRODUCTION: Data on attendance at birth by midwives in the United States have been available on the national level since 1989, allowing for the documentation of long-term trends. New items on payer source and prepregnancy body mass index (BMI) from a 2003 revision of the birth certificate provide an opportunity to examine additional aspects of US midwifery practice. METHODS: The data in this report are based on records on birth attendant gathered as part of the US National Standard Certificate of Live Birth from a public use Web site, Vital Stats (http://www.cdc.gov/nchs/VitalStats.htm), which allows users to create and download specialized tables. Analysis of new items on prepregnancy BMI and birth payer source are limited to the 38 states (86% of US births) that adopted the revised birth certificate by 2012. RESULTS: Between 1989 and 2012, the proportion of all births attended by certified nurse-midwives (CNMs) increased from 3.3% to 7.9%. The proportion of vaginal births attended by CNMs reached an all-time high of 11.9%. Births attended by "other midwives" (typically certified professional midwives) rose to a peak of 28,343, or 0.7% of all US births. The distribution of payer source for CNM-attended births (44% Medicaid; 44% private insurance; 6% self-pay) is very similar to the national distribution, whereas the majority (53%) of births attended by other midwives are self-pay. Women whose births are attended by other midwives are less likely (13%) to have a prepregnancy BMI in the obese range than women attended by CNMs (19%) or overall (24%). DISCUSSION: The total number of births attended by CNMs and other midwives has remained steady or grown at a time when total US births have declined, resulting in the largest proportions of midwife-attended births in the quarter century that such data have been collected. PMID- 25712277 TI - An update on current prenatal testing options: first trimester and noninvasive prenatal testing. AB - Prenatal genetic testing is rapidly evolving and requires that prenatal care providers stay up-to-date with accurate, evidence-based knowledge. Noninvasive prenatal testing (NIPT), first trimester maternal serum markers, and fetal nuchal translucency are the most recently developed screening tests added to the testing repertoire for detection of chromosomal disorders such as trisomy 21 (Down syndrome). NIPT is a new, highly accurate technique that uses maternal serum and is rapidly being introduced as a first trimester screening tool and increasingly being requested by pregnant women. The American College of Obstetricians and Gynecologists recommends that all pregnant women be offered first and second trimester screening options, regardless of risk status, but does not yet recommend NIPT. It is important for prenatal care providers to be aware of and understand these testing options in order to assist women and their families in making well-informed decisions during pregnancy. The purpose of this article is to update midwives and other prenatal care providers on the current prenatal genetic testing options available and how to appropriately offer and discuss them with their clients. We discuss how these tests work; what to do with the results; and most importantly, how to support and communicate accurate information to women and families as they navigate through an increasingly complicated array of testing choices. PMID- 25712278 TI - Obstetric anal sphincter injury and anal incontinence following vaginal birth: a systematic review and meta-analysis. AB - INTRODUCTION: The aim of this study was to systematically review current evidence for the relationship between obstetric anal sphincter injury (ie, episiotomy and third- or fourth-degree perineal lacerations) and anal incontinence in parous women. METHODS: PubMed, Ovid (MEDLINE), Cochrane Trials, and Cumulative Index to Nursing and Allied Health Literature were searched. Studies eligible for review assessed the relationship between episiotomy and/or third- or fourth-degree perineal laceration and anal incontinence. Two reviewers independently searched for studies for review and used the Meta-Analysis of Observational Studies in Epidemiology guidelines. Quality of individual studies was appraised using the Downs and Black criteria. Pooled effect sizes were estimated for the relationships between episiotomy and third- or fourth-degree perineal laceration with anal incontinence using random effects meta-analysis models. Heterogeneity of each model was assessed using Cochran Q and I(2) statistics. RESULTS: Of 578 articles, 19 studies (7 prospective cohort studies, 6 retrospective studies, one case-control study, and 5 population-based cross-sectional studies) met inclusion/exclusion criteria for the systematic review. Of the 19 studies, 3 examined episiotomy, 7 examined third- or fourth-degree perineal laceration, and 9 studies examined both risk factors for anal incontinence. Eight studies (N = 2929 women) examining the relationship between episiotomy and anal incontinence and 12 studies (N = 2288 women) examining the relationship between third- or fourth-degree perineal laceration and anal incontinence met criteria for inclusion in the meta-analyses. Pooled odds ratios (ORs) demonstrated a significant association between perineal trauma (episiotomy [OR, 1.74; 95% confidence interval [CI], 1.28-2.38; Q = 8.9; P < .26; I(2) = 21.4] and third- or fourth-degree perineal laceration (OR, 2.66; 95% CI, 1.77-3.98; Q = 27.9; P = .002; I2 = 64.1) and anal incontinence. DISCUSSION: Both episiotomy and third- or fourth-degree perineal laceration are significantly associated with anal incontinence after vaginal birth. The evidence provided in this systematic review and meta-analysis highlights the importance of reducing perineal trauma during vaginal births in order to ameliorate anal incontinence in parous women. PMID- 25712279 TI - The Midwifery Legacies Project: history, progress, and future directions. AB - The Midwifery Legacies Project, formerly known as the OnGoing Group, was founded as an annual greeting card outreach aimed at maintaining contact with midwives as they approached retirement and beyond. In 2009, the importance of documenting personal and professional stories of midwives arose out of a bequest by a midwife who was relatively unknown outside of the community she served. The result has been the evolution of a robust collection of stories, which are known as the 20th Century Midwife Story Collection. Between 2009 and 2014, more than 120 US midwives aged 65 years or older were interviewed by a midwife, a student midwife, or a professional filmmaker. Collectively, these midwives' stories offer an intimate snapshot of the social, political, and cultural influences that have shaped US midwifery during the past half century. Individually, the stories honor and recognize midwives' contributions to the profession and the women they have served. This article details the development, progress, and future directions of the Midwifery Legacies Project. PMID- 25712280 TI - Isolated intracardiac echogenic focus on routine ultrasound: implications for practice. AB - Ultrasound is widely used as a screening tool for fetal anomalies. An intracardiac echogenic focus (ICEF) is associated with fetal aneuploidy, particularly trisomy 21, when found with other minor abnormalities known as soft markers. However, when found in isolation, intracardiac echogenic foci are morphologic variations with little or no pathologic significance for the fetus. Ambiguity about the significance of ICEF and other soft markers and the lack of preparation prior to ultrasound can result in unnecessary worry for women and their partners. A variety of tools exist that providers can use to help pregnant women and their partners make informed decisions about ultrasound and fetal screening. PMID- 25712281 TI - Honoring U.S. midwife researchers. Part I: theorists and historical influences. PMID- 25712285 TI - Share with women. Alcohol and pregnancy. PMID- 25712287 TI - Do Cardiovascular Risk Factors and Coronary SYNTAX Score Predict Contrast Volume Use During Cardiac Catheterization? AB - The association of cardiovascular risk factors and complexity and severity of coronary artery disease with contrast volume (CV) remains unknown. We assessed the predictive factors of CV use during elective and emergent cardiac catheterization (CC). Electronic medical records from 2010 to 2013 were retrospectively reviewed. A total of 708 patients were eligible. On multivariable regression analysis, the presence of obstructed coronary arteries was associated with CV (P = .01, beta = -14.17), with greater CV used in patients with single or double vessel disease compared to those with triple vessel disease. The presence of lesions with >70% stenosis in major epicardial arteries (P = .019, beta = 24.39) and ST-segment elevation myocardial infarction (P = .001, beta = 36.14) was associated with increased CV use. Elevated B-type natriuretic peptide (P = .036, beta = -17.23) and increase in Synergy between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery score (P = .024, beta = -29.06) were associated with decreased CV use. These aforementioned associations were attenuated after adjusting for percutaneous coronary intervention. Our findings may help predict patient populations who could be exposed to increased CV during CC, thereby possibly increasing their risk of contrast-induced nephropathy. PMID- 25712288 TI - Relationship of Systolic Blood Pressure and Body Mass Index With Left Ventricular Mass and Mass Index in Adolescents. AB - Prevalence of hypertension (HT) is growing among children and adolescents. Its diagnosis is commonly ignored as it does not produce any end-organ damage in adolescents. We evaluated whether the blood pressure (BP) and confounding factors were related to myocardial mass increase; an earlier representative of HT; among adolescents. We have demonstrated that heart rate, body mass index (BMI), left ventricular mass (LVM), interventricular septum, and LV mass indexed to body surface area (BSA) and height significantly increased as the category of BP increased. We have also showed that the systolic BP (SBP), diastolic BP (DBP), and BMI were significantly correlated with the LVM and LVM indexed to BSA and height. Linear regression analysis revealed a significant relationship between SBP, BMI, and LVM, LVM indexed to BSA and height. Hypertension may cause myocardial hypertrophy even at a young age. Height is an alternative and practical way of determining the left ventricular mass index (LVMI) in adolescents. The BMI is significantly related to LVM and LVMI as well as SBP and DBP are. The results support that overweight and obesity should be controlled strictly in the management of HT in a young population. PMID- 25712289 TI - High Ankle-Brachial Index Indicates Cardiovascular and Peripheral Arterial Disease in Patients With Type 2 Diabetes. AB - We assessed the association between high ankle-brachial index (ABI) and cardiovascular disease (CVD) and peripheral arterial disease (PAD) in Chinese patients with type 2 diabetes mellitus (T2DM). The ABI was measured, and foot inspection was performed in 2080 outpatients with T2DM. The clinical characters in different ABI levels were analyzed, and the diagnostic value of high ABI to CVD and PAD was determined. Compared with the normal ABI group, the high ABI (>1.3) group had a higher prevalence of CVD and PAD but less than the low ABI (<=0.9) group. High ABI was an independent risk factor for the development of CVD and PAD. Receiver-operating characteristic curve analysis showed that the optimal cutoff of high ABI to predict CVD and PAD was 1.43 and 1.45, respectively. The odds ratio of high ABI for CVD and PAD was 2.25 and 6.97, respectively, after adjusting for other confounding risk factors. In conclusion, high ABI indicated the risk of CVD and PAD in Chinese populations with T2DM. PMID- 25712290 TI - Platelet to Lymphocyte Ratio Can be a Predictor of Infarct-Related Artery Patency in Patients With ST-Segment Elevation Myocardial Infarction. AB - Patency of infarct-related artery (IRA) in patients with ST-segment elevation myocardial infarction (STEMI) before primary percutaneous coronary intervention (pPCI) is associated with lower mortality and better clinical outcome. However, there were little data regarding the predictors of IRA patency before pPCI in the setting of STEMI. We aimed to assess the association of platelet to lymphocyte ratio (PLR) with IRA patency in STEMI. A total of 452 patients were enrolled and categorized as occluded or patent IRA. Patency IRA was assessed by the thrombolysis in myocardial infarction (TIMI) flow grade. Blood samples were obtained on admission to calculate PLR. Of all patients, 92 (20.4%) patients revealed pre-pPCI TIMI 3 flow in IRA. The PLR was significantly higher in occluded IRA group (138.4 +/- 51.4 vs 95.4 +/- 43.5, P < .001). Glucose, troponin I, and neutrophil to lymphocyte ratio (NLR) levels were also higher in occluded IRA group (P < .05). Multivariate regression analysis demonstrated the PLR (odds ratio [OR]: 0.987; 95% confidence interval [CI]: 0.978-0.995, P = .002) and NLR (OR: 0.758; 95% CI: 0.584-0.985, P = .038) on admission as independent predictors of IRA patency. In conclusion, a higher PLR is a powerful and independent predictor of IRA patency in patients with STEMI before pPCI. PMID- 25712291 TI - Metal oxide-coating PMMA or Talc as a new IR blocker inhibits IR-induced decrease of collagens in human dermal fibroblasts. AB - OBJECTIVES: The purpose of this study was whether P/M or T/M inhibits IR-induced decrease of collagens in human dermal fibroblasts, using P/M or T/M blocked near IR (NIR) transmittance significantly in spectrophotometer measurement. METHODS: As metal oxides are effective inorganic molecules for intercepting IR radiation, we have developed metal oxide-coating PMMA (P/M) or Talc (T/M) as a new IR blocker. Inhibitory effect of the new IR blocker on collagen degradation was measured by gene and protein expressions of procollagens and MMPs, respectively, in IR-irradiated Hs68 cell line. RESULTS: Using P/M or T/M inhibited IR-induced increases of MMP-1, MMP-3 and MMP-9, and IR-induced decreases of type 1 and 4 procollagen in a dose-dependent manner in dermal fibroblasts. In addition, using both P/M and T/M blocked the increase of cell media temperature induced by IR lamp. CONCLUSION: The results suggest that P/M or T/M can inhibit decrease of collagens by blocking IR-induced heat transmission in human dermal fibroblasts. PMID- 25712292 TI - Aortic valve disease as a first manifestation of Alcaptonuria in surgically treated patient. Case report. AB - BACKGROUND: Alcaptonuria, a rare metabolic disorder (1:250 000), is usually presented with symptoms such as arthropathies of weight bearing joints. CASE REPORT: In this case, a 65 year old woman was admitted to our hospital with severe aortic stenosis and no other symptoms that would suggest the existance of Alcaptonuria. Intraoperative findings of black discoloration of the affected valve and ascending aorta, pointed towards the diagnosis of cardiac ochronosis, what was then confirmed by a PH examination. CONCLUSION: This case suggests that although alcaptonuria is a slow progressive disease with cardiac ochronosis as a predictable late complication, it can nevertheless be a first sign. In that case the attention should be brought to the surely affected lumbar spine and weight bearing joints, and other connective tissue. KEY WORDS: Alcaptonuria, Aortic valve, Cardiac ochronosis, Surgery. PMID- 25712294 TI - What is wilderness medicine? PMID- 25712293 TI - HER2 expression status in diverse cancers: review of results from 37,992 patients. AB - Human epidermal growth factor receptor 2 (HER2) amplification/overexpression is an effective therapeutic target in breast and gastric cancer. Although HER2 positivity has been reported in other malignancies, previous studies generally focused on one cancer type, making it challenging to compare HER2 positivity across studies/malignancies. Herein, we examined 37,992 patient samples for HER2 expression (+/- amplification) in a single laboratory. All 37,992 patients were tested by immunohistochemistry (IHC); 21,642 of them were also examined for HER2 amplification with either fluorescent in situ hybridization (FISH) (11,670 patients) or chromogenic in situ hybridization (CISH) (9,972 patients); 18,262 patients had tumors other than breast or gastric cancer. All tissues were analyzed in a Clinical Laboratory Improvement Amendments (CLIA) laboratory (Caris Life Sciences) at the request of referring physicians. HER2 protein overexpression was found in 2.7 % of samples. Over-expressed HER2 was detected predominantly in malignancies of epithelial origin; for cancers derived from mesenchyme, neuroendocrine tissue, central nervous system, and kidney, HER2 expression and amplification were remarkably rare or non-existent. Bladder carcinomas, gallbladder, extrahepatic cholangiocarcinomas, cervical, uterine, and testicular cancers showed HER2 positivity rates of 12.4, 9.8, 6.3, 3.9, 3.0, and 2.4 %, respectively. HER2 overexpression and/or amplification is frequently found across tumor types. These observations may have significant therapeutic implications in cancers not traditionally thought to benefit from anti-HER2 therapies. PMID- 25712295 TI - Protection against cold in prehospital care: wet clothing removal or addition of a vapor barrier. AB - OBJECTIVE: The purpose of this study was to evaluate the effect of wet clothing removal or the addition of a vapor barrier in shivering subjects exposed to a cold environment with only limited insulation available. METHODS: Volunteer subjects (n = 8) wearing wet clothing were positioned on a spineboard in a climatic chamber (-18.5 degrees C) and subjected to an initial 20 minutes of cooling followed by 30 minutes of 4 different insulation interventions in a crossover design: 1) 1 woolen blanket; 2) vapor barrier plus 1 woolen blanket; 3) wet clothing removal plus 1 woolen blanket; or 4) 2 woolen blankets. Metabolic rate, core body temperature, skin temperature, and heart rate were continuously monitored, and cold discomfort was evaluated at 5-minute intervals. RESULTS: Wet clothing removal or the addition of a vapor barrier significantly reduced metabolic rate (mean difference +/- SE; 14 +/- 4.7 W/m(2)) and increased skin temperature rewarming (1.0 degrees +/- 0.2 degrees C). Increasing the insulation rendered a similar effect. There were, however, no significant differences in core body temperature or heart rate among any of the conditions. Cold discomfort (median; interquartile range) was significantly lower with the addition of a vapor barrier (4; 2-4.75) and with 2 woolen blankets (3.5; 1.5-4) compared with 1 woolen blanket alone (5; 3.25-6). CONCLUSIONS: In protracted rescue scenarios in cold environments with only limited insulation available, wet clothing removal or the use of a vapor barrier is advocated to limit the need for shivering thermogenesis and improve the patient's condition on admission to the emergency department. PMID- 25712296 TI - Presence of L-canavanine in Hedysarum alpinum seeds and its potential role in the death of Chris McCandless. AB - OBJECTIVE: For the past 2 decades there has been vigorous disagreement over the purported toxicity of Hedysarum alpinum seeds, and whether the consumption of such seeds was a factor in the 1992 death of Chris McCandless, the subject of the book Into the Wild. Our objective was to confirm or disprove the presence of L canavanine (a nonprotein amino acid known to induce systemic lupuslike symptoms in humans) in H alpinum seeds. METHODS: Liquid chromatography-tandem mass spectrometry analysis of H alpinum seeds was performed. RESULTS: Our analysis confirmed the presence of L-canavanine in H alpinum seeds and demonstrated that it is a significant component of the seeds, with a concentration of 1.2% (weight/weight), roughly half of that found in Canavalia ensiformis. CONCLUSIONS: The data led us to conclude it is highly likely that the consumption of H alpinum seeds contributed to the death of Chris McCandless. PMID- 25712297 TI - Injury trends in rock climbers: evaluation of a case series of 911 injuries between 2009 and 2012. AB - OBJECTIVE: Rock climbing is a widely performed sport. This prospective single institution study evaluated the demographics of climbing-related injuries to improve our comprehension of current injury characteristics. METHODS: During a 4 year period, 836 patients with a total of 911 independent climbing injuries were prospectively evaluated using a standard questionnaire and examination protocol. RESULTS: Of all injuries, 833 were on the upper extremities, 58 on the lower. Seventeen injuries were Union International des Associations d'Alpinisme (UIAA) grade 1 injuries, 881 were grade 2, and 13 were grade 3. No higher UIAA graded injuries occurred. Overall, 380 were acute injuries (359 were seen in clinic, 21 were seen through the emergency department), and 531 were overstrain injuries (all seen in clinic). Finger injuries accounted for 52% of all injuries, the shoulder being the second most frequent location. Pulley injuries were the most frequent finger injuries. Of 20 injured young climbers under the age of 15 years, 14 had an epiphyseal fracture (all epiphyseal fractures: mean age 14 years, range 12 to 15 years). Male climbers were significantly older (P < .05), had more climbing years (P < .05), and were climbing at a higher climbing level (P < .01). Older, more experienced climbers had significantly more overstrain injuries than acute injuries (P < .05). CONCLUSIONS: When comparing this study with our previous study from 1998 to 2001, there are some notable differences. Although pulley injuries are still the most common climbing injury, there are now more A4 pulley injuries than A2. Shoulder injuries are becoming more common, as are epiphyseal fractures among young climbers. It is important to understand current patterns of climbing injuries so that health providers can target interventions appropriately. PMID- 25712298 TI - The effect of acetazolamide on saccadic latency at 3459 meters. AB - OBJECTIVE: The effect of altitude on brain function is not yet well understood, nor is the influence of height and speed of ascent. Additionally, the relationship between acute mountain sickness (AMS) symptoms and brain function at altitude is unclear. We hypothesized that a deterioration from baseline measures of brain function occurs after rapid, mechanical ascent to 3459 m and would be less pronounced in persons taking acetazolamide. METHODS: In this double blind, randomized, placebo-controlled study, 20 healthy volunteers (14 men, 6 women; mean age [+/-SD] 43 +/- 16 years) were alternately allocated to acetazolamide 250 mg or to placebo, taken every 12 hours commencing 3 days before ascent. Prosaccadic and antisaccadic eye movements, heart rate, arterial saturation, and Lake Louise AMS scores were assessed at sea level and 15 to 22 hours after ascent to 3459 m. RESULTS: Arterial oxygen saturation was significantly lower in the placebo group compared to the acetazolamide group at altitude (Wilcoxon signed rank test, median [interquartile range]: acetazolamide vs placebo: 92% [5] vs 85% [5]; P = .007), with no differences in prosaccadic latency, heart rate, or Lake Louise score. No differences in saccadic latencies from baseline to altitude were observed in the placebo group, whereas prosaccadic latencies were significantly longer at altitude with acetazolamide (altitude vs baseline: 153 ms [41] vs 176 ms [52], P = .008). CONCLUSIONS: Brain function, measured by saccadic eye movements, appears to be unimpaired after rapid ascent to 3459 m. Although acetazolamide improves oxygen saturations, it may worsen prosaccades, possibly indicating adverse effects of acetazolamide on brain function at moderate altitude. PMID- 25712299 TI - Injury patterns at Isle Royale National Park: an epidemiologic review of injuries and illnesses sustained in a remote environment. AB - OBJECTIVE: Isle Royale National Park is a remote island in northern Lake Superior that attracts 16,000 visitors annually. The epidemiology of injuries and illnesses sustained by Isle Royale's visitors has not been previously studied. The purpose of this study is to examine these data and evaluate them for injury patterns. METHODS: This is a retrospective observational study examining the epidemiology of injuries and illnesses sustained during the period from 2008 to 2012. Incident reports completed by park rangers were reviewed and the data sorted according to time of year, time of day, type of medical encounter, and whether the patient was stable, unstable, or required transport. RESULTS: Two hundred and seventy patient care reports were obtained from the National Park Service. Sixty-four percent of encounters occurred in July and August, and most patients sought care in the afternoon. Care was provided by park rangers, the majority of whom were trained to the level of emergency medical technician. Fifty eight percent of cases were trauma related, and 20% of all cases were evacuated. CONCLUSIONS: The majority of incidents were trauma related. The majority of the rangers on the island are trained to the level of emergency medical technician-B and appear to offer appropriate care to the island's many visitors, utilizing the National Park Service treatment protocols and comprehensive medical kits. In addition, access to advanced medical care is readily available by air and water evacuation. PMID- 25712300 TI - Nonsurgical treatment of two cases of infantile facial growths in a resource-poor setting. PMID- 25712301 TI - Intentional ingestion of Strychnos nux-vomica seeds causing severe muscle spasms and cardiac arrest: a postmortem report. PMID- 25712302 TI - Krait envenomation disguised as heat exhaustion in a wilderness setting. PMID- 25712303 TI - The economic impact of a medical adventure race. PMID- 25712304 TI - Flying for CME--a big carbon footprint. PMID- 25712305 TI - Concussions: a succinct clinical picture. PMID- 25712306 TI - A family of distal arthrogryposis type 5 due to a novel PIEZO2 mutation. AB - Distal arthrogryposis (DA) encompasses a heterogeneous group of hereditary disorders with multiple congenital contractures predominant in the distal extremities. A total of 10 subtypes are proposed based on the pattern of contractures and association with extraarticular symptoms. DA5 is defined as a subtype with ptosis/oculomotor limitation. However, affected individuals have a variety of non-ocular features as well. We report on a two-generation family, including four affected individuals who all had congenital contractures of the distal joints, ptosis, restricted ocular movements, distinct facial appearance with deep-set eyes, and shortening of the 1st and 5th toes. The proband and her affected mother had restrictive lung disease, a recently recognized syndromic component of DA5, while younger patients did not. The proband had metacarpal and metatarsal synostosis, and the mother showed excavation of the optic disk. Whole exome sequencing revealed a novel heterozygous mutation c.4456G>C (p.A1486P) of PIEZO2. PIEZO2 encodes a mechanosensitive ion channel, malfunction of which provides pleiotropic effects on joints, ocular muscles, lung function, and bone development. PMID- 25712307 TI - A small-scale hyperacute compound eye featuring active eye tremor: application to visual stabilization, target tracking, and short-range odometry. AB - In this study, a miniature artificial compound eye (15 mm in diameter) called the curved artificial compound eye (CurvACE) was endowed for the first time with hyperacuity, using similar micro-movements to those occurring in the fly's compound eye. A periodic micro-scanning movement of only a few degrees enables the vibrating compound eye to locate contrasting objects with a 40-fold greater resolution than that imposed by the interommatidial angle. In this study, we developed a new algorithm merging the output of 35 local processing units consisting of adjacent pairs of artificial ommatidia. The local measurements performed by each pair are processed in parallel with very few computational resources, which makes it possible to reach a high refresh rate of 500 Hz. An aerial robotic platform with two degrees of freedom equipped with the active CurvACE placed over naturally textured panels was able to assess its linear position accurately with respect to the environment thanks to its efficient gaze stabilization system. The algorithm was found to perform robustly at different light conditions as well as distance variations relative to the ground and featured small closed-loop positioning errors of the robot in the range of 45 mm. In addition, three tasks of interest were performed without having to change the algorithm: short-range odometry, visual stabilization, and tracking contrasting objects (hands) moving over a textured background. PMID- 25712308 TI - Comparison of flexible ureterorenoscopy and micropercutaneous nephrolithotomy in the treatment for moderately size lower-pole stones. AB - PURPOSE: To present a retrospective comparative clinical study of micropercutaneous nephrolithotomy (microperc) versus flexible ureterorenoscopy (F URS) in treatment of moderate-size lower-pole stones (LPSs). METHODS: We retrospectively reviewed data on patients with isolated LPSs <=2 cm in diameter treated with F-URS and/or microperc in two referral centers. Patients were divided into two groups by treatment modality: F-URS (Group 1) and microperc (Group 2). Demographics and perioperative parameters were analyzed. RESULTS: A total of 127 patients with isolated LPSs were treated via F-URS (Group 1, n = 59) and microperc (Group 2, n = 68). Mean patient age in microperc group was slightly lower than in F-URS group (p = 0.112). We found no statistically significant difference in terms of either the size or number of stones in two groups (p = 0.113 and p = 0.209, respectively). Operative time was shorter in microperc, whereas fluoroscopy time was shorter in F-URS (60.1 +/- 26.2 vs. 46.2 +/- 24.3 min, p < 0.001; and 28.3 +/- 19.1 vs. 108.9 +/- 65.2 s, p < 0.001). Mean fall in hemoglobin level was statistically significantly lower in F-URS and hospitalization time was also significantly shorter in F-URS (0.68 +/- 0.51 vs. 1.29 +/- 0.88 mg/dL, p < 0.001; and 23.0 +/- 58.1 vs. 33.8 +/- 17.2 h, p < 0.001, respectively). Stone-free rates (SFRs) were 74.5 % (44/59) in Group 1 and 88.2 % (60/68) in Group 2 (p < 0.001). CONCLUSIONS: We found that microperc was safe and efficacious when used to treat moderate-size LPSs and may be considered as an alternative to F-URS, affording a higher SFR. Our study supports the notion that microperc should play an increasing role in treatment of LPSs. PMID- 25712309 TI - Impact of pulse duration on Ho:YAG laser lithotripsy: treatment aspects on the single-pulse level. AB - OBJECTIVES: Holmium-YAG (Ho:YAG) laser lithotripsy is a multi-pulse treatment modality with stochastic effects on the fragmentation. In vitro investigation on the single-pulse-induced effects on fiber, repulsion as well as fragmentation was performed to identify potential impacts of different Ho:YAG laser pulse durations. MATERIALS AND METHODS: A Ho:YAG laser system (Swiss LaserClast, EMS S.A., Nyon, Switzerland) with selectable long- or short-pulse mode was tested with regard to fiber burn back, the repulsion capacity using an underwater pendulum setup and single-pulse-induced fragmentation capacity using artificial (BEGO) stones. The laser parameters were chosen in accordance with clinical application modes (laser fiber: 365 and 200 um; output power: 4, 6 and 10 W in different combinations of energy per pulse and repetition rate). Evaluation parameters were reduction in fiber length, pendulum deviation and topology of the crater. RESULTS: Using the long-pulse mode, the fiber burn back was nearly negligible, while in short-pulse mode, an increased burn back could be observed. The results of the pendulum test showed that the deviation induced by the momentum of short pulses was by factor 1.5-2 higher compared to longer pulses at identical energy per pulse settings. The ablation volumes induced by single pulses either in short-pulse or long-pulse mode did not differ significantly although different crater shapes appeared. CONCLUSION: Reduced stone repulsion and reduced laser fiber burn back with longer laser pulses may result in a more convenient handling during clinical application and thus in an improved clinical outcome of laser lithotripsy. PMID- 25712310 TI - TOOKAD(r) Soluble focal therapy: pooled analysis of three phase II studies assessing the minimally invasive ablation of localized prostate cancer. AB - PURPOSE: To evaluate the 6-month effects of the recommended drug and light dosage in focal vascular-targeted photodynamic therapy (VTP) using TOOKAD((r)) Soluble in patients with localized prostate cancer (LPCa). METHODS: We performed a pooled analysis of 117 men with LPCa, PSA <10 ng/mL, and Gleason score <= 7 (3 + 4), from 3 studies who received a 10-min intravenous infusion of a single dose of 4 mg/kg TOOKAD((r)) Soluble, activated by a 753-nm light at 200 J/cm delivered in the prostate by transperineal fibres under transrectal ultrasound guidance. Primary endpoint was 6-month negative biopsies in the treated lobe(s). PSA was measured at month 1, 3, and 6. Magnetic resonance imaging was performed at day 7, month 3, and 6. International Prostate Symptom Score (IPSS), International Index of Erectile Function (IIEF-5) and adverse events were reported at day 7, month 1, 3, and 6. RESULTS: Month 6 negative biopsy rate was 68.4 % in the overall evaluable population (N = 114) and 80.6 % for patients treated by hemiablation with light density index (LDI) >= 1 (N = 67). Mean prostate necroses at week-1 were 76.5 and 86.3 %, respectively. In both groups, PSA levels at month 6 decreased by 2.0 ng/mL. Small changes from baseline for IPSS and IIEF-5 indicated a slight improvement in urinary function and a slight deterioration in sexual function. CONCLUSIONS: Focal VTP treatment with TOOKAD((r)) Soluble at 4 mg/kg and 200 J/cm resulted in a negative 6-month biopsy rate of 68.4 % for the whole population and 80.6 % for patients treated by hemiablation with LDI >= 1. The treatment was well tolerated. Two phase III studies will reach completion in early 2015. PMID- 25712311 TI - Epidemiology of hypospadias in Europe: a registry-based study. AB - BACKGROUND: Hypospadias is a common congenital malformation. The prevalence of hypospadias has a large geographical variation, and recent studies have reported both increasing and decreasing temporal trends. It is unclear whether hypospadias prevalence is associated with maternal age. AIM: To analyze the prevalence and trends of total hypospadias, isolated hypospadias, hypospadias with multiple congenital anomalies, hypospadias with a known cause, and hypospadias severity subtypes in Europe over a 10-year period and to investigate whether maternal age is associated with hypospadias. METHODS: We included all children with hypospadias born from 2001 to 2010 who were registered in 23 EUROCAT registries. Information on the total number of births and maternal age distribution for the registry population was also provided. We analyzed the total prevalence of hypospadias and relative risks by maternal age. RESULTS: From 2001 to 2010, 10,929 hypospadias cases were registered in 5,871,855 births, yielding a total prevalence of 18.61 per 10,000 births. Prevalence varied considerably between different registries, probably due to differences in ascertainment of hypospadias cases. No significant temporal trends were observed with the exceptions of an increasing trend for anterior and posterior hypospadias and a decreasing trend for unspecified hypospadias. After adjusting for registry effects, maternal age was not significantly associated with hypospadias. CONCLUSIONS: Total hypospadias prevalence was stable in 23 EUROCAT registries from 2001 to 2010 and was not significantly influenced by maternal age. PMID- 25712312 TI - Open-label, 9-month extension study investigating the uro-selective alpha-blocker silodosin in men with LUTS associated with BPH. AB - OBJECTIVES: To evaluate the long-term safety (primary objective) and efficacy/impact on quality of life (QoL, secondary objectives) of silodosin 8 mg once daily in men with LUTS/BPH. PATIENTS AND METHODS: Men who completed the 12 week double-blind study with silodosin 8 mg, tamsulosin 0.4 mg, or placebo were offered to continue with the 9-month open-label study during which all patients received silodosin 8 mg once daily. Safety was assessed by analysing vital signs, electrocardiograms, laboratory tests, and adverse events. Efficacy was evaluated with the International Prostate Symptom Score (IPSS), IPSS voiding and storage sub-scores, IPSS-QoL, and maximum urinary flow rate (Q max). RESULTS: A total of 500 patients (mean age 66 years) entered the 9-month open-label study. Treatment emergent adverse events (TEAE) were experienced by 33.4% patients. Ejaculation dysfunction was the most common TEAE (9.0%) but led to study discontinuations in only 1.6% of patients. Dizziness without orthostatic hypotension occurred in 0.8%. A marked reduction in total IPSS (-2.7 +/- 3.8) was documented at the first visit of this extension phase in patients having de novo silodosin compared with lesser improvement in patients previously treated with silodosin (-0.82 +/- 4.2) or tamsulosin (-0.83 +/- 3.8). Improvements were maintained throughout the open label phase. QoL also improved, with the greatest improvement in de novo silodosin patients. No relevant changes in Q max occurred. CONCLUSIONS: Long-term treatment with silodosin was safe and efficacious. Abnormal ejaculation was the most common TEAE, but led to treatment discontinuation in only 1.6% of patients. Orthostatic hypotension was not seen, and only a few patients experienced dizziness. PMID- 25712313 TI - Colistin and doripenem combinations against Pseudomonas aeruginosa: profiling the time course of synergistic killing and prevention of resistance. AB - OBJECTIVES: Colistin is an 'old' drug, which is being increasingly utilized due to limited therapeutic options. However, resistance emergence during monotherapy is concerning. Here, our objective was to optimize colistin combinations against Pseudomonas aeruginosa by profiling the time course of synergistic killing and prevention of resistance. METHODS: Hollow-fibre infection models over 10 days simulated clinically relevant dosage regimens of colistin and doripenem against two heteroresistant P. aeruginosa strains (MIC 1 mg/L) and one resistant (MIC 128 mg/L) strain (inoculum 10(9.3) cfu/mL). New mathematical mechanism-based models (MBMs) were developed using S-ADAPT. RESULTS: Against heteroresistant P. aeruginosa strains, colistin monotherapy resulted in initial killing (up to 2.64 log10 cfu/mL) within 24 h followed by regrowth. High-intensity combinations involving free steady-state colistin concentrations of 5 mg/L achieved complete eradication (>9.3 log10 killing) within 48 h. These combinations achieved synergy with up to 9.38 log10 greater killing compared with the most active monotherapy. Against the colistin-resistant strain, the combination yielded marked initial synergy with up to 6.11 log10 cfu/mL bacterial reductions within 72 h followed by regrowth. The MBMs quantified total and resistant subpopulations and the proposed synergy between colistin and doripenem. CONCLUSIONS: Our findings provide insight into optimal antibiotic treatment and may serve as a framework for new drug combinations and combination modelling. PMID- 25712314 TI - In vitro activity of gentamicin, vancomycin or amikacin combined with EDTA or l arginine as lock therapy against a wide spectrum of biofilm-forming clinical strains isolated from catheter-related infections. AB - OBJECTIVES: Treatment of catheter-related bloodstream infections (CRBSI) is hampered by the characteristic tolerance of bacterial biofilms towards antibiotics. Our objective was to study the effect of the combination of antibiotics and the alkaline amino acid l-arginine or the cation chelator EDTA on the bacterial killing of in vitro biofilms formed by an array of clinical strains responsible for CRBSI and representative of epidemiologically relevant bacterial species. METHODS: Among 32 strains described in a previous clinical study, we focused on the most antibiotic-tolerant strains including CoNS (n = 4), Staphylococcus aureus (n = 4), Enterococcus faecalis (n = 2), Pseudomonas aeruginosa (n = 4) and Enterobacteriaceae (n = 4). We used an in vitro biofilm model (96-well plate assay) to study biofilm tolerance and tested various combinations of antibiotics and non-antibiotic adjuvants. Gentamicin, amikacin or vancomycin was combined with disodium EDTA or l-arginine for 24 h to reproduce the antibiotic lock therapy (ALT) approach. Killing of biofilm bacteria was measured by cfu quantification after a vigorous step of pipetting up and down in order to detach all biofilm bacteria from the surface of the wells. RESULTS: Both of our adjuvant strategies significantly increased the effect of antibiotics against biofilms formed by Gram-positive and Gram-negative bacterial pathogens. The combination of gentamicin + EDTA was active against all tested strains apart from one P. aeruginosa. The combination of gentamicin + l-arginine was active against most of the tested strains with the notable exception of CoNS for which no potentiation was observed. We also demonstrated that amikacin + EDTA was active against Gram-negative bacteria and that vancomycin + EDTA was active against Gram-positive bacteria. CONCLUSIONS: The addition of EDTA enhanced the activity of gentamicin, amikacin and vancomycin against biofilms formed by a wide spectrum of bacterial strains responsible for CRBSI. PMID- 25712315 TI - Small molecule inhibitors of the annexin A2 heterotetramer prevent human papillomavirus type 16 infection. AB - OBJECTIVES: High-risk human papillomavirus (HPV) infection leads to the development of several human cancers that cause significant morbidity and mortality worldwide. HPV type 16 (HPV16) is the most common of the cancer-causing genotypes and gains entry to the basal cells of the epithelium through a non canonical endocytic pathway that involves the annexin A2/S100A10 heterotetramer (A2t). A2t is composed of two annexin A2 monomers bound to an S100A10 dimer and this interaction is a potential target to block HPV16 infection. Here, recently identified small molecule inhibitors of A2t (A2ti) were investigated for their ability to prevent HPV16 infection in vitro. METHODS: A2ti were added to HeLa cells in increasing concentrations prior to the addition of HPV16. Cytotoxicity was evaluated via trypan blue exclusion. HPV16 pseudovirion infection and fluorescently labelled HPV16 capsid internalization was measured with flow cytometry. RESULTS: A2ti blocked HPV16 infection by 100% without substantial cellular toxicity or reduction in cell growth. Furthermore, A2ti blocked HPV16 entry into epithelial cells by 65%, indicating that the observed inhibition of HPV16 infection is in part due to a block in entry and that non-infectious entry may occur in the absence of A2t binding. CONCLUSIONS: These results demonstrate that targeting A2t may be an effective strategy to prevent HPV16 infection. PMID- 25712316 TI - Modulation of the activity of moxifloxacin and solithromycin in an in vitro pharmacodynamic model of Streptococcus pneumoniae naive and induced biofilms. AB - OBJECTIVES: Bacterial biofilms developing in the bronchial tree of patients experiencing acute exacerbations of chronic bronchitis (AECBs) are suggested to cause relapses and recurrences of the disease because the matrix barrier impairs antibiotic access to the offending organisms. We examined whether bronchodilators could modulate pneumococcal biofilm development and antibiotic action using an in vitro model. METHODS: Streptococcus pneumoniae strains from patients hospitalized for AECBs and two reference strains (ATCC 49619 and R6) were screened for biofilm formation (multi-well plates; 2-11 days of growth). Ipratropium and salbutamol (alone or in combination) were added at concentrations of 1.45 and 7.25 mg/L, respectively (mimicking those in the bronchial tree), and their effects were measured on biofilm formation and modulation of the activity of antibiotics [full antibiotic concentration-dependent effects (pharmacodynamic model)] with a focus on moxifloxacin and solithromycin. Bacterial viability and biomass were measured by the reduction of resazurin and crystal violet staining, respectively. Release of sialic acid (from biofilm) and neuraminidase activity were measured using enzymatic and HPLC-MS detection of sialic acid. RESULTS: All clinical isolates produced biofilms, but with fast disassembly if from patients who had received muscarinic antagonists. Ipratropium caused: (i) reduced biomass formation and faster biofilm disassembly with free sialic acid release; and (ii) a marked improvement of antibiotic activity (bacterial killing and biomass reduction). Salbutamol stimulated neuraminidase activity associated with improved antibiotic killing activity (reversed by zanamivir) but modest biomass reduction. CONCLUSIONS: Ipratropium and, to a lesser extent, salbutamol may cooperate with antibiotics for bacterial clearance and disassembly of pneumococcal biofilms. PMID- 25712317 TI - Wide dissemination of linezolid-resistant Staphylococcus epidermidis in Greece is associated with a linezolid-dependent ST22 clone. AB - OBJECTIVES: Dependence on linezolid was recently described as significant growth acceleration of linezolid-resistant Staphylococcus epidermidis (LRSE) isolates upon linezolid exposure. We investigated the possible contribution of linezolid dependence to LRSE dissemination in Greece. METHODS: Linezolid resistance rates were estimated in six tertiary hospitals located throughout Greece between 2011 and 2013. Sixty-three randomly selected LRSE recovered in these hospitals during this period were studied. Growth curve analysis was conducted with and without linezolid. Clonality of the isolates was investigated by PFGE and MLST. RESULTS: During the study period, the LRSE rate in the participating hospitals rose significantly from 6.9% to 9% (P = 0.006); the increase was more prominent in ICUs (from 15.1% to 20.9%; P = 0.005). Forty-seven (74.6%) of the 63 LRSE, derived from all study hospitals, clearly exhibited linezolid dependence, growing significantly faster in the presence of 16 and 32 mg/L linezolid. Of note, 61 (96.8%) LRSE exhibited a single macrorestriction pattern and belonged to ST22, which included all linezolid-dependent LRSE. The remaining two LRSE belonged to unique STs. Five of six linezolid-dependent isolates tested also exhibited linezolid dependence upon exposure to 8 mg/L linezolid. Interestingly, five of six ST22 linezolid-non-dependent isolates tested developed linezolid dependence when linezolid exposure preceded growth analysis. CONCLUSIONS: The rapid LRSE dissemination in Greek hospitals threatens linezolid activity. The observation that most LRSE belonged to ST22 and expressed dependence on linezolid clearly implies that the spread of linezolid resistance should have been driven by this trait, which provided the LRSE with a selective advantage under linezolid pressure. PMID- 25712319 TI - Glia: Anchored at the axon. PMID- 25712318 TI - HIV-1 integrase genotyping is reliable and reproducible for routine clinical detection of integrase resistance mutations even in patients with low-level viraemia. AB - OBJECTIVES: Integrase drug resistance monitoring deserves attention because of the increasing number of patients being treated with integrase strand-transfer inhibitors. Therefore, we evaluated the integrase genotyping success rate at low level viraemia (LLV, 51-1000 copies/mL) and resistance in raltegravir-failing patients. METHODS: An integrase genotypic resistance test (GRT) was performed on 1734 HIV-1 samples collected during 2006-13. Genotyping success rate was determined according to the following viraemia levels: 51-500, 501-1000, 1001-10 000, 10 001-100 000 and >100 000 copies/mL. The reproducibility of integrase GRT was evaluated in 41 plasma samples processed in duplicate in two reference centres. The relationship between LLV and resistance prevalence was evaluated in a subset of 120 raltegravir-failing patients. RESULTS: Overall, the integrase genotyping success rate was 95.7%. For viraemia levels 51-500 and 501-1000 copies/mL, the rate of success was 82.1% and 94.0%, respectively. GRT was reproducible, producing sequences with a high similarity and an equal resistance profile regardless of the sequencing centre or viraemia level. Resistance was detected both at LLV and at viraemia >1000 copies/mL (51-500 copies/mL = 18.2%; 501-1000 = 37.5%; 1001-10 000 = 53.7%; 10 001-100 000 = 30.0%; and >100 000 = 30.8%). At viraemia <=500 copies/mL, Q148H/K/R and N155H had the same prevalence (9.1%), while the Y143C/H/R was completely absent. At early genotyping (within 3 months of raltegravir treatment), Q148H/K/R and N155H mutations were detected regardless of the viraemia level, while Y143C/H/R was observed only in samples with viraemia >1000 copies/mL. CONCLUSIONS: Our findings prove the reliability of HIV-1 integrase genotyping and reinforce the concept that this assay may be useful in the management of failures even at LLV. PMID- 25712320 TI - Hyperandrogenism secondary to Leydig ovarian tumor. PMID- 25712321 TI - Molecular Phylogeny of the Family Ophryscolecidae (Ciliophora, Litostomatea) Inferred from 18S rDNA Sequences. AB - The 18S rDNA was used to infer oral ciliature patterns of evolution within the family Ophryoscolecidae, with the addition of five new sequences of ciliates from the genus Ostracodinium. Our data confirmed the monophyly of the subfamilies Entodiniinae and Ophryoscolecinae, but more analysis would be required for the definition of the status of the subfamily Diplodiniinae. The oral infraciliature patterns reflect evolutionary divergence in the family Ophryscolecidae, observing monophyly on Entodinium-type, Diplodinium-type, Ostracodinium-type, Epidinium type, and Ophryoscolex-type. The ancestral infraciliature of Entodinium-type cannot be proven, however, the position of Entodinium-type showed closer of Diplodinium-type than Ophryoscolex-type, corroborating previous studies using morphological characters. The observed inconsistencies reflect the need to increase the number of 18S rDNA sequences to family Ophryoscolecidae and investigate the evolution of this group using other molecular markers. PMID- 25712322 TI - The possible protective effect of simvastatin and pioglitazone separately and in combination on bleomycin-induced changes in mice thin skin. AB - Bleomycin is a chemotherapeutic agent with side effects especially on skin. Simvastatin is a cholesterol-lowering drug with immunomodulatory, anti inflammatory, and antifibrotic effects. Pioglitazone is a peroxisome proliferator activated receptor-gamma antidiabetic agent with antiproliferative effects on smooth muscle cells (SMCs), and antioxidant and anti-inflammatory actions. The aim of this study was to investigate the anti-inflammatory and antifibrotic efficiencies of simvastatin and pioglitazone separately and in combination against bleomycin-induced changes in mice thin skin using histological, immunohistochemical, and biochemical techniques. In this study, the mice were divided into seven groups, with each group undergoing treatment for 3 weeks: the control group, group 1 was administered 100 MUl of bleomycin, group 2 was administered simvastatin (5mg/kg/day), group 3 received pioglitazone (10mg/kg/day), group 4 received simvastatin (5mg/kg/day) 1h before bleomycin, group 5 received pioglitazone (10mg/kg/day) 1h before bleomycin, and group 6 was administered simvastatin (5mg/kg/day) and pioglitazone (10mg/kg/day) 1h before bleomycin. In group 2, dermal thickening, subcutaneous fat atrophy, degeneration of hair follicles, and thickening of cutaneous vessel walls were observed in addition to a significant increase in caspase-3 reaction, transforming growth factor beta 1 (TGF-beta1) expression, and hydroxyproline content. A reversal of the previous findings was markedly observed in group 6 compared with groups 4 and 5. We conclude that the concurrent administration of pioglitazone and simvastatin enhanced their beneficial effects in the reversal of bleomycin-induced changes in mice thin skin. PMID- 25712323 TI - Phosphine-mediated reaction of 3-methyl allenoate and isatins: a protocol for the synthesis of spirofuran oxindoles. AB - A facile synthesis of spirofuran oxindoles via phosphine-mediated reaction of 3 alkyl allenoate with isatins is presented. PMID- 25712324 TI - Development of a cross-cultural item bank for measuring quality of life related to mental health in multiple sclerosis patients. AB - OBJECTIVE: Quality of life (QoL) measurements are considered important outcome measures both for research on multiple sclerosis (MS) and in clinical practice. Computerized adaptive testing (CAT) can improve the precision of measurements made using QoL instruments while reducing the burden of testing on patients. Moreover, a cross-cultural approach is also necessary to guarantee the wide applicability of CAT. The aim of this preliminary study was to develop a calibrated item bank that is available in multiple languages and measures QoL related to mental health by combining one generic (SF-36) and one disease specific questionnaire (MusiQoL). METHODS: Patients with MS were enrolled in this international, multicenter, cross-sectional study. The psychometric properties of the item bank were based on classical test and item response theories and approaches, including the evaluation of unidimensionality, item response theory model fitting, and analyses of differential item functioning (DIF). Convergent and discriminant validities of the item bank were examined according to socio demographic, clinical, and QoL features. RESULTS: A total of 1992 patients with MS and from 15 countries were enrolled in this study to calibrate the 22-item bank developed in this study. The strict monotonicity of the Cronbach's alpha curve, the high eigenvalue ratio estimator (5.50), and the adequate CFA model fit (RMSEA = 0.07 and CFI = 0.95) indicated that a strong assumption of unidimensionality was warranted. The infit mean square statistic ranged from 0.76 to 1.27, indicating a satisfactory item fit. DIF analyses revealed no item biases across geographical areas, confirming the cross-cultural equivalence of the item bank. External validity testing revealed that the item bank scores correlated significantly with QoL scores but also showed discriminant validity for socio demographic and clinical characteristics. CONCLUSION: This work demonstrated satisfactory psychometric characteristics for a QoL item bank for MS in multiple languages. This work may offer a common measure for the assessment of QoL in different cultural contexts and for international studies conducted on MS. PMID- 25712325 TI - Comparative evaluation of three surveillance systems for infectious equine diseases in France and implications for future synergies. AB - It is necessary to assess surveillance systems for infectious animal diseases to ensure they meet their objectives and provide high-quality health information. Each system is generally dedicated to one disease and often comprises various components. In many animal industries, several surveillance systems are implemented separately even if they are based on similar components. This lack of synergy may prevent optimal surveillance. The purpose of this study was to assess several surveillance systems within the same industry using the semi-quantitative OASIS method and to compare the results of the assessments in order to propose improvements, including future synergies. We have focused on the surveillance of three major equine diseases in France. We have identified the mutual and specific strengths and weaknesses of each surveillance system. Furthermore, the comparative assessment has highlighted many possible synergies that could improve the effectiveness and efficiency of surveillance as a whole, including the implementation of new joint tools or the pooling of existing teams, tools or skills. Our approach is an original application of the OASIS method, which requires minimal financial resources and is not very time-consuming. Such a comparative evaluation could conceivably be applied to other surveillance systems, other industries and other countries. This approach would be especially relevant to enhance the efficiency of surveillance activities when resources are limited. PMID- 25712326 TI - Prevalence and changes over time of ideal cardiovascular health metrics among African-Americans: the Jackson Heart Study. AB - OBJECTIVES: The aim of this study is to assess the prevalence and changes over time of ideal Life's Simple Seven (LSS) in African-Americans. METHODS: Prospective cohort of 5301 African-Americans from the Jackson Heart Study (JHS) from 2000 to 2013. Each of the LSS metrics was categorized as poor, intermediate, or ideal. RESULTS: Among men, the prevalence of having 0, 1, 2, 3, 4, 5, 6, and 7 ideal LSS was 3.3%, 23.0%, 33.5%, 24.7%, 11.6%, 3.6%, 0.3%, and 0%, respectively. Corresponding values for women were 1.7%, 26.3%, 33.1%, 22.8%, 11.9%, 3.7%, 0.6%, and 0%. Prevalence of ideal diet was 0.9%. The proportions of those meeting LSS ideal recommendations for cholesterol and fasting glucose declined from the first through third JHS visits across all age groups, whereas prevalence of ideal BMI declined only in participants <40 years at a given visit. Prevalence of ideal blood pressure did not change over time and being ideal on physical activity improved from the first [18.3% (95% CI: 17.3% to 19.3%)] to third visit [24.8% (95% CI: 23.3% to 26.3%)]. CONCLUSIONS: Our data show a low prevalence of ideal LSS (especially diet, physical activity, and obesity) in the JHS and a slight improvement in adherence to physical activity recommendations over time. PMID- 25712327 TI - Association between participation in outdoor play and sport at 10 years old with physical activity in adulthood. AB - OBJECTIVE: This study aimed to investigate whether active outdoor play and/or sports at age 10 is associated with sport/physical activity at 32 year follow-up using a birth cohort study. METHODS: Data were from the 1970 British Cohort Study, a longitudinal observational study. The present paper included data from the age 10 years and age 42 years surveys. At age 10 the participant's mother provided information regarding how often their child played sports, and played outside on streets, parks or playgrounds. At age 42 participants reported frequency of participation in physical activities and sports. Associations between participation in sport/active outdoor play at age 10 years and adult sport/physical activity were investigated using adjusted (gender, fathers socio occupational class, child's BMI, father's BMI, self-rated health at age 42, assessment of own weight at age 42, participant's education) Cox regression. RESULTS: Final adjusted Cox regression models showed that participants (n=6458) who often participated in sports at age 10 were significantly more likely to participate in sport/physical activity at age 42 (RR 1.10; 95% CI 1.01 to 1.19). Active outdoor play at age 10 was not associated with participation in sport/physical activity at age 42 (RR 0.99; 95% CI 0.91 to 1.07). CONCLUSION: Childhood activity interventions might best achieve lasting change by promoting engagement in sport rather than active outdoor play. PMID- 25712329 TI - Proteome reallocation in Escherichia coli with increasing specific growth rate. AB - Cells usually respond to changing growth conditions with a change in the specific growth rate (MU) and adjustment of their proteome to adapt and maintain metabolic efficiency. Description of the principles behind proteome resource allocation is important for understanding metabolic regulation in response to changing MU. Thus, we analysed the proteome resource allocation dynamics of Escherichia coli into different metabolic processes in response to changing MU. E. coli was grown on minimal and defined rich media in steady state continuous cultures at different MU and characterised combining two LC-MS/MS-based proteomics methods: stable isotope labelling by amino acids in cell culture (SILAC) and intensity based label-free absolute quantification. We detected slowly growing cells investing more proteome resources in energy generation and carbohydrate transport and metabolism whereas for achieving faster growth cells needed to devote most resources to translation and processes closely related to the protein synthesis pipeline. Furthermore, down-regulation of energy generation and carbohydrate metabolism proteins with faster growth displayed very similar expression dynamics with the global transcriptional regulator CRP (cyclic AMP receptor protein), pointing to a dominant protein resource allocating role of this protein. Our data also suggest that acetate overflow may be the result of global proteome resource optimisation as cells saved proteome resources by switching from fully respiratory to respiro-fermentative growth. The presented results give a quantitative overview of how E. coli adjusts its proteome to achieve faster growth and in future could contribute to the design of more efficient cell factories through proteome optimisation. PMID- 25712328 TI - Insufficient sleep among elementary and middle school students is linked with elevated soda consumption and other unhealthy dietary behaviors. AB - OBJECTIVE: This study examines the extent to which insufficient sleep is associated with diet quality in students taking part in the Massachusetts Childhood Obesity Research Demonstration Project. METHODS: Data were collected in Fall 2012 for all 4th and 7th grade children enrolled in public schools in two Massachusetts communities. During annual body mass index (BMI) screening, students completed a survey that assessed diet, physical activity, screen time, and sleep. Of the 2456 enrolled students, 1870 (76%) had complete survey data. Generalized estimating equations were used to examine associations between sleep duration and dietary outcomes (vegetables, fruits, 100% juice, juice drinks, soda, sugar-sweetened beverages and water), accounting for clustering by school. Models were adjusted for community, grade, race/ethnicity, gender, television in the bedroom, screen time, and physical activity. RESULTS: In adjusted models, students who reported sleeping < 10 hours/day consumed soda more frequently (beta = 0.11, 95% CI: 0.03, 0.20) and vegetables less frequently (beta = -0.09, 95% CI: -0.18, -0.01) compared with students who reported >= 10 hours/day. No significant associations were observed between sleep duration and fruits, 100% juice, juice drinks or water. CONCLUSIONS: In this population, insufficient sleep duration was associated with more frequent soda and less frequent vegetable consumption. Longitudinal research is needed to further examine these relationships. PMID- 25712330 TI - In vivo biocompatibility assessment of poly (ether imide) electrospun scaffolds. AB - Poly(ether imide) (PEI), which can be chemically functionalized with biologically active ligands, has emerged as a potential biomaterial for medical implants. Electrospun PEI scaffolds have shown advantageous properties, such as enhanced endothelial cell adherence, proliferation and low platelet adhesion in in vitro experiments. In this study, the in vivo behaviour of electrospun PEI scaffolds and PEI films was examined in a murine subcutaneous implantation model. Electrospun PEI scaffolds and films were surgically implanted subcutaneously in the dorsae of mice. The surrounding subcutaneous tissue response was examined via histopathological examination at 7 and 28 days after implantation. No serious adverse events were observed for both types of PEI implants. The presence of macrophages or foreign body giant cells in the vicinity of the implants and the formation of a fibrous capsule indicated a normal foreign body reaction towards PEI films and scaffolds. Capsule thickness and inflammatory infiltration cells significantly decreased for PEI scaffolds during days 7-28 while remaining unchanged for PEI films. The infiltration of cells into the implant was observed for PEI scaffolds 7 days after implantation and remained stable until 28 days of implantation. Additionally some, but not all, PEI scaffold implants induced the formation of functional blood vessels in the vicinity of the implants. Conclusively, this study demonstrates the in vivo biocompatibility of PEI implants, with favourable properties of electrospun PEI scaffolds regarding tissue integration and wound healing. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 25712331 TI - Extended implementation of educational programs for atopic dermatitis in childhood. AB - Children with atopic dermatitis (AD) suffer from chronic relapsing inflammatory skin lesions accompanied by insatiable itching, dryness, excoriated skin, or even (super-)infections. This burden impairs the quality of life of affected children and their families. Due particularly to the recurrent course of the disease, patients often lose confidence in treatment and fear side effects of steroids. Family education programs for AD have been established in the last decades to provide appropriate education and psychosocial support. However, the need for long-lasting strategies in treatment and prevention has even increased. Recent findings not only underline the importance of an intact skin barrier in regard to acute therapy but also suggest that an impairment of skin barrier integrity promotes the development of subsequent atopic diseases in the course of the atopic march. Moreover, in addition to the psychosocial burden due to stigmatized appearance or sleep disturbance, new observations document an increased presence of psychosomatic comorbidities in patients with AD. We reviewed recent educational interventions regarding the theoretical background and here will discuss the heterogeneous approaches of existing programs in childhood. Despite high variations of educational strategies, an overriding aim should be the broader integration of supporting programs in the treatment of children with AD to empower the affected child and its caregiver's to obtain the best possible care, quality of life, and to promote (secondary) prevention. PMID- 25712332 TI - A lithotrophic microbial fuel cell operated with pseudomonads-dominated iron oxidizing bacteria enriched at the anode. AB - In this study, we attempted to enrich neutrophilic iron bacteria in a microbial fuel cell (MFC)-type reactor in order to develop a lithotrophic MFC system that can utilize ferrous iron as an inorganic electron donor and operate at neutral pHs. Electrical currents were steadily generated at an average level of 0.6 mA (or 0.024 mA cm(-2) of membrane area) in reactors initially inoculated with microbial sources and operated with 20 mM Fe(2+) as the sole electron donor and 10 ohm external resistance; whereas in an uninoculated reactor (the control), the average current level only reached 0.2 mA (or 0.008 mA cm(-2) of membrane area). In an inoculated MFC, the generation of electrical currents was correlated with increases in cell density of bacteria in the anode suspension and coupled with the oxidation of ferrous iron. Cultivation-based and denaturing gradient gel electrophoresis analyses both show the dominance of some Pseudomonas species in the anode communities of the MFCs. Fluorescent in-situ hybridization results revealed significant increases of neutrophilic iron-oxidizing bacteria in the anode community of an inoculated MFC. The results, altogether, prove the successful development of a lithotrophic MFC system with iron bacteria enriched at its anode and suggest a chemolithotrophic anode reaction involving some Pseudomonas species as key players in such a system. The system potentially offers unique applications, such as accelerated bioremediation or on-site biodetection of iron and/or manganese in water samples. PMID- 25712333 TI - Economic evaluation of typhoid vaccination in a prolonged typhoid outbreak setting: the case of Kasese district in Uganda. AB - BACKGROUND: Vaccination has been increasingly promoted to help control epidemic and endemic typhoid fever in high-incidence areas. Despite growing recognition that typhoid incidence in some areas of sub-Saharan Africa is similar to high incidence areas of Asia, no large-scale typhoid vaccination campaigns have been conducted there. We performed an economic evaluation of a hypothetical one-time, fixed-post typhoid vaccination campaign in Kasese, a rural district in Uganda where a large, multi-year outbreak of typhoid fever has been reported. METHODS: We used medical cost and epidemiological data retrieved on-site and campaign costs from previous fixed-post vaccination campaigns in Kasese to account for costs from a public sector health care delivery perspective. We calculated program costs and averted disability-adjusted life years (DALYs) and medical costs as a result of vaccination, to calculate the cost of the intervention per DALY and case averted. RESULTS: Over the 3 years of projected vaccine efficacy, a one-time vaccination campaign was estimated to avert 1768 (90%CI: 684-4431) typhoid fever cases per year and a total of 3868 (90%CI: 1353-9807) DALYs over the duration of the immunity conferred by the vaccine. The cost of the intervention per DALY averted was US$ 484 (90%CI: 18-1292) and per case averted US$ 341 (90%CI: 13-883). CONCLUSION: We estimated the vaccination campaign in this setting to be highly cost-effective, according to WHO's cost-effective guidelines. Results may be applicable to other African settings with similar high disease incidence estimates. PMID- 25712334 TI - Strong and stiff aramid nanofiber/carbon nanotube nanocomposites. AB - Small but strong carbon nanotubes (CNTs) are fillers of choice for composite reinforcement owing to their extraordinary modulus and strength. However, the mechanical properties of the nanocomposites are still much below those for mechanical parameters of individual nanotubes. The gap between the expectation and experimental results arises not only from imperfect dispersion and poor load transfer but also from the unavailability of strong polymers that can be effectively utilized within the composites of nanotubes. Aramid nanofibers (ANFs) with analogous morphological features to nanotubes represent a potential choice to complement nanotubes given their intrinsic high mechanical performance and the dispersible nature, which enables solvent-based processing methods. In this work, we showed that composite films made from ANFs and multiwalled CNTs (MWCNTs) by vacuum-assisted flocculation and vacuum-assisted layer-by-layer assembly exhibited high ultimate strength of up to 383 MPa and Young's modulus (stiffness) of up to 35 GPa, which represent the highest values among all the reported random CNT nanocomposites. Detailed studies using different imaging and spectroscopic characterizations suggested that the multiple interfacial interactions between nanotubes and ANFs including hydrogen bonding and pi-pi stacking are likely the key parameters responsible for the observed mechanical improvement. Importantly, our studies further revealed the attractive thermomechanical characteristics of these nanocomposites with high thermal stability (up to 520 degrees C) and ultralow coefficients of thermal expansion (2-6 ppm.K(-1)). Our results indicated that ANFs are promising nanoscale building blocks for functional ultrastrong and stiff materials potentially extendable to nanocomposites based on other nanoscale fillers. PMID- 25712335 TI - Upper-extremity deep venous thrombosis after whole blood donation: report of three cases from a single blood center. AB - BACKGROUND: There are two upper-extremity deep venous thrombosis (UEDVT) cases after whole blood donation reported in the English medical literature. Three additional UEDVT cases after whole blood donation were reported to our blood center within a 13-month period. STUDY DESIGN AND METHODS: A case study was done for each case in collaboration with a clinical physician. A description of the donation event, donor demographics, risk factors for thrombosis, treatment, and outcome were described. RESULTS: A 33-year-old woman and two 17-year-old, first time-donating men presented with arm pain, swelling, and bruising within hours to 3 days after donation. Two had distal UEDVTs in the basilic or brachial veins, and one had a proximal UEDVT in the subclavian and axillary veins extending into the basilic vein. One donor (woman) had known risk factors for DVT and the other two did not. Anticoagulant therapy was initiated on all patients and was continued for 3, 4, and 9 months. Two donors with the distal UEDVTs recovered completely while the donor with the proximal UEDVT was treated with anticoagulation for 9 months and continued to have a slight residual, nonobstructive thrombosis. The donor was switched to low-dose aspirin prevention. The two donors reported in the literature had complete resolution of thrombosis. CONCLUSIONS: Four of five donors recovered completely after anticoagulation treatment for UEDVT, including two of three donors in this study. A review of all cases in the medical literature, including 20 recent Australian cases described in an abstract, provides a more complete description of this adverse donation injury. PMID- 25712336 TI - Amidinatogermylene derivatives of ruthenium carbonyl: new insights into the reactivity of [Ru3(CO)12] with two-electron-donor reagents of high basicity. AB - The reactivity of ruthenium carbonyl with amidinatogermylenes of the type Ge(R2bzam)(t)Bu (R2bzam = N,N'-disubstituted benzamidinate) was studied for R = (t)Bu (1tBu) and (i)Pr (1iPr). The mono-, bi-, and/or trinuclear derivatives [Ru(1R)(CO)4], [Ru(1R)2(CO)3], [Ru2(1iPr)(CO)7], [Ru3(1tBu)(CO)11], [Ru3(1tBu)2(CO)10], and [Ru3(1R)3(CO)9] (R = (t)Bu, (i)Pr) were isolated in yields that depend upon the reactant ratio and the reaction temperature. The experimental data are consistent with the proposal that, at room temperature, the trinuclear complexes [Ru3(CO)12], [Ru3(1R)(CO)11], and [Ru3(1R)2(CO)10] form an adduct with the germylene 1R that may evolve through two different reaction pathways, (a) releasing a CO ligand (thus leading to the corresponding trinuclear CO-substituted product) and/or (b) cleaving the cluster framework (thus leading to mononuclear germylene-containing products). At 90 degrees C, additional processes are also possible, such as the reactions of 1R with [Ru(1R)(CO)4] or [Ru3(1R)3(CO)9], which both give [Ru(1R)2(CO)3], or the reactions of [Ru(1tBu)(CO)4] and [Ru(1iPr)(CO)4] with [Ru3(CO)12], which give [Ru3(1tBu)(CO)11] and [Ru2(1iPr)(CO)7], respectively. This wide reaction panorama helps rationalize previously reported outcomes of reactions of [Ru3(CO)12] with other reagents of high basicity, such as trialkylphosphines or N-heterocyclic carbenes, including results for which no satisfactory explanation has been hitherto provided. PMID- 25712337 TI - Innovation in the biochemistry/molecular biology laboratory. PMID- 25712338 TI - Understanding the reactivity of endohedral metallofullerenes: C78 versus Sc3N@C78. AB - The physical factors behind the reduced Diels-Alder reactivity of the Sc3N@C78 metallofullerene as compared with free C78 have been investigated in detail by means of computational tools. To this end, the reactions between 1,3-butadiene and free C78 and endohedral Sc3N@C78 have been analysed in terms of regioselectivity and reactivity by using the activation strain model of reactivity in combination with the energy decomposition analysis method. Additional factors such as the molecular orbital overlap or the aromaticity of the corresponding transition states have been also explored. Our results indicate that the lower reactivity of the metallofullerene finds its origin mainly in the less stabilizing interaction between the deformed reactants along the reaction coordinate induced by the triscandium nitride moiety. PMID- 25712339 TI - B cell responses in pregnancy and vaccine efficacy. PMID- 25712340 TI - Reply: Maternal vaccination: moving the science forward. PMID- 25712341 TI - FOXP3-miR-146-NF-kappaB Axis and Therapy for Precancerous Lesions in Prostate. AB - The tumor-suppressive activity of FOXP3 has been observed in tumor initiation, but the underlying mechanism still remains largely unknown. Here, we identified a FOXP3-microRNA-146 (miR-146)-NF-kappaB axis in vitro and in vivo in prostate cancer cells. We observed that FOXP3 dramatically induced the expression of miR 146a/b, which contributed to transcriptional inhibition of IRAK1 and TRAF6, in prostate cancer cell lines. Tissue-specific deletion of Foxp3 in mouse prostate caused a significant reduction of miR-146a and upregulation of NF-kappaB activation. In addition, prostatic intraepithelial neoplasia lesions were observed in miR-146a-mutant mice as well as in Foxp3-mutant mice. Notably, the NF kappaB inhibitor bortezomib inhibited cell proliferation and induced apoptosis in prostate epithelial cells, attenuating prostatic intraepithelial neoplasia formation in Foxp3-mutant mice. Our data suggest that the FOXP3-miR-146-NF-kappaB axis has a functional role during tumor initiation in prostate cancer. Targeting the miR-146-NF-kappaB axis may provide a new therapeutic approach for prostate cancers with FOXP3 defects. PMID- 25712342 TI - FOXP3 Controls an miR-146/NF-kappaB Negative Feedback Loop That Inhibits Apoptosis in Breast Cancer Cells. AB - FOXP3 functions not only as the master regulator in regulatory T cells, but also as an X-linked tumor suppressor. The tumor-suppressive activity of FOXP3 has been observed in tumor initiation, but its role during tumor progression remains controversial. Moreover, the mechanism of FOXP3-mediated tumor-suppressive activity remains largely unknown. Using chromatin immunoprecipitation (ChIP) sequencing, we identified a series of potential FOXP3-targeted miRNAs in MCF7 cells. Notably, FOXP3 significantly induced the expression of miR-146a/b. In vitro, FOXP3-induced miR-146a/b prevented tumor cell proliferation and enhanced apoptosis. Functional analyses in vitro and in vivo revealed that FOXP3-induced miR-146a/b negatively regulates NF-kappaB activation by inhibiting the expression of IRAK1 and TRAF6. In ChIP assays, FOXP3 directly bound the promoter region of miR-146a but not of miR-146b, and FOXP3 interacted directly with NF-kappaB p65 to regulate an miR-146-NF-kappaB negative feedback regulation loop in normal breast epithelial and tumor cells, as demonstrated with luciferase reporter assays. Although FOXP3 significantly inhibited breast tumor growth and migration in vitro and metastasis in vivo, FOXP3-induced miR-146a/b contributed only to the inhibition of breast tumor growth. These data suggest that miR-146a/b contributes to FOXP3-mediated tumor suppression during tumor growth by triggering apoptosis. The identification of a FOXP3-miR-146-NF-kappaB axis provides an underlying mechanism for disruption of miR-146 family member expression and constitutive NF kappaB activation in breast cancer cells. Linking the tumor suppressor function of FOXP3 to NF-kappaB activation reveals a potential therapeutic approach for cancers with FOXP3 defects. PMID- 25712343 TI - Evaluating patient-derived colorectal cancer xenografts as preclinical models by comparison with patient clinical data. AB - Development of targeted therapeutics required translationally relevant preclinical models with well-characterized cancer genome alterations. Here, by studying 52 colorectal patient-derived tumor xenografts (PDX), we examined key molecular alterations of the IGF2-PI3K and ERBB-RAS pathways and response to cetuximab. PDX molecular data were compared with that published for patient colorectal tumors in The Cancer Genome Atlas. We demonstrated a significant pattern of mutual exclusivity of genomic abnormalities in the IGF2-PI3K and ERBB RAS pathways. The genomic anomaly frequencies observed in microsatellite stable PDX reproduce those detected in nonhypermutated patient tumors. We found frequent IGF2 upregulation (16%), which was mutually exclusive with IRS2, PIK3CA, PTEN, and INPP4B alterations, supporting IGF2 as a potential drug target. In addition to maintaining the genomic and histologic diversity, correct preclinical models need to reproduce drug response observed in patients. Responses of PDXs to cetuximab recapitulate also clinical data in patients, with partial or complete response in 15% (8 of 52) of PDXs and response strictly restricted to KRAS wild type models. The response rate reaches 53% (8 of 15) when KRAS, BRAF, and NRAS mutations are concomitantly excluded, proving a functional cross-validation of predictive biomarkers obtained retrospectively in patients. Collectively, these results show that, because of their clinical relevance, colorectal PDXs are appropriate tools to identify both new targets, like IGF2, and predictive biomarkers of response/resistance to targeted therapies. PMID- 25712344 TI - Upregulation of cytosolic phosphoenolpyruvate carboxykinase is a critical metabolic event in melanoma cells that repopulate tumors. AB - Although metabolic defects have been investigated extensively in differentiated tumor cells, much less attention has been directed to the metabolic properties of stem-like cells that repopulate tumors [tumor-repopulating cells (TRC)]. Here, we show that melanoma TRCs cultured in three-dimensional soft fibrin gels reprogram glucose metabolism by hijacking the cytosolic enzyme phosphoenolpyruvate carboxykinase (PCK1), a key player in gluconeogenesis. Surprisingly, upregulated PCK1 in TRCs did not mediate gluconeogenesis but promoted glucose side-branch metabolism, including in the serine and glycerol-3-phosphate pathways. Moreover, this retrograde glucose carbon flow strengthened rather than antagonized glycolysis and glucose consumption. Silencing PCK1 or inhibiting its enzymatic activity slowed the growth of TRCs in vitro and impeded tumorigenesis in vivo. Overall, our work unveiled metabolic features of TRCs in melanoma that have implications for targeting a unique aspect of this disease. PMID- 25712346 TI - Xerosis is associated with asthma in men independent of atopic dermatitis and filaggrin gene mutations. AB - BACKGROUND: Epidermal filaggrin deficiency due to common filaggrin gene (FLG) mutations causes xerosis and strongly increases the risk of atopic dermatitis and even asthma. However, it is unknown whether xerosis independent of FLG mutations could also increase the risk of asthma. OBJECTIVE: To evaluate whether generalized xerosis was associated with asthma, independent of atopic dermatitis and common FLG mutations in a cross-sectional study on adult Danes. METHODS: A total of 3396 adults from the general population participated in a health examination. Lung function and serum-specific IgE levels to inhalant allergens were measured and information on xerosis and atopic diseases was obtained by means of a questionnaire. Participants were genotypes for the three most common FLG mutations in Northern Europeans: R501X, 2282del4 and R2447X. RESULTS: Fully adjusted logistic regression analyses showed that asthma (either current or at some point in life) was significantly associated with reporting generalized xerosis (OR 1.32; 95% CI 1.02-1.72). The association was stronger in men (OR 1.79; 95% CI 1.13-2.84) when compared to women (OR 1.18; 95% CI 0.86-1.62). Furthermore, a significant association was observed between xerosis and 'allergic asthma' in men (OR 2.13; 95% CI 1.08-4.19). CONCLUSION: Our findings indicate an association between xerosis and asthma in men independent of atopic dermatitis and FLG mutations. Both facilitated allergen sensitization and secondary degradation of filaggrin following T-helper cell 2 inflammation might be key elements to understanding this relationship. PMID- 25712345 TI - PDK1 and SGK3 Contribute to the Growth of BRAF-Mutant Melanomas and Are Potential Therapeutic Targets. AB - Melanoma development involves members of the AGC kinase family, including AKT, PKC, and, most recently, PDK1, as elucidated recently in studies of Braf::Pten mutant melanomas. Here, we report that PDK1 contributes functionally to skin pigmentation and to the development of melanomas harboring a wild-type PTEN genotype, which occurs in about 70% of human melanomas. The PDK1 substrate SGK3 was determined to be an important mediator of PDK1 activities in melanoma cells. Genetic or pharmacologic inhibition of PDK1 and SGK3 attenuated melanoma growth by inducing G1 phase cell-cycle arrest. In a synthetic lethal screen, pan-PI3K inhibition synergized with PDK1 inhibition to suppress melanoma growth, suggesting that focused blockade of PDK1/PI3K signaling might offer a new therapeutic modality for wild-type PTEN tumors. We also noted that responsiveness to PDK1 inhibition associated with decreased expression of pigmentation genes and increased expression of cytokines and inflammatory genes, suggesting a method to stratify patients with melanoma for PDK1-based therapies. Overall, our work highlights the potential significance of PDK1 as a therapeutic target to improve melanoma treatment. PMID- 25712347 TI - Exercise as a therapy for improvement of walking ability in adults with multiple sclerosis: a meta-analysis. AB - OBJECTIVE: To quantify improvements in walking performance commonly observed in patients with multiple sclerosis (pwMS), a systematic literature search and meta analysis were conducted quantifying the expected benefits of exercise on walking ability in pwMS. DATA SOURCES: Potential studies were identified by systematic search using PubMed (1966 to March 31, 2014), EMBASE (1974 to March 31, 2014), CINAHL (1998 to March 31, 2014), SPORTDiscus (1991 to March 31, 2014), and the Cochrane Central Register of Controlled Trials (1966 to March 31, 2014). The search used key concepts of "multiple sclerosis" AND "exercise." STUDY SELECTION: Randomized controlled trials of exercise training in adult pwMS. DATA EXTRACTION: Data on patient and study characteristics, walking ability, 10-m walk test (10mWT), timed 25-foot walk test (T25FW), 2-minute walk test (2MWT), 6-minute walk test (6MWT), and timed Up and Go (TUG) were extracted and archived. DATA SYNTHESIS: Data from 13 studies were included. In pwMS who exercised, significant improvements were found in walking speed, measured by the 10mWT (mean difference [MD] reduction in walking time of -1.76s; 95% confidence interval [CI], -2.47 to 1.06; P<.001), but no change in the T25FW (MD=-.59s; 95% CI, -2.55 to 1.36; P=.55). In pwMS who exercised, significant improvements were found in walking endurance as measured by the 6MWT and 2MWT, with an increased walking distance of MD=36.46m (95% CI, 15.14-57.79; P<.001) and MD=12.51m (95% CI, 4.79-20.23; P=.001), respectively. No improvement was found for TUG (MD=-1.05s; 95% CI, -2.19 to .09; P=.07). CONCLUSIONS: Our meta-analysis suggests that exercise improves walking speed and endurance in pwMS. PMID- 25712348 TI - Rebuttal: Fluoroscopic characterization of surgical bioprosthetic heart valves. PMID- 25712349 TI - Modulation of cellular glucose metabolism in human HepG2 cells by combinations of structurally related flavonoids. AB - SCOPE: Insulin-regulated glucose metabolism in cells is critical for proper metabolic functioning, and insulin resistance leads to type 2 diabetes. We performed a human study to assess the availability of structurally related dietary flavonols and tested their ability to affect cellular glucose uptake, metabolism, and glucose transporter gene expression in a liver HepG2 cell model. METHODS AND RESULTS: Eight healthy volunteers consumed a meal containing galangin, kaempferol, quercetin, and myricetin. In plasma, myricetin was absent, but the others were present, mostly as conjugates. In HepG2 cells, a combination of galangin, kaempferol, and quercetin (5 MUM each) for 12 h increased the acute uptake of [U-(14)C]-glucose and 2-[U-(14)C]-deoxyglucose by almost 100 and ~10%, respectively. All of the combinations increased glucose metabolism, but the effect on transport was less pronounced and mixed. A mixture of all flavonols significantly increased mRNA expression of the main glucose transporter Glut1 in HepG2 cells. CONCLUSION: These results for the first time show the presence of galangin conjugates in human plasma, and allow direct comparison between absorption of flavonols. A combination of flavonols has the potential to modulate sugar metabolism, both uptake into cells as evident from effects on deoxyglucose, and also further cellular glucose metabolism. PMID- 25712350 TI - Abstracts of the 2014 Annual Meeting of the American Society for Bone and Mineral Research, September 12-15, 2014, Houston, Texas . AB - Searchable abstracts may be found at http://www.asbmr.org/education/abstracts. PMID- 25712351 TI - Persistence and epidemic propagation of a Pseudomonas aeruginosa sequence type 235 clone harboring an IS26 composite transposon carrying the blaIMP-1 integron in Hiroshima, Japan, 2005 to 2012. AB - A 9-year surveillance for multidrug-resistant (MDR) Pseudomonas aeruginosa in the Hiroshima region showed that the number of isolates harboring the metallo-beta lactamase gene bla(IMP-1) abruptly increased after 2004, recorded the highest peak in 2006, and showed a tendency to decline afterwards, indicating a history of an epidemic. PCR mapping of the variable regions of the integrons showed that this epidemic was caused by the clonal persistence and propagation of an MDR P. aeruginosa strain harboring the bla(IMP-1) gene and an aminoglycoside 6'-N acetyltransferase gene, aac(6')-Iae in a class I integron (In113), whose integrase gene intl1 was disrupted by an IS26 insertion. Sequence analysis of the representative strain PA058447 resistance element containing the In113-derived gene cassette array showed that the element forms an IS26 transposon embedded in the chromosome. It has a Tn21 backbone and is composed of two segments sandwiched by three IS26s. In Japan, clonal nationwide expansion of an MDR P. aeruginosa NCGM2.S1 harboring chromosomally encoded In113 with intact intl1 is reported. Multilocus sequence typing and genomic comparison strongly suggest that PA058447 and NCGM2.S1 belong to the same clonal lineage. Moreover, the structures of the resistance element in the two strains are very similar, but the sites of insertion into the chromosome are different. Based on tagging information of the IS26 present in both resistance elements, we suggest that the MDR P. aeruginosa clone causing the epidemic in Hiroshima for the past 9 years originated from a common ancestor genome of PA058447 and NCGM2.S1 through an IS26 insertion into intl1 of In113 and through IS26-mediated genomic rearrangements. PMID- 25712352 TI - Azithromycin resistance and its mechanism in Neisseria gonorrhoeae strains in Hyogo, Japan. AB - Therapeutic options are limited for Neisseria gonorrhoeae infection, especially for oral drugs. The purpose of this study was to investigate the susceptibility of N. gonorrhoeae to oral azithromycin (AZM) and the correlation between AZM resistance-related gene mutations and MIC. We examined the AZM MICs of clinical strains of N. gonorrhoeae, sequenced the peptidyltransferase loop in domain V of 23S rRNA, and investigated the statistical correlation between AZM MIC and the presence and number of the mutations. Among 59 N. gonorrhoeae strains, our statistical data showed that a deletion mutation was seen significantly more often in the higher-MIC group (0.5 MUg/ml or higher) (35/37; 94.6%) than in the lower-MIC group (0.25 MUg/ml or less) (4/22; 18.2%) (P < 0.0001). However, a mutation of codon 40 (Ala -> Asp) in the mtrR gene (helix-turn-helix) was seen significantly more often in the lower-MIC group (12/22; 54.5%) (P < 0.0001). In N. gonorrhoeae multiantigen sequence typing (NG-MAST) analyses, ST4777 was representative of the lower-MIC group and ST1407, ST6798, and ST6800 were representative of the higher-MIC group. NG-MAST type 1407 was detected as the most prevalent type in AZM-resistant or -intermediate strains, as previously described. In conclusion, a deletion mutation in the mtrR promoter region may be a significant indicator for higher MIC (0.5 MUg/ml or higher). ST4777 was often seen in the lower-MIC group, and ST1407, ST6798, and ST6800 were characteristic of the higher-MIC group. Further research with a greater number of strains would help elucidate the mechanism of AZM resistance in N. gonorrhoeae infection. PMID- 25712353 TI - Synthesis of a sugar-based thiosemicarbazone series and structure-activity relationship versus the parasite cysteine proteases rhodesain, cruzain, and Schistosoma mansoni cathepsin B1. AB - The pressing need for better drugs against Chagas disease, African sleeping sickness, and schistosomiasis motivates the search for inhibitors of cruzain, rhodesain, and Schistosoma mansoni CB1 (SmCB1), the major cysteine proteases from Trypanosoma cruzi, Trypanosoma brucei, and S. mansoni, respectively. Thiosemicarbazones and heterocyclic analogues have been shown to be both antitrypanocidal and inhibitory against parasite cysteine proteases. A series of compounds was synthesized and evaluated against cruzain, rhodesain, and SmCB1 through biochemical assays to determine their potency and structure-activity relationships (SAR). This approach led to the discovery of 6 rhodesain, 4 cruzain, and 5 SmCB1 inhibitors with 50% inhibitory concentrations (IC50s) of <= 10 MUM. Among the compounds tested, the thiosemicarbazone derivative of peracetylated galactoside (compound 4i) was discovered to be a potent rhodesain inhibitor (IC50 = 1.2 +/- 1.0 MUM). The impact of a range of modifications was determined; removal of thiosemicarbazone or its replacement by semicarbazone resulted in virtually inactive compounds, and modifications in the sugar also diminished potency. Compounds were also evaluated in vitro against the parasites T. cruzi, T. brucei, and S. mansoni, revealing active compounds among this series. PMID- 25712354 TI - Impacts of global transcriptional regulators on persister metabolism. AB - Bacterial persisters are phenotypic variants with an extraordinary capacity to tolerate antibiotics, and they are hypothesized to be a main cause of chronic and relapsing infections. Recent evidence has suggested that the metabolism of persisters can be targeted to develop therapeutic countermeasures; however, knowledge of persister metabolism remains limited due to difficulties associated with isolating these rare and transient phenotypic variants. By using a technique to measure persister catabolic activity, which is based on the ability of metabolites to enable aminoglycoside (AG) killing of persisters, we investigated the role of seven global transcriptional regulators (ArcA, Cra, cyclic AMP [cAMP] receptor protein [CRP], DksA, FNR, Lrp, and RpoS) on persister metabolism. We found that removal of CRP resulted in a loss of AG potentiation in persisters for all metabolites tested. These results highlight a central role for cAMP/CRP in persister metabolism, as its perturbation can significantly diminish the metabolic capabilities of persisters and effectively eliminate the ability of AGs to eradicate these troublesome bacteria. PMID- 25712356 TI - In vivo activities of simulated human doses of cefepime and cefepime-AAI101 against multidrug-resistant Gram-negative Enterobacteriaceae. AB - The combination of cefepime with AAI101, a novel extended-spectrum beta-lactamase inhibitor, possesses potent in vitro activity against many resistant Gram negative pathogens. Against a panel of 20 mostly carbapenemase-producing cefepime nonsusceptible strains of the family Enterobacteriaceae, we evaluated the MICs of cefepime in the presence of various fixed AAI101 concentrations (1, 2, 4, 8, and 16 mg/liter) and the in vivo efficacy of simulated human doses of cefepime and cefepime-AAI101 in a neutropenic murine thigh infection model. At 2 h after inoculation, mice were dosed with regimens that provided a profile mimicking the free drug concentration-time profile observed in humans given cefepime at 2 g every 8 h (q8h; as a 30-min infusion) or cefepime-AAI101 at 2 g/0.5 g q8h (as a 30-min infusion). Efficacy was determined by calculation of the change in thigh bacterial density (log10 number of CFU) after 24 h relative to the starting inoculum (0 h). After 24 h, bacterial growth of 2.7 +/- 0.1 log10 CFU (mean +/- standard error) was observed in control animals. Efficacy for cefepime monotherapy was observed against only 3 isolates, whereas increases in bacterial density similar to that in the control animals were noted for the remaining 17 strains (all with cefepime MICs of >= 64 mg/liter). The humanized cefepime-AAI101 dosing regimen resulted in bacterial reductions of >= 0.5 log10 CFU for 12 of the 20 strains. Evaluation of efficacy as a function of the fraction of the dosing interval during which free drug concentrations were above the MIC determined with different fixed concentrations of AAI101 suggested that a fixed concentration of 8 mg/liter AAI101 is most predictive of in vivo activity for the studied regimen. PMID- 25712357 TI - Chemical inhibition of bacterial ribosome biogenesis shows efficacy in a worm infection model. AB - The development of antibacterial compounds that perturb novel processes is an imperative in the challenge presented by widespread antibiotic resistance. While many antibiotics target the ribosome, molecules that inhibit ribosome assembly have yet to be used in this manner. Here we show that a novel inhibitor of ribosome biogenesis, lamotrigine, is capable of rescuing Caenorhabditis elegans from an established Salmonella infection, revealing that ribosome biogenesis is a promising target for the development of new antibiotics. PMID- 25712355 TI - Relationship between azithromycin susceptibility and administration efficacy for nontypeable Haemophilus influenzae respiratory infection. AB - Nontypeable Haemophilus influenzae (NTHI) is an opportunistic pathogen that is an important cause of acute exacerbations of chronic obstructive pulmonary disease (AECOPD). COPD is an inflammatory disease of the airways, and exacerbations are acute inflammatory events superimposed on this background of chronic inflammation. Azithromycin (AZM) is a macrolide antibiotic with antibacterial and anti-inflammatory properties and a clinically proven potential for AECOPD prevention and management. Relationships between AZM efficacy and resistance by NTHI and between bactericidal and immunomodulatory effects on NTHI respiratory infection have not been addressed. In this study, we employed two pathogenic NTHI strains with different AZM susceptibilities (NTHI 375 [AZM susceptible] and NTHI 353 [AZM resistant]) to evaluate the prophylactic and therapeutic effects of AZM on the NTHI-host interplay. At the cellular level, AZM was bactericidal toward intracellular NTHI inside alveolar and bronchial epithelia and alveolar macrophages, and it enhanced NTHI phagocytosis by the latter cell type. These effects correlated with the strain MIC of AZM and the antibiotic dose. Additionally, the effect of AZM on NTHI infection was assessed in a mouse model of pulmonary infection. AZM showed both preventive and therapeutic efficacies by lowering NTHI 375 bacterial counts in lungs and bronchoalveolar lavage fluid (BALF) and by reducing histopathological inflammatory lesions in the upper and lower airways of mice. Conversely, AZM did not reduce bacterial loads in animals infected with NTHI 353, in which case a milder anti-inflammatory effect was also observed. Together, the results of this work link the bactericidal and anti inflammatory effects of AZM and frame the efficacy of this antibiotic against NTHI respiratory infection. PMID- 25712358 TI - Kidney injury associated with telavancin dosing regimen in an animal model. AB - The elevation of serum creatinine levels is a concern with telavancin therapy. We examined the onset of kidney injury associated with telavancin in an animal model. Urine samples were collected at baseline and daily to determine the concentrations of kidney injury molecule 1 (KIM-1), a marker for early kidney injury. When a clinically relevant exposure of telavancin was given daily to rats, some differences in kidney injury were attributed to the dosing regimen. Further investigations of alternative telavancin dosing regimens are warranted. PMID- 25712359 TI - Bestatin induces specific changes in Trypanosoma cruzi dipeptide pool. AB - Proteases and peptidases in Trypanosoma cruzi are considered potential targets for antichagasic chemotherapy. We monitored changes in low-mass metabolites in T. cruzi epimastigotes treated with bestatin, a dipeptide metalloaminopeptidase inhibitor. After treatment, multiple dipeptides were shown to be increased, confirming in situ inhibition of the leucine aminopeptidase of T. cruzi (LAPTc) and probably other peptidases. PMID- 25712360 TI - Persistence of vancomycin resistance in multiple clones of Enterococcus faecium isolated from Danish broilers 15 years after the ban of avoparcin. AB - The occurrence and diversity of vancomycin-resistant Enterococcus faecium (VREF) were investigated in 100 Danish broiler flocks 15 years after the avoparcin ban. VREF occurred in 47 flocks at low fecal concentrations detectable only by selective enrichment. Vancomycin resistance was prevalently associated with a transferable nontypeable plasmid lineage occurring in multiple E. faecium clones. Coselection of sequence type 842 by tetracycline use only partly explained the persistence of vancomycin resistance in the absence of detectable plasmid coresistance and toxin-antitoxin systems. PMID- 25712361 TI - Drug resistance of clinical varicella-zoster virus strains confirmed by recombinant thymidine kinase expression and by targeted resistance mutagenesis of a cloned wild-type isolate. AB - In this study, approaches were developed to examine the phenotypes of nonviable clinical varicella-zoster virus (VZV) strains with amino acid substitutions in the thymidine kinase (TK) (open reading frame 36 [ORF36]) and/or DNA polymerase (Pol) (ORF28) suspected to cause resistance to antivirals. Initially, recombinant TK proteins containing amino acid substitutions described as known or suspected causes of antiviral resistance were analyzed by measuring the TK activity by applying a modified commercial enzyme immunoassay. To examine the effects of these TK and Pol substitutions on the replication of recombinant virus strains, the method of en passant mutagenesis was used. Targeted mutations within ORF36 and/or ORF28 and an autonomously expressed gene of the monomeric red fluorescent protein for plaque identification were introduced into the European wild-type VZV strain HJO. Plaque reduction assays revealed that the amino acid substitutions with unknown functions in TK, Q303stop, N334stop, A163stop, and the deletion of amino acids 7 to 74 aa (Deltaaa 7 to 74), were associated with resistance against acyclovir (ACV), penciclovir, or brivudine, whereas the L73I substitution and the Pol substitutions T237K and A955T revealed sensitive viral phenotypes. The results were confirmed by quantitative PCR by measuring the viral load under increasing ACV concentrations. In conclusion, analyzing the enzymatic activities of recombinant TK proteins represent a useful tool for evaluating the significance of amino acid substitutions in the antiviral resistance of clinical VZV strains. However, direct testing of replication-competent viruses by the introduction of nonsynonymous mutations in a VZV bacterial artificial chromosome using en passant mutagenesis led to reliable phenotypic characterization results. PMID- 25712362 TI - Assessment of minocycline and polymyxin B combination against Acinetobacter baumannii. AB - Antimicrobial resistance among Acinetobacter baumannii is increasing worldwide, often necessitating combination therapy. The clinical utility of using minocycline with polymyxin B is not well established. In this study, we investigated the activity of minocycline and polymyxin B against 1 laboratory isolate and 3 clinical isolates of A. baumannii. Minocycline susceptibility testing was performed with and without an efflux pump inhibitor, phenylalanine arginine beta-naphthylamide (PAbetaN). The intracellular minocycline concentration was determined with and without polymyxin B (0.5 MUg/ml). Time-kill studies were performed over 24 h using approximately 10(6) CFU/ml of each strain with clinically relevant minocycline concentrations (2 MUg/ml and 8 MUg/ml), with and without polymyxin B (0.5 MUg/ml). The in vivo efficacy of the combination was assessed in a neutropenic murine pneumonia model. Infected animals were administered minocycline (50 mg/kg), polymyxin B (10 mg/kg), or both to achieve clinically equivalent exposures in humans. A reduction in the minocycline MIC (>= 4*) was observed in the presence of PAbetaN. The intracellular concentration and in vitro bactericidal effect of minocycline were both enhanced by polymyxin B. With 2 minocycline-susceptible strains, the bacterial burden in lung tissue at 24 h was considerably reduced by the combination compared to monotherapy with minocycline or polymyxin B. In addition, the combination prolonged survival of animals infected with a minocycline-susceptible strain. Polymyxin B increased the intracellular concentration of minocycline in bacterial cells and enhanced the bactericidal activity of minocycline, presumably due to efflux pump disruption. The clinical utility of this combination should be further investigated. PMID- 25712363 TI - Pharmacodynamics of amphotericin B deoxycholate, amphotericin B lipid complex, and liposomal amphotericin B against Aspergillus fumigatus. AB - Amphotericin B is a first-line agent for the treatment of invasive aspergillosis. However, relatively little is known about the pharmacodynamics of amphotericin B for invasive pulmonary aspergillosis. We studied the pharmacokinetics (PK) and pharmacodynamics (PD) of amphotericin B deoxycholate (DAMB), amphotericin B lipid complex (ABLC), and liposomal amphotericin B (LAMB) by using a neutropenic-rabbit model of invasive pulmonary aspergillosis. The study endpoints were lung weight, infarct score, and levels of circulating galactomannan and (1 -> 3)-beta-D glucan. Mathematical models were used to describe PK-PD relationships. The experimental findings were bridged to humans by Monte Carlo simulation. Each amphotericin B formulation induced a dose-dependent decline in study endpoints. Near-maximal antifungal activity was evident with DAMB at 1 mg/kg/day and ABLC and LAMB at 5 mg/kg/day. The bridging study suggested that the "average" patient receiving LAMB at 3 mg/kg/day was predicted to have complete suppression of galactomannan and (1 -> 3)-beta-D-glucan levels, but 20 to 30% of the patients still had a galactomannan index of >1 and (1 -> 3)-beta-D-glucan levels of >60 pg/ml. All formulations of amphotericin B induce a dose-dependent reduction in markers of lung injury and circulating fungus-related biomarkers. A clinical dosage of liposomal amphotericin B of 3 mg/kg/day is predicted to cause complete suppression of galactomannan and (1 -> 3)-beta-D-glucan levels in the majority of patients. PMID- 25712364 TI - Evolution of hepatitis C virus quasispecies during repeated treatment with the NS3/4A protease inhibitor telaprevir. AB - In treating hepatitis B virus (HBV) and human immunodeficiency virus (HIV) infections, the rapid reselection of resistance-associated variants (RAVs) is well known in patients with repeated exposure to the same class of antiviral agents. For chronic hepatitis C patients who have experienced virologic failure with direct-acting antiviral drugs, the potential for the reselection of persistent RAVs is unknown. Nine patients who received 14 days of telaprevir monotherapy were retreated with telaprevir-based triple therapy 4.3 to 5.7 years later. In four patients with virologic failure with both telaprevir-containing regimens, population-based and deep sequencing (454 GS-FLX) of the NS3 protease gene were performed before and at treatment failure (median coverage, 4,651 reads). Using deep sequencing, with a threshold of 1.0% for variant calling, no isolates were found harboring RAVs at the baseline time points. While population based sequencing uncovered similar resistance patterns (V36M plus R155K for subtype 1a and V36A for subtype 1b) in all four patients after the first and second telaprevir treatments, deep sequencing analysis revealed a median of 7 (range, 4 to 23) nucleotide substitutions on the NS3 backbone of the resistant strains, together with large phylogenetic differences between viral quasispecies, making the survival of resistant isolates highly unlikely. In contrast, in a comparison of the two baseline time points, the median number of nucleotide exchanges in the wild-type isolates was only 3 (range, 2 to 8), reflecting the natural evolution of the NS3 gene. In patients with repeated direct antiviral treatment, a continuous evolution of HCV quasispecies was observed, with no clear evidence of persistence and reselection but strong signs of independent de novo generation of resistance. Antiviral therapy for chronic viral infections, like HIV, hepatitis B virus (HBV), or hepatitis C virus (HCV), faces several challenges. These viruses have evolved survival strategies and proliferate by escaping the host's immune system. The development of direct-acting antiviral agents is an important achievement in fighting these infections. Viral variants conferring resistance to direct antiviral drugs lead to treatment failure. For HIV/HBV, it is well known that viral variants associated with treatment failure will be archived and reselected rapidly during retreatment with the same drug/class of drugs. We explored the mechanisms and rules of how resistant variants are selected and potentially reselected during repeated direct antiviral therapies in chronically HCV-infected patients. Interestingly, in contrast to HIV and HBV, we could not prove long-term persistence and reselection of resistant variants in HCV patients who failed protease inhibitor-based therapy. This may have important implications for the potential to reuse direct-acting antivirals in patients who failed the initial direct antiviral treatment. (The phase IIIb study described in this paper is registered at ClinicalTrials.gov under registration number NCT01054573.). PMID- 25712365 TI - Decreasing pfmdr1 copy number suggests that Plasmodium falciparum in Western Cambodia is regaining in vitro susceptibility to mefloquine. AB - Dihydroartemisinin-piperaquine is the current frontline artemisinin combination therapy (ACT) for Plasmodium falciparum malaria in Cambodia but is now failing in several western provinces. To investigate artesunate plus mefloquine (AS+MQ) as a replacement ACT, we measured the prevalence of multiple pfmdr1 copies--a molecular marker for MQ resistance--in 844 P. falciparum clinical isolates collected in 2008 to 2013. The pfmdr1 copy number is decreasing in Western Cambodia, suggesting that P. falciparum is regaining in vitro susceptibility to MQ. PMID- 25712367 TI - Effect of continuous vs pulsed iontophoresis of treprostinil on skin blood flow. AB - INTRODUCTION: Systemic sclerosis (SSc) is a rare disease affecting digital microcirculation, leading to finger ulcers and in some cases to amputation. Prostacyclin analogues can be used intravenously but their therapeutic effect is counterbalanced by potentially serious vasodilatation-induced side effects. Iontophoresis of treprostinil could be a promising local therapeutic alternative for SSc-related digital ulcers. Iontophoretic drug delivery is complex, and whether continuous or periodic current should be used remains debated. The objective of the present work is to compare the effect of continuous vs pulsed iontophoresis of treprostinil in rats. MATERIALS AND METHODS: Treprostinil (0.64 mM and 0.064 mM) and NaCl were delivered by cathodal iontophoresis onto the hindquarters of anaesthetized rats. Three protocols delivering the same quantity of current were compared: one was continuous (100 MUA during 20 min) and two were periodic (B: twenty 1-min cycles with 200 MUA during 30 s followed by 30 s Off; and C: twenty 1-min cycles with 600 MUA during 10s followed by 50s Off) (n=8 for each protocol with each concentration). Skin blood flow was quantified using laser Doppler imaging and skin resistance was calculated with Ohm's law. RESULTS: All protocols induced a significant increase in skin blood flow. At the lower concentration (0.064 mM treprostinil) the pulsed 10/50 sequence significantly enhanced cutaneous blood flow (Table 1; Fig. 1B) compared to continuous iontophoresis or the 30/30 sequence. We noted that the pulsed iontophoresis of NaCl (10/50 sequence) induced a significant early increase in cutaneous blood flow in comparison with continuous iontophoresis. Skin resistance measures were negatively correlated with current intensity delivered. CONCLUSION: In conclusion, pulsed iontophoresis of treprostinil with a 10 s/50 s (On/Off) protocol at 600 MUA increases the efficacy of iontophoresis at 0.064 mM but not at a tenfold higher concentration. Pulsed iontophoresis could be used to optimize treprostinil iontophoresis, to provide similar efficacy with decreased costs, and should now be tested on humans. PMID- 25712366 TI - Entry into mitosis: a solution to the decades-long enigma of MPF. AB - Maturation or M phase-promoting factor (MPF) is the universal inducer of M phase common to eukaryotic cells. MPF was originally defined as a transferable activity that can induce the G2/M phase transition in recipient cells. Today, however, MPF is assumed to describe an activity that exhibits its effect in donor cells, and furthermore, MPF is consistently equated with the kinase cyclin B-Cdk1. In some conditions, however, MPF, as originally defined, is undetectable even though cyclin B-Cdk1 is fully active. For over three decades, this inconsistency has remained a long-standing puzzle. The enigma is now resolved through the elucidation that MPF, defined as an activity that exhibits its effect in recipient cells, consists of at least two separate kinases, cyclin B-Cdk1 and Greatwall (Gwl). Involvement of Gwl in MPF can be explained by its contribution to the autoregulatory activation of cyclin B-Cdk1 and by its stabilization of phosphorylations on cyclin B-Cdk1 substrates, both of which are essential when MPF induces the G2/M phase transition in recipient cells. To accomplish these tasks, Gwl helps cyclin B-Cdk1 by suppressing protein phosphatase 2A (PP2A)-B55 that counteracts cyclin B-Cdk1. MPF, as originally defined, is thus not synonymous with cyclin B-Cdk1, but is instead a system consisting of both cyclin B-Cdk1 that directs mitotic entry and Gwl that suppresses the anti-cyclin B-Cdk1 phosphatase. The current view that MPF is a synonym for cyclin B-Cdk1 in donor cells is thus imprecise; instead, MPF is best regarded as the entire pathway involved in the autoregulatory activation of cyclin B-Cdk1, with specifics depending on the experimental system. PMID- 25712368 TI - Decreased liver distribution of entecavir is related to down-regulation of Oat2/Oct1 and up-regulation of Mrp1/2/3/5 in rat liver fibrosis. AB - AIMS: We aimed to elucidate whether entecavir was taken-up into liver by transporters and clarify the possible molecular mechanisms of changes in the distribution of entecavir in rat liver fibrosis. METHODS: Thioacetamide (TAA) was applied to induce rat liver fibrosis. Samples of liver uptake index (LUI) study and uptake of entecavir in isolated rat hepatocytes were determined by LC-MS/MS. qRT-PCR and western blotting were used to examine the expression of transporters in rat liver. RESULTS: The uptake of entecavir in hepatocytes was significantly higher at 37 degrees C compared to 4 degrees C. Furthermore, TEA and PAH could inhibit significantly the uptake of entecavir by the hepatocytes. It indicated that Oat2 and Oct1 were contributed to uptake of entecavir. Compared with control group, LUI and the uptake of entecavir, PAH and TEA in hepatocytes were significantly reduced in liver fibrosis group. Further study indicated that entecavir Vmax in liver fibrosis group was significantly decreased while the Km was not changed. These results indicated that transport capacity TAA treated isolated rat liver hepatocytes were reduced. Oat2 and Oct1 expressions were down regulated and Mrp1/2/3/5 mRNA expressions were up-regulated in liver fibrosis group. CONCLUSIONS: The changes of these transporters were contributed to decrease liver distribution of entecavir. PMID- 25712369 TI - Intravenous pentamidine for Pneumocystis carinii/jiroveci pneumonia prophylaxis in pediatric transplant patients. AB - SMX/TMP is the current gold standard for prophylaxis against PCP in immunocompromised pediatric patients. Currently, there are several second-line options for prophylaxis but many, including intravenous (IV) pentamidine, have not been reported to be as effective or as safe as SMX/TMP in the pediatric transplant population. This study is to determine the efficacy and safety of IV pentamidine in preventing PCP in pediatric transplant patients. A retrospective chart review was conducted to evaluate all transplant patients that received at least one dose of IV pentamidine from January 2010 to July 2013. The primary outcome, IV pentamidine efficacy, was evaluated by the incidence of PCP diagnosis for 28 days after the last dose of IV pentamidine if patient was transitioned to another agent for PCP prophylaxis. Patients on IV pentamidine for entire course of PCP prophylaxis were followed at least six months after discontinuation of IV pentamidine. The safety of IV pentamidine was assessed by the incidence of adverse events leading to pentamidine discontinuation. All data were analyzed using descriptive statistics. All transplant patients at CCHMC who had received IV pentamidine were reviewed, and 333 patients met inclusion criteria. The overall incidence of PCP was found to be 0.3% for pediatric transplant patients on pentamidine. Pentamidine was found to be safe, and the incidence of adverse events leading to discontinuation was 6% with the most common reason being tachycardia 2.1%. IV pentamidine is safe and effective as PCP prophylaxis in pediatric transplant patients with a PCP breakthrough rate of 0.3% (1 of 333 patients), and only 20 adverse events led to discontinuation. We recommend that IV pentamidine be considered as a second-line option in pediatric transplant patients who cannot tolerate SMX/TMP. PMID- 25712371 TI - US medical societies call for action on gun violence. PMID- 25712370 TI - Toll-like receptor 4 contributes to vascular remodelling and endothelial dysfunction in angiotensin II-induced hypertension. AB - BACKGROUND AND PURPOSE: Toll-like receptor 4 (TLR4) signalling contributes to inflammatory cardiovascular diseases, but its role in hypertension and the associated vascular damage is not known. We investigated whether TLR4 activation contributed to angiotensin II (AngII)-induced hypertension and the associated vascular structural, mechanical and functional alterations. EXPERIMENTAL APPROACH: AngII was infused (1.44 mg . kg(-1) . day(-1), s.c.) for 2 weeks in C57BL6 mice, treated with a neutralizing anti-TLR4 antibody or IgG (1 MUg . day( 1); systolic BP (SBP) and aortic cytokine levels were measured. Structural, mechanical and contractile properties of aortic and mesenteric arterial segments were measured with myography and histology. RT-PCR and Western blotting were used to analyse these tissues and cultured vascular smooth muscle cells (VSMC) from hypertensive rats (SHR). KEY RESULTS: Aortic TLR4 mRNA levels were raised by AngII infusion. Anti-TLR4 antibody treatment of AngII-treated mice normalised: (i) increased SBP and TNF-alpha, IL-6 and CCL2 levels; (ii) vascular structural and mechanical changes; (iii) altered aortic phenylephrine- and ACh-induced responses; (iv) increased NOX-1 mRNA levels, superoxide anion production and NAD(P)H oxidase activity and effects of catalase, apocynin, ML-171 and Mito-TEMPO on vascular responses; and (v) reduced NO release and effects of L-NAME on phenylephrine-induced contraction. In VSMC, the MyD88 inhibitor ST-2825 reduced AngII-induced NAD(P)H oxidase activity. The TLR4 inhibitor CLI-095 reduced AngII induced increased phospho-JNK1/2 and p65 NF-kappaB subunit nuclear protein expression. CONCLUSIONS AND IMPLICATIONS: TLR4 up-regulation by AngII contributed to the inflammation, endothelial dysfunction, vascular remodelling and stiffness associated with hypertension by mechanisms involving oxidative stress. MyD88 dependent activation and JNK/NF-kappaB signalling pathways participated in these alterations. PMID- 25712372 TI - Four things to know about myosin light chains as reporters for non-muscle myosin 2 dynamics in live cells. AB - The interplay between non-muscle myosins-2 and filamentous actin results in cytoplasmic contractility which is essential for eukaryotic life. Concomitantly, there is tremendous interest in elucidating the physiological function and temporal localization of non-muscle myosin-2 in cells. A commonly used method to study the function and localization of non-muscle myosin-2 is to overexpress a fluorescent protein (FP)-tagged version of the regulatory light chain (RLC) which binds to the myosin-2 heavy chain by mass action. Caveats about this approach include findings from recent studies indicating that the RLC does not bind exclusively to the non-muscle myosin-2 heavy chain. Rather, it can also associate with the myosin heavy chains of several other classes as well as other targets than myosin. In addition, the presence of the FP moiety may compromise myosin's enzymatic and mechanical performance. This and other factors to be discussed in this commentary raise questions about the possible complications in using FP-RLC as a marker for the dynamic localization and regulatory aspects of non-muscle myosin-2 motor functions in cell biological experiments. PMID- 25712373 TI - MicroRNA-335 represents an independent prognostic marker in cervical cancer. AB - Advanced stages with distant metastases or recurrence lack reliable prognostic predictor for cervical cancer. Therefore, the purpose of this study was to investigate the clinical significance of miR-335 expression in cervical cancer. A total of 138 cervical cancer samples were collected, and normal cervical tissues were obtained as matched-pair controls. The level of miR-335 expression was examined using quantitative real-time polymerase chain reaction. Overall survival was analyzed using Kaplan-Meier method. Moreover, the relationship between the expression of miR-335 and the clinicopathological features was further analyzed using Cox regression. Lower miR-335 expression was found in cervical cancer specimens. Cervical cancer patients with reduced miR-335 level had shorter survival time, compared with those with high levels of miR-335 expression (P = 0.011, log-rank = 6.458). Through Cox regression, we found that miR-335 expression was associated with the survival of cervical cancer (RR = 0.251, 95 % CI 0.095-0.663, P = 0.005). The results suggested that miR-335 expression was decreased in cervical cancer specimens and lower miR-335 expression resulted in poorer survival in patients with cervical cancer. Our findings indicated that miR 335 may be a candidate factor for predicting prognosis for cervical cancer. PMID- 25712374 TI - Differential expression of the UGT1A family of genes in stomach cancer tissues. AB - Uridine 5'-diphospho-glucuronosyltransferases (UGT) are the key players in the biotransformation of drugs, xenobiotics, and endogenous compounds. Particularly, UDP-glucuronosyltransferase 1A (UGT1A) participates in a wide range of biological and pharmacological processes and plays a critical role in the conjugation of endogenous and exogenous components. Thirteen alternative splicing products were produced from UGT1A gene locus designated as UGT1A1 and UGT1A3-10. A growing amount of evidence suggests that they have important roles in the carcinogenesis which is well documented by colon, liver, pancreas, and kidney cancer studies. Here, we report differential expressions of UGT1A genes in normal and tumor tissues of stomach cancer patients. Total numbers of 49 patients were enrolled for this study, and expression analysis of UGT1A genes was evaluated by the real time PCR method. Accordingly, UGT1A1, UGT1A8, and UGT1A10 were found to be upregulated, and UGT1A3, UGT1A5, UGT1A7, and UGT1A9 were downregulated in stomach tumors. No expression changes were observed in UGT1A4. Also, UGT1A6 transcription variants were significantly upregulated in stomach cancer tissues compared to normal stomach tissue. Additionally, UGT1A7 gene showed highest expression in both normal and tumoral tissues, and interestingly, UGT1A7 gene expression was significantly reduced in stage II patients as compared to other patients. In conclusion, UGT1A genes are differentially expressed in normal and tumoral stomach tissues and expression changes of these genes may affect the development and progression of various types of cancer including the cancer of the stomach. PMID- 25712375 TI - Effect of cancer-associated fibroblasts on the migration of glioma cells in vitro. AB - Cancer-associated fibroblasts (CAFs) significantly influence biological properties of many tumors. The role of these mesenchymal cells is also anticipated in human gliomas. To evaluate the putative role of CAFs in glioblastoma, we tested the effect of CAF conditioned media on the proliferation and chemotaxis of glioma cells. The proliferation of glioma cells was stimulated to similar extent by both the normal fibroblasts (NFs) and CAF-conditioned media. Nevertheless, CAF-conditioned media enhanced the chemotactic migration of glioma cells significantly more potently than the media from normal fibroblasts. In order to determine whether CAF-like cells are present in human glioblastomas, immunofluorescence staining was performed on tissue samples from 20 patients using markers typical for CAFs. This analysis revealed regular presence of mesenchymal cells expressing characteristic CAF markers alpha-smooth muscle actin and TE-7 in human glioblastomas. These observations indicate the potential role of CAF-like cells in glioblastoma biology. PMID- 25712376 TI - Differentially expressed gene profiles of intrahepatic cholangiocarcinoma, hepatocellular carcinoma, and combined hepatocellular-cholangiocarcinoma by integrated microarray analysis. AB - Intrahepatic cholangiocarcinoma (ICC) and hepatocellular carcinoma (HCC) are common primary liver cancers worldwide. However, the survival and prognosis of ICC are much poorer than those of HCC, indicating the different molecular characteristics and mechanisms between ICC and HCC. To identify differentially expressed (DE) genes between ICC and HCC or combined hepatocellular cholangiocarcinoma (CHC), we performed integrated analysis of publicly available microarray Gene Expression Omnibus (GEO) datasets by MetaOmics. Three GEO datasets comprising 32 ICC biochips, 77 HCC biochips, and 34 CHC biochips were available for the data integration. We identified 7313 DE genes between ICC and HCC, including 3650 upregulated genes and 3663 downregulated genes. The S100 family members on chromosome 1q21 were extensively upregulated in ICC, and S100A11 had the greatest degree of upregulation in ICC. Based on the DE genes, combined gene ontology and Kyoto Encyclopedia of Genes and Genomes analysis showed the enhanced pathways of local adhesion, ECM-receptor interaction, and regulation of action cytoskeleton, suggesting the enhanced communication between ICC and the microenvironment. Additionally, development-related genes and development-related pathways, including the Notch, Wnt, and TGF-beta signaling pathways, were shown to be active prominently in ICC. Taken together, we identified the characteristically upregulated or downregulated DE genes and pathways in ICC compared with HCC or CHC. These DE genes and pathways supply new transcriptomics evidence for ICC and could help identify new therapeutic targets. PMID- 25712377 TI - DYRK2 regulates epithelial-mesenchymal-transition and chemosensitivity through Snail degradation in ovarian serous adenocarcinoma. AB - Epithelial-mesenchymal-transition (EMT) plays essential roles in ovarian cancer invasion, metastasis, and drug resistance. A hallmark of EMT is the loss of E cadherin, which is regulated by Snail. Recently, it was shown that dual specificity tyrosine-regulated kinase 2 (DYRK2) controls Snail degradation in breast cancer. The aim of this study is to clarify whether DYRK2 regulates EMT through Snail degradation in ovarian serous adenocarcinoma (SA). Expression of DYRK2 and Snail in two pairs of cisplatin-resistant and the original cisplatin sensitive ovarian cancer cell line were analyzed by immunoblotting and real-time RT-PCR analysis. Morphological change, invasion ability, and chemosensitivity were evaluated by using DYRK2 stable knockdown cell line in 2008 (2008 shDYRK2). Immunohistochemical analyses for DYRK2 and Snail were performed with surgical specimens. The correlations between the expression of these proteins and the clinicopathological parameters, including prognosis, were determined. Moreover, we conducted a hypodermic administration test in nude mice and examined reproductive and cisplatin response activities. DYRK2 protein expression was posttranslationally reduced in cisplatin-resistant SA cell lines. 2008 shDYRK2 showed mesenchymal phenotype and resistant to cisplatin. Immunohistochemistry demonstrated that DYRK2 expression inversely correlated with Snail expression, and reduced expression of DYRK2 was associated with shorter overall survival in SA. DYRK2 may regulate EMT through Snail degradation in ovarian SA and might be a predictive marker for a favorable prognosis in the treatment of this cancer. PMID- 25712378 TI - The relationship between gestational diabetes and antenatal depression. AB - OBJECTIVE: To determine whether women with gestational diabetes mellitus (GDM) had more symptoms of depression than women without GDM. A secondary aim was to determine if factors predictive of symptoms of depression in women with GDM were different than women without GDM. DESIGN: A cross sectional, descriptive design was used. SETTING: An outpatient clinic at an academic medical center. PARTICIPANTS: The sample included 135 pregnant women between 24 and 40 weeks gestation, of which 65 had GDM and 70 did not. METHODS: The Edinburgh Postnatal Depression Screen (EPDS) was used to measure symptoms of depression in pregnant women attending routine prenatal care visits. Descriptive statistics, logistic regression, and multiple regressions were done to analyze the data. RESULTS: Twenty percent of women with GDM and 13% of women without GDM had significant symptoms of depression. Women with GDM were 3.79 times more likely to have a history of depression (95% confidence interval [CI] [1.07, 13.45], p = .04) than women without GDM after controlling for age, income, marital status, body mass index, and gravida. Trait anxiety and perceived stress were significant predictor factors of symptoms of depression (R(2) = .82, p < .001) for women with and without GDM. CONCLUSIONS: Results suggest that symptoms of depression are common during the antepartum period, thus assessment and education regarding this disorder are important. In addition, a history of depression may be a risk factor for the development of GDM. PMID- 25712380 TI - Maternal Phenylketonuria: Long-term Outcomes in Offspring and Post-pregnancy Maternal Characteristics. AB - Maternal phenylketonuria (MPKU) is a well-recognized complication of PKU and one of the most potent teratogenic syndromes of pregnancy. Virtually all offspring from untreated pregnancies in women with classic PKU have intellectual disabilities and microcephaly. Congenital heart disease and intrauterine growth retardation occur many times more often than expected in the general population. Control of maternal blood phenylalanine during pregnancy prevents most if not all of these complications. Previous studies demonstrated the benefits of treatment in terms of birth parameters and early development. In this study, physical examinations, a medical history, and neuropsychological evaluation were obtained in 47 children from 24 mothers with PKU who received treatment during pregnancy. Mothers were interviewed and administered an abbreviated IQ test. Associations between maternal factors and offspring outcomes were also analyzed.The 21 male and 26 female offspring ranged in age from 1 month to 26 years with 21 (62%) over 6 years. Results indicated mean intercanthal distances above the 70th percentile. Microcephaly was present in 19% of offspring, with head circumference below the third percentile. None of the offspring had cardiac anomalies. Mean offspring IQ was 94 +/- 19, with 12% performing in the range of intellectual disability (IQ < 70). Among children >5 years of age, 25% had learning disabilities, 31% had attention deficit hyperactivity disorder (ADHD), 22% were on ADHD medication, and 34% had a diagnosis of anxiety and/or depression. Among the 24 mothers, 12 reported following the diet for PKU. Only one woman on diet had a blood phenylalanine concentration <360 MUmol/L (recommended range) and the majority had indications of poor nutritional status. Mean maternal Full Scale IQ was 94 +/- 16 (range = 61-117), with 25% performing in the borderline intellectual range (IQ < 85). Verbal IQ was significantly lower than Performance IQ (p = 0.01, CI 2.7, 16.1). On the self-report Beck Depression Inventory, Second Edition, 25% received scores indicating mild to moderate depression, and on the Beck Anxiety Inventory, 46% reported mild to moderate anxiety. Offspring IQ correlated with maternal metabolic control during pregnancy (r = 0.51), maternal IQ (r = -0.62), and socioeconomic position (r = -0.48). Offspring with ADHD, learning disabilities, or emotional disturbances were more likely to have mothers with anxiety and/or depression. To ensure optimal offspring outcomes, healthcare providers need to assess maternal nutrition, blood phenylalanine concentrations, cognitive abilities, and socioeconomic position. Interventions can then be initiated that reduce psychosocial stressors and enhance adherence to diet and positive parenting, which in turn can lead to better cognitive functioning, behavior, and emotional well-being in their children. PMID- 25712379 TI - Di-sulfated Keratan Sulfate as a Novel Biomarker for Mucopolysaccharidosis II, IVA, and IVB. AB - Keratan sulfate (KS) is a storage material in mucopolysaccharidosis IV (MPS IV). However, no detailed analysis has been reported on subclasses of KS: mono sulfated KS and di-sulfated KS. We established a novel method to distinguish and quantify mono- and di-sulfated KS using liquid chromatography-tandem mass spectrometry and measured both KS levels in various specimens.Di-sulfated KS was dominant in shark cartilage and rat serum, while mono-sulfated KS was dominant in bovine cornea and human serum. Levels of both mono- and di-sulfated KS varied with age in the blood and urine from control subjects and patients with MPS II and IVA. The mean levels of both forms of KS in the plasma/serum from patients with MPS II, IVA, and IVB were elevated compared with that in age-matched controls. Di-sulfated KS provided more significant difference between MPS IVA and the age-matched controls than mono-sulfated KS. The ratio of di-sulfated KS to total KS in plasma/serum increased with age in control subjects and patients with MPS II but was age independent in MPS IVA patients. Consequently, this ratio can discriminate younger MPS IVA patients from controls. Levels of mono- and di sulfated KS in urine of MPS IVA and IVB patients were all higher than age-matched controls for all ages studied.In conclusion, the level of di-sulfated KS and its ratio to total KS can distinguish control subjects from patients with MPS II, IVA, and IVB, indicating that di-sulfated KS may be a novel biomarker for these disorders. PMID- 25712381 TI - Assessing Psychological Functioning in Metabolic Disorders: Validation of the Adaptive Behavior Assessment System, Second Edition (ABAS-II), and the Behavior Rating Inventory of Executive Function (BRIEF) for Identification of Individuals at Risk. AB - Long-term follow-up of neuropsychological functioning in metabolic disorders remains difficult due to limited opportunities for comprehensive neuropsychological evaluations. This study examined the validity of using the Adaptive Behavior Assessment System, Second Edition (ABAS-II), and the Behavior Rating Inventory of Executive Function (BRIEF) for assessing developmental status in metabolic disorders and for identifying individuals at risk for cognitive deficits. Results from individuals with urea cycle disorders, phenylketonuria, galactosemia, and fatty acid oxidation disorders were obtained on the ABAS-II and BRIEF and were compared to results obtained from neuropsychological testing performed on the same day. Correlations between scores on the ABAS-II and developmental or IQ tests for individuals with urea cycle disorders ranged from 0.48 to 0.72 and concordance rates for scores greater than a standard deviation below the normative mean ranged from 69 to 89%. Correlations ranged from 0.20 to 0.68 with concordance ranging from 73 to 90% in the other metabolic disorders. For the BRIEF, correlations with other tests of executive functioning were significant for urea cycle disorders, with concordance ranging from 52 to 80%. For the other metabolic disorders, correlations ranged from -0.09 to -0.55. Concordance rates for at-risk status on the BRIEF and executive functioning tests ranged from 55% in adults to 80% in children with other metabolic disorders. These results indicate that the ABAS-II and BRIEF together can confidently be used as an adjunct or supplementary method for clinical follow-up and for research on functional status involving infants, children, and adults with metabolic disorders. PMID- 25712382 TI - Autophagy in Natural History and After ERT in Glycogenosis Type II. AB - We studied the role of autophagy in a series of 10 infantile-, juvenile-, and adult-onset GSDII patients and investigated autophagy blockade in successive biopsies of adult cases during disease natural history. We also correlated the autophagosome accumulation and efficiency of enzyme replacement therapy (ERT) in four treated cases (two infantile and two juvenile-adult onsets).The autophagic flux was monitored by measuring the amount of p62-positive protein aggregates and compared, together with fibre vacuolisation, to fibre atrophy.A blocked autophagic flux resulted in p62 accumulation, increased vacuolisation, and progressive atrophy of muscle fibres in biopsies collected from patients during natural history. On the contrary, in the GSDII cases early treated with ERT, the autophagic flux improved and muscle fibre atrophy, fibre vacuolisation, and acid phosphatase activity decreased.The functionality of the autophagy-lysosome system is essential in GSDII muscle, which is characterised by the presence of swollen glycogen-filled lysosomes and autophagic build-up. Defining the role of autophagy and its relationship with muscle loss is critical for understanding the disease pathogenesis, for developing new therapies, and for improving ERT efficacy in GSDII. PMID- 25712383 TI - Neurodevelopmental and Cognitive Outcomes of Classical Homocystinuria: Experience from Qatar. AB - BACKGROUND: Classical homocystinuria due to cystathionine beta-synthase (CBS) deficiency (OMIM 236200) is a recessively inherited condition caused by mutations in the CBS gene. The founder mutation p.R336C accounts for almost all CBS deficiency in Qatar, affecting approximately 1 in 1,800 births, making it the most prevalent monogenic disease among the Qatari population. Untreated patients can have severe intellectual disability (ID), devastating multisystem complications and premature death. Current treatment is based on pharmacology therapy and life-long methionine-restricted diet, which is difficult to maintain particularly in late diagnosed individuals. Data on the neurodevelopmental and psychological impact of the disease on outcomes among Qatari patients are generally lacking and have not been studied. OBJECTIVES: To examine the cognitive, educational and psychological outcomes of classical homocystinuria on Qatari patients. SUBJECTS AND METHODS: Thirty-two cases with classical homocystinuria and 25 sibling controls were recruited to evaluate the neurodevelopmental and cognitive outcomes. We reviewed the subjects' medical record and collected pertinent clinical and educational data from parents. Stanford-Binet Intelligence Test (Arabic translation - 4th ed.) was used for cognitive (IQ) testing. RESULTS: The mean age for the subjects was 11.2 years (range 0.6-29) with 56% males. The majority of cases (93%) carried the mutation (p.R336C), and parental consanguinity was 84%. There were no differences between the two groups in the fine motor, expressive language, behavioural and visual skills. However, cases have much lower total IQ particularly in the domains of short memory, quantitative reasoning and visual-spatial domains. A significant number of adolescents and adult cases had medical co-morbidities as well as behavioural and emotional problems. CONCLUSION: Individuals with classical homocystinuria have many developmental and cognitive difficulties with significant number of cases having learning disability and lower IQs (cf. sibling controls) with adolescents and adults more affected. Those diagnosed by newborn screening have better developmental and cognitive outcomes compared to late diagnosed cases. Psychological and psychiatric referrals should be part of the standard of care for those cases. PMID- 25712384 TI - In vivo study of magnesium plate and screw degradation and bone fracture healing. AB - Each year, millions of Americans suffer bone fractures, often requiring internal fixation. Current devices, like plates and screws, are made with permanent metals or resorbable polymers. Permanent metals provide strength and biocompatibility, but cause long-term complications and may require removal. Resorbable polymers reduce long-term complications, but are unsuitable for many load-bearing applications. To mitigate complications, degradable magnesium (Mg) alloys are being developed for craniofacial and orthopedic applications. Their combination of strength and degradation make them ideal for bone fixation. Previously, we conducted a pilot study comparing Mg and titanium devices with a rabbit ulna fracture model. We observed Mg device degradation, with uninhibited healing. Interestingly, we observed bone formation around degrading Mg, but not titanium, devices. These results highlighted the potential for these fixation devices. To better assess their efficacy, we conducted a more thorough study assessing 99.9% Mg devices in a similar rabbit ulna fracture model. Device degradation, fracture healing, and bone formation were evaluated using microcomputed tomography, histology and biomechanical tests. We observed device degradation throughout, and calculated a corrosion rate of 0.40+/-0.04mm/year after 8 weeks. In addition, we observed fracture healing by 8 weeks, and maturation after 16 weeks. In accordance with our pilot study, we observed bone formation surrounding Mg devices, with complete overgrowth by 16 weeks. Bend tests revealed no difference in flexural load of healed ulnae with Mg devices compared to intact ulnae. These data suggest that Mg devices provide stabilization to facilitate healing, while degrading and stimulating new bone formation. PMID- 25712385 TI - Brain derived neurotrophic factor release from layer-by-layer coated agarose nerve guidance scaffolds. AB - Agarose nerve guidance scaffolds (NGS) seeded with cells expressing brain derived neurotrophic factor (BDNF) have demonstrated robust nerve regeneration in the rat central nervous system. The purpose of this work was to explore whether agarose NGS coated with hydrogen-bonded layer-by-layer (HLbL) could provide an acellular method of delivering prolonged and consistent dosages of active BDNF. Our results show that HLbL-coated agarose NGS could release BDNF over 10days in consistent dosages averaging 80.5+/-12.5(SD)ng/mL. Moreover, the BDNF released from HLbL was confirmed active by in vitro cell proliferation assays. To our knowledge, this is the first report demonstrating that HLbL assembled onto a hydrogel can provide consistent, prolonged release of active BDNF in clinically relevant dosages. PMID- 25712386 TI - Some design considerations for polymer-free drug-eluting stents: a mathematical approach. AB - In this paper we provide the first model of drug elution from polymer-free arterial drug-eluting stents. The generalised model is capable of predicting drug release from a number of polymer-free systems including those that exhibit nanoporous, nanotubular and smooth surfaces. We derive analytical solutions which allow us to easily determine the important parameters that control drug release. Drug release profiles are provided, and we offer design recommendations so that the release profile may be tailored to achieve the desired outcome. The models presented here are not specific to drug-eluting stents and may also be applied to other biomedical implants that use nanoporous surfaces to release a drug. PMID- 25712387 TI - Micromechanical modeling of calcifying human costal cartilage using the generalized method of cells. AB - Various tissues in the human body, including cartilage, are known to calcify with aging. There currently is no material model that accounts for the calcification in the costal cartilage, which could affect the overall structural response of the rib cage, and thus change the mechanisms and resistance to injury. The goal of this study is to investigate, through the development of a calcifying cartilage model, whether the calcification morphologies present in the costal cartilage change its effective material properties. A calcified cartilage material model was developed using the morphologies of calcifications obtained from microCT and the relaxed elastic modulus of the human costal cartilage obtained from indentation testing. The homogenized model of calcifying cartilage found that calcifications alter the effective material behavior of the cartilage, and this effect is highly dependent on the microstructural connectivity of the calcification. Calcifications which are not contiguous with the rib bone and constitute 0-18% of the cartilage volume increase the effective elastic modulus from its baseline value of 5MPa to up to 8MPa. Calcifications which are attached to the rib bone, which typically constitute 18-25% of the cartilage volume, result in effective moduli of 20-66MPa, depending on the microstructure, and introduce marked anisotropy into the material. The calcifying cartilage model developed in this study can be incorporated into biomechanical models of the aging thorax to better understand how calcifications in the aging thorax affect the structural response of the rib cage. PMID- 25712388 TI - A polymer-extracellular matrix composite with improved thromboresistance and recellularization properties. AB - Organ engineering using decellularized scaffolds is a potential long-term solution to donor organ shortage. However, this technology is severely limited by small vessel thrombosis due to incompletely recellularized vessels, resulting in exposure of extracellular matrix (ECM) components to platelets and clotting factors in flowing blood. To address this limitation, we designed a polymer-ECM composite and demonstrated its potential to reduce thrombosis and facilitate re endothelialization in a vascular graft model. Rat aortas were decellularized using a sequential combination of weak detergents followed by a nuclease treatment that resulted in 96.5+/-1.3% DNA removal, while ECM components and mechanical properties were well maintained. A biodegradable and biocompatible elastomer poly(1,8 octanediol citrate) (POC, 1wt.%) was infused throughout the ECM at mild conditions (37 degrees C and 45 degrees C) and was functionalized with heparin using carbodiimide chemistry. The polymer-ECM composite significantly reduced platelet adhesion (67.4+/-8.2% and 82.7+/-9.6% reduction relative to untreated ECM using one of two processing temperatures, 37 degrees C or 45 degrees C, respectively); inhibited whole blood clotting (85.9+/-4.3% and 87.0+/-11.9% reduction relative to untreated ECM at 37 degrees C or 45 degrees C processing temperature, respectively); and supported endothelial cell-and to a lesser extent smooth muscle cell-adhesion in vitro. Taken together, this novel POC composite may provide a solution for thrombosis of small vessel conduits commonly seen in decellularized scaffolds used in tissue engineering applications. PMID- 25712389 TI - Use of precisely sculptured thin film (STF) substrates with generalized ellipsometry to determine spatial distribution of adsorbed fibronectin to nanostructured columnar topographies and effect on cell adhesion. AB - Sculptured thin film (STF) substrates consist of nanocolumns with precise orientation, intercolumnar spacing, and optical anisotropy, which can be used as model biomaterial substrates to study the effect of homogenous nanotopogrophies on the three-dimensional distribution of adsorbed proteins. Generalized ellipsometry was used to discriminate between the distributions of adsorbed FN either on top of or within the intercolumnar void spaces of STFs, afforded by the optical properties of these precisely crafted substrates. Generalized ellipsometry indicated that STFs with vertical nanocolumns enhanced total FN adsorption two-fold relative to flat control substrates and the FN adsorption studies demonstrate different STF characteristics influence the degree of FN immobilization both on top and within intercolumnar spaces, with increasing spacing and surface area enhancing total protein adsorption. Mouse fibroblasts or mouse mesenchymal stem cells were subsequently cultured on STFs, to investigate the effect of highly ordered and defined nanotopographies on cell adhesion, spreading, and proliferation. All STF nanotopographies investigated in the absence of adsorbed FN were found to significantly enhance cell adhesion relative to flat substrates; and the addition of FN to STFs was found to have cell dependent effects on enhancing cell-material interactions. Furthermore, the amount of FN adsorbed to the STFs did not correlate with comparative enhancements of cell-material interactions, suggesting that nanotopography predominantly contributes to the biocompatibility of homogenous nanocolumnar surfaces. This is the first study to correlate precisely defined nanostructured features with protein distribution and cell-nanomaterial interactions. STFs demonstrate immense potential as biomaterial surfaces for applications in tissue engineering, drug delivery, and biosensing. PMID- 25712390 TI - Effective and durable genetic modification of human mesenchymal stem cells via controlled release of rAAV vectors from self-assembling peptide hydrogels with a maintained differentiation potency. AB - Controlling the release of recombinant adeno-associated virus (rAAV) vectors from biocompatible materials is a novel, attractive approach to increase the residence time and effectiveness of a gene carrier at a defined target site. Self assembling peptides have an ability to form stable hydrogels and encapsulate cells upon exposure to physiological pH and ionic strength. Here, we examined the capacity of the peptide hydrogel RAD16-I in a pure (RAD) form or combined with hyaluronic acid (RAD-HA) to release rAAV vectors as a means to genetically modify primary human bone marrow-derived mesenchymal stem cells (hMSCs), a potent source of cells for regenerative medicine. Specifically, we demonstrate the ability of the systems to efficiently encapsulate and release rAAV vectors in a sustained, controlled manner for the effective transduction of hMSCs (up to 80%) without deleterious effects on cell viability (up to 100%) or on their potential for chondrogenic differentiation over time (up to 21days). The present study demonstrates that RAD16-I is an advantageous material with tunable properties to control the release of rAAV vectors as a promising tool to develop new, improved therapeutic approaches for tissue engineering in vivo. PMID- 25712392 TI - Atrazine exposure affects the ability of crayfish (Orconectes rusticus) to localize a food odor source. AB - Environmental pollutants, found in aquatic ecosystems, have been shown to have an effect on olfactory-mediated behaviors including feeding, mate attraction, and other important social behaviors. Crayfish are polytrophic, meaning that they feed on and become prey for all levels of the aquatic food web as well as are also important for the transfer of energy between benthic and terrestrial food webs. Because crayfish are a keystone species, it is important to investigate any factors that may affect their population size. Crayfish are active at night and rely heavily on their sensory appendages (e.g., antennulues, maxillipeds, and pereopods) to localize food sources. In this experiment, we investigated the effects of atrazine (ATR) exposure on the chemosensory responses of male and female crayfish to food odors. We exposed crayfish to environmentally relevant, sublethal levels of ATR [80 ppb (ug/L)] for 72 h and then examined the behavioral responses of both ATR-treated and control crayfish to food odor delivered from one end of a test arena. We used Noldus Ethovision XT software to measure odor localization and locomotory behaviors of crayfish in response to food (fish) odor. We found that control crayfish spent more time in the proximal region of the test arena and at the odor source compared with ATR-treated crayfish. Furthermore, there were no differences in the time spent moving and not moving, total distance travelled in the tank, and walking speed (cm/s) when control and ATR-treated crayfish were compared. Overall, this indicates that acute ATR exposure alters chemosensory abilities of crayfish, whereas overall motor function remains unchanged. PMID- 25712393 TI - Coculnol, a new penicillic acid produced by a coculture of Fusarium solani FKI 6853 and Talaromyces sp. FKA-65. PMID- 25712391 TI - Bone tissue engineering via human induced pluripotent, umbilical cord and bone marrow mesenchymal stem cells in rat cranium. AB - Human induced pluripotent stem cells (hiPSCs) are an exciting cell source with great potential for tissue engineering. Human bone marrow mesenchymal stem cells (hBMSCs) have been used in clinics but are limited by several disadvantages, hence alternative sources of MSCs such as umbilical cord MSCs (hUCMSCs) are being investigated. However, there has been no report comparing hiPSCs, hUCMSCs and hBMSCs for bone regeneration. The objectives of this pilot study were to investigate hiPSCs, hUCMSCs and hBMSCs for bone tissue engineering, and compare their bone regeneration via seeding on biofunctionalized macroporous calcium phosphate cement (CPC) in rat cranial defects. For all three types of cells, approximately 90% of the cells remained alive on CPC scaffolds. Osteogenic genes were up-regulated, and mineral synthesis by cells increased with time in vitro for all three types of cells. The new bone area fractions at 12weeks (mean+/-sd; n=6) were (30.4+/-5.8)%, (27.4+/-9.7)% and (22.6+/-4.7)% in hiPSC-MSC-CPC, hUCMSC CPC and hBMSC-CPC respectively, compared to (11.0+/-6.3)% for control (p<0.05). No significant differences were detected among the three types of stem cells (p>0.1). New blood vessel density was higher in cell-seeded groups than control (p<0.05). De novo bone formation and participation by implanted cells was confirmed via immunohistochemical staining. In conclusion, (1) hiPSCs, hUCMSCs and hBMSCs greatly enhanced bone regeneration, more than doubling the new bone amount of cell-free CPC control; (2) hiPSC-MSCs and hUCMSCs represented viable alternatives to hBMSCs; (3) biofunctionalized macroporous CPC-stem cell constructs had a robust capacity for bone regeneration. PMID- 25712394 TI - Penicillimide, an open-chain hemisuccinimide from Okinawan marine-derived Penicillium copticola. PMID- 25712395 TI - The stereostructure of candicidin D. AB - The candicidin D stereostructure was established based on NMR studies including DQF-COSY, ROESY, HSQC and HMBC experiments. The relative configurations of the candicidin D stereogenic centers were assigned as the following: 9R*, 11S*, 13S*, 15R*, 17S*, 18R*, 19S*, 21R*, 36S*, 37R*, 38S*, 40S* and 41S*. The geometry of the heptaene chromophore was defined as 22E, 24E, 26Z, 28Z, 30E, 32E and 34E. PMID- 25712396 TI - Endophytic fungal compounds active against Cryptococcus neoformans and C. gattii. AB - Infections with Cryptococcus are invasive mycoses associated with significant morbidity and mortality, mainly in immunosuppressed patients. Several drugs have been introduced to combat these opportunistic infections. However, resistance of this organism to antifungal drugs has increased, causing difficulties in the treatment. The goal of this work was to evaluate the antifungal activity of ethanol extracts from endophytic fungi isolated from plants collected from different Brazilian ecosystems and to perform the fractionation of the most promising extract. Four-hundred fungal extracts were investigated by microdilution broth assays against Cryptococcus neoformans and Cryptococcus gattii at a concentration of 500 MUg ml(-1). Among them, the extract of Mycosphaerella sp. UFMGCB 2032, an endophytic fungus isolated from the plant Eugenia bimarginata DC. (Myrtaceae) exhibited outstanding antifungal activity against C. neoformans and C. gattii, with MIC values of 31.2 MUg ml(-1) and 7.8 MUg ml(-1), respectively. The fractionation of this extract using liquid-liquid partitioning and semi-preparative HPLC afforded two eicosanoic acids with antifungal activity, compound 1, (2S,3R,4R)-(E)-2-amino-3,4-dihydroxy-2 (hydroxymethyl)-14-oxoeicos-6,12-dienoic acid with MIC values ranging from 1.3 2.50 MUg ml(-1), and compound 2, known as myriocin, with MIC values of 0.5 MUg ml(-1) against C. neoformans and C. gattii. These compounds are reported for the first time in the Mycosphaerella genus. PMID- 25712397 TI - Novel thioviridamide derivative--JBIR-140: heterologous expression of the gene cluster for thioviridamide biosynthesis. PMID- 25712398 TI - Two new stemphol sulfates from the mangrove endophytic fungus Stemphylium sp. 33231. AB - Two new stemphol sulfates, stemphol A (1) and stemphol B (2), along with known compound stemphol (3) were isolated from the EtOAc extract of the fermentation of an endophytic Stemphylium sp. 33231. The structures of these compounds were elucidated on the basis of spectroscopic analysis. The isolated compounds exhibited potent antibacterial activities against six terrestrial pathogenic bacteria with MIC values of 0.6-10 MUg ml(-1). The inhibitory activities of all compounds against five cancer cell lines were evaluated. PMID- 25712399 TI - Synthesis and antibacterial activity of 1-N-[(S)-omega-amino-2-hydroxyalkyl] derivatives of dibekacin, 5-deoxydibekacin, 3'-deoxykanamycin A and gentamicin B. PMID- 25712400 TI - Malignant Vagal Paraganglioma. AB - Paragangliomas are rare, typically benign neuroendocrine tumors that represent a small portion of head and neck tumors. A small percentage of these are known to have malignant potential. They arise from the carotid body, jugular bulb or vagus nerves. There is limited literature discussing the management of malignant vagal paragangliomas. We present a case of a 25 year old female with a left malignant vagal paraganglioma. The following case presentation will describe the presentation, classic radiologic findings, and management of a malignant vagal paraganglioma along with a review of the literature. PMID- 25712401 TI - Quantitative motor assessment of dyskinesias in Parkinson's disease. AB - Although Levodopa-induced dyskinesias (LID) are one of the most compromising complications of dopaminergic treatment in Parkinson's disease (PD), there is no widely accepted assessment tool available that evaluates LID quantitatively. This is of relevance as objective assessment may help to facilitate proof-of-concept studies with novel treatments and thus eventually contribute to better patient care. PD patients were asked to perform a grip-lift task as well as tapping tasks assessed with the "Q-Motor" system. PD patients were separated into three groups according to their modified abnormal involuntary movement scale (M-AIMS)-score: PD patients without dyskinesias (PD(LID-) n = 17), with slight dyskinesias (PD(LID+) n = 15) and with severe dyskinesias (PD(LID++) n = 15). An explorative analysis to identify measures detecting LID was performed with 5 PD(LID-) and 5 PD(LID++) patients; these measures were then used in the remaining patients to assess the accuracy of the system to differentiate LID. The measures "Orientation Index" and "Position-Index" of the grip-lift task differed significantly between the explorative cohorts. Using these two parameters for the differentiation of the remaining cohorts, the area under the ROC curve (AUC) yielded 0.809 for the differentiation of PD(LID-) vs. PD(LID++), 0.852 for the differentiation of PD(LID-) vs. PD(LID+) patients, and 0.830 for the differentiation of PD(LID+) and PD(LID++). The "Orientation-Index" and "Position-Index" of the Q-Motor assessment are sensitive, easy to apply and non-invasive measures for the objective assessment of manifestation and severity of LID. PMID- 25712402 TI - Evaluation of use of reading comprehension strategies to improve reading comprehension of adult college students with acquired brain injury. AB - Adults with mild to moderate acquired brain injury (ABI) often pursue post secondary or professional education after their injuries in order to enter or re enter the job market. An increasing number of these adults report problems with reading-to-learn. The problem is particularly concerning given the growing population of adult survivors of ABI. Despite the rising need, empirical evaluation of reading comprehension interventions for adults with ABI is scarce. This study used a within-subject design to evaluate whether adult college students with ABI with no more than moderate cognitive impairments benefited from using reading comprehension strategies to improve comprehension of expository text. Integrating empirical support from the cognitive rehabilitation and special education literature, the researchers designed a multi-component reading comprehension strategy package. Participants read chapters from an introductory level college anthropology textbook in two different conditions: strategy and no strategy. The results indicated that reading comprehension strategy use was associated with recall of more correct information units in immediate and delayed free recall tasks; more efficient recall in the delayed free recall task; and increased accuracy recognising statements from a sentence verification task designed to reflect the local and global coherence of the text. The findings support further research into using reading comprehension strategies as an intervention approach for the adult ABI population. Future research needs include identifying how to match particular reading comprehension strategies to individuals, examining whether reading comprehension performance improves further through the incorporation of systematic training, and evaluating texts from a range of disciplines and genres. PMID- 25712403 TI - Influence of chlorine coordination number on the catalytic mechanism of ruthenium chloride catalysts in the acetylene hydrochlorination reaction: a DFT study. AB - The catalytic mechanism of Ru-based catalysts in the acetylene hydrochlorination reaction has been investigated via the density functional theory (DFT) method. To study the effect of the chlorine coordination number on the catalytic mechanism, Ru3Cl9, Ru3Cl7, Ru5Cl7, Ru3Cl3 and Ru3 clusters were chosen as the catalytic models. Our results show that the energy barrier for acetylene hydrochlorination on Ru3Cl9 was as high as 1.51 eV at 458 K. When the chlorine coordination number decreased, the energy barriers on Ru3Cl7, Ru5Cl7, Ru3Cl3 and Ru3 were 1.29, 0.89, 1.01 and 1.42 eV, respectively. On Ru3Cl9, the H and Cl atoms of HCl were simultaneously added to C2H2 to form C2H3Cl, while the reaction was divided into two steps on Ru3Cl7, Ru3Cl3 and Ru3 clusters. The first step was the addition of H atom of HCl to C2H2 to form C2H3, and the second step was the addition of Cl atom to C2H3 to form C2H3Cl. The step involving the addition of Cl was the rate controlling step during the whole reaction. On Ru5Cl7 cluster, there was an additional step before the steps involving the addition of H and Cl: the transfer of H atom from HCl to Ru atom. This step was the rate-controlling step during the reaction of acetylene hydrochlorination on Ru5Cl7 and its energy barrier was the lowest among all the above-mentioned catalytic models. Therefore, the Ru5Cl7 cluster played the most predominant role in acetylene hydrochlorination with the largest reaction rate constant kTST of 10(3). PMID- 25712404 TI - Discovery and reconstitution of the cycloclavine biosynthetic pathway--enzymatic formation of a cyclopropyl group. AB - The ergot alkaloids, a class of fungal-derived natural products with important biological activities, are derived from a common intermediate, chanoclavine-I, which is elaborated into a set of diverse structures. Herein we report the discovery of the biosynthetic pathway of cycloclavine, a complex ergot alkaloid containing a cyclopropyl moiety. We used a yeast-based expression platform along with in vitro biochemical experiments to identify the enzyme that catalyzes a rearrangement of the chanoclavine-I intermediate to form a cyclopropyl moiety. The resulting compound, cycloclavine, was produced in yeast at titers of >500 mg L(-1) , thus demonstrating the feasibility of the heterologous expression of these complex alkaloids. PMID- 25712405 TI - Reduced sleep duration and history of work-related injuries among Washington State adolescents with a history of working. AB - BACKGROUND: The relationship between sleep and occupational injury risk has not been adequately explored for working adolescents. METHODS: Data were analyzed from the 2010 Washington State Healthy Youth Survey of 8th, 10th, and 12th grade public school students. Teens reported average school and weekend night sleep hours and history of work-related injury that received medical treatment. Multivariable logistic regression evaluated the association between sleep duration and occupational injury. RESULTS: Of 4,144 working teens, 6.4% reported ever having an occupational injury. Teens who sleep <=5 hr/school night had greater odds of a history of occupational injury than those sleeping 8 hr (OR:2.91, 95% CI:1.85-4.57). No significant association was observed for weekend night sleep duration. CONCLUSIONS: Reduced school night sleep was associated with increased odds of work-related injury in adolescents. Long hours and late night schedules may contribute to decreased sleep time and potentially have other health and developmental impacts for youth. PMID- 25712406 TI - Experimental on-demand recovery of entanglement by local operations within non Markovian dynamics. AB - In many applications entanglement must be distributed through noisy communication channels that unavoidably degrade it. Entanglement cannot be generated by local operations and classical communication (LOCC), implying that once it has been distributed it is not possible to recreate it by LOCC. Recovery of entanglement by purely local control is however not forbidden in the presence of non-Markovian dynamics, and here we demonstrate in two all-optical experiments that such entanglement restoration can even be achieved on-demand. First, we implement an open-loop control scheme based on a purely local operation, without acquiring any information on the environment; then, we use a closed-loop scheme in which the environment is measured, the outcome controling the local operations on the system. The restored entanglement is a manifestation of "hidden" quantum correlations resumed by the local control. Relying on local control, both schemes improve the efficiency of entanglement sharing in distributed quantum networks. PMID- 25712407 TI - Development of an improved method for quantitative analysis of skin blotting: increasing reliability and applicability for skin assessment. AB - OBJECTIVE: A novel skin assessment tool named 'skin blotting' has been recently developed, which can easily predict the skin status to avoid its deterioration. The aim of this study was to propose a normalization method for skin blotting to compensate for individual differences that can hamper the quantitative comparisons and clinical applications. METHODS: To normalize individual differences, we utilized a total protein as a 'normalizer' with calibration curves. For evaluation, we performed a simple simulation experiment, in which the same concentration of a protein of interest [tumour necrosis factor (TNF)-alpha] was applied at different volumes as a virtual individual difference. Moreover, to demonstrate the applicability of this normalization, male volunteers were recruited for skin blotting followed by the estimation of TNF-alpha with normalization. RESULTS: We obtained good calibration curves for total protein (R(2) = 0.995) and TNF-alpha (R(2) = 0.997), both of which were necessary for an exact quantification. In the simulation experiment, we estimated the exact concentration of TNF-alpha regardless of the applied volume, demonstrating the applicability of this normalization method in skin blotting. Further, skin blotting on human subjects showed a wide range of variation in the total protein content, although the normalization was thought to reduce such individual variations. CONCLUSION: This study has proposed total protein normalization for skin blotting with calibration curves. This method may strengthen the quantitative performance of skin blotting, which may expand the applicability of this method as a skin assessment tool in broader fields, such as nursing and cosmetology. PMID- 25712408 TI - Pulmonary arteriovenous malformation in children. AB - Although pulmonary arteriovenous malformations (PAVM) are relatively rare in children, they are important in the differential diagnosis of common pulmonary problems, such as hypoxemia, hemoptysis and dyspnea on exertion. We report the cases of two PAVM patients with different presentations and describe the treatment strategies. PMID- 25712409 TI - Acylative Suzuki coupling of amides: acyl-nitrogen activation via synergy of independently modifiable activating groups. AB - A highly efficient palladium-catalyzed acylative cross-coupling of carboxylic amides with arylboronic acids has been achieved via synergistic activation of the C(acyl)-N bond by independently modifiable activating groups. Coupling of amides features not only good functional group tolerance but also modifiable reactivities to overcome steric hindrance. PMID- 25712410 TI - Electrochemical activation of commercial polyacrylonitrile-based carbon fiber for the oxygen reduction reaction. AB - Nitrogen (N)-doped carbon and its non-noble metal composite replacing platinum based oxygen reduction reaction (ORR) electrocatalysts still have some fundamental problems that remain. Here the micron-sized commercial polyacrylonitrile-based carbon fiber (PAN-CF) electrode was modified using an electrochemical method, converting its inherent pyridinic-N into 2-pyridone (or 2 hydroxyl pyridine) functional group existing in three-dimensional active layers with remarkable ORR catalytic activity and stability. The carbon atom adjacent to the nitrogen and oxygen atoms is prone to act as an active site to efficiently catalyze a two-electron ORR process. However, after coordinating pyridone to the Cu(2+) ion, together with the electrochemical reaction, the chemical redox between Cu(+) and ORR intermediates synergistically tends towards a four-electron pathway in alkaline solution. In different medium, the complexation and dissociation can induce the charge transfer and reconstruction among proton, metal ion and pyridone functionalities, eventually leading to the changes of ORR performance. PMID- 25712411 TI - Variable response of cholinesterase activities following human exposure to different types of organophosphates. AB - We investigated the red blood cell (RBC) acetylcholinesterase (AChE) activities and butyrylcholinesterase (BChE) activities at presentation to the emergency department (ED) and at 24 h after presentation following poisoning by dichlorvos, fenitrothion, or ethyl p-nitrophenol thio-benzene phosphonate (EPN). Although the patients from different groups had similar characteristics at presentation such as time interval from ingestion to presentation to the ED and the amount of organophosphate ingested, the dichlorvos group had significantly lower BChE levels than the fenitrothion group and lower RBC cholinesterase activity than the EPN group. Patients poisoned with EPN or dichlorvos had significantly higher inhibition of BChE activities from baseline than RBC AChE activities at presentation. Twenty four hours after administration of pralidoxime, RBC AChE activities had increased in patients in the dichlorvos and EPN groups, while RBC AChE activities had slightly decreased in the fenitrothion group. BChE activities increased significantly in the dichlorvos group but decreased in the EPN group. The recovery patterns of RBC AChE and BChE activities did not match in any particular individual. This study showed that the patterns of inhibition and recovery of the activities of two cholinesterases after treatment are highly variable according to the organophosphate and in different individuals. PMID- 25712412 TI - Genetic basis for developmental toxicity due to statin intake using embryonic stem cell differentiation model. AB - The in utero environment is a key factor controlling the fate of the growing embryo. The deleterious effects of statins during the fetal development are still not very well understood. Data from animal studies and retrospective studies performed in pregnant women give conflicting reports. In this study, using in vitro differentiation model of embryonic stem cells, which mimic the differentiation process of the embryo, we have systematically exposed the cells to lipophilic statins, simvastatin, and atorvastatin at various doses and at critical times during differentiation. The analysis of key genes controlling the differentiation into ecto-, meso- and endodermal lineages was assessed by quantitative polymerase chain reaction. Our results show that genes of the mesodermal lineage were most sensitive to statins, leading to changes in the transcript levels of brachyury, Flk-1, Nkx2.5, and alpha/beta-myosin heavy chain. In addition, changes to endodermal marker alpha-fetoprotein, along with ectodermal Nes and Neurofilament 200 kDa, imply that during early differentiation exposure to these drugs leads to altered signaling, which could translate to the congenital abnormalities seen in the heart and limbs. PMID- 25712413 TI - Nursing, chronotherapeutics and ambulatory blood pressure: commentary on Cheng M et al. (2014) The effect of continuous nursing intervention guided by chronotherapeutics on ambulatory blood pressure of older hypertensive patients in the community. Journal of Clinical Nursing. doi: 10.1111/jocn.12502. PMID- 25712416 TI - Effect of High Dose Statin Pretreatment on Endothelial Progenitor Cells After Percutaneous Coronary Intervention (HIPOCRATES Study). AB - BACKGROUND: Pretreatment with high-dose statins given before percutaneous coronary intervention (PCI) has been shown to have beneficial effects, in particular by reducing peri-procedural myocardial infarction. The mechanism of these lipid-independent beneficial statin effects is unclear. Circulating endothelial progenitor cells (EPCs) have an important role in the process of vascular repair, by promoting re-endothelization following injury. We hypothesized that statins can limit the extent of endothelial injury induced by PCI and promote re-endothelization by a positive effect on EPCs. We, therefore, aimed to examine the effect of high-dose statins given prior to PCI on EPCs profile. METHODS: Included were patients, either statin naive or treated chronically with low-dose statins, with stable or unstable angina who underwent PCI. Patients were randomized to receive either high-dose atorvastatin (80 mg the day before PCI and 40 mg 2-4 h before PCI) or low- dose statin. EPCs profile was examined before PCI and 24 h after it. Circulating EPCs levels were assessed by flow cytometry as the proportion of peripheral mononuclear cells co-expressing VEGFR-2+ CD133+ and VEGFR-2+ CD34+. The capacity of the cells to form colony forming units (CFUs) was quantified after 7 days of culture. RESULTS: Twenty three patients (mean age 61.4 +/- 7.4 years, 87.0% men) were included in the study, of which 12 received high-dose atorvastatin prior to PCI. The mean number of EPC-CFUs before PCI was higher in patients treated with high-dose atorvastatin vs. low-dose statins (165.8 +/- 58.8 vs. 111.7 +/- 38.2 CFUs/plate, respectively, p < 0.001). However, 24 h after the PCI, the number of EPC-CFUs was similar (188.0 +/- 85.3 vs. 192.9 +/- 66.5 CFUs/plate in patients treated with high-dose atorvastatin vs. low- dose statins, respectively, p = 0.15). There were no statistical significant differences in FACS analyses between the 2 groups. CONCLUSIONS: The current study showed higher EPC- CFUs levels in patients treated with high-dose atorvastatin before PCI and a lower increment in EPC-CFUs after PCI. These findings could account for the beneficial effects of statins given prior to PCI, yet further investigation is required. PMID- 25712415 TI - 17-AAG suppresses growth and invasion of lung adenocarcinoma cells via regulation of the LATS1/YAP pathway. AB - The large tumour suppressor 1 (LATS1) signalling network has been proved to be an essential regulator within the cell, participating in multiple cellular phenotypes. However, it is unclear concerning the clinical significance of LATS1 and the regulatory mechanisms of 17-Allylamino-17- demethoxygeldanamycin (17-AAG) in lung adenocarcinoma (LAC). The aim of the present study was to investigate the correlation of LATS1 and yes-associated protein (YAP) expression with clinicopathological characteristics in LAC patients, and the effects of 17-AAG on biological behaviours of LAC cells. Subcutaneous LAC tumour models were further established to observe the tumour growth in nude mice. The results showed that the positive expression of LATS1 was significantly lowered (26.7% versus 68.0%, P < 0.001), while that of YAP was elevated (76.0% versus 56.0%, P = 0.03) in LAC tissues compared to the adjacent non-cancerous tissues; LAST1 expression was negatively correlated with YAP expression (r = 0.432, P < 0.001) and lymphatic invasion of the tumour (P = 0.015). In addition, 17-AAG inhibited proliferation and invasion, and induced cell apoptosis and cycle arrest in LAC cells together with increased expression of E-cadherin and p-LATS1, and decreased expression of YAP and connective tissue growth factor. Tumour volumes and weight were much smaller in 17-AAG-treated groups than those in untreated group (P < 0.01). Taken together, our findings indicate that decreased expression of LATS1 is associated with lymphatic invasion of LAC, and 17-AAG suppresses growth and invasion of LAC cells via regulation of the LATS1/YAP pathway in vitro and in vivo, suggesting that we may provide a promising therapeutic strategy for the treatment of human LAC. PMID- 25712417 TI - Endothelial Progenitor Cells and Percutaneous Coronary Artery Intervention : Editorial to: "Effect of High Dose Statin Pretreatment on Endothelial Progenitor Cells after Percutaneous Coronary Intervention (HIPOCRATES Study)" by A. Eisen et al. PMID- 25712419 TI - Chiral anomaly and transport in Weyl metals. AB - We present an overview of our recent work on transport phenomena in Weyl metals, which may be connected to their nontrivial topological properties, particularly to chiral anomaly. We argue that there are two basic phenomena, which are related to chiral anomaly in Weyl metals: anomalous Hall effect (AHE) and chiral magnetic effect (CME). While AHE is in principle present in any ferromagnetic metal, we demonstrate that a magnetic Weyl metal is distinguished from an ordinary ferromagnetic metal by the absence of the extrinsic and the Fermi surface part of the intrinsic contributions to the AHE, as long as the Fermi energy is sufficiently close to the Weyl nodes. The AHE in a Weyl metal is thus shown to be a purely intrinsic, universal property, fully determined by the location of the Weyl nodes in the first Brillouin zone. In other words, a ferromagnetic Weyl metal may be thought of as the only example of a ferromagnetic metal with a purely intrinsic AHE. We further develop a fully microscopic theory of diffusive magnetotransport in Weyl metals. We derive coupled diffusion equations for the total and axial (i.e. node-antisymmetric) charge densities and show that chiral anomaly manifests as a magnetic-field-induced coupling between them. We demonstrate that an experimentally-observable consequence of CME in magnetotransport in Weyl metals is a quadratic negative magnetoresistance, which will dominate all other contributions to magnetoresistance under certain conditions and may be regarded as a smoking-gun transport characteristic, unique to Weyl metals. PMID- 25712418 TI - [Trabeculectomy versus canaloplasty]. AB - BACKGROUND: Trabeculectomy provides an excellent reduction of intraocular pressure (IOP) and is the reference technique in the treatment of glaucoma patients. Canaloplasty is a relatively new surgical non-penetrating procedure for restoring the natural outflow pathway of aqueous humour. The aim of canaloplasty is to permanently distend the collapsed Schlemm's canal with the placement of a 360 degrees intracanalicular tension suture. OBJECTIVES: This review article describes the comparison between trabeculectomy and canaloplasty with and without cataract surgery. MATERIAL AND METHODS: Original studies, case reports and reviews are described and the results are discussed. RESULTS: Although canaloplasty may not be as effective in reducing IOP, trabeculectomy can be associated with severe vision-threatening complications however, the combination of canaloplasty with cataract surgery achieves a higher IOP reduction than canaloplasty alone. In contrast, trabeculectomy alone provides better IOP control than phacotrabeculectomy due to a higher risk of early bleb scarring induced by an increased intraocular inflammatory reaction. CONCLUSION: If a higher postoperative IOP is acceptable and additional topical glaucoma medication tolerable, canaloplasty can be considered as an alternative to trabeculectomy as the incidence of complications is low and postoperative care less intensive. Canaloplasty may also be suitable for patients with high risk of bleb failure and early glaucoma with a target IOP not necessarily requiring a filtering procedure. Therefore, canaloplasty offers a treatment option for the management of open angle glaucoma, especially in combination with cataract surgery. PMID- 25712421 TI - Comparing oncological outcomes of laparoscopic versus open surgery for colon cancer: Analysis of a large prospective clinical database. AB - BACKGROUND: Oncological outcomes of laparoscopic colon cancer surgery have been shown to be equivalent to those of open surgery, but only in the setting of randomized controlled trials on highly selected patients. The aim of this study is to investigate whether this finding is generalizable to real world practice. METHODS: Analysis of prospectively collected data from the BioGrid Australia database was undertaken. Overall and cancer specific survival rates were compared with cox regression analysis controlling for the confounders of age, sex, BMI, ASA score, hospital site, year surgery performed, procedure, tumor stage, and adjuvant chemotherapy. RESULTS: Between 2003 and 2009, 1,106 patients underwent elective colon cancer resection. There were differences between the laparoscopic and open cohorts in BMI, procedure, post-operative complication rate, and tumor stage. When baseline confounders were accounted for using cox regression analysis, there was no difference in 5 year overall survival (chi(2) test 1.302, P = 0.254), or cancer specific survival (chi(2) test 0.028, P = 0.866). CONCLUSION: This large prospective clinical study validates previous trial results, and confirms that there is no difference in oncological outcome between laparoscopic and open surgery for colon cancer. PMID- 25712420 TI - The relationship between herpes zoster and stroke. AB - Varicella zoster virus (VZV) infects >95 % of the world population. Typically, varicella (chickenpox) results from primary infection. The virus then becomes latent in ganglionic neurons along the entire neuraxis. In immunocompromised individuals, VZV reactivates and causes herpes zoster (shingles), pain, and rash in 1-2 dermatomes. Multiple case reports showed a link between stroke and zoster, and recent studies have emerged which reveal that VZV infection of the cerebral arteries directly causes pathological vascular remodeling and stroke (VZV vasculopathy). In the past few years, several large epidemiological studies in Taiwan, Denmark, and the U.K. demonstrated that zoster is a risk factor for stroke and that antiviral therapy may reduce this risk. Herein, the history, clinical features, and putative mechanisms of VZV vasculopathy, as well as recent epidemiological studies demonstrating that zoster increases the risk of stroke, are discussed. PMID- 25712422 TI - Origin, diversification and substrate specificity in the family of NCS1/FUR transporters. AB - NCS1 proteins are H(+)/Na(+) symporters specific for the uptake of purines, pyrimidines and related metabolites. In this article, we study the origin, diversification and substrate specificity of fungal NCS1 transporters. We show that the two fungal NCS1 sub-families, Fur and Fcy, and plant homologues originate through independent horizontal transfers from prokaryotes and that expansion by gene duplication led to the functional diversification of fungal NCS1. We characterised all Fur proteins of the model fungus Aspergillus nidulans and discovered novel functions and specificities. Homology modelling, substrate docking, molecular dynamics and systematic mutational analysis in three Fur transporters with distinct specificities identified residues critical for function and specificity, located within a major substrate binding site, in transmembrane segments TMS1, TMS3, TMS6 and TMS8. Most importantly, we predict and confirm that residues determining substrate specificity are located not only in the major substrate binding site, but also in a putative outward-facing selective gate. Our evolutionary and structure-function analysis contributes in the understanding of the molecular mechanisms underlying the functional diversification of eukaryotic NCS1 transporters, and in particular, forward the concept that selective channel-like gates might contribute to substrate specificity. PMID- 25712423 TI - Multidisciplinary approach to follicular thyroid carcinoma with giant mandibular and multiple sites metastases Case report. AB - Multidisciplinary approach to follicular thyroid carcinoma with giant mandibular and multiple sites metastases. Case report Metastatic tumors generally have poor prognosis, with short survival period and rarely indication to surgical treatment. In case of thyroid-differentiated cancer with distant metastases, prognosis is usually better, because of the possibility of treating metastasis by Radio Ablation by 131Iodine, after surgery. We report the case of a 65 years old woman, presenting with a giant mandibular metastasis from follicular thyroid carcinoma, originating from a cervico-mediastinal nonfunctioning goiter, with lung metastases. After the diagnostic work-up, she underwent left hemi mandibulectomy, reconstruction by the placement of a precustomized titanium plate with condylar prosthesis and total thyroidectomy. Subsequently the Patient was treated by Radio Ablation by 131 Iodine, in four consecutive sessions. She is alive with no progression of the neoplasm after forty-six months follow-up. Even in advanced differentiated thyroid carcinoma, surgery should be taken into consideration, to treat the patient by complementary therapies and to improve the prognosis in term of survival. KEY WORDS: Advanced differentiated thyroid carcinoma, Metastatic differentiated thyroid carcinoma. PMID- 25712424 TI - Abstracts of the 48th A.I.S.F. - Italian Association for the Study of the Liver - Annual Meeting 2015, February 19-20, 2015, Rome, Italy. PMID- 25712425 TI - Effects of porous properties on cold-start behavior of polymer electrolyte fuel cells from sub-zero to normal operating temperatures. AB - In this investigation, a parametric study was performed using the transient cold start model presented in our previous paper, in which the ice melting process and additional constitutive relations were newly included for transient cold-start simulations of polymer electrolyte fuel cells (PEFCs) from a sub-zero temperature (-20 degrees C) to a normal operating temperature (80 degrees C). The focus is placed on exploring the transient cold-start behavior of a PEFC for different porous properties of the catalyst layer (CL) and gas diffusion layer (GDL). This work elucidates the detailed effects of these properties on key cold-start phenomena such as ice freezing/melting and membrane hydration/dehydration processes. In particular, the simulation results highlight that designing a cathode CL with a high ionomer fraction helps to retard the rate of ice growth whereas a high ionomer fraction in the anode CL is not effective to mitigate the anode dry-out and membrane dehydration issues during PEFC cold-start. PMID- 25712426 TI - Expanding the phenotypic spectrum in EP300-related Rubinstein-Taybi syndrome. AB - Rubinstein-Taybi syndrome (RSTS) can be caused by heterozygous mutations or deletions involving CREBBP or, less commonly, EP300. To date, only 15 patients with EP300 mutations have been clinically described. Frequently reported manifestations in these patients include characteristic facial and limb features, varying degrees of neurocognitive dysfunction, and maternal preeclampsia. Other congenital anomalies are less frequently reported. We describe a child found to have a de novo EP300 mutation (c.4933C>T, predicted to result in p.Arg1645X) through research-based whole-genome sequencing of the family trio. The child's presentation involved dysmorphic features as well as unilateral renal agenesis, a myelomeningocele, and minor genitourinary anomalies. The involvement of congenital anomalies in all 16 clinically described patients with EP300 mutations (25% of which have been identified by "hypothesis free" methods, including microarray, exome, and whole-genome sequencing) is reviewed. In summary, genitourinary anomalies have been identified in 38%, cardiovascular anomalies in 25%, spinal/vertebral anomalies in 19%, other skeletal anomalies in 19%, brain anomalies in 13%, and renal anomalies in 6%. Our patient expands the phenotypic spectrum in EP300-related RSTS; this case demonstrates the evolving practice of clinical genomics related to increasing availability of genomic sequencing methods. PMID- 25712428 TI - Investigation of a cup-shaped ultrasonic transducer operated in the full-wave vibrational mode. AB - Cup-shaped horn has significant applications in ultrasonic machining, such as continuous bonding of plastic sheet or strips. Generally, it is excited by a sandwich piezoelectric transducer and both together constitute a cup-shaped ultrasound transducer (CUT). To provide a concise theoretical model for its engineering applications, the equivalent circuit of the cup-shaped ultrasonic transducer is deduced and the resonance/anti-resonance frequency equations are obtained. Meanwhile, the vibrational characteristics of the cup-shaped ultrasonic transducer have been investigated by using the analytical and numerical methods, and then confirmed by the experiment. The results show that the cup-shaped horn has a distinctive equivalent circuit, and the cup-shaped ultrasonic transducer has a good vibrational performance. PMID- 25712427 TI - An investigation of gender differences in a representative sample of juveniles detained in Connecticut. AB - As the number of females served by the juvenile justice system in the United States continues to grow, both in absolute terms and relative to the number of males, it is important to understand both the general and specific characteristics of delinquent girls and boys regarding their patterns of offending and risk variables. Using systematic random sampling, 20% of all admittees to the state-run juvenile detention centers in the state of Connecticut, USA, were included in a chart review study, forming a sample (n = 371, 30.2% girls, age range 11-19 years; mean age = 14.45, sd = 1.05) that was analyzed for gender differences with regard to characteristics of offenses. These characteristics were examined for their potential associations with indicators of risk that are routinely collected at admission to detention. Findings indicate a complex set of associations between indicators of offense and risk, highlighting the importance not only of gender, but also of racial/ethnic differences, whose modulating effects appear to be important in understanding these associations. Specifically, girls in detention are characterized by a number of dimensions, some of which align with those for boys and some that are more gender-specific. For example, girls, as a group, demonstrated higher levels of substance abuse, suicide ideation, victimization, and mental-health variability, but these higher scores are more characteristic of girls from minority backgrounds. More research is needed to understand the profiles of juveniles in detention as the variables considered in this work that map onto the literature at large have resulted in effects of small magnitude. PMID- 25712429 TI - Modern Management Practices and Hospital Admissions. AB - We investigate whether the modern management practices and publicly reported performance measures are associated with choice of hospital for patients with acute myocardial infarction (AMI). We define and measure management practices at approximately half of US cardiac care units using a novel survey approach. A patient's choice of a hospital is modeled as a function of the hospital's performance on publicly reported quality measures and the quality of its management. The estimates, based on a grouped conditional logit specification, reveal that higher management scores and better performance on publicly reported quality measures are positively associated with hospital choice. Management practices appear to have a direct correlation with admissions for AMI- potentially through reputational effects--and indirect association, through better performance on publicly reported measures. Overall, a one standard deviation change in management practice scores is associated with an 8% increase in AMI admissions. PMID- 25712430 TI - Haemodynamic impact of stent implantation for lateral tunnel Fontan stenosis: a patient-specific computational assessment. AB - BACKGROUND: The physiological importance of the lateral tunnel stenosis in the Fontan pathway for children with single ventricle physiology can be difficult to determine. The impact of the stenosis and stent implantation on total cavopulmonary connection resistance has not been characterized, and there are no clear guidelines for intervention. Methods and results A computational framework for haemodynamic assessment of stent implantation in patients with lateral tunnel stenosis was developed. Cardiac magnetic resonances images were reconstructed to obtain total cavopulmonary connection anatomies before stent implantation. Stents with 2-mm diameter increments were virtually implanted in each patient to understand the impact of stent diameter. Numerical simulations were performed in all geometries with patient-specific flow rates. Exercise conditions were simulated by doubling and tripling the lateral tunnel flow rate. The resulting total cavopulmonary connection vascular resistances were computed. A total of six patients (age: 14.4 +/- 3.1 years) with lateral tunnel stenosis were included for preliminary analysis. The mean baseline resistance was 1.54 +/- 1.08 WU . m(2) and dependent on the stenosis diameter. It was further exacerbated during exercise. It was observed that utilising a stent with a larger diameter lowered the resistance, but the resistance reduction diminished at larger diameters. CONCLUSIONS: Using a computational framework to assess the severity of lateral tunnel stenosis and the haemodynamic impact of stent implantation, it was observed that stenosis in the lateral tunnel pathway was associated with higher total cavopulmonary connection resistance than unobstructed pathways, which was exacerbated during exercise. Stent implantation could reduce the resistance, but the improvement was specific to the minimum diameter. PMID- 25712431 TI - Visible-light-induced cleavage of 4-alpha-amino acid substituted naphthalimides and its application in DNA photocleavage. AB - A new kind of visible-light photocleavable molecule, 4-alpha-amino acid substituted naphthalimide, is reported. The cleavage occurred at the C-N bond between the 4-amino and the amino acid residue and released a 4 aminonaphthalimide. A lysine substituted naphthalimide exhibited a strong DNA photocleavage activity when irradiated with a blue light LED. PMID- 25712432 TI - Fronto-striatal glutamatergic compounds in compulsive and impulsive syndromes: a review of magnetic resonance spectroscopy studies. AB - Compulsivity and impulsivity are cross-disorder traits observed in autism spectrum disorders (ASD), attention deficit hyperactivity disorder (ADHD) and obsessive compulsive disorder (OCD). Aberrant fronto-striatal glutamatergic signalling is core to the understanding of compulsive and impulsive disorders. In this review, the glutamate (Glu) neurochemistry of fronto-striatal circuits in paediatric and adult ASD, ADHD and OCD, as described in 59 studies, is outlined from the perspective of proton magnetic resonance spectroscopy ((1)H MRS). Despite the methodological inconsistencies between studies, two observations stand out that form possible hypotheses for future studies. Firstly, a possible increase in Glx (combination of Glu, glutamine and GABA) in the striatum across ADHD, OCD and ASD. Secondly, an increased Glx signal in the anterior cingulate cortex in paediatric ASD and ADHD but a lower Glx signal in adult ASD and ADHD. This suggests neurodevelopmental changes in fronto-striatal glutamatergic circuits across the lifespan. Future studies should incorporate more homogeneous samples, perform MRS at field strengths of at least 3 Tesla and provide much more precise and standardized information on methods to improve our understanding of fronto-striatal glutamatergic transmission in compulsive and impulsive syndromes. PMID- 25712433 TI - A blurring of life-history lines: Immune function, molt and reproduction in a highly stable environment. AB - Rufous-collared sparrows (Zonotrichia capensis peruviensis) from valleys in the Atacama Desert of Chile, live in an extremely stable environment, and exhibit overlap in molt and reproduction, with valley-specific differences in the proportion of birds engaged in both. To better understand the mechanistic pathways underlying the timing of life-history transitions, we examined the relationships among baseline and stress-induced levels of corticosterone (CORT), testosterone, and bacteria-killing ability of the blood plasma (BKA), as well as haemosporidian parasite infections and the genetic structure of two groups of sparrows from separate valleys over the course of a year. Birds neither molting nor breeding had the lowest BKA, but there were no differences among the other three categories of molt-reproductive stage. BKA varied over the year, with birds in May/June exhibiting significantly lower levels of BKA than the rest of the year. We also documented differences in the direction of the relationship between CORT and BKA at different times during the year. The direction of these relationships coincides with some trends in molt and reproductive stage, but differs enough to indicate that these birds exhibit individual-level plasticity, or population-level variability, in coordinating hypothalamo-pituitary-adrenal axis activity with life-history stage. We found weak preliminary evidence for genetic differentiation between the two populations, but not enough to indicate genetic isolation. No birds were infected with haemosporidia, which may be indicative of reduced parasite pressure in deserts. The data suggest that these birds may not trade off among different life-history components, but rather are able to invest in multiple life-history components based on their condition. PMID- 25712434 TI - Non-invasive endocrine monitoring of ovarian and adrenal activity in chinchilla (Chinchilla lanigera) females during pregnancy, parturition and early post-partum period. AB - The chinchilla is a rodent that bears one of the finest and most valuable pelts in the world. The wild counterpart is, however, almost extinct because of a drastic past and ongoing population decline. The present work was developed to increase our knowledge of the reproductive physiology of pregnancy and post partum estrus in the chinchilla, characterizing the endocrine patterns of urinary progesterone, estradiol, LH and cortisol metabolites throughout gestation and post-partum estrus and estimating the ovulation timing at post-partum estrus. Longitudinal urine samples were collected once per week throughout pregnancy and analyzed for creatinine, cortisol, LH, estrogen and progesterone metabolite concentrations. To indirectly determine the ovulation timing at post-partum estrus, a second experiment was performed using pregnant females subjected to a post-partum in vivo fertilization scheme. Urinary progestagen metabolites increased above baseline levels in early pregnancy between weeks-8 and -11 respectively to parturition, and slightly declined at parturition time. Urinary estrogens showed rising levels throughout mid- and late pregnancy (weeks-9 to -6 and a further increase at week-5 to parturition) and decreased in a stepwise manner after parturition, returning to baseline levels two weeks thereafter. Cortisol metabolite levels were relatively constant throughout pregnancy with a tendency for higher levels in the last third of gestation and after the pups' birth. Parturition was associated with dramatic reductions in urinary concentrations of sex steroids (especially progestagens). Observations in breeding farms indicated that the females that resulted in a second pregnancy after mating, did so on the second day after parturition. These data were in agreement with an LH peak detected 24h after parturition. Urinary steroid hormone patterns of estrogen and progestagen metabolites provided valuable information on endocrine events during pregnancy and after parturition in the chinchilla. Results presented in this study enhance our understanding of natural reproductive dynamics in the chinchilla and support empirical observations of breeders that post-partum ovulation occurs ~ 48 h after parturition. PMID- 25712435 TI - NiO(x)-Fe2O3-coated p-Si photocathodes for enhanced solar water splitting in neutral pH water. AB - We report successful growth of a uniform and scalable nanocomposite film of Fe2O3 nanorods (NRs) and NiOx nanoparticles (NPs), their properties and application for enhanced solar water reduction in neutral pH water on the surface of p-Si photocathodes. PMID- 25712436 TI - Enhanced bone healing using collagen-hydroxyapatite scaffold implantation in the treatment of a large multiloculated mandibular aneurysmal bone cyst in a thoroughbred filly. AB - An unmet need remains for a bone graft substitute material that is biocompatible, biodegradable and capable of promoting osteogenesis safely in vivo. The aim of this study was to investigate the use of a novel collagen-hydroxyapatite (CHA) bone graft substitute in the clinical treatment of a mandibular bone cyst in a young horse and to assess its potential to enhance repair of the affected bone. A 2 year-old thoroughbred filly, presenting with a multilobulated aneurysmal bone cyst, was treated using the CHA scaffold. Post-operative clinical follow-up was carried out at 2 weeks and 3, 6 and 14 months. Cortical thickening in the affected area was observed from computed tomography (CT) examination as early as 3 months post-surgery. At 14 months, reduced enlargement of the operated mandible was observed, with no fluid-filled area. The expansile cavity was occupied by moderately dense mineralized tissue and fat and the compact bone was remodelled, with a clearer definition between cortex and medulla observed. This report demonstrates the promotion of enhanced bone repair following application of the CHA scaffold material in this craniomaxillofacial indication, and thus the potential of this material for translation to human applications. PMID- 25712437 TI - Tacrolimus vs. cyclosporine eyedrops in severe cyclosporine-resistant vernal keratoconjunctivitis: A randomized, comparative, double-blind, crossover study. AB - BACKGROUND: Vernal keratoconjunctivitis (VKC) is a chronic sight-threatening ocular disease. Topical cyclosporine A (Cyc) has been widely administered as a steroid-sparing drug, although in about 7-10% of cases, it has been ineffective. The purpose of this study was to evaluate the efficacy of 0.1% topical tacrolimus (Tcr) in patients with severe VKC who failed to respond to 1% Cyc eyedrops. METHODS: Consecutive patients with severe, Cyc-resistant VKC were enrolled in a double-blind, comparative, crossover (DBCO) trial; all patients were treated with 1% Cyc in one eye and 0.1% Tcr in the other eye for 3 wk. After a washout period of 7 days, patients were instructed to cross over the medications for three additional weeks. Objective ocular score, subjective score, and quality-of-life questionnaires (QoLQ) were collected during the trial. Blood samples were drawn to assess several safety parameters. RESULTS: Thirty patients have been enrolled (mean age 9.05 +/- 2.12 yr). In each of the two phases of the DBCO trial, a significant improvement in objective and subjective scores was observed in the eyes treated with 0.1% Tcr (p < 0.001). Likewise, the quality of life significantly improved despite only half the eyes being successfully treated. Serum creatinine and blood parameters were constantly within the normal range, and both blood Cyc and Tcr concentrations remained below the lowest detectable levels. CONCLUSIONS: Topical Tcr is very effective and safe in the short term for patients suffering from severe VKC resistant to topical Cyc. PMID- 25712438 TI - Linkage mapping with paralogs exposes regions of residual tetrasomic inheritance in chum salmon (Oncorhynchus keta). AB - Gene sequence similarity due to shared ancestry after a duplication event, that is paralogy, complicates the assessment of genetic variation, as sequences originating from paralogs can be difficult to distinguish. These confounded sequences are often removed prior to further analyses, leaving the underlying loci uncharacterized. Salmonids have only partially rediploidized subsequent to a whole-genome duplication; residual tetrasomic inheritance has been observed in males. We present a maximum-likelihood-based method to resolve confounded paralogous loci by observing the segregation of alleles in gynogenetic haploid offspring and demonstrate its effectiveness by constructing two linkage maps for chum salmon (Oncorhynchus keta), with and without these newly resolved loci. We find that the resolved paralogous loci are not randomly distributed across the genome. A majority are clustered in expanded subtelomeric regions of 14 linkage groups, suggesting a significant fraction of the chum salmon genome may be missed by the exclusion of paralogous loci. Transposable elements have been proposed as drivers of genome evolution and, in salmonids, may have an important role in the rediploidization process by driving differentiation between homeologous chromosomes. Consistent with that hypothesis, we find a reduced fraction of transposable element annotations among paralogous loci, and these loci predominately occur in the genomic regions that lag in the rediploidization process. PMID- 25712439 TI - The Rapid Measurement of Benzodiazepines in a Milk-Based Alcoholic Beverage Using QuEChERS Extraction and GC-MS Analysis. AB - Benzodiazepines (BDZs) are widely used as tranquilizers and anti-depressive drugs in common clinical practice. However, their ready availability and their synergistic effects with alcohol make them attractive for criminal intentions. To prove criminal action for legal reasons, it is often necessary to analyze beverage residues from a crime scene. Milk-based alcoholic drinks (whiskey creams) are gaining popularity due to their lower alcohol content pleasant taste. However, the complexity of this sample, containing proteins and fatty acids, can mask the presence of drugs or other substances in standard analysis methods. These characteristics make whiskey creams highly suitable for illicit purposes. In this study, eight BDZs, including diazepam, chlordiazepoxide, clobazam, flunitrazepam, bromazepam, flurazepam, nitrazepam and clonazepam, were extracted from whiskey cream using the Quick, Easy, Cheap, Effective, Rugged and Safe (QuEChERS) method and analyzed using GC-MS. The QuEChERS protocol can efficiently separate most of the matrix from the target compounds while maintaining acceptable recoveries. The presented method is simple and rapid and has been validated in terms of precision, accuracy and recoveries. Limits of detection and limits of quantitation were in the range of 0.02-0.1 and 0.1-0.5 ug/mL, respectively. Whiskey cream beverages, fortified with commercial drugs at 20 ug/mL, were extracted and analyzed demonstrating the applicability of the method in forensic analysis. PMID- 25712440 TI - Evidence of Sulfur Mustard Exposure in Human Plasma by LC-ESI-MS-MS Detection of the Albumin-Derived Alkylated HETE-CP Dipeptide and Chromatographic Investigation of Its Cis/Trans Isomerism. AB - Sulfur mustard (SM) is a chemical warfare agent that causes painful blisters and chemically modifies endogenous biomacromolecules by alkylation to hydroxyethylthioethyl (HETE) adducts representing valuable long-term markers for post-exposure analysis. The albumin adduct formed in human plasma in vitro (HETE bound to the side chain of cysteine 34) was isolated and cleaved by current lots of pronase primarily generating the internal modified dipeptide (HETE-cysteine proline, HETE-CP) instead of the formerly reported HETE-CPF tripeptide. The analyte was detected by liquid chromatography-electrospray ionization tandem-mass spectrometry (LC-ESI-MS-MS). In principle, HETE-CP undergoes a dynamic on-column equilibrium of cis-trans isomerism thus requiring separation at 50 degrees C to obtain one narrow peak. Accordingly, we developed both a novel longer lasting but more sensitive microbore (1 mm i.d., flow 30 uL/min, cycle time 60 min, LOD 50 nM) and a faster, less sensitive narrowbore (2.1 mm i.d., 200 uL/min, cycle time 16 min, LOD 100 nM, both on Atlantis T3 material at 50 degrees C) LC-ESI-MS-MS method suitable for verification analysis. The corresponding tri- and tetrapeptide, Q(HETE)-CPF were monitored simultaneously. HETE-CP peak areas were directly proportional to SM concentrations added to plasma in vitro (0.05-100 uM). Albumin adducts formed by deuterated SM (d8-SM) served as internal standard. PMID- 25712441 TI - Effects of acupuncture at ST36 on pharmacokinetics of Schisandra lignans in rats. AB - OBJECTIVE: To investigate the influence of acupuncture at ST36 on the pharmacokinetics of Schisandra lignans including schisandrin, deoxyschisandrin and schisandrin B after intragastric administration of Schisandra chinensis (SC) in rats. METHODS: Twelve male Sprague-Dawley rats were randomly divided into two study groups: SC and SC+acupuncture. Rats in both groups received intragastric SC extract at 5.0 g/kg. Rats in the SC+acupuncture group additionally received acupuncture stimulation at ST36 for 30 min after SC administration. Acupuncture needles were rotated bilaterally for 1 min, left in situ for 20 min, then electrically stimulated for 10 min at 50 Hz frequency and 1-3 mA intensity. A sensitive and specific high performance liquid chromatography electrospray tandem mass spectrometry procedure was developed and validated for simultaneous analysis of three bioactive lignans (schisandrin, deoxyschisandrin and schisandrin B) in rat plasma. RESULTS: There were significant differences (p<0.05) between the two study groups in various pharmacokinetic parameters. Area under the plasma concentration-time curve (AUC0-t), area under the plasma concentration-time curve to time infinity (AUC0-infinity) and peak plasma concentration (Cmax) for schisandrin, absorption half-life (T1/2alpha) and AUC0-t for deoxyschisandrin, and Cmax for schisandrin B were increased in the SC+acupuncture group compared with the SC group. T1/2alpha for schisandrin B only and time to peak concentration (Tmax) for all three lignans were reduced following acupuncture. CONCLUSIONS: Acupuncture stimulation at ST36 affects the pharmacokinetics of SC in rats. Acupuncture may have a beneficial role in promoting the absorption of lignans from extracts of SC. PMID- 25712442 TI - WHO urges introduction of single use syringes. PMID- 25712443 TI - Comparing fracture absolute risk assessment (FARA) tools: an osteoporosis clinical informatics tool to improve identification and care of men at high risk of first fracture. AB - BACKGROUND: Fracture absolute risk assessment (FARA) is recommended for guiding osteoporosis treatment decisions in males. The best strategy for applying FARA in the clinic setting is not known. OBJECTIVES: We compared 2 FARA tools for use with electronic health records (EHRs) to determine which would more accurately identify patients known to be high risk for fracture. Tools evaluated were an adaptation of the World Health Organization's Fracture Risk Assessment Tool used with electronic data (eFRAX) and the Veterans Affairs (VA)-based tool, VA-FARA. METHODS: We compared accuracies of VA-FARA and eFRAX for correctly classifying male veterans who fractured and who were seen in the VA's Sierra Pacific Network in 2002-2013. We then matched those cases to nonfracture controls to compare odds of fracture in patients classified as high risk by either tool. RESULTS: Among 8740 patients, the mean (SD) age was 67.0 (11.1) years. Based on risk factors present in the EHR, VA-FARA correctly classified 40.1% of fracture patients as high risk (33.0% and 34.6% for hip and any major fracture, respectively); eFRAX classified 17.4% correctly (17.4% for hip and 0.2% for any major fracture). Compared with non-high-risk patients, those classified as high risk by VA-FARA were 35% more likely to fracture (95% CI = 23%-47%; P < 0.01) compared with 17% for eFRAX (95% CI = 5%-32%; P < 0.01). CONCLUSIONS: VA-FARA is more predictive of first fracture than eFRAX using EHR data. Decision support tools based on VA-FARA may improve early identification and care of men at risk. PMID- 25712444 TI - Empagliflozin, an SGLT2 inhibitor for the treatment of type 2 diabetes mellitus: a review of the evidence. AB - OBJECTIVE: To review available studies of empagliflozin, a sodium glucose co transporter-2 (SGLT2) inhibitor approved in 2014 by the European Commission and the United States Food and Drug Administration for the treatment of type 2 diabetes mellitus (T2DM). DATA SOURCES: PubMed was searched using the search terms empagliflozin, BI 10773, and BI10773, for entries between January 1, 2000, and December 1, 2014. Reference lists from retrieved articles were searched manually for additional peer-reviewed publications. STUDY SELECTION AND DATA EXTRACTION: All publications reporting clinical trials of empagliflozin were eligible for inclusion. DATA SYNTHESIS: Empagliflozin is a new once-daily oral SGLT2 inhibitor with a mechanism of action that is independent of beta-cell function and the insulin pathway. Data from a comprehensive phase III clinical trial program have demonstrated its efficacy as monotherapy, as add-on to other glucose-lowering agents, and in different patient populations. In these studies, empagliflozin resulted in improvements in blood glucose levels as well as reductions in body weight and blood pressure. Empagliflozin was well tolerated and was not associated with an increased risk of hypoglycemia versus placebo. CONCLUSION: The oral antidiabetes agent, empagliflozin, can be used as monotherapy or alongside other glucose-lowering treatments, including insulin, to treat T2DM. PMID- 25712445 TI - Vancomycin loading doses: a systematic review. AB - OBJECTIVE: To systematically assess the literature to ascertain the pharmacokinetics, pharmacodynamics, and clinical efficacy and safety associated with administration of a vancomycin loading dose (LD). DATA SOURCES: MEDLINE (1948-December 31, 2014), EMBASE (1980-December 31, 2014), Cochrane Central Register of Controlled Trials, International Pharmaceutical Abstracts (1970 December 31, 2014), Google and Google Scholar, and International Clinical Trials Registry Platform were searched using the following terms: vancomycin, glycopeptides, loading dose, dose-response relationship. STUDY SELECTION AND DATA EXTRACTION: Pharmacokinetic, pharmacodynamic, and clinical efficacy studies using vancomycin LDs to achieve trough concentrations of 15 to 20 mg/L were included. Nonhuman, non-English, oral vancomycin, and dialysis patient studies were excluded. Abstracts were included. Study quality was ranked using US Preventative Services Task Force 1996 classification system. Data on study design, baseline characteristics, exclusion criteria, dosing, study outcomes, and conclusions were extracted. DATA SYNTHESIS: A total of 8 studies (5 manuscripts [2 level I, 3 level II-3] and 3 abstracts) were cited. Of 6 adult studies, 4 concluded that administration of vancomycin LDs resulted in significantly more patients achieving troughs of 15 to 20 mg/L. Studies in children found that LDs did not lead to rapid attainment of vancomycin levels >=15 mg/L. No studies assessed clinical or microbiological outcomes. Limitations included heterogeneity and inconsistent timing of concentration measurements. CONCLUSIONS: High-quality data to guide the use of vancomycin LDs are lacking. LDs may more rapidly attain vancomycin troughs of 15 to 20 mg/L in adults, but information in pediatrics, obesity, and renal impairment is limited. Further studies are required to determine benefit of LDs on clinical and microbiological outcomes. PMID- 25712446 TI - Copper nanowire-graphene core-shell nanostructure for highly stable transparent conducting electrodes. AB - A copper nanowire-graphene (CuNW-G) core-shell nanostructure was successfully synthesized using a low-temperature plasma-enhanced chemical vapor deposition process at temperatures as low as 400 degrees C for the first time. The CuNW-G core-shell nanostructure was systematically characterized by scanning electron microscopy, transmission electron microscopy, X-ray diffraction, Raman, and X-ray photoelectron spectroscopy measurements. A transparent conducting electrode (TCE) based on the CuNW-G core-shell nanostructure exhibited excellent optical and electrical properties compared to a conventional indium tin oxide TCE. Moreover, it showed remarkable thermal oxidation and chemical stability because of the tight encapsulation of the CuNW with gas-impermeable graphene shells. The potential suitability of CuNW-G TCE was demonstrated by fabricating bulk heterojunction polymer solar cells. We anticipate that the CuNW-G core-shell nanostructure can be used as an alternative to conventional TCE materials for emerging optoelectronic devices such as flexible solar cells, displays, and touch panels. PMID- 25712447 TI - Accounting for Heterogeneity in Relative Treatment Effects for Use in Cost Effectiveness Models and Value-of-Information Analyses. AB - Cost-effectiveness analysis (CEA) models are routinely used to inform health care policy. Key model inputs include relative effectiveness of competing treatments, typically informed by meta-analysis. Heterogeneity is ubiquitous in meta analysis, and random effects models are usually used when there is variability in effects across studies. In the absence of observed treatment effect modifiers, various summaries from the random effects distribution (random effects mean, predictive distribution, random effects distribution, or study-specific estimate [shrunken or independent of other studies]) can be used depending on the relationship between the setting for the decision (population characteristics, treatment definitions, and other contextual factors) and the included studies. If covariates have been measured that could potentially explain the heterogeneity, then these can be included in a meta-regression model. We describe how covariates can be included in a network meta-analysis model and how the output from such an analysis can be used in a CEA model. We outline a model selection procedure to help choose between competing models and stress the importance of clinical input. We illustrate the approach with a health technology assessment of intravenous immunoglobulin for the management of adult patients with severe sepsis in an intensive care setting, which exemplifies how risk of bias information can be incorporated into CEA models. We show that the results of the CEA and value-of information analyses are sensitive to the model and highlight the importance of sensitivity analyses when conducting CEA in the presence of heterogeneity. The methods presented extend naturally to heterogeneity in other model inputs, such as baseline risk. PMID- 25712449 TI - The pivotal role of PDGF and its receptor isoforms in adipose-derived stem cells. AB - Platelet-derived growth factor (PDGF) is one of the growth factors that reportedly regulates cell growth and division of mesenchymal cells. Although PDGF isoforms and their receptors reportedly play a pivotal role in mesenchymal stem cell regulation, there is a paucity of literature reviewing the role of PDGF in adipose-derived stem cells (ASCs). Therefore, we summarized previous reports on the expression and functional roles of PDGF and its receptor isoforms in this review. In addition, we examined findings pertaining to underlying molecular mechanisms and signaling pathways with special focus on PDGF-D/PDGFRbeta. ASCs only express PDGF-A, -C, -D, PDGFRalpha, and PDGFRbeta. PDGFRalpha expression decreases with adipocyte lineage, while PDGFRbeta inhibits white adipocyte differentiation. In addition, PDGFRbeta induces proliferation, migration, and angiogenesis and up-regulates the expression of paracrine factors in ASCs. Although PDGF-B and -D mediate their functions mainly by PDGFRbeta and ROS generation, there are many differences between them in terms of regulating ASCs. PDGF-D is endogenous, generates ROS via the mitochondrial electron transport system, and regulates the autocrine loop of ASCs in vivo. Furthermore, PDGF-D has stronger mitogenic effects than PDGF-B. PMID- 25712448 TI - Relationship between Physicians' Uncertainty about Clinical Assessments and Patient-Centered Recommendations for Colorectal Cancer Screening in the Elderly. AB - OBJECTIVE: The goal of this study was to examine associations between physicians' clinical assessments, their certainty in these assessments, and the likelihood of a patient-centered recommendation about colorectal cancer (CRC) screening in the elderly. METHODS: Two hundred seventy-six primary care physicians in the United States read 3 vignettes about an 80-year-old female patient and answered questions about her life expectancy, their confidence in their life expectancy estimate, the balance of benefits/downsides of CRC screening, their certainty in their benefit/downside assessment, and the best course of action regarding CRC screening. We used logistic regression to determine the relationship between these variables and patient-centered recommendations about CRC screening. RESULTS: In bivariate analyses, physicians had higher odds of making a patient centered recommendation about CRC screening when their clinical assessments did not lead to a clear screening recommendation or when they experienced uncertainty in their clinical assessments. However, in a multivariate regression model, only benefit/downside assessment and best course of action remained statistically significant predictors of a patient-centered recommendation. CONCLUSIONS: Our findings demonstrate that when the results of clinical assessments do not lead to obvious screening decisions or when physicians feel uncertain about their clinical assessments, they are more likely to make patient-centered recommendations. Existing uncertainty frameworks do not adequately describe the uncertainty associated with patient-centered recommendations found in this study. Adapting or modifying these frameworks to better reflect the constructs associated with uncertainty and the interactions between uncertainty and the complexity inherent in clinical decisions will facilitate a more complete understanding of how and when physicians choose to include patients in clinical decisions. PMID- 25712450 TI - Modulation of colon cancer by nutmeg. AB - Colon cancer is the most common cancer and the third leading cause of cancer mortality in humans. Using mass spectrometry-based metabolomics, the current study revealed the accumulation of four uremic toxins (cresol sulfate, cresol glucuronide, indoxyl sulfate, and phenyl sulfate) in the serum of mice harboring adenomatous polyposis coli (APC) gene mutation-induced colon cancer. These uremic toxins, likely generated from the gut microbiota, were associated with an increase in the expression of the proinflammatory cytokine IL-6 and a disorder of lipid metabolism. Nutmeg, which exhibits antimicrobial activity, attenuated the levels of uremic toxins and decreased intestinal tumorigenesis in Apc(min/+) mice. Nutmeg-treated Apc(min/+) mice had decreased IL-6 levels and normalized dysregulated lipid metabolism, suggesting that uremic toxins are responsible, in part, for the metabolic disorders that occur during tumorigenesis. These studies demonstrate a potential biochemical link among gut microbial metabolism, inflammation, and metabolic disorders and suggest that modulation of gut microbiota and lipid metabolism using dietary intervention or drugs may be effective in colon cancer chemoprevention strategies. PMID- 25712451 TI - Systematic syntheses and metalloligand doping of flexible porous coordination polymers composed of a Co(III)-metalloligand. AB - A series of flexible porous coordination polymers (PCPs) RE-Co, composed of a Co(III)-metalloligand [Co(dcbpy)3](3-) (Co; H2dcbpy = 4,4'-dicarboxy-2,2' bipyridine) and lanthanide cations (RE(3+) = La(3+), Ce(3+), Pr(3+), Nd(3+), Sm(3+), Eu(3+), Gd(3+), Tb(3+), Er(3+)), was systematically synthesized. X-ray crystallographic analysis revealed that the six carboxylates at the top of each coordination octahedron of Co(III)-metalloligand were commonly bound to RE(3+) cations to form a rock-salt-type porous coordination framework. When RE-Co contains a smaller and heavier RE(3+) cation than Nd(3+), the RE-Co crystallized in the cubic Fm-3m space group, whereas the other three RE-Co with larger RE(3+) crystallized in the lower symmetrical orthorhombic Fddd space group, owing to the asymmetric 10-coordinated bicapped square antiprism structure of the larger RE(3+) cation. Powder X-ray diffraction and vapor-adsorption isotherm measurements revealed that all synthesized RE-Co PCPs show reversible amorphous crystalline transitions, triggered by water-vapor-adsorption/desorption. This transition behavior strongly depends on the kind of RE(3+); the transition of orthorhombic RE-Co was hardly observed under exposure to CH3OH vapor, but the RE Co with smaller cations such as Gd(3+) showed the transition under exposure to CH3OH vapors. Further tuning of vapor-adsorption property was examined by doping of Ru(II)-metalloligands, [Ru(dcbpy)3](4-), [Ru(dcbpy)2Cl2](4-), [Ru(dcbpy)(tpy)Cl](-), and [Ru(dcbpy)(dctpy)](3-) (abbreviated as RuA, RuB, RuC, and RuD, respectively; tpy = 2,2':6',2"-terpyridine, H2dctpy = 4,4"-dicarboxy 2,2':6',2"-terpyridine), into the Co(III)-metalloligand site of Gd-Co to form the Ru(II)-doped PCP RuX@Gd-Co (X = A, B, C, or D). Three Ru(II)-metalloligands, RuA, RuB, and RuD dopants, were found to be uniformly incorporated into the Gd-Co framework by replacing the original Co(III)-metalloligand, whereas the doping of RuC failed probably because of the less number of coordination sites. In addition, we found that the RuA doping into the Gd-Co PCP had a large effect on vapor-adsorption due to the electrostatic interaction originating from the negatively charged RuA sites in the framework and the charge-compensating Li(+) cations in the porous channel. PMID- 25712452 TI - Oral isotretinoin as the most effective treatment in folliculitis decalvans: a retrospective comparison of different treatment regimens in 28 patients. AB - BACKGROUND: Folliculitis decalvans leads to scarring alopecia through inflammatory destruction of the hair follicle. Currently, antibiotics are most commonly used to treat this disease. However, treatment regimens with antibiotics feature a high relapse rate and encourage the development of resistant bacteria. OBJECTIVE: To evaluate the outcome of different treatment options for folliculitis decalvans. METHODS: Retrospective study to compare the efficacy of different treatment regimens in 28 patients with folliculitis decalvans. RESULTS: The success of treatment with clindamycin and rifampicin, clarithromycin, dapsone and isotretinoin was analysed. The evaluation of the combination of clindamycin and rifampicin showed the lowest success rate in achieving long-term remission, since 80% of the patients relapsed shortly after end of treatment. Clarithromycin and dapsone were more successful with long-term and stable remission rates of 33% and 43% respectively. Treatment with isotretinoin was the most successful oral treatment in our analysis with 90% of the patients experiencing stable remission during and up to two years after cessation of the treatment. CONCLUSION: The common use of antibiotics as first-line therapy in folliculitis decalvans needs to be re-evaluated critically and oral isotretinoin should be considered as valid treatment alternative. PMID- 25712453 TI - CT outperforms radiographs at a comparable radiation dose in the assessment for spondylolysis. AB - BACKGROUND: Lumbar spondylolysis, a unilateral or bilateral fracture at pars interarticularis, is a common cause of low back pain in children. The initial imaging study in the diagnosis of lumbar spondylolysis has historically been lumbar spine radiographs; however, radiographs can be equivocal or false negative. Definitive diagnosis can be achieved with computed tomography (CT), but its use has been limited due to the dose of ionizing radiation to the patient. OBJECTIVE: By limiting the z-axis coverage to the relevant anatomy and optimizing the CT protocol, we are able to provide a definitive diagnosis of fractures of the pars interarticularis at comparable or lower radiation dose than commonly performed lumbar spine radiographs. As there is no gold standard for the diagnosis of spondylolysis besides surgery, we compared interobserver agreement and degree of confidence to determine which modality is preferable. MATERIALS AND METHODS: Sixty-two patients with low back pain ages 5-18 years were assessed for the presence of spondylolyis. Forty-seven patients were evaluated by radiography and 15 patients were evaluated by limited field-of-view CT. Both radiographic and CT examinations were assessed anonymously in random order for the presence or absence of spondylolyisis by six raters. Agreement was assessed among raters using a Fleiss Kappa statistic for multiple raters. RESULTS: CT provided a significantly higher level of agreement among raters than radiographs (P < 0.001). The overall Kappa for rater agreement with radiographs was 0.24, 0.34 and 0.40 for 2, 3 or 4 views, respectively, and 0.88 with CT. CONCLUSION: Interobserver agreement is significantly greater using limited z-axis coverage CT when compared with radiographs. Radiologist confidence improved significantly with CT compared to radiographs regardless of the number of views. PMID- 25712454 TI - Patients with mantle cell lymphoma failing ibrutinib are unlikely to respond to salvage chemotherapy and have poor outcomes. AB - BACKGROUND: Although ibrutinib is highly effective in patients with relapsed/refractory mantle cell lymphoma (MCL), a substantial proportion of patients have resistant disease. The subsequent outcomes of such patients are unknown. PATIENTS AND METHODS: We carried out a retrospective review of all patients with MCL treated with ibrutinib at MD Anderson Cancer Center between January 2011 and January 2014 using pharmacy and clinical databases. Patients who had discontinued ibrutinib for any reason were included in the study. RESULTS: We identified 42 patients with MCL who discontinued therapy due to disease progression on treatment (n = 28), toxicity (n = 6), elective stem-cell transplant in remission (n = 4) or withdrawn consent (n = 4). The median age was 69 years, 35 (83%) were male; the median number of prior treatments was 2 (range 1-8) and the median time from initial diagnosis of MCL to commencing ibrutinib was 3.0 (range 0.5-15.5) years. Patients had received a median of 6.5 (range 1 43) cycles of ibrutinib. Among 31 patients who experienced disease progression following ibrutinib and underwent salvage therapy, the overall and complete response rates were 32% and 19%, respectively. After a median follow-up of 10.7 (range 2.4-38.9) months from discontinuation of ibrutinib, the median overall survival (OS) among patients with disease progression was 8.4 months. By univariate analysis, elevated serum lactate dehydrogenase at progression was associated with inferior OS. CONCLUSION: The outcome of patients with MCL who experience disease progression following ibrutinib therapy is poor, with both low response rates to salvage therapy and short duration of responses. Further studies to better understand and overcome ibrutinib resistance are urgently needed. PMID- 25712455 TI - A personalised medicine approach for ponatinib-resistant chronic myeloid leukaemia. AB - BACKGROUND: Chronic myeloid leukaemia (CML) is characterised by the presence of a fusion driver oncogene, BCR-ABL1, which is a constitutive tyrosine kinase. Tyrosine kinase inhibitors (TKIs) are the central treatment strategy for CML patients and have significantly improved survival rates, but the T315I mutation in the kinase domain of BCR-ABL1 confers resistance to all clinically approved TKIs, except ponatinib. However, compound mutations can mediate resistance even to ponatinib and remain a clinical challenge in CML therapy. Here, we investigated a ponatinib-resistant CML patient through whole-genome sequencing (WGS) to identify the cause of resistance and to find alternative therapeutic targets. PATIENTS AND METHODS: We carried out WGS on a ponatinib-resistant CML patient and demonstrated an effective combination therapy against the primary CML cells derived from this patient in vitro. RESULTS: Our findings demonstrate the emergence of compound mutations in the BCR-ABL1 kinase domain following ponatinib treatment, and chromosomal structural variation data predicted amplification of BCL2. The primary CD34(+) CML cells from this patient showed increased sensitivity to the combination of ponatinib and ABT-263, a BCL2 inhibitor with a negligible effect against the normal CD34(+) cells. CONCLUSION: Our results show the potential of personalised medicine approaches in TKI-resistant CML patients and provide a strategy that could improve clinical outcomes for these patients. PMID- 25712456 TI - Early tumor shrinkage and depth of response predict long-term outcome in metastatic colorectal cancer patients treated with first-line chemotherapy plus bevacizumab: results from phase III TRIBE trial by the Gruppo Oncologico del Nord Ovest. AB - BACKGROUND: Early tumor shrinkage (ETS) and depth of response (DoR) predict overall survival (OS) in first-line trials of chemotherapy +/- anti-EGFR monoclonal antibodies in metastatic colorectal cancer (mCRC). These associations and the predictive accuracy of response measurements for survival parameters were investigated in the phase III TRIBE trial of FOLFOXIRI plus bevacizumab (bev) versus FOLFIRI plus bev. PATIENTS AND METHODS: A landmark approach was adopted to define the assessable population. The distribution of RECIST response rate, ETS and DoR was compared in the two arms. Associations between response measurements and progression-free survival (PFS), post-progression survival (PPS) and OS were tested by univariate and multivariate Cox models. Prediction performance of each factor was estimated by C-index. RESULTS: A significantly higher percentage of patients in the FOLFOXIRI plus bev arm achieved ETS >=20%, when compared with the control arm (62.7% versus 51.9%, P = 0.025). Also the DoR was significantly higher in the triplet plus bev arm (43.4% versus 37.8%, P = 0.003). Both ETS and DoR were associated with PFS, PPS and OS at the univariate analyses and in the multivariate models stratified for other prognostic variables. Both ETS and DoR were able to predict survival as accurately as RECIST response. CONCLUSION: FOLFOXIRI plus bev improves ETS and DoR when compared with FOLFIRI plus bev. Achieving rapid and deep tumor shrinkage consistently delays tumor progression and prolongs survival in patients treated with first-line chemotherapy plus bev. ETS is a promising and valuable end point for clinical trials' design deserving further investigation. PMID- 25712457 TI - Ki-67 is a strong predictor of central nervous system relapse in patients with mantle cell lymphoma (MCL). AB - BACKGROUND: Central nervous system (CNS) relapse is an uncommon but challenging complication in patients with mantle cell lymphoma (MCL). Survival after CNS relapse is extremely poor. Identification of high-risk populations is therefore critical in determining patients who might be candidates for a prophylactic approach. PATIENTS AND METHODS: A total of 608 patients (median age, 67 years; range 22-92) with MCL newly diagnosed between 1994 and 2012 were evaluated. Pretreatment characteristics and treatment regimens were evaluated for their association with CNS relapse by competing risk regression analysis. RESULTS: None of the patients received intrathecal prophylaxis. Overall, 33 patients (5.4%) experienced CNS relapse during a median follow-up of 42.7 months. Median time from diagnosis to CNS relapse was 20.3 months (range: 2.2-141.3 months). Three year cumulative incidence of CNS relapse was 5.6% [95% confidence interval (95% CI) 3.7% to 8.0%]. Univariate analysis revealed several risk factors including blastoid variant, leukemic presentation, high-risk MCL International Prognostic Index and high Ki-67 (proliferation marker). Multivariate analyses revealed that Ki-67 >= 30 was the only significant risk factor for CNS relapse (hazard ratio: 6.0, 95% CI 1.9-19.4, P = 0.003). Two-year cumulative incidence of CNS relapse in patients with Ki-67 >= 30 was 25.4% (95% CI 13.5-39.1), while that in the patients with Ki-67 < 30 was 1.6% (95% CI 0.4-4.2). None of the treatment modalities, including rituximab, high-dose cytarabine, high-dose methotrexate or consolidative autologous stem-cell transplant, were associated with a lower incidence of CNS relapse. Survival after CNS relapse was poor, with median survival time of 8.3 months. There was no significant difference in the survival by the site of CNS involvement. PMID- 25712458 TI - A comprehensive review of lenalidomide therapy for B-cell non-Hodgkin lymphoma. AB - Lenalidomide is an oral non-chemotherapy immunomodulator with direct and indirect effects on non-Hodgkin lymphoma (NHL) cells and with single-agent activity in relapsed/refractory aggressive and indolent B-cell NHL, including mantle cell lymphoma (MCL), diffuse large B-cell lymphoma, and follicular lymphoma. Based on the pivotal phase II MCL-001 trial of lenalidomide in heavily pretreated patients with relapsed/refractory MCL, lenalidomide was approved by the US Food and Drug Administration for the treatment of relapsed/refractory MCL after failure of two prior therapies, one of which includes bortezomib, at a recommended starting dose of 25 mg on days 1-21 of each 28-day cycle. Lenalidomide enhanced the survival benefit in combination with rituximab in preclinical models, prompting clinical evaluation of the lenalidomide-rituximab (R2) combination. In phase II trials, lenalidomide 20 mg on days 1-21 in combination with different standard-dose rituximab schedules exhibited promising activity in both first-line and relapsed/refractory disease across multiple B-cell NHL subtypes. The feasibility of combining lenalidomide with immunochemotherapy, including R-CHOP and rituximab bendamustine, has been demonstrated in phase I/II trials. These latter regimens are currently being evaluated in ongoing phase II and III trials. The role of lenalidomide monotherapy and R2 in maintenance therapy is also being examined. Based on available evidence, a comprehensive review of lenalidomide in all treatment phases of B-cell NHL-relapsed/refractory disease, first-line, and maintenance-is presented here. PMID- 25712459 TI - Survival in stage I-III breast cancer patients by surgical treatment in a publicly funded health care system. AB - BACKGROUND: Recent investigations of breast cancer survival in the United States suggest that patients who receive mastectomy have poorer survival than those who receive breast-conserving surgery (BCS) plus radiotherapy, despite clinically established equivalence. This study investigates breast cancer survival in the publicly funded health care system present in Alberta, Canada. PATIENTS AND METHODS: Surgically treated stage I-III breast cancer cases diagnosed in Alberta from 2002 to 2010 were included. Demographic, treatment and mortality information were collected from the Alberta Cancer Registry. Unadjusted overall and breast cancer-specific mortality was assessed using Kaplan-Meier and cumulative incidence curves, respectively. Cox proportional hazards models were used to calculate stage-specific mortality hazard estimates associated with surgical treatment received. RESULTS: A total of 14 939 cases of breast cancer (14 633 patients) were included in this study. The unadjusted 5-year all-cause survival probabilities for patients treated with BCS plus radiotherapy, mastectomy, and BCS alone were 94% (95% CI 93% to 95%), 83% (95% CI 82% to 84%) and 74% (95% CI 70% to 78%), respectively. Stage II and III patients who received mastectomy had a higher all-cause (stage II HR = 1.36, 95% CI 1.13-1.48; stage III HR = 1.74, 95% CI 1.24-2.45) and breast cancer-specific (stage II HR = 1.39, 95% CI 1.09 1.76; stage III HR = 1.79, 95% CI 1.21-2.65) mortality hazard compared with those who received BCS plus radiotherapy, adjusting for patient and clinical characteristics. BCS alone was consistently associated with poor survival. CONCLUSIONS: Stage II and III breast cancer patients diagnosed in Alberta, Canada, who received mastectomy had a significantly higher all-cause and breast cancer-specific mortality hazard compared with those who received BCS plus radiotherapy. We suggest greater efforts toward educating and encouraging patients to receive BCS plus radiotherapy rather than mastectomy when it is medically feasible and appropriate. PMID- 25712461 TI - Adjuvant systemic therapy in breast cancer: quo vadis? AB - The premise that breast cancer (BC) has a tendency toward early systemic dissemination, together with empirical findings showing that drugs given after breast tumor surgery improve outcome, led to the development of systemic adjuvant therapy. This strategy, which started more than 50 years ago, revolutionized BC treatment and improved patient outcome in a substantial way. However, in recent years, several large trials that incorporated new systemic treatments in the adjuvant setting of BC failed to demonstrate a benefit. In the present review, we discuss the progress made in the adjuvant treatment of BC in the past decade, the possible reasons for the recent failures, and practical strategies that may be incorporated in the design of future trials. PMID- 25712460 TI - Genomic alterations in head and neck squamous cell carcinoma determined by cancer gene-targeted sequencing. AB - BACKGROUND: To determine genomic alterations in head and neck squamous cell carcinoma (HNSCC) using formalin-fixed, paraffin-embedded (FFPE) tumors obtained through routine clinical practice, selected cancer-related genes were evaluated and compared with alterations seen in frozen tumors obtained through research studies. PATIENTS AND METHODS: DNA samples obtained from 252 FFPE HNSCC were analyzed using next-generation sequencing-based (NGS) clinical assay to determine sequence and copy number variations in 236 cancer-related genes plus 47 introns from 19 genes frequently rearranged in cancer. Human papillomavirus (HPV) status was determined by presence of the HPV DNA sequence in all samples and corroborated with high-risk HPV in situ hybridization (ISH) and p16 immunohistochemical (IHC) staining in a subset of tumors. Sequencing data from 399 frozen tumors in The Cancer Genome Atlas and University of Chicago public datasets were analyzed for comparison. RESULTS: Among 252 FFPE HNSCC, 84 (33%) were HPV positive and 168 (67%) were HPV negative by sequencing. A subset of 40 tumors with HPV ISH and p16 IHC results showed complete concordance with NGS derived HPV status. The most common genes with genomic alterations were PIK3CA and PTEN in HPV-positive tumors and TP53 and CDKN2A/B in HPV-negative tumors. In the pathway analysis, the PI3K pathway in HPV-positive tumors and DNA repair-p53 and cell cycle pathways in HPV-negative tumors were frequently altered. The HPV positive oropharynx and HPV-positive nasal cavity/paranasal sinus carcinoma shared similar mutational profiles. CONCLUSION: The genomic profile of FFPE HNSCC tumors obtained through routine clinical practice is comparable with frozen tumors studied in research setting, demonstrating the feasibility of comprehensive genomic profiling in a clinical setting. However, the clinical significance of these genomic alterations requires further investigation through application of these genomic profiles as integral biomarkers in clinical trials. PMID- 25712462 TI - Differential requirements for beta-catenin in murine prostate cancer originating from basal versus luminal cells. AB - A driver mutation occurring in different cells of origin may impact cancer progression differently. Previously, we demonstrated higher invasiveness in Pten deficient prostate cancer (CaP) arising from basal cells compared to that arising from luminal cells in mice. Here, we show higher expression of epithelial mesenchymal transition (EMT)-inducing transcription factors and stem/progenitor properties in basal-derived CaP compared to luminal-derived CaP. We further explore the requirement for beta-catenin in basal and luminal prostate cells during CaP progression. Genetic ablation and pharmacological inhibition of beta catenin specifically suppress basal-derived CaP progression through reduction of stemness and cell proliferation and increased gammaH2Ax-associated apoptosis. Lineage tracing revealed that loss of beta-catenin in basal cells impairs basal to-luminal differentiation; conversely, beta-catenin loss is dispensable for luminal-derived CaP progression. Our findings suggest that beta-catenin is required for basal-derived normal luminal cells and cancer cells, but not for luminal derivatives. Although the cellular origin of CaP in patients cannot be easily determined at present, the results imply that beta-catenin inhibition is a potential therapeutic option for a subset of patients with basal-derived CaP. PMID- 25712463 TI - Myosin motor isoforms direct specification of actomyosin function by tropomyosins. AB - Myosins and tropomyosins represent two cytoskeletal proteins that often work together with actin filaments in contractile and motile cellular processes. While the specialized role of tropomyosin in striated muscle myosin-II regulation is well characterized, its role in nonmuscle myosin regulation is poorly understood. We previously showed that fission yeast tropomyosin (Cdc8p) positively regulates myosin-II (Myo2p) and myosin-V (Myo52p) motors. To understand the broader implications of this regulation we examined the role of two mammalian tropomyosins (Tpm3.1cy/Tm5NM1 and Tpm4.2cy/Tm4) recently implicated in cancer cell proliferation and metastasis. Like Cdc8p, the Tpm3.1cy and Tpm4.2cy isoforms significantly enhance Myo2p and Myo52p motor activity, converting nonprocessive Myo52p molecules into processive motors that can walk along actin tracks as single molecules. In contrast to the positive regulation of Myo2p and Myo52p, Cdc8p and the mammalian tropomyosins potently inhibited skeletal muscle myosin II, while having negligible effects on the highly processive mammalian myosin-Va. In support of a conserved role for certain tropomyosins in regulating nonmuscle actomyosin structures, Tpm3.1cy supported normal contractile ring function in fission yeast. Our work reveals that actomyosin regulation by tropomyosin is dependent on the myosin isoform, highlighting a general role for specific isoforms of tropomyosin in sorting myosin motor outputs. PMID- 25712465 TI - Task switching mediates direct interference of intertarget distractors in the attentional blink: An event-related potential study. AB - The attentional blink (AB) refers to the difficulty in reporting a second target (T2) presented shortly after a first target (T1) in a stream of distractors. The goal of the present study was to investigate distractor-based interference in the AB by recording the P3 component of the event-related potential to both targets. An intertarget distractor was presented at lag 1 (T1+1), at lag 2 (T1+2), or at neither of these two lags (no distractor). T2 was always presented at lag 3, as the last item in the stream. In two experiments, the P3 from T1 was attenuated in the T1+1 condition compared to the two other distractor conditions. In absence of a task switch (Experiment 1), the P3 from T2 was delayed in both the T1+1 and T1+2 conditions. In the presence of a task switch (Experiment 2), the P3 from T2 was delayed only in the T1+1 condition. Results demonstrate that intertarget distractors can modulate the AB directly but only in absence of a task switch. PMID- 25712464 TI - Efficacy of transcatheter aortic valve implantation in patients with aortic stenosis and reduced LVEF. A systematic review. AB - BACKGROUND: Transcatheter aortic valve implantation (TAVI) is safe and effective for patients with aortic stenosis (AS) who have a high operative risk. However, there is still debate on the effect of TAVI in AS patients with reduced left ventricular ejection fraction (REF). The objective of the review is to clarify the efficacy of TAVI and the impact of REF on the 30-day and midterm mortality in these patients. METHODS: Studies on TAVI were searched in PubMed, Embase, and the Cochrane Library databases and were included in this review following predefined criteria. Data were extracted and pooled risk ratios (RR) were synthesized to explore the relationship between REF and 30-day plus midterm mortality. RESULTS: Twenty-eight studies comprising 14,099 patients were included in the analysis of the association of REF with the prognosis of patients after TAVI. An average increase in left ventricular ejection fraction of 8-10 % was observed among these patients after TAVI. REF was not related to the 30-day mortality [RR = 1.90, 95 % confidence interval (CI) = 0.80-4.47]; however, it was related to the midterm mortality (RR = 1.49, 95 %CI = 1.14-1.93) of patients undergoing TAVI. Patients with low-flow and low-gradient AS had a higher 30-day mortality (RR = 1.54, 95 %CI = 1.11-2.13) and midterm mortality rate (RR = 1.69, 95 %CI = 1.33-2.14) compared with AS patients without these characteristics. The mortality of TAVI patients was significantly lower than that of those undergoing conservative therapy, and was similar to that of patients undergoing surgical aortic valve replacement. CONCLUSION: REF was not associated with 30-day mortality, but it was associated with the midterm mortality of TAVI patients. Patients with REF could benefit from TAVI compared with conservative therapy. PMID- 25712466 TI - Edelman's view on the discovery of antibodies. AB - Gerald M. Edelman began working to the structure of antibodies when joined as graduate student the laboratory of Henry Kunkel in 1958 at the "Rockefeller University" in New York, obtaining his doctorate in 1960. Edelman's focus on the structure of antibodies led to the 1972 Nobel Prize in Physiology or Medicine along with Rodney R. Porter. Edelman and Porter decided to approach the problem of antibodies structure by splitting. In 1959, Porter published a report in which he used the enzyme papain to cleave the antibody molecule into three pieces of about 50,000 Da, corresponding to the two Fab (antigen-binding) and constant Fc (crystallizable) fragments. In the same year, Edelman showed that reduction of the disulfide bonds of antibodies in the presence of denaturizing agents led to dissociation of the molecule into smaller pieces, now known to be the light (L) and heavy (H) chains. PMID- 25712467 TI - Identification and characterization of the lamprey IRF gene. AB - Interferon regulatory factors (IRFs) are named for their ability to bind to and regulate interferon genes when an organism becomes infected with a virus. Numerous studies have revealed the versatile and critical functions of IRFs. In this study, an IRF gene from Lampetra japonica was identified and analyzed using bioinformatic methods. The L. japonica IRF (Lj-IRF) shares high sequence homology with other vertebrate IRFs but low sequence homology with an ascidian IRF-like protein. We also used recombinant Lj-IRF protein (rLj-IRF) to immunize New Zealand rabbits to prepare specific anti-rLj-IRF polyclonal antibodies. Enzyme linked immunosorbent assays (ELISAs) and Western blotting assays were performed to detect the valence and specificity of the antibody. FACS analysis revealed that the Lj-IRF protein was expressed in approximately 21.14% of leukocytes and 9.60% of supraneural body cells in L. japonica, with immunofluorescence staining indicating a cytoplasmic location. The immunohistochemistry results demonstrated that IRF is distributed in the epithelial cells of the heart, supraneural body, kidneys and gills but is not detectable in intestinals or oral gland tissues. However, the expression of IRF was upregulated in lamprey intestinal tissues upon stimulation with the rLj-HMGB1 protein. Lj-IRF gene expression levels were higher in the rLj-HMGB1-stimulated group than the control group, and the expression level of Lj-IRF was significantly increased in the intestines as determined by quantitative real-time PCR. These results provide a foundation for studying the origin and evolution of the innate immune system in lampreys. PMID- 25712468 TI - Kinetic mechanism of L-alpha-glycerophosphate oxidase from Mycoplasma pneumoniae. AB - L-alpha-glycerophosphate oxidase is an FAD-dependent enzyme that catalyzes the oxidation of L-alpha-glycerophosphate (Glp) by molecular oxygen to generate dihydroxyacetone phosphate (DHAP) and hydrogen peroxide (H2O2). The catalytic properties of recombinant His6-GlpO from Mycoplasma pneumoniae (His6-MpGlpO) were investigated through transient and steady-state kinetics and ligand binding studies. The results indicate that the reaction mechanism of His6-MpGlpO follows a ping-pong model. Double-mixing mode stopped-flow experiments show that, after flavin-mediated substrate oxidation, DHAP leaves rapidly prior to the oxygen reaction. The values determined for the individual rate constants and kcat (4.2 s(-1) at 4 degrees C), in addition to the finding that H2 O2 binds to the oxidized enzyme, suggest that H2O2 release is the rate-limiting step for the overall reaction. The results indicate that His6 -MpGlpO contains mixed populations of fast- and slow-reacting species. It is predominantly the fast reacting species that participates in turnover. In contrast to other GlpO enzymes previously described, His6-MpGlpO is able to catalyze the reverse reaction of reduced enzyme and DHAP. This result may be explained by the standard reduction potential value of His6-MpGlpO (-167 +/- 1 mV), which is lower than those of GlpO from other species. We found that D,L-glyceraldehyde 3-phosphate (GAP) may be used as a substrate in the His6-MpGlpO reaction, although it exhibited an approximately 100-fold lower kcat value in comparison with the reaction of Glp. These results also imply involvement of GlpO in glycolysis, as well as in lipid and glycerol metabolism. The kinetic models and distinctive properties of His6 MpGlpO reported here should be useful for future drug development against Mycoplasma pneumoniae infection. PMID- 25712469 TI - Academic Benchmarks for Otolaryngology Leaders. AB - OBJECTIVE: This study aimed to characterize current benchmarks for academic otolaryngologists serving in positions of leadership and identify factors potentially associated with promotion to these positions. METHODS: Information regarding chairs (or division chiefs), vice chairs, and residency program directors was obtained from faculty listings and organized by degree(s) obtained, academic rank, fellowship training status, sex, and experience. Research productivity was characterized by (a) successful procurement of active grants from the National Institutes of Health and prior grants from the American Academy of Otolaryngology-Head and Neck Surgery Foundation Centralized Otolaryngology Research Efforts program and (b) scholarly impact, as measured by the h-index. RESULTS: Chairs had the greatest amount of experience (32.4 years) and were the least likely to have multiple degrees, with 75.8% having an MD degree only. Program directors were the most likely to be fellowship trained (84.8%). Women represented 16% of program directors, 3% of chairs, and no vice chairs. Chairs had the highest scholarly impact (as measured by the h-index) and the greatest external grant funding. CONCLUSION: This analysis characterizes the current picture of leadership in academic otolaryngology. Chairs, when compared to their vice chair and program director counterparts, had more experience and greater research impact. Women were poorly represented among all academic leadership positions. PMID- 25712470 TI - Assessing Proprioception: A Systematic Review of Possibilities. AB - Proprioception is a vital aspect of motor control and when degraded or lost can have a profound impact on function in diverse clinical populations. This systematic review aimed to identify clinically related tools to measure proprioceptive acuity, to classify the construct(s) underpinning the tools, and to report on the clinimetric properties of the tools. We searched key databases with the pertinent search terms, and from an initial list of 935 articles, we identified 57 of relevance. These articles described 32 different tools or methods to quantify proprioception. There was wide variation in methods, the joints able to be tested, and the populations sampled. The predominant construct was active or passive joint position detection, followed by passive motion detection and motion direction discrimination. The clinimetric properties were mostly poorly evaluated or reported. The Rivermead Assessment of Somatosensory Perception was generally considered to be a valid and reliable tool but with low precision; other tools with higher precision are potentially not clinically feasible. Clinicians and clinical researchers can use the summary tables to make more informed decisions about which tool to use to match their predominant requirements. Further discussion and research is needed to produce measures of proprioception that have improved validity and utility. PMID- 25712471 TI - Firing properties of Renshaw cells defined by Chrna2 are modulated by hyperpolarizing and small conductance ion currents Ih and ISK. AB - Renshaw cells in the spinal cord ventral horn regulate motoneuron output through recurrent inhibition. Renshaw cells can be identified in vitro using anatomical and cellular criteria; however, their functional role in locomotion remains poorly defined because of the difficulty of functionally isolating Renshaw cells from surrounding motor circuits. Here we aimed to investigate whether the cholinergic nicotinic receptor alpha2 (Chrna2) can be used to identify Renshaw cells (RCs(alpha2)) in the mouse spinal cord. Immunohistochemistry and electrophysiological characterization of passive and active RCs(alpha2) properties confirmed that neurons genetically marked by the Chrna2-Cre mouse line together with a fluorescent reporter mouse line are Renshaw cells. Whole-cell patch-clamp recordings revealed that RCs(alpha2) constitute an electrophysiologically stereotyped population with a resting membrane potential of -50.5 +/- 0.4 mV and an input resistance of 233.1 +/- 11 MOmega. We identified a ZD7288-sensitive hyperpolarization-activated cation current (Ih) in all RCs(alpha2), contributing to membrane repolarization but not to the resting membrane potential in neonatal mice. Additionally, we found RCs(alpha2) to express small calcium-activated potassium currents (I(SK)) that, when blocked by apamin, resulted in a complete attenuation of the afterhyperpolarisation potential, increasing cellular firing frequency. We conclude that RCs(alpha2) can be genetically targeted through their selective Chrna2 expression and that they display currents known to modulate rebound excitation and firing frequency. The genetic identification of Renshaw cells and their electrophysiological profile is required for genetic and pharmacological manipulation as well as computational simulations with the aim to understand their functional role. PMID- 25712472 TI - Titanium-catalyzed reductive umpolung reactions with a metal-free terminal reducing agent. AB - A new method for titanium-catalyzed reductive umpolung reactions is reported that overcomes the traditional requirement for a stoichiometric metallic reductant. With N,N'-disilylated tetramethyldihydropyrazine as a potent organic reducing agent, reductive carbonyl-nitrile, enone-acrylonitrile and pinacol coupling reactions can be achieved in good yields and stereoselectivities. [Cp2TiI2] is a superior catalyst to [Cp2TiCl2], which is rationalized by a faster generation of the active catalyst [Cp2TiI]. A mechanism is proposed that is in agreement with the experimental results. PMID- 25712473 TI - A pragmatic descriptive study of rewarming the newborn after the first bath. AB - OBJECTIVES: To evaluate two methods of rewarming newborns after the first bath: radiant rewarming and skin-to-skin maternal newborn contact. DESIGN: A nonrandomized clinical trial in which mothers chose the rewarming method, with 200 participants in the skin-to-skin rewarming group (experimental condition), and 200 in the radiant rewarming group (control). SETTING: A teaching hospital in the Southeast United States. PARTICIPANTS: Healthy, term infants after vaginal delivery. METHODS: Newborn temperatures were taken immediately prior to the bath (T1), and 30 minutes (T2) and 60 minutes (T3) after the bath. Descriptive statistics and t tests were used to determine differences between groups and between time points. Logistic regression was employed to assess risk factors for newborns with temperatures less than 36.4 degrees C 30 minutes after the bath. RESULTS: Because 96 of the first 100 mothers chose skin-to-skin rewarming, we concluded the study early and analyzed the data. Of the 96 mothers who chose skin to-skin, 91 infants were successfully rewarmed and five required rescue rewarming under the radiant warmer. Careful review of newborns requiring rescuing showed inadequate skin-to-skin contact or removal of the protective covering. In this sample, African American mothers were significantly younger, had smaller newborns, and their newborns had lower temperatures than non-African American newborns. CONCLUSIONS: Given a choice, mothers overwhelmingly preferred skin-to skin rewarming. Newborns can safely rewarm skin-to-skin if staff pay special attention to how they are positioning the newborn and recheck mother and newborn frequently. The unexpected finding of racial differences in maternal and newborn characteristics will require further investigation. PMID- 25712474 TI - Pericentral hydroxychloroquine retinopathy in Korean patients. AB - PURPOSE: A pericentral pattern of hydroxychloroquine (HCQ) retinopathy recently has been recognized in the United States in patients of Asian heritage. We report on an investigation of this pericentral retinopathy within a Korean population. DESIGN: Retrospective, observational study. PARTICIPANTS: Patients taking HCQ who were referred to ophthalmology for screening of HCQ retinopathy. METHODS: The medical records of patients were reviewed, including spectral domain optical coherence tomography, fundus autofluorescence, and visual fields. MAIN OUTCOME MEASURES: Frequency of pericentral pattern of HCQ retinopathy and features of progression. RESULTS: Among 218 patients referred, 9 (4.1%) were diagnosed with toxicity. Of these, 8 had a predominantly pericentral pattern of retinal change, whereas only 1 had the classic parafoveal distribution of retinal damage. Progression of retinopathy was documented in 3 patients followed more than 12 months while taking HCQ. No progression was seen in 2 patients without retinal pigment epithelial (RPE) damage who were followed for at least 12 months after discontinuation of HCQ. CONCLUSIONS: We found that a pericentral pattern of HCQ retinopathy was predominant among Korean patients, rather than the traditional (bull's eye) parafoveal pattern of damage. Retinopathy progressed while on the drug, but the progression stopped in patients with toxicity detected before RPE damage. These observations suggest the need for new approaches when screening for HCQ toxicity in Asian patients. PMID- 25712475 TI - Cyclin O (Ccno) functions during deuterosome-mediated centriole amplification of multiciliated cells. AB - Mucociliary clearance and fluid transport along epithelial surfaces are carried out by multiciliated cells (MCCs). Recently, human mutations in Cyclin O (CCNO) were linked to severe airway disease. Here, we show that Ccno expression is restricted to MCCs and the genetic deletion of Ccno in mouse leads to reduced numbers of multiple motile cilia and characteristic phenotypes of MCC dysfunction including severe hydrocephalus and mucociliary clearance deficits. Reduced cilia numbers are caused by compromised generation of centrioles at deuterosomes, which serve as major amplification platform for centrioles in MCCs. Ccno-deficient MCCs fail to sufficiently generate deuterosomes, and only reduced numbers of fully functional centrioles that undergo maturation to ciliary basal bodies are formed. Collectively, this study implicates CCNO as first known regulator of deuterosome formation and function for the amplification of centrioles in MCCs. PMID- 25712476 TI - The Spectrin cytoskeleton regulates the Hippo signalling pathway. AB - The Spectrin cytoskeleton is known to be polarised in epithelial cells, yet its role remains poorly understood. Here, we show that the Spectrin cytoskeleton controls Hippo signalling. In the developing Drosophila wing and eye, loss of apical Spectrins (alpha/beta-heavy dimers) produces tissue overgrowth and mis regulation of Hippo target genes, similar to loss of Crumbs (Crb) or the FERM domain protein Expanded (Ex). Apical beta-heavy Spectrin binds to Ex and co localises with it at the apical membrane to antagonise Yki activity. Interestingly, in both the ovarian follicular epithelium and intestinal epithelium of Drosophila, apical Spectrins and Crb are dispensable for repression of Yki, while basolateral Spectrins (alpha/beta dimers) are essential. Finally, the Spectrin cytoskeleton is required to regulate the localisation of the Hippo pathway effector YAP in response to cell density human epithelial cells. Our findings identify both apical and basolateral Spectrins as regulators of Hippo signalling and suggest Spectrins as potential mechanosensors. PMID- 25712479 TI - Regulatory T cell differentiation: cooperation saves the day. PMID- 25712480 TI - Determinants of Coach Communication About Concussion Safety in US Collegiate Sport. AB - BACKGROUND: Communication between coaches and athletes about concussion safety can reinforce or undermine a sport culture in which concussion under-reporting is often endemic. METHOD: This study tested a model in which self-reported coach communication about concussion safety was predicted by factors including concussion knowledge, attitudes and beliefs, sex of the coach, and sex of the team coached. Participants were 997 coaches of contact and collision sports teams competing in National Collegiate Athletic Association Division I, II, or III. RESULTS: Concussion attitudes and beliefs were the strongest predictors of communication, and the small effect of knowledge on communication was transmitted nearly entirely through its effect on attitudes and beliefs. Much of the variability in communication was attributable to the sex of the coach and the sex of the team coached. CONCLUSIONS: These results serve as a starting point for the design of coach-targeted interventions that encourage communication about health and safety with athletes. PMID- 25712481 TI - Reversible photochemical modifications in dicarbene-derived metallacycles with coumarin pendants. AB - Molecular rectangles were obtained from two bis(NHC) ligands, each featuring two terminal coumarin groups and two Ag(+), Au(+), or Cu(+) ions. Upon UV irradiation (lambda=365 nm), the dinuclear complexes undergo photochemical modification through a [2+2] cycloaddition reaction of two adjacent coumarin moieties to give a macrocyclic tetra(NHC) ligand. The photodimerization of the coumarin pendants proceeds stereoselectively to give the syn-head-head isomers in all cases. Subsequent irradiation at lambda=254 nm initiates a photocleavage reaction with reconstitution of the initial dinuclear complexes with coumarin pendants. PMID- 25712478 TI - Induced miR-99a expression represses Mtor cooperatively with miR-150 to promote regulatory T-cell differentiation. AB - Peripheral induction of regulatory T (Treg) cells provides essential protection from inappropriate immune responses. CD4(+) T cells that lack endogenous miRNAs are impaired to differentiate into Treg cells, but the relevant miRNAs are unknown. We performed an overexpression screen with T-cell-expressed miRNAs in naive mouse CD4(+) T cells undergoing Treg differentiation. Among 130 candidates, the screen identified 29 miRNAs with a negative and 10 miRNAs with a positive effect. Testing reciprocal Th17 differentiation revealed specific functions for miR-100, miR-99a and miR-10b, since all of these promoted the Treg and inhibited the Th17 program without impacting on viability, proliferation and activation. miR-99a cooperated with miR-150 to repress the expression of the Th17-promoting factor mTOR. The comparably low expression of miR-99a was strongly increased by the Treg cell inducer "retinoic acid", and the abundantly expressed miR-150 could only repress Mtor in the presence of miR-99a. Our data suggest that induction of Treg cell differentiation is regulated by a miRNA network, which involves cooperation of constitutively expressed as well as inducible miRNAs. PMID- 25712482 TI - Mortality among sheet metal workers participating in a respiratory screening program. AB - BACKGROUND: The Sheet Metal Occupational Health Institute Trust (SMOHIT) established a screening program in 1985 to examine the health hazards of the sheet metal industry in the U.S. and Canada. METHODS: 17,345 individuals with over 20 years in the trade and who participated in the program were followed for causes of death between 1986 and 2010. Both SMRs and Cox proportional hazards models investigated predictors of death due to lung cancer, mesothelioma, and chronic obstructive pulmonary disease (COPD). RESULTS: Significant excess mortality was seen for mesothelioma and asbestosis. Controlling for smoking, a strong trend for increasing lung cancer risk with increasing chest x-ray profusion >0/0 was observed. With an profusion score <1/0, FEV1 /FVC <80% was associated with lung cancer risk. COPD risk increased with increasing profusion score. CONCLUSIONS: This study demonstrates asbestos-related diseases among workers with largely indirect exposures and an increased lung cancer risk with low ILO scores. PMID- 25712477 TI - Autophagy in malignant transformation and cancer progression. AB - Autophagy plays a key role in the maintenance of cellular homeostasis. In healthy cells, such a homeostatic activity constitutes a robust barrier against malignant transformation. Accordingly, many oncoproteins inhibit, and several oncosuppressor proteins promote, autophagy. Moreover, autophagy is required for optimal anticancer immunosurveillance. In neoplastic cells, however, autophagic responses constitute a means to cope with intracellular and environmental stress, thus favoring tumor progression. This implies that at least in some cases, oncogenesis proceeds along with a temporary inhibition of autophagy or a gain of molecular functions that antagonize its oncosuppressive activity. Here, we discuss the differential impact of autophagy on distinct phases of tumorigenesis and the implications of this concept for the use of autophagy modulators in cancer therapy. PMID- 25712484 TI - California measure would require porn actors to use condoms. PMID- 25712483 TI - Complete biosynthetic pathway of the C50 carotenoid bacterioruberin from lycopene in the extremely halophilic archaeon Haloarcula japonica. AB - Haloarcula japonica, an extremely halophilic archaeon that requires high concentrations of NaCl for growth, accumulates the C50 carotenoid bacterioruberin (BR). By homology analysis, a gene cluster, including c0507, c0506, and c0505, was found and predicted to be involved in the synthesis of bacterioruberin. To elucidate the function of the encoded enzymes, we constructed Ha. japonica mutants of these genes and analyzed carotenoids produced by the mutants. Our research showed that c0507, c0506, and c0505 encoded a carotenoid 3,4-desaturase (CrtD), a bifunctional lycopene elongase and 1,2-hydratase (LyeJ), and a C50 carotenoid 2",3"-hydratase (CruF), respectively. The above three carotenoid biosynthetic enzymes catalyze the reactions that convert lycopene to bacterioruberin in Ha. japonica. This is the first identification of functional CrtD and CruF in archaea and elucidation of the complete biosynthetic pathway of bacterioruberin from lycopene. IMPORTANCE: Haloarcula japonica, an extremely halophilic archaeon, accumulates the C50 carotenoid bacterioruberin (BR). In this study, we have identified three BR biosynthetic enzymes and have elucidated their functions. Among them, two enzymes were found in an archaeon for the first time. Our results revealed the biosynthetic pathway responsible for production of BR in Ha. japonica and provide a basis for investigating carotenoid biosynthetic pathways in other extremely halophilic archaea. Elucidation of the carotenoid biosynthetic pathway in Ha. japonica may also prove useful for producing the C50 carotenoid BR efficiently by employing genetically modified haloarchaeal strains. PMID- 25712485 TI - Cells for tissue engineering of cardiac valves. AB - Heart valve tissue engineering is a promising alternative to prostheses for the replacement of diseased or damaged heart valves, because tissue-engineered valves have the ability to remodel, regenerate and grow. To engineer heart valves, cells are harvested, seeded onto or into a three-dimensional (3D) matrix platform to generate a tissue-engineered construct in vitro, and then implanted into a patient's body. Successful engineering of heart valves requires a thorough understanding of the different types of cells that can be used to obtain the essential phenotypes that are expressed in native heart valves. This article reviews different cell types that have been used in heart valve engineering, cell sources for harvesting, phenotypic expression in constructs and suitability in heart valve tissue engineering. Natural and synthetic biomaterials that have been applied as scaffold systems or cell-delivery platforms are discussed with each cell type. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 25712486 TI - Successful rescue of stuck rotablator burr entrapment using a Kiwami straight catheter. AB - Rotational atherectomy is an indispensable modality for percutaneous coronary intervention of severely calcified lesions. An entrapped rotablator burr is a rare but life-threatening complication because retrieval is difficult. Although emergent surgical removal is a reliable option for this complication, it is invasive. There are various methods to retrieve an entrapped burr by bailout endovascular approaches. We present two cases of successful rescue of stuck rotablator burr entrapment using a Kiwami straight catheter (4 Fr, Heartrail II, Terumo, Tokyo, Japan). PMID- 25712487 TI - Nano-carrier systems: Strategies to overcome the mucus gel barrier. AB - The present review provides an overview of nanotechnology-based strategies to overcome various mucus gel barriers including the intestinal, nasal, ocular, vaginal, buccal and pulmonary mucus layer without destroying them. It focuses on the one hand on strategies to improve the mucus permeation behavior of particles and on the other hand on systems avoiding the back-diffusion of particles out of the mucus gel layer. Nanocarriers with improved mucus permeation behavior either exhibit a high density of positive and negative charges, bearing mucolytic enzymes such as papain and bromelain on their surface or display a slippery surface due to PEG-ylation. Furthermore, self-nanoemulsifying-drug-delivery systems (SNEDDS) turned out to exhibit comparatively high mucus permeating properties. Strategies in order to avoid back-diffusion are based on thiolated polymers reacting to a higher extent with cysteine subunits of the mucus at pH 7 in deeper mucus regions than at pH 5 being prevalent in luminal mucus regions of the intestinal and vaginal mucosa. Furthermore, particles changing their zeta potential from negative to positive once they have reached the epithelium seem to be promising carriers. The summarized knowledge should provide a good starting point for further developments in this field. PMID- 25712488 TI - Can risk and illness perceptions predict breast cancer worry in healthy women? AB - Predictors of breast cancer worry in healthy women remain unclear. Healthy women less than 50 years (N = 857) completed measures of family history, anxiety, absolute and comparative risk perceptions, illness perceptions, and breast cancer worry. Regression analyses revealed that having a family history of breast cancer, greater anxiety, higher absolute risk perceptions and negative illness perceptions predicted 45 per cent of the variance in breast cancer worry. Risk perceptions also partially mediated the relationship between illness perceptions and worry. This study provides novel evidence that both illness and risk perceptions are predictors of breast cancer worry in younger women from the community. PMID- 25712489 TI - Another look at depressive symptoms and antiretroviral therapy adherence: The role of treatment self-efficacy. AB - Depression has been strongly associated with poor HIV treatment adherence, but little research has explored how individuals manage to follow their regimens despite symptoms of major depression. Using a sample of antiretroviral therapy patients with clinically significant depressive symptoms (n = 84), we examined whether patients with optimal adherence differed from those with suboptimal adherence in terms of the types of depressive symptoms experienced and treatment self-efficacy. There were no significant differences between participants with regard to types of depressive symptoms. Findings indicate that patients with high treatment self-efficacy were more likely to report optimal levels of adherence than patients with low self-efficacy. PMID- 25712490 TI - Health behaviour mediates the relationship between Type D personality and subjective health in the general population. AB - Type D personality is associated with unhealthy behaviour and poor subjective health in the general population. This study investigated whether health behaviour mediates the relationship between Type D and subjective health. There were 217 participants who completed measures of Type D, health-related behaviour, physical symptoms and quality of life. Type D individuals reported significantly less healthy behaviour and significantly poorer subjective health than non-Type Ds. In addition, it was found that health behaviour partially mediates these relationships. The study demonstrates that health behaviour may partly explain the relationship between Type D and poor health outcomes. PMID- 25712491 TI - The Learning About My Pain study protocol: Reducing disparities with literacy adapted psychosocial treatments for chronic pain, a comparative behavioral trial. AB - Chronic pain is a critical public health problem that affects over 100 million Americans. Medical pain treatments carry undesirable side effects, whereas low risk psychosocial treatments offer notable benefits, in combination or in isolation. This report presents the protocol for the Learning About My Pain study, one of the first comparative-effectiveness trials funded by the Patient Centered Outcomes Research Institute. Adhering to published standards for clinical trials (e.g. Standard Protocol Items: Recommendations for Intervention Trials), it provides an overview of the trial (n = 294), comparing cognitive behavioral and education pain interventions to usual care, and a detailed description of how its methodology reduces the risks from bias. PMID- 25712492 TI - Graphene microelectrode arrays for neural activity detection. AB - We demonstrate a method to fabricate graphene microelectrode arrays (MEAs) using a simple and inexpensive method to solve the problem of opaque electrode positions in traditional MEAs, while keeping good biocompatibility. To study the interface differences between graphene-electrolyte and gold-electrolyte, graphene and gold electrodes with a large area were fabricated. According to the simulation results of electrochemical impedances, the gold-electrolyte interface can be described as a classical double-layer structure, while the graphene electrolyte interface can be explained by a modified double-layer theory. Furthermore, using graphene MEAs, we detected the neural activities of neurons dissociated from Wistar rats (embryonic day 18). The signal-to-noise ratio of the detected signal was 10.31 +/- 1.2, which is comparable to those of MEAs made with other materials. The long-term stability of the MEAs is demonstrated by comparing differences in Bode diagrams taken before and after cell culturing. PMID- 25712493 TI - Polyphenols as active ingredients for cosmetic products. AB - Polyphenols are secondary plant metabolites with antioxidant, anti-inflammatory and anti-microbial activity. They are ubiquitously distributed in the plant kingdom; high amounts contain, for example, green tea and grape seeds. Polyphenolic extracts are attractive ingredients for cosmetics and pharmacy due to their beneficial biological properties. This review summarizes the effects of polyphenols in the context of anti-ageing activity. We have explored in vitro studies, which investigate antioxidant activity, inhibition of dermal proteases and photoprotective activity, mostly studied using dermal fibroblasts or epidermal keratinocytes cell lines. Possible negative effects of polyphenols were also discussed. Further, some physicochemical aspects, namely the possible interactions with emulsifiers and the influence of the cosmetic formulation on the skin delivery, were reported. Finally, few clinical studies, which cover the anti-ageing action of polyphenols on the skin after topical application, were reviewed. PMID- 25712494 TI - A glimpse of public health in China. PMID- 25712495 TI - Inappropriate antibiotic prescribing and demand for antibiotics in patients with upper respiratory tract infections is hardly different in female versus male patients as seen in primary care. AB - BACKGROUND: Unnecessary prescribing of antibiotics is a major public health concern. General practitioners (GPs) prescribe most antibiotics, often for upper respiratory tract infections (URTIs), and have in general been shown to prescribe antibiotics more often to women. No studies have examined the influence of patient gender on unnecessary antibiotic prescribing. OBJECTIVES: To study a possible gender difference in unnecessary antibiotic prescriptions for URTIs in general practice; to assess whether a possible difference is explained by patient demand for antibiotics. METHODS: Post-hoc analysis of a cross-sectional study including 15,022 patients with URTI (acute rhinitis, acute otitis media, acute sinusitis, acute pharyngotonsillitis) from Argentina, Denmark, Lithuania, Russia, Spain and Sweden (HAPPY AUDIT Project). The association between gender and unnecessary antibiotic prescriptions, unadjusted and adjusted for treatment demand, was analysed using logistic regression models. RESULTS: A total of 25% of patients with URTI received antibiotics; in 45% of the cases, antibiotics were unnecessary. Overall, no gender difference for unnecessary prescribing of antibiotics for URTIs was found. Women with acute otitis media received an unnecessary antibiotic twice as often as men (14.4% versus 7.1%). In Danish patients with acute pharyngotonsillitis, there was a gender difference in unnecessary prescriptions for antibiotics (women 29.1% versus men 48.6%). Some 14% of patients receiving unnecessary antibiotics demonstrated a demand for antibiotics, but no gender difference was found in this group. CONCLUSION: This study indicated a high rate of unnecessary antibiotic prescribing for URTIs in general practice, but overall found no gender differences in receiving unnecessary antibiotic prescriptions. PMID- 25712496 TI - Effects of thoracic pressure changes on MRI signals in the brain. AB - Cerebrovascular stressors, such as breath holding or CO2 inhalation, cause global magnetic resonance imaging (MRI) signal changes. In this study, we show that intrathoracic pressure changes cause rapid MRI signal alterations that have similar spatial patterns to the changes associated with breath holding or CO2 inhalation. Nine subjects performed the Valsalva maneuver during functional MRI data collection. Expiratory pressures ranged from 10 to 40 mm Hg. Breath holds ending on either inhalation or exhalation were also collected. The maximal and minimal functional MRI (fMRI) signal scaled with thoracic pressure load, and the overall amplitude of responses to the Valsalva varied, depending on brain tissue. Additionally, a Valsalva effort as short as 5 seconds yielded signal changes similar in spatial distribution and magnitude to a 20-second breath hold, suggesting potential applications of the Valsalva maneuver for calibrated fMRI experiments. PMID- 25712497 TI - Sustained functional improvement by hepatocyte growth factor-like small molecule BB3 after focal cerebral ischemia in rats and mice. AB - Hepatocyte growth factor (HGF), efficacious in preclinical models of acute central nervous system injury, is burdened by administration of full-length proteins. A multiinstitutional consortium investigated the efficacy of BB3, a small molecule with HGF-like activity that crosses the blood-brain barrier in rodent focal ischemic stroke using Stroke Therapy Academic Industry Roundtable (STAIR) and Good Laboratory Practice guidelines. In rats, BB3, begun 6 hours after temporary middle cerebral artery occlusion (tMCAO) reperfusion, or permanent middle cerebral artery occlusion (pMCAO) onset, and continued for 14 days consistently improved long-term neurologic function independent of sex, age, or laboratory. BB3 had little effect on cerebral infarct size and no effect on blood pressure. BB3 increased HGF receptor c-Met phosphorylation and synaptophysin expression in penumbral tissue consistent with a neurorestorative mechanism from HGF-like activity. In mouse tMCAO, BB3 starting 10 minutes after reperfusion and continued for 14 days improved neurologic function that persisted for 8 weeks in some, but not all measures. Study in animals with comorbidities and those exposed to common stroke drugs are the next steps to complete preclinical assessment. These data, generated in independent, masked, and rigorously controlled settings, are the first to suggest that the HGF pathway can potentially be harnessed by BB3 for neurologic benefit after ischemic stroke. PMID- 25712498 TI - Chronic monitoring of vascular progression after ischemic stroke using multiexposure speckle imaging and two-photon fluorescence microscopy. AB - Monitoring the progression of the vascular structure and cerebral blood flow (CBF) after brain injury is vital to understand the neurovascular recovery process. Multiexposure speckle imaging (MESI) provides a quantitatively accurate technique for chronically measuring the postocclusion CBF perfusion of the infarct and peri-infarct regions in rodent stroke models, while multiphoton microscopy offers direct visualization of the microvascular structure. In this paper, we present imaging outcomes extending 35 days after photo-thrombotic occlusion, tracking the progression of the vasculature throughout this period. We compare MESI flow estimates within the unresolvable parenchyma with subsurface microvascular volume fractions taken with two-photon microscopy in the same regions to assess how the vascular density influences the surface-integrated MESI flow values. The MESI flow measurements and volume fractions are shown to have high correlations (r=0.90) within areas of recovering vasculature in the peri infarct region. We also observe vascular reorientation occurring within the microvascular structure throughout the 35-day postocclusion period. With the combination of a chronic mouse model and relatively noninvasive optical imaging techniques, we present an imaging protocol for monitoring long-term vascular progression after photo-thrombotic occlusion with the potential to test the efficacy of rehabilitation and pharmacological therapies. PMID- 25712499 TI - Hypoxia-induced neuroinflammatory white-matter injury reduced by minocycline in SHR/SP. AB - Hypertensive small vessel disease is a major cause of vascular cognitive impairment (VCI). Spontaneously hypertensive/stroke prone rats (SHR/SP) with unilateral carotid artery occlusion (UCAO) and a Japanese permissive diet (JPD) have white-matter (WM) damage similar to that seen in VCI. We hypothesized that WM injury was due to hypoxia-mediated, blood-brain barrier (BBB) disruption. Twelve-week-old SHR/SP had UCAO/JPD and were studied with immunohistochemistry, biochemistry, multimodal magnetic resonance imaging (MRI), and Morris water maze (MWM) testing. One week after UCAO/JPD, WM showed a significant increase in hypoxia inducible factor-1alpha (HIF-1alpha), which increased further by 3 weeks. Prolyl hydroxylase-2 (PHD2) expression decreased at 1 and 3 weeks. Infiltrating T cells and neutrophils appeared around endothelial cells from 1 to 3 weeks after UCAO/JPD, and matrix metalloproteinase-9 (MMP-9) colocalized with inflammatory cells. At 3 weeks, WM immunostained for IgG, indicating BBB leakage. Minocycline (50 mg/kg intraperitoneally) was given every other day from weeks 12 to 20. Multimodal MRI showed that treatment with minocycline significantly reduced lesion size and improved cerebral blood flow. Minocycline improved performance in the MWM and prolonged survival. We propose that BBB disruption occurred secondary to hypoxia, which induced an MMP-9-mediated infiltration of leukocytes. Minocycline significantly reduced WM damage, improved behavior, and prolonged life. PMID- 25712501 TI - Successful living domino liver transplantation in a child with protein C deficiency. AB - PC is produced in the liver and inhibits blood coagulation by catalyzing active factors V and VIII. PC deficiency causes abnormal blood clotting that is difficult to regulate by anticoagulative treatments. Four reports of PC deficiency treated with LTx have been published; however, no report of DLT as a therapy for PC deficiency is available. We describe a case of a 23-month-old girl who received DLT for compound heterozygous PC deficiency. Her PC activity was below 5%. She developed intracranial lesion and frequent refractory purpura fulminans. Both her parents had heterozygous mutations of PC genes and were excluded as living donors. Furthermore, she was a low priority on the waiting list of deceased-donor transplantation. We performed living DLT using the liver from a patient with MSUD. Activated PC concentrate safely supported the perioperative period. After DLT, she maintained normal PC activities and BCAA levels. This is the first case of PC deficiency successfully treated by living DLT with MSUD. We propose that DLT using liver from patients with MSUD is a treatment option for PC deficiency. PMID- 25712500 TI - Calibrated MRI to evaluate cerebral hemodynamics in patients with an internal carotid artery occlusion. AB - The purpose of this study was to assess whether calibrated magnetic resonance imaging (MRI) can identify regional variances in cerebral hemodynamics caused by vascular disease. For this, arterial spin labeling (ASL)/blood oxygen level dependent (BOLD) MRI was performed in 11 patients (65+/-7 years) and 14 controls (66+/-4 years). Cerebral blood flow (CBF), ASL cerebrovascular reactivity (CVR), BOLD CVR, oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen (CMRO2) were evaluated. The CBF was 34+/-5 and 36+/-11 mL/100 g per minute in the ipsilateral middle cerebral artery (MCA) territory of the patients and the controls. Arterial spin labeling CVR was 44+/-20 and 53+/-10% per 10 mm Hg ?EtCO2 in patients and controls. The BOLD CVR was lower in the patients compared with the controls (1.3+/-0.8 versus 2.2+/-0.4% per 10 mm Hg ?EtCO2, P<0.01). The OEF was 41+/-8% and 38+/-6%, and the CMRO2 was 116+/-39 and 111+/-40 MUmol/100 g per minute in the patients and the controls. The BOLD CVR was lower in the ipsilateral than in the contralateral MCA territory of the patients (1.2+/-0.6 versus 1.6+/-0.5% per 10 mmHg ?EtCO2, P<0.01). Analysis was hampered in three patients due to delayed arrival time. Thus, regional hemodynamic impairment was identified with calibrated MRI. Delayed arrival artifacts limited the interpretation of the images in some patients. PMID- 25712502 TI - Detection and Correction of Laterality Errors in Radiology Reports. AB - The objectives of the study are to introduce the development of supervising software for double-checking of laterality error in radiology reports and to evaluate the usefulness of detection and correction software by applying it to radiology report systems. An AutoHotkey macro program was applied to the design for double-checking of laterality errors. The software was performed according to the flowchart below: (1) detecting laterality discrepancies between radiologic examination names and the context of the radiology report and (2) providing conditioned discrepancy correction with a pop-up window. The accuracy of the detection was evaluated with 300 radiologic examinations that include the intended discrepancies and concordance of lateralities. The number of detections and corrections were quantified, and the confidence intervals were calculated for accuracy. We also applied this module to previous radiology reports with laterality errors from the radiologic examination database to validate the module. The AutoHotkey-scripted macro program functioned well in the reading workstation, and it was acted successfully as additional software. The detection accuracy was 99.67% (95% CI; 99.01-%) in the 300 radiologic examinations from the radiologic reading session. There was one running failure, caused by a temporary lag in the hospital's computer network, but no failures resulted during the second trial. We found that there were laterality errors in 0.048% (n = 14/29,257) of the examinations from the database. We developed detection and correction software aimed at double-checking for laterality errors. This method can be successfully adopted in any hospital software and is expected to be included for a better radiologic reading environment. PMID- 25712503 TI - An unusual case of penile non-pigmenting fixed drug eruption in a child. PMID- 25712504 TI - Natural-cause mortality and long-term exposure to particle components: an analysis of 19 European cohorts within the multi-center ESCAPE project. AB - BACKGROUND: Studies have shown associations between mortality and long-term exposure to particulate matter air pollution. Few cohort studies have estimated the effects of the elemental composition of particulate matter on mortality. OBJECTIVES: Our aim was to study the association between natural-cause mortality and long-term exposure to elemental components of particulate matter. METHODS: Mortality and confounder data from 19 European cohort studies were used. Residential exposure to eight a priori-selected components of particulate matter (PM) was characterized following a strictly standardized protocol. Annual average concentrations of copper, iron, potassium, nickel, sulfur, silicon, vanadium, and zinc within PM size fractions <= 2.5 MUm (PM2.5) and <= 10 MUm (PM10) were estimated using land-use regression models. Cohort-specific statistical analyses of the associations between mortality and air pollution were conducted using Cox proportional hazards models using a common protocol followed by meta-analysis. RESULTS: The total study population consisted of 291,816 participants, of whom 25,466 died from a natural cause during follow-up (average time of follow-up, 14.3 years). Hazard ratios were positive for almost all elements and statistically significant for PM2.5 sulfur (1.14; 95% CI: 1.06, 1.23 per 200 ng/m3). In a two-pollutant model, the association with PM2.5 sulfur was robust to adjustment for PM2.5 mass, whereas the association with PM2.5 mass was reduced. CONCLUSIONS: Long-term exposure to PM2.5 sulfur was associated with natural-cause mortality. This association was robust to adjustment for other pollutants and PM2.5. PMID- 25712505 TI - Early memory in the parasitoid wasp Nasonia vitripennis. AB - We studied early memory in Nasonia vitripennis, a parasitoid of fly pupae and emerging model organism for ecological questions in the context of learning. After associative training consisting of one drilling experience in a host in the presence of cinnamon, females showed a preference to cinnamon for at least 24 h. To study sensitisation, wasps were trained by one drilling in a host without cinnamon. These wasps were not attracted to cinnamon immediately afterwards. Obviously, sensitisation is not involved in early memory. Wasps that were anaesthetised by CO2 directly after associative training did not react to cinnamon 30-45 min later, but after 1 and 24 h. CO2 treatment>=5 min after training did not erase the reaction to cinnamon. This indicates the existence of four early memory phases. (a) One phase<5 min after training, in which CO2 has to be applied to become effective. (b) One subsequent phase which is resistant to CO2. (c) One phase<1 h in which memory can be erased by CO2 treatment directly after training. (d) One phase 1-24 h not affected by CO2 treatment. Together with earlier data this enables us to establish a complete memory structure for N. vitripennis. PMID- 25712506 TI - To know or not to know? Integrating ethical aspects of genomic healthcare in the education of health professionals. AB - Novel possibilities for employing genetic testing as part of the diagnostic process for a wide variety of diseases and conditions are emerging almost every day. This development brings prospects of more efficient treatment and prevention of serious and often lethal conditions. However, it also raises ethical questions concerning the issue of knowing or not knowing about our genetic make-up. Thus, as techniques for genetic testing are increasingly employed, demands on health professionals are changing. Health professionals must be able to inform and guide patients, and therefore they need knowledge and competencies related to both the technical and the ethical dimensions of genetic testing. This paper explores the requirements of the general education of health professionals if this need for ethics is acknowledged. It is suggested that it is important to include both an individualised and a societal ethical perspective to the development of genomic healthcare and that a key concept in doing so is 'professional reflectivity'. Employing one concrete example of teaching, this concept of reflectivity is operationalised in the health educational setting at the bachelor's level with a special focus on biomedical laboratory science, and three key concepts are developed: Gap sensitive interaction, professional humility, and contextual awareness. Additionally, anchored ethical dialog is explored as an instructional design that may support the development of reflectivity among health professionals. PMID- 25712507 TI - Some 'ant'swers: Application of a layered barcode approach to problems in ant taxonomy. AB - DNA barcoding has emerged as a routine tool in modern taxonomy. Although straightforward, this approach faces new challenges, when applied to difficult situation such as defining cryptic biodiversity. Ants are prime examples for high degrees of cryptic biodiversity due to complex population differentiation, hybridization and speciation processes. Here, we test the DNA barcoding region, cytochrome c oxidase 1 and two supplementary markers, 28S ribosomal DNA and long wavelength rhodopsin, commonly used in ant taxonomy, for their potential in a layered, character-based barcoding approach across different taxonomic levels. Furthermore, we assess performance of the character-based barcoding approach to determine cryptic species diversity in ants. We found (i) that the barcode potential of a specific genetic marker varied widely among taxonomic levels in ants; (ii) that application of a layered, character-based barcode for identification of specimens can be a solution to taxonomical challenging groups; (iii) that the character-based barcoding approach allows us to differentiate specimens even within locations based on pure characters. In summary, (layered) character-based barcoding offers a reliable alternative for problematic species identification in ants and can be used as a fast and cost-efficient approach to estimate presence, absence or frequency of cryptic species. PMID- 25712508 TI - Andrographolide derivative AL-1 improves insulin resistance through down regulation of NF-kappaB signalling pathway. AB - BACKGROUND AND PURPOSE: Andrographolide is the most active constituent of the medicinal plant Andrographis paniculata. Previously, we synthesized a novel andrographolide derivative AL-1, conjugating andrographolide with lipoic acid. Although the antioxidative and/or anti-inflammatory activity of AL-1 contributes to its cytoprotective effects, whether AL-1 can improve insulin resistance and the mechanisms responsible for its action have not been elucidated. EXPERIMENTAL APPROACH: We investigated the anti-hyperlipidaemic and anti-hyperglycaemic effects of AL-1 in a high-fat diet/streptozocin-induced animal diabetic model. In addition, we investigated the effect of AL-1 on the NF-kappaB signalling pathway in rat islet derived insulinoma cells (RIN-m cells) with a focus on the link between reactive oxygen species-associated inflammation and insulin resistance. KEY RESULTS: AL-1, at doses of 40 and 80 mg . kg(-1), had a significant hypoglycaemic effect; it significantly reduced the level of cholesterol and increased HDL. AL-1 also reduced the homeostasis model assessment of insulin resistance and enhanced insulin sensitivity. In addition, AL-1 improved the morphology of pancreatic islets and their function. Furthermore, AL-1 suppressed high glucose-induced phosphorylation of p65 and IkappaBalpha in RIN-m cells. CONCLUSION AND IMPLICATIONS: AL-1 has a hypoglycaemic effect and improves insulin resistance in type 2 diabetic rats. It protected islet from high glucose-induced oxidative damage by down-regulating the NF-kappaB signalling pathway. Further investigations of AL-1 as a promising new agent for treatment and/or prevention of diabetes are warranted. PMID- 25712509 TI - Reply to Wilms tumor and breast cancer. PMID- 25712510 TI - The improved electrochemical performance of cross-linked 3D graphene nanoribbon monolith electrodes. AB - Technical advancement in the field of ultra-small sensors and devices demands the development of novel micro- or nano-based architectures. Here we report the design and assembly of cross-linked three dimensional graphene nanoribbons (3D GNRs) using solution based covalent binding of individual 2D GNRs and demonstrate its electrochemical application as a 3D electrode. The enhanced performance of 3D GNRs over individual 2D GNRs is established using standard redox probes- [Ru(NH3)6](3+/2+), [Fe(CN)6](3-/4-) and important bio-analytes--dopamine and ascorbic acid. 3D GNRs are found to have high double layer capacitance (2482 MUF cm(-2)) and faster electron transfer kinetics; their exceptional electrocatalytic activity towards the oxygen reduction reaction is indicative of their potential over a wide range of electrochemical applications. Moreover, this study opens a new platform for the design of novel point-of-care devices and electrodes for energy devices. PMID- 25712511 TI - Immunolocalization of the telomerase-1 component in cells of the regenerating tail, testis, and intestine of lizards. AB - Using an antibody against a lizard telomerase-1 component the presence of telomerase has been detected in regenerating lizard tails where numerous cells are proliferating. Immunoblots showed telomerase positive bands at 75-80 kDa in normal tissues and at 50, 75, and 90 kDa in those regenerating. Immunofluorescence and ultrastructural immunolocalization showed telomerase immunoreactivity in sparCe (few/diluted) mesenchymal cells of the blastema, early regenerating muscles, perichondrium of the cartilaginous tube, ependyma of the spinal cord, and in the regenerating epidermis. Clusters of gold particles were detected in condensing chromosomes of few mesenchymal and epithelial cells in the regenerating tail, but a low to undetectable labeling in interphase cells. Telomerase-immunoreactivity was intense in the nucleus and sparCe (few/diluted) in the cytoplasm of spermatogonia and spermatocytes and drastically decreased in early spermatids where some nuclear labeling remains. Some intense immunoreactivity was seen in few cells near the basal membrane of intestinal enterocytes or in leukocytes (likely lymphocytes) of the intestine mucosa. In spermatogonia, spermatids and in enterocytes part of the nuclear labeling formed cluster of gold particles in dense areas identified as Cajal Bodies, suggesting that telomerase is a marker for these stem cells. This therefore suggests that also the sparCe (few/diluted) telomerase positive cells detected in the regenerating tail may represent sparCe (few/diluted) stem cells localized in regenerating tissues where transit amplifying cells are instead preponderant to allow for tail growth. This observation supports previous studies indicating that few stem cells are present in the stump after tail amputation and give rise to transit amplifying cells for tail regeneration. PMID- 25712512 TI - Allergic bronchopulmonary aspergillosis in children. AB - Allergic bronchopulmonary aspergillosis (ABPA) is a disease of the lungs resulting from a hypersensitivity reaction to spores of Aspergillus fumigatus. Here we report the case of a 13-year-old girl with ABPA who presented with productive cough, bronchiectasis and decline in lung function, and review the clinical features and treatment for pediatric ABPA. PMID- 25712513 TI - An ensemble-averaged, cell density-based digital model of zebrafish embryo development derived from light-sheet microscopy data with single-cell resolution. AB - A new era in developmental biology has been ushered in by recent advances in the quantitative imaging of all-cell morphogenesis in living organisms. Here we have developed a light-sheet fluorescence microscopy-based framework with single-cell resolution for identification and characterization of subtle phenotypical changes of millimeter-sized organisms. Such a comparative study requires analyses of entire ensembles to be able to distinguish sample-to-sample variations from definitive phenotypical changes. We present a kinetic digital model of zebrafish embryos up to 16 h of development. The model is based on the precise overlay and averaging of data taken on multiple individuals and describes the cell density and its migration direction at every point in time. Quantitative metrics for multi-sample comparative studies have been introduced to analyze developmental variations within the ensemble. The digital model may serve as a canvas on which the behavior of cellular subpopulations can be studied. As an example, we have investigated cellular rearrangements during germ layer formation at the onset of gastrulation. A comparison of the one-eyed pinhead (oep) mutant with the digital model of the wild-type embryo reveals its abnormal development at the onset of gastrulation, many hours before changes are obvious to the eye. PMID- 25712514 TI - Association between hand-grip strength and depressive symptoms: Locomotive Syndrome and Health Outcomes in Aizu Cohort Study (LOHAS). AB - BACKGROUND: no study has examined the longitudinal association between hand-grip strength and mental health, such as depressive symptoms. OBJECTIVE: we investigated the relationship between baseline hand-grip strength and the risk of depressive symptoms. DESIGN: a prospective cohort study. SETTING AND SUBJECTS: a prospective cohort study with a 1-year follow-up was conducted using 4,314 subjects from community-dwelling individuals aged 40-79 years in two Japanese municipalities, based on the Locomotive Syndrome and Health Outcomes in Aizu Cohort Study (LOHAS, 2008-10). METHODS: we assessed baseline hand-grip strength standardised using national representative data classified by age and gender, and depressive symptoms at baseline and after the follow-up using the five-item version of the Mental Health Inventory (MHI-5). RESULTS: the 4,314 subjects had a mean age of 66.3 years, 58.5% were women, and mean unadjusted hand-grip strength was 29.8 kg. Multivariable random-effect logistic regression analysis revealed that subjects with lower hand-grip strength (per 1SD decrease) had higher odds of having depressive symptoms at baseline [adjusted odds ratio (AOR) 1.15, 95% confidence interval (CI) 1.06-1.24; P = 0.001]. Further, lower hand-grip strength (per 1SD decrease) was associated with the longitudinal development of depressive symptoms after 1 year (AOR 1.13, 95% CI 1.01-1.27; P = 0.036). CONCLUSIONS: using a large population-based sample, our results suggest that lower hand-grip strength, standardised using age and gender, is both cross-sectionally and longitudinally associated with depressive symptoms. PMID- 25712515 TI - A Patient Reported Experience Measure (PREM) for use by older people in community services. AB - BACKGROUND: intermediate care (IC) services operate between health and social care and are an essential component of integrated care for older people. Patient Reported Experience Measures (PREMs) offer an objective measure of user experience and a practical way to measure person-centred, integrated care in IC settings. OBJECTIVE: to describe the development of PREMs suitable for use in IC services and to examine their feasibility, acceptability and scaling properties. SETTING: 131 bed-based and 143 home-based or re-ablement IC services in England. METHODS: PREMs for each of home- and bed-based IC services were developed through consensus. These were incorporated into the 2013 NAIC and distributed to 50 consecutive users of each bed-based and 250 users of each home-based service. Return rates and patterns of missing data were examined. Scaling properties of the PREMs were examined with Mokken analysis. RESULTS: 1,832 responses were received from users of bed-based and 4,627 from home-based services (return rates 28 and 13%, respectively). Missing data were infrequent. Mokken analysis of completed bed-based PREMs (1,398) revealed 8 items measuring the same construct and forming a medium strength (Loevinger H 0.44) scale with acceptable reliability (rho = 0.76). Analysis of completed home-based PREMs (3,392 records) revealed a medium-strength scale of 12 items (Loevinger H 0.41) with acceptable reliability (rho = 0.81). CONCLUSIONS: the two PREMs offer a method to evaluate user experience of both bed- and home-based IC services. Each scale measures a single construct with moderate scaling properties, allowing summation of scores to give an overall measure of experience. PMID- 25712516 TI - AF is associated with self-reported syncope and falls in a general population cohort. AB - BACKGROUND: syncope is an important, but underestimated clinical problem in older persons. It is often overlooked in clinical practice or mistaken for falls. Atrial fibrillation (AF) is the most common cardiac arrhythmia, but little evidence exists regarding the association between AF, falls and syncope in the general population. METHODS: cross-sectional analyses within a population sample of people aged 50+, taken from The Irish Longitudinal Study on Ageing. Ten-minute electrocardiogram recordings (n = 4,885) were analysed to detect AF. Syncope (self-reported faints or blackouts) and falls in the past year, co-morbidities, health measures and medications were gathered through computer-aided personal interviews. Multivariable logistic regression was performed to study associations between AF, falls and syncope. RESULTS: mean age was 62 years (range: 50-91), 54% were female. Prevalence of AF was 3%, increasing to 8% in participants aged 75+. Of participants, 5% (n = 223) reported syncope and 20% (n = 972) reported falls. After adjustment for confounders, AF was significantly associated with faints and blackouts (odds ratio (OR) 2.0 [95% confidence interval (CI) 1.0-3.9]). After stratification by age category, we found that this association was strongest and only significant in participants aged 50-64 years (OR 4.4 [1.5-12.6]). Stratified for age group, AF was significantly associated with falls in participants aged 65 74 years (OR 2.0 [1.0-4.1]). CONCLUSIONS: adults aged 50+ with self-reported syncope and adults aged 65-74 years with falls are twice as likely to have AF at physical examination. These associations are independent of stroke, cardiovascular and psychotropic drugs and other confounders. Further longitudinal studies are needed to explore this association and potential causality further. PMID- 25712517 TI - Obesity and dissociable forms of impulsivity in young adults. AB - OBJECTIVE: Obesity is one of the leading causes of preventable morbidity and mortality, and young people are increasingly affected. The aim of this study was to examine relationships between obesity and dissociable forms of impulsivity in young adults. METHODS: A group of young adults (511) was recruited from city areas in the United States using media advertisements. These young adults were administered careful and extensive clinical and neurocognitive assessment in order to quantify different aspects of impulsivity (behavioral/phenomenological-, cognitive-, and personality-related measures). Associations between obesity and impulsivity were explored using multivariate analysis of variance and discriminant function analysis. RESULTS: 10.8% of the sample was obese, and 21.5% was overweight. Compared to controls, subjects with obesity showed significantly elevated rates of maladaptive gambling behaviors, monetary amounts lost to gambling, nicotine consumption, impulsive action (prolonged stop-signal reaction times in the Stop-Signal Test), and impulsive decision-making (reduced modulation of behavior as a function of risk in the Cambridge Gamble Test). Even accounting for potential confounding variables, obesity was significantly predicted by female gender, older age, more maladaptive gambling behaviors, and worse inhibitory control (stop-signal reaction times). CONCLUSION: Obesity is associated with several dissociable forms of impulsivity in young people, especially gambling and impulse dyscontrol. Family doctors should screen for gambling problems in obese young adults. Successful treatment of nicotine dependence in young obese people is likely to require intensive weight management support. Neuropsychological deficits relating to impulsivity occur in obese people in early adulthood, and may represent vulnerability markers rather than being due to chronic untoward metabolic effects on brain function. PMID- 25712518 TI - Toxoplasma gondii: biochemical and biophysical characterization of recombinant soluble dense granule proteins GRA2 and GRA6. AB - The most prominent structural feature of the parasitophorous vacuole (PV) in which the intracellular parasite Toxoplasma gondii proliferates is a membranous nanotubular network (MNN), which interconnects the parasites and the PV membrane. The MNN function remains unclear. The GRA2 and GRA6 proteins secreted from the parasite dense granules into the PV have been implicated in the MNN biogenesis. Amphipathic alpha-helices (AAHs) predicted in GRA2 and an alpha-helical hydrophobic domain predicted in GRA6 have been proposed to be responsible for their membrane association, thereby potentially molding the MMN in its structure. Here we report an analysis of the recombinant proteins (expressed in detergent free conditions) by circular dichroism, which showed that full length GRA2 displays an alpha-helical secondary structure while recombinant GRA6 and GRA2 truncated of its AAHs are mainly random coiled. Dynamic light scattering and transmission electron microscopy showed that recombinant GRA6 and truncated GRA2 constitute a homogenous population of small particles (6-8 nm in diameter) while recombinant GRA2 corresponds to 2 populations of particles (~8-15 nm and up to 40 nm in diameter, respectively). The unusual properties of GRA2 due to its AAHs are discussed. PMID- 25712519 TI - FGF21 attenuates pathological myocardial remodeling following myocardial infarction through the adiponectin-dependent mechanism. AB - Ischemic heart disease is one of the leading causes of death. Fibroblast growth factor 21 (FGF21) is a circulating factor with an anti-diabetic property. Skeletal muscle is an important source of FGF21 production. Here, we investigated whether skeletal muscle-derived FGF21 modulates cardiac remodeling in a murine model of myocardial infarction. Myocardial infarction was produced in C57BL/6J wild-type (WT) mice by the permanent ligation of the left anterior descending coronary artery (LAD). Adenoviral vectors expressing FGF21 (Ad-FGF21) or control beta-galactosidase were intramuscularly injected into mice at 3 days before permanent LAD ligation. Intramuscular injection of Ad-FGF21 increased plasma FGF21 levels in WT mice compared with control. Treatment of WT mice with Ad-FGF21 led to improvement of left ventricular systolic dysfunction and dilatation at 2 weeks after LAD ligation. Ad-FGF21 administration to WT mice also led to enhancement of capillary density in the infarct border zone, and reduction of myocyte apoptosis in the remote zone, which were accompanied by decreased expression of pro-inflammatory cytokines. Furthermore, treatment of WT mice with Ad-FGF21 increased plasma levels of adiponectin, which is a cardioprotective adipokine. The beneficial effects of Ad-FGF21 on cardiac dysfunction and inflammatory response after myocardial infarction were diminished in adiponectin knockout mice. These data suggest that muscle-derived FGF21 ameliorates adverse cardiac remodeling after myocardial infarction, at least in part, through an adiponectin-dependent mechanism. PMID- 25712520 TI - Cardiomyocyte lipotoxicity is mediated by Il-6 and causes down-regulation of PPARs. AB - Here we sought to evaluate the effect of palmitate on cytokine and PPAR activity/expression. We investigated the effect of BSA conjugated palmitate and oleate on PPAR activity, PPAR-alpha and delta expression, as well as the expression of cytokines and key factors responsible for beta-oxidation by qRT-PCR and western blotting in primary rat neonatal cardiomyocytes (NCMs). Furthermore we evaluated the effect of anti-inflammatory actions of AICAR and PPAR agonists on cytokine expression and cell death in palmitate treated NCMs. We found that palmitate caused down regulation of PPARs and increased cytokine expression and cell death, all of which was significantly attenuated by the co-administration of either AICAR or PPAR agonists. This work supports the pro-inflammatory actions of intracellular lipid and provides further insight into the pathological mechanism of cardiac lipotoxicity as occurs in diabetic hearts. PMID- 25712521 TI - Atorvastatin prevents angiotensin II-induced high permeability of human arterial endothelial cell monolayers via ROCK signaling pathway. AB - Intracranial aneurysm, as a common cause of cerebral hemorrhage, is often discovered when the aneurysm ruptures, causing subarachnoid hemorrhage. Unfortunately, the formation of cerebral aneurysm, which is associated with endothelial damage and macrophage migration, still cannot be prevented now. Tight junctions (TJs) open due to the disappearance of TJ proteins occludin and zona occludens-1 (ZO-1) in damaged endothelia, thus allowing macrophage migration and forming cerebral aneurysm. Therefore, cerebral aneurysm formation can be prevented by increasing TJs of the artery endothelium. Interestingly, statin, which can reduce saccular aneurysm, may prevent aneurysm formation through acting on different steps, but the underlying mechanism remains unclear. In this study, angiotensin II (Ang II) significantly increased the permeability of human arterial endothelial cell (HAEC). Moreover, the distribution of ZO-1 in cell-cell junction area and the total expression in HAECs were significantly decreased by Ang II treatment. However, the abnormal distribution and decreased expression of ZO-1 and hyperpermeability of HAECs were significantly reversed by pretreatment with atorvastatin. Furthermore, Ang II-induced phosphorylations of MYPT1, LIMK and MLC2 were significantly inhibited with atorvastatin or Rho kinase (ROCK) inhibitor (H1152) pretreatment. Knockdown of ROCK-II probably abolished Ang II induced abnormal ZO-1 distribution and expression deficiency and hyperpermeability of HAECs. In conclusion, atorvastatin prevented Ang II-induced rupture of HAEC monolayers by suppressing the ROCK signaling pathway. Our results may explain, at least in part, some beneficial effects of statins on cardiovascular diseases such as intracranial aneurysm. PMID- 25712522 TI - 1,25-(OH)2-vitamin D3 prevents activation of hepatic stellate cells in vitro and ameliorates inflammatory liver damage but not fibrosis in the Abcb4(-/-) model. AB - BACKGROUND/PURPOSE OF THE STUDY: Vitamin D3-deficiency is common in patients with chronic liver-disease and may promote disease progression. Vitamin D3 administration has thus been proposed as a therapeutic approach. Vitamin D3 has immunomodulatory effects and may modulate autoimmune liver-disease such as primary sclerosing cholangitis. Although various mechanisms of action have been proposed, experimental evidence is limited. Here we test the hypothesis that active 1,25-(OH)2-vitamin D3 inhibits activation of hepatic stellate cells (HSC) in vitro and modulates liver-injury in vivo. METHODS: Proliferation and activation of primary murine HSC were assessed by BrdU- and PicoGreen((r)) assays, immunoblotting, immunofluorescence-microscopy, quantitative-PCR, and zymography following calcitriol-treatment. Wild-type and ATP-binding cassette transporter b4(-/-) (Abcb4(-/-))-mice received calcitriol for 4 weeks. Liver damage, inflammation, and fibrosis were assessed by serum liver-tests, Sirius-red staining, quantitative-PCR, immunoblotting, immunohistochemistry and hydroxyproline quantification. RESULTS: In vitro, calcitriol inhibited activation and proliferation of murine HSC as shown by reduced alpha-smooth muscle actin and platelet-derived growth factor-receptor-beta-protein-levels, BrdU and PicoGreen(r)-assays. Furthermore, mRNA-levels and activity of matrix metalloproteinase 13 were profoundly increased. In vivo, calcitriol ameliorated inflammatory liver-injury reflected by reduced levels of alanine aminotransferase in Abcb4(-/-)-mice. In accordance, their livers had lower mRNA-levels of F4/80, tumor necrosis factor-receptor 1 and a lower count of portal CD11b positive cells. In contrast, no effect on overall fibrosis was observed. CONCLUSION: Calcitriol inhibits activation and proliferation of HSCs in vitro. In Abcb4(-/-) mice, administration of calcitriol ameliorates inflammatory liver-damage but has no effect on biliary fibrosis after 4 weeks of treatment. PMID- 25712523 TI - Quadruplex forming promoter region of c-myc oncogene as a potential target for a telomerase inhibitory plant alkaloid, chelerythrine. AB - Guanine rich sequences present in the promoter region of oncogenes could fold into G-quadruplexes and modulate transcription. Equilibrium between folding and unfolding of the quadruplexes in these regions play important role in disease processes. We have studied the effect of a putative anticancer agent chelerythrine on G-rich NHE III1 present in the promoter region of c-myc oncogene. We have demonstrated the ability of chelerythrine, a telomerase inhibitor, to block the hybridization of Pu27 with its complementary strand via folding it into a quadruplex structure. Calorimetry shows that the association of Pu27 with chelerythrine is primarily enthalpy driven with high binding affinity (~10(5) M(-1)). The association does not lead to any major structural perturbation of Pu27. The resulting 2:1 complex has enhanced stability as compared to free Pu27. Another notable feature is that the presence of molecular crowding agent like ficoll 70 does not change the mode of recognition though the binding affinity decreases. We suggest that the anticancer activity of chelerythrine could be ascribed to its ability to stabilize the quadruplex structure in the c-myc promoter region thereby downregulating its transcription. PMID- 25712524 TI - GPR30 decreases cardiac chymase/angiotensin II by inhibiting local mast cell number. AB - Chronic activation of the novel estrogen receptor GPR30 by its agonist G1 mitigates the adverse effects of estrogen (E2) loss on cardiac structure and function. Using the ovariectomized (OVX) mRen2.Lewis rat, an E2-sensitive model of diastolic dysfunction, we found that E2 status is inversely correlated with local cardiac angiotensin II (Ang II) levels, likely via Ang I/chymase-mediated production. Since chymase is released from cardiac mast cells during stress (e.g., volume/pressure overload, inflammation), we hypothesized that GPR30 related cardioprotection after E2 loss might occur through its opposing actions on cardiac mast cell proliferation and chymase production. Using real-time quantitative PCR, immunohistochemistry, and immunoblot analysis, we found mast cell number, chymase expression, and cardiac Ang II levels were significantly increased in the hearts of OVX-compared to ovary-intact mRen2.Lewis rats and the GPR30 agonist G1 (50 mg/kg/day, s.c.) administered for 2 weeks limited the adverse effects of estrogen loss. In vitro studies revealed that GPR30 receptors are expressed in the RBL-2H3 mast cell line and G1 inhibits serum-induced cell proliferation in a dose-dependent manner, as determined by cell counting, BrdU incorporation assay, and Ki-67 staining. Using specific antagonists to estrogen receptors, blockage of GPR30, but not ERalpha or ERbeta, attenuated the inhibitory effects of estrogen on BrdU incorporation in RBL-2H3 cells. Further study of the mechanism underlying the effect on cell proliferation showed that G1 inhibits cyclin-dependent kinase 1 (CDK1) mRNA and protein expression in RBL-2H3 cells in a dose-dependent manner. PMID- 25712525 TI - Zinc preconditioning protects against neuronal apoptosis through the mitogen activated protein kinase-mediated induction of heat shock protein 70. AB - During brain ischemic preconditioning (PC), mild bursts of ischemia render neurons resistant to subsequent strong ischemic injuries. Previously, we reported that zinc plays a key role in PC-induced neuroprotection in vitro and in vivo. Zinc-triggered p75(NTR) induction transiently activates caspase-3, which cleaves poly(ADP-ribose) polymerase-1 (PARP-1). Subsequently, the PARP-1 over-activation induced depletion of nicotinamide adenine dinucleotide (NAD(+))/adenosine triphosphate (ATP) after exposures to lethal doses of zinc or N-methyl-D aspartate is significantly attenuated in cortical neuronal cultures. In the present study, zinc-mediated preconditioning (Zn PC) reduced apoptotic neuronal death that was caused by N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN), etoposide, or staurosporine in mouse cortical cells. We focused on heat shock protein 70 (HSP70) because NAD(+)/ATP depletion does not directly cause apoptosis, and HSP70 can inhibit the activation of caspase-9 or caspase-3 by preventing apoptosome formation or cytochrome C release. Zn PC-mediated HSP70 induction was required for neuroprotection against neuronal apoptosis, and geldanamycin-induced HSP70 induction sufficiently blocked neuronal apoptotic cell death. Furthermore, Zn PC-mediated HSP70 induction was blocked by chemical inhibitors of extracellular signal-regulated kinase (ERK) or p38 mitogen activated protein kinase (MAPK) signaling, but not c-Jun N-terminal protein kinase. Similarly, neuroprotection by Zn PC against TPEN-induced apoptosis was almost completely reversed by the blockade of ERK or p38 MAPK signaling. Our findings suggest that the ERK- or p38 MAPK-mediated induction of HSP70 plays a key role in inhibiting caspase-3 activation during Zn PC. PMID- 25712526 TI - MiRNA-30a-mediated autophagy inhibition sensitizes renal cell carcinoma cells to sorafenib. AB - Chemotherapy-induced autophagy activation often contributes to cancer resistance. MiRNA-30a (miR-30a) is a potent inhibitor of autophagy by downregulating Beclin 1. In this study, we characterized the role of miR-30a in sorafenib-induced activity in renal cell carcinoma (RCC) cells. We found that expression of miR-30a was significantly downregulated in several human RCC tissues and in RCC cell lines. Accordingly, its targeted gene Beclin-1 was upregulated. Sorafenib activated autophagy in RCC cells (786-0 and A489 lines), evidenced by p62 degradation, Beclin-1/autophagy protein 5 (ATG-5) upregulation and light chain (LC)3B-I/-II conversion. Exogenously expressing miR-30a in 786-0 or A489 cells inhibited Beclin-1 expression and enhanced sorafenib-induced cytotoxicity. In contrast, knockdown of miR-30a by introducing antagomiR-30a increased Beclin-1 expression, and inhibited sorafenib-induced cytotoxicity against RCC cells. Autophagy inhibitors, including chloroquine, 3-methyaldenine or Bafliomycin A1, enhanced sorafenib activity, causing substantial cell apoptosis. Meanwhile, knockdown of Beclin-1 or ATG-5 by targeted siRNAs also increased sorafenib induced cytotoxicity in above RCC cells. These findings indicate that dysregulation of miR-30a in RCC may interfere with the effectiveness of sorafenib mediated apoptosis by an autophagy-dependent pathway, thus representing a novel potential therapeutic target for RCC. PMID- 25712527 TI - Biophysical characterization of interactions between the C-termini of peripheral nerve claudins and the PDZ1 domain of zonula occludens. AB - Our recent study has shown that cellular junctions in myelin and in the epi /perineruium that encase nerve fibers regulate the permeability of the peripheral nerves. This permeability may affect propagation of the action potential. Direct interactions between the PDZ1 domain of zonula occludens (ZO1 or ZO2) and the C termini of claudins are known to be crucial for the formation of tight junctions. Using the purified PDZ1 domain of ZO2 and a variety of C-terminal mutants of peripheral nerve claudins (claudin-1, claudin-2, claudin-3, claudin-5 in epi /perineurium; claudin-19 in myelin), we have utilized NMR spectroscopy to determine specific roles of the 3 C-terminal claudin residues (position -2, -1, 0) for their interactions with PDZ1 of ZO2. In contrast to the canonical model that emphasizes the importance of residues at the -2 and 0 positions, our results demonstrate that, for peripheral nerve claudins, the residue at position -1 plays a critical role in association with PDZ1, while the side-chain of residue 0 plays a significant but lesser role. Surprisingly, claudin-19, the most abundant claudin in myelin, exhibited no binding to ZO2. These findings reveal that the binding mechanism of claudin/ZO in epi-/perineurium is distinct from the canonical interactions between non-ZO PDZ-containing proteins with their ligands. This observation provides the molecular basis for a strategy to develop drugs that target tight junctions in the epi-/perineurium of peripheral nerves. PMID- 25712528 TI - SUMO modification regulates the protein stability of NDRG1. AB - N-myc Downstream Regulated Gene 1 (NDRG1) is a metastasis suppressor protein which suppresses metastasis without affecting primary tumorigenesis. There have been many reports about the anti-metastatic function of NDRG1 in various cancers. However, the regulatory mechanism of NDRG1 at the protein level has not been studied widely. Here, we found that NDRG1 is posttranslationally modified by Small Ubiquitin-like Modifier (SUMO), preferentially by SUMO-2, and the major SUMO acceptor site of NDRG1 is Lys 14. Using various SUMO-2 modification status mimicking NDRG1 mutants, we characterized the role of SUMO-2 modification on NDRG1. SUMO-2 modification does not affect the subcellular distribution of NDRG1. However, the protein stability of NDRG1 is influenced by SUMO-2 modification. We found that both the wildtype and the SUMO modification site mutant form of the NDRG1 protein were very stable but the protein stability of SUMO-2 fused NDRG1 K14R had dramatically decreased. In addition, the expression of p21 is downregulated by overexpression of SUMO-2 fused NDRG1 K14R mutants. These results indicate that SUMO-2 modification is implicated in the modulation of NDRG1 protein level and function. This novel link between SUMO modification and regulation of NDRG1 could be a therapeutic target for treatment of various metastatic cancers. PMID- 25712529 TI - Kinetics of benzophenone ketyl free radicals recombination in a polymer: reactivity in the polymer cage vs. reactivity in the polymer bulk. AB - The decay kinetics of intermediates produced under photolysis of benzophenone (B) dissolved in soft rubber poly(ethylene-co-butylene) films (abbreviated as E) was studied by ns laser flash photolysis in the temperature range of 263-313 K. We monitored decay kinetics of the triplet state of (3)B* and of benzophenone ketyl free radical BH. The fast exponential decay of (3)B* (life-time tauT ~ 200 ns) is accompanied by hydrogen atom abstraction from E with a formation of BH and a polymer free radical R. Decay of (3)B* was followed by decay of BH in the polymer cage (geminate recombination) with tauc ~ 1 MUs. Cage recombination in turn was followed by a decay of BH in the polymer bulk (taub ~ 100 MUs). Fortunately, all three processes are separated in time. Both cage and bulk reactions were decelerated by the application of magnetic field (MF) of 0.2 T by approximately 20%. Geminate recombination was fit to the first-order kinetic law, and recombination in the solvent bulk fits well to the second-order law. Both geminate recombination and recombination in the solvent bulk are predominantly a reaction between BH and R. It was assumed that the reaction radius rho12 and a mutual diffusion coefficient D12 of BH and R are the same for the cage and bulk recombination, respectively. This led to an estimation of rho12 = 3.3 nm and D12 = 1 * 10(-7) cm(2) s(-1). These values are discussed. We obtained activation energy, Eact, equal to 6 kcal mol(-1) and 7 kcal mol(-1) for cage decay and for recombination in the polymer bulk, respectively. These Eact coincide with each other within experimental error of their determination (+/-0.5 kcal mol(-1)). This indicates the same diffusion character in the cage and in the polymer bulk. It was demonstrated that an exponential model of cage effect sufficiently describes the obtained experimental data in rubber. PMID- 25712530 TI - Test-retest reliability of a new device for assessing ankle joint threshold to detect passive movement in healthy adults. AB - This study aimed to evaluate the test-retest reliability of a new device for assessing ankle joint kinesthesia. This device could measure the passive motion threshold of four ankle joint movements, namely plantarflexion, dorsiflexion, inversion and eversion. A total of 21 healthy adults, including 13 males and 8 females, participated in the study. Each participant completed two sessions on two separate days with 1-week interval. The sessions were administered by the same experimenter in the same laboratory. At least 12 trials (three successful trials in each of the four directions) were performed in each session. The mean values in each direction were calculated and analysed. The ICC values of test retest reliability ranged from 0.737 (dorsiflexion) to 0.935 (eversion), whereas the SEM values ranged from 0.21 degrees (plantarflexion) to 0.52 degrees (inversion). The Bland-Altman plots showed that the reliability of plantarflexion dorsiflexion was better than that of inversion-eversion. The results evaluated the reliability of the new device as fair to excellent. The new device for assessing kinesthesia could be used to examine the ankle joint kinesthesia. PMID- 25712532 TI - Moderate consumption of wine, through both its phenolic compounds and alcohol content, promotes hydroxytyrosol endogenous generation in humans. A randomized controlled trial. AB - In humans, urinary hydroxytyrosol (OHTyr) concentrations have been associated to alcohol and wine consumption. To explore the role of wine components on promoting an endogenous OHTyr generation we performed a cross-over, double-blind, randomized controlled clinical trial (n = 28 healthy volunteers). Ethanol (wine and vodka), dealcoholized wine, and placebo were administered. Alcohol, dealcoholized wine, and particularly wine promoted a de novo OHTyr generation in vivo in humans. Potential OHTyr precursors (tyrosine, tyrosol, tyramine) were investigated in rats. Tyrosol was metabolized to OHTyr. Collating both studies, it is postulated that an increased Tyr bioavailability, a shift to a reductive pathway in dopamine and tyramine oxidative metabolism, and the biotransformation of Tyr to OHTyr were mechanisms involved in the OHTyr endogenous generation. PMID- 25712533 TI - Prospective, retrospective or clinical audit: A label that sticks. PMID- 25712531 TI - A high-resolution genomic analysis of multidrug-resistant hospital outbreaks of Klebsiella pneumoniae. AB - Multidrug-resistant (MDR) Klebsiella pneumoniae has become a leading cause of nosocomial infections worldwide. Despite its prominence, little is known about the genetic diversity of K. pneumoniae in resource-poor hospital settings. Through whole-genome sequencing (WGS), we reconstructed an outbreak of MDR K. pneumoniae occurring on high-dependency wards in a hospital in Kathmandu during 2012 with a case-fatality rate of 75%. The WGS analysis permitted the identification of two MDR K. pneumoniae lineages causing distinct outbreaks within the complex endemic K. pneumoniae. Using phylogenetic reconstruction and lineage-specific PCR, our data predicted a scenario in which K. pneumoniae, circulating for 6 months before the outbreak, underwent a series of ward-specific clonal expansions after the acquisition of genes facilitating virulence and MDR. We suggest that the early detection of a specific NDM-1 containing lineage in 2011 would have alerted the high-dependency ward staff to intervene. We argue that some form of real-time genetic characterisation, alongside clade-specific PCR during an outbreak, should be factored into future healthcare infection control practices in both high- and low-income settings. PMID- 25712534 TI - Discovery of genetic polymorphism: Richard Lewontin and Tomoko Ohta awarded the Crafoord Prize in Biosciences 2015. PMID- 25712535 TI - Thrombosis in leukemia: incidence, causes, and practical management. AB - In patients with acute leukemia (AL), coagulation disorders, which include both thrombotic and hemorrhagic events, are part of the clinical spectrum both at diagnosis and during its evolution. The incidence of these events has been reported by several authors in the range of 1-36 %. This heterogeneity appears to be related to the type of patients included, the study design, and patient related factors as well as the treatment used. The pathophysiology of thrombosis in AL is complex and multifactorial and includes a myriad of factors that contribute to cancer procoagulant state: synthesis of procoagulant factors by circulating blasts, cellular microparticles, use of endovascular devices (catheters), type of chemotherapy used (L-asparaginase) to name a few. Currently, treatment relies in the use of heparin, followed by vitamin K antagonists for 3 to 6 months. However, randomized controlled studies are required in patients with AL and thrombosis to confirm its safety, duration, and effectiveness. PMID- 25712536 TI - Contraceptive use in Flanders (Belgium): A comparison between a general population sample and a Turkish ethnic minority sample. AB - OBJECTIVES: To identify contraceptive profiles, and factors affecting these, among women of childbearing age, living in Flanders. METHODS: The prevalence of knowledge and use of the emergency contraceptive pill (ECP) and contraceptive use is assessed in two samples from the SEXPERT-survey 'Sexual health in Flanders': (i) a population-based sample (n = 724); and (ii) a probability sample of respondents of Turkish descent (n = 216). RESULTS: Knowledge, but not use, of the ECP is significantly lower among women from the ethnic minority sample, even after correction for income and educational background. A lower educational level is associated with less knowledge of the ECP in both samples. In the general population sample, 16% of sexually active women of childbearing age are at risk of an unplanned pregnancy, compared to 14% of their peers of Turkish origin. These rates are comparable, even after controlling for the different socio economic status (income and educational level) in both samples. CONCLUSIONS: Contraceptive profiles of sexually active women of Turkish descent residing in Flanders are mostly similar to those of their counterparts in the general population. Further research is required to develop strategies to improve ECP knowledge among women with lower educational achievements. PMID- 25712537 TI - Comparative analysis of the effects of nomegestrol acetate/17 beta-estradiol and drospirenone/ethinylestradiol on premenstrual and menstrual symptoms and dysmenorrhea. AB - OBJECTIVES: To compare premenstrual and menstrual symptoms in healthy women using nomegestrol acetate/17beta-estradiol (NOMAC/E2) and drospirenone/ethinylestradiol (DRSP/EE) via the Moos Menstrual Distress Questionnaire Form C (MDQ-C). METHODS: Women completed the MDQ-C at baseline and after completion of cycles 1, 3, 6 and 13, for the premenstrual (four days before most recent flow) and menstrual (most recent flow) phases in two randomized controlled trials. Treatment effects of NOMAC/E2 and DRSP/EE on the t-scores of eight MDQ-C symptom domains from 3522 women were examined, and the effects of both treatments on the score for cramps from 1779 women with moderate to severe cramps at baseline. Longitudinal data analysis methods were applied in both analyses. RESULTS: NOMAC/E2 users experienced a significant improvement in Pain, Water Retention, Negative Affect, Impaired Concentration and Behaviour Change domain scores in the menstrual phase compared with DRSP/EE users (p < 0.001 for all comparisons). However, Arousal (emotional and mental) scores worsened with NOMAC/E2 but not with DRSP/EE. Women with moderate to severe cramps experienced an improvement in the cramps score with NOMAC/E2 and DRSP/EE. CONCLUSIONS: NOMAC/E2 was effective in reducing most premenstrual and menstrual symptoms, and was associated with significantly greater improvements in many MDQ-C domain scores compared with DRSP/EE. ( ClinicalTrials.gov: NCT00413062 and NCT00511199). PMID- 25712538 TI - The Unanticipated Benefits of Behavioral Assessments and Interviews on Anxiety, Self-Esteem and Depression Among Women Engaging in Transactional Sex. AB - Women engaging in transactional sex have disproportional mental health co morbidity and face substantial barriers to accessing social services. We hypothesized that participation in a longitudinal research study, with no overt intervention, would lead to short-term mental health improvements. For 4-weeks, 24 women disclosed information about their lives via twice daily cell-phone diaries and weekly interviews. We used t tests to compare self-esteem, anxiety, and depression at baseline and exit. Tests were repeated for hypothesized effect modifiers (e.g., substance abuse severity; age of sex work debut). For particularly vulnerable women (e.g., less educated, histories of abuse, younger initiation of sex work) participation in research conferred unanticipated mental health benefits. Positive interactions with researchers, as well as discussing lived experiences, may explain these effects. Additional studies are needed to confirm findings and identify mechanisms of change. This work contributes to the growing body of literature documenting that study participation improves mental health. PMID- 25712539 TI - Recurrent genomic rearrangements in primary testicular lymphoma. AB - Primary testicular diffuse large B cell lymphoma (PTL) is an aggressive malignancy that occurs in the immune-privileged anatomical site of the testis. We have previously shown that structural genomic rearrangements involving the MHC class II transactivator CIITA and programmed death ligands (PDLs) 1 and 2 are frequent across multiple B cell lymphoma entities. Specifically in PTL, we found rearrangements in the PDL locus by fluorescence in situ hybridization (FISH). However, breakpoint anatomy and rearrangement partners were undetermined, while CIITA rearrangements had not been reported previously in PTL. Here, we performed bacterial artificial chromosome capture sequencing on three archival, formalin fixed, paraffin-embedded tissue biopsies, interrogating 20 known rearrangement hotspots in B cell lymphomas. We report novel CIITA, FOXP1 and PDL rearrangements involving IGHG4, FLJ45248, RFX3, SMARCA2 and SNX29. Moreover, we present immunohistochemistry data supporting the association between PDL rearrangements and increased protein expression. Finally, using FISH, we show that CIITA (8/82; 10%) and FOXP1 (5/74; 7%) rearrangements are recurrent in PTL. In summary, we describe rearrangement frequencies and novel rearrangement partners of the CIITA, FOXP1 and PDL loci at base-pair resolution in a rare, aggressive lymphoma. Our data suggest immune-checkpoint inhibitor therapy as a promising intervention for PTL patients harbouring PDL rearrangements. PMID- 25712540 TI - Decidual stromal cell-derived IL-33 contributes to Th2 bias and inhibits decidual NK cell cytotoxicity through NF-kappaB signaling in human early pregnancy. AB - Decidual stromal cells (DSCs) are an important component of decidual tissues where they are in strict proximity with immune cells. Although previous research has indicated that DSCs participate in the regulation of immune cells during pregnancy, the crosstalk between DSCs and decidual NK cells (dNKs) has not been fully elucidated. The aim of this study was to ascertain the effect of DSC derived IL-33 on dNK function and explore the underlying mechanism. Flow cytometry showed a considerable increase in ST2 expression on dNKs compared with peripheral NKs (pNKs). Subsequent research found that perforin production, granzyme A production, and the cytolytic activity of dNKs were impaired by DSC media. Furthermore, the addition of DSC media induced an increase in Th2 cytokine production (IL-4, IL-13, and IL-10) with a concomitant decrease in Th1 cytokine expression (TNF-alpha) of dNKs. However, IFN-gamma, another member of the Th1 cytokine family that is thought to be necessary during early gestation increased after IL-33 stimulation. DSC media sharply inhibited the expression of major activating receptors (NKp30, NKG2D) while up-regulating the levels of inhibitory receptor (KIR2DL1) on dNKs. The biological effect of DSC media on dNKs was abrogated by the administration of sST2. Moreover, Western blot analysis suggested that the NF-kappaB pathway was involved in the IL-33-induced changes in the phenotype and function of dNKs, which was further confirmed by pharmacological inhibition with the NF-kappaB inhibitor BAY 11-7082. Our results suggest that the crosstalk between DSCs and dNKs might play a crucial role in maintaining successful pregnancy. PMID- 25712541 TI - The outcome spectrum of multiple sclerosis: disability, mortality, and a cluster of predictors from onset. AB - Interest in the long-term natural history of multiple sclerosis (MS) is being revived, as disability endpoints become increasingly important with the advent of highly efficacious long range but potentially harmful drugs. MS had an increasingly benign course, probably due to better assessment and changing diagnostic criteria. Incidence cohorts reduce inclusion bias, capturing both extreme benign and severe cases. We conducted a 50-year follow-up of an incidence cohort of Gothenburg residents with MS onset in 1950-1964 (n = 254; 212 with an initial relapsing-remitting course and 42 with a monophasic course, diagnostic criteria according to Poser). Patients were followed longitudinally until censoring, death, or study termination in 2012 and evaluated using Kaplan-Meier estimates and Cox regression analysis. Median time to secondary progression was 15 years. Median time to EDSS6 and EDSS7 was 26 and 48 years (n = 254), respectively. The cumulative risk of reaching EDSS6 was 50% at 55 years of age and 80% at 80 years of age (n = 212). A score based on a cluster of clinical features at onset predicted secondary progression, EDSS6, EDSS7, and EDSS10 (hazard ratio 1.6-2.3 per score unit for women, 0.99-1.49 for men). This score predicted the disease course during five decades indirectly, by predicting time to secondary progression. Age at onset predicted the course in men, with 3-6% yearly increase in the risk of reaching disability milestones. The present incidence cohort provided hard outcome data in untreated patients over several decades. PMID- 25712542 TI - Polyneuritis cranialis: oculopharyngeal subtype of Guillain-Barre syndrome. AB - Guillain-Barre syndrome (GBS) constitutes a spectrum of related post-infectious neuropathies, which are characterized by their anatomical patterns of weakness and neurological involvement. Historically, the term polyneuritis cranialis has been used to describe some patients with GBS presenting with multiple cranial neuropathies in the absence of limb weakness. We examine previous reports of polyneuritis cranialis to determine disease characteristics and define new diagnostic criteria. Disease characteristics were determined from 15 historical case reports of patients presenting with isolated 'polyneuritis cranialis', 'cranial polyneuropathy', 'multiple cranial neuropathy' and 'multiple cranial neuropathies' due to GBS. Median age was 40 years. 80% displayed antecedent infectious symptoms. In all cases, disease course was monophasic with clinical improvement within weeks or months. Initial symptoms were ocular (73%) or bulbar (33%). Mean number of cranial nerves involved was 6 (range, 3-10). 93% displayed ocular signs, 73% facial weakness or numbness and 87% bulbar signs. In 3 patients (20%), there was significant asymmetry. Cerebrospinal fluid albuminocytological dissociation was present in 67% of cases. Serum anti-ganglioside antibodies were tested for in 8 of 15 patients and anti-GQ1b antibodies were found in 3 patients, whilst anti-GT1a antibodies were found in 1 patient. Polycranial neuritis (the oculopharyngeal subtype of GBS) can be defined in patients with disease characteristics of GBS who display ocular and pharyngeal weakness in the absence of limb weakness or ataxia. In half of cases tested for, anti-ganglioside antibodies were present and most frequently against GQ1b. PMID- 25712543 TI - Clinicopathological features of sarcoidosis manifesting as generalized chronic myopathy. AB - Although chronic myopathy has been reported to affect skeletal muscle in sarcoidosis, its clinicopathological features have not been fully elucidated. We characterized the clinical, histopathological, and prognostic features of eleven patients with sarcoidosis manifesting with chronically progressive, generalized myopathy that was confirmed with muscle biopsy. Generalized muscle weakness extending to the four extremities and trunk was the cardinal feature of these cases. Muscle atrophy was evident in nine patients, particularly in the lower limbs, whereas myalgia was reported in only two patients. Myopathy was the first manifestation of sarcoidosis in five patients. Only six patients showed elevated plasma creatine kinase levels. Using skeletal muscle computed tomography, the distribution of muscle atrophy was predominant in the hip adductors, knee flexors and ankle plantarflexors. Radiological assessments, including magnetic resonance imaging, gallium scintigraphy, and fluorodeoxyglucose positron emission tomography-computed tomography imaging, revealed findings suggestive of skeletal muscle inflammation in only half of the patients examined. However, in all patients, muscle biopsy specimens revealed an active inflammatory process, as observed by focal non-caseating epithelioid granuloma with predominant CD4 positive lymphocytic infiltration. Sarcolemmas were diffusely stained with HLA ABC, HLA-DR and intercellular adhesion molecule-1 antibodies, suggesting diffuse and active antigen presentation. Functional improvement after immunomodulatory treatment was significantly better in patients with short disease durations (p < 0.05). The therapeutic response was poor in patients with long disease durations; thus, early diagnosis and early initiation of treatment are important. PMID- 25712544 TI - Voice features of Parkinson's disease patients with subthalamic nucleus deep brain stimulation. AB - Voice and speech disorders are one of the most important issues after subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson's disease patients; however, their characteristics remain unclear. We performed a comprehensive voice evaluation including the multi-dimensional voice program for acoustic analysis, the GRBAS scale for perceptual analysis, and the evaluation of the voice handicap index (VHI) for psychosocial analysis. In total, 68 patients who had undergone STN-DBS (37 assessed in the on- and off-stimulation conditions) and 40 who had been treated with medical therapy alone were evaluated. Further, we performed laryngoscopic examinations in 13 STN-DBS and 19 medical-therapy-alone patients. The STN-DBS group, especially females, showed widespread impairment of voice parameters and significantly poorer VHI scores than the medical-therapy-alone group. The degree of voiceless (DUV) and strained voice were the most impaired factors in the STN-DBS group; and DUV significantly improved after stopping stimulation. Furthermore strained voice, breathiness, and asthenia improved after stopping stimulation. Laryngoscopic examination showed that abnormal laryngeal muscle contraction and incomplete glottal closure were more prominent in the STN DBS group than in the medical-therapy-alone group. We demonstrated that (1) more widespread voice impairment in females, (2) poorer voice-related QOL, (3) worse DUV and strained voice, and (4) abnormal laryngeal muscle contraction were the characteristic voice and laryngeal findings in the STN-DBS group compared with those in the medical-therapy-alone group. PMID- 25712545 TI - Volume of olfactory bulb and depth of olfactory sulcus in 378 consecutive patients with olfactory loss. AB - The aim of this study was to investigate the olfactory bulb (OB) and sulcus (OS) in a large group of patients who have been well-characterized in terms of olfactory function, with a specific focus on the comparison between patients with olfactory loss due to chronic rhinosinusitis, head trauma, or acute infections. A retrospective study of 378 patients with olfactory loss was performed. Orthonasal olfactory function was assessed with the"Sniffin' Sticks" test kit, including tests for odor threshold, odor discrimination, and odor identification. Magnetic resonance imaging analyses were focused on OB volume and OS depth. Major results of the present study included the (1) demonstration of a correlation between olfactory function and OB volume across the various pathologies in a very large group of subjects; (2) the three functional tests exhibited a similar degree of correlation with OB volume. (3) The right, but not the left OS correlated with olfactory function; in addition, (4) OS was negatively correlated with age. In contrast to OS, (5) no side differences were found for the OB. Finally, (6) the three different causes of olfactory loss exhibited different patterns of results for the three olfactory tests. The present data suggest that the morphological assessment of the OB volume and OS depth produces useful clinical indicators of olfactory dysfunction. PMID- 25712546 TI - Appendix stump closure with endoloop in laparoscopic appendectomy. AB - AIM: To address the question of the appendix stump closure in laparoscopic appendectomy and evaluate the incidence of intraoperative and postoperative complications after application of endoloops. MATERIAL OF STUDY: Data included age and gender, ASA score, co-morbid illness, prior abdominal surgery, clinical presentation, operative time, conversion rate and reasons for conversion, postoperative morbidity and mortality rates, pathologic diagnosis, and length of hospital stay. RESULTS: Laparoscopic appendectomy with stump closure using endoloops was performed in 35 consecutive patients. Postoperative complications occurred in three patients. The mean postoperative hospital stay was 2 days. The perioperative mortality rate was 0%. DISCUSSION: The treatment of appendiceal stump closure in laparoscopic appendectomy represents the main technical aspect and it is an important step for its potentially serious postoperative complications due from an inappropriate management. Endostapling, hem-o-lok clips and intracorporeal knotting are the most commonly recommended methods. All alternatives have advantages and disadvantages against the different clinical stages of acute appendicitis, and it should be noted that the different forms of appendiceal stump closure have never been assessed in prospective randomized studies. CONCLUSIONS: From our experience we can confirm that the endoloop can be safely used and should be the preferred modality in treating the appendiceal stump, especially for low-grade appendicitis. Alternative methods should be used in case of phlegmonous or gangrenous appendicitis, perityphlitic abscess or simultaneous operation for Meckel's diverticulum. Knowledge about and appropriate use of all of them are important for a safe and more cost-effective procedure. KEY WORDS: Appendiceal stump closure, Laparoscopic appendectomy. PMID- 25712547 TI - Anticipation in myotonic dystrophy type 1 parents with small CTG expansions. AB - Myotonic dystrophy type 1 is the most common form of adult muscular dystrophy and has the world's highest prevalence in the Saguenay-Lac-St-Jean region, due to a founder effect. This autosomal dominant disorder results from an unstable CTG repeat expansion in DMPK. This region of Canada has had a family screening and predictive testing program for this disorder since 1988. Heterozygotes for small expansions (50-100 CTG repeats) can be asymptomatic or minimally affected. The aim of this study was to assess anticipation for these individuals. At the time of this study, the molecular data of 40 individuals and their 76 affected children were available. We compared 76 parent-child pairs. Most offspring (92.1%) had a larger number of repeats than their parent and the median number of repeats in the offspring was 325 (range, 57-2000). The number of CTG repeats was significantly greater when the mutation was transmitted by a father (median, 425 repeats; range, 70-2000), than when it was transmitted by a mother (median, 200 repeats; range, 57-1400). The majority (65.8%) of children also had a more severe phenotype than their parent but the sex of the parent had no significant influence on the severity of the child's phenotype. No congenital phenotype was observed. These results confirm that anticipation is present even when the parent is heterozygous for a small CTG expansion. The parental sex has an impact on the size of the repeat in the next generation, larger increases being transmitted by males with a small expansion. PMID- 25712548 TI - Functional characterization of mutants in the transmembrane domains of the rat P2X7 receptor that regulate pore conductivity and agonist sensitivity. AB - In the sustained presence of agonist, the opening of P2X7R channel is followed by pore dilatation, which causes an increase in its permeability to larger organic cations, accompanied by receptor sensitization. To explore the molecular mechanisms by which the conductivity and sensitivity are increased, we analyzed the electrophysiological properties and YO-PRO-1 uptake of selected alanine mutants in the first and second transmembrane domains of the rat P2X7R. Substitution of residues Y40, F43, G338, and D352 with alanine reduced membrane trafficking, and the D352A was practically non-functional. The Y40A and F43A mutants that were expressed in the membrane lacked pore dilation ability. Moreover, the Y40A and Y40F displayed desensitization, whereas the Y40W partially recovered receptor function. The G338A/S mutations favored the open state of the channel and displayed instantaneous permeability to larger organic cations. The G338P was non-functional. The L341A and G345A displayed normal trafficking, current amplitude, and sensitization, but both mutations resulted in a decreased pore formation and dye uptake. These results showed that the increase in P2X7R conductivity and sensitivity is critically dependent on residues Y40 and F43 in the TM1 domain and that the region located at the intersection of TM2 helices controls the rate of large pore opening. We investigated the mechanism of the proapoptotic receptor P2X7R's large pore opening and its sensitization. We found that aromatic residues in the upper part of the first transmembrane domain (TM1) are critical for both the P2X7R channel pore opening and receptor sensitization, and residues located at or below the intersection of the second transmembrane domains (TM2) control the rate of pore opening. These findings identify new residues involved in pore formation of P2X7R. PMID- 25712549 TI - [Ebola virus disease: one year later]. PMID- 25712550 TI - Parkin structure and function. AB - Mutations in the parkin or PINK1 genes are the leading cause of the autosomal recessive form of Parkinson's disease. The gene products, the E3 ubiquitin ligase parkin and the serine/threonine kinase PINK1, are neuroprotective proteins, which act together in a mitochondrial quality control pathway. Here, we review the structure of parkin and mechanisms of its autoinhibition and function as a ubiquitin ligase. We present a model for the recruitment and activation of parkin as a key regulatory step in the clearance of depolarized or damaged mitochondria by autophagy (mitophagy). We conclude with a brief overview of other functions of parkin and considerations for drug discovery in the mitochondrial quality control pathway. PMID- 25712552 TI - Copper-catalyzed ortho-halogenation of arenes and heteroarenes directed by a removable auxiliary. AB - Copper-catalyzed ortho-halogenation of C(sp(2))-H bonds directed by a PIP directing group with NXS (X = Cl, Br, I) has been developed. The reaction is scalable and tolerates a broad range of functional groups and heteroarenes, providing an efficient access to halogenated arenes and heteroarenes. PMID- 25712551 TI - Estimating the temporal and spatial extent of gene flow among sympatric lizard populations (genus Sceloporus) in the southern Mexican highlands. AB - Interspecific gene flow is pervasive throughout the tree of life. Although detecting gene flow between populations has been facilitated by new analytical approaches, determining the timing and geography of hybridization has remained difficult, particularly for historical gene flow. A geographically explicit phylogenetic approach is needed to determine the overlap of ancestral populations. In this study, we performed population genetic analyses, species delimitation, simulations and a recently developed approach of species tree diffusion to infer the phylogeographic history, timing and geographic extent of gene flow in lizards of the Sceloporus spinosus group. The two species in this group, S. spinosus and S. horridus, are distributed in eastern and western portions of Mexico, respectively, but populations of these species are sympatric in the southern Mexican highlands. We generated data consisting of three mitochondrial genes and eight nuclear loci for 148 and 68 individuals, respectively. We delimited six lineages in this group, but found strong evidence of mito-nuclear discordance in sympatric populations of S. spinosus and S. horridus owing to mitochondrial introgression. We used coalescent simulations to differentiate ancestral gene flow from secondary contact, but found mixed support for these two models. Bayesian phylogeography indicated more than 60% range overlap between ancestral S. spinosus and S. horridus populations since the time of their divergence. Isolation-migration analyses, however, revealed near-zero levels of gene flow between these ancestral populations. Interpreting results from both simulations and empirical data indicate that despite a long history of sympatry among these two species, gene flow in this group has only recently occurred. PMID- 25712553 TI - Reactive oxygen species induce a procoagulant state in endothelial cells by inhibiting tissue factor pathway inhibitor. AB - Tissue factor pathway inhibitor (TFPI) is a serine-protease inhibitor, which modulates coagulation tissue factor-dependent (TF). It binds directly and inhibits the TF-FVII/FVIIa complex as well as FXa. Time to reperfusion of acute ischemic myocardium is essential for tissue salvage. However, reperfusion also results in a unique form of myocardial damage, such as contractile dysfunction, decreased coronary flow and altered vascular reactivity. Oxidants and reactive oxygen species (ROS) formation is increased in the post-ischemic heart and is responsible of post-ischemic injury. It has been reported that ROS promote a procoagulant state via TF expression while no data are available on the effect on TFPI. Endothelial cells were incubated with two different ROS generating systems, xanthine (X)/xanthine oxidase (XO) for 5 min, or H2O2 (500 MUM) for 24 h. TFPI activity was measured in supernatants by chromogenic assay and TFPI-mRNA analyzed by RT-PCR 2 h after ROS exposure. Unstimulated cells and cells exposed to either X or XO served as controls. Western blot and ligand dot blot was performed to evaluate ROS effect on TFPI structure and binding to FXa. ROS generated by X/XO as well as H2O2 system resulted in decreased TFPI activity compared to unstimulated cells while X or XO alone had no effect. No differences in TFPI mRNA levels versus controls was observed. A significant degradation of TFPI was induced by ROS exposure, resulting in a decreased ability to bind FXa. ROS induce a procoagulant state in endothelial cells by altering TFPI structure, resulting in inhibition of TFPI binding to Factor Xa and loss of activity. This phenomenon might have important consequences during reperfusion of post-ischemic myocardium. PMID- 25712555 TI - Chronic kidney disease in disadvantaged populations. PMID- 25712554 TI - Comparative Metagenomics of Eight Geographically Remote Terrestrial Hot Springs. AB - Hot springs are natural habitats for thermophilic Archaea and Bacteria. In this paper, we present the metagenomic analysis of eight globally distributed terrestrial hot springs from China, Iceland, Italy, Russia, and the USA with a temperature range between 61 and 92 (?)C and pH between 1.8 and 7. A comparison of the biodiversity and community composition generally showed a decrease in biodiversity with increasing temperature and decreasing pH. Another important factor shaping microbial diversity of the studied sites was the abundance of organic substrates. Several species of the Crenarchaeal order Thermoprotei were detected, whereas no single bacterial species was found in all samples, suggesting a better adaptation of certain archaeal species to different thermophilic environments. Two hot springs show high abundance of Acidithiobacillus, supporting the idea of a true thermophilic Acidithiobacillus species that can thrive in hyperthermophilic environments. Depending on the sample, up to 58 % of sequencing reads could not be assigned to a known phylum, reinforcing the fact that a large number of microorganisms in nature, including those thriving in hot environments remain to be isolated and characterized. PMID- 25712556 TI - Segmental arterial mediolysis mimicking medium-vessel vasculitis. PMID- 25712558 TI - Authors' reply to Huwez. PMID- 25712557 TI - Autoimmune pancreatitis and minimal change nephrotic syndrome: an unusual association? PMID- 25712559 TI - Folding behavior of four silks of giant honey bee reflects the evolutionary conservation of aculeate silk proteins. AB - Multiple gene duplication events in the precursor of the Aculeata (bees, ants, hornets) gave rise to four silk genes. Whilst these homologs encode proteins with similar amino acid composition and coiled coil structure, the retention of all four homologs implies they each are important. In this study we identified, produced and characterized the four silk proteins from Apis dorsata, the giant Asian honeybee. The proteins were readily purified, allowing us to investigate the folding behavior of solutions of individual proteins in comparison to mixtures of all four proteins at concentrations where they assemble into their native coiled coil structure. In contrast to solutions of any one protein type, solutions of a mixture of the four proteins formed coiled coils that were stable against dilution and detergent denaturation. The results are consistent with the formation of a heteromeric coiled coil protein complex. The mechanism of silk protein coiled coil formation and evolution is discussed in light of these results. PMID- 25712560 TI - Open abdomen and VAC(r) in severe diffuse peritonitis. AB - BACKGROUND: Currently, the open abdomen technique is the widely recognised method for treatment of life-threatening trauma, intra-abdominal sepsis, abdominal compartment syndrome and wound dehiscence. The techniques for temporary closure using negative pressure have gained increasing popularity. Although negative pressure wound therapy has been proved as an effective method in trauma, the results in diffuse peritonitis are contradictory. METHODS: Overall, 108 patients with diffuse peritonitis and open abdomen were prospectively enrolled from January 2006 to December 2013--69 treated with mesh-foil laparostomy without negative pressure and 49 with vacuum-assisted closure (VAC((r))) The primary endpoints were the rate of primary fascial closure and mortality. The secondary outcomes were the rate of complications--enteroatmospheric fistulas, intra abdominal abscesses, wound infection and necrotising fasciitis, intensive care unit (ICU) and overall hospital stay. RESULTS: VAC was associated with higher overall (73% vs 53%) and late primary fascial closure rates (31% vs 7%), lower rates of necrotising fasciitis (2% vs 15%, p=0.012), intra-abdominal abscesses (10% vs 20%), enteroatmospheric fistulas (8% vs 19%), overall mortality (31% vs 53%, p<0.05), shorter ICU (6.1 vs 10.6 days, p=0.002) and hospital stay (15.1 vs 25.9 days, p=0.000). CONCLUSIONS: The results clearly suggest the obvious advantage of VAC in comparison to the temporary abdominal closure without negative pressure in the cases with severe diffuse peritonitis. However, to a large extent, our results might be attributed to the combination of VAC with dynamic fascial closure. PMID- 25712561 TI - Relation between dietary pattern analysis (principal component analysis) and body mass index: a 5-year follow-up study in a Belgian military population. AB - INTRODUCTION: Increasing body mass index (BMI) has been related to many chronic diseases. Knowledge of nutritional determinants of BMI increase may be important to detect persons at risk. METHODS: A longitudinal prospective study design was used in 805 Belgian soldiers. Daily nutrition was recorded with a validated food frequency questionnaire. Weight and height were recorded from medical military data and principal component analysis was used to detect dietary patterns. RESULTS: During the 5 years follow-up, mean BMI increased from 25.8 (+/-3.3) kg/m(2) to 27.1 (+/-3.6) kg/m(2) (p<0.05). Consequently, the prevalence of being overweight and obesity increased from 46.2% and 9.6% to 51.6% and 19.9% (p<0.05), respectively. Mean (SD) weight gain differed between the BMI categories at baseline with a respective weight gain of 3.8 (+/-3.1) kg for normal weight at baseline, 4.2 (+/-3.2) kg for overweight and 5.1 (+/-3.4) kg for obesity (p for trend <0.05). Three dietary patterns were detected by principal component analysis: Meat, Sweet and Healthy dietary pattern. In energy-unadjusted and adjusted linear regressions, no dietary pattern was associated with BMI increase. CONCLUSIONS: No specific dietary pattern was related to BMI increase. Prevention of obesity should focus on total energy intake at all BMI categories. PMID- 25712562 TI - Antiepileptic prophylaxis following severe traumatic brain injury within a military cohort. AB - INTRODUCTION: Traumatic brain injury increases the risk of both early and late seizures. Antiepileptic prophylaxis reduces early seizures, but their use beyond 1 week does not prevent the development of post-traumatic epilepsy. Furthermore, prolonged prophylaxis exposes patients to side effects of the drugs and has occupational implications. The American Academy of Neurology recommends that antiepileptic prophylaxis should be started for patients with severe traumatic brain injury and discontinued after 1 week. An audit is presented here that investigates the use of prophylaxis in a cohort of military patients admitted to the UK Defence Medical Rehabilitation Centre (DMRC). METHODS: Data were collected and analysed retrospectively from electronic and paper records between February 2009 and August 2012. The timing and duration of antiepileptic drug use and the incidence of seizures were recorded. RESULTS: During the study period, 52 patients with severe traumatic brain injury were admitted to the rehabilitation centre: 25 patients (48%) were commenced on prophylaxis during the first week following injury while 27 (52%) did not receive prophylaxis. Only one patient (2%) received prophylaxis for the recommended period of 1 week, 22 patients (42%) received prophylaxis for longer than 1 week with a mean duration of 6.2 months. Two patients (4%) had post-traumatic epilepsy and started on treatment at DMRC. CONCLUSIONS: The use of antiepileptic prophylaxis varies widely and is generally inconsistent with evidence-based guidance. This exposes some patients to a higher risk of early seizures and others to unnecessary use of antiepileptics. Better implementation of prophylaxis is required. PMID- 25712563 TI - Optimization of an enzyme-linked lectin assay suitable for rapid antigenic characterization of the neuraminidase of human influenza A(H3N2) viruses. AB - Antibodies to neuraminidase (NA), the second most abundant surface protein of the influenza virus, contribute to protection against influenza virus infection. Although traditional and miniaturized thiobarbituric acid (TBA) neuraminidase inhibition (NI) assays have been successfully used to characterize the antigenic properties of NA, these methods are cumbersome and not easily amendable to rapid screening. An additional difficulty of the NI assay is the interference by hemagglutinin (HA)-specific antibodies. To prevent interference of HA-specific antibodies, most NI assays are performed with recombinant viruses containing a mismatched HA. However, generation of these viruses is time consuming and unsuitable for large-scale surveillance. The feasibility of using the recently developed enzyme-linked lectin assay (ELLA) to evaluate the antigenic relatedness of NA of wild type A(H3N2) viruses was assessed. Rather than using recombinant viruses, wild type A(H3N2) viruses were used as antigen with ferret sera elicited against recombinant viruses with a mismatched HA. In this study, details of the critical steps that are needed to modify and optimize the NI ELLA in a format that is reproducible, highly sensitive, and useful for influenza virus surveillance to monitor antigenic drift of NA are provided. PMID- 25712564 TI - HIV-1 gp120 dimers decrease the overall affinity of gp120 preparations for CD4 induced ligands. AB - For several years, tools to study the conformational changes of HIV-1 envelope glycoproteins have been developed in order to comprehend those changes and their role in the fusion process and immunogenicity of HIV-1. To facilitate these studies, expression of the HIV-1 gp120 envelope glycoprotein has been done in several over-expression settings. However, over-expression of HIV-1 gp120 in mammalian cells leads to the formation of aberrant disulfide-linked dimers that can bias the results of experiments aimed at measuring gp120 affinity with different ligands. The presence of these gp120 dimers, generated in a widely used gp120 expression system, affects the affinity of gp120 for CD4-induced ligands, as evaluated by surface plasmon resonance. Upon monomeric gp120 purification, neither the removal of potential glycosylation sites on V4 nor the removal of the V5 variable region affect the overall affinity of gp120 for 17b and A32 CD4 induced ligands. Removal of these aberrant disulfide-linked gp120 dimers by standard size exclusion chromatography is sufficient to restore the overall affinity of gp120 preparations for these ligands. PMID- 25712565 TI - Development of an integrase-based ELISA for specific diagnosis of individuals infected with HIV. AB - Currently, enzyme immunoassays (EIAs) are the most common immunological diagnostic methods that are used as the screening tool in HIV detection. Among all three major genes of HIV, the products of gag and env are usually used in EIAs (ELISAs and rapid tests). Hence, the presence of cross reacting antibodies against these antigens leads to the appearance of repetitive false positive results in screening tests. Re-testing the primary reactive samples with EIAs using other HIV antigens can considerably reduce the rate of false positive results. The products of pol gene may act as an appropriate candidate in this context. Integrase is a conserved and immunogenic product of HIV, encoded by the pol gene. The aim of this research was to determine the sensitivity and specificity of an ELISA detecting integrase antibodies. Recombinant integrase was produced in Escherichia coli to develop the integrase-based ELISA. Assay performance was evaluated by HIV positive and negative sera and an HIV panel of BBI (PRB-601). The sensitivity and specificity of assay was determined as 96.7 [95% confidence interval: 91.3-98.9%] and 100% [95% CI: 96.1-100%], respectively. High specificity of this assay may suggest its possible use in the detection of HIV. PMID- 25712566 TI - Converting a light-driven proton pump into a light-gated proton channel. AB - There are two types of membrane-embedded ion transport machineries in nature. The ion pumps generate electrochemical potential by energy-coupled active ion transportation, while the ion channels produce action potential by stimulus dependent passive ion transportation. About 80% of the amino acid residues of the light-driven proton pump archaerhodopsin-3 (AR3) and the light-gated cation channel channelrhodopsin (ChR) differ although they share the close similarity in architecture. Therefore, the question arises: How can these proteins function differently? The absorption maxima of ion pumps are red-shifted about 30-100 nm compared with ChRs, implying a structural difference in the retinal binding cavity. To modify the cavity, a blue-shifted AR3 named AR3-T was produced by replacing three residues located around the retinal (i.e., M128A, G132V, and A225T). AR3-T showed an inward H(+) flux across the membrane, raising the possibility that it works as an inward H(+) pump or an H(+) channel. Electrophysiological experiments showed that the reverse membrane potential was nearly zero, indicating light-gated ion channeling activity of AR3-T. Spectroscopic characterization of AR3-T revealed similar photochemical properties to some of ChRs, including an all-trans retinal configuration, a strong hydrogen bond between the protonated retinal Schiff base and its counterion, and a slow photocycle. From these results, we concluded that the functional determinant in the H(+) transporters is localized at the center of the membrane-spanning domain, but not in the cytoplasmic and extracellular domains. PMID- 25712567 TI - Molecular damage and lung tumors in cigarette smoke-exposed mice. AB - Cigarette smoke (CS) induces lung cancer through a multistep process that is now being depicted by molecular analyses. During the early phase (weeks), DNA damage occurs in nuclear and mitochondrial DNA, triggering adaptive responses activated by transient microRNA downregulation in the expression of defensive genes and proteins. During the intermediate phase (months), damaged cells are removed by apoptosis and the resulting cell loss is counteracted by a recruitment of stem cells that are highly sensitive to genotoxic damage. In parallel, microRNA downregulation becomes irreversible because of an accumulation of molecular damage in DICER. During the late phase (years), apoptosis efficacy is decreased by fragile histidine triad loss, while irreversible microRNA downregulation triggers the expression of mutated oncogenes, resulting in adenoma appearance. Furthermore, deletions occur in microRNA-encoding genes, causing carcinoma formation and uncontrolled growth. All reported pathogenic steps are required to obtain a fully developed lung cancer. This complex pathogenesis develops over a long period of time; therefore, it is difficult to induce cancer in short-living animals exposed to CS, whereas in humans there is a long latency from the start of smoke exposure to the onset of cancer. PMID- 25712568 TI - Impact of 'high-profile' public reporting on utilization and quality of maternity care in England: a difference-in-difference analysis. AB - OBJECTIVES: To evaluate the impact of 'high-profile' (with extensive media coverage) public reporting versus public reporting without 'high profile' coverage on utilization and perceived quality of maternity services in England's National Health Service. METHODS: Analysis of national hospital administrative data using difference-in-difference models with propensity score matching, and of two maternity surveys from 2007 and 2010. Outcomes were counts of women admitted for delivery of a baby and the percentage of women rating their care positively in 2007 and 2010. RESULTS: Hospitals highly publicized as providing the best maternity care in England had fewer admissions annually and lower occupancy rates than the national comparison group (63.0% vs. 77.3%; p = 0.09). There was no statistically significant change in overall maternity admissions in the best hospitals (+2.2%, p = 0.40 at six months), or the worst hospitals (-2.8%, p = 0.49 at six months) during any period in the 36 months after public reporting relative to their matched comparison groups. Survey analyses found that compared to the national comparison group of hospitals without 'high profile' media coverage, the worst rated hospitals experienced greater improvements in perceived quality after public reporting but these findings were not maintained in the analysis of matched hospitals. CONCLUSIONS: 'High-profile' public reporting of maternity care in England was not associated with changes in the use of maternity services or improvements in patient-reported quality. These findings provide further evidence that public reporting is unlikely to drive major improvements in health system performance through the mechanism of patient choice. PMID- 25712569 TI - Solvent-free Liquid Crystals and Liquids from DNA. AB - As DNA exhibits persistent structures with dimensions that exceed the range of their intermolecular forces, solid-state DNA undergoes thermal degradation at elevated temperatures. Therefore, the realization of solvent-free DNA fluids, including liquid crystals and liquids, still remains a significant challenge. To address this intriguing issue, we demonstrate that combining DNA with suitable cationic surfactants, followed by dehydration, can be a simple generic scheme for producing these solvent-free DNA fluid systems. In the anhydrous smectic liquid crystalline phase, DNA sublayers are intercalated between aliphatic hydrocarbon sublayers. The lengths of the DNA and surfactant are found to be extremely important in tuning the physical properties of the fluids. Stable liquid crystalline and liquid phases are obtained in the -20 degrees C to 200 degrees C temperature range without thermal degradation of the DNA. Thus, a new type of DNA-based soft biomaterial has been achieved, which will promote the study and application of DNA in a much broader context. PMID- 25712570 TI - Behavior of stem cells under outer-space microgravity and ground-based microgravity simulation. AB - With rapid development of space engineering, research on life sciences in space is being conducted extensively, especially cellular and molecular studies on space medicine. Stem cells, undifferentiated cells that can differentiate into specialized cells, are considered a key resource for regenerative medicine. Research on stem cells under conditions of microgravity during a space flight or a ground-based simulation has generated several excellent findings. To help readers understand the effects of outer space and ground-based simulation conditions on stem cells, we reviewed recent studies on the effects of microgravity (as an obvious environmental factor in space) on morphology, proliferation, migration, and differentiation of stem cells. PMID- 25712571 TI - Rapidly progressing squamous cell carcinoma (SCC) on the scrotum following cerebral infarction likely due to cardiac metastasis of SCC: a case report. PMID- 25712572 TI - Intrinsic membrane plasticity via increased persistent sodium conductance of cholinergic neurons in the rat laterodorsal tegmental nucleus contributes to cocaine-induced addictive behavior. AB - The laterodorsal tegmental nucleus (LDT) is a brainstem nucleus implicated in reward processing and is one of the main sources of cholinergic afferents to the ventral tegmental area (VTA). Neuroplasticity in this structure may affect the excitability of VTA dopamine neurons and mesocorticolimbic circuitry. Here, we provide evidence that cocaine-induced intrinsic membrane plasticity in LDT cholinergic neurons is involved in addictive behaviors. After repeated experimenter-delivered cocaine exposure, ex vivo whole-cell recordings obtained from LDT cholinergic neurons revealed an induction of intrinsic membrane plasticity in regular- but not burst-type neurons, resulting in increased firing activity. Pharmacological examinations showed that increased riluzole-sensitive persistent sodium currents, but not changes in Ca(2+) -activated BK, SK or voltage-dependent A-type potassium conductance, mediated this plasticity. In addition, bilateral microinjection of riluzole into the LDT immediately before the test session in a cocaine-induced conditioned place preference (CPP) paradigm inhibited the expression of cocaine-induced CPP. These findings suggest that intrinsic membrane plasticity in LDT cholinergic neurons is causally involved in the development of cocaine-induced addictive behaviors. PMID- 25712573 TI - Pregnancy outcomes following 24-chromosome preimplantation genetic diagnosis in couples with balanced reciprocal or Robertsonian translocations. AB - OBJECTIVE: To report live birth rates (LBR) and total aneuploidy rates in a series of patients with balanced translocations who pursued in vitro fertilization (IVF)-preimplantation genetic diagnosis (PGD) cycles. DESIGN: Retrospective cohort analysis. SETTING: Genetic testing reference laboratory. PATIENT(S): Seventy-four couples who underwent IVF-PGD due to a parental translocation. INTERVENTION(S): IVF cycles and embryo biopsies were performed by referring clinics. Biopsy samples were sent to a single reference lab for PGD for the translocation plus 24-chromosome aneuploidy screening with the use of a single-nucleotide polymorphism (SNP) microarray. MAIN OUTCOME MEASURE(S): LBR per biopsy cycle, aneuploidy rate, embryo transfer (ET) rate, miscarriage rate. RESULT(S): The LBR per IVF biopsy cycle was 38%. LBR for patients reaching ET was 52%. Clinical miscarriage rate was 10%. Despite a mean age of 33.8 years and mean of 7 embryos biopsied, there was a 30% chance for no chromosomally normal embryos. Maternal age >35 years, day 3 biopsy, and having fewer than five embryos available for biopsy increased the risk of no ET. CONCLUSION(S): IVF-PGD for translocation and aneuploidy screening had good clinical outcomes. Patients carrying a balanced translocation who are considering IVF-PGD should be aware of the high risk of no ET, particularly in women >=35 years old. PMID- 25712574 TI - In defense of publishing baseline data from clinical trials. PMID- 25712575 TI - Basic understanding of gonadotropin-releasing hormone-agonist triggering. AB - A single bolus of human chorionic gonadotropin (hCG) at midcycle has been the gold standard for triggering final oocyte maturation and ovulation in assisted reproductive technology cycles. More recently, gonadotropin-releasing hormone (GnRH)-agonist (GnRH-a) triggering has been introduced. The GnRH-a trigger may allow a more physiologic surge of both luteinizing hormone (LH) and follicle stimulating hormone, although whether the combined surge will result in improved oocyte and embryo quality remains to be seen. However, the short duration of the LH surge with the GnRH-a trigger (approximately 34 hours) has been shown to be beneficial for preventing ovarian hyperstimulation syndrome in GnRH antagonist in vitro fertilization (IVF) cycles when compared with the prolonged elevation of hCG (>=6 days) after exposure to an hCG bolus. This review discusses the physiologic basis for the use of a GnRH-a trigger in IVF cycles. PMID- 25712576 TI - Techniques for contained morcellation in gynecologic surgery. AB - OBJECTIVE: To demonstrate 2 step-by-step techniques for contained morcellation of uterine tissue. DESIGN: Instructional video showing laparoscopic electromechanical morcellation within an endoscopic pouch, and alternatively, tissue extraction via ultra-minilaparotomy. SETTING: Academic medical center. PATIENT(S): Women undergoing laparoscopic myomectomy or hysterectomy. INTERVENTION(S): For contained electromechanical morcellation, the specimen is placed within an endoscopic pouch, the edges of which are exteriorized through a 15-mm cannula. The cannula is repositioned inside the pouch for insufflation. A bladed fixation trocar enters the pouch through an assistant port and is secured by its retention disk and balloon tip. Gas inflow is changed to this assistant port, through which the laparoscope is inserted. A power morcellator is introduced via the 15-mm port site, and morcellation thus proceeds within the containment system. Residual fragments of tissue are collectively retrieved by withdrawing the endoscopic pouch. For tissue extraction via ultra-minilaparotomy, the specimen is placed within a pouch that is drawn up through a flexible, self retaining retractor seated in a 2 to 3-cm incision. The specimen is cored out sharply with a scalpel. MAIN OUTCOME MEASURE(S): None. RESULT(S): Contained morcellation is technically feasible, efficient (mean additional operative time is approximately 30 minutes), and prevents intraperitoneal dispersion of tissue fragments. Our group has safely performed >100 such procedures and removed specimens weighing nearly 1,500 grams. Potential complications include viscous injury upon insertion of the bladed trocar, and pouch failure. CONCLUSION(S): These techniques allow surgeons to adopt the new standard of contained morcellation and permit removal of extensive pathology with a minimally invasive approach. PMID- 25712577 TI - Comparison of vaginal misoprostol and dinoprostone for cervical ripening before diagnostic hysteroscopy in nulliparous women. AB - OBJECTIVE: To compare the effectiveness of vaginal misoprostol and dinoprostone for cervical ripening before diagnostic hysteroscopy in nulliparous women. DESIGN: Placebo-controlled, double blind, randomized trial. SETTING: Teaching and research hospital. PATIENT(S): Ninety women of reproductive age eligible for diagnostic hysteroscopy. INTERVENTION(S): Randomly assignment to receive 400 MUg of misoprostol (n = 30) or 10 mg of dinoprostone (n = 30) vaginally before diagnostic hysteroscopy, with a control group (n = 30) not receiving any cervical priming agent. MAIN OUTCOME MEASURE(S): PRIMARY OUTCOME: the number of women requiring cervical dilatation; secondary outcomes: cervical width before surgery, duration of dilatation time, ease of dilatation, complications during surgical procedure, and side effects of the drugs. RESULT(S): In the placebo group, 23 patients required cervical dilatation compared with 17 in the misoprostol group and 9 in the dinoprostone group. The mean (+/- standard deviation) cervical widths for the placebo, misoprostol, and dinoprostone groups were 4.23 +/- 0.43 mm, 5.43 +/- 0.5 mm, and 5.83 +/- 0.64 mm, respectively. These widths were statistically significantly different. The duration of dilatation was also statistically significantly longer in the control group. CONCLUSION(S): Vaginally administered dinoprostone before diagnostic hysteroscopy is more effective than misoprostol for inducing cervical priming. Further studies are required to elucidate the most efficient option with the least side effects for cervical ripening. CLINICAL TRIAL REGISTRATION NUMBER: NCT01620814. PMID- 25712578 TI - Self-suspended suspensions of covalently grafted hairy nanoparticles. AB - Dispersions of small particles in liquids have been studied continuously for almost two centuries for their ability to simultaneously advance understanding of physical properties of fluids and their widespread use in applications. In both settings, the suspending (liquid) and suspended (solid) phases are normally distinct and uncoupled on long length and time scales. In this study, we report on the synthesis and physical properties of a novel family of covalently grafted nanoparticles that exist as self-suspended suspensions with high particle loadings. In such suspensions, we find that the grafted polymer chains exhibit unusual multiscale structural transitions and enhanced conformational stability on subnanometer and nanometer length scales. On mesoscopic length scales, the suspensions display exceptional homogeneity and colloidal stability. We attribute this feature to steric repulsions between grafted chains and the space-filling constraint on the tethered chains in the single-component self-suspended materials, which inhibits phase segregation. On macroscopic length scales, the suspensions exist as neat fluids that exhibit soft glassy rheology and, counterintuitively, enhanced elasticity with increasing temperature. This feature is discussed in terms of increased interpenetration of the grafted chains and jamming of the nanoparticles. PMID- 25712579 TI - Hospitalization due to cancer among German seafarers. AB - OBJECTIVES: To evaluate the relative risk of cancer among male German seafarers employed on German vessels in respect of various shipboard ranks and types of vessel. METHODS: The seafarers' cancer discharge diagnoses from hospital were compared with those discharge diagnoses from the German general population and expressed as a standardized hospitalization ratio (SHR). RESULTS: The examined seafarers (on average 23,436 per year) showed a higher SHR for malignant neoplasms at all sites, in decreasing order for leukemia, non-Hodgkin lymphoma (NHL), respiratory cancer, and non-melanoma skin cancer. Seafarers employed on tankers showed a considerably elevated SHR for malignant neoplasms at all sites, which was mainly attributable to their high SHR for leukemia and respiratory cancer. CONCLUSIONS: Seafaring occupations pose an elevated risk of certain cancers. Further studies are required to evaluate to what extent occupational exposure to carcinogenic substances and lifestyle-related unhealthy behaviours contribute to the increased risk of cancer in seafarers. PMID- 25712580 TI - High-resolution dynamic pressure sensor array based on piezo-phototronic effect tuned photoluminescence imaging. AB - A high-resolution dynamic tactile/pressure display is indispensable to the comprehensive perception of force/mechanical stimulations such as electronic skin, biomechanical imaging/analysis, or personalized signatures. Here, we present a dynamic pressure sensor array based on pressure/strain tuned photoluminescence imaging without the need for electricity. Each sensor is a nanopillar that consists of InGaN/GaN multiple quantum wells. Its photoluminescence intensity can be modulated dramatically and linearly by small strain (0-0.15%) owing to the piezo-phototronic effect. The sensor array has a high pixel density of 6350 dpi and exceptional small standard deviation of photoluminescence. High-quality tactile/pressure sensing distribution can be real time recorded by parallel photoluminescence imaging without any cross-talk. The sensor array can be inexpensively fabricated over large areas by semiconductor product lines. The proposed dynamic all-optical pressure imaging with excellent resolution, high sensitivity, good uniformity, and ultrafast response time offers a suitable way for smart sensing, micro/nano-opto-electromechanical systems. PMID- 25712581 TI - A fermented sorghum/millet-based beverage, Obiolor, extenuates high-fat diet induced dyslipidaemia and redox imbalance in the livers of rats. AB - BACKGROUND: Obiolor, a non-alcoholic beverage produced from fermented sorghum and millet malts, is widely consumed on a daily basis by the Igala tribe in Nigeria and is closely associated with good health. The effect of Obiolor on dyslipidaemia, protein oxidation, lipid peroxidation and DNA fragmentation in the liver of rats fed a high-fat diet was investigated. RESULTS: High-fat diet mediated alterations in liver and serum total cholesterol, triacylglycerol, high density lipoprotein cholesterol, low-density cholesterol and very low-density lipoprotein cholesterol were significantly (P < 0.05) reversed by Obiolor. The beverage increased the activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glucose 6-phosphate dehydrogenase in the liver of rats. These increases significantly (P < 0.05) attenuated the high-fat diet-mediated decrease in antioxidant enzymes. High-fat diet-mediated elevations in the levels of conjugated dienes, lipid hydroperoxides, malondialdehyde, protein carbonyl and DNA fragmentation in the livers of rats were lowered by the beverage. CONCLUSION: This study showed that Obiolor extenuated high-fat diet mediated dyslipidaemia, protein oxidation, lipid peroxidation and DNA fragmentation in rats. PMID- 25712582 TI - Cyclophanes containing bowl-shaped aromatic chromophores: three isomers of anti [2.2](1,4)subphthalocyaninophane. AB - The connection of bowl-shaped aromatic boron subphthalocyanines with anti [2.2]paracyclophane resulted in the first observation of electronic communication between convex and concave surfaces. Three isomers of anti [2.2](1,4)subphthalocyaninophane, described as concave-concave (CC), convex concave (CV), and convex-convex (VV) according to the orientation of the subphthalocyanine units, were synthesized and characterized by various spectroscopic techniques, including (1) H NMR, electronic absorption, fluorescence, and magnetic circular dichroism spectroscopy and X-ray crystallography, together with molecular-orbital calculations. On going from the CC system to CV and further to VV, the Q band broadened and finally split as a result of through-space expansion of the conjugated systems, which were also reproduced theoretically. PMID- 25712583 TI - Continuous graphene and carbon nanotube based high flexible and transparent pressure sensor arrays. AB - The transparent pressure sensing arrays durable to severe deformation are fabricated by covering the continuous graphene sheets on the tip of thermal plastic polyurethane (TPU) pyramids, while most of the TPU surface is covered by a layer of densely entangled single wall carbon nanotubes. The transparency of the conducting layer exceeds 91%. The capacitance variations between TPU surface and flat electrode under compressive deformation show high sensitivity and a broad dynamic range from hundreds Pa to MPa. The measured capacitance variations show high load sensitivity and stability under repeated deformation cycles. Finite element numerical simulations present that the contact area change under deformation increases the capacitance variation. The high stability of the capacitance response to fluctuated loads demonstrates that graphene layer on the surface of TPU pyramids maintains the continuity of electric contact under a large deformation ratio and high repeating cycles. 16 * 16 arrays are connected to a circuit and a typical load distribution is regenerated by mapping the local capacitance variations on the arrays with sub-minimeter spatial resolution. PMID- 25712584 TI - Fluoroscopic characterization of surgical bioprosthetic heart valves. PMID- 25712585 TI - Effect of cobedding twins on coregulation, infant state, and twin safety. AB - OBJECTIVE: To evaluate the efficacy of cobedding on twin coregulation and twin safety. DESIGN: Randomized controlled trial (RCT). SETTING: Two university affiliated Level III neonatal intensive care units (NICUs). PARTICIPANTS: One hundred and seventeen sets (N = 234) of stable preterm twins (<37 weeks gestational age at birth) admitted to the NICU. METHODS: Sets of twins were randomly assigned to be cared for in a single cot (cobedded) or in separate cots (standard care). State response was obtained from videotaped and physiologic data measured and recorded for three, 3-hour sessions over a one-week study period. Tapes were coded for infant state by an assessor blind to the purpose of the study. RESULTS: Twins who were cobedded spent more time in the same state (p < .01), less time in opposite states (p < .01), were more often in quiet sleep (p < .01) and cried less (p < .01) than twins who were cared for in separate cots. There was no difference in physiological parameters between groups (p = .85). There was no difference in patient safety between groups (incidence of sepsis, p = .95), incidence of caregiver error (p = .31), and incidence of apnea (p = .70). CONCLUSIONS: Cobedding promotes self-regulation and sleep and decreases crying without apparent increased risk. PMID- 25712586 TI - Metabolic Regulation and Coordination of the Metabolism in Bacteria in Response to a Variety of Growth Conditions. AB - Living organisms have sophisticated but well-organized regulation system. It is important to understand the metabolic regulation mechanisms in relation to growth environment for the efficient design of cell factories for biofuels and biochemicals production. Here, an overview is given for carbon catabolite regulation, nitrogen regulation, ion, sulfur, and phosphate regulations, stringent response under nutrient starvation as well as oxidative stress regulation, redox state regulation, acid-shock, heat- and cold-shock regulations, solvent stress regulation, osmoregulation, and biofilm formation, and quorum sensing focusing on Escherichia coli metabolism and others. The coordinated regulation mechanisms are of particular interest in getting insight into the principle which governs the cell metabolism. The metabolism is controlled by both enzyme-level regulation and transcriptional regulation via transcription factors such as cAMP-Crp, Cra, Csr, Fis, P(II)(GlnB), NtrBC, CysB, PhoR/B, SoxR/S, Fur, MarR, ArcA/B, Fnr, NarX/L, RpoS, and (p)ppGpp for stringent response, where the timescales for enzyme-level and gene-level regulations are different. Moreover, multiple regulations are coordinated by the intracellular metabolites, where fructose 1,6-bisphosphate (FBP), phosphoenolpyruvate (PEP), and acetyl-CoA (AcCoA) play important roles for enzyme-level regulation as well as transcriptional control, while alpha-ketoacids such as alpha-ketoglutaric acid (alphaKG), pyruvate (PYR), and oxaloacetate (OAA) play important roles for the coordinated regulation between carbon source uptake rate and other nutrient uptake rate such as nitrogen or sulfur uptake rate by modulation of cAMP via Cya. PMID- 25712587 TI - Surface Trafficking of APP and BACE in Live Cells. AB - Amyloid-beta (Abeta)-peptide, the major constituent of the plaques that develop during Alzheimer's disease, is generated via the cleavage of Abeta precursor protein (APP) by beta-site APP-cleaving enzyme (BACE). Using live-cell imaging of APP and BACE labeled with pH-sensitive proteins, we could detect the release events of APP and BACE and their distinct kinetics. We provide kinetic evidence for the cleavage of APP by alpha-secretase on the cellular surface after exocytosis. Furthermore, simultaneous dual-color evanescent field illumination revealed that the two proteins are trafficked to the surface in separate compartments. Perturbing the membrane lipid composition resulted in a reduced frequency of exocytosis and affected BACE more strongly than APP. We propose that surface fusion frequency is a key factor regulating the aggregation of APP and BACE in the same membrane compartment and that this process can be modulated via pharmacological intervention. PMID- 25712588 TI - Epidemiological knowledge on human immunodeficiency virus infection as a basic for programme of prophylactic measures. AB - OBJECTIVES: An epidemic situation on human immunodeficiency virus infection can be stopped and even compelled to step back, if adequate and comprehensive prophylactic measures are performed in the proper time. METHODS: Prophylactic measures should be, directed on those groups, who are at high risk for becoming infected or who are carriers of HIV as the top priority. The epidemic situation in HIV infection in the northwestern region of Russia has been analyzed. The ways of the spread of HIV infection among the infected persons, residents of the St. Petersburg region, Kaliningrad, Novgorod, and Murmansk, have been studied. The infection is transmitted mainly through sexual contacts, both homosexual and heterosexual. High migration activity of HIV-infected persons, homo- and heterosexuals, has been established and a great number of unknown (casual) sexual contacts among them noted. RESULTS: The results of these observations may be useful in the prognostication of the epidemic situation in HIV infection not only in the northwestern region, but also beyond its boundaries, and later in the optimization of screening. CONCLUSIONS: The pandemic of HIV infection causes enormous economic damage, destabilizes the socio-political situation in many countries of the world, and hinders the achievement of aims for the development of millennium, both in the area of health protection and in other spheres. In Novgorod region an epidemic situation on HIV infection is estimated as one of most strained one. The basic indexes and tempos of their growth in a region are higher in relation to average federal data. But it can be stopped and even compelled to step back. PMID- 25712589 TI - New Zealand University students' knowledge of fertility decline in women via natural pregnancy and assisted reproductive technologies. AB - Female fertility declines with age. University students are the group of people most likely to postpone parenthood, yet several international studies have shown that they overestimate their fertility. We designed a questionnaire based on a previous study in Israel, where university students were asked to answer questions related to their awareness of fertility decline in spontaneous and in vitro fertilisation (IVF) pregnancies, and methods they considered would prolong their reproductive lifespan. Our study has shown that New Zealand University students overestimated the rates of pregnancy for both spontaneous natural and IVF pregnancies. Students are mainly aware of the availability of assisted reproductive technologies (ARTs), but overestimate their effectiveness. Few students mentioned non-medical or well-being initiatives as measures to prolong parenthood. It is important that university students are aware of the rate of fertility decline in women, as although ARTs can be effective at times, they are not a guaranteed solution to an ageing woman's fertility. New Zealand University students, like other cohorts, overestimated the chances of a woman getting pregnant and predicted the fertility decline to occur much later than it does in reality. PMID- 25712590 TI - Risk of death among those awaiting treatment for HIV infection in Zimbabwe: adolescents are at particular risk. AB - INTRODUCTION: Mortality among HIV-positive adults awaiting antiretroviral therapy (ART) has previously been found to be high. Here, we compare adolescent pre-ART mortality to that of adults in a public sector HIV care programme in Bulawayo, Zimbabwe. METHODS: In this retrospective cohort study, we compared adolescent pre ART outcomes with those of adults enrolled for HIV care in the same clinic. Adolescents were defined as those aged 10-19 at the time of registration. Comparisons of means and proportions were carried out using two-tailed sample t tests and chi-square tests respectively, for normally distributed data, and the Mann-Whitney U-tests for non-normally distributed data. Loss to follow-up (LTFU) was defined as missing a scheduled appointment by three or more months. RESULTS: Between 2004 and 2010, 1382 of 1628 adolescents and 7557 of 11,106 adults who registered for HIV care met the eligibility criteria for ART. Adolescents registered at a more advanced disease stage than did adults (83% vs. 73% WHO stage III/IV, respectively, p<0.001), and the median time to ART initiation was longer for adolescents than for adults [21 (10-55) days vs. 15 (7-42) days, p<0.001]. Among the 138 adolescents and 942 adults who never commenced ART, 39 (28%) of adolescents and 135 (14%) of adults died, the remainder being LTFU. Mortality among treatment-eligible adolescents awaiting ART was significantly higher than among adults (3% vs. 1.8%, respectively, p=0.004). CONCLUSIONS: Adolescents present to ART services at a later clinical stage than adults and are at an increased risk of death prior to commencing ART. Improved and innovative HIV case-finding approaches and emphasis on prompt ART initiation in adolescents are urgently needed. Following registration, defaulter tracing should be used, whether or not ART has been commenced. PMID- 25712591 TI - Involvement of DNA methylation in the control of cell growth during heat stress in tobacco BY-2 cells. AB - The alteration of growth patterns, through the adjustment of cell division and expansion, is a characteristic response of plants to environmental stress. In order to study this response in more depth, the effect of heat stress on growth was investigated in tobacco BY-2 cells. The results indicate that heat stress inhibited cell division, by slowing cell cycle progression. Cells were stopped in the pre-mitotic phases, as shown by the increased expression of CycD3-1 and by the decrease in the NtCycA13, NtCyc29 and CDKB1-1 transcripts. The decrease in cell length and the reduced expression of Nt-EXPA5 indicated that cell expansion was also inhibited. Since DNA methylation plays a key role in controlling gene expression, the possibility that the altered expression of genes involved in the control of cell growth, observed during heat stress, could be due to changes in the methylation state of their promoters was investigated. The results show that the altered expression of CycD3-1 and Nt-EXPA5 was consistent with changes in the methylation state of the upstream region of these genes. These results suggest that DNA methylation, controlling the expression of genes involved in plant development, contributes to growth alteration occurring in response to environmental changes. PMID- 25712592 TI - Confocal laser scanning microscopy elucidation of the micromorphology of the leaf cuticle and analysis of its chemical composition. AB - Electron microscopy techniques such as transmission electron microscopy (TEM) and scanning electron microscopy (SEM) have been invaluable tools for the study of the micromorphology of plant cuticles. However, for electron microscopy, the preparation techniques required may invariably introduce artefacts in cuticle preservation. Further, there are a limited number of methods available for quantifying the image data obtained through electron microscopy. Therefore, in this study, optical microscopy techniques were coupled with staining procedures and, along with SEM were used to qualitatively and quantitatively assess the ultrastructure of plant leaf cuticles. Leaf cryosections of Triticum aestivum (wheat), Zea mays (maize), and Lupinus angustifolius (lupin) were stained with either fat-soluble azo stain Sudan IV or fluorescent, diarylmethane Auramine O and were observed under confocal laser scanning microscope (CLSM). For all the plant species tested, the cuticle on the leaf surfaces could be clearly resolved in many cases into cuticular proper (CP), external cuticular layer (ECL), and internal cuticular layer (ICL). Novel image data analysis procedures for quantifying the epicuticular wax micromorphology were developed, and epicuticular waxes of L. angustifolius were described here for the first time. Together, application of a multifaceted approach involving the use of a range of techniques to study the plant cuticle has led to a better understanding of cuticular structure and provides new insights into leaf surface architecture. PMID- 25712594 TI - Enhanced D-arabitol production by Zygosaccharomyces rouxii JM-C46: isolation of strains and process of repeated-batch fermentation. AB - A new strain producing high yield of D-arabitol was isolated from hyperosmotic environments and the ITS rDNA sequencing analysis revealed it as Zygosaccharomyces rouxii. In addition, using a pH control and repeated-batch fermentation strategy in a 5-L reactor, the maximum yield and the highest volumetric productivity of D-arabitol were 93.48 +/- 2.79 g/L and 1.143 g/L h, respectively. Volumetric productivity was successfully improved from 0.86 to 1.143 g/L h, which was increased by 32.9 % after 72 h of fermentation. Z. rouxii JM-C46 has potential to be used for D-arabitol and xylitol production from glucose via D-arabitol route. PMID- 25712595 TI - Pulsed electrical stimulation modulates fibroblasts' behaviour through the Smad signalling pathway. AB - The aim of this study was to investigate the healing characteristics and the underlying signalling pathway of human dermal fibroblasts under the influence of pulsed electrical stimulation (PES). Primary human dermal fibroblasts were seeded on polypyrrole-coated polyester fabrics and subjected to four different PES protocols. The parameters of the rectangular pulse included potential intensity (50 and 100 mV/mm) and stimulation time (pulse width 300 s within a period of 600 s, and pulse width 10 s within a period of 1200 s). Our study revealed that PES moderately improved the ability of the cells to migrate in association with a statistically significant (p < 0.05) increase of FGF2 secretion by the PES exposed fibroblasts. These exposed fibroblasts were able to contract collagen gel matrix up to 48 h and this collagen gel contraction paralleled an increase in alpha-SMA mRNA expression and protein production from the PES-exposed fibroblasts. Interestingly, the effect of PES on the human fibroblasts involved the Smad signalling pathway, as we observed higher levels of phosphorylated Smad2 and Smad3 in the stimulated groups compared to the control groups. Overall, this study demonstrated that PES modulates fibroblast activities through the Smad signalling pathway, thus providing new mechanistic insights related to the use of PES to promote wound healing in humans. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 25712593 TI - Ambient air pollution and adult asthma incidence in six European cohorts (ESCAPE). AB - BACKGROUND: Short-term exposure to air pollution has adverse effects among patients with asthma, but whether long-term exposure to air pollution is a cause of adult-onset asthma is unclear. OBJECTIVE: We aimed to investigate the association between air pollution and adult onset asthma. METHODS: Asthma incidence was prospectively assessed in six European cohorts. Exposures studied were annual average concentrations at home addresses for nitrogen oxides assessed for 23,704 participants (including 1,257 incident cases) and particulate matter (PM) assessed for 17,909 participants through ESCAPE land-use regression models and traffic exposure indicators. Meta-analyses of cohort-specific logistic regression on asthma incidence were performed. Models were adjusted for age, sex, overweight, education, and smoking and included city/area within each cohort as a random effect. RESULTS: In this longitudinal analysis, asthma incidence was positively, but not significantly, associated with all exposure metrics, except for PMcoarse. Positive associations of borderline significance were observed for nitrogen dioxide [adjusted odds ratio (OR) = 1.10; 95% CI: 0.99, 1.21 per 10 MUg/m3; p = 0.10] and nitrogen oxides (adjusted OR = 1.04; 95% CI: 0.99, 1.08 per 20 MUg/m3; p = 0.08). Nonsignificant positive associations were estimated for PM10 (adjusted OR = 1.04; 95% CI: 0.88, 1.23 per 10 MUg/m3), PM2.5 (adjusted OR = 1.04; 95% CI: 0.88, 1.23 per 5 MUg/m3), PM2.5absorbance (adjusted OR = 1.06; 95% CI: 0.95, 1.19 per 10-5/m), traffic load (adjusted OR = 1.10; 95% CI: 0.93, 1.30 per 4 million vehicles * meters/day on major roads in a 100-m buffer), and traffic intensity (adjusted OR = 1.10; 95% CI: 0.93, 1.30 per 5,000 vehicles/day on the nearest road). A nonsignificant negative association was estimated for PMcoarse (adjusted OR = 0.98; 95% CI: 0.87, 1.14 per 5 MUg/m3). CONCLUSIONS: Results suggest a deleterious effect of ambient air pollution on asthma incidence in adults. Further research with improved personal-level exposure assessment (vs. residential exposure assessment only) and phenotypic characterization is needed. PMID- 25712596 TI - Pd-mediated rapid cross-couplings using [(11) C]methyl iodide: groundbreaking labeling methods in (11) C radiochemistry. AB - Prof. Bengt Langstrom is a pioneer in the field of chemistry-driven positron emission tomography (PET) imaging. He has developed a variety of excellent radiolabeling methodologies using the methods of organic chemistry, with the aim of widening the potential of PET in the study of life. Among his groundbreaking achievements in (11) C radiochemistry, there is the discovery of the Pd-mediated rapid cross-coupling reaction using [(11) C]methyl iodide. It was first reported by his Uppsala group in 1994-1995 and was further investigated by his and other groups with a view of enhancing its generality and practicability. This reaction is currently considered one of the basic methods for (11) C-labeling of low weight organic compounds. This paper presents a short summary of the background and the development of Pd-mediated rapid cross-couplings of [(11) C]methyl iodide, with a focus not only on organostannanes, but also on organoboranes, organozincs, and terminal acetylene compounds. All these reactions have proven to be dependable (11) C-labeling methodologies that use chemically reliable carbon carbon bond formation reactions. PMID- 25712597 TI - Discrepancy in fetal sex assignment between cell free fetal DNA and ultrasound. AB - Noninvasive prenatal testing utilizing free fetal DNA is commonly used in pregnancy to screen for trisomy 13, 18, 21 and also fetal sex aneuploidy. We report on two cases of discrepancy between phenotypic and genotypic sex and potential medical implications. In our first case, a patient with known male gender via cell free fetal DNA (cffDNA) testing had an ultrasound at 18 weeks' gestation, which identified Dandy-Walker malformation and female-appearing ambiguous genitalia. As Dandy-Walker malformation could not be considered isolated in the presence of ambiguous genitalia, this finding allowed for more complete counseling of the parents as well as extensive genetic workup. Our second case involved a fetus with intrauterine growth restriction diagnosed by ultrasound and normal-appearing female genitalia. After birth, adrenal insufficiency was diagnosed and chromosome analysis identified normal male chromosomes. These two cases showed that fetal sex determination by cffDNA can be used as a tool for earlier identification of affected pregnancies, allowing for parental decision-making, genetic testing and earlier intervention. PMID- 25712598 TI - Respiratory failure in a term infant with cis and trans mutations in ABCA3. AB - A full-term female neonate presented with persistent respiratory failure and radiologic studies consistent with surfactant deficiency. Sequencing of the ATP binding cassette transporter A3 gene (ABCA3) revealed three mutations: R280C, V1399M and Q1589X. The infant underwent bilateral lung transplantation at 9 months of age and is alive at 3 years of age. Parental sequencing demonstrated that two of the mutations (R280C and Q1589X) were oriented on the same allele (cis), whereas V1399M was oriented on the opposite allele (trans). As more than one mutation in ABCA3 can be present on the same allele, parental studies are needed to determine allelic orientation to inform clinical decision making and future reproductive counseling. PMID- 25712599 TI - 3-C Ritscher-Schinzel syndrome with spinal subarachnoid cyst. PMID- 25712600 TI - Quality assessment of cataract surgery in Denmark - risk of retinal detachment and postoperative endophthalmitis. AB - The main purpose of this thesis was to examine whether the Danish National Patient Registry (NPR) could be used to monitor and assess the quality of cataract surgery in Denmark by studying the risks of two serious postoperative complications following cataract surgery - retinal detachment (RD) and postoperative endophthalmitis (PE). The thesis consists of four retrospective studies. In the first study (paper I), we used data from the NPR in the calendar period 2000-2010 to investigate the risk of pseudophakic retinal detachment (PRD) using the fellow non-operated eyes of the patients as reference. The study showed that over a 10-year study period, the risk of PRD was increased by a factor of 4.2 irrespective of sex and age. The risk of PRD was highest in the first part of the postoperative period and then gradually decreased but remained statistically significantly higher than the risk of RD in non-operated fellow eyes up to 10 years after cataract surgery. The epidemiology of RD in the non-operated fellow eyes was different from the epidemiology of RD in the background population as young men had the highest risk of RD in the non-operated fellow eyes. This means that the absolute risk of PRD was highest for young men because they had a higher risk of RD before they underwent cataract surgery. In the second study (paper II), we used data from the NPR and reviewed patient charts to assess the risk of PE after cataract surgery performed in public eye departments and private hospitals/clinics in the study period 2002-2010. The overall risk of PE among the seven public eye departments was 0.36 per 1000 registered cataract operations, and the PE risk among the departments was homogeneous. The overall risk of PE among the 28 private hospitals/clinics was 0.73 per 1000 registered cataract operations, and the risk among the private hospitals/clinics was heterogeneous. Most private hospitals/clinics had a risk of PE that was lower than or similar to the risk of PE after registered cataract surgery in public eye departments, but six private hospitals/clinics had a statistically significantly higher risk of PE compared to the public eye departments. We used PE as a proxy measure of the registration of cataract surgery and found that 98% of the cataract operations performed in public eye departments were registered in the NPR while only 38% of the cataract operations performed in private hospitals/clinics were registered in the NPR. In general, the coding of the PE cases was not uniform and the lack of registration by the private hospitals/clinics meant that the NPR could not be used to monitor the true risk of PE. NPR data were also used in the third study (paper III) to examine whether patients who had surgical intervention for PE following cataract surgery with either a pars plana vitrectomy (PPV) or a vitreous tap (VT) had a higher risk of subsequent surgical complications. There was no statistically significant difference in the overall risk of complications among the two groups, but the risk of surgery for vitreous opacities was statistically significantly higher for patients who underwent a VT. A surgical complication occurred in 27.3% of the patients and 9.9% of the patients developed more than one surgical complication. Ninety-seven per cent of the primary surgical complications occurred within the first 5 months. The risk of surgical complications in this study was similar to or higher than the risk of complications in the landmark Endophthalmitis Vitrectomy Study from the early 1990s. In the fourth study (paper IV), we used data from all three Danish cataract registries to describe the epidemiology of cataract operations performed in public hospitals and private hospitals/clinics in the study period 2004-2012. Again, PE was used as a proxy measure of the registration of cataract surgery. There were several noticeable differences in the epidemiology of the cataract operations performed in public hospitals and private hospitals/clinics. Patients who had cataract surgery in public hospitals had a statistically significantly higher mortality compared to patients who had cataract surgery in private hospitals/clinics during the entire period. The decrease in the mean age at first eye cataract surgery in private hospitals/clinics was statistically significantly greater compared to public hospitals during the study period. There was a statistically significantly shorter median time interval between first and second eye cataract surgery at private hospitals/clinics compared to public hospitals during the entire study period. The study showed that only 54% of the cataract operations performed in private hospitals/clinics that led to PE were registered. The lack of registration of cataract surgery is the main reason why the NPR has limitations when used as a tool to monitor and assess the quality of cataract surgery in Denmark. PMID- 25712601 TI - Enhancement of radiosensitivity in human esophageal carcinoma cells by fenofibrate and its potential mechanism. AB - AIMS AND BACKGROUND: Fenofibrate is a specific agonist of PPARalpha, and is characterized by relatively low systemic toxicity. Recent studies have revealed that fenofibrate suppresses the growth of several cancer lines in vitro, but the exact relation between fenofibrate and irradiation has not been explored. The purpose of this study was to investigate the radiosensitivity enhancement effects of fenofibrate combined with radiation on the human esophageal carcinoma cell lines Eca-109 and TE1, and the potential mechanism underlying these effects. METHODS AND STUDY DESIGN: The Eca-109 and TE1 cell lines were tested by the CCK-8 assay for cell proliferation. The multitarget click model was used to delineate the survival curve and radiosensitivity was determined after cells were treated with fenofibrate and/or x-ray radiation. Flow cytometry was used to examine the effect of fenofibrate and radiation on the cell cycle. The expression of vascular endothelial growth factor (VEGF) protein was detected by Western blot analysis. RESULTS: When given alone, fenofibrate had a time- and concentration-dependent cytotoxic effect on cells. The dose-enhancement ratio for combined fenofibrate and radiation increased markedly compared with fenofibrate alone. Further, the ratio of cells in the G2/M phase after fenofibrate and radiation was higher than that after fenofibrate or irradiation alone. The expression of VEGF protein was suppressed after treatment with fenofibrate alone or fenofibrate plus radiation. CONCLUSIONS: Fenofibrate can enhance the radiosensitivity of human esophageal carcinoma cells by increasing G2/M phase arrest. Modulation of VEGF expression could contribute in vivo to a favorable interaction. PMID- 25712602 TI - Adjuvant chemoradiotherapy in gastric cancer: a pooled analysis of the AIRO gastrointestinal group experience. AB - BACKGROUND: Given the poor compliance with adjuvant chemoradiotherapy (CRT) in gastric cancer reported in previous studies, a survey was conducted among 18 Italian institutions within the AIRO Gastrointestinal Group to investigate current treatment modalities, toxicities, and compliance with adjuvant CRT. PATIENTS AND METHODS: Data from 348 patients operated on for gastric cancer were collected retrospectively from September 2000 to June 2008 and analyzed. The adjuvant treatments included CRT according to center guidelines. In multivariate analysis, acute hematological, gastrointestinal, and renal toxicity (according to the RTOG Acute Radiation Morbidity Scoring Criteria) and compliance with treatment were studied, as well as risk factors for local control, metastasis free survival, disease-free survival, and overall survival. RESULTS: Compliance with treatment was excellent: 95.7% of patients completed CRT. During CRT, acute G3-G4 -hematological toxicity was 3.7% and acute G3-G4 gastrointestinal toxicity 4%. 78.4% of patients completed chemotherapy (CT), either before or after CRT. During CT acute G3-G4 hematological toxicity was 5.4% and acute G3-G4 gastrointestinal toxicity 6%. Overall, 74.1% of patients completed the prescribed treatment (CRT and CT). Doses greater than 4500 cGy did not compensate for more aggressive disease. The 5-year overall survival was 51%. CONCLUSIONS: The adjuvant treatment of gastric cancer within the AIRO group was diverse, but radiotherapy treatment was homogeneous (in terms of technique) and well tolerated. Toxicity was low and compliance with treatment was good during CRT; these results may be due to the radiotherapy technique applied. This survey could be used as a benchmark for further studies. PMID- 25712603 TI - Reference values of the Functional Assessment of Chronic Illness Therapy Spiritual Well-Being: a report from the American Cancer Society's studies of cancer survivors. AB - BACKGROUND: Health-related quality of life measures are common in oncology research, trials, and practice. Spiritual well-being has emerged as an important aspect of health-related quality of life and the Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being; The 12-item Spiritual Well-Being Scale (FACIT-Sp-12) is the most widely used measure of spiritual well-being among those with cancer. However, there is an absence of reference values with which to facilitate the interpretation of scores in research and clinical practice. The objective of the current study was to provide FACIT-Sp-12 reference values from a representative sample of adult cancer survivors. METHODS: As part of the American Cancer Society's Study of Cancer Survivors-II, a national cross-sectional study of cancer survivors (8864 survivors) completed questionnaires assessing demographic characteristics, clinical information, and the FACIT-Sp-12. Scores were calculated and summarized by FACIT-Sp-12 subscale and total scores across age, sex, race/ethnicity, time after treatment, and cancer type. RESULTS: Student t tests for independent samples found that women reported significantly higher FACIT-Sp-12 scores (P<.001). Analyses of variance found significant main effects for FACIT-Sp-12 scores by age (P<.01), race/ethnicity (P<.05), and cancer type (P<.001). Post hoc comparisons revealed that older adults (those aged 60-69 years and 70-79 years) and black non-Hispanic individuals reported the highest FACIT-Sp 12 scores compared with those aged 18 to 39 years (P<.05; Cohen d [an effect size used to indicate the standardized difference between 2 means], 0.20-0.50) and white non-Hispanic individuals (P<.05; Cohen d, 0.02-0.62), respectively. All other significant main effects were small in magnitude (effect size range, 0.001 0.032). CONCLUSIONS: These data will aid in the interpretation of the magnitude and meaning of FACIT-Sp-12 scores, and allow for comparisons of scores across studies. PMID- 25712605 TI - Proposal of a classification system for opportunities to innovate in skin care products. AB - OBJECTIVES: What are the opportunities to innovate in a skin care product? There are certainly many opportunities and many technologies involved. In this work, we assumed the role of identifying and categorizing these opportunities to develop a comprehensive and intelligible classification system, which could be used as a tool to support decision-making in different professional contexts. METHODS: Initially, we employed the Delphi method to identify, discuss and standardize the opportunities to innovate in a skin care product. Finally, we used the classification system obtained in the previous phase to label patent applications, therefore, testing the suitability and utility of the system. RESULTS: At the end of the process, we achieved a 10-category classification system for opportunities to innovate in skin care products, and we also illustrated how this system could be used. CONCLUSION: The resultant classification system offers a normalized terminology for cosmetic scientists interested in dealing with the particularities of incremental and radical innovations in skin care products. PMID- 25712604 TI - Plasma metabolite profiling and chemometric analyses of lung cancer along with three controls through gas chromatography-mass spectrometry. AB - Lung cancer has been the most common death causing cancer in the world for several decades. This study is focused on the metabolite profiling of plasma from lung cancer (LC) patients with three control groups including healthy non-smoker (NS), smokers (S) and chronic obstructive pulmonary disease patients (COPD) samples using gas chromatography-mass spectrometry (GC-MS) in order to identify the comparative and distinguishing metabolite pattern for lung cancer. Metabolites obtained were identified through National Institute of Standards and Technology (NIST) mass spectral (Wiley registry) and Fiehn Retention Time Lock (RTL) libraries. Mass Profiler Professional (MPP) Software was used for the alignment and for all the statistical analysis. 32 out of 1,877 aligned metabolites were significantly distinguished among three controls and lung cancer using p-value <= 0.001. Partial Least Square Discriminant Analysis (PLSDA) model was generated using statistically significant metabolites which on external validation provide high sensitivity (100%) and specificity (78.6%). Elevated level of fatty acids, glucose and acids were observed in lung cancer in comparison with control groups apparently due to enhanced glycolysis, gluconeogenesis, lipogenesis and acidosis, indicating the metabolic signature for lung cancer. PMID- 25712606 TI - Magnetic nanoparticle assembly arrays prepared by hierarchical self-assembly on a patterned surface. AB - Inverted pyramid hole arrays were fabricated by photolithography and used as templates to direct the growth of colloidal nanoparticle assemblies. Cobalt ferrite nanoparticles deposit in the holes to yield high quality pyramid magnetic nanoparticle assembly arrays by carefully controlling the evaporation of the carrier fluid. Magnetic measurements indicate that the pyramid magnetic nanoparticle assembly arrays preferentially magnetize perpendicular to the substrate. PMID- 25712607 TI - Fragmented QRS complex is a diagnostic tool in patients with left ventricular diastolic dysfunction. AB - Fragmented QRS complex (fQRS) on 12-lead ECG is associated with myocardial fibrosis and ischemic scar. Interstitial fibrosis is one of the histological characteristics of left ventricular diastolic dysfunction (LVDD). However, the clinical importance of fQRS in patients with LVDD remains unclear. Here, we assessed the hypothesis that the presence of fQRS is associated with disease severity in patients with LVDD, and could be used as an additional parameter to differentiate patients with heart failure with preserved ejection fraction (HFpEF) from LVDD. We analyzed 12-lead ECG of 239 patients with LVDD. The patients were divided into two groups according to the presence or absence of fQRS; 88 patients had fQRS (fQRS group) and 151 patients did not have fQRS (non fQRS group). The percentage of patients with heart failure in the fQRS group was significantly higher than that in the non-fQRS group. The levels of B-type natriuretic peptide (BNP) and high-sensitive troponin T were significantly higher in the fQRS group than those in the non-fQRS group. In univariate logistic regression analysis, fQRS was associated with the presence of heart failure in patients with LVDD. Multivariate logistic regression analysis identified fQRS and BNP as independent indicators for HFpEF. In conclusion, the presence of fQRS on the ECG could be used as an additional tool to differentiate HFpEF from LVDD. PMID- 25712608 TI - Characteristic patterns of the longitudinal and circumferential distribution of calcium deposits by parent coronary arteries observed from computed tomography angiography. AB - Many investigators have reported that the total amount of coronary calcium correlates with the overall magnitude of atherosclerotic plaque burden in the entire coronary tree and is a powerful predictor of future cardiovascular events. However, the development and spatial distribution of coronary calcifications remain unclear. We investigated the spatial distribution of calcifications throughout the coronary tree during coronary artery evaluation using coronary computed tomography angiography (CTA). A further aim was to assess the progression of existing calcifications and the development of new deposits in a follow-up study. The study population consisted of 287 patients for the cross sectional study using CTA to evaluate the spatial distribution of calcifications by parent coronary arteries. Next, we analyzed a CTA dataset of 57 patients who had undergone two CTA examinations. In this group, the two CTA images were used for assessing the progression of existing calcifications and the development of new deposits. The coronary calcifications tended to be clustered within the proximal and middle portions. Moreover, in the proximal left anterior descending coronary artery (LAD), small calcifications were located more toward the inner pericardial side. Finally, new calcium deposits developed within the proximal and middle portions of the LAD and left circumflex coronary artery, but those in the right coronary artery were likely to appear evenly from the proximal to the distal portion. This study shows the characteristic patterns of the longitudinal and circumferential distribution of calcifications by parent coronary arteries. PMID- 25712609 TI - Sinus floor elevation outcomes following perforation of the Schneiderian membrane. An experimental study in sheep. AB - OBJECTIVE: To assess the influence of a collagen membrane covering a perforation of the sinus (Schneiderian) membrane on the outcome (bone fill) of a sinus floor elevation. MATERIALS AND METHODS: Eighteen Pelibuey sheep were used. The animals underwent sinus floor elevation on both sides of the upper jaw. A perforation of 5 * 4 mm in dimension of the sinus mucosa was performed on both sides and, at a randomly selected test site, a collagen membrane was placed to cover the perforation. A graft of biphasic calcium phosphate (60% HA/40% beta-TCP) was subsequently placed bilaterally, and the access window was closed with a membrane made of polylactic acid and a citric acid ester acetyl. The sacrifices were performed after 2, 4, and 12 weeks of healing. RESULTS: After 2 weeks of healing, the augmented volume was filled with biomaterial surrounded by connective tissue and minimal new bone was detected. After 4 weeks of healing, new bone was found mainly in connection with the sinus bony walls with percentages of 18.0 +/- 12.9% at the test and 12.3 +/- 7.9% at the control sites. After 12 weeks of healing, similar amounts of newly formed bone were found compared to the previous healing period, namely 16.7 +/- 8.0% and 13.7 +/- 10.1% at the test and control sites, respectively, with the highest amount detected in the bottom of the sinus cavity. The newly formed bone was distributed more evenly within the sinus cavity also including the central areas. The differences between test and control sites did not reach statistical significance. CONCLUSION: Even though there were trends for more bone formation when applying a collagen membrane on a sinus mucosal perforation of relatively small dimensions, this study failed to establish the absolute necessity of such a procedure to achieve bone fill in the sinus cavity. PMID- 25712610 TI - Leaching of DOC, DN, and inorganic constituents from scrap tires. AB - One concern for recycle and reuse of scrap tires is the leaching of tire constituents (organic and inorganic) with time, and their subsequent potential harmful impacts in environment. The main objective of this study was to examine the leaching of dissolved organic carbon (DOC), dissolved nitrogen (DN), and selected inorganic constituents from scrap tires. Different sizes of tire chips and crumb rubber were exposed to leaching solutions with pH's ranging from 3.0 to 10.0 for 28days. The leaching of DOC and DN were found to be higher for smaller size tire chips; however, the leaching of inorganic constituents was independent of the size. In general, basic pH conditions increased the leaching of DOC and DN, whereas acidic pH conditions led to elevated concentrations of metals. Leaching was minimal around the neutral pH values for all the monitored parameters. Analysis of the leaching rates showed that components associated with the rubbery portion of the tires (DOC, DN, zinc, calcium, magnesium, etc.) exhibited an initial rapid followed by a slow release. On the other hand, a constant rate of leaching was observed for iron and manganese, which are attributed to the metal wires present inside the tires. Although the total amounts that leached varied, the observed leaching rates were similar for all tire chip sizes and leaching solutions. Operation under neutral pH conditions, use of larger size tire chips, prewashing of tires, and removal of metal wires prior to application will reduce the impact of tire recycle and reuse. PMID- 25712613 TI - Rotavirus-associated hemophagocytic lymphohistiocytosis (HLH) after hematopoietic stem cell transplantation for familial HLH. AB - Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disorder of immune regulation. HLH consists of two forms: familial and acquired, the latter which occurs in association with infection, malignancy, rheumatic disease and acquired immune deficiency. Herein, we report a case of acquired HLH in a child who had received allogeneic hematopoietic stem cell transplantation for familial HLH with UNC13D mutation. Based on microbiology, only rotavirus was identified as a possible organism triggering HLH. The patient's fulminant clinical course included acute respiratory failure, a sepsis-like pattern, disseminated intravascular coagulopathy, and rhabdomyolysis, leading to multiorgan failure and death from septic shock. PMID- 25712614 TI - The psychiatrist's duty to protect. AB - Responding to the California Supreme Court's decision and its related legal obligations in Tarasoff v. Regents of Univ. of California over 30 years ago has become a standard part of mental health practice. This case influenced legal requirements governing therapists' duty to protect third parties in nearly every state in the country. The final ruling in Tarasoff emphasized that therapists have a duty to protect individuals who are being threatened with bodily harm by their patients. This article will provide a brief overview and update on duty to protect legal requirements. Clinical guidelines for addressing threats and the duty to protect will be discussed, along with risk management approaches. The article will conclude with a sample vignette illustrating these principles. PMID- 25712611 TI - Reduced frequencies of polyfunctional CMV-specific T cell responses in infants with congenital CMV infection. AB - PURPOSE: CMV infection remains a priority for vaccine development. Vaccination of infants could modify congenital infection and provide lifetime immunity. Properties of CMV-specific T cells associated with control of viral replication in early life have not been fully defined. METHODS: CMV-specific CD4 and CD8 T cell responses were investigated in infants with congenital CMV infection and compared to adults with primary or chronic infection. PBMC were stimulated with UL83 (pp65) or UL122 (IE-2) peptide pools then stained with antibodies to markers of T cell subset (CD4 or CD8), phenotype (CD45RA, CCR7), or function (MIP1beta, CD107, IFNgamma, IL2) for flow cytometry analysis. RESULTS: Detection of CMV pp65 specific CD4 T cells was less common in infants than adults. Responder cells were primarily effector memory (EM, CD45RA-CCR7-) in adults, but mixed memory subsets in infants. Detection of CMV pp65-specific CD8 T cells did not differ between the groups, but infants had lower frequencies of total responding cells and of MIP1beta- or CD107-expressing cells. Responder cells were EM or effector memory RA (CD45RA + CCR7-) in all groups. Polyfunctional T cells were less commonly detected in infants than adults. Responses to IE-2 were detected in adults but not infants. All infants had detectable circulating CMV DNA at initial study (versus 60 % of adults with primary infection) despite longer duration of CMV infection. CONCLUSIONS: Reduced frequencies and altered functional profile of CMV specific CD4 and CD8 T cell responses were detected in infants compared to adults, and were associated with persistent CMV DNA in peripheral blood. PMID- 25712612 TI - A dual-intein autoprocessing domain that directs synchronized protein co expression in both prokaryotes and eukaryotes. AB - Being able to coordinate co-expression of multiple proteins is necessary for a variety of important applications such as assembly of protein complexes, trait stacking, and metabolic engineering. Currently only few options are available for multiple recombinant protein co-expression, and most of them are not applicable to both prokaryotic and eukaryotic hosts. Here, we report a new polyprotein vector system that is based on a pair of self-excising mini-inteins fused in tandem, termed the dual-intein (DI) domain, to achieve synchronized co-expression of multiple proteins. The DI domain comprises an Ssp DnaE mini-intein N159A mutant and an Ssp DnaB mini-intein C1A mutant connected in tandem by a peptide linker to mediate efficient release of the flanking proteins via autocatalytic cleavage. Essentially complete release of constituent proteins, GFP and RFP (mCherry), from a polyprotein precursor, in bacterial, mammalian, and plant hosts was demonstrated. In addition, successful co-expression of GFP with chloramphenicol acetyltransferase, and thioredoxin with RFP, respectively, further substantiates the general applicability of the DI polyprotein system. Collectively, our results demonstrate the DI-based polyprotein technology as a highly valuable addition to the molecular toolbox for multi-protein co-expression which finds vast applications in biotechnology, biosciences, and biomedicine. PMID- 25712615 TI - Oscillatory synchrony as a mechanism of attentional processing. AB - The question of how the brain selects which stimuli in our visual field will be given priority to enter into perception, to guide our actions and to form our memories has been a matter of intense research in studies of visual attention. Work in humans and animal models has revealed an extended network of areas involved in the control and maintenance of attention. For many years, imaging studies in humans constituted the main source of a systems level approach, while electrophysiological recordings in non-human primates provided insight into the cellular mechanisms of visual attention. Recent technological advances and the development of sophisticated analytical tools have allowed us to bridge the gap between the two approaches and assess how neuronal ensembles across a distributed network of areas interact in visual attention tasks. A growing body of evidence suggests that oscillatory synchrony plays a crucial role in the selective communication of neuronal populations that encode the attended stimuli. Here, we discuss data from theoretical and electrophysiological studies, with more emphasis on findings from humans and non-human primates that point to the relevance of oscillatory activity and synchrony for attentional processing and behavior. These findings suggest that oscillatory synchrony in specific frequencies reflects the biophysical properties of specific cell types and local circuits and allows the brain to dynamically switch between different spatio temporal patterns of activity to achieve flexible integration and selective routing of information along selected neuronal populations according to behavioral demands. This article is part of a Special Issue entitled SI: Prediction and Attention. PMID- 25712616 TI - A crossed molecular beam and ab initio study on the formation of 5- and 6-methyl 1,4-dihydronaphthalene (C11H12) via the reaction of meta-tolyl (C7H7) with 1,3 butadiene (C4H6). AB - The crossed molecular beam reactions of the meta-tolyl radical with 1,3-butadiene and D6-1,3-butadiene were conducted at collision energies of 48.5 kJ mol(-1) and 51.7 kJ mol(-1). The reaction dynamics propose a complex-forming reaction mechanism via addition of the meta-tolyl radical with its radical center either to the C1 or C2 carbon atom of the 1,3-butadiene reactant forming two distinct intermediates, which are connected via migration of the meta-tolyl group. Considering addition to C1 proceeds by formation of a van-der-Waals complex below the energy of the separated reactants, we propose that in cold molecular clouds holding temperatures as low as 10 K, the reaction of the meta-tolyl radical with 1,3-butadiene is de-facto barrier less. At elevated temperatures such as in combustion processes, the reaction can also proceed via addition to C2 by overcoming the entrance barrier to addition (11 kJ mol(-1)). Eventually, the resonantly stabilized free radical intermediate C11H13 undergoes isomerization to a cis form, followed by rearrangement through two distinct ring closures at the para- and ortho-position of tolyl radical to yield cyclic intermediates. These intermediates then emit a hydrogen atom forming 6- and 5-methyl-1,4 dihydronaphthalene via tight exit transition states. The steady state branching ratio, 70.0% and 29.2%, at the collision energy of 51.7 kJ mol(-1), of 6- and 5 methyl-1,4-dihydronaphthalene, respectively, is determined mainly by the rates of reverse ring opening of cyclic intermediates. The formation of the thermodynamically less stable 1-meta-tolyl-trans-1,3-butadiene was found to be a less important pathway (0.8%). The reaction of the meta-tolyl radical with 1,3 butadiene leads without entrance barrier to two methyl substituted PAH derivatives holding 1,4-dihydronapthalene cores: 5- and 6-methyl-1,4 dihydronaphthalene thus providing a barrierless route to odd-numbered PAH derivatives under single collision conditions. PMID- 25712617 TI - New self-assembling multifunctional templates for the biofabrication and controlled self-release of cultured tissue. AB - The need to source live human tissues for research and clinical applications has been a major driving force for the development of new biomaterials. Ideally, these should elicit the formation of scaffold-free tissues with native-like structure and composition. In this study, we describe a biologically interactive coating that combines the fabrication and subsequent self-release of live purposeful tissues using template-cell-environment feedback. This smart coating was formed from a self-assembling peptide amphiphile comprising a protease cleavable sequence contiguous with a cell attachment and signaling motif. This multifunctional material was subsequently used not only to instruct human corneal or skin fibroblasts to adhere and deposit discreet multiple layers of native extracellular matrix but also to govern their own self-directed release from the template solely through the action of endogenous metalloproteases. Tissues recovered through this physiologically relevant process were carrier-free and structurally and phenotypically equivalent to their natural counterparts. This technology contributes to a new paradigm in regenerative medicine, whereby materials are able to actively direct and respond to cell behavior. The novel application of such materials as a coating capable of directing the formation and detachment of complex tissues solely under physiological conditions can have broad use for fundamental research and in future cell and tissue therapies. PMID- 25712618 TI - IL-6 and IGF-1 Signaling Within and Between Muscle and Bone: How Important is the mTOR Pathway for Bone Metabolism? AB - Insulin-like growth factor 1 (IGF-1) and interleukin 6 (IL-6) play an important role in the adaptation of both muscle and bone to mechanical stimuli. Here, we provide an overview of the functions of IL-6 and IGF-1 in bone and muscle metabolism, and the intracellular signaling pathways that are well known to mediate these functions. In particular, we discuss the Akt/mammalian target of rapamycin (mTOR) pathway which in skeletal muscle is known for its key role in regulating the rate of mRNA translation (protein synthesis). Since the role of the mTOR pathway in bone is explored to a much lesser extent, we discuss what is known about this pathway in bone and the potential role of this pathway in bone remodeling. We will also discuss the possible ways of influencing IGF-1 or IL-6 signaling by osteocytes and the clinical implications of pharmacological or nutritional modulation of the Akt/mTOR pathway. PMID- 25712619 TI - Chemotherapy- and irradiation-induced bone loss in adults with solid tumors. AB - It is estimated that bone loss occurs in 70 % of all patients dying from cancer, causing a significant disease burden in cancer patients. Bone loss is caused by cancer itself and its metastases, but also by cancer therapies. Of the cancer therapy-induced bone loss, hormone therapies are best known for their bone damaging abilities. However, chemo- and radiotherapy may result in bone loss too. In this review, direct and indirect effects of various chemotherapies (such as methotrexate, imatinib, and taxanes) that cause bone loss are discussed. Furthermore, we discuss bone loss caused by radiotherapy and radionuclides, of which the latter may be reduced with the introduction of the alpha-emitter Radium 223. Finally, agents preventing chemotherapy- or radiotherapy-induced bone loss, in particular denosumab and bisphosphonates, are being reviewed for their efficacy in preventing chemotherapy- and irradiation-induced bone loss in cancer patients. PMID- 25712620 TI - Dosimetry determines the initial OH radical concentration in fast photochemical oxidation of proteins (FPOP). AB - Fast photochemical oxidation of proteins (FPOP) employs laser photolysis of hydrogen peroxide to give OH radicals that label amino acid side-chains of proteins on the microsecond time scale. A method for quantitation of hydroxyl radicals after laser photolysis is of importance to FPOP because it establishes a means to adjust the yield of *OH, offers the opportunity of tunable modifications, and provides a basis for kinetic measurements. The initial concentration of OH radicals has yet to be measured experimentally. We report here an approach using isotope dilution gas chromatography/mass spectrometry (GC/MS) to determine quantitatively the initial *OH concentration (we found ~0.95 mM from 15 mM H2O2) from laser photolysis and to investigate the quenching efficiencies for various *OH scavengers. PMID- 25712621 TI - Editorial comment for Sharma et al. PMID- 25712622 TI - Quercetin ameliorates dysregulation of lipid metabolism genes via the PI3K/AKT pathway in a diet-induced mouse model of nonalcoholic fatty liver disease. AB - SCOPE: Flavonoids and related compounds seem to have favorable effects on nonalcoholic fatty liver disease (NAFLD) progression, although the exact mechanisms implicated are poorly understood. In this study, we aimed to investigate the effect of the flanovol quercetin on gene expression deregulation involved in the development of NAFLD, as well as the possible implication of phosphatidylinositol 3-kinase (PI3K)/AKT pathway modulation. METHODS AND RESULTS: We used an in vivo model based on methionine- and choline-deficient (MCD) diet fed mice and an in vitro model consisting of Huh7 cells incubated with MCD medium. MCD-fed mice showed classical pathophysiological characteristics of nonalcoholic steatohepatitis, associated with altered transcriptional regulation of fatty acid uptake- and trafficking-related gene expression, with increased lipoperoxidation. PI3K/AKT pathway was activated by MCD and triggered gene deregulation causing either activation or inhibition of all studied genes as demonstrated through cell incubation with the PI3K-inhibitor LY294002. Treatment with quercetin reduced AKT phosphorylation, and oxidative/nitrosative stress, inflammation and lipid metabolism-related genes displayed a tendency to normalize in both in vivo and in vitro models. CONCLUSION: These results place quercetin as a potential therapeutic strategy for preventing NAFLD progression by attenuating gene expression deregulation, at least in part through PI3K/AKT pathway inactivation. PMID- 25712623 TI - A qualitative method for prediction of amine oxidation in methanol and water. AB - We have developed a predictive method, based on quantum chemical calculations, that qualitatively predicts N-oxidation by hydrogen peroxides in drug structures. The method uses linear correlations of two complementary approaches to estimate the activation barrier without calculating it explicitly. This method can therefore be automated as it avoids demanding transition state calculations. As such, it may be used by chemists without experience in molecular modeling and provide additional understanding to experimental findings. The predictive method gives relative rates for N,N-dimethylbenzylamine and N-methylmorpholine in good agreement with experiments. In water, the experimental rate constants show that N,N-dimethylbenzylamine is oxidized three times faster than N-methylmorpholine and in methanol it is two times faster. The method suggests it to be two and five times faster, respectively. The method was also used to correlate experimental with predicted activation barriers, linear free-energy relationships, for a test set of tertiary amines. A correlation coefficient R(2) = 0.74 was obtained, where internal diagnostics in the method itself allowed identification of outliers. The method was applied to four drugs: caffeine, azelastine, buspirone, and clomipramine, all possessing several nitrogens. Both overall susceptibility and selectivity of oxidation were predicted, and verified by experiments. PMID- 25712624 TI - Exercise-induced pulmonary haemorrhage: A progressive disease affecting performance? PMID- 25712626 TI - Idelalisib- a PI3Kdelta targeting agent for B-cell malignancies. AB - Idelalisib, the first in-class phosphotidlyinositol 3-kinase delta (PI3Kdelta) inhibitor, was approved by the US Food and Drug Administration in July 2014. It simultaneously received breakthrough therapy designation in combination with rituximab for the treatment of relapsed chronic lymphocytic leukemia (CLL) as well as accelerated approval as monotherapy for the treatment of relapsed follicular lymphoma and relapsed small lymphocytic lymphoma. In a pivotal phase III study of 220 patients with relapsed CLL, the overall response rate of patients who received rituximab plus idelalisib was 81%. The median progression free survival (PFS) was 5 months with rituximab plus placebo group, but was not reached in the idelalisib arm. At 24 weeks, the PFS in patients receiving idelalisib was 93%. In a phase II trial of 125 patients with relapsed or refractory indolent non-Hodgkin lymphoma who received idelalisib 150 mg twice daily, the response rate was 57%. Complete response was seen in 6% of patients. The median duration of response was 12.5 months, and median PFS was 11 months. Idelalisib is a promising new therapy for relapsed indolent B-cell malignancies. PMID- 25712625 TI - Synchronous gastric and ampullary adenocarcinomas in a hairy cell leukemia patient treated with pentostatin eight years prior. AB - Hairy cell leukemia patients are at increased risk for second malignancies, including both solid and lymphoid neoplasms. Along with other factors, multiple immune defects present in hairy cell leukemia likely contribute to subsequent carcinogenesis. We report herein a case of synchronous high-grade gastric and ampullary adenocarcinomas in a patient with a history of hairy cell leukemia treated eight years prior with pentostatin. We include a review of immune alterations induced by both hairy cell leukemia and its therapies, and link them with the occurrence of second cancers in these patients. PMID- 25712627 TI - Ipilimumab-induced necrotic myelopathy in a patient with metastatic melanoma: A case report and review of literature. AB - Ipilimumab is a novel humanized monoclonal antibody directed against cytotoxic T lymphocyte antigen 4, a T-cell surface molecule involved in down-regulation and suppression of the T cell response to stimuli. Patients treated with ipilimumab are at risk for immune-related adverse events involving the skin, digestive tract, liver and endocrine organs. Few case reports of immune-related adverse effects involving central or peripheral nervous system due to ipilimumab are published. These include inflammatory myopathy, aseptic meningitis, severe meningo-radiculo-neuritis, temporal arteritis, Guillain-Barre syndrome, and posterior reversible encephalopathy syndrome. We report the first case of ipilimumab-induced progressive necrotic myelopathy. PMID- 25712628 TI - Tracking quicksilver: estimation of mercury waste from consumer products and subsequent verification by analysis of soil, water, sediment, and plant samples from the Cebu City, Philippines, landfill. AB - Source attribution of mercury (Hg) is critical for policy development to minimize the impact of Hg in wastes. Mercury content of consumer products and its subsequent release into the waste stream of Cebu City, Philippines, is estimated through surveys that employed validated, enumerator-administered questionnaires. Initially, a citywide survey (n = 1636) indicates that each household annually generates 1.07 ppm Hg (i.e., mg Hg/kg waste) and that linear and compact fluorescent lamps (17.2 %) and thermometers (52.1 %) are the major sources of Hg. A subsequent survey (n = 372) in the vicinity of the city's municipal solid waste landfill shows that residents in the area annually generate 0.38 ppm Hg per household, which is less than the citywide mean; surprisingly though, less affluent respondents living closer to the landfill site reported more Hg from thermometers and sphygmomanometers. Analysis of collected soil (0.238 ppm), leachate water (6.5 ppb), sediment (0.109 ppm), and three plants (0.393 to 0.695 ppm) shows no significant variation throughout five stations in and around the landfill site, although the period of collection is significant for soil (P = 0.001) and Cenchrus echinatus (P = 0.016). Detected Hg in the landfill is considerably less than the annual estimated release, indicating that there is minimal accumulation of Hg in the soil or in plants. As a result of this project, a policy brief has been provided to the Cebu City council in aid of hazardous waste legislation. PMID- 25712629 TI - Occurrence and analysis of endocrine-disrupting compounds in a water supply system. AB - This paper presents the study of the occurrence of 10 endocrine-disrupting compounds (EDCs) in 60 water samples using a method for simultaneous quantification and confirmation of the presence of these emerging compounds, using ultra-performance liquid chromatography with electrospray ionization and tandem mass spectrometry (UPLC-ESI-MS/MS). All samples were previously extracted by solid-phase extraction (SPE). Several natural and synthetic hormones (17-beta estradiol, ethinylestradiol, estriol, estrone, progesterone, mestranol, and diethylstilbestrol) and some industrial products (4-n-nonylphenol, 4-tert octylphenol, and bisphenol A) were chosen for this survey. The analytical limits were calculated for each compound and were used in the identification and quantification of these target compounds in EPAL's water supply system. In this study, several samples were taken from the main intakes of water (surface and groundwater) used for production of water for human consumption and from different sampling points of the drinking water distribution system (piping, nets, and reservoirs). Some target compounds, such as estriol, 4-tert octylphenol, mestranol, and nonylphenol, were found in trace amounts in several water samples. However, the studied endocrine-disrupting appeared in very low concentrations when compared with the assessed analytical limits. PMID- 25712630 TI - Association of rhinostomy shape and surgical outcome after endoscopic endonasal dacryocystorhinostomy. AB - PURPOSE: The purpose of this study was to investigate surgical outcomes and complications after endoscopic endonasal dacryocystorhinostomy (EDCR) in relation to rhinostomy shape. METHODS: A retrospective electronic medical record review of patients who underwent EDCR for primary acquired nasolacrimal duct obstruction (PANDO) was performed. Surgical success rates and postoperative complications were compared among three groups of patients in relation to rhinostomy shape (alcove, cavern, or concealed cavern). RESULTS: A total of 280 patients (358 eyes) were included in the study. Of the 358 eyes, 194 rhinostomies were alcove shaped, 157 were cavern-shaped, and 7 were concealed cavern-shaped. There were no patients with flat-shaped rhinostomies. The nasal cavity was wider in patients in the alcove group than those in the cavern and concealed cavern groups (p = 0.012). The mean time to tube removal was longest in the concealed cavern group (p = 0.029). There were no significant differences in anatomical success rates among the three groups (p = 0.338). With regard to functional success for patients with anatomically patent DCR, the cavern and concealed cavern groups had significantly poorer results than the alcove group (p = 0.001). Functional success rates were 91.6 %, 84.8 %, and 57.1 % for the alcove, cavern, and concealed cavern groups, respectively. Development of postoperative granuloma was more frequent in the concealed cavern group (85.7 %) than in the alcove (29.3 %) or cavern groups (26.1 %) (p= 0.003). Multiple logistic regression models for surgical outcome showed that rates of functional failure after EDCR were influenced by patient age and rhinostomy shape (odds ratio 1.824, p = 0.045 for age; odds ratio = 9.605, p = 0.000 for rhinostomy shape) (Table 5). CONCLUSIONS: The incidence rate of symptomatic epiphora after EDCR was approximately 12 %, and this result may have been associated with cavernous and concealed rhinostomy shapes. For patients with persistent epiphora and anatomically patent DCR, it is important to identify rhinostomy shape by endoscopy in order to differentiate causes of functional failure. PMID- 25712632 TI - Etiology of non-immune hydrops fetalis: An update. AB - Hydrops fetalis is an excessive fluid accumulation within the fetal extra vascular compartments and body cavities. Non-immune hydrops fetalis (NIHF), due to causes other than Rh alloimmunization, is the cause in >85% of all affected individuals. Herein we present an update of our earlier systematic literature review [Bellini et al., 2009] using all publications between 2007 and 2013. We excluded most of the initial 31,783 papers by using strict selection criteria, thus resulting in 24 relevant NIHF publications describing 1,338 individuals with NIHF. We subdivided the affected individuals into 14 classification groups based on the cause of NIHF (percentage of the total group): Cardiovascular (20.1%), Hematologic (9.3%), Chromosomal (9.0%), Syndromic (5.5%), Lymphatic Dysplasia (15.0%), Inborn Errors of Metabolism (1.3%), Infections (7.0%), Thoracic (2.3%), Urinary Tract Malformations (0.9%), Extra Thoracic Tumors (0.7%), TTTF-Placental (4.1%), Gastrointestinal (1.3%), Miscellaneous (3.6%), Idiopathic (19.8%). We discuss the results of the review. There may be some shifts in the percentages of etiological categories as compared to the previous review, but the small numbers within each category make drawing firm conclusions hazardous. We highlight the need for multi-center series of NIHF cases collected and classified using the same schemes in diagnostic work-ups to allow for comparisons of larger numbers of cases. PMID- 25712631 TI - Separate and interactive contributions of weak inhibitory control and threat sensitivity to prediction of suicide risk. AB - Biobehavioral dispositions can serve as valuable referents for biologically oriented research on core processes with relevance to many psychiatric conditions. The present study examined two such dispositional variables-weak response inhibition (or disinhibition; INH-) and threat sensitivity (or fearfulness; THT+)-as predictors of the serious transdiagnostic problem of suicide risk in two samples: male and female outpatients from a U.S. clinic (N=1078), and a population-based male military cohort from Finland (N=3855). INH- and THT+ were operationalized through scores on scale measures of disinhibition and fear/fearlessness, known to be related to DSM-defined clinical conditions and brain biomarkers. Suicide risk was assessed by clinician ratings (clinic sample) and questionnaires (both samples). Across samples and alternative suicide indices, INH- and THT+ each contributed uniquely to prediction of suicide risk beyond internalizing and externalizing problems in the case of the clinic sample where diagnostic data were available. Further, in both samples, INH- and THT+ interactively predicted suicide risk, with individuals scoring concurrently high on both dispositions exhibiting markedly augmented risk. Findings demonstrate that dispositional constructs of INH- and THT+ are predictive of suicide risk, and hold potential as referents for biological research on suicidal behavior. PMID- 25712633 TI - Characterization of traumatic brain injury in human brains reveals distinct cellular and molecular changes in contusion and pericontusion. AB - Traumatic brain injury (TBI) contributes to fatalities and neurological disabilities worldwide. While primary injury causes immediate damage, secondary events contribute to long-term neurological defects. Contusions (Ct) are primary injuries correlated with poor clinical prognosis, and can expand leading to delayed neurological deterioration. Pericontusion (PC) (penumbra), the region surrounding Ct, can also expand with edema, increased intracranial pressure, ischemia, and poor clinical outcome. Analysis of Ct and PC can therefore assist in understanding the pathobiology of TBI and its management. This study on human TBI brains noted extensive neuronal, astroglial and inflammatory changes, alterations in mitochondrial, synaptic and oxidative markers, and associated proteomic profile, with distinct differences in Ct and PC. While Ct displayed petechial hemorrhages, thrombosis, inflammation, neuronal pyknosis, and astrogliosis, PC revealed edema, vacuolation of neuropil, axonal loss, and dystrophic changes. Proteomic analysis demonstrated altered immune response, synaptic, and mitochondrial dysfunction, among others, in Ct, while PC displayed altered regulation of neurogenesis and cytoskeletal architecture, among others. TBI brains displayed oxidative damage, glutathione depletion, mitochondrial dysfunction, and loss of synaptic proteins, with these changes being more profound in Ct. We suggest that analysis of markers specific to Ct and PC may be valuable in the evaluation of TBI pathobiology and therapeutics. We have characterized the primary injury in human traumatic brain injury (TBI). Contusions (Ct) - the injury core displayed hemorrhages, inflammation, and astrogliosis, while the surrounding pericontusion (PC) revealed edema, vacuolation, microglial activation, axonal loss, and dystrophy. Proteomic analysis demonstrated altered immune response, synaptic and mitochondrial dysfunction in Ct, and altered regulation of neurogenesis and cytoskeletal architecture in PC. Ct displayed more oxidative damage, mitochondrial, and synaptic dysfunction compared to PC. PMID- 25712634 TI - Features of chemical bonds based on the overlap polarizabilities: diatomic and solid-state systems with the frozen-density embedding approach. AB - The chemical bond overlap properties were obtained for alkali halides NaY (Y = F, Cl, Br), alkaline-earth chalcogenides MX (M = Ca, Mg and X = O, S, Se) and alkali and alkali-earth metals (Li, Na, and Mg) in diatomic and solid-state systems using an embedding approach based on the frozen density functional theory to simulate the crystalline effects. The computational protocol established provides errors for bond distances smaller than 1%. The results indicate that larger chemical bond covalency leads to larger absorption or scattering by the overlap region. The ionic specific valence and overlap polarizability are closely related to the valence orbital compactness measured by the sum of Mulliken electronegativities. The embedding approach used in this work makes it possible to quantify the effects of the crystalline environment on the chemical bond overlap properties. In the solid-state, the bond overlap charges are less polarizable, in cases of well-known ionic systems (provided by electronegativity differences), leading to smaller chemical bond covalency in solids than in diatomics. The spectroscopic properties of the polarizability of the electron density in the overlap region of a chemical bond could be measured in the 1-20 eV spectral region and could be used to characterize some bands in several spectra whose assignments are ambiguous or not available. PMID- 25712635 TI - Activation enthalpies and entropies of the atropisomerization of substituted butyl-bridged biphenyls. AB - A combined quantum chemical and experimental study of the atropisomerization energies of di-para-substituted butyl-bridged biphenyl cyclophanes is presented. We studied the influence of electron donor and electron acceptor substituents on the height of the enantiomerization barrier and examined the enthalpic and entropic contributions. The reaction pathway with minimum and transition state structures was established using density functional theory calculations. The Gibbs free activation energies derived from this pathway correspond well to the ones determined by temperature dependent high performance liquid chromatography (HPLC) measurements. Surprisingly, large discrepancies were found for the contributions of enthalpy and entropy. Thermodynamic data derived from circular dichroism (CD) measurements support the quantum chemical calculations for the distribution of enthalpy and entropy, contrary to the HPLC measurements. Rationalizations for this are given. PMID- 25712636 TI - Impact of aliskiren on some hemostatic parameters in experimental arterial thrombosis in rats. AB - BACKGROUND: Aliskiren is the first orally active inhibitor of renin to be approved for clinical use as an antihypertensive agent. A number of studies show a link between aliskiren and intravascular thrombosis. MATERIALS AND METHODS: The goal of the present study was to investigate the impact of aliskiren on arterial thrombosis in normotensive and renovascular hypertensive rats. The contribution of each coagulation and fibrinolytic parameters in the mode of aliskiren action was determined. Six weeks after clipping of the left renal artery rats developed hypertension which was confirmed by the "tail cuff" method. Animals were treated with aliskiren (10, 30 and 100mg/kg/day) per os for 10 days. Arterial thrombosis was induced by electrical stimulation of the common carotid artery. RESULTS: It was found that aliskiren in a dose-dependent manner decreased weight of the arterial thrombus in normotensive and hypertensive rats. It has been shown that this result was not associated with the effects on blood pressure, TF, PT, APTT, fibrinogen and hematological parameters. It was found that aliskiren caused increase of t-PA activity and decrease of its inhibitor activity. CONCLUSIONS: The presented results indicate that aliskiren inhibits hemostasis in the arterial thrombosis in rats. The antithrombotic effect is related with improvement of the fibrinolytic balance, and also depends on antiplatelet action. PMID- 25712637 TI - Differentiation of adult rat mesenchymal stem cells to GABAergic, dopaminergic and cholinergic neurons. AB - BACKGROUND: Mesenchymal stem cells (MSCs) are able to differentiate into cells from all three germ layers. The aim of the current work was the differentiation rat MSCs into GABAergic, cholinergic and dopaminergic cells. NEW METHOD: In this paper, we present differentiation cocktails with a hippocampal astrocyte conditioned medium and with a glioblastoma conditioned medium. We wanted to maximize the role of endogenous secreted substances by cells from the central nervous system in both combinations. These modifications create a microenvironment of differentiation that is similar to natural conditions. Moreover, the presence of the Cxcr4 receptor on neuron-like cells was investigated first time. RESULTS: Our results show that a differentiation cocktail with a hippocampal astrocyte conditioned medium is the most effective and that 17% Gad67(+) and 7% Acht(+) cells were observed using this protocol. After differentiation using the glioblastoma conditioned medium, 12% Gad67 (+) was observed. The presence of the Cxcr4 migration receptor on Gad67(+) and Th(+) cells were observed, which might suggest the transplantation potential of differentiated cells. COMPARISON WITH EXISTING METHODS: Our results are slightly lower than those of previous studies but when differences in counting cells is taken into account, a comparison of results is really difficult. CONCLUSIONS: These new differentiation cocktails should be further investigated and in the next experiment only a part of MSCs that expressed the Cxcr4 receptor will be differentiated. We suppose that the Cxcr4(+) cells may differentiate more easily and as a result, we may achieve a homogenous population of one phenotype of neurons. PMID- 25712638 TI - Essential elements in depression and anxiety. Part II. AB - In this paper we continue to discuss the involvement of essential elements in depression and anxiety, and the possible mechanisms that link elements to the neurobiology underlying depression/anxiety. The present paper is focused on copper, selenium, manganese, iodine and vanadium. Different aspects of relationship between elements and depression or anxiety are reviewed, e.g. the association of the amount of an element in a diet or the serum level of an element and depressive or anxiety-like symptoms. Moreover, the relation of selected elements to the pathophysiology of depression or anxiety is discussed in the context of enzymes which require these elements as co-factors and are involved in the underlying pathophysiology of these disorders. PMID- 25712639 TI - A review on Alzheimer's disease pathophysiology and its management: an update. AB - Alzheimer's disease acknowledged as progressive multifarious neurodegenerative disorder, is the leading cause of dementia in late adult life. Pathologically it is characterized by intracellular neurofibrillary tangles and extracellular amyloidal protein deposits contributing to senile plaques. Over the last two decades, advances in the field of pathogenesis have inspired the researchers for the investigation of novel pharmacological therapeutics centered more towards the pathophysiological events of the disease. Currently available treatments i.e. acetylcholinesterase inhibitors (rivastigmine, galantamine, donepezil) and N methyl d-aspartate receptor antagonist (memantine) contribute minimal impact on the disease and target late aspects of the disease. These drugs decelerate the progression of the disease, provide symptomatic relief but fail to achieve a definite cure. While the neuropathological features of Alzheimer's disease are recognized but the intricacies of the mechanism have not been clearly defined. This lack of understanding regarding the pathogenic process may be the likely reason for the non-availability of effective treatment which can prevent onset and progression of the disease. Owing to the important progress in the field of pathophysiology in the last couple of years, new therapeutic targets are available that should render the underlying disease process to be tackled directly. In this review, authors will discusses the different aspects of pathophysiological mechanisms behind Alzheimer's disease and its management through conventional drug therapy, including modern investigational therapeutic strategies, recently completed and ongoing. PMID- 25712640 TI - Transcriptional and post-transcriptional regulation of CCN genes in failing heart. AB - BACKGROUND: CCN family of proteins has been implicated in various processes in cardiovascular physiology and pathology, including angiogenesis, regeneration and fibrosis. In this study we assessed long term changes of CCN1 and CCN2 gene products abundance in the failing ventricular myocardium. METHODS: Male, 12-14 weeks-old C57BL6/J and C57BL6/J (IL-6-/-) mice were used. To assess short term changes, a transient reversible ischemia model was utilized. Heart failure was caused by ligation of anterior descending coronary artery. The presence of systolic dysfunction was confirmed by echocardiography and left ventricular ANP RNA expression. Molecular analysis was performed on left ventricular samples from animals sacrificed 12-14 weeks after infarction. Western blotting and QT-PCR were used to investigate abundance of CCN proteins and RNAs, respectively. RESULTS: Short ischemia resulted in marked increase of CCN1 transcript. However, three months after myocardial infarction (MI), remote myocardium showed a markedly increased expression of CCN1 protein, but not RNA. In the case of CCN2, the RNA was distinctly up-regulated, whereas the protein presented only modest, non significant increase in failing myocardium. Expression of CCN2 RNA closely correlated with expression of ANP. Long-term telmisartan administration after infarction decreased the expression of CCN1 protein. Interleukin 6 (IL-6) deficiency caused increased CCN2 protein abundance in control animals, but the difference was absent after MI. Infarction did not increase CCN1 protein in the hearts of IL-6 deficient mice. CONCLUSION: CCN genes are activated in heart failure. Their regulation is multidimensional both transcriptional and posttranscriptional. The involved pathways include angiotensin II and IL-6. PMID- 25712641 TI - Influence of nitric oxide synthase or cyclooxygenase inhibitors on cannabinoids activity in streptozotocin-induced neuropathy. AB - BACKGROUND: Influence of a relatively specific inhibitor cyclooxygenase (COX)-2, celecoxib, a relatively specific inhibitor of neuronal nitric oxide synthase (NOS), 7-Ni, and a relatively selective inhibitor of inducible NOS, L-NIL, on the action of a preferentially selective CB1 cannabinoid receptor agonist, Met-F-AEA and a selective CB2 cannabinoid receptor agonist, AM 1241 was investigated, in a streptozotocin (STZ)-induced neuropathy. METHODS: Studies were performed on male Wistar rats. Changes in nociceptive thresholds were determined using mechanical stimuli - the modification of the classic paw withdrawal test described by Randall-Selitto. Diabetes was induced by a single administration of STZ. RESULTS: In a diabetic neuropathic pain model, pretreatment with celecoxib, L-NIL and 7 Ni, significantly increased the antihyperalgesic activity of both Met-F-AEA and AM 1241. CONCLUSIONS: The results of this study seemed to indicate that the interaction between cannabinoid, COX-2 and NOS(s) systems might exist. Concomitant administration of small doses of CB1 and/or CB2 receptor agonists and COX-2 or NOS inhibitors can be effective in the alleviation of diabetic neuropathic pain. PMID- 25712642 TI - Gambogic amide selectively upregulates TrkA expression and triggers its activation. AB - BACKGROUND: Gambogic amide is the first identified small molecular agonist for TrkA receptor. It mimics NGF functions by selectively activating TrkA receptor and preventing neuron death. However, its function different from that of NGF remains unknown. METHODS: In the current study, we detect the effect of gambogic amide on TrkA expression using TrkA-expressing cell lines in vitro and hippocampi from mice treated with gambogic amide. RESULTS: We have confirmed that gambogic amide displays robust neurotrophic activities in provoking neurite outgrowth in vitro. However, gambiogic amide displays a different kinetics from NGF in activating TrkA signals. NGF swiftly provokes TrkA activation and quickly induces TrkA degradation, while gambogic amid selectively upregulates TrkA protein and mRNA levels in a time-dependent manner. Administration of this compound in mice also activates TrkA receptor in hippocampus and promotes TrkA transcription and expression. CONCLUSION: This study provides a novel mechanism of how gambogic amide regulates TrkA receptor, other than mimicking NGF in triggering TrkA activation. PMID- 25712643 TI - Current scenario in inflammatory bowel disease: drug development prospects. AB - BACKGROUND: Inflammatory bowel disease (IBD) pathophysiology have led to the development of various compounds that might ameliorate the disease process. Recently several failures in terms of developing disease-modifying therapies needs to be communicated effectively as per their process and cause which have led to a debate about the potential deficiencies in our understanding of the pathogenesis of IBD and choice of therapeutic targets. So that the thoroughly development of drug candidates and study design of clinical trials is done. METHODS: Various online medical databases were searched for relevant study and publications. Different clinical trials were reviewed and the available data in clinical trials describing the effective drug development status of IBD medications. RESULTS: The aminosalicylates, anti-inflammatory and biological molecules tested for the treatment of Crohn's disease (CD) and ulcerative colitis (UC) but the risks of common and rare adverse events were found with treatment. Antibiotics and steroid help in reducing the immune response but further studies required on each molecule to substantiate treatment strategies. There has been significant research on different drug molecules as per the phase, which is summarized in this review. CONCLUSIONS: Preclinical research on the complex IBD puzzle coupled with an active and vibrant research agenda in recent decades which might reveal patterns of pharmacological interactions instead of single potential drug targets. The increased collaboration between pharmaceutical companies, basic researchers and clinical researchers has the potential to bring us closer to developing an optimum pharmaceutical approach for the treatment of IBD. PMID- 25712644 TI - Protective effects of various dosage of Curcumin against morphine induced apoptosis and oxidative stress in rat isolated hippocampus. AB - BACKGROUND: During recent years, the defensive role of Curcumin against oxidative stress and apoptosis has been experimentally documented. Long term consumption of morphine induces apoptosis and oxidative stress which may cause serious damage to brain cells. To investigate whether Curcumin could protect rat's hippocampus against morphine induced destruction, we assessed isolated hippocampus cells for oxidative stress, anti oxidant factor and apoptotic factor activities. METHODS: For this, 40 adult male rats were taken and randomly allocated to one of the five groups. Groups 1 and 2 received morphine (45 mg/kg) and normal saline (0.2 ml/rat) respectively for four weeks. Groups 3, 4 and 5 concurrently were treated with morphine (45 mg/kg, sc) and Curcumin (10, 20 and 40 mg/kg) for four weeks. RESULTS: The results showed that morphine significantly increased lipid peroxidation, mitochondrial GSH level, concentration of Bax; caspase-3 and caspase-9 activities while decreasing Bcl-2 concentration. Further, a significant decrease in superoxide dismutase and glutathione peroxidase activity was also observed. Various dosage of Curcumin attenuated these effects by significantly lowering lipid peroxidation, GSSG level, Bax concentration, caspase-3 and caspase 9 activities, while increasing superoxide dismutase and glutathione peroxidase activity, GSH level and Bcl-2 concentration. CONCLUSIONS: These findings have demonstrated that Curcumin can act as an antioxidant and antiapoptotic agent against damage induced by morphine dependence. PMID- 25712645 TI - Synthesis and anticancer activity of 7-hydroxycoumarinyl gallates. AB - BACKGROUND: The search for anti-cancer agents includes naturally occurring substances and theirs modifications. Therefore we invented and designed compounds that represent fused derivatives of gallic acid with coumarins. METHODS: As a result, a series of 8 novel esters of gallic acid and 7-hydroxycoumarins were synthesized and evaluated for anticancer activity. The structures of the compounds were established by IR, (1)H, (13)C NMR and HR MS spectra. The esters were assayed for antiproliferative activity against human leukemia HL-60 and prostate cancer DU145 cell lines. The activity of novel esters was evaluated by cell viability assays as well as by analysis of cell cycle and cell death mechanism. RESULTS: The esters were found to be of similar or higher activity than gallic acid. No pronounced harmful effect was observed in non-cancer cells. CONCLUSIONS: The novel compounds represent an excellent starting point for the further optimization and the design of therapeutically effective anti-cancerous drugs. PMID- 25712646 TI - Antineoplastic effects of deoxypodophyllotoxin, a potent cytotoxic agent of plant origin, on glioblastoma U-87 MG and SF126 cells. AB - BACKGROUND: Deoxypodophyllotoxin (DPT) is a semi-synthetic compound derived from the extract of Dysosma versipellis (Hance) M. Cheng, one of the most popular Chinese herbal medicines. The present study evaluates the in vitro cytotoxicity of DPT on a wide panel of human cancer cell lines and investigates its molecular mechanism of action on high grade glioma U-87 MG and SF126 cells. METHODS: The growth inhibitory effect of DPT on different types of human cancer cells was measured by the Cell Counting Kit-8 (CCK-8) assay. For the elucidation of the nature of the cellular response to DPT-treatment; flow cytometry-based assays, light and fluorescent microscopy, caspase colorimetric and inhibition assays, and Western blot analysis were performed. RESULTS: Our data show that DPT possesses a potent growth-inhibitory action, with IC50 values in nanomolar ranges. Cell cycle analysis revealed G2/M phase arrest in a dose- and time-dependent manner before cell death occurred. Additional studies indicated that DPT induced G2 arrest in U 87 MG cells by decreasing the expression of Cdc2, cyclin B1, and Cdc25C proteins. In contrast, DPT failed to down-regulate these cell cycle regulatory molecules in SF126 glioblastoma cells and stopped the cell cycle at M phase. Interestingly, morphological changes and biochemical markers such as phosphatydylserine externalization, DNA fragmentation, and caspase activation, confirmed that DPT treatment resulted in an induction of apoptosis in both examined cell lines via caspase-dependent pathways. CONCLUSIONS: Taken together, our data demonstrated that DPT possesses a potent in vitro cytotoxic activity and exerts its effect via G2/M arrest and apoptosis. PMID- 25712647 TI - Low-dose ouabain administration increases Na+,K+-ATPase activity and reduces cardiac force development in rats. AB - BACKGROUND: Ouabain is a digitalis compound that inhibits the Na(+),K(+)-ATPase (NKA) activity inducing increment in cardiac force. However, this effect seems to be dose dependent. At low concentration, ouabain can induce an increase of NKA activity. METHODS: We investigated the effects of ouabain administration (25 MUg/kg/day) for 15 days on cardiac contractility and NKA activity. Blood pressure and left ventricular papillary muscle contraction from placebo and ouabain treated rats for 15 (OUA15) days were evaluated. Isometric force, post-rest potentiation, positive inotropic intervention produced by isoproterenol, and tetanic tension were measured. The activity and protein expression levels of alpha1 and alpha2 isoforms of NKA, sodium calcium exchanger (NCX), sarcoplasmic reticulum calcium ATPase (SERCA2a) and phospholamban (PLB) were also measured. RESULTS: Systolic and diastolic blood pressures increased after treatment with ouabain. However, isometric tension was reduced in the ouabain treated group. Post-rest potentiation, time parameters, inotropic interventions by isoproterenol and tetanic tension did not change. In the ouabain treated group, NKA activity was increased (Oua 406.16 +/- 70.6 vs. CT 282.80 +/- 80.5) while protein expression of the alpha1 isoform of NKA was reduced (Oua 0.97 +/- 0.06 vs. CT 0.76 +/- 0.05). No changes were observed in protein expression of alpha2 isoform of NKA, NCX, SERCA2a and PLB. Therefore, although 15-day ouabain treatment increases blood pressure (Oua: 116.4 +/- 3 vs. CT: 99.9 +/- 3), treatment also reduces isometric tension development (Oua: 0.34 +/- 0.14 vs. CT: 0.56 +/- 0.22). CONCLUSION: We suggest that the effects induced by ouabain in the isolated cardiac muscle could be related at least in part, to changes in NKA activity. PMID- 25712648 TI - IL28B polymorphism (rs12979860) associated with clearance of HCV infection in Poland: systematic review of its prevalence in chronic hepatitis C patients and general population frequency. AB - BACKGROUND: A common single nucleotide polymorphism (rs12979860) of the interleukin-28B (IL28B) gene is strongly associated with spontaneous and treatment-related eradication of HCV infection. In this study we estimated rs12979860 genotypes distribution among chronic hepatitis C patients in Poland using a systematic review of published studies and compared this data with the prevalence of rs12979860 variants of IL28B in representative sample of the Southern Poland population. METHODS: Systematic review on rs12979860 variant prevalence in the Polish chronic HCV subjects was performed. Additionally, age- and gender-stratified population sample was recruited from inhabitants of Krakow using a randomized municipal census data, DNA samples available for 538 individuals were genotyped using a real-time PCR method. RESULTS: The frequency of homozygotes TT was from 15 to 27% and carriers of unfavorable T alleles (genotypes CT and TT) were present in 70-80% of chronic HCV subjects. In the general population, 47% individuals were CC homozygous, 42% CT heterozygous and 11% TT homozygous. The population frequency of T allele was 0.318 (95% CI: 0.291 0.347) and the variant was in Hardy-Weinberg equilibrium. Distributions of IL28B genotypes in chronic HCV patients were characterized by a departure from the genetic equilibrium and differed significantly from the random population sample. CONCLUSIONS: Events of spontaneous viral clearance can fully explain differences between genotype distributions in general population and chronic HCV subjects and a departure from the genetic equilibrium. This is the first study estimating the prevalence of IL28B rs12979860 SNP in the Southern Poland population based on a random representative sample. PMID- 25712649 TI - Biofunctional studies of new 2-methoxyphenylpiperazine xanthone derivatives with alpha1-adrenolytic properties. AB - BACKGROUND: The aim of this study was to assess the selectivity of the studied xanthone derivatives for alpha1-adrenoceptor subtypes (alpha1A, alpha1B, alpha1D, alpha1L) in functional experiments in order to verify if they possess any selectivity for a distinct subtype of alpha1-adrenoceptor. Moreover, several pharmacological tests were carried out to assess whether they reveal other than alpha1-adrenoceptor blocking properties such as: antagonistic for 5-HT2 receptors, vasorelaxant or spasmolytic. METHODS: The influence on alpha1A adrenoceptors was examined in biofunctional studies employing isolated rat vas deferens, on alpha1B-adrenoceptors in guinea-pig spleen, on alpha1D-adrenoceptors in rat aorta, and on alpha1L-adrenoceptors in rabbit spleen. Affinity for 5-HT2 receptors was measured in radioligand binding assay, whereas antagonistic potency for 5-HT2 receptors was studied on isolated rat aorta. Vasorelaxant effect of tested compounds was assessed in functional study employing rat aorta, whereas direct spasmolytic activity was investigated using the isolated rabbit small intestine. RESULTS: The present study provides evidences that the tested 2 methoxyphenylpiperazine xanthone derivatives are non-selective alpha1 adrenoceptor blockers. However, at higher concentrations the direct spasmolytic effect could enhance their hypotensive activity. The obtained results indicate that the studied xanthones possessed weak calcium entry blocking activity, as well as antagonistic properties for 5-HT2A receptors. CONCLUSIONS: The results of the present study support the idea that the hypotensive activity of the studied compounds is related to their alpha1-adrenolytic properties. PMID- 25712650 TI - The effects of valproate and olanzapine on the abnormal behavior of diacylglycerol kinase beta knockout mice. AB - BACKGROUND: Diacylglycerol kinase (DGK) is an enzyme that converts diacylglycerol to phosphatidic acid. Previously, we reported that DGKbeta knockout (KO) mice showed mania-like behaviors such as hyperactivity, reduced anxiety, and cognitive impairment. Furthermore, lithium ameliorated the hyperactivity and reduced anxiety of DGKbeta KO mice. In this study, we investigated the effects of the clinically active antimanic drugs valproate and olanzapine on the abnormal behaviors of DGKbeta KO mice. METHODS: Valproate (100mg/kg/day) and olanzapine (1mg/kg/day) were administered intraperitoneally. Following drugs treatments, behavioral tests were performed to investigate locomotor activity, anxiety levels, and cognitive function of the mice. RESULTS: A single treatment of valproate and olanzapine did not ameliorate the hyperactivity or abnormal anxiety level of DGKbeta KO mice. Chronic treatment with valproate and olanzapine significantly decreased locomotor activity and abnormal anxiety levels of DGKbeta KO mice. Additionally, valproate also ameliorated cognitive function of DGKbeta KO mice. CONCLUSION: These results suggest that the abnormal behaviors of DGKbeta KO mice is responsive to antimanic drugs, and that DGKbeta KO mice are useful as an animal model of mania. PMID- 25712651 TI - Neuroprotective effect of noscapine on cerebral oxygen-glucose deprivation injury. AB - BACKGROUND: The present study aims to investigate the effect of noscapine (0.5 2.5 MUM), an alkaloid from the opium poppy, on primary murine fetal cortical neurons exposed to oxygen-glucose deprivation (OGD), an in vitro model of ischemia. METHODS: Cells were transferred to glucose-free DMEM and were exposed to hypoxia in a small anaerobic chamber. Cell viability and nitric oxide production were evaluated by MTT assay and the Griess method, respectively. RESULTS: The neurotoxicities produced by all three hypoxia durations tested were significantly inhibited by 0.5 MUM noscapine. Increasing noscapine concentration up to 2.5 MUM produced a concentration-dependent inhibition of neurotoxicity. Pretreatment of cells with MK-801 (10 MUM), a non-competitive NMDA antagonist, and nimodipine (10nM), an L-type Ca(2+) channel blockers, increased cell viability after 30 min OGD, while the application of NBQX (30 MUM), a selective AMPA-kainate receptor antagonist partially attenuated cell injury. Subsequently, cells treated with noscapine in the presence of thapsigargin (1 MUM), an inhibitor of endoplasmic reticulum Ca(2+) ATPases. After 60 min OGD, noscapine could inhibit the cell damage induced by thapsigargin. However, noscapine could not reduce cell damage induced by 240 min OGD in the presence of thapsigargin. Noscapine attenuated nitric oxide (NO) production in cortical neurons after 30 min OGD. CONCLUSIONS: We concluded that noscapine had a neuroprotective effect, which could be due to its interference with multiple targets in the excitotoxicity process. These effects could be mediated partially by a decrease in NO production and the modulation of intracellular calcium levels. PMID- 25712652 TI - Testicular effect of a mixture of 2-methoxyethanol and 2-ethoxyethanol in rats. AB - BACKGROUND: 2-Methoxyethanol (ME) and 2-ethoxyethanol (EE) represent a large group of chemicals which are used separately or as mixtures. These compounds exert multidirectional toxic effects. The present studies aimed to demonstrate the effects of ME and EE alone and their mixture on the reproductive organs in the rats. METHODS: Male Wistar rats were treated subcutaneously with ME and EE alone (1.25-5.0mM/kg/day) or with their mixture (1:1) for 4 weeks. After completion of the experiment, the testes, epididymides, and prostate were weighed. In post-mitochondrial supernatant of the testes, the level of total protein, non-protein and protein sulfhydryl groups, malondialdehyde, total antioxidant status, and glutathione peroxidase and glutathione reductase activities were determined. RESULTS: Exposure to ME alone resulted in a dose dependent decrease in the organ weights, the total protein, non-protein and protein sulfhydryl groups. EE alone led to less marked alterations. Co-exposure to ME and EE caused alterations similar as in the rats treated with ME alone. CONCLUSIONS: Marked testicular atrophy, decrease in epididymis and prostate weights are predominant effects of the repeated exposure to relatively low doses of ME and EE. A decrease in the total protein level, and protein sulfhydryl groups may be responsible for testicular atrophy. A significant depletion of non protein sulfhydryl groups and occasionally elevated glutathione peroxidase activity may indicate that ME and EE resulted in disturbances of pro oxidant/antioxidant balance. The study suggests that testicular toxicity in male rats co-exposed to ME and EE is mainly caused by the former compound. PMID- 25712653 TI - Genetic polymorphism of ABCB1 gene (C3435T) in patients with inflammatory bowel diseases. Is there any gender dependency? AB - BACKGROUND: In recent years, an increasing incidence of inflammatory bowel disease (IBD) has been reported, mainly as Crohn's disease (CD) and ulcerative colitis (UC). The individual susceptibility, the disease's course and response to the applied therapy is likely due to genetic factors such as ABCB1 gene mutations, exemplified by C3435T polymorphism. The aim of the study was to evaluate the distribution of C3435T polymorphism regarding the gender in IBD patients and control subjects from Lower Silesia region and its possible association with IBD susceptibility. METHODS: The research was conducted in groups of 61 IBD patients and 101 healthy subjects from the Lower Silesia region. Polymorphism of C3435T was determined using PCR-RFLP method. RESULTS: Frequency distributions of C3435T genotype and of 3435T or 3435C gene alleles of IBD, CD or UC patients were compared to control group; each treated as a whole or split further by gender. The statistically significant correlation was discovered between gender and C3435T genotype both for IBD and CD patients, with 3435CT heterozygote prevailing in IBD and CD males. Odds ratio calculations revealed statistically significant difference for the 3435CT genotype between control and: IBD group considered as a whole; IBD males; CD males; and for 3435TT variant between control and IBD males. Conclusions. The 3435CT genotype could be a risk factor for IBD and CD in men. The 3435TT genotype in males seems to be associated with the lower chance of IBD presence. PMID- 25712654 TI - In vivo induction of CYP in mice by carbamazepine is independent on PXR. AB - BACKGROUND: The antiepileptic drug carbamazepine (CBZ) is a typical inducer of cytochrome P450 (CYP) 3A and 2C in the clinic. It is considered a strong constitutive androstane receptor activator, however both CBZ and its main metabolite CBZ 10, 11-epoxide have been reported to be pregnane X receptor (PXR) activators whose maximal efficacy and potency are comparable with the human PXR ligand rifampicin. It is unknown whether or not PXR plays a substantially important role in in vivo induction of CYP by CBZ administration. METHODS: In this study, wild type and Pxr-/- mice were administered with CBZ for 5 days. Serum and liver samples were collected and subjected to hepatotoxicity assessment and CYP induction analysis. RESULTS: CYP2b, 2c and 3a were induced similarly in terms of transcription level, enzyme activity and protein abundance in both wild type and Pxr-/- mice. Inductive profile of CYPs in mice by CBZ administration accorded with those reported in rats, but differed from clinically reported data. CONCLUSIONS: These data suggest that in vivo induction of CYP in mice by multiple administration of CBZ is independent of PXR. Knowledge of the featured CYP induction profile in mice helps us understand species related CYP induction profiles among rodents and humans resulting from administration of CBZ. PMID- 25712655 TI - The effect of ezetimibe-statin combination on steroid hormone production in men with coronary artery disease and low cholesterol levels. AB - BACKGROUND: Aggressive statin treatment was found to slightly reduce testosterone production. The aim of this study was to compare the effects of ezetimibe-statin combination and high-dose statin therapy on testicular and adrenal cortex function in men with LDL cholesterol levels below 70 mg/dL. METHODS: The study included 26 adult men with coronary artery disease. Twelve of these patients did not tolerate high-dose statin therapy and were treated with lower doses of a statin plus ezetimibe. Fourteen patients tolerating high-dose simvastatin or rosuvastatin treatment continued high-dose statin therapy throughout the study period. Plasma lipids, glucose homeostasis markers and plasma levels of testosterone, cortisol, dehydroepiandrosterone sulphate, sex hormone-binding globulin, gonadotropins and ACTH, as well as urine free cortisol were assessed at baseline and after 16 weeks of treatment. RESULTS: Replacing high-dose statin therapy with ezetimibe/statin combination therapy reduced plasma levels of LH by 32% (p=0.043), as well as increased plasma levels of testosterone by 20% (p=0.038). Ezetimibe/statin combination did not induce any significant changes in plasma levels or urine excretion of the remaining hormones. At the end of the study, plasma LH levels were higher, while plasma testosterone levels were lower in patients receiving the combination therapy than in those treated only with high-dose statin. CONCLUSIONS: Our results indicate that ezetimibe combined with moderate statin dose exerts a less pronounced effect on testicular function in comparison with high-dose statin therapy. PMID- 25712656 TI - Ability of natural astaxanthin from shrimp by-products to attenuate liver oxidative stress in diabetic rats. AB - BACKGROUND: Reactive oxygen species play a crucial role in the pathogenesis of diabetes and its complications. The present study was undertaken, in vivo, to examine the protective effect of astaxanthin extracted from the shell waste of deep-water pink shrimp (Parapenaeus longirostris) against oxidative stress of alloxanic adult male rats. RESULTS: Alloxan treatment revealed a significant elevation in plasma glycemia and lipid parameters such as total lipid, total cholesterol and triglycerides compared to the control group (C). In addition, liver malonaldialdehyde levels (MDA), an index of lipid peroxidation, significantly increased compared to control group. The activities of antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GR) and reduced glutathione (GSH) levels decreased significantly compared to control group. Moreover, diabetic rats presented a significant increase in the activities of aspartate transaminase (AST) alanine transaminase (ALT) and alkaline phosphatase (ALP) in plasma, indicating considerable hepatocellular injury. Astaxanthin treatment restores these parameters near to control values. Histological studies on the liver tissue of alloxan and astaxanthin treated rats confirmed the protective effects of astaxanthin. CONCLUSIONS: The results revealed that astaxanthin may be helpful in preventing diabetic complications in adult rats by reversing hepatotoxicity. It can be one of the ingredients in a number of healthy products. PMID- 25712657 TI - Neurotrophic and antioxidant effects of silymarin comparable to 4-methylcatechol in protection against gentamicin-induced ototoxicity in guinea pigs. AB - BACKGROUND: Despite that gentamicin is a very effective aminoglycoside, its potential ototoxicity which is of irreversible nature makes a challenge and limitation for its use. This study was designed to investigate possible neurotrophic and antioxidant effects of silymarin comparable to 4-methylcatechol in protection against gentamicin-induced ototoxicity. METHODS AND RESULTS: Twenty pigmented guinea pigs were divided into four equal groups, where group I served as normal control group. The other groups received gentamicin (120 mg/kg/day, ip) for 19 days where group II given vehicle of 1% CMC, group III and group IV were pre-treated 2h before gentamicin by 4-methylcatechol (10 MUg/kg, ip) and silymarin (100mg/kg, oral gavage), respectively. The main findings indicated that silymarin exhibited restoration of nerve growth factor (NGF) levels and increased tropomyosin-related kinase receptors-A (Trk-A) m-RNA expression in cochlear tissue and preservation of hair cells of organ of Corti by scanning electron microscopy (SEM) with significant decrease in auditory brainstem response (ABR) threshold compared to 4-methylcatechol. Only silymarin caused significant amelioration in oxidative stress state by reducing malondialdehyde (MDA) levels and increasing catalase activity. CONCLUSIONS: Silymarin exerts superiority over 4-methylcatechol when recommended as protective agent against gentamicin ototoxicity based on its efficient neurotrophic and antioxidant activities. PMID- 25712659 TI - The cyclic AMP effects and neuroprotective activities of PACAP and VIP in cultured astrocytes and neurons exposed to oxygen-glucose deprivation. AB - BACKGROUND: Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) are endogenous peptides, widely expressed in the central and peripheral nervous system. The adenylyl cyclase (AC)/cyclic AMP (cAMP) is their main intracellular signal transduction pathway. Numerous data suggest that PACAP and VIP have considerable neuroprotective potential, indicating the possibility for their use as new therapeutic strategies in stroke treatment. The aim of this study was to evaluate the effect of oxygen-glucose deprivation (OGD) - an established in vitro model for ischemic cell stress - on PACAP and VIP-evoked receptor-mediated cAMP generation in glial and neuronal cells, and to determine whether PACAP and VIP have neuroprotective activity under these conditions. METHODS: The formation of [(3)H]cAMP by PACAP, VIP and forskolin (a direct activator of AC) was measured in [(3)H]adenine prelabeled primary rat glial and neuronal cells under normoxia and OGD conditions. The effects of PACAP and VIP on cell viability were measured using the MTT conversion method, and were compared to tacrolimus (FK506), a well known neuroprotective agent. RESULTS: The OGD model inhibited the PACAP and VIP-induced cAMP formation in rat astrocytes and neurons. Incubation of neuronal cells with PACAP prevented OGD-induced cell death, more efficiently than VIP and FK506. CONCLUSION: The obtained results showed that hypoxia/ischemia may trigger down-regulation of the brain AC-coupled PACAP/VIP receptors, with a consequent decrease of PACAP- and/or VIP-ergic-dependent cAMP-driven signaling. Moreover, our findings indicate that PACAP and VIP can prevent the deleterious effect of OGD on rat neuronal cells. PMID- 25712658 TI - Study of the protective effects of nootropic agents against neuronal damage induced by amyloid-beta (fragment 25-35) in cultured hippocampal neurons. AB - BACKGROUND: Alzheimer's disease (AD) is a common neurodegenerative disorder, in which progressive neuron loss, mainly in the hippocampus, is observed. The critical events in the pathogenesis of AD are associated with accumulation of beta-amyloid (Abeta) peptides in the brain. Deposits of Abeta initiate a neurotoxic "cascade" leading to apoptotic death of neurons. Aim of this study was to assess a putative neuroprotective effects of two nootropic drugs: piracetam (PIR) and levetiracetam (LEV) on Abeta-injured hippocampal neurons in culture. METHODS: Primary cultures of rat's hippocampal neurons at 7 day in vitro were exposed to Abeta(25-35) in the presence or absence of nootropics in varied concentrations. Flow cytometry with Annexin V/PI staining was used for counting and establishing neurons as viable, necrotic or apoptotic. Additionally, release of lactate dehydrogenase (LDH) to the culture medium, as a marker of cell death, was evaluated. RESULTS: Abeta(25-35) caused concentration-dependent death of about one third number of hippocampal neurons, mainly through an apoptotic pathway. In drugs-containing cultures, number of neurons injured with 20 MUM Abeta(25-35) was about one-third lesser for PIR and almost two-fold lesser for LEV. When 40 MUM Abeta(25-35) was used, only LEV exerted beneficial neuroprotective action, while PIR was ineffective. CONCLUSIONS: Our results suggest the protective potential of both studied nootropics against Abeta-induced death of cultured hippocampal neurons with more powerful neuroprotective effects of LEV. PMID- 25712660 TI - Effect of diosmin on the intestinal absorption and pharmacokinetics of fexofenadine in rats. AB - BACKGROUND: Diosmin is a natural flavone glycoside, a potent P-glycoprotein (P gp) inhibitor in cultured cells and have the potential to alter the bioavailability of P-gp substrate drugs. However, the interaction between diosmin and fexofenadine is unreported. Hence, the present study was performed to investigate the effect of diosmin on the intestinal absorption and pharmacokinetics of fexofenadine, a P-gp substrate in rats. METHODS: Fexofenadine intestinal transport and permeability were evaluated by in vitro non-everted sac and in situ single pass intestinal perfusion (SPIP) studies. These results were confirmed by an in vivo pharmacokinetic study of oral administered fexofenadine (10mg/kg) in rats. RESULTS: The intestinal transport and apparent permeability (Papp) of fexofenadine were significantly increased in duodenum, jejunum and ileum of diosmin pretreated group as compared with the control. Similarly effective permeability (Peff) of fexofenadine was increased significantly in ileum of diosmin pretreated group as compared with control. In comparison with control, pretreatment with diosmin significantly increased peak plasma concentration (Cmax) and area under the concentration-time curve (AUC), while there was no significant change was observed in half life (T1/2), time to reach peak plasma concentration (Tmax) and elimination rate constant (Kel) of fexofenadine. CONCLUSIONS: Diosmin significantly enhanced the oral bioavailability of fexofenadine by the inhibition of P-gp mediated drug efflux during the intestinal absorption. Co-administration of diosmin with fexofenadine can reduce the dosage and results in reduced side effects of fexofenadine. The clinical relevance of this interaction should be further evaluated in human subjects. PMID- 25712661 TI - Effect of desipramine on gene expression in the mouse frontal cortex - microarray study. AB - BACKGROUND: These studies aimed to identify the genes differentially expressed in the frontal cortex of mice treated repeatedly with either saline or desipramine (DMI). METHODS: Differences in gene expression in the mouse frontal cortex were studied using a whole-genome microarray approach. RESULTS: The analyses revealed a group of 88 transcripts (18 genes) that were differentially expressed between the mice treated with saline and those treated with DMI. These genes include Spnb2, Mef2c, Ncam1, Hsp90ab1, Kif1b, Ddx6 and Gsk3b, which were connected in the gene relationship network. CONCLUSIONS: It appears that one week of DMI administration measurably altered the expression of a small number of genes, including genes connected with neuroplasticity and cytoskeletal changes, the regulation of calcium levels in the cell or translation processes. PMID- 25712662 TI - Anxiogenic- and antidepressant-like behavior in corneally kindled rats. AB - BACKGROUND: Anxiety and depression affect epileptic patients much more often than individuals from the general population. We were interested in whether corneal kindling in rats, which is a model of complex partial seizures with secondary generalization, would influence animal behavior in models of anxiety and depression. METHODS: Kindling was achieved by transcorneal electric stimulation and fully kindled rats were used in this study. Kindled and sham-stimulated rats were subjected to the elevated plus maze and forced swim test which are believed to be predictive models for anxiety and depression in humans, respectively. RESULTS: Kindling significantly decreased the percentage of time spent by the rats in open arms relative to time spent in open plus closed arms and it reduced immobility time in the swim test as compared with sham-stimulated rats. CONCLUSIONS: Our results suggest that corneal kindling produces antidepressant- and anxiety-like effects in rats and it may be a useful model to study epilepsy associated anxiety. PMID- 25712663 TI - Therapeutic effect of aripiprazole in chronic schizophrenia is accompanied by anti-inflammatory activity. AB - BACKGROUND: Weight gain and metabolic abnormalities occur in chronic schizophrenia patients treated with atypical antipsychotics. The purpose of the study was to evaluate changes in serum levels of C-reactive protein (CRP), insulin and cytokines (IL-6, TNF-alpha, IL-1beta, IFN-gamma, sTNF-R1, IL-12, IL 23, IL-1Ra, TGF-beta1, IL-4, and IL-10) after switching to aripiprazole. METHODS: Cytokine, hsCRP and insulin measurements were performed in patients (n=17) on day 0 and day 28 of the study using standard ELISA assays. The psychopathological status was assessed using PANSS. WC and BMI were measured and calculated, respectively. RESULTS: We observed high clinical efficacy in aripiprazole linked to a 2.7% weight loss. There were statistically significant reductions in PANSS scores and body parameters (p<0.001). After 28 days we detected a significant reduction in hsCRP (p<0.001), insulin (p<0.001), IL-1beta, IL-6, TNF-alpha, sTNF R1, IL-12, IL-23, IL-1Ra, TGF-beta1, IL-4 (p<0.001), IFN-gamma (p<0.05) and a significant elevation of IL-10 (p<0.001). There was a significant negative correlation between IL-10 levels and PANSS positive, negative and total scores after the study (p=0.022, p=0.003, p=0.008, respectively). CONCLUSIONS: Aripiprazole limits inflammatory processes by enhancing anti-inflammatory signaling. Aripiprazole also reduces the risk of metabolic abnormalities. PMID- 25712664 TI - Ergotamine and nicergoline - facts and myths. AB - Ergotamine, being a representative of naturally occurring ergoline alkaloids, derived from d-lysergic acid, and nicergoline, a d-lumilysergic acid derivative belonging to semi-synthetic ergot-derived alkaloids, display diversified affinity for adrenergic, serotoninergic, and dopamine receptors. Although introduction of triptans marginalized use of ergotamine, nicergoline is used in cerebral metabolic-vascular disorders, and dementia. Additionally, nicergoline exhibits a safety profile comparable to that of placebo, and none of the reviewed studies reported any incidence of fibrosis or ergotism with nicergoline treatment. In line with the recent data, activation of 5-HT2B receptor by ergot derivatives i.e. ergotamine, methysergide, pergolide, and carbegoline is involved in pathogenesis of drug-induced valvulopathy. In contrary structurally related drugs - lisuride and terguride do not increase the risk of valvular heart disease. It seems, that more detailed mechanistic studies on nicergoline and ergotamine might be beneficial for determining structural requirements related to activation of G protein as well as alternative signal transduction pathways e.g. beta-arrestins or different kinases, and responsible for drug liabilities. PMID- 25712665 TI - Thioflavin T effect in diabetic Wistar rats: reporting the antihyperglycemic property of an amyloid probing dye. AB - BACKGROUND: Thioflavin T (ThT) is a well-known probe of amyloid fibrils with a benzothiazole core structure. As a compound with partial inhibitory effect on alpha-amylase, the results of oral ThT administration were investigated on a streptozotocin (STZ)-induced rat model of diabetes. METHODS: STZ was administered intraperitoneally for induction of diabetes. Afterwards, doses of 2, 8, 16, and 32 mg/kg of ThT were used in diabetic and non-diabetic rats. Blood glucose levels, lipid profiles, alpha-amylase activity, food and water intake and urine volume were assessed. Docking was also performed to evaluate the inhibitory effect of ThT on alpha-amylase. RESULTS: Upon treatment with ThT, blood glucose levels and lipid profile of diabetic rats improved significantly. Furthermore, alpha-amylase serum levels of treated animals decreased compared to the control group, suggesting a possible effect of ThT on this digestive enzyme. On the other hand, the food intake of treated animals showed a decrease. ThT effects were also seen to some extent in the non-diabetic group. CONCLUSION: ThT is suggested to be a potentially useful compound in treatment and prevention of diabetes and associated complications. PMID- 25712666 TI - Omega-3 fatty acids prevent LPS-induced passive avoidance learning and memory and CaMKII-alpha gene expression impairments in hippocampus of rat. AB - BACKGROUND: Neuroinflammation is considered to be a major factor in several neurodegenerative diseases. Recently, the polyunsaturated fatty acid omega-3 has been shown to have anti-inflammatory effects and might play an effective role in improving memory impairment due to inflammation. In order to test this, we stimulated neuroinflammation in an animal model and induced memory dysfunction as measured by reduced retention of passive avoidance learning (PAL) and altered expression of CaMKII-alpha, a gene known to be crucial for memory formation. We then investigated whether treatment with dietary omega-3 prevents inflammation induced memory dysfunction in this model. METHODS: Male wistar rats (200-220 g) were fed either a control diet or a diet containing omega-3 (400mg/kg, po) for 1 month prior. Rats then received injection of either saline or LPS (500 MUg/kg, ip) and were subjected to the PAL acquisition task. The retention test was performed 24h later, and animals were sacrificed immediately. Hippocampi were dissected and stored at -80 degrees C. Finally, TNF-alpha levels and CaMKII-alpha gene expression were measured by ELISA and qRT-PCR, respectively. RESULTS: We found that LPS treatment significantly impaired PAL and memory, increased TNF alpha levels and impaired CaMKII-alpha gene expression. In control and LPS injected animals, pre-treatment with omega-3 improved performance on the PAL task and increased CAMKII-alpha gene expression. CONCLUSION: Taken together, these data suggest that dietary omega-3 may improve cognitive function and provide a potential therapy for memory impairment due to neuroinflammation. PMID- 25712667 TI - The effect of interleukin-35 on the integrity, ICAM-1 expression and apoptosis of human aortic smooth muscle cells. AB - BACKGROUND: Interleukin-35 (IL-35) is a novel immunomodulatory cytokine produced by CD4+ 25+ foxp3+ regulatory T-cells (T regs). Vascular smooth muscle cells (VSMCs) are involved in local immune homeostasis and certain chronic inflammatory pathologies. The effect of IL-35 on electrical impedance reflecting tissue integrity, the surface expression of ICAM-1 and mRNA expression of IL-32, as well as apoptosis in human primary aortic smooth muscle cells (Ao-SMCs) was investigated. METHODS: The influence of IL-35 on Ao-SMC integrity was assessed with the real-time cell electric impedance sensing system (RTCA-DP) based on normalized Cell Index (nCI). Additionally, Ao-SMCs were stimulated with IL-35 in order to assess ICAM-1 surface expression and apoptosis in flow cytometer. IL-32 mRNA expression was measured using real-time PCR. RESULTS: We found that the nCI of Ao-SMCs induced with IL-35 was lower after 12, 24 and 48h of incubation than the nCI of unstimulated cells. IL-35 slightly enhanced ICAM-1 surface expression and increased IL-32 mRNA expression in Ao-SMCs after 24h of induction. However, IL-35 did not affect Ao-SMC apoptosis, necrosis or viability. CONCLUSION: Our data suggest that IL-35 may be an agent affecting the inflammatory properties of AoSMCs and thus it may regulate immune homeostasis of the vascular wall. Hence, IL-35 may be a novel player affecting Ao-SMC-controlled arterial wall immune homeostasis. PMID- 25712668 TI - Tectorigenin ablates the inflammation-induced epithelial-mesenchymal transition in a co-culture model of human lung carcinoma. AB - OBJECTIVES: Tumors not only manage to escape from the host immune system, but they effectively contrive to benefit from infiltrating immune cells by modifying their functions so as to create a pro-inflammatory microenvironment favorable for tumor progression and metastasis. In this study we investigated if tectorigenin could suppress lung cancer-induced pro-inflammatory response generated from monocytes. MATERIALS AND METHODS: A549:THP1 co-culture model was set-up favoring release of pro-inflammatory cytokines interleukin (IL)-6 and tumor necrosis factor alpha (TNF-alpha). Effect of tectorigenin on A549 imparted invasive phenotype of A549:THP-1 co-culture was monitored by cytokine release from monocytes, and metastasis/epithelial-mesenchymal transitiom (EMT) in A549 cells. RESULTS: In a contact A549:THP1 co-culture model, THP-1 cells were activated by A549 cells favoring secretion of pro-inflammatory cytokines, TNF-alpha and IL-6. However, priming of A549 cells with tectorigenin for 24h repressed A549 cell induced secretion of TNF-alpha and IL-6 by THP-1 cells. Tectorigenin induced change in functional phenotype of A549 cells rendered THP-1 cells non-responsive for the secretion of IL-6 and TNF-alpha in a contact co-culture setup. Additionally, conditioned media from this non-responsive A549:THP-1 co-culture suppressed metastatic potential of A549 cells as confirmed by the wound healing and transwell migration assays. These finding were further corroborated by decrease in expression of Snail with a concomitant increase in E-cadherin, the two signature markers of EMT. CONCLUSION: These results clearly demonstrate the therapeutic potential of tectorigenin to prevent lung cancer elicited inflammatory and pro-metastatic response in monocytes and warrants further investigations to elucidate its mechanism of action. PMID- 25712669 TI - Matrine suppresses proliferation and induces apoptosis in human cholangiocarcinoma cells through suppression of JAK2/STAT3 signaling. AB - BACKGROUND: Constitutive activation of signal transducer and activator of transcription 3 (STAT3) signaling contributes to apoptosis resistance in cholangiocarcinoma. The aim of this study is to check whether matrine, an alkaloid isolated from traditional Chinese herb Sophora flavescens ait, can exert cytotoxic effects against cholangiocarcinoma cells via inactivation of STAT3 signaling. METHODS: Mz-ChA-1 and KMCH-1 cholangiocarcinoma cells were treated with matrine at 0.25-2.0 g/L for 48 h and cell viability and apoptosis were assessed. Apoptosis-related molecular changes and STAT3 phosphorylation and transcriptional activities were measured after matrine treatment for 48 h. The effect of expression of a constitutively active STAT3 mutant on matrine-induced apoptosis was determined. RESULTS: Matrine significantly inhibited the viability and induced apoptosis in cholangiocarcinoma cells. Matrine treatment caused loss of mitochondrial membrane potential, release of mitochondrial cytochrome c, and activation of caspase-9 and -3. Matrine-induced apoptosis was inhibited in the presence of the caspase-3 inhibitor Ac-DEVD-CHO. Matrine reduced the phosphorylation levels of Janus kinase 2 (JAK2) and STAT3, inhibited STAT3 dependent transcriptional activity, and downregulated STAT3 target gene Mcl-1. Notably, expression of the constitutively active form of STAT3 significantly antagonized matrine-induced apoptosis of cholangiocarcinoma cells. CONCLUSION: Matrine can trigger mitochondrial apoptotic death of cholangiocarcinoma cells largely through inhibition of JAK2/STAT3 signaling. Therefore, matrine represents a potentially effective anticancer agent for cholangiocarcinoma. PMID- 25712670 TI - The effects of vasoactive peptide urocortin 2 on hemodynamics in spontaneous hypertensive rat and the role of L-type calcium channel and CRFR2. AB - BACKGROUND: Urocortin (UCN) is a newly identified vascular-active peptide that has been shown to reverse cardiovascular remodeling and improve left ventricular (LV) function. The effects and mechanism of urocortin 2 (UCN2) in vivo on the electrical remodeling of left ventricle and the hemodynamics of hypertensive objectives have not been investigated. METHODS: UCN2 (1 MUg/kg/d, 3.5 MUg/kg/d or 7 MUg/kg/d) was intravenously injected for 2 weeks and its effects on hemodynamics in spontaneously hypertensive rats (SHRs) observed. The whole-cell patch clamp technique was used to explore the effects of UCN2 on the electrical remodeling of left ventricular cardiomyocytes. The flow cytometry method was used to determine the content of fluorescence calcium in myocardium. RESULTS: UCN2 improved the systolic and diastolic function of SHRs as demonstrated by decreased left ventricular systolic pressure (LVSP), left ventricular end diastolic pressure (LVEDP), increased +dp/dtmax and -dp/dtmax and decreased cAMP level. UCN2 inhibited the opening of L-type calcium channel and decreased the calcium channel current of cardiomyocytes. In addition, UCN2 also decreased the contents of fluorescence calcium in SHR myocardium. However, astressin2-B (AST-2B), the antagonist of corticotropin-releasing factor receptor 2 (CRFR2), could reverse the inhibitory effects of UCN2 on calcium channel. CONCLUSION: UCN2 can modulate electrical remodeling of the myocardium and hemodynamics in an experimental model of SHR via inhibition of L-type calcium channel and CRFR2 in cardiomyocytes. PMID- 25712671 TI - Involvement of nitridergic and opioidergic pathways in the antinociception of gabapentin in the orofacial formalin test in mice. AB - BACKGROUND: Pain is one of the most common problems in clinical medicine. There is considerable evidence that pharmacologic approaches are the most widely used therapeutic options to ameliorate persistent or chronic pain. In this study it was evaluated the effect of l-NAME and naltrexone in the antinociception induced by administration of gabapentin in the orofacial formalin test of mice. METHODS: The algesiometer assay was performed by the administration of 20 MUl of 2% formalin solution injected into the upper right lip of each mouse. RESULTS: The dose of gabapentin that produces the 50% of the maximum possible effect (ED50) was significantly increased by the pretreatment with l-NAME or naltrexone. CONCLUSIONS: These results suggest that gabapentin produce antinociception partly via the activation nitridergic pathways and opioid system. PMID- 25712672 TI - Annexin A2 is required for the early steps of cytokinesis. AB - Cytokinesis requires the formation of an actomyosin contractile ring between the two sets of sister chromatids. Annexin A2 is a calcium- and phospholipid-binding protein implicated in cortical actin remodeling. We report that annexin A2 accumulates at the equatorial cortex at the onset of cytokinesis and depletion of annexin A2 results in cytokinetic failure, due to a defective cleavage furrow assembly. In the absence of annexin A2, the small GTPase RhoA-which regulates cortical cytoskeletal rearrangement-fails to form a compact ring at the equatorial plane. Furthermore, annexin A2 is required for cortical localization of the RhoGEF Ect2 and to maintain the association between the equatorial cortex and the central spindle. Our results demonstrate that annexin A2 is necessary in the early phase of cytokinesis. We propose that annexin A2 participates in central spindle-equatorial plasma membrane communication. PMID- 25712673 TI - What Does the Shipley-2 Measure for Children and Adolescents? Integrated and Conjoint Confirmatory Factor Analysis With the WISC-IV. AB - We used integrated and conjoint confirmatory factor analysis of Shipley-2 and Wechsler Intelligence Scale for Children-Fourth Edition (WISC-IV) data to investigate constructs measured in the Shipley-2 for children and adolescents. We also estimated Shipley-2 composite reliability at the subtest level rather than the item level. The three Shipley-2 subtests for the most part measured what was described in the manual, although Block Patterns measured visual spatial ability in addition to fluid ability and Abstraction was best considered a measure of psychometric g. The g factors derived from the WISC-IV and Shipley-2 were similar but not identical. Internal reliability estimates for Shipley-2 composites that were based on correlations between the subtests were substantially lower than those based on the items. Last, based on WISC-IV derived g factors, 37% to 53% of the variance in Shipley-2 composites was explained by g. Some of the reliable variance in the Shipley-2 composites was due to something specific that the subtests had in common not explained by psychometric g. PMID- 25712674 TI - Development and Validation of a Measure of Self-Critical Rumination. AB - Self-criticism is a form of negative self-evaluation that has strong associations with many forms of psychopathology. Rumination is a maladaptive form of repetitive thinking that is associated with many psychological disorders. Although measures of several different types of rumination (e.g., general rumination, depressive rumination, anger rumination) have been developed, none focuses specifically on self-critical rumination. An initial pool of items addressing self-critical rumination was developed by adapting items from existing rumination measures and through a writing task administered to both student and clinical samples. Following an evaluation of content validity, 24 items were administered to a large sample of undergraduates along with measures of related constructs. The final 10-item version of the Self-Critical Rumination Scale showed excellent internal consistency, a clear single-factor structure, convergent relationships with related constructs, and incremental validity over other measures of self-criticism and rumination in predicting both general distress and features of borderline personality disorder. PMID- 25712675 TI - Mathematics interventions for children and adolescents with Down syndrome: a research synthesis. AB - BACKGROUND: Many children and adolescents with Down syndrome fail to achieve proficiency in mathematics. Researchers have suggested that tailoring interventions based on the behavioural phenotype may enhance efficacy. METHOD: The research questions that guided this review were (1) what types of mathematics interventions have been empirically evaluated with children and adolescents with Down syndrome?; (2) do the studies demonstrate sufficient methodological rigor?; (3) is there evidence of efficacy for the evaluated mathematics interventions?; and (4) to what extent have researchers considered aspects of the behavioural phenotype in selecting, designing and/or implementing mathematics interventions for children and adolescents with Down syndrome? Nine studies published between 1989 and 2012 were identified for inclusion. RESULTS: Interventions predominantly focused on early mathematics skills and reported positive outcomes. However, no study met criteria for methodological rigor. Further, no authors explicitly considered the behavioural phenotype. CONCLUSIONS: Additional research using rigorous experimental designs is needed to evaluate the efficacy of mathematics interventions for children and adolescents with Down syndrome. Suggestions for considering the behavioural phenotype in future research are provided. PMID- 25712676 TI - Iron-catalyzed asymmetric hydrosilylation of ketones. AB - A series of iron complexes of chiral iminopyridine-oxazoline (IPO) ligands have been synthesized. The most sterically hindered iron catalyst exhibits excellent activity (up to 99% yield) and high enantioselectivity (up to 93% ee) in asymmetric hydrosilylation of aryl ketones. PMID- 25712677 TI - Risk factors for and prophylactic effect of povidone-iodine rectal cleansing on infectious complications after prostate biopsy: a retrospective cohort study. AB - PURPOSE: To evaluate the risk factors and efficacy of a povidone-iodine enema on infectious complications after transrectal ultrasound-guided prostate biopsy. METHODS: A total of 814 males who underwent transrectal ultrasound-guided prostate biopsy from January 2011 to December 2013 were evaluated retrospectively. Clinical variables, including demographics, prior antibiotic, or quinolone exposure, rectal swab culture results, povidone-iodine rectal cleansing, antibiotic prophylaxis, and infectious complications, were evaluated. RESULTS: Overall, 16 of 814 (2.0%) patients developed infectious complications after prostate biopsy. Of the patients with infectious complications, five had fever, two had urinary tract infections, and nine had bacteremia or sepsis. Infectious complication rates were not significantly different between povidone iodine rectal cleansing (n = 613) and no cleansing (n = 201) groups (1.5 vs. 3.5%, p = 0.083). However, povidone-iodine rectal cleansing reduced severe infectious complications such as bacteremia and sepsis (0.3 vs. 3.5%, p = 0.001). A rectal swab culture was performed in 552 patients, and extended-spectrum beta lactamase (ESBL)-producing and quinolone-resistant Escherichia coli were detected in 4.5 and 7.8% of cultures, respectively. Quinolone and antibiotic exposure within 6 months prior to prostate biopsy were associated with quinolone resistance and ESBL positivity of rectal flora and infectious complications. CONCLUSIONS: In the era of quinolone resistance, a povidone-iodine enema may reduce the infectious complication rate by reducing bacterial load. Quinolone exposure prior to prostate biopsy was a risk factor for antibiotic resistance to rectal flora and infectious complications. PMID- 25712679 TI - Erratum to: characterization and gene cloning of a maltotriose-forming exo amylase from Kitasatospora sp. MK-1785. PMID- 25712678 TI - Biotransformation of artemisinin by Aspergillus niger. AB - Biotransformation of artemisinin (1) by Aspergillus niger was investigated. During 12 days at 28 degrees C and pH 6.0, A. niger transformed artemisinin into four products. They were identified as 3beta-hydroxy-4,12-epoxy-1 deoxyartemisinin (2), artemisinin G (3), 3,13-epoxyartemisinin (4), and 4alpha hydroxy-1-deoxyartemisinin (5). Products 2 and 4 are new compounds and are being reported here for the first time. The product 4 contains a 3,13-epoxy structure. This is the first report of epoxidation of artemisinin using microbial strains. The product 4 still has an intact peroxide bridge and therefore can be used as a scaffold for further structural modification using chemical and biological methods in the search for new antimalarial drugs. PMID- 25712680 TI - Comparison of the biological activities of Saccharomyces cerevisiae-expressed intracellular EGF, extracellular EGF, and tagged EGF in early-weaned pigs. AB - Epidermal growth factor (EGF) ameliorates stress and prevents incomplete gastrointestinal development in early-weaned piglets in commercial swine farming. This study aimed to further analyze the biological activities of intracellularly expressed EGF (IE-EGF), extracellularly expressed EGF (EE-EGF), and tagged EGF (T EGF) from Saccharomyces cerevisiae in early-weaned pigs. In this study, we assigned 24 pigs to each of 5 groups that were provided a basic diet (the control group) or a diet supplemented with empty vector-expressing S. cerevisiae [the INVSc1(EV) group], T-EGF-expressing S. cerevisiae [the INVSc1-TE(-) group], EE EGF-expressing S. cerevisiae [the INVSc1-EE(+) group], or IE-EGF-expressing S. cerevisiae [the INVSc1-IE(+) group]. All treatments were delivered at a dose of 60 MUg EGF/kg body weight (BW) everyday. All the piglets were sacrificed after 21 day to determine their physio-biochemical indexes, immune functions, and intestinal development. In the piglet experiments, recombinant S. cerevisiae survived throughout the intestinal tract. The BW and intestinal development (e.g., mean villous height, crypt depth, villous height:crypt depth ratio (IVR), and total protein, DNA, and RNA contents) of the piglets were significantly enhanced in the INVSc1-IE(+) group compared with the animals in the INVSc1-EE(+) and INVSc1-TE(-) groups (P < 0.05). In addition, increased proliferating cell nuclear antigen (PCNA) staining was observed in the piglets that received the INVSc1-IE(+) treatment (approximately 80 %) compared with those that received the INVSc1-TE(-) (approximately 70 %) and INVSc1-EE(+) treatments (approximately 70 %). The levels of lactate dehydrogenase (LDH), creatine kinase (CK), alkaline phosphatase (ALP), immunoglobulin A (IgA), immunoglobulin M (IgM), and immunoglobulin G (IgG) were also significantly increased in the INVSc1-IE(+) group compared with the INVSc1-EE(+) and INVSc1-TE(-) groups (P < 0.05). Furthermore, the proliferation of piglet enterocytes was also significantly stimulated by both IE-EGF and EE-EGF compared with T-EGF in vitro (P < 0.05). Our data further demonstrate the previously reported hypothesis that IE-EGF is more suitable than EE-EGF or T-EGF for applications in early-weaned pigs. PMID- 25712681 TI - Optimal Patient Selection for Trastuzumab Treatment in HER2-Positive Advanced Gastric Cancer. AB - PURPOSE: Chemotherapy plus trastuzumab is standard of care for HER2-positive advanced gastric cancer (AGC). However, not all patients with HER2-positive AGC seem to benefit from trastuzumab. We evaluated the association between treatment outcomes with trastuzumab and HER2 status in patients with HER2-positive AGC. EXPERIMENTAL DESIGN: We enrolled 126 patients with HER2-positive AGC treated with trastuzumab plus chemotherapy in a training cohort. HER2 IHC (N = 126), HER2/CEP17 ratio (N = 66), and HER2 gene copy number (GCN; N = 59) were analyzed, and the optimal values for discriminating overall survival (OS) were determined using receiver operating characteristic (ROC) curve analysis. We validated the findings from the training cohort using an independent validation cohort (N = 72). RESULTS: Patients with HER2 IHC 3+ showed significantly longer OS (29 vs. 15.3 months; P = 0.025) than patients with IHC <= 2+. An HER2/CEP17 ratio of 4.48 was the optimal cutoff for predicting longer OS (26.9 vs. 14.7 months; P = 0.027). In subgroup analysis, treatment outcomes of patients with IHC 3+ were not influenced by the level of HER2 gene amplification. However, in patients with IHC <= 2+, an HER2/CEP17 ratio more than 3.69 and HER2 GCN more than 7.75 were positive predictive factors for better outcomes with trastuzumab-based chemotherapy. These findings were confirmed in both the validation cohort and the combined cohort. CONCLUSIONS: HER2 IHC status, HER2/CEP17 ratio, and HER2 GCN were correlated with clinical outcomes of trastuzumab-based treatment in HER2 positive AGC. Clinical outcomes of patients with IHC <= 2+ were strongly dependent on the HER2/CEP17 ratio and HER2 GCN. PMID- 25712682 TI - Intracellular Targeting of the Oncogenic MUC1-C Protein with a Novel GO-203 Nanoparticle Formulation. AB - PURPOSE: The MUC1-C oncoprotein is an intracellular target that is druggable with cell-penetrating peptide inhibitors. However, development of peptidyl drugs for treating cancer has been a challenge because of unfavorable pharmacokinetic parameters and limited cell-penetrating capabilities. EXPERIMENTAL DESIGN: Encapsulation of the MUC1-C inhibitor GO-203 in novel polymeric nanoparticles was studied for effects on intracellular targeting of MUC1-C signaling and function. RESULTS: Our results show that loading GO-203 into tetrablock polylactic acid (PLA)-polyethylene glycol (PEG)-polypropylene glycol (PPG)-PEG copolymers is achievable and, notably, is enhanced by increasing PEG chain length. In addition, we found that release of GO-203 from these nanoparticles is controllable over at least 7 days. GO-203/nanoparticle treatment of MUC1-C-positive breast and lung cancer cells in vitro was more active with less frequent dosing than that achieved with nonencapsulated GO-203. Moreover, treatment with GO 203/nanoparticles blocked MUC1-C homodimerization, consistent with on-target effects. GO-203/nanoparticle treatment was also effective in downregulating TIGAR, disrupting redox balance, and inhibiting the self-renewal capacity of cancer cells. Significantly, weekly administration of GO-203/nanoparticles to mice bearing syngeneic or xenograft tumors was associated with regressions that were comparable with those found when dosing on a daily basis with GO-203. CONCLUSIONS: These findings thus define an effective approach for (i) sustained administration of GO-203 in polymeric PLA-(PEG-PPG-PEG) nanoparticles to target MUC1-C in cancer cells and (ii) the potential delivery of other anticancer peptide drugs. PMID- 25712683 TI - Androgen Receptor Gene Aberrations in Circulating Cell-Free DNA: Biomarkers of Therapeutic Resistance in Castration-Resistant Prostate Cancer. AB - PURPOSE: Although novel agents targeting the androgen-androgen receptor (AR) axis have altered the treatment paradigm of metastatic castration-resistant prostate cancer (mCRPC), development of therapeutic resistance is inevitable. In this study, we examined whether AR gene aberrations detectable in circulating cell free DNA (cfDNA) are associated with resistance to abiraterone acetate and enzalutamide in mCRPC patients. EXPERIMENTAL DESIGN: Plasma was collected from 62 mCRPC patients ceasing abiraterone acetate (n = 29), enzalutamide (n = 19), or other agents (n = 14) due to disease progression. DNA was extracted and subjected to array comparative genomic hybridization (aCGH) for chromosome copy number analysis, and Roche 454 targeted next-generation sequencing of exon 8 in the AR. RESULTS: On aCGH, AR amplification was significantly more common in patients progressing on enzalutamide than on abiraterone or other agents (53% vs. 17% vs. 21%, P = 0.02, chi(2)). Missense AR exon 8 mutations were detected in 11 of 62 patients (18%), including the first reported case of an F876L mutation in an enzalutamide-resistant patient and H874Y and T877A mutations in 7 abiraterone resistant patients. In patients switched onto enzalutamide after cfDNA collection (n = 39), an AR gene aberration (copy number increase and/or an exon 8 mutation) in pretreatment cfDNA was associated with adverse outcomes, including lower rates of PSA decline >= 30% (P = 0.013, chi(2)) and shorter time to radiographic/clinical progression (P = 0.010, Cox proportional hazards regression). CONCLUSIONS: AR gene aberrations in cfDNA are associated with resistance to enzalutamide and abiraterone in mCRPC. Our data illustrate that genomic analysis of cfDNA is a minimally invasive method for interrogating mechanisms of therapeutic resistance in mCRPC. PMID- 25712684 TI - The Ovarian Cancer Chemokine Landscape Is Conducive to Homing of Vaccine-Primed and CD3/CD28-Costimulated T Cells Prepared for Adoptive Therapy. AB - PURPOSE: Chemokines are implicated in T-cell trafficking. We mapped the chemokine landscape in advanced stage ovarian cancer and characterized the expression of cognate receptors in autologous dendritic cell (DC)-vaccine primed T cells in the context of cell-based immunotherapy. EXPERIMENTAL DESIGN: The expression of all known human chemokines in patients with primary ovarian cancer was analyzed on two independent microarray datasets and validated on tissue microarray. Peripheral blood T cells from five HLA-A2 patients with recurrent ovarian cancer, who previously received autologous tumor DC vaccine, underwent CD3/CD28 costimulation and expansion ex vivo. Tumor-specific T cells were identified by HER2/neu pentamer staining and were evaluated for the expression and functionality of chemokine receptors important for homing to ovarian cancer. RESULTS: The chemokine landscape of ovarian cancer is heterogeneous with high expression of known lymphocyte-recruiting chemokines (CCL2, CCL4, and CCL5) in tumors with intraepithelial T cells, whereas CXCL10, CXCL12, and CXCL16 are expressed quasi-universally, including in tumors lacking tumor-infiltrating T cells. DC-vaccine primed T cells were found to express the cognate receptors for the above chemokines. Ex vivo CD3/CD28 costimulation and expansion of vaccine primed Tcells upregulated CXCR3 and CXCR4, and enhanced their migration toward universally expressed chemokines in ovarian cancer. CONCLUSIONS: DC-primed tumor specific T cells are armed with the appropriate receptors to migrate toward universal ovarian cancer chemokines, and these receptors are further upregulated by ex vivo CD3/CD28 costimulation, which render T cells more fit for migrating toward these chemokines. Clin Cancer Res; 21(12); 2840-50. (c)2015 AACR. PMID- 25712685 TI - Rilotumumab exposure-response relationship in patients with advanced or metastatic gastric cancer. AB - PURPOSE: Rilotumumab is an investigational, fully human monoclonal antibody to hepatocyte growth factor. In a randomized phase II study, trends toward improved survival were observed with rilotumumab (7.5 or 15 mg/kg) plus epirubicin, cisplatin, and capecitabine (ECX) versus placebo plus ECX in gastric/gastroesophageal junction (GEJ) cancer patients, especially in MET positive patients. Here, we quantitatively characterized the longitudinal exposure-response [tumor growth (TG) and overall survival (OS)] relationship for rilotumumab. EXPERIMENTAL DESIGN: Rilotumumab concentrations, tumor sizes, and survival time from the phase II study were pooled to develop a longitudinal exposure versus TG model and parametric OS model that explored predictive/prognostic/treatment effects (MET expression, rilotumumab exposure, relative tumor size). Model evaluation included visual predictive checks, nonparametric bootstrap, and normalized prediction distribution errors. Simulations were undertaken to predict the relationship between rilotumumab dose and OS. RESULTS: Rilotumumab exhibited linear time-independent pharmacokinetics not affected by MET expression. The TG model adequately described tumor size across arms. A Weibull distribution best described OS. Rilotumumab exposure and change in tumor size from baseline at week 24 were predictive of OS. MET-positive patients showed shorter survival and responded better to rilotumumab than MET negative patients. Simulations predicted a median (95% confidence interval) HR of 0.38 (0.18-0.60) in MET-positive patients treated with 15 mg/kg rilotumumab Q3W. CONCLUSIONS: Rilotumumab plus ECX demonstrated concentration-dependent effects on OS, influenced by MET expression, and tumor size in gastric/GEJ cancer patients. These findings support the phase II testing of rilotumumab 15 mg/kg every 3 weeks in MET-positive gastric/GEJ cancer (RILOMET-1; NCT01697072). PMID- 25712687 TI - A Phase I Dose-Escalation Study of Antibody BI-505 in Relapsed/Refractory Multiple Myeloma. AB - PURPOSE: This multicenter, first-in-human study evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of BI-505, a human anti-ICAM-1 monoclonal antibody, in advanced relapsed/refractory multiple myeloma patients. EXPERIMENTAL DESIGN: BI-505 was given intravenously, every 2 weeks, at escalating doses from 0.0004 to 20 mg/kg, with extension of therapy until disease progression for responding or stable patients receiving 0.09 mg/kg or higher doses. RESULTS: A total of 35 patients were enrolled. The most common adverse events were fatigue, pyrexia, headache, and nausea. Adverse events were generally mild to moderate, and those attributed to study medication were mostly limited to the first dose and manageable with premedication and slower infusion. No maximum tolerated dose was identified. BI-505's half-life increased with dose while clearance decreased, suggesting target-mediated clearance. The ICAM-1 epitopes on patient bone marrow myeloma were completely saturated at 10 mg/kg doses. Using the International Myeloma Working Group criteria, 7 patients on extended therapy had stable disease for more than 2 months. CONCLUSIONS: BI-505 can be safely administered at doses that saturate myeloma cell ICAM-1 receptors in patients. This study was registered at www.clinicaltrials.gov (NCT01025206). PMID- 25712688 TI - Aspergillus fungal ball in central cavity of a pulmonary cryptococcal nodal lesion. PMID- 25712689 TI - Photosensitizing metal-organic framework enabling visible-light-driven proton reduction by a Wells-Dawson-type polyoxometalate. AB - A simple and effective charge-assisted self-assembly process was developed to encapsulate a noble-metal-free polyoxometalate (POM) inside a porous and phosphorescent metal-organic framework (MOF) built from [Ru(bpy)3](2+)-derived dicarboxylate ligands and Zr6(MU3-O)4(MU3-OH)4 secondary building units. Hierarchical organization of photosensitizing and catalytic proton reduction components in such a POM@MOF assembly enables fast multielectron injection from the photoactive framework to the encapsulated redox-active POMs upon photoexcitation, leading to efficient visible-light-driven hydrogen production. Such a modular and tunable synthetic strategy should be applicable to the design of other multifunctional MOF materials with potential in many applications. PMID- 25712686 TI - The Neoadjuvant Model Is Still the Future for Drug Development in Breast Cancer. AB - The many improvements in breast cancer therapy in recent years have so lowered rates of recurrence that it is now difficult or impossible to conduct adequately powered adjuvant clinical trials. Given the many new drugs and potential synergistic combinations, the neoadjuvant approach has been used to test benefit of drug combinations in clinical trials of primary breast cancer. A recent FDA led meta-analysis showed that pathologic complete response (pCR) predicts disease free survival (DFS) within patients who have specific breast cancer subtypes. This meta-analysis motivated the FDA's draft guidance for using pCR as a surrogate endpoint in accelerated drug approval. Using pCR as a registration endpoint was challenged at ASCO 2014 Annual Meeting with the presentation of ALTTO, an adjuvant trial in HER2-positive breast cancer that showed a nonsignificant reduction in DFS hazard rate for adding lapatinib, a HER-family tyrosine kinase inhibitor, to trastuzumab and chemotherapy. This conclusion seemed to be inconsistent with the results of NeoALTTO, a neoadjuvant trial that found a statistical improvement in pCR rate for the identical lapatinib containing regimen. We address differences in the two trials that may account for discordant conclusions. However, we use the FDA meta-analysis to show that there is no discordance at all between the observed pCR difference in NeoALTTO and the observed HR in ALTTO. This underscores the importance of appropriately modeling the two endpoints when designing clinical trials. The I-SPY 2/3 neoadjuvant trials exemplify this approach. PMID- 25712690 TI - LCR-eXXXplorer: a web platform to search, visualize and share data for low complexity regions in protein sequences. AB - MOTIVATION: Local compositionally biased and low complexity regions (LCRs) in amino acid sequences have initially attracted the interest of researchers due to their implication in generating artifacts in sequence database searches. There is accumulating evidence of the biological significance of LCRs both in physiological and in pathological situations. Nonetheless, LCR-related algorithms and tools have not gained wide appreciation across the research community, partly due to the fact that only a handful of user-friendly software is currently freely available. RESULTS: We developed LCR-eXXXplorer, an extensible online platform attempting to fill this gap. LCR-eXXXplorer offers tools for displaying LCRs from the UniProt/SwissProt knowledgebase, in combination with other relevant protein features, predicted or experimentally verified. Moreover, users may perform powerful queries against a custom designed sequence/LCR-centric database. We anticipate that LCR-eXXXplorer will be a useful starting point in research efforts for the elucidation of the structure, function and evolution of proteins with LCRs. AVAILABILITY AND IMPLEMENTATION: LCR-eXXXplorer is freely available at the URL http://repeat.biol.ucy.ac.cy/lcr-exxxplorer. CONTACT: vprobon@ucy.ac.cy SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25712692 TI - specL--an R/Bioconductor package to prepare peptide spectrum matches for use in targeted proteomics. AB - MOTIVATION: Targeted data extraction methods are attractive ways to obtain quantitative peptide information from a proteomics experiment. Sequential Window Acquisition of all Theoretical Spectra (SWATH) and Data Independent Acquisition (DIA) methods increase reproducibility of acquired data because the classical precursor selection is omitted and all present precursors are fragmented. However, especially for targeted data extraction, MS coordinates (retention time information precursor and fragment masses) are required for the particular entities (peptide ions). These coordinates are usually generated in a so-called discovery experiment earlier on in the project if not available in public spectral library repositories. The quality of the assay panel is crucial to ensure appropriate downstream analysis. For that, a method is needed to create spectral libraries and to export customizable assay panels. RESULTS: Here, we present a versatile set of functions to generate assay panels from spectral libraries for use in targeted data extraction methods (SWATH/DIA) in the area of proteomics. AVAILABILITY AND IMPLEMENTATION: specL is implemented in the R language and available under an open-source license (GPL-3) in Bioconductor since BioC 3.0 (R-3.1) http://www.bioconductor.org (Trachsel et al., 2015). A vignette with a complete tutorial describing data import/export and analysis is included in the package and can also be found as supplement material of this article. CONTACT: cp@fgcz.ethz.ch or jg@fgcz.ethz.ch SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25712691 TI - EpiToolKit--a web-based workbench for vaccine design. AB - EpiToolKit is a virtual workbench for immunological questions with a focus on vaccine design. It offers an array of immunoinformatics tools covering MHC genotyping, epitope and neo-epitope prediction, epitope selection for vaccine design, and epitope assembly. In its recently re-implemented version 2.0, EpiToolKit provides a range of new functionality and for the first time allows combining tools into complex workflows. For inexperienced users it offers simplified interfaces to guide the users through the analysis of complex immunological data sets. AVAILABILITY AND IMPLEMENTATION: http://www.epitoolkit.de CONTACT: schubert@informatik.uni-tuebingen.de SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25712693 TI - GlycanAnalysis Plug-in: a database search tool for N-glycan structures using mass spectrometry. AB - Tandem mass spectrometry (MS/MS or MS(n)) is a potent technique for characterizing N-glycan structures. GlycanAnalysis searches a glycan database to support the identification of glycan structures from MS/MS spectra. It also calculates diagnostic ions of glycan structures registered in a glycan database (GlycomeDB or KEGG GLYCAN) and searches for MS/MS spectra of N-glycans that match diagnostic ions to determine the structures. This program functions as a plug-in for Mass++, a freeware mass spectrum visualization and analysis program. AVAILABILITY AND IMPLEMENTATION: The executable files of Mass++ are available for free at http://www.first-ms3d.jp/english/. The GlycanAnalysis plug-in is included in the standard package of Mass++ for Windows. CONTACT: k-morimt@shimadzu.co.jp or nishikaz@shimadzu.co.jp or acyshzw@shimadzu.co.jp SUPPLEMENTARY INFORMATION: Supplementary material are available at Bioinformatics online. PMID- 25712694 TI - Oxidative metabolism of chemical pollutants in marine organisms: molecular and biochemical biomarkers in environmental toxicology. AB - Oxidative stress biomarkers are widely used in marine ecotoxicology. Environmental pollutants enhance intracellular formation of oxyradicals through several mechanisms, but complex oxidative interactions occur in response to chemical mixtures. Metabolism of individual classes of pollutants can be influenced by a sophisticated network of prooxidant relationships, reciprocal and cascade effects, changes of redox-sensitive signaling proteins, and transcription factors. Chemically mediated pathways can affect antioxidant responses at different levels, including pretranscriptional, transcriptional, protein, and catalytic functions; such mechanisms remain largely unexplored in marine organisms. Molecular responses of antioxidants are frequently not paralleled by expected biochemical changes or cellular effects, and caution is needed when interpreting the effects of environmental pollutants. Results on antioxidant variations can be influenced by mRNA stability and protein turnover, different timing for transcriptional and translational mechanisms, metabolic capability of tissues, posttranscriptional modifications of proteins, biphasic responses of antioxidant enzymes, and adaptation mechanisms to chronic pollution. PMID- 25712695 TI - De Novo Design and Synthesis of a gamma-Turn Peptidomimetic Scaffold and Its Application as JNK3 Allosteric Ligand. AB - As a way to develop a neuroprotective agent for the JNK3-JIP1-binding site, peptidomimetics of JIP-1 as JNK3 allosteric regulators have been examined. The study consisted of in silico scaffold hopping, molecular docking, solution and solid-phase peptide syntheses, and Kd measurements using surface plasmon resonance. As a peptidomimetic of JIP1, heptamer mimetic 16 (Kd =2.72 MUm) displayed a higher affinity than decamer JIP1 (Kd =23.6 MUm). The high affinity of 16 implies that the characteristic gamma-turn mimetic structure, ""Phi-X-Phi" hydrophobic motif in 16, increased its affinity toward the JIP-site of JNK3. PMID- 25712696 TI - Rest mutant zebrafish swim erratically and display atypical spatial preferences. AB - The Rest/Nrsf transcriptional repressor modulates expression of a large set of neural specific genes. Many of these target genes have well characterized roles in nervous system processes including development, plasticity and synaptogenesis. However, the impact of Rest-mediated transcriptional regulation on behavior has been understudied due in part to the embryonic lethality of the mouse knockout. To investigate the requirement for Rest in behavior, we employed the zebrafish rest mutant to explore a range of behaviors in adults and larva. Adult rest mutants of both sexes showed abnormal behaviors in a novel environment including increased vertical swimming, erratic swimming patterns and a proclivity for the tank walls. Adult males also had diminished reproductive success. At 6 days post fertilization (dpf), rest mutant larva were hypoactive, but displayed normal evoked responses to light and sound stimuli. Overall, these results provide evidence that rest dysfunction produces atypical swimming patterns and preferences in adults, and reduced locomotor activity in larvae. This study provides the first behavioral analysis of rest mutants and reveals specific behaviors that are modulated by Rest. PMID- 25712698 TI - Total synthesis of an exceptional brominated 4-pyrone derivative of algal origin: an exercise in gold catalysis and alkyne metathesis. AB - A concise approach to the algal metabolite 1 is described, which also determines the previously unknown stereostructure of this natural product. Compound 1 is distinguished by a rare brominated 4-pyrone nucleus linked as a ketene-acetal to a polyunsaturated macrocyclic scaffold comprising an extra homoallylic bromide entity. The synthesis of 1 is based on the elaboration and selective functionalization of the linear precursor 23 endowed with no less than six different sites of unsaturation including the highly enolized oxo-alkanoate function. Key to success was the formation of the 2-alkoxy-4-pyrone ring by a novel gold-catalyzed transformation which engages only the acetylenic beta ketoester substructure of 23 but leaves all other pi-bonds untouched. The synthesis was completed by a ring-closing alkyne metathesis to forge the signature cycloalkyne motif of 1 followed by selective bromination of the ketene acetal site in the resulting product 27 without touching the skipped diene-yne substructure resident within the macrocyclic tether. PMID- 25712697 TI - Single prolonged stress effects on sensitization to cocaine and cocaine self administration in rats. AB - Posttraumatic stress disorder (PTSD) is often comorbid with substance use disorders (SUD). Single prolonged stress (SPS) is a well-validated rat model of PTSD that provides a framework to investigate drug-induced behaviors as a preclinical model of the comorbidity. We hypothesized that cocaine sensitization and self-administration would be increased following exposure to SPS. Male Sprague-Dawley rats were exposed to SPS or control treatment. After SPS, cocaine (0, 10 or 20 mg/kg, i.p.) was administered for 5 consecutive days and locomotor activity was measured. Another cohort was assessed for cocaine self administration (0.1 or 0.32 mg/kg/i.v.) after SPS. Rats were tested for acquisition, extinction and cue-induced reinstatement behaviors. Control animals showed a dose-dependent increase in cocaine-induced locomotor activity after acute cocaine whereas SPS rats did not. Using a sub-threshold sensitization paradigm, control rats did not exhibit enhanced locomotor activity at Day 5 and therefore did not develop behavioral sensitization, as expected. However, compared to control rats on Day 5 the locomotor response to 20mg/kg repeated cocaine was greatly enhanced in SPS-treated rats, which exhibited enhanced cocaine locomotor sensitization. The effect of SPS on locomotor activity was unique in that SPS did not modify cocaine self-administration behaviors under a simple schedule of reinforcement. These data show that SPS differentially affects cocaine-mediated behaviors causing no effect to cocaine self-administration, under a simple schedule of reinforcement, but significantly augmenting cocaine locomotor sensitization. These results suggest that SPS shares common neurocircuitry with stimulant-induced plasticity, but dissociable from that underlying psychostimulant-induced reinforcement. PMID- 25712699 TI - Fixed sunlight eruption: a case report. PMID- 25712701 TI - Minimally invasive clamp-assisted reduction and cephalomedullary nailing without cerclage cables for subtrochanteric femur fractures in the elderly: Surgical technique and results. AB - INTRODUCTION: The treatment of subtrochanteric fractures in the elderly remains technically challenging, due to instability and osteoporosis, with high reoperation rates. Even if intramedullary nailing is the most reliable treatment, reduction is difficult and cerclage wiring remains controversial. The purpose of this study was to evaluate 26 consecutive subtrochanteric fractures in elderly patients treated with a minimally invasive clamp-assisted reduction and cephalomedullary nailing without cerclage wiring. PATIENTS AND METHODS: A retrospective analysis was conducted between January 2010 and September 2013. Data obtained from the medical records included patient's age, sex, classification of the fracture, the quality of reduction after surgery, and the presence of postoperative complications, especially fracture displacement and delayed union or nonunion. RESULTS: Twenty-six patients had adequate radiographic and clinical follow-up. Mean age was 84.4 (range 75-96) years. The mean duration of follow-up was 7.6 months (6-14 months). Mean surgical time was 74.42 min (range 45-115 min). Twenty-four (92.3%) showed acceptable varus/valgus alignment, and no sagittal plane malunions were noted. The tip-apex distance was <25 mm in all cases. Distraction at the fracture was <10mm in 21 fractures. Three patients had limb length discrepancy of 1cm. All fractures healed uneventfully. DISCUSSION: Reducing the fracture before nailing is mandatory to achieve good results. Minimally invasive clamp reduction without cerclage wires, even if challenging, has proven to be a safe, reproducible, and effective surgical technique, with at least the same results as other series. PMID- 25712700 TI - High-level expression and purification of soluble bioactive recombinant human heparin-binding epidermal growth factor in Escherichia coli. AB - Heparin-binding epidermal growth factor (HB-EGF) is a member of highly conserved superfamily of proteins that has potential mitogenic activity and stimulates differentiation and migration of various cell types. Since HB-EGF has three intra molecular disulfide bonds, a high expression pattern of active HB-EGF in an E. coli expression system was not successfully established. The aim of this study was to increase production of soluble bioactive recombinant human HB-EGF in E. coli by modifying growth conditions and codon optimization. The open reading frame codons of human HB-EGF were optimized to achieve high level expression in E. coli. The optimized codon was amplified, cloned into plasmid pET-32a, and transformed into E. coli BL21 for further expression. The cultivation parameters (temperature and inducer) were optimized to produce a high yield of soluble HB EGF. The fusion protein was purified by Nickel-nitrilotriacetic acid (Ni-NTA) affinity chromatography. Amethylthiazole tetrazolium assay was used to evaluate the bioactivity of the produced recombinant protein. After codon optimization, the codon adaptation index (CAI) was increased from 0.255 in native gene to 0.829 using the optimized sequence. By lowering the temperature to 22 degrees C and the inducer to 0.4 MUM, we obtained 35% soluble expression of recombinant and biologically active human HB-EGF. Our data demonstrate that codon optimization increases the yield of HB-EGF in an E. coli expression system. Furthermore, the chosen modifications in cell culturing increase the solubility of recombinant human HB-EGF. PMID- 25712702 TI - Treatment of the femoral shaft nonunion with double plate fixation and bone grafting: A case series of 14 patients. AB - INTRODUCTION: The management of femoral shaft nonunion still remains a challenge in orthopaedic surgery. It represents a serious postoperative problem for the patient, associated with plate breakage and loosening, bone defect, shortening deformity and infection. A double plate fixation combined with bone grafting may become a promising therapeutic strategy for the treatment of patients with femoral shaft nonunion. In this study, our goal was to evaluate the clinical outcome of a novel approach for 14 consecutive patients with femoral shaft nonunion using double plate fixation with bone grafting. METHODS: Retrospective data from June 2010 to August 2012 were obtained from records for 14 consecutive femoral shaft aseptic nonunion patients treated with double plate fixation combined with bone grafting. Nine patients were men and five patients were woman and average age of the patients was 26 years (range from 22 to 32 years). The mean time since injury was 26.2 months. The nonunion had resulted from repeated internal fixation failure (including plate or intramedullary nail fixation) in nine cases and primary internal fixation in five cases. RESULTS: All the 14 patients were followed up for an average of 14.8 (10-25) months. All cases achieved bony union without wound infection or fixation failure and the mean time to union was 5.2 months (range 4-7 months). CONCLUSION: Double plate fixation and bone grafting are a promising method for femoral shaft nonunion. In addition, this strategy is useful for such a nonunion caused by a repeated plate or intramedullary nail fixation failure with bone defect due to its strong stability with three-dimensional fixation and fully bone graft availability. PMID- 25712703 TI - High-frequency stimulation of the medial prefrontal cortex decreases cellular firing in the dorsal raphe. AB - High-frequency deep brain stimulation (HFS-DBS) of the subcallosal cingulate (SCC) region has been investigated as a treatment for refractory forms of depression with a ~50% remission rate in open label studies. However, the therapeutic mechanisms of DBS are still largely unknown. Using anaesthetized Sprague Dawley rats, we recorded neuronal spiking activity in 102 neurons of the dorsal raphe (DR) before, during and after the induction of a 5-min HFS train in the infralimbic region (IL) of the medial prefrontal cortex (mPFC), the rodent homologue of the human SCC. The majority of DR cells (82%) significantly decreased firing rate during HFS (P < 0.01, 55.7 +/- 4.5% of baseline, 35 rats). To assess whether mPFC-HFS mediates inhibition of DR cellular firing by stimulating local GABAergic interneurons, the GABAA antagonist bicuculline (Bic, 100 MUm) was injected directly into the DR during HFS. Neurons inhibited by HFS recovered their firing rate during Bic+HFS (P < 0.01, n = 15, seven rats) to levels not different from baseline. Cells that were not affected by HFS did not change firing rate during Bic+HFS (P = 0.968, n = 7, three rats). These results indicate that blocking GABAA reverses HFS-mediated inhibition of DR neurons. As the cells that were not inhibited by HFS were also unaffected by HFS+Bic, they are probably not innervated by local GABA. Taken together, our results suggest that mPFC-HFS may exert a preferential effect on DR neurons with GABAA receptors. PMID- 25712704 TI - Workers' compensation claims for musculoskeletal disorders and injuries of the upper extremity and knee among union carpenters in Washington State, 1989-2008. AB - BACKGROUND: Numerous aspects of construction place workers at risk of musculoskeletal disorders and injuries (MSDIs). Work organization and the nature of MSDIs create surveillance challenges. METHODS: By linking union records with workers' compensation claims, we examined 20-year patterns of MSDIs involving the upper extremity (UE) and the knee among a large carpenter cohort. RESULTS: MSDIs were common and accounted for a disproportionate share of paid lost work time (PLT) claims; UE MSDIs were three times more common than those of the knee. Rates declined markedly over time and were most pronounced for MSDIs of the knee with PLT. Patterns of risk varied by extremity, as well as by age, gender, union tenure, and predominant work. Carpenters in drywall installation accounted for the greatest public health burden. CONCLUSIONS: A combination of factors likely account for the patterns observed over time and across worker characteristics. Drywall installers are an intervention priority. PMID- 25712705 TI - Atmospheric influence upon crystallization and electronic disorder and its impact on the photophysical properties of organic-inorganic perovskite solar cells. AB - Recently, solution-processable organic-inorganic metal halide perovskites have come to the fore as a result of their high power-conversion efficiencies (PCE) in photovoltaics, exceeding 17%. To attain reproducibility in the performance, one of the critical factors is the processing conditions of the perovskite film, which directly influences the photophysical properties and hence the device performance. Here we study the effect of annealing parameters on the crystal structure of the perovskite films and correlate these changes with its photophysical properties. We find that the crystal formation is kinetically driven by the annealing atmosphere, time and temperature. Annealing in air produces an improved crystallinity and large grain domains as compared to nitrogen. Lower photoluminescence quantum efficiency (PLQE) and shorter photoluminescence (PL) lifetimes are observed for nitrogen annealed perovskite films as compared to the air-annealed counterparts. We note that the limiting nonradiative pathways (i.e., maximizing PLQE) is important for obtaining the highest device efficiency. This indicates a critical impact of the atmosphere upon crystallization and the ultimate device performance. PMID- 25712707 TI - Iron-catalyzed dehydropolymerization: a convenient route to poly(phosphinoboranes) with molecular-weight control. AB - The catalyst loading is the key to control the molecular weight of the polymer in the iron-catalyzed dehydropolymerization of phosphine-borane adducts. Studies showed that the reaction proceeds through a chain-growth coordination-insertion mechanism. PMID- 25712706 TI - Hepatitis B virus genotype and subgenotype prevalence and distribution in Montenegro. AB - The Mediterranean area and the Balkans in particular show the highest level of genetic heterogeneity of HBV in Europe. Data about the circulation of HBV genotypes in Montenegro are lacking. It was studied the prevalence and distribution of HBV genot/subgenotypes in a total of 150 HBV infected patients living in Montenegro. Phylogenetic analysis of 136 successfully amplified P sequences showed a high degree of genetic heterogeneity of HBV in Montenegro. Subgenotype D2 (36.8%) and D3 (32.3%) were the most prevalent, followed by genotype A (subgenotype A2 in all of the cases-19.8%). Eight patients were infected with recombinant strains. HBV-D1 which is the most spread HBV subgenotype in the south-eastern Mediterranean countries, seems to be relatively rare in Montenegro, suggesting a penetration of HBV more probably from North-East or West than from Eastern Mediterranean countries. The relatively different prevalence of D3 and A2 among subjects infected through sexual route, seems to confirm the association of these subgenotypes with different route of transmissions (mainly parenteral for D3 and mainly sexual for A2) even in Montenegro. The low prevalence of D2 among children and its absence in perinatal transmission, suggests that this subgenotype circulated prevalently in the past. If this is due to changes in the most prevalent way of transmission and in the recent different contacts of Montenegro with other European countries, it remains to be established by other larger studies. PMID- 25712708 TI - Growth process of nanosized aluminum thin films by pulsed laser deposition for fluorescence enhancement. AB - Pulsed laser deposition was used to deposit aluminum thin films of various thicknesses (tAl) ranging from 5 to 40 nm and to investigate their growth process when they are deposited onto SiO2 and Y2O3. Atomic force microscopy and x-ray reflectivity measurements show that the structure of the Al films are related to the wettability properties of the underlaying layer. Onto SiO2, ultra-smooth layers of aluminum are obtained, due to a perfect wetting of SiO2 by Al. In contrast when deposited onto Y2O3, percolated Al layers are observed with apparent pore size decreasing from 200 to 82 nm as t(Al) is increased from 5 to 40 nm, respectively. This particular morphology is related to partial dewetting of Al on Y2O3. These two different growth mechanisms of aluminum depend therefore on the surface properties of SiO2 and Y2O3. The plasmon resonance of such Al nanostructures in the UV region was then analyzed by studying the coupling between Eu(3+) rare earth emitters and Al. PMID- 25712709 TI - Iatrogenic subclavian artery and aortic dissection with mesenteric ischemia following subclavian artery angioplasty: Endovascular management. AB - Subclavian stenosis affects up to 5% of patients referred for coronary artery bypass grafting. Albeit usually asymptomatic, this condition can cause myocardial ischemia due to a steal phenomenon from the distal subclavian artery when the left internal mammary artery is used as a coronary bypass. We describe a case of proximal subclavian artery angioplasty complicated with aortic dissection and subsequent life-threatening mesenteric ischemia. For the first time, we illustrate an endovascular approach to both complications consisting in urgent stenting of the celiac trunk and the superior mesenteric artery followed by staged thoracic endovascular aortic repair due to progressive aortic dilatation. PMID- 25712710 TI - Implications of epigenetics and stress regulation on research and developmental care of preterm infants. AB - Epigenetics refers to chemical modifications leading to changes in gene expression without any alteration of the DNA structure. We suggest ways through which epigenetic mechanisms might contribute to alter developmental trajectories in preterm infants. Although theoretical and methodological issues still need to be addressed, we discuss how epigenetics might be an emergent research field with potential innovative insights for researchers and clinicians involved in the neonatal care of preterm infants. PMID- 25712714 TI - Sinonasal and skull base pleomorphic adenoma: a case series and literature review. AB - BACKGROUND: Pleomorphic adenoma (PA) is the most common benign neoplasm of the major salivary glands. PA of the paranasal sinuses and skull base is an extremely rare pathologic entity. We report 3 cases of sinonasal and skull-base PA (including locoregionally advanced parotid disease) and review other cases in the literature, with special attention to clinical presentation, diagnosis, and management. METHODS: Retrospective review of patients with PA of the sinuses and skull base treated at 2 tertiary academic medical centers between January 1, 1993 and July 1, 2014. The MEDLINE database was additionally searched for all case series or reports of sinonasal or skull-base PA. RESULTS: A total of 32 articles were identified for review. In combination with the authors' cases, a total of 39 patients were found to have sinonasal and/or skull-base PA. The most common primary sites were the nasal septum and lateral nasal wall. Endoscopic resection was employed in 66% of cases, which achieved oncologic control in more than 80% of cases at a mean follow-up of 2 years. CONCLUSION: PA of the sinonasal tract and skull base is a rare, benign tumor that often may be surgically accessible through an endonasal, endoscopic approach. Recurrent disease may behave more aggressively than PA found in the major salivary glands. Accurate tumor sampling is essential for surgical planning, because malignant transformation does occur. In certain cases of unresectable tumors, endoscopic debulking may improve patient symptoms and quality of life. PMID- 25712715 TI - High-resolution membrane capacitance measurements for studying endocytosis and exocytosis in yeast. AB - Fusion of exocytotic vesicles with the plasma membrane gives rise to an increase in membrane surface area, whereas the surface area is decreased when vesicles are internalized during endocytosis. Changes in membrane surface area, resulting from fusion and fission of membrane vesicles, can be followed by monitoring the corresponding proportional changes in membrane capacitance. Using the cell attached configuration of the patch-clamp techniques we were able to resolve the elementary processes of endo- and exocytosis in yeast protoplasts at high temporal and spatial resolution. Spontaneous capacitance changes were predominantly in the range of 0.2-1 fF which translates to vesicle diameters of 90-200 nm. The size distribution revealed that endocytotic vesicles with a median at about 132 nm were smaller than exocytotic vesicles with a median at 155 nm. In energized and metabolizing protoplasts, endo- and exocytotic events occurred at frequencies of 1.6 and 2.7 events per minute, respectively. Even though these numbers appear very low, they are in good agreement with the observed growth rate of yeast cells and protoplasts. PMID- 25712716 TI - Protein models docking benchmark 2. AB - Structural characterization of protein-protein interactions is essential for our ability to understand life processes. However, only a fraction of known proteins have experimentally determined structures. Such structures provide templates for modeling of a large part of the proteome, where individual proteins can be docked by template-free or template-based techniques. Still, the sensitivity of the docking methods to the inherent inaccuracies of protein models, as opposed to the experimentally determined high-resolution structures, remains largely untested, primarily due to the absence of appropriate benchmark set(s). Structures in such a set should have predefined inaccuracy levels and, at the same time, resemble actual protein models in terms of structural motifs/packing. The set should also be large enough to ensure statistical reliability of the benchmarking results. We present a major update of the previously developed benchmark set of protein models. For each interactor, six models were generated with the model-to-native C(alpha) RMSD in the 1 to 6 A range. The models in the set were generated by a new approach, which corresponds to the actual modeling of new protein structures in the "real case scenario," as opposed to the previous set, where a significant number of structures were model-like only. In addition, the larger number of complexes (165 vs. 63 in the previous set) increases the statistical reliability of the benchmarking. We estimated the highest accuracy of the predicted complexes (according to CAPRI criteria), which can be attained using the benchmark structures. The set is available at http://dockground.bioinformatics.ku.edu. PMID- 25712717 TI - Association between TNFSF10 polymorphism and migraine susceptibility in a Chinese population. AB - OBJECTIVE: To investigate the correlation between migraine in a Chinese population and a 4 base pair (GAGT) insertion/deletion polymorphism (rs35975099) localized near the 3' end of the tumour necrosis factor superfamily 10 gene, TNFSF10. METHODS: Ethnically Han Chinese patients with migraine and healthy control subjects were recruited. TNFSF10 genotype and allele frequencies were determined via polymerase chain reaction and polyacrylamide gel electrophoresis. RESULTS: Rs35975099 was in Harvey-Weinberg equilibrium in patients with migraine (n = 269) and control subjects (n = 374). There were no significant relationships between allele or genotype frequency and migraine. CONCLUSION: There was no functional significance of the TNFSF10 gene polymorphism rs35975099 in migraine pathogenesis. PMID- 25712718 TI - Characteristics and determinants of the sublingual microcirculation in populations of different ethnicity. AB - No previous population study assessed sublingual capillary density (CD) or perfused boundary region (PBR). Lower PBR indicates greater glycocalyx width. In 252 Han and 220 She Chinese and 254 Flemish people (mean age, 51.1 years; 54.7% women), representing random population samples, we measured total and perfused CD and PBR in the sublingual capillary bed, using oblique profiled epi-illumination, and cardiovascular risk factors. In multivariable analyses, we modeled ethnicity as random effect. Significance level was alpha <= 0.05. Compared with Chinese, Flemish had lower total (577 versus 546 n degrees /mm(2)) and perfused (338 versus 320 n degrees /mm(2)) CD, but similar perfused-to-total CD ratio (mean, 0.59). Perfused-to-total CD ratio increased with age (effect size per 1-SD increase, +0.015 per year), body mass index (+0.008 per kg/m(2)), total cholesterol (+0.012 per mmol/L), and Framingham risk score (+0.018 per point) with no ethnic differences in these associations. For age and Framingham risk score, associations with perfused-to-total CD ratio were driven by positive relationships with perfused CD, whereas associations with total CD were nonsignificant. Chinese when compared with Flemish had higher hematocrit (43.0 versus 41.1%), PBR (2010 versus 1876 nm), and pulse rate (72.6 versus 63.3 bpm). PBR standardized for hematocrit, perfused CD, and pulse rate decreased with body mass index (-26.7 nm/kg/m2), mean arterial pressure (-30.6 nm/mm Hg), and diastolic pressure (-28.5 nm/mm Hg) with no ethnic differences in these associations. In conclusion, a higher cardiovascular risk profile is associated with functional recruitment of capillaries with preserved glycocalyx that protects the endothelial lining. PMID- 25712719 TI - Mineralocorticoid receptor antagonism treats obesity-associated cardiac diastolic dysfunction. AB - Patients with obesity and diabetes mellitus exhibit a high prevalence of cardiac diastolic dysfunction (DD), an independent predictor of cardiovascular events for which no evidence-based treatment exists. In light of renin-angiotensin aldosterone system activation in obesity and the cardioprotective action of mineralocorticoid receptor (MR) antagonists in systolic heart failure, we examined the hypothesis that MR blockade with a blood pressure-independent low dose spironolactone (LSp) would treat obesity-associated DD in the Zucker obese (ZO) rat. Treatment of ZO rats exhibiting established DD with LSp normalized cardiac diastolic function, assessed by echocardiography. This was associated with reduced cardiac fibrosis, but not reduced hypertrophy, and restoration of endothelium-dependent vasodilation of isolated coronary arterioles via a nitric oxide-independent mechanism. Further mechanistic studies revealed that LSp reduced cardiac oxidative stress and improved endothelial insulin signaling, with no change in arteriolar stiffness. Infusion of Sprague-Dawley rats with the MR agonist aldosterone reproduced the DD noted in ZO rats. In addition, improved cardiac function in ZO-LSp rats was associated with attenuated systemic and adipose inflammation and an anti-inflammatory shift in cardiac immune cell mRNAs. Specifically, LSp increased cardiac markers of alternatively activated macrophages and regulatory T cells. ZO-LSp rats had unchanged blood pressure, serum potassium, systemic insulin sensitivity, or obesity-associated kidney injury, assessed by proteinuria. Taken together, these data demonstrate that MR antagonism effectively treats established obesity-related DD via blood pressure independent mechanisms. These findings help identify a particular population with DD that might benefit from MR antagonist therapy, specifically patients with obesity and insulin resistance. PMID- 25712720 TI - Recent clinical and translational advances in pediatric hypertension. AB - Epidemiological reports describe a child population increase in BP level and an increase in prevalence of hypertension, that is largely, but not entirely, driven by a concurrent increase in childhood obesity. Given current estimates, ~10% of adolescents have hypertension or prehypertension. In addition to obesity, dietary salt intake and waist circumference, a marker of visceral obesity, are found to be independently associated with the rise in BP among children and adolescents. Dietary salt intake in urban children is well above recommended levels largely because of consumption of processed and fast foods. Childhood exposures, such as stress,52 salt, and fructose, as well as lifestyles, including food sources, sleep patterns, and reductions in physical activity may have a role in obesity high BP associations. In addition, clinical and translational evidence is mounting that intrauterine exposures alter can effect changes in fetal development that have an enduring effect on cardiovascular and metabolic function later in life. These effects can be detected even in children who are products of a term otherwise normal pregnancy. Hypertension in childhood has been defined statistically (BP >= 95th percentile) because of lack of outcome data that links a BP level with heightened risk for future cardiovascular events. Therefore, primary hypertension had been considered a risk factor for later hypertension in adulthood. Intermediate markers of TOD, including cardiac hypertrophy, vascular stiffness, and increases in cIMT, are detectable in adolescents with primary hypertension. Evidence that vascular injury is present in the early phase of hypertension and even in prehypertension warrants consideration on the current definition of pediatric hypertension. With further studies on TOD and other risk factors in addition to high BP, it may be possible to shift from a statistical definition to a definition of childhood hypertension that is evidence based. Preventing or reducing childhood obesity would have substantial benefit in countering the documented increase in BP levels and prevalence of high BP in childhood. Weight control in overweight and obese children, along with dietary changes 53 and increases in physical activity,54 has benefit on BP levels in childhood. Prevention of childhood obesity and BP risk will require multiple levels of intervention, including public health, health policy, and attention to food supply to foster the necessary lifestyle changes to prevent and reduce childhood obesity. PMID- 25712721 TI - Design, characterization, and first-in-human study of the vascular actions of a novel biased apelin receptor agonist. AB - [Pyr(1)]apelin-13 is an endogenous vasodilator and inotrope but is downregulated in pulmonary hypertension and heart failure, making the apelin receptor an attractive therapeutic target. Agonists acting at the same G-protein-coupled receptor can be engineered to stabilize different conformational states and function as biased ligands, selectively stimulating either G-protein or beta arrestin pathways. We used molecular dynamics simulations of apelin/receptor interactions to design cyclic analogues and identified MM07 as a biased agonist. In beta-arrestin and internalization assays (G-protein-independent), MM07 was 2 orders of magnitude less potent than [Pyr(1)]apelin-13. In a G-protein-dependent saphenous vein contraction assay, both peptides had comparable potency (pD2:[Pyr(1)]apelin-13 9.93+/-0.24; MM07 9.54+/-0.42) and maximum responses with a resulting bias for MM07 of ~350- to 1300-fold for the G-protein pathway. In rats, systemic infusions of MM07 (10-100nmol) caused a dose-dependent increase in cardiac output that was significantly greater than the response to [Pyr(1)]apelin 13. Similarly, in human volunteers, MM07 produced a significant dose-dependent increase in forearm blood flow with a maximum dilatation double that is seen with [Pyr(1)]apelin-13. Additionally, repeated doses of MM07 produced reproducible increases in forearm blood flow. These responses are consistent with a more efficacious action of the biased agonist. In human hand vein, both peptides reversed an established norepinephrine constrictor response and significantly increased venous flow. Our results suggest that MM07 acting as a biased agonist at the apelin receptor can preferentially stimulate the G-protein pathway, which could translate to improved efficacy in the clinic by selectively stimulating vasodilatation and inotropic actions but avoiding activating detrimental beta arrestin-dependent pathways. PMID- 25712722 TI - Interplay between connexin40 and nitric oxide signaling during hypertension. AB - Connexins (Cxs) and endothelial nitric oxide synthase (eNOS) contribute to the adaptation of endothelial and smooth muscle cells to hemodynamic changes. To decipher the in vivo interplay between these proteins, we studied Cx40-null mice, a model of renin-dependent hypertension which displays an altered endothelium dependent relaxation of the aorta because of reduced eNOS levels. These mice, which were either untreated or subjected to the 1-kidney, 1-clip (1K1C) procedure, a model of volume-dependent hypertension, were compared with control mice submitted to either the 1K1C or the 2-kidney, 1-clip (2K1C) procedure, a model of renin-dependent hypertension. All operated mice became hypertensive and featured hypertrophy and altered Cx expression of the aorta. The combination of volume- and renin-dependent hypertension in Cx40-/- 1K1C mice raised blood pressure and cardiac weight index. Under these conditions, all aortas showed increased levels of Cx40 in endothelial cells and of both Cx37 and Cx45 in smooth muscle cells. In the wild-type 1K1C mice, the interactions between Cx40 and Cx37 with eNOS were enhanced, resulting in increased NO release. The Cx40-eNOS interaction could not be observed in mice lacking Cx40, which also featured decreased levels of eNOS. In these animals, the volume overload caused by the 1K1C procedure resulted in increased phosphorylation of eNOS and in a higher NO release. The findings provide evidence that Cx40 and Cx37 play an in vivo role in the regulation of eNOS. PMID- 25712723 TI - Exposure to experimental preeclampsia in mice enhances the vascular response to future injury. AB - Cardiovascular disease (CVD) remains the leading killer of women in developed nations. One sex-specific risk factor is preeclampsia, a syndrome of hypertension and proteinuria that complicates 5% of pregnancies. Although preeclampsia resolves after delivery, exposed women are at increased long-term risk of premature CVD and mortality. Pre-existing CVD risk factors are associated with increased risk of developing preeclampsia but whether preeclampsia merely uncovers risk or contributes directly to future CVD remains a critical unanswered question. A mouse preeclampsia model was used to test the hypothesis that preeclampsia causes an enhanced vascular response to future vessel injury. A preeclampsia-like state was induced in pregnant CD1 mice by overexpressing soluble fms-like tyrosine kinase-1, a circulating antiangiogenic protein that induces hypertension and glomerular disease resembling human preeclampsia. Two months postpartum, soluble fms-like tyrosine kinase-1 levels and blood pressure normalized and cardiac size and function by echocardiography and renal histology were indistinguishable in preeclampsia-exposed compared with control mice. Mice were then challenged with unilateral carotid injury. Preeclampsia-exposed mice had significantly enhanced vascular remodeling with increased vascular smooth muscle cell proliferation (180% increase; P<0.01) and vessel fibrosis (216% increase; P<0.001) compared with control pregnancy. In the contralateral uninjured vessel, there was no difference in remodeling after exposure to preeclampsia. These data support a new model in which vessels exposed to preeclampsia retain a persistently enhanced vascular response to injury despite resolution of preeclampsia after delivery. This new paradigm may contribute to the substantially increased risk of CVD in woman exposed to preeclampsia. PMID- 25712724 TI - Brainstem hypoxia contributes to the development of hypertension in the spontaneously hypertensive rat. AB - Systemic arterial hypertension has been previously suggested to develop as a compensatory condition when central nervous perfusion/oxygenation is compromised. Principal sympathoexcitatory C1 neurons of the rostral ventrolateral medulla oblongata (whose activation increases sympathetic drive and the arterial blood pressure) are highly sensitive to hypoxia, but the mechanisms of this O2 sensitivity remain unknown. Here, we investigated potential mechanisms linking brainstem hypoxia and high systemic arterial blood pressure in the spontaneously hypertensive rat. Brainstem parenchymal PO2 in the spontaneously hypertensive rat was found to be ~15 mm Hg lower than in the normotensive Wistar rat at the same level of arterial oxygenation and systemic arterial blood pressure. Hypoxia induced activation of rostral ventrolateral medulla oblongata neurons was suppressed in the presence of either an ATP receptor antagonist MRS2179 or a glycogenolysis inhibitor 1,4-dideoxy-1,4-imino-d-arabinitol, suggesting that sensitivity of these neurons to low PO2 is mediated by actions of extracellular ATP and lactate. Brainstem hypoxia triggers release of lactate and ATP which produce excitation of C1 neurons in vitro and increases sympathetic nerve activity and arterial blood pressure in vivo. Facilitated breakdown of extracellular ATP in the rostral ventrolateral medulla oblongata by virally driven overexpression of a potent ectonucleotidase transmembrane prostatic acid phosphatase results in a significant reduction in the arterial blood pressure in the spontaneously hypertensive rats (but not in normotensive animals). These results suggest that in the spontaneously hypertensive rat, lower PO2 of brainstem parenchyma may be associated with higher levels of ambient ATP and l lactate within the presympathetic circuits, leading to increased central sympathetic drive and concomitant sustained increases in systemic arterial blood pressure. PMID- 25712726 TI - Safety of beta2-Agonists in Asthma: Linking Mechanisms, Meta-Analyses and Regulatory Practice. AB - An epidemic of asthma fatalities in the 1970s prompted a series of case-control studies which indicated that short acting beta-agonists increased the risk of death. Subsequent mechanistic and pharmacodynamic studies have suggested that beta-agonist monotherapy facilitates airway inflammation, although when co administered with inhaled corticosteroids (ICSs), similar evidence is lacking. The Salmeterol Multicenter Asthma Research Trial, which revealed a fourfold increase in asthma-related deaths in salmeterol-treated patients, prompted a paradigm shift in the evidential assessment of beta-agonist safety. The FDA's meta-analysis of over 60,000 patients ultimately concluded that long-acting beta agonist (LABA) therapy increased the risk of serious asthma-related events. However, this meta-analysis itself raised questions given a large body of omitted data and a limited emphasis on the risk of ICS-LABA co-administration. Subsequently, the FDA mandated the conduct of five large studies to definitively ascertain whether ICS-LABAs increase asthma-related risk. Whether this ambitious programme will provide certainty remains to be seen given issues of multiplicity, the very low frequency of fatal and near-fatal asthma, and the administration of a free combination of ICS and LABA in one trial. The FDA's de facto use of FEV1 as a safety parameter, based on findings from the Foradil NDA, is a further topical issue: subsequent clinical study data, considerations relating to regional pulmonary drug deposition and pharmacological differences between different beta-agonists suggest that FEV1 may be a suboptimal safety metric. Models evaluating airway inflammation and bronchial reactivity may be more appropriate to assess the relative risk of asthma-related events. PMID- 25712725 TI - Gained in translation: protective paradigms for the poststenotic kidney. PMID- 25712728 TI - In vitro activity of Brucella melitensis isolates to various antimicrobials in Turkey. AB - BACKGROUND: Brucellosis is a systemic infectious disease caused by Brucella bacteria. A successful treatment requires antibiotics that can penetrate into the cell at high concentrations. The aim of this study was to assess the biotype and in vitro activity of 80 Brucella isolates obtained from blood against various antimicrobials for human brucellosis in Turkey. METHODS: Identification of the types of the species designated Brucella species was made using the polymerase chain reaction (PCR), with type-specific primers. Serotyping was performed using mono-specific A and M antisera. The minimum inhibitory concentrations (MICs) of antibiotics known to have good intracellular penetration (doxycycline, rifampicin, ofloxacin, levofloxacin, moxifloxacin, clarithromycin, and azithromycin) were determined by the agar dilution method. RESULTS: All of the 80 Brucella isolates were determined to be Brucella melitensis: 75 B. melitensis biotype 3 (93.7%) and 5 B. melitensis biotype 1 (6.3%). Doxycycline was the most effective among the tested antibiotics against Brucella species (MIC(50)-MIC(90), 0.25-0.5 MUg/ml), and it was followed by levofloxacin (MIC(50)-MIC(90), 0.5-1 MUg/ml), moxifloxacin (MIC(50)-MIC(90), 1-1 MUg/ml), ofloxacin (MIC(50)-MIC(90), 1-1 MUg/ml), rifampicin (MIC(50)-MIC(90), 2-4 MUg/ml), azithromycin (MIC(50) MIC(90), 4-8 MUg/ml), and clarithromycin (MIC(50)-MIC(90), 8-32 MUg/ml), respectively. CONCLUSIONS: The in vitro activity of doxycycline and rifampicin, which are used in the classic treatment of brucellosis, was found to be very good. Quinolones were found to have in vitro activity against Brucella isolates. Among the macrolides, azithromycin had a higher level of activity compared with clarithromycin. A combination of quinolones and azithromycin could be an alternative to doxycycline and rifampicin in the treatment of brucellosis. PMID- 25712727 TI - Delftia lacustris septicemia in a pheochromocytoma patient: case report and literature review. AB - We report the first case of true Delftia lacustris bacteremia in a patient with pheochromocytoma. The organism was identified using 16S rRNA gene sequencing and biochemical tests. A peripheral intravenous catheter was the suspected source of infection, and the patient was successfully treated with piperacillin/tazobactam. We also present a review of the literature describing bacteremia caused by Delftia species. PMID- 25712729 TI - Combined use of biomarkers for distinguishing between bacterial and viral etiologies in pediatric lower respiratory tract infections. AB - BACKGROUND: In clinical practice it is often troublesome to discriminate bacterial etiologies from viral etiologies in pediatric lower respiratory tract infections (LRTIs). The aim of this study was to develop an accurate analytic method to improve diagnostic determination for bacterial and viral etiologies in pediatric LRTIs. METHODS: A total of 45 children with confirmed bacterial LRTIs and 51 children with viral LRTIs were finally included after assessment of the children visiting the emergency department with a suspected infection and identification of pathogens. C-reactive protein (CRP), procalcitonin (PCT), interleukin-6 (IL-6), CD35, and CD64 were assessed and then the areas under receiver operating characteristic (ROC) curves (AUC) of PCT, IL-6, CD35, and CD64 in combination with CRP were compared to the AUC of CRP alone in all subjects. RESULTS: The levels of CRP, PCT, IL-6, CD45, and CD64 observed in children with bacterial LRTIs were statistically higher than for viral infections. The AUC of CRP combined with CD53 (0.963, 95% confidence interval (CI) 0.921-1.002) or CD64 (0.952, 95% CI 0.907-0.998) or CD35/CD64 (0.971, 95% CI 0.932-1.004) increased compared with that of the single biomarker. CONCLUSIONS: The combined analysis improved diagnostic accuracy in children with bacterial and viral LRTIs. PMID- 25712730 TI - Oxidative degradation of N(epsilon)-fructosylamine-substituted peptides in heated aqueous systems. AB - Glycation, or non-enzymatic glycosylation, is a common protein modification formed by reactions between reducing sugars (i.e. aldoses and ketoses) with protein amino groups. Resulting Amadori and Heyns compounds, respectively, can be oxidatively degraded yielding a structurally heterogeneous group of advanced glycation end-products. We have studied this process in aqueous conditions at 95 degrees C in terms of appearing products and their formation kinetics in the presence or absence of reactive oxygen species (ROS)-generating systems (iron(II) sulfate). RP-HPLC-ESI-MS revealed 20 products, 12 of which were confirmed after synthesis by identical retention times and fragmentation patterns. These products accumulated during the incubation period of 4 h (N(epsilon)-carboxymethyl-, N(epsilon)-formyl- and N(epsilon)-methyl lysine) or appeared intermediately (2 aminoadipic semialdehyde, N(epsilon)-ethanalyl lysine). Acidic and basic amino acid residues near the glycation site and elevated ROS levels in the reaction mixture had significant effects on both product formation and degradation kinetics. PMID- 25712731 TI - A Case-Cohort Study of Cadmium Body Burden and Gestational Diabetes Mellitus in American Women. AB - BACKGROUND: Environmental cadmium (Cd) exposure is associated with type 2 diabetes. However, the association of Cd and gestational diabetes mellitus (GDM) is unknown. OBJECTIVES: We examined the association between body burden of Cd and GDM risk. METHODS: We used 140 GDM cases and 481 randomly selected noncase subcohort members from the Omega Study to conduct a case-cohort study. Creatinine (Cr)-corrected Cd in early pregnancy urine (U-Cd) was measured by inductively coupled plasma mass spectrometry. Tertiles (< 0.29; 0.29-0.42; >= 0.43 MUg/g Cr) were defined using the subcohort's U-Cd distribution. GDM was diagnosed using the 2004 American Diabetes Association guidelines. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression. RESULTS: GDM cases had higher geometric mean U-Cd (0.39 MUg/g Cr; 95% CI: 0.37, 0.41) than noncases (0.31 MUg/g Cr; 95% CI: 0.29, 0.33). Odds ratios for GDM increased with increasing U-Cd tertile (OR = 1.64; 95% CI: 0.88, 3.05 for middle vs. low tertile; OR = 2.07; 95% CI: 1.15, 3.73 for high vs. low tertile; p-trend = 0.015). Overweight/obesity (body mass index >= 25 kg/m(2)) did not modify the association between U-Cd and GDM (p = 0.26). CONCLUSIONS: Our findings suggest that body burden of Cd increases risk of GDM in a dose-dependent manner. Improved understanding of environmental factors influencing GDM may facilitate early identification of women at high risk of GDM. PMID- 25712732 TI - An L1-norm phase constraint for half-Fourier compressed sensing in 3D MR imaging. AB - OBJECTIVE: In most half-Fourier imaging methods, explicit phase replacement is used. In combination with parallel imaging, or compressed sensing, half-Fourier reconstruction is usually performed in a separate step. The purpose of this paper is to report that integration of half-Fourier reconstruction into iterative reconstruction minimizes reconstruction errors. MATERIALS AND METHODS: The L1 norm phase constraint for half-Fourier imaging proposed in this work is compared with the L2-norm variant of the same algorithm, with several typical half-Fourier reconstruction methods. Half-Fourier imaging with the proposed phase constraint can be seamlessly combined with parallel imaging and compressed sensing to achieve high acceleration factors. RESULTS: In simulations and in in-vivo experiments half-Fourier imaging with the proposed L1-norm phase constraint enables superior performance both reconstruction of image details and with regard to robustness against phase estimation errors. CONCLUSION: The performance and feasibility of half-Fourier imaging with the proposed L1-norm phase constraint is reported. Its seamless combination with parallel imaging and compressed sensing enables use of greater acceleration in 3D MR imaging. PMID- 25712733 TI - Characterization of putative haematopoietic cells from bovine yolk sac. AB - The yolk sac is an extra-embryonic membrane that plays an important role in early embryonic survival. It is the production site for blood cells during embryonic mammalian development and is a likely source of stem cells. The aim of this study was to identify and characterize the putative haematopoietic cells from the yolk sac of bovine embryos at different stages of gestation. The yolk sac regresses according to gestational age and embryos are characterized into groups (I-V) according to the crown-rump measurement. Groups I-III survived in culture longer and exhibited the formation of cell clusters, whereas groups IV and V could not be maintained in culture for an extended period of time. Flow-cytometry analysis revealed that groups I-III had similar characteristics, including high expression levels of the haematopoietic markers CD34, CD90 and CD117. In groups IV and V, decreases were observed in the expression levels of CD117 and CD34. Cells were found to be capable of survival post-cryopreservation and exhibited varying abilities to form colonies in a methylcellulose matrix, depending on gestational age. Cytological analysis revealed the presence of blood cells (lymphocytes and monocytes). Quantitative PCR analysis demonstrated the presence of the haematopoietic progenitor genes GATA3 and LMO2, but not RUNX1. Thus, we have successfully isolated and characterized haematopoietic cells from the bovine embryo yolk sac at varying gestational ages. This study is crucial for the understanding of the development of the haematopoietic system and the embryonic function of this organ. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 25712734 TI - B-cell very late antigen-4 deficiency reduces leukocyte recruitment and susceptibility to central nervous system autoimmunity. AB - Natalizumab, which binds very late antigen-4 (VLA-4), is a potent therapy for multiple sclerosis (MS). Studies have focused primarily upon its capacity to interfere with T-cell migration into the central nervous system (CNS). B cells are important in MS pathogenesis and express high levels of VLA-4. Here, we report that the selective inhibition of VLA-4 expression on B cells impedes CNS accumulation of B cells, and recruitment of Th17 cells and macrophages, and reduces susceptibility to experimental autoimmune encephalomyelitis. These results underscore the importance of B-cell VLA-4 expression in the pathogenesis of CNS autoimmunity and provide insight regarding mechanisms that may contribute to the benefit of natalizumab in MS, as well as candidate therapeutics that selectively target B cells. PMID- 25712736 TI - Comparison of metolazone versus chlorothiazide in acute decompensated heart failure with diuretic resistance. AB - AIMS: Sequential nephron blockade with thiazide-like diuretics is a strategy used to overcome diuretic resistance in acute decompensated heart failure (ADHF), but head-to-head studies are lacking and equipoise exists regarding the preferred thiazide-like diuretic in this setting. We thus compared the effectiveness of oral metolazone versus intravenous (IV) chlorothiazide as add-on therapy to loop diuretics in hospitalized patients with ADHF and renal dysfunction. METHODS: This retrospective cohort study evaluated the efficacy and safety of oral metolazone versus IV chlorothiazide as add-on therapy to loop diuretics in patients hospitalized with ADHF and renal dysfunction. The primary endpoint was net urine output (UOP) at 72 h after initiation of thiazide-like diuretics. Safety endpoints included worsening renal function, hypotension, and electrolyte abnormalities. RESULTS: Fifty-five patients were enrolled with 33 patients receiving metolazone and 22 patients receiving chlorothiazide. There was no difference in median net UOP at 72 h in those receiving metolazone (4828 mL, interquartile range [IQR] 2800-7209 mL) compared to chlorothiazide (3779 mL, IQR 1885-6535 mL) (P = 0.16). There was no difference in hypotension, worsening renal function, hyponatremia, or hypokalemia (P = NS for all comparisons). Hospital length of stay was shorter in the metolazone cohort (median 7 days) compared to chlorothiazide (median 15 days), suggesting the chlorothiazide cohort was likely sicker. CONCLUSION: Sequential nephron blockade with either metolazone or chlorothiazide appears to be efficacious and safe in ADHF, renal dysfunction, and diuretic resistance. Given the considerable cost difference favoring oral metolazone, larger randomized studies are warranted to confirm our findings and to exclude the possibility of confounding by indication. PMID- 25712735 TI - Interferon alpha 2 maintenance therapy may enable high rates of treatment discontinuation in chronic myeloid leukemia. AB - A minority of chronic myeloid leukemia (CML) patients is capable of successfully discontinuing imatinib. Treatment modalities to increase this proportion are currently unknown. Here, we assessed the role of interferon alpha 2a (IFN) on therapy discontinuation in a previously reported cohort of 20 chronic phase CML patients who were treated upfront with IFN alpha plus imatinib followed by IFN monotherapy to maintain cytogenetic or molecular remission (MR) after imatinib discontinuation. After a median follow-up of 7.9 years (range, 5.2-12.2), relapse free survival was 73% (8/11 patients) and 84% (5/6 patients) for patients who discontinued imatinib in major MR (MMR) and MR4/MR4.5, respectively. Ten patients discontinued IFN after a median of 4.5 years (range, 0.24-9.3). After a median of 2.8 years (range, 0.7-5.1), nine of them remain in ongoing treatment-free remission with MR5 (n=6) and MR4.5 (n=3). The four patients who still administer IFN are in stable MR5, MR4.5, MR4, and MMR, respectively. In conclusion, an IFN/imatinib induction treatment followed by a temporary IFN maintenance therapy may enable a high rate of treatment discontinuation in CML patients in at least MMR when stopping imatinib. PMID- 25712738 TI - Prevalence of Lynch syndrome in a Middle Eastern population with colorectal cancer. AB - BACKGROUND: Lynch syndrome (LS; hereditary nonpolyposis colorectal cancer) is a common cause of hereditary colorectal cancer (CRC). CRC is the most common cancer diagnosed among males in Saudi Arabia but to the authors' knowledge there is a lack of data regarding the prevalence of LS in patients with CRC. There currently are no clear guidelines for the selection criteria for these patients to screen for LS. METHODS: A comprehensive molecular characterization was performed in a cohort of 807 CRC cases by immunohistochemical and microsatellite analysis using polymerase chain reaction. BRAF mutation screening, high CpG island methylator phenotype, and analysis for germline mutations were performed in 425 CRC samples. These were all high microsatellite instability (MSI-H) samples (91 cases), all low MSI samples (143 cases), and selected cases from the microsatellite stable group (191 cases) that met revised Bethesda guidelines. RESULTS: Polymerase chain reaction identified 91 MSI-H cases (11.3%) and sequencing revealed mismatch repair germline mutations in 8 CRC cases only. Of the total of 807 CRC cases, these 8 cases (0.99%) were MSI-H, met the revised Bethesda guidelines, and did not harbor BRAF mutations. CONCLUSIONS: The results of the current study confirmed cases of LS in approximately 1.0% of CRC samples and reflects the efficacy of screening among MSI-H cases that lack BRAF mutations. This comprehensive study from Saudi Arabia will help in implementing a universal screening/reflex testing strategy in a clinical setting in Saudi Arabia and in conducting a national screening program that benefits both patients and their relatives. PMID- 25712739 TI - Cross-talk between signaling pathways: the link between plant secondary metabolite production and wounding stress response. AB - Plants subjected to wounding stress produce secondary metabolites. Several of these metabolites prevent chronic diseases and can be used as colorants, flavors, and as antimicrobials. This wound-induced production of plant secondary metabolites is mediated by signaling-molecules such as reactive oxygen species (ROS), ethylene (ET) and jasmonic acid (JA). However, their specific role and interactions that modulate the wound-respond in plants is not fully understood. In the present study, a subtractive cDNA library was generated, to better understand the global response of plants to wounding stress. Carrot (Daucus carota) was used as a model system for this study. A total of 335 unique expressed sequence tags (ESTs) sequences were obtained. ESTs sequences with a putative identity showed involvement in stress-signaling pathways as well as on the primary and secondary metabolism. Inhibitors of ROS biosynthesis, ET action, and JA biosynthesis alone and in combination were applied to wounded-carrots in order to determine, based on relative gene expression data, the regulatory role of ET, JA, and ROS on the wound-response in plants. Our results demonstrate that ROS play a key role as signaling-molecules for the wound-induced activation of the primary and secondary metabolism whereas ET and JA are essential to modulate ROS levels. PMID- 25712740 TI - Multielectrode left ventricular mapping: too much or not enough? PMID- 25712741 TI - Pathological evaluation of the filum terminale tissue after surgical excision. AB - PURPOSE: Tethered cord syndrome (TCS) is an important disease and can produce progressive neurological symptoms. Studies about the filum terminale (FT) have drawn attention to the importance of histopathological investigation of this structure. The most interesting of these subtypes is the FT that incorporates peripheral nerve fibers (PNF). Our study aimed to analyze the frequency of PNF in the FT of 40 cases diagnosed with TCS. METHODS: We performed a retrospective histopathological investigation of FT excised during surgery of patients with TCS who underwent de-tethering. Neurologic and other types of postoperative complications were also revised. RESULTS: Analysis of the samples showed six dominant histopathological subtypes in the FT: fibroadipose tissues including peripheral nerve bundles (n = 14, 37 %), fibroadipose tissue (n = 10, 25 %), fibrous or adipose tissue (n = 7, 17 %), glial tissues including peripheral nerve sections (n = 4, 10 %), and ependymal and glial tissues (n = 4, 10 %). None of the patients presented with neurologic postoperative complications. CONCLUSION: Embryologic studies revealed that it is common to encounter different histological subtypes of FT pathology. However, the presence of peripheral nerve cells in the FT is important for neurosurgical practice due to the risk of sectioning a functional structure during surgery. In our analysis, we demonstrated the high frequency of PNF in FT pathology. However, since none of the patients showed any symptoms of neurologic deterioration, we considered that these fibers were probably not functional. Our findings emphasize the importance of neuromonitoring in TCS surgery. Although we consider that most of the fibers are probably not functional, neuromonitoring after surgery may prevent serious complications. PMID- 25712742 TI - Toxicity evaluation of convection-enhanced delivery of small-molecule kinase inhibitors in naive mouse brainstem. AB - PURPOSE: Diffuse intrinsic pontine gliomas (DIPGs) are inoperable and lethal high grade gliomas lacking definitive therapy. Platelet-derived growth factor receptor (PDGFR) and its downstream signaling molecules are the most commonly overexpressed oncogenes in DIPG. This study tested the effective concentration of PDGFR pathway inhibitors in cell culture and then toxicity of these small molecule kinase inhibitors delivered to the mouse brainstem via convection enhanced delivery (CED) for potential clinical application. METHODS: Effective concentrations of small-molecule kinase inhibitors were first established in cell culture from a mouse brainstem glioma model. Sixteen mice underwent CED, a local drug delivery technique, of saline or of single and multidrug combinations of dasatinib (2 M), everolimus (20 M), and perifosine (0.63 mM) in the pons. Animals were kept alive for 3 days following the completion of infusion. RESULTS: No animals displayed any immediate or delayed neurological deficits postoperatively. Histological analysis revealed edema, microgliosis, acute inflammation, and/or axonal injury in the experimental animals consistent with mild acute drug toxicity. CONCLUSIONS: Brainstem CED of small-molecule kinase inhibitors in the mouse did not cause serious acute toxicities. Future studies will be necessary to evaluate longer-term safety to prepare for potential clinical application. PMID- 25712745 TI - SiO2-coated sulfur particles with mildly reduced graphene oxide as a cathode material for lithium-sulfur batteries. AB - For the first time, SiO2-coated sulfur particles (SCSPs) were fabricated via a facile two-step wet chemical process for application as a novel lithium-sulfur cathode material. With the addition of mildly reduced graphene oxide (mrGO), SCSPs demonstrate even greater cycling stability, maintaining over 700 mA h g(-1) after the 50(th) cycle. PMID- 25712744 TI - Combined transnasal and transoral endoscopic approach to a transsphenoidal encephalocele in an infant. AB - PURPOSE: This paper reports an unusual case of a transsphenoidal encephalocele and discusses our experience with a minimally invasive management. To the best of our knowledge, we present the first case of a combined endoscopic transnasal and transoral approach to a transsphenoidal encephalocele in an infant. METHODS: A 17 day-old boy, who was referred for further assessment of upper airway obstruction, presented with respiratory distress and feeding difficulties. Bronchoscopy and imaging revealed a transsphenoidal encephalocele. At the age of 48 days, he underwent a combined endoscopic transnasal and transoral excision of the nasal component of the encephalocele. This approach, with the aid of neuronavigation, allows good demarcation of the extra-cranial neck of the transsphenoidal encephalocele. We were able to cauterize and carefully dissect the sac prior to excision. The defect of the neck was clearly visualized, and Valsalva manoeuvre was performed to exclude any CSF leak. As the defect was small, it was allowed to heal by secondary intention. RESULTS: The patient's recovery was uneventful, and he tolerated full feeds orally on day 2. Postoperative imaging demonstrated no evidence of recurrence of the nasal encephalocele. Endoscopic follow-up showed good healing of the mucosa and no cerebrospinal fluid leak. CONCLUSIONS: The surgical management of transsphenoidal encephalocele in neonates and infants is challenging. We describe a safe technique with low morbidity in managing such a condition. The combined endoscopic transnasal and transoral approach with neuronavigation is a minimally invasive, safe and feasible alternative, even for children below 1 year of age. PMID- 25712743 TI - Analysis of the potential risk of central intravenous lines and/or total parenteral nutrition with ventriculoatrial shunts. AB - OBJECT: The distal catheter of a ventriculoatrial (VA) cerebrospinal fluid shunt is potentially exposed to bacterial seeding from a subclavian central line. The risk of blood stream infections (BSIs) from central lines increases with administration of total parenteral nutrition (TPN). The potential risks of shunt malfunction or infection in patients with a VA shunt and a concurrent subclavian central line and/or TPN administration have not been studied. METHODS: A retrospective review of 49 pediatric patients with placement of a VA shunt was performed. Three outcome measures were studied: shunt malfunction, shunt infection, and bacteremia/fungemia requiring shunt removal. All outcomes were measured by 1 year after shunt insertion. We analyzed the following potential risk factors: age at shunt insertion, prior ventriculoperitoneal (VP) shunt, prior shunt infection, abdominal infection/necrotizing enterocolitis (NEC), concurrent subclavian central line, and administration of TPN. The association between each risk factor and outcome was evaluated using Fisher's exact test to generate the relative risk. Additionally, a logistic regression analysis was performed to evaluate the odds ratio of the outcomes to risk factors considering age as a covariate. RESULTS: The average age at shunt insertion was 6.3 +/- 7.6 years. The most common diagnosis was posthemorrhagic hydrocephalus of prematurity (53.1 %). Fifteen patients (30.1 %) had a shunt malfunction within 1 year, 6 (12.2 %) had a shunt infection, and 3 (6.1 %) required removal of the shunt due to bacteremia/fungemia. The age at shunt insertion was not a statistically significant independent risk factor for any of the three outcomes. Prior shunt infection predicted an increased risk for both future shunt malfunction and infection in both the associative relative risk analysis and the age-dependent logistic regression analysis, although the correlation did not reach statistical significance. The presence of a subclavian central line or TPN administration did not statistically increase the risk over baseline for any of the outcomes in either analysis. CONCLUSIONS: The relatively small number of patients limits the power of the study. Considering this limitation, the data suggests that the presence of a concurrent subclavian central line or administration of TPN does not increase the risk of shunt malfunction or infection over the baseline of this high-risk cohort. PMID- 25712746 TI - Current frontiers in systemic sclerosis pathogenesis. AB - Systemic sclerosis is an autoimmune disease characterised by vascular dysfunction, impaired angiogenesis, inflammation and fibrosis. There is no currently accepted disease-modifying treatment with only autologous stem cell transplant showing clinically meaningful benefit. The lack of treatment options reflects our lack of understanding of the precise molecular mechanisms occurring in the disease. Recent investigations have begun to decipher the molecular pathways underpinning the different aspects of the disease and may provide a rational clinical target(s). Uncovering the molecular mechanisms of the disease is important in understanding systemic sclerosis treatment. The aim of this review was to examine the current thinking in SSc pathogenesis and will offer novel areas for research which may yield novel therapeutics. PMID- 25712747 TI - Regime shifts, thresholds and multiple stable states in freshwater ecosystems; a critical appraisal of the evidence. AB - The concepts of ecosystem regime shifts, thresholds and alternative or multiple stable states are used extensively in the ecological and environmental management literature. When applied to aquatic ecosystems, these terms are used inconsistently reflecting differing levels of supporting evidence among ecosystem types. Although many aquatic ecosystems around the world have become degraded, the magnitude and causes of changes, relative to the range of historical variability, are poorly known. A working group supported by the Australian Centre for Ecological Analysis and Synthesis (ACEAS) reviewed 135 papers on freshwater ecosystems to assess the evidence for pressure-induced non-linear changes in freshwater ecosystems; these papers used terms indicating sudden and non-linear change in their titles and key words, and so was a positively biased sample. We scrutinized papers for study context and methods, ecosystem characteristics and focus, types of pressures and ecological responses considered, and the type of change reported (i.e., gradual, non-linear, hysteretic or irreversible change). There was little empirical evidence for regime shifts and changes between multiple or alternative stable states in these studies although some shifts between turbid phytoplankton-dominated states and clear-water, macrophyte dominated states were reported in shallow lakes in temperate climates. We found limited understanding of the subtleties of the relevant theoretical concepts and encountered few mechanistic studies that investigated or identified cause-and effect relationships between ecological responses and nominal pressures. Our results mirror those of reviews for estuarine, nearshore and marine aquatic ecosystems, demonstrating that although the concepts of regime shifts and alternative stable states have become prominent in the scientific and management literature, their empirical underpinning is weak outside of a specific environmental setting. The application of these concepts in future research and management applications should include evidence on the mechanistic links between pressures and consequent ecological change. Explicit consideration should also be given to whether observed temporal dynamics represent variation along a continuum rather than categorically different states. PMID- 25712748 TI - Testing the joint effects hypothesis of elemental defense using Spodoptera exigua. AB - Metal hyperaccumulation may be an elemental defense, in which high concentrations of a metal in plant tissues decrease herbivore survival or growth rate. The Joint Effects Hypothesis suggests that a combination of metals, or a combination of a metal with an organic compound, may have an enhanced defensive effect. The enhancement may be additive or synergistic: in either case the concentration of a particular metal necessary to provide a defensive benefit for the plant is lowered. We tested the Joint Effects Hypothesis using Spodoptera exigua (beet armyworm) neonates fed artificial diets. Metal + metal experiments utilized diets amended with metal pairs, using four metals commonly hyperaccumulated by plants (Co, Cu, Ni, and Zn). We also conducted metal + organic compound experiments, pairing each metal with nicotine, mustard seed powder, or tannic acid. We tested for joint effects using both lethal (LC20 levels) and sublethal concentrations (10-25 % reduced larval weight) of the chemicals tested. For all experiments, either additive or synergistic effects were found. Of the metal + metal pairs tested, three (Co + Cu, Cu + Zn, and Ni + Zn) were synergistic in lethal concentration tests and only Co + Cu was synergistic in sublethal tests. For metal + organic combination lethal tests, synergism occurred for all combinations except for Co or Ni + nicotine, Ni + mustard seed powder, and Zn + nicotine. For sublethal tests, Zn + all three organic chemicals, Co + mustard seed powder or tannic acid, and Cu + nicotine, were synergistic. These results support the Joint Effects Hypothesis, suggesting that metals combined with other metals or organic compounds may be more effective against herbivores than individual metals. PMID- 25712749 TI - Idiopathic mitral valve chordae rupture in an infant: importance of rapid diagnosis and surgery. AB - Mitral valve chordae rupture in infancy is a rare, but life-threatening disease. The progression of acute cardiac failure has been reported, with emergency surgery being required in most cases. Mitral valve chordae rupture typically occurs at the age of 4-6 months. Echocardiography is needed to diagnose this disease, and accurate diagnosis is difficult for general pediatricians. We herein describe the case of an acutely ill 4-month-old infant, who was saved and discharged without neurological sequelae due to the early diagnosis of mitral valve chordae rupture, life support, and surgery. We confirm the importance of acute pre-surgery treatment and immediate surgery for the survival and good outcome of infants. PMID- 25712750 TI - Establishment and characterization of patient-derived tumor xenograft using gastroscopic biopsies in gastric cancer. AB - The patient-derived tumor xenograft (PDTX) model has become the most realistic model for preclinical studies. PDTX models of gastric cancer using surgical tissues are reported occasionally; however, the PDTX models using gastroscopic biopsies, which are best for evaluating new drugs, are unreported. In our study, a total of 185 fresh gastroscopic biopsies of gastric cancer were subcutaneously transplanted into NOD/SCID (Nonobese Diabetic/Severe Combined Immunodeficiency) mice. Sixty-three PDTX models were successfully established (34.1%, 63/185) and passaged to maintain tumors in vivo, and the mean latency period of xenografts was 65.86 +/- 32.84 days (11-160 days). Biopsies of prior chemotherapy had a higher transplantation rate (52.1%, 37/71) than biopsies after chemotherapy (21.9%, 25/114; P = 0.000). No differences were found between the latency period of xenografts and characteristics of patients. The pathological and molecular features of PDTX as well as chemosensitivity were highly consistent with those of primary tumors of patients. The genetic characteristics were stable during passaging of PDTX models. In summary PDTX models using gastroscopic biopsies in gastric cancer were demonstrated for the first time, and the biological characteristics of the PDTX models were highly consistent with patients, which provided the best preclinical study platform for gastric cancer. PMID- 25712751 TI - Relationship between serum cytokine and growth factor concentrations and coronary artery disease. AB - BACKGROUND: We have assessed the association between serum concentrations of 12 cytokines/growth factors and angiographically-defined coronary artery disease, comparing the concentrations in four groups (one control group and three case groups). METHODS: We studied a total of 426 subjects including; 98 control subjects and 3 case groups. The patient groups consisted of: coronary artery bypass graft (CABG) candidates (n=48) and patients undergoing coronary angiography, with, or without obstructive coronary artery disease. Twelve cytokines (IL-1alpha, IL-1beta, IL-2, IL-4, IL-6, IL-8, IL-10, TNF-alpha, MCP-1, IFN-gamma, EGF, and VEGF) were measured using a sandwich chemi-luminescence assays, on the Evidence Investigator(r) system. RESULTS: The four groups were well matched for demographic and clinical characteristics, except waist circumference, fasting blood glucose (FBG), total and LDL cholesterol and diastolic blood pressure that were significantly higher in case groups compared to the control group (P<0.05 for all). There were significant differences between control group and the other three groups regarding the measured cytokines, such as IL-1alpha, IL-8, MCP-1, and VEGF (P<0.01). Furthermore, IL-4, IL-6 and EGF were also significantly different between the control, obstructive coronary disease and CABG candidate groups (P<0.01). Analysis of the ROC curve showed 92.1% sensitivity, 99.2% specificity and 100% positive predictive value (PPV) for VEGF in its ability to distinguish the CABG group at the cut-off point of 37.18 pg/ml. CONCLUSION: The results of this study suggest that cytokines such as IL 1alpha, IL-4, IL-8, IL-10 and VEGF may play major roles in pathogenesis of CAD. PMID- 25712752 TI - Validation of a HPLC-MS/MS assay for the determination of total and unbound concentration of temocillin in human serum. AB - OBJECTIVES: The aim of this study was to develop and validate a HPLC-MS/MS assay to determine total and unbound concentrations of temocillin in serum samples. DESIGN AND METHODS: Methanolic protein precipitation and ultrafiltration were used for total and unbound concentration extraction, respectively. Extract was injected into a LC-MS/MS system. Reversed phase chromatography was performed on a phenyl grafted column in gradient mode. Temocillin and internal standard (ticarcillin) were identified in positive electrospray ionization mode using ion transitions of m/z 415.34>339.1 and 385.31>160.3, respectively. RESULTS: Temocillin total and unbound concentration quantification assays were linear over concentrations ranging from 1 to 500 mg/L and from 0.5 to 300 mg/L, respectively. Both assays presented acceptable intra and inter-assay precision and accuracy <13.9%. Limits of quantification and detection were of 1 and 0.10mg/L, and 0.5 and 0.05 mg/L for total and unbound concentration respectively. Total temocillin concentration recovery ranged from 85.80 to 99.40%. Temocillin ion suppression effect was <36.2 % in both assays. CONCLUSION: The method described is fast, sensitive and selective, with no interferences. This method may be used for both pharmacokinetic studies and therapeutic drug monitoring purposes. PMID- 25712753 TI - Food at checkouts in non-food stores: a cross-sectional study of a large indoor shopping mall. AB - OBJECTIVE: To investigate the display of food at non-food store checkouts; and to classify foods by type and nutrient content, presence of price promotions and whether food was at child height. DESIGN: Cross-sectional survey of checkout displays at non-food stores. Foods were classified as 'less healthy' or healthier using the UK Food Standards Agency's Nutrient Profile Model. Written price promotions were recorded. Child height was defined as the sight line of an 11 year-old approximated from UK growth charts. SETTING: A large indoor shopping mall, Gateshead, UK, February-March 2014. SUBJECTS: Two hundred and five out of 219 non-food stores in the shopping mall directory which were open for trading. RESULTS: Thirty-two (15.6%) of 205 non-food stores displayed food at the checkout. All displayed less healthy foods, and fourteen (43.8%) had healthier foods. Overall, 5911 checkout foods were identified. Of these, 4763 (80.6%) were 'less healthy'. No fruits, vegetables, nuts or seeds were found. Of 4763 less healthy foods displayed, 195 (4.1%) were subject to price promotions, compared with twelve of 1148 (1.0%) healthier foods (chi 2(df=1)=25.4, P<0.0001). There was no difference in the proportion of less healthy (95.1%) and healthier (96.2%) foods displayed at child height. CONCLUSIONS: Almost one-sixth of non-food stores displayed checkout food, the majority of which was 'less healthy' and displayed at child height. Less healthy food was more likely to be subject to a written price promotion than healthier food. Further research into the drivers and consequences of checkout food in non-food stores is needed. Public health regulation may be warranted. PMID- 25712754 TI - Double Redox-Responsive Release of Encoded and Encapsulated Molecules from Patchy Nanocapsules. AB - Redox-responsive nanocapsules with surface regularities are presented. Two functional molecules are loaded in the nanocapsules. One molecule is chemically encoded in the capsule shell via a disulfide bond while the other one is physically entrapped in the capsule core. External reducing trigger can induce cascade release of the two payloads. PMID- 25712755 TI - Full-length cDNA cloning, molecular characterization and differential expression analysis of peroxiredoxin 6 from Ovis aries. AB - Peroxiredoxin 6 (Prdx6), an important antioxidant enzyme that can eliminate reactive oxygen species (ROS) to maintain homeostasis, is a bifunctional protein that possesses the activities of both glutathione peroxidase and phospholipase A2. In this study, a novel full-length Prdx6 cDNA (OaPrdx6) was cloned from Sheep (Ovis aries) using rapid amplification of cDNA ends (RACE). The full-length cDNA of OaPrdx6 was 1753bp containing a 5'-untranslated region (UTR) of 93bp, a 3'-UTR of 985bp with a poly(A) tail, and an open reading frame (ORF) of 675bp encoding a protein of 224 amino acid residues with a predicted molecular weight of 25.07kDa. The recombinant protein OaPrdx6 was expressed and purified, and its DNA protection activity was identified. In order to analyze the Prdx6 protein expression in tissues from O. aries, monoclonal antibodies against OaPrdx6 were prepared. Western blotting results indicated that OaPrdx6 protein could be detected in heart, liver, spleen, lung, kidney, stomach, intestine, muscle, lymph node and white blood cells, and the highest expression was found in lung while the lowest expression in muscle. Compared to the normal sheep group, the mRNA transcription level of Prdx6 in buffy coat was up-regulated in the group infected with a virulent field strain of Brucella melitensis, and down-regulated in the group inoculated with a vaccine strain S2 of brucellosis. The results indicated that Prdx6 was likely to be involved in the host immune responses against Brucella infection, and probably regarded as a molecular biomarker for distinguishing between animals infected with virulent Brucella infection and those inoculated with vaccine against brucellosis. PMID- 25712756 TI - A new enterotoxigenic Escherichia coli vaccine candidate constructed using a Salmonella ghost delivery system: comparative evaluation with a commercial vaccine for neonatal piglet colibacillosis. AB - In this study, a comparative evaluation between a Salmonella ghost vaccine expressing enterotoxigenic Escherichia coli (ETEC) fimbrial antigens and a commercial ETEC vaccine was conducted in neonatal piglets. Genes encoding the ETEC K88ab, K88ac, K99, FasA, and F41 fimbrial proteins were individually cloned into an expression/ghost plasmid (pJHLP184) carrying the pBR origin, asd, the ompA signal sequence to direct antigens to the cell membrane, cI857/lambdaPR promoter, araC ParaBAD, and the phiX174 lysis gene E. Individual clones were subsequently used to electroporate a Deltaasd S. Typhimurium strain, and positive clones were used to generate Salmonella ghosts. Pregnant sows (n=12) were equally divided into four groups. Pregnant sows were primed and boosted at 11 and 14 weeks of pregnancy, respectively. Group A, B, and C sows were intramuscularly inoculated with PBS as a control, a commercial vaccine, and with 2*10(10) ghost cells, respectively, while group D sows were orally immunized with 2*10(10) ghost cells. All the vaccinated sows and their offspring exhibited increased ETEC fimbrial antigen antibody levels relative to those in the unimmunized group A. Especially, serum IgG and colostrum IgA levels in the group D sows and serum IgG and IgA levels in their piglets were significantly higher than those in control group sows and offspring, respectively. The levels of interleukin-4 against all the fimbrial proteins in peripheral blood lymphocytes of group D sows also increased significantly, whereas no difference between the control group and any of the immunized groups was detected for interferon-gamma. In addition, the piglets of group D did not experience diarrhea following challenge with virulent ETEC strains. Diarrhea was observed in 88.9%, 30.4%, and 23.5% of the piglets in groups A, B and C, respectively. Mortality was observed in 16.7% and 5.9% of the piglets in groups A and C, respectively. These findings indicate that immunization of sows with the ghost vaccine candidate, especially by the oral route, can effectively protect their offspring against E. coli colibacillosis. PMID- 25712757 TI - MEIS2 involvement in cardiac development, cleft palate, and intellectual disability. AB - MEIS2 has been associated with cleft palate and cardiac septal defects as well as varying degrees of intellectual disability. We present a female patient with a more severe phenotype compared to previous reported patients. She has multiple congenital malformations; cleft palate and congenital heart defect characterized by septal defects and aortic coarctation. She has severe feeding problems, facial dysmorphism, severely delayed gross motor and verbal development, and autism spectrum disorder. Facial dysmorphism consisting of bitemporal narrowing, arched and laterally extended eyebrows, mild upslanting palpebral fissures, deep-set eyes, a tented upper lip, thin upper vermilion, full lower vermilion, broad first ray of hands and feet, a gap between the first and second toes, and syndactyly of toe II-III. Exome sequencing revealed a non-frameshift deletion (c.998_1000del:p.Arg333del) of three base pairs in the MEIS2 homeodomain. The more severe phenotype is most probably due to dominant-negative mechanisms. This is the first report showing a de novo small intragenic mutation in MEIS2 and further confirms the important role of this gene in normal development. PMID- 25712758 TI - The effect of lower extremity nerve decompression on health-related quality of life and perception of pain in patients with painful diabetic polyneuropathy: a prospective randomized trial. AB - AIMS: The aim of this study was to assess whether surgical decompression of nerves in the lower extremity in people with painful diabetic polyneuropathy would have an effect on health-related quality of life and to determine minimal clinically important differences in pain and quality of life scores. METHODS: The design was a randomized controlled trial in which 42 participants with painful diabetic painful neuroapthy underwent unilateral decompression of nerves in their left or right leg, using the other leg as a control, with 12 months follow-up. Surgical decompression was performed at the tibial, superficial, deep and common peroneal nerves. Preoperatively, and at 6 and 12 months post operatively, a visual analogue scale for pain and the 36 item short-form health survey and EuroQual 5 Dimensions questionnaires were completed. RESULTS: At 12 months follow up, the visual analogue scale was significantly reduced, but decompression surgery did not significantly alter health-related quality of life scores. The minimal clinically important difference for visual analogue scale reduction was determined at 2.9 points decrease, a threshold reached by 42.5% of the study population. CONCLUSIONS: Although decompression surgery does not influence health related quality of life, it achieves a clinically relevant reduction of pain in ~42.5% of people with diabetic peripheral neuropathy. It can therefore be considered for patients who do not adequately respond to pain medication. PMID- 25712759 TI - Animal Farm: Considerations in Animal Gastrointestinal Physiology and Relevance to Drug Delivery in Humans. AB - "All animals are equal, but some are more equal than others" was the illustrious quote derived from British writer George Orwell's famed work, Animal Farm. Extending beyond the remit of political allegory, however, this statement would appear to hold true for the selection of appropriate animal models to simulate human physiology in preclinical studies. There remain definite gaps in our current knowledge with respect to animal physiology, notably those of intra- and inter-species differences in gastrointestinal (GI) function, which may affect oral drug delivery and absorption. Factors such as cost and availability have often influenced the choice of animal species without clear justification for their similarity to humans, and lack of standardization in techniques employed in past studies using various animals may also have contributed to the generation of contradictory results. As it stands, attempts to identify a single animal species as appropriately representative of human physiology and which may able to adequately simulate human in vivo conditions are limited. In this review, we have compiled and critically reviewed data from numerous studies of GI anatomy and physiology of various animal species commonly used in drug delivery modeling, commenting on the appropriateness of these animals for in vivo comparison and extrapolation to humans. PMID- 25712760 TI - The effect of orally administered probiotic Lactobacillus reuteri-containing tablets in peri-implant mucositis: a double-blind randomized controlled trial. AB - BACKGROUND AND OBJECTIVES: Probiotics create a biofilm and protect the oral tissues against the action of periodontal pathogenic bacteria. The aim of this study was to evaluate the effects of the oral probiotic Lactobacillus reuteri Prodentis upon the peri-implant health of edentulous patients with dental implants and peri-implant mucositis, establishing comparisons vs implants without peri-implant disease. MATERIAL AND METHODS: A double-blind, placebo-controlled, prospective cross-over study was made. The patients were all edentulous and were divided into two groups, (A) no peri-implant disease, and (B) peri-implant mucositis affecting one or more implants. Patients with peri-implantitis were excluded. The dosage was one tablet every 24 h over 30 d. All patients in both groups initially received the oral probiotic Lactobacillus reuteri Prodentis, followed by placebo. Patients started with probiotic treatment during 30 d, followed by a 6 mo washout period and the administration of placebo for the same period. The following parameters were studied: crevicular fluid volume, modified plaque index, probing depth, modified gingival index, and concentrations of interleukin 1beta, interleukin 6 and interleukin 8. RESULTS: A total of 77 implants were evaluated in 34 patients. Group A involved 22 patients with 54 implants without peri-implant alterations, and group B, 12 patients with mucositis affecting one or more implants (23 implants). After treatment with the probiotic, both the patients with mucositis and the patients without peri-implant disease showed improvements in the clinical parameters, with reductions in cytokine levels. In contrast, no such changes were observed with placebo. CONCLUSIONS: After treatment with the probiotic Lactobacillus reuteri in patients with implants presenting mucositis, the clinical parameters improved, and the cytokine levels decreased - in contraposition to the observations in the placebo group. Probiotic administration may be regarded as a good alternative for both the treatment of peri-implant mucositis and its prevention, as it also improved clinical parameters in the healthy individuals. Further studies involving larger patient series are needed regarding the effects of probiotics upon peri-implant health. PMID- 25712762 TI - The pedagogic evolution in Surgery: the University at the centre of a training which becomes territorialized The model of the region Marche. AB - AIM: We want to show a new organisational model of General Surgery training, in act in Universita Politecnica delle Marche, which sees its strength in the territorial formative network. MATERIAL OF STUDY: In our Athenaeum, this organization is not a recent realization, but the firsts to have benefited completely of this system are the four residents who have completed the General Surgery formation in March 2014, for this reason we report their experience. RESULTS: The four residents benefited of the two years in the peripheral structures, two also performed a period in a foreign country, two chose to spend other 6 months in the peripheral structure to prepare the thesis of specialization; surgical activity has been, for each resident, of 400 interventions on average as first operator (237-476) distributed in great surgery 44 (13-80), middle 172 (129-268) and small 209 (70-378). DISCUSSION: The Formative NETWORK becomes an essential strength at the service of the academic world, the network foresees a continuous update, it can be easily standardized for every resident and it doesn't raise barriers to the foreign countries experiences. CONCLUSIONS: With the purpose to conform the model of specialistic formation in General Surgery, we propose a new tailored italian organizational model, tested the lasts 6 years, which seems to give good results and conform to the european standard of surgical training. KEY WORDS: Formative network, General Surgery, Resident, Training. PMID- 25712761 TI - Disease-generic factors of work participation of workers with a chronic disease: a systematic review. AB - PURPOSE: The purpose of this review was to search systematically for disease generic factors associated with either work retention (WR) or return to work (RTW) in people of working age with a chronic disease. METHODS: An extensive search was performed in PubMed, EMBASE, PsycINFO and CINAHL for English-, Dutch- and German-language studies searching on synonyms of the terms chronic disease, WR and RTW. Studies were selected if they described factors related to WR or RTW and included participants with a chronic disease of working age (15-67 years old). RESULTS: From 2597 hits in the electronic databases, we identified six studies reporting 23 factors associated with work participation. Categorized according to the International Classification of Functioning, Disability and Health, health-related factors (comorbidity, duration of symptoms and less dysfunction), environmental factors (work environment and duration of absence) and personal factors (age, gender, education and own prediction of RTW) were identified. CONCLUSIONS: Various disease-generic factors are associated with work participation, of which most of the reported factors are independent of diagnosis. Evidence of the retrieved factors is restricted due to the limited availability of studies focusing on disease-generic factors and overall low quality of the retrieved studies. PMID- 25712763 TI - Strategies for penile prosthesis placement in Peyronie's disease and corporal fibrosis. AB - Peyronie's disease (PD) is a wound healing disorder of the tunica albuginea of the penis. PD is generally categorized into two phases: the early acute inflammatory and late chronic fibrotic. Surgical reconstruction is only recommended during the latter established phase. There are a variety of options when erections are functional. However, when erectile dysfunction is present, the gold standard treatment is the placement of an inflatable penile prosthesis with or without additional straightening procedures. General recommendations include that after implanting and inflating the cylinders, if a clinically significant curvature is present, manual modeling is performed. If a residual curve >30 degrees remains after modeling, then various techniques, including plaque releasing incision, is the next step. Grafting can be considered if tunical defects are >2.0 cm. Causes of corporal fibrosis include complications from an infected implant such as explantation, priapism, penile trauma, and prolonged use of an intracavernosal injection agent. Implant placement in the setting of corporal fibrosis can be technically challenging. Available strategies include incision or excision of the scar, corporotomies with or without grafting, the use of cavernotomes, or other specialized dilators, implant downsizing, and transcorporeal resection. PMID- 25712764 TI - Heterozygous germline mutations in NBS1 among Korean patients with high-risk breast cancer negative for BRCA1/2 mutation. AB - The purpose of the present study was to analyze genetic variations in the NBS1 gene and to evaluate the contribution of heterozygous NBS1 mutation to the risk of breast cancer among Korean patients with high-risk breast cancer negative for BRCA1/2 mutation. We screened 235 non-BRCA1/2 Korean patients with high-risk breast cancer for NBS1 mutations. The entire NBS1 gene was sequenced using fluorescent conformation-sensitive capillary electrophoresis. In silico analysis of the NBS1 variants was performed using PolyPhen-2 and SIFT. The frequency of variants predicted to be deleterious by in silico analysis was compared between breast cancer patients and controls. Twenty-eight sequence variants in the NBS1 gene were identified: 9 exonic variants, including 5 missense mutations (p.R169C, p.I171V, p.E185Q, p.E564K, and p.F603L) and 4 silent mutations, and 19 variants within introns. Among the five missense variants, p.I171V (c.511A > G) was the only variant predicted to be deleterious by in silico analysis. Heterozygosity for p.I171V was found in 4/235 patients with breast cancer and 3/281 individuals in the control group. The frequency of p.I171V was not significantly different between the patient and control groups (1.7 vs. 1.06%, p = 0.7). Heterozygosity of p.I171V in the NBS1 gene was found in a small proportion of Korean patients with high-risk breast cancer. The contribution of the p.I171V variant to the development of breast cancer among Korean patients was not significant. PMID- 25712765 TI - The importance of proper bioinformatics analysis and clinical interpretation of tumor genomic profiling: a case study of undifferentiated sarcoma and a constitutional pathogenic BRCA2 mutation and an MLH1 variant of uncertain significance. AB - Next-generation sequencing (NGS) technology is increasingly utilized to identify therapeutic targets for patients with malignancy. This technology also has the capability to reveal the presence of constitutional genetic alterations, which may have significant implications for patients and their family members. Here we present the case of a 23 year old Caucasian patient with recurrent undifferentiated sarcoma who had NGS-based tumor analysis using an assay which simultaneously analyzed the entire coding sequence of 236 cancer-related genes (3769 exons) plus 47 introns from 19 genes often rearranged or altered in cancer. Pathogenic alterations were reported in tumor as the predicted protein alterations, BRCA2 "R645fs*15" and MLH1 "E694*". Because constitutional BRCA2 and MLH1 gene mutations are associated with Hereditary Breast Ovarian Cancer Syndrome (HBOCS) and Lynch syndrome respectively, sequence analysis of DNA isolated from peripheral blood was performed. The presence of the alterations, BRCA2 c.1929delG and MLH1 c.2080G>T, corresponding to the previously reported predicted protein alterations, were confirmed by Sanger sequencing in the constitutional DNA. An additional DNA finding was reported in this analysis, MLH1 c.2081A>C at the neighboring nucleotide. Further evaluation of the family revealed that all alterations were paternally inherited and the two MLH1 substitutions were in cis, more appropriately referred to as MLH1 c.2080_2081delGAinsTC, which is classified as a variant of uncertain significance. This case illustrates important considerations related to appropriate interpretation of NGS tumor results and follow-up of patients with potentially deleterious constitutional alterations. PMID- 25712766 TI - A label-free electrochemical strategy for highly sensitive methyltransferase activity assays. AB - A new electrochemical strategy for the simple and ultrasensitive evaluation of DNA methyltransferase (MTase) activity was developed based on electrocatalytic oxidation of ascorbic acid by graphene. In addition, the suitability of this sensing platform for MTase inhibitor screening was also demonstrated. PMID- 25712767 TI - Crystal structure and substrate-binding mode of GH63 mannosylglycerate hydrolase from Thermus thermophilus HB8. AB - Glycoside hydrolase family 63 (GH63) proteins are found in eukaryotes such as processing alpha-glucosidase I and also many bacteria and archaea. Recent studies have identified two bacterial and one plant GH63 mannosylglycerate hydrolases that act on both glucosylglycerate and mannosylglycerate, which are compatible solutes found in many thermophilic prokaryotes and some plants. Here we report the 1.67-A crystal structure of one of these GH63 mannosylglycerate hydrolases, Tt8MGH from Thermus thermophilus HB8, which is 99% homologous to mannosylglycerate hydrolase from T. thermophilus HB27. Tt8MGH consists of a single (alpha/alpha)6-barrel catalytic domain with two additional helices and two long loops which form a homotrimer. The structures of this protein in complexes with glucose or glycerate were also determined at 1.77- or 2.10-A resolution, respectively. A comparison of these structures revealed that the conformations of three flexible loops were largely different from each other. The conformational changes may be induced by ligand binding and serve to form finger-like structures for holding substrates. These findings represent the first-ever proposed substrate recognition mechanism for GH63 mannosylglycerate hydrolase. PMID- 25712768 TI - Giant cell tumor: rapid recurrence after cessation of long-term denosumab therapy. AB - We report a case of rapid recurrence of a giant cell tumor (GCT) of the distal radius in a 24-year-old woman following the cessation of long-term denosumab therapy. GCT of bone is a histologically benign tumor with multinucleated giant cells on a background of mononuclear giant cells usually presenting as a well defined epi-metaphyseal lytic lesion without sclerotic margins. Denosumab, a monoclonal antibody to the receptor activator of nuclear factor kappa-B ligand (RANKL), has proven to be an effective neoadjuvant treatment for GCT. The tumor in this case had demonstrated a good response with sustained control for over 2 years while on denosumab therapy. However, within 2 months of cessation of therapy, the tumor demonstrated rapid recurrence and progression with growth, osteolysis, and increased soft tissue component. Despite reinitiating denosumab therapy, there was progressive tumor growth and destruction, ultimately necessitating below-the-elbow amputation. This case illustrates the need for maintenance of denosumab therapy for GCT of bone or definitive surgical treatment prior to its cessation. PMID- 25712769 TI - Reossification in Gorham's disease of the hand and wrist with unusual CT and MR imaging features. AB - Gorham's disease (GD) rarely occurs in the hand and wrist. Only nine cases of GD in the hand and wrist have been reported in the literature. The imaging technique used in all nine cases was mainly radiography. The natural history of GD is unpredictable. Spontaneous regression has been reported in a few cases. There is no consensus about the most efficient treatment of GD. Surgical resection and reconstruction with bone grafts and/or prostheses are used sparingly as bone grafts tend to be resorbed in most cases. We report a case of GD that involved the right hand and wrist in a 26-year-old male. The lesion displayed multiple areas of osteolysis in the metacarpals, carpals and proximal phalanx of the base of the thumb on radiography, while on CT and MRI, the osteolytic areas showed homogeneous density and signal intensity, similar to that of fluid. The patient was successfully treated by surgical reconstruction with autogenous iliac bone grafts. Gradual reossification in the osteolytic areas had occurred by the 3-year follow-up evaluation. This case merits special attention because of the unusual location of the involvement, unusual CT and MR imaging findings and unusual reossification in the osteolytic areas. PMID- 25712770 TI - Transient transfection and expression of foreign and endogenous genes in the intracellular stages of Trypanosoma cruzi. AB - The capacity for rapid localization of epitope-tagged or fluorescent fusion proteins in cells is an important tool for biological discovery and functional analysis. For Trypanosoma cruzi, the protozoan parasite that causes human Chagas disease, visualization of ectopically-expressed proteins in the clinically relevant mammalian stages is hindered by the necessity to first perform transfection and lengthy selection procedures in the insect vector form of the parasite. Here, we demonstrate the ability to by-pass the insect stage with the delivery of plasmid DNA to non-dividing, tissue culture trypomastigotes such that upon host cell infection, transgenes are expressed and rapidly localized in intracellular T. cruzi amastigotes. The inclusion of a sorting step prior to host cell infection by trypomastigotes greatly enriches (>90%) the number of transgene expressing amastigotes observed in mammalian host cells. This is a significant methodological advance that has the potential to accelerate the pace of discovery in the Chagas disease field. PMID- 25712771 TI - Foucault's notion of problematization: a methodological discussion of the application of Foucault's later work to nursing research. AB - This study takes its point of departure in an oft-voiced critique that the French philosopher Michel Foucault gives discourse priority over practice, thereby being deterministic and leaving little space for the individual to act as an agent. Based on an interpretation of the latter part of Foucault's oeuvre, we argue against this critique and provide a methodological discussion of the perception that Foucault's method constitutes, primarily, discourse analysis. We argue that it is possible to overcome this critique of Foucault's work by the application of methodological tools adapted from Foucault's later writings and his diagnosis of his own work as studies of forms of problematization. To shed light on the possibilities that this approach offers to the researcher, we present a reading of aspects of Foucault's work, with a focus on his notion of forms of problematization. Furthermore, we elaborate on concepts from his so-called genealogical period, namely 'the dispositive', strategy and tactics. Our interpretation is supported by examples from a study of the emergence of Danish nursing education, which is based on an analytical framework that we developed in the light of an interpretation of aspects of Foucault's work. PMID- 25712772 TI - Full genome sequence of guinea fowl coronavirus associated with fulminating disease. AB - Guinea fowl coronavirus (GfCoV), a recently characterized avian coronavirus, was identified from outbreaks of fulminating disease (peracute enteritis) in guinea fowl in France. The full-length genomic sequence was determined to better understand its genetic relationship with avian coronaviruses. The full-length coding genome sequence was 26,985 nucleotides long with 11 open reading frames and no hemagglutinin-esterase gene: a genome organization identical to that of turkey coronavirus [5' untranslated region (UTR)-replicase (ORFs 1a, 1ab)-spike (S) protein-ORF3 (ORFs 3a, 3b)-small envelop (E or 3c) protein-membrane (M) protein-ORF5 (ORFs 4b, 4c, 5a, 5b)-nucleocapsid (N) protein (ORFs N and 6b)-3' UTR]. This is the first complete genome sequence of a GfCoV and confirms that the new virus belongs to group gammacoronaviruses. PMID- 25712773 TI - Generation of resonance-dependent oscillation by mGluR-I activation switches single spiking to bursting in mesencephalic trigeminal sensory neurons. AB - The primary sensory neurons supplying muscle spindles of jaw-closing muscles are unique in that they have their somata in the mesencephalic trigeminal nucleus (MTN) in the brainstem, thereby receiving various synaptic inputs. MTN neurons display bursting upon activation of glutamatergic synaptic inputs while they faithfully relay respective impulses arising from peripheral sensory organs. The persistent sodium current (IN aP ) is reported to be responsible for both the generation of bursts and the relay of impulses. We addressed how IN aP is controlled either to trigger bursts or to relay respective impulses as single spikes in MTN neurons. Protein kinase C (PKC) activation enhanced IN aP only at low voltages. Spike generation was facilitated by PKC activation at membrane potentials more depolarized than the resting potential. By injection of a ramp current pulse, a burst of spikes was triggered from a depolarized membrane potential whereas its instantaneous spike frequency remained almost constant despite the ramp increases in the current intensity beyond the threshold. A puff application of glutamate preceding the ramp pulse lowered the threshold for evoking bursts by ramp pulses while chelerythrine abolished such effects of glutamate. Dihydroxyphenylglycine, an agonist of mGluR1/5, also caused similar effects, and increased both the frequency and impedance of membrane resonance. Immunohistochemistry revealed that glutamatergic synapses are made onto the stem axons, and that mGluR1/5 and Nav1.6 are co-localized in the stem axon. Taken together, glutamatergic synaptic inputs onto the stem axon may be able to switch the relaying to the bursting mode. PMID- 25712774 TI - Human papillomavirus infections in Mexican women with normal cytology, precancerous lesions, and cervical cancer: type-specific prevalence and HPV coinfections. AB - The prevalence and genotype distribution of human papillomavirus (HPV) provides the basis for designing HPV prevention programs. The prevalence rates of type specific HPV and coinfections in samples of Mexican women were investigated in 822 women aged 18-87 years. HPV detection was performed using a Linear ArrayTM genotyping test. HPV infection was found in 12.4% of controls, 46.3% of those with cervical intraepithelial neoplasia 1, and 100% of those with cervical intraepithelial neoplasia 3 or cervical cancer. HPV 16 was the most prevalent type in all diagnosis groups. The HPV types most frequently found in cervical cancers were 16, 18, 45, 52, 58, and 39; HPV types 16, 62, 51, 84, 18, 53, and CP6108 were the most prevalent in control women. Considering HPV-positive samples only, coinfections occurred most often in controls (63%) and were less frequent in those with cervical cancer (26%). The most frequent viral types in coinfections with HPV 16 in control women were HPV 62, 51, and 84; in women with cervical cancers, HPV 18, 39, and 70 were most common. In conclusion, in addition to HPV types 16 and 18, types 45, 39, 58, 52, and 71 were found in cervical cancers in Mexican women (78%); among them, only 65% were attributable to HPV types 16 and 18. Therefore, it is necessary to consider these viral types in the design of new vaccines, and to determine whether certain HPV types coinfecting with HPV 16 in precursor lesions determine tumor progression or regression. PMID- 25712776 TI - HIV vaccine development and broadly neutralizing antibodies. PMID- 25712775 TI - Altered interoceptive awareness in anorexia nervosa: Effects of meal anticipation, consumption and bodily arousal. AB - OBJECTIVE: Impaired interoceptive awareness (IA), the subjective perception of internal body sensations, has been proposed as a vulnerability or maintaining factor in anorexia nervosa (AN). We examined whether IA of heartbeat and breathing sensations was impaired in AN across a range of arousal levels, and whether it was influenced by meal anticipation and consumption. METHOD: IA was assessed using randomized, double-blinded, bolus intravenous infusions of isoproterenol, a peripheral beta-adrenergic sympathetic agonist, and saline. Fifteen women with AN and 15 age-, and sex- matched healthy comparisons (HC) were evaluated before and after consumption of a 1,000 Calorie meal. During each infusion participants rated their moment-to-moment intensity of heartbeat and breathing sensations with a dial. To measure IA we evaluated interoceptive detection thresholds, retrospective ratings of palpitation and dyspnea intensity, and interoceptive accuracy via correlations between subjective dial ratings and observed heart rate responses. RESULTS: Contrary to prediction the AN group was more likely to report detection of interoceptive sensations across all conditions, an effect driven by false discriminations at low arousal levels. Concordant with prediction, meal anticipation was associated with intensified interoceptive sensations, particularly dyspnea. There were no differences in interoceptive accuracy. DISCUSSION: This represents the first demonstration of interoceptive prediction errors in AN. Although IA is unimpaired at high arousal levels in AN, prediction signals are abnormal at low arousal levels, especially during meal anticipation. Altered interoceptive prediction signaling during meal anticipation could contribute to phenotypes of high anxiety in AN or alternatively, might be explained by enhanced meal associated anxiety. PMID- 25712777 TI - Ambipolar insulator-to-metal transition in black phosphorus by ionic-liquid gating. AB - We report ambipolar transport properties in black phosphorus using an electric double-layer transistor configuration. The transfer curve clearly exhibits ambipolar transistor behavior with an ON-OFF ratio of ~5 * 10(3). The band gap was determined as ?0.35 eV from the transfer curve, and Hall-effect measurements revealed that the hole mobility was ~190 cm(2)/(V s) at 170 K, which is 1 order of magnitude larger than the electron mobility. By inducing an ultrahigh carrier density of ~10(14) cm(-2), an electric-field-induced transition from the insulating state to the metallic state was realized, due to both electron and hole doping. Our results suggest that black phosphorus will be a good candidate for the fabrication of functional devices, such as lateral p-n junctions and tunnel diodes, due to the intrinsic narrow band gap. PMID- 25712778 TI - Human rights advances in women's reproductive health in Africa. AB - The African Commission on Human and Peoples' Rights recently adopted General Comment No 2 to interpret provisions of Article 14 of the Protocol to the African Charter on the Rights Women. The provisions relate to women's rights to fertility control, contraception, family planning, information and education, and abortion. The present article highlights the General Comment's potential to promote women's sexual and reproductive rights in multiple ways. The General Comment's human rights value goes beyond providing states with guidance for framing their domestic laws, practices, and policies to comply with treaty obligations. General Comment No 2 is invaluable in educating all stakeholders-including healthcare providers, lawyers, policymakers, and judicial officers at the domestic level about pertinent jurisprudence. Civil society and human rights advocates can use the General Comment to render the state accountable for failure to implement its treaty obligations. PMID- 25712779 TI - An outbreak of contact allergy to cocamide diethanolamide? PMID- 25712780 TI - In vitro-induced differentiation of bone marrow mesenchymal stem cells into melanocytes. AB - Large numbers of autogenous melanocytes (Mcs) are required when conducting studies on tissue engineering of skin and performing surgical treatment of depigmentation diseases. This study was conducted to explore the possibility of inducing differentiation of bone marrow mesenchymal stem cells (MSCs) into Mcs as a means of providing autogenous Mcs for purposes of tissue engineering and clinical treatment. MSCs were harvested from the bone marrows of black mice; and after six passages, hydrocortisone, insulin, transferrin and fibroblast growth factor were applied to induce their differentiation into Mcs. The morphological and ultrastructural characteristics of the newly differentiated cells were observed. The transcription and expression of multiple markers were examined using qRT-PCR, Western blot, and immunofluorescence analysis. Cell cycle phases and yields of Mcs were analyzed by flow cytometry. Following 120-180 days induction, differentiated cells were morphologically similar to Mcs, and mature melanosomes were observed. Multiple markers of Mcs, but not melanoma cells, were expressed by the differentiated cells. Most induced Mcs were in phase G1 or S, and yield of target cells was ~80%. Mcs induced from bone marrow MSCs for periods of 120-180 days represent a potential source of autogenous Mcs. PMID- 25712781 TI - Energetic oxygen-containing tetrazole salts based on 3,4-diaminotriazole. AB - Energetic mono- and dicationic 3,4-diaminotriazolium salts have been prepared by combining stoichiometric amounts (1:1 or 2:1 molar ratio) of 3,4-diaminotriazole with various oxygen-containing tetrazoles, and the structures have been confirmed by single-crystal XRD for the first time. All structures are dominated by a strong hydrogen-bond network owing to both amino groups and oxygen in the molecule. All salts, except 7, exhibit excellent thermal stabilities with decomposition temperatures over 200 degrees C. Based on experimental densities and theoretical calculations carried out by using the Gaussian 03 suite of programs, all salts have calculated detonation pressures (20.3-33.9 GPa) and velocities (7095-8642 m s(-1)). PMID- 25712782 TI - Ring opening of donor-acceptor cyclopropanes with the azide ion: a tool for construction of N-heterocycles. AB - Invited for the cover of this issue is the group of Ekaterina M. Budynina and Igor V. Trushkov at Lomonosov Moscow State University. The image depicts the diversity of synthetic outcomes that can be achieved by using the ring-opening of donor-acceptor cyclopropanes with the azide ion as a triggering reaction. Read the full text of the article at 10.1002/chem.201405551. PMID- 25712783 TI - Relationships among stress coping styles and pregnancy complications among women exposed to Hurricane Katrina. AB - OBJECTIVE: To examine the relationship between maternal stress exposure, stress coping styles, and pregnancy complications. DESIGN: Quantitative, cross sectional, and prospective study. SETTING: Tulane-Lakeside Hospital, New Orleans, LA and Women's Hospital, Baton Rouge, LA. PARTICIPANTS: The study included 146 women (122 from New Orleans and 24 from Baton Rouge), who were pregnant during or immediately after Hurricane Katrina. METHODS: Participants were interviewed regarding their hurricane experiences and perceived stress, and coping styles were assessed using the Brief COPE. Medical charts were also reviewed to obtain information about pregnancy outcomes. Logistic regression was performed to determine possible associations. RESULTS: Hurricane exposure was significantly associated with induction of labor (adjusted odds ratio [aOR] = 1.39; 95% confidence interval [CI] [1.03, 1.86], P = .03) and current perceived stress (aOR = 1.50, CI [1.34, 1.99], P < .01). Stress perception significantly predisposed to pregnancy-induced hypertension (aOR = 1.16, CI [1.05, 1.30], P < .01) and gestational diabetes (aOR = 1.13, CI [1.02, 1.25], P = .03). Use of planning, acceptance, humor, instrumental support, and venting coping styles were associated with a significantly reduced occurrence of pregnancy complications (P < .05). Higher rates for gestational diabetes was found among women using the denial coping style (aOR = 2.25, CI [1.14, 4.45], P = .02). CONCLUSION: Exposure to disaster-related stress may complicate pregnancy, whereas some coping styles may mitigate its effects. Further research should explore how coping styles may mitigate or exacerbate the effect of major stressors and how positive coping styles can be encouraged or augmented. PMID- 25712784 TI - [Prefabrication of vascularized facial bones]. AB - Critical size defects in the craniomaxillofacial region often result from ablative tumor surgery, inflammation and posttraumatic deformities. To date, autologous bone grafts are still the gold standard for the reconstruction of these defects; however, they are frequently associated with severe donor site morbidity as well as functional and aesthetic compromises. In this context various resorbable and non-resorbable bone replacement materials have been developed and intensively investigated. Particularly in critical size defects these materials fail due to their lack of osteogenic potential and endogenous vascularization. The combination of alloplastic osteoconductive scaffolds, osteogenic cells, and axial prevascularization in bioartificial bone grafts might present an innovative approach for the microsurgical reconstruction of critical size defects. PMID- 25712785 TI - [Prefabrication of transplants in plastic surgery]. AB - Complex three-dimensional defects with destruction of the external form, loss of functional stability and inner lining are associated with tactical and technical challenges in reconstructive plastic surgery. Causative factors are mutilating infections, resection of malignant tumors and trauma, predominantly located at the aerodigestive junction, the urogenital region and the extremities. Three dimensional tissue constructions are preformed distant to the defect site allowing safe pedicled or microsurgical transfer into the defect. PMID- 25712786 TI - Prediction and design of efficient exciplex emitters for high-efficiency, thermally activated delayed-fluorescence organic light-emitting diodes. AB - High-efficiency, thermally activated delayed-fluorescence organic light-emitting diodes based on exciplex emitters are demonstrated. The best device, based on a TAPC:DPTPCz emitter, shows a high external quantum efficiency of 15.4%. Strategies for predicting and designing efficient exciplex emitters are also provided. This approach allow prediction and design of efficient exciplex emitters for achieving high-efficiency organic light-emitting diodes, for future use in displays and lighting applications. PMID- 25712787 TI - Syntheses and luminescent properties of a copolymer of terbium-p-aminobenzoic acid-methacrylic acid and styrene. AB - A reactive Tb(III) complex with p-aminobenzoic acid (p-ABA) and methacrylic acid (MAA) as ligands was synthesized. A novel copolymer was synthesized by free radical copolymerization of styrene and the reactive Tb(III) complex in dimethyl sulfoxide (DMSO) with 2,2'-azobis(2-methylpropionitrile) (AIBN) as the initiator. IR and UV/Vis spectra indicate that the copolymer exhibited absorption from polystyrene and the complex. Thermogravimetric analysis indicates that the copolymer remained stable up to 357 degrees C and the thermal stability was significantly improved in comparison with polymer matrix and the Tb(III) complex. The luminescent intensity of the synthetic terbium macromolecular complexes increased with increasing complex monomer content. Moreover, concentration quenching was not observed. PMID- 25712788 TI - Vitamin D enhances the efficacy of photodynamic therapy in a murine model of breast cancer. AB - Cutaneous metastasis occurs more frequently in breast cancer than in any other malignancy in women, causing significant morbidity. Photodynamic therapy (PDT), which combines a porphyrin-based photosensitizer and activation by light, can be employed for breast cancer (especially cutaneous metastases) but tumor control after PDT has not surpassed traditional treatments methods such as surgery, radiation, and chemotherapy up to now. Here, we report that breast cancer nodules in mice can be effectively treated by preconditioning the tumors with 1alpha, 25 dihydroxyvitamin D3 (calcitriol; Vit D) prior to administering 5-aminolevulinate (ALA)-based PDT. Breast carcinoma tumors (MDA-MB-231 cells implanted subcutaneously in nude mice) received systemic Vit D (1 MUg/kg) for 3 days prior to receiving ALA. The addition of Vit D increased intratumoral accumulation of protoporphyrin IX (PpIX) by 3.3 +/- 0.5-fold, relative to mice receiving ALA alone. Bioluminescence imaging in vivo and immunohistochemical staining confirmed that tumor-specific cell death after ALA-PDT was markedly enhanced (36.8 +/- 7.4 fold increase in TUNEL-positive nuclei; radiance decreased to 14% of control) in Vit D pretreated tumors as compared to vehicle-pretreated tumors. Vit D stimulated proliferation (10.7 +/- 2.8-fold) and differentiation (9.62 +/- 1.7 fold) in tumor cells, underlying an augmented cellular sensitivity to ALA-PDT. The observed enhancement of tumor responses to ALA-PDT after low, nontoxic doses of Vit D supports a new combination approach that deserves consideration in the clinical setting, and offers potential for improved remission of cutaneous breast cancer metastases. PMID- 25712789 TI - Immunohistochemical Panel for Differentiating Renal Cell Carcinoma with Clear and Papillary Features. AB - Renal cell carcinoma (RCC) in which clear cells with papillary architecture are present is a difficult diagnostic challenge. The most common type, clear cell RCC, only rarely has papillary architecture. The second most common one, papillary RCC, only rarely contains clear cells. However, two recently described less-common types, clear cell papillary and Xp11 translocation RCC characteristically feature both papillary architecture and cells with clear cytoplasm. Accurate diagnosis has both prognostic and therapeutic implications. This study aims to highlight the helpful cytomorphologic and immunohistochemical features of each of these entities to enable reproducible classification. Sixty RCC cases with clear cells and papillary architecture were selected and classified according to The International Society of Urological Pathology (ISUP) Vancouver Classification of Renal Neoplasia and graded according to The International Society of Urological Pathology (ISUP) grading system for renal cell carcinoma then stained for CK7, carbonic anhydrase IX (CA IX), alpha methylacyl-CoA-racemase (AMACR) and TFE-3. The characteristic immunoprofile of Clear RCC is CK7-, AMACR-, CA IX+ and TFE3-, papillary RCC is CK7+, AMACR+, CAIX- and TFE3-, while for clear cell papillary RCC it is CK7+, AMACR-, CAIX+ and TFE3- and lastly Xp11translocation RCC is CK7-, AMACR+, CAIX- and TFE3+. Immunohistochemical staining for CA IX, CK7, AMACR and TFE3 comprises a concise panel for distinguishing RCC with papillary and clear pattern. PMID- 25712790 TI - Circulating regulatory T cells in patients with severe fever with thrombocytopenia syndrome. AB - BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS) is a newly emerging infectious disease caused by SFTS virus (SFTSV). Immunologic factors have been proved to be related to the occurrence and development of SFTS; however, their role still remains to be further elucidated. METHODS: Samples from 30 patients with laboratory-confirmed SFTS and 15 healthy controls were subjected to flow cytometry to detect the proportion of CD4+/total lymphocytes, CD4 + CD25+/CD4 + cells and CD4 + CD25+ Foxp3+/CD4 + CD25+ cells in circulating blood and to evaluate their potential function in the development of SFTS. RESULTS: The data showed that a reduced proportion of CD4+/total lymphocytes and CD4 + CD25+/CD4 + cells was observed in patients with SFTS compared with healthy controls. In contrast, the percentage of CD4 + CD25+ Foxp3+/CD4 + CD25+ cells in the patients in the SFTS group was significantly elevated. Furthermore, we investigated the dynamic changes of the circulating regulatory T cells (Tregs) in patients with SFTS at different stages. The results showed that the proportion of CD4+/total lymphocytes and CD4 + CD25+/CD4 + cells in the non-severe group was prominently higher than that in patients with severe SFTS. Conversely, the proportion of CD4 + CD25+ Foxp3+/CD4 + CD25+ cells was lower in the non-severe group than in the severe group. Additionally, the circulating Tregs reverted to normal ranges during the convalescent phase of SFTSV infection. Moreover, the Tregs level correlated with various clinical parameters. CONCLUSION: We demonstrated that SFTSV infection resulted in a robust circulating Treg response in patients with SFTS. Our investigation suggested that the proportions of CD4+/total lymphocytes and CD4 + CD25+ Foxp3+/CD4 + CD25+ cells in circulating blood could serve as sensitive indices to evaluate the changes in Tregs in SFTS and predict the progression of SFTS. PMID- 25712791 TI - Changes in pneumococcal nasopharyngeal colonization among children with respiratory tract infections before and after use of the two new extended-valency pneumococcal conjugated vaccines. AB - BACKGROUND: The 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) and the 13-valent pneumococcal conjugate vaccine (PCV13) replaced the 7-valent PCV (PCV7) in May 2010 in Korea. We investigated the dynamics of pneumococcal nasopharyngeal (NP) colonization in children with a respiratory illness before and after use of PHiD-CV and PCV13. METHODS: From March 2009 to December 2012 NP secretions were obtained from 2176 children aged < 5 years with respiratory diseases. We used the multiplex polymerase chain reaction (PCR) technique to determine pneumococcal serotypes. RESULTS: Among the samples, 468 (21.5%) specimens were positive by multiplex PCR. The overall pneumococcal colonization rate remained stable during the 2009-2012 periods. The serotypes present in PCV7 and serotype 19A decreased in frequency from 36.8% and 26.4% in 2009 to 10.1% and 11.4% in 2012, respectively (chi(2) for trend, P < 0.001 and P = 0.007, respectively). The frequency of non-PCV13 serotypes increased from 36.8% in 2009 to 78.5% in 2012 (chi(2) for trend, P < 0.001). There was no significant difference in carriage rates of each serotype between groups of children that received PCV7, PHiD-CV, or PCV13. CONCLUSIONS: Compared with the period of PCV7 vaccination, overall carriage rate was not affected by the introduction of new PCVs. However, serotype distribution now consists mostly of non-vaccine serotypes. PCVs affect mucosal immunity against Streptococcus pneumoniae (SP) in NP carriage; but, global SP colonization seems to be maintained by replacement. PMID- 25712792 TI - Development and evaluation of a new interferon-gamma release assay for the diagnosis of tuberculosis infection in HIV-infected individuals in China. AB - BACKGROUND: Human immunodeficiency virus (HIV)-infected individuals are at high risk of contracting tuberculosis (TB) disease, and current methods for diagnosing TB infection are less effective in this population. We developed and evaluated a new interferon-gamma release assay (IGRA), named A.TB, in HIV-infected individuals, with and without active TB, in a setting of high TB burden and low HIV prevalence. METHODS: A total of 255 subjects were divided into 3 groups according to their HIV and TB status: HIV+ without active TB (n = 123), HIV+/TB+ (n = 79), and HIV-/TB+ (n = 65). The A.TB assay was performed in parallel with the QuantiFERON-TB Gold In-Tube (QFT-GIT) and tuberculin skin test (TST). RESULTS: The positive rate was 59.3% (n = 123) by A.TB and 53.8% (n = 106) by QFT GIT. We observed a strong concordance of 81.2% (k = 0.612) between the two IGRAs. The QFT-GIT results were affected by low CD4(+) cell count (p = 0.013), while A.TB results were not. A.TB was also performed in patients with active TB (n = 65) and patients with active TB and HIV co-infection (n = 79). The sensitivity of A.TB in these groups was 80.0% and 81.0%, respectively. CONCLUSION: The A.TB results were not affected by low CD4(+) cell count in the co-infected cohort. With further evaluation, A.TB may prove to be a valuable tool for diagnosing TB in HIV-infected patients. PMID- 25712793 TI - Risk factors of severe hand, foot and mouth disease complicated with cardiopulmonary collapse. AB - BACKGROUND: The aim of this study was to investigate the risk factors for severe hand, foot and mouth disease (HFMD) complicated with cardiopulmonary collapse in children. METHODS: In total, 176 children aged 6-45 months with severe HFMD from March 2013 to May 2014 were enrolled in the study and divided into two groups, one with cardiopulmonary collapse and the other without. Univariate analysis and multiple logistic regression analysis were used to analyze the risk factors for severe HFMD complicated with cardiopulmonary collapse. RESULTS: The univariate analysis showed that there was no significant correlation between age, body temperature, consciousness disorders, blood glucose level and severe HFMD complicated with cardiopulmonary collapse. The multiple logistic regression analysis demonstrated that vomiting, circulatory disturbance, enterovirus 71 infection, dysfunction of respiratory rhythm and high level of brain natriuretic peptide were five independent risk factors for severe HFMD complicated with cardiopulmonary collapse. CONCLUSION: Children with HFMD and the above five risk factors may be at risk for cardiopulmonary collapse and poor prognosis. PMID- 25712795 TI - Maternal attitudes, depression, and anxiety in pregnant and postpartum multiparous women. AB - The Attitudes Toward Motherhood (AToM) Scale was developed to assess women's beliefs about motherhood, a specific risk factor for emotional distress in perinatal populations. As the measure was initially developed and validated for use among first-time mothers, this study assessed the reliability and validity of the AToM Scale in a sample of multiparous women. Maternal attitudes were significantly associated with symptoms of depression, even after controlling for demographic, cognitive, and interpersonal risk factors. Maternal attitudes were also associated with symptoms of anxiety after controlling for demographic risk factors, but this association was not significant after accounting for cognitive and interpersonal risk factors. Compared to primiparous women from the initial validation study of the AToM Scale, multiparous women reported lower levels of social support and marital satisfaction. The relationships between cognitive and interpersonal risk factors and symptoms of depression and anxiety were comparable between multiparous and primiparous women. PMID- 25712794 TI - Drug susceptibility and molecular epidemiology of Escherichia coli in bloodstream infections in Shanghai, China, 2011-2013. AB - BACKGROUND: Prevention and management of Escherichia coli bloodstream infections (EC-BSIs) have become increasingly complicated by antimicrobial resistance and rapid dissemination. We investigated the antimicrobial epidemiology and phylogenetic background of clinical E. coli isolates from patients with bloodstream infections in Shanghai from 2011 to 2013. METHODS: Escherichia coli isolates causing bloodstream infections were consecutively collected between June 2011 and June 2013. Antimicrobial susceptibility testing was performed by disk diffusion. Drug resistance genes coding for extended-spectrum beta-lactamases (ESBLs) and carbapenemases, and phylogenetic groups were detected by polymerase chain reaction. eBURST was used for multilocus sequence typing. RESULTS: Of the strains 128 collected, 80 produced ESBLs. No carbapenem-resistant isolates were found. The resistance rates to penicillins, fluoroquinolone, folate pathway inhibitors, tetracyclines and second generation cephalosporins were high. Molecular analysis showed that CTX-M-14 (40/80) was the most common beta lactamase, followed by CTX-M-55 (17/80) and CTX-M-15 (14/80). Phylogenetic group B2 predominated (37.5%), but phylogenetic group D exhibited the highest rates of ESBL production. ST131 (17/128) was the most common sequence type, followed by ST69 (12/128) and ST648 (10/128). CONCLUSIONS: The antimicrobial resistance rate was high among EC-BSI isolates, but amikacin, piperacillin-tazobactam and carbapenem could be options for empiric therapy. Genetic diversity showed no correlation with the nosocomial origin of the isolates. PMID- 25712796 TI - Highly biocompatible nanofibrous microspheres self-assembled from chitin in NaOH/urea aqueous solution as cell carriers. AB - In this work, chitin microspheres (NCM) having a nanofibrous architecture were constructed using a "bottom-up" fabrication pathway. The chitin chains rapidly self-assembled into nanofibers in NaOH/urea aqueous solution by a thermally induced method and subsequently formed weaved microspheres. The diameter of the chitin nanofibers and the size of the NCM were tunable by controlling the temperature and the processing parameters to be in the range from 26 to 55 nm and 3 to 130 MUm, respectively. As a result of the nanofibrous surface and the inherent biocompatibility of chitin, cells could adhere to the chitin microspheres and showed a high attachment efficiency, indicating the great potential of the NCM for 3D cell microcarriers. PMID- 25712797 TI - Controlled 1.1-1.6 MUm luminescence in gold-free multi-stacked InAs/InP heterostructure nanowires. AB - We report controlled 1.1-1.6 MUm luminescence in gold-free multi-stacked InAs/InP heterostructure nanowires (NWs). We realized the NWs by using an indium-particle assisted vapor-liquid-solid synthesis approach. The growth temperature, as low as 320 degrees C, enables the formation of an atomically abrupt InP/InAs interface by supressing the diffusion and weakening the reservoir effect in the indium droplet. The low growth temperature also enables us to grow multi-stacked InAs/InP NWs in the axial direction without any growth on the NW side face. The high controllability of the growth technology ensures that the luminescence can be tailored by the thickness of InAs segment in InP NWs and cover the 1.3-1.5 MUm telecommunication window range. By using the nanoscale-spatial-resolution technology combing cathodoluminescence with scanning electron microscopy, we directly correlated the site of different-thickness InAs segments with its luminescence property in a single NW and demonstrate the InAs-thickness controlled energy of optical emission in 1.1-1.6 MUm. PMID- 25712799 TI - The Contemporary Role of Major Amputation in the Management of Advanced Limb Melanoma. AB - BACKGROUND: Major amputations are rarely performed for melanoma, with limb preserving techniques used whenever possible. This article reviews the indications for major amputation in patients with melanoma and reports outcomes with the aim of better classifying progressive and potentially curable disease patterns. METHODS: At a single institution in Australia, 55 major amputations were performed for melanoma in 51 patients treated between 1984 and 2012. Clinicopathologic characteristics, treatments before amputation, and outcomes were analyzed. RESULTS: The 55 cases included 17 upper limb (9 forequarter) and 38 lower limb (3 hindquarter) amputations. The most common reasons for amputation were progressive in-transit metastases (ITM, 67 %), troublesome limb metastases from distant sites (14 %), pain or ulceration after regional chemotherapy (14 %) and otherwise inoperable regional recurrence (6 %). Regional chemotherapy was used before amputation for 58 % of the patients, and for those with ITM, it was associated with an increased interval between ITM diagnosis and amputation. The overall 5-year survival rate (5YS) from the time of amputation was 22.8 %. For stage 3 patients with either ITM or regional recurrence, who had all known disease resected at the time of amputation, the 5YS was 38.4 %. CONCLUSION: Major amputation may be indicated for advanced limb melanoma when limb-preserving strategies have been exhausted. Although they have advanced locoregional disease, some patients undergoing potentially curative amputation can achieve long-term survival. PMID- 25712798 TI - IARC monographs: 40 years of evaluating carcinogenic hazards to humans. AB - BACKGROUND: Recently, the International Agency for Research on Cancer (IARC) Programme for the Evaluation of Carcinogenic Risks to Humans has been criticized for several of its evaluations, and also for the approach used to perform these evaluations. Some critics have claimed that failures of IARC Working Groups to recognize study weaknesses and biases of Working Group members have led to inappropriate classification of a number of agents as carcinogenic to humans. OBJECTIVES: The authors of this Commentary are scientists from various disciplines relevant to the identification and hazard evaluation of human carcinogens. We examined criticisms of the IARC classification process to determine the validity of these concerns. Here, we present the results of that examination, review the history of IARC evaluations, and describe how the IARC evaluations are performed. DISCUSSION: We concluded that these recent criticisms are unconvincing. The procedures employed by IARC to assemble Working Groups of scientists from the various disciplines and the techniques followed to review the literature and perform hazard assessment of various agents provide a balanced evaluation and an appropriate indication of the weight of the evidence. Some disagreement by individual scientists to some evaluations is not evidence of process failure. The review process has been modified over time and will undoubtedly be altered in the future to improve the process. Any process can in theory be improved, and we would support continued review and improvement of the IARC processes. This does not mean, however, that the current procedures are flawed. CONCLUSIONS: The IARC Monographs have made, and continue to make, major contributions to the scientific underpinning for societal actions to improve the public's health. PMID- 25712800 TI - Low Visceral Fat Content is Associated with Poor Prognosis in a Database of 507 Upper Gastrointestinal Cancers. AB - BACKGROUND: Excess visceral adipose tissue may promote cancer development and progression via an obesity-related metabolic derangements, including adipocytokine-related inflammation, insulin resistance, and hypoxia. The relationship between visceral fat content and patient prognosis has been reported in some types of cancers, but not in the upper gastrointestinal cancer. The purpose of this retrospective study was to investigate the relationship between visceral fat status and clinical outcome in patients with upper gastrointestinal cancers (esophageal cancer and gastric cancer) treated by surgical resection. METHODS: This retrospective study was conducted in a single, academic hospital in Kumamoto, Japan, and involved 507 patients with upper gastrointestinal cancers between April 2005 and December 2010. Preoperative visceral fat content was quantified by radiologic measures using standard computed tomography scans. RESULTS: Higher visceral fat mount was correlated with male sex, presence of preoperative comorbidity, absence of preoperative therapy, low tumor depth, low tumor stage, and gastric cancer. Compared to high visceral fat cases, low visceral fat cases experienced a higher overall mortality rate [log-rank p = 0.0050; univariate hazard ratio (HR) = 1.73, 95 % confidence interval (CI) 1.16 2.54; p = 0.0075; multivariate HR 1.57; 95 % CI 1.02-2.37; p = 0.031]. Interestingly, the influence of low visceral fat on patient outcome was modified by age at surgery (p for interaction = 0.036); low visceral fat was associated with a poor prognosis, especially in elderly patients (log-rank p < 0.0001). CONCLUSION: Visceral fat content in the upper gastrointestinal cancers was associated with a poor prognosis, thus suggesting that it has potential for use as a prognostic biomarker. PMID- 25712801 TI - Sentinel Lymph Node Dissection in Head and Neck Melanoma has Prognostic Impact on Disease-Free and Overall Survival. AB - BACKGROUND: Sentinel lymph node biopsy (SLNB) plays an important role in the prognostic classification of melanoma and is now a standard staging procedure. However, due to the complex drainage pattern and the risk of site associated morbidity, the potential survival benefit of SLNB is controversial in head and neck (H&N) melanoma. METHODS: Patients with primary H&N melanoma with a tumor thickness >=1.00 mm diagnosed in the Department of Dermatology, University of Tuebingen, Germany between 1991 and 2010 were included in this study. Regarding patterns of metastases, disease-free, and overall-survival, 259 patients with SLNB were compared retrospectively to 218 patients without SLNB. RESULTS: The detection of micrometastasis in SLN proved to be a significant prognostic factor in H&N patients [hazard ratio (HR) 3.69, p < 0.0001]. A significant improvement of recurrence-free survival (RFS, p = 0.011), regional lymph node metastasis-free survival (LFS, p = 0.007), and distant metastasis-free survival (DMSF, p = 0.015) was observed for patients with SLNB versus non-SLNB. Furthermore, a trend towards better overall survival (OS) was found (p = 0.053) for the SLNB group. CONCLUSIONS: SLNB improved prognostic outcome in H&N melanoma in terms of disease free and distant metastases survival, reduced subsequent regional lymph node metastases, and showed a trend towards a better OS. PMID- 25712802 TI - Brain-computer interface boosts motor imagery practice during stroke recovery. AB - OBJECTIVE: Motor imagery (MI) is assumed to enhance poststroke motor recovery, yet its benefits are debatable. Brain-computer interfaces (BCIs) can provide instantaneous and quantitative measure of cerebral functions modulated by MI. The efficacy of BCI-monitored MI practice as add-on intervention to usual rehabilitation care was evaluated in a randomized controlled pilot study in subacute stroke patients. METHODS: Twenty-eight hospitalized subacute stroke patients with severe motor deficits were randomized into 2 intervention groups: 1 month BCI-supported MI training (BCI group, n = 14) and 1-month MI training without BCI support (control group; n = 14). Functional and neurophysiological assessments were performed before and after the interventions, including evaluation of the upper limbs by Fugl-Meyer Assessment (FMA; primary outcome measure) and analysis of oscillatory activity and connectivity at rest, based on high-density electroencephalographic (EEG) recordings. RESULTS: Better functional outcome was observed in the BCI group, including a significantly higher probability of achieving a clinically relevant increase in the FMA score (p < 0.03). Post-BCI training changes in EEG sensorimotor power spectra (ie, stronger desynchronization in the alpha and beta bands) occurred with greater involvement of the ipsilesional hemisphere in response to MI of the paralyzed trained hand. Also, FMA improvements (effectiveness of FMA) correlated with the changes (ie, post-training increase) at rest in ipsilesional intrahemispheric connectivity in the same bands (p < 0.05). INTERPRETATION: The introduction of BCI technology in assisting MI practice demonstrates the rehabilitative potential of MI, contributing to significantly better motor functional outcomes in subacute stroke patients with severe motor impairments. PMID- 25712803 TI - Characterization and biocompatibility of a fibrous glassy scaffold. AB - Bioactive glasses (BGs) are known for their ability to bond to living bone and cartilage. In general, they are readily available in powder and monolithic forms, which are not ideal for the optimal filling of bone defects with irregular shapes. In this context, the development of BG-based scaffolds containing flexible fibres is a relevant approach to improve the performance of BGs. This study is aimed at characterizing a new, highly porous, fibrous glassy scaffold and evaluating its in vitro and in vivo biocompatibility. The developed scaffolds were characterized in terms of porosity, mineralization and morphological features. Additionally, fibroblast and osteoblast cells were seeded in contact with extracts of the scaffolds to assess cell proliferation and genotoxicity after 24, 72 and 144 h. Finally, scaffolds were placed subcutaneously in rats for 15, 30 and 60 days. The scaffolds presented interconnected porous structures, and the precursor bioglass could mineralize a hydroxyapatite (HCA) layer in simulated body fluid (SBF) after only 12 h. The biomaterial elicited increased fibroblast and osteoblast cell proliferation, and no DNA damage was observed. The in vivo experiment showed degradation of the biomaterial over time, with soft tissue ingrowth into the degraded area and the presence of multinucleated giant cells around the implant. At day 60, the scaffolds were almost completely degraded and an organized granulation tissue filled the area. The results highlight the potential of this fibrous, glassy material for bone regeneration, due to its bioactive properties, non-cytotoxicity and biocompatibility. Future investigations should focus on translating these findings to orthotopic applications. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 25712805 TI - Macrophage migration inhibitory factor promotes eosinophil accumulation and tissue remodeling in eosinophilic esophagitis. AB - Macrophage migration inhibitory factor (MIF) is involved in eosinophil biology and in type 2 inflammation, contributing to allergic and helminthic diseases. We hypothesized that MIF participates in the pathogenesis of eosinophilic esophagitis (EoE), an allergic condition characterized by esophageal eosinophilic inflammation. MIF is highly expressed in esophageal mucosa of patients with EoE, compared with gastro-esophageal reflux disease and control patients, where it co localizes predominantly with eosinophils. In vitro, recombinant MIF promotes human eosinophil chemotaxis, while MIF antagonist and CXCR4 antagonist, AMD3100, revert this effect. In a model of EoE induced by ovalbumin, Mif-deficient mice have reduced inflammation and collagen deposition compared with wild-type (WT) mice. Importantly, treatment of WT mice with anti-MIF or with AMD3100 during the challenge phase prevents accumulation of eosinophils and tissue remodeling. Conversely, recombinant MIF promoted tissue eosinophil inflammation in allergic mice. Together, these results implicate MIF in the pathogenesis of esophageal inflammation and suggest that targeting MIF might represent a novel therapy for EoE. PMID- 25712806 TI - Feasibility of Transseptal Puncture Using a Nonfluoroscopic Catheter Tracking System. AB - BACKGROUND: Radiation exposure in the electrophysiology lab is a major occupational hazard to the electrophysiologists. A catheter localization system (MediGuide Technology, St. Jude Medical Inc., St. Paul, MN, USA) allows the integration of electroanatomical mapping and x-ray imaging, and has been shown to be effective in reducing radiation exposure during several electrophysiological procedures. We intended to evaluate the feasibility of this catheter tracking system to guide transseptal (TS) access. METHODS: The feasibility of performing TS puncture with MediGuide (MDG) was assessed in a prospective observational study in 16 patients undergoing radiofrequency ablation for atrial fibrillation. These patients were compared to 16 matched patients undergoing similar procedures during the same time frame using conventional approach. There were no differences in mean age, gender distribution, and body mass index between the two groups. Total duration of fluoroscopic exposure during TS puncture was compared between the two groups. RESULTS: All patients underwent successful TS puncture. Fluoroscopy time for double TS puncture using the MDG system was significantly lower than the control group (0.48 +/- 0.17 minutes vs. 5.9 +/- 0.65 minutes; P < 0.0001). No major complications occurred during the procedures in either group. CONCLUSIONS: TS puncture can be successfully performed using MDG, and results in significant reduction in radiation exposure. PMID- 25712807 TI - ATP exhibits antimicrobial action by inhibiting bacterial utilization of ferric ions. AB - ATP up-regulates macrophage antimycobacterial activity in a P2X7-dependent manner, but little is known about whether ATP directly exhibits antimicrobial effects against intracellular mycobacteria. In this study, we found that ATP inhibited the growth of various bacteria, including Staphylococcus, Pseudomonas, and mycobacteria, without damaging bacterial surface structures. Using gene technology, we newly established an enterobactin-deficient (entB(-)) mutant from ATP-resistant Klebsiella pneumoniae, and found the recovery of ATP susceptibility in the enterobactin-deleted mutant. Therefore, ATP's antibacterial activity is attributable to its iron-chelating ability. Since ATP distributed in the cytosol of macrophages at high concentrations, ATP appears to augment macrophage's antimicrobial activity by directly attacking intracytosolic and intra autophagosomal pathogens. Furthermore, ATP exhibited combined effects with some antimicrobials against methicillin-resistant S. aureus (MRSA) and M. intracellulare, suggesting its usefulness as an adjunctive drug in the chemotherapy of certain intractable infections. PMID- 25712808 TI - Reduced luminal circumference of tumors plays a key role in anorectal function during the early period after neoadjuvant chemoradiation therapy in rectal cancer patients. AB - PURPOSE: The deterioration of anorectal function after neoadjuvant chemoradiation therapy (nCRT) combined with surgery for rectal cancer has not been well defined. The aim of this study was to evaluate the relationship between the tumor response to nCRT and changes in anorectal function during a short-term period after nCRT. METHODS: We analyzed 100 consecutive patients with available preoperative anorectal manometry data, both before and after nCRT, from 2010 to 2013. RESULTS: Comparing the manometric data before and after nCRT, the values reflecting rectal sensory function after nCRT was significantly lower than those before nCRT. However, in patients who experienced changed tumor morphology and a reduction in luminal circumferential ratio (LCIR) of tumor after nCRT, the values reflecting rectal sensory function were significantly less decreased after nCRT. On multivariate analysis, the reduction of LCIR after nCRT was a very important factor preventing the impairment of anorectal function during the short-term period in terms of the first rectal sensory threshold (RST) (P = 0.002), the RST of "desire to defecate" (P = 0.006), and rectal compliance (P = 0.003). Additionally, in linear regression analysis, the RST for the desire to defecate was positively affected by tumor morphology (P = 0.015) and the reduced LCIR (P = 0.025), and rectal compliance was positively affected by the reduced LCIR (P = 0.001). CONCLUSION: The nCRT impaired significantly rectal sensory function during the short-term period after nCRT and before a radical operation. However, this reduced LCIR of tumors after nCRT may prevent or minimize impediments to anorectal function during the short-term period after nCRT. PMID- 25712809 TI - Increasing diagnosis of subclinical thyroid cancers leads to spurious improvements in survival rates. AB - BACKGROUND: Survival rates are commonly used to measure success in treating cancer, but can be misleading. Modern diagnostic practices can lead to the appearance of improving cancer survival, as tumors are diagnosed earlier (lead time bias) or as an increasing proportion are slow-growing (length bias), whereas the actual burden of cancer deaths is unchanged. Increasingly, more subclinical thyroid cancers are being diagnosed. The objective of the current study was to determine whether thyroid cancer survival rates have been affected by this phenomenon. METHODS: The authors analyzed survival data from patients with thyroid cancer who were treated at Memorial Sloan Kettering Cancer Center (MSKCC) from 1950 to 2005, and United States population-based incidence, prevalence, and survival data from 1973 to 2009 in the Surveillance, Epidemiology, and End Results data set. RESULTS: US thyroid cancer incidence has increased 3-fold from 1975 to 2009. Over time, the proportion of thyroid cancers that are subcentimeter in size has increased from 23% (1983) to 36% (2009). At MSKCC, this percentage rose from 20% (1950) to 35% (2005). The incidence rates of large tumors (>6 cm) and distant metastasis have not changed. In the United States, 10-year relative survival improved from 95.4% to 98.6% (1983-1999). At MSKCC, 10-year disease specific survival improved from 91.1% to 96.1% (1950-2005). However, when stratified by tumor size and stage, no changes in survival outcomes were observed. US thyroid cancer mortality rates have remained stable (1975-2009). CONCLUSIONS: Modern medical practices increasingly uncover small, asymptomatic thyroid cancers. Survival rates appear improved, but this finding is spurious, attributable instead to shifts in the characteristics of disease being diagnosed. Relying on survival rates to measure success in treating thyroid cancer may reinforce inappropriately aggressive management. Treatment decisions in thyroid cancer should be made based on mortality, not survival data. PMID- 25712810 TI - Elevated matrix metalloproteinase-8 in saliva and serum in polycystic ovary syndrome and association with gingival inflammation. AB - This study aimed to investigate the levels of matrix metalloproteinase-8 (MMP-8) and tissue inhibitors of MMP-1 (TIMP-1) in saliva and serum samples of women with polycystic ovary syndrome (PCOS; n = 80) and matched systemically healthy controls (n = 45), with varying degrees of gingival inflammation. Salivary levels of MMP-8 and the MMP-8/TIMP-1 ratio were significantly elevated in women with PCOS, who also exhibited more gingivitis than systemically healthy women. No major changes were observed in salivary TIMP-1 levels with regard to PCOS. Serum levels of MMP-8 and the MMP-8/TIMP-1 ratio were significantly higher in women with PCOS, irrespective of the presence of gingivitis, while there were no differences in TIMP-1 levels. A positive correlation was indicated between probing depth, bleeding on probing, plaque index and salivary or serum MMP-8 levels or MMP-8/TIMP-1 ratio in the case of PCOS, while a negative such correlation was revealed for TIMP-1 in systemically healthy women. Increased levels of MMP-8 in saliva and serum seem to be more pronounced in women with PCOS, and potentiated in the presence of gingival inflammation. Alterations in MMP/TIMP system triggered by local and systemic inflammation may be implicated in the pathogenesis of PCOS, or the deterioration of its clinical presentation. PMID- 25712811 TI - Room-temperature ferromagnetism of 2H-SiC-alpha-Al2O3 solid solution nanowires and the physical origin. AB - In this work we report the first synthesis of 2H-SiC-alpha-Al2O3 solid solution (SS) nanowires with 2H-SiC as the host phase. The one dimensional (1D) fake binary-system exhibits interesting room-temperature ferromagnetism and spin-glass like (SGL) behavior. This novel diluted magnetic semiconductor (DMS) was designed on the basis of SiC which is the most promising fundamental semiconductor used in next-generation electronics as the substitute for Si. A systematic investigation of the magnetic properties reveals the origin of the material's room-temperature ferromagnetism and spin-glass behavior. Spin-polarized density functional theory (DFT) calculations reveal that the net moment originates from a strong coupling between atoms around local Si vacancies produced by the SS defect reaction. Unlike random defects derived magnetic behavior, the SS resulted magnetism is significant to be utilized in functional devices since it belongs to a stable crystal structure that is possible to be prepared rationally in a controlled manner. PMID- 25712812 TI - Etanercept in refractory lupus arthritis: An observational study. AB - OBJECTIVE: To investigate the long-term safety and preliminary efficacy of etanercept in patients with refractory lupus arthritis. METHODS: We evaluated 43 patients in this observational cohort study. All received etanercept (50mg/week) in addition to concomitant immunosuppressive agents. Patient and disease characteristics were collected. Incidence of adverse events and the effect on autoantibody levels were evaluated. Clinical efficacy was measured by the 28 joint count and the SLEDAI-2K scores. Remission of lupus arthritis was defined by a 28-joint score = 0. Clinically inactive systemic disease was defined by a SLEDAI-2K score <4. RESULTS: The total follow-up time was 93 patient-years (median: 2.3 years per patient; range: 0.4-6.8 years). Most side effects were minor and related to local reactions. Only 2 significant adverse events occurred (8%), both were of infectious nature. The rate of autoantibody production was low (18%). A mild increase in titres of ANA (2), IgG anti-dsDNA (3) and IgM anticardiolipin (aCL) (2) antibodies was observed. All anti-dsDNA antibody increments were transient and coincided with systemic flares. No vascular events occurred. In general, disease activity declined during therapy. Most patients (83%) with lupus arthritis achieved clinical remission by week 12. All patients with simultaneous serositis experienced clinical and radiological resolution of this condition. Relapses were frequent (23%), mostly mild and related to etanercept reduction. A total of 24 patients discontinued treatment, 12 of them due to clinical remission. CONCLUSIONS: Long-term therapy with etanercept was relatively safe and had remarkable long-term efficacy for refractory lupus arthritis. In view of these results, further controlled trials are warranted. PMID- 25712813 TI - Extra-cranial giant cell arteritis and Takayasu arteritis: How similar are they? AB - OBJECTIVE: To compare clinical and imaging characteristics of patients with giant cell arteritis (GCA) and upper extremity (UE) arterial involvement to patients with Takayasu arteritis (TAK). METHODS: A cohort of patients seen at the Mayo Clinic with TAK diagnosed between 1984 and 2009 and a cohort of patients with GCA and UE arterial involvement diagnosed between 1999 and 2008 were studied. RESULTS: The TAK cohort consisted of 125 patients (91% female); the mean age (+/ SD) at diagnosis was 30.9 (+/-10) years. The cohort of patients with GCA and UE involvement comprised of 120 patients (80% female); the mean age (+/-SD) at diagnosis was 67.8 (+/-7.5) years. The mean time from onset of symptoms to diagnosis was significantly longer in TAK (3.2 years) than GCA (0.5 years), p < 0.001. UE claudication was reported in 40% with TAK and 53% with GCA, p = 0.04. UE blood pressure discrepancy was present in 65% with TAK versus 28% with GCA, p < 0.001. Involvement of the thoracic aorta, abdominal aorta, carotid arteries, innominate artery, mesenteric artery, and left renal artery was more frequently observed in TAK (p < 0.05). Among patients with luminal changes of the thoracic aorta, stenotic/occlusive lesions were predominant in TAK (81% compared to 0% in GCA), whereas aneurysmal disease was more common in GCA (100% compared with 19% in TAK, p < 0.001). CONCLUSION: Patients with GCA and UE involvement differ from patients with TAK in clinical and imaging characteristics. Aortic aneurysms were more common in GCA, while stenotic changes of the aorta were more common in TAK, suggesting different pathophysiologic mechanisms or vascular response to injury. PMID- 25712814 TI - Applying under-sampling techniques and cost-sensitive learning methods on risk assessment of breast cancer. AB - Breast cancer is one of the most common cause of cancer mortality. Early detection through mammography screening could significantly reduce mortality from breast cancer. However, most of screening methods may consume large amount of resources. We propose a computational model, which is solely based on personal health information, for breast cancer risk assessment. Our model can be served as a pre-screening program in the low-cost setting. In our study, the data set, consisting of 3976 records, is collected from Taipei City Hospital starting from 2008.1.1 to 2008.12.31. Based on the dataset, we first apply the sampling techniques and dimension reduction method to preprocess the testing data. Then, we construct various kinds of classifiers (including basic classifiers, ensemble methods, and cost-sensitive methods) to predict the risk. The cost-sensitive method with random forest classifier is able to achieve recall (or sensitivity) as 100 %. At the recall of 100 %, the precision (positive predictive value, PPV), and specificity of cost-sensitive method with random forest classifier was 2.9 % and 14.87 %, respectively. In our study, we build a breast cancer risk assessment model by using the data mining techniques. Our model has the potential to be served as an assisting tool in the breast cancer screening. PMID- 25712815 TI - Familial IPEX syndrome: different glomerulopathy in two siblings. AB - Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome (OMIM 304790) is a rare hereditary disorder of the immune regulatory system caused by FOXP3 mutations. The clinical features of this syndrome include a wide spectrum of severe autoimmune diseases and renal involvement, mostly due to tubulointerstitial diseases, in some patients. Glomerulopathy of membranous nephropathy (MN) and minimal change nephrotic syndrome (MCNS), however, have also been reported. We encountered two children with IPEX syndrome from the same family. Interestingly, they had different glomerular lesions: one had MN and the other had MCNS. Herein we describe the cases of these siblings and review the possible mechanisms for the development of two different renal lesions. PMID- 25712816 TI - Childhood maltreatment and personality disorders in patients with a major depressive disorder: A comparative study between France and Togo. AB - Few studies have examined the association between childhood maltreatment (CM) and personality disorders (PDs) in adulthood in two different cultural contexts, including sub-Saharan Africa. The aims of this study were to compare the frequency of CM between patients in treatment in France and Togo for a major depressive disorder (MDD), to explore the link between CM and PDs, and to examine the mediating effect of personality dimensions in the pathway from CM to PDs in 150 participants (75 in each country). The 28-item Childhood Trauma Questionnaire, the International Personality Item Pool, and the Personality Diagnostic Questionnaire (PDQ-4+) were used to assess CM, personality dimensions, and PDs respectively. Togolese participants reported sexual and physical abuse (PA) and emotional and physical neglect significantly more frequently than French participants. In Togo, severe PA was associated with schizoid, antisocial, narcissistic, obsessive-compulsive, depressive, and negativist PDs whereas in France, PA was only linked to paranoid PD. In Togo, emotional instability partly mediated the relationship between CM and PDs while in France, no personality dimension appeared to mediate this link. Our results support the hypothesis that CM is more common in low-income countries and suggest that the links between CM and PDs are influenced by social environment. PMID- 25712817 TI - Abortion legislation, maternal healthcare, fertility, female literacy, sanitation, violence against women and maternal deaths: a natural experiment in 32 Mexican states. AB - OBJECTIVE: To test whether there is an association between abortion legislation and maternal mortality outcomes after controlling for other factors thought to influence maternal health. DESIGN: Population-based natural experiment. SETTING AND DATA SOURCES: Official maternal mortality data from 32 federal states of Mexico between 2002 and 2011. MAIN OUTCOMES: Maternal mortality ratio (MMR), MMR with any abortive outcome (MMRAO) and induced abortion mortality ratio (iAMR). INDEPENDENT VARIABLES: Abortion legislation grouped as less (n=18) or more permissive (n=14); constitutional amendment protecting the unborn (n=17); skilled attendance at birth; all-abortion hospitalisation ratio; low birth weight rate; contraceptive use; total fertility rates (TFR); clean water; sanitation; female literacy rate and intimate-partner violence. MAIN RESULTS: Over the 10-year period, states with less permissive abortion legislation exhibited lower MMR (38.3 vs 49.6; p<0.001), MMRAO (2.7 vs 3.7; p<0.001) and iAMR (0.9 vs 1.7; p<0.001) than more permissive states. Multivariate regression models estimating effect sizes (beta-coefficients) for mortality outcomes showed independent associations (p values between 0.001 and 0.055) with female literacy (beta=-0.061 to -1.100), skilled attendance at birth (beta=-0.032 to -0.427), low birth weight (beta=0.149 to 2.166), all-abortion hospitalisation ratio (beta=-0.566 to 0.962), clean water (beta=-0.048 to -0.730), sanitation (beta=-0.052 to -0.758) and intimate-partner violence (beta=0.085 to 0.755). TFR showed an inverse association with MMR (beta=-14.329) and MMRAO (beta=-1.750) and a direct association with iAMR (beta=1.383). Altogether, these factors accounted for (R(2)) 51-88% of the variance among states in overall mortality rates. No statistically independent effect was observed for abortion legislation, constitutional amendment or other covariates. CONCLUSIONS: Although less permissive states exhibited consistently lower maternal mortality rates, this finding was not explained by abortion legislation itself. Rather, these differences were explained by other independent factors, which appeared to have a more favourable distribution in these states. PMID- 25712818 TI - Mental illness, poverty and stigma in India: a case-control study. AB - OBJECTIVE: To assess the effect of experienced stigma on depth of multidimensional poverty of persons with severe mental illness (PSMI) in Delhi, India, controlling for gender, age and caste. DESIGN: Matching case (hospital) control (population) study. SETTING: University Hospital (cases) and National Capital Region (controls), India. PARTICIPANTS: A case-control study was conducted from November 2011 to June 2012. 647 cases diagnosed with schizophrenia or affective disorders were recruited and 647 individuals of same age, sex and location of residence were matched as controls at a ratio of 1:2:1. Individuals who refused consent or provided incomplete interview were excluded. MAIN OUTCOME MEASURES: Higher risk of poverty due to stigma among PSMI. RESULTS: 38.5% of PSMI compared with 22.2% of controls were found poor on six dimensions or more. The difference in multidimensional poverty index was 69% between groups with employment and income of the main contributors. Multidimensional poverty was strongly associated with stigma (OR 2.60, 95% CI 1.27 to 5.31), scheduled castes/scheduled tribes/other backward castes (2.39, 1.39 to 4.08), mental illness (2.07, 1.25 to 3.41) and female gender (1.87, 1.36 to 2.58). A significant interaction between stigma, mental illness and gender or caste indicates female PSMI or PSMI from 'lower castes' were more likely to be poor due to stigma than male controls (p<0.001) or controls from other castes (p<0.001). CONCLUSIONS: Public stigma and multidimensional poverty linked to SMI are pervasive and intertwined. In particular for low caste and women, it is a strong predictor of poverty. Exclusion from employment linked to negative attitudes and lack of income are the highest contributors to multidimensional poverty, increasing the burden for the family. Mental health professionals need to be aware of and address these issues. PMID- 25712819 TI - Association between C reactive protein level and depressive symptoms in an elderly Korean population: Korean Social Life, Health and Aging Project. AB - OBJECTIVE: The relationship between inflammatory markers and depressive symptoms has been reported inconsistently. Moreover, there were only a few studies conducted in an Asian population. The purpose of this study was to examine the association between C reactive protein (CRP) and depressive symptoms in an elderly Korean population. DESIGN, SETTING AND PARTICIPANTS: This study used data from the Korean Social Life, Health and Aging Project Health Examination Cohort, which started in 2011. Among participants aged 60 or over recruited from a rural community, 569 (224 men and 345 women) without a history of stroke, angina pectoris, myocardial infarction or CRP>=20 mg/L were employed for cross-sectional analyses. As a marker of systemic inflammation, CRP was measured. Depressive symptoms were measured with the Center for Epidemiologic Studies Depression (CES D) scale. Multiple linear regression analysis was used to investigate the relationship between CRP and depressive symptoms. RESULTS: In men, CRP levels had significant associations with depressive symptoms before (beta=0.420, p=0.010) and after (beta=0.336, p=0.025) adjusting for age, body mass index, systolic blood pressure, number of comorbidities, smoking status, alcohol intake, marital status, education and sleep duration. However, in women, the association between CRP and depressive symptoms was not significant before (p=0.250) and after (p=0.256) adjustment. CONCLUSIONS: Our findings suggest that elevated CRP levels are independently associated with the presence of depressive symptoms in elderly Korean men. PMID- 25712821 TI - Evaluating variation in use of definitive therapy and risk-adjusted prostate cancer mortality in England and the USA. AB - OBJECTIVES: Prostate cancer mortality (PCM) in the USA is among the lowest in the world, whereas PCM in England is among the highest in Europe. This paper aims to assess the association of variation in use of definitive therapy on risk-adjusted PCM in England as compared with the USA. DESIGN: Observational study. SETTING: Cancer registry data from England and the USA. PARTICIPANTS: Men diagnosed with non-metastatic prostate cancer (PCa) in England and the USA between 2004 and 2008. OUTCOME MEASURES: Competing-risks survival analyses to estimate subhazard ratios (SHR) of PCM adjusted for age, ethnicity, year of diagnosis, Gleason score (GS) and clinical tumour (cT) stage. RESULTS: 222,163 men were eligible for inclusion. Compared with American patients, English patients were more likely to present at an older age (70-79 years: England 44.2%, USA 29.3%, p<0.001), with higher tumour stage (cT3-T4: England 25.1%, USA 8.6%, p<0.001) and higher GS (GS 8-10: England 20.7%, USA 11.2%, p<0.001). They were also less likely to receive definitive therapy (England 38%, USA 77%, p<0.001). English patients were more likely to die of PCa (SHR=1.9, 95% CI 1.7 to 2.0, p<0.001). However, this difference was no longer statistically significant when also adjusted for use of definitive therapy (SHR=1.0, 95% CI 1.0 to 1.1, p=0.3). CONCLUSIONS: Risk adjusted PCM is significantly higher in England compared with the USA. This difference may be explained by less frequent use of definitive therapy in England. PMID- 25712820 TI - Large regional differences in incidence of arthroscopic meniscal procedures in the public and private sector in Denmark. AB - OBJECTIVES: A recent study reported a large increase in the number of meniscal procedures from 2000 to 2011 in Denmark. We examined the nation-wide distribution of meniscal procedures performed in the private and public sector in Denmark since different incentives may be present and the use of these procedures may differ from region to region. SETTING: We included data on all patients who underwent an arthroscopic meniscal procedure performed in the public or private sector in Denmark. PARTICIPANTS: Data were retrieved from the Danish National Patient Register on patients who underwent arthroscopic meniscus surgery as a primary or secondary procedure in the years 2000 to 2011. Hospital identification codes enabled linkage of performed procedures to specific hospitals. PRIMARY AND SECONDARY OUTCOME MEASURES: Yearly incidence of meniscal procedures per 100,000 inhabitants was calculated with 95% CIs for public and private procedures for each region. RESULTS: Incidence of meniscal procedures increased at private and at public hospitals. The private sector accounted for the largest relative and absolute increase, rising from an incidence of 1 in 2000 to 98 in 2011. In 2011, the incidence of meniscal procedures was three times higher in the Capital Region than in Region Zealand. CONCLUSIONS: Our study identified a large increase in the use of meniscal procedures in the public and private sector in Denmark. The increase was particularly conspicuous in the private sector as its proportion of procedures performed increased from 1% to 32%. Substantial regional differences were present in the incidence and trend over time of meniscal procedures. PMID- 25712822 TI - Implications of private sector Hib vaccine coverage for the introduction of public sector Hib-containing pentavalent vaccine in India: evidence from retrospective time series data. AB - OBJECTIVE: Haemophilus influenzae type b (Hib) vaccine has been available in India's private sector market since 1997. It was not until 14 December 2011 that the Government of India initiated the phased public sector introduction of a Hib (and DPT, diphtheria, pertussis, tetanus)-containing pentavalent vaccine. Our objective was to investigate the state-specific coverage and behaviour of Hib vaccine in India when it was available only in the private sector market but not in the public sector. This baseline information can act as a guide to determine how much coverage the public sector rollout of pentavalent vaccine (scheduled April 2015) will need to bear in order to achieve complete coverage. SETTING: 16 of 29 states in India, 2009-2012. DESIGN: Retrospective descriptive secondary data analysis. DATA: (1) Annual sales of Hib vaccines, by volume, from private sector hospitals and retail pharmacies collected by IMS Health and (2) national household surveys. OUTCOME MEASURES: State-specific Hib vaccine coverage (%) and its associations with state-specific socioeconomic status. RESULTS: The overall private sector Hib vaccine coverage among the 2009-2012 birth cohort was low (4%) and varied widely among the studied Indian states (minimum 0.3%; maximum 4.6%). We found that private sector Hib vaccine coverage depends on urban areas with good access to the private sector, parent's purchasing capacity and private paediatricians' prescribing practices. Per capita gross domestic product is a key explanatory variable. The annual Hib vaccine uptake and the 2009-2012 coverage levels were several times higher in the capital/metropolitan cities than the rest of the state, suggesting inequity in access to Hib vaccine delivered by the private sector. CONCLUSIONS: If India has to achieve high and equitable Hib vaccine coverage levels, nationwide public sector introduction of the pentavalent vaccine is needed. However, the role of private sector in universal Hib vaccine coverage is undefined as yet but it should not be neglected as a useful complement to public sector services. PMID- 25712823 TI - Electrophysiological and spinal imaging evidences for sensory dysfunction in amyotrophic lateral sclerosis. AB - OBJECTIVES: The prevalence of sensory impairment at an early stage of amyotrophic lateral sclerosis (ALS) is still debated. The study aim was to investigate the anatomofunctional properties of sensory pathways in patients with ALS, combining spinal diffusion tensor imaging (DTI) and somatosensory evoked potentials (SEPs). DESIGN: Case-control study. SETTINGS: ALS referral centre and laboratory of biomedical imaging (Paris, France). PARTICIPANTS: Well-characterised group of 21 patients with ALS with moderate disability (mean amyotrophic lateral sclerosis Functional Rating Scale (ALSFRS) score 39.3+/-1.0) and no clinical sensory signs and control group of 21 gender and age-matched healthy subjects. OUTCOME MEASURES: Fractional anisotropy and diffusivity of the dorsal columns at C5-T1 levels (DTI metrics) and SEPs after median and ulnar nerve stimulations (latency and amplitude of N9 and N20 components). RESULTS: Abnormal DTI metrics indicated anatomical damages of ascending sensory fibres in ~60% of patients (p<0.05). Raw SEPs (MUV) were smaller in ~40% of patients but the difference with healthy subjects was not significant (p>0.16). Their normalisation to prestimulus activity strengthened the difference between groups (p<0.05) and allowed identification of ~60% of patients with abnormal values. According to N9 latency, the peripheral conduction time was normal in patients (p>0.32) but based on N20 latency, the central conduction time (between spinal cord and parietal cortex) was found to be slower (p<0.05). Significant correlation was found between DTI metrics and N9 amplitude (p<0.05). Altered SEPs were also correlated with the disease duration (p<0.05). Taken together, spinal imaging and electrophysiology helped to identify ~85% of patients with subclinical sensory defect while separated methods revealed abnormal values in ~60%. CONCLUSIONS: Sensory impairments have been underestimated at early stages of ALS. These results show for the first time the interest to combine electrophysiology and imaging to assess non-motor system involvement in ALS. TRIAL REGISTRATION NUMBER: IDRCB2012 A00016-37. PMID- 25712824 TI - Normative data for three tests of visuocognitive function in primary school children: cross-sectional study. AB - BACKGROUND/AIMS: There is an increasing recognition that visuocognitive difficulties occur in children with neurodevelopmental problems. We obtained normative data for the performance of primary school children using three tests of visuocognitive function that are practicable in a clinical setting. METHODS: We tested 214 children aged between 4 and 11 years without known developmental problems, using tests to assess (1) orientation recognition and adaptive movement (postbox task), (2) object recognition (rectangles task) and (3) spatial integration (contours task). RESULTS: 96% could do the postbox task with ease only 4% (all aged <9 years) exhibited minor difficulties. Errors in the rectangles task decreased with age: 33% of children aged 4-5 years had major difficulties but >99% of children aged >=6 years had no, or minor, difficulties. Median scores for the contours task improved with age, and after age 8 years, 99% could see the contour using long-range spatial integration rather than density. CONCLUSIONS: These different aspects of children's visuocognitive performance were testable in a field setting. The data provide a benchmark by which to judge performance of children with neurodevelopmental problems and may be useful in assessment with a view to providing effective supportive strategies for children whose visuocognitive skills are lower than the expectation for their age. PMID- 25712825 TI - Prevalence of age-related macular degeneration in the Republic of Ireland. AB - BACKGROUND: Age-related macular degeneration (AMD) remains the most common cause of visual loss among subjects over 50 years of age in the developed world. The Irish Longitudinal study on Ageing (TILDA) is a population-based study of subjects aged 50 years or older, designed to investigate factors that influence ageing, and has enabled this investigation of the prevalence of AMD in the Republic of Ireland (ROI). METHODS: Data collected from a nationally representative sample of community-living older adults aged 50 years and over in ROI over the period November 2009 to July 2011. 5035 participants attended the TILDA health centre for assessment. Retinal photographs were obtained in 4859 of these participants. Retinal grading was performed in a masked fashion using a modified version of the International Classification and Grading System for AMD. RESULTS: Adjusting for lower response rates among older subjects, the estimated overall prevalence of any AMD was 7.2% (95% CI 6.5% to 7.9%) in the population aged 50 years or older. The estimated prevalence of early AMD was 6.6% (95% CI 5.9% to 7.3%), and the estimated prevalence of late AMD was 0.6% (95% CI 0.4% to 0.8%). Statistically significant associations with AMD included increasing age and family history of the condition. CONCLUSIONS: This is the first study to provide prevalence estimates of AMD in ROI and will inform eye care professionals and policymakers involved in the delivery and planning of care for those afflicted with this condition. PMID- 25712826 TI - Six-month results of intravitreal aflibercept injections for patients with polypoidal choroidal vasculopathy. AB - BACKGROUND: This study aims to evaluate the therapeutic effect of intravitreal aflibercept injection for polypoidal choroidal vasculopathy (PCV). METHODS: Eighteen eyes of 17 consecutive patients with PCV received three consecutive monthly intravitreal injections of aflibercept and one additional injection 2 months later (four injections totally). All patients underwent eye examinations, which included best-corrected visual acuity (BCVA), fluorescein angiography, indocyanine green angiography, and optical coherence tomography. The primary endpoint of the study was the regression of polypoidal lesions. The secondary endpoints were BCVA, central retinal thickness (CRT) and changes in retinal exudation. RESULTS: Six months after the first aflibercept injection, the polypoidal lesions were completely resolved in 14 eyes (77.7%) and partially resolved in 4 eyes (22.2%). Although branching choroidal vascular networks were still present in all eyes, retinal exudative changes had completely resolved in 17 eyes (94.4%), and the mean CRT decreased significantly from 407.2+/-100.1 um to 229.1+/-57.2 um (p<0.0001). BCVA (logarithm of the minimal angle of resolution, logMAR) improved significantly from 0.414+/-0.384 at baseline to 0.297+/-0.334 after 6 months (p=0.016). CONCLUSIONS: At 6 months, aflibercept monotherapy effectively reduced polyps, retinal exudation and CRT in patients with PCV. PMID- 25712828 TI - A case with neonatal hyperinsulinemic hypoglycemia: It is a characteristic complication of Sotos syndrome. AB - Sotos syndrome (SoS, OMIM #117550) is an overgrowth syndrome. Deletions or intragenic mutations of the NSD1 , which is located at chromosome 5q35, are responsible for more than 75% of SoS. Conventionally, neonatal hypoglycemia was reported briefly as one of the infrequent symptoms of SoS. However, Matsuo et al. published a report describing five patients with SoS who presented with transient hyperinsulinemic hypoglycemia (HIH) in the neonatal period. We report on an additional patient of SoS, who presented transient HIH in the neonatal period. All of this patient and previous patients have microdeletions at the 5q35 chromosome. Therefore, we examined the following three in considering the possibility that other factor than NSD1 caused HIH. 1) This patient had no mutation of four currently known HIH related genes, ABCC8, KCNJ11, GLUD1, and GCK. 2) He had no further deletion than commonly observed region encompassing NSD1 by comparative genomic hybridization to DNA microarrays. 3) He had no mutation in the 5q35 region in the non-deleted chromosome using exsome sequence analysis. In conclusion, our patient supported that HIH could be one of the characteristic symptoms of SoS in the neonatal period, and could be useful for early diagnosis. PMID- 25712827 TI - Reliable genotypic tropism tests for the major HIV-1 subtypes. AB - Over the past decade antiretroviral drugs have dramatically improved the prognosis for HIV-1 infected individuals, yet achieving better access to vulnerable populations remains a challenge. The principal obstacle to the CCR5 antagonist, maraviroc, from being more widely used in anti-HIV-1 therapy regimens is that the pre-treatment genotypic "tropism tests" to determine virus susceptibility to maraviroc have been developed primarily for HIV-1 subtype B strains, which account for only 10% of infections worldwide. We therefore developed PhenoSeq, a suite of HIV-1 genotypic tropism assays that are highly sensitive and specific for establishing the tropism of HIV-1 subtypes A, B, C, D and circulating recombinant forms of subtypes AE and AG, which together account for 95% of HIV-1 infections worldwide. The PhenoSeq platform will inform the appropriate use of maraviroc and future CCR5 blocking drugs in regions of the world where non-B HIV-1 predominates, which are burdened the most by the HIV-1 pandemic. PMID- 25712829 TI - Environmental impacts on the gonadotropic system in female Atlantic salmon (Salmo salar) during vitellogenesis: Photothermal effects on pituitary gonadotropins, ovarian gonadotropin receptor expression, plasma sex steroids and oocyte growth. AB - The gonadotropic system and ovarian growth and development were studied during vitellogenesis in female Atlantic salmon subjected to either simulated natural photoperiod and ambient water temperature (NL-amb), or an accelerating photoperiod (short day of LD8:16 from May 10) combined with either warmed (ca 2 degrees C above ambient; 8L-warm) or cooled water (ca 2 degrees C below ambient; 8L-cold) from May to September. Monthly samples were collected from 10 females/group for determination of transcript levels of pituitary gonadotropin subunits (fshb and lhb) and ovarian gonadotropin receptors (fshr and lhr), plasma sex steroids (testosterone: T and estradiol-17beta: E2), gonadosomatic index (GSI) and oocyte size. Short day in combination with either warmed or cooled water induced an earlier increase in pituitary fshb and lhb levels compared with NL-amb controls, and advanced ovarian growth and the seasonal profiles of T, E2. By contrast only minor effects were seen of the photothermal treatments on ovarian fshr and lhr. The 8L-cold had earlier increase in fshb, lhb and E2, but similar oocyte and gonadal growth as 8L-warm, suggesting that the 8L-cold group tried to compensate for the lower water temperature during the period of rapid gonadal growth by increasing fshb and E2 production. Both the 8L-warm and 8L-cold groups showed incomplete ovulation in a proportion of the females, possibly due to the photoperiod advancement resulting in earlier readiness of spawning occurring at a higher ambient temperature, or due to some reproductive dysfunction caused by photothermal interference with normal neuroendocrine regulation of oocyte development and maturation. PMID- 25712830 TI - Rate- and Extent-Limiting Factors of Oral Drug Absorption: Theory and Applications. AB - The oral absorption of drugs has been represented by various concepts such as the absorption potential, the maximum absorbable dose, the biopharmaceutics classification system, and in vitro-in vivo correlation. The aim of this article is to provide an overview of the theoretical relationships between these concepts. It shows how a simple analytical solution for the fraction of a dose absorbed (Fa equation) can offer a theoretical base to tie together the various concepts, and discusses how this solution relates to the rate-limiting cases of oral drug absorption. The article introduces the Fa classification system as a framework in which all the above concepts were included, and discusses its applications for food effect prediction, active pharmaceutical ingredient form selection, formulation design, and biowaiver strategy. PMID- 25712832 TI - "Welcome to the China Special Issues of IJC". PMID- 25712831 TI - Daily physical activity as determined by age, body mass and energy balance. AB - AIM: Insight into the determinants of physical activity, including age, body mass and energy balance, facilitates the design of intervention studies with body mass and energy balance as determinants of health and optimal performance. METHODS: An analysis of physical activity energy expenditure in relation to age and body mass and in relation to energy balance, where activity energy expenditure is derived from daily energy expenditure as measured with doubly labelled water and body movement is measured with accelerometers, was conducted in healthy subjects under daily living conditions over intervals of one or more weeks. RESULTS: Activity energy expenditure as a fraction of daily energy expenditure is highest in adults at the reproductive age. Then, activity energy expenditure is a function of fat free mass. Excess body mass as fat does not affect daily activity energy expenditure, but body movement decreases with increasing fatness. Overweight and obesity possibly affect daily physical activity energy expenditure through endurance. Physical activity is affected by energy availability; a negative energy balance induces a reduction of activity expenditure. CONCLUSION: Optimal performance and health require prevention of excess body fat and maintenance of energy balance, where energy balance determines physical activity rather than physical activity affecting energy balance. PMID- 25712833 TI - Is endoscopic sphincterotomy plus large-balloon dilation a better option than endoscopic large-balloon dilation alone in removal of large bile duct stones? A retrospective comparison study. AB - BACKGROUND: Several comparison studies have demonstrated that endoscopic sphincterotomy (EST) combined with large-balloon dilation (LBD) may be a better option than EST alone to manage large bile duct stones. However, limited data were available to compare this combination method with LBD alone in removal of large bile duct stones. OBJECTIVE: To compare EST plus LBD and LBD alone for the management of large bile duct stones, and analyze the outcomes of each method. PATIENTS AND METHODS: Sixty-one patients were included in the EST plus LBD group, and 48 patients were included in the LBD alone group retrospectively. The therapeutic success, clinical characteristics, procedure-related parameters and adverse events were compared. RESULTS: Compared with EST plus LBD, LBD alone was more frequently performed in patients with potential bleeding diathesis or anatomical changes (P = 0.021). The procedure time from successful cannulating to complete stone removal was shorter in the LBD alone group significantly (21.5 vs. 17.3 min, P = 0.041). The EST plus LBD group and the LBD alone group had similar outcomes in terms of overall complete stone removal (90.2% vs. 91.7%, P = 1.000) and complete stone removal without the need for mechanical lithotripsy (78.7% vs. 83.3%, P = 0.542). Massive bleeding occurred in one patient of the EST plus LBD group, and successfully coagulated. Postoperative pancreatitis did not differ significantly between the EST plus LBD group and the LBD alone group (4.9% vs. 6.3%; P = 1.000). CONCLUSION: Endoscopic sphincterotomy combined with LBD offers no significant advantage over LBD alone for the removal of large bile duct stones. LBD can simplify the procedure compared with EST plus LBD in terms of shorten the procedure time. PMID- 25712835 TI - The minimally invasive thoracic surgery for lung cancer: a voice from China. AB - The video assisted thoracoscopic surgery (VATS) was first introduced to thoracic surgeons of China in 1990s. In the past 20 years, the VATS technique has been extensively applied in treatment of lung cancer all over the land. By the end of 2014, more than 300 thousands thoracic surgeries per year are operated that nearly half of these are finished by VATS. As China has been one of the most important forces to fight against lung cancer in the world, it is essential and inevitable to understand the status and future of China's VATS in the treatment of lung cancer during this historic period. PMID- 25712834 TI - Two-incision approach for video-assisted thoracoscopic sleeve lobectomy treating the central lung cancer. AB - BACKGROUND: We review our experiences with video-assisted thoracoscopic surgery (VATS) sleeve lobectomy with bronchoplasty for nonsmall-cell lung cancer, using only two incisions. The aim of this study was to evaluate the technical feasibility and safety of surgical approach. MATERIALS AND METHODS: From January 2013 to January 2014, we completed 15 cases of VATS sleeve lobectomy with bronchoplasty in our hospital. The patients underwent sleeve lobectomy with bronchoplasty at the following locations: right upper lobe (n = 4), right lower and middle lobes (n = 1), left lower lobe (n = 5), and left upper lobe (n = 6). The operation consisted of VATS anatomic sleeve lobectomy with bronchoplasty combined with systematic lymph node dissection, using only two incisions. RESULTS: The patients underwent sleeve lobectomy with bronchoplasty were no postoperative complications. Median operative time was 183 min; median bronchial anastomosis time was 39 min; median blood loss was 170 ml. Pathological examination showed 12 squamous cell carcinomas and 3 adenocarcinoma. Median postoperative chest tube drainage duration was 4.5 days, and median hospital stay was 6.9 days. CONCLUSIONS: Video-assisted thoracoscopic surgery sleeve lobectomy with bronchoplasty is a feasible and safe surgical approach, using only two incisions. This way of operation can promote the development of surgical technology. PMID- 25712836 TI - A meta-analysis of limb-salvage versus amputation in the treatment of patients with Enneking?U pathologic fracture osteosarcoma. AB - INTRODUCTION: The aim of this meta-analysis was to further explore whether the relapse, 5-year survival and metastasis the same or not between limb-salvage and amputation in the treatment of patients with limited stage Enneking II pathologic fracture osteosarcoma. MATERIALS AND METHODS: An electronic search of the Medline, EMBASE and CNKI was done on October 2014. The clinical studies about amputation or limb-salvage surgery in the treatment of patients with limited stage Enneking II pathologic fracture osteosarcoma were searched and reviewed. The effect size of relapse, 5-year survival and metastasis between the amputation and limb-salvage surgery were pooled by stata11.0 software (Stata Corporation, College Station, TX, USA, http://www.stata.com;) using random or fixed effect model. The funnel plot and Egger's line regression test were used for evaluation of publication bias. RESULTS: A total of 89 studies were identified and seven articles with 200 cases in the limb-salvage surgery group and 84 subjects in the amputation group were finally included in the meta-analysis. The pooled data indicated that no statistical different of risk for developing relapse between limb-salvage and amputation was found relative risk (RR) =1.40, 95% confidence interval (CI): 0.71-2.79, (P = 0.33). The 5-year survival rate of patients underwent limb-salvage surgery was smaller than patients received amputation RR = 1.86, 95%CI: 1.19-2.89, (P = 0.01); the metastasis rate of patients underwent limb-salvage surgery was significant decreased compared with patients received amputation RR = 0.56, 95% CI: 0.34-0.94, (P = 0.03). No publication bias was existed in this meta-analysis. CONCLUSION: Limb-salvage surgery does not increased the risk of relapse compared with amputation in the treatment of patients with limited stage Enneking II pathologic fracture osteosarcoma. PMID- 25712837 TI - Anastomosis in minimally invasive Ivor Lewis esophagectomy via two ports provides equivalent perioperative outcomes to open. AB - OBJECTIVE: Minimally invasive esophagectomy (MIE) is becoming a selective treatment of esophageal cancer; however, it's a complex and technically demanding surgical operation. MIE can be performed in high volume centers in a variety of ways using different techniques. Transthoracic staplers have traditionally been used in open transthoracic Ivor Lewis Esophagectomy (ILE) with good success. An investigation of the safety and utility of transthoracic stapler via two ports on thorax for esophageal anastomosis in minimally invasive ILE is reviewed. METHODS: Patients of esophageal cancer were selected between November 2012 and July 2014. All the patients received minimally invasive (MIE) or open transthoracic ILE. Transthoracic stapler for MIE anastomosis was performed through the major port located at subaxillary region. Patients' demographics, indications for esophagectomy, perioperative treatments, intraoperative data, postoperative complications, hospital length of stay, 7 and in-hospital mortality were evaluated. RESULTS: Totally, 63 consecutive patients underwent MIE or ILE. All the patients were Han with a mean age of 60 years (52-74). The indication of surgery is esophageal cancer, and squamous cell carcinoma was defined by pathologist before operation. None of the patients had neoadjuvant chemotherapy or radiation. All the MIE patients were no conversions to open thoracotomy or laparotomy. Mean operative time was 4.5 h. One patient (3.03%) suffered postoperative pneumonia, no leak from the gastric conduit staple line or esophageal anastomoses, no postoperative complication required surgical intervention was observed. The median hospital length of stay was 13 days (range 7-18). There were no in-hospital mortalities. CONCLUSIONS: In our study, transthoracic stapler through the major port at subaxillary seems technically feasible and safe for minimally invasive ILE with comparable morbidity and oncologic data to open. PMID- 25712838 TI - Different limited resection of pulmonary lobe methods under the thoracoscopy in the treatment of early nonsmall cell lung cancer occurred in the old age. AB - OBJECTIVES: The objective was to explore clinical effect of limited resection of lung lobe under the thoracoscopy in the treatment of early nonsmall cell lung cancer occurred in the old age. METHODS: A total of 150 patients with nonsmall cell lung cancer in the old age is treated by limited resection of lung lobe under thoracoscope. It can be divided into segmental resection group and wedge resection group by surgical methods, to make a comparative analysis of operation time, intraoperative blood loss, hospital stays, and complications during the perioperative period. And there will be postoperation follow-up on survival, relapse and death situation etc., RESULTS: 10 cases are changed to make other operation because of maladaptation to limited resection, and a total of 140 patients have undergone limited resection. Operation time and hospital stays of wedge resection group are shorter than those of segmental resection group (P < 0.05); compared with the bleeding and indwelling drainage tube time in two groups, differences have no statistical significance (P > 0.05). Compared with cases of complications, recurrence and death for groups of segmental resection and wedge resection group, the differences have no statistical significance (P > 0.05). CONCLUSION: Limited resection of lung lobe in the early treatment of nonsmall cell lung cancer occurred in the old age under the thoracoscopy is safe and feasible. PMID- 25712839 TI - Incidence, risk factors, and prognosis of acute kidney injury following transarterial chemoembolization in patients with hepatocellular carcinoma: a prospective cohort study. AB - BACKGROUND: Transcatheter arterial chemoembolization (TACE) is an effective first line therapy for intermediate stage hepatocellular carcinoma (HCC). Acute renal injury may be induced after transarterial chemoembolization because of iodinated radiocontrast medium, but its incidence, risk factors, and prognosis remain unclear. PATIENTS AND METHODS: This prospective study enrolled 166 HCC patients with a total of 316 TACE treatments. The incidence, risk factors, and prognosis of acute kidney injury (AKI) were examined. RESULTS: The incidence of post-TACE AKI was 21.84% (69/316) according to Barrett and Parfrey criteria, whereas 7.59% (24/316) according to acute kidney injury network (AKIN) criteria. Multivariate logistic regression analysis showed that serum total bilirubin (TB) (>13.5 MUmol/L; odds ratio [OR]: 1.871 95% confidence interval [CI]: 1.044-3.352; P = 0.035) and hemoglobin (HGB) level (<120 g/L; OR: 1.823, 95% CI: 1.019-3.264; P = 0.043) were associated with the development of AKI after TACE procedure in accordance to Barrett and Parfrey criteria. Meanwhile, age (>55 years; OR: 3.456, 95% CI: 1.107-10.790; P = 0.033), post-TACE AKI history (OR: 7.108, 95% CI: 1.387 36.434, P = 0.019), and serum aminotransferase level (>55 U/L; OR: 4.420, 95% CI: 1.792-10.906; P = 0.001) were associated with the development of AKI after TACE procedure in accordance to AKIN criteria. Total hospitalization cost was significantly higher (P = 0.034) in the patients with AKI after TACE procedure according to Barrett and Parfrey criteria. A post-TACE AKI diagnosis was associated with mortality in any definition used (P = 0.034 and P = 0.001 for Barrett and Parfrey and AKIN criteria, respectively). CONCLUSION: The present study showed that the incidence of post-TACE AKI was high in HCC patients (i.e., 7.59-21.84%) depending on criteria used. HGB (<120 g/L), serum TB (>13.5), and aminotransferase level (>55 U/L), age (>55 years) and post-TACE AKI history may be predictors of post-TACE AKI in HCC patients. The development of post-TACE AKI was associated with the risk of renal replacement treatment, prolonged renal insufficiency, or mortality according to AKIN criteria. PMID- 25712840 TI - Outcome analysis of benign vocal cord tumors treated by laryngeal endoscopy under low temperature-controlled radiofrequency. AB - OBJECTIVE: This study aimed to evaluate the outcome of benign vocal cord tumors treated using a laryngeal endoscopy under low temperature-controlled radiofrequency and to elucidate the application of a dynamic laryngoendoscopy in the operation. MATERIALS AND METHODS: 85 patients with benign vocal cord tumors were treated by laryngeal endoscopy under low temperature-controlled radiofrequency from September 2011 to October 2013. A XION electronic dynamic laryngoendoscopy (Germany) was used to observe curative effects 3 months after operation. Wave images were recorded with larynx-wave recording software to analyze tumor characteristics. RESULTS: Among the 85 patients, 81 showed smooth surface of operation wounds without any residue. The mucosal wave was also basically normal. Sound was generally recovered after 1-3 months. Three cases presented improved pronunciation function after the operation, whereas 1 patient with residual tumor at the front of vocal chords underwent another operation after 6 months. CONCLUSION: Low temperature-controlled radiofrequency exhibited many advantages, including minimal trauma, minimal bleeding, high safety, and few complications. Moreover, treatment of benign vocal cord tumors with a laryngeal endoscopy presented satisfactory outcomes. Therefore, this technology has broad application prospects. PMID- 25712841 TI - Short term curative effect of video assisted thoracoscopic lobectomy for early stage lung cancer. AB - OBJECTIVE: To investigate the feasibility, safety and short term efficacy of video assisted thoracoscopic (VATS) lobectomy for patients with early-stage lung cancer. METHODS: We reviewed clinical data of 138 consecutive patients with early stage lung cancer who underwent lobectomy in the First People's Hospital of Jining during the January 2010 to May 2012. Of them, 71 cases were performed complete VATS, male 39 cases, female 32 cases, age (57.9 +/- 10.6) years old; 67 cases were performed thoracotomy, male 36 cases, female 31 cases, age (60.3 +/- 8.2) years old. Clinical features were collected and compared. RESULTS: Operations of two groups were successfully finished. Compared with thoracotomy group, the differences in intraoperative blood loss (147 +/- 113 ml vs. 146 +/- 91 ml), number of lymph node dissection group (3.1 +/- 1.3 vs. 3.4 +/- 1.3), the number of lymph node dissection (9.9 +/- 3.6 vs. 10.0 +/- 3.6), and vision analog score (VAS) of postoperative 1st and 3rd day in VATS group were not statistically significant (P > 0.05). Statistical differences were observed in operation time (119 +/- 27 min vs. 135 +/- 29 min), the thoracic drainage tube time (3.0 +/- 0.9 d vs. 3.8 +/- 1.2 d), postoperative hospital stay (8.0 +/- 2.1 d vs. 10.2 +/- 5.4 d), postoperative VAS of 30th day (2.6 +/- 0.7 vs. 3.2 +/- 1.1), and postoperative complications (8.5% vs. 19.4%) between the two groups (P < 0.05). CONCLUSION: Video assisted thoracoscopic lobectomy for early lung cancer is safe and effective, with fewer traumas, fewer complications, faster postoperative recovery, milder chronic chest pain, and other advantages. At the same time, the lymph node dissection of VATS lobectomy is similar to that of thoracotomy. PMID- 25712842 TI - Risk of postoperative deep venous thrombosis in patients with colorectal cancer treated with open or laparoscopic colorectal surgery: a meta-analysis. AB - INTRODUCTION: Whether the incidence rate of deep venous thrombosis (DVT) between laparoscopic and open colorectal cancer surgery the same or not were under the debated without conclusion. The aim of this study was to compare the incidence of DVT after laparoscopic or open colorectal cancer surgery by meta-analysis. MATERIALS AND METHODS: The open published articles comparing the incidence of DVT after laparoscopic or open colorectal cancer were collected in the data bases of Medline, the Cochrane central register of controlled trials and CNKI. The relative risk (RR) was pooled by using random or fixed effect mode to evaluate the incidence of DVT between laparoscopic or open colorectal cancer surgery. RESULTS: After searching the databases, 9 randomized clinical studies with 2606 colorectal cancer cases were included in this meta-analysis. The mean operation time was 201.8 +/- 17.28 min with its range of 180.0-224.4 min in the laparoscopic surgery group and 148.1 +/- 18.8 min with its range of 135.0-184.0 min in the open surgery group. The operation time for laparoscopic surgery group were significant lower than in the open surgery group (P < 0.05). The RR of DVT between the laparoscopy and open surgery groups was 0.71 with its 95% confidence interval of 0.35-1.45 (P = 0.35). CONCLUSIONS: The operation time in laparoscopic colorectal cancer surgery was statistical longer than in the open colorectal cancer surgery, but the DVT risk of the two surgery approach was not different according to this meta-analysis. PMID- 25712843 TI - A retrospective study of diaphragmatic motion, pulmonary function, and quality-of life following video-assisted thoracoscopic lobectomy in patients with nonsmall cell lung cancer. AB - BACKGROUND: Diaphragmatic dysfunction and its negative physiologic disadvantages are less commonly reported in patients with lung cancer video-assisted thoracoscopic lobectomy. The aim of this study was to investigate the outcomes of this complication on pulmonary function and quality-of-life in patients following video-assisted thoracoscopic lobectomy. OBJECTIVES: The aim of this study was to investigate potential benefits on pulmonary function and quality-of-life with normal diaphragmatic motion. MATERIALS AND METHODS: A retrospective study was conducted in 64 patients with nonsmall cell lung cancer after video-assisted thoracoscopic lobectomy. The population were divided into groups 1 (with diaphragmatic paralysis, n = 32) and group 2 (without diaphragmatic paralysis, n = 32) according diaphragmatic motion after postoperatively 6 months. And then, we investigated the difference between the two groups on pulmonary function and quality-of-life. RESULTS: (1) At 6 months after resection, the patients in group 1 had lost 25% of their preoperative forced expiratory volume in the 1 s (FEV 1 ) (P < 0.001), and the patients in group 2 had lost 15% of their preoperative FEV 1 (P < 0.001). And the other spirometric variables in group 1 were significantly worse than that of group 2 (P < 0.001). (2) The most frequently reported postoperative symptoms were fatigue, coughing, dyspnea, and thoracotomy pain in two groups. Of all the symptom scales, only the dyspnea scale showed a significant difference which subject has a higher proportion and scale compared to control. CONCLUSIONS: The present study indicates that unilateral diaphragmatic paralysis following video-assisted thoracoscopic lobectomy caused adverse effects on postoperative pulmonary function and quality-of-life. PMID- 25712844 TI - Arterial embolization of massive hepatocellular carcinoma with lipiodol and gelatin sponge. AB - BACKGROUND: Transarterial chemoembolization (TACE) has been used to treat unresectable massive hepatocellular carcinoma (HCC). Lots of embolic agents have been applied in embolization because of it can decrease patient discomfort and side-effects. AIM: The aim was to evaluate the clinical efficacy and safety of TACE with lipiodol and gelatin sponge. MATERIALS AND METHODS: A total of 109 patients with massive HCC (the size of tumor >10 cm and unresectable) from January 2011 to August 2014 in our institution was divided into group A and group B based on the different embolitic agents. Before and about 1-month after each case of TACE, clinical and biological data such as tumor size, Child-Pugh stage, serum alpha-fetoprotein (AFP), complications, were recorded at the same time. RESULTS: In group A, the diameter of the tumor reduced from 12.57 +/- 1.26 cm to 9.04 +/- 0.89 cm. No patient was complete response (CR), partial response (PR) 36, stable disease (SD) 7 and PD 6; in group B, the diameter of tumor decreased from 12.08 +/- 1.42 cm to 8.43 +/- 1.05 cm, CR 0, but PR 27, SD 18 and PD 15. RR in group A was significantly higher than in group B (P < 0.05).The change of Child-Pugh stage and AFP pre- and post-operative in group A can be found significantly better than in group B. CONCLUSIONS: TACE with lipiodol and gelatin sponge is a highly effective for massive HCC. PMID- 25712845 TI - Submucosal tunneling endoscopic resection for upper gastrointestinal multiple submucosal tumors originating from the muscular propria layer: a feasibility study. AB - BACKGROUND AND AIMS: In recent years, submucosal tunneling endoscopic resection (STER) was applied more and more often for single gastrointestinal (GI) submucosal tumor (SMT). However, little is known about this technique for treating multiple SMTs in GI tract. In the present study, we investigated the feasibility and outcome of STER for upper GI multiple SMTs originating from the muscularis propria (MP) layer. PATIENTS AND METHODS: A feasibility study was carried out including a consecutive cohort of 23 patients with multiple SMTs from MP layer in esophagus, cardia, and upper corpus who were treated by STER from June 2011 to June 2014. Clinicopathological, demographic, and endoscopic data were collected and analyzed. RESULTS: All of the 49 SMTs were resected completely by STER technique. Furthermore, only one tunnel was built for multiple SMTs of each patient in this study. En bloc resection was achieved in all 49 tumors. The median size of all the resected tumors was 1.5 cm (range 0.8-3.5 cm). The pathological results showed that all the tumors were leiomyoma, and the margins of the resected specimens were negative. The median procedure time was 40 min (range: 20-75 min). Gas-related complications were of the main complications, the rates of subcutaneous emphysema and pneumomediastinum, pneumothorax, and pneumoperitoneum were 13.0%, 8.7% and 4.3%. Another common complication was thoracic effusion that occurred in 2 cases (8.7%), among which only 1 case (4.3%) with low-grade fever got the drainage. Delayed bleeding, esophageal fistula or hematocele, and infection in tunnel were not detected after the operation there were no treatment-related deaths. The median hospital stay was 4 days (range, 2-9 days). No residual or recurrent lesion was found during the follow-up period (median 18, ranging 3-36 months). CONCLUSION: Submucosal tunneling endoscopic resection is a safe and efficient technique for treating multiple esophageal SMTs originating from MP layer, which can avoid patients suffering repeated resections. PMID- 25712846 TI - Transcatheter arterial embolization of acute gastrointestinal tumor hemorrhage with Onyx. AB - BACKGROUND: Endovascular embolization has been used to control gastrointestinal tumor bleeding. Lots of embolic agents have been applied in embolization, but liquid embolic materials such as Onyx have been rarely used because of concerns about severe ischemic complications. AIM: To evaluate the clinical efficacy and safety of transcatheter arterial embolization (TAE) with Onyx for acute gastrointestinal tumor hemorrhage. MATERIALS AND METHODS: Between September 2011 and July 2013, nine patients were diagnosed as acute gastrointestinal tumor hemorrhage by clinical feature and imaging examination. The angiographic findings were extravasation of contrast media in the five patients. The site of hemorrhage included upper gastrointestinal bleeding in seven cases and lower gastrointestinal bleeding in two cases. TAE was performed using Onyx in all the patients, and the blood pressure and heart rate were monitored, the angiographic and clinical success rate, recurrent bleeding rate, procedure related complications and clinical outcomes were evaluated after therapy. The clinical parameters and embolization data were studied retrospectively. RESULTS: All the patients (100%) who underwent TAE with Onyx achieved complete hemostasis without rebleeding and the patients were discharged after clinical improvement without a second surgery. No one of the patients expired during the hospital course. All the patients were discharged after clinical improvement without a second surgery. Postembolization bowel ischemia or necrosis was not observed in any of the patients who received TAE with Onyx. CONCLUSIONS: TAE with Onyx is a highly effective and safe treatment modality for acute gastrointestinal tumor hemorrhage, even with pre-existing coagulopathy. PMID- 25712847 TI - Feasibility and safety of early chest tube removal after complete video-assisted thoracic lobectomy. AB - OBJECTIVE: The aim was to evaluate the feasibility and safety of early chest tube removal after complete video-assisted thoracic lobectomy (CVATL). METHODS: Retrospective analysis was performed on effects of chest tube removal on patients with lung cancer after pulmonary lobectomy between November 2013 and October 2014. 154 eligible patients included 97 cases for CVATL and 57 cases for open thoracic lobectomy. Patients with CVATL were divided randomly into experimental group (EG) and control group (CG), in which 51 patients in EG had chest tube removal on the 2 nd day after operation; 46 patients in CG had the tube removal when the drainage volume <100 ml/day. Patients in open thoracic lobectomy group (OG) had the tubes removal as CG. The drainage volumes of the 1 st and 2 nd 24 h after operation, duration of chest tubes, cases of pain alleviation, and recurrent pleural effusions requiring reintervention were measured. RESULTS: The average drainage volume of the 1 st 24 h after operation of CVATL group from EG and CG was significantly reduced than that in OG (260.41 ml vs. 353.16 ml, P < 0.001). The average drainage volume of the 2 nd 24 h after operation of CG was significantly reduced than that in OG (163.91 ml vs. 222.98 ml, P < 0.001). The average duration of chest tube of CG for 2.98 days showed significant different compared with OG for 3.81 days (P < 0.001). Chest tube removal in CVATL group increased more chest pain alleviation than OG (80.4% vs. 56.1%, P = 0.001). The frequencies of recurrent pleural effusions requiring reintervention were 5.88% (3/51), 4.35% (2/46) and 5.26% (3/57), respectively, which had no significant differences between three groups (P = 1.000). CONCLUSIONS: Complete video assisted thoracic lobectomy brings less drainage volume after operation. Early removal of chest tube in CVATL shows feasible and safe and demonstrates that it may reduce postoperative pain and help fast recovery. PMID- 25712848 TI - A modified method using a two-port approach for accessing the hilar vasculature without transferring an endostapler from camera port to utility port during thoracoscopic right upper lobectomy. AB - For thoracoscopic upper lobectomies, most cutting endostaplers must be inserted through the camera port when using a two-port approach. Access to the hilar vasculature through only the utility port remains a challenge. In this study, we describe a procedure to access the hilar vasculature without transferring the endostapler site during a thoracoscopic right upper lobectomy. A 2.5-cm utility anterior incision was made in the fourth intercostal space. The posterior mediastinal visceral pleura were dissected to expose the posterior portion of the right upper bronchus and the anterior trunk of the right pulmonary artery. The pleura over the right hilar vasculature were then peeled with an electrocoagulation hook. The anterior trunk of the right pulmonary artery was then transected with a cutting endostapler through the utility port firstly. This crucial maneuver allowed the endostapler access to the right upper lobe pulmonary vein. The hilar structures were then easily handled in turn. This novel technique was performed successfully in 32 patients, with no perioperative deaths. The average operation time was 120.6 min (range 75-180 min). This novel technique permits effective control of the hilar vessels through the utility port, enabling simple, safe, quick and effective resection. PMID- 25712849 TI - A new technique for dissection of the vessels simultaneously. PMID- 25712850 TI - Computed tomography-guided iodine-125 interstitial implantation as an alternative treatment option for lung cancer. AB - PURPOSE: The aim was to evaluate the safety, feasibility and efficacy of computed tomography (CT)-guided percutaneous interstitial brachytherapy using radioactive iodine-125 ( 125 I) seeds for the treatment of lung cancer. MATERIALS AND METHODS: Included in this study were 45 male and 35 female patients aged 52-85 years (mean 72-year) who were diagnosed with lung cancer. Of the 80 cases of lung cancer, 38 were pathologically confirmed as squamous cell carcinoma, 29 as adenocarcinoma, 2 as small cell lung cancer, and 11 as metastatic lung cancer. Percutaneous interstitial implantation of radioactive 125 I seeds was performed under CT guidance. The treatment planning system was used to reconstruct three dimensional images of the tumor to determine the quantity and distribution of 125 I seeds to be implanted. Under CT guidance, 125 I seeds were embedded into the tumor, with the matched peripheral dose set at 100-130 Gy. Follow-up CT scan was done in 2-month to explore the treatment efficacy. RESULTS: The procedure was successful in all patients. No major procedure-associated death occurred. The duration of follow-up was 6-month. Complete response (CR) was seen in 38 cases (47.5%), partial response (PR) in 27 cases (33.75%), stable disease (SD) in 10 cases (12.5%), and progressive disease in 5 cases (6.25%), with a local control rate (CR + PR + SD) of 93.75%. The 2-, 4- and 6-month overall response rate (CR + PR) was 78%, 83% and 81%, respectively. CONCLUSION: Implantation of CT-guided 125 I seeds is a safe and effective alternative option for the treatment of lung cancer. PMID- 25712851 TI - Appealing to our broad audience. PMID- 25712853 TI - Engineering poly(ethylene glycol) particles for improved biodistribution. AB - We report the engineering of poly(ethylene glycol) (PEG) hydrogel particles using a mesoporous silica (MS) templating method via tuning the PEG molecular weight, particle size, and the presence or absence of the template and investigate the cell association and biodistribution of these particles. An ex vivo assay based on human whole blood that is more sensitive and relevant than traditional cell line based assays for predicting in vivo circulation behavior is introduced. The association of MS@PEG particles (template present) with granulocytes and monocytes is higher compared with PEG particles (template absent). Increasing the PEG molecular weight (from 10 to 40 kDa) or decreasing the PEG particle size (from 1400 to 150 nm) reduces phagocytic blood cell association of the PEG particles. Mice biodistribution studies show that the PEG particles exhibit extended circulation times (>12 h) compared with the MS@PEG particles and that the retention of smaller PEG particles (150 nm) in blood, when compared with larger PEG particles (>400 nm), is increased at least 4-fold at 12 h after injection. Our findings highlight the influence of unique aspects of polymer hydrogel particles on biological interactions. The reported PEG hydrogel particles represent a new class of polymer carriers with potential biomedical applications. PMID- 25712854 TI - Resistance of Black-lip learl oyster, Pinctada margaritifera, to infection by Ostreid herpes virus 1MUvar under experimental challenge may be mediated by humoral antiviral activity. AB - Ostreid herpesvirus 1 (OsHV-1) has induced mass mortalities of the larvae and spat of Pacific oysters, Crassostrea gigas, in Europe and, more recently, in Oceania. The production of pearls from the Black-lip pearl oyster, Pinctada margaritifera, represents the second largest source of income to the economies of French Polynesia and many Pacific Island nations that could be severely compromised in the event of a disease outbreak. Coincidentally with the occurrence of OsHV-1 in the southern hemisphere, C. gigas imported from New Zealand and France into French Polynesia tested positive for OsHV-1. Although interspecies viral transmission has been demonstrated, the transmissibility of OsHV-1 to P. margaritifera is unknown. We investigated the susceptibility of juvenile P. margaritifera to OsHV-1 MUvar that were injected with tissue homogenates sourced from either naturally infected or healthy C. gigas. The infection challenge lasted 14 days post-injection (dpi) with sampling at 0, 1, 2, 3, 5, 7 and 14 days. Mortality rate, viral prevalence, and cellular immune responses in experimental animals were determined. Tissues were screened by light microscopy and TEM. Pacific oysters were also challenged and used as a positive control to validate the efficiency of OsHV-1 MUvar infection. Viral particles and features such as marginated chromatin and highly electron dense nuclei were observed in C. gigas but not in P. margaritifera. Mortality rates and hemocyte immune parameters, including phagocytosis and respiratory burst, were similar between challenged and control P. margaritifera. Herpesvirus-inhibiting activity was demonstrated in the acellular fraction of the hemolymph from P. margaritifera, suggesting that the humoral immunity is critical in the defence against herpesvirus in pearl oysters. Overall, these results suggest that under the conditions of the experimental challenge, P. margaritifera was not sensitive to OsHV-1 MUvar and was not an effective host/carrier. The nature and spectrum of activity of the humoral antiviral activity is worthy of further investigation. PMID- 25712855 TI - Evidence for the involvement of dopamine in stress-induced suppression of reproduction in the cichlid fish Oreochromis mossambicus. AB - In the present study, we examined whether stress-induced suppression of reproduction is mediated through the catecholaminergic neurotransmitter dopamine (DA) in the female cichlid fish Oreochromis mossambicus. In the first experiment, application of antibody against tyrosine hydroxylase (TH; a marker for DA) in brain sections revealed the presence of intensely stained TH immunoreactive cells in the preoptic area (POA) and nucleus preopticus (NPO) during the previtellogenic phase. These cells showed weak immunoreactivity during the vitellogenic and prespawning phases concomitant with darkly stained luteinising hormone (LH) immunoreactive content in the proximal pars distalis (PPD) of the pituitary gland and fully ripened follicles (stage V) in the ovary of control fish. However, in fish exposed to aquacultural stressors, TH secreting cells remained intensely stained in POA and NPO regions during the prespawning phase, indicating increased synthetic and secretory activity, which was reflected by a significantly higher DA content compared to controls. Increased DA activity as a result of stress was associated with a decrease in the LH immunoreactive content in the PPD and an absence of stage V follicles in the ovary. In the second experiment, administration of DA caused effects similar to those in stressed fish, whereas DA receptor antagonist domperidone (DOM) treatment significantly increased the LH content in the PPD and the number of stage V follicles in unstressed fish. On the other hand, treatment of stressed fish with DOM resulted in dark accumulations of LH immunoreactive content in the PPD accompanied by the presence of stage V follicles in the ovary. Taken together, these results suggest an additional pathway for the inhibitory effects of stress through dopaminergic neurones along the reproductive axis. PMID- 25712856 TI - Influence of histamine on the expression of CCL20 in human gingival fibroblasts. AB - BACKGROUND AND OBJECTIVE: Histamine plays an important role during allergic and inflammatory reactions, and it has been suggested to influence periodontal inflammation. The aim of this study was to investigate the effects of histamine on the expression of the antimicrobial peptide C-C chemokine ligand 20 (CCL20) in human gingival fibroblasts (HGFs) when exposed to toll-like receptor (TLR) agonists. MATERIAL AND METHODS: Monolayers of HGFs from three different donors were exposed to histamine, alone, and in combination with Pam3CSK4 (a TLR2 agonist) or lipopolysaccharide (LPS) from Escherichia coli (a TLR4 agonist), for 2, 4, 6 or 12 h. In another experimental group, cells were pretreated with a specific histamine-1 receptor antagonist (H1R) antagonist, cetirizine. Real-time PCR analysis was performed to detect expression of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), CCL20 and interleukin-8 (IL8) genes. The levels of CCL20 and IL-8 protein were determined by ELISA. RESULTS: In HGFs, histamine induced expression of CCL20 and IL8 genes in a time-dependent manner (p < 0.05). Combined stimulation with histamine and Pam3CSK4 or LPS led to a significant amplification in expression of CCL20 and IL-8 when compared with treatment with each stimulant alone (p < 0.05), and this effect was mediated via pathways involving the H1R (p < 0.05). CONCLUSION: The results of this study suggest a sensitizing effect of histamine on early innate immune responses of HGFs when simultaneously exposed to bacterial virulence factors. PMID- 25712857 TI - Leflunomide and teriflunomide: altering the metabolism of pyrimidines for the treatment of autoimmune diseases. AB - Leflunomide modulates T-cell responses and induces a shift from the Th1 to Th2 subpopulation. This process results in a beneficial effect in diseases in which there is good evidence that T cells play a major role in both initiation and perpetuation of the inflammatory condition. Leflunomide has been successfully used for treating rheumatoid arthritis and psoriatic arthritis for many years. The active metabolite of leflunomide is teriflunomide, which has been approved for treating multiple sclerosis. Teriflunomide, just like the mother drug, inhibits dihydro-orotate dehydrogenase and synthesis of pyrimidine. The present review presents and discusses the safety profiles of leflunomide and teriflunomide, two drugs that are indeed the same, considering that much can be learned from the reported side effects of both. PMID- 25712858 TI - Multi-responsive metal-organic lantern cages in solution. AB - Soluble copper-based M4L4 lantern-type metal-organic cages bearing internal amines were synthesized. The solution state integrity of the paramagnetic metal organic cages was demonstrated using NMR, DLS, MS, and AFM spectroscopy. 1D supramolecular pillars of pre-formed cages or covalent host-guest complexes selectively formed upon treatment with 4,4'-bipyridine and acetic anhydride, respectively. PMID- 25712859 TI - Ablating N-acetylaspartate prevents leukodystrophy in a Canavan disease model. AB - Canavan disease is caused by inactivating ASPA (aspartoacylase) mutations that prevent cleavage of N-acetyl-L-aspartate (NAA), resulting in marked elevations in central nervous system (CNS) NAA and progressively worsening leukodystrophy. We now report that ablating NAA synthesis by constitutive genetic disruption of Nat8l (N-acetyltransferase-8 like) permits normal CNS myelination and prevents leukodystrophy in a murine Canavan disease model. PMID- 25712860 TI - Does surgical technique influence post-tonsillectomy haemorrhage? Our experience. AB - INTRODUCTION AND OBJECTIVES: Tonsillectomy represents one of the main surgical procedures for the otolaryngologist, with haemorrhage being the most common postoperative. The objective of this study was to determine the post tonsillectomy haemorrhage rate, and relate the surgical technique, diagnosis and patient age. METHODS: This was a retrospective study, from April 2012 to January 2014, covering 429 patients. We used the following surgical-dissection techniques: cold, Colorado needle and monopolar forceps. Haemostasis was carried out in every case with monopolar forceps and gauze compression. RESULTS: Post tonsillectomy haemorrhage rate was 6.99%. According to the surgical technique used, with Colorado needle dissection, the bleeding rate we found was 7.07%; with monopolar forceps dissection, the rate was 20.4%; and with cold dissection, 2.9%. Of all haemorrhages, only 9 (2.09%) needed reintervention, of which 40% were performed with monopolar forceps dissection. The group with the largest bleeding rate was that of more than 14 years old. The diagnosis most associated with bleeding was peritonsillar abscess. CONCLUSION: The lowest bleeding rate was found with cold dissection and monopolar forceps haemostasis (2.09%). Consequently, based on our experience and the results obtained in the study, we consider that surgical technique does influence post-tonsillectomy haemorrhage. PMID- 25712861 TI - Analysis of HBV genotype, drug resistant mutations, and pre-core/basal core promoter mutations in Korean patients with acute hepatitis B. AB - Acute hepatitis B, caused by hepatitis B virus (HBV) strains with drug resistant mutations or pre-core/basal core promoter (PC/BCP) mutations, is a public health concern, because this infection is often associated with poor disease outcome or difficulty in therapeutic choice. The HBV genotype, the prevalence of drug resistant mutations, and PC/BCP mutations in Korean patients with acute hepatitis B were studied. From 2006 to 2008, 36 patients with acute hepatitis B were enrolled prospectively in four general hospitals. Among them, 20 showed detectable HBV DNA (median value was 4.8 log copies/mL). HBV genotyping and analysis of HBV mutations that conferred resistance against lamivudine, adefovir, or entecavir and of PC/BCP mutations were performed using highly sensitive restriction fragment mass polymorphism (RFMP) analysis. All 20 patients were infected with HBV genotype C, which causes almost all cases of chronic hepatitis B in Korea. No patient showed mutations that conferred resistance against lamivudine (L180M, M204V/I), adefovir (A181T, N236S), or entecavir (I169M, A184T/V, S202I/G, M250V/I/L). However, four patients had BCP mutations, and two had PC mutations. Platelet counts were significantly lower in the four patients with PC/BCP mutations compared to those with wild type. In this study, all acute hepatitis B patients had genotype C HBV strains with no drug resistant mutations. However, 20% showed PC/BCP mutations. This highlights the need for further study on the significance of PC/BCP mutations. PMID- 25712862 TI - Sex Differences in Arm Muscle Fatigability With Cognitive Demand in Older Adults. AB - BACKGROUND: Muscle fatigability can increase when a stressful, cognitively demanding task is imposed during a low-force fatiguing contraction with the arm muscles, especially in women. Whether this occurs among older adults (>60 years) is currently unknown. QUESTIONS/PURPOSES: We aimed to determine if higher cognitive demands, stratified by sex, increased fatigability in older adults (>60 years). Secondarily, we assessed if varying cognitive demand resulted in decreased steadiness and was explained by anxiety or cortisol levels. METHODS: Seventeen older women (70+/-6 years) and 13 older men (71+/-5 years) performed a sustained, isometric, fatiguing contraction at 20% of maximal voluntary contraction until task failure during three sessions: high cognitive demand (high CD=mental subtraction by 13); low cognitive demand (low CD=mental subtraction by 1); and control (no subtraction). RESULTS: Fatigability was greater when high and low CD were performed during the fatiguing contraction for the women but not for the men. In women, time to failure with high CD was 16+/-8 minutes and with low CD was 17+/-4 minutes, both of which were shorter than time to failure in control contractions (21+/-7 minutes; high CD mean difference: 5 minutes [95% confidence interval {CI}, 0.78-9.89], p=0.02; low CD mean difference: 4 minutes [95% CI, 0.57-7.31], p=0.03). However, in men, no differences were detected in time to failure with cognitive demand (control: 13+/-5 minutes; high CD mean difference: 0.09 minutes [95% CI, -2.8 to 2.7], p=1.00; low CD mean difference: 0.75 minutes [95% CI, -1.1 to 2.6], p=0.85). Steadiness decreased (force fluctuations increased) more during high CD than control. Elevated anxiety, mean arterial pressure, and salivary cortisol levels in both men and women did not explain the greater fatigability during high CD. CONCLUSIONS: Older women but not men showed marked increases in fatigability when low or high CD was imposed during sustained static contractions with the elbow flexor muscles and contrasts with previous findings for the lower limb. Steadiness decreased in both sexes when high CD was imposed. CLINICAL RELEVANCE: Older women are susceptible to greater fatigability of the upper limb with heightened mental activity during sustained postural contractions, which are the foundation of many work-related tasks. PMID- 25712863 TI - Editor's Spotlight/Take 5: surgeons' attitudes are associated with reoperation and readmission rates. PMID- 25712864 TI - Promising Mid-term Results With a Cup-cage Construct for Large Acetabular Defects and Pelvic Discontinuity. AB - BACKGROUND: Restoring normal anatomy and achieving stable fixation of the acetabular component can be especially challenging when the surgeon must deal with severe acetabular defects and/or pelvic discontinuity. The cup-cage (CC) construct, where an ilioischial cage is cemented within a biologically fixed porous metal cup, has emerged as an excellent option to treat such challenges. QUESTIONS/PURPOSES: We sought to determine (1) mid-term Kaplan-Meier survival; (2) clinical outcomes based on Merle d'Aubigne-Postel scores; (3) radiological outcomes based primarily on construct migration; and (4) the complication rate for a series of 67 CC procedures performed at our institution. METHODS: All hip revision procedures between January 2003 and March 2012 where a CC was used (with the exception of tumor cases or acute fracture; four total cases) that had a minimum 2-year followup and that had been seen within the last 2 years were included in this retrospective review. Acetabular bone loss and presence of pelvic discontinuity were assessed according to the Gross classification. Sixty seven CC procedures with an average followup of 74 months (range, 24-135 months; SD, 34.3) months were identified; 26 of 67 (39%) were Gross Type IV and 41 of 67 (61%) were Gross Type V (pelvic discontinuity). Postoperative clinical and radiological evaluation was done annually. Merle d'Aubigne-Postel scores were recorded and all radiographs were compared with the 6-week postoperative radiographs to evaluate for radiographic loosening or migration. Failure was defined as revision surgery for any cause, including infection. RESULTS: The 5 year Kaplan-Meier survival rate with revision for any cause representing failure was 93% (95% confidence interval [CI], 83.1-97.4), and the 10-year survival rate was 85% (95% CI, 67.2-93.8). The Merle d'Aubigne-Postel score improved significantly from a mean of 6 preoperatively to 13 postoperatively (p < 0.001). Four CC had nonprogressive radiological migration of the ischial flange and they remain stable. CONCLUSIONS: We believe that the CC construct is a suitable choice to treat chronic pelvic discontinuity; it also remains a reliable option for the treatment of severe acetabular bone defects if stable fixation cannot be obtained through the use of a trabecular metal cup with or without augments. LEVEL OF EVIDENCE: Level IV, therapeutic study. PMID- 25712866 TI - Recurrent Hemarthroses After TKA Treated With an Intraarticular Injection of Yttrium-90. AB - BACKGROUND: Recurrent hemarthroses after a TKA are uncommon and usually respond to nonoperative treatment or intervention using angiographic embolization or synovectomy. However, in rare circumstances, the problem can be resistant to treatment. CASE DESCRIPTION: We report the case of a patient who had recurrent hemarthroses after a TKA. During the first 18 months after surgery, the patient experienced 48 episodes consistent with bleeding into the knee. The bleeding episodes recurred despite use of traditional treatments, including arthroscopy, open synovectomy and embolization of a small, false aneurysm. The patient ultimately received an intraarticular injection of yttrium-90 silica/citrate, and the hemarthroses ceased soon after the injection. At last review, 25 months after the injection, the patient had experienced no additional bleeding episodes. LITERATURE REVIEW: On review of the literature, we found only one other report in which yttrium-90 was used successfully in a similar situation. CLINICAL RELEVANCE: Yttrium-90 may be considered a treatment option in patients with recurrent hemarthroses after TKA, especially when the condition has not responded to more traditional treatments. The long-term risk of treatment with yttrium-90 for recurrent hemarthroses after a TKA remains unclear. PMID- 25712865 TI - The Mark Coventry Award: Custom Cutting Guides Do Not Improve Total Knee Arthroplasty Clinical Outcomes at 2 Years Followup. AB - BACKGROUND: Custom cutting guides (CCGs; sometimes called patient-specific instrumentation [PSI]) in total knee arthroplasty (TKA) use preoperative three dimensional imaging to fabricate cutting blocks specific to a patient's native anatomy. QUESTIONS/PURPOSES: The purposes of this study were to determine if CCGs (1) improve clinical outcomes as measured by UCLA activity, SF-12, and Oxford knee scores; and (2) coronal mechanical alignment versus standard alignment guides. METHODS: This was a retrospective cohort study of patients undergoing primary TKA using the same cruciate-retaining, cemented TKA system between January 2009 and April 2012. Patients were included if they were candidates for a unilateral, cruciate-retaining TKA and met other prespecified criteria; patients were allowed to self-select either an MRI-based CCG procedure or standard TKA. Ninety-seven of 120 (80.8%) patients in the standard and 104 of 124 (83.9%, p = 0.5) in the CCG cohort with a minimum of 1-year followup were available for analysis. The first 95 patients in the standard (mean followup, 3 years; range, 1 4 years) and CCG (mean followup, 2 years; range, 1-4 years) cohorts were compared. The alignment goal for all TKAs was a hip-knee-ankle (HKA) angle of 0 degrees . UCLA, SF-12, and Oxford knee scores were collected preoperatively and at each patient's most recent followup visit. Postoperative, rotationally controlled coronal scout CT scans were used to measure HKA alignment. Independent sample t-tests and chi-square tests were used for comparisons with a p value <= 0.05 considered significant. RESULTS: At the most recent followup, no differences were present between the two cohorts for range of motion (114 degrees +/- 14 degrees in CCG versus 115 degrees +/- 15 degrees in standard, p = 0.7), UCLA (6 +/- 2 in CCG versus 6 +/- 2 in standard, p = 0.7), SF-12 physical (44 +/- 12 in CCG versus 41 +/- 12 in standard, p = 0.07), or Oxford knee scores (39 +/- 9 in CCG versus 37 +/- 10 in standard, p = 0.1). No differences were present for the incremental improvement in the UCLA (1 +/- 4 in CCG versus 1 +/- 3 in standard, p = 0.5), SF-12 physical (12 +/- 20 in CCG versus 11 +/- 21, p = 0.8), or Oxford knee scores (16 +/- 9 in CCG versus 19 +/- 10 in standard, p = 0.1) from preoperatively to postoperatively. There was no difference in the percentage of outliers for alignment (23% in standard versus 31% in CCG with HKA outside of 0 degrees +/- 3 degrees ; p = 0.2) between the two cohorts. CONCLUSIONS: At a mean followup of greater than 2 years, CCGs fail to demonstrate any advantages in validated knee outcome measure scores or coronal alignment as measured by CT scan versus the use of standard instrumentation in TKA. The clinical benefit of CCGs must be proven before continued implementation of this technology. LEVEL OF EVIDENCE: Level III, retrospective controlled study. PMID- 25712867 TI - Sensitivity to anti-Fas is independent of increased cathepsin D activity and adrenodoxin reductase expression occurring in NOS-3 overexpressing HepG2 cells. AB - Stable overexpression of endothelial nitric oxide synthase (NOS-3) in HepG2 cells (4TO-NOS) leads to increased nitro-oxidative stress and upregulation of the cell death mediators p53 and Fas. Thus, NOS-3 overexpression has been suggested as a useful antiproliferative mechanism in hepatocarcinoma cells. We aimed to identify the underlying mechanism of cell death induced by NOS-3 overexpression at basal conditions and with anti-Fas treatment. The intracellular localization of NOS-3, the nitro-oxidative stress and the mitochondrial activity were analysed. In addition, the protein expression profile in 4TO-NOS was screened for differentially expressed proteins potentially involved in the induction of apoptosis. NOS-3 localization in the mitochondrial outer membrane was not associated with changes in the respiratory cellular capacity, but was related to the mitochondrial biogenesis increase and with a higher protein expression of mitochondrial complex IV. Nitro-oxidative stress and cell death in NOS-3 overexpressing cells occurred with the expression increase of pro-apoptotic genes and a higher expression/activity of the enzymes adrenodoxin reductase mitochondrial (AR) and cathepsin D (CatD). CatD overexpression in 4TO-NOS was related to the apoptosis induction independently of its catalytic activity. In addition, CatD activity inhibition by pepstatin A was not effective in blocking apoptosis induced by anti-Fas. In summary, NOS-3 overexpression resulted in an increased sensitivity to anti-Fas induced cell death, independently of AR expression and CatD activity. PMID- 25712868 TI - Homer proteins mediate the interaction between STIM1 and Cav1.2 channels. AB - STIM1 is a ubiquitous Ca2+ sensor of the intracellular, agonist-sensitive, Ca2+ stores that communicates the filling state of the Ca2+ compartments to plasma membrane store-operated Ca2+ (SOC) channels. STIM1 has been presented as a point of convergence between store-operated and voltage-operated Ca2+ influx, both inducing activation of SOC channels while suppressing Cav1.2 channels. Here we report that Homer proteins play a relevant role in the communication between STIM1 and Cav1.2 channels. HEK-293 cells transiently expressing Cav1.2 channel subunits alpha1, beta2 and alpha2delta-1 exhibited a significant Ca2+ entry upon treatment with a high concentration of KCl. In Cav1.2-expressing cells, treatment with thapsigargin (TG), to induce passive discharge of the intracellular Ca2+ stores, resulted in Ca2+ influx that was significantly greater than in cells not expressing Cav1.2 channels, a difference that was abolished by nifedipine and diltiazem. Treatment with TG induces co-immunoprecipitation of Homer1 with STIM1 and the Cav1.2 alpha1 subunit. Impairment of Homer function by introduction of the synthetic PPKKFR peptide into cells, which emulates the proline-rich sequences of the PPXXF motif, or using siRNA Homer1, reduced the association of STIM1 and the Cav1.2 alpha1 subunit. These findings indicate that Homer is important for the association between both proteins. Finally, treatment with siRNA Homer1 or the PPKKFR peptide enhanced the nifedipine-sensitive component of TG response in Cav1.2-expressing cells. Altogether, these findings provide evidence for a new role of Homer1 supporting the regulation of Cav1.2 channels by STIM1. PMID- 25712869 TI - Aptamer-based sensing of beta-casomorphin-7. AB - beta-Casomorphin-7 (BCM-7), a seven amino acid peptide, is released during digestion of beta-casein A1 variant of milk which is speculated to be associated with certain diseases. Fifteen ssDNA aptamers having high affinity toward BCM-7 were identified from a 72 nt long random library after ten rounds of systematic evolution of ligands by exponential enrichment. Dissociation constant values of selected aptamers were in the range of 7.7-156.7 nM. Seq6 aptamer exhibited the lowest Kd value. Nine aptamers were evaluated for their binding toward BCM-7, BCM 9A1, and BCM-9A2 peptides, and binding was variable. SeqU5 exhibited the lowest binding with BCM-9A1 and BCM-9A2. Aptamer-coated gold nanoparticles (GNPs) resulted in color change of GNPs in the presence of BCM-7, thereby establishing recognition of BCM-7 by aptamers. The enzyme-linked aptamer-sorbent assay (ELASA) was evaluated as an assay of BCM-7 in biological fluids. BCM-7-peroxidase competed with BCM-7 in ELASA, performed with BCM-7 solution and BCM-7 spiked urine pretreated with urease, plasma, and beta-casein digest samples. PMID- 25712870 TI - Application of a novel spinal posture and motion measurement system in active and static sitting. AB - The quantification of work-related musculoskeletal risk factors is of great importance; however, only a few tools allow objective, unrestricted measurements of spinal posture and motion in workplaces. This study was performed to evaluate the applicability of the Epionics system in a sedentary workplace. The system is mobile and wireless and assesses lumbar lordosis, pelvic orientation and spinal motion, without restricting subjects in their movements. In total, 10 males were monitored while sitting for 2 h on static and dynamic office chairs and on an exercise ball, to evaluate the effect of dynamic sitting. The volunteers were able to perform their work unhampered. No differences among the tested furniture could be detected with respect to either the lordosis or the number of spinal movements after habituation to the furniture; however, differences in pelvic orientation were statistically significant. The results of the present study indicate that Epionics may be useful for the quantitative assessment of work related risk factors. Practitioner Summary: Only a few tools allow objective, unrestricted measurements of spinal posture and motion in the workplace. Epionics SPINE measures lumbar lordosis, pelvic orientation and spinal motion under nearly unrestricted conditions and can be used to quantify work-related musculoskeletal risk factors. We demonstrated the use of this tool in the workplace-analysis. PMID- 25712873 TI - Fine Tuning the Emission Properties of Nanoemitters in Multilayered Structures by Deterministic Control of their Local Photonic Environment. AB - Deterministic control on the dynamics of organic nanoemitters is achieved through precise control of its photonic environment. Resonators are fabricated by a combination of spin- and dip-coating techniques, which allows placement of the emitters at different positions within the sample, thus acting as a probe of the local density of states. PMID- 25712871 TI - The neuroanatomical delineation of agentic and affiliative extraversion. AB - Extraversion is a fascinating personality dimension that consists of two major components, agentic extraversion and affiliative extraversion. Agentic extraversion involves incentive motivation and is expressed as a tendency toward assertiveness, persistence, and achievement. Affiliative extraversion involves the positive emotion of social warmth and is expressed as a tendency toward amicability, gregariousness, and affection. Here we investigate the neuroanatomical correlates of the personality traits of agentic and affiliative extraversion using the Multidimensional Personality Questionnaire Brief Form, structural magnetic resonance imaging, and voxel-based morphometry in a sample of 83 healthy adult volunteers. We found that trait agentic extraversion and trait affiliative extraversion were each positively associated with the volume of the medial orbitofrontal cortex bilaterally (t's >= 2.03, r's >= .23, p's < .05). Agentic extraversion was specifically and positively related to the volume of the left parahippocampal gyrus (t = 4.08, r = .21, p < .05), left cingulate gyrus (t = 4.75, r = .28, p < .05), left caudate (t = 4.29, r = .24, p < .05), and left precentral gyrus (t = 4.00, r = .18, p < .05) in males and females, and the volume of the right nucleus accumbens in males (t = 2.92, r = .20, p < .05). Trait affiliative extraversion was not found to be associated with additional regions beyond the medial orbitofrontal cortex. The findings provide the first evidence of a neuroanatomical dissociation between the personality traits of agentic and affiliative extraversion in healthy adults. PMID- 25712874 TI - Meta-analysis of diagnostic tests accounting for disease prevalence: a new model using trivariate copulas. AB - In real life and somewhat contrary to biostatistical textbook knowledge, sensitivity and specificity (and not only predictive values) of diagnostic tests can vary with the underlying prevalence of disease. In meta-analysis of diagnostic studies, accounting for this fact naturally leads to a trivariate expansion of the traditional bivariate logistic regression model with random study effects. In this paper, a new model is proposed using trivariate copulas and beta-binomial marginal distributions for sensitivity, specificity, and prevalence as an expansion of the bivariate model. Two different copulas are used, the trivariate Gaussian copula and a trivariate vine copula based on the bivariate Plackett copula. This model has a closed-form likelihood, so standard software (e.g., SAS PROC NLMIXED) can be used. The results of a simulation study have shown that the copula models perform at least as good but frequently better than the standard model. The methods are illustrated by two examples. PMID- 25712875 TI - A general and scalable synthesis of aeruginosin marine natural products based on two strategic C(sp3)-H activation reactions. AB - An efficient and scalable access to the aeruginosin family of marine natural products, which exhibit potent inhibitory activity against serine proteases, is reported. This synthesis was enabled by the strategic use of two different, recently implemented C(sp(3))-H activation reactions. The first method led to the common 2-carboxy-6-hydroxyoctahydroindole (Choi) core of the target molecules on a large scale, whereas the second one provided rapid and divergent access to the various hydroxyphenyllactic (Hpla) subunits. This strategy allowed the synthesis of the aeruginosins 98B and 298A, with the latter being obtained in unprecedentedly large quantities. PMID- 25712877 TI - Synthesis, characterization, and energetic properties of 6-amino-tetrazolo[1,5-b] 1,2,4,5-tetrazine-7-N-oxide: a nitrogen-rich material with high density. AB - The synthesis and energetic properties of a novel N-oxide high-nitrogen compound, 6-amino-tetrazolo[1,5-b]-1,2,4,5-tetrazine-7-N-oxide, are described. Resulting from the N-oxide and fused rings system, this molecule exhibits high density, excellent detonation properties, and acceptable impact and friction sensitivities, which suggests potential applications as an energetic material. Compared to known high-nitrogen compounds, such as 3,6-diazido-1,2,4,5-tetrazine (DiAT), 2,4,6-tri(azido)-1,3,5-triazine (TAT), and 4,4',6,6'-tetra(azido)azo 1,3,5-triazine (TAAT), a marked performance and stability increase is seen. This supports the superior qualities of this new compound and the advantage of design strategy. PMID- 25712876 TI - Can simple mobile phone applications provide reliable counts of respiratory rates in sick infants and children? An initial evaluation of three new applications. AB - BACKGROUND: Respiratory rate is an important sign that is commonly either not recorded or recorded incorrectly. Mobile phone ownership is increasing even in resource-poor settings. Phone applications may improve the accuracy and ease of counting of respiratory rates. OBJECTIVES: The study assessed the reliability and initial users' impressions of four mobile phone respiratory timer approaches, compared to a 60-second count by the same participants. METHODS: Three mobile applications (applying four different counting approaches plus a standard 60 second count) were created using the Java Mobile Edition and tested on Nokia C1 01 phones. Apart from the 60-second timer application, the others included a counter based on the time for ten breaths, and three based on the time interval between breaths ('Once-per-Breath', in which the user presses for each breath and the application calculates the rate after 10 or 20 breaths, or after 60s). Nursing and physiotherapy students used the applications to count respiratory rates in a set of brief video recordings of children with different respiratory illnesses. Limits of agreement (compared to the same participant's standard 60 second count), intra-class correlation coefficients and standard errors of measurement were calculated to compare the reliability of the four approaches, and a usability questionnaire was completed by the participants. RESULTS: There was considerable variation in the counts, with large components of the variation related to the participants and the videos, as well as the methods. None of the methods was entirely reliable, with no limits of agreement better than -10 to +9 breaths/min. Some of the methods were superior to the others, with ICCs from 0.24 to 0.92. By ICC the Once-per-Breath 60-second count and the Once-per-Breath 20 breath count were the most consistent, better even than the 60-second count by the participants. The 10-breath approaches performed least well. Users' initial impressions were positive, with little difference between the applications found. CONCLUSIONS: This study provides evidence that applications running on simple phones can be used to count respiratory rates in children. The Once-per-Breath methods are the most reliable, outperforming the 60-second count. For children with raised respiratory rates the 20-breath version of the Once-per-Breath method is faster, so it is a more suitable option where health workers are under time pressure. PMID- 25712878 TI - Deficiency of decorin induces expression of Foxp3 in CD4+CD25+ T cells in a murine model of allergic asthma. AB - BACKGROUND AND OBJECTIVE: Decorin (Dcn), an extracellular matrix proteoglycan, has several important biological functions, and its deposition is altered in the airway wall of humans with asthma and animal models of asthma. Due to its high affinity for transforming growth factor beta (TGF)-beta, Dcn can function as part of a negative feedback mechanism, resulting in the regulation of this factor's bioavailability. Dcn deficient (Dcn(-/-) ) mice develop reduced airway inflammation, hyperresponsiveness and remodeling in response to repeated allergen challenge; we investigated whether regulatory T cells play a role in the diminished airway response of Dcn(-/-) mice. METHODS: Dcn(-/-) and Dcn(+/+) mice (C57Bl/6) were sensitized with ovalbumin (OVA) and challenged intra-nasally 3 days/week * 3 weeks. After allergen challenge, bronchoalveolar lavage was collected to quantify total and differential cell counts and cytokine levels. Inflammatory cell number and cytokine messenger ribonucleic acid (mRNA) production were assessed in lung tissues. Cells from lung and spleen were extracted to evaluate regulatory T cells. RESULTS: Tissue inflammation and interleukin (IL)-13 mRNA expression were significantly increased in OVA challenged Dcn(+/+) mice, only. The increased expression of Foxp3 in CD4(+) CD25(+) T cells found in lung of OVA-challenged Dcn(-/-) mice was accompanied by an increase in IL-10 mRNA. CONCLUSIONS: Our data demonstrated that a diminished lung inflammation in OVA challenged Dcn(-/-) mice was accompanied by a higher expression of regulatory T cells and IL-10 mRNA levels. These results reinforce the importance of Dcn in biological processes, particularly in an allergic model of asthma. PMID- 25712879 TI - Historical gene flow within and among populations of Luehea divaricata in the Brazilian Pampa. AB - Within and among population gene flow is a central aspect of the evolutionary history of ecosystems and essential for the potential for adaptive evolution of populations. We employed nuclear microsatellite markers to assess inter- and intra-population gene flow in five natural populations of Luehea divaricata growing in the Pampa biome, in southern Brazil. This species occurs in practically all secondary forests of the Pampa and has recognized ecological significance for these formations. The genetic structuring of the studied populations suggests limited gene dispersal among forest fragments, despite a homogeneous level of migration among populations. Notwithstanding the gene flow among populations, significant SGS is still found in some fragments. Significant spatial genetic structure within population was also found likely as result of limited seed and/or pollen dispersal. The scattered distribution of the populations and their relatively high density seem to limit pollen dispersal. Also seed dispersal by wind is not efficient due to large distances among forest formations. As conservationist actions towards preserving the genetic resources of L. divaricata and the Brazilian Pampa, we suggest the protection of the existing forest formations and the maintenance of the natural expansion of the forests over the grasslands in the biome. PMID- 25712880 TI - Environmental surveillance and molecular epidemiology of waterborne pathogen Legionella pneumophila in health-care facilities of Northeastern Greece: a 4-year survey. AB - A 4-year proactive environmental surveillance of Legionella spp. in the water distribution and cooling systems of five health-care facilities was carried out as part of the strategy for the prevention of hospital-acquired Legionnaires' disease in Northeastern Greece. Legionella spp. were detected in 71 out of 458 collected samples. The majority of strains belonged to Legionella pneumophila serogroups 2-15 (75.0%), while all L. pneumophila serogroup 1 strains (23.6%) were isolated from a single hospital. The highest percentage of positive samples was found in distal sites (19.4%), while no Legionella strains were detected in cooling systems. Each hospital was colonized at least once with L. pneumophila, while remedial actions resulted in significant reduction of Legionella concentration. The molecular epidemiology of environmental L. pneumophila strains was also investigated using random amplified polymorphic DNA (RAPD) and multi gene sequence-based analysis. Based on RAPD patterns, L. pneumophila serogroups 2 15 and serogroup 1 strains were classified into 24 and 9 operational taxonomic units (OTUs), respectively. Sequencing of housekeeping and diversifying pressure related genes recommended by European Working Group for Legionella Infections (EWGLI) revealed not only a high intraspecies variability but also the circulation and persistence of one specific genotyping profile in the majority of hospitals. This study highlights the necessity for diachronic surveillance of Legionella in health-care facilities by adopting both cultural and molecular methods. PMID- 25712881 TI - When are total concentrations not total? Factors affecting geochemical analytical techniques for measuring element concentrations in soil. AB - Inductively coupled plasma (ICP) following aqua regia digestion and X-ray fluorescence (XRF) are both geochemical techniques used to determine 'total' concentrations of elements in soil. The aim of this study is to compare these techniques, identify elements for which inconsistencies occur and investigate why they arise. A study area (~14,000 km(2)) with a variety of total concentration controls and a large geochemical dataset (n = 7950) was selected. Principal component analysis determined underlying variance in a dataset composed of both geogenic and anthropogenic elements. Where inconsistencies between the techniques were identified, further numerical and spatial analysis was completed. The techniques are more consistent for elements of geogenic sources and lead, whereas other elements of anthropogenic sources show less consistency within rural samples. XRF is affected by sample matrix, while the form of element affects ICP concentrations. Depending on their use in environmental studies, different outcomes would be expected from the techniques employed, suggesting the choice of analytical technique for geochemical analyses may be more critical than realised. PMID- 25712882 TI - Is soil dressing a way once and for all in remediation of arsenic contaminated soils? A case study of arsenic re-accumulation in soils remediated by soil dressing in Hunan Province, China. AB - The investigation of arsenic (As) re-accumulation in an area previously remediated by soil dressing will help in sustainable controlling the risks of As to local ecosystems and should influence management decisions about remediation strategies. In this study, As content in an area remediated by soil dressing and the possible As accumulation risk in agricultural products were investigated. The results indicated that after 7 years of agricultural activities, the average As content (24.6 mg kg(-1)) in surface soil of the investigated area increased by 83.6% compared with that (13.4 mg kg(-1)) in clean soil. Of the surface soil samples (n = 88), 21.6% had As levels that exceeded the limits of the Environmental Quality Standard for Soils of China (GB 15618-1995) and 98.9% of the surface soil samples with As contents exceeding that in clean soil was observed. Soil dressing might be not a remediation method once and for all in some contaminated areas, even though no significant difference in available As content was found between clean (0.18 mg kg(-1)) and surface (0.22 mg kg(-1)) soils. The foreign As in surface soil of the investigated area mainly specifically sorbed with soil colloid or associated with hydrous oxides of Fe and Al, or existed in residual fraction. The upward movement of contaminated soil from the deeper layers and the atmospheric deposition of slag particles might be responsible for the re-accumulation of As in the investigated area. Decreases in soil pH in the investigated soils and the fact that no plant samples had As levels exceeding the limits of the National Food Safety Standards for Contaminants of China (GB 2762-2012) were also observed. PMID- 25712883 TI - Enrichment of trace elements in the clay size fraction of mining soils. AB - Reactive waste dumps with sulfide minerals promote acid mine drainage (AMD), which results in water and soil contamination by metals and metalloids. In these systems, contamination is regulated by many factors, such as mineralogical composition of soil and the presence of sorption sites on specific mineral phases. So, the present study dedicates itself to understanding the distribution of trace elements in different size fractions (<2-mm and <2-MUm fractions) of mining soils and to evaluate the relationship between chemical and mineralogical composition. Cerdeirinha and Penedono, located in Portugal, were the waste dumps under study. The results revealed that the two waste dumps have high degree of contamination by metals and arsenic and that these elements are concentrated in the clay size fraction. Hence, the higher degree of contamination by toxic elements, especially arsenic in Penedono as well as the role of clay minerals, jarosite, and goethite in retaining trace elements has management implications. Such information must be carefully thought in the rehabilitation projects to be planned for both waste dumps. PMID- 25712884 TI - Identification and quantification of biomarkers and polycyclic aromatic hydrocarbons (PAHs) in an aged mixed contaminated site: from source to soil. AB - The sources of the spill and the contaminated soils of an aged oil spill contaminated site with unknown mixed pollutants were investigated by using a set of developed forensic chemical procedures which include analysis of oil products, site investigation, gas chromatography/mass spectrometry (GC/MS) screening, biomarker identification, and finally, the confirmation of pollutants. Adamantanes (17 compounds), 10 bicyclic sesquiterpanes, 6 newly detected compounds, 16 polycyclic aromatic hydrocarbons, and 10 alkylated naphthalenes compounds in several gasoline, diesel oil samples, and contaminated soil samples were examined and quantified. GC/MS method, retention indices, relative response factors, and diagnostic ratio were used to identify and quantify pollutant compounds. The study revealed the key factors for distinguishing among gasoline and diesel oil products in the market, created a new set of retention indices for 10 bicyclic sesquiterpane compounds, and discovered 6 quantifiable compounds in analysis of fresh oil products. The suggested diagnostic ratios for BSs and the new compounds in the analysis of the biomarker show the differences among diesel products, link between the source of pollutants with contaminated soil, and the recognition of the signs of an aged spill, and the indications of weathering effects. PMID- 25712886 TI - The Involvement of Serotonin in the Hypoglycemic Effects Produced by Administration of the Aqueous Extract of Xylaria nigripes with Steroid-Induced Insulin-Resistant Rats. AB - Xylaria nigripes (XN) is a medicinal fungus with a high-economic value. The aim of this study was to explore the hypoglycemic effects and mechanisms of the XN aqueous extract in steroid-induced insulin-resistant (SIIR) rats. Significant hypoglycemic effects were observed 60 min after administration of XN aqueous extract. In normal Wistar, hypoglycemic effects were 21% (the plasma glucose level decreased from 128.6 +/- 12.5 to 100.9 +/- 10.7 mg/dL). In SIIR, hypoglycemic effects were 26% (the plasma glucose level decreased from 177.6 +/- 12.5 to 133.3 +/- 29.7 mg/dL) rats refer to their baseline. The signaling proteins for insulin-receptor substrate-1 and glucose transporter-4 increased 0.51-fold and 1.12-fold, respectively, as determined by Western blotting; the increase in the proteins was 13% and 9%, respectively, as determined by immunohistochemistry. The serotonin antagonist, alpha-p-chlorophenylalanine, effectively blocked the hypoglycemic effects and increased the signaling protein levels. After XN administration, none of the animals showed significant changes in plasma-free fatty acids in 60 min. In summary, the XN extract may have hypoglycemic effects in normal Wistar and SIIR rats that may have a serotonin related hypoglycemic effect and enhance insulin sensitivity in the SIIR rats. PMID- 25712885 TI - Exploring Actinobacteria assemblages in coastal marine sediments under contrasted Human influences in the West Istria Sea, Croatia. AB - The exploration of marine Actinobacteria has as major challenge to answer basic questions of microbial ecology that, in turn, will provide useful information to exploit Actinobacteria metabolisms in biotechnological processes. The ecological functions performed by Actinobacteria in marine sediments are still unclear and belongs to the most burning basic questions. The comparison of Actinobacteria communities inhabiting marine sediments that are under the influence of different contamination types will provide valuable information in the adaptation capacities of Actinobacteria to colonize specific ecological niche. In the present study, the characterization of different Actinobacteria assemblages according to contamination type revealed the ecological importance of Actinobacteria for maintaining both general biogeochemical functions through a "core" Actinobacteria community and specific roles associated with the presence of contaminants. Indeed, the results allowed to distinguish Actinobacteria genera and species operational taxonomic units (OTUs) able to cope with the presence of either (i) As, (ii) metals Ni, Fe, V, Cr, and Mn, or (iii) polycyclic aromatic hydrocarbons (PAHs) and toxic metals (Hg, Cd, Cu, Pb, and Zn). Such observations highlighted the metabolic capacities of Actinobacteria and their potential that should be taken into consideration and advantage during the implementation of bioremediation processes in marine ecosystems. PMID- 25712887 TI - Effects of CYP2C9*1/*3 genotype on the pharmacokinetics of flurbiprofen in Korean subjects. AB - The aim of this study was to investigate the impact of CYP2C9*1/*3 genotype on the pharmacokinetics of flurbiprofen and its metabolite. The CYP2C9 genotypes were determined with the use of polymerase chain reaction and restriction fragment and DNA sequencing analysis in 358 healthy Koreans. Among them, twenty individuals with CYP2C9*1/*1 (n = 12) or CYP2C9*1/*3 (n = 8) genotypes received a single 40 mg oral dose of flurbiprofen. The plasma concentrations of flurbiprofen and its metabolite, 4'-hydroxyflurbiprofen were measured by HPLC. AUCinf of flurbiprofen was significantly higher and its clearance was significantly lower in the CYP2C9*1/*3 individuals than in those with CYP2C9*1/*1. The AUC ratio of 4'-hydroxyflurbiprofen to flurbiprofen was significantly lower in the CYP2C9*1/*3 individuals than in those with CYP2C9*1/*1. These results indicate that the individuals carrying of CYP2C9*3 have significant reduction in flurbiprofen metabolism. The clinical use of this information may allow for more efficient personalized pharmacotherapy. PMID- 25712888 TI - Inhibition of matrix metalloproteinase-13 expression in IL-1beta-treated articular chondrocytes by a steroidal saponin, spicatoside A, and its cellular mechanisms of action. AB - Matrix metalloproteinase-13 (MMP-13) plays a critical role in degrading major collagens in human cartilage under some pathological conditions such as osteoarthritis. To establish the therapeutic potential against cartilage degradation, the effects of 12 naturally-occurring triterpenoids and steroids on MMP-13 induction were examined in the human chondrocyte cell line, SW1353. They included coreanoside F1, suavissimoside R1, spicatoside A, 25(S)-ruscogenin, methyl protogracillin, hederagenin, loniceroside A, loniceroside B, loniceroside C, smilaxin A, smilaxin C, and ursolic acid. Among these, only spicatoside A and 25(S)-ruscogenin were found to inhibit MMP-13 expression in IL-1beta-treated SW1353 cells at a pharmacologically-relevant concentration of 10 MUM. These effects were also supported by the finding that spicatoside A (20 MUM) reduced glycosaminoglycan release from IL-1alpha-treated rabbit joint cartilage culture to some degree. When the cellular mechanisms of action of spicatoside A in MMP-13 inhibition were investigated, the blocking point was not found among the MMP-13 signaling molecules examined such as mitogen-activated protein kinases, activator protein-1, and nuclear transcription factor-kappaB. Instead, spicatoside A was found to reduce MMP-13 mRNA stability. All of these findings suggest that spicatoside A and 25(S)-ruscogenin have a therapeutic potential for protecting against cartilage breakdown in arthritic disorders. PMID- 25712890 TI - [Innovative healthcare strategies in geriatric psychiatry and psychotherapy]. AB - BACKGROUND: The development of efficacious treatment strategies in older adults with mental illnesses is necessary. The growing number of homebound patients and the incidence of physical comorbidities and impairment of activities of daily living are important factors for interdisciplinary treatment strategies in old age and there is a need for home-based services providing medical and psychosocial interventions. OBJECTIVE: Recent studies have provided information on home-based and collaborative treatment strategies in mentally ill elderly patients. METHODS: This article provides an overview on selected randomized controlled trials (RCT) conducted with mentally ill older adults. RESULTS: Studies have shown promising effects when applying stepped care interventions, collaborative care and assertive community treatment in old patients suffering from mental diseases when compared to usual care. Long-standing home-based mental health programs have been designed and successfully implemented showing improved identification, treatment and ongoing care of mental health problems. In-home tele-psychotherapy has been shown to be efficacious in homebound older adults with limited access to evidence-based psychotherapy and showed a sustained effect in one study. CONCLUSION: Collaborative care models, stepped care interventions in primary care settings and an enhanced inter-professional approach to patient care in old age psychiatry is necessary to improve detection, treatment and ongoing care. Tele-mental health services may become important parts of the provision of mental health services and the effectiveness revealed for in-home tele-health problem solving therapy in old age depression may be an approach to make psychotherapy available to a large number of underserved elderly patients with mental illness. PMID- 25712889 TI - Synthesis and evaluation of new salicylaldehyde-2-picolinylhydrazone Schiff base compounds of Ru(II), Rh(III) and Ir(III) as in vitro antitumor, antibacterial and fluorescence imaging agents. AB - Reaction of salicylaldehyde-2-picolinylhydrazone (HL) Schiff base ligand with precursor compounds [{(p-cymene)RuCl2}2] 1, [{(C6H6)RuCl2}2] 2, [{Cp*RhCl2}2] 3 and [{Cp*IrCl2}2] 4 yielded the corresponding neutral mononuclear compounds 5-8, respectively. The in vitro antitumor evaluation of the compounds 1-8 against Dalton's ascites lymphoma (DL) cells by fluorescence-based apoptosis study and by their half-maximal inhibitory concentration (IC50) values revealed the high antitumor activity of compounds 3, 4, 5 and 6. Compounds 1-8 render comparatively lower apoptotic effect than that of cisplatin on model non-tumor cells, i.e., peripheral blood mononuclear cells (PBMC). The antibacterial evaluation of compounds 5-8 by agar well-diffusion method revealed that compound 6 is significantly effective against all the eight bacterial species considered with zone of inhibition up to 35 mm. Fluorescence imaging study of compounds 5-8 with plasmid circular DNA (pcDNA) and HeLa RNA demonstrated their fluorescence imaging property upon binding with nucleic acids. The docking study with some key enzymes associated with the propagation of cancer such as ribonucleotide reductase, thymidylate synthase, thymidylate phosphorylase and topoisomerase II revealed strong interactions between proteins and compounds 5-8. Conformational analysis by density functional theory (DFT) study has corroborated our experimental observation of the N, N binding mode of ligand. Compounds 5-8 exhibited a HOMO (highest occupied molecular orbital)-LUMO (lowest unoccupied molecular orbital) energy gap 2.99-3.04 eV. Half-sandwich ruthenium, rhodium and iridium compounds were obtained by treatment of metal precursors with salicylaldehyde-2 picolinylhydrazone (HL) by in situ metal-mediated deprotonation of the ligand. Compounds under investigation have shown potential antitumor, antibacterial and fluorescence imaging properties. Arene ruthenium compounds exhibited higher activity compared to that of Cp*Rh/Cp*Ir in inhibiting the cancer cells growth and pathogenic bacteria. At a concentration 100 ug/mL, the apoptosis activity of arene ruthenium compounds, 5 and 6 (~30 %) is double to that of Cp*Rh/Cp*Ir compounds, 7 and 8 (~12 %). Among the four new compounds 5-8, the benzene ruthenium compound, i.e., compound 6 is significantly effective against the pathogenic bacteria under investigation. PMID- 25712891 TI - G551D-CFTR needs more bound actin than wild-type CFTR to maintain its presence in plasma membranes. AB - Cystic Fibrosis is due to mutations in the CFTR gene. The missense mutation G551D (approx. 5% of cases) encodes a CFTR chloride channel with normal cell surface expression but with an altered chloride channel activity, leading to a severe phenotype. Our aim was to identify specific interacting proteins of G551D-CFTR which could explain the channel defect. Wild-type CFTR (Wt-CFTR) was co immunoprecipitated from stably transfected HeLa cells and resolved by 2D gel electrophoresis. Among the detected spots, one was expressed at a high level. Mass Spectrometry revealed that it corresponded to actin which is known to be involved in the CFTR's channel function. To assess whether actin could be involved in the altered G551D-CFTR function, its basal expression was studied. Because actin expression was the same in wt- and in G551D-CFTR expressing cells, its interaction with both wt- and G551D-CFTR was studied by co immunoprecipitation, and we found that a higher amount of actin was bound onto G551D-CFTR than onto Wt-CFTR. The role of actin upon wt- and G551D-CFTR function was further studied by patch-clamp experiments after cytochalasin D treatment of the cells. We found a decrease of the very weak currents in G551D-CFTR expressing cells. Because a higher amount of actin is bound onto G551D-CFTR than onto Wt CFTR, it is likely to be not involved in the mutated CFTR's defect. Nevertheless, because actin is necessary to maintain the very weak global currents observed in G551D-CFTR expressing HeLa cells, we conclude that more actin is necessary to maintain G551D-CFTR in the plasma membrane than for Wt-CFTR. PMID- 25712892 TI - Arg72Pro polymorphism of p53 may predict poor response to medical treatment in ulcerative colitis. AB - AIM: Arg72Pro is a polymorphism commonly occurring in the proline-rich domain of Tp53. It can determine the development of different types of cancers, such as breast, lung, cervical, colorectal and hepatocellular carcinoma. Previous studies reported a correlation between Pro72 homozygosity and the clinical course of ulcerative colitis (UC). Our aim was to evaluate Arg72Pro genotype in patients who underwent proctocolectomy with ileo-pouch-anal anastomosis (IPAA) for UC compared with those who did not need surgery. MATERIAL OF STUDY: The distribution of the different genotype of Arg72Pro was studied in 264 (234 medically treated [MT] and 30 IPAA) patients affected with UC observed between 2008 and 2011. IPAA patients underwent restorative proctocolectomy for refractory UC; MT ones were managed medically. Blood samples for genotyping were collected from all patients. Arg72Pro genotype analysis was carried out by polymerase chain reaction confronting two-pair primers (PCR-CTPP). RESULTS: In MT patients (n=234) Arg/Arg, Arg/Pro and Pro/Pro frequencies were 51.28%, 41.02% and 7.7%, respectively, while in IPAA patients (n=30) were 53.4%, 23.3% and 23.3%, respectively. A statistically significant association was found between Pro/Pro and need for surgery (p=<0.0059, chi =7.59). CONCLUSION: Our results showed that the Pro/Pro genotype was higher in IPAA (23.3%) than in MT (7.7%) patients. In UC patients the proline homozygosity identifies likeliness to resist to any standard pharmacologic therapy. It could potentially identify patients who would benefit from early surgical treatment, thereby reducing the rate of emergency colectomies and complications related to them. KEY WORDS: Arg72Pro, Arg72Pro polymorphism, Ileopouch-anal anastomosis, IPAA, p53 polymorphism, Ulcerative colitis. PMID- 25712894 TI - Ultra-flexible, "invisible" thin-film transistors enabled by amorphous metal oxide/polymer channel layer blends. AB - Ultra-flexible and transparent metal oxide transistors are developed by doping In2 O3 films with poly(vinylphenole) (PVP). By adjusting the In2 O3 :PVP weight ratio, crystallization is frustrated, and conducting pathways for efficient charge transport are maintained. In2 O3 :5%PVP-based transistors exhibit mobilities approaching 11 cm(2) V(-1) s(-1) before, and retain up to ca. 90% performance after 100 bending/relaxing cycles at a radius of 10 mm. PMID- 25712893 TI - BRAF mutation is not predictive of long-term outcome in papillary thyroid carcinoma. AB - The BRAF mutation occurs commonly in papillary thyroid carcinoma (PTC). Previous investigations of its utility to predict recurrence-free survival (RFS) and disease-specific survival (DSS) have reported conflicting results and its role remains unclear. The purpose of this retrospective study was to determine the incidence of the BRAF mutation and analyze its relationship to clinicopathologic risk factors and long-term outcomes in the largest, single-institution American cohort to date. BRAF mutational status was determined in 508 PTC patients using RFLP analysis. The relationships between BRAF mutation status, patient and tumor characteristics, RFS, and DSS were analyzed. The BRAF mutation was present in 67% of patients. On multivariate analysis, presence of the mutation predicted only for capsular invasion (HR, 1.7; 95% CI, 1.1-2.6), cervical lymph node involvement (HR, 1.7; 95% CI, 1.1-2.7), and classic papillary histology (HR, 1.8; 95% CI 1.1 2.9). There was no significant relationship between the BRAF mutation and RFS or DSS, an observation that was consistent across univariate, multivariate, and Kaplan-Meier analyses. This is the most extensive study to date in the United States to demonstrate that BRAF mutation is of no predictive value for recurrence or survival in PTC. We found correlations of BRAF status and several clinicopathologic characteristics of high-risk disease, but limited evidence that the mutation correlates with more extensive or aggressive disease. This analysis suggests that BRAF is minimally prognostic in PTC. However, prevalence of the BRAF mutation is 70% in the general population, providing the opportunity for targeted therapy. PMID- 25712895 TI - Increased frequency and changed methods in the treatment of sea lice (Lepeophtheirus salmonis) in Scottish salmon farms 2005-2011. AB - BACKGROUND: The sea louse is the most economically and environmentally serious ectoparasite of marine salmonids. Sea lice have been largely controlled by treatment with a variety of medicines. In order to understand the sustainability of medicine usage, an analysis of sea louse treatment data has been carried out for all Scottish salmon farms from 2005 to 2011. RESULTS: Overall, there was an increase from 0.156 to 0.282 treatments month(-1) ; treatments could involve one or multiple agents. This increase was mostly in bath treatments (cypermethrin in 2007, largely replaced by deltamethrin and azamethiphos in 2008). Treatments using in-feed treatments (emamectin benzoate and teflubenzuron) increased only slowly. Treatments involving more than one medicine in a single month also increased, as did the probability of follow-up treatments. Treatments were seasonal, with peaks of in-feed treatments in March and August and bath treatments more frequent between August and December. CONCLUSION: Frequency of sea louse treatment increased substantially, with an increase in multiagent and follow-up treatments. This increase in treatment activity is expensive to the industry and increases exposure of the neighbouring environment. This indicates that earlier louse control practices were not sustainable and so adapted. PMID- 25712896 TI - TNF-alpha down-regulates sarcoplasmic reticulum Ca2+ ATPase expression and leads to left ventricular diastolic dysfunction through binding of NF-kappaB to promoter response element. AB - AIMS: TNF-alpha (TNF-alpha) causes left ventricular diastolic dysfunction. Down regulation of sarcoplasmic reticulum Ca(2+)-ATPase 2a protein (SERCA2a) expression is one of the major mechanisms underlying diastolic dysfunction. We investigated whether TNF-alpha modulates SERCA2a expression and alters cardiac diastolic function, and its detailed signalling pathway. METHODS AND RESULTS: We used both in vitro cellular cardiomyocyte model and in vivo rat model to address this issue. We found that TNF-alpha decreased the levels of both SERCA2a mRNA and protein in the cardiomyocytes, with corresponding impairment of diastolic calcium reuptake, a cellular phenotype of cardiac diastolic function. An ~2 kb promoter of the SERCA2a gene (atp2a2) along with its serial deletions was cloned into the luciferase reporter system. TNF-alpha significantly decreased the promoter activity, and truncation of the SERCA2a gene promoter with the putative nuclear factor kappa-B (NF-kappaB) response element abolished TNF-alpha-induced SERCA2a gene suppression. Chromatin immunoprecipitation and gel retardation also confirmed the binding of NF-kappaB to this putative-binding site. TNF-alpha increased the phosphorylation of IKK and the degradation of IkappaB, resulted in NF-kappaB nuclear translocation, and decreased SERCA2a gene promoter activity. This process was attenuated by NF-kappaB blockers and simvastatin. In the in vivo rat model, lipopolysaccharide treatment significantly elevated the serum TNF alpha level, as well as phosphorylation of IKK, resulting in a decrease in myocardial SERCA2a expression, diastolic calcium reuptake, and diastolic dysfunction. Oral treatment with simvastatin led to an increase in SERCA2a expression, alleviation, and prevention of the diastolic dysfunction. CONCLUSIONS: TNF-alpha suppresses SERCA2a gene expression via the IKK/IkappaB/NF kappaB pathway and binding of NF-kappaB to the SERCA2a gene promoter, and its effect is blocked by simvastatin, demonstrating the potential therapeutic effect of statins in treating inflammation-related diastolic dysfunction. PMID- 25712897 TI - Therapeutic effectiveness of bone marrow-derived mesenchymal stem cell administration against acute pulmonary thromboembolism in a mouse model. AB - INSTRUCTION: Acute pulmonary thromboembolism (APTE) is a common clinical condition associated with significant morbidity and mortality. Although promising, bone marrow-derived mesenchymal stem cell (BMSC) treatment for thrombus resolution remains controversial. The therapeutic effectiveness of BMSC against APTE has not been evaluated. This study aims to determine whether BMSCs administration is effective in mouse model. MATERIALS AND METHODS: Therapeutic efficacy of female and male BMSCs were evaluated by applying serial sectioning analysis method for the whole lungs of APTE mice and calculating each thrombus size in volume. Plasmid construction and stable transfection were used to manipulate expression of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in both genders of BMSCs. Western blot were performed to detect GAPDH and urokinase plasminogen activator expression in BMSCs. RESULTS: Our data showed, 1) compared with non-serial sectioning method, the serial sectioning method detected more thrombi, larger size ranges of thrombus area, and the volume of each individual thrombus. 2) BMSCs significantly decreased the thrombi size in APTE mice, with female BMSCs superior to male ones. 3) female BMSCs showed a higher GAPDH protein level and manipulations of GAPDH expression in female or male BMSCs profoundly affected their therapeutic efficacies as well as urokinase plasminogen activator expression. CONCLUSION: This study indicates serial-sectioning analysis method is necessary for evaluating APTE and provides strong evidences for BMSCs possessing therapeutic effectiveness against APTE, with female BMSCs superior to male counterparts. GAPDH played a critical role in the superior function of female BMSCs, possibly by regulating the expression of urokinase plasminogen activator. PMID- 25712898 TI - The water deprivation test and a potential role for the arginine vasopressin precursor copeptin to differentiate diabetes insipidus from primary polydipsia. AB - The water deprivation test is the gold standard test to differentiate central or nephrogenic diabetes insipidus (DI) from primary polydipsia (PP) in patients with polyuria and polydipsia. Few studies have addressed the diagnostic performance of this test. The aim of this retrospective cohort study was to evaluate the diagnostic performance of the standard water deprivation test, including plasma arginine vasopressin (AVP) measurements, in 40 consecutive patients with polyuria. We compared initial test results with the final clinical diagnosis, i.e., no DI, central DI, or nephrogenic DI. The median length of follow-up was 8 years. In a subset of ten patients, the novel marker copeptin (CP) was measured in plasma. Using the final diagnosis as a gold standard, a threshold for urine osmolality of >800 mOsmol/kg after water deprivation yielded a sensitivity and specificity of 96 and 100%, respectively, for diagnosing PP. Sensitivity increased to 100% if the cut-off value for urine osmolality was set at 680 mOsmol/kg. Plasma AVP levels did not differ between patient groups and did not differentiate among central DI, nephrogenic DI, or PP. In all three patients with central DI, plasma CP was <2.5 pmol/l with plasma osmolality >290 mOsmol/kg, and >2.5 pmol/l in patients without DI. The optimal cut-off value for differentiating PP from DI during a water deprivation test was urine osmolality >680 mOsmol/kg. Differentiating between central and nephrogenic DI should be based on clinical judgment as AVP levels did not discriminate. PMID- 25712899 TI - Intensive glycaemic control and cognitive decline in patients with type 2 diabetes: a meta-analysis. AB - The aim of this meta-analysis was to compare the effect of intensive vs standard glycaemic control on cognitive decline in type 2 diabetic patients. A systematic search of PubMed and ALOIS was conducted from inception up to October 30, 2014. Randomised controlled trials (RCTs) of type 2 diabetic patients comparing the rate of change in cognitive function among participants assigned to intensive vs standard glycaemic control were included. An inverse-variance-weighted random effects model was used to calculate standardised mean differences (SMDs) and 95% CIs. A total of 24 297 patients from five RCTs were included in the meta analysis. Follow-up ranged from 3.3 to 6.2 years. The result from the pooled analysis showed that intensive glycaemic control was not associated with a slower rate of cognitive decline in patients with type 2 diabetes, compared with standard glycaemic control (SMD=0.02; 95% CI=-0.03 to 0.08) although there was some heterogeneity across individual studies (I(2)=68%, P for heterogeneity=0.01). There are few diabetes control trials including cognitive endpoints and a small number of trials comparing intensive and standard treatment strategies. Currently, intensive glycaemic control should not be recommended for prevention of cognitive decline in patients with type 2 diabetes because there is no evidence of its effectiveness. Moreover, the use of intensive diabetes treatment results in an increase of risk of hypoglycaemia, which is linked to a greater risk of poor cognition. PMID- 25712900 TI - A herpes-like virus in king crabs: Characterization and transmission under laboratory conditions. AB - A herpes-like virus was found infecting the antennal gland and bladder epithelium in the blue king crab Paralithodes platypus from the eastern area of the Sea of Okhotsk. Electron microscopic analysis of antennal gland samples from blue king crabs with histologically confirmed signs of disease revealed virus particles, which were mostly hexagonal in shape and located primarily in the nucleus; these particles were rarely observed in the cytoplasm of infected cells. Most virus particles ranged in size from 115 to 125nm. Hemocytes of the red king crab Paralithodes camtschaticus in cell culture could be experimentally infected with virus from thawed antennal gland samples of the blue king crabs with histologically confirmed signs of viral infection. Clear signs of infection were observed in hemocyte cultures at 3-4days post-inoculation as small foci of highly vacuolated formations. These formations included several nuclei and were surrounded by a halo of small cytoplasmic bubbles containing actin and tubulin. As demonstrated by electron microscopic studies, no virus-like particles were found in the cells 1day post-inoculation, but particles become abundant at 7days post-inoculation. We developed a consensus primer PCR method for amplification of a region of the herpesviral DNA-directed DNA polymerase. Primers were designed to target sequences encoding highly conserved amino acid motifs covering a region of approximately 800bp. Thus, macroscopic, histological and ultra-structural examinations of blue king crabs infected with a virus and the molecular identification of the pathogen revealed the presence of herpesviruses. The frequency of the herpes-like viral infection in natural populations of blue king crabs in the Sea of Okhotsk ranged from 0% to 3% in different years. PMID- 25712901 TI - Synthesis and characterization of ZnS with controlled amount of S vacancies for photocatalytic H2 production under visible light. AB - Controlling amount of intrinsic S vacancies was achieved in ZnS spheres which were synthesized by a hydrothermal method using Zn and S powders in concentrated NaOH solution with NaBH4 added as reducing agent. These S vacancies efficiently extend absorption spectra of ZnS to visible region. Their photocatalytic activities for H2 production under visible light were evaluated by gas chromatograph, and the midgap states of ZnS introduced by S vacancies were examined by density functional calculations. Our study reveals that the concentration of S vacancies in the ZnS samples can be controlled by varying the amount of the reducing agent NaBH4 in the synthesis, and the prepared ZnS samples exhibit photocatalytic activity for H2 production under visible-light irradiation without loading noble metal. This photocatalytic activity of ZnS increases steadily with increasing the concentration of S vacancies until the latter reaches an optimum value. Our density functional calculations show that S vacancies generate midgap defect states in ZnS, which lead to visible-light absorption and responded. PMID- 25712902 TI - Psychiatric disorders in children with Prader-Willi syndrome-Results of a 2-year longitudinal study. AB - Psychiatric disorders such as psychosis are highly prevalent in adults with Prader-Willi syndrome (PWS). However, knowledge about the presence and progression of psychiatric disorders in children with PWS is very limited. Sixty one children with PWS aged 7-17 years were tested using the Diagnostic Interview Schedule for Children (DISC) and Compulsive Behaviour Checklist (CBC), and 38/61 were retested after 2 years. Prevalence of psychiatric disorders and the association with age, gender, genetic subtype, and total IQ were assessed. In addition, occurrence and characteristics of compulsions were determined. Prior to the study, two boys were known with psychotic symptoms and treated with antipsychotics. At baseline, none scored positive for psychotic disorder. During the follow-up, only one boy with known psychotic symptoms required a dose adjustment of his antipsychotic medication. After 2 years, none of the children had a psychotic disorder according to the DISC. Oppositional defiant disorder (ODD) was the most common diagnosis and present in 20% of children with PWS, and this was not associated with age (beta = -0.081, P = 0.546), gender (beta = 0.013, P = 0.923), genetic subtype (beta = -0.073, P = 0.584), or total IQ (beta = -0.150, P = 0.267). The most common compulsions were hoarding and fixed hygiene sequences. In our large group of 61 children with PWS, the majority had no psychotic disorder and no progression was found during 2-year follow-up. ODD was present in 20% of children. No changes in the prevalence of psychiatric disorders were found during the 2-year follow-up study and genetic subtype was not related to psychosis, depression, or ODD. PMID- 25712903 TI - Energy transfer during freeze-drying in dual-chamber cartridges. AB - Freeze-drying essentially requires knowledge about the heat and mass transfer characteristics to assure product quality. Whereas this understanding has been created for freeze-drying in vials, only limited information is available for state-of-the-art multiple compartment container systems such as dual-chamber cartridges (DCCs). Therefore, the aim of this study was to investigate the heat transfer characteristics of this novel container format. Sublimation tests were carried out using pure water at 60, 100, 150, and 200 mTorr chamber pressure at a shelf temperature of 0 degrees C. Custom-made aluminum blocks were used as holder systems. Two heat transfer coefficients could be identified: the coefficient characterizing heat transfer between shelf and block, KAl , and between block and cartridge, KDCC . KAl was dependent on all three modes of heat transfer: contact conduction, gas conduction, and radiation. For KDCC , contact conduction was negligible. Radiation strongly influenced the overall energy transfer as it is the major mode of heat transfer for KDCC and contributes up to 44% to KAl . A third coefficient, Ktot , was defined as an overall heat transfer coefficient. This knowledge about heat transfer enables a purposeful development and control of optimized lyophilization processes for this novel container system. PMID- 25712904 TI - Mechanical basis of osmosensory transduction in magnocellular neurosecretory neurones of the rat supraoptic nucleus. AB - Rat magnocellular neurosecretory cells (MNCs) release vasopressin and oxytocin to promote antidiuresis and natriuresis at the kidney. The osmotic control of oxytocin and vasopressin release at the neurohypophysis is required for osmoregulation in these animals, and this release is mediated by a modulation of the action potential firing rate by the MNCs. Under basal (isotonic) conditions, MNCs fire action potentials at a slow rate, and this activity is inhibited by hypo-osmotic conditions and enhanced by hypertonicity. The effects of changes in osmolality on MNCs are mediated by a number of different factors, including the involvement of synaptic inputs, the release of taurine by local glial cells and regulation of ion channels expressed within the neurosecretory neurones themselves. We review recent findings that have clarified our understanding of how osmotic stimuli modulate the activity of nonselective cation channels in MNCs. Previous studies have shown that osmotically-evoked changes in membrane potential and action potential firing rate in acutely isolated MNCs are provoked mainly by a modulation of nonselective cation channels. Notably, the excitation of isolated MNCs during hypertonicity is mediated by the activation of a capsaicin-insensitive cation channel that MNCs express as an N-terminal variant of the transient receptor potential vanilloid 1 (Trpv1) channel. The activation of this channel during hypertonicity is a mechanical process associated with cell shrinking. The effectiveness of this mechanical process depends on the presence of a thin layer of actin filaments (F-actin) beneath the plasma membrane, as well as a densely interweaved network of microtubules (MTs) occupying the bulk of the cytoplasm of MNCs. Although the mechanism by which F-actin contributes to Trpv1 activation remains unknown, recent data have shown that MTs interact with Trpv1 channels via binding sites on the C-terminus, and that the force mediated through this complex is required for channel gating during osmosensory transduction. Indeed, displacement of this interaction prevents channel activation during shrinking, whereas increasing the density of these interaction sites potentiates shrinking-induced activation of Trpv1. Therefore, the gain of the osmosensory transduction process can be regulated bi-directionally through changes in the organisation of F-actin and MTs. PMID- 25712905 TI - Investigating inter-segmental connections between thoracic ganglia in the stick insect by means of experimental and simulated phase response curves. AB - The neuronal networks that control the motion of the individual legs in insects, in particular in the stick insect, are located in the pro-, meso- and meta thoracic ganglia. They ensure high flexibility of movement control. Thus, the legs can move in an apparently independent way, e.g., during search movements, but also in tight coordination during locomotion. The latter is evidently a very important behavioural mode. It has, therefore, inspired a large number of studies, all aiming at uncovering the nature of the inter-leg coordination. One of the basic questions has been as to how the individual control networks in the three thoracic ganglia are connected to each other. One way to study this problem is to use phase response curves. They can reveal properties of the coupling between oscillatory systems, such as the central pattern generators in the control networks in the thoracic ganglia. In this paper, we report results that we have achieved by means of a combined experimental and modelling approach. We have calculated phase response curves from data obtained in as yet unpublished experiments as well as from those in previously published ones. By using models of the connected pro- and meso-thoracic control networks of the protractor and retractor neuromuscular systems, we have also produced simulated phase response curves and compared them with the experimental ones. In this way, we could gain important information of the nature of the connections between the aforementioned control networks. Specifically, we have found that connections from both the protractor and the retractor "sides" of the pro-thoracic network to the meso thoracic one are necessary for producing phase response curves that show close similarity to the experimental ones. Furthermore, the strength of the excitatory connections has been proven to be crucial, while the inhibitory connections have essentially been irrelevant. We, thus, suggest that this type of connection might also be present in the stick insect, and possibly in other insect species. PMID- 25712906 TI - The use of biosimilar drugs in psoriasis: a position paper. PMID- 25712907 TI - A new arylalkylamine N-acetyltransferase in silkworm (Bombyx mori) affects integument pigmentation. AB - Dopamine is a precursor for melanin synthesis. Arylalkylamine N-acetyltransferase (AANAT) is involved in the melatonin formation in insects because it could catalyze the transformation from dopamine to dopamine-N-acetyldopamine. In this study, we identified a new AANAT gene in the silkworm (Bombyx mori) and assessed its role in the silkworm. The cDNA of this gene encodes 233 amino acids that shares 57 % amino acid identity with the Bm-iAANAT protein. We thus refer to this gene as Bm-iAANAT2. To investigate the role of Bm-iAANAT2, we constructed a transgenic interference system using a 3xp3 promoter to suppress the expression of Bm-iAANAT2 in the silkworm. We observed that melanin deposition occurs in the head and integument in transgenic lines. To verify the melanism pattern, dopamine content and the enzyme activity of AANAT were determined by high-performance liquid chromatography (HPLC). We found that an increase in dopamine levels affects melanism patterns on the heads of transgenic B. mori. A reduction in the enzyme activity of AANAT leads to changes in dopamine levels. We analyzed the expression of the Bm-iAANAT2 genes by qPCR and found that the expression of Bm iAANAT2 gene is significantly lower in transgenic lines. Our results lead us to conclude that Bm-iAANAT2 is a new arylalkylamine N-acetyltransferase gene in the silkworm and is involved in the metabolism of the dopamine to avoid the generation of melanin. PMID- 25712908 TI - Evaluation of Mut(S) and Mut+ Pichia pastoris strains for membrane-bound catechol O-methyltransferase biosynthesis. AB - Catechol-O-methyltransferase (COMT, EC 2.1.1.6) is an enzyme that catalyzes the methylation of catechol substrates, and while structural and functional studies of its membrane-bound isoform (MBCOMT) are still hampered by low recombinant production, Pichia pastoris has been described as an attractive host for the production of correctly folded and inserted membrane proteins. Hence, in this work, MBCOMT biosynthesis was developed using P. pastoris X33 and KM71H cells in shake flasks containing a semidefined medium with different methanol concentrations. Moreover, after P. pastoris glass beads lysis, biologically and immunologically active hMBCOMT was found mainly in the solubilized membrane fraction whose kinetic parameters were identical to its correspondent native enzyme. In addition, mixed feeds of methanol and glycerol or sorbitol were also employed, and its levels quantified using liquid chromatography coupled to refractive index detection. Overall, for the first time, two P. pastoris strains with opposite phenotypes were applied for MBCOMT biosynthesis under the control of the strongly methanol-inducible alcohol oxidase (AOX) promoter. Moreover, this eukaryotic system seems to be a promising approach to deliver MBCOMT in high quantities from fermentor cultures with a lower cost-benefit due to the cheaper cultivation media coupled with the higher titers tipically achieved in biorreactors, when compared with previously reported mammallian cell cultures. PMID- 25712909 TI - Development of PCR-based technique for detection of purity of Pashmina fiber from textile materials. AB - Pashmina fiber is one of major specialty animal fiber in India. The quality of Pashmina obtained from Changthangi and Chegu goats in India is very good. Due to restricted availability and high prices, adulteration of natural prized fibers is becoming a common practice by the manufacturers. Sheep wool is a cheap substitute, which is usually used for adulteration and false declaration of Pashmina-based products. Presently, there is lack of cost-effective and readily available methodology to identify the adulteration of Pashmina products from other similar looking substitutes like sheep wool. Polymerase chain reaction (PCR)-based detection method can be used to identify origin of animal fiber. Extraction of quality DNA from dyed and processed animal fiber and textile materials is a limiting factor in the development of such detection methods. In the present study, quality DNA was extracted from textile materials, and PCR based technique using mitochondrial gene (12S rRNA) specific primers was developed for detection of the Pashmina in textile blends. This technique has been used for detection of the adulteration of the Pashmina products with sheep wool. The technique can detect adulteration level up to 10 % of sheep/goat fibers in textile blends. PMID- 25712910 TI - Cytotoxicity of Ultrasmall Gold Nanoparticles on Planktonic and Biofilm Encapsulated Gram-Positive Staphylococci. AB - The emergence of multidrug resistant bacteria, especially biofilm-associated Staphylococci, urgently requires novel antimicrobial agents. The antibacterial activity of ultrasmall gold nanoparticles (AuNPs) is tested against two gram positive: S. aureus and S. epidermidis and two gram negative: Escherichia coli and Pseudomonas aeruginosa strains. Ultrasmall AuNPs with core diameters of 0.8 and 1.4 nm and a triphenylphosphine-monosulfonate shell (Au0.8MS and Au1.4MS) both have minimum inhibitory concentration (MIC) and minimum bactericidal concentration of 25 * 10(-6) m [Au]. Disc agar diffusion test demonstrates greater bactericidal activity of the Au0.8MS nanoparticles over Au1.4MS. In contrast, thiol-stabilized AuNPs with a diameter of 1.9 nm (AuroVist) cause no significant toxicity in any of the bacterial strains. Ultrasmall AuNPs cause a near 5 log bacterial growth reduction in the first 5 h of exposure, and incomplete recovery after 21 h. Bacteria show marked membrane blebbing and lysis in biofilm-associated bacteria treated with ultrasmall AuNP. Importantly, a twofold MIC dosage of Au0.8MS and Au1.4MS each cause around 80%-90% reduction in the viability of Staphylococci enveloped in biofilms. Altogether, this study demonstrates potential therapeutic activity of ultrasmall AuNPs as an effective treatment option against staphylococcal infections. PMID- 25712911 TI - Movement of loads with trunk rotation. AB - Movements with participants standing at a bench and moving loads up to 6 kg were studied, with participants using two hands to hold the load and trunk rotation in order to move the loads to specified locations. Tasks were performed with rapid ballistic movements and also with ongoing visual control. Data for ballistic movements were modelled in terms of a modified form of the (Gan, K.-C. and Hoffmann, E.R. 1988. "Geometrical conditions for ballistic and visually controlled movements." Ergonomics 5 (31): 829-839) model for ballistic movements, taking into account the inertial properties of trunk rotation. Visually controlled movements were modelled in terms of Fitts' law and a term that allowed for the ballistic form of the first submovement of the visually-controlled movement. Practitioner Summary: Movement times to move masses up to 6 kg, for workers at a bench using trunk rotation, are given. Theoretical models fit the experimental data very well and allow prediction of movement times. PMID- 25712912 TI - Lack of usutu virus RNA in cerebrospinal fluid of patients with encephalitis of unknown etiology, Tuscany, Italy. AB - Usutu virus (USUV) is an African mosquito-borne flavivirus associated with human neurological disorders in Europe. Recently, USUV introduction in Europe has been traced back to Eurasian blackbirds deaths in the Tuscany region of Italy in 1996. Ninety-six cerebrospinal fluid (CSF) samples from patients with encephalitis of unknown etiology diagnosed in 2010-2013 were screened to determine whether USUV circulates in humans in Tuscany. Using real-time polymerase chain reaction, no positive patient was found. USUV does not seem to cause neuroinvasive disorders in humans in Tuscany. PMID- 25712913 TI - Randomly dividing homologous samples leads to overinflated accuracies for emotion recognition. AB - There are numerous studies measuring the brain emotional status by analyzing EEGs under the emotional stimuli that have occurred. However, they often randomly divide the homologous samples into training and testing groups, known as randomly dividing homologous samples (RDHS), despite considering the impact of the non emotional information among them, which would inflate the recognition accuracy. This work proposed a modified method, the integrating homologous samples (IHS), where the homologous samples were either used to build a classifier, or to be tested. The results showed that the classification accuracy was much lower for the IHS than for the RDHS. Furthermore, a positive correlation was found between the accuracy and the overlapping rate of the homologous samples. These findings implied that the overinflated accuracy did exist in those previous studies where the RDHS method was employed for emotion recognition. Moreover, this study performed a feature selection for the IHS condition based on the support vector machine-recursive feature elimination, after which the average accuracies were greatly improved to 85.71% and 77.18% in the picture-induced and video-induced tasks, respectively. PMID- 25712914 TI - A proteomic study of the regulatory role for STAT-1 in cytokine-induced beta-cell death. AB - PURPOSE: Signal transducer and activator of transcription 1 (STAT-1) plays a crucial role in cytokine-induced beta-cell destruction. However, its precise downstream pathways have not been completely clarified. We performed a proteome analysis of cytokine-exposed C57Bl/6 and STAT-1(-/-) mouse islets and prioritized proteins for their potential in relation to type 1 diabetes (T1D). EXPERIMENTAL DESIGN: Differential proteins were identified using a combination of 2D-DIGE and MALDI-TOF/TOF analysis and were subjected to ingenuity pathway analysis (IPA). Protein-protein interaction networks were created and a phenome-interactome ranking of the differential proteins based on their assignment to T1D was performed. RESULTS: Numerous STAT-1-regulated proteins were identified and divided in different groups according to their biological function. The largest group of proteins was the one involved in protein synthesis and processing. Network analysis revealed a complex interaction between proteins from different functional groups and IPA analysis confirmed the protective effect of STAT-1 deletion on cytokine-induced beta-cell death. Finally, a central role in this STAT-1-regulated mechanism was assigned to small ubiquitin-related modifier 4 (SUMO4). CONCLUSIONS AND CLINICAL RELEVANCE: These findings confirm a central role for STAT-1 in pancreatic islet inflammation induced destruction and most importantly elucidate the underlying proteomic pathways involved. PMID- 25712915 TI - The Hebb repetition effect in simple and complex memory span. AB - The Hebb repetition effect refers to the finding that immediate serial recall is improved over trials for memory lists that are surreptitiously repeated across trials, relative to new lists. We show in four experiments that the Hebb repetition effect is also observed with a complex-span task, in which encoding or retrieval of list items alternates with an unrelated processing task. The interruption of encoding or retrieval by the processing task did not reduce the size of the Hebb effect, demonstrating that incidental long-term learning forms integrated representations of lists, excluding the interleaved processing events. Contrary to the assumption that complex-span performance relies more on long-term memory than standard immediate serial recall (simple span), the Hebb effect was not larger in complex-span than in simple-span performance. The Hebb effect in complex span was also not modulated by the opportunity for refreshing list items, questioning a role of refreshing for the acquisition of the long-term memory representations underlying the effect. PMID- 25712916 TI - Seeing is believing: increasing intraoperative awareness to scattered radiation in interventional procedures by combining augmented reality, Monte Carlo simulations and wireless dosimeters. AB - PURPOSE: Surgical staff performing image-guided minimally invasive surgical procedures are chronically exposed to harmful ionizing radiation. Currently, no means exist to intraoperatively depict the 3D shape and intensity of scattered radiation fields or to assess the body-part exposure of clinicians. We propose a system for simulating and visualizing intraoperative scattered radiation using augmented reality. METHODS: We use a multi-camera RGBD system to obtain a 3D point cloud reconstruction of the current room layout. The positions of the clinicians, patient, table and C-arm are used to build a radiation propagation simulation model and compute the deposited dose distribution in the room. We use wireless dosimeters to calibrate the simulation and to evaluate its accuracy at each time step. The computed 3D risk map is shown in an augmented reality manner by overlaying the simulation results onto the 3D model. RESULTS: Several 3D visualizations showing scattered radiation propagation, clinicians' body-part exposure and radiation risk maps under different irradiation conditions are proposed. The system is evaluated in an operating room equipped with a robotized X-ray imaging device by comparing the radiation simulation results to experimental measurements under several X-ray acquisition setups and room configurations. CONCLUSIONS: The proposed system is capable to display intraoperative scattered radiation intuitively in 3D by using augmented reality. This can have a strong impact on improving clinicians' awareness of their exposure to ionizing radiation and on reducing overexposure risks. PMID- 25712918 TI - Erratum to: The fixed-dose combination of olmesartan/amlodipine was superior in central aortic blood pressure reduction compared with perindopril/amlodipine: a randomized, double-blind trial in patients with hypertension. PMID- 25712917 TI - Augmented reality in neurovascular surgery: feasibility and first uses in the operating room. AB - PURPOSE: The aim of this report is to present a prototype augmented reality (AR) intra-operative brain imaging system. We present our experience of using this new neuronavigation system in neurovascular surgery and discuss the feasibility of this technology for aneurysms, arteriovenous malformations (AVMs), and arteriovenous fistulae (AVFs). METHODS: We developed an augmented reality system that uses an external camera to capture the live view of the patient on the operating room table and to merge this view with pre-operative volume-rendered vessels. We have extensively tested the system in the laboratory and have used the system in four surgical cases: one aneurysm, two AVMs and one AVF case. RESULTS: The developed AR neuronavigation system allows for precise patient-to image registration and calibration of the camera, resulting in a well-aligned augmented reality view. Initial results suggest that augmented reality is useful for tailoring craniotomies, localizing vessels of interest, and planning resection corridors. CONCLUSION: Augmented reality is a promising technology for neurovascular surgery. However, for more complex anomalies such as AVMs and AVFs, better visualization techniques that allow one to distinguish between arteries and veins and determine the absolute depth of a vessel of interest are needed. PMID- 25712919 TI - Identification of prognosis-related proteins in gingival squamous cell carcinoma by twodimensional gel electrophoresis and mass spectrometry-based proteomics. AB - OBJECTIVES: The aim of this study was to identify differentially expressed proteins in oral squamous carcinoma cells that could be potential prognosis related cancer biomarkers. MATERIALS AND METHODS: We compared protein expression patterns from gingival squamous cellc carcinoma (GSCC) tissues and adjacent non cancerous matched tissues by proteomic analysis using two-dimensional gel electrophoresis coupled to mass spectrometry (2D-PAGE/MS). RESULTS: Seventeen protein spots were found to be over-expressed and eight were under-expressed in cancerous tissue compared to the normal counterpart. Of these, annexin A2 and ezrin were validated by Western blot. We also demonstrated by immunohistochemistry that POSTN is highly expressed in the neoplastic tissues examined. Among the differentially expressed proteins, we focused our attention on Chloride intracellular channel 1 (CLIC1). CONCLUSION: The 2D-PAGE/MS-based proteomics appears an efficient approach in detecting and identifying differentially expressed proteins that might function as potential biomarkers and/or molecular targets for early cancer diagnosis and prognosis and that might contribute to a innovative therapeutic strategies in GSCC. However, further validation and functional studies are needed to confirm and to support these promising, still preliminary data. KEY WORDS: Cancer biomarkers, Oral squamous cell carcinoma, Proteomics. PMID- 25712920 TI - A crosstalk between chromatin remodeling and histone H3K4 methyltransferase complexes in endothelial cells regulates angiotensin II-induced cardiac hypertrophy. AB - Angiotensin II (Ang II) induces cardiac hypertrophy and fibrosis in part by stimulating endothelin (ET-1) transcription. The involvement of the epigenetic machinery in this process is largely undefined. In the present study, we examined the epigenetic maneuvering underlying cardiac hypertrophy and fibrosis following ET-1 transactivation by Ang II. In response to Ang II stimulation, core components of the mammalian chromatin remodeling complex (Brahma-related gene 1, or Brg1, and Brahma or Brm) and histone H3K4 methylation complex (Ash2, absent, small, or homeotic discs 2, or Ash2 and WD domain repeat 5, or Wdr5) were recruited to the ET-1 promoter region in endothelial cells. Over-expression of Brg1/Brm or Ash2/Wdr5 enhanced while depletion of Brg1/Brm or Ash2/Wdr5 attenuated Ang II-induced ET-1 transactivation. Endothelial-specific knockdown of Brg1/Brm or Ash2/Wdr5 ameliorated cardiac hypertrophy both in vitro and in vivo. More important, Brg1/Brm interacted with Ash2/Wdr5 on the ET-1 promoter to catalyze H3K4 methylation. The crosstalk between Brg11/Brm and Ash2/Wdr5 was mediated by myocardin-related transcription factor A (MRTF-A). In conclusion, our data have unveiled an epigenetic complex that links ET-1 transactivation in endothelial cells to Ang II-induced cardiac hypertrophy and fibrosis. PMID- 25712921 TI - Regarding Ening et al. Charlson comorbidity index: an additional prognostic parameter for preoperative glioblastoma patient stratification. PMID- 25712925 TI - The CpxRA two-component system is essential for Citrobacter rodentium virulence. AB - Citrobacter rodentium is a murine intestinal pathogen used as a model for the foodborne human pathogens enterohemorrhagic Escherichia coli and enteropathogenic E. coli. During infection, these pathogens use two-component signal transduction systems to detect and adapt to changing environmental conditions. In E. coli, the CpxRA two-component signal transduction system responds to envelope stress by modulating the expression of a myriad of genes. Quantitative real-time PCR showed that cpxRA was expressed in the colon of C57BL/6J mice infected with C. rodentium. To determine whether CpxRA plays a role during C. rodentium infection, a cpxRA deletion strain was generated and found to have a colonization defect during infection. This defect was independent of an altered growth rate or a defective type III secretion system, and single-copy chromosomal complementation of cpxRA restored virulence. The C. rodentium strains were then tested in C3H/HeJ mice, a lethal intestinal infection model. Mice infected with the DeltacpxRA strain survived infection, whereas mice infected with the wild-type or complemented strains succumbed to infection. Furthermore, we found that the cpxRA expression level was higher during early infection than at a later time point. Taken together, these data demonstrate that the CpxRA two-component signal transduction system is essential for the in vivo virulence of C. rodentium. In addition, these data suggest that fine-tuned cpxRA expression is important for infection. This is the first study that identifies a C. rodentium two-component transduction system required for pathogenesis. This study further indicates that CpxRA is an interesting target for therapeutics against enteric pathogens. PMID- 25712922 TI - X-linked acrogigantism syndrome: clinical profile and therapeutic responses. AB - X-linked acrogigantism (X-LAG) is a new syndrome of pituitary gigantism, caused by microduplications on chromosome Xq26.3, encompassing the gene GPR101, which is highly upregulated in pituitary tumors. We conducted this study to explore the clinical, radiological, and hormonal phenotype and responses to therapy in patients with X-LAG syndrome. The study included 18 patients (13 sporadic) with X LAG and microduplication of chromosome Xq26.3. All sporadic cases had unique duplications and the inheritance pattern in two families was dominant, with all Xq26.3 duplication carriers being affected. Patients began to grow rapidly as early as 2-3 months of age (median 12 months). At diagnosis (median delay 27 months), patients had a median height and weight standard deviation scores (SDS) of >+3.9 SDS. Apart from the increased overall body size, the children had acromegalic symptoms including acral enlargement and facial coarsening. More than a third of cases had increased appetite. Patients had marked hypersecretion of GH/IGF1 and usually prolactin, due to a pituitary macroadenoma or hyperplasia. Primary neurosurgical control was achieved with extensive anterior pituitary resection, but postoperative hypopituitarism was frequent. Control with somatostatin analogs was not readily achieved despite moderate to high levels of expression of somatostatin receptor subtype-2 in tumor tissue. Postoperative use of adjuvant pegvisomant resulted in control of IGF1 in all five cases where it was employed. X-LAG is a new infant-onset gigantism syndrome that has a severe clinical phenotype leading to challenging disease management. PMID- 25712926 TI - In vitro passage selects for Chlamydia muridarum with enhanced infectivity in cultured cells but attenuated pathogenicity in mouse upper genital tract. AB - Although modern Chlamydia muridarum has been passaged for decades, there are no reports on the consequences of serial passage with strong selection pressure on its fitness. In order to explore the potential for Pasteurian selection to induce genomic and phenotypic perturbations to C. muridarum, a starter population was passaged in cultured cells for 28 generations without standard infection assistance. The resultant population, designated CMG28, displays markedly reduced in vitro dependence on centrifugation for infection and low incidence and severity of upper genital tract pathology following intravaginal inoculation into mice compared to the parental C. muridarum population, CMG0. Deep sequencing of CMG0 and CMG28 revealed novel protein variants in the hypothetical genes TC0237 (Q117E) and TC0668 (G322R). In vitro attachment assays of isogenic plaque clone pairs with mutations in either TC0237 and TC0668 or only TC0237 reveal that TC0237(Q117E) is solely responsible for enhanced adherence to host cells. Paradoxically, double mutants, but not TC0237(Q117E) single mutants, display severely attenuated in vivo pathogenicity. These findings implicate TC0237 and TC0668 as novel genetic factors involved in chlamydial attachment and pathogenicity, respectively, and show that serial passage under selection pressure remains an effective tool for studying Chlamydia pathogenicity. PMID- 25712927 TI - TleA, a Tsh-like autotransporter identified in a human enterotoxigenic Escherichia coli strain. AB - Enterotoxigenic Escherichia coli (ETEC), a leading cause of acute diarrhea, colonizes the intestine by means of adhesins. However, 15 to 50% of clinical isolates are negative for known adhesins, making it difficult to identify antigens for broad-coverage vaccines. The ETEC strain 1766a, obtained from a child with watery diarrhea in Chile, harbors the colonization factor CS23 but is negative for other known adhesins. One clone, derived from an ETEC 1766a genomic library (clone G10), did not produce CS23 yet was capable of adhering to Caco-2 cells. The goal of this study was to identify the gene responsible for this capacity. Random transposon-based mutagenesis allowed the identification of a 4,110-bp gene that codes for a homologue of the temperature-sensitive hemagglutinin (Tsh) autotransporter described in avian E. coli strains (97% identity, 90% coverage) and that is called TleA (Tsh-like ETEC autotransporter) herein. An isogenic ETEC 1766a strain with a tleA mutation showed an adhesion level similar to that of the wild-type strain, suggesting that the gene does not direct attachment to Caco-2 cells. However, expression of tleA conferred the capacity for adherence to nonadherent E. coli HB101. This effect coincided with the detection of TleA on the surface of nonpermeabilized bacteria, while, conversely, ETEC 1766a seems to secrete most of the produced autotransporter to the medium. On the other hand, TleA was capable of degrading bovine submaxillary mucin and leukocyte surface glycoproteins CD45 and P-selectin glycoprotein ligand 1 (PSGL-1). These results suggest that TleA promotes colonization of the intestinal epithelium and that it may modulate the host immune response. PMID- 25712929 TI - The IbeA invasin of adherent-invasive Escherichia coli mediates interaction with intestinal epithelia and macrophages. AB - Adherent-invasive Escherichia coli (AIEC) pathogroup isolates are a group of isolates from the intestinal mucosa of Crohn's disease patients that can invade intestinal epithelial cells (IECs) or macrophages and survive and/or replicate within. We have identified the ibeA gene in the genome of AIEC strain NRG857c and report the contribution of IbeA to the interaction of AIEC with IECs and macrophages and colonization of the mouse intestine. An ibeA deletion mutant strain (NRG857cDeltaibeA) was constructed, and the in vitro effect on AIEC adhesion and invasion of nonpolarized and polarized Caco-2 cells, the adhesion and transcytosis of M-like cells, the intracellular survival in THP-1 macrophages, and the contribution to intestinal colonization of the CD-1 murine model of infection were evaluated. A significant reduction in invasion was observed with the ibeA mutant in Caco-2 and M-like cells, whereas adhesion was not affected. Complementation of the mutant reestablished Caco-2 invasive phenotype to wild-type levels. Reduction in invasion did not significantly affect transcytosis through M-like cells at early time points. The absence of ibeA significantly affected AIEC intramacrophage survival up to 24 h postinfection. No significant changes associated with IbeA were found in AIEC colonization across the murine gastrointestinal tract, but a slight reduction of gamma interferon was observed in the ceca of mice infected with the ibeA mutant. In addition, a decrease in the pathology scores was observed in the ilea and ceca of mice infected with the ibeA mutant. Our data support the function of IbeA in the AIEC invasion process, macrophage survival, and inflammatory response in the murine intestine. PMID- 25712930 TI - Monitoring F1651 P-like fimbria expression at the single-cell level reveals a highly heterogeneous phenotype. AB - F1651 and the pyelonephritis-associated pili (Pap) are two members of the type P family of adhesive factors. They play a key role in establishing disease caused by extraintestinal pathogenic Escherichia coli (ExPEC) strains in animals and humans. Both F1651 and Pap are under the control of an epigenetic and reversible switch that defines the number of fimbriated (ON) and afimbriated (OFF) cells within a clonal population. Using the Gfp reporter system, we monitored in vitro the level of fluorescence intensity corresponding to the F1651 and Pap fimbrial synthesis. Monitoring individual Escherichia coli cells by flow cytometry and by real-time fluorescence microscopy, we identified cells associated with a low or high level of fluorescence intensity and a large amount of cells with partial levels of fluorescence, mostly present in the F1651 system. This mixed population identified through fluorescence intensity could be attributed to the high switching rate previously observed in F1651-positive bacteria. The fimbrial heterogeneous phenotype for these ExPEC could represent increased fitness in unpredictable environments. Our study illustrates that within the large repertoire of fimbrial variants such as the well-characterized Pap, F1651 is an exquisite example of regulatory expression that arms the bacterium with strategies for surviving in more than one particular environment. PMID- 25712928 TI - Crucial and diverse role of the interleukin-33/ST2 axis in infectious diseases. AB - Interleukin-33 (IL-33) has now emerged as a cytokine with diverse and pleiotropic functions in various infectious and inflammatory diseases. IL-33 is expressed by epithelial cells, endothelial cells, fibroblasts, and hepatocytes. The target cells of IL-33 are Th2 cells, basophils, dendritic cells, mast cells, macrophages, NKT cells, and nuocytes, newly discovered natural helper cells/innate lymphoid cells bearing the ST2 receptor. IL-33 has dual functions, both as a traditional cytokine and as a nuclear factor that regulates gene transcription. IL-33 functions as an "alarmin" released following cell death, as a biomarker, and as a vaccine adjuvant, with proinflammatory and protective effects during various infections. The exacerbated or protective role of the IL 33/ST2 axis during different infections is dependent upon the organ involved, type of infectious agent, whether the infection is acute or chronic, the invasiveness of the infectious agent, the host immune compartment, and cellular and cytokine microenvironments. In this review, we focus on recent advances in the understanding of the role of the IL-33/ST2 axis in various viral, bacterial, fungal, helminth, and protozoal infectious diseases gained from animal models and studies in human patients. The functional role of IL-33 and ST2 during experimentally induced infections has been summarized by accumulating the data for IL-33- and ST2-deficient mice or for mice exogenously administered IL-33. In summary, exploring the crucial and diverse roles of the IL-33/ST2 axis during infections may help in the development of therapeutic interventions for a wide range of infectious diseases. PMID- 25712931 TI - Induction of caspase-11 by aspartyl proteinases of Candida albicans and implication in promoting inflammatory response. AB - We recently demonstrated that the secreted aspartyl proteinases (Saps), Sap2 and Sap6, of Candida albicans have the potential to induce the canonical activation of the NLRP3 inflammasome, leading to the secretion of interleukin-1beta (IL 1beta) and IL-18 via caspase-1 activation. We also observed that the activation of caspase-1 is partially independent from the NLRP3 activation pathway. In this study, we examined whether Sap2 and Sap6 are also able to activate the noncanonical inflammasome pathway in murine macrophages. Our data show that both Sap2 and Sap6 can activate caspase-11 through type I interferon (IFN) production. Caspase-11 cooperates to activate caspase-1, with a subsequent increase of IL 1beta secretion. Endocytosis and internalization of Saps are required for the induction of type I IFN production, which is essential for induction of noncanonical inflammasome activation. Our study indicates a sophisticated interplay between caspase-1 and caspase-11 that connects the canonical and noncanonical pathways of inflammasome activation in response to C. albicans Saps. PMID- 25712933 TI - Progenitor cell-derived extracellular vesicles: an emerging diagnostic and therapeutic tool for renal disease. PMID- 25712932 TI - Ixodes ricinus salivary serpin IRS-2 affects Th17 differentiation via inhibition of the interleukin-6/STAT-3 signaling pathway. AB - Th17 cells constitute a subset of CD4(+) T lymphocytes that play a crucial role in protection against extracellular bacteria and fungi. They are also associated with tissue injury in autoimmune and inflammatory diseases. Here, we report that serpin from the tick Ixodes ricinus, IRS-2, inhibits Th17 differentiation by impairment of the interleukin-6 (IL-6)/STAT-3 signaling pathway. Following activation, mature dendritic cells produce an array of cytokines, including the pleiotropic cytokine IL-6, which triggers the IL-6 signaling pathway. The major transcription factor activated by IL-6 is STAT-3. We show that IRS-2 selectively inhibits production of IL-6 in dendritic cells stimulated with Borrelia spirochetes, which leads to attenuated STAT-3 phosphorylation and finally to impaired Th17 differentiation. The results presented extend the knowledge about the effect of tick salivary serpins on innate immunity cells and their function in driving adaptive immune responses. PMID- 25712935 TI - Opponent's comments. PMID- 25712934 TI - Pro: cardiovascular calcifications are clinically relevant. AB - It is increasingly acknowledged that mineral and bone disorders (MBDs) contribute to the excessively high cardiovascular (CV) disease morbidity and mortality observed in patients with chronic kidney disease (CKD). There is ongoing debate as to whether screening for CV calcification, one of the hallmarks of CKD-MBD, should be implemented in clinical practice in patients with CKD. Issues to be considered in this controversy relate to prevalence, severity, relevance, and last but not least, modifiability and reversibility of vascular and valvular calcifications in the setting of CKD. The recent expansion of the armamentarium to treat CKD-MBD (calcium-free phosphate binders and calcimimetics) creates new opportunities. Mounting experimental and clinical evidence indicates that progression of CV calcification may indeed be attenuated. Whether this will translate into better outcomes remains to be proven. We acknowledge that hard outcome data so far are limited and, overall, yielded inconclusive results. Nevertheless, in an era in which personalized medicine has gained much popularity, we consider it reasonable, awaiting the results of additional studies, to screen for CV calcification in selected individuals. This policy may help to stratify CV risk and to guide therapy. We speculate that such an approach will ultimately improve outcomes and reduce health costs. PMID- 25712936 TI - Con: vascular calcification is a surrogate marker, but not the cause of ongoing vascular disease, and it is not a treatment target in chronic kidney disease. AB - In this narrative review, we discuss the dynamics and pathobiology of calcium accumulation in the arterial system and then appraise the validity of vascular calcification as a surrogate end point in cardiovascular (CV) diseases and in chronic kidney disease (CKD) in particular. Calcification follows inflammation in human atherosclerosis and therefore most likely represents a secondary phenomenon. This phenomenon is proportional to the severity of antecedent inflammation and is perhaps a healing process. As such, vascular calcification is a disease marker and a prognostic factor but not a relevant aetiological factor in arterial disease in CKD patients. Therefore, targeting vascular calcifications per se is unlikely to improve clinical outcomes. To maximize health benefits, the approach to vascular disease in CKD patients should focus on the prevention of arterial lesions by correcting the several, traditional and non-traditional, pro atherogenic risk factors responsible for arterial injury, hyperphoshataemia and CKD-mineral and bone disorder disorders included. Interventions aiming at modifying late arterial lesions like calcifications are unlikely to produce tangible health benefits in these patients. PMID- 25712938 TI - Moderator's view: treatment of vascular calcification is a physical impossibility, so far. PMID- 25712937 TI - Opponent's comments. PMID- 25712940 TI - The role of radiotherapy in the carotid stenosis. AB - OBJECTIVE: Cervical radiation for head and neck cancer has been associated with an increased incidence of carotid arterial stenosis. Modern radiation therapy delivers higher doses with increasing long-term survival. In our study 50 patients with head and neck malignancies treated with radiotherapy are analized with colour Doppler ultrasonographic scanning of the carotid arteries. These patients were compared with a population of asymptomatic historical controls (40) These findings suggest that radiation has an adverse effect on large vessels. Colour Doppler follow-up may be indicated for patients receiving head and neck radiation therapy. METHODS: 50-70 Gy is the local dose that all patients received. during a period of about 8 weeks. The ecodoppler scan of carotid arteries was performed in all patients with estimation of Common and internal carotid artery's intimal medial thickness (IMT). Stenosis grade were divided into low (0-30%), moderate (31-49 %) and severe (= >50%). In add we considered ematochimics and flogosys parameters. Patients recruited from a hospital Radiation-oncology-surgery department from April 2007 to September 2011, 90 consecutive head and neck cancer patients were enrolled in this study. 50 of these patients had previously undergone RT (RT group) and 40 had no RT (control group). All patients were screened with bilateral carotid arterial duplex ultrasonography. We defined disease as "normal or mild" if the carotid stenosis was <50%, and "significant" if >50%. The relationship between standard demographic risk factors and screening outcomes was then analyzed. RESULTS: We found that severe carotid stenosis (= >50% ) was higher (41%) in patients who underwent to radiotherapy than in control group. The Eco Doppler examination demonstrated that the most affected site was Internal Carotid Arthery 's fork . There were no differences in age or gender between the two groups. The RT group had a significantly higher plaque score than the non-irradiated group. Bilateral plaque score was significantly correlated with age, hyperlipidemia, and RT. This analysis showed that in RT patients > 50 years old, age was inversely correlated with plaque score; however, in RT patients T substitution in HTRA1 in both siblings. CONCLUSION: This report highlights the need of considering this entity in the differential diagnosis of cerebral small-vessel disease in young patients, even in the non-Asian populations. PMID- 25712944 TI - Prognostic significance of perihematomal edema in acute intracerebral hemorrhage: pooled analysis from the intensive blood pressure reduction in acute cerebral hemorrhage trial studies. AB - BACKGROUND AND PURPOSE: Controversy exists over the prognostic significance of perihematomal edema (PHE) in intracerebral hemorrhage. We aimed to determine the association of early PHE and clinical outcome among participants of the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT) studies. METHODS: Pooled analyses of computed tomographic substudies in the pilot phase (INTERACT1) and main phase (INTERACT2), both international, prospective, open, blinded end point, randomized controlled trials, of patients with spontaneous intracerebral hemorrhage (<6 hours) and elevated systolic blood pressure, randomly assigned to intensive (target systolic blood pressure, <140 mm Hg) or guideline-based (systolic blood pressure, <180 mm Hg) blood-pressure management. Substudy participants (n=1310; 346 INTERACT1, 964 INTERACT2) had blinded central analyses of digital images from standardized baseline and 24-hour computed tomography. Predictors of death or dependency (modified Rankin scale scores, >=3) at 90 days were assessed in logistic regression models and reported with odds ratios and 95% confidence intervals. INTERACT studies are registered at ClinicalTrials.gov (NCT00226096 and NCT00716079). RESULTS: Of 1138 (87%) patients with 2 CTs available for edema analysis and outcome information, time from intracerebral hemorrhage onset to baseline computed tomography, baseline hematoma volume, 24-hour hematoma growth, and intraventricular extension were independent predictors of 24-hour PHE growth. Absolute growth in PHE volume was significantly associated with death or dependency (adjusted odds ratio, 1.17; 95% confidence interval, 1.02-1.33 per 5 mL increase from baseline; P=0.025) at 90 days after adjustment for demographic, clinical, and hematoma parameter prognostic factors. Associations were consistent across various sensitivity analyses. CONCLUSION: PHE growth is an independent prognostic factor in intracerebral hemorrhage. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00226096 and NCT00716079. PMID- 25712945 TI - Natural history and management of basilar trunk artery aneurysms. AB - BACKGROUND AND PURPOSE: Basilar trunk aneurysms (BTAs), defined as aneurysms distal to the basilar origin and proximal to the origin of the superior cerebellar artery, are rare and challenging to manage. We describe the natural history and management in a consecutive series of BTAs. METHODS: Between 2000 and 2013, 2522 patients with 3238 aneurysms were referred to our institution for aneurysm management. A retrospective review of this database was conducted to identify all patients with BTAs. RESULTS: In total, 52 patients had a BTA. Mean age was 56 (SD+/-18) years. Median clinical follow-up was 33 (interquartile range, 8-86) months, and imaging follow-up was 26 (interquartile range, 2-80.5) months. BTAs were classified into 4 causal subtypes: acute dissecting aneurysms, segmental fusiform ectasia, mural bleeding ectasia, and saccular aneurysms. Multiple aneurysms were more frequently noticed among the 13 saccular aneurysms when compared with overall population (P=0.021). There was preponderance of segmental ectasia or mural bleeding ectasia (P=0.045) in patients presenting with transit ischemic attack/stroke or mass effect. Six patients with segmental and 4 with mural bleeding ectasia demonstrated increasing size of their aneurysm, with 2 having subarachnoid hemorrhage caused by aneurysm rupture. None of the fusiform aneurysms that remained stable bled. CONCLUSIONS: BTAs natural histories may differ depending on subtype of aneurysm. Saccular aneurysms likely represent an underlying predisposition to aneurysm development because more than half of these cases were associated with multiple intracranial aneurysms. Intervention should be considered in segmental ectasia and chronic dissecting aneurysms, which demonstrate increase in size over time as there is an increased risk of subarachnoid hemorrhage. PMID- 25712946 TI - Serum levels of retinol-binding protein 4 and risk of colon adenoma. PMID- 25712947 TI - Surgical approach to TIR3 cytology class A prospective evaluation. AB - AIM: Fine-needle aspiration (FNA) has proven to be a safe and reliable method of investigation of thyroid lesions. Referencing to European classification, the associated risk of malignancy for TIR3, category reserved for aspirates that contain architectural and/or nuclear atypia, is variable in such studies. Aims of study were evaluating safety of surgical approach, assessing perioperative parameters surgically related, and estimating neoplastic rate for TIR3 group. MATERIAL AND METHODS: A prospective evaluation of all TIR3 submitted to thyroidectomy was conducted by assessing histopatohologic results between January 2005 and December 2012, considering two categories, positive (neoplastic) and negative (not neoplastic) group. Intraoperative and complication rate was analyzed on TIR3 population. RESULTS: A total of 1514 total thyroidectomy was performed from 2005 to 2012: a total of 148 cases was considered on TIR3 group. Positive cases amounted to 64 (43.2%), 29 of which were carcinoma (19.6% of total population) and 35 of which were adenoma, while negative cases amounted to 84 (56.8%). Sensitivity and specificity of TIR3 as neoplastic screening was 43.2% and 82.1%. A total of 32 linfectomies was performed (21.6% of group). Positive group presented a significant lower mean age than negative group (42.1 vs 56.2 years) CONCLUSIONS: TIR3 group represents a various category, with probably different malignancy risk. Our results and neoplasms rate confirmed that surgical option should be gold standard, in order to define atypical pattern and reduce delayed diagnoses. Choice of a second FNA or a imaging monitoring should be adopted for specific condition. KEY WORDS: Fine-needle aspiration, Thyroidectomy, TIR3, Thyroid cancer. PMID- 25712948 TI - Physician income: a look behind the numbers. PMID- 25712949 TI - Norwegian editor's exit sparks alarm. PMID- 25712952 TI - Most palliative physicians want no role in assisted death. PMID- 25712950 TI - Factors associated with physician follow-up among patients with chest pain discharged from the emergency department. AB - BACKGROUND: Many patients with chest pain do not receive follow-up from a physician after discharge from the emergency department despite significant survival benefit associated with follow-up care. Our objective was to evaluate factors associated with physician follow-up to understand this gap in practice. METHODS: We conducted an observational study involving patients at high risk who were assessed for chest pain and discharged from an emergency department in Ontario between April 2004 and March 2010. We used multivariable logistic regression to determine the association of clinical and nonclinical characteristics with physician follow-up. RESULTS: We identified 56 767 patients, of whom 25.1% did not receive any follow-up by a physician, 69.0% were seen by their primary care physician, and 17.3% were seen by a cardiologist within 30 days. Patients who had medical comorbidities and cardiac conditions such as myocardial infarction or heart failure were less likely to have follow-up. In contrast, a previous visit to a primary care physician was associated with the highest odds of having physician follow-up (odds ratio [OR] 6.44, 95% confidence interval [CI] 5.91-7.01). Similarly, a previous visit to a cardiologist was strongly associated with follow-up by a cardiologist (OR 3.01, 95% CI 2.85-3.17). Patients evaluated in emergency departments with the highest tertile of chest pain volume were more likely to receive follow-up from any physician (OR 1.52, 95% CI 1.31-1.77) and from a cardiologist (OR 2.04, 95% CI 1.61-2.57). INTERPRETATION: Nonclinical factors are strongly associated with physician follow up for patients with chest pain after discharge from the emergency department. However, patients with comorbidities and at higher risk for future adverse events are less likely to receive follow-up care. PMID- 25712953 TI - Fair pricing of "old" orphan drugs: considerations for Canada's orphan drug policy. PMID- 25712956 TI - Pitted keratolysis: an infective cause of foot odour. PMID- 25712957 TI - Ras-mediated modulation of pyruvate dehydrogenase activity regulates mitochondrial reserve capacity and contributes to glioblastoma tumorigenesis. AB - BACKGROUND: Even though altered metabolism representing a hallmark of cancer was proposed nearly a century ago, recent technological advances have allowed investigators to continue uncovering a previously unrecognized complexity of metabolic programs that drive tumorigenesis beyond that of aerobic glycolysis. METHODS: The bioenergetic state of a diverse panel of glioblastoma models, including isogenic lines derived from a genetically engineered adult astrocytic mouse model and patient-derived glioblastoma stem cells, was determined at baseline and in stressed conditions. Mechanisms contributing to the discovered metabolic phenotypes were determined through molecular and chemical perturbation, and their biological consequences were evaluated in vivo and in patient samples. RESULTS: Attenuated mitochondrial reserve capacity was identified as a common metabolic phenotype in glioblastoma lines. This phenotype was linked mechanistically with the capacity of Ras-mediated signaling to inhibit pyruvate dehydrogenase (PDH) activity through downregulation of PDH phosphatase (PDP) expression. PDP1 repression was validated clinically in patient-derived samples, suggesting that aberrant cellular signaling typical of glioblastoma actively modulates PDH activity. This phenotype was reversed through both chemical and molecular perturbation. Restoration of PDH activity through stable expression of PDP1-impaired tumorigenic potential. CONCLUSIONS: These findings support the central role that PDH regulation plays as a downstream consequence of aberrant signaling associated with gliomagenesis and the scientific rationale to continue to develop and test clinical strategies designed to activate PDH as a form of anticancer therapy in glioblastoma. PMID- 25712958 TI - In Vitro Assessment of Interaction Between Amino Acids and Copper in Neonatal Parenteral Nutrition. AB - BACKGROUND: The repeated blackening of in-line filters has been observed during the infusion of parenteral nutrition 2-in-1 mixtures (binary parenteral nutrition [BPN]) delivered in a neonatal intensive care unit. This study aimed to examine the elemental content of precipitates isolated from infused BPN bags and determine the main physicochemical interactions occurring in these bags. MATERIALS AND METHODS: The infusion of BPN mixtures was simulated in vitro following hospital practices. Filter membranes were examined by scanning electron microscopy and energy dispersion spectroscopy (EDS). Amino acid (AA) profiles were obtained from BPN mixtures to determine the concentrations of each AA. RESULTS: Analyzed filter membranes revealed conglomerates of particles on filter surfaces. An EDS analysis generated spectra from isolated particles, identifying copper and sulfur as the major chemical elements. AA mean concentrations were relatively close to the expected value for each AA, except cysteine. Cysteine concentrations were very significantly lower than the expected values. CONCLUSION: A specific interaction was identified between 1 AA (cysteine) and a trace element (copper) in our BPN mixtures. PMID- 25712959 TI - Cross-Sectional Study of U.S. Interns' Perceptions of Clinical Nutrition Education. AB - Background Medical students have historically perceived a lack of training in clinical nutrition. Rapid advances in medical science have compelled significant changes in medical education pedagogy. It is unclear what effect this has had on student's perceptions. Objective To assess interns' perception of clinical nutrition education during medical school. Design A cross-sectional survey of medical, surgical, and obstetric interns from 6 academic hospitals across the United States during the middle of their first year in November of 2010 (n = 289). Bivariate analysis and logistic regression was used to describe interns' perceptions and evaluate for factors that determined these perceptions. Results A total of 122 interns responded to the survey, for a response rate of 42%. These interns represented 72 different medical schools. Only 29% of interns reported they had been sufficiently trained in nutrition. On average, interns who reported being prepared reported a mean of 4 +/- 3.4 weeks of training during medical school, while unprepared interns reported a mean of 2 +/- 2.6 weeks of training (P = .02). Interns with prior graduate training in nutrition (n = 18) almost exclusively reported that medical school training was insufficient (94%, P = .02). After adjusting for age, gender, internship, undergraduate training, and being a foreign graduate, only the number of weeks of training remained significantly associated with perceived preparation (P = .03). Conclusion Most interns in medicine, surgery, and obstetrics feel unprepared to handle cases requiring knowledge of clinical nutrition. Interns feel that medical school is not adequately preparing them for the needs of clinical practice. PMID- 25712960 TI - Cardiac Fgf21 synthesis and release: an autocrine loop for boosting up antioxidant defenses in failing hearts. PMID- 25712962 TI - Platelets in leucocyte recruitment and function. AB - Platelets have a longstanding recognition as an essential cellular component of the coagulation system. However, substantial research over the last decade has added another important aspect to platelet function in that they are also an integral part of the innate immune system. Complex organisms are facing a constant threat of infections by invading pathogens, and they have developed a sophisticated and elegant measure to combat this threat, namely the immune system. Leucocyte recruitment to sites of infections is an essential step at the forefront of the immune response. Platelets have been shown to be involved in several steps of this process and they are an integrated connecting element among haemostasis, host defence, and additional immunological functions (e.g. neutrophil extracellular traps formation). However, the immune system also requires a tight regulation, as an overshooting immune response carries the risk of harming the host itself. This review aims at highlighting the unique features and molecular mechanisms that allow for the interactions of platelets and leucocytes and the regulation of this process. Furthermore, this article identifies the functional relevance of these events for the immune response. PMID- 25712961 TI - Ageing is associated with deterioration of calcium homeostasis in isolated human right atrial myocytes. AB - AIMS: Ageing-related cardiac disorders such as heart failure and atrial fibrillation often present with intracellular calcium homeostasis dysfunction. However, knowledge of the intrinsic effects of ageing on cellular calcium handling in the human heart is sparse. Therefore, this study aimed to analyse how ageing affects key mechanisms that regulate intracellular calcium in human atrial myocytes. METHODS AND RESULTS: Whole membrane currents and intracellular calcium transients were measured in isolated human right atrial myocytes from 80 patients with normal left atrial dimensions and no history of atrial fibrillation. Patients were categorized as young (<55 years, n = 21), middle aged (55-74 years, n = 42), and old (>=75 years, n = 17). Protein levels were determined by western blot. Ageing was associated with the following electrophysiological changes: (i) a 3.2-fold decrease in the calcium transient (P < 0.01); (ii) reduction of the L type calcium current (ICa) amplitude (2.4 +/- 0.3 pA/pF vs. 1.4 +/- 0.2 pA/pF, P < 0.01); (iii) lower levels of L-type calcium channel alpha-subunit (P < 0.05); (iv) lower rates of both fast (14.5 +/- 0.9 ms vs. 20.9 +/- 1.9, P < 0.01) and slow (73 +/- 3 vs. 120 +/- 12 ms, P < 0.001) ICa inactivation; and (v) a decrease in the sarcoplasmic reticulum calcium content (10.1 +/- 0.8 vs. 6.4 +/- 0.6 amol/pF, P < 0.005) associated with a significant decrease in both SERCA2 (P < 0.05) and calsequestrin-2 (P < 0.05) protein levels. In contrast, ageing did not affect spontaneous sarcoplasmic reticulum calcium release. CONCLUSION: Ageing is associated with depression of SR calcium content, L-type calcium current, and calcium transient amplitude that may favour a progressive decline in right atrial contractile function with age. PMID- 25712963 TI - Deaf native signers are better readers than nonnative signers: myth or truth? AB - The central aim of this study was to clarify whether sign language (SL) nativeness is a significant factor in determining prelingually deaf individuals' reading skills and whether its contribution is modified by the reader's orthographic background. A second aim was to elucidate similarities and differences between native and nonnative signers in processing written information at different processing levels in order to understand how SL nativeness sustains the reading process, if at all. Participants were 176 students with prelingual deafness recruited from two education levels (6th-7th graders and 9th-10th graders) and three orthographic backgrounds (Hebrew, German, and Turkish). Sixty-six students were native and the remainder nonnative signers. They were tested with a battery of eight experimental paradigms, each assessing their information processing skills in a specific reading-related or reading unrelated domain. Findings corroborate SL nativeness enhancing the reading process in some regard. However, its contribution was not found to scaffold the structural processing of a written text to turn reading into a tool for learning. Rather, gains were restricted to facilitating processing written words from a perceptual to a conceptual level. Evidence suggests that compared with other determining factors, the contribution of SL nativeness to proficient reading may be rather marginal. PMID- 25712964 TI - Selection and Counterselection of Hia Expression Reveals a Key Role for Phase Variable Expression of Hia in Infection Caused by Nontypeable Haemophilus influenzae. AB - Hia is a major adhesin of nontypeable Haemophilus influenzae (NTHi) and has long been investigated as a vaccine candidate. Here we show that Hia phase variation is controlled by changes in the length of a polythymidine tract located in the hia promoter. Studies of an invasive clinical isolate (strain R2866) show that strains expressing high Hia levels are more efficiently killed by opsonophagocytosis. An opsonophagocytic assay was used to select for a subpopulation of variants that expressed a low level of Hia, which facilitated their escape from killing by anti-Hia antisera. Conversely, a subpopulation of variants expressing a high level of Hia was selected for during passaging through Chang cells. In both cases, phase variation of Hia expression corresponded directly with discrete modal changes in polythymidine tract length. In the chinchilla model of NTHi infection, we observed consistent selection for high Hia expression upon nasopharyngeal colonization, confirming the key role of phase variable expression of Hia within a specific niche in vivo. PMID- 25712965 TI - Biofilm-like aggregation of Staphylococcus epidermidis in synovial fluid. PMID- 25712967 TI - Safety and Immunogenicity of a Single Low Dose or High Dose of Clade 2 Influenza A(H5N1) Inactivated Vaccine in Adults Previously Primed With Clade 1 Influenza A(H5N1) Vaccine. AB - Influenza A(H5N1) vaccination strategies that improve the speed of the immunological response and cross-clade protection are desired. We compared the immunogenicity of a single 15-MUg or 90-MUg dose of A/H5N1/Indonesia/05/05 (clade 2) vaccine in adults who were previously primed with A/H5N1/Vietnam/1203/2004 (clade 1) vaccine. High-dose vaccine resulted in significantly higher titers to both clade 1 and 2 antigens. Clade 2 titers were unaffected by the previous dose of clade 1 vaccine. Low-dose priming with a mismatched pandemic influenza A(H5N1) vaccine would improve the rapidity, magnitude, and cross-reactivity of the immunological response following a single high-dose, unadjuvanted, pandemic vaccine. PMID- 25712966 TI - Longitudinal Genetic Characterization Reveals That Cell Proliferation Maintains a Persistent HIV Type 1 DNA Pool During Effective HIV Therapy. AB - BACKGROUND: The stability of the human immunodeficiency virus type 1 (HIV-1) reservoir and the contribution of cellular proliferation to the maintenance of the reservoir during treatment are uncertain. Therefore, we conducted a longitudinal analysis of HIV-1 in T-cell subsets in different tissue compartments from subjects receiving effective antiretroviral therapy (ART). METHODS: Using single-proviral sequencing, we isolated intracellular HIV-1 genomes derived from defined subsets of CD4(+) T cells from peripheral blood, gut-associated lymphoid tissue and lymph node tissue specimens from 8 subjects with virologic suppression during long-term ART at 2 time points (time points 1 and 2) separated by 7-9 months. RESULTS: DNA integrant frequencies were stable over time (<4-fold difference) and highest in memory T cells. Phylogenetic analyses showed that subjects treated during chronic infection contained viral populations with up to 73% identical sequence expansions, only 3 of which were observed in specimens obtained before therapy. At time points 1 and 2, such clonally expanded populations were found predominantly in effector memory T cells from peripheral blood and lymph node tissue specimens. CONCLUSIONS: Memory T cells maintained a relatively constant HIV-1 DNA integrant pool that was genetically stable during long-term effective ART. These integrants appear to be maintained by cellular proliferation and longevity of infected cells, rather than by ongoing viral replication. PMID- 25712968 TI - Asymptomatic Multiclonal Plasmodium falciparum Infections Carried Through the Dry Season Predict Protection Against Subsequent Clinical Malaria. AB - BACKGROUND: Immunity to the antigenically diverse parasite Plasmodium falciparum is acquired gradually after repeated exposure. Studies in areas of high malaria transmission have shown that asymptomatic individuals infected with multiclonal infections are at reduced risk of febrile malaria during follow-up. METHODS: We assessed the relationship between the genetic diversity of clones in P. falciparum infections that persist through the dry season and the subsequent risk of febrile malaria in 225 individuals aged 2-25 years in Mali, where the 6-month malaria and dry seasons are sharply demarcated. Polymerase chain reaction-based genotyping of the highly polymorphic merozoite surface protein 2 gene was performed on blood samples collected at 5 cross-sectional surveys. RESULTS: In an age-adjusted analysis, individuals with multiclonal P. falciparum infections before the rainy season were at reduced risk of febrile malaria, compared with individuals who were uninfected (hazard ratio [HR], 0.28; 95% confidence interval [CI], .11-.69). In contrast, there was no significant association between risk of malaria and having 1 clone at baseline (HR, 0.71; 95% CI, .36-1.40). CONCLUSIONS: The results suggest that persistent multiclonal infections carried through the dry season contribute to protection against subsequent febrile malaria, possibly by maintaining protective immune responses that depend on ongoing parasite infection. PMID- 25712969 TI - A Systematic Review and Meta-Analysis of the Seroprevalence of Influenza A(H9N2) Infection Among Humans. AB - INTRODUCTION: Given that influenza A(H9N2) is recognized as a pandemic threat, we evaluated the overall burden of influenza A(H9N2) infections among avian-exposed human populations. METHODS: We performed a systematic search of PubMed, AGRICOLA, and CAB Abstracts databases for literature published during 1997-2013. Studies reporting serological evidence of human influenza A(H9N2) infection among avian exposed populations were included. We used a World Health Organization (WHO) recommended case definition for serological evidence of infection based on results of hemagglutination inhibition (HI) and microneutralization (MN) assays. We calculated overall seroprevalence through a random effects meta-analysis model. RESULTS: Seroprevalence data reported by the studies ranged from 1% to 43% (median, 9%) by HI, which was not significantly different from the seroprevalence estimated through the WHO-recommended case definition (median, 1.3%; range, 0.5% 42.6%). Reported seroprevalence by MN ranged from 0.6% to 9% (median, 2.7%), which was greater than the seroprevalence estimated through the WHO-recommended case definition (median, 0.3%; range, 0.1%-1.4%). CONCLUSIONS: A small proportion of avian-exposed humans had evidence of influenza A(H9N2) infection. As the virus has a near global distribution in poultry, it seems likely that present surveillance efforts are missing mild or asymptomatic infections among avian exposed persons. It seems prudent to closely monitor avian-exposed populations for influenza A(H9N2) infection to provide prepandemic warnings. PMID- 25712971 TI - Severe Acute Respiratory Illness in Sub-Saharan Africa. PMID- 25712970 TI - Severe Acute Respiratory Illness Deaths in Sub-Saharan Africa and the Role of Influenza: A Case Series From 8 Countries. AB - BACKGROUND: Data on causes of death due to respiratory illness in Africa are limited. METHODS: From January to April 2013, 28 African countries were invited to participate in a review of severe acute respiratory illness (SARI)-associated deaths identified from influenza surveillance during 2009-2012. RESULTS: Twenty three countries (82%) responded, 11 (48%) collect mortality data, and 8 provided data. Data were collected from 37 714 SARI cases, and 3091 (8.2%; range by country, 5.1%-25.9%) tested positive for influenza virus. There were 1073 deaths (2.8%; range by country, 0.1%-5.3%) reported, among which influenza virus was detected in 57 (5.3%). Case-fatality proportion (CFP) was higher among countries with systematic death reporting than among those with sporadic reporting. The influenza-associated CFP was 1.8% (57 of 3091), compared with 2.9% (1016 of 34 623) for influenza virus-negative cases (P < .001). Among 834 deaths (77.7%) tested for other respiratory pathogens, rhinovirus (107 [12.8%]), adenovirus (64 [6.0%]), respiratory syncytial virus (60 [5.6%]), and Streptococcus pneumoniae (57 [5.3%]) were most commonly identified. Among 1073 deaths, 402 (37.5%) involved people aged 0-4 years, 462 (43.1%) involved people aged 5-49 years, and 209 (19.5%) involved people aged >=50 years. CONCLUSIONS: Few African countries systematically collect data on outcomes of people hospitalized with respiratory illness. Stronger surveillance for deaths due to respiratory illness may identify risk groups for targeted vaccine use and other prevention strategies. PMID- 25712972 TI - Reply to Perez and Patel. PMID- 25712973 TI - Antibody Maturation in Women Who Acquire HIV Infection While Using Antiretroviral Preexposure Prophylaxis. AB - The CAPRISA 004 preexposure prophylaxis (PrEP) randomized trial demonstrated that women who used a vaginal gel containing the antiretroviral drug tenofovir (TFV) had a 39% lower risk of acquiring human immunodeficiency virus (HIV). It is not known whether topical TFV alters the antibody response to breakthrough HIV infection. In this study, antibody maturation was evaluated using 3 serologic assays: the BED capture enzyme immunoassay (CEIA), the Bio-Plex (Luminex) assay, and the Bio-Rad avidity assay. Tests were performed using serum samples collected 3, 6, 9, 12, 24, 36, 48, and >48 months after seroconversion from 95 women in the CAPRISA 004 trial (35 in the TFV gel arm and 60 in the placebo arm). For the BED CEIA and Luminex assay, linear mixed effects models were used to examine test results by study arm. Cox proportional hazard analysis was used to examine time to avidity cutoff. Anti-HIV antibody titers did not differ between study arms. Women assigned to TFV gel demonstrated slower antibody avidity maturation, as determined by the Bio-Rad (P = .04) and gp120 Bio-Plex (P = .028) assays. Women who were assigned to receive topical TFV but became infected had slower antibody avidity maturation, with potential implications for diagnosis and antibody-based incidence assays as access to antiretroviral therapy-based PrEP is increased. PMID- 25712974 TI - A Potent Virus-Specific Antibody-Secreting Cell Response to Acute Enterovirus 71 Infection in Children. AB - BACKGROUND: Enterovirus 71 (EV71) remains a leading pathogen for acute infectious diseases in children, especially in Asia. The cellular basis for establishing a virus-specific antibody response to acute EV71 infections is unclear in children. METHODS: We studied the magnitude of virus-specific antibody-secreting B cells (ASCs) and its relationship with serological response, clinical parameters, and virological parameters among children with laboratory-confirmed EV71 infection. RESULTS: A potent EV71 genogroup B- and virus-specific ASC response was detected in the first week of illness among genotype B5 EV71-infected children. The cross reactive EV71-specific ASC response to genogroup C viral antigens composed about 10% of the response. The EV71-specific ASC response in children aged >=3 years produced immunoglobulin G predominantly, but immunoglobulin M was predominant in younger children. Proliferation marker was expressed by the majority of circulating ASCs in the acute phase of EV71 infection. Virus-specific ASC responses significantly correlated with throat viral load, fever duration, and serological genogroup-specific neutralization titer. CONCLUSIONS: The presence of a virus-specific ASC response serves an early cellular marker of an EV71-specific antibody response. Further detailed study of EV71-specific ASCs at the monoclonal level is crucial to delineate the specificity and function of antibody immunity in children. PMID- 25712975 TI - Impact of Adjuvants on the Immunogenicity and Efficacy of Split-Virion H7N9 Vaccine in Ferrets. AB - BACKGROUND: An effective vaccine is urgently needed against the H7N9 avian influenza virus. We evaluated the immunogenicity and protective efficacy of a split-virion H7N9 vaccine with or without the oil-in-water adjuvants in ferrets. METHODS: Ferrets were vaccinated with 2 doses of unadjuvanted, MF59 or AS03 adjuvanted A/Shanghai/2/2013 (H7N9) vaccine, and the induction of antibodies to hemagglutinin (HA) or neuraminidase proteins was evaluated. Ferrets were then challenged with wild-type H7N9 virus to assess the vaccine's protective efficacy. The vaccine composition and integrity was also evaluated in vitro. RESULTS: Adjuvanted vaccines stimulated robust serum antibody titers against HA and neuraminidase compared with the unadjuvanted vaccines. Although there was a difference in adjuvanticity between AS03 and MF59 at a lower dose (3.75 ug of HA), both adjuvants induced comparable antibody responses after 2 doses of 15 ug. On challenge, ferrets that received adjuvanted vaccines showed lower viral burden than the control or unadjuvanted vaccine group. In vitro examinations revealed that the vaccine contained visible split-virus particles and retained the native conformation of HA recognizable by polyclonal and monoclonal antibodies. CONCLUSIONS: The adjuvanted H7N9 vaccines demonstrated superior immunogenicity and protective efficacy against H7N9 infection in ferrets and hold potential as a vaccination regimen. PMID- 25712977 TI - Etiology of Metabolic Changes in Severe Plasmodium falciparum Malaria. PMID- 25712976 TI - Novel Insights Into the Protective Role of Hemoglobin S and C Against Plasmodium falciparum Parasitemia. AB - Although hemoglobin S (HbS) and hemoglobin C (HbC) are well known to protect against severe Plasmodium falciparum malaria, conclusive evidence on their role against infection has not yet been obtained. Here we show, in 2 populations from Burkina Faso (2007-2008), that HbS is associated with a 70% reduction of harboring P. falciparum parasitemia at the heterozygous state (odds ratio [OR] for AS vs AA, 0.27; 95% confidence interval [CI], .11-.66; P = .004). There is no evidence of protection for HbC in the heterozygous state (OR for AC vs AA, 1.49; 95% CI, .69-3.21; P = .31), whereas protection even higher than that observed with AS is observed in the homozygous and double heterozygous states (OR for CC + SC vs AA, 0.04; 95% CI, .01-.29; P = .002). The abnormal display of parasite adhesive molecules on the surface of HbS and HbC infected erythrocytes, disrupting the pathogenic process of sequestration, might displace the parasite from the deep to the peripheral circulation, promoting its elimination at the spleen level. PMID- 25712978 TI - Reply to Eisenhut. PMID- 25712979 TI - Haemoptysis and pulmonary haemorrhage associated with cryoballoon ablation. PMID- 25712980 TI - Management of antithrombotic therapy in patients undergoing electrophysiological device surgery. AB - The aim of this review is to formulate practical recommendations for the management of antithrombotic therapy in patients undergoing cardiac implantable electronic device (CIED) surgery by providing indications for a systematic approach to the problem integrating general technical considerations with patient specific elements based on a careful evaluation of the balance between haemorrhagic and thromboembolic risk. Hundreds of thousands patients undergo implantation or replacement of CIEDs annually in Europe, and up to 50% of these subjects receive antiplatelet agents or oral anticoagulants. The rate of CIED related complications, mainly infective, has also significantly increased so that transvenous lead extraction procedures are, consequently, often required. Cardiac implantable electronic device surgery is peculiar and portends specific intrinsic risks of developing potentially fatal haemorrhagic complications; on the other hand, the periprocedural suspension of antithrombotic therapy in patients with high thromboembolic risk cardiac conditions may have catastrophic consequences. Accordingly, the management of the candidate to CIED surgery receiving concomitant antithrombotic therapy is a topic of great clinical relevance yet controversial and only partially, if at all, adequately addressed in evidence based current guidelines. In spite of the fact that in many procedures it seems reasonably safe to proceed with aspirin only or without interruption of anticoagulants, restricting to selected cases the use of bridging therapy with parenteral heparins, there are lots of variables that may make the therapeutic choices challenging. The decision-making process applied in this document relies on the development of a stratification of the procedural haemorrhagic risk and of the risk deriving from the suspension of antiplatelet or anticoagulant therapy combined to generate different clinical scenarios with specific indications for optimal management of periprocedural antithrombotic therapy. PMID- 25712981 TI - Treatment of Postpartum Hemorrhage With Blood Products in a Tertiary Hospital: Outcomes and Predictive Factors Associated With Severe Hemorrhage. AB - Postpartum hemorrhage (PPH) remains a leading cause of maternal mortality and morbidity worldwide. This retrospective observational study describes patient characteristics and hemostatic therapies administered to 352 parturients experiencing PPH and analyzes risk factors for developing severe PPH. During the study period, bleeding was controlled in all cases and 99.4% survived. The majority (98%) of patients received packed red blood cells. The most frequent hemostatic therapies administered were fibrinogen concentrate (56%), fresh frozen plasma (49%), and platelets (30%). A total of 124 (35%) women experienced severe PPH. Significant independent predictors for evolution to severe PPH were age, obstetric comorbidity, and plasma fibrinogen concentration. The latter was based on records from 267 (76%) patients. Plasma fibrinogen concentration before labor was the only modifiable prepartum risk factor independently associated with severe PPH, indicating that fibrinogen monitoring is warranted in these patients. PMID- 25712982 TI - Improvement of sudden bilateral hearing loss after vertebral artery stenting. AB - Bilateral deafness is a rare but possible symptom of vertebrobasilar ischemia. We report a case of sudden bilateral sensorineural hearing loss caused by bilateral vertebral artery (VA) occlusion which dramatically improved after stenting. A 54 year-old man was admitted with sudden onset of bilateral deafness, vertigo, and drowsy mental status. Brain diffusion-weighted MRI showed acute infarction involving both the posterior inferior cerebellar artery and left posterior cerebral artery territory. Cerebral angiography showed bilateral distal VA occlusion, and emergency intracranial stenting was performed in the left VA. After reperfusion therapy his symptoms gradually improved, including hearing impairment. Endovascular stenting may be helpful in a patient with sudden deafness caused by bilateral VA occlusion. PMID- 25712983 TI - Angiographic suppression of the artery of Adamkiewicz by venous hypertension resolving after embolization in a case of spinal epidural arteriovenous fistula. AB - A case of complete angiographic suppression of the artery of Adamkiewicz and anterior spinal artery in a patient with a spinal epidural arteriovenous fistula (AVF) is reported. Slow flow AVFs typically present with progressive myelopathy secondary to spinal venous hypertension (SVH). The lack of a normal venous phase during angiography and its restoration after treatment is commonly observed with these lesions, yet a similar phenomenon seems exceptional at the arterial level. Right T11 intercostal artery angiograms obtained before and after treatment of a left L4 epidural AVF documented the initial suppression of the artery of Adamkiewicz and anterior spinal artery, and their normal appearance immediately after correction of the SVH by embolization. This report confirms that SVH can angiographically suppress prominent and functionally important spinal arteries, re-emphasizing the potential role played by secondary arterial changes in SVH induced myelopathy. This hemodynamic phenomenon also represents a potential pitfall during diagnostic and therapeutic endovascular procedures. PMID- 25712984 TI - Thoracoscopic diaphragm plication. AB - Diaphragm plication is a relatively common operation in thoracic surgery and can be a major benefit to patients who have suffered phrenic nerve injury and who are left short of breath as a result [1]. With the advent of video-assisted thoracoscopic surgery (VATS) many surgeons have attempted diaphragm plication endoscopically. Barriers to implementation of VATS diaphragm plication include concerns regarding initial port entry with such a high diaphragm, the technical ability to suture by VATS and concern regarding the placement of sutures to a thin diaphragm draped tightly over a spleen, liver or large intestine. We present a simple way to overcome these barriers using carbon dioxide to increase the size of the hemithorax and relax the tension on the diaphragm, an Endostitch device that makes pledgeted suturing straightforward and a novel endograsper that allows a wide range of angles to be achieved when handling the diaphragm. PMID- 25712985 TI - Outcomes in surgically managed non-small-cell lung cancer patients with evidence of interstitial pneumonia identified on preoperative radiology or incidentally on postoperative histology. AB - OBJECTIVES: Although some interstitial pneumonia (IP) cases are not detected on computed tomography (CT) before surgery, they are confirmed by pathological diagnosis after pulmonary resection. In the present study, we aimed to investigate patients who underwent pulmonary resection for non-small-cell lung cancer (NSCLC) and subsequently showed pathological findings of IP but no apparent interstitial changes on CT. METHODS: We retrospectively analysed 1688 patients with NSCLC who underwent pulmonary resection and presented with a radiological or pathological diagnosis of IP in 64 institutions between January 2000 and December 2009. We compared 135 patients without radiological findings but with pathological findings of IP (Group A) with 1553 patients with radiological findings of IP (Group B). RESULTS: The percent vital capacity and predicted diffusing capacity for carbon monoxide were higher in Group A than in Group B. Although there was no significant difference in the occurrence of acute exacerbation (AE) between both groups, the mortality after AE in Group A was significantly lower than that in Group B. The overall survival rates of patients in Groups A and B at 5 years were 59.1 and 40.9%, respectively (P = 0.0031). CONCLUSIONS: The mortality after AE in patients with only pathological findings of IP was significantly lower than in those with radiological findings of IP. Moreover, the patients with only pathological findings of IP had a better prognosis than those with radiological findings of IP. Thus, our findings suggest that patients with pathological findings of IP and without radiological abnormality had early-stage IP. PMID- 25712986 TI - Direct percutaneous transaortic approach for treatment of aortic pseudoaneurysms. AB - Aortic pseudoaneurysms (APAs) can develop months or years after aortic and cardiac surgery. If not treated appropriately, APAs can lead to fatal complications and ultimately death. We describe a case of a 61-year old patient with a diagnosed large pseudoaneurysm 5 years after his aortic valve surgery, who was treated with a novel transcatheter direct transaortic approach. The patient had dilated cardiomyopathy with an APA adjacent to the lower sternal plate. An Amplatzer septal occlusion device followed by coils was delivered transcutaneously through the APA to close its neck and fill the false aneurysm, respectively. Triple fusion multimodality imaging was used to guide the placement of the occlusion devices. The merging of computed tomography (CT) and echocardiography with real-time fluoroscopy was fundamental in procedural planning and guidance. Post-procedural transoesophageal echocardiogram (TOE) and CT angiography showed complete exclusion of the APA. A direct transaortic approach is a valid option for closure of an APA if the surgical risk is prohibitive, and the use of triple fusion technology is an essential tool in the hands of interventionalists and surgeons for preoperative planning and conduction of these procedures. PMID- 25712987 TI - Does a skeletonized internal thoracic artery give fewer postoperative complications than a pedicled artery for patients undergoing coronary artery bypass grafting? AB - A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was 'Does a skeletonized internal thoracic artery (ITA) give fewer postoperative complications than a pedicled artery for patients undergoing coronary artery bypass grafting?' Altogether, 98 papers were found using the reported search, of which 11 represented the best evidence to answer the clinical question. Papers about patency of skeletonized versus pedicled internal thoracic artery were excluded. The analysed complications were essentially mediastinitis, superficial sternal infection, wound infection, chest pain and pulmonary function. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. Grafts used were either single ITA (LITA or RITA, left or right, respectively) or bilateral ITAs (BITAs). One prospective randomized controlled trial was identified, which found that benefits of skeletonized harvesting included increased graft length, increased graft flow and decreased incidence of mediastinitis. All of the six studies concerning wound infection demonstrate fewer complications when ITA is skeletonized. One of the three papers describing postoperative mortality demonstrated lower 30-day mortality, but there was no long-term analysis. Three studies describing postoperative chest pain reported a lower score on the visual analogue scale (VAS) within 30 days. One of them indicates that the pedicled group has a significantly greater VAS, pain disability index and short-form McGill Pain questionnaire score at 1 and 3 months. The hospital stay was shorter for three studies conducted on this subject. One study about pulmonary function reported a better ratio of pre- versus postoperative values of forced vital capacity. Despite longer operating times, skeletonization leads to fewer wound infections, reduced chest pain, allows a shorter hospital stay and better preserves pulmonary function. PMID- 25712988 TI - Tyrosine kinase inhibitors induce mesenchymal stem cell-mediated resistance in BCR-ABL+ acute lymphoblastic leukemia. AB - Tyrosine kinase inhibitors (TKIs) are used as a frontline therapy for BCR-ABL(+) acute lymphoblastic leukemia (ALL). However, resistance to TKI therapy arises rapidly, and its underlying molecular mechanisms are poorly understood. In this study, we identified a novel cascade of events initiated by TKIs and traversing through mesenchymal stem cells (MSCs) to leukemic cells, leading to resistance. MSCs exposed to TKIs acquired a new functional status with the expression of genes encoding for chemo-attractants, adhesion molecules, and prosurvival growth factors, and this priming enabled leukemic cells to form clusters underneath the MSCs. This cluster formation was associated with the protection of ALL cells from therapy as leukemic cells switched from BCR-ABL signaling to IL-7R/Janus kinase signaling to survive in the MSC milieu. Our findings illustrate a novel perspective in the evolution of TKI resistance and provide insights for advancing the treatment of BCR-ABL(+) ALL. PMID- 25712989 TI - Plasminogen associates with phosphatidylserine-exposing platelets and contributes to thrombus lysis under flow. AB - The interaction of plasminogen with platelets and their localization during thrombus formation and fibrinolysis under flow are not defined. Using a novel model of whole blood thrombi, formed under flow, we examine dose-dependent fibrinolysis using fluorescence microscopy. Fibrinolysis was dependent upon flow and the balance between fibrin formation and plasminogen activation, with tissue plasminogen activator-mediated lysis being more efficient than urokinase plasminogen activator-mediated lysis. Fluorescently labeled plasminogen radiates from platelet aggregates at the base of thrombi, primarily in association with fibrin. Hirudin attenuates, but does not abolish plasminogen binding, denoting the importance of fibrin. Flow cytometry revealed that stimulation of platelets with thrombin/convulxin significantly increased the plasminogen signal associated with phosphatidylserine (PS)-exposing platelets. Binding was attenuated by tirofiban and Gly-Pro-Arg-Pro amide, confirming a role for fibrin in amplifying plasminogen binding to PS-exposing platelets. Confocal microscopy revealed direct binding of plasminogen and fibrinogen to different platelet subpopulations. Binding of plasminogen and fibrinogen co-localized with PAC-1 in the center of spread platelets. In contrast, PS-exposing platelets were PAC-1 negative, and bound plasminogen and fibrinogen in a protruding "cap." These data show that different subpopulations of platelets harbor plasminogen by diverse mechanisms and provide an essential scaffold for the accumulation of fibrinolytic proteins that mediate fibrinolysis under flow. PMID- 25712991 TI - von Willebrand factor biosynthesis, secretion, and clearance: connecting the far ends. AB - To understand the placement of a certain protein in a physiological system and the pathogenesis of related disorders, it is not only of interest to determine its function but also important to describe the sequential steps in its life cycle, from synthesis to secretion and ultimately its clearance. von Willebrand factor (VWF) is a particularly intriguing case in this regard because of its important auxiliary roles (both intra- and extracellular) that implicate a wide range of other proteins: its presence is required for the formation and regulated release of endothelial storage organelles, the Weibel-Palade bodies (WPBs), whereas VWF is also a key determinant in the clearance of coagulation factor VIII. Thus, understanding the molecular and cellular basis of the VWF life cycle will help us gain insight into the pathogenesis of von Willebrand disease, design alternative treatment options to prolong the factor VIII half-life, and delineate the role of VWF and coresidents of the WPBs in the prothrombotic and proinflammatory response of endothelial cells. In this review, an update on our current knowledge on VWF biosynthesis, secretion, and clearance is provided and we will discuss how they can be affected by the presence of protein defects. PMID- 25712990 TI - Diagnostic approach to von Willebrand disease. PMID- 25712993 TI - Rare bleeding disorders: diagnosis and treatment. AB - Despite the worldwide prevalence of rare bleeding disorders (RBDs), knowledge of these conditions and their management is suboptimal; health care professionals often have little diagnostic and treatment experience with variable access to diagnostic modalities required for accurate identification. Therefore, patients often experience morbidity and mortality due to delayed diagnosis. As RBDs represent a small potential commercial market, few, if any, specific therapies exist for these conditions. As a result, affected individuals commonly face delayed diagnosis, incomplete laboratory evaluation, and limited treatment options. Standardization and customization of coagulation assays, full genome sequencing, and global clotting assays will significantly improve diagnosis of patients with RBDs. In addition, new therapeutic modalities, both recombinant and plasma derived, are emerging, at least in developed countries. Registries and clinical trials have demonstrated decreased bleeding and improved outcomes when patients are appropriately diagnosed and properly treated. Expansion and harmonization of international registries has been initiated to correlate genotype, laboratory, and clinical phenotypes including bleeding severity to improve the diagnosis and therapeutic approach. This review focuses on the latest advances in our understanding, diagnosis, and treatment of RBDs. PMID- 25712992 TI - Optimal treatment strategies for hemophilia: achievements and limitations of current prophylactic regimens. AB - Prophylactic application of clotting factor concentrates is the basis of modern treatment of severe hemophilia A. In children, the early start of prophylaxis as primary or secondary prophylaxis has become the gold standard in most countries with adequate resources. In adults, prophylaxis is reasonably continued when started as primary or secondary prophylaxis in childhood to maintain healthy joint function. Initial data support that adult patients with already existing advanced joint arthropathy benefit from tertiary prophylaxis with significantly lowered number of bleeds, almost complete absence of target joints, and less time off from work. Current prophylactic regimens, although very effective, do not completely prevent joint disease in a long-term perspective. Joint arthropathy in primary prophylaxis develops over many years, sometimes over a decade or even longer time periods. The ankle joints are the first and most severely affected joints in those patients and thus may serve in outcome assessment as an indicator of early joint arthropathy when followed by ultrasound or magnetic resonance imaging. Optimized outcome and best use of available resources is expected from individualization of therapy regimens, which comprises the individual's bleeding pattern, condition of the musculoskeletal system, level of physical activity and the pharmacokinetic profile of the substituted coagulation factor, and most recently includes novel products with extended half-lives. PMID- 25712995 TI - Introduction to a series of reviews on inherited bleeding disorders. PMID- 25712994 TI - FVIII inhibitors: pathogenesis and avoidance. AB - The pathogenesis of inhibitory antibodies has been the focus of major scientific interest over the last decades, and several studies on underlying immune mechanisms and risk factors for formation of these antibodies have been performed with the aim of improving the ability to both predict and prevent their appearance. It seems clear that the decisive factors for the immune response to the deficient factor are multiple and involve components of both a constitutional and therapy-related nature. A scientific concern and obstacle for research in the area of hemophilia is the relatively small cohorts available for studies and the resulting risk of confounded and biased results. Careful interpretation of data is recommended to avoid treatment decisions based on a weak scientific platform. This review will summarize current concepts of the underlying immunological mechanisms and risk factors for development of inhibitory antibodies in patients with hemophilia A and discuss how these findings may be interpreted and influence our clinical management of patients. PMID- 25712997 TI - Neuroimaging in headache: Lessons not learned. PMID- 25712998 TI - Migraine affects white-matter tract integrity: A diffusion-tensor imaging study. AB - BACKGROUND: Specific white-matter tract alterations in migraine remain to be elucidated. Using diffusion tensor imaging (DTI), this study investigated whether the integrity of white-matter tracts that underlie regions of the "pain matrix" is altered in migraine and interrogated whether the number of years lived with migraine modifies fibertract structure. METHODS: Global probabilistic tractography was used to assess the anterior thalamic radiations, the corticospinal tracts and the inferior longitudinal fasciculi in 23 adults with migraine and 18 healthy controls. RESULTS: Migraine patients show greater mean diffusivity (MD) in the left and right anterior thalamic radiations, the left corticospinal tract, and the right inferior longitudinal fasciculus tract. Migraine patients also show greater radial diffusivity (RD) in the left anterior thalamic radiations, the left corticospinal tract as well as the left and right inferior longitudinal fasciculus tracts. No group fractional anisotropy (FA) differences were identified for any tracts. Migraineurs showed a positive correlation between years lived with migraine and MD in the right anterior thalamic radiations (r = 0.517; p = 0.012) and the left corticospinal tract (r = 0.468; p = 0.024). CONCLUSION: Results indicate that white-matter integrity is altered in migraine and that longer migraine history is positively correlated with greater alterations in tract integrity. PMID- 25712999 TI - Return to sports after stress fractures of the tibial diaphysis: a systematic review. AB - INTRODUCTION: This review aims to provide information on the time taken to resume sport following tibial diaphyseal stress fractures (TDSFs). SOURCES OF DATA: A systematic search of Medline, EMBASE, CINHAL, Cochrane, Web of Science, PEDro, Sports Discus, Scopus and Google Scholar was performed using the keywords 'tibial', 'tibia', 'stress', 'fractures', 'athletes', 'sports', 'non-operative', 'conservative', 'operative' and 'return to sport'. AREAS OF AGREEMENT: Twenty seven studies were included: 16 reported specifically on anterior TDSFs and 5 on posterior TDSFs. The general principles were to primarily attempt non-operative management for all TDSFs and to consider operative intervention for anterior TDSFs that remained symptomatic after 3-6 months. Anterior TDSFs showed a prolonged return to sport. AREAS OF CONTROVERSY: The best time to return to sport and the optimal management modalities for TDSFs remain undefined. GROWING POINTS: Management of TDSFs should include a full assessment of training methods, equipment and diet to modify pre-disposing factors. AREAS TIMELY FOR DEVELOPING RESEARCH: Future prospective studies should aim to establish the optimal treatment modalities for TDSFs. PMID- 25713000 TI - Ion channels in nociceptors: recent developments. PMID- 25712996 TI - Age- and sex-specific causal effects of adiposity on cardiovascular risk factors. AB - Observational studies have reported different effects of adiposity on cardiovascular risk factors across age and sex. Since cardiovascular risk factors are enriched in obese individuals, it has not been easy to dissect the effects of adiposity from those of other risk factors. We used a Mendelian randomization approach, applying a set of 32 genetic markers to estimate the causal effect of adiposity on blood pressure, glycemic indices, circulating lipid levels, and markers of inflammation and liver disease in up to 67,553 individuals. All analyses were stratified by age (cutoff 55 years of age) and sex. The genetic score was associated with BMI in both nonstratified analysis (P = 2.8 * 10(-107)) and stratified analyses (all P < 3.3 * 10(-30)). We found evidence of a causal effect of adiposity on blood pressure, fasting levels of insulin, C-reactive protein, interleukin-6, HDL cholesterol, and triglycerides in a nonstratified analysis and in the <55-year stratum. Further, we found evidence of a smaller causal effect on total cholesterol (P for difference = 0.015) in the >=55-year stratum than in the <55-year stratum, a finding that could be explained by biology, survival bias, or differential medication. In conclusion, this study extends previous knowledge of the effects of adiposity by providing sex- and age specific causal estimates on cardiovascular risk factors. PMID- 25713001 TI - Resting brain activity in disorders of consciousness: a systematic review and meta-analysis. AB - OBJECTIVE: To quantitatively synthesize results from neuroimaging studies that evaluated patterns of resting functional activity in patients with disorders of consciousness (DOC). METHODS: We performed a systematic review and coordinate based meta-analysis of studies published up to May 2014. Studies were included if they compared resting-state functional neuroimaging data acquired in patients with DOC (coma, minimally conscious state, emergence from minimally conscious state, or vegetative state) with a group of healthy controls. Coordinate-based meta-analysis was performed in studies that included voxel-based comparisons at the whole-brain level and if analysis was accomplished with data-driven approaches. RESULTS: A total of 36 studies (687 patients, 637 healthy controls) were included in the systematic review. Reported DOC were vegetative state (43.2%), coma (23.4%), minimally conscious state (22.8%), and emergence from minimally conscious state (1.6%); the most common etiologies of DOC were traumatic brain injury (37.7%) and anoxic brain injury (36.9%). Functional neuroimaging was accomplished using fMRI (16 studies), PET (15 studies), SPECT (4 studies), and both PET and SPECT in one study. Meta-analysis in 13 studies (272 patients, 259 healthy controls) revealed consistently reduced activity in patients with DOC in bilateral medial dorsal nucleus of the thalamus, left cingulate, posterior cingulate, precuneus, and middle frontal and medial temporal gyri. CONCLUSIONS: In patients with DOC evaluated in the resting state, functional neuroimaging indicates markedly reduced activity within midline cortical and subcortical sites, anatomical structures that have been linked to the default-mode network. Studies are needed to determine the relation between activation (and coherence) within these structures and the emergence of conscious awareness. PMID- 25713002 TI - Initial use of a novel noninvasive vagus nerve stimulator for cluster headache treatment. AB - OBJECTIVE: To report our initial experience with a novel device, designed to provide portable, noninvasive, transcutaneous stimulation of the vagus nerve, both acutely and preventively, as a treatment for cluster headache. METHODS: Patients with cluster headache (11 chronic, 8 episodic), from 2 centers, including 7 who were refractory to drug treatment, had sufficient data available for analysis in this open-label observational cohort study. The device, known as the gammaCore, was used acutely to treat individual attacks as well as to provide prevention. Patient-estimated efficacy data were collected by systematic inquiry during follow-up appointments up to a period of 52 weeks of continuous use. RESULTS: Fifteen patients reported an overall improvement in their condition, with 4 reporting no change, providing a mean overall estimated improvement of 48%. Of all attacks treated, 47% were aborted within an average of 11 +/- 1 minutes of commencing stimulation. Ten patients reduced their acute use of high flow oxygen by 55% with 9 reducing triptan use by 48%. Prophylactic use of the device resulted in a substantial reduction in estimated mean attack frequency from 4.5/24 hours to 2.6/24 hours (p < 0.0005) posttreatment. CONCLUSION: These data suggest that noninvasive vagus nerve stimulation may be practical and effective as an acute and preventive treatment in chronic cluster headache. Further evaluation of this treatment using randomized sham-controlled trials is thus warranted. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with cluster headache, transcutaneous stimulation of the vagus nerve aborts acute attacks and reduces the frequency of attacks. PMID- 25713003 TI - NHS England and Monitor offer compromise deal to hospitals on payments for procedures. PMID- 25713004 TI - Visual Outcome and Recurrence Rate in Children With Idiopathic Intracranial Hypertension. AB - The purpose of this retrospective study was to evaluate the visual outcome and recurrence rate of idiopathic intracranial hypertension in children. The study included 68 patients who were diagnosed with idiopathic intracranial hypertension according to the modified Dandy criteria. Permanent visual impairment was rare. Three percent remained with mild visual impairment, 4% with minimal visual field defects, and only 1 patient had severe visual impairment. However, 26% had either a prolonged course of disease or a recurring condition. Higher cerebrospinal fluid opening pressure was the only clinical predictor at presentation (P = .04). Recurrence rate was 18%, and in most cases, the second episode occurred during the first year after remission. There was no significant difference between the group of patients with only 1 episode and the group of patients with more than 1 episode. We suggest long-term follow-up after remission, for at least a year, for all children with idiopathic intracranial hypertension. PMID- 25713005 TI - Sleep Structure in Children With Attention-Deficit/Hyperactivity Disorder. AB - The authors evaluated basic sleep architecture and non-rapid eye movement (NREM) sleep alterations in drug-naive attention-deficit/hyperactivity disorder (ADHD) children without psychiatric or other comorbidities. This cross-sectional case control study included 28 drug-naive children with ADHD and 15 healthy controls. This subjective studies revealed that children with ADHD had a worse sleep quality and increased daytime sleepiness. Polysomnography data showed that the sleep macrostructure was not significantly different in children with ADHD. Sleep microstructure was altered in ADHD children by means of reduced total cyclic alternating pattern rate and duration of cyclic alternating pattern sequences. This reduction was associated with a selective decrease of A1 index during stage 2 NREM. SpO2 in total sleep was slightly decreased; however, the incidence of sleep disordered breathing showed no significant difference. The authors suggest that cyclic alternating pattern scoring would provide a further insight to obtain a better understanding of the sleep structure in children with ADHD. PMID- 25713006 TI - The Clinical Characteristics and Treatment Response in Children with West Syndrome in a Developing Country: A Retrospective Case Record Analysis. AB - This study describes the clinical characteristics, treatment, and outcome of children with West syndrome in a tertiary care hospital in north India. Overall, 310 case records diagnosed from January 2009 to June 2012 were reviewed. The median age of onset of spasms was 5 months (interquartile range = 2.5-7 months). The predominant underlying etiology was perinatal cerebral ischemia (55%). Adrenocorticotropic hormone or oral steroids were received by 92% children, of whom 43% became seizure free. Median lag time for appropriate treatment initiation was significantly less in patients who became seizure free as compared to those with persisting seizures (11 vs 15 months, P = .001) soon after receiving treatment of choice. Later age at onset of spasms was associated with a favorable seizure outcome (P = .03). In a resource-limited setting, unawareness along with treatment costs and repeated visits to the hospital are significant obstacles to optimum management. PMID- 25713007 TI - Afrikaans-speaking parents' perceptions of the rights of their children with mild to moderate intellectual disabilities: A descriptive investigation. AB - This study aimed to describe the perceptions of Afrikaans-speaking parents regarding the human rights, as defined by the United Nation's Convention on the Rights of the Child (CRC), of their children, aged between 8.0 and 14.11 (years/months), with mild to moderate intellectual disabilities. The underlying premise is that the CRC defines the rights of children, whereas the International Classification of Functioning, Disability and Health, Child and Youth version (ICF-CY) can provide the framework for documenting a deprivation of rights and the conditions under which those rights can be realized. Forty-seven Afrikaans speaking parents completed a custom-designed survey. The results of the closed ended questions indicated that most parents felt that their children had rights and that these rights were met. A theme analysis performed on the open-ended questions revealed that parents were mostly concerned about their children's rights pertaining to school education and safety. These rights were discussed in terms of the CRC articles and linked to environmental codes of the ICF-CY. Finally, the limitations and implications of the study are discussed and recommendations are made. PMID- 25713008 TI - Teacher-reported prevalence and management of child health problems at primary school. AB - We explored primary school teacher-reported experiences, prevalence and management of child health and developmental problems and medication administration from one multi-ethnic urban community in England. A survey was delivered to 90 reception class teachers in 45 primary schools, and semi structured interviews were conducted with a purposive sample of eight respondents. Fifty-six percent of teachers completed the questionnaire. Findings suggest that teachers and school staff may represent an underused resource for identifying children with developmental and health conditions and that the connections formed between schools and families could be utilized by other services by delivering interventions in schools where possible. Whilst most schools use a policy to inform the management of child health in school, some key areas such as training and documentation of medication administration may not be followed in practice. Interview findings supported and expanded on survey data by identifying barriers to collaboration between services and families. PMID- 25713009 TI - Oral health status, knowledge, attitudes and behaviours among marginalized children in Addis Ababa, Ethiopia. AB - Data on oral health status in Ethiopia are scarce. We assessed the prevalence of dental decay and gum disease and oral health practices and its barriers. We performed a cross-sectional study using comprehensive questionnaires and oral examination of 132 children aged 6-15 years in Addis Ababa. Mean age was 10 years and 50% were females. A significant number of children were HIV positive and orphaned. Forty-eight percent did not brush teeth and 43% brushed only once daily. The majority consumed sugary food despite knowing its relationship with dental decay. Seventy-four percent had between 1 and 13 dental caries and 52% showed evidence of bleeding upon brushing. Seventy-eight percent did not clean between teeth and were more likely to consume sugary food (p < 0.05) with oral pain within past six months (p < 0.01). In logistic regression, bleeding upon brushing and caries were not predicted by age or gender. We provided oral health trainings with illustrative flip-book, games and interactive discussions. Marginalized children suffer from poor oral health. We recommend national oral health strategies, targeted health education tailored towards Ethiopian societal norms and resources, improving access to local preventive tools and provision of oral care by training community health workers in the World Health Organization basic oral care package. PMID- 25713010 TI - CCGs were "queuing up" behind rationing pioneer to implement same policy, conference hears. PMID- 25713011 TI - Dronedarone and digitalis: individually reduced post-repolarization refractoriness enhances life-threatening arrhythmias. AB - AIMS: Interaction between dronedarone and digitalis has been discussed as a possible cause for increased mortality in the presence of dronedarone observed in the PALLAS trial. The aim of this study was to assess possible proarrhythmic effects of dronedarone in combination with digitalis in an experimental whole heart model. METHODS AND RESULTS: Twenty-six female rabbits underwent chronic oral treatment with dronedarone (50 mg/kg/day for 6 weeks). Twenty-four rabbits received placebo. Heart failure was induced by rapid ventricular pacing. Sham operated rabbits received a right-ventricular pacing lead but were not paced. Thereafter, hearts were isolated and Langendorff-perfused. Monophasic action potentials and a 12 lead electrocardiogram showed a dose-dependent decrease of QT interval, APD90, effective refractory periods, and postrepolarization refractoriness in control hearts and dronedarone-pretreated hearts after application of ouabain (0.1 and 0.2 uM). After acute application of ouabain, ventricular fibrillation (VF) was inducible by programmed ventricular stimulation in 6 of 12 untreated sham hearts (38 episodes) as compared with 7 of 11 dronedarone-pretreated sham hearts (76 episodes). In untreated failing hearts, 6 of 12 hearts were inducible (47 episodes) as compared with 7 of 15 hearts dronedarone-pretreated failing hearts (93 episodes). CONCLUSION: In this study, ouabain treatment resulted in an increased ventricular vulnerability in chronically dronedarone-pretreated control and failing hearts. Ouabain led to a significant abbreviation of ventricular repolarization. This was more marked in dronedarone-pretreated hearts and resulted in an elevated incidence of VF. This may help to interpret the results of the PALLAS trial. PMID- 25713012 TI - Implementation and reimbursement of remote monitoring for cardiac implantable electronic devices in Europe: a survey from the health economics committee of the European Heart Rhythm Association. AB - Remote monitoring (RM) of cardiac implantable electronic devices (CIEDs) permits early detection of arrhythmias, device, and lead failure and may also be useful in risk-predicting patient-related outcomes. Financial benefits for patients and healthcare organizations have also been shown. We sought to assess the implementation and funding of RM of CIEDs, including conventional pacemakers (PMs), implantable cardioverter defibrillators (ICDs), and cardiac resynchronization therapy (CRT) devices in Europe. Electronic survey from 43 centres in 15 European countries. In the study sample, RM was available in 22% of PM patients, 74% of ICD patients, and 69% of CRT patients. The most significant perceived benefits were the early detection of atrial arrhythmias in pacemaker patients, lead failure in ICD patients, and worsening heart failure in CRT patients. Remote monitoring was reported to lead a reduction of in-office follow ups for all devices. The most important reported barrier to the implementation of RM for all CIEDs was lack of reimbursement (80% of centres). Physicians regard RM of CIEDs as a clinically useful technology that affords significant benefits for patients and healthcare organizations. Remote monitoring, however, is perceived as increasing workload. Reimbursement for RM is generally perceived as a major barrier to implementation. PMID- 25713014 TI - "Because everything changes that day; you don't do the routine": Alterations and activities chronically ill women undertake on days with health care provider appointments. AB - OBJECTIVES: Research points to the importance of interactions with health care providers for chronically ill patients. Meanwhile, we know little about how visits to providers' offices are accommodated in these patients' lives. This analysis identifies the full scope of routine alterations and preparatory activities that require chronically will women's time and energy specifically on appointment days. METHODS: 55 semi-structured interviews were conducted with women with fibromyalgia syndrome living in Ontario, Canada. Interviews were transcribed verbatim and analyzed using the constant-comparative technique. RESULTS: Two trajectories are identified: (1) alterations to daily routines on appointment days; and (2) activities to prepare for the provider-patient interaction. Factors such as wanting to minimize symptom exacerbation, desires to come across as informed patients, limited time afforded to interactions, and access to transportation explain why these particular routine alterations and preparatory activities were undertaken. DISCUSSION: Findings demonstrate that the health care provider-patient interaction does not start or end in the space of the provider's office but is, rather, an event that is part of a larger process primarily focused on its successful negotiation. This suggests that the boundaries of the appointment need to be reconsidered, which holds implications for appointment-focused interventions aimed at chronically ill patients. PMID- 25713013 TI - The safety and efficacy of antithrombotic therapy in patients undergoing cardiac rhythm device implantation: a meta-analysis. AB - AIMS: The meta-analysis was to assess the safety and efficacy of periprocedural antithrombotic therapy and to evaluate the risk factors potentially associated with bleeding among patients undergoing cardiac implantable electronic devices implantations. METHODS AND RESULTS: A systematic literature search of PubMed, EMBASE, and Cochrane Controlled Trials Register was performed. Anticoagulation and antiplatelet therapies were assessed separately. Uninterrupted anticoagulation was associated with significant lower bleeding risk compared with heparin bridging strategy [odds ratio (OR) = 0.31, 95% confidence interval (CI) 0.18-0.53, and P < 0.0001], but there was no significant difference in thromboembolic risk between these two strategies (OR = 0.82, 95% CI 0.32-2.09, and P = 0.65). The haematoma rate was significantly increased in dual antiplatelet therapy group (OR = 6.84, 95% CI 4.16-11.25, and P < 0.00001), but not in single antiplatelet therapy (OR = 1.52, 95% CI 0.93-2.46, and P = 0.09). Clopidogrel increased the risk of haematoma vs. aspirin (OR = 2.91, 95% CI 1.27 6.69, and P = 0.01). Otherwise, a lower risk of haematoma was observed in pacemaker group vs. cardiac resynchronization therapy and/or implantable cardioverter defibrillator group (OR = 0.64, 95% CI 0.50-0.82, and P = 0.0004). CONCLUSION: This meta-analysis suggested that uninterrupted oral anticoagulation seems to be the better strategy, associated with a lower risk of bleeding complications rather than heparin bridging, and dual antiplatelet therapy carried a significant risk of bleeding whereas single antiplatelet therapy was relatively safe among patients undergoing cardiac implantable electronic devices implantations. Meanwhile, cardiac resynchronization therapy and/or implantable cardioverter defibrillator implantations increase the bleeding. PMID- 25713016 TI - Socioeconomic inequalities in adolescent smoking across 35 countries: a multilevel analysis of the role of family, school and peers. AB - BACKGROUND: Tobacco-related heath inequalities are a major public health concern, with smoking being more prevalent among lower socioeconomic groups. The aim of this study is to investigate the mechanisms leading to socioeconomic inequalities in smoking among 15-year-old adolescents by examining the mediating role of psychosocial factors in the peer group, family and school environment. METHODS: Data were derived from the international WHO-collaborative 'Health Behaviour in School-aged Children (HBSC)' study 2005/2006, including 52 907 15-year-old students from 35 European and North American countries. Socioeconomic position was measured by the Family Affluence Scale. Multilevel logistic regression models were conducted to examine the contribution of family, school and peer factors in explaining the association between family affluence and weekly smoking. RESULTS: Across countries, adolescents from low affluent families had an increased risk of weekly smoking (OR(boys) 1.14, confidence interval (CI) 1.05-1.23; OR(girls) 1.36, CI 1.26-1.46) compared with adolescents from high affluent families. Family and school factors mediated the association between family affluence and smoking to a high extent up to 100% (boys) and 81% (girls) in joint analyses. The most important single factors were family structure, relationships with parents, academic achievement and school satisfaction. Peer factors did not mediate the association between family affluence and adolescent smoking. CONCLUSION: The association between socioeconomic status and adolescent weekly smoking can largely be explained by an unequal distribution of family- and school-related factors. Focusing on the parent-adolescent relationship and adolescent school achievement can help to better understand inequalities in adolescent smoking behaviour. PMID- 25713015 TI - Patient controlled analgesia with remifentanil versus epidural analgesia in labour: randomised multicentre equivalence trial. AB - OBJECTIVE: To determine women's satisfaction with pain relief using patient controlled analgesia with remifentanil compared with epidural analgesia during labour. DESIGN: Multicentre randomised controlled equivalence trial. SETTING: 15 hospitals in the Netherlands. PARTICIPANTS: Women with an intermediate to high obstetric risk with an intention to deliver vaginally. To exclude a clinically relevant difference in satisfaction with pain relief of more than 10%, we needed to include 1136 women. Because of missing values for satisfaction this number was increased to 1400 before any analysis. We used multiple imputation to correct for missing data. INTERVENTION: Before the onset of active labour consenting women were randomised to a pain relief strategy with patient controlled remifentanil or epidural analgesia if they requested pain relief during labour. MAIN OUTCOME MEASURES: Primary outcome was satisfaction with pain relief, measured hourly on a visual analogue scale and expressed as area under the curve (AUC), thus providing a time weighted measure of total satisfaction with pain relief. A higher AUC represents higher satisfaction with pain relief. Secondary outcomes were pain intensity scores, mode of delivery, and maternal and neonatal outcomes. Analysis was done by intention to treat. The study was defined as an equivalence study for the primary outcome. RESULTS: 1414 women were randomised, of whom 709 were allocated to patient controlled remifentanil and 705 to epidural analgesia. Baseline characteristics were comparable. Pain relief was ultimately used in 65% (447/687) in the remifentanil group and 52% (347/671) in the epidural analgesia group (relative risk 1.32, 95% confidence interval 1.18 to 1.48). Cross over occurred in 7% (45/687) and 8% (51/671) of women, respectively. Of women primarily treated with remifentanil, 13% (53/402) converted to epidural analgesia, while in women primarily treated with epidural analgesia 1% (3/296) converted to remifentanil. The area under the curve for total satisfaction with pain relief was 30.9 in the remifentanil group versus 33.7 in the epidural analgesia group (mean difference -2.8, 95% confidence interval -6.9 to 1.3). For who actually received pain relief the area under the curve for satisfaction with pain relief after the start of pain relief was 25.6 in the remifentanil group versus 36.1 in the epidural analgesia group (mean difference -10.4, -13.9 to 7.0). The rate of caesarean section was 15% in both groups. Oxygen saturation was significantly lower (SpO2 <92%) in women who used remifentanil (relative risk 1.5, 1.4 to 1.7). Maternal and neonatal outcomes were comparable between both groups. CONCLUSION: In women in labour, patient controlled analgesia with remifentanil is not equivalent to epidural analgesia with respect to scores on satisfaction with pain relief. Satisfaction with pain relief was significantly higher in women who were allocated to and received epidural analgesia. TRIAL REGISTRATION: Netherlands Trial Register NTR2551. PMID- 25713017 TI - Hundreds of deaths of detainees with mental health conditions were avoidable, inquiry says. PMID- 25713018 TI - Increased A&E pressure and agency staff costs put foundation trusts further into red. PMID- 25713019 TI - Margaret McCartney: politicians: if you love the NHS then set it free from your non-evidence based meddling. PMID- 25713020 TI - Study finds "know-do" gap in treatment of pneumonia and diarrhoea in children in rural areas. PMID- 25713021 TI - Risk of peanut allergy can be reduced by 80% by including peanuts in infant diets, study finds. PMID- 25713022 TI - Development and validation of a melanoma risk score based on pooled data from 16 case-control studies. AB - BACKGROUND: We report the development of a cutaneous melanoma risk algorithm based upon seven factors; hair color, skin type, family history, freckling, nevus count, number of large nevi, and history of sunburn, intended to form the basis of a self-assessment Web tool for the general public. METHODS: Predicted odds of melanoma were estimated by analyzing a pooled dataset from 16 case-control studies using logistic random coefficients models. Risk categories were defined based on the distribution of the predicted odds in the controls from these studies. Imputation was used to estimate missing data in the pooled datasets. The 30th, 60th, and 90th centiles were used to distribute individuals into four risk groups for their age, sex, and geographic location. Cross-validation was used to test the robustness of the thresholds for each group by leaving out each study one by one. Performance of the model was assessed in an independent UK case control study dataset. RESULTS: Cross-validation confirmed the robustness of the threshold estimates. Cases and controls were well discriminated in the independent dataset [area under the curve, 0.75; 95% confidence interval (CI), 0.73-0.78]. Twenty-nine percent of cases were in the highest risk group compared with 7% of controls, and 43% of controls were in the lowest risk group compared with 13% of cases. CONCLUSION: We have identified a composite score representing an estimate of relative risk and successfully validated this score in an independent dataset. IMPACT: This score may be a useful tool to inform members of the public about their melanoma risk. PMID- 25713024 TI - Offering Self-Sampling Kits for HPV Testing to Reach Women Who Do Not Attend in the Regular Cervical Cancer Screening Program. AB - In 2016, the Netherlands will switch, as first European country, from cytology based to HPV-based cervical cancer screening, with cytology triage for those with a positive HPV test. The new Dutch program includes sending self-sampling devices to women who do not respond to an invitation to have a cervical sample taken by their general practitioner. The cost-effectiveness of this additional strategy will depend on its capacity to recruit nonscreened women and in particular those at increased risk of cervical (pre)cancer, the possible switch of previous responders to self-sampling, the accuracy and cost of the HPV assay-self-sampler combination, and the compliance of women being self-sample HPV-positive with further follow-up. Validated PCR-based assays, detecting high-risk HPV DNA, are as accurate on self-samples as on clinician-collected samples. On the contrary, HPV assays, based on signal amplification, are less sensitive and specific on self-samples. The introduction of self-sampling strategies should be carefully prepared and evaluated in pilot studies integrated in well-organized settings before general rollout. Opt-in procedures involving a request for a self-sampler may reduce response rates. Therefore, an affordable device that can be included with the invitation to all nonattendees may yield a stronger effect on participation. PMID- 25713023 TI - Survival among HIV-infected and HIV-uninfected individuals with common non-AIDS defining cancers. AB - BACKGROUND: Non-AIDS-defining cancers increasingly contribute to mortality among human immunodeficiency virus (HIV)-infected individuals. However, few studies have compared cancer prognosis by HIV status with adjustment for risk factors. METHODS: We conducted a cohort study of HIV-infected and HIV-uninfected adults in Kaiser Permanente California during 1996 to 2011, following subjects diagnosed with Hodgkin lymphoma or anal, prostate, colorectal, or lung cancers. We used Kaplan-Meier curves and Cox regression to assess cancer-related mortality within 5 years, comparing HIV-infected with HIV-uninfected subjects. Adjusted models included age, race/ethnicity, sex, cancer stage, cancer treatment, and smoking. RESULTS: Among HIV-infected and HIV-uninfected subjects, there were 68 and 51 cases of Hodgkin lymphoma, 120 and 28 of anal cancer, 150 and 2,050 of prostate cancer, 53 and 646 of colorectal cancer, and 80 and 507 of lung cancer, respectively. Five-year cancer-related survival was reduced for HIV-infected compared with HIV-uninfected subjects, reaching statistical significance for lung cancer (10% vs. 19%, P = 0.002) but not Hodgkin lymphoma (83% vs. 89%, P = 0.40) or anal (64% vs. 74%, P = 0.38), prostate (86% vs. 92%, P = 0.074), or colorectal cancers (49% vs. 58%, P = 0.55). Adjusted results were similar, with lung cancer [HR, 1.3; 95% confidence interval (CI), 1.0-1.7] and prostate cancer (HR, 2.1; 95% CI, 1.1-4.1) reaching significance. CONCLUSIONS: Cancer-related mortality was higher among HIV-infected compared with HIV-uninfected individuals for prostate and lung cancers, but not Hodgkin lymphoma, anal cancer, or colorectal cancer. IMPACT: Our findings emphasize the need for a focus on prevention, early detection, and adequate treatment of cancer among HIV-infected individuals. PMID- 25713025 TI - Association between Regular Aspirin Use and Circulating Markers of Inflammation: A Study within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. AB - BACKGROUND: Regular aspirin use may decrease cancer risk by reducing chronic inflammation. However, associations between aspirin use and circulating markers of inflammation have not been well studied. METHODS: Serum levels of 78 inflammatory markers were measured in 1,819 55- to 74-year-old men and women in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Data were combined from three completed case-control studies and reweighted to the PLCO screening arm. Self-reported aspirin and ibuprofen use (number of tablets taken per day/week/month) over the previous 12 months was collected at baseline. Associations between (i) nonregular (<4 tablets/month), (ii) low (1-4 tablets/week), (iii) moderate (1 tablet/day), or (iv) high (2+ tablets/day) regular aspirin or ibuprofen use and marker levels were assessed with weighted logistic regression. RESULTS: Aspirin use was nominally associated with (Ptrend across categories <= 0.05) decreased levels of chemokine C-C motif ligand 15 [CCL15; OR, 0.5; 95% confidence intervals (CI), 0.3-0.8; moderate versus nonregular use]; soluble vascular endothelial growth factor receptor 2 (sVEGFR2; OR, 0.7; 95% CI, 0.4-1.0); soluble tumor necrosis factor receptor 1 (sTNFR1; OR, 0.6; 95% CI, 0.4-0.9) and increased levels of CCL13 (OR, 1.3; 95% CI, 0.8-2.1); CCL17 (OR, 1.1; 95% CI, 0.7-1.9) and interleukin 4 (IL4; OR, 1.6; 95% CI, 0.9 2.8). Trends were not statistically significant following correction for multiple comparisons. Likewise, no statistically significant associations were observed between ibuprofen use and marker levels. CONCLUSIONS: No significant associations were observed between regular aspirin use and the inflammatory markers assessed. IMPACT: Additional studies are needed to better understand the relationship between aspirin use, chronic inflammation, and cancer risk. PMID- 25713026 TI - The innate immune system contributes to tissue-engineered vascular graft performance. AB - The first clinical trial of tissue-engineered vascular grafts (TEVGs) identified stenosis as the primary cause of graft failure. In this study, we aimed to elucidate the role of the host immune response in the development of stenosis using a murine model of TEVG implantation. We found that the C.B-17 wild-type (WT) mouse (control) undergoes a dramatic stenotic response, which is nearly completely abolished in the immunodeficient SCID/beige (bg) variant. SCID mice, which lack an adaptive immune system due to the absence of T and B lymphocytes, experienced rates of stenosis comparable to WT controls (average luminal diameter, WT: 0.071 +/- 0.035 mm, SCID: 0.137 +/- 0.032 mm, SCID/bg: 0.804 +/- 0.039 mm; P < 0.001). The bg mutation is characterized by NK cell and platelet dysfunction, and systemic treatment of WT mice with either NK cell-neutralizing (anti-NK 1.1 antibody) or antiplatelet (aspirin/Plavix [clopidogrel bisulfate]; Asp/Pla) therapy achieved nearly half the patency observed in the SCID/bg mouse (NK Ab: 0.356 +/- 0.151 mm, Asp/Pla: 0.452 +/- 0.130 mm). Scaffold implantation elicited a blunted immune response in SCID/bg mice, as demonstrated by macrophage number and mRNA expression of proinflammatory cytokines in TEVG explants. Implicating the initial innate immune response as a critical factor in graft stenosis may provide a strategy for prognosis and therapy of second-generation TEVGs. PMID- 25713027 TI - Novel proresolving and tissue-regenerative resolvin and protectin sulfido conjugated pathways. AB - Local mediators orchestrate the host response to both sterile and infectious challenge and resolution. Recent evidence demonstrates that maresin sulfido conjugates actively resolve acute inflammation and promote tissue regeneration. In this report, we investigated self-limited infectious exudates for novel bioactive chemical signals in tissue regeneration and resolution. By use of spleens from Escherichia coli infected mice, self-resolving infectious exudates, human spleens, and blood from patients with sepsis, we identified 2 new families of potent molecules. Characterization of their physical properties and isotope tracking demonstrated that the bioactive structures contained a docosahexaenoate backbone and sulfido-conjugated triene or tetraene double-bond systems. Activated human phagocytes converted 17-hydro(peroxy)-4Z,7Z,10Z,13Z,15E,19Z-docosahexaenoic acid to these bioactive molecules. Regeneration of injured planaria was accelerated with nanomolar amounts of 16-glutathionyl, 17-hydroxy 4Z,7Z,10,12,14,19Z-docosahexaenoic acid and 16-cysteinylglycinyl, 17-hydroxy 4Z,7Z,10,12,14,19Z-docosahexaenoic acid (Protectin sulfido-conjugates) or 8 glutathionyl, 7,17-dihydroxy-4Z,9,11,13Z,15E,19Z-docosahexaenoic acid and 8 cysteinylglycinyl, 7,17-dihydroxy-4Z,9,11,13Z,15E,19Z-docosahexaenoic acid (Resolvin sulfido-conjugates). Each protectin and resolvin sulfido-conjugate dose dependently (0.1-10 nM) stimulated human macrophage bacterial phagocytosis, phagolysosomal acidification, and efferocytosis. Together, these results identify 2 novel pathways and provide evidence for structural elucidation of new resolution moduli. These resolvin and protectin conjugates identified in mice and human infected tissues control host responses promoting catabasis. PMID- 25713028 TI - Neisseria meningitis GNA1030 is a ubiquinone-8 binding protein. AB - Bexsero, a new vaccine against Neisseria meningitidis serogroup B (MenB), is composed of 3 main recombinant proteins and an outer membrane vesicle component. One of the main bactericidal antigens, neisseria heparin binding antigen (NHBA), is present as a fusion protein with the accessory protein genome-derived neisserial antigen (GNA) 1030 to further increase its immunogenicity. The gene encoding for GNA1030 is present and highly conserved in all Neisseria strains, and although orthologs are present in numerous species, its biologic function is unknown. Native mass spectrometry was used to demonstrate that GNA1030 forms a homodimer associated with 2 molecules of ubiquinone-8 (Ub8), a cofactor mainly involved in the electron transport chain and with antioxidant properties. Disc diffusion assays on the wild-type and knockout mutant of GNA1030, in the presence of various compounds, suggested that GNA1030 is not involved in oxidative stress or electron chain transport per se, although it contributes to constitutive refilling of the inner membrane with Ub8. These studies shed light on an accessory protein present in Bexsero and reveal functional insights into the family of related proteins. On the basis of our findings, we propose to name the protein neisseria ubiquinone binding protein (NUbp). PMID- 25713029 TI - Genetic ablation of androgen receptor signaling in fetal Leydig cell lineage affects Leydig cell functions in adult testis. AB - It is commonly accepted that androgen-producing fetal Leydig cells (FLC) are substituted by adult Leydig cells (ALC) during perinatal testis development. The mechanisms influencing this process are unclear. We used mice with a retinoid acid receptor 2 promoter-Cre recombinase transgene (Rarb-cre) expressed in embryonic FLC precursors, but not in postnatal testis, and a dual fluorescent Cre recombinase reporter to label FLC and ALC in vivo. All FLC in newborn testis had the recombinant, whereas the majority of LC in adult testis had the nonrecombinant reporter. Primary LC cultures from adult testis had either recombinant (20%) or nonrecombinant (80%) cells, demonstrating that the FLC survive in adult testis and their ontogeny is distinct from ALC. Conditional inactivation of androgen receptor (AR) allele using the Rarb-cre transgene resulted in a 50% increase of AR-negative LC in adult testis. The mutant males became infertile with age, with all LC in older testis showing signs of incomplete differentiation, such as a large number of big lipid droplets, an increase of finger-like protrusions, and a misexpression of steroidogenic or FLC- and ALC-specific genes. We propose that the antiandrogenic exposure during early development may similarly result in an increase of FLC in adult testis, leading to abnormal LC differentiation. PMID- 25713030 TI - Alteration of gut microbiota by vancomycin and bacitracin improves insulin resistance via glucagon-like peptide 1 in diet-induced obesity. AB - Firmicutes and Bacteroidetes, 2 major phyla of gut microbiota, are involved in lipid and bile acid metabolism to maintain systemic energy homeostasis in host. Recently, accumulating evidence has suggested that dietary changes promptly induce the alteration of abundance of both Firmicutes and Bacteroidetes in obesity and its related metabolic diseases. Nevertheless, the metabolic roles of Firmicutes and Bacteroidetes on such disease states remain unclear. The aim of this study was to determine the effects of antibiotic-induced depletion of Firmicutes and Bacteroidetes on dysregulation of energy homeostasis in obesity. Treatment of C57BL/6J mice with the antibiotics (vancomycin [V] and bacitracin [B]), in the drinking water, before diet-induced obesity (DIO) greatly decreased both Firmicutes and Bacteroidetes in the gut as revealed by pyrosequencing of the microbial 16S rRNA gene. Concomitantly, systemic glucose intolerance, hyperinsulinemia, and insulin resistance in DIO were ameliorated via augmentation of GLP-1 secretion (active form; 2.03-fold, total form; 5.09-fold) independently of obesity as compared with untreated DIO controls. Furthermore, there were increases in metabolically beneficial metabolites derived from the gut. Together, our data suggest that Firmicutes and Bacteroidetes potentially mediate insulin resistance through modulation of GLP-1 secretion in obesity. PMID- 25713031 TI - Biochemical features and antiviral activity of a monomeric catalytic antibody light-chain 23D4 against influenza A virus. AB - Catalytic antibodies have exhibited interesting functions against some infectious viruses such as HIV, rabies virus, and influenza virus in vitro as well as in vivo. In some cases, a catalytic antibody light chain takes on several structures from the standpoint of molecular size (monomer, dimer, etc.) and/or isoelectronic point. In this study, we prepared a monomeric 23D4 light chain by mutating the C terminal Cys to Ala of the wild-type. The mutated 23D4 molecule took a simple monomeric form, which could hydrolyze synthetic 4-methyl-coumaryl-7-amide substrates and a plasmid DNA. Because the monomeric 23D4 light chain suppressed the infection of influenza virus A/Hiroshima/37/2001 in an in vitro assay, the corresponding experiments were conducted in vivo, after the virus strain (which was taken from a human patient) was successfully adapted into BALB/cN Sea mice. In the experiments, a mixture of the monomeric 23D4 and the virus was nasally administered 1) with preincubation and 2) without preincubation. As a result, the monomeric 23D4 clearly exhibited the ability to suppress the influenza virus infection in both cases, indicating a potential drug for preventing infection of the influenza A virus. PMID- 25713032 TI - Recommendations concerning the new U.S. National Institutes of Health initiative to balance the sex of cells and animals in preclinical research. AB - The U.S. National Institutes of Health (NIH) announced last May that steps will be taken to address the over-reliance on male cells and animals in preclinical research. To further address this announcement, in September 2014, scientists with varying perspectives came together at Georgetown University to discuss the following questions. (1) What metrics should the NIH use to assess tangible progress on policy changes designed to address the over-reliance on male cells and animals in preclinical research? (2) How effective can education be in reducing the over-reliance on male cells and animals in preclinical research and what educational initiatives sponsored by the NIH would most likely effect change? (3) What criteria should the NIH use to determine rigorously defined exceptions to the future proposal requirement of a balance of male and female cells and animals in preclinical studies? (4) What additional strategies in addition to proposal requirements should NIH use to reduce the overreliance of male cells and animals in preclinical research? The resulting consensus presented herein includes input from researchers not only from diverse disciplines of basic and translational science including biology, cell and molecular biology, biochemistry, physiology, pharmacology, neuroscience, cardiology, endocrinology, nephrology, psychiatry, and obstetrics and gynecology, but also from recognized experts in publishing, industry, advocacy, science policy, clinical medicine, and population health. We offer our recommendations to aid the NIH as it selects, implements, monitors, and optimizes strategies to correct the over-reliance on male cells and animals in preclinical research. PMID- 25713033 TI - Subjective global assessment versus sarcopenia detected by computed tomography. PMID- 25713034 TI - Response to Dr Khursheed Jeejeebhoy. PMID- 25713035 TI - JPEN Journal Club 11. Early Stopping. PMID- 25713036 TI - Paenibacillus tibetensis sp. nov., a psychrophilic bacterium isolated from alpine swamp meadow soil. AB - A novel psychrophilic strain, SSB001(T), was isolated from an alpine swamp meadow soil in Tibet, China, and identified as a representative of a novel phylogenetic subclade in the genus Paenibacillus , with Paenibacillus antarcticus (96.2%), Paenibacillus macquariensis (96.53%) and Paenibacillus glacialis (96.2%) as the most closely related species on the basis of 16S rRNA gene sequence analyses. The strain was distinguished from defined species of the genus Paenibacillus by further study of rpoB gene sequences, phenotypic characterization, cellular fatty acid composition, quinones, polar lipids and meso-diaminopimelic acid in the peptidoglycan. Based upon these results, we propose the strain as a representative of a novel species named Paenibacillus tibetensis sp. nov., with SSB001(T) ( =ACCC 19728(T) =DSM 29321(T)) as the type strain. The DNA G+C content (mol%) of strain SSB001(T) was 40.18 mol% (HPLC). PMID- 25713037 TI - Glycomyces tarimensis sp. nov., an actinomycete isolated from a saline-alkali habitat. AB - A novel actinomycete strain, designated TRM 45387(T), was isolated from a saline alkali soil in Xinjiang Province (40 degrees 22' N 79 degrees 08' E), north west China. The isolate was characterized using a polyphasic approach. 16S rRNA gene sequence analysis indicated that strain TRM 45387(T) belonged to the genus Glycomyces and was closely related to Glycomyces arizonensis DSM 44726(T) (96.59% 16S rRNA gene sequence similarity). The G+C content of the DNA was 71.26 mol%. The isolate contained meso-diaminopimelic acid as the diagnostic diamino acid, and xylose, glucose, galactose, arabinose and ribose as the major whole-cell sugars. The diagnostic phospholipids were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol and phosphatidylinositolmannosides. The predominant menaquinone was MK-10(H6). The major fatty acids were iso-C16 : 0, anteiso-C17 : 0 and anteiso-C15 : 0. On the basis of the evidence from this polyphasic study, a novel species, Glycomyces tarimensis sp. nov., is proposed. The type strain of Glycomyces tarimensis is TRM 45387(T) ( =CCTCC AA 2014007(T) =JCM 30184(T)). PMID- 25713038 TI - Rufibacter immobilis sp. nov., isolated from a high-altitude saline lake. AB - Two pinkish-red, Gram-stain-negative, non-motile aerobic bacterial strains (MCC P1(T) and MCC P2), capable of growing at low temperatures (15 degrees C), were isolated from water of a saline lake located in the western Himalayas of India. The strains were capable of growth in the presence of 0-2.0% NaCl and at pH 6.5 9.0. Phylogenetic analysis based on 16S rRNA gene sequences revealed the closest similarity of 96.3% to the type strain of the only species of the genus Rufibacter , Rufibacter tibetensis CCTCC AB 208084(T). Strains MCC P1(T) and MCC P2 shared 99.0% 16S rRNA gene sequence similarity and 88.6% DNA-DNA relatedness. The major cellular fatty acids were iso-C15 : 0, C17 : 1omega6c, summed feature 3 (C16 : 1omega6c/C16 : 1omega7c) and summed feature 4 (anteiso-C17 : 1 B/iso-C17 : 1 I). Predominant polar lipids were phosphatidylethanolamine, phosphatidylglycerol and diphosphatidylglycerol. The respiratory quinone was MK 7. The DNA G+C content of the strains was 52.6-52.8 mol%. Based on morphological, physiological, chemotaxonomical and molecular characteristics, strains MCC P1(T) and MCC P2 represent a novel species of the genus Rufibacter , for which the name Rufibacter immobilis sp. nov. is proposed. The type strain is MCC P1(T) ( =MCC 2268(T) =CCTCC AB 2013351(T)). PMID- 25713039 TI - Prauserella isguenensis sp. nov., a halophilic actinomycete isolated from desert soil. AB - Two actinomycete strains, designated H225(T) and H137, were isolated from two soil samples collected from the arid region of Ahbas at Beni-Isguen (Mzab), located in the Algerian Sahara. Phylogenetic analyses based on 16S rRNA gene sequences indicated that the novel strains should be assigned to the genus Prauserella of the family Pseudonocardiaceae , and they were therefore subjected to a polyphasic taxonomic study. These two strains contained meso-diaminopimelic acid as the diagnostic diamino acid and arabinose and galactose as major whole cell sugars. The diagnostic phospholipid was phosphatidylethanolamine. The predominant menaquinone was MK-9(H4), and the major fatty acid was iso-C16 : 0. DNA-DNA hybridization values between strain H225(T) and its closest phylogenetic neighbours, namely Prauserella flava DSM 45265(T), Prauserella alba DSM 44590(T), Prauserella aidingensis DSM 45266(T), Prauserella salsuginis DSM 45264(T) and Prauserella sediminis DSM 45267(T), were clearly below the 70% threshold used for species delineation. The genomic DNA G+C content of strains H225(T) and H137 was 70.4 mol%. On the basis of phenotypic and genotypic data, strains H225(T) and H137(T) are considered to represent a novel species of the genus Prauserella , for which the name Prauserella isguenensis sp. nov. is proposed. The type strain is H225(T) ( =DSM 46664(T) = CECT 8577(T)). PMID- 25713041 TI - Marinomonas mangrovi sp. nov., isolated from mangrove sediment. AB - A Gram-stain-negative, Na(+)-requiring bacterial strain, designated B20-1(T), was isolated from soil of the root system of mangrove forest. Cells were curved rods and motile by means of a polar flagellum. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain B20-1(T) belonged to the genus Marinomonas , sharing highest sequence similarities with Marinomonas rhizomae IVIA-Po-145(T) (97.6%), Marinomonas dokdonensis DSW10-10(T) (97.0%) and Marinomonas foliarum IVIA-Po-155(T) (96.9%). The predominant cellular fatty acids of strain B20-1(T) were C10 : 0 3-OH, C18 : 1omega7c, summed feature 3 (C16 : 1omega7c and/or iso C15 : 0 2-OH) and C16 : 0. Phosphatidylethanolamine and phosphatidylglycerol were identified as the predominant phospholipids. The predominant ubiquinone was Q-8. The genomic DNA G+C content of strain B20-1(T) was 46.6 mol%. On the basis of phenotypic characteristics, phylogenetic analysis and DNA-DNA relatedness, a novel species, Marinomonas mangrovi sp. nov., is proposed with B20-1(T) ( =DSM 28136(T) =LMG 28077(T)) as the type strain. PMID- 25713040 TI - Croceicoccus naphthovorans sp. nov., a polycyclic aromatic hydrocarbons-degrading and acylhomoserine-lactone-producing bacterium isolated from marine biofilm, and emended description of the genus Croceicoccus. AB - A polycyclic aromatic hydrocarbons-degrading and acylhomoserine-lactone-producing marine bacterium, designated strain PQ-2(T), was isolated from marine biofilm collected from a boat shell at a harbour of Zhoushan island in Zhejiang Province, PR China. Strain PQ-2(T) is Gram-stain-negative, yellow-pigmented, non-motile and short rod-shaped. Optimal growth of strain PQ-2(T) was observed at 32 degrees C, at pH 7.0 and in 2% (w/v) NaCl. The 16S rRNA gene sequence of strain PQ-2(T) showed highest similarity to Croceicoccus marinus E4A9(T) (96.3%) followed by Novosphingobium malaysiense MUSC 273(T) (95.6%) and Altererythrobacter marinus H32(T) (95.6%). Phylogenetic analysis with all species of the family Erythrobacteraceae with validly published names revealed that strain PQ-2(T) formed a phyletic line with Croceicoccus marinus E4A9(T) that was distinct from other members of the family Erythrobacteraceae . The sole respiratory quinone was ubiquinone 10 (Q-10). The predominant fatty acids were C18 : 1omega7c, C17 : 1omega6c and summed feature 3 (C16 : 1omega7c and/or iso-C15 : 0 2-OH). The genomic DNA G+C content was 61.7 mol%. In the polar lipid profile, phosphatidylethanolamine, phosphatidylcholine, phosphatidylglycerol, one unidentified phospholipid and one sphingoglycolipid were the major compounds; and another sphingoglycolipid was present in a minor amount. Based on the genotypic and phenotypic data, strain PQ-2(T) represents a novel species of the genus Croceicoccus , for which the name Croceicoccus naphthovorans sp. nov. is proposed. The type strain is PQ-2(T) ( =CGMCC 1.12805(T) =NBRC 110381(T)). In addition, emended descriptions for the genus Croceicoccus and the species C. marinus are given. PMID- 25713042 TI - Pseudohalocynthiibacter aestuariivivens gen. nov., sp. nov., isolated from a tidal flat. AB - A Gram-stain-negative, non-motile, aerobic and coccoid, ovoid or rod-shaped bacterial strain, designated BS-W9(T), was isolated from a tidal flat of the South Sea, South Korea. Strain BS-W9(T) grew optimally at 25-30 degrees C, at pH 7.0-8.0 and in the presence of approximately 2.0% (w/v) NaCl. Phylogenetic trees, based on 16S rRNA gene sequences, revealed that strain BS-W9(T) clustered with the type strain of Halocynthiibacter namhaensis , showing a highest sequence similarity of 97.3%. It exhibited sequence similarity values of less than 95.6% to the type strains of other species with validly published names. Strain BS W9(T) contained Q-10 as the predominant ubiquinone and C18:1omega7c as the predominant fatty acid. The major polar lipids of strain BS-W9(T) were phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, one unidentified lipid and one unidentified aminolipid. The fatty acid and polar lipid profiles of strain BS-W9(T) were distinguished from those of the type strains of H. namhaensis and other phylogenetically related genera. The DNA G+C content of strain BS-W9(T) was 53.2 mol% and its mean DNA-DNA relatedness value with H. namhaensis RA2-3(T) was 14%. On the basis of the phylogenetic, chemotaxonomic and other phenotypic properties, strain BS-W9(T) is considered to represent a novel genus and species within the family Rhodobacteraceae , for which the name Pseudohalocyntiibacter aestuariivivens gen. nov., sp. nov. is proposed. The type strain of Pseudohalocyntiibacter aestuariivivens is BS-W9(T) ( =KCTC 42348(T) =CECT 8726(T)). PMID- 25713043 TI - Bradymonas sediminis gen. nov., sp. nov., isolated from coastal sediment, and description of Bradymonadaceae fam. nov. and Bradymonadales ord. nov. AB - A novel Gram-stain-negative, rod-shaped, gliding, facultatively anaerobic, oxidase-negative and catalase-positive bacterium, designated FA350(T), was isolated from coastal sediment from Xiaoshi Island, Weihai, China. Strain FA350(T) showed growth on modified nutrient agar supplemented with 0.1% d-(+) trehalose and with distilled water replaced by seawater. Optimal growth occurred at 33 degrees C and pH 8.5 with 4% NaCl. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain FA350(T) belongs to a novel bacterial order in the class Deltaproteobacteria , and the most closely related type strains belong to the order Desulfuromonadales , with 85.1-85.6% 16S rRNA gene sequence similarity. The polar lipid profile of the novel strain consisted of phosphatidylethanolamine, phosphatidylglycerol and two unknown phospholipids. Major cellular fatty acids were iso-C15 : 0, iso-C17 : 0 and iso-C17 : 1omega10c and menaquinone MK-7 was the sole respiratory quinone. The DNA G+C content of strain FA350(T) was 60.3 mol%. The isolate and closely related environmental clones formed a novel order-level clade in the class Deltaproteobacteria . Comparative analysis of 16S rRNA gene sequences and characterization indicated that strain FA350(T) may represent a novel order of the Deltaproteobacteria . Here, we propose the name Bradymonas sediminis gen. nov., sp. nov. to accommodate strain FA350(T). The type strain of Bradymonas sediminis is FA350(T) ( =DSM 28820(T) =CICC 10904(T)); Bradymonadales ord. nov. and Bradymonadaceae fam. nov. are also proposed to accommodate the novel taxon. PMID- 25713044 TI - Algibacter amylolyticus sp. nov., isolated from intertidal sediment. AB - A Gram-reaction-negative, rod-shaped, yellow-pigmented, motile by gliding bacterial strain, designated RU-4-M-4(T), was isolated from intertidal sediment of Sakhalin Island in Russia. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain RU-4-M-4(T) was related to the genus Algibacter and had highest 16S rRNA gene sequence similarity with Algibacter pectinivorans KACC 14153(T) (97.2%). The major cellular fatty acids were iso-C15 : 0 3-OH, C15: 0 and iso-C15 : 1 G. The predominant menaquinone was MK-6. The polar lipid profile contained phosphatidylethanolamine, three unidentified aminolipids and two unidentified lipids. The genomic DNA G+C content of strain RU-4-M-4(T) was 36.4 mol%. Combined data from phenotypic, phylogenetic and DNA-DNA relatedness studies demonstrated that strain RU-4-M-4(T) is a representative of a novel species of the genus Algibacter , for which we propose the name Algibacter amylolyticus sp. nov. (type strain RU-4-M-4(T) =LMG 28383(T) =DSM 29199(T)). PMID- 25713045 TI - Aliiglaciecola aliphaticivorans sp. nov., an aliphatic hydrocarbon-degrading bacterium, isolated from a sea-tidal flat and emended description of the genus Aliiglaciecola Jean et al. 2013. AB - A Gram-stain-negative heterotrophic bacterium, designated GSD6(T), capable of growth on aliphatic hydrocarbons as a sole carbon and energy source, was isolated from sea-tidal flat sediment of the Yellow Sea, South Korea. Cells were facultatively aerobic, catalase- and oxidase-positive, motile rods with a single polar flagellum. Growth of strain GSD6(T) was observed at 4-37 degrees C (optimum 30 degrees C), at pH 5.5-9.0 (optimum pH 6.5-7.5) and in the presence of 1-9% (w/v) NaCl (optimum 2%). Strain GSD6(T) contained ubiquinone-8 (Q-8) as the sole isoprenoid quinone and summed feature 3 (comprising C16 : 1omega7c and/or iso-C15 : 0 2-OH), C16 : 0, C18 : 1omega7c, C17 : 0 10-methyl and C17 : 1omega8c as the major fatty acids. Phosphatidylethanolamine and phosphatidylglycerol were identified as the major polar lipids. The G+C content of the genomic DNA was 44.6 mol%. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain GSD6(T) formed a phylogenetic lineage with members of the genus Aliiglaciecola . Strain GSD6(T) was most closely related to Aliiglaciecola lipolytica E3(T) with a 16S rRNA gene sequence similarity of 97.4%, but their DNA-DNA hybridization value was 39.1 +/- 7.1%. On the basis of phenotypic, chemotaxonomic and molecular features, strain GSD6(T) represents a novel species of the genus Aliiglaciecola , for which the name Aliiglaciecola aliphaticivorans sp. nov. is proposed. The type strain is GSD6(T) ( =KACC 18129(T) =JCM 30133(T)). An emended description of the genus Aliiglaciecola is also proposed. PMID- 25713046 TI - Rufibacter roseus sp. nov., isolated from radiation-polluted soil. AB - A rose, Gram-stain-negative, aerobic, rod-shaped bacterium that was motile by gliding, and designated strain H359(T), was isolated from radiation-polluted soil (with high Cs(137)) from the Xinjiang Uygur Autonomous Region of PR China and subjected to a polyphasic taxonomic analysis. The isolate grew optimally at 30 degrees C and pH 7.0. It grew with NaCl up to 4% (w/v). 16S rRNA gene sequence analysis indicated that strain H359(T) belonged to the genus Rufibacter, a member of the family Cytophagaceae, with Rufibacter tibetensis CCTCC AB 208084(T) as its closest phylogenetic relative, having 96.1% 16S rRNA gene sequence similarity to the type strain. Strain H359(T) contained menaquinone-7 (MK-7) as the predominant menaquinone, and the major fatty acids were iso-C15 : 0, summed feature 4 (iso C17 : 1 I and/or anteiso-C17 : 1 B), summed feature 3 (C16 : 1omega7c and/or C16 : 1omega6c) and C16 : 1omega5c. The polar lipid profile had phosphatidylethanolamine as the major component. The DNA G+C content was 43.9 mol%. Based on phenotypic, genotypic and phylogenetic evidence, strain H359(T) represents a novel species of the genus Rufibacter, for which the name Rufibacter roseus sp. nov. is proposed. The type strain is H359(T) ( =CPCC 100615(T) =KCTC 42217(T)). PMID- 25713047 TI - Sediminicola arcticus sp. nov., a psychrophilic bacterium isolated from deep-sea sediment, and emended description of the genus Sediminicola. AB - A Gram-stain-negative, rod-shaped and non-motile strain, designated PAMC 27266(T), was isolated from deep-sea sediment of the Arctic Ocean. Analysis of the 16S rRNA gene sequence of strain PAMC 27266(T) showed closest affiliation with the genus Sediminicola . Phylogenetic analyses revealed that strain PAMC 27266(T) formed a robust clade with Sediminicola luteus CNI-3(T), with which it shared 98.9% 16S rRNA gene sequence similarity. Genomic relatedness analyses based on the average nucleotide identity and genome-to-genome distance showed that strain PAMC 27266(T) is clearly distinguished from S. luteus . Cells of strain PAMC 27266(T) grew optimally at 15 degrees C and pH 6.5-7.5 in the presence of 3.5% (w/v) sea salts. The major polar lipids were phosphatidylethanolamine, two unidentified aminophospholipids and two unidentified lipids. The only respiratory quinone was menaquinone-6. The major cellular fatty acids (>10%) were C16 : 1omega6c and/or C16 : 1omega7c and C15 : 0. The genomic DNA G+C content was 37.9 mol%. Based on the phylogenetic, genomic, chemotaxonomic and phenotypic data presented, we propose strain PAMC 27266(T) ( =KCCM 43038(T) =JCM 19894(T)) as the type strain of a novel species, with the name Sediminicola arcticus sp. nov. PMID- 25713048 TI - Occultifur tropicalis f.a., sp. nov., a novel cystobasidiomycetous yeast species isolated from tropical regions. AB - Five strains representing a single novel anamorphic yeast species were isolated from sugar cane. Two strains were from tissue (DMKU-SE38, DMKU-SE59(T)) and two from the external surface (DMKU-SP385, DMKU-SP403) of leaves collected in Thailand and the fifth (IMUFRJ 52020) from the rhizoplane of sugar cane in an organically cultivated field in Brazil. On the basis of sequence analysis of the D1/D2 region of the large subunit (LSU) rRNA gene and the internal transcribed spacer (ITS) region, they were classified as representing a single species of the genus Occultifur. The sequences of the D1/D2 region of the LSU rRNA genes and the ITS regions of the five strains were either identical or differed from each other by only one nucleotide substitution. The novel species was related most closely to Occultifur brasiliensis f.a. CBS 12687(T) but with 0.7-1.0% nucleotide substitutions (4-6 nt) in the D1/D2 region of the LSU rRNA gene and 2.5-2.7% nucleotide substitutions (14-15 nt) in the ITS region. The name Occultifur tropicalis f.a., sp. nov. is proposed. The type strain is DMKU-SE59(T) ( =BCC 61184(T) =NBRC 109696(T) =CBS 13389 (T)). PMID- 25713049 TI - Bacillus crassostreae sp. nov., isolated from an oyster (Crassostrea hongkongensis). AB - A novel Gram-stain-positive, motile, catalase- and oxidase-positive, endospore forming, facultatively anaerobic rod, designated strain JSM 100118(T), was isolated from an oyster (Crassostrea hongkongensis) collected from the tidal flat of Naozhou Island in the South China Sea. Strain JSM 100118(T) was able to grow with 0-13% (w/v) NaCl (optimum 2-5%), at pH 5.5-10.0 (optimum pH 7.5) and at 5-50 degrees C (optimum 30-35 degrees C). The cell-wall peptidoglycan contained meso diaminopimelic acid as the diagnostic diamino acid. The predominant respiratory quinone was menaquinone-7 and the major cellular fatty acids were anteiso-C15 : 0, iso-C15 : 0, C16 : 0 and C16 : 1omega11c. The polar lipids consisted of diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, an unknown glycolipid and an unknown phospholipid. The genomic DNA G+C content was 35.9 mol%. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain JSM 100118(T) belonged to the genus Bacillus , and was most closely related to Bacillus litoralis SW-211(T) (98.9% 16S rRNA gene sequence similarity), Bacillus halosaccharovorans E33(T) (98.3%), Bacillus niabensis 4T19(T) (97.8%) and Bacillus herbersteinensis D-1,5a(T) (97.1%). The combination of results from the phylogenetic analysis, DNA-DNA hybridization, and phenotypic and chemotaxonomic characterization supported the conclusion that strain JSM 100118(T) represents a novel species of the genus Bacillus , for which the name Bacillus crassostreae sp. nov. is proposed. The type strain is JSM 100118(T) ( = CTCC AB 2010452(T) =DSM 24486(T) =JCM 17523(T)). PMID- 25713050 TI - Investigation of established genetic risk variants for glioma in prediagnostic samples from a population-based nested case-control study. AB - BACKGROUND: Although glioma etiology is poorly understood in general, growing evidence indicates a genetic component. Four large genome-wide association studies (GWAS) have linked common genetic variants with an increased glioma risk. However, to date, these studies are based largely on a case-control design, where cases have been recruited at the time of or after diagnosis. They may therefore suffer from a degree of survival bias, introduced when rapidly fatal cases are not included. METHODS: To confirm glioma risk variants in a prospective setting, we have analyzed 11 previously identified risk variants in a set of prediagnostic serum samples with 598 cases and 595 matched controls. Serum samples were acquired from The Janus Serum Bank, a Norwegian population-based biobank reserved for cancer research. RESULTS: We confirmed the association with glioma risk for variants within five genomic regions: 8q24.21 (CCDC26), 9p21.3 (CDKN2B-AS1), 11q23.3 (PHLDB1), 17p13.1 (TP53), and 20q13.33 (RTEL1). However, previously identified risk variants within the 7p11.2 (EGFR) region were not confirmed by this study. CONCLUSIONS: Our results indicate that the risk variants that were confirmed by this study are truly associated with glioma risk and may, consequently, affect gliomagenesis. Though the lack of positive confirmation of EGFR risk variants may be attributable to relatively limited statistical power, it nevertheless raises the question whether they truly are risk variants or markers for glioma prognosis. IMPACT: Our findings indicate the need for further studies to clarify the role of glioma risk loci with respect to prolonged survival versus etiology. PMID- 25713051 TI - Synchronization in stress p53 network. AB - We study transition of the temporal behaviours of p53 and MDM2 in a stress p53 MDM2-NO regulatory network induced by a bioactive molecule NO (Nitric Oxide). We further study synchronization among a group of identical stress systems arranged in a 3D array with nearest neighbour diffusive coupling. The role of NO and the effect of noise are investigated. In the single system study, we found three distinct types of temporal behaviour of p53, namely oscillation death, damped oscillation and sustained oscillation, depending on the amount of stress induced by NO, indicating how p53 responds to incoming stress. The correlation among coupled systems increases as the value of the coupling constant (epsilon) is increased (gamma increases) and becomes constant after a certain value of epsilon. The permutation entropy spectra H(epsilon) for p53 and MDM2 as a function of epsilon are found to be different due to direct and indirect interaction of NO with respective proteins. We find gamma versus epsilon for p53 and MDM2 to be similar in a deterministic approach but different in a stochastic approach, and the separation between gamma of the respective proteins as a function of epsilon decreases as system size increases. The role of NO is found to be two-fold: stress induced by NO is prominent at small and large values of epsilon but synchrony induced by it dominates in the moderate range of epsilon. Excess stress induces apoptosis. PMID- 25713052 TI - Variation in duplex peak systolic velocity measurement in a multi-site vascular service. AB - OBJECTIVE: Duplex US (DUS) is increasingly utilised as a first-line investigation for the assessment of carotid disease. For clinical decision-making, DUS assessment must be accurate and reproducible to ensure reliability. We aimed to investigate the variability in peak systolic velocity (PSV) measurement in a multi-site vascular network. METHODS: DUS measurements of PSV were taken from continuous and pulsatile flow, generated by a high fidelity phantom, by 12 experienced vascular scientists across four hospitals. Participants were blinded to the actual PSV value (50 cm/s). RESULTS: We observed an average error of 13.2% (+/- 8.3) and 11.6% (+/- 7.5) in PSV measurements taken from pulsatile and continuous waveforms, respectively. Measurements of PSV using the pulsatile waveform demonstrated statistically significant variation across all hospitals; ((hospital/mean) A 43.9 cm/s, B 61.7 cm/s, C 57.4 cm/s, D 47.7 cm/s, p=0.001). Further analysis demonstrated statistically significant variation in 4 instrumentation-related factors when measuring from a pulsatile waveform (Doppler angle, angle of insonation, velocity range, scale range). CONCLUSION: We observed a significant level of error and variation in PSV measurements across four sites within our vascular network. Variation in instrumentation-related factors may be accountable for this. In light of the centralisation of vascular services, it is increasingly important to unify and implement scanning protocols in order to reduce error and inter-site variability. PMID- 25713053 TI - The effect of pre-operative blood withdrawal, with or without sequestration, on allogeneic blood product requirements. AB - A common effect of autologous blood withdrawal before cardiopulmonary bypass (CPB) is a decrease in haematocrit (Hct) and haemoglobin (Hb) content. A refinement of this technique is autologous blood withdrawal with the sequestration of platelet rich plasma (PRP) and red blood cells (RBCs). METHODS: One hundred and four patients were included in a randomized study stratified into three groups: the autologous blood withdrawal group (Group 1), the autologous blood withdrawal group with blood loss sequestration (Group 2) and the control group (Control group). In Group 1, the amount of withdrawn blood was transfused after CPB. In Group 2, the RBCs were transfused immediately after sequestration and the PRP was transfused after the termination of CPB. In the Control group, no autologous blood withdrawal was employed. The following variables were analysed: blood loss, blood products transfusion, fluid transfusion, diuresis, haematological and coagulation data and the duration of the operation and intensive care unit stay. RESULTS: We found no significant differences in peri operative blood loss and transfused blood products among the three groups. There was a trend towards a lower amount of transfused fresh frozen plasma (FFP) for Group 1 (p =0.057) in the operation room (OR). The use of plasma expanders post CPB was significantly higher in the Control group (p=0.024). RBCs coming from the auto-transfusion device were, for Group 1, significantly lower (p=0.007). The Hb and Hct values in Group 1, at start and end of CPB, were significantly lower (p=0.023-0.003 / 0.001-0.001, respectively). All other parameters were not significantly different. CONCLUSION: there were no significant differences between the study groups. This randomized trial shows that, although sequestration immediately after autologous blood withdrawal has no added value, autologous blood withdrawal in patients with a normal pre-operative Hb and Hct is simple, inexpensive and allows for autologous blood transfusion. PMID- 25713054 TI - Type I phosphatidylinositol 4-phosphate 5-kinase homo- and heterodimerization determines its membrane localization and activity. AB - Type I phosphatidylinositol 4-phosphate 5-kinases (PIP5KIs; alpha, beta, and gamma) are a family of isoenzymes that produce phosphatidylinositol 4,5 bisphosphate [PI(4,5)P2] using phosphatidylinositol 4-phosphate as substrate. Their structural homology with the class II lipid kinases [type II phosphatidylinositol 5-phosphate 4-kinase (PIP4KII)] suggests that PIP5KI dimerizes, although this has not been formally demonstrated. Neither the hypothetical structural dimerization determinants nor the functional consequences of dimerization have been studied. Here, we used Forster resonance energy transfer, coprecipitation, and ELISA to show that PIP5KIbeta forms homo- and heterodimers with PIP5KIgamma_i2 in vitro and in live human cells. Dimerization appears to be a general phenomenon for PIP5KI isoenzymes because PIP5KIbeta/PIP5KIalpha heterodimers were also detected by mass spectrometry. Dimerization was independent of actin cytoskeleton remodeling and was also observed using purified proteins. Mutagenesis studies of PIP5KIbeta located the dimerization motif at the N terminus, in a region homologous to that implicated in PIP4KII dimerization. PIP5KIbeta mutants whose dimerization was impaired showed a severe decrease in PI(4,5)P2 production and plasma membrane delocalization, although their association to lipid monolayers was unaltered. Our results identify dimerization as an integral feature of PIP5K proteins and a central determinant of their enzyme activity. PMID- 25713055 TI - 15-Lipoxygenase-1 suppression of colitis-associated colon cancer through inhibition of the IL-6/STAT3 signaling pathway. AB - The IL-6/signal transducer and activator of transcription 3 (STAT3) pathway is a critical signaling pathway for colitis-associated colorectal cancer (CAC). Peroxisome proliferator-activated receptor (PPAR)-delta, a lipid nuclear receptor, up-regulates IL-6. 15-Lipoxygenase-1 (15-LOX-1), which is crucial to production of lipid signaling mediators to terminate inflammation, down-regulates PPAR-delta. 15-LOX-1 effects on IL-6/STAT3 signaling and CAC tumorigenesis have not been determined. We report that intestinally targeted transgenic 15-LOX-1 expression in mice inhibited azoxymethane- and dextran sodium sulfate-induced CAC, IL-6 expression, STAT3 phosphorylation, and IL-6/STAT3 downstream target (Notch3 and MUC1) expression. 15-LOX-1 down-regulation was associated with IL-6 up-regulation in human colon cancer mucosa. Reexpression of 15-LOX-1 in human colon cancer cells suppressed IL-6 mRNA expression, STAT3 phosphorylation, IL-6 promoter activity, and PPAR-delta mRNA and protein expression. PPAR-delta overexpression in colonic epithelial cells promoted CAC tumorigenesis in mice and increased IL-6 expression and STAT3 phosphorylation, whereas concomitant 15-LOX-1 expression in colonic epithelial cells (15-LOX-1-PPAR-delta-Gut mice) suppressed these effects: the number of tumors per mouse (mean +/- sem) was 4.22 +/- 0.68 in wild-type littermates, 6.67 +/- 0.83 in PPAR-delta-Gut mice (P = 0.026), and 2.25 +/- 0.25 in 15-LOX-1-PPAR-delta-Gut mice (P = 0.0006). Identification of 15-LOX-1 suppression of PPAR-delta to inhibit IL-6/STAT3 signaling-driven CAC tumorigenesis provides mechanistic insights that can be used to molecularly target CAC. PMID- 25713056 TI - Vitamin D and the omega-3 fatty acids control serotonin synthesis and action, part 2: relevance for ADHD, bipolar disorder, schizophrenia, and impulsive behavior. AB - Serotonin regulates a wide variety of brain functions and behaviors. Here, we synthesize previous findings that serotonin regulates executive function, sensory gating, and social behavior and that attention deficit hyperactivity disorder, bipolar disorder, schizophrenia, and impulsive behavior all share in common defects in these functions. It has remained unclear why supplementation with omega-3 fatty acids and vitamin D improve cognitive function and behavior in these brain disorders. Here, we propose mechanisms by which serotonin synthesis, release, and function in the brain are modulated by vitamin D and the 2 marine omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Brain serotonin is synthesized from tryptophan by tryptophan hydroxylase 2, which is transcriptionally activated by vitamin D hormone. Inadequate levels of vitamin D (~70% of the population) and omega-3 fatty acids are common, suggesting that brain serotonin synthesis is not optimal. We propose mechanisms by which EPA increases serotonin release from presynaptic neurons by reducing E2 series prostaglandins and DHA influences serotonin receptor action by increasing cell membrane fluidity in postsynaptic neurons. We propose a model whereby insufficient levels of vitamin D, EPA, or DHA, in combination with genetic factors and at key periods during development, would lead to dysfunctional serotonin activation and function and may be one underlying mechanism that contributes to neuropsychiatric disorders and depression. This model suggests that optimizing vitamin D and marine omega-3 fatty acid intake may help prevent and modulate the severity of brain dysfunction. PMID- 25713057 TI - Genomic DNA nanoparticles rescue rhodopsin-associated retinitis pigmentosa phenotype. AB - Mutations in the rhodopsin gene cause retinal degeneration and clinical phenotypes including retinitis pigmentosa (RP) and congenital stationary night blindness. Effective gene therapies have been difficult to develop, however, because generating precise levels of rhodopsin expression is critical; overexpression causes toxicity, and underexpression would result in incomplete rescue. Current gene delivery strategies routinely use cDNA-based vectors for gene targeting; however, inclusion of noncoding components of genomic DNA (gDNA) such as introns may help promote more endogenous regulation of gene expression. Here we test the hypothesis that inclusion of genomic sequences from the rhodopsin gene can improve the efficacy of rhodopsin gene therapy in the rhodopsin knockout (RKO) mouse model of RP. We utilize our compacted DNA nanoparticles (NPs), which have the ability to transfer larger and more complex genetic constructs, to deliver murine rhodopsin cDNA or gDNA. We show functional and structural improvements in RKO eyes for up to 8 months after NP-mediated gDNA but not cDNA delivery. Importantly, in addition to improvements in rod function, we observe significant preservation of cone function at time points when cones in the RKO model are degenerated. These results suggest that inclusion of native expression elements, such as introns, can significantly enhance gene expression and therapeutic efficacy and may become an essential option in the array of available gene delivery tools. PMID- 25713058 TI - NADH fluorescence lifetime is an endogenous reporter of alpha-synuclein aggregation in live cells. AB - alpha-Synuclein (aS) aggregation has been amply investigated for its involvement in Parkinson's disease because its amyloid fibrils are the main constituent of Lewy bodies, one of the hallmarks of the disease. aS aggregation was studied here in vitro and in cellular models to correlate aggregation products with toxicity mechanisms. Independent results published elsewhere suggested that aS overexpression and/or aggregation may impair cellular metabolism and cause mitochondrial damage. In this context, we report the characterization of changes in NADH fluorescence properties in vitro and in human embryonic kidney 293 cells upon aS aggregation. The application of the phasor approach to study NADH fluorescence lifetime and emission allowed us to identify changes that correlate with aS aggregation. In particular, the fraction of bound NADH, characterized by longer lifetimes in comparison to free NADH, is increased, and the maximum of the NADH emission is shifted toward shorter wavelengths in the presence of aggregating aS both in vitro and in cells. These data suggest that NADH binds to aggregated aS. NMR experiments in vitro substantiate such binding, which occurs during aggregation. NADH fluorescence is thus useful to detect aS aggregation and by extension the associated oxidative stress. PMID- 25713059 TI - Increasing mitochondrial muscle fatty acid oxidation induces skeletal muscle remodeling toward an oxidative phenotype. AB - Adult skeletal muscle is a dynamic, remarkably plastic tissue, which allows myofibers to switch from fast/glycolytic to slow/oxidative types and to increase mitochondrial fatty acid oxidation (mFAO) capacity and vascularization in response to exercise training. mFAO is the main muscle energy source during endurance exercise, with carnitine palmitoyltransferase 1 (CPT1) being the key regulatory enzyme. Whether increasing muscle mFAO affects skeletal muscle physiology in adulthood actually remains unknown. To investigate this, we used in vivo electrotransfer technology to express in mouse tibialis anterior (TA), a fast/glycolytic muscle, a mutated CPT1 form (CPT1mt) that is active but insensitive to malonyl-CoA, its physiologic inhibitor. In young (2-mo-old) adult mice, muscle CPT1mt expression enhanced mFAO (+40%), but also increased the percentage of oxidative fibers (+28%), glycogen content, and capillary-to-fiber density (+45%). This CPT1mt-induced muscle remodeling, which mimicked exercise induced oxidative phenotype, led to a greater resistance to muscle fatigue. In the context of aging, characterized by sarcopenia and reduced oxidative capacity, CPT1mt expression in TAs from aged (20-mo-old) mice partially reversed aging associated sarcopenia and fiber-type transition, and increased muscle capillarity. These findings provide evidence that mFAO regulates muscle phenotype and may be a potential target to combat age-related decline in muscle function. PMID- 25713060 TI - Challenges and opportunities in developing respiratory syncytial virus therapeutics. AB - Two meetings, one sponsored by the Wellcome Trust in 2012 and the other by the Global Virology Foundation in 2013, assembled academic, public health and pharmaceutical industry experts to assess the challenges and opportunities for developing antivirals for the treatment of respiratory syncytial virus (RSV) infections. The practicalities of clinical trials and establishing reliable outcome measures in different target groups were discussed in the context of the regulatory pathways that could accelerate the translation of promising compounds into licensed agents. RSV drug development is hampered by the perceptions of a relatively small and fragmented market that may discourage major pharmaceutical company investment. Conversely, the public health need is far too large for RSV to be designated an orphan or neglected disease. Recent advances in understanding RSV epidemiology, improved point-of-care diagnostics, and identification of candidate antiviral drugs argue that the major obstacles to drug development can and will be overcome. Further progress will depend on studies of disease pathogenesis and knowledge provided from controlled clinical trials of these new therapeutic agents. The use of combinations of inhibitors that have different mechanisms of action may be necessary to increase antiviral potency and reduce the risk of resistance emergence. PMID- 25713061 TI - Key residues in the nicotinic acetylcholine receptor beta2 subunit contribute to alpha-conotoxin LvIA binding. AB - alpha-Conotoxin LvIA (alpha-CTx LvIA) is a small peptide from the venom of the carnivorous marine gastropod Conus lividus and is the most selective inhibitor of alpha3beta2 nicotinic acetylcholine receptors (nAChRs) known to date. It can distinguish the alpha3beta2 nAChR subtype from the alpha6beta2* (* indicates the other subunit) and alpha3beta4 nAChR subtypes. In this study, we performed mutational studies to assess the influence of residues of the beta2 subunit versus those of the beta4 subunit on the binding of alpha-CTx LvIA. Although two beta2 mutations, alpha3beta2[F119Q] and alpha3beta2[T59K], strongly enhanced the affinity of LvIA, the beta2 mutation alpha3beta2[V111I] substantially reduced the binding of LvIA. Increased activity of LvIA was also observed when the beta2-T59L mutant was combined with the alpha3 subunit. There were no significant difference in inhibition of alpha3beta2[T59I], alpha3beta2[Q34A], and alpha3beta2[K79A] nAChRs when compared with wild-type alpha3beta2 nAChR. alpha-CTx LvIA displayed slower off-rate kinetics at alpha3beta2[F119Q] and alpha3beta2[T59K] than at the wild-type receptor, with the latter mutant having the most pronounced effect. Taken together, these data provide evidence that the beta2 subunit contributes to alpha-CTx LvIA binding and selectivity. The results demonstrate that Val(111) is critical and facilitates LvIA binding; this position has not previously been identified as important to binding of other 4/7 framework alpha-conotoxins. Thr(59) and Phe(119) of the beta2 subunit appear to interfere with LvIA binding, and their replacement by the corresponding residues of the beta4 subunit leads to increased affinity. PMID- 25713063 TI - Multidomain human peroxidasin 1 is a highly glycosylated and stable homotrimeric high spin ferric peroxidase. AB - Human peroxidasin 1 (hsPxd01) is a multidomain heme peroxidase that uses bromide as a cofactor for the formation of sulfilimine cross-links. The latter confers critical structural reinforcement to collagen IV scaffolds. Here, hsPxd01 and various truncated variants lacking nonenzymatic domains were recombinantly expressed in HEK cell lines. The N-glycosylation site occupancy and disulfide pattern, the oligomeric structure, and unfolding pathway are reported. The homotrimeric iron protein contains a covalently bound ferric high spin heme per subunit with a standard reduction potential of the Fe(III)/Fe(II) couple of -233 +/- 5 mV at pH 7.0. Despite sequence homology at the active site and biophysical properties similar to human peroxidases, the catalytic efficiency of bromide oxidation (kcat/KM(app)) of full-length hsPxd01 is rather low but increased upon truncation. This is discussed with respect to its structure and proposed biosynthetic function in collagen IV cross-linking. PMID- 25713062 TI - A triple mutant in the Omega-loop of TEM-1 beta-lactamase changes the substrate profile via a large conformational change and an altered general base for catalysis. AB - beta-Lactamases are bacterial enzymes that hydrolyze beta-lactam antibiotics. TEM 1 is a prevalent plasmid-encoded beta-lactamase in Gram-negative bacteria that efficiently catalyzes the hydrolysis of penicillins and early cephalosporins but not oxyimino-cephalosporins. A previous random mutagenesis study identified a W165Y/E166Y/P167G triple mutant that displays greatly altered substrate specificity with increased activity for the oxyimino-cephalosporin, ceftazidime, and decreased activity toward all other beta-lactams tested. Surprisingly, this mutant lacks the conserved Glu-166 residue critical for enzyme function. Ceftazidime contains a large, bulky side chain that does not fit optimally in the wild-type TEM-1 active site. Therefore, it was hypothesized that the substitutions in the mutant expand the binding site in the enzyme. To investigate structural changes and address whether there is an enlargement in the active site, the crystal structure of the triple mutant was solved to 1.44 A. The structure reveals a large conformational change of the active site Omega-loop structure to create additional space for the ceftazidime side chain. The position of the hydroxyl group of Tyr-166 and an observed shift in the pH profile of the triple mutant suggests that Tyr-166 participates in the hydrolytic mechanism of the enzyme. These findings indicate that the highly conserved Glu-166 residue can be substituted in the mechanism of serine beta-lactamases. The results reveal that the robustness of the overall beta-lactamase fold coupled with the plasticity of an active site loop facilitates the evolution of enzyme specificity and mechanism. PMID- 25713065 TI - Fo-driven Rotation in the ATP Synthase Direction against the Force of F1 ATPase in the FoF1 ATP Synthase. AB - Living organisms rely on the FoF1 ATP synthase to maintain the non-equilibrium chemical gradient of ATP to ADP and phosphate that provides the primary energy source for cellular processes. How the Fo motor uses a transmembrane electrochemical ion gradient to create clockwise torque that overcomes F1 ATPase driven counterclockwise torque at high ATP is a major unresolved question. Using single FoF1 molecules embedded in lipid bilayer nanodiscs, we now report the observation of Fo-dependent rotation of the c10 ring in the ATP synthase (clockwise) direction against the counterclockwise force of ATPase-driven rotation that occurs upon formation of a leash with Fo stator subunit a. Mutational studies indicate that the leash is important for ATP synthase activity and support a mechanism in which residues aGlu-196 and cArg-50 participate in the cytoplasmic proton half-channel to promote leash formation. PMID- 25713064 TI - Mechanisms of membrane binding of small GTPase K-Ras4B farnesylated hypervariable region. AB - K-Ras4B belongs to a family of small GTPases that regulates cell growth, differentiation and survival. K-ras is frequently mutated in cancer. K-Ras4B association with the plasma membrane through its farnesylated and positively charged C-terminal hypervariable region (HVR) is critical to its oncogenic function. However, the structural mechanisms of membrane association are not fully understood. Here, using confocal microscopy, surface plasmon resonance, and molecular dynamics simulations, we observed that K-Ras4B can be distributed in rigid and loosely packed membrane domains. Its membrane binding domain interaction with phospholipids is driven by membrane fluidity. The farnesyl group spontaneously inserts into the disordered lipid microdomains, whereas the rigid microdomains restrict the farnesyl group penetration. We speculate that the resulting farnesyl protrusion toward the cell interior allows oligomerization of the K-Ras4B membrane binding domain in rigid microdomains. Unlike other Ras isoforms, K-Ras4B HVR contains a single farnesyl modification and positively charged polylysine sequence. The high positive charge not only modulates specific HVR binding to anionic phospholipids but farnesyl membrane orientation. Phosphorylation of Ser-181 prohibits spontaneous farnesyl membrane insertion. The mechanism illuminates the roles of HVR modifications in K-Ras4B targeting microdomains of the plasma membrane and suggests an additional function for HVR in regulation of Ras signaling. PMID- 25713066 TI - Rescue of Na+ affinity in aspartate 928 mutants of Na+,K+-ATPase by secondary mutation of glutamate 314. AB - The Na(+),K(+)-ATPase binds Na(+) at three transport sites denoted I, II, and III, of which site III is Na(+)-specific and suggested to be the first occupied in the cooperative binding process activating phosphorylation from ATP. Here we demonstrate that the asparagine substitution of the aspartate associated with site III found in patients with rapid-onset dystonia parkinsonism or alternating hemiplegia of childhood causes a dramatic reduction of Na(+) affinity in the alpha1-, alpha2-, and alpha3-isoforms of Na(+),K(+)-ATPase, whereas other substitutions of this aspartate are much less disruptive. This is likely due to interference by the amide function of the asparagine side chain with Na(+) coordinating residues in site III. Remarkably, the Na(+) affinity of site III aspartate to asparagine and alanine mutants is rescued by second-site mutation of a glutamate in the extracellular part of the fourth transmembrane helix, distant to site III. This gain-of-function mutation works without recovery of the lost cooperativity and selectivity of Na(+) binding and does not affect the E1-E2 conformational equilibrium or the maximum phosphorylation rate. Hence, the rescue of Na(+) affinity is likely intrinsic to the Na(+) binding pocket, and the underlying mechanism could be a tightening of Na(+) binding at Na(+) site II, possibly via movement of transmembrane helix four. The second-site mutation also improves Na(+),K(+) pump function in intact cells. Rescue of Na(+) affinity and Na(+) and K(+) transport by second-site mutation is unique in the history of Na(+),K(+)-ATPase and points to new possibilities for treatment of neurological patients carrying Na(+),K(+)-ATPase mutations. PMID- 25713067 TI - beta-Cyclodextrin-threaded biocleavable polyrotaxanes ameliorate impaired autophagic flux in Niemann-Pick type C disease. AB - Niemann-Pick type C (NPC) disease is characterized by the lysosomal accumulation of cholesterols and impaired autophagic flux due to the inhibited fusion of autophagosomes to lysosomes. We have recently developed beta-cyclodextrin (beta CD)-threaded biocleavable polyrotaxanes (PRXs), which can release threaded beta CDs in response to intracellular environments as a therapeutic for NPC disease. The biocleavable PRXs exhibited effective cholesterol reduction ability and negligible toxic effect compared with hydroxypropyl-beta-CD (HP-beta-CD). In this study, we investigated the effect of biocleavable PRX and HP-beta-CD on the impaired autophagy in NPC disease. The NPC patient-derived fibroblasts (NPC1 fibroblasts) showed an increase in the number of LC3-positive puncta compared with normal fibroblasts, even in the basal conditions; the HP-beta-CD treatment markedly increased the number of LC3-positive puncta and the levels of p62 in NPC1 fibroblasts, indicating that autophagic flux was further perturbed. In sharp contrast, the biocleavable PRX reduced the number of LC3-positive puncta and the levels of p62 in NPC1 fibroblasts through an mTOR-independent mechanism. The mRFP GFP-LC3 reporter gene expression experiments revealed that the biocleavable PRX facilitated the formation of autolysosomes to allow for autophagic protein degradation. Therefore, the beta-CD-threaded biocleavable PRXs may be promising therapeutics for ameliorating not only cholesterol accumulation but also autophagy impairment in NPC disease. PMID- 25713068 TI - Chaperone-mediated 26S proteasome remodeling facilitates free K63 ubiquitin chain production and aggresome clearance. AB - Efficient elimination of misfolded proteins by the proteasome system is critical for proteostasis. Inadequate proteasome capacity can lead to aberrant aggregation of misfolded proteins and inclusion body formation, a hallmark of neurodegenerative disease. The proteasome system cannot degrade aggregated proteins; however, it stimulates autophagy-dependent aggregate clearance by producing unanchored lysine (K)63-linked ubiquitin chains via the proteasomal deubiquitinating enzyme Poh1. The canonical function of Poh1, which removes ubiquitin chains en bloc from proteasomal substrates prior to their degradation, requires intact 26S proteasomes. Here we present evidence that during aggresome clearance, 20S proteasomes dissociate from protein aggregates, while Poh1 and selective subunits of 19S proteasomes are retained. The dissociation of 20S proteasome components requires the molecular chaperone Hsp90. Hsp90 inhibition suppresses 26S proteasome remodeling, unanchored ubiquitin chain production, and aggresome clearance. Our results suggest that 26S proteasomes undergo active remodeling to generate a Poh1-dependent K63-deubiquitinating enzyme to facilitate protein aggregate clearance. PMID- 25713069 TI - Recruitment of beta-catenin to N-cadherin is necessary for smooth muscle contraction. AB - beta-Catenin is a key component that connects transmembrane cadherin with the actin cytoskeleton at the cell-cell interface. However, the role of the beta catenin/cadherin interaction in smooth muscle has not been well characterized. Here stimulation with acetylcholine promoted the recruitment of beta-catenin to N cadherin in smooth muscle cells/tissues. Knockdown of beta-catenin by lentivirus mediated shRNA attenuated smooth muscle contraction. Nevertheless, myosin light chain phosphorylation at Ser-19 and actin polymerization in response to contractile activation were not reduced by beta-catenin knockdown. In addition, the expression of the beta-catenin armadillo domain disrupted the recruitment of beta-catenin to N-cadherin. Force development, but not myosin light chain phosphorylation and actin polymerization, was reduced by the expression of the beta-catenin armadillo domain. Furthermore, actin polymerization and microtubules have been implicated in intracellular trafficking. In this study, the treatment with the inhibitor latrunculin A diminished the interaction of beta-catenin with N-cadherin in smooth muscle. In contrast, the exposure of smooth muscle to the microtubule depolymerizer nocodazole did not affect the protein-protein interaction. Together, these findings suggest that smooth muscle contraction is mediated by the recruitment of beta-catenin to N-cadherin, which may facilitate intercellular mechanotransduction. The association of beta-catenin with N cadherin is regulated by actin polymerization during contractile activation. PMID- 25713070 TI - Exploration of the arrest peptide sequence space reveals arrest-enhanced variants. AB - Translational arrest peptides (APs) are short stretches of polypeptides that induce translational stalling when synthesized on a ribosome. Mechanical pulling forces acting on the nascent chain can weaken or even abolish stalling. APs can therefore be used as in vivo force sensors, making it possible to measure the forces that act on a nascent chain during translation with single-residue resolution. It is also possible to score the relative strengths of APs by subjecting them to a given pulling force and ranking them according to stalling efficiency. Using the latter approach, we now report an extensive mutagenesis scan of a strong mutant variant of the Mannheimia succiniciproducens SecM AP and identify mutations that further increase the stalling efficiency. Combining three such mutations, we designed an AP that withstands the strongest pulling force we are able to generate at present. We further show that diproline stretches in a nascent protein act as very strong APs when translation is carried out in the absence of elongation factor P. Our findings highlight critical residues in APs, show that certain amino acid sequences induce very strong translational arrest and provide a toolbox of APs of varying strengths that can be used for in vivo force measurements. PMID- 25713071 TI - Cyclic AMP signaling reduces sirtuin 6 expression in non-small cell lung cancer cells by promoting ubiquitin-proteasomal degradation via inhibition of the Raf MEK-ERK (Raf/mitogen-activated extracellular signal-regulated kinase/extracellular signal-regulated kinase) pathway. AB - The cAMP signaling system regulates various cellular functions, including metabolism, gene expression, and death. Sirtuin 6 (SIRT6) removes acetyl groups from histones and regulates genomic stability and cell viability. We hypothesized that cAMP modulates SIRT6 activity to regulate apoptosis. Therefore, we examined the effects of cAMP signaling on SIRT6 expression and radiation-induced apoptosis in lung cancer cells. cAMP signaling in H1299 and A549 human non-small cell lung cancer cells was activated via the expression of constitutively active Galphas plus treatment with prostaglandin E2 (PGE2), isoproterenol, or forskolin. The expression of sirtuins and signaling molecules were analyzed by Western blotting. Activation of cAMP signaling reduced SIRT6 protein expression in lung cancer cells. cAMP signaling increased the ubiquitination of SIRT6 protein and promoted its degradation. Treatment with MG132 and inhibiting PKA with H89 or with a dominant-negative PKA abolished the cAMP-mediated reduction in SIRT6 levels. Treatment with PGE2 inhibited c-Raf activation by increasing inhibitory phosphorylation at Ser-259 in a PKA-dependent manner, thereby inhibiting downstream MEK-ERK signaling. Inhibiting ERK with inhibitors or with dominant negative ERKs reduced SIRT6 expression, whereas activation of ERK by constitutively active MEK abolished the SIRT6-depleting effects of PGE2. cAMP signaling also augmented radiation-induced apoptosis in lung cancer cells. This effect was abolished by exogenous expression of SIRT6. It is concluded that cAMP signaling reduces SIRT6 expression by promoting its ubiquitin-proteasome dependent degradation, a process mediated by the PKA-dependent inhibition of the Raf-MEK-ERK pathway. Reduced SIRT6 expression mediates the augmentation of radiation-induced apoptosis by cAMP signaling in lung cancer cells. PMID- 25713072 TI - A metal-containing nucleoside that possesses both therapeutic and diagnostic activity against cancer. AB - Nucleoside transport is an essential process that helps maintain the hyperproliferative state of most cancer cells. As such, it represents an important target for developing diagnostic and therapeutic agents that can effectively detect and treat cancer, respectively. This report describes the development of a metal-containing nucleoside designated Ir(III)-PPY nucleoside that displays both therapeutic and diagnostic properties against the human epidermal carcinoma cell line KB3-1. The cytotoxic effects of Ir(III)-PPY nucleoside are both time- and dose-dependent. Flow cytometry analyses validate that the nucleoside analog causes apoptosis by blocking cell cycle progression at G2/M. Fluorescent microscopy studies show rapid accumulation in the cytoplasm within 4 h. However, more significant accumulation is observed in the nucleus and mitochondria after 24 h. This localization is consistent with the ability of the metal-containing nucleoside to influence cell cycle progression at G2/M. Mitochondrial depletion is also observed after longer incubations (Deltat ~48 h), and this effect may produce additional cytotoxic effects. siRNA knockdown experiments demonstrate that the nucleoside transporter, hENT1, plays a key role in the cellular entry of Ir(III)-PPY nucleoside. Collectively, these data provide evidence for the development of a metal-containing nucleoside that functions as a combined therapeutic and diagnostic agent against cancer. PMID- 25713073 TI - Alcohol inhibits osteopontin-dependent transforming growth factor-beta1 expression in human mesenchymal stem cells. AB - Alcohol (EtOH) intoxication is a risk factor for increased morbidity and mortality with traumatic injuries, in part through inhibition of bone fracture healing. Animal models have shown that EtOH decreases fracture callus volume, diameter, and biomechanical strength. Transforming growth factor beta1 (TGF beta1) and osteopontin (OPN) play important roles in bone remodeling and fracture healing. Mesenchymal stem cells (MSC) reside in bone and are recruited to fracture sites for the healing process. Resident MSC are critical for fracture healing and function as a source of TGF-beta1 induced by local OPN, which acts through the transcription factor myeloid zinc finger 1 (MZF1). The molecular mechanisms responsible for the effect of EtOH on fracture healing are still incompletely understood, and this study investigated the role of EtOH in affecting OPN-dependent TGF-beta1 expression in MSC. We have demonstrated that EtOH inhibits OPN-induced TGF-beta1 protein expression, decreases MZF1-dependent TGF-beta1 transcription and MZF1 transcription, and blocks OPN-induced MZF1 phosphorylation. We also found that PKA signaling enhances OPN-induced TGF-beta1 expression. Last, we showed that EtOH exposure reduces the TGF-beta1 protein levels in mouse fracture callus. We conclude that EtOH acts in a novel mechanism by interfering directly with the OPN-MZF1-TGF-beta1 signaling pathway in MSC. PMID- 25713074 TI - Transcriptional activity of erythroid Kruppel-like factor (EKLF/KLF1) modulated by PIAS3 (protein inhibitor of activated STAT3). AB - Erythroid Kruppel-like factor (EKLF or KLF1) is a transcription factor crucial for red cell development that is directly involved in regulation of a large number of erythroid genes. EKLF serves mostly as an activator of expression of these genes; however, it can act also as a repressor. Here, we present evidence that EKLF interacts with proteins from the PIAS (protein inhibitor of activated STAT) family that convey repressive activity to EKLF in the absence of sumoylation. Our studies identify PIAS3 as a transcriptional corepressor of EKLF for at least a subset of its target genes during erythropoiesis (e.g. beta globin, alpha-hemoglobin stabilizing protein). We demonstrate an interaction between EKLF and PIAS proteins confirmed by in vivo coimmunoprecipitation assays with both exogenous and endogenous proteins. We identified an LXXLL signature motif located near the N terminus of PIAS proteins that, although not involved in the EKLF-PIAS3 interaction, is required for the transrepression activity. Knockdown of endogenous PIAS3 accelerates differentiation of both murine erythroleukemia cells, as well as fetal liver cells, whereas an increase in PIAS3 levels inhibits this increase. Using chromatin immunoprecipitation assays, we show that PIAS3 preferentially occupies the beta-globin promoter in undifferentiated murine erythroleukemia cells. Together these results demonstrate that an interaction between EKLF and PIAS3 provides a novel mode of regulation of EKLF activity in the absence of sumolylation and furthermore shows an important involvement of PIAS proteins in erythropoiesis. PMID- 25713075 TI - Family 46 Carbohydrate-binding Modules Contribute to the Enzymatic Hydrolysis of Xyloglucan and beta-1,3-1,4-Glucans through Distinct Mechanisms. AB - Structural carbohydrates comprise an extraordinary source of energy that remains poorly utilized by the biofuel sector as enzymes have restricted access to their substrates within the intricacy of plant cell walls. Carbohydrate active enzymes (CAZYmes) that target recalcitrant polysaccharides are modular enzymes containing noncatalytic carbohydrate-binding modules (CBMs) that direct enzymes to their cognate substrate, thus potentiating catalysis. In general, CBMs are functionally and structurally autonomous from their associated catalytic domains from which they are separated through flexible linker sequences. Here, we show that a C terminal CBM46 derived from BhCel5B, a Bacillus halodurans endoglucanase, does not interact with beta-glucans independently but, uniquely, acts cooperatively with the catalytic domain of the enzyme in substrate recognition. The structure of BhCBM46 revealed a beta-sandwich fold that abuts onto the region of the substrate binding cleft upstream of the active site. BhCBM46 as a discrete entity is unable to bind to beta-glucans. Removal of BhCBM46 from BhCel5B, however, abrogates binding to beta-1,3-1,4-glucans while substantially decreasing the affinity for decorated beta-1,4-glucan homopolymers such as xyloglucan. The CBM46 was shown to contribute to xyloglucan hydrolysis only in the context of intact plant cell walls, but it potentiates enzymatic activity against purified beta-1,3 1,4-glucans in solution or within the cell wall. This report reveals the mechanism by which a CBM can promote enzyme activity through direct interaction with the substrate or by targeting regions of the plant cell wall where the target glucan is abundant. PMID- 25713076 TI - The pivotal role of the mitochondrial amidoxime reducing component 2 in protecting human cells against apoptotic effects of the base analog N6 hydroxylaminopurine. AB - N-Hydroxylated nucleobases and nucleosides as N-hydroxylaminopurine (HAP) or N hydroxyadenosine (HAPR) may be generated endogenously in the course of cell metabolism by cytochrome P450, by oxidative stress or by a deviating nucleotide biosynthesis. These compounds have shown to be toxic and mutagenic for procaryotic and eucaryotic cells. For DNA replication fidelity it is therefore of great importance that organisms exhibit effective mechanisms to remove such non canonical base analogs from DNA precursor pools. In vitro, the molybdoenzymes mitochondrial amidoxime reducing component 1 and 2 (mARC1 and mARC2) have shown to be capable of reducing N-hydroxylated base analogs and nucleoside analogs to the corresponding canonical nucleobases and nucleosides upon reconstitution with the electron transport proteins cytochrome b5 and NADH-cytochrome b5 reductase. By RNAi-mediated down-regulation of mARC in human cell lines the mARC-dependent N reductive detoxication of HAP in cell metabolism could be demonstrated. For HAPR, on the other hand, the reduction to adenosine seems to be of less significance in the detoxication pathway of human cells as HAPR is primarily metabolized to inosine by direct dehydroxylamination catalyzed by adenosine deaminase. Furthermore, the effect of mARC knockdown on sensitivity of human cells to HAP was examined by flow cytometric quantification of apoptotic cell death and detection of poly (ADP-ribose) polymerase (PARP) cleavage. mARC2 was shown to protect HeLa cells against the apoptotic effects of the base analog, whereas the involvement of mARC1 in reductive detoxication of HAP does not seem to be pivotal. PMID- 25713077 TI - Breaking and restoring the hydrophobic core of a centromere-binding protein. AB - The ribbon-helix-helix (RHH) superfamily of DNA-binding proteins is dispersed widely in procaryotes. The dimeric RHH fold is generated by interlocking of two monomers into a 2-fold symmetrical structure that comprises four alpha-helices enwrapping a pair of antiparallel beta-strands (ribbon). Residues in the ribbon region are the principal determinants of DNA binding, whereas the RHH hydrophobic core is assembled from amino acids in both the alpha-helices and ribbon element. The ParG protein encoded by multiresistance plasmid TP228 is a RHH protein that functions dually as a centromere binding factor during segrosome assembly and as a transcriptional repressor. Here we identify residues in the alpha-helices of ParG that are critical for DNA segregation and in organization of the protein hydrophobic core. A key hydrophobic aromatic amino acid at one position was functionally substitutable by other aromatic residues, but not by non-aromatic hydrophobic amino acids. Nevertheless, intramolecular suppression of the latter by complementary change of a residue that approaches nearby from the partner monomer fully restored activity in vivo and in vitro. The interactions involved in assembling the ParG core may be highly malleable and suggest that RHH proteins are tractable platforms for the rational design of diverse DNA binding factors useful for synthetic biology and other purposes. PMID- 25713078 TI - Sarcolipin Is a Key Determinant of the Basal Metabolic Rate, and Its Overexpression Enhances Energy Expenditure and Resistance against Diet-induced Obesity. AB - Sarcolipin (SLN) is a novel regulator of sarcoplasmic reticulum Ca(2+) ATPase (SERCA) in muscle. SLN binding to SERCA uncouples Ca(2+) transport from ATP hydrolysis. By this mechanism, SLN promotes the futile cycling of SERCA, contributing to muscle heat production. We recently showed that SLN plays an important role in cold- and diet-induced thermogenesis. However, the detailed mechanism of how SLN regulates muscle metabolism remains unclear. In this study, we used both SLN knockout (Sln(-/-)) and skeletal muscle-specific SLN overexpression (Sln(OE)) mice to explore energy metabolism by pair feeding (fixed calories) and high-fat diet feeding (ad libitum). Our results show that, upon pair feeding, Sln(OE) mice lost weight compared with the WT, but Sln(-/-) mice gained weight. Interestingly, when fed with a high-fat diet, Sln(OE) mice consumed more calories but gained less weight and maintained a normal metabolic profile in comparison with WT and Sln(-/-) mice. We found that oxygen consumption and fatty acid oxidation were increased markedly in Sln(OE) mice. There was also an increase in both mitochondrial number and size in Sln(OE) muscle, together with increased expression of peroxisome proliferator-activated receptor delta (PPARdelta) and PPAR gamma coactivator 1 alpha (PGC1alpha), key transcriptional activators of mitochondrial biogenesis and enzymes involved in oxidative metabolism. These results, taken together, establish an important role for SLN in muscle metabolism and energy expenditure. On the basis of these data we propose that SLN is a novel target for enhancing whole-body energy expenditure. PMID- 25713079 TI - A role for the tyrosine kinase Pyk2 in depolarization-induced contraction of vascular smooth muscle. AB - Depolarization of the vascular smooth muscle cell membrane evokes a rapid (phasic) contractile response followed by a sustained (tonic) contraction. We showed previously that the sustained contraction involves genistein-sensitive tyrosine phosphorylation upstream of the RhoA/Rho-associated kinase (ROK) pathway leading to phosphorylation of MYPT1 (the myosin-targeting subunit of myosin light chain phosphatase (MLCP)) and myosin regulatory light chains (LC20). In this study, we addressed the hypothesis that membrane depolarization elicits activation of the Ca(2+)-dependent tyrosine kinase Pyk2 (proline-rich tyrosine kinase 2). Pyk2 was identified as the major tyrosine-phosphorylated protein in response to membrane depolarization. The tonic phase of K(+)-induced contraction was inhibited by the Pyk2 inhibitor sodium salicylate, which abolished the sustained elevation of LC20 phosphorylation. Membrane depolarization induced autophosphorylation (activation) of Pyk2 with a time course that correlated with the sustained contractile response. The Pyk2/focal adhesion kinase (FAK) inhibitor PF-431396 inhibited both phasic and tonic components of the contractile response to K(+), Pyk2 autophosphorylation, and LC20 phosphorylation but had no effect on the calyculin A (MLCP inhibitor)-induced contraction. Ionomycin, in the presence of extracellular Ca(2+), elicited a slow, sustained contraction and Pyk2 autophosphorylation, which were blocked by pre-treatment with PF-431396. Furthermore, the Ca(2+) channel blocker nifedipine inhibited peak and sustained K(+)-induced force and Pyk2 autophosphorylation. Inhibition of Pyk2 abolished the K(+)-induced translocation of RhoA to the particulate fraction and the phosphorylation of MYPT1 at Thr-697 and Thr-855. We conclude that depolarization induced entry of Ca(2+) activates Pyk2 upstream of the RhoA/ROK pathway, leading to MYPT1 phosphorylation and MLCP inhibition. The resulting sustained elevation of LC20 phosphorylation then accounts for the tonic contractile response to membrane depolarization. PMID- 25713080 TI - Histone H2A and H4 N-terminal tails are positioned by the MEP50 WD repeat protein for efficient methylation by the PRMT5 arginine methyltransferase. AB - The protein arginine methyltransferase PRMT5 is complexed with the WD repeat protein MEP50 (also known as Wdr77 or androgen coactivator p44) in vertebrates in a tetramer of heterodimers. MEP50 is hypothesized to be required for protein substrate recruitment to the catalytic domain of PRMT5. Here we demonstrate that the cross-dimer MEP50 is paired with its cognate PRMT5 molecule to promote histone methylation. We employed qualitative methylation assays and a novel ultrasensitive continuous assay to measure enzyme kinetics. We demonstrate that neither full-length human PRMT5 nor the Xenopus laevis PRMT5 catalytic domain has appreciable protein methyltransferase activity. We show that histones H4 and H3 bind PRMT5-MEP50 more efficiently compared with histone H2A(1-20) and H4(1-20) peptides. Histone binding is mediated through histone fold interactions as determined by competition experiments and by high density histone peptide array interaction studies. Nucleosomes are not a substrate for PRMT5-MEP50, consistent with the primary mode of interaction via the histone fold of H3-H4, obscured by DNA in the nucleosome. Mutation of a conserved arginine (Arg-42) on the MEP50 insertion loop impaired the PRMT5-MEP50 enzymatic efficiency by increasing its histone substrate Km, comparable with that of Caenorhabditis elegans PRMT5. We show that PRMT5-MEP50 prefers unmethylated substrates, consistent with a distributive model for dimethylation and suggesting discrete biological roles for mono- and dimethylarginine-modified proteins. We propose a model in which MEP50 and PRMT5 simultaneously engage the protein substrate, orienting its targeted arginine to the catalytic site. PMID- 25713081 TI - Golgi anti-apoptotic proteins are highly conserved ion channels that affect apoptosis and cell migration. AB - Golgi anti-apoptotic proteins (GAAPs) are multitransmembrane proteins that are expressed in the Golgi apparatus and are able to homo-oligomerize. They are highly conserved throughout eukaryotes and are present in some prokaryotes and orthopoxviruses. Within eukaryotes, GAAPs regulate the Ca(2+) content of intracellular stores, inhibit apoptosis, and promote cell adhesion and migration. Data presented here demonstrate that purified viral GAAPs (vGAAPs) and human Bax inhibitor 1 form ion channels and that vGAAP from camelpox virus is selective for cations. Mutagenesis of vGAAP, including some residues conserved in the recently solved structure of a related bacterial protein, BsYetJ, altered the conductance (E207Q and D219N) and ion selectivity (E207Q) of the channel. Mutation of residue Glu-207 or -178 reduced the effects of GAAP on cell migration and adhesion without affecting protection from apoptosis. In contrast, mutation of Asp-219 abrogated the anti-apoptotic activity of GAAP but not its effects on cell migration and adhesion. These results demonstrate that GAAPs are ion channels and define residues that contribute to the ion-conducting pore and affect apoptosis, cell adhesion, and migration independently. PMID- 25713083 TI - Radicals in Berkeley? AB - In a previous autobiographical sketch for DNA Repair (Linn, S. (2012) Life in the serendipitous lane: excitement and gratification in studying DNA repair. DNA Repair 11, 595-605), I wrote about my involvement in research on mechanisms of DNA repair. In this Reflections, I look back at how I became interested in free radical chemistry and biology and outline some of our bizarre (at the time) observations. Of course, these studies could never have succeeded without the exceptional aid of my mentors: my teachers; the undergraduate and graduate students, postdoctoral fellows, and senior lab visitors in my laboratory; and my faculty and staff colleagues here at Berkeley. I am so indebted to each and every one of these individuals for their efforts to overcome my ignorance and set me on the straight and narrow path to success in research. I regret that I cannot mention and thank each of these mentors individually. PMID- 25713082 TI - Transcriptional activity of the islet beta cell factor Pdx1 is augmented by lysine methylation catalyzed by the methyltransferase Set7/9. AB - The transcription factor Pdx1 is crucial to islet beta cell function and regulates target genes in part through interaction with coregulatory factors. Set7/9 is a Lys methyltransferase that interacts with Pdx1. Here we tested the hypothesis that Lys methylation of Pdx1 by Set7/9 augments Pdx1 transcriptional activity. Using mass spectrometry and mutational analysis of purified proteins, we found that Set7/9 methylates the N-terminal residues Lys-123 and Lys-131 of Pdx1. Methylation of these residues occurred only in the context of intact, full length Pdx1, suggesting a specific requirement of secondary and/or tertiary structural elements for catalysis by Set7/9. Immunoprecipitation assays and mass spectrometric analysis using beta cells verified Lys methylation of endogenous Pdx1. Cell-based luciferase reporter assays using wild-type and mutant transgenes revealed a requirement of Pdx1 residue Lys-131, but not Lys-123, for transcriptional augmentation by Set7/9. Lys-131 was not required for high affinity interactions with DNA in vitro, suggesting that its methylation likely enhances post-DNA binding events. To define the role of Set7/9 in beta cell function, we generated mutant mice in which the gene encoding Set7/9 was conditionally deleted in beta cells (Set(Delta)beta). Set(Delta)beta mice exhibited glucose intolerance similar to Pdx1-deficient mice, and their isolated islets showed impaired glucose-stimulated insulin secretion with reductions in expression of Pdx1 target genes. Our results suggest a previously unappreciated role for Set7/9-mediated methylation in the maintenance of Pdx1 activity and beta cell function. PMID- 25713084 TI - Analysis of the cooperative ATPase cycle of the AAA+ chaperone ClpB from Thermus thermophilus by using ordered heterohexamers with an alternating subunit arrangement. AB - The ClpB/Hsp104 chaperone solubilizes and reactivates protein aggregates in cooperation with DnaK/Hsp70 and its cofactors. The ClpB/Hsp104 protomer has two AAA+ modules, AAA-1 and AAA-2, and forms a homohexamer. In the hexamer, these modules form a two-tiered ring in which each tier consists of homotypic AAA+ modules. By ATP binding and its hydrolysis at these AAA+ modules, ClpB/Hsp104 exerts the mechanical power required for protein disaggregation. Although ATPase cycle of this chaperone has been studied by several groups, an integrated understanding of this cycle has not been obtained because of the complexity of the mechanism and differences between species. To improve our understanding of the ATPase cycle, we prepared many ordered heterohexamers of ClpB from Thermus thermophilus, in which two subunits having different mutations were cross-linked to each other and arranged alternately and measured their nucleotide binding, ATP hydrolysis, and disaggregation abilities. The results indicated that the ATPase cycle of ClpB proceeded as follows: (i) the 12 AAA+ modules randomly bound ATP, (ii) the binding of four or more ATP to one AAA+ ring was sensed by a conserved Arg residue and converted another AAA+ ring into the ATPase-active form, and (iii) ATP hydrolysis occurred cooperatively in each ring. We also found that cooperative ATP hydrolysis in at least one ring was needed for the disaggregation activity of ClpB. PMID- 25713085 TI - Substrate efflux propensity is the key determinant of Ca2+-independent phospholipase A-beta (iPLAbeta)-mediated glycerophospholipid hydrolysis. AB - The A-type phospholipases (PLAs) are key players in glycerophospholipid (GPL) homeostasis and in mammalian cells; Ca(2+)-independent PLA-beta (iPLAbeta) in particular has been implicated in this essential process. However, the regulation of this enzyme, which is necessary to avoid futile competition between synthesis and degradation, is not understood. Recently, we provided evidence that the efflux of the substrate molecules from the bilayer is the rate-limiting step in the hydrolysis of GPLs by some secretory (nonhomeostatic) PLAs. To study whether this is the case with iPLAbeta as well, a mass spectrometric assay was employed to determine the rate of hydrolysis of multiple saturated and unsaturated GPL species in parallel using micelles or vesicle bilayers as the macrosubstrate. With micelles, the hydrolysis decreased with increasing acyl chain length independent of unsaturation, and modest discrimination between acyl positional isomers was observed, presumably due to the differences in the structure of the sn-1 and sn-2 acyl-binding sites of the protein. In striking contrast, no significant discrimination between positional isomers was observed with bilayers, and the rate of hydrolysis decreased with the acyl chain length logarithmically and far more than with micelles. These data provide compelling evidence that efflux of the substrate molecule from the bilayer, which also decreases monotonously with acyl chain length, is the rate-determining step in iPLAbeta mediated hydrolysis of GPLs in membranes. This finding is intriguing as it may help to understand how homeostatic PLAs are regulated and how degradation and biosynthesis are coordinated. PMID- 25713086 TI - Functional analysis of NK cell subsets activated by 721.221 and K562 HLA-null cells. AB - HLA-null cell lines [721.221 (henceforth, 721) and K562] are often used to study NK cell activation. NK cells are innate immune lymphocytes that express a variety of stochastically expressed inhibitory and activating receptors. Although it is known that 721 and K562 have divergent origins, they have been used interchangeably to stimulate NK cells in many studies. We hypothesized that the differences between 721 and K562 cells may result in differential NK cell activation patterns. In this report, we assessed all possible combinations of CD107a expression and IFN-gamma and CCL4 secretion in total NK and 3DL1(+/-) NK cell populations induced by these 2 cell lines. 721 activates a significantly higher frequency of NK cells and 3DL1(+) NK cells than K562. The NK cell functional subsets that are stimulated to a higher degree by 721 than K562 include those secreting IFN-gamma and/or CCL4. On the other hand, the functional subsets that include CD107 expression contribute to a higher proportion of the total NK cell response following stimulation with K562 than 721. These results have implications for the selection of HLA-null cell lines to use as NK cell stimuli in investigations of their role in infectious diseases, cancer, and transplantation. PMID- 25713088 TI - Science and culture: data visualization nurtures an artistic movement. PMID- 25713089 TI - Inner Workings: Endoliths hunker down and survive in extreme environments. PMID- 25713087 TI - Delta9-Tetrahydrocannabinol-mediated epigenetic modifications elicit myeloid derived suppressor cell activation via STAT3/S100A8. AB - MDSCs are potent immunosuppressive cells that are induced during inflammatory responses, as well as by cancers, to evade the anti-tumor immunity. We recently demonstrated that marijuana cannabinoids are potent inducers of MDSCs. In the current study, we investigated the epigenetic mechanisms through which THC, an exogenous cannabinoid, induces MDSCs and compared such MDSCs with the naive MDSCs found in BM of BL6 (WT) mice. Administration of THC into WT mice caused increased methylation at the promoter region of DNMT3a and DNMT3b in THC-induced MDSCs, which correlated with reduced expression of DNMT3a and DNMT3b. Furthermore, promoter region methylation was decreased at Arg1 and STAT3 in THC-induced MDSCs, and consequently, such MDSCs expressed higher levels of Arg1 and STAT3. In addition, THC-induced MDSCs secreted elevated levels of S100A8, a calcium-binding protein associated with accumulation of MDSCs in cancer models. Neutralization of S100A8 by use of anti-S100A8 (8H150) in vivo reduced the ability of THC to trigger MDSCs. Interestingly, the elevated S100A8 expression also promoted the suppressive function of MDSCs. Together, the current study demonstrates that THC mediates epigenetic changes to promote MDSC differentiation and function and that S100A8 plays a critical role in this process. PMID- 25713090 TI - Root surface as a frontier for plant microbiome research. PMID- 25713092 TI - It's personal: biology instructors prioritize personal evidence over empirical evidence in teaching decisions. AB - Despite many calls for undergraduate biology instructors to incorporate active learning into lecture courses, few studies have focused on what it takes for instructors to make this change. We sought to investigate the process of adopting and sustaining active-learning instruction. As a framework for our research, we used the innovation-decision model, a generalized model of how individuals adopt innovations. We interviewed 17 biology instructors who were attempting to implement case study teaching and conducted qualitative text analysis on interview data. The overarching theme that emerged from our analysis was that instructors prioritized personal experience-rather than empirical evidence-in decisions regarding case study teaching. We identified personal experiences that promote case study teaching, such as anecdotal observations of student outcomes, and those that hinder case study teaching, such as insufficient teaching skills. By analyzing the differences between experienced and new case study instructors, we discovered that new case study instructors need support to deal with unsupportive colleagues and to develop the skill set needed for an active learning classroom. We generated hypotheses that are grounded in our data about effectively supporting instructors in adopting and sustaining active-learning strategies. We also synthesized our findings with existing literature to tailor the innovation-decision model. PMID- 25713093 TI - Relations between intuitive biological thinking and biological misconceptions in biology majors and nonmajors. AB - Research and theory development in cognitive psychology and science education research remain largely isolated. Biology education researchers have documented persistent scientifically inaccurate ideas, often termed misconceptions, among biology students across biological domains. In parallel, cognitive and developmental psychologists have described intuitive conceptual systems- teleological, essentialist, and anthropocentric thinking--that humans use to reason about biology. We hypothesize that seemingly unrelated biological misconceptions may have common origins in these intuitive ways of knowing, termed cognitive construals. We presented 137 undergraduate biology majors and nonmajors with six biological misconceptions. They indicated their agreement with each statement, and explained their rationale for their response. Results indicate frequent agreement with misconceptions, and frequent use of construal-based reasoning among both biology majors and nonmajors in their written explanations. Moreover, results also show associations between specific construals and the misconceptions hypothesized to arise from those construals. Strikingly, such associations were stronger among biology majors than nonmajors. These results demonstrate important linkages between intuitive ways of thinking and misconceptions in discipline-based reasoning, and raise questions about the origins, persistence, and generality of relations between intuitive reasoning and biological misconceptions. PMID- 25713094 TI - Drawing-to-learn: a framework for using drawings to promote model-based reasoning in biology. AB - The drawing of visual representations is important for learners and scientists alike, such as the drawing of models to enable visual model-based reasoning. Yet few biology instructors recognize drawing as a teachable science process skill, as reflected by its absence in the Vision and Change report's Modeling and Simulation core competency. Further, the diffuse research on drawing can be difficult to access, synthesize, and apply to classroom practice. We have created a framework of drawing-to-learn that defines drawing, categorizes the reasons for using drawing in the biology classroom, and outlines a number of interventions that can help instructors create an environment conducive to student drawing in general and visual model-based reasoning in particular. The suggested interventions are organized to address elements of affect, visual literacy, and visual model-based reasoning, with specific examples cited for each. Further, a Blooming tool for drawing exercises is provided, as are suggestions to help instructors address possible barriers to implementing and assessing drawing-to learn in the classroom. Overall, the goal of the framework is to increase the visibility of drawing as a skill in biology and to promote the research and implementation of best practices. PMID- 25713095 TI - Research-based implementation of peer instruction: a literature review. AB - Current instructional reforms in undergraduate science, technology, engineering, and mathematics (STEM) courses have focused on enhancing adoption of evidence based instructional practices among STEM faculty members. These practices have been empirically demonstrated to enhance student learning and attitudes. However, research indicates that instructors often adapt rather than adopt practices, unknowingly compromising their effectiveness. Thus, there is a need to raise awareness of the research-based implementation of these practices, develop fidelity of implementation protocols to understand adaptations being made, and ultimately characterize the true impact of reform efforts based on these practices. Peer instruction (PI) is an example of an evidence-based instructional practice that consists of asking students conceptual questions during class time and collecting their answers via clickers or response cards. Extensive research has been conducted by physics and biology education researchers to evaluate the effectiveness of this practice and to better understand the intricacies of its implementation. PI has also been investigated in other disciplines, such as chemistry and computer science. This article reviews and summarizes these various bodies of research and provides instructors and researchers with a research-based model for the effective implementation of PI. Limitations of current studies and recommendations for future empirical inquiries are also provided. PMID- 25713096 TI - A tale of two sections: an experiment to compare the effectiveness of a hybrid versus a traditional lecture format in introductory microbiology. AB - Two sections of an introductory microbiology course were taught by one instructor. One was taught through a hybrid format and the other through a traditional format. Students were randomly assigned to the two sections. Both sections were provided with identical lecture materials, in-class worksheets, in class assessments, and extra credit opportunities; the main difference was in the way the lecture material was delivered-online for the hybrid section and in person for the traditional section. Analysis of final grades revealed that students in the traditional section did significantly better than those in the hybrid section (p<0.001). There was a significant main effect of class standing (p<0.01). When performance in the two sections was compared for each class year separately, the differences were only significant for sophomores (p<0.001); freshmen, juniors, and seniors did not perform differently in the hybrid versus the traditional section. An anonymous midterm survey suggested factors likely contributing to the overall lower success of students in the hybrid section: some students in the hybrid section did not take lecture notes and/or use the audio component of the online lectures, suggesting minimal interaction with the lecture material for these students. PMID- 25713097 TI - Scientific teaching: defining a taxonomy of observable practices. AB - Over the past several decades, numerous reports have been published advocating for changes to undergraduate science education. These national calls inspired the formation of the National Academies Summer Institutes on Undergraduate Education in Biology (SI), a group of regional workshops to help faculty members learn and implement interactive teaching methods. The SI curriculum promotes a pedagogical framework called Scientific Teaching (ST), which aims to bring the vitality of modern research into the classroom by engaging students in the scientific discovery process and using student data to inform the ongoing development of teaching methods. With the spread of ST, the need emerges to systematically define its components in order to establish a common description for education researchers and practitioners. We describe the development of a taxonomy detailing ST's core elements and provide data from classroom observations and faculty surveys in support of its applicability within undergraduate science courses. The final taxonomy consists of 15 pedagogical goals and 37 supporting practices, specifying observable behaviors, artifacts, and features associated with ST. This taxonomy will support future educational efforts by providing a framework for researchers studying the processes and outcomes of ST-based course transformations as well as a concise guide for faculty members developing classes. PMID- 25713098 TI - The molecular biology capstone assessment: a concept assessment for upper division molecular biology students. AB - Measuring students' conceptual understandings has become increasingly important to biology faculty members involved in evaluating and improving departmental programs. We developed the Molecular Biology Capstone Assessment (MBCA) to gauge comprehension of fundamental concepts in molecular and cell biology and the ability to apply these concepts in novel scenarios. Targeted at graduating students, the MBCA consists of 18 multiple-true/false (T/F) questions. Each question consists of a narrative stem followed by four T/F statements, which allows a more detailed assessment of student understanding than the traditional multiple-choice format. Questions were iteratively developed with extensive faculty and student feedback, including validation through faculty reviews and response validation through student interviews. The final assessment was taken online by 504 students in upper-division courses at seven institutions. Data from this administration indicate that the MBCA has acceptable levels of internal reliability (alpha=0.80) and test-retest stability (r=0.93). Students achieved a wide range of scores with a 67% overall average. Performance results suggest that students have an incomplete understanding of many molecular biology concepts and continue to hold incorrect conceptions previously documented among introductory level students. By pinpointing areas of conceptual difficulty, the MBCA can provide faculty members with guidance for improving undergraduate biology programs. PMID- 25713100 TI - IL-6 blockade by monoclonal antibodies inhibits apolipoprotein (a) expression and lipoprotein (a) synthesis in humans. AB - Lipoprotein (a) [Lp(a)] is a highly atherogenic lipid particle. Although earlier reports suggested that Lp(a) levels are mostly determined by genetic factors, several recent studies have revealed that Lp(a) induction is also caused by chronic inflammation. Therefore, we aimed to examine whether cytokine blockade by monoclonal antibodies may inhibit Lp(a) metabolism. We found that interleukin 6 (IL-6) blockade by tocilizumab (TCZ) reduced Lp(a) while TNF-alpha-inhibition by adalimumab in humans had no effect. The specificity of IL-6 in regulating Lp(a) was further demonstrated by serological measurements of human subjects (n = 1,153) revealing that Lp(a) levels are increased in individuals with elevated serum IL-6. Transcriptomic analysis of human liver biopsies (n = 57) revealed typical IL-6 response genes being correlated with the LPA gene expression in vivo. On a molecular level, we found that TCZ inhibited IL-6-induced LPA mRNA and protein expression in human hepatocytes. Furthermore, examination of IL-6 responsive signal transducer and activator of transcription 3 binding sites within the LPA promoter by reporter gene assays, promoter deletion experiments, and electrophoretic mobility shift assay analysis showed that the Lp(a)-lowering effect of TCZ is specifically mediated via a responsive element at -46 to -40. Therefore, IL-6 blockade might be a potential therapeutic option to treat elevated Lp(a) serum concentrations in humans and might be a noninvasive alternative to lipid apheresis in the future. PMID- 25713101 TI - Dietary and biliary phosphatidylcholine activates PKCzeta in rat intestine. AB - Chylomicron output by the intestine is proportional to intestinal phosphatidylcholine (PC) delivery. Using five different variations of PC delivery to the intestine, we found that lyso-phosphatidylcholine (lyso-PC), the absorbed form of PC, concentrations in the cytosol (0 to 0.45 nM) were proportional to the input rate. The activity of protein kinase C (PKC)zeta, which controls prechylomicron output rate by the endoplasmic reticulum (ER), correlated with the lyso-PC concentration suggesting that it may be a PKCzeta activator. Using recombinant PKCzeta, the Km for lyso-PC activation was 1.49 nM and the Vmax 1.12 nM, more than the maximal lyso-PC concentration in cytosol, 0.45 nM. Among the phospholipids and their lyso derivatives, lyso-PC was the most potent activator of PKCzeta and the only one whose cytosolic concentration suggested that it could be a physiological activator because other phospholipid concentrations were negligible. PKCzeta was on the surface of the dietary fatty acid transport vesicle, the caveolin-1-containing endocytic vesicle. Once activated, PKCzeta, eluted off the vesicle. A conformational change in PKCzeta on activation was suggested by limited proteolysis. We conclude that PKCzeta on activation changes its conformation resulting in elution from its vesicle. The downstream effect of dietary PC is to activate PKCzeta, resulting in greater chylomicron output by the ER. PMID- 25713102 TI - Thyroid-stimulating hormone decreases HMG-CoA reductase phosphorylation via AMP activated protein kinase in the liver. AB - Cholesterol homeostasis is strictly regulated through the modulation of HMG-CoA reductase (HMGCR), the rate-limiting enzyme of cholesterol synthesis. Phosphorylation of HMGCR inactivates it and dephosphorylation activates it. AMP activated protein kinase (AMPK) is the major kinase phosphorylating the enzyme. Our previous study found that thyroid-stimulating hormone (TSH) increased the hepatocytic HMGCR expression, but it was still unclear whether TSH affected hepatic HMGCR phosphorylation associated with AMPK. We used bovine TSH (bTSH) to treat the primary mouse hepatocytes and HepG2 cells with or without constitutively active (CA)-AMPK plasmid or protein kinase A inhibitor (H89), and set up the TSH receptor (Tshr)-KO mouse models. The p-HMGCR, p-AMPK, and related molecular expression were tested. The ratios of p-HMGCR/HMGCR and p-AMPK/AMPK decreased in the hepatocytes in a dose-dependent manner following bTSH stimulation. The changes above were inversed when the cells were treated with CA AMPK plasmid or H89. In Tshr-KO mice, the ratios of liver p-HMGCR/HMGCR and p AMPK/AMPK were increased relative to the littermate wild-type mice. Consistently, the phosphorylation of acetyl-CoA carboxylase, a downstream target molecule of AMPK, increased. All results suggested that TSH could regulate the phosphorylation of HMGCR via AMPK, which established a potential mechanism for hypercholesterolemia involved in a direct action of the TSH in the liver. PMID- 25713103 TI - Epithelial Xbp1 is required for cellular proliferation and differentiation during mammary gland development. AB - Xbp1, a key mediator of the unfolded protein response (UPR), is activated by IRE1alpha-mediated splicing, which results in a frameshift to encode a protein with transcriptional activity. However, the direct function of Xbp1 in epithelial cells during mammary gland development is unknown. Here we report that the loss of Xbp1 in the mammary epithelium through targeted deletion leads to poor branching morphogenesis, impaired terminal end bud formation, and spontaneous stromal fibrosis during the adult virgin period. Additionally, epithelial Xbp1 deletion induces endoplasmic reticulum (ER) stress in the epithelium and dramatically inhibits epithelial proliferation and differentiation during lactation. The synthesis of milk and its major components, alpha/beta-casein and whey acidic protein (WAP), is significantly reduced due to decreased prolactin receptor (Prlr) and ErbB4 expression in Xbp1-deficient mammary epithelium. Reduction of Prlr and ErbB4 expression and their diminished availability at the cell surface lead to reduced phosphorylated Stat5, an essential regulator of cell proliferation and differentiation during lactation. As a result, lactating mammary glands in these mice produce less milk protein, leading to poor pup growth and postnatal death. These findings suggest that the loss of Xbp1 induces a terminal UPR which blocks proliferation and differentiation during mammary gland development. PMID- 25713105 TI - Application of In-Syringe Dispersive Liquid-Liquid Microextraction Coupled to GC/FID for Determination of Trace Contamination of Phthalate Esters in Water Samples. AB - In this work, a simple and easy to handle one-step in-syringe setup for the dispersive liquid-liquid microextraction method has been developed for preconcentration of trace quantities of four kinds of phthalate esters (PEs) in water samples as a prior step to its determination by gas chromatography/flame ionization detector. The environmental pollution at this method has been limited due to using a glass syringe as extraction unit and also a very small amount of n hexane as a safe solvent. Some important parameters such as the type of extraction and disperser solvents, extraction and disperser solvents volume, sample volume and ionic strength were investigated and optimized. Validation experiments showed that the optimized method had precision (1.7-6.9%) and high recovery (94.32-104.7%), and the limits of detection were from 0.406 to 1.33 ug L(-1). At the end, the method was successfully applied for the determination of PEs in real water samples. PMID- 25713104 TI - Shp2 in forebrain neurons regulates synaptic plasticity, locomotion, and memory formation in mice. AB - Shp2 (Src homology 2 domain-containing protein tyrosine phosphatase 2) regulates neural cell differentiation. It is also expressed in postmitotic neurons, however, and mutations of Shp2 are associated with clinical syndromes characterized by mental retardation. Here we show that conditional-knockout (cKO) mice lacking Shp2 specifically in postmitotic forebrain neurons manifest abnormal behavior, including hyperactivity. Novelty-induced expression of immediate-early genes and activation of extracellular-signal-regulated kinase (Erk) were attenuated in the cerebral cortex and hippocampus of Shp2 cKO mice, suggestive of reduced neuronal activity. In contrast, ablation of Shp2 enhanced high-K(+) induced Erk activation in both cultured cortical neurons and synaptosomes, whereas it inhibited that induced by brain-derived growth factor in cultured neurons. Posttetanic potentiation and paired-pulse facilitation were attenuated and enhanced, respectively, in hippocampal slices from Shp2 cKO mice. The mutant mice also manifested transient impairment of memory formation in the Morris water maze. Our data suggest that Shp2 contributes to regulation of Erk activation and synaptic plasticity in postmitotic forebrain neurons and thereby controls locomotor activity and memory formation. PMID- 25713106 TI - Electromembrane Extraction of Organic Acid Compounds in Biological Samples Followed by High-Performance Liquid Chromatography. AB - Electromembrane extraction (EME) coupled with high-performance liquid chromatography was developed for determination of organic compounds including citric, tartaric and oxalic acid in biological samples. Organic compounds moved from aqueous samples, through a thin layer of 1-octanol immobilized in the pores of a porous hand-made polypropylene tube, and into a basic aqueous acceptor solution present inside the lumen of the tube. This new set-up for EME has a future potential such as simple, cheap and fast sample preparation technique for extraction of organic compounds in various complicated matrices. The pH of acceptor phase, extraction time, voltage, ionic strength, temperature and stirring speed were studied and optimized. Optimum conditions were: the pH of acceptor phase, 7; extraction time, 30 min; voltage, 30 V and stirring speed, 500 rpm. At the optimum conditions, the preconcentration factors of 175-200, the limits of detection of 1.9-3.1 ug L(-1) were obtained for the analytes. The developed procedure was then applied to the extraction and determination of organic acid compounds from biological samples. PMID- 25713107 TI - A Validated RP-HPLC Method for the Analysis of 1-Fluoronaphthalene and Its Process-Related Impurities. AB - A simple and precise reversed-phase high-performance liquid chromatography method was developed and validated for the determination of 1-fluoronaphthalene and its process-related impurities, 1-aminonaphthalene, 1-nitronaphthalene, naphthalene and 2-fluoronaphthalene. 1-Fluoronaphthalene is the key starting material for the synthesis of duloxetine hydrochloride active pharmaceutical ingredient and is therefore a potential impurity of the API. The determination of the impurity profile is critical for the safety assessment of a substance and manufacturing process thereof. In duloxetine hydrochloride active pharmaceutical ingredient, only 1-fluoronaphthalene is detected and neither of its related impurities of 1 aminonaphthalene, 1-nitronaphthalene, naphthalene and 2-fluoronaphthalene. Chromatography was carried out on a Symmetry C18 (250 * 4.6 mm, 5 MUm) column, using mobile phase A-a mixture of 0.01 MU KH2PO4 buffer (pH 2.5 +/- 0.1):methanol:acetonitrile in the ratio of 35:52:13 v/v/v and mobile phase B-a mixture of methanol:acetonitrile in the ratio of 80:20 v/v at a flow rate of 1.0 mL/min. The analytes were monitored using photo diode array detector at 230 nm. The proposed method is found to be having linearity in the concentration of 0.075 5.000 MUg/mL, 0.150-5.000 MUg/mL, 0.3125-5.000 MUg/mL and 0.3125-5.000 MUg/mL for 1-aminonaphthalene, 1-nitronaphthalene, naphthalene and 2-fluoronaphthalene, respectively, with correlation coefficients of 0.9998, 0.9998, 0.9997 and 0.9997, respectively. The proposed method was validated as per the International Conference on Harmonization guidelines. The mean recoveries for all the studied impurities are in the range of 90-110%. Due to its specificity, high precision and accuracy, the developed method can be used for the determination of 1 fluoronaphthalene, key starting material for the synthesis of duloxetine hydrochloride API. PMID- 25713108 TI - HPLC Determination of Esculin and Esculetin in Rat Plasma for Pharmacokinetic Studies. AB - An optimized, sensitive and validated reversed-phase high-performance liquid chromatography (RP-HPLC) method with UV detection is described for simultaneous determination of esculin and its aglycone, esculetin, in rat plasma. After addition of internal standard (chrysin), plasma samples were pretreated by solid phase extraction and introduced into the HPLC system. Analytes were separated on a RP C18 column with a mobile phase of 0.075% acetic acid in water (solvent A) and 90% acetonitrile in solvent A (solvent B) using gradient elution at a flow rate of 1.0 mL/min. The wavelength for UV detection was set at 338 nm. Calibration curves for esculin and esculetin were constructed over a range of 10 1,000 ng/mL. The developed method was found to be specific, precise and accurate. The method was successfully applied to study the pharmacokinetics of esculin and esculetin in rats. After oral administration of 120 mg/kg, the mean Cmax values were 340.3 and 316.5 ng/mL and the AUClast values were 377.3 and 1276.5 h ng/mL for esculin and esculetin, respectively. The bioavailability of esculin was calculated to be 0.62%. PMID- 25713109 TI - CRISPR-Cas9: a new and promising player in gene therapy. AB - First introduced into mammalian organisms in 2013, the RNA-guided genome editing tool CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated nuclease 9) offers several advantages over conventional ones, such as simple-to-design, easy-to-use and multiplexing (capable of editing multiple genes simultaneously). Consequently, it has become a cost-effective and convenient tool for various genome editing purposes including gene therapy studies. In cell lines or animal models, CRISPR-Cas9 can be applied for therapeutic purposes in several ways. It can correct the causal mutations in monogenic disorders and thus rescue the disease phenotypes, which currently represents the most translatable field in CRISPR-Cas9-mediated gene therapy. CRISPR-Cas9 can also engineer pathogen genome such as HIV for therapeutic purposes, or induce protective or therapeutic mutations in host tissues. Moreover, CRISPR-Cas9 has shown potentials in cancer gene therapy such as deactivating oncogenic virus and inducing oncosuppressor expressions. Herein, we review the research on CRISPR-mediated gene therapy, discuss its advantages, limitations and possible solutions, and propose directions for future research, with an emphasis on the opportunities and challenges of CRISPR-Cas9 in cancer gene therapy. PMID- 25713111 TI - The internationalization of the American Academy of Neurology. PMID- 25713110 TI - Positional mapping of PRKD1, NRP1 and PRDM1 as novel candidate disease genes in truncus arteriosus. AB - BACKGROUND: Truncus arteriosus (TA) is characterised by failure of septation of the outflow tract into aortic and pulmonary trunks and is associated with high morbidity and mortality. Although ranked among the least common congenital heart defects, TA provides an excellent model for the role of individual genes in cardiac morphogenesis as exemplified by TBX1 deficiency caused by point mutations or, more commonly, hemizygosity as part of the 22q11.2 deletion syndrome. The latter genetic lesion, however, is only observed in a proportion of patients with TA, which suggests the presence of additional disease genes. OBJECTIVE: To identify novel genes that cause Mendelian forms of TA. METHODS AND RESULTS: We exploited the occurrence of monogenic forms of TA in the Saudi population, which is characterised by high consanguinity, a feature conducive to the occurrence of Mendelian phenocopies of complex phenotypes as we and others have shown. Indeed, we demonstrate in two multiplex consanguineous families that we are able to map TA to regions of autozygosity in which whole-exome sequencing revealed homozygous truncating mutations in PRKD1 (encoding a kinase derepressor of MAF2) and NRP1 (encoding a coreceptor of vascular endothelial growth factor (VEGFA)). Previous work has demonstrated that Prkd1(-/-) is embryonic lethal and that its tissue specific deletion results in abnormal heart remodelling, whereas Nrp1(-/-) develops TA. Surprisingly, molecular karyotyping to exclude 22q11.2 deletion syndrome in the replication cohort of 17 simplex TA cases revealed a de novo hemizygous deletion that encompasses PRDM1, deficiency of which also results in TA phenotype in mouse. CONCLUSIONS: Our results expand the repertoire of molecular lesions in chromatin remodelling and transcription factors that are implicated in the pathogenesis of congenital heart disease in humans and attest to the power of monogenic forms of congenital heart diseases as a complementary approach to dissect the genetics of these complex phenotypes. PMID- 25713112 TI - Anti-NMDAR encephalitis: demonstration of neuroinflammation and the effect of immunotherapy. PMID- 25713113 TI - Congenital mirror movements: from piano player to opera singer. PMID- 25713114 TI - Legal and ethical implications in the evaluation and management of sports-related concussion. PMID- 25713115 TI - Severe anemia in a patient with multiple sclerosis treated with natalizumab. PMID- 25713116 TI - Clinical-pathologic study of depressive symptoms and cognitive decline in old age. PMID- 25713117 TI - MS disease activity in RESTORE: a randomized 24-week natalizumab treatment interruption study. PMID- 25713118 TI - Mystery case: giant cervico-thoraco-lumbar intraspinal arachnoid cyst. PMID- 25713119 TI - Teaching video neuroimages: how to unmask respiratory strength confounded by facial diplegia. PMID- 25713120 TI - Teaching NeuroImages: hypertrophic olivary degeneration in a young man with POLG gene mutation. PMID- 25713121 TI - Discovery and targeted proteomics on cutaneous biopsies infected by borrelia to investigate lyme disease. AB - Lyme disease is the most important vector-borne disease in the Northern hemisphere and represents a major public health challenge with insufficient means of reliable diagnosis. Skin is rarely investigated in proteomics but constitutes in the case of Lyme disease the key interface where the pathogens can enter, persist, and multiply. Therefore, we investigated proteomics on skin samples to detect Borrelia proteins directly in cutaneous biopsies in a robust and specific way. We first set up a discovery gel prefractionation-LC-MS/MS approach on a murine model infected by Borrelia burgdorferi sensu stricto that allowed the identification of 25 Borrelia proteins among more than 1300 mouse proteins. Then we developed a targeted gel prefractionation-LC-selected reaction monitoring (SRM) assay to detect 9/33 Borrelia proteins/peptides in mouse skin tissue samples using heavy labeled synthetic peptides. We successfully transferred this assay from the mouse model to human skin biopsies (naturally infected by Borrelia), and we were able to detect two Borrelia proteins: OspC and flagellin. Considering the extreme variability of OspC, we developed an extended SRM assay to target a large set of variants. This assay afforded the detection of nine peptides belonging to either OspC or flagellin in human skin biopsies. We further shortened the sample preparation and showed that Borrelia is detectable in mouse and human skin biopsies by directly using a liquid digestion followed by LC-SRM analysis without any prefractionation. This study thus shows that a targeted SRM approach is a promising tool for the early direct diagnosis of Lyme disease with high sensitivity (<10 fmol of OspC/mg of human skin biopsy). PMID- 25713122 TI - A Human Platelet Receptor Protein Microarray Identifies the High Affinity Immunoglobulin E Receptor Subunit alpha (FcepsilonR1alpha) as an Activating Platelet Endothelium Aggregation Receptor 1 (PEAR1) Ligand. AB - Genome-wide association studies to identify loci responsible for platelet function and cardiovascular disease susceptibility have repeatedly identified polymorphisms linked to a gene encoding platelet endothelium aggregation receptor 1 (PEAR1), an "orphan" cell surface receptor that is activated to stabilize platelet aggregates. To investigate how PEAR1 signaling is initiated, we sought to identify its extracellular ligand by creating a protein microarray representing the secretome and receptor repertoire of the human platelet. Using an avid soluble recombinant PEAR1 protein and a systematic screening assay designed to detect extracellular interactions, we identified the high affinity immunoglobulin E (IgE) receptor subunit alpha (FcepsilonR1alpha) as a PEAR1 ligand. FcepsilonR1alpha and PEAR1 directly interacted through their membrane proximal Ig-like and 13th epidermal growth factor domains with a relatively strong affinity (KD ~ 30 nm). Precomplexing FcepsilonR1alpha with IgE potently inhibited the FcepsilonR1alpha-PEAR1 interaction, and this was relieved by the anti-IgE therapeutic omalizumab. Oligomerized FcepsilonR1alpha potentiated platelet aggregation and led to PEAR1 phosphorylation, an effect that was also inhibited by IgE. These findings demonstrate how a protein microarray resource can be used to gain important insight into the function of platelet receptors and provide a mechanistic basis for the initiation of PEAR1 signaling in platelet aggregation. PMID- 25713123 TI - Automated Validation of Results and Removal of Fragment Ion Interferences in Targeted Analysis of Data-independent Acquisition Mass Spectrometry (MS) using SWATHProphet. AB - Proteomics by mass spectrometry technology is widely used for identifying and quantifying peptides and proteins. The breadth and sensitivity of peptide detection have been advanced by the advent of data-independent acquisition mass spectrometry. Analysis of such data, however, is challenging due to the complexity of fragment ion spectra that have contributions from multiple co eluting precursor ions. We present SWATHProphet software that identifies and quantifies peptide fragment ion traces in data-independent acquisition data, provides accurate probabilities to ensure results are correct, and automatically detects and removes contributions to quantitation originating from interfering precursor ions. Integration in the widely used open source Trans-Proteomic Pipeline facilitates subsequent analyses such as combining results of multiple data sets together for improved discrimination using iProphet and inferring sample proteins using ProteinProphet. This novel development should greatly help make data-independent acquisition mass spectrometry accessible to large numbers of users. PMID- 25713124 TI - Scanning electron microscopy for flow-diverting stent research: technical tips and tricks. AB - Flow-diverting (FD) stents represent a new concept in the treatment of intracranial aneurysms with challenging anatomical dispositions. Having been introduced to clinical practice only in the last 5 years and featuring complex mechanisms of action, they are still under research. Scanning electron microscopy, as part of an animal research protocol, provides detailed surface observations of neointimal healing at the aneurysm's neck, as well as covered side branch ostia, allowing for the confirmation of scientific hypotheses and observations. Technical adaptations of preparation protocols are presented based on a pilot study on Large White pigs, stented with FD stents at carotid bifurcations. PMID- 25713125 TI - Correction for Mankin et al., Neuronal code for extended time in the hippocampus. PMID- 25713126 TI - Correction for Haag et al., Evolution of a morphological novelty occurred before genome compaction in a lineage of extreme parasites. PMID- 25713128 TI - Correction for Reed et al., B-catenin deficiency, but not Myc deletion, suppresses the immediate phenotypes of APC loss in the liver. PMID- 25713127 TI - Core questions in domestication research. AB - The domestication of plants and animals is a key transition in human history, and its profound and continuing impacts are the focus of a broad range of transdisciplinary research spanning the physical, biological, and social sciences. Three central aspects of domestication that cut across and unify this diverse array of research perspectives are addressed here. Domestication is defined as a distinctive coevolutionary, mutualistic relationship between domesticator and domesticate and distinguished from related but ultimately different processes of resource management and agriculture. The relative utility of genetic, phenotypic, plastic, and contextual markers of evolving domesticatory relationships is discussed. Causal factors are considered, and two leading explanatory frameworks for initial domestication of plants and animals, one grounded in optimal foraging theory and the other in niche-construction theory, are compared. PMID- 25713129 TI - Correction for Bartesaghi et al., Inhibition of oxidative metabolism leads to p53 genetic inactivation and transformation in neural stem cells. PMID- 25713131 TI - Reply to Mackenzie: A comparison of Neu5Gc and alpha-gal xenoantigens. PMID- 25713130 TI - Multimodular biosensors reveal a novel platform for activation of G proteins by growth factor receptors. AB - Environmental cues are transmitted to the interior of the cell via a complex network of signaling hubs. Receptor tyrosine kinases (RTKs) and trimeric G proteins are two such major signaling hubs in eukaryotes. Conventionally, canonical signal transduction via trimeric G proteins is thought to be triggered exclusively by G protein-coupled receptors. Here we used molecular engineering to develop modular fluorescent biosensors that exploit the remarkable specificity of bimolecular recognition, i.e., of both G proteins and RTKs, and reveal the workings of a novel platform for activation of G proteins by RTKs in single living cells. Comprised of the unique modular makeup of guanidine exchange factor Galpha-interacting vesicle-associated protein (GIV)/girdin, a guanidine exchange factor that links G proteins to a variety of RTKs, these biosensors provide direct evidence that RTK-GIV-Galphai ternary complexes are formed in living cells and that Galphai is transactivated within minutes after growth factor stimulation at the plasma membrane. Thus, GIV-derived biosensors provide a versatile strategy for visualizing, monitoring, and manipulating the dynamic association of Galphai with RTKs for noncanonical transactivation of G proteins in cells and illuminate a fundamental signaling event regulated by GIV during diverse cellular processes and pathophysiologic states. PMID- 25713132 TI - Implications of xenoglycan sensitivity for increased cancer risk. PMID- 25713133 TI - Reply to Gonsamo et al.: Effect of the Eastern Atlantic-West Russia pattern on Amazon vegetation has not been demonstrated. PMID- 25713134 TI - Underestimated role of East Atlantic-West Russia pattern on Amazon vegetation productivity. PMID- 25713135 TI - Transport rates of a glutamate transporter homologue are influenced by the lipid bilayer. AB - The aspartate transporter from Pyrococcus horikoshii (GltPh) is a model for the structure of the SLC1 family of amino acid transporters. Crystal structures of GltPh provide insight into mechanisms of ion coupling and substrate transport; however, structures have been solved in the absence of a lipid bilayer so they provide limited information regarding interactions that occur between the protein and lipids of the membrane. Here, we investigated the effect of the lipid environment on aspartate transport by reconstituting GltPh into liposomes of defined lipid composition where the primary lipid is phosphatidylethanolamine (PE) or its methyl derivatives. We showed that the rate of aspartate transport and the transmembrane orientation of GltPh were influenced by the primary lipid in the liposomes. In PE liposomes, we observed the highest transport rate and showed that 85% of the transporters were orientated right-side out, whereas in trimethyl PE liposomes, 50% of transporters were right-side out, and we observed a 4-fold reduction in transport rate. Differences in orientation can only partially explain the lipid composition effect on transport rate. Crystal structures of GltPh revealed a tyrosine residue (Tyr-33) that we propose interacts with lipid headgroups during the transport cycle. Based on site directed mutagenesis, we propose that a cation-pi interaction between Tyr-33 and the lipid headgroups can influence conformational flexibility of the trimerization domain and thus the rate of transport. These results provide a specific example of how interactions between membrane lipids and membrane-bound proteins can influence function and highlight the importance of the role of the membrane in transporter function. PMID- 25713136 TI - Conformational flexibility and subunit arrangement of the modular yeast Spt-Ada Gcn5 acetyltransferase complex. AB - The Spt-Ada-Gcn5 acetyltransferase (SAGA) complex is a highly conserved, 19 subunit histone acetyltransferase complex that activates transcription through acetylation and deubiquitination of nucleosomal histones in Saccharomyces cerevisiae. Because SAGA has been shown to display conformational variability, we applied gradient fixation to stabilize purified SAGA and systematically analyzed this flexibility using single-particle EM. Our two- and three-dimensional studies show that SAGA adopts three major conformations, and mutations of specific subunits affect the distribution among these. We also located the four functional modules of SAGA using electron microscopy-based labeling and transcriptional activator binding analyses and show that the acetyltransferase module is localized in the most mobile region of the complex. We further comprehensively mapped the subunit interconnectivity of SAGA using cross-linking mass spectrometry, revealing that the Spt and Taf subunits form the structural core of the complex. These results provide the necessary restraints for us to generate a model of the spatial arrangement of all SAGA subunits. According to this model, the chromatin-binding domains of SAGA are all clustered in one face of the complex that is highly flexible. Our results relate information of overall SAGA structure with detailed subunit level interactions, improving our understanding of its architecture and flexibility. PMID- 25713137 TI - Eosinophil-associated ribonuclease 11 is a macrophage chemoattractant. AB - RNase A is the prototype of an extensive family of divergent proteins whose members share a unique disulfide-bonded tertiary structure, conserved catalytic motifs, and the ability to hydrolyze polymeric RNA. Several members of this family maintain independent roles as ribonucleases and modulators of innate immunity. Here we characterize mouse eosinophil-associated RNase (Ear) 11, a divergent member of the eosinophil ribonuclease cluster, and the only known RNase A ribonuclease expressed specifically in response to Th2 cytokine stimulation. Mouse Ear 11 is differentially expressed in somatic tissues at baseline (brain ? liver < lung < spleen); systemic stimulation with IL-33 results in 10-5000-fold increased expression in lung and spleen, respectively. Ear 11 is also expressed in response to protective priming of the respiratory mucosa with Lactobacillus plantarum; transcripts are detected both locally in lung as well as systemically in bone marrow and spleen. Mouse Ear 11 is enzymatically active, although substantially less so than mEar 1 and mEar 2; the relative catalytic efficiency (kcat/Km) of mEar 11 is diminished ~1000-1500-fold. However, in contrast to RNase 2/EDN and mEar 2, which have been characterized as selective chemoattractants for CD11c(+) dendritic cells, mEar 11 has prominent chemoattractant activity for F4/80(+)CD11c(-) tissue macrophages. Chemoattractant activity is not dependent on full enzymatic activity, and requires no interaction with the pattern recognition receptor, Toll-like receptor 2 (TLR2). Taken together, this work characterizes a divergent RNase A ribonuclease with a unique expression pattern and function, and highlights the versatility of this family in promoting innate immunity. PMID- 25713138 TI - Structure of a BAG6 (Bcl-2-associated athanogene 6)-Ubl4a (ubiquitin-like protein 4a) complex reveals a novel binding interface that functions in tail-anchored protein biogenesis. AB - BAG6 is an essential protein that functions in two distinct biological pathways, ubiquitin-mediated protein degradation of defective polypeptides and tail anchored (TA) transmembrane protein biogenesis in mammals, although its structural and functional properties remain unknown. We solved a crystal structure of the C-terminal heterodimerization domains of BAG6 and Ubl4a and characterized their interaction biochemically. Unexpectedly, the specificity and structure of the C terminus of BAG6, which was previously classified as a BAG domain, were completely distinct from those of the canonical BAG domain. Furthermore, the tight association of BAG6 and Ubl4a resulted in modulation of Ubl4a protein stability in cells. Therefore, we propose to designate the Ubl4a binding region of BAG6 as the novel BAG-similar (BAGS) domain. The structure of Ubl4a, which interacts with BAG6, is similar to the yeast homologue Get5, which forms a homodimer. These observations indicate that the BAGS domain of BAG6 promotes the TA protein biogenesis pathway in mammals by the interaction with Ubl4a. PMID- 25713139 TI - COPS5 protein overexpression increases amyloid plaque burden, decreases spinophilin-immunoreactive puncta, and exacerbates learning and memory deficits in the mouse brain. AB - Brain accumulation of neurotoxic amyloid beta (Abeta) peptide because of increased processing of amyloid precursor protein (APP), resulting in loss of synapses and neurodegeneration, is central to the pathogenesis of Alzheimer disease (AD). Therefore, the identification of molecules that regulate Abeta generation and those that cause synaptic damage is crucial for future therapeutic approaches for AD. We demonstrated previously that COPS5 regulates Abeta generation in neuronal cell lines in a RanBP9-dependent manner. Consistent with the data from cell lines, even by 6 months, COPS5 overexpression in APDeltaE9 mice (APDeltaE9/COPS5-Tg) significantly increased Abeta40 levels by 32% (p < 0.01) in the cortex and by 28% (p < 0.01) in the hippocampus, whereas the increases for Abeta42 were 37% (p < 0.05) and 34% (p < 0.05), respectively. By 12 months, the increase was even more robust. Abeta40 levels increased by 63% (p < 0.001) in the cortex and by 65% (p < 0.001) in the hippocampus. Similarly, Abeta42 levels were increased by 69% (p < 0.001) in the cortex and by 71% (p < 0.011) in the hippocampus. Increased Abeta levels were translated into an increased amyloid plaque burden both in the cortex (54%, p < 0.01) and hippocampus (64%, p < 0.01). Interestingly, COPS5 overexpression increased RanBP9 levels in the brain, which, in turn, led to increased amyloidogenic processing of APP, as reflected by increased levels of sAPPbeta and decreased levels of sAPPalpha. Furthermore, COPS5 overexpression reduced spinophilin in both the cortex (19%, p < 0.05) and the hippocampus (20%, p < 0.05), leading to significant deficits in learning and memory skills. Therefore, like RanBP9, COPS5 also plays a pivotal role in amyloid pathology in vivo. PMID- 25713140 TI - Cystathionine is a novel substrate of cystine/glutamate transporter: implications for immune function. AB - The cystine/glutamate transporter, designated as system xc(-), is important for maintaining intracellular glutathione levels and extracellular redox balance. The substrate-specific component of system xc(-), xCT, is strongly induced by various stimuli, including oxidative stress, whereas it is constitutively expressed only in specific brain regions and immune tissues, such as the thymus and spleen. Although cystine and glutamate are the well established substrates of system xc( ) and the knockout of xCT leads to alterations of extracellular redox balance, nothing is known about other potential substrates. We thus performed a comparative metabolite analysis of tissues from xCT-deficient and wild-type mice using capillary electrophoresis time-of-flight mass spectrometry. Although most of the analyzed metabolites did not show significant alterations between xCT deficient and wild-type mice, cystathionine emerged as being absent specifically in the thymus and spleen of xCT-deficient mice. No expression of either cystathionine beta-synthase or cystathionine gamma-lyase was observed in the thymus and spleen of mice. In embryonic fibroblasts derived from wild-type embryos, cystine uptake was significantly inhibited by cystathionine in a concentration-dependent manner. Wild-type cells showed an intracellular accumulation of cystathionine when incubated in cystathionine-containing buffer, which concomitantly stimulated an increased release of glutamate into the extracellular space. By contrast, none of these effects could be observed in xCT deficient cells. Remarkably, unlike knock-out cells, wild-type cells could be rescued from cystine deprivation-induced cell death by cystathionine supplementation. We thus conclude that cystathionine is a novel physiological substrate of system xc(-) and that the accumulation of cystathionine in immune tissues is exclusively mediated by system xc(-). PMID- 25713141 TI - Phosphorylation-independent suppression of light-activated visual pigment by arrestin in carp rods and cones. AB - Visual pigment in photoreceptors is activated by light. Activated visual pigment (R*) is believed to be inactivated by phosphorylation of R* with subsequent binding of arrestin. There are two types of photoreceptors, rods and cones, in the vertebrate retina, and they express different subtypes of arrestin, rod and cone type. To understand the difference in the function between rod- and cone type arrestin, we first identified the subtype of arrestins expressed in rods and cones in carp retina. We found that two rod-type arrestins, rArr1 and rArr2, are co-expressed in a rod and that a cone-type arrestin, cArr1, is expressed in blue- and UV-sensitive cones; the other cone-type arrestin, cArr2, is expressed in red- and green-sensitive cones. We quantified each arrestin subtype and estimated its concentration in the outer segment of a rod or a cone in the dark; they were ~0.25 mm (rArr1 plus rArr2) in a rod and 0.6-0.8 mm (cArr1 or cArr2) in a cone. The effect of each arrestin was examined. In contrast to previous studies, both rod and cone arrestins suppressed the activation of transducin in the absence of visual pigment phosphorylation, and all of the arrestins examined (rArr1, rArr2, and cArr2) bound transiently to most probably nonphosphorylated R*. One rod arrestin, rArr2, bound firmly to phosphorylated pigment, and the other two, rArr1 and cArr2, once bound to phosphorylated R* but dissociated from it during incubation. Our results suggested a novel mechanism of arrestin effect on the suppression of the R* activity in both rods and cones. PMID- 25713142 TI - Ion transporter NKCC1, modulator of neurogenesis in murine olfactory neurons. AB - Olfaction is one of the most crucial senses for vertebrates regarding foraging and social behavior. Therefore, it is of particular interest to investigate the sense of smell, its function on a molecular level, the signaling proteins involved in the process and the mechanism of required ion transport. In recent years, the precise role of the ion transporter NKCC1 in olfactory sensory neuron (OSN) chloride accumulation has been a controversial subject. NKCC1 is expressed in OSNs and is involved in chloride accumulation of dissociated neurons, but it had not been shown to play a role in mouse odorant sensation. Here, we present electro-olfactogram recordings (EOG) demonstrating that NKCC1-deficient mice exhibit significant defects in perception of a complex odorant mixture (Henkel100) in both air-phase and submerged approaches. Using next generation sequencing (NGS) and RT-PCR experiments of NKCC1-deficient and wild type mouse transcriptomes, we confirmed the absence of a highly expressed ion transporter that could compensate for NKCC1. Additional histological investigations demonstrated a reduced number of cells in the olfactory epithelium (OE), resulting in a thinner neuronal layer. Therefore, we conclude that NKCC1 is an important transporter involved in chloride ion accumulation in the olfactory epithelium, but it is also involved in OSN neurogenesis. PMID- 25713143 TI - Manganese redistribution by calcium-stimulated vesicle trafficking bypasses the need for P-type ATPase function. AB - Regulation of intracellular ion homeostasis is essential for eukaryotic cell physiology. An example is provided by loss of ATP2C1 function, which leads to skin ulceration, improper keratinocyte adhesion, and cancer formation in Hailey Hailey patients. The yeast ATP2C1 orthologue PMR1 codes for a Mn(2+)/Ca(2+) transporter that is crucial for cis-Golgi manganese supply. Here, we present evidence that calcium overcomes the lack of Pmr1 through vesicle trafficking stimulated manganese delivery and requires the endoplasmic reticulum Mn(2+) transporter Spf1 and the late endosome/trans-Golgi Nramp metal transporter Smf2. Smf2 co-localizes with the putative Mn(2+) transporter Atx2, and ATX2 overexpression counteracts the beneficial impact of calcium treatment. Our findings suggest that vesicle trafficking promotes organelle-specific ion interchange and cytoplasmic metal detoxification independent of calcineurin signaling or metal transporter re-localization. Our study identifies an alternative mode for cis-Golgi manganese supply in yeast and provides new perspectives for Hailey-Hailey disease treatment. PMID- 25713144 TI - Thermodynamic and kinetic characterization of the protein Z-dependent protease inhibitor (ZPI)-protein Z interaction reveals an unexpected role for ZPI Lys-239. AB - The anticoagulant serpin, protein Z-dependent protease inhibitor (ZPI), circulates in blood as a tight complex with its cofactor, protein Z (PZ), enabling it to function as a rapid inhibitor of membrane-associated factor Xa. Here, we show that N,N'-dimethyl-N-(acetyl)-N'-(7-nitrobenz-3-oxa-1,3-diazol-4 yl)ethylenediamine (NBD)-fluorophore-labeled K239C ZPI is a sensitive, moderately perturbing reporter of the ZPI-PZ interaction and utilize the labeled ZPI to characterize in-depth the thermodynamics and kinetics of wild-type and variant ZPI-PZ interactions. NBD-labeled K239C ZPI bound PZ with ~3 nM KD and ~400% fluorescence enhancement at physiologic pH and ionic strength. The NBD-ZPI-PZ interaction was markedly sensitive to ionic strength and pH but minimally affected by temperature, consistent with the importance of charged interactions. NBD-ZPI-PZ affinity was reduced ~5-fold by physiologic calcium levels to resemble NBD-ZPI affinity for gamma-carboxyglutamic acid/EGF1-domainless PZ. Competitive binding studies with ZPI variants revealed that in addition to previously identified Asp-293 and Tyr-240 hot spot residues, Met-71, Asp-74, and Asp-238 made significant contributions to PZ binding, whereas Lys-239 antagonized binding. Rapid kinetic studies indicated a multistep binding mechanism with diffusion-limited association and slow complex dissociation. ZPI complexation with factor Xa or cleavage decreased ZPI-PZ affinity 2-7-fold by increasing the rate of PZ dissociation. A catalytic role for PZ was supported by the correlation between a decreased rate of PZ dissociation from the K239A ZPI-PZ complex and an impaired ability of PZ to catalyze the K239A ZPI-factor Xa reaction. Together, these results reveal the energetic basis of the ZPI-PZ interaction and suggest an important role for ZPI Lys-239 in PZ catalytic action. PMID- 25713145 TI - The Fab1/PIKfyve phosphoinositide phosphate kinase is not necessary to maintain the pH of lysosomes and of the yeast vacuole. AB - Lysosomes and the yeast vacuole are degradative and acidic organelles. Phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2), a master architect of endolysosome and vacuole identity, is thought to be necessary for vacuolar acidification in yeast. There is also evidence that PtdIns(3,5)P2 may play a role in lysosomal acidification in higher eukaryotes. Nevertheless, these conclusions rely on qualitative assays of lysosome/vacuole pH. For example, quinacrine, an acidotropic fluorescent base, does not accumulate in the vacuoles of fab1Delta yeast. Fab1, along with its mammalian ortholog PIKfyve, is the lipid kinase responsible for synthesizing PtdIns(3,5)P2. In this study, we employed several assays that quantitatively assessed the lysosomal and vacuolar pH in PtdIns(3,5)P2-depleted cells. Using ratiometric imaging, we conclude that lysosomes retain a pH < 5 in PIKfyve-inhibited mammalian cells. In addition, quantitative fluorescence microscopy of vacuole-targeted pHluorin, a pH-sensitive GFP variant, indicates that fab1Delta vacuoles are as acidic as wild-type yeast. Importantly, we also employed fluorimetry of vacuoles loaded with cDCFDA, a pH sensitive dye, to show that both wild-type and fab1Delta vacuoles have a pH < 5.0. In comparison, the vacuolar pH of the V-ATPase mutant vph1Delta or vph1Delta fab1Delta double mutant was 6.1. Although the steady-state vacuolar pH is not affected by PtdIns(3,5)P2 depletion, it may have a role in stabilizing the vacuolar pH during salt shock. Overall, we propose a model in which PtdIns(3,5)P2 does not govern the steady-state pH of vacuoles or lysosomes. PMID- 25713146 TI - ADP ribosylation factor 6 (ARF6) promotes acrosomal exocytosis by modulating lipid turnover and Rab3A activation. AB - Regulated secretion is a central issue for the specific function of many cells; for instance, mammalian sperm acrosomal exocytosis is essential for egg fertilization. ARF6 (ADP-ribosylation factor 6) is a small GTPase implicated in exocytosis, but its downstream effectors remain elusive in this process. We combined biochemical, functional, and microscopy-based methods to show that ARF6 is present in human sperm, localizes to the acrosomal region, and is required for calcium and diacylglycerol-induced exocytosis. Results from pulldown assays show that ARF6 exchanges GDP for GTP in sperm challenged with different exocytic stimuli. Myristoylated and guanosine 5'-3-O-(thio)triphosphate (GTPgammaS)-loaded ARF6 (active form) added to permeabilized sperm induces acrosome exocytosis even in the absence of extracellular calcium. We explore the ARF6 signaling cascade that promotes secretion. We demonstrate that ARF6 stimulates a sperm phospholipase D activity to produce phosphatidic acid and boosts the synthesis of phosphatidylinositol 4,5-bisphosphate. We present direct evidence showing that active ARF6 increases phospholipase C activity, causing phosphatidylinositol 4,5 bisphosphate hydrolysis and inositol 1,4,5-trisphosphate-dependent intra acrosomal calcium release. We show that active ARF6 increases the exchange of GDP for GTP on Rab3A, a prerequisite for secretion. We propose that exocytic stimuli activate ARF6, which is required for acrosomal calcium efflux and the assembly of the membrane fusion machinery. This report highlights the physiological importance of ARF6 as a key factor for human sperm exocytosis and fertilization. PMID- 25713147 TI - Protein kinase A (PknA) of Mycobacterium tuberculosis is independently activated and is critical for growth in vitro and survival of the pathogen in the host. AB - The essential mycobacterial protein kinases PknA and PknB play crucial roles in modulating cell shape and division. However, the precise in vivo functional aspects of PknA have not been investigated. This study aims to dissect the role of PknA in mediating cell survival in vitro as well as in vivo. We observed aberrant cell shape and severe growth defects when PknA was depleted. Using the mouse infection model, we observe that PknA is essential for survival of the pathogen in the host. Complementation studies affirm the importance of the kinase, juxtamembrane, and transmembrane domains of PknA. Surprisingly, the extracytoplasmic domain is dispensable for cell growth and survival in vitro. We find that phosphorylation of the activation loop at Thr(172) of PknA is critical for bacterial growth. PknB has been previously suggested to be the receptor kinase, which activates multiple kinases, including PknA, by trans phosphorylating their activation loop residues. Using phospho-specific PknA antibodies and conditional pknB mutant, we find that PknA autophosphorylates its activation loop independent of PknB. Fluorescently tagged PknA and PknB show distinctive distribution patterns within the cell, suggesting that although both kinases are known to modulate cell shape and division, their modes of action are likely to be different. This is supported by our findings that expression of kinase-dead PknA versus kinase-dead PknB in mycobacterial cells leads to different cellular phenotypes. Data indicate that although PknA and PknB are expressed as part of the same operon, they appear to be regulating cellular processes through divergent signaling pathways. PMID- 25713149 TI - The bipartisan colon. PMID- 25713148 TI - Primary tumor location as a prognostic factor in metastatic colorectal cancer. AB - BACKGROUND: We sought to clarify the prognostic impact of primary tumor location in metastatic colorectal cancer (mCRC). METHODS: We evaluated the association between tumor location and survival parameters in patients with previously untreated mCRC receiving first-line chemotherapy +/- bevacizumab in three independent cohorts: a prospective pharmacogenetic study (PROVETTA) and two randomized phase III trials, AVF2107g and NO16966. Cancers proximal or distal of the splenic flexure were classified as right-sided or left-sided, respectively. The primary end point was overall survival (OS). Data were analyzed with Cox proportional hazards and logistic regression models. All statistical tests were two-sided. RESULTS: Among evaluable patients in the PROVETTA (n = 200), AVF2107g (n = 559), and NO16966 (n = 1268) studies, 72.0%, 63.1%, and 73.7% had left-sided tumors, respectively. In PROVETTA, patients with left-sided tumors had superior OS (left-sided vs right-sided: hazard ratio [HR] = .44, 95% confidence interval [CI] = .28 to .70, P < .001) and progression-free survival (HR = .52, 95% CI = .36 to .75, P < .001) outcomes. Multivariable analyses confirmed right-sided location as a negative prognostic variable, independent of mucinous histology and BRAF mutational status. Data from the AVF2107g (HR for OS = .55, 95% CI = .43 to .70) and NO16966 trials (HR for OS = .71, 95% CI = .62 to .82 both P < .001) also showed favorable outcomes in patients with left-sided tumors. In both randomized studies, the efficacy of bevacizumab was independent of tumor location. CONCLUSIONS: These data demonstrate that primary tumor location is an important prognostic factor in previously untreated mCRC. Given the consistency across an exploratory set and two confirmatory phase III studies, side of tumor origin should be considered for stratification in randomized trials. PMID- 25713151 TI - Re: Survival outcomes after contralateral prophylactic mastectomy: a decision analysis. PMID- 25713150 TI - JNCI and cancer prevention. AB - The Journal of the National Cancer Institute (JNCI), with its broad coverage of bench research, epidemiologic studies, and clinical trials, has a long history of publishing practice-changing studies in cancer prevention and public health. These include studies of tobacco cessation, chemoprevention, and nutrition. The landmark Breast Cancer Prevention Trial (BCPT)-the first large trial to prove efficacy of a preventive medication for a major malignancy-was published in the Journal, as were key ancillary papers to the BCPT. Even when JNCI was not the publication venue for the main trial outcomes, conceptual and design discussions leading to the trial as well as critical follow-up analyses based on trial data from the Prostate Cancer Prevention Trial (PCPT) and the Selenium and Vitamin E Chemoprevention Trial (SELECT) were published in the Journal. The Journal has also published important evidence on very charged topics, such as the purported link between abortion and breast cancer risk. In summary, JNCI has been at the forefront of numerous major publications related to cancer prevention. PMID- 25713152 TI - Response. PMID- 25713154 TI - A comparison between standard methods and structural nested modelling when bias from a healthy worker survivor effect is suspected: an iron-ore mining cohort study. AB - OBJECTIVES: Iron-ore miners are exposed to extremely dusty and physically arduous work environments. The demanding activities of mining select healthier workers with longer work histories (ie, the Healthy Worker Survivor Effect (HWSE)), and could have a reversing effect on the exposure-response association. The objective of this study was to evaluate an iron-ore mining cohort to determine whether the effect of respirable dust was confounded by the presence of an HWSE. METHODS: When an HWSE exists, standard modelling methods, such as Cox regression analysis, produce biased results. We compared results from g-estimation of accelerated failure-time modelling adjusted for HWSE with corresponding unadjusted Cox regression modelling results. RESULTS: For all-cause mortality when adjusting for the HWSE, cumulative exposure from respirable dust was associated with a 6% decrease of life expectancy if exposed >=15 years, compared with never being exposed. Respirable dust continued to be associated with mortality after censoring outcomes known to be associated with dust when adjusting for the HWSE. In contrast, results based on Cox regression analysis did not support that an association was present. CONCLUSIONS: The adjustment for the HWSE made a difference when estimating the risk of mortality from respirable dust. The results of this study, therefore, support the recommendation that standard methods of analysis should be complemented with structural modelling analysis techniques, such as g-estimation of accelerated failure-time modelling, to adjust for the HWSE. PMID- 25713153 TI - Asthma history, job type and job changes among US nurses. AB - OBJECTIVES: Nurses are at increased risk of occupational asthma, an observation that may be related to disinfectants exposure. Whether asthma history influences job type or job changes among nurses is unknown. We investigated this issue in a large cohort of nurses. METHODS: The Nurses' Health Study II is a prospective study of US female nurses enrolled in 1989 (ages 24-44 years). Job status and asthma were assessed in biennial (1989-2011) and asthma-specific questionnaires (1998, 2003). Associations between asthma history at baseline (diagnosis before 1989, n=5311) and job type at baseline were evaluated by multinomial logistic regression. The relations of asthma history and severity during follow-up to subsequent job changes were evaluated by Cox models. RESULTS: The analytic cohort included 98 048 nurses. Compared with nurses in education/administration (likely low disinfectant exposure jobs), women with asthma history at baseline were less often employed in jobs with likely high disinfectant exposure, such as operating rooms (odds ratio 0.73 (95% CI 0.63 to 0.86)) and emergency room/inpatient units (0.89 (0.82 to 0.97)). During a 22-year follow-up, nurses with a baseline history of asthma were more likely to move to jobs with lower exposure to disinfectants (HR 1.13 (1.07 to 1.18)), especially among those with more severe asthma (HR for mild persistent: 1.13; moderate persistent 1.26; severe persistent: 1.50, compared with intermittent asthma, p trend: 0.004). CONCLUSIONS: Asthma history was associated with baseline job type and subsequent job changes among nurses. This may partly reflect avoidance of tasks involving disinfectant use, and may introduce bias in cross-sectional studies on disinfectant exposure and asthma in nurses. PMID- 25713155 TI - Occupational health guidelines for mental disorders and stress-related complaints, a challenge for occupational health. PMID- 25713156 TI - Occupational exposures and Parkinson's disease mortality in a prospective Dutch cohort. AB - OBJECTIVES: We investigated the association between six occupational exposures (ie, pesticides, solvents, metals, diesel motor emissions (DME), extremely low frequency magnetic fields (ELF-MF) and electric shocks) and Parkinson's disease (PD) mortality in a large population-based prospective cohort study. METHODS: The Netherlands Cohort Study on diet and cancer enrolled 58,279 men and 62,573 women aged 55-69 years in 1986. Participants were followed up for cause-specific mortality over 17.3 years, until December 2003, resulting in 402 male and 207 female PD deaths. Following a case-cohort design, a subcohort of 5,000 participants was randomly sampled from the complete cohort. Information on occupational history and potential confounders was collected at baseline. Job exposure matrices were applied to assign occupational exposures. Associations with PD mortality were evaluated using Cox regression. RESULTS: Among men, elevated HRs were observed for exposure to pesticides (eg, ever high exposed, HR 1.27, 95% CI 0.86 to 1.88) and ever high exposed to ELF-MF (HR 1.54, 95% CI 1.00 to 2.36). No association with exposure duration or trend in cumulative exposure was observed for any of the occupational exposures. Results among women were unstable due to small numbers of high-exposed women. CONCLUSIONS: Associations with PD mortality were observed for occupational exposure to pesticides and ELF MF. However, the weight given to these findings is limited by the absence of a monotonic trend with either duration or cumulative exposure. No associations were found between PD mortality and occupational exposure to solvents, metals, DME or electric shocks. PMID- 25713157 TI - Characteristics of work-related fatal and hospitalised injuries not captured in workers' compensation data. AB - OBJECTIVES: (1) To identify work-related fatal and non-fatal hospitalised injuries using multiple data sources, (2) to compare case-ascertainment from external data sources with accepted workers' compensation claims and (3) to investigate the characteristics of work-related fatal and hospitalised injuries not captured by workers' compensation. METHODS: Work-related fatal injuries were ascertained from vital statistics, coroners and hospital discharge databases using payment and diagnosis codes and injury and work descriptions; and work related (non-fatal) injuries were ascertained from the hospital discharge database using admission, diagnosis and payment codes. Injuries for British Columbia residents aged 15-64 years from 1991 to 2009 ascertained from the above external data sources were compared to accepted workers' compensation claims using per cent captured, validity analyses and logistic regression. RESULTS: The majority of work-related fatal injuries identified in the coroners data (83%) and the majority of work-related hospitalised injuries (95%) were captured as an accepted workers' compensation claim. A work-related coroner report was a positive predictor (88%), and the responsibility of payment field in the hospital discharge record a sensitive indicator (94%), for a workers' compensation claim. Injuries not captured by workers' compensation were associated with female gender, type of work (natural resources and other unspecified work) and injury diagnosis (eg, airway-related, dislocations and undetermined/unknown injury). CONCLUSIONS: Some work-related injuries captured by external data sources were not found in workers' compensation data in British Columbia. This may be the result of capturing injuries or workers that are ineligible for workers' compensation, or the result of injuries that go unreported to the compensation system. Hospital discharge records and coroner reports may provide opportunities to identify workers (or family members) with an unreported work-related injury and to provide them with information for submitting a workers' compensation claim. PMID- 25713158 TI - Factors associated with the length of fit note-certified sickness episodes in the UK. AB - OBJECTIVES: To identify diagnostic, patient/employee, general practitioner (GP) and practice factors associated with length of certified sickness episodes. METHODS: Twelve-month collection of fit note data at 68 general practices in eight regions of England, Wales and Scotland between 2011 and 2013. Secondary analysis of sick note data collected at seven general practices in 2001/2002. All employed patients receiving at least one fit note at practices within the collection period were included in the study. Main study outcomes were certified sickness episodes lasting longer than 3, 6 and 12 weeks. RESULTS: The data from seven practices contributing in 2013, and a decade previously, suggest that periods of long-term sickness absence may be falling overall (risk >12 weeks absence, OR=0.65) but the proportion of mild-moderate mental disorder-related (M MMD) episodes is rising (26% to 38%). Over 32% (8064/25 078) of fit notes issued to working patients in the 68 practices were for a M-MMD. A total of 13 994 patient sickness 'episodes' were identified. Diagnostic category of episode, male patients, older patient age and higher social deprivation were significantly associated with the >3 week, >6 week and long-term (>12 week) outcomes, and GP partner status with the long-term outcome only. CONCLUSIONS: In the context of a rapidly changing legislative environment, the study used the largest sickness certification database constructed in the UK to enhance the evidence base relating to factors contributing to long-term work incapacity. PMID- 25713159 TI - Certified sickness absence: does the 'fit-note' work? PMID- 25713160 TI - The power of negative thinking--the glass is half full. PMID- 25713161 TI - Commentary on: successful use of extracorporeal membrane oxygenation for pulmonary embolism, prolonged cardiac arrest, post-partum: a cannulation dilemma. PMID- 25713162 TI - Commentary on: towards a proactive therapy utilizing the modern spectrum of extracorporeal life support: a single-centre experience. PMID- 25713163 TI - Minimizing the perfusion system by integration of the components. Does it affect the hematocrit drop and transfused red blood cells? A retrospective audit. AB - BACKGROUND: We evaluate the affect on the hematocrit (Hct) drop and the amount of transfused red blood cells (RBCs) during cardiopulmonary bypass (CPB) in adult cardiac surgery patients due to minimizing the CPB circuit by using integrated components. METHODS: Two hundred and seventy-two patients were included in this retrospective audit. Patients were assigned to three cohorts: the first cohort consisted of patients operated on with a CPB circuit volume of 1630 ml in 2008; the second cohort of such patients in 2010, with 1380 ml; and the third cohort of such patients in 2011, with 1250 ml. RESULTS: There were no significant differences with respect to patient demographics. The priming volume was consecutively significantly reduced; (1635 +/- 84 ml, 1384 +/- 72 ml and 1256 +/- 130 ml, p<0.0001). A trend of decreased amount of RBCs during CPB was visible (cohort 1630: 98 +/- 195 ml, cohort 1380: 35 +/- 151 ml and cohort 1250: 48 +/- 113 ml, p=0.02). Also, the amount of RBCs during the total CPB procedure shows a decreased trend (cohort 1630: 122 +/- 230 ml, cohort 1380: 52 +/- 180 ml and cohort 1250: 71 +/- 156 ml, p=0.04). Blood loss during CPB was significantly lower in cohorts 1380 and 1250 (1630: 922 +/- 378 ml, 1380: 706 +/- 347 ml and 1250: 708 +/- 418 ml, p<0.0001). The volume of diuresis was significantly larger in cohort 1630 (1630: 1166 +/- 800 ml, 1380: 477 +/- 530 ml and 1250: 523 +/- 504 ml, p<0.0001). The Hct drop at the start and end of CPB was significantly reduced comparing cohort 1630 with cohort 1250 (1630: 32 +/- 7%, 1380: 30 +/- 7% and 1250: 28 +/- 10%, p=0.002) at the start of CPB and (1630: 31 +/- 7%, 1380: 29 +/- 7% and 1250: 28 +/- 8%, p=0.016) at the end of CPB. The Hct values at the start and end of CPB were significantly different between the cohorts (1680: 0.23 +/- 0.03 L/L - 0.22 +/- 0.02 L/L, 1380: 0.25 +/- 0.03 L/L - 0.25 +/- 0.03 L/L and 1250: 0.25 +/- 0.03 L/L- 0.25 +/- 0.03 L/L, p= 0.001 and 0.0001). CONCLUSIONS: Minimizing our CPB circuit by using integrated components has affected the drop of Hct and the amount of transfused RBCs. PMID- 25713164 TI - Risk of valvular heart disease after treatment for Hodgkin lymphoma. AB - BACKGROUND: Hodgkin lymphoma (HL) survivors are at increased risk of developing valvular heart disease (VHD). We evaluated the determinants of the risk and the radiation dose-response. METHODS: A case-control study was nested in a cohort of 1852 five-year HL survivors diagnosed at ages 15 to 41 years and treated between 1965 and 1995. Case patients had VHD of at least moderate severity as their first cardiovascular diagnosis following HL treatment. Control patients were matched to case patients for age, gender, and HL diagnosis date. Treatment and follow-up data were abstracted from medical records. Radiation doses to heart valves were estimated by reconstruction of individual treatments on representative computed tomography datasets. All statistical tests were two-sided. RESULTS: Eighty-nine case patients with VHD were identified (66 severe or life-threatening) and 200 control patients. Aortic (n = 63) and mitral valves (n = 42) were most frequently affected. Risks increased more than linearly with radiation dose. For doses to the affected valve(s) of less than or equal to 30, 31-35, 36-40, and more than 40 Gy, VHD rates increased by factors of 1.4, 3.1, 5.4, and 11.8, respectively (P trend < .001). Approximate 30-year cumulative risks were 3.0%, 6.4%, 9.3%, and 12.4% for the same dose categories. VHD rate increased with splenectomy by a factor of 2.3 (P = .02). CONCLUSIONS: Radiation dose to the heart valves can increase the risk of clinically significant VHD, especially at doses above 30 Gy. However, for patients with mediastinal involvement treated today with 20 or 30 Gy, the 30-year risk will be increased by only about 1.4%. These findings may be useful for patients and doctors both before treatment and during follow-up. PMID- 25713166 TI - Breast cancer genomics from microarrays to massively parallel sequencing: paradigms and new insights. AB - Rapid advancements in massively parallel sequencing methods have enabled the analysis of breast cancer genomes at an unprecedented resolution, which have revealed the remarkable heterogeneity of the disease. As a result, we now accept that despite originating in the breast, estrogen receptor (ER)-positive and ER negative breast cancers are completely different diseases at the molecular level. It has become apparent that there are very few highly recurrently mutated genes such as TP53, PIK3CA, and GATA3, that no two breast cancers display an identical repertoire of somatic genetic alterations at base-pair resolution and that there might not be a single highly recurrently mutated gene that defines each of the "intrinsic" subtypes of breast cancer (ie, basal-like, HER2-enriched, luminal A, and luminal B). Breast cancer heterogeneity, however, extends beyond the diversity between tumors. There is burgeoning evidence to demonstrate that at least some primary breast cancers are composed of multiple, genetically diverse clones at diagnosis and that metastatic lesions may differ in their repertoire of somatic genetic alterations when compared with their respective primary tumors. Several biological phenomena may shape the reported intratumor genetic heterogeneity observed in breast cancers, including the different mutational processes and multiple types of genomic instability. Harnessing the emerging concepts of the diversity of breast cancer genomes and the phenomenon of intratumor genetic heterogeneity will be essential for the development of optimal methods for diagnosis, disease monitoring, and the matching of patients to the drugs that would benefit them the most. PMID- 25713165 TI - A prospective study of the immune system activation biomarker neopterin and colorectal cancer risk. AB - BACKGROUND: Neopterin may be relevant for colorectal cancer (CRC) development, as a biomarker of cellular immune activity exerting pleiotropic effects on cellular ageing, oxidative stress, and inflammation. So far, the association between prediagnostic neopterin and colon and rectal cancer risk has not been evaluated in human populations. METHODS: A nested case-control study was conducted within the European Prospective Investigation into Cancer and Nutrition cohort using data on plasma concentrations of total neopterin (T-N, sum of neopterin and 7,8 dihydroneopterin) in 830 incident CRC case patients (561 colon and 269 rectal) matched within risk sets to 830 control participants. A subsequent replication study used data from the Hordaland Health Study, where 173 CRC case patients have been diagnosed among 6594 healthy participants over 12 years of follow-up. RESULTS: After multivariable adjustment for a priori chosen CRC risk factors, a "U-shaped" association of T-N with CRC was revealed. Compared with the second quintile of the T-N distribution, the relative risks for the first, third, fourth, and fifth quintiles were 2.37 (95% CI = 1.66 to 3.39), 1.24 (95% CI = 0.87 to 1.77), 1.55 (95% CI = 1.08 to 2.22), and 2.31 (95% CI = 1.63 to 3.27), respectively. Replication of these associations within the Hordaland Health Study yielded similar results. No differences have been observed when the associations were explored by colon and rectal cancer site (two-sided P difference = .87) and after excluding case patients diagnosed within the first four follow-up years. CONCLUSIONS: These novel findings provide evidence of the role of both suppressed and activated cell-mediated immunity as reflected by prediagnostic T-N concentrations in the development of CRC. PMID- 25713169 TI - Understanding diversity: the importance of social acceptance. AB - Two studies investigated how people define and perceive diversity in the historically majority-group dominated contexts of business and academia. We hypothesized that individuals construe diversity as both the numeric representation of racial minorities and the social acceptance of racial minorities within a group. In Study 1, undergraduates' (especially minorities') perceptions of campus diversity were predicted by perceived social acceptance on a college campus, above and beyond perceived minority representation. Study 2 showed that increases in a company's representation and social acceptance independently led to increases in perceived diversity of the company among Whites. Among non-Whites, representation and social acceptance only increased perceived diversity of the company when both qualities were high. Together these findings demonstrate the importance of both representation and social acceptance to the achievement of diversity in groups and that perceiver race influences the relative importance of these two components of diversity. PMID- 25713167 TI - The role of BPTF in melanoma progression and in response to BRAF-targeted therapy. AB - BACKGROUND: Bromodomain PHD finger transcription factor (BPTF) plays an important role in chromatin remodeling, but its functional role in tumor progression is incompletely understood. Here we explore the oncogenic effects of BPTF in melanoma. METHODS: The consequences of differential expression of BPTF were explored using shRNA-mediated knockdown in several melanoma cell lines. Immunoblotting was used to assess the expression of various proteins regulated by BPTF. The functional role of BPTF in melanoma progression was investigated using assays of colony formation, invasion, cell cycle, sensitivity to selective BRAF inhibitors, and in xenograft models of melanoma progression (n = 12 mice per group). The biomarker role of BPTF in melanoma progression was assessed using fluorescence in situ hybridization and immunohistochemical analyses. All statistical tests were two-sided. RESULTS: shRNA-mediated BPTF silencing suppressed the proliferative capacity (by 65.5%) and metastatic potential (by 66.4%) of melanoma cells. Elevated BPTF copy number (mean >= 3) was observed in 28 of 77 (36.4%) melanomas. BPTF overexpression predicted poor survival in a cohort of 311 melanoma patients (distant metastasis-free survival P = .03, and disease-specific survival P = .008), and promoted resistance to BRAF inhibitors in melanoma cell lines. Metastatic melanoma tumors progressing on BRAF inhibitors contained low BPTF-expressing, apoptotic tumor cell subclones, indicating the continued presence of drug-responsive subclones within tumors demonstrating overall resistance to anti-BRAF agents. CONCLUSIONS: These studies demonstrate multiple protumorigenic functions for BPTF and identify it as a novel target for anticancer therapy. They also suggest the combination of BPTF targeting with BRAF inhibitors as a novel therapeutic strategy for melanomas with mutant BRAF. PMID- 25713168 TI - 15q12 variants, sputum gene promoter hypermethylation, and lung cancer risk: a GWAS in smokers. AB - BACKGROUND: Lung cancer is the leading cause of cancer-related mortality worldwide. Detection of promoter hypermethylation of tumor suppressor genes in exfoliated cells from the lung provides an assessment of field cancerization that in turn predicts lung cancer. The identification of genetic determinants for this validated cancer biomarker should provide novel insights into mechanisms underlying epigenetic reprogramming during lung carcinogenesis. METHODS: A genome wide association study using generalized estimating equations and logistic regression models was conducted in two geographically independent smoker cohorts to identify loci affecting the propensity for cancer-related gene methylation that was assessed by a 12-gene panel interrogated in sputum. All statistical tests were two-sided. RESULTS: Two single nucleotide polymorphisms (SNPs) at 15q12 (rs73371737 and rs7179575) that drove gene methylation were discovered and replicated with rs73371737 reaching genome-wide significance (P = 3.3*10(-8)). A haplotype carrying risk alleles from the two 15q12 SNPs conferred 57% increased risk for gene methylation (P = 2.5*10(-9)). Rs73371737 reduced GABRB3 expression in lung cells and increased risk for smoking-induced chronic mucous hypersecretion. Furthermore, subjects with variant homozygote of rs73371737 had a two-fold increase in risk for lung cancer (P = .0043). Pathway analysis identified DNA double-strand break repair by homologous recombination (DSBR-HR) as a major pathway affecting susceptibility for gene methylation that was validated by measuring chromatid breaks in lymphocytes challenged by bleomycin. CONCLUSIONS: A functional 15q12 variant was identified as a risk factor for gene methylation and lung cancer. The associations could be mediated by GABAergic signaling that drives the smoking-induced mucous cell metaplasia. Our findings also substantiate DSBR-HR as a critical pathway driving epigenetic gene silencing. PMID- 25713170 TI - Personality, effective goal-striving, and enhanced well-being: comparing 10 candidate personality strengths. AB - In a three-wave, year-long, large-sample dataset (N = 755), 10 candidate "personality strengths" (Grit, Gratitude, Curiosity, Savoring, Control Beliefs, Meaning in Life-Presence, Strengths Use, and Engagement, Pleasure, and Meaning Based Orientations Toward Happiness) were compared as predictors of 6-month increases in goal attainment, and as moderators of goal attainment effects upon boosted subjective well-being (SWB). Seeking internal replication, we tested our models twice, both during T1-T2 and during T2-T3. We also examined whether any Personality * Attainment moderator effects upon change in SWB at T2 still persisted at T3. Grit was the only candidate strength that predicted increased goal attainment from T1 to T2 and from T2 to T3, and Curiosity was the only candidate strength that moderated attainment effects on well-being from T1 to T2 and from T2 to T3. T2 Goal attainment effects on SWB were best sustained at T3 when Meaning Orientation increased from T1 to T2. Implications for identifying keystone constructs in personality (and positive) psychology are discussed. PMID- 25713171 TI - Perceptions of a changing world induce hope and promote peace in intractable conflicts. AB - The importance of hope in promoting conciliatory attitudes has been asserted in the field of conflict resolution. However, little is known about conditions inducing hope, especially in intractable conflicts, where reference to the outgroup may backfire. In the current research, five studies yielded convergent support for the hypothesis that hope for peace stems from a general perception of the world as changing. In Study 1, coders observed associations between belief in a changing world, hope regarding peace, and support for concessions. Study 2 revealed the hypothesized relations using self-reported measures. Studies 3 and 4 established causality by instilling a perception of the world as changing (vs. unchanging) using narrative and drawing manipulations. Study 5 compared the changing world message with a control condition during conflict escalation. Across studies, although the specific context was not referred to, the belief in a changing world increased support for concessions through hope for peace. PMID- 25713172 TI - Threats to social identity can trigger social deviance. AB - We hypothesized that threats to people's social (i.e., group) identity can trigger deviant attitudes and behaviors. A correlational study and five experiments showed that experiencing or recalling situations associated with the devaluation of a social identity caused participants to endorse or engage in deviant actions, including stealing, cheating, and lying. The effect was driven by the tendency to construe social identity threats not as isolated incidents but as symbolic of the continuing devaluation and disrespectful treatment of one's group. Supplementing sociological approaches to deviance and delinquency, the results suggest the relevance and utility of a social-psychological account. PMID- 25713173 TI - The Plant-Specific RAB5 GTPase ARA6 is Required for Starch and Sugar Homeostasis in Arabidopsis thaliana. AB - Endosomal trafficking plays integral roles in various eukaryotic cell activities. In animal cells, a member of the RAB GTPase family, RAB5, is a key regulator of various endosomal functions. In addition to orthologs of animal RAB5, plants harbor the plant-specific RAB5 group, the ARA6 group, which is conserved in land plant lineages. In Arabidopsis thaliana, ARA6 and conventional RAB5 act in distinct endosomal trafficking pathways; ARA6 mediates trafficking from endosomes to the plasma membrane, whereas conventional RAB5 acts in endocytic and vacuolar trafficking pathways. ARA6 is also required for normal salt and osmotic stress tolerance, although the functional link between ARA6 and stress tolerance remains unclear. In this study, we investigated ARA6 function in stress tolerance by monitoring broad-scale changes in gene expression in the ara6 mutant. A comparison of the expression profiles between wild-type and ara6-1 plants revealed that the expression of the Qua-Quine Starch (QQS) gene was significantly affected by the ara6-1 mutation. QQS is involved in starch homeostasis, consistent with the starch content decreasing in the ara6 mutants to approximately 60% of that of the wild-type plant. In contrast, the free and total glucose content increased in the ara6 mutants. Moreover, the proliferation of Pseudomonas syringae pv. tomato DC3000 was repressed in ara6 mutants, which could be attributed to the elevated sugar content. These results suggest that ARA6 is responsible for starch and sugar homeostasis, most probably through the function of QQS. PMID- 25713174 TI - Involvement of the Putative N-Acetylornithine Deacetylase from Arabidopsis thaliana in Flowering and Fruit Development. AB - In eukaryotic cells, the non-proteinogenic amino acid ornithine is the precursor of arginine and polyamines (PAs). The final step of ornithine biosynthesis occurs in plants via a cyclic pathway catalyzed by N(2)-acetylornithine:N acetylglutamate acetyltransferase (NAOGAcT). An alternative route for ornithine formation, the linear pathway, has been reported for enteric bacteria and a few other organisms; the acetyl group of N(2)-acetylornithine is released as acetate by N(2)-acetylornithine deacetylase (NAOD). NAOD activity has never been demonstrated in plants, although many putative NAOD-like genes have been identified. In this investigation, we examined the effect of down-regulation of the putative Arabidopsis thaliana NAOD gene by using AtNAOD-silenced (sil#17) and T-DNA insertional mutant (atnaod) plants. The ornithine content was consistently reduced in sil#17 and atnaod plants compared with wild-type plants, suggesting that in addition to NAOGAcT action, AtNAOD contributes to the regulation of ornithine levels in plant cells. Ornithine depletion was associated with altered levels of putrescine and spermine. Reduced AtNAOD expression resulted in alterations at the reproductive level, causing early flowering and impaired fruit setting. In this regard, the highest level of AtNAOD expression was observed in unfertilized ovules. Our findings suggest that AtNAOD acts as a positive regulator of fruit setting and agree with those obtained in tomato auxin synthesizing parthenocarpic plants, where induction of SlNAOD was associated with the onset of ovary growth. Thus, here we have uncovered the first hints of the functions of AtNAOD by connecting its role in flower and fruit development with the regulation of ornithine and PA levels. PMID- 25713175 TI - Live Imaging and Laser Disruption Reveal the Dynamics and Cell-Cell Communication During Torenia fournieri Female Gametophyte Development. AB - The female gametophytes of many flowering plants contain one egg cell, one central cell, two synergid cells and three antipodal cells with respective morphological characteristics and functions. These cells are formed by cellularization of a multinuclear female gametophyte. However, the dynamics and mechanisms of female gametophyte development remain largely unknown due to the lack of a system to visualize directly and manipulate female gametophytes in living material. Here, we established an in vitro ovule culture system to examine female gametophyte development in Torenia fournieri, a unique plant species with a protruding female gametophyte. The four-nucleate female gametophyte became eight nucleate by the final (third) mitosis and successively cellularized and matured to attract a pollen tube. The duration of final mitosis was 28 +/- 6.5 min, and cellularization was completed in 54 +/- 20 min after the end of the third mitosis. Fusion of polar nuclei in the central cell occurred in 13.1 +/- 1.1 h, and onset of expression of LURE2, a pollen tube attractant gene, was visualized by a green fluorescent protein reporter 10.7 +/- 2.3 h after cellularization. Laser disruption analysis demonstrated that the egg and central cells were required for synergid cells to acquire the pollen tube attraction function. Moreover, aberrant nuclear positioning and down-regulation of LURE2 were observed in one of the two synergid cells after disrupting an immature egg cell, suggesting that cell specification was affected. Our system provides insights into the precise dynamics and mechanisms of female gametophyte development in T. fournieri. PMID- 25713176 TI - Structural Requirements of Strigolactones for Shoot Branching Inhibition in Rice and Arabidopsis. AB - The structural requirements of strigolactones (SLs) involved in germination induction of root parasitic plants and hyphal branching in arbuscular mycorrhizal (AM) fungi have been extensively studied. However, our knowledge of the requirements of SLs involved in shoot branching inhibition in plants is still limited. To address this question, we investigated the structure-activity relationships of SLs in shoot branching inhibition in rice and Arabidopsis. SLs possess a four-ring structure, with a tricyclic lactone (ABC-rings) connected to a methylbutenolide part (D-ring) via an enol ether bridge. Here, we show that the the (R) configuration at C-2', which determines the steric position of the D-ring relative to the enol ether olefin bond, is critical for the hormonal activity in rice. Replacement of the enol ether moiety by an alkoxy or imino ether resulted in a severe reduction in biological activity in rice. Moreover, yeast two-hybrid experiments using a possible SL receptor, DWARF14 (D14), and a repressor in the SL signaling pathway, DWARF53 (D53), showed that D14 can interact with D53 in the presence of (2'R) stereoisomers of SLs, but not (2'S) stereoisomers, suggesting that the stereostructure of SLs is crucial for the interaction of these proteins. When GR5, an AB-ring-truncated analog, was applied to the hydroponic culture medium, strong inhibition of shoot branching was observed both in rice and in Arabidopsis. However, GR5 was only weakly active when directly applied to the axillary buds of Arabidopsis. Our results indicate that the difference in plant species and application methods greatly influences the apparent SL biological activity. PMID- 25713177 TI - CjbHLH1 homologs regulate sanguinarine biosynthesis in Eschscholzia californica cells. AB - Isoquinoline alkaloids (IQAs), terpenoid indole alkaloid and nicotine are some of the most studied alkaloids. Recently, several groups have reported that the biosynthesis of these alkaloids is regulated by basic helix-loop-helix (bHLH) transcription factors. Whereas the biosyntheses of nicotine and terpenoid indole alkaloid in Nicotiana plants and Catharanthus roseus are directly or indirectly regulated by Arabidopsis thaliana MYC2 homologs, a non-MYC2-type bHLH transcription factor, CjbHLH1, comprehensively regulates berberine biosynthesis in Coptis japonica. Interestingly, CjbHLH1 homologous genes were found in many IQA-producing plant species, which suggests that non-MYC2-type CjbHLH homologs are specifically associated with IQA biosynthesis. To test whether CjbHLH1 homologs are involved in the biosynthesis of IQA in a plant other than C. japonica, we isolated two genes homologous to CjbHLH1, i.e. EcbHLH1-1 and EcbHLH1 2, from Eschscholzia californica (California poppy). Stable transformants in which the expression levels of EcbHLH1 genes were constitutively suppressed by RNA interference (RNAi) showed a reduced expression of some IQA biosynthetic enzyme genes. A metabolite analysis confirmed that the suppression of EcbHLH1, particularly EcbHLH1-2, caused a decrease in sanguinarine accumulation in transgenic cultured cells. These results indicate that non-MYC2-type EcbHLH1s regulate IQA biosynthesis in California poppy like CjbHLH1 in C. japonica. PMID- 25713178 TI - Conflicting clinical duties. PMID- 25713181 TI - Roquilly a et al (Clin Infect Dis 2015; 60:64-75). PMID- 25713180 TI - Chalmers et al (Clin Infect Dis 2014; 58:330-9). PMID- 25713182 TI - Stevens DL et al (Clin Infect Dis 2014; 59: e10-52). PMID- 25713184 TI - IDSA Response to Factors Contributing to the Decline of Medical Residents Choosing the Field of Infectious Diseases. PMID- 25713185 TI - Reply to Eljaaly et al. PMID- 25713186 TI - Antibiotic dosing discrepancies in the 2014 skin and soft tissue infections guidelines. PMID- 25713190 TI - Whenever you lose connection, take intranasal insulin? PMID- 25713188 TI - Mitochondrial hormesis and diabetic complications. AB - The concept that excess superoxide production from mitochondria is the driving, initial cellular response underlying diabetes complications has been held for the past decade. However, results of antioxidant-based trials have been largely negative. In the present review, the data supporting mitochondrial superoxide as a driving force for diabetic kidney, nerve, heart, and retinal complications are reexamined, and a new concept for diabetes complications--mitochondrial hormesis- is presented. In this view, production of mitochondrial superoxide can be an indicator of healthy mitochondria and physiologic oxidative phosphorylation. Recent data suggest that in response to excess glucose exposure or nutrient stress, there is a reduction of mitochondrial superoxide, oxidative phosphorylation, and mitochondrial ATP generation in several target tissues of diabetes complications. Persistent reduction of mitochondrial oxidative phosphorylation complex activity is associated with the release of oxidants from nonmitochondrial sources and release of proinflammatory and profibrotic cytokines, and a manifestation of organ dysfunction. Restoration of mitochondrial function and superoxide production via activation of AMPK has now been associated with improvement in markers of renal, cardiovascular, and neuronal dysfunction with diabetes. With this Perspective, approaches that stimulate AMPK and PGC1alpha via exercise, caloric restriction, and medications result in stimulation of mitochondrial oxidative phosphorylation activity, restore physiologic mitochondrial superoxide production, and promote organ healing. PMID- 25713189 TI - Insulin resistance as a physiological defense against metabolic stress: implications for the management of subsets of type 2 diabetes. AB - Stratifying the management of type 2 diabetes (T2D) has to take into account marked variability in patient phenotype due to heterogeneity in its pathophysiology, different stages of the disease process, and multiple other patient factors including comorbidities. The focus here is on the very challenging subgroup of patients with T2D who are overweight or obese with insulin resistance (IR) and the most refractory hyperglycemia due to an inability to change lifestyle to reverse positive energy balance. For this subgroup of patients with T2D, we question the dogma that IR is primarily harmful to the body and should be counteracted at any cost. Instead we propose that IR, particularly in this high-risk subgroup, is a defense mechanism that protects critical tissues of the cardiovascular system from nutrient-induced injury. Overriding IR in an effort to lower plasma glucose levels, particularly with intensive insulin therapy, could therefore be harmful. Treatments that nutrient off-load to lower glucose are more likely to be beneficial. The concepts of "IR as an adaptive defense mechanism" and "insulin-induced metabolic stress" may provide explanation for some of the unexpected outcomes of recent major clinical trials in T2D. Potential molecular mechanisms underlying these concepts; their clinical implications for stratification of T2D management, particularly in overweight and obese patients with difficult glycemic control; and future research requirements are discussed. PMID- 25713191 TI - Adipose modulation of ABCG1 uncovers an intimate link between sphingomyelin and triglyceride storage. PMID- 25713192 TI - New insights of u-calpain in the pathogenesis of diabetic vascular injury. PMID- 25713193 TI - Is brain insulin action relevant to the control of plasma glucose in humans? PMID- 25713194 TI - Disruption of insulin receptor signaling in endothelial cells shows the central role of an intact islet blood flow for in vivo beta-cell function. PMID- 25713195 TI - Nonesterified fatty acids, albumin, and platelet aggregation. PMID- 25713196 TI - Solving the riddle of the sphinx may provide new insights into diabetes and polyneuropathy. PMID- 25713197 TI - Cadherins in islet beta-cells: more than meets the eye. PMID- 25713198 TI - Air pollution and insulin resistance: do all roads lead to Rome? PMID- 25713199 TI - Hepato-incretin function of GLP-1: novel concept and target in type 1 diabetes. PMID- 25713200 TI - Metabolomics and diabetes: analytical and computational approaches. AB - Diabetes is characterized by altered metabolism of key molecules and regulatory pathways. The phenotypic expression of diabetes and associated complications encompasses complex interactions between genetic, environmental, and tissue specific factors that require an integrated understanding of perturbations in the network of genes, proteins, and metabolites. Metabolomics attempts to systematically identify and quantitate small molecule metabolites from biological systems. The recent rapid development of a variety of analytical platforms based on mass spectrometry and nuclear magnetic resonance have enabled identification of complex metabolic phenotypes. Continued development of bioinformatics and analytical strategies has facilitated the discovery of causal links in understanding the pathophysiology of diabetes and its complications. Here, we summarize the metabolomics workflow, including analytical, statistical, and computational tools, highlight recent applications of metabolomics in diabetes research, and discuss the challenges in the field. PMID- 25713201 TI - Deletion of placental growth factor prevents diabetic retinopathy and is associated with Akt activation and HIF1alpha-VEGF pathway inhibition. diabetes 2015;64:200-212. PMID- 25713202 TI - Expression of concern. PMID- 25713204 TI - Comment on Rondas et al. Citrullinated glucose-regulated protein 78 is an autoantigen in type 1 diabetes. Diabetes 2015;64:573-586. PMID- 25713205 TI - Performance evaluation of two microbial transport media designed for preservation and transport of Chlamydiae, Mycoplasma and Ureaplasma. AB - The ability of a non-propagating transport device (test device) to maintain the viability of clinically relevant bacteria was compared with a similar commercial device (predicate device) to establish performance equivalence. Test bacteria, namely Chlamydia trachomatis, Chlamydia pneumoniae, Mycoplasma hominis, Mycoplasma pneumoniae and Ureaplasma urealyticum, were inoculated into the test [Puritan Medical Products Universal Transport System (UniTranz-RT(TM))] and predicate (BD Universal Viral Transport System) devices, and incubated at 4 degrees C and room temperature for up to 72 h. Bacterial viability was assessed at selected time points post-incubation using shell vial assays followed by immunofluorescence staining (for Chlamydia) or by standard culture techniques (for Mycoplasma and Ureaplasma). Results indicated that the Chlamydia strains were equally stable in both test and predicate devices through 72 h storage, at both test temperatures. Quantifiable levels of Mycoplasma and Ureaplasma were recovered from the test and predicate devices throughout the storage period. Low temperature storage improved bacterial viability when compared with room temperature storage. In addition, the predicate device demonstrated slightly improved performance versus the test device in the context of Mycoplasma and Ureaplasma following 72 h storage. The overall results of the study confirmed the full performance of UniTranz-RT(TM) as a microbial transport medium and established equal performance with the predicate device. PMID- 25713206 TI - Microbial aetiology of acute diarrhoea in children under five years of age in Khartoum, Sudan. AB - Diarrhoea is one of leading causes of morbidity and mortality worldwide. Recent estimations suggested the number of deaths is close to 2.5 million. This study examined the causative agents of diarrhoea in children under 5 years of age in suburban areas of Khartoum, Sudan. A total of 437 stool samples obtained from children with diarrhoea were examined by culture and PCR for bacteria, by microscopy and PCR for parasites and by immunoassay for detection of rotavirus A. Of the 437 samples analysed, 211 (48%) tested positive for diarrhoeagenic Escherichia coli, 96 (22%) for rotavirus A, 36 (8%) for Shigella spp., 17 (4%) for Salmonella spp., 8 (2%) for Campylobacter spp., 47 (11%) for Giardia intestinalis and 22 (5%) for Entamoeba histolytica. All isolates of E. coli (211, 100 %) and Salmonella (17, 100%), and 30 (83%) isolates of Shigella were sensitive to chloramphenicol; 17 (100%) isolates of Salmonella, 200 (94%) isolates of E. coli and (78%) 28 isolates of Shigella spp. were sensitive to gentamicin. In contrast, resistance to ampicillin was demonstrated in 100 (47%) isolates of E. coli and 16 (44%) isolates of Shigella spp. In conclusion, E. coli proved to be the main cause of diarrhoea in young children in this study, followed by rotavirus A and protozoa. Determination of diarrhoea aetiology and antibiotic susceptibility patterns of diarrhoeal pathogens and improved hygiene are important for clinical management and controlled strategic planning to reduce the burden of infection. PMID- 25713207 TI - Induction of human UDP-Glucuronosyltransferase 2B7 gene expression by cytotoxic anticancer drugs in liver cancer HepG2 cells. AB - We recently reported induction of UGT2B7 by its substrate epirubicin, a cytotoxic anthracycline anticancer drug, via activation of p53 and subsequent recruitment of p53 to the UGT2B7 promoter in hepatocellular carcinoma HepG2 cells. Using the same HepG2 model cell line, the present study assessed the possibility of a similar induction of UGT2B7 by several other cytotoxic drugs. We first demonstrated by reverse transcriptase quantitative real-time polymerase chain reaction that, as observed with epirubicin, nine cytotoxic drugs including three anthracyclines (doxorubicin, daunorubicin, and idarubicin) and six nonanthracyclines (mitomycin C, 5-fluorouracil, camptothecin, 7-ethyl-10 hydroxycamptothecin, topotecan, and etoposide) significantly increased UGT2B7 mRNA levels. To investigate a potential involvement of p53 in this induction, we conducted further experiments with four of the nine drugs (doxorubicin, daunorubicin, idarubicin, and mitomycin C). The cytotoxic drugs studied increased p53 and UGT2B7 protein levels. Knockdown of p53 expression by small interfering RNA reduced cytotoxic drug-induced UGT2B7 expression. Luciferase reporter assays showed activation of the UGT2B7 promoter by cytotoxic drugs via a previously reported p53 site. Finally, chromatin immunoprecipitation assays demonstrated p53 recruitment to the UGT2B7 p53 site upon exposure to mitomycin C, the most potent UGT2B7 inducer among the nine tested drugs. Taken together, these results provide further evidence supporting UGT2B7 as a p53 target gene. The cytotoxic drug induced UGT2B7 activity in target liver cancer cells or possibly in normal liver cells may affect the therapeutic efficacy of co-administered cytotoxic drugs (e.g., epirubicin) and noncytotoxic drugs (e.g., morphine), which are UGT2B7 substrates. PMID- 25713208 TI - No contribution of the ABCB11 p.444A polymorphism in Japanese patients with drug induced cholestasis. AB - European studies have revealed that the ABCB11 c.1331T>C (V444A) polymorphism (rs2287622) C-allele frequency is higher among patients with drug-induced cholestasis. Given the low incidence of this disease, however, this association has not been sufficiently elucidated. We aimed to investigate the significance of this polymorphism in Japanese patients. We determined ABCB11 V444A polymorphism frequencies and HLA genotypes in two independent drug-induced cholestasis cohorts. Expression and taurocholate transport activity of proteins from 444A variants were analyzed using Madin-Darby canine kidney II cells. In cohort 1 (n = 40), the V444A polymorphism C-allele frequency (66%) was lower than that in controls (n = 190, 78%), but this difference was not significant (P = 0.09). In cohort 2 (n = 119), comprising patients with cholestatic (n = 19), hepatocellular (n = 74), and mixed (n = 26) liver injuries, the C-allele frequency was lower among patients with cholestatic liver injury (68%) than among those with hepatocellular (75%) or mixed liver injury (83%), although this difference was not significant. In cohort 1, HLA-A*0201 was observed more frequently in patients (22%) than in controls [11%; P = 0.003; odds ratio, 2.4 (95% confidence interval, 1.4-4.0)]. Taurocholate transport activity of 444A-encoded protein was significantly lower than that of 444V-encoded protein (81% of 444V, P < 0.05) because of the reduced protein stability. In conclusion, ABCB11 444A had slightly reduced transport activity, but it did not contribute to the occurrence of drug induced cholestasis in Japanese patients. Therefore, genetic susceptibility to acquired cholestasis may differ considerably by ethnicity. PMID- 25713211 TI - Positive Selection Drives Preferred Segment Combinations during Influenza Virus Reassortment. AB - Influenza A virus (IAV) has a segmented genome that allows for the exchange of genome segments between different strains. This reassortment accelerates evolution by breaking linkage, helping IAV cross species barriers to potentially create highly virulent strains. Challenges associated with monitoring the process of reassortment in molecular detail have limited our understanding of its evolutionary implications. We applied a novel deep sequencing approach with quantitative analysis to assess the in vitro temporal evolution of genomic reassortment in IAV. The combination of H1N1 and H3N2 strains reproducibly generated a new H1N2 strain with the hemagglutinin and nucleoprotein segments originating from H1N1 and the remaining six segments from H3N2. By deep sequencing the entire viral genome, we monitored the evolution of reassortment, quantifying the relative abundance of all IAV genome segments from the two parent strains over time and measuring the selection coefficients of the reassorting segments. Additionally, we observed several mutations coemerging with reassortment that were not found during passaging of pure parental IAV strains. Our results demonstrate how reassortment of the segmented genome can accelerate viral evolution in IAV, potentially enabled by the emergence of a small number of individual mutations. PMID- 25713212 TI - Discovery of novel genes derived from transposable elements using integrative genomic analysis. AB - Complex eukaryotes contain millions of transposable elements (TEs), comprising large fractions of their nuclear genomes. TEs consist of structural, regulatory, and coding sequences that are ordinarily associated with transposition, but that occasionally confer on the organism a selective advantage and may thereby become exapted. Exapted transposable element genes (ETEs) are known to play critical roles in diverse systems, from vertebrate adaptive immunity to plant development. Yet despite their evident importance, most ETEs have been identified fortuitously and few systematic searches have been conducted, suggesting that additional ETEs may await discovery. To explore this possibility, we develop a comprehensive systematic approach to searching for ETEs. We use TE-specific conserved domains to identify with high precision genes derived from TEs and screen them for signatures of exaptation based on their similarities to reference sets of known ETEs, conventional (non-TE) genes, and TE genes across diverse genetic attributes including repetitiveness, conservation of genomic location and sequence, and levels of expression and repressive small RNAs. Applying this approach in the model plant Arabidopsis thaliana, we discover a surprisingly large number of novel high confidence ETEs. Intriguingly, unlike known plant ETEs, several of the novel ETE families form tandemly arrayed gene clusters, whereas others are relatively young. Our results not only identify novel TE-derived genes that may have practical applications but also challenge the notion that TE exaptation is merely a relic of ancient life, instead suggesting that it may continue to fundamentally drive evolution. PMID- 25713213 TI - Role of high-resolution image integration to visualize left phrenic nerve and coronary arteries during epicardial ventricular tachycardia ablation. AB - BACKGROUND: Epicardial ventricular tachycardia (VT) ablation is associated with risks of coronary artery (CA) and phrenic nerve (PN) injury. We investigated the role of multidetector computed tomography in visualizing CA and PN during VT ablation. METHODS AND RESULTS: Ninety-five consecutive patients (86 men; age, 57 +/- 15) with VT underwent cardiac multidetector computed tomography. The PN detection rate and anatomic variability were analyzed. In 49 patients undergoing epicardial mapping, real-time multidetector computed tomographic integration was used to display CAs/PN locations in 3-dimensional mapping systems. Elimination of local abnormal ventricular activities (LAVAs) was used as ablation end point. The distribution of CAs/PN with respect to LAVA was analyzed and compared between VT etiologies. Multidetector computed tomography detected PN in 81 patients (85%). Epicardial LAVAs were observed in 44 of 49 patients (15 ischemic cardiomyopathy, 15 nonischemic cardiomyopathy, and 14 arrhythmogenic right ventricular cardiomyopathy) with a mean of 35 +/- 37 LAVA points/patient. LAVAs were located within 1 cm from CAs and PN in 35 (80%) and 18 (37%) patients, respectively. The prevalence of LAVA adjacent to CAs was higher in nonischemic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy than in ischemic cardiomyopathy (100% versus 86% versus 53%; P < 0.01). The prevalence of LAVAs adjacent to PN was higher in nonischemic cardiomyopathy than in ischemic cardiomyopathy (93% versus 27%; P < 0.001). Epicardial ablation was performed in 37 patients (76%). Epicardial LAVAs could not be eliminated because of the proximity to CAs or PN in 8 patients (18%). CONCLUSIONS: The epicardial electrophysiological VT substrate is often close to CAs and PN in patients with nonischemic cardiomyopathy. High resolution image integration is potentially useful to minimize risks of PN and CA injury during epicardial VT ablation. PMID- 25713214 TI - Catecholaminergic polymorphic ventricular tachycardia in children: analysis of therapeutic strategies and outcomes from an international multicenter registry. AB - BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia is an uncommon, potentially lethal, ion channelopathy. Standard therapies have high failure rates and little is known about treatment in children. Newer options such as flecainide and left cardiac sympathetic denervation are not well validated. We sought to define treatment outcomes in children with catecholaminergic polymorphic ventricular tachycardia. METHODS AND RESULTS: This is a Pediatric and Congenital Electrophysiology Society multicenter, retrospective cohort study of catecholaminergic polymorphic ventricular tachycardia patients diagnosed before 19 years of age. The cohort included 226 patients, including 170 probands and 56 relatives. Symptomatic presentation was reported in 176 (78%). Symptom onset occurred at 10.8 (interquartile range, 6.8-13.2) years with a delay to diagnosis of 0.5 (0-2.6) years. Syncope (P<0.001), cardiac arrest (P<0.001), and treatment failure (P=0.008) occurred more often in probands. beta-Blockers were prescribed in 205 of 211 patients (97%) on medication, and 25% experienced at least 1 treatment failure event. Implantable cardioverter defibrillators were placed in 121 (54%) and was associated with electrical storm in 22 (18%). Flecainide was used in 24% and left cardiac sympathetic denervation in 8%. Six deaths (3%) occurred during a cumulative follow-up of 788 patient-years. CONCLUSIONS: This study demonstrates a malignant phenotype and lengthy delay to diagnosis in catecholaminergic polymorphic ventricular tachycardia. Probands were typically severely affected. beta-Blockers were almost universally initiated; however, treatment failure, noncompliance and subtherapeutic dosing were often reported. Implantable cardioverter defibrillators were common despite numerous device related complications. Treatment failure was rare in the quarter of patients on flecainide. Left cardiac sympathetic denervation was not uncommon although the indication was variable. PMID- 25713215 TI - Quantification of the transmural dynamics of atrial fibrillation by simultaneous endocardial and epicardial optical mapping in an acute sheep model. AB - BACKGROUND: Therapy strategies for atrial fibrillation based on electric characterization are becoming viable personalized medicine approaches to treat a notoriously difficult disease. In light of these approaches that rely on high density surface mapping, this study aims to evaluate the presence of 3 dimensional electric substrate variations within the transmural wall during acute episodes of atrial fibrillation. METHODS AND RESULTS: Optical signals were simultaneously acquired from the epicardial and endocardial tissue during acute fibrillation in ovine isolated left atria. Dominant frequency, regularity index, propagation angles, and phase dynamics were assessed and correlated across imaging planes to gauge the synchrony of the activation patterns compared with paced rhythms. Static frequency parameters were well correlated spatially between the endocardium and the epicardium (dominant frequency, 0.79 +/- 0.06 and regularity index, 0.93 +/- 0.009). However, dynamic tracking of propagation vectors and phase singularity trajectories revealed discordant activity across the transmural wall. The absolute value of the difference in the number, spatial stability, and temporal stability of phase singularities between the epicardial and the endocardial planes was significantly >0 with a median difference of 1.0, 9.27%, and 19.75%, respectively. The number of wavefronts with respect to time was significantly less correlated and the difference in propagation angle was significantly larger in fibrillation compared with paced rhythms. CONCLUSIONS: Atrial fibrillation substrates are dynamic 3-dimensional structures with a range of discordance between the epicardial and the endocardial tissue. The results of this study suggest that transmural propagation may play a role in atrial fibrillation maintenance mechanisms. PMID- 25713216 TI - Three-dimensional 123I-meta-iodobenzylguanidine cardiac innervation maps to assess substrate and successful ablation sites for ventricular tachycardia: feasibility study for a novel paradigm of innervation imaging. AB - BACKGROUND: Innervation is a critical component of arrhythmogenesis and may present an important trigger/substrate modifier not used in current ventricular tachycardia (VT) ablation strategies. METHODS AND RESULTS: Fifteen patients referred for ischemic VT ablation underwent preprocedural cardiac (123)I- meta iodobenzylguanidine ((123)I-mIBG) imaging, which was used to create 3-dimensional (3D) innervation models and registered to high-density voltage maps. 3D (123)I mIBG innervation maps demonstrated areas of complete denervation and (123)I-mIBG transition zone in all patients, which corresponded to 0% to 31% and 32% to 52% uptake. (123)I-mIBG denervated areas were ~2.5-fold larger than bipolar voltage defined scar (median, 24.6% [Q1-Q3, 18.3%-34.4%] versus 10.6% [Q1-Q3, 3.9% 16.4%]; P<0.001) and included the inferior wall in all patients, with no difference in the transition/border zone (11.4% [Q1-Q3, 9.5%-13.2%] versus 16.6% [Q1-Q3, 12.0%-18.8%]; P=0.07). Bipolar/unipolar voltages varied widely within areas of denervation (0.8 mV [Q1-Q3, 0.3-1.7 mV] and 4.0 mV [Q1-Q3, 2.9-5.6 mV]) and (123)I-mIBG transition zones (0.8 mV [Q1-Q3, 0.4-1.8 mV] and 4.6 mV [Q1-Q3, 3.2-6.3 mV]). Bipolar voltages in denervated areas and (123)I-mIBG transition zones were <0.5 mV, 0.5 to 1.5 mV, and >1.5 mV in 35%, 36%, and 29%, as well as 35%, 35%, and 30%, respectively (P>0.05). Successful ablation sites were within bipolar voltage-defined scar (7%), border zone (57%), and areas of normal voltage (36%), but all ablation sites were abnormally innervated (denervation/(123)I-mIBG transition zone in 50% each). CONCLUSIONS: (123)I-mIBG innervation defects are larger than bipolar voltage-defined scar and cannot be detected with standard voltage criteria. Thirty-six percent of successful VT ablation sites demonstrated normal voltages (>1.5 mV), but all ablation sites were within the areas of abnormal innervation. (123)I-mIBG innervation maps may provide critical information about triggers/substrate modifiers and could improve understanding of VT substrate and facilitate VT ablation. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique Identifier: NCT01250912. PMID- 25713217 TI - Catheter-based renal denervation reduces atrial nerve sprouting and complexity of atrial fibrillation in goats. AB - BACKGROUND: Atrial fibrillation (AF) leads to structural and neural remodeling in the atrium, which enhances AF complexity and perpetuation. Renal denervation (RDN) can reduce renal and whole-body sympathetic activity. Aim of this study was to determine the effect of sympathetic nervous system modulation by RDN on atrial arrhythmogenesis. METHODS AND RESULT: Eighteen goats were instrumented with an atrial endocardial pacemaker lead and a burst pacemaker. Percutaneous catheter based RDN was performed in 8 goats (RDN-AF). Ten goats undergoing a sham procedure served as control (SHAM-AF). AF was induced and maintained by burst pacing for 6 weeks. High-resolution mapping was used to record epicardial conduction patterns of the right and left atrium. RDN reduced tyrosine hydroxylase-positive sympathetic nerve staining and resulted in lower transcardiac norepinephrine levels. This was associated with reduced expression of nerve growth factor-beta, indicating less atrial nerve sprouting. Atrial endomysial fibrosis content was lower and myocyte diameter was smaller in RDN-AF. Median conduction velocity was higher (75 +/- 9 versus 65 +/- 10 cm/s, P = 0.02), and AF cycle length was shorter in RDN-AF compared with SHAM-AF. Left atrial AF complexity (4.8 +/- 0.8 fibrillation waves/AF cycle length versus 8.5 +/- 0.8 waves/AF cycle length, P = 0.001) and incidence of breakthroughs (2.0 +/- 0.3 versus 4.3 +/- 0.5 waves/AF cycle length, P = 0.059) were lower in RDN-AF compared with SHAM-AF. Blood pressure was normal and not significantly different between the groups. CONCLUSIONS: RDN reduces atrial sympathetic nerve sprouting, structural alterations, and AF complexity in goats with persistent AF, independent of changes in blood pressure. PMID- 25713219 TI - Separated at birth? PMID- 25713220 TI - Mind the gap: a step forward in supporting hospice-based research. PMID- 25713223 TI - Grumpy old ethicist. PMID- 25713273 TI - Correction to: "Imperatorin is a mechanism-based inactivator of CYP2B6". PMID- 25713275 TI - Butyrfentanyl overdose resulting in diffuse alveolar hemorrhage. AB - Butyrfentanyl is a potent short-acting opioid and a fentanyl analog with uncertain clinical effects. A review of the literature reveals no human case reports of butyrfentanyl overdose. As the use of analog and synthetic drugs continues to increase, clinicians are often faced with tremendous uncertainty when they encounter patients exposed to these synthetic drugs. We describe, to our knowledge, the first case of a butyrfentanyl overdose that resulted in clinically significant hemoptysis, acute lung injury, hypoxic respiratory failure, and diffuse alveolar hemorrhage. Complicating this case was a false positive urine drug screen for fentanyl. Clinicians who encounter fentanyl exposures should be aware they may in fact be dealing with butyrfentanyl. As little is known of butyrfentanyl and our patient suffered a significant pulmonary hemorrhage, those who encounter butyrfentanyl exposures should monitor for hemorrhagic complications. PMID- 25713274 TI - Intellectual and academic functioning of school-age children with single-suture craniosynostosis. AB - OBJECTIVE: We compared the developmental status of school-age children with single-suture craniosynostosis (case group) and unaffected children (control group). Within the case group we compared the performance of children distinguished by location of suture fusion (sagittal, metopic, unicoronal, lambdoid). METHODS: We administered standardized tests of intelligence, reading, spelling, and math to 182 case participants and 183 control participants. This sample represented 70% of those tested during infancy before case participants had corrective surgery. RESULTS: After adjustment for demographics, case participants' average scores were lower than those of control participants on all measures. The largest observed differences were in Full-Scale IQ and math computation, where case participants' adjusted mean scores were 2.5 to 4 points lower than those of control participants (Ps ranged from .002 to .09). Adjusted mean case-control differences on other measures of achievement were modest, although case deficits became more pronounced after adjustment for participation in developmental interventions. Among case participants, 58% had no discernible learning problem (score <25th percentile on a standardized achievement test). Children with metopic, unicoronal, and lambdoid synostosis tended to score lower on most measures than did children with sagittal fusions (Ps ranged from <.001 to .82). CONCLUSIONS: The developmental delays observed among infants with single suture craniosynostosis are partially evident at school age, as manifested by lower average scores than those of control participants on measures of IQ and math. However, case participants' average scores were only slightly lower than those of control participants on reading and spelling measures, and the frequency of specific learning problems was comparable. Among case participants, those with unicoronal and lambdoid fusions appear to be the most neurodevelopmentally vulnerable. PMID- 25713276 TI - Evaluation of a quality improvement intervention to increase use of telephonic interpretation. AB - BACKGROUND: Language barriers are associated with poor health care outcomes, and barriers exist for timely in-person interpretation. Although available on-demand, telephonic interpretation remains underutilized. This study evaluates whether a quality improvement (QI) intervention was associated with rates of interpretation and parent-reported language service use at a children's hospital. METHODS: The QI intervention was developed by a multidisciplinary team and included provider education, electronic alerts, standardized dual-handset telephones, and 1-touch dialing in all hospital rooms. Interpreter use was tracked for 12 months before, 5 months during, and 12 months after the intervention. Weekly rates of interpretation per limited English proficient (LEP) patient-day were evaluated by using segmented linear regression. LEP parents were surveyed about professional interpretation and delays in care. Responses before, during, and after the intervention were compared by using the chi(2) test for trend. RESULTS: Telephonic interpretation rates increased by 53% after the intervention (baseline 0.38 per patient-day, increased 0.20 [0.13-0.28]). Overall (telephonic and in person) interpretation increased by 54% (baseline 0.96, increased by 0.51 [0.38 0.64]). Parent-reported interpreter use improved, including more frequent use of professional interpreters (53.3% before, 71.8% during, 69.3% after, P trend = .001), less frequent use of ad hoc interpreters (52.4% before, 38.1% during, 41.4% after, P trend = .03), and fewer interpretation-related delays in care (13.3% before, 7.9% during, 6.0% after, P trend = .01). CONCLUSIONS: This QI intervention was associated with increased telephonic interpreter use and improved parent-reported use of professional language services. This is a promising approach to deliver safe, timely, and equitable care for the growing population of LEP children and families. PMID- 25713277 TI - Snacks, sweetened beverages, added sugars, and schools. AB - Concern over childhood obesity has generated a decade-long reformation of school nutrition policies. Food is available in school in 3 venues: federally sponsored school meal programs; items sold in competition to school meals, such as a la carte, vending machines, and school stores; and foods available in myriad informal settings, including packed meals and snacks, bake sales, fundraisers, sports booster sales, in-class parties, or other school celebrations. High energy, low-nutrient beverages, in particular, contribute substantial calories, but little nutrient content, to a student's diet. In 2004, the American Academy of Pediatrics recommended that sweetened drinks be replaced in school by water, white and flavored milks, or 100% fruit and vegetable beverages. Since then, school nutrition has undergone a significant transformation. Federal, state, and local regulations and policies, along with alternative products developed by industry, have helped decrease the availability of nutrient-poor foods and beverages in school. However, regular access to foods of high energy and low quality remains a school issue, much of it attributable to students, parents, and staff. Pediatricians, aligning with experts on child nutrition, are in a position to offer a perspective promoting nutrient-rich foods within calorie guidelines to improve those foods brought into or sold in schools. A positive emphasis on nutritional value, variety, appropriate portion, and encouragement for a steady improvement in quality will be a more effective approach for improving nutrition and health than simply advocating for the elimination of added sugars. PMID- 25713278 TI - Maternal cautopyreiophagia as a rare cause of neonatal hemolysis: a case report. AB - Hyperbilirubinemia in the first 24 hours of life in a newborn is pathologic, necessitating additional evaluation. We report the first case of hemolysis and subsequent hyperbilirubinemia in an otherwise normal term neonate resulting from oxidative stress in the form of maternal cautopyreiophagia: the ingestion of burnt matchstick heads. During the third trimester of pregnancy, the infant's mother consumed more than 300 burnt matchstick heads weekly for 4 weeks. Matches contain potassium chlorate, a powerful oxidant that when ingested can ultimately lead to the destruction of erythrocytes, disseminated intravascular coagulation, kidney injury, or death. The infant's bilirubin rose as high as 17 mg/dL at 22 hours of life; however, the infant did well with a brief course of phototherapy. This case highlights the importance of prenatal questioning about maternal ingestion of potentially oxidative substances and assessing the possible risk for the infant. PMID- 25713279 TI - Dishing it out to allergies. PMID- 25713281 TI - Allergy in children in hand versus machine dishwashing. AB - BACKGROUND AND OBJECTIVE: The hygiene hypothesis stipulates that microbial exposure during early life induces immunologic tolerance via immune stimulation, and hence reduces the risk of allergy development. Several common lifestyle factors and household practices, such as dishwashing methods, may increase microbial exposure. The aim of this study was to investigate if such lifestyle factors are associated with allergy prevalence. METHODS: Questionnaire-based study of 1029 children aged 7 to 8 years from Kiruna, in the north of Sweden, and Molndal, in the Gothenburg area on the southwest coast of Sweden. Questions on asthma, eczema, and rhinoconjunctivitis were taken from the International Study of Asthma and Allergies in Childhood questionnaire. RESULTS: Hand dishwashing was associated with a reduced risk of allergic disease development (multivariate analysis, odds ratio 0.57; 95% confidence interval: 0.37-0.85). The risk was further reduced in a dose-response pattern if the children were also served fermented food and if the family bought food directly from farms. CONCLUSIONS: In families who use hand dishwashing, allergic diseases in children are less common than in children from families who use machine dishwashing. We speculate that a less-efficient dishwashing method may induce tolerance via increased microbial exposure. PMID- 25713282 TI - Pediatric aspects of inpatient health information technology systems. AB - In the past 3 years, the Health Information Technology for Economic and Clinical Health Act accelerated the adoption of electronic health records (EHRs) with providers and hospitals, who can claim incentive monies related to meaningful use. Despite the increase in adoption of commercial EHRs in pediatric settings, there has been little support for EHR tools and functionalities that promote pediatric quality improvement and patient safety, and children remain at higher risk than adults for medical errors in inpatient environments. Health information technology (HIT) tailored to the needs of pediatric health care providers can improve care by reducing the likelihood of errors through information assurance and minimizing the harm that results from errors. This technical report outlines pediatric-specific concepts, child health needs and their data elements, and required functionalities in inpatient clinical information systems that may be missing in adult-oriented HIT systems with negative consequences for pediatric inpatient care. It is imperative that inpatient (and outpatient) HIT systems be adapted to improve their ability to properly support safe health care delivery for children. PMID- 25713283 TI - Child sex trafficking and commercial sexual exploitation: health care needs of victims. AB - Child sex trafficking and commercial sexual exploitation of children (CSEC) are major public health problems in the United States and throughout the world. Despite large numbers of American and foreign youth affected and a plethora of serious physical and mental health problems associated with CSEC, there is limited information available to pediatricians regarding the nature and scope of human trafficking and how pediatricians and other health care providers may help protect children. Knowledge of risk factors, recruitment practices, possible indicators of CSEC, and common medical and behavioral health problems experienced by victims will help pediatricians recognize potential victims and respond appropriately. As health care providers, educators, and leaders in child advocacy, pediatricians play an essential role in addressing the public health issues faced by child victims of CSEC. Their roles can include working to increase recognition of CSEC, providing direct care and anticipatory guidance related to CSEC, engaging in collaborative efforts with medical and nonmedical colleagues to provide for the complex needs of youth, and educating child-serving professionals and the public. PMID- 25713280 TI - Cognitive outcomes after neonatal encephalopathy. AB - OBJECTIVES: To describe the spectrum of cognitive outcomes of children with and without cerebral palsy (CP) after neonatal encephalopathy, evaluate the prognostic value of early developmental testing and report on school services and additional therapies. METHODS: The participants of this study are the school-aged survivors of the National Institute of Child Health and Human Development Neonatal Research Network randomized controlled trial of whole-body hypothermia. Children underwent neurologic examinations and neurodevelopmental and cognitive testing with the Bayley Scales of Infant Development-II at 18 to 22 months and the Wechsler intelligence scales and the Neuropsychological Assessment Developmental Neuropsychological Assessment at 6 to 7 years. Parents were interviewed about functional status and receipt of school and support services. We explored predictors of cognitive outcome by using multiple regression models. RESULTS: Subnormal IQ scores were identified in more than a quarter of the children: 96% of survivors with CP had an IQ <70, 9% of children without CP had an IQ <70, and 31% had an IQ of 70 to 84. Children with a mental developmental index <70 at 18 months had, on average, an adjusted IQ at 6 to 7 years that was 42 points lower than that of those with a mental developmental index >84 (95% confidence interval, -49.3 to -35.0; P < .001). Twenty percent of children with normal IQ and 28% of those with IQ scores of 70 to 84 received special educational support services or were held back >=1 grade level. CONCLUSIONS: Cognitive impairment remains an important concern for all children with neonatal encephalopathy. PMID- 25713285 TI - Epidemiology of pediatric herpes zoster after varicella infection: a population based study. AB - BACKGROUND: There are limited population-based data regarding pediatric herpes zoster (HZ). METHODS: Children aged <12 years with varicella infections between 2000 and 2006 were identified from a national population-based database and followed-up for a diagnosis of HZ until December 2008. Since a routine varicella vaccination program was started in 2004, vaccinated children without medically attended varicella were identified between 2004 and 2006, and followed-up for a diagnosis of HZ until December 2008. RESULTS: Of 27 517 children with medically attended varicella, 428 developed HZ. The incidence of HZ was 262.1 per 100 000 person-years. Of 25 132 vaccinated children without medically attended varicella, 106 developed HZ. The incidence of HZ was 93.3 per 100 000 person-years. The mean duration from varicella to HZ was 4.12 years. Children diagnosed with varicella at aged <2 years had a higher incidence (P < .001) and shorter duration (P = .04) than those diagnosed aged ?2 years. Children diagnosed with varicella aged >=2 but <8 years had a significantly increased incidence of HZ after than before the vaccination program (relative risk = 1.85 at 3 years of follow-up, P = .03). Children with varicella infections had a significantly greater risk of HZ than vaccinated children without a history of varicella (relative risk = 2.31 at 4 years of follow-up, P < .001). CONCLUSIONS: This study demonstrates the population-based epidemiologic characteristics of pediatric HZ among those who contracted varicella. In the early postvaricella vaccination period, an increased HZ incidence was observed among children with varicella infection aged >=2 years. PMID- 25713284 TI - Idiopathic systemic capillary leak syndrome in children. AB - Adult subjects with systemic capillary leak syndrome (SCLS) present with acute and recurrent episodes of vascular leak manifesting as severe hypotension, hypoalbuminemia, hemoconcentration, and generalized edema. We studied clinical disease characteristics, serum cytokine profiles, and treatment modalities in a cohort of children with documented SCLS. Six children with SCLS were recruited from the United States, Australia, Canada, and Italy. Serum cytokines from SCLS subjects and a group of 10 healthy children were analyzed. Children with SCLS (aged 5-11 years old) presented with at least 1 acute, severe episode of hypotension, hypoalbuminemia, and hemoconcentration in the absence of underlying causes for these abnormalities. In contrast to what is observed in adult SCLS, identifiable infectious triggers precipitated most episodes in these children, and none of them had a monoclonal gammopathy. We found elevated levels of chemokine (C-C motif) ligand 2 (CCL2), interleukin-8, and tumor necrosis factor alpha in baseline SCLS sera compared with the control group. All patients are alive and well on prophylactic therapy, with 4 patients receiving intravenous or subcutaneous immunoglobulins at regular intervals. The clinical manifestations of pediatric and adult SCLS are similar, with the notable exceptions of frequent association with infections and the lack of monoclonal gammopathy. Prophylactic medication, including high dose immunoglobulins or theophylline plus verapamil, appears to be safe and efficacious therapy for SCLS in children. PMID- 25713286 TI - Advancing informed consent for vulnerable populations. PMID- 25713287 TI - International Union of Basic and Clinical Pharmacology. XCIII. The parathyroid hormone receptors--family B G protein-coupled receptors. AB - The type-1 parathyroid hormone receptor (PTHR1) is a family B G protein-coupled receptor (GPCR) that mediates the actions of two polypeptide ligands; parathyroid hormone (PTH), an endocrine hormone that regulates the levels of calcium and inorganic phosphate in the blood by acting on bone and kidney, and PTH-related protein (PTHrP), a paracrine-factor that regulates cell differentiation and proliferation programs in developing bone and other tissues. The type-2 parathyroid hormone receptor (PTHR2) binds a peptide ligand, called tuberoinfundibular peptide-39 (TIP39), and while the biologic role of the PTHR2/TIP39 system is not as defined as that of the PTHR1, it likely plays a role in the central nervous system as well as in spermatogenesis. Mechanisms of action at these receptors have been explored through a variety of pharmacological and biochemical approaches, and the data obtained support a basic "two-site" mode of ligand binding now thought to be used by each of the family B peptide hormone GPCRs. Recent crystallographic studies on the family B GPCRs are providing new insights that help to further refine the specifics of the overall receptor architecture and modes of ligand docking. One intriguing pharmacological finding for the PTHR1 is that it can form surprisingly stable complexes with certain PTH/PTHrP ligand analogs and thereby mediate markedly prolonged cell signaling responses that persist even when the bulk of the complexes are found in internalized vesicles. The PTHR1 thus appears to be able to activate the Galpha(s)/cAMP pathway not only from the plasma membrane but also from the endosomal domain. The cumulative findings could have an impact on efforts to develop new drug therapies for the PTH receptors. PMID- 25713289 TI - Endothelial p53 deletion improves angiogenesis and prevents cardiac fibrosis and heart failure induced by pressure overload in mice. AB - BACKGROUND: Cardiac dysfunction developing in response to chronic pressure overload is associated with apoptotic cell death and myocardial vessel rarefaction. We examined whether deletion of tumor suppressor p53 in endothelial cells may prevent the transition from cardiac hypertrophy to heart failure. METHODS AND RESULTS: Mice with endothelial-specific deletion of p53 (End.p53-KO) were generated by crossing p53fl/fl mice with mice expressing Cre recombinase under control of an inducible Tie2 promoter. Cardiac hypertrophy was induced by transverse aortic constriction. Serial echocardiography measurements revealed improved cardiac function in End.p53-KO mice that also exhibited better survival. Cardiac hypertrophy was associated with increased p53 levels in End.p53-WT controls, whereas banded hearts of End.p53-KO mice exhibited lower numbers of apoptotic endothelial and non-endothelial cells and altered mRNA levels of genes regulating cell cycle progression (p21), apoptosis (Puma), or proliferation (Pcna). A higher cardiac capillary density and improved myocardial perfusion was observed, and pharmacological inhibition or genetic deletion of p53 also promoted endothelial sprouting in vitro and new vessel formation following hindlimb ischemia in vivo. Hearts of End.p53-KO mice exhibited markedly less fibrosis compared with End.p53-WT controls, and lower mRNA levels of p53-regulated genes involved in extracellular matrix production and turnover (eg, Bmp-7, Ctgf, or Pai 1), or of transcription factors involved in controlling mesenchymal differentiation were observed. CONCLUSIONS: Our analyses reveal that accumulation of p53 in endothelial cells contributes to blood vessel rarefaction and fibrosis during chronic cardiac pressure overload and suggest that endothelial cells may be a therapeutic target for preserving cardiac function during hypertrophy. PMID- 25713291 TI - Contemporary trends and predictors of postacute service use and routine discharge home after stroke. AB - BACKGROUND: Returning home after the hospital is a primary aim for healthcare; however, additional postacute care (PAC) services are sometimes necessary for returning stroke patients to their pre-event status. Recent trends in hospital discharge disposition specifying PAC use have not been examined across age groups or health insurance types. METHODS AND RESULTS: We examined trends in discharge to inpatient rehabilitation facilities (IRFs), skilled nursing facilities (SNFs), home with home health (HH), and home without services for 849 780 patients >=18 years of age with ischemic or hemorrhagic stroke at 1687 hospitals participating in Get With The Guidelines-Stroke. Multivariable analysis was used to identify factors associated with discharge to any PAC (IRF, SNF, or HH) versus discharge home without services. From 2003 to 2011, there was a 2.1% increase (unadjusted P=0.001) in PAC use after a stroke hospitalization. Change was greatest in SNF use, an 8.3% decrease over the period. IRF and HH increased 6.9% and 3.6%, respectively. The 2 strongest clinical predictors of PAC use after acute care were patients not ambulating on the second day of their hospital stay (ambulation odds ratio [OR], 3.03; 95% confidence interval [CI], 2.86 to 3.23) and those who failed a dysphagia screen or had an order restricting oral intake (OR, 2.48; 95% CI, 2.37 to 2.59). CONCLUSIONS: Four in 10 stroke patients are discharged home without services. Although little has changed overall in PAC use since 2003, further research is needed to explain the shift in service use by type and its effect on outcomes. PMID- 25713290 TI - Cardiac energy dependence on glucose increases metabolites related to glutathione and activates metabolic genes controlled by mechanistic target of rapamycin. AB - BACKGROUND: Long chain acyl-CoA synthetases (ACSL) catalyze long-chain fatty acids (FA) conversion to acyl-CoAs. Temporal ACSL1 inactivation in mouse hearts (Acsl1(H-/-)) impaired FA oxidation and dramatically increased glucose uptake, glucose oxidation, and mTOR activation, resulting in cardiac hypertrophy. We used unbiased metabolomics and gene expression analyses to elucidate the cardiac cellular response to increased glucose use in a genetic model of inactivated FA oxidation. METHODS AND RESULTS: Metabolomics analysis identified 60 metabolites altered in Acsl1(H-/-) hearts, including 6 related to glucose metabolism and 11 to cysteine and glutathione pathways. Concurrently, global cardiac transcriptional analysis revealed differential expression of 568 genes in Acsl1(H /-) hearts, a subset of which we hypothesized were targets of mTOR; subsequently, we measured the transcriptional response of several genes after chronic mTOR inhibition via rapamycin treatment during the period in which cardiac hypertrophy develops. Hearts from Acsl1(H-/-) mice increased expression of several Hif1alpha responsive glycolytic genes regulated by mTOR; additionally, expression of Scl7a5, Gsta1/2, Gdf15, and amino acid-responsive genes, Fgf21, Asns, Trib3, Mthfd2, were strikingly increased by mTOR activation. CONCLUSIONS: The switch from FA to glucose use causes mTOR-dependent alterations in cardiac metabolism. We identified cardiac mTOR-regulated genes not previously identified in other cellular models, suggesting heart-specific mTOR signaling. Increased glucose use also changed glutathione-related pathways and compensation by mTOR. The hypertrophy, oxidative stress, and metabolic changes that occur within the heart when glucose supplants FA as a major energy source suggest that substrate switching to glucose is not entirely benign. PMID- 25713292 TI - Implantable cardioverter-defibrillator therapy in patients with ventricular fibrillation out of hospital cardiac arrest secondary to acute coronary syndrome. AB - BACKGROUND: Survivors of ventricular fibrillation out of hospital cardiac arrest (VF-OHCA) due to a potentially reversible cause such as acute myocardial infarction (MI) or ischemia are considered to be at low risk of recurrent arrhythmia. Implantable cardioverter defibrillators (ICD) are not routinely recommended in such patients. However, the outcome of these patients in the era of rapid coronary revascularization and ICD therapy is not known. METHODS AND RESULTS: We examined the outcome of 114 consecutive survivors of VF OHCA due to acute MI or ischemia in Olmsted County, MN from 1990 to 2011. An ICD was implanted in 45/114 patients. ICD recipients had lower EF [median (IQR) 38 (26 to 54) versus 48 (35 to 58) %, P=0.04]. During a median (IQR) follow-up of 9.9 (4.4 to 14.6) years, ICD implantation was associated with reduced cardiac mortality (HR 0.24 [0.07 to 0.88], P=0.031) and a trend towards reduced all-cause mortality (HR 0.56 [0.30 to 1.02], P=0.059) after adjusting for the first principal component. One or more appropriate ICD therapies were delivered in 19/45, with half of the patients receiving therapy within 1 year. Patients with EF <=35% at discharge continued to be at long-term risk for ICD therapy compared with those with EF >35% who were at increased risk predominantly in the first 8 months. EF and revascularization were not significantly associated with ICD therapy in the multivariable analysis. CONCLUSIONS: Patients with VF-OHCA in the setting of acute MI or myocardial ischemia remain at high risk of recurrent ventricular arrhythmias, particularly if EF <=35%. This suggests that ICD implantation may be reasonable if EF <=35%. PMID- 25713288 TI - International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G protein coupled receptors. AB - The Adhesion family forms a large branch of the pharmacologically important superfamily of G protein-coupled receptors (GPCRs). As Adhesion GPCRs increasingly receive attention from a wide spectrum of biomedical fields, the Adhesion GPCR Consortium, together with the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification, proposes a unified nomenclature for Adhesion GPCRs. The new names have ADGR as common dominator followed by a letter and a number to denote each subfamily and subtype, respectively. The new names, with old and alternative names within parentheses, are: ADGRA1 (GPR123), ADGRA2 (GPR124), ADGRA3 (GPR125), ADGRB1 (BAI1), ADGRB2 (BAI2), ADGRB3 (BAI3), ADGRC1 (CELSR1), ADGRC2 (CELSR2), ADGRC3 (CELSR3), ADGRD1 (GPR133), ADGRD2 (GPR144), ADGRE1 (EMR1, F4/80), ADGRE2 (EMR2), ADGRE3 (EMR3), ADGRE4 (EMR4), ADGRE5 (CD97), ADGRF1 (GPR110), ADGRF2 (GPR111), ADGRF3 (GPR113), ADGRF4 (GPR115), ADGRF5 (GPR116, Ig-Hepta), ADGRG1 (GPR56), ADGRG2 (GPR64, HE6), ADGRG3 (GPR97), ADGRG4 (GPR112), ADGRG5 (GPR114), ADGRG6 (GPR126), ADGRG7 (GPR128), ADGRL1 (latrophilin-1, CIRL-1, CL1), ADGRL2 (latrophilin-2, CIRL-2, CL2), ADGRL3 (latrophilin-3, CIRL-3, CL3), ADGRL4 (ELTD1, ETL), and ADGRV1 (VLGR1, GPR98). This review covers all major biologic aspects of Adhesion GPCRs, including evolutionary origins, interaction partners, signaling, expression, physiologic functions, and therapeutic potential. PMID- 25713295 TI - Psychotropic medications and the risk of sudden cardiac death. PMID- 25713294 TI - Antipsychotic drugs and the risk of ventricular arrhythmia and/or sudden cardiac death: a nation-wide case-crossover study. AB - BACKGROUND: Antipsychotics have been linked to prolongation of the QT interval. However, little is known about the risk of ventricular arrhythmia (VA) and/or sudden cardiac death (SCD) associated with individual antipsychotic drug use. This study was designed to investigate the association between specific antipsychotic drugs and the risk of VA and/or SCD. METHODS AND RESULTS: We conducted a case-crossover study using a nation-wide population-based sample obtained from Taiwan's National Health Insurance Research Database. A total of 17 718 patients with incident VA and/or SCD were enrolled. Conditional logistic regression models were applied to examine the effects of antipsychotic drug use on the risk of VA/SCD during various case and control time windows of 7, 14, and 28 days. The effect of the potency of a human ether-a-go-go-related gene (hERG) potassium channel blockade was also assessed. Antipsychotic drug use was associated with a 1.53-fold increased risk of VA and/or SCD. Antipsychotic drugs with increased risk included clothiapine, haloperidol, prochlorperazine, thioridazine, olanzapine, quetiapine, risperidone, and sulpiride. The association was significantly higher among those with short-term use. Antipsychotics with a high potency of the hERG potassium channel blockade had the highest risk of VA and/or SCD. CONCLUSION: Use of antipsychotic drugs is associated with an increased risk of VA and/or SCD. Careful evaluations of the risks and benefits of antipsychotic treatment are highly recommended. PMID- 25713296 TI - The putative tumor suppressor gene EphA3 fails to demonstrate a crucial role in murine lung tumorigenesis or morphogenesis. AB - Treatment of non-small cell lung cancer (NSCLC) is based on histological analysis and molecular profiling of targetable driver oncogenes. Therapeutic responses are further defined by the landscape of passenger mutations, or loss of tumor suppressor genes. We report here a thorough study to address the physiological role of the putative lung cancer tumor suppressor EPH receptor A3 (EPHA3), a gene that is frequently mutated in human lung adenocarcinomas. Our data shows that homozygous or heterozygous loss of EphA3 does not alter the progression of murine adenocarcinomas that result from Kras mutation or loss of Trp53, and we detected negligible postnatal expression of EphA3 in adult wild-type lungs. Yet, EphA3 was expressed in the distal mesenchyme of developing mouse lungs, neighboring the epithelial expression of its Efna1 ligand; this is consistent with the known roles of EPH receptors in embryonic development. However, the partial loss of EphA3 leads only to subtle changes in epithelial Nkx2-1, endothelial Cd31 and mesenchymal Fgf10 RNA expression levels, and no macroscopic phenotypic effects on lung epithelial branching, mesenchymal cell proliferation, or abundance and localization of CD31-positive endothelia. The lack of a discernible lung phenotype in EphA3-null mice might indicate lack of an overt role for EPHA3 in the murine lung, or imply functional redundancy between EPHA receptors. Our study shows how biological complexity can challenge in vivo functional validation of mutations identified in sequencing efforts, and provides an incentive for the design of knock-in or conditional models to assign the role of EPHA3 mutation during lung tumorigenesis. PMID- 25713297 TI - Modeling autosomal recessive cutis laxa type 1C in mice reveals distinct functions for Ltbp-4 isoforms. AB - Recent studies have revealed an important role for LTBP-4 in elastogenesis. Its mutational inactivation in humans causes autosomal recessive cutis laxa type 1C (ARCL1C), which is a severe disorder caused by defects of the elastic fiber network. Although the human gene involved in ARCL1C has been discovered based on similar elastic fiber abnormalities exhibited by mice lacking the short Ltbp-4 isoform (Ltbp4S(-/-)), the murine phenotype does not replicate ARCL1C. We therefore inactivated both Ltbp-4 isoforms in the mouse germline to model ARCL1C. Comparative analysis of Ltbp4S(-/-) and Ltbp4-null (Ltbp4(-/-)) mice identified Ltbp-4L as an important factor for elastogenesis and postnatal survival, and showed that it has distinct tissue expression patterns and specific molecular functions. We identified fibulin-4 as a previously unknown interaction partner of both Ltbp-4 isoforms and demonstrated that at least Ltbp-4L expression is essential for incorporation of fibulin-4 into the extracellular matrix (ECM). Overall, our results contribute to the current understanding of elastogenesis and provide an animal model of ARCL1C. PMID- 25713298 TI - Downregulation of Wnt signaling by sonic hedgehog activation promotes repopulation of human tumor cell lines. AB - Tumor repopulation after radiotherapy is a big obstacle for clinical cancer therapy. The molecular mechanisms of tumor cell repopulation after radiotherapy remain unclear. This study investigated the role of sonic hedgehog (SHH) and Wnt signaling pathways in tumor repopulation after radiotherapy in an in vitro repopulation model. In this model, irradiated dying tumor cells functioned as feeder cells, whereas luciferase-labeled living tumor cells acted as reporter cells. Proliferation of reporter cells was measured by bioluminescence imaging. Results showed that irradiated dying HT29 and Panc1 tumor cells significantly stimulated the repopulation of living cells in their respective cultures. In HT29 and Panc1 cells, radiation significantly inhibited Wnt activity. In the irradiated dying HT29 and Panc1 cells, the level of the activated nuclear beta catenin was significantly decreased. Treatment with the Wnt agonist 68166 significantly decreased, whereas treatment with Wnt antagonist significantly increased, repopulation in HT29 and Panc1 tumor cells in a dose-dependent manner. beta-catenin short-hairpin RNA (shRNA) also significantly promoted tumor cell repopulation. The level of secreted frizzled related protein-1 (SFRP1), hedgehog and Gli1 were increased in irradiated cells. Our results highlight the interaction between Wnt and SHH signaling pathways in dying tumor cells and suggest that downregulation of Wnt signaling after SHH activation is negatively associated with tumor repopulation. PMID- 25713293 TI - Patterns of use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers among patients with acute myocardial infarction in China from 2001 to 2011: China PEACE-Retrospective AMI Study. AB - BACKGROUND: Chinese and U.S. guidelines recommend angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) for all patients with acute myocardial infarction (AMI) in the absence of contraindications as either a Class I or Class IIa recommendation. Little is known about the use and trends of ACEI/ARB therapy in China over the past decade. METHODS AND RESULTS: Using nationally representative data from the China Patient-centered Evaluative Assessment of Cardiac Events Retrospective Study of Acute Myocardial Infarction (China PEACE-Retrospective AMI Study), we assessed use of ACEI/ARB therapy in 2001, 2006, and 2011, overall and across geographic regions and strata of estimated mortality risk, and predictors of ACEI/ARB therapy, among patients with Class I indication by Chinese guidelines. The weighted rate of ACEI/ARB therapy increased from 62.0% in 2001 to 71.4% in 2006, decreasing to 67.6% in 2011. Use was low across all 5 geographic regions. By strata of estimated mortality risk, in 2001, rates of therapy increased with increasing risk; however, by 2011, this reversed and those at higher risk were less likely to be treated (70.7% in lowest risk quintile vs. 63.5% in the highest-risk quintile; P<0.001). CONCLUSION: One third of Chinese AMI patients with Class I indications do not receive ACEI/ARB therapy during hospitalization, with little improvement in rates over time. Patients at higher mortality risk in 2011 were less likely to be treated, highlighting important opportunities to optimize the use of this cost-effective therapy. CLINICAL TRIAL REGISTRATION URL: ClinicalTrials.gov. Unique identifier: NCT01624883. PMID- 25713302 TI - Correction. PMID- 25713299 TI - Nuclear p120-catenin regulates the anoikis resistance of mouse lobular breast cancer cells through Kaiso-dependent Wnt11 expression. AB - E-cadherin inactivation underpins the progression of invasive lobular breast carcinoma (ILC). In ILC, p120-catenin (p120) translocates to the cytosol where it controls anchorage independence through the Rho-Rock signaling pathway, a key mechanism driving tumor growth and metastasis. We now demonstrate that anchorage independent ILC cells show an increase in nuclear p120, which results in relief of transcriptional repression by Kaiso. To identify the Kaiso target genes that control anchorage independence we performed genome-wide mRNA profiling on anoikis resistant mouse ILC cells, and identified 29 candidate target genes, including the established Kaiso target Wnt11. Our data indicate that anchorage-independent upregulation of Wnt11 in ILC cells is controlled by nuclear p120 through inhibition of Kaiso-mediated transcriptional repression. Finally, we show that Wnt11 promotes activation of RhoA, which causes ILC anoikis resistance. Our findings thereby establish a mechanistic link between E-cadherin loss and subsequent control of Rho-driven anoikis resistance through p120- and Kaiso dependent expression of Wnt11. PMID- 25713303 TI - Correction. PMID- 25713300 TI - Treatment of cardiac arrhythmias in a mouse model of Rett syndrome with Na+ channel-blocking antiepileptic drugs. AB - One quarter of deaths associated with Rett syndrome (RTT), an X-linked neurodevelopmental disorder, are sudden and unexpected. RTT is associated with prolonged QTc interval (LQT), and LQT-associated cardiac arrhythmias are a potential cause of unexpected death. The standard of care for LQT in RTT is treatment with beta-adrenergic antagonists; however, recent work indicates that acute treatment of mice with RTT with a beta-antagonist, propranolol, does not prevent lethal arrhythmias. In contrast, acute treatment with the Na(+) channel blocker phenytoin prevented arrhythmias. Chronic dosing of propranolol may be required for efficacy; therefore, we tested the efficacy of chronic treatment with either propranolol or phenytoin on RTT mice. Phenytoin completely abolished arrhythmias, whereas propranolol showed no benefit. Surprisingly, phenytoin also normalized weight and activity, but worsened breathing patterns. To explore the role of Na(+) channel blockers on QT in people with RTT, we performed a retrospective analysis of QT status before and after Na(+) channel blocker antiepileptic therapies. Individuals with RTT and LQT significantly improved their QT interval status after being started on Na(+) channel blocker antiepileptic therapies. Thus, Na(+) channel blockers should be considered for the clinical management of LQT in individuals with RTT. PMID- 25713304 TI - Cathepsin B deficiency attenuates cardiac remodeling in response to pressure overload via TNF-alpha/ASK1/JNK pathway. AB - Cathepsin B (CTSB), a member of the lysosomal cathepsin family that is expressed in both murine and human hearts, was previously shown to participate in apoptosis, autophagy, and the progression of certain types of cancers. Recently, CTSB has been linked to myocardial infarction. Given that cathepsin L, another member of the lysosomal cathepsin family, ameliorates pathological cardiac hypertrophy, we hypothesized that CTSB plays a role in pressure overload-induced cardiac remodeling. Here we report that CTSB was upregulated in cardiomyocytes in response to hypertrophic stimuli both in vivo and in vitro. Moreover, knockout of CTSB attenuated pressure overload-induced cardiac hypertrophy, fibrosis, dysfunction, and apoptosis. Furthermore, the aortic banding-induced activation of TNF-alpha, apoptosis signal-regulating kinase 1 (ASK1), c-Jun NH2-terminal kinases (JNK), c-Jun, and release of cytochrome c was blunted by CTSB deficiency, which was further confirmed in in vitro studies induced by angiotensin II. In cardiomyocytes pretreatment with SP600125, a JNK inhibitor, suppressed the cardiomyocytes hypertrophy by inhibiting the ASK1/JNK pathway. Altogether, these data indicate that the CTSB protein functions as a necessary modulator of hypertrophic response by regulating TNF-alpha/ASK1/JNK signaling pathway involved in cardiac remodeling. PMID- 25713305 TI - Activation of PPARdelta signaling improves skeletal muscle oxidative metabolism and endurance function in an animal model of ischemic left ventricular dysfunction. AB - Exercise intolerance in heart failure has been linked to impaired skeletal muscle oxidative capacity. Oxidative metabolism and exercise capacity are regulated by PPARdelta signaling. We hypothesized that PPARdelta stimulation reverts skeletal muscle oxidative dysfunction. Myocardial infarction (MI) was induced in C57BL/6 mice and the development of ventricular dysfunction was monitored over 8 wk. Mice were randomized to the PPARdelta agonist GW501516 (5 mg/kg body wt per day for 4 wk) or placebo 8 wk post-MI. Muscle function was assessed through running tests and grip strength measurements. In muscle, we analyzed muscle fiber cross sectional area and fiber types, metabolic gene expression, fatty acid (FA) oxidation and ATP content. Signaling pathways were studied in C2C12 myotubes. FA oxidation and ATP levels decreased in muscle from MI mice compared with sham- operated mice. GW501516 administration increased oleic acid oxidation levels in skeletal muscle of the treated MI group compared with placebo treatment. This was accompanied by transcriptional changes including increased CPT1 expression. Further, the PPARdelta-agonist improved running endurance compared with placebo. Cell culture experiments revealed protective effects of GW501516 against the cytokine-induced decrease of FA oxidation and changes in metabolic gene expression. Skeletal muscle dysfunction in HF is associated with impaired PPARdelta signaling and treatment with the PPARdelta agonist GW501516 corrects oxidative capacity and FA metabolism and improves exercise capacity in mice with LV dysfunction. Pharmacological activation of PPARdelta signaling could be an attractive therapeutic intervention to counteract the progressive skeletal muscle dysfunction in HF. PMID- 25713307 TI - Approximate Bayesian Computation Reveals the Crucial Role of Oceanic Islands for the Assembly of Continental Biodiversity. AB - The perceived low levels of genetic diversity, poor interspecific competitive and defensive ability, and loss of dispersal capacities of insular lineages have driven the view that oceanic islands are evolutionary dead ends. Focusing on the Atlantic bryophyte flora distributed across the archipelagos of the Azores, Madeira, the Canary Islands, Western Europe, and northwestern Africa, we used an integrative approach with species distribution modeling and population genetic analyses based on approximate Bayesian computation to determine whether this view applies to organisms with inherent high dispersal capacities. Genetic diversity was found to be higher in island than in continental populations, contributing to mounting evidence that, contrary to theoretical expectations, island populations are not necessarily genetically depauperate. Patterns of genetic variation among island and continental populations consistently fitted those simulated under a scenario of de novo foundation of continental populations from insular ancestors better than those expected if islands would represent a sink or a refugium of continental biodiversity. We, suggest that the northeastern Atlantic archipelagos have played a key role as a stepping stone for transoceanic migrants. Our results challenge the traditional notion that oceanic islands are the end of the colonization road and illustrate the significant role of oceanic islands as reservoirs of novel biodiversity for the assembly of continental floras. PMID- 25713306 TI - beta-Adrenergic stimulation and rapid pacing mutually promote heterogeneous electrical failure and ventricular fibrillation in the globally ischemic heart. AB - Global ischemia, catecholamine surge, and rapid heart rhythm (RHR) due to ventricular tachycardia or ventricular fibrillation (VF) are the three major factors of sudden cardiac arrest (SCA). Loss of excitability culminating in global electrical failure (asystole) is the major adverse outcome of SCA with increasing prevalence worldwide. The roles of catecholamines and RHR in the electrical failure during SCA remain unclear. We hypothesized that both beta adrenergic stimulation (betaAS) and RHR accelerate electrical failure in the globally ischemic heart. We performed optical mapping of the action potential (OAP) in the right ventricular (RV) and left (LV) ventricular epicardium of isolated rabbit hearts subjected to 30-min global ischemia. Hearts were paced at a cycle length of either 300 or 200 ms, and either in the presence or in the absence of beta-agonist isoproterenol (30 nM). 2,3-Butanedione monoxime (20 mM) was used to reduce motion artifact. We found that RHR and betaAS synergistically accelerated the decline of the OAP upstroke velocity and the progressive expansion of inexcitable regions. Under all conditions, inexcitability developed faster in the LV than in the RV. At the same time, both RHR and betaAS shortened the time to VF (TVF) during ischemia. Moreover, the time at which 10% of the mapped LV area became inexcitable strongly correlated with TVF (R(2) = 0 .72, P < 0.0001). We conclude that both betaAS and RHR are major factors of electrical depression and failure in the globally ischemic heart and may contribute to adverse outcomes of SCA such as asystole and recurrent/persistent VF. PMID- 25713308 TI - Can epidemiology inform global health and development targets? PMID- 25713309 TI - Commentary: Randomized trials of controversial social interventions: slow progress in 50 years. PMID- 25713310 TI - Response to the commentaries on JW Palmer. Smoking, caning and delinquency in a secondary modern school. PMID- 25713311 TI - Population health and status of epidemiology in Western European, Balkan and Baltic countries. AB - BACKGROUND: This article is part of a series commissioned by the International Epidemiological Association, aimed at describing population health and epidemiological resources in the six World Health Organization (WHO) regions. It covers 32 of the 53 WHO European countries, namely the Western European countries, the Balkan countries and the Baltic countries. METHODS: The burdens of mortality and morbidity and the patterns of risk factors and inequalities have been reviewed in order to identify health priorities and challenges. Literature and internet searches were conducted to stock-take epidemiological teaching, research activities, funding and scientific productivity. FINDINGS: These countries have among the highest life expectancies worldwide. However, within- and between-country inequalities persist, which are largely due to inequalities in distribution of main health determinants. There is a long tradition of epidemiological research and teaching in most countries, in particular in the Western European countries. Cross-national networks and collaborations are increasing through the support of the European Union which fosters procedures to standardize educational systems across Europe and provides funding for epidemiological research through framework programmes. The number of Medline indexed epidemiological research publications per year led by Western European countries has been increasing. The countries accounts for nearly a third of the global epidemiological publication. CONCLUSIONS: Although population health has improved considerably overall, persistent within- and between-country inequalities continue to challenge national and European health institutions. More research, policy and action on the social determinants of health are required in the region. Epidemiological training, research and workforce in the Baltic and Balkan countries should be strengthened. European epidemiologists can play pivotal roles and must influence legislation concerning production and access to high-quality data. PMID- 25713312 TI - A comparison of two methods for assessing awareness of antitobacco television advertisements. AB - BACKGROUND: This study uses an online survey panel to compare two approaches for assessing ad awareness. The first uses a screenshot of a television ad and the second shows participants a full-length video of the ad. METHODS: We randomly assigned 1034 Minnesota respondents to view a screenshot or a streaming video from two antitobacco ads. The study used one ad from ClearWay Minnesota's ITALIC! We All Pay the Price campaign, and one from the Centers for Disease Control ITALIC! Tips campaign. The key measure used to assess ad awareness was aided ad recall. Multivariate analyses of recall with cessation behaviour and attitudinal beliefs assessed the validity of these approaches. RESULTS: The respondents who saw the video reported significantly higher recall than those who saw the screenshot. Associations of recall with cessation behaviour and attitudinal beliefs were stronger and in the anticipated direction using the screenshot method. Over 20% of the respondents assigned to the video group could not see the ad. People who were under 45 years old, had incomes greater than $35,000 and women were reportedly less able to access the video. CONCLUSIONS: The methodology used to assess recall matters. Campaigns may exaggerate the successes or failures of their media campaigns, depending on the approach they employ and how they compare it to other media campaign evaluations. When incorporating streaming video, researchers should consider accessibility and report possible response bias. Researchers should fully define the measures they use, specify any viewing accessibility issues, and make ad comparisons only when using comparable methods. PMID- 25713313 TI - The revision of the 2014 European tobacco products directive: an analysis of the tobacco industry's attempts to 'break the health silo'. AB - BACKGROUND: The 2014 European Union (EU) Tobacco Products Directive (TPD) was negotiated in a changed policy context, following adoption of the EU's 'Smart Regulation' agenda, which transnational tobacco companies (TTCs) anticipated would increase their influence on health policy, and the WHO Framework Convention on Tobacco Control (FCTC), which sought to reduce it. This study aims to explore the scale and nature of the TTCs' lobby against the EU TPD and evaluate how these developments have affected their ability to exert influence. METHODS: Analysis of 581 documents obtained through freedom of information requests, 28 leaked Philip Morris International (PMI) documents, 17 TTC documents from the Legacy Library, web content via Google alerts and searches of the EU institutions' websites, plus four stakeholder interviews. RESULTS: The lobby was massive. PMI alone employed over 160 lobbyists. Strategies mainly used third parties. Efforts to 'Push' (amend) or 'Delay' the proposal and block 'extreme policy options' were partially successful, with plain packaging and point of sales display ban removed during the 3-year delay in the Commission. The Smart Regulation mechanism contributed to changes and delays, facilitating meetings between TTC representatives (including ex-Commission employees) and senior Commission staff. Contrary to Article 5.3, these meetings were not disclosed. CONCLUSIONS: During the legislative process, Article 5.3 was not consistently applied by non-health Directorates of the European Commission, while the tools of the Smart Regulation appear to have facilitated TTC access to, and influence on, the 2014 TPD. The use of third parties undermines Article 5.3. PMID- 25713315 TI - Demonstration of the disease activity by serial carotid artery ultrasonography, magnetic resonance imaging and 18-fluoro-deoxyglucose positron emission tomography in a Behcet's disease patient with carotid artery stenosis. PMID- 25713316 TI - Reversal of right-ventricular dysfunction in pulmonary arterial hypertension following sildenafil therapy. PMID- 25713314 TI - Plaque rupture and intact fibrous cap assessed by optical coherence tomography portend different outcomes in patients with acute coronary syndrome. AB - AIMS: Patients presenting with acute coronary syndrome (ACS) may have different plaque morphologies at the culprit lesion. In particular, plaque rupture (PR) has been shown as the more frequent culprit plaque morphology in ACS. However, its prognostic value is still unknown. In this study, we evaluated the prognostic value of PR, compared with intact fibrous cap (IFC), in patients with ACS. METHODS AND RESULTS: We enrolled consecutive patients admitted to our Coronary Care Unit for ACS and undergoing coronary angiography followed by interpretable optical coherence tomography (OCT) imaging. Culprit lesion was classified as PR and IFC by OCT criteria. Prognosis was assessed according to such culprit lesion classification. Major adverse cardiac events (MACEs) were defined as the composite of cardiac death, non-fatal myocardial infarction, unstable angina, and target lesion revascularization (follow-up mean time 31.58 +/- 4.69 months). The study comprised 139 consecutive ACS patients (mean age 64.3 +/- 12.0 years, male 73.4%, 92 patients with non-ST elevation ACS and 47 with ST-elevation ACS). Plaque rupture was detected in 82/139 (59%) patients. There were no differences in clinical, angiographic, or procedural data between patients with PR when compared with those having IFC. Major adverse cardiac events occurred more frequently in patients with PR when compared with those having IFC (39.0 vs. 14.0%, P = 0.001). Plaque rupture was an independent predictor of outcome at multivariable analysis (odds ratio 3.735, confidence interval 1.358-9.735). CONCLUSION: Patients with ACS presenting with PR as culprit lesion by OCT have a worse prognosis compared with that of patients with IFC. This finding should be taken into account in risk stratification and management of patients with ACS. PMID- 25713317 TI - A rare cause of cardiogenic shock. PMID- 25713320 TI - CYR61 (CCN1) overexpression induces lung injury in mice. AB - Cysteine-rich protein-61 (CYR61), also known as connective tissue growth factor, CYR61, and nephroblastoma overexpressed gene 1 (CCN1), is a heparin-binding protein member of the CCN family of matricellular proteins. Gene expression profiles showed that Cyr61 is upregulated in human acute lung injury (ALI), but its functional role is unclear. We hypothesized that CYR61 contributes to ALI in mice. First, we demonstrated that CYR61 expression increases after bleomycin induced lung injury. We then used adenovirus-mediated gene transfer to determine whether CYR61 overexpression in the lungs was sufficient to cause ALI. Mice instilled with CYR61 adenovirus showed greater weight loss, increased bronchoalveolar lavage total neutrophil counts, increased protein concentrations, and increased mortality compared with mice instilled with empty-vector adenovirus. Immunohistochemical studies in lungs from humans with idiopathic pulmonary fibrosis revealed CYR61 expression on the luminal membrane of alveolar epithelial cells in areas of injury. We conclude that CYR61 is upregulated in ALI and that CYR61 overexpression exacerbates ALI in mice. PMID- 25713318 TI - Estradiol improves right ventricular function in rats with severe angioproliferative pulmonary hypertension: effects of endogenous and exogenous sex hormones. AB - Estrogens are disease modifiers in PAH. Even though female patients exhibit better right ventricular (RV) function than men, estrogen effects on RV function (a major determinant of survival in PAH) are incompletely characterized. We sought to determine whether sex differences exist in RV function in the SuHx model of PAH, whether hormone depletion in females worsens RV function, and whether E2 repletion improves RV adaptation. Furthermore, we studied the contribution of ERs in mediating E2's RV effects. SuHx-induced pulmonary hypertension (SuHx-PH) was induced in male and female Sprague-Dawley rats as well as OVX females with or without concomitant E2 repletion (75 MUg.kg(-1).day(-1)). Female SuHx rats exhibited superior CI than SuHx males. OVX worsened SuHx-induced decreases in CI and SuHx-induced increases in RVH and inflammation (MCP-1 and IL 6). E2 repletion in OVX rats attenuated SuHx-induced increases in RV systolic pressure (RVSP), RVH, and pulmonary artery remodeling and improved CI and exercise capacity (Vo2max). Furthermore, E2 repletion ameliorated SuHx-induced alterations in RV glutathione activation, proapoptotic signaling, cytoplasmic glycolysis, and proinflammatory cytokine expression. Expression of ERalpha in RV was decreased in SuHx-OVX but was restored upon E2 repletion. RV ERalpha expression was inversely correlated with RVSP and RVH and positively correlated with CO and apelin RNA levels. RV-protective E2 effects observed in females were recapitulated in male SuHx rats treated with E2 or with pharmacological ERalpha or ERbeta agonists. Our data suggest significant RV-protective ER-mediated effects of E2 in a model of severe PH. PMID- 25713319 TI - CXCL8 histone H3 acetylation is dysfunctional in airway smooth muscle in asthma: regulation by BET. AB - Asthma is characterized by airway inflammation and remodeling and CXCL8 is a CXC chemokine that drives steroid-resistant neutrophilic airway inflammation. We have shown that airway smooth muscle (ASM) cells isolated from asthmatic individuals secrete more CXCL8 than cells from nonasthmatic individuals. Here we investigated chromatin modifications at the CXCL8 promoter in ASM cells from nonasthmatic and asthmatic donors to further understand how CXCL8 is dysregulated in asthma. ASM cells from asthmatic donors had increased histone H3 acetylation, specifically histone H3K18 acetylation, and increased binding of histone acetyltransferase p300 compared with nonasthmatic donors but no differences in CXCL8 DNA methylation. The acetylation reader proteins Brd3 and Brd4 were bound to the CXCL8 promoter and Brd inhibitors inhibited CXCL8 secretion from ASM cells by disrupting Brd4 and RNA polymerase II binding to the CXCL8 promoter. Our results show a novel dysregulation of CXCL8 transcriptional regulation in asthma characterized by a promoter complex that is abnormal in ASM cells isolated from asthmatic donors and can be modulated by Brd inhibitors. Brd inhibitors may provide a new therapeutic strategy for steroid-resistant inflammation. PMID- 25713321 TI - Oxidized glutathione (GSSG) inhibits epithelial sodium channel activity in primary alveolar epithelial cells. AB - Amiloride-sensitive epithelial Na(+) channels (ENaC) regulate fluid balance in the alveoli and are regulated by oxidative stress. Since glutathione (GSH) is the predominant antioxidant in the lungs, we proposed that changes in glutathione redox potential (Eh) would alter cell signaling and have an effect on ENaC open probability (Po). In the present study, we used single channel patch-clamp recordings to examine the effect of oxidative stress, via direct application of glutathione disulfide (GSSG), on ENaC activity. We found a linear decrease in ENaC activity as the GSH/GSSG Eh became less negative (n = 21; P < 0.05). Treatment of 400 MUM GSSG to the cell bath significantly decreased ENaC Po from 0.39 +/- 0.06 to 0.13 +/- 0.05 (n = 8; P < 0.05). Likewise, back-filling recording electrodes with 400 MUM GSSG reduced ENaC Po from 0.32 +/- 0.08 to 0.17 +/- 0.05 (n = 10; P < 0.05), thus implicating GSSG as an important regulatory factor. Biochemical assays indicated that oxidizing potentials promote S glutathionylation of ENaC and irreversible oxidation of cysteine residues with N ethylmaleimide blocked the effects of GSSG on ENaC Po. Additionally, real-time imaging studies showed that GSSG impairs alveolar fluid clearance in vivo as opposed to GSH, which did not impair clearance. Taken together, these data show that glutathione Eh is an important determinant of alveolar fluid clearance in vivo. PMID- 25713323 TI - Voluntary physical activity prevents insulin resistance in a tissue specific manner. AB - Physical inactivity and a sedentary lifestyle are risk factors for the development of type 2 diabetes. Here, we identified the effects 8 weeks of voluntary physical activity had on the prevention of insulin resistance in mouse skeletal muscles and liver (a hallmark of T2D). To do this, 8 week old C57BL/6J mice with (RUN) and without (SED) voluntary access to running wheels were fed a standard rodent chow ad libitum for 8 weeks. In the liver, there was a 2.5-fold increase in insulin stimulated Akt(SER) (473) phosphorylation, and a threefold increase in insulin-stimulated (0.5 U/kg) GSK3beta(SER) (9) phosphorylation in RUN compared to SED mice. Although not induced in skeletal muscles, there was a twofold increase in SOCS3 expression in SED compared to RUN mice in the liver. There was no difference in the glucose tolerance test between groups. This study was the first to show differences in liver insulin sensitivity after 8 weeks of voluntary physical activity, and increased SOCS3 expression in the liver of sedentary mice compared to active mice. These findings demonstrate that even in young mice that would normally be considered healthy, the lack of physical activity leads to insulin resistance representing the initial pathogenesis of impaired glucose metabolism leading to type 2 diabetes. PMID- 25713322 TI - p53 protects against LPS-induced lung endothelial barrier dysfunction. AB - New therapies toward heart and blood vessel disorders may emerge from the development of Hsp90 inhibitors. Several independent studies suggest potent anti inflammatory activities of those agents in human tissues. The molecular mechanisms responsible for their protective effects in the vasculature remain unclear. The present study demonstrates that the transcription factor p53, an Hsp90 client protein, is crucial for the maintenance of vascular integrity, protects again LPS-induced endothelial barrier dysfunction, and is involved in the mediation of the anti-inflammatory activity of Hsp90 inhibitors in lung tissues. p53 silencing by siRNA decreased transendothelial resistance (a measure of endothelial barrier function). A similar effect was induced by the p53 inhibitor pifithrin, which also potentiated the LPS-induced hyperpermeability in human lung microvascular endothelial cells (HLMVEC). On the other hand, p53 induction by nutlin suppressed the LPS-induced vascular barrier dysfunction. LPS decreased p53 expression in lung tissues and that effect was blocked by pretreatment with Hsp90 inhibitors both in vivo and in vitro. Furthermore, the Hsp90 inhibitor 17-allyl-amino-demethoxy-geldanamycin suppressed the LPS-induced overexpression of the p53 negative regulator MDMX as well as p53 and MDM2 (another p53 negative regulator) phosphorylation in HLMVEC. Both negative p53 regulators were downregulated by LPS in vivo. Chemically induced p53 overexpression resulted in the suppression of LPS-induced RhoA activation and MLC2 phosphorylation, whereas p53 suppression caused the opposite effects. These observations reveal new mechanisms for the anti-inflammatory actions of Hsp90 inhibitors, i.e., the induction of the transcription factor p53, which in turn can orchestrate robust vascular anti-inflammatory responses both in vivo and in vitro. PMID- 25713324 TI - Manual therapy ameliorates delayed-onset muscle soreness and alters muscle metabolites in rats. AB - Delayed-onset muscle soreness (DOMS) can be induced by lengthening contraction (LC); it can be characterized by tenderness and movement-related pain in the exercised muscle. Manual therapy (MT), including compression of exercised muscles, is widely used as physical rehabilitation to reduce pain and promote functional recovery. Although MT is beneficial for reducing musculoskeletal pain (i.e. DOMS), the physiological mechanisms of MT remain unclear. In the present study, we first developed an animal model of MT in DOMS; LC was applied to the rat gastrocnemius muscle under anesthesia, which induced mechanical hyperalgesia 2-4 days after LC. MT (manual compression) ameliorated mechanical hyperalgesia. Then, we used capillary electrophoresis time-of-flight mass spectroscopy (CE TOFMS) to investigate early effects of MT on the metabolite profiles of the muscle experiencing DOMS. The rats were divided into the following three groups; (1) normal controls, (2) rats with LC application (LC group), and (3) rats undergoing MT after LC (LC + MT group). According to the CE-TOFMS analysis, a total of 171 metabolites were detected among the three groups, and 19 of these metabolites were significant among the groups. Furthermore, the concentrations of eight metabolites, including branched-chain amino acids, carnitine, and malic acid, were significantly different between the LC + MT and LC groups. The results suggest that MT significantly altered metabolite profiles in DOMS. According to our findings and previous data regarding metabolites in mitochondrial metabolism, the ameliorative effects of MT might be mediated partly through alterations in metabolites associated with mitochondrial respiration. PMID- 25713325 TI - Exhausting treadmill running causes dephosphorylation of sMLC2 and reduced level of myofilament MLCK2 in slow twitch rat soleus muscle. AB - Myosin light chain 2 (MLC2) is a small protein in the myosin complex, regulating muscle contractile function by modulating Ca(2+) sensitivity of myofilaments. MLC2 can be modified by phosphorylation and O-GlcNAcylation, two reversible and dynamic posttranslational modifications. The slow isoform of MLC2 (sMLC2) is dephosphorylated in soleus muscle during in situ loaded shortening contractions, which correlates with reduction in shortening capacity. Here, we hypothesize that exhausting in vivo treadmill running induces dephosphorylation of MLC2 in slow twitch soleus, but not in fast twitch EDL muscle, and that there are reciprocal changes in MLC2 O-GlcNAcylation. At rest, both phosphorylation and O GlcNAcylation of MLC2 were lower in slow than fast twitch muscles. One bout of exhausting treadmill running induced dephosphorylation of sMLC2 in soleus, paralleled by reduced levels of the kinase MLCK2 associated to myofilaments, suggesting that the acute reduction in phosphorylation is mediated by dissociation of MLCK2 from myofilaments. O-GlcNAcylation of MLC2 did not change significantly, and seems of limited importance in the regulation of MLC2 phosphorylation during in vivo running. After 6 weeks of treadmill running, the dephosphorylation of sMLC2 persisted in soleus along with reduction in MLCK2 both in myofilament- and total protein fraction. In EDL on the contrary, phosphorylation of MLC2 was not altered after one exercise bout or after 6 weeks of treadmill running. Thus, in contrast to fast twitch muscle, MLC2 dephosphorylation occurs in slow twitch muscle during in vivo exercise and may be linked to reduced myofilament-associated MLCK2 and reduced shortening capacity. PMID- 25713326 TI - Synergistic induction of CCL2/MCP-1 expression driven by oncostatin M and IL 1beta in human proximal tubular cells depends on STAT3 and p65 NFkappaB/RelA. AB - In response to tubular injury, production, and secretion of cytokines, chemokines or extracellular matrix components by human proximal tubular epithelial cells (PTC) directly contribute to the development of tubulointerstitial inflammation and fibrosis. Here, we report a novel stimulatory and synergistic effect of oncostatin M (OSM) on proinflammatory CCL2/MCP-1 mRNA expression in human PTC. Although OSM inhibited IL-1beta- and TNF-alpha-mediated mRNA expression of matricellular proteins TSP-1 and tenascin C (TNC), it acted synergistically with these two proinflammatory cytokines to induce CCL2 mRNA expression for up to 24 h. Stimulation of two independent human PTC lines with OSM alone led to a rapid and strong induction of this chemokine within the first hour of ligand administration, which subsequently returned toward basal levels in between 3 and 24 h and finally switched into a significant OSM-mediated 70% inhibition of basal CCL2 mRNA expression after 48 h of incubation. In contrast to OSM, which stimulated both STAT1/3 and ERK1/2 signaling, IL-1beta led to a strong phosphorylation of p65 NFkappaB/RelA, SMAD2/3, and p38 MAPK in human PTC. Selective silencing of these signaling molecules revealed that p65 NFkappaB/RelA is involved in IL-1beta-mediated stimulation of CCL2 mRNA, and that superinduction of CCL2 mRNA expression in the presence of both OSM and IL-1beta at least partially depends on STAT3 signaling. Thus, with respect to the expression of the proinflammatory chemokine CCL2, OSM may stimulate acute inflammation via its synergistic effect with other proinflammatory cytokines early after injury. PMID- 25713327 TI - Potential explanation of limb combination performance differences for two-limb coordination tasks. AB - Rhythmic two-limb coordinated movements in the sagittal plane are variable and inaccurate when the movements are in the opposite direction as compared with those in the same direction (directional constraint). The magnitude of directional constraint depends on the particular limb combination. It is prominent in ipsilateral hand-foot coordination, but minimal in bimanual hand coordination. The reason for such differences remains unclear. In this study, we investigated the possible mechanisms underlying the production of the difference that depend on limb combination. Subjects performed two-limb rhythmic coordinated movements either in the same or in the opposite direction for three separate limb combinations (bilateral hands, contralateral hand and foot, and ipsilateral hand and foot). For each combination two different tasks were performed. In the first condition, subjects actively moved two limbs (active condition). Second, subjects actively moved one limb in coordination with a passively moved limb (passive condition). In the active condition, the directional constraint was dependent upon the limb combination, as reported in previous studies; the directional constraint was quite prominent in ipsilateral combinations, intermediate in contralateral combinations, and minimal for bilateral combination. However, differences in the directional constraint did not depend on limb combination for any combination in the passive conditions which apparently utilized closed-loop control. In other word, the difference depending on limb combination disappeared when control strategies become uniformly closed-loop. Thus, we speculate that the control strategy utilized depends on limb combination in the active condition. Additionally, different mechanisms other than closed-loop control also would have influence depending on the particular limb combination. This may result in differences in performance depending upon the limb combination. PMID- 25713328 TI - Cardiac adaptations from 4 weeks of intensity-controlled vigorous exercise are lost after a similar period of detraining. AB - Intensity-controlled (relative to VO2max) treadmill exercise training in adult rats results in the activation and ensuing differentiation of endogenous c kit(pos) cardiac stem/progenitor cells (eCSCs) into newly formed cardiomyocytes and capillaries. Whether these training-induced adaptations persist following detraining is undetermined. Twelve male Wistar rats (~230 g) were exercised at 80 85% of their VO2max for 30 min day(-1), 4 days week(-1) for 4 weeks (TR; n = 6), followed by 4 weeks of detraining (DTR; n = 6). Twelve untrained rats acted as controls (CTRL). Exercise training significantly enhanced VO2max (11.34 mL kg(-1) min(-1)) and wet heart weight (29%) above CTRL (P < 0.05). Echocardiography revealed that exercise training increased LV mass (~32%), posterior and septal wall thickness (~15%), ejection fraction and fractional shortening (~10%) compared to CTRL (P < 0.05). Cardiomyocyte diameter (17.9 +/- 0.1 MUm vs. 14.9 +/ 0.6 MUm), newly formed (BrdU(pos)/Ki67(pos)) cardiomyocytes (7.2 +/- 1.3%/1.9 +/ 0.7% vs. 0.2 +/- 0.1%/0.1 +/- 0.1%), total cardiomyocyte number (45.6 +/- 0.6 * 10(6) vs. 42.5 +/- 0.4 * 10(6)), c-kit(pos) eCSC number (884 +/- 112 per 10(6) cardiomyocytes vs. 482 +/- 132 per 10(6) cardiomyocytes), and capillary density (4123 +/- 227 per mm(2) vs. 2117 +/- 118 per mm(2)) were significantly greater in the LV of trained animals (P < 0.05) than CTRL. Detraining removed the stimulus for c-kit(pos) eCSC activation (640 +/- 98 per 10(6) cardiomyocytes) and resultant cardiomyocyte hyperplasia (0.4 +/- 0.3% BrdU(pos)/0.2 +/- 0.2% Ki67(pos) cardiomyocytes). Capillary density (3673 +/- 374 per mm(2)) and total myocyte number (44.7 +/- 0.5 * 10(6)) remained elevated following detraining, but cardiomyocyte hypertrophy (15.0 +/- 0.4 MUm) was lost, resulting in a reduction of anatomical (wall thickness ~4%; LV mass ~10% and cardiac mass ~8%, above CTRL) and functional (EF & FS ~2% above CTRL) parameters gained through exercise training. These findings demonstrate that cardiac adaptations, produced by 4 weeks of intensity-controlled exercise training are lost after a similar period of detraining. PMID- 25713329 TI - Impact of ischemic preconditioning on functional sympatholysis during handgrip exercise in humans. AB - Repeated bouts of ischemia followed by reperfusion, known as ischemic preconditioning (IPC), is found to improve exercise performance. As redistribution of blood from the inactive areas to active skeletal muscles during exercise (i.e., functional sympatholysis) is important for exercise performance, we examined the hypothesis that IPC improves functional sympatholysis in healthy, young humans. In a randomized study, 15 healthy young men performed a 10-min resting period, dynamic handgrip exercise at 10% maximal voluntary contraction (MVC), and 25% MVC. This protocol was preceded by IPC (IPC; 4 * 5-min 220-mmHg unilateral occlusion) or a sham intervention (CON; 4 * 5-min 20-mmHg unilateral occlusion). Near-infrared spectroscopy was used to assess changes in oxygenated hemoglobin and myoglobin in skeletal muscle (HbO2 + MbO2) in response to sympathetic activation (via cold pressor test (CPT)) at baseline and during handgrip exercise (at 10% and 25%). In resting conditions, HbO2 + MbO2 significantly decreased during CPT (-11.0 +/- 1.0%), which was significantly larger during the IPC-trial (-13.8 +/- 1.2%, P = 0.006). During handgrip exercise at 10% MVC, changes in HbO2 + MbO2 in response to the CPT were blunted after IPC (-8.8 +/- 1.5%) and CON (-8.3 +/- 0.4%, P = 0.593). During handgrip exercise at 25% MVC, HbO2 + MbO2 in response to the CPT increased (2.0 +/- 0.4%), whereas this response was significantly larger when preceded by IPC (4.2 +/- 0.6%, P = 0.027). Collectively, these results indicate that IPC-induced different vascular changes at rest and during moderate exercise in response to sympathetic activation. This suggests that, in healthy volunteers, exposure to IPC may alter tissue oxygenation during sympathetic stimulation at rest and during exercise. PMID- 25713330 TI - Posttranscriptional regulation of adrenal TH gene expression contributes to the maladaptive responses triggered by insulin-induced recurrent hypoglycemia. AB - Acute metabolic stress such as insulin-induced hypoglycemia triggers a counterregulatory response during which the release of catecholamines (epinephrine), the activation of tyrosine hydroxylase (TH) enzyme and subsequent compensatory catecholamine biosynthesis occur in the adrenal medulla. However, recurrent exposure to hypoglycemia (RH), a consequence of tight glycemic control in individuals with type 1 and type 2 diabetes compromises this physiological response. The molecular mechanisms underlying the maladaptive response to repeated glucose deprivation are incompletely understood. We hypothesize that impaired epinephrine release following RH reflects altered regulation of adrenal catecholamine biosynthesis. To test this hypothesis, we compared the effect of single daily (RH) and twice-daily episodes of insulin-induced hypoglycemia (2RH) on adrenal epinephrine release and production in normal rats. Control animals received saline injections under similar conditions (RS and 2RS, respectively). Following 3 days of treatment, we assessed the counterregulatory hormonal responses during a hypoglycemic clamp. Changes in adrenal TH gene expression were also analyzed. The counterregulatory responses, relative TH transcription and TH mRNA levels and Ser40-TH phosphorylation (marker for enzyme activation) were induced to a similar extent in RS, 2RS, and RH groups. In contrast, epinephrine and glucagon responses were attenuated in the 2RH group and this was associated with a limited elevation of adrenal TH mRNA, rapid inactivation of TH enzyme and no significant changes in TH protein. Our results suggest that novel posttranscriptional mechanisms controlling TH mRNA and activated TH enzyme turnover contribute to the impaired epinephrine responses and may provide new therapeutic targets to prevent HAAF. PMID- 25713331 TI - Gene expression in salivary glands: effects of diet and mouse chromosome 17 locus regulating macronutrient intake. AB - Dcpp2, Prrt1, and Has1 are plausible candidate genes for the Mnic1 (macronutrient intake-carbohydrate) locus on mouse chromosome 17, based on their map positions and sequence variants, documented expression in salivary glands, and the important role of saliva in oral food processing and taste. We investigated the effects of genotype and diet on gene expression in salivary glands (parotid, submandibular, sublingual) of carbohydrate-preferring, C57BL6J.CAST/EiJ-17.1 subcongenic mice compared to fat-preferring wild-type C57BL/6J. To achieve accurate normalization of real-time quantitative RT-PCR data, we evaluated multiple reference genes to identify the most stably expressed control genes in salivary gland tissues, and then used geometric averaging to produce a reliable normalization factor. Gene expression was measured in mice fed different diets: (1) rodent chow, (2) macronutrient selection diets, (3) high-fat diet, and (4) low-fat diet. In addition, we measured salivary hyaluronan concentrations. All three genes showed strain differences in expression, in at least one major salivary gland, and diet effects were observed in two glands. Dcpp2 expression was limited primarily to sublingual gland, and strongly decreased in B6.CAST-17.1 subcongenic mice compared to wild-type B6, regardless of diet. In contrast, both genotype and diet affected Prrt1 and Has1 expression, in a gland-specific manner, for example, Prrt1 expression in the parotid gland alone was strongly reduced in both mouse strains when fed macronutrient selection diet compared to chow. Notably, we discovered an association between diet composition and salivary hyaluronan content. These results demonstrate robust effects of genetic background and diet composition on candidate gene expression in mouse salivary glands. PMID- 25713332 TI - The contribution of IL-6 to beta 3 adrenergic receptor mediated adipose tissue remodeling. AB - The chronic activation of beta 3 adrenergic receptors results in marked alterations in adipose tissue morphology and metabolism, including increases in mitochondrial content and the expression of enzymes involved in lipogenesis and glyceroneogenesis. Acute treatment with CL 316,243, a beta 3 adrenergic agonist, induces the expression of interleukin 6. Interestingly, IL-6 has been shown to induce mitochondrial genes in cultured adipocytes. Therefore, the purpose of this paper was to examine the role of interleukin 6 in mediating the in vivo effects of CL 316,243 in white adipose tissue. Circulating IL-6, and markers of IL-6 signaling in white adipose tissue were increased 4 h following a single injection of CL 316,243 in C57BL6/J mice. Once daily injections of CL 316,243 for 5 days increased the protein content of a number of mitochondrial proteins including CORE1, Cytochrome C, PDH, MCAD, and Citrate Synthase to a similar extent in adipose tissue from WT and IL-6(-/-) mice. Conversely, CL 316,243-induced increases in COXIV and phosphorylated AMPK were attenuated in IL-6(-/-) mice. Likewise, the slight, but significant, CL 316,243-induced increases in ATGL, PEPCK, and PPARgamma, were reduced or absent in adipose tissue IL-6(-/-) mice. The attenuated response to CL 316,243 in white adipose tissue in IL-6(-/-) mice was associated with reductions in whole-body oxygen consumption and energy expenditure in the light phase. Our findings suggest that IL-6 plays a limited role in CL 316,243-mediated adipose tissue remodeling. PMID- 25713333 TI - Multiple molecular subtypes of triple-negative breast cancer critically rely on androgen receptor and respond to enzalutamide in vivo. AB - Triple-negative breast cancer (TNBC) has the lowest 5-year survival rate of invasive breast carcinomas, and currently there are no approved targeted therapies for this aggressive form of the disease. The androgen receptor (AR) is expressed in up to one third of TNBC and we find that all AR(+) TNBC primary tumors tested display nuclear localization of AR, indicative of transcriptionally active receptors. While AR is most abundant in the "luminal AR (LAR)" molecular subtype of TNBC, here, for the first time, we use both the new-generation anti androgen enzalutamide and AR knockdown to demonstrate that the other non-LAR molecular subtypes of TNBC are critically dependent on AR protein. Indeed, AR inhibition significantly reduces baseline proliferation, anchorage-independent growth, migration, and invasion and increases apoptosis in four TNBC lines (SUM159PT, HCC1806, BT549, and MDA-MB-231), representing three non-LAR TNBC molecular subtypes (mesenchymal-like, mesenchymal stem-like, and basal-like 2). In vivo, enzalutamide significantly decreases viability of SUM159PT and HCC1806 xenografts. Furthermore, mechanistic analysis reveals that AR activation upregulates secretion of the EGFR ligand amphiregulin (AREG), an effect abrogated by enzalutamide in vitro and in vivo. Exogenous AREG partially rescues the effects of AR knockdown on proliferation, migration, and invasion, demonstrating that upregulation of AREG is one mechanism by which AR influences tumorigenicity. Together, our findings indicate that non-LAR subtypes of TNBC are AR dependent and, moreover, that enzalutamide is a promising targeted therapy for multiple molecular subtypes of AR(+) TNBC. PMID- 25713334 TI - Urinary biomarkers of catechins and risk of hepatocellular carcinoma in the Shanghai Cohort Study. AB - Dietary catechins are phytochemicals with both antioxidative and prooxidative stress properties. Green tea is a major source of catechins and may be associated with hepatocellular carcinoma (HCC) risk, but the catechin-HCC relationship has not been evaluated using a biomarker-based approach. A nested case-control study of HCC (211 cases and 1,067 matched controls) was conducted within the Shanghai Cohort Study, which enrolled 18,244 men between 1986 and 1989. Concentrations of specific catechins, including epicatechin, epigallocatechin (EGC), and 4'-O methyl-epigallocatechin, were measured in urine specimens that had been collected prior to HCC diagnosis. None of the catechins measured were associated with HCC risk. In stratified analyses, there was a statistically significant trend for an association of higher urinary EGC with increased HCC risk among subjects with positive serology for hepatitis B surface antigen (P for trend = 0.02). This positive EGC-HCC association became stronger for hepatitis B surface antigen positive persons who also had low serum retinol levels (for detectable levels vs. undetectable levels, odds ratio = 2.62, 95% confidence interval: 1.25, 5.51). There was no evidence supporting a protective role of catechins in the development of HCC. Instead, exposure to high levels of catechins may increase the risk of developing HCC for high-risk individuals. PMID- 25713335 TI - Mendelian randomization studies for a continuous exposure under case-control sampling. AB - In this article, we assess the impact of case-control sampling on mendelian randomization analyses with a dichotomous disease outcome and a continuous exposure. The 2-stage instrumental variables (2SIV) method uses the prediction of the exposure given genotypes in the logistic regression for the outcome and provides a valid test and an approximation of the causal effect. Under case control sampling, however, the first stage of the 2SIV procedure becomes a secondary trait association, which requires proper adjustment for the biased sampling. Through theoretical development and simulations, we compare the naive estimator, the inverse probability weighted estimator, and the maximum likelihood estimator for the first-stage association and, more importantly, the resulting 2SIV estimates of the causal effect. We also include in our comparison the causal odds ratio estimate derived from structural mean models by double-logistic regression. Our results suggest that the naive estimator is substantially biased under the alternative, yet it remains unbiased under the null hypothesis of no causal effect; the maximum likelihood estimator yields smaller variance and mean squared error than other estimators; and the structural mean models estimator delivers the smallest bias, though generally incurring a larger variance and sometimes having issues in algorithm stability and convergence. PMID- 25713336 TI - Associations of non-Hodgkin Lymphoma (NHL) risk with autoimmune conditions according to putative NHL loci. AB - Autoimmune conditions and immune system-related genetic variations are associated with risk of non-Hodgkin lymphoma (NHL). In a pooled analysis of 8,692 NHL cases and 9,260 controls from 14 studies (1988-2007) within the International Lymphoma Epidemiology Consortium, we evaluated the interaction between immune system genetic variants and autoimmune conditions in NHL risk. We evaluated the immunity related single nucleotide polymorphisms rs1800629 (tumor necrosis factor gene (TNF) G308A), rs1800890 (interleukin-10 gene (IL10) T3575A), rs6457327 (human leukocyte antigen gene (HLA) class I), rs10484561 (HLA class II), and rs2647012 (HLA class II)) and categorized autoimmune conditions as primarily mediated by B cell or T-cell responses. We constructed unconditional logistic regression models to measure associations between autoimmune conditions and NHL with stratification by genotype. Autoimmune conditions mediated by B-cell responses were associated with increased NHL risk, specifically diffuse large B-cell lymphoma (odds ratio (OR) = 3.11, 95% confidence interval (CI): 2.25, 4.30) and marginal zone lymphoma (OR = 5.80, 95% CI: 3.82, 8.80); those mediated by T-cell responses were associated with peripheral T-cell lymphoma (OR = 2.14, 95% CI: 1.35, 3.38). In the presence of the rs1800629 AG/AA genotype, B-cell-mediated autoimmune conditions increased NHL risk (OR = 3.27, 95% CI: 2.07, 5.16; P-interaction = 0.03) in comparison with the GG genotype (OR = 1.82, 95% CI: 1.31, 2.53). This interaction was consistent across major B-cell NHL subtypes, including marginal zone lymphoma (P-interaction = 0.02) and follicular lymphoma (P-interaction = 0.04). PMID- 25713338 TI - Priming of wheat with the green leaf volatile Z-3-hexenyl acetate enhances defense against Fusarium graminearum but boosts deoxynivalenol production. AB - Priming refers to a mechanism whereby plants are sensitized to respond faster and/or more strongly to future pathogen attack. Here, we demonstrate that preexposure to the green leaf volatile Z-3-hexenyl acetate (Z-3-HAC) primed wheat (Triticum aestivum) for enhanced defense against subsequent infection with the hemibiotrophic fungus Fusarium graminearum. Bioassays showed that, after priming with Z-3-HAC, wheat ears accumulated up to 40% fewer necrotic spikelets. Furthermore, leaves of seedlings showed significantly smaller necrotic lesions compared with nonprimed plants, coinciding with strongly reduced fungal growth in planta. Additionally, we found that F. graminearum produced more deoxynivalenol, a mycotoxin, in the primed treatment. Expression analysis of salicylic acid (SA) and jasmonic acid (JA) biosynthesis genes and exogenous methyl salicylate and methyl jasmonate applications showed that plant defense against F. graminearum is sequentially regulated by SA and JA during the early and later stages of infection, respectively. Interestingly, analysis of the effect of Z-3-HAC pretreatment on SA- and JA-responsive gene expression in hormone-treated and pathogen-inoculated seedlings revealed that Z-3-HAC boosts JA-dependent defenses during the necrotrophic infection stage of F. graminearum but suppresses SA regulated defense during its biotrophic phase. Together, these findings highlight the importance of temporally separated hormone changes in molding plant health and disease and support a scenario whereby the green leaf volatile Z-3-HAC protects wheat against Fusarium head blight by priming for enhanced JA-dependent defenses during the necrotrophic stages of infection. PMID- 25713337 TI - UDP-glucosyltransferase71c5, a major glucosyltransferase, mediates abscisic acid homeostasis in Arabidopsis. AB - Abscisic acid (ABA) plays a key role in plant growth and development. The effect of ABA in plants mainly depends on its concentration, which is determined by a balance between biosynthesis and catabolism of ABA. In this study, we characterize a unique UDP-glucosyltransferase (UGT), UGT71C5, which plays an important role in ABA homeostasis by glucosylating ABA to abscisic acid -: glucose ester (GE) in Arabidopsis (Arabidopsis thaliana). Biochemical analyses show that UGT71C5 glucosylates ABA in vitro and in vivo. Mutation of UGT71C5 and down-expression of UGT71C5 in Arabidopsis cause delay in seed germination and enhanced drought tolerance. In contrast, overexpression of UGT71C5 accelerates seed germination and reduces drought tolerance. Determination of the content of ABA and ABA-GE in Arabidopsis revealed that mutation in UGT71C5 and down expression of UGT71C5 resulted in increased level of ABA and reduced level of ABA GE, whereas overexpression of UGT71C5 resulted in reduced level of ABA and increased level of ABA-GE. Furthermore, altered levels of ABA in plants lead to changes in transcript abundance of ABA-responsive genes, correlating with the concentration of ABA regulated by UGT71C5 in Arabidopsis. Our work shows that UGT71C5 plays a major role in ABA glucosylation for ABA homeostasis. PMID- 25713339 TI - A critical update on endothelial nitric oxide synthase gene variations in women with idiopathic recurrent spontaneous abortion: genetic association study, systematic review and meta-analyses. AB - A number of case-control studies investigated the association between idiopathic recurrent spontaneous abortion (IRSA) and variations in the gene encoding endothelial nitric oxide synthase (NOS3), but yielded contradictory results. Our aim was to test the association of the NOS3 variable number of tandem repeats (VNTR) in intron 4 and +894 G/T single-nucleotide polymorphism (SNP) with IRSA in Slovenian women (148 IRSA and 149 control women), conduct a systematic review of literature on the association between NOS3 gene variations and IRSA, and perform meta-analyses of studies that met the inclusion criteria, defined by virtue of the European Society for Human Reproduction and Embryology evidence-based guidelines for recurrent spontaneous abortion. Genotyping was performed using PCR and restriction fragment length polymorphism methods. The systematic review of literature (English language) was conducted using PubMed and Scopus databases, to 1 November 2014. We determined no association of IRSA with the VNTR in intron 4 and +894 G/T SNP in Slovenian women. Furthermore, 16 case-control studies were identified on the association between 15 NOS3 gene variations and IRSA. However, significant inconsistencies exist in the selection criteria of patients and controls between studies. The meta-analysis of VNTR in intron 4 was performed on five studies (894 patients, 944 controls), whereas the meta-analysis of +894 G/T SNP included six studies (1111 patients, 1121 controls). The association with IRSA was significant for the +894 G/T SNP under the dominant genetic model (GT+TT versus GG) based on fixed (odds ratio (OR) = 1.54, 95% confidence interval (CI) = 1.28-1.86, P = <0.01) and random effects models (OR = 1.54, 95% CI = 1.03-2.31, P = 0.03). In conclusion, the GT and TT genotypes of the +894 G/T SNP in women might contribute to a predisposition to IRSA. Additional genetic association and functional studies in different populations with larger numbers of participants and a uniformly defined IRSA are needed to clarify the contribution of NOS3 +894 G/T gene variation to IRSA. PMID- 25713340 TI - Photoprotection conferred by changes in photosynthetic protein levels and organization during dehydration of a homoiochlorophyllous resurrection plant. AB - During desiccation, homoiochlorophyllous resurrection plants retain most of their photosynthetic apparatus, allowing them to resume photosynthetic activity quickly upon water availability. These plants rely on various mechanisms to prevent the formation of reactive oxygen species and/or protect their tissues from the damage they inflict. In this work, we addressed the issue of how homoiochlorophyllous resurrection plants deal with the problem of excessive excitation/electron pressures during dehydration using Craterostigma pumilum as a model plant. To investigate the alterations in the supramolecular organization of photosynthetic protein complexes, we examined cryoimmobilized, freeze-fractured leaf tissues using (cryo)scanning electron microscopy. These examinations revealed rearrangements of photosystem II (PSII) complexes, including a lowered density during moderate dehydration, consistent with a lower level of PSII proteins, as shown by biochemical analyses. The latter also showed a considerable decrease in the level of cytochrome f early during dehydration, suggesting that initial regulation of the inhibition of electron transport is achieved via the cytochrome b6f complex. Upon further dehydration, PSII complexes are observed to arrange into rows and semicrystalline arrays, which correlates with the significant accumulation of sucrose and the appearance of inverted hexagonal lipid phases within the membranes. As opposed to PSII and cytochrome f, the light-harvesting antenna complexes of PSII remain stable throughout the course of dehydration. Altogether, these results, along with photosynthetic activity measurements, suggest that the protection of retained photosynthetic components is achieved, at least in part, via the structural rearrangements of PSII and (likely) light harvesting antenna complexes into a photochemically quenched state. PMID- 25713341 TI - A calcium sensor-regulated protein kinase, CALCINEURIN B-LIKE PROTEIN-INTERACTING PROTEIN KINASE19, is required for pollen tube growth and polarity. AB - Calcium plays an essential role in pollen tube tip growth. However, little is known concerning the molecular basis of the signaling pathways involved. Here, we identified Arabidopsis (Arabidopsis thaliana) CALCINEURIN B-LIKE PROTEIN INTERACTING PROTEIN KINASE19 (CIPK19) as an important element to pollen tube growth through a functional survey for CIPK family members. The CIPK19 gene was specifically expressed in pollen grains and pollen tubes, and its overexpression induced severe loss of polarity in pollen tube growth. In the CIPK19 loss-of function mutant, tube growth and polarity were significantly impaired, as demonstrated by both in vitro and in vivo pollen tube growth assays. Genetic analysis indicated that disruption of CIPK19 resulted in a male-specific transmission defect. Furthermore, loss of polarity induced by CIPK19 overexpression was associated with elevated cytosolic Ca2+ throughout the bulging tip, whereas LaCl3, a Ca2+ influx blocker, rescued CIPK19 overexpression-induced growth inhibition. Our results suggest that CIPK19 may be involved in maintaining Ca2+ homeostasis through its potential function in the modulation of Ca2+ influx. PMID- 25713342 TI - On convex relaxation of graph isomorphism. AB - We consider the problem of exact and inexact matching of weighted undirected graphs, in which a bijective correspondence is sought to minimize a quadratic weight disagreement. This computationally challenging problem is often relaxed as a convex quadratic program, in which the space of permutations is replaced by the space of doubly stochastic matrices. However, the applicability of such a relaxation is poorly understood. We define a broad class of friendly graphs characterized by an easily verifiable spectral property. We prove that for friendly graphs, the convex relaxation is guaranteed to find the exact isomorphism or certify its inexistence. This result is further extended to approximately isomorphic graphs, for which we develop an explicit bound on the amount of weight disagreement under which the relaxation is guaranteed to find the globally optimal approximate isomorphism. We also show that in many cases, the graph matching problem can be further harmlessly relaxed to a convex quadratic program with only n separable linear equality constraints, which is substantially more efficient than the standard relaxation involving n2 equality and n2 inequality constraints. Finally, we show that our results are still valid for unfriendly graphs if additional information in the form of seeds or attributes is allowed, with the latter satisfying an easy to verify spectral characteristic. PMID- 25713343 TI - Precarious development: the uncertain social life of cellular slime molds. PMID- 25713344 TI - Robust Hadley Circulation changes and increasing global dryness due to CO2 warming from CMIP5 model projections. AB - In this paper, we investigate changes in the Hadley Circulation (HC) and their connections to increased global dryness (suppressed rainfall and reduced tropospheric relative humidity) under CO2 warming from Coupled Model Intercomparison Project Phase 5 (CMIP5) model projections. We find a strengthening of the HC manifested in a "deep-tropics squeeze" (DTS), i.e., a deepening and narrowing of the convective zone, enhanced ascent, increased high clouds, suppressed low clouds, and a rise of the level of maximum meridional mass outflow in the upper troposphere (200-100 hPa) of the deep tropics. The DTS induces atmospheric moisture divergence and reduces tropospheric relative humidity in the tropics and subtropics, in conjunction with a widening of the subsiding branches of the HC, resulting in increased frequency of dry events in preferred geographic locations worldwide. Among various water-cycle parameters examined, global dryness is found to have the highest signal-to-noise ratio. Our results provide a physical basis for inferring that greenhouse warming is likely to contribute to the observed prolonged droughts worldwide in recent decades. PMID- 25713345 TI - Conformation and dynamics of the Gag polyprotein of the human immunodeficiency virus 1 studied by NMR spectroscopy. AB - Assembly and maturation of the human immunodeficiency virus type 1 (HIV-1) are governed by the Gag polyprotein. Here we study the conformation and dynamics of a large HIV-1 Gag fragment comprising the matrix, capsid, spacer peptide 1 and nucleocapsid domains (referred to as DeltaGag) by heteronuclear multidimensional NMR spectroscopy. In solution, DeltaGag exists in a dynamic equilibrium between monomeric and dimeric states. In the presence of nucleic acids and at low ionic strength DeltaGag assembles into immature virus-like particles. The structured domains of DeltaGag (matrix, the N- and C-terminal domains of capsid, and the N- and C-terminal zinc knuckles of nucleocapsid) retain their fold and reorient semi independently of one another; the linkers connecting the structural domains, including spacer peptide 1 that connects capsid to nucleocapsid, are intrinsically disordered. Structural changes in DeltaGag upon proteolytic processing by HIV-1 protease, monitored by NMR in real-time, demonstrate that the conformational transition of the N-terminal 13 residues of capsid from an intrinsically disordered coil to a beta-hairpin upon cleavage at the matrix|capsid junction occurs five times faster than cleavage at the capsid|spacer peptide 1 junction. Finally, nucleic acids interact with both nucleocapsid and matrix domains, and proteolytic processing at the spacer peptide 1|nucleocapsid junction by HIV-1 protease is accelerated in the presence of single-stranded DNA. PMID- 25713347 TI - Variability of stalagmite-inferred Indian monsoon precipitation over the past 252,000 y. AB - A speleothem delta(18)O record from Xiaobailong cave in southwest China characterizes changes in summer monsoon precipitation in Northeastern India, the Himalayan foothills, Bangladesh, and northern Indochina over the last 252 kyr. This record is dominated by 23-kyr precessional cycles punctuated by prominent millennial-scale oscillations that are synchronous with Heinrich events in the North Atlantic. It also shows clear glacial-interglacial variations that are consistent with marine and other terrestrial proxies but are different from the cave records in East China. Corroborated by isotope-enabled global circulation modeling, we hypothesize that this disparity reflects differing changes in atmospheric circulation and moisture trajectories associated with climate forcing as well as with associated topographic changes during glacial periods, in particular redistribution of air mass above the growing ice sheets and the exposure of the "land bridge" in the Maritime continents in the western equatorial Pacific. PMID- 25713346 TI - On the principle of ion selectivity in Na+/H+-coupled membrane proteins: experimental and theoretical studies of an ATP synthase rotor. AB - Numerous membrane transporters and enzymes couple their mechanisms to the permeation of Na(+) or H(+), thereby harnessing the energy stored in the form of transmembrane electrochemical potential gradients to sustain their activities. The molecular and environmental factors that control and modulate the ion specificity of most of these systems are, however, poorly understood. Here, we use isothermal titration calorimetry to determine the Na(+)/H(+) selectivity of the ion-driven membrane rotor of an F-type ATP synthase. Consistent with earlier theoretical predictions, we find that this rotor is significantly H(+) selective, although not sufficiently to be functionally coupled to H(+), owing to the large excess of Na(+) in physiological settings. The functional Na(+) specificity of this ATP synthase thus results from two opposing factors, namely its inherent chemical selectivity and the relative availability of the coupling ion. Further theoretical studies of this membrane rotor, and of two others with a much stronger and a slightly weaker H(+) selectivity, indicate that, although the inherent selectivity of their ion-binding sites is largely set by the balance of polar and hydrophobic groups flanking a conserved carboxylic side chain, subtle variations in their structure and conformational dynamics, for a similar chemical makeup, can also have a significant contribution. We propose that the principle of ion selectivity outlined here may provide a rationale for the differentiation of Na(+)- and H(+)-coupled systems in other families of membrane transporters and enzymes. PMID- 25713348 TI - Model-guided quantitative analysis of microRNA-mediated regulation on competing endogenous RNAs using a synthetic gene circuit. AB - Competing endogenous RNAs (ceRNAs) cross-regulate each other at the posttranscriptional level by titrating shared microRNAs (miRNAs). Here, we established a computational model to quantitatively describe a minimum ceRNA network and experimentally validated our model predictions in cultured human cells by using synthetic gene circuits. We demonstrated that the range and strength of ceRNA regulation are largely determined by the relative abundance and the binding strength of miRNA and ceRNAs. We found that a nonreciprocal competing effect between partially and perfectly complementary targets is mainly due to different miRNA loss rates in these two types of regulations. Furthermore, we showed that miRNA-like off targets with high expression levels and strong binding sites significantly diminish the RNA interference efficiency, but the effect caused by high expression levels could be compensated by introducing more small interference RNAs (siRNAs). Thus, our results provided a quantitative understanding of ceRNA cross-regulation via shared miRNA and implied an siRNA design strategy to reduce the siRNA off-target effect in mammalian cells. PMID- 25713350 TI - Kelvin-Helmholtz instability in an ultrathin air film causes drop splashing on smooth surfaces. AB - When a fast-moving drop impacts onto a smooth substrate, splashing will be produced at the edge of the expanding liquid sheet. This ubiquitous phenomenon lacks a fundamental understanding. Combining experiment with model, we illustrate that the ultrathin air film trapped under the expanding liquid front triggers splashing. Because this film is thinner than the mean free path of air molecules, the interior airflow transfers momentum with an unusually high velocity comparable to the speed of sound and generates a stress 10 times stronger than the airflow in common situations. Such a large stress initiates Kelvin-Helmholtz instabilities at small length scales and effectively produces splashing. Our model agrees quantitatively with experimental verifications and brings a fundamental understanding to the ubiquitous phenomenon of drop splashing on smooth surfaces. PMID- 25713349 TI - Network compensation of cyclic GMP-dependent protein kinase II knockout in the hippocampus by Ca2+-permeable AMPA receptors. AB - Gene knockout (KO) does not always result in phenotypic changes, possibly due to mechanisms of functional compensation. We have studied mice lacking cGMP dependent kinase II (cGKII), which phosphorylates GluA1, a subunit of AMPA receptors (AMPARs), and promotes hippocampal long-term potentiation (LTP) through AMPAR trafficking. Acute cGKII inhibition significantly reduces LTP, whereas cGKII KO mice show no LTP impairment. Significantly, the closely related kinase, cGKI, does not compensate for cGKII KO. Here, we describe a previously unidentified pathway in the KO hippocampus that provides functional compensation for the LTP impairment observed when cGKII is acutely inhibited. We found that in cultured cGKII KO hippocampal neurons, cGKII-dependent phosphorylation of inositol 1,4,5-trisphosphate receptors was decreased, reducing cytoplasmic Ca(2+) signals. This led to a reduction of calcineurin activity, thereby stabilizing GluA1 phosphorylation and promoting synaptic expression of Ca(2+)-permeable AMPARs, which in turn induced a previously unidentified form of LTP as a compensatory response in the KO hippocampus. Calcineurin-dependent Ca(2+) permeable AMPAR expression observed here is also used during activity-dependent homeostatic synaptic plasticity. Thus, a homeostatic mechanism used during activity reduction provides functional compensation for gene KO in the cGKII KO hippocampus. PMID- 25713351 TI - Phosphorus sequestration in the form of polyphosphate by microbial symbionts in marine sponges. AB - Marine sponges are major habitat-forming organisms in coastal benthic communities and have an ancient origin in evolution history. Here, we report significant accumulation of polyphosphate (polyP) granules in three common sponge species of the Caribbean coral reef. The identity of the polyP granules was confirmed by energy-dispersive spectroscopy (EDS) and by the fluorescence properties of the granules. Microscopy images revealed that a large proportion of microbial cells associated with sponge hosts contained intracellular polyP granules. Cyanobacterial symbionts cultured from sponges were shown to accumulate polyP. We also amplified polyphosphate kinase (ppk) genes from sponge DNA and confirmed that the gene was expressed. Based on these findings, we propose here a potentially important phosphorus (P) sequestration pathway through symbiotic microorganisms of marine sponges. Considering the widespread sponge population and abundant microbial cells associated with them, this pathway is likely to have a significant impact on the P cycle in benthic ecosystems. PMID- 25713352 TI - Profile of Stephen T. Warren. PMID- 25713353 TI - An underlying mechanism for the increased mutagenesis of lagging-strand genes in Bacillus subtilis. AB - We previously reported that lagging-strand genes accumulate mutations faster than those encoded on the leading strand in Bacillus subtilis. Although we proposed that orientation-specific encounters between replication and transcription underlie this phenomenon, the mechanism leading to the increased mutagenesis of lagging-strand genes remained unknown. Here, we report that the transcription dependent and orientation-specific differences in mutation rates of genes require the B. subtilis Y-family polymerase, PolY1 (yqjH). We find that without PolY1, association of the replicative helicase, DnaC, and the recombination protein, RecA, with lagging-strand genes increases in a transcription-dependent manner. These data suggest that PolY1 promotes efficient replisome progression through lagging-strand genes, thereby reducing potentially detrimental breaks and single stranded DNA at these loci. Y-family polymerases can alleviate potential obstacles to replisome progression by facilitating DNA lesion bypass, extension of D-loops, or excision repair. We find that the nucleotide excision repair (NER) proteins UvrA, UvrB, and UvrC, but not RecA, are required for transcription dependent asymmetry in mutation rates of genes in the two orientations. Furthermore, we find that the transcription-coupling repair factor Mfd functions in the same pathway as PolY1 and is also required for increased mutagenesis of lagging-strand genes. Experimental and SNP analyses of B. subtilis genomes show mutational footprints consistent with these findings. We propose that the interplay between replication and transcription increases lesion susceptibility of, specifically, lagging-strand genes, activating an Mfd-dependent error-prone NER mechanism. We propose that this process, at least partially, underlies the accelerated evolution of lagging-strand genes. PMID- 25713354 TI - Initial viral load determines the magnitude of the human CD8 T cell response to yellow fever vaccination. AB - CD8 T cells are a potent tool for eliminating intracellular pathogens and tumor cells. Thus, eliciting robust CD8 T-cell immunity is the basis for many vaccines under development. However, the relationship between antigen load and the magnitude of the CD8 T-cell response is not well-described in a human immune response. Here we address this issue by quantifying viral load and the CD8 T-cell response in a cohort of 80 individuals immunized with the live attenuated yellow fever vaccine (YFV-17D) by sampling peripheral blood at days 0, 1, 2, 3, 5, 7, 9, 11, 14, 30, and 90. When the virus load was below a threshold (peak virus load < 225 genomes per mL, or integrated virus load < 400 genome days per mL), the magnitude of the CD8 T-cell response correlated strongly with the virus load (R(2) ~ 0.63). As the virus load increased above this threshold, the magnitude of the CD8 T-cell responses saturated. Recent advances in CD8 T-cell-based vaccines have focused on replication-incompetent or single-cycle vectors. However, these approaches deliver relatively limited amounts of antigen after immunization. Our results highlight the requirement that T-cell-based vaccines should deliver sufficient antigen during the initial period of the immune response to elicit a large number of CD8 T cells that may be needed for protection. PMID- 25713355 TI - Pharmacological recruitment of aldehyde dehydrogenase 3A1 (ALDH3A1) to assist ALDH2 in acetaldehyde and ethanol metabolism in vivo. AB - Correcting a genetic mutation that leads to a loss of function has been a challenge. One such mutation is in aldehyde dehydrogenase 2 (ALDH2), denoted ALDH2*2. This mutation is present in ~ 0.6 billion East Asians and results in accumulation of toxic acetaldehyde after consumption of ethanol. To temporarily increase metabolism of acetaldehyde in vivo, we describe an approach in which a pharmacologic agent recruited another ALDH to metabolize acetaldehyde. We focused on ALDH3A1, which is enriched in the upper aerodigestive track, and identified Alda-89 as a small molecule that enables ALDH3A1 to metabolize acetaldehyde. When given together with the ALDH2-specific activator, Alda-1, Alda-89 reduced acetaldehyde-induced behavioral impairment by causing a rapid reduction in blood ethanol and acetaldehyde levels after acute ethanol intoxication in both wild type and ALDH2-deficient, ALDH2*1/*2, heterozygotic knock-in mice. The use of a pharmacologic agent to recruit an enzyme to metabolize a substrate that it usually does not metabolize may represent a novel means to temporarily increase elimination of toxic agents in vivo. PMID- 25713356 TI - Whole-genome RNAi screen highlights components of the endoplasmic reticulum/Golgi as a source of resistance to immunotoxin-mediated cytotoxicity. AB - Immunotoxins (antibody-toxin fusion proteins) target surface antigens on cancer cells and kill these cells via toxin-mediated inhibition of protein synthesis. To identify genes controlling this process, an RNAi whole-genome screen (~ 22,000 genes at three siRNAs per gene) was conducted via monitoring the cytotoxicity of the mesothelin-directed immunotoxin SS1P. SS1P, a Pseudomonas exotoxin-based immunotoxin, was chosen because it is now in clinical trials and has produced objective tumor regressions in patients. High and low concentrations of SS1P were chosen to allow for the identification of both mitigators and sensitizers. As expected, silencing known essential genes in the immunotoxin pathway, such as mesothelin, furin, KDEL receptor 2, or members of the diphthamide pathway, protected cells. Of greater interest was the observation that many RNAi targets increased immunotoxin sensitivity, indicating that these gene products normally contribute to inefficiencies in the killing pathway. Of the top sensitizers, many genes encode proteins that locate to either the endoplasmic reticulum (ER) or Golgi and are annotated as part of the secretory system. Genes related to the ER associated degradation system were not among high-ranking mitigator or sensitizer candidates. However, the p97 inhibitor eeyarestatin 1 enhanced immunotoxin killing. Our results highlight potential targets for chemical intervention that could increase immunotoxin killing of cancer cells and enhance our understanding of toxin trafficking. PMID- 25713357 TI - SWI/SNF chromatin remodeling regulates alcohol response behaviors in Caenorhabditis elegans and is associated with alcohol dependence in humans. AB - Alcohol abuse is a widespread and serious problem. Understanding the factors that influence the likelihood of abuse is important for the development of effective therapies. There are both genetic and environmental influences on the development of abuse, but it has been difficult to identify specific liability factors, in part because of both the complex genetic architecture of liability and the influences of environmental stimuli on the expression of that genetic liability. Epigenetic modification of gene expression can underlie both genetic and environmentally sensitive variation in expression, and epigenetic regulation has been implicated in the progression to addiction. Here, we identify a role for the switching defective/sucrose nonfermenting (SWI/SNF) chromatin-remodeling complex in regulating the behavioral response to alcohol in the nematode Caenorhabditis elegans. We found that SWI/SNF components are required in adults for the normal behavioral response to ethanol and that different SWI/SNF complexes regulate different aspects of the acute response to ethanol. We showed that the SWI/SNF subunits SWSN-9 and SWSN-7 are required in neurons and muscle for the development of acute functional tolerance to ethanol. Examination of the members of the SWI/SNF complex for association with a diagnosis of alcohol dependence in a human population identified allelic variation in a member of the SWI/SNF complex, suggesting that variation in the regulation of SWI/SNF targets may influence the propensity to develop abuse disorders. Together, these data strongly implicate the chromatin remodeling associated with SWI/SNF complex members in the behavioral responses to alcohol across phyla. PMID- 25713358 TI - Rapid selection against arbovirus-induced apoptosis during infection of a mosquito vector. AB - Millions of people are infected each year by arboviruses (arthropod-borne viruses) such as chikungunya, dengue, and West Nile viruses, yet for reasons that are largely unknown, only a relatively small number of mosquito species are able to transmit arboviruses. Understanding the complex factors that determine vector competence could facilitate strategies for controlling arbovirus infections. Apoptosis is a potential antiviral defense response that has been shown to be important in other virus-host systems. However, apoptosis is rarely seen in arbovirus-infected mosquito cells, raising questions about its importance as an antiviral defense in mosquitoes. We tested the effect of stimulating apoptosis during arbovirus infection by infecting Aedes aegypti mosquitoes with a Sindbis virus (SINV) clone called MRE/Rpr, in which the MRE-16 strain of SINV was engineered to express the proapoptotic gene reaper from Drosophila. MRE/Rpr exhibited an impaired infection phenotype that included delayed midgut infection, delayed virus replication, and reduced virus accumulation in saliva. Nucleotide sequencing of the reaper insert in virus populations isolated from individual mosquitoes revealed evidence of rapid and strong selection against maintenance of Reaper expression in MRE/Rpr-infected mosquitoes. The impaired phenotype of MRE/Rpr, coupled with the observed negative selection against Reaper expression, indicates that apoptosis is a powerful defense against arbovirus infection in mosquitoes and suggests that arboviruses have evolved mechanisms to avoid stimulating apoptosis in mosquitoes that serve as vectors. PMID- 25713359 TI - Tunable assembly of amyloid-forming peptides into nanosheets as a retrovirus carrier. AB - Using and engineering amyloid as nanomaterials are blossoming trends in bionanotechnology. Here, we show our discovery of an amyloid structure, termed "amyloid-like nanosheet," formed by a key amyloid-forming segment of Alzheimer's Abeta. Combining multiple biophysical and computational approaches, we proposed a structural model for the nanosheet that is formed by stacking the amyloid fibril spines perpendicular to the fibril axis. We further used the nanosheet for laboratorial retroviral transduction enhancement and directly visualized the presence of virus on the nanosheet surface by electron microscopy. Furthermore, based on our structural model, we designed nanosheet-forming peptides with different functionalities, elucidating the potential of rational design for amyloid-based materials with novel architecture and function. PMID- 25713360 TI - Thiopeptide antibiotics stimulate biofilm formation in Bacillus subtilis. AB - Bacteria have evolved the ability to produce a wide range of structurally complex natural products historically called "secondary" metabolites. Although some of these compounds have been identified as bacterial communication cues, more frequently natural products are scrutinized for antibiotic activities that are relevant to human health. However, there has been little regard for how these compounds might otherwise impact the physiology of neighboring microbes present in complex communities. Bacillus cereus secretes molecules that activate expression of biofilm genes in Bacillus subtilis. Here, we use imaging mass spectrometry to identify the thiocillins, a group of thiazolyl peptide antibiotics, as biofilm matrix-inducing compounds produced by B. cereus. We found that thiocillin increased the population of matrix-producing B. subtilis cells and that this activity could be abolished by multiple structural alterations. Importantly, a mutation that eliminated thiocillin's antibiotic activity did not affect its ability to induce biofilm gene expression in B. subtilis. We go on to show that biofilm induction appears to be a general phenomenon of multiple structurally diverse thiazolyl peptides and use this activity to confirm the presence of thiazolyl peptide gene clusters in other bacterial species. Our results indicate that the roles of secondary metabolites initially identified as antibiotics may have more complex effects--acting not only as killing agents, but also as specific modulators of microbial cellular phenotypes. PMID- 25713361 TI - CD47 regulates the phagocytic clearance and replication of the Plasmodium yoelii malaria parasite. AB - Several Plasmodium species exhibit a strong age-based preference for the red blood cells (RBC) they infect, which in turn is a major determinant of disease severity and pathogenesis. The molecular basis underlying this age constraint on the use of RBC and its influence on parasite burden is poorly understood. CD47 is a marker of self on most cells, including RBC, which, in conjunction with signal regulatory protein alpha (expressed on macrophages), prevents the clearance of cells by the immune system. In this report, we have investigated the role of CD47 on the growth and survival of nonlethal Plasmodium yoelii 17XNL (PyNL) malaria in C57BL/6 mice. By using a quantitative biotin-labeling procedure and a GFP expressing parasite, we demonstrate that PyNL parasites preferentially infect high levels of CD47 (CD47(hi))-expressing young RBC. Importantly, C57BL/6 CD47(-/ ) mice were highly resistant to PyNL infection and developed a 9.3-fold lower peak parasitemia than their wild-type (WT) counterparts. The enhanced resistance to malaria observed in CD47(-/-) mice was associated with a higher percentage of splenic F4/80(+) cells, and these cells had a higher percentage of phagocytized parasitized RBC than infected WT mice during the acute phase of infection, when parasitemia was rapidly rising. Furthermore, injection of CD47-neutralizing antibody caused a significant reduction in parasite burden in WT C57BL/6 mice. Together, these results strongly suggest that CD47(hi) young RBC may provide a shield to the malaria parasite from clearance by the phagocytic cells, which may be an immune escape mechanism used by Plasmodium parasites that preferentially infect young RBC. PMID- 25713362 TI - Cardiac ferroportin regulates cellular iron homeostasis and is important for cardiac function. AB - Iron is essential to the cell. Both iron deficiency and overload impinge negatively on cardiac health. Thus, effective iron homeostasis is important for cardiac function. Ferroportin (FPN), the only known mammalian iron-exporting protein, plays an essential role in iron homeostasis at the systemic level. It increases systemic iron availability by releasing iron from the cells of the duodenum, spleen, and liver, the sites of iron absorption, recycling, and storage respectively. However, FPN is also found in tissues with no known role in systemic iron handling, such as the heart, where its function remains unknown. To explore this function, we generated mice with a cardiomyocyte-specific deletion of Fpn. We show that these animals have severely impaired cardiac function, with a median survival of 22 wk, despite otherwise unaltered systemic iron status. We then compared their phenotype with that of ubiquitous hepcidin knockouts, a recognized model of the iron-loading disease hemochromatosis. The phenotype of the hepcidin knockouts was far milder, with normal survival up to 12 mo, despite far greater iron loading in the hearts. Histological examination demonstrated that, although cardiac iron accumulates within the cardiomyocytes of Fpn knockouts, it accumulates predominantly in other cell types in the hepcidin knockouts. We conclude, first, that cardiomyocyte FPN is essential for intracellular iron homeostasis and, second, that the site of deposition of iron within the heart determines the severity with which it affects cardiac function. Both findings have significant implications for the assessment and treatment of cardiac complications of iron dysregulation. PMID- 25713363 TI - Mutations in early follicular lymphoma progenitors are associated with suppressed antigen presentation. AB - Follicular lymphoma (FL) is incurable with conventional therapies and has a clinical course typified by multiple relapses after therapy. These tumors are genetically characterized by B-cell leukemia/lymphoma 2 (BCL2) translocation and mutation of genes involved in chromatin modification. By analyzing purified tumor cells, we identified additional novel recurrently mutated genes and confirmed mutations of one or more chromatin modifier genes within 96% of FL tumors and two or more in 76% of tumors. We defined the hierarchy of somatic mutations arising during tumor evolution by analyzing the phylogenetic relationship of somatic mutations across the coding genomes of 59 sequentially acquired biopsies from 22 patients. Among all somatically mutated genes, CREBBP mutations were most significantly enriched within the earliest inferable progenitor. These mutations were associated with a signature of decreased antigen presentation characterized by reduced transcript and protein abundance of MHC class II on tumor B cells, in line with the role of CREBBP in promoting class II transactivator (CIITA) dependent transcriptional activation of these genes. CREBBP mutant B cells stimulated less proliferation of T cells in vitro compared with wild-type B cells from the same tumor. Transcriptional signatures of tumor-infiltrating T cells were indicative of reduced proliferation, and this corresponded to decreased frequencies of tumor-infiltrating CD4 helper T cells and CD8 memory cytotoxic T cells. These observations therefore implicate CREBBP mutation as an early event in FL evolution that contributes to immune evasion via decreased antigen presentation. PMID- 25713364 TI - Tetramers reveal IL-17-secreting CD4+ T cells that are specific for U1-70 in lupus and mixed connective tissue disease. AB - Antigen-specific CD4(+) T cells are implicated in the autoimmune disease systemic lupus erythematosus (SLE), but little is known about the peptide antigens that they recognize and their precise function in disease. We generated a series of MHC class II tetramers of I-E(k)-containing peptides from the spliceosomal protein U1-70 that specifically stain distinct CD4(+) T-cell populations in MRL/lpr mice. The T-cell populations recognize an epitope differing only by the presence or absence of a single phosphate residue at position serine(140). The frequency of CD4(+) T cells specific for U1-70(131-150):I-E(k) (without phosphorylation) correlates with disease severity and anti-U1-70 autoantibody production. These T cells also express RORgammat and produce IL-17A. Furthermore, the U1-70-specific CD4(+) T cells that produce IL-17A are detected in a subset of patients with SLE and are significantly increased in patients with mixed connective tissue disease. These studies provide tools for studying antigen specific CD4(+) T cells in lupus, and demonstrate an antigen-specific source of IL-17A in autoimmune disease. PMID- 25713365 TI - Extraordinary diversity of visual opsin genes in dragonflies. AB - Dragonflies are colorful and large-eyed animals strongly dependent on color vision. Here we report an extraordinary large number of opsin genes in dragonflies and their characteristic spatiotemporal expression patterns. Exhaustive transcriptomic and genomic surveys of three dragonflies of the family Libellulidae consistently identified 20 opsin genes, consisting of 4 nonvisual opsin genes and 16 visual opsin genes of 1 UV, 5 short-wavelength (SW), and 10 long-wavelength (LW) type. Comprehensive transcriptomic survey of the other dragonflies representing an additional 10 families also identified as many as 15 33 opsin genes. Molecular phylogenetic analysis revealed dynamic multiplications and losses of the opsin genes in the course of evolution. In contrast to many SW and LW genes expressed in adults, only one SW gene and several LW genes were expressed in larvae, reflecting less visual dependence and LW-skewed light conditions for their lifestyle under water. In this context, notably, the sand burrowing or pit-dwelling species tended to lack SW gene expression in larvae. In adult visual organs: (i) many SW genes and a few LW genes were expressed in the dorsal region of compound eyes, presumably for processing SW-skewed light from the sky; (ii) a few SW genes and many LW genes were expressed in the ventral region of compound eyes, probably for perceiving terrestrial objects; and (iii) expression of a specific LW gene was associated with ocelli. Our findings suggest that the stage- and region-specific expressions of the diverse opsin genes underlie the behavior, ecology, and adaptation of dragonflies. PMID- 25713366 TI - Cross-language differences in the brain network subserving intelligible speech. AB - How is language processed in the brain by native speakers of different languages? Is there one brain system for all languages or are different languages subserved by different brain systems? The first view emphasizes commonality, whereas the second emphasizes specificity. We investigated the cortical dynamics involved in processing two very diverse languages: a tonal language (Chinese) and a nontonal language (English). We used functional MRI and dynamic causal modeling analysis to compute and compare brain network models exhaustively with all possible connections among nodes of language regions in temporal and frontal cortex and found that the information flow from the posterior to anterior portions of the temporal cortex was commonly shared by Chinese and English speakers during speech comprehension, whereas the inferior frontal gyrus received neural signals from the left posterior portion of the temporal cortex in English speakers and from the bilateral anterior portion of the temporal cortex in Chinese speakers. Our results revealed that, although speech processing is largely carried out in the common left hemisphere classical language areas (Broca's and Wernicke's areas) and anterior temporal cortex, speech comprehension across different language groups depends on how these brain regions interact with each other. Moreover, the right anterior temporal cortex, which is crucial for tone processing, is equally important as its left homolog, the left anterior temporal cortex, in modulating the cortical dynamics in tone language comprehension. The current study pinpoints the importance of the bilateral anterior temporal cortex in language comprehension that is downplayed or even ignored by popular contemporary models of speech comprehension. PMID- 25713367 TI - Heritable symbiosis: The advantages and perils of an evolutionary rabbit hole. AB - Many eukaryotes have obligate associations with microorganisms that are transmitted directly between generations. A model for heritable symbiosis is the association of aphids, a clade of sap-feeding insects, and Buchnera aphidicola, a gammaproteobacterium that colonized an aphid ancestor 150 million years ago and persists in almost all 5,000 aphid species. Symbiont acquisition enables evolutionary and ecological expansion; aphids are one of many insect groups that would not exist without heritable symbiosis. Receiving less attention are potential negative ramifications of symbiotic alliances. In the short run, symbionts impose metabolic costs. Over evolutionary time, hosts evolve dependence beyond the original benefits of the symbiosis. Symbiotic partners enter into an evolutionary spiral that leads to irreversible codependence and associated risks. Host adaptations to symbiosis (e.g., immune-system modification) may impose vulnerabilities. Symbiont genomes also continuously accumulate deleterious mutations, limiting their beneficial contributions and environmental tolerance. Finally, the fitness interests of obligate heritable symbionts are distinct from those of their hosts, leading to selfish tendencies. Thus, genes underlying the host-symbiont interface are predicted to follow a coevolutionary arms race, as observed for genes governing host-pathogen interactions. On the macroevolutionary scale, the rapid evolution of interacting symbiont and host genes is predicted to accelerate host speciation rates by generating genetic incompatibilities. However, degeneration of symbiont genomes may ultimately limit the ecological range of host species, potentially increasing extinction risk. Recent results for the aphid-Buchnera symbiosis and related systems illustrate that, whereas heritable symbiosis can expand ecological range and spur diversification, it also presents potential perils. PMID- 25713368 TI - L-cysteine reversibly inhibits glucose-induced biphasic insulin secretion and ATP production by inactivating PKM2. AB - Increase in the concentration of plasma L-cysteine is closely associated with defective insulin secretion from pancreatic beta-cells, which results in type 2 diabetes (T2D). In this study, we investigated the effects of prolonged L cysteine treatment on glucose-stimulated insulin secretion (GSIS) from mouse insulinoma 6 (MIN6) cells and from mouse pancreatic islets, and found that the treatment reversibly inhibited glucose-induced ATP production and resulting GSIS without affecting proinsulin and insulin synthesis. Comprehensive metabolic analyses using capillary electrophoresis time-of-flight mass spectrometry showed that prolonged L-cysteine treatment decreased the levels of pyruvate and its downstream metabolites. In addition, methyl pyruvate, a membrane-permeable form of pyruvate, rescued L-cysteine-induced inhibition of GSIS. Based on these results, we found that both in vitro and in MIN6 cells, L-cysteine specifically inhibited the activity of pyruvate kinase muscle isoform 2 (PKM2), an isoform of pyruvate kinases that catalyze the conversion of phosphoenolpyruvate to pyruvate. L-cysteine also induced PKM2 subunit dissociation (tetramers to dimers/monomers) in cells, which resulted in impaired glucose-induced ATP production for GSIS. DASA-10 (NCGC00181061, a substituted N,N'-diarylsulfonamide), a specific activator for PKM2, restored the tetramer formation and the activity of PKM2, glucose-induced ATP production, and biphasic insulin secretion in L-cysteine treated cells. Collectively, our results demonstrate that impaired insulin secretion due to exposure to L-cysteine resulted from its direct binding and inactivation of PKM2 and suggest that PKM2 is a potential therapeutic target for T2D. PMID- 25713369 TI - Dynamic evolutionary change in post-Paleozoic echinoids and the importance of scale when interpreting changes in rates of evolution. AB - How ecological and morphological diversity accrues over geological time has been much debated by paleobiologists. Evidence from the fossil record suggests that many clades reach maximal diversity early in their evolutionary history, followed by a decline in evolutionary rates as ecological space fills or due to internal constraints. Here, we apply recently developed methods for estimating rates of morphological evolution during the post-Paleozoic history of a major invertebrate clade, the Echinoidea. Contrary to expectation, rates of evolution were lowest during the initial phase of diversification following the Permo-Triassic mass extinction and increased over time. Furthermore, although several subclades show high initial rates and net decreases in rates of evolution, consistent with "early bursts" of morphological diversification, at more inclusive taxonomic levels, these bursts appear as episodic peaks. Peak rates coincided with major shifts in ecological morphology, primarily associated with innovations in feeding strategies. Despite having similar numbers of species in today's oceans, regular echinoids have accrued far less morphological diversity than irregular echinoids due to lower intrinsic rates of morphological evolution and less morphological innovation, the latter indicative of constrained or bounded evolution. These results indicate that rates of evolution are extremely heterogenous through time and their interpretation depends on the temporal and taxonomic scale of analysis. PMID- 25713371 TI - Quantitative relations between cooperative motion, emergent elasticity, and free volume in model glass-forming polymer materials. AB - The study of glass formation is largely framed by semiempirical models that emphasize the importance of progressively growing cooperative motion accompanying the drop in fluid configurational entropy, emergent elasticity, or the vanishing of accessible free volume available for molecular motion in cooled liquids. We investigate the extent to which these descriptions are related through computations on a model coarse-grained polymer melt, with and without nanoparticle additives, and for supported polymer films with smooth or rough surfaces, allowing for substantial variation of the glass transition temperature and the fragility of glass formation. We find quantitative relations between emergent elasticity, the average local volume accessible for particle motion, and the growth of collective motion in cooled liquids. Surprisingly, we find that each of these models of glass formation can equally well describe the relaxation data for all of the systems that we simulate. In this way, we uncover some unity in our understanding of glass-forming materials from perspectives formerly considered as distinct. PMID- 25713370 TI - Decorrelation of retinal response to natural scenes by fixational eye movements. AB - Under natural viewing conditions the input to the retina is a complex spatiotemporal signal that depends on both the scene and the way the observer moves. It is commonly assumed that the retina processes this input signal efficiently by taking into account the statistics of the natural world. It has recently been argued that incessant microscopic eye movements contribute to this process by decorrelating the input to the retina. Here we tested this theory by measuring the responses of the salamander retina to stimuli replicating the natural input signals experienced by the retina in the presence and absence of fixational eye movements. Contrary to the predictions of classic theories of efficient encoding that do not take behavior into account, we show that the response characteristics of retinal ganglion cells are not sufficient in themselves to disrupt the broad correlations of natural scenes. Specifically, retinal ganglion cells exhibited strong and extensive spatial correlations in the absence of fixational eye movements. However, the levels of correlation in the neural responses dropped in the presence of fixational eye movements, resulting in effective decorrelation of the channels streaming information to the brain. These observations confirm the predictions that microscopic eye movements act to reduce correlations in retinal responses and contribute to visual information processing. PMID- 25713372 TI - Rapid labeling of intracellular His-tagged proteins in living cells. AB - Small molecule-based fluorescent probes have been used for real-time visualization of live cells and tracking of various cellular events with minimal perturbation on the cells being investigated. Given the wide utility of the (histidine)6-Ni(2+)-nitrilotriacetate (Ni-NTA) system in protein purification, there is significant interest in fluorescent Ni(2+)-NTA-based probes. Unfortunately, previous Ni-NTA-based probes suffer from poor membrane permeability and cannot label intracellular proteins. Here, we report the design and synthesis of, to our knowledge, the first membrane-permeable fluorescent probe Ni-NTA-AC via conjugation of NTA with fluorophore and arylazide followed by coordination with Ni(2+) ions. The probe, driven by Ni(2+)-NTA, binds specifically to His-tags genetically fused to proteins and subsequently forms a covalent bond upon photoactivation of the arylazide, leading to a 13-fold fluorescence enhancement. The arylazide is indispensable not only for fluorescence enhancement, but also for strengthening the binding between the probe and proteins. Significantly, the Ni-NTA-AC probe can rapidly enter different types of cells, even plant tissues, to target His-tagged proteins. Using this probe, we visualized the subcellular localization of a DNA repair protein, Xeroderma pigmentosum group A (XPA122), which is known to be mainly enriched in the nucleus. We also demonstrated that the probe can image a genetically engineered His-tagged protein in plant tissues. This study thus offers a new opportunity for in situ visualization of large libraries of His tagged proteins in various prokaryotic and eukaryotic cells. PMID- 25713373 TI - Histone titration against the genome sets the DNA-to-cytoplasm threshold for the Xenopus midblastula transition. AB - During early development, animal embryos depend on maternally deposited RNA until zygotic genes become transcriptionally active. Before this maternal-to-zygotic transition, many species execute rapid and synchronous cell divisions without growth phases or cell cycle checkpoints. The coordinated onset of transcription, cell cycle lengthening, and cell cycle checkpoints comprise the midblastula transition (MBT). A long-standing model in the frog, Xenopus laevis, posits that MBT timing is controlled by a maternally loaded inhibitory factor that is titrated against the exponentially increasing amount of DNA. To identify MBT regulators, we developed an assay using Xenopus egg extract that recapitulates the activation of transcription only above the DNA-to-cytoplasm ratio found in embryos at the MBT. We used this system to biochemically purify factors responsible for inhibiting transcription below the threshold DNA-to-cytoplasm ratio. This unbiased approach identified histones H3 and H4 as concentration dependent inhibitory factors. Addition or depletion of H3/H4 from the extract quantitatively shifted the amount of DNA required for transcriptional activation in vitro. Moreover, reduction of H3 protein in embryos induced premature transcriptional activation and cell cycle lengthening, and the addition of H3/H4 shortened post-MBT cell cycles. Our observations support a model for MBT regulation by DNA-based titration and suggest that depletion of free histones regulates the MBT. More broadly, our work shows how a constant concentration DNA binding molecule can effectively measure the amount of cytoplasm per genome to coordinate division, growth, and development. PMID- 25713374 TI - Anticancer drug nanomicelles formed by self-assembling amphiphilic dendrimer to combat cancer drug resistance. AB - Drug resistance and toxicity constitute challenging hurdles for cancer therapy. The application of nanotechnology for anticancer drug delivery is expected to address these issues and bring new hope for cancer treatment. In this context, we established an original nanomicellar drug delivery system based on an amphiphilic dendrimer (AmDM), which could generate supramolecular micelles to effectively encapsulate the anticancer drug doxorubicin (DOX) with high drug-loading capacity (>40%), thanks to the unique dendritic structure creating large void space for drug accommodation. The resulting AmDM/DOX nanomicelles were able to enhance drug potency and combat doxorubicin resistance in breast cancer models by significantly enhancing cellular uptake while considerably decreasing efflux of the drug. In addition, the AmDM/DOX nanoparticles abolished significantly the toxicity related to the free drug. Collectively, our studies demonstrate that the drug delivery system based on nanomicelles formed with the self-assembling amphiphilic dendrimer constitutes a promising and effective drug carrier in cancer therapy. PMID- 25713375 TI - Distinct populations of neurons respond to emotional valence and arousal in the human subthalamic nucleus. AB - Both animal studies and studies using deep brain stimulation in humans have demonstrated the involvement of the subthalamic nucleus (STN) in motivational and emotional processes; however, participation of this nucleus in processing human emotion has not been investigated directly at the single-neuron level. We analyzed the relationship between the neuronal firing from intraoperative microrecordings from the STN during affective picture presentation in patients with Parkinson's disease (PD) and the affective ratings of emotional valence and arousal performed subsequently. We observed that 17% of neurons responded to emotional valence and arousal of visual stimuli according to individual ratings. The activity of some neurons was related to emotional valence, whereas different neurons responded to arousal. In addition, 14% of neurons responded to visual stimuli. Our results suggest the existence of neurons involved in processing or transmission of visual and emotional information in the human STN, and provide evidence of separate processing of the affective dimensions of valence and arousal at the level of single neurons as well. PMID- 25713376 TI - Selective molecular transport through the protein shell of a bacterial microcompartment organelle. AB - Bacterial microcompartments are widespread prokaryotic organelles that have important and diverse roles ranging from carbon fixation to enteric pathogenesis. Current models for microcompartment function propose that their outer protein shell is selectively permeable to small molecules, but whether a protein shell can mediate selective permeability and how this occurs are unresolved questions. Here, biochemical and physiological studies of structure-guided mutants are used to show that the hexameric PduA shell protein of the 1,2-propanediol utilization (Pdu) microcompartment forms a selectively permeable pore tailored for the influx of 1,2-propanediol (the substrate of the Pdu microcompartment) while restricting the efflux of propionaldehyde, a toxic intermediate of 1,2-propanediol catabolism. Crystal structures of various PduA mutants provide a foundation for interpreting the observed biochemical and phenotypic data in terms of molecular diffusion across the shell. Overall, these studies provide a basis for understanding a class of selectively permeable channels formed by nonmembrane proteins. PMID- 25713377 TI - Rational design of a split-Cas9 enzyme complex. AB - Cas9, an RNA-guided DNA endonuclease found in clustered regularly interspaced short palindromic repeats (CRISPR) bacterial immune systems, is a versatile tool for genome editing, transcriptional regulation, and cellular imaging applications. Structures of Streptococcus pyogenes Cas9 alone or bound to single guide RNA (sgRNA) and target DNA revealed a bilobed protein architecture that undergoes major conformational changes upon guide RNA and DNA binding. To investigate the molecular determinants and relevance of the interlobe rearrangement for target recognition and cleavage, we designed a split-Cas9 enzyme in which the nuclease lobe and alpha-helical lobe are expressed as separate polypeptides. Although the lobes do not interact on their own, the sgRNA recruits them into a ternary complex that recapitulates the activity of full length Cas9 and catalyzes site-specific DNA cleavage. The use of a modified sgRNA abrogates split-Cas9 activity by preventing dimerization, allowing for the development of an inducible dimerization system. We propose that split-Cas9 can act as a highly regulatable platform for genome-engineering applications. PMID- 25713378 TI - Spatiotemporally dynamic, cell-type-dependent premeiotic and meiotic phasiRNAs in maize anthers. AB - Maize anthers, the male reproductive floral organs, express two classes of phased small-interfering RNAs (phasiRNAs). PhasiRNA precursors are transcribed by RNA polymerase II and map to low-copy, intergenic regions similar to PIWI-interacting RNAs (piRNAs) in mammalian testis. From 10 sequential cohorts of staged maize anthers plus mature pollen we find that 21-nt phased siRNAs from 463 loci appear abruptly after germinal and initial somatic cell fate specification and then diminish, whereas 24-nt phasiRNAs from 176 loci coordinately accumulate during meiosis and persist as anther somatic cells mature and haploid gametophytes differentiate into pollen. Male-sterile ocl4 anthers defective in epidermal signaling lack 21-nt phasiRNAs. Male-sterile mutants with subepidermal defects- mac1 (excess meiocytes), ms23 (defective pretapetal cells), and msca1 (no normal soma or meiocytes)--lack 24-nt phasiRNAs. ameiotic1 mutants (normal soma, no meiosis) accumulate both 21-nt and 24-nt phasiRNAs, ruling out meiotic cells as a source or regulator of phasiRNA biogenesis. By in situ hybridization, miR2118 triggers of 21-nt phasiRNA biogenesis localize to epidermis; however, 21-PHAS precursors and 21-nt phasiRNAs are abundant subepidermally. The miR2275 trigger, 24-PHAS precursors, and 24-nt phasiRNAs all accumulate preferentially in tapetum and meiocytes. Therefore, each phasiRNA type exhibits independent spatiotemporal regulation with 21-nt premeiotic phasiRNAs dependent on epidermal and 24-nt meiotic phasiRNAs dependent on tapetal cell differentiation. Maize phasiRNAs and mammalian piRNAs illustrate putative convergent evolution of small RNAs in male reproduction. PMID- 25713379 TI - Predator diversity, intraguild predation, and indirect effects drive parasite transmission. AB - Humans are altering biodiversity globally and infectious diseases are on the rise; thus, there is interest in understanding how changes to biodiversity affect disease. Here, we explore how predator diversity shapes parasite transmission. In a mesocosm experiment that manipulated predator (larval dragonflies and damselflies) density and diversity, non-intraguild (non-IG) predators that only consume free-living cercariae (parasitic trematodes) reduced metacercarial infections in tadpoles, whereas intraguild (IG) predators that consume both parasites and tadpole hosts did not. This likely occurred because IG predators reduced tadpole densities and anticercarial behaviors, increasing per capita exposure rates of the surviving tadpoles (i.e., via density- and trait-mediated effects) despite the consumption of parasites. A mathematical model demonstrated that non-IG predators reduce macroparasite infections, but IG predation weakens this "dilution effect" and can even amplify parasite burdens. Consistent with the experiment and model, a wetland survey revealed that the diversity of IG predators was unrelated to metacercarial burdens in amphibians, but the diversity of non-IG predators was negatively correlated with infections. These results are strikingly similar to generalities that have emerged from the predator diversity pest biocontrol literature, suggesting that there may be general mechanisms for pest control and that biocontrol research might inform disease management and vice versa. In summary, we identified a general trait of predators--where they fall on an IG predation continuum--that predicts their ability to reduce infections and possibly pests in general. Consequently, managing assemblages of predators represents an underused tool for the management of human and wildlife diseases and pest populations. PMID- 25713380 TI - Analysis of 13 cell types reveals evidence for the expression of numerous novel primate- and tissue-specific microRNAs. AB - Two decades after the discovery of the first animal microRNA (miRNA), the number of miRNAs in animal genomes remains a vexing question. Here, we report findings from analyzing 1,323 short RNA sequencing samples (RNA-seq) from 13 different human tissue types. Using stringent thresholding criteria, we identified 3,707 statistically significant novel mature miRNAs at a false discovery rate of <= 0.05 arising from 3,494 novel precursors; 91.5% of these novel miRNAs were identified independently in 10 or more of the processed samples. Analysis of these novel miRNAs revealed tissue-specific dependencies and a commensurate low Jaccard similarity index in intertissue comparisons. Of these novel miRNAs, 1,657 (45%) were identified in 43 datasets that were generated by cross-linking followed by Argonaute immunoprecipitation and sequencing (Ago CLIP-seq) and represented 3 of the 13 tissues, indicating that these miRNAs are active in the RNA interference pathway. Moreover, experimental investigation through stem-loop PCR of a random collection of newly discovered miRNAs in 12 cell lines representing 5 tissues confirmed their presence and tissue dependence. Among the newly identified miRNAs are many novel miRNA clusters, new members of known miRNA clusters, previously unreported products from uncharacterized arms of miRNA precursors, and previously unrecognized paralogues of functionally important miRNA families (e.g., miR-15/107). Examination of the sequence conservation across vertebrate and invertebrate organisms showed 56.7% of the newly discovered miRNAs to be human-specific whereas the majority (94.4%) are primate lineage specific. Our findings suggest that the repertoire of human miRNAs is far more extensive than currently represented by public repositories and that there is a significant number of lineage- and/or tissue-specific miRNAs that are uncharacterized. PMID- 25713381 TI - Multicolor CRISPR labeling of chromosomal loci in human cells. AB - The intranuclear location of genomic loci and the dynamics of these loci are important parameters for understanding the spatial and temporal regulation of gene expression. Recently it has proven possible to visualize endogenous genomic loci in live cells by the use of transcription activator-like effectors (TALEs), as well as modified versions of the bacterial immunity clustered regularly interspersed short palindromic repeat (CRISPR)/CRISPR-associated protein 9 (Cas9) system. Here we report the design of multicolor versions of CRISPR using catalytically inactive Cas9 endonuclease (dCas9) from three bacterial orthologs. Each pair of dCas9-fluorescent proteins and cognate single-guide RNAs (sgRNAs) efficiently labeled several target loci in live human cells. Using pairs of differently colored dCas9-sgRNAs, it was possible to determine the intranuclear distance between loci on different chromosomes. In addition, the fluorescence spatial resolution between two loci on the same chromosome could be determined and related to the linear distance between them on the chromosome's physical map, thereby permitting assessment of the DNA compaction of such regions in a live cell. PMID- 25713382 TI - Mother's voice and heartbeat sounds elicit auditory plasticity in the human brain before full gestation. AB - Brain development is largely shaped by early sensory experience. However, it is currently unknown whether, how early, and to what extent the newborn's brain is shaped by exposure to maternal sounds when the brain is most sensitive to early life programming. The present study examined this question in 40 infants born extremely prematurely (between 25- and 32-wk gestation) in the first month of life. Newborns were randomized to receive auditory enrichment in the form of audio recordings of maternal sounds (including their mother's voice and heartbeat) or routine exposure to hospital environmental noise. The groups were otherwise medically and demographically comparable. Cranial ultrasonography measurements were obtained at 30 +/- 3 d of life. Results show that newborns exposed to maternal sounds had a significantly larger auditory cortex (AC) bilaterally compared with control newborns receiving standard care. The magnitude of the right and left AC thickness was significantly correlated with gestational age but not with the duration of sound exposure. Measurements of head circumference and the widths of the frontal horn (FH) and the corpus callosum (CC) were not significantly different between the two groups. This study provides evidence for experience-dependent plasticity in the primary AC before the brain has reached full-term maturation. Our results demonstrate that despite the immaturity of the auditory pathways, the AC is more adaptive to maternal sounds than environmental noise. Further studies are needed to better understand the neural processes underlying this early brain plasticity and its functional implications for future hearing and language development. PMID- 25713384 TI - Dual role of tree florigen activation complex component FD in photoperiodic growth control and adaptive response pathways. AB - A complex consisting of evolutionarily conserved FD, flowering locus T (FT) proteins is a regulator of floral transition. Intriguingly, FT orthologs are also implicated in developmental transitions distinct from flowering, such as photoperiodic control of bulbing in onions, potato tuberization, and growth cessation in trees. However, whether an FT-FD complex participates in these transitions and, if so, its mode of action, are unknown. We identified two closely related FD homologs, FD-like 1 (FDL1) and FD-like 2 (FDL2), in the model tree hybrid aspen. Using gain of function and RNAi-suppressed FDL1 and FDL2 transgenic plants, we show that FDL1 and FDL2 have distinct functions and a complex consisting of FT and FDL1 mediates in photoperiodic control of seasonal growth. The downstream target of the FT-FD complex in photoperiodic control of growth is Like AP1 (LAP1), a tree ortholog of the floral meristem identity gene APETALA1. Intriguingly, FDL1 also participates in the transcriptional control of adaptive response and bud maturation pathways, independent of its interaction with FT, presumably via interaction with abscisic acid insensitive 3 (ABI3) transcription factor, a component of abscisic acid (ABA) signaling. Our data reveal that in contrast to its primary role in flowering, FD has dual roles in the photoperiodic control of seasonal growth and stress tolerance in trees. Thus, the functions of FT and FD have diversified during evolution, and FD homologs have acquired roles that are independent of their interaction with FT. PMID- 25713385 TI - Century-scale trends and seasonality in pH and temperature for shallow zones of the Bering Sea. AB - No records exist to evaluate long-term pH dynamics in high-latitude oceans, which have the greatest probability of rapid acidification from anthropogenic CO2 emissions. We reconstructed both seasonal variability and anthropogenic change in seawater pH and temperature by using laser ablation high-resolution 2D images of stable boron isotopes (delta(11)B) on a long-lived coralline alga that grew continuously through the 20th century. Analyses focused on four multiannual growth segments. We show a long-term decline of 0.08 +/- 0.01 pH units between the end of the 19th and 20th century, which is consistent with atmospheric CO2 records. Additionally, a strong seasonal cycle (~ 0.22 pH units) is observed and interpreted as episodic annual pH increases caused by the consumption of CO2 during strong algal (kelp) growth in spring and summer. The rate of acidification intensifies from -0.006 +/- 0.007 pH units per decade (between 1920s and 1960s) to -0.019 +/- 0.009 pH units per decade (between 1960s and 1990s), and the episodic pH increases show a continuous shift to earlier times of the year throughout the centennial record. This is indicative of ecosystem shifts in shallow water algal productivity in this high-latitude habitat resulting from warming and acidification. PMID- 25713383 TI - Differential fates of biomolecules delivered to target cells via extracellular vesicles. AB - Extracellular vesicles (EVs), specifically exosomes and microvesicles (MVs), are presumed to play key roles in cell-cell communication via transfer of biomolecules between cells. The biogenesis of these two types of EVs differs as they originate from either the endosomal (exosomes) or plasma (MVs) membranes. To elucidate the primary means through which EVs mediate intercellular communication, we characterized their ability to encapsulate and deliver different types of macromolecules from transiently transfected cells. Both EV types encapsulated reporter proteins and mRNA but only MVs transferred the reporter function to recipient cells. De novo reporter protein expression in recipient cells resulted only from plasmid DNA (pDNA) after delivery via MVs. Reporter mRNA was delivered to recipient cells by both EV types, but was rapidly degraded without being translated. MVs also mediated delivery of functional pDNA encoding Cre recombinase in vivo to tissues in transgenic Cre-lox reporter mice. Within the parameters of this study, MVs delivered functional pDNA, but not RNA, whereas exosomes from the same source did not deliver functional nucleic acids. These results have significant implications for understanding the role of EVs in cellular communication and for development of EVs as delivery tools. Moreover, studies using EVs from transiently transfected cells may be confounded by a predominance of pDNA transfer. PMID- 25713386 TI - Large number of rebounding/founder HIV variants emerge from multifocal infection in lymphatic tissues after treatment interruption. AB - Antiretroviral therapy (ART) suppresses HIV replication in most individuals but cannot eradicate latently infected cells established before ART was initiated. Thus, infection rebounds when treatment is interrupted by reactivation of virus production from this reservoir. Currently, one or a few latently infected resting memory CD4 T cells are thought be the principal source of recrudescent infection, but this estimate is based on peripheral blood rather than lymphoid tissues (LTs), the principal sites of virus production and persistence before initiating ART. We, therefore, examined lymph node (LN) and gut-associated lymphoid tissue (GALT) biopsies from fully suppressed subjects, interrupted therapy, monitored plasma viral load (pVL), and repeated biopsies on 12 individuals as soon as pVL became detectable. Isolated HIV RNA-positive (vRNA+) cells were detected by in situ hybridization in LTs obtained before interruption in several patients. After interruption, multiple foci of vRNA+ cells were detected in 6 of 12 individuals as soon as pVL was measureable and in some subjects, in more than one anatomic site. Minimal estimates of the number of rebounding/founder (R/F) variants were determined by single-gene amplification and sequencing of viral RNA or DNA from peripheral blood mononuclear cells and plasma obtained at or just before viral recrudescence. Sequence analysis revealed a large number of R/F viruses representing recrudescent viremia from multiple sources. Together, these findings are consistent with the origins of recrudescent infection by reactivation from many latently infected cells at multiple sites. The inferred large pool of cells and sites to rekindle recrudescent infection highlights the challenges in eradicating HIV. PMID- 25713389 TI - Oxytocin prevents ethanol actions at delta subunit-containing GABAA receptors and attenuates ethanol-induced motor impairment in rats. AB - Even moderate doses of alcohol cause considerable impairment of motor coordination, an effect that substantially involves potentiation of GABAergic activity at delta subunit-containing GABA(A) receptors (delta-GABA(A)Rs). Here, we demonstrate that oxytocin selectively attenuates ethanol-induced motor impairment and ethanol-induced increases in GABAergic activity at delta-GABA(A)Rs and that this effect does not involve the oxytocin receptor. Specifically, oxytocin (1 ug i.c.v.) given before ethanol (1.5 g/kg i.p.) attenuated the sedation and ataxia induced by ethanol in the open-field locomotor test, wire hanging test, and righting-reflex test in male rats. Using two-electrode voltage clamp electrophysiology in Xenopus oocytes, oxytocin was found to completely block ethanol-enhanced activity at alpha4beta1delta and alpha4beta3delta recombinant GABA(A)Rs. Conversely, ethanol had no effect when applied to alpha4beta1 or alpha4beta3 cells, demonstrating the critical presence of the delta subunit in this effect. Oxytocin had no effect on the motor impairment or in vitro effects induced by the delta-selective GABA(A)R agonist 4,5,6,7 tetrahydroisoxazolo(5,4-c)pyridin-3-ol, which binds at a different site on delta GABA(A)Rs than ethanol. Vasopressin, which is a nonapeptide with substantial structural similarity to oxytocin, did not alter ethanol effects at delta GABA(A)Rs. This pattern of results confirms the specificity of the interaction between oxytocin and ethanol at delta-GABA(A)Rs. Finally, our in vitro constructs did not express any oxytocin receptors, meaning that the observed interactions occur directly at delta-GABA(A)Rs. The profound and direct interaction observed between oxytocin and ethanol at the behavioral and cellular level may have relevance for the development of novel therapeutics for alcohol intoxication and dependence. PMID- 25713387 TI - Hadal biosphere: insight into the microbial ecosystem in the deepest ocean on Earth. AB - Hadal oceans at water depths below 6,000 m are the least-explored aquatic biosphere. The Challenger Deep, located in the western equatorial Pacific, with a water depth of ~11 km, is the deepest ocean on Earth. Microbial communities associated with waters from the sea surface to the trench bottom (0~10,257 m) in the Challenger Deep were analyzed, and unprecedented trench microbial communities were identified in the hadal waters (6,000~10,257 m) that were distinct from the abyssal microbial communities. The potentially chemolithotrophic populations were less abundant in the hadal water than those in the upper abyssal waters. The emerging members of chemolithotrophic nitrifiers in the hadal water that likely adapt to the higher flux of electron donors were also different from those in the abyssal waters that adapt to the lower flux of electron donors. Species-level niche separation in most of the dominant taxa was also found between the hadal and abyssal microbial communities. Considering the geomorphology and the isolated hydrotopographical nature of the Mariana Trench, we hypothesized that the distinct hadal microbial ecosystem was driven by the endogenous recycling of organic matter in the hadal waters associated with the trench geomorphology. PMID- 25713388 TI - Detecting cancers through tumor-activatable minicircles that lead to a detectable blood biomarker. AB - Earlier detection of cancers can dramatically improve the efficacy of available treatment strategies. However, despite decades of effort on blood-based biomarker cancer detection, many promising endogenous biomarkers have failed clinically because of intractable problems such as highly variable background expression from nonmalignant tissues and tumor heterogeneity. In this work we present a tumor-detection strategy based on systemic administration of tumor-activatable minicircles that use the pan-tumor-specific Survivin promoter to drive expression of a secretable reporter that is detectable in the blood nearly exclusively in tumor-bearing subjects. After systemic administration we demonstrate a robust ability to differentiate mice bearing human melanoma metastases from tumor-free subjects for up to 2 wk simply by measuring blood reporter levels. Cumulative change in reporter levels also identified tumor-bearing subjects, and a receiver operator-characteristic curve analysis highlighted this test's performance with an area of 0.918 +/- 0.084. Lung tumor burden additionally correlated (r(2) = 0.714; P < 0.05) with cumulative reporter levels, indicating that determination of disease extent was possible. Continued development of our system could improve tumor detectability dramatically because of the temporally controlled, high reporter expression in tumors and nearly zero background from healthy tissues. Our strategy's highly modular nature also allows it to be iteratively optimized over time to improve the test's sensitivity and specificity. We envision this system could be used first in patients at high risk for tumor recurrence, followed by screening high-risk populations before tumor diagnosis, and, if proven safe and effective, eventually may have potential as a powerful cancer screening tool for the general population. PMID- 25713390 TI - Climate-driven introduction of the Black Death and successive plague reintroductions into Europe. AB - The Black Death, originating in Asia, arrived in the Mediterranean harbors of Europe in 1347 CE, via the land and sea trade routes of the ancient Silk Road system. This epidemic marked the start of the second plague pandemic, which lasted in Europe until the early 19th century. This pandemic is generally understood as the consequence of a singular introduction of Yersinia pestis, after which the disease established itself in European rodents over four centuries. To locate these putative plague reservoirs, we studied the climate fluctuations that preceded regional plague epidemics, based on a dataset of 7,711 georeferenced historical plague outbreaks and 15 annually resolved tree-ring records from Europe and Asia. We provide evidence for repeated climate-driven reintroductions of the bacterium into European harbors from reservoirs in Asia, with a delay of 15 +/- 1 y. Our analysis finds no support for the existence of permanent plague reservoirs in medieval Europe. PMID- 25713391 TI - Morphogenesis checkpoint kinase Swe1 is the executor of lipolysis-dependent cell cycle progression. AB - Cell growth and division requires the precise duplication of cellular DNA content but also of membranes and organelles. Knowledge about the cell-cycle-dependent regulation of membrane and storage lipid homeostasis is only rudimentary. Previous work from our laboratory has shown that the breakdown of triacylglycerols (TGs) is regulated in a cell-cycle-dependent manner, by activation of the Tgl4 lipase by the major cyclin-dependent kinase Cdc28. The lipases Tgl3 and Tgl4 are required for efficient cell-cycle progression during the G1/S (Gap1/replication phase) transition, at the onset of bud formation, and their absence leads to a cell-cycle delay. We now show that defective lipolysis activates the Swe1 morphogenesis checkpoint kinase that halts cell-cycle progression by phosphorylation of Cdc28 at tyrosine residue 19. Saturated long chain fatty acids and phytosphingosine supplementation rescue the cell-cycle delay in the Tgl3/Tgl4 lipase-deficient strain, suggesting that Swe1 activity responds to imbalanced sphingolipid metabolism, in the absence of TG degradation. We propose a model by which TG-derived sphingolipids are required to activate the protein phosphatase 2A (PP2A(Cdc55)) to attenuate Swe1 phosphorylation and its inhibitory effect on Cdc28 at the G1/S transition of the cell cycle. PMID- 25713393 TI - Diagnosis and sequence analysis of avian leukosis virus subgroup J isolated from Chinese Partridge Shank chickens. AB - The diagnosis of avian leukosis virus subgroup J (ALV-J) infection in Chinese Partridge Shank chickens was confirmed by necropsy, histopathological examinations, antibody tests, viral isolation, immunofluorescence assays, and sequence analysis. Myelocytoma, myeloma, and fibrosarcoma were simultaneously found in Partridge Shank flock with ALV-J infection. Sequence analysis of the env genes of ALV-J demonstrated that both gp85 and gp37 were highly homologous among the three strains from local chickens of those among ALV-J strains isolated from white meat-type chickens. The phylogenetic trees indicated that the three strains isolated in this study were closely related to reference strains isolated in so called Chinese yellow chickens and some strains isolated from white meat-type chickens, both from the USA and China. The observed ALV-J infection was the first report on Partridge Shank chickens, and myelocytoma, myeloma, and fibrosarcoma were found at the same time in this batch of local chickens. PMID- 25713392 TI - Coincidental loss of DOCK8 function in NLRP10-deficient and C3H/HeJ mice results in defective dendritic cell migration. AB - Dendritic cells (DCs) are the primary leukocytes responsible for priming T cells. To find and activate naive T cells, DCs must migrate to lymph nodes, yet the cellular programs responsible for this key step remain unclear. DC migration to lymph nodes and the subsequent T-cell response are disrupted in a mouse we recently described lacking the NOD-like receptor NLRP10 (NLR family, pyrin domain containing 10); however, the mechanism by which this pattern recognition receptor governs DC migration remained unknown. Using a proteomic approach, we discovered that DCs from Nlrp10 knockout mice lack the guanine nucleotide exchange factor DOCK8 (dedicator of cytokinesis 8), which regulates cytoskeleton dynamics in multiple leukocyte populations; in humans, loss-of-function mutations in Dock8 result in severe immunodeficiency. Surprisingly, Nlrp10 knockout mice crossed to other backgrounds had normal DOCK8 expression. This suggested that the original Nlrp10 knockout strain harbored an unexpected mutation in Dock8, which was confirmed using whole-exome sequencing. Consistent with our original report, NLRP3 inflammasome activation remained unaltered in NLRP10-deficient DCs even after restoring DOCK8 function; however, these DCs recovered the ability to migrate. Isolated loss of DOCK8 via targeted deletion confirmed its absolute requirement for DC migration. Because mutations in Dock genes have been discovered in other mouse lines, we analyzed the diversity of Dock8 across different murine strains and found that C3H/HeJ mice also harbor a Dock8 mutation that partially impairs DC migration. We conclude that DOCK8 is an important regulator of DC migration during an immune response and is prone to mutations that disrupt its crucial function. PMID- 25713394 TI - Vitamin E and selenium in broiler breeder diets: Effect on live performance, hatching process, and chick quality. AB - This study evaluated the effect of different dietary vitamin E levels and different selenium sources on the productive and reproductive performance of broiler breeders. In total 640 females and 64 males between 22 and 52 weeks old were studied. A completely randomized experimental design in factorial arrangement, with 4 treatments of 8 replicates with 20 females and 2 males each, was applied. Treatments consisted of 2 vitamin E levels (30 and 120 mg/kg) and two selenium sources (sodium selenite and zinc-L-selenomethionine). Egg production (rate of lay and eggs per breeder), egg characteristics (egg, yolk, eggshell, and albumen weights), fertility, incubation responses (egg weight loss during incubation, hatchability, and hatching window), and hatchling characteristics (weight and yield) were evaluated. There was no influence of dietary vitamin E levels or selenium sources on egg production (P > 0.05). Mature breeders (47 weeks old) fed zinc-L-selenomethionine and 120 mg vitamin E/kg feed produced heavier eggs and albumen. Hatchability of the eggs of breeders fed 120 mg vitamin E/kg feed was higher than breeders fed 30 mg vitamin at 29 wks. The dietary inclusion of organic selenium also promoted heavier hatchling weight until egg production peak (33 wk), but did not influence hatchling quality or hatching window. It was concluded that the dietary supplementation of zinc-L selenomethione and vitamin E (120 mg/kg feed) could be used to improve egg characteristics and incubation response. PMID- 25713395 TI - Antioxidative effect of ginseng stem-leaf saponins on oxidative stress induced by cyclophosphamide in chickens. AB - Previous investigation demonstrated that oral administration of ginseng stem-leaf saponins in chickens could enhance the immune response. The present study was designed to evaluate the effects of ginseng stem-leaf saponins on oxidative stress induced by cyclophosphamide in chickens. One hundred and twenty chickens were randomly divided into 5 groups. Groups 1 to 4 received intramuscular injection of cyclophosphamide to induce oxidative stress while group 5 was injected with saline solution and served as control. Following administration of cyclophosphamide, groups 1 to 3 were orally administered ginseng stem-leaf saponins at 2.5, 5, and 10 mg/kg BW in drinking water for 7 d, respectively. After that, the spleen, thymus, bursa, and serum were collected to measure the indices of the organs and oxidative parameters. The results showed that ginseng stem-leaf saponins significantly inhibited cyclophosphamide-induced oxidative stress by increasing the organ indices, total antioxidant capacity, and the levels of glutathione, ascorbic acid, and alpha-tocopherol, while elevating the activity of total superoxide dismutase, catalase, and glutathione peroxidase, as well as decreasing the protein carbonyl content and malondialdehyde. Therefore, ginseng stem-leaf saponins could be a promising agent against oxidative stress in the poultry industry. PMID- 25713396 TI - Combined effects of presalted prerigor and postrigor batter mixtures on chicken breast gelation. AB - We examined the combined effects of prerigor and postrigor batter mixtures on protein gelation. The postrigor batter was prepared with 2% salt, whereas the prerigor meat at 5 min postmortem was used to prepare postrigor batters at different salt levels. For 5 treatments, prerigor batters were mixed with postrigor batter that had 2% salt (control) as follows: T1: ground presalted (1%) hot-boned breast with 1% salt for 50% total batch; T2: ground presalted (2%) hot boned breast for 50% total batch; T3: ground presalted (3%) hot-boned breast for 30% total batch that was mixed with cold-boned batter for 50% total batch; T4: ground presalted (4%) hot-boned breast for 25% total batch that was mixed with cold-boned batter for 50% total batch; and T5: ground presalted (5%) hot-boned breast for 20% total batch that was mixed with cold-boned batter for 50% total batch. Treatments with both presalted prerigor and postrigor muscle showed less cooking loss and lower emulsion stability than the control, except T5. The protein solubility and apparent viscosity of the control was the lowest. Thus, presalted hot-boned muscle combined with cold-boned muscle positively affected physicochemical properties. PMID- 25713397 TI - Using multiple regression, Bayesian networks and artificial neural networks for prediction of total egg production in European quails based on earlier expressed phenotypes. AB - The prediction of total egg production (TEP) potential in poultry is an important task to aid optimized management decisions in commercial enterprises. The objective of the present study was to compare different modeling approaches for prediction of TEP in meat type quails (Coturnix coturnix coturnix) using phenotypes such as weight, weight gain, egg production and egg quality measurements. Phenotypic data on 30 traits from two lines (L1, n=180; and L2, n=205) of quail were modeled to predict TEP. Prediction models included multiple linear regression and artificial neural network (ANN). Moreover, Bayesian network (BN) and a stepwise approach were used as variable selection methods. BN results showed that TEP is independent from other earlier expressed traits when conditioned on egg production from 35 to 80 days of age (EP1). In addition, the prediction accuracy was much lower when EP1 was not included in the model. The best predictive model was ANN, after feature selection, showing prediction correlations of r=0.792 and r=0.714 for L1 and L2, respectively. In conclusion, machine learning methods may be useful, but reasonable prediction accuracies are obtained only when partial egg production measurements are included in the model. PMID- 25713398 TI - On-farm comparison of keel fracture prevalence and other welfare indicators in conventional cage and floor-housed laying hens in Ontario, Canada. AB - The objective of this study was to compare the flock-level prevalence of healed keel bone fractures and to benchmark other indicators of well-being in laying hens housed in conventional cages and single-tier floor housing systems at several points during the production period. Commercial farms in Ontario, Canada, that housed hens in cages (n=9) or floor barns (n=8) were included. Flocks were beak-trimmed brown hens of various strains. Each flock was visited at 20, 35, 50, and 65 wk of age. At each visit, 50 hens were weighed, palpated for healed keel fractures, and feather scored over 4 areas of the body. Data were collected from the farm records on cumulative mortality. Keel fracture prevalence was higher in floor-housed flocks compared to cage-housed flocks (48.3+/-0.04% vs. 24.8+/ 0.03%; P<0.001). The majority of keel fractures occurred by 50 wk. Cumulative mortality tended to be higher in floor-housed flocks compared to cage-housed flocks (2.13+/-0.42% vs. 1.29+/-0.19%; P=0.078). Mean BW was lower (1,827+/-28.8 g vs. 1,888+/-26.8 g; P=0.02) yet more uniform (CV of BW 9.43+/-0.40% vs. 10.10+/ 0.32%; P<0.001) in floor-housed flocks compared to cage-housed flocks. Feather condition was not affected by housing system type (P=0.618), although it declined with age (P<0.001). Individual hen factors assessed using Pearson partial correlations indicated that hens with fractures were heavier at 65 wk in both housing types (P<0.05) and that heavier hens housed on the floor had better feather scores (P<0.001) from 35 wk onward. Floor-housed hens with fractures had lower feather scores at 35 wk (P<0.05) but not at 50 or 65 wk. Housing hens in single-tier floor systems increased the flock-level prevalence of keel fractures and resulted in a lower, yet more uniform, BW compared to hens in conventional cages under commercial conditions in Ontario. Benchmarking welfare indicators from alternative housing systems for laying hens is important to ensure that progress is made in improving their well-being. PMID- 25713399 TI - Brain. Editorial. PMID- 25713400 TI - Early detection of nerve injury in transthyretin-related familial amyloid polyneuropathy. PMID- 25713401 TI - Temporal lobe epilepsy: a unique window into living human brain epigenetic gene regulation. PMID- 25713402 TI - Imaging in Parkinson's disease: time to look below the neck. PMID- 25713403 TI - What does it mean to be 'amyloid-positive'? PMID- 25713404 TI - Specific disulfide cross-linking to constrict the mobile carrier domain of nonribosomal peptide synthetases. AB - Nonribosomal peptide synthetases are large, multi-domain enzymes that produce peptide molecules with important biological activity such as antibiotic, antiviral, anti-tumor, siderophore and immunosuppressant action. The adenylation (A) domain catalyzes two reactions in the biosynthetic pathway. In the first reaction, it activates the substrate amino acid by adenylation and in the second reaction it transfers the amino acid onto the phosphopantetheine arm of the adjacent peptide carrier protein (PCP) domain. The conformation of the A domain differs significantly depending on which of these two reactions it is catalyzing. Recently, several structures of A-PCP di-domains have been solved using mechanism based inhibitors to trap the PCP domain in the A domain active site. Here, we present an alternative strategy to stall the A-PCP di-domain, by engineering a disulfide bond between the native amino acid substrate and the A domain. Size exclusion studies showed a significant shift in apparent size when the mutant A PCP was provided with cross-linking reagents, and this shift was reversible in the presence of high concentrations of reducing agent. The cross-linked protein crystallized readily in several of the conditions screened and the best crystals diffracted to ~8 A. PMID- 25713405 TI - HD1, a thrombin-directed aptamer, binds exosite 1 on prothrombin with high affinity and inhibits its activation by prothrombinase. PMID- 25713406 TI - Long range communication between exosites 1 and 2 modulates thrombin function. PMID- 25713407 TI - Class-specific regulation of pro-inflammatory genes by MyD88 pathways and IkappaBzeta. PMID- 25713408 TI - Double PHD fingers protein DPF2 recognizes acetylated histones and suppresses the function of estrogen-related receptor alpha through histone deacetylase 1. PMID- 25713409 TI - Preparation of monoPEGylated Cyanovirin-N's derivative and its anti-influenza A virus bioactivity in vitro and in vivo. AB - Influenza A virus (IAV) has been raising public health and safety concerns worldwide. Cyanovirin-N (CVN) is a prominent anti-IAV candidate, but both cytotoxicity and immunogenicity have hindered the development of this protein as a viable therapy. In this article, linker-CVN (LCVN) with a flexible and hydrophilic polypeptide at the N-terminus was efficiently produced from the cytoplasm of Escherichia coli at a >15-l scale. PEGylation at the N-terminal alpha-amine of LCVN was also reformed as 20 kDa PEGylated linkered Cyanovirin-N (PEG20k-LCVN). The 50% effective concentrations of PEG20k-LCVN were 0.43 +/- 0.11 uM for influenza A/HK/8/68 (H3N2) and 0.04 +/- 0.02 uM for A/Swan/Hokkaido/51/96 (H5N3), dramatically lower than that of the positive control, Ribavirin (2.88 +/- 0.66 * 10(3) uM and 1.79 +/- 0.62 * 10(3) uM, respectively). A total of 12.5 uM PEG20k-LCVN effectively inactivate the propagation of H3N2 in chicken embryos. About 2.0 mg/kg/day PEG20k-LCVN increased double the survival rate (66.67%, P = 0.0378) of H3N2 infected mice, prolonged the median survival period, downregulated the mRNA level of viral nuclear protein and decreased (attenuated) the pathology lesion in mice lung. A novel PEGylated CVN derivative, PEG20k-LCVN, exhibited potent and strain-dependent anti-IAV activity in nanomolar concentrations in vitro, as well as in micromolar concentration in vivo. PMID- 25713410 TI - Close association of B2 bradykinin receptors with P2Y2 ATP receptors. AB - Two G-protein-coupled receptors (GPCRs) that couple with Galphaq/11, B2 bradykinin (BK) receptor (B2R) and ATP/UTP receptor P2Y2 (P2Y2R), are ubiquitously expressed and responsible for vascular tone, inflammation, and pain. We analysed the cellular signalling of P2Y2Rs in cells that express B2Rs. B2R desensitization induced by BK or B2R internalization-inducing glycans cross desensitized the P2Y2R response to ATP/UTP. Fluorescence resonance energy transfer from P2Y2R-AcGFP to B2R-DsRed was detected in the cells and on the cell surfaces, showing the close association of these GPCRs. BK- and ATP-induced cross internalization of P2Y2R and B2R, respectively, was shown in a beta-galactosidase complementation assay using P2Y2R or B2R fused to the H31R substituted alpha donor peptide of a beta-galactosidase reporter enzyme (P2Y2R-alpha or B2R-alpha) with coexpression of the FYVE domain of endofin, an early endosome protein, fused to the M15 acceptor deletion mutant of beta-galactosidase (the omega peptide, FYVE-omega). Arrestin recruitment to the GPCRs by cross-activation was also shown with the similar way. Coimmunoprecipitation showed that B2R and P2Y2R were closely associated in the cotransfected cells. These results indicate that B2R couples with P2Y2R and that these GPCRs act together to fine-tune cellular responsiveness. The collaboration between these receptors may permit rapid onset and turning off of biological events. PMID- 25713411 TI - Albumin overload down-regulates integrin-beta1 through reactive oxygen species endoplasmic reticulum stress pathway in podocytes. AB - Proteinuria is a major hallmark of glomerular nephropathy and endoplasmic reticulum (ER) stress plays an important role in glomerular nephropathy. The protein levels of integrin-beta1 in podocytes are found to be negative correlation with amount of proteinuria. This study investigated whether urinary protein, particularly albumin, induced ER stress that consequently reduced integrin-beta1 expression. All experiments were performed using primary cultured rat podocyte. Protein and mRNA expression were measured by western blotting and semiquantified reverse transcriptase polymerase chain reaction. Albumin uptake was found at 1 h after albumin addition. Albumin reduced precursor and mature forms of integrin-beta1, but did not change mRNA levels of integrin-beta1. Albumin induced reactive oxygen species (ROS) generation and ER stress. Antioxidant (N-acetylcysteine) suppressed albumin-induced ER stress and decrements in precursor and mature forms of integrin-beta1. Then, ER stress inhibitors (4-phenylbutyrate and salubrinal) also inhibited albumin-induced decrements in precursor and mature forms of integrin-beta1. The potent ER stress inducers (thapsigargin and tunicamycin) directly decreased precursor and mature forms of integrin-beta1 and led appearance of unglycosylated core protein of integrin-beta1. Our results show that in proteinuric disease, albumin decreases precursor and mature forms of integrin-beta1 through ROS-ER stress pathway in podocytes. PMID- 25713412 TI - Three distinct ribosome assemblies modulated by translation are the building blocks of polysomes. AB - Translation is increasingly recognized as a central control layer of gene expression in eukaryotic cells. The overall organization of mRNA and ribosomes within polysomes, as well as the possible role of this organization in translation are poorly understood. Here we show that polysomes are primarily formed by three distinct classes of ribosome assemblies. We observe that these assemblies can be connected by naked RNA regions of the transcript. We show that the relative proportions of the three classes of ribosome assemblies reflect, and probably dictate, the level of translational activity. These results reveal the existence of recurrent supra-ribosomal building blocks forming polysomes and suggest the presence of unexplored translational controls embedded in the polysome structure. PMID- 25713413 TI - Both tails and the centromere targeting domain of CENP-A are required for centromere establishment. AB - The centromere-defined by the presence of nucleosomes containing the histone H3 variant, CENP-A-is the chromosomal locus required for the accurate segregation of chromosomes during cell division. Although the sequence determinants of human CENP-A required to maintain a centromere were reported, those that are required for early steps in establishing a new centromere are unknown. In this paper, we used gain-of-function histone H3 chimeras containing various regions unique to CENP-A to investigate early events in centromere establishment. We targeted histone H3 chimeras to chromosomally integrated Lac operator sequences by fusing each of the chimeras to the Lac repressor. Using this approach, we found surprising contributions from a small portion of the N-terminal tail and the CENP A targeting domain in the initial recruitment of two essential constitutive centromere proteins, CENP-C and CENP-T. Our results indicate that the regions of CENP-A required for early events in centromere establishment differ from those that are required for maintaining centromere identity. PMID- 25713414 TI - PolyQ-dependent RNA-protein assemblies control symmetry breaking. AB - Dendritic growth in fungi and neurons requires that multiple axes of polarity are established and maintained within the same cytoplasm. We have discovered that transcripts encoding key polarity factors including a formin, Bni1, and a polarisome scaffold, Spa2, are nonrandomly clustered in the cytosol to initiate and maintain sites of polarized growth in the fungus Ashbya gossypii. This asymmetric distribution requires the mRNAs to interact with a polyQ-containing protein, Whi3, and a Pumilio protein with a low-complexity sequence, Puf2. Cells lacking Whi3 or Puf2 had severe defects in establishing new sites of polarity and failed to localize Bni1 protein. Interaction of mRNAs with Whi3 and Puf2 promotes enrichment of transcripts at established sites of polarized growth and clustering of polarity transcripts throughout the cell body. Thus, aggregation-prone proteins make functional assemblies to position polarity transcripts, and nonrandom positioning of transcripts is required for symmetry-breaking events. This reveals a physiological function for polyQ-driven assemblies in regulating cell polarity. PMID- 25713415 TI - DENND2B activates Rab13 at the leading edge of migrating cells and promotes metastatic behavior. AB - The small guanosine triphosphatase Rab13 functions in exocytic vesicle trafficking in epithelial cells. Alterations in Rab13 activity have been observed in human cancers, yet the mechanism of Rab13 activation and its role in cancer progression remain unclear. In this paper, we identify the DENN domain protein DENND2B as the guanine nucleotide exchange factor for Rab13 and develop a novel Forster resonance energy transfer-based Rab biosensor to reveal activation of Rab13 by DENND2B at the leading edge of migrating cells. DENND2B interacts with the Rab13 effector MICAL-L2 at the cell periphery, and this interaction is required for the dynamic remodeling of the cell's leading edge. Disruption of Rab13-mediated trafficking dramatically limits the invasive behavior of epithelial cells in vitro and the growth and migration of highly invasive cancer cells in vivo. Thus, blocking Rab13 activation by DENND2B may provide a novel target to limit the spread of epithelial cancers. PMID- 25713416 TI - Regulation of C-X-C chemokine gene expression by keratin 17 and hnRNP K in skin tumor keratinocytes. AB - High levels of the intermediate filament keratin 17 (K17) correlate with a poor prognosis for several types of epithelial tumors. However, the causal relationship and underlying mechanisms remain undefined. A recent study suggested that K17 promotes skin tumorigenesis by fostering a specific type of inflammation. We report here that K17 interacts with the RNA-binding protein hnRNP K, which has also been implicated in cancer. K17 is required for the cytoplasmic localization of hnRNP K and for its role in regulating the expression of multiple pro-inflammatory mRNAs. Among these are the CXCR3 ligands CXCL9, CXCL10, and CXCL11, which together form a signaling axis with an established role in tumorigenesis. The K17-hnRNP K partnership is regulated by the ser/thr kinase RSK and required for CXCR3-dependent tumor cell growth and invasion. These findings functionally integrate K17, hnRNP K, and gene expression along with RSK and CXCR3 signaling in a keratinocyte-autonomous axis and provide a potential basis for their implication in tumorigenesis. PMID- 25713417 TI - LEF1: a highly specific marker for the diagnosis of chronic lymphocytic B cell leukaemia/small lymphocytic B cell lymphoma. AB - AIMS: Chronic lymphocytic B cell leukaemia (CLL)/small lymphocytic B cell lymphoma (SLL) has proven to be not a uniform entity but to consist of various disease subtypes. CLL might also pose diagnostic challenges by demonstrating an uncommon immunohistochemical profile. Recently, the role of lymphocyte enhancer binding factor 1 (LEF1) in CLL was elucidated being highly expressed and seeming to have a prognostic value. Our aim was to test the applicability of LEF1 as marker for CLL in a diagnostic setting. METHODS: We investigated LEF1 expression in lymphomas by immunohistochemistry on tissue microarrays containing several lymphoma entities (altogether 720 cases, including 61 CLL cases). We also separated CLL cases by zeta-chain-associated protein kinase 70 (ZAP70) and CD38 stainings and fluorescence in situ hybridisation analyses for TP53 deletions and trisomy 12 into respective groups and correlated data with LEF1 expression. RESULTS: The area under the receiver operating characteristic curve for LEF1 as a diagnostic marker for CLL was 0.815 (95% CI 0.742 to 0.888). The relevant diagnostic cut-off value for LEF1 positivity determined by the Youden's index was 10% (specificity 92%, sensitivity 70%). The majority of CLL cases (70%) expressed LEF1. Eighteen per cent of (transformed) diffuse large B cell lymphoma cases also expressed LEF1. In most other lymphoma entities, LEF1 was negative. There was a positive correlation of LEF1 staining with ZAP70 expression (Spearman's rho: 0.438, p<0.001), but not with CD38 expression, TP53 deletions or trisomy 12. CONCLUSIONS: LEF1 is a useful marker in the differential diagnosis of CLL in difficult cases. It shows a high specificity (92%) and a reasonable sensitivity (70%) for this entity. PMID- 25713418 TI - Low-grade fibromatosis-like spindle cell carcinomas of the breast are molecularly exiguous. AB - BACKGROUND: Low-grade fibromatosis-like spindle cell carcinomas are very rare breast carcinomas comprising <0.5% of all breast cancers. They demonstrate immunohistochemical (IHC) features of basal-like/metaplastic breast carcinomas, but the underlying molecular characteristics are unknown. We hypothesised that, as with IHC similarities, there may be common genomic alterations between spindle cell and basal-like/metaplastic carcinomas. METHODS AND RESULTS: Genomic mutational profile and genomic copy number aberration (CNA) analyses were performed on three cases of this unusual entity, and findings were compared with that reported for basal-like/metaplastic breast carcinomas. Copy number analyses by molecular inversion probe assays of the three spindle cell carcinoma samples revealed little overall genomic CNAs with only minor changes identified (fraction of the genome altered; 1.3%-6.4%), but with a common 9p21.3 loss in 2 out of 3 samples, with CDKN2A (p16) being a likely candidate. No areas of commonality were identified in an in silico analysis compared with publically available basal like/metaplastic carcinoma copy number data. CONCLUSIONS: These tumours are characterised by low genomic instability, and share no CNAs with other metaplastic carcinomas. These findings favour this entity being a unique group genotype and belie their apparent homogeneous morphology and phenotype. PMID- 25713419 TI - Angiotensin II causes cellular proliferation in infantile haemangioma via angiotensin II receptor 2 activation. AB - AIMS: To investigate the effect of the angiotensin peptides and their agonists and antagonists on cellular proliferation in proliferating infantile haemangioma (IH) in vitro explants. METHODS: Proliferating IH samples from six patients were cultured in vitro in the presence of angiotensin I (ATI) alone, or AT1 and the ACE inhibitor, ramipril, or ATII alone, or ATII with the ATII receptor 1 (ATIIR1) blocker, losartan, or ATII with the ATIIR2 blocker, PD123319, or the ATIIR2 agonist, CGP42112. After 6 days in culture, the IH tissue pieces were harvested, formalin-fixed and paraffin-embedded. The effect of each treatment type on cellular proliferation was evaluated by immunohistochemical staining of these tissue pieces using the proliferation marker, Ki67. RESULTS: There was a significant increase in cellular proliferation in the ATI and ATII treated IH tissues compared with control samples. Their effect on cellular proliferation was reduced by adding ramipril and PD123319, respectively. CGP42112, but not losartan, significantly increased cellular proliferation. CONCLUSIONS: Our findings suggest a key regulatory role of ATI and ATII in promoting cellular proliferation in IH, and establish a role for ACE and ATIIR2 in the proliferation of this tumour. PMID- 25713420 TI - CD10 expression in 325 testicular germ cell tumours. PMID- 25713422 TI - Research collaborations in Tajikistan: lessons to be learnt. AB - We have been working on an association of physicians 'links with developing countries' scheme in Tajikistan, which is a nation of 7.5 million people, 93% of which is mountainous, of a similar size to England and Wales, landlocked, resource-poor and richly licked by the brush of history. Understanding the challenges faced by academics working with Tajikistan today requires a cursory understanding of Tajikistan's genesis. Through this lens, present-day technical, organizational and socio-political challenges can be appropriately considered, with a view to improving academic collaboration in the future. PMID- 25713423 TI - High risk factors of atrial fibrillation in type 2 diabetes: results from the Chinese Kailuan study. AB - BACKGROUND: The pathophysiological mechanisms for atrial fibrillation (AF) vulnerability in diabetic patients are largely unclear. AIM: To investigate the high risk factors of AF in Chinese Kailuan diabetes. DESIGN: A retrospective review of AF in Chinese Kailuan diabetes. METHODS: Research and statistic analysis on the clinical data of 9050 diabetic patients from Kailuan Coal Mine Group Corporation who participated in a health survey from July 2006 to October 2007. RESULTS: Sixty diabetic patients (50 males and 10 females) were diagnosed with AF during the health checkup, with a prevalence of 0.66% (0.67% in males and 0.62% in females). Univariate analysis showed that patients with AF were older and had higher levels of serum uric acid (UA), pulse pressure, serum c-reactive protein and anti-hypertensive medication usage, but lower levels of fasting blood glucose and triglycerides (TG). Multivariate analysis indicated that older age (OR = 1.09; 95% CI: 1.06-1.12), increased UA (OR = 1.01; 95% CI: 1.00-1.01) and decreased TG (OR = 0.71; 95% CI: 0.55-0.92) were independent predictive factors of AF after adjusting for other variables. After gender stratification, age and UA remained as independent predictive factors of AF in both male and female patients. However, TG had an independent inverse association with AF in male patients only. CONCLUSIONS: Age and UA are independent predictive factors of AF in both male and female diabetic patients. TG is inversely correlated with AF in male diabetic patients only. PMID- 25713424 TI - Superficial siderosis of central nervous system of unknown cause. PMID- 25713425 TI - Decreased STAT3 in human idiopathic fetal growth restriction contributes to trophoblast dysfunction. AB - Abnormal trophoblast function is associated with fetal growth restriction (FGR). The JAK-STAT pathway is one of the principal signalling mechanisms by which cytokines and growth factors modulate cell proliferation, differentiation, cell migration and apoptosis. The expression of placental JAK-STAT genes in human idiopathic FGR is unknown. In this study, we propose the hypothesis that JAK-STAT pathway genes are differentially expressed in idiopathic FGR-affected pregnancies and contribute to abnormal feto-placental growth by modulating the expression of the amino acid transporter SNAT2, differentiation marker CGB/human chorionic gonadotrophin beta-subunit (beta-hCG) and apoptosis markers caspases 3 and 8, and TP53. Expression profiling of FGR-affected placentae revealed that mRNA levels of STAT3, STAT2 and STAT5B decreased by 69, 52 and 50%, respectively, compared with gestational-age-matched controls. Further validation by real-time PCR and immunoblotting confirmed significantly lower STAT3 mRNA and STAT3 protein (total and phosphorylated) levels in FGR placentae. STAT3 protein was localised to the syncytiotrophoblast (ST) in both FGR and control placentae. ST differentiation was modelled by in vitro differentiation of primary villous trophoblast cells from first-trimester and term placentae, and by treating choriocarcinoma-derived BeWo cells with forskolin in cell culture. Differentiation in these models was associated with increased STAT3 mRNA and protein levels. In BeWo cells treated with siRNA targeting STAT3, the mRNA and protein levels of CGB/beta-hCG, caspases 3 and 8, and TP53 were significantly increased, while that of SNAT2 was significantly decreased compared with the negative control siRNA. In conclusion, we report that decreased STAT3 expression in placentae may contribute to abnormal trophoblast function in idiopathic FGR-affected pregnancies. PMID- 25713426 TI - Kisspeptin antagonist prevents RF9-induced reproductive changes in female rats. AB - The aim of this study was to determine the modulatory effects of peptide 234 (p234) (an antagonist of GPR54 receptors) on kisspeptin and RF9 (an RFamide related peptide antagonist)-induced changes in reproductive functions and energy balance in female rats. Female Sprague-Dawley rats were weaned on postnatal day (pnd) 21. The animals were intracerebroventricularly cannulated under general anesthesia on pnd 23. Groups of female rats were injected with kisspeptin, RF9, p234, kisspeptin plus p234, or RF9 plus p234, daily. The experiments were ended on the day of first diestrus following pnd 60. Kisspeptin or RF9 alone advanced vaginal opening (VO), which was delayed by administration of kisspeptin antagonist alone. In the rats given kisspeptin plus p234 or RF9 plus p234, VO was not different from control rats. Kisspeptin and RF9 elicited significant elevations in circulating LH levels. Coadministrations of kisspeptin or RF9 with p234 decreased LH levels significantly. The use of p234 alone did not cause any significant change in LH secretion. Kisspeptin decreased both food intake and body weight while RF9 decreased only food intake without affecting body weight. The effects of kisspeptin on energy balance were also reversed by central administration of p234. In conclusion, kisspeptin antagonist, p234, modulates the effects of kisspeptin on reproductive functions and energy balance, whereas RF9 seems to exert only its effects on reproductive functions by means of GPR54 signaling in female rats. PMID- 25713427 TI - Psychosocial distress screening implementation in cancer care: an analysis of adherence, responsiveness, and acceptability. AB - PURPOSE: The American College of Surgeons Commission on Cancer has mandated implementation of a systematic protocol for psychosocial distress screening and referral as a condition for cancer center accreditation beginning in 2015. Compliance with standards requires evidence that distress screening protocols are carried out as intended and result in appropriate referral and follow-up when indicated. The purpose of this study was to examine the fidelity of distress screening protocols at two tertiary cancer treatment centers. METHODS: A retrospective review and analysis of electronic medical records over a 12-week period examined clinic adherence to a prescribed distress screening protocol and responsiveness to patients whose scores on the National Comprehensive Cancer Network Distress Thermometer (DT) indicated clinically significant levels of distress requiring subsequent psychosocial contact. A weekly online survey assessed clinician perspectives on the acceptability of the protocol. RESULTS: Across clinics, rates of adherence to the distress screening protocol ranged from 47% to 73% of eligible patients. For patients indicating clinically significant distress (DT score >= 4), documentation of psychosocial contact or referral occurred, on average, 50% to 63% of the time, and was more likely to occur at one of two participating institutions when DT scores were high (DT score of 8 to 10). Clinician assessments of the protocol's utility in addressing patient concerns and responding to patient needs were generally positive. CONCLUSION: Systematic tracking of distress screening protocols is needed to demonstrate compliance with new standards of care and to demonstrate how well institutions are responding to their clinical obligation to address cancer patients' emotional and psychosocial needs. PMID- 25713428 TI - Randomized phase III trial of gemcitabine plus docetaxel plus bevacizumab or placebo as first-line treatment for metastatic uterine leiomyosarcoma: an NRG Oncology/Gynecologic Oncology Group study. AB - PURPOSE: Fixed-dose rate gemcitabine plus docetaxel achieves objective response in 35% of patients with uterine leiomyosarcoma (uLMS). This study aimed to determine whether the addition of bevacizumab to gemcitabine-docetaxel increases progression-free survival (PFS) in uLMS. PATIENTS AND METHODS: In this phase III, double-blind, placebo-controlled trial, patients with chemotherapy-naive, metastatic, unresectable uLMS were randomly assigned to gemcitabine-docetaxel plus bevacizumab or gemcitabine-docetaxel plus placebo. PFS, overall survival (OS), and objective response rates (ORRs) were compared to determine superiority. Target accrual was 130 patients to detect an increase in median PFS from 4 months (gemcitabine-docetaxel plus placebo) to 6.7 months (gemcitabine-docetaxel plus bevacizumab). Treatment effects on PFS and OS were described by hazard ratios (HRs), median times to event, and 95% CIs. RESULTS: In all, 107 patients were accrued: gemcitabine-docetaxel plus placebo (n = 54) and gemcitabine-docetaxel plus bevacizumab (n = 53). Accrual was stopped early for futility. No statistically significant differences in grade 3 to 4 toxicities were observed. Median PFS was 6.2 months for gemcitabine-docetaxel plus placebo versus 4.2 months for gemcitabine-docetaxel plus bevacizumab (HR, 1.12; P = .58). Median OS was 26.9 months for gemcitabine-docetaxel plus placebo and 23.3 months for gemcitabine-docetaxel plus bevacizumab (HR, 1.07; P = .81). Objective responses were observed in 17 (31.5%) of 54 patients randomly assigned to gemcitabine docetaxel plus placebo and 19 (35.8%) of 53 patients randomly assigned to gemcitabine-docetaxel plus bevacizumab. Mean duration of response was 8.6 months for gemcitabine-docetaxel plus placebo versus 8.8 months for gemcitabine docetaxel plus bevacizumab. CONCLUSION: The addition of bevacizumab to gemcitabine-docetaxel for first-line treatment of metastatic uLMS failed to improve PFS, OS, or ORR. Gemcitabine-docetaxel remains a standard first-line treatment for uLMS. PMID- 25713429 TI - Psychosocial telephone counseling for survivors of cervical cancer: results of a randomized biobehavioral trial. AB - PURPOSE: Survivors of cervical cancer experience quality-of-life (QOL) disruptions that persist years after treatment. This study examines the effect of a psychosocial telephone counseling (PTC) intervention on QOL domains and associations with biomarkers. PATIENTS AND METHODS: We conducted a randomized clinical trial in survivors of cervical cancer, who were >= 9 and less than 30 months from diagnosis (n = 204), to compare PTC to usual care (UC). PTC included five weekly sessions and a 1-month booster. Patient-reported outcomes (PROs) and biospecimens were collected at baseline and 4 and 9 months after enrollment. Changes in PROs over time and associations with longitudinal change in cytokines as categorical variables were analyzed using multivariable analysis of variance for repeated measures. RESULTS: Participant mean age was 43 years; 40% of women were Hispanic, and 51% were non-Hispanic white. Adjusting for age and baseline scores, participants receiving PTC had significantly improved depression and improved gynecologic and cancer-specific concerns at 4 months compared with UC participants (all P < .05); significant differences in gynecologic and cancer specific concerns (P < .05) were sustained at 9 months. Longitudinal change in overall QOL and anxiety did not reach statistical significance. Participants with decreasing interleukin (IL) -4, IL-5, IL-10, and IL-13 had significantly greater improvement in QOL than those with increasing cytokine levels. CONCLUSION: This trial confirms that PTC benefits mood and QOL cancer-specific and gynecologic concerns for a multiethnic underserved population of survivors of cancer. The improvement in PROs with decreases in T-helper type 2 and counter-regulatory cytokines supports a potential biobehavioral pathway relevant to cancer survivorship. PMID- 25713430 TI - Triple-modality screening trial for familial breast cancer underlines the importance of magnetic resonance imaging and questions the role of mammography and ultrasound regardless of patient mutation status, age, and breast density. AB - PURPOSE: To evaluate the breast cancer screening efficacy of mammography, ultrasound, and magnetic resonance imaging (MRI) in a high-risk population and in various population subgroups. PATIENTS AND METHODS: In a single-center, prospective, nonrandomized comparison study, BRCA mutation carriers and women with a high familial risk (> 20% lifetime risk) for breast cancer were offered screening with mammography, ultrasound, and MRI every 12 months. Diagnostic performance was compared between individual modalities and their combinations. Further comparisons were based on subpopulations dichotomized by screening rounds, mutation status, age, and breast density. RESULTS: There were 559 women with 1,365 complete imaging rounds included in this study. The sensitivity of MRI (90.0%) was significantly higher (P < .001) than that of mammography (37.5%) and ultrasound (37.5%). Of 40 cancers, 18 (45.0%) were detected by MRI alone. Two cancers were found by mammography alone (a ductal carcinoma in situ [DCIS] with microinvasion and a DCIS with < 10-mm invasive areas). This did not lead to a significant increase of sensitivity compared with using MRI alone (P = .15). No cancers were detected by ultrasound alone. Similarly, of 14 DCISs, all were detected by MRI, whereas mammography and ultrasound each detected five DCISs (35.7%). Age, mutation status, and breast density had no influence on the sensitivity of MRI and did not affect the superiority of MRI over mammography and ultrasound. CONCLUSION: MRI allows early detection of familial breast cancer regardless of patient age, breast density, or risk status. The added value of mammography is limited, and there is no added value of ultrasound in women undergoing MRI for screening. PMID- 25713431 TI - Oral bisphosphonate use and risk of postmenopausal endometrial cancer. AB - PURPOSE: Bisphosphonates are common medications used for the treatment of osteoporosis and are also used to reduce metastases to bone in patients with cancer. Several studies, including the Women's Health Initiative (WHI), have found that use of bisphosphonates is associated with reduced risk of developing breast cancer, but less is known about associations with other common malignancies. This study was aimed at examining the effects of bisphosphonates on the risk of endometrial cancer. METHODS: We evaluated the relationship between use of oral bisphosphonates and endometrial cancer risk in a cohort of 89,918 postmenopausal women participating in the WHI. A detailed health interview was conducted at baseline, and bisphosphonate use was ascertained from an inventory of regularly used medications at baseline and over follow-up. All women had an intact uterus at the time of study entry. RESULTS: During a median follow-up of 12.5 years, 1,123 women were diagnosed with incident invasive endometrial cancer. Ever use of bisphosphonates was associated with reduced endometrial cancer risk (adjusted hazard ratio, 0.80; 95% CI, 0.64 to 1.00; P = .05), with no interactions observed with age, body mass index, or indication for use. CONCLUSION: In this large prospective cohort of postmenopausal women, bisphosphonate use was associated with a statistically significant reduction in endometrial cancer risk. PMID- 25713432 TI - Reply to S. Gupta et al. PMID- 25713433 TI - Clinical trial ethics: one standard does not fit all. PMID- 25713435 TI - Reply to D. Adkins et al. PMID- 25713434 TI - Prognostic significance of NPM1 mutations in the absence of FLT3-internal tandem duplication in older patients with acute myeloid leukemia: a SWOG and UK National Cancer Research Institute/Medical Research Council report. AB - PURPOSE: Younger patients with acute myeloid leukemia (AML) harboring NPM1 mutations without FLT3-internal tandem duplications (ITDs; NPM1-positive/FLT3-ITD negative genotype) are classified as better risk; however, it remains uncertain whether this favorable classification can be applied to older patients with AML with this genotype. Therefore, we examined the impact of age on the prognostic significance of NPM1-positive/FLT3-ITD-negative status in older patients with AML. PATIENTS AND METHODS: Patients with AML age >= 55 years treated with intensive chemotherapy as part of Southwest Oncology Group (SWOG) and UK National Cancer Research Institute/Medical Research Council (NCRI/MRC) trials were evaluated. A comprehensive analysis first examined 156 patients treated in SWOG trials. Validation analyses then examined 1,258 patients treated in MRC/NCRI trials. Univariable and multivariable analyses were used to determine the impact of age on the prognostic significance of NPM1 mutations, FLT3-ITDs, and the NPM1 positive/FLT3-ITD-negative genotype. RESULTS: Patients with AML age 55 to 65 years with NPM1-positive/FLT3-ITD-negative genotype treated in SWOG trials had a significantly improved 2-year overall survival (OS) as compared with those without this genotype (70% v 32%; P < .001). Moreover, patients age 55 to 65 years with NPM1-positive/FLT3-ITD-negative genotype had a significantly improved 2-year OS as compared with those age > 65 years with this genotype (70% v 27%; P < .001); any potential survival benefit of this genotype in patients age > 65 years was marginal (27% v 16%; P = .33). In multivariable analysis, NPM1 positive/FLT3-ITD-negative genotype remained independently associated with an improved OS in patients age 55 to 65 years (P = .002) but not in those age > 65 years (P = .82). These results were confirmed in validation analyses examining the NCRI/MRC patients. CONCLUSION: NPM1-positive/FLT3-ITD-negative genotype remains a relatively favorable prognostic factor for patients with AML age 55 to 65 years but not in those age > 65 years. PMID- 25713436 TI - Feasibility and cardiac safety of trastuzumab emtansine after anthracycline-based chemotherapy as (neo)adjuvant therapy for human epidermal growth factor receptor 2-positive early-stage breast cancer. AB - PURPOSE: Trastuzumab emtansine (T-DM1), an antibody-drug conjugate comprising the cytotoxic agent DM1, a stable linker, and trastuzumab, has demonstrated substantial activity in human epidermal growth factor receptor 2 (HER2) -positive metastatic breast cancer, raising interest in evaluating the feasibility and cardiac safety of T-DM1 in early-stage breast cancer (EBC). PATIENTS AND METHODS: Patients (N = 153) with HER2-positive EBC and prechemotherapy left ventricular ejection fraction (LVEF) >= 55% received (neo)adjuvant doxorubicin plus cyclophosphamide or fluorouracil plus epirubicin plus cyclophosphamide followed by T-DM1 for four cycles. Patients could then receive three to four cycles of optional docetaxel with or without trastuzumab. T-DM1 was then resumed with optional radiotherapy (sequential or concurrent) for 1 year (planned) of HER2 directed therapy. The coprimary end points were rate of prespecified cardiac events and safety. RESULTS: Median follow-up was 24.6 months. No prespecified cardiac events or symptomatic congestive heart failures were reported. Four patients (2.7%) had asymptomatic LVEF declines (>= 10 percentage points from baseline to LVEF < 50%), leading to T-DM1 discontinuation in one patient. Of 148 patients who received >= one cycle of T-DM1, 82.4% completed the planned 1-year duration of HER2-directed therapy. During T-DM1 treatment, 38.5% and 2.7% of patients experienced grade 3 and 4 adverse events, respectively. Approximately 95% of patients receiving T-DM1 plus radiotherapy completed >= 95% of the planned radiation dose with delay <= 5 days. CONCLUSION: Use of T-DM1 for approximately 1 year after anthracycline-based chemotherapy was feasible and generally well tolerated by patients with HER2-positive EBC, providing support for phase III trials of T-DM1 in this setting. PMID- 25713437 TI - Five-year survival rates for treatment-naive patients with advanced melanoma who received ipilimumab plus dacarbazine in a phase III trial. AB - PURPOSE: There is evidence from nonrandomized studies that a proportion of ipilimumab-treated patients with advanced melanoma experience long-term survival. To demonstrate a long-term survival benefit with ipilimumab, we evaluated the 5 year survival rates of patients treated in a randomized, controlled phase III trial. PATIENTS AND METHODS: A milestone survival analysis was conducted to capture the 5-year survival rate of treatment-naive patients with advanced melanoma who received ipilimumab in a phase III trial. Patients were randomly assigned 1:1 to receive ipilimumab at 10 mg/kg plus dacarbazine (n = 250) or placebo plus dacarbazine (n = 252) at weeks 1, 4, 7, and 10 followed by dacarbazine alone every 3 weeks through week 22. Eligible patients could receive maintenance ipilimumab or placebo every 12 weeks beginning at week 24. A safety analysis was conducted on patients who survived at least 5 years and continued to receive ipilimumab as maintenance therapy. RESULTS: The 5-year survival rate was 18.2% (95% CI, 13.6% to 23.4%) for patients treated with ipilimumab plus dacarbazine versus 8.8% (95% CI, 5.7% to 12.8%) for patients treated with placebo plus dacarbazine (P = .002). A plateau in the survival curve began at approximately 3 years. In patients who survived at least 5 years and continued to receive ipilimumab, grade 3 or 4 immune-related adverse events were observed exclusively in the skin. CONCLUSION: The additional survival benefit of ipilimumab plus dacarbazine is maintained with twice as many patients alive at 5 years compared with those who initially received placebo plus dacarbazine. These results demonstrate a durable survival benefit with ipilimumab in advanced melanoma. PMID- 25713438 TI - Reply to D. Adkins et al. PMID- 25713440 TI - RTOG 0522: huge Investment in patients and resources and no benefit with addition of cetuximab to radiotherapy--why did this occur? PMID- 25713441 TI - Breast cancer axillary staging: much ado about micrometastatic disease. PMID- 25713442 TI - Micromechanics of fracturing in nanoceramics. AB - An overview of key experimental data and theoretical representations on fracture processes in nanoceramics is presented. The focuses are placed on crack growth in nanoceramics and their toughening micromechanics. Conventional toughening micromechanisms are discussed which effectively operate in both microcrystalline matrix ceramics containing nanoinclusions and nanocrystalline-matrix ceramics. Particular attention is devoted to description of special (new) toughening micromechanisms related to nanoscale deformation occurring near crack tips in nanocrystalline-matrix ceramics. In addition, a new strategy for pronounced improvement of fracture toughness of ceramic materials through fabrication of ceramic-graphene nanocomposites is considered. Toughening micromechanisms are discussed which operate in such nanocomposites containing graphene platelets and/or few-layer sheets. PMID- 25713443 TI - The transition from subsonic to supersonic cracks. AB - We present the full analytical solution for steady-state in-plane crack motion in a brittle triangular lattice. This allows quick numerical evaluation of solutions for very large systems, facilitating comparisons with continuum fracture theory. Cracks that propagate faster than the Rayleigh wave speed have been thought to be forbidden in the continuum theory, but clearly exist in lattice systems. Using our analytical methods, we examine in detail the motion of atoms around a crack tip as crack speed changes from subsonic to supersonic. Subsonic cracks feature displacement fields consistent with a stress intensity factor. For supersonic cracks, the stress intensity factor disappears. Subsonic cracks are characterized by small-amplitude, high-frequency oscillations in the vertical displacement of an atom along the crack line, while supersonic cracks have large-amplitude, low frequency oscillations. Thus, while supersonic cracks are no less physical than subsonic cracks, the connection between microscopic and macroscopic behaviour must be made in a different way. This is one reason supersonic cracks in tension had been thought not to exist. PMID- 25713439 TI - Lessons from anti-vascular endothelial growth factor and anti-vascular endothelial growth factor receptor trials in patients with glioblastoma. AB - Treatment of glioblastoma (GBM), the most common primary malignant brain tumor in adults, remains a significant unmet need in oncology. Historically, cytotoxic treatments provided little durable benefit, and tumors recurred within several months. This has spurred a substantial research effort to establish more effective therapies for both newly diagnosed and recurrent GBM. In this context, antiangiogenic therapy emerged as a promising treatment strategy because GBMs are highly vascular tumors. In particular, GBMs overexpress vascular endothelial growth factor (VEGF), a proangiogenic cytokine. Indeed, many studies have demonstrated promising radiographic response rates, delayed tumor progression, and a relatively safe profile for anti-VEGF agents. However, randomized phase III trials conducted to date have failed to show an overall survival benefit for antiangiogenic agents alone or in combination with chemoradiotherapy. These results indicate that antiangiogenic agents may not be beneficial in unselected populations of patients with GBM. Unfortunately, biomarker development has lagged behind in the process of drug development, and no validated biomarker exists for patient stratification. However, hypothesis-generating data from phase II trials that reveal an association between increased perfusion and/or oxygenation (ie, consequences of vascular normalization) and survival suggest that early imaging biomarkers could help identify the subset of patients who most likely will benefit from anti-VEGF agents. In this article, we discuss the lessons learned from the trials conducted to date and how we could potentially use recent advances in GBM biology and imaging to improve outcomes of patients with GBM who receive antiangiogenic therapy. PMID- 25713444 TI - Theory and modelling of diamond fracture from an atomic perspective. AB - Discussed in this paper are several theoretical and computational approaches that have been used to better understand the fracture of both single-crystal and polycrystalline diamond at the atomic level. The studies, which include first principles calculations, analytic models and molecular simulations, have been chosen to illustrate the different ways in which this problem has been approached, the conclusions and their reliability that have been reached by these methods, and how these theory and modelling methods can be effectively used together. PMID- 25713445 TI - Computational aspects of steel fracturing pertinent to naval requirements. AB - Modern high strength and ductile steels are a key element of US Navy ship structural technology. The development of these alloys spurred the development of modern structural integrity analysis methods over the past 70 years. Strength and ductility provided the designers and builders of navy surface ships and submarines with the opportunity to reduce ship structural weight, increase hull stiffness, increase damage resistance, improve construction practices and reduce maintenance costs. This paper reviews how analytical and computational tools, driving simulation methods and experimental techniques, were developed to provide ongoing insights into the material, damage and fracture characteristics of these alloys. The need to understand alloy fracture mechanics provided unique motivations to measure and model performance from structural to microstructural scales. This was done while accounting for the highly nonlinear behaviours of both materials and underlying fracture processes. Theoretical methods, data acquisition strategies, computational simulation and scientific imaging were applied to increasingly smaller scales and complex materials phenomena under deformation. Knowledge gained about fracture resistance was used to meet minimum fracture initiation, crack growth and crack arrest characteristics as part of overall structural integrity considerations. PMID- 25713446 TI - Driving force for indentation cracking in glass: composition, pressure and temperature dependence. AB - The occurrence of damage at the surface of glass parts caused by sharp contact loading is a major issue for glass makers, suppliers and end-users. Yet, it is still a poorly understood problem from the viewpoints both of glass science and solid mechanics. Different microcracking patterns are observed at indentation sites depending on the glass composition and indentation cracks may form during both the loading and the unloading stages. Besides, we do not know much about the fracture toughness of glass and its composition dependence, so that setting a criterion for crack initiation and predicting the extent of the damage yet remain out of reach. In this study, by comparison of the behaviour of glasses from very different chemical systems and by identifying experimentally the individual contributions of the different rheological processes leading to the formation of the imprint--namely elasticity, densification and shear flow--we obtain a fairly straightforward prediction of the type and extent of the microcracks which will most likely form, depending on the physical properties of the glass. Finally, some guidelines to reduce the driving force for microcracking are proposed in the light of the effects of composition, temperature and pressure, and the areas for further research are briefly discussed. PMID- 25713447 TI - Brittle fracture in structural steels: perspectives at different size-scales. AB - This paper describes characteristics of transgranular cleavage fracture in structural steel, viewed at different size-scales. Initially, consideration is given to structures and the service duty to which they are exposed at the macroscale, highlighting failure by plastic collapse and failure by brittle fracture. This is followed by sections describing the use of fracture mechanics and materials testing in carrying-out assessments of structural integrity. Attention then focuses on the microscale, explaining how values of the local fracture stress in notched bars or of fracture toughness in pre-cracked test pieces are related to features of the microstructure: carbide thicknesses in wrought material; the sizes of oxide/silicate inclusions in weld metals. Effects of a microstructure that is 'heterogeneous' at the mesoscale are treated briefly, with respect to the extraction of test-pieces from thick sections and to extrapolations of data to low failure probabilities. The values of local fracture stress may be used to infer a local 'work-of-fracture' that is found experimentally to be a few times greater than that of two free surfaces. Reasons for this are discussed in the conclusion section on nano-scale events. It is suggested that, ahead of a sharp crack, it is necessary to increase the compliance by a cooperative movement of atoms (involving extra work) to allow the crack-tip bond to displace sufficiently for the energy of attraction between the atoms to reduce to zero. PMID- 25713448 TI - Dynamic fracture of inorganic glasses by hard spherical and conical projectiles. AB - In this article, high-speed photographic investigations of the dynamic crack initiation and propagation in several inorganic glasses by the impact of small spherical and conical projectiles are described. These were carried out at speeds of up to approximately 2*10(6) frames s(-1). The glasses were fused silica, 'Pyrex' (a borosilicate glass), soda lime and B(2)O(3). The projectiles were 0.8 2 mm diameter spheres of steel, glass, sapphire and tungsten carbide, and their velocities were up to 340 m s(-1). In fused silica and Pyrex, spherical projectiles' impact produced Hertzian cone cracks travelling at terminal crack velocities, whereas in soda-lime glass fast splinter cracks were generated. No crack bifurcation was observed, which has been explained by the nature of the stress intensity factor of the particle-impact-generated cracks, which leads to a stable crack growth. Crack bifurcation was, however, observed in thermally tempered glass; this bifurcation has been explained by the tensile residual stress and the associated unstable crack growth. A new explanation has been proposed for the decrease of the included angle of the Hertzian cone cracks with increasing impact velocity. B(2)O(3) glass showed dynamic compaction and plasticity owing to impact with steel spheres. Other observations, such as total contact time, crack lengths and response to oblique impacts, have also been explained. PMID- 25713449 TI - Influence of structural hierarchy on the fracture behaviour of tooth enamel. AB - Tooth enamel has the critical role of enabling the mastication of food and also of protecting the underlying vital dentin and pulp structure. Unlike most vital tissue, enamel has no ability to repair or remodel and as such has had to develop robust damage tolerance to withstand contact fatigue events throughout the lifetime of a species. To achieve such behaviour, enamel has evolved a complex hierarchical structure that varies slightly between different species. The major component of enamel is apatite in the form of crystallite fibres with a nanometre sized diameter that extend from the dentin-enamel junction to the oral surface. These crystallites are bound together by proteins and peptides into a range of hierarchical structures from micrometre diameter prisms to 50-100 MUm diameter bundles of prisms known as Hunter-Schreger bands. As a consequence of such complex structural organization, the damage tolerance of enamel increases through various toughening mechanisms in the hierarchy but at the expense of fracture strength. This review critically evaluates the role of hierarchy on the development of the R-curve and the stress-strain behaviour. It attempts to identify and quantify the multiple mechanisms responsible for this behaviour as well as their impact on damage tolerance. PMID- 25713450 TI - Couple stresses and the fracture of rock. AB - An assessment is made here of the role played by the micropolar continuum theory on the cracked Brazilian disc test used for determining rock fracture toughness. By analytically solving the corresponding mixed boundary-value problems and employing singular-perturbation arguments, we provide closed-form expressions for the energy release rate and the corresponding stress-intensity factors for both mode I and mode II loading. These theoretical results are augmented by a set of fracture toughness experiments on both sandstone and marble rocks. It is further shown that the morphology of the fracturing process in our centrally pre-cracked circular samples correlates very well with discrete element simulations. PMID- 25713451 TI - Crossing grain boundaries in metals by slip bands, cleavage and fatigue cracks. AB - The size and the character (low and large angle, special boundaries, tilt and twist boundaries, twins) of the grain boundaries (GBs) in polycrystalline materials influence their strength and their fracture toughness. Recent studies devoted to nanocrystalline (NC) materials have shown a deviation from the Hall Petch law. Special GBs formed by Sigma3 twins in face-centred cubic metals are also known to have a strong effect on the mechanical behaviour of these metals, in particular their work-hardening rate. Grain orientation influences also crack path, the fracture toughness of body-centred cubic (BCC) metals and the fatigue crack growth rate of microstructurally short cracks. This paper deals both with slip transfer at GBs and with the interactions between propagating cracks with GBs. In the analysis of slip transfer, the emphasis is placed on twin boundaries (TBs) for which the dislocation reactions during slip transfer are analysed theoretically, experimentally and using the results of atomic molecular simulations published in the literature. It is shown that in a number of situations this transfer leads to a normal motion of the TB owing to the displacement of partial dislocations along the TB. This motion can generate a de twinning effect observed in particular in NC metals. Crack propagation across GBs is also considered. It is shown that cleavage crack path behaviour in BCC metals is largely dependent on the twist component of the GBs. A mechanism for the propagation of these twisted cracks involving a segmentation of the crack front and the existence of intergranular parts is discussed and verified for a pressure vessel steel. A similar segmentation seems to occur for short fatigue cracks although, quite surprisingly, this crossing mechanism for fatigue cracks does not seem to have been examined in very much detail in the literature. Metallurgical methods used to improve the strength of the materials, via grain boundaries, are briefly discussed. PMID- 25713452 TI - On localization and void coalescence as a precursor to ductile fracture. AB - Two modes of plastic flow localization commonly occur in the ductile fracture of structural metals undergoing damage and failure by the mechanism involving void nucleation, growth and coalescence. The first mode consists of a macroscopic localization, usually linked to the softening effect of void nucleation and growth, in either a normal band or a shear band where the thickness of the band is comparable to void spacing. The second mode is coalescence with plastic strain localizing to the ligaments between voids by an internal necking process. The ductility of a material is tied to the strain at macroscopic localization, as this marks the limit of uniform straining at the macroscopic scale. The question addressed is whether macroscopic localization occurs prior to void coalescence or whether the two occur simultaneously. The relation between these two modes of localization is studied quantitatively in this paper using a three-dimensional elastic-plastic computational model representing a doubly periodic array of voids within a band confined between two semi-infinite outer blocks of the same material but without voids. At sufficiently high stress triaxiality, a clear separation exists between the two modes of localization. At lower stress triaxialities, the model predicts that the onset of macroscopic localization and coalescence occur simultaneously. PMID- 25713453 TI - Microstructural aspects of fatigue in Ni-base superalloys. AB - Nickel-base superalloys are primarily used as components in jet engines and land based turbines. While compositionally complex, they are microstructurally simple, consisting of small (50-1000 nm diameter), ordered, coherent Ni(3)(Al,Ti)-type L1(2) or Ni(3)Nb-type DO(22) precipitates (called gamma(') and gamma(''), respectively) embedded in an FCC substitutional solid solution consisting primarily of Ni and other elements which confer desired properties depending upon the application. The grain size may vary from as small as 2 MUm for powder metallurgy alloys used in discs to single crystals the actual size of the component for turbine blades. The fatigue behaviour depends upon the microstructure, deformation mode, environment and cycle time. In many cases, it can be controlled or modified through small changes in composition which may dramatically change the mechanism of damage accumulation and the fatigue life. In this paper, the fundamental microstructural, compositional, environmental and deformation mode factors which affect fatigue behaviour are critically reviewed. Connections are made across a range of studies to provide more insight. Modern approaches are pointed out in which the wealth of available microstructural, deformation and damage information is used for computerized life prediction. The paper ends with a discussion of the very important and highly practical subject of thermo-mechanical fatigue (TMF). It is shown that physics-based modelling leads to significantly improved life prediction. Suggestions are made for moving forward on the critical subject of TMF life prediction in notched components. PMID- 25713454 TI - The mechanics and physics of fracturing: application to thermal aspects of crack propagation and to fracking. AB - By way of introduction, the general invariant integral (GI) based on the energy conservation law is presented, with mention of cosmic, gravitational, mass, elastic, thermal and electromagnetic energy of matter application to demonstrate the approach, including Coulomb's Law generalized for moving electric charges, Newton's Law generalized for coupled gravitational/cosmic field, the new Archimedes' Law accounting for gravitational and surface energy, and others. Then using this approach the temperature track behind a moving crack is found, and the coupling of elastic and thermal energies is set up in fracturing. For porous materials saturated with a fluid or gas, the notion of binary continuum is used to introduce the corresponding GIs. As applied to the horizontal drilling and fracturing of boreholes, the field of pressure and flow rate as well as the fluid output from both a horizontal borehole and a fracture are derived in the fluid extraction regime. The theory of fracking in shale gas reservoirs is suggested for three basic regimes of the drill mud permeation, with calculating the shape and volume of the local region of the multiply fractured rock in terms of the pressures of rock, drill mud and shale gas. PMID- 25713455 TI - Mechanical properties of micro- and nanocrystalline diamond foils. AB - Diamond coating of suitable template materials and subsequent delamination allows for the manufacturing of free-standing diamond foil. The evolution of the microstructure can be influenced by secondary nucleation via control of process conditions in the hot-filament chemical vapour deposition process. Bending tests show extraordinarily high strength (more than 8 GPa), especially for diamond foils with nanocrystalline structure. A detailed fractographic analysis is conducted in order to correlate measured strength values with crack-initiating defects. The size of the failure causing flaw can vary from tens of micrometres to tens of nanometres, depending on the diamond foil microstructure as well as the loading conditions. PMID- 25713456 TI - Material grain size and crack size influences on cleavage fracturing. AB - A review is given of the analogous dependence on reciprocal square root of grain size or crack size of fracture strength measurements reported for steel and other potentially brittle materials. The two dependencies have much in common. For onset of cleavage in steel, attention is focused on relationship of the essentially athermal fracture stress compared with a quite different viscoplastic yield stress behaviour. Both grain-size-dependent stresses are accounted for in terms of dislocation pile-up mechanics. Lowering of the cleavage stress occurs in steel because of carbide cracking. For crack size dependence, there is complication of localized crack tip plasticity in fracture mechanics measurements. Crack-size-dependent conventional and indentation fracture mechanics measurements are described also for results obtained on the diverse materials: polymethylmethacrylate, silicon crystals, alumina polycrystals and WC Co (cermet) composites. PMID- 25713457 TI - Microstructural mechanisms of cyclic deformation, fatigue crack initiation and early crack growth. AB - In this survey, the origin of fatigue crack initiation and damage evolution in different metallic materials is discussed with emphasis on the responsible microstructural mechanisms. After a historical introduction, the stages of cyclic deformation which precede the onset of fatigue damage are reviewed. Different types of cyclic slip irreversibilities in the bulk that eventually lead to the initiation of fatigue cracks are discussed. Examples of trans- and intercrystalline fatigue damage evolution in the low cycle, high cycle and ultrahigh cycle fatigue regimes in mono- and polycrystalline face-centred cubic and body-centred cubic metals and alloys and in different engineering materials are presented, and some microstructural models of fatigue crack initiation and early crack growth are discussed. The basic difficulties in defining the transition from the initiation to the growth of fatigue cracks are emphasized. In ultrahigh cycle fatigue at very low loading amplitudes, the initiation of fatigue cracks generally occupies a major fraction of fatigue life and is hence life controlling. PMID- 25713458 TI - Cleaving the Halqeh-ye-nur diamonds: a dynamic fracture analysis. AB - The degree of surface roughness and clarity with which a surface in a brittle material can be formed via fracture is known to be related to the speed of the propagating crack. Cracks traversing a brittle material at low speed produce very smooth surfaces, while those propagating faster create less reflective and rough surfaces (Buehler MJ, Gao H. 2006 Nature 439, 307-310 (doi:10.1038/nature04408)). The elastic wave speeds (c(l)~18 000 m s(-1), c(s)~11 750 m s(-1)) in diamond are fast (Willmott GR, Field JE. 2006 Phil. Mag. 86, 4305-4318 (doi:10.1080/14786430500482336)) and present a particular problem in creating smooth surfaces during the cleaving of diamond-a routine operation in the fashioning of diamonds for gemstone purposes--as the waves are reflected from the boundaries of the material and can add a tensile component to the propagating crack tip causing the well-known cleavage steps observed on diamond surfaces (Field JE. 1971 Contemp. Phys. 12, 1-31 (doi:10.1080/00107517108205103); Field JE. 1979 Properties of diamond, 1st edn, Academic Press; Wilks EM. 1958 Phil. Mag. 3, 1074-1080 (doi:10.1080/14786435808237036)). Here we report an analysis of two diamonds, having large dimensions and high aspect ratio, which from a gemological analysis are shown to have been cleaved from the same 200 carat specimen. A methodology for their manufacture is calculated by an analysis of a model problem. This takes into account the effect of multiple reflections from the sample boundaries. It is suggested that the lapidary had an intuitive guide to how to apply the cleavage force in order to control the crack speed. In particular, it is shown that it is likely that this technique caused the fracture to propagate at a lower speed. The sacrifice of a large diamond with the intention of creating thin plates, rather than a faceted gemstone, demonstrates how symbolism and beliefs associated with gemstones have changed over the centuries (Harlow GE. 1998 The nature of diamonds, Cambridge University Press). The scientific insights gained by studying these gemstones suggest a method of producing macroscale atomically flat and stress-free surfaces on other brittle materials. PMID- 25713459 TI - Fracture and fracture toughness of nanopolycrystalline metals produced by severe plastic deformation. AB - The knowledge of the fracture of bulk metallic materials developed in the last 50 years is mostly based on materials having grain sizes, d, in the range of some micrometres up to several hundred micrometres regarding the possibilities of classical metallurgical methods. Nowadays, novel techniques provide access to much smaller grain sizes, where severe plastic deformation (SPD) is one of the most significant techniques. This opens the door to extend basic research in fracture mechanics to the nanocrystalline (NC) grain size regime. From the technological point of view, there is also the necessity to evaluate standard fracture mechanics data of these new materials, such as the fracture toughness, in order to allow their implementation in engineering applications. Here, an overview of recent results on the fracture behaviour of several different ultrafine-grained (d<1 MUm) and NC (d<100 nm) metals and alloys covering examples of body- and face-centred cubic structures produced by SPD will be given. PMID- 25713460 TI - Fracturing across the multi-scales of diverse materials. AB - Everyone has to deal with fracturing of materials at one level or another, beginning from normal household chores and extending to the largest scale of observations reported for catastrophic events occurring on a geological level or even expanded to events in outer space. Such wide perspective is introduced in the current introduction of this theme issue. The follow-on organization of technical articles provides a flavour of the range in size scales at which fracturing occurs in a wide diversity of materials-from 'fracking' oil extraction and earth moving to laboratory testing of rock material and extending to the cracking of tooth enamel. Of important scientific interest are observations made and analysed at the smallest dimensions corresponding to the mechanisms by which fracture is either enhanced or hindered by permanent deformation or other processes. Such events are irrevocably linked to the atomic structure in all engineering materials, a sampling of which is presented, including results for crystalline and amorphous materials. Hooray for the broad subject description that is hoped to be appealing to the interested reader. PMID- 25713461 TI - Indoor radon activity concentration measurements in the great historical museums of University of Naples, Italy. AB - Indoor radon activity concentrations were measured in seven Museums of University of Naples, very old buildings of great historical value. The measurements were performed using a time-integrated technique based on LR-115 solid-state nuclear track detectors. The annual average concentrations were found to range from 40 up to 1935 Bq m(-3) and in 26 % of measurement sites, the values were higher than 500 Bq m(-3) which is the limit value of Italian legislation for workplace. Moreover, we analysed the seasonal variations of radon concentrations observing the highest average in cold weather than in warm. PMID- 25713462 TI - One-year randomized controlled trial and follow-up of integrated neurocognitive therapy for schizophrenia outpatients. AB - OBJECTIVE: Cognitive remediation (CR) approaches have demonstrated to be effective in improving cognitive functions in schizophrenia. However, there is a lack of integrated CR approaches that target multiple neuro- and social-cognitive domains with a special focus on the generalization of therapy effects to functional outcome. METHOD: This 8-site randomized controlled trial evaluated the efficacy of a novel CR group therapy approach called integrated neurocognitive therapy (INT). INT includes well-defined exercises to improve all neuro- and social-cognitive domains as defined by the Measurement And Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative by compensation and restitution. One hundred and fifty-six outpatients with a diagnosis of schizophrenia or schizoaffective disorder according to DSM-IV-TR or ICD-10 were randomly assigned to receive 15 weeks of INT or treatment as usual (TAU). INT patients received 30 bi-weekly therapy sessions. Each session lasted 90min. Mixed models were applied to assess changes in neurocognition, social cognition, symptoms, and functional outcome at post-treatment and at 9-month follow-up. RESULTS: In comparison to TAU, INT patients showed significant improvements in several neuro- and social-cognitive domains, negative symptoms, and functional outcome after therapy and at 9-month follow-up. Number-needed-to-treat analyses indicate that only 5 INT patients are necessary to produce durable and meaningful improvements in functional outcome. CONCLUSIONS: Integrated interventions on neurocognition and social cognition have the potential to improve not only cognitive performance but also functional outcome. These findings are important as treatment guidelines for schizophrenia have criticized CR for its poor generalization effects. PMID- 25713463 TI - Characterization and angiogenic potential of human neonatal and infant thymus mesenchymal stromal cells. AB - Resident mesenchymal stromal cells (MSCs) are involved in angiogenesis during thymus regeneration. We have previously shown that MSCs can be isolated from enzymatically digested human neonatal and infant thymus tissue that is normally discarded during pediatric cardiac surgical procedures. In this paper, we demonstrate that thymus MSCs can also be isolated by explant culture of discarded thymus tissue and that these cells share many of the characteristics of bone marrow MSCs. Human neonatal thymus MSCs are clonogenic, demonstrate exponential growth in nearly 30 population doublings, have a characteristic surface marker profile, and express pluripotency genes. Furthermore, thymus MSCs have potent proangiogenic behavior in vitro with sprout formation and angiogenic growth factor production. Thymus MSCs promote neoangiogenesis and cooperate with endothelial cells to form functional human blood vessels in vivo. These characteristics make thymus MSCs a potential candidate for use as an angiogenic cell therapeutic agent and for vascularizing engineered tissues in vitro. PMID- 25713464 TI - NG2+ progenitors derived from embryonic stem cells penetrate glial scar and promote axonal outgrowth into white matter after spinal cord injury. AB - The glial scar resulting from spinal cord injury is rich in chondroitin sulfate proteoglycan (CSPG), a formidable barrier to axonal regeneration. We explored the possibility of breaching that barrier by first examining the scar in a functional in vitro model. We found that embryonic stem cell-derived neural lineage cells (ESNLCs) with prominent expression of nerve glial antigen 2 (NG2) survived, passed through an increasingly inhibitory gradient of CSPG, and expressed matrix metalloproteinase 9 (MMP-9) at the appropriate stage of their development. Outgrowth of axons from ESNLCs followed because the migrating cells sculpted pathways in which CSPG was degraded. The degradative mechanism involved MMP-9 but not MMP-2. To confirm these results in vivo, we transplanted ESNLCs directly into the cavity of a contused spinal cord 9 days after injury. A week later, ESNLCs survived and were expressing both NG2 and MMP-9. Their axons had grown through long distances (>10 mm), although they preferred to traverse white rather than gray matter. These data are consistent with the concept that expression of inhibitory CSPG within the injury scar is an important impediment to regeneration but that NG2+ progenitors derived from ESNLCs can modify the microenvironment to allow axons to grow through the barrier. This beneficial action may be partly due to developmental expression of MMP-9. We conclude that it might eventually be possible to encourage axonal regeneration in the human spinal cord by transplanting ESNLCs or other cells that express NG2. PMID- 25713465 TI - Efficient generation of megakaryocytes from human induced pluripotent stem cells using food and drug administration-approved pharmacological reagents. AB - Megakaryocytes (MKs) are rare hematopoietic cells in the adult bone marrow and produce platelets that are critical to vascular hemostasis and wound healing. Ex vivo generation of MKs from human induced pluripotent stem cells (hiPSCs) provides a renewable cell source of platelets for treating thrombocytopenic patients and allows a better understanding of MK/platelet biology. The key requirements in this approach include developing a robust and consistent method to produce functional progeny cells, such as MKs from hiPSCs, and minimizing the risk and variation from the animal-derived products in cell cultures. In this study, we developed an efficient system to generate MKs from hiPSCs under a feeder-free and xeno-free condition, in which all animal-derived products were eliminated. Several crucial reagents were evaluated and replaced with Food and Drug Administration-approved pharmacological reagents, including romiplostim (Nplate, a thrombopoietin analog), oprelvekin (recombinant interleukin-11), and Plasbumin (human albumin). We used this method to induce MK generation from hiPSCs derived from 23 individuals in two steps: generation of CD34(+)CD45(+) hematopoietic progenitor cells (HPCs) for 14 days; and generation and expansion of CD41(+)CD42a(+) MKs from HPCs for an additional 5 days. After 19 days, we observed abundant CD41(+)CD42a(+) MKs that also expressed the MK markers CD42b and CD61 and displayed polyploidy (>=16% of derived cells with DNA contents >4N). Transcriptome analysis by RNA sequencing revealed that megakaryocytic-related genes were highly expressed. Additional maturation and investigation of hiPSC derived MKs should provide insights into MK biology and lead to the generation of large numbers of platelets ex vivo. PMID- 25713466 TI - Dental pulp stem cells: a new cellular resource for corneal stromal regeneration. AB - Corneal blindness afflicts millions of individuals worldwide and is currently treated by grafting with cadaveric tissues; however, there are worldwide donor tissue shortages, and many allogeneic grafts are eventually rejected. Autologous stem cells present a prospect for personalized regenerative medicine and an alternative to cadaveric tissue grafts. Dental pulp contains a population of adult stem cells and, similar to corneal stroma, develops embryonically from the cranial neural crest. We report that adult dental pulp cells (DPCs) isolated from third molars have the capability to differentiate into keratocytes, cells of the corneal stoma. After inducing differentiation in vitro, DPCs expressed molecules characteristic of keratocytes, keratocan, and keratan sulfate proteoglycans at both the gene and the protein levels. DPCs cultured on aligned nanofiber substrates generated tissue-engineered, corneal stromal-like constructs, recapitulating the tightly packed, aligned, parallel fibrillar collagen of native stromal tissue. After injection in vivo into mouse corneal stroma, human DPCs produced corneal stromal extracellular matrix containing human type I collagen and keratocan and did not affect corneal transparency or induce immunological rejection. These findings demonstrate a potential for the clinical application of DPCs in cellular or tissue engineering therapies for corneal stromal blindness. PMID- 25713467 TI - Rapid exclusion of acute myocardial infarction in patients with undetectable troponin using a sensitive troponin I assay. AB - OBJECTIVE: With a high-sensitivity troponin assay, it may be possible to exclude acute myocardial infarction with a single blood test on arrival in the emergency department by using a novel 'rule out' cut-off set at the limit of detection of the assay. We aimed to determine whether this can also be achieved using a contemporary sensitive troponin assay that does not meet 'high-sensitivity' criteria. METHODS: In a prospective diagnostic cohort study, we included patients presenting to the emergency department with suspected cardiac chest pain. For this secondary analysis, serum samples drawn on arrival were tested using a contemporary sensitive troponin I assay (s-cTnI; Siemens Ultra ADVIA Centaur, 99th percentile 40 ng/L, limit of detection 6 ng/L). Acute myocardial infarction was adjudicated by two independent investigators based on reference standard troponin testing >=12 h after symptom onset. RESULTS: Of 414 participants, 70 (16.9%) had acute myocardial infarction and 205 (49.5%) had initial s-cTnI concentrations below the limit of detection. Using the limit of detection as a 'rule out' cut-off gave a sensitivity of 94.3% (95% CI 86.0-98.4%) for acute myocardial infarction. If only patients with s-cTnI below the limit of detection and no electrocardiogram ischaemia were considered to have acute myocardial infarction 'ruled out' (41.8% of the cohort, n = 174), sensitivity would rise to 97.1% (90.1-99.7%) and negative predictive value to 98.8% (95.9-99.9%). CONCLUSIONS: Acute myocardial infarction cannot be excluded in patients with s cTnI concentrations below the limit of detection using the contemporary sensitive assay evaluated. Future work with this assay should focus on serial sampling over 1-3 h and combination with clinical information and/or additional biomarkers. PMID- 25713468 TI - Triggering of acute coronary occlusion by episodes of anger. AB - AIMS: The aim of this study was to report the association between episodes of anger and acute myocardial infarction (MI) in patients with angiographically confirmed coronary occlusion. METHODS AND RESULTS: 313 participants with acute coronary occlusion (Thrombolysis In Myocardial Infarction 0 or 1 at emergency angiography) reported frequency of anger episodes in the 48 h prior to MI. In primary analysis, anger exposures within 2 h and 2-4 h prior to symptom onset were compared with subjects' own usual yearly exposure to anger using case crossover methodology. Anger level >=5 (on an anger scale of 1-7) was reported by seven (2.2%) participants within 2 h of MI. Compared with usual frequency, the relative risk of onset of MI symptoms occurring within 2 h of anger level >=5 (defined as very angry) was 8.5 (95% confidence interval 4.1-17.6). Anger level <5 was not associated with onset of MI symptoms. Compared with 24-26 h pre MI, anxiety scores >75th percentile on State-Trait Personality Inventory were associated with a relative risk of 2.0 (95% confidence interval 1.1-3.8) and in those above the 90th percentile, the relative risk of MI symptom onset was 9.5 (95% confidence interval 2.2-40.8). CONCLUSION: Findings confirm that episodes of intense anger, defined as being 'very angry, body tense, clenching fists or teeth' (within 2 h) are associated with increased relative risk for acute coronary occlusion. Additionally, increased anxiety was associated with coronary occlusion. Further study, including the role of potential modifiers, may provide insight into prevention of MI during acute emotional episodes. PMID- 25713469 TI - Signature of high Tc above 25 K in high quality superconducting diamond. AB - We have observed zero resistivity above 10 K and an onset of resistivity reduction at 25.2 K in a heavily B-doped diamond film. However, the effective carrier concentration is similar to that of superconducting diamond with a lower Tc. We found that the carrier has a longer mean free path and lifetime than in the previous report, indicating that this highest Tc diamond has better crystallinity compared to that of other superconducting diamond films. In addition, the susceptibility shows a small transition above 20 K in the high quality diamond, suggesting a signature of superconductivity above 20 K. These results strongly suggest that heavier carrier doped defect-free crystalline diamond could give rise to high Tc diamond. PMID- 25713470 TI - Temperature dependence of self-consistent full matrix material constants of lead zirconate titanate ceramics. AB - Up to date, there are no self-consistent data in the literature on the temperature dependence of full matrix material properties for piezoelectric materials because they are extremely difficult to determine. Using only one sample, we have measured the temperature dependence of full matrix constants of lead zirconate titanate (PZT-4) from room temperature to 120 degrees C by resonant ultrasound spectroscopy. Self-consistency is guaranteed here because all data at different temperatures come from one sample. Such temperature dependence data would make it a reality to accurately predict device performance at high temperatures using computer simulations. PMID- 25713472 TI - FDA's Expedited Approval Mechanisms for New Drug Products. PMID- 25713471 TI - Electronic desalting for controlling the ionic environment in droplet-based biosensing platforms. AB - The ability to control the ionic environment in saline waters and aqueous electrolytes is useful for desalination as well as electronic biosensing. We demonstrate a method of electronic desalting at micro-scale through on-chip micro electrodes. We show that, while desalting is limited in bulk solutions with unlimited availability of salts, significant desalting of >=1 mM solutions can be achieved in sub-nanoliter volume droplets with diameters of ~250 MUm. Within these droplets, by using platinum-black microelectrodes and electrochemical surface treatments, we can enhance the electrode surface area to achieve >99% and 41% salt removal in 1 mM and 10 mM salt concentrations, respectively. Through self-consistent simulations and experimental measurements, we demonstrate that conventional double-layer theory over-predicts the desalting capacity and, hence, cannot be used to model systems that are mass limited or undergoing significant salt removal from the bulk. Our results will provide a better understanding of capacitive desalination, as well as a method for salt manipulation in high throughput droplet-based microfluidic sensing platforms. PMID- 25713473 TI - Biparental incubation-scheduling: no experimental evidence for major energetic constraints. AB - Incubation is energetically demanding, but it is debated whether these demands constrain incubation-scheduling (i.e., the length, constancy, and timing of incubation bouts) in cases where both parents incubate. Using 2 methods, we experimentally reduced the energetic demands of incubation in the semipalmated sandpiper, a biparental shorebird breeding in the harsh conditions of the high Arctic. First, we decreased the demands of incubation for 1 parent only by exchanging 1 of the 4 eggs for an artificial egg that heated up when the focal bird incubated. Second, we reanalyzed the data from the only published experimental study that has explicitly tested energetic constraints on incubation scheduling in a biparentally incubating species (Cresswell et al. 2003). In this experiment, the energetic demands of incubation were decreased for both parents by insulating the nest cup. We expected that the treated birds, in both experiments, would change the length of their incubation bouts, if biparental incubation-scheduling is energetically constrained. However, we found no evidence that heating or insulation of the nest affected the length of incubation bouts: the combined effect of both experiments was an increase in bout length of 3.6min (95% CI: -33 to 40), which is equivalent to a 0.5% increase in the length of the average incubation bout. These results demonstrate that the observed biparental incubation-scheduling in semipalmated sandpipers is not primarily driven by energetic constraints and therefore by the state of the incubating bird, implying that we still do not understand the factors driving biparental incubation scheduling. PMID- 25713474 TI - Effects of age, size, and mating history on sex role decision of a simultaneous hermaphrodite. AB - Contrasting with separate-sexed animals, simultaneous hermaphrodites display unique reproductive strategies as they are male and female at the same time. Simultaneous hermaphrodites that copulate unilaterally, for instance, make a decision to mate as a male or female. Previous studies have demonstrated that sex role preference in hermaphrodites is flexible and is controlled by several, often confounding, factors. We examined the relationship between sex role decisions and 3 life-history traits (age, size, and mating history) in the great pond snail, Lymnaea stagnalis. Based on our field observations, which indicate that adult individuals show overlapping generations and large variation in body size during the breeding season, we performed a sex role choice experiment in the laboratory. We found that young and small snails mate as males first. Both age and size significantly affected sex role decision, with age having a stronger effect. Furthermore, we tested whether L. stagnalis becomes reluctant to inseminate a mate after being inseminated because it is known that after insemination, male investment substantially reduces. Contrary to expectations, our results indicate that the receipt of seminal fluid does not seem to reduce male motivation. In sum, sex role decisions in L. stagnalis are largely determined by age and size but not by having received seminal fluid. This mating pattern, however, does not fully support the size-advantage model because large or old individuals did not perform better as females in our experiment. These results imply a conflicting mating interest, rather than harmonious agreement, between age- and size different hermaphrodites. PMID- 25713476 TI - Reliability of marginal microleakage assessment by visual and digital methods. AB - OBJECTIVE: The aim of this study was to investigate the reliability of visual and digital methods to assess marginal microleakage in vitro. MATERIALS AND METHODS: Typical Class V preparations were made in bovine teeth and filled with composite resin. After dye penetration (0.5% basic fuchsin), teeth were sectioned and the 53 obtained fragments were assessed according to visual (stereomicroscope) and digital methods (Image Tool Software((r))-ITS) (University of Texas Health Science Center-San Antonio Dental School, USA). Two calibrated examiners (A and B) evaluated dye penetration, by means of a stereomicroscope with *20 magnification (scores), and by the ITS (millimeters). The intra- and inter examiner agreement was estimated according to Kappa statistics (kappa), and intraclass correlation coefficient (rho). RESULTS: In relation to the visual method, the intra-examiner agreement was almost perfect (kappaA = 0.87) and substantial (kappaB = 0.76), respectively to the examiner A and B. The inter examiner agreement showed an almost perfect reliability (kappa = 0.84). For the digital method, the intra-examiner agreement was almost perfect for both examiners and equal to rho = 0.99, and so was the inter-examiner agreement value. CONCLUSION: Visual (stereomicroscope) and digital methods (ITS) showed high levels of intra- and inter-examiner reproducibility when marginal microleakage was assessed. PMID- 25713475 TI - Cortisol in mother's milk across lactation reflects maternal life history and predicts infant temperament. AB - The maternal environment exerts important influences on offspring mass/growth, metabolism, reproduction, neurobiology, immune function, and behavior among birds, insects, reptiles, fish, and mammals. For mammals, mother's milk is an important physiological pathway for nutrient transfer and glucocorticoid signaling that potentially influences offspring growth and behavioral phenotype. Glucocorticoids in mother's milk have been associated with offspring behavioral phenotype in several mammals, but studies have been handicapped by not simultaneously evaluating milk energy density and yield. This is problematic as milk glucocorticoids and nutrients likely have simultaneous effects on offspring phenotype. We investigated mother's milk and infant temperament and growth in a cohort of rhesus macaque (Macaca mulatta) mother-infant dyads at the California National Primate Research Center (N = 108). Glucocorticoids in mother's milk, independent of available milk energy, predicted a more Nervous, less Confident temperament in both sons and daughters. We additionally found sex differences in the windows of sensitivity and the magnitude of sensitivity to maternal-origin glucocorticoids. Lower parity mothers produced milk with higher cortisol concentrations. Lastly, higher cortisol concentrations in milk were associated with greater infant weight gain across time. Taken together, these results suggest that mothers with fewer somatic resources, even in captivity, may be "programming" through cortisol signaling, behaviorally cautious offspring that prioritize growth. Glucocorticoids ingested through milk may importantly contribute to the assimilation of available milk energy, development of temperament, and orchestrate, in part, the allocation of maternal milk energy between growth and behavioral phenotype. PMID- 25713477 TI - Comparison of cytotoxicity of various concentrations origanum extract solution with 2% chlorhexidine gluconate and 5.25% sodium hypochlorite. AB - OBJECTIVE: The purpose of this in vitro study was to compare the cytotoxicity of 0.5-4.5 origanum extract solution (OES), 2% chlorhexidine gluconate (CHX) and 5.25% sodium hypochlorite (NaOCl) with WST-1 test on human periodontal ligament (hPDL) fibroblasts. MATERIALS AND METHODS: About 0.5-4.5% OES, 2% CHX and 5.25% NaOCl solutions cytotoxicity was evaluated with cell culture test using PDL fibroblasts. Viability of hPDL cells was evaluated with WST-1 (Cell Proliferation Reagent WST-1 Roche) test at 1, 24 and 72(nd) h. hPDL cells were plated at 20 * 10(3) cells per well in 96-well plates. Absorbance values were read in optical density 480 nm by ELISA plate reader spectrophotometer. The statistical differences between various groups were evaluated using one-way ANOVA, post-hoc Duncan's Multiple Range test using SAS software. Statistically, a significant difference was considered at P < 0.001. RESULTS: According to the 1-h cytotoxicity results, 0.5% OES showed the least cytotoxic effect in test groups. There were not found any statistical significance between 1% OES and 2% CHX. About 5.25% NaOCl showed more cytotoxic effect than 1% OES and 2% CHX. In 24 and 72 h, different concentrations of OES, 5.25% NaOCl, 2% CHX solutions showed similar cytotoxic effect. CONCLUSIONS: Based on these results, 1% OES and 2% CHX showed similar results and less cytotoxic effect than 5.25% NaOCl. It could be considered as a favorable solution concentration when OES was used as root canal irrigation solution. PMID- 25713478 TI - A cone-beam computed tomographic study of root canal systems in mandibular premolars in a Turkish population: Theoretical model for determining orifice shape. AB - OBJECTIVE: The purposes of this retrospective study were to represent a newly designed theoretical model for determining orifice shape and morphologic properties of mandibular premolars and to correlate these findings with each other. MATERIALS AND METHODS: A total of 287 mandibular premolar images obtained from 88 patients by cone-beam computed tomography were included in this study. The measurements were performed below the cementoenamel junction, and different orifice configurations were defined in accordance with various ratios. The age and gender of the patient, the tooth type and position, the number of roots, orifice configuration, root canal configuration, presence of C-shaped canal, and the presence of radicular groove were recorded. It was also recorded whether the root canal becomes round or not and if any, length of the root canal from the orifice to the section in which it becomes round. Furthermore, the theoretical model for determining orifice shape was defined after measurements. The orifice shape was determined as round, oval, flat, keyhole-shaped, and T-shaped, and orifices with short, normal length, and long isthmus. Statistical analyses were performed using Chi-square and Spearman's rank correlation tests (P = 0.05). RESULTS: Orifice configurations were, usually, flat (37%), or keyhole-shaped (23%). The prevalence of T-shaped was found to be 3.8%. The prevalence of C shaped canals was found to be 2.1%. The percentage of root canals that became round in the middle or apical thirds was 95.1%. Radicular grooves were detected in 37 (24%) of first premolars and six (4.5%) of second premolars. Statistical analysis revealed that the mean length of distance until the canal reached a round shape varied according to age group (r = -0.270; P < 0.001). There was a statistically significant difference between radicular groove and tooth type (P < 0.001). CONCLUSIONS: The mean length of distance until the canal reached a round shape correlated with the patient's age. The new theoretical model could be beneficial to determine orifice configurations. PMID- 25713479 TI - Antibacterial and smear layer removal capability of oregano extract solution. AB - OBJECTIVE: The aim of this in vitro study was to evaluate the antimicrobial effect of oregano extract solution (OES) against Enterococcus faecalis within root canals and dentin tubules, and its effect on smear layer. MATERIALS AND METHODS: A total of 180 human maxillary central incisors was selected. After removal of coronal part of the teeth, root canals were prepared using ProTaper rotary files (Dentsply, Tulsa Endodontics, OK, USA) to #F3 with the crown-down manner. The roots were randomly assigned to 15 groups (n = 12 for each). In the first seven groups, the antimicrobial effects of the test groups were evaluated. Suspensions of E. faecalis cultures were adjusted to 1.0 McFarland (1 * 10(8) colony-forming unit [CFU]/ml), and sterilized teeth were placed in Eppendorf tubes and kept at 37 degrees C for 4 weeks. Samples were then taken from the root canals before irrigation using three sterile paper points. Dentin samples were taken from root canals with ProTaper #F4 and #F5 series rotary instruments after irrigation. The aliquots of samples were placed into the brain heart infusion and incubated at 37 degrees C for 48 h and then the CFUs were counted. In the other eight groups, the efficacy of the irrigation solutions on removing the smear layer was evaluated using scanning electron microscope (Leo 440, Oxford Microscopy Ltd., Cambridge, England) analysis. Statistical evaluation of the microbiological data was performed using the Kruskall-Wallis and Mann-Witney U test (P < 0.05). RESULTS: There was a statistically difference between the groups (P < 0.05). Chlorhexidine gluconate (CHX), 5% and 2% OES wasn't found to be statistically significant regarding their antibacterial activities against E. faecalis (P > 0.05). 1% OES and NaOCl showed similar antimicrobial effect (P > 0.05), and 1% OES and NaOCl were better than ethylenediaminetetraacetic acid (EDTA) and saline (P < 0.05) but not as successful as CHX. According to the results obtained from dentin, CHX is the most effective solution within dentinal tubules. Different concentrations of OES were not achieved smear layer removal alone but OES in conjunction with 17% EDTA was the final irrigating solution achieved the smear layer removal without dentin erosion. CONCLUSIONS: Within the limitations of this study, OES appears to be a possible alternative to NaOCl as a root canal irrigant on the eradication of E. faecalis and removal of smear layer. PMID- 25713481 TI - Biocompatibility of a new epoxy resin-based root canal sealer in subcutaneous tissue of rat. AB - OBJECTIVE: The objective was to evaluate the subcutaneous biocompatibility of two root canal sealers. MATERIALS AND METHODS: Thirty female rats were distributed into two groups of 15 animals. Each received subcutaneous dorsal implants: Silicone tubes filled with AH Plus or Obtuseal. After the 11(th), 14(th), and 45(th) days, tissues were collected for biopsy and fixed and processed for histologic evaluation. Observations of the cellular inflammatory components, such as lymphocytes and macrophages, were made. The data were analyzed using Kruskal Wallis and Connover tests (P < 0.05). RESULTS: By the 7(th) day, lymphocyte infiltration increased in both groups (P = 0.0104). However, macrophage infiltration increased only in the AH Plus group (P = 0.0011). By the 14(th) and 45(th) days, lymphocyte and macrophage infiltrations were reduced. At the end of the experimental period, no statistically significant differences were found between the AH Plus group and the Obtuseal group (P > 0.05). CONCLUSION: After 45 days, Obtuseal yielded a satisfactory tissue reaction; it was biocompatible when tested in subcutaneous rat tissue. On the basis of the obtained results, it was concluded that Obtuseal root canal sealer caused a satisfactory tissue reaction as AH plus, because it was biocompatible when tested in the subcutaneous tissue of rats. PMID- 25713480 TI - Do different bleaching protocols affect the enamel microhardness? AB - OBJECTIVE: Tooth bleaching tends to increase enamel roughness and porosity, in addition to reducing surface microhardness. The aim of this in vitro study was to evaluate the effects of bleaching treatments using different hydrogen peroxide (HP) concentrations, with and without light activation on bovine enamel microhardness. MATERIALS AND METHODS: The buccal surfaces of sixty bovine incisors were flattened and polished and the enamel specimens were divided into six groups: G1 : c0 ontrol, exposed to artificial saliva; G2: 35% HP applied in two sessions (45' each); G3: 35% HP applied in two sessions (3 * 15' each); G4: 35% HP applied in one session (3 * 7'30") plus hybrid light (HL); G5: 25% HP applied in one session (3 * 7'30") plus HL; and G6: 15% HP applied in one session (3 * 7'30") plus HL. After the treatment, the enamel specimens were stored in artificial saliva. The surface microhardness (Knoop) was measured at the baseline, 24 h and 7 days after bleaching. The data was analyzed using the ANOVA test, followed by the Tukey-Krummer test (P < 0.05). RESULTS: All bleaching procedures lead to a decrease in surface microhardness when compared with the control group after 24 h. The lowest change in surface microhardness was found in the specimens treated with 15% HP plus HL. However, 35% HP plus HL induced the highest decrease in surface microhardness. After 7 days of remineralization, the surface microhardness returned to normal levels for all bleached specimens. CONCLUSION: Therefore, it can be concluded that the bleaching protocols caused a slight enamel surface alteration. However, the remineralization process minimized these effects. PMID- 25713482 TI - Assessment of gingival health among school children in Sharjah, United Arab Emirates. AB - OBJECTIVES: The present study evaluated the gingival condition among school going children in Sharjah, United Arab Emirates and determined its relationship with tooth brushing frequency, diet and dental caries. MATERIALS AND METHODS: Four hundred and five children participated in the study. There were 232 boys (57%) and 173 (43%) girls. Children were grouped based on age as <=6 years (n = 84) mean age 4.72 +/- 0.50 and >6 years (n = 321) mean age 8.47 +/- 1.65. The amount of dental plaque and gingival condition were assessed on the inner and outer surface of six index teeth using Silness and Loe and Loe and Silness criteria. Dental caries status was assessed using WHO 1997 criteria. Dental examination, tooth brushing frequency and 24 h diet chart were recorded by calibrated dentists. Logistic regression analysis was used to determine the predictors of gingivitis. RESULTS: Increase in decayed, missing, and filled teeth values corresponds to increase in plaque index and gingival index scores (P <= 0.05). A logistic regression analysis of the predictors of gingivitis showed that males were 2.11 times less likely to have gingivitis compared with females (odds ratio [OR]: 0.47,95% confidence interval [CI]: 0.24-0.93, P = 0.03) and children aged <=6 years were 3.06 times less likely to have gingivitis than those aged >6 years (OR: 0.33, 95% CI: 0.17-0.62, P = 0.00). Tooth brushing frequency and diet were not significant predictors. CONCLUSION: Current study clearly demonstrated that female gender and children more than 6 years were more likely to have gingivitis. PMID- 25713483 TI - The effects of different nickel-titanium instruments on dentinal microcrack formations during root canal preparation. AB - OBJECTIVE: The aim of the present study was to investigate the incidence of dentinal microcracks caused by different preparation techniques. MATERIALS AND METHODS: 120 extracted human mandibular incisor teeth were divided into five experimental groups and one control group (n = 20): Group 1: Hand preparation with balanced force technique up to #25 K-file. Group 2: Preparation with only ProTaper F2 instrument in a reciprocating movement. Group 3: Preparation with Reciproc R25 instrument in a reciprocating movement. Group 4: Preparation with ProTaper instruments up to F2 instrument. Group 5: Preparation with ProTaper Next instruments up to X2 instrument. No procedure was applied to control group. The roots were sectioned horizontally at 3, 6 and 9 mm from the apex and examined. Absence or presence of dentinal microcracks was noted. RESULTS: The Chi-square test was performed to compare the appearance of cracked roots between all groups. There were no significant differences among the groups (P > 0.05). CONCLUSIONS: In conclusion, except the hand file and control group, all experimental groups showed microcrack formations. PMID- 25713484 TI - The effect of highly active antiretroviral therapy on the prevalence of oral manifestation in human immunodeficiency virus-infected patients in Karnataka, India. AB - OBJECTIVES: Acquired Immunodeficiency Syndrome (AIDS) is a highly lethal, progressively epidemic viral infection characterized by profound impairment of the immune system. Oral manifestations are common in Human Immunodeficiency Virus (HIV) infected AIDS patients, and are usually the first indicator of symptom and disease progression. The main objective of the current study was to compare the prevalence of oral manifestations in HIV patients on Highly Active Antiretroviral Therapy (HAART) with those, not on HAART therapies. MATERIALS AND METHODS: A cross sectional study was conducted among 100 patients diagnosed as human immune virus sero-positive. These patients were divided equally into two groups (50 each); Group I patients on HAART and Group II patients who were not on HAART. Information regarding age, sex and cluster of differentiation 4 cell count was obtained from the medical records. Oral examination was done, and findings were recorded by using internationally accepted presumptive clinical criteria. Statistical analysis was performed using Chi-square statistical test. RESULTS: The presence of oral manifestations was significantly decreased in subjects on HAART (32%) compared to those who are not on HAART (56%). The most common oral lesions detected in patients on HAART were increased oral hyper-pigmentation (14%), recurrent aphthous stomatitis (8%), non-specific ulcerations (4%), pseudo membranous candidiasis (2%), periodontitis (2%) and xerostomia (2%), whereas in non HAART oral hyperpigmentation (10%), pseudo-membranous candidiasis (8%), angular cheilitis (4%), and erythematous candidiasis (4%) and Periodontitis (14%) were more prevalent. CONCLUSION: The number and severity of oral manifestation decreased, and even there was a change in the type of oral manifestations on HAART, which may be because of the improvement in immunity gained by the therapy. PMID- 25713485 TI - Impact of metronidazole and amoxicillin combination on matrix metalloproteinases 1 and tissue inhibitors of matrix metalloproteinases balance in generalized aggressive periodontitis. AB - OBJECTIVE: Generalized aggressive periodontitis (GAgP) is a complex periodontal disease affecting the entire dentition with a rapid destruction of the periodontium and resulting in loss of teeth. We hypothesized that better clinical healing of adjunctive use of amoxicillin plus metronidazole combination may be related to the effect of this combination therapy to restore imbalance between matrix metalloproteinases (MMP) and their tissue inhibitors (TIMP) which is associated with connective tissue and alveolar bone destruction in patients with GAgP. MATERIALS AND METHODS: Twenty-eight subjects diagnosed with GAgP were recruited. Patients were randomly assigned to test or control groups. MMP-1/TIMP 1 ratio was compared between groups receiving scaling and root planning (SRP) alone (control) or in combination with amoxicillin plus metronidazole (test). Clinical periodontal variables were measured. Gingival crevicular fluid samples were obtained and analyzed for MMP-1 and TIMP-1. Measurements were taken at baseline and repeated at 3 and 6 months after therapy. RESULTS: Total MMP-1 levels were significantly decreased in both groups (P < 0.05) at 3 and 6 months. MMP-1 concentration levels showed a similar pattern to MMP-1 total levels decreasing significantly at 3 months (P < 0.05). TIMP-1 concentration levels increased in the test group throughout the study period, while the difference did not reach statistical significance (P > 0.05). TIMP-1/MMP-1 balance was restored in test group at 6 months significantly better than the control group (P < 0.05). CONCLUSION: The results of this study suggest that metronidazole and amoxicillin combination as an adjunct to SRP results in better clinical healing through restoring TIMP-1/MMP-1 balance. PMID- 25713486 TI - Crevicular fluid levels of interleukin-8, interleukin-17 and soluble intercellular adhesion molecule-1 after regenerative periodontal therapy. AB - OBJECTIVE: The aim of this study is to evaluate the influence of regenerative periodontal therapy on clinical parameters and interleukin-8 (IL-8), IL-17 and soluble intercellular adhesion molecule-1 (sICAM-1) levels in gingival crevicular fluid (GCF) of subjects with chronic periodontitis (CP). MATERIALS AND METHODS: Fifteen patients received demineralized freeze-dried bone allograft (DFDBA) surgically to the site of infrabony defect. Clinical periodontal indices were recorded, and GCF samples were collected at baseline and at the 6(th) and the 9(th) month after the surgery. RESULTS: Except plaque index, all clinical parameters improved following surgery (P < 0.05). The volume of GCF diminished from baseline to follow-up periods (P < 0.05). However, no effect was observed on the total amount of IL-8, IL-17 and sICAM-1 in GCF. CONCLUSION: DFDBA improved clinical outcome in CP subjects and was effective on decreasing the volume of GCF, but no effect was determined on IL-8, IL-17 and sICAM-1. Findings did not indicate a direct relationship between biochemical parameters and periodontal healing after demineralized freeze-dried bone grafting. PMID- 25713487 TI - The effect of home-use and in-office bleaching treatments combined with experimental desensitizing agents on enamel and dentin. AB - OBJECTIVE: This study aimed to evaluate in vitro the effect of formulations containing Biosilicate to treat enamel and dentin bovine samples exposed to dental bleaching agents. MATERIALS AND METHODS: On enamel and dentin bleached with commercial gels containing 16% carbamide peroxide (CP) (14 days/4 h) or 35% hydrogen peroxide (single session/45 min), desensitizing dentifrices (Sensodyne((r)); experimental dentifrice of Biosilicate((r)); Odontis RX((r)); Sorriso((r))) were applied along 14 days and desensitizing pastes (Biosilicate((r))/water 1:1; Dessensebilize NanoP((r)); Bioglass type 45S5/water 1:1) were applied on days 1, 3, 7, 10 and 14. Distilled water was the control. Microhardness (MH) and roughness measurements were the variables measured on the samples before and after the treatments. Student's t-test analyzed differences before and after the treatments. Two-way analysis of variance and post-hoc Tukey test analyzed differences among the factors desensitizing, bleaching agents and substrate. RESULTS: Tukey test showed no differences in roughness for both bleaching treatments and among the desensitizing agents (P > 0.05). Differences in MH appeared on enamel treated with in-home bleaching when control group (lower values) was compared with Sensodyne, Biosilicate dentifrice, Biosilicate paste, and Bioglass paste (higher values). Comparisons between desensitizing agents on dentin treated with both bleaching gels showed no statistical differences. CONCLUSIONS: The effect of formulations containing Biosilicate (Biosilicate dentifrice and paste) was significant in the MH of enamel bleached with 16% CP. PMID- 25713488 TI - Effect of ultraviolet light irradiation on bond strength of fiber post: Evaluation of surface characteristic and bonded area of fiber post with resin cement. AB - OBJECTIVE: Fiber post is cemented to a root canal to restore coronal tooth structure. This research aims to evaluate the effect of ultraviolet (UV) irradiation on bond strength of fiber post with resin cement. MATERIALS AND METHODS: A total of 40 of the two types of fiber posts, namely, FRC Prostec (FRC) and Fiber KOR (KOR), were used for the experiment. UV irradiation was applied on top of the fiber post surface for 0, 15, 20, and 30 min. The irradiated surface of the fiber posts (n = 5) were immediately bonded with resin cement (Rely X U200) after UV irradiation. Shear bond strength (SBS) MPa was measured, and the dislodged area of post surfaces was examined with scanning electron microscopes. Changes in surface roughness (Ra) of the FRC group after UV irradiation were observed (n = 3) using atomic force microscopy. Data of SBS were statistically analyzed using one-way analysis of variance, followed by multiple comparisons (P < 0.05). RESULTS: SBS was significantly higher for 20 min of UV irradiation of the FRC group while significantly higher SBS was observed with 15 min of UV irradiation of the KOR group. Resin cement was more evident (cohesive failure) on the dislodged post surface of the UV treated groups compared with the control. The surface roughness of the FRC post was Ra = 175.1 nm and Ra = 929.2 nm for the control and the 20 min group, respectively. CONCLUSIONS: Higher surface roughness of the UV irradiated group indicated formation of mechanical retention on the fiber post surface. Evidence of cohesive failure was observed which indicated higher SBS of fiber post with the UV irradiated group. PMID- 25713489 TI - Histological evaluation of the cleaning effectiveness of two reciprocating single file systems in severely curved root canals: Reciproc versus WaveOne. AB - OBJECTIVE: The aim of this study was to evaluate the cleaning effectiveness achieved with two reciprocating single-file systems in severely curved root canals: Reciproc and WaveOne. MATERIALS AND METHODS: Twenty-five mesial roots of mandibular molars were randomly separated into two groups, according to the instrumentation system used. The negative control group consisted of five specimens that were not instrumented. The mesial canals (buccal and lingual) in Reciproc Group were instrumented with file R25 and the WaveOne group with the Primary file. The samples were submitted to histological processing and analyzed under a digital microscope. RESULTS: The WaveOne group presented a larger amount of debris than the Reciproc Group, however, without statistically significant difference (P > 0.05). A larger amount of debris in the control group was observed, with statistically significant difference to Reciproc and WaveOne groups (P < 0.05). CONCLUSIONS: The two reciprocating single-file instrumentation systems presented similar effectiveness for root canal cleaning. PMID- 25713490 TI - Evaluation of the effectiveness of early or delayed treatment upon healing of mandibular fractures: A retrospective study. AB - OBJECTIVES: This study was aimed to assess the impacts of delay treatment of mandibular fracture and its complications. In addition risk variables related such as time to repair, fracture types, substance abuse, causes, surgical management, muddling or complications and duration of clinic stay were also evaluated. MATERIALS AND METHODS: The data of patients attending the Newcastle General Hospital, UK for the management of mandibular fractures were probed. This retrospective clinical trial conducted over 6 months, included 91 patients attending trauma operating theatre during weekdays or weekends. Data were analyzed for time to admission and treatment and its relationships to various factors using SPSS version 20 (SPSS Inc., Chicago, IL). RESULTS: Time to treatment from the point of admission was 31.50 +/- 3.83 h during week days that has been significantly more for patients attending the hospital at weekends or nights. Similar trend was observed for total summative time from the incident to treatment analysis. CONCLUSIONS: This investigation has demonstrated that the rate of infection and postoperative complications following surgical treatment of mandible fractures can be eased off by reducing the waiting time from presentation to the emergency and to the operating theater. PMID- 25713491 TI - Resin composite repair: Quantitative microleakage evaluation of resin-resin and resin-tooth interfaces with different surface treatments. AB - OBJECTIVE: The aim was to evaluate the effect of different adhesive systems and surface treatments on the integrity of resin-resin and resin-tooth interfaces after partial removal of preexisting resin composites using quantitative image analysis for microleakage testing protocol. MATERIALS AND METHODS: A total of 80 human molar teeth were restored with either of the resin composites (Filtek Z250/GrandioSO) occlusally. The teeth were thermocycled (1000*). Mesial and distal 1/3 parts of the restorations were removed out leaving only middle part. One side of the cavity was finished with course diamond bur and the other was air abraded with 50 MUm Al2O3. They were randomly divided into four groups (n = 10) to receive: Group 1: Adper Single Bond 2; Group 2: All Bond 3; Group 3: ClearfilSE; Group 4: BeautiBond, before being repaired with the same resin composite (Filtek Z250). The specimens were re-thermocycled (1000*), sealed with nail varnish, stained with 0.5% basic fuchsin, sectioned mesiodistally and photographed digitally. The extent of dye penetration was measured by image analysis software (ImageJ) for both bur-finished and air-abraded surfaces at resin-tooth and resin-resin interfaces. The data were analyzed statistically. RESULTS: BeautiBond exhibited the most microleakage at every site. Irrespective of adhesive and initial composite type, air-abrasion showed less microleakage except for BeautiBond. The type of initial repaired restorative material did not affect the microleakage. BeautiBond adhesive may not be preferred in resin composite repair in terms of microleakage prevention. CONCLUSIONS: Surface treatment with air-abrasion produced the lowest microleakage scores, independent of the adhesive systems and the pre-existing resin composite type. Pre-existing composite type does not affect the microleakage issue. All-in-one adhesive resin (BeautiBond) may not be preferred in resin composite repair in terms of microleakage prevention. PMID- 25713492 TI - Evaluation of intrabony defects treated with platelet-rich fibrin or autogenous bone graft: A comparative analysis. AB - OBJECTIVE: The primary objective of this study was to compare clinically and radiographically the efficacy of autologous platelet rich fibrin (PRF) and autogenous bone graft (ABG) obtained using bone scrapper in the treatment of intrabony periodontal defects. MATERIALS AND METHODS: Thirty-eight intrabony defects (IBDs) were treated with either open flap debridement (OFD) with PRF or OFD with ABG. Clinical parameters were recorded at baseline and 6 months postoperatively. The defect-fill and defect resolution at baseline and 6 months were calculated radiographically (intraoral periapical radiographs [IOPA] and orthopantomogram [OPG]). RESULTS: Significant probing pocket depth (PPD) reduction, clinical attachment level (CAL) gain, defect fill and defect resolution at both PRF and ABG treated sites with OFD was observed. However, inter-group comparison was non-significant (P > 0.05). The bivariate correlation results revealed that any of the two radiographic techniques (IOPA and OPG) can be used for analysis of the regenerative therapy in IBDs. CONCLUSION: The use of either PRF or ABG were effective in the treatment of three wall IBDs with an uneventful healing of the sites. PMID- 25713493 TI - Interleukin-1 receptor antagonist levels in gingival crevicular fluid and serum in nonsmoking women with preterm low birth weight and intrauterine growth retardation. AB - OBJECTIVE: The aim of this study was to evaluate interleukin (IL)-1 beta and IL-1 receptor antagonist (IL-1ra) levels in gingival crevicular fluid (GCF) and serum (S) in nonsmoking women with normal birth (NB), preterm low birth weight (PLBW), and intra-uterine growth retardation (IUGR). MATERIALS AND METHODS: In this unmatched case-control study design, 64 women with NB, 45 women with PLBW, and 47 women with IUGR were recruited within 24 h delivery. Clinical periodontal parameters were recorded. IL-1 beta and IL-1ra levels in GCF (pg/30 s) and serum (pg/ml) of were evaluated using commercial enzyme immunoassay and ELISA kits. RESULTS: Greater pocket depth and clinical attachment loss were observed in PLBW and IUGR women than in NB women (P < 0.05). The total amounts of IL-1ra and IL beta of GCF were higher levels in NB women than PLBW and IUGR women (P < 0.05). The lowest total amount of IL-1ra of GCF was found in IUGR women (P < 0.05). The concentrations of IL-1ra in serum samples were not statistically significant for any of the study groups (P > 0.05). CONCLUSION: It can be suggested that worse periodontal conditions and the low levels of IL-1ra in GCF may be an important factor in adverse pregnancy outcomes. PMID- 25713494 TI - Microleakage under orthodontic brackets bonded with different adhesive systems. AB - OBJECTIVE: This in vitro study aimed to compare the microleakage of orthodontic brackets between enamel-adhesive and adhesive-bracket interfaces at the occlusal and gingival margins bonded with different adhesive systems. MATERIALS AND METHODS: A total of 144 human maxillary premolar teeth extracted for orthodontic reasons was randomly divided into four groups. Each group was then further divided into three sub-groups. Three total-etching bonding systems (Transbond XT, Greengloo and Kurasper F), three one-step self-etching bonding systems (Transbond Plus SEP, Bond Force and Clearfil S3), three two-step self-etching bonding systems (Clearfil SE Bond, Clearfil Protectbond and Clearfil Liner Bond), and three self-adhesive resin cements (Maxcem Elite, Relyx U 100 and Clearfil SA Cement) were used to bond the brackets to the teeth. After bonding, all teeth were sealed with nail varnish and stained with 0.5% basic fuchsine for 24 h. All samples were sectioned and examined under a stereomicroscope to score for microleakage at the adhesive-enamel and adhesive-bracket interfaces from both occlusal and gingival margins. STATISTICAL ANALYSIS USED: Statistical analyses were performed with Kruskal-Wallis and Wilcoxon signed-rank tests. RESULTS: The results indicate no statistically significant differences between the microleakage scores of the adhesives; microleakage was detected in all groups. Comparison of the average values of the microleakage scores in the enamel adhesive and adhesive-bracket interfaces indicated statistically significant differences (P < 0.05). The amount of the microleakage was higher at the enamel adhesive interface than at the bracket-adhesive interface. CONCLUSIONS: All of the brackets exhibited some amount of microleakage. This result means that microleakage does not depend on the type of adhesive used. PMID- 25713495 TI - Association between early childhood caries and maternal caries status: A cross section study in Sao Luis, Maranhao, Brazil. AB - OBJECTIVE: This study aims to evaluate the association between early childhood caries (ECC) and maternal caries status, and the maternal perception of ECC risk factors. MATERIALS AND METHODS: A cross-sectional study was carried out with 77 mother-child pairs, the children ranging from 12 to 36 months of age and their mothers, who were seeking dental care at a health center in Sao Luis, Maranhao, Brazil. Data collection was conducted using a specific questionnaire for mothers. Oral clinical examination of the mother-child binomial to assess caries incidence, gingival bleeding (GB) and visible plaque was done. Home visits were performed in 10% of the sample in order to observe the environmental conditions, dietary habits and dental hygiene practices. RESULTS: The findings showed that the caries prevalence in children was 22.5 times higher in the mother who had decayed tooth (prevalence ratio [PR] = 22.5, confidence interval [CI] 95% = 3.2 156.6, P < 0.001). GB also was observed in 14 mothers and children, the PR in pair was 12.2 (CI95% = 1.6-88.9, P < 0.001). The variables are related for the mother-child binomial in regression linear analysis. CONCLUSION: The maternal caries status was associated with ECC. PMID- 25713496 TI - 16S rRNA gene-based metagenomic analysis identifies a novel bacterial co prevalence pattern in dental caries. AB - OBJECTIVE: To identify the prevalence of acidogenic and nonacidogenic bacteria in patients with polycaries lesions, and to ascertain caries specific bacterial prevalence in relation to noncaries controls. MATERIALS AND METHODS: Total genomic DNA extracted from saliva of three adults and four children from the same family were subjected to 16S rRNA gene sequencing analysis on a next generation sequencer, the PGS-Ion Torrent. Those bacterial genera with read counts > 1000 were considered as significant in each of the subject and used to associate the occurrence with caries. RESULTS AND CONCLUSION: Sequencing analysis indicated a higher prevalence of Streptococcus, Rothia, Granulicatella, Gemella, Actinomyces, Selenomonas, Haemophilus and Veillonella in the caries group relative to controls. While higher prevalence of Streptococcus, Rothia and Granulicatella were observed in all caries samples, the prevalence of others was observable in 29-57% of samples. Interestingly, Rothia and Selenomonas, which are known to occur within anaerobic environments of dentinal caries and subgingival plaque biofilms, were seen in the saliva of these caries patients. Taken together, the study has identified for the first time a unique co-prevalence pattern of bacteria in caries patients that may be explored as distinct caries specific bacterial signature to predict cariogenesis in high-risk primary and mixed dentition age groups. PMID- 25713498 TI - Xeroderma pigmentosum and its dental implications. AB - Xeroderma pigmentosum (XP) is a rare autosomal recessive genetic disorder characterized by defective DNA repair leading to clinical and cellular hypersensitivity to ultraviolet (UV) radiation and carcinogenic agents. Important clinical features are: Intense cutaneous photosensitivity, xerosis, poikiloderma, actinic keratosis, acute burning under minimal sun exposure, erythemas, hyperpigmented lentiginous macules, and malignant lesions in sun-exposed areas, including basocellular carcinoma, squamous cell carcinoma, and melanoma. There is a great involvement of many parts of the body, especially head and neck. Oral implications such as severe oral pain and mouth opening limitation were present due to perioral scars. The disorder is associated more commonly in populations where marriage of close blood relatives is common. Treatment of the disorder includes avoidance of UV radiation, topical application of 5-fluorouracil to treat actinic keratoses, and regular evaluation by an ophthalmologist, dermatologist, and neurologist. Genetic counseling is important aspects as an increased incidence of consanguineous marriages have been reported with this disorder. In addition, this paper discuss some important aspects concerning the role of the dental professional management of this entity, since XP patients require constant dental care and follow-up in order to control the occurrence of new lesions on the lips or inside oral cavity. PMID- 25713497 TI - Root canal morphology of South Asian Indian maxillary molar teeth. AB - OBJECTIVE: The objective was to study the root canal morphology of South Asian Indian Maxillary molars using a tooth clearing technique. MATERIALS AND METHODS: Hundred teeth each comprising of first, second, and third molars collected from different dental schools and clinics in India were subjected to standard dye penetration, decalcification and clearing procedure before being studied. RESULTS: The first molar mesiobuccal roots exhibited 69% Type I, 24% Type II, 4% Type IV, 2% Type V, and 1% exhibited a Vertuccis Type VIII canal anatomy. In the group with three separate roots the second molar mesiobuccal roots in exhibited 80.6% Type I, 15.3% Type II, 2.7% Type IV, and 1.4% Type V canal anatomy while the third molars mesiobuccal roots exhibited 57.4% Type I, 32% Type II, 2.1% Type III, 8.5% Type IV, 1% had a Type V canal anatomy in the similar group. CONCLUSION: A varied root canal anatomy was seen in the mesiobuccal root canal of the maxillary molars. PMID- 25713499 TI - Clinical and radiological findings of a bilateral coronoid hyperplasia case. AB - Coronoid hyperplasia (CH) is an infrequent condition that can be defined as an abnormal bony elongation of histologically normal bone. Progressive and painless difficulty in opening the mouth is the main clinical finding of CH. In this case report, the clinical and radiological findings for a 23-year-old male patient with bilateral CH are presented. When plain radiographies are not sufficient for diagnosis and evaluation of the CH, cone-beam computed tomography can be used. PMID- 25713500 TI - Genetic background of supernumerary teeth. AB - Supernumerary teeth (ST) are odontostomatologic anomaly characterized by as the existence excessive number of teeth in relation to the normal dental formula. This condition is commonly seen with several congenital genetic disorders such as Gardner's syndrome, cleidocranial dysostosis and cleft lip and palate. Less common syndromes that are associated with ST are; Fabry Disease, Ellis-van Creveld syndrome, Nance-Horan syndrome, Rubinstein-Taybi Syndrome and Trico-Rhino Phalangeal syndrome. ST can be an important component of a distinctive disorder and an important clue for early diagnosis. Certainly early detecting the abnormalities gives us to make correct management of the patient and also it is important for making well-informed decisions about long-term medical care and treatment. In this review, the genetic syndromes that are related with ST were discussed. PMID- 25713501 TI - A survey of thrombosis experts evaluating practices and opinions regarding venous thromboprophylaxis in patients with active cancer hospitalized with an acute medical illness. AB - BACKGROUND: Current clinical practice guidelines recommend the use of prophylactic doses of low molecular weight heparins for cancer patients requiring hospitalization for acute medical illness. However, a recently published meta analysis suggested that the risk-benefit ratio of current thromboprophylaxis regimens administered to all cancer patients admitted for medical illness is unclear. We sought to assess the clinical equipoise in using thromboprophylaxis for hospitalized medically ill cancer patients. METHODS: An electronic survey was conducted. The target sample included Thrombosis experts and members of Thrombosis Canada or the VECTOR research group. RESULTS: The survey was distributed 54 participants. The final response rate was 67% (36/54). The majority (75%; 95% CI: 60.3 to 85%) of responders indicated that the benefits of pharmacological parenteral thromboprophylaxis outweigh the risks. However, 63.9% (95% CI: 50.6 to 77.3%) believe that there is still clinical equipoise around the use of thromboprophylaxis in this patient population, and 88.9% (95% CI: 77.3 to 95.8%) would consider participating in a randomized trial-30.6% and 58.3% in a placebo-controlled or comparison of different agents/dosing-controlled randomized trial, respectively. For participants who would consider a randomized-controlled trial comparing different doses of thromboprophylaxis agents, the MCID was 2% between the two arms. The most common drug to be compared was enoxaparin (26%), and the two suggested doses were 30 mg and 40 mg SC twice daily. CONCLUSIONS: Our clinical survey of thrombosis experts confirms that there is equipoise regarding the use of current regimens of parenteral pharmacological thromboprophylaxis in medically ill cancer patients. A majority of physicians would participate in a randomized-controlled trial comparing different dose of LMWH. The MCID in the risk of VTE identified was 2%. PMID- 25713503 TI - Regulation of intestinal immune system by dendritic cells. AB - Innate immune cells survey antigenic materials beneath our body surfaces and provide a front-line response to internal and external danger signals. Dendritic cells (DCs), a subset of innate immune cells, are critical sentinels that perform multiple roles in immune responses, from acting as principal modulators to priming an adaptive immune response through antigen-specific signaling. In the gut, DCs meet exogenous, non-harmful food antigens as well as vast commensal microbes under steady-state conditions. In other instances, they must combat pathogenic microbes to prevent infections. In this review, we focus on the function of intestinal DCs in maintaining intestinal immune homeostasis. Specifically, we describe how intestinal DCs affect IgA production from B cells and influence the generation of unique subsets of T cell. PMID- 25713504 TI - A molecular mucosal adjuvant to enhance immunity against pneumococcal infection in the elderly. AB - Streptococcus pneumoniae (the pneumococcus) causes a major upper respiratory tract infection often leading to severe illness and death in the elderly. Thus, it is important to induce safe and effective mucosal immunity against this pathogen in order to prevent pnuemocaccal infection. However, this is a very difficult task to elicit protective mucosal IgA antibody responses in older individuals. A combind nasal adjuvant consisting of a plasmid encoding the Flt3 ligand cDNA (pFL) and CpG oligonucleotide (CpG ODN) successfully enhanced S. pneumoniae-specific mucosal immunity in aged mice. In particular, a pneumococcal surface protein A-based nasal vaccine given with pFL and CpG ODN induced complete protection from S. pneumoniae infection. These results show that nasal delivery of a combined DNA adjuvant offers an attractive potential for protection against the pneumococcus in the elderly. PMID- 25713505 TI - Immune cells in the female reproductive tract. AB - The female reproductive tract has two main functions: protection against microbial challenge and maintenance of pregnancy to term. The upper reproductive tract comprises the fallopian tubes and the uterus, including the endocervix, and the lower tract consists of the ectocervix and the vagina. Immune cells residing in the reproductive tract play contradictory roles: they maintain immunity against vaginal pathogens in the lower tract and establish immune tolerance for sperm and an embryo/fetus in the upper tract. The immune system is significantly influenced by sex steroid hormones, although leukocytes in the reproductive tract lack receptors for estrogen and progesterone. The leukocytes in the reproductive tract are distributed in either an aggregated or a dispersed form in the epithelial layer, lamina propria, and stroma. Even though immune cells are differentially distributed in each organ of the reproductive tract, the predominant immune cells are T cells, macrophages/dendritic cells, natural killer (NK) cells, neutrophils, and mast cells. B cells are rare in the female reproductive tract. NK cells in the endometrium significantly expand in the late secretory phase and further increase their number during early pregnancy. It is evident that NK cells and regulatory T (Treg) cells are extremely important in decidual angiogenesis, trophoblast migration, and immune tolerance during pregnancy. Dysregulation of endometrial/decidual immune cells is strongly related to infertility, miscarriage, and other obstetric complications. Understanding the immune system of the female reproductive tract will significantly contribute to women's health and to success in pregnancy. PMID- 25713506 TI - Protection against salmonella typhimurium, salmonella gallinarum, and salmonella enteritidis infection in layer chickens conferred by a live attenuated salmonella typhimurium strain. AB - In the present study, we investigated the protection conferred by a live attenuated Salmonella enterica serovar Typhimurium (ST) strain against Salmonella Typhimurium, Salmonella Gallinarum (SG), and Salmonella Enteritidis (SE) infection in layer chickens. Birds were orally primed with the attenuated ST strain at 7 days of age and then boosted at 4 weeks post prime immunization (PPI). Sequential monitoring of plasma IgG and mucosal secretory IgA (sIgA) levels revealed that inoculation with ST induced a significant antibody response to antigens against ST, SE, and SG. Moreover, significant lymphoproliferative responses to the 3 Salmonella serovars were observed in the immunized group. We also investigated protection against virulent ST, SE, and SG strain challenge. Upon virulent SG challenge, the immunized group showed significantly reduced mortality compared to the non-immunized group. The reduced persistence of the virulent ST and SE challenge strains in the liver, spleen, and cecal tissues of the immunized group suggests that immunization with the attenuated ST strain may not only protect against ST infection but can also confer cross protection against SE and SG infection. PMID- 25713507 TI - Lactoferrin Combined with Retinoic Acid Stimulates B1 Cells to Express IgA Isotype and Gut-homing Molecules. AB - It is well established that TGF-beta1 and retinoic acid (RA) cause IgA isotype switching in mice. We recently found that lactoferrin (LF) also has an activity of IgA isotype switching in spleen B cells. The present study explored the effect of LF on the Ig production by mouse peritoneal B cells. LF, like TGF-beta1, substantially increased IgA production in peritoneal B1 cells but little in peritoneal B2 cells. In contrast, LF increased IgG2b production in peritoneal B2 cells much more strongly than in peritoneal B1 cells. LF in combination with RA further enhanced the IgA production and, interestingly, this enhancement was restricted to IgA isotype and B1 cells. Similarly, the combination of the two molecules also led to expression of gut homing molecules alpha4beta7 and CCR9 on peritoneal B1 cells, but not on peritoneal B2 cells. Thus, these results indicate that LF and RA can contribute to gut IgA response through stimulating IgA isotype switching and expression of gut-homing molecules in peritoneal B1 cells. PMID- 25713508 TI - Expression of the ATP-gated P2X7 Receptor on M Cells and Its Modulating Role in the Mucosal Immune Environment. AB - Interactions between microbes and epithelial cells in the gastrointestinal tract are closely associated with regulation of intestinal mucosal immune responses. Recent studies have highlighted the modulation of mucosal immunity by microbe derived molecules such as ATP and short-chain fatty acids. In this study, we undertook to characterize the expression of the ATP-gated P2X7 receptor (P2X7R) on M cells and its role in gastrointestinal mucosal immune regulation because it was poorly characterized in Peyer's patches, although purinergic signaling via P2X7R and luminal ATP have been considered to play an important role in the gastrointestinal tract. Here, we present the first report on the expression of P2X7R on M cells and characterize the role of P2X7R in immune enhancement by ATP or LL-37. PMID- 25713509 TI - Neurovisceral phenotypes in the expression of psychiatric symptoms. AB - This review explores the proposal that vulnerability to psychological symptoms, particularly anxiety, originates in constitutional differences in the control of bodily state, exemplified by a set of conditions that include Joint Hypermobility, Postural Tachycardia Syndrome and Vasovagal Syncope. Research is revealing how brain-body mechanisms underlie individual differences in psychophysiological reactivity that can be important for predicting, stratifying and treating individuals with anxiety disorders and related conditions. One common constitutional difference is Joint Hypermobility, in which there is an increased range of joint movement as a result of a variant of collagen. Joint hypermobility is over-represented in people with anxiety, mood and neurodevelopmental disorders. It is also linked to stress-sensitive medical conditions such as irritable bowel syndrome, chronic fatigue syndrome and fibromyalgia. Structural differences in "emotional" brain regions are reported in hypermobile individuals, and many people with joint hypermobility manifest autonomic abnormalities, typically Postural Tachycardia Syndrome. Enhanced heart rate reactivity during postural change and as recently recognized factors causing vasodilatation (as noted post-prandially, post-exertion and with heat) is characteristic of Postural Tachycardia Syndrome, and there is a phenomenological overlap with anxiety disorders, which may be partially accounted for by exaggerated neural reactivity within ventromedial prefrontal cortex. People who experience Vasovagal Syncope, a heritable tendency to fainting induced by emotional challenges (and needle/blood phobia), are also more vulnerable to anxiety disorders. Neuroimaging implicates brainstem differences in vulnerability to faints, yet the structural integrity of the caudate nucleus appears important for the control of fainting frequency in relation to parasympathetic tone and anxiety. Together there is clinical and neuroanatomical evidence to show that common constitutional differences affecting autonomic responsivity are linked to psychiatric symptoms, notably anxiety. PMID- 25713510 TI - Quantitative analysis of axonal fiber activation evoked by deep brain stimulation via activation density heat maps. AB - BACKGROUND: Cortical modulation is likely to be involved in the various therapeutic effects of deep brain stimulation (DBS). However, it is currently difficult to predict the changes of cortical modulation during clinical adjustment of DBS. Therefore, we present a novel quantitative approach to estimate anatomical regions of DBS-evoked cortical modulation. METHODS: Four different models of the subthalamic nucleus (STN) DBS were created to represent variable electrode placements (model I: dorsal border of the posterolateral STN; model II: central posterolateral STN; model III: central anteromedial STN; model IV: dorsal border of the anteromedial STN). Axonal fibers of passage near each electrode location were reconstructed using probabilistic tractography and modeled using multi-compartment cable models. Stimulation-evoked activation of local axon fibers and corresponding cortical projections were modeled and quantified. RESULTS: Stimulation at the border of the STN (models I and IV) led to a higher degree of fiber activation and associated cortical modulation than stimulation deeply inside the STN (models II and III). A posterolateral target (models I and II) was highly connected to cortical areas representing motor function. Additionally, model I was also associated with strong activation of fibers projecting to the cerebellum. Finally, models III and IV showed a dorsoventral difference of preferentially targeted prefrontal areas (models III: middle frontal gyrus; model IV: inferior frontal gyrus). DISCUSSION: The method described herein allows characterization of cortical modulation across different electrode placements and stimulation parameters. Furthermore, knowledge of anatomical distribution of stimulation-evoked activation targeting cortical regions may help predict efficacy and potential side effects, and therefore can be used to improve the therapeutic effectiveness of individual adjustments in DBS patients. PMID- 25713511 TI - Neuropeptide co-expression in hypothalamic kisspeptin neurons of laboratory animals and the human. AB - Hypothalamic peptidergic neurons using kisspeptin (KP) and its co-transmitters for communication are critically involved in the regulation of mammalian reproduction and puberty. This article provides an overview of neuropeptides present in KP neurons, with a focus on the human species. Immunohistochemical studies reveal that large subsets of human KP neurons synthesize neurokinin B, as also shown in laboratory animals. In contrast, dynorphin described in KP neurons of rodents and sheep is found rarely in KP cells of human males and postmenopausal females. Similarly, galanin is detectable in mouse, but not human, KP cells, whereas substance P, cocaine- and amphetamine-regulated transcript and proenkephalin-derived opioids are expressed in varying subsets of KP neurons in humans, but not reported in ARC of other species. Human KP neurons do not contain neurotensin, cholecystokinin, proopiomelanocortin-derivatives, agouti-related protein, neuropeptide Y, somatostatin or tyrosine hydroxylase (dopamine). These data identify the possible co-transmitters of human KP cells. Neurochemical properties distinct from those of laboratory species indicate that humans use considerably different neurotransmitter mechanisms to regulate fertility. PMID- 25713512 TI - Interference of TRPV1 function altered the susceptibility of PTZ-induced seizures. AB - Transient receptor potential vanilloid 1 (TRPV1) is widely distributed in the central nervous system (CNS) including hippocampus, and regulates the balance of excitation and inhibition in CNS, which imply its important role in epilepsy. We used both pharmacological manipulations and transgenic mice to disturb the function of TRPV1 and then studied the effects of these alterations on the susceptibility of pentylenetetrazol (PTZ)-induced seizures. Our results showed that systemic administration of TRPV1 agonist capsaicin (CAP, 40 mg/kg) directly induced tonic-clonic seizures (TCS) without PTZ induction. The severity of seizure was increased in lower doses of CAP groups (5 and 10 mg/kg), although the latency to TCS was delayed. On the other hand, systemic administration of TRPV1 antagonist capsazepine (CPZ, 0.05 and 0.5 mg/kg) and TRPV1 knockout mice exhibited delayed latency to TCS and reduced mortality. Furthermore, hippocampal administration of CPZ (10 and 33 nmol/MUL/side) was firstly reported to increase the latency to TCS, decrease the maximal grade of seizure and mortality. It is worth noting that decreased susceptibility of PTZ-induced seizures was observed in hippocampal TRPV1 overexpression mice and hippocampal CAP administration (33 nmol/MUL/side), which is opposite from results of systemic agonist CAP. Our findings suggest that the systemic administration of TRPV1 antagonist may be a novel therapeutic target for epilepsy, and alteration of hippocampal TRPV1 function exerts a critical role in seizure susceptibility. PMID- 25713513 TI - Mitochondrial dynamism and the pathogenesis of Amyotrophic Lateral Sclerosis. AB - Research on mitochondria in the last years has been characterized by the fundamental finding that the morphology of mitochondria is deeply connected to the regulation of a vast number of different processes, including oxidative phosphorylation and ATP production, calcium buffering, and apoptosis. This has immediately focused the attention of the neuroscience community to the possible involvement of mitochondrial dynamism, the process underlying morphological features of mitochondria, in neurodegeneration, where mitochondrial dysfunction is believed to represent an important contributing event, or even a primary causative factor. Amyotrophic Lateral Sclerosis (ALS), a disease of motor neurons and their neighboring cells, has long been considered as a neurodegenerative disease with an important mitochondrial issue. Yet, whether mitochondria have a causative, primary role in the pathogenic process has always been debated, and the specific defects which account for this role are elusive. Here we discuss recent genetic advances suggesting that defective mitochondrial dynamism is primarily involved in the pathogenic mechanisms of ALS, and that foster the longstanding concept that disruption of mitochondrial function is a vulnerable factor for motor neurons. PMID- 25713514 TI - Editorial for "Regulatory RNAs in the nervous system". PMID- 25713515 TI - Modulation of spontaneous locomotor and respiratory drives to hindlimb motoneurons temporally related to sympathetic drives as revealed by Mayer waves. AB - In this study we investigated how the networks mediating respiratory and locomotor drives to lumbar motoneurons interact and how this interaction is modulated in relation to periodic variations in blood pressure (Mayer waves). Seven decerebrate cats, under neuromuscular blockade, were used to study central respiratory drive potentials (CRDPs, usually enhanced by added CO2) and spontaneously occurring locomotor drive potentials (LDPs) in hindlimb motoneurons, together with hindlimb and phrenic nerve discharges. In four of the cats both drives and their voltage-dependent amplification were absent or modest, but in the other three, one or other of these drives was common and the voltage dependent amplification was frequently strong. Moreover, in these three cats the blood pressure showed marked periodic variation (Mayer waves), with a slow rate (periods 9-104 s, mean 39 +/- 17 SD). Profound modulation, synchronized with the Mayer waves was seen in the occurrence and/or in the amplification of the CRDPs or LDPs. In one animal, where CRDPs were present in most cells and the amplification was strong, the CRDP consistently triggered sustained plateaux at one phase of the Mayer wave cycle. In the other two animals, LDPs were common, and the occurrence of the locomotor drive was gated by the Mayer wave cycle, sometimes in alternation with the respiratory drive. Other interactions between the two drives involved respiration providing leading events, including co activation of flexors and extensors during post-inspiration or a locomotor drive gated or sometimes entrained by respiration. We conclude that the respiratory drive in hindlimb motoneurons is transmitted via elements of the locomotor central pattern generator. The rapid modulation related to Mayer waves suggests the existence of a more direct and specific descending modulatory control than has previously been demonstrated. PMID- 25713516 TI - A wirelessly controlled implantable LED system for deep brain optogenetic stimulation. AB - In recent years optogenetics has rapidly become an essential technique in neuroscience. Its temporal and spatial specificity, combined with efficacy in manipulating neuronal activity, are especially useful in studying the behavior of awake behaving animals. Conventional optogenetics, however, requires the use of lasers and optic fibers, which can place considerable restrictions on behavior. Here we combined a wirelessly controlled interface and small implantable light emitting diode (LED) that allows flexible and precise placement of light source to illuminate any brain area. We tested this wireless LED system in vivo, in transgenic mice expressing channelrhodopsin-2 in striatonigral neurons expressing D1-like dopamine receptors. In all mice tested, we were able to elicit movements reliably. The frequency of twitches induced by high power stimulation is proportional to the frequency of stimulation. At lower power, contraversive turning was observed. Moreover, the implanted LED remains effective over 50 days after surgery, demonstrating the long-term stability of the light source. Our results show that the wireless LED system can be used to manipulate neural activity chronically in behaving mice without impeding natural movements. PMID- 25713517 TI - Choking under pressure: the neuropsychological mechanisms of incentive-induced performance decrements. AB - In contrast to the assumption of efficiency wage models, which state that wage incentives should be positively correlated with productivity, high incentives may produce performance decrements in real life scenarios. Such a "choking under pressure" phenomenon exemplifies how psychological stress can profoundly shape human behavior, for good or for bad. Previous theories suggest that individual choking under pressure because that high pressure may distract individuals' attention away from the task (the distraction account), raise the attention paid to step-by-step skill processes (the explicit monitoring account), or elevate the arousal in general (the over-arousal account). Recent neuroimaging studies have shown that several brain regions implicated in motivation and top-down control of attention also play a key role in stress-induced choking, supporting for the over arousal and distraction theories of choking. This review aims to identify psychological factors that determine choking and the neural underpinnings of these processes. Insights into how incentives influence performance may aid engineering training regimens and interventions that equip individuals to better handle high-stakes-induced psychological stress, and to thrive under stress. PMID- 25713518 TI - The effects of long-term resistance exercise on the relationship between neurocognitive performance and GH, IGF-1, and homocysteine levels in the elderly. AB - This study aimed to investigate the effects of a long-term resistance exercise intervention on executive functions in healthy elderly males, and to further understand the potential neurophysiological mechanisms mediating the changes. The study assessed forty-eight healthy elderly males randomly assigned to exercise (n = 24) or control (n = 24) groups. The assessment included neuropsychological and neuroelectric measures during a variant of the oddball task paradigm, as well as growth hormone (GH), insulin-like growth factor-1 (IGF-1), and homocysteine levels at baseline and after either a 12 month intervention of resistance exercise training or control period. The results showed that the control group had a significantly lower accuracy rate and smaller P3a and P3b amplitudes in the oddball condition after 12 months. The exercise group exhibited improved reaction times (RTs), sustained P3a and P3b amplitudes, increased levels of serum IGF-1, and decreased levels of serum homocysteine. The changes in IGF-1 levels were significantly correlated with the changes in RT and P3b amplitude of the oddball condition in the exercise group. In conclusion, significantly enhanced serum IGF 1 levels after 12 months of resistance exercise were inversely correlated with neurocognitive decline in the elderly. These findings suggest that regular resistance exercise might be a promising strategy to attenuate the trajectory of cognitive aging in healthy elderly individuals, possibly mediated by IGF-1. PMID- 25713519 TI - Hierarchical and homotopic correlations of spontaneous neural activity within the visual cortex of the sighted and blind. AB - Spontaneous neural activity within visual cortex is synchronized by both monosynaptic, hierarchical connections between visual areas and indirect, network level activity. We examined the interplay of hierarchical and network connectivity in human visual cortex by measuring the organization of spontaneous neural signals within the visual cortex in total darkness using functional magnetic resonance imaging (fMRI). Twenty-five blind (14 congenital and 11 postnatal) participants with equally severe vision loss and 22 sighted subjects were studied. An anatomical template based on cortical surface topology was used for all subjects to identify the quarter-field components of visual areas V1-V3, and assign retinotopic organization. Cortical visual areas that represent the same quadrant of the visual field were considered to have a hierarchical relationship, while the spatially separated quarters of the same visual area were considered homotopic. Blindness was found to enhance correlations between hierarchical cortical areas as compared to indirect, homotopic areas at both the level of visual areas (p = 0.000031) and fine, retinotopic scale (p = 0.0024). A specific effect of congenital, but not postnatal, blindness was to further broaden the cortico-cortico connections between hierarchical visual areas (p = 0.0029). This finding is consistent with animal studies that observe a broadening of axonal terminal arborization when the visual cortex is deprived of early input. We therefore find separable roles for vision in developing and maintaining the intrinsic neural activity of visual cortex. PMID- 25713520 TI - Metaphors are physical and abstract: ERPs to metaphorically modified nouns resemble ERPs to abstract language. AB - Metaphorical expressions very often involve words referring to physical entities and experiences. Yet, figures of speech such as metaphors are not intended to be understood literally, word-by-word. We used event-related brain potentials (ERPs) to determine whether metaphorical expressions are processed more like physical or more like abstract expressions. To this end, novel adjective-noun word pairs were presented visually in three conditions: (1) Physical, easy to experience with the senses (e.g., "printed schedule"); (2) Abstract, difficult to experience with the senses (e.g., "conditional schedule"); and (3) novel Metaphorical, expressions with a physical adjective, but a figurative meaning (e.g., "thin schedule"). We replicated the N400 lexical concreteness effect for concrete vs. abstract adjectives. In order to increase the sensitivity of the concreteness manipulation on the expressions, we divided each condition into high and low groups according to rated concreteness. Mirroring the adjective result, we observed a N400 concreteness effect at the noun for physical expressions with high concreteness ratings vs. abstract expressions with low concreteness ratings, even though the nouns per se did not differ in lexical concreteness. Paradoxically, the N400 to nouns in the metaphorical expressions was indistinguishable from that to nouns in the literal abstract expressions, but only for the more concrete subgroup of metaphors; the N400 to the less concrete subgroup of metaphors patterned with that to nouns in the literal concrete expressions. In sum, we not only find evidence for conceptual concreteness separable from lexical concreteness but also that the processing of metaphorical expressions is not driven strictly by either lexical or conceptual concreteness. PMID- 25713521 TI - Detection of EEG-resting state independent networks by eLORETA-ICA method. AB - Recent functional magnetic resonance imaging (fMRI) studies have shown that functional networks can be extracted even from resting state data, the so called "Resting State independent Networks" (RS-independent-Ns) by applying independent component analysis (ICA). However, compared to fMRI, electroencephalography (EEG) and magnetoencephalography (MEG) have much higher temporal resolution and provide a direct estimation of cortical activity. To date, MEG studies have applied ICA for separate frequency bands only, disregarding cross-frequency couplings. In this study, we aimed to detect EEG-RS-independent-Ns and their interactions in all frequency bands. We applied exact low resolution brain electromagnetic tomography-ICA (eLORETA-ICA) to resting-state EEG data in 80 healthy subjects using five frequency bands (delta, theta, alpha, beta and gamma band) and found five RS-independent-Ns in alpha, beta and gamma frequency bands. Next, taking into account previous neuroimaging findings, five RS-independent-Ns were identified: (1) the visual network in alpha frequency band, (2) dual-process of visual perception network, characterized by a negative correlation between the right ventral visual pathway (VVP) in alpha and beta frequency bands and left posterior dorsal visual pathway (DVP) in alpha frequency band, (3) self referential processing network, characterized by a negative correlation between the medial prefrontal cortex (mPFC) in beta frequency band and right temporoparietal junction (TPJ) in alpha frequency band, (4) dual-process of memory perception network, functionally related to a negative correlation between the left VVP and the precuneus in alpha frequency band; and (5) sensorimotor network in beta and gamma frequency bands. We selected eLORETA-ICA which has many advantages over the other network visualization methods and overall findings indicate that eLORETA-ICA with EEG data can identify five RS-independent-Ns in their intrinsic frequency bands, and correct correlations within RS-independent Ns. PMID- 25713522 TI - Familiarity differentially affects right hemisphere contributions to processing metaphors and literals. AB - The role of the two hemispheres in processing metaphoric language is controversial. While some studies have reported a special role of the right hemisphere (RH) in processing metaphors, others indicate no difference in laterality relative to literal language. Some studies have found a role of the RH for novel/unfamiliar metaphors, but not conventional/familiar metaphors. It is not clear, however, whether the role of the RH is specific to metaphor novelty, or whether it reflects processing, reinterpretation or reanalysis of novel/unfamiliar language in general. Here we used functional magnetic resonance imaging (fMRI) to examine the effects of familiarity in both metaphoric and non metaphoric sentences. A left lateralized network containing the middle and inferior frontal gyri, posterior temporal regions in the left hemisphere (LH), and inferior frontal regions in the RH, was engaged across both metaphoric and non-metaphoric sentences; engagement of this network decreased as familiarity decreased. No region was engaged selectively for greater metaphoric unfamiliarity. An analysis of laterality, however, showed that the contribution of the RH relative to that of LH does increase in a metaphor-specific manner as familiarity decreases. These results show that RH regions, taken by themselves, including commonly reported regions such as the right inferior frontal gyrus (IFG), are responsive to increased cognitive demands of processing unfamiliar stimuli, rather than being metaphor-selective. The division of labor between the two hemispheres, however, does shift towards the right for metaphoric processing. The shift results not because the RH contributes more to metaphoric processing. Rather, relative to its contribution for processing literals, the LH contributes less. PMID- 25713523 TI - The effects of a Self-Alert Training (SAT) program in adults with ADHD. AB - Attention-Deficit/Hyperactivity Disorder (ADHD), a neuropsychiatric condition characterized by attention and impulsivity problems, is one of the most common behavioral disorders. The first line of treatment for ADHD is psychostimulant medication, but this has limited effectiveness, particularly in adults, and is often associated with adverse side-effects. Thus, it is imperative that new non pharmaceutical approaches to treatment are developed. This study aims to evaluate the impact of a non-pharmacological Self-Alert Training (SAT) intervention on ADHD symptom prevalence, psychological and cognitive functioning, and on everyday functional impairment in adults with ADHD. Fifty-one adult participants with a current diagnosis of ADHD were randomized to either SAT or a Control Training (CT) program. They were assessed at baseline, immediately following the 5-week training period, and after 3-months using ADHD symptoms scales, as well as a series of neuropsychological tests and psychological questionnaires. Subjective ratings of everyday life attention and memory problems were also collected. The SAT group showed significant improvements in ADHD inattentive and impulsive symptoms, depressive symptoms and in self-efficacy ratings compared to the CT group at both post-training and at the 3-month assessment. Pre-post improvements in SAT participants on untrained cognitive tasks measuring selective attention and executive functions were also observed. Finally, the SAT group reported improved subjective ratings of everyday life attention at both assessment points. This pattern of results suggests that SAT may be beneficial in treating ADHD symptoms as well as psychological and cognitive impairments in adult ADHD. A large-scale randomized controlled trial (RCT) is needed. PMID- 25713524 TI - Effects of aging on eye movements in the real world. AB - The effects of aging on eye movements are well studied in the laboratory. Increased saccade latencies or decreased smooth-pursuit gain are well established findings. The question remains whether these findings are influenced by the rather untypical environment of a laboratory; that is, whether or not they transfer to the real world. We measured 34 healthy participants between the age of 25 and 85 during two everyday tasks in the real world: (I) walking down a hallway with free gaze, (II) visual tracking of an earth-fixed object while walking straight-ahead. Eye movements were recorded with a mobile light-weight eye tracker, the EyeSeeCam (ESC). We find that age significantly influences saccade parameters. With increasing age, saccade frequency, amplitude, peak velocity, and mean velocity are reduced and the velocity/amplitude distribution as well as the velocity profile become less skewed. In contrast to laboratory results on smooth pursuit, we did not find a significant effect of age on tracking eye-movements in the real world. Taken together, age-related eye movement changes as measured in the laboratory only partly resemble those in the real world. It is well-conceivable that in the real world additional sensory cues, such as head-movement or vestibular signals, may partially compensate for age-related effects, which, according to this view, would be specific to early motion processing. In any case, our results highlight the importance of validity for natural situations when studying the impact of aging on real-life performance. PMID- 25713525 TI - Identification of muscle synergies associated with gait transition in humans. AB - There is no theoretical or empirical evidence to suggest how the central nervous system (CNS) controls a variety of muscles associated with gait transition between walking and running. Here, we examined the motor control during a gait transition based on muscle synergies, which modularly organize functionally similar muscles. To this end, the subjects walked or ran on a treadmill and performed a gait transition spontaneously as the treadmill speed increased or decreased (a changing speed condition) or voluntarily following an experimenter's instruction at constant treadmill speed (a constant speed condition). Surface electromyograms (EMGs) were recorded from 11 lower limb muscles bilaterally. We then extracted the muscle weightings of synergies and their activation coefficients from the EMG data using non-negative matrix factorization. As a result, the gait transition was controlled by approximately 9 muscle synergies, which were common during a walking and running, and their activation profiles were changed before and after a gait transition. Near a gait transition, the peak activation phases of the synergies, which were composed of plantar flexor muscles, were shifted to an earlier phase at the walk-to-run transition, and vice versa. The shifts were gradual in the changing speed condition, but an abrupt change was observed in the constant speed condition. These results suggest that the CNS low-dimensionally regulate the activation profiles of the specific synergies based on afferent information (spontaneous gait transition) or by changing only the descending neural input to the muscle synergies (voluntary gait transition) to achieve a gait transition. PMID- 25713526 TI - In Experts, underlying processes that drive visuomotor adaptation are different than in Novices. AB - Processes responsible for improvements in motor performance are often contrasted in an explicit and an implicit part. Explicit learning enables task success by using strategic (declarative) knowledge. Implicit learning refers to a change in motor performance without conscious effort. In this study, we tested the contribution of explicit and implicit processes in a visuomotor adaptation task in subjects with different expertise in the task they were asked to adapt. Thirty handball players (Experts) and 30 subjects without handball experience (Novices) participated. Three experiments tested visuomotor adaptation of a free throw in team handball using prismatic glasses. The difference between experiments was that in Experiment 2 and 3, contribution of explicit processes was prevented, whereas Experiment 1 allowed contribution of explicit and implicit processes. Retention was assessed in Experiment 3. There were three main findings: (i) contribution of explicit processes to adaptation was stronger in Experts than Novices (Experiment 1); (ii) adaptation took longer in Experts when preventing contribution of explicit processes (Experiment 2); and (iii) retention was stronger in Experts (Experiment 3). This study shows that learning processes involved in visuomotor adaptation change by expertise, with more involvement of explicit processes and most likely other implicit processes to adaptation in Experts. PMID- 25713527 TI - Emotional discrimination during viewing unpleasant pictures: timing in human anterior ventrolateral prefrontal cortex and amygdala. AB - The ventrolateral prefrontal cortex (VLPFC) and amygdala have critical roles in the generation and regulation of unpleasant emotions, and in this study the dynamic neural basis of unpleasant emotion processing was elucidated by using paired-samples permutation t-tests to identify the timing of emotional discrimination in various brain regions. We recorded the temporal dynamics of blood-oxygen-level-dependent (BOLD) signals in those brain regions during the viewing of unpleasant pictures by using functional magnetic resonance imaging (fMRI) with high temporal resolution, and we compared the time course of the signal within the volume of interest (VOI) across emotional conditions. Results show that emotional discrimination in the right amygdala precedes that in the left amygdala and that emotional discrimination in both those regions precedes that in the right anterior VLPFC. They support the hypotheses that the right amygdala is part of a rapid emotional stimulus detection system and the left amygdala is specialized for sustained stimulus evaluation and that the right anterior VLPFC is implicated in the integration of viscerosensory information with affective signals between the bilateral anterior VLPFCs and the bilateral amygdalae. PMID- 25713528 TI - Analyzing the association between functional connectivity of the brain and intellectual performance. AB - Measurements of functional connectivity support the hypothesis that the brain is composed of distinct networks with anatomically separated nodes but common functionality. A few studies have suggested that intellectual performance may be associated with greater functional connectivity in the fronto-parietal network and enhanced global efficiency. In this fMRI study, we performed an exploratory analysis of the relationship between the brain's functional connectivity and intelligence scores derived from the Portuguese language version of the Wechsler Adult Intelligence Scale (WAIS-III) in a sample of 29 people, born and raised in Brazil. We examined functional connectivity between 82 regions, including graph theoretic properties of the overall network. Some previous findings were extended to the Portuguese-speaking population, specifically the presence of small-world organization of the brain and relationships of intelligence with connectivity of frontal, pre-central, parietal, occipital, fusiform and supramarginal gyrus, and caudate nucleus. Verbal comprehension was associated with global network efficiency, a new finding. PMID- 25713529 TI - Sleep spindles predict stress-related increases in sleep disturbances. AB - BACKGROUND AND AIM: Predisposing factors place certain individuals at higher risk for insomnia, especially in the presence of precipitating conditions such as stressful life events. Sleep spindles have been shown to play an important role in the preservation of sleep continuity. Lower spindle density might thus constitute an objective predisposing factor for sleep reactivity to stress. The aim of this study was therefore to evaluate the relationship between baseline sleep spindle density and the prospective change in insomnia symptoms in response to a standardized academic stressor. METHODS: Twelve healthy students had a polysomnography recording during a period of lower stress at the beginning of the academic semester, along with an assessment of insomnia complaints using the insomnia severity index (ISI). They completed a second ISI assessment at the end of the semester, a period coinciding with the week prior to final examinations and thus higher stress. Spindle density, amplitude, duration, and frequency, as well as sigma power were computed from C4-O2 electroencephalography derivation during stages N2-N3 of non-rapid-eye-movement (NREM) sleep, across the whole night and for each NREM sleep period. To test for the relationship between spindle density and changes in insomnia symptoms in response to academic stress, spindle measurements at baseline were correlated with changes in ISI across the academic semester. RESULTS: Spindle density (as well as spindle amplitude and sigma power), particularly during the first NREM sleep period, negatively correlated with changes in ISI (p < 0.05). CONCLUSION: Lower spindle activity, especially at the beginning of the night, prospectively predicted larger increases in insomnia symptoms in response to stress. This result indicates that individual differences in sleep spindle activity contribute to the differential vulnerability to sleep disturbances in the face of precipitating factors. PMID- 25713530 TI - Tracking cortical entrainment in neural activity: auditory processes in human temporal cortex. AB - A primary objective for cognitive neuroscience is to identify how features of the sensory environment are encoded in neural activity. Current auditory models of loudness perception can be used to make detailed predictions about the neural activity of the cortex as an individual listens to speech. We used two such models (loudness-sones and loudness-phons), varying in their psychophysiological realism, to predict the instantaneous loudness contours produced by 480 isolated words. These two sets of 480 contours were used to search for electrophysiological evidence of loudness processing in whole-brain recordings of electro- and magneto-encephalographic (EMEG) activity, recorded while subjects listened to the words. The technique identified a bilateral sequence of loudness processes, predicted by the more realistic loudness-sones model, that begin in auditory cortex at ~80 ms and subsequently reappear, tracking progressively down the superior temporal sulcus (STS) at lags from 230 to 330 ms. The technique was then extended to search for regions sensitive to the fundamental frequency (F0) of the voiced parts of the speech. It identified a bilateral F0 process in auditory cortex at a lag of ~90 ms, which was not followed by activity in STS. The results suggest that loudness information is being used to guide the analysis of the speech stream as it proceeds beyond auditory cortex down STS toward the temporal pole. PMID- 25713531 TI - Microbial-generated amyloids and Alzheimer's disease (AD). PMID- 25713532 TI - A marine analgesic peptide, Contulakin-G, and neurotensin are distinct agonists for neurotensin receptors: uncovering structural determinants of desensitization properties. AB - Neurotensin receptors have been studied as molecular targets for the treatment of pain, schizophrenia, addiction, or cancer. Neurotensin (NT) and Contulakin-G, a glycopeptide isolated from a predatory cone snail Conus geographus, share a sequence similarity at the C-terminus, which is critical for activation of neurotensin receptors. Both peptides are potent analgesics, although affinity and agonist potency of Contulakin-G toward neurotensin receptors are significantly lower, as compared to those for NT. In this work, we show that the weaker agonist properties of Contulakin-G result in inducing significantly less desensitization of neurotensin receptors and preserving their cell-surface density. Structure activity relationship (SAR) studies suggested that both glycosylation and charged amino acid residues in Contulakin-G or NT played important roles in desensitizing neurotensin receptors. Computational modeling studies of human neurotensin receptor NTS1 and Contulakin-G confirmed the role of glycosylation in weakening interactions with the receptors. Based on available SAR data, we designed, synthesized, and characterized an analog of Contulakin-G in which the glycosylated amino acid residue, Gal-GalNAc-Thr10, was replaced by memantine Glu10 residue. This analog exhibited comparable agonist potency and weaker desensitization properties as compared to that of Contulakin-G, while producing analgesia in the animal model of acute pain following systemic administration. We discuss our study in the context of feasibility and safety of developing NT therapeutic agents with improved penetration across the blood-brain barrier. Our work supports engineering peptide-based agonists with diverse abilities to desensitize G-protein coupled receptors and further emphasizes opportunities for conotoxins as novel pharmacological tools and drug candidates. PMID- 25713534 TI - Herbal medicines for the treatment of cancer chemotherapy-induced side effects. AB - Accumulating evidence suggests that Japanese herbal medicines, called Kampo, have beneficial effects on cancer chemotherapy-induced side effects. Rikkunshito ameliorates cisplatin-induced anorexia through an antagonistic effect on the 5-HT receptors and by increasing the serum ghrelin levels. Hangeshashinto improves irinotecan-induced diarrhea and chemotherapy-induced mucositis by inhibiting the activity of beta-glucuronidase as well as the synthesis of prostaglandin E2. Goshajinkigan prevents oxaliplatin-induced neurotoxicity, possibly through suppressing functional alterations of the transient receptor potential channels. In this review, we will summarize the currently available literature regarding the clinical efficacy and potential mechanisms of Kampo medicines in the treatment of cancer chemotherapy-induced side effects. PMID- 25713535 TI - Consensus statement from the first international conference for in utero stem cell transplantation and gene therapy. PMID- 25713533 TI - Nucleoside transporter proteins as biomarkers of drug responsiveness and drug targets. AB - Nucleoside and nucleobase analogs are currently used in the treatment of solid tumors, lymphoproliferative diseases, viral infections such as hepatitis and AIDS, and some inflammatory diseases such as Crohn. Two gene families are implicated in the uptake of nucleosides and nucleoside analogs into cells, SCL28 and SLC29. The former encodes hCNT1, hCNT2, and hCNT3 proteins. They translocate nucleosides in a Na(+) coupled manner with high affinity and some substrate selectivity, being hCNT1 and hCNT2 pyrimidine- and purine-preferring, respectively, and hCNT3 a broad selectivity transporter. SLC29 genes encode four members, being hENT1 and hENT2 the only two which are unequivocally implicated in the translocation of nucleosides and nucleobases (the latter mostly via hENT2) at the cell plasma membrane. Some nucleoside-derived drugs can also interact with and be translocated by members of the SLC22 gene family, particularly hOCT and hOAT proteins. Inter-individual differences in transporter function and perhaps, more importantly, altered expression associated with the disease itself might modulate the transporter profile of target cells, thereby determining drug bioavailability and action. Drug transporter pharmacology has been periodically reviewed. Thus, with this contribution we aim at providing a state-of-the-art overview of the clinical evidence generated so far supporting the concept that these membrane proteins can indeed be biomarkers suitable for diagnosis and/or prognosis. Last but not least, some of these transporter proteins can also be envisaged as drug targets, as long as they can show "transceptor" functions, in some cases related to their role as modulators of extracellular adenosine levels, thereby providing a functional link between P1 receptors and transporters. PMID- 25713536 TI - Early steps in inner ear development: induction and morphogenesis of the otic placode. AB - Various cellular replacement therapies using in vitro generated cells to replace damaged tissue have been proposed as strategies to alleviate hearing loss. All such therapies must involve a complete understanding of the earliest steps in inner ear development; its induction as a thickened plate of cells in the non neural, surface ectoderm of the embryo, to its internalization as an otocyst embedded in the head mesenchyme of the embryo. Such knowledge informs researchers addressing the feasibility of the proposed strategy and present alternatives if needed. In this review we describe the mechanisms of inner ear induction, concentrating on the factors that steer the fate of ectoderm into precursors of the inner ear. Induction then leads to inner ear morphogenesis and we describe the cellular changes that occur as the inner ear is converted from a superficial placode to an internalized otocyst, and how they are coordinated with a particular emphasis on how the signaling environment surrounding the inner ear influences these processes. PMID- 25713538 TI - Cytosolic calcium ions exert a major influence on the firing rate and maintenance of pacemaker activity in guinea-pig sinus node. AB - The sino-atrial node (SAN) provides the electrical stimulus to initiate every heart beat. Cellular processes underlying this activity have been debated extensively, especially with regards to the role of intracellular calcium. We have used whole-cell application of 1,2-bis(o-aminophenoxy)ethane-N,N,N',N' tetraacetic acid (BAPTA), a rapid calcium chelator, to guinea pig isolated SAN myocytes to assess the effect of rapid reduction of intracellular calcium on SAN cell electrical activity. High-dose (10 mM) BAPTA induced rapid and complete cessation of rhythmic action potential (AP) firing (time to cessation 5.5 +/- 1.7 s). Over a range of concentrations, BAPTA induced slowing of action potential firing and disruption of rhythmic activity, which was dose-dependent in its time of onset. Exposure to BAPTA was associated with stereotyped action potential changes similar to those previously reported in the presence of ryanodine, namely depolarization of the most negative diastolic potential, prolongation of action potentials and a reduction in action potential amplitude. These experiments are consistent with the view that cytosolic calcium is essential to the maintenance of rhythmic pacemaker activity. PMID- 25713539 TI - Cardiovascular and metabolic consequences of obesity. PMID- 25713537 TI - Voltage sensitive phosphatases: emerging kinship to protein tyrosine phosphatases from structure-function research. AB - The transmembrane protein Ci-VSP from the ascidian Ciona intestinalis was described as first member of a fascinating family of enzymes, the voltage sensitive phosphatases (VSPs). Ci-VSP and its voltage-activated homologs from other species are stimulated by positive membrane potentials and dephosphorylate the head groups of negatively charged phosphoinositide phosphates (PIPs). In doing so, VSPs act as control centers at the cytosolic membrane surface, because they intervene in signaling cascades that are mediated by PIP lipids. The characteristic motif CX5RT/S in the active site classifies VSPs as members of the huge family of cysteine-based protein tyrosine phosphatases (PTPs). Although PTPs have already been well-characterized regarding both, structure and function, their relationship to VSPs has drawn only limited attention so far. Therefore, the intention of this review is to give a short overview about the extensive knowledge about PTPs in relation to the facts known about VSPs. Here, we concentrate on the structural features of the catalytic domain which are similar between both classes of phosphatases and their consequences for the enzymatic function. By discussing results obtained from crystal structures, molecular dynamics simulations, and mutagenesis studies, a possible mechanism for the catalytic cycle of VSPs is presented based on that one proposed for PTPs. In this way, we want to link the knowledge about the catalytic activity of VSPs and PTPs. PMID- 25713540 TI - Mitochondrial uncoupling proteins and energy metabolism. AB - Understanding the metabolic factors that contribute to energy metabolism (EM) is critical for the development of new treatments for obesity and related diseases. Mitochondrial oxidative phosphorylation is not perfectly coupled to ATP synthesis, and the process of proton-leak plays a crucial role. Proton-leak accounts for a significant part of the resting metabolic rate (RMR) and therefore enhancement of this process represents a potential target for obesity treatment. Since their discovery, uncoupling proteins have stimulated great interest due to their involvement in mitochondrial-inducible proton-leak. Despite the widely accepted uncoupling/thermogenic effect of uncoupling protein one (UCP1), which was the first in this family to be discovered, the reactions catalyzed by its homolog UCP3 and the physiological role remain under debate. This review provides an overview of the role played by UCP1 and UCP3 in mitochondrial uncoupling/functionality as well as EM and suggests that they are a potential therapeutic target for treating obesity and its related diseases such as type II diabetes mellitus. PMID- 25713541 TI - Referential shift in Nicaraguan Sign Language: a transition from lexical to spatial devices. AB - Even the simplest narratives combine multiple strands of information, integrating different characters and their actions by expressing multiple perspectives of events. We examined the emergence of referential shift devices, which indicate changes among these perspectives, in Nicaraguan Sign Language (NSL). Sign languages, like spoken languages, mark referential shift grammatically with a shift in deictic perspective. In addition, sign languages can mark the shift with a point or a movement of the body to a specified spatial location in the three dimensional space in front of the signer, capitalizing on the spatial affordances of the manual modality. We asked whether the use of space to mark referential shift emerges early in a new sign language by comparing the first two age cohorts of deaf signers of NSL. Eight first-cohort signers and 10 second-cohort signers watched video vignettes and described them in NSL. Narratives were coded for lexical (use of words) and spatial (use of signing space) devices. Although the cohorts did not differ significantly in the number of perspectives represented, second-cohort signers used referential shift devices to explicitly mark a shift in perspective in more of their narratives. Furthermore, while there was no significant difference between cohorts in the use of non-spatial, lexical devices, there was a difference in spatial devices, with second-cohort signers using them in significantly more of their narratives. This suggests that spatial devices have only recently increased as systematic markers of referential shift. Spatial referential shift devices may have emerged more slowly because they depend on the establishment of fundamental spatial conventions in the language. While the modality of sign languages can ultimately engender the syntactic use of three-dimensional space, we propose that a language must first develop systematic spatial distinctions before harnessing space for grammatical functions. PMID- 25713543 TI - Lightness dependence of achromatic loci in color-appearance coordinates. AB - Shifts in the appearance of color under different illuminant chromaticity are known to be incomplete, and fit nicely with a simple linear transformation of cone responses that aligns the achromatic points under two illuminants. Most chromaticity-transfer functions with von-Kries-like transformations use only one set of values to fit the color shifts from one illuminant to another. However, an achromatic point shifts its chromaticity depending on the lightness of the test stimulus. This lightness dependence of the achromatic-point locus is qualitatively similar to a phenomenon known as the Helson-Judd effect. The present study suggests that the lightness dependency of achromatic points appears to be a general trend, which is supported by the results from deriving the optimal von-Kries coefficients for different lightness levels that best fit the color shifts under a different illuminant chromaticity. Further, we report that such a lightness dependence of the achromatic-point loci can be represented simply as a straight line in coordinates defined using color-appearance models such as CIECAM when normalized for daylight. PMID- 25713542 TI - Toward a neural basis for peer-interaction: what makes peer-learning tick? AB - Many of the instructional practices that have been advanced as intrinsically motivating are inherent in socio-constructivist learning environments. There is now emerging scientific evidence to explain why interactive learning environments promote the intrinsic motivation to learn. The "two-body" and "second person" approaches have begun to explore the "dark matter" of social neuroscience: the intra- and inter-individual brain dynamics during social interaction. Moreover, studies indicate that when young learners are given expanded opportunities to actively and equitably participate in collaborative learning activities they experienced feelings of well-being, contentment, or even excitement. Neuroscience starts demonstrating how this naturally rewarding aspect is strongly associated with the implication of the mesolimbic dopaminergic pathway during social interaction. The production of dopamine reinforces the desire to continue the interaction, and heightens feelings of anticipation for future peer-learning activities. Here we review how cooperative learning and problem-solving interactions can bring about the "intrinsic" motivation to learn. Overall, the reported theoretical arguments and neuroscientific results have clear implications for school and organization approaches and support social constructivist perspectives. PMID- 25713544 TI - Assessing embodied interpersonal emotion regulation in somatic symptom disorders: a case study. AB - The aim of the present study was to examine the intra- and interpersonal emotion regulation of patients with somatic symptom disorders (SSDs) during interactions with significant others (i.e., romantic partners). We presented two case couples for analysis. The first couple consisted of a patient with SSD and his healthy partner, whereas the second couple consisted of two healthy partners. The couples underwent an interpersonal experiment that involved baseline, anger and relaxation tasks. During each task, partners' cutaneous facial temperature, heart rate and skin conductance levels were measured simultaneously. Participants' trait-emotion regulation, state-affect reports for self and other, and attachment styles were also examined. The experimental phases were successful in creating variations in physiological processes and affective experience. As expected, emotion regulation difficulties predicted higher increase in the course of temperature at each phase. Besides, the patient showed restricted awareness and reflection to emotions despite his higher autonomic activity compared to healthy controls. Both partners of the first couple revealed limited ability in understanding the other's emotions, whereas the second couple performed relatively better in that domain. The temperature variations between the patient and his partner were significantly correlated while the correlations of temperature changes between the second couple were negligible except anger task. The study supported the merits of an embodied interpersonal approach in clinical studies. The tentative results of the cases were discussed in the light of findings in emotion regulation and attachment research. PMID- 25713545 TI - EI competencies as a related but different characteristic than intelligence. AB - Amid the swarm of debate about emotional intelligence (EI) among academics are claims that cognitive intelligence, or general mental ability (g), is a stronger predictor of life and work outcomes as well as the counter claims that EI is their strongest predictor. Nested within the tempest in a teapot are scientific questions as to what the relationship is between g and EI. Using a behavioral approach to EI, we examined the relationship of a parametric measure of g as the person's GMAT scores and collected observations from others who live and work with the person as to the frequency of his or her EI behavior, as well as the person's self-assessment. The results show that EI, as seen by others, is slightly related to g, especially for males with assessment from professional relations. Further, we found that cognitive competencies are more strongly related to GMAT than EI competencies. For observations from personal relationships or self-assessment, there is no relationship between EI and GMAT. Observations from professional relations reveal a positive relationship between cognitive competencies and GMAT and EI and GMAT for males, but a negative relationship between EI and GMAT for females. PMID- 25713546 TI - The effect of endpoint congruency on bimanual transport and rotation tasks. AB - The completion of many goal oriented skills requires the tight coordination of the right and left hands to achieve the task objective. Although the coordination of wrist transport and orientation of the hand before object contact has been studied in detail for discrete bimanual tasks, as yet, very few studies have examined bimanual coordination when the target is already in hand. It has been shown that congruency of the goal facilitates the production of discrete bimanual responses. The purpose of this study was to investigate the role of goal congruency on precision bimanual transport and rotate tasks. In the current investigation, participants transported two cubic objects while rotating them laterally to place them into tight-fitting targets. The magnitude of the rotation could be the same for both hands (i.e., both 45 or 90(?)) or different (i.e., one 45 and 90(?)) and the endpoint orientations (i.e., goal) could either be congruent or incongruent. Results indicated that when the endpoint orientation was congruent for the two hands, movement times were similar regardless of hand (left or right), rotation magnitude (45, 90(?)) and whether the rotation magnitude for the two hands was the same or different. These results suggest that congruency of the endpoint goal facilitates the temporal synchronization of the transport component for two limbs. In contrast, a different pattern of results was obtained when considering the rotation component. Specifically, regardless of whether the hands were rotating the same magnitude or ending in congruent endpoint positions, the coordination of the rotation component between the hands was asynchronous. We hypothesize that the greater requirement to shift visual fixation from one hand/target to the other to ascertain the separate goal orientations may explain these differences. These results provide further evidence that multiple constraints act to influence the performance of skilled bimanual tasks. PMID- 25713547 TI - Transcutaneous Vagal Nerve Stimulation (tVNS): a new neuromodulation tool in healthy humans? PMID- 25713548 TI - The use of intonation for turn anticipation in observed conversations without visual signals as source of information. AB - The anticipation of a speaker's next turn is a key element of successful conversation. This can be achieved using a multitude of cues. In natural conversation, the most important cue for adults to anticipate the end of a turn (and therefore the beginning of the next turn) is the semantic and syntactic content. In addition, prosodic cues, such as intonation, or visual signals that occur before a speaker starts speaking (e.g., opening the mouth) help to identify the beginning and the end of a speaker's turn. Early in life, prosodic cues seem to be more important than in adulthood. For example, it was previously shown that 3-year-old children anticipated more turns in observed conversations when intonation was available compared with when not, and this beneficial effect was present neither in younger children nor in adults (Keitel et al., 2013). In the present study, we investigated this effect in greater detail. Videos of conversations between puppets with either normal or flattened intonation were presented to children (1-year-olds and 3-year-olds) and adults. The use of puppets allowed the control of visual signals: the verbal signals (speech) started exactly at the same time as the visual signals (mouth opening). With respect to the children, our findings replicate the results of the previous study: 3-year-olds anticipated more turns with normal intonation than with flattened intonation, whereas 1-year-olds did not show this effect. In contrast to our previous findings, the adults showed the same intonation effect as the 3 year-olds. This suggests that adults' cue use varies depending on the characteristics of a conversation. Our results further support the notion that the cues used to anticipate conversational turns differ in development. PMID- 25713549 TI - Revisiting Wittgenstein's puzzle: hierarchical encoding and comparison facilitate learning of probabilistic relational categories. AB - Kittur et al. (2004, 2006) and Jung and Hummel (2011, 2014) showed that people have great difficulty learning relation-based categories with a probabilistic (i.e., family resemblance) structure, in which no single relation is shared by all members of a category. Yet acquisition of such categories is not strictly impossible: in all these studies, roughly half the participants eventually learned to criterion. What are these participants doing that the other half are not? We hypothesized that successful participants were those who divided the nominal categories into two or more sub-categories, each of which individually had a deterministic structure. We report three experiments testing this hypothesis: explicitly presenting participants with hierarchical (category and sub-category) structures facilitated the acquisition of otherwise probabilistic relational categories, but only when participants learned the subordinate-level (i.e., deterministic) categories prior to learning the nominal (i.e., probabilistic) categories and only when they were permitted to view multiple exemplars of the same category simultaneously. These findings suggest that one way to learn natural relational categories with a probabilistic structure [e.g., Wittgenstein's (1953), category game, or even mother] is by learning deterministic subordinate-level concepts first and connecting them together under a common concept or label. They also add to the literature suggesting that comparison of multiple exemplars plays an instrumental role in relational learning. PMID- 25713550 TI - Ambulatory assessed implicit affect is associated with salivary cortisol. AB - One of the presumed pathways linking negative emotions to adverse somatic health is an overactive HPA-axis, usually indicated by elevated cortisol levels. Traditionally, research has focused on consciously reported negative emotions. Yet, given that the majority of information processing occurs without conscious awareness, stress physiology might also be influenced by affective processes that people are not aware of. In a 24-h ambulatory study we examined whether cortisol levels were associated with two implicit measures. Implicit affect was assessed using the Implicit Positive and Negative Affect Test, and implicit negative memory bias was assessed with the word fragment completion tasks. In 55 healthy participants, we measured subjective stress levels, worries, implicit, and explicit affect each hour during waking hours. Also, saliva samples were collected at three fixed times during the day, as well as upon waking and 30 min thereafter (cortisol awakening response). Multilevel analyses of the daytime cortisol levels revealed that the presence of an implicit negative memory bias was associated with increased cortisol levels. Additionally, implicit PA and, unexpectedly, implicit NA were negatively associated with cortisol levels. Finally, participants demonstrating higher levels of implicit sadness during the first measurement day, had a stronger cortisol rise upon awakening at the next day. Contrary to previous research, no associations between explicit affect and cortisol were apparent. The current study was the first to examine the concurrent relation between implicit measures and stress physiology in daily life. The results suggest that the traditional focus on consciously reported feelings and emotions is limited, and that implicit measures can add to our understanding of how stress and emotions contribute to daily physiological activity and, in the long term, health problems. PMID- 25713551 TI - Enhancing perceptual and attentional skills requires common demands between the action video games and transfer tasks. AB - Despite increasing evidence that shows action video game play improves perceptual and cognitive skills, the mechanisms of transfer are not well-understood. In line with previous work, we suggest that transfer is dependent upon common demands between the game and transfer task. In the current study, participants played one of four action games with varying speed, visual, and attentional demands for 20 h. We examined whether training enhanced performance for attentional blink, selective attention, attending to multiple items, visual search and auditory detection. Non-gamers who played the game (Modern Combat) with the highest demands showed transfer to tasks of attentional blink and attending to multiple items. The game (MGS Touch) with fewer attentional demands also decreased attentional blink, but to a lesser degree. Other games failed to show transfer, despite having many action game characteristics but at a reduced intensity. The results support the common demands hypothesis. PMID- 25713553 TI - Automaticity revisited: when print doesn't activate semantics. AB - It is widely accepted that the presentation of a printed word "automatically" triggers processing that ends with full semantic activation. This processing, among other characteristics, is held to occur without intention, and cannot be stopped. The results of the present experiment show that this account is problematic in the context of a variant of the Stroop paradigm. Subjects named the print color of words that were either neutral or semantically related to color. When the letters were all colored, all spatially cued, and the spaces between letters were filled with characters from the top of the keyboard (i.e., 4, #, 5, %, 6, and *), color naming yielded a semantically based Stroop effect and a semantically based negative priming effect. In contrast, the same items yielded neither a semantic Stroop effect nor a negative priming effect when a single target letter was uniquely colored and spatially cued. These findings (a) undermine the widespread view that lexical-semantic activation in word reading is automatic in the sense that it occurs without intention and cannot be derailed, and (b) strengthens the case that both implicit and explicit forms of visual word recognition require spatial attention as a necessary preliminary to lexical semantic processing. PMID- 25713552 TI - Creativity and working memory capacity in sports: working memory capacity is not a limiting factor in creative decision making amongst skilled performers. AB - The goal of the study was to investigate the relationship between domain-general working memory capacity and domain-specific creativity amongst experienced soccer players. We administered the automated operation span task in combination with a domain-specific soccer creativity task to a group of 61 experienced soccer players to address the question whether an athlete's domain-specific creativity is restricted by their domain-general cognitive abilities (i.e., working memory capacity). Given that previous studies have either found a positive correlation, a negative correlation, or no correlation between working memory capacity and creativity, we analyzed the data in an exploratory manner by following recent recommendations to report effect-size estimations and their precision in form of 95% confidence intervals. The pattern of results provided evidence that domain general working memory capacity is not associated with creativity in a soccer specific creativity task. This pattern of results suggests that future research and theorizing on the role of working memory in everyday creative performance needs to distinguish between different types of creative performance while also taking the role of domain-specific experience into account. PMID- 25713554 TI - Text-fading based training leads to transfer effects on children's sentence reading fluency. AB - Previous studies used a text-fading procedure as a training tool with the goal to increase silent reading fluency (i.e., proficient reading rate and comprehension). In recently published studies, this procedure resulted in lasting reading enhancements for adult and adolescent research samples. However, studies working with children reported mixed results. While reading rate improvements were observable for Dutch reading children in a text-fading training study, reading fluency improvements in standardized reading tests post-training attributable to the fading manipulation were not detectable. These results raise the question of whether text-fading training is not effective for children or whether research design issues have concealed possible transfer effects. Hence, the present study sought to investigate possible transfer effects resulting from a text-fading based reading training program, using a modified research design. Over a period of 3 weeks, two groups of German third-graders read sentences either with an adaptive text-fading procedure or at their self-paced reading rate. A standardized test measuring reading fluency at the word, sentence, and text level was conducted pre- and post-training. Text level reading fluency improved for both groups equally. Post-training gains at the word level were found for the text-fading group, however, no significant interaction between groups was revealed for word reading fluency. Sentence level reading fluency gains were found for the text-fading group, which significantly differed from the group of children reading at their self-paced reading routine. These findings provide evidence for the efficacy of text-fading as a training method for sentence reading fluency improvement also for children. PMID- 25713556 TI - Disorder perception is the adaptive interpretation of social cues, not just a sensitivity to randomness. PMID- 25713555 TI - Gaze-cueing effect depends on facial expression of emotion in 9- to 12-month-old infants. AB - Efficient processing of gaze direction and facial expression of emotion is crucial for early social and emotional development. Toward the end of the first year of life infants begin to pay more attention to negative expressions, but it remains unclear to what extent emotion expression is processed jointly with gaze direction at this age. This study sought to establish the interactions of gaze direction and emotion expression in visual orienting in 9- to 12-month-olds. In particular, we tested whether these interactions can be explained by the negativity bias hypothesis and the shared signal hypothesis. We measured saccadic latencies in response to peripheral targets in a gaze-cueing paradigm with happy, angry, and fearful female faces. In the Pilot Experiment three gaze directions were used (direct, congruent with target location, incongruent with target location). In the Main Experiment we sought to replicate the results of the Pilot experiment using a simpler design without the direct gaze condition. In both experiments we found a robust gaze-cueing effect for happy faces, i.e., facilitation of orienting toward the target in the gaze-cued location, compared with the gaze-incongruent location. We found more rapid orienting to targets cued by happy relative to angry and fearful faces. We did not find any gaze-cueing effect for angry or fearful faces. These results are not consistent with the shared signal hypothesis. While our results show differential processing of positive and negative emotions, they do not support a general negativity bias. On the contrary, they indicate that toward the age of 12 months infants show a positivity bias in gaze-cueing tasks. PMID- 25713557 TI - Noise Trauma Induced Neural Plasticity Throughout the Auditory System of Mongolian Gerbils: Differences between Tinnitus Developing and Non-Developing Animals. AB - In this study, we describe differences between neural plasticity in auditory cortex (AC) of animals that developed subjective tinnitus (group T) after noise induced hearing loss (NIHL) compared to those that did not [group non-tinnitus (NT)]. To this end, our analysis focuses on the input activity of cortical neurons based on the temporal and spectral analysis of local field potential (LFP) recordings and an in-depth analysis of auditory brainstem responses (ABR) in the same animals. In response to NIHL in NT animals we find a significant general reduction in overall cortical activity and spectral power as well as changes in all ABR wave amplitudes as a function of loudness. In contrast, T animals show no significant change in overall cortical activity as assessed by root mean square analysis of LFP amplitudes, but a specific increase in LFP spectral power and in the amplitude of ABR wave V reflecting activity in the inferior colliculus (IC). Based on these results, we put forward a refined model of tinnitus prevention after NIHL that acts via a top-down global (i.e., frequency-unspecific) inhibition reducing overall neuronal activity in AC and IC, thereby counteracting NIHL-induced bottom-up frequency-specific neuroplasticity suggested in current models of tinnitus development. PMID- 25713558 TI - Restless legs syndrome and poliomyelitis: new evidences of an old observation? PMID- 25713559 TI - On the Path toward Classifying Hormones of the Vasoinhibin-Family. PMID- 25713560 TI - Phosphoproteomics analysis of a clinical Mycobacterium tuberculosis Beijing isolate: expanding the mycobacterial phosphoproteome catalog. AB - Reversible protein phosphorylation, regulated by protein kinases and phosphatases, mediates a switch between protein activity and cellular pathways that contribute to a large number of cellular processes. The Mycobacterium tuberculosis genome encodes 11 Serine/Threonine kinases (STPKs) which show close homology to eukaryotic kinases. This study aimed to elucidate the phosphoproteomic landscape of a clinical isolate of M. tuberculosis. We performed a high throughput mass spectrometric analysis of proteins extracted from an early logarithmic phase culture. Whole cell lysate proteins were processed using the filter-aided sample preparation method, followed by phosphopeptide enrichment of tryptic peptides by strong cation exchange (SCX) and Titanium dioxide (TiO2) chromatography. The MaxQuant quantitative proteomics software package was used for protein identification. Our analysis identified 414 serine/threonine/tyrosine phosphorylated sites, with a distribution of S/T/Y sites; 38% on serine, 59% on threonine and 3% on tyrosine; present on 303 unique peptides mapping to 214 M. tuberculosis proteins. Only 45 of the S/T/Y phosphorylated proteins identified in our study had been previously described in the laboratory strain H37Rv, confirming previous reports. The remaining 169 phosphorylated proteins were newly identified in this clinical M. tuberculosis Beijing strain. We identified 5 novel tyrosine phosphorylated proteins. These findings not only expand upon our current understanding of the protein phosphorylation network in clinical M. tuberculosis but the data set also further extends and complements previous knowledge regarding phosphorylated peptides and phosphorylation sites in M. tuberculosis. PMID- 25713561 TI - Feasible metabolisms in high pH springs of the Philippines. AB - A field campaign targeting high pH, H2-, and CH4-emitting serpentinite-associated springs in the Zambales and Palawan Ophiolites of the Philippines was conducted in 2012-2013, and enabled description of several springs sourced in altered pillow basalts, gabbros, and peridotites. We combine field observations of pH, temperature, conductivity, dissolved oxygen, and oxidation-reduction potential with analyses of major ions, dissolved inorganic carbon, dissolved organic carbon, and dissolved gas phases in order to model the activities of selected phases important to microbial metabolism, and to rank feasible metabolic reactions based on energy yield. We document changing geochemical inventories in these springs between sampling years, and examine how the environment supports or prevents the function of certain microbial metabolisms. In all, this geochemistry based assessment of feasible metabolisms indicates methane cycling, hydrogen oxidation, some iron and sulfur metabolisms, and ammonia oxidation are feasible reactions in this continental site of serpentinization. PMID- 25713562 TI - Analysis of the Salmonella regulatory network suggests involvement of SsrB and H NS in sigma(E)-regulated SPI-2 gene expression. AB - The extracytoplasmic functioning sigma factor sigma(E) is known to play an essential role for Salmonella enterica serovar Typhimurium to survive and proliferate in macrophages and mice. However, its regulatory network is not well characterized, especially during infection. Here we used microarray to identify genes regulated by sigma(E) in Salmonella grown in three conditions: a nutrient rich condition and two others that mimic early and late intracellular infection. We found that in each condition sigma(E) regulated different sets of genes, and notably, several global regulators. When comparing nutrient-rich and infection like conditions, large changes were observed in the expression of genes involved in Salmonella pathogenesis island (SPI)-1 type-three secretion system (TTSS), SPI 2 TTSS, protein synthesis, and stress responses. In total, the expression of 58% of Salmonella genes was affected by sigma(E) in at least one of the three conditions. An important finding is that sigma(E) up-regulates SPI-2 genes, which are essential for Salmonella intracellular survival, by up-regulating SPI-2 activator ssrB expression at the early stage of infection and down-regulating SPI 2 repressor hns expression at a later stage. Moreover, sigma(E) is capable of countering the silencing of H-NS, releasing the expression of SPI-2 genes. This connection between sigma(E) and SPI-2 genes, combined with the global regulatory effect of sigma(E), may account for the lethality of rpoE-deficient Salmonella in murine infection. PMID- 25713563 TI - Rhizobiales as functional and endosymbiontic members in the lichen symbiosis of Lobaria pulmonaria L. AB - Rhizobiales (Alphaproteobacteria) are well-known beneficial partners in plant microbe interactions. Less is known about the occurrence and function of Rhizobiales in the lichen symbiosis, although it has previously been shown that Alphaproteobacteria are the dominating group in growing lichen thalli. We have analyzed the taxonomic structure and assigned functions to Rhizobiales within a metagenomic dataset of the lung lichen Lobaria pulmonaria L. One third (32.2%) of the overall bacteria belong to the Rhizobiales, in particular to the families Methylobacteriaceae, Bradyrhizobiaceae, and Rhizobiaceae. About 20% of our metagenomic assignments could not be placed in any of the Rhizobiales lineages, which indicates a yet undescribed bacterial diversity. SEED-based functional analysis focused on Rhizobiales and revealed functions supporting the symbiosis, including auxin and vitamin production, nitrogen fixation and stress protection. We also have used a specifically developed probe to localize Rhizobiales by confocal laser scanning microscopy after fluorescence in situ hybridization (FISH CLSM). Bacteria preferentially colonized fungal surfaces, but there is clear evidence that members of the Rhizobiales are able to intrude at varying depths into the interhyphal gelatinous matrix of the upper lichen cortical layer and that at least occasionally some bacteria also are capable to colonize the interior of the fungal hyphae. Interestingly, the gradual development of an endosymbiotic bacterial life was found for lichen- as well as for fungal- and plant-associated bacteria. The new tools to study Rhizobiales, FISH microscopy and comparative metagenomics, suggest a similar beneficial role for lichens than for plants and will help to better understand the Rhizobiales-host interaction and their biotechnological potential. PMID- 25713565 TI - Multiple mechanisms contribute to the development of clinically significant azole resistance in Aspergillus fumigatus. AB - Infections caused by the filamentous fungus Aspergillus fumigatus are a significant clinical issue and represent the second most-common form of fungal infection. Azole drugs are effective against this pathogen but resistant isolates are being found more frequently. Infections associated with azole resistant A. fumigatus have a significantly increased mortality making understanding drug resistance in this organism a priority. The target of azole drugs is the lanosterol alpha-14 demethylase enzyme encoded by the cyp51A gene in A. fumigatus. Mutations in cyp51A have been described that give rise to azole resistance and been argued to be the primary, if not sole, contributor to azole resistance. Here, I discuss recent developments that indicate multiple mechanisms, including increased expression of ATP-binding cassette (ABC) transporter proteins, contribute to azole resistance. ABC transporters are well established determinants of drug resistance in other fungal pathogens and seem likely to play a similar role in A. fumigatus. PMID- 25713564 TI - Phylogenetic shifts of bacterioplankton community composition along the Pearl Estuary: the potential impact of hypoxia and nutrients. AB - The significance of salinity in shaping bacterial communities dwelling in estuarine areas has been well documented. However, the influences of other environmental factors such as dissolved oxygen and nutrients in determining distribution patterns of both individual taxa and bacterial communities inhabited local estuarine regions remain elusive. Here, bacterioplankton community structures of surface and bottom waters from eight sites along the Pearl Estuary were characterized with 16S rRNA gene pyrosequencing. The results showed significant differences of bacterioplankton community between freshwater and saltwater sites, and further between surface and bottom waters of saltwater sites. Synechococcus dominated the surface water of saltwater sites while Oceanospirillales, SAR11 and SAR406 were prevalent in the bottom water. Betaproteobacteria was abundant in freshwater sites, with no significant difference between water layers. Occurrence of phylogenetic shifts in taxa affiliated to the same clade was also detected. Dissolved oxygen explained most of the bacterial community variation in the redundancy analysis targeting only freshwater sites, whereas nutrients and salinity explained most of the variation across all samples in the Pearl Estuary. Methylophilales (mainly PE2 clade) was positively correlated to dissolved oxygen, whereas Rhodocyclales (mainly R.12up clade) was negatively correlated. Moreover, high nutrient inputs to the freshwater area of the Pearl Estuary have shifted the bacterial communities toward copiotrophic groups, such as Sphingomonadales. The present study demonstrated that the overall nutrients and freshwater hypoxia play important roles in determining bacterioplankton compositions and provided insights into the potential ecological roles of specific taxa in estuarine environments. PMID- 25713566 TI - PB2 segment promotes high-pathogenicity of H5N1 avian influenza viruses in mice. AB - H5N1 influenza viruses with high lethality are a continuing threat to humans and poultry. Recently, H5N1 high-pathogenicity avian influenza virus (HPAIV) has been shown to transmit through aerosols between ferrets in lab experiments by acquiring some mutation. This is another deeply aggravated threat of H5N1 HPAIV to humans. To further explore the molecular determinant of H5N1 HPAIV virulence in a mammalian model, we compared the virulence of A/Duck/Guangdong/212/2004 (DK212) and A/Quail/Guangdong/90/2004 (QL90). Though they were genetically similar, they had different pathogenicity in mice, as well as their 16 reassortants. The results indicated that a swap of the PB2 gene could dramatically decrease the virulence of rgDK212 in mice (1896-fold) but increase the virulence of rgQL90 in mice (60-fold). Furthermore, the polymerase activity assays showed that swapping PB2 genes between these two viruses significantly changed the activity of polymerase complexes in 293T cells. The mutation Ser715Asn in PB2 sharply attenuated the virulence of rgDK212 in mice (2710-fold). PB2 segment promotes high-pathogenicity of H5N1 avian influenza viruses in mice and 715 Ser in PB2 plays an important role in determining high virulence of DK212 in mice. PMID- 25713567 TI - Dynamic nature of SecA and its associated proteins in Escherichia coli. AB - Mechanical properties such as physical constraint and pushing of chromosomes are thought to be important for chromosome segregation in Escherichia coli and it could be mediated by a hypothetical molecular "tether." However, the actual tether that mediates these features is not known. We previously described that SecA (Secretory A) and Secretory Y (SecY), components of the membrane protein translocation machinery, and AcpP (Acyl carrier protein P) were involved in chromosome segregation and homeostasis of DNA topology. In the present work, we performed three-dimensional deconvolution of microscopic images and time-lapse experiments of these proteins together with MukB and DNA topoisomerases, and found that these proteins embraced the structures of tortuous nucleoids with condensed regions. Notably, SecA, SecY, and AcpP dynamically localized in cells, which was interdependent on each other requiring the ATPase activity of SecA. Our findings imply that the membrane protein translocation machinery plays a role in the maintenance of proper chromosome partitioning, possibly through "tethering" of MukB [a functional homolog of structural maintenance of chromosomes (SMC) proteins], DNA gyrase, DNA topoisomerase IV, and SeqA (Sequestration A). PMID- 25713568 TI - Heterologous production of fungal secondary metabolites in Aspergilli. AB - Fungal natural products comprise a wide range of compounds. Some are medically attractive as drugs and drug leads, some are used as food additives, while others are harmful mycotoxins. In recent years the genome sequence of several fungi has become available providing genetic information of a large number of putative biosynthetic pathways. However, compound discovery is difficult as the genes required for the production of the compounds often are silent or barely expressed under laboratory conditions. Furthermore, the lack of available tools for genetic manipulation of most fungal species hinders pathway discovery. Heterologous expression of the biosynthetic pathway in model systems or cell factories facilitates product discovery, elucidation, and production. This review summarizes the recent strategies for heterologous expression of fungal biosynthetic pathways in Aspergilli. PMID- 25713569 TI - Extensive amplification of GI-VII-6, a multidrug resistance genomic island of Salmonella enterica serovar Typhimurium, increases resistance to extended spectrum cephalosporins. AB - GI-VII-6 is a chromosomally integrated multidrug resistance genomic island harbored by a specific clone of Salmonella enterica serovar Typhimurium (S.Typhimurium). It contains a gene encoding CMY-2 beta-lactamase (bla CMY-2), and therefore contributes to extended-spectrum cephalosporin resistance. To elucidate the significance of GI-VII-6 on adaptive evolution, spontaneous mutants of S. Typhimurium strain L-3553 were selected on plates containing cefotaxime (CTX). The concentrations of CTX were higher than its minimum inhibition concentration to the parent strain. The mutants appeared on the plates containing 12.5 and 25 mg/L CTX at a frequency of 10(-6) and 10(-8), respectively. No colonies were observed at higher CTX concentrations. The copy number of bla CMY-2 increased up to 85 per genome in the mutants, while the parent strain contains one copy of that in the chromosome. This elevation was accompanied by increased amount of transcription. The bla CMY-2 copy number in the mutants drastically decreased in the absence of antimicrobial selection pressure. Southern hybridization analysis and short-read mapping indicated that the entire 125 kb GI VII-6 or parts of it were tandemly amplified. GI-VII-6 amplification occurred at its original position, although it also transposed to other locations in the genome in some mutants, including an endogenous plasmid in some of the mutants, leading to the amplification of GI-VII-6 at different loci. Insertion sequences were observed at the junction of the amplified regions in the mutants, suggesting their significant roles in the transposition and amplification. Plasmid copy number in the selected mutants was 1.4 to 4.4 times higher than that of the parent strain. These data suggest that transposition and amplification of the bla CMY-2-containing region, along with the copy number variation of the plasmid, contributed to the extensive amplification of bla CMY-2 and increased resistance to CTX. PMID- 25713570 TI - Microcalorimetric study of the growth of Streptococcus thermophilus in renneted milk. AB - The growth of Streptococcus thermophilus ST12 (ST12) in liquid milk, reconstituted from low-heat skim milk powder reconstituted skim milk (RSM) and in RSM with rennet addition (r-RSM) at 40 degrees C was monitored by microcalorimetry. It was shown that the growth rate of bacteria decreased in renneted samples in comparison with liquid RSM starting from certain sizes of the colonies ("deviation moments"), which depended on the inoculation rates. The hydrolysis of lactose was delayed for about 1 h in the r-RSM in comparison with RSM but otherwise the metabolism of carbohydrates in the renneted and non renneted milks was similar. The total free amino acids (TFAA) content by the end of fermentations was higher in r-RSM than in RSM presumably due to the enzymatic hydrolytic activity of rennet. The quantitatively dominating amino acids were remarkably different in the r-RSM and RSM indicating that the hydrolysis cascade of caseins and/or metabolism of amino acids by the bacteria functioned differently in the two cases. The data obtained showed potential of microcalorimetry to characterize quantitative differences of growth and metabolism of the bacteria in renneted and liquid samples of milk. PMID- 25713571 TI - Label-free SRM-based relative quantification of antibiotic resistance mechanisms in Pseudomonas aeruginosa clinical isolates. AB - Both acquired and intrinsic mechanisms play a crucial role in Pseudomonas aeruginosa antibiotic resistance. Many clinically relevant resistance mechanisms result from changes in gene expression, namely multidrug efflux pump overproduction, AmpC beta-lactamase induction or derepression, and inactivation or repression of the carbapenem-specific porin OprD. Changes in gene expression are usually assessed using reverse-transcription quantitative real-time PCR (RT qPCR) assays. Here, we evaluated label-free Selected Reaction Monitoring (SRM) based mass spectrometry to directly quantify proteins involved in antibiotic resistance. We evaluated the label-free SRM using a defined set of P. aeruginosa isolates with known resistance mechanisms and compared it with RT-qPCR. Referring to efflux systems, we found a more robust relative quantification of antibiotic resistance mechanisms by SRM than RT-qPCR. The SRM-based approach was applied to a set of clinical P. aeruginosa isolates to detect antibiotic resistance proteins. This multiplexed SRM-based approach is a rapid and reliable method for the simultaneous detection and quantification of resistance mechanisms and we demonstrate its relevance for antibiotic resistance prediction. PMID- 25713572 TI - Novel Flp pilus biogenesis-dependent natural transformation. AB - Natural transformation has been described in bacterial species spread through nearly all major taxonomic groups. However, the current understanding of the structural components and the regulation of competence development is derived from only a few model organisms. Although natural transformation was discovered in members of the Actinobacteria (high GC Gram-positive bacteria) more than four decades ago, the structural components or the regulation of the competence system have not been studied in any representative of the entire phylum. In this report we identify a new role for a distinct type of pilus biogenesis genes (tad genes, for tight adherence), which so far have been connected only with biofilm formation, adherence and virulence traits. The tad-like genes found in the genome of Micrococcus luteus were shown to be required for genetic transformation in this actinobacterial species. We generated and analyzed individual knockout mutants for every open reading frame of the two predicted tad gene clusters as well as for a potential prepilin processing peptidase and identified the major component of the putative pili. By expressing a tagged variant of the major prepilin subunit and immunofluorescence microscopy we visualized filamentous structures extending from the cell surface. Our data indicate that the two tad gene islands complementarily contribute to the formation of a functional competence pilus in this organism. It seems likely that the involvement of tad genes in natural transformation is not unique only for M. luteus but may also prove to be the case in other representatives of the Actinobacteria, which contains important medically and biotechnologically relevant species. PMID- 25713573 TI - Post-translational modifications are key players of the Legionella pneumophila infection strategy. AB - Post-translational modifications (PTMs) are widely used by eukaryotes to control the enzymatic activity, localization or stability of their proteins. Traditionally, it was believed that the broad biochemical diversity of the PTMs is restricted to eukaryotic cells, which exploit it in extensive networks to fine tune various and complex cellular functions. During the last decade, the advanced detection methods of PTMs and functional studies of the host-pathogen relationships highlight that bacteria have also developed a large arsenal of PTMs, particularly to subvert host cell pathways to their benefit. Legionella pneumophila, the etiological agent of the severe pneumonia legionellosis, is the paradigm of highly adapted intravacuolar pathogens that have set up sophisticated biochemical strategies. Among them, L. pneumophila has evolved eukaryotic-like and rare/novel PTMs to hijack host cell processes. Here, we review recent progress about the diversity of PTMs catalyzed by Legionella: ubiquitination, prenylation, phosphorylation, glycosylation, methylation, AMPylation, and de AMPylation, phosphocholination, and de-phosphocholination. We focus on the host cell pathways targeted by the bacteria catalyzed PTMs and we stress the importance of the PTMs in the Legionella infection strategy. Finally, we highlight that the discovery of these PTMs undoubtedly made significant breakthroughs on the molecular basis of Legionella pathogenesis but also lead the way in improving our knowledge of the eukaryotic PTMs and complex cellular processes that are associated to. PMID- 25713574 TI - Proteinase PrtP impairs lactococcin LcnB activity in Lactococcus lactis BGMN1 501: new insights into bacteriocin regulation. AB - Proteinases and bacteriocins are of great importance to the dairy industry, but their interactions have not been studied so far. Lactococcus lactis subsp. lactis BGMN1-5 is a natural isolate from homemade semi-hard cheese which produces two bacteriocins (Lactococcin B and LsbB), as well as proteinase PrtP. A medium dependent increase in the bacteriocin LcnB activity of L. lactis BGMN1-501, a derivate of L. lactis subsp. lactis BGMN1-5, was shown to be accompanied by a decrease in its promoter activity. A similar effect of media components on gene expression was reported for proteinase PrtP, whose gene is co-localized on the same plasmid as the lcnB gene. Thus, the PrtP-LcnB interplay was investigated. Single gene knockout mutants were constructed with disrupted prtP or lcnB genes. PrtP(-) mutants showed higher bacteriocin activity that had lost its growth medium dependence, which was in contrast to the original strain. When LcnB from this mutant was combined with proteinase from the LcnB(-) mutant in vitro, its activity was rendered to the original level, suggesting that proteinase reduces bacteriocin activity. We propose a new model of medium dependent expression of these genes with regard to the effects of their interaction in vivo. PMID- 25713575 TI - P. gingivalis in Periodontal Disease and Atherosclerosis - Scenes of Action for Antimicrobial Peptides and Complement. AB - According to the NHS, it is estimated that over 50% of the adult population are, to some extent, affected by gum disease and approximately 15% of UK population have been diagnosed with severe periodontitis. Periodontitis, a chronic polymicrobial disease of the gums, causes inflammation in its milder form, whereas in its severe form affects the surrounding tissues and can result in tooth loss. During periodontitis, plaque accumulates and sits between the junctional epithelium and the tooth itself, resulting in inflammation and the formation of a periodontal pocket. An interface is formed directly between the subgingival bacteria and the junctional epithelial cells. Bacterial pathogens commonly associated with periodontal disease are, among others, Porphyromonas gingivalis, Tannerella forsythia, and Treponema denticola, together known as the "red complex." This review will mostly concentrate on the role of P. gingivalis, a Gram-negative anaerobic bacterium and one of the major and most studied contributors of this disease. Because periodontal disease is associated with the development of atherosclerosis, it is important to understand the local immune response to P. gingivalis. Innate immune players, in particular, complement and antimicrobial peptides and their effects with regard to P. gingivalis during periodontitis and in the development of atherosclerosis will be presented. PMID- 25713576 TI - The regulatory network of ThbZIP1 in response to abscisic acid treatment. AB - Previously, a bZIP transcription factor from Tamarix hispida, ThbZIP1, was characterized: plants overexpressing ThbZIP1 displayed improved salt stress tolerance but were sensitive to abscisic acid (ABA). In the current study, we further characterized the regulatory network of ThbZIP1 and the mechanism of ABA sensitivity mediated by ThbZIP1. An ABF transcription factor from T. hispida, ThABF1, directly regulates the expression of ThbZIP1. Microarray analysis identified 1662 and 1609 genes that were respectively significantly upregulated or downregulated by ThbZIP1 when exposed to ABA. Gene ontology (GO) analysis showed that the processes including "response to stimulus," "catalytic activity," "binding function," and "metabolic process" were highly altered in ThbZIP1 expressing plants exposed to ABA. The gene expression in ThbZIP1 transformed plants were compared between exposed to ABA and salt on the genome scale. Genes differentially regulated by both salt and ABA treatment only accounted for 9.75% of total differentially regulated genes. GO analysis showed that structural molecule activity, organelle part, membrane-enclosed lumen, reproduction, and reproductive process are enhanced by ABA but inhibited by salt stress. Conversely, immune system and multi-organism process were improved by salt but inhibited by ABA. Transcription regulator activity, enzyme regulator activity, and developmental process were significantly altered by ABA but were not affected by salt stress. Our study provides insights into how ThbZIP1 mediates ABA and salt stress response at the molecular level. PMID- 25713577 TI - Physiological and proteomic analyses of leaves from the halophyte Tangut Nitraria reveals diverse response pathways critical for high salinity tolerance. AB - Soil salinization poses a serious threat to the environment and agricultural productivity worldwide. Studies on the physiological and molecular mechanisms of salinity tolerance in halophytic plants provide valuable information to enhance their salt tolerance. Tangut Nitraria is a widely distributed halophyte in saline alkali soil in the northern areas of China. In this study, we used a proteomic approach to investigate the molecular pathways of the high salt tolerance of T. Nitraria. We analyzed the changes in biomass, photosynthesis, and redox-related enzyme activities in T. Nitraria leaves from plant seedlings treated with high salt concentration. Comparative proteomic analysis of the leaves revealed that the expression of 71 proteins was significantly altered after salinity treatments of T. Nitraria. These salinity-responsive proteins were mainly involved in photosynthesis, redox homeostasis, stress/defense, carbohydrate and energy metabolism, protein metabolism, signal transduction, and membrane transport. Results showed that the reduction of photosynthesis under salt stress was attributed to the down-regulation of the enzymes and proteins involved in the light reaction and Calvin cycle. Protein-protein interaction analysis revealed that the proteins involved in redox homeostasis, photosynthesis, and energy metabolism constructed two types of response networks to high salt stress. T. Nitraria plants developed diverse mechanisms for scavenging reactive oxygen species (ROS) in their leaves to cope with stress induced by high salinity. This study provides important information regarding the salt tolerance of the halophyte T. Nitraria. PMID- 25713578 TI - Lost in traffic? The K(+) channel of lily pollen, LilKT1, is detected at the endomembranes inside yeast cells, tobacco leaves, and lily pollen. AB - Fertilization in plants relies on fast growth of pollen tubes through the style tissue toward the ovules. This polarized growth depends on influx of ions and water to increase the tube's volume. K(+) inward rectifying channels were detected in many pollen species, with one identified in Arabidopsis. Here, an Arabidopsis AKT1-like channel (LilKT1) was identified from Lilium longiflorum pollen. Complementation of K(+) uptake deficient yeast mutants was only successful when the entire LilKT1 C-terminus was replaced by the AKT1 C-terminus. No signals were observed in the plasma membrane (PM) of pollen tubes after expression of fluorescence-tagged LilKT1 nor were any LilKT1-derived peptides detectable in the pollen PM by mass spectrometry analysis. In contrast, fluorescent LilKT1 partly co-localized with the lily PM H(+) ATPase LilHA2 in the PM of tobacco leaf cells, but exhibited a punctual fluorescence pattern and also sub-plasma membrane localization. Thus, incorporation of LilKT1 into the pollen PM seems tighter controlled than in other cells with still unknown trafficking signals in LilKT1's C-terminus, resulting in channel densities below detection limits. This highly controlled incorporation might have physiological reasons: an uncontrolled number of K(+) inward channels in the pollen PM will give an increased water influx due to the raising cytosolic K(+) concentration, and finally, causing the tube to burst. PMID- 25713580 TI - Laser capture microdissection in Ectocarpus siliculosus: the pathway to cell specific transcriptomics in brown algae. AB - Laser capture microdissection (LCM) facilitates the isolation of individual cells from tissue sections, and when combined with RNA amplification techniques, it is an extremely powerful tool for examining genome-wide expression profiles in specific cell-types. LCM has been widely used to address various biological questions in both animal and plant systems, however, no attempt has been made so far to transfer LCM technology to macroalgae. Macroalgae are a collection of widespread eukaryotes living in fresh and marine water. In line with the collective effort to promote molecular investigations of macroalgal biology, here we demonstrate the feasibility of using LCM and cell-specific transcriptomics to study development of the brown alga Ectocarpus siliculosus. We describe a workflow comprising cultivation and fixation of algae on glass slides, laser microdissection, and RNA amplification. To illustrate the effectiveness of the procedure, we show qPCR data and metrics obtained from cell-specific transcriptomes generated from both upright and prostrate filaments of Ectocarpus. PMID- 25713581 TI - Learning about the X from our parents. AB - The X chromosome is generally understudied in association studies, in part because the analyst has had limited methodological options. For nuclear-family based association studies, most current methods extend the transmission disequilibrium test (TDT) to the X chromosome. We present a new method to study association in case-parent triads: the parent-informed likelihood ratio test for the X chromosome (PIX-LRT). Our method enables estimation of relative risks and takes advantage of parental genotype information and the sex of the affected offspring to increase statistical power to detect an effect. Under a parental exchangeability assumption for the X, if case-parent triads are complete, the parents of affected offspring provide an independent replication sample for estimates based on transmission distortion to their affected offspring. For each offspring sex we combine the parent-level and the offspring-level information to form a likelihood ratio test statistic; we then combine the two to form a combined test statistic. Our method can estimate relative risks under different modes of inheritance or a more general co-dominant model. In triads with missing parental genotypes, the method accounts for missingness with the Expectation Maximization algorithm. We calculate non-centrality parameters to assess the power gain and robustness of our method compared to alternative methods. We apply PIX-LRT to publically available data from an international consortium of genotyped families affected by the birth defect oral cleft and find a strong, internally-replicated signal for a SNP marker related to cleft lip with or without cleft palate. PMID- 25713582 TI - Dynamic reprogramming of chromatin: paradigmatic palimpsests and HES factors. AB - Temporal and spatial control of transcription in development is dictated to a great extent by transcriptional repressors. Some repressor complexes, such as Polycomp-group proteins, induce relatively long-term non-permissive states, whereas others such as hairy/enhancer of split (HES) family repressors are linked to dynamically modulated chromatin states associated with cycling expression of target genes. The mode of action and specificity of repressors involved in mediating this latter form of epigenetic control are unknown. Oscillating expression of HES repressors controlled by signaling pathways such as Notch suggests that the entire ensemble of HES-associated co-repressors and histone modifying complexes readily cycle on and off genes. Dynamic interactions between these factors and chromatin seem to be crucial in maintaining multipotency of progenitor cells, but the significance of such interactions in more differentiated cells is less well understood. We discuss here how genome-wide analyses and real-time gene expression measurements of HES regulated genes can help decipher the detailed mechanisms and biological importance of highly dynamic transcriptional switching mediated by epigenetic changes. PMID- 25713579 TI - Emerging roles for microtubules in angiosperm pollen tube growth highlight new research cues. AB - In plants, actin filaments have an important role in organelle movement and cytoplasmic streaming. Otherwise microtubules (MTs) have a role in restricting organelles to specific areas of the cell and in maintaining organelle morphology. In somatic plant cells, MTs also participate in cell division and morphogenesis, allowing cells to take their definitive shape in order to perform specific functions. In the latter case, MTs influence assembly of the cell wall, controlling the delivery of enzymes involved in cellulose synthesis and of wall modulation material to the proper sites. In angiosperm pollen tubes, organelle movement is generally attributed to the acto-myosin system, the main role of which is in distributing organelles in the cytoplasm and in carrying secretory vesicles to the apex for polarized growth. Recent data on membrane trafficking suggests a role of MTs in fine delivery and repositioning of vesicles to sustain pollen tube growth. This review examines the role of MTs in secretion and endocytosis, highlighting new research cues regarding cell wall construction and pollen tube-pistil crosstalk, that help unravel the role of MTs in polarized growth. PMID- 25713583 TI - Genomic data as the "hitchhiker's guide" to cattle adaptation: tracking the milestones of past selection in the bovine genome. AB - The bovine species have witnessed and played a major role in the drastic socio economical changes that shaped our culture over the last 10,000 years. During this journey, cattle "hitchhiked" on human development and colonized the world, facing strong selective pressures such as dramatic environmental changes and disease challenge. Consequently, hundreds of specialized cattle breeds emerged and spread around the globe, making up a rich spectrum of genomic resources. Their DNA still carry the scars left from adapting to this wide range of conditions, and we are now empowered with data and analytical tools to track the milestones of past selection in their genomes. In this review paper, we provide a summary of the reconstructed demographic events that shaped cattle diversity, offer a critical synthesis of popular methodologies applied to the search for signatures of selection (SS) in genomic data, and give examples of recent SS studies in cattle. Then, we outline the potential and challenges of the application of SS analysis in cattle, and discuss the future directions in this field. PMID- 25713585 TI - Sexual absorption of vaginal progesterone: a randomized control trial. AB - Objective. To determine if sexual intercourse reduces absorption of vaginal progesterone gel in women and to determine if progesterone is absorbed by the male during intercourse. Study Design. Prospective, randomized, cross over, controlled study of 20 reproductive-aged women and their male sexual partners randomized to receive vaginal progesterone gel (Crinone 8% gel, Actavis Inc., USA) or placebo cream. Serum progesterone for both male and female partners were measured 10 hours after intercourse. One week later, subjects were crossed over to receive the opposite formulation. In the third week, women used progesterone gel at night and abstained from intercourse. Results. Serum progesterone was significantly reduced with vaginal progesterone gel + intercourse compared with vaginal progesterone gel + abstinence (P = 0.0075). Men absorbed significant progesterone during intercourse with a female partner using vaginal progesterone gel compared to placebo (P = 0.0008). Conclusion(s). Vaginal progesterone gel is reduced in women after intercourse which may decrease drug efficacy during luteal phase support. Because men absorb low levels of progesterone during intercourse, exposure could cause adverse effects such as decreased libido. This study is registered under Clinical Trial number NCT01959464. PMID- 25713584 TI - What can livestock breeders learn from conservation genetics and vice versa? AB - The management of livestock breeds and threatened natural population share common challenges, including small effective population sizes, high risk of inbreeding, and the potential benefits and costs associated with mixing disparate gene pools. Here, we consider what has been learnt about these issues, the ways in which the knowledge gained from one area might be applied to the other, and the potential of genomics to provide new insights. Although there are key differences stemming from the importance of artificial versus natural selection and the decreased level of environmental heterogeneity experienced by many livestock populations, we suspect that information from genetic rescue in natural populations could be usefully applied to livestock. This includes an increased emphasis on maintaining substantial population sizes at the expense of genetic uniqueness in ensuring future adaptability, and on emphasizing the way that environmental changes can influence the relative fitness of deleterious alleles and genotypes in small populations. We also suspect that information gained from cross-breeding and the maintenance of unique breeds will be increasingly important for the preservation of genetic variation in small natural populations. In particular, selected genes identified in domestic populations provide genetic markers for exploring adaptive evolution in threatened natural populations. Genomic technologies in the two disciplines will be important in the future in realizing genetic gains in livestock and maximizing adaptive capacity in wildlife, and particularly in understanding how parts of the genome may respond differently when exposed to population processes and selection. PMID- 25713586 TI - Interim Report from Burden of Obstructive Lung Disease (BOLD Study) in Tehran: Prevalence and Risk Factors of Chronic Obstructive Pulmonary Disease. AB - BACKGROUND: Chronic Obstructive Pulmonary Diseases (COPD) is estimated to rank fifth in burden of disease and third in terms of mortality by 2020 worldwide. It is characterized by chronic inflammation and non-fully reversible airflow obstruction, causing structural changes in the lungs that can be demonstrated by a post bronchodilator FEV1/FVC ratio <70%. MATERIALS AND METHODS: The sampling frame of the current study was the population of Tehran, the capital of Iran with the current population of nearly 8.1 million. A stratified cluster sampling strategy with proportional allocation within strata was used in this study. The target population was all Tehran residents, aged 18 to 40 in one group and over 40 in another, in the year 2013. The stratification process of the sample according to the 22 municipal districts of Tehran city has been incorporated in the sampling process. Proportional to the number of households in the 22 districts, the appropriate number of clusters is weighted according to each district. The decision about the number of clusters is based on total sample size; mean household members; and logistical facilities for subject enumeration, transport, and examination. RESULTS: The overall COPD prevalence defined by the spirometric functional criteria was 10%, higher in men 12 (11.9%) than in women 15 (8.8%); the prevalence was significantly higher in subjects aged over 55 years (P =0.001). Only 10(3.7%) of these COPD patients had already been diagnosed by a physician. Of all subjects fulfilling the criteria for COPD according to the Burden of Obstructive Lung Disease (BOLD) guidelines (post bronchodilator FEV1/FVC<70%), 90(33.3%) had chronic productive cough, and 262(96.7%) had either long-standing cough, sputum production, recurrent wheeze, dyspnea, or attacks of shortness of breath. CONCLUSION: Due to the small sample size at this stage of project, conclusions should be drawn with caution. In this first epidemiological report in Tehran about COPD, a moderate prevalence of the disease was determined, and a high percentage of this figure had not been diagnosed before by a physician. PMID- 25713587 TI - Effect of Platelet Glycoprotein IIb/IIIa PLA2 Polymorphism on Severity of Pulmonary Thromboembolism. AB - BACKGROUND: Pulmonary thromboembolism (PTE) is among the leading causes of death following surgery and/or hospital admission. Role of thrombophilic risk factors in the etiology of PTE is well known; But not much data is available on their role in severity of PTE. The aim of this study was to investigate the role of thrombotic risk factors especially PLA2 polymorphism of platelet glycoprotein IIb/IIIa in the severity of PTE. MATERIALS AND METHODS: Genotyping from Factor-V (FVL) and prothrombin 20210A (PT20210A) mutations were shown to be significant risk factors for PTE and recurrent PTE. The plasma concentrations of platelet glycoprotein IIb/IIIa PLA2 polymorphism, presence of FVL and PT20210A mutations were studied in 37 patients with PTE. RESULTS: Eleven of these patients had recurrent PTE. Lung perfusion scans were scored according to the percentage of vascular obstruction. Patients who had a pulmonary vascular obstruction (PVO) score >50%were compared to those with PVO score<50%. There was no significant difference between patients with PVO score>50% and those with PVO score<50% with regard to the presence of FVL and PT20210A mutations. However, patients with PVO score>50% had a significantly higher frequency of platelet glycoprotein IIb/IIIaPLA2 polymorphism than those with PVO score <50%. CONCLUSION: Our data suggest that presence of PLA2 is associated with an increased risk of PTE in the Iranian population. The association between recurrent events and coinheritance of more than one thrombophilic genetic risk factor shows that such carriers are at a higher risk of PTE. PMID- 25713588 TI - Relationship of Coping Styles with Suicidal Behavior in Hospitalized Asthma and Chronic Obstructive Pulmonary Disease Patients: Substance Abusers versus Non- Substance Abusers. AB - BACKGROUND: Treatment of patients with chronic conditions requiring hospitalization requires patient acceptance and cooperation and adoption of coping strategies. Inappropriate coping strategies such as substance abuse are concerning in the course of treatment. This study sought to explore the association of coping strategies with suicidal behavior in substance abusers and non substance abuser patients with chronic pulmonary diseases namely asthma and chronic obstructive pulmonary disease (COPD). MATERIALS AND METHODS: This comparative study was performed on 100 patients with asthma and COPD selected via convenience sampling. Subjects with and without substance abuse were separated into two groups of 50 patients each. Ways of Coping Questionnaire of Lazarus (WOCQ) and Suicide Behavior Questionnaire-Revised (SBQ-R) were completed by them. Five Persian speaking patients rated this questionnaire to be easily understandable in the pre-test stage. Cronbach's alpha was calculated to measure the internal consistency. RESULTS: The mean (+/-standard deviation) age of participants was 40 (+/-14) years; 58% of individuals were men; 62% had chosen problem-focused coping. The most abused substances were cigarettes (78%) and opium (42%); 6% of substance abusers had thought about suicide five times or more in the past year; 5% of substance abusers had seriously attempted suicide. Tendency to commit suicide was greater in men, substance abusers and participants who had chosen emotion-focused coping strategies, based on a regression model. Average score of suicide tendency was significantly higher in substance abusers (B=2.196, P =0.007). CONCLUSION: Chronic disease is a crisis and patients need to acquire appropriate coping strategies to deal with it, especially in substance abusers and suicidal patients. Precise recognition of coping strategies in chronic pulmonary patients with substance abuse is necessary via a team cooperation among psychiatrics, psychologists and an internal physician in hospitals because medical treatment alone is not sufficient in such cases. PMID- 25713589 TI - Low dose aminophylline effectively decreases the risk of post-operative apnea in premature infants. AB - BACKGROUND: Retinopathy of prematurity (ROP) is the most common reason behind surgical procedures in premature newborns. Anesthesia in these patients is life threatening due to post-operative apnea of prematurity (POA). This study aimed to determine the predisposing factors to POA in premature infants and to explore the role of prophylactic aminophylline in decreasing the incidence of POA. MATERIALS AND METHODS: Fifty patients with prematurity who were candidates for elective eye surgery (less than one hour) were selected and received aminophylline (3 mg/kg) 5 minutes after the induction of anesthesia with sevoflurane. Patients were kept in the recovery room for 2 hours post-operation in an incubator and were monitored for SPO2, apnea, bradycardia and other signs of desaturation and apnea. RESULTS: There were no statistically significant differences in the gestational age and weight, sex, postconceptual age and weight and other demographic characteristics between the experimental and control groups. Gestational age<28 weeks, postconceptual age<60 weeks, birth weight, operation weight and anemia (OR=1.91; 95% CI: 1.24-3.73; P=0.012) were the predisposing factors associated with postoperative apnea. Treatment with aminophylline as compared with the placebo was associated with a significantly decreased risk of post-operative apnea (OR=0.53; 95% CI 0.28-0.98; P=0.034). CONCLUSION: Aminophylline can be used prophylactically to decrease the risk of postoperative apnea with no major adverse effects. PMID- 25713590 TI - Improved Method for Analysis of Airborne Asbestos Fibers Using Phase Contrast Microscopy and FTIR Spectrometry. AB - BACKGROUND: In recent years, some studies have tried to improve Phase Contrast Microscopy (PCM) for counting asbestos fibers. Due to the lack of a universally accepted alternative method, this study aimed to improve PCM for better counting of asbestos fibers. MATERIALS AND METHODS: Confirmed asbestos standards were applied using a dust generator for sampling. Sampling from the dust generator was carried out according to the Occupational Safety and Health Administration (OSHA) ID-160 method and 95 samples with diverse densities were prepared to be counted using conventional and modern PCM. All samples were counted single blindly by a co-author of this study and the obtained data were analyzed by paired t-test, correlation coefficient and Bland-Altman analysis. Duplicate samples were prepared for qualitative analysis by Fourier transform infrared spectroscopy (FT IR), scanning electron microscopy (SEM) and X ray. RESULTS: Asbestos densities on filters were in the range of less than 100 to 600 fibers/mm(2). Statistically, significant differences were observed for the count density of the 95 samples counted by the two phase contrast microscopes (P<0.001). Nikon microscope demonstrated higher counts compared to conventional microscope and had a lower coefficient of variation. Samples were analyzed qualitatively using FT-IR and SEM, and the presence of asbestos fibers was confirmed. CONCLUSION: The improved PCM and FT-IR methods presented in this study demonstrated more precise and accurate determination of personal exposure to airborne asbestos fibers and subsequent risk assessment. PMID- 25713591 TI - Hemoptysis as a complication of capitonnage for management of pulmonary hydatid cyst. AB - The surgical approach to hydatid cyst of the lung is based on complete removal of the parasite, and management of the residual pericyst cavity. For the latter, capitonnage is a recognized method, by which the walls of the evacuated pericyst cavity are approximated with multiple sutures. Capitonnage without suturing and ligation of bronchial openings individually may lead to postoperative air leakage with resultant pneumothorax or pneumatocele. The pulmonary parenchyma may also become distorted. Herein, we report another complication of capitonnage: presence of large amounts of unabsorbed suture material acting as foreign body within the residual pericyst cavity, leading to chronic infection and hemoptysis. PMID- 25713592 TI - Tuberculous liver abscess in an immunocompetent patient: a case report. AB - INTRODUCTION: Tuberculous or tubercular liver abscess (TLA) is a rare manifestation of extrapulmonary tuberculosis (TB) and it should be considered in the differential diagnosis of mass or cystic lesions of the liver especially in a high TB prevalence country like Iran. CASE PRESENTATION: We report an immunocompetent 48 year-old woman with TLA and peritoneal infection. Although hepatic TLA is very rare, it should be considered in the differential diagnosis of mass or cystic lesions of the liver especially in a high TB prevalence country. PMID- 25713593 TI - Thoracoscopic lobectomy in a patient with permanent tracheostomy. AB - One Lung Ventilation (OLV) is the preferred method of anesthesia in the vast majority of thoracic operations, especially thoracoscopic procedures. Although double lumen endotracheal tubes are usually used to conduct OLV during thoracic operations, in patients with permanent tracheostomy, because of short trachea, keeping these tubes safe in place is usually difficult. Thus, OLV in patients with permanent tracheostomy may be challenging or even impossible. Herein, we report a patient with permanent tracheostomy who underwent successful OLV and thoracoscopic lobectomy. PMID- 25713594 TI - The Effect of Crocus sativus L. and Its Constituents on Memory: Basic Studies and Clinical Applications. AB - Memory-related disorders are a common public health issue. Memory impairment is frequent in degenerative diseases (such as Alzheimer's disease and Parkinson disease), cerebral injuries, and schizophrenia. The dried stigma of the plant Crocus sativus L. (C. sativus), commonly known as saffron, is used in folk medicine for various purposes. Several lines of evidence suggest that C. sativus and its constituents are implicated in cognition. Here we critically review advances in research of these emerging molecular targets for the treatment of memory disorders, and discuss their advantages over currently used cognitive enhancers as well remaining challenges. Current analysis has shown that C. sativus and its components might be a promising target for cognition impairments. PMID- 25713595 TI - Anticancer and Anti-Inflammatory Activities of a Standardized Dichloromethane Extract from Piper umbellatum L. Leaves. AB - Despite the advances in anticancer drug discovery field, the worldwide cancer incidence is remarkable, highlighting the need for new therapies focusing on both cancer cell and its microenvironment. The tumor microenvironment offers multiple targets for cancer therapy, including inflammation. Nowadays, almost 75% of the anticancer agents used in chemotherapy are derived from natural products, and plants are an important source of new promising therapies. Continuing our research on Piper umbellatum species, here we describe the anticancer (in vitro antiproliferative activity and in vivo Ehrlich solid tumor model) and anti inflammatory (carrageenan-induced paw edema and peritonitis models) activities of a standardized dichloromethane extract (SDE) from P. umbellatum leaves, containing 23.9% of 4-nerolidylcatechol. SDE showed in vitro and in vivo antiproliferative activity, reducing Ehrlich solid tumor growth by 38.7 and 52.2% when doses of 200 and 400 mg/kg, respectively, were administered daily by oral route. Daily treatments did not produce signals of toxicity. SDE also reduced paw edema and leukocyte migration on carrageenan-induced inflammation models, suggesting that the anticancer activity of SDE from Piper umbellatum leaves could involve antiproliferative and anti-inflammatory effects. These findings highlight P. umbellatum as a source of compounds against cancer and inflammation. PMID- 25713598 TI - Fitting the epidemiology and neuropathology of the early stages of Alzheimer's disease to prevent dementia. AB - INTRODUCTION: Recent research on biomarkers has made possible the diagnosis of pre-dementia and even preclinical Alzheimer's disease (AD), thus providing the ideal context for prevention. The aim of this study was to investigate the epidemiology of the early stages of AD by fitting neuropathologic and epidemiological data to assess the feasibility of prevention programs. METHODS: The study addressed primarily the construction of a discrete event simulation model of the stages of dementia. Age was included in the mathematical functions to combine the two competitive risks that determine the epidemiology of AD, that is, time to onset of dementia and time until death by other causes. Subsequently, this model was calibrated to reproduce the prevalence of pathological findings associated with AD. The beginning of the preclinical stage was taken to coincide with Thal phase 1 deposition of amyloid-beta. The duration of the prodromal stage, marked by mild cognitive impairment, was based on a 10% annual conversion rate from this level of impairment to dementia. The validation of prevalence figures also permitted estimation of the incidence and duration of preclinical and prodromal stages. RESULTS: In Spain, half of the nearly 10 million people aged more than 60 years are in the early stages of AD; 35.9% are in a preclinical stage, and up to 14.2% are in a prodromal stage. However, dementia will develop in only 38% of this population. The weighted mean time to dementia was 22.0 years from the start of Thal phase 1 and 9.0 years from the start of phase 2. Results of simulation models showed a lack of correlation between clinical and pathological classifications. CONCLUSIONS: These findings raise questions about the feasibility of drug-based prevention strategies. Currently, screening programs with biomarkers in the early stages of AD cannot be applied to the half of the general population older than 60 years. Hence, intensive research is needed regarding risk factors, so that more affordable strategies may be planned. More efficient criteria are also needed to select those subjects with mild cognitive impairment who have an increased probability of positive screening for biomarkers (prodromal stage). PMID- 25713597 TI - Assessment of aneuploidy formation in human blastocysts resulting from cryopreserved donor eggs. AB - BACKGROUND: Increased embryo implantation rates were reported after transfer of euploid embryos selected by preimplantation genetic screening (PGS). Egg cryopreservation by vitrification has become one of the most important assisted human reproduction technologies. Although reports indicate that development and implantation of human embryos derived from frozen donor eggs are comparative to fresh eggs, it is still unknown whether egg vitrification increases chromosomal abnormalities in eggs, which in turn causes formation of embryonic aneuploidy. Therefore, in this study, we evaluated the aneuploidy formation in the blastocysts derived from frozen donor eggs and also evaluated the efficiency of egg vitrification as an advanced technology for egg cryopreservation. RESULTS: In this study, donated human eggs from young women were cryopreserved by vitrification and PGS was performed in the resulted blastocysts by DNA microarray. A total of 764 frozen eggs from 75 egg thawing cycles were warmed and 38 blastocysts were biopsied for PGS before embryo transfer. A 97.1% of egg survival rate was obtained and 59.1% of embryos developed to blastocyst stage. After biopsy and PGS, it was found that 84.2% of blastocysts were euploid and 15.8% were aneuploid. Aneuploidy rates varied among donors. Transfers of blastocysts without PGS resulted in higher clinical pregnancy and implantation rates as compared with transfer of blastocysts with PGS. CONCLUSIONS: Although the overall aneuploidy rate was low in the blastocysts derived from frozen donor eggs, high aneuploidy rates were observed in the embryos resulting from some donated eggs. Clinical pregnancy rate was not improved by PGS of embryos resulting from donor eggs, indicating that PGS may not be necessary for embryos derived from donor eggs in most cases. PMID- 25713599 TI - Donepezil for dementia with Lewy bodies: a randomized, placebo-controlled, confirmatory phase III trial. AB - INTRODUCTION: The efficacy of a cholinesterase inhibitor, donepezil, in patients with dementia with Lewy bodies (DLB) was investigated to confirm the superiority over placebo in the 12-week, double-blind phase of this phase III study. METHODS: Patients with probable DLB (n = 142) were randomly assigned to placebo or to 5 mg or 10 mg of donepezil administered once daily for 12 weeks. The co-primary endpoints were changes in cognitive function assessed using the Mini-Mental State Examination (MMSE) and behavioral and neuropsychiatric symptoms using the Neuropsychiatric Inventory (NPI-2: hallucinations and fluctuations). The superiority of each active group over placebo was determined with simultaneous statistical significance in both endpoints. Safety evaluations included adverse events (AEs) and the unified Parkinson's disease rating scale (UPDRS) part III. RESULTS: The predefined superiority of donepezil to the placebo was not confirmed in either active group in the primary analysis. MMSE score significantly improved compared to placebo in the 10 mg group (10 mg: 2.2 +/- 0.4, placebo: 0.6 +/- 0.5 (mean +/- standard error); P = 0.016). The change in MMSE score in the 5 mg group was not significant (1.4 +/- 0.5 (mean +/- standard error); P = 0.232). Although NPI-2 improved compared to baseline in the active groups, the differences from placebo were not significant. Most AEs were mild or moderate. Although the incidence of parkinsonism was slightly higher in the 10 mg group, the change in the UPDRS score was minimal and without a significant difference from the placebo group. CONCLUSIONS: The co-primary endpoints were not achieved in this trial. However, significant improvement in MMSE score was demonstrated with 10 mg, but not 5 mg, of donepezil. The evaluation of psychiatric symptoms might be affected by advanced education and instructions given to caregivers. Overall, donepezil was well tolerated in patients with DLB. With careful attention on gastrointestinal or parkinsonian symptoms, patients with DLB can safely benefit from treatment with donepezil. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01278407 (trial registration date: 14 January 2011). PMID- 25713596 TI - Algorithmic approaches to protein-protein interaction site prediction. AB - Interaction sites on protein surfaces mediate virtually all biological activities, and their identification holds promise for disease treatment and drug design. Novel algorithmic approaches for the prediction of these sites have been produced at a rapid rate, and the field has seen significant advancement over the past decade. However, the most current methods have not yet been reviewed in a systematic and comprehensive fashion. Herein, we describe the intricacies of the biological theory, datasets, and features required for modern protein-protein interaction site (PPIS) prediction, and present an integrative analysis of the state-of-the-art algorithms and their performance. First, the major sources of data used by predictors are reviewed, including training sets, evaluation sets, and methods for their procurement. Then, the features employed and their importance in the biological characterization of PPISs are explored. This is followed by a discussion of the methodologies adopted in contemporary prediction programs, as well as their relative performance on the datasets most recently used for evaluation. In addition, the potential utility that PPIS identification holds for rational drug design, hotspot prediction, and computational molecular docking is described. Finally, an analysis of the most promising areas for future development of the field is presented. PMID- 25713601 TI - Continuous efforts in the clinical and paraclinical management of the human brain pathology. PMID- 25713600 TI - Long-term donepezil use for dementia with Lewy bodies: results from an open-label extension of Phase III trial. AB - INTRODUCTION: The long-term efficacy and safety of donepezil 10 mg in patients with dementia with Lewy bodies (DLB) were investigated in a 52-week Phase 3 trial. METHODS: This 52-week study consisted of 16-week randomized placebo controlled (RCT) and 36-week open-label extension phases. Of 142 DLB patients enrolled in the RCT phase (three arms: placebo, 5 mg, and 10 mg), 110 entered the extension phase. The placebo group of the RCT phase initiated active treatment at week 16, and the active groups maintained allocated treatment and dosages until week 24. After week 24, all patients received 10 mg. Dose reduction to 5 mg for safety concerns was allowed. Efficacy measures included Mini-Mental State Examination (MMSE) for cognitive function and Neuropsychiatric Inventory (NPI) for behavioral symptoms. Safety evaluations included adverse events (AEs) and the unified Parkinson disease rating scale. RESULTS: In total, 100 subjects completed the study. Cognitive function improvement was sustained for 52 weeks (MMSE at week 52 in 10 mg: 2.8 +/- 3.5 (mean +/- standard deviation); P <0.001, Student paired t test)). Those who received placebo in the RCT phase showed an improvement after starting active treatment. NPI improved in all the groups throughout the study, including the placebo period. In the subgroup of the 5 mg group without remarkable cognitive or behavioral improvement at week 24, further improvement was observed after a dose increase to 10 mg. After week 24, 21 patients experienced dose reduction. The incidence of any AEs did not increase over time. CONCLUSIONS: The long-term administration of donepezil at 10 mg/day improved cognitive function for up to 52 weeks in patients with DLB without increasing the risk of clinically significant safety events. TRIAL REGISTRATION: NCT01278407. Trial registration date: January 14, 2011. PMID- 25713602 TI - 2nd International Salzburg Conference on Neurorecovery (ISCN 2013) Salzburg/Austria|November 28th-29th, 2013. AB - The 2nd International Salzburg Conference on Neurorecovery was held on the 28th and 29th of November, 2013, in Salzburg, one of the most beautiful cities in Austria, which is well known for its rich cultural heritage, world-famous music and beautiful surrounding landscapes. The aim of the conference was to discuss the progress in the field of neurorecovery. The conference brought together internationally renowned scientists and clinicians, who described the clinical and therapeutic relevance of translational research and its applications in neurorehabilitation. PMID- 25713603 TI - Cardiovascular disease risk scores in the current practice: which to use in rheumatoid arthritis? AB - Cardiovascular disease (CVD) is the highest prevalence disease in the general population (GP) and it accounts for 20 million deaths worldwide each year. Its prevalence is even higher in rheumatoid arthritis. Early detection of subclinical disease is critical and the use of cardiovascular risk prediction models and calculators is widely spread. The impact of such techniques in the GP was previously studied. Despite their common background and similarities, some disagreement exists between most scores and their importance in special high-risk populations like rheumatoid arthritis (RA), having a low level of evidence. The current article aims to single out those predictive models (models) that could be most useful in the care of rheumatoid arthritis patients. PMID- 25713604 TI - Psoriasis and Metabolic Syndrome--scientific evidence and therapeutic implications. AB - Psoriasis is a chronic inflammatory disease, predominantly affecting the skin, being included in the group of Immune Mediated Inflammatory Diseases. Growing evidence from the last 10 years suggests that several systemic conditions like metabolic syndrome, cardiovascular disease, diabetes, psychological disorders or inflammatory bowel disease are prevalent in psoriasis patients. The linker might be the chronic secretion of pro-inflammatory cytokines. In this current review, the scientific evidence that explains the relationship between psoriasis and the metabolic syndrome in particular will be addressed, as the metabolic syndrome comprises a group of risk factors for cardiovascular disease, thus offering an overall picture of the systemic involvement in psoriasis. An integrated approach, with an early detection and treatment of the components of the metabolic syndrome, are important steps in psoriasis management. Attention should be paid on influence of psoriasis treatment upon comorbidities and vice-versa. PMID- 25713605 TI - Tobacco-alcohol optic neuropathy--clinical challenges in diagnosis. AB - Part of the large group of nutritional and toxic optic neuropathies, tobacco alcohol optic neuropathy is a disease often underdiagnosed or detected at a stage when the full recovery of vision is not possible. This article summarizes its signs and symptoms, describes the pathophysiological processes involved and provides the necessary information for diagnosis and treatment of the entity previously known as tobacco-alcohol amblyopia, reporting in the end, a challenging case along with its findings. PMID- 25713606 TI - Hepatocellular carcinoma among cirrhotics--utility of screening and surveillance programs--review article. AB - Screening of known cirrhotics for hepatocellular cancer (HCC) has long been a contentious topic. Studies to date have failed to conclusively prove or disprove the validity of alpha-fetoprotein (AFP) and hepatic ultrasound as screening mechanisms for HCC among cirrhotics. It is not clear whether these screening mechanisms provide any benefit in terms of reduced morbidity and mortality. Screening for HCC among cirrhotics by using AFP and/or imaging at every 6 months correlate with HCC diagnosis, thus portending better treatment options and an improved prognosis. Screening all the known cirrhotics for HCC may lead to decreased mortality. PMID- 25713607 TI - The regulator of calcineurin (RCAN1) an important factor involved in atherosclerosis and cardiovascular diseases development. AB - Atherosclerosis, one of the main causes of cardiovascular diseases, is a complex process that involves manifold factors. Besides the vascular lipids accumulation, inflammatory factors could be considered as a proatherogenic factor - RCAN1. RCAN1 is a regulator of calcineurin, both of them being calcium dependent proteins. Recent studies have shown that RCAN1 has an important role in heart valve development. In the same time researchers found that, the atherosclerotic plaques have an up-regulated RCAN1 gene expression. In the near future, it is desirable to elucidate the RCAN1 function and classify it as a possible biochemical marker to diagnose infancy atherosclerosis. PMID- 25713608 TI - Role of melatonin in embryo fetal development. AB - Melatonin is an indoleamine produced by the pineal gland and secreted in a circadian manner. In the past few decades, research over this topic has been enhanced. Melatonin has many important roles in the human physiology: regulator of the circadian rhythms, sleep inducer, antioxidant, anticarcinogenic. This paper reviews the involvement of melatonin in embryo fetal development. The pineal gland develops completely postpartum, so both the embryo and the fetus are dependent on the maternal melatonin provided transplacentally. Melatonin appears to be involved in the normal outcome of pregnancy beginning with the oocyte quality and finishing with the parturition. Its pregnancy night-time concentrations increase after 24 weeks of gestation, with significantly high levels after 32 weeks. Melatonin receptors are widespread in the embryo and fetus since early stages. There is solid evidence that melatonin is neuroprotective and has a positive effect on the outcome of the compromised pregnancies. In addition, chronodisruption leads to a reproductive dysfunction. Thus, the influence of melatonin on the developing human fetus may not be limited to the entertaining of circadian rhythmicity, but further studies are needed. PMID- 25713609 TI - Dental dam clamp adaptation method on carved gypsum cast. AB - RATIONALE: Dental Dam is the safest and most efficient isolation technique in endodontics and restorative dentistry, but it also used in esthetics, orthodontics, prosthetics, pedodontics and periodontology (for teeth immobilization). While in most cases the standard clamps are efficient, in some clinical situations clamp adaptation is mandatory in order to assure a tight contact on the tooth. OBJECTIVE: The purpose of this study is to list the elements of the clamp, which should be modified in order to assure a secure constriction of the clamp on the anchor tooth, by using the carved gypsum cast method. METHODS AND RESULTS: 100 patients were examined, diagnosed and treated for various diagnoses like simple decay, gangrene, chronic apical periodontitis, and endodontic retreatments. The clamps used in this study were produced by Hu Friedy, Hygenic, KKD, SDI, Hager & Werken. In 10 cases, the anchor tooth did not provide enough stability to the standard clamp--as provided by the producer. Therefore, we have done some adjustments to some of the elements of the clamp: the arch, the wings, the plateau, the active area, and the contact points. In 6 cases, major clamp adaptations on carved gypsum cast were imperative. DISCUSSION: The classic clamps cannot provide a grip to be enough in all the clinical cases due to the huge variety and position and implantation of the anchor teeth. Therefore, in such situations, the clamps should be adapted in order to provide stability and assure the safe isolation during the treatment. The modified clamps will be useful in similar cases, so they must be kept. PMID- 25713610 TI - Genetics of colorectal cancer. AB - The occurrence of colorectal cancer is related to the interaction that takes place at several levels between hereditary factors, environmental and individual ones. Understanding the molecular basis is important because it can identify factors that contribute to the initiation of development, maintenance of progression but also determine the response or resistance to antitumor agents. Understanding colorectal cancer at the molecular level has provided data used for genetic tests of family forms, it defined predictive markers used to select patients susceptible to certain forms of therapy and also for the development of molecular diagnostic tests to detect early non-invasive cancers. PMID- 25713611 TI - Burning mouth syndrome: a review on diagnosis and treatment. AB - Burning mouth syndrome (BMS) is defined as a chronic pain condition characterized by a burning sensation in the clinically healthy oral mucosa. It is difficult to diagnose BMS because there is a discrepancy between the severity, extensive objective pain felt by the patient and the absence of any clinical changes of the oral mucosa. This review presents some aspects of BMS, including its clinical diagnosis, classification, differential diagnosis, general treatment, evolution and prognosis. PMID- 25713612 TI - Tracheoesophageal fistula--a complication of prolonged tracheal intubation. AB - Tracheoesophageal fistula most commonly occurs as a complication of prolonged tracheal intubation. The incidence decreased after the use of low pressure and high volume endotracheal cuffs, but the intensive care units continue to provide such cases. The abnormal tracheoesophageal communication causes pulmonary contamination (with severe suppuration) and impossibility to feed the patient. The prognosis is reserved, because most patients are debilitated and ventilator dependent, with severe neurological and cardiovascular diseases. The therapeutic options are elected based on respiratory, neurological and nutritional status. The aim of conservative treatment is to stop the contamination (drainage gastrostomy, feeding jejunostomy) and to treat the pulmonary infection and biological deficits. Endoscopic therapies can be tried in cases with surgical contraindication. Operation is addressed to selected cases and consists in the dissolution of the fistula, esophageal suture with or without segmental tracheal resection associated. Esophageal diversion is rarely required. The correct indication and timing of surgery, proper surgical technique and postoperative care are prerequisites for adequate results. PMID- 25713613 TI - Laparoscopic myomectomy. AB - Uterine leiomyoma is the most common benign tumour occurring in women in the reproductive age. It is typically found during the middle and later reproductive years. The prevalence quoted in literature ranges from 20-50% based on post mortem studies. The symptoms usually reported by women with fibroids are the following: abnormal gynaecologic haemorrhage, chronic pelvic pain, dyspareunia, as well as urinary and bowel symptoms, urinary frequency or retention and, in some cases, infertility. During pregnancy, premature labor might be caused, interfering with the position of the fetus or abortion could be induced. However, only 30% of the women develop symptoms, most of them being asymptomatic. It was proved that the factors that can cause fibroids are the following: genetic, hormonal, and growth factors, especially transforming the growth factor beta (TGFb)-related cellular changes. As diagnosis tools, studies are revealing that ultrasound has been shown to be an insufficient method of myoma mapping, and magnetic resonance imaging should be preferred for surgical therapy planning. The contour of the endometrial cavity is delineated by using trans vaginal ultrasound and saline infusion hysterosonography, but hysteroscopy is the gold standard to evaluate the uterine cavity. PMID- 25713615 TI - A series of images of digestive cancers using Pill Cam COLON2 video capsule endoscopy. AB - Colon capsule endoscopy is regarded as an option to complement or even replace diagnostic colonoscopy in selected cases. Since capsule lacks the capability of taking biopsies, a diagnosis of colon cancer usually requires a further confirmation by colonoscopy. A series of seven patients who had highly suspicious lesions at capsule endoscopy (five-colon tumors, one gastric tumor and one small bowel tumor) and in whom the clinical decision and treatment was solely based on capsule findings, are presented. The diagnosis of cancer was confirmed in all cases by surgery and histology. CONCLUSION: In selected patients with a high index of clinical suspicion of cancer, PillCam colon 2 capsule endoscopy might be a sufficient tool for diagnosis. PMID- 25713614 TI - Prognostic biological factors in severe acute pancreatitis. AB - Acute pancreatitis is a serious disease. Many clinical and laboratory prognostic scores for the severity of acute pancreatitis have been proposed over the years. The aim was to identify the biological factors of prognostic severity. The study was prospective, including a four-year period between 2007 and 2010. 103 patients were diagnosed with severe acute pancreatitis and treated in a surgical clinic in Bucharest. 58 were males, accounting for 56.31%, and 45 were women, 43.69% respectively. Numerous biochemical analyses of blood, especially the number of leukocytes, glucose, urea and bilirubin were monitored. They proposed generic profiles for patients with severe acute pancreatitis. CONCLUSIONS: There is no single biological prognostic factor, but a combination of different markers may contribute to a more precise prediction of severity, as confirmed by international literature. PMID- 25713616 TI - Diagnosis and operatory treatment of the patients with failed back surgery caused by herniated disk relapse. AB - THE OBJECT OF STUDY: Analysis of surgical treatment results in patients with recurrent lumbar disc herniation by transforaminal lumbar interbody fusion (TLIF) and repeated laminotomy and discectomy for the improvement of pain and disability. MATERIAL AND METHODS: Data analysis was performed on a complex diagnosis and treatment of 56 patients with recurrent lumbar disc herniation who had previously underwent 1-3 lumbar disc surgeries. An MRI investigation with paramagnetic contrast agent (gadolinium) was used for the diagnosis and differentiation of epidural fibrosis, and a dynamic lateral X-ray investigation was carried out for the identification of segmental instability. The evolution period after the previous surgery was between 1 and 3 years after the index surgery. Pain expression degree and dynamics were assessed with the pain visual analog scale (VAS) in early and late postoperative periods. Postoperative success was assessed by using a modified MacNab scale. The follow-up recording period after the last operation was of at least 1 year, ranging from 1 to 4 years. RESULTS: The surgical treatment was effective in most cases, recording a reduction in pain expression level from 7.2-7.7 points on the VAS scale to 1.7 2.1 in the early period and 2.2-2.6 in the late period (1 year). Repeated surgery was effective in 21 of 30 (70%) cases who underwent decompression surgery without fusion and in 20 of 26 (76.9%) cases who underwent repeated surgery with transforaminal lumbar interbody fusion (TLIF). Overall, postoperative success was assessed by using a modified MacNab scale. CONCLUSION: Repeated surgery is a viable option for patients who have clinical manifestations of recurrent disc herniation. Investigation with contrast agent by MRI allows differentiating disk herniation recurrences from epidural fibrosis. Supplementing repeated discectomies and decompression with intervertebral transforaminal fusion provide superior clinical outcomes, especially in patients with clinical and radiological signs of lumbar segment instability. PMID- 25713617 TI - Optical coherence tomography versus visual evoked potentials in detecting subclinical visual impairment in multiple sclerosis. AB - RATIONALE: Visual impairment is one of the most common clinical manifestations of multiple sclerosis (MS). Some multiple sclerosis patients complain of poor vision although the Snellen visual acuity is 20/20. This study reveals that sensitive measurements like visual evoked potential (VEP) and optical coherence tomography (OCT) can evidence subclinical disturbances of visual pathway. These methods examine the relation between the visual function (VEP) and retinal nerve fiber layer (RNFL) thickness, as a structural biomarker for axonal loss in patients with multiple sclerosis (MS). The findings in this study indicate the utility of combining structural and functional testing in clinical research on patients with MS. PURPOSE: To detect visual impairment in a population of visually asymptomatic patients affected by clinically definite multiple sclerosis (MS) and to compare the utility of optical coherence tomography (OCT) versus visual evoked potentials (VEP). MATERIAL AND METHODS: Fourteen patients (28 eyes) affected by clinically definite MS, without a history of optic neuritis and asymptomatic for visual disturbances, were initially fully examined (visual acuity, ocular fundus, biomicroscopy) from an ophthalmic point of view and then measured by OCT (RNFL thickness) and VEP. Patients with a history of glaucoma or other retinal or optic nerve disease were excluded. RESULTS: Of fourteen patients (28 eyes), VEP was abnormal in 11 cases (78,57%) and OCT (RNFL thickness) was abnormal in 5 cases (35,71%), while 3 patients had no abnormalities on neither tests. CONCLUSIONS: Optical coherence tomography (OCT) is less sensitive than visual evoked potentials (VEPs) in detecting visual subclinical impairment in patients with multiple sclerosis (MS). VEP remains the preferred test for the detection of clinical and subclinical optic neuritis. OCT may provide complementary information to VEP in cases with clinical definite MS and represent a valuable research instrument for the study of optic nerve disease in populations. The findings in this study reveal the utility of combining structural and functional testing in clinical research on patients with MS. PMID- 25713618 TI - Endo-periodontal lesion--endodontic approach. AB - Endo-perio lesions might be interdependent because of the vascular and anatomic connections between the pulp and the periodontium. The aim of this study is to emphasise that primary endodontic lesion heals after a proper instrumentation, disinfection and sealing of the endodontic space. The primary endodontic lesion with a secondary periodontal involvement first requires an endodontic therapy and, in the second stage, a periodontal therapy. The prognosis is good, with an adequate root canal treatment; it depends on the severity of the periodontal disease, appropriate healing time and the response to the treatment. A correct diagnosis is sometimes difficult; an accurate identification of the etiologic factors is important for an adequate treatment. Primary perio-endo lesion may heal after a proper disinfection and sealing of the endodontic system, the one year follow-up radiograph showing bonny repair. Invasive periodontal procedures should be avoided at that moment. The microorganisms and by-products from the infected root canal may cross accessory and furcal canals and determine sinus tract and loss of attachment. In both clinical cases presented in this article, successful healing was obtained after a proper disinfection and sealing of the endodontic system. PMID- 25713620 TI - A study of prevalence and distribution of tooth agenesis. AB - INTRODUCTION: Tooth agenesis is a phenomenon that occurs relatively commonly. The incidence of the missing teeth presented in the previous reports varies according to the studied population. OBJECTIVE: The aim of this study was to find the prevalence of tooth agenesis in a population group in Bucharest. METHODS AND RESULTS: The prevalence and distribution of dental agenesis was determined in a sample of 518 patients, 285 females and 233 males, aged 6 to 41 years, who had been treated in the Clinic of Orthodontics and Dentofacial Orthopedics in Bucharest. The tooth agenesis was diagnosed by using the orthodontic records and study casts for each patient. 35 of the patients, 17 males and 18 females, were diagnosed with at least one absent permanent tooth and 47 missing permanent teeth were reported. A prevalence of 6.757% was observed for tooth agenesis. The mandibular second premolar was found to be the most affected tooth, followed by the maxillary lateral incisor, maxillary second premolar, mandibular central incisors, mandibular second molar and mandibular lateral incisor. DISCUSSION: The incidence of dental agenesis, its pattern and distribution per tooth type are in accordance with the previous published studies. PMID- 25713621 TI - Stereometric parameters change vs. Topographic Change Analysis (TCA) agreement in Heidelberg Retina Tomography III (HRT-3) early detection of clinical significant glaucoma progression. AB - PURPOSE: to investigate the sensitivity and specificity of the stereometric parameters change analysis vs. Topographic Change Analysis in early detection of glaucoma progression. METHODS: 81 patients with POAG were monitored for 4 years (GAT monthly, SAP at every 6 months, optic disc photographs and HRT3 yearly). The exclusion criteria were other optic disc or retinal pathology; topographic standard deviation (TSD>30; inter-test variation of reference height>25 MUm. The criterion for structural progression was the following: at least 20 adjacent super-pixels with a clinically significant decrease in height (>5%). RESULTS: 16 patients of the total 81 presented structural progression on TCA. The most useful stereometric parameters for the early detection of glaucoma progression were the following: Rim Area change (sensitivity 100%, specificity 74.2% for a "cut-off " value of -0.05), C/D Area change (sensitivity 85.7%, specificity 71.5% for a "cut off " value of 0.02), C/D linear change (sensitivity 85.7%, specificity 71.5% for a "cut-off " value of 0.02), Rim Volume change (sensitivity 71.4%, specificity 88.8% for a "cut-off " value of -0.04). RNFL Thickness change (<0) was highly sensitive (82%), but less specific for glaucoma progression (45,2%). Changes of the other stereometric parameters have a limited diagnostic value for the early detection of glaucoma progression. CONCLUSION: TCA is a valuable tool for the assessment of the structural progression in glaucoma patients and its inter-test variability is low. On long-term, the quantitative analysis according to stereometric parameters change is also very important. The most relevant parameters to detect progression are RA, C/D Area, Linear C/D and RV. PMID- 25713619 TI - Dispersion of ventricular repolarization in relation to cardiovascular risk factors in hypertension. AB - RATIONALE: Hypertension associates with sudden cardiac death, its relationship with ventricular arrhythmias being demonstrated by multiple studies, an increased dispersion of repolarization being an important arrhythmogenesis mechanism. Only a small percentage of hypertensive patients presents increased blood pressure values exclusively as risk factor, most of them presenting additional risk factors that reinforce each other leading to increased total cardiovascular risk. AIM: to analyze the dispersion of repolarization parameters (QT interval, QT dispersion, Tpeak-Tend interval (Tpe), Tpe/QT, Tpe dispersion) in relation to cardiovascular risk factors, as well as total cardiovascular risk estimated by SCORE model, in mild to moderate essential hypertension. METHOD: 62 consecutive patients, mean age 55+/-11 years, were evaluated by 24 hours Holter electrocardiography monitoring. Manual measurement of dispersion of repolarization parameters was performed. RESULTS: Based on SCORE model, 33.9% patients presented low risk, 40.3% moderate risk, 16.1% high risk and 9.1% very high risk. Age had a positive correlation with QT and reverse correlations with QT dispersion, Tpe and Tpe/QT in lead V1. Tpe/QT showed significantly higher values in men versus women. Glucose metabolism disorders associated with higher values of QT and Tpe dispersion were present. However, dispersion of repolarization parameters was similar between risk categories assessed by SCORE model, Tpe in lead V3 correlated significantly with SCORE score. CONCLUSIONS: In mild to moderate hypertension, the dispersion of repolarization parameters is influenced by age, gender and glucose metabolism disorders. Among these, Tpe in lead V3 correlates with total cardiovascular risk assessed by SCORE model. PMID- 25713622 TI - Segmentary ureteral resection followed by ureteroneocystostomy associated with radical hysterectomy and partial cystectomy in a patient with bulky residual disease after chemoirradiation for invasive cervical cancer--a case report. AB - Cervical cancer represents the second most frequent malignancy in women worldwide, a significant number of cases still being diagnosed in an advanced stage of the disease. In some of these cases, local invasion is already present at the moment of diagnosis and even if neo-adjuvant chemoirradiation is performed in some patients, it persists at the moment of surgery. In these cases, more aggressive surgical procedures are needed in order to obtain a good control of the disease. The case of a 50-year-old patient diagnosed with locally advanced cervical cancer invading the right ureter is presented, in whom this aspect was present even after neo-adjuvant chemoirradiation and in whom a total radical hysterectomy with bilateral en bloc adnexectomy with partial cystectomy and the invaded zone of the right ureter was performed. The ureter was then mobilized and reimplanted in the urinary bladder through a neocystostomy. The postoperative course was uneventful. PMID- 25713623 TI - Proteus Syndrome: a difficult diagnosis and management plan. AB - RATIONALE: Proteus Syndrome (PS) is an extremely rare congenital pathology that causes overgrowth of multiple tissues, in particular bone and fat, following a mosaic pattern. The estimated incidence is of less than 1 per 1,000.000 live births and represents a significant challenge to the pediatric and orthopedic surgeons in order to establish a diagnosis and to elaborate a management plan. OBJECTIVES: We had the opportunity of treating many children who were afflicted by overgrowth syndromes and have been previously misdiagnosed as Proteus Syndrome in our department of pediatric and orthopedic surgery of "Maria Sklodowska Curie" Clinical Emergency Hospital for Children. This study helped us develop a diagnostic for these patients and report the first case of a confirmed PS in Romania. METHODS AND RESULTS: We report the case of a 5-year-old white male who is in the attention of the clinic since birth. He presented with multiple overgrowth bone segments, fatty subcutaneous or intraabdominal tumors and other connective tissues abnormalities. All the tests performed confirmed the diagnosis of PS at the age of 4 and the management is still to be decided. DISCUSSIONS: We followed the latest diagnostic indications and the patient fulfilled the general and specific criteria. The treatment is still in progress and it represents a challenge for the multidisciplinary medical team. PMID- 25713625 TI - Survival rates of patients with metastatic malignant melanoma. AB - RATIONALE: Malignant melanoma (MM) is the cutaneous neoplasia with the greatest mortality rates and one of the malignancies with the highest potential of dissemination. The prognosis of patients with metastatic MM is grim, with a 5 years survival rate between 5-19%, and is dictated by the location and the number of metastases. OBJECTIVE: We aimed to estimate the survival of patients with metastatic MM from our study and find out if the metastasis' location influences survival. METHODS AND RESULTS: Between 2008 and 2013, 155 patients with cutaneous MM were diagnosed in our clinic. All the patients were staged according to 2009 AJCC staging system. The median follow-up period was of 24 months. Survival was calculated by using the Kaplan-Meier method with a confidence level of 95%. 40.5% of the patients developed metastases in different organs, especially the brain. 80.6% of those with metastases died during the study. The median overall survival, estimated for the entire group of patients who developed metastases, was of 5.3 months. DISCUSSION: The influence of metastases distribution on the overall survival was examined and it was noticed that there were statistically significant differences between the risks of death of various groups of patients, depending on metastasis topography. Thus, the death probability of a patient with brain metastases is twice that of a patient with digestive metastasis, about 7 times higher than that of a patient with lung metastasis (p=0.0004) and 12 times higher than the death risk of a patient with extra-regional lymph nodes or subcutaneous metastasis (p=0.0000). PMID- 25713624 TI - Hereditary Thrombophilia and thrombotic events in pregnancy: single-center experience. AB - Pregnancy is a normal physiological state that predisposes to thrombosis, determined by hormonal changes in the body. These changes occur in the blood flow (venous stasis), changes in the vascular wall (hypotonia, endothelial lesion) and changes in the coagulation factors (increased levels of factor VII, factor VIII, factor X, von Willebrand factor) and decreased activity levels of natural anticoagulants (protein C, protein S). In this study, we tried to determine a possible association between thrombosis and inherited thrombophilia in pregnant women. This is a retrospective study of 151 pregnant women with a history of complicated pregnancy: maternal thrombosis and placental vascular pathology (intrauterine growth restriction, preeclampsia, recurrent pregnancy loss), who were admitted in our hospital during the period January 2010 to July 2014. We performed genetic analyses to detect the factor V Leiden mutation, the G20210A mutation in the prothrombin gene, the C677T mutation and the A1298C mutation in methylenetetrahydrofolate reductase (MTHFR) gene. The risk of thrombosis in patients with factor V Leiden is 2.66 times higher than the patients negative for this mutation (OR 2.66 95% CI 0.96-7.37 P=0.059). We did not find any statistical association with mutations in the MTHFR gene. Pregnant women with a family history of thrombosis present a 2.18-fold higher risk of thrombosis (OR 2.18 CI 0.9-5.26 P=0.085). Of 151 pregnant women, thrombotic events occurred in 24 patients: deep vein thrombosis, pulmonary embolism, cerebral venous sinus thrombosis and ischemic stroke. The occurrence of thrombotic events was identified in the last trimester of pregnancy, but especially postpartum. Thrombosis in pregnancy is a redoubtable complication requiring an excellent cooperation between the obstetrician and anesthesiologist. PMID- 25713626 TI - Salivary changes related to systemic diseases in the edentulous patients. AB - INTRODUCTION: The relatively frequent systemic comorbidities of geriatric patients can be linked to salivary changes, which may induce oral alteration and discomfort with the removable prosthesis. The aim of the study was to evaluate the salivary parameters in completely edentulous patients treated by removable prosthesis, in relation to their general health status. MATERIAL AND METHOD: A cross-sectional study was performed on 30 completely edentulous patients, 53% male and 47% female, aged between 53 and 84. The evaluation of the salivary parameters (oral hydration index, pH and salivary flow, viscosity and saliva buffer capacity) was performed with the Saliva Check Buffer kit (GC Corporation). RESULTS: The salivary changes encountered were the following: low hydration level (63%), high saliva viscosity (57%), below-average pH (27%), reduced salivary flow (77%) and low saliva buffer capacity (80%). A reduced salivary flow and saliva buffer capacity was found in women. A lower buffer capacity of the saliva was found in patients with respiratory and gastro-intestinal disease. CONCLUSIONS: The alterations of the salivary flow are relatively frequent in geriatric patients, removable denture wearers, with compromised systemic status. These changes may be a risk factor for denture stomatitis and oral candidiasis, with a negative effect on the patient's comfort and quality of life. PMID- 25713627 TI - Prognostic significance of KRAS gene mutations in colorectal cancer--preliminary study. AB - OBJECTIVE: The prognostic significance of KRAS gene mutations, evaluated by using two methods in patients with colorectal cancer (CRC). MATERIAL AND METHODS: Retrospective study involving 58 patients diagnosed with CRC and treated between 2003 and 2010 in the General and Esophageal Surgery Clinic of "Sf. Maria" Hospital, Bucharest. The macroscopic and microscopic examination of the resected specimens was also processed for genetic analysis in NIRDPBS, where KRAS status was determined by using two methods: PCR-RFLP and pyrosequencing. RESULTS: The clinical and biological parameters of the patients were assessed for 72 months in average. A relapse in 21 patients and a 5-year survival rate of 79.3% was discovered. The genetic analyses of KRAS gene found mutations in 22 cases (45.3%): 17 cases had mutations in codon 12, 5 cases in codon 13. The survival rate analyses of patients with wild KRAS gene compared with the patients carrying the mutation on codon 12 /13 revealed a superposition of the survival curve. The statistical analysis based on the TNM stage revealed different survival curves in stage I and II, shorter survival period in patients with KRAS mutation on codon 13 than in those with wild type gene (stage I--p_value=0.015; stage II- p_value=0.000). CONCLUSIONS: It was not found that KRAS gene status had any prognostic significance. Nevertheless, for stage I and II patients, the mutation found on codon 13 determined a statistic significant shorter survival rate than for those with wild type. The results obtained by using the pyrosequencing method for the determination of KRAS gene status proved that it represented a reliable and reproducible method. PMID- 25713628 TI - Utility of different cardiovascular disease prediction models in rheumatoid arthritis. AB - BACKGROUND: Rheumatoid arthritis comes with a 30% higher probability for cardiovascular disease than the general population. Current guidelines advocate for early and aggressive primary prevention and treatment of risk factors in high risk populations but this excess risk is under-addressed in RA in real life. This is mainly due to difficulties met in the correct risk evaluation. This study aims to underline the differences in results of the main cardiovascular risk screening models in the real life rheumatoid arthritis population. METHODS: In a cross sectional study, patients addressed to a tertiary care center in Romania for an biannual follow-up of rheumatoid arthritis and the ones who were considered free of any cardiovascular disease were assessed for subclinical atherosclerosis. Clinical, biological and carotidal ultrasound evaluations were performed. A number of cardiovascular disease prediction scores were performed and differences between tests were noted in regard to subclinical atherosclerosis as defined by the existence of carotid intima media thickness over 0,9 mm or carotid plaque. RESULTS: In a population of 29 Romanian rheumatoid arthritis patients free of cardiovascular disease, the performance of Framingham Risk Score, HeartSCORE, ARIC cardiovascular disease prediction score, Reynolds Risk Score, PROCAM risk score and Qrisk2 score were compared. All the scores under-diagnosed subclinical atherosclerosis. With an AUROC of 0,792, the SCORE model was the only one that could partially stratify patients in low, intermediate and high-risk categories. The use of the EULAR recommended modifier did not help to reclassify patients. CONCLUSION: The only score that showed a statistically significant prediction capacity for subclinical atherosclerosis in a Romanian rheumatoid arthritis population was SCORE. The additional calibration or the use of imaging techniques in CVD risk prediction for the intermediate risk category might be warranted. PMID- 25713629 TI - Pesamosca osteoplasty: surgical procedure for the spatial correction of cubitus varus or valgus post malunited supracondylar fractures of the humerus. AB - INTRODUCTION: Supracondylar fractures of the humerus represent a current concern in the child's and adolescent's osteo-articular pathology. Even though orthopedic reductions are made correctly, fractures can become displaced when managed only by cast immobilization and complications may arise. The most frequent complications encountered in "Prof. Dr. Alexandru Pesamosca" Clinique, Bucharest, Romania, due to supracondylar humeral fractures, are valgus or varus deviations with angles that can sometimes exceed 40 degrees as a result of malunion. Varus or valgus deformations were rarely encountered after surgical treatment. The goal of this study is to present an alternative surgical technique to correct varus and valgus deformations as well as malrotation. MATERIAL AND METHOD: The study is a retrospective analysis of a 96 children study group surgically managed during 1985 and 2013. In the first period, various surgical techniques have been performed: cuneiform resections, step-cut osteotomies, open wedge osteotomies with external fixation, epiphysiodesis, hemichondrodiatasis and Pesamosca metaphyseal diaphyseal osteoplasty. Starting with 2005, all the cases that presented such complications--28 out of 96 (29.1%)--were managed with the Pesamosca procedure. Due to the malunion of supracondylar humeral fractures only varus or valgus deformities were admitted in the study. The malunion due to the pathologic fractures encountered in osteogenesis imperfecta or fibrous dysplasia was precluded. The experience accumulated with the other surgical techniques used in 68 out of 96 patients (70.9%) determined us to exclusively use the Pesamosca osteoplasty following the year 2005, seeing the simplicity and the efficiency of this procedure. RESULTS: The outcome was very good. In 5 cases out of the 28 (17%) an apparent residual elbow was encountered and one case of relapse (3%) was noted due to inadequate term of cast immobilization. The elbow's mobility was completely recovered, the thoracic member's axis was appropriate and the metaphyseal diaphyseal osteotomy site healed completely in 3 months' time. CONCLUSIONS: Compared to other surgical techniques, the Pesamosca technique offers to the surgeon the possibility of correcting the varus or the valgus deformity as well as the malrotation in a simple, secure and efficient manner. PMID- 25713630 TI - Bionic hand exoprosthesis--perspectives for the future in Romania. AB - Prosthetics is a modern area of interest and a challenge in Orthopedics. Over time, there has been a transition from an artisanal method of prosthetics production to modern concepts and materials, including a re-education through virtual reality. The conditions for an efficient fitting of a prosthesis include the necessity that the prosthesis respects the form and function of the lost limb, both anatomically and biomechanically. Prosthetics are made individually, personalized according to sex, age, physiological characteristics, profession and preference. In our country, thoracic limb prosthetics has a relatively short recorded history of approximately a century, the most preeminent centers being in Iasi, Cluj and Bucharest. Currently, thoracic limb prosthetics, and particularly hand prosthetics, are in a period of development. A technique for amputation and stump reamputation called "circumferential osteoneuromioplasty" (CONM) is currently being used in the Orthopedics and Trauma Clinic of the Central Military University Emergency Hospital in Bucharest. The method was created with the purpose of obtaining distinct myoelectric signals of better quality, following the contraction of each muscle. The CONM method can be used in conjuncture with both the new hand prostheses that are currently available in Romania, and with the model that is being developed by a mixed team from the Polytechnic University in Bucharest, in collaboration with the Central Military University Emergency Hospital in Bucharest. PMID- 25713631 TI - Sonotubometry, a useful tool for the evaluation of the Eustachian tube ventilatory function. AB - From the three Eustachian tube (ET) functions: middle ear protection, secretion clearance and middle ear ventilation, the ventilatory function is unanimously considered the most important one, because proper hearing is established only when tympanic membrane compliance is normal. This requires equilibrium between the middle ear and ambient gas pressure, which makes the normal functioning of active ET opening of critical importance. There are several methods and tests that can assess such a complex and variable mechanism. Sonotubometry is one such method; despite the fact that it has been continuously improved in the last 20 years, it is not yet systematically used to evaluate the ET ventilatory function, because its measurement pattern, context mapping (patient, clinic data, medication, treatment), validation, reproducibility and value for clinic practice, have not yet been fully consolidated and integrated in a knowledge based, service-oriented system, that can provide decision support or even diagnostic. The paper reviews the role of tubal sonometry as a non-invasive, physiologic and easy to use method in assessing the ventilatory function and investigates the validity and reproducibility of a measuring pattern and test in a group of children. The paper describes the test pattern used, and the computer based platform based on: (1) Digital Signal Processing (DSP) for sound acquisition and low-level processing; (2) Artificial Intelligence techniques to extract significant sound features from sonotubograms and learn a manifold context database. Results are reported from test series carried out in healthy children; a similar study between tests is included in the final Discussions section. PMID- 25713632 TI - Influence of GSH synthesis inhibition on temporal distribution of NAD+/NADH during vascular endothelial cells proliferation. AB - Pathological conditions states such as stroke, diabetes mellitus, hypertension, dyslipidemia are associated with increased levels of free radicals that alter normal function of the vascular endothelium and perturb vascular homeostasis. The redox couples reduced glutathione (GSH)/oxidized glutathione (GSSG), NADH/NAD+, and NADPH/NADP+ play major functions in the intracellular redox balance. Any decrease in tissue or systemic GSH levels under the aforementioned pathologies would enhance oxidative damage to the vascular endothelium. Beside their role as coenzyme that participate in cellular metabolism, pyridine nucleotides serve also as substrate for enzymes involved in DNA repair and longevity. There is scant data on NAD+/NADH kinetics and distribution during human cells proliferation. Here, we determined the influence of cellular GSH status on the early dynamics of nuclear-to-cytosol (N-to-C) NAD+ and nuclear NADH kinetics (6 h interval) over 72 h of endothelial cell proliferation. The IHEC cell line was used as a surrogate for human brain micro vascular endothelial cells. Inhibition of GSH synthesis by buthionine sulfoximine (BSO) and sustained low cellular GSH significantly increased nuclear NADH levels (p<0.01), which correlated with lower nuclear GSH and prolonged cell cycle S-phase. When BSO was removed the pattern of nuclear NAD+ resembled that of control group, but nuclear NADH concentrations remained elevated, as in GSH deficient cells (p<0.01). The coincidence of high nuclear NADH and lower nuclear NAD+ with S-phase prolongation are suggestive of CtBP and NAD+-dependent DNA repair enzyme activation under conditions of decreased cellular GSH. These results provide important insights into GSH control of vascular endothelial growth and restitution, key processes in the restoration of the endothelium adjacent to the post-injury lesion site. PMID- 25713633 TI - Stimulatory and possible antioxidant effects of High Density Green Photons (HDGP) on cellular systems. AB - The interactions between the electromagnetic field and the biological systems were extensively investigated, with remarkable results and advanced technologies. Nevertheless, the visible domain of the spectrum has been rather neglected, since the classic physics did not allow electronic transitions induced by visible light. Recently, the interaction of light with the matter has generated a new scientific domain known in Physics as optical manipulation, with the new concepts of optical matter and optical force. This article presents the results of our work concerning in vitro effects of High Density Green Photons (HDGP) irradiation on cell cultures: stimulation of cell proliferation and migration and a possible antioxidant action. PMID- 25713634 TI - Maternal Deprivation of Lewis Rat Pups Increases the Severity of Experi-mental Periodontitis in Adulthood. AB - BACKGROUND AND OBJECTIVE: Early life adverse events may influence susceptibility/resistance to chronic inflammatory diseases later in life by permanently dysregulating brain-controlled immune-regulatory systems. We have investigated the impact of infant-mother separation during early postnatal life on the severity of experimental periodontitis, as well as systemic stress and immune responses, in adulthood. MATERIAL AND METHODS: Pups of periodontitis resistant Lewis rats were separated from their mothers for 3 h daily during postnatal days 2-14 (termed maternal deprivation; MD), separated for 15 min daily during the same time period (termed handling; HD), or left undisturbed. As adults, their behaviour was tested in a novel stressful situation, and ligature induced periodontitis applied for 21 days. Two h before sacrifice all rats were exposed to a gram-negative bacterial lipopolysaccharide (LPS) challenge to induce a robust immune and stress response. RESULTS: Compared to undisturbed controls, MD rats developed significantly more periodontal bone loss as adults, whereas HD rats showed a tendency to less disease. MD and HD rats exhibited depression-like behaviour in a novel open field test, while MD rats showed higher glucocorticoid receptor (Gr) expression in the hippocampus, and HD rats had altered methylation of genes involved in the expression of hippocampal Gr. LPS provoked a significantly lower increase in circulating levels of the cytokine TGF-1beta in MD and HD rats, but there were no significant differences in levels of the stress hormone corticosterone. CONCLUSION: Stressful environmental exposures in very early life may alter immune responses in a manner that influences susceptibility/resistance to periodontitis. PMID- 25713636 TI - The effect of time and storage environment on dimensional changes of acrylic resin post patterns. AB - Introduction : Post and core are needed to regain retentions and functions after endodontic therapies. Also, risk of cross contamination from dental prosthesis is so high. The aim of this study was to compare dimensional changes of acrylic resin patterns (ARP) in three different storing environments. Materials and methods : conventional root canal therapy was done on one first premolar tooth and the canal filled with Guttapercha. 2/3 of the filling was expelled and 30 direct APRs were prepared by Duralay. The samples were divided into 3 groups based on storing environments: water, NaOCl 5% and air. Finally dimensional changes in coronoapical length (CAL), coronal (CD) and apical diameter (AD) of APRs were measured in 7 consecutive times (immediately after polymerization, 1, 2, 4, 8, 24, 48 hours later). All the data were analyzed by Paired T-test and Duncon test using SPSS software ver.13 at significant level of 0.05. Results : After 24 hours, the ARPs, which were stored in air, contracted 0.07, 0.06 and 0.12 mm in AD, CD and CAL; the ARPs, which were stored in water, showed 0.03, 0.06 and 0.12 mm decrease in AD, CD and CAL; But the ARPs, which were stored in NaOCl 5%, showed significant expansion in AD, CD and CAL (0.03, 0.06 and 0.10 mm) (all P values < 0.01). Conclusion : It is better not to use NaOCl for disinfecting; also the best time for storing APRs is 8 hours for water and 2 hours for air environments after setting time. PMID- 25713635 TI - Root Surface Bio-modification with Erbium Lasers- A Myth or a Reality?? AB - The objective of this literature review was to critically review the evidence available in the literature regarding the expediency of erbium family of lasers for root bio modification as a part of periodontal therapy. The literature search was performed on the Pubmed using MeSH words such as "lasers/therapeutic use, scaling, dental calculus, tooth root/anatomy and histology, ultrasonic therapy". The studies were screened and were grouped as follows: those evaluating a) efficacy for calculus removal with the Erbium family of laser b) root surface changes following Er YAG and Er Cr YSGG application c) comparative studies of the Er YAG, Er Cr YSGG lasers versus conventional methods of root surface modification d) Bio compatibility of root surface following Erbium laser treatment e) Studies on the combined efficacy of laser root modification with conventional methods towards root surface bio-modification f) Studies on effectiveness of root surface bio-modification prior to root coverage procedures. In conclusion, the erbium family has a proven anti-bacterial action, predictable calculus removal, minimal root substance removal, and appears to favor cell attachment. The Erbium family of lasers appears to be a useful adjunct for the management of periodontal disease. PMID- 25713637 TI - Prevalence of Punctate Keratopathy of West Indians in a Colombian Referral Center and a New Name Proposed: Rice's Keratopathy. AB - PURPOSE: To perform a prevalence study of Punctate Keratopathy of West Indians in Colombian individuals and to propose a new name for the condition. METHODS: Prospective, population-based epidemiological study. All patients evaluated between November 1 and December 31, 2012, in the Centro Oftalmologico Virgilio Galvis and Fundacion Oftalmologica de Santander (FOSCAL), Floridablanca, Colombia, with clinical findings of white corneal opacities corresponding to Punctate Keratopathy of West Indians were identified. Careful slit-lamp examination was performed for clinical diagnosis and findings were reported in the electronic medical record indicating number and location of the lesions. Prevalence was calculated for the total population, and for gender and age groups. Furthermore a literature review was performed and a new name for the condition proposed. RESULTS: In the whole group of patients, prevalence was 1.0%. No one case was diagnosed in a patient younger than 21 year-old. No one lesion was located within 2.5 mm of the corneal apex. 96% of affected patients had unilateral involvement. 58.5% of eyes had a single corneal lesion; 7% of eyes had 6 or 7 corneal lesions. CONCLUSION: The condition heretofore known as Punctate Keratopathy of West Indians was present in 1% of our patients in Colombia (South America). Thus, this non-infectious, non-inflammatory, asymptomatic ailment of unknown etiology is not restricted to people of Antillean descent, or who have lived in these islands. We propose the new name "Rice's keratopathy". Age and male gender were independent risk factors for the presence of the keratopathy. PMID- 25713638 TI - Tell me how much you move, I'll tell you how much you'll live. Editorial of the JONAFES I International Symposium of Physical Activity, Sport & Health. PMID- 25713639 TI - Relationship between Depression and Strength Training in Survivors of the Ischemic Stroke. AB - The Cerebral Vascular Accident is responsible for a significant increase in the mortality rate in individuals who have suffered this condition, regardless of the level of subsequent disability. This study aimed to analyze the influence of a strength training program on indicators of depression in survivors of the ischemic stroke. The study sample included subjects from both genders who were divided into two groups: an experimental group (EG) consisting of 11 subjects aged 51.7 8.0 years, and a control group (CG) consisting of 13 subjects aged 52.5 7.7 years. The EG underwent 12 weeks of strength training. Assessment was made in the pre-test before training and at the re-test after 12 weeks of training. We used the Beck Depression Inventory and evaluated 1RM. Significant differences in depression were found between post-test and pretest measurements (Delta% = 21.47%, p = 0,021) in the EG; furthermore, there were significant differences in all indicators of depression between the EG and CG after completing 12 weeks of training. There were significant gains in strength of the EG in relation to the CG. There was a negative correlation between the strength gains as determined with the 1RM test and the levels of depression, especially in lower-limb exercises. The results of this study suggest that improvements in strength are negatively correlated with levels of depression. Improvements in strength are therefore associated with a reduction in levels of depression. PMID- 25713640 TI - Resistance Training in Type 2 Diabetic Patients Improves Uric Acid levels. AB - Resistance training (RT) can provide several benefits for individuals with Type 2 diabetes. The aim of this study was to investigate the effects of resistance training on the strength levels and uric acid (UA) concentration in individuals with Type 2 diabetes. The study included 68 patients (57.7+/-9.0 years) that participated in an organized program of RT for 12 weeks. The volunteers were divided into two groups: an experimental group (EG; n=34) that performed the resistance training program consisting of seven exercises executed in an alternating order based on segments; and a control group (CG; n=34) that maintained their normal daily life activities. Muscle strength and uric acid were measured both pre- and post-experiment. The results showed a significant increase in strength of the subjects in the EG for all exercises included in the study (p<0.001). Comparing the strength levels of the post-test, intergroup differences were found in supine sitting (p<0.001), leg extension (p<0.001), shoulder press (p<0.001), leg curl (p=0.001), seated row (p<0.001), leg press (p=0.001) and high pulley (p<0.001). The measured uric acid was significantly increased in both experimental and control groups (p<0.001 and p=0.001, respectively). The intergroup comparison showed a significant increase for the EG (p=0.024). We conclude that the training program was effective for strength gains despite an increase in uric acid in Type 2 diabetics. PMID- 25713641 TI - Body dissatisfaction and self-esteem in female students aged 9-15: the effects of age, family income, body mass index levels and dance practice. AB - This study aimed to analyze the effects of age, family income, body mass index and dance practice on levels of body dissatisfaction and self-esteem in female students. The sample consisted of 283 female subjects attending a public school with a mean age of 11.51+/-1.60 years and a mean body mass index of 18.72 kg/m2 (SD=3.32). The instruments used were the Body Dissatisfaction Scale for Adolescents and the Rosenberg Self-Esteem Scale, both of which showed good internal consistency (0.77 and 0.81, respectively). The tests were applied (two factor ANOVA) to compare the students practicing and those not practicing dance; the differences in the levels of body dissatisfaction (p=0.104) and self-esteem (p=0.09) were considered significant. The results demonstrated that age negatively correlated with body dissatisfaction (r=-0.19; p<0.01) and that higher body mass index levels were associated with greater body dissatisfaction (r=0.15, p=0.016) and lower levels of self-esteem (r=-0.17, p<0.01) only in non practitioners. The practice of dance had a significant effect on levels of body dissatisfaction (F=4.79; p=0.030; eta(2)=0.02), but there was no significant difference in self-esteem (F=1.88; p=0.172; eta(2)=0.02). It can be concluded that female children and adolescents practicing dance have higher self-esteem, and are more satisfied with their body weight and their appearance. Moreover, results showed that self-esteem and body dissatisfaction were influenced by the body mass index levels only in the non-practitioners group. PMID- 25713642 TI - Soccer practice and functional and social performance of men with lower limb amputations. AB - Practicing sports together with rehabilitative treatment improves the development of motor, social and emotional abilities of lower limb amputees. The aim of this study was to compare the functional and social performance of individuals with lower limb amputations between those who played soccer and those who did not engage in any sports activities. A total of 138 individuals participated in the study and were divided into two groups: soccer players (n = 69, 34 +/- 8.1 years) and non-athletes (n = 69, 38 +/- 8.9 years). A checklist, based on the International Classification of Functioning, Disability and Health, was used. Data were analyzed using the Chi-square and Mann-Whitney tests. The soccer players group showed significantly better performance than the non-athletes group in most items of body function, body structure, occupational performance components and daily activities (p < 0.001 for all), and also in some important items of social and environment factors (p < 0.001 for all). The results strongly suggest that amputee soccer significantly improves the functional and social performance in individuals with lower limb amputations. PMID- 25713643 TI - The effect of a long-term, community-based exercise program on bone mineral density in postmenopausal women with pre-diabetes and type 2 diabetes. AB - The aim of this study was to evaluate the impact of a community-based exercise program on bone mineral density and body composition in postmenopausal women with pre-diabetes and type 2 diabetes. Twenty postmenopausal women (aged 61.3 +/- 6.0 years) with pre-diabetes and type 2 diabetes were randomly assigned to a community-based exercise program group (n=10) or a control group (n=10). The community-based exercise program was multicomponent, three days per week for 32 weeks, and included walking, resistance and aquatic exercises. Body composition and bone mineral density were measured pre and post-training by dual X-ray absorptiometry. In the exercise group significant increases were found in the ward's triangle bone mineral density (+7.8%, p=0.043), and in fat-free mass (+2.4%, p=0.018). The findings suggest that regular multicomponent training is effective in preventing osteoporosis and sarcopenia among postmenopausal women with pre-diabetes and type 2 diabetes. PMID- 25713644 TI - Can a single session of a community-based group exercise program combining step aerobics and bodyweight resistance exercise acutely reduce blood pressure? AB - This study aimed to analyze the acute effects of a single session of a community based group exercise program combining step aerobics and bodyweight resistance exercise on blood pressure in healthy young adult women. Twenty-three healthy young adult women (aged 31.57 +/- 7.87 years) participated in two experimental sessions (exercise and control) in a crossover study design. Blood pressure was monitored before, immediately after and at 10, 20 and 30 min of recovery. The exercise session consisted of four phases: 1) a warm-up (5 min of dance aerobics); 2) aerobic exercise training (30 min of step aerobics); 3) resistance exercise training (six sets of 12 repetitions of three bodyweight exercises in a circuit mode, 10 min); and 4) a cool-down (5 min of breathing and flexibility exercises); totaling 50 min of duration. Systolic blood pressure after exercise was significantly lower compared to control at the 10th min (-10.83 +/- 2.13 vs. 2.6 +/- 2.13 mmHg; p = 0.009), 20th min (-11.26 +/- 2.13 vs. -3.04 +/- 2.13 mmHg; p = 0.009) and 30th min of recovery (-10.87 +/- 2.39 vs. -0.48 +/- 2.39 mmHg; p = 0.004). A single session of a community-based group exercise program combining step aerobics and bodyweight resistance exercise was effective in inducing significant post-exercise hypotension in healthy young adult women. This type of low-cost exercise interventions may have an important role in the prevention of cardiovascular diseases and in community health promotion. PMID- 25713645 TI - Chronic effects of strength training vs. Hydro aerobics on functional and cardiorespiratory ability in postmenopausal women. AB - The current study aimed to compare the effects of two exercise programs (Strength Training and Hydro Gymnastics) on the functional and cardiorespiratory abilities of Portuguese postmenopausal women. The study population consisted of 38 volunteers (age: 66.9 +/- 6.1 years, body mass: 73.70 +/- 10.38 kg, and body height: 1.55 +/- 0.10 m). Subjects were randomly divided into two experimental groups and one control group: one group performed 24 weeks of strength training (GST; n = 14), another performed 24 weeks of hydro gymnastics (GH; n = 17) and a control group (CG; n = 7), where the subjects continued with their regular daily activities without involvement in any physical exercise program. Three assessments were performed: before the beginning of the program, 12 weeks after the start of the training program and 24 weeks after the start of the program. To assess the functional ability of the participants, several tests proposed by Jones and Rikli (2002) were performed. To evaluate the cardiorespiratory ability of the participants, a modified treadmill Bruce test was applied. Significant differences (p<0.05) were found between the two training methods in the tests, which primarily demanded muscular strength. Body mass and the body mass index showed significant differences during the three stages of assessment in the GST group (p<0.05). With respect to the values that represent the variables of cardiorespiratory ability, positive and significant changes were observed in the two experimental groups. It was concluded that both exercise programs promoted improvements in some indicators of the functional and cardiorespiratory abilities of Portuguese postmenopausal women. PMID- 25713646 TI - The effects of different exercise programmes on female body composition. AB - The purpose of this study was to verify the effects of 16 weeks of practicing different exercise programmes on body composition. This is an exploratory and descriptive study of 89 women aged 25 to 55 years (41.42 +/- 9.23 years). The subjects were randomly divided into three experimental groups (EG): practitioners of strength training (SG), dance (DG), hydrogymnastics (HG), and a control group (CG) with sedentary women. Measurements of body mass and height, circumferences of the chest, waist, abdomen, hips, thighs, calves, and skinfolds of the triceps, suprailiac and thigh were registered in three different moments: prior to the commencement of the training program, again after 8 weeks of training, and finally after 16 weeks of training. Body density was estimated by using the trifold protocol by Jackson, Pollock and Ward. The ANOVA and deltas of change (Delta%) were used for data analysis. The level of significance was set at p<0.05. The effects of greater statistical significance on body composition related the variables "time", "group" and the interaction between the two (time * group) were observed for the percentage of fat - F% (F (1.79, 152.52) = 24.59, p <0.001, eta (2) = 0.22), fat mass - FM (F (1.75, 149.01) = 12.65, p <0.001, eta (2) = 0.13) and lean mass - LM (F (1.77, 150.66) = 47.38, p <0.001, eta (2) = 0.36). The HG and SG were more beneficial in reducing F%. It was observed that the EG indicated healthier anthropometric aspects compared to the CG, regardless of the type of exercise programmes practiced. The time factor was more representative over the effects of exercise on anthropometric dimensions. PMID- 25713647 TI - The acute effect of resistance exercise with blood flow restriction with hemodynamic variables on hypertensive subjects. AB - The purpose of this study was to analyze systolic blood pressure (SBP), diastolic blood pressure (DBP) and the heart rate (HR) before, during and after training at moderate intensity (MI, 50%-1RM) and at low intensity with blood flow restriction (LIBFR). In a randomized controlled trial study, 14 subjects (average age 45+/ 9,9 years) performed one of the exercise protocols during two separate visits to the laboratory. SBP, DBP and HR measurements were collected prior to the start of the set and 15, 30, 45 and 60 minutes after knee extension exercises. Repeated measures of analysis of variance (ANOVA) were used to identify significant variables (2 * 5; group * time). The results demonstrated a significant reduction in SBP in the LIBFR group. These results provide evidence that strength training performed acutely alters hemodynamic variables. However, training with blood flow restriction is more efficient in reducing blood pressure in hypertensive individuals than training with moderate intensity. PMID- 25713648 TI - Influence of resistance training on blood pressure in patients with metabolic syndrome and menopause. AB - This study investigated the chronic and acute influence of resistance exercise on blood pressure in women with metabolic syndrome before and after climacteric. Twenty sedentary women, nine non-menopausal (RNM) and 11 menopausal (RM), performed training for 12 weeks. Meanwhile, 23 controls, 11 not menopausal (CNM) and 12 menopausal (CM), remained sedentary. Blood pressure was measured before and after the training period in conditions of rest and after a session of exercise. Training promoted variations in blood pressure at rest from 116+/-13 to 118+/-10 mmHg (p=0.73) and from 128+/-12 mmHg to 120+/-11mmHg (p=0.12) in RNM and RM, respectively. CNM and CM varied from 115+/-11 to 116+/-12 mmHg (p=0.9) and from 115+/-14 mmHg to 116+/-13 mmHg (p=0.74). Blood pressure values in one acute session did not differ between groups (p>0.05). Resistance training did not improve blood pressure in women with metabolic syndrome, regardless of climacteric. PMID- 25713649 TI - Nutritional Status Associated with Metabolic Syndrome in Middle-School Children in the City of Montes Claros - MG, Brazil. AB - The aim of this study was to investigate the association between nutritional status and prevalence of metabolic syndrome (MS) in middle-school students in the city of Montes Claros - MG. The sample consisted of 382 students, aged 10-16 years. Nutritional status was evaluated using the Body Mass Index (BMI). Metabolic syndrome (MS) was defined as the presence of two or more criteria in accordance with definition of the International Diabetes Federation. The overall prevalence of MS was 7.9%. 9.7% of students with MS were overweight and 72.4% were obese. Therefore, it can be inferred that carrying excess weight considerably increases the chances for a child to develop MS, and concomitantly increases the child's risk for developing cardiovascular disease. PMID- 25713650 TI - Short-term effects of complex training on agility with the ball, speed, efficiency of crossing and shooting in youth soccer players. AB - Complex training (CXT) is the result of a combination of strength and plyometric exercises in the same session. This method has recently been used in the preparation of athletes of different sports. The aim of the present study was to observe the acute effects of a CXT program of 6 weeks: i) on agility with the ball, sprinting and the efficiency of crossing and shooting in youth soccer players; ii) and the influence of the number of CXT sessions per week (one vs. two). Sixteen youth male soccer players were randomly divided into three groups: a group that performed one weekly CXT session (GCT1, n = 5, age: 13.80 +/- 0.45 years); or a group that performed two weekly CXT sessions (GCT2, n = 5, age: 14.20 +/- 0.45 years); or a control group that did not perform the CTX (n = 6, age: 14.20 +/- 0.84 years). All groups maintained their regular soccer training sessions. No significant interactions were found between GCT1 and GCT2 in all variables. Significant statistical differences were identified (F = 1139, p = 0.02, MUp (2) = 0531) in the pre-test versus post-test, for both experimental groups, in shot effectiveness. In conclusion, the CXT program proved to be an effective method in boosting abilities and motor skills associated with soccer among young athletes, particularly in increasing shot effectiveness. PMID- 25713651 TI - Development and validation of an automated step ergometer. AB - Laboratory ergometers have high costs, becoming inaccessible for most of the population, hence, it is imperative to develop affordable devices making evaluations like cardiorespiratory fitness feasible and easier. The objective of this study was to develop and validate an Automated Step Ergometer (ASE), adjusted according to the height of the subject, for predicting VO2max through a progressive test. The development process was comprised by three steps, the theoretical part, the prototype assembly and further validation. The ASE consists in an elevating platform that makes the step at a higher or lower level as required for testing. The ASE validation was obtained by comparing the values of predicted VO2max (equation) and direct gas analysis on the prototype and on a, treadmill. For the validation process 167 subjects with average age of 31.24 +/- 14.38 years, of both genders and different degrees of cardiorespiratory fitness, were randomized and divided by gender and training condition, into untrained (n=106), active (n=24) and trained (n=37) subjects. Each participant performed a progressive test on which the ASE started at the same height (20 cm) for all. Then, according to the subject's height, it varied to a maximum of 45 cm. Time in each stage and rhythm was chosen in accordance with training condition from lowest to highest (60-180 s; 116-160 bpm, respectively). Data was compared with the student's t test and ANOVA; correlations were tested with Pearson's r. The value of alpha was set at 0.05. No differences were found between the predicted VO2max and the direct gas analysis VO2max, nor between the ASE and treadmill VO2max (p= 0.365) with high correlation between ergometers (r= 0.974). The values for repeatability, reproducibility, and reliability of male and female groups measures were, respectively, 4.08 and 5.02; 0.50 and 1.11; 4.11 and 5.15. The values of internal consistency (Cronbach's alpha) among measures were all >0.90. It was verified that the ASE prototype was appropriate for a step test, provided valid measures of VO2max and could therefore, be used as an ergometer to measure cardiorespiratory fitness. PMID- 25713652 TI - Can programmed or self-selected physical activity affect physical fitness of adolescents? AB - The aim of this study was to verify the effects of programmed and self-selected physical activities on the physical fitness of adolescents. High school adolescents, aged between 15 and 17 years, were divided into two experimental groups: a) a self-selected physical activity group (PAS) with 55 students (aged 15.7 +/- 0.7 years), who performed physical activities with self-selected rhythm at the following sports: basketball, volleyball, handball, futsal and swimming; and b) a physical fitness training group (PFT) with 53 students (aged 16.0 +/- 0.7 years), who performed programmed physical fitness exercises. Both types of activity were developed during 60 min classes. To assess physical fitness the PROESP-BR protocol was used. The statistical analysis was performed by repeated measures ANOVA. The measurements of pre and post-tests showed significantly different values after PFT in: 9 minute running test, medicine ball throw, horizontal jump, abdominal endurance, running speed and flexibility. After PAS differences were detected in abdominal endurance, agility, running speed and flexibility. The intervention with programmed physical activity promoted more changes in the physical abilities; however, in the self-selected program, agility was improved probably because of the practice of sports. Therefore, physical education teachers can use PFT to improve cardiorespiratory fitness and power of lower and upper limbs and PAS to improve agility of high school adolescents. PMID- 25713654 TI - Cardiorespiratory fitness and body composition in postmenopausal women. AB - The object of the study was to analyze the relationship between aerobic fitness and body composition in postmenopausal women. We hypothesized that postmenopausal women that had higher adiposity had lower cardiorespiratory capacity, regardless of the characteristics of menopause. The sample included 208 women (57.57 +/- 6.62 years), whose body composition and the basal metabolic rate were evaluated by octopolar bioimpedance (InBody 720) and the oxygen uptake by the modified Bruce protocol. Most of the sample showed obesity and a high visceral fat area. The visceral fat area and the basal metabolic rate explained 30% of the variation of oxygen uptake, regardless of age, time, nature or hormone therapy. The values of the latter variables were reduced in the presence of high central adiposity ( 6.16 ml/kg/min) and the basal metabolic rate of less than 1238 kcal/day (-0.18 ml/kg/min). The women with oxygen uptake above 30.94 ml/kg/min showed lower values of total and central adiposity when compared with other groups. With an increase of aerobic fitness, there was a growing tendency of the average values of the soft lean mass index, with differences between the groups low-high and moderate-high. These results suggest worsening of the cardiorespiratory condition with an increase of central adiposity and a decrease of the BMR, regardless of age and menopause characteristics. PMID- 25713653 TI - Is long term creatine and glutamine supplementation effective in enhancing physical performance of military police officers? AB - The objective of this study was to analyze the effect of supplementation with creatine and glutamine on physical fitness of military police officers. Therefore, an experimental double blind study was developed, with the final sample composed by 32 men randomly distributed into three groups: a group supplemented with creatine (n=10), glutamine (n=10) and a placebo group (n=12) and evaluated in three distinct moments, in an interval of three months (T1, T2 and T3). The physical training had a weekly frequency of 5 sessions * 90 min, including strength exercises, local muscular resistance, flexibility and both aerobic and anaerobic capacity. After analyzing the effect of time, group and interaction (group * time) for measures that indicated the physical capabilities of the subjects, a significant effect of time for the entire variable was identified (p<0,05). However, these differences were not observed when the univaried intragroups and intergroups analysis was performed (p>0,05). In face of the results it was concluded that supplementation with creatine and glutamine showed no ergogenic effect on physical performance in military police officers. PMID- 25713655 TI - Relationship of different perceived exertion scales in walking or running with self-selected and imposed intensity. AB - The aims of this study were to: (1) compare the Heart Rate (HR) and Rating Perceived Exertion (RPE) in training with self-selected and imposed loads, and (2) associate the OMNI-Walk/Run and Borg scales with self-selected and imposed loads, both on a treadmill. Ten trained men (20.3 +/- 2.0 years, 75.6 +/- 9.8 kg, 175.1 +/- 5.1 cm) participated in a training program with self-selected load (time and speed individually preferred) and another with imposed load (even self selected time and speed 10% higher). The HR and RPE were measured, every minute of training, by the OMNI-Walk/Run and Borg scales. No significant differences were found in the HR and RPE between training sessions. The correlation between the OMNI-Walk/Run and Borg scales showed a moderate association (r = 0.55) in training with self-selected load and a strong association in imposed load (r = 0.79). In this study, self-selected load induced a suboptimal stimulus to elicit favorable organic adaptations. Moreover, high correlation of OMNI Walk/Run and Borg scales with the imposed load showed that the greater the load of training the best were answers of RPE. PMID- 25713656 TI - Gender's Effect on a School-Based Intervention in The Prepubertal Growth Spurt. AB - Children aged 10-11 years pass through a dynamic developmental period marked by rapid changes in body size, shape, and composition, all of which are sexually dimorphic. The purpose of this study was to analyze the effects of gender on a school-based intervention in the prepubertal growth spurt. One hundred twenty five healthy children (58 boys, 67 girls), fifth and sixth grade students from an urban public elementary school in Portugal (10.8 +/- 0.4 years), were randomly assigned into two experimental groups: a strength training group (19 boys, 22 girls), and an endurance training group (21 boys, 24 girls); and a control group (18 boys, 21 girls; no training program). Training program for the two experimental groups was conducted twice a week for 8 weeks. Compared with the values at the beginning of the protocol, both strength and endurance training programs produced significant improvements (p< 0.05) in vertical and horizontal jumps, a 1 kg and 3 kg medicine ball throw, a 20 m sprint and VO2max, for both boys and girls. No significant changes were observed related to gender in training-induced strength (p> 0.05, eta_p^2= 0.16, Power= 0.29) and aerobic (p> 0.05, eta_p^2= 0.05, Power= 0.28) capacity. The results of the present study should be taken into consideration in order to optimize strength training school based programs. PMID- 25713657 TI - Biological Maturation, Body Morphology and Physical Performance in 8-16 year-old obese girls from Montes Claros - MG. AB - Measurements of maturity depend on the biological system considered since differences are often found in performance and body size in subjects of the same chronological age. The objective of this study was to identify associations between biological maturation, body morphology and physical performance in girls aged from 8.0 to 15.9 year-old and to verify the bone age in obese girls and compare it with chronological age. For that purpose 2040 (11.9 +/- 2.3 years) school girls from Montes Claros, participated in this study. Regular anthropometric measures as height and body mass were taken. Triceps, biceps, subscapular, abdominal, suprailiac and calf skinfolds were also registered. Physical performance was assessed trough the test of a standing long jump, handgrip strength and 20 m multistage shuttle run. Maturational status, the average age at menarche and identification of PHV (maturity off set) were determined by means of the retrospective method. Girls with the BMI above the 95th percentile got their bone age evaluated through X-ray of the left hand/wrist, in accordance with the FELS method. It was possible to find an average age at menarche of 11.30 +/- 0.70, while the average age at PHV was 12.17 +/- 0.71 years of age. It was observed that both body composition and physical performance showed a tendency to increase with advancing age. However, when controlling the effect of maturation, despite having higher values in body composition the post-menarche girls group did not show higher levels of physical performance. In all age groups, obese girls showed mean rates of bone age higher than chronologic age (12.25 +/- 2.09 and 14.09 +/- 2.35, respectively, p=0.000). Chronological age should be used with caution when evaluating obese teenagers as it may underestimate biological age. PMID- 25713658 TI - Do 12-week yoga program influence respiratory function of elderly women? AB - Aging produces several respiratory limitations and reduces tolerance to physical efforts, sometimes leading to pulmonary diseases in the elderly. The literature draws attention to the possible benefits of Yoga practice among the elderly, presenting evidence for significant improvements in quality of life. It was hypothesized that yoga practice can improve respiratory function in the elderly. The effects of a yoga program on pulmonary volumes and respiratory muscle strength were verified in 36 elderly women divided into a yoga group [YG] (63.1 +/- 13.3 years of age) and a control group (61.0 +/- 6.9 years of age). Maximal inspiratory and expiratory pressure (MIP and MEP) were assessed by a manovacuometer and tidal volume (VT), vital capacity (VC) and minute ventilation (VE) were measured by a ventilometer. The program comprised 65 min sessions, 3 times/week during 12 weeks. The heart rate and respiratory rate decreased significantly in the YG (76-39 +/- 8-03 vs. 74-61+/-10.26 bpm and 18.61 +/- 3.15 vs. 16.72 +/- 3.12 resp/min, respectively). In the YG, VT and VE increased significantly (0.55 +/- 0.22 vs. 0.64 +/- 0.2 ml and 9.19 +/- 2.39 vs. 10.05 +/- 2.11 ml, respectively), as well as VC (1.48 +/- 0.45 vs. 2.03 +/- 0.72 ml). Improvements were also found in MIP and MEP in the YG (62.17 +/- 14.77 vs. 73.06 +/- 20.16 cmH2O and 80.56 +/- 23.94 vs. 86.39 +/- 20.16 cmH2O, respectively). It was concluded that a 12-week yoga program significantly improves pulmonary function of aged women. PMID- 25713659 TI - Physiological Responses Associated with Nordic-walking training in Systolic Hypertensive Postmenopausal Women. AB - Loss of physical strength and hypertension are among the most pronounced detrimental factors accompanying aging. The aim of this study was to evaluate the influence of a supervised 8-week Nordic-walking training program on systolic blood pressure in systolic-hypertensive postmenopausal women. This study was a randomized control trial on a sample of 24 subjects who did not take any hypertension medications. There was a statistically significant decrease in systolic blood pressure and an increase in lower and upper-body strength in the group following Nordic-walking training. There was a decrease in serum levels of total cholesterol, triglycerides, and low-density cholesterol. The obtained results indicate that an 8-week Nordic-walking program may be efficiently employed for counteracting systolic hypertension through a direct abatement of systolic blood pressure and an increase of maximal aerobic capacity. PMID- 25713660 TI - The Body Mass Index and Waist Circumference as Predictors Of Body Composition in Post CSCI Wheelchair Rugby Players (Preliminary Investigations). AB - The enforced sedentary lifestyle and muscle paresis below the level of injury are associated with adipose tissue accumulation in the trunk. The value of anthropometric indicators of obesity in patients with spinal cord injuries has also been called into question. We hypothesized that the Body Mass Index recommended by the WHO to diagnose obesity in general population has too low sensitivity in case of wheelchair rugby players. The study group comprised 14 wheelchair rugby players, aged 32.6 +/- 5.1 years, who had sustained CSCI (paralysis of lower limbs and upper extremities). The research tool was the Tanita Viscan visceral and trunk fat analyzer AB140 using the abdominal bioelectrical impedance analysis (BIA) to estimate the visceral fat level (Vfat) and trunk fat percentage (Tfat). The AB140 analyzer also allowed the measurement of body composition of those individuals who could not assume an upright position. Our analyses revealed high and very high correlation coefficients between Vfat and WC (r=0.9), WHtR (r=0.7) and Tfat (r=0.9) whereas the correlation between Vfat and the BMI was weak, especially in the subgroup with Vfat < 13.5% (r=0.2). The subgroup with Vfat>13.5 exhibited a moderate-level relationship between the BMI and visceral fat increase. It was concluded that the BMI had a low sensitivity for predicting obesity risk in wheelchair rugby players after CSCI. The sensitivity of WC measurement was higher and thus, it may be stated that it constitutes an objective tool for predicting obesity risk in post CSCI wheelchair rugby players. PMID- 25713661 TI - Influence of different hip joint centre locations on hip and knee joint kinetics and kinematics during the squat. AB - Identification of the hip joint centre (HJC) is important in the biomechanical examination of human movement. However, there is yet to be any published information regarding the influence of different HJC locations on hip and knee joint kinetics during functional tasks. This study aimed to examine the influence of four different HJC techniques on 3-D hip and knee joint kinetics/kinematics during the squat. Hip and knee joint kinetics/kinematics of the squat were obtained from fifteen male participants using an eight camera motion capture system. The 3-D kinetics/kinematics of the squat were quantified using four hip joint centre estimation techniques. Repeated measures ANOVAs were used to compare the discrete parameters as a function of each HJC location. The results show that significant differences in joint angles and moment parameters were evident at both the hip and knee joint in the coronal and transverse planes. These observations indicate that when calculating non-sagittal joint kinetics/kinematics during the squat, researchers should carefully consider their HJC method as it may significantly affect the interpretation of their data. PMID- 25713662 TI - Training effectiveness of the inertial training and measurement system. AB - The purpose of this study was to evaluate the efficacy of inertial training with different external loads using a new original device - the Inertial Training and Measurement System (ITMS). Forty-six physical education male students were tested. The participants were randomly divided into three training groups and a control group (C group). The training groups performed inertial training with three different loads three times weekly for four weeks. The T0 group used only the mass of the ITMS flywheel (19.4 kg), the T5 and T10 groups had an additional 5 and 10 kg on the flywheel, respectively. Each training session included three exercise sets involving the shoulder joint adductors. Before and after training, the maximal torque and power were measured on an isokinetic dynamometer during adduction of the shoulder joint. Simultaneously, the electromyography activity of the pectoralis major muscle was recorded. Results of the study indicate that ITMS training induced a significant increase in maximal muscle torque in the T0, T5, T10 groups (15.5%, 13.0%, and 14.0%, respectively). Moreover, ITMS training caused a significant increase in power in the T0, T5, T10 groups (16.6%, 19.5%, and 14.5%, respectively). The percentage changes in torque and power did not significantly differ between training groups. Electromyography activity of the pectoralis major muscle increased only in the T0 group after four weeks of training. Using the ITMS device in specific workouts allowed for an increase of shoulder joint adductors torque and power in physical education students. PMID- 25713663 TI - Changes in the balance performance of polish recreational skiers after seven days of alpine skiing. AB - Alpine skiing is one of the most popular leisure time winter sporting activities. Skiing imposes high requirements concerning physical fitness, particularly regarding balance abilities. The main objective of this study was to evaluate the changes in balance performance of recreational skiers after a seven-day ski camp. A total of 78 students - 24 women and 54 men - participated in the study. The ski course was held in accordance with the official program of the Polish Ski Federation. The study sample was comprised of 43 beginners and 35 intermediate skiers. All students were tested with the MFT S3-Check, the day before and the day after the ski camp. The test system consisted of an unstable uniaxial platform, with an integrated sensor and corresponding software. Changes in balance performance (sensory and stability index) were evaluated using paired t tests. Additionally, changes in sensory and stability categories, which were based on the norm data, were analyzed. Female and male participants showed significantly better sensory and stability indices after skiing. Considerable changes from weak or very weak to average or good balance categories could be seen after skiing for both sexes. Regarding skiing experience, both beginners and intermediate skiers improved their sensory and stability indices significantly after skiing. Hence, recreational alpine skiing resulted in better balance performance regardless of sex or skiing experience. Skiing as an outdoor activity offers the opportunity to improve balance performance with a positive impact on everyday life activities. PMID- 25713664 TI - Impact of Center-of-Mass Acceleration on the Performance of Ultramarathon Runners. AB - Ultramarathon races are rapidly gaining popularity in several countries, raising interest for the improvement of training programs. The aim of this study was to use a triaxial accelerometer to compare the three-dimensional center-of-mass accelerations of two groups of ultramarathon runners with distinct performances during different running speeds and distances. Ten runners who participated in the 12-h Taipei International Ultramarathon Race underwent laboratory treadmill testing one month later. They were divided into an elite group (EG; n = 5) and a sub-elite group (SG; n = 5). The triaxial center-of-mass acceleration recorded during a level-surface progressive intensity running protocol (3, 6, 8, 9, 10, and 12 km/h; 5 min each) was used for correlation analyses with running distance during the ultramarathon. The EG showed negative correlations between mediolateral (ML) acceleration (r = -0.83 to -0.93, p < 0.05), and between anterior-posterior (AP) acceleration and running distance (r = -0.8953 to 0.9653, p < 0.05), but not for vertical control of the center of mass. This study suggests that runners reduce stride length to minimize mediolateral sway and the effects of braking on the trunk; moreover, cadence must be increased to reduce braking effects and enhance impetus. Consequently, the competition level of ultramarathons can be elevated. PMID- 25713666 TI - Intracyclic velocity variation and arm coordination for different skilled swimmers in the front crawl. AB - The aim of this study was to examine whether the intracyclic velocity variation (IVV) was lower in elite swimmers than in beginner swimmers at various velocities, and whether differences may be related to arm coordination. Seven elite and nine beginner male swimmers swam front crawl at four different swimming velocities (maximal velocity, 75%, 85%, and 95% of maximal swimming velocity). The index of arm coordination (IDC) was calculated as the lag time between the propulsive phases of each arm. IVV was determined from the coefficient of variation of horizontal velocity within one stroke cycle. IVV for elite swimmers was significantly lower (26%) than that for beginner swimmers at all swimming velocities (p<0.01, 7.28 1.25% vs. 9.80 1.70%, respectively). In contrast, the IDC was similar between elite and beginner swimmers. These data suggest that IVV is a strong predictor of the skill level for front crawl, and that elite swimmers have techniques to decrease IVV. However, the IDC does not contribute to IVV differences between elite and beginner swimmers. PMID- 25713667 TI - The effect of climbing ability and slope inclination on vertical foot loading using a novel force sensor instrumentation system. AB - The aim of the study was to assess the effects of climbing ability and slope inclination on vertical loading both in terms the forces involved and physiological responses. Five novice and six intermediate female climbers completed a climbing route at three slope inclinations (85 degrees , 90 degrees , and 98 degrees ). The vertical loading during the climb was assessed by force time integral using a Novel Pedar-X insole and physiological responses via oxygen uptake and heart rate. The novice climbers had a significantly lower (p < 0.05) vertical loading on foot holds and higher oxygen uptake and heart rate compared to intermediate climbers. A significant negative correlation was identified between the force-time integral and oxygen uptake (R = -0.72), and with heart rate (R = -0.64), respectively. The time-force integral decreased across the ascents with increasing slope inclination (p < 0.001). The results indicate that more advanced ability climbers make greater use of foot holds, with associated lowering in physiological response (oxygen uptake and heart rate) across all slope inclinations. PMID- 25713665 TI - Spine buddy(r) supportive pad impact on single-leg static balance and a jogging gait of individuals wearing a military backpack. AB - The Spine Buddy(r) supportive pad was developed to be inserted underneath military backpacks to help disperse the heavy load of the backpack. The purpose of this study was to determine the impact the additional supportive pad had on static balance and a running gait while wearing a military backpack. Forty healthy subjects (age= 27.5 + 5.6 yrs, body height= 1.78 + 0.06 m, body mass= 86.5 + 14.0 kg: mean + SD) participated in a static single-leg balance test on a force plate with each lower limb while wearing a 15.9 kg military backpack for 30 s. Following this, participants were randomized to one of two interventions: 1) Intervention, which wore the Spine Buddy(r) supportive pad underneath their backpack or 2) Control, with no additional supportive pad. Post-intervention measurements of static single-leg balance were then recorded. Afterwards, a similar pre vs post testing schedule and randomization scheme was used to test the impact of the supportive pad on a 5 mph jogging gait using Vicon(r) cameras. Within-group data were analyzed with a 2-way repeated measures ANOVA. Statistically significant differences were not seen between the control and experimental group for balance and gait variables. Preliminarily, this suggests that the Spine Buddy(r) supportive pad causes no deleterious effect on static balance and a jogging gait in 18-45 year-old asymptomatic individuals. PMID- 25713668 TI - Effect of Selective Muscle Training Using Visual EMG Biofeedback on Infraspinatus and Posterior Deltoid. AB - We investigated the effects of visual electromyography (EMG) biofeedback during side-lying shoulder external rotation exercise on the EMG amplitude for the posterior deltoid, infraspinatus, and infraspinatus/posterior deltoid EMG activity ratio. Thirty-one asymptomatic subjects were included. Subjects performed side-lying shoulder external rotation exercise with and without visual EMG biofeedback. Surface EMG was used to collect data from the posterior deltoid and infraspinatus muscles. The visual EMG biofeedback applied the pre-established threshold to prevent excessive posterior deltoid muscle contraction. A paired t test was used to determine the significance of the measurements between without vs. with visual EMG biofeedback. Posterior deltoid activity significantly decreased while infraspinatus activity and the infraspinatus/posterior activity ratio significantly increased during side-lying shoulder external rotation exercise with visual EMG biofeedback. This suggests that using visual EMG biofeedback during shoulder external rotation exercise is a clinically effective training method for reducing posterior deltoid activity and increasing infraspinatus activity. PMID- 25713669 TI - Prevalence of stress urinary incontinence in elite female endurance athletes. AB - The goal of the study was to assess the prevalence of stress urinary incontinence in a group of elite female endurance athletes, as professional sport is one of the risk factors for stress urinary incontinence. SUI rates in the groups of female cross-country skiers and runners were compared to determine whether the training weather conditions like temperature and humidity influenced the prevalence of urinary incontinence. An anonymous questionnaire was distributed among 112 elite female athletes ie., 57 cross-country skiers and 55 runners. We used a short form of the Urogenital Distress Inventory (UDI-6) to assess the presence of SUI symptoms and the level of urogenital distress. Only women who had been practicing sport professionally for at least 3 years, on an international and national level, were included in the research. The study group consisted of 76% nulliparous and 24% parous women. 45.54% of all participants reported leakage of urine associated with sneezing or coughing which indicates stress urinary incontinence. 29.46% were not bothered by the urogenital distress symptoms. 42.86% of the participants were slightly bothered by the symptoms, 18.75% were moderately bothered, 8.04% were significantly bothered and 0.89% were heavily bothered. The absence of statistically significant differences between both groups seems to indicate that training weather conditions did not influence the prevalence of SUI in elite female endurance athletes. PMID- 25713670 TI - The Effects of Sprint Interval vs. Continuous Endurance Training on Physiological And Metabolic Adaptations in Young Healthy Adults. AB - The purpose of this study was to compare the effects of sprint interval training (SIT) and continuous endurance training (CET) on selected anthropometric, aerobic, and anaerobic performance indices as well as the blood lipid profile, inflammatory and muscle damage markers in healthy young males. Fifteen recreationally active male volunteers (age: 21.7 +/-2.2 years, body mass: 83.0 +/ 8.0 kg, body height: 1.82 +/-0.05 m) were divided into two groups according to their initial VO2max levels. Training programs were conducted 3 times per week for 7 weeks. The SIT program consisted of 4-6 Wingate anaerobic sprints with a 4.5 min recovery, while CET consisted of 30-50 min cycling at 60% VO2max. Biochemical, anthropometric and fitness assessments were performed both pre and post-intervention. Significant improvements in VO2max, anaerobic power and capacity, and VO2 utilization during the submaximal workout and significant decreases in body fat and in waist circumference after the intervention occurred in both SIT and CET groups. Significantly greater gross efficiency was measured in the CET group. No differences in the lipid profile or serum levels of inflammatory, myocardial and skeletal muscle damage markers were observed after the training period. The study results agree with the effectiveness of a 30 s all out training program with a reduced time commitment for anthropometric, aerobic and anaerobic adaptation and eliminate doubts about its safety as a model. PMID- 25713671 TI - Acute endocrine responses to different strength exercise order in men. AB - This study compared the effects of order of muscle groups' exercised (larger to smaller muscles vs. smaller to larger muscles) on the acute levels of total testosterone, free testosterone and cortisol during resistance training (RT) sessions. Healthy male participants (n=8; age: 28.8 +/- 6.4 years; body mass: 87.0 +/- 10.6 kg; body height: 181.0 +/- 0.7 cm; BMI: 26.5 +/- 4.1) were randomly separated into two experimental groups. The first group (LG-SM) performed an RT session (3 sets of 10 repetitions and a 2 min rest period) of the exercises in following order: bench press (BP), lat pulldown (LP), barbell shoulder press (BSP), triceps pushdown (TP) and barbell cut (BC). The second group (SM-LG) performed an RT session in following order: BC, TP, BSP, LA, BP. Blood was collected at the end of the last repetition of each session. Control samples of blood were taken after 30 min of rest. Significant differences were observed in the concentrations of total testosterone (p < 0.05), free testosterone (p < 0.0001) and cortisol (p < 0.0001) after both RT sessions in comparison to rest. However, when comparing LG-SM and SM-LG, no significant differences were found. The results suggest that, while RT sessions induce an acute change in the levels of testosterone and cortisol, this response is independent of the order of exercising muscle groups. PMID- 25713672 TI - Reference values of maximal oxygen uptake for polish rowers. AB - The aim of this study was to characterize changes in maximal oxygen uptake over several years and to elaborate current reference values of this index based on determinations carried out in large and representative groups of top Polish rowers. For this study 81 female and 159 male rowers from the sub-junior to senior categories were recruited from the Polish National Team and its direct backup. All the subjects performed an incremental exercise test on a rowing ergometer. During the test maximal oxygen uptake was measured with the BxB method. The calculated reference values for elite Polish junior and U23 rowers allowed to evaluate the athletes' fitness level against the respective reference group and may aid the coach in controlling the training process. Mean values of VO2max achieved by members of the top Polish rowing crews who over the last five years competed in the Olympic Games or World Championships were also presented. The results of the research on the "trainability" of the maximal oxygen uptake may lead to a conclusion that the growth rate of the index is larger in case of high-level athletes and that the index (in absolute values) increases significantly between the age of 19-22 years (U23 category). PMID- 25713673 TI - Changes in energy cost and total external work of muscles in elite race walkers walking at different speeds. AB - The aim of the study was to assess energy cost and total external work (total energy) depending on the speed of race walking. Another objective was to determine the contribution of external work to total energy cost of walking at technical, threshold and racing speed in elite competitive race walkers. The study involved 12 competitive race walkers aged 24.9 4.10 years with 6 to 20 years of experience, who achieved a national or international sports level. Their aerobic endurance was determined by means of a direct method involving an incremental exercise test on the treadmill. The participants performed three tests walking each time with one of the three speeds according to the same protocol: an 8-minute walk with at steady speed was followed by a recovery phase until the oxygen debt was repaid. To measure exercise energy cost, an indirect method based on the volume of oxygen uptake was employed. The gait of the participants was recorded using the 3D Vicon opto-electronic motion capture system. Values of changes in potential energy and total kinetic energy in a gate cycle were determined based on vertical displacements of the centre of mass. Changes in mechanical energy amounted to the value of total external work of muscles needed to accelerate and lift the centre of mass during a normalised gait cycle. The values of average energy cost and of total external work standardised to body mass and distance covered calculated for technical speed, threshold and racing speeds turned out to be statistically significant (p 0.001). The total energy cost ranged from 51.2 kJ.m-1 during walking at technical speed to 78.3 kJ.m-1 during walking at a racing speed. Regardless of the type of speed, the total external work of muscles accounted for around 25% of total energy cost in race walking. Total external work mainly increased because of changes in the resultant kinetic energy of the centre of mass movement. PMID- 25713674 TI - Questioning the Resistance/Aerobic Training Dichotomy: A commentary on physiological adaptations determined by effort rather than exercise modality. AB - This paper discusses and challenges the current opinion that exercise adaptation is generally defined by modality; resistance exercise (RE), or aerobic exercise (AE). In presenting a strong body of recent research which demonstrably challenges these perceptions we suggest alternate hypotheses towards physiological adaptation which is hinged more upon the effort than the exercise modality. Practical implications of this interpretation of exercise adaptation might effect change in exercise adherence since existing barriers to exercise of time, costs, specialized equipment, etc. become nullified. In presenting the evidence herein we suggest that lay persons wishing to attain the health and fitness (including strength and muscle hypertrophy) benefits of exercise can choose from a wide range of potential exercise modalities so long as the effort is high. Future research should consider this hypothesis by directly comparing RE and AE for acute responses and chronic adaptations. PMID- 25713675 TI - Analysis of speed performance in soccer by a playing position and a sports level using a laser system. AB - The purpose of this study was to determine the kinematic variables that identify the quality of velocity in soccer players at different competitive levels and playing positions. This study had two independent variables: 1) a competitive level (competitive and non-competitive players); and 2) a playing position, with four levels (central defenders, wide defenders/midfielders, central midfielders and forwards). Forty-two soccer players took part in a 30 m sprint-test, which was measured using a laser sensor-type 1 (LDM301-Jenoptik) at 2000 Hz. Absolute and relative times, average velocities and absolute and relative maximum velocities over 10 m sections were analyzed at 200 Hz with BioLaserSport((r)). There were no significant differences in average velocity between competitive and non-competitive players; however, the former reached a greater maximum velocity in the 10-20 m section. Average velocity in the 0-10 m section identified specificity among playing positions in competitive players. The forwards were the fastest followed by the central midfielders, the wide defenders/midfielders and the central defenders. No differences were found among the non-competitive players. Average velocity over the 0-10 meter section may be an important indicator when assigning a playing position for competitive players. These results support the use of more accurate systems, such as a laser system, to identify soccer players' speed qualities (including maximum velocity) during short sprints. PMID- 25713676 TI - Comparison of achilles tendon loading between male and female recreational runners. AB - Recreational running is an activity with multiple reported health benefits for both sexes, however, chronic injuries caused by excessive and/or repetitive loading of the Achilles tendon are common. Males have been identified as being at an increased risk of suffering an injury to the Achilles tendon and as such, knowledge of differences in loading between the sexes may provide further information to better understand why this is the case. The aim of the current investigation was to determine whether gender differences in the Achilles tendon load exist in recreational runners. Fifteen male (age 26.74 +/- 5.52 years, body height 1.80 +/- 0.11 m and body mass 74.22 +/- 7.27 kg) and fifteen female (age 25.13 +/- 6.39 years, body height 1.68 +/- 0.12 m and body mass 67.12 +/- 9.11 kg) recreational runners volunteered to take part in the current investigation. Participants completed 10 trials running at 4.0 m.s(-1) +/-5% striking a force platform (1000 Hz) with their right foot. Ankle joint kinematics were synchronously recorded (250 Hz) using an optoelectric motion capture system. Ankle joint kinetics were computed using Newton-Euler inverse-dynamics. Net external ankle joint moments were then calculated. To estimate Achilles tendon kinetics the plantarflexion moment calculated was divided by an estimated Achilles tendon moment arm of 0.05 m. Differences in Achilles tendon kinetics were examined using independent sample t-tests (p<0.05). The results indicate that males were associated with significantly (p<0.05) greater Achilles tendon loads than females. The findings from this study support the notion that male recreational runners may be at greater risk of Achilles tendon pathology. PMID- 25713677 TI - Predicting Power Output of Upper Body using the OMNI-RES Scale. AB - The main aim of this study was to determine the optimal training zone for maximum power output. This was to be achieved through estimating mean bar velocity of the concentric phase of a bench press using a prediction equation. The values for the prediction equation would be obtained using OMNI-RES scale values of different loads of the bench press exercise. Sixty males (age 23.61 2.81 year; body height 176.29 6.73 cm; body mass 73.28 4.75 kg) voluntarily participated in the study and were tested using an incremental protocol on a Smith machine to determine one repetition maximum (1RM) in the bench press exercise. A linear regression analysis produced a strong correlation (r = -0.94) between rating of perceived exertion (RPE) and mean bar velocity (Velmean). The Pearson correlation analysis between real power output (PotReal) and estimated power (PotEst) showed a strong correlation coefficient of r = 0.77, significant at a level of p = 0.01. Therefore, the OMNI-RES scale can be used to predict Velmean in the bench press exercise to control the intensity of the exercise. The positive relationship between PotReal and PotEst allowed for the identification of a maximum power training zone. PMID- 25713678 TI - Strength training prior to endurance exercise: impact on the neuromuscular system, endurance performance and cardiorespiratory responses. AB - This study aimed to investigate the acute effects of two strength-training protocols on the neuromuscular and cardiorespiratory responses during endurance exercise. Thirteen young males (23.2 +/- 1.6 years old) participated in this study. The hypertrophic strength-training protocol was composed of 6 sets of 8 squats at 75% of maximal dynamic strength. The plyometric strength-training protocol was composed of 6 sets of 8 jumps performed with the body weight as the workload. Endurance exercise was performed on a cycle ergometer at a power corresponding to the second ventilatory threshold until exhaustion. Before and after each protocol, a maximal voluntary contraction was performed, and the rate of force development and electromyographic parameters were assessed. After the hypertrophic strength-training and plyometric strength-training protocol, significant decreases were observed in the maximal voluntary contraction and rate of force development, whereas no changes were observed in the electromyographic parameters. Oxygen uptake and a heart rate during endurance exercise were not significantly different among the protocols. However, the time-to-exhaustion was significantly higher during endurance exercise alone than when performed after hypertrophic strength-training or plyometric strength-training (p <0.05). These results suggest that endurance performance may be impaired when preceded by strength-training, with no oxygen uptake or heart rate changes during the exercise. PMID- 25713679 TI - Effectiveness of the call in beach volleyball attacking play. AB - In beach volleyball the setter has the opportunity to give her or his hitter a "call". The call intends that the setter suggests to her or his partner where to place the attack in the opponent's court. The effectiveness of a call is still unknown. We investigated the women's and men's Swiss National Beach Volleyball Championships in 2011 and analyzed 2185 attacks. We found large differences between female and male players. While men called in only 38.4% of attacks, women used calls in 85.5% of attacks. If the male players followed a given call, 63% of the attacks were successful. The success rate of attacks without any call was 55.8% and 47.6% when the call was ignored. These differences were not significant (chi(2)(2) = 4.55, p = 0.103). In women's beach volleyball, the rate of successful attacks was 61.5% when a call was followed, 35% for attacks without a call, and 42.6% when a call was ignored. The differences were highly significant (chi(2)(2) = 23.42, p < 0.0005). Taking into account the findings of the present study, we suggested that the call was effective in women's beach volleyball, while its effect in men's game was unclear. Considering the quality of calls we indicate that there is a significant potential to increase the effectiveness of a call. PMID- 25713680 TI - Quantification and analysis of offensive situations in different formats of sided games in soccer. AB - There has been a lot of research that enabled soccer to improve: its technique, tactics and strategy through analysis and training. Nevertheless, players' need to interact with each other turns any defending or attacking situation into complex solutions with a wide range of variables to be considered, in which the player is never isolated and must make the move that has the most positive impact on play. Fifty-four sided games played in three different formats (5v5, 7v7 and 9v9) and with two age groups (U9 and U14) were filmed at three soccer clubs in Spain in order to identify the most relevant attacking moves, from a technical and tactical perspective. This study used the observational method; it is descriptive and is applied through well-prepared systematic quantitative observation in a natural environment. A key part of the method involved viewing the match recordings and logging moves that had been categorised beforehand. Cohen's Kappa analysis showed that the results for the most representative variables presented a substantial degree of concordance (0.61-0.80). The results show that there were significant variations depending on the game format, and the following study will present a description and analysis of the aspects that had considerable influence on attacking moves in different formats of sided games (5v5, 7v7 and 9v9). The study also presents various practical applications for the area of training and analysing both youth and professional soccer. PMID- 25713682 TI - Game intensity analysis of elite adolescent ice hockey players. AB - The purpose of this study was to determine ice-hockey players' playing intensity based on their heart rates (HRs) recorded during a game and on the outcomes of an incremental maximum oxygen uptake test. Twenty ice-hockey players, members of the Polish junior national team (U18), performed an incremental test to assess their maximal oxygen uptake (VO2max) in the two week's period preceding 5 games they played at the World Championships. Players' HRs at the first and second ventilatory thresholds obtained during the test were utilized to determine intensity zones (low, moderate, and high) that were subsequently used to classify HR values recorded during each of the games. For individual intensity zones, the following HRs expressed as mean values and as percentages of the maximal heart rate (HRmax) were obtained: forwards 148-158 b.min(-1) (79.5-84.8% HRmax), 159 178 b.min(-1) (85.4-95.6% HRmax), 179-186 b.min(-1) (96.1-100.0% HRmax); defensemen 149-153 b.min(-1) (80.0-82.1% HRmax), 154-175 b.min(-1) (82.6-94.0% HRmax), 176-186 b.min(-1) (94.5-100.0% HRmax). The amount of time the forwards and defensemen spent in the three intensity zones expressed as percentages of the total time of the game were: 54.91 vs. 55.62% (low), 26.40 vs. 22.38% (moderate) and 18.68 vs. 22.00% (high). The forwards spent more time in the low intensity zone than the defensemen, however, the difference was not statistically significant. The results of the study indicate that using aerobic and anaerobic metabolism variables to determine intensity zones can significantly improve the reliability of evaluation of the physiological demands of the game, and can be a useful tool for coaches in managing the training process. PMID- 25713681 TI - Influence of exercise order on electromyographic activity during upper body resistance training. AB - The purpose of this study was to investigate the effects of exercise order on electromyographic activity in different muscle groups among youth men with experience in strength training. Three sets of 8 RM were performed of each exercise in two sequences order: (a) sequence A: bench press, chest fly, shoulder press, shoulder abduction, close grip bench press and lying triceps extension; (b) sequence B: the opposite order. The electromyographic activity was analyzed in the sternocostal head of the pectoralis major, anterior deltoid, and long head triceps brachii, normalized for maximal voluntary isometric contraction. The muscles activity of the sternocostal head of the pectoralis major, anterior deltoid, and long head triceps brachii showed significant interaction between sequence and exercise. The sternocostal head of the pectoralis major showed considerably higher activity in sequence A (100.13 +/- 13.56%) than sequence B (81.47 +/- 13.09%) for the chest fly. The anterior deltoid showed significantly higher electromyographic activity in sequence B (86.81 +/- 40.43%) than sequence A (66.15 +/- 22.02%) for the chest fly, whereas for the lying triceps extension, the electromyographic activity was significantly higher in sequence A (53.89 +/- 27.09%) than sequence B (34.32 +/- 23.70%). For the long head triceps brachii, only the shoulder press showed differences between sequences (A = 52.43 +/- 14.64 vs. B = 38.53 +/- 16.26). The present study showed that the exercise order could modify the training results even though there was no alteration in volume and intensity of the exercise. These changes may result in different training adaptations. PMID- 25713683 TI - Anthropometric, physical, and age differences by the player position and the performance level in volleyball. AB - The purpose of this paper was to study the ranges in height, weight, age, spike reach, and block reach of volleyball players in relation to the player position and the level of their respective teams in peak performance. The analysed sample included 1454 male and 1452 female players who participated in the volleyball competitions of the Olympic Games and World Championships in the 2000-2012 period. A descriptive, correlational, and longitudinal design was used. The variables studied were: the player position, body height, weight, body mass index, spike reach, block reach, age, and team level. The results show differences between body height, spike and block reaches, and the age of the players by their position. These differences are related to the needs of the different positions with regard to the actions they execute. Middle-blockers, outside-hitters, and opposites have the characteristics that are most suitable for blocking and spiking, and the setters and liberos appear to have characteristics conducive to setting and receiving as well as digging, respectively. The differences found in the studied variables with regard to the playing position are related to players' needs regarding the actions they perform. Player's age was a variable that differentiated first teams at this level of competition for males, and physical capacities (body height, weight, spike reach, and block reach) were variables that differentiated first teams at this level of competition for females. PMID- 25713684 TI - The Properties of Water and their Applications for Training. AB - The biological effects of immersion in water, which are related to the fundamental principles of hydrodynamics, may be beneficial in certain training contexts. The effects and physical properties of water, such as density, hydrostatic pressure and buoyancy are highly useful resources for training, when used as a counterbalance to gravity, resistance, a compressor and a thermal conductor. Not only does the aquatic medium enable a wider range of activities to be used in a context of low joint impact, but it also constitutes a useful tool in relation to sports rehabilitation, since it allows the athlete to return to training earlier or to continue with high-intensity exercise while ensuring both low joint impact and greater comfort for the individual concerned. Moreover, this medium enables the stimulation of metabolic and neuromuscular systems, followed by their corresponding physiological adaptations allowing both to maintain and improve athletic performance. Hydrotherapy can also play a beneficial role in an athlete's recovery, helping to prevent as well as treat muscle damage and soreness following exercise. PMID- 25713685 TI - Neuromuscular responses to simulated brazilian jiu-jitsu fights. AB - The aim of this study was to investigate the neuromuscular performance responses following successive Brazilian Jiu-Jitsu (BJJ) fights. Twenty-three BJJ athletes (age: 26.3 +/- 6.3 years; body mass: 79.4 +/- 9.7 kg; body height: 1.80 +/- 0.1 m) undertook 3 simulated BJJ fights (10 min duration each separated by 15 min of rest). Neuromuscular performance was measured by the bench press throw (BPT) and vertical counter movement jump (VCMJ) tests, assessed before the 1st fight (Pre) and after the last one (Post). Blood lactate (LA) was measured at Pre, 1 min Post, and 15 min Post fights. Paired t-tests were employed in order to compare the BPT and VCMJ results. One-way ANOVA with Bonferroni post hoc tests were utilized to compare LA responses. The results revealed a significant (p < 0.05) increase in VCMJ performance (40.8 +/- 5.5 cm Pre vs. 42.0 +/- 5.8 cm Post), but no significant changes in the BPT (814 +/- 167 W Pre vs. 835 +/- 213 W Post) were observed. LA concentration increased significantly (p < 0.05) at Post, both in the 1st min (10.4 +/- 2.7 mmol L-1) and the 15th min (6.4 +/- 2.5 mmol L-1) of recovery. We concluded that successive simulated BJJ fights demanded considerable anaerobic contribution of ATP supply, reinforcing the high-intensity intermittent nature of the sport. Nevertheless, no negative impact on acute neuromuscular performance (power) was observed. PMID- 25713686 TI - Review of Platonov's "Sports Training Periodization. General Theory and its Practical Application" - Kiev: Olympic Literature, 2013. PMID- 25713688 TI - Phaseguide-assisted blood separation microfluidic device for point-of-care applications. AB - We propose a blood separation microfluidic device suitable for point-of-care (POC) applications. By utilizing the high gas permeability of polydimethylsiloxane (PDMS) and phaseguide structures, a simple blood separation device is presented. The device consists of two main parts. A separation chamber with the phaseguide structures, where a sample inlet, a tape-sealed outlet, and a dead-end ring channel are connected, and pneumatic chambers, in which manually operating syringes are plugged. The separation chamber and pneumatic chambers are isolated by a thin PDMS wall. By manually pulling out the plunger of the syringe, a negative pressure is instantaneously generated inside the pneumatic chamber. Due to the gas diffusion from the separation chamber to the neighboring pneumatic chamber through the thin permeable PDMS wall, low pressure can be generated, and then the whole blood at the sample inlets starts to be drawn into the separation chamber and separated through the phaseguide structures. Reversely, after removing the tape at the outlet and manually pushing in the plunger of the syringe, a positive pressure will be created which will cause the air to diffuse back into the ring channel, and therefore allow the separated plasma to be recovered at the outlet on demand. In this paper, we focused on the study of the plasma separation and associated design parameters, such as the PDMS wall thickness, the air permeable overlap area between the separation and pneumatic chambers, and the geometry of the phaseguides. The device required only 2 MUl of whole blood but yielding approximately 0.38 MUl of separated plasma within 12 min. Without any of the requirements of sophisticated equipment or dilution techniques, we can not only separate the plasma from the whole blood for on-chip analysis but also can push out only the separated plasma to the outlet for off chip analysis. PMID- 25713687 TI - Two-dimensional spatial manipulation of microparticles in continuous flows in acoustofluidic systems. AB - We report a modeling and experimental study of techniques to acoustically focus particles flowing through a microfluidic channel. Our theoretical model differs from prior works in that we solve an approximate 2-D wave transmission model that accounts for wave propagation in both the solid and fluid phases. Our simulations indicate that particles can be effectively focused at driving frequencies as high as 10% off of the resonant condition. This conclusion is supported by experiments on the acoustic focusing of particles in nearly square microchannels, which are studied for different flow rates, driving frequencies and placements of the lead zirconate titanate transducer, either underneath the microchannel or underneath a parallel trough. The relative acoustic potential energy and the resultant velocity fields for particles with positive acoustic contrast coefficients are estimated in the 2-D limit. Confocal microscopy was used to observe the spatial distribution of the flowing microparticles in three dimensions. Through these studies, we show that a single driving frequency from a single piezoelectric actuator can induce the 2-D concentration of particles in a microchannel with a nearly square cross section, and we correlate these behaviors with theoretical predictions. We also show that it is possible to control the extent of focusing of the microparticles, and that it is possible to decouple the focusing of microparticles in the vertical direction from the lateral direction in rectangular channels with anisotropic cross sections. This study provides guidelines to design and operate microchip-based acoustofluidic devices for precise control over the spatial arrangement of microparticles for applications such as flow cytometry and cellular sorting. PMID- 25713689 TI - One-heater flow-through polymerase chain reaction device by heat pipes cooling. AB - This study describes a novel microfluidic reactor capable of flow-through polymerase chain reactions (PCR). For one-heater PCR devices in previous studies, comprehensive simulations and experiments for the chip geometry and the heater arrangement were usually needed before the fabrication of the device. In order to improve the flexibility of the one-heater PCR device, two heat pipes with one fan are used to create the requisite temperature regions in our device. With the integration of one heater onto the chip, the high temperature required for the denaturation stage can be generated at the chip center. By arranging the heat pipes on the opposite sides of the chip, the low temperature needed for the annealing stage is easy to regulate. Numerical calculations and thermal measurements have shown that the temperature distribution in the five-temperature region PCR chip would be suitable for DNA amplification. In order to ensure temperature uniformity at specific reaction regions, the Re of the sample flow is less than 1. When the microchannel width increases and then decreases gradually between the denaturation and annealing regions, the extension region located in the enlarged part of the channel can be observed numerically and experimentally. From the simulations, the residence time at the extension region with the enlarged channel is 4.25 times longer than that without an enlarged channel at a flow rate of 2 MUl/min. The treated surfaces of the flow-through microchannel are characterized using the water contact angle, while the effects of the hydrophilicity of the treated polydimethylsiloxane (PDMS) microchannels on PCR efficiency are determined using gel electrophoresis. By increasing the hydrophilicity of the channel surface after immersing the PDMS substrates into Tween 20 (20%) or BSA (1 mg/ml) solutions, efficient amplifications of DNA segments were proved to occur in our chip device. To our knowledge, our group is the first to introduce heat pipes into the cooling module that has been designed for a PCR device. The unique architecture utilized in this flow-through PCR device is well applied to a low-cost PCR system. PMID- 25713690 TI - Viscoelastic effects on electrokinetic particle focusing in a constricted microchannel. AB - Focusing suspended particles in a fluid into a single file is often necessary prior to continuous-flow detection, analysis, and separation. Electrokinetic particle focusing has been demonstrated in constricted microchannels by the use of the constriction-induced dielectrophoresis. However, previous studies on this subject have been limited to Newtonian fluids only. We report in this paper an experimental investigation of the viscoelastic effects on electrokinetic particle focusing in non-Newtonian polyethylene oxide solutions through a constricted microchannel. The width of the focused particle stream is found NOT to decrease with the increase in DC electric field, which is different from that in Newtonian fluids. Moreover, particle aggregations are observed at relatively high electric fields to first form inside the constriction. They can then either move forward and exit the constriction in an explosive mode or roll back to the constriction entrance for further accumulations. These unexpected phenomena are distinct from the findings in our earlier paper [Lu et al., Biomicrofluidics 8, 021802 (2014)], where particles are observed to oscillate inside the constriction and not to pass through until a chain of sufficient length is formed. They are speculated to be a consequence of the fluid viscoelasticity effects. PMID- 25713691 TI - Osteocyte culture in microfluidic devices. AB - This paper presents a microfluidic device (poly-dimethylsiloxane micro channels bonded with glass slides) enabling culture of MLO-Y4 osteocyte like cells. In this study, on-chip collagen coating, cell seeding and culture, as well as staining were demonstrated in a tubing-free manner where gravity was used as the driving force for liquid transportation. MLO-Y4 cells were cultured in microfluidic channels with and without collagen coating where cellular images in a time sequence were taken and analyzed, confirming the positive effect of collagen coating on phenotype maintaining of MLO-Y4 cells. The proliferating cell nuclear antigen based proliferation assay was used to study cellular proliferation, revealing a higher proliferation rate of MLO-Y4 cells seeded in microfluidic channels without collagen coating compared to the substrates coated with collagen. Furthermore, the effects of channel dimensions (variations in width and height) on the viability of MLO-Y4 cells were explored based on the Calcein-AM and propidium iodide based live/dead assay and the Hoechst 33258 based apoptosis assay, locating the correlation between the decrease in channel width or height and the decrease in cell viability. As a platform technology, this microfluidic device may function as a new cell culture model enabling studies of osteocytes. PMID- 25713692 TI - Co-ordinated detection of microparticles using tunable resistive pulse sensing and fluorescence spectroscopy. AB - Tunable resistive pulse sensing (TRPS) has emerged as a useful tool for particle by-particle detection and analysis of microparticles and nanoparticles as they pass through a pore in a thin stretchable membrane. We have adapted a TRPS device in order to conduct simultaneous optical measurements of particles passing through the pore. High-resolution fluorescence emission spectra have been recorded for individual 1.9 MUm diameter particles at a sampling period of 4.3 ms. These spectra are time-correlated with RPS pulses in a current trace sampled every 20 MUs. The flow rate through the pore, controlled by altering the hydrostatic pressure, determines the rate of particle detection. At pressures below 1 kPa, more than 90% of fluorescence and RPS events were matching. At higher pressures, some peaks were missed by the fluorescence technique due to the difference in sampling rates. This technique enhances the particle-by-particle specificity of conventional RPS measurements and could be useful for a range of particle characterization and bioanalysis applications. PMID- 25713693 TI - Colored polydimethylsiloxane micropillar arrays for high throughput measurements of forces applied by genetic model organisms. AB - Measuring forces applied by multi-cellular organisms is valuable in investigating biomechanics of their locomotion. Several technologies have been developed to measure such forces, for example, strain gauges, micro-machined sensors, and calibrated cantilevers. We introduce an innovative combination of techniques as a high throughput screening tool to assess forces applied by multiple genetic model organisms. First, we fabricated colored Polydimethylsiloxane (PDMS) micropillars where the color enhances contrast making it easier to detect and track pillar displacement driven by the organism. Second, we developed a semi-automated graphical user interface to analyze the images for pillar displacement, thus reducing the analysis time for each animal to minutes. The addition of color reduced the Young's modulus of PDMS. Therefore, the dye-PDMS composite was characterized using Yeoh's hyperelastic model and the pillars were calibrated using a silicon based force sensor. We used our device to measure forces exerted by wild type and mutant Caenorhabditis elegans moving on an agarose surface. Wild type C. elegans exert an average force of ~1 MUN on an individual pillar and a total average force of ~7.68 MUN. We show that the middle of C. elegans exerts more force than its extremities. We find that C. elegans mutants with defective body wall muscles apply significantly lower force on individual pillars, while mutants defective in sensing externally applied mechanical forces still apply the same average force per pillar compared to wild type animals. Average forces applied per pillar are independent of the length, diameter, or cuticle stiffness of the animal. We also used the device to measure, for the first time, forces applied by Drosophila melanogaster larvae. Peristaltic waves occurred at 0.4 Hz applying an average force of ~1.58 MUN on a single pillar. Our colored microfluidic device along with its displacement tracking software allows us to measure forces applied by multiple model organisms that crawl or slither to travel through their environment. PMID- 25713694 TI - Rapid inertial solution exchange for enrichment and flow cytometric detection of microvesicles. AB - Exosomes, nanosized membrane-bound vesicles released by cells, play roles in cell signaling, immunology, virology, and oncology. Their study, however, has been hampered by difficulty in isolation and quantification due to their size and the complexity of biological samples. Conventional approaches to improved isolation require specialized equipment and extensive sample preparation time. Therefore, isolation and detection methods of exosomes will benefit biological and clinical studies. Here, we report a microfluidic platform for inline exosome isolation and fluorescent detection using inertial manipulation of antibody-coated exosome capture beads from biological fluids. PMID- 25713695 TI - A novel alternating current multiple array electrothermal micropump for lab-on-a chip applications. AB - The AC electrothermal technique is very promising for biofluid micropumping, due to its ability to pump high conductivity fluids. However, compared to electroosmotic micropumps, a lack of high fluid flow is a disadvantage. In this paper, a novel AC multiple array electrothermal (MAET) micropump, utilizing multiple microelectrode arrays placed on the side-walls of the fluidic channel of the micropump, is introduced. Asymmetric coplanar microelectrodes are placed on all sides of the microfluidic channel, and are actuated in different phases: one, two opposing, two adjacent, three, or all sides at the same time. Micropumps with different combinations of side electrodes and cross sections are numerically investigated in this paper. The effect of the governing parameters with respect to thermal, fluidic, and electrical properties are studied and discussed. To verify the simulations, the AC MAET concept was then fabricated and experimentally tested. The resulted fluid flow achieved by the experiments showed good agreement with the corresponding simulations. The number of side electrode arrays and the actuation patterns were also found to greatly influence the micropump performance. This study shows that the new multiple array electrothermal micropump design can be used in a wide range of applications such as drug delivery and lab-on-a-chip, where high flow rate and high precision micropumping devices for high conductivity fluids are needed. PMID- 25713696 TI - On-chip actuation transmitter for enhancing the dynamic response of cell manipulation using a macro-scale pump. AB - An on-chip actuation transmitter for achieving fast and accurate cell manipulation is proposed. Instead of manipulating cell position by a directly connected macro-scale pump, polydimethylsiloxane deformation is used as a medium to transmit the actuation generated from the pump to control the cell position. This actuation transmitter has three main advantages. First, the dynamic response of cell manipulation is faster than the conventional method with direct flow control based on both the theoretical modeling and experimental results. The cell can be manipulated in a simple harmonic motion up to 130 Hz by the proposed actuation transmitter as opposed to 90 Hz by direct flow control. Second, there is no need to fill the syringe pump with the sample solution because the actuation transmitter physically separates the fluids between the pump and the cell flow, and consequently, only a very small quantity of the sample is required (<1 MUl). In addition, such fluid separation makes it easy to keep the experiment platform sterilized because there is no direct fluid exchange between the sample and fluid inside the pump. Third, the fabrication process is simple because of the single-layer design, making it convenient to implement the actuation transmitter in different microfluidic applications. The proposed actuation transmitter is implemented in a lab-on-a-chip system for red blood cell (RBC) evaluation, where the extensibility of red blood cells is evaluated by manipulating the cells through a constriction channel at a constant velocity. The application shows a successful example of implementing the proposed transmitter. PMID- 25713697 TI - Case Report: Paroxysmal nocturnal hemoglobinuria in a woman heterozygous for G6PD A-. AB - We describe a case of paroxysmal nocturnal hemoglobinuria (PNH) in a woman who is heterozygous for the glucose-6-phosphate dehydrogenase A- ( G6PDA-) allele. PNH is associated with one or more clones of cells that lack complement inhibition due to loss of function somatic mutations in the PIGA gene. PIGA encodes the enzyme phosphatidylinositol glycan anchor biosynthesis, class A, which catalyses the first step of glycosylphosphatidylinisotol ( GPI) anchor synthesis. Two GPI anchored red cell surface antigens regulate complement lysis. G6PD catalyses the first step of the pentose phosphate pathway and enzyme variants, frequent in some populations have been because they confer resistance to malaria, are associated with hemolysis in the presence of oxidizing agents including several drugs. The patient had suffered a hemolytic attack after taking Bactrim, a drug that precipitates hemolysis in G6PD deficient individuals. Since both G6PD and PIGA are X-linked we hypothesized that the PIGA mutation was on the X-chromosome carrying the G6PDA- allele. Investigations showed that in fact the PIGA mutation was on the X-chromosome carrying the normal G6PD B allele. We speculate that complement activation on G6PD A- red cells exposed to Bactrim might have triggered complement activation inducing the lysis of G6PD B PNH Type II red blood cells or that the patient may have had a PNH clone expressing G6PDA- at the time of the hemolytic episode. PMID- 25713698 TI - Subdivisions of the adult zebrafish pallium based on molecular marker analysis. AB - BACKGROUND: The telencephalon shows a remarkable structural diversity among vertebrates. In particular, the everted telencephalon of ray-finned fishes has a markedly different morphology compared to the evaginated telencephalon of all other vertebrates. This difference in development has hampered the comparison between different areas of the pallium of ray-finned fishes and the pallial nuclei of all other vertebrates. Various models of homology between pallial subdivisions in ray-finned fishes and the pallial nuclei in tetrapods have been proposed based on connectional, neurochemical, gene expression and functional data. However, no consensus has been reached so far. In recent years, the analysis of conserved developmental marker genes has assisted the identification of homologies for different parts of the telencephalon among several tetrapod species. RESULTS: We have investigated the gene expression pattern of conserved marker genes in the adult zebrafish ( Danio rerio) pallium to identify pallial subdivisions and their homology to pallial nuclei in tetrapods. Combinatorial expression analysis of ascl1a, eomesa, emx1, emx2, emx3, and Prox1 identifies four main divisions in the adult zebrafish pallium. Within these subdivisions, we propose that Dm is homologous to the pallial amygdala in tetrapods and that the dorsal subdivision of Dl is homologous to part of the hippocampal formation in mouse. We have complemented this analysis be examining the gene expression of emx1, emx2 and emx3 in the zebrafish larval brain. CONCLUSIONS: Based on our gene expression data, we propose a new model of subdivisions in the adult zebrafish pallium and their putative homologies to pallial nuclei in tetrapods. Pallial nuclei control sensory, motor, and cognitive functions, like memory, learning and emotion. The identification of pallial subdivisions in the adult zebrafish and their homologies to pallial nuclei in tetrapods will contribute to the use of the zebrafish system as a model for neurobiological research and human neurodegenerative diseases. PMID- 25713699 TI - Case Report: Bilateral reexpansion pulmonary edema following treatment of a unilateral hemothorax. AB - Bilateral re-expansion pulmonary edema (RPE) is an extremely rare entity. We report the unique case of bilateral RPE following a traumatic, unilateral hemopneumothorax in a young healthy male. Bilateral RPE occurred only one hour after drainage of a unilateral hemopneumothorax. The patient was treated with diuretics and supplemental oxygen. Diagnosis was confirmed by excluding other causes, using laboratory findings, chest radiography, pulmonary and cardiac ultrasound and high resolution computed tomography. His recovery was uneventful. The pathophysiology of bilateral RPE is not well known. Treatment is mainly supportive and consists of diuretics, mechanical ventilation, inotropes and steroids. In case of a pulmonary deterioration after the drainage of a traumatic pneumothorax, bilateral RPE should be considered after exclusion of more common causes of dyspnea. PMID- 25713700 TI - Small molecules with antiviral activity against the Ebola virus. AB - The recent outbreak of the Ebola virus in West Africa has highlighted the clear shortage of broad-spectrum antiviral drugs for emerging viruses. There are numerous FDA approved drugs and other small molecules described in the literature that could be further evaluated for their potential as antiviral compounds. These molecules are in addition to the few new antivirals that have been tested in Ebola patients but were not originally developed against the Ebola virus, and may play an important role as we await an effective vaccine. The balance between using FDA approved drugs versus novel antivirals with minimal safety and no efficacy data in humans should be considered. We have evaluated 55 molecules from the perspective of an experienced medicinal chemist as well as using simple molecular properties and have highlighted 16 compounds that have desirable qualities as well as those that may be less desirable. In addition we propose that a collaborative database for sharing such published and novel information on small molecules is needed for the research community studying the Ebola virus. PMID- 25713701 TI - Moving in extreme environments: inert gas narcosis and underwater activities. AB - Exposure to the underwater environment for pleasure or work poses many challenges on the human body including thermal stress, barotraumas, decompression sickness as well as the acute effects of breathing gases under pressure. With the popularity of recreational self-contained underwater breathing apparatus (SCUBA) diving on the increase and deep inland dive sites becoming more accessible, it is important that we understand the effects of breathing pressurised gas at depth can have on the body. One of the common consequences of hyperbaric gas is the narcotic effect of inert gas. Nitrogen (a major component of air) under pressure can impede mental function and physical performance at depths of as little as 10 m underwater. With increased depth, symptoms can worsen to include confusion, disturbed coordination, lack of concentration, hallucinations and unconsciousness. Narcosis has been shown to contribute directly to up to 6% of deaths in divers and is likely to be indirectly associated with other diving incidents at depth. This article explores inert gas narcosis, the effect on divers' movement and function underwater and the proposed physiological mechanisms. Also discussed are some of the factors that affect the susceptibility of divers to the condition. In conclusion, understanding the cause of this potentially debilitating problem is important to ensure that safe diving practices continue. PMID- 25713702 TI - Welcome to the new ckj: an open-access resource integrating clinical, translational and educational research into clinical practice. PMID- 25713703 TI - Chronic kidney disease (CKD) in disadvantaged populations. AB - Twelve March 2015 will mark the 10th anniversary of World Kidney Day (WKD), an initiative of the International Society of Nephrology and the International Federation of Kidney Foundations. Since its inception in 2006, WKD has become the most successful effort ever mounted to raise awareness among decision-makers and the general public about the importance of kidney disease. Each year WKD reminds us that kidney disease is common, harmful and treatable. The focus of WKD 2015 is on chronic kidney disease (CKD) in disadvantaged populations. This article reviews the key links between poverty and CKD and the consequent implications for the prevention of kidney disease and the care of kidney patients in these populations. PMID- 25713704 TI - Spatial distribution of end-stage renal disease (ESRD) and social inequalities in mixed urban and rural areas: a study in the Bretagne administrative region of France. AB - BACKGROUND: Several studies have investigated the implication of biological and environmental factors on geographic variations of end-stage renal disease (ESRD) incidence at large area scales, but none of them assessed the implication of neighbourhood characteristics (healthcare supply, socio-economic level and urbanization degree) on spatial repartition of ESRD. We evaluated the spatial implications of adjustment for neighbourhood characteristics on the spatial distribution of ESRD incidence at the smallest geographic unit in France. METHODS: All adult patients living in Bretagne and beginning renal replacement therapy during the 2004-09 period were included. Their residential address was geocoded at the census block level. Each census block was characterized by socio economic deprivation index, healthcare supply and rural/urban typology. Using a spatial scan statistic, we examined whether there were significant clusters of high risk of ESRD incidence. RESULTS: The ESRD incidence was non-randomly spatially distributed, with a cluster of high risk in the western Bretagne region (relative risk, RR = 1.28, P-value = 0.0003). Adjustment for sex, age and neighbourhood characteristics induced cluster shifts. After these adjustments, a significant cluster (P = 0.013) persisted. CONCLUSIONS: Our spatial analysis of ESRD incidence at a fine scale, across a mixed rural/urban area, indicated that, beyond age and sex, neighbourhood characteristics explained a great part of spatial distribution of ESRD incidence. However, to better understand spatial variation of ESRD incidence, it would be necessary to research and adjust for other determinants of ESRD. PMID- 25713705 TI - Translational nephrology: what translational research is and a bird's-eye view on translational research in nephrology. AB - The ultimate aim of biomedical research is to preserve health and improve patient outcomes. However, by a variety of measures, preservation of kidney health and patient outcomes in kidney disease are suboptimal. Severe acute kidney injury has been treated solely by renal replacement therapy for over 50 years and mortality still hovers at around 50%. Worldwide deaths from chronic kidney disease (CKD) increased by 80% in 20 years--one of the greatest increases among major causes of death. This dramatic data concur with huge advances in the cellular and molecular pathophysiology of kidney disease and its consequences. The gap appears to be the result of sequential roadblocks that impede an adequate flow from basic research to clinical development [translational research type 1 (T1), bench-to-bed and back] and from clinical development to clinical practice and widespread implementation (translational research T2) that supported by healthcare policy making reaches all levels of society throughout the globe (sometimes called translational research T3). Thus, it is more than 10 years since the introduction of the last new-concept drug for CKD patients, cinacalcet; and 30 years since the introduction of reninangiotensin system (RAS) blockade, the current mainstay to prevent progression of CKD, illustrating the basic science-clinical practice disconnect. Roadblocks from clinical advances to widespread implementation, together with lag time-to-benefit may underlie the 20 years since the description of the antiproteinuric effect of RAS blockade to the observation of decreased age adjusted incidence of endstage renal disease due to diabetic kidney disease. Only a correct understanding of the roadblocks in translational medicine and a full embracement of a translational research culture will spread the benefits of the biomedical revolution to its ultimate destinatary, the society. PMID- 25713706 TI - Extracellular vesicles in the urine: markers and mediators of tissue damage and regeneration. AB - As in several body fluids, urine is a rich reservoir of extracellular vesicles (EVs) directly originating from cells facing the urinary lumen, including differentiated tubular cells, progenitor cells and infiltrating inflammatory cells. Several markers of glomerular and tubular damage, such as WT-1, ATF3 and NGAL, as well as of renal regeneration, such as CD133, have been identified representing an incredible source of information for diagnostic purposes. In addition, urinary extracellular vesicles (uEVs) appear to be involved in the cell to-cell communication along the nephron, although this aspect needs further elucidation. Finally, uEVs emerge as potential amplifying or limiting factors in renal damage. Vesicles from injured cells may favour fibrosis and disease progression whereas those from cells with regenerative potential appear to promote cell survival. Here, we will discuss the most recent findings of the literature, on the light of the role of EVs in diagnosis and therapy for damage and repair of the renal tissue. PMID- 25713707 TI - Low concentrations of citrate reduce complement and granulocyte activation in vitro in human blood. AB - BACKGROUND: The use of acetate in haemodialysis fluids may induce negative effects in patients including nausea and increased inflammation. Therefore, haemodialysis fluids where acetate is substituted with citrate have recently been developed. In this study, we investigated the biocompatibility of citrate employing concentrations used in haemodialysis. METHODS: The effects of citrate and acetate were investigated in human whole blood in vitro under conditions promoting biomaterial-induced activation. Complement activation was measured as generation of C3a, C5a and the sC5b-9 complex, and granulocyte activation as up regulation of CD11b expression. For the experimental set-up, a mathematical model was created to calculate the concentrations of acetate and citrate attained during haemodialysis. RESULTS: Citrate reduced granulocyte activation and did not induce higher complement activation compared with acetate at concentrations attained during haemodialysis. Investigating different citrate concentrations clearly showed that citrate is a potent complement inhibitor already at low concentrations, i.e. 0.25 mM, which is comparable with concentrations detected in the blood of patients during dialysis with citrate-containing fluids. Increased citrate concentration up to 6 mM further reduced the activation of C3a, C5a and sC5b-9, as well as the expression of CD11b. CONCLUSIONS: Our results suggest that citrate is a promising substitute for acetate for a more biocompatible dialysis, most likely resulting in less adverse effects for the patients. PMID- 25713708 TI - The beneficial impact of vitamin D treatment in CKD patients: what's next? PMID- 25713709 TI - Effect of oral vitamin D analogs on mortality and cardiovascular outcomes among adults with chronic kidney disease: a meta-analysis. AB - BACKGROUND: Vitamin D deficiency is highly prevalent in patients with chronic kidney disease (CKD) and has been associated with all-cause and cardiovascular mortality in observational studies. However, evidence from randomized controlled trials (RCTs) supporting vitamin D supplementation is lacking. We sought to assess whether vitamin D supplementation alters the relative risk (RR) of all cause and cardiovascular mortality, as well as serious adverse cardiovascular events, in patients with CKD, compared with placebo. METHODS: PubMed/MEDLINE, EMBASE, Cochrane Library, and selected nephrology journals and conference proceedings were searched in October 2013. RCTs considered for inclusion were those that assessed oral vitamin D supplementation versus placebo in adults with CKD (<=60 mL/min/1.73 m(2)), including end-stage CKD requiring dialysis. We calculated pooled RR of mortality (all-cause and cardiovascular) and that of cardiovascular events and stratified by CKD stage, vitamin D analog and diabetes prevalence. RESULTS: The search identified 4246 articles, of which 13 were included. No significant treatment effect of oral vitamin D on all-cause mortality (RR: 0.84; 95% CI: 0.47, 1.52), cardiovascular mortality (RR: 0.79; 95% CI: 0.26, 2.28) or serious adverse cardiovascular events (RR: 1.20; 95% CI: 0.49, 2.99) was observed. The pooled analysis demonstrated large variation in trials with respect to dosing (0.5 ug-200 000 IU/week) and duration (3-104 weeks). CONCLUSIONS: Current RCTs do not provide sufficient or precise evidence that vitamin D supplementation affects mortality or cardiovascular risk in CKD. While its effect on biochemical endpoints is well documented, the results demonstrate a lack of appropriate patient-level data within the CKD literature, which warrants larger trials with clinical primary outcomes related to vitamin D supplementation. PMID- 25713710 TI - Overweight and body fat are predictors of hypovitaminosis D in renal transplant patients. AB - BACKGROUND: Hypovitaminosis D has been frequently reported after renal transplantation, but the impact of obesity and other factors in the reduction of vitamin D levels is not well established. We aimed to evaluate risk factors contributing to hypovitaminosis D among nondiabetic renal transplant recipients (RTR) with serum creatinine <2.0 mg/dL, at least 6 months after transplantation. METHODS: One hundred RTR were subjected to anthropometric evaluation and body composition assessment through bioelectrical impedance analysis; blood samples were drawn for biochemical and hormonal determinations and clinical data were retrieved from the medical records. RESULTS: Hypovitaminosis D was observed in 65% and overweight (body mass index, BMI >25 kg/m(2)) in 59% of cases with a significant median weight gain after transplantation of 5.1 kg. An inadequate distribution of body fat was evidenced in 50% of males and in 58% of females. Patients with either vitamin D deficiency or insufficiency presented significantly higher median values of body fat and weight gain since transplantation, as well as lower lean mass compared with patients with normal vitamin D levels (P < 0.001). Moreover, median values of waist circumference, BMI, serum leptin and parathyroid hormone levels were significantly higher in the group with vitamin D deficiency. A multivariate linear regression analysis then revealed that body fat and leptin levels, but not skin color, gender, age, glucocorticoid use, renal function, microalbuminuria and other confounding factors, were independently associated with low levels of 25 hydroxyvitamin D3 even after adjustments for seasonal variations. CONCLUSION: In conclusion, the present study showed body fat and serum leptin levels to be the only independent risk factors for hypovitaminosis D among RTR. PMID- 25713711 TI - Challenges and opportunities in late-stage chronic kidney disease. AB - There is increasing recognition that chronic diseases are a major challenge for health delivery systems and treasuries. These are highly prevalent and costly diseases and frequency is expected to increase greatly as the population of many countries ages. Chronic kidney disease (CKD) has not received the same attention as other chronic diseases such as congestive heart failure; yet, the prevalence and costs of CKD are substantial. Greater recognition and support for CKD may require that the disease no longer be viewed as one continuous disease state. Early CKD stages require less complex care and generate lower costs. In contrast, late-stage CKD is every bit as complex and costly as other major chronic diseases. Health authorities may not recognize and fund CKD care appropriately until late-stage CKD is defined clearly as separate and distinct from earlier stages of disease. In this review, we describe the burden of chronic diseases, consider the challenges and barriers and propose processes to improve late-stage CKD care. In particular, we recommend the need for improved continuity of care, enhanced use of information technology, multidisciplinary care, timely referral to nephrologists, protocol use and improved patient engagement. PMID- 25713712 TI - Low-protein diets in CKD: how can we achieve them? A narrative, pragmatic review. AB - Low-protein diets (LPDs) have encountered various fortunes, and several questions remain open. No single study, including the famous Modification of Diet in Renal Disease, was conclusive and even if systematic reviews are in favour of protein restriction, at least in non-diabetic adults, implementation is lagging. LPDs are considered difficult, malnutrition is a threat and compliance is poor. LPDs have been reappraised in this era of reconsideration of dialysis indications and timing. The definition of a normal-adequate protein diet has shifted in the overall population from 1 to 1.2 to 0.8 g/kg/day. Vegan-vegetarian diets are increasingly widespread, thus setting the groundwork for easier integration of moderate protein restriction in Chronic Kidney Disease. There are four main moderately restricted LPDs (0.6 g/kg/day). Two of them require careful planning of quantity and quality of food: a 'traditional' one, with mixed proteins that works on the quantity and quality of food and a vegan one, which integrates grains and legumes. Two further options may be seen as a way to simplify LPDs while being on the safe side for malnutrition: adding supplements of essential amino and keto acids (various doses) allows an easier shift from omnivorous to vegan diets, while protein-free food intake allows for an increase in calories. Very-low-protein diets (vLPDs: 0.3 g/kg/day) combine both approaches and usually require higher doses of supplements. Moderately restricted LPDs may be adapted to virtually any cuisine and should be tailored to the patients' preferences, while vLPDs usually require trained, compliant patients; a broader offer of diet options may lead to more widespread use of LPDs, without competition among the various schemas. PMID- 25713713 TI - Transplant renal artery stenosis: clinical manifestations, diagnosis and therapy. AB - Transplant renal artery stenosis (TRAS) is a well-recognized vascular complication after kidney transplant. It occurs most frequently in the first 6 months after kidney transplant, and is one of the major causes of graft loss and premature death in transplant recipients. Renal hypoperfusion occurring in TRAS results in activation of the renin-angiotensin-aldosterone system; patients usually present with worsening or refractory hypertension, fluid retention and often allograft dysfunction. Flash pulmonary edema can develop in patients with critical bilateral renal artery stenosis or renal artery stenosis in a solitary kidney, and this unique clinical entity has been named Pickering Syndrome. Prompt diagnosis and treatment of TRAS can prevent allograft damage and systemic sequelae. Duplex sonography is the most commonly used screening tool, whereas angiography provides the definitive diagnosis. Percutaneous transluminal angioplasty with stent placement can be performed during angiography if a lesion is identified, and it is generally the first-line therapy for TRAS. However, there is no randomized controlled trial examining the efficacy and safety of percutaneous transluminal angioplasty compared with medical therapy alone or surgical intervention. PMID- 25713714 TI - Renal denervation of the native kidneys for drug-resistant hypertension after kidney transplantation. AB - There is a strong rationale for renal denervation (RDN) of the native kidneys in kidney transplant recipients with treatment-resistant hypertension. We present a patient with a stable graft function, who underwent RDN for posttransplant therapy-resistant hypertension (24-h ambulatory blood pressure measurement (ABPM) 143/89 mmHg, while compliantly using five different antihypertensive agents). After RDN, BP measurements and orthostatic complaints required withdrawal of two antihypertensive agents and halving a third. At 6 months, ABPM was 134/84 mmHg and allograft function remained unchanged. This case calls for designing well designed prospective studies on RDN in kidney transplant recipients. PMID- 25713715 TI - Successful restoration of arteriovenous dialysis access patency after late intervention. AB - BACKGROUND: Arteriovenous dialysis access may be lost due to stenosis and thrombosis. Patency may be restored by thrombectomy or thrombolysis, but this is often not undertaken when the presentation is delayed. The success rate of delayed intervention is largely unknown. METHODS: In this single-centre study, we identified all instances of arteriovenous vascular access (VA) failure treated with angioplasty, thrombectomy or thrombolysis between August 2010 and July 2013. Patency rates immediately after intervention, and after 3 months, were assessed using multilevel mixed effects logistic regression. RESULTS: Sixty failures occurred in 41 accesses (38 patients). The access age at failure was 495 (316 888) days. Intervention was carried out after >48 h in 19 failures (32%). Immediate patency was achieved in 46 failures, of which 32 remained patent after 3 months. Delaying intervention increased the likelihood of achieving immediate patency (OR 0.55, 95% CI 0.31-1.0, P = 0.05). Having lost arteriovenous accesses previously increased the risk of immediate failure (OR 4.0, 95% CI 1.07-14.95, P = 0.04). There was no association between failure-to-intervention-time and 3 month patency rates (P = 0.23). Effect estimates did not differ between arteriovenous fistulae and synthetic arteriovenous grafts. CONCLUSION: Delayed intervention for failed arteriovenous VA may result in superior early patency rates and yields equivalent 3-month patency rates. PMID- 25713716 TI - Assessing continuous renal replacement therapy as a rescue strategy in cardiorenal syndrome 1. AB - BACKGROUND: Patients with acute decompensated heart failure (ADHF) and cardiorenal syndrome (CRS) 1 have poor outcomes. Ultrafiltration (UF) is used to mechanically remove salt and water in ADHF patients with diuretic resistance. However, little is known about the outcomes of ADHF patients on inotropes and/or vasopressors who require continuous renal replacement therapy (CRRT) for both UF and solute clearance in severe acute kidney injury. METHODS: We retrospectively analyzed 37 consecutive critically ill patients who were admitted for ADHF from 2005-13 and were on inotropes and/or vasopressors at the time of CRRT initiation. The primary outcome was in-hospital mortality. RESULTS: In-hospital mortality rate was 62%. Median survival was 15.5 days after CRRT initiation, and 10 months following hospital discharge. When comparing renal and cardiovascular variables for survivors and non-survivors at baseline, admission and CRRT initiation, survivors were less likely to need vasopressors. After controlling for multiple predictors, vasopressor use remained associated with time to death (HR 9.9; 95% CI 2.3-43.3; P = 0.002). Patients with isolated right ventricular dysfunction had an in-hospital mortality of 45% compared with 69% in those with left ventricular dysfunction (P = 0.27). Age of >70 years was associated with 100% in-hospital mortality. CONCLUSIONS: Rescue therapy using CRRT in refractory CRS1 was associated with high in-hospital mortality, especially when vasopressors were used and when patient age exceeded 70 years. Additionally, survivors had a poor long-term prognosis. PMID- 25713717 TI - Healthcare-associated infections: new challenges looking for answers. AB - Nosocomial transmission of multiresistant bacteria is a growing healthcare issue. In addition, new pathogens and pathogenic mechanisms, associated with therapies based on the use of live microorganisms, can be of importance in the near future. The current issue of CKJ illustrates healthcare-associated infections that go beyond common bacteria. First, the therapeutic use of live BCG mycobacteria is not without risks in the chronic kidney disease patients. Familiarity with these complications will allow their rapid recognition and optimized management. Second, strict adherence to universal precautions and healthcare guidelines is still mandatory in order to avoid undesirable risks such as transmission of hepatitis B virus. PMID- 25713719 TI - Peritoneal tuberculosis presenting as recurrent peritonitis secondary to treatment with intravesical Bacillus Calmette-Guerin in a patient receiving peritoneal dialysis. AB - Intravesical Bacillus Calmette-Guerin (BCG) is an established treatment for high risk superficial bladder cancer [Morales A, Eidinger D, Bruce AW. Intracavitary Bacillus Calmette-Guerin in the treatment of superficial bladder tumors.1976. J Urol 2002; 167: 891-893, Lamm DL, van der Meijden APM, Morales A et al. Incidence and treatment of complications of Bacillus Calmette-Guerin intravesical therapy in superficial bladder cancer. J Urol 1992; 147: 596-600]. We describe a patient receiving peritoneal dialysis (PD), who developed peritoneal tuberculosis following treatment of bladder cancer with intravesical BCG instillations. To the best of our knowledge, this is the first case of peritoneal tuberculosis following intravesical BCG treatment in which the mycobacterium has been typed and confirmed as a BCG strain with genetic analysis. PMID- 25713718 TI - Identification, investigation and management of patient-to-patient hepatitis B transmission within an inpatient renal ward in North West England. AB - BACKGROUND: Transmission of hepatitis B virus (HBV) is rare within healthcare settings in developed countries. The aim of the article is to outline the process of identification and management of transmission of acute hepatitis B in a renal inpatient ward. METHODS: The case was identified through routine reporting to public health specialists, and epidemiological, virological and environmental assessment was undertaken to investigate the source of infection. An audit of HBV vaccination in patients with chronic kidney disease was undertaken. RESULTS: Investigations identified inpatient admission to a renal ward as the only risk factor and confirmed a source patient with clear epidemiological, virological and environmental links to the case. Multiple failures in infection control leading to a contaminated environment and blood glucose testing equipment, failure to isolate a non-compliant, high-risk patient and incomplete vaccination for patients with chronic kidney disease may have contributed to the transmission. CONCLUSIONS: Patient-to-patient transmission of hepatitis B was shown to have occurred in a renal ward in the UK, due to multiple failures in infection control. A number of policy changes led to improvements in infection control, including reducing multi-function use of wards, developing policies for non compliant patients, improving cleaning policies and implementing competency assessment for glucometer use and decontamination. HBV vaccination of renal patients may prevent patient-to-patient transmission of HBV. Consistent national guidance should be available, and clear pathways should be in place between primary and secondary care to ensure appropriate hepatitis B vaccination and follow-up testing. PMID- 25713720 TI - Fatal oxidative haemolysis and methaemoglobinaemia in a patient with alkaptonuria and acute kidney injury. AB - Alkaptonuria (AKU) is a rare inherited disorder of tyrosine metabolism, which leads to an accumulation of homogentisic acid (HGA) and is associated with a progressive arthropathy. Fatal complications are unusual and usually result from cardiac disease or progressive renal impairment; rapidly fatal haematological complications are exceptionally rare and described in only a handful of case reports. This case involves a 63-year-old male with AKU and modest chronic kidney disease who developed rapidly fatal haemolysis and methaemoglobinuria following an episode of acute kidney injury triggered by an obstructing ureteric calculus and urosepsis. The patient succumbed despite aggressive antioxidant therapy with ascorbic acid and n-acetyl cysteine. A rapid build-up of HGA due to reduced renal clearance, triggering oxidative haemolysis and methaemoglobinuria is proposed as the mechanism. Alternative strategies to consider when conventional antioxidants fail are discussed including the potent inhibitor of HGA production, nitisonone. PMID- 25713721 TI - A novel LMX1B mutation in a family with end-stage renal disease of 'unknown cause'. AB - End-stage renal disease (ESRD) presenting in a familial autosomal dominant pattern points to an underlying monogenic cause. Nail-patella syndrome (NPS) is an autosomal dominant disorder that may lead to ESRD caused by mutations in the transcription factor LMX1B. Renal-limited forms of this disease, termed nail patella-like renal disease (NPLRD), and LMX1B nephropathy have recently been described. We report a large family, from the North East of England, with seven affected members with varying phenotypes of renal disease, ranging from ESRD at 28 years of age to microscopic haematuria and proteinuria and relatively preserved renal function. In this family, there were no extra-renal manifestations to suggest NPS. Genome-wide linkage studies and inheritance by descent (IBD) suggested disease loci on Chromosome 1 and 9. Whole exome sequencing (WES) analysis identified a novel sequence variant (p.R249Q) in the LMX1B gene in each of the three samples submitted, which was confirmed using Sanger sequencing. The variant segregated with the disease in all affected individuals. In silico modelling revealed that R249 is putatively located in close proximity to the DNA phosphoskeleton, supporting a role for this residue in the interaction between the LMX1B homeodomain and its target DNA. WES and analysis of potential target genes, including CD2AP, NPHS2, COL4A3, COL4A4 and COL4A5, did not reveal any co-inherited pathogenic variants. In conclusion, we confirm a novel LMX1B mutation in a large family with an autosomal dominant pattern of nephropathy. This report confirms that LMX1B mutations may cause a glomerulopathy without extra-renal manifestations. A molecular genetic diagnosis of LMX1B nephropathy thus provides a definitive diagnosis, prevents the need for renal biopsies and allows at risk family members to be screened. PMID- 25713722 TI - The clinical features and outcomes of systemic AL amyloidosis: a cohort of 231 Chinese patients. AB - BACKGROUND: Few data are available on the clinical features and outcomes of Chinese patients with systemic immunoglobulin light-chain (AL) amyloidosis. The aim of this study is to reveal the clinical picture and risk factors of disease progression in a large cohort of Chinese patients with AL amyloidosis. METHODS: Patients in the Jinling Hospital amyloidosis registry from 2003 to 2011 were studied. The clinical and laboratory information were collected from first presentation to death or until the last available clinical follow-up. The patients' survival and renal outcomes were analyzed, and the relationships between the clinical parameters and survival were also assessed. RESULTS: A total of 231 patients were enrolled in this study, all the patients studied had renal involvement. One hundred and fifty-three (66.2%) were male, and the median age at diagnosis was 56 years. A total of 198 (85.7%) cases had light-chain lambda-type. One hundred and forty-seven (63.6%) cases presented as nephrotic syndrome (NS), and 25% of patients had renal insufficiency at diagnosis. Liver involvement and NS appeared to be more common in patients of kappa-type amyloidosis, and renal impairment is more severe in kappa-type amyloidosis. The median survival time of all patients was 36.3 months, and the 1-, 2-, 3- and 5-year cumulative survival rates were 67, 53, 48 and 35%, respectively. Multivariate COX analysis showed that age, hepatic involvement and heart involvement can significantly influence survival in these patients. The median time that patients remained dialysis free was 50 months. The percentage of patients that remained dialysis free at 1, 2, 3 and 5 years were 78, 69, 62 and 37%, respectively. Multivariate COX analysis showed that serum creatinine and hypotension were the important risk factors of renal failure. CONCLUSION: lambda-Type is the most dominant type of AL amyloidosis in Chinese patients. The survival of patients with AL amyloidosis is poor. The risk factors included heart and hepatic involvement, hypotension and impairment of renal function. The high serum creatinine level and hypotension at diagnosis are associated with poor renal outcome. PMID- 25713723 TI - Mitochondrial complex I and III gene mRNA levels in schizophrenia, and their relationship with clinical features. AB - BACKGROUND: The etiology of schizophrenia is not precisely known; however, mitochondrial function and cerebral energy metabolism abnormalities were determined to be possible factors associated with the etiology of schizophrenia. Impaired mitochondrial function negatively affects neuronal plasticity, and can cause cognitive deficits and behavioral abnormalities observed during the clinical course of schizophrenia. The present study aimed to investigate the relationship between the clinical features of schizophrenia, and mitochondrial complex activation, based on measurement of mRNA levels in the NDUFV1, NDUFV2, NDUFS1, and UQCR10 genes involved in the peripheral mitochondrial complex. METHODS: The study included 138 schizophrenia patients and 42 healthy controls. The schizophrenia group was divided into a chronic schizophrenia subgroup (n = 84) and a first-episode schizophrenia subgroup (n = 54). The symptoms profile and severity of disorder were evaluated using the Scale for the Assessment of Negative Symptoms (SANS), Scale for the Assessment of Positive Symptoms (SAPS), and Brief Psychiatric Rating Scale (BPRS). RESULTS: The level of mRNA expression of NDUFV1, NDUFV2, and NDUFS1 was significantly higher in the schizophrenia group than in the control group. The mRNA level of NDUFV2 was positively correlated with BPRS and SAPS scores in the first-episode schizophrenia subgroup. CONCLUSION: The findings showed that there was a positive correlation between gene mRNA levels and psychotic symptomatology, especially positive symptoms. Our results suggest that mRNA levels of the NDUFV1, NUDFV2, and NDUFS1 genes of complex I of the mitochondrial electron transport chain might become a possible peripheral marker for the diagnosis of schizophrenia. PMID- 25713724 TI - Ventilation impairment of residents around a cement plant. AB - OBJECTIVES: To identify adverse health effects due to air pollution derived from a cement plant in Korea. The ventilation impairment in residents around a cement plant was compared to another group through a pulmonary function test (PFT). METHODS: From June to August of 2013, both a pre and post-bronchodilator PFT was conducted on a "more exposed group (MEG)" which consisted of 318 people who lived within a 1 km radius of a cement plant and a "less exposed group (LEG)" which consisted of 129 people who lived more than 5 km away from the same plant. The largest forced expiratory volume in a one second (FEV1) reading and a functional residual capacity (FVC) reading were recorded after examining the data from all of the usable curves that were agreed upon as valid by PFT experts of committee of National Institute of Environmental Research. The global initiative for chronic obstructive lung disease (GOLD) criteria for COPD, defined the FEV1/FVC ratio < 0.7 as the obstructive type, and the FEV1/FVC ratio ? 0.7 and FVC% predicted < 80% were as the restrictive type. The FVC% predicted value was estimated using Korean equation. We compared the proportion of lung function impairments between the MEG and the LEG by using a chi-square, and estimated the OR of obstructive and restrictive ventilation impairments by logistic regression. RESULTS: The obstructive type impairment proportion was 9.7% in the MEG, whereas it was 8.5% in the LEG. The restrictive type was 21.6% in the MEG which was more than the 12.4% of the LEG. The odds ratio (OR) of total ventilation impairment in the MEG was 2.63 (95% CI 1.50 ~ 4.61) compared to the LEG. The OR of obstructive type in the MEG was 1.60 (95% CI 0.70 ~ 3.65), the smoking history was 3.10 (CI 1.10 ~ 8.66) whereas OR of restrictive type in the MEG was 2.55 (95% CI 1.37 ~ 4.76), the smoking history was 0.75 (95% CI 0.35 ~ 1.60) after adjusting for sex and age. Level of exposure to particulate played a role in both types. However, it appeared to be a significant variable in restrictive type, while smoking history was also an important variable in obstructive type. CONCLUSION: Although this study is a limited cross-section study with a small number of subjects, ventilation impairment rate is higher in the MEG. There might be a possibility that it is due to long-term exposure to particulate dust generated by the cement plant. PMID- 25713725 TI - Complication characteristics between young-onset type 2 versus type 1 diabetes in a UK population. AB - BACKGROUND: In the UK, the care of young people with diabetes has focused predominantly on type 1 diabetes (T1D). However, young-onset T2D has become increasingly prevalent. At present, it is unclear which type of diabetes represents the more adverse phenotype to develop complications. This study aims to determine the complication burden and its predictive factors in young-onset T2D compared with T1D. METHODS: A cross-sectional study using a hospital diabetes register to identify patients with young-onset T2D and T1D. Young-onset T2D was defined as age of diagnosis below 40 years. The T1D cohort with a similar age of diagnosis was used as a comparator. Data from the last clinic visit was used for analysis. Clinical characteristics and diabetes complications were evaluated at diabetes durations <10, 10-20, and >20 years. Predictive factors for diabetes complications (age, sex, glycated hemoglobin, creatinine, diabetes duration, hypertension, dyslipidemia, and body mass index >25) were determined by logistic regression analysis. RESULTS: Data were collected on 1287 patients, of which 760 and 527 had T1D and T2D, respectively. In all diabetes durations, the T2D cohort had an older age of onset (p<0.0005) with a higher prevalence of obesity, hypertension, and dyslipidemia (all p<0.0005) while glycemic control was similar in both groups. Cardiovascular disease (p<0.005) and neuropathy (p<0.05) were more prevalent in the young-onset T2D cohort in all diabetes durations. There was no difference in retinopathy. Cardiovascular disease was predominantly due to ischemic heart disease. Stroke and peripheral vascular disease became significantly higher in T2D after 20 years duration. After controlling for traditional risk factors, young-onset T2D was an independent predictor for cardiovascular disease (p<0.005) and neuropathy (p<0.05) but not for retinopathy. CONCLUSIONS: Young-onset T2D is a more aggressive phenotype than T1D to develop diabetes complications, particularly for ischemic heart disease and neuropathy. PMID- 25713726 TI - Evidence of poor adherence to secondary prevention after acute coronary syndromes: possible remedies through the application of new technologies. AB - Adherence to secondary prevention medications following acute coronary syndrome (ACS) is disappointingly low, standing around 40-75% by various estimates. This is an inefficient use of the resources devoted to their development and implementation, and also puts patients at higher risk of poor outcomes post-ACS. Numerous factors contribute to low adherence including poor motivation, forgetfulness, lack of education about medications, complicated polypharmacy of ACS regimens, (fear of) adverse side effects and limited practical support. Using technology to improve adherence in ACS is an emerging strategy and has the potential to address many of the above factors-computer-based education and mobile phone reminders are among the interventions trialled and appear to improve adherence in patients with ACS. As we move into an increasingly technological future, there is potential to use devices such as smartphones and tablets to encourage patient responsibility for medications. These handheld technologies have great scope for allowing patients to view online medical records, education modules and reminder systems, and although research specific to ACS is limited, they have shown initial promise in terms of uptake and improved adherence among similar patient populations. Given the overwhelming enthusiasm for handheld technologies, it would seem timely to further investigate their role in improving ACS medication adherence. PMID- 25713727 TI - Practical issues in the management of novel oral anticoagulants-cardioversion and ablation. AB - Recent research and publication of various landmark trials have led to the approval and subsequent use of novel oral anticoagulants (NOACs) in clinical practice. The use of these newer agents for anticoagulation offers several benefits such as greater specificity, relatively rapid onset and offset of action and a predictable pharmacological profile as compared to warfarin. With the increasing use of these agents, several key issues ranging from appropriate selection to management of complications and considerations for concurrent procedures (cardioversion and catheter ablation) have also emerged. The timing of interruption of anticoagulants prior to catheter ablation and re-initiation after the procedure to minimize the peri-procedural thromboembolism risk without increasing the bleeding risk is of key relevance in electrophysiology practice. The use of NOACs in patients undergoing catheter ablation and cardioversion also requires special considerations based on the pharmacological properties of the individual agent and the presence of comorbidities such as renal and or hepatic impairment. In this review we aim to discuss the practical considerations with the use of NOACs in the setting of cardioversion and catheter ablation based on the currently available data. PMID- 25713728 TI - Is pulmonary vein isolation still the cornerstone in atrial fibrillation ablation? AB - Radiofrequency catheter ablation for atrial fibrillation (AF) has become a frequently used therapy after failure of at least one antiarrhythmic drug. The cornerstone of AF ablation has been durable pulmonary vein isolation. However, understanding the positive and negative outcomes of catheter ablation of AF is severely limited by diverse ablation methodologies that do not seem to result in durable pulmonary vein isolation. Without durable pulmonary isolation ablation, it is unclear if ablation strategies need to be modified to include extrapulmonary vein ablation targets in combination with pulmonary vein isolation or alone to improve long-term procedural success rates. The marked discrepancy between AF ablation procedure success rates and actual long-term pulmonary vein isolation rates does suggest that targeting other mechanisms can be considered to achieve similar or better results when compared to pulmonary vein isolation alone. PMID- 25713729 TI - The role of rotors in atrial fibrillation. AB - Despite significant advances in our understanding of atrial fibrillation (AF) mechanisms in the last 15 years, ablation outcomes remain suboptimal. A potential reason is that many ablation techniques focus on anatomic, rather than patient specific functional targets for ablation. Panoramic contact mapping, incorporating phase analysis, repolarization and conduction dynamics, and oscillations in AF rate, overcomes many prior difficulties with mapping AF. This approach provides evidence that the mechanisms sustaining human AF are deterministic, largely due to stable electrical rotors and focal sources in either atrium. Ablation of such sources (Focal Impulse and Rotor Modulation: FIRM ablation) has been shown to improve ablation outcome compared with conventional ablation alone; independent laboratories directly targeting stable rotors have shown similar results. Clinical trials examining the role of stand-alone FIRM ablation are in progress. Looking forward, translating insights from patient specific mapping to evidence-based guidelines and clinical practice is the next challenge in improving patient outcomes in AF management. PMID- 25713730 TI - The role of transcription factors in atrial fibrillation. AB - Atrial fibrillation (AF) is a complex disease that results from genetic and environmental factors and their interactions. In recent years, genome-wide association studies (GWAS) and family-based linkage analysis have found amounts of genetic variants associated with AF. Some of them lie in coding sequences and thus mediate the encoded proteins, some in non-coding regions and influence the expression of adjacent genes. These variants exert influence on the development of cardiovascular system and normal cardiac electrical activity in different levels, and eventually contribute to the occurrence of AF. Among these affected genes, as a crucial means of transcriptional regulation, several transcription factors play important roles in the pathogenesis of AF. In this review, we will focus on the potential role of PITX2, PRRX1, ZHFX3, TBX5, and NKX2.5 in AF. PMID- 25713731 TI - Hybrid approaches in atrial fibrillation ablation: why, where and who? AB - Hybrid strategies involving surgical and catheter ablation of atrial fibrillation (AF) are rapidly evolving. Hybrid techniques may improve procedural success and minimize risks by combining the strengths and minimizing limitations of either surgical or catheter ablation alone. Further study, including randomized controlled trials, will be necessary to determine the optimal approach to hybrid ablation. PMID- 25713732 TI - Are the novel anticoagulants better than warfarin for patients with atrial fibrillation? AB - Atrial fibrillation (AF) is associated with significant morbidity and mortality related to stroke due to thromboembolism. Several novel oral anticoagulants (NOACs) have been developed that dose-dependently inhibit thrombin or activated factor X (factor Xa). These new agents offer potential advantages over vitamin K antagonists, however, several limitations exist. We will review the four large randomized trials comparing the efficacy and safety of new oral anticoagulants with warfarin for stroke prevention in patients with AF as well as assess "real world" data and discuss the limitations of the new agents. PMID- 25713733 TI - Can oral anticoagulants be stopped safely after a successful atrial fibrillation ablation? AB - Ablations of atrial fibrillation (AF) have become more widely performed, and the strategy about long-term usage of oral anticoagulants (OACs) after catheter ablation is an important issue, especially for patients without obvious evidences of recurrences. The annual rate of thromboembolic (TE) event after catheter ablation was less than 1%. CHADS2 and CHA2DS2-VASc scores could be used to identify patients at the risk of TE events after ablations who should continue OACs regardless of the status of recurrence. Despite the improvement in understanding of AF and advancement of technology in catheter ablation, the long term successful rates of paroxysmal and non-paroxysmal AF are around 50% and 30%, respectively. Patients with a high CHADS2 score are at a high risk of recurrence which could continuously occur after the catheter ablation without reaching a plateau. Among the patients with a CHADS2 score of >=3, 26.9% of the recurrences happened 2 years post catheter ablation. Compared to the episodes of AF before catheter ablation, the AF episodes after ablation procedures are less symptomatic and shorter in duration. Therefore, it may not be safe to stop OACs for patients with a high risk score since the AF episodes are difficult to be detected after ablation procedures, but remain dangerous. In conclusion, the decision about the long-term strategy of OACs should be based on patients' baseline clinical risk scores, such as CHADS2 and CHA2DS2-VASc scores, rather than the status of recurrence. PMID- 25713734 TI - Adjunct ablation strategies for persistent atrial fibrillation-beyond pulmonary vein isolation. AB - Atrial fibrillation (AF) is the most common sustained arrhythmia. Recent guidelines recommend pulmonary vein isolation (PVI) as the main procedural endpoint to control recurrent AF in symptomatic patients resistant to antiarrhythmic drugs. The efficacy of such procedure is higher in paroxysmal AF while is still unsatisfactory in persistent and long-standing persistent AF. This review will summarize the state-of-the-art of AF ablation techniques in patients with persistent AF, discussing the evidence underlying different approaches with a particular focus on adjunctive ablation strategies beyond PVI including linear ablation, ablation of complex fractionated atrial electrograms (CFAE), ablation of ganglionated plexi, dominant frequency, rotors and other anatomical sites frequently involved in AF triggers. PMID- 25713735 TI - Alternative medicine in atrial fibrillation treatment-Yoga, acupuncture, biofeedback and more. AB - The last decade has seen a significant improvement in the management of atrial fibrillation (AF) with the development of newer medications and improvement in catheter ablation techniques. Recurrence of AF remains a significant problem in these patients and medications offer limited supportive role. Complementary and alternative treatment strategies therefore remain a viable option for these AF patients. Several studies have shown improvement in AF symptoms with yoga therapy, acupuncture and biofeedback. There are also several herbal medicine and supplements such as omega-3 fatty acids, antioxidant vitamins, barberry, motherwort, cinchona, Shensongyangxin, hawthorn, Kella and Wenxin Keli that have been evaluated as potential therapeutic options in AF. These studies are however limited by small sample sizes with mixed results. Besides the pharmacological action, metabolism, interactions with other medications and the adverse effects of the herbal medications and supplements remain poorly understood. In spite of the above limitations, complementary therapies remain a promising option in the management of AF and further studies are necessary to validate their safety and efficacy. PMID- 25713736 TI - Dysfunction of the autonomic nervous system in atrial fibrillation. PMID- 25713737 TI - Left atrial appendage closure for thromboembolism prevention in patients with atrial fibrillation: advances and perspectives. AB - Atrial fibrillation (AF) is a frequent cause of stroke. More than 90% of thrombi were found in the left atrial appendage (LAA) in non-valvular AF. Transcatheter LAA closure has been developed as a novel approach to reduce the risk of stroke in patients with AF over the last decade. In this article, we review the recent advances and propose the possible challenges regarding the LAA closure for thromboembolism prevention in patients with AF. PMID- 25713739 TI - Dental extrusion with orthodontic miniscrew anchorage: a case report describing a modified method. AB - In recent years, the skeletal anchorage through miniscrews has expanded the treatment options in orthodontics (Yamaguchi et al., 2012). We hereby present a modified method for tooth extrusion for cases where crown-lengthening surgery is contraindicated for aesthetic reasons. This modified method uses three orthodontic appliances: a mini-implant, an orthodontic wire, and a bracket. The aim of this case report was to increase the length of the clinical crown of a fractured tooth (tooth 23) by means of an orthodontic extrusion with the modified method of Roth and Diedrich. PMID- 25713738 TI - Surgical options in atrial fibrillation. AB - Atrial fibrillation (AF) is not benign and its prevalence is increasing. The two main goals in management of atrial fibrillation are to optimize hemodynamics through rate or rhythm control and to prevent systemic thrombo-embolism. To date, these two goals are still sub-optimally achieved, raising the need for alternative methods and strategies both pharmacologically and through interventions. In this review, we discuss surgical strategies of achieving both goals with insights on the evolution and potential future of these strategies. PMID- 25713740 TI - Brucella endocarditis as a late onset complication of brucellosis. AB - Brucella endocarditis (BE) is a rare but life threatening complication of brucellosis. We present a case report of a patient with relapsing brucellosis complicated with aortic valve endocarditis. The patient underwent valve replacement and required prolonged antibiotic treatment because of rupture of the noncoronary leaflet and development of congestive heart failure. Since the onset of endocarditis in patients with brucellosis is not known, proper follow-up is required in order to identify any late onset complications, especially in endemic areas. PMID- 25713741 TI - Shaggy photoreceptors with subfoveal fluid associated with a distant choroidal melanoma. AB - Purpose. To describe the enhanced depth imaging optical coherence tomography (EDI OCT) findings in a patient with an extra macula choroidal melanoma before and after treatment. Methods. Observational case report. Results. A 45 year-old Caucasian male patient was referred to retina clinic for management of choroidal melanoma. Examination revealed a nasal choroidal melanoma while EDI-OCT illustrated subfoveal fluid pocket with elongated shaggy photoreceptors distant and separate from the tumor. The patient was treated with plaque brachytherapy and intravitreal bevacizumab. One week after plaque removal, there was a dramatic reduction in the shaggy photoreceptors. Conclusion. Choroidal melanomas have effects that are not localized to the area of the tumor. This loculated pocket of subretinal fluid and coinciding changes to photoreceptor morphology may be related to global changes in choroidal function or release of tumor related cytokines. PMID- 25713742 TI - Bilateral pseudoexfoliation deposits on intraocular lens implants. AB - We present a rare case of bilateral pseudoexfoliative deposits on both intraocular lens (IOL) implants in an 83-year-old woman with no other associated pathology, 5 years after cataract surgery. Pseudoexfoliation syndrome is the most common cause of secondary open-angle glaucoma worldwide and these deposits are usually found on the natural lens. The fact that pseudoexfoliative deposits have been found on IOL implants implies the need for a thorough examination in pseudophakic patients, for it could be the only sign of secondary glaucoma. PMID- 25713743 TI - Complex liver resections for colorectal metastases: are they safe in the low volume, resource-poor Caribbean setting? AB - Introduction. Although many authorities suggest that major liver resections should only be carried out in high-volume specialized centres, many patients in the Caribbean do not have access to these health care systems. Presentation of a Case. A 50-year-old woman with a solitary colorectal metastasis invading the inferior vena cava underwent an extended left hepatectomy with caval resection and reconstruction. Several technical maneuvers were utilized that were suited to the resource-poor environment. Conclusion. We suggest that good outcomes can still be attained in the resource-poor, low-volume centres once dedicated and appropriately trained teams are available. PMID- 25713744 TI - Measles vaccination coverage survey in moba, katanga, democratic republic of congo, 2013: need to adapt routine and mass vaccination campaigns to reach the unreached. AB - The Democratic Republic of Congo (DRC) has committed to eliminate measles by 2020. In 2013, in response to a large outbreak, Medecins Sans Frontieres conducted a mass vaccination campaign (MVC) in Moba, Katanga, DRC. We estimated the measles vaccination coverage for the MVC, the Expanded Programme on Immunization routine measles vaccination (EPI) and assessed reasons for non vaccination. We conducted a household-based survey among caretakers of children aged 6 months-15 years in Moba from November to December 2013. We used a two stage-cluster-sampling, where clusters were allocated proportionally to village size and households were randomly selected from each cluster. The questionnaire included demographic variables, vaccination status (card or oral history) during MVC and EPI and reasons for non-vaccination. We estimated the coverage by gender, age and the reasons for non-vaccination and calculated 95% confidence intervals (95% CI). We recruited 4,768 children living in 1,684 households. The MVC coverage by vaccination card and oral history was 87% (95% CI 84-90) and 66% (95% CI 61-70) if documented by card. The EPI coverage was 76% (95% CI 72-81) and 3% (95% CI 1-4) respectively. The MVC coverage was significantly higher among children previously vaccinated during EPI 91% (95% CI 88-93), compared to 74% (95% CI 66-80) among those not previously vaccinated. Six percent (n=317) of children were never vaccinated. The main reason for non-vaccination was family absence 68% (95% CI 58-78). The MVC and EPI measles coverage was insufficient to prevent the recurrence of outbreaks in Moba. Lack of EPI vaccination and lack of accessibility by road were associated with lower MVC coverage. We recommend intensified social mobilization and extended EPI and MVCs to increase the coverage of absent residents and unreached children. Routine and MVCs need to be adapted accordingly to improve coverage in hard-to-reach populations in DRC. PMID- 25713745 TI - Whole Genome Sequencing for the Retrospective Investigation of an Outbreak of Salmonella Typhimurium DT 8. AB - BACKGROUND: Salmonella enterica serovar Typhimurium DT8 is uncommon within the European Union. An increase in this phage type was reported in the summer of 2013 in the States of Jersey. METHODS: A total of 21 human cases with this phage type were microbiologically confirmed. Salmonella isolates from mayonnaise made using raw eggs were also confirmed as being Salmonella Typhimurium DT8. The epidemiological investigations strongly supported a link between mayonnaise consumption and illness. Whole genome sequencing (WGS) was used to retrospectively investigate this outbreak with a view to assess the similarity between the suspect food and the human isolates and to characterise a known point source outbreak to assist in development of algorithms for outbreak detection. RESULTS: Sequence data showed that the outbreak associated isolates, including the food isolates, formed a tightly clustered monophyletic group, with a maximum pairwise distance of 3 single nucleotide polymorphisms. CONCLUSIONS: WGS data is useful in confirming the causative agent of outbreaks where food and clinical isolates are available. This dataset, comprising a known outbreak, will be useful in the development of automatic algorithms for outbreak detection. PMID- 25713747 TI - The role of dopamine and dopaminergic pathways in dystonia: insights from neuroimaging. AB - BACKGROUND: Dystonia constitutes a heterogeneous group of movement abnormalities, characterized by sustained or intermittent muscle contractions causing abnormal postures. Overwhelming data suggest involvement of basal ganglia and dopaminergic pathways in dystonia. In this review, we critically evaluate recent neuroimaging studies that investigate dopamine receptors, endogenous dopamine release, morphology of striatum, and structural or functional connectivity in cortico basal ganglia-thalamo-cortical and related cerebellar circuits in dystonia. METHOD: A PubMed search was conducted in August 2014. RESULTS: Positron emission tomography (PET) imaging offers strong evidence for altered D2/D3 receptor binding and dopaminergic release in many forms of idiopathic dystonia. Functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) data reveal likely involvement of related cerebello-thalamo-cortical and sensory-motor networks in addition to basal ganglia. DISCUSSION: PET imaging of dopamine receptors or transmitter release remains an effective means to investigate dopaminergic pathways, yet may miss factors affecting dopamine homeostasis and related subcellular signaling cascades that could alter the function of these pathways. fMRI and DTI methods may reveal functional or anatomical changes associated with dysfunction of dopamine-mediated pathways. Each of these methods can be used to monitor target engagement for potential new treatments. PET imaging of striatal phosphodiesterase and development of new selective PET radiotracers for dopamine D3-specific receptors and Mechanistic target of rampamycin (mTOR) are crucial to further investigate dopaminergic pathways. A multimodal approach may have the greatest potential, using PET to identify the sites of molecular pathology and magnetic resonance methods to determine their downstream effects. PMID- 25713746 TI - Uncommon applications of deep brain stimulation in hyperkinetic movement disorders. AB - BACKGROUND: In addition to the established indications of tremor and dystonia, deep brain stimulation (DBS) has been utilized less commonly for several hyperkinetic movement disorders, including medication-refractory myoclonus, ballism, chorea, and Gilles de la Tourette (GTS) and tardive syndromes. Given the lack of adequate controlled trials, it is difficult to translate published reports into clinical use. We summarize the literature, draw conclusions regarding efficacy when possible, and highlight concerns and areas for future study. METHODS: A Pubmed search was performed for English-language articles between January 1980 and June 2014. Studies were selected if they focused primarily on DBS to treat the conditions of focus. RESULTS: We identified 49 cases of DBS for myoclonus-dystonia, 21 for Huntington's disease, 15 for choreacanthocytosis, 129 for GTS, and 73 for tardive syndromes. Bilateral globus pallidus interna (GPi) DBS was the most frequently utilized procedure for all conditions except GTS, in which medial thalamic DBS was more common. While the majority of cases demonstrate some improvement, there are also reports of no improvement or even worsening of symptoms in each condition. The few studies including functional or quality of life outcomes suggest benefit. A limited number of studies included blinded on/off testing. There have been two double blind controlled trials performed in GTS and a single prospective double-blind, uncontrolled trial in tardive syndromes. Patient characteristics, surgical target, stimulation parameters, and duration of follow-up varied among studies. DISCUSSION: Despite these extensive limitations, the literature overall supports the efficacy of DBS in these conditions, in particular GTS and tardive syndromes. For other conditions, the preliminary evidence from small studies is promising and encourages further study. PMID- 25713748 TI - Vascular risk factors and clinical progression in spinocerebellar ataxias. AB - BACKGROUND: The contributions of vascular risk factors to spinocerebellar ataxia (SCA) are not known. METHODS: We studied 319 participants with SCA 1, 2, 3, and 6 and repeatedly measured clinical severity using the Scale for Assessment and Rating of Ataxia (SARA) for 2 years. Vascular risk factors were summarized by CHA2DS2-VASc scores as the vascular risk factor index. We employed regression models to study the effects of vascular risk factors on ataxia onset and progression after adjusting for age, sex, and pathological CAG repeats. Our secondary analyses took hyperlipidemia into account. RESULTS: Nearly 60% of SCA participants were at low vascular risks with CHA2DS2-VASc = 0, and 31% scored 2 or greater. Higher CHA2DS2-VASc scores were not associated with either earlier onset or faster progression of ataxia. These findings were not altered after accounting for hyperlipidemia. DISCUSSION: Vascular risks are not common in SCAs and are not associated with earlier onset or faster ataxia progression. PMID- 25713749 TI - A Multicenter Randomized Controlled Trial Comparing Treatment of Venous Leg Ulcers Using Mechanically Versus Electrically Powered Negative Pressure Wound Therapy. AB - Objective: This study compares two different negative pressure wound therapy (NPWT) modalities in the treatment of venous leg ulcers (VLUs), the ultraportable mechanically powered (MP) Smart Negative Pressure (SNaP(r)) Wound Care System to the electrically powered (EP) Vacuum-Assisted Closure (V.A.C.(r)) System. Approach: Patients with VLUs from 13 centers participated in this prospective randomized controlled trial. Each subject was randomly assigned to treatment with either MP NPWT or EP NPWT and evaluated for 16 weeks or complete wound closure. Results: Forty patients (n=19 MP NPWT and n=21 EP NPWT) completed the study. Primary endpoint analysis of wound size reduction found wounds in the MP NPWT group had significantly greater wound size reduction than those in the EP NPWT group at 4, 8, 12, and 16 weeks (p-value=0.0039, 0.0086, 0.0002, and 0.0005, respectively). Kaplan-Meier analyses showed greater acceleration in complete wound closure in the MP NPWT group. At 30 days, 50% wound closure was achieved in 52.6% (10/19) of patients treated with MP NPWT and 23.8% (5/21) of patients treated with EP NPWT. At 90 days, complete wound closure was achieved in 57.9% (11/19) of patients treated with MP NPWT and 38.15% (8/21) of patients treated with EP NPWT. Innovation: These data support the use of MP-NPWT for the treatment of VLUs. Conclusions: In this group of venous ulcers, wounds treated with MP NPWT demonstrated greater improvement and a higher likelihood of complete wound closure than those treated with EP NPWT. PMID- 25713750 TI - Full-Thickness Thermal Injury Delays Wound Closure in a Murine Model. AB - Objective: The contemporary treatment of a full-thickness burn consists of early eschar excision followed by immediate closure of the open wound using autologous skin. However, most animal models study burn wound healing with the persistence of the burn eschar. Our goal is to characterize a murine model of burn eschar excision to study wound closure kinetics. Approach: C57BL/6 male mice were divided into three groups: contact burn, scald burn, or unburned control. Mice were burned at 80 degrees C for 5, 10, or 20 s. After 2 days, the eschar was excised and wound closure was documented until postexcision day 13. Biopsies were examined for structural morphology and alpha-smooth muscle actin. In a subsequent interval-excision experiment (80 degrees C scald for 10 s), the burn eschar was excised after 5 or 10 days postburn to determine the effect of a prolonged inflammatory focus. Results: Histology of both contact and scald burns revealed characteristics of a full-thickness injury marked by collagen coagulation and tissue necrosis. Excision at 2 days after a 20-s burn from either scald or contact showed significant delay in wound closure. Interval excision of the eschar, 5 or 10 days postburn, also showed significant delay in wound closure. Both interval-excision groups showed prolonged inflammation and increased myofibroblasts. Innovation and Conclusions: We have described the kinetics of wound closure in a murine model of a full-thickness burn excision. Both contact and scald full-thickness burn resulted in significantly delayed wound closure. In addition, prolonged interval-excision of the eschar appeared to increase and prolong inflammation. PMID- 25713752 TI - The Lipid Portion of Activated Platelet-Rich Plasma Significantly Contributes to Its Wound Healing Properties. AB - Objective: Platelet-rich plasma (PRP) is a popular choice for the treatment of chronic wounds. Current dogma attributes these healing properties to the peptide growth factors of PRP. However, PRP is also rich in bioactive lipids whose contribution to healing has not been characterized and warrants investigation due to the protease-rich environment of chronic wounds. Approach: The lipid fraction of PRP was tested with respect to proliferation and migration of primary adult human dermal fibroblasts (HDFa)+/-exposure to chronic wound fluid (CWF). This fraction was also characterized via LC-MS/MS for bioactive lipids. A synthetic formulation of the bioactive lipid composition was developed and tested for the ability to overcome proliferative growth arrest induced by CWF. Results: The data demonstrate the ability of the lipid fraction of PRP to significantly enhance the migration and proliferation of HDFa, and to overcome the proliferative growth arrest induced by CWF. Furthermore, the synthetic lipid formulation generated following characterization of the PRP lipidome demonstrated a similar ability to overcome proliferative arrest of HDFa in the presence of CWF. Innovation: For the first time, we demonstrate the relevance of the lipid fraction of PRP toward the biology of wound healing. These studies open the possibility of altering the lipid profile of PRP via diet or exogenous pathway manipulation to obtain a better healing outcome. Conclusion: The lipid fraction of PRP is under investigated and yet relevant component in wound healing. The current study demonstrates the relevance of this fraction in wound healing by PRP. PMID- 25713751 TI - Effects of High Estrogen Levels on Monocyte Chemoattractant Protein-1 and Wound Healing. AB - Objective: Herein, we tested the effects of high levels of supplemental estrogen treatment on cutaneous wound healing. Approach: Female mice were implanted with a 17beta-estradiol (E2) secreting pellet or placebo before receiving a full thickness dermal excisional wound. Mice receiving the E2 pellet attained hormone levels that are comparable to those achieved during pregnancy. At 1, 3, and 5 days after injury, the dermal excision wound was examined for their histologic appearance, rate of closure, and chemokine levels. Results: Wound closure, assessed by percent reepithelialization, was slower in E2-treated mice relative to placebo (42.6%+/-6.6% vs. 70.0%+/-5.3%, respectively, 3 days after injury). In addition, there was a marked reduction in the subepithelial inflammatory infiltrate and granulation tissue in E2-treated mice relative to placebo. Wound levels of monocyte chemoattractant protein-1 (MCP-1) were increased by 3 days after injury and continued to rise at 5 days after injury in placebo-treated mice (p<0.01). By contrast, MCP-1 levels were significantly reduced at 3 and 5 days after injury in E2-treated mice relative to placebo-treated controls (p<0.01). This attenuation could be reversed by treatment with an estrogen receptor antagonist. Innovation: High levels of estrogen are able to suppress normal wound closure. Conclusion: Dermal wound healing can be altered by manipulating the gonadal steroid hormone levels. In particular, high levels of estrogen can be utilized to slow down the rate of wound healing through a reduction in the inflammatory response. PMID- 25713753 TI - Preclinical Evaluation of TegadermTM Supported Nanofibrous Wound Matrix Dressing on Porcine Wound Healing Model. AB - Objective: Nanofibers for tissue scaffolding and wound dressings hold great potential in realizing enhanced healing of wounds in comparison with conventional counterparts. Previously, we demonstrated good fibroblast adherence and growth on a newly developed scaffold, TegadermTM-Nanofiber (TG-NF), made from poly E caprolactone (PCL)/gelatin nanofibers electrospun onto Tegaderm (TG). The purpose of this study is to evaluate the performance and safety of TG-NF dressings in partial-thickness wound in a pig healing model. Approach: To evaluate the rate of reepithelialization, control TG, human dermal fibroblast-seeded TG-NF(+) and unseeded TG-NF(-) were randomly dressed onto 80 partial-thickness burns created on four female and four male pigs. Wound inspections and dressings were done after burns on day 7, 14, 21, and 28. On day 28, full-thickness biopsies were taken for histopathological evaluation by Masson-Trichrome staining for collagen and hematoxylin-eosin staining for cell counting. Results: No infection and severe inflammation were recorded. Wounds treated with TG-NF(+) reepithelialized significantly faster than TG-NF(-) and control. Wound site inflammatory responses to study groups were similar as total cell counts on granulation tissues show no significant differences. Most of the wounds completely reepithelialized by day 28, except for two wounds in control and TG-NF(-). A higher collagen coverage was also recorded in the granulation tissues treated with TG-NF(+). Innovation and Conclusion: With better reepithelialization achieved by TG-NF(+) and similar rates of wound closure by TG-NF(-) and control, and the absence of elevated inflammatory responses to TG-NF constructs, TG-NF constructs are safe and demonstrated good healing potentials that are comparable to Tegaderm. PMID- 25713754 TI - Family history of breast and ovarian cancer and triple negative subtype in hispanic/latina women. AB - Familial breast and ovarian cancer prevalence was assessed among 1150 women of Mexican descent enrolled in a case-only, binational breast cancer study. Logistic regression was conducted to compare odds of triple negative breast cancer (TNBC) to non-TNBC according to family history of breast and breast or ovarian cancer among 914 of these women. Prevalence of breast cancer family history in a first- and first- or second-degree relative was 13.1% and 24.1%, respectively; that for breast or ovarian cancer in a first-degree relative was 14.9%. After adjustment for age and country of residence, women with a first-degree relative with breast cancer were more likely to be diagnosed with TNBC than non-TNBC (OR=1.98; 95% CI, 1.26-3.11). The odds of TNBC compared to non-TNBC were 1.93 (95% CI, 1.26-2.97) for women with a first-degree relative with breast or ovarian cancer. There were non-significant stronger associations between family history and TNBC among women diagnosed at age <50 compared to >=50 years for breast cancer in a first-degree relative (P-interaction = 0.14) and a first- or second-degree relative (P interaction = 0.07). Findings suggest that familial breast cancers are associated with triple negative subtype, possibly related to BRCA mutations in Hispanic/Latina women, which are strongly associated with TNBC. Family history is an important tool to identify Hispanic/Latina women who may be at increased risk of TNBC, and could benefit from prevention and early detection strategies. PMID- 25713755 TI - An experimental result of estimating an application volume by machine learning techniques. AB - In this study, we improved the usability of smartphones by automating a user's operations. We developed an intelligent system using machine learning techniques that periodically detects a user's context on a smartphone. We selected the Android operating system because it has the largest market share and highest flexibility of its development environment. In this paper, we describe an application that automatically adjusts application volume. Adjusting the volume can be easily forgotten because users need to push the volume buttons to alter the volume depending on the given situation. Therefore, we developed an application that automatically adjusts the volume based on learned user settings. Application volume can be set differently from ringtone volume on Android devices, and these volume settings are associated with each specific application including games. Our application records a user's location, the volume setting, the foreground application name and other such attributes as learning data, thereby estimating whether the volume should be adjusted using machine learning techniques via Weka. PMID- 25713756 TI - The effects of prior high intensity double poling on subsequent diagonal stride skiing characteristics. AB - PURPOSE: To investigate the influence of prior high intensity double poling (DP) on physiological and biomechanical responses during subsequent diagonal stride (DIA). METHODS: Eight well-trained male cross-country skiers (age 22 +/- 3 yr; VO2max 69 +/- 3 ml . kg(-1) . min(-1)) roller-skied on a treadmill sequentially for 3 min at 90% DIA VO2max (DIA1), 3 min at 90% DP VO2peak and 3 min at 90% DIA VO2max (DIA2). Cardio-respiratory responses were monitored continuously and gases and metabolites in blood from the a. femoralis, v. femoralis and v. subclavia determined. Pole and plantar forces and EMG from 6 lower- and upper-body muscles were measured. RESULTS: VO2 decreased from DIA1 to DP and increased again to DIA2 (both P < 0.05), with no difference between the DIA sessions. Blood lactate rose from DIA1 to DP to DIA2. O2 extraction was attenuated during DP (P < 0.05), but was the same during DIA1 and DIA2. EMGRMS for arm muscles during poling phase, as well as peak pole force and cycle rate were higher, while leg muscle activity was lower during DP than both sessions of DIA (all P < 0.05). The ratio of upper /whole-body EMGRMS correlated negatively with O2 extraction in the arms during both sessions of DIA (P < 0.05). CONCLUSIONS: In well-trained skiers skiing at high-intensity DP prior to DIA did not influence VO2, muscle activation or forces in the latter. At race intensity DP does not influence the distribution of work between upper- and lower-body during a subsequent bout of DIA. O2 extraction is coupled to technical skills during skiing. PMID- 25713757 TI - Downstream optimization of fungal-based simultaneous saccharification and fermentation relevant to lignocellulosic ethanol production. AB - To support the inefficient limitation of long-term biosystem by well-known simultaneous saccharification and fermentation (SSF), electron beam irradiated rice straw (at 80 kGy, 1 MeV, and 0.12 mA) was fermented using fungal-based simultaneous saccharification and fermentation (FBSSF) by saprophytic zygomycetes Mucor indicus. Based on the growth optimization (by response surface methodology), this eco-friendly bioprocess either without metabolic inhibitors (especially furfurals and acetic acids) or byproducts (especially glycerols) significantly increased the biodegradability and fermentability of lignocellulosic rice straw. Specifically, when irradiated straw was simultaneously bioconverted by M. indicus for 48 h, the ethanol yield was 57.2% of the theoretical maximum. This value was on the similar level as the 59.8% (for 144 h) measured from processed straw by well-known SSF. Furthermore, after FBSSF for 144 h based on large-scale mass balance, the ethanol concentration and production yield, and productivity were 34.6 g/L, 72.3% of the theoretical maximum, and 0.24 g/L/h, respectively. PMID- 25713758 TI - Neural stem/progenitor cells react to non-glial cns neoplasms. AB - It is well established that the normal human brain contains populations of neural stem/progenitor cells. Recent studies suggest that they migrate toward a variety of CNS tissue injuries. In an investigation of the potential role of neural stem cells in the pathogenesis of primary CNS lymphomas (NHL-CNS), we observed that neural stem/progenitor cells appeared to accumulate at the border of the tumors with the brain and in the advancing edge of the tumors, in a pattern similar to that seen with reactive gliosis. We identified neural stem/progenitor cells using standard immunohistochemical markers thereof, including CD133, nestin, Group II Beta-tubulin, Musashi1, and the transcription factor Sox2, in neurosurgically obtained specimens of NHL-CNS metastatic carcinoma , and metastatic melanoma . We had similar results with each of these markers but found that Sox2 antibodies provided the clearest and most robust labeling of the cells at the borders of these non-glial tumors. To exclude that the immunoreactive cells were actually neoplastic, double-label immunohistochemistry for Sox2 and CD20 (for NHL-CNS), Sox2 and cytokeratin (CAM5.2, for carcinomas), or Sox2 and HMB45 (for melanomas) showed that in each tumor type, Sox2-immunoreactive cells adjacent to and among the tumor cells were separate from neoplastic cells. Sox2/GFAP double-labeling revealed a consistent pattern of Sox2 immunopositivity both in reactive GFAP immunopositive astrocytes and in GFAP-negative cells, at the interface of tumor and non-neoplastic brain. These results suggest that neural stem/progenitor cells migrate to non-glial neoplasms in the CNS, are a source of reactive astrocytes, and that Sox2 is a reliable immunohistochemical marker for these cells. PMID- 25713760 TI - Knowledge of prostate cancer among males attending a urology clinic, a South African study. AB - BACKGROUND: In South Africa, the rate of histologically diagnosed prostate cancer is 40.1 per 100 000 in whites and 14 per 100 000 in blacks. However, blacks have limited access to diagnostic facilities and present late with an advanced disease. Knowledge about prostate cancer in the South African male population is necessary in order to increase the acceptance of early prostate cancer screening. OBJECTIVE: This study assessed the knowledge of prostate cancer among men attending the urology outpatient clinic at a tertiary hospital in South Africa. METHODS: A cross-sectional study was conducted from February to March 2010. A structured questionnaire was administered to participants using consecutive sampling of eligible patients and consisted of sections on sociodemographic details and knowledge about prostate cancer. A total of 346 males, 35 years of age and older, participated in the study. RESULTS: The majority of the respondents (n = 258; 75.0%) were black, married (n = 220; 64.0%), from the Free State Province (n = 320; 92.8%), and had access to television (n = 248; 71.7%). Only 38 (11.0%) knew the three main symptoms and signs associated with prostate cancer. Level of school education, race and language were statistically significantly associated with level of knowledge whereas age and marital status were not. CONCLUSION: More than half (54.4%) of the respondents had not heard of prostate cancer. The majority of men who had heard of prostate cancer had a moderate level of knowledge. The factors significantly associated with level of knowledge need to be considered in educational campaigns, prostate cancer screening and treatment. PMID- 25713761 TI - Prognostic significance of tumour stroma ratio in inflammatory breast cancer. AB - Tumour stroma ratio (TSR) is emerging as an important prognostic indicator in cancer. We have previously shown TSR to be prognostic in oestrogen receptor positive breast cancer. Its role in inflammatory breast cancer, a rare but aggressive form of breast cancer, has not been identified. Here we aimed to determine the prognostic significance of TSR in a cohort of patients with inflammatory breast carcinoma. TSR was measured by point counting virtual H&E stained tissue sections in 45 inflammatory breast cancer cases. The whole tumour area was sampled. Optimum cut-offs to distinguish high and low TSR was determined by log-rank test. The relationship of TSR to overall survival and disease-free survival (DFS) was analysed alongside multivariate analysis. The optimal cut-offs between high and low TSR were determined to be 31% for OS and 46% for DFS. There was no significant difference in OS (p = 0.53) nor DFS (p = 0.66) between high and low TSR groups. Multivariate analysis did not demonstrate any new trends, within the limits of a small data sample. A significant correlation was found between pathological response to neoadjuvant chemotherapy and survival (p = 0.008). There is no evidence that TSR has prognostic significance in inflammatory breast cancer. When compared with published data in non-inflammatory breast carcinoma, this supports the view that differences in stromal biology exist between tumour types and highlights the importance of considering this when interpreting the prognostic value of TSR. However, these findings must be interpreted in the light of the small sample size. PMID- 25713762 TI - Alterations in bone mineral density and lower extremity lean mass after hip arthroscopy in a professional female Ironman triathlete: a case study. AB - INTRODUCTION: Femoroacetabular impingement is a pathomechanical condition of the hip, which is often treated through arthroscopic techniques. The ensuing immobilization period is associated with decreases in muscle mass and bone mass. To date, minimal knowledge is present about the development of tissue mass during the considerably short rehabilitation period before returning to competition in elite endurance athletes. CASE DESCRIPTION: Before and after surgery, a professional female Ironman triathlete underwent dual-energy X-ray absorptiometry and peripheral quantitative computed tomography measurements. DISCUSSION AND EVALUATION: Areal bone mineral density (aBMD) of the proximal femur and lower extremity lean mass decreased in the surgically treated lower extremity during the two-month period of immobilization after the hip arthroscopy. These losses were compensated for after only six weeks of rehabilitation. A similar progression of aBMD values was observed in the lumbar spine. The adaptational pattern in volumetric BMD (vBMD) and volumetric bone mineral content (vBMC) of the tibiae were more complex, but attained pre-immobilization values for most variables also after six weeks of rehabilitation. All other variables attained pre-immobilization values no later than nine months after the surgical intervention. CONCLUSIONS: The athlete showed a high plasticity of bone and lean tissue with an optimal short- and midterm outcome. Following a two months immobilization period after a hip arthroscopy, aBMD, vBMD and vBMC achieved pre surgical levels after four months of rehabilitation in a female Ironman triathlete. A nine-month follow-up measurement confirmed the safety of the fast return to sport. PMID- 25713763 TI - Growth effect on liver fatty acid composition of damselfishes genus Abudefduf collected in coral reef habitats of the Malaysian South China Sea. AB - In order to understand feeding ecology, habitat use and migration of coral reef fish, fatty acid composition was examined in damselfish species Abudefduf bengalensis and A. sexfasciatus collected in the Malaysian South China Sea. Proportions of saturated fatty acids (SAFA) ranged from 49.5% to 74.2%, with the highest proportions in fatty acids, the second highest was monounsaturated fatty acids (MUFA) ranged from 21.4% to 47.4% and the proportion of polyunsaturated fatty acids (PUFA) was the lowest ranged from 3.1% to 6.0%. Palmitic acid (16:0) was the most common in SAFA, oleic acid (C18:1omega9c) was the dominant in MUFA and linolenic acid (C18:3n3) showed the highest proportion in PUFA. Fatty acid concentrations, especially in SAFA and MUFA, could be related to physiological condition, sexual development, and recent feeding events. The diet shift revealed by the fatty acid composition suggests changes in habitat use and migration scale in coral reef environment of genus Abudefduf. PMID- 25713764 TI - Helicobacter cinaedi infection in patients with diabetes: a case report. AB - BACKGROUND: Helicobacter cinaedi causes bacteremia without characteristic clinical symptoms and is firstly isolated from human immunodeficiency virus (HIV) positive homosexual men. FINDINGS: Here we describe, for the first time case report, two female patients with diabetes who had H. cinaedi bacteremia. Some cases of H. cinaedi bacteremia may require long-term administration of multiple antibiotics prior to the resolution of infection. CONCLUSIONS: Therefore, these cases indicate that it is important to consider H. cinaedi in patients with diabetes presenting with bacteremia, especially in patients with poor glycemic control. PMID- 25713759 TI - A systematic review of non-hormonal treatments of vasomotor symptoms in climacteric and cancer patients. AB - The cardinal climacteric symptoms of hot flushes and night sweats affect 24-93% of all women during the physiological transition from reproductive to post reproductive life. Though efficacious, hormonal therapy and partial oestrogenic compounds are linked to a significant increase in breast cancer. Non-hormonal treatments are thus greatly appreciated. This systematic review of published hormonal and non-hormonal treatments for climacteric, and breast and prostate cancer-associated hot flushes, examines clinical efficacy and therapy-related cancer risk modulation. A PubMed search included literature up to June 19, 2014 without limits for initial dates or language, with the search terms, (hot flush* OR hot flash*) AND (clinical trial* OR clinical stud*) AND (randomi* OR observational) NOT review). Retrieved references identified further papers. The focus was on hot flushes; other symptoms (night sweats, irritability, etc.) were not specifically screened. Included were some 610 clinical studies where a measured effect of the intervention, intensity and severity were documented, and where patients received treatment of pharmaceutical quality. Only 147 of these references described studies with alternative non-hormonal treatments in post menopausal women and in breast and prostate cancer survivors; these results are presented in Additional file 1. The most effective hot flush treatment is oestrogenic hormones, or a combination of oestrogen and progestins, though benefits are partially outweighed by a significantly increased risk for breast cancer development. This review illustrates that certain non-hormonal treatments, including selective serotonin reuptake inhibitors, gabapentin/pregabalin, and Cimicifuga racemosa extracts, show a positive risk-benefit ratio. Key pointsSeveral non-hormonal alternatives to hormonal therapy have been established and registered for the treatment of vasomotor climacteric symptoms in peri- and post-menopausal women.There are indications that non-hormonal treatments are useful alternatives in patients with a history of breast and prostate cancer. However, confirmation by larger clinical trials is required. PMID- 25713765 TI - Prostate cancer screening in Primary Health Care: the current state of affairs. AB - This study aims to examine the current practice of General practitioners (GPs)/primary care physicians in opportunistic screening for prostate cancer (PC) by digital rectal examination(DRE) and Prostate Specific Antigen(PSA) testing and identify any difference in screening practice. Printed copies and/or electronic versions of a survey was distributed amongst 438 GPs throughout Australia in 2012. Statistical analyses (Wilcoxon rank-sum test, Fisher's exact test or Pearson chi-square test)were performed by outcomes and GP characteristics.There were a total of 149 responses received (34%), with similar gender distribution in rural and metropolitan settings. 74% GPs believed PSA testing was at least 'somewhat effective' in reducing PC mortality with annual PSA screening being conducted by more GPs in the metropolitan setting compared to the rural GPs (35% vs 18.4%), while 25% of rural GPs would not advocate routine PSA screening. When examining the concordance between DRE and PSA testing by gender of GP, the male GPs reported performing PSA testing more frequently than DRE in patients between ages 40 to 69 (p = 0.011). Urology Society guidelines (77.2%) and College of GPs (73.2%) recommendations for PC screening were thought to be at least 'somewhat useful'. Although reference ranges for PSA tests were felt to be useful, the majority (65.8%) found it easier to refer to an urologist due to the disagreements in guidelines. In conclusion, the current guidelines for PSA screening appear to cause more confusion due to their conflicting advice, leaving GPs to formulate their own practice methods, calling for an urgent need for uniform collaborative guidelines. PMID- 25713766 TI - Responses of the soft coral Xenia elongata following acute exposure to a chemical dispersant. AB - Limited toxicology data are available regarding oil dispersant exposure to coral species. Corexit(r) EC9500A (Corexit) is a commonly applied dispersant most well known for its use after the Deepwater Horizon spill in April, 2010. There is limited evidence that Corexit can cause a bleaching response in corals. The aims of the study were: (1) to determine the extent of bleaching after acute 24 h and 72 h exposures of sublethal concentrations (0-50 ppm) of Corexit to the pulsing soft coral Xenia elongata and (2) to investigate a percent symbiont loss calculation using zooxanthellae density. The percent symbiont loss calculation was compared to a traditional metric of normalizing zooxanthellae density to soluble protein content. Percent symbiont loss was an effective measure of coral stress in acute Corexit exposures, while protein normalized zooxanthellae density was more variable. The bleaching data suggest a positive relationship between dispersant concentration and percent symbiont loss, culminating in excessive tissue necrosis and coral mortality within 72 h in high concentration exposures (p < 0.001). Percent beaching ranged from 25% in 5 ppm exposures to 100% in 50 ppm exposures. Corexit also caused a significant decrease in pulse activity (p < 0.0001) and relative oxygen saturation (p < 0.001), possibly indicating a reduction in photosynthetic efficiency. This study and other similar research indicate that dispersant exposure is highly damaging to marine organisms, including ecologically important coral species. PMID- 25713767 TI - Effects of cold-treatment and strain-rate on mechanical properties of NbTi/Cu superconducting composite wires. AB - During design and winding of superconducting magnets at room temperature, a pre tension under different rate is always applied to improve the mechanical stability of the magnets. However, an inconsistency rises for superconductors usually being sensitive to strain and oversized pre-stress which results in degradation of the superconducting composites' critical performance at low temperature. The present study focused on the effects of the cold-treatment and strain-rate of tension deformation on mechanical properties of NbTi/Cu superconducting composite wires. The samples were immersed in a liquid nitrogen (LN2) cryostat for the adiabatic cold-treatment, respectively with 18-hour, 20 hour, 22-hour and 24-hour. A universal testing machine was utilized for tension tests of the NbTi/Cu superconducting composite wires at room temperature; a small scale extensometer was used to measure strain of samples with variable strain rate. The strength, elongation at fracture and yield strength of pre-cold treatment NbTi/Cu composite wires were drawn. It was shown that, the mechanical properties of the superconducting wires are linearly dependent on the holding time of cold-treatment at lower tensile strain-rate, while they exhibit notable nonlinear features at higher strain-rate. The cold-treatment in advance and the strain-rate of pre-tension demonstrate remarkable influences on the mechanical property of the superconducting composite wires. PMID- 25713768 TI - Influence of joint angular velocity on electrically evoked concentric force potentiation induced by stretch-shortening cycle in young adults. AB - BACKGROUND: During a stretch- shortening cycle (SSC), muscle force attained during concentric contractions (shortening phase) is potentiated by the preceding eccentric contractions (lengthening phase). The purpose of this study was to examine the influence of joint angular velocity on force potentiation induced by SSC (SSC effect). FINDINGS: Twelve healthy men (age, 24.2 +/- 3.2 years; height, 1.73 +/- 0.05 m; body mass, 68.1 +/- 11.0 kg) participated in this study. Ankle joint angle was passively moved by a dynamometer, with range of motion from dorsiflexion (DF) 15 degrees to plantarflexion (PF) 15 degrees . Muscle contractions were evoked by tetanic electrical stimulation. Joint angular velocity of concentric contraction was set at 30 degrees /s and 150 degrees /s. Magnitude of SSC effect was calculated as the ratio of joint torque obtained by concentric contraction with preliminary eccentric contraction trial relative to that obtained by concentric contraction without preliminary eccentric contraction trial. As a result, magnitude of SSC effect calculated at three joint angles was significantly larger in the 150 degrees /s condition than in the 30 degrees /s condition (p < 0.05). CONCLUSIONS: These results indicate that the magnitude of SSC effect is affected by joint angular velocity, which is larger when joint angular velocity is larger. This phenomenon would be caused by insufficient duration to increase activation level in the large joint angular velocity condition. When the duration to increase activation level is insufficient due to short contraction duration, preactivation (one of the factors of SSC effect) leads to a significant increase in joint torque. PMID- 25713769 TI - PNPLA3 I148M associations with liver carcinogenesis in Japanese chronic hepatitis C patients. AB - AIM: To investigate associations between patatin-like phospholipase domain containing 3 (PNPLA3) genotypes and fibrosis and hepatocarcinogenesis in Japanese chronic hepatitis C (CHC) patients. METHODS: Two hundred and thirty-one patients with CHC were examined for PNPLA3 genotypes, liver stiffness measurements (LSM), and hepatocellular carcinoma (HCC) from May 2010 to October 2012 at Fujita Health University Hospital. The rs738409 single nucleotide polymorphism (SNP) encoding for a functional PNPLA3 I148M protein variant was genotyped using a TaqMan predesigned SNP genotyping assay. LSM was determined as the velocity of a shear wave (Vs) with an acoustic radiation force impulse. Vs cut-off values for cirrhosis were set at 1.55 m/s. We excluded CHC patients with a sustained virological response or relapse after interferon treatment. RESULTS: PNPLA3 genotypes were CC, CG, and GG for 118, 72, and 41 patients, respectively. Multivariable logistic regression analysis selected older age (OR = 1.06; 95% CI: 1.03-1.09; p < 0.0001), higher body mass index (BMI) (OR= 1.12; 95% CI: 1.03 1.22; p = 0.0082), and PNPLA3 genotype GG (OR = 2.07; 95% CI: 0.97-4.42; p = 0.0599) as the factors independently associated with cirrhosis. When 137 patients without past history of interferon treatment were separately assessed, multivariable logistic regression analysis selected older age (OR = 1.05; 95% CI: 1.02-1.09; p = 0.0034), and PNPLA3 genotype GG (OR = 3.35; 95% CI: 1.13-9.91; p = 0.0291) as the factors independently associated with cirrhosis. Multivariable logistic regression analysis selected older age (OR = 1.12; 95% CI: 1.07-1.17; p < 0.0001), PNPLA3 genotype GG (OR = 2.62; 95% CI: 1.15-5.96; p = 0.0218), and male gender (OR = 1.83; 95% CI: 0.90-3.71); p = 0.0936) as the factors independently associated with HCC. CONCLUSION: PNPLA3 genotype I148M is one of risk factors for developing HCC in Japanese CHC patients, and is one of risk factors for progress to cirrhosis in the patients without past history of interferon treatment. PMID- 25713770 TI - Impact of childhood trauma and affective temperament on resilience in bipolar disorder. AB - BACKGROUND: The aim of this study was to investigate whether childhood trauma (CT) and affective temperament have an impact on resilience in bipolar patients. METHODS: One hundred cases with bipolar disorder (BD) diagnosis according to the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) were evaluated consecutively in their euthymic period during outpatient follow-up interviews. Diagnostic interviews were done with SCID-I, affective temperament was evaluated with the Temperament Evaluation of Memphis, Pisa, Paris and San Diego Autoquestionnaire, and resilience was evaluated with the Resilience Scale for Adults (RSA). The presence of CT was determined and measured with the Childhood Trauma Questionnaire (CTQ). RESULTS: Among the bipolar patients, it was found that 35 cases (35%) were CT+. Depressive, cyclothymic, and anxious temperament scores were higher in CT+ cases. However, resilience scores were higher in CT- cases. In bipolar patients with and without childhood trauma, the relationship between temperament and resilience appears to be different. A negative relation between sexual abuse, emotional abuse, emotional neglect, and anxious temperament scores and resilience scores was shown in regression analysis. CONCLUSIONS: CT and affective temperament both have an impact on resilience in bipolar patients. PMID- 25713771 TI - Switch to mania after ayahuasca consumption in a man with bipolar disorder: a case report. AB - BACKGROUND: There is an increasing use of ayahuasca for recreational purposes. Furthermore, there is a growing evidence for the antidepressant properties of its components. However, there are no reports on the effects of this substance in the psychiatric setting. Harmaline, one of the main components of ayahuasca, is a selective and reversible MAO-A inhibitor and a serotonin reuptake inhibitor. CASE REPORT: We present the case of a man with bipolar disorder who had a manic episode after an ayahuasca consumption ritual. This patient had had at least one hypomanic episode in the past and is currently depressed. We discuss the diagnostic repercussion of this manic episode. CONCLUSION: There is lack of specificity in the diagnosis of substance-induced mental disorder. The knowledge of the pharmacodynamic properties of ayahuasca consumption allows a more physiopathological approach to the diagnosis of the patient. PMID- 25713772 TI - Multi-state models for investigating possible stages leading to bipolar disorder. AB - BACKGROUND: It has been proposed that bipolar disorder onsets in a predictable progressive sequence of clinical stages. However, there is some debate in regard to a statistical approach to test this hypothesis. The objective of this paper is to investigate two different analysis strategies to determine the best suited model to assess the longitudinal progression of clinical stages in the development of bipolar disorder. METHODS: Data previously collected on 229 subjects at high risk of developing bipolar disorder were used for the statistical analysis. We investigate two statistical approaches for analyzing the relationship between the proposed stages of bipolar disorder: 1) the early stages are considered as time-varying covariates affecting the hazard of bipolar disorder in a Cox proportional hazards model, 2) the early stages are explicitly modelled as states in a non-parametric multi-state model. RESULTS: We found from the Cox model thatthere was evidence that the hazard of bipolar disorder is increased by the onset of major depressive disorder. From the multi-state model, in high-risk offspring the probability of bipolar disorder by age 29 was estimated as 0.2321. Cumulative incidence functions representing the probability of bipolar disorder given major depressive disorder at or before age 18 were estimated using both approaches and found to be similar. CONCLUSIONS: Both the Cox model and multi-state model are useful approaches to the modelling of antecedent risk syndromes. They lead to similar cumulative incidence functions but otherwise each method offers a different advantage. PMID- 25713773 TI - Unexplained perioperative vertebrobasilar stroke in a patient undergoing anterior cervical decompression and disc arthroplasty. AB - BACKGROUND: Vertebrobasilar stroke associated with the anterior approach to the cervical spine is rare and has not been reported in cervical disc arthroplasty surgery. We report the case of a 60-year-old patient who underwent cervical disc arthroplasty at C4-5, C5-6 and C6-7. Postoperatively, due to symptoms and signs of a cerebellar stroke, magnetic resonance imaging of the brain was obtained confirming this diagnosis. Despite thorough investigation no specific identifiable cause for the stroke has been identified. We hypothesis an unrecognised period of intraoperative hypotension may have caused a temporary reduction in vertebrobasilar blood flow. METHODS: A retrospective review of the patient's case notes and a focused review of literature has been performed. RESULTS: Now two years postoperatively the patient has regained full power but has residual problems with balance. She has neuralgic pain down the right side of her body which following investigation is believed to result from the stroke. CONCLUSIONS / LEVEL OF EVIDENCE: Surgeons should be aware vertebrobasilar stroke is a possible rare perioperative complication associated with anterior cervical decompression and disc arthroplasty. Level V. PMID- 25713774 TI - The current situation of Endocrine Surgery in Latin America. AB - The management of patients with surgical endocrine diseases requires a multidisciplinary team of endocrinologists, radiologists, pathologists and surgeons. As the incidence of surgical endocrine disorders has increased, Endocrine Surgery has emerged as a recognized specialty within general surgery. The number of endocrine surgeons has gradually increased worldwide, however, different from Europe and North America, the specialty has not developed enough in Latin America. We have conducted an extensive research throughout the continent in order to quantify how many trained endocrine surgeons were practicing, how many training programs exist, where we are today and where are we going in the future. PMID- 25713775 TI - Is there a case for selective, rather than routine, preoperative laryngoscopy in thyroid surgery? AB - BACKGROUND: According to some authors, routine preoperative laryngoscopy should be the standard of care in all patients undergoing thyroid surgery. The rationale for this approach is (I) the risk that a patient has a preoperative vocal cord palsy (VCP) without symptoms; (II) the presence of VCP preoperatively is suggestive of invasive malignancy; (III) it is relevant for the use of intraoperative nerve monitoring; and (IV) surgical strategy may be better defined if a paralysed vocal cord is detected preoperatively. METHODS: This is a review of studies of patients who underwent routine preoperative laryngoscopy to anticipate preoperative VCP and that evaluated related risk factors, including previous surgery, voice function complaints, and a diagnosis of malignancy. The estimated risk of sustaining preoperative VCF in the absence of these factors was determined. The relevant current guidelines from different professional bodies are also addressed. RESULTS: The level of evidence that supports routine preoperative laryngoscopy is weak. The risk of harboring preoperative VCP in the absence of previous neck or other risk-related surgery, advanced malignancy or voice symptoms is very low (0.5% of cases). CONCLUSIONS: Selective rather than routine use of preoperative laryngoscopy may be acceptable provided that the risk of undetected paralysis is as low as can be reasonably ascertained from the available literature. PMID- 25713776 TI - Loss of signal in recurrent nerve neuromonitoring: causes and management. AB - During recurrent laryngeal nerve (RLN) neuromonitoring in thyroid surgery, laryngeal electromyography (EMG) amplitude may be correlated with the number of muscle fibers participating in the polarization and these might be correlated with the function of RLN. If RLN is severely injured during the operation, most nerve fibers do not transmit nerve impulse and substantial decrease of EMG amplitude or loss of signal (LOS) will occur. True LOS at the end of an operation often indicates a postoperative fixed vocal cord, and the surgeon should consider the optimal contralateral surgery timing in patients with planned bilateral thyroid operation to avoid the disaster of bilateral vocal cord palsy. However, LOS recovery and false LOS may occur and may lead to an unnecessary 2(nd) operation. Therefore, a reliable modality for intraoperative LOS evaluation and management would afford the surgeon real-time information that could help guide surgical procedure and planning. The updated causes, algorithm, and management of LOS during RLN neuromonitoring are reviewed and summarized. PMID- 25713778 TI - The current status of intraoperative iPTH assay in surgery for primary hyperparathyroidism. AB - Intraoperative intact parathyroid hormone (iPTH) monitoring has been accepted by many centers specializing in parathyroid surgery as a useful adjunct during surgery for primary hyperparathyroidism. This method can be utilized in three discreet modes of application: (I) to guide surgical decisions during parathyroidectomy in one of the following clinical contexts: (i) to confirm complete removal of all hyperfunctioning parathyroid tissue, which allows for termination of surgery with confidence that the hyperparathyroid state has been successfully corrected; (ii) to identify patients with additional hyperfunctioning parathyroid tissue following the incomplete removal of diseased parathyroid/s, which necessitates extended neck exploration in order to minimize the risk of operative failure; (II) to differentiate parathyroid from non parathyroid tissue by iPTH measurement in the fine-needle aspiration washout; (III) to lateralize the side of the neck harboring hyperfunctioning parathyroid tissue by determination of jugular venous gradient in patients with negative or discordant preoperative imaging studies, in order to increase the number of patients eligible for unilateral neck exploration. There are many advantages of minimally invasive parathyroidectomy guided by intraoperative iPTH monitoring, including focused dissection in order to remove the image-indexed parathyroid adenoma with a similar or even higher operative success rate, lower prevalence of complications and shorter operative time when compared to conventional bilateral neck exploration. However, to achieve such excellent results, the surgeon needs to be aware of hormone dynamics during parathyroidectomy and carefully choose the protocol and interpretation criteria that best fit the individual practice. Understanding the nuances of intraoperative iPTH monitoring allows the surgeon for achieving intraoperative confidence in predicting operative success and preventing failure in cases of unsuspected multiglandular disease, while safely limiting neck exploration in the majority of patients with sporadic primary hyperparathyroidism. Thus, parathyroidectomy guided by intraoperative iPTH monitoring for the management of sporadic primary hyperparathyroidism is an ideal option for the treatment of this disease entity. However, the cost-benefit aspects of the standard application of this method still remain a matter of controversy. PMID- 25713777 TI - Recovery of laryngeal function after intraoperative injury to the recurrent laryngeal nerve. AB - Loss of function in the recurrent laryngeal nerve (RLN) during thyroid/parathyroid surgery, despite a macroscopically intact nerve, is a challenge which highlights the sensitivity and complexity of laryngeal innervation. Furthermore, the uncertain prognosis stresses a lack of capability to diagnose the reason behind the impaired function. There is a great deal of literature considering risk factors, surgical technique and mechanisms outside the nerve affecting the incidence of RLN paresis during surgery. To be able to prognosticate recovery in cases of laryngeal dysfunction and voice changes after thyroid surgery, the surgeon would first need to define the presence, location, and type of laryngeal nerve injury. There is little data describing the events within the nerve and the neurobiological reasons for the impaired function related to potential recovery and prognosis. In addition, very little data has been presented in order to clarify any differences between the transient and permanent injury of the RLN. This review aims, from an anatomical and neurobiological perspective, to provide an update on the current understandings of surgically-induced injury to the laryngeal nerves. PMID- 25713779 TI - Management of anaplastic thyroid cancer. AB - Anaplastic thyroid cancer (ATC) is a deadly disease with a dismal prognosis. Molecular analyses of ATC tumors have yielded interesting results, which could help in understanding the underlying mechanisms of this aggressive disease process. Managing ATC can be challenging and includes rapid diagnosis, adequate staging, and interdisciplinary, multimodal treatments to optimize patient outcome. Treatments include surgical resection to gross negative margins when possible, as well as neo- or adjuvant treatment with chemotherapy or external beam radiation (XRT) for locoregional disease. New treatment strategies include evaluating the benefits of vascular disrupting agents and tyrosine kinase inhibitors for advanced ATC with driver mutations, which can be targeted. This review summarizes key concepts in managing ATC. PMID- 25713780 TI - Recurrence of papillary thyroid cancer after optimized surgery. AB - Recurrence of papillary thyroid cancer (PTC) after optimized surgery requires a full understanding of the disease, especially as it has changed in the last 15 years, what comprises optimized surgery, and the different types and implications of disease relapse that can be encountered. PTC has evolved to tumors that are much smaller than previously seen, largely due to various high quality imaging studies obtained for different reasons, but serendipitously identifying thyroid nodules that prove to be papillary thyroid microcarcinomas (PTMC). With rare exception, these cancers are cured by conservative surgery without additional therapy, and seldom result in recurrent disease. PTC is highly curable in 85% of cases because of its rather innocent biologic behavior. Therefore, the shift in emphasis from disease survival to recurrence is appropriate. As a result of three technologic advances-high-resolution ultrasound (US), recombinant TSH, and highly sensitive thyroglobulin (Tg)-disease relapse can be discovered when it is subclinical. Endocrinologists who largely control administration of radioactive iodine have used it to ablate barely detectable or even biochemically apparent disease, hoping to reduce recurrence and perhaps improve survival. Surgeons, in response to this new intense postoperative surveillance that has uncovered very small volume disease, have responded by utilizing US preoperatively to image this disease, and incorporated varying degrees of lymphadenectomy into their initial treatment algorithm. Bilateral thyroid resection-either total or near-total thyroidectomy-remains the standard for PTC >1 cm, although recent data has re emphasized the value of unilateral lobectomy in treating even some PTC measuring 1-4 cm. Therapeutic lymphadenectomy has universal approval, but when lymph nodes in the central neck are not worrisome to the surgeon's intraoperative assessment, although that judgment in incorrect up to 50%, whether they should be excised has reached a central point of controversy. Disease relapse can occur individually or in combination of three different forms: lymph node metastasis (LNM), true soft tissue local recurrence, and distant disease. The latter two are worrisome for potentially life-threatening consequences whereas nodal metastases are often persistent from the initial operation, and mostly comprise a biologic nuisance rather than virulent disease. A moderate surgical approach of bilateral thyroid resection, with usual central neck nodal clearance, and lateral internal jugular lymphadenectomy for node-positive disease can be performed safely, and with about a 5% recurrence rate. PMID- 25713781 TI - Management of pancreatic neuroendocrine tumors in patients with MEN 1. AB - Pancreatic neuroendocrine tumors (PNETs) are frequent and can be non-functional (NF) in patients with multiple endocrine neoplasia type 1 (MEN1). Their identification is of clinical importance because malignant PNETs are reported to be the most common cause of death in patients with MEN1. Once the diagnosis of MEN1 is established in an individual based on clinical manifestations and/or genetic testing results, an active surveillance program is instituted for early detection and treatment of MEN1-associated disease. Ultrasonography, endoscopic ultrasonography (EUS), CT, MRI, selective arterial angiography and somatostatin receptor scintigraphy are all used for localization of tumors. Managing PNETs can be challenging and includes diagnosis, surveillance, adequate staging, and interdisciplinary, multimodal treatments to optimize patient outcome. Treatment includes surgical resection for loco-regional disease, as well as liver directed and targeted chemotherapies for advanced progressive disease. To date, the recommendation for surgical resection in NF-PNETs is based on tumor size, as a higher rate of metastases was found in patients with larger tumors. This review summarizes key concepts in managing PNETs in patients with MEN1. PMID- 25713782 TI - Approach to the surgical management of primary aldosteronism. AB - Primary aldosteronism (PA) is the most common cause of endocrine hypertension; it has been reported in more than 11% of referred hypertensive patients. PA may be caused by unilateral adrenal involvement [aldosterone producing adenoma (APA) or unilateral adrenal hyperplasia (UAH)], and bilateral disease (idiopathic adrenal hyperplasia). Only patients with unilateral adrenal hypersecretion may be cured by unilateral adrenalectomy, while patients with bilateral and non-surgically correctable PA are usually treated by mineralocorticoid receptor antagonists; thus the distinction between unilateral and bilateral aldosterone hypersecretion is crucial. Most experts agree that the referral diagnostic test for lateralization of aldosterone hypersecretion should be adrenal venous sampling (AVS) because the interpretation of other imaging techniques [computed tomography (CT), magnetic resonance imaging (MRI) and scintigraphy] may lead to inappropriate treatment. Adrenalectomy represents the elective treatment in unilateral PA variants. Laparoscopic surgery, using transperitoneal or retroperitoneal approaches, is the preferred strategy. Otherwise, the indications to laparoscopic unilateral total or partial adrenalectomy in patients with unilateral PA remain controversial. Adrenalectomy is highly successful in curing the PA, with correction of hypokalemia in virtually all patients, cure of hypertension in about 30-60% of cases, and a marked improvement of blood pressure values in the remaining patients. Interestingly, in several papers the outcomes of surgery focus only on blood pressure changes and the normalization of serum potassium levels is often used as a surrogate of PA recovery. However, the goal of surgery is the normalization of aldosterone, because chronically elevated levels of this hormone can lead to cardiovascular complications, independently from blood pressure levels. Thus, we strongly advocate the need of considering the postoperative normalization of aldosterone-renin ratio (ARR) as the main endpoint for determining outcomes of PA. PMID- 25713783 TI - Defining the syndromes of parathyroid failure after total thyroidectomy. AB - Acute and chronic parathyroid insufficiency syndromes are the most common complication after total thyroidectomy. Permanent hypoparathyroidism imposes an important medical burden on patient lifestyle due to the need for lifetime medication, regular visits and significant long-term costs. Its true prevalence has been underestimated due to lack of clear definitions, inadequate follow-up and conflicts of interest when reporting individual patient series. The aim of this review is to propose precise definitions for the different syndromes associated to parathyroid failure based on the follow-up and management of patients developing hypocalcemia (<8 mg/dL at 24 hours) after first-time total thyroidectomy for cancer or goiter at our unit. Short and long-term post thyroidectomy parathyroid failure presents as three different metabolic syndromes: (I) postoperative hypocalcemia is defined as a s-Ca <8 mg/dL (<2 mmol/L) within 24 hours after surgery requiring calcium/vit D replacement therapy at the time of hospital discharge; (II) protracted hypoparathyroidism as a subnormal iPTH concentration (<13 pg/mL) and/or need for calcium/vit D replacement at 4-6 weeks; and (III) permanent hypoparathyroidism as a subnormal iPTH concentration (<13 pg/mL) and/or need for calcium/vit D replacement 1 year after total thyroidectomy. Each of these syndromes has its own pattern of recovery and should be approached with different therapeutic strategies. PMID- 25713786 TI - Transduction-mediated horizontal gene transfer in the oral microbiome. PMID- 25713787 TI - The role of calcium in human aging. AB - Calcium is an essential nutrient that is necessary for many functions in human health. Calcium is the most abundant mineral in the body with 99% found in teeth and bone. Only 1% is found in serum. The serum calcium level is tightly monitored to remain within normal range by a complex metabolic process. Calcium metabolism involves other nutrients including protein, vitamin D, and phosphorus. Bone formation and maintenance is a lifelong process. Early attention to strong bones in childhood and adulthood will provide more stable bone mass during the aging years. Research has shown that adequate calcium intake can reduce the risk of fractures, osteoporosis, and diabetes in some populations. The dietary requirements of calcium and other collaborative nutrients vary slightly around the world. Lactose intolerance due to lactase deficiency is a common cause of low calcium intake. Strategies will be discussed for addressing this potential barrier to adequate intake. The purpose of this narrative review is a) to examine the role of calcium in human health, b) to compare nutrient requirements for calcium across lifecycle groups and global populations, c) to review relationships between calcium intake, chronic disease risk, and fractures, and d) to discuss strategies to address diet deficiencies and lactose intolerance. PMID- 25713788 TI - Association of Sugar-Sweetened Beverage Intake during Infancy with Dental Caries in 6-year-olds. AB - To examine whether sugar-sweetened beverage (SSB) intake during infancy is associated with dental caries by age 6, a longitudinal analysis of 1,274 U.S. children was conducted using data from the 2005-2007 Infant Feeding Practices Study II and the 2012 Follow-up Study at 6 years of age. The exposure variables were maternal-reported SSB intakes during infancy (i.e., any SSB intake during infancy, age at SSB introduction during infancy, and average frequency of SSB intake during 10-12 months of age). The outcome variable was maternal-reported dental caries of their 6-year-old in his/her lifetime. Multivariable logistic regression analyses were used to calculate adjusted odds ratios (aOR) for associations of SSB intake during infancy with having dental caries among 6-year olds after controlling for baseline characteristics of children and mothers and child's tooth brushing habits and sweet food intake at follow-up. Based on maternal recall, almost 40% of 6-year-olds had dental caries in their lifetime. Adjusted odds of having dental caries was significantly associated with higher frequency of SSB intake during 10-12 months (aOR=1.83 for >=3 times/week, vs. none). Any SSB intake during infancy and age at SSB introduction during infancy were not associated with dental caries. In conclusion, frequent SSB intake during 10-12 months of age significantly increased the likelihood of having dental caries among 6-year-olds. Late infancy may be an important time for mothers to establish healthy beverage practices for their children. These findings can be used to inform efforts to reduce dental caries among children. PMID- 25713785 TI - Polysaccharide intercellular adhesin in biofilm: structural and regulatory aspects. AB - Staphylococcus aureus and Staphylococcus epidermidis are the leading etiologic agents of implant-related infections. Biofilm formation is the main pathogenetic mechanism leading to the chronicity and irreducibility of infections. The extracellular polymeric substances of staphylococcal biofilms are the polysaccharide intercellular adhesin (PIA), extracellular-DNA, proteins, and amyloid fibrils. PIA is a poly-beta(1-6)-N-acetylglucosamine (PNAG), partially deacetylated, positively charged, whose synthesis is mediated by the icaADBC locus. DNA sequences homologous to ica locus are present in many coagulase negative staphylococcal species, among which S. lugdunensis, however, produces a biofilm prevalently consisting of proteins. The product of icaA is an N acetylglucosaminyltransferase that synthetizes PIA oligomers from UDP-N acetylglucosamine. The product of icaD gives optimal efficiency to IcaA. The product of icaC is involved in the externalization of the nascent polysaccharide. The product of icaB is an N-deacetylase responsible for the partial deacetylation of PIA. The expression of ica locus is affected by environmental conditions. In S. aureus and S. epidermidis ica-independent alternative mechanisms of biofilm production have been described. S. epidermidis and S. aureus undergo to a phase variation for the biofilm production that has been ascribed, in turn, to the transposition of an insertion sequence in the icaC gene or to the expansion/contraction of a tandem repeat naturally harbored within icaC. A role is played by the quorum sensing system, which negatively regulates biofilm formation, favoring the dispersal phase that disseminates bacteria to new infection sites. Interfering with the QS system is a much debated strategy to combat biofilm-related infections. In the search of vaccines against staphylococcal infections deacetylated PNAG retained on the surface of S. aureus favors opsonophagocytosis and is a potential candidate for immune-protection. PMID- 25713789 TI - Dietary compliance, dietary supplementation and traditional remedy usage of type 2 diabetic patients with and without cardiovascular disease. AB - This analytical cross-sectional study examined the nutrient intakes, dietary compliance, dietary supplementation and traditional remedy usage in type 2 diabetes mellitus (T2DM) patients from selected tertiary hospitals in multi racial Malaysia. We compared the different characteristics of T2DM patients with and without cardiovascular disease (CVD). Socio-demographic status, dietary intakes, dietary supplementation, traditional remedy use, medical history, anthropometric measurements and clinical characteristics were obtained from face to-face interviews. A total of 313 patients who were treated for T2DM participated in this study, in which 36.1% of them had CVD. The mean age of study subjects was 55.7 +/- 9.2 years; mean diabetes duration was 10.1 +/- 8.1 years; 52.1% were females; and 47.0% were Malays. The mean total energy intake of the subjects was 1674 +/- 694 kcal/day, and patients with CVD consumed higher total calories (p = 0.001). Likewise, the mean carbohydrate, protein and total fat intake of CVD patients were significantly higher than non-CVD patients (p < 0.05), while mean intakes of cholesterol, fibre, minerals and all vitamins were comparable between CVD and non-CVD patients. Regardless of CVD status, a notably high proportion of the subjects did not meet the recommendations of the Medical Nutrition Therapy Guidelines for Type 2 Diabetes for total energy, carbohydrate, protein, total fat, and fibre intakes. Meanwhile, 52.4% used at least one dietary supplement and 12.1% took single traditional remedy or in various combinations. Traditional remedies and supplement intake did not differ between CVD and non-CVD subjects. It is suggested that T2DM patients should be educated based on their personalized dietary intake, dietary supplementation and traditional remedy usage. The recommendations for T2DM patients shall be met to achieve the optimal metabolic goals and minimize the potential diabetic complications. PMID- 25713790 TI - Use of bioelectrical impedance analysis for the assessment of nutritional status in critically ill patients. AB - Malnutrition is common in the critically ill patients and known to cause a variety of negative clinical outcomes. However, various conventional methods for nutrition assessment have several limitations. We hypothesized that body composition data, as measured using bioelectrical impedance analysis (BIA), may have a significant role in evaluating nutritional status and predicting clinical outcomes in critically ill patients. We gathered clinical, biochemical, and BIA data from 66 critically ill patients admitted to an intensive care unit. Patients were divided into three nutritional status groups according to their serum albumin level and total lymphocyte counts. The BIA results, conventional indicators of nutrition status, and clinical outcomes were compared and analyzed retrospectively. Results showed that the BIA indices including phase angle (PhA), extracellular water (ECW), and ECW/total body water (TBW) were significantly associated with the severity of nutritional status. Particularly, PhA, an indicator of the health of the cell membrane, was higher in the well-nourished patient group, whereas the edema index (ECW/TBW) was higher in the severely malnourished patient group. PhA was positively associated with albumin and ECW/TBW was negatively associated with serum albumin, hemoglobin, and duration of mechanical ventilation. In non-survivors, PhA was significantly lower and both ECW/TBW and %TBW/fat free mass were higher than in survivors. In conclusion, several BIA indexes including PhA and ECW/TBW may be useful for nutritional assessment and represent significant prognostic factors in the care of critically ill patients. PMID- 25713791 TI - Diet, sleep and metabolic syndrome among a legal Amazon population, Brazil. AB - Metabolic syndrome incidence is increasing worldwide then it is important to study the possible risk and protective factors. Our previous study suggested an association between coffee consumption and metabolic syndrome. The aim of this study was to address possible associations between dietary lifestyle factors with metabolic syndrome. In a case-control study we compared 74 metabolic syndrome patients with 176-matched controls attended at a public health central unit. Incident cases diagnosed according to ATP III criteria were matched with control group composed of healthy subjects performing routine examinations. Having lower educational level compared to highest levels tend to increase metabolic syndrome prevalence, which was not statistically significant. Similar pattern was observed for marital status. No difference was found regarding gender and metabolic syndrome odds. Interestingly, daily drinking two to three cups of coffee (OR=0.0646, 95% CI, 0.0139-0.3005, p=0.0005) or until 2 cups of milk were inversely associated with metabolic syndrome odds (OR=0.5368, 95% CI, 0.3139 0.9181, p=0.0231). Sleeping seven to eight hours per night was also associated with decreased odds of metabolic syndrome (OR=0.0789, 95% CI, 0.0396-0.1570, p<0.0001). Eating at least two portions of chocolate was also associated with decreased risk of metabolic syndrome (OR=0.3475, 95%CI, 0.1865-0.6414, p=0.0009). Adequate sleeping and dietary intake of some foods materially decreased the metabolic syndrome. PMID- 25713792 TI - A Better Diet Quality is Attributable to Adequate Energy Intake in Hemodialysis Patients. AB - Poor diet quality is one of strong predictors of subsequent increased mortality in hemodialysis patients. To determine diet quality and to define major problems contributing to poor diet quality in hemodialysis patients, a cross-sectional study was conducted between June 2009 and October 2010. Sixty-three hemodialysis patients (31 men, 32 women; aged 55.3 +/- 11.9 years) in stable condition were recruited from the Artificial Kidney Center in Kyung Hee University, Seoul, Korea. Three-day diet records were obtained for dietary assessment. Mean adequacy ratio (MAR) is the average of the ratio of intakes to Dietary Reference Intakes (DRI) for 12 nutrients. Index of nutritional quality (INQ) was determined as the nutritional density per 1,000 kcal of calories. Overall diet quality was evaluated using the Diet Quality Index-International (DQI-I). Statistics were used to determine diet quality, comparing dietary intake to DRI. Dietary calories (21.9 +/- 6.7 kcal/kg/day) and protein (0.9 +/- 0.3 g/kg/day) were found insufficient in the participants. The overall intake of 12 nutrients appeared to be also inadequate (0.66 +/- 0.15), but INQs of overall nutrients, except for folate (0.6) and calcium (0.8), were found relatively adequate (INQ >= 1). As a result of diet quality assessment using DQI-I, dietary imbalance and inadequacy were found to be the most problematic in hemodialysis patients. This study suggests that the main reason for insufficient intake of essential nutrients is insufficient calorie intake. Hemodialysis patients should be encouraged to use various food sources to meet their energy requirements as well as satisfy overall balance and nutrient adequacy. PMID- 25713793 TI - Comparison of nursing records and the catholic medical center nutritional risk screening as a nutrition screening tool for intensive care unit patients. AB - In the present study, we aimed to compare the results from nutritional risk screening based on nursing records with those using the Catholic Medical Center Nutritional Risk Screening (CMCNRS) tool. A cross-sectional study was performed involving 91 patients aged >= 18 years from an intensive care unit. We collected general characteristics of the patients and nutrition screening was conducted for each patient by using computerized hospital program for the nursing records as well as the CMCNRS conducted by clinical dietitians. The subjects were aged 64.0 +/- 17.5 years, and 52 (57.1%) patients had a NPO (nothing by mouth) status. Neurological disease was the most common diagnosis (25.3%). Compared with the CMCNRS results from the clinical dietitians, the results for the nursing records had a sensitivity of 40.5% (95% CI 32.0-40.5) and a specificity of 100.0% (95% CI 92.8-100.0). The agreement was fair between the CMCNRS results obtained by clinical dietitians and the nursing records (k = 0.423). Analysis of the errors from the screening using the nursing records revealed significant differences for all subjective indicators (p < 0.001), compared with the CMCNRS by the clinical dietitians. Thus, after assessing the methods used for nutrition screening and the differences in the search results regarding malnourished status, we noted that the nursing records had a lower sensitivity than the screening by the CMCNRS. PMID- 25713794 TI - Nutritional intervention using nutrition care process in a malnourished patient with chemotherapy side effects. AB - In this case study, the process of nutritional diagnosis and intervention conducted at a hospital on a malnourished patient who underwent treatment for a chronic illness (chemotherapy for cancer treatment) was recorded. The patient received his first round of chemotherapy for colorectal cancer, and then a second round after the cancer metastasized to the liver. The patient was malnourished and had experienced weight loss (17% loss in the most recent 3 months) due to side effects of chemotherapy including stomatitis, nausea, and vomiting. Nutritional diagnosis and intervention via the nutrition care process were implemented through two screening rounds, and the quantity of oral intake increased from 28% to 62% of the recommended daily intake. The patient required continuous monitoring and outpatient care after hospital discharge. It is speculated that if a more active patient education and dietary regimen with respect to chemotherapy side effects had been offered after the patient's first chemotherapy cycle, it might have been possible to treat ingestion problems due to stomatitis during the second cycle of chemotherapy and prevent the weight loss. Henceforth, patients receiving chemotherapy should be educated about nutrition management methods and monitored continuously to prevent malnutrition. PMID- 25713795 TI - Progress in the articulation of undergraduate and graduate public health? PMID- 25713796 TI - A biological perspective toward the interaction of theranostic nanoparticles with the bloodstream - what needs to be considered? PMID- 25713797 TI - Quantum chemical calculations predict biological function: the case of T cell receptor interaction with a peptide/MHC class I. AB - A combination of atomic correlation statistics and quantum chemical calculations are shown to predict biological function. In the present study, various antigenic peptide-Major Histocompatibility Complex (pMHC) ligands with near-identical stereochemistries, in complexation with the same T cell receptor (TCR), were found to consistently induce distinctly different quantum chemical behavior, directly dependent on the peptide's electron spin density and intrinsically expressed by the protonation state of the peptide's N-terminus. Furthermore, the cumulative coordination difference of any variant in respect to the native peptide was found to accurately reflect peptide biological function and immerges as the physical observable which is directly related to the immunological end effect of pMHC-TCR interaction. PMID- 25713798 TI - Promiscuous functions of the prion protein family. PMID- 25713799 TI - Retroperitoneal liposarcoma: current insights in diagnosis and treatment. AB - Retroperitoneal liposarcoma (RLS) is a rare, biologically heterogeneous tumor that present considerable challenges due to its size and deep location. As a consequence, the majority of patients with high-grade RLS will develop locally recurrent disease following surgery, and this constitutes the cause of death in most patients. Here, we review current insights and controversies regarding histology, molecular biology, extent of surgery, (neo)adjuvant treatment, and systemic treatment including novel targeted agents in RLS. PMID- 25713800 TI - Hepatitis B virus large surface protein: function and fame. AB - Chronic infection with hepatitis B virus (HBV) is the leading cause of liver cirrhosis and hepatocellular carcinoma worldwide. HBV life cycle begins with viral attachment to hepatocytes, mediated by the large HBV surface protein (LHBs). Identification of the sodium-taurocholate cotransporting polypeptide (NTCP) as a HBV receptor has revealed a suitable target for viral entry inhibition. Analysis of serum hepatitis B surface antigen (HBsAg) level is a non invasive diagnostic parameter that improves HBV treatment opportunities. Furthermore, HBsAg plays an important role in manipulation of host immune response by HBV. However, observations in patients with chronic hepatitis B under conditions of immune suppression and in transgenic mouse models of HBV infection suggest, that in absence of adaptive immune responses cellular mechanisms induced by HBV may also lead to the development of liver diseases. Thus, the multifaceted pathological aspects of HBsAg predetermine the design of new therapeutical options modulating associated biological implications. PMID- 25713801 TI - Immunoregulation by lipids during the development of non-alcoholic steatohepatitis. AB - Non-alcoholic fatty liver disease (NAFLD) represents the most common liver disorder in western countries and it is commonly associated with obesity and progression of the metabolic syndrome. Comprehending a wide spectrum of pathologic features, it is currently well recognized that a key point for the integrity of hepatocyte functionality in NAFLD is the progression from simple steatosis to non-alcoholic steatohepatitis (NASH). Indeed, activation of the innate immune system in response to hepatic metabolic stresses represents a central process that determines the evolution and the reversibility of liver damage. Despite of the burden of studies published in recent years, it is still intriguingly unclear how accumulation of lipids in hepatocytes triggers the activation of the inflammatory response leading to the recruitment of infiltrating cells of extra-hepatic origins. In this review we offer a general view on recent advances pointing out how different classes of lipids are able to specifically affect hepatocytes functionality and survival, thus differently influencing the organization of the hepatic immune response. On the other hand, we gathered recent studies intending to illustrate the basic mechanisms through which several non-parenchymal hepatic and extra-hepatic cell populations get activated in response to lipids. Finally, we indicate latter findings proposing how the immune system majorly contributes to the progression of NASH. PMID- 25713802 TI - The role of miRNAs in the regulation of inflammatory processes during hepatofibrogenesis. AB - Liver cirrhosis represents the end stage of most chronic inflammatory liver diseases and is a major global health burden. Despite the enormous relevance of cirrhotic disease, pharmacological strategies for prevention or treatment of hepatic fibrosis are still limited, underlining the need to establish a better understanding of the molecular mechanisms underlying the pathogenesis of hepatic cirrhosis. Recently, miRNAs have emerged as a new class of RNAs that do not withhold the information to encode for proteins but regulate whole gene expression networks during different physiological and pathological processes. Various authors demonstrated that miRNA species are functionally involved in the regulation of chronic liver damage and development of liver cirrhosis in inflamed livers. Moreover, circulating miRNA patterns were suggested to serve as blood based biomarkers indicating liver injury and progression to hepatic cirrhosis and cancer. Here we summarize current findings on a potential role of miRNAs in the cascade leading from liver inflammation to liver fibrosis and finally hepatocellular carcinoma. We compare data from animal models with findings on miRNAs dysregulated in human patients and finally highlight a potential use of miRNAs as biomarkers for liver injury, fibrosis and cancer. PMID- 25713803 TI - Contribution of bone marrow-derived fibrocytes to liver fibrosis. AB - Since the discovery of fibrocytes in 1994 by Dr. Bucala and colleagues, these bone marrow (BM)-derived collagen Type I producing CD45(+) cells remain the most fascinating cells of the hematopoietic system. Despite recent reports on the emerging contribution of fibrocytes to fibrosis of parenchymal and non parenchymal organs and tissues, fibrocytes remain the most understudied pro fibrogenic cellular population. In the past years fibrocytes were implicated in the pathogenesis of liver, skin, lung, and kidney fibrosis by giving rise to collagen type I producing cells/myofibroblasts. Hence, the role of fibrocytes in fibrosis is not well defined since different studies often contain controversial results on the number of fibrocytes recruited to the site of injury versus the number of fibrocyte-derived myofibroblasts in the same fibrotic organ. Furthermore, many studies were based on the in vitro characterization of fibrocytes formed after outgrowth of BM and/or peripheral blood cultures. Therefore, the fibrocyte function(s) still remain(s) lack of understanding, mostly due to (I) the lack of mouse models that can provide complimentary in vivo real-time and cell fate mapping studies of the dynamic differentiation of fibrocytes and their progeny into collagen type I producing cells (and/or possibly, other cell types of the hematopoietic system); (II) the complexity of hematopoietic cell differentiation pathways in response to various stimuli; (III) the high plasticity of hematopoietic cells. Here we summarize the current understanding of the role of CD45(+) collagen type I(+) BM-derived cells in the pathogenesis of liver injury. Based on data obtained from various organs undergoing fibrogenesis or other type of chronic injury, here we also discuss the most recent evidence supporting the critical role of fibrocytes in the mediation of pro-fibrogenic and/or pro-inflammatory responses. PMID- 25713804 TI - Role of liver progenitors in liver regeneration. AB - During massive liver injury and hepatocyte loss, the intrinsic regenerative capacity of the liver by replication of resident hepatocytes is overwhelmed. Treatment of this condition depends on the cause of liver injury, though in many cases liver transplantation (LT) remains the only curative option. LT for end stage chronic and acute liver diseases is hampered by shortage of donor organs and requires immunosuppression. Hepatocyte transplantation is limited by yet unresolved technical difficulties. Since currently no treatment is available to facilitate liver regeneration directly, therapies involving the use of resident liver stem or progenitor cells (LPCs) or non-liver stem cells are coming to fore. LPCs are quiescent in the healthy liver, but may be activated under conditions where the regenerative capacity of mature hepatocytes is severely impaired. Non liver stem cells include embryonic stem cells (ES cells) and mesenchymal stem cells (MSCs). In the first section, we aim to provide an overview of the role of putative cytokines, growth factors, mitogens and hormones in regulating LPC response and briefly discuss the prognostic value of the LPC response in clinical practice. In the latter section, we will highlight the role of other (non-liver) stem cells in transplantation and discuss advantages and disadvantages of ES cells, induced pluripotent stem cells (iPS), as well as MSCs. PMID- 25713806 TI - Perioperative chemotherapy and hepatic resection for resectable colorectal liver metastases. AB - The role of perioperative chemotherapy in the management of initially resectable colorectal liver metastases (CRLM) is still unclear. The EPOC trial [the European Organization for Research and Treatment of Cancer (EORTC) 40983] is an important study that declares perioperative chemotherapy as the standard of care for patients with resectable CRLM, and the strategy is widely accepted in western countries. Compared with surgery alone, perioperative FOLFOX therapy significantly increased progression-free survival (PFS) in eligible patients or those with resected CRLM. Overall survival (OS) data from the EPOC trial were recently published in The Lancet Oncology, 2013. Here, we discussed the findings and recommendations from the EORTC 40983 trial. PMID- 25713805 TI - Pancreatic cancer surgery and nutrition management: a review of the current literature. AB - Surgery remains the only curative treatment for pancreaticobiliary tumors. These patients typically present in a malnourished state. Various screening tools have been employed to help with preoperative risk stratification. Examples include the subjective global assessment (SGA), malnutrition universal screening tool (MUST), and nutritional risk index (NRI). Adequate studies have not been performed to determine if perioperative interventions, based on nutrition risk assessment, result in less morbidity and mortality. The routine use of gastric decompression with nasogastric sump tubes may be unnecessary following elective pancreatic resections. Instead, placement should be selective and employed on a case-by-case basis. A wide variety of feeding modalities are available, oral nutrition being the most effective. Artificial nutrition may be provided by temporary nasal tube (nasogastric, nasojejunal, or combined nasogastrojejunal tube) or surgically placed tube [gastrostomy (GT), jejunostomy (JT), gastrojejunostomy tubes (GJT)], and intravenously (parenteral nutrition, PN). The optimal tube for enteral feeding cannot be determined based on current data. Each is associated with a specific set of complications. Dual lumen tubes may be useful in the presence of delayed gastric emptying (DGE) as the stomach may be decompressed while feeds are delivered to the jejunum. However, all feeding tubes placed in the small intestine, except direct jejunostomies, commonly dislodge and retroflex into the stomach. Jejunostomies are associated with less frequent, but more serious complications. These include intestinal torsion and bowel necrosis. PN is associated with septic, metabolic, and access-related complications and should be the feeding strategy of last-resort. Enteral feeds are clearly preferred over parental nutrition. A sound understanding of perioperative nutrition may improve patient outcomes. Patients undergoing pancreatic cancer surgery should undergo multidisciplinary nutrition screening and intervention, and the surgical/oncological team should include nutrition professionals in managing these patients in the perioperative period. PMID- 25713807 TI - Uncertainty about the safety of supplemental glutamine: an editorial on "A randomized trial of glutamine and antioxidants in critically ill patients". AB - Previously small randomized clinical trials and several meta-analyses have suggested improved patient outcomes from parenteral glutamine supplementation. A recent large multi-center randomized trial conducted in critically ill patients with documented multiple organ failure at enrollment demonstrated an increase in mortality among those receiving supplemental glutamine. This article discusses the discrepancies in trial outcomes and the risks associated with glutamine administration during critical illness. PMID- 25713808 TI - Perioperative chemotherapy for resectable colorectal hepatic metastases-What does the EORTC 40983 trial update mean? AB - The liver is the most common site of colorectal cancer metastasis. Although successful resection leads to durable overall survival (OS), local and distant recurrence is common. As a result, multidisciplinary strategies have been developed to decrease recurrence rates as well as increase the number of candidates for resection. A recent update to the European Organisation for Research and Treatment of Cancer (EORTC) Intergroup trial 40983 has been published comparing perioperative chemotherapy to surgery alone. This randomized trial initially demonstrated a benefit in progression free survival (PFS) with the administration of perioperative FOLFOX chemotherapy, albeit with an increased rate of complications. Although this led many investigators and clinicians to adopt the perioperative approach, the recent update failed to report any advantage in OS and therefore results in further controversy as to the role of perioperative systemic chemotherapy in the treatment of resectable colorectal hepatic metastases. PMID- 25713809 TI - Living legend in surgery: Professor Stig Bengmark. PMID- 25713810 TI - Fascioliasis simulating an intrahepatic cholangiocarcinoma-Case report with imaging and pathology correlation. AB - Human fascioliasis is a rare zoonosis in Chile. Clinically it presents with a highly polymorphous group of symptoms that evolve in two periods. The first, acute or a result of hepatic invasion, lasts 2 weeks to 4 months and is characterized essentially by pain in the right hypochondrium and/or epigastrium, continuous fever and painful hepatomegaly. This clinical picture, associated with eosinophilia and a history of raw watercress consumption, corresponds to the classic presentation of the disease in its initial stage. We report the case of a 57-year-old female patient with no risk factors for and no clinical signs of fascioliasis, with a lesion in the right hepatic lobe compatible with intrahepatic cholangiocarcinoma, studied with computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography (PET-CT). With the clinical suspicion of intrahepatic cholangiocarcinoma, a regulated right hepatectomy was performed, the pathological study of which revealed cholangitis and granulomatous pericholangitis resulting from trematode eggs, compatible with Fasciola hepatica. PMID- 25713811 TI - Ruptured choledochal cyst: a rare presentation and unique approach to management. AB - We present the rare case of a ruptured choledochal cyst (CC) in a young woman presenting with a two-day history of worsening upper abdominal pain. Imaging revealed a contracted gallbladder, dilated common bile duct (CBD), and a large amount of peritoneal fluid. Percutaneous paracentesis was performed, obtaining bilious fluid. Further imaging revealed cystic dilatation of the CBD and the diagnosis of rupture CC type I was made. The patient was initially managed conservatively with percutaneous drains, IV antibiotic therapy, and sphincterotomy through an ERCP. Elective cyst resection and Roux-en-Y hepatojejunostomy was performed 8 weeks later. It is important to differentiate a ruptured CC from other surgical emergencies without exploratory laparotomy. Initial conservative management could be considered, followed by elective resection once inflammation, infection, and other complications have resolved, avoiding the increased risk associated with an emergency operation or two-stage laparotomy. PMID- 25713813 TI - Research on bacterial virulence in the developing countries. PMID- 25713812 TI - Impaired translocation of GLUT4 results in insulin resistance of atrophic soleus muscle. AB - Whether or not the atrophic skeletal muscle induces insulin resistance and its mechanisms are not resolved now. The antigravity soleus muscle showed a progressive atrophy in 1-week, 2-week, and 4-week tail-suspended rats. Hyperinsulinemic-euglycemic clamp showed that the steady-state glucose infusion rate was lower in 4-week tail-suspended rats than that in the control rats. The glucose uptake rates under insulin- or contraction-stimulation were significantly decreased in 4-week unloaded soleus muscle. The key protein expressions of IRS-1, PI3K, and Akt on the insulin-dependent pathway and of AMPK, ERK, and p38 on the insulin-independent pathway were unchanged in unloaded soleus muscle. The unchanged phosphorylation of Akt and p38 suggested that the activity of two signal pathways was not altered in unloaded soleus muscle. The AS160 and GLUT4 expression on the common downstream pathway also was not changed in unloaded soleus muscle. But the GLUT4 translocation to sarcolemma was inhibited during insulin stimulation in unloaded soleus muscle. The above results suggest that hindlimb unloading in tail-suspended rat induces atrophy in antigravity soleus muscle. The impaired GLUT4 translocation to sarcolemma under insulin stimulation may mediate insulin resistance in unloaded soleus muscle and further affect the insulin sensitivity of whole body in tail-suspended rats. PMID- 25713815 TI - The price of success. PMID- 25713814 TI - De novo assembly and characterization of Oryza officinalis leaf transcriptome by using RNA-seq. AB - Although endeavors have been made to identify useful wild rice genes that can be used to improve cultivated rice, the virtual reservoir of genetic variation hidden within the wild relatives of cultivated rice is largely untapped. Here, using next-generation sequencing technology, we investigated the leaf transcriptome of a wild rice O. officinalis with CC genome. Approximately 23 million reads were produced in the species leaf transcriptome analysis and de novo assembly methods constructed 68,132 unigenes. Functional annotations for the unigenes were conducted using sequence similarity comparisons against the following databases: the nonredundant nucleotide database, the nonredundant protein database, the SWISS-PROT database, the Clusters of Orthologous Groups of proteins database, the Kyoto Encyclopedia of Genes and Genomes database, the Gene Ontology Consortium database, and the InterPro domains database. In addition, a total of 476 unigenes related to disease resistance were identified in O. officinalis, and these unigenes can serve as important genetic resources for cultivated rice breeding and quality improvement. The present study broadens our understanding of the genetic background of non-AA genomic wild rice species and it also provides a bridge to extend studies to other Oryza species with CC genomes. PMID- 25713816 TI - A high-throughput and selective method for the measurement of surface areas of silver nanoparticles. AB - A high-throughput and selective method based on biomolecule affinity coordination was employed for measuring nanoparticle surface area in solutions. In this design, silver binding peptides (AgBPs) are immobilized on bacterial cellulose via fusion with cellulose binding domains to capture silver nanoparticles whereas green fluorescent proteins are fused with AgBPs as reporters for surface area quantification. PMID- 25713817 TI - A colorimetric and smartphone readable method for uracil-DNA glycosylase detection based on the target-triggered formation of G-quadruplex. AB - A simple, visible and smartphone readable strategy for the sensitive detection of uracil-DNA glycosylase (UDG) activity has been developed. This is based on the UDG-catalyzed removal of uracil bases, which induces the formation of a G quadruplex-cofactor complex. The guanine-rich DNA probe can form a special G quadruplex structure with hemin to display peroxidase activity and catalyze the H2O2-mediated oxidation of ABTS(2-) to the colored ABTS(-), providing a visible signal for UDG detection. The proposed sensing platform exhibits a good linear response to UDG concentrations ranging from 0.008 to 0.2 U mL(-1), with a low detection limit of 0.008 U mL(-1). Based on the theory of chromatics, we can directly read out the color value using a smartphone app to reflect the content of UDG with high resolution, providing a new vision for the portable assay strategy. Furthermore, the utility of this method for screening potential UDG inhibitors has also been demonstrated. PMID- 25713818 TI - Neutral binuclear rare-earth metal complexes with four MU2-bridging hydrides. AB - The first neutral rare-earth metal dinuclear dihydrido complexes [(NPNPN)LnH2]2 (2-Ln; Ln = Y, Lu; NPNPN: N[Ph2PNC6H3((i)Pr)2]2) bearing MU2-bridging hydride ligands have been synthesized. In the presence of THF, 2-Y undergoes intramolecular activation of the sp(2) C-H bond to form dinuclear aryl-hydride complex 3-Y containing three MU2-bridging hydride ligands. PMID- 25713820 TI - Obituary. PMID- 25713821 TI - Many, diverse topics have been covered in recent years in CTMC. Preface. PMID- 25713819 TI - Mechanochemical synthesis of advanced nanomaterials for catalytic applications. AB - Mechanochemical synthesis emerged as the most advantageous, environmentally sound alternative to traditional routes for nanomaterials preparation with outstanding properties for advanced applications. Featuring simplicity, high reproducibility, mild/short reaction conditions and often solvent-free condition (dry milling), mechanochemistry can offer remarkable possibilities in the development of advanced catalytically active materials. The proposed contribution has been aimed to provide a brief account of remarkable recent findings and advances in the mechanochemical synthesis of solid phase advanced catalysts as opposed to conventional systems. The role of mechanical energy in the synthesis of solid catalysts and their application is critically discussed as well as the influence of the synthesis procedure on the physicochemical properties and the efficiency of synthesized catalysts is studied. The main purpose of this feature article is to highlight the possibilities of mechanochemical protocols in (nano)materials engineering for catalytic applications. PMID- 25713822 TI - The joy of science communication. PMID- 25713823 TI - John K. Tsotsos. PMID- 25713827 TI - Potential impacts of hydraulic fracturing for oil and gas on drinking water resources. PMID- 25713828 TI - Drinking water while fracking: now and in the future. AB - The data provided by the PA DEP are incomplete because confidential data are not released. It is impossible to make firm conclusions about water quality impacts when data availability is limited. Nonetheless, the PA experience appears to be characterized by a low rate of problems per gas well or unit of gas produced. Only about 160 of the complaints from homeowners about groundwater to the PA DEP between 2008 and 2012 were problems attributed to oil and gas activity-and only half of these were caused by companies known to drill unconventional shale wells. These problematic wells in turn represent only 0.1 to 1% of the unconventional shale gas wells drilled in that time period (Brantley et al. 2014). Management practices appear to be improving as well; the rate of problems has decreased since 2010 (Figure 1). Apparently, however, the public responds not only to the number of problems per gas well or per unit of gas produced but rather to the number of problems per unit time and per unit area. Thus, even though the r ate of problems with shale gas wells has remained small on a per well basis, pushback has grown in areas of increasing density of drilling and fracking. This may be especially true when consequences are fearsome such as flaming tapwater, toxic contamination, or earthquakes. It is natural that the social license for shale gas development is influenced by short-term, local thinking. But, such thinking may not be helpful given that Marcellus Shale gas wells generate one third the waste per unit volume of gas as compared to conventional shallow gas wells (Vidic et al. 2013). In addition, the release of pollutants such as carbon dioxide, particulates, mercury, nitrogen, and sulfur generated per unit of heat energy is lower f or unconventional shale gas than for fuels such as coal (Heath et al. 2014). Public pushback could nonetheless be a blessing. After all, pushback represents intensified interest in environmental issues. This interest may be seen in the PA DEP data for the rate of well integrity issues in conventional oil and gas wells-the increase in problem rate from 2008 to 2012 (Figure 1) is more likely due to heightened public attention and inspector scrutiny rather than a sudden deterioration in the management practices of the drilling companies (Brantley et al. 2014) During the next decades, the rate of hydraulic fracturing in PA will eventually slow. At some point, the use of produced brines to hydrofracture new wells will cease. Once recycling of brine to frack new wells stops, hundreds of gallons of brine will accumulate as waste at each well per day (Rahm et al. 2013). Disposal of this slightly radioactive brine will then become increasingly problematic. Interest on the part of the public for such issues is warranted. Public engagement today is needed to develop sustainable waste management and sustainable energy practices for the future. PMID- 25713829 TI - Noble gases: a new technique for fugitive gas investigation in groundwater. PMID- 25713831 TI - Concern over private sector tilt in India's new health policy. PMID- 25713830 TI - Reforming England's National Health Service. PMID- 25713832 TI - Twitter campaign highlights top women in global health. PMID- 25713833 TI - The historical epidemiology of global disease challenges. PMID- 25713834 TI - Robert Frederick Schilling. PMID- 25713835 TI - Developing judgment, not being judgmental. PMID- 25713837 TI - Qatar forges ahead with science vision. PMID- 25713838 TI - Willy Burgdorfer. PMID- 25713841 TI - GAVI exceeds US$7.5 billion fundraising target. PMID- 25713840 TI - Neuroligin-1 regulates excitatory synaptic transmission, LTP and EPSP-spike coupling in the dentate gyrus in vivo. AB - Neuroligins are transmembrane cell adhesion proteins with a key role in the regulation of excitatory and inhibitory synapses. Based on previous in vitro and ex vivo studies, neuroligin-1 (NL1) has been suggested to play a selective role in the function of glutamatergic synapses. However, the role of NL1 has not yet been investigated in the brain of live animals. We studied the effects of NL1 deficiency on synaptic transmission in the hippocampal dentate gyrus using field potential recordings evoked by perforant path stimulation in urethane anesthetized NL1 knockout (KO) mice. We report that in NL1 KOs the activation of glutamatergic perforant path granule cell inputs resulted in reduced synaptic responses. In addition, NL1 KOs displayed impairment in long-term potentiation. Furthermore, field EPSP-population spike (E-S) coupling was greater in NL1 KO than WT mice and paired-pulse inhibition was reduced, indicating a compensatory rise of excitability in NL1 KO granule cells. Consistent with changes in excitatory transmission, NL1 KOs showed a significant reduction in hippocampal synaptosomal expression levels of the AMPA receptor subunit GluA2 and NMDA receptor subunits GluN1, GluN2A and GluN2B. Taken together, we provide first evidence that NL1 is essential for normal excitatory transmission and long-term synaptic plasticity in the hippocampus of intact animals. Our data provide insights into synaptic and circuit mechanisms of neuropsychiatric abnormalities such as learning deficits and autism. PMID- 25713839 TI - Dynamic brain functional connectivity modulated by resting-state networks. AB - Studies of large-scale brain functional connectivity using the resting-state functional magnetic resonance imaging have advanced our understanding of human brain functions. Although the evidence of dynamic functional connectivity is accumulating, the variations of functional connectivity over time have not been well characterized. In the present study, we aimed to associate the variations of functional connectivity with the intrinsic activities of resting-state networks during a single resting-state scan by comparing functional connectivity differences between when a network had higher and lower intrinsic activities. The activities of the salience network, default mode network (DMN), and motor network were associated with changes of resting-state functional connectivity. Higher activity of the salience network was accompanied by greater functional connectivity between the fronto-parietal regions and the DMN regions, and between the regions within the DMN. Higher DMN activity was associated with less connectivity between the regions within the DMN, and greater connectivity between the regions within the fronto-parietal network. Higher motor network activity was correlated with greater connectivity between the regions within the motor network, and smaller connectivity between the DMN regions and fronto-parietal regions, and between the DMN regions and the motor regions. In addition, the whole brain network modularity was positively correlated with the motor network activity, suggesting that the brain is more segregated as sub-systems when the motor network is intrinsically activated. Together, these results demonstrate the association between the resting-state connectivity variations and the intrinsic activities of specific networks, which can provide insights on the dynamic changes in large-scale brain connectivity and network configurations. PMID- 25713842 TI - Health care collapsing amid fighting in east Ukraine. PMID- 25713843 TI - Housing triggers health problems for Canada's First Nations. PMID- 25713844 TI - The human lifecycle's neglected stepchild. PMID- 25713845 TI - Haiyan Wang. PMID- 25713846 TI - Patients take centre stage at US research institute. PMID- 25713847 TI - Miscarriage: you don't have to be strong for me. PMID- 25713848 TI - Maurizio Luisetti. PMID- 25713850 TI - PMNCH gains traction and a new leader. PMID- 25713849 TI - NIH budget shrinks despite Ebola emergency funds. PMID- 25713851 TI - The Lancet Technology: January, 2015. PMID- 25713852 TI - Robert Louis Stevenson's The Body Snatcher. PMID- 25713853 TI - Ian George Jacobs. PMID- 25713854 TI - UCL geneticist faces questions over image duplication. PMID- 25713856 TI - 50 years of neuroscience. PMID- 25713855 TI - Long-term planning needed for Iraq's displaced. PMID- 25713857 TI - Carl Djerassi. PMID- 25713858 TI - Aesthetic Surgery Journal ushers in 2015 with all things "new". PMID- 25713859 TI - Image of the month: Gastric metastasis of renal clear cell carcinoma. PMID- 25713860 TI - USAID: Rajiv Shah's legacy. PMID- 25713861 TI - Barrie Patrick Marmion. PMID- 25713862 TI - In the current issue of Current Molecular Pharmacology (CMP-7-1), we are publishing three articles and a special issue. Preface. PMID- 25713863 TI - [Consolidation, reactivation and reconsolidation of memory]. AB - In this review the data on consolidation and reconsolidation of memory by its reactivation (reminding) by a conditional stimulus or context are presented. A special attention is paid to "time windows" when amnesic and other interventions during memory reconsolidation become effective. The similarities and differences between consolidation of original learning and repeated consolidation (reconsolidation) during reactivation of memory by a conditional stimulus or context are considered. The hypotheses about memory updating during reconsolidation and some possible ways affecting memory are also discussed. PMID- 25713865 TI - [EEG spectral characteristics in the dynamics of planned movements]. AB - The spectral characteristics of the EEG in 11 healthy right-handed volunteers with no neurological disorders in dynamics of the unusual finger movements of both hands in random rhythm have been investigated. In particular, it is shown that the preparation and execution of voluntary finger movements compared to the rest were accompanied by a reduction level of activation within almost all the surface of cerebral cortex, except for right frontal lobe. It has been experimentally demonstrated that a significant increasing EEG activity of the right frontal area in high-frequency domain power spectrum was independent of the working limb. This might testify the direct participation of this cortical area in the processes of voluntary muscular activity planning, initiation and control. PMID- 25713864 TI - [The role of NGF and BDNF in mature brain activity regulation]. AB - Neurotrophins are associated with the maintenance of optimal functional state of CNS neurons and modulation of synaptic plasticity for more than 20 years. However, integral and noncontradictory hypotheses of their true role in those processes were proposed only recently. This review describes the modern concepts of the involvement of nerve growth factor and brain-derived neurotrophic factor in the maintenance of brain activity and the prospects for their use in therapy. PMID- 25713866 TI - [Dependence N200 and P300 ERPs in P300-based brain-computer interface on the variations of voluntary attention]. AB - Hypothesis about dependence P300 and N200 potentials evoked by flashes of rows and columns of the stimulation matrix on type of the task and voluntary attention was evaluated. We tested three types of the task: 1) just look at target symbol; 2) look at the target symbol, count its flashes and report the amount of flashes after finishing the task; 3) type target symbol in P300-based brain-computer interface (BCI). In 17 subjects research we showed that maximum amplitudes of P300 and N200 ERPs was occurred in the second type of the task ("look at and count flashes"). Also in this type of task we observed most of all cases statistically reliable difference between target and nontarget P300 and N200 ERPs. Lowest amplitudes of ERPs and number of cases of statistically reliable differences between target and nontarget were showed in the first type of the task ("just look at the symbol"). So we assume that succesful working in P300 based BCI doesn't need the maximum amplitudes of the relevent ERPs but most depend on spatiotemporal complex of these potentials. PMID- 25713867 TI - [Human traveling wave EEG during voluntary movement of the hand]. AB - The traveling wave trajectories connected with the movements of the right hand were revealed. Above sensomotor cortex 28 electrodes were set as a rectangle--4 rows with 7 electrodes in each one. 2D center-out reaching task was used. The target appeared on the screen edge through the random intervals 0.5-2.5 s equiprobably at the left, on the right, from above or from below. The task was to touch the target with the joystick-operated cursor displacing the cursor in one of the sides from the center to edge. EEG from the target occurrence till cursor contact with it was analyzed. Leading on phase of spontaneous EEG waves in the local area of the left sensomotor cortex and in the centre of back-parietal cortex during cursor movement downwards (the hand with joystick moves to oneself) comparing to rest state and movements in three other directions is revealed. The over time smoothing of data concerning phase alignment reveals hidden constant components in EEG resembling evoked potentials. PMID- 25713868 TI - [The changes of EEG correlation synchrony at depressive disorder of psychogenic type]. AB - In this work we use the alternative method of assessing the EEG-synchrony which previously has proved its high sensitivity to the differentiation of psychopathological and functional states. The original recording of EEG had been performed in the state of quiet wakefulness with eyes closed for two groups of examinees/patients at the age of 49-82 years: a group of normal subjects (n = 29) and the group of subjects with depressive deviations of F43.21 category according to ICD-10 (n = 51). As a result of research it is received the comprehensive picture of significant topographical, interhemispheric and regional differences between groups of norm and depression. One of basic features of the obtained integrated picture is existence at a depression of the extended zones of reduced EEG-synchrony covering the entire premedial region in the frontal-occiptal direction, including intrahemispheric connections as well as lateral frontal temporal connections in both hemispheres. It testifies to the deep deprivation with depression frontal-occipital and interhemispheric interaction. As a compensatory reaction during depression the increase of synchrony in axial aimed intrahemispheric pairs of derivations. It is noted the similarity of changes in EEG-synchrony topography of depression to those observed in schizophrenia. The used method has provided close to 100% reliability of the classification of the EEG norms and depressive deviations, which makes possible and promising its use as an auxiliary quantitative differential indicator. PMID- 25713869 TI - [The functional brain organization during preparation for recognizing incomplete images]. AB - The functional interaction between prefrontal cortex and other cortices was analyzed during the pre-stimulus period in the task in which human subjects (n = 36) were asked to recognize a set of incomplete images of different degree of fragmentation. The imaginary part of the complex-valued coherency was used to measure a strength of inter-area coupling at the alpha-rhythm frequency. Based on the analysis of individual responses the two equal sub-groups (n = 13) showing the lowest and highest recognition scores were extracted from the whole group of subjects. It is shown that the pattern of the functional cortico-cortical interactions as well as the direction of its' changes differ in the two sub groups. In those subjects who successfully solve the cognitive task, the changes in functional connectivity indices in the situation of focused attention are most pronounced in the right hemisphere if stimulus-to-come would not be recognized. Period preceding recognized stimulus is characterized by the increased cortico cortical coupling in the left hemisphere. In that sub-group, the values of imaginary part of alpha-coherency show the growth in both hemispheres when the period of focused attention is compared against the period of nonspecific attention. On the contrary, the similar comparison for the sub-group of the least successful subjects shows the imaginary coherency decreases in both hemispheres. These results suggest the constructive role of the alpha-rhythm in functional assembling the prefrontal cortex during the period that precedes the recognition of incomplete images. PMID- 25713870 TI - [Motor asymmetry and learning new skills in animals]. AB - The aim was to examine the relationship between the ability to learn new motor skills and preference to the right or left front paw when performing manipulation movements in rats. As a new skill used the Morris water maze, in which the animals are initially trained to detect platform hidden under water at the swim of the sector of the opposite platform, and then when sailing from sectors on the left or the right of the platform. Preference paw was determined by using the taking of animal food from a narrow horizontal tube and, accordingly, the rats were divided into left-handedness and right-handedness. We found that when changing the place of launch, that is the first voyage from the left or right of the sector, are right-handed, unlike left-handed, spent significantly more time to find the platform. PMID- 25713871 TI - [EEG in altricial pied flycatcher nestlings during the functional sates related with natural behavior cycle]. AB - Electrical brain activity accompanying various forms of behavior was studied in 11-day-old pied flycatcher nestlings. Wavelet analysis of EEG, recorded from symmetrical areas of caudomedial nidopallium (higher avian auditory center) during rest, passive and active wakefulness and movements showed that the major rhythmical EEG component was confined to low-frequency range in all four states. The significant difference from other states was observed only during movements: spectral power in the range of 1-3 Hz decreased while that in the range of 5-20 Hz--increased. The range of 3-5 Hz revealed, in all functional states, the interhemispheric asymmetry of spectral power that could be due to asymmetrical embryonic development of avian visual projections. Active wakefulness and movements were characterized by high positive correlations between spectral power in right and left hemispheres. During rest this correlation was negative. The correlation values during passive wakefulness and rest were rather low that could indicate disintegration of neural connections. PMID- 25713872 TI - [Functional dissociation of parts of the "sensorimotor complex" in the human cortex with the method of magnetoencephalography]. AB - A method of non-invasive human primary motor cortex mapping has been developed. In 18 healthy right-handed subjects magnetic brain responses caused by repeated voluntary left or right index finger movements were studied. Movement onsets were derived from the accelerometer signal. Recordings of magnetic activity throughout whole experimental sessions in all subjects were concatenated into a single sequence, which was separated into independent components using independent component analysis and ranked according to the amount of mutual information with the modified accelerometer signal. Independent components that demonstrated maximum relation to the finger movement were averaged relative to the movement onset. The results of the distributed brain source modeling of the two independent components that manifested maximum amount of mutual information has demonstrated that their sources localize in the cortical areas corresponding to anatomical markers of hand representation in the primary motor and the primary sensory cortices contralateral to the movement. The method developed has demonstrated the fundamental possibility of localizing the M1 area in healthy subjects. PMID- 25713873 TI - [Inhibition of morphine intake by antibodies to serotonin-modulating anticonsolidation protein in model of self-administration in rats]. AB - The article concerns study of effects of polyclonal antibodies to serotonin modulating anticonsolidation protein (SMAP) being in direct dependence on serotonin level and providing intracellular transduction of serotonergic signal, on positive reinforcement effect of morphine in rats. The task was formed in Wistar male rats in the model of morphine self-administration as a result of pressing of one of two levers attached to the wall, joined to the pump delivering each time 100 MUg of morphine directly into the vena jugularis. In the 1st series of studies brain cingulate cortex and hypothalamus were taken from the rats achieved stable level of morphine intake and SMAP level was measured with indirect immune-enzyme assay. It was shown that in the morphine-self-injected rats SMAP level in the cingulate cortex is significantly upregulated (p = 0.01), while in the hypothalamus it was left unchanged. In the 2nd series of studies the rats with stable level of morphine intake were administered intraperitoneally with anti-SMAP rabbit polyclonal antibodies (experimental group) or non-immune gamma-globulins (control group). Soon after antibodies administration the animals of the experimental group demonstrated manifold decrease of morphine intake lasted for 8 days (p < 0.008), whereas it did not change in the controls. SMAP upregulation in the brain cingulate cortex in the rats with stable morphine intake, obviously, indicates to its engagement in positive reinforcement effect of morphine. Blockade of SMAP activity with anti-SMAP antibodies in the nerve cells induced sharp decrease of morphine intake due to disturbances of transduction through intracellular serotonin's signal channels. PMID- 25713874 TI - [Method for correction of perspective distortions during videotracking of the animal in Morris watermaze]. AB - Analysis of correlations between the neuronal activity and animal behavior requires recordings of neuronal activity combined with video tracking. Recordings of neuronal activity in animals performing spatial task in Morris water maze requires angular position of recording camera to avoid "dead zones". If optical axe forms the angle with the water surface, perspective distortions occur. This leads to false results in analysis of trajectories. The paper suggests the method for correction of perspective distortions. PMID- 25713875 TI - In honor of Robert Bittman 1942-2014. PMID- 25713876 TI - Regulatory T cells and their prognostic value in hepatopancreatobiliary tumours. AB - BACKGROUND/AIMS: The aim of this study was to determine the prognostic values of Foxp3+ Treg cells, CD4+ Tcells and CD8+ T cells in cancer cases of gallbladder, pancreas and liver. METHODOLOGY: This study included 20 patients with gallbladder cancer, 25 patients with pancreatic cancer and 8 patients with liver cancer. Foxp3, CD4 and CD8 were immunohistochemically evaluated and compared with histopathological and clinical prognostic parameters. RESULTS: Foxp3, CD4 and CD8 expression levels were significantly higher in peritumoral areas than in intratumoral areas in patients with gallbladder, pancreas, liver cancers (p<0,05). Positivity of Foxp3, CD4 and CD8 was correlated with advanced stage (p<0,05), poor differentiation, lymphovascular invasion, perineural invasion, advanced age. Patients with high positivity of Foxp3 had a shorter disease free survival (p<0,05). CONCLUSION: Our results indicate that the ratio of Tregs/T helper cells (Foxp3+/CD4+) cells was higher in intratumoral area in hepatopancreatobiliary tumors. We conclude that intratumoral inlamatory cells might work for cancer cells, besides peritumoral cells work against cancer cells. PMID- 25713877 TI - Difference from bile duct cancer and relationship between bile duct wall thickness and serum IgG/IgG4 levels in IgG4-related sclerosing cholangitis. AB - BACKGROUND/AIMS: IgG4-related sclerosing cholangitis (IgG4-SC) is a newly established entity. The purpose of this study was to investigate the differences in intraductal ultrasonography (IDUS) findings between IgG4-SC and bile duct (BD) cancer (BDC) as well as the relationship among BD wall thickness, serological and pathological findings in IgG4-SC. METHODOLOGY: Based on the diagnostic criteria of IgG4-SC, we reviewed patients in our hospital between April 2005 and June 2013, and analyzed the data obtained from 32 patients with IgG4-SC and 40 patients with BDC. RESULTS: Regarding IDUS findings, significantly more cases in BDC indicated rigid/papillary inner margin than in IgG4-SC, while biopsy was more efficient. There were no significant correlations between BD wall thickness and serum IgG/IgG4 levels or the number of IgG4-positive cells of the BD specimens. All the IgG4-SC patients without steroid treatment revealed discordant results in the shifts of IgG, IgG4 and BD wall thickness between the 1st and 2nd examinations, while all patients with steroid had completely concordant results of the shifts. CONCLUSIONS: IDUS findings alone are insufficient for differentiation between IgG4-SC and BDC. BD wall thickness, serum IgG and IgG4 proportionally shift and reflect the effect of steroid on IgG4-SC after steroid treatment, not before it. PMID- 25713878 TI - Technical procedures causing biliary complications after hepaticojejunostomy in pancreaticoduodenectomy. AB - BACKGROUND: Although pancreaticoduodenectomy has been established as a standard operation for pancreatobiliary diseases, postoperative biliary complications still exist and impair patient quality of life. METHODS: We enrolled 67 patients who underwent pancreaticoduodenectomy. Patients were divided into 2 chronological groups representing different surgical procedures: group A (G-A) included patients treated between 2003 and 2006 and group B (G-B) included patients treated later. We compared surgical procedures and postoperative biliary complications between the groups. RESULTS: The number of stitches at hepaticojejunostomy was 33.2 +/- 8.4 in G-A and 14.0 +/- 2.3 in G-B. A biliary drainage stent was placed in 31 of 32 cases in G-A and in none of the 35 cases in G-B. For each surgical procedure, there was a significant difference between the groups. Bile leakage occurred in 9.4% of G-A patients and 2.9% of G-B patients. The serum alkaline phosphatase level was significantly higher in G-A than in G-B. Moreover, the number of patients hospitalized for cholangitis was significantly greater in G-A than in G-B. CONCLUSION: Among procedure-related factors pertaining to hepaticojejunostomy in pancreaticoduodenectomy, the number of anastomotic stitches and the placement of a biliary drainage stent were confirmed to affect the development of an anastomotic stricture. PMID- 25713879 TI - Obstructive jaundice due to intraductal tumour thrombus in recurrent hepatocellular carcinoma: what is the optimal therapeutic approach? AB - Icteric Hepatocellular Carcinoma (HCC) is known to cause intraluminal biliary obstruction by one of three mechanisms: hemobilia from the tumour, migration of tumor debris, or continuous growth along the biliary tree. It is however a very rare presentation of HCC and an important differential diagnosis in the approach to obstructive jaundice. We report a case of a recurrent intraductal hepatocellular carcinoma. The patient initially underwent surgical resection of segment five HCC nine months ago with clear margins. The patient now presents with obstructive jaundice and imaging showed a right intraductal tumour involving the confluence, left and common hepatic ducts. He underwent a right hepatectomy and bile duct tumour thrombectomy despite the apparent absence of a parenchymal tumour. Histological examination showed a 2 mm focus of parenchymal tumour with extension of the tumour into the bile duct. In this case report, we reviewed the literature and describe the different surgical approaches to intraductal hepatocellular carcinomas and discuss the pathological aspects of these bile duct tumour thrombus. We report the favourable outcome of surgical resection for intraductal hepatocellular carcinoma and emphasize that intraductal HCC is not a late stage of disease and adequate surgical resection can still provide a reasonable disease free survival. PMID- 25713880 TI - Risk of abscess formation after liver tumor radiofrequency ablation: a review of 8 cases wtih a history of enterobiliary anastomosis. AB - BACKGROUND/AIMS: Rates of postoperative complications after radiofrequency ablation (RFA) remain high for patients who have previously undergone surgery associated with the bile duct. Our purpose is to clarify the rate of postoperative complication and identify preoperative risk factors. METHODOLOGY: This retrospective study reviewed patient backgrounds, ablation areas, and preoperative laboratory data in 8 patients (9 tumors) who underwent RFA after enterobiliary anastomosis. RESULTS: Postoperative complications occurred in 6 of the 8 cases (75%). Postoperative liver abscesses occurred in both the cases of tumor located in the hepatic hilum, i.e., tumor located 5-30 mm from the site of enterobiliary anastomosis. Of the 6 patients with peripherally located tumors, postoperative liver abscesses occurred in 4 patients with elevated preoperative levels of alkaline phosphate (ALP), 3 of whom required abscess drainage. No postoperative complications occurred in the 2 patients with tumors located in the periphery of the liver and with normal preoperative ALP levels. CONCLUSIONS: Postoperative complications are frequent when RFA is performed in patients who have previously undergone enterobiliary anastomosis. These results suggest that RFA after enterobiliary anastomosis should not be recommended. However, the risk may be lower in cases where the nodules are located in the liver periphery and the preoperative ALP level is low. PMID- 25713881 TI - Is end stage renal disease a risk factor for the mortality of cirrhotic patients with esophageal variceal bleeding? AB - BACKGROUND/AIMS: End stage renal disease (ESRD) patients are prone to have bleeding due to uremic platelet dysfunction. However, it is still unknown if ESRD is a risk factor for the mortality of cirrhotic patients with esophageal variceal bleeding (EVB). METHODOLOGY: The National Health Insurance Database, derived from the Taiwan National Health Insurance Program, was used to enroll 6740 cirrhotic patients who were hospitalized with EVB from January 1 to December 31, 2007. The patients were matched with individuals from a national mortality database to calculate their survival time. RESULTS: Of all, 418 patients had renal function impairment (RFI) during their hospitalization. There were 209 (50%) patients with acute renal failure (ARF), and 110 (26.3%) patients with ESRD. The adjusted hazard ratios (HR) of ARF for 6-week and 1-year mortalities of cirrhotic patients with EVB were 4.90 (P<0.001) and 4.34 (P<0.001), compared to the non-RFI group. However, the adjusted HRs of ESRD for 6-week and 1-year mortalities were 1.19 (P=0.404) and 1.50 (P<0.001), compared to the non-RFI impairment group. CONCLUSION: ESRD is associated with 1-year mortality, but not a risk factor for 6 week mortality in cirrhotic patients with EVB. PMID- 25713882 TI - Treatment of locally advanced gastric cancer with the XELOX program of neoadjuvantchemotherapy combined with laparoscopic surgery: the experience in China. AB - BACKGROUND/AIMS: Although the XELOX regimen has been recommended as first-line adjuvant chemotherapy for advanced gastric cancer (AGC), its role in a neoadjuvant setting is not well established. Therefore, we aimed to assess the clinical effect of XELOX neoadjuvant chemotherapy on AGC when combined with laparoscopic surgery. METHODOLOGY: We compared the effects of perioperative XELOX (neoadjuvant chemotherapy group, NCG) with the effects of adjuvant XELOX (direct surgical group, DSG) in patients with locally AGC. The response to chemotherapy was assessed according to Recist criteria and pathological changes. The Kaplan Meier log-rank test was used to calculate and compare survival differences. RESULTS: Seventy patients were included (neoadjuvant=35). The rate of effective neoadjuvant chemotherapy was 62.9%, and the disease control rate was 91.5%. In the NCG, 32 (94.7%) of the patients underwent laparoscopic-assisted D2 radical gastrectomy. The R0 resection rate was 100%. However, rates were 26 (74.3%) and 85.7% in the DSG, respectively (P<0.05). The 3-year overall survival (OS) in the NCG was 77.1% vs. 62.3% in the DSG (P=0.119). The 3-year disease-free survival (DFS) was 74.3% in the NCG, and the DFS was 59.3% in the DSG (P=0.033). CONCLUSIONS: XELOX can enhance the R0 resection rate, increase potential for laparoscopic surgery with rather good safety and improve the 3-year DFS of patients with AGC. PMID- 25713883 TI - Sixteen consecutive adult intestinal transplantation: a single-center clinical experience in China. AB - BACKGROUND/AIMS: The aim of the paper is to describe a single-center experience of adult small intestine transplantation (ITx). METHODOLOGY: 15 ITx and 1 combined liver and ITx(L/ITx) had performed. The immunosuppressive regimen was based on induction therapy with two different protocols: In Period I (pre-2006, n=10), daclizumab or without for induction, high dose tacrolimus, mycophenolate mofetil and steroids as maintenance therapy; In Period II (post-2006, n=6), alemtuzumab for induction and low dose tacrolimus as maintenance anti-rejection treatment unless required for, steroids were not routinely used. RESULTS: In Period I, 9 ITx and 1 L/ITx were performed. One patient survived more than 1-year with normal bowel function and 1 recipient survived more than 4 years with partial PN. Seven patients died within one year. The main cause of death was sepsis. In period II, 4 patients have a normal bowel function with a regular diet without PN, while 2 patients are on partial PN. The main cause of death was rejection. CONCLUSION: The survival of intestinal transplantation has greatly improved over time as management strategies evolved. However, certain unresolved issues still requires future investigation include new strategies to prevent late complications and the causes. PMID- 25713884 TI - Serum cytokine levels in patients with colorectal cancers according to tumor stages and VEGF gene polymorphism. AB - BACKGROUND/AIMS: Colorectal cancers are the most common cancers of the gastrointestinal system. A significant relationship was detected between the metastasis and tumor angiogenesis of colorectal cancer. The aim of the present study was to investigate the association between some cytokines and tumor stages. Additionally, association between VEGF gene polymorphisms and colorectal cancer was studied. METHODS: In this study, we measured serum IL-18, IL-2, VEGF, endothelin (ET), and nitric oxide (NO) levels in 44 patients with colorectal cancer and 44 healthy controls. Also we investigated VEGF G634C (rs2010963) and VEGF C936T (rs3025039) polymorphisms of VEGF gene in these groups by using a PCR RFLP method. Data were analyzed statistically. RESULTS: Serum levels of IL-18, VEGF, IL-2 and NO were significantly higher in patients with colorectal cancer when compared to controls (p<0,05). Serum ET levels were found to be similar in colorectal cancer patients and healthy controls. When we compared the two subgroups constituted by tumor stages (Stage 1-2 and Stage 3-4) with each other, serum VEGF levels were found significantly higher in stage 3-4 group than stage 1 2 group (p<0,05). No significant difference was found between subgroups with regard to other parameters. We found that investigated VEGF G634C and VEGF C936T polymorphisms were not associated with the severity of colorectal cancer. (P=0.228 for VEGF G-634-C; P= 0.484 for VEGF C-936-T) CONCLUSION: In the future, serum levels of IL-18, VEGF, IL-2 and NO may be a useful marker for diagnosis of patients with colorectal cancer. Additionally we consider that serum VEGF levels can be used as a tumor marker to predict prognosis of cancer. However, larger studies with long-term follow-up are necessary to clarify this hypothesis. On the other hand, there is necessity for the new studies for determination of association between VEGF gene polymorphism and colorectal cancer. PMID- 25713885 TI - Gemcitabine + platinum combination chemotherapy in patients with metastatic cancer who suffer from severe and irreversible hepatic impairment: a single center experience. AB - There is limited information on chemotherapeutic agent doses suitable for patients with metastatic cancer who suffer from and irreversible hepatic impairment and who could potentially benefit from chemotherapy and on their results. In this retrospective study, we aimed to share our center's experience of Gemcitabine + Platinum Combination chemotherapy in these patients. Data of 13 patients matching the criteria were analyzed. In our study the patients were treated with a dose of Gemcitabine + Platinum Combination, 50% of the original dose and the dose was increased gradually on the following days. Thirteen of one patient was given Gemcitabine & Carboplatin protocol and the others were given Gemcitabine & Cisplatin . In 42 chemotherapy cycles in total grade 3-4 thrombocytopenia occurred after 7 cycles, grade 3-4 neutropenia was not observed. While liver functions in 8 patients improved slightly, no change was observed in 2 patients and in 3 patients they deteriorated. Total survival period was calculated as 3.78 (95CI% : 0,17-7.54) months. As a consequence, Gemcitabine + Platinum Combination chemotherapy in patients with metastatic cancer who suffer from severe and irreversible hepatic impairment can be implemented when clinical benefits are expected. PMID- 25713886 TI - A comparative study of the diagnostic accuracy of the medical image three dimensional visualization system, MRCP, CT and US in hepatolithiasis. AB - BACKGROUND/AIMS: The aim of this study was to compare the results of the Three Dimensional Visualization System (MI-3DVS or 3D) in the diagnostic accuracy of hepatolithiasis. METHODOLOGY: From February 2007 to March 2013, forty-eight patients with hepatolithiasis were admitted to our department. Meanwhile, choosing forty-one patients without hepatolithiasis as controlgroup. MI-3DVS, MRCP, CT, and US were performed and the results of these imaging methods in detecting calculi distribution, bile duct dilatation/stricture, and liver atrophy/hypertrophy were analyzed. RESULTS: The total display accuracy on bile duct stricture/dilatation using by 3D was higher than using by MRCP, CT, US. The total accuracy of 3D in detecting the liver atrophy was 96.6%, which was superior to that of US (p=0.009) and CT (p=0.044), and there was no significant difference compared with MRCP (P=0.120). The results on diagnosis of calculi distribution by 3D was better than US (p=0.003) and MRCP (p=0.029), but had no significantly difference compared with CT (P=0.246), and they were all close to intraoperative findings. CONCLUSIONS: MI-3DVS could be used to select patients with hepatolithiasis as a supplement approach to other imaging methods and as an innovative means in pre-operative assessment and post-operative follow-ups in hepatolithiasis. PMID- 25713887 TI - Hepatitis B virus infection is an independent factor influencing the occurrence of liver metastasis in colorectal cancer: a retrospective analysis of 1413 cases. AB - BACKGROUND/AIMS: The relationships between Hepatitis B virus infection, cirrhosis and colorectal cancer liver metastasis have not been investigated simultaneously and it remained unclear that whether the immune changes caused by Hepatitis B virus infection or the structural changes caused by cirrhosis conduce to the lower incidence of liver metastasis. METHODOLOGY: Data of 1413 colorectal cancer patients were reviewed to investigate the impacts of Hepatitis B virus infection and cirrhosis on the occurrence and prognosis of liver metastasis. RESULTS: The incidence of liver metastasis in the Hepatitis B virus infection group or in the cirrhotic group was lower than the control groups (9.4% vs 23.9%, P<0.001; 6.3% vs 22.9%, P=0.03, respectively). However, a multivariate logistic regression analysis showed that only Hepatitis B virus, the T and N classifications were independent factors for the occurrence of liver metastasis in colorectal cancer. There was no statistically significant difference in 5-years survival rates between hepatitis B virus infection group and the non-infection group, nor between cirrhotic group and non-cirrhosis group (P>0.05). CONCLUSION: Hepatitis B virus infection was one of the independent factors for the occurrence of liver metastasis in colorectal cancer but not for the survival. PMID- 25713888 TI - Clinical study on the therapeutic role of midodrine in non azotemic cirrhotic patients with tense ascites: a double-blind, placebo-controlled, randomized trial. AB - BACKGROUND: Midodrine is an alpha-agonist prodrug of desglymidodrine used for the management of hypotension. Midodrine has demonstrated usefulness in hepatorenal syndrome. OBJECTIVE: The objective of the present work was to study the role of midodrine in patients with non-azotemic cirrhosis with tense ascites. METHODS: This prospective randomized double blind placebo-controlled study was conducted on 67 non azotemic inpatients with liver cirrhosis and tense ascites (52 men and 15 women; age range, 45-72). One patient declined to participate in the study, 33 patients were randomly assigned to take midodrine hydrochloride, and 33 patients were randomly assigned to take placebo. Out of 67 enrolled patients, 60 patients (30: in midodrine group; 30: in placebo group) completed the study and 6 patients lost to follow up. Patients were assessed for patients' characteristics, history of tapping their ascetic fluid, laboratory values, and Doppler parameters before and after the study. Average 24-h urine volume was assessed before and after the start of the study. RESULTS: significant reduction in body weight and abdominal girth was observed after 2 weeks of midodrine therapy. CONCLUSION: Midodrine appeared to be effective in lowering body weights and abdominal girths of non azotemic cirrhotic patients with tense ascites. PMID- 25713890 TI - Evaluation of three types of platforms in single-incision laparoscopic surgery for performing transanal endoscopic microsurgery (SILSTEM). AB - BACKGROUND/AIMS: Transanal endoscopic microsurgery using a platform for single incision laparoscopic surgery (SILSTEM) is safe for excising rectal lesions. We tested three types of platforms. METHODOLOGY: Nine patients underwent SILSTEM by one surgeon. Tumors located 5-15 cm from the anal verge were eligible. After measuring their dimensions, length, and trocar channels, the platforms tested were the SILSTM port (SP), EZTM access (EA), and GelPOINTTM Path (GP). Clinicopathology, intraoperative parameters, and postoperative outcomes were recorded. RESULTS: Six men and three women (median age 63 years) underwent SILSTEM using platform SP in three patients, EA in four, GP in two. Median operation time was 128 min (range 71-313). Median blood loss was 3 ml (range 1 71). Pathology confirmed adenocarcinoma in five patients, adenoma in three, and carcinoid in one. Patients were discharged within 2-13 days postoperatively. There was no postoperative fecal incontinence or soiling. Overall median follow up was 13.3 months (range 1.3-27.2). There were no recurrences. CONCLUSION: SILSTEM can effectively resect rectal tumors using any of three platforms. Large prospective trials are needed to define the advantages, disadvantages, and indications for each platform and to draw conclusions regarding operation time, anorectal function, and costs. PMID- 25713889 TI - Patient age and extent of liver resection influence outcome of liver resection for hepatocellular carcinoma in non-cirrhotic liver. AB - BACKGROUND/AIMS: Data about the clinical course after liver resection for HCC in non-cirrhotic liver (NCL) is rare in western countries. Although the patients with HCC in NCL tolerate major liver resections, it is less clear if an underlying steatosis or NASH increase the perioperative and postoperative risk. The purpose of this study was to characterize the clinical course after hepatic resection in patients with HCC in the absence of liver cirrhosis and in the absence of viral hepatitis. METHODOLOGY: The data of 148 patients with HCC in non cirrhotic liver, who underwent curatively intented liver resection, were analyzed. Patients with hepatitis B or C infection were excluded. Patients with fibrolamellar HCC or liver cirrhosis or fibrosis higher than grade 2 according to the Desmet-Scheuer score were also excluded. RESULTS: The overall 1-, 3- and 5 year survival rates were 75.4%, 54.7% and 38.9%. Increased patient age (elder than 70 years) influenced the cumulative survival significantly. Especially the combination of increased patient age and major resection (>2 segments) at once influenced the cumulative survival. The overall postoperative morbidity was 37.8 %. No intraoperative death was observed. Postoperative increased leucocytes, urea and creatinin increased the postoperative complications. In the subgroup with major resection increased GGT correlated with steatosis, and raised AST correlated with elevated patient age. CONCLUSIONS: In Western countries HCC in non-cirrhotic liver is rare. Liver resection is safe and is the only curative therapy option for the time by HCC without liver cirrhosis. Further studies are necessary for identification of more prognostic factors and optionally special treatment PMID- 25713891 TI - Staged surgery after colonic decompression may be safer for the treatment of obstructive left-sided colorectal cancer in a non-specialized hospital. AB - BACKGROUND/AIMS: The management for the obstructive left sided colorectal cancer is still controversial. METHODOLOGY: A retrospective study was performed on 249 consecutive patients who underwent surgical intervention for left sided colorectal cancer in our hospital. Among 36 patients who had colonic obstruction, 25 patients received tumor resection while the rest of the patients received palliative stoma creation. Clinical characteristics and outcome following tumor resection was compared between patients with and without colonic obstruction. RESULTS: Prior to tumor resection, all patients received colonic decompression. Flowingly, 20 patients received staged surgeries and five patients underwent one stage surgery, with three of the latter requiring reoperation due to anastomotic leakage. The five-year overall survival rate for patients following tumor resection was 75.5 % and 69.1 % for those with and without colonic obstruction respectively. Log-rank test showed no significant difference in overall survival between the two groups (p = 0.91). CONCLUSIONS: Onestage surgery for patients with obstructive colorectal cancer in our hospital was associated with frequent anastomotic leakage. Colonic obstruction itself may not be a poor prognostic factor when decompression preceded surgical resection. PMID- 25713892 TI - Gene expression analysis of colorectal cancer by bioinformatics strategy. AB - BACKGROUND/AIMS: We used bioinformatics technology to analyze gene expression profiles involved in colorectal cancer tissue samples and healthy controls. METHODOLOGY: In this paper, we downloaded the gene expression profile GSE4107 from Gene Expression Omnibus (GEO) database, in which a total of 22 chips were available, including normal colonic mucosa tissue from normal healthy donors (n=10), colorectal cancer tissue samples from colorectal patients (n=33). To further understand the biological functions of the screened DGEs, the KEGG pathway enrichment analysis were conducted. Then we built a transcriptome network to study differentially co-expressed links. RESULTS: A total of 3151 DEGs of CRC were selected. Besides, total 164 DCGs (Differentially Coexpressed Gene, DCG) and 29279 DCLs (Differentially Co-expressed Link, DCL) were obtained. Furthermore, the significantly enriched KEGG pathways were Endocytosis, Calcium signaling pathway, Vascular smooth muscle contraction, Linoleic acid metabolism, Arginine and proline metabolism, Inositol phosphate metabolism and MAPK signaling pathway. CONCLUSION: Our results show that the generation of CRC involves multiple genes, TFs and pathways. Several signal and immune pathways are linked to CRC and give us more clues in the process of CRC. Hence, our work would pave ways for novel diagnosis of CRC, and provided theoretical guidance into cancer therapy. PMID- 25713893 TI - Impact of KRAS mutation on outcome of patients with metastatic colorectal cancer. AB - BACKGROUND/AIMS: KRAS mutation is present in 30%-50% of colorectal cancers and is associated with the inefficacy of anti-epidermal growth factor receptor therapy, while the impact of KRAS on survival is seldom discussed. The aim of this study was to elucidate the impact of KRAS status on the survival of patients with metastatic colorectal cancer. METHODOLOGY: Two hundred and one patients with metastatic colorectal cancer were enrolled. Amplification and sequencing of the KRAS gene were performed, with the overall survival according to KRAS status analyzed. RESULTS: KRAS mutations were present in 72 (35.8%) of patients, including 55 (27.3%) codon 12 mutations and 17 (8.5%) codon 13 mutations. Lymphovascular invasion (hazard ratio 1.841, 95% confidence interval 1.043-3.247, p = 0.035) and KRAS mutation (hazard ratio 1.919, 95% confidence interval 1.104 3.333, p = 0.021) were independent prognostic factors for overall survival. The median overall survival for patients with KRAS mutation at codon 12 was 27.3 months, and was similar to those with KRAS mutation at codon 13 (20.4 months, p = 0.628). CONCLUSIONS: KRAS mutation is a poor prognostic factor in patients with metastatic colorectal cancer. In KRAS mutation metastatic colorectal cancer, mutation at codon 12 or at codon 13 had no relationship with prognosis. PMID- 25713894 TI - Umbilical single incisional approach plus one port for partial transverse colectomy: initial operative experience. AB - BACKGROUND/AIMS: Although single incision laparoscopy surgery (SILS) has recently been applied to various kinds of disease, there are few reports on partial transverse colectomy by SILS. We have been performing SILS plus one port procedure, SILS plus One. SURGICAL PROCEDURE: After placing 3cm incision in the umbilical fossa, a SILS portTM was introduced, and a 5-mm port was inserted in the upper left quadrant of the abdomen, and laparoscopic procedure was started. After the greater omentum was divided, inferior margin of the pancreas was dissected in order to detect the gastrocolic trunk and root of the middle colic artery and vein. After a small mesocolon window was created near the root of middle colic artery, the middle colic artery and vein as well as accessory right colic vein were divided at their root. Both oral and anal margin of the mesocolon were incised by LigaSureTM. The surgical specimen was extracted through the umbilical wound and intestinal anastomosis was performed manually using absorbent sutures. RESULTS: Between 2010 and 2012, six consecutive early transverse colon cancer patients including three male underwent this procedure. The mean operative time was 165.0 (range = 150-180) min, the mean operative blood loss was 7.5 (range = 0-30) ml, the mean hospitalization after surgery was 10.5 (range = 10 12) days, and postoperative complications were not encountered. CONCLUSION: SILS plus One for partial transverse colectomy is feasible and safe. PMID- 25713895 TI - Hand-sewn anastomotic technique after esophageal cancer resection. AB - BACKGROUND/AIMS: Mechanical stapled anastomosis can be performed easily and quickly in esophagogastrostomy after esophageal cancer resection. However, we have performed cervical hand-sewn anastomosis in the esophagogastrostomy. Here we introduce the surgical technique and report the outcomes after the anastomosis. METHODOLOGY: The gastric tube is pulled up via the posterior mediastinal route. A single layer of Gambee sutures is used to approximate the cervical esophagus and the posterior wall of the gastric tube in end-to-side fashion. After the anastomosis, the redundant part in the gastric tube apex is removed. We analyzed 152 consecutive patients who underwent this anastomosis in our institute from 1999 to 2012. RESULTS: There was no postoperative mortality. We experienced anastomotic leakage in 7 patients (5%) and anastomotic stenosis in 5 patients (3%). CONCLUSIONS: The anastomotic complication rates in the hand-sewn anastomosis were comparable to those of the mechanical stapled anastomosis in the previous reports. PMID- 25713896 TI - Short and long-term results of laparoscopic total fundic wrap (Nissen) or semifundoplication (Toupet) for gastroesophageal reflux disease. AB - INTRODUCTION: Gastroesophageal reflux disease (GERD) is a common upper GIT disorder. The choice of surgical management options is debatable between laparoscopic Nissen fundoplication (LNF) and Toupet fundoplication (LTF) especially in cases with esophageal dysmotility. PATIENTS AND METHODS/AIMS: 102 patients with chronic GERD divided into 2 groups. Group (1): Patients with good peristalsis (n=70) done LNF. Group (2): Patients with poor peristalsis (n=32) patients done LTF to compare the outcome. They were included in this study. They subjected to clinical, radiological and esophageal motility investigations. RESULTS: In postoperative period, Recurrent of heartburn, dysphagia and abdominal distension were found in 5.71% , 14.28% and 27.14% post LNF and in 9.37%, 15.62% and 15.62% post LTF respectively. Pre operative LESP was 10.16+/-5.4 mmHg in LNF & 9.56+/-3.51 mmHg in LTF group increased to 20.7+/-7.84 mmHg early after LNF (p<0.0001) & 15.26+/-6.47 early after LTF (p = 0.0002). Esophageal 24hrs pH metry in early and late post operative showed a significant improvement of % reflux (p < 0.001) in both groups. CONCLUSION: Toupet fundoplication became the procedure of choice of cases with esophageal dysmotility due to its ease of application, patient satisfaction, low dysphagia rate and low levels of abdominal distension. PMID- 25713898 TI - Eus combined with ESD or EMR for the diagnosis and treatment of protruding gastrointestinal lesions. AB - BACKGROUND/AIMS: To investigate the use of endoscopic ultrasound combined with endoscopic submucosal dissection (ESD) or endoscopic mucosal resection (EMR) for the diagnosis and treatment of protruding gastrointestinal lesions. METHODOLOGY: Endoscopic and clinicopathological data were available for 158 patients with protruding gastrointestinal lesions who underwent endoscopic ultrasound. We selected for ESD or EMR treatment 138 patients with gastrointestinal protruding lesions that did not reach the muscular layer of the mucosa according to their endoscopic ultrasound findings. We compared the consistency of the diagnoses made with normal gastrocoloscopy, endoscopic ultrasound, and pathology after the ESD or EMR treatment, and evaluated the therapeutic effects of ESD or EMR on protruding gastrointestinal lesions. We also performed follow-ups with gastrocoloscopy and endoscopic ultrasound one, three, and six months after surgery. RESULTS: Of 158 patients who underwent endoscopic ultrasound, 138 were treated with ESD or EMR. Postoperative oozing of blood occurred in 12 patients and hemorrhage in four patients, and the complication rate was 2.9% (4/138). There were no serious complications. The pathological diagnoses were consistent their endoscopic ultrasound diagnoses, so the accuracy of endoscopic ultrasound was 97.8% (135/138). CONCLUSION: Endoscopic ultrasound combined with ESD or EMR can improve the diagnosis of protruding gastrointestinal lesions. PMID- 25713897 TI - Semi-radical chemoradiotherapy for 53 esophageal squamous cell carcinomas with supraclavicular lymph node metastasis in a single institutional retrospective study. AB - OBJECTIVE: Outcomes were examined for the cases that received radiotherapy (RT) for esophageal cancer with metastasis to supraclavicular lymph nodes (ScLN) in a single institutional retrospective study. MATERIALS AND METHODS: Cases examined were 53 consecutive patients with pathologically confirmed esophageal cancer enrolled from our institution who received semi-radical RT from 2001 to 2013. Radiotherapy consisted of a total dose of from 50-50.4 Gy given in 25-28 fractions of 1.8-2.0 Gy with five fractions per week. The chemotherapy regimen included nedaplatin and 5-fluorouracil. All had ScLN metastasis, and all diseases were included in the RT field. RESULTS: The median follow up time was 42 months for survival patients. Overall survival (OS) and progression free survival (PFS) for 1-, 2-, and 3 years were 39%, 19%, and 12% and 14%, 9%, and 6%, respectively. Acute grade 3-5 esophagitis and neutropenia was seen in 11% and 81%, respectively. Late grade 3-5 toxicity in esophagus, lung, and heart was seen in 4%, 0%, and 0%. Five patients (9%) survived more than 4 year. CONCLUSION: Although the 2-year PFS was less than 10% and very poor, long term survival for over 4 year was seen in 9% cases. In other words, despite the poor results, the fact remains that some patients were cured with CRT. PMID- 25713899 TI - Imatinib plasma levels during successful long-term treatment of metastatic gastrointestinal stromal tumors. AB - BACKGROUND/AIMS: To investigate whether imatinib dosage correlated with effective plasma levels and clinical characteristics for Japanese patients undergoing long term (>=2 years) imatinib therapy for GISTs. METHODOLOGY: Twenty-five patients who received imatinib for a metastatic pathologically diagnosed GISTs at our hospital were enrolled. Imatinib response was assessed according to Choi's criteria. Blood samples were collected 22-26 h after the previous imatinib dose before the next scheduled dose. Results: Fourteen patients were male and the median age was 65 years. The median duration of imatinib therapy was 3.8 years (range, 2.0-11.5 years). The median plasma level of imatinib was 1098 ng/ml and the minimal plasma level after >=5 years of therapy was 789 ng/ml. Imatinib dosage was significantly correlated with history of gastrectomy. The minimum body surface area of patients who received 400-mg/day imatinib dosage was 1.560 m2. CONCLUSIONS: The minimum level in all patients showing response for >=5 years of treatment was 789 ng/ml, suggesting an effective plasma imatinib level of >=800 ng/ml. Our results suggest that imatinib dosage of 400 mg/day is recommended for a patient with a large BSA (>=1.56 m2) and that of 300 mg/day might be sufficient for patients who have undergone a gastrectomy. PMID- 25713900 TI - Comparison of urgent video capsule endoscopy and urgent double-balloon endoscopy in massive obscure gastrointestinal bleeding. AB - BACKGROUND/AIMS: Urgent video capsule endoscopy (VCE) and urgent double-balloon endoscopy (DBE) provide high diagnostic yields in overt obscure gastrointestinal bleeding (OGIB). However, no studies have specifically compared VCE and DBE in massive OGIB. The aim of this study was to compare the diagnostic yield and clinical outcomes of the two approaches. METHODOLOGY: Between October 2010 and March 2013, there were 1,672 consecutive patients with gastrointestinal bleeding and 30 massive OGIB were identified. After non-diagnostic EGD and colonoscopy, VCE and DBE were performed in tandem within 72hr after hospitalization. RESULTS: Of these, 30 patients were identified as massive OGIB. DBE identified more bleeding lesions than VCE (26(87%) vs. 18(60%), p<0.05). Only DBE was positive in 8 patients (27%). No patient had positive VCE and negative DBE. VCE demonstrated only fresh blood without identifiable lesions in 8 (27%) patients, and all had bleeding lesions identified subsequently by DBE. The number of patients with therapeutic intervention guided by DBE was higher than those with VCE-guided intervention (17(57%) vs. 11(37%); p<0.05). Four patients (13%) had a negative study by both tests, and no further bleeding was reported. CONCLUSIONS: In massive OGIB, urgent DBE had a higher diagnostic yield than VCE. (ClinicalTrials.gov number, NCT01654770) PMID- 25713901 TI - Predictors and outcomes of superior mesenteric artery syndrome in patients with constipation: a prospective, nested case-control study. AB - BACKGROUND/AIMS: Superior mesenteric artery (SMA) syndrome may occur in patients with constipation, whereas the association between these two distinct diseases has not been confirmed yet. We investigated the incidence, risk factors and treatment strategy associated with SMA syndrome in constipated patients. METHODOLOGY: We conducted a prospective nested case-control study from a 9-year hospitalization cohort (n=973). Cases were matched to controls 1:4 on factors of age and gender. Cases developed SMA syndrome in long term follow-up (n=26) and controls did not (n=104). Independent risk factors were identified by using univariate analysis and conditional logistic regression analysis. Enteral nutritional support was applied in all cases and its curative effect was evaluated by retrospective analysis. RESULTS: The incidence of SMA syndrome was 2.67%. The risk factors under scrutiny were body mass index (BMI)<=18 (odds ratio (OR) 2.89, 95% CI 1.14 to 9.31) and abnormal colon transit time (OR 3.57, 95% CI 1.36 to 9.35). Twenty-two patients recovered after treatment of nutritional support, and the success rate of conservative treatment was 84.6%. CONCLUSIONS: BMI<=18 and prolonged colon transit time both were risk factors associated with SMA syndrome in constipated patients. Enteral nutritional support should be adopted as the first-line treatment for this condition. PMID- 25713902 TI - Treatment of hepatocellular carcinoma in elderly patients. AB - BACKGROUND/AIMS: The aim of this study was to compare the survival in elderly hepatocellular carcinoma (HCC) patients treated with curative modalities (radiofrequency ablation (RFA), percutaneous ethanol injection (PEIT) and surgery) to those treated with transcatheter arterial chemoembolization (TACE) and supportive care. METHODOLOGY: Medical records of patients with HCC older than 75 years who had visited a single tertiary medical center from January 2000 to December 2011 were reviewed (n = 58). Multivariable-adjusted hazard ratios (HR) for mortality with 95% confidence intervals (CI) were estimated using Cox proportional hazard models. RESULTS: Twenty-nine patients were treated by TACE, 19 patients by supportive care, and 10 patients by curative treatment (four by PEIT, three by surgery and three by RFA).Variables associated with increased survival were better Child-Pugh class and lower TNM stage. Treatment with curative intent showed significant survival benefit compared to TACE (HR for mortality, 0.10; 95% CI, 0.01-0.95). In a subgroup analysis among patients with resectable HCC, supportive care showed significantly worse survival over TACE (HR for mortality, 6.47; 95% CI, 2.14-19.56) and curative intent (HR for mortality, 16.23; 95% CI, 1.92-136.83). CONCLUSIONS: Curative treatment seems to have a better survival benefit in comparison with other treatment modalities in elderly HCC patients. PMID- 25713903 TI - Hepatectomy for hemangioma; safe, but is it successful? AB - BACKGROUND/AIMS: Large hepatic hemangiomata may give rise to abdominal discomfort, prompting consultation with a hepatobiliary surgeon. The effectiveness of liver resection to treat such symptoms has varied in previously published reports. We sought to examine outcomes related to resection of hepatic hemangioma at a high-volume HPB center. METHODOLOGY: Consecutive patients between 1995-2011 undergoing resection for a hepatic hemangioma were identified. Demographic, operative, imaging, and complication-related data were collected. RESULTS: Fifty-four patients (41 female, 76%) underwent liver resection for hemangioma. Median age was 48 years (range: 25-80), and median lesion size was 8.0 cm (range: 1.6-25). Indications for resection included pain (28 patients, 52%), increasing size (9, 17%), patient anxiety (5, 9%), and inability to exclude malignancy (12, 22%). There were no perioperative deaths, and 16 patients (30%) had Clavien grade >=II complications. Of the 28 patients with preoperative pain, 8 (28%) continued to report similar abdominal discomfort at a median follow-up of 10 months. CONCLUSIONS: Liver resection for hemangiomata can be performed safely, albeit with significant morbidity. The majority of patients,but not all, have pain relief following hepatic resection.A cautious approach should be taken when evaluating patients for hemangioma resection. PMID- 25713904 TI - Primary results of salvage liver transplantation in the patients with unresectable recurrent hepatocellular carcinoma after initial liver resection. AB - BACKGROUND/AIMS: Salvage liver transplantation (SLT) is a treatment choice for recurrent HCC fulfilling the Milan criteria. However, there is no consensus on the value of SLT for recurrent HCC beyond the Milan criteria, especially for unresectable HCC. METHODOLOGY: Eleven patients with recurrent HCC underwent SLT in Tongji Hospital between January 2003 and July 2010. All the 11 patients were considered unresectable because of deteriorated liver function, multiple bilobar tumors or vascular invasion. The outcomes and prognostic factors of these patients were analyzed. RESULTS: At a median follow up of 30 months, six patients were alive. Four patients died from HCC recurrence, and one died from gastric cancer. The 1-, 2-, and 3- year recurrence and overall survival rates after SLT were 58.4%, 72.3% and 86.1%, respectively, and 90.9%, 40.6% and 40.6%, respectively. Vascular invasion, recurrent HCC beyond the Milan criteria and early recurrence within 18 months after initial resection were negative prognostic factors of SLT for recurrent HCC. CONCLUSIONS: SLT can be recommended as an alternative treatment for recurrent HCC fulfilling the Milan criteria. For those beyond the Milan criteria or with vascular invasion, or early recurrence after initial resection, however, SLT is not beneficial and should not be recommended. PMID- 25713905 TI - Plasma from patients with acute liver failure dampens HepG2 cells to epidermal growth factor induced proliferation response. AB - BACKGROUND/AIMS: The aims of this study are to explore the effects of epidermal growth factor (EGF) on hepatocyte proliferation in presence of plasma from patients with acute liver failure (ALF). METHODOLOGY: HepG2 cells were cultured with 50% plasma from patients with ALF for 6, 12, 24, 48 and 72h with or without different concentrations of EGF. Cell proliferation was determined by the MTT assay and intracellular cyclin D1, cyclin-dependent kinase 4 (CDK4) expressions were analyzed by western blotting. RESULTS: The proliferation of HepG2 cells was significantly inhibited by treatment with plasma from patients with ALF from 12 to 72 h. Intracellular expression of cyclin D1 and CDK4 was also markedly down regulated. 5ng/ml, 10ng/ml and 20ng/ml EGF dose dependently induced HepG2 proliferation in presence of plasma from normal control, but only 20ng/ml EGF showed a transient promoting effect on proliferation of HepG2 cells in presence of plasma from patients with ALF. CONCLUSIONS: Plasma from patients with ALF inhibits HepG2 cell proliferation via downregulation of cyclin D1 and CDK4 expression. Plasma from patient with ALF dampens HepG2 cells to EGF induced proliferation response. PMID- 25713906 TI - Higher complication rate in hepatocellular carcinoma patients undergoing prophylactic cholecystectomy with curative hepatic resection. AB - AIMS: We performed a retrospective analysis to evaluate the short and long-term impact of simultaneous prophylactic cholecystectomy with hepatectomy in these patients. METHODS: We identified 642 patients who underwent curative hepatocellular carcinoma resection between 2001 and 2005 at five university hospitals. One hundred and twenty-five hepatocellular carcinoma patients who received left lateral sectionectomy or partial resection in the left lateral and Spiegel lobes were identified and followed. They were divided into two groups, 74 with and 51 without simultaneous cholecystectomy. None of these patients had gallbladder stones or polyps at preoperative diagnosis. RESULTS: Although not statistically significant, the operating time was longer and blood loss was greater in the cholecystectomy group. Patients in the cholecystectomy group had a significantly higher postoperative morbidity rate. Surgical complications according to the Clavien classification differed significantly between the two groups. Variables significantly associated with complications in the univariate and multivariate analyses were simultaneous cholecystectomy and operative blood loss >= 1000 ml. CONCLUSION: Simultaneous cholecystectomy of the asymptomatic gallbladder with curative resection of hepatocellular carcinoma in the left lateral section or Spiegel lobe resulted in higher postoperative complications. Consequently, the gallbladder should be preserved except in cases of gallbladder stones or polyps. PMID- 25713907 TI - Early recurrence in large hepatocellular carcinoma after curative hepatic resection: prognostic significance and risk factors. AB - BACKGROUND/AIMS: So far, prognostic significance and risk factors of early recurrence after curative resection in large hepatocellular carcinoma (LHCC) remain unclear. The present study aimed to answer these questions. METHODOLOGY: Clinical, pathologic and follow-up data of consecutive 116 patients with LHCC (>5cm) after curative resection were collected and analyzed. The recurrence pattern of LHCC was also compared with that of 55 patients with small HCC (SHCC, <=5cm). RESULTS: Forty-five patients (38.8%) with LHCC developed recurrence within 1 year after surgery (defined as early recurrence), with a significantly higher ratio contrast to those with SHCC. Univariate analysis showed that age, HBsAg positivity, satellite nodule, TNM stage, resection extent and early recurrence served as significant indicators of post-recurrence overall survival in recurrent LHCC. In addition, only early recurrence was proven to be significant in multivariate Cox regression test. On the other hand, age, HBsAg positivity, portal vein tumor thrombosis, microvascular invasion, TNM stage, Edmondson-Steiner grade and resection extentwere related to early recurrence in LHCC. Among them, microvascular invasion and Edmondson-Steiner grade were independent predictors. CONCLUSIONS: Patients with early recurrence carried very poor post-recurrence prognosis in LHCC. The microvascular involvement and differentiation grade might be particularly helpful for prediction of early recurrence. PMID- 25713908 TI - Supplemental transcatheter arterial chemoembolization for hepatocellular carcinoma fed by collateral omental artery. AB - PURPOSE: To evaluate the efficacy and safety of supplemental transcatheter arterial chemoembolization (TACE) through the extrahepatic collateral omental artery (OA) for hepatocellular carcinoma (HCC). METHODS: We retrospective evaluated extrahepatic collateral OA on 34 patients, among 1826 patients with HCC who had undergone TACE. TACE of the OA was performed, and the dosage of emulsion was judged by tumor size and achievement of stagnant arterial flow. RESULTS: Blood supply from the OA was demonstrated at the initial TACE in 7 patients, and after several TACE (mean 2.8th) sessions in 27 patients. The technical success rate was 100%. Total occlusion of the OA collateral was achieved in 85.3%. On one month later, complete, more than 50% and less than 50% uptake of iodized oil in the tumor were in 12, 16, and 6 patients, respectively. Alpha-fetoprotein level 1 month later was significantly lower than pre-procedure (P<0.05). There was no serious complication that related to the omental embolization. The cumulative survival rates at 6, 12 months were 94.1%, 85.3%, respectively. CONCLUSION: TACE of the OA is safe and reduce the incidence of post-TACE recurrence and/or residual of HCC, and could improve the therapeutic effect of TACE in the treatment of HCC. PMID- 25713909 TI - Prognosis in liver transplantation recipients after hepatitis B virus recurrence. AB - BACKGROUND/AIMS: To analyze the data from hepatitis B virus (HBV) infected patients with HBV recurrence after orthotopic liver transplantation (OLT) to determine their prognosis and survival. METHODOLOGY: We retrospectively analyzed data from patients who experienced HBV recurrence following OLT at our center between January 2000 and September 2011. All patients were monitored until June 2012 or their death. RESULTS: The total number of cases of HBV recurrence after liver transplantation was 56. Of these cases, 21 had benign liver disease and 35 had hepatocellular carcinoma (HCC). The median follow-up time was 48.8 months (range: 5.0-138.1 months). The median time to recurrence following transplantation was 44.4 months (range: 0.3-116.3 months) and 12.2 months (range: 0.3-135.1 months) for patients with benign liver disease and HCC, respectively. Nine patients were diagnosed with HBV recurrence first (1.2-8.2 months prior to HCC recurrence), seven patients showed HCC recurrence first (0.4-27.1 months prior to HBV recurrence), and the remaining 5 patients had HBV and HCC recurrence at the same time. Correlation analysis demonstrated a strong correlation between HBV and HCC recurrence times. Of the 56 patients with HBV recurrence, 24 had died at the time of data cut off, and the main cause of death was HCC recurrence. In patients with malignant liver disease, the survival rates were 78.8%, 48.8%, and 40.1% at 1, 3, and 5 years, respectively, which were lower than those in patients with benign liver disease, which were 94.7%, 89.5%, and 77.5% at 1, 3, and 5 years, respectively, P=0.001. CONCLUSION: Patients with HBV recurrence and benign liver disease have a better prognosis than HCC patients. Treatment with the addition of adefovir and/or entecavir is necessary for patients with HBV recurrence. A correlation between HBV and HCC recurrence times was observed. Hepatitis B recurrence can be used as a warning signal for tumor recurrence. PMID- 25713910 TI - Rimonabant inhibits proliferation, collagen secretion and induces apoptosis in hepatic stellate cells. AB - BACKGROUND/AIMS: Liver fibrosis represents a significant health problem worldwide. Hepatic stellate cells (HSCs) play a critical role in the live fibrosis. Rimonabant (SR141716) is cannabinoid receptor type 1 (CB1) antagonist. The pharmacological effects of rimonabant on HSCs are not well characterized in HSCs. METHODS: CB1 receptor was detected by immunohistochemistry in human liver fibrosis specimens. Cell proliferation was detected by MTT assay. Cell apoptosis, caspase-3 protein expression and cell cycle were detected by TEM and flow cytometry, respectively. Caspase-3 activity was measured using caspase-3 activity assay kit. Collagen secretion was evaluated by radioimmunoassay. CB1 receptor and signaling molecules were evaluated by qRTPCR and Western blot. RESULTS: Immunohistochemistry showed a discrete, punctuated CB1 immunoreactivity in human liver fibrosis specimens. Rimonabant reduced HSC proliferation and increased HSC apoptosis. Cell cycle analysis showed a decrease in G2/M phase cells and an increase in G0/G1 phase cells in HSC-T6 cells treated with rimonabant. Caspase-3 protein expression and activity were increased by rimonabant. Rimonabant decreased collagen secretion in HSC-T6 cells. Moreover, rimonabant inhibited the expression of phosphorylated FAK and ERK and down-regulated CB1 mRNA expression. CONCLUSION: The study provides new insights toward the pharmacological effect of rimonabant on HSCs in vitro. Rimonabant inhibits proliferation, collagen secretion and induces apoptosis in HSCs. PMID- 25713911 TI - Robotic liver resection: a single surgeon's experience. AB - BACKGROUND: Liver resection has long been a complicated challenge in terms of minimally invasive surgery. However, robotic surgery has expanded the number of surgical procedures that can be performed using minimally invasive techniques. This study describes the authors' experience of 17 robotic liver resections performed using the da Vinci Surgical System. METHODS: From May 2010 to May 2012, 17 patients underwent robotic liver resection at Asan Medical Center, Seoul, Korea. Only patients who underwent left hepatectomy or left lateral sectionectomy were included in the study. RESULTS: Thirteen patients had hepatocellular carcinoma, one had a biliary cyst, one had a dysplastic nodule, one had fibronodular hyperplasia, and one had a left intrahepatic duct stone. The mean operative time was 267.06 +/- 84.62 minutes and the mean estimated blood loss was 264.71 +/- 104.23 mL. No open conversion was required. The mean tumor size was 2.98 +/- 1.47 cm and the mean hospital stay was 7.58 +/- 2.26 days. CONCLUSION: The results confirm the safety and feasibility of robotic liver resection. As surgeons become more experienced with robotic liver resection and the technology improves, more patients will benefit from this approach. PMID- 25713913 TI - How to select suitable hepatocellular carcinoma for liver transplantation by preoperative neutrophil-lymphocyte ratio. AB - BACKGROUND/AIMS: The liver transplantation (LT) criteria for hepatocellular carcinoma (HCC) is expanding. However, most of the existing criteria are based on tumor characteristics of radiology. We aimed to build a preoperative scoring model including the neutrophil-lymphocyte ratio (NLR) to select HCC patients for LT. METHODOLOGY: Using receiver operating characteristic curve (ROC) analysis the sensitivity and specificity were highest when NLR was 3.79, so we defined NLR > 4 as elevated. By univariate and multivariate analysis, the significant predictors including NLR were used to establish a scoring model to predict outcome of HCC patients after LT. RESULTS: Of 280 HCC patients, there were 114 patients with elevated NLR. The one-, three- and five-year recurrence-free survival rates of patients with high and low NLR were 64.9%, 30.1%, 30.1% vs. 83.9%, 62.9%, 60.7% (p < 0.001). On univariate and multivariate analysis, the raised NLR (p = 0.007), total tumor size > 9 cm (p < 0.001) and vascular invasion (p < 0.001) were the significant factors in predicting outcome. By ROC analysis, the patients with a score >= 1 had an area under the curve (AUC) of 0.745. CONCLUSION: This scoring model including NLR can aid in selecting HCC candidates for LT. PMID- 25713912 TI - Is liver resection for hepatocellular carcinoma in cirrhotic patients with high preoperative serum alanine aminotransferase level unadvisable? AB - BACKGROUND/AIMS: High operative mortality has been reported after liver resection for hepatocellular carcinoma (HCC) in cirrhotic patients with high preoperative serum alanine aminotransferase (sALT) level. Their long-term prognosis has never been investigated. The aim of this study is to evaluate the benefit of liver resection for HCC in this subgroup of patients. METHODOLOGY: A retrospective review of the medical records of 978 cirrhotic patients who underwent curative liver resection for HCC between 2000 and 2012 was conducted. The preoperative sALT level of 218 patients was > 100 U/l (normal 5 -50) (group 1). The clinicopathological characteristics as well as early and long-term results after hepatectomy of group 1 were compared with those of the other 760 cirrhotic patients whose sALT was < 100 U/l (group 2). Liver resection extent was decided by tumor extent and a modified version of Makuuchi's criteria. RESULTS: Group 1 patients had a significantly higher indocyanine 15-minute retention rate, higher hepatitis infection rates and a higher rate of macronodular cirrhosis. Although group 1 patients had a higher postoperative complication rate, the complication severity and 90-day mortality did not significantly differ. In 81.2 % of group 1 patients, sALT level returned to the normal range within 12 weeks after operation. The 5-year disease-free and overall survival rates in group 1 and 2 were 55.1% and 57.5% (P = 0.540) and 51.5% and 60.9%, (P=0.485), respectively. CONCLUSIONS: Liver resection for HCC remains advisable in selected cirrhotic patients with preoperatively high sALT level when liver resection extent fulfills Makuuchi's criteria for cirrhotic liver resection. PMID- 25713914 TI - Real-time tissue elastography: non-invasive evaluation of liver fibrosis in chronic liver disease due to HCV. AB - BACKGROUND/AIMS: We evaluated the diagnostic efficacy for advanced fibrosis of real-time tissue elastography (RTE), is a newly introduced non-invasive method, in hepatitis C virus (HCV) patients. METHODOLOGY: Sixty-six chronic liver diseases with HCV (CLD-HCV) were evaluated by RTE, FIB-4, and APRI, as well as biopsy or hepatectomy findings. Seventeen healthy volunteers, and 1 with elevation of transaminase and 5 with liver tumors within their normal liver were enrolled for normal controls. Severe fibrosis was defined as METAVIR score 3 or 4. The tissue elasticity value was expressed by LF-index created by the program incorporated in the ultrasound device. The percentage of fibrosis area in each specimen (%FA) was determined with a personal computer. A receiver operating characteristic curve (ROC) was calculated for each non-invasive method of estimation of fibrosis. RESULTS: The values for the area under the ROC for LF index, APRI, and FIB-4 were 0.88, 0.81, and 0.84, respectively. Accuracy, sensitivity, and specificity for prediction of LF-index (>2.8) for severe fibrosis were 86.5%, 78.6%, and 93.6%, respectively, which were better than those of FIB-4 and APRI. LF-index showed a good relationship to %FA (r=0.276, P=0.020). CONCLUSION: RTE is an effective method for predicting severe fibrosis in CLD-HCV. PMID- 25713915 TI - Risk factors of postoperative complications of pancreatoduodenectomy. AB - BACKGROUND/AIMS: To investigate the risk factors of postoperative complications of pancreaticoduodenectomy. METHODOLOGY: 207 cases suffered from pancreatic carcinoma or periampullary carcinoma received pancreatoduodenectomy in the Anhui Provincial Hospital from Dec. 2007 to Dec. 2012 were analyzed. 17 clinicopathologic factors that could possibly influence postoperative mortality and morbidity were selected for univariate analysis and multivariate analysis using Logistic Regression. RESULTS: Univariate analysis showed that major risk factors of postoperative mortality and morbidity of the patients were operation history, pre-operative drainage, total serum bilirubin level, alanine aminotransferase, serum albumin, serum pre-albumin, pancreatic texture and pancreatic duct diameter (P<0.05). Multivariate analysis showed that alanine aminotransferase, pancreatic texture and pancreatic duct diameter were the independent risk factors of complications after pancreatoduodenectomy. Pancreatic duct diameter was the independent risk factor of pancreatic fistula. Pancreatic fistula was the independent risk factor of hemorrhage. CONCLUSION: Postoperative complications of pancreatoduodenectomy are closed related to alanine aminotransferase, parenchyma texture and pancreatic duct diameter. PMID- 25713916 TI - Embryonal natural orifice transluminal endoscopic surgery treating severe acute pancreatitis complicated by abdominal compartment syndrome. AB - BACKGROUND/AIMS: This study aims to estimate the value of embryonal natural orifice transluminal endoscopic surgery (ENOTES) as a treatment for severe acute pancreatitis (SAP) complicated by abdominal compartment syndrome (ACS). METHODOLOGY: The patients who were randomized into ENOTES group and surgery group underwent ENOTES and laparotomy, respectively. The Efficacy and complications of these two treatments were compared. RESULTS: Enterocinesia was observed earlier in patients of ENOTES group than that of surgery group. Acute Physiology and Chronic Health Evaluation II (APACHE II) score of patients in ENOTES group was superior to that of surgery group on the 1st, 3rd and 5th day after treatment (P < 0.05). The cure rate was 96.87% in ENOTES group, which was statistically different from 78.12% in surgery group (P < 0.05). Significant differences in complications and mortality were observed between two groups (P < 0.01). CONCLUSION: Compared with surgical abdominal decompression, ENOTES and flexible endoscope therapy is a more effective and minimal invasive surgery with less complications. PMID- 25713917 TI - Pancreatic ductal adenocarcinoma presenting with acute and chronic pancreatitis as initial presentation: is prognosis better? A comparison study.. AB - BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) may present with acute and /or chronic pancreatitis due to pancreatic ductal obstruction causing diagnostic dilemma. The aim of this retrospective study was to investigate the outcome and prognosis of the patients of PDAC presenting with pancreatitis. METHODS: From 1991 to 2009, 298 patients with PDAC that underwent surgical treatment were retrospectively studied and divided in two groups depending upon initial symptomatic presentation. Group A (n=254) comprised patients without pancreatitis while group B (n=44) patients presented with acute and/or chronic pancreatitis initially. RESULTS: All the patients in studied cohort were surgically treated. Mean age of group A was 63.1 years & for group B it was 62.9 years. Location of tumor was in head of the pancreas in 66.14% of group A patients (n=168) and 61.36% of group B patients (n=27). Although statistically insignificant, the patients in group B had overall better 5-year survival than the patients in group A (20% vs 15.9%). CONCLUSIONS: This retrospective study highlights the overall better survival of PDAC patients presenting with acute and/or chronic pancreatitis than those without as contrary to previous reports which stated the poor prognosis of PDAC patients if associated with underlying pancreatitis. PMID- 25713918 TI - Incremental value of cell block preparations over conventional smears alone in the evaluation of EUS-FNA for pancreatic masses. AB - BACKGROUND/AIMS: The effectiveness of endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) has been established for a definite pathological diagnosis of pancreatic solid masses. We investigated the usefulness of cell block preparations in EUS-FNA, by evaluating the added value of cell block preparations over conventional smears alone. METHODOLOGY: Between March 2011 and June 2013, 61 patients were retrospectively evaluated who underwent EUS-FNA for pancreatic solid masses. Diagnostic values for diagnosing pancreatic malignancy were compared for a combination of the conventional smear and cell block (CSCB) and the conventional smear alone (CS). RESULTS: The addition of the cell block technique increased the sensitivity of conventional smear for diagnosing the pancreatic malignancy from 79% (CS) to 90% (CSCB, p=0.0313) and the accuracy from 81% to 91% (p=0.0313). The specificity and positive predictive value were 100% in both methods. The negative predictive value was increased from 33% (CS) to 50% (CSCB), but this difference was not statistically significant (p=0.0833). CONCLUSION: The addition of the cell block method after a conventional smear may increase the sensitivity and negative predictive value for diagnosing the pancreatic malignancy in patients with pancreatic masses who undergo EUS-FNA. Further study may be warranted to determine whether the cell block method can replace the conventional smear. PMID- 25713919 TI - The influence of post-operative surveillance on the prognosis after curative surgery for gastric cancer. AB - BACKGROUND/AIMS: Although routine post-operative surveillance after curative resection for gastric cancer is recommended, there are few reports on the value of postoperative follow-up. The aim of this study was to assess the possible role of post-operative surveillance as a prognostic factor after curative resection for gastric cancer. METHODOLOGY: A total of 192 gastric cancer patients who suffered recurrences after curative resection between January 2001 and June 2012 were included in this study. Clinicopathological factors and survival were retrospectively analyzed according to the presence or absence of symptoms related to tumor recurrence at the time of relapse. RESULTS: One-hundred-and-twenty-six of the patients (65.6%) had asymptomatic recurrences. Peritoneal recurrence (60.6%) predominated among the symptomatic recurrences, whereas locoregional recurrences (42.1%) were dominant among the asymptomatic recurrence. Median recurrence-free survival times did not differ between the two groups (p=0.507). However, median post-recurrence (p<0.001) and overall survival times (p=0.022) were longer in the asymptomatic group. CONCLUSIONS: Time to recurrence did not differ between the symptomatic and asymptomatic recurrence groups, but post recurrence survival and overall survival were better in the asymptomatic group. Prior to the execution of a large scale randomized controlled trial, close follow up should be considered. PMID- 25713920 TI - Long-term follow-up and characteristics of cancer negative cases after endoscopic resection and gastrectomy for early gastric cancer. AB - BACKGROUND: Endoscopic resection (ER) and gastrectomy are widely used for early gastric cancer (EGC). However, unexpected cases, which show no cancer after treatment, have occurred. The present study was designed to characterize cancer negative cases after ER and gastrectomy, and determine their long term prognosis. METHODS: Patients with EGC who underwent ER from January 2004 to October 2012 and gastrectomy from January 2000 to December 2007 were analyzed. RESULTS: There were 13 CFG from 1508 EGC cases after ER (0.9%) and 13 CFG from 4,101 gastrectomy (0.3%), respectively. The tumor size of the CFG group after ER was smaller than the control group (median value of tumor area of CFG vs. control groups, 48.0 mm2 vs. 146.0 mm2, respectively, P = 0.008). However, the CFG group, after gastrectomy, showed marginal differences in size and biopsy number when compared with the control group. There was no mortality in the all CFG. CONCLUSIONS: The small diameter and area of EGC are factors which determine if the lesion can be completely removed by forcep biopsy. A final pathology report of "No cancer was detected" after ER and surgery of EGC is not detrimental to the patient. PMID- 25713921 TI - Ratio of metastatic to examined lymph nodes is a predictor of mortality in locally advanced gastric cancer treated chemo-radiotherapy. AB - BACKGROUND/AIMS: To evaluate whether the ratio between the number of metastatic lymph nodes and the number of total removed lymph nodes (MLR) is related survival in patients with locally advanced (stage 3) gastric cancer treated chemo radiotherapy. METHODOLOGY: We included 179 patients with locally advanced lymph node-positive gastric cancer treated chemo-radiotherapy within this study. The cut-off values, area under curve (AUC), sensitivity, and specificity were calculated using the receiver operating characteristic (ROC) curve technique for MLR. RESULTS: The sensitivity and specificity of MLR for mortality were 71.54% and 51.79%, respectively, when the cutoff level was accepted as the ratio >= 0.3. The AUC for the predictive value of MLR with regard to mortality was 0.609 (95% confidence interval [CI]: 0.533-0.681, p: 0.0135). Overall survival rates were significantly lower in patients with high MLR than in those with low MLR (15 months vs. 35 months, p: 0.002, respectively). In multivariate analysis, overall survival rates were significantly associated with MLR status (low or high). CONCLUSION: The simple and easily obtainable MLR is an independent predictor for mortality in patients with locally advanced gastric cancer even if chemo radiotherapy, which is known to increase local control, was given. PMID- 25713923 TI - Successful distal gastrectomy after distal pancreatectomy combined with splenectomy by assuring the blood flow to the remnant stomach from the left inferior phrenic artery. AB - BACKGROUND/AIMS: The current literature would suggest that patients with gastric cancer who have a previous history of ligation of the splenic artery undergo total gastrectomy. However, an analysis of the risk factors for postoperative complications in elderly patients showed a higher rate of morbidities for total gastrectomy compared to subtotal gastrectomy. Case REPORT: We herein report a rare case of successful distal gastrectomy in a 78-year-old female diagnosed with gastric cancer with a previous history of distal pancreatectomy combined with splenectomy, because an adequate blood flow was provided by the fundic branches from the left inferior phrenic artery. Preoperative computed tomography demonstrated a ligated splenic artery and left gastric artery with developed fundic branches from the left inferior phrenic artery. The intraoperative findings showed a sufficient blood flow to the proximal stomach after ligation of all main gastric arteries, thus suggesting that the gastric remnant could be supplied by the fundic branches from the LIPA. The patient's postoperative course was uneventful. CONCLUSION: This case suggests that a distal gastrectomy is a possible treatment modality even after distal pancreatectomy combined with splenectomy. PMID- 25713922 TI - The differences in clinicopathological features and prognosis among the subtypes of signet ring cell, mucinous, papillary, and lymphoepithelioma-like carcinoma in advanced gastric cancer. AB - BACKGROUND/AIMS: There are differing histologic subtypes of gastric cancer. We investigated the clinicopathological features and prognosis of: signet ring cell (SRC), mucinous (MGC), papillary (PGC), and lymphoepithelioma-like (LELC) carcinoma in advanced gastric cancer. METHODOLOGY: One hundred thirty six advanced gastric cancer patients, including 62 SRCs, 43 MGCs, 9 PGCs, and 22 LELCs, who underwent R0 gastrectomy between 2002 and 2013, were retrospectively evaluated. RESULTS: There were significant differences in several clinicopathological features. There were found to be statistical differences in postoperative outcomes in the type of gastrectomy and type of anastomosis (p<0.001 and p<0.001, respectively). In terms of overall survival analysis, there was no statistical survival difference among the subtypes of advanced gastric cancer (p=0.088). However, LELC had a better prognosis than the other groups. CONCLUSIONS: There were some differences in several of the clinicopathological features of the subtypes advanced gastric cancer. Although there were no statistical differences in survival, those with LELC showed a better prognosis than did the other groups. Therefore, the treatment of advanced gastric cancer should be individualized, and prognosis considered, according to the subtype. PMID- 25713924 TI - Correlation between gastric transit time measured by video capsule endoscopy and gastric emptying determined by the continuous real-time 13C breath test (BreathID system). AB - BACKGROUND/AIMS: The aim of this study was to determine the possible existence of a correlation between the gastric transit time (GTT) measured by video capsule endoscopy (VCE) and the parameters of gastric emptying determined using 13C breath test (BreathID system). METHODS: Eight healthy male volunteers participated in this randomized, two-way crossover study. The subjects were randomly assigned to undergo VCE using the PillCam SB capsule endoscopy system or the 13C breath test for 4 hours after a test meal (400 kcal per 400 mL) containing 100 mg of 13C acetic acid administered after overnight fasting. The VCE images were analyzed and the GTT was determined using the proprietary RAPID software. The parameters, namely T lag, T 1/2 and GEC were calculated using the Oridion Research Software (beta version). The GTT measured by VCE and the parameters of gastric emptying were compared statistically. RESULTS: No significant correlation was observed between the GTT and T lag (p = 0.5263), T 1/2 (p = 0.4100) or GEC (p = 0.2410), as determined by calculation of the Spearman's rank correlation coefficient. CONCLUSIONS: GTT measured by VCE cannot serve as asubstitute for the gastric emptying time measured bythe 13C breath test. PMID- 25713926 TI - Pharmacogenomic Characterization of Cytotoxic Compounds from Salvia officinalis in Cancer Cells. AB - Salvia officinalis is used as a dietary supplement with diverse medicinal activity (e.g. antidiabetic and antiatherosclerotic effects). The plant also exerts profound cytotoxicity toward cancer cells. Here, we investigated possible modes of action to explain its activity toward drug-resistant tumor cells. Log10IC50 values of two constituents of S. officinalis (ursolic acid, pomolic acid) were correlated to the expression of ATP-binding cassette (ABC) transporters (P-glycoprotein/ABCB1/MDR1, MRP1/ABCC1, BCRP/ABCG2) and epidermal growth factor receptor (EGFR) or mutations in RAS oncogenes and the tumor suppressor gene TP53 of the NCI panel of cell lines. Gene expression profiles predicting sensitivity and resistance of tumor cells to these compounds were determined by microarray-based mRNA expressions, COMPARE, and hierarchical cluster analyses. Furthermore, the binding of both plant acids to key molecules of the NF-kappaB pathway (NF-kappaB, I-kappaB, NEMO) was analyzed by molecular docking. Neither expression nor mutation of ABC transporters, oncogenes, or tumor suppressor genes correlated with log10IC50 values for ursolic acid or pomolic acid. In microarray analyses, many genes involved in signal transduction processes correlated with cellular responsiveness to these compounds. Molecular docking indicated that the two plant acids strongly bound to target proteins of the NF-kappaB pathway with even lower free binding energies than the known NF kappaB inhibitor MG-132. They interacted more strongly with DNA-bound NF-kappaB than free NF-kappaB, pointing to inhibition of DNA binding by these compounds. In conclusion, the lack of cross-resistance to classical drug resistance mechanisms (ABC-transporters, oncogenes, tumor suppressors) may indicate a promising role of the both plant acids for cancer chemotherapy. Genes involved in signal transduction may contribute to the sensitivity or resistance of tumor cells to ursolic and pomolic acids. Ursolic and pomolic acid may target different steps of the NF-kappaB pathway to inhibit NF-kappaB-mediated functions. PMID- 25713927 TI - Modulation of Amide Bond Rotamers in 5-Acyl-6,7-dihydrothieno[3,2-c]pyridines. AB - 2-Substituted N-acyl-piperidine is a widespread and important structural motif, found in approximately 500 currently available structures, and present in nearly 30 pharmaceutically active compounds. Restricted rotation of the acyl substituent in such molecules can give rise to two distinct chemical environments. Here we demonstrate, using NMR studies and density functional theory modeling of the lowest energy structures of 5-acyl-6,7-dihydrothieno[3,2-c]pyridine derivatives, that the amide E:Z equilibrium is affected by non-covalent interactions between the amide oxygen and adjacent aromatic protons. Structural predictions were used to design molecules that promote either the E- or Z-amide conformation, enabling preparation of compounds with a tailored conformational ratio, as proven by NMR studies. Analysis of the available X-ray data of a variety of published N-acyl piperidine-containing compounds further indicates that these molecules are also clustered in the two observed conformations. This finding emphasizes that directed conformational isomerism has significant implications for the design of both small molecules and larger amide-containing molecular architectures. PMID- 25713929 TI - Absence of colossal magnetoresistance in the oxypnictide PrMnAsO0.95F0.05. AB - We have recently reported a new mechanism of colossal magnetoresistance (CMR) in electron doped manganese oxypnictides NdMnAsO1-xFx. Magnetoresistances of up to 95% at 3 K have been observed. Here we show that upon replacing Nd for Pr, the CMR is surprisingly no longer present. Instead a sizable negative magnetoresistance is observed for PrMnAsO0.95F0.05 below 35 K (MR7T (12 K) = 13.4% for PrMnAsO0.95F0.05). A detailed neutron and synchrotron X-ray diffraction study of PrMnAsO0.95F0.05 has been performed, which shows that a structural transition, Ts, occurs at 35 K from tetragonal P4/nmm to orthorhombic Pmmn symmetry. The structural transition is driven by the Pr 4f electrons degrees of freedom. The sizable -MR observed below the transition most likely arises due to a reduction in magnetic and/or multipolar scattering upon application of a magnetic field. PMID- 25713928 TI - A Cyclic Peptide Mimic of the beta-Amyloid Binding Domain on Transthyretin. AB - Self-association of beta-amyloid (Abeta) into oligomers and fibrils is associated with Alzheimer's disease (AD), motivating the search for compounds that bind to and inhibit Abeta oligomerization and/or neurotoxicity. Peptides are an attractive class of such compounds, with potential advantages over small molecules in affinity and specificity. Self-complementation and peptide library screening are two strategies that have been employed in the search for peptides that bind to Abeta. Alternatively, one could design Abeta-binding peptides based on knowledge of complementary binding proteins. One candidate protein, transthyretin (TTR), binds Abeta, inhibits aggregation, and reduces its toxicity. Previously, strand G of TTR was identified as part of a specific Abeta binding domain, and G16, a 16-mer peptide with a sequence that spans strands G and H of TTR, was synthesized and tested. Although both TTR and G16 bound to Abeta, they differed significantly in their effect on Abeta aggregation, and G16 was less effective than TTR at protecting neurons from Abeta toxicity. G16 lacks the beta strand/loop/beta-strand structure of TTR's Abeta binding domain. To enforce proper residue alignment, we transplanted the G16 sequence onto a beta-hairpin template. Two peptides with 18 and 22 amino acids were synthesized using an orthogonally protected glutamic acid derivative, and an N-to-C cyclization reaction was carried out to further restrict conformational flexibility. The cyclized 22-mer (but not the noncyclized 22-mer nor the 18-mer) strongly suppressed Abeta aggregation into fibrils, and protected neurons against Abeta toxicity. The imposition of structural constraints generated a much-improved peptidomimetic of the Abeta binding epitope on TTR. PMID- 25713930 TI - Tyrosinase-catalyzed metabolism of rhododendrol (RD) in B16 melanoma cells: production of RD-pheomelanin and covalent binding with thiol proteins. AB - RS-4-(4-Hydroxyphenyl)-2-butanol (rhododendrol, RD) was reported to induce leukoderma of the skin. To explore the mechanism underlying that effect, we previously showed that oxidation of RD with mushroom tyrosinase produces RD quinone, which is converted to secondary quinone products, and we suggested that those quinones are cytotoxic because they bind to cellular proteins and produce reactive oxygen species. We then confirmed that human tyrosinase can oxidize both enantiomers of RD. In this study, we examined the metabolism of RD in B16F1 melanoma cells in vitro. Using 4-amino-3-hydroxy-n-butylbenzene as a specific indicator, we detected moderate levels of RD-pheomelanin in B16F1 cells exposed to 0.3 to 0.5 mM RD for 72 h. We also confirmed the covalent binding of RD quinone to non-protein thiols and proteins through cysteinyl residues. The covalent binding of RD-quinone to proteins was 20- to 30-fold greater than dopaquinone. These results suggest that the tyrosinase-induced metabolism of RD causes melanocyte toxicity. PMID- 25713931 TI - Isolation and characterization of rubisco small subunit gene promoter from common wheat (Triticum aestivum L.). AB - Choice of an appropriate promoter is critical to express target genes in intended tissues and developmental stages. However, promoters capable of directing gene expression in specific tissues and stages are not well characterized in monocot species. To identify such a promoter in wheat, this study isolated a partial sequence of the wheat small subunit of RuBisCO (TarbcS) promoter. In silico analysis revealed the presence of elements that are characteristic to rbcS promoters of other, mainly dicot, species. Transient expression of the TarbcS:GUS in immature wheat embryos and tobacco leaves but not in the wheat roots indicate the functionality of the TarbcS promoter fragment in directing the expression of target genes in green plant tissues. PMID- 25713932 TI - Reproductive justice and the pace of change: socioeconomic trends in US infant death rates by legal status of abortion, 1960-1980. AB - US infant death rates for 1960 to 1980 declined most quickly in (1) 1970 to 1973 in states that legalized abortion in 1970, especially for infants in the lowest 3 income quintiles (annual percentage change = -11.6; 95% confidence interval = 18.7, -3.8), and (2) the mid-to-late 1960s, also in low-income quintiles, for both Black and White infants, albeit unrelated to abortion laws. These results imply that research is warranted on whether currently rising restrictions on abortions may be affecting infant mortality. PMID- 25713933 TI - Integrating fundamental concepts of obesity and eating disorders: implications for the obesity epidemic. AB - Physiological mechanisms promote weight gain after famine. Because eating disorders, obesity, and dieting limit food intake, they are famine-like experiences. The development of the concept of meeting an ideal weight was the beginning of increasing obesity. Weight stigma, the perception of being fat, lack of understanding of normal growth and development, and increased concern about obesity on the part of health providers, parents, and caregivers have reinforced each other to promote dieting. Because weight suppression and disinhibition provoke long-term weight increase, dieting is a major factor producing the obesity epidemic. The integrated eating disorder-obesity theory included in this article emphasizes that, contrary to dieters, lifetime weight maintainers depend on physiological processes to control weight and experience minimal weight change. PMID- 25713934 TI - Advancing family health through the Garden of Eatin': on-site food gardens in early childhood education. AB - Nutritional practices develop over the life course. Developing healthy habits at an early age can contribute to combating increasing child obesity rates. Through a range of activities that rely on the presence of an on-site food garden, North Bay Children's Center (NBCC), an early childhood education program, has enacted a "culture of health" into all aspects of the curriculum to promote healthy eating practices among children, families, teachers and staff. NBCC's garden program serves as a model in early childhood education and as a community-based intervention to improve family health and prevent child obesity. PMID- 25713935 TI - Storytelling to enhance the value of research. PMID- 25713936 TI - Squeezing blood from a stone: how income inequality affects the health of the American workforce. AB - Income inequality is very topical-in both political and economic circles-but although income and socioeconomic status are known determinants of health status, income inequality has garnered scant attention with respect to the health of US workers. By several measures, income inequality in the United States has risen since 1960. In addition to pressures from an increasingly competitive labor market, with cash wages losing out to benefits, workers face pressures from changes in work organization. We explored these factors and the mounting evidence of income inequality as a contributing factor to poorer health for the workforce. Although political differences may divide the policy approaches undertaken, addressing income inequality is likely to improve the overall social and health conditions for those affected. PMID- 25713937 TI - Effectiveness of residential wood-burning regulation on decreasing particulate matter levels and hospitalizations in the San Joaquin Valley Air Basin. AB - OBJECTIVES: We examined the impact of Rule 4901, aimed at reducing residential wood burning, on particulate matter levels and hospitalizations in the San Joaquin Valley Air Basin (SJVAB). METHODS: Using general linear mixed models and generalized estimating equation models, we compared levels of particulate matter and of hospital admissions (age groups = 45-64 and >= 65 years) in the SJVAB for cardiovascular disease (CVD), ischemic heart disease (IHD), and chronic obstructive pulmonary disease during the burn seasons before (2000-2003) and after (2003-2006) implementation. RESULTS: After implementation, we observed reductions of 12%, 11%, and 15% in particulate matter 2.5 micrometers in diameter or smaller (PM2.5), and 8%, 7%, and 11% in coarse particles, in the entire SJVAB and in rural and urban regions of the air basin, respectively. Among those aged 65 years and older, Rule 4901 was estimated to prevent 7%, 8%, and 5% of CVD cases, and 16%, 17%, and 13% of IHD cases, in the entire SJVAB and in rural and urban regions, respectively. CONCLUSIONS: The study suggests that Rule 4901 is effective at reducing wintertime ambient PM2.5 levels and decreasing hospital admissions for heart disease among people aged 65 years and older. PMID- 25713938 TI - "It's not a priority when we're in combat": public health professionals and military tobacco control policy. AB - Tobacco use is prevalent among service members, but civilian public health groups have not effectively addressed military tobacco control policy issues. We conducted focus groups in 2010 and 2012 with participants from public health and tobacco control organizations regarding their understanding of the military and of tobacco use in that context. Misperceptions were common. Military personnel were believed to be young, from marginalized populations, and motivated to join by lack of other options. Tobacco use was considered integral to military life; participants were sometimes reluctant to endorse stronger tobacco control policies than those applied to civilians, although some believed the military could be a social policy leader. Engaging public health professionals as effective partners in tobacco-free military efforts may require education about and reframing of military service and tobacco control policy. PMID- 25713939 TI - Paid leave mandates may fail to reach part-time workers. PMID- 25713940 TI - The intended and unintended consequences of a legal measure to cut the flow of illegal cigarettes into New York City: the case of the South Bronx. AB - OBJECTIVES: We examined the impact of a change in New York tax law on the numbers of untaxed cigarettes bootlegged from Native American reservations and resold in the South Bronx. METHODS: Discarded cigarette packs were systematically collected in 30 randomized South Bronx census tracks before and after the amended tax law went into effect in 2011. Also, administrative data were gathered on the number of taxed cigarettes sold in New York State, including sales to Native American reservations. RESULTS: Before the tax amendment, 42% of discarded cigarette packs collected in the South Bronx had no tax stamp. After the tax law went into effect, the percentage of cigarette packs without tax stamps declined to 6.2%. Simultaneously, the percentage of packs with out-of-state tax stamps rose from 18.3% to 66.3%. The percentage of packs with a combined New York State and New York City tax stamp did not change after the tax amendment. CONCLUSIONS: After the tax amendment, the supply of contraband cigarettes appears to have quickly shifted from one lower-priced jurisdiction to another without a change in the overall prevalence of contraband cigarettes. PMID- 25713941 TI - Systematic review of racial disparities in human papillomavirus-associated anal dysplasia and anal cancer among men who have sex with men. AB - We systematically reviewed the literature on anal human papillomavirus (HPV) infection, dysplasia, and cancer among Black and White men who have sex with men (MSM) to determine if a racial disparity exists. We searched 4 databases for articles up to March 2014. Studies involving Black MSM are nearly absent from the literature. Of 25 eligible studies, 2 stratified by race and sexual behavior. Both reported an elevated rate of abnormal anal outcomes among Black MSM. White MSM had a 1.3 times lower prevalence of group-2 HPV (P < .01) and nearly 13% lower prevalence of anal dysplasia than did Black MSM. We were unable to determine factors driving the absence of Black MSM in this research and whether disparities in clinical care exist. Elevated rates of abnormal anal cytology among Black MSM in 2 studies indicate a need for future research in this population. PMID- 25713942 TI - Evaluating a bilingual patient navigation program for uninsured women with abnormal screening tests for breast and cervical cancer: implications for future navigator research. AB - OBJECTIVES: The DuPage Patient Navigation Collaborative evaluated the Patient Navigation Research Program (PNRP) model for uninsured women receiving free breast or cervical cancer screening through the Illinois Breast and Cervical Cancer Program in DuPage County, Illinois. METHODS: We used medical records review and patient surveys of 477 women to compare median follow-up times with external Illinois Breast and Cervical Cancer Program and Chicago PNRP benchmarks of performance. We examined the extent to which we mitigated community-defined timeliness risk factors for delayed follow-up, with a focus on Spanish-speaking participants. RESULTS: Median follow-up time (29.0 days for breast and 56.5 days for cervical screening abnormalities) compared favorably to external benchmarks. Spanish-speaking patients had lower health literacy, lower patient activation, and more health care system distrust than did English-speaking patients, but despite the prevalence of timeliness risk factors, we observed no differences in likelihood of delayed (> 60 days) follow-up by language. CONCLUSIONS: Our successful replication and scaling of the PNRP navigation model to DuPage County illustrates a promising approach for future navigator research. PMID- 25713943 TI - Posttraumatic stress disorder and incident heart failure among a community-based sample of US veterans. AB - OBJECTIVES: We investigated the association between posttraumatic stress disorder (PTSD) and incident heart failure in a community-based sample of veterans. METHODS: We examined Veterans Affairs Pacific Islands Health Care System outpatient medical records for 8248 veterans between 2005 and 2012. We used multivariable Cox regression to estimate hazard ratios and 95% confidence intervals for the development of heart failure by PTSD status. RESULTS: Over a mean follow-up of 7.2 years, veterans with PTSD were at increased risk for developing heart failure (hazard ratio [HR] = 1.47; 95% confidence interval [CI] = 1.13, 1.92) compared with veterans without PTSD after adjustment for age, gender, diabetes, hyperlipidemia, hypertension, body mass index, combat service, and military service period. Additional predictors for heart failure included age (HR = 1.05; 95% CI = 1.03, 1.07), diabetes (HR = 2.54; 95% CI = 2.02, 3.20), hypertension (HR = 1.87; 95% CI = 1.42, 2.46), overweight (HR = 1.72; 95% CI = 1.25, 2.36), obesity (HR = 3.43; 95% CI = 2.50, 4.70), and combat service (HR = 4.99; 95% CI = 1.29, 19.38). CONCLUSIONS: Ours is the first large-scale longitudinal study to report an association between PTSD and incident heart failure in an outpatient sample of US veterans. Prevention and treatment efforts for heart failure and its associated risk factors should be expanded among US veterans with PTSD. PMID- 25713944 TI - Adequate evidence to challenge the paradigm of dental caries prevention in early age? PMID- 25713945 TI - Health among Black children by maternal and child nativity. AB - OBJECTIVES: We examined 5 health outcomes among Black children born to US-born and foreign-born mothers and whether differences by mother's region of birth could be explained by maternal duration of US residence, child's place of birth, and familial sociodemographic characteristics. METHODS: Data were from the 2000 2011 National Health Interview Surveys. We examined 3 groups of children, based on mother's region of birth: US origin, African origin, and Latin American or Caribbean origin. We estimated multivariate regression models. RESULTS: Children of foreign-born mothers were healthier across all 5 outcomes than were children of US-born mothers. Among children of foreign-born mothers, US-born children performed worse on all health outcomes than children born abroad. African-origin children had the most favorable health profile. Longer duration of US residence among foreign-born mothers was associated with poorer child health. Maternal educational attainment and other sociodemographic characteristics did little to explain these differences. CONCLUSIONS: Further studies are needed to understand the role of selective migration and the behavioral, cultural, socioeconomic, and contextual origins of the health advantage of Black children of foreign-born mothers. PMID- 25713946 TI - The CDC clearance process: an obstacle to progress in public health. PMID- 25713948 TI - Snus use and smoking behaviors: preliminary findings from a prospective cohort study among US Midwest young adults. AB - The effect of snus use on smoking behaviors among US young adults is largely unknown. Data from the Minnesota Adolescent Community Cohort Study collected in 2010 to 2011 and 2011 to 2012 (participants aged 20-28 years) showed that young adult nonsmokers who had tried snus were subsequently more likely than those who had not tried snus to become current smokers (n = 1696; adjusted odds ratio = 1.79; 95% confidence interval = 1.01, 3.14). Snus use was not associated with subsequent smoking cessation or reduction among young adult current smokers (n = 488; P > .46). PMID- 25713947 TI - The contribution of national disparities to international differences in mortality between the United States and 7 European countries. AB - OBJECTIVES: This study examined to what extent the higher mortality in the United States compared to many European countries is explained by larger social disparities within the United States. We estimated the expected US mortality if educational disparities in the United States were similar to those in 7 European countries. METHODS: Poisson models were used to quantify the association between education and mortality for men and women aged 30 to 74 years in the United States, Belgium, Denmark, Finland, France, Norway, Sweden, and Switzerland for the period 1989 to 2003. US data came from the National Health Interview Survey linked to the National Death Index and the European data came from censuses linked to national mortality registries. RESULTS: If people in the United States had the same distribution of education as their European counterparts, the US mortality disadvantage would be larger. However, if educational disparities in mortality within the United States equaled those within Europe, mortality differences between the United States and Europe would be reduced by 20% to 100%. CONCLUSIONS: Larger educational disparities in mortality in the United States than in Europe partly explain why US adults have higher mortality than their European counterparts. Policies to reduce mortality among the lower educated will be necessary to bridge the mortality gap between the United States and European countries. PMID- 25713949 TI - Patient preference as a barrier to needed care. PMID- 25713950 TI - Development and implementation of client-centered nutrition education programs in a 4-stage framework. AB - The Texas Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) sought to engage the WIC staff and community in the implementation of relevant and effective client-centered nutrition education. The program was implemented in a 4-stage framework. The collaborative process of developing client-centered nutrition education allowed members to learn from one another, thus ensuring commitment to client-centered nutrition education from all levels of staff. The co-created materials and trainings developed during the implementation played a key role. Evaluation feedback started at the infancy of implementation and gave all community members a stake in developing client centered nutrition education and an opportunity to be invested in its success, which led to increased execution at the local agency level over the implementation stages. PMID- 25713951 TI - Drug Use, Sexual Risk, and Syndemic Production Among Men Who Have Sex With Men Who Engage in Group Sexual Encounters. AB - OBJECTIVES: We surveyed men who have sex with men (MSM) to determine whether sexual risk behaviors, recent drug use, and other psychosocial problems differed between men who engaged in one-on-one and group sexual encounters. METHODS: We conducted an Internet-based cross-sectional survey of 7158 MSM aged 18 years or older in the United States recruited from a gay-oriented sexual networking Web site in 2008. Among MSM who engaged in group sexual encounters, we compared their past-60-day sexual behaviors in one-on-one encounters and group sexual encounters. We also compared risk profiles and syndemic production between men who did and did not participate in group sex. RESULTS: Men reporting a group-sex encounter had significantly higher polydrug use and sexual risk than did the men not reporting group sex in the past 60 days. The odds of engaging in group sex with 4 or more sexual partners significantly increased with the number of psychosocial problems, supporting evidence of syndemic production. CONCLUSIONS: We identified a particularly high-risk subgroup in the MSM population with considerable psychosocial problems that may be reached online. Research is needed on how to engage these high-risk men in combination prevention interventions. PMID- 25713952 TI - Pathways to colonoscopy in the South: seeds of health disparities. AB - OBJECTIVES: We aimed to highlight sociodemographic differences in how patients access colonoscopy. METHODS: We invited all eligible patients (n = 2500) from 2 academy-affiliated colonoscopy centers in Alachua County, Florida (1 free standing, 1 hospital based), to participate in a precolonoscopy survey (September 2011-October 2013); patients agreeing to participate (n = 1841, response rate = 73.6%) received a $5.00 gift card. RESULTS: We found sociodemographic differences in referral pathway, costs, and reasons associated with obtaining the procedure. Patients with the ideal pathway (referred by their regular doctor for age appropriate screening) were more likely to be Black (compared with other minorities), male, high income, employed, and older. Having the colonoscopy because of symptoms was associated with being female, younger, and having lower income. We found significant differences for 1 previously underestimated barrier, having a spouse to accompany the patient to the procedure. CONCLUSIONS: Patients' facilitators and barriers to colonoscopy differed by sociodemographics in our study, which implies that interventions based on a single facilitator will not be effective for all subgroups of a population. PMID- 25713953 TI - Buffering Syndemic Effects in a Sexual Risk-Reduction Intervention for Male Clients of Female Sex Workers: Results From a Randomized Controlled Trial. AB - OBJECTIVES: We sought to test the efficacy of a sexual risk intervention for male clients of female sex workers (FSWs) and examine whether efficacy was moderated by syndemic risk. METHODS: From 2010 to 2014, we conducted a 2-arm randomized controlled trial (60-minute, theory-based, safer sex intervention versus a didactic time-equivalent attention control) that included 400 male clients of FSWs on the US-Mexico border with follow-up at 4, 8, and 12 months. We measured 5 syndemic risk factors, including substance use and depression. Primary outcomes were sexually transmitted infections incidence and total unprotected sex with FSWs. RESULTS: Although participants in both groups became safer, there was no significant difference in behavior change between groups. However, baseline syndemic risk moderated intervention efficacy. At baseline, there was a positive association between syndemic risk and unprotected sex. Then at 12 months, longitudinal analyses showed the association depended on intervention participation (B = -0.71; 95% confidence interval [CI] = -1.22, -0.20; P = .007). Among control participants there still existed this modest association (B = 0.36; 95% CI = -0.49, 1.22; P = .09); among intervention participants there was a significant negative association (B = -0.35; 95% CI = -0.63, -0.06; P = .02). CONCLUSION: A brief intervention might attenuate syndemic risks among clients of FSWs. Other populations experiencing syndemic problems may also benefit from such programs. PMID- 25713954 TI - Community water fluoridation and intelligence. PMID- 25713955 TI - Flavored alcoholic beverage use, risky drinking behaviors, and adverse outcomes among underage drinkers: results from the ABRAND Study. AB - OBJECTIVES: We examined associations between consumption of different types of flavored alcoholic beverages (FABs) and risky drinking and drinking-related harms among underage drinkers. METHODS: For the Alcohol Brand Research among Underage Youth study, we applied multivariable logistic regression analyses to data from underage drinkers (n = 1031, aged 13-20 years), recruited from a national Internet panel in 2011 to 2012, to estimate associations between consumption of malt-based drinks; spirits-based, premixed- or ready-to-drink cocktails; and supersized alcopops, alone or in combination, and alcohol-related outcomes. RESULTS: After adjustment for confounding variables, the exclusive consumption of alcopops was associated with episodic heavy drinking (odds ratio [OR] = 4.35; 95% confidence interval [CI] = 1.24, 15.31; P < .05) and alcohol-related injuries (OR = 6.25; 95% CI = 1.34, 29.10; P < .05). Exclusive consumption of cocktails was associated with episodic heavy drinking (odds ratio [OR] = 2.61; 95% CI = 1.26, 5.41; P < .05) and injuries requiring medical attention (OR = 6.50; 95% CI = 2.09, 20.17; P < .001. Exclusive consumption of 2 or more FABs was associated with episodic heavy drinking (OR = 2.78; 95% CI = 1.25, 6.16; P < .05), fighting (OR = 3.30; 95% CI = 1.46, 7.47; P < .001), and alcohol-related injuries (OR = 2.83; 95% CI = 1.43, 5.58; P < .001). CONCLUSIONS: FABs present an emerging public health problem among youths. PMID- 25713956 TI - Carpenter et al. respond. PMID- 25713957 TI - Bernabe and Sheiham respond. PMID- 25713959 TI - State-level relationships cannot tell us anything about individuals. PMID- 25713960 TI - Anderson et al. respond. PMID- 25713961 TI - Envisioning a healthier future. PMID- 25713962 TI - Old myths, new myths: challenging myths in public health. AB - Myths are widely held beliefs and are frequently perpetuated through telling and retelling. We examined 10 myths in public health research and practice. Where possible, we traced their origins, interrogated their current framing in relation to the evidence, and offered possible alternative ways of thinking about them. These myths focus on the nature of public health and public health interventions, and the nature of evidence in public health. Although myths may have some value, they should not be privileged in an evidence-informed public health context. PMID- 25713963 TI - Accountable care for the poor and underserved: Minnesota's Hennepin Health model. AB - Hennepin Health provides integrated medical and social services to low-income Medicaid patients in a large county located in Minneapolis, Minnesota. Data sharing is critical to program operations along with care coordination provided by community health workers. Early evidence indicates fewer emergency department visits and increased use of outpatient primary care. By focusing on prevention, coordination, and team-based care, the county hopes to improve individuals' quality of life while reducing costs through better care management and reductions in emergency department use. PMID- 25713965 TI - Effect of US health policies on health care access for Marshallese migrants. AB - The Republic of the Marshall Islands is a sovereign nation previously under the administrative control of the United States. Since 1986, the Compacts of Free Association (COFA) between the Republic of the Marshall Islands and the United States allows Marshall Islands citizens to freely enter, lawfully reside, and work in the United States, and provides the United States exclusive military control of the region. When the COFA was signed, COFA migrants were eligible for Medicaid and other safety net programs. However, these migrants were excluded from benefits as a consequence of the Personal Responsibility and Work Opportunity Reconciliation Act. Currently, COFA migrants have limited access to health care benefits in the United States, which perpetuates health inequalities. PMID- 25713966 TI - Public health agenda setting in a global context: the International Labor Organization's decent work agenda. AB - We drew on two agenda-setting theories usually applied at the state or national level to assess their utility at the global level: Kingdon's multiple streams theory and Baumgartner and Jones's punctuated equilibrium theory. We illustrate our analysis with findings from a qualitative study of the International Labor Organization's Decent Work Agenda. We found that both theories help explain the agenda-setting mechanisms that operate in the global context, including how windows of opportunity open and what role institutions play as policy entrepreneurs. Future application of these theories could help characterize power struggles between global actors, whose voices are heard or silenced, and their impact on global policy agenda setting. PMID- 25713964 TI - Influence of school architecture and design on healthy eating: a review of the evidence. AB - We examined evidence regarding the influence of school physical environment on healthy-eating outcomes. We applied a systems perspective to examine multiple disciplines' theoretical frameworks and used a mixed-methods systematic narrative review method, considering both qualitative and quantitative sources (published through March 2014) for inclusion. We developed a causal loop diagram from 102 sources identified. We found evidence of the influence of many aspects of a school's physical environment on healthy-eating outcomes. The causal loop diagram highlights multilevel and interrelated factors and elucidates the specific roles of design and architecture in encouraging healthy eating within schools. Our review highlighted the gaps in current evidence and identified areas of research needed to refine and expand school architecture and design strategies for addressing healthy eating. PMID- 25713967 TI - Investing in justice: ethics, evidence, and the eradication investment cases for lymphatic filariasis and onchocerciasis. AB - It has been suggested that initiatives to eradicate specific communicable diseases need to be informed by eradication investment cases to assess the feasibility, costs, and consequences of eradication compared with elimination or control. A methodological challenge of eradication investment cases is how to account for the ethical importance of the benefits, burdens, and distributions thereof that are salient in people's experiences of the diseases and related interventions but are not assessed in traditional approaches to health and economic evaluation. We have offered a method of ethical analysis grounded in theories of social justice. We have described the method and its philosophical rationale and illustrated its use in application to eradication investment cases for lymphatic filariasis and onchocerciasis, 2 neglected tropical diseases that are candidates for eradication. PMID- 25713968 TI - A hierarchy of unhealthy food promotion effects: identifying methodological approaches and knowledge gaps. AB - We assessed the evidence for a conceptual "hierarchy of effects" of marketing, to guide understanding of the relationship between children's exposure to unhealthy food marketing and poor diets and overweight, and drive the research agenda. We reviewed studies assessing the impact of food promotions on children from MEDLINE, Web of Science, ABI Inform, World Health Organization library database, and The Gray Literature Report. We included articles published in English from 2009 to 2013, with earlier articles from a 2009 systematic review. We grouped articles by outcome of exposure and assessed outcomes within a framework depicting a hierarchy of effects of marketing exposures. Evidence supports a logical sequence of effects linking food promotions to individual-level weight outcomes. Future studies should demonstrate the sustained effects of marketing exposure, and exploit variations in exposures to assess differences in outcomes longitudinally. PMID- 25713969 TI - Disentangling the relative influence of schools and neighborhoods on adolescents' risk for depressive symptoms. AB - OBJECTIVES: Although schools and neighborhoods influence health, little is known about their relative importance, or the influence of one context after the influence of the other has been taken into account. We simultaneously examined the influence of each setting on depression among adolescents. METHODS: Analyzing data from wave 1 (1994-1995) of the National Longitudinal Study of Adolescent Health, we used cross-classified multilevel modeling to examine between-level variation and individual-, school-, and neighborhood-level predictors of adolescent depressive symptoms. Also, we compared the results of our cross classified multilevel models (CCMMs) with those of a multilevel model wherein either school or neighborhood was excluded. RESULTS: In CCMMs, the school-level random effect was significant and more than 3 times the neighborhood-level random effect, even after individual-level characteristics had been taken into account. Individual-level indicators (e.g., race/ethnicity, socioeconomic status) were associated with depressive symptoms, but there was no association with either school- or neighborhood-level fixed effects. The between-level variance in depressive symptoms was driven largely by schools as opposed to neighborhoods. CONCLUSIONS: Schools appear to be more salient than neighborhoods in explaining variation in depressive symptoms. Future work incorporating cross-classified multilevel modeling is needed to understand the relative effects of schools and neighborhoods. PMID- 25713971 TI - Reducing sugary drink consumption: New York City's approach. AB - Studies have linked the consumption of sugary drinks to weight gain, obesity, and type 2 diabetes. Since 2006, New York City has taken several actions to reduce consumption. Nutrition standards limited sugary drinks served by city agencies. Mass media campaigns educated New Yorkers on the added sugars in sugary drinks and their health impact. Policy proposals included an excise tax, a restriction on use of Supplemental Nutrition Assistance Program benefits, and a cap on sugary drink portion sizes in food service establishments. These initiatives were accompanied by a 35% decrease in the number of New York City adults consuming one or more sugary drinks a day and a 27% decrease in public high school students doing so from 2007 to 2013. PMID- 25713972 TI - The potential and reality of physical education in controlling overweight and obesity. AB - Although preventing youth overweight and obesity is a public health priority, quality physical education (PE) is marginalized in practice. In May 2014, we estimated energy expenditure (EE; derived from PE frequency, duration, and intensity; mean student mass; and class size) from national recommendations and data from the 19 US states with PE duration guidelines, under 3 scenarios: potential (quality PE, defined as 50% moderate-to-vigorous physical activity [MVPA]), reality (MVPA = 35%), and classroom instruction only. Students in schools following nationally recommended PE standards from grades 1 through 10 could expend from 35 000 to 90 000 more kilocalories than students who received classroom instruction instead. PE's potential for increasing student EE will only be realized with stronger school policies and increased accountability. PMID- 25713970 TI - A systematic review of randomized controlled trials of interventions to improve the health of persons during imprisonment and in the year after release. AB - We systematically reviewed randomized controlled trials of interventions to improve the health of people during imprisonment or in the year after release. We searched 14 biomedical and social science databases in 2014, and identified 95 studies. Most studies involved only men or a majority of men (70/83 studies in which gender was specified); only 16 studies focused on adolescents. Most studies were conducted in the United States (n = 57). The risk of bias for outcomes in almost all studies was unclear or high (n = 91). In 59 studies, interventions led to improved mental health, substance use, infectious diseases, or health service utilization outcomes; in 42 of these studies, outcomes were measured in the community after release. Improving the health of people who experience imprisonment requires knowledge generation and knowledge translation, including implementation of effective interventions. PMID- 25713973 TI - Previous violent events and mental health outcomes in Guatemala. AB - OBJECTIVES: We analyzed a probability sample of Guatemalans to determine if a relationship exists between previous violent events and development of mental health outcomes in various sociodemographic groups, as well as during and after the Guatemalan Civil War. METHODS: We used regression modeling, an interaction test, and complex survey design adjustments to estimate prevalences and test potential relationships between previous violent events and mental health. RESULTS: Many (20.6%) participants experienced at least 1 previous serious violent event. Witnessing someone severely injured or killed was the most common event. Depression was experienced by 4.2% of participants, with 6.5% experiencing anxiety, 6.4% an alcohol-related disorder, and 1.9% posttraumatic stress disorder (PTSD). Persons who experienced violence during the war had 4.3 times the adjusted odds of alcohol-related disorders (P < .05) and 4.0 times the adjusted odds of PTSD (P < .05) compared with the postwar period. Women, indigenous Maya, and urban dwellers had greater odds of experiencing postviolence mental health outcomes. CONCLUSIONS: Violence that began during the civil war and continues today has had a significant effect on the mental health of Guatemalans. However, mental health outcomes resulting from violent events decreased in the postwar period, suggesting a nation in recovery. PMID- 25713974 TI - Population-wide folic acid fortification and preterm birth: testing the folate depletion hypothesis. AB - OBJECTIVES: We assess whether population-wide folic acid fortification policies were followed by a reduction of preterm and early-term birth rates in Quebec among women with short and optimal interpregnancy intervals. METHODS: We extracted birth certificate data for 1.3 million births between 1981 and 2010 to compute age-adjusted preterm and early-term birth rates stratified by short and optimal interpregnancy intervals. We used Joinpoint regression to detect changes in the preterm and early term birth rates and assess whether these changes coincide with the implementation of population-wide folic acid fortification. RESULTS: A change in the preterm birth rate occurred in 2000 among women with short (95% confidence interval [CI] = 1994, 2005) and optimal (95% CI = 1995, 2008) interpregnancy intervals. Changes in early term birth rates did not coincide with the implementation of folic acid fortification. CONCLUSIONS: Our results do not indicate a link between folic acid fortification and early term birth but suggest an improvement in preterm birth rates after implementation of a nationwide folic acid fortification program. PMID- 25713975 TI - The potential for glycemic control monitoring and screening for diabetes at dental visits using oral blood. AB - OBJECTIVES: We examined the potential for glycemic control monitoring and screening for diabetes in a dental setting among adults (n = 408) with or at risk for diabetes. METHODS: In 2013 and 2014, we performed hemoglobin A1c (HbA1c) tests on dried blood samples of gingival crevicular blood and compared these with paired "gold-standard" HbA1c tests with dried finger-stick blood samples in New York City dental clinic patients. We examined differences in sociodemographics and diabetes-related risk and health care characteristics for 3 groups of at-risk patients. RESULTS: About half of the study sample had elevated HbA1c values in the combined prediabetes and diabetes ranges, with approximately one fourth of those in the diabetes range. With a correlation of 0.991 between gingival crevicular and finger-stick blood HbA1c, measures of concurrence between the tests were extremely high for both elevated HbA1c and diabetes-range HbA1c levels. Persons already diagnosed with diabetes and undiagnosed persons aged 45 years or older could especially benefit from HbA1c testing at dental visits. CONCLUSIONS: Gingival crevicular blood collected at the dental visit can be used to screen for diabetes and monitor glycemic control for many at-risk patients. PMID- 25713976 TI - Use of life course work-family profiles to predict mortality risk among US women. AB - OBJECTIVES: We examined relationships between US women's exposure to midlife work family demands and subsequent mortality risk. METHODS: We used data from women born 1935 to 1956 in the Health and Retirement Study to calculate employment, marital, and parenthood statuses for each age between 16 and 50 years. We used sequence analysis to identify 7 prototypical work-family trajectories. We calculated age-standardized mortality rates and hazard ratios (HRs) for mortality associated with work-family sequences, with adjustment for covariates and potentially explanatory later-life factors. RESULTS: Married women staying home with children briefly before reentering the workforce had the lowest mortality rates. In comparison, after adjustment for age, race/ethnicity, and education, HRs for mortality were 2.14 (95% confidence interval [CI] = 1.58, 2.90) among single nonworking mothers, 1.48 (95% CI = 1.06, 1.98) among single working mothers, and 1.36 (95% CI = 1.02, 1.80) among married nonworking mothers. Adjustment for later-life behavioral and economic factors partially attenuated risks. CONCLUSIONS: Sequence analysis is a promising exposure assessment tool for life course research. This method permitted identification of certain lifetime work-family profiles associated with mortality risk before age 75 years. PMID- 25713977 TI - Hot spot dynamics in carbon nanotube array devices. AB - We report on the dynamics of spatial temperature distributions in aligned semiconducting carbon nanotube array devices with submicrometer channel lengths. By using high-resolution optical microscopy in combination with electrical transport measurements, we observe under steady state bias conditions the emergence of time-variable, local temperature maxima with dimensions below 300 nm, and temperatures above 400 K. On the basis of time domain cross-correlation analysis, we investigate how the intensity fluctuations of the thermal radiation patterns are correlated with the overall device current. The analysis reveals the interdependence of electrical current fluctuations and time-variable hot spot formation that limits the overall device performance and, ultimately, may cause device degradation. The findings have implications for the future development of carbon nanotube-based technologies. PMID- 25713978 TI - Functional Exchangeability of Oxidase and Dehydrogenase Reactions in the Biosynthesis of Hydroxyphenylglycine, a Nonribosomal Peptide Building Block. AB - A key problem in the engineering of pathways for the production of pharmaceutical compounds is the limited diversity of biosynthetic enzymes, which restricts the attainability of suitable traits such as less harmful byproducts, enhanced expression features, or different cofactor requirements. A promising synthetic biology approach is to redesign the biosynthetic pathway by replacing the native enzymes by heterologous proteins from unrelated pathways. In this study, we applied this method to effectively re-engineer the biosynthesis of hydroxyphenylglycine (HPG), a building block for the calcium-dependent antibiotic of Streptomyces coelicolor, a nonribosomal peptide. A key step in HPG biosynthesis is the conversion of 4-hydroxymandelate to 4 hydroxyphenylglyoxylate, catalyzed by hydroxymandelate oxidase (HmO), with concomitant generation of H2O2. The same reaction can also be catalyzed by O2 independent mandelate dehydrogenase (MdlB), which is a catabolic enzyme involved in bacterial mandelate utilization. In this work, we engineered alternative HPG biosynthetic pathways by replacing the native HmO in S. coelicolor by both heterologous oxidases and MdlB dehydrogenases from various sources and confirmed the restoration of calcium-dependent antibiotic biosynthesis by biological and UHPLC-MS analysis. The alternative enzymes were isolated and kinetically characterized, confirming their divergent substrate specificities and catalytic mechanisms. These results demonstrate that heterologous enzymes with different physiological contexts can be used in a Streptomyces host to provide an expanded library of enzymatic reactions for a synthetic biology approach. This study thus broadens the options for the engineering of antibiotic production by using enzymes with different catalytic and structural features. PMID- 25713980 TI - Molecular characterization of black Aspergillus species from onion and their potential for ochratoxin A and fumonisin B2 production. AB - Onion bulbs can become contaminated with various molds during the storage period, the most important causal agents being black aspergilli (Aspergillus section Nigri). Taxonomic studies have revealed that this group of Aspergillus contains many species that cannot be reliably identified using standard morphological methods. Therefore, it is necessary to define the fungus causing this problem in the onion exactly, especially since some species assigned to section Nigri are well known as ochratoxin and/or fumonisin producers. Sixty fungal isolates belonging to 10 fungal genera were isolated from 40 onion samples originated from the Taif region in Saudi Arabia. Black aspergilli were detected in 37 onion samples. Using primer pairs (awaspec and Cmd6) designed based on partial calmodulin gene sequence data, 37 isolates were identified as A. welwitschiae. The ochratoxin A and fumonisin B2 contents of the onion samples were examined. No ochratoxins were detected in the collected samples, while fumonisin B2 was detected in 37.5% of the onion samples. Eighteen of 37 isolates of Aspergillus welwitschiae were recognized as potential producers for fumonisin B2. Multiplex polymerase chain reactions designed to detect biosynthetic genes of fumonisins confirmed these results. PMID- 25713979 TI - Dynamics of Increasing IFN-gamma Exposure on Murine MH-S Cell-Line Alveolar Macrophage Phagocytosis of Streptococcus pneumoniae. AB - Previous investigations have demonstrated that activation with the type II interferon, IFN-gamma, downregulates alveolar macrophage (AM) phagocytosis of Streptococcus pneumoniae. While these studies have shown clear effects at discrete time points, the kinetics of the macrophage response to IFN-gamma over time, with respect to pneumococcal phagocytosis, have not been shown. Here, we describe these kinetics in the murine MH-S AM cell-line, a well-established model useful for investigations of AM phenotype and function. We measure binding and internalizing rates of S. pneumoniae following exposure to increasing durations of physiologic levels of IFN-gamma. When MH-S murine alveolar macrophage (mAM) were exposed to IFN-gamma for increasing durations of time, from 0 to 6 days before inoculation with the type II S. pneumoniae, D39, exposure for 6 h transiently reduced bacterial binding by 50%, which was temporarily restored at 2 and 3 days of exposure. Bacterial internalization was also reduced shortly following initial exposure, however, internalization continued to fall to less than 5% that of IFN-gamma naive controls after 6 days of exposure. These data may help explain otherwise contradictory reports from the literature regarding timing between infections and reductions in macrophage function. PMID- 25713981 TI - A case of pachyonychia congenita with unusual manifestations: an unusual type or a new syndrome? AB - A 30-year-old man presented with lesions on his oral mucosa and soles. There were no similar complaints in his family members. The dermatological examination revealed follicular hyperkeratosis on his trunk and upper extremities and flesh colored, firm cystic lesions on his axillae. He had focal, painful, hyperkeratotic areas sited particularly on both his soles and palms. In addition to these, leukokeratosis and ulcerative areas on buccal, labial mucosa, tongue, and at corners of the mouth, and complete loss of teeth was observed. The proximal layering was revealed on all of his nails. The laboratory investigations produced normal results except the deficiency of immunoglobulin A. The psychiatric examination revealed mild mental retardation. Keratin gene (KRT6a, KRT6b, KRT16, and KRT17) mutations for pachyonychia congenita were negative. He got removable dental prosthesis because of inadequate alimentation. Squamous cell cancer developed on lower lip mucosa during follow-up. We present an individual who had different nail dystrophy, epidermal cysts, mental retardation, blepharitis, complete loss of teeth, and negative keratin gene mutations for pachyonychia congenita and developed squamous cell cancer on the oral leukokeratosis lesions. We think that the present case may be an unusual new type of pachyonychia congenita. PMID- 25713982 TI - The ibuprofen-famotidine combined pill - a promise fulfilled. PMID- 25713984 TI - Designing vaccines to prevent breast cancer recurrence or invasive disease. PMID- 25713985 TI - Progress in biosimilar monoclonal antibody development: the infliximab biosimilar CT-P13 in the treatment of rheumatic diseases. AB - Biosimilars are biologic medical products whose active drug substance is made by a living organism or derived from it. The term is used to describe a subsequent version of an innovator biopharmaceutical product aiming at approval following patent expiry on the reference product. Biosimilars of monoclonal need to demonstrate similar but not identical quality of nonclinical and clinical attributes. Not all data of the originator product need to be recapitulated, as large numbers of patient-years of exposure data are already available. Thus, biosimilar development is largely based on the safety profiles of the originator product. The evaluation of biosimilarity includes immunogenicity attributed risks. CT-P13 (RemsimaTM/InflectraTM, Celltrion/Hospira), a biosimilar of the innovator drug infliximab (INF), was the first approved complex biosimilar monoclonal antibody in the EU, within the framework of WHO, EMA and US FDA biosimilar guidelines. CT-P13 has shown analytical and nonclinical features highly similar to INF including pharmacokinetics, efficacy, safety and immunogenicity profiles in ankylosing spondylitis and rheumatoid arthritis. The objective of this article is to highlight the recent biosimilar development and to review the results from the studies PLANETRA and PLANETAS, which have supported the approval of CT-P13 for several indications. PMID- 25713983 TI - The human CD5L/AIM-CD36 axis: A novel autophagy inducer in macrophages that modulates inflammatory responses. AB - CD5L (CD5 molecule-like) is a secreted glycoprotein that participates in host response to bacterial infection. CD5L influences the monocyte inflammatory response to the bacterial surface molecules lipopolysaccharide (LPS) and lipoteichoic acid (LTA) by inhibiting TNF secretion. Here we studied the intracellular events that lead to macrophage TNF inhibition by human CD5L. To accomplish this goal, we performed functional analyses with human monocytic THP1 macrophages, as well as with peripheral blood monocytes. Inhibition of phosphatidylinositol 3-kinase (PtdIns3K) reversed the inhibitory effect of CD5L on TNF secretion. Among the various PtdIns3K isoforms, our results indicated that CD5L activates PtdIns3K (whose catalytic subunit is termed PIK3C3), a key modulator involved in autophagy. Further analysis revealed a concomitant enhancement of autophagy markers such as cellular LC3-II content, increased LC3 puncta, as well as LC3-LysoTracker Red colocalization. Moreover, electron microscopy showed an increased presence of cytosolic autophagosomes in THP1 macrophages overexpressing CD5L. Besides preventing TNF secretion, CD5L also inhibited IL1B and enhanced IL10 secretion. This macrophage anti-inflammatory pattern of CD5L was reverted upon silencing of autophagy protein ATG7 by siRNA transfection. Additional siRNA experiments in THP1 macrophages indicated that the induction of autophagy mechanisms by CD5L was achieved through cell-surface scavenger receptor CD36, a multiligand receptor expressed in a wide variety of cell types. Our data represent the first evidence that CD36 is involved in autophagy and point to a significant contribution of the CD5L-CD36 axis to the induction of macrophage autophagy. PMID- 25713986 TI - Rapamycin-conditioned dendritic cells activated with monophosphoryl lipid-A promote allograft acceptance in vivo. AB - AIM: To date, there is no human dendritic cell (DC) based therapy to prevent allograft rejection in transplanted patients. Here, we evaluate a potential protocol using a murine in vivo transplant model. MATERIALS & METHODS: We generated murine bone marrow-derived DCs (BM-DCs), modulated with rapamycin (Rapa) and activated with monophosphoryl lipid A (Rapamycin-treated and monophosphoryl lipid A-matured DCs [Rapa-mDCs]). DCs phenotype was evaluated by flow cytometry, cytokine production by ELISA and their T-cell stimulatory ability was tested in co-cultures with CD4(+) T cells. Using an in vivo skin graft model, we evaluated DCs tolerogenicity. RESULTS: In vitro, Rapa-mDCs exhibit a semi mature phenotype given by intermediate levels of co-stimulatory molecules and cytokines, and inhibit CD4(+) T-cell proliferation. In vivo, skin-grafted mice treated with Rapa-mDCs show high allograft survival, accumulation of Foxp3(+) Tregs and cytokine pattern modification. CONCLUSION: Rapa-mDCs re-educate the inflammatory microenvironment, promoting skin-allograft survival. PMID- 25713987 TI - Effect of CD40 silenced dendritic cells by RNA interference on mice skin allograft rejection. AB - AIM: Tolerogenic dendritic cells (DCs) play a critical role in inducing and maintaining tolerance. CD40 is a member of tumor necrosis factor receptor super family and is a potent T-cell costimulatory molecule. Therefore, in this study we evaluated the effect of CD40 silenced DCs by RNA interference on mice skin allograft rejection. MATERIALS & METHODS: Skin transplantation was performed from C57BL/6 to BALB/c mouse. Skin allograft recipients were assigned to four groups (n = 5). CD40 downregulated DCs were injected to the BALB/c mice intravenously 7 days before transplantation. Then, graft survival time, Treg generation, CD4(+) and CD8(+) T cells infiltration and cytokine levels in serum of this group were compared with those of untreated and cyclosporine groups. RESULTS: In comparison with untreated group, BALB/c mice injected with CD40 siRNA transfected DCs showed an increased graft survival time, Treg cells, IL-4 and IL-10 cytokine levels as well as decreased number of intragraft CD4(+) and CD8(+) T cells. IFN-gamma and IL-12 secretion were diminished, too. CONCLUSION: Taken together, these data demonstrate that downregulation of CD40 in DCs can expand Treg cells and increase skin allograft survival. PMID- 25713988 TI - Efficacy and safety of emerging immunotherapies in psoriasis. AB - Psoriasis is a common chronic inflammatory disease of the skin. Current biologic therapies are highly effective in the treatment of psoriasis, transforming the lives of patients with this significantly disabling disease. Advances in the understanding of the immunological pathogenesis of psoriasis have led to the development of new biologic therapies, targeting specific inflammatory cytokines upregulated in psoriasis. These include the IL-17 antagonists, secukinumab, brodalumab and ixekizumab; the IL-23 antagonists, guselkumab and tildrakizumab; and the oral small molecule therapies, tofacitinib and apremilast. Here, we review evidence for the efficacy and safety of these novel psoriasis therapies, providing clinicians with an overview of the next era in immunotherapy for psoriasis. PMID- 25713990 TI - Immunotherapy for food allergies: a myth or a reality? AB - Food allergy is a worldwide issue, with an estimated prevalence of 2-10%. An effective treatment is not available for people affected and the only management is the avoidance of the allergen. Oral immunotherapy and sublingual immunotherapy have been tested by several authors, in particular for milk, egg and peanuts allergy, with significant results in term of desensitization induction. The achievement of tolerance is by the contrary doubtful, with different results obtained. In this review, we reviewed protocols of oral and sublingual immunotherapy for food allergy published in literature, mainly against milk, egg and peanut. At present, immunotherapy does not represent the gold standard in the treatment of food allergy, even if it can desensitize patients. PMID- 25713989 TI - Cytomegalovirus-specific T-cell therapies: current status and future prospects. AB - Adoptive transfer of T cells specific for viral pathogens offers an attractive method for hastening immune reconstitution and protective immunity in patients following stem cell transplantation. The largest experience to date has been in the context of treatment or prevention of cytomegalovirus or Epstein-Barr virus. A number of technical hurdles have now been overcome allowing consideration of more widespread application of products compliant with Good Manufacturing Practice regulations, and of the development of commercialization pathways for these products. This review summarizes progress to date and highlights some of the areas that remain problematic and that require further innovation and evaluation before more widespread adoption is considered. PMID- 25713991 TI - Impact of disease heterogeneity on treatment efficacy of immunotherapy in Type 1 diabetes: different shades of gray. AB - Type 1 diabetes results from selective destruction of insulin-producing pancreatic beta-cells by a progressive autoimmune process. Type 1 diabetes proves very heterogeneous in pathology, disease progression and efficacy of therapeutic intervention. Indeed, several immunotherapies that appear ineffective for the entire treated patient population in fact look promising in subgroups of patients. It therefore seems inconceivable that one standard therapy will provide the golden bullet of disease intervention. Instead, personalized medicine may improve immune intervention efficacy rates. We discuss the effect of disease heterogeneity on treatment outcome of immunotherapies, identifying apparent gaps in our understanding of treatment efficacy in subgroups of Type 1 diabetic patients as well as identifying future opportunities for immunotherapy. PMID- 25713992 TI - Progress with anti-tumor necrosis factor therapeutics for the treatment of inflammatory bowel disease. AB - Anti-tumor necrosis factor (TNF) therapy is a valid, effective and increasingly used option in inflammatory bowel disease management. Nevertheless, further knowledge and therapeutic indications regarding these drugs are still evolving. Anti-TNF therapy may be essential to achieve recently proposed end points, namely mucosal healing, prevention of bowel damage and prevention of patient's disability. Anti-TNF drugs are also suggested to be more effective in early disease, particularly in early Crohn's disease. Moreover, its efficacy for prevention of postoperative recurrence in Crohn's disease is still debated. Costs and adverse effects, the relevance of drug monitoring and the possibility of anti TNF therapy withdrawal in selected patients are still debated issues. This review aimed to describe and discuss the most relevant data about the progress with anti TNF therapy for the management of inflammatory bowel disease. PMID- 25713994 TI - Linking BRCA1 to NAD World. PMID- 25713993 TI - The Yin and Yang aspects of IL-27 in induction of cancer-specific T-cell responses and immunotherapy. AB - Accumulating evidences from animal studies have indicated that both endogenous and exogenous IL-27, an IL-12 family of cytokine, can increase antitumor T-cell activities and inhibit tumor growth. IL-27 can modulate Treg responses, and program effector T cells into a unique T-effector stem cell (TSEC) phenotype, which enhances T-cell survival in the tumor microenvironment. However, animal studies also suggest that IL-27 induces molecular pathways such as IL-10, PD-L1 and CD39, which may downregulate tumor-specific T-cell responses. In this review paper, we will discuss the Yin and Yang aspects of IL-27 in the induction of tumor-specific T-cell responses, and the potential impacts of these functions of IL-27 in the design of cancer immunotherapy. PMID- 25713995 TI - Activation of transient receptor potential vanilloid-1 (TRPV1) influences how retinal ganglion cell neurons respond to pressure-related stress. AB - Our recent studies implicate the transient receptor potential vanilloid-1 (TRPV1) channel as a mediator of retinal ganglion cell (RGC) function and survival. With elevated pressure in the eye, TRPV1 increases in RGCs, supporting enhanced excitability, while Trpv1 -/- accelerates RGC degeneration in mice. Here we find TRPV1 localized in monkey and human RGCs, similar to rodents. Expression increases in RGCs exposed to acute changes in pressure. In retinal explants, contrary to our animal studies, both Trpv1 -/- and pharmacological antagonism of the channel prevented pressure-induced RGC apoptosis, as did chelation of extracellular Ca(2+). Finally, while TRPV1 and TRPV4 co-localize in some RGC bodies and form a protein complex in the retina, expression of their mRNA is inversely related with increasing ocular pressure. We propose that TRPV1 activation by pressure-related insult in the eye initiates changes in expression that contribute to a Ca(2+)-dependent adaptive response to maintain excitatory signaling in RGCs. PMID- 25713997 TI - In situ Raman spectroscopic measurement of near-surface proton concentration changes during electrochemical reactions. AB - We report a simple in situ Raman spectroscopic measurement of near-surface proton concentration changes at commercial Pt black nanoparticle surfaces using the well known methanol oxidation, oxygen reduction, Pt oxidation and reduction reactions as the representative illustrating examples. PMID- 25713996 TI - Comparative effectiveness of continuous subcutaneous insulin infusion using insulin analogs and multiple daily injections in pregnant women with diabetes mellitus: a systematic review and meta-analysis. AB - We systematically reviewed the effectiveness and safety of continuous subcutaneous insulin infusion (CSII) with insulin analogs compared with multiple daily injections (MDI) in pregnant women with diabetes mellitus. We searched Medline(r), Embase(r), and the Cochrane Central Register of Controlled Trials through May 2013. Studies comparing CSII with MDI in pregnant women with diabetes mellitus were included. Studies using regular insulin CSII were excluded. We conducted meta-analyses where there were two or more comparable studies based on the type of insulin used in the MDI arm. Seven cohort studies of pregnant women with type 1 diabetes reported improvement in hemoglobin A1c (HbA1c) in both groups. Meta-analysis showed no difference in maternal and fetal outcomes for CSII versus MDI. Results were similar when CSII was compared with MDI with insulin analogs or regular insulin. Studies had moderate to high risk bias with incomplete descriptions of study methodology, populations, treatments, follow up, and outcomes. We conclude that observational studies reported similar improvements in HbA1c with CSII and MDI during pregnancy, but evidence was insufficient to rule out possible important differences between CSII and MDI for maternal and fetal outcomes. This highlights the need for future studies to examine the effectiveness and safety of CSII with insulin analogs and MDI in pregnant women with diabetes mellitus. PMID- 25713998 TI - Incidental findings on computed tomography angiography in patients evaluated for pulmonary embolism. AB - RATIONALE: To investigate how often computed tomography (CT) pulmonary angiography contributes to establishing a diagnosis in patients presenting to the emergency department and how it performs compared to chest radiograph. OBJECTIVES: The objective of this study was to measure the ability to identify a diagnosis and to investigate the prevalence and significance of incidental findings in patients evaluated with computed tomography pulmonary angiography in the emergency department. METHODS: All adult patients evaluated with CT angiography over a 2-year period (January 1, 2011 to December 31, 2012) were included in the analysis. A total of 641 records were identified. Chest radiographs and CT angiography reports were reviewed to determine whether they could provide a diagnosis in patients without pulmonary embolism (PE). Studies negative for PE were stratified into three categories according to significance: type I prompted immediate action, type II required follow up, and type III had findings of limited significance. MEASUREMENTS AND MAIN RESULTS: CT angiography identified a diagnosis in 22.46% of the patient population and in 14.31% of patients without PE. In patients who had CT angiography with chest radiograph, diagnoses were provided in 14.01 and 9.86% of patients, respectively. When analysis was isolated to patients with low probability for PE, CT angiography provided a diagnosis in 20% and chest radiography in 10.23% of patients. The majority of missed cases represented infiltrates too small to be detected by radiography and were believed to represent lung infections by the interpreting radiologist. Among studies negative for PE, 15% were type I, 17.07% were type II, 48.1% were type III, and the rest were normal. CONCLUSIONS: CT angiography is superior to chest radiography at providing a diagnosis in patients investigated for PE, even when no PE is present. However, in patients at low risk for PE, the clinical benefit of the additional diagnoses is questionable. PMID- 25713999 TI - VDR gene polymorphisms impact on anemia at 2 weeks of anti-HCV therapy: a possible mechanism for early RBV-induced anemia. AB - OBJECTIVES: Vitamin D receptors (VDR) bind calcitriol and modulate several physiological systems through genomic and nongenomic pathways. Calcitriol stimulates store-operated channels Ca2+ influx by translocation of the caveolar VDR to the plasma membrane. Intracellular Ca2+ levels in erythrocytes control biophysical properties and an increase in its concentration can deregulate membrane composition, cell volume, glycolytic enzymes regulation, redox state, and cell clearance.We evaluated the role of single nucleotide polymorphisms in ITPA, CYP27B1, CYP24A1, and VDR genes in the prediction of ribavirin-induced anemia in HCV-1/2/3/4 patients at 2 and 4 weeks of treatment. PATIENTS AND METHODS: Two hundred and twenty-five patients treated with ribavirin and pegylated interferon-alpha were genotyped by real-time PCR. RESULTS: BMI at baseline more than 30 kg/m2 [P=0.013, odds ratio (OR): 10.95, 95% confidence interval (CI): 1.66-74.21], alanine aminotransferase at baseline more than 37 IU/l (P=0.020, OR: 0.26, 95% CI: 0.09-0.81), and the VDR BsmI AA profile (P=0.003, OR: 5.09, 95% CI: 1.72-15.05) were anemia-predictive factors at 2 weeks of therapy. At week 4, the ITPA rs6051702 AC/CC profile (P=0.001, OR: 0.19, 95% CI: 0.07-0.51) was the only factor that could predict this side effect. CONCLUSION: The BsmI AA genotype is a predictive factor of 2-week anemia and it could be related to a VDR-enhanced activity, and thus an increased calcium influx, resulting in the deregulation of the Ca2+-dependent signaling, which can lead to erythrocytes hemolysis. This rapid mechanism could be responsible for the development of early anemia.These results indicate for the first time the strong, significant, and independent role of VDR in the early development of ribavirin induced anemia and confirm the ITPA function in the prediction of anemia at week 4. PMID- 25714000 TI - Large-scale candidate gene study to identify genetic risk factors predictive of paliperidone treatment response in patients with schizophrenia. AB - OBJECTIVE: Clinical response to antipsychotic medications can vary markedly in patients with schizophrenia. Identifying genetic variants associated with treatment response could help optimize patient care and outcome. To this end, we carried out a large-scale candidate gene study to identify genetic risk factors predictive of paliperidone efficacy. PATIENTS AND METHODS: A central nervous system custom chip containing single nucleotide polymorphisms from 1204 candidate genes was utilized to genotype a discovery cohort of 684 schizophrenia patients from four clinical studies of paliperidone extended-release and paliperidone palmitate. Variants predictive of paliperidone efficacy were identified and further tested in four independent replication cohorts of schizophrenic patients (N=2856). RESULTS: We identified an SNP in ERBB4 that may contribute toward differential treatment response to paliperidone. The association trended in the same direction as the discovery cohort in two of the four replication cohorts, but ultimately did not survive multiple testing corrections. The association was not replicated in the other two independent cohorts. We also report several SNPs in well-known schizophrenia candidate genes that show suggestive associations with paliperidone efficacy. CONCLUSION: These preliminary findings suggest that genetic variation in the ERBB4 gene may differentially affect treatment response to paliperidone in individuals with schizophrenia. They implicate the neuregulin 1 (NRG1)-ErbB4 pathway for modulating antipsychotic response. However, these findings were not robustly reproduced in replication cohorts. PMID- 25714001 TI - HLA-allelotype associations with nevirapine-induced hypersensitivity reactions and hepatotoxicity: a systematic review of the literature and meta-analysis. AB - OBJECTIVE: Various studies have investigated associations between immunogenetic (HLA-allelotypes) factors and the risk of nevirapine-induced hypersensitivity reactions. However, results from individual studies have been inconsistent. To evaluate the association between HLA alleles and nevirapine hypersensitivity, a systematic review and meta-analysis was carried out. METHODS: A literature review of articles published up to December 2014 was performed. Where both allelotype and phenotype data from two or more studies could be combined, a Mantel-Haenszel random effects model was used to obtain a pooled odds ratio (OR) and 95% confidence intervals (CIs). RESULTS: Thirteen case-control studies investigating nevirapine hypersensitivity and HLA-allelotypes were identified. The OR (95% CI) for HLA-B*35 and cutaneous adverse drug reactions (cADRs) was 2.45 (95% CI: 1.10 5.48), with significant heterogeneity (I2=69%). The association between HLA B*58:01 and hepatotoxicity in black African patients showed an OR of 3.51 (95% CI: 1.72-7.19) with no between study heterogeneity (I2=0%). For HLA-C*04 carriage, the OR in four different ethnic populations for cADRs was 2.63 (95% CI: 1.97-3.52; I2=0%). The OR for carriage of HLA-DRB1*01 in a multiethnic cohort was 2.94 (95% CI: 1.92-4.50; I2=0%) for nevirapine hepatotoxicity. CONCLUSION: HLA C*04 carriage may be a common risk factor for cADRs to nevirapine in populations of differing ethnicity, whereas HLA-B*35 and HLA-DRB1*01 appear to be driven predominantly by an association within Thai and White populations, respectively. Heterogeneity between studies could be reduced by undertaking an individual patient data meta-analysis allowing the standardization of phenotype definitions and investigation of common haplotypes between populations. PMID- 25714003 TI - Association of VEGFA gene polymorphisms and VEGFA plasma levels with spontaneous preterm birth. AB - BACKGROUND: Angiogenic pathway regulating genes such as vascular endothelial growth factor A (VEGFA) have been implicated in preterm birth (PTB) complications. Research shows that the VEGFA/VEGF receptor system plays an important role in the regulation of circulating progesterone level. Attenuation of VEGFA signaling at mid pregnancy results in onset of labor and parturition because of a reduction in circulating progesterone levels. The aim of this study was to investigate the association of VEGFA gene polymorphisms (rs2010963, rs3025039, rs699947, and rs10434) with spontaneous PTB and VEGFA plasma levels in preterm and term women. STUDY DESIGN: Peripheral maternal blood from 495 women was used for extraction of DNA and genotyping was carried out using the SequenomMassARRAY platform. Maternal plasma was used to measure VEGFA levels. RESULTS: Results showed a significant association between rs2010963 variants and PTB at both allelic and genotypic levels. The frequencies of CG and GG genotypes were significantly higher in the preterm group (96%) than in the term group (87%) (P=0.012). The odds of the G allele occurring among the preterm group was 1.8 times higher than those in the term group (odds ratio 1.8, 95% confidence interval 1.2-2.6, P=0.003). After adjustment for Bonferroni correction, the association between rs2010963 variants and PTB remained significant (P=0.004). The rs69947 was associated with PTB at a nominal significance level (P=0.030). There was no significant association between rs3025039, rs10434, and PTB in this population. VEGFA gene polymorphisms were not associated with VEGFA plasma levels. This study indicated for the first time that the VEGFA rs2010963 polymorphisms may play a potential role in preterm complications. PMID- 25714002 TI - Evaluation of CYP2D6 enzyme activity using a 13C-dextromethorphan breath test in women receiving adjuvant tamoxifen. AB - BACKGROUND: In tamoxifen-treated patients, breast cancer recurrence differs according to CYP2D6 genotype and endoxifen steady-state concentrations (Endx Css). The 13C-dextromethorphan breath test (DM-BT), labeled with 13C at the O-CH3 moiety, measures CYP2D6 enzyme activity. We sought to examine the ability of the DM-BT to identify known CYP2D6 genotypic poor metabolizers and examine the correlation between DM-BT and Endx Css. METHODS: DM-BT and tamoxifen pharmacokinetics were obtained at baseline, 3, and 6 months following tamoxifen initiation. Potent CYP2D6 inhibitors were prohibited. The correlation between baseline DM-BT with CYP2D6 genotype and Endx Css was determined. The association between baseline DM-BT (where values <=0.9 is an indicator of poor in vivo CYP2D6 metabolism) and Endx Css (using values<=11.2 known to be associated with poorer recurrence free survival) was explored. RESULTS: A total of 91 patients were enrolled and 77 were eligible. CYP2D6 genotype was positively correlated with baseline, 3, and 6 months DM-BT (r ranging from 0.457-0. 60; P<0.001). Both CYP2D6 genotype (r=0.47, 0.56, P<0.0001), and baseline DM-BT (r=0.60, 0.54, P<0.001) were associated with 3 and 6 months Endx Css, respectively. Seven (78%) of nine patients with low (<=11.2 nmol/l) 3 month Endx Css also had low DM-BT (<=0.9) including 2/2 CYP2D6 PM/PM and 5/5 IM/PM. In contrast, one (2%) of 48 patients with a low DM-BT had Endx Css more than 11.2 nmol/l. CONCLUSION: In patients not taking potent CYP2D6 inhibitors, DM-BT was associated with CYP2D6 genotype and 3 and 6 months Endx Css but did not provide better discrimination of Endx Css compared with CYP2D6 genotype alone. Further studies are needed to identify additional factors which alter Endx Css. PMID- 25714004 TI - Asymmetric polarization and hysteresis behaviour in ferroelectric P(VDF-TrFE) (76 : 24) copolymer thin films spatially resolved via LIMM. AB - The concept of charge-polarization coupling in the ferroelectric copolymer PVDF TrFE (poly[vinylidene fluoride-co-trifluoroethylene]) has been revisited by employing high resolution (<50 nm) pyroelectric depth profiling (LIMM). By virtue of probing the pyroelectric activity over the film thickness in the presence of a variable, external electrical field, the local ferroelectric response and spatially resolved hysteresis could be obtained. A large asymmetry was found between the positive and negative electrode-polymer interface. Differences in amplitude of polarization, contribution of interface charges and length scale of the polarization-free zone near the electrodes suggest a higher availability of compensation charges at the negative electrode that finally stabilize the local polarization. The resulting asymmetries in the polarization distribution are hence attributed to excess charges as a result of electron injection as a specific charge generation mechanism at the negative electrode. PMID- 25714005 TI - Nuclear architecture and gene silencing in olfactory sensory neurons. AB - Odorants are discriminated by hundreds of odorant receptor (OR) genes, which are dispersed throughout the mammalian genome. The OR genes are expressed in a highly specialized type of cell, the olfactory sensory neuron. Each one of these neurons expresses one of the 2 alleles from one single OR gene type. The mechanisms underlying OR gene expression are unclear. Here we describe recent work demonstrating that the olfactory sensory neuron shows a particular nuclear architecture, and that the genomic OR loci are colocalized in silencing heterochromatin compartments within the nucleus. These discoveries highlight the important role played by epigenetic modifications and nuclear genome organization in the regulation of OR gene expression. PMID- 25714006 TI - Identification of rictor as a novel substrate of Polo-like kinase 1. AB - Plk1 has been essentially described as a critical regulator of many mitotic events. However, increasing evidence supports the notion that its molecular functions are not restricted to the cell cycle. In particular, recent reports suggest the existence of a molecular and functional link between Plk1 and the mammalian target of rapamycin (mTOR) pathway, which controls cell growth and proliferation via the raptor-mTOR (TORC1) and rictor-mTOR (TORC2) protein complexes. Herein, we have identified rapamycin-insensitive companion of mTOR (Rictor), a core component of mTORC2, as a new Plk1 substrate and have shown that Plk1 phosphorylates Rictor at Ser1162 in vitro and in vivo. Surprisingly, cells expressing the unphosphorylatable mutant (S1162A) of Rictor did not show any effect on well characterized canonical PI3K-mTOR pathway. However, we found that cells expressing the unphosphorylatable form of Rictor have an elevated level of mSin1 isoform (mSin1.5). Considering that mSin1.5-containing mTORC2 was reported to associate with stress signaling, we propose that phosphorylation of Rictor at Ser1162 by Plk1 might be involved in a novel signaling pathway by regulating the mSin1.5-defined mTORC2. PMID- 25714007 TI - Expression of recombinant protein using Corynebacterium Glutamicum: progress, challenges and applications. AB - Corynebacterium glutamicum (C. glutamicum) is a highly promising alternative prokaryotic host for recombinant protein expression, as it possesses several significant advantages over Escherichia coli (E. coli), the currently leading bacterial protein expression system. During the past decades, several experimental techniques and vector components for genetic manipulation of C. glutamicum have been developed and validated, including strong promoters for tightly regulating target gene expression, various types of plasmid vectors, protein secretion systems and methods of genetically modifying the host strain genome to improve protein production potential. This review critically discusses current progress in establishing C. glutamicum as a host for recombinant protein expression, and examines, in depth, some successful case studies of actual application of this expression system. The established "expression tool box" for developing novel constructs based on C. glutamicum as a host are also evaluated. Finally, the existing issues and solutions in process development with C. glutamicum as a host are specifically addressed. PMID- 25714008 TI - Superomniphobic and easily repairable coatings on copper substrates based on simple immersion or spray processes. AB - Textures that resemble typical fern or bracken plant species (dendrite structures) were fabricated for liquid repellency by dipping copper substrates in a single-step process in solutions containing AgNO3 or by a simple spray liquid application. Superhydrophobic surfaces were produced using a solution containing AgNO3 and trimethoxypropylsilane (TMPSi), and superomniphobic surfaces were produced by a two-step procedure, immersing the copper substrate in a AgNO3 solution and, after that, in a solution containing 1H,1H,2H,2H perfluorodecyltriethoxysilane (PFDTES). The simple functionalization processes can also be used when the superomniphobic surfaces were destroyed by mechanical stress. By immersion of the wrecked surfaces in the above solutions or by the spray method and soft heating, the copper substrates could be easily repaired, regenerating the surfaces' superrepellency to liquids. The micro- and nanoroughness structures generated on copper surfaces by the deposition of silver dendrites functionalized with TMPSi presented apparent contact angles greater than 150 degrees with a contact angle hysteresis lower than 10 degrees when water was used as the test liquid. To avoid total wettability with very low surface tension liquids, such as rapeseed oil and hexadecane, a thin perfluorinated coating of poly(tetrafluoroethylene) (PTFE), produced by physical vapor deposition, was used. A more efficient perfluorinated coating was obtained when PFDTES was used. The superomniphobic surfaces produced apparent contact angles above 150 degrees with all of the tested liquids, including hexadecane, although the contact angle hysteresis with this liquid was above 10 degrees . The coupling of dendritic structures with TMPSi/PTFE or directly by PFDTES coatings was responsible for the superrepellency of the as-prepared surfaces. These simple, fast, and reliable procedures allow the large area, and cost-effective scale fabrication of superrepellent surfaces on copper substrates for various industrial applications with the advantage of easy recovery of the surface repellency after damage. PMID- 25714009 TI - Ultrafast structural pathway of charge transfer in n,n,n',n' tetramethylethylenediamine. AB - We have explored the ultrafast molecular structural dynamics associated with charge transfer in N,N,N',N'-tetramethylethylenediamine using Rydberg fingerprint spectroscopy in conjunction with self-interaction corrected density functional theory. Excitation at 239 nm prepares the molecule in the Franck-Condon region of the 3s state with the charge localized on one of the two amine groups. As seen from the time-dependent Rydberg electron binding energies, the pathway of the rapidly ensuing dynamics leads through several structurally distinct conformers with various degrees of charge localization before reaching the fully charge delocalized structure on a picosecond time scale. At several steps along the reaction path, the transient structures are identified through a comparison of the spectroscopically observed binding energies with computed values. The molecular structure is seen to evolve dynamically from an initially folded conformer to the stretched form that supports charge delocalization before an equilibrium sets in with forward and backward time constants of 1.19 (0.14) and 2.61 (0.31) ps, respectively. A coherent wavepacket motion in the charge localized state with a period of 270 (17) fs and damping of 430 (260) fs is observed and tentatively assigned to the nitrogen umbrella motion. The damping time constant indicates the rate of the energy flow into other vibrations that are not activated by the optical excitation. PMID- 25714010 TI - Downregulation of microRNA-23a suppresses prostate cancer metastasis by targeting the PAK6-LIMK1 signaling pathway. AB - Here we found that levels of miR-23a were decreased in prostate cancer cell lines and tumor tissues. These low levels were associated with poor patients' prognosis. MiR-23a inhibited migration and invasion of prostate cancer in vivo and in orthotopic prostate cancer mice model. MiR-23a decreased levels of p21 activated kinase 6 (PAK6). Expression of miR-23a inhibited phosphorylation of LIM kinase 1 (LIMK1) and cofilin, in turn suppressing formation of stress fibers and actin filaments, which was required for cell motility and invasion. PAK6 bound to LIMK1 and activated it via phosphorylation at Thr-508. Also, PAK6 and LIMK1 were colocalized in the cytoplasma. Thus, miR-23a regulated cytoskeleton by affecting LIMK1 and cofilin. In summary, we have identified the miR-23a-PAK6-LIMK1 pathway of prostate cancer metastasis. Potential therapeutic approach by targeting miR-23 is suggested. PMID- 25714011 TI - Immunological data from cancer patients treated with Ad5/3-E2F-Delta24-GMCSF suggests utility for tumor immunotherapy. AB - Oncolytic viruses that selectively replicate in tumor cells can be used for treatment of cancer. Accumulating data suggests that virus induced oncolysis can enhance anti-tumor immunity and break immune tolerance. To capitalize on the immunogenic nature of oncolysis, we generated a quadruple modified oncolytic adenovirus expressing granulocyte-macrophage colony-stimulating factor (GMCSF). Ad5/3-E2F-Delta24-GMCSF (CGTG-602) was engineered to contain a tumor specific E2F1 promoter driving an E1 gene deleted at the retinoblastoma protein binding site ("Delta24"). The fiber features a knob from serotype 3 for enhanced gene delivery to tumor cells. The virus was tested preclinically in vitro and in vivo and then 13 patients with solid tumors refractory to standard therapies were treated. Treatments were well tolerated and frequent tumor- and adenovirus specific T-cell immune responses were seen. Overall, with regard to tumor marker or radiological responses, signs of antitumor efficacy were seen in 9/12 evaluable patients (75%). The radiological disease control rate with positron emission tomography was 83% while the response rate (including minor responses) was 50%. Tumor biopsies indicated accumulation of immunological cells, especially T-cells, to tumors after treatment. RNA expression analyses of tumors indicated immunological activation and metabolic changes secondary to virus replication. PMID- 25714013 TI - Poor survival is associated with the methylated degree of zinc-finger protein 545 (ZNF545) DNA promoter in gastric cancer. AB - Zinc-finger protein 545 (ZNF545) was identified as a gastric tumour suppressor and potentially independent prognostic factor. At the present study, we found that lower expression of ZNF545 was specific in gastric cancer (GC) tissues, and the inconsistently methylated levels of ZNF545 promoter were identified in the gastric cancer tissues. In the methylation-specific PCR (MSP) analysis cohort, we found that GC patients with hypermethylated ZNF545 promoter exhibited significantly shorter median OS than those with unmethylated ZNF545 promoter and those with hypomethylated ZNF545 promoter. In the other cohort, we also demonstrated that GC patients with three or more methylated CpG sites in the ZNF545 promoter were significantly associated with poor survival by using the bisulphite gene sequencing (BGS). The methylated degrees of five CpG sites (-232, -214, -176, -144 and -116) could also provide distinct survival discrimination of patients with GC. These findings indicated that the methylated CpG sites of the ZNF545 promoter could be used for the clinical prediction of the prognosis of GC. PMID- 25714012 TI - Harnessing Noxa demethylation to overcome Bortezomib resistance in mantle cell lymphoma. AB - Bortezomib (BZM) is the first proteasome inhibitor approved for relapsed Mantle Cell Lymphoma (MCL) with durable responses seen in 30%-50% of patients. Given that a large proportion of patients will not respond, BZM resistance is a significant barrier to use this agent in MCL. We hypothesized that a subset of aberrantly methylated genes may be modulating BZM response in MCL patients. Genome-wide DNA methylation analysis using a NimbleGen array platform revealed a striking promoter hypomethylation in MCL patient samples following BZM treatment. Pathway analysis of differentially methylated genes identified molecular mechanisms of cancer as a top canonical pathway enriched among hypomethylated genes in BZM treated samples. Noxa, a pro-apoptotic Bcl-2 family member essential for the cytotoxicity of BZM, was significantly hypomethylated and induced following BZM treatment. Therapeutically, we could demethylate Noxa and induce anti-lymphoma activity using BZM and the DNA methytransferase inhibitor Decitabine (DAC) and their combination in vitro and in vivo in BZM resistant MCL cells. These findings suggest a role for dynamic Noxa methylation for the therapeutic benefit of BZM. Potent and synergistic cytotoxicity between BZM and DAC in vitro and in vivo supports a strategy for using epigenetic priming to overcome BZM resistance in relapsed MCL patients. PMID- 25714014 TI - miR-106b-5p targets tumor suppressor gene SETD2 to inactive its function in clear cell renal cell carcinoma. AB - Inactivation of human SET domain containing protein 2 (SETD2) is a common event in clear cell renal cell carcinoma (ccRCC). However, the mechanism underlying loss of SETD2 function, particularly the post-transcriptional regulatory mechanism, still remains unclear. In the present study, we found that SETD2 was downregulated and inversely correlated with high expression of miR-106b-5p in ccRCC tissues and cell lines. Over-expression of miR-106b-5p resulted in the decreased mRNA and protein levels of SETD2 in ccRCC cells. In an SETD2 3'-UTR luciferase reporter system, miR-106b-5p downregulated the luciferase activity, and the effects were abolished by mutating the predicted miR-106b-5p binding site. Moreover, attenuation of miR-106b-5p induced cell cycle arrest at G0/G1 phase, suppressed cell proliferation, enhanced processing of caspase-3, and promoted cell apoptosis in ccRCC cells, whereas these effects were reversed upon knockdown of SETD2. In addition, transfection of miR-106b-5p antagomir resulted in the increased binding of H3K36me3 to the promoter of p53 and enhanced its activity, as well as upregulated the mRNA and protein levels of p53, and the effects were also abolished by cotransfection with si-SETD2. Collectively, our findings extend the knowledge about the regulation of SETD2 at the posttranscriptional level by miRNA and regulatory mechanism downstream of SETD2 in ccRCC. PMID- 25714015 TI - Increase of miR-199a-5p by protoporphyrin IX, a photocatalyzer, directly inhibits E2F3, sensitizing mesenchymal tumor cells to anti-cancer agents. AB - Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths. Protoporphyrin IX (PPIX) has been used for photodynamic therapy. Mesenchymal cancer cells adapt to tumor microenvironments for growth and metastasis possibly in association with miRNA dysregulation. In view of the effect of PPIX on cancer related genes, and its potential to inhibit tumor growth and migration/invasion, this study investigated whether PPIX enables mesenchymal liver tumor to restore dysregulated miRNAs, and if so, whether it sensitizes the cancer cells to chemotherapy. In addition, we explored new target(s) of the miRNA(s) that contribute to the anti-cancer effects. Of the ten miRNAs predicted by the 3'-UTR of HIF-1alpha mRNA, PPIX treatment increased miR-199a-5p, leading to the inhibition of E2F3 expression which is upregulated in mesenchymal liver tumor. miR-199a-5p levels were downregulated in HCC with E2F3 overexpression. An approach modulating epithelial-mesenchymal transition provided the expected changes in miR-199a-5p and E2F3 in vivo. PPIX prevented tumor cell growth and migration/invasion, and had a synergistic anti-cancer effect when combined with chemotherapeutics. In a xenograft model, PPIX treatment decreased overall growth and average tumor volume, which paralleled E2F3 inhibition. Overall, PPIX inhibited growth advantage and migratory ability of cancer cells and sensitized mesenchymal liver tumor cells to chemotherapeutics. PMID- 25714016 TI - Circulation long non-coding RNAs act as biomarkers for predicting tumorigenesis and metastasis in hepatocellular carcinoma. AB - BACKGROUND & AIMS: Alpha Fetal Protein (AFP) was one of the traditional biomarker for diagnosis of Hepatocellular carcinoma (HCC) clinically, however, with the low specificity of AFP, the early diagnosis or the metastasis prediction of HCC is inferior. A new, minimally invasive and more specificity biomarker for the diagnosis or metastasis prediction of HCC are necessary. METHODS: In this study, we applied an lncRNA microarray to screen the potential biomarker for HCC. The multi-stage validation and risk score formula detection was used for validation. RESULTS: We discovered three lncRNA, RP11-160H22.5, XLOC_014172 and LOC149086, which were up-regulated in HCC comparing with the cancer-free controls with the merged area under curve (AUC) in training set and validation set of 0.999 and 0.896. Furthermore, XLOC_014172 and LOC149086 was confirmed highly increased in metastasis HCC patients with the merged AUC in training set and validation set of 0.900 and 0.934. Besides, most patients presented a decreased level of the three lncRNAs after operation, while the patients with secondary increased level might be associated with tumor hematogenous metastasis. CONCLUSIONS: RP11-160H22.5, XLOC_014172 and LOC149086 might be the potential biomarker for the tumorigenesis prediction and XLOC_014172 and LOC149086 for metastasis prediction in the future. PMID- 25714017 TI - Molecular landscape of pancreatic cancer: implications for current clinical trials. AB - Despite recent improvements, overall survival for advanced adenocarcinoma of the pancreas continues to be poor. In comparison to other tumor types that have enjoyed marked survival benefit by targeting aberrant cell signaling pathways, standard of care treatment for pancreatic cancer is limited to conventional cytotoxic chemotherapy. Multiple pathway aberrations have been documented in pancreatic cancer. A review of the COSMIC database reveals that most pancreatic cancers contain somatic mutations, with the five most frequent being KRAS, TP53, CDKN2A, SMAD4, and ARID1A, and multiple other abnormalities seen including, but not limited to, mutations in STK11/LKB1, FBXW7, PIK3CA, and BRAF. In the era of tumor profiling, these aberrations may provide an opportunity for new therapeutic approaches. Yet, searching clinicaltrials.gov for recent drug intervention trials for pancreatic adenocarcinoma, remarkably few (10 of 116 (8.6%)) new study protocols registered in the last three years included a molecular/biomarker stratification strategy. Enhanced efforts to target subsets of patients with pancreatic cancer in order to optimize therapy benefit are warranted. PMID- 25714018 TI - Mucin1 shifts Smad3 signaling from the tumor-suppressive pSmad3C/p21(WAF1) pathway to the oncogenic pSmad3L/c-Myc pathway by activating JNK in human hepatocellular carcinoma cells. AB - Mucin1 (MUC1) is a transmembrane glycoprotein that acts as an oncogene in human hepatic tumorigenesis. Hepatocellular carcinoma (HCC) cells often gain advantage by reducing the tumor-suppressive activity of transforming growth factor beta (TGF-beta) together with stimulation of its oncogenic activity as in MUC1 expressing HCC cells; however, molecular mechanisms remain largely unknown. Type I TGF-beta receptor (TbetaRI) and c-Jun NH2-terminal kinase (JNK) differentially phosphorylate Smad3 mediator to create 2 phosphorylated forms: COOH-terminally phosphorylated Smad3 (pSmad3C) and linker-phosphorylated Smad3 (pSmad3L). Here, we report that MUC1 overexpression in HCC cell lines suppresses TbetaRI-mediated pSmad3C signaling which involves growth inhibition by up-regulating p21(WAF1). Instead, MUC1 directly activates JNK to stimulate oncogenic pSmad3L signaling, which fosters cell proliferation by up-regulating c-Myc. Conversely, MUC1 gene silencing in MUC1 expressing HCC cells results in preserved tumor-suppressive function via pSmad3C, while eliminating pSmad3L-mediated oncogenic activity both in vitro and in vivo. In addition, high correlation between MUC1 and pSmad3L/c Myc but not pSmad3C/p21(WAF1) expression was observed in HCC tissues from patients. Collectively, these results indicate that MUC1 shifts Smad3 signaling from a tumor-suppressive pSmad3C/p21(WAF1) to an oncogenic pSmad3L/c-Myc pathway by directly activating JNK in HCC cells, suggesting that MUC1 is an important target for HCC therapy. PMID- 25714019 TI - NSCLC cells demonstrate differential mode of cell death in response to the combined treatment of radiation and a DNA-PKcs inhibitor. AB - The current standard of care for lung cancer consists of concurrent chemotherapy and radiation. Several studies have shown that the DNA-PKcs inhibitor NU7441 is a highly potent radiosensitizer, however, the mechanism of NU7441's anti proliferation effect has not been fully elucidated. In this study, the combined effect of NU7441 and ionizing radiation (IR) in a panel of non-small cell lung cancer cell lines (A549, H460 and H1299) has been investigated. We found that NU7441 significantly enhances the effect of IR in all cell lines. The notable findings in response to this combined treatment are (i) prolonged delay in IR induced DNA DSB repair, (ii) induced robust G2/M checkpoint, (iii) increased aberrant mitosis followed by mitotic catastrophe specifically in H1299, (iv) dramatically induced autophagy in A549 and (v) IR-induced senescence specifically in H460. H1299 cells show greater G2 checkpoint adaptation after combined treatment, which can be attributed to higher expression level of Plk1 compared to A549 and H460. The enhanced autophagy after NU7441 treatment in A549 is possibly due to the higher endogenous expression of pS6K compared to H1299 and H460 cells. In conclusion, choice of cell death pathway is dependent on the mutation status and other genetic factors of the cells treated. PMID- 25714020 TI - EBV-LMP1 targeted DNAzyme enhances radiosensitivity by inhibiting tumor angiogenesis via the JNKs/HIF-1 pathway in nasopharyngeal carcinoma. AB - LMP1, which is encoded by the Epstein-Barr virus, is proposed to be one of the major oncogenic factors involved in nasopharyngeal carcinoma (NPC). Previous studies demonstrated that down-regulation of LMP1 by LMP1-targeted DNAzyme (DZ1) increases the radiosensitivity of NPC. However, the mechanism by which DZ1 contributes to this radiosensitivity remains unclear. In this study, we determined whether a DZ1 blockade of LMP1 expression has an overall positive effect on the radiotherapy of NPCs by repressing HIF-1/VEGF activity and to investigate the mechanisms underlying LMP1-induced HIF-1 activation in NPC cells. The results showed that DZ1 inhibited the microtubule-forming ability of HUVECs co-cultured with NPC cells, which occurs with the down-regulation of VEGF expression and secretion. Moreover, LMP1 increases phosphorylated JNKs/c-Jun signaling, which is involved in the regulation of HIF-1/VEGF activity. After silencing LMP1 and decreasing phosphorylation of JNKs, NPC cells exhibited an enhanced radiosensitivity. Furthermore, in vivo experiments revealed a significant inhibition of tumor growth and a marked reduction of the Ktrans parameter, which reflects the condition of tumor micro-vascular permeability. Taken together, our data suggested that VEGF expression is increased by LMP1 through the JNKs/c-Jun signaling pathway and indicated that DZ1 enhances the radiosensitivity of NPC cells by inhibiting HIF-1/VEGF activity. PMID- 25714021 TI - Afatinib increases sensitivity to radiation in non-small cell lung cancer cells with acquired EGFR T790M mutation. AB - Afatinib is a second-generation of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor and has shown a significant clinical benefit in non small cell lung cancer (NSCLC) patients with EGFR-activating mutations. However, the potential therapeutic effects of afatinib combining with other modalities, including ionizing radiation (IR), are not well understood. In this study, we developed a gefitinib-resistant cell subline (PC-9-GR) with a secondary EGFR mutation (T790M) from NSCLC PC-9 cells after chronic exposures to increasing doses of gefitinib. The presence of afatinib significantly increases the cell killing effect of radiation in PC-9-GR cells harboring acquired T790M, but not in H1975 cells with de novo T790M or in H460 cells that express wild-type EGFR. In PC-9-GR cells, afatinib remarkable blocks baseline of EGFR and ERK phosphorylations, and causes delay of IR-induced AKT phosphorylation. Afatinib treatment also leads to increased apoptosis and suppressed DNA damage repair in irradiated PC-9-GR cells, and enhanced tumor growth inhibition when combined with IR in PC-9-GR xenografts. Our findings suggest a potential therapeutic impact of afatinib as a radiation sensitizer in lung cancer cells harboring acquired T790M mutation, providing a rationale for a clinical trial with combination of afatinib and radiation in NSCLCs with EGFR T790M mutation. PMID- 25714023 TI - Discrete functions of GSK3alpha and GSK3beta isoforms in prostate tumor growth and micrometastasis. AB - Isoform specific function of glycogen synthase kinase-3 (GSK3) in cancer is not well defined. We report that silencing of GSK3alpha, but not GSK3beta expression inhibited proliferation, survival and colony formation by the PC3, DU145 and LNCaP prostate cancer cells, and the growth of PC3 tumor xenografts in athymic nude mice. Silencing of GSK3alpha, but not GSK3beta resulted in reduced proliferation and enhanced apoptosis in tumor xenografts. ShRNA-mediated knockdown of GSK3alpha and GSK3beta equally inhibited the ability of prostate cancer cells to migrate and invade the endothelial-barrier in vitro, and PC3 cell micrometastasis to lungs in vivo. Mechanistically, whereas silencing GSK3alpha resulted in increased expression of pro-apoptotic markers cleaved caspase-3 and cleaved caspase-9 in LNCaP, PC3 and DU145 cells, silencing GSK3beta resulted in the inhibition of cell scattering, establishment of cell-cell contacts, increased expression and membrane localization of beta-catenin, and reduced expression of epithelial to mesenchymal transition (EMT) markers such as Snail and MMP-9. This indicated the specific role of GSK3beta in EMT, acquisition of motility and invasive potential. Overall, our data demonstrated the isoform specific role of GSK3alpha and GSK3beta in prostate cancer cells in vitro, and tumor growth and micrometastasis in vivo, via distinct molecular and cellular mechanisms. PMID- 25714022 TI - ROS generation mediates the anti-cancer effects of WZ35 via activating JNK and ER stress apoptotic pathways in gastric cancer. AB - Gastric cancer is one of the leading causes of cancer mortality in the world, and finding novel agents and strategies for the treatment of advanced gastric cancer is of urgent need. Curcumin is a well-known natural product with anti-cancer ability, but is limited by its poor chemical stability. In this study, an analog of curcumin with high chemical stability, WZ35, was designed and evaluated for its anti-cancer effects and underlying mechanisms against human gastric cancer. WZ35 showed much stronger anti-proliferative effects than curcumin, accompanied by dose-dependent induction of cell cycle arrest and apoptosis in gastric cancer cells. Mechanistically, our data showed that WZ35 induced reactive oxygen species (ROS) production, resulting in the activation of both JNK-mitochondrial and ER stress apoptotic pathways and eventually cell apoptosis in SGC-7901 cells. Blockage of ROS production totally reversed WZ35-induced JNK and ER stress activation as well as cancer cell apoptosis. In vivo, WZ35 showed a significant reduction in SGC-7901 xenograft tumor size in a dose-dependent manner. Taken together, this work provides a novel anticancer candidate for the treatment of gastric cancer, and importantly, reveals that increased ROS generation might be an effective strategy in human gastric cancer treatment. PMID- 25714024 TI - Dihydroartemisinin and its derivative induce apoptosis in acute myeloid leukemia through Noxa-mediated pathway requiring iron and endoperoxide moiety. AB - Anti-apoptotic protein Mcl-1 plays an important role in protecting cell from death in acute myeloid leukemia (AML). The apoptosis blocking activity of Mcl-1 is inhibited by BH3-only protein Noxa. We found that dihydroartemisinin (DHA) and its derivative X-11 are potent apoptosis inducers in AML cells and act through a Noxa-mediate pathway; X-11 is four-fold more active than DHA. DHA and X-11 induced apoptosis is associated with induction of Noxa; apoptosis is blocked by silencing Noxa. DHA and X-11 induce Noxa expression by upregulating the transcription factor FOXO3a in a reactive oxygen species-mediated pathway. Interfering with the integrity of the endoperoxide moiety of DHA and X-11, as well as chelating intracellular iron with deferoxamine, diminish apoptosis and Noxa induction. AML cells expressing Bcl-xL, or with overexpression of Bcl-2, have decreased sensitivity to DHA and X-11-induced apoptosis which could be overcome by addition of Bcl-2/Bcl-xL inhibitor ABT-737. DHA and X-11 represent a new group of AML cells-apoptosis inducing compounds which work through Noxa up regulation utilizing the specific endoperoxide moiety and intracellular iron. PMID- 25714025 TI - The over-expression of survivin enhances the chemotherapeutic efficacy of YM155 in human hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide. The inability of chemotherapeutic drugs to selectively target HCC tumor cells because of their predominant resistant phenotype to most conventional anticancer agents bestows a major obstacle for the clinical management of HCC. In this report, we have examined and demonstrated the remarkable heterogeneity of expression of survivin and its phosphorylated active form (p-survivin) in HCC patients' tissues and cell lines. Furthermore, the expression of survivin and p-survivin in HCC cell lines was found to be associated with response to the small-molecule survivin suppressant YM155. Therefore, in the HCC cell lines that express elevated level of survivin and p survivin, YM155 efficiently inhibited their proliferation, induced cell cycle arrest and apoptosis resulting in DNA damage through the dysregulation of cell cycle checkpoint-related regulatory genes. Importantly, YM155 yielded significantly better therapeutic effect than sorafenib when tested in an orthotopic mouse model using patient-derived HCC xenografts with elevated survivin and p-survivin expression. Our results clearly demonstrated that the level of survivin and p-survivin expression could serve as molecular predictive biomarkers to select potential YM155-responsive patients, in a move towards delivering precision medicine for HCC patients. PMID- 25714026 TI - miR-1236 down-regulates alpha-fetoprotein, thus causing PTEN accumulation, which inhibits the PI3K/Akt pathway and malignant phenotype in hepatoma cells. AB - Alpha fetoprotein (AFP) is a clinical biomarker of hepatocellular carcinoma (HCC). Here, we found that miR-1236 is down-regulated, whereas AFP is highly expressed in HCC tissues and cells. We demonstrated that miR-1236 directly targets the 3'UTR of AFP and down-regulates its expression. Also, miR-1236 inhibited and AFP stimulated proliferation, migration, invasion and vasculogenic mimicry (VM) of HCC. In agreement, AFP over-expression counteracted the inhibitory effect of miR-1236. We demonstrated that AFP promoted the ubiquitination of PTEN, thus decreasing PTEN levels, while miR-1236 inhibited the PI3K/Akt pathway. PMID- 25714027 TI - Initiation of esophageal squamous cell carcinoma (ESCC) in a murine 4 nitroquinoline-1-oxide and alcohol carcinogenesis model. AB - Esophageal squamous cell carcinomas (ESCCs) are very common, aggressive tumors, and are often associated with alcohol and tobacco abuse. Because ESCCs exhibit high recurrence rates and are diagnosed at late stages, identification of prognostic and drug targets for prevention and treatment is critical. We used the 4-nitroquinoline-1-oxide (4-NQO) murine model of oral carcinogenesis and the Meadows-Cook model of alcohol abuse to assess changes in the expression of molecular markers during the initial stages of ESCC. Combining these two models, which mimic chronic alcohol and tobacco abuse in humans, we detected increased cellular proliferation (EGFR and Ki67 expression), increased canonical Wnt signaling and downstream elements (beta-catenin, FoxM1, and S100a4 protein levels), changes in cellular adhesive properties (reduced E-cadherin in the basal layer of the esophageal epithelium), and increased levels of phosphorylated ERK1/2 and p38. Additionally, we found that treatment with ethanol alone increased the numbers of epithelial cells expressing solute carrier family 2 (facilitated glucose transporter, member 1) (SLC2A1) and carbonic anhydrase IX (CAIX), and increased the phosphorylation of p38. Thus, we identified both 4-NQO- and ethanol-specific targets in the initial stages of esophageal carcinogenesis, which should lead to the development of potential markers and therapeutic targets for human ESCC. PMID- 25714028 TI - miR-372 inhibits p62 in head and neck squamous cell carcinoma in vitro and in vivo. AB - Here we showed that exogenous miR-372 expression and knockdown of p62 (sequestosome1 or SQSTM1), both increased migration of head and neck squamous cell carcinoma (HNSCC) cells. p62 induced phase II detoxification enzyme NADPH quinone oxidoreductase 1 (NQO1), which decreased ROS levels and cell migration. Also, miR-372 decreased p62 during hypoxia, thus increasing cell migration. Levels of miR-372 and p62 inversely correlated in human HNSCC tissues. Plasma levels of miR-372 was associated with advanced tumor stage and patient mortality. Both plasma and salivary miR-372 levels were decreased after tumor resection. We conclude that miR-372 decreases p62, thus increasing ROS and motility in HNSCC cells. PMID- 25714029 TI - miR-188-5p inhibits tumour growth and metastasis in prostate cancer by repressing LAPTM4B expression. AB - Elucidation of the molecular targets and pathways regulated by the tumour suppressive miRNAs can shed light on the oncogenic and metastatic processes in prostate cancer (PCa). Using miRNA profiling analysis, we find that miR-188-5p was significantly down-regulated in metastatic PCa. Down-regulation of miR-188-5p is an independent prognostic factor for poor overall and biochemical recurrence free survival. Restoration of miR-188-5p in PCa cells (PC-3 and LNCaP) significantly suppresses proliferation, migration and invasion in vitro and inhibits tumour growth and metastasis in vivo. We also find overexpression of miR 188-5p in PC-3 cells can significantly enhance the cells' chemosensitivity to adriamycin. LAPTM4B is subsequently identified as a direct target of miR-188-5p in PCa, and is found to be significantly over-expressed in PCa. Knockdown of LAPTM4B phenotypically copies miR-188-5p-induced phenotypes, whereas ectopic expression of LAPTM4B reverses the effects of miR-188-5p. We also find that restoration of miR-188-5p can inhibit the PI3K/AKT signaling pathway via the suppression of LAPTM4B. Taken together, this is the first report unveils that miR 188-5p acts as a tumour suppressor in PCa and may therefore serve as a useful therapeutic target for the development of new anticancer therapy. PMID- 25714030 TI - Comparison of the selective targeting efficacy of Salmonella typhimurium A1-R and VNP20009 on the Lewis lung carcinoma in nude mice. AB - Salmonella typhimurium A1-R is auxotrophic for arg and leu, which attenuates growth in normal tissue but allows high tumor targeting and virulence. A1-R is effective against metastatic human prostate, breast, and pancreatic cancer as well as osteosarcoma, fibrosarcoma, and glioma in clinically-relevant mouse models. VNP20009 is also a genetically-modified strain of Salmonella typhimurium that has been tested in Phase I clinical trials, but is more attenuated than S. typhimurium A1-R and in addition of multiple amino-acid auxotrophs, is purine auxotropic with the purI mutation. In the present study, mouse Lewis lung carcinoma-bearing nude mouse models were treated with S. typhimurium A1-R or VNP20009. S. typhimurium A1-R and VNP20009 were both eliminated from the liver and spleen approximately 3-5 days after administration via the tail vein. However, A1-R showed higher tumor targeting and inhibited the Lewis lung carcinoma to a greater extent than VNP20009, with less body weight loss. The mice tolerated S. typhimurium A1-R to at a least 2-fold higher dose than VNP20009 when the bacteria were administered iv. The results of the present study suggest that S. typhimurium A1-R has greater clinical potential than VNP20009. PMID- 25714032 TI - Late-phase miRNA-controlled oncolytic adenovirus for selective killing of cancer cells. AB - Tissue-specific detargeting by miRNAs has been demonstrated to be a potent strategy to restrict adenoviral replication to cancer cells. These studies have generated adenoviruses with miRNA target sites placed in the 3'UTR of early gene products. In this work, we have studied the feasibility of providing tissue specific selectivity to replication-competent adenoviruses through the regulation of the late structural protein fiber (L5 gene). We have engineered a 3'UTR containing eight miR-148a binding sites downstream the L5 coding sequence (Ad-L5 8miR148aT). We present in vitro and in vivo evidences of Ad-L5-8miR148aT miRNA dependent regulation. In vitro data show that at 72 hours post-infection miR-148a regulation impaired fiber expression leading to a 70% reduction of viral release. The application of seven consecutive rounds of infection in miR-148a cells resulted in 10.000-fold reduction of viral genomes released. In vivo, liver production of infective viral particles was highly impaired, similarly to that triggered by an adenovirus with miRNA target sites regulating the early E1A gene. Noticeably, mice treated with Ad-L5-8miR148aT showed an attenuation of adenoviral induced hepatotoxicity but retained full lytic activity in cancer cells and exhibited robust antitumoral responses in patient-derived xenografts. Thus, miRNA control of late proteins constitutes a novel strategy to provide selectivity to adenoviruses. PMID- 25714031 TI - High neuropeptide Y release associates with Ewing sarcoma bone dissemination - in vivo model of site-specific metastases. AB - Ewing sarcoma (ES) develops in bones or soft tissues of children and adolescents. The presence of bone metastases is one of the most adverse prognostic factors, yet the mechanisms governing their formation remain unclear. As a transcriptional target of EWS-FLI1, the fusion protein driving ES transformation, neuropeptide Y (NPY) is highly expressed and released from ES tumors. Hypoxia up-regulates NPY and activates its pro-metastatic functions. To test the impact of NPY on ES metastatic pattern, ES cell lines, SK-ES1 and TC71, with high and low peptide release, respectively, were used in an orthotopic xenograft model. ES cells were injected into gastrocnemius muscles of SCID/beige mice, the primary tumors excised, and mice monitored for the presence of metastases. SK-ES1 xenografts resulted in thoracic extra-osseous metastases (67%) and dissemination to bone (50%) and brain (25%), while TC71 tumors metastasized to the lungs (70%). Bone dissemination in SK-ES1 xenografts associated with increased NPY expression in bone metastases and its accumulation in bone invasion areas. The genetic silencing of NPY in SK-ES1 cells reduced bone degradation. Our study supports the role for NPY in ES bone invasion and provides new models for identifying pathways driving ES metastases to specific niches and testing anti-metastatic therapeutics. PMID- 25714033 TI - 'They think that gays have money': gender identity and transactional sex among Black men who have sex with men in four South African townships. AB - Transactional sex has not been studied much among men who have sex with men in Africa. Consequently, little is understood about attitudes towards the practice, the circumstances that give rise to it or how transactional sex relationships are managed. We conducted in-depth interviews with 81 Black men aged 20-44 from four low-resourced townships in Tshwane, South Africa. We found that transactional sex was a widely used strategy for initiating and sustaining relationships with regular and casual partners, and was motivated by both the need for subsistence and for consumption. Alcohol-based exchanges in particular provided men in the townships with a covert and safe platform to communicate erotic, sexual and romantic attraction to other men, and bars and other drinking places were a popular venue for meeting potential sexual partners. The majority of 'feminine identifying' men had engaged in transactional sex as the providers of money and material goods compared to men who identified as either 'masculine' or as 'both masculine and feminine'. Surprisingly, however, this did not necessarily give them greater control in these relationships. Our study provides an initial foray into a complex sociosexual phenomenon and suggests that gender identity is an important construct for understanding transactional sex relationships among men in Africa. PMID- 25714034 TI - A water soluble additive to suppress respirable dust from concrete-cutting chainsaws: a case study. AB - Respirable dust is of particular concern in the construction industry because it contains crystalline silica. Respirable forms of silica are a severe health threat because they heighten the risk of numerous respirable diseases. Concrete cutting, a common work practice in the construction industry, is a major contributor to dust generation. No studies have been found that focus on the dust suppression of concrete-cutting chainsaws, presumably because, during normal operation water is supplied continuously and copiously to the dust generation points. However, there is a desire to better understand dust creation at low water flow rates. In this case study, a water-soluble surfactant additive was used in the chainsaw's water supply. Cutting was performed on a free-standing concrete wall in a covered outdoor lab with a hand-held, gas-powered, concrete cutting chainsaw. Air was sampled at the operator's lapel, and around the concrete wall to simulate nearby personnel. Two additive concentrations were tested (2.0% and 0.2%), across a range of fluid flow rates (0.38-3.8 Lpm [0.1-1.0 gpm] at 0.38 Lpm [0.1 gpm] increments). Results indicate that when a lower concentration of additive is used exposure levels increase. However, all exposure levels, once adjusted for 3 hours of continuous cutting in an 8-hour work shift, are below the Occupational Safety and Health Administration (OSHA) permissible exposure limit (PEL) of 5 mg/m(3). Estimates were made using trend lines to predict the fluid flow rates that would cause respirable dust exposure to exceed both the OSHA PEL and the American Conference of Governmental Industrial Hygienists (ACGIH(r)) threshold limit value (TLV). PMID- 25714035 TI - Effects of green and black tea consumption on brain wave activities in healthy volunteers as measured by a simplified Electroencephalogram (EEG): A feasibility study. AB - OBJECTIVES: Tea has been associated with many mental benefits, such as attention enhancement, clarity of mind, and relaxation. These psychosomatic states can be measured in terms of brain activity using an electroencephalogram (EEG). Brain activity can be assessed either during a state of passive activity or when performing attention tasks and it can provide useful information about the brain's state. This study investigated the effects of green and black consumption on brain activity as measured by a simplified EEG, during passive activity. METHODS: Eight healthy volunteers participated in the study. The EEG measurements were performed using a two channel EEG brain mapping instrument - HeadCoachTM. Fast Fourier transform algorithm and EEGLAB toolbox using the Matlab software were used for data processing and analysis. RESULTS: Alpha, theta, and beta wave activities were all found to increase after 1 hour of green and black tea consumption, albeit, with very considerable inter-individual variations. DISCUSSION: Our findings provide further evidence for the putative beneficial effects of tea. The highly significant increase in theta waves (P < 0.004) between 30 minutes and 1 hour post-consumption of green tea may be an indication of its putative role in cognitive function, specifically alertness and attention. There were considerable inter-individual variations in response to the two teas which may be due genetic polymorphisms in metabolism and/or influence of variety/blend, dose and content of the selected products whose chemistry and therefore efficacy will have been influenced by 'from field to shelf practices'. PMID- 25714037 TI - Splenic cyst. PMID- 25714036 TI - Conquering 2-aminopurine's deficiencies: highly emissive isomorphic guanosine surrogate faithfully monitors guanosine conformation and dynamics in DNA. AB - The archetypical fluorescent nucleoside analog, 2-aminopurine (2Ap), has been used in countless assays, though it suffers from very low quantum yield, especially when included in double strands, and from the fact that its residual emission frequently does not represent biologically relevant conformations. To conquer 2Ap's deficiencies, deoxythienoguanosine (d(th)G) was recently developed. Here, steady-state and time-resolved fluorescence spectroscopy was used to compare the ability of 2Ap and d(th)G, to substitute and provide relevant structural and dynamical information on a key G residue in the (-) DNA copy of the HIV-1 primer binding site, (-)PBS, both in its stem loop conformation and in the corresponding (-)/(+)PBS duplex. In contrast to 2Ap, this fluorescent nucleoside when included in (-)PBS or (-)/(+)PBS duplex fully preserves their stability and exhibits a respectable quantum yield and a simple fluorescence decay, with marginal amounts of dark species. In further contrast to 2Ap, the fluorescently detected d(th)G species reflect the predominantly populated G conformers, which allows exploring their relevant dynamics. Being able to perfectly substitute G residues, d(th)G will transform nucleic acid biophysics by allowing, for the first time, to selectively and faithfully monitor the conformations and dynamics of a given G residue in a DNA sequence. PMID- 25714038 TI - Dynamic contrast-enhanced MRI of ocular melanoma. AB - Dynamic contrast-enhanced MRI is used for the assessment of microvasculature in several tumours. We aimed to assess the contrast signal enhancement characteristics of ocular melanoma. Forty patients with ocular melanoma were prospectively investigated with ocular MRI including dynamic contrast-enhanced sequences over a 13-month period. A region-of-interest analysis of the images was carried out to calculate signal enhancement characteristics after a contrast injection. Clinical follow-up data such as extraocular spread and development of liver metastasis were compared with the signal enhancement characteristics of the ocular melanoma. In 39 patients (98%), the ocular melanomas showed an early strong signal enhancement after contrast injection, resulting in a mean time of maximum enhancement of 49 s. Clinical follow-up was available in 28 patients (70%) and indicated that the peak signal intensity was significantly increased (P=0.039) in patients who developed extraocular spread or liver metastasis at a later stage. Ocular melanoma shows signal enhancement characteristics of hypervascular neoplasms. This study provides baseline curve pattern data that may be useful for assessing changes in vascularity, for example during therapy response. Furthermore, the study showed that a strong signal enhancement of the ocular melanoma might be linked to a less favourable prognosis. PMID- 25714039 TI - Having and fighting Ebola--public health lessons from a clinician turned patient. PMID- 25714040 TI - Hospitalization for total hip replacement among inpatients aged 45 and over: United States, 2000-2010. AB - Total hip replacement, in which both the head of the femur and its socket are replaced, is done to restore movement to hips damaged by osteoarthritis, late stage degenerative bone and cartilage disease, or other injuries and disease (1). The number of total hip replacements is expected to increase over the next few decades (2). National Hospital Discharge Survey (NHDS) data show trends and estimates of the number and rate of total hip replacements and average length of stay among inpatients aged 45 and over. PMID- 25714041 TI - Progress with electronic health record adoption among emergency and outpatient departments: United States, 2006-2011. AB - The Health Information Technology for Economic and Clinical Health (HITECH) Act of 2009 provides incentive payments to eligible hospitals and providers that demonstrate the meaningful use of a certified electronic health record (EHR) system . This report describes the adoption of EHRs in hospital emergency departments (EDs) and outpatient departments (OPDs) from 2006 through 2011 using the National Hospital Ambulatory Medical Care Survey (NHAMCS). PMID- 25714042 TI - Trends in long-acting reversible contraception use among U.S. women aged 15-44. AB - Long-acting reversible contraceptives (LARCs), which include intrauterine devices (IUDs) and subdermal hormonal implants, are gaining popularity due to their high efficacy in preventing unintended pregnancies. IUD use was more common among U.S. women in the 1970s before concerns over safety led to a decline in use (1); however, since approval of a 5-year contraceptive implant in 1990 and redesigned IUDs, there has been growing interest in the use of LARCs for unintended pregnancy prevention. Using data from the 1982, 1988, 1995, 2002, 2006-2010, and 2011-2013 National Survey of Family Growth (NSFG), this report examines trends in current LARC use among women aged 15-44 and describes patterns of use by age, race and Hispanic origin, and parity. PMID- 25714043 TI - Prescription opioid analgesic use among adults: United States, 1999-2012. AB - Prescription opioid analgesics are used to treat pain from surgery, injury, and health conditions such as cancer. Opioid dependence and opioid-related deaths are growing public health problems. Opioid analgesic sales (in kilograms per 10,000) quadrupled from 1999 to 2010 (1), and from 1999 to 2012, opioid-related deaths (per 100,000) more than tripled (2). During 1999-2002, 4.2% of persons aged 18 and over used a prescription opioid analgesic in the past 30 days (3). This report provides updated estimates and trends in prescription opioid analgesic use among adults aged 20 and over, overall and by selected subgroups. PMID- 25714044 TI - The effect of a booster dose of quadrivalent or bivalent HPV vaccine when administered to girls previously vaccinated with two doses of quadrivalent HPV vaccine. AB - This randomized, blinded study evaluated the immunogenicity and safety of a booster dose of Gardasil (qHPV) or Cervarix (bHPV) when administered to 12-13 year-old girls who were vaccinated at the age of 9-10 with 2 doses of qHPV (0-6 months). 366 out of 416 eligible girls participated in this follow-up study. Antibody titers were measured just before and one month post-booster. A Luminex Total IgG assay was used for antibody assessment and results are presented in Liminex Units (LU). Three years post-primary vaccination, 99-100% of subjects had detectable antibodies to 4HPV genotypes included in the qHPV with GMTs varying from 50 to 322 LU depending on genotype. After a booster dose of qHPV, a >=4 fold increase of antibody titers to genotypes included in the vaccine was observed in 88-98% of subjects. Post-booster GMTs varied from 1666 to 4536 LU depending on genotype. These GMTs were 1.1 to 1.8-fold higher when compared to those observed one month post-second dose. After a booster of bHPV, a >=4 fold increase of antibody titers to HPV16 and HPV18 was observed in 93-99% of subjects. The anti HPV16 and HPV18 GMTs were 5458 and 2665 LU, respectively. These GMTs were 1.2 and 1.8 higher than those observed in the qHPV group (both P < 0.01). In bHPV group a 1.4-1.6-fold increase of antibody GMTs to HPV6 and HPV11was also observed (P < 0.001). The safety profile was acceptable for both vaccines. Both qHPV and bHPV increase antibody titers when given as a booster to girls previously vaccinated with 2 doses of qHPV. The magnitude of the immune response after booster is vaccine-dependent and has the same pattern as that reported after primary vaccination with qHPV or bHPV. When given as a booster, both vaccines have an acceptable safety profile. Longer follow-up studies are warranted to assess the need of booster doses. PMID- 25714045 TI - Rapid (<3 min) microwave synthesis of block copolymer templated ordered mesoporous metal oxide and carbonate films using nitrate-citric acid systems. AB - Rapid chemical transformation from micelle templated precursors (metal nitrate and citric acid) to ordered mesoporous metal carbonates and oxides is demonstrated using microwave heating for cobalt, copper, manganese and zinc. Without aging requirements, <3 min of microwave processing yields highly ordered mesoporous films. PMID- 25714046 TI - Synthesis of a cyclometalated 1,3,5-triphenylpyrazole palladium dimer and its activity towards cross coupling reactions. AB - A phosphine free 1,3,5-triphenylpyrazole acetate-bridged palladacycle was prepared from simple commercially available starting materials. The activity of the palladacycle in the Mizoroki-Heck and Suzuki-Miyaura cross-coupling reactions was evaluated. The palladacycle precatalyst shows a wide substrate scope, both in Mizoroki-Heck as well as in Suzuki-Miyaura cross-coupling reactions using low catalyst loadings viz., 0.2 mol% and 0.1 mol% respectively. PMID- 25714047 TI - Structural distortion in graphitic-C3N4 realizing an efficient photoreactivity. AB - Introducing structural distortion to semiconductors can dramatically modify their electronic structures, resulting in efficient separation of electron-hole pairs and achieving high photocatalytic activity of catalysts. Herein, we systematically studied the role that structural distortion played in the photocatalytic process by taking graphitic-C3N4 (g-C3N4) as an example, where the structural distortion can be introduced by elemental doping and heat treatment. Through the controllable structural distortion engineering, the photocatalytic activity of g-C3N4 can be significantly improved, which benefits from the effective separation of photogenerated electron-hole pairs, showing intriguing structural distortion-dependent photocatalytic activity. This study not only offers a new insight into the in-depth understanding of the effect of structural distortion on the photoreactivity of catalysts, but also provides a new pathway for designing advanced photocatalysts. PMID- 25714048 TI - Epigenetics in gastric carcinogenesis: TET genes as important players. AB - Epigenetic processes including aberrant promoter methylation of tumor suppressor gene play a key role in gastric carcinogenesis. TET proteins are involved in DNA demethylation; many cancers, haematological or solid, present loss-of-function mutations and aberrant expression/regulation of TET. In gastric cancer there are few studies reporting a decreased expression of TET and associations between these proteins and signaling pathways involved in carcinogenesis. Identifying connections between aberrant expression of TET, disruption of the balance between DNA methylation and demethylation and their association with gastric carcinogenesis might be useful for the development of novel therapeutic approaches. PMID- 25714052 TI - Trends in varicella mortality in the United States: Data from vital statistics and the national surveillance system. AB - This manuscript describes trends in US varicella mortality using national vital statistics system data for 2008-2011, the first years of the routine 2-dose varicella vaccination program, and characteristics of varicella deaths reported to CDC during 1996-2013. We obtained data on deaths with varicella as underlying or contributing cause from the 2008-2011 Mortality Multiple Cause-of Death records and calculated rates to compare with the prevaccine and mature 1-dose varicella vaccination program eras. We also reviewed available records of varicella deaths reported to CDC through the national varicella death surveillance. The annual average age-adjusted mortality rate for varicella as the underlying cause was 0.05 per million population during 2008-2011, an 87% reduction from the prevaccine years. Varicella deaths among persons aged <20 y declined by 99% in 2008-2011 compared with prevaccine years. There was a 70% decline in varicella mortality rates among those <20 y in 2008-2011 compared to 2005-2007. Among the 83 deaths reported to CDC during 1996-2013 classified as likely due to varicella, 24 (29%) were among immunocompromised individuals. Five were among persons previously vaccinated with 1 dose of varicella vaccine. In conclusion, although the US varicella vaccination program has significantly reduced varicella disease burden, there are still opportunities to prevent varicella and its associated morbidity and mortality through routine varicella vaccination, catch-up vaccination, and ensuring that household contacts of immunocompromised persons have evidence of immunity. PMID- 25714053 TI - Three-dimensional heterogeneous assembly of coded microgels using an untethered mobile microgripper. AB - Three-dimensional (3D) heterogeneous assembly of coded microgels in enclosed aquatic environments is demonstrated using a remotely actuated and controlled magnetic microgripper by a customized electromagnetic coil system. The microgripper uses different 'stick-slip' and 'rolling' locomotion in 2D and also levitation in 3D by magnetic gradient-based pulling force. This enables the microrobot to precisely manipulate each microgel by controlling its position and orientation in all x-y-z directions. Our microrobotic assembly method broke the barrier of limitation on the number of assembled microgel layers, because it enabled precise 3D levitation of the microgripper. We used the gripper to assemble microgels that had been coded with different colours and shapes onto prefabricated polymeric microposts. This eliminates the need for extra secondary cross-linking to fix the final construct. We demonstrated assembly of microgels on a single micropost up to ten layers. By increasing the number and changing the distribution of the posts, complex heterogeneous microsystems were possible to construct in 3D. PMID- 25714049 TI - Neural circular RNAs are derived from synaptic genes and regulated by development and plasticity. AB - Circular RNAs (circRNAs) have re-emerged as an interesting RNA species. Using deep RNA profiling in different mouse tissues, we observed that circRNAs were substantially enriched in brain and a disproportionate fraction of them were derived from host genes that encode synaptic proteins. Moreover, on the basis of separate profiling of the RNAs localized in neuronal cell bodies and neuropil, circRNAs were, on average, more enriched in the neuropil than their host gene mRNA isoforms. Using high-resolution in situ hybridization, we visualized circRNA punctae in the dendrites of neurons. Consistent with the idea that circRNAs might regulate synaptic function during development, many circRNAs changed their abundance abruptly at a time corresponding to synaptogenesis. In addition, following a homeostatic downscaling of neuronal activity many circRNAs exhibited substantial up- or downregulation. Together, our data indicate that brain circRNAs are positioned to respond to and regulate synaptic function. PMID- 25714055 TI - Piezoelectricity in two-dimensional materials. PMID- 25714054 TI - Scoring the quality of total mesorectal excision for the prediction of cancer specific outcome. AB - AIM: A three-grade system for macroscopic evaluation of the resection plane is used to describe the quality of total mesorectal excision (TME). In several studies, two of the three grades have been combined when analysing the outcome. The aim of our study was to compare the predictive value of the three-graded with that of a two-graded TME score. METHOD: The quality of TME in 1382 patients who underwent elective resection for mid or low rectal adenocarcinoma was registered by 65 hospitals in PROCARE, a Belgian multidisciplinary improvement project. Prediction of outcome based on the classic three-grade score was compared with a two-grade scoring system in which intramesorectal resection (IMR) was combined with mesorectal (MRR) or with muscularis propria resection (MPR). End-points included the local recurrence rate, distant metastasis rate (DMR), disease-free survival (DFS) and overall survival (OS). RESULTS: Among the 1382 resections, 63% were MRR, 27% IMR and 9% MPR. No significant differences were found in local recurrence between the different grades of TME. A two-grade score distinguishing MRR from the others was found to predict DMR, DFS and OS as well as the three grade score. CONCLUSION: The discriminatory and predictive value of a two-grade score, differentiating MRR from the combined IMR and MPR, was as good as the classic three-grade score. PMID- 25714056 TI - Colorectal cancer awareness issue. PMID- 25714057 TI - Water and carbon dioxide - turning back the clock to unsedated colonoscopy. PMID- 25714058 TI - Optical diagnosis of colorectal polyps: can this be learned by everyone? PMID- 25714059 TI - Quality programs in endoscopy: for the patient, the doctor and society. PMID- 25714064 TI - Video Comment on Kjetil Garborg et al., pages 192-199. PMID- 25714065 TI - Culinary Metaphors in Dermatology: Eating Our Words. PMID- 25714066 TI - Relation of red cell distribution width to contrast-induced acute kidney injury in patients undergoing a primary percutaneous coronary intervention. AB - BACKGROUND AND AIM: We investigated the utility of the preprocedural red cell distribution width (RDW) for predicting contrast-induced acute kidney injury (CI AKI) in patients with ST-segment-elevation myocardial infarction (STEMI) who underwent a primary percutaneous coronary intervention. MATERIALS AND METHODS: A total of 630 consecutive patients who were routinely referred to coronary angiography for STEMI were included in the present study. RESULTS: CI-AKI was observed in 79 patients (12.5%). The RDW, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and the mean platelet volume were significantly higher in the CI-AKI group than in the non-CI-AKI group (P<0.001, P=032, P=0.025, and P=0.039, respectively). Serum total bilirubin and direct bilirubin levels were not different among the study groups. Using multivariate logistic regression analysis, we found that left ventricular ejection fraction [odds ratio (OR)=0.972, 95% confidence interval (CI) 0.945-0.998, P=0.033], estimated glomerular filtration rate (OR=0.970, 95% CI 0.959-0.981, P<0.001), contrast volume (OR=1.007, 95% CI 1.002-1.012, P=0.009), and RDW (OR=1.406, 95% CI 1.120 1.792, P=0.005) were independent predictors of CI-AKI. CONCLUSION: Red blood cell distribution width, an inexpensive and easily measurable laboratory variable, is associated independently with the development of CI-AKI. Our data suggest that RDW may be a useful marker in CI-AKI risk stratification. PMID- 25714067 TI - Individualized reduction of radiation dose with a chest circumference-adapted technique and iterative reconstructions in 256-slice retrospective and prospective ECG-triggered computed tomography coronary angiography. AB - PURPOSE: To assess the impact of chest circumference (CC)-adjusted tube current and iterative reconstructions (iDose) on individualized radiation dose reduction and image quality (IQ) in ECG-triggered computed tomography coronary angiography (CTCA). MATERIALS AND METHODS: A total of 102 patients underwent retrospectively ECG-triggered CTCA utilizing CC-adapted tube current [mAs=1000*(0.051*CC 23.765)/900] and filtered back projection (FBP) reconstruction (group A). On the basis of the CC-adjusted tube current technique, 54 patients (group B) underwent retrospective ECG-triggered CTCA with a 20% mAs reduction compared with group A and 90 patients (group C) underwent prospective ECG-triggered CTCA with an 80% mAs reduction compared with group A; both groups B and C were reconstructed with FBP and iDose. Subjective IQ was assessed, and image noise, signal-to-noise, and contrast-to-noise ratios (SNR and CNR) were quantified. RESULTS: Patients in group A had the highest radiation dose, followed by group B and group C. iDose provided decreased image noise and increased SNR and CNR, as did subjective IQ. The image noise was higher and SNR and CNR in group B were obviously lower than those in group A with FBP, but in group B, iDose4 increased the mean objective IQ. There was no difference between group B with iDose and group A with FBP, as was the case with subjective IQ. CONCLUSION: The combination of a CC-adapted technique, prospective triggering, and partial iterative reconstruction techniques reduces the radiation dose significantly, without significant degradation of IQ. PMID- 25714069 TI - Multivessel spontaneous coronary artery dissection with angiographic documentation before and after the acute event. PMID- 25714068 TI - Impact of increased admission lipid levels on periprocedural myocardial injury following an elective percutaneous coronary intervention. AB - OBJECTIVE: Periprocedural myocardial injury (PMI) is known to be a predictor of in-hospital cardiac events and long-term adverse outcomes following a percutaneous coronary intervention (PCI). We aimed to evaluate the correlation between preprocedural serum lipid levels and PMI in patients undergoing elective PCI. PATIENTS AND METHODS: The final study group included 195 patients (60.1+/ 0.7 years old, 68 women and 127 men). Serum high-sensitive troponin T (hscTnT) concentrations were measured immediately before PCI and 12 h after PCI. Serum total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C), and triglyceride (TG) levels were determined immediately before PCI. Serum hscTnT concentrations were adjusted for the clinical and procedural characteristics of the patients using the weighted least square regression analysis. RESULTS: The average preprocedural hscTnT concentration was 8.1+/-0.2 ng/l. The average serum hscTnT concentration increased to 34.1+/-2.8 ng/l (P<0.001) 12 h after PCI. Postprocedural hscTnT concentrations were correlated positively to serum concentrations of TC (r=0.435; P<0.001), LDL-C (r=0.349; P<0.001), and TG (r=0.517; P<0.001). There was also a positive correlation (r=0.205; P<0.01) between postprocedural hscTnT and lesion length. Mild-moderate PMI (postprocedural hscTnT>=14 to <70 ng/l) and severe PMI (postprocedural hscTnT>=70 ng/l) were observed in 122 (48.7%) and 27 (13.9%) patients, respectively. The patients with severe PMI had higher serum TC (P<0.001), LDL-C (P<0.001), and TG (P<0.001) concentrations. CONCLUSION: The present study indicates that increased preprocedural TC, LDL-C, and TG serum levels are associated with PMI and its severity following elective PCI. PMID- 25714070 TI - Plasma nuclear and mitochondrial DNA levels in acute myocardial infarction patients. AB - OBJECTIVE: Plasma nuclear and mitochondrial DNA (mtDNA) levels are altered in many diseases. However, it is not known whether they are also altered in acute myocardial infarction (AMI). In the present study, we examined plasma nuclear and mtDNA levels in the patients with AMI before and after a percutaneous coronary intervention (PCI) to explore their potential as biomarkers. METHODS AND RESULTS: Plasma nuclear and mtDNA levels were measured by quantitative PCR in 25 AMI patients, 25 non-myocardial infarction (MI) control participants (with MI risk), and 20 healthy individuals during the study period. The concentrations of nuclear and mtDNA were significantly higher in the AMI group on hospital day 1 than that in the non-MI controls (nuclear: 0.4948+/-0.0830 vs. 0.2047+/-0.0222 ng/MUl, P<0.05; mitochondrial: 3.754+/-0.384 vs. 1.851+/-0.3483 ng/MUl, P<0.05) and healthy individuals (nuclear: 0.4948+/-0.0830 vs. 0.1683+/-0.0254 ng/MUl, P=0.001; mitochondrial: 3.754+/-0.384 vs. 0.1517+/-0.0924 ng/MUl, P<0.05) and decreased shortly after PCI. CONCLUSION: Both plasma nuclear and mtDNA levels are elevated in AMI patients, but return to normal levels immediately after PCI, suggesting that they are potentially novel biomarkers for AMI. PMID- 25714071 TI - Progression of cardiac allograft vasculopathy detected by optical coherence tomography. PMID- 25714072 TI - Clinical and pathological characteristics of homogeneous and nonhomogeneous tissue of in-stent restenosis visualized by optical coherence tomography. AB - BACKGROUND: Although it is known that in-stent restenosis (ISR) patterns appear homogeneous or nonhomogeneous by optical coherence tomography (OCT), interpretations of the ISR inflammatory response, of the OCT image, and its pathological implications are unclear. The aim of this study was to use OCT to characterize ISR and its inflammatory index in patients after coronary stenting. METHODS: OCT was performed at follow-up in 100 angiographic ISR lesions. ISR lesions were divided into two groups: (a) homogeneous (n=48) and (b) nonhomogeneous (n=52) image groups. We assessed the ISR images produced by OCT for tissue heterogeneity and neo-intimal hyperplasia using the normalized standard deviation of OCT signal-intensity (OCT-NSD) observed in neo-intimal hyperplasia tissue. In some patients with a nonhomogeneous OCT image, we collected pathological tissue. RESULTS: The prevalence of drug-eluting stents was 48% in the nonhomogeneous group and 29% in the homogeneous group (P=0.05). The OCT-NSD value in the nonhomogeneous group (0.223+/-0.019) was significantly higher than that in the homogeneous group (0.203+/-0.025; P<0.0001). Pathological tissue showed fibrin thrombi with infiltrating macrophage in 12 cases of nonhomogeneous ISR. The area under the receiver operating characteristic curve for the prediction of a nonhomogeneous image was 0.73 for OCT-NSD (95% confidence interval: 0.62-0.83: P<0.0001). The odds ratio for the prediction of a nonhomogeneous image was 3.47 (95% confidence interval: 1.18-10.2: P=0.02) for smoking by logistic regression analysis. CONCLUSION: Nonhomogeneous ISR visualized by OCT showed a high OCT-NSD value, which was a useful predictor for nonhomogeneous images. Moreover, the nonhomogeneous ISR image visualized by OCT may show chronic inflammation and fibrin thrombi. PMID- 25714074 TI - Antimicrobial, antioxidant and cytotoxicity potential of Manihot multifida (L.) Crantz (Euphorbiaceae). AB - Manihot multifida (L.) Crantz (Euphorbiaceae) is widely used in popular medicine for the treatment of infected wounds. This study evaluated the in vitro antioxidant and antimicrobial potential of this species against strains of Gram positive and Gram-negative bacteria and fungi, known to cause infections in humans. The extracts showed minimal inhibitory concentration (MIC) varying from 39 to 2500 ug/mL for antimicrobial activity. The methanolic extract of fruits, aqueous and hexane extracts of leaves showed a very strong activity against Candida albicans (ATCC 18804) with MIC of 39 ug/mL. Furthermore, the methanolic extract of M. multifida leaves exhibited DPPH (1,1-diphenyl-2-picrylhydrazyl) scavenging potential with inhibitory concentration (IC50) values of 46.9 MUg/mL, followed by hexane extract of leaves with IC50 values of 59.2 MUg/mL. The cytotoxic activity against brine shrimp was stronger for the methanolic extract of leaves (lethal concentration - LC50 of 15.6 ug/mL). These results suggest that M. multifida has interesting antimicrobial and antioxidant activities. Moreover, these results corroborate the popular use of this specie in treating fungal infections since it demonstrates significant activity against C. albicans. PMID- 25714075 TI - Altered hyaluronic acid content in tear fluid of patients with adenoviral conjunctivitis. AB - The adenoviral conjunctivitis is one of the biggest causes of conjunctival infection in the world. Conjunctivitis causes relatively nonspecific symptoms, as hyperaemia and chemosis. Even after biomicroscopy, complex laboratory tests, such as viral culture, are necessary to identify the pathogen or its etiology. To contribute to the better understanding of the pathobiology of the adenoviral conjunctivitis, the tear fluids of patients with unilateral acute adenovirus conjunctivitis (UAAC), normal donors (control) and patients with allergic conjunctivitis were analyzed. Tear samples were collected with Schirmer strips from control, allergic conjunctivitis and UAAC patients, diagnosed by clinical signs. UAAC tears were tested positive in viral cultures. After the elution, HA was quantified using an ELISA-like fluorometric assay and the protein profile was determined by SDS-PAGE. A profound increase in the HA tear content in UAAC patients was found when compared to control and ALC. This HA increase in UAAC tears remarkably was not observed in tears from contralateral eyes without clinical signs, nor in allergic conjunctivitis. In addition a distinct profile of UAAC tear proteins was observed in patients with UAAC. The quantification of HA in the tear fluid is a rapid, sensitive and specific test. This molecule might be a biomarker candidate for acute conjunctivitis. PMID- 25714076 TI - Phenotypic plasticity of Neonotonia wightii and Pueraria phaseoloides grown under different light intensities. AB - Plants have the ability to undergo morphophysiological changes based on availability of light. The present study evaluated biomass accumulation, leaf morphoanatomy and physiology of Neonotonia wightii and Pueraria phaseoloides grown in full sunlight, as well as in 30% and 50% shade. Two assays were performed, one for each species, using a randomized block design with 10 replicates. A higher accumulation of fresh mass in the shoot of the plants was observed for both species under cultivation in 50% shade, while no differences were detected between the full sunlight and 30% shade. N. wightii and P. phaseoloides showed increase in area and reduction in thickness leaf when cultivated in 50% shade. There were no changes in photosynthetic rate, stomatal conductance, water use efficiency and evapotranspiration of P. phaseoloides plants because growth environment. However, the shade treatments caused alterations in physiological parameters of N. wightii. In both species, structural changes in the mesophyll occurred depending on the availability of light; however, the amount of leaf blade tissue remained unaltered. Despite the influence of light intensity variation on the morphophysiological plasticity of N. wightii and P. phaseoloides, no effects on biomass accumulation were observed in response to light. PMID- 25714077 TI - Gestational diabetes: a risk of puerperal hypovitaminosis A? AB - The influence of gestational diabetes on vitamin A deficiency in lactating women and, consequently, in their newborn has been verified through a cross-sectional case-control study conducted with volunteer puerperal women. The control group consisted of healthy women and the test group was composed of women with gestational diabetes. One hundred and seven women were recruited, corresponding to 71 controls and 36 cases. Personal, gestational and newborn data were collected directly from medical records during hospitalization. The retinol was determined in maternal colostrum and serum by High Performance Liquid Chromatography. Postpartum women with gestational diabetes were older, had more children and a higher prevalence of cesarean delivery. No difference was found in retinol concentration in maternal milk and serum between the groups. However, it was observed that 16.7% had vitamin A deficiency in the group of patients with diabetes and only 4.1% had such deficiency in the control group. Although no difference was found in colostrum and serum retinol concentration between women with and without gestational diabetes, the individual analysis shows that those with diabetes are at higher risk of being vitamin A deficient. PMID- 25714078 TI - Behavioral alterations and Fos protein immunoreactivity in brain regions of bile duct-ligated cirrhotic rats. AB - Hepatic encephalopathy (HE) encompasses a variety of neuropsychiatric symptoms, including anxiety and psychomotor dysfunction. Although HE is a frequent complication of liver cirrhosis, the neurobiological substrates responsible for its clinical manifestations are largely unclear. In the present study, male Wistar rats were bile duct-ligated (BDL), a procedure which induces liver cirrhosis, and on the 21st day after surgery tested in the elevated plus-maze (EPM) and in an open field for anxiety and locomotor activity measurements. Analysis of Fos protein immunoreactivity (Fos-ir) was used to better understand the neurobiological alterations present in BDL animals. Plasma levels of ammonia were quantified and histopathological analysis of the livers was performed. BDL rats showed a significant decrease in the percentage of entries and time spent in the open arms of the EPM, an anxiogenic effect. These animals also presented significant decreases in Fos-ir in the lateral septal nucleus and medial amygdalar nucleus. Their ammonia plasma levels were significantly higher when compared to the sham group and the diagnosis of cirrhosis was confirmed by histopathological analysis. These results indicate that the BDL model induces anxiogenic results, possibly related to changes in the activation of anxiety mediating circuitries and to increases in ammonia plasma levels. PMID- 25714084 TI - Liquid crystalline macrocyclic azacalix[4]pyridine and its complexes with the zinc ion: conformational change from the saddle to flattened shape. AB - Substituted with four 3,4,5-tris(alkoxy)benzyl mini-dendrons, azacalix[4]pyridine (1) with the saddle-shaped core is the first liquid crystal (LC) of heteracalixaromatics. Conformational regulation of azacalix[4]pyridine by complexing with the zinc ion leads to a significant change in LC properties. PMID- 25714085 TI - Retracting globe: enophthalmos and retraction due to an accessory extraocular muscle. PMID- 25714086 TI - Biomechanical 3-dimensional finite element analysis of obturator protheses retained with zygomatic and dental implants in maxillary defects. AB - BACKGROUND: The objective of this study was to investigate the stress distribution in the bone around zygomatic and dental implants for 3 different implant-retained obturator prostheses designs in a Aramany class IV maxillary defect using 3-dimensional finite element analysis (FEA). MATERIAL AND METHODS: A 3-dimensional finite element model of an Aramany class IV defect was created. Three different implant-retained obturator prostheses were modeled: model 1 with 1 zygomatic implant and 1 dental implant, model 2 with 1 zygomatic implant and 2 dental implants, and model 3 with 2 zygomatic implants. Locator attachments were used as a superstructure. A 150-N load was applied 3 different ways. Qualitative analysis was based on the scale of maximum principal stress; values obtained through quantitative analysis are expressed in MPa. RESULTS: In all loading conditions, model 3 (when compared models 1 and 2) showed the lowest maximum principal stress value. Model 3 is the most appropirate reconstruction in Aramany class IV maxillary defects. Two zygomatic implants can reduce the stresses in model 3. The distribution of stresses on prostheses were more rational with the help of zygoma implants, which can distribute the stresses on each part of the maxilla. CONCLUSIONS: Aramany class IV obturator prosthesis placement of 2 zygomatic implants in each side of the maxilla is more advantageous than placement of dental implants. In the non-defective side, increasing the number of dental implants is not as suitable as zygomatic implants. PMID- 25714087 TI - Chabamide induces cell cycle arrest and apoptosis by the Akt/MAPK pathway and inhibition of P-glycoprotein in K562/ADR cells. AB - One of the major mechanisms of multidrug resistance in cancer therapy is the overexpression of P-glycoprotein (P-gp). Chabamide, a dimeric alkaloid isolated from Piper chaba Hunter, shows antimalarial, antituberculosis, and cytotoxic activities. However, its mechanism of action has not been elucidated. In this study, the molecular mechanism underlying the cytotoxicity and downregulation of P-gp expression by chabamide in adriamycin-resistant human leukemia cells (K562/ADR) was clarified. Results show that chabamide inhibited the growth of K562/ADR cells in a dose-dependent and time-dependent manner, and significantly inhibited cell proliferation by cell cycle arrest in the G0/G1 phase, which was associated with an obvious increase in p21 and decrease in cyclin D1 and CDK2/4/6 protein expression. Moreover, chabamide could regulate the changes in the mitochondrial membrane potential, increase the expression of apoptosis-related proteins, such as Bax and cytochrome c, and decrease the protein expression levels of Bcl-2, caspase-9, caspase-3, PARP-1, and p-Akt. In addition, we found that JNK, ERK1/2, and p38 were regulated by chabamide in K562/ADR cells. Further studies indicated that the decrease in the reactive oxygen species level inhibited intrinsic P-gp expression. Therefore, chabamide-induced apoptosis in K562/ADR cells was associated with Akt/MAPK and the inhibition of P-gp. These results provide a biochemical basis for possible clinical applications of chabamide in the treatment of leukemia. PMID- 25714088 TI - Re: The new Canadian Association for the Study of the Liver HCV guidelines. PMID- 25714089 TI - Effects of methionine supplementation on the expression of protein deposition related genes in acute heat stress-exposed broilers. AB - The objective of this study was to evaluate the effect of heat stress and methionine supplementation on the gene expression of insulin-like growth factor I (IGF-I), growth hormone receptor (GHR), phosphatidylinositol 3-kinase, and regulatory 1 (PI3KR1) in the liver, as well as the expression of the atrogin 1 and cathepsin L2 (CTSL2) genes in the breast muscle of broilers. Broilers from 1 21 and 22-42 days of age were divided into three treatments related to methionine supplementation as follows: without methionine supplementation (MD), recommended level of methionine (DL1), and excess supplementation of methionine (DL2). The animals were either maintained at a thermal comfort temperature or exposed to heat stress (HS) (38 degrees C for 24 hours, starting on day 20 or day 41 for experiments 1 and 2, respectively). The heat stress increased the body temperature at both ages. Starter period: The HS animals presented increased plasma creatinine content (P<0.0001) and the highest CTSL2 gene expression (P<0.0001). The methionine supplementation increased the IGF-I (P = 0.0144) and GHR (P = 0.0011) gene expression and decreased the CTSL2 (P = 0.0004) and atrogin 1 (P = 0.0012) gene expression. Grower period: Significant effects for the interaction between supplementation and environment were observed for GHR (P = 0.0252) and CTSL2 (P = 0.0011) gene expression. The highest GHR expression was observed in animals that remained in thermal comfort on the DL2 diet, and the lowest expression occurred in the HS animals fed the MD diet. For CTSL2, the HS animals fed the MD diet presented the highest CTSL2 gene expression, and the lowest expression was observed in the animals maintained at thermal comfort on DL1 and DL2 diets. Only methionine supplementation had effect on atrogin-1 gene expression (P<0.0001), with higher methionine content in the diet lower atrogin-1 gene expression was observed. Our results suggest that heat stress induces greater protein degradation and that methionine supplementation could induce protein deposition because methionine increased the expression of genes related to protein synthesis and decreased the expression of genes related to protein breakdown. PMID- 25714090 TI - Ocean warming-acidification synergism undermines dissolved organic matter assembly. AB - Understanding the influence of synergisms on natural processes is a critical step toward determining the full-extent of anthropogenic stressors. As carbon emissions continue unabated, two major stressors--warming and acidification- threaten marine systems on several scales. Here, we report that a moderate temperature increase (from 30 degrees C to 32 degrees C) is sufficient to slow- even hinder--the ability of dissolved organic matter, a major carbon pool, to self-assemble to form marine microgels, which contribute to the particulate organic matter pool. Moreover, acidification lowers the temperature threshold at which we observe our results. These findings carry implications for the marine carbon cycle, as self-assembled marine microgels generate an estimated global seawater budget of ~1016 g C. We used laser scattering spectroscopy to test the influence of temperature and pH on spontaneous marine gel assembly. The results of independent experiments revealed that at a particular point, both pH and temperature block microgel formation (32 degrees C, pH 8.2), and disperse existing gels (35 degrees C). We then tested the hypothesis that temperature and pH have a synergistic influence on marine gel dispersion. We found that the dispersion temperature decreases concurrently with pH: from 32 degrees C at pH 8.2, to 28 degrees C at pH 7.5. If our laboratory observations can be extrapolated to complex marine environments, our results suggest that a warming acidification synergism can decrease carbon and nutrient fluxes, disturbing marine trophic and trace element cycles, at rates faster than projected. PMID- 25714091 TI - First 'Rauisuchian' archosaur (Pseudosuchia, Loricata) for the Middle Triassic Santacruzodon assemblage zone (Santa Maria Supersequence), Rio Grande do Sul State, Brazil. AB - The 'Rauisuchia' are a group of Triassic pseudosuchian archosaurs that displayed a near worldwide distribution. In Brazil, their fossils are found only in the Santa Maria Formation (Parana Basin) of the Rio Grande do Sul State, specifically in the Middle Triassic Dinodontosaurus assemblage zone (AZ) and the Late Triassic Hyperodapedon AZ (Rauisuchus tiradentes). Between these two cenozones is the Santacruzodon AZ (Middle Triassic), whose record was, until now, restricted to non-mammalian cynodonts and the proterochampsian Chanaresuchus bonapartei. Here we present the first occurrence of a rauisuchian archosaur for this cenozone, from the Schoenstatt outcrop, located near the city of Santa Cruz do Sul and propose a new species, based on biostratigraphical evidence and a comparative osteological analysis. PMID- 25714092 TI - Spatial niche partitioning in sub-tropical solitary ungulates: four-horned antelope and barking deer in Nepal. AB - Differential resource use allows a diversity of species to co-exist in a particular area by specializing in individual ecological niches. Four-horned antelope Tetracerus quadricornis is endemic to the Indian subcontinent and has a restricted distribution in Nepal and India; however, the barking deer Muntiacus vaginalis is relatively common throughout its wide distribution range. We wanted a better understanding of their habitats and how these two similarly sized solitary ungulates manage to coexist in lowland Nepal. We used fecal pellet belt transect surveys in the Babai valley, Bardia National Park to study the habitat associations of both species. We found empirical evidence that four-horned antelope prefer hill sal forest and deciduous hill forest at higher elevations, whereas barking deer preferred riverine and sal forest in lower elevations. We found a clear niche differentiation of four-horned antelope and barking deer that made the coexistence of these similarly sized solitary ungulates possible. Hence, resource partitioning is the key to coexistence of these solitary ungulates, and the fine-grained habitat mosaic of different forest types in the study landscape appears to be the underlying feature. Therefore, maintaining the habitat mosaic and preserving valuable hill sal and deciduous hill forests will facilitate the coexistence of herbivores in sub-tropical regions. PMID- 25714093 TI - Milk-derived tripeptides IPP (Ile-Pro-Pro) and VPP (Val-Pro-Pro) promote adipocyte differentiation and inhibit inflammation in 3T3-F442A cells. AB - Milk derived tripeptides IPP (Ile-Pro-Pro) and VPP (Val-Pro-Pro) have shown promise as anti-hypertensive agents due to their inhibitory effects on angiotensin converting enzyme (ACE). Due to the key inter-related roles of hypertension, chronic inflammation and insulin resistance in the pathogenesis of metabolic syndrome, there is growing interest in investigating established anti hypertensive agents for their effects on insulin sensitivity and inflammation. In this study, we examined the effects of IPP and VPP on 3T3-F442A murine pre adipocytes, a widely used model for studying metabolic diseases. We found that both IPP and VPP induced beneficial adipogenic differentiation as manifested by intracellular lipid accumulation, upregulation of peroxisome proliferator activated receptor gamma (PPARgamma) and secretion of the protective lipid hormone adiponectin by these cells. The observed effects were similar to those induced by insulin, suggesting potential benefits in the presence of insulin resistance. IPP and VPP also inhibited cytokine induced pro-inflammatory changes such as reduction in adipokine levels and activation of the nuclear factor kappa B (NF-kappaB) pathway. Taken together, our findings suggest that IPP and VPP exert insulin-mimetic adipogenic effects and prevent inflammatory changes in adipocytes, which may offer protection against metabolic disease. PMID- 25714094 TI - Using an improved SIFT algorithm and fuzzy closed-loop control strategy for object recognition in cluttered scenes. AB - Partial occlusions, large pose variations, and extreme ambient illumination conditions generally cause the performance degradation of object recognition systems. Therefore, this paper presents a novel approach for fast and robust object recognition in cluttered scenes based on an improved scale invariant feature transform (SIFT) algorithm and a fuzzy closed-loop control method. First, a fast SIFT algorithm is proposed by classifying SIFT features into several clusters based on several attributes computed from the sub-orientation histogram (SOH), in the feature matching phase only features that share nearly the same corresponding attributes are compared. Second, a feature matching step is performed following a prioritized order based on the scale factor, which is calculated between the object image and the target object image, guaranteeing robust feature matching. Finally, a fuzzy closed-loop control strategy is applied to increase the accuracy of the object recognition and is essential for autonomous object manipulation process. Compared to the original SIFT algorithm for object recognition, the result of the proposed method shows that the number of SIFT features extracted from an object has a significant increase, and the computing speed of the object recognition processes increases by more than 40%. The experimental results confirmed that the proposed method performs effectively and accurately in cluttered scenes. PMID- 25714095 TI - Single aggressive interactions increase urinary glucocorticoid levels in wild male chimpanzees. AB - A basic premise in behavioural ecology is the cost-benefit arithmetic, which determines both behavioural decisions and evolutionary processes. Aggressive interactions can be costly on an energetic level, demanding increased energy or causing injuries, and on a psychological level, in the form of increased anxiety and damaged relationships between opponents. Here we used urinary glucocorticoid (uGC) levels to assess the costs of aggression in wild chimpanzees of Budongo Forest, Uganda. We collected 169 urine samples from nine adult male chimpanzees following 14 aggressive interactions (test condition) and 10 resting events (control condition). Subjects showed significantly higher uGC levels after single aggressive interactions compared to control conditions, likely for aggressors as well as victims. Higher ranking males had greater increases of uGC levels after aggression than lower ranking males. In contrast, uGC levels showed no significant change in relation to aggression length or intensity, indicating that psychological factors might have played a larger role than mere energetic expenditure. We concluded that aggressive behaviour is costly for both aggressors and victims and that costs seem poorly explained by energetic demands of the interaction. Our findings are relevant for studies of post-conflict interactions, since we provide evidence that both aggressors and victims experience a stress response to conflict. PMID- 25714097 TI - Correction: Pdsg1 and Pdsg2, novel proteins involved in developmental genome remodelling in Paramecium. PMID- 25714096 TI - Ultrasonic vocalizations in golden hamsters (Mesocricetus auratus) reveal modest sex differences and nonlinear signals of sexual motivation. AB - Vocal signaling is one of many behaviors that animals perform during social interactions. Vocalizations produced by both sexes before mating can communicate sex, identity and condition of the caller. Adult golden hamsters produce ultrasonic vocalizations (USV) after intersexual contact. To determine whether these vocalizations are sexually dimorphic, we analyzed the vocal repertoire for sex differences in: 1) calling rates, 2) composition (structural complexity, call types and nonlinear phenomena) and 3) acoustic structure. In addition, we examined it for individual variation in the calls. The vocal repertoire was mainly composed of 1-note simple calls and at least half of them presented some degree of deterministic chaos. The prevalence of this nonlinear phenomenon was confirmed by low values of harmonic-to-noise ratio for most calls. We found modest sexual differences between repertoires. Males were more likely than females to produce tonal and less chaotic calls, as well as call types with frequency jumps. Multivariate analysis of the acoustic features of 1-note simple calls revealed significant sex differences in the second axis represented mostly by entropy and bandwidth parameters. Male calls showed lower entropy and inter quartile bandwidth than female calls. Because the variation of acoustic structure within individuals was higher than among individuals, USV could not be reliably assigned to the correct individual. Interestingly, however, this high variability, augmented by the prevalence of chaos and frequency jumps, could be the result of increased vocal effort. Hamsters motivated to produce high calling rates also produced longer calls of broader bandwidth. Thus, the sex differences found could be the result of different sex preferences but also of a sex difference in calling motivation or condition. We suggest that variable and complex USV may have been selected to increase responsiveness of a potential mate by communicating sexual arousal and preventing habituation to the caller. PMID- 25714098 TI - Are fluoride levels in drinking water associated with hypothyroidism prevalence in England? A large observational study of GP practice data and fluoride levels in drinking water. AB - BACKGROUND: While previous research has suggested that there is an association between fluoride ingestion and the incidence of hypothyroidism, few population level studies have been undertaken. In England, approximately 10% of the population live in areas with community fluoridation schemes and hypothyroidism prevalence can be assessed from general practice data. This observational study examines the association between levels of fluoride in water supplies with practice level hypothyroidism prevalence. METHODS: We used a cross-sectional study design using secondary data to develop binary logistic regression models of predictive factors for hypothyroidism prevalence at practice level using 2012 data on fluoride levels in drinking water, 2012/2013 Quality and Outcomes Framework (QOF) diagnosed hypothyroidism prevalence data, 2013 General Practitioner registered patient numbers and 2012 practice level Index of Multiple Deprivation scores. FINDINGS: We found that higher levels of fluoride in drinking water provide a useful contribution for predicting prevalence of hypothyroidism. We found that practices located in the West Midlands (a wholly fluoridated area) are nearly twice as likely to report high hypothyroidism prevalence in comparison to Greater Manchester (non-fluoridated area). INTERPRETATION: In many areas of the world, hypothyroidism is a major health concern and in addition to other factors-such as iodine deficiency-fluoride exposure should be considered as a contributing factor. The findings of the study raise particular concerns about the validity of community fluoridation as a safe public health measure. PMID- 25714099 TI - Interactions of Lipid Genetic Risk Scores With Estimates of Metabolic Health in a Danish Population. AB - BACKGROUND: There are several well-established lifestyle factors influencing dyslipidemia and currently; 157 genetic susceptibility loci have been reported to be associated with serum lipid levels at genome-wide statistical significance. However, the interplay between lifestyle risk factors and these susceptibility loci has not been fully elucidated. We tested whether genetic risk scores (GRS) of lipid-associated single nucleotide polymorphisms associate with fasting serum lipid traits and whether the effects are modulated by lifestyle factors or estimates of metabolic health. METHODS AND RESULTS: The single nucleotide polymorphisms were genotyped in 2 Danish cohorts: inter99 (n=5961) for discovery analyses and Health2006 (n=2565) for replication. On the basis of published effect sizes of single nucleotide polymorphisms associated with circulating fasting levels of total cholesterol, low-density lipoprotein-cholesterol, high density lipoprotein-cholesterol, or triglyceride, 4 weighted GRS were constructed. In a cross-sectional design, we investigated whether the effect of these weighted GRSs on lipid levels were modulated by diet, alcohol consumption, physical activity, and smoking or the individual metabolic health status as estimated from body mass index, waist circumference, and insulin resistance assessed using homeostasis model assessment of insulin resistance. All 4 lipid weighted GRSs associated strongly with their respective trait (from P=3.3*10(-69) to P=1.1*10(-123)). We found interactions between the triglyceride weighted GRS and body mass index and waist circumference on fasting triglyceride levels in Inter99 and replicated these findings in Health2006 (P(interaction)=9.8*10(-5) and 2.0*10(-5), respectively, in combined analysis). CONCLUSIONS: Our findings suggest that individuals who are obese may be more susceptible to the cumulative genetic burden of triglyceride single nucleotide polymorphisms. Therefore, it is suggested that especially these genetically at-risk individuals may benefit more from targeted interventions aiming at obesity prevention. PMID- 25714100 TI - A tale of two recent spills--comparison of 2014 Galveston Bay and 2010 Deepwater Horizon oil spill residues. AB - Managing oil spill residues washing onto sandy beaches is a common worldwide environmental problem. In this study, we have analyzed the first-arrival oil spill residues collected from two Gulf of Mexico (GOM) beach systems following two recent oil spills: the 2014 Galveston Bay (GB) oil spill, and the 2010 Deepwater Horizon (DWH) oil spill. This is the first study to provide field observations and chemical characterization data for the 2014 GB oil spill. Here we compare the physical and chemical characteristics of GB oil spill samples with DWH oil spill samples and present their similarities and differences. Our field observations indicate that both oil spills had similar shoreline deposition patterns; however, their physical and chemical characteristics differed considerably. We highlight these differences, discuss their implications, and interpret GB data in light of lessons learned from previously published DWH oil spill studies. These analyses are further used to assess the long-term fate of GB oil spill residues and their potential environmental impacts. PMID- 25714101 TI - Impact of visual context on public perceptions of non-human primate performers. AB - Prior research has shown that the use of apes, specifically chimpanzees, as performers in the media negatively impacts public attitudes of their conservation status and desirability as a pet, yet it is unclear whether these findings generalize to other non-human primates (specifically non-ape species). We evaluated the impact of viewing an image of a monkey or prosimian in an anthropomorphic or naturalistic setting, either in contact with or in the absence of a human. Viewing the primate in an anthropomorphic setting while in contact with a person significantly increased their desirability as a pet, which also correlated with increased likelihood of believing the animal was not endangered. The majority of viewers felt that the primates in all tested images were "nervous." When shown in contact with a human, viewers felt they were "sad" and "scared", while also being less "funny." Our findings highlight the potential broader implications of the use of non-human primate performers by the entertainment industry. PMID- 25714104 TI - Drug delivery design for regenerative medicine. PMID- 25714103 TI - microRNAs regulate cell-to-cell variability of endogenous target gene expression in developing mouse thymocytes. AB - The development and homeostasis of multicellular organisms relies on gene regulation within individual constituent cells. Gene regulatory circuits that increase the robustness of gene expression frequently incorporate microRNAs as post-transcriptional regulators. Computational approaches, synthetic gene circuits and observations in model organisms predict that the co-regulation of microRNAs and their target mRNAs can reduce cell-to-cell variability in the expression of target genes. However, whether microRNAs directly regulate variability of endogenous gene expression remains to be tested in mammalian cells. Here we use quantitative flow cytometry to show that microRNAs impact on cell-to-cell variability of protein expression in developing mouse thymocytes. We find two distinct mechanisms that control variation in the activation-induced expression of the microRNA target CD69. First, the expression of miR-17 and miR 20a, two members of the miR-17-92 cluster, is co-regulated with the target mRNA Cd69 to form an activation-induced incoherent feed-forward loop. Another microRNA, miR-181a, acts at least in part upstream of the target mRNA Cd69 to modulate cellular responses to activation. The ability of microRNAs to render gene expression more uniform across mammalian cell populations may be important for normal development and for disease. PMID- 25714102 TI - Prevalence of sexually transmitted infections including HIV in street-connected adolescents in western Kenya. AB - PURPOSE: The objectives of this study were to characterise the sexual health of street-connected adolescents in Eldoret, Kenya, analyse gender disparity of risks, estimate the prevalence of sexually transmitted infections (STIs), and identify factors associated with STIs. METHODS: A cross-sectional study of street connected adolescents ages 12-21 years was conducted in Eldoret, Kenya. Participants were interviewed and screened for Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas vaginalis, herpes simplex virus-2, syphilis and HIV. Descriptive statistics and logistic regression were used to identify factors associated with having any STI. RESULTS: Of the 200 participants, 81 (41%) were female. 70.4% of females and 60.5% of males reported sexual activity. Of those that participated in at least one STI test, 28% (55/194) had >=1 positive test, including 56% of females; 14% (28/194) had >1 positive test. Twelve females and zero males (6% overall, 14.8% of females) were HIV positive. Among females, those with HIV infection more frequently reported transactional sex (66.7% vs. 26.1%, p=0.01), drug use (91.7% vs. 56.5%, p=0.02), and reported a prior STI (50.0% vs. 14.7%, p<0.01). Having an adult caregiver was less likely among those with HIV infection (33.3% vs. 71.0%, p=0.04). Transactional sex (AOR 3.02, 95% CI (1.05 to 8.73)), a previous STI (AOR 3.46 95% CI (1.05 to 11.46)) and >=2 sexual partners (AOR 5.62 95% (1.67 to 18.87)) were associated with having any STI. CONCLUSIONS: Street-connected adolescents in Eldoret, Kenya are engaged in high-risk sexual behaviours and females in particular have a substantial burden of STIs and HIV. There is a need for STI interventions targeted to street-connected youth. PMID- 25714105 TI - Clinical findings, diagnostics and outcome in 33 cats with adrenal neoplasia (2002-2013). AB - OBJECTIVES: The objective of this retrospective study was to describe the clinical signs and diagnostic findings in cats with histopathologically confirmed adrenal neoplasms, and to assess correlations with survival data. METHODS: Study data were acquired by reviewing medical records for all cats diagnosed with adrenal neoplasms at seven referral institutions between 2002 and 2013. Inclusion criteria required a histopathologic diagnosis of an adrenal neoplasm (ante-mortem or on necropsy). RESULTS: Thirty-three cats met the inclusion criteria for the study. The most common presenting complaints included weakness (n = 12), respiratory signs (n = 4), blindness (n = 4) or gastrointestinal signs (n = 3). Laboratory abnormalities included hypokalemia (n = 18), alkalemia (n = 12), elevated creatine kinase (>3000, n = 5) and azotemia (n = 4). In addition, hypertension was noted in 13 cats. Thirty cats were diagnosed with cortical tumors (17 carcinomas, 13 adenomas) and three cats were diagnosed with pheochromocytomas. Twenty-five cats underwent tests to evaluate the function of the adrenal tumors; 19/25 cats had functional tumors (hyperaldosteronism [n = 16], hypercortisolemia [n = 1], high estradiol [n = 1], and hypersecretion of aldosterone, estradiol and progesterone [n = 1]). Twenty-six cats underwent adrenalectomy, one cat was medically managed and six were euthanized without treatment. Long-term survival postoperatively ranged from 4-540 weeks, with 20 (77%) cats surviving the perioperative period of 2 weeks. The only variable that was found to be negatively associated with survival was female sex. The most common complications noted during the perioperative period were hemorrhage and progressive lethargy and anorexia. CONCLUSIONS AND RELEVANCE: Surgical treatment for feline adrenal tumors (regardless of tumor type) resulted in good long-term survival. Given that pre- and postoperative hypocortisolemia was identified in this study, and, in addition, hypersecretion of more than one adrenal hormone occurred in one cat, adrenal panels prior to surgery may be beneficial as part of the preoperative work-up. PMID- 25714106 TI - Perimortem caesarean section. AB - This review describes a simple approach to perimortem caesarean section (PMCS) that can be used by a doctor in the resuscitation room or prehospital environment when faced with a mother of more than 20 weeks gestation in cardiac arrest. It explores the indications for and contraindications to the procedure, the physiological rationale behind it, equipment needed, technical aspects of the procedure and reviews recent literature on maternal and fetal outcomes. Like other uncommon procedures such as emergency department thoracotomy, rehearsal and preparation for a PMCS is essential to give both mother and baby the best chance of survival. PMID- 25714107 TI - Prevalence of nosocomial pathogens in German ambulances: the SEKURE study. AB - OBJECTIVE: The increasing prevalence of multidrug resistant bacteria is a problem in the inpatient care setting, and in the emergency care system. The aim of this observational, cross-sectional study was to evaluate the prevalence of pathogens on well-defined surfaces in German ambulances that have been designated as 'ready for service'. METHODS: After informed consent was obtained, ambulance surfaces were sampled with agar plates for microbiological examination during an unannounced visit. A standardised questionnaire was used to obtain information regarding the disinfection protocols used at each rescue station. RESULTS: Methicillin resistant staphylococcus aureus contamination was present in 18 sampling surfaces from 11 out of 150 ambulance vehicles (7%) that were designated as ready for service. Contact surfaces directly surrounding patients or staff were most frequently contaminated with pathogens. However, bacterial contamination was not related to annual missions, methods or frequency of disinfection. CONCLUSIONS: In accordance with previous studies, disinfection and cleaning of areas with direct contact to patients or staff seem to be the most challenging. This should also be reflected in disinfection guidelines and the related continuing education. PMID- 25714108 TI - A comparison of pregabalin and gabapentin in palliative care #289. PMID- 25714111 TI - The effects of commonly used intravitreal steroids on proliferation index of ciliary body-derived mesenchymal stem cells: an in vitro study. AB - AIM: To investigate the effects of commonly used intravitreal steroids on survival and proliferation (namely, proliferation index) of ciliary body-derived mesenchymal stem cells (CB-MSC). METHODS: CB-MSCs were isolated from newborn rats' eye, and they were expanded in the medium. Commonly used intravitreal steroids such as dexamethasone (Dex) and triamcinolone acetonide (TA) were added into the medium at commonly used concentration in clinical practice (0.1 mg/mL) and at lower concentration (0.01 mg/mL). Proliferation indexes of CB-MSCs were analyzed with the xCELLigence system at nine consecutive times (at 3rd, 6th, 21th, 30th, 45th, 60th, 75th, 90th and 100th h). RESULTS: Both TA and Dex at both 0.01 mg/mL and 0.1 mg/mL concentrations had negative effect on proliferation indexes of CB-MSC. Although negative effect of TA on proliferation index of CB MSC at both concentrations was not statistically significant, statistically significant negative effect of Dex at 0.01 mg/mL concentration started 60th h (p = 0.017) and 0.1 mg/mL concentration started 30th h (p = 0.014). DISCUSSION: Even therapeutic doses of intravitreal corticosteroid agents might have negative effects on limited numbers of stem cells. Especially, Dex caused statistically significant toxic effects on CB-MSCs even at lower concentrations of those used clinically. These novel findings deserve further in vivo investigations. PMID- 25714109 TI - Disease-promoting effects of type I interferons in viral, bacterial, and coinfections. AB - While type I interferons (IFNs) are universally acknowledged for their antiviral and immunostimulatory functions, there is increasing appreciation of the detrimental effects of inappropriate, excessive, or mistimed type I IFN responses in viral and bacterial infections. The underlying mechanisms by which type I IFNs promote susceptibility or severity include direct tissue damage by apoptosis induction or suppression of proliferation in tissue cells, immunopathology due to excessive inflammation, and cell death induced by TRAIL- and Fas-expressing immune cells, as well as immunosuppression through IL-10, IL-27, PD-L1, IL-1Ra, and other regulatory molecules that antagonize the induction or action of IL-1, IL-12, IL-17, IFN-gamma, KC, and other effectors of the immune response. Bacterial superinfections following influenza infection are a prominent example of a situation where type I IFNs can misdirect the immune response. This review discusses current understanding of the parameters of signal strength, duration, timing, location, and cellular recipients that determine whether type I IFNs have beneficial or detrimental effects in infection. PMID- 25714110 TI - Candida albicans-epithelial interactions and pathogenicity mechanisms: scratching the surface. AB - Until recently, epithelial cells have been a largely ignored component of host responses to microbes. However, this has been largely overturned over the last decade as an ever increasing number of studies have highlighted the key role that these cells play in many of our interactions with our microbiota and pathogens. Interactions of these cells with Candida albicans have been shown to be critical not just in host responses, but also in fungal cell responses, regulating fungal morphology and gene expression profile. In this review, we will explore the interactions between C. albicans and epithelial cells, and discuss how these interactions affect our relationship with this fungus. PMID- 25714112 TI - Novel inducers of BECN1-independent autophagy: cis-unsaturated fatty acids. AB - The induction of autophagy usually requires the activation of PIK3C3/VPS34 (phosphatidylinositol 3-kinase, catalytic subunit type 3) within a multiprotein complex that contains BECN1 (Beclin 1, autophagy related). PIK3C3 catalyzes the conversion of phosphatidylinositol into phosphatidylinositol 3-phosphate (PtdIns3P). PtdIns3P associates with growing phagophores, which recruit components of the autophagic machinery, including the lipidated form of MAP1LC3B/LC3 (microtubule-associated protein 1 light chain 3 beta). Depletion of BECN1, PIK3C3 or some of their interactors suppresses the formation of MAP1LC3B(+) phagophores or autophagosomes elicited by most physiological stimuli, including saturated fatty acids. We observed that cis-unsaturated fatty acids stimulate the generation of cytosolic puncta containing lipidated MAP1LC3B as well as the autophagic turnover of long-lived proteins in the absence of PtdIns3P accumulation. In line with this notion, cis-unsaturated fatty acids require neither BECN1 nor PIK3C3 to stimulate the autophagic flux. Such a BECN1 independent autophagic response is phylogenetically conserved, manifesting in yeast, nematodes, mice and human cells. Importantly, MAP1LC3B(+) puncta elicited by cis-unsaturated fatty acids colocalize with Golgi apparatus markers. Moreover, the structural and functional collapse of the Golgi apparatus induced by brefeldin A inhibits cis-unsaturated fatty acid-triggered autophagy. It is tempting to speculate that the well-established health-promoting effects of cis unsaturated fatty acids are linked to their unusual capacity to stimulate noncanonical, BECN1-independent autophagic responses. PMID- 25714113 TI - Implementing a radiology-information technology project: mobile image viewing use case and a general guideline for radiologist-information technology team collaboration. AB - OBJECTIVE: This article illustrates the importance of radiologist engagement in the successful implementation of radiology-information technology (IT) projects through the example of establishing a mobile image viewing solution for health care professionals. CONCLUSION: With an understanding of the types of decisions that benefit from radiologist input, this article outlines an overall project framework to provide a context for how radiologists might engage in the project cycle. PMID- 25714114 TI - Fire Tests on E-vehicle Battery Cells and Packs. AB - OBJECTIVE: The purpose of this study was to investigate the effects of abuse conditions, including realistic crash scenarios, on Li ion battery systems in E vehicles in order to develop safe practices and priorities when responding to accidents involving E-vehicles. METHOD: External fire tests using a single burning item equipment were performed on commercial Li ion battery cells and battery packs for electric vehicle (E-vehicle) application. The 2 most common battery cell technologies were tested: Lithium iron phosphate (LFP) and mixed transition metal oxide (lithium nickel manganese cobalt oxide, NMC) cathodes against graphite anodes, respectively. The cell types investigated were "pouch" cells, with similar physical dimensions, but the NMC cells have double the electric capacity of the LFP cells due to the higher energy density of the NMC chemistry, 7 and 14 Ah, respectively. Heat release rate (HRR) data and concentrations of toxic gases were acquired by oxygen consumption calorimetry and Fourier transform infrared spectroscopy (FTIR), respectively. RESULTS: The test results indicate that the state of charge (SOC) affects the HRR as well as the amount of toxic hydrogen fluoride (HF) gas formed during combustion. A larger number of cells increases the amount of HF formed per cell. There are significant differences in response to the fire exposure between the NMC and LFP cells in this study. The LFP cells generate a lot more HF per cell, but the overall reactivity of the NMC cells is higher. However, the total energy released by both batteries during combustion was independent of SOC, which indicates that the electric energy content of the test object contributes to the activation energy of the thermal and heat release process, whereas the chemical energy stored in the materials is the main source of thermal energy in the batteries. CONCLUSIONS: The results imply that it is difficult to draw conclusions about higher order system behavior with respect to HF emissions based on data from tests on single cells or small assemblies of cells. This applies to energy release rates as well. The present data show that mass and shielding effects between cells in multicell assemblies affect the propagation of a thermal event. PMID- 25714115 TI - Spray-Dried Influenza Antigen with Trehalose and Leucine Produces an Aerosolizable Powder Vaccine Formulation that Induces Strong Systemic and Mucosal Immunity after Pulmonary Administration. AB - BACKGROUND: Pulmonary immunization has recently gained increased interest as a means to induce both systemic and mucosal immunity while eliminating issues associated with the use of needles in parenteral vaccination. However, in contrast to the inhaled delivery of small molecule drugs, a dry powder carrier platform that is readily adaptable to the incorporation of biomacromolecules (e.g., vaccine antigens) as a common standard is lacking. Spray-dried trehalose with leucine has previously been characterized and demonstrated to produce highly aerosolizable powders containing an amorphous glassy matrix suitable for stabilization of biomacromolecules. This study aimed to further extend the understanding in the use of this formulation as a dry powder carrier platform in an in vivo setting, using influenza antigen as a model, for pulmonary delivery of biomacromolecules. METHODS: Spray-dried influenza vaccine was produced using previously established spray-drying conditions. The formulations were characterized to examine the impact of influenza antigen on the solid-state properties of the spray-dried powders. The optimal vaccine formulation was then selected for in vivo immunogenicity study in rats to evaluate the efficacy of the reconstituted spray-dried vaccine compared to liquid vaccine administered via pulmonary and subcutaneous routes. RESULTS: The formation of amorphous glassy matrix and morphology of the spray-dried particles, within the protein concentration range used in the study, was not affected by the incorporation of the influenza antigen. However, the amount of proteins incorporated increased water content and reduced the glass transition temperature (Tg) of the formulation. Nevertheless, the spray-dried vaccine induced strong mucosal and systemic immunity comparable to liquid vaccine after pulmonary and subcutaneous immunization without causing any inflammation to the lung parenchyma. CONCLUSIONS: The study demonstrated the usability of the spray-dried carrier as a promising platform for pulmonary delivery of influenza vaccine. The potential utility of this delivery system for other biomacromolecules may also be further explored. PMID- 25714116 TI - Synthesis of trifluoromethyl-containing vicinal diamines by asymmetric decarboxylative mannich addition reactions. AB - Herein is reported a study of asymmetric decarboxylative Mannich addition reactions between (Ss)-N-t-butylsulfinyl-3,3,3-trifluoroacetaldimine and Schiff bases derived from various aldehydes and lithium 2,2-diphenylglycinate. These reactions proceed with excellent diastereoselectivities and good chemical yields, providing a practical method for preparation of trifluoromethyl-containing vicinal diamines. The procedures can be conducted under convenient conditions, rendering this approach of high synthetic value. PMID- 25714117 TI - Digital NMR profiles as building blocks: assembling 1H fingerprints of steviol glycosides. AB - This report describes a fragment-based approach to the examination of congeneric organic compounds by NMR spectroscopy. The method combines the classic interpretation of 1D- and 2D-NMR data sets with contemporary computer-assisted NMR analysis. Characteristic NMR profiles of key structural motifs were generated by (1)H iterative full spin analysis and then joined together as building blocks to recreate the (1)H NMR spectra of increasingly complex molecules. To illustrate the methodology described, a comprehensive analysis of steviol (1), seven steviol glycosides (2-8) and two structurally related isosteviol compounds (9, 10) was carried out. The study also assessed the potential impact of this method on relevant aspects of natural product research including structural verification, chemical dereplication, and mixture analysis. PMID- 25714119 TI - Mitotic kinases and phosphatases cooperate to shape the right response. AB - Kinases and phosphatases, two sides of the same coin; are they opposing forces that switch signals on and off or enzymes that work together to give the right type of response at the right time? It depends on how close you stand when you view the big picture. Up close and detailed, and you'll see individual phosphorylation sites as binary switches - lights being toggled on/off by antagonistic forces. Take a step back and multiple copies of the same light are being toggled, perhaps leading to a range of intensities, or a flickering pattern, lights flashing in unison or at random. It depends what the signal requires. Stand even further back, let the story unfold, and you'll see a dazzling multicolour array of different lights. A coordinated sequence of color that appears to burst into life at different times in different places, with a pace that is both frantic and serene. This is a vision of mitosis and what a true spectacle it is. PMID- 25714118 TI - Immunogenicity of GX301 cancer vaccine: Four (telomerase peptides) are better than one. AB - Peptide540-548, peptide611-626, peptide672-686 and peptide766-780, which are derived from human telomerase, constitute the immunogenic component of the GX301 cancer vaccine. The relative immunogenicity of these peptides is unknown, thus it is unsure whether their combined use offers real advantages over single peptide stimulation. Hence, this study compared the number of specific immune responses and responders to each peptide, as well as to their mixture (meaning the co presence of the 4 peptides in the same culture well), achieved after ex vivo stimulation of PBMC from 21, HLA-A2+ (n.11) or HLA-A2- (n.10), healthy donors. The study was performed on freshly collected PBMC (T0) and on PBMC stimulated for 10 d with single peptides or their mixture (T1). Peptide-specific immune responses were analyzed by Elispot and cytokine intracellular staining by flow cytometry. The results showed that each peptide induced specific immune responses in some subjects, with different panels of responders among the peptides. Moreover, the numbers of responses and responders to the single peptides or their mixture were comparable. Importantly, the overall number of responders to the 4 peptides was higher than to each single peptide, or to their mixture, both at T0 and T1. These data demonstrate the immunogenicity of each of the 4 GX301 telomerase peptides. Moreover, they show the advantage of multi-peptide over single peptide stimulation, providing a clear support to their combined administration in vaccination protocols. However, the data pose a warning against peptide administration as a mixture due to possible interference phenomena during antigen presentation processes. PMID- 25714120 TI - S-Nitrosothiol analysis via photolysis and amperometric nitric oxide detection in a microfluidic device. AB - A 530 nm light emitting diode was coupled to a microfluidic sensor to facilitate photolysis of nitrosothiols (i.e., S-nitrosoglutathione, S-nitrosocysteine, and S nitrosoalbumin) and amperometric detection of the resulting nitric oxide (NO). This configuration allowed for maximum sensitivity and versatility, while limiting potential interference from nitrate decomposition caused by ultraviolet light. Compared to similar measurements of total S-nitrosothiol content in bulk solution, use of the microfluidic platform permitted significantly enhanced analytical performance in both phosphate-buffered saline and plasma (6-20* improvement in sensitivity depending on nitrosothiol type). Additionally, the ability to reduce sample volumes from milliliters to microliters provides increased clinical utility. To demonstrate its potential for biological analysis, this device was used to measure basal nitrosothiol levels from the vasculature of a healthy porcine model. PMID- 25714121 TI - Corrections. AB - In the January 2015 issue of Journal of Women's Health (2015; vol. 24, no. 1: 62 79), the article "Intimate Partner Violence and its Health Impact on Ethnic Minority Women" was published with an incorrect title ("Intimate Partner Violence and its Health Impact on Disproportionately Affected Populations, Including Minorities and Impoverished Groups"). The online version of the article has been corrected to reflect this change. The editorial office sincerely regrets the error. In this March 2015 issue of Journal of Women's Health (2015; vol. 24, no. 3: 228-236), the article "Association Between Pre-Pregnancy Depression/Anxiety Symptoms and Hypertensive Disorders of Pregnancy" was published online ahead of print with an incorrect title ("Life Course Depression/Anxiety Symptoms Ascertained During Pregnancy and Pregnancy Hypertensive Disorders"). The online version of the article has been corrected to reflect this change. The editorial office sincerely regrets the error. PMID- 25714122 TI - Meeting the milestones. Strategies for including high-value care education in pulmonary and critical care fellowship training. AB - Physician decision making is partially responsible for the roughly 30% of U.S. healthcare expenditures that are wasted annually on low-value care. In response to both the widespread public demand for higher-quality care and the cost crisis, payers are transitioning toward value-based payment models whereby physicians are rewarded for high-value, cost-conscious care. Furthermore, to target physicians in training to practice with cost awareness, the Accreditation Council for Graduate Medical Education has created both individual objective milestones and institutional requirements to incorporate quality improvement and cost awareness into fellowship training. Subsequently, some professional medical societies have initiated high-value care educational campaigns, but the overwhelming majority target either medical students or residents in training. Currently, there are few resources available to help guide subspecialty fellowship programs to successfully design durable high-value care curricula. The resource-intensive nature of pulmonary and critical care medicine offers unique opportunities for the specialty to lead in modeling and teaching high-value care. To ensure that fellows graduate with the capability to practice high-value care, we recommend that fellowship programs focus on four major educational domains. These include fostering a value-based culture, providing a robust didactic experience, engaging trainees in process improvement projects, and encouraging scholarship. In doing so, pulmonary and critical care educators can strive to train future physicians who are prepared to provide care that is both high quality and informed by cost awareness. PMID- 25714123 TI - Dynamic DNA methylation discovered during HSC differentiation. PMID- 25714124 TI - Homogeneous lithium electrodeposition with pyrrolidinium-based ionic liquid electrolytes. AB - In this study, we report on the electroplating and stripping of lithium in two ionic liquid (IL) based electrolytes, namely N-butyl-N-methylpyrrolidinium bis(fluorosulfonyl) imide (Pyr14FSI) and N-butyl-N-methylpyrrolidinium bis(trifluoromethanesulfonyl)imide (Pyr14TFSI), and mixtures thereof, both on nickel and lithium electrodes. An improved method to evaluate the Li cycling efficiency confirmed that homogeneous electroplating (and stripping) of Li is possible with TFSI-based ILs. Moreover, the presence of native surface features on lithium, directly observable via scanning electron microscope imaging, was used to demonstrate the enhanced electrolyte interphase (SEI)-forming ability, that is, fast cathodic reactivity of this class of electrolytes and the suppressed dendrite growth. Finally, the induced inhomogeneous deposition enabled us to witness the SEI cracking and revealed previously unreported bundled Li fibers below the pre-existing SEI and nonrod-shaped protuberances resulting from Li extrusion. PMID- 25714125 TI - E-nose based rapid prediction of early mouldy grain using probabilistic neural networks. AB - In this paper, early mouldy grain rapid prediction method using probabilistic neural network (PNN) and electronic nose (e-nose) was studied. E-nose responses to rice, red bean, and oat samples with different qualities were measured and recorded. E-nose data was analyzed using principal component analysis (PCA), back propagation (BP) network, and PNN, respectively. Results indicated that PCA and BP network could not clearly discriminate grain samples with different mouldy status and showed poor predicting accuracy. PNN showed satisfying discriminating abilities to grain samples with an accuracy of 93.75%. E-nose combined with PNN is effective for early mouldy grain prediction. PMID- 25714126 TI - Structural Properties of wurtzite InP-InGaAs nanowire core-shell heterostructures. AB - We report on growth and characterization of wurtzite InP-In(1-x)Ga(x)As core shell nanowire heterostructures. A range of nanowire structures with different Ga concentration in the shell was characterized with transmission electron microscopy and X-ray diffraction. We found that the main part of the nanowires has a pure wurtzite crystal structure, with occasional stacking faults occurring only at the top and bottom. This allowed us to determine the structural properties of wurtzite In(1-x)Ga(x)As. The InP-In(1-x)Ga(x)As core-shell nanowires show a triangular and hexagonal facet structure of {1100} and {1010} planes. X-ray diffraction measurements showed that the core and the shell are pseudomorphic along the c-axis, and the strained axial lattice constant is closer to the relaxed In(1-x)Ga(x)As shell. Microphotoluminescence measurements of the nanowires show emission in the infrared regime, which makes them suitable for applications in optical communication. PMID- 25714127 TI - The Respecting the Circle of Life trial for American Indian adolescents: rationale, design, methods, and baseline characteristics. AB - This paper describes the rationale, design, methods, and baseline results of a randomized controlled trial to evaluate the impact of an adapted evidence-based intervention (EBI), "Respecting the Circle of Life" (RCL) to reduce behavioral risks for HIV/AIDS among American Indian (AI) adolescents. A participatory approach shaped intervention adaptation and study design. A total of 267 participants (aged 13-19) were randomized by peer groups of the same sex to receive the RCL intervention or a control condition. Self-report assessments were administered at four intervals. The sample was predominately female (57%), had low HIV knowledge prevention scores, early sexual initiation (mean 14.6 years), and 56% reported intention to use a condom at next sex. Baseline characteristics were evenly distributed between groups with the exception of age and extrinsic reward scores. This is the first rigorous evaluation of an adapted EBI for HIV/AIDS prevention among AI adolescents, an at-risk and understudied population. PMID- 25714128 TI - The missing entry in the agostic-anagostic series: Rh(I)-eta(1)-C interactions in P(CH)P pincer complexes. AB - The missing entry, namely, the "C-anagostic" or eta(1)-C interaction, closing the agostic-anagostic series of metal-CH(aryl) interactions is found in a bis(amidiniophosphine) P(CH)P pincer rhodium complex. The three entries, namely, agostic eta(2)-(C,H), anagostic (related to hydrogen bonding, thus recoined here as "H-anagostic"), and C-anagostic interactions, are unambiguously characterized by electron localization function (ELF) topological analysis. Other theoretical tools such as noncovalent interaction (NCI) analysis and multicenter electron delocalization indices (MCIs) support the ELF characterization. A eta(2)-(C,H) agostic interaction is evidenced by a disynaptic V(C,H) or trisynaptic V(M,C,H) ELF basin with a significant quantum topological atoms in molecules (QTAIM) atomic contribution of the metal M and a large covariance (in absolute value) with the metal core basin C(M). The C-anagostic eta(1)-C interaction is characterized by a disynaptic V(M,C) basin, a weak covariance (in absolute value) of V(C,H) and C(M) populations, and a negligible QTAIM atomic contribution of M to V(C,H). The relevance of these ELF signatures is evidenced in a selected series of related rhodium and osmium complexes. PMID- 25714129 TI - Mechanical Characterization and Shape Optimization of Fascicle-Like 3D Skeletal Muscle Tissues Contracted with Electrical and Optical Stimuli. AB - In this study, we present a quantitative approach to construct effective 3D muscle tissues through shape optimization and load impedance matching with electrical and optical stimulation. We have constructed long, thin, fascicle-like skeletal muscle tissue and optimized its form factor through mechanical characterization. A new apparatus was designed and built, which allowed us to measure force-displacement characteristics with diverse load stiffnesses. We have found that (1) there is an optimal form factor that maximizes the muscle stress, (2) the energy transmitted to the load can be maximized with matched load stiffness, and (3) optical stimulation using channelrhodopsin2 in the muscle tissue can generate a twitch force as large as its electrical counterpart for well-developed muscle tissue. Using our tissue construct method, we found that an optimal initial diameter of 500 MUm outperformed tissues using 250 MUm by more than 60% and tissues using 760 MUm by 105%. Using optimal load stiffness, our tissues have generated 12 pJ of energy per twitch at a peak generated stress of 1.28 kPa. Additionally, the difference in optically stimulated twitch performance versus electrically stimulated is a function of how well the overall tissue performs, with average or better performing strips having less than 10% difference. The unique mechanical characterization method used is generalizable to diverse load conditions and will be used to match load impedance to muscle tissue impedance for a wide variety of applications. PMID- 25714130 TI - Identification of NDUFAF1 in mediating K-Ras induced mitochondrial dysfunction by a proteomic screening approach. AB - Increase in aerobic glycolysis and mitochondrial dysfunction are important biochemical features observed in human cancers. Recent studies suggest oncogenic K-Ras can cause suppression of mitochondrial respiration and up-regulation of glycolytic activity through a yet unknown mechanism. Here we employed proteomic approach and used a K-RasG12V inducible cell system to investigate the impact of oncogenic K-Ras on mitochondria and cell metabolism. Mitochondria isolated from cells before and after K-Ras induction were subjected to protein analysis using stable isotope labeling with amino acids (SILAC) and liquid chromatography coupled with mass spectrometry (LC-MS). 70 mitochondrial proteins with significant expression alteration after K-Ras induction were identified. A majority of these proteins were involved in energy metabolism. Five proteins with significant decrease belong to mitochondrial respiratory chain complex I. NADH dehydrogenase 1 alpha subcomplex assembly factor 1 (NDUFAF1) showed most significant decrease by 50%. Such decrease was validated in primary human pancreatic cancer tissues. Knockdown of NDUFAF1 by siRNA caused mitochondrial respiration deficiency, accumulation of NADH and subsequent increase of glycolytic activity. Our study revealed that oncogenic K-Ras is able to induce significant alterations in mitochondrial protein expression, and identified NDUFAF1 as an important molecule whose low expression contributes to mitochondrial dysfunction induced by K-Ras. PMID- 25714131 TI - A Combination of Intravenous Genistein Plus Mg2+ Enhances Antihypertensive Effects in SHR by Endothelial Protection and BKCa Channel Inhibition. AB - BACKGROUND: The effects of combining genistein (GST) plus magnesium (Mg) upon the development of hypertension were examined in 28 twelve-week-old male spontaneous hypertension rats (SHRs). Four experimental groups were tested: SHR (0.9% NaCl and DMSO), SHR + GST (0.9% NaCl and GST 5mg/kg/day), SHR + Mg (Mg(2+) 0.75 mmol/kg/day and DMSO), and SHR + GST + Mg (Mg(2+) 0.75 mmol/kg/day and GST 5mg/kg/day). A group of normotensive genetic control, Wistar-Kyoto (WKY) rats were also included for comparison. Drugs were administrated intravenously daily for 30 days. METHODS: Systolic blood pressure (SBP) and heart rate were measured by tail-cuff plethysmography every five days. Vascular tone of mesenteric arteries was examined by an isometric force transducer. Big-conductance calcium activated potassium channel (BKCa) currents were detected by whole-cell patch clamp techniques. RESULTS: SBP in SHRs was significantly elevated vs. that in WKY rats. GST or Mg lowered SBP of SHRs. Their combination enhanced antihypertensive effects, as indicated by significantly lowered SBP and shorter onset times. GST or Mg individually improved endothelial dysfunction of SHRs. However, again their combination enhanced endothelial protection, nearly restoring maximal relaxation responses to those seen in WKY. BKCa currents in SHRs were increased compared with WKY rats. GST, Mg, and their combination restored BKCa currents to those of WKY rats. CONCLUSIONS: The combination of GST and Mg produces antihypertensive effects and improvement of endothelial dysfunction, which are substantially greater than that when either is used individually. These results suggest a novel and feasible protocol for the prevention and treatment of hypertension and related cardio- and cerebro-vascular diseases. PMID- 25714133 TI - Carotid-Femoral Pulse Wave Velocity: An Urgent Need for a Harmonization of Denominations. PMID- 25714132 TI - Lower Blood Pressure Is Associated With Smaller Subcortical Brain Volumes in Older Persons. AB - BACKGROUND: Both high and low blood pressure (BP) have been positively as well as negatively associated with brain volumes in a variety of populations. The objective of this study was to investigate whether BP is associated with cortical and subcortical brain volumes in older old persons with mild cognitive deficits. METHODS: Within the Discontinuation of Antihypertensive Treatment in the Elderly trial, the cross-sectional relation of BP parameters with both cortical and subcortical brain volumes was investigated in 220 older old persons with mild cognitive deficits (43% men, mean age = 80.7 (SD = 4.1), median Mini-Mental State Examination score = 26 (interquartile range: 25-27)), using linear regression analysis. All analyses were adjusted for age, gender, volume of white matter hyperintensities, and duration of antihypertensive treatment. Brain volumes were determined on 3DT1-weighted brain magnetic resonance imaging scans. RESULTS: Lower systolic BP, diastolic BP, and mean arterial pressure (MAP) were significantly associated with lower volumes of thalamus and putamen (all P <= 0.01). In addition, lower MAP was also associated with reduced hippocampal volume (P = 0.035). There were no associations between any of the BP parameters with cortical gray matter or white matter volume. CONCLUSION: In an older population using antihypertensive medication with mild cognitive deficits, a lower BP, rather than a high BP is associated with reduced volumes of thalamus, putamen, and hippocampus. PMID- 25714134 TI - Interactions of univalent counterions with headgroups of monomers and dimers of an anionic surfactant. AB - Specific ion effects in solution are related to the hydrated ion size and ion hydration, electrostatic interactions, dispersion forces, ion effects on water structure, and ion modification of surface tension. In this study, we tried to identify which factor determines the ion specificity observed. The preference and energy of metal cations binding with the headgroups of dodecylsulfate (DS) monomers and dimers were determined by mass spectrometry. In the gas phase, cation binding to DS dimer headgroups depends strongly on the cation radius. On the other hand, the interactions between DS monomer headgroups and chaotropic ions depend on the cation polarizability, and the binding of kosmotropic cations to DS monomer headgroups strongly depends on the Gibbs free energies of ion hydration. DS dimers are related to surfactants having doubly charged headgroups, and DS monomers are related to surfactants with singly charged headgroups. Our spectrometric study of the strength of counterion binding to free monomers of a surfactant provides insight into surfactant-counterion interactions at micellar interfaces in bulk solution. PMID- 25714135 TI - Effects of Risk Factors on Anti-HBs Development in Hepatitis B Vaccinated and Nonvaccinated Populations. AB - Hepatitis B infection is still a major global health problem even though safe and effective vaccines have been available for more than 30 years. Although development of protective antibody to hepatitis B surface antigen (anti-HBs) is a common phenomenon after vaccination as well as natural infection, sometimes it does not appear even after complete vaccination. In the present study, whether the impairment of the development of anti-HBs in naturally infected and/or vaccinated populations is associated with immunomodulating risk factors (i.e., age, gender, smoking, and diabetes) and/or other risk factors (i.e., socioeconomic status, dental, and saloon exposure) was investigated through a cross-sectional study. Among 204 nonvaccinated patients, 132 (64.7%) tested positive for anti-HBc, indicating that they had been exposed to hepatitis B virus (HBV) at least once in their lifetime. Exposure to HBV (anti-HBc positive) was significantly higher among low-income people, dental exposed, and saloon users. Among anti-HBc positive patients, only 44 (33.3%) developed natural immunity with anti-HBs. Impairment in anti-HBs formation was found to be significantly high among cigarette smokers. However, no significant association of anti-HBs development was observed with age, gender, socioeconomic status, diabetes, dental exposure, and using saloon. Consistently, the frequency of developing protective anti-HBs (>=10 IU/L) among a vaccinated population was almost nine times less among smokers. These data suggest that anti-HBs development, either naturally or after vaccination, is significantly lower among smokers. It emphasizes the need to check the anti-HBs status in smokers after vaccination, and a booster vaccination should be administered if the anti-HBs antibody titer decreases below the protective level. PMID- 25714137 TI - Sequential linker installation: precise placement of functional groups in multivariate metal-organic frameworks. AB - A unique strategy, sequential linker installation (SLI), has been developed to construct multivariate MOFs with functional groups precisely positioned. PCN-700, a Zr-MOF with eight-connected Zr6O4(OH)8(H2O)4 clusters, has been judiciously designed; the Zr6 clusters in this MOF are arranged in such a fashion that, by replacement of terminal OH(-)/H2O ligands, subsequent insertion of linear dicarboxylate linkers is achieved. We demonstrate that linkers with distinct lengths and functionalities can be sequentially installed into PCN-700. Single crystal to single-crystal transformation is realized so that the positions of the subsequently installed linkers are pinpointed via single-crystal X-ray diffraction analyses. This methodology provides a powerful tool to construct multivariate MOFs with precisely positioned functionalities in the desired proximity, which would otherwise be difficult to achieve. PMID- 25714139 TI - Identification of five highly priced tuna species by quantitative real-time polymerase chain reaction. AB - Tunas are economically important fishery worldwide, and are often used for commercial processed production. For effective fishery management and protection of consumers' rights, it is important to develop a molecular method to identify species in canned tuna products rapidly and reliably. Here, we have developed a duplex quantitative real-time PCR (qPCR) for identification of five highly priced tuna species (Thunnus maccoyii, Thunnus obesus, Thunnus albacares, Thunnus alalunga and Katsuwonus pelamis) from processed as well as fresh fish. After amplification and sequencing of seven genetic markers commonly used for species identification, 16S rDNA and control region (CR) of mitochondrial DNA were selected as the reference gene markers for genus Thunnus and tuna species identification, respectively. Subsequently, a 73 bp fragment of 16S rDNA and 85 99 bp fragment of CR were simultaneously amplified from each target species by qPCR. The qPCR efficiency of each reaction was calculated according to the standard curves, and the method was validated by amplification DNA extracted from single or mixed tuna specimen. The developed duplex qPCR system was applied to authenticate species of 14 commercial tuna products successfully, which demonstrated it was really a useful and academic technique to identify highly priced tuna species. PMID- 25714138 TI - Immunogenicity of intramuscular MF59-adjuvanted and intradermal administered influenza enhanced vaccines in subjects aged over 60: A literature review. AB - Because of the age-related immune system decline, 2 potentiated influenza vaccines were specifically licensed for the elderly: Fluad((r)), an MF59 adjuvanted vaccine administered intramuscularly (IM-MF59), and Intanza 15 mcg((r)), a non adjuvanted vaccine administered intradermally (ID). The objective of this paper was to conduct a systematic review of studies that evaluated antibody responses in the elderly following immunization with IM-MF59 or ID vaccines. The two potentiated vaccines induced immune responses satisfying, in most instances, the European Medicine Agency immunogenicity criteria, both against vaccine antigens and heterovariant drifted strains. Considering pooled data reported in the articles analyzed and papers directly comparing the 2 vaccines, the antibody responses elicited by IM-MF59 and ID were found to be generally comparable. The use of IM-MF59 and ID vaccines can be proposed as an appropriate strategy for elderly seasonal influenza vaccination although further studies are required for a more complete characterization of the 2 vaccines. PMID- 25714141 TI - Complete mitochondrial genome of the Saker falcon, Falco cherrug (Falco, Falconidae). AB - The Falco cherrug (Saker falcon) is a large bird of prey. In this article, the complete mitochondrial genome of F. cherrug has been determined for the first time. The mitogenome (18,059 bp) comprised 13 protein-coding genes, 22 tRNA genes, 2 rRNA genes and 1 control region. Most protein-coding genes started with an ATG or ATA codon except for COI, which initiated with nontypical start codon of GTG instead, and terminated with the typical stop codon (TAA/TAG/AGA/AGG) or a single T. Two tandem repeats were identified in the control region, which was almost identical to Falco peregrinus, and the length of these two repeats are 204 bp and 291 bp, respectively. PMID- 25714140 TI - Complete mitochondrial genome sequence and mutations of the prostate cancer model inbred Sprague-Dawley strain. AB - In the present work we undertook the complete mitochondrial genome sequencing of a important prostate cancer model inbred Sprague-Dawley strain for the first time. The total length of the mitogenome was 16,308 bp. It harbored 13 protein coding genes, two ribosomal RNA genes, 22 transfer RNA genes and one non-coding control region (D-loop region). The mutation events were also reported. PMID- 25714142 TI - The mitochondrial genome of Pseudolaubuca sinensis (Cypriniformes, Cyprinidae). AB - In the present study, the complete mitogenome sequence of Pseudolaubuca sinensis was determined using PCR amplificationand DNA sequencing, which contains 13 protein-coding genes, 22 tRNA genes, 2 rRNA genes, and a non-coding control region with the total length of 16,617 bp. Except for eight tRNA and ND6 genes, all other mitochondrial genes are encoded on the heavy strand. The codon usage followed the typical vertebrate mitochondrial pattern (ATG or GTG for start codon and TAA or TAG for stop codon). There are 6 regions of gene share totaling 22 bp and 14 intergenic spacer regions totaling 66 bp. The complete mitochondrial genome sequence is useful for phylogenetic analysis and studies of population genetics of Pseudolaubuca sinensis. PMID- 25714143 TI - The complete chloroplast genome sequence of Perilla frutescens (L.). AB - Perilla frutescens (L.) is a traditionally medical herb of East Asia. The complete chloroplast genome of P. frutescens (L.) Britton var. frutescens was assembled in this study. Total chloroplast genome size of Perilla was 153,666 bp in length, containing a pair of inverted repeats (IRs) of 25,677 bp, separated by large single copy (LSC) and small single copy (SSC) of 84,288 bp and 17,925 bp, respectively. Overall GC contents of the genome were 37.6%. The chloroplast genome harbored 127 annotated genes, including 89 protein-coding genes, 29 tRNA genes and 8 rRNA genes. Eleven genes contained one or two introns. PMID- 25714144 TI - Searching the co-occurrence of pathogenic mutations for Leber's hereditary optic neuropathy and hearing loss in more than 26,000 whole mitochondrial genomes. AB - The co-occurrence of pathogenic or candidate mutations for Leber's hereditary optic neuropathy (LHON) and hearing loss has long been suggested to be a rare incident. The "rare" is probably caused by inadequate database searches. In this study, we created and released a comprehensive database with detailed information of haplogroup, variants, coding sites, and potential pathogenic mutations for more than 26,000 whole mitochondrial genomes. We found the co-occurrence in more than 200 individuals including not only LHON or hearing loss patients but also individuals sampled from general populations with various haplogroup backgrounds. The results highlighted the significant importance of adequate database searching in the genetic analysis of mitochondrial disorders. PMID- 25714145 TI - Complete mitochondrial genome of "Xenopus tropicalis" Asashima line (Anura: Pipidae), a possible undescribed species. AB - The diploid Xenopus tropicalis, with its small nuclear genomic size and short generation time compared to the traditional experimental amphibian X. laevis, is considered a next-generation model animal. Several experimental X. tropicalis lines have been used in research studies. Previous studies showed that the mtDNA sequence of the Asashima line is divergent from other lines and that this line may represent a distinct species. Here, we report the complete nucleotide sequence of this unique X. tropicalis experimental line. The genome is 17,700 bp in length and contains 37 genes commonly found in animal mtDNAs. The 16S rRNA gene sequence in Asashima line differed by over 6% from the standard Nigerian lines (a 3% difference is considered the species threshold in anurans), suggesting that this experimental line is a distinct species from the true X. tropicalis. PMID- 25714146 TI - Mitochondrial genome of the polychaete Tylorrhynchus heterochaetus (Phyllodocida, Nereididae). AB - We firstly reported the complete mitochondrial genome (mitogenome) of the polychaete Tylorrhynchus heterochaetus. Illumina next-generation sequencing generated a total of 19,796 reads with an average depth of 122.91*. The mitogenome is 16,106 bp in length including the typical structure of 13 protein coding genes, two rRNA genes, 22 tRNA genes and a putative control region. However, T. heterochaetus differs from other Nereididae species in the positions of four genes (tRNA-Met, tRNA-Asp, ATP8, tRNA-Tyr). All 37 genes are encoded on the heavy strand whose nucleotide composition is 32.20 % A, 13.67% C, 21.33% G and 32.80% T. PMID- 25714147 TI - The complete mitochondrial genome of Polydactylus sextarius (Teleostei, Mugiliformes). AB - The complete mitogenome of Polydactylus sextarius was firstly determined in this study using a long polymerase chain reaction (PCR) method and genome walking. It is 16,836 bp in length and has 13 protein-coding genes, 2 rRNA genes, 22 tRNA genes and 1 control region. The genes composition and order of which are similar to most other vertebrates. All mitochondrial genes are encoded on the heavy strand, except for eight tRNA and ND6 genes. The overall base composition of the heavy strand is 27.4% A, 26.0% T, 29.9% C, and 16.7% G, with a slight AT bias of 53.4%. There are eight regions of gene overlap totaling 27 bp and 16 intergenic spacer regions totaling 344 bp. The mitogenome sequence of P. sextarius could contribute to the solution of its phylogenetic position within Polynemidae fishes based on the whole mitogenomic data. PMID- 25714148 TI - The complete mitochondrial genome sequence of an Isospora sp. (Eimeriidae, Eucoccidiorida, Coccidiasina, Apicomplexa) causing systemic coccidiosis in domestic Canaries (Serinus canaria Linn.). AB - We report a complete mitochondrial genome sequence for an Isospora sp. causing systemic coccidiosis in canaries, Serinus canaria. The A + T rich (65.2%) genome was 6216 bp in length and possessed 3 protein-coding genes, (COI; COIII and CytB), 19 LSU and 14 SSU rDNA fragments, including 1 newly identified putative LSU fragment. Arrangement of coding regions was identical to that of available Eimeria sp. mt genomes and start codon usage for protein-coding genes was conventional. The similar mitochondrial genome sequences and structures of Isospora and Eimeria species confirm the close relationship between these eimeriid genera of apicomplexan parasites. PMID- 25714149 TI - Complete DNA sequence of the mitochondrial genome of the treehopper Leptobelus gazella (Membracoidea: Hemiptera). AB - The first complete DNA sequence of the mitochondrial genome (mitogenome) of Leptobelus gazelle (Membracoidea: Hemiptera) is determined in this study. The circular molecule is 16,007 bp in its full length, which encodes a set of 37 genes, including 13 proteins, 2 ribosomal RNAs, 22 transfer RNAs, and contains an A + T-rich region (CR). The gene numbers, content, and organization of L. gazelle are similar to other typical metazoan mitogenomes. Twelve of the 13 PCGs are initiated with ATR methionine or ATT isoleucine codons, except the atp8 gene that uses the ATC isoleucine as start signal. Ten of the 13 PCGs have complete termination codons, either TAA (nine genes) or TAG (cytb). The remaining 3 PCGs (cox1, cox2 and nad5) have incomplete termination codons T (AA). All of the 22 tRNAs can be folded in the form of a typical clover-leaf structure. The complete mitogenome sequence data of L. gazelle is useful for the phylogenetic and biogeographic studies of the Membracoidea and Hemiptera. PMID- 25714150 TI - Complete mitochondrial genome of Acrossocheilus parallens (Cypriniformes, Barbinae). AB - The omnivorous fish Acrossocheilus parallens (Cypriniformes, Barbinae) is endemic to China. In this paper, the complete mitochondrial genome sequence of A. parallens was firstly determined. The circle genome (16,592 bp) comprises 13 protein-coding genes, 22 tRNA genes, 2 rRNA genes and 1 control region. The overall base composition of A. parallens is 31.0% for A, 24.7% for T, 28.0% for C, and 16.3% for G, with a slight A + T bias of 55.7%. The termination-associated sequence and conserved sequence block domains were found in the control region. It has the typical vertebrate mitochondrial gene arrangement. PMID- 25714151 TI - The complete mitochondrial genome of silver fox (Caniformia: Canidae). AB - Silver fox is color variant of Vulpes vulpes. At present, there are few studies on phylogeny of Canidae and Caniformia. In this article, we determined and described the complete mitogenome of silver fox for the first time, which is 16,723 bp in length, containing 13 protein-coding genes, 2 rRNA genes, 22 tRNA genes, one origin of replication on the light-strand (OL) and a putative control region (CR). The overall base composition is 31.4% A, 27.9% T, 26.0% C, 14.7% G, respectively, with a AT bias (59.3%). Ten protein-coding genes use the initiation codon ATG while ND2, ND3 and ND5 use ATA. Most of them have TAA as the stop codon, except ND2 uses TAG, Cytb uses AGA, and COX3, ND3, ND4 use an incomplete stop codon TA. The information is expected to provide useful molecular data for further taxonomic and phylogenetic studies of Canidae and Caniformia. PMID- 25714152 TI - Complete mitochondrial genome of Gnathopogon taeniellus (Cypriniformes: Cyprinidae). AB - The complete mitochondrial genome of Gnathopogon taeniellus was first determined in this study. It is 16,596 bp in length, contains 13 protein-coding genes, 2 rRNA genes, 22 tRNA genes and one control region in the typical vertebrate gene order and transcriptional direction. There are total of 29 bp short overlaps and 34 bp non-coding intergenic spacers were found in the mitogenome. Overall nucleotide base composition of light strand is 29.3% A, 25.8% C, 17.9% G and 27.0% T. Two start codons (ATG and GTG) and two stop codons (TAG and TAA/T) were used in the protein-coding genes. The origin of light strand replication (OL) was identified between tRNA(Asn) and tRNA(Cys) genes and could fold a hairpin structure. The nucleotide composition of control region is 31.8% A, 20.9% C, 14.0% G and 33.3% T. PMID- 25714153 TI - The complete mitochondrial genome of longfin yellowtail S. rivoliana (Perciformes: Carangidae). AB - The complete mitochondrial genome of the longfin yellowtail Seriola rivoliana (Perciformes: Carangidae) was obtained in this study. The entire genome was sequenced via primer walking after long PCRs. The size of the genome was 16,530 bp in length, containing the usual 2 rRNA genes, 13 protein-coding genes, 22 tRNA genes, and one non-coding control region. The genome composition and gene order were similar to most vertebrates. Most mitochondrial genes (excepted for ND6 and eight tRNA genes) were encoded on the heavy strand. The complete mitogenome of S. rivoliana could provide a basic data for studies on species identification, molecular systematics and conservation genetics. PMID- 25714154 TI - Characterization of the complete mitochondrial genome of the firefly, Luciola substriata (Coleoptera: Lampyridae). AB - The firefly, Luciola substriata (Coleoptera: Lampyridae), is an aquatic firefly species, whose larvae inhabit ponds or lakes. Here we present the complete mitochondrial (mt) genome of the firefly (GenBank accession number KP313820) and provide its annotation. This circular genome is 16,248 bp in length and contains 13 protein-coding genes, 22 transfer RNA genes, 2 ribosomal RNA genes, and a non coding AT-rich region. Similar to other firefly species, the base composition of this mitochondrial genome is also biased toward A and T (44.09% A, 34.00% T, 12.89% C, and 9.01% G). All 13 protein-coding genes start with a typical mitochondrial start codon, and terminate with a usual stop codon TAA, or TAG or a single T. The non-coding AT-rich region (1636 bp in length) include one (A)20, and two (T)15 tandem repeats, and one (AAT)5 element. This mitochondrial genome sequence will promote a better understanding for firefly evolution in the future. PMID- 25714155 TI - The complete mitochondrial genome of Caryospora bigenetica (Eimeriidae, Eucoccidiorida, Coccidiasina, Apicomplexa). AB - The 6313 bp complete mitochondrial (mt) genome of Caryospora bigenetica was sequenced directly from PCR products. The mt genome was comparable in size, gene content and order to those of other Eimeriid coccidia (e.g. Isospora or Eimeria species). Three protein-coding genes encoding COI, COIII and CytB were identified; numerous rDNA fragments (19 LSU and 14 SSU) were interspersed among the CDS. Nucleotide composition was A + T biased (66%). The mitochondrial genomes of Eimeriid coccidia appear to share the same gene order and content; mt genome sequences can provide molecular data useful for diagnostics, taxonomy and phylogenetic relationships of Eimeriid coccidia. PMID- 25714156 TI - The mitochondrial genomes of the caddisflies Sericostoma personatum and Thremma gallicum (Insecta: Trichoptera). AB - The mitochondrial genomes of the caddisfly species Sericostoma personatum and Thremma gallicum were sequenced on a 454 FLX and Illumina MiSeq platform, respectively. Reads were assembled de novo and remaining gaps in the S. personatum mitogenome closed by Sanger sequencing. The lengths of the assembled mitogenomes were 15,260 bp and 15,343 bp for S. personatum and T. gallicum, respectively. Both mitogenomes contained all 13 protein-coding genes, two ribosomal RNA genes, 22 transfer RNA genes, and the control region. The mitochondrial gene order of both caddisflies is identical with the typical insect gene order. These are the third and fourth published mitogenomes of the order Trichoptera of two formerly unexplored families and thus will be useful in future phylogenetic analysis. PMID- 25714157 TI - Anesthetic neurotoxicity--clinical implications of animal models. AB - Some anesthetics and sedatives have been shown to cause neurotoxic effects in laboratory animals. The FDA collaboration SmartTots recommends undertaking large scale clinical studies and avoiding nonurgent surgical procedures requiring anesthesia in children younger than 3 years of age. PMID- 25714158 TI - In memory of Daniel--reviving research to prevent gun violence. PMID- 25714159 TI - Outcomes of pregnancy after bariatric surgery. AB - BACKGROUND: Maternal obesity is associated with increased risks of gestational diabetes, large-for-gestational-age infants, preterm birth, congenital malformations, and stillbirth. The risks of these outcomes among women who have undergone bariatric surgery are unclear. METHODS: We identified 627,693 singleton pregnancies in the Swedish Medical Birth Register from 2006 through 2011, of which 670 occurred in women who had previously undergone bariatric surgery and for whom presurgery weight was documented. For each pregnancy after bariatric surgery, up to five control pregnancies were matched for the mother's presurgery body-mass index (BMI; we used early-pregnancy BMI in the controls), age, parity, smoking history, educational level, and delivery year. We assessed the risks of gestational diabetes, large-for-gestational-age and small-for-gestational-age infants, preterm birth, stillbirth, neonatal death, and major congenital malformations. RESULTS: Pregnancies after bariatric surgery, as compared with matched control pregnancies, were associated with lower risks of gestational diabetes (1.9% vs. 6.8%; odds ratio, 0.25; 95% confidence interval [CI], 0.13 to 0.47; P<0.001) and large-for-gestational-age infants (8.6% vs. 22.4%; odds ratio, 0.33; 95% CI, 0.24 to 0.44; P<0.001). In contrast, they were associated with a higher risk of small-for-gestational-age infants (15.6% vs. 7.6%; odds ratio, 2.20; 95% CI, 1.64 to 2.95; P<0.001) and shorter gestation (273.0 vs. 277.5 days; mean difference -4.5 days; 95% CI, -2.9 to -6.0; P<0.001), although the risk of preterm birth was not significantly different (10.0% vs. 7.5%; odds ratio, 1.28; 95% CI, 0.92 to 1.78; P=0.15). The risk of stillbirth or neonatal death was 1.7% versus 0.7% (odds ratio, 2.39; 95% CI, 0.98 to 5.85; P=0.06). There was no significant between-group difference in the frequency of congenital malformations. CONCLUSIONS: Bariatric surgery was associated with reduced risks of gestational diabetes and excessive fetal growth, shorter gestation, an increased risk of small-for-gestational-age infants, and possibly increased mortality. (Funded by the Swedish Research Council and others.). PMID- 25714160 TI - Burden of Clostridium difficile infection in the United States. AB - BACKGROUND: The magnitude and scope of Clostridium difficile infection in the United States continue to evolve. METHODS: In 2011, we performed active population- and laboratory-based surveillance across 10 geographic areas in the United States to identify cases of C. difficile infection (stool specimens positive for C. difficile on either toxin or molecular assay in residents >= 1 year of age). Cases were classified as community-associated or health care associated. In a sample of cases of C. difficile infection, specimens were cultured and isolates underwent molecular typing. We used regression models to calculate estimates of national incidence and total number of infections, first recurrences, and deaths within 30 days after the diagnosis of C. difficile infection. RESULTS: A total of 15,461 cases of C. difficile infection were identified in the 10 geographic areas; 65.8% were health care-associated, but only 24.2% had onset during hospitalization. After adjustment for predictors of disease incidence, the estimated number of incident C. difficile infections in the United States was 453,000 (95% confidence interval [CI], 397,100 to 508,500). The incidence was estimated to be higher among females (rate ratio, 1.26; 95% CI, 1.25 to 1.27), whites (rate ratio, 1.72; 95% CI, 1.56 to 2.0), and persons 65 years of age or older (rate ratio, 8.65; 95% CI, 8.16 to 9.31). The estimated number of first recurrences of C. difficile infection was 83,000 (95% CI, 57,000 to 108,900), and the estimated number of deaths was 29,300 (95% CI, 16,500 to 42,100). The North American pulsed-field gel electrophoresis type 1 (NAP1) strain was more prevalent among health care-associated infections than among community associated infections (30.7% vs. 18.8%, P<0.001). CONCLUSIONS: C. difficile was responsible for almost half a million infections and was associated with approximately 29,000 deaths in 2011. (Funded by the Centers for Disease Control and Prevention.). PMID- 25714162 TI - 2014 MERS-CoV outbreak in Jeddah--a link to health care facilities. AB - BACKGROUND: A marked increase in the number of cases of Middle East respiratory syndrome coronavirus (MERS-CoV) infection occurred in Jeddah, Saudi Arabia, in early 2014. We evaluated patients with MERS-CoV infection in Jeddah to explore reasons for this increase and to assess the epidemiologic and clinical features of this disease. METHODS: We identified all cases of laboratory-confirmed MERS CoV infection in Jeddah that were reported to the Saudi Arabian Ministry of Health from January 1 through May 16, 2014. We conducted telephone interviews with symptomatic patients who were not health care personnel, and we reviewed hospital records. We identified patients who were reported as being asymptomatic and interviewed them regarding a history of symptoms in the month before testing. Descriptive analyses were performed. RESULTS: Of 255 patients with laboratory confirmed MERS-CoV infection, 93 died (case fatality rate, 36.5%). The median age of all patients was 45 years (interquartile range, 30 to 59), and 174 patients (68.2%) were male. A total of 64 patients (25.1%) were reported to be asymptomatic. Of the 191 symptomatic patients, 40 (20.9%) were health care personnel. Among the 151 symptomatic patients who were not health care personnel, 112 (74.2%) had data that could be assessed, and 109 (97.3%) of these patients had had contact with a health care facility, a person with a confirmed case of MERS-CoV infection, or someone with severe respiratory illness in the 14 days before the onset of illness. The remaining 3 patients (2.7%) reported no such contacts. Of the 64 patients who had been reported as asymptomatic, 33 (52%) were interviewed, and 26 of these 33 (79%) reported at least one symptom that was consistent with a viral respiratory illness. CONCLUSIONS: The majority of patients in the Jeddah MERS-CoV outbreak had contact with a health care facility, other patients, or both. This highlights the role of health care-associated transmission. (Supported by the Ministry of Health, Saudi Arabia, and by the U.S. Centers for Disease Control and Prevention.). PMID- 25714163 TI - Enduring and emerging challenges of informed consent. AB - The author summarizes emerging standards for informed consent as the underpinning of ethical research in humans. PMID- 25714161 TI - Community-acquired pneumonia requiring hospitalization among U.S. children. AB - BACKGROUND: Incidence estimates of hospitalizations for community-acquired pneumonia among children in the United States that are based on prospective data collection are limited. Updated estimates of pneumonia that has been confirmed radiographically and with the use of current laboratory diagnostic tests are needed. METHODS: We conducted active population-based surveillance for community acquired pneumonia requiring hospitalization among children younger than 18 years of age in three hospitals in Memphis, Nashville, and Salt Lake City. We excluded children with recent hospitalization or severe immunosuppression. Blood and respiratory specimens were systematically collected for pathogen detection with the use of multiple methods. Chest radiographs were reviewed independently by study radiologists. RESULTS: From January 2010 through June 2012, we enrolled 2638 of 3803 eligible children (69%), 2358 of whom (89%) had radiographic evidence of pneumonia. The median age of the children was 2 years (interquartile range, 1 to 6); 497 of 2358 children (21%) required intensive care, and 3 (<1%) died. Among 2222 children with radiographic evidence of pneumonia and with specimens available for bacterial and viral testing, a viral or bacterial pathogen was detected in 1802 (81%), one or more viruses in 1472 (66%), bacteria in 175 (8%), and both bacterial and viral pathogens in 155 (7%). The annual incidence of pneumonia was 15.7 cases per 10,000 children (95% confidence interval [CI], 14.9 to 16.5), with the highest rate among children younger than 2 years of age (62.2 cases per 10,000 children; 95% CI, 57.6 to 67.1). Respiratory syncytial virus was more common among children younger than 5 years of age than among older children (37% vs. 8%), as were adenovirus (15% vs. 3%) and human metapneumovirus (15% vs. 8%). Mycoplasma pneumoniae was more common among children 5 years of age or older than among younger children (19% vs. 3%). CONCLUSIONS: The burden of hospitalization for children with community-acquired pneumonia was highest among the very young, with respiratory viruses the most commonly detected causes of pneumonia. (Funded by the Influenza Division of the National Center for Immunization and Respiratory Diseases.). PMID- 25714164 TI - Images in clin medicine: Femoral-head dislocation to the scrotum. AB - A 33-year-old man was admitted to the emergency department after a motorcycle accident. Examination of the intubated patient showed a hard, swollen, bluish scrotum and an externally rotated and slightly shortened left leg. PMID- 25714165 TI - Case Records of the Mass General Hospital. Case 7-2015: A 25-year-old man with oral ulcers, rash, and odynophagia. AB - A 25-year-old man presented with oral ulcers and odynophagia. On examination, there were scattered pink papules and plaques on the trunk, thighs, and buttocks and multiple raised, erythematous nodules on both shins. A diagnostic procedure was performed. PMID- 25714166 TI - Guns, society, and medicine. AB - Given the 96 incidents of firearm violence on school campuses since Sandy Hook and the ongoing toll on lives and health, the lack of relevant data and a research pipeline in this area should be anathema to all physicians. PMID- 25714167 TI - Bariatric surgery before pregnancy--is this a solution to a big problem? PMID- 25714168 TI - Glycemic control and excess mortality in type 1 diabetes. PMID- 25714169 TI - Glycemic control and excess mortality in type 1 diabetes. PMID- 25714170 TI - Glycemic control and excess mortality in type 1 diabetes. PMID- 25714171 TI - Glycemic control and excess mortality in type 1 diabetes. PMID- 25714173 TI - Mutations in NPC1L1 and coronary heart disease. PMID- 25714174 TI - Mutations in NPC1L1 and coronary heart disease. PMID- 25714175 TI - Mutations in NPC1L1 and coronary heart disease. PMID- 25714176 TI - Mutations in NPC1L1 and coronary heart disease. PMID- 25714177 TI - The concept of risk in comparative effectiveness research. PMID- 25714178 TI - The concept of risk in comparative effectiveness research. PMID- 25714179 TI - The concept of risk in comparative effectiveness research. PMID- 25714180 TI - Outpatient oral treatment for acute promyelocytic leukemia. PMID- 25714181 TI - Outpatient oral treatment for acute promyelocytic leukemia. PMID- 25714185 TI - Images in clin medicine: Ectopia lentis. AB - A 31-year-old woman with Marfan's syndrome presented with amblyopia and a history of gradual bilateral vision loss over the previous 3 to 4 months. She had also had mild sensorineural hearing loss within the previous 2 weeks. PMID- 25714186 TI - Relationship between illness uncertainty, anxiety, fear of progression and quality of life in men with favourable-risk prostate cancer undergoing active surveillance. AB - OBJECTIVES: To evaluate prospectively the associations between illness uncertainty, anxiety, fear of progression and general and disease-specific quality of life (QoL) in men with favourable-risk prostate cancer undergoing active surveillance (AS). PATIENTS AND METHODS: After meeting stringent enrollment criteria for an AS cohort study at a single tertiary care cancer centre, 180 men with favourable-risk prostate cancer completed questionnaires at the time of enrollment and every 6 months for up to 30 months. Questionnaires assessed illness uncertainty, anxiety, prostate-specific QoL (using the Expanded Prostate Cancer Index Composite [EPIC] scale) and general QoL (using the 12-time short-form health survey [SF-12]) and fear of progression. We used linear mixed model analyses and multilevel mediation analyses. RESULTS: Sexual scores on the EPIC scale significantly declined over time (P < 0.05). Illness uncertainty was a significant predictor of all EPIC summary scores, SF-12 physical component summary (PCS) scores, mental component summary (MCS) scores and fear of progression scores (all P < 0.05), after controlling for demographic and clinicopathological factors. Anxiety predicted all EPIC summary, MCS and fear of progression scores (all P < 0.05) but not PCS scores (P = 0.08). Scores on PCS, MCS, EPIC summary scales (except sexual scale), and fear of progression did not change significantly over the study period (all P > 0.10). CONCLUSION: Over the 2.5-year follow-up, QoL remained stable; only sexual function scores significantly declined. Illness uncertainty and anxiety were significant predictors of general and prostate-specific QoL and fear of progression. Interventions to reduce uncertainty and anxiety may enhance QoL for men with prostate cancer on AS. PMID- 25714187 TI - Fate of growth plate hypertrophic chondrocytes: death or lineage extension? AB - The vertebrate growth plate is an essential tissue that mediates and controls bone growth. It forms through a multistep differentiation process in which chondrocytes differentiate, proliferate, stop dividing and undergo hypertrophy, which entails a 20-fold increase in size. Hypertrophic chondrocytes are specialized cells considered to be the end state of the chondrocyte differentiation pathway, and are essential for bone growth. They are characterized by expression of type X collagen encoded by the Col10a1 gene, and synthesis of a calcified cartilage matrix. Whether hypertrophy marks a transition preceding osteogenesis, or it is the terminal differentiation stage of chondrocytes with cell death as the ultimate fate has been the subject of debate for over a century. In this review, we revisit this debate in the light of new findings arising from genetic-mediated lineage tracing studies showing that hypertrophic chondrocytes can survive at the chondro-osseous junction and further make the transition to become osteoblasts and osteocytes. The contribution of chondrocytes to the osteoblast lineage has important implications in bone development, disease and repair. PMID- 25714189 TI - [Risk factors affecting life expectancy]. PMID- 25714188 TI - 24 year outcomes of hepatitis B vaccination in Hangzhou, China. AB - To evaluate the impact of the universal infant HepB vaccination program on hepatitis B virus infection in Hangzhou, China. Hepatitis B incidences and HepB vaccination rates of Hangzhou from 1990 to 2003 were acquired from the historical paper-documents, while which were derived from China Information System for Diseases Control and Prevention and Zhejiang Information System for Immunization Program respectively from 2004 to 2013. A serology survey among person aged 0-59 y was conducted in Hangzhou in 2006. Participants were selected by stratified, multi-stage random sampling. Serum specimens were tested for HBsAg, anti-HBs , anti-HBc , HBeAg and anti-HBe by ELISA. For the past 24 years, hepatitis B incidence and mortality of Hangzhou declined dramatically (chi(2) = 3.2 * 10(4); chi(2) = 172.443; both P for trend < 0.001). Both urban and rural incidence descended (chi(2)urban = 1.904 * 10(4); chi(2)rural = 1.633 * 10(4) ; both P for trend < 0.001).Hepatitis B patients mainly concentrated in 20-40 y old; workers and farmers were the main infection occupations, which was varies in different years (chi(2) = 1.619 * 10(3), P < 0.001). Significant association was found between incidence of hepatitis B and HepB vaccination rate (r = 0 .946, chi(2) = 11.813, Pfor trend = 0.001). A total of 5605 participants aged 0-59 y included in this serological survey. The prevalence of HBsAg, anti-HBs, anti-HBc, HBeAg and anti-HBe were 6.19%, 45.83%, 57.25%, 0.62%, and 4.37%, respectively. Hangzhou has successfully integrated the HepB into routine immunization programs and this has had a significant impact on decreasing the incidence of hepatitis B infection. PMID- 25714190 TI - [Wilfried Lorenz Health Services Research Award]. PMID- 25714191 TI - [Long-distance travelers importing pathogens]. PMID- 25714192 TI - [Good tasting is half the battle: it could all be so simple, but it's not]. PMID- 25714193 TI - [Deterministic record linkage with indirect identifiers: data of the Berlin Myocardial Infarction Registry and the AOK Nordost for patients with myocardial infarction]. AB - AIM OF THE STUDY: How can 2 pseudonymised data sets be linked? Using the example of data from the Berlin Myocardial Infarction Registry and from a German sickness fund (AOK Nordost) we will demonstrate how record linkage can be achieved without personal identifiers. METHODS: In different steps the method of deterministic record linkage with indirect identifiers: age, sex, hospital admission date and time, will be explained. RESULTS: We were able to show that 80.6% of the expected maximum number of patients were matched with our approach. As a result we had no duplicate matches in the linkage process, where one AOK patient was linked to 2 or more BMIR patients or vice versa. The matching variables produced enough uniqueness to be used as indirect patient identifiers. CONCLUSION: Deterministic record linkage with the following indirect indicators: age, sex, hospital admission date and time was possible in our study of patients with myocardial infarction in a circumscribed geographical region, which limited the number of cases and avoided mismatches. PMID- 25714194 TI - [Integration of primary and secondary data in the Study of Health in Pomerania and description of clinical outcomes using stroke as an example]. AB - OBJECTIVE: This study describes (i) the procedure of obtaining patients' consent for secondary data usage, (ii) the complexity of integrating data from multiple sources, and (iii) the correspondence among patients' self-reports, physician reports, routine data, hospital discharge diagnosis, and cause-of-death coding regarding stroke. METHODS: Data from the first follow-up (N=3 186) of the population-based Study of Health in Pomerania (SHIP) were used. These data were combined with secondary data from the Greifswald University Hospital, the association of statutory health insurance physicians Mecklenburg-Western Pomerania, physician reports, and death certificates. RESULTS: Consent for using health-related information from all data sources in question was obtained from more than 90% of the SHIP participants. Follow-up data from at least one source were available for 2 747 (86%) participants. For 92 participants information about the occurrence of stroke was found in at least one data source. In 59 cases the event appeared in only one data source, in 24 cases the event was found in 2 sources, and for 9 participants 3 data sources reported on the event. CONCLUSION: Participants of a population-based cohort are highly willing to give consent for using their health-related information from secondary data sources. Yet, data integration is challenging due to considerable differences in data type, structure and coverage. PMID- 25714197 TI - Assessment of Myocardial Ischemia in Obese Individuals Undergoing Physical Stress Echocardiography (PSE). AB - BACKGROUND: Physical stress echocardiography is an established methodology for diagnosis and risk stratification of coronary artery disease in patients with physical capacity. In obese (body mass index >= 30 kg/m2) the usefulness of pharmacological stress echocardiography has been demonstrated; however, has not been reported the use of physical stress echocardiography in this growing population group. OBJECTIVE: To assess the frequency of myocardial ischemia in obese and non-obese patients undergoing physical stress echocardiography and compare their clinical and echocardiographic differences. METHODS: 4,050 patients who underwent treadmill physical stress echocardiography were studied according to the Bruce protocol, divided into two groups: obese (n = 945; 23.3%) and non obese (n = 3,105; 76.6%). RESULTS: There was no difference regarding gender. Obese patients were younger (55.4 +/- 10.9 vs. 57.56 +/- 11.67) and had a higher frequency of hypertension (75.2% vs. 57, 2%; p < 0.0001), diabetis mellitus (15.2% vs. 10.9%; p < 0.0001), dyslipidemia (59.5% vs 51.9%; p < 0.0001), family history of coronary artery disease (59.3% vs. 55.1%; p = 0.023) and physical inactivity (71.4% vs. 52.9%, p < 0.0001). The obese had greater aortic dimensions (3.27 vs. 3.14 cm; p < 0.0001), left atrium (3.97 vs. 3.72 cm; p < 0.0001) and the relative thickness of the ventricule (33.7 vs. 32.8 cm; p < 0.0001). Regarding the presence of myocardial ischemia, there was no difference between groups (19% vs. 17.9%; p = 0.41). In adjusted logistic regression, the presence of myocardial ischemia remained independently associated with age, female gender, diabetes and hypertension. CONCLUSION: Obesity did not behave as a predictor of the presence of ischemia and the physical stress echocardiography. The application of this assessment tool in large scale sample demonstrates the feasibility of the methodology, also in obese. PMID- 25714198 TI - Adib Jatene: June 4, 1929 November 14, 2014. PMID- 25714199 TI - New contribution to the study of ventricular remodeling and valve rings in dilated cardiomyopathy: anatomical and histological evaluation. AB - INTRODUCTION: Idiopathic dilated cardiomyopathy causes great impact but many aspects of its pathophysiology remain unknown. OBJECTIVE: To evaluate anatomical and histological aspects of hearts with idiopathic dilated cardiomyopathy and compare them to a control group, evaluating the behavior of the perimeters of the atrioventricular rings and ventricles and to compare the percentage of collagen and elastic fibers of the atrioventricular rings. METHODS: Thirteen hearts with cardiomyopathy and 13 normal hearts were analysed. They were dissected keeping the ventricular mass and atrioventricular rings, with lamination of segments 20%, 50% and 80% of the distance between the atrioventricular groove and the ventricular apex. The sections were subjected to photo scanning, with measurement of perimeters. The atrioventricular rings were dissected and measured digitally to evaluate their perimeters, later being sent to the pathology laboratory, and stained by hematoxylin-eosin, picrosirius and oxidized resorcin fuccin. RESULTS: Regarding to ventricles, dilation occurs in all segments in the pathological group, and the right atrioventricular ring measurement was higher in idiopathic dilated cardiomyopathy group, with no difference in the left side. With respect to collagen, both sides had lower percentage of fibers in the pathological group. With respect to the elastic fibers, there was no difference between the groups. CONCLUSION: There is a change in ventricular geometry in cardiomyopathy group. The left atrioventricular ring does not dilate, in spite of the fact that in both ventricles there is lowering of collagen. PMID- 25714200 TI - Risk factors of atheromatous aorta in cardiovascular surgery. AB - OBJECTIVE: To determine the prevalence and profile of ascending aorta or aortic arch atheromatous disease in cardiovascular surgery patients, its risk factors and its prognostic implication early after surgery. METHODS: Between January 2007 and June 2011, 2042 consecutive adult patients were analyzed, with no exclusion criteria. Atheromatous aorta diagnosis was determined intraoperatively by surgeon palpation of the aorta. Determinants of atheromatous aorta, as well as its prognostic implication were studied by multivariate logistic regression. RESULTS: Prevalence of atheromatous aorta was 3.3% (68 patients). Determinants were age > 61 years (OR= 2.79; CI95%= 2.43 - 3.15; P<0.0001), coronary artery disease (OR=3.1; CI95%=2.8 - 3.44; P=0.002), hypertension (OR=2.26; CI95%=1.82 - 2.7; P=0.03) and peripheral vascular disease (OR=3.15; CI95%= 2.83 - 3.46; P=0.04). Atheromatous aorta was an independent predictor of postoperative cerebrovascular accident (OR=3.46; CI95%=3.18 - 3.76; P=0.01). CONCLUSION: Although infrequent, the presence of atheromatous aorta is associated with advanced age, hypertension, coronary artery disease and peripheral vascular disease. In those patients, a more detailed preoperative and intraoperative assessment of the aorta is justified, due to greater risk of postoperative cerebrovascular accident. PMID- 25714201 TI - Aortic Center: specialized care improves outcomes and decreases mortality. AB - OBJECTIVE: To compare in-hospital outcomes in aortic surgery in our cardiac surgery unit, before and after foundation of our Center for Aortic Surgery (CTA). METHODS: Prospective cohort with non-concurrent control. Foundation of CTA required specialized training of surgical, anesthetic and intensive care unit teams, routine neurological monitoring, endovascular and hybrid facilities, training of the support personnel, improvement of the registry and adoption of specific protocols. We included 332 patients operated on between: January/2003 to December/2007 (before-CTA, n=157, 47.3%); and January/2008 to December/2010 (CTA, n=175, 52.7%). Baseline clinical and demographic data, operative variables, complications and in-hospital mortality were compared between both groups. RESULTS: Mean age was 58+/-14 years, with 65% male. Group CTA was older, had higher rate of diabetes, lower rates of COPD and HF, more non-urgent surgeries, endovascular procedures, and aneurysms. In the univariate analysis, CTA had lower mortality (9.7 vs. 23.0%, P=0.008), which occurred consistently across different diseases and procedures. Other outcomes which were reduced in CTA included lower rates of reinterventions (5.7 vs 11%, P=0.046), major complications (20.6 vs. 33.1%, P=0.007), stroke (4.6 vs. 10.9%, P=0.045) and sepsis (1.7 vs. 9.6%, P=0.001), as compared to before-CTA. Multivariable analysis adjusted for potential confounders revealed that CTA was independently associated with mortality reduction (OR=0.23, IC 95% 0.08 - 0.67, P=0.007). CTA independent mortality reduction was consistent in the multivariable analysis stratified by disease (aneurysm, OR=0.18, CI 95% 0.03 - 0.98, P=0.048; dissection, OR=0.31, CI 95% 0.09 - 0.99, P=0.049) and by procedure (hybrid, OR=0.07, CI 95% 0.007 - 0.72, P=0.026; Bentall, OR=0.18, CI 95% 0.038 - 0.904, P=0.037). Additional multivariable predictors of in-hospital mortality included creatinine (OR=1.7 [1.1-2.6], P=0.008), urgent surgery (OR=5.0 [1.5-16.7], P=0.008) and thoracoabdominal aneurysm (OR=24.6 [3.1-194.1], P=0.002). CONCLUSION: Thoracic aorta surgery in specialized center was associated with lower incidence of complications and all-cause mortality as compared to usual care. PMID- 25714202 TI - Comparison of two surgical techniques for creating an acute myocardial infarct in rats. AB - OBJECTIVE: To perform a comparative assessment of two surgical techniques that are used creating an acute myocardial infarc by occluding the left anterior descending coronary artery in order to generate rats with a left ventricular ejection fraction of less than 40%. METHODS: The study was completely randomized and comprised 89 halothane-anaesthetised rats, which were divided into three groups. The control group (SHAM) comprised fourteen rats, whose left anterior descending coronary artery was not occluded. Group 1 (G1): comprised by 35 endotracheally intubated and mechanically ventilated rats, whose left anterior descending coronary artery was occluded. Group 2 (G2): comprised 40 rats being manually ventilated using a nasal respirator whose left anterior descending coronary artery was occluded. Other differences between the two techniques include the method of performing the thoracotomy and removing the pericardium in order to expose the heart, and the use of different methods and suture types for closing the thorax. Seven days after surgery, the cardiac function of all surviving rats was determined by echocardiography. RESULTS: No rats SHAM group had progressed to death or had left ventricular ejection fraction less than 40%. Nine of the 16 surviving G1 rats (56.3%) and six of the 20 surviving G2 rats (30%) had a left ventricular ejection fraction of less than 40%. CONCLUSION: The results indicate a tendency of the technique used in G1 to be better than in G2. This improvement is probably due to the greater duration of the open thorax, which reduces the pressure over time from the surgeon, allowing occlusion of left anterior descending coronary artery with higher accuracy. PMID- 25714203 TI - Risk factors for mortality of patients undergoing coronary artery bypass graft surgery. AB - INTRODUCTION: Coronary artery bypass grafting is a safe procedure performed worldwide with low rates of mortality and morbidity in general population. OBJECTIVE: To investigate risk factors for mortality of patients undergoing coronary artery bypass grafting coronary artery bypass grafting surgery. METHODS: A total of 1,628 consecutive patients undergoing on-pump coronary artery bypass grafting were retrospectively studied from December 1999 to February 2012. Data analysis involved paired Student t test, Mann-Whitney test and Fisher's exact test for the categorical data. Logistic regression, Odds Ratio and 95%CI were used for definition of risk factors for mortality. RESULTS: Of a total of 1,628 patients undergoing on-pump coronary artery bypass grafting, 141 (8.7%) died. The following risk factors for mortality were identified after logistic regression: dialysis (OR=7.61; 95%CI 3.58-16.20), neurologic dysfunction type I (OR=4.42; 95%CI 2.48-7.81), use of IABP (OR=3.38; 95%CI 1.98-5.79), cardiopulmonary bypass time (OR=3.09; 95%CI 2.04-4.68), serum creatinine on admission and peak values > 0.4mg/dL (OR=2.67; 95%CI 1.79-4.00), age > 65 years (OR=2.31; 95%CI 1.55-3.44), and time between hospital admission and and surgical procedure (OR=1.53; 95%CI 1.03-2.27). CONCLUSION: Dialysis, type I neurologic dysfunction, use of IABP, cardiopulmonary bypass time (> 115 minutes), serum creatinine on admission and peak values>0.4mg/dL, age > 65 years and time between hospital admission and surgical procedure were considered as risk factors for mortality in patients undergoing on-pump coronary artery bypass grafting surgery. PMID- 25714204 TI - Very short cycles of postconditioning have no protective effect against reperfusion injury. Experimental study in rats. AB - INTRODUCTION: Ischemic postconditioning has been recognized as effective in the prevention of reperfusion injury in situations of ischemia and reperfusion in various organs and tissues. However, it remains unclear what would be the best way to accomplish it, since studies show great variation in the method of their application. OBJECTIVE: To assess the protective effect of ischemic postconditioning on ischemia and reperfusion in rats undergoing five alternating cycles of reperfusion and ischemia of 30 seconds each one. METHODS: We studied 25 Wistar rats distributed in three groups: group A (10 rats), which underwent mesenteric ischemia (30 minutes) and reperfusion (60 minutes); Group B (10 rats), undergoing ischemia (30 minutes) and reperfusion (60 minutes), intercalated by postconditioning (5 alternating cycles of reperfusion and ischemia of 30 seconds each one); and group C - SHAM (5 rats), undergoing only laparotomy and manipulation of mesenteric artery. All animals underwent resection of an ileum segment for histological analysis. RESULTS: The mean lesions degree according to Chiu et al. were: group A, 2.77, group B, 2.67 and group C, 0.12. There was no difference between groups A and B (P>0.05). CONCLUSION: Ischemic postconditioning was not able to minimize or prevent the intestinal tissue injury in rats undergoing ischemia and reperfusion process when used five cycles lasting 30 seconds each one. PMID- 25714205 TI - Hybrid treatment of aortic arch disease. AB - INTRODUCTION: The management of thoracic aortic disease involving the ascending aorta, aortic arch and descending thoracic aorta are technically challenging and is an area in constant development and innovation. OBJECTIVE: To analyze early and midterm results of hybrid treatment of arch aortic disease. METHODS: Retrospective study of procedures performed from January 2010 to December 2012. The end points were the technical success, therapeutic success, morbidity and mortality, neurologic outcomes, the rate of endoleaks and reinterventions. RESULTS: A total of 95 patients treated for thoracic aortic diseases in this period, 18 underwent hybrid treatment and entered in this study. The average ages were 62.3 years. The male was present in 66.7%. The technical and therapeutic success was 94.5% e 83.3%. The perioperative mortality rate of 11.1%. There is any death during one-year follow- up. The reoperation rates were 16.6% due 2 cases of endoleak Ia and one case of endoleak II. There is any occlusion of anatomic or extra anatomic bypass during follow up. CONCLUSION: In our study, the hybrid treatment of aortic arch disease proved to be a feasible alternative of conventional surgery. The therapeutic success rates and re- interventions obtained demonstrate the necessity of thorough clinical follow-up of these patients in a long time. PMID- 25714207 TI - Graft pathology at the time of harvest: impact on long-term survival. AB - OBJECTIVE: This study aims to present the graft pathology at the time of harvest and its impact on long-term survival. METHODS: The remnants of the bypass grafts from 66 consecutive patients with coronary artery disease receiving a coronary artery bypass grafting were investigated pathologically, and pertinent predictive risk factors and survival were analyzed. RESULTS: Medial degenerative changes with or without intimal proliferation were present in 36.8%, 37.8% and 35.6% of left internal mammary artery (IMA), radial artery and saphenous vein grafts. There were 2 (3.0%) hospital deaths and 9 (14.1%) late deaths. Multinomial logistic regression revealed left IMA pathological changes, dyslipidemia, history of percutaneous transluminal coronary angioplasty/stent deployment and Y-graft were significant predictive risk factors negatively influencing the patients' long-term survival. Kaplan-Meier survival analysis revealed that the long-term survival of patients with left IMA pathological changes were significantly reduced compared with those without (74.1% vs. 91.4%, P=0.002); whereas no differences were noted in long-term survivals between patients with and without pathological changes of the radial arterial or saphenous vein grafts. CONCLUSION: Pathological changes may be seen in the bypass graft at the time of harvest. The subtle ultrastructural modifications and the expressions of vascular tone regulators might be responsible for late graft patency. The pathological changes of the left IMA at the time of harvest rather than those of the radial artery or saphenous vein graft affect significantly longterm survival. Non-traumatic maneuver of left IMA harvest, well-controlled dyslipidemia and avoidance of using composite grafts can be helpful in maintaining the architecture of the grafts. PMID- 25714206 TI - Evaluation of variables responsible for hospital mortality in patients with rheumatic heart disease undergoing double valve replacement. AB - OBJECTIVE: To describe the hospital mortality and associated clinical and echocardiographic variables in patients with rheumatic disease who underwent double valve replacement surgery. METHODS: This is a cross sectional descriptive study of mortality, performed in a referral hospital in Salvador, Bahia. Records from patients with rheumatic disease who underwent double valve replacement surgery during the years 2007-2011 were analyzed. RESULTS: The studied sample comprises 104 patients and 60 (57.7%) were male. The mean age was 38.04+/-14.45. Sixty five bioprostheses and 38 mechanical prostheses were used in these patients at the time of surgery. There were statistically significant differences between the two groups, when we analyzed the following variables: the mean age (36.30+/ 13.03 vs. 45.35+/-17.8 years-old, P=0.011), mean hemoglobin (11.10+/-2.19 vs. 9.22+/-2.26 g/dL, P=0.002), mean hematocrit (34.22+/-5.86 vs. 28.44+/-6.62%, P<0.001). New York Heart Association functional class III and IV (NYHA) (P=0.022) was statistically associated with mortality. CONCLUSION: We concluded that the mean hemoglobin/hematocrit level and the NYHA functional class was the major variables associated to the mortality among these patients. Based on these data one may concern about the patient best moment for surgery and the patient hemoglobin level. PMID- 25714208 TI - Effectiveness of the endotracheal tube cuff on the trachea: physical and mechanical aspects. AB - INTRODUCTION: The inflation pressure of the endotracheal tube cuff can cause ischemia of the tracheal mucosa at high pressures; thus, it can cause important tracheal morbidity and tracheal microaspiration of the oropharyngeal secretion, or it can even cause pneumonia associated with mechanical ventilation if the pressure of the cuff is insufficient. OBJECTIVE: In order to investigate the effectiveness of the RUSCH(r) 7.5 mm endotracheal tube cuff, this study was designed to investigate the physical and mechanical aspects of the cuff in contact with the trachea. METHODS: For this end, we developed an in vitro experimental model to assess the flow of dye (methylene blue) by the inflated cuff on the wall of the artificial material. We also designed an in vivo study with 12 Large White pigs under endotracheal intubation. We instilled the same dye in the oral cavity of the animals, and we analyzed the presence or not of leakage in the trachea after the region of the cuff after their deaths (animal sacrifice). All cuffs were inflated at the pressure of 30 cmH2O. RESULTS: We observed the passage of fluids through the cuff in all in vitro and in vivo experimental models. CONCLUSION: We conclude that, as well as several other cuff models in the literature, the RUSCH(r) 7.5 mm tube cuffs are also not able to completely seal the trachea and thus prevent aspiration of oropharyngeal secretions. Other prevention measures should be taken. PMID- 25714209 TI - Influence of valve prosthesis type on early mortality in patients undergoing valve surgery. AB - OBJECTIVE: To evaluate the influence of the type of prosthesis in-hospital mortality in the post-operative period in patients who had valve replacement. METHODS: A cross-sectional data, such as gender, origin, age, etiology, echocardiograph data, the type of surgery performed and the prosthesis used in cases of valve replacement were analyzed retrospectively. RESULTS: We reviewed 353 charts of patients who underwent valve replacement surgery. The mean age was 41.87+/-17.9 years. Regarding gender, 52.8% were female. As for the origin, 61.1% came from small cities within the state. Of all patients, 58.5% suffered from rheumatic disease. Assessing the type of prosthesis implanted, 70% held replace by bioprosthesis and 30% metallic. The hospital mortality in this study was 11%, with no significant difference between the types of prosthesis utilized. CONCLUSION: The type of implant used had no effect on in-hospital mortality. PMID- 25714210 TI - Distribution of saphenous vein valves and its practical importance. AB - OBJECTIVE: Among the veins used as a graft in myocardial revascularizations and ends, great saphenous vein is the most used. Knowing the presence and location of valves has great importance when evaluating the surgical anatomy of the great saphenous vein. Despite major surgical application and many works involving great saphenous vein, the number of valves present in it from the saphenous hiatus to the medial epicondyle of the femur is still described inaccurately. The objective of this study is to quantify the valves of the great saphenous vein from the saphenous hiatus to the medial epicondyle of the femur to determine the best portion of the great saphenous vein to perform revascularization surgeries. METHODS: This is a cross sectional observational study in which it was analyzed great saphenous vein extracted from 30 cadavers. It was measured the length of the veins; (diameter) at its proximal, middle and distal, quantifying the number of valves in each one and the total number of valves at the great saphenous vein. RESULTS: The frequency of valves in the great saphenous vein taken from the medial epicondyle of the femur to the saphenous hiatus was 4.82, ranging between 2 and 9. Moreover, there is a significant difference in the number of valves in the proximal and distal relative to the average. CONCLUSION: the median and distal portions of the saphenous vein in the thigh, are the best options for the realization of bridges due to the fact that these portions have fewer valves which therefore would tend to decrease the risk of complications connected with the valves in these grafts. PMID- 25714211 TI - The effect of gender on the early results of coronary artery bypass surgery in the younger patients' group. AB - INTRODUCTION: In this retrospective study, we aimed to determine the risk factors for coronary artery bypass surgery in patients under 45 years of age, and evaluate the early postoperative results and the effect of gender. METHODS: A total of 324 patients under 45 years of age who undergone on-pump coronary artery bypass surgery between April 12, 2004 and January 10, 2012 were included to the study. Patients divided into groups as follows: Group 1 consisted of 269 males (mean age 41.3), Group 2 consisted of 55 females (mean age 41.6). Preoperative risk factors, intraoperative and postoperative data and early mortality rates of the groups were compared. RESULTS: Smoking rate was significantly higher in Group 1. Diabetes mellitus incidence and body mass index were significantly higher in Group 2 (P values P=0.01; P=0.0001; P=0.04 respectively). The aortic cross clamping and cardiopulmonary bypass time and number of grafts per patient were significantly higher in Group 1 (P values P=0.04; P=0.04; P=0.002 respectively). There were no deaths in either group. CONCLUSION: We found that gender has no effect on early mortality rates of the coronary bypass surgery patients under 45 years. PMID- 25714212 TI - Carotid endarterectomy in awake patients: safety, tolerability and results. AB - OBJECTIVE: To analyze the results of 125 carotid endarterectomies under loco regional anesthesia, with selective use of shunt and bovine pericardium patch. METHODS: One hundred and seventeen patients with stenosis >= 70% in the internal carotid artery on duplex-scan + arteriography or magnetic resonance angiography underwent 125 carotid endarterectomies. Intraoperative pharmacological cerebral protection included intravenous administration of alfentanil and dexametasone. Clopidogrel, aspirin and statins were used in all cases. Seventy-seven patients were males (65.8%). Mean age was 70.8 years, ranging from 48 to 88 years. Surgery was performed to treat symptomatic stenosis in 69 arteries (55.2%) and asymptomatic stenosis in 56 arteries (44.8%). RESULTS: A carotid shunt was used in 3 cases (2.4%) due to signs and symptoms of cerebral ischemia after carotid artery clamping during the operation, and all 3 patients had a good outcome. Bovine pericardium patch was used in 71 arteries <= 6 mm in diameter (56.8%). Perioperative mortality was 0.8%: one patient died from a myocardial infarction. Two patients (1.6%) had minor ipsilateral strokes with good recovery, and 2 patients (1.6%) had non-fatal myocardial infarctions with good recovery. The mean follow-up period was 32 months. In the late postoperative period, there was restenosis in only three arteries (2.4%). CONCLUSION: Carotid artery endarterectomy can be safely performed in the awake patient, with low morbidity and mortality rates. PMID- 25714213 TI - Nebivolol in preventing atrial fibrillation following coronary surgery in patients over 60 years of age. AB - OBJECTIVE: Postoperative atrial fibrillation is a common complication after cardiac surgery, with an incidence as high as 20-50%. Increased age is associated with a significant increase in postoperative atrial fibrillation risk. This common complication is associated with higher morbidity and mortality rates. The aim of this study was to assess the efficacy of nebivolol in preventing atrial fibrillation following coronary artery bypass surgery in patients over 60 years of age. METHODS: In this prospective randomized study, 200 patients who were candidates for elective coronary artery bypass surgery were divided into two groups. The first group was administered with nebivolol and the second group was administered with metoprolol. Treatment was initiated four days prior to surgery, and patients were monitored for atrial fibrillation until discharge. Forty-one patients received 50 mg metoprolol succinate daily, which was initiated minimum 4 days before surgery. RESULTS: Demographic data were similar in both groups. The incidence of postoperative atrial fibrillation in both groups was similar, with no significant difference being identified [n=20 (20%); n=18 (18%), P=0.718; respectively]. There were not any mortality at both groups during study. Inotropic agent requirement at ICU was similar for both groups [n=12 (12%), n=18 (18%), P=0.32]. CONCLUSION: We compared the effectiveness of nebivolol and metoprolol in decreasing the incidence of postoperative atrial fibrillation, and determined that nebivolol was as effective as metoprolol in preventing postoperative atrial fibrillation at patients. Nebivolol may be the drug of choice due to its effects, especially after elective coronary artery bypass surgery. PMID- 25714214 TI - Pleural subxyphoid drain confers better pulmonary function and clinical outcomes in chronic obstructive pulmonary disease after off-pump coronary artery bypass grafting: a randomized controlled trial. AB - OBJECTIVE: To evaluate the lung function and clinical outcome in severe chronic obstructive pulmonary disease in patients undergoing off-pump coronary artery bypass grafting with left internal thoracic artery graft, comparing the pleural drain insertion in the intercostal versus subxyphoid region. METHODS: A randomized controlled trial. Chronic obstructive pulmonary disease patients were randomized into two groups according pleural drain site: II group (n=27) - pleural drain in intercostal space; SI group (n=29) - pleural drain in the subxyphoid region. Spirometry values (Forced Vital Capacity - and Forced expiratory volume in 1 second) were obtained on preoperative and 1, 3 and 5 postoperative days. Chest x-ray from preoperative until postoperative day 5 (POD5) was performed for monitoring respiratory events, such as atelectasis and pleural effusion. Pulmonary shunt fraction and pain score was evaluate preoperatively and on postoperative day 1. RESULTS: In both groups there was a significant decrease of the spirometry values (Forced Vital Capacity and Forced expiratory volume in 1 second) until POD5 (P<0.05). However, when compared, SI group presented less decrease in these parameters (P<0.05). Pulmonary shunt fraction was significantly lower in SI group (P<0.05). Respiratory events, pain score, orotracheal intubation time and postoperative length of hospital stay were lower in the SI group (P<0.05). CONCLUSION: Subxyphoid pleural drainage in severe Chronic obstructive pulmonary disease patients determined better preservation and recovery of pulmonary capacity and volumes with lower pulmonary shunt fraction and better clinical outcomes on early postoperative off-pump coronary artery bypass grafting. PMID- 25714215 TI - Comparative trial of the use of antiplatelet and oral anticoagulant in thrombosis prophylaxis in patients undergoing total cavopulmonary operation with extracardiac conduit: echocardiographic, tomographic, scintigraphic, clinical and laboratory analysis. AB - OBJECTIVE: To compare the efficacy of aspirin and warfarin for prophylaxis of thrombosis in patients undergoing total cavopulmonary anastomosis. Evaluate whether coagulation factors (VII, VIII and protein C), clinical data, fenestration or hemodynamic factors, interfere with postoperative thrombosis. METHODS: A prospective, randomized study of 30 patients, randomized into Group I (Warfarin) and Group II (AAS), underwent total cavopulmonary shunt with extracardiac conduit, between 2008 and 2011, with follow-up by clinical visits to evaluate side effects and adhesion. Performed transesophageal echocardiography in post operatory time, 3, 6,12 and 24 months; angiotomography at 6, 12 and 24 months to evaluate changes in the internal tube wall or thrombi and pulmonary scintigraphy to evaluate possible PTE. RESULTS: Two deaths in group I; 33.3% of patients had thrombus (46.7% in Group II). The previous occurrence of thrombus and low levels of coagulation protein C were the only factors that influenced the time free of thrombus (P=0.035 and 0.047). Angiotomographic evaluation: 35.7% in group II presented material accumulation greater than 2 mm (P=0.082). Scintigraphy: two patients had PTE in group II. Five patients had difficulty to comply with the treatment, 4 in group I with INR ranging from 1 to 6.4. CONCLUSION: The previous occurrence of thrombus is a risk factor for thrombosis in the postoperative period. Patients using AAS tend to deposit material in the tube wall. The small sample size did not allow to conclude which is the most effective drug in the prevention of thrombosis in this population. PMID- 25714216 TI - Therapeutic options to minimize allogeneic blood transfusions and their adverse effects in cardiac surgery: a systematic review. AB - INTRODUCTION: Allogeneic blood is an exhaustible therapeutic resource. New evidence indicates that blood consumption is excessive and that donations have decreased, resulting in reduced blood supplies worldwide. Blood transfusions are associated with increased morbidity and mortality, as well as higher hospital costs. This makes it necessary to seek out new treatment options. Such options exist but are still virtually unknown and are rarely utilized. OBJECTIVE: To gather and describe in a systematic, objective, and practical way all clinical and surgical strategies as effective therapeutic options to minimize or avoid allogeneic blood transfusions and their adverse effects in surgical cardiac patients. METHODS: A bibliographic search was conducted using the MeSH term "Blood Transfusion" and the terms "Cardiac Surgery" and "Blood Management." Studies with titles not directly related to this research or that did not contain information related to it in their abstracts as well as older studies reporting on the same strategies were not included. RESULTS: Treating anemia and thrombocytopenia, suspending anticoagulants and antiplatelet agents, reducing routine phlebotomies, utilizing less traumatic surgical techniques with moderate hypothermia and hypotension, meticulous hemostasis, use of topical and systemic hemostatic agents, acute normovolemic hemodilution, cell salvage, anemia tolerance (supplementary oxygen and normothermia), as well as various other therapeutic options have proved to be effective strategies for reducing allogeneic blood transfusions. CONCLUSION: There are a number of clinical and surgical strategies that can be used to optimize erythrocyte mass and coagulation status, minimize blood loss, and improve anemia tolerance. In order to decrease the consumption of blood components, diminish morbidity and mortality, and reduce hospital costs, these treatment strategies should be incorporated into medical practice worldwide. PMID- 25714217 TI - Anomalous origin of coronary artery: taxonomy and clinical implication. AB - OBJECTIVE: Anomalous origin of coronary artery is uncommon. The taxonomies of anomalous origin of coronary artery are inconsistent and complex. Conceptual and therapeutic debates remain. The aim of the present study is to reappraise the concept of anomalous origin of coronary artery and to discuss the potential hazards and treatment rationale of this anomaly on basis of literature review. METHODS: A comprehensive literature review was made in terms of the taxonomies including "simple", "multiple" and "complex" types of anomalous origin of coronary artery. RESULTS: Anomalous origin of coronary artery can be simply categorized according to the ectopically originated coronary artery. There are a couple of complex anatomical variants: "multiple" type, involving more than one coronary artery or branch, which can be subdivided into 2 subtypes, A) more than one coronary arteries or branches arising from one place; and B) two coronary arteries/branches arising from separate ectopic sites; and "complex" type, associated with acquired heart disease, or congenital heart defects. CONCLUSION: Sudden cardiac death in anomalous origin of coronary artery is associated with the anatomical features including abnormal coursing, acute angle take-off and ostial abnormalities. Atherosclerosis is prone to be in the right-sided ectopic and retroaortic coursing coronary artery. Surgical treatment is a definitive therapy. Simple coronary artery bypass grafting is not recommended due to the potential hazards of coronary steal phenomenon and poor patency of mammary arterial grafts, and modified maneuvers such as coronary ostial reimplantation, impinged coronary segment unroofing and coronary stent deployment are advocated instead. PMID- 25714219 TI - Saccular aneurysm formation of the descending aorta associated with aortic coarctation in an infant. AB - Aneurysm of the descending aorta associated with CoA is an extremely rare congenital abnormality. In this report, we present a 16 months old female patient in whom cardiac catheterization had been performed which had revealed a segment of coarctation and saccular aneurysm in the descending aorta. The patient was operated and a 3x2 centimeters aneurysm which embraces the coarcted segment in descending aorta was resected. In summary, we present a case of saccular aortic aneurysm distal to aortic coarctation in an infant without any history of intervention or vascular inflammatory disease. Our case report seems to be the youngest patient in literature with this pathology. PMID- 25714218 TI - S100 and S100beta: biomarkers of cerebral damage in cardiac surgery with or without the use of cardiopulmonary bypass. AB - OBJECTIVE: The present study is to describe the clinical impact of S100 and S100beta for the evaluation of cerebral damage in cardiac surgery with or without the use of cardiopulmonary bypass (CPB). METHODS: Quantitative results of S100 and S100beta reported in the literature of the year range 1990-2014 were collected, screened and analyzed. RESULTS: Cerebrospinal fluid and serum S100 levels showed a same trend reaching a peak at the end of CPB. The cerebrospinal fluid/serum S100 ratio decreased during CPB, reached a nadir at 6 h after CPB and then increased and kept high untill 24 h after CPB. Serum S100 at the end of CPB was much higher in infant than in adults, and in on-pump than in off-pump coronary artery bypass patients. ?S100 increased with age and CPB time but lack of statistical significances. Patients receiving an aorta replacement had a much higher ?S100 than those receiving a congenital heart defect repair. Serum S100beta reached a peak at the end of CPB, whereas cerebrospinal fluid S100 continued to increase and reached a peak at 6 h after CPB. The cerebrospinal fluid/serum S100beta ratio decreased during CPB, increased at the end of CPB, peaked 1 h after CPB, and then decreased abruptly. The increase of serum S100beta at the end of CPB was associated with type of operation, younger age, lower core temperature and cerebral damages. ?S100beta displayed a decreasing trend with age, type of operation, shortening of CPB duration, increasing core temperature, lessening severity of cerebral damage and the application of intervenes. Linear correlation analysis revealed that serum S100beta concentration at the end of CPB correlated closely with CPB duration. CONCLUSION: S100 and S100beta in cerebrospinal fluid can be more accurate than in the serum for the evaluations of cerebral damage in cardiac surgery. However, cerebrospinal fluid biopsies are limited. But serum S100beta and ?S100beta seem to be more sensitive than serum S100 and ?S100. The cerebral damage in cardiac surgery might be associated with younger age, lower core temperature and longer CPB duration during the operation. Effective intervenes with modified CPB circuit filters or oxygenators and supplemented anesthetic agents or priming components may alleviate the cerebral damage. PMID- 25714220 TI - A variant technique for the surgical treatment of left ventricular aneurysms. AB - OBJECTIVE: To present a surgical variant technique to repair left ventricular aneurysms. METHODS: After anesthesia, cardiopulmonary bypass, and myocardial protection with hyperkalemic tepic blood cardioplegia: 1) The left ventricle is opened through the infarct and an endocardial encircling suture is placed at the transitional zone between the scarred and normal tissue; 2) Next, the scar tissue is circumferentially plicated with deep stitches using the same suture thread, taking care to eliminate the entire septal scar; 3) Then, a second encircling suture is placed, completing the occlusion of the aneurysm, and; 4) Finally, the remaining scar tissue is oversewn with an invaginating suture, to ensure hemostasis. Myocardium revascularization is performed after correction of the left ventricle aneurysm. The same surgeon performed all the operations. RESULTS: Regarding the post-surgical outcome 4 patients (40%) had surgery 8 eight years ago, 2 patients (20%) were operated on over 6 years ago, and 1 patient (10%) was operated on more than 5 years ago. Three patients (30%) were in functional class I, class II in 2 patients (20%) and 2 patients (20%) with severe comorbidities remains in class III of the NYHA. There were three deaths (at four days, 15 days and eight months) in septuagenarians with acute myocardial infarction, diabetes and pulmonary emphysema. CONCLUSION: The technique is easy to perform, safe and it can be an option for the correction of left ventricle aneurysms. PMID- 25714221 TI - Implantation of transcatheter aortic valve prosthesis through the ascending aorta concomitant with coronary artery bypass grafting without cardiopulmonary bypass. AB - INTRODUCTION: The transcatheter aortic valve implantation in the treatment of high-risk symptomatic aortic stenosis has increased the number of implants every year. The learning curve for transcatheter aortic valve implantation has improved since the last 12 years, allowing access alternatives. OBJECTIVE: The aim of this study is to approach the implantation of transcatheter aortic valve through transaortic via associated with off-pump cardiopulmonary bypass surgery in a 67 year-old man, with chronic obstructive pulmonary disease, arterial hypertension and kidney transplant. METHODS: Off-pump coronary artery bypass surgery was performed and the valve in the aortic position was released successfully. RESULTS: There were no complications in the intraoperative and postoperative period. Gradient reduction, effective orifice increasing of the prosthesis and absence of valvular regurgitation after implantation were observed by transesophageal echocardiography. CONCLUSION: Procedural success demonstrates that implantation of transcatheter aortic valve through the ascending aorta associated with coronary artery bypass surgery without CPB is a new option for these patients. PMID- 25714222 TI - How to perform a coronary artery anastomosis in complete endoscopic fashion with robotic assistance. AB - Current technology in robotic surgery allows us to perform myocardial revascularization procedures in a totally endoscopic fashion. We will describe the technique of choice for left internal mammary artery to left anterior descendent artery anastomosis with the use of cardiopulmonary bypass machine. The method is efficient and there is long term follow-up showing similar patency of the graft when compared to conventional methods (when performed through sternotomy). PMID- 25714223 TI - Right-sided reverse T composite arterial grafting to complete revascularization of the right coronary artery. AB - Complete arterial revascularization for the right coronary artery is underused mainly due to technical issues. Herein we report on a new approach for complete arterial revascularization of arterial revascularization for the right coronary artery branches. Complete arterial revascularization for the right coronary artery revascularization was performed in 8 patients using a reverse T composite arterial graft. None of the patients suffered perioperative myocardial infarction. All patients underwent noninvasive coronary imaging, displaying an early patency rate of 100%. Complete arterial arterial revascularization for the right coronary artery revascularization using a reverse T graft offers a new paradigm with enhanced technical flexibility in performing all arterial myocardial complete revascularizations in selected patients. PMID- 25714224 TI - Surgical treatment of a giant left ventricular aneurysm- a case report. AB - An aneurysm of the left ventricle is a complication of acute myocardial infarction. We report a case of a giant aneurysm of the left ventricle after myocardial infarction in a 59 year-old male patient. The surgery to correct the aneurysm was performed with the use of cardiopulmonary bypass under normothermia. A bovine pericardial patch was used for the geometric reconstruction of the ventricular wall affected by the aneurysm. After the procedure, echocardiography and magnetic resonance imaging revealed improvement in left ventricular ejection fraction and volume reduction. PMID- 25714225 TI - Comments on "Impact of type of procedure and surgeon on EuroSCORE operative risk validation". PMID- 25714226 TI - Reply to the editor on "Impact of type of procedure and surgeon on EuroSCORE operative risk validation". PMID- 25714227 TI - Adib Domingos Jatene (1929-2014). PMID- 25714228 TI - High hydrostatic pressure upon the vasa vasorum of the greater saphenous and splenic vein walls: a comparative study. AB - AIMS: Hypoxia and high hydrostatic pressure can induce an increase in the thickness of the tunica media and intima; secondary vasa vasorum (VV) increase to fit the remodeling of the vessel wall. We aimed to investigate the impact of high hydrostatic pressure on VV in the varicose greater saphenous veins (VGSVs) and diseased splenic veins (DSVs). METHODS: We collected 34 VGSVs and DSVs. Thirty four normal greater saphenous veins (GSVs) and splenic veins (SVs) were also collected (control group). Samples were cut into slices, and observed under both light and electron microscopy. The mean density and cross-sectional areas of the VV in the adventitia were measured. RESULTS: In both VGSVs and DSVs, VV density increased, in the adventitia and exterior tunica media, offering an intensive linear distribution. However, sporadic distribution of the interior tunica media and intima were seen on light microscopy. The integrated structure of the cell nucleus of endothelial cells in VV, normal morphology and distribution of chromatin, partially hyperchromatic mitochondria matrix, fuzzy or fractured mitochondria cristae, and medullary cristae changes were observed by electron microscopy. Mean density and cross-sectional areas of VV in the adventitia of GSVs and SVs were significantly different. CONCLUSION: Under high hydrostatic pressure conditions, the number of VV were increased in the wall of VGSVs and DSVs. There was heterogeneity between both types of veins. The splenic vein has a higher number of VV, but the greater saphenous vein has a higher average cross sectional area. The same ultrastructural changes are seen in the endothelial cells of the VV in both vessels. PMID- 25714229 TI - One hydrogen bond does not a separation make, or does it? Resolution of amines by diacetoneketogulonic acid. AB - Diacetoneketogulonic acid was used to separate primary amines from their racemic modifications and the selectivity of the acid was rationalized by lattice energy calculations and analyzing the weak interactions around the captured amines. PMID- 25714230 TI - Multifunctional mononuclear bisthienylethene-cobalt(II) complexes: structures, slow magnetic relaxation and photochromic behavior. AB - Based on two new bisthienylethenes containing N,O-donor binding sites, 2-(2 hydroxy-5-bromo-phenyl)-4,5-bis(2,5-dimethyl(3-thienyl))-1H-imidazole (BrLH) and 2-(2-hydroxy-5-diethylphosphono-phenyl)-4,5-bis(2,5-dimethyl(3-thienyl))-1H imidazole (PLH), multifunctional mononuclear complexes Co(BrL)2.3CH3OH (1) and Co(PL)2.2CH3OH (2) have been synthesized and characterized by crystallographic analysis. In the molecular structures of 1 and 2, the Co(II) ion adopts a distorted tetrahedral coordination geometry, and is coordinated by two nonequivalent bisthienylethene molecules (BrL- in 1, PL- in 2), showing non photoactive parallel and photoactive antiparallel conformations, respectively. Compounds 1 and 2 show a distinct distortion of Co(II) coordination geometry, with bond angles of N-Co-N = 112.71(12) degrees and O-Co-O = 99.87(11) degrees for 1 and N-Co-N = 119.93(12) degrees and O-Co-O = 107.31(13) degrees for 2. Thus, 1 and 2 revealed different magnetic behaviors, which are demonstrated by the chiMT vs. T plots, and the frequency dependence of the chi'M and chi''M signals at low temperature. Besides the field-induced slow magnetic relaxation, both 1 and 2 also showed photochromic behavior. Upon irradiation with 360 nm light for 1 and 343 nm light for 2, their CH2Cl2-CH3CN solutions could change color from being nearly colorless to blue purple. It was demonstrated that the substituent groups of Br atom and -PO(OEt)2 in 1 and 2, respectively, could significantly influence their crystal structures, magnetic relaxations and photochromic properties. PMID- 25714231 TI - Continuous aerosol size separator using inertial microfluidics and its application to airborne bacteria and viruses. AB - A microchannel-based aerosol size separator that separates submicron aerosols according to particle inertial differences and Dean vortices in the airflow was developed for use in low-cost, portable, real-time aerosol collectors, detectors, concentrators and other such devices. The microfluidic inertial separator was furthermore applied to simultaneously separate airborne microorganisms by size, such as airborne viruses and bacteria from larger aerosols and viral particles from bacterial cells. The entire system was designed by numerical simulation and analysis. In addition, its performance was evaluated experimentally using airborne standard polystyrene latex (PSL) particles. In addition, two airborne microorganisms, Adenovirus 40 and Staphylococcus epidermidis, were used to verify the performance of the separator. The separation ratios of each bioaerosol were measured using real-time aerosol measurement instruments and quantitative polymerase chain reaction (qPCR) analysis. The system was composed of two 90 degrees curved microchannels and three outlets for separating the virus, bacteria and larger particles. About 70% of 3 MUm particles but almost none of the bioaerosols were separated out at the first outlet. In addition, more than 70% of S. epidermidis and ~70% Adenovirus were separated out at the second and third outlets, respectively. Unwanted particle loss in the system was less than 10%. The results indicated not only good separation of bioaerosols but also the potential of our separator for use in bioaerosol applications. PMID- 25714232 TI - Gas storage and separation in a water-stable [Cu(I)5BTT3](4-) anion framework comprising a giant multi-prismatic nanoscale cage. AB - A novel water-stable open poly-nuclear Cu(I)-based metal-organic framework, [NC2H8]4Cu5(BTT)3.xG (G = guest of DMA and H2O) (1), featuring a giant multi prismatic nanoscale cage and high CO2/N2 and CO2/H2 sorption selectivities, was successfully assembled by using the nitrogen-rich ligand of 1,3,5-tris(2H tetrazol-5-yl)benzene (H3BTT) to bridge two types of Cu3 and Cu2 clusters. PMID- 25714233 TI - Modeling ultrafast exciton deactivation in oligothiophenes via nonadiabatic dynamics. AB - Ultrafast excited-state processes play a key role in organic electronics and photovoltaics, governing the way of how excitons can relax and separate. Through the use of nonadiabatic excited-state dynamics, relaxation processes were investigated at the sub-picosecond timescale in thiophene and oligothiophenes (nT, n = 2, 3, 4), prototype oligomers for efficient pi-electron conjugated polymers adopted in photovoltaics. For thiophene, TDDFT and TDA nonadiabatic excited-state dynamics revealed ultrafast nonradiative relaxation processes through ring opening and ring puckering, bringing the system to an S1/S0 conical intersection seam. The computed relaxation time is 110 fs, matching well the experimental one (~105 fs). In oligothiophenes (n = 2-4), high-energy (hot) excitations were considered. Exciton relaxation through the manifold of excited states to the lowest excited state is predicted to occur within ~150-200 fs, involving bond stretching, ring puckering, and torsional oscillations. For the longer oligomer (4T), the ultrafast relaxation process leads to exciton localization over three thiophene rings in 150 fs. These data agree with the self localization mechanism (~100-200 fs) observed for poly(3-hexylthiophene) (P3HT) and shed light on the complex exciton relaxation dynamics occurring in pi conjugated oligomers of potential interest for optoelectronic applications. PMID- 25714234 TI - Faulty analysis in study of robotic-assisted minimally invasive radical prostatectomy. PMID- 25714235 TI - Jose Gay Prieto: Teacher of Dermatologists. PMID- 25714236 TI - Incremental direct and indirect costs of untreated vasomotor symptoms. AB - OBJECTIVE: Most women with moderate to severe vasomotor symptoms (VMS) are untreated. This retrospective matched-cohort study aims to evaluate the healthcare resource utilization, work loss, and cost burden associated with untreated VMS. METHODS: Health insurance claims (1999-2011) were used to match (1:1) women with untreated VMS with control women using propensity score. Healthcare resource utilization, work productivity loss (disability + medically related absenteeism), and associated costs were compared between cohorts. RESULTS: During the 12-month follow-up, women with untreated VMS (n = 252,273; mean age, 56 y) had significantly higher healthcare resource utilization than women in the control cohort: 82% higher for all-cause outpatient visits (95% CI, 81-83; P < 0.001) and 121% higher (95% CI, 118-124; P < 0.001) for VMS-related outpatient visits. Mean direct costs per patient per year were significantly higher for VMS women (direct cost difference, US$1,346; 95% CI, 1,249-1,449; P < 0.001). VMS women had 57% (95% CI, 51-63; P < 0.001) more indirect work productivity loss days than controls, corresponding to an incremental indirect cost per patient per year associated with untreated VMS of US$770 (95% CI, 726 816; P < 0.001). CONCLUSIONS: This study shows that untreated VMS are associated with significantly higher frequency of outpatient visits and incremental direct and indirect costs. PMID- 25714238 TI - Defining 'progression' and triggers for curative intervention during active surveillance. AB - PURPOSE OF REVIEW: Low-risk and many cases of low-intermediate risk prostate cancer have little or no metastatic potential, and do not pose a threat to the patient in his lifetime. Substantial recent evidence, reviewed in this article, has clarified who these patients are and supports the use of conservative management in such individuals. RECENT FINDINGS: A key element of conservative management is the early identification of those 'low-risk' patients who harbour higher risk disease and benefit from definitive therapy. This represents about 30% of newly diagnosed low-risk patients. A further small proportion of patients with low-risk disease demonstrates true biological progression over time to higher grade disease (as distinct from grade increase on repeat biopsy due to resampling). Men with lower risk disease can defer treatment, in most cases for life. The results of active surveillance, embodying conservative management with selective delayed intervention for the subset who are reclassified as higher risk over time based on repeat biopsy, imaging or biomarker results, are associated with a 5% cancer-specific mortality at 15 years. SUMMARY: Active surveillance for low-risk prostate cancer is well tolerated in the intermediate-long term time frame. Further refinement of the surveillance approach is ongoing, incorporating MRI, targeted biopsies and molecular biomarkers to improve appropriate patient selection and triggers for intervention. PMID- 25714237 TI - Consistent ovulation may not be enough to make women healthy when approaching menopause: an update from the Study of Women's Health Across the Nation. AB - OBJECTIVE: This study aims to test the hypothesis that consistently ovulatory premenopausal/perimenopausal women have a more favorable cardiometabolic profile than anovulatory women. METHODS: The first four collections from the Study of Women's Health Across the Nation Daily Hormone Study (DHS) were used. DHS enrollees annually completed a daily collection of first morning voided urine for an entire menstrual cycle or up to 50 days (whichever comes first). A woman was categorized as consistently ovulatory annually (COA) if four ovulatory cycles or two to three ovulatory cycles followed by the final menstrual period (FMP) were observed. A woman was categorized as not consistently ovulatory annually (nCOA) if at least one anovulatory year was observed. Cross-sectional and longitudinal differences were compared between COA and nCOA women. Data were centered at FMP and adjusted for age and body mass index (BMI). RESULTS: Six hundred thirty-six DHS participants (mean [SD] age, 47.3 [2.5] y; mean [SD] BMI, 27.4 [7.1] kg/m(2)) were included. Thirty-six percent of the DHS participants were COA women. On the fourth follow-up collection, COA women had lower high-density lipoprotein than nCOA women (mean [95% CI], 55.7 [54.0-57.4] vs 59.5 [57.9-61.0] mg/dL, P = 0.002, respectively), which persisted after adjustment. Among 460 women with FMP, 39% were COA women. COA women were slightly older (52.9 vs 52.0 y, P = 0.002) and had lower BMI (geometric mean, 26.1 vs 27.5 kg/m(2), P = 0.06) than nCOA women at FMP. Other cardiometabolic factors did not significantly differ by COA status through FMP. CONCLUSIONS: Consistent ovulation across the menopausal transition does not seem to reflect superior cardiometabolic health. PMID- 25714239 TI - Reply: primary intranasal lining injury: cause, deformities, and treatment plan. PMID- 25714240 TI - Reply: The Effects of Whole-Vault Cranioplasty versus Strip Craniectomy on Long Term Neuropsychological Outcomes in Sagittal Craniosynostosis. PMID- 25714241 TI - Reply: a systematic review comparing furlow double-opposing z-plasty and straight line intravelar veloplasty methods of cleft palate repair. PMID- 25714242 TI - Reply: Transversus Abdominis Plane Block Reduces Morphine Consumption in the Early Postoperative Period following Microsurgical Abdominal Tissue Breast Reconstruction: A Double-Blind, Placebo-Controlled, Randomized Trial. PMID- 25714243 TI - Reply: facial nerve grading scales: systematic review of the literature and suggestion for uniformity. PMID- 25714244 TI - Transversus Abdominis Plane Block Reduces Morphine Consumption in the Early Postoperative Period following Microsurgical Abdominal Tissue Breast Reconstruction: A Double-Blind, Placebo-Controlled, Randomized Trial. PMID- 25714245 TI - Brief report: Time from infection with the human immunodeficiency virus to diagnosis, United States. AB - HIV testing efforts increased in recent years to reduce the percentage of persons with HIV unaware of their infection and to detect HIV early. An analysis of CD4 data from national HIV surveillance indicates that diagnosis delays decreased during 2003-2011; on average, persons diagnosed in 2011 had been infected 5.6 years before their diagnosis compared with 7.0 years among those diagnosed in 2003. Diagnosis delays were longer among females, blacks, Hispanics/Latinos, and older persons, but shorter among men who have sex with men, compared with their counterparts. Continued efforts to implement routine testing can help reduce diagnosis delays. PMID- 25714246 TI - High Drop-off Along the HIV Care Continuum and ART Interruption Among Female Sex Workers in the Dominican Republic. AB - BACKGROUND: Engagement in HIV care offers clear individual and societal benefits, but little evidence exists on the care experiences of key populations. METHODS: A cross-sectional survey was conducted with 268 female sex workers (FSWs) living with HIV in Santo Domingo, Dominican Republic, to describe the HIV care continuum and to determine factors associated with antiretroviral therapy (ART) interruption. RESULTS: FSWs disengaged throughout the care continuum with the highest drop-off after ART initiation. Most participants were linked to care (92%), retained in care (85%), and initiated onto ART (78%), but ART discontinuation and irregular adherence were frequent. Only 48% of participants had an undetectable HIV viral load. Overall, 36% of participants ever initiated onto ART reported lifetime experience with ART interruption. The odds of ART interruption were 3.24 times higher among women who experienced FSW-related discrimination [95% confidence interval (CI): 1.28 to 8.20], 2.41 times higher among women who used any drug (95% CI: 1.09 to 5.34), and 2.35 times higher among women who worked in an FSW establishment (95% CI: 1.20 to 4.60). Internalized stigma related to FSW was associated with higher odds of interruption (adjusted odds ratio: 1.09; 95% CI: 1.02 to 1.16), and positive perceptions of HIV providers were protective (adjusted odds ratio: 0.91; 95% CI: 0.85 to 0.98). CONCLUSIONS: FSWs living with HIV confront multiple barriers throughout the HIV care continuum, many of which are related to the social context and stigmatization of sex work. Given the clear importance of maximizing the potential benefits of engagement in HIV care, there is an urgent need for interventions to support FSWs throughout the HIV care continuum. PMID- 25714247 TI - HIV-1 Coreceptor CXCR4 Antagonists Promote Clonal Expansion of Viral Epitope Specific CD8+ T Cells During Acute SIV Infection in Rhesus Monkeys In Vivo. AB - BACKGROUND: The underlying molecular mechanisms and the kinetics of T cell receptor (TCR) repertoire selection during administration of CXCR4 or CCR5 inhibitors in infection of AIDS viruses in vivo have remained largely unexplored. Viral epitope-specific CD8(+) T lymphocytes play a dominant role in the control of HIV and simian immunodeficiency virus (SIV). We hypothesized that blockade of CXCR4 or CCR5 might influence the clonal expansion of epitope-specific CD8(+) T cells, contributing to antiviral immune responses in vivo. METHODS: We measured frequencies of the dominant epitope p11C-specific CD8(+) T cells and analyzed the TCR repertoire of those cells in SIV-infected rhesus monkeys treated by CXCR4 or CCR5 inhibitors and vMIP-II, which binds multiple chemokine receptors. RESULTS: A significantly increase in the levels of epitope-specific CD8(+) T cells was observed after blockade of CXCR4 or CCR5 compared with untreated control groups. Those CD8(+) T cells exhibited selected usage of TCR Vbeta families and complementarity-determining region 3 (CDR3) segments. The clonal expansion of distinct Vbeta populations could efficiently inhibit SIV replication in vitro, and CXCR4 inhibitor induced more expansion of epitope-specific CD8(+) T cells than CCR5 antagonist (P < 0.01), whereas vMIP-II treatment showed the most marked augmentation of p11C-specific CD8(+) T cells. CONCLUSIONS: Antagonists of HIV coreceptors, particularly CXCR4, play an important role in the clonal expansion of SIV epitope-specific CD8(+) T cells in vivo, thus inhibitors of chemokine receptors such as CXCR4 or CCR5 may contribute to the ability of epitope-specific CD8(+) T cells to inhibit SIV or HIV infection. PMID- 25714248 TI - Breast cancer brain metastases responding to lapatinib plus capecitabine as second-line primary systemic therapy. AB - Brain metastases (BM) are diagnosed in up to 40% of HER2-positive breast cancer patients. Standard treatment includes local approaches such as whole-brain radiotherapy (WBRT), radiosurgery, and neurosurgery. The landscape trial established primary systemic therapy as an effective and safe alternative to WBRT in selected patients with Her2-positive BM. We aim to further focus on the role of systemic therapy in oligosymptomatic patients by presenting this case report. We report on a 50-year-old patient diagnosed with multiple BM 5 years after early breast cancer diagnosis. As the patient was asymptomatic and had a favorable diagnosis-specific GPA score, she received primary systemic treatment with T-DM1. She achieved partial remission within the brain for eight treatment cycles and then progressed despite stable extracranial disease. As the patient remained asymptomatic and refused WBRT, we decided upon trastuzumab, lapatinib plus capecitabine as second-line therapy. Another partial remission of BM was observed; to date, she has received 11 treatment cycles without any sign of disease progression. In this case, WBRT was delayed by at least 14 months, again indicating the activity of systemic treatment in BM. Apparently, in selected patients, BM can be controlled with multiple lines of systemic therapy similar to extracranial disease. Further investigation of systemic treatment approaches is therefore warranted. PMID- 25714249 TI - Chlorogenic acid enhances the effects of 5-fluorouracil in human hepatocellular carcinoma cells through the inhibition of extracellular signal-regulated kinases. AB - There is an urgent need to search for novel chemosensitizers in the field of cancer therapy. Chlorogenic acid (CGA), a type of polyphenol present in the diet, has many biological activities. The present study is designed to explore the influence of CGA on the effects of 5-fluorouracil (5-FU) on human hepatocellular carcinoma cells (HepG2 and Hep3B). Treatment with 5-FU induced the inhibition of hepatocellular carcinoma cells' proliferation, and the combined treatment with CGA enhanced this inhibition. 5-FU also increased the production of reactive oxygen species (ROS). The combination of 5-FU and CGA led to a more prominent production of ROS and significantly inactivated ERK1/2, although CGA and 5-FU exerted no significant changes when used alone. A previous report has shown that ROS are upstream mediators that inactivate ERK in hepatocellular carcinoma cells. Combined with our results, this indicates that the combination of 5-FU and CGA leads to the inactivation of ERK through the overproduction of ROS. This mediates the enhancement of 5-FU-induced inhibition of hepatocellular carcinoma cells' proliferation, that is, CGA sensitizes hepatocellular carcinoma cells to 5-FU treatment by the suppression of ERK activation through the overproduction of ROS. CGA has shown potential as a chemosensitizer of 5-FU chemotherapy in hepatocellular carcinoma. PMID- 25714250 TI - Plasma homocysteine levels and hematological toxicity in NSCLC patients after the first cycle of pemetrexed under folate supplementation. AB - Although baseline plasma homocysteine levels are related to pemetrexed toxicities in patients treated without folate supplementation, the relationship between these parameters in patients treated with folate supplementation is not well understood. The pretreatment plasma homocysteine levels were measured in non small-cell lung cancer patients treated with pemetrexed alone under folate supplementation. Pemetrexed (500 mg/m) was administered every 3 weeks. As folate supplementation, folic acid (0.5 mg) was orally administered daily and vitamin B12 (1 mg) was injected intramuscularly every 9 weeks starting at least 1 week before treatment. The rate of toxicities during the first cycle of pemetrexed treatment with folate supplementations was evaluated and the relationship between the plasma homocysteine levels and toxicities was examined. Between June 2009 and November 2010, 58 patients were enrolled in this study. The median pretreatment plasma homocysteine level was 7.7 MUmol/ml (3.5-34.6 MUmol/ml). The pretreatment plasma homocysteine levels were above 11.5 MUmol/ml in nine patients (15.5%). The pretreatment plasma homocysteine level correlated significantly with the nadir of the absolute counts of leukocytes, neutrophils, and thrombocytes (r = -0.374, P = 0.004; r = -0.286, P = 0.028; r = -0.324, P = 0.012, respectively). In addition, the rates of decrease in leukocytes, neutrophils, and thrombocytes correlated significantly with the pretreatment plasma homocysteine level (r = +0.378, P = 0.003; r = +0.335, P = 0.009; r = +0.363, P = 0.005, respectively). The plasma homocysteine level is associated with hematological toxicities in patients receiving pemetrexed with folate supplementation. PMID- 25714251 TI - A Schiff base derivative for effective treatment of diethylnitrosamine-induced liver cancer in vivo. AB - Hepatocellular carcinoma is one of the most prevalent cancers, with a high morbidity rate, even in developed countries. In the present study, the curative effect of the Schiff base (SB) heterodinuclear copper(II)Mn(II) complex on diethylnitrosamine (DEN)-induced liver carcinoma was investigated. Hepatocarcinoma was initiated by an injection of DEN and promoted by phenobarbital (0.05%) in the diet. In addition, the potential nephrotoxicity of SB was evaluated in a cisplatin-induced nephrotoxicity model. Rats were administered the SB complex (1 and 2 mg/kg body weight/day) for 24 weeks, and cancer progression was investigated by macroscopic, histopathological, and western blot examinations. The administration of SB decreased the incidence and the number of hepatic nodules in a dose-dependent manner by regulating inflammation response and the apoptotic pathway. Western blot analyses from the livers of rats treated with SB after DEN induction showed significantly enhanced Bax and caspase-3 levels, with a marked decrease in the levels of Bcl-2, NF kappaB p65 and cyclooxygenase (COX)-2. Results from the nephrotoxicity study showed that, whereas cisplatin increased serum urea nitrogen and creatinine levels, no increase in serum biochemical parameters was detected in SB-treated animals. Moreover, protein levels of NF-E2-related factor-2 (Nrf2) and heme oxygenase-1 were lower, whereas nuclear factor-kappaB (NF-kappaB p65) and activator protein-1 levels were higher in the kidneys of cisplatin-treated animals compared with that of the SB groups. Therefore, the SB complex could be an alternative chemotherapeutic option for liver cancer treatment once its safety in clinical applications has been examined. PMID- 25714252 TI - Controversies about the use of antidepressants in pregnancy. AB - There is controversy about the use of antidepressant medication during pregnancy. Decisions about their use are affected by understanding the risks of these medications causing pregnancy loss, congenital malformations, neonatal adaptation syndrome, persistent pulmonary hypertension of the newborn, autism spectrum disorder, or long-term neurocognitive deficits. Although some research has raised concerns about antidepressants causing harm to the fetus and neonate, other studies have disputed these findings or noted that any risks found do not exceed the risk of congenital problems found in 1% to 3% of neonates in the general population. Untreated depression during pregnancy can also cause harm from poor diet, substance abuse, suicidal behavior, or prematurity. Decisions about the use of antidepressants during pregnancy must be based on a risk-benefit analysis based on the best evidence of the risks of treating or not treating maternal depression. PMID- 25714253 TI - Antidepressants, pregnancy, and stigma: how we are failing mothers and babies. AB - There is considerable public debate over the use of antidepressants in pregnancy. In this article, we offer a commentary on Gail Robinson's important overview of the current controversies. Dr Ronbinson gives a thorough review of the literature, including the risks posed by both antidepressants and depression itself. We summarize her arguments and point out that, in the public conversation, the risks posed to a fetus from antidepressants are consistently overestimated while the risks of untreated depression are consistently underestimated because of the pervasive stigma against mental health. We review recent lay media analyses and urge our fellow physicians to make decisions about prescribing in pregnancy on the basis of evidence and individual patient needs rather than media and stigma. PMID- 25714254 TI - Use of selective serotonin reuptake inhibitor antidepressants in pregnancy does carry risks, but the risks are small. AB - The paper by Robinson posits that risks from prenatal exposure to selective serotonin reuptake inhibitor (SSRI) antidepressants are not different from the risks encountered in the general population and that untoward effects of SSRIs are difficult to distinguish from those of the mood disorder. Indeed, maternal depression and anxiety can have negative consequences for fetal and postnatal development. Fortunately, experimental evidence suggests that mood and anxiety disorder symptoms often respond to psychosocial interventions. If pharmacotherapy becomes necessary, it is, however, important to know that even if SSRI drugs have been shown to be safe overall, research has shown that fetal development can be adversely affected by in utero exposure to SSRIs in a subgroup of neonates. Examples would be the transient neonatal adaptation syndrome, an increased risk of persistent pulmonary hypertension of the newborn, and small, albeit measurable, changes in motor and social adaptability in infancy and childhood. PMID- 25714255 TI - Personality and dementia. AB - Personality describes persistent human behavioral responses to broad classes of environmental stimuli. Change in personality may be an early sign of dementia. Our goal was to review scientific literature on the association between personality and dementia. Medline and Google Scholar searches were conducted for relevant articles, chapters, and books published since 1980. Search terms used included personality, dementia, Alzheimer's disease, frontotemporal dementia, dementia with Lewy bodies. People with dementia commonly exhibit changes in personality that sometimes precede the other early clinical manifestations of the condition, such as cognitive impairment. Premorbid personality might be a determining factor so that caricature or exaggeration of original personality emerges as dementia progresses. Although it is generally accepted that these personality changes reflect the impact of progressive brain damage, there are several possible patterns of personality alterations with dementia. Early identification of personality modifications might assist with the timely diagnosis of dementia. PMID- 25714257 TI - Predictors of depression among a sample of South African mortuary workers. AB - Mortuary workers are at high risk of developing depression and other psychiatric disorders owing to the nature of their work and exposure to deceased victims of violent deaths. Few studies have investigated mental health among mortuary workers in low- and middle-income countries. Participants (N = 45) were recruited from mortuaries in South Africa and completed a battery of questionnaires measuring depression, physical health, perceived stress, fear of blood/injury/mutilation, and resilience. Participants with self-reported depression and posttraumatic stress disorder (PTSD) comprised 13.3% and 4.4% of the sample, respectively. Inexperienced mortuary workers had a higher prevalence rate of depression (16.7%) compared with experienced workers (9.5%). Prevalence of PTSD did not differ significantly between inexperienced (4.2%) and experienced (4.8%) workers. Physical health, perceived stress, fear of blood/injury/mutilation, and resilience were significant predictors of depression in the combined group (experienced and inexperienced). However, perceived stress was the only significant predictor of depression, in multiple regression, in the combined group. Inexperienced workers had significantly higher levels of blood/injury/mutation fear and depression. Mortuary workers seem to be at increased risk of depression, especially inexperienced workers. Perceived poor health, lower levels of resilience, and blood/injury/mutilation fears may lead to increased perceived stress among mortuary workers, which may, in turn, lead to depression. Interventions focused on promoting mental health may be beneficial to all mortuary workers, and preparatory training related to mental health may be beneficial to inexperienced mortuary workers before occupational uptake. PMID- 25714256 TI - Duration of untreated psychosis and the pathway to care in KwaZulu-Natal, South Africa. AB - Considerable controversy surrounds the role of traditional health practitioners (THPs) as first-contact service providers and their influence on the duration of untreated psychosis (DUP) in sub-Saharan Africa. This study examined first contact patterns and pathways to psychiatric care among individuals with severe mental illness in South Africa. A cross-sectional study was conducted at a referral-based tertiary psychiatric government hospital in KwaZulu-Natal Province. Information on pathways to care was collected using the World Health Organization's Encounter Form. General hospital was the most common first point of contact after mental disorder symptom onset and the strongest link to subsequent psychiatric treatment. Family members were the most common initiators in seeking care. First contact with THPs was associated with longer DUP and higher number of provider contacts in the pathway based on adjusted regression analyses. Strengthening connections between psychiatric and general hospitals and provision of culturally competent family-based psychoeducation to reduce DUP are warranted. PMID- 25714258 TI - Sports concussion: time for a culture change. PMID- 25714259 TI - In response to: Canadian Academy of Sport and Exercise Medicine position statement: athletes at high altitude. PMID- 25714260 TI - Authors' reply. PMID- 25714261 TI - Reduction of secondary and tertiary phosphine oxides to phosphines. AB - Achiral or chiral phosphines are widely used in two main domains: ligands in organometallic catalysis and organocatalysis. For this reason, the obtention of optically pure phosphine has always been challenging in the development of asymmetric catalysis. The simplest method to obtain phosphines is the reduction of phosphine oxides. The essential difficulty is the strength of the P=O bond which involves new procedures to maintain a high chemio- and stereoselectivity. The reduction can occur with retention or inversion of the stereogenic phosphorus atom depending on the nature of the reducing agent and the presence of additives. In fact, the reactivity of the phosphine oxides and the mechanism of the reduction are not always well understood. Since the first work in the 1950's, numerous studies have been realised in order to develop methodologies with different reagents or to understand the mechanism of the reaction. In the last decade, efficient stereospecific methodologies have been developed to obtain optically pure tertiary phosphines from P-stereogenic phosphine oxides. In this review, we intend to provide a comprehensive and critical overview of these methodologies. PMID- 25714262 TI - Long-term continuous subcutaneous infusion of ketorolac in hospice patients. PMID- 25714263 TI - The prevalence of complications and healthcare costs during pregnancy. AB - OBJECTIVE: To study the economic burden of pregnancy in the US, common complications during pregnancy, and the incremental costs attributable to these complications. METHODS: A retrospective comparative cohort study was conducted of pregnant women aged 15-49 years using de-identified medical and pharmacy claims from the Truven Health MarketScan Commercial Claims and Encounters database incurred between January 1, 2007 and December 31, 2011. The total healthcare costs are reported (adjusted to 2011 dollars) from the date of the first pregnancy-related claim through to 3 months post-delivery and these costs were compared to matched controls of non-pregnant women. Pregnancy-related complications were categorized, and the incremental costs associated with each complication were estimated using multivariate analyses. RESULTS: A total of 322,141 eligible women with live births were studied. Compared to matched controls, the average costs of care for pregnant women were nearly $13,000 higher through 3 months post-delivery. A total of 46.9% of women had at least one pre specified pregnancy complication; the most commonly observed were fetal abnormality (24.7%) and early or threatened labor (16.3%). Multiple gestation (1.9%) resulted in the highest adjusted incremental cost ($12,212; 95% CI = 11,298, 13,216); hypertension ($6152; 95% CI = 5312, 6992) and diabetes ($5081; 95% CI = 4244, 5918) were also among those complications that led to high incremental costs of care. CONCLUSION: Pregnancy and delivery are frequently compounded by complications that lead to increased costs and resource utilization. PMID- 25714266 TI - Curvilinear transformation of z-shaped upper lip scar by diamond-shaped excision in secondary cleft lip deformities: a photogrammetric evaluation. AB - Purpose : The visible Z-shaped upper lip scar that occurs after the Tennison and Randall triangular flap technique remains a cleft stigma. Herein, we present our curvilinear transformation technique for the Z-shaped upper lip scar by diamond shaped excision and evaluate the results using photogrammetric analyses. Patients and Methods : From 1997 to 2006, 23 patients with secondary cleft lip deformity with the visible Z-shaped upper lip scar underwent correction with the technique. The scar was excised in the diamond shape above the muscle. After curvilinear closure, the elongated length of the upper lip was excised just below the nostril sill, as the measured Cupid's bow height discrepancy. The result was assessed by the authors' standardized photogrammetry technique. Results : There was a statistically significant decrease between the preoperative central limb of the Z shaped scar and the width of the postoperative curvilinear upper lip scar. The pre- and postoperative Cupid's bow height differences were not statistically significant. Conclusions : The curvilinear transformation of the Z-shaped scar is an efficient procedure that provides (1) a significant decrease in the width of an upper lip scar to make it less conspicuous, (2) incorporation of the scar into the philtral column, (3) a biconcave natural philtral column shape in frontal view, and (4) formation of the natural concave philtral contour in profile view. PMID- 25714267 TI - Nasal profile changes with le fort I maxillary advancement surgery. AB - Introduction : The purpose of this study was to quantify anteroposterior facial soft tissue changes with respect to underlying skeletal movements after Le Fort I maxillary advancement surgery by using lateral cephalograms taken before and after the operation. Materials and Methods : The study group consisted of 20 patients (10 women, 10 men; mean age 23.4 +/- 1.4 years) having a Class III skeletal deformity caused by a retrognathic maxilla. All patients were treated by Le Fort I maxillary advancement osteotomy. Lateral cephalograms were taken before and 1.6 +/- 0.4 years after surgery. Results : The anteroposterior position of A point and anteroposterior position of maxillary incisor were significantly protracted (-2.69 +/- 3.34 and -2.68 +/- 3.21, respectively; P < .01). The nasal anteroposterior and superoinferior positions (NASALAP and NASALSI, respectively) were significantly changed (-2.70 +/- 6.81, P < .01, and -2.55 +/- 5.80, P < .05, respectively) and nasal elevation and protraction were observed after Le Fort I maxillary advancement surgery. Conclusions : The changes in anteroposterior and superoinferior positions of A-point were correlated with the nasal superoinferior position (r = -0.71 , P < .05; r = 0.72, P < .05) after Le Fort I maxillary advancement surgery. PMID- 25714268 TI - Application of linear discriminant analysis to the nasometric assessment of resonance disorders: a pilot study. AB - Objective : Nasalance scores have traditionally been used to assess hypernasality. However, resonance disorders are often complex, and hypernasality and nasal obstruction may co-occur in patients with cleft palate. In this study, normal speakers simulated different resonance disorders, and linear discriminant analysis was used to create a tentative diagnostic formula based on nasalance scores for nonnasal and nasal speech stimuli. Materials and Methods : Eleven female participants were recorded with the Nasometer 6450 while reading nonnasal and nasal speech stimuli. Nasalance measurements were taken of their normal resonance and their simulations of hyponasal, hypernasal, and mixed resonance. Results : A repeated-measures analysis of variance revealed a resonance condition stimuli interaction effect (P < .001). A linear discriminant analysis of the participants' nasalance scores led to formulas correctly classifying 64.4% of the resonance conditions. When the hyponasal and mixed resonance conditions with obstruction of the less patent nostril were removed from the analysis, the resultant formulas correctly classified 88.6% of the resonance conditions. Conclusion : The simulations produced distinctive nasalance scores, enabling the creation of formulas that predicted resonance condition above chance level. The preliminary results demonstrate the potential of this approach for the diagnosis of resonance disorders. PMID- 25714269 TI - Unusual foreign body in the nasal cavity of an adult with repaired cleft lip and palate. AB - Intranasal foreign bodies arising from dental clinical practice, especially in patients with cleft lip and palate (CLP) occur rarely and are very scarce in the literature. This article reports an unusual case of a dental impression material presenting as a foreign body in the nasal cavity of an adult with repaired CLP who presented for dental prosthetic rehabilitation. To our knowledge, this is only the second report presenting nasal foreign body in a cleft patient arising due to a dental impression procedure. PMID- 25714264 TI - The role of pattern recognition receptors in the innate recognition of Candida albicans. AB - Candida albicans is both a commensal microorganism in healthy individuals and a major fungal pathogen causing high mortality in immunocompromised patients. Yeast hypha morphological transition is a well known virulence trait of C. albicans. Host innate immunity to C. albicans critically requires pattern recognition receptors (PRRs). In this review, we summarize the PRRs involved in the recognition of C. albicans in epithelial cells, endothelial cells, and phagocytic cells separately. We figure out the differential recognition of yeasts and hyphae, the findings on PRR-deficient mice, and the discoveries on human PRR related single nucleotide polymorphisms (SNPs). PMID- 25714270 TI - Prosthodontic rehabilitation of congenital auricular defect: a clinical report. AB - This clinical report presents the prosthetic rehabilitation of a congenital auricular defect. The rehabilitation was initially performed with an adhesive retained silicone prosthesis. After careful evaluation of the patient's retentive needs, two endo-osseous craniofacial implants were placed in the mastoid region. After integration, an implant-retained silicone prosthesis was fabricated using a Hader bar with two ERA attachments, which restored the defect with good aesthetic and functional outcome. Prosthetic rehabilitation is a viable treatment option for restoring auricular defects and can be indicated in situations where surgical reconstruction may not be feasible. PMID- 25714272 TI - FKBP5/FKBP51 enhances autophagy to synergize with antidepressant action. AB - Levels of autophagy markers rise upon treatment of cells with antidepressants. However, it was not known whether this phenomenon might be linked to other antidepressant pathways or to any physiological effect. In this punctum, we summarize and discuss our recent findings that provide evidence for a role of the cochaperone FKBP5/FKBP51 (FK506 binding protein 5) in autophagy as a prerequisite for antidepressant action in cells, mice, and humans. FKBP5 associates with BECN1, changes its phosphorylation and protein levels and enhances markers of autophagy and autophagic flux. The effects of antidepressants on autophagy as well as their physiological effects in mice and human depend on FKBP5. PMID- 25714274 TI - The copyright transfer agreement: key points. PMID- 25714275 TI - Cardiac CT angiography in the emergency department. AB - OBJECTIVE. Nearly 8 million patients present annually to emergency departments (EDs) in the United States with acute chest pain. Identifying those with a sufficiently low risk of acute coronary syndrome (ACS) remains challenging. Early imaging is important for risk stratification of these individuals. The objective of this article is to discuss the role of cardiac CT angiography (CTA) as a safe, efficient, and cost-effective tool in this setting and review state-of-the-art technology, protocols, advantages, and limitations from the perspective of our institution's 10-year experience. CONCLUSION. Early utilization of cardiac CTA in patients presenting to the ED with chest pain and a low to intermediate risk of ACS quickly identifies a group of particularly low-risk patients (< 1% risk of adverse events within 30 days) and allows safe and expedited discharge. By preventing unnecessary admissions and prolonged lengths of stay, a strategy based on early cardiac CTA has been shown to be efficient, although potential overutilization and other issues require long-term study. PMID- 25714276 TI - Radiologic manifestations of bronchoscopic lung volume reduction in severe chronic obstructive pulmonary disease. AB - OBJECTIVE. Bronchoscopic lung volume reduction promises to become an effective treatment option in severe chronic obstructive pulmonary disease. Several techniques are currently being investigated, including implantation of devices into the lung and instillation of hot water vapor or polymer. This article reviews the spectrum of radiologic manifestations on chest radiography and CT that occur after the intervention. CONCLUSION. Familiarity with the intended effects and adverse events will aid the radiologist in supporting bronchoscopic lung volume reduction. PMID- 25714277 TI - CT myocardial perfusion imaging. AB - OBJECTIVE. CT myocardial perfusion imaging is rapidly becoming an important adjunct to coronary CT angiography for the anatomic and functional assessment of coronary artery disease with a single modality. Existing techniques for CT myocardial perfusion imaging include static techniques, which provide a snapshot of the myocardial blood pool, and dynamic techniques. CONCLUSION. This review provides a systematic overview of the presently available approaches for the assessment of myocardial perfusion at CT, including diagnostic accuracy and limitations. PMID- 25714278 TI - Consensus statements from a multidisciplinary expert panel on the utilization and application of a liver-specific MRI contrast agent (gadoxetic acid). AB - OBJECTIVE. This systematic review presents evidence-based consensus statements as reported by a multidisciplinary expert panel (six abdominal radiologists, four hepatobiliary surgeons, and two hepatologists) regarding the use of gadoxetic acid for liver MRI. CONCULSION. Although this review highlights the incremental diagnostic value of hepatobiliary phase imaging with gadoxetic acid-enhanced liver MRI in multiple clinical scenarios, there remains a need for further impact studies for some clinical applications, such as hepatocellular carcinoma in cirrhosis. PMID- 25714280 TI - Journal Club: the Alvarado score as a method for reducing the number of CT studies when appendiceal ultrasound fails to visualize the appendix in adults. AB - OBJECTIVE. The purpose of this article is to evaluate the hypothesis that Alvarado scores of 3 or lower identify adult patients who are unlikely to benefit from CT after appendiceal ultrasound fails to show the appendix and is otherwise normal. MATERIALS AND METHODS. We identified 119 consecutive adults for whom the appendix was not seen on otherwise normal appendiceal sonography performed as the first imaging study for suspected appendicitis, who subsequently underwent CT within 48 hours, and whose data permitted retrospective calculation of admission Alvarado scores. Specific benefits of CT were defined as diagnoses of appendicitis or significant alternative findings, and specific benefits were compared between patients with Alvarado scores of 3 or less and 4 or higher. Significant alternative findings on CT were findings other than appendicitis that were treated with medical or surgical therapy during the admission or that were to be addressed during follow-up care. Diagnostic reference standards were discharge diagnoses, pathologic examinations, and clinical follow-up. RESULTS. No patients (0.0%, 0/49) with Alvarado scores 3 or lower had appendicitis, compared with 17.1% (12/70) of patients with Alvarado scores 4 or higher (p = 0.001), and CT showed neither appendicitis nor significant alternative findings in 85.7% (42/49) versus 58.6% (41/70) of these patients, respectively (p = 0.002). The rates of perforated appendicitis, as well as significant alternative CT findings, did not differ significantly. CONCLUSION. Adults with Alvarado scores 3 or lower who have nonvisualized appendixes and otherwise normal appendiceal sonography are at very low risk for appendicitis or significant alternative findings and therefore are not likely to benefit from CT. PMID- 25714279 TI - Quantification of hepatic blood flow using a high-resolution phase-contrast MRI sequence with compressed sensing acceleration. AB - OBJECTIVE. The objective of our study was to evaluate the performance of a high spatial-resolution 2D phase-contrast (PC) MRI technique accelerated with compressed sensing for portal vein (PV) and hepatic artery (HA) flow quantification in comparison with a standard PC MRI sequence. SUBJECTS AND METHODS. In this prospective study, two PC MRI sequences were compared, one with parallel imaging acceleration and low spatial resolution (generalized autocalibrating partial parallel acquisition [GRAPPA]) and one with compressed sensing acceleration and high spatial resolution (sparse). Seventy-six patients were assessed, including 37 patients with cirrhosis. Two observers evaluated PC image quality. Quantitative analyses yielded a mean velocity, flow, and vessel area for the PV and HA and an arterial fraction. The PC techniques were compared using the paired Wilcoxon test and Bland-Altman statistics. The sensitivity of the flow parameters to the severity of cirrhosis was also assessed. RESULTS. Vessel delineation was significantly improved using the PC sparse sequence (p < 0.034). For both in vitro and in vivo measurements, PC sparse yielded lower estimates for vessel area and flow, and larger differences between PC GRAPPA and PC sparse were observed in the HA. PV velocity and flow were significantly lower in patients with cirrhosis on both PC sparse (p < 0.001 and p = 0.042, respectively) and PC GRAPPA (p < 0.001 and p = 0.005, respectively). PV velocity correlated negatively with Child-Pugh class (r = -0.50, p < 0.001), whereas the arterial fraction measured with PC sparse was higher in patients with Child-Pugh class B or C disease than in those with Child-Pugh class A disease, with a trend toward significance (p = 0.055). CONCLUSION. A high-spatial-resolution highly accelerated compressed sensing technique (PC sparse) allows total hepatic blood flow measurements obtained in 1 breath-hold, provides improved delineation of the hepatic vessels compared with a standard PC MRI sequence (GRAPPA), and can potentially be used for the noninvasive assessment of liver cirrhosis. PMID- 25714281 TI - Diagnostic per-patient accuracy of an abbreviated hepatobiliary phase gadoxetic acid-enhanced MRI for hepatocellular carcinoma surveillance. AB - OBJECTIVE. The purpose of this study is to evaluate the per-patient diagnostic performance of an abbreviated gadoxetic acid-enhanced MRI protocol for hepatocellular carcinoma (HCC) surveillance. MATERIALS AND METHODS. A retrospective review identified 298 consecutive patients at risk for HCC enrolled in a gadoxetic acid-enhanced MRI-based HCC surveillance program. For each patient, the first gadoxetic acid-enhanced MRI was analyzed. To simulate an abbreviated protocol, two readers independently read two image sets per patient: set 1 consisted of T1-weighted 20-minute hepatobiliary phase and T2-weighted single-shot fast spin-echo (SSFSE) images; set 2 included diffusion-weighted imaging (DWI) and images from set 1. Image sets were scored as positive or negative according to the presence of at least one nodule 10 mm or larger that met the predetermined criteria. Agreement was assessed using Cohen kappa statistics. A composite reference standard was used to determine the diagnostic performance of each image set for each reader. RESULTS. Interreader agreement was substantial for both image sets (kappa = 0.72 for both) and intrareader agreement was excellent (kappa = 0.97-0.99). Reader performance for image set 1 was sensitivity of 85.7% for reader A and 79.6% for reader B, specificity of 91.2% for reader A and 95.2% for reader B, and negative predictive value of 97.0% for reader A and 96.0% for reader B. Reader performance for image set 2 was nearly identical, with only one of 298 examinations scored differently on image set 2 compared with set 1. CONCLUSION. An abbreviated MRI protocol consisting of T2 weighted SSFSE and gadoxetic acid-enhanced hepatobiliary phase has high negative predictive value and may be an acceptable method for HCC surveillance. The inclusion of a DWI sequence did not significantly alter the diagnostic performance of the abbreviated protocol. PMID- 25714282 TI - Characterization of adrenal lesions at chemical-shift MRI: a direct intraindividual comparison of in- and opposed-phase imaging at 1.5 T and 3 T. AB - OBJECTIVE. The purpose of this article is to perform an intraindividual comparison between 1.5 T and 3 T chemical-shift MRI in differentiating adrenal adenomas and nonadenomas, including comparison of quantitative thresholds. MATERIALS AND METHODS. In this retrospective study, 37 adrenal lesions in 36 patients (20 men and 16 women; mean [+/- SD] age, 66.7 +/- 12.9 years; 27 benign adenomas in 27 patients; 10 nonadenomas in nine patients) imaged at 1.5 T and 3 T were identified. Two readers qualitatively assessed intralesional signal loss between in- and opposed-phase images. One reader placed ROIs on adrenal lesions, spleen, liver, and muscle. Quantitative measures of signal loss, such as signal intensity (SI) index, adrenal-to-spleen ratio, adrenal-to-liver ratio, and adrenal-to-muscle ratio, were calculated. Qualitative and quantitative measures between field strengths were assessed with McNemar test and ROC analysis, respectively. RESULTS. Accuracy in qualitative adenoma identification (86.5% [32/37] at 1.5 T and 81.1% [30/37] at 3 T for reader 1; 81.1% [30/37] at 1.5 T and 83.8% [31/37] at 3 T for reader 2; both p >= 0.180) was equivalent at both field strengths. AUCs were not statistically significantly different between field strengths for quantitative measures: AUCs at 1.5 T versus 3 T were 0.956 versus 0.915 for SI index, 0.963 versus 0.870 for adrenal-to-spleen ratio, 0.935 versus 0.852 for adrenal-to-liver ratio, and 0.948 versus 0.948 for adrenal-to muscle ratio (all p > 0.11). The optimal threshold for SI index was lower at 3 T (> 7.4%) than at 1.5 T (> 21.6%) but had similar sensitivity (1.5 T, 92.6% [25/27]; 3 T, 88.9% [24/27]) and specificity (1.5 T, 90.0% [9/10]; 3 T, 90.0% [9/10]). CONCLUSION. Chemical-shift imaging has similar diagnostic efficacy for differentiating adrenal adenomas and nonadenomas at 1.5 T and 3 T. However, quantitative measures have different thresholds for this differentiation at 3 T; in particular, the commonly applied SI index is much lower at 3 T. PMID- 25714283 TI - MDCT findings of renal cell carcinoma associated with Xp11.2 translocation and TFE3 gene fusion and papillary renal cell carcinoma. AB - OBJECTIVE. The purpose of this study was to compare the MDCT features of renal cell carcinoma (RCC) associated with Xp11.2 translocation and TFE3 gene fusion (Xp11 RCC) and papillary RCC. MATERIALS AND METHODS. The study included 19 and 39 patients with histologically proven Xp11 RCC and papillary RCC, respectively, who underwent multiphase renal MDCT before nephrectomy. CT findings were compared between Xp11 RCC and papillary RCC using the Student t test and chi-square test. Subgroup analyses of small (< 4 cm) renal masses for these features were performed. RESULTS. Patients with Xp11 RCC were younger (p < 0.001), and it was more prevalent in women (p = 0.007). Tumor size was greater in Xp11 RCC (p = 0.004) and more common in cystic change (p < 0.001). Calcification and unenhanced high-attenuating areas were more frequent in Xp11 RCC (p = 0.001 and 0.026, respectively). Xp11 RCCs were more prevalent in lymph node and distant metastasis (p < 0.001 and p = 0.031, respectively). Xp11 RCC and papillary RCC showed no significant difference in epicenter, margin, and venous and collecting duct invasion (p = 0.403-1.000). Although Xp11 RCC and papillary RCC had lower attenuation than the renal cortex on corticomedullary and early excretory phases (p < 0.001), only Xp11 RCCs were hyperattenuating to the cortex on the unenhanced phase (p < 0.001). Xp11 RCCs had significantly higher attenuation compared with papillary RCCs on all phases (p <= 0.02). Regarding small masses, cystic change, calcification, and lymph node metastasis were still more frequent in Xp11 RCCs (p <= 0.016). CONCLUSION. Greater size, more cystic change, calcification, high attenuating areas on unenhanced imaging, and lymph node and distant metastasis were helpful for differentiating Xp11 RCC from papillary RCC. PMID- 25714284 TI - Apparent diffusion coefficient value and ratio as noninvasive potential biomarkers to predict prostate cancer grading: comparison with prostate biopsy and radical prostatectomy specimen. AB - OBJECTIVE. The purpose of this study is to test the association between diffusion weighted MRI and prostate cancer Gleason score at both biopsy and final pathologic analysis after radical prostatectomy. SUBJECTS AND METHODS. Patients with prostate cancer (n = 72) underwent diffusion-weighted MRI (b values, 0, 800, and 1600 s/mm(2)) with an endorectal coil. Apparent diffusion coefficient (ADC) and ADC ratio were obtained in normal and pathologic tissue and were correlated with transrectal ultrasound-guided biopsy (n = 72) and histopathologic (n = 39) Gleason scores using the ANOVA test. ADC accuracy was estimated using ROC curves. RESULTS. Lesions suspicious for prostate cancer were detected in 65 patients. The mean ADC was 1.47 and 0.87 * 10(-3) mm(2)/s for normal and pathologic tissue, respectively (p < 0.001). When we divided the population into four groups (normal tissue and biopsy Gleason scores of 6, 7, and 8-10), then the mean ADC value was 1.47, 0.96, 0.80, and 0.78 * 10(-3) mm(2)/s, respectively (p < 0.001). The ADC ratio decreased along with an increase in biopsy Gleason score (66.9%, 56.7%, and 51.5% for Gleason scores of 6, 7 and 8-10, respectively) (ANOVA, p = 0.003) and pathologic Gleason score (ANOVA, p < 0.001). ROC curves had an AUC of 0.94 and 0.86 for ADC and ADC ratio, respectively (p = 0.012 and 0.042, respectively). CONCLUSION. Decreasing ADC values may represent a strong risk factor of harboring a poorly differentiated prostate cancer, independently of biopsy characteristics. PMID- 25714285 TI - Rising utilization of CT in adult fall patients. AB - OBJECTIVE. Falls are a common cause of emergency department (ED) visits in the United States. We evaluated trends in CT utilization for adult fall patients in the United States from 2001 to 2010. MATERIALS AND METHODS. Using the National Hospital Ambulatory Medical Care Survey, we identified all visits from 2001 to 2010 of adult patients presenting to EDs after falls. This database surveys approximately 500 EDs annually for 4 weeks, providing national estimates on ED resource utilization and outcomes. We studied trends in CT utilization and proportion of visits with life-threatening conditions (intracranial hemorrhage, organ laceration, axial skeletal fractures) after falls. We also studied the association between CT utilization rates and demographic characteristics and admission status. RESULTS. A total of 22,166 unweighted observations representing 73,241,368 visits were identified. The proportion of adult fall patient visits during which CT was performed increased from 11.4% in 2001 to 28.0% in 2010 (p < 0.0001), whereas the proportion of adult fall visits with life-threatening conditions increased from 5.7% to 8.2% (p < 0.0001). On adjusted analysis (adjusting for life-threatening condition and demographic variables), each successive year was independently associated with CT utilization (odds ratio, 1.21 [95% CI, 1.21-1.21]). The odds of CT utilization in 2010 compared with 2001 were 2.62 (95% CI, 2.61-2.62). CONCLUSION. There was a 2.5-fold increase in CT utilization among adult fall patient visits from 2001 to 2010. When demographic and clinical variables were controlled for, increasing year was independently associated with CT utilization. These findings suggest that CT may be overutilized among adult fall patients. PMID- 25714286 TI - Ultralow-dose CT of the craniofacial bone for navigated surgery using adaptive statistical iterative reconstruction and model-based iterative reconstruction: 2D and 3D image quality. AB - OBJECTIVE. The purpose of this article is to evaluate 2D and 3D image quality of high-resolution ultralow-dose CT images of the craniofacial bone for navigated surgery using adaptive statistical iterative reconstruction (ASIR) and model based iterative reconstruction (MBIR) in comparison with standard filtered backprojection (FBP). MATERIALS AND METHODS. A formalin-fixed human cadaver head was scanned using a clinical reference protocol at a CT dose index volume of 30.48 mGy and a series of five ultralow-dose protocols at 3.48, 2.19, 0.82, 0.44, and 0.22 mGy using FBP and ASIR at 50% (ASIR-50), ASIR at 100% (ASIR-100), and MBIR. Blinded 2D axial and 3D volume-rendered images were compared with each other by three readers using top-down scoring. Scores were analyzed per protocol or dose and reconstruction. All images were compared with the FBP reference at 30.48 mGy. A nonparametric Mann-Whitney U test was used. Statistical significance was set at p < 0.05. RESULTS. For 2D images, the FBP reference at 30.48 mGy did not statistically significantly differ from ASIR-100 at 3.48 mGy, ASIR-100 at 2.19 mGy, and MBIR at 0.82 mGy. MBIR at 2.19 and 3.48 mGy scored statistically significantly better than the FBP reference (p = 0.032 and 0.001, respectively). For 3D images, the FBP reference at 30.48 mGy did not statistically significantly differ from all reconstructions at 3.48 mGy; FBP and ASIR-100 at 2.19 mGy; FBP, ASIR-100, and MBIR at 0.82 mGy; MBIR at 0.44 mGy; and MBIR at 0.22 mGy. CONCLUSION. MBIR (2D and 3D) and ASIR-100 (2D) may significantly improve subjective image quality of ultralow-dose images and may allow more than 90% dose reductions. PMID- 25714287 TI - Evaluation of lossy data compression in primary interpretation for full-field digital mammography. AB - OBJECTIVE. For full-field digital mammography (FFDM), federal regulations prohibit lossy data compression for primary reading and archiving, unlike all other medical images, where reading physicians can apply their professional judgment in implementing lossy compression. Faster image transfer, lower costs, and greater access to expert mammographers would result from development of a safe standard for primary interpretation and archive of lossy-compressed FFDM images. This investigation explores whether JPEG 2000 80:1 lossy data compression affects clinical accuracy in digital mammography. MATERIALS AND METHODS. Randomized FFDM cases (n = 194) were interpreted by six experienced mammographers with and without JPEG 2000 80:1 lossy compression applied. A cancer-enriched population was used, with just less than half of the cases (42%) containing subtle (< 1 cm) biopsy-proven cancerous lesions, and the remaining cases were negative as proven by 2-year follow-up. Data were analyzed using the jackknife alternative free-response ROC (JAFROC) method. RESULTS. The differences in reader performance between lossy-compressed and non-lossy-compressed images using lesion localization (0.660 vs 0.671), true-positive fraction (0.879 vs 0.879), and false positive fraction (0.283 vs 0.271) were not statistically significant. There was no difference in the JAFROC figure of merit between lossy-compressed and non lossy-compressed images, with a mean difference of -0.01 (95% CI, -0.03 to 0.01; F1,5 = 2.30; p = 0.189). CONCLUSION. These results suggest that primary interpretation of JPEG 2000 80:1 lossy-compressed FFDM images may be viable without degradation of clinical quality. Benefits would include lower storage costs, faster telemammography, and enhanced access to expert mammographers. PMID- 25714288 TI - Improved efficiency in clinical workflow of reporting measured oncology lesions via PACS-integrated lesion tracking tool. AB - OBJECTIVE. Imaging provides evidence for the response to oncology treatment by the serial measurement of reference lesions. Unfortunately, the identification, comparison, measurement, and documentation of several reference lesions can be an inefficient process. We tested the hypothesis that optimized workflow orchestration and tight integration of a lesion tracking tool into the PACS and speech recognition system can result in improvements in oncologic lesion measurement efficiency. SUBJECTS AND METHODS. A lesion management tool tightly integrated into the PACS workflow was developed. We evaluated the effect of the use of the tool on measurement reporting time by means of a prospective time motion study on 86 body CT examinations with 241 measureable oncologic lesions with four radiologists. RESULTS. Aggregated measurement reporting time per lesion was 11.64 seconds in standard workflow, 16.67 seconds if readers had to register measurements de novo, and 6.36 seconds for each subsequent follow-up study. Differences were statistically significant (p < 0.05) for each reader, except for one difference for one reader. CONCLUSION. Measurement reporting time can be reduced by using a PACS workflow-integrated lesion management tool, especially for patients with multiple follow-up examinations, reversing the onetime efficiency penalty at baseline registration. PMID- 25714289 TI - Ultrasound assessment of medial meniscal extrusion: a validation study using MRI as reference standard. AB - OBJECTIVE. The purpose of this article is to validate both semiquantitative and quantitative ultrasound assessment of medial meniscal extrusion using MRI assessment as the reference standard. SUBJECTS AND METHODS. Ninety-three consecutive patients with chronic knee pain referred for knee MRI were evaluated by ultrasound and MRI on the same day. Two musculoskeletal radiologists assessed meniscal extrusion on ultrasound and MRI separately and independently and graded it semiquantitatively as follows: 0 (< 2 mm), 1 (>= 2 mm and < 4 mm), and 2 (>= 4 mm). Agreement between the ultrasound and MRI evaluations was determined using weighted kappa statistics. Intraclass correlation coefficients were used to evaluate agreement using the absolute values of extrusion (quantitative assessment). We further evaluated the diagnostic performance of ultrasound for the detection of medial meniscal extrusion using MRI as the reference standard. RESULTS. For semiquantitative grading, agreement between ultrasound and MRI was moderate for reader 1 (kappa = 0.57) and substantial for reader 2 (kappa = 0.64). Substantial agreement was found for both readers (intraclass correlation coefficients, 0.73 and 0.70) when comparing quantitative assessment of meniscal extrusion between ultrasound and MRI. Ultrasound showed excellent sensitivity (95% and 96% for each reader) and good specificity (82% and 70% for each reader) in the detection of meniscal extrusion. CONCLUSION. Ultrasound assessment of meniscal extrusion is reliable and can be used for both quantitative and semiquantitative assessment, exhibiting excellent diagnostic performance for the detection of meniscal extrusion compared with MRI. PMID- 25714290 TI - Spectrum of suprascapular nerve lesions: normal and abnormal neuromuscular imaging appearances on 3-T MR neurography. AB - OBJECTIVE. In this article, we will review the normal anatomy and imaging features of various neuromuscular abnormalities related to suprascapular neuropathy. CONCLUSION. Suprascapular neuropathy can be difficult to distinguish from rotator cuff pathology, plexopathy, and radiculopathy. Electrodiagnostic studies are considered the reference standard for diagnosis; however, high resolution 3-T MR neurography (MRN) can play an important role. MRN enables direct visualization of the nerve and simultaneous assessment of the cervical spine, brachial plexus, and rotator cuff. PMID- 25714291 TI - Effect of spatial resolution of T2-weighted imaging on diagnostic efficacy of MRI in detection of papilledema. AB - OBJECTIVE. Morphologic changes associated with papilledema may be masked by partial volume averaging effects in images obtained at a slice thickness greater than normal optic nerve thickness. We aimed to compare the diagnostic accuracy of high-resolution 3D T2-weighted imaging performed at submillimeter slice thickness with conventional T2-weighted imaging performed at 5-mm slice thickness for detection of papilledema. MATERIALS AND METHODS. Two blinded neuroradiologists evaluated conventional and high-resolution axial T2-weighted imaging across orbits from 25 patients with clinically proven papilledema and 66 control participants without papilledema. They graded optic nerve sheath distention and optic nerve head configuration, also making a binary determination for presence or absence of papilledema for each set of images. The diagnostic accuracy of each technique was assessed in terms of sensitivity, specificity, positive likelihood ratio, and interobserver agreement. These parameters were compared using the homogeneity of odds ratio and McNemar tests. RESULTS. High-resolution T2-weighted imaging was associated with higher sensitivity (83.3% vs 56.2%, p = 0.0072 for reader 1; 87.5% vs 54.2% for reader 2, p = 0.0001) but unchanged specificity. High-resolution T2-weighted imaging was significantly better than conventional T2 weighted imaging in detecting optic nerve head deformity in patients with papilledema, but there was no difference between two techniques in detection of optic nerve sheath distention. High-resolution imaging also enabled greater interobserver agreement (kappa = 0.82) compared with conventional T2-weighted image (kappa = 0.62). CONCLUSION. Improved visualization of the optic nerve head afforded by high-resolution T2-weighted imaging translates into better diagnostic performance of MRI in detection of papilledema, with higher sensitivity and interobserver reliability. PMID- 25714292 TI - MRI findings of new uptake in the femoral head detected on follow-up bone scans. AB - OBJECTIVE. The purpose of this article is to suggest clinical indications for MRI in patients with breast cancer who have new uptake lesions in the femoral head on follow-up bone scans, by evaluating the incidence and causes of new uptake lesions. MATERIALS AND METHODS. Between January 2002 and July 2013, a total of 145 patients with breast cancer who showed new uptake in the femoral head on follow-up bone scans were included in our study. They were classified into two groups: group 1 consisted of 125 patients without known bone metastases, and group 2 consisted of 20 patients who already had bone metastases other than that in the femoral head. The Fisher exact test was performed for the statistical analysis. Thereafter, we reviewed MR images for characterization of the new abnormal uptake in the femoral head. RESULTS. New uptake lesions in the femoral head were metastatic in only 4.8% (6/125) of group 1 patients but in 75% (15/20) of group 2 patients (p < 0.0001). In both groups, no patient with a single uptake lesion in the femoral head had bone metastasis, whereas all patients with more than five new uptake lesions, including those of the femoral head, showed bone metastasis. Most MRI diagnoses for new uptake in the femoral head were fibrocystic change (15/30, 50%) and subchondral fracture (11/30, 36.7%). CONCLUSION. Most of the new uptake lesions in the femoral head detected on the follow-up bone scans in patients with breast cancer were benign. However, MRI could be considered in patients with known bone metastasis or with multiple new uptake lesions on bone scans. PMID- 25714293 TI - Comparison of gonadal radiation doses from CT enterography and small-bowel follow through in pediatric patients. AB - OBJECTIVE. CT enterography is superior to small-bowel follow-through (SBFT) for diagnosis of inflammatory bowel disease (IBD). It is widely assumed that the radiation dose from CT enterography is greater than that from SBFT in the pediatric patient. This study was designed to compare gonadal doses from CT enterography and SBFT to verify the best imaging choice for IBD evaluation in children. This study also challenges the assumption that CT enterography imparts a higher radiation dose through comparison of calculated radiation doses from CT enterography and SBFT. MATERIALS AND METHODS. Patients 0-18 years old who underwent either CT enterography or SBFT over a 2-year period were included. The CT enterography group consisted of 39 boys and 51 girls, whereas the SBFT group consisted of 89 boys and 113 girls. CT enterography was performed at 120 kVp and approximately 132 mAs (range, 54-330 mAs) using weight-based protocols. SBFT used automated control of kilovoltage and tube current-exposure time product. Patient demographics and technical parameters were collected for CT enterography and SBFT, data were cross-paired between CT enterography and SBFT, and gonadal dose was calculated. RESULTS. Mean (+/- SD) CT enterography testis and ovarian doses were 0.93 +/- 0.3 cGy (n = 39) and 0.64 +/- 0.2 cGy (n = 51), respectively. Mean SBFT testis and ovarian doses were 2.3 +/- 1.6 cGy (n = 89) and 1.49 +/- 0.3 cGy (n = 113), respectively. Mean fluoroscopy time for SBFT was 2.6 +/- 2 minutes. Gonadal dose for CT enterography was significantly lower than that for SBFT in boys and girls (p < 0.001). SBFT dose was lower in girls than boys (p < 0.001), whereas CT enterography dose was higher in boys than girls (p < 0.001). CONCLUSION. Gonadal dose for CT enterography was lower than that for SBFT for boys and girls of all sizes and age. Controlled exposure time made CT enterography dose more consistent, whereas the range of dose for SBFT was highly operator dependent and related to extent of disease. Thus, for IBD, CT enterography is preferred over SBFT for all children. PMID- 25714294 TI - Ultrasound assessment of breast development: distinction between premature thelarche and precocious puberty. AB - OBJECTIVE. We analyzed the correlation between breast development and ultrasound measured breast bud diameter. We also evaluated different breast ultrasound findings in pediatric subjects with precocious puberty and premature thelarche while comparing bone age and hormone levels. MATERIALS AND METHODS. We performed a retrospective study with a sample of 90 girls (mean age, 7.8 years) who underwent breast ultrasound for evaluation of early breast development between March 2011 and February 2013. We evaluated breast ultrasound grade, bud diameter, and clinical characteristics including bone age and hormone levels. Among the 90 girls, 69 were up to 8 years old (mean age, 7.3 years). We divided them into healthy, precocious puberty, and premature thelarche groups and evaluated the clinicoradiologic findings for each group. RESULTS. Breast ultrasound grade was correlated with age, bone age, bud diameter, luteinizing hormone (LH), follicle stimulating hormone (FSH), and estradiol (E2). Bud diameter was correlated with age, bone age, LH, FSH, and E2. However, the difference between bone age and chronological age was not correlated with ultrasound grade or bud diameter. Among 69 girls up to 8 years old, including 11 healthy girls (15.9%), 26 girls with precocious puberty (37.7%) (mean [SD] age, 7.3 years), and 32 girls with premature thelarche (46.4%) (mean age, 7.2 years), there were no significant differences in other variables except values for bone age (p = 0.001) and difference between bone age and chronological age (p < 0.001). CONCLUSION. Breast ultrasound might be useful for evaluating sexual development with respect to bud diameter or ultrasound grade. However, its ability to distinguish precocious puberty from premature thelarche is limited. PMID- 25714295 TI - Effect of inversion recovery fat suppression on hepatic R2* quantitation in transfusional siderosis. AB - OBJECTIVE. The purpose of this study is to evaluate whether the application of spectral pre-saturation inversion recovery (SPIR) fat suppression in standard multiecho gradient-echo sequences has a significant effect on hepatic R2* quantitation in patients with iron overload syndromes. MATERIALS AND METHODS. Eighty patients were scanned with a multiecho gradient-echo sequence without and with the application of SPIR. Six different postprocessing approaches were used to extract R2* values for maximum generality. RESULTS. SPIR fat suppression lowered R2* values by 3.9-7.0% (p < 0.0001 in all pairwise comparisons), independently of the postprocessing algorithm. Coefficients of variation for R2* ranged from 4.5% to 10.0%. Regardless of the size of the ROI (area of homogeneous tissue or entire liver profile in the slice), pixelwise approaches combined with an exponential-plus-constant fitting model yielded the lowest coefficients of variation (4.5% and 5.1%), whereas truncated exponential fits of the averaged signals produced the highest coefficients of variation (7.8% and 10%). For R2* values exceeding 200 Hz, a Bland-Altman analysis showed a bias that grew linearly for all postprocessing methods. CONCLUSION. SPIR fat suppression resulted in systematically lower hepatic R2* estimates. Because calibration curves were derived using images without fat suppression, these biases should be corrected when reporting liver iron concentrations estimated from fat-suppressed multiecho T2*-weighted images. PMID- 25714296 TI - Clinical value of ultrasound in diagnosing pediatric choledochal cyst perforation. AB - OBJECTIVE. The objective of our study was to evaluate ultrasound images of pediatric patients with choledochal cyst perforation and establish imaging findings that can be used as the basis for timely surgical intervention. MATERIALS AND METHODS. Our study group was composed of 23 pediatric patients who presented with various symptoms of acute abdomen and were admitted to our institution between 1996 and 2013. All had undergone preoperative ultrasound examination and had a final diagnosis of choledochal cyst perforation that was confirmed at exploratory laparotomy. The imaging and surgical data were reviewed and analyzed retrospectively. RESULTS. The 23 patients included nine males and 14 females with a mean age of 2.55 years and mean disease duration of 12.48 days. The most common initial diagnoses were intestinal obstruction and peritonitis. Real-time ultrasound imaging with multislice views revealed characteristics of choledochal cyst perforation, including changes in the shape of the bile duct, loss of local gallbladder tension, thickened gallbladder wall, changes in the morphology of the gallbladder, and peritoneal effusion. The inability to visualize the gallbladder, gallbladder enlargement, the presence of gallbladder sludge and of pebblelike stones, and dilatation of the intrahepatic ducts were also noted on ultrasound. Choledochectasia was present in a majority of the patients (17/23), and ascites was seen in all 23 patients. The ultrasound signs corresponded to the surgical findings, thus showing the high clinical diagnostic value of ultrasound in this setting. CONCLUSION. Real-time ultrasound imaging with its multislice views and good reproducibility-allows definitive preoperative diagnosis of pediatric choledochal cyst perforation. PMID- 25714297 TI - Pediatric CT dose reduction for suspected appendicitis: a practice quality improvement project using artificial gaussian noise--part 2, clinical outcomes. AB - OBJECTIVE. The purpose of this study was to determine the effect of a nominal 50% reduction in median absorbed radiation dose on sensitivity, specificity, and negative appendectomy rate of CT for acute appendicitis in children. MATERIALS AND METHODS. On the basis of a departmental practice quality improvement initiative using computer-generated gaussian noise for CT dose reduction, we applied a nominal dose reduction of 50% to abdominal CT techniques used for bowel imaging. This retrospective study consisted of 494 children who underwent a CT for suspected acute appendicitis before (n = 244; mean age, 133 months) and after (n = 250; mean age, 145 months) the nominal 50% dose reduction. Test performance characteristics of CT for acute appendicitis and impact on the negative appendectomy rate were compared for both time periods. Primary analyses were performed with histologic diagnosis as the outcome standard. Volume CT dose index and dose-length product were recorded from dose reports and size-specific dose estimates were calculated. RESULTS. The nominal 50% dose reduction resulted in an actual 39% decrease in median absorbed radiation dose. Sensitivity of CT for diagnosis of acute appendicitis was 98% (95% CI, 91-100%) versus 97% (91-100%), and specificity was 93% (88-96%) versus 94% (90-97%) before and after dose reduction, respectively. The negative appendectomy rate was 4.5% (0.8-10.25%) before dose reduction and 4.0% (0.4-7.6%) after dose reduction. CONCLUSION. The negative appendectomy rate and performance characteristics of the CT-based diagnosis of acute appendicitis were not affected by a 39% reduction in median absorbed radiation dose. PMID- 25714298 TI - Hybrid and model-based iterative reconstruction techniques for pediatric CT. AB - OBJECTIVE. Radiation exposure from CT examinations should be reduced to a minimum in children. Iterative reconstruction (IR) is a method to reduce image noise that can be used to improve CT image quality, thereby allowing radiation dose reduction. This article reviews the use of hybrid and model-based IRs in pediatric CT and discusses the possibilities, advantages, and disadvantages of IR in pediatric CT and the importance of radiation dose reduction for CT of children. CONCLUSION. IR is a promising and potentially highly valuable technique that can be used to substantially reduce the amount of radiation in pediatric imaging. Future research should determine the maximum achievable radiation dose reduction in pediatric CT that is possible without a loss of diagnostic image quality. PMID- 25714299 TI - TIPS for refractory ascites: a 6-year single-center experience with expanded polytetrafluoroethylene-covered stent-grafts. AB - OBJECTIVE. This single-center study evaluated the use of expanded polytetrafluoroethylene (ePTFE)-covered stent-grafts for transjugular intrahepatic portosystemic shunt (TIPS) placement to manage portal hypertension related refractory ascites. MATERIALS AND METHODS. One hundred patients at a single tertiary care center in a major metropolitan hospital underwent TIPS placement with an ePTFE-covered stent-graft (Viatorr TIPS Endoprosthesis). Patients with portal hypertension-related ascites and preexisting hepatocellular carcinoma or liver transplant were excluded from the analysis. Records were reviewed for demographic characteristics, technical success of the TIPS procedures, and stent follow-up findings. Clinical results were assessed at 90- and 180-day intervals. RESULTS. Immediate technical success of the TIPS procedure was 100%. Of the 61 patients with documented follow-up, 55 (90.2%) had a partial or complete ascites response to TIPS creation. Of these 55 patients, nine experienced severe encephalopathy. Six of 61 patients (9.8%) did not experience a significant ascites response. Overall survival was 78.7% at 365-day follow-up. The 365-day survival was 84.2% for patients with a model for end-stage liver disease (MELD) score of less than 15, 67.0% for those with a score of 15-18, and 53.8% for those with a score of greater than 18 (p = 0.01). For patients with a MELD score of less than 18, the 365-day survival was 88.0% for those with an albumin value of 3 mg/dL or greater and 72.8% for those with an albumin value of less than 3 mg/dL (p = 0.04). CONCLUSION. TIPS placement using an ePTFE-covered stent-graft is an efficacious therapy for refractory ascites. Patients with preserved liver function-characterized by a MELD score of less than 15 or a MELD score of less than 18 and an albumin value of 3 mg/dL or greater-experience the greatest survival benefit. PMID- 25714300 TI - Clinical outcome of transcatheter arterial embolization with N-butyl-2 cyanoacrylate for control of acute gastrointestinal tract bleeding. AB - OBJECTIVE. The purpose of this article is to evaluate the clinical effectiveness of trans-catheter arterial embolization (TAE) with N-butyl-2-cyanoacrylate (NBCA), with or without other embolic materials for acute nonvariceal gastrointestinal tract bleeding, and to determine the factors associated with clinical outcomes. MATERIALS AND METHODS. TAE using NBCA only or in conjunction with other materials was performed for 102 patients (80 male and 22 female patients; mean age, 61.3 years) with acute nonvariceal gastrointestinal tract bleeding. Technical success, clinical success, and clinical factors, including age, sex, bleeding tendency, endoscopic attempts at hemostasis, number of transfusions, and bleeding causes (i.e., cancer vs noncancer), were retrospectively evaluated. Univariate and multivariable logistic regression analyses were performed to evaluate clinical factors and their ability to predict patient outcomes. Survival curves were obtained using Kaplan-Meier analyses and log-rank tests. RESULTS. There were 36 patients with cancer-related bleeding and 66 with non-cancer-related bleeding. Overall technical and clinical success rates were 100% (102/102) and 76.5% (78/102), respectively. Procedure-related complications included bowel infarction, which was noted in two patients. Recurrent bleeding and bleeding-related 30-day mortality rates were 15.7% (16/102) and 8.8% (9/102), respectively. Cancer-related bleeding increased clinical failure significantly (p = 0.003) and bleeding-related 30-day mortality with marginal significance (p = 0.05). Overall survival was poorer in patients with cancer-related bleeding. CONCLUSION. TAE with NBCA with or without other embolic agents showed high technical and clinical effectiveness in the management of acute nonvariceal gastrointestinal tract bleeding. Cancer-related bleeding was the only factor related to clinical failure, and possibly related to bleeding related 30-day mortality. PMID- 25714301 TI - Breast MRI fibroglandular volume and parenchymal enhancement in BRCA1 and BRCA2 mutation carriers before and immediately after risk-reducing salpingo oophorectomy. AB - OBJECTIVE. The purpose of this article is to assess the difference in fibroglandular volume and background parenchymal enhancement in BRCA1 and BRCA2 mutation carriers on contrast-enhanced breast MRI (CE-MRI) performed before and immediately after risk-reducing salpingo-oophorectomy (RRSO). MATERIALS AND METHODS. We retrospectively compared fibroglandular volume and background parenchymal enhancement in 55 female BRCA1 and BRCA2 mutation carriers before and after RRSO using standard BI-RADS categories and a paired Wilcoxon and Mann Whitney U test. A two-sample Wilcoxon test was performed to compare fibroglandular volume and background parenchymal enhancement in women with and without subsequent breast cancer diagnosis on follow-up. RESULTS. The median time to post-RRSO CE-MRI was 8 months (range, 1-40 months). There was no difference in fibroglandular volume before and after RRSO (p = 0.65). The mean background parenchymal enhancement was 2.5 (range, 1-4) before and 1.5 (range, 1-4) after RRSO (overall range, -2.5 to 1.5; p = 0.0001). Breast cancer was detected in nine women at a median time of 4.8 years (range, 1.8-13.3 years) after RRSO. For women who received a diagnosis of breast cancer after RRSO compared with those who did not, mean background parenchymal enhancement before RRSO was 3 (range, 2-4) versus 2.5 (range, 1-4; p = 0.001), and mean background parenchymal enhancement after RRSO was 2.5 (range, 1.5-4) versus 1.5 (range 2-4; p = 0.0018). There was no difference in fibroglandular volume before and after RRSO. CONCLUSION. In BRCA1 and BRCA2 mutation carriers, we observed a significant reduction in background parenchymal enhancement on the first CE-MRI after RRSO and no significant change in fibroglandular volume. Higher background parenchymal enhancement before and after RRSO was observed in women who subsequently received a diagnosis of breast cancer. This suggests that background parenchymal enhancement, rather than fibro-glandular volume, may be a more sensitive imaging biomarker of breast cancer risk. PMID- 25714302 TI - The clinical impact of gynecologic MRI. AB - OBJECTIVE. This study assessed the clinical impact of pelvic MRI performed after the diagnosis of an indeterminate pelvic mass on ultrasound or CT. MATERIALS AND METHODS. The radiologic records of 567 patients who underwent pelvic MRI at our hospital from 2004 to 2006 were reviewed. Of these patients, 214 patients underwent pelvic MRI for evaluation of a gynecologic mass detected on a preceding ultrasound or CT examination; this group of patients constituted the basis of our study. The imaging and clinical records from the database were used for our analysis. The medical records were reviewed for the impact of the radiologic findings on patient treatment, and the results were tabulated for the findings of the first modality, whether the first modality provided a diagnosis, what management plan would be made according to the first modality, and what management plan would be made as a result of the MRI. The adequacy of the imaging study was assessed on the basis of either obtaining an accurate exact diagnosis or ascertaining at the minimum whether the mass was benign or malignant. Further endpoints included specificity and sensitivity of the individual modalities in the diagnosis of a specific gynecologic mass and whether clinical management was altered. Exact binomial CIs were computed for individual proportions. RESULTS. The clinical management of the patient was altered as a result of MRI in 77% of the cases (CI = 0.70-0.82). Surgery was avoided in 36% (CI = 0.29-0.43), and surgery was changed to a more appropriate method (laparoscopy vs laparotomy, involvement or not of a gynecologic oncologist) in an additional 17% (CI = 0.12 0.23). CONCLUSION. Without having undergone MRI, many of the women and girls in this study would have undergone unnecessary surgery; a more costly type of surgery; or long-term follow-up with the associated financial costs, personal and physical costs, and mental costs from the resultant anxiety of an unresolved indeterminate mass. PMID- 25714303 TI - Issues to consider before implementing digital breast tomosynthesis into a breast imaging practice. AB - OBJECTIVE. The purpose of this article is to discuss issues surrounding the implementation of digital breast tomosynthesis (DBT) into a clinical breast imaging practice and assist radiologists, technologists, and administrators who are considering the addition of this new technology to their practices. CONCLUSION. When appropriate attention is given to image acquisition, interpretation, storage, technologist and radiologist training, patient selection, billing, radiation dose, and marketing, implementation of DBT into a breast imaging practice can be successful. PMID- 25714304 TI - Cholera. PMID- 25714305 TI - CT and MRI of aortic coarctation: pre- and postsurgical findings. AB - OBJECTIVE. The purpose of this article is to summarize the roles of CT and MRI in the diagnosis and follow-up of patients with aortic coarctation. CONCLUSION. Aortic coarctation is a common congenital heart disease accounting for approximately 6-8% of congenital heart defects. Despite its deceptively simple anatomic presentation, it is a complex medical problem with several associated anatomic and physiologic abnormalities. CT and MRI may provide very accurate information of the coarctation anatomy and other associated cardiac abnormalities. PMID- 25714306 TI - What makes and keeps radiation risks associated with CT a hot topic? PMID- 25714307 TI - A comparative study of strain and shear-wave elastography in an elasticity phantom. AB - OBJECTIVE. The purpose of this study was to assess the diagnostic accuracy of strain and shear-wave elastography for determining targets of varying stiffness in a phantom. The effect of target diameter on elastographic assessments and the effect of depth on shear-wave velocity were also investigated. MATERIALS AND METHODS. We examined 20 targets of varying diameters (2.5-16.7 mm) and stiffnesses (8, 14, 45, and 80 kPa) with a 4-9-MHz linear-array transducer. Targets were evaluated 10 times with three different methods-shear-wave elastography, strain ratio, and strain histogram analysis-yielding 600 evaluations. AUCs were calculated for data divided between different stiffnesses. A 1.5-6-MHz curved-array transducer was used to assess the effect of depth (3.5 vs 6 cm) on shear-wave elastography in 80 scans. Mixed model analysis was performed to assess the effect of target diameter and depth. RESULTS. Strain ratio and strain histogram AUCs were higher than the shear-wave velocity AUC (p < 0.001) in data divided as 80 versus 45, 14, and 8 kPa. In data divided as 80 and 45 versus 14 and 8 kPa, the methods were equal (p = 0.959 and p = 1.000, respectively). Strain ratios were superior (p = 0.030), whereas strain histograms were not significantly better (p = 0.083) than shear-wave elastography in data divided as 80, 45, and 14 versus 8 kPa. Target diameter had an effect on all three methods (p = 0.001). Depth had an effect on shear-wave velocity (p = 0.001). CONCLUSION. The ability to discern different target stiffnesses varies between shear-wave and strain elastography. Target diameter affected all methods. Shear-wave elastography is affected by target depth. PMID- 25714308 TI - Fractional flow reserve modeled from resting coronary CT angiography: state of the science. AB - OBJECTIVE. The purpose of this article is to discuss recent technologic innovations that enable noninvasive calculation of fractional flow reserve (FFR) from CT. CONCLUSION. FFR CT is superior to coronary CT angiography (CTA) stenosis for the diagnosis of ischemia-causing lesions. FFR CT improves the diagnostic accuracy mostly by reducing the false-positive rates incorrectly classified by CTA stenosis alone. Furthermore, in patients in whom CT shows an intermediate stenosis-wherein the results of CT alone are the most clinically ambiguous for ischemia diagnosis-FFR CT shows significantly higher diagnostic performance than CT alone. PMID- 25714309 TI - Coronary plaque characterization using CT. AB - OBJECTIVE. In this article, we review the histopathologic classification of coronary atherosclerotic plaques and describe the possibilities and limitations of CT regarding the evaluation of coronary artery plaques. CONCLUSION. The composition of atherosclerotic plaques in the coronary arteries displays substantial variability and is associated with the likelihood for rupture and downstream ischemic events. Accurate identification and quantification of coronary plaque components on CT is challenging because of the limited temporal, spatial, and contrast resolutions of current scanners. Nonetheless, CT may provide valuable information that has potential for characterization of coronary plaques. For example, the extent of calcification can be determined, lipid-rich lesions can be separated from more fibrous ones, and positive remodeling can be identified. PMID- 25714310 TI - Coronary fractional flow reserve. AB - OBJECTIVE. This article presents the basic definitions and concepts of fractional flow reserve (FFR), a focused understanding of the need for hyperemia during assessment, key clinical studies supporting its use, and an introduction to newer noninvasive methods using FFR CT. CONCLUSION. Although it is still a new procedure, FFR CT may prove to be of tremendous use as the computational processing improves to reduce calculation times and enhance accuracy. PMID- 25714311 TI - Transition zone prostate cancer: revisiting the role of multiparametric MRI at 3 T. AB - OBJECTIVE. The purpose of this study was to retrospectively evaluate the impact of multiparametric prostate MRI, including diffusion-weighted imaging (DWI) performed using different b values as well as dynamic contrast-enhanced MRI (DCE MRI) on the accuracy, sensitivity, and specificity for transition zone (TZ) tumor detection and localization. MATERIALS AND METHODS. We included 106 prostate cancer patients (mean age [+/- SD], 62 +/- 7 years) who underwent 3-T MRI with a pelvic phased-array coil before radical prostatectomy. Three radiologists independently reviewed cases to record the likelihood of tumor in each of six TZ regions. Scores were initially assigned using T2-weighted imaging alone, reassigned after integration of DWI at b = 1000 s/mm(2) and corresponding apparent diffusion coefficient (ADC) maps, reassigned again after integration of DWI at b = 2000 s/mm(2), and reassigned a final time after integration of DCE MRI. Generalized estimating equations based on binary logistic regression were used to compare sessions for TZ tumor detection, using prostatectomy findings as reference standard. RESULTS. Of the TZ sextants, 9.7% (62/636) contained tumor. All readers had higher sensitivity for T2-weighted imaging integrated with DWI at b = 1000 s/mm(2) and ADC compared with T2-weighted imaging alone (reader 1, 54.8% vs 33.9%; reader 2, 53.2% vs 22.6%; and reader 3, 50.0% vs 19.4% [p <= 0.002]); two readers had further increased sensitivity also incorporating b = 2000 s/mm(2) (reader 1, 74.2% and reader 2, 62.9%; p <= 0.011), and one reader had further increased sensitivity also incorporating both b = 2000 s/mm(2) and DCE-MRI (reader 3, 61.3%, p = 0.013). DCE-MRI otherwise did not improve sensitivity (p >= 0.054). Other measures were similar across the four sessions (reader 1, specificity 97.4-98.3% and accuracy 91.2-95.9%; reader 2, specificity 95.8-98.4% and accuracy 91.0-92.6%; reader 3, specificity 90.9-96.7% and accuracy 88.1 89.2%). CONCLUSION. DWI assists TZ tumor detection through higher sensitivity, particularly when using a very high b value; DCE-MRI lacks further additional benefit. PMID- 25714312 TI - Use of 3D DCE-MRI for the estimation of renal perfusion and glomerular filtration rate: an intrasubject comparison of FLASH and KWIC with a comprehensive framework for evaluation. AB - OBJECTIVE. The purpose of this article is to compare two 3D dynamic contrast enhanced (DCE) MRI measurement techniques for MR renography, a radial k-space weighted image contrast (KWIC) sequence and a cartesian FLASH sequence, in terms of intrasubject differences in estimates of renal functional parameters and image quality characteristics. SUBJECTS AND METHODS. Ten healthy volunteers underwent repeated breath-hold KWIC and FLASH sequence examinations with temporal resolutions of 2.5 and 2.8 seconds, respectively. A two-compartment model was used to estimate MRI-derived perfusion parameters and glomerular filtration rate (GFR). The latter was compared with the iohexol GFR and the estimated GFR. Image quality was assessed using a visual grading characteristic analysis of relevant image quality criteria and signal-to-noise ratio calculations. RESULTS. Perfusion estimates from FLASH were closer to literature reference values than were the KWIC sequences. In relation to the iohexol GFR (mean [+/- SD], 103 +/- 11 mL/min/1.73 m(2)), KWIC produced significant underestimations and larger bias in GFR values (mean, 70 +/- 30 mL/min/1.73 m(2); bias = -33.2 mL/min/1.73 m(2)) compared with the FLASH GFR (110 +/- 29 mL/min/1.73 m(2); bias = 6.4 mL/min/1.73 m(2)). KWIC was statistically significantly (p < 0.005) more impaired by artifacts than was FLASH (AUC = 0.18). The average signal-enhancement ratio (delta ratio) in the cortex was significantly lower for KWIC (delta ratio = 0.99) than for FLASH (delta ratio = 1.40). Other visually graded image quality characteristics and signal-to-noise ratio measurements were not statistically significantly different. CONCLUSION. Using the same postprocessing scheme and pharmacokinetic model, FLASH produced more accurate perfusion and filtration parameters than did KWIC compared with clinical reference methods. Our data suggest an apparent relationship between image quality characteristics and the degree of stability in the numeric model-based renal function estimates. PMID- 25714314 TI - Introduction of a virtual workstation into radiology medical student education. AB - OBJECTIVE. This article describes the creation of a virtual workstation for use by medical students and implementation of that workstation in the reading room. CONCLUSION. A radiology virtual workstation for medical students was created using OsiriX imaging software to authentically simulate the experience of interacting with cases selected to cover important musculoskeletal imaging diagnoses. A workstation that allows the manipulation and interpretation of complete anonymized DICOM images may enhance the educational experience of medical students. PMID- 25714313 TI - RECIST 1.1 compared with RECIST 1.0 in patients with advanced renal cell carcinoma receiving vascular endothelial growth factor-targeted therapy. AB - OBJECTIVE. Response Evaluation Criteria in Solid Tumors (RECIST) is the most widely accepted method to objectively assess response to therapy in renal cell carcinoma (RCC) treated with vascular endothelial growth factor (VEGF)-targeted therapy. Both RECIST 1.0 and 1.1 have been used to assess response to VEGF targeted therapies; however, systematic comparisons are lacking. MATERIALS AND METHODS. Sixty-two patients with metastatic RCC treated with VEGF-targeted therapies were retrospectively studied. Tumor measurements and response assessment according to RECIST 1.1 and RECIST 1.0 were compared, including the number of target lesions, baseline measurements, response at each follow-up, best overall response, and time to progression (TTP). Morphologic changes and new enhancement were also assessed over the course of treatment, and TTP was evaluated using morphologic change criteria in combination with RECIST 1.1. RESULTS. The number of target lesions according to RECIST 1.1 was significantly fewer than by RECIST 1.0 (median, 2 vs 4; p < 0.0001). At first imaging follow up, the percentage change of the sums of the diameter measurements by RECIST 1.1 and RECIST 1.0 were highly concordant (R = 0.857; mean shrinkage, 12.1% by RECIST 1.1 vs 10.8% by RECIST 1.0). Best response assessment was highly concordant between the two criteria (weighted kappa = 0.819). There was no evidence of a difference in TTP by the two criteria, with a median TTP of 8.9 months (95% CI for the median, 5.5-13.9) by RECIST 1.1 and 8.9 months (95% CI for the median, 5.8-13.6) by RECIST 1.0. The median TTP by RECIST 1.1 alone was 8.9 months compared with 5.6 months for RECIST 1.1 and morphologic changes combined. CONCLUSION. RECIST 1.1 and RECIST 1.0 response assessments were overall highly concordant in patients with RCC treated with VEGF-targeted therapy, with fewer target lesions according to RECIST 1.1 but no difference in TTP. PMID- 25714315 TI - Variation in CT pediatric head examination radiation dose: results from a national survey. AB - OBJECTIVE. The purpose of this article is to examine the variation in radiation dose, CT dose index volume (CTDIvol), and dose-length product (DLP) for pediatric head CT examinations as a function of hospital characteristics across the United States. MATERIALS AND METHODS. A survey inquiring about hospital information, CT scanners, pediatric head examination protocol, CTDIvol, and DLP was mailed to a representative sample of U.S. hospitals. Follow-up mailings were sent to nonrespondents. Descriptive characteristics of respondents and nonrespondents were compared using design-based Pearson chi-square tests. Dose estimates were compared across hospital characteristics using Bonferroni-adjusted Wald test. Hospital-level factors associated with dose estimates were evaluated using multiple linear regressions and modified Poisson regression models. RESULTS. Surveys were sent out to 751 hospitals; 292 responded to the survey, of which 253 were eligible (35.5% response rate, calculated as number of hospitals who completed surveys [n = 253] divided by sum of number who were eligible and initially consented [n = 712] plus estimated number who were eligible among those who refused [n = 1]). Most respondents reported using MDCT scanners (99.2%) and having a dedicated pediatric head CT protocol (93%). Estimated mean reported CTDIvol values were 27.3 mGy (95% CI, 24.4-30.1 mGy), and DLP values were 390.9 mGy * cm (95% CI, 346.6-435.1 mGy * cm). These values did not vary significantly by region, trauma level, teaching status, CT accreditation, number of CT scanners, or report of a dedicated pediatric CT protocol. However, estimated CTDIvol reported by children's hospitals was 19% lower than that reported by general hospitals (p < 0.01). CONCLUSION. Most hospitals (82%) report doses that meet American College of Radiology accreditation levels. However, [corrected] the mean CTDI(vol) at children's hospitals was approximately 7 mGy (21%, adjusted for covariates), lower than that at nonchildren's hospitals. PMID- 25714317 TI - High-resolution 3-T MRI of the fingers: review of anatomy and common tendon and ligament injuries. AB - OBJECTIVE. With high-resolution 3-T MRI, the complex anatomy of the fingers can be imaged in exquisite detail to provide an accurate diagnosis of clinically important ligament and tendon injuries. CONCLUSION. We present our 3-T MRI protocol using a dedicated hand-and-wrist coil and review normal MRI anatomy of the fingers. We emphasize a systematic approach to the interpretation of finger MRI examinations and illustrate this approach with examples of tendon and ligament abnormalities. PMID- 25714316 TI - Iron-based superparamagnetic nanoparticle contrast agents for MRI of infection and inflammation. AB - OBJECTIVE. In this article, we summarize the progress to date on the use of superparamagnetic iron oxide nanoparticles (SPIONs) as contrast agents for MRI of inflammatory processes. CONCLUSION. Phagocytosis by macrophages of injected SPIONs results in a prolonged shortening of both T2 and T2* leading to hypointensity of macrophage-infiltrated tissues in contrast-enhanced MR images. SPIONs as contrast agents are therefore useful for the in vivo MRI detection of macrophage infiltration, and there is substantial research and clinical interest in the use of SPION-based contrast agents for MRI of infection and inflammation. This technique has been used to identify active infection in patients with septic arthritis and osteomyelitis; importantly, the MRI signal intensity of the tissue has been found to return to its unenhanced value on successful treatment of the infection. In SPION contrast-enhanced MRI of vascular inflammation, animal studies have shown decreased macrophage uptake in atherosclerotic plaques after treatment with statin drugs. Human studies have shown that both coronary and carotid plaques that take up SPIONs are more prone to rupture and that abdominal aneurysms with increased SPION uptake are more likely to grow. Studies of patients with multiple sclerosis suggest that MRI using SPIONs may have increased sensitivity over gadolinium for plaque detection. Finally, SPIONs have enabled the tracking and imaging of transplanted stem cells in a recipient host. PMID- 25714318 TI - Dual-energy CT: virtual calcium subtraction for assessment of bone marrow involvement of the spine in multiple myeloma. AB - OBJECTIVE. Dual-energy CT (DECT) enables subtraction of calcium, facilitating the visualization of bone marrow (BM) in the axial skeleton. The purpose of this study was to assess whether DECT BM images have the potential to improve the detection of multifocal and diffuse BM infiltration in multiple myeloma (MM) in comparison with regular CT with MRI as the reference standard. SUBJECTS AND METHODS. This study included 32 consecutive patients who had known MM or presented with monoclonal gammopathy of unknown significance and underwent DECT and MRI of the axial skeleton. The degrees (none, n = 14; moderate, n = 10; and high, n = 8) and patterns (diffuse, n = 10 or multifocal, n = 8) of infiltration were assessed on MR images. Attenuation in BM and CT images in known uninvolved and involved areas was measured. Cutoff values of attenuation in BM images for infiltration in lytic and nonlytic lesions were established by ROC analysis. At least 120 days later, sensitivity and specificity for reading CT images alone and when using additional BM images were evaluated. RESULTS. ROC analysis revealed larger AUC in BM images than in CT images; cutoff values for marrow invasion in BM images were 4 and -3 HU in lytic and nonlytic lesions, respectively. In the blinded reading session, BM images improved the sensitivity for the detection of diffuse infiltration from 0 to as much as 75% for cases with high-grade infiltration. In multifocal patterns, BM images did not significantly change the detection rate. CONCLUSION. BM images have the potential to improve the sensitivity for detection of diffuse BM involvement in comparison with regular CT. PMID- 25714319 TI - MRI of the thyroid for differential diagnosis of benign thyroid nodules and papillary carcinomas. AB - OBJECTIVE. The purpose of this study was to evaluate the diagnostic performance of MRI in differentiating thyroid papillary carcinomas from benign thyroid nodules. MATERIALS AND METHODS. The study included 36 patients who had solid thyroid nodules detected by thyroid sonography and underwent MRI. A total of 42 solid thyroid nodules, including 28 benign nodules (maximal diameter range, 6-95 mm; mean diameter [+/- SD], 23.3 +/- 18.1 mm) and 14 papillary carcinomas (maximal diameter range, 11-35 mm; mean, 21.7 +/- 8.1 mm) were histopathologically diagnosed. The T1 and T2 signal intensity ratio (SIR) of each thyroid nodule was calculated by measuring the mean signal intensity divided by that of paraspinal muscle. Apparent diffusion coefficient (ADC) values of nodules were also computed. The SIRs and ADCs were then compared between benign nodules and papillary carcinomas. RESULTS. The mean T2 SIR (p < 0.0001) and ADC (p < 0.0001) were significantly lower for papillary carcinomas than for benign nodules, but no significant difference was found in T1 SIR (p = 0.54). The sensitivity, specificity, and AUC for the differentiation of papillary carcinomas were 86%, 100%, and 0.929, respectively, on T2 SIR; 93%, 93%, and 0.929, respectively, on ADC; and 93%, 93%, and 0.929, respectively, on combined T2 SIR and ADC. CONCLUSION. Papillary thyroid carcinomas could be accurately differentiated from benign nodules on the basis of MRI T2 SIR or ADC values. PMID- 25714320 TI - Diagnostic accuracy of ultrasound for assessment of hemophilic arthropathy: MRI correlation. AB - OBJECTIVE. The purpose of this article is to assess the reliability of interpretation of ultrasound findings according to data blinding in maturing hemophilic joints and to determine the diagnostic accuracy of ultrasound compared with MRI for assessing joint components. SUBJECTS AND METHODS. Ankles (n = 34) or knees (n = 25) of boys with hemophilia or von Willebrand disease (median age, 13 years; range, 5-17 years) were imaged by ultrasound, MRI, and radiography in two centers (Toronto, Canada, and Vellore, India). Ultrasound scans were performed by two operators (one blinded and one unblinded to MRI data) and were reviewed by four reviewers who were unblinded to corresponding MRI findings according to a proposed 0- to 14-item scale that matches 14 of 17 items of the corresponding MRI scale. MRI examinations were independently reviewed by two readers. RESULTS. When data were acquired by radiologists, ultrasound was highly reliable for assessing soft-tissue changes (intraclass correlation coefficient [ICC], 0.98 for ankles and 0.97 for knees) and substantially to highly reliable for assessing osteochondral changes (ICC, 0.61 for ankles and 0.89 for knees). Ultrasound was highly sensitive (> 92%) for assessing synovial hypertrophy and hemosiderin in both ankles and knees but had borderline sensitivity for detecting small amounts of fluid in ankles (70%) in contrast to knees (93%) and variable sensitivity for evaluating osteochondral abnormalities (sensitivity range, 86-100% for ankles and 12-100% for knees). CONCLUSION. If it is performed by experienced radiologists using a standardized protocol, ultrasound is highly reliable for assessing soft tissue abnormalities of ankles and knees and substantially to highly reliable for assessing osteochondral changes in these joints. PMID- 25714321 TI - MRI kinetics with volumetric analysis in correlation with hormonal receptor subtypes and histologic grade of invasive breast cancers. AB - OBJECTIVE. The aim of this study was to assess whether computer-assisted detection-processed MRI kinetics data can provide further information on the biologic aggressiveness of breast tumors. MATERIALS AND METHODS. We identified 194 newly diagnosed invasive breast cancers presenting as masses on contrast enhanced MRI by a HIPAA-compliant pathology database search. Computer-assisted detection-derived data for the mean and median peak signal intensity percentage increase, most suspicious kinetic curve patterns, and volumetric analysis of the different kinetic patterns by mean percentage tumor volume were compared against the different hormonal receptor (estrogen-receptor [ER], progesterone-receptor [PR], ERRB2 (HER2/neu), and triple-receptor expressivity) and histologic grade subgroups, which were used as indicators of tumor aggressiveness. RESULTS. The means and medians of the peak signal intensity percentage increase were higher in ER-negative, PR-negative, and triple-negative (all p <= 0.001), and grade 3 tumors (p = 0.011). Volumetric analysis showed higher mean percentage volume of rapid initial enhancement in biologically more aggressive ER-negative, PR negative, and triple-negative tumors compared with ER-positive (64% vs 53.6%, p = 0.013), PR-positive (65.4% vs 52.5%, p = 0.001), and nontriple-negative tumors (65.3% vs 54.6%, p = 0.028), respectively. A higher mean percentage volume of rapid washout component was seen in ERRB2-positive tumors compared with ERRB2 negative tumors (27.5% vs 17.9%, p = 0.020). CONCLUSION. Peak signal intensity percentage increase and volume analysis of the different kinetic patterns of breast tumors showed correlation with hormonal receptor and histologic grade indicators of cancer aggressiveness. Computer-assisted detection-derived MRI kinetics data have the potential to further characterize the aggressiveness of an invasive cancer. PMID- 25714322 TI - Significance of incidentally detected subcentimeter enhancing lesions on preoperative breast MRI: role of second-look ultrasound in lesion detection and management. AB - OBJECTIVE. The purpose of this article is to evaluate the clinical significance of subcentimeter enhancing lesions incidentally detected on preoperative breast MRI in patients with breast cancer and the role of second-look ultrasound in lesion detection and characterization. MATERIALS AND METHODS. From January 2010 through December 2010, 180 lesions measuring less than 10 mm incidentally detected on MRI in 108 women with second-look ultrasound examinations were included (mean patient age, 47.9 years; mean [+/- SD] lesion size, 5.56 +/- 1.64 mm). Seventy-two (40.0%) lesions were smaller than 5 mm, and 108 (60.0%) were 5 mm or larger. Of the 180 lesions, 103 (57.2%) had been biopsied or excised by localization, and 77 (42.8%) with benign ultrasound features had been followed with ultrasound for at least 2 years. Clinical and imaging features were recorded for analysis. RESULTS. Of the 180 enhancing lesions detected on MRI, 14 (7.8%) were malignant and 166 (92.2%) were benign. The malignancy rate of lesions 5 mm or larger was higher than that for lesions smaller than 5 mm (10.2% vs 4.2%), without statistical significance (p = 0.344). The washout enhancement pattern was statistically significantly associated with malignancy (p = 0.032). Although malignant ultrasound features such as nonparallel orientation were more common in malignant lesions, most malignancies had benign features, including oval shape, parallel orientation, and circumscribed margins, with BI-RADS category 4a (n = 12; 85.8%) as the final assessment. CONCLUSION. Second-look ultrasound is a feasible method for evaluating MRI-detected subcentimeter sized lesions in preoperative assessment of patients with breast cancer. A lower threshold should be applied with consideration of MRI features in deciding whether to biopsy or excise these lesions. PMID- 25714323 TI - Background parenchymal uptake during molecular breast imaging and associated clinical factors. AB - OBJECTIVE. The purposes of this study were to describe the prevalence of background parenchymal uptake categories observed at screening molecular breast imaging (MBI) and to examine the association of background parenchymal uptake with mammographic density and other clinical factors. MATERIALS AND METHODS. Adjunct MBI screening was performed for women with dense breasts on previous mammograms. Two radiologists reviewed images from the MBI examinations and subjectively categorized background parenchymal uptake into four groups: photopenic, minimal-mild, moderate, or marked. Women with breast implants or a personal history of breast cancer were excluded. The association between background parenchymal uptake categories and patient characteristics was examined with Kruskal-Wallis and chi-square tests as appropriate. RESULTS. In 1149 eligible participants, background parenchymal uptake was photopenic in 252 (22%), minimal-mild in 728 (63%), and moderate or marked in 169 (15%). The distribution of categories differed across BI-RADS density categories (p < 0.0001). In 164 participants with extremely dense breasts, background parenchymal uptake was photopenic in 72 (44%), minimal-mild in 55 (34%), and moderate or marked in 37 (22%). The moderate-marked group was younger on average, more likely to be premenopausal or perimenopausal, and more likely to be using postmenopausal hormone therapy than the photopenic or minimal-mild groups (p < 0.0001). CONCLUSION. Among women with similar-appearing mammographic density, background parenchymal uptake ranged from photopenic to marked. Background parenchymal uptake was associated with menopausal status and postmenopausal hormone therapy but not with premenopausal hormonal contraceptives, phase of menstrual cycle, or Gail model 5-year risk of breast cancer. Additional work is necessary to fully characterize the underlying cause of background parenchymal uptake and determine its utility in predicting subsequent risk of breast cancer. PMID- 25714324 TI - Medicolegal--malpractice and ethical issues in radiology. PMID- 25714325 TI - Insights in local extrathyroidal invasion of papillary thyroid carcinoma on Doppler ultrasound examination. PMID- 25714326 TI - Upper extremity trauma radiographs. PMID- 25714327 TI - Reply to "upper extremity trauma radiographs". PMID- 25714328 TI - Bacteriophage Delivery by Nebulization and Efficacy Against Phenotypically Diverse Pseudomonas aeruginosa from Cystic Fibrosis Patients. AB - BACKGROUND: The rise in antibiotic-resistant Pseudomonas aeruginosa and the considerable difficulty in eradicating it from patients has re-motivated the study of bacteriophages as a therapeutic option. For this to be effective, host range and viability following nebulization need to be assessed. Host-range has not previously been assessed for the Liverpool Epidemic Strain (LES) isolates that are the most common cystic fibrosis-related clone of P. aeruginosa in the UK. Nebulization studies have not previously been linked to clinically relevant phages. METHODS: 84 phenotypically variable isolates of the LES were tested for susceptibility to seven bacteriophages known to have activity against P. aeruginosa. Five of the phages were from the Eliava Institute (IBMV) and 2 were isolated in this study. The viability of the two bacteriophages with the largest host ranges was characterized further to determine their ability to be nebulized and delivered to the lower airways. Phages were nebulized into a cascade impactor and the phage concentration was measured. RESULTS: The bacteriophages tested killed between 66%-98% of the 84 Liverpool Epidemic Strain isolates. Two isolates were multi phage resistant, but were sensitive to most first line anti Pseudomonal antibiotics. The amount of viable bacteriophages contained in particles that are likely to reach the lower airways (<4.7 MUm) was 1% for the Omron and 12% AeroEclipse nebulizer. CONCLUSIONS: Individual P. aeruginosa bacteriophages can lyse up to 98% of 84 phenotypically diverse LES strains. High titers of phages can be effectively nebulized. PMID- 25714329 TI - Asymmetric epoxidation of allylic alcohols catalyzed by vanadium binaphthylbishydroxamic Acid complex. AB - A vanadium-binaphthylbishydroxamic acid (BBHA) complex-catalyzed asymmetric epoxidation of allylic alcohols is described. The optically active binaphthyl based ligands BBHA 2a and 2b were synthesized from (S)-1,1'-binaphthyl-2,2' dicarboxylic acid and N-substituted-O-trimethylsilyl (TMS)-protected hydroxylamines via a one-pot, three-step procedure. The epoxidations of 2,3,3 trisubstituted allylic alcohols using the vanadium complex of 2a were easily performed in toluene with a TBHP water solution to afford (2R)-epoxy alcohols in good to excellent enantioselectivities. PMID- 25714330 TI - Effects of resveratrol on benign prostatic hyperplasia by the regulation of inflammatory and apoptotic proteins. AB - Resveratrol (1) is a natural polyphenolic compound that has cardioprotective, anticancer, and anti-inflammatory properties. Although diverse biological studies of compound 1 have been conducted, no antiproliferative effects of 1 have been reported in benign prostatic hyperplasia (BPH). BPH is a progressive disease related to inflammation and an imbalance in cell growth and apoptosis. The aims of this study were to determine whether 1suppressed BPH progression in rats and to explore the underlying mechanisms related to regulation of inflammation and apoptosis. Compound 1 treatment decreased prostate weight and cell proliferation in this animal model and markedly decreased BPH-related upregulation of iNOS and COX-2 protein expression. In addition, 1 induced Bax expression and suppressed Bcl-2 and Bcl-xL expressions. Furthermore, 1 triggered caspase-3 activation and decreased levels of its substrate, PARP-1. These results suggested that 1 produced an antiproliferative effect by regulating the expression levels of proteins involved in inflammation and apoptosis during BPH. PMID- 25714331 TI - Functional specialization of chordate CDK1 paralogs during oogenic meiosis. AB - Cyclin-dependent kinases (CDKs) are central regulators of eukaryotic cell cycle progression. In contrast to interphase CDKs, the mitotic phase CDK1 is the only CDK capable of driving the entire cell cycle and it can do so from yeast to mammals. Interestingly, plants and the marine chordate, Oikopleura dioica, possess paralogs of the highly conserved CDK1 regulator. However, whereas in plants the 2 CDK1 paralogs replace interphase CDK functions, O. dioica has a full complement of interphase CDKs in addition to its 5 odCDK1 paralogs. Here we show specific sub-functionalization of odCDK1 paralogs during oogenesis. Differential spatiotemporal dynamics of the odCDK1a, d and e paralogs and the meiotic polo like kinase 1 (Plk1) and aurora kinase determine the subset of meiotic nuclei in prophase I arrest that will seed growing oocytes and complete meiosis. Whereas we find odCDK1e to be non-essential, knockdown of the odCDK1a paralog resulted in the spawning of non-viable oocytes of reduced size. Knockdown of odCDK1d also resulted in the spawning of non-viable oocytes. In this case, the oocytes were of normal size, but were unable to extrude polar bodies upon exposure to sperm, because they were unable to resume meiosis from prophase I arrest, a classical function of the sole CDK1 during meiosis in other organisms. Thus, we reveal specific sub-functionalization of CDK1 paralogs, during the meiotic oogenic program. PMID- 25714332 TI - Risk of behaviors associated with lethal violence and functional outcomes for abused women who do and do not return to the abuser following a community-based intervention. AB - BACKGROUND: To determine the differential risk of behaviors associated with lethal violence and functioning outcomes for abused women with children who received an intervention of shelter or justice services and return to the abuser were compared with women who did not return. METHODS: The study was carried out using a matched-pair analysis of 152 women. Measures of risk of behaviors associated with lethal violence, type, and severity of abuse, and poor mental health symptoms were measured every 4 months for 24 months. RESULTS: Irrespective of service used, women returning to the abuser reported significantly (p<0.001) more risk of behaviors associated with lethal violence compared to women who did not return. Additionally, severity of physical abuse was significantly higher (p<0.01) for women returning to the abuser who had been in a shelter but not for women who received a protection order. Similarly, levels of depression, posttraumatic stress disorder, and anxiety were significantly higher (p<0.01) for sheltered women who returned to the abuser but not for women using a protection order who returned. CONCLUSIONS: Risk of behaviors associated with lethal violence increases when abused women return to live with the abuser. Abused women should be informed of the heightened risk and greater probability for poor mental health. PMID- 25714333 TI - Disorder in milk proteins: caseins, intrinsically disordered colloids. AB - This article opens a series of reviews on the abundance and roles of intrinsic disorder in milk proteins. The focus of this introductory article on caseins is symbolic, since caseins were among the first recognized functional unfolded proteins and since they are definitely the most disordered, the most abundant, and the most studied of all milk proteins. In eutherian milks, the casein family includes at least three and usually four major members (alphas1-, alphas2-, beta , and kappa-caseins) that are unrelated in sequence. However, in some species, two different alphaS2-casein genes are active, and therefore the total number of caseins can be as high as five. These proteins have found a number of uses in food industry. The functional repertoire of caseins ranges from nutritional function to involvement in the improving and/or maintaining cardiovascular health, to crucial contribution to the milk capacity to transport calcium phosphate, to serve as molecular chaperones, and to protect the mother's mammary gland against amyloidoses and ectopic calcification. An intricate feature of caseins is their ability to assemble to colloidal protein particles, casein micelles, serving to sequester and transport amorphous calcium phosphate. These and many other functions of caseins are obviously dependent on their intrinsically disordered nature and are controlled by various posttranslational modifications. Since various aspects of casein structure and function are rather well studied and since several recent reviews emphasized the functional roles of caseins' intrinsic disorder, the major goal of this article is to show how intrinsic disorder is encoded in the amino acid sequences of these proteins. PMID- 25714334 TI - Lipase-catalyzed dissipative self-assembly of a thixotropic Peptide bolaamphiphile hydrogel for human umbilical cord stem-cell proliferation. AB - We report lipase-catalyzed inclusion of p-hydroxy benzylalcohol to peptide bolaamphiphiles. The lipase-catalyzed reactions of peptide bolaamphiphiles with p hydroxy benzylalcohol generate dynamic combinatorial libraries (DCL) in aqueous medium that mimic the natural dissipative system. The peptide bolaamphiphile 1 (HO-WY-Suc-YW-OH) reacts with p-hydroxy benzylalcohol in the presence of lipase forming an activated diester building block. The activated diester building block self-assembles to produce nanofibrillar thixotropic hydrogel. The subsequent hydrolysis results in the dissipation of energy to form nonassembling bolaamphiphile 1 with collapsed nanofibers. The thixotropic DCL hydrogel matrix is used for 3D cell culture experiments for different periods of time, significantly supporting the cell survival and proliferation of human umbilical cord mesenchymal stem cells. PMID- 25714336 TI - Emergence of localized states in narrow GaAs/AlGaAs nanowire quantum well tubes. AB - We use low-temperature photoluminescence, photoluminescence excitation, and photoluminescence imaging spectroscopy to explore the optical and electronic properties of GaAs/AlGaAs quantum well tube (QWT) heterostructured nanowires (NWs). We find that GaAs QWTs with widths >5 nm have electronic states which are delocalized and continuous along the length of the NW. As the NW QWT width decreases from 5 to 1.5 nm, only a single electron state is bound to the well, and no optical excitations to a confined excited state are present. Simultaneously, narrow emission lines (fwhm < 600 MUeV) appear which are localized to single spatial points along the length of the NW. We find that these quantum-dot-like states broaden at higher temperatures and quench at temperatures above 80 K. The lifetimes of these localized states are observed to vary from dot to dot from 160 to 400 ps. The presence of delocalized states and then localized states as the QWTs become more confined suggests both opportunities and challenges for possible incorporation into quantum-confined device structures. PMID- 25714335 TI - Structural studies on Laz, a promiscuous anticancer Neisserial protein. AB - Azurin and Laz (lipidated azurin) are 2 bacterial proteins with anticancer, anti viral and anti-parasitic activities. Azurin, isolated from the bacterium Pseudomonas aeruginosa, termed Paz, demonstrates anticancer activity against a range of cancers but not against brain tumors. In contrast, Laz is produced by members of Gonococci/Meningococci, including Neisseria meningitides which can cross the blood-brain barrier to infect brain meninges. It has been previously reported that Laz has an additional 39 amino acid moiety, called an H.8 epitope, in the N-terminal part of the azurin moiety that allows Laz to cross the entry barrier to brain tumors such as glioblastomas. Exactly, how the H.8 epitope helps the azurin moiety of Laz to cross the entry barriers to attack glioblastoma cells is unknown. In this paper, we describe the structural features of the H.8 moiety in Laz using X-ray crystallography and demonstrate that while the azurin moiety of Laz adopts a beta-sandwich fold with 2 beta-sheets arranged in the Greek key motif, the H.8 epitope was present as a disordered structure outside the Greek key motif. Structures of Paz and H.8 epitope-deficient Laz are well superimposed. The structural flexibility of the H.8 motif in Laz explains the extracellular location of Laz in Neisseria where it can bind the key components of brain tumor cells to disrupt their tight junctions and allow entry of Laz inside the tumors to exert cytotoxicity. PMID- 25714337 TI - Small but powerful: top predator local extinction affects ecosystem structure and function in an intermittent stream. AB - Top predator loss is a major global problem, with a current trend in biodiversity loss towards high trophic levels that modifies most ecosystems worldwide. Most research in this area is focused on large-bodied predators, despite the high extinction risk of small-bodied freshwater fish that often act as apex consumers. Consequently, it remains unknown if intermittent streams are affected by the consequences of top-predators' extirpations. The aim of our research was to determine how this global problem affects intermittent streams and, in particular, if the loss of a small-bodied top predator (1) leads to a 'mesopredator release', affects primary consumers and changes whole community structures, and (2) triggers a cascade effect modifying the ecosystem function. To address these questions, we studied the top-down effects of a small endangered fish species, Barbus meridionalis (the Mediterranean barbel), conducting an enclosure/exclosure mesocosm experiment in an intermittent stream where B. meridionalis became locally extinct following a wildfire. We found that top predator absence led to 'mesopredator release', and also to 'prey release' despite intraguild predation, which contrasts with traditional food web theory. In addition, B. meridionalis extirpation changed whole macroinvertebrate community composition and increased total macroinvertebrate density. Regarding ecosystem function, periphyton primary production decreased in apex consumer absence. In this study, the apex consumer was functionally irreplaceable; its local extinction led to the loss of an important functional role that resulted in major changes to the ecosystem's structure and function. This study evidences that intermittent streams can be affected by the consequences of apex consumers' extinctions, and that the loss of small-bodied top predators can lead to large ecosystem changes. We recommend the reintroduction of small-bodied apex consumers to systems where they have been extirpated, to restore ecosystem structure and function. PMID- 25714338 TI - A review of Shamosuchus and Paralligator (Crocodyliformes, Neosuchia) from the Cretaceous of Asia. AB - The crocodyliform Shamosuchus is known from numerous Late Cretaceous localities in southern and eastern Mongolia and fragmentary remains from Uzbekistan. Seven species of Shamosuchus have been named from six localities in Mongolia and three in Uzbekistan. Six species originally described as Paralligator were later referred to Shamosuchus. Only the type species, Shamosuchus djadochtaensis has been examined in detail. Many of the named species of Shamosuchus show striking similarity in size and cranial morphology but most are based on partial remains suggesting that the true species diversity is overestimated. A review of all species referred to Shamosuchus recognizes three valid taxa: Shamosuchus djadochtaensis, S. gradilifrons, and S. major. Shamosuchus sungaricus, S. borealis, and S. karakalpakensis are nomena dubia, whereas S. ancestralis, S. ulgicus, S. tersus, and S. ulanicus are junior subjective synonyms of S. gradilifrons. Phylogenetic analysis of 318 phenotypic characters recovers a Paralligatoridae clade consisting of Shamosuchus, Rugosuchus, Batrachomimus, Glen Rose Form, and Wannchampsus. Shamosuchus is non-monophyletic: S. djadochtaensis is near the base of Paralligatoridae whereas S. gradilifrons + S. major are the most deeply nested. The name Paralligator is resurrected for this clade. Rugosuchus and Batrachomimus are sister taxa to Paralligator. Paralligatoridae is closely related to Theriosuchus, hylaeochampsids and a speciose Allodaposuchus clade, which together are the sister group of Borealosuchus plus Crocodylia. These results support the presence of a diverse clade in eastern Asia and western North America throughout the Cretaceous with origins in the Late Jurassic. PMID- 25714339 TI - Superoxide dismutases, SOD1 and SOD2, play a distinct role in the fat body during pupation in silkworm Bombyx mori. AB - One way that aerobic biological systems counteract the generation of reactive oxygen species (ROS) is with superoxide dismutase proteins SOD1 and SOD2 that metabolize superoxide radicals to molecular oxygen and hydrogen peroxide or scavenge oxygen radicals produced by the extensive oxidation-reduction and electron-transport reactions that occur in mitochondria. We characterized SOD1 and SOD2 of Bombyx mori isolated from the fat body of larvae. Immunological analysis demonstrated the presence of BmSOD1 and BmSOD2 in the silk gland, midgut, fat body, Malpighian tubules, testis and ovary from larvae to adults. We found that BmSOD2 had a unique expression pattern in the fat body through the fifth instar larval developmental stage. The anti-oxidative functions of BmSOD1 and BmSOD2 were assessed by exposing larvae to insecticide rotenone or vasodilator isosorbide dinitrate, which is an ROS generator in BmN4 cells; however, exposure to these compounds had no effect on the expression levels of either BmSOD protein. Next, we investigated the physiological role of BmSOD1 and BmSOD2 under environmental oxidative stress, applied through whole-body UV irradiation and assayed using quantitative RT-PCR, immunoblotting and microarray analysis. The mRNA expression level of both BmSOD1 and BmSOD2 was markedly increased but protein expression level was increased only slightly. To examine the differences in mRNA and protein level due to UV irradiation intensity, we performed microarray analysis. Gene set enrichment analysis revealed that genes in the insulin signaling pathway and PPAR signaling pathway were significantly up regulated after 6 and 12 hours of UV irradiation. Taken together, the activities of BmSOD1 and BmSOD2 may be related to the response to UV irradiation stress in B. mori. These results suggest that BmSOD1 and BmSOD2 modulate environmental oxidative stress in the cell and have a specific role in fat body of B. mori during pupation. PMID- 25714341 TI - Diverse staghorn coral fauna on the mesophotic reefs of north-east Australia. AB - Concern for the future of reef-building corals in conditions of rising sea temperatures combined with recent technological advances has led to a renewed interest in documenting the biodiversity of mesophotic coral ecosystems (MCEs) and their potential to provide lineage continuation for coral taxa. Here, we examine species diversity of staghorn corals (genera Acropora and Isopora) in the mesophotic zone (below 30 m depth) of the Great Barrier Reef and western Coral Sea. Using specimen-based records we found 38 staghorn species in the mesophotic zone, including three species newly recorded for Australia and five species that only occurred below 30 m. Staghorn corals became scarce at depths below 50 m but were found growing in-situ to 73 m depth. Of the 76 staghorn coral species recorded for shallow waters (depth <= 30 m) in north-east Australia, 21% extended to mesophotic depths with a further 22% recorded only rarely to 40 m depth. Extending into the mesophotic zone provided shallow water species no significant advantage in terms of their estimated global range-size relative to species restricted to shallow waters (means 86.2 X 10(6) km2 and 85.7 X 10(6) km2 respectively, p = 0.98). We found four staghorn coral species at mesophotic depths on the Great Barrier Reef that were previously considered rare and endangered on the basis of their limited distribution in central Indonesia and the far western Pacific. Colonies below 40 m depth showed laterally flattened branches, light and fragile skeletal structure and increased spacing between branches and corallites. The morphological changes are discussed in relation to decreased light, water movement and down-welling coarse sediments. Staghorn corals have long been regarded as typical shallow-water genera, but here we demonstrate the significant contribution of this group to the region's mesophotic fauna and the importance of considering MCEs in reef biodiversity estimates and management. PMID- 25714340 TI - Increased risk of genetic and epigenetic instability in human embryonic stem cells associated with specific culture conditions. AB - The self-renewal and differentiation capacities of human pluripotent stem cells (hPSCs) make them a promising source of material for cell transplantation therapy, drug development, and studies of cellular differentiation and development. However, the large numbers of cells necessary for many of these applications require extensive expansion of hPSC cultures, a process that has been associated with genetic and epigenetic alterations. We have performed a combinatorial study on both hESCs and hiPSCs to compare the effects of enzymatic vs. mechanical passaging, and feeder-free vs. mouse embryonic fibroblast feeder substrate, on the genetic and epigenetic stability and the phenotypic characteristics of hPSCs. In extensive experiments involving over 100 continuous passages, we observed that both enzymatic passaging and feeder-free culture were associated with genetic instability, higher rates of cell proliferation, and persistence of OCT4/POU5F1-positive cells in teratomas, with enzymatic passaging having the stronger effect. In all combinations of culture conditions except for mechanical passaging on feeder layers, we noted recurrent deletions in the genomic region containing the tumor suppressor gene TP53, which was associated with decreased mRNA expression of TP53, as well as alterations in the expression of several downstream genes consistent with a decrease in the activity of the TP53 pathway. Among the hESC cultures, we also observed culture-associated variations in global gene expression and DNA methylation. The effects of enzymatic passaging and feeder-free conditions were also observed in hiPSC cultures. Our results highlight the need for careful assessment of the effects of culture conditions on cells intended for clinical therapies. PMID- 25714342 TI - Resilience of alternative states in spatially extended ecosystems. AB - Alternative stable states in ecology have been well studied in isolated, well mixed systems. However, in reality, most ecosystems exist on spatially extended landscapes. Applying existing theory from dynamic systems, we explore how such a spatial setting should be expected to affect ecological resilience. We focus on the effect of local disturbances, defining resilience as the size of the area of a strong local disturbance needed to trigger a shift. We show that in contrast to well-mixed systems, resilience in a homogeneous spatial setting does not decrease gradually as a bifurcation point is approached. Instead, as an environmental driver changes, the present dominant state remains virtually 'indestructible', until at a critical point (the Maxwell point) its resilience drops sharply in the sense that even a very local disturbance can cause a domino effect leading eventually to a landscape-wide shift to the alternative state. Close to this Maxwell point the travelling wave moves very slow. Under these conditions both states have a comparable resilience, allowing long transient co-occurrence of alternative states side-by-side, and also permanent co-existence if there are mild spatial barriers. Overall however, hysteresis may mostly disappear in a spatial context as one of both alternative states will always tend to be dominant. Our results imply that local restoration efforts on a homogeneous landscape will typically either fail or trigger a landscape-wide transition. For extensive biomes with alternative stable states, such as tundra, steppe and forest, our results imply that, as climatic change reduces the stability, the effect might be difficult to detect until a point where local disturbances inevitably induce a spatial cascade to the alternative state. PMID- 25714343 TI - Species-specific antimonial sensitivity in Leishmania is driven by post transcriptional regulation of AQP1. AB - Leishmania is a digenetic protozoan parasite causing leishmaniasis in humans. The different clinical forms of leishmaniasis are caused by more than twenty species of Leishmania that are transmitted by nearly thirty species of phlebotomine sand flies. Pentavalent antimonials (such as Pentostam or Glucantime) are the first line drugs for treating leishmaniasis. Recent studies suggest that pentavalent antimony (Sb(V)) acts as a pro-drug, which is converted to the more active trivalent form (Sb(III)). However, sensitivity to trivalent antimony varies among different Leishmania species. In general, Leishmania species causing cutaneous leishmaniasis (CL) are more sensitive to Sb(III) than the species responsible for visceral leishmaniasis (VL). Leishmania aquaglyceroporin (AQP1) facilitates the adventitious passage of antimonite down a concentration gradient. In this study, we show that Leishmania species causing CL accumulate more antimonite, and therefore exhibit higher sensitivity to antimonials, than the species responsible for VL. This species-specific differential sensitivity to antimonite is directly proportional to the expression levels of AQP1 mRNA. We show that the stability of AQP1 mRNA in different Leishmania species is regulated by their respective 3' untranslated regions. The differential regulation of AQP1 mRNA explains the distinct antimonial sensitivity of each species. PMID- 25714344 TI - Keratinocyte progenitor cells reside in human subcutaneous adipose tissue. AB - The differentiation of adipose-derived stem cells (ASCs) towards epithelial lineages has yet to be demonstrated using a standardized method. This study investigated whether keratinocyte progenitor cells are present in the ASC population. ASCs isolated from subcutaneous adipose tissue were cultured and examined for the expression of the keratinocyte progenitor markers p63 and desmoglein 3 (DSG3) by immunofluorescence microscopy and flow cytometry. In addition, p63 and DSG3 expression levels were assessed before and after differentiation of ASCs into adipocytes by real-time PCR and western blot analysis, as well as in subcutaneous adipose tissue by real-time reverse transcriptase polymerase chain reaction. Both markers were expressed in ASCs, but were downregulated after the differentiation of ASCs into adipocytes; p63 positive cells were also detected in subcutaneous adipose tissue. ASCs co cultured with human fibroblasts and incubated with all-trans retinoic acid and bone morphologic protein 4 showed an upregulation in DSG3 level, which was also increased in the presence of type IV collagen. They also showed an upregulation in cytokeratin-5 level only in the presence of type IV collagen. These results provide the demonstration that keratinocyte progenitor cells reside in subcutaneous adipose tissue. PMID- 25714345 TI - Overcoming Workplace Barriers: A Focus Group Study Exploring African American Mothers' Needs for Workplace Breastfeeding Support. AB - BACKGROUND: Persistent racial disparities in breastfeeding show that African American women breastfeed at the lowest rates. Return to work is a critical breastfeeding barrier for African American women who return to work sooner than other ethnic groups and more often encounter unsupportive work environments. They also face psychosocial burdens that make breastfeeding at work uniquely challenging. Participants share personal struggles with combining paid employment and breastfeeding and suggest workplace and personal support strategies that they believe will help continue breastfeeding after a return to work. OBJECTIVE: To explore current perspectives on ways to support African American mothers' workplace breastfeeding behavior. METHODS: Pregnant African American women (n = 8), African American mothers of infants (n = 21), and lactation support providers (n = 9) participated in 1 of 6 focus groups in the Greater Detroit area. Each focus group audiotape was transcribed verbatim. Thematic analysis was used to inductively analyze focus group transcripts and field notes. Focus groups explored thoughts, perceptions, and behavior on interventions to support African American women's breastfeeding. RESULTS: Participants indicate that they generally believed breastfeeding was a healthy option for the baby; however, paid employment is a critical barrier to successful breastfeeding for which mothers receive little help. Participants felt breastfeeding interventions that support working African American mothers should include education and training for health care professionals, regulation and enforcement of workplace breastfeeding support policies, and support from peers who act as breastfeeding role models. CONCLUSION: Culturally appropriate interventions are needed to support breastfeeding among working African American women. PMID- 25714346 TI - Primary care in Switzerland gains strength. AB - BACKGROUND: Although there is widespread agreement on health- and cost-related benefits of strong primary care in health systems, little is known about the development of the primary care status over time in specific countries, especially in countries with a traditionally weak primary care sector such as Switzerland. OBJECTIVE: The aim of our study was to assess the current strength of primary care in the Swiss health care system and to compare it with published results of earlier primary care assessments in Switzerland and other countries. METHODS: A survey of experts and stakeholders with insights into the Swiss health care system was carried out between February and March 2014. The study was designed as mixed-modes survey with a self-administered questionnaire based on a set of 15 indicators for the assessment of primary care strength. Forty representatives of Swiss primary and secondary care, patient associations, funders, health care authority, policy makers and experts in health services research were addressed. Concordance between the indicators of a strong primary care system and the real situation in Swiss primary care was rated with 0-2 points (low-high concordance). RESULTS: A response rate of 62.5% was achieved. Participants rated concordance with five indicators as 0 (low), with seven indicators as 1 (medium) and with three indicators as 2 (high). In sum, Switzerland achieved 13 of 30 possible points. Low scores were assigned because of the following characteristics of Swiss primary care: inequitable local distribution of medical resources, relatively low earnings of primary care practitioners compared to specialists, low priority of primary care in medical education and training, lack of formal guidelines for information transfer between primary care practitioners and specialists and disregard of clinical routine data in the context of medical service planning. CONCLUSION: Compared to results of an earlier assessment in Switzerland, an improvement of seven indicators could be stated since 1995. As a result, Switzerland previously classified as a country with low primary care strength was reclassified as country with intermediate primary care strength compared to 14 other countries. Low scored characteristics represent possible targets of future health care reforms. PMID- 25714347 TI - The scientific consensus on climate change as a gateway belief: experimental evidence. AB - There is currently widespread public misunderstanding about the degree of scientific consensus on human-caused climate change, both in the US as well as internationally. Moreover, previous research has identified important associations between public perceptions of the scientific consensus, belief in climate change and support for climate policy. This paper extends this line of research by advancing and providing experimental evidence for a "gateway belief model" (GBM). Using national data (N = 1104) from a consensus-message experiment, we find that increasing public perceptions of the scientific consensus is significantly and causally associated with an increase in the belief that climate change is happening, human-caused and a worrisome threat. In turn, changes in these key beliefs are predictive of increased support for public action. In short, we find that perceived scientific agreement is an important gateway belief, ultimately influencing public responses to climate change. PMID- 25714348 TI - ACR presidential address: the wide (and flat) world of rheumatology. PMID- 25714352 TI - Comparison of the electronic properties of diarylamido-based PNZ pincer ligands: redox activity at the ligand and donor ability toward the metal. AB - This paper presents the synthesis and characterization of a series of pincer ligands and their Ni, Pd, Pt, and Rh complexes. The ligands under examination are based on a diarylamine which is modified either by two phosphino (-PR2) substituents in the ortho-positions (PNP ligands) or by a combination of a phosphino and an iminyl (-CH?NX) substituent (PNN ligands). The ligands can be broken down into three groups: (a) C2v-symmetric PNP ligands with identical side PR2 donors, (b) Cs-symmetric PNP' ligands with different -PR2 side donors, and (c) PNN ligands containing a -P(i)Pr2 side donor. All of the ligands under study readily formed square-planar complexes of the types (PNZ)PdCl, (PNZ)Pd(OAc), and (PNZ)RhCO, where PNZ is the corresponding anionic tridentate pincer ligand. For select PNP ligands, (PNP)NiCl and (PNP)PtCl were also studied. The (PNZ)MCl complexes (M = Ni, Pd, Pt) underwent quasireversible oxidation in cyclic voltammetry experiments. Based on the close similarity of formal potentials for Ni, Pd, and Pt analogs, and based on the previous literature evidence, these oxidation events are ascribed primarily to the PNZ ligand, and the E1/2 values can be used to compare the ease of oxidation of different ligands. A (PNP)PdCl complex containing methoxy substituents para- to the central nitrogen underwent two quasireversible oxidations. Two mono-oxidized complexes were isolated and structurally characterized in comparison to their neutral analog, revealing minimal changes in the bond distances and angles. Several other neutral complexes were also structurally characterized. The carbonyl stretching frequency in (PNZ)RhCO complexes was used to gauge the donating ability of the various pincer ligands toward the metal. Comparison of E1/2 values for (PNZ)PdCl and nuCO values for (PNZ)RhCO revealed that the two are not consistently correlated across all the studied ligands and can be tuned to different degrees through judicious ligand alteration. PMID- 25714353 TI - The homogeneous reduction of CO2 by [Ni(cyclam)]+: increased catalytic rates with the addition of a CO scavenger. AB - The homogeneous electrochemical reduction of CO2 by the molecular catalyst [Ni(cyclam)](2+) is studied by electrochemistry and infrared spectroelectrochemistry. The electrochemical kinetics are probed by varying CO2 substrate and proton concentrations. Products of CO2 reduction are observed in infrared spectra obtained from spectroelectrochemical experiments. The two major species observed are a Ni(I) carbonyl, [Ni(cyclam)(CO)](+), and a Ni(II) coordinated bicarbonate, [Ni(cyclam)(CO2OH)](+). The rate-limiting step during electrocatalysis is determined to be CO loss from the deactivated species, [Ni(cyclam)(CO)](+), to produce the active catalyst, [Ni(cyclam)](+). Another macrocyclic complex, [Ni(TMC)](+), is deployed as a CO scavenger in order to inhibit the deactivation of [Ni(cyclam)](+) by CO. Addition of the CO scavenger is shown to dramatically increase the catalytic current observed for CO2 reduction. Evidence for the [Ni(TMC)](+) acting as a CO scavenger includes the observation of [Ni(TMC)(CO)](+) by IR. Density functional theory (DFT) calculations probing the optimized geometry of the [Ni(cyclam)(CO)](+) species are also presented. PMID- 25714354 TI - Silver-mediated oxidative aliphatic C-H trifluoromethylthiolation. AB - The first example of a practical and direct trifluoromethylthiolation reaction of unactivated aliphatic C?H bonds employs a silver-based reagent. The reaction is operationally simple, scalable, and proceeds under aqueous conditions in air. Furthermore, its broad scope and good functional-group compatibility were demonstrated by applying this method to the selective trifluoromethylthiolation of natural products and natural-product derivatives. PMID- 25714355 TI - Olive ridley sea turtle hatching success as a function of the microbial abundance in nest sand at Ostional, Costa Rica. AB - Several studies have suggested that significant embryo mortality is caused by microbes, while high microbial loads are generated by the decomposition of eggs broken by later nesting turtles. This occurs commonly when nesting density is high, especially during mass nesting events (arribadas). However, no previous research has directly quantified microbial abundance and the associated effects on sea turtle hatching success at a nesting beach. The aim of this study was to test the hypothesis that the microbial abundance in olive ridley sea turtle nest sand affects the hatching success at Ostional, Costa Rica. We applied experimental treatments to alter the microbial abundance within the sand into which nests were relocated. We monitored temperature, oxygen, and organic matter content throughout the incubation period and quantified the microbial abundance within the nest sand using a quantitative polymerase chain reaction (qPCR) molecular analysis. The most successful treatment in increasing hatching success was the removal and replacement of nest sand. We found a negative correlation between hatching success and fungal abundance (fungal 18S rRNA gene copies g(-1) nest sand). Of secondary importance in determining hatching success was the abundance of bacteria (bacterial 16S rRNA gene copies g(-1) g(-1) nest sand). Our data are consistent with the hypothesis that high microbial activity is responsible for the lower hatching success observed at Ostional beach. Furthermore, the underlying mechanism appears to be the deprivation of oxygen and exposure to higher temperatures resulting from microbial decomposition in the nest. PMID- 25714356 TI - Fluctuating asymmetry in Menidia beryllina before and after the 2010 Deepwater Horizon oil spill. AB - Assessing the impacts of the Deepwater Horizon oil spill with a dependable baseline comparison can provide reliable insight into environmental stressors on organisms that were potentially affected by the spill. Fluctuating asymmetry (small, non-random deviations from perfect bilateral symmetry) is an informative metric sensitive to contaminants that can be used to assess environmental stress levels. For this study, the well-studied and common Gulf of Mexico estuarine fish, Menidia beryllina, was used with pre and post-oil spill collections. Comparisons of fluctuating asymmetry in three traits (eye diameter, pectoral fin length, and pelvic fin length) were made pre and post-oil spill across two sites (Old Fort Bayou and the Pascagoula River), as well as between years of collection (2011, 2012)--one and two years, respectfully, after the spill in 2010. We hypothesized that fluctuating asymmetry would be higher in post-Deepwater Horizon samples, and that this will be replicated in both study areas along the Mississippi Gulf coast. We also predicted that fluctuating asymmetry would decrease through time after the oil spill as the oil decomposed and/or was removed. Analyses performed on 1135 fish (220 pre and 915 post Deepwater Horizon) showed significantly higher post spill fluctuating asymmetry in the eye but no difference for the pectoral or pelvic fins. There was also higher fluctuating asymmetry in one of the two sites both pre and post-spill, indicating observed asymmetry may be the product of multiple stressors. Fluctuating asymmetry decreased in 2012 compared to 2011. Fluctuating asymmetry is a sensitive measure of sub lethal stress, and the observed variability in this study (pre vs. post spill or between sites) could be due to a combination of oil, dispersants, or other unknown stressors. PMID- 25714357 TI - Live imaging of companion cells and sieve elements in Arabidopsis leaves. AB - The phloem is a complex tissue composed of highly specialized cells with unique subcellular structures and a compact organization that is challenging to study in vivo at cellular resolution. We used confocal scanning laser microscopy and subcellular fluorescent markers in companion cells and sieve elements, for live imaging of the phloem in Arabidopsis leaves. This approach provided a simple framework for identifying phloem cell types unambiguously. It highlighted the compactness of the meshed network of organelles within companion cells. By contrast, within the sieve elements, unknown bodies were observed in association with the PP2-A1:GFP, GFP:RTM1 and RTM2:GFP markers at the cell periphery. The phloem lectin PP2-A1:GFP marker was found in the parietal ground matrix. Its location differed from that of the P-protein filaments, which were visualized with SEOR1:GFP and SEOR2:GFP. PP2-A1:GFP surrounded two types of bodies, one of which was identified as mitochondria. This location suggested that it was embedded within the sieve element clamps, specific structures that may fix the organelles to each another or to the plasma membrane in the sieve tubes. GFP:RTM1 was associated with a class of larger bodies, potentially corresponding to plastids. PP2-A1:GFP was soluble in the cytosol of immature sieve elements. The changes in its subcellular localization during differentiation provide an in vivo blueprint for monitoring this process. The subcellular features obtained with these companion cell and sieve element markers can be used as landmarks for exploring the organization and dynamics of phloem cells in vivo. PMID- 25714358 TI - The impact of side-chain packing on protein docking refinement. AB - We study the impact of optimizing the side-chain positions in the interface region between two proteins during the process of binding. Mathematically, the problem is similar to side-chain prediction, which has been extensively explored in the process of protein structure prediction. The protein-protein docking application, however, has a number of characteristics that necessitate different algorithmic and implementation choices. In this work, we implement a distributed approximate algorithm that can be implemented on multiprocessor architectures and enables a trade-off between accuracy and running speed. We report computational results on benchmarks of enzyme-inhibitor and other types of complexes, establishing that the side-chain flexibility our algorithm introduces substantially improves the performance of docking protocols. Furthermore, we establish that the inclusion of unbound side-chain conformers in the side-chain positioning problem is critical in these performance improvements. The code is available to the community under open source license. PMID- 25714360 TI - Drowning mortality and morbidity rates in children and adolescents 0-19 yrs: a population-based study in Queensland, Australia. AB - OBJECTIVE: To redress the lack of Queensland population incidence mortality and morbidity data associated with drowning in those aged 0-19 yrs, and to understand survival and patient care. DESIGN, SETTING AND PARTICIPANTS: Retrospective population-based study used data linkage to capture both fatal and non-fatal drowning cases (N = 1299) among children aged 0-19 years in Queensland, from 2002 2008 inclusive. Patient data were accessed from pre-hospital, emergency department, hospital admission and death data, and linked manually to collate data across the continuum of care. MAIN OUTCOME MEASURES: Incidence rates were calculated separately by age group and gender for events resulting in death, hospital admission, and non-admission. Trends over time were analysed. RESULTS: Drowning death to survival ratio was 1:10, and two out of three of those who survived were admitted to hospital. Incidence rates for fatal and non-fatal drowning increased over time, primarily due to an increase in non-fatal drowning. There were non-significant reductions in fatal and admission rates. Rates for non fatal drowning that did not result in hospitalisation more than doubled over the seven years. Children aged 5-9 yrs and 10-14 yrs incurred the lowest incidence rates 6.38 and 4.62 (expressed as per 100,000), and the highest rates were among children aged 0-4 yrs (all drowning events 43.90; fatal 4.04; non-fatal 39.85 comprising admission 26.69 and non-admission 13.16). Males were over-represented in all age groups except 10-14 yrs. Total male drowning events increased 44% over the seven years (P<0.001). CONCLUSION: This state-wide data collection has revealed previously unknown incidence and survival ratios. Increased trends in drowning survival rates may be viewed as both positive and challenging for drowning prevention and the health system. Males are over-represented, and although infants and toddlers did not have increased fatality rates, they had the greatest drowning burden demonstrating the need for continued drowning prevention efforts. PMID- 25714359 TI - Physical determinants of fibrinolysis in single fibrin fibers. AB - Fibrin fibers form the structural backbone of blood clots; fibrinolysis is the process in which plasmin digests fibrin fibers, effectively regulating the size and duration of a clot. To understand blood clot dissolution, the influence of clot structure and fiber properties must be separated from the effects of enzyme kinetics and perfusion rates into clots. Using an inverted optical microscope and fluorescently-labeled fibers suspended between micropatterned ridges, we have directly measured the lysis of individual fibrin fibers. We found that during lysis 64 +/- 6% of fibers were transected at one point, but 29 +/- 3% of fibers increase in length rather than dissolving or being transected. Thrombin and plasmin dose-response experiments showed that the elongation behavior was independent of plasmin concentration, but was instead dependent on the concentration of thrombin used during fiber polymerization, which correlated inversely with fiber diameter. Thinner fibers were more likely to lyse, while fibers greater than 200 +/- 30 nm in diameter were more likely to elongate. Because lysis rates were greatly reduced in elongated fibers, we hypothesize that plasmin activity depends on fiber strain. Using polymer physics- and continuum mechanics-based mathematical models, we show that fibers polymerize in a strained state and that thicker fibers lose their prestrain more rapidly than thinner fibers during lysis, which may explain why thick fibers elongate and thin fibers lyse. These results highlight how subtle differences in the diameter and prestrain of fibers could lead to dramatically different lytic susceptibilities. PMID- 25714361 TI - Between the Baltic and Danubian Worlds: the genetic affinities of a Middle Neolithic population from central Poland. AB - For a long time, anthropological and genetic research on the Neolithic revolution in Europe was mainly concentrated on the mechanism of agricultural dispersal over different parts of the continent. Recently, attention has shifted towards population processes that occurred after the arrival of the first farmers, transforming the genetically very distinctive early Neolithic Linear Pottery Culture (LBK) and Mesolithic forager populations into present-day Central Europeans. The latest studies indicate that significant changes in this respect took place within the post-Linear Pottery cultures of the Early and Middle Neolithic which were a bridge between the allochthonous LBK and the first indigenous Neolithic culture of north-central Europe--the Funnel Beaker culture (TRB). The paper presents data on mtDNA haplotypes of a Middle Neolithic population dated to 4700/4600-4100/4000 BC belonging to the Brzesc Kujawski Group of the Lengyel culture (BKG) from the Kuyavia region in north-central Poland. BKG communities constituted the border of the "Danubian World" in this part of Europe for approx. seven centuries, neighboring foragers of the North European Plain and the southern Baltic basin. MtDNA haplogroups were determined in 11 individuals, and four mtDNA macrohaplogroups were found (H, U5, T, and HV0). The overall haplogroup pattern did not deviate from other post-Linear Pottery populations from central Europe, although a complete lack of N1a and the presence of U5a are noteworthy. Of greatest importance is the observed link between the BKG and the TRB horizon, confirmed by an independent analysis of the craniometric variation of Mesolithic and Neolithic populations inhabiting central Europe. Estimated phylogenetic pattern suggests significant contribution of the post-Linear BKG communities to the origin of the subsequent Middle Neolithic cultures, such as the TRB. PMID- 25714362 TI - Functional network overlap as revealed by fMRI using sICA and its potential relationships with functional heterogeneity, balanced excitation and inhibition, and sparseness of neuron activity. AB - Functional magnetic resonance imaging (fMRI) studies traditionally use general linear model-based analysis (GLM-BA) and regularly report task-related activation, deactivation, or no change in activation in separate brain regions. However, several recent fMRI studies using spatial independent component analysis (sICA) find extensive overlap of functional networks (FNs), each exhibiting different task-related modulation (e.g., activation vs. deactivation), different from the dominant findings of GLM-BA. This study used sICA to assess overlap of FNs extracted from four datasets, each related to a different cognitive task. FNs extracted from each dataset overlapped with each other extensively across most or all brain regions and showed task-related concurrent increases, decreases, or no changes in activity. These findings indicate that neural substrates showing task related concurrent but different modulations in activity intermix with each other and distribute across most of the brain. Furthermore, spatial correlation analyses found that most FNs were highly consistent in spatial patterns across different datasets. This finding indicates that these FNs probably reflect large scale patterns of task-related brain activity. We hypothesize that FN overlaps as revealed by sICA might relate to functional heterogeneity, balanced excitation and inhibition, and population sparseness of neuron activity, three fundamental properties of the brain. These possibilities deserve further investigation. PMID- 25714363 TI - Serology for trachoma surveillance after cessation of mass drug administration. AB - BACKGROUND: Trachoma, caused by Chlamydia trachomatis (Ct), is the leading infectious cause of blindness worldwide. Yearly azithromycin mass drug administration (MDA) plays a central role in efforts to eliminate blinding trachoma as a public health problem. Programmatic decision-making is currently based on the prevalence of the clinical sign "trachomatous inflammation follicular" (TF) in children. We sought to test alternative tools for trachoma surveillance based on serology in the 12-year cohort of Kahe Mpya, Rombo District, Tanzania, where ocular chlamydial infection was eliminated with azithromycin MDA by 2005. METHODOLOGY AND PRINCIPAL FINDINGS: The present study was a community-based cross-sectional survey in Kahe Mpya. Of 989 residents, 571 people aged 6 months to 87 years were enrolled: 58% of the total population and 73% of 1-9 year olds, the key WHO indicator age group. Participants were examined for TF, had conjunctival swabs collected for nucleic acid amplification test (NAAT)-based detection of Ct, and blood collected for analysis of antibodies to the Ct antigens pgp3 and CT694 by multiplex bead-based immunoassay. Seroconversion rate was used to estimate changes in the force of infection in a reversible catalytic model. No conjunctival swabs tested positive for Ct infection by NAAT. Among 1-9 year olds, TF prevalence was 6.5%, whereas only 3.5% were seropositive. Force of infection modelling indicated a 10-fold decrease in seroconversion rate at a time corresponding to MDA commencement. Without baseline serological data, the inferences we can make about antibody status before MDA and the longevity of the antibody response are limited, though our use of catalytic modelling overcomes some of these limitations. CONCLUSIONS/SIGNIFICANCE: Serologic tests support NAAT findings of very low to zero prevalence of ocular Ct in this community and have potential to provide objective measures of transmission and useful surveillance tools for trachoma elimination programs. PMID- 25714364 TI - Trends in cancer diagnoses and survival among persons with AIDS in a high HIV prevalence urban area. AB - Washington, DC (DC), has among the highest AIDS prevalence and cancer incidence in the USA. This study compared cancer diagnoses and survival among AIDS cases with AIDS-defining cancers (ADCs) to those with non-AIDS-defining cancers (NADCs) in DC from 1996 to 2006. Survival by cancer type and time period was also examined for 300 individuals diagnosed with AIDS who developed cancer; 49% of AIDS cases developed an ADC. ADC cases were younger at both AIDS and cancer diagnosis and had significantly lower median CD4 counts at AIDS diagnosis than NADC cases. The most frequent cancers were non-Hodgkin lymphoma (NHL; 44% of ADC), Kaposi's sarcoma (40% of ADC), and lung cancer (20% of NADC). There was no significant difference in distribution of cancers when comparing ADCs to NADCs, or over time (1996-2001 vs. 2002-2006). Survival among NHL, oral cavity, and lung cancer cases was 0.4, 0.8, and 0.3 years, respectively; the risk of death was approximately two times higher for each of these cancers when compared to other cancers. Given the high burden of cancer and HIV in DC, early highly active antiretroviral therapy initiation, routine cancer screening, and risk reduction through behavioral modification should be emphasized to prevent cancer among HIV infected persons. PMID- 25714365 TI - SPINE: SParse eIgengene NEtwork linking gene expression clusters in Dehalococcoides mccartyi to perturbations in experimental conditions. AB - We present a statistical model designed to identify the effect of experimental perturbations on the aggregate behavior of the transcriptome expressed by the bacterium Dehalococcoides mccartyi strain 195. Strains of Dehalococcoides are used in sub-surface bioremediation applications because they organohalorespire tetrachloroethene and trichloroethene (common chlorinated solvents that contaminate the environment) to non-toxic ethene. However, the biochemical mechanism of this process remains incompletely described. Additionally, the response of Dehalococcoides to stress-inducing conditions that may be encountered at field-sites is not well understood. The constructed statistical model captured the aggregate behavior of gene expression phenotypes by modeling the distinct eigengenes of 100 transcript clusters, determining stable relationships among these clusters of gene transcripts with a sparse network-inference algorithm, and directly modeling the effect of changes in experimental conditions by constructing networks conditioned on the experimental state. Based on the model predictions, we discovered new response mechanisms for DMC, notably when the bacterium is exposed to solvent toxicity. The network identified a cluster containing thirteen gene transcripts directly connected to the solvent toxicity condition. Transcripts in this cluster include an iron-dependent regulator (DET0096-97) and a methylglyoxal synthase (DET0137). To validate these predictions, additional experiments were performed. Continuously fed cultures were exposed to saturating levels of tetrachloethene, thereby causing solvent toxicity, and transcripts that were predicted to be linked to solvent toxicity were monitored by quantitative reverse-transcription polymerase chain reaction. Twelve hours after being shocked with saturating levels of tetrachloroethene, the control transcripts (encoding for a key hydrogenase and the 16S rRNA) did not significantly change. By contrast, transcripts for DET0137 and DET0097 displayed a 46.8+/-11.5 and 14.6+/-9.3 fold up-regulation, respectively, supporting the model. This is the first study to identify transcripts in Dehalococcoides that potentially respond to tetrachloroethene solvent-toxicity conditions that may be encountered near contamination source zones in sub-surface environments. PMID- 25714367 TI - Novel GLI3 mutation in a Greek-Cypriot patient with Greig cephalopolysyndactyly syndrome. AB - Greig cephalopolysyndactyly syndrome (GCPS) is typically characterized by preaxial or mixed preaxial and postaxial polydactyly with or without syndactyly and craniofacial features including hypertelorism and macrocephaly. Although GLI3 shows considerable pleiotropy, it is the only gene known to cause this particular phenotype. We report on a patient with GCPS caused by a novel GLI3 mutation. In addition, the patient had asymmetry of the calf muscles, most likely secondary to chronic hypertrophic radiculopathy. The GLI3 mutation identified by targeted Sanger sequencing analysis in our patient is predicted to lead to premature termination of translation. This is the first report of a Cypriot patient with a GCPS because of a novel GLI3 mutation. The report provides additional evidence in support of the rich variability in phenotypic expression, the mutational heterogeneity and ethnic diversity associated with this rare condition. PMID- 25714366 TI - Brown adipose tissue harbors a distinct sub-population of regulatory T cells. AB - Regulatory T (Treg) cells are critical determinants of both immune responses and metabolic control. Here we show that systemic ablation of Treg cells compromised the adaptation of whole-body energy expenditure to cold exposure, correlating with impairment in thermogenic marker gene expression and massive invasion of pro inflammatory macrophages in brown adipose tissue (BAT). Indeed, BAT harbored a unique sub-set of Treg cells characterized by a unique gene signature. As these Treg cells respond to BAT activation upon cold exposure, this study defines a BAT specific Treg sub-set with direct implications for the regulation of energy homeostasis in response to environmental stress. PMID- 25714368 TI - Pre-HIV Test Counseling and the Perpetuation of Stigma. PMID- 25714369 TI - Pharmacokinetic study of 14-(3-methylbenzyl)matrine and 14-(4 methylbenzyl)matrine in rat plasma using liquid chromatography-tandem mass spectrometry. AB - A rapid, sensitive and selective high-performance liquid chromatography-tandem mass spectrometric method (HPLC-MS) was developed and validated to determine the 14-(3-methylbenzyl)matrine (3MBM) and 14-(4-methylbenzyl)matrine (4MBM) levels in rat plasma in the present study. The analytes were separated using a C18 column (1.9 MUm, 2.1 mm * 100 mm) equipped with a Security Guard C18 column (5 MUm, 2.1 mm * 10 mm), followed by detection via triple-quadrupole mass spectrometry using an electrospray ionization (ESI) source. Sample pretreatment involved one-step protein precipitation with isopropanol:ethyl acetate (v/v, 25:75), and pseudoephedrine hydrochloride was used as an internal standard. The method was linear in the concentration range of 5-2000 ng/ml for both compounds. The intra day and inter-day relative standard deviations (RSDs) were less than 15%, and all relative errors (REs) were within 15%. The proposed method enables the unambiguous identification and quantification of these two compounds in vivo. This study is the first to determine the 3MBM and 4MBM levels in rat plasma after oral administration of these compounds. These results provide a meaningful basis for evaluating the clinical applications of these medicines. PMID- 25714370 TI - Genome wide association study for drought, aflatoxin resistance, and important agronomic traits of maize hybrids in the sub-tropics. AB - The primary maize (Zea mays L.) production areas are in temperate regions throughout the world and this is where most maize breeding is focused. Important but lower yielding maize growing regions such as the sub-tropics experience unique challenges, the greatest of which are drought stress and aflatoxin contamination. Here we used a diversity panel consisting of 346 maize inbred lines originating in temperate, sub-tropical and tropical areas testcrossed to stiff-stalk line Tx714 to investigate these traits. Testcross hybrids were evaluated under irrigated and non-irrigated trials for yield, plant height, ear height, days to anthesis, days to silking and other agronomic traits. Irrigated trials were also inoculated with Aspergillus flavus and evaluated for aflatoxin content. Diverse maize testcrosses out-yielded commercial checks in most trials, which indicated the potential for genetic diversity to improve sub-tropical breeding programs. To identify genomic regions associated with yield, aflatoxin resistance and other important agronomic traits, a genome wide association analysis was performed. Using 60,000 SNPs, this study found 10 quantitative trait variants for grain yield, plant and ear height, and flowering time after stringent multiple test corrections, and after fitting different models. Three of these variants explained 5-10% of the variation in grain yield under both water conditions. Multiple identified SNPs co-localized with previously reported QTL, which narrows the possible location of causal polymorphisms. Novel significant SNPs were also identified. This study demonstrated the potential to use genome wide association studies to identify major variants of quantitative and complex traits such as yield under drought that are still segregating between elite inbred lines. PMID- 25714371 TI - Dual electrical behavior of multivalent metal cation-based oxide and its application to thin-film transistors with high mobility and excellent photobias stability. AB - The effect of multivalent metal cations, including vanadium(V) and tin (Sn), on the electrical properties of vanadium-doped zinc tin oxide (VZTO) was investigated in the context of the fabrication of thin-film transistors (TFTs) using a single VZTO film and VZTO/ZTO bilayer as channel layers. The single VZTO TFT did not show any response to the gate voltage (insulator-like behavior). On the other hand, the VZTO/ZTO bilayer TFT exhibited a typical TFT transfer characteristic (semiconducting behavior). X-ray photoelectron spectroscopy revealed that, in contrast to what is commonly true in many oxides, oxygen vacancies (V(O)) in VZTO did not provide a dominant contribution to the total carrier concentration, because the V(O) peak area in the single VZTO film was 5.4% and reduced to 4.5% in VZTO/ZTO bilayer. Instead, Sn 3d5/2 and V 2p3/2 spectra suggest that the significant reduction in Sn and V ions is strongly related to the insulator-like behavior of the VZTO film. In negative-bias illumination tests and illumination tests with various photon energies, the VZTO/ZTO bilayer TFT had much better stability than the ZTO TFT. This result is attributed to the reduction of donor-like states ([Formula: see text]O) that can be positively ionized by blue and green illumination. PMID- 25714372 TI - Thickness-dependent SERS activities of gold nanosheets controllably synthesized via photochemical reduction in lamellar liquid crystals. AB - Gold nanosheets (AuNSs) with well-tuned thicknesses were synthesized by a facile photochemical reduction method in lamellar liquid crystals. It is found that ~50 nm thick AuNSs present much stronger surface-enhanced Raman scattering (SERS) effect than that of AuNSs with thicknesses of ~8 nm and 100 nm. PMID- 25714373 TI - Effect of treatment modality on long-term outcomes in attention deficit/hyperactivity disorder: a systematic review. AB - BACKGROUND: Evaluation of treatments for attention-deficit/hyperactivity disorder (ADHD) previously focused on symptom control, but attention has shifted to functional outcomes. The effect of different ADHD treatment periods and modalities (pharmacological, non-pharmacological, and combination) on long-term outcomes needs to be more comprehensively understood. METHODS: A systematic search of 12 literature databases using Cochrane's guidelines yielded 403 English language peer-reviewed, primary studies reporting long-term outcomes (>=2 years). We evaluated relative effects of treatment modalities and durations and effect sizes of outcomes reported as statistically significantly improved with treatment. RESULTS: The highest proportion of improved outcomes was reported with combination treatment (83% of outcomes). Among significantly improved outcomes, the largest effect sizes were found for combination treatment. The greatest improvements were associated with academic, self-esteem, or social function outcomes. A majority of outcomes improved regardless of age of treatment initiation (60%-75%) or treatment duration (62%-72%). Studies with short treatment duration had shorter follow-up times (mean 3.2 years total study length) than those with longer treatment durations (mean 7.1 years total study length). Studies with follow-up times <3 years reported benefit with treatment for 93% of outcomes, whereas those with follow-up times >=3 years reported treatment benefit for 57% of outcomes. Post-hoc analysis indicated that this result was related to the measurement of outcomes at longer periods (3.2 versus 0.4 years) after treatment cessation in studies with longer total study length. CONCLUSIONS: While the majority of long-term outcomes of ADHD improve with all treatment modalities, the combination of pharmacological and non-pharmacological treatment was most consistently associated with improved long-term outcomes and large effect sizes. Older treatment initiation age or longer durations did not markedly affect proportion of improved outcomes reported, but measurement of outcomes long periods after treatment cessation may attenuate results. PMID- 25714374 TI - Programmed evolution for optimization of orthogonal metabolic output in bacteria. AB - Current use of microbes for metabolic engineering suffers from loss of metabolic output due to natural selection. Rather than combat the evolution of bacterial populations, we chose to embrace what makes biological engineering unique among engineering fields - evolving materials. We harnessed bacteria to compute solutions to the biological problem of metabolic pathway optimization. Our approach is called Programmed Evolution to capture two concepts. First, a population of cells is programmed with DNA code to enable it to compute solutions to a chosen optimization problem. As analog computers, bacteria process known and unknown inputs and direct the output of their biochemical hardware. Second, the system employs the evolution of bacteria toward an optimal metabolic solution by imposing fitness defined by metabolic output. The current study is a proof-of concept for Programmed Evolution applied to the optimization of a metabolic pathway for the conversion of caffeine to theophylline in E. coli. Introduced genotype variations included strength of the promoter and ribosome binding site, plasmid copy number, and chaperone proteins. We constructed 24 strains using all combinations of the genetic variables. We used a theophylline riboswitch and a tetracycline resistance gene to link theophylline production to fitness. After subjecting the mixed population to selection, we measured a change in the distribution of genotypes in the population and an increased conversion of caffeine to theophylline among the most fit strains, demonstrating Programmed Evolution. Programmed Evolution inverts the standard paradigm in metabolic engineering by harnessing evolution instead of fighting it. Our modular system enables researchers to program bacteria and use evolution to determine the combination of genetic control elements that optimizes catabolic or anabolic output and to maintain it in a population of cells. Programmed Evolution could be used for applications in energy, pharmaceuticals, chemical commodities, biomining, and bioremediation. PMID- 25714375 TI - Co-expression of two subtypes of melatonin receptor on rat M1-type intrinsically photosensitive retinal ganglion cells. AB - Intrinsically photosensitive retinal ganglion cells (ipRGCs) are involved in circadian and other non-image forming visual responses. An open question is whether the activity of these neurons may also be under the regulation mediated by the neurohormone melatonin. In the present work, by double-staining immunohistochemical technique, we studied the expression of MT1 and MT2, two known subtypes of mammalian melatonin receptors, in rat ipRGCs. A single subset of retinal ganglion cells labeled by the specific antibody against melanopsin exhibited the morphology typical of M1-type ipRGCs. Immunoreactivity for both MT1 and MT2 receptors was clearly seen in the cytoplasm of all labeled ipRGCs, indicating that these two receptors were co-expressed in each of these neurons. Furthermore, labeling for both the receptors were found in neonatal M1 cells as early as the day of birth. It is therefore highly plausible that retinal melatonin may directly modulate the activity of ipRGCs, thus regulating non-image forming visual functions. PMID- 25714376 TI - Borrelia burgdorferi sensu lato spirochetes in wild birds in northwestern California: associations with ecological factors, bird behavior and tick infestation. AB - Although Borrelia burgdorferi sensu lato (s.l.) are found in a great diversity of vertebrates, most studies in North America have focused on the role of mammals as spirochete reservoir hosts. We investigated the roles of birds as hosts for subadult Ixodes pacificus ticks and potential reservoirs of the Lyme disease spirochete B. burgdorferi sensu stricto (s.s.) in northwestern California. Overall, 623 birds representing 53 species yielded 284 I. pacificus larvae and nymphs. We used generalized linear models and zero-inflated negative binomial models to determine associations of bird behaviors, taxonomic relationships and infestation by I. pacificus with borrelial infection in the birds. Infection status in birds was best explained by taxonomic order, number of infesting nymphs, sampling year, and log-transformed average body weight. Presence and counts of larvae and nymphs could be predicted by ground- or bark-foraging behavior and contact with dense oak woodland. Molecular analysis yielded the first reported detection of Borrelia bissettii in birds. Moreover, our data suggest that the Golden-crowned Sparrow (Zonotrichia atricapilla), a non-resident species, could be an important reservoir for B. burgdorferi s.s. Of 12 individual birds (9 species) that carried B. burgdorferi s.l.-infected larvae, no birds carried the same genospecies of B. burgdorferi s.l. in their blood as were present in the infected larvae removed from them. Possible reasons for this discrepancy are discussed. Our study is the first to explicitly incorporate both taxonomic relationships and behaviors as predictor variables to identify putative avian reservoirs of B. burgdorferi s.l. Our findings underscore the importance of bird behavior to explain local tick infestation and Borrelia infection in these animals, and suggest the potential for bird-mediated geographic spread of vector ticks and spirochetes in the far-western United States. PMID- 25714378 TI - Toxins targeting voltage-activated Ca2+ channels and their potential biomedical applications. AB - Voltage-gated Ca(2+) (CaV) channels are transmembrane proteins primarily formed by an ion-conducting alpha 1 subunit that can associate with auxiliary beta and alpha2δ subunits. Ca(2+) entering the cell through these channels serves as a versatile second messenger of electrical signaling, initiating numerous different cellular processes ranging from gene expression to cell fertilization, neuronal transmission and cell death. CaV channels, as other ion channels, are targets for numerous ligands including naturally occurring peptide toxins. Some of these peptide toxins are invaluable tools for studying their structure and function and have potential therapeutic applications. Here, we present an overview of the current knowledge regarding the structure and function of CaV channels as well as their role in human disease, and highlight some of the growing applications of peptide toxins targeting CaV channels. Analysis and understanding of the molecular strategy used by these peptide toxins might allow the design of novel classes of therapeutic agents acting on specific targets with high selectivity and efficacy. PMID- 25714377 TI - Snake venom derived molecules in tumor angiogenesis and its application in cancer therapy; an overview. AB - Snake venom is a complex mixture of biologically and pharmacologically active components, comprising hydrolytic enzymes, non-enzymatic proteins/peptides, and small amounts of organic and inorganic molecules. The venom components are known to vary with geographic location, season, species and age of the snakes. The role of the venom in the snake is not primarily for self-defense, but in prey immobilization and its subsequent digestion. Hence, several digestive enzymes in venoms, in addition to their hydrolytic activity have evolved to interfere in diverse physiological processes that help in the immobilization of prey/victim. As snake components are capable of modulating the physiological response of envenomated prey/victim, they show promise as potential pharmacological tools, as drug leads and in diagnostic applications. This, in a practical sense to be a reality has to be linked to the advances in toxinology that provide investigators with an understanding of the pharmacodynamics of toxins together with improved understanding of the etiology of many human diseases and identification of potential sites for therapeutic intervention. This review aims at providing an overview on snake venom toxins and their derivatives that have potential anti angiogenic effects for cancer treatment. Some of the anti-angiogenic components of snake venom like Snake venom metalloproteinases (SVMPs), Disintegrins, Phospholipases A2 (PLA2), CType Lectins (CLP), Vascular Apoptosis inducing Proteins (VAP) and L-Amino Acid Oxidases (LAAO) are discussed. This review aims at giving an overall view of these molecules and their mechanism of action as an effective antiangiogenic agent towards the treatment of cancer. PMID- 25714379 TI - Anesthetics act in quantum channels in brain microtubules to prevent consciousness. AB - The mechanism by which anesthetic gases selectively prevent consciousness and memory (sparing non-conscious brain functions) remains unknown. At the turn of the 20(th) century Meyer and Overton showed that potency of structurally dissimilar anesthetic gas molecules correlated precisely over many orders of magnitude with one factor, solubility in a non-polar, 'hydrophobic' medium akin to olive oil. In the 1980s Franks and Lieb showed anesthetics acted in such a medium within proteins, suggesting post-synaptic membrane receptors. But anesthetic studies on such proteins yielded only confusing results. In recent years Eckenhoff and colleagues have found anesthetic action in microtubules, cytoskeletal polymers of the protein tubulin inside brain neurons. 'Quantum mobility' in microtubules has been proposed to mediate consciousness. Through molecular modeling we have previously shown: (1) olive oil-like non-polar, hydrophobic quantum mobility pathways ('quantum channels') of tryptophan rings in tubulin, (2) binding of anesthetic gas molecules in these channels, and (3) capabilities for pi-electron resonant energy transfer, or exciton hopping, among tryptophan aromatic rings in quantum channels, similar to photosynthesis protein quantum coherence. Here, we show anesthetic molecules can impair pi-resonance energy transfer and exciton hopping in tubulin quantum channels, and thus account for selective action of anesthetics on consciousness and memory. PMID- 25714380 TI - Electromagnetic energy as a bridge between atomic and cellular levels in the genetics approach to cancer treatment. AB - Literature on magnetic fields (MF) and gene expression, as well as on DNA damage, supports the hypothesis that electromagnetic energy may act at atomic level influencing genetic stability. According to quantum physics, MF act on the interconversion of singlet and triplet spin states, and therefore on genetic instability, activating oxidative processes connected to biological free radicals formation, particularly ROS. In the above frame, the results of in vitro and in vivo laboratory trials have been analyzed. The use of a static MF amplitude modulated by 50 Hz MF, with a time average total intensity of 5.5 mT, has been shown to influence tumor cell functions such as cell proliferation, apoptosis, p53 expression, inhibition of tumor growth and prolongation of survival in animals, evidence that MF can be more effective than chemotherapy (cyclophosphamide) in inhibiting metastatic spread and growth, having synergistic activity with chemotherapy (Cis-platin), and no observable side effects or toxicity in animals or in humans. The beneficial biological/clinical effects observed, without any adverse effects, have been confirmed by various authors and augur well for the potentiality of this new approach to treat genetically based diseases like cancer. Further studies are needed to develop a quantum physics approach to biology, allowing a stable bridge to be built between atomic and cellular levels, therefore developing quantum biology. PMID- 25714381 TI - Evaluation of a method based on coherence in aqueous systems and resonance-based isotherapeutic remedy in the treatment of chronic psoriasis vulgaris. AB - Psoriasis is a chronic skin disorder that exhibits three main features: lymphocytic infiltration into the dermis and epidermis, uncontrolled proliferation and abnormal differentiation of keratinocytes. In this study we have evaluated the effect of treatment with WHITE Holographic Bioresonance Method and a resonance-based isotherapeutic remedy on patients affected by chronic psoriasis vulgaris. The WHITE Holographic Bioresonance Method is based on the principles of electrodynamic coherence. By exploiting the phenomenon of bio resonance, it uses a transfer plate to produce resonance- and light-based isotherapeutic coherent acqueous remedies and gels that emit coherent oscillations which "imprint" the area of psoriasis-affected skin. Levels of proinflammatory cytokines have been evaluated in the plasma of psoriatic patients treated with isotherapeutic remedies. The obtained results demonstrate a positive effect on the natural course of the disease and matched the results obtained by psoriatic patients treated with narrow band UVB. A significant reduction in plasma levels of cytokines involved in pathogenesis of psoriasis has been observed. Our findings may suggest that WHITE Holographic Bioresonance method used in combination with resonance-based isotherapeutic remedy could well be a new useful treatment option for patients with limited psoriatic plaques. PMID- 25714382 TI - Spectral perspective on the electromagnetic activity of cells. AB - In this mini-review, we summarize the current hypotheses, theories and experimental evidence concerning the electromagnetic activity of living cells. We systematically classify the bio-electromagnetic phenomena in terms of frequency and we assess their general acceptance in scientific community. We show that the electromagnetic activity of cells is well established in the low frequency range below 1 kHz and on optical wavelengths, while there is only limited evidence for bio-electromagnetic processes in radio- frequency and millimeter-wave ranges. This lack of generally accepted theory or trustful experimental results is the cause for controversy which accompanies this topic. We conclude our review with the discussion of the relevance of the electromagnetic activity of cells to human medicine. PMID- 25714383 TI - Permanent dissipative structures in water: the matrix of life? Experimental evidences and their quantum origin. AB - This paper presents a short review of the evidence - both experimental and theoretical - of the formation of dissipative structures in liquid water induced by three kinds of physical perturbations having a low energy content: extremely diluted solution (EDS), iteratively filtered water (IFW), and iteratively nafionated water (INW). Particular attention is devoted to the very recent discovery that such structures are tremendously persistent even in the solid phase: large ponderal quantities of supramolecular aggregates of water (with each nucleus hundreds of nanometers in size) have been observed - at ambient pressure and temperature - using easily-reproducible experimental methods. The nature of these dissipative structures is analyzed and explained in terms of the thermodynamics of far-from-equilibrium systems and irreversible processes, showing their spontaneous quantum origin. Are these kinds of structures the matrix itself of life?. PMID- 25714384 TI - A novel model of interaction between high frequency electromagnetic non-ionizing fields and microtubules viewed as coupled two-degrees of freedom harmonic oscillators. AB - The question regarding the potential biological and adverse health effects of non ionizing electromagnetic fields on living organisms is of primary importance in biophysics and medicine. Despite the several experimental evidences showing such occurrence in a wide frequency range from extremely low frequency to microwaves, a definitive theoretical model able to explain a possible mechanism of interaction between electromagnetic fields and living matter, especially in the case of weak and very weak intensities, is still missing. In this paper it has been suggested a possible mechanism of interaction involving the resonant absorption of electromagnetic radiation by microtubules. To this aim these have been modeled as non-dissipative forced harmonic oscillators characterized by two coupled "macroscopic" degrees of freedom, respectively describing longitudinal and transversal vibrations induced by the electromagnetic field. We have shown that the proposed model, although at a preliminary stage, is able to explain the ability of even weak electromagnetic radiating electromagnetic fields to transfer high quantities of energy to living systems by means of a resonant mechanism, so capable to easily damage microtubules structure. PMID- 25714385 TI - Resonant oscillation language of a futuristic nano-machine-module: eliminating cancer cells & Alzheimer abeta plaques. AB - Nano-machine-module is designed and synthesized as a futuristic drug (PCMS) for cancer and Alzheimers by doping 2 Nile Red molecules in the cavity of a 5(th) generation PAM AM dendrimer P, and attaching 32 molecular rotors M, 4 pH sensors S on its surface. Molecular rotors and sensors enable the dendritic box surface to target specific sites, minimizing termination of healthy cells, e.g. cancer cells, nuclei acids (DNA) & spirals of Abeta Amyloid are disintegrated. Combined Excitation Emission Spectroscopy (CEES) shows directed energy transfer along M< >C<->S, this energy transmission path is itself an oscillation, and we image live resonant oscillation of the PCMS and the target molecular system. PCMS engages into resonant oscillations with spiral molecular structures. PCMS is designed to sense microsatellite instability & spirals with resonance frequencies in the kHz range. PCM is toxic, but the toxicity disappears as S is added to derive PCMS. PCMS does not even affect the dynamic instability of microtubule, a basic operator of living cells. PMID- 25714386 TI - Electromagnetic effects in medicinal chemistry. PMID- 25714387 TI - Effect of low-level laser therapy in an experimental model of osteoarthritis in rats evaluated through Raman spectroscopy. AB - OBJECTIVE: This work aimed to investigate the biochemical changes associated with low-level laser therapy (LLLT) using 660 and 780 nm, on a well-established experimental model of osteoarthritis (OA) in the knees of rats with induced collagenase, using histomorphometry and Raman spectroscopy. MATERIALS AND METHODS: Thirty-six Wistar rats were divided into four groups: control (GCON, n=9), collagenase without treatment (GCOL, n=9), collagenase with LLLT 660 nm treatment (G660, n=8), and collagenase with LLLT 780 nm treatment (G780, n=10). LLLT protocol was: 30 mW power output, 10 sec irradiation time, 0.04 cm(2) spot size, 0.3 J energy, 0.75 W/cm(2) irradiance, and 7.5 J/cm(2) fluence per session per day, during 14 days. Then, knees were withdrawn and submitted to histomorphometry and Raman spectroscopy analysis. Principal components analysis (PCA) and Mahalanobis distance were employed to characterize the spectral findings. RESULTS: Histomorphometry revealed a significant increase in the amount of collagen III for the group irradiated with 660 nm. The Raman bands at 1247, 1273, and 1453 cm(-1) (from principal component score PC2), attributed to collagen type II, and 1460 cm(-1) (from PC3), attributed to collagen type III, suggested that the LLLT causes acceleration in cellular activity, especially on the cells that repair cartilage, accelerating the breakdown of cartilage destroyed by collagenase and stimulating the fibroblast to synthesize repairing collagen III. CONCLUSIONS: LLLT accelerated the initial breakdown of cartilage destroyed by collagenase and stimulated the fibroblast to synthesize the repairing collagen III, suggesting a beneficial effect of LLLT on OA. PMID- 25714388 TI - Vaccination attitudes and mobile readiness: A survey of expectant and new mothers. AB - Sub-optimal vaccination coverage and recent outbreaks of vaccine-preventable diseases serve as a reminder that vaccine hesitancy remains a concern. ImmunizeCA, a new smartphone app to help track immunizations, may address several reasons for not vaccinating. We conducted a study to describe demographic variables, attitudes, beliefs and information sources regarding pediatric vaccination in a sample of childbearing women who were willing to download an immunization app. We also sought to measure their current mobile usage behaviors and determine if there is an association between participant demographics, attitudes, beliefs and information sources regarding pediatric vaccination and mobile usage. We recruited participants using a combination of passive and active methods at a tertiary care hospital in Ottawa, Canada. We used surveys to collect demographic information, examine attitudes, behavior, and information sources regarding immunization and self-reported mobile phone usage. A total of 54 women participated. The majority had positive attitudes toward vaccination (96%) and intended to vaccinate their children (98%). Participants were interested in information on pediatric vaccination (94%), and found information from public health the most reliable and accessible (78%). Participants also trusted immunization information from their doctor or nurse and public health (83%) more than other sources. There was variability in participant use of mobile apps for other purposes. The median participant mobile readiness score was 3.2. We found no significant associations between participant age, behavior and attitudes regarding vaccination and mobile readiness scores. This is the first evaluation of mobile readiness for a smartphone app to track immunizations. Our findings suggest that there exists an opportunity to provide reliable information on vaccination through mobile devices to better inform the public, however predictors of individual engagement with these technologies merits further study. PMID- 25714389 TI - Design of universal cancer vaccines using natural tumor vessel-specific antigens (SANTAVAC). AB - Vaccination against endothelial cells (ECs) lining the tumor vasculature represents one of the most attractive potential cancer immunotherapy options due to its ability to prevent solid tumor growth. Using this approach, target antigens can be derived from ECs and used to develop a universal cancer vaccine. Unfortunately, direct immunization with EC preparations can elicit autoimmune vasculitis in normal tissues. Recently, tumor-induced changes to the human EC surface were described that provided a basis for designing efficient EC-based vaccines capable of eliciting immune responses that targeted the tumor endothelium directly. This review examines these data from the perspective of designing EC-based cancer vaccines for the treatment of all solid tumors, including the antigen composition of vaccine formulations, the selection ECs for antigen derivation, the production and control of antigens, and the method for estimating vaccine efficacy and safety. As the vaccine preparation requires a specifically derived set of natural cell surface antigens, a new vaccine preparation concept was formulated. Antigen compositions prepared according to this concept were named SANTAVAC (Set of All Natural Target Antigens for Vaccination Against Cancer). PMID- 25714390 TI - Cost-effectiveness analysis of a multicomponent meningococcal serogroup B vaccine in hypothetic epidemic situation in a middle-income country. AB - NmenB vaccine (4CMenB) is now available, but studies on the cost-effectiveness of vaccine introduction in a country outbreak situation are lacking. The aim of this study was to evaluate the cost-effectiveness of 4CMenB in the context of a hypothetical epidemic outbreak in Chile. We analyzed the direct and indirect costs of acute disease, sequelae and death for each case of meningococcal disease (MD) based on information obtained during the latest NmenB outbreak in Santiago, Chile, occurring between 1993-1999, with an incidence of 5.9/100,000 inhabitants and a mortality of 7.3%. We analyzed the cost of a mass vaccination campaign, considering one dose of 4CMenB for population between 12 months and 25 y of age and 3 doses for infants. Cost-effectiveness analysis was based on 80% and 92% 4CMenB immunogenicity for individual's bellow and over 12 months respectively. Sensitivity analysis was applied to different vaccine costs. RESULTS: The total cost of the epidemic was USD $59,967,351, considering individual cost of each acute case (USD$2,685), sequelae (USD$2,374) and death (USD $408,086). In Chile, the 4CMenB mass vaccination strategy would avoid 215 cases, 61 sequelae, and 16 deaths per year. The strategy would be cost-effective at a vaccine dose cost <= of USD$18. CONCLUSIONS: Implementation of a mass vaccination campaign to control a hypothetical NmenB outbreak in Chile would be cost-effective at a vaccine cost per dose <= of USD$18. This is the first report of a cost-effectiveness analysis for use of 4CMenB as a single intervention strategy to control an epidemic outbreak of NmenB. PMID- 25714391 TI - Three-year outcomes associated with embolic protection in saphenous vein graft intervention: results in 49 325 senior patients in the Medicare-linked National Cardiovascular Data Registry CathPCI Registry. AB - BACKGROUND: Information is limited on contemporary use and outcomes of embolic protection devices (EPDs) in saphenous vein graft interventions. METHODS AND RESULTS: We formed a longitudinal cohort (2005-2009; n=49 325) by linking National Cardiovascular Data Registry CathPCI Registry to Medicare claims to examine the association between EPD use and both procedural and long-term outcomes among seniors (65+ years), adjusting for clinical factors using propensity and instrumental variable methodologies. Prespecified high-risk subgroups included acute coronary syndrome and de novo or graft body lesions. EPDs were used in 21.2% of saphenous vein grafts (median age, 75; 23% women) and were more common in acute coronary syndrome (versus non-acute coronary syndrome; 22% versus 19%), de novo (versus restenotic; 22% versus 14%), and graft body lesions (versus aortic and distal anastomosis; 24% versus 20% versus 8%, respectively). EPDs were associated with a slightly higher incidence of procedural complications, including no reflow (3.9% versus 2.8%; P<0.001), vessel dissection (1.3% versus 1.1%; P=0.05), perforation (0.7% versus 0.4%; P=0.001), and periprocedural myocardial infarction (2.8% versus 1.8%; P<0.001). By 3 years, death, myocardial infarction, and repeat revascularization occurred in 25%, 15%, and 30% of cases, respectively. EPD use was associated with a similar adjusted risk of death (propensity score-matched hazard ratio, 0.96; 95% confidence interval, 0.91-1.02), myocardial infarction (propensity score-matched hazard ratio, 1.00; 95% confidence interval, 0.93-1.09), and repeat revascularization (propensity score-matched hazard ratio, 1.02; 95% confidence interval, 0.96-1.08) in the overall cohort and high-risk subgroups. CONCLUSIONS: In this contemporary cohort, EPDs were used more commonly among patients with high-risk clinical indications, yet there was no evidence of improved acute- or long-term outcomes. Further prospective studies are needed to support routine EPD use. PMID- 25714392 TI - Embolic protection device for saphenous vein graft intervention: too early to take off the seat belt. PMID- 25714393 TI - Remarkably selective, non-linear allosteric regulation of anion binding by a tetracationic calix[4]pyrrole homodimer. AB - A covalently coupled, dimeric tetra-cationic calix[4]pyrrolehomodimer bearing anthracene linkers displayed distinctive cooperativity and fluoride selectivity with positive allosterism. The exclusive and successive binding of fluoride anions is accompanied by large 'turn-on' fluorescence (K2/K1 = 311). PMID- 25714394 TI - Transition of Eocene whales from land to sea: evidence from bone microstructure. AB - Cetacea are secondarily aquatic amniotes that underwent their land-to-sea transition during the Eocene. Primitive forms, called archaeocetes, include five families with distinct degrees of adaptation to an aquatic life, swimming mode and abilities that remain difficult to estimate. The lifestyle of early cetaceans is investigated by analysis of microanatomical features in postcranial elements of archaeocetes. We document the internal structure of long bones, ribs and vertebrae in fifteen specimens belonging to the three more derived archaeocete families--Remingtonocetidae, Protocetidae, and Basilosauridae--using microtomography and virtual thin-sectioning. This enables us to discuss the osseous specializations observed in these taxa and to comment on their possible swimming behavior. All these taxa display bone mass increase (BMI) in their ribs, which lack an open medullary cavity, and in their femora, whereas their vertebrae are essentially spongious. Humeri and femora show opposite trends in microanatomical specialization in the progressive independence of cetaceans from a terrestrial environment. Humeri change from very compact to spongious, which is in accordance with the progressive loss of propulsive role for the forelimbs, which were used instead for steering and stabilizing. Conversely, hind-limbs in basilosaurids became strongly reduced with no involvement in locomotion but display strong osteosclerosis in the femora. Our study confirms that Remingtonocetidae and Protocetidae were almost exclusively aquatic in locomotion for the taxa sampled, which probably were shallow water suspended swimmers. Basilosaurids display osseous specializations similar to those of modern cetaceans and are considered more active open-sea swimmers. This study highlights the strong need for homologous sections in comparative microanatomical studies, and the importance of combining information from several bones of the same taxon for improved functional interpretation. PMID- 25714395 TI - Negative emotional events that people ruminate about feel closer in time. AB - Rumination is intrusive, perseverative cognition. We suggest that one psychological consequence of ruminating about negative emotional events is that the events feel as though they happened metaphorically "just yesterday". Results from three studies showed that ruminating about real world anger provocations, guilt-inducing events, and sad times in the last year made these past events feel as though they happened more recently. The relationship between rumination and reduced temporal psychological distance persisted even when controlling for when the event occurred and the emotional intensity of the event. Moreover, angry rumination was correlated with enhanced approach motivation, which mediated the rumination-distance relationship. The relationship between guilty rumination and distance was mediated by enhanced vividness. Construal level and taking a 3rd person perspective contributed to the sense of distance when participants were prompted to think about less emotionally charged situations. A meta-analysis of the data showed that the relationship between rumination and reduced distance was significant and twice as large as the same relationship for neutral events. These findings have implications for understanding the role of emotional rumination on memory processes in clinical populations and people prone to rumination. This research suggests that rumination may be a critical mechanism that keeps negative events close in the heart, mind, and time. PMID- 25714396 TI - Enhanced neurite outgrowth of human model (NT2) neurons by small-molecule inhibitors of Rho/ROCK signaling. AB - Axonal injury in the adult human central nervous system often results in loss of sensation and motor functions. Promoting regeneration of severed axons requires the inactivation of growth inhibitory influences from the tissue environment and stimulation of the neuron intrinsic growth potential. Especially glial cell derived factors, such as chondroitin sulfate proteoglycans, Nogo-A, myelin associated glycoprotein, and myelin in general, prevent axon regeneration. Most of the glial growth inhibiting factors converge onto the Rho/ROCK signaling pathway in neurons. Although conditions in the injured nervous system are clearly different from those during neurite outgrowth in vitro, here we use a chemical approach to manipulate Rho/ROCK signalling with small-molecule agents to encourage neurite outgrowth in cell culture. The development of therapeutic treatments requires drug testing not only on neurons of experimental animals, but also on human neurons. Using human NT2 model neurons, we demonstrate that the pain reliever Ibuprofen decreases RhoA (Ras homolog gene family, member A GTPase) activation and promotes neurite growth. Inhibition of the downstream effector Rho kinase by the drug Y-27632 results in a strong increase in neurite outgrowth. Conversely, activation of the Rho pathway by lysophosphatidic acid results in growth cone collapse and eventually to neurite retraction. Finally, we show that blocking of Rho kinase, but not RhoA results in an increase in neurons bearing neurites. Due to its anti-inflammatory and neurite growth promoting action, the use of a pharmacological treatment of damaged neural tissue with Ibuprofen should be explored. PMID- 25714398 TI - Evaluation of the microcirculation in a rabbit hemorrhagic shock model using laser Doppler imaging. AB - The aim of this study is to evaluate the feasibility of Laser Doppler imaging (LDI) for noninvasive and dynamic assessment of hemorrhagic shock in a rabbit model. A rabbit model of hemorrhagic shock was generated and LDI of the microcirculation in the rabbit ears was performed before and at 0, 30, 60, and 90 min after hemorrhage. The CCD (Charge Coupled Device) image of the ears, the mean arterial pressure (MAP) and the heart rate (HR) were monitored. The mean LDI flux was calculated. The HR of rabbits was significantly (p < 0.05) elevated and the MAP was decreased after hemorrhage, compared to the pre-hemorrhage level. Within the initial 30 min after hemorrhage, the perfusion flux lineally dropped down. In contrast, the MAP values did not differ significantly between the time points of 0 and 30 after hemorrhage (p > 0.05). Both the flux numbers and the red-to-blue color changes on LDI imaging showed the reduction of the microcirculation. LDI imaging is a noninvasive and non-contact approach to evaluate the microcirculation and may offer benefits in the diagnosis and treatment of hemorrhage shock. Further studies are needed to confirm its effectiveness in clinical practice. PMID- 25714397 TI - Combinatorial Action of MicroRNAs let-7 and miR-34 Effectively Synergizes with Erlotinib to Suppress Non-small Cell Lung Cancer Cell Proliferation. AB - Lung cancer represents the leading cause of cancer-related deaths in men and women worldwide. Targeted therapeutics, including the epidermal growth factor receptor (EGFR) inhibitor erlotinib, have recently emerged as clinical alternatives for the treatment of non-small cell lung cancer (NSCLC). However, the development of therapeutic resistance is a major challenge, resulting in low 5-year survival rates. Due to their ability to act as tumor suppressors, microRNAs (miRNAs) are attractive candidates as adjuvant therapeutics for the treatment of NSCLC. In this study, we examine the ability of 2 tumor suppressor miRNAs, let-7b and miR-34a to sensitize KRAS;TP53 mutant non-small cell lung cancer cells to the action of erlotinib. Treatment with these miRNAs, individually or in combination, resulted in synergistic potentiation of the anti proliferative effects of erlotinib. This effect was observed over a wide range of miRNA and erlotinib interactions, suggesting that let-7b and miR-34a target oncogenic pathways beyond those inhibited by EGFR. Combinatorial treatment with let-7b and miR-34a resulted in the strongest synergy with erlotinib, indicating that these miRNAs can effectively target multiple cellular pathways involved in cancer cell proliferation and resistance to erlotinib. Together, our findings indicate that NSCLC cells can be effectively sensitized to erlotinib by supplementation with tumor suppressor miRNAs, and suggest that the use of combinations of miRNAs as adjuvant therapeutics for the treatment of lung cancer is a viable clinical strategy. PMID- 25714399 TI - Pain inhibition by optogenetic activation of specific anterior cingulate cortical neurons. AB - Cumulative evidence from both humans and animals suggests that the anterior cingulate cortex (ACC) is important for pain-related perception, and thus a likely target for pain relief therapy. However, use of existing electrode based ACC stimulation has not significantly reduced pain, at least in part due to the lack of specificity and likely co-activation of both excitatory and inhibitory neurons. Herein, we report a dramatic reduction of pain behavior in transgenic mice by optogenetic stimulation of the inhibitory neural circuitry of the ACC expressing channelrhodopsin-2. Electrophysiological measurements confirmed that stimulation of ACC inhibitory neurons is associated with decreased neural activity in the ACC. Further, a distinct optogenetic stimulation intensity and frequency-dependent inhibition of spiking activity in the ACC was observed. Moreover, we confirmed specific electrophysiological responses from different neuronal units in the thalamus, in response to particular types of painful stimuli (i,e., formalin injection, pinch), which we found to be modulated by optogenetic control of the ACC inhibitory neurons. These results underscore the inhibition of the ACC as a clinical alternative in inhibiting chronic pain, and leads to a better understanding of the pain processing circuitry of the cingulate cortex. PMID- 25714401 TI - Nano- and micro-sized rare-earth carbonates and their use as precursors and sacrificial templates for the synthesis of new innovative materials. AB - This review focuses on rare-earth carbonate materials of nano- and micro-size. It discusses in depth the different types of rare-earth carbonate compounds, diverse synthetic approaches and possibilities for chemical tuning of the size, shape and morphology. The interesting luminescence properties of lanthanide doped rare earth carbonates and their potential applications for example as efficient white light sources and biolabels are reviewed. Additionally the use of these materials as precursors for the synthesis of nano-/micro-sized oxides, and their application as sacrificial templates for morphology-controlled synthesis of other materials such as YVO4, LaF3, NaYF4 and others is overviewed. PMID- 25714400 TI - Significance of rat mammary tumors for human risk assessment. AB - We have previously indicated that the ideal animal tumor model should mimic the human disease. This means that the investigator should be able to ascertain the influence of host factors on the initiation of tumorigenesis, mimic the susceptibility of tumor response based on age and reproductive history, and determine the response of the tumors induced to chemotherapy. The utilization of experimental models of mammary carcinogenesis in risk assessment requires that the influence of ovarian, pituitary, and placental hormones, among others, as well as overall reproductive events are taken into consideration, since they are important modifiers of the susceptibility of the organ to neoplastic development. Several species, such as rodents, dogs, cats, and monkeys, have been evaluated for these purposes; however, none of them fulfills all the criteria specified previously. Rodents, however, are the most widely used models; therefore, this work will concentrate on discussing the rat rodent model of mammary carcinogenesis. PMID- 25714403 TI - Which patients with resectable pancreatic cancer truly benefit from oncological resection: is it destiny or biology? AB - Pancreatic cancer has a dismal prognosis. A technically perfect surgical operation may still not provide a survival advantage for patients with technically resectable pancreatic cancer. Appropriate selection of patients for surgical resections is an imminent issue. Recent studies have provided an important clue on what serum biomarkers may be used to select out the patients who would unlikely benefit from the surgical resection. PMID- 25714402 TI - Frostbite protection in mice expressing an antifreeze glycoprotein. AB - Ectotherms in northern latitudes are seasonally exposed to cold temperatures. To improve survival under cold stress, they use diverse mechanisms to increase temperature resistance and prevent tissue damage. The accumulation of anti-freeze proteins that improve cold hardiness occurs in diverse species including plants, arthropods, fish, and amphibians. We previously identified an Ixodes scapularis anti-freeze glycoprotein, named IAFGP, and demonstrated its cold protective function in the natural tick host and in a transgenic Drosophila model. Here we show, in a transgenic mouse model expressing an anti-freeze glycoprotein, that IAFGP protects mammalian cells and mice from cold shock and frostbite respectively. Transgenic skin samples showed reduced cell death upon cold storage ex vivo and transgenic mice demonstrated increased resistance to frostbite injury in vivo. IAFGP actively protects mammalian tissue from freezing, suggesting its application for the prevention of frostbite, and other diseases associated with cold exposure. PMID- 25714404 TI - Primates decline rapidly in unprotected forests: evidence from a monitoring program with data constraints. AB - Growing threats to primates in tropical forests make robust and long-term population abundance assessments increasingly important for conservation. Concomitantly, monitoring becomes particularly relevant in countries with primate habitat. Yet monitoring schemes in these countries often suffer from logistic constraints and/or poor rigor in data collection, and a lack of consideration of sources of bias in analysis. To address the need for feasible monitoring schemes and flexible analytical tools for robust trend estimates, we analyzed data collected by local technicians on abundance of three species of arboreal monkey in the Udzungwa Mountains of Tanzania (two Colobus species and one Cercopithecus), an area of international importance for primate endemism and conservation. We counted primate social groups along eight line transects in two forest blocks in the area, one protected and one unprotected, over a span of 11 years. We applied a recently proposed open metapopulation model to estimate abundance trends while controlling for confounding effects of observer, site, and season. Primate populations were stable in the protected forest, while the colobines, including the endemic Udzungwa red colobus, declined severely in the unprotected forest. Targeted hunting pressure at this second site is the most plausible explanation for the trend observed. The unexplained variability in detection probability among transects was greater than the variability due to observers, indicating consistency in data collection among observers. There were no significant differences in both primate abundance and detectability between wet and dry seasons, supporting the choice of sampling during the dry season only based on minimizing practical constraints. Results show that simple monitoring routines implemented by trained local technicians can effectively detect changes in primate populations in tropical countries. The hierarchical Bayesian model formulation adopted provides a flexible tool to determine temporal trends with full account for any imbalance in the data set and for imperfect detection. PMID- 25714405 TI - Perspectives and evolution of research in cardiology and cardiovascular sciences in Latin America. PMID- 25714406 TI - Behavioral cardiology: cardiology's new frontier of action. PMID- 25714407 TI - Cardiovascular research publications from Latin America between 1999 and 2008. A bibliometric study. AB - BACKGROUND: Cardiovascular research publications seem to be increasing in Latin America overall. OBJECTIVE: To analyze trends in cardiovascular publications and their citations from countries in Latin America between 1999 and 2008, and to compare them with those from the rest of the countries. METHODS: We retrieved references of cardiovascular publications between 1999 and 2008 and their five year post-publication citations from the Web of Knowledge database. For countries in Latin America, we calculated the total number of publications and their citation indices (total citations divided by number of publications) by year. We analyzed trends on publications and citation indices over time using Poisson regression models. The analysis was repeated for Latin America as a region, and compared with that for the rest of the countries grouped according to economic development. RESULTS: Brazil (n = 6,132) had the highest number of publications in 1999-2008, followed by Argentina (n = 1,686), Mexico (n = 1,368) and Chile (n = 874). Most countries showed an increase in publications over time, leaded by Guatemala (36.5% annually [95%CI: 16.7%-59.7%]), Colombia (22.1% [16.3%-28.2%]), Costa Rica (18.1% [8.1%-28.9%]) and Brazil (17.9% [16.9%-19.1%]). However, trends on citation indices varied widely (from -33.8% to 28.4%). From 1999 to 2008, cardiovascular publications of Latin America increased by 12.9% (12.1%-13.5%) annually. However, the citation indices of Latin America increased 1.5% (1.3% 1.7%) annually, a lower increase than those of all other country groups analyzed. CONCLUSIONS: Although the number of cardiovascular publications of Latin America increased from 1999 to 2008, trends on citation indices suggest they may have had a relatively low impact on the research field, stressing the importance of considering quality and dissemination on local research policies. PMID- 25714408 TI - Heart rate variability and Chagas heart disease. PMID- 25714409 TI - Case 1/2015. A 76-year-old male patient with Ebstein anomaly in natural course. PMID- 25714410 TI - Left ventricular diverticulum of the interventricular septum. PMID- 25714411 TI - Pseudo-pulmonary embolism--a case of hypoxemia associated with right-to-left shunt. PMID- 25714413 TI - Ecological change, sliding baselines and the importance of historical data: lessons from Combining [corrected] observational and quantitative data on a temperate reef over 70 years. AB - Understanding the effects of environmental change on ecosystems requires the identification of baselines that may act as reference conditions. However, the continuous change of these references challenges our ability to define the true natural status of ecosystems. The so-called sliding baseline syndrome can be overcome through the analysis of quantitative time series, which are, however, extremely rare. Here we show how combining historical quantitative data with descriptive 'naturalistic' information arranged in a chronological chain allows highlighting long-term trends and can be used to inform present conservation schemes. We analysed the long-term change of a coralligenous reef, a marine habitat endemic to the Mediterranean Sea. The coralligenous assemblages of Mesco Reef (Ligurian Sea, NW Mediterranean) have been studied, although discontinuously, since 1937 thus making available both detailed descriptive information and scanty quantitative data: while the former was useful to understand the natural history of the ecosystem, the analysis of the latter was of paramount importance to provide a formal measure of change over time. Epibenthic assemblages remained comparatively stable until the 1990s, when species replacement, invasion by alien algae, and biotic homogenisation occurred within few years, leading to a new and completely different ecosystem state. The shift experienced by the coralligenous assemblages of Mesco Reef was probably induced by a combination of seawater warming and local human pressures, the latter mainly resulting in increased water turbidity; in turn, cumulative stress may have favoured the establishment of alien species. This study showed that the combined analysis of quantitative and descriptive historical data represent a precious knowledge to understand ecosystem trends over time and provide help to identify baselines for ecological management. PMID- 25714414 TI - Efficient photon collection from a nitrogen vacancy center in a circular bullseye grating. AB - Efficient collection of the broadband fluorescence from the diamond nitrogen vacancy (NV) center is essential for a range of applications in sensing, on demand single photon generation, and quantum information processing. Here, we introduce a circular "bullseye" diamond grating which enables a collected photon rate of (2.7 +/- 0.09) * 10(6) counts per second from a single NV with a spin coherence time of 1.7 +/- 0.1 ms. Back-focal-plane studies indicate efficient redistribution of the NV photoluminescence into low-NA modes by the bullseye grating. PMID- 25714412 TI - Binding of the pathogen receptor HSP90AA1 to avibirnavirus VP2 induces autophagy by inactivating the AKT-MTOR pathway. AB - Autophagy is an essential component of host innate and adaptive immunity. Viruses have developed diverse strategies for evading or utilizing autophagy for survival. The response of the autophagy pathways to virus invasion is poorly documented. Here, we report on the induction of autophagy initiated by the pathogen receptor HSP90AA1 (heat shock protein 90 kDa alpha [cytosolic], class A member 1) via the AKT-MTOR (mechanistic target of rapamycin)-dependent pathway. Transmission electron microscopy and confocal microscopy revealed that intracellular autolysosomes packaged avibirnavirus particles. Autophagy detection showed that early avibirnavirus infection not only increased the amount of light chain 3 (LC3)-II, but also upregulated AKT-MTOR dephosphorylation. HSP90AA1-AKT MTOR knockdown by RNA interference resulted in inhibition of autophagy during avibirnavirus infection. Virus titer assays further verified that autophagy inhibition, but not induction, enhanced avibirnavirus replication. Subsequently, we found that HSP90AA1 binding to the viral protein VP2 resulted in induction of autophagy and AKT-MTOR pathway inactivation. Collectively, our findings suggest that the cell surface protein HSP90AA1, an avibirnavirus-binding receptor, induces autophagy through the HSP90AA1-AKT-MTOR pathway in early infection. We reveal that upon viral recognition, a direct connection between HSP90AA1 and the AKT-MTOR pathway trigger autophagy, a critical step for controlling infection. PMID- 25714416 TI - A colloid model system for interfacial sorption kinetics. AB - Particle adsorption to an interface may be a complicated affair, motivating detailed measurements of various processes involved, to discover better understanding of the role of particle characteristics and solution conditions on adsorption coverage and rate. Here we use micron size colloids with a weak interfacial interaction potential as a model system to track particle motion and measure the rates of desorption and adsorption. The colloid-interface interaction strength is tuned to be less than 10 kBT so that it is comparable to many nanoscale systems of interest such as proteins at interfaces. The tuning is accomplished using a combination of depletion, electrostatic, and gravitational forces. The colloids transition between an entropically trapped adsorbed state and a desorbed state through Brownian motion. Observations are made using an light-emitting diode (LED)-based total internal reflection microscopy (TIRM) setup. The observed adsorption and desorption rates are compared to theoretical predictions based on the measured interaction potential and near-wall particle diffusivity. The results demonstrate that diffusion dynamics play a significant role when the barrier energy is small. This experimental system will allow for the future study of more complex dynamics such as nonspherical colloids and collective effects at higher concentrations. PMID- 25714415 TI - Addition of lidocaine injection immediately before physiotherapy for frozen shoulder: a randomized controlled trial. AB - The intraarticular injection of lidocaine immediately before a physiotherapy session may relieve pain during the stretching and mobilization of the affected joint in patients with a frozen shoulder, thus enhancing the treatment effect. To compare the effects of intraarticular injection of lidocaine plus physiotherapy to that of physiotherapy alone in the treatment of a frozen shoulder, a prospective randomized controlled trial was conducted in the rehabilitation department of a private teaching hospital. Patients with a frozen shoulder were randomized into the physiotherapy group or the lidocaine injection plus physiotherapy (INJPT) group. The subjects in the INJPT group underwent injection of 3 ml of 1% lidocaine into the affected shoulder 10 to 20 minutes before each physiotherapy session. In each group, the treatment lasted 3 months. The primary outcome measures were the active and passive range of motion of the affected shoulder. The secondary outcome measures were the results of the Shoulder Disability Questionnaire, the Shoulder Pain and Disability Index, and the 36-item Short-Form Health Survey (SF-36). The outcome measures were evaluated before treatment and 1, 2, 3, 4, and 6 months after the start of treatment. The group comparisons showed significantly greater improvement in the INJPT group, mainly in active and passive shoulder range of motion in flexion and external rotation and improvements in pain and disability (P < 0.05); however, no significant group difference was seen in the SF-36 results. The intraarticular injection of lidocaine immediately before a physiotherapy session might be superior to physiotherapy alone in the treatment of a frozen shoulder. Trial registration: ClinicalTrials.gov NCT01817348. PMID- 25714417 TI - Increasing breadth of semantic associations with left frontopolar direct current brain stimulation: a role for individual differences. AB - The aim of this study was to evaluate the influence of left frontopolar versus auditory (control) cortex transcranial direct current stimulation (tDCS) on the breadth of semantic associations produced in a cued free association task. A within-participants design administered anodal tDCS over the left frontopolar or auditory cortex, centered at electrode site AFZ or T7 using a 4*1 targeted stimulation montage. During stimulation, participants produced free associates in response to cues designed to promote narrow, moderate, or broad semantic associations. We measured the latent semantic associative strength of generated words relative to cues. The cue manipulation produced expected effects on the associative breadth of generated words, but there was no main effect of stimulation site, and calculated Bayes factors showed strong support for the null hypothesis. However, individual differences in creative potential, as assessed by the remote associates test, reliably and positively predicted increases in associative breadth under the frontopolar versus the auditory control condition, but only in response to narrow cues. In conclusion, the present data support neuroimaging studies demonstrating the involvement of left frontopolar cortical regions in generating relatively broad semantic associations. They also provide novel evidence that individual differences in creative potential may modulate the influence of brain stimulation on the breadth of generated semantic associations. PMID- 25714418 TI - Motor area activity for action-related and nonaction-related sounds in a three dimensional sound field reproduction system. AB - The motor cortical area is often activated to auditory stimuli in the human brain. In this study, we examined whether the motor area shows differential activation for action-related and nonaction-related sounds and whether it is susceptible to the quality of the sounds. A three-dimensional sound field recording and reproduction system based on the boundary surface control principle (BoSC system) was used for this purpose. We measured brain activity during hearing action-related or nonaction-related sounds with electroencephalography using mu rhythm suppression (mu-suppression) as an index of motor cortical activation. The results showed that mu-suppression was observed when the participant heard action-related sounds, but it was not evident when hearing nonaction-related sounds. Moreover, this suppression was significantly larger in the 3D sound field (62-ch loudspeaker condition), which generates a more realistic sound field, than in the 1-ch loudspeaker condition. Our results indicate that the motor area was indeed activated for action-related sounds and that its activation was enhanced with a 3D realistic sound field. We discuss our findings in relation to the mirror neuron system and the possibility of using its activity as an objective measure that reflects the subjective sense of reality in various virtual reality settings when interacting with others. PMID- 25714419 TI - Intraperirhinal cortex administration of the synthetic cannabinoid, HU210, disrupts object recognition memory in rats. AB - Cannabinoids disrupt learning and memory in human and nonhuman participants. Object recognition memory, which is particularly susceptible to the impairing effects of cannabinoids, relies critically on the perirhinal cortex (PRh); however, to date, the effects of cannabinoids within PRh have not been assessed. In the present study, we evaluated the effects of localized administration of the synthetic cannabinoid, HU210 (0.01, 1.0 MUg/hemisphere), into PRh on spontaneous object recognition in Long-Evans rats. Animals received intra-PRh infusions of HU210 before the sample phase, and object recognition memory was assessed at various delays in a subsequent retention test. We found that presample intra-PRh HU210 dose dependently (1.0 MUg but not 0.01 MUg) interfered with spontaneous object recognition performance, exerting an apparently more pronounced effect when memory demands were increased. These novel findings show that cannabinoid agonists in PRh disrupt object recognition memory. PMID- 25714420 TI - A de-novo STXBP1 gene mutation in a patient showing the Rett syndrome phenotype. AB - This study reports on a 9-year-old girl who developed West syndrome and showed clinical features fulfilling the main revised diagnostic criteria for typical Rett syndrome (hand washing, severe cognitive impairment with absence of language, ataxic gait, progressive scoliosis and autistic features). Mutation analyses for methyl-CpG-binding protein 2 (MECP2), cyclin-dependent kinase-like 5 (CDKL5/STK9), ARX and Forkhead box G1 (FOXG1) genes were carried out, with negative results. A known de-novo c.1217G>A missense mutation in exon 14 leading to the substitution of a conserved residue, p.R406H in domain3b of the syntaxin binding protein 1 (STXBP1) gene, was detected. The STXBP1 gene encodes the syntaxin-binding protein 1, a neuron-specific protein involved in synaptic vesicle release at both glutaminergic and GABAergic synapses. This function is also affected by MECP2 gene mutations, which are known to lead to a decrease in glutamate and GABA receptors' density. It is possible to speculate that the impairment in synaptic plasticity represents the pathogenic link between MECP2 and STXBP1 gene mutations. On reviewing the clinical features of the reported patients with the same mutation in the STXBP1 gene, it has been observed that poor eye contact, tremour, dyskinesia, head/hand stereotypies and both cognitive and motor progressive deterioration are common symptoms, although never considered as indicative of a Rett syndrome phenotype. In conclusion, the case described here suggests a relationship between the Rett syndrome and the STXBP1 gene not described so far, making the search for STXBP1 gene mutations advisable in patients with Rett syndrome and early onset of epilepsy. PMID- 25714421 TI - Differentiation among parkinsonisms using quantitative diffusion kurtosis imaging. AB - Differential diagnoses among Parkinson's disease (PD), multiple system atrophy (MSA), and progressive supranuclear palsy syndrome (PSPS) are often difficult. Hence, we investigated whether diffusion kurtosis imaging (DKI) could detect pathological changes that occur in these disorders and be used to differentiate between such patients. Fourteen patients (five with PD, four MSA, and five PSPS) and six healthy controls were examined using a 1.5-T scanner. Mean kurtosis (MK), fractional anisotropy, and mean diffusivity maps were generated, and these values of the midbrain tegmentum (MBT) and pontine crossing tract (PCT), as well as MBT/PCT ratios, were obtained. We found no significant differences in MBT and PCT values on DKI maps among the groups. In contrast, MBT/PCT ratios from MK maps were significantly increased in the MSA group and decreased in the PSPS group compared with the other groups. MBT/PCT ratios from mean diffusivity maps showed a significant increase in the PSPS group. Therefore, quantitative DKI analyses, particularly the MBT/PCT ratio from MK maps, can differentiate patients with parkinsonisms. PMID- 25714422 TI - Optimal hemoglobin concentration in patients with aneurysmal subarachnoid hemorrhage after surgical treatment to prevent symptomatic cerebral vasospasm. AB - Medical complications occur frequently after aneurismal subarachnoid hemorrhage (aSAH), such as cerebral vasospasm (CVS), anemia, etc. The relationship between hemoglobin (Hgb) concentration and the occurrence of CVS after aSAH remains largely elusive. A total of 218 patients with postoperative aSAH were recruited. Symptomatic cerebral vasospasm (SCVS) was initially diagnosed on the basis of their clinical signs and symptoms, and confirmed by imaging tests. The patients were then divided into four groups on the basis of the postoperative mean Hgb concentration (<11, 11-12, 12-13, and >13 g/dl). The possible influential factors that were statistically significant in the initial univariate analysis were subjected to a multivariable logistic regression analysis. Univariate analysis showed that Hunt and Hess neurological grade on admission, intraoperative aneurysm rupture, CT Fisher grade, and postoperative mean Hgb were associated significantly with SCVS in aSAH patients after surgical treatment (P<0.05). Subsequent multivariable analysis showed that postoperative mean Hgb remained significant after adjustment for Hunt and Hess neurological grade on admission and CT fisher grade. The incidence of SCVS in the group with an Hgb concentration 11-12 g/dl was found to be the lowest among all groups [odds ratio (OR), 3.29, 95% confidence interval (CI), 1.43-7.58, P=0.005; OR, 3.63, 95% CI, 1.41-9.34, P=0.007; OR, 5.34, 95% CI, 1.85-15.43, P=0.002]. Postoperative Hgb concentration is an independent risk factor for SCVS in aSAH patients following surgery, and maintaining the concentration at 11-12 g/dl may reduce the incidence of SCVS. PMID- 25714423 TI - Influence of negative emotion on the framing effect: evidence from event-related potentials. AB - The framing effect is the phenomenon in which different descriptions of an identical problem can result in different choices. The influence of negative emotions on the framing effect and its neurocognitive basis are important issues, especially in the domain of saving lives, which is essential and highly risky. In each trial of our experiment, the emotion stimulus is presented to the participants, followed by the decision-making stimulus, which comprises certain and risky options with the same expected value. Each pair of options is positively or negatively framed. The behavioral results indicate a significant interactive effect between negative emotion and frame; thus, the risk preference under the positive frame can be enhanced by negative emotions, whereas this finding is not true under the negative frame. The event-related potential analysis indicates that choosing certain options under the positive frame with negative emotion priming generates smaller P2 and P3 amplitudes and a larger N2 amplitude than with neutral emotion priming. The event-related potential findings indicate that individuals can detect risk faster and experience more conflict and increased decision difficulty if they choose certain options under the positive frame with negative priming compared with neutral priming. PMID- 25714425 TI - Role of the posterior temporal lobe during language tasks: a virtual lesion study using repetitive transcranial magnetic stimulation. AB - Functional brain imaging studies have suggested that the superior temporal gyrus (STG) and the middle temporal gyrus (MTG) are involved in phonological and lexical-semantic processing, respectively. However, the precise role of the posterior temporal lobe is not fully understood. To clarify the functional relevance of the left posterior STG and MTG during language processing, we used neuronavigation-guided repetitive transcranial magnetic stimulation (rTMS). The reaction times and error rates for 12 healthy volunteers performing auditory repetition and lexical-semantic decision tasks were compared before and during rTMS stimulation. We applied 1 Hz rTMS over the left posterior STG or MTG or sham stimulation for 10 min in a random order. Stimulation of the left posterior MTG significantly slowed the response time for the lexical-semantic decision task from 478.9+/-56.5 to 583.1+/-80.0 ms. However, stimulation over the left posterior STG or MTG did not affect the response time or the error rate for the auditory repetition task. Our results suggest that the left posterior MTG might be involved in lexical decision making. Neuronavigation-guided rTMS virtual lesion studies could help determine the functional roles of specific brain areas in language processing, and our findings provide new evidence supporting the use of neuromodulation through rTMS for patients with aphasia. PMID- 25714424 TI - Decreased plasma levels of lipoxin A4 in children with autism spectrum disorders. AB - The aim of this study was to evaluate the plasma levels of lipoxin A4 (LXA4), a mediator involved in the resolution of inflammation in Chinese children with autism spectrum disorders (ASD). From January 2013 to June 2014, a total of 150 children (75 confirmed ASD cases and 75 their age-matched and sex-matched control cases) participated in this study after consent was obtained from their parents. Clinical information was collected. Plasma levels of LXA4 were measured at baseline. The severity of ASD was assessed at admission using the Childhood Autism Rating Scale total score. The results indicated that the mean plasma levels of LXA4 were significantly lower in autistic children compared with the normal children (P<0.0001). There was a significant negative relationship between circulating LXA4 levels and severity of autism evaluated by Childhood Autism Rating Scale scores (P=0.006) after adjustment for the possible covariates. On the basis of the receiver operating characteristic curve, the optimal cutoff value of plasma LXA4 levels as an indicator for an auxiliary diagnosis of ASD was projected to be 81.5 pg/ml, which yielded a sensitivity of 90.7% and a specificity of 76.0%, with the area under the curve at 0.911 (95% confidence interval, 0.867-0.955). These results suggested that autistic children had lower plasma LXA4 levels, suggesting an increased susceptibility to recurring inflammation in these samples. PMID- 25714426 TI - Mosaic pattern of Cre recombinase expression in cochlear outer hair cells of the Brn3.1 Cre mouse. AB - The Brn3.1 gene encodes for the protein Brn3.1, which is a member of the POU-IV class of transcription factors. Mutation leads to nonsyndromic human progressive hearing loss (DFNA15). To investigate the suitability of the Brn3.1 promoter for Cre recombinase-induced genetic recombination in cochlear hair cells, we established a transgenic Brn3.1 Cre mouse. This mouse line was crossbred with floxed ROSA26 and ROSA26 reporter mice. The cochleae were histologically analysed in cryosections at E16.5 and whole-mount preparations from P2 until P85. In addition, mice from all used strains and their recombinant offspring were tested electrophysiologically by auditory brainstem responses (ABR) and distorsion product otoacoustic emissions (DPOAE). Cre recombinase activity could be detected in P14 and P21 animals in a mosaic pattern in 26.3 and 9.9% of the outer hair cells, respectively. All investigated mice showed normal ABR and DPOAE values, indicating that neither insertion of the internal ribosome entry site (IRES) Cre cassette into the Brn3.1 gene led to abnormal auditory development nor did the reporter strains show inherited hearing disorders. This study shows that Cre expression under the control of the Brn3.1 promoter is feasible and that the insertion of the internal ribosome entry site Cre cassette into this locus exerted no effects on hearing development. Because of the inconstant pattern and the limited duration of expression, the application of the developed mouse line might be restricted. Also, the unchanged hearing capacity and structural integrity of the organ of Corti in available reporter lines indicate that they may be useful tools for hearing research. PMID- 25714427 TI - Imaging method for changes in venous dynamics: a preliminary study. AB - The present study proposes a novel functional magnetic resonance venography (fMRV) method to examine changes in venous dynamics that are difficult to detect with commonly used MRV methods such as susceptibility-weighted imaging (SWI). We used a fast gradient echo imaging sequence, known as a time-resolved angiography with interleaved stochastic trajectories, at 7T MRI; it achieves a high temporal resolution of 3 s, which enables detection of dynamic changes in blood oxygenation within the cerebral veins. Twelve healthy individuals participated in this functional imaging study. SWI was also performed using optimized parameters for comparison with fMRV. We measured the average signal change from representative veins in the visual cortex between resting and stimulation conditions. fMRV showed signal changes between the resting and the stimulation conditions in venous vessels more clearly than SWI. Dynamic changes in venous vessel oxygenation signals were observed in the 3 s measurement windows, and these changes showed an ~3 s delay at the onset and offset of stimulation. The average increase in the venous signal intensity was 6.86+/-0.82% (mean+/-SEM) during stimulation relative to the resting condition. This study shows that fMRV can directly visualize individual venous vessel blood oxygenation changes during visual stimulation, suggesting that it could be a useful method to investigate venous dynamics induced by visual stimulation. PMID- 25714428 TI - Caffeine's antioxidant potency optically sensed with double-stranded DNA-encased single-walled carbon nanotubes. AB - There is great interest in developing a sensitive method being able to quantitatively measure and compare antioxidant potencies of samples of interest against multiple reactive oxygen species (ROS) whose imbalance could cause oxidative stress. Here, a sensitive nanoprobe, double-stranded DNA encased single walled carbon nanotubes (SWNTs) has been developed to determine antioxidant potencies of selected samples (caffeine, regular coffee, and decaffeinated coffee) against ROS, hydrogen peroxide, and hydroxyl radicals. Antioxidant vitamin C and uric acid are used as standards. The method focuses on unique dual optical sensing capability of SWNTs, the rate of spectral suppression when exposed to ROS, and the magnitude of spectral recovery of the ROS-suppressed SWNTs when an antioxidant is added. It is found that the dual sensing capability of SWNTs is still sustained when reacting with the reactive hydroxyl radicals. The results show that caffeine's antioxidant potency is weak, about one millionth of those of vitamin C and uric acid. It is a better scavenger of hydrogen peroxide and a little less effective for hydroxyl radicals. In comparison, coffee, regardless of regular or decaffeinated, is a more efficient antioxidant than caffeine, having an antioxidant potency about ten thousand times stronger. This work provides a versatile detection method for evaluating the antioxidant potencies of samples of interest against various ROS for chemical, biological, and medical applications. PMID- 25714429 TI - Meet the editorial board. PMID- 25714430 TI - Oxidative stress as a pharmacological target for medicinal chemistry: synthesis and evaluation of compounds with redox activity--part 3. PMID- 25714431 TI - Predation risk, resource quality, and reef structural complexity shape territoriality in a coral reef herbivore. AB - For many species securing territories is important for feeding and reproduction. Factors such as competition, habitat availability, and male characteristics can influence an individual's ability to establish and maintain a territory. The risk of predation can have an important influence on feeding and reproduction; however, few have studied its effect on territoriality. We investigated territoriality in a haremic, polygynous species of coral reef herbivore, Sparisoma aurofrenatum (redband parrotfish), across eight reefs in the Florida Keys National Marine Sanctuary that were either protected or unprotected from fishing of piscivorous fishes. We examined how territory size and quality varied with reef protection status, competition, predation risk, and male size. We then determined how territory size and quality influenced harem size and female size to understand the effect of territoriality on reproductive potential. We found that protected reefs trended towards having more large predatory fishes and that territories there were smaller but had greater algal nutritional quality relative to unprotected reefs. Our data suggest that even though males in protected sites have smaller territories, which support fewer females, they may improve their reproductive potential by choosing nutritionally rich areas, which support larger females. Thus, reef protection appears to shape the trade-off that herbivorous fishes make between territory size and quality. Furthermore, we provide evidence that males in unprotected sites, which are generally less complex than protected sites, choose territories with higher structural complexity, suggesting the importance of this type of habitat for feeding and reproduction in S. aurofrenatum. Our work argues that the loss of corals and the resulting decline in structural complexity, as well as management efforts to protect reefs, could alter the territory dynamics and reproductive potential of important herbivorous fish species. PMID- 25714432 TI - Environmental gradients explain species richness and community composition of coastal breeding birds in the Baltic Sea. AB - Scientifically-based systematic conservation planning for reserve design requires knowledge of species richness patterns and how these are related to environmental gradients. In this study, we explore a large inventory of coastal breeding birds, in total 48 species, sampled in 4646 1 km2 squares which covered a large archipelago in the Baltic Sea on the east coast of Sweden. We analysed how species richness (alpha diversity) and community composition (beta diversity) of two groups of coastal breeding birds (specialists, i.e. obligate coastal breeders; generalists, i.e. facultative coastal breeders) were affected by distance to open sea, land area, shoreline length and archipelago width. The total number of species per square increased with increasing shoreline length, but increasing land area counteracted this effect in specialists. The number of specialist bird species per square increased with decreasing distance to open sea, while the opposite was true for the generalists. Differences in community composition between squares were associated with differences in land area and distance to open sea, both when considering all species pooled and each group separately. Fourteen species were nationally red-listed, and showed similar relationships to the environmental gradients as did all species, specialists and generalists. We suggest that availability of suitable breeding habitats, and probably also proximity to feeding areas, explain much of the observed spatial distributions of coastal birds in this study. Our findings have important implications for systematic conservation planning of coastal breeding birds. In particular, we provide information on where coastal breeding birds occur and which environments they seem to prefer. Small land areas with long shorelines are highly valuable both in general and for red-listed species. Thus, such areas should be prioritized for protection against human disturbance and used by management in reserve selection. PMID- 25714433 TI - Proportional upregulation of CD97 isoforms in glioblastoma and glioblastoma derived brain tumor initiating cells. AB - CD97 is a novel glioma antigen that confers an invasive phenotype and poor survival in patients with glioblastoma (GBM), the most aggressive primary malignant brain tumor. The short isoform of CD97, known as EGF(1,2,5), has been shown to promote invasion and metastasis, but its role in gliomas and GBM-derived brain tumor initiating cells (BTICs) has not been studied. We sought to characterize CD97 expression among gliomas and identify the specific isoforms expressed. The short isoform of CD97 was identified in GBM and GBM-derived BTICs, but not low grade or anaplastic astrocytomas. All samples expressing the EGF(1,2,5) isoform were also found to express the EGF(1,2,3,5) isoform. These isoforms are believed to possess similar ligand binding patterns and interact with chondroitin sulfate, a component of the extracellular matrix, and the integrin alpha5beta1. Using data acquired from the Cancer Genome Atlas (TCGA), we show that CD97 is upregulated among the classical and mesenchymal subtypes of GBM and significantly decreased among IDH1 mutant GBMs. Given its proven roles in tumor invasion, expression among aggressive genetic subtypes of GBM, and association with overall survival, CD97 is an attractive therapeutic target for patients with GBM. PMID- 25714434 TI - Successful decoding of famous faces in the fusiform face area. AB - What are the neural mechanisms of face recognition? It is believed that the network of face-selective areas, which spans the occipital, temporal, and frontal cortices, is important in face recognition. A number of previous studies indeed reported that face identity could be discriminated based on patterns of multivoxel activity in the fusiform face area and the anterior temporal lobe. However, given the difficulty in localizing the face-selective area in the anterior temporal lobe, its role in face recognition is still unknown. Furthermore, previous studies limited their analysis to occipito-temporal regions without testing identity decoding in more anterior face-selective regions, such as the amygdala and prefrontal cortex. In the current high-resolution functional Magnetic Resonance Imaging study, we systematically examined the decoding of the identity of famous faces in the temporo-frontal network of face-selective and adjacent non-face-selective regions. A special focus has been put on the face area in the anterior temporal lobe, which was reliably localized using an optimized scanning protocol. We found that face-identity could be discriminated above chance level only in the fusiform face area. Our results corroborate the role of the fusiform face area in face recognition. Future studies are needed to further explore the role of the more recently discovered anterior face-selective areas in face recognition. PMID- 25714435 TI - Interaction between oblongifolin C and UDP-glucuronosyltransferase isoforms in human liver and intestine microsomes. AB - 1. Oblongifolin C (OC) is a potential natural anticancer candidate, and its metabolic profile has not yet been established. 2. One major OC glucuronidation metabolite (OCG) has been identified in a pool of human liver microsomes (HLMs). Chemical inhibition experiments suggested that OCG was mainly formed by UGT1A. A screen of recombinant UDP-glucuronosyltransferase isoforms (UGTs) indicated that UGT1A1 primarily mediates OC conjugation, with minor contributions from UGT1A3 and UGT1A8. Enzyme kinetic studies showed that UGT1A1 was the main UGT isoform involved in OCG in HLMs. 3. Further investigation suggested that OC is a broad inhibitor of UGTs. Additionally, OC competitively inhibited UGT1A6 with a Ki value of 3.49 +/- 0.57 MUM, whereas non-competitively inhibited UGT1A10 with a Ki value of 2.12 +/- 0.18 MUM. 4. Understanding the interaction between OC and UGTs will greatly contribute to future investigations regarding the inter-individual differences in OC metabolism in clinical trials and potential drug-drug interactions. PMID- 25714436 TI - Does company compliance with RS-17 influence the characterization of a casual nexus in expert testimony? AB - OBJECTIVE: To examine whether company compliance with RS-17 influences the characterization of the casual nexus in physical therapists' expert reports of cumulative trauma disorders in the labor court of Pernambuco, Brazil. METHOD: The sample was composed of seven physical therapists who provided expert testimony regarding cumulative trauma disorder cases in the labor court of Pernambuco, Brazil. Data collection was performed across two stages. In the first stage, the experts answered a sociodemographic survey and requested the identification numbers of recent cases where expert testimony was provided to characterize the causal nexus. In the second stage, the researchers went to the labor court to collect expert testimony data. These experts indicated that of 75 total cases, 31% (N=23) of the companies fulfilled RS-17, whereas 69% (N=52) did not comply with the law. RESULTS: Among the organizations that complied with legislation, 30% of the analyzed expert testimonies showed a positive causal nexus. However, of the companies that did not comply with RS-17, 71% of the expert testimonies revealed a causal nexus. These results indicate that the breach of the law increases the probability that a causal nexus will be determined by 54.8%. CONCLUSION: The results showed that failure to comply with RS-17 significantly increases the probability that a causal nexus will be determined in physical therapists' expert testimony of cumulative trauma disorders. PMID- 25714437 TI - Relation between hand function and gross motor function in full term infants aged 4 to 8 months. AB - BACKGROUND: In children, reaching emerges around four months of age, which is followed by rapid changes in hand function and concomitant changes in gross motor function, including the acquisition of independent sitting. Although there is a close functional relationship between these domains, to date they have been investigated separately. OBJECTIVE: To investigate the longitudinal profile of changes and the relationship between the development of hand function (i.e. reaching for and manipulating an object) and gross motor function in 13 normally developing children born at term who were evaluated every 15 days from 4 to 8 months of age. METHOD: The number of reaches and the period (i.e. time) of manipulation to an object were extracted from video synchronized with the Qualisys(r) movement analysis system. Gross motor function was measured using the Alberta Infant Motor Scale. ANOVA for repeated measures was used to test the effect of age on the number of reaches, the time of manipulation and gross motor function. Hierarchical regression models were used to test the associations of reaching and manipulation with gross motor function. RESULTS: RESULTS revealed a significant increase in the number of reaches (p<0.001), the time of manipulation (p<0.001) and gross motor function (p<0.001) over time, as well as associations between reaching and gross motor function (R2=0.84; p<0.001) and manipulation and gross motor function (R2=0.13; p=0.02) from 4 to 6 months of age. Associations from 6 to 8 months of age were not significant. CONCLUSION: The relationship between hand function and gross motor function was not constant, and the age span from 4 to 6 months was a critical period of interdependency of hand function and gross motor function development. PMID- 25714438 TI - Associations between low back pain, urinary incontinence, and abdominal muscle recruitment as assessed via ultrasonography in the elderly. AB - BACKGROUND: Low back pain (LBP) and urinary incontinence (UI) are highly prevalent among elderly individuals. In young adults, changes in trunk muscle recruitment, as assessed via ultrasound imaging, may be associated with lumbar spine stability. OBJECTIVE: To assess the associations between LBP, UI, and the pattern of transversus abdominis (TrA), internal (IO), and external oblique (EO) muscle recruitment in the elderly as evaluated by ultrasound imaging. METHOD: Fifty-four elderly individuals (mean age: 72+/-5.2 years) who complained of LBP and/or UI as assessed by the McGill Pain Questionnaire, Incontinence Questionnaire-Short Form, and ultrasound imaging were included in the study. The statistical analysis comprised a multiple linear regression model, and a p-value <0.05 was considered significant. RESULTS: The regression models for the TrA, IO, and EO muscle thickness levels explained 2.0% (R2=0.02; F=0.47; p=0.628), 10.6% (R2=0.106; F=3.03; p=0.057), and 10.1% (R2=0.101; F=2.70; p=0.077) of the variability, respectively. None of the regression models developed for the abdominal muscles exhibited statistical significance. A significant and negative association (p=0.018; beta=-0.0343) was observed only between UI and IO recruitment. CONCLUSION: These results suggest that age-related factors may have interfered with the findings of the study, thus emphasizing the need to perform ultrasound imaging-based studies to measure abdominal muscle recruitment in the elderly. PMID- 25714439 TI - Dynamic Locked Plating of Distal Femur Fractures. AB - OBJECTIVES: Nonunion after locked bridge plating of comminuted distal femur fractures is not uncommon. "Dynamic" locked plating may create an improved mechanical environment, thereby achieving higher union rates than standard locked plating constructs. SETTING: Academic Level 1 Trauma Center. PATIENTS/PARTICIPANTS: Twenty-eight patients with comminuted supracondylar femur fractures treated with either dynamic or standard locked plating. INTERVENTION: Dynamic plating was achieved using an overdrilling technique of the near cortex to allow for a 0.5-mm "halo" around the screw shaft at the near cortex. Standard locked plating was done based on manufacturer's suggested technique. The patients treated with dynamic plating were matched 1:1 with those treated with standard locked plating based on OTA classification and working length. MAIN OUTCOME MEASUREMENTS: Three blinded observers made callus measurements on 6-week radiographs using a 4-point ordinal scale. The results were analyzed using a 2 tailed t test and 2-way intraclass correlations. RESULTS: The dynamic plating group had significantly greater callus (2.0; SD, 0.7) compared with the control group (1.3: SD, 0.8, P = 0.048) with substantial agreement amongst observers in both consistency (0.724) and absolute score (0.734). With dynamic plating group, 1 patient failed to unite, versus three in the control group (P = 0.59). The dynamic group had a mean change in coronal plane alignment of 0.5 degrees (SD, 2.6) compared with 0.6 (SD, 3.0) for the control group (P = 0.9) without fixation failure in either group. CONCLUSIONS: Overdrilling the near cortex in metaphyseal bridge plating can be adapted to standard implants to create a dynamic construct and increase axial motion. This technique seems to be safe and leads to increased callus formation, which may decrease nonunion rates seen with standard locked plating. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 25714440 TI - Nonoperative Treatment of Posterior Wall Acetabular Fractures After Dynamic Stress Examination Under Anesthesia: Revisited. AB - OBJECTIVES: Performing an examination under general anesthesia (EUA) using dynamic stress fluoroscopy of patients with posterior wall acetabular fractures has been used as a tool to determine hip stability and the need for surgical intervention. The purpose of this study was to further evaluate the effectiveness of this technique, from a source other than its primary advocates, in patients with posterior wall acetabular fractures less than or equal to 50% who were stable on EUA and treated nonoperatively. DESIGN: Retrospective case series. SETTING: University Level 1 Trauma Center. PARTICIPANTS: Seventeen patients with a posterior wall acetabular fracture stable on EUA treated nonoperatively. INTERVENTION: The patients were treated nonoperatively as guided by an EUA negative for instability. Patient follow-up averaged 30 months (range, 6-64 months). MAIN OUTCOME MEASUREMENTS: Outcome evaluation included the modified Merle d'Aubigne clinical score and the Short Musculoskeletal Function Assessment Questionnaire. Radiographic evaluation for subluxation or arthritis consisted of the 3 standard pelvic radiographs. RESULTS: Radiographic evaluation showed all hips to be congruent with a normal joint space. Sixteen of the 17 patients had radiographic outcomes rated as "excellent"; 1 patient was rated "good." The modified Merle d'Aubigne score (obtained in 12 patients) averaged very good, with only 1 having less than a good (graded as fair) clinical outcome. The Short Musculoskeletal Function Assessment Questionnaire scores (from 11 patients) were not significantly different from normal and were within the normal reported values for all indices and categories. There was no correlation between fracture fragment size and outcome. CONCLUSIONS: This study further supports the contention that a stable hip joint, as determined by EUA, after posterior wall acetabular fracture treated nonoperatively is predictive of continued joint congruity, an excellent radiographic outcome, and good-to-excellent early clinical and functional outcomes. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 25714441 TI - The Epidemiology of Upper Extremity Fractures in the United States, 2009. AB - BACKGROUND: No single epidemiological study of upper extremity fractures exists in the United States using data from all payers. Current epidemiological estimates are based on case series, foreign databases, or Medicare data, which are not representative of the entire US population. The objective of this project was to accurately describe the incidence of fractures of the upper extremity in a representative sample of the US population. METHODS: Using International Classification of Disease, Ninth Edition codes for patient visits reported in the 2009 State Emergency Department Database and the State Inpatient Database, available from the Healthcare Cost and Utilization Project, and 2010 US Census data, we calculated the annual incidence rates per 10,000 persons of upper extremity fractures of all patients, regardless of age or payer type. This was done using a representative national sample from 8 states: Arizona, California, Iowa, Maryland, Massachusetts, New Jersey, and Vermont. RESULTS: Overall, in this population of over 87 million Americans, there were 590,193 fractures of the upper extremity, yielding an annual incidence of 67.6 fractures per 10,000 persons. Distal radius and ulna fractures were the most common upper extremity fractures (16.2 fractures per 10,000 persons), followed by hand fractures (phalangeal and metacarpal fractures; 12.5 and 8.4 per 10,000, respectively), proximal humerus fractures (6.0 per 10,000), and clavicle fractures (5.8 per 10,000). The most common type of fracture for all age groups was distal radius fractures, except in the 18- to 34-year-old group, in which metacarpal and phalangeal fractures were more common (16.1 and 12.5 per 10,000, respectively) and the 35- to 49-year-old group, in which phalangeal fractures were most common (11.5 per 10,000). The incidence of distal radius fractures was bimodal, with the highest rates in the under 18 and over 65 age groups (30.18 and 25.42 per 10,000, respectively) with lower rates in the middle age groups. The most common type of fracture for males was phalangeal fractures (11.5 per 10,000), and distal radius and ulna fractures were the most common type for females (11.8 per 10,000). Interestingly, phalangeal and metacarpal fractures varied by socioeconomic status (SES), which decreased with increasing SES. No other fracture type varied by SES. CONCLUSIONS: Epidemiological studies are necessary for research, clinical applications, and public health and health policy initiatives. This study reports national estimates of upper extremity fractures with subgroup analysis. PMID- 25714442 TI - Delay in Hip Fracture Surgery: An Analysis of Patient-Specific and Hospital Specific Risk Factors. AB - OBJECTIVES: To empirically define a "delay" for hip fracture surgery based on clinical outcomes, and to identify patient demographics and hospital factors contributing to surgical delay. DESIGN: Retrospective database analysis. SETTING: Hospital discharge data. PATIENTS/PARTICIPANTS: A total of 2,121,215 patients undergoing surgical repair of hip fracture in the National Inpatient Sample between 2000 and 2009. INTERVENTION: Internal fixation or partial/total hip replacement. MAIN OUTCOME MEASUREMENTS: Logistic regressions were performed to assess the effect of surgical timing on in-hospital complication and mortality rates, controlling for patient characteristics and hospital attributes. Subsequent regressions were performed to analyze which patient characteristics (age, gender, race, comorbidity burden, insurance status, and day of admission) and hospital factors (size, teaching status, and region) independently contributed to the likelihood of surgical delay. RESULTS: Compared to same-day surgery, each additional day of delay was associated with a significantly higher overall complication rate. However, next-day surgery was not associated with an increased risk of in-hospital mortality. Surgery 2 calendar days (odds ratio: 1.13) and 3+ days (odds ratio: 1.33) after admission was associated with higher mortality rates. Based on these findings, "delay" was defined as surgery performed 2 or more days after admission. Significant factors related to surgical delay included comorbidity score, race, insurance status, hospital region, and day of admission. CONCLUSIONS: Surgical delay in hip fracture care contributes to patient morbidity and mortality. A variety of patient and hospital characteristics seem to contribute to surgical delay and point to important health care disparities. LEVEL OF EVIDENCE: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence. PMID- 25714443 TI - A diverse assemblage of reef corals thriving in a dynamic intertidal reef setting (Bonaparte Archipelago, Kimberley, Australia). AB - The susceptibility of reef-building corals to climatic anomalies is well documented and a cause of great concern for the future of coral reefs. Reef corals are normally considered to tolerate only a narrow range of climatic conditions with only a small number of species considered heat-tolerant. Occasionally however, corals can be seen thriving in unusually harsh reef settings and these are cause for some optimism about the future of coral reefs. Here we document for the first time a diverse assemblage of 225 species of hard corals occurring in the intertidal zone of the Bonaparte Archipelago, north western Australia. We compare the environmental conditions at our study site (tidal regime, SST and level of turbidity) with those experienced at four other more typical tropical reef locations with similar levels of diversity. Physical extremes in the Bonaparte Archipelago include tidal oscillations of up to 8 m, long subaerial exposure times (>3.5 hrs), prolonged exposure to high SST and fluctuating turbidity levels. We conclude the timing of low tide in the coolest parts of the day ameliorates the severity of subaerial exposure, and the combination of strong currents and a naturally high sediment regime helps to offset light and heat stress. The low level of anthropogenic impact and proximity to the Indo-west Pacific centre of diversity are likely to further promote resistance and resilience in this community. This assemblage provides an indication of what corals may have existed in other nearshore locations in the past prior to widespread coastal development, eutrophication, coral predator and disease outbreaks and coral bleaching events. Our results call for a re evaluation of what conditions are optimal for coral survival, and the Bonaparte intertidal community presents an ideal model system for exploring how species resilience is conferred in the absence of confounding factors such as pollution. PMID- 25714444 TI - The usefulness of a cholesterol absorption inhibitor in Japanese type 2 diabetes patients with dyslipidemia. AB - AIM: Cholesterol absorption has been suggested to be an independent risk factor for cerebral and cardiovascular events. We studied the clinical efficacy of ezetimibe in Japanese patients with type 2 diabetes mellitus complicated by dyslipidemia, in whom increased cholesterol absorption had been reported. SUBJECTS AND METHODS: Ninety-six patients with type 2 diabetes complicated by dyslipidemia received ezetimibe at 10 mg/day for 12 weeks. The lipid profile, a cholesterol synthesis marker (lathosterol), and cholesterol absorption markers (cholestanol, sitosterol, and campesterol) were measured before and after the therapy to evaluate the clinical efficacy of ezetimibe. RESULTS: Serum low density lipoprotein-cholesterol (LDL-C) levels were positively associated with cholesterol absorption markers but not associated with a cholesterol synthesis marker, suggesting that serum LDL-C levels are more strongly related to cholesterol absorption than synthesis. During the 12-week ezetimibe treatment period, cholesterol absorption markers significantly decreased, and serum lipid profiles, including LDL-C levels, significantly improved. The LDL-C-lowering rate was greater in those patients who had been receiving statin therapy and were newly started on ezetimibe additionally than in the ezetimibe monotherapy group ( 31.4% vs. -18.4%; P<0.001). CONCLUSIONS: It is suggested that ezetimibe improves the lipid profile in Japanese type 2 diabetes patients with dyslipidemia through the substantial reduction of cholesterol absorption. PMID- 25714445 TI - Erratum: the significance of a large number of health insurance funds and fusions for health services research with statutory health insurance data in Germany - experiences of the lidA study. PMID- 25714446 TI - Sex, age and smoking, but not genetic variation in LEPR (rs1137101), are associated with depressive symptoms. PMID- 25714447 TI - Association of GRIN1, ABCB1, and DRD4 genes and response to antipsychotic drug treatment in schizophrenia. PMID- 25714448 TI - Investigating the role of early childhood abuse and HPA axis genes in suicide attempters with bipolar disorder. AB - OBJECTIVE: Genes and the environment both play a major role in the risk for attempted suicide, and environments harboring stressors, such as early childhood abuse, have been linked to suicidal behavior. Such environments also disrupt the hypothalamic-pituitary-adrenal (HPA) axis pathway, which has been hypothesized to play a role in suicidal behavior. We investigated whether the risk for attempted suicide was attributable in part to the interaction between childhood physical and/or sexual abuse and genetic variation in 19 genes (+/-5 kb) integral to the HPA axis pathway. MATERIALS AND METHODS: Using the Genetic Association Information Network Bipolar Disorder and Translational Genomics Research Institute cohorts, we implemented PLINK's logistic regression-based 'interaction' approach to search for evidence of an interaction between 235 genotyped HPA axis single-nucleotide polymorphisms and early childhood abuse. Our study included 631 bipolar disorder suicide attempters and 657 bipolar disorder nonattempters with information on abuse. RESULTS: After correction for multiple testing, no significant interaction between the 235 HPA axis single-nucleotide polymorphisms and early childhood abuse was found. In our study, the strongest interaction was found with rs2664008 in the corticotropin-releasing hormone receptor 1 (CRHR1) gene, with a nominal interaction P-value of 1.22*10 and an interaction odds ratio of 0.47. CONCLUSION: Our findings suggest that further work and larger sample sizes are required to elucidate the link between early childhood abuse and the HPA axis in suicidal behavior. PMID- 25714449 TI - Tic symptom dimensions and their heritabilities in Tourette's syndrome. AB - INTRODUCTION: Gilles de la Tourette's syndrome (TS) is both genotypically and phenotypically heterogeneous. Gene-finding strategies have had limited success, possibly because of symptom heterogeneity. OBJECTIVE: This study aimed at specifically investigating heritabilities of tic symptom factors in a relatively large sample of TS patients and family members. PARTICIPANTS AND METHODS: Lifetime tic symptom data were collected in 494 diagnosed individuals in two cohorts of TS patients from the USA (n=273) and the Netherlands (n=221), and in 351 Dutch family members. Item-level factor analysis, using a tetrachoric correlation matrix in SAS (v9.2), was carried out on 23 tic symptoms from the Yale Global Tic Severity Scale. RESULTS: Three factors were identified explaining 49% of the total variance: factor 1, complex vocal tics and obscene behaviour; factor 2, body tics; and factor 3, head/neck tics. Using Sequential Oligogenic Linkage Analysis Routine, moderate heritabilities were found for factor 1 (h2r=0.21) and factor 3 (h2r=0.25). Lower heritability was found for overall tic severity (h2r=0.19). Bivariate analyses indicated no genetic associations between tic factors. CONCLUSION: These findings suggest that (i) three tic factors can be discerned with a distinct underlying genetic architecture and that (ii) considering the low tic heritabilities found, only focusing on the narrow-sense TS phenotype and leaving out comorbidities that are part of the broader sense tic phenotype may lead to missing heritability. Although these findings need replication in larger independent samples, they might have consequences for future genetic studies in TS. PMID- 25714450 TI - Depressed patients in remission show an interaction between variance in the mineralocorticoid receptor NR3C2 gene and childhood trauma on negative memory bias. AB - BACKGROUND: Genetic, environmental, and cognitive factors play a role in the development and recurrence of depression. More specifically, cognitive biases have been associated with depression risk genes and life events. Recently, the mineralocorticoid receptor NR3C2 gene, and in particular the rs5534 polymorphism, has been associated with negative memory bias, at least in healthy individuals who experienced severe life adversity. The current study examined the interaction between the rs5534 genotype and different types of adverse life events in a sample of depressed patients in remission. MATERIALS AND METHODS: A total of 298 depressed patients in remission performed an incidental emotional memory task (negative and positive words). Life adversity, childhood trauma, and recent adversity were measured using a self-report questionnaire. NR3C2 rs5534 by life adversity, as well as childhood trauma and recent adversity interactions were analyzed for negative and positive memory bias using analyses of covariance. RESULTS: The significant interaction between rs5534 and childhood trauma on negative memory bias (P=0.046) indicated that risk 'A' allele carriers with childhood trauma tended to show more negative memory bias compared to individuals homozygous for the G allele who had experienced childhood trauma and A allele carriers without childhood trauma. No interaction effects with life adversity or recent adversity were found. Also, no main effect of rs5534 on memory bias was found, although we had insufficient power for this analysis. CONCLUSION: An association of the NR3C2 gene and childhood trauma with negative memory bias was found in depressed patients in remission, which extends previous findings in a healthy population. PMID- 25714451 TI - Development of a [177Lu]BPAMD labeling kit and an automated synthesis module for routine bone targeted endoradiotherapy. AB - Painful bone lesions, both benign and metastatic, are often managed using conventional analgesics. However, the treatment response is not immediate and is often associated with side-effects. Radionuclide therapy is used for pain palliation in bone metastases as well as some benign neoplasms. Endoradiotherapy has direct impact on the pain-producing bone elements, and hence, response is significant, with minimal or no side-effects. A new potential compound for endoradiotherapy is [(177)Lu]BPAMD. It combines a highly affine bisphosphonate, covalently bridged with DOTA through an amide bond, with the low-energy beta(-) emitting therapeutic radiolanthanide (177)Lu. For routine chemical application, an automated synthesis of this radiopharmaceutical and a Kit-type labeling procedure appears to be a basic requirement for its good manufacturing practice (GMP) based production. A Kit formulation combining BPAMD, acetate buffer, and ethanol resulted in almost quantitative labeling yields. The use of ethanol and ascorbic acid as quenchers prevented radiolysis over 48 hours. An automated synthesis unit was designed for the production of therapeutic doses of [(177)Lu]BPAMD up to 5 GBq. The procedure was successfully applied for patient treatments. PMID- 25714452 TI - Boric acid-mediated B,N-codoped chitosan-derived porous carbons with a high surface area and greatly improved supercapacitor performance. AB - This work reports an efficient strategy to synthesize B,N-codoped porous carbons with a high specific surface area using chitosan as the carbon precursor with the help of boric acid, featuring a high specific capacitance, large operation voltage and excellent cycle stability for supercapacitors. PMID- 25714453 TI - Skin Leg Ulcer in an Immunocompromised Patient With Pseudomonas aeruginosa Sepsis. Cytomegalovirus ulcer. PMID- 25714454 TI - Sorption, desorption and leaching potential of sulfonylurea herbicides in Argentinean soils. AB - The sulfonylurea (SUs) herbicides are used to control broadleaf weeds and some grasses in a variety of crops. They have become popular because of their low application rates, low mammalian toxicity and an outstanding herbicidal activity. Sorption is a major process influencing the fate of pesticides in soil. The objective of this study was to characterize sorption-desorption of four sulfonylurea herbicides: metsulfuron-methyl (methyl 2-[(4-methoxy-6-methyl-1,3,5 triazin-2-yl)carbamoylsulfamoyl)]benzoate), sulfometuron-methyl (methyl 2-[(4,6 dimethylpyrimidin-2-yl)carbamoylsulfamoyl]benzoate), rimsulfuron (1-(4,6 dimethoxypyrimidin-2-yl)-3-(3-ethylsulfonyl-2-pyridylsulfonyl)urea) and nicosulfuron (2-[(4,6-dimethoxypyrimidin-2-yl)carbamoylsulfamoyl]-N,N dimethylnicotinamide) from different soil horizons of different landscape positions. Sorption was studied in the laboratory by batch equilibration method. Sorption coefficients (K(d-SE)) showed that rimsulfuron (K(d-SE) = 1.18 to 2.08 L kg(-1)) and nicosulfuron (K(d-SE) = 0.02 to 0.47 L kg(-1)) were more highly sorbed than metsulfuron-methyl (K(d-SE) = 0.00 to 0.05 L kg(-1)) and sulfometuron methyl (K(d-SE) = 0.00 to 0.05 L kg(-1)). Sorption coefficients (K(d-SE)) were correlated with pH and organic carbon content. All four herbicides exhibited desorption hysteresis where the desorption coefficients (K(d-D)) > K(d-SE). To estimate the leaching potential, K(oc) and ground-water ubiquity score (GUS) were used to calculate the half-life (t1/2) required to be classified as "leacher" or "nonleacher". According to the results, rimsulfuron and nicosulfuron herbicides would be classified as leachers, but factors such as landscape position, soil depth and the rate of decomposition in surface and subsurface soils could change the classification. In contrast, these factors do not affect classification of sulfometuron-methyl and metsulfuron-methyl; they would rank as leachers. PMID- 25714455 TI - Effects of soil attributes and straw accumulation on the sorption of hexazinone and tebuthiuron in tropical soils cultivated with sugarcane. AB - Brazil is the largest sugarcane producer in the world in which hexazinone (3 cyclohexyl-6-dimethylamino-1-methyl-1,3,5-triazine-2,4-dione) and tebuthiuron (1 (5-tert-butyl-1,3,4-thiadiazol-2-yl)-1,3-dimethylurea) are heavily used. Sugarcane harvesting is changing from the manual system with previous straw burning to the mechanized system without straw burning. The lack of burning results in soil organic carbon accumulation mainly in clayey soils, which should affect herbicides availability and fate. Therefore, we evaluated sorption of these herbicides in soil samples with and without straw burning. Both herbicides presented low apparent sorption coefficients (mean K(d,app)= 0.6 and 2.4 L kg(-1) for hexazinone and tebuthiuron, respectively), suggesting that they may leach to groundwater. Moreover, their sorption correlated primarily with soil organic carbon (SOC), but iron oxide contents extracted with ammonium oxalate (Fe2O3(AOX)) also affected it (K(d,app) = -0.228 + 0.0397 SOC + 0.117 Fe2O3(AOX) for hexazinone and K(d,app) = -1.407 + 0.201 SOC + 0.348 Fe2O3(AOX) for tebuthiuron). Soil organic carbon accumulation due to straw maintenance in the field positively affected sorption of both herbicides, but its effects were not enough to classify them as "non-leachers." PMID- 25714456 TI - Photocatalytic degradation of p,p'-DDT under UV and visible light using interstitial N-doped TiO2. AB - 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (or p,p'-DDT) is one of the most persistent pesticides. It is resistant to breakdown in nature and cause the water contamination problem. In this work, a major objective was to demonstrate the application of N-doped TiO2 in degradation and mineralization of the p,p'-DDT under UV and visible light in aqueous solution. The N-doped TiO2 nanopowders were prepared by a simple modified sol-gel procedure using diethanolamine (DEA) as a nitrogen source. The catalyst characteristics were investigated using XRD, SEM, TEM, and XPS. The adsorption and photocatalytic oxidation of p,p'-DDT using the synthesized N-doped TiO2 under UV and visible light were conducted in a batch photocatalytic experiment. The kinetics and p,p'-DDT degradation performance of the N-doped TiO2 were evaluated. Results show that the N-doped TiO2 can degrade p,p'-DDT effectively under both UV and visible lights. The rate constant of the p,p'-DDT degradation under UV light was only 0.0121 min(-1), whereas the rate constant of the p,p'-DDT degradation under visible light was 0.1282 min(-1). Under visible light, the 100% degradation of p,p'-DDT were obtained from N-doped TiO2 catalyst. The reaction rate of p,p'-DDT degradation using N-doped TiO2 under visible light was sixfold higher than that under UV light. According to Langmuir Hinshelwood model, the adsorption equilibrium constant (K) for the N-doped TiO2 under visible light was 0.03078 L mg(-1), and the apparent reaction rate constant (k) was 1.3941 mg L(-1)-min. Major intermediates detected during the p,p'-DDT degradation were p,p'-DDE, o,p'-DDE, p,p'-DDD and p,p'-DDD. Results from this work can be applied further for the breakdown of p,p'-DDT molecule in the real contaminated water using this technology. PMID- 25714457 TI - Pesticide effects on crabs: how environmental concentrations of endosulfan and chlorpyrifos affect embryos. AB - The objectives of this work were to evaluate the effects of environmentally relevant chlorpyrifos and endosulfan, concentrations in the incubation period, effective hatching and survival of embryos and neonates of the freshwater burrowing crab, Zilchiopsis collastinensis (Decapoda, Trichodactylidae). Both pesticides were prepared from commercial and technical grade products. The exposure to about 100, 200, and 400 ng endosulfan L(-1), and 48, 240, and 1,200 ng chlorpyrifos L(-1) did not cause differences in the incubation period or in effective hatching but decreased survival of neonates, especially in the concentrations prepared from the technical grade product. Even if these concentrations are below the median lethal concentration (LC50) values for embryos, these caused a significant decrease in the survival of neonates, i.e. when crabs are outside the egg and not protected by chorion. The decrease in the neonate population caused by these concentrations, which could be found in the environment, might impact aquatic communities. PMID- 25714458 TI - Bioavailability and influence of 14C-carbofuran on Eisenia andrei avoidance, growth and reproduction in treated natural tropical soils. AB - The bioavailability of carbofuran to the compost worms Eisenia andrei and the influence of its residual amounts on the avoidance, reproduction and growth of this species were studied in two natural tropical soils: a Typic Humaquept (GM) and a Typic Hapludox (LVD), as indicated by the Brazilian environmental authorities for ecotoxicological tests. The worms avoided the soil LVD treated with different doses of carbofuran. The pesticide also affected the production of juvenile specimens in both soils, but cocoon production was reduced only in the GM soil. The earthworms' growth and weight loss were affected by carbofuran (2,2 dimethyl-2,3-dihydro-1-1-benzofuran-7-yl methylcarbamate. CAS number 1563-66-2) only in the LVD and the mortality detected at 56 days of contact with the treated soils was not statistically significant in both of them. Fourteen days after the soil treatment with(14) c-carbofuran, most residues detected in the soils were bound residues (approximately 36% and 30% in the GM and LVD, respectively) and neither mortality nor bioaccumulation was detected in the earthworms, even with absorptions of 13% and 43%, respectively. The LVD soil has lower organic matter content, and the effects of carbofuran on different aspects of the earthworms' life were more pronounced in this soil, most likely due to the higher bioavailability of the pesticide in the soil solution. The results for carbofuran clearly demonstrate that even small quantities of residues do not assure lack of toxicity. They also make evident the necessity of studying the effects of pesticides in natural agricultural soils. Furthermore, as the bound residues and the earthworm contamination are not detected by conventional techniques, they are not taken into account and may be underestimated on environmental risk assessments. PMID- 25714459 TI - An indirect competitive biotin-streptavidin enzyme-linked immunosorbent assay for the determination of dimethyl phthalate (DMP) in milk and milk products. AB - After the "plasticizer event" in Taiwan, phthalic acid esters (PAEs) have been listed in "Inedible materials possibly added into food illegally" and "Commonly abused food additives." As one of the PAEs family, DMP has long been a problem of great concern due to its potential impacts on human health. In order to detect DMP with high sensitivity and specificity, a sensitive indirect competitive biotin-streptavidin enzyme-linked immunosorbent assay (BA-ELISA) has been established in this study. A high-titer rabbit polyclonal antibody (pAb-DMP) targeting DMP was obtained, and the procedures of BA-ELISA were optimized for the determination of DMP in milk and milk products. Under optimal conditions, good linearity was achieved within a range of 0.024 to 6.027 MUg L(-1), with low cross reactivity values for DMP structural analogues (lower than 10%). The median inhibitory concentration (IC50) was 0.356 MUg L(-1) and the limit of detection (LOD) was 0.0082 MUg L(-1). Finally, the concentrations of DMP in milk and milk products ranged from 1.03 MUg kg(-1) to 7.23 MUg kg(-1) by BA-ELISA. Satisfactory recoveries (90.26-112.38%) and coefficient of variation (CV) values (5.08-8.46%) were obtained. These results were consistent with those using gas chromatography mass spectrometry (GC-MS), which further confirmed that the proposed BA-ELISA was accurate, specific, reliable and rapid for routine monitoring trace DMP residues in foodstuff, especially milk and milk products. PMID- 25714460 TI - Response of alpha-glucosidase in gypsy moth larvae to acute and chronic dietary cadmium. AB - We investigated the effects of acute and chronic treatments with cadmium at 10 MUg Cd/g dry food and 30 MUg Cd/g dry food on alpha-glucosidase activity of the 4th instar larvae of Lymantria dispar (Lepidoptera: Lymantriidae) as well as subsequent recovery. Enzyme inhibition was recorded during acute exposure to 30 MUg Cd/g dry food and during chronic treatment at the lower metal concentration. After three days recovery from 10 MUg Cd/g dry food, the alpha-glucosidase activity returned to the control level. One-way ANOVA showed that cadmium significantly influenced the activity of alpha-glucosidase during all treatments. The index of phenotypic plasticity was higher during chronic treatment at 10 MUg Cd/g dry food than at 30 MUg Cd/g as well as during the recovery. We detected four glucosidase isoforms by NATIVE PAGE. The activities and expressions of the isoforms depended on both larval genotype and cadmium treatment. PMID- 25714461 TI - Effects of 25-(OH)D3 on fecal Ca and P excretion, bone mineralization, Ca and P transporter mRNA expression and performance in growing female pigs. AB - A study was conducted to examine the effects of 25-hydroxyvitamin D3 (25-(OH)D3) on fecal Ca and P excretion, bone mineralization, performance and the mRNA expression of intestinal transporter genes in growing female pigs. Sixty-day old gilts (n = 24) with an average initial BW of 23.13 +/- 1.49 kg were randomly allocated to a control diet (diet 1) containing wheat/corn/soybean meal and 150 IU kg(-1) of Vitamin D3, diet 1 + 50 MUg of 25-(OH)D3 kg(-1) (diet 2) and diet 1 + 100 MUg of 25-(OH)D3 kg(-1) (diet 3). The pigs were housed in an individual pen and had ad libitum access to feed and water for 42 days, and BWG and feed intake were measured weekly. Measures of bone mineralization and expression of Ca and P transporters mRNA were analyzed using Dual Energy X-Ray Absortiometry (DEXA) and quantitative real-time polymerase chain reaction (qRT-PCR), respectively. Data were analyzed using GLM procedure of the Statistical Analysis System (SAS Institute version 9.2). Fecal Ca and P concentration were significantly reduced (P <= 0.05) in pigs fed diets 2 and 3 compared with the control diet. Supplementation of 25-(OH)D3 did not significantly improve bone mineralization, animal performance and intestinal transporters mRNA expression except for SLC34A1, a sodium-dependent phosphate transporter 1. In conclusion, supplementation of 25-(OH)D3 in swine nutrition may not improve animal performance but has the potential to reduce environmental pollution by increasing dietary Ca and P retention while reducing their excretion. PMID- 25714463 TI - Mer signaling increases the abundance of the transcription factor LXR to promote the resolution of acute sterile inflammation. AB - The receptor tyrosine kinase Mer plays a central role in inhibiting the inflammatory response of immune cells to pathogens. We aimed to understand the function of Mer signaling in the resolution of sterile inflammation in experiments with a Mer-neutralizing antibody or with Mer-deficient (Mer-/-) mice in a model of sterile, zymosan-induced acute inflammation. We found that inhibition or deficiency of Mer enhanced local and systemic inflammatory responses. The exacerbated inflammatory responses induced by the lack of Mer signaling were associated with reduced abundance of the transcription factors liver X receptor alpha (LXRalpha) and LXRbeta and decreased expression of their target genes in peritoneal macrophages, spleens, and lungs. Similarly, treatment of mice with a Mer/Fc fusion protein, which prevents the Mer ligand Gas6 (growth arrest-specific protein 6) from binding to Mer, exacerbated the inflammatory response and decreased the abundance of LXR. Coadministration of the LXR agonist T0901317 with the Mer-neutralizing antibody inhibited the aggravating effects of the antibody on inflammation in mice. In vitro exposure of RAW264.7 cells or primary peritoneal macrophages to Gas6 increased LXR abundance in an Akt dependent manner. Thus, we have elucidated a previously uncharacterized pathway involved in the resolution of acute sterile inflammation: Enhanced Mer signaling during the recovery phase increases the abundance and activity of LXR to inactivate the inflammatory response in macrophages. PMID- 25714462 TI - Recruitment of the adaptor protein Nck to PECAM-1 couples oxidative stress to canonical NF-kappaB signaling and inflammation. AB - Oxidative stress stimulates nuclear factor kappaB (NF-kappaB) activation and NF kappaB-dependent proinflammatory gene expression in endothelial cells during several pathological conditions, including ischemia/reperfusion injury. We found that the Nck family of adaptor proteins linked tyrosine kinase signaling to oxidative stress-induced activation of NF-kappaB through the classic IkappaB kinase-dependent pathway. Depletion of Nck prevented oxidative stress induced by exogenous hydrogen peroxide or hypoxia/reoxygenation injury from activating NF kappaB in endothelial cells, increasing the abundance of the proinflammatory molecules ICAM-1 (intracellular adhesion molecule-1) and VCAM-1 (vascular cell adhesion molecule-1) and recruiting leukocytes. Nck depletion also attenuated endothelial cell expression of genes encoding proinflammatory factors but not those encoding antioxidants. Nck promoted oxidative stress-induced activation of NF-kappaB by coupling the tyrosine phosphorylation of PECAM-1 (platelet endothelial cell adhesion molecule-1) to the activation of p21-activated kinase, which mediates oxidative stress-induced NF-kappaB signaling. Consistent with this mechanism, treatment of mice subjected to ischemia/reperfusion injury in the cremaster muscle with a Nck inhibitory peptide blocked leukocyte adhesion and emigration and the accompanying vascular leak. Together, these data identify Nck as an important mediator of oxidative stress-induced inflammation and a potential therapeutic target for ischemia/reperfusion injury. PMID- 25714464 TI - The E3 ubiquitin ligase Itch inhibits p38alpha signaling and skin inflammation through the ubiquitylation of Tab1. AB - Deficiency in the E3 ubiquitin ligase Itch causes a skin-scratching phenotype in mice. We found that there was increased phosphorylation and activation of the mitogen-activated protein kinase p38alpha in spontaneous and experimentally induced skin lesions of Itch-deficient (Itch-/-) mice. Itch bound directly to the TGF-beta-activated kinase 1-binding protein 1 (Tab1) through a conserved PPXY motif and inhibited the activation of p38alpha. Knockdown of Tab1 by short hairpin RNA attenuated the prolonged p38alpha phosphorylation exhibited by Itch-/ cells. Similarly, reconstitution of Itch-/- cells with wild-type Itch, but not the ligase-deficient Itch-C830A mutant, inhibited the phosphorylation and activation of p38alpha. Compared to the skin of wild-type mice, the skin of Itch /- mice contained increased amounts of the mRNAs of proinflammatory cytokines, including tumor necrosis factor (TNF), interleukin-6 (IL-6), IL-1beta, IL-11, and IL-19. Inhibition of p38 or blocking the interaction between p38alpha and Tab1 with a cell-permeable peptide substantially attenuated skin inflammation in Itch /- mice. These findings provide insight into how Itch-mediated regulatory mechanisms prevent chronic skin inflammation, which could be exploited therapeutically. PMID- 25714465 TI - A biosensor for the activity of the "sheddase" TACE (ADAM17) reveals novel and cell type-specific mechanisms of TACE activation. AB - Diverse environmental conditions stimulate protein "shedding" from the cell surface through proteolytic cleavage. The protease TACE [tumor necrosis factor alpha (TNFalpha)--converting enzyme, encoded by ADAM17] mediates protein shedding, thereby regulating the maturation and release of various extracellular substrates, such as growth factors and cytokines, that induce diverse cellular responses. We developed a FRET (fluorescence resonance energy transfer)-based biosensor called TSen that quantitatively reports the kinetics of TACE activity in live cells. In combination with chemical biology approaches, we used TSen to probe the dependence of TACE activation on the induction of the kinases p38 and ERK (extracellular signal-regulated kinase) in various epithelial cell lines. Using TSen, we found that disruption of the actin cytoskeleton in keratinocytes induced rapid and robust TSen cleavage and the accumulation of TACE at the plasma membrane. Cytoskeletal disruption also increased the cleavage of endogenous TACE substrates, including transforming growth factor-alpha. Thus, TSen is a useful tool for unraveling the mechanisms underlying the spatiotemporal activation of TACE in live cells. PMID- 25714466 TI - Context-dependent survival, fecundity and predicted population-level consequences of brucellosis in African buffalo. AB - Chronic infections may have negative impacts on wildlife populations, yet their effects are difficult to detect in the absence of long-term population monitoring. Brucella abortus, the bacteria responsible for bovine brucellosis, causes chronic infections and abortions in wild and domestic ungulates, but its impact on population dynamics is not well understood. We report infection patterns and fitness correlates of bovine brucellosis in African buffalo based on (1) 7 years of cross-sectional disease surveys and (2) a 4-year longitudinal study in Kruger National Park (KNP), South Africa. We then used a matrix population model to translate these observed patterns into predicted population level effects. Annual brucellosis seroprevalence ranged from 8.7% (95% CI = 1.8 15.6) to 47.6% (95% CI = 35.1-60.1) increased with age until adulthood (>6) and varied by location within KNP. Animals were on average in worse condition after testing positive for brucellosis (F = -5.074, P < 0.0001), and infection was associated with a 2.0 (95% CI = 1.1-3.7) fold increase in mortality (chi(2) = 2.039, P = 0.036). Buffalo in low body condition were associated with lower reproductive success (F = 2.683, P = 0.034), but there was no association between brucellosis and pregnancy or being observed with a calf. For the range of body condition scores observed in the population, the model-predicted growth rate was lambda = 1.11 (95% CI = 1.02-1.21) in herds without brucellosis and lambda = 1.00 (95% CI = 0.85-1.16) when brucellosis seroprevalence was 30%. Our results suggest that brucellosis infection can potentially result in reduced population growth rates, but because these effects varied with demographic and environmental conditions, they may remain unseen without intensive, longitudinal monitoring. PMID- 25714467 TI - Recommendations for the use of the non-obese diabetic/severe combined immunodeficiency mouse model in autoimmune and drug-induced thrombocytopenia: communication from the SSC of the ISTH. PMID- 25714470 TI - Aripiprazole for the treatment of depression in palliative care. PMID- 25714469 TI - Induction and adaptation of chaperone-assisted selective autophagy CASA in response to resistance exercise in human skeletal muscle. AB - Chaperone-assisted selective autophagy (CASA) is a tension-induced degradation pathway essential for muscle maintenance. Impairment of CASA causes childhood muscle dystrophy and cardiomyopathy. However, the importance of CASA for muscle function in healthy individuals has remained elusive so far. Here we describe the impact of strength training on CASA in a group of healthy and moderately trained men. We show that strenuous resistance exercise causes an acute induction of CASA in affected muscles to degrade mechanically damaged cytoskeleton proteins. Moreover, repeated resistance exercise during 4 wk of training led to an increased expression of CASA components. In human skeletal muscle, CASA apparently acts as a central adaptation mechanism that responds to acute physical exercise and to repeated mechanical stimulation. PMID- 25714468 TI - A systematic approach to the reporting of medically relevant findings from whole genome sequencing. AB - BACKGROUND: The MedSeq Project is a randomized clinical trial developing approaches to assess the impact of integrating genome sequencing into clinical medicine. To facilitate the return of results of potential medical relevance to physicians and patients participating in the MedSeq Project, we sought to develop a reporting approach for the effective communication of such findings. METHODS: Genome sequencing was performed on the Illumina HiSeq platform. Variants were filtered, interpreted, and validated according to methods developed by the Laboratory for Molecular Medicine and consistent with current professional guidelines. The GeneInsight software suite, which is integrated with the Partners HealthCare electronic health record, was used for variant curation, report drafting, and delivery. RESULTS: We developed a concise 5-6 page Genome Report (GR) featuring a single-page summary of results of potential medical relevance with additional pages containing structured variant, gene, and disease information along with supporting evidence for reported variants and brief descriptions of associated diseases and clinical implications. The GR is formatted to provide a succinct summary of genomic findings, enabling physicians to take appropriate steps for disease diagnosis, prevention, and management in their patients. CONCLUSIONS: Our experience highlights important considerations for the reporting of results of potential medical relevance and provides a framework for interpretation and reporting practices in clinical genome sequencing. PMID- 25714471 TI - The Equine Movement Disorder "Shivers" Is Associated With Selective Cerebellar Purkinje Cell Axonal Degeneration. AB - "Shivers" is a progressive equine movement disorder of unknown etiology. Clinically, horses with shivers show difficulty walking backward, assume hyperflexed limb postures, and have hind limb tremors during backward movement that resembles shivering. At least initially, forward movements are normal. Given that neither the neurophysiologic nor the pathologic mechanisms of the disease is known, nor has a neuroanatomic locus been identified, we undertook a detailed neuroanatomic and neuropathologic analysis of the complete sensorimotor system in horses with shivers and clinically normal control horses. No abnormalities were identified in the examined hind limb and forelimb skeletal muscles nor the associated peripheral nerves. Eosinophilic segmented axonal spheroids were a common lesion. Calretinin-positive axonal spheroids were present in many regions of the central nervous system, particularly the nucleus cuneatus lateralis; however, their numbers did not differ significantly from those of control horses. When compared to controls, calretinin-negative, calbindin-positive, and glutamic acid decarboxylase-positive spheroids were increased 80-fold in Purkinje cell axons within the deep cerebellar nuclei of horses with shivers. Unusual lamellar or membranous structures resembling marked myelin decompaction were present between myelin sheaths of presumed Purkinje cell axons in the deep cerebellar nuclei of shivers but not control horses. The immunohistochemical and ultrastructural characteristics of the lesions combined with their functional neuroanatomic distribution indicate, for the first time, that shivers is characterized by end-terminal neuroaxonal degeneration in the deep cerebellar nuclei, which results in context-specific hypermetria and myoclonus. PMID- 25714472 TI - Low-order non-spatial effects dominate second-order spatial effects in the texture quantifier analysis of 18F-FDG-PET images. AB - BACKGROUND: There is increasing interest in applying image texture quantifiers to assess the intra-tumor heterogeneity observed in FDG-PET images of various cancers. Use of these quantifiers as prognostic indicators of disease outcome and/or treatment response has yielded inconsistent results. We study the general applicability of some well-established texture quantifiers to the image data unique to FDG-PET. METHODS: We first created computer-simulated test images with statistical properties consistent with clinical image data for cancers of the uterine cervix. We specifically isolated second-order statistical effects from low-order effects and analyzed the resulting variation in common texture quantifiers in response to contrived image variations. We then analyzed the quantifiers computed for FIGOIIb cervical cancers via receiver operating characteristic (ROC) curves and via contingency table analysis of detrended quantifier values. RESULTS: We found that image texture quantifiers depend strongly on low-effects such as tumor volume and SUV distribution. When low-order effects are controlled, the image texture quantifiers tested were not able to discern only the second-order effects. Furthermore, the results of clinical tumor heterogeneity studies might be tunable via choice of patient population analyzed. CONCLUSION: Some image texture quantifiers are strongly affected by factors distinct from the second-order effects researchers ostensibly seek to assess via those quantifiers. PMID- 25714473 TI - Neuroprotective mechanism of Lycium barbarum polysaccharides against hippocampal dependent spatial memory deficits in a rat model of obstructive sleep apnea. AB - Chronic intermittent hypoxia (CIH) is a hallmark of obstructive sleep apnea (OSA), which induces hippocampal injuries mediated by oxidative stress. This study aims to examine the neuroprotective mechanism of Lycium barbarum polysaccharides (LBP) against CIH-induced spatial memory deficits. Adult Sprague Dawley rats were exposed to hypoxic treatment resembling a severe OSA condition for a week. The animals were orally fed with LBP solution (1 mg/kg) daily 2 hours prior to hypoxia or in air for the control. The effect of LBP on the spatial memory and levels of oxidative stress, inflammation, endoplasmic reticulum (ER) stress, apoptosis and neurogenesis in the hippocampus was examined. There was a significant deficit in the spatial memory and an elevated level of malondialdehyde with a decreased expression of antioxidant enzymes (SOD, GPx-1) in the hypoxic group when compared with the normoxic control. In addition, redox sensitive nuclear factor kappa B (NFKB) canonical pathway was activated with a translocation of NFKB members (p65, p50) and increased expression levels of NFKB dependent inflammatory cytokines and mediator (TNFalpha, IL-1beta, COX-2); also, a significantly elevated level of ER stress (GRP78/Bip, PERK, CHOP) and autophagic flux in the hypoxic group, leading to neuronal apoptosis in hippocampal subfields (DG, CA1, CA3). Remarkably, LBP administration normalized the elevated level of oxidative stress, neuroinflammation, ER stress, autophagic flux and apoptosis induced by hypoxia. Moreover, LBP significantly mitigated both the caspase-dependent intrinsic (Bax, Bcl2, cytochrome C, cleaved caspase-3) and extrinsic (FADD, cleaved caspase-8, Bid) signaling apoptotic cascades. Furthermore, LBP administration prevented the spatial memory deficit and enhanced the hippocampal neurogenesis induced by hypoxia. Our results suggest that LBP is neuroprotective against CIH-induced hippocampal-dependent spatial memory deficits by promoting hippocampal neurogenesis and negatively modulating the apoptotic signaling cascades activated by oxidative stress and inflammation. PMID- 25714475 TI - Mini Nutritional Assessment (MNA) is Rather a Reliable and Valid Instrument to Assess Nutritional Status in Iranian Healthy Adults and Elderly with a Chronic Disease. AB - This study aimed to evaluate the usefulness of the Mini Nutritional Assessment (MNA) to assess nutritional status of Iranian population and to compare its psychometric properties between patients suffering from a chronic disease, healthy elderly and younger adults. As a group of elderly with a chronic disease, 143 Parkinson's disease (PD) patients and as the control group, 467 healthy persons were enrolled. The Persian-translated version of MNA was filled-up through interviews together with anthropometric measurements. Cronbach's alpha coefficient of entire MNA was 0.66 and 0.70 in healthy individuals and PD patients, respectively. The total MNA score could significantly discriminate the ones with BMI >= 24kg/m(2) in both groups. In general, MNA was a valid and reliable tool for nutritional assessment. We acknowledge study limitations including lack of serum measurements and a selection bias towards mild-to moderate PD. MNA is a more reliable tool in older healthy individuals and rather younger elderly with PD. PMID- 25714474 TI - EuroSCORE models in a cohort of patients with valvular heart disease and a high prevalence of rheumatic fever submitted to surgical procedures. AB - OBJECTIVES: Epidemiological differences can be found between Brazilian and European valvular heart disease patients. The prevalence of heart valve diseases due to rheumatic disease is significantly higher in the Brazilian compared with the European population. Therefore, they could have different risks during and after cardiac surgery. The aim of this study was to evaluate the applicability of the additive and logistic EuroSCORE and EuroSCORE II in a cohort of high-risk patients with valvular heart disease of predominantly rheumatic aetiology submitted to surgery. METHODS: Between 1 February and 30 December 2009, 540 consecutive patients scheduled for valvular heart surgery were included in this study. In this set of patients, we examined the performance of the additive, logistic, and EuroSCORE II models for predicting in-hospital mortality. Calibration of each model was assessed by comparing predicted and observed in hospital mortality and by the goodness of fit of the Hosmer-Lemeshow chi-square test. Discrimination performance of the model was evaluated with the receiver operating characteristic (ROC) curve analysis. RESULTS: The mean age was 56 +/- 16 years, 50.6% were female, and the mortality rate was 16.0% (6.0% in elective surgery and 34.0% in emergency/urgency surgery). Mortality rates were estimated according to the additive and logistic EuroSCORE and EuroSCORE II at 6.1%, 8.7%, and 4.3%, respectively. The AUC was 0.76 (95% confidence interval [95% CI] 0.70 0.81) for the additive EuroSCORE, 0.76 (95% CI 0.70-0.81) for the logistic EuroSCORE and 0.81 (95% CI 0.76-0.86) for EuroSCORE II. Hosmer-Lemeshow goodness of-fit statistics were P = 0.52, P = 0.07, and P = 0.12 for additive, logistic EuroSCORE, and EuroSCORE II. CONCLUSIONS: In this cohort of Brazilian patients with valvular heart disease submitted to surgical procedure, the EuroSCORE models had a good discriminatory capacity; however, the calibration was compromised because of an underestimation of the mortality rate. PMID- 25714476 TI - Is diet flexibility an adaptive life trait for relictual and peri-urban populations of the endangered primate Macaca sylvanus? AB - Habitat loss, fragmentation and urban expansion may drive some species to marginal habitats while others succeed in exploiting urban areas. Species that show dietary flexibility are more able to take advantage of human activities to supplement their diet with anthropogenically abundant and accessible resources. The Barbary macaque (Macaca sylvanus) is an endangered species due to the loss of its habitat, and human pressure. The population of Gouraya National Park (Algeria) lives in a relictual habitat that constitutes about 0.6% of the species range. In addition, this population is a unique case where urban expansion favours contact zones between Barbary macaque habitats and a big city (Bejaia). We quantified the dietary composition of Gouraya macaques over an annual cycle with the objective to understand how diet flexibility of this species may help it adapt to a relictual habitat or cope with urban expansion. We recorded the phenology of plant species every month. This study shows that Gouraya macaques, compared to those living in other forest types of the distribution area, are under lower seasonal constraints. They consume a greater amount of fruit and seeds that are available throughout much of the year, and a lesser amount of costly to find and extract subterranean foods. Therefore the Gouraya relictual habitat appears as a favourable environment compared to other major habitats of that species. This study also shows that colonizing peri-urban zones increases the availability and species richness of diet resources for Barbary macaques as they consume more human foods and exotic plants than in farther sites. Adult males eat more human foods than adult females and immatures do. The exploitation of high-energy anthropogenic food could favour macaque population growth and expansion towards the city center associated with human/macaque conflicts. We recommend applying management actions to restore macaques back to their natural habitat. PMID- 25714477 TI - Risk factors associated with respiratory disorders in late preterm infants. AB - OBJECTIVE: Late preterm infants are still high risk for respiratory problems. The aim of this study was to identify risk factors associated with respiratory problems in Japanese late preterm infants. METHODS: In this retrospective multicenter study, we included singleton late preterm deliveries at 34+(0/7) 36+(6/7) weeks of gestation. We excluded cases with congenital anomalies. We defined neonatal respiratory disorders (NRD) as the combination of the need for mechanical ventilation or the use of nasal continuous positive airway pressure. We examined the perinatal risk factors associated with NRD. RESULTS: We included 683 late preterm infants. We found that 13.7%, 6.8% and 2.6% of the infants with NRD were born at 34, 35 and 36 weeks of gestation, respectively. In a multivariate logistic regression analysis adjusting for confounders, the gestational age (GA) at birth (adjusted odds ratio 0.40 per week [95% confidence interval, 0.25-0.61]), cesarean birth (4.18 [2.11-8.84]), and a low Apgar score (33.3 [9.93-121.3]) were independent risk factors associated with NRD. CONCLUSIONS: An earlier GA, cesarean delivery, and a low Apgar score are independent risk factors associated with NRD in singleton late preterm infants. Patients with late preterm deliveries exhibiting these risk factors should be managed in the intensive delivery setting. PMID- 25714478 TI - High blood carbon dioxide variability and adverse outcomes in neonatal hypoxic ischemic encephalopathy. AB - OBJECTIVE: Hypocarbia during the first 12 h of life is associated with mortality and disability in neonatal hypoxic ischemic encephalopathy (HIE). Notable variation in arterial carbon dioxide tension (PaCO2) during the first 4 d of life is related to severe intraventricular hemorrhages in preterm infants. We examined the association between PaCO2 during 72 h of whole-body therapeutic hypothermia for neonatal HIE and 2-year neurodevelopmental outcomes. METHODS: A retrospective review of 23 term neonates treated with whole-body hypothermia documented clinical, demographic and arterial blood gas data. Comparisons were made across good and severe neurodevelopmental outcome groups at 2 years of age. RESULTS: Severe neurodevelopmental outcomes were documented in 8 of 23 toddlers. There were no significant differences between outcome groups with regard to the number of patients with hypocarbic means or measurements. There were also no significant differences with mean PaCO2, PaO2, pH, time-weighted cumulative hypocarbia, and PaCO2 range. The severe neurodevelopmental outcomes group had a significantly higher mean PaCO2 standard deviation (p = 0.04; 95% CI, -5.46 to -0.39). CONCLUSION: Severe neurodevelopmental outcomes were significantly associated with high PaCO2 variability over 72 h in whole-body-cooled HIE neonates. Mitigating these fluctuations may be a potential management strategy. PMID- 25714479 TI - Hypoxic ischemic encephalopathy in newborns linked to placental and umbilical cord abnormalities. AB - OBJECTIVE: Birth asphyxia and hypoxic ischemic encephalopathy (HIE) of the newborn remain serious complications. We present a study investigating if placental or umbilical cord abnormalities in newborns at term are associated with HIE. MATERIALS AND METHODS: A prospective cohort study of the placenta and umbilical cord of infants treated with hypothermia (HT) due to hypoxic brain injury and follow-up at 12 months of age has been carried out. The study population included 41 infants treated for HT whose placentas were submitted for histopathological analysis. Main outcome measures were infant development at 12 months, classified as normal, cerebral palsy, or death. A healthy group of 100 infants without HIE and normal follow-up at 12 months of age were used as controls. RESULTS: A velamentous or marginal umbilical cord insertion and histological abruption was associated with the risk of severe HIE, OR = 5.63, p = 0.006, respectively, OR = 20.3, p = 0.01 (multiple-logistic regression). Velamentous or marginal umbilical cord insertion was found in 39% among HIE cases compared to 7% in controls. CONCLUSIONS: Placental and umbilical cord abnormalities have a profound association with HIE. A prompt examination of the placentas of newborns suffering from asphyxia can provide important information on the pathogenesis behind the incident and contribute to make a better early prognosis. PMID- 25714480 TI - Average fetal weekly weight gain: a novel measure of fetal growth velocity. AB - OBJECTIVE: To develop a simplified measure of intrauterine fetal growth velocity from birth weight and gestational age at term. METHODS: This concept is based on the observation that intrauterine fetal growth in the third trimester is quasi linear. The average fetal weekly weight gain (AWG) was calculated by dividing the difference between birth weight (in g) and the 24-week median weight by the difference between gestational age at birth and 24 weeks, as follows: [Formula: see text] An obstetric database of 12,425 term live singleton pregnancies was studied to validate this measure. RESULTS: The mean AWG was 176.5 g/week, SD 29.1. There was a close correlation between birth weight z-scores and the AWG (R = 0.993). Pregnancy characteristics correlated with the AWG, the strongest being fetal gender and cigarette smoking (p < 0.0001). Females had an AWG 9 g lower than males; multiparae had an AWG 7 g higher. Other significant correlates include maternal weight, height and body mass index. CONCLUSIONS: The AWG is a novel estimate of intrauterine fetal growth velocity that is computationally simple, and could be used as an alternative to the birth weight z-score. PMID- 25714481 TI - Outcomes following intra-amniotic instillation with indigo carmine to diagnose prelabor rupture of membranes in singleton pregnancies: a single center experience. AB - OBJECTIVE: To evaluate clinical outcomes of women with singleton pregnancies that underwent intra-amniotic dye instillation (amniodye test) following equivocal diagnosis of prelabor rupture of membranes (PROM). METHOD: Records of 34 pregnant women who underwent amniodye test for equivocal PROM were reviewed. Comparisons of characteristics, amniotic fluid (AF) cultures, AF interleukin (IL)-6 concentrations, and placenta pathology results between women who tested positive and those who tested negative were performed. A sub-analysis of women who were amniodye test-negative was also performed. RESULTS: (1) Commonest indication for amniodye test was a typical history of PROM with positive conventional tests and persistently normal AF volume, (2) amniodye test-positive women had a shorter procedure-to-delivery interval (p = 0.008), and a greater proportion of histologic acute chorioamnionitis (p = 0.04) and funisitis (p = 0.01) than amniodye-negative women, and (3) in addition to similarities to women with amniodye-positive test, amniodye test-negative women who delivered <34 weeks, had a greater proportion of women with risk for preterm birth (p = 0.04), than their counterparts who delivered between 34 0/7 and 36 6/7 weeks. CONCLUSION: Equivocal diagnosis of PPROM should warrant an amniodye test to avoid iatrogenic intervention in women with intact amniotic membranes. AF analysis should be performed in amniodye test-negative women. PMID- 25714482 TI - Anti-angiogenic effect of Nelumbo nucifera leaf extracts in human umbilical vein endothelial cells with antioxidant potential. AB - Nelumbo nucifera Gaertn (Nymphaeaceae) has long been used as a traditional herb in Chinese, Japanese, Indian, and Korean medicinal practices since prehistoric times and flourishes today as the primary form of medicine. This study reports for the first time the potent ability of N. nucifera leaf extracts to inhibit vascular endothelial growth factor (VEGF)-induced angiogenesis in vitro and in vivo, as well as their antioxidant efficacy in various scavenging models and an analysis of their chemical composition. In vivo anti-angiogenic activity was evaluated in a chick chorioallantoic membrane (CAM) model using fertilized chicken eggs, in human umbilical vein endothelial cells (HUVECs) by using cell viability, cell proliferation and tube formation assays, and by determining intracellular reactive oxygen species (ROS) in vitro. The antioxidant efficacy of N. nucifera leaf extracts was determined in various scavenging models, including total phenolic and flavonoid content. The chemical composition of N. nucifera leaf extracts was determined by GC-MS analysis, which revealed the presence of different phytochemicals. The IC50 values for the DPPH radical scavenging activities of water and methanol extracts were found to be 1699.47 and 514.36 MUg ml(-1), and their total phenolic and flavonoid contents were 85.01 +/- 2.32 and 147.63 +/- 2.23 mg GAE g dry mass(-1) and 35.38 +/- 1.32 and 41.86 +/- 1.07 mg QA g dry mass(-1), respectively. N. nucifera leaf extracts (10-100 MUg ml(-1)) exhibited significant dose-dependent inhibition of VEGF-induced angiogenesis, as well as VEGF-induced proliferation and tube formation in HUVECs. In this study, N. nucifera leaf extracts displayed potent antioxidant and inhibitory effects on VEGF-induced angiogenesis. N. nucifera exerted an inhibitory effect on VEGF induced proliferation and tube formation, as well as CAM angiogenesis in vivo. Moreover, N. nucifera leaf extracts significantly blocked VEGF-induced ROS production in HUVECs, confirming their possible anti-angiogenic mechanism. PMID- 25714484 TI - A homochiral magnet based on D3 symmetric [(NaO3)Co3] clusters: from spontaneous resolution to absolute chiral induction. AB - A pair of novel enantiomeric 3D magnetic complexes [NaCo3(IA)6](NO3).H2O (1Delta and 1Lambda) have been synthesized using an achiral ligand HIA via spontaneous resolution, which crystallize in the hexagonal crystal system with a chiral P63 space group, and diamagnetic sodium cations are located at the center of D3 symmetric clusters. This kind of spontaneous resolution is uncontrollable and dependent on batches. By utilizing cheap enantiopure mandelic acid as a chiral inducing agent, they are driven to controllable homochiral crystallization of the desired enantiomorph, confirmed by circular dichroism spectra. PMID- 25714483 TI - Proteasome Dysfunction Associated to Oxidative Stress and Proteotoxicity in Adipocytes Compromises Insulin Sensitivity in Human Obesity. AB - AIMS: Obesity is characterized by a low-grade systemic inflammatory state and adipose tissue (AT) dysfunction, which predispose individuals to the development of insulin resistance (IR) and metabolic disease. However, a subset of obese individuals, referred to as metabolically healthy obese (MHO) individuals, are protected from obesity-associated metabolic abnormalities. Here, we aim at identifying molecular factors and pathways in adipocytes that are responsible for the progression from the insulin-sensitive to the insulin-resistant, metabolically unhealthy obese (MUHO) phenotype. RESULTS: Proteomic analysis of paired samples of adipocytes from subcutaneous (SC) and omental (OM) human AT revealed that both types of cells are altered in the MUHO state. Specifically, the glutathione redox cycle and other antioxidant defense systems as well as the protein-folding machinery were dysregulated and endoplasmic reticulum stress was increased in adipocytes from IR subjects. Moreover, proteasome activity was also compromised in adipocytes of MUHO individuals, which was associated with enhanced accumulation of oxidized and ubiquitinated proteins in these cells. Proteasome activity was also impaired in adipocytes of diet-induced obese mice and in 3T3-L1 adipocytes exposed to palmitate. In line with these data, proteasome inhibition significantly impaired insulin signaling in 3T3-L1 adipocytes. INNOVATION: This study provides the first evidence of the occurrence of protein homeostasis deregulation in adipocytes in human obesity, which, together with oxidative damage, interferes with insulin signaling in these cells. CONCLUSION: Our results suggest that proteasomal dysfunction and impaired proteostasis in adipocytes, resulting from protein oxidation and/or misfolding, constitute major pathogenic mechanisms in the development of IR in obesity. PMID- 25714485 TI - A hierarchical porous bowl-like PLA@MSNs-COOH composite for pH-dominated long term controlled release of doxorubicin and integrated nanoparticle for potential second treatment. AB - We chemically integrated mesoporous silica nanoparticles (MSNs) and macroporous bowl-like polylactic acid (pBPLA) matrix, for noninvasive electrostatic loading and long-term controlled doxorubicin (DOX) release, to prepare a hierarchical porous bowl-like pBPLA@MSNs-COOH composite with a nonspherical and hierarchical porous structure. Strong electrostatic interaction with DOX rendered excellent encapsulation efficiency (up to 90.14%) to the composite. DOX release showed pH dominated drug release kinetics; thus, maintaining a weak acidic pH (e.g., 5.0) triggered sustained release, suggesting the composite's great potential for long term therapeutic approaches. In-vitro cell viability assays further confirmed that the composite was biocompatible and that the loaded drugs were pharmacologically active, exhibiting dosage-dependent cytotoxicity. Additionally, a wound-healing assay revealed the composite's intrinsic ability to inhibit cell migration. Moreover, pH- and time-dependent leaching of the integrated MSNs due to pBPLA matrix degradation allow us to infer that the leached (and drug loaded) MSNs may be engulfed by cancer cells contributing to a second wave of DOX mediated cytotoxicity following pH-triggered DOX release. PMID- 25714486 TI - Cognitive representations and cognitive processing of team-specific tactics in soccer. AB - Two core elements for the coordination of different actions in sport are tactical information and knowledge about tactical situations. The current study describes two experiments to learn about the memory structure and the cognitive processing of tactical information. Experiment 1 investigated the storage and structuring of team-specific tactics in humans' long-term memory with regard to different expertise levels. Experiment 2 investigated tactical decision-making skills and the corresponding gaze behavior, in presenting participants the identical match situations in a reaction time task. The results showed that more experienced soccer players, in contrast to less experienced soccer players, possess a functionally organized cognitive representation of team-specific tactics in soccer. Moreover, the more experienced soccer players reacted faster in tactical decisions, because they needed less fixations of similar duration as compared to less experienced soccer players. Combined, these experiments offer evidence that a functionally organized memory structure leads to a reaction time and a perceptual advantage in tactical decision-making in soccer. The discussion emphasizes theoretical and applied implications of the current results of the study. PMID- 25714488 TI - Ga4B2O9: an efficient borate photocatalyst for overall water splitting without cocatalyst. AB - Borates are well-known candidates for optical materials, but their potentials in photocatalysis are rarely studied. Ga(3+)-containing oxides or sulfides are good candidates for photocatalysis applications because the unoccupied 4s orbitals of Ga usually contribute to the bottom of the conducting band. It is therefore anticipated that Ga4B2O9 might be a promising photocatalyst because of its high Ga/B ratio and three-dimensional network. Various synthetic methods, including hydrothermal (HY), sol-gel (SG), and high-temperature solid-state reaction (HTSSR), were employed to prepare crystalline Ga4B2O9. The so-obtained HY-Ga4B2O9 are micrometer single crystals but do not show any UV-light activity unless modified by Pt loading. The problem is the fast recombination of photoexcitons. Interestingly, the samples obtained by SG and HTSSR methods both possess a fine micromorphology composed of well-crystalline nanometer strips. Therefore, the excited e(-) and h(+) can move to the surface easily. Both samples exhibit excellent intrinsic UV-light activities for pure water splitting without the assistance of any cocatalyst (47 and 118 MUmol/h/g for H2 evolution and 22 and 58 MUmol/h/g for O2 evolution, respectively), while there is no detectable activity for P25 (nanoparticles of TiO2 with a specific surface area of 69 m(2)/g) under the same conditions. PMID- 25714489 TI - Mono(boratabenzene) rare-earth metal dialkyl complexes: synthesis, structure and catalytic behaviors for styrene polymerization. AB - Four mono(boratabenzene) rare-earth metal dialkyl complexes, [(3,5-Me2 C5H3BR)Ln(CH2SiMe3)2(THF)] (1: R = NEt2, Ln = Sc; 2: R = NEt2, Ln = Lu; 3: R = Ph, Ln = Sc; 4: R = Ph, Ln = Lu), were synthesized efficiently via a one-pot strategy with Li[3,5-Me2-C5H3BR] (R = NEt2, Ph), LnCl3(THF)x (Ln = Sc, x = 3; Ln = Lu, x = 0), and LiCH2SiMe3. The solid-state structures of 1 and 2 were determined by single-crystal X-ray diffraction. Variable-temperature NMR studies indicated that the energy barrier for the rotation of aminoboratabenzene in 1 (DeltaG? ~ 71 kJ mol-1) is higher than that of phenylboratabenzene in 3 (DeltaG? ~ 59 kJ mol-1). These mono(boratabenzene) rare-earth metal dialkyl complexes' catalytic behaviors for styrene polymerization were investigated, and found that mono(boratabenzene) scandium dialkyl complexes show high catalytic activities for syndiotactic polymerization upon activation with cocatalysts. PMID- 25714490 TI - Water wires in aqueous solutions from first-principles calculations. AB - We elucidate the concept of water wires in aqueous solutions in view of their structural and dynamical properties by means of first-principles molecular dynamics simulations. We employ a specific set of hydroxyquinoline derivatives (heteroaromatic fluorescent dyes) as probe molecules that provide a well-defined initial and final coordinate for possible water wires by means of their photoacid and photobase functionalities. Besides the geometric structure of the hydrogen bond network connecting these functional sites, we focus on the dependence of the length of the resulting water wire on the initial/final coordinates determined by the chromophore. Special attention is devoted to the persistence of the wires on the picosecond time scale and their capability of shifting the nature of the proton transfer process from a concerted to a stepwise mechanism. Our results shed light on the long debate on whether water wires represent characteristic structural motifs or transient phenomena. PMID- 25714487 TI - Ultrastructural relationship of the phagophore with surrounding organelles. AB - Phagophore nucleates from a subdomain of the endoplasmic reticulum (ER) termed the omegasome and also makes contact with other organelles such as mitochondria, Golgi complex, plasma membrane and recycling endosomes during its formation. We have used serial block face scanning electron microscopy (SB-EM) and electron tomography (ET) to image phagophore biogenesis in 3 dimensions and to determine the relationship between the phagophore and surrounding organelles at high resolution. ET was performed to confirm whether membrane contact sites (MCSs) are evident between the phagophore and those surrounding organelles. In addition to the known contacts with the ER, we identified MCSs between the phagophore and membranes from putative ER exit sites, late endosomes or lysosomes, the Golgi complex and mitochondria. We also show that one phagophore can have simultaneous MCSs with more than one organelle. Future membrane flux experiments are needed to determine whether membrane contacts also signify lipid translocation. PMID- 25714491 TI - Synthesis of carbon/sulfur nanolaminates by electrochemical extraction of titanium from Ti2SC. AB - Herein we electrochemically and selectively extract Ti from the MAX phase Ti2SC to form carbon/sulfur (C/S) nanolaminates at room temperature. The products are composed of multi-layers of C/S flakes, with predominantly amorphous and some graphene-like structures. Covalent bonding between C and S is observed in the nanolaminates, which render the latter promising candidates as electrode materials for Li-S batteries. We also show that it is possible to extract Ti from other MAX phases, such as Ti3AlC2, Ti3SnC2, and Ti2GeC, suggesting that electrochemical etching can be a powerful method to selectively extract the "M" elements from the MAX phases, to produce "AX" layered structures, that cannot be made otherwise. The latter hold promise for a variety of applications, such as energy storage, catalysis, etc. PMID- 25714492 TI - Pollution breaks down the genetic architecture of life history traits in Caenorhabditis elegans. AB - When pollution occurs in an environment, populations present suffer numerous negative and immediate effects on their life history traits. Their evolutionary potential to live in a highly stressful environment will depend on the selection pressure strengths and on the genetic structure, the trait heritability, and the genetic correlations between them. If expression of this structure changes in a stressful environment, it becomes necessary to quantify these changes to estimate the evolutionary potential of the population in this new environment. We studied the genetic structure for survival, fecundity, and early and late growth in isogenic lines of a Caenorhabditis elegans population subject to three different environments: a control environment, an environment polluted with uranium, and a high salt concentration environment. We found a heritability decrease in the polluted environments for fecundity and early growth, two traits that were the most heritable in the control environment. The genetic structure of the traits was particularly affected in the uranium polluted environment, probably due to generally low heritability in this environment. This could prevent selection from acting on traits despite the strong selection pressures exerted on them. Moreover, phenotypic traits were more strongly affected in the salt than in the uranium environment and the heritabilities were also lower in the latter environment. Consequently the decrease in heritability was not proportional to the population fitness reduction in the polluted environments. Our results suggest that pollution can alter the genetic structure of a C. elegans population, and thus modify its evolutionary potential. PMID- 25714494 TI - Non-adherence to CPAP and prevention of postoperative complications in OSA: what are the limits of anesthesia consultation? PMID- 25714493 TI - INVESTIGATE-I (INVasive Evaluation before Surgical Treatment of Incontinence Gives Added Therapeutic Effect?): a mixed-methods study to assess the feasibility of a future randomised controlled trial of invasive urodynamic testing prior to surgery for stress urinary incontinence in women. AB - BACKGROUND: The position of invasive urodynamic testing in the diagnostic pathway for urinary incontinence (UI) is unclear. Systematic reviews have called for further trials evaluating clinical utility, although a preliminary feasibility study was considered appropriate. OBJECTIVES: To inform the decision whether or not to proceed to a definitive randomised trial of invasive urodynamic testing compared with clinical assessment with non-invasive tests, prior to surgery in women with stress UI (SUI) or stress predominant mixed UI (MUI). DESIGN: A mixed methods study comprising a pragmatic multicentre randomised pilot trial; economic evaluation; survey of clinicians' views about invasive urodynamic testing; qualitative interviews with clinicians and trial participants. SETTING: Urogynaecology, female urology and general gynaecology units in Newcastle, Leicester, Swansea, Sheffield, Northumberland, Gateshead and South Tees. PARTICIPANTS: Trial recruits were women with SUI or stress predominant MUI who were considering surgery after unsuccessful conservative treatment. Relevant clinicians completed two online surveys. Subsets of survey respondents and trial participants took part in separate qualitative interview studies. INTERVENTIONS: Pilot trial participants were randomised to undergo clinical assessment with non invasive tests (control arm); or assessment as controls, plus invasive urodynamic testing (intervention arm). MAIN OUTCOME MEASURES: Confirmation that units can identify and recruit eligible women; acceptability of investigation strategies and data collection tools; acquisition of outcome data to determine the sample size for a definitive trial. The proposed primary outcome for the definitive trial was International Consultation on Incontinence Modular Questionnaire (ICIQ) Female Lower Urinary Tract Symptoms (ICIQ-FLUTS) (total score) 6 months after surgery or the start of non-surgical treatment; secondary outcomes included: ICIQ FLUTS (subscales); ICIQ Urinary Incontinence Short Form; ICIQ Lower Urinary Tract Symptoms Quality of Life; Urogenital Distress Inventory; EuroQol-5D; costs, quality-adjusted life-years (QALYs) and incremental cost per QALY, Short Form 12; 3-day bladder diary. RESULTS: Of 284 eligible women, 222 (78%) were recruited; 165/219 (75%) returned questionnaires at baseline and 125/200 (63%) who were sent questionnaires at follow-up. There were few missing data items in returned questionnaires, with individual outcome scales calculable for 81%-94%. Most women underwent surgery; management plans were changed in 19 (19%) participants following invasive urodynamic testing. Participant Costs Questionnaires were returned by 53% 6 months after treatment; complete data to undertake cost-utility analysis were available in 27% (intervention) and 47% (control). While insufficient to recommend changes in practice, the results suggest further research would be valuable. All clinicians responding to the survey had access to invasive urodynamic testing, and most saw it as essential prior to surgery in women with SUI with or without other symptoms; nevertheless, 70% considered the research question underlying INVESTIGATE important and most were willing to randomise patients in a definitive trial. Participants interviewed were positive about the trial and associated documentation; the desire of some women to avoid invasive urodynamic testing contrasted with opinions expressed by clinicians through both survey and interview responses. CONCLUSIONS: All elements of a definitive trial and economic evaluation were rehearsed; several areas for protocol modification were identified. Such a trial would require to 400-900 participants, depending on the difference in primary outcome sought. FUTURE WORK: A definitive trial of invasive urodynamic testing versus clinical assessment prior to surgery for SUI or stress predominant MUI should be undertaken. TRIAL REGISTRATION: Current Controlled Trials ISRCTN71327395. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 25714496 TI - Biofilm Formation and Colistin Susceptibility of Acinetobacter baumannii Isolated from Korean Nosocomial Samples. AB - Biofilm formation, a virulence factor of Acinetobacter baumannii, is associated with long-term survival in hospital environments and provides resistance to antibiotics. Standard tests for antibiotic susceptibility involve analyzing bacteria in the planktonic state. However, the biofilm formation ability can influence antibiotic susceptibility. Therefore, here, the biofilm formation ability of A. baumannii clinical isolates from Korea was investigated and the susceptibility of biofilm and planktonic bacteria to colistin was compared. Of the 100 clinical isolates examined, 77% exhibited enhanced biofilm formation capacity relative to a standard A. baumannii strain (ATCC 19606). Differences between the minimal inhibitory concentrations and minimal biofilm-inhibitory concentrations of colistin were significantly greater in the group of A. baumannii that exhibited enhanced biofilm formation than the group that exhibited less ability for biofilm formation. Thus, the ability to form a biofilm may affect antibiotic susceptibility and clinical failure, even when the dose administered is in the susceptible range. PMID- 25714495 TI - The emerging role of lysine demethylases in DNA damage response: dissecting the recruitment mode of KDM4D/JMJD2D to DNA damage sites. AB - KDM4D is a lysine demethylase that removes tri- and di- methylated residues from H3K9 and is involved in transcriptional regulation and carcinogenesis. We recently showed that KDM4D is recruited to DNA damage sites in a PARP1-dependent manner and facilitates double-strand break repair in human cells. Moreover, we demonstrated that KDM4D is an RNA binding protein and mapped its RNA-binding motifs. Interestingly, KDM4D-RNA interaction is essential for its localization on chromatin and subsequently for efficient demethylation of its histone substrate H3K9me3. Here, we provide new data that shed mechanistic insights into KDM4D accumulation at DNA damage sites. We show for the first time that KDM4D binds poly(ADP-ribose) (PAR) in vitro via its C-terminal region. In addition, we demonstrate that KDM4D-RNA interaction is required for KDM4D accumulation at DNA breakage sites. Finally, we discuss the recruitment mode and the biological functions of additional lysine demethylases including KDM4B, KDM5B, JMJD1C, and LSD1 in DNA damage response. PMID- 25714497 TI - Nickel-catalyzed three-component domino reactions of aryl Grignard reagents, alkynes, and aryl halides producing tetrasubstituted alkenes. AB - Three-component reaction of aryl Grignard reagents, alkynes, and aryl halides in the presence of 1 mol % of NiCl2 proceeded sequentially through carbomagnesiation of the alkyne followed by cross-coupling of the resulting alkenyl Grignard reagent with aryl halide to give tetrasubstituted alkenes in high yields. PMID- 25714498 TI - Progress and developments in the turbo Grignard reagent i-PrMgCl.LiCl: a ten-year journey. AB - Over the past decade, the effectiveness of i-PrMgCl.LiCl has been constantly highlighted by a number of research groups. Its enhanced nucleophilicity brings prosperity to highly functionalized Grignard reagents, other useful bimetallic (alkali-metal) agents and nucleophilic alkylation products under mild reaction conditions. In this feature article, a comprehensive, systematical and in-depth overview of i-PrMgCl.LiCl is provided in a multidisciplinary idea. It involves the structural and kinetic perspectives of i-PrMgCl.LiCl as well as its unique reactivity and selectivity, with knowledge of the former helping to rationalize trends of the later. PMID- 25714500 TI - Pulmonary specialty training to improve respiratory health in low- and middle income countries. Needs and challenges. AB - It is estimated that 85% of the world's population lives in low- and middle income countries (LMICs). Although economic conditions are improving in these countries, health expenditures have not kept pace with the overall economic growth, and health systems remain weak. These already inadequate systems are being further stressed by the epidemiologic transition that is taking place, characterized by a slow decrease in communicable diseases and an increase in noninfectious chronic diseases, resulting in a "double burden" of infectious and noninfectious diseases. Respiratory diseases comprise the largest category of illness within this combined burden of disease. Although there are chronic respiratory disease programs of proven effectiveness appropriate for LMICs, implementation has been greatly hampered by the lack of physicians who have special knowledge and skills in addressing the full spectrum of lung diseases. Thus, there is an urgent need to create training programs for specialists in respiratory diseases. Such programs should be developed and conducted by institutions in LMICs and tailored to fit the prevailing circumstances of the country. Existing curriculum blueprints may be used to guide training program development with appropriate modifications. Academic institutions and professional societies in high-income countries may be called upon to provide technical assistance in developing and implementing training programs. In order to better define the burden of respiratory diseases and identify effective interventions, research, moved forward by persons committed and specialized in this area of health, will be essential. PMID- 25714499 TI - Pertussis models to inform vaccine policy. AB - Pertussis remains a challenging public health problem with many aspects of infection, disease and immunity poorly understood. Initially controlled by mass vaccination, pertussis resurgence has occurred in some countries with well established vaccination programs, particularly among adolescents and young adults. Several studies have used mathematical models to investigate drivers of pertussis epidemiology and predict the likely impact of different vaccination strategies. We reviewed a number of these models to evaluate their suitability to answer questions of public health importance regarding optimal vaccine scheduling. We critically discuss the approaches adopted and the impact of chosen model structures and assumptions on study conclusions. Common limitations were a lack of contemporary, population relevant data for parameterization and a limited understanding of the relationship between infection and disease. We make recommendations for future model development and suggest epidemiologic data collections that would facilitate efforts to reduce uncertainty and improve the robustness of model-derived conclusions. PMID- 25714501 TI - Magnetic nanoparticle-supported lipid bilayers for drug delivery. AB - Magnetic nanoparticle-supported lipid bilayers (SLBs) constructed around core shell Fe3O4-SiO2 nanoparticles (SNPs) were prepared and evaluated as potential drug carriers. We describe how an oxime ether lipid can be mixed with SNPs to produce lipid-particle assemblies with highly positive zeta potential. To demonstrate the potential of the resultant cationic SLBs, the particles were loaded with either the anticancer drug doxorubicin or an amphiphilic analogue, prepared to facilitate integration into the supported lipid bilayer, and then examined in studies against MCF-7 breast cancer cells. The assemblies were rapidly internalized and exhibited higher toxicity than treatments with doxorubicin alone. The magnetic SLBs were also shown to increase the efficacy of unmodified doxorubicin. PMID- 25714502 TI - Glucose fluctuations in association with oxidative stress among children with T1DM: comparison of different phases. AB - CONTEXT: Previous studies on the association between glucose fluctuations and oxidative stress in diabetes mellitus were all conducted in adults, and most study participants had type 2 diabetes mellitus. OBJECTIVE: The study objective was to examine the association of glucose fluctuation and oxidative stress in children with type 1 diabetes mellitus (T1DM) across different phases. DESIGN: This was a case-control study. SETTING: The setting was the Beijing Children's Hospital (2010-2013). PATIENTS: Children treated for T1DM were divided into three study groups, including group A (newly diagnosed cases in the acute metabolic disturbance phase), group B (the honeymoon phase), and group C (the long-standing phase). Healthy control children were matched to the T1DM patients by age and sex. INTERVENTIONS: There were no interventions. MAIN OUTCOME MEASURES: The 24 hour urinary free 8-iso-prostaglandin F2alpha to creatinine (8-iso-PGF2alpha/Cr) ratio indicated oxidative stress. Glucose fluctuation parameters (GFPs) included mean blood glucose levels, standard deviation of daily blood glucose levels, mean amplitude of glucose excursions, and incremental area under the curve for postprandial glucose. RESULTS: In each study group, 8-iso-PGF2alpha/Cr and all GFPs in children with T1DM were significantly higher than those in normal controls. 8-iso-PGF2alpha/Cr was significantly correlated with all GFPs in all three T1DM groups. A stronger association with 8-iso-PGF2alpha/Cr for mean amplitude of glucose excursions than for glycated hemoglobin was observed in both the acute metabolic disturbance and long-standing phases of T1DM. CONCLUSIONS: Glucose fluctuations were positively associated with oxidative stress in T1DM patients in different phases. Glucose fluctuations may have a stronger effect than sustained chronic hyperglycemia on triggering oxidative stress, but coexisting high levels of blood glucose may be required. PMID- 25714503 TI - Spontaneous self-welding of silver nanowire networks. AB - As an alternative to the traditional indium tin oxide transparent electrode, solution-processed metal nanowire thin film has been a promising candidate due to its flexibility. However, high contact resistance between the nanowires remains a major challenge to improve the performance. Here, we have investigated a one-step process of coating and welding of nanowires on flexible film. An electric field assisted spray coating method developed in this study could generate finely charged droplets of nanowire solution at high flow rate. While charged droplets deposited on the flexible film, electric charges were flowing through the nanowire network producing electrical current. It induced Joule heating and welding at junctions of the nanowires without post-processing steps. Using the coating method, the silver nanowire thin film could be uniformly deposited evenly on a large area substrate, and spontaneously self-welding was carried out between the nanowire networks. The transparent electrode of the silver nanowire prepared by the concurrent deposition and the self-welding process could improve uniformity, roughness and sheet resistance. PMID- 25714504 TI - High-throughput assay for measuring monoclonal antibody self-association and aggregation in serum. AB - Subcutaneous delivery is one of the preferred administration routes for therapeutic monoclonal antibodies (mAbs). High antibody dosing requirements and small injection volumes necessitate formulation and delivery of highly concentrated mAb solutions. Such elevated antibody concentrations can lead to undesirable solution behaviors such as mAb self-association and aggregation, which are relatively straightforward to detect using various biophysical methods because of the high purity and concentration of antibody formulations. However, the biophysical properties of mAbs in serum can also impact antibody activity, but these properties are less well understood because of the difficulty characterizing mAbs in such a complex environment. Here we report a high throughput assay for directly evaluating mAb self-association and aggregation in serum. Our approach involves immobilizing polyclonal antibodies specific for human mAbs on gold nanoparticles, and then using these conjugates to capture human antibodies at a range of subsaturating to saturating mAb concentrations in serum. Antibody aggregation is detected at subsaturating mAb concentrations via blue-shifted plasmon wavelengths due to the reduced efficiency of capturing mAb aggregates relative to monomers, which reduces affinity cross-capture of mAbs by multiple conjugates. In contrast, antibody self-association is detected at saturating mAb concentrations via red-shifted plasmon wavelengths due to attractive interparticle interactions between immobilized mAbs. The high throughput nature of this assay along with its compatibility with unusually dilute mAb solutions (0.1-10 MUg per mL) should make it useful for identifying antibody candidates with high serum stability during early antibody discovery. PMID- 25714505 TI - Omitted citation to related article. PMID- 25714506 TI - Cost-effectiveness of quadrivalent influenza vaccine in Hong Kong - A decision analysis. AB - Trivalent influenza vaccine (TIV) selects one of the 2 co-circulating influenza B lineages whereas quadrivalent influenza vaccine (QIV) includes both lineages. We examined potential cost-effectiveness of QIV versus TIV from perspectives of healthcare provider and society of Hong Kong. A decision tree was designed to simulate the outcomes of QIV vs. TIV in 6 age groups: 0-4 years, 5-9 years, 10-14 years, 15-64 years, 65-79 y and >=80 years. Direct cost alone, direct and indirect costs, and quality-adjusted life-years (QALYs) loss due to TIV-unmatched influenza B infection were simulated for each study arm. Outcome measure was incremental cost per QALY (ICER). In base-case analysis, QIV was more effective than TIV in all-age population with additional direct cost per QALY (ICER-direct cost) and additional total cost per QALY (ICER-total cost) of USD 22,603 and USD 12,558, respectively. Age-stratified analysis showed that QIV was cost-effective in age groups 6 months to 9 y and >=80 years from provider's perspective, and it was cost-effective in all age group except 15-64 y from societal perspective. Percentage of TIV-unmatched influenza B in circulation and additional vaccine cost of QIV were key influential factors. From perspectives of healthcare provider and society, QIV was the preferred option in 52.77% and 66.94% of 10,000 Monte Carlo simulations, respectively. QIV appears to be cost-effective in Hong Kong population, except for age group 15-64 years, from societal perspective. From healthcare provider's perspective, QIV seems to be cost-effective in very young (6 months-9 years) and older (>=80 years) age groups. PMID- 25714507 TI - The Aza-Wharton reaction: syntheses of cyclic allylic amines and vicinal hydroxyamines from the respective acylaziridines. AB - The Wharton reaction, initially described for acyl epoxides, has been studied using the structurally similar aziridines. By this reaction, a range of cyclic allylic amines and vicinal amino alcohols have been prepared stereoselectively and, in some cases, enantiomerically pure. PMID- 25714508 TI - A highly reliable copper nanowire/nanoparticle ink pattern with high conductivity on flexible substrate prepared via a flash light-sintering technique. AB - In this work, copper nanowires (NWs) and Cu nanoparticles (NPs) were employed to increase the reliability of a printed electrode pattern under mechanical bending fatigue. The fabricated Cu NW/NP inks with different weight fractions of Cu NWs were printed on a polyimide substrate and flash light-sintered within a few milliseconds at room temperature under ambient conditions. Then, 1000 cycles of outer and inner bending fatigue tests were performed using a lab-made fatigue tester. The flash light-sintered Cu NW/NP ink film with 5 wt % Cu NWs prepared under the flash light-sintering conditions (12.5 J.cm-2 irradiation energy, 10 ms pulse duration, and one pulse) showed a lower resistivity (22.77 MUOmega.cm) than those of the only Cu NPs and Cu NWs ink (94.01 MUOmega.cm and 104.15 MUOmega.cm, respectively). In addition, the resistance change (DeltaR.R0(-1)) of the 5 wt % Cu NWs Cu NW/NP film was greatly enhanced to 4.19 compared to the 92.75 of the Cu NPs film obtained under mechanical fatigue conditions over 1000 cycles and an outer bending radius of 7 mm. These results were obtained by the densification and enhanced mechanical flexibility of flash light-sintered Cu NW/NP network, which resulted in prevention of crack initiation and propagation. To characterize the Cu NW/NP ink film, X-ray diffraction and scanning electron microscopy were used. PMID- 25714509 TI - Fe-P: a new class of electroactive catalyst for oxygen reduction reaction. AB - It has been long thought that Fe-N-C structure, where Fe is bonded with an electronegative heteroatom N, plays a key role as nonprecious metal catalyst for oxygen reduction reaction (ORR) in fuel cells. However, electrocatalytic activity of Fe bonded with electropositive heteroatom P has never been considered for ORR. Herein we report the electrocatalytic activity for ORR of new Fe-P-C. PMID- 25714510 TI - The development of a recombinant hepatitis E vaccine HEV 239. AB - Hepatitis E virus (HEV) infection is one of the main causes of acute hepatitis worldwide. A recombinant hepatitis E vaccine, HEV 239, has been licensed in China for immunizing adults of 16 y old and above. The vaccine antigen contains pORF2 aa 368 - 606 of the HEV genotype 1 expressed in E. coli. The quality of the vaccine is controlled through a combination of biophysical, biochemical and immunochemical methods. The vaccine is well tolerated in adults. The efficacy of the HEV 239 vaccine against symptomatic and asymptomatic infection had been proven to be high during a Phase III clinical trial and long-term follow up. The safety and efficacy of HEV 239 vaccine in certain high-risk populations remains to be further investigated. PMID- 25714512 TI - Minimally invasive clip ligation of anterior communicating artery aneurysms through the eyebrow keyhole supraorbital craniotomy: 3-dimensional operative video. PMID- 25714511 TI - Prevention of falls for adults with intellectual disability (PROFAID): a feasibility study. AB - PURPOSE: A novel physiotherapy intervention for people with intellectual disability (ID) to improve balance was developed and evaluated in a feasibility study which quantitatively assessed potential benefits on measures of balance, gait and activity participation, and qualitatively explored its acceptability, utility and feasibility. METHODS: Participants were 27 adults with mild to profound ID (mean age 53 years SD 10.9). We used a mixed methods approach: an uncontrolled before-after study (data analysed with the related samples sign test) and a qualitative interview evaluation (data analysed with the general inductive approach). Balance, gait and participation were assessed at baseline and 6 months after introduction of the physiotherapy intervention with four standardised measures and two questionnaires. RESULTS: Appropriate exercises and a physical activity could be found for all participants, irrespective of the level of ID, although for many this required a high level of assistance from support staff. Only the Balance Scale for ID changed significantly by a median score of 2 (95% CI = 0.00-2.50, p = 0.04). No other outcomes changed significantly. Four themes emerged: "Understanding the intervention"; "Routine and reality"; "Remembering what I have to do" and "What happens beyond the study itself"? CONCLUSIONS: The findings provide some evidence for the benefit, acceptability, utility and feasibility of the intervention justifying further evaluation. IMPLICATIONS FOR REHABILITATION: Falling is a frequent and serious problem for many adults with intellectual disability. Two to three exercises targeted at increasing lower limb strength and challenging balance, performed each day as part of daily routine may help improve balance in adults with intellectual disability. The importance of exercising needs to be stressed to those who support adults with intellectual disability to encourage ongoing adherence. PMID- 25714513 TI - A pilot cost-effectiveness analysis of treatments in newly diagnosed high-grade gliomas: the example of 5-aminolevulinic Acid compared with white-light surgery. AB - BACKGROUND: High-grade gliomas are aggressive, incurable tumors characterized by extensive diffuse invasion of the normal brain parenchyma. Novel therapies at best prolong survival; their costs are formidable and benefit is marginal. Economic restrictions thus require knowledge of the cost-effectiveness of treatments. Here, we show the cost-effectiveness of enhanced resections in malignant glioma surgery using a well-characterized tool for intraoperative tumor visualization, 5-aminolevulinic acid (5-ALA). OBJECTIVE: To evaluate the cost effectiveness of 5-ALA fluorescence-guided neurosurgery compared with white-light surgery in adult patients with newly diagnosed high-grade glioma, adopting the perspective of the Portuguese National Health Service. METHODS: We used a Markov model (cohort simulation). Transition probabilities were estimated with the use of data from 1 randomized clinical trial and 1 noninterventional prospective study. Utility values and resource use were obtained from published literature and expert opinion. Unit costs were taken from official Portuguese reimbursement lists (2012 values). The health outcomes considered were quality-adjusted life years, life-years, and progression-free life-years. Extensive 1-way and probabilistic sensitivity analyses were performed. RESULTS: The incremental cost effectiveness ratios are below &OV0556;10 000 in all evaluated outcomes, being around &OV0556;9100 per quality-adjusted life-year gained, &OV0556;6700 per life year gained, and &OV0556;8800 per progression-free life-year gained. The probability of 5-ALA fluorescence-guided surgery cost-effectiveness at a threshold of &OV0556;20000 is 96.0% for quality-adjusted life-year, 99.6% for life-year, and 98.8% for progression-free life-year. CONCLUSION: 5-ALA fluorescence-guided surgery appears to be cost-effective in newly diagnosed high grade gliomas compared with white-light surgery. This example demonstrates cost effectiveness analyses for malignant glioma surgery to be feasible on the basis of existing data. PMID- 25714514 TI - Silent arteriovenous malformation hemorrhage and the recognition of "unruptured" arteriovenous malformation patients who benefit from surgical intervention. AB - BACKGROUND: Arteriovenous malformation (AVM) patients present in 4 ways relative to hemorrhage: (1) unruptured, without a history or radiographic evidence of old hemorrhage (EOOH); (2) silent hemorrhage, without a bleeding history but with EOOH; (3) ruptured, with acute bleeding but without EOOH; and (4) reruptured, with acute bleeding and EOOH. OBJECTIVE: We hypothesized that characteristics and outcomes in the unrecognized group of silent hemorrhage patients may differ from those of unruptured patients. METHODS: Two hundred forty-two patients operated-on since 1997 were categorized by hemorrhage status and hemosiderin positivity in this cohort study: unruptured (group 1), silent hemorrhage (group 2), and ruptured/reruptured (group 3/4). Group 3/4 was combined because hemosiderin cannot distinguish acute hemorrhage from older silent hemorrhage. RESULTS: Hemosiderin was found in 45% of specimens. Seventy-five patients (31.0%) had unruptured AVMs, 30 (12.4%) had silent hemorrhage, and 137 (56.6%) had ruptured/reruptured AVMs. Deep drainage, posterior fossa location, preoperative modified Rankin Scale (mRS) score, outcome, and macrophage score were different across groups. Only the macrophage score was different between the groups without clinical hemorrhage. Outcomes were better in silent hemorrhage patients than in those with frank rupture (mean mRS scores of 1.2 and 1.7, respectively). CONCLUSION: One-third of patients present with silent AVM hemorrhage. No clinical or anatomic features differentiate these patients from unruptured patients, except the presence of hemosiderin and macrophages. Silent hemorrhage can be diagnosed using magnetic resonance imaging with iron-sensitive imaging. Silent hemorrhage portends an aggressive natural history, and surgery halts progression to rerupture. Good final mRS outcomes and better outcomes than in those with frank rupture support surgery for silent hemorrhage patients, despite the findings of ARUBA. PMID- 25714515 TI - The relationship between preoperative general mental health and postoperative quality of life in minimally invasive lumbar spine surgery. AB - BACKGROUND: In assessing poor lumbar surgery outcomes, researchers continue to investigate psychosocial predictors of patient postoperative quality of life. This is the first study of its kind to investigate this relationship in an exclusively minimally invasive patient sample. OBJECTIVE: To determine the association between preoperative mental health and postoperative patient-centered outcomes in patients undergoing minimally invasive lumbar surgery. METHODS: In 83 adults undergoing single-level minimally invasive lumbar spine surgery, Pearson correlation and partial correlation analyses were conducted between all demographic and clinical baseline variables and Oswestry Disability Index (ODI), Visual Analogue Scale (VAS), and 36-item Short-Form Health Survey Version 2.0 (SF 36v2) scores at 6 to 12 months postoperatively. SF-36v2 mental component summary scores (MCS) were used to assess pre- and postoperative general mental health. Post hoc analysis consisted of Pearson correlations between baseline SF-36v2, ODI, and VAS scores, and an identical set of correlations at outcomes. RESULTS: Preoperative MCS showed no significant association with outcomes VAS, ODI, or physical component summary scores. Baseline disability correlated significantly and more strongly with baseline MCS (P < .001, r = -0.40) than baseline pain levels (VAS back not significant, VAS leg P = .015, r = 0.27). Outcomes disability correlated significantly and more strongly with outcome back and leg pain levels (P < .001, r = 0.60 and 0.66) than outcome MCS (P = .031, r = -0.24). CONCLUSION: In a patient sample with mental health scores comparable to the population mean, there is no relationship between preoperative general mental health and postoperative patient-centered outcomes. Surgeons should consider the dynamic relationships between patient disability, mental health, and pain levels in assessing quality of life at different time points. PMID- 25714516 TI - Modern paradigm for peritoneal catheter insertion: single port optical access laparoscopic shunt insertion. AB - BACKGROUND: Ventriculoperitoneal shunting is one of the most commonly performed neurosurgical procedures. Typically, for insertion of the peritoneal catheter, a mini-laparotomy technique is used. Although generally safe, it can be cosmetically undesirable and time consuming. Complications include malpositioning, bowel injury, and delayed hernias. Laparoscopic techniques have been advocated to address these issues, but have been slow to gain traction with neurosurgeons. OBJECTIVE: To describe our experience with single port optical access laparoscopy for placement of ventriculoperitoneal shunts. Our technique simplifies adoption of a laparoscopic technique for neurosurgeons looking to incorporate its benefits. METHODS: All ventriculoperitoneal shunts placed by the senior author since April 2011 were retrospectively reviewed. Surgical and perioperative complications, length of postoperative stay, and need for revisions were analyzed. RESULTS: Fifty-six patients were included in the study. There were no cases of peritoneal catheter misplacement. One intraoperative complication occurred early in the series, in which there was an injury to the gallbladder necessitating cholecystectomy. There were 7 cases followed by shunt revision inclusive of the abdomen. In 3 cases, pseudocysts were noted. CONCLUSION: Single port optical access laparoscopy is a fast and minimally invasive technique that allows direct visualization of the layers of the abdominal wall as they are traversed and visualization of the peritoneal catheter during placement. It uses a small cosmetic incision and obviates the need for postoperative abdominal radiographic studies. The procedure has a modest learning curve, but can be safely used without the assistance of an assist surgeon after the skills are acquired. PMID- 25714517 TI - Feasibility, Safety, and Efficacy of Flow-Diverting Stent-Assisted Microsphere Embolization of Fusiform and Sidewall Aneurysms. AB - BACKGROUND: Treatment of wide-necked internal carotid artery aneurysms is frequently associated with incomplete occlusion and high recurrence rates. Furthermore, platinum coils cause strong beam-hardening artifacts, hampering subsequent image analyses. OBJECTIVE: To assess the feasibility, safety, and efficacy of flow-diverting, stent-assisted microsphere embolization of fusiform and sidewall aneurysms in vitro and in vivo. METHODS: Using a recirculating pulsatile in vitro flow model, 5 different aneurysm geometries (inner/outer curve, narrow/wide neck, and fusiform) were treated (each n = 1) by flow diverting stent (FDS) implantation and subsequent embolization through a jailed microcatheter using calibrated microspheres (500-900 MUm) larger than the pores of the FDS mesh. Treatment effects were analyzed angiographically and by micro computed tomography. The fluid of the in vitro model was filtered to ensure that no microspheres evaded the aneurysm. The experiment was repeated once in vivo. RESULTS: In vitro, all 5 aneurysms were safely and completely occluded by FDS assisted microsphere embolization. Virtually complete aneurysm occlusion was confirmed by angiography and micro computed tomography. No microspheres escaped into the circulation. The experiment was successfully repeated in 1 pig with a sidewall aneurysm generated by vessel occlusion. An embolic protection system placed distally of the FDS in vitro and in vivo (each n = 1) contained no microspheres after the embolization. Thus, no microspheres were lost in the circulation, and the use of an embolic protection system seems feasible to provide additional safety. CONCLUSION: FDS-assisted microsphere embolization of fusiform and sidewall aneurysms is feasible and yields virtually complete aneurysm occlusion while avoiding coil-associated beam-hardening artifacts. PMID- 25714518 TI - Retained transcranial knife blade with transection of the internal carotid artery treated by staged endovascular and surgical therapy: technical case report. AB - BACKGROUND AND IMPORTANCE: We describe the use of proximal and distal endovascular coil embolization of the internal carotid artery followed by operative removal of a retained foreign object transecting the petrocavernous portion of the internal carotid artery. CLINICAL PRESENTATION: A 20-year-old man sustained a stab wound to the left temporal skull and presented with a retained knife blade. He reported a headache at presentation, but remained neurologically intact with a Glasgow Coma Scale of 15. Computed tomography imaging and subsequent angiography confirmed complete transection of the petrocavernous segment of the left internal carotid artery with effective tamponade by the knife blade in situ and satisfactory collateral flow across the Circle of Willis. Coil embolization of the left internal carotid artery was performed. Retrograde embolization of the petrocavernous internal carotid segment distal to the injury was performed via vertebral and posterior communicating artery access. Antegrade embolization of the internal carotid artery proximal to the injury was completed and the patient was transferred to the operating room for craniectomy and foreign body extraction. Postoperative computed tomography angiography revealed no parenchymal hemorrhage, mass effect, or midline shift, and successful embolization of the internal carotid artery. At 6-week follow-up, the patient remained neurologically intact with no infectious or vascular complications. CONCLUSION: Staged endovascular and surgical therapy provides complete assessment and effective control of damaged vessels when retained intracranial foreign bodies are present. Given the high risk of vascular injury with retained transcranial foreign bodies, this strategy should be considered a safe approach for these challenging cases. PMID- 25714519 TI - Time course and risk factors for myocardial dysfunction after aneurysmal subarachnoid hemorrhage. AB - BACKGROUND: Myocardial wall motion abnormalities (WMAs) are independent risk factors for a poor outcome in patients with aneurysmal subarachnoid hemorrhage (aSAH). OBJECTIVE: To study the time course of WMAs during the initial phase after aSAH and to investigate which clinical, electrocardiographic, or myocardial serum markers are predictors of early or late development of WMAs. METHODS: In a prospective, multicenter cohort study in patients with aSAH, we performed serial electrocardiography and echocardiography and measured troponin T and N-terminal pro-B-type natriuretic peptide. WMAs present on admission were considered early WMAs; those that developed during the clinical course were considered late WMAs. Using multivariable regression analysis, we calculated odds ratios with corresponding 95% confidence intervals for clinical parameters, electrocardiography, and myocardial serum makers with early or late occurrence of WMAs. RESULTS: We included 301 patients (mean age +/- SD, 57 +/- 13) years. Multivariable odds ratios for early WMAs were poor clinical condition, 2.7 (95% confidence interval: 1.1-6.8); sinus tachycardia, 5.0 (1.3-19.9); ST-segment depression, 3.7 (1.02-13.1); ST-segment elevation, 16.6 (1.5-178.9); and increased troponin T, 2.8 (1.1-7.3). Multivariable odds ratios (95% confidence intervals) for late development of WMAs were 6.8 (1.6-30) for a myocardial infarct pattern on admission electrocardiography and 3.4 (1.4-8.5) for increased troponin T on admission. CONCLUSION: WMAs may be present on admission or develop during the course of aSAH. Poor neurological condition on admission, sinus tachycardia, ST-segment depression, and ST-segment elevation on admission electrocardiography and increased troponin T are independent predictors of early WMAs; a myocardial infarct pattern on admission ECG and increased troponin T independently predict late WMAs. CLINICAL TRIAL REGISTRATION: NCT00123695. PMID- 25714520 TI - Initial multicenter technical experience with the Apollo device for minimally invasive intracerebral hematoma evacuation. AB - BACKGROUND: No conventional surgical intervention has been shown to improve outcomes for patients with spontaneous intracerebral hemorrhage (ICH) compared with medical management. OBJECTIVE: We report the initial multicenter experience with a novel technique for the minimally invasive evacuation of ICH using the Penumbra Apollo system (Penumbra Inc, Alameda, California). METHODS: Institutional databases were queried to perform a retrospective analysis of all patients who underwent ICH evacuation with the Apollo system from May 2014 to September 2014 at 4 centers (Medical University of South Carolina, Stony Brook University, University of California at San Diego, and Semmes-Murphy Clinic). Cases were performed either in the neurointerventional suite, operating room, or in a hybrid operating room/angiography suite. RESULTS: Twenty-nine patients (15 female; mean age, 62 +/- 12.6 years) underwent the minimally invasive evacuation of ICH. Six of these parenchymal hemorrhages had an additional intraventricular hemorrhage component. The mean volume of ICH was 45.4 +/- 30.8 mL, which decreased to 21.8 +/- 23.6 mL after evacuation (mean, 54.1 +/- 39.1% reduction; P < .001). Two complications directly attributed to the evacuation attempt were encountered (6.9%). The mortality rate was 13.8% (n = 4). CONCLUSION: Minimally invasive evacuation of ICH and intraventricular hemorrhage can be achieved with the Apollo system. Future work will be required to determine which subset of patients are most likely to benefit from this promising technology. PMID- 25714521 TI - Long-term functional outcomes and predictors of shunt-dependent hydrocephalus after treatment of ruptured intracranial aneurysms in the BRAT trial: revisiting the clip vs coil debate. AB - BACKGROUND: Acute hydrocephalus is a well-known sequela of aneurysmal subarachnoid hemorrhage (SAH). Controversy exists about whether open microsurgical methods serve to reduce shunt dependency compared with endovascular techniques. OBJECTIVE: To determine predictors of shunt-dependent hydrocephalus and functional outcomes after aneurysmal SAH. METHODS: A total of 471 patients who were part of a prospective, randomized, controlled trial from 2003 to 2007 were retrospectively reviewed. All variables including demographic data, medical history, treatment, imaging, and functional outcomes were included as part of the trial. No additional variables were retrospectively collected. RESULTS: Ultimately, 147 patients (31.2%) required a ventriculoperitoneal shunt (VPS) in our series. Age, dissecting aneurysm type, ruptured vertebrobasilar aneurysm, Fisher grade, Hunt and Hess grade, admission intraventricular hemorrhage, admission intraparenchymal hemorrhage, blood in the fourth ventricle on admission, perioperative ventriculostomy, and hemicraniectomy were significant risk factors (P < .05) associated with shunt-dependent hydrocephalus on univariate analysis. On multivariate analysis, intraventricular hemorrhage and intraparenchymal hemorrhage were independent risk factors for shunt dependency (P < .05). Clipping vs coiling treatment was not statistically associated with VPS after SAH on both univariate and multivariate analyses. Patients who did not receive a VPS at discharge had higher Glasgow Outcome Scale and Barthel Index scores and were more likely to be functionally independent and to return to work 72 months after surgery (P < .05). CONCLUSION: There is no difference in shunt dependency after SAH among patients treated by endovascular or microsurgical means. Patients in whom shunt-dependent hydrocephalus does not develop after SAH tend to have improved long-term functional outcomes. PMID- 25714522 TI - Clinical features and prognosis of intracranial artery dissection. AB - BACKGROUND: Intracranial artery dissections (IADs) are an important cause of stroke or subarachnoid hemorrhage (SAH). Outcome of IAD in the anterior circulation or presentation without SAH is rarely investigated and might be different. OBJECTIVE: To evaluate the clinical features and prognosis of patients with IAD, with special emphasis on the location (anterior vs posterior circulation) and clinical presentation (SAH or cerebral ischemia). METHODS: Between January 1998 and May 2012, 60 patients with IAD were included in this single-center cohort study. Clinical features, functional outcome, mortality, and prognostic factors were evaluated. Unfavorable functional outcome was defined as a modified Rankin scale score of 3 to 6. RESULTS: In 18 patients (30%), IAD was located in the anterior circulation. At a median follow-up of 6.4 months, 35.3% of patients with IAD in the anterior circulation had an unfavorable functional outcome vs 39.0% in patients with IAD in the posterior circulation (P = .79). Forty-two patients (70%) presented with SAH. Clinical presentation with SAH was not significantly associated with poor functional outcome (41.5% vs 29.4%, P = .39). Low Glasgow Coma Scale score on admission (odds ratio, 0.72, P = .003) and older age (odds ratio, 1.04, P = .04) were independent predictors of unfavorable functional outcome. Mortality rate was 13% and did not significantly differ with location or clinical presentation. CONCLUSION: Low Glasgow Coma Scale score on admission and older age were independent predictors of unfavorable functional outcome. IAD presenting with SAH was not significantly associated with poor functional outcome. PMID- 25714523 TI - Optical chirality sensing using macrocycles, synthetic and supramolecular oligomers/polymers, and nanoparticle based sensors. AB - Optical sensors that respond to enantiomeric excess of chiral analytes are highly demanded in chirality related research fields and demonstrate their potential in many applications, for example, screening of asymmetric reaction products. Most sensors developed so far are small molecules. This Tutorial Review covers recent advances in chirality sensing systems that are different from the traditional small molecule-based sensors, by using macrocycles, synthetic oligomers/polymers, supramolecular polymers and nanoparticles as the sensors, in which supramolecular interactions operate. PMID- 25714524 TI - Donepezil rescues spatial learning and memory deficits following traumatic brain injury independent of its effects on neurogenesis. AB - Traumatic brain injury (TBI) is ubiquitous and effective treatments for it remain supportive largely due to uncertainty over how endogenous repair occurs. Recently, we demonstrated that hippocampal injury-induced neurogenesis is one mechanism underlying endogenous repair following TBI. Donepezil is associated with increased hippocampal neurogenesis and has long been known to improve certain aspects of cognition following many types of brain injury through unknown mechanisms. By coupling donepezil therapy with temporally regulated ablation of injury-induced neurogenesis using nestin-HSV transgenic mice, we investigated whether the pro-cognitive effects of donepezil following injury might occur through increasing neurogenesis. We demonstrate that donepezil itself enhances neurogenesis and improves cognitive function following TBI, even when injury induced neurogenesis was inhibited. This suggests that the therapeutic effects of donepezil in TBI occur separately from its effects on neurogenesis. PMID- 25714525 TI - Characterization and solubility study of norfloxacin-polyethylene glycol, polyvinylpyrrolidone and carbopol 974p solid dispersions. AB - OBJECTIVE: Norfloxacin has a low aqueous solubility which leads to poor dissolution. Keeping this fact in mind the purpose of the present study is to formulate and evaluate norfloxacin solid dispersion. METHODS: Solid dispersions were prepared using hydrophilic carriers like polyethylene glycol (PEG) 4000, polyvinylpyrrolidone (PVP) k30 and carbopol 974pNF (CP) in various ratios using solvent evaporation technique. These formulations were evaluated using solubility studies, dissolution studies; Fourier transmitted infrared spectroscopy (FTIR), X ray diffraction (XRD), and differential scanning calorimetery (DSC). The influence of polymer type and drug to polymer ratio on the solubility and dissolution rate of norfloxacin was also evaluated. RESULTS: FTIR analysis showed no interaction of all three polymers with norfloxacin. The results from XRD and DSC analyses of the solid dispersion preparations showed that norfloxacin existsin its amorphous form. Among the Norfloxacin: PEG solid dispersions, Norfloxacin: PEG 1:14 ratio showed the highest dissolution rate at pH 6.8. For norfloxacin: PVP solid dispersions, norfloxacin: PVP 1:10 ratio showed the highest dissolution rate at pH 6.8. For Norfloxacin: CP solid dispersions, norfloxacin: P 1:2 ratio showed the highest dissolution rate at pH 6.8. CONCLUSION: The solid dispersion of norfloxacin with polyethylene glycol (PEG) 4000, polyvinylpyrrolidone (PVP) k30 and carbopol 974p NF (CP), lends an ample credence for better therapeutic efficacy. PMID- 25714526 TI - New insights into karyotypic relationships among populations of Astyanax bockmanni (Teleostei, Characiformes) of different watersheds. AB - The fish constitute about 50% of all vertebrates, including a wide morphological and biological diversity, where the genus Astyanax is the most common and diverse, as described in virtually all freshwater environments. By occupying a basal position in the phylogeny of vertebrates, fish are an extremely favorable group for cytogenetic and evolutionary studies. The karyotype found in genus Astyanax diversity may involve a number of polymorphisms, which may be related to ploidy and karyotypic macrostructure, presence of B chromosomes, heterochromatin polymorphisms, and location of ribosomal genes. Nevertheless, the relationship between populations of this species is still poorly studied. Thus, the present work aimed to investigate karyotype variation, chromosomal relationships, and the behavior of 5S and 18S ribosomal genes in six populations of Astyanax bockmanni. The results confirmed the diploid number of 50 chromosomes in all the populations sampled, with the occurrence of one supernumerary chromosome in just one of them. In addition, all populations showed divergent patterns of constitutive heterochromatin and repetitive nucleolar sites. The fluorescence in situ hybridization (FISH) technique using 5S and 18S rDNA probes revealed distinct patterns of distribution for these conserved genes, while 5S rDNA genes were found located in two chromosome pairs, the 18S genes showed multiple marks dispersed in the genome characterizing an inter and intraindividual polymorphic behavior, as previously reported to occur with the utilization of the Ag-NOR technique. Thus, besides minor modifications observed in chromosome morphology, the populations of A. bockmanni analyzed revealed a preserved macrostructural feature, especially concerning to the diploid number; on the other hand, differences in microstructural characteristics indicated by the nucleolus organizer region (NOR) location, constitutive heterochromatin patterns, and distribution of ribosomal genes along the genome were clearly evident in the populations from different river basins, even located at short distances. PMID- 25714527 TI - Synthesis and characterisation of an open-cage fullerene encapsulating hydrogen fluoride. AB - The first encapsulation of hydrogen fluoride in an open-cage fullerene is reported. Solution and solid-state NMR spectra of the novel open-cage endofullerene are described. PMID- 25714528 TI - Preoperative tranilast as adjunctive therapy to primary pterygium surgery with a 1-year follow-up. AB - PURPOSE: To determine the efficacy of tranilast as an adjunctive therapy in conjunctival autograft. METHODS: Twenty-nine patients were randomly allocated to the Tranilast Group (n=15) or the Control Group (n=14). The Tranilast Group received a subconjunctival injection of 0.5% tranilast 30 days prior to surgery. Conjunctival autograft was performed in both groups using fibrin sealant and 0.02% subconjunctival mitomycin C at the end of the surgery. After the resection of the pterygium, immunohistochemistry was performed with 100 cells to identify epithelial cells positive for transforming growth factor-beta (TGF-beta). Subjective symptoms were evaluated using a 5-point scale, and the recurrence rate was assessed. RESULTS: Both groups showed improvements in their symptoms and similar clinical results. Compared with the Control Group, the Tranilast Group failed to show a decreased recurrence rate (p=0.59). However, the number of epithelial cells expressing TGF-beta was lower in the Tranilast Group (5 cells; 95% CI: 2.56-13.15; Control Group, 16 cells, 95% CI: 11.53-24.76; p=0.01). Minimal but reversible complications, including glaucoma secondary to corticosteroids and granuloma, occurred during the study. CONCLUSION: Tranilast was effective in decreasing the number of pterygium epithelial cells expressing TGF-beta. PMID- 25714529 TI - Subconjunctival and topical application of recombinant tissue plasminogen activator in rabbits. AB - PURPOSE: To quantify fibrin degradation products after topical and subconjunctival administration of recombinant tissue plasminogen activator in rabbits. METHODS: Fibrin formation was induced in the anterior chamber in 25 rabbits. Subsequently, five rabbits received an injection of r-TPA (positive control) in the anterior chamber, another 10 received a subconjunctival injection of r-TPA, and the remaining 10 received instillations of topical r-TPA. Afterwards, samples of aqueous humor were collected and semi-quantitative analysis of fibrin degradation products (FDP) was performed. RESULTS: No statistical differences were noted between the treatment and control groups at any time point. Fibrin degradation products semi-quantification showed statistical improvement in the control group and the subconjunctival group. CONCLUSION: Fibrin degradation products were observed in the anterior chamber after subconjunctival administration of r-TPA. However, it was probably not sufficient to cause fibrin degradation. Topical r-TPA did not effectively absorb anterior chamber fibrin. PMID- 25714531 TI - Surgical results of strabismus correction in patients with myelomeningocele. AB - PURPOSE: Myelomeningocele is one of the most common birth defects. It is associated with severe neurological deficiencies, and ocular changes, such as strabismus, are very common. The purpose of this study was to describe indications for strabismus surgery in patients with myelomeningocele and to evaluate the results achieved with surgical correction. METHODS: We retrospectively reviewed records of all patients with myelomeningocele who underwent surgery for strabismus correction in a 5-year period in an institution for disabled children. RESULTS: The main indications for strabismus surgery were esotropia and A-pattern anisotropia. Excellent surgical results were achieved in 60.9% of patients, satisfactory in 12.2%, and unsatisfactory in 26.9%. CONCLUSION: Patients with myelomeningocele and strabismus had a high incidence of esotropia and A-pattern anisotropia. Strabismus surgery in these patients had an elevated percentage of excellent and satisfactory results, not only for the ocular deviation, but also for improvement of head posture. PMID- 25714530 TI - Approach of Turkish ophthalmologists to micronutrition in age-related macular degeneration. AB - PURPOSE: To evaluate the knowledge and behaviors of ophthalmologists in Turkey concerning micronutrition support in patients with age related macular degeneration (ARMD). METHODS: This study involved 1,845 ophthalmologists. A scientific poll was sent to all participants by email. The survey covered the following: demographic features, subspecialty knowledge about micronutrition preference for prescribing micronutrition to age related macular degeneration patients, and the reason for this preference. If a participant indicated that he or she prescribed micronutrition, the participant was also asked to indicate the source of the treatment and supplemental treatments. RESULTS: Of 1,845 ophthalmologists, 249 responded to the survey. Of the respondents, 9% (22) never, 43% (107) sometimes, 37% (92) frequently, and 11% (27) always used micronutrition. The most frequent prescribing subgroup was general ophthalmology (22%), followed by the retina-uvea subspecialty (13.9%). The micronutrition prescribing ratio was 54.8% in retina-uvea specialists when the "frequent" and "always" responses were combined. There was no statistically significant difference between subgroups with respect to prescribing micronutrition. Among the ophthalmologists prescribing micronutrition, 57.1% of them did not use the Age-Related Eye Disease Study-1 (AREDS) criteria, and only 31.3% prescribe micronutrition according to AREDS criteria. The results for the general ophthalmologist and retina-uvea specialist subgroups were similar, 56.3% vs 20.2%, and 54.1% vs 36.1%, respectively. Micronutrition was not recommended for the following reasons: expensive (55.4%), low patient expectancy (40%), no effect (30%), and low patient drug compliance (25.4%). Moreover, 55.2% of the clinicians recommended physical activities, dietary changes, and smoking cessation; 7.3% did not recommend these behavioral changes. CONCLUSION: This survey demonstrated that micronutrition preference in age related macular degeneration was low in ophthalmologists in Turkey. Additionally, retina specialists have a lower rate of prescribing micronutrition. Micronutrition support and behavior such as smoking cessation, dietary changes, etc. should be recommended more often to patients with age related macular degeneration. PMID- 25714532 TI - Mini-flared Kelman tip, reverse tip, and sidewinder tip with torsional phaco: a prospective randomized comparative study. AB - PURPOSE: To compare the efficiency of surgical procedures using three phaco tip designs in torsional phacoemulsification using the bevel-down technique. METHODS: In this prospective, comparative, masked study, patients were randomly assigned to have torsional coaxial microincision cataract surgery using the mini-flared 45 degree Kelman tip, reversed mini-flared 30-degree Kelman tip, or Sidewinder 30 degree Kelman tip. Clinical measurements included preoperative and 3-month postoperative corrected distance visual acuity (CDVA), endothelial cell counts (ECC), and preoperative and 1-day postoperative central corneal thickness (CCT). Intraoperative measurements included phaco time, torsional time, aspiration time, case time, cumulative dissipated energy (CDE), and balanced salt solution volume (BSS). RESULTS: The study evaluated 150 eyes of 150 patients. Intraoperatively, there was no statistically significant difference in cumulative dissipated energy, case time, torsional time, and aspiration time between the three tip configurations. However, less phaco time was used with the mini-flared 45-degree Kelman tip (p=0.02) than that with the Sidewinder 30-degree Kelman tip or reversed mini-flared 30-degree Kelman tip. The mini-flared 45-degree Kelman tip and the reversed mini-flared 30-degree Kelman tip required significantly less balanced salt solution volume than that required by the Sidewinder 30-degree Kelman tip (p=0.009). There was no statistically significant difference in corrected distance visual acuity and endothelial cell counts between tips 3 months postoperatively (p>0.05). CONCLUSION: All three tips were effective with no intraoperative complications. When using torsional phacoemulsification through microincisions and the prefracture technique with the bevel-down technique, the mini-flared 45-degree Kelman tip required a lower mean phaco time than the reversed mini-flared 30-degree Kelman tip and the Sidewinder 30-degree Kelman tip. PMID- 25714533 TI - Choroidal thickness measurement in healthy pediatric population using Cirrus HD optical coherence tomography. AB - PURPOSE: To investigate the association between central choroidal thickness (CT), axial length (AL), age, gender, and refractive error in a healthy pediatric population using optical coherence tomography (OCT). METHODS: This institutional study involved 137 healthy children (57 boys, 80 girls) aged between 4 and 18 years. Each child underwent a dilated eye examination, cycloplegic refraction, and AL measurement using a Nidek AL-Scan optical biometer. The central foveal thickness (CFT) and CT were measured using Cirrus high definition (HD)-OCT. The right eye of each subject was selected for analysis. RESULTS: The mean age of the children was 10.0 +/- 4.7 years (range, 4-18 years). The mean spherical equivalent (SE) was -0.24 +/- 1.24 diopters (D) (range, -2.00 D to +2.25 D). The mean AL was 23.1 +/- 1.2 mm (range, 20-27 mm). The mean central CT was 388.2 +/- 50.0 MUm and was not correlated with age, gender, AL, or refractive error. CONCLUSION: The data provide a pediatric normative database of CT using enhanced depth imaging OCT. This information may be useful in the diagnosis and monitoring of retino-choroidal diseases in children. PMID- 25714534 TI - Comparison of 3 different anesthetic approaches for intravitreal injections: a prospective randomized trial. AB - PURPOSE: To compare the anesthetic effectiveness of topical proparacaine drops, subconjunctival lidocaine, and 2% lidocaine gel. METHODS: Ninety-two patients undergoing intravitreal injections were randomized to 1 of 3 groups: proparacaine 0.5% drops (Group Drops), proparacaine 0.5% drops plus subconjunctival lidocaine (Group SC), or 2% lidocaine gel (Group Gel). Patients were asked to score their pain experience using a visual analog scale of 0 to 10 immediately following the injections and 10 min, 1 h, 6 h, and 24 h after the injections. Patients also graded the overall injection experience as Excellent, Very Good, Fair, Poor, or Awful. The physician evaluated the patients' eye movement during intravitreal injection on 3 levels: (0) none or minimal, (1) not compromising the injection, and (2) compromising the injection. RESULTS: The patients in Group Drops had the worst mean pain scores during the injection and 10 min after, with the highest occurrence of movements compromising the procedure (Grade 2; 38.7%). The patients in Group SC had a higher percentage of good experiences (37.9%) but a higher incidence of chemosis (16.7%). The patients in Group Gel had similar overall pain scores to Group Drops patients but a higher incidence of keratitis (19.4%). There was no statistically significant correlation between the use of aspirin or anticoagulants and the occurrence of hyperemia or hyposphagma. CONCLUSION: Subconjunctival lidocaine was most effective in preventing pain and eye movements during intravitreal injections. Although 2% lidocaine gel produced a good overall experience for the patients, the incidence of keratitis was very high (19.4%). Therefore, we do not recommend 2% lidocaine gel as the first anesthetic choice for intravitreal injections. There is no evidence to suspend the use of aspirin or other anticoagulants drugs prior to intravitreal injections. PMID- 25714535 TI - Survey: technique of performing intravitreal injection among members of the Brazilian Retina and Vitreous Society (SBRV). AB - PURPOSE: To evaluate and describe the precautions involved in the technique of intravitreal injection of antiangiogenic drugs adopted by the ophthalmologists who are members of the Brazilian Society of Retina and Vitreous (SBRV). METHODS: A questionnaire containing 22 questions related to precautions taken before, during, and after intravitreal injection was sent electronically to 920 members of SBRV between November 15, 2013 and April 31, 2014. RESULTS: 352 responses (38%) were obtained. There was a predominance of men (76%) from the southwest region of Brazil (51%). The professional experience varied between 6 and 15 years after medical specialization (50%). Most professionals (76%) performed an average of 1 to 10 intravitreal injections a week, and 88% of the procedures were performed in the operating room using povidone iodine (99%), sterile gloves, and blepharostat (94%). For inducing topical anesthesia, usage of anesthetic eye drops was the most used technique (65%). Ranibizumab (Lucentis(r)) was the most common drug (55%), and age-related macular degeneration (AMD) was the most treated disease (57%). Regarding the complications treated, 6% of the ophthalmologists had treated at least one case of retinal detachment, 20% had treated cases of endophthalmitis, 9% had treated cases of vitreous hemorrhage, and 12% had encountered cases of crystalline lens touch. CONCLUSION: Intravitreal injection is a procedure routinely performed by retina specialists and has a low incidence of complications. Performing the procedure in the operating room using an aseptic technique was preferred by most of the respondents. Ranibizumab was the most used drug, and AMD was the most treated disease. PMID- 25714537 TI - Ocular diseases at geriatric clinics in Rio de Janeiro: social and epidemiological considerations among patients with motor locomotion deficit. AB - OBJECTIVE: To identify the causes of low visual acuity and systemic morbidities that limit ambulation and access to eye care in geriatric clinics in Rio de Janeiro. METHODS: This cross-sectional study evaluated 187 patients from three geriatric clinics in Rio de Janeiro between January 2010 and January 2011. The inclusion criteria were individuals with a visual acuity of less than of equal to 20/200 in either eye (118 individuals), without optical correction. The exclusion criteria were individuals who refused to participate and those unable to undergo screening because of mental disabilities (6 individuals). Of the 187 individuals evaluated, 63 had visual acuity above 20/200. RESULTS: A total of 118 individuals with a visual acuity of <=20/200 effectively participated in the study after meeting the inclusion and exclusion criteria. In addition, 57 participants (48.3%) presented systemic disabling morbidities. Of the 118 individuals with low visual acuity, 27.96% had cataract and 26.27% had refractive errors. CONCLUSION: Most of the patients from geriatric clinics experienced ocular morbidities, but their proper treatment resulted in improved visual acuity. A more socially oriented problem associated with eye care involved the difficulty of access to ophthalmologic consultations. PMID- 25714536 TI - Evaluation of a simulation tool in ophthalmology: application in teaching funduscopy. AB - PURPOSE: The aim of this study was to evaluate the Eye Retinopathy Trainer(r) as a teaching tool for direct ophthalmoscopy examination by comparing it with the traditional method using volunteers. METHODS: Fourth year medical students received training in direct ophthalmoscopy using a simulation tool and human volunteers. Ninety students were randomized into a Simulation Group or a Control Group by the inclusion or absence of the simulation model in classroom practice. Differences between the groups were analyzed using unpaired Student's t-test. RESULTS: The Simulation Group was superior to the Control Group, with 51.06% successful in performing fundus examination in both the anatomical model simulation and the human model in comparison with 21.15% in the Control Group. CONCLUSION: The Eye Retinopathy Trainer(r) appears to be an effective teaching tool for practice and improvement of ophthalmologic examination among fourth year medical students. PMID- 25714539 TI - Internal eye wall resection of uveal tumors: long-term evaluation. AB - The authors report five cases of uveal tumors managed with internal eye wall resection and evaluate the long-term results. Patient age varied from 31 to 61 years. Four patients were female and one was male. Uveal tumors involved ciliary body and choroid in three patients and choroid alone in the other two. Histopathological examination demonstrated three uveal melanomas, one leiomyoma, and one meduloepithelioma. The largest tumor diameter ranged from 8 to 15 mm and tumor thickness from 5 to 11 mm. Follow-up of the patients was over a period of 6 to 23 years. Final visual acuity was 20/20 in 3 patients and 20/200 in one patient, and in the fifth patient, the affected eye was enucleated. No cases of metastatic disease or local recurrence of the tumor were observed, suggesting that internal eye wall resection is a valid alternative for the treatment of selected cases of uveal tumors. PMID- 25714538 TI - Recurrent myopic foveoschisis: resolution after internal limiting membrane removal. AB - We report a case of a 66-year-old man with a history of high myopia and who was referred for acute decreased visual acuity of the right eye. Fundus examination and optical coherence tomography (OCT) showed a mild epiretinal membrane (ERM) and splitting of retinal layers. Pars plana vitrectomy was performed with intravitreous triamcinolone injection, posterior hyaloid and ERM peeling, and 12% perfluoropropane (C3F8) gas tamponade. After remaining asymptomatic for 17 months, the patient reported a new episode of sudden decreased visual acuity in his right eye, and OCT showed recurrent myopic foveoschisis (MF). He underwent vitrectomy and internal limiting membrane (ILM) peeling. Six months later, the patient's best corrected visual acuity had improved to 20/25. Optical coherence tomography showed a remarkably improved macular anatomy, with residual traction along the inferotemporal arcade, which was attributed to the vessel stiffness itself. We conclude that removing the internal limiting membrane is a challenging maneuver in myopic foveoschisis, even with staining approaches. Although myopic foveoschisis may be resolved without peeling the internal limiting membrane, its removal should be considered if the condition recurs. PMID- 25714540 TI - Case report: pneumatic retinopexy for the treatment of progressive retinal detachment in senile retinoschisis. AB - Retinoschisis is an abnormal separation of the retinal layers and is asymptomatic in most cases. Enlargement of the area of retinoschisis and retinal tear and detachment are possible complications of the disease, and the treatment of retinoschisis is controversial. In this case report, we present a case of retinal detachment associated with senile retinoschisis in which pneumatic retinopexy was chosen as the treatment of choice and was performed successfully in one of the eyes. After a literature review on retinoschisis and pneumatic retinopexy for the treatment of associated retinal detachment, we found only one case that was successfully treated without drainage of subretinal fluid, using air as the filler. However, no previous reports have been found in the literature on the effectiveness of pneumatic retinopexy using C3F8 as the sole treatment for progressive retinal detachment in senile retinoschisis. PMID- 25714541 TI - An uncommon ocular manifestation of Sweet syndrome: peripheral ulcerative keratitis and nodular scleritis. AB - Sweet syndrome (acute febrile neutrophilic dermatosis) is characterized by fever, neutrophilic leukocytosis, and abrupt appearance of painful erythematous nodules and plaques, particularly on the face, neck, and limbs. In this study, we report a very rare case of Sweet syndrome in which the patient presented nodular scleritis and peripheral ulcerative keratitis during the dermatologically inactive period of the disease. PMID- 25714542 TI - Birdshot retinochoroidopathy review. AB - Birdshot retinochoroidopathy (BSRC) is a distinct type of posterior uveitis originally described in the 1940s. Its characteristics include minimal anterior segment inflammation and diffuse posterior choroidopathy with vitritis and retinal vasculitis. The precise etiology of this disease is yet to be elucidated. However, various treatment modalities have been employed with the ultimate goal of durable remission of this vision threatening intraocular disease. The purpose of this review is not only to emphasize the importance of recognizing BSRC, but also to discuss the new discoveries, immune mediators, current and new therapies, and techniques applied to monitor and accomplish disease remission. PMID- 25714543 TI - Measurement of choroid thickness in pregnant women using enhanced depth imaging optical coherence tomography. PMID- 25714544 TI - Peer review. PMID- 25714545 TI - The miRNA-Kallikrein interactions: adding a new dimension. PMID- 25714547 TI - The C-terminal extension of PrhG impairs its activation of hrp expression and virulence in Ralstonia solanacearum. AB - Ralstonia solanacearum is the second most destructive bacterial plant pathogens worldwide and HrpG is the master regulator of its pathogenicity. PrhG is a close paralogue of HrpG and both belong to OmpR/PhoB family of two-component response regulators. Despite a high similarity (72% global identity and 96% similarity in helix-loop-helix domain), they display distinct roles in pathogenicity. HrpG is necessary for the bacterial growth in planta and pathogenicity, while PrhG is dispensable for bacterial growth in planta and contributes little to pathogenicity. The main difference between HrpG and PrhG is the 50-amino-acid long C-terminal extension in PrhG (amino-acid residues 230-283), which is absent in HrpG. When this extension is deleted, truncated PrhGs (under the control of its native promoter) allowed complete recovery of bacterial growth in planta and wild-type virulence of hrpG mutant. This novel finding demonstrates that the extension region in PrhG is responsible for the functional difference between HrpG and PrhG, which may block the binding of PrhG to target promoters and result in impaired activation of hrp expression by PrhG and reduced virulence of R. solanacearum. PMID- 25714548 TI - First draft genome sequence of Aureimonas altamirensis, isolated from patient blood culture. AB - Aureimonas altamirensis (A. altamirensis) is a recently described aerobic Gram negative bacillus related to Brucella species, which is a potential opportunistic pathogen of humans. Aureimonas altamirensis ON-56566 was isolated from the blood culture of a patient who presented with cellulitis. This brief report describes a short case report and the first draft genome (13 contigs) of A. altamirensis ON 56566 which consists of 4,202,944 nucleotides with G+C content of 65.2%. PMID- 25714546 TI - The RB tumor suppressor at the intersection of proliferation and immunity: relevance to disease immune evasion and immunotherapy. AB - The retinoblastoma tumor suppressor (RB) was the first identified tumor suppressor based on germline predisposition to the pediatric eye tumor. Since these early studies, it has become apparent that the functional inactivation of RB is a common event in nearly all human malignancy. A great deal of research has gone into understanding how the loss of RB promotes tumor etiology and progression. Since malignant tumors are characterized by aberrant cell division, much of this research has focused upon the ability of RB to regulate the cell cycle by repression of proliferation-related genes. However, it is progressively understood that RB is an important mediator of multiple functions. One area that is gaining progressive interest is the emerging role for RB in regulating diverse features of immune function. These findings suggest that RB is more than simply a regulator of cellular proliferation; it is at the crossroads of proliferation and the immune response. Here we review the data related to the functional roles of RB on the immune system, relevance to immune evasion, and potential significance to the response to immune-therapy. PMID- 25714549 TI - Identification of the correct form of the mis-annotated response regulator Rre1 from the cyanobacterium Synechocystis sp. PCC 6803. AB - Two-component systems have been extensively described in the control of gene expression in response to different environmental signals in the cyanobacterium Synechocystis sp. PCC 6803. The Hik34-Rre1 two-component system has been shown to regulate a set of genes under certain stress conditions. Some evidence indicates that another histidine kinase, probably Hik2, is acting upstream of Rre1 in the regulation of some genes in response to hyperosmotic and salt stress. In the present study, a mis-annotation of the Rre1 protein has been identified and the correct version has been functionally characterized in vitro. By using EMSA assays, we have demonstrated that phosphorylation of Rre1 by Hik2 increases the affinity of the response regulator for the adhA promoter region, a gene that has been demonstrated previously to be specifically regulated by the Hik34-Rre1 system. These results suggest that Hik2 might cooperate with Hik34 in the regulation of the adhA gene by transferring the phosphoryl group to Rre1 under salt and hyperosmotic stress conditions. PMID- 25714550 TI - Evaluation of T3B fingerprinting for identification of clinical and environmental Sporothrix species. AB - In this study, PCR fingerprinting using the universal primer T3B was applied to distinguish among clinical and environmental species of the Sporothrix complex, Sporothrix brasiliensis, S. globosa, S. mexicana, S. pallida, S. luriei and S. schenckii sensu stricto. The T3B fingerprinting generated clearly distinct banding patterns, allowing the correct identification of all 43 clinical and environmental isolates at the species level, what was confirmed by partial calmodulin gene sequence analyses. This technique is reproducible and provides the identification of all species of the Sporothrix complex with sufficient accuracy to be applied in clinical mycology laboratories as well as in epidemiological studies in order to obtain a better understanding of the epidemiology of sporotrichosis. PMID- 25714551 TI - Characterization of a new ViI-like Erwinia amylovora bacteriophage phiEa2809. AB - Erwinia amylovora is a Gram-negative plant pathogenic bacteria causing fire blight disease in many Rosaceae species. A novel E. amylovora bacteriophage, phiEa2809, was isolated from symptomless apple leaf sample collected in Belarus. This phage was also able to infect Pantoea agglomerans strains. The genome of phiEa2809 is a double-stranded linear DNA 162,160 bp in length, including 145 ORFs and one tRNA gene. The phiEa2809 genomic sequence is similar to the genomes of the Serratia plymutica phage MAM1, Shigella phage AG-3, Dickeya phage vB DsoM LIMEstone1 and Salmonella phage ViI and lacks similarity to described E. amylovora phage genomes. Based on virion morphology (an icosahedral head, long contractile tail) and genome structure, phiEa2809 was classified as a member of Myoviridae, ViI-like bacteriophages group. PhiEa2809 is the firstly characterized ViI-like bacteriophage able to lyse E. amylovora. PMID- 25714552 TI - The effects of stimulus variability on the perceptual learning of speech and non speech stimuli. AB - Previous studies suggest fundamental differences between the perceptual learning of speech and non-speech stimuli. One major difference is in the way variability in the training set affects learning and its generalization to untrained stimuli: training-set variability appears to facilitate speech learning, while slowing or altogether extinguishing non-speech auditory learning. We asked whether the reason for this apparent difference is a consequence of the very different methodologies used in speech and non-speech studies. We hypothesized that speech and non-speech training would result in a similar pattern of learning if they were trained using the same training regimen. We used a 2 (random vs. blocked pre and post-testing) * 2 (random vs. blocked training) * 2 (speech vs. non-speech discrimination task) study design, yielding 8 training groups. A further 2 groups acted as untrained controls, tested with either random or blocked stimuli. The speech task required syllable discrimination along 4 minimal-pair continua (e.g., bee-dee), and the non-speech stimuli required duration discrimination around 4 base durations (e.g., 50 ms). Training and testing required listeners to pick the odd-one-out of three stimuli, two of which were the base duration or phoneme continuum endpoint and the third varied adaptively. Training was administered in 9 sessions of 640 trials each, spread over 4-8 weeks. Significant learning was only observed following speech training, with similar learning rates and full generalization regardless of whether training used random or blocked schedules. No learning was observed for duration discrimination with either training regimen. We therefore conclude that the two stimulus classes respond differently to the same training regimen. A reasonable interpretation of the findings is that speech is perceived categorically, enabling learning in either paradigm, while the different base durations are not well-enough differentiated to allow for categorization, resulting in disruption to learning. PMID- 25714553 TI - The spacing principle for unlearning abnormal neuronal synchrony. AB - Desynchronizing stimulation techniques were developed to specifically counteract abnormal neuronal synchronization relevant to several neurological and psychiatric disorders. The goal of our approach is to achieve an anti-kindling, where the affected neural networks unlearn abnormal synaptic connectivity and, hence, abnormal neuronal synchrony, by means of desynchronizing stimulation, in particular, Coordinated Reset (CR) stimulation. As known from neuroscience, psychology and education, learning effects can be enhanced by means of the spacing principle, i.e. by delivering repeated stimuli spaced by pauses as opposed to delivering a massed stimulus (in a single long stimulation session). To illustrate that the spacing principle may boost the anti-kindling effect of CR neuromodulation, in this computational study we carry this approach to extremes. To this end, we deliver spaced CR neuromodulation at particularly weak intensities which render permanently delivered CR neuromodulation ineffective. Intriguingly, spaced CR neuromodulation at these particularly weak intensities effectively induces an anti-kindling. In fact, the spacing principle enables the neuronal population to successively hop from one attractor to another one, finally approaching attractors characterized by down-regulated synaptic connectivity and synchrony. Our computational results might open up novel opportunities to effectively induce sustained desynchronization at particularly weak stimulation intensities, thereby avoiding side effects, e.g., in the case of deep brain stimulation. PMID- 25714555 TI - Manganese catalysed sulfenylation of N-methyl amides with arenesulfonyl hydrazides. AB - A convenient oxidative sulfenylation method for the formation of various sulfenyl amides has been reported. Arenesulfonyl hydrazine as a sulfur source in the presence of a manganese salt can activate the sp(3) C-H bond of N-methyl amides through a free-radical pathway using di-tert-butyl peroxide (DTBP). PMID- 25714554 TI - Tinned fruit consumption and mortality in three prospective cohorts. AB - Dietary recommendations to promote health include fresh, frozen and tinned fruit, but few studies have examined the health benefits of tinned fruit. We therefore studied the association between tinned fruit consumption and mortality. We followed up participants from three prospective cohorts in the United Kingdom: 22,421 participants from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk cohort (1993-2012), 52,625 participants from the EPIC Oxford cohort (1993-2012), and 7440 participants from the Whitehall II cohort (1991-2012), all reporting no history of heart attack, stroke, or cancer when entering these studies. We estimated the association between frequency of tinned fruit consumption and all cause mortality (primary outcome measure) using Cox regression models within each cohort, and pooled hazard ratios across cohorts using random-effects meta-analysis. Tinned fruit consumption was assessed with validated food frequency questionnaires including specific questions about tinned fruit. During 1,305,330 person years of follow-up, 8857 deaths occurred. After adjustment for lifestyle factors and risk markers the pooled hazard ratios (95% confidence interval) of all cause mortality compared with the reference group of tinned fruit consumption less often than one serving per month were: 1.05 (0.99, 1.12) for one to three servings per month, 1.10 (1.03, 1.18) for one serving per week, and 1.13 (1.04, 1.23) for two or more servings per week. Analysis of cause specific mortality showed that tinned fruit consumption was associated with mortality from cardiovascular causes and from non-cardiovascular, non-cancer causes. In a pooled analysis of three prospective cohorts from the United Kingdom self-reported tinned fruit consumption in the 1990s was weakly but positively associated with mortality during long-term follow-up. These findings raise questions about the evidence underlying dietary recommendations to promote tinned fruit consumption as part of a healthy diet. PMID- 25714557 TI - Rutherfurd syndrome revisited: intellectual disability is not a feature. PMID- 25714556 TI - Relevance and therapeutic possibility of PTEN-long in renal cell carcinoma. AB - PTEN-Long is a translational variant of PTEN (Phosphatase and Tensin Homolog). Like PTEN, PTEN-Long is able to antagonize the PI3K-Akt pathway and inhibits tumor growth. In this study, we investigated the role PTEN-Long plays in the development and progression of clear cell renal cell carcinoma (ccRCC) and explored the therapeutic possibility using proteinaceous PTEN-Long to treat ccRCC. We found that the protein levels of PTEN-Long were drastically reduced in ccRCC, which was correlated with increased levels of phosphorylated Akt (pAkt). Gain of function experiments showed overexpression of PTEN-Long in the ccRCC cell line 786-0 suppressed PI3K-Akt signaling, inhibited cell proliferation, migration and invasion, and eventually induced cell death. When purified PTEN-Long was added into cultured 786-0 cells, it entered cells, blocked Akt activation, and induced apoptosis involving Caspase 3 cleavage. Furthermore, PTEN-Long inhibited proliferation of 786-0 cells in xenograft mouse model. Our results implicated that understanding the roles of PTEN-Long in renal cell carcinogenesis has therapeutic significance. PMID- 25714558 TI - Total anomalous pulmonary venous drainage in a patient with Koolen syndrome (del17q21.31). PMID- 25714559 TI - Familial craniosynostosis associated with a microdeletion involving the NFIA gene. PMID- 25714560 TI - A novel KIF7 mutation in two affected siblings with acrocallosal syndrome. AB - Acrocallosal syndrome (ACLS) is a rare genetic disorder typically characterized by craniofacial dysmorphism, agenesis, or hypoplasia of the corpus callosum, and duplication of the phalanges of halluces and/or the thumbs. ACLS is a recessive ciliopathy caused by mutations in KIF7. We identified a Turkish family who had a novel homozygous sequence change, c.2593-2A>C, located at the acceptor splice site of intron 12 of KIF7 (IVS12-2A>C). The present report will contribute towards further understanding of the genotype-phenotype correlation in ACLS caused by KIF7 mutations. PMID- 25714561 TI - An interstitial de-novo microdeletion of 3q26.33q27.3 causing severe intrauterine growth retardation. AB - Chromosomal abnormalities involving an interstitial or a terminal deletion of 3q26.33 and/or 3q27 have rarely been described. Here we report on a fetus of 22+1 weeks' gestational age with severe intrauterine growth restriction and multiple abnormalities detected by ultrasound examination. Post-mortem molecular cytogenetic investigation (array-comparative genomic hybridization) identified a de-novo interstitial ~6.17 Mbp microdeletion of 3q26.33q27.3. The clinical and molecular findings in this patient are compared with the previous literature on cases with overlapping interstitial 3q-deletions (seven cases in total). The common phenotype observed in patients with a microdeletion involving 3q26.33q27.3 includes severe prenatal and postnatal growth retardation (including microcephaly), developmental delay, central nervous system anomalies, and several facial characteristics (abnormally shaped ears, broad nasal tip, epicanthal folds, micrognathia/retrognathia, short philtrum). No genotype-phenotype correlation could be established for severe (intrauterine) growth retardation. We conclude that deletions of 3q26.33q27.3 are associated with a profoundly abnormal phenotype, with severe intrauterine growth retardation as its most striking feature. PMID- 25714562 TI - A third report of Apert syndrome in association with diaphragmatic hernia. PMID- 25714563 TI - A clinical case report and literature review of the 3q29 microdeletion syndrome. AB - We report on a 15-year-old male with the 3q29 microdeletion syndrome and summarize the medical literature. He had intellectual disability, autism spectrum disorder, anxiety, obsessive compulsive tendencies, speech delay, delayed walking, a hypernasal voice, gait abnormalities, chronic constipation, gastroesophageal reflux disorder, urinary voiding dysfunction, abnormal skin pigmentation, and dysmorphic features. We present a review of the literature for the 3q29 microdeletion syndrome by comparing both the phenotype and the genetic defects in reported cases. Of the 38 previously reported cases with deletion size information, the most common chromosome deletion was 1.6 Mb in size including ~ 30 genes. This emerging microdeletion syndrome is characterized by intellectual disability, speech delay, behavioral problems, craniofacial dysmorphism, and musculoskeletal abnormalities. PMID- 25714564 TI - New lithium metal polymer solid state battery for an ultrahigh energy: nano C LiFePO4 versus nano Li1.2V3O8. AB - Novel lithium metal polymer solid state batteries with nano C-LiFePO4 and nano Li1.2V3O8 counter-electrodes (average particle size 200 nm) were studied for the first time by in situ SEM and impedance during cycling. The kinetics of Li-motion during cycling is analyzed self-consistently together with the electrochemical properties. We show that the cycling life of the nano Li1.2V3O8 is limited by the dissolution of the vanadium in the electrolyte, which explains the choice of nano C-LiFePO4 (1300 cycles at 100% DOD): with this olivine, no dissolution is observed. In combination with lithium metal, at high loading and with a stable SEI an ultrahigh energy density battery was thus newly developed in our laboratory. PMID- 25714565 TI - Eye movements are coordinated with pectoral fin beats during locomotion in a marine teleost fish. AB - Animals must simultaneously engage multiple functional systems in order to navigate, feed and survive in complex environments. Nearly all vertebrates perform rapid gaze-shifting eye movements called saccades, but we know little about the behaviour of saccades during rhythmic locomotion. This study examined how saccades are coordinated with locomotor movements in a pectoral-fin-propelled teleost fish, Cymatogaster aggregata, the shiner surfperch. Individual fish were filmed swimming in a flow tank at 10 cm s(-1), and timing data were analysed using circular statistics. The results reveal that C. aggregata generates saccades non-uniformly throughout the pectoral fin cycle. Saccades primarily occur during fin abduction, when a large amount of thrust is produced, and rarely occur during the thrust-free refractory phase. Because vision is known to be impaired during saccades, we hypothesize that C. aggregata synchronizes saccades with periods of high acceleration in order to stabilize retinal images during low acceleration phases, which are nearly saccade-free. PMID- 25714566 TI - Thermoregulatory consequences of salt loading in the lizard Pogona vitticeps. AB - Previous research has demonstrated that dehydration increases the threshold temperature for panting and decreases the thermal preference of lizards. Conversely, it is unknown whether thermoregulatory responses such as shuttling and gaping are similarly influenced. Shuttling, as an active behavioural response, is considered one of the most effective thermoregulatory behaviours, whereas gaping has been proposed to be involved in preventing brain over-heating in lizards. In this study we examined the effect of salt loading, a proxy for increased plasma osmolality, on shuttling and gaping in Pogona vitticeps. Then, we determined the upper and lower escape ambient temperatures (UETa and LETa), the percentage of time spent gaping, the metabolic rate (VO2 ), the evaporative water loss (EWL) during gaping and non-gaping intervals and the evaporative effectiveness (EWL/VO2 ) of gaping. All experiments were performed under isotonic (154 mmol l(-1)) and hypertonic saline injections (625, 1250 or 2500 mmol l(-1)). Only the highest concentration of hypertonic saline altered the UETa and LETa, but this effect appeared to be the result of diminishing the animal's propensity to move, instead of any direct reduction in thermoregulatory set-points. Nevertheless, the percentage of time spent gaping was proportionally reduced according to the saline concentration; VO2 was also decreased after salt loading. Thermographic images revealed lower head than body surface temperatures during gaping; however this difference was inhibited after salt loading. Our data suggest that EWL/VO2 is raised during gaping, possibly contributing to an increase in heat transfer away from the lizard, and playing a role in head or brain cooling. PMID- 25714567 TI - Generating an in vitro 3D cell culture model from zebrafish larvae for heart research. AB - We describe here a novel, fast and inexpensive method for producing a 3D 'heart' structure that forms spontaneously, in vitro, from larval zebrafish (ZF). We have named these 3D 'heart' structures 'zebrafish heart aggregate(s)' (ZFHAs) and have characterised their basic morphology and structural composition using histology, immunohistochemistry, electron microscopy and mass spectrometry. After 2 days in culture, the ZFHA spontaneously form and become a stable contractile syncytium consisting of cardiac tissue derived by in vitro maturation, which beats rhythmically and consistently for more than 8 days. We propose this model as a platform technology, which can be developed further to study in vitro cardiac maturation, regeneration, tissue engineering and safety pharmacological/toxicology testing. PMID- 25714568 TI - The activity of isolated neurons and the modulatory state of an isolated nervous system represent a recent behavioural state. AB - Behavioural/motivational state is known to influence nearly all aspects of physiology and behaviour. The cellular basis of behavioural state control is only partially understood. Our investigation, performed on the pond snail Lymnaea stagnalis whose nervous system is useful for work on completely isolated neurons, provided several results related to this problem. First, we demonstrated that the behavioural state can produce long-term changes in individual neurons that persist even after neuron isolation from the nervous system. Specifically, we found that pedal serotonergic neurons that control locomotion show higher activity and lower membrane potential after being isolated from the nervous systems of hungry animals. Second, we showed that the modulatory state (the chemical neuroactive microenvironment of the central ganglia) changes in accordance with the nutritional state of an animal and produces predicted changes in single isolated locomotor neurons. Third, we report that observed hunger induced effects can be explained by the increased synthesis of serotonin in pedal serotonergic neurons, which has an impact on the electrical activity of isolated serotonergic neurons and the intensity of extrasynaptic serotonin release from the pedal ganglia. PMID- 25714569 TI - Ways to be different: foraging adaptations that facilitate higher intake rates in a northerly wintering shorebird compared with a low-latitude conspecific. AB - At what phenotypic level do closely related subspecies that live in different environments differ with respect to food detection, ingestion and processing? This question motivated an experimental study on rock sandpipers (Calidris ptilocnemis). The species' nonbreeding range spans 20 deg of latitude, the extremes of which are inhabited by two subspecies: C. p. ptilocnemis that winters primarily in upper Cook Inlet, Alaska (61 degrees N) and C. p. tschuktschorum that overlaps slightly with C. p. ptilocnemis but whose range extends much farther south (~40 degrees N). In view of the strongly contrasting energetic demands of their distinct nonbreeding distributions, we conducted experiments to assess the behavioral, physiological and sensory aspects of foraging and we used the bivalve Macoma balthica for all trials. C. p. ptilocnemis consumed a wider range of prey sizes, had higher maximum rates of energy intake, processed shell waste at higher maximum rates and handled prey more quickly. Notably, however, the two subspecies did not differ in their abilities to find buried prey. The subspecies were similar in size and had equally sized gizzards, but the more northern ptilocnemis individuals were 10-14% heavier than their same-sex tschuktschorum counterparts. The higher body mass in ptilocnemis probably resulted from hypertrophy of digestive organs (e.g. intestine, liver) related to digestion and nutrient assimilation. Given the previously established equality of the metabolic capacities of the two subspecies, we propose that the high-latitude nonbreeding range of ptilocnemis rock sandpipers is primarily facilitated by digestive (i.e. physiological) aspects of their foraging ecology rather than behavioral or sensory aspects. PMID- 25714570 TI - Adhesive pad differentiation in Drosophila melanogaster depends on the Polycomb group gene Su(z)2. AB - The ability of many insects to walk on vertical smooth surfaces such as glass or even on the ceiling has fascinated biologists for a long time, and has led to the discovery of highly specialized adhesive organs located at the distal end of the animals' legs. So far, research has primarily focused on structural and ultrastructural investigations leading to a deeper understanding of adhesive organ functionality and to the development of new bioinspired materials. Genetic approaches, e.g. the analysis of mutants, to achieve a better understanding of adhesive organ differentiation have not been used so far. Here, we describe the first Drosophila melanogaster mutant that develops malformed adhesive organs, resulting in a complete loss of climbing ability on vertical smooth surfaces. Interestingly, these mutants fail to make close contact between the setal tips and the smooth surface, a crucial condition for wet adhesion mediated by capillary forces. Instead, these flies walk solely on their claws. Moreover, we were able to show that the mutation is caused by a P-element insertion into the Su(z)2 gene locus. Remobilization of the P-element restores climbing ability. Furthermore, we provide evidence that the P-element insertion results in an artificial Su(z)2 transcript, which most likely causes a gain-of-function mutation. We presume that this transcript causes deregulation of yet unknown target genes involved in pulvilli differentiation. Our results nicely demonstrate that the genetically treatable model organism Drosophila is highly suitable for future investigations on adhesive organ differentiation. PMID- 25714572 TI - Use of WHO growth curves for patients with cystic fibrosis may provide a false sense of security. PMID- 25714571 TI - Exercise-induced Natural Killer Cell Activation is Driven by Epigenetic Modifications. AB - Exercise has been proven to reduce the risk and progression of various diseases, such as cancer, diabetes and neurodegenerative disorders. Increasing evidence suggests that exercise affects the cytokine profile and changes distribution and function of tumor-competitive immune cells. Initial studies have shown that different exercise interventions are associated with epigenetic modifications in different tissues and cell types, such as muscle, fat, brain and blood. The present investigation examines the effect of an intense endurance run (half marathon) on global epigenetic modifications in natural killer (NK) cells in 14 cancer patients compared to 14 healthy controls. We were able to show that histone acetylation and NKG2D expression, a functional NK cell marker, were elevated for at least 24 h after the run. Thus, this is the first study to present a potential mechanism of how exercise may impact NK cell activity on the subcellular level. Further studies should focus on epigenetic mechanisms and dose dependent effects of exercise. PMID- 25714573 TI - The vitamin D controversy. PMID- 25714574 TI - Practice patterns of pediatricians and trainees for the management of functional constipation compared with 2006 NASPGHAN guidelines. AB - OBJECTIVES: The North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition has formulated guidelines for managing functional constipation. There have been no studies that have investigated how pediatricians apply the constipation guideline since it was revised in 2006. The purpose of this study was to examine how pediatricians approach functional constipation and how closely their approaches adhere to the guidelines. METHODS: An anonymous multiple-choice questionnaire was developed by general pediatricians and pediatric gastroenterologists. This was distributed to pediatricians and pediatric residents at 7 academic institutions, and to the American Academy of Pediatrics section on medical students, residents, and fellowship trainees mailing list. RESULTS: A total of 1202 responses were received (952 trainees, 250 attendings). Of these, 84.3% reported being unfamiliar/slightly familiar with the guidelines. The most common initial interventions for constipation without fecal incontinence included fluids (92.1%), fiber (89.5%), juice (77.7%), behavioral interventions (71.2%), follow-up (53.4%), and reducing constipating foods (50.1%). The most common initial interventions for constipation with fecal incontinence included bowel cleanout (73.4%), maintenance medication (70.0%), fluids (67.9%), behavioral interventions (67.6%), fiber (66.1%), and follow-up (57.8%). Osmotics were the most commonly prescribed as needed (83.0%) and maintenance medications (96.8%), with stimulants prescribed PRN by 35.6% and as maintenance by 16.8%. Some individuals (39.7%) reported concern that osmotics could result in dependence, addiction, or electrolyte imbalances, compared with 73.0% for stimulants. CONCLUSIONS: Our results show that more education regarding medication in functional constipation is necessary, including the use of medication reducing time to remission, the necessity of disimpaction, and misconceptions regarding adverse effects. PMID- 25714575 TI - Concordant parent-child reports of anxiety predict impairment in youth with functional abdominal pain. AB - BACKGROUND: Functional abdominal pain (FAP) is associated with significant anxiety and impairment. Prior investigations of child anxiety in youth with FAP are generally limited by small sample sizes, based on child report, and use lengthy diagnostic tools. It is unknown whether a brief anxiety-screening tool is feasible, whether parent and child reports of anxiety are congruent, and whether parent and child agreement of child anxiety corresponds to increased impairment. The purpose of this investigation was to examine anxiety characteristics in youth with FAP using parent and child reports. Parent-child agreement of child anxiety symptoms was examined in relation to pain and disability. METHODS: One hundred patients with FAP (8-18 years of age) recruited from pediatric gastroenterology clinics completed measures of pain intensity (Numeric Rating Scale) and disability (Functional Disability Inventory). Patients and caregivers both completed a measure of child anxiety characteristics (Screen for Child Anxiety and Related Disorders). RESULTS: Clinically significant anxiety symptoms were more commonly reported by youth (54%) than their parents (30%). Panic/somatic symptoms, generalized anxiety, and separation anxiety were most commonly endorsed by patients, whereas generalized anxiety, separation anxiety, and school avoidance were most commonly reported by parents. The majority (65%) of parents and children agreed on the presence (26%) or absence (39%) of clinically significant anxiety. Parent-child agreement of clinically significant anxiety was related to increased impairment. CONCLUSIONS: A brief screening instrument of parent and child reports of anxiety can provide clinically relevant information for comprehensive treatment planning in children with FAP. PMID- 25714576 TI - In vivo ultrasound assessment of gastric emptying in newborn mice. AB - OBJECTIVES: The aim of the present study was to develop an ultrasonographic approach to comparatively assess gastric emptying in newborn wild-type and guanosine triphosphate cyclohydrolase knockout hph-1 mice, because we previously reported gastroparesis early in life in this strain. METHODS: Stomach transverse, anteroposterior, and longitudinal ultrasonographic measurements were obtained with a 40-MHz transducer in pups immediately after maternal separation and 4 hours later. A conventional equation was used and the predicted values validated by obtaining postmortem gastric content volume measurements. Wild-type and hph-1 mice gastric emptying rates were comparatively evaluated at 1 to 3 and 5 to 8 days of age, respectively. RESULTS: The ultrasound equation closely predicted the newborn stomach content volumes with a correlation coefficient (R) of 0.93 and 0.81 (P < 0.01) for measurements obtained on full stomach and after 4 hours of fasting, respectively. In wild-type mice, gastric emptying was age dependent and associated with a greater residual volume at 1 to 3 days (65% +/- 7%), as compared with 5- to 8-day-old pups (33% +/- 4%; P < 0.01), after fasting. In contrast, an equal duration of fasting resulted in a significantly greater residual gastric content volume in 5- to 8-day-old hph-1 mice (68% +/- 7%; P < 0.01), as compared with same-age wild-type mice. CONCLUSIONS: Ultrasonography offers a sensitive and accurate estimate of gastric content volume in newborn mice. In wild-type newborn mice, gastric emptying rate is age dependent and significantly reduced in the immediate postnatal period. The newborn hph-1 mice have a significantly higher gastric residual volume, as compared with wild-type same-age animals. PMID- 25714577 TI - Expanding phenotypic and allelic heterogeneity of tricho-hepato-enteric syndrome. AB - Molecular genetics studies are of increasing importance in the diagnosis and classification of congenital diarrheal disorders. We describe the molecular genetic basis of tricho-hepato-enteric syndrome in patients from Saudi Arabia with novel mutations of SKIV2L (c.3559_3579del, p.1187_1193del) and TTC37 (C4102T, p.Q1368X). Interestingly, the congenital presence of cafe-au-lait spots and their distribution in the pelvis and lower limbs were a unique and consistent clinical feature of these patients and may aid differential diagnosis of congenital diarrheal disorders. This study expands allelic and phenotypic heterogeneity of syndromic diarrhea/tricho-hepato-enteric syndrome. PMID- 25714578 TI - Rate of celiac disease in children: view from the endoscopy suite. AB - OBJECTIVES: The low rate of celiac disease diagnosed in children from the United States may be limited by the practice of "serology-led" diagnosis. The frequency of seronegative celiac disease is unknown, but is underestimated in children and may result in misdiagnosis of celiac disease. The aim of the present study was to investigate the rate of celiac disease after upper endoscopy (esophagogastroduodenescopy [EGD]) with no prior positive celiac serology compared with the rate of celiac disease followed by positive serology. METHODS: Charts of all of the first diagnostic EGDs in children (2009-2013) were retrospectively reviewed. Patients with confirmed celiac disease were divided into 4 groups: group A, positive EGD/positive serology (histology-led diagnosis); group B, positive serology/positive histology (serology-led diagnosis); group C, positive histology followed by negative serology (control 1); and group D, positive serology followed by negative histology (control 2). RESULTS: A total of 761 upper endoscopic charts were reviewed. Of these, 15 children were confirmed with celiac disease (1.97%). There was no significant difference in the demographic data or clinical symptoms between group A and group B. No significant difference was observed in the rate of celiac disease between histology-led celiac diagnosis (group A) and serology-led celiac diagnosis (group B) (1.18% vs 0.79%, P = 0.273). CONCLUSIONS: The rate of celiac disease in endoscopy-led diagnosis was comparable to that in the serology-led diagnosis, suggesting that to increase the detection of celiac disease in children, an adequate number of intestinal biopsies should be performed in every diagnostic upper endoscopic procedure. PMID- 25714580 TI - Preservation of biochemical liver function with low-dose soy-based lipids in children with intestinal failure-associated liver disease. AB - OBJECTIVES: Intestinal failure-associated liver disease (IFALD) contributes to significant morbidity in pediatric patients with intestinal failure (IF); however, the use of parenteral nutrition (PN) with a fish oil-based intravenous (IV) emulsion (FO) has been associated with biochemical reversal of cholestasis and improved outcomes. Unfortunately, FO increases the complexity of care: because it can be administered only under Food and Drug Administration compassionate use protocols requiring special monitoring, it is not available as a 3-in-1 solution and is more expensive than comparable soy-based IV lipid emulsion (SO). Because of these pragmatic constraints, a series of patient families were switched to low-dose (1 g kg(-1) day(-1)) SO following biochemical resolution of cholestasis. The present study examines whether reversal of cholestasis and somatic growth are maintained following this transition. METHODS: The present study is a chart review of all children with IFALD who switched from FO to SO following resolution of cholestasis. Variables are presented as medians (interquartile ranges). Comparisons were performed using the Wilcoxon signed-rank test. RESULTS: Seven patients ages 25.9 (16.2-43.2) months were transitioned to SO following reversal of cholestasis using FO. At a median follow-up of 13.9 (4.3 50.1) months, there were no significant differences between pretransition and post-transition serum alanine and aspartate aminotransferases, direct bilirubin, and weight-for-age z scores. Because of recurrence of cholestasis, 1 patient was restarted on FO after 4 months on SO. CONCLUSIONS: Biochemical reversal of IFALD and growth were preserved after transition from FO to SO in 6 of 7 (86%) patients. Given the challenges associated with the use of FO, SO may be a viable alternative in select patients with home PN. PMID- 25714581 TI - Comparison of WHO and CDC growth charts in predicting pulmonary outcomes in cystic fibrosis. AB - OBJECTIVES: The relation of weight-for-length (WFL) and weight-for-age (WFA) measurements with pulmonary function in patients with cystic fibrosis (CF) using the World Health Organization (WHO) growth standards has not been evaluated. The objective of the present study was to show that the relation of WFL and WFA measurements at 2 years with forced expiratory volume in 1 second (FEV1) at 6 to 8 years differs when using the WHO versus the Centers for Disease Control and Prevention (CDC) growth charts. METHODS: We assessed 1155 patients in the CF Foundation Patient Registry born between 2001 and 2004. Comparisons were made between the CDC and WHO growth charts. RESULTS: The WFL percentiles are significantly higher for the WHO growth standards compared with those for the CDC growth charts (median and interquartile range [IQR] WHO--64.8 [41.7-84.9], CDC- 48.1 [23.7-75.7], P < 0.0001). WFL and WFA percentiles at 2 years on both charts are strongly associated with FEV1 at 6 to 8 years of age. The FEV1 at 6 to 8 years was statistically significantly lower for children who were classified as reaching a WFL >= 50 th percentile at 2 years by WHO standards alone versus those who qualified by both growth charts (median and IQR 103 [94-115] vs 107 [96-117], P < 0.05). Continued weight gain between 2 and 6 years was associated with a higher lung function at age 6 to 8 years. CONCLUSIONS: Although children attaining the 50th WFL percentile on the WHO growth chart by age 2 years have a lower FEV1 at 6 years than children attaining the same percentile on the CDC chart, both groups of children attain clinically normal FEV1. Further studies are needed to determine whether this difference is clinically meaningful. PMID- 25714582 TI - Infections in infants fed formula supplemented with bovine milk fat globule membranes. AB - OBJECTIVES: Observational studies have shown that even in high-income countries formula-fed infants have a higher incidence of acute otitis media (AOM), and gastrointestinal and respiratory tract infections during the first year of life compared with breast-fed infants. We hypothesized that components of the milk fat globule membrane (MFGM) may be responsible for some of these differences and that supplementation with bovine MFGM would decrease the infectious morbidity in formula-fed infants. METHODS: In a double-blind randomized controlled trial, 160 formula-fed infants received experimental formula (EF) supplemented with bovine MFGM (EF) or unsupplemented standard formula (SF) from <2 months until 6 months of age. A breast-fed reference group consisted of 80 infants. Disease symptoms, health care contacts, and medication were recorded by the parents until 12 months of age. Serum immunoglobulin G for 10 pneumococcal serotypes was analyzed at 6 months of age. RESULTS: The cumulative incidence of AOM during the intervention was lower in the EF group than in the SF group (1% vs 9%, P = 0.034), and did not differ from the breast-fed reference group (0%, P = 1.0). The incidence (25% vs 43%, P = 0.021) and longitudinal prevalence (P = 0.012) of antipyretic use were significantly lower in the EF group than in the SF group. Serum immunoglobulin G concentrations against pneumococcal serotypes 1, 5, and 14 were lower in the EF group than in the SF group. CONCLUSIONS: Supplementation of formula with bovine MFGM reduces the risk of AOM, decreases antipyretics use in formula-fed infants, and has immunomodulatory effects on humoral response against pneumococcus vaccine. PMID- 25714579 TI - Improvement in liver histology is associated with reduction in dyslipidemia in children with nonalcoholic fatty liver disease. AB - OBJECTIVES: Nonalcoholic fatty liver disease (NAFLD), the most common cause of liver disease among US children, may be associated with cardiovascular disease (CVD) risk. The present study sought to determine the prevalence of dyslipidemia in children with NAFLD and assess dyslipidemia by liver histology and histologic changes. METHODS: Individuals in the Treatment of NAFLD in Children (TONIC) trial were included (N = 173). In the TONIC trial, children with NAFLD were randomized to vitamin E, metformin, or placebo for 96 weeks. Nonalcoholic steatohepatitis (NASH) improved in 56 children. Change in lipid levels from baseline and 96 weeks was compared between patients with and without histologic improvement and with and without NASH. RESULTS: Dyslipidemia was frequent, with low high-density lipoprotein (HDL) (< 40 mg/dL) in 61.8%, hypertriglyceridemia (>= 130 mg/dL) in 50.3%, hypercholesterolemia (>= 200 mg/dL) in 23.7%, elevated low-density lipoprotein (LDL) (>= 130 mg/dL) in 21.5%, elevated non-HDL cholesterol (non-HDL C) (>= 145 mg/dL) in 35.2%, and triglycerides/HDL > 3.0 in 57.2% of patients. Histologic improvement was associated with significant decreases in cholesterol ( 11.4 mg/dL vs -1.9 mg/dL, P = 0.04), LDL (-11.2 mg/dL vs -2.1 mg/dL, P = 0.04), and non-HDL-C (-8.8 mg/dL vs 0.5 mg/dL, P = 0.03) compared with those without improvement. Children with NASH resolution had significant decreases in cholesterol (-10.0 mg/dL vs -0.9 mg/dL, P = 0.02) and non-HDL-C (-7.3 mg/dL vs 1.1 mg/dL, P = 0.01) compared with those without NASH resolution. There was no improvement in triglycerides, HDL level, or triglycerides/HDL ratio in either group. CONCLUSIONS: Dyslipidemia is frequent in children with NAFLD. NASH resolution and histologic improvement are associated with improvements in some forms of dyslipidemia. PMID- 25714583 TI - Coeliac disease screening among a large cohort of overweight/obese children. AB - Coeliac disease (CD) is a chronic, gluten-dependent enteropathy with a prevalence of approximately 1% in Western countries. Up to now, CD has been described only in sporadic cases of obesity. Our study aimed to evaluate retrospectively CD prevalence in a large series of overweight/obese children and adolescents. Among the 1527 overweight/obese children and adolescents consecutively evaluated, 17 (7 boys, 1.11%) were positive for serology and showed villous atrophy. In all of the patients with CD a well-balanced gluten-free diet was started, and a loss of weight rapidly obtained. Our study demonstrates that CD prevalence in overweight/obese children is similar to the general paediatric population in Italy. PMID- 25714584 TI - Anticlockwise swirl: a potential pitfall for malrotation. PMID- 25714585 TI - Authors' response. PMID- 25714586 TI - Psychotropic medications for pediatric functional gastrointestinal disorders. PMID- 25714587 TI - Opportunities and pitfalls of molecular testing for detecting sexually transmitted pathogens. AB - In the last 20 years, nucleic acid amplification tests (NAATs) have gradually replaced traditional methods for the detection of sexually transmitted infections. NAAT technology comes with some considerable benefits for diagnosis, including increased sensitivity, rapid result turnaround and suitability for high throughput screening of asymptomatic individuals using more-readily available specimens. However, the transition to NAAT has not come without its problems. False-negative and false-positive results have been reported owing to various technical issues. Furthermore, increased reliance on NAATs for diagnosis have created the need to develop NAAT-based methods to inform treatment, being an area that presents its own set of challenges. In this review article, we explore NAAT based detection of Chlamydia trachomatis, Neisseria gonorrhoeae, Mycoplasma genitalium and Trichomonas vaginalis. In doing so, we consider the benefits and limitations of NAAT-based technology and highlight areas where further research and development is in need. PMID- 25714588 TI - Rapid identification of pathogens using molecular techniques. AB - Real-time PCR is the traditional face of nucleic acid detection in the diagnostic microbiology laboratory and is now generally regarded as robust enough to be widely adopted. Methods based on nucleic acid detection of this type are bringing increased accuracy to diagnosis in areas where culture is difficult and/or expensive, and these methods are often effective partners to other rapid molecular diagnostic tools such as matrix-assisted laser desorption ionisation time of flight mass spectrometry (MALDI-TOF MS). This change in practice has particularly affected the recognition of viruses and fastidious or antibiotic exposed bacteria, but has been also shown to be effective in the recognition of troublesome or specialised phenotypes such as antiviral resistance and transmissible antibiotic resistance in the Enterobacteriaceae. Quantitation and high-intensity sequencing (of multiple whole genomes) has brought new opportunities as well as new challenges to the microbiology community. Diagnostic microbiologists currently training might be expected to deal less with the culture-based techniques of the last half-century than with the high-volume data and complex analyses of the next. PMID- 25714589 TI - Contemporary molecular approaches in the clinical microbiology laboratory: progress and pitfalls. PMID- 25714590 TI - Evaluation of Immune Restoration Potential of PD-1 Blockers. AB - The programmed death 1 (PD-1) receptor and its primary ligand (PD-L1) have crucial roles in tumor-induced immune suppression. PD-1/PD-L1 blockers are designed to restore the immune system and induce potent antitumor effects. In this study we established a direct and reliable method to evaluate the immune restoration potential of human PD-1 blockers. We found anti-human PD-1 antibody could reverse PD-L1 induced suppression of human CD3+ cells proliferation and IL 2 production. This method is suitable for all kinds of PD-1 blockers including antibodies and chemical drugs. This function assay could be easily applied and provide valuable information for drug development. PMID- 25714591 TI - Innate and adoptive immune cells contribute to natural resistance to systemic metastasis of B16 melanoma. AB - The greatest hurdle in cancer treatment is the metastasis of primary tumors to distant organs. Our knowledge on how different immune cells, in the absence of exogenous stimulation, prevent tumor metastasis in distant organs is poorly understood. Using a highly metastatic murine lung B16 melanoma cell line BL6-10, we employed naive mice that genetically lack CD4(+) or CD8(+) T cells, or are depleted of dendritic cells (DCs) or natural killer (NK) cells to understand the relative importance of these cells in metastasis prevention. Irrespective of the presence of naive CD4(+) T, CD8(+) T, DCs, or NK cells, lungs, which act as primary site of predilection for B16 melanoma, readily developed numerous lung BL6-10 melanoma colonies. However, their absence led to B16 melanoma metastasis in variable proportions to distant organs, particularly livers, kidneys, adrenals, ovaries, and hearts. NK cells mediate prevention of BL6-10 metastasis to various organs, especially to livers. Mechanistically, CD40L signaling, a critical factor required for DC licensing and CD8(+) cytotoxic T lymphocyte (CTL) responses, was required for CD4(+) T cell-mediated prevention of systemic BL6-10 metastasis. These results suggest that the composition and functions of different immune cells in distant tissue microenvironments (distant organs other than primary sites of predilection) robustly mediate natural resistance against melanoma metastasis. Thus, harnessing these immune cells' responses in immunotherapeutics would considerably limit organ metastasis. PMID- 25714592 TI - Space-use behaviour of woodland caribou based on a cognitive movement model. AB - Movement patterns offer a rich source of information on animal behaviour and the ecological significance of landscape attributes. This is especially useful for species occupying remote landscapes where direct behavioural observations are limited. In this study, we fit a mechanistic model of animal cognition and movement to GPS positional data of woodland caribou (Rangifer tarandus caribou; Gmelin 1788) collected over a wide range of ecological conditions. The model explicitly tracks individual animal informational state over space and time, with resulting parameter estimates that have direct cognitive and ecological meaning. Three biotic landscape attributes were hypothesized to motivate caribou movement: forage abundance (dietary digestible biomass), wolf (Canis lupus; Linnaeus, 1758) density and moose (Alces alces; Linnaeus, 1758) habitat. Wolves are the main predator of caribou in this system and moose are their primary prey. Resulting parameter estimates clearly indicated that forage abundance is an important driver of caribou movement patterns, with predator and moose avoidance often having a strong effect, but not for all individuals. From the cognitive perspective, our results support the notion that caribou rely on limited sensory inputs from their surroundings, as well as on long-term spatial memory, to make informed movement decisions. Our study demonstrates how sensory, memory and motion capacities may interact with ecological fitness covariates to influence movement decisions by free-ranging animals. PMID- 25714593 TI - Homocysteine Levels Influence Platelet Reactivity in Coronary Artery Disease Patients Treated With Acetylsalicylic Acid. AB - BACKGROUND: Suboptimal platelet inhibition with antiplatelet treatments is associated with a severe prognosis in patients with coronary artery disease (CAD), and the identification of its determinants is still challenging. Homocysteine elevation has emerged as a prothrombotic factor, influencing coagulative status and endothelial function and potentially modulating platelet aggregation. We therefore aimed to evaluate the effects of homocysteine (Hcy) levels on platelet reactivity in patients receiving acetylsalicylic acid (ASA) with or without ADP antagonists. METHODS: Patients undergoing coronary angiography and receiving ASA (100-160 mg daily) for >7 days, with or without ADP antagonists, were included. Aggregation tests were performed by multiple electrode aggregometry. Suboptimal platelet inhibition was defined as on treatment aggregation above the lower limit of normality. RESULTS: Our population is represented by 508 ASA-treated patients, 406 (80.1%) of whom on dual antiplatelet therapy (ASA and ADP antagonists). Hcy levels above the median (15.1 nmol/mL) were associated with male gender (P = 0.04), hypertension (P = 0.004), hypercholesterolemia (P = 0.03), aging, renal failure (P < 0.001, respectively), previous coronary bypass grafting (P = 0.04), therapy with calcium antagonists (P = 0.04) and diuretics (P = 0.001), and multivessel CAD (P = 0.03). Higher Hcy is directly related with serum creatinine and uric acid (P < 0.001). Suboptimal platelet inhibition was found in 16 patients (3.2%) for ASA and for ADP antagonists in 80 patients (19.7%). Hcy levels significantly affected suboptimal response to ASA, but not to ADP-mediated aggregation. In fact, a linear relationship was found between homocysteine and platelet reactivity after stimulation with arachidonic acid (r = 0.14, P = 0.004) and collagen (r = 0.12, P = 0.02), but not with ADP (r = 0.02, P = 0.77). Moreover, after correction for baseline differences, Hcy above the median was confirmed as an independent predictor of impaired ASA response [adjusted odds ratio (95% confidence interval) = 3.7 (1.08-12.4), P = 0.04]. CONCLUSIONS: Among patients with CAD, elevated homocysteine is an independent predictor of suboptimal response to ASA, but not to ADP antagonists. PMID- 25714594 TI - Gap Junction-associated Na+ Influx Is Involved in the Mediation of Ca2+ Transients in Neonatal Rat Ventricular Myocytes. AB - Gap junction (GJ) coupling is involved in the regulation of spontaneous Ca(2+) transients in neonatal rat ventricular myocytes (NRVMs); however, the underlying mechanism(s) remains incompletely clear. In this study, we investigated Na influx mediated by Cx43-associated GJ modulating the spontaneous NRVM excitation. Intracellular Na(+) and Ca(2+) concentrations ([Na(+)](i) and [Ca(2+)](i)) were assessed using CoroNa Green and Fluo-4 fluorescent probes, respectively, by confocal microscopy. GJ function was evaluated by measuring fluorescence recovery after photobleaching. The results showed that [Na(+)](i) and spontaneous Ca(2+) oscillating were significantly decreased by the treatment of NRVMs with GJ uncouplers or adenovirus-mediated Cx43 gene knockdown using short hairpin RNA, while both of the intracellular cation levels were increased by adenovirus mediated Cx43 overexpression. Neither Na(+) channel blocker (tetrodotoxin) nor the GJ uncoupler (Gap27) or Cx43-short hairpin RNA adenovirus could completely suppress the Ca(2+) transients, but their combination usage could. In addition, Ca(2+) transients disappeared in NRVMs incubated in Na(+)-free, but not in Ca(2+) -free medium, in which the remained transients could be further abolished by Gap27. Collectively, our findings suggest that Cx43-associated GJ function is involved in the regulation of Na(+) influx into cardiomyocytes, which contributes, at least in part, to triggering spontaneous excitation and regulation of cardiomyocyte automaticity. PMID- 25714595 TI - Ayahuasca Alters Structural Parameters of the Rat Aorta. AB - Ayahuasca is a hallucinogenic brew traditionally used by Northwestern Amazonian indigenous groups for therapeutic purposes. It is prepared by the decoction of Banisteriopsis caapi with the leaves of Psychotria viridis. Banisteriopsis caapi contains beta-carbolines that are inhibitors of monoamine oxidase and P. viris is rich in dimethyltryptamine, a 5-HT(1A/2A/2C) agonist. Acute ayahuasca administration produces moderate cardiovascular effects in healthy volunteers, but information regarding long-term use is lacking. This study investigated the effects of ayahuasca (2-4 mL/kg) in the rat aorta after acute and chronic (14 days) administration. Ayahuasca caused flattening and stretching of vascular smooth muscle cells and changes in the arrangement and distribution of collagen and elastic fibers. Chronic treatment with the higher dose significantly increased media thickness and the ratio of media thickness to lumen diameter. More research is needed on the cardiovascular function of long-term ayahuasca consumers. PMID- 25714596 TI - Impact of Enhanced Production of Endogenous Heme Oxygenase-1 by Pitavastatin on Survival and Functional Activities of Bone Marrow-derived Mesenchymal Stem Cells. AB - Although mesenchymal stem cells (MSCs) have a therapeutic potential for the repair of tissue injuries, their poor viability in damaged tissue limits their effectiveness. Statins can induce an increased production of heme oxygenase-1 (HO 1), which may prevent this detrimental effect in MSCs. We investigated the protective effect of statin-induced overexpression of HO-1 by examining changes in gene expression and function in MSCs after pitavastatin treatment. The relative expression of the HO-1 and endothelial nitric oxide synthase genes in MSCs was significantly increased after treatment with pitavastatin (MSCs). Immunocytological analysis showed that MSCs also stained with phospho-Akt. After exposure to oxidative stress, MSCs showed increased resistance to induced cell death compared with control MSCs. Under serum starvation conditions, MSCs treated with 1 MUM pitavastatin showed enhanced cell proliferation and a marked increase in vascular endothelial growth factor production compared with control MSCs. Interestingly, MSCs showed enhanced tube formation under both normoxia and hypoxia. These results demonstrate that pitavastatin can enhance endogenous HO-1 expression in MSCs, which may protect the cells into the environment of oxidative stress with partial activation of endothelial nitric oxide synthase and Akt phosphorylation. PMID- 25714597 TI - Endothelial NO Production Is Mandatory for Epigallocatechin-3-Gallate-induced Vasodilation: Results From eNOS Knockout (eNOS-/-) Mice. AB - The underlying mechanisms for the vasodilating effects of the tea catechin epigallocatechin-3-gallate (EGCG) are still not fully understood. Besides nitric oxide (NO)-dependent effects, other modes of action are discussed. To elucidate whether the NO pathway is a prerequisite in mediating vasodilating effects, we investigated EGCG-induced vasorelaxation in isolated aortic rings of endothelial nitric oxide knockout (eNOS) mice. Vasodilation to acetylcholine was fully prevented in aortic rings of eNOS mice, confirming lack of vascular NO production. Vasodilation to the exogenous NO donor sodium nitroprusside was preserved in eNOS mice aortic rings. Low concentrations of EGCG (5-15 uM) resulted in strong vasorelaxation in aortic rings of wild type mice, whereas it was completely absent in eNOS mice. In corroboration, relaxation in response to green tea was significantly inhibited in aortic rings of eNOS mice. These results demonstrate that EGCG-induced vasodilation strongly relies on functional NO synthase in endothelial cells and subsequent stimulation of NO production in vessels. PMID- 25714598 TI - First-in-Man Study With Inclacumab, a Human Monoclonal Antibody Against P selectin. AB - Inclacumab, a novel monoclonal antibody against P-selectin in development for the treatment and prevention of atherosclerotic cardiovascular diseases, was administered in an ascending single-dose study as intravenous infusion to evaluate safety, pharmacokinetics, and pharmacodynamics. Fifty-six healthy subjects were enrolled in this randomized, double-blind placebo-controlled study. Each dose level (0.03-20 mg/kg) was investigated in separate groups of 8 subjects (6 on inclacumab, 2 on placebo). Platelet-leukocyte aggregates, free/total soluble P-selectin concentration ratio, drug concentrations, bleeding time, platelet aggregation, antibody formation, and routine laboratory parameters were measured frequently until 32 weeks. Pharmacokinetic profiles were indicative of target-mediated drug disposition. Platelet-leukocyte aggregate inhibition and soluble P-selectin occupancy showed dose dependency and were strongly correlated to inclacumab plasma concentrations, with IC50 of 740 and 4600 ng/mL, respectively. Inclacumab was well tolerated by the majority of subjects and did neither affect bleeding time nor platelet aggregation. These findings allowed the investigation of the potential beneficial therapeutic use of inclacumab in patient study. PMID- 25714600 TI - Ivabradine in Cardiovascular Disease: Heart Rate Isn't Everything. PMID- 25714599 TI - Probucol Protects Against Atherosclerosis Through Lipid-lowering and Suppressing Immune Maturation of CD11c+ Dendritic Cells in STZ-induced Diabetic LDLR-/- Mice. AB - Probucol, an agent characterized by lipid-lowering and antioxidant property, retards atherosclerosis effectively. To test the hypothesis that probucol might act its antiatherosclerotic role by suppressing immune maturation of dendritic cells (DCs), 7-week-old LDLR mice were rendered diabetic with streptozotocin (STZ) and then fed either a high-fat diet only or added with 0.5% (wt/wt) probucol for 4 months, and human monocyte-derived dendritic cells were preincubated with or without probucol and stimulated by oxidized low-density lipoprotein. In STZ-induced diabetic LDLR mice, probucol treatment significantly lowered plasma total cholesterol and high-density lipoprotein-cholesterol levels; regressed aortic atherosclerotic lesions; reduced splenic CD40, CD80, CD86, MHC II expression, and plasma IL-12p70 production; and decreased the expression of CD11c DCs within atherosclerotic lesions. In vitro, oxidized low-density lipoprotein promoted human monocyte-derived dendritic cells maturation; stimulated CD40, CD86, CD1a, HLA-DR expression; increased tumor necrosis factor alpha production; and decreased IL-4 production. However, these effects were obviously inhibited by probucol pretreatment. In conclusion, our study indicated that probucol effectively retarded atherosclerosis at least partly through lipid lowering and inhibiting immune maturation of CD11c DCs in STZ-induced diabetic LDLR mice. PMID- 25714601 TI - Kuala Lumpur emerging in vascular biology. PMID- 25714602 TI - Pain intensity and cervical range of motion in women with myofascial pain treated with acupuncture and electroacupuncture: a double-blinded, randomized clinical trial. AB - BACKGROUND: Acupuncture stimulates points on the body, influencing the perception of myofascial pain or altering physiologic functions. OBJECTIVE: The aim was to evaluate the effect of electroacupuncture (EAC) and acupuncture (AC) for myofascial pain of the upper trapezius and cervical range of motion, using SHAM acupuncture as control. METHOD: Sixty women presenting at least one trigger point at the upper trapezius and local or referred pain for more than six months were randomized into EAC, AC, and SHAM groups. Eight sessions were scheduled and a follow-up was conducted after 28 days. The Visual Analog Scale assessed the intensity of local and general pain. A fleximeter assessed cervical movements. Data were analyzed using paired t or Wilcoxon's tests, ANOVA or Friedman or Kruskal-Wallis tests and Pearson's correlation (alpha=0.05). RESULTS: There was reduction in general pain in the EAC and AC groups after eight sessions (P<0.001). A significant decrease in pain intensity occurred for the right trapezius in all groups and for the left trapezius in the EAC and AC groups. Intergroup comparisons showed improvement in general pain in the EAC and AC groups and in local pain intensity in the EAC group (P<0.05), which showed an increase in left rotation (P=0.049). The AC group showed increases in inclination (P=0.005) sustained until follow-up and rotation to the right (P=0.032). CONCLUSION: EAC and AC were effective in reducing the pain intensity compared with SHAM. EAC was better than AC for local pain relief. These treatments can assist in increasing cervical range of motion, albeit subtly. PMID- 25714603 TI - Spatiotemporal gait parameters and recurrent falls in community-dwelling elderly women: a prospective study. AB - BACKGROUND: Falling is a common but devastating and costly problem of aging. There is no consensus in the literature on whether the spatial and temporal gait parameters could identify elderly people at risk of recurrent falls. OBJECTIVE: To determine whether spatiotemporal gait parameters could predict recurrent falls in elderly women. METHOD: One hundred and forty-eight elderly women (65-85 years) participated in this study. Seven spatiotemporal gait parameters were collected with the GAITRite(r) system. Falls were recorded prospectively during 12 months through biweekly phone contacts. Elderly women who reported two or more falls throughout the follow-up period were considered as recurrent fallers. Principal component analysis (PCA) and discriminant analysis followed by biplot graph interpretation were applied to the gait parameters. RESULTS: After 12 months, 23 elderly women fell twice or more and comprised the recurrent fallers group and 110 with one or no falls comprised the non-recurrent fallers group. PCA resulted in three components that explained 88.3% of data variance. Discriminant analysis showed that none of the components could significantly discriminate the groups. However, visual inspection of the biplot showed a trend towards group separation in relation to gait velocity and stance time. PC1 represented gait rhythm and showed that recurrent fallers tend to walk with lower velocity and cadence and increased stance time in relation to non-recurrent fallers. CONCLUSIONS: The analyzed spatiotemporal gait parameters failed to predict recurrent falls in this sample. The PCA-biplot technique highlighted important trends or red flags that should be considered when evaluating recurrent falls in elderly females. PMID- 25714605 TI - Your own sweet time: discontinuing ventilator support at home. PMID- 25714604 TI - Do lambs perceive regular human stroking as pleasant? Behavior and heart rate variability analyses. AB - Stroking by humans is beneficial to the human-animal relationship and improves welfare in many species that express intraspecific allogrooming, but very few studies have looked at species like sheep that do not express such contact except around parturition. This study investigated the way lambs perceive regular human tactile contact using behavioral and physiological responses. Twenty-four lambs were reared and bucket-fed in groups of four. All were stroked daily by their familiar caregiver. At 8 weeks of age, the lambs were individually tested in their home pen but in a 1*1m open-barred pen after a 15 h period of habituation to physical separation from peers while remaining in visual and auditory contact. Half of the lambs received stroking by their caregiver for 8 min and half were exposed to their caregiver's immobile presence. Heart rate and heart rate variability were recorded and analyzed by 2-min slots over the same interval based on three measures: mean heart rate value (HR), root mean square of successive differences (RMSSD) and standard deviation of all intervals measured between consecutive sinus beats (SDNN). Behavioral responses (ear postures of the lamb and time spent in contact with the familiar caregiver, on the knees of the familiar caregiver, and moving) were recorded throughout the test. Lamb HR decreased continuously while in the presence of their caregiver. Lambs being stroked showed slower HR and higher RMSSD which reflected positive emotional states compared to lambs left unstroked. All behavioral variables were highly correlated with the main component axis of the PCA analyses: the more the animals stayed in contact with their caregiver, the less they moved and the more their ears were hanging. This first component clearly differentiates lambs being stroked or not. Behavioral and physiological observations support the hypothesis that gentle physical contact with the caregiver is perceived positively by lambs. PMID- 25714606 TI - Effects of toxic compounds in Montipora capitata on exogenous and endogenous zooxanthellae performance and fertilization success. AB - Studies have identified chemicals within the stony coral genus Montipora that have significant biological activities. For example, Montiporic acids A and B and other compounds have been isolated from the adult tissue and eggs of Montipora spp. and have displayed antimicrobial activity and cytotoxicity in cultured cells. The ecological role of these toxic compounds is currently unclear. This study examines the role these toxins play in reproduction. Toxins were found in the eggs and larvae of the coral Montipora capitata. Releasing these toxins by crushing both the eggs and larvae resulted in irreversible inhibition of photosynthesis in endogenous and exogenous zooxanthellae within minutes. Moreover, these toxins were stable, as frozen storage of eggs and larvae did not affect toxicity. Photosynthetic competency of Porites compressa zooxanthellae treated with either frozen or fresh, crushed eggs was inhibited similarly (P > 0.05, ANCOVA). Addition of toxic eggs plugs to live P. compressa fragments caused complete tissue necrosis under the exposed area on the fragments within 1 week. Small volumes of M. capitata crushed eggs added to sperm suspensions reduced in vitro fertilization success by killing the sperm. After 30 min, untreated sperm maintained 90 +/- 1.9% SEM motility while those treated with crushed eggs were rendered immotile, 4 +/- 1.4% SEM. Flow cytometry indicated membrane disruption of the immotile sperm. Fertilization success using untreated sperm was 79 +/- 4% SEM, whereas the success rate dropped significantly after exposure to the crushed eggs, 1.3 +/- 0% SEM. Unlike the eggs and the larvae, M. capitata sperm did not reduce the photosynthetic competency of P. compressa zooxanthellae, suggesting the sperm was nontoxic. The identity of the toxins, cellular mechanism of action, advantage of the toxins for M. capitata and their role on the reef are still unknown. PMID- 25714607 TI - Performance of the First Step of the 2-Step Dermoscopy Algorithm. AB - IMPORTANCE: The 2-step dermoscopy algorithm aims to guide the decision-making process to biopsy or not biopsy a skin lesion by providing the most probable diagnosis via a systematic approach. OBJECTIVE: To evaluate the diagnostic accuracy and potential limitations of the first step (to differentiate melanocytic from nonmelanocytic lesions) of the 2-step dermoscopy algorithm. DESIGN, SETTING, AND PARTICIPANTS: Retrospective study in a clinical practice of one dermatologist of biopsy data of all skin lesions from one clinic during a 10 year period. The prebiopsy and histopathology diagnoses were classified as melanocytic or nonmelanocytic. MAIN OUTCOMES AND MEASURES: The diagnostic accuracy, sensitivity, specificity, positive predictive value, and negative predictive value for the first step were estimated using the histopathological lesion classifications as the standard. RESULTS: The sensitivity of the first step for correctly identifying melanocytic lesions was 85%, and the specificity was 94%. Approximately 7% of all lesions (667 of 9168) had discordant classifications, with 415 (4.5%) being false-positive lesions (clinically classified as melanocytic and histopathologically classified as nonmelanocytic) and 252 (2.7%) being false negatives (clinically classified as nonmelanocytic and histopathologically classified as melanocytic). Common classification errors included intradermal nevus misclassified as basal cell carcinoma and nonmelanocytic lesions (eg, seborrheic keratosis, lichen planus-like keratosis, basal cell carcinomas) misclassified as melanocytic because they mimic melanoma. Clinically, 8 of 381 melanomas were misclassified as nonmelanocytic (primarily as pigmented basal cell carcinomas and squamous cell carcinomas). CONCLUSIONS AND RELEVANCE: The 2-step dermoscopy algorithm, including its first step, has high sensitivity, specificity, and accuracy and can be relied on to provide an accurate and specific prebiopsy diagnosis and to help guide management decisions. Some lesions had a higher chance of being misclassified, with the most common being intradermal nevi. This algorithm helps toward maximizing the detection of skin cancer to ensure that malignant lesions are not missed and aims at making more precise clinical diagnoses. PMID- 25714608 TI - How do "mute" cicadas produce their calling songs? AB - Insects have evolved a variety of structures and mechanisms to produce sounds, which are used for communication both within and between species. Among acoustic insects, cicada males are particularly known for their loud and diverse sounds which function importantly in communication. The main method of sound production in cicadas is the tymbal mechanism, and a relative small number of cicada species possess both tymbal and stridulatory organs. However, cicadas of the genus Karenia do not have any specialized sound-producing structures, so they are referred to as "mute". This denomination is quite misleading, as they indeed produce sounds. Here, we investigate the sound-producing mechanism and acoustic communication of the "mute" cicada, Karenia caelatata, and discover a new sound production mechanism for cicadas: i.e., K. caelatata produces impact sounds by banging the forewing costa against the operculum. The temporal, frequency and amplitude characteristics of the impact sounds are described. Morphological studies and reflectance-based analyses reveal that the structures involved in sound production of K. caelatata (i.e., forewing, operculum, cruciform elevation, and wing-holding groove on scutellum) are all morphologically modified. Acoustic playback experiments and behavioral observations suggest that the impact sounds of K. caelatata are used in intraspecific communication and function as calling songs. The new sound-production mechanism expands our knowledge on the diversity of acoustic signaling behavior in cicadas and further underscores the need for more bioacoustic studies on cicadas which lack tymbal mechanism. PMID- 25714609 TI - Retinol improves in vitro differentiation of pre-pubertal mouse spermatogonial stem cells into sperm during the first wave of spermatogenesis. AB - Testicular tissue freezing has been proposed for fertility preservation in pre pubertal boys. Thawed frozen testicular tissue must undergo a maturation process to restore sperm production. The purpose of the current study was to evaluate the ability of retinol to improve the in vitro differentiation of pre-pubertal mouse spermatogonial stem cells into sperm. Testes from pre-pubertal mice, aged 2.5 and 6.5 days post-partum, were cultured on agarose gel at a gas-liquid interphase for 34, 38 and 60 days (D) and for 16, 30 and 36 D respectively. Assessment of basal medium (BM) supplemented with retinol (RE) alone, FSH/LH alone or a combination of both, was performed. Stereological analyses and tissue lesion scoring were performed at the culture time points indicated above. Sperm production was quantified at D30 and D34 after mechanical dissection of the testicular tissues. FSH/LH significantly increased the percentage of round spermatids at D30 and D38, when compared to BM alone. However, RE significantly increased the percentages of round but also elongated spermatids at D30 and D34. Moreover, RE significantly increased the number of spermatozoa per milligram of tissue at D30 and D34 when compared to BM. Therefore, RE improved the in vitro production of spermatids and spermatozoa from pre-pubertal SSCs during the first wave of spermatogenesis. The use of RE could be a useful tool for in vitro spermatogenesis from pre-pubertal human testicular tissue. PMID- 25714610 TI - Wnt antagonist secreted frizzled-related protein 4 upregulates adipogenic differentiation in human adipose tissue-derived mesenchymal stem cells. AB - With more than 1.4 billion overweight or obese adults worldwide, obesity and progression of the metabolic syndrome are major health and economic challenges. To address mechanisms of obesity, adipose tissue-derived mesenchymal stem cells (ADSCs) are being studied to detail the molecular mechanisms involved in adipogenic differentiation. Activation of the Wnt signalling pathway has inhibited adipogenesis from precursor cells. In our study, we examined this anti adipogenic effect in further detail stimulating Wnt with lithium chloride (LiCl) and 6-bromo indirubin 3'oxime (BIO). We also examined the effect of Wnt inhibition using secreted frizzled-related protein 4 (sFRP4), which we have previously shown to be pro-apoptotic, anti-angiogenic, and anti-tumorigenic. Wnt stimulation in LiCl and BIO-treated ADSCs resulted in a significant reduction (2.7-fold and 12-fold respectively) in lipid accumulation as measured by Oil red O staining while Wnt inhibition with sFRP4 induced a 1.5-fold increase in lipid accumulation. Furthermore, there was significant 1.2-fold increase in peroxisome proliferator-activated receptor gamma (PPARgamma) and CCAAT/enhancer binding protein alpha (C/EBPalpha), and 1.3-fold increase in acetyl CoA carboxylase protein levels. In contrast, the expression of adipogenic proteins (PPARgamma, C/EBPalpha, and acetyl CoA carboxylase) were decreased significantly with LiCl (by 1.6, 2.6, and 1.9-fold respectively) and BIO (by 7, 17, and 5.6-fold respectively) treatments. These investigations demonstrate interplay between Wnt antagonism and Wnt activation during adipogenesis and indicate pathways for therapeutic intervention to control this process. PMID- 25714611 TI - "Repurposing" of Xanthine Oxidoreductase as a Nitrite Reductase: A New Paradigm for Therapeutic Targeting in Hypertension. AB - SIGNIFICANCE: In contrast to nitric oxide (NO), which has well-established, important effects in regulation of cardiovascular homeostasis, its oxidative metabolite nitrite has, until recently, been considered to be of minor functional significance. RECENT ADVANCES: However, this view of nitrite has been radically revised over the past 10 years with evidence now supporting a critical role for this anion as a storage form of NO. CRITICAL ISSUES: Importantly, while hypoxia and acidosis have been shown to play a pivotal role in the generation of nitrite to NO, a number of mammalian nitrite reductases have been identified that facilitate the reduction of nitrite. Critically, these nitrite reductases have been demonstrated to operate under physiological pH conditions and in normoxia, extending the functional remit of this anion from an ischemic mediator to an important regulator of physiology. One particular nitrite reductase that has been shown to operate under a wide range of environmental conditions is the enzyme xanthine oxidoreductase (XOR). FUTURE DIRECTIONS: In this review, we discuss the evidence supporting a role for XOR as a nitrite reductase while focusing particularly on its function in hypertension. In addition, we discuss the potential merit in exploiting this activity of XOR in the therapeutics of hypertension. PMID- 25714612 TI - L-ascorbic acid 2-phosphate and fibroblast growth factor-2 treatment maintains differentiation potential in bone marrow-derived mesenchymal stem cells through expression of hepatocyte growth factor. AB - l-ascorbic acid 2-phosphate (Asc-2P) acts as an antioxidant and a stimulator of hepatocyte growth factor (HGF) production. Previously, we reported that depletion of growth factors such as fibroblast growth factor (FGF)-2, epidermal growth factor (EGF), FGF-4 and HGF during serial passage could induce autophagy, senescence and down-regulation of stemness (proliferation via FGF-2/-4 and differentiation via HGF). In this study, we investigated the proliferation and differentiation potential of BMSCs by FGF-2 and Asc-2P. Co-treatment with FGF-2 and Asc-2P induced optimal proliferation of BMSCs and increased the accumulation rate of BMSC numbers during a 2-month culture period. Moreover, differentiation potential was maintained by co-treatment with FGF-2 and Asc-2P via HGF expression. Adipogenic differentiation potential by FGF-2 and Asc-2P was dramatically suppressed by c-Met inhibitors (SU11274). These data suggest that co treatment with FGF-2 and Asc-2P would be beneficial in obtaining BMSCs that possess "stemness" during long-term culture. PMID- 25714613 TI - The immune suppressive function of transforming growth factor-beta (TGF-beta) in human diseases. AB - Transforming growth factor-beta (TGF-beta) functions as an immune suppressor by influencing immune cells' development, differentiation, tolerance induction and homeostasis. In human diseases, TGF-beta has been revealed as an essential regulator of both innate and adaptive functions in autoimmune diseases. Furthermore, it plays a significant role in cancer by inhibiting immunosurveillance in the tumor-bearing host. A variety of TGF-beta neutralizing anti-cancer therapies have been investigated based on the role of TGF-beta in immunosuppression. New studies are focusing on combining TGF-beta blockade with tumor vaccinations and immunogene therapies. PMID- 25714614 TI - Asymmetry in food handling behavior of a tree-dwelling rodent (Sciurus vulgaris). AB - Asymmetry in motor patterns is present in a wide variety of animals. Many lateralized behaviors seem to depend on brain asymmetry, as it is the case of different tasks associated to food handling by several bird and mammal species. Here, we analyzed asymmetry in handling behavior of pine cones by red squirrels (Sciurus vulgaris). Red squirrels devote most of their daily activity to feeding, thus this species constitutes an appropriate model for studying asymmetry in food processing. We aimed to explore 1) the potential lateralization in handling of pine cones by squirrels, 2) the dominant pattern for this behavior (left- vs. right-handed), and 3) whether this pattern varies among populations and depending on the pine tree species available. Results revealed that red squirrels handle pine cones in an asymmetrical way, and that direction of asymmetry varies among populations and seems to be determined more by local influences rather than by the pine tree species. PMID- 25714616 TI - Oxygen nonstoichiometry and thermodynamic characterization of Zr doped ceria in the 1573-1773 K temperature range. AB - This work encompasses the thermodynamic characterization and critical evaluation of Zr(4+) doped ceria, a promising redox material for the two-step solar thermochemical splitting of H2O and CO2 to H2 and CO. As a case study, we experimentally examine 5 mol% Zr(4+) doped ceria and present oxygen nonstoichiometry measurements at elevated temperatures ranging from 1573 K to 1773 K and oxygen partial pressures ranging from 4.50 * 10(-3) atm to 2.3 * 10( 4) atm, yielding higher reduction extents compared to those of pure ceria under all conditions investigated, especially at the lower temperature range and at higher pO2. In contrast to pure ceria, a simple ideal solution model accounting for the formation of isolated oxygen vacancies and localized electrons accurately describes the defect chemistry. Thermodynamic properties are determined, namely: partial molar enthalpy, entropy, and Gibbs free energy. In general, partial molar enthalpy and entropy values of Zr(4+) doped ceria are lower. The equilibrium hydrogen yields are subsequently extracted as a function of the redox conditions for dopant concentrations as high as 20%. Although reduction extents increase greatly with dopant concentration, the oxidation of Zr(4+) doped ceria is thermodynamically less favorable compared to pure ceria. This leads to substantially larger temperature swings between reduction and oxidation steps, ultimately resulting in lower theoretical solar energy conversion efficiencies compared to ceria under most conditions. In effect, these results point to the importance of considering oxidation thermodynamics in addition to reduction when screening potential redox materials. PMID- 25714615 TI - A randomised controlled trial of azithromycin therapy in bronchiolitis obliterans syndrome (BOS) post lung transplantation. AB - BACKGROUND: We conducted a placebo-controlled trial of azithromycin therapy in bronchiolitis obliterans syndrome (BOS) post lung transplantation. METHODS: We compared azithromycin (250 mg alternate days, 12 weeks) with placebo. Primary outcome was FEV1 change at 12 weeks. RESULTS: 48 patients were randomised; (25 azithromycin, 23 placebo). It was established, post randomisation that two did not have BOS. 46 patients were analysed as intention to treat (ITT) with 33 'Completers'. ITT analysis included placebo patients treated with open-label azithromycin after study withdrawal. OUTCOME: The ITT analysis (n=46, 177 observations) estimated mean difference in FEV1 between treatments (azithromycin minus placebo) was 0.035 L, with a 95% CI of -0.112 L to 0.182 L (p=0.6). Five withdrawals, who were identified at the end of the study as having been randomised to placebo (four with rapid loss in FEV1, one withdrawn consent) had received rescue open-label azithromycin, with improvement in subsequent FEV1 at 12 weeks. Study Completers showed an estimated mean difference in FEV1 between treatment groups (azithromycin minus placebo) of 0.278 L, with 95% CI for the mean difference: 0.170 L to 0.386 L (p=<0.001). Nine of 23 ITT patients in the azithromycin group had >=10% gain in FEV1 from baseline. No patients in the placebo group had >=10% gain in FEV1 from baseline while on placebo (p=0.002). Seven serious adverse events, three azithromycin, four in the placebo group, were deemed unrelated to study medication. CONCLUSIONS: Azithromycin therapy improves FEV1 in patients with BOS and appears superior to placebo. This study strengthens evidence for clinical practice of initiating azithromycin therapy in BOS. TRIAL REGISTRATION NUMBER: EU-CTR, 2006-000485-36/GB. PMID- 25714617 TI - Real-world variability in dabigatran levels in patients with atrial fibrillation: comment. PMID- 25714618 TI - Olive Leaf Extract Elevates Hepatic PPAR alpha mRNA Expression and Improves Serum Lipid Profiles in Ovariectomized Rats. AB - We hypothesized that olive leaf extract might alleviate dyslipidemia resulting from estrogen deficiency. Serum lipid profile and mRNA expression of the related genes in the liver and adipose tissue were analyzed after providing olive leaf extract (200 or 400 mg/kg body weight; n=7 for each group) to ovariectomized rats for 10 weeks. After 10 weeks' administration, the rats in the olive leaf extract administered groups showed significantly lower levels of serum triglyceride and very-low-density lipoprotein (VLDL)-cholesterol compared with the rats in the control group, whereas the administration of olive leaf extract did not significantly change the elevated low-density lipoprotein cholesterol levels. In addition, administration of high dose of olive leaf extract significantly decreased the liver triglyceride and increased serum estradiol levels. mRNA expressions of peroxisome proliferator-activated receptor alpha (PPAR alpha) and acyl-CoA oxidase (ACO) were not affected by ovariectomy, however, administration of olive leaf extract significantly increased both PPAR alpha and ACO mRNA expression. Expression of adiponectin mRNA in adipose tissue was significantly decreased in the ovariectomized control group. Rats administered low-dose olive leaf extract showed significantly elevated adiponectin mRNA expression compared with rats in the ovariectomized control group. Even though dose-dependent effects were not observed in most of the measurements, these results suggest that genes involved in lipid metabolism may be regulated by olive leaf extract administration in ovariectomized rats. PMID- 25714621 TI - Electrochemical water oxidation by in situ-generated copper oxide film from [Cu(TEOA)(H2O)2][SO4] complex. AB - Although many noble-metal oxide catalysts show high activities and low overpotentials for water oxidation, there remain challenges in the sustainable developments of more inexpensive, efficient, and robust catalysts. Here, we report a heterogeneous copper oxide film toward water oxidation formed upon the oxidative polarization of an acetate electrolyte containing Earth-abundant Cu(II) salts in combination with commercially available triethanolamine (TEOA) as the catalyst precursor. A 1:1 molar ratio of TEOA coordinates to Cu(II) is favored in aqueous solution and the single crystal of the complex was obtained. The film has a modest overpotential of 550 mV and the catalytic performance of the material is demonstrated by long-term electrolysis at 1.3 V vs normal hydrogen electrode, a stable current density persists for at least 3 h, and a Faradaic efficiency of almost 100% is obtained. PMID- 25714620 TI - A rapid and high content assay that measures cyto-ID-stained autophagic compartments and estimates autophagy flux with potential clinical applications. AB - The lack of a rapid and quantitative autophagy assay has substantially hindered the development and implementation of autophagy-targeting therapies for a variety of human diseases. To address this critical issue, we developed a novel autophagy assay using the newly developed Cyto-ID fluorescence dye. We first verified that the Cyto-ID dye specifically labels autophagic compartments with minimal staining of lysosomes and endosomes. We then developed a new Cyto-ID fluorescence spectrophotometric assay that makes it possible to estimate autophagy flux based on measurements of the Cyto-ID-stained autophagic compartments. By comparing to traditional autophagy approaches, we found that this assay yielded a more sensitive, yet less variable, quantification of the stained autophagic compartments and the estimate of autophagy flux. Furthermore, we tested the potential application of this autophagy assay in high throughput research by integrating it into an RNA interference (RNAi) screen and a small molecule screen. The RNAi screen revealed WNK2 and MAP3K6 as autophagy-modulating genes, both of which inhibited the MTOR pathway. Similarly, the small molecule screen identified sanguinarine and actinomycin D as potent autophagy inducers in leukemic cells. Moreover, we successfully detected autophagy responses to kinase inhibitors and chloroquine in normal or leukemic mice using this assay. Collectively, this new Cyto-ID fluorescence spectrophotometric assay provides a rapid, reliable quantification of autophagic compartments and estimation of autophagy flux with potential applications in developing autophagy-related therapies and as a test to monitor autophagy responses in patients being treated with autophagy-modulating drugs. PMID- 25714622 TI - Enteric polymer based on pH-responsive aliphatic polycarbonate functionalized with vitamin E to facilitate oral delivery of tacrolimus. AB - To improve the bioavailability of orally administered drugs, we synthesized a pH sensitive polymer (poly(ethylene glycol)-poly(2-methyl-2-carboxyl-propylene carbonate)-vitamin E, mPEG-PCC-VE) attempting to integrate the advantages of enteric coating and P-glycoprotein (P-gp) inhibition. The aliphatic polycarbonate chain was functionalized with carboxyl groups and vitamin E via postpolymerization modification. Optimized by comparison and central composite design, mPEG113-PCC32-VE4 exhibited low critical micelle concentration of 1.7 * 10(-6) mg/mL and high drug loading ability for tacrolimus (21.2% +/- 2.7%, w/w). The pH-responsive profile was demonstrated by pH-dependent swelling and in vitro drug release. Less than 4.0% tacrolimus was released under simulated gastric fluid after 2.5 h, whereas an immediate release was observed under simulated intestinal fluid. The mPEG113-PCC32-VE4 micelles significantly increased the absorption of P-gp substrate tacrolimus in the whole intestine. The oral bioavailability of tacrolimus micelles was 6-fold higher than that of tacrolimus solution in rats. This enteric polymer therefore has the potential to become a useful nanoscale carrier for oral delivery of drugs. PMID- 25714619 TI - Heat shock response and autophagy--cooperation and control. AB - Protein quality control (proteostasis) depends on constant protein degradation and resynthesis, and is essential for proper homeostasis in systems from single cells to whole organisms. Cells possess several mechanisms and processes to maintain proteostasis. At one end of the spectrum, the heat shock proteins modulate protein folding and repair. At the other end, the proteasome and autophagy as well as other lysosome-dependent systems, function in the degradation of dysfunctional proteins. In this review, we examine how these systems interact to maintain proteostasis. Both the direct cellular data on heat shock control over autophagy and the time course of exercise-associated changes in humans support the model that heat shock response and autophagy are tightly linked. Studying the links between exercise stress and molecular control of proteostasis provides evidence that the heat shock response and autophagy coordinate and undergo sequential activation and downregulation, and that this is essential for proper proteostasis in eukaryotic systems. PMID- 25714624 TI - Hyperglycaemia and lipid differentially impair mouse oocyte developmental competence. AB - Maternal diabetes and obesity are characterised by elevated blood glucose, insulin and lipids, resulting in upregulation of specific fuel-sensing and stress signalling pathways. Previously, we demonstrated that, separately, upregulation of the hexosamine biosynthetic pathway (HBP; under hyperglycaemic conditions) and endoplasmic reticulum (ER) stress (due to hyperlipidaemia) pathways reduce blastocyst development and alter oocyte metabolism. In order to begin to understand how both glucose and lipid metabolic disruptions influence oocyte developmental competence, in the present study we exposed mouse cumulus-oocyte complexes to hyperglycaemia (30mM) and/or lipid (40MUM) and examined the effects on embryo development. The presence of glucosamine (GlcN; a hyperglycaemic mimetic) or increased lipid during in vitro maturation severely perturbed blastocyst development (P<0.05). Hyperglycaemia, GlcN and hyperglycaemia + lipid treatments significantly increased HBP activity, increasing total O-linked glycosylation (O-GlcNAcylation) of proteins (P<0.0001). All treatments also induced ER stress pathways, indicated by the expression of specific ER stress genes. The expression of genes encoding the HBP enzymes glutamine:fructose-6 phosphate amidotransferase 2 (Gfpt2) and O-linked beta-N acetylglucosaminyltransferase (Ogt) was repressed following lipid treatment (P<0.001). These findings partially implicate the mechanism of O-GlcNAcylation and ER stress as likely contributors to compromised fertility of obese women. PMID- 25714623 TI - Human biosample authentication using the high-throughput, cost-effective SNPtrace(TM) system. AB - Cell lines are the foundation for much of the fundamental research into the mechanisms underlying normal biologic processes and disease mechanisms. It is estimated that 15%-35% of human cell lines are misidentified or contaminated, resulting in a huge waste of resources and publication of false or misleading data. Here we evaluate a panel of 96 single-nucleotide polymorphism (SNP) assays utilizing Fluidigm microfluidics technology for authentication and sex determination of human cell lines. The SNPtrace Panel was tested on 907 human cell lines. Pairwise comparison of these data show the SNPtrace Panel discriminated among identical, related and unrelated pairs of samples with a high degree of confidence, equivalent to short tandem repeat (STR) profiling. We also compared annotated sex calls with those determined by the SNPtrace Panel, STR and Illumina SNP arrays, revealing a high number of male samples are identified as female due to loss of the Y chromosome. Finally we assessed the sensitivity of the SNPtrace Panel to detect intra-human cross-contamination, resulting in detection of as little as 2% contaminating cell population. In conclusion, this study has generated a database of SNP fingerprints for 907 cell lines used in biomedical research and provides a reliable, fast, and economic alternative to STR profiling which can be applied to any human cell line or tissue sample. PMID- 25714625 TI - Seeing is believing: no adult oogenesis in mammals. PMID- 25714626 TI - Management of chronic spontaneous urticaria: practical parameters. AB - Chronic urticaria (CU) is a skin disorder characterized by transient, pruritic wheals persisting for longer than 6 weeks. According to the European Academy of Allergy and Clinical Immunology (EAACI) guidelines, CU can be categorized into two main types: chronic spontaneous urticaria (CSU), in which the wheals appear spontaneously, and inducible urticaria, that is triggered by physical agents. CSU may be due to triggering factors such as food allergens or infections, but in at least 40% of cases it is autoimmune in origin, caused by circulating autoantibodies anti-FcepsilonR1 or anti-IgE, or autoreactive. In the present paper, re-evaluating the EAACI guidelines, we have developed a document containing some practical indications which are useful for diagnosis and management of CSU in the context of the Italian situation. Concerning CSU treatment, second generation antihistamines are the first-line treatment; these drugs can be used, as second-line treatment, at a higher than licensed dose in patients who do not respond adequately at licensed doses. The third-line treatment includes leukotriene receptor antagonists which, however, do not have a specific indication for the treatment of CSU, cyclosporine, whose use in this disease is still off-label, and omalizumab. The latter is a recombinant monoclonal IgG antibody that binds free IgE, down regulates mast cell function and induces eosinophil apoptosis. Recently, it has emerged as an effective and safe treatment for antihistamine-unresponsive CSU of both autoimmune/autoreactive and non-autoimmune/non-autoreactive, and has been officially approved for use against this disease. PMID- 25714627 TI - The Surface Potential of the Water-Vapor Interface from Classical Simulations. AB - The electrochemical surface potential across the water-vapor interface provides a measure of the orientation of water molecules at the interface. However, the large discrepancies between surface potentials calculated from ab initio (AI) and classical molecular dynamics (MD) simulations indicate that what is being calculated may be relevant to different test probes. Although a method for extracting the electrochemical surface potential from AIMD simulations has been given, methods for MD simulations have not been clarified. Here, two methods for extracting the surface potential relevant to electrochemical measurements from MD simulations are presented. This potential is shown to be almost entirely due to the dipole contribution. In addition, the molecular origin of the dipole contribution is explored by using different potential energy functions for water. The results here show that the dipole contribution arises mainly from distortions in the hydration shell of the full hydrogen bonded waters on the liquid side of the interface, which is determined by the charge distribution of the water model. Disturbingly, the potential varies by 0.4 eV depending on the model. Although there is still no consensus on what that charge distribution should be, recent results indicate that it contains both a large quadrupole and negative charge out of the molecular plane, i.e., three-dimensional (3D) charge. Water models with 3D charge give the least distortion of the hydration shell and the best agreement with experimental surface potentials, although there is still uncertainty in the experimental values. PMID- 25714628 TI - Nanofiltration technology in water treatment and reuse: applications and costs. AB - Nanofiltration (NF) is a relatively recent development in membrane technology with characteristics that fall between ultrafiltration and reverse osmosis (RO). While RO membranes dominate the seawater desalination industry, NF is employed in a variety of water and wastewater treatment and industrial applications for the selective removal of ions and organic substances, as well as certain niche seawater desalination applications. The purpose of this study was to review the application of NF membranes in the water and wastewater industry including water softening and color removal, industrial wastewater treatment, water reuse, and desalination. Basic economic analyses were also performed to compare the profitability of using NF membranes over alternative processes. Although any detailed cost estimation is hampered by some uncertainty (e.g. applicability of estimation methods to large-scale systems, labor costs in different areas of the world), NF was found to be a cost-effective technology for certain investigated applications. The selection of NF over other treatment technologies, however, is dependent on several factors including pretreatment requirements, influent water quality, treatment facility capacity, and treatment goals. PMID- 25714629 TI - Combination of a novel electrode material and artificial mediators to enhance power generation in an MFC. AB - This study focuses on two main aspects: developing a novel cost-effective electrode material and power production from domestic wastewater using three different mediators. Methylene blue (MB), neutral red (NR) and 2-hydroxy-1,4 naphthoquinone (HNQ) were selected as electrode mediators with different concentrations. A tin-coated copper mesh electrode was tested as anode electrode. Maximum power density of the microbial fuel cell (MFC) with 300 MUM MB was 636 mW/m2. Optimal mediator concentrations with respect to the achieved maximum power output for MB, NR and HNQ were 300 MUM, 200 MUM and 50 MUM, respectively. The results demonstrate that tin-coated copper mesh showed a higher biocompatibility and electrical conductivity. PMID- 25714630 TI - Comparison of simple, small, full-scale sewage treatment systems in Brazil: UASB maturation ponds-coarse filter; UASB-horizontal subsurface-flow wetland; vertical flow wetland (first stage of French system). AB - This paper presents a comparison between three simple sewage treatment lines involving natural processes: (a) upflow anaerobic sludge blanket (UASB) reactor three maturation ponds in series-coarse rock filter; (b) UASB reactor-horizontal subsurface-flow constructed wetland; and (c) vertical-flow constructed wetlands treating raw sewage (first stage of the French system). The evaluation was based on several years of practical experience with three small full-scale plants receiving the same influent wastewater (population equivalents of 220, 60 and 100 inhabitants) in the city of Belo Horizonte, Brazil. The comparison included interpretation of concentrations and removal efficiencies based on monitoring data (organic matter, solids, nitrogen, phosphorus, coliforms and helminth eggs), together with an evaluation of practical aspects, such as land and volume requirements, sludge production and handling, plant management, clogging and others. Based on an integrated evaluation of all aspects involved, it is worth emphasizing that each system has its own specificities, and no generalization can be made on the best option. The overall conclusion is that the three lines are suitable for sewage treatment in small communities in warm-climate regions. PMID- 25714631 TI - Evaluation of different configurations of hybrid membrane bioreactors for treatment of domestic wastewater. AB - Four membrane bioreactors (MBRs) with the same dimensions were studied for 180 days: three hybrid growth membrane bioreactors with biofilm attached in different packing media and a conventional MBR (C-MBR). The four MBRs had an identical membrane module of hollow fiber with a nominal porous diameter of 0.4 MUm. The MBRs were: (1) a C-MBR; (2) a moving bed membrane bioreactor (MB-MBR), which was packed with 2 L of carrier Kaldnes-K1, presenting an exposed surface area of 678.90 m2/m3; (3) a non-submerged organic fixed bed (OFB-MBR) packed with 6.5 L of organic packing media composed of a mixture of cylindrical pieces of wood, providing an exposed surface area of 178.05 m2/m3; and (4) an inorganic fixed bed non-submerged membrane bioreactor (IFB-MBR) packed with 6 L of spherical volcanic pumice stone with an exposed surface area of 526.80 m2/m3. The four MBRs were fed at low organic loading (0.51 +/- 0.19 kgCOD/m3 d). The results were recorded according to the behavior of the total resistance, transmembrane pressure (TMP), permeability, and removal percentages of the nutrients during the experimental time. The results showed that the MB-MBR presented the better performance on membrane filtration, while the higher nutrient removals were detected in the OFB MBR and IFB-MBR. PMID- 25714632 TI - Prediction of cavitation damage on spillway using K-nearest neighbor modeling. AB - Cavitation is a common and destructive process on spillways that threatens the stability of the structure and causes damage. In this study, based on the nearest neighbor model, a method has been presented to predict cavitation damage on spillways. The model was tested using data from the Shahid Abbaspour dam spillway in Iran. The level of spillway cavitation damage was predicted for eight different flow rates, using the nearest neighbor model. Moreover, based on the cavitation index, five damage levels from no damage to major damage have been determined. Results showed that the present model predicted damage locations and levels close to observed damage during past floods. Finally, the efficiency and precision of the model was quantified by statistical coefficients. Appropriate values of the correlation coefficient, root mean square error, mean absolute error and coefficient of residual mass show the present model is suitable and efficient. PMID- 25714633 TI - Hexavalent chromium reduction and energy recovery by using dual-chambered microbial fuel cell. AB - Microbial fuel cell (MFC) technology is utilized to treat hexavalent chromium (Cr(VI)) from wastewater and to generate electricity simultaneously. The Cr(VI) is bioelectrochemically reduced to non-toxic Cr(III) form in the presence of an organic electron donor in a dual-chambered MFC. The Cr(VI) as catholyte and artificial wastewater inoculated with anaerobic sludge as anolyte, Cr(VI) at 100 mg/L was completely removed within 48 h (initial pH value 2.0). The total amount of Cr recovered was 99.87% by the precipitation of Cr(III) on the surface of the cathode. In addition to that 78.4% of total organic carbon reduction was achieved at the anode chamber within 13 days of operation. Furthermore, the maximum power density of 767.01 mW/m2 (2.08 mA/m2) was achieved by MFCs at ambient conditions. The present work has successfully demonstrated the feasibility of using MFCs for simultaneous energy production from wastewater and reduction of toxic Cr(VI) to non-toxic Cr(III). PMID- 25714634 TI - Intensified-Fenton process for the treatment of phenol aqueous solutions. AB - An intensified-Fenton process for the treatment of phenol aqueous solutions has been studied as a continuous catalytic wet hydrogen peroxide oxidation system. This process consists of coupling the catalytic activity of a heterogeneous Fenton-like catalyst with the homogeneous contribution of its dissolved iron species. Agglomerated mesoporous SBA-15 silica-supported iron oxide (Fe2O3/SBA 15) material was used as heterogeneous catalyst. The influence of the reaction temperature and the initial hydrogen peroxide dosages was studied in order to minimize the operation cost of the process. The catalytic performance of the process was assessed in terms of total organic carbon (TOC) and hydrogen peroxide conversions. Likewise, the stability of the solid Fenton-like catalyst was also evaluated in terms of the dissolved iron species. The increase of the reaction temperature enhanced the TOC conversion and reduced the iron leaching from the heterogeneous catalyst. These results were related to the degradation of oxalic acid as responsible for iron extraction by formation of soluble stable iron complexes into the aqueous medium. Finally, the use of a moderate hydrogen peroxide concentration (2.6 g/L) and milder temperatures (80-120 degrees C) has led to remarkable results of TOC and phenol reductions as well as oxidant efficiency through the intensified-Fenton process. PMID- 25714635 TI - A simple empirical model for the clarification-thickening process in wastewater treatment plants. AB - In wastewater treatment plants (WWTPs), activated sludge is thickened in secondary settling tanks and recycled into the biological reactor to maintain enough biomass for wastewater treatment. Accurately estimating the activated sludge concentration in the lower portion of the secondary clarifiers is of great importance for evaluating and controlling the sludge recycled ratio, ensuring smooth and efficient operation of the WWTP. By dividing the overall activated sludge-thickening curve into a hindered zone and a compression zone, an empirical model describing activated sludge thickening in the compression zone was obtained by empirical regression. This empirical model was developed through experiments conducted using sludge from five WWTPs, and validated by the measured data from a sixth WWTP, which fit the model well (R2 = 0.98, p < 0.001). The model requires application of only one parameter, the sludge volume index (SVI), which is readily incorporated into routine analysis. By combining this model with the conservation of mass equation, an empirical model for compression settling was also developed. Finally, the effects of denitrification and addition of a polymer were also analysed because of their effect on sludge thickening, which can be useful for WWTP operation, e.g., improving wastewater treatment or the proper use of the polymer. PMID- 25714636 TI - Effect of sampling duration on the performance evaluation of a stormwater wetland. AB - In this study, the effect of sampling duration on the performance estimate for a stormwater wetland over both rainy and dry days was evaluated for the appropriate design of sampling duration. As the cumulative percentage volume (Vp), the ratio of cumulative stormwater volume concerning time to the total stormwater volume, varied between 60 and 100%, generally, the inflow total suspended solids, turbidity and total chemical oxygen demand (TCOD) event mean concentrations (EMCs) did not vary significantly, whereas the total nitrogen (TN) and total phosphorus (TP) EMCs were relatively stable. Compared to the inflow, the corresponding outflow EMCs changed much less as Vp changed. And these variations both from inflow and outflow EMCs did not result in significant changes in the removal efficiencies. The investigation during the dry days between two consecutive storm events showed that outflow pollutants did not change to a considerable extent after 1 day of the previous rainfall event. This study identifies the possibility of shortening the rainy sampling duration, because the performance of stormwater wetlands is usually estimated based on removal efficiencies rather than pollutant concentrations. Also, the sampling during dry days should be performed at least 1 day after a rainfall event. PMID- 25714638 TI - Microwave-assisted oxidative digestion of lignin with hydrogen peroxide for TOC and color removal. AB - Dilute lignin solution was successfully digested into colorless and clarified liquor under microwave-assisted oxidative digestion with hydrogen peroxide. High dosage of hydrogen peroxide is needed to effectively digest lignin, but excessive hydrogen peroxide may lead to recondensation of formed fragments in digested lignin. Microwave irradiation greatly facilitates the oxidative digestion of lignin. Compared with conventional heating technique, microwave-assisted digestion achieves the same or higher digestion rate within a shorter time and/or at lower temperature. After digestion, total organic carbon content of lignin solution decreases by 93.9%, and a small amount of aliphatic alkane, alcohol, acid and ester are formed via the cleavage of aromatic rings as well as the deprivation of side chains in original lignin. This work provides an alternative way to efficiently treat spent pulping liquor. PMID- 25714637 TI - Post-treatment of anaerobic effluent by ozone and ozone/UV of a kraft cellulose pulp mill. AB - Pulp and paper mill effluents represent a challenge when treatment technologies are considered, not only to reduce organic matter, but also to reduce the toxicological effects. Although anaerobic treatment has shown promising results, as well as advantages when compared with an aerobic system, this process alone is not sufficient to reduce recalcitrant compounds. Thus, an advanced oxidation process was applied. This experiment was performed to determine the effect of ozone and ozone/UV treating a horizontal anaerobic immobilized biomass reactor effluent from a kraft cellulose pulp mill for 306 days with an organic volumetric load of 2.33 kgCOD/m3/day. The removal of organic compounds was measured by the following parameters: adsorbable organically bound halogens (AOX), total phenols, chemical oxygen demand (COD), dissolved organic carbon and absorbance values in the UV-visible spectral region. Moreover, ecotoxicity and genotoxicity tests were conducted before and after treatment with ozone and ozone/UV. At an applied ozone dosage of 0.76 mgO3/mgCOD and an applied UV dosage of 3.427 Wh/m(3), the organochlorine compounds measured as AOX reached removal efficiencies of 40%. Although the combination of ozone/UV showed better results in colour (79%) and total phenols (32%) compared with only ozone, the chronic toxicity and the genotoxicity that had already been removed in the anaerobic process were slightly increased. PMID- 25714639 TI - Factors influencing hydroquinone degradation in aqueous solution using a modified microelectrolysis method. AB - The discharge of hydroquinone (HQ), an important chemical raw material, to natural waters poses different ecological threats to aquatic organisms. In this study, we investigated the removal performance of traditional and modified microelectrolysis methods in aqueous solutions. The traditional microelectrolysis packing was modified by adding manganese (Mn), zinc (Zn), and copper (Cu) powder as additives. The factors affecting the removal performance of HQ, such as catalytic metal type, mass fraction of additive, reaction time, and initial pH, were examined. The results showed that the Mn modified packing exhibited the best performance compared to Zn and Cu powder. The removal rate of HQ using Mn modified packing can reach 94% after 4 h. In addition, 9% of Mn packing has a higher removal rate than other mass fractions. The acidic solution pH shows a more favorable degradation than a neutral and alkaline solution. The intermediates of HQ degradation by modified microelectrolysis were identified and then the pathway of HQ degradation was proposed. Our result indicates that Mn as catalytic metal holds promising potential to enhance HQ removal in water using the microelectrolysis method. PMID- 25714640 TI - Degradability of hexachlorocyclohexanes in water using ferrate (VI). AB - Regarding environmental pollution, the greatest public and scientific concern is aimed at the pollutants listed under the Stockholm Convention. These pollutants are not only persistent but also highly toxic with a high bioaccumulation potential. One of these pollutants, gamma-hexachlorocyclohexane (gamma-HCH), has been widely used in agriculture, which has resulted in wide dispersion in the environment. Remediation of this persistent and hazardous pollutant is difficult and remains unresolved. Of the many different approaches tested, to date, none has used ferrates. This is unexpected as ferrates are generally believed to be an ideal chemical reagent for water treatment due to their strong oxidation potential and the absence of harmful by-products. In this paper, the degradation/transformation of HCHs by ferrates under laboratory conditions was studied. HCH was degraded during this reaction, producing trichlorobenzenes and pentachlorocyclohexenes as by-products. A detailed investigation of pH conditions during Fe(VI) application identified pH as the main factor affecting degradation. We conclude that ferrate itself is unreactive with HCH and that high pH values, produced by K2O impurity and the reaction of ferrate with water, are responsible for HCH transformation. Finally, a comparison of Fe(VI) with Fe(0) is provided in order to suggest their environmental applicability for HCH degradation. PMID- 25714641 TI - Photodegradation of sulfonamide antimicrobial compounds (sulfadiazine, sulfamethizole, sulfamethoxazole and sulfathiazole) in various UV/oxidant systems. AB - This study used Na2S2O8, NaBrO8 and H2O2to degrade sulfadiazine (SDZ), sulfamethizole (SFZ), sulfamethoxazole (SMX) and sulfathiazole (STZ) under ultraviolet (UV) irradiation. The initial concentration of sulfonamide and oxidant in all experiments was 20 mg/L and 5 mM, respectively. The degradation rate for sulfonamides satisfies pseudo-first-order kinetics in all UV/oxidant systems. The highest degradation rate for SDZ, SFZ, SMX and STZ was in the UV/Na2S2O8, UV/NaBrO3, UV/Na2S2O8 and UV/H2O2 system, respectively. In the UV/Na2S2O8 system, the photodegradation rate of SDZ, SFZ, SMX and STZ was 0.0245 min-1, 0.0096 min-1, 0.0283 min-1 and 0.0141 min-1, respectively; moreover, for the total organic carbon removal rate for SDZ, SFZ, SMX and STZ it was 0.0057 min 1, 0.0081 min-1, 0.0130 min-1 and 0.0106 min-1, respectively. Experimental results indicate that the ability of oxidants to degrade sulfonamide varied with pollutant type. Moreover, UV/Na2S2O8 had the highest mineralization rate for all tested sulfonamides. PMID- 25714642 TI - Identifying climate analogues for precipitation extremes for Denmark based on RCM simulations from the ENSEMBLES database. AB - Climate analogues, also denoted Space-For-Time, may be used to identify regions where the present climatic conditions resemble conditions of a past or future state of another location or region based on robust climate variable statistics in combination with projections of how these statistics change over time. The study focuses on assessing climate analogues for Denmark based on current climate data set (E-OBS) observations as well as the ENSEMBLES database of future climates with the aim of projecting future precipitation extremes. The local present precipitation extremes are assessed by means of intensity-duration frequency curves for urban drainage design for the relevant locations being France, the Netherlands, Belgium, Germany, the United Kingdom, and Denmark. Based on this approach projected increases of extreme precipitation by 2100 of 9 and 21% are expected for 2 and 10 year return periods, respectively. The results should be interpreted with caution as the best region to represent future conditions for Denmark is the coastal areas of Northern France, for which only little information is available with respect to present precipitation extremes. PMID- 25714643 TI - Simulation and verification of hydraulic properties and organic matter degradation in sand filters for greywater treatment. AB - To evaluate the treatment performance of vertical flow sand filters, the HYDRUS wetland module was used to simulate treatment in an experimental set-up. The laboratory filters were intermittently dosed with artificial greywater at a hydraulic loading rate of 0.032 m3 m-2 day-1 and an organic loading rate of 0.014 kg BOD5 m-2 day-1. The hydraulic properties of the filter were characterised, as were inflow and outflow concentrations of chemical oxygen demand (COD), biochemical oxygen demand (BOD), ammonia, nitrate and total nitrogen. The inverse simulation function of the HYDRUS software was used to calibrate the water flow model. The observed effect of water flowing faster along the column wall was included in the inverse simulations. The biokinetic model was calibrated by fitting heterotrophic biomass growth to measurements of potential respiration rate. Emphasis was put on simulating outflow concentrations of organic pollutants. The simulations were conducted using three models of varying degree of calibration effort and output accuracy. The effluent concentration was 245 mg COD L-1 for the laboratory filters, 134 mg COD mg L-1 for the model excluding wall flow effects and 338 mg COD mg L-1 for the model including wall flow effects. PMID- 25714644 TI - A rapid and simple capillary electrophoresis method for indirect determination of the biocide 2,2-dibromo-3-nitrilo-propionamide (DBNPA) in cooling waters. AB - A capillary zone electrophoresis (CE) method was developed for the determination of the biocide 2,2-dibromo-3-nitrilo-propionamide (DBNPA) in water used in cooling systems. The biocide is indirectly determined by CE measurement of the concentration of bromide ions produced by the reaction between the DBNPA and bisulfite. The relationship between the bromide peak areas and the DBNPA concentrations showed a good linearity and a coefficient of determination (R2) of 0.9997 in the evaluated concentration range of 0-75 MUmol L-1. The detection and quantification limits for DBNPA were 0.23 and 0.75 MUmol L-1, respectively. The proposed CE method was successfully applied for the analysis of samples of tap water and cooling water spiked with DBNPA. The intra-day and inter-day (intermediary) precisions were lower than 2.8 and 6.2%, respectively. The DBNPA concentrations measured by the CE method were compared to the values obtained by a spectrophotometric method and were found to agree well. PMID- 25714645 TI - Continuous flow aerobic granular sludge reactor for dairy wastewater treatment. AB - The focus of this study was to assess the treatment performance and granule progression over time within a continuous flow reactor. A continuous flow airlift reactor was seeded with aerobic granules from a laboratory scale sequencing batch reactor (SBR) and fed with dairy wastewater. Stereomicroscopic investigations showed that the granules maintained their integrity during the experimental period. Laser diffraction investigation showed proof of new granules formation with 100-500 MUm diameter after only 2 weeks of operation. The treatment performances were satisfactory and more or less similar to the ones obtained from the SBR. Thus, removal efficiencies of 81-93% and 85-94% were observed for chemical oxygen demand and biological oxygen demand, respectively. The N-NH(+)(4) was nitrified with removal efficiencies of 83-99% while the nitrate produced was simultaneously denitrified - highest nitrate concentration determined in the effluent was 4.2 mg/L. The removal efficiency of total nitrogen was between 52 and 80% depending on influent nitrogen load (39.3-76.2 mg/L). Phosphate removal efficiencies ranged between 65 and above 99% depending on the influent phosphate concentration, which varied between 11.2 and 28.3 mg/L. PMID- 25714646 TI - Nonylphenols degradation in the UV, UV/H2O2, O3and UV/O3processes - comparison of the methods and kinetic study. AB - This paper describes the results of experiments on the decomposition of selected nonylphenols (NPs) in aqueous solutions using the UV, UV/H2O2, O3and UV/O3processes. The goal of the research was to determine the kinetic parameters of the above-mentioned processes, and to estimate their effectiveness. These substances were selected because of their ubiquitous occurrence in the aquatic environment, resistance to biodegradation and environmental significance. As a result of the experiments, the quantum yields of the 4-n-nonylphenol (4NP) and NP (technical mixture) photodegradation in aqueous solution were calculated to be 0.15 and 0.17, respectively. The values of the second-order rate constants of the investigated compounds with hydroxyl radical and NP with ozone were also determined. The estimated second-order rate constants of 4NP and NP with hydroxyl radicals were equal to 7.6 * 108-1.3 * 109 mol-1 L s-1. For NP, the determined rate constant with ozone was equal to 2.01 * 106 mol-1 L s-1. The performed experiments showed that NP was slightly more susceptible to degradation by the UV radiation and hydroxyl radicals than 4NP. The study demonstrated also that the polychromatic UV-light alone and also in combination with selected oxidizers (i.e. hydrogen peroxide, ozone) may be successfully used for the removal of selected NPs from the aqueous medium. PMID- 25714647 TI - Microbial community structure of a simultaneous nitrogen and phosphorus removal reactor following treatment in a UASB-DHS system. AB - The anaerobic-anoxic sequence batch reactor (A2SBR) was applied to achieve nitrogen and phosphorus removal in an energy-saving sewage treatment system involving an up-flow anaerobic sludge blanket combined with a down-flow hanging sponge reactor to treat municipal sewage. After sludge acclimation, the A2SBR showed satisfactory denitrification and phosphorus removal performance with total phosphate and nitrate concentrations of the effluent of 8.4 +/- 3.4 mg-N L-1 and 0.9 +/- 0.6 mg-P L-1, respectively. 16S rRNA gene sequence and fluorescence in situ hybridization analyses revealed that 'Candidatus Accumulibacter phosphatis' was the dominant phosphate-accumulating micro-organism. Although a competitive bacterium for polyphosphate-accumulating organisms, 'Ca. Competibacter phosphatis', was not detected, Dechloromonas spp. were abundant. The ppk1 gene sequence analysis showed that the type II lineage of 'Ca. Accumulibacter' was dominant. The results suggest that denitrification and phosphorus removal in the A2SBR could be achieved by cooperative activity of 'Ca. Accumulibacter' and nitrate-reducing bacteria. PMID- 25714648 TI - Cyclic endogenous estrogen and progesterone vary by mammographic density phenotypes in premenopausal women. AB - Estrogen and progesterone are key factors in the development of breast cancer, but it remains unclear whether these hormones are associated with mammographic density phenotypes in premenopausal women. We measured percent mammographic density, nondense area, and absolute mammographic density using computer-assisted breast density readings (Madena) from digitized mammograms taken on a scheduled day of the menstrual cycle (day 7-12) among 202 healthy, premenopausal women (Energy Balance and Breast cancer Aspects Study-I). Daily salivary concentrations of 17beta-estradiol and progesterone throughout an entire menstrual cycle and fasting morning serum concentrations of hormones on 3 specific days of the menstrual cycle were assessed. Salivary and serum 17beta-estradiol and progesterone were positively associated with percent mammographic density, we observed by 1 SD increase in overall salivary estradiol (beta-value equal to 2.07, P=0.044), luteal salivary progesterone (beta-value equal to 2.40, P=0.020). Women with above-median percent mammographic density had a 20% higher mean salivary 17beta-estradiol level throughout the menstrual cycle. The odds ratio for having above-median percent mammographic density (>28.5%) per 1 SD increase in overall salivary 17beta-estradiol was 1.66 (95% confidence interval 1.13 2.45). Women in the top tertile of the overall average daily 17beta-estradiol concentrations had an odds ratio of 2.54 (confidence interval 1.05-6.16) of above median percent mammographic density compared with women in the bottom tertile. Our finding of a relationship between estrogen, progesterone, and percent mammographic density and not with other mammographic density phenotypes in premenopausal women is biologically plausible, but needs to be replicated in larger studies. PMID- 25714649 TI - Predictors for local invasive recurrence of ductal carcinoma in situ of the breast: a meta-analysis. AB - The introduction of mammographic screening has considerably increased the detection rate of ductal carcinoma in situ (DCIS), which has a high probability of recurrence. We carried out a meta-analysis to evaluate the predictive factors including biomarkers, tumor characteristics, and modes of detection on the risk of local invasive recurrence (LIR) following DCIS. Searches were performed in PubMed and EMBASE up to 8 July 2014. Risk estimates (hazard ratios, odds ratios, and relative risks) and their 95% confidence intervals (CIs) were extracted to calculate the strength of the associations between predictive factors and the risk of LIR after treatment of DCIS. STATA 12.0 was used to combine results in this meta-analysis. A total of 18 articles were included in the analysis. Pooled risk estimates and 95% CIs were 1.36 (1.04-1.69) for the positive margin, 1.38 (1.12-1.63) for the nonscreening detection method, 1.04 (0.84-1.24) for high nuclear grade 1, 1.32 (0.98-1.66) for intermediate nuclear grade 2, 1.18 (0.98 1.37) for comedonecrosis, 1.00 (0.92-1.08) for large tumor size, 1.34 (0.82-1.87) for multifocality, 0.74 (0.36-1.12) for estrogen receptor-positive tumors, 0.89 (0.47-1.31) for progesterone receptor-positive tumors, and 1.25 (0.7-1.81) for HER2/neu-positive tumors. Positive margin and non-screening-detected cancers were associated with a higher risk of LIR following DCIS. These predictive factors, after further validation, could be considered to tailor treatment for individual patients. PMID- 25714650 TI - Comparison of plasma levels of obesity-related biomarkers among Japanese populations in Tokyo, Japan, Sao Paulo, Brazil, and Hawaii, USA. AB - Although Japanese in Japan and the USA are high-risk populations for colorectal cancer, the prevalence of obesity, one of the established risk factors for this disease, is low in these populations compared with other high-risk populations. To understand this inconsistency, we compared plasma obesity-related biomarkers in cross-sectional studies carried out in Tokyo, Sao Paulo, and Hawaii. We measured plasma levels of insulin-like growth factor-I (IGF-I), insulin-like growth factor-binding protein (IGFBP)-1, IGFBP-3, C-peptide, adiponectin, leptin, tumor necrosis factor-alpha, and interleukin-6 by immunoassay and total C reactive protein, total cholesterol, low-density lipoprotein cholesterol, high density lipoprotein cholesterol, and triglycerides using a clinical chemistry autoanalyzer. A total of 299 participants were included in the present analysis, comprising 142 Japanese in Tokyo, 79 Japanese Brazilians in Sao Paulo, and 78 Japanese Americans in Hawaii. We found significantly lower plasma levels of C peptide and IGF-I in Japanese in Tokyo than in Japanese Americans, and lower levels of leptin and triglycerides and higher levels of adiponectin, IGFBP-3, and high-density lipoprotein cholesterol in Japanese in Tokyo than in the other two populations. We also observed a significantly higher plasma IGFBP-1 level in Japanese Brazilians, and lower plasma levels of total cholesterol and low-density lipoprotein in Japanese Americans than in the other two populations. We observed significant differences in obesity-related biomarkers between the three Japanese populations. If our results are confirmed, the risk of colorectal cancer predicted on the basis of these biomarkers would be lowest for Japanese in Tokyo, followed by Japanese Brazilians and Japanese Americans. PMID- 25714652 TI - Corynomycolic acid-containing glycolipids signal through the pattern recognition receptor Mincle. AB - An enantioselective synthesis of (+)-corynomycolic acid, and its elaboration to esters of trehalose, glucose and glycerol, is described. Trehalose dicorynomycolate and trehalose monocorynomycolate activate human and mouse Mincle as effectively as trehalose dicorynomycolate (cord factor). Glucose monomycolate is revealed to be a potent activator of both mouse and human Mincle. Glycerol monocorynomycolate signals through human Mincle, with the activity predominantly residing in the 2'S-isomer. PMID- 25714653 TI - Molecular Epidemiology and Mechanisms of Carbapenem Resistance of Acinetobacter spp. in Asia and Oceania. AB - Acinetobacter baumannii is emerging as a pathogen that is commonly involved in nosocomial infections. A. baumannii has exhibited the ability to develop multidrug resistance (MDR), including resistance to carbapenems, the last-line class of antibiotics to treat these infections. In particular, MDR A. baumannii International Clone (IC) 2 has disseminated worldwide causing substantial problems in hospitals, including in Asia and Oceania. The global spread of this clonal lineage emphasizes the importance of tracking molecular epidemiology to obtain greater understanding of the population dynamics of A. baumannii. Carbapenem resistance in A. baumannii occurs mainly as a result of acquisition of OXA-type carbapenemase genes, and to some extent by acquisition of metallo-beta lactamase genes. The acquisition of carbapenemase genes, particularly the bla(OXA 23), bla(OXA-40), and bla(OXA-58), by specific clonal lineages may be one of the attributes responsible for the relative homogeneity of the MDR A. baumannii population. PMID- 25714651 TI - Molecular targets of luteolin in cancer. AB - Many food-derived phytochemical compounds and their derivatives represent a cornucopia of new anticancer compounds. Despite extensive study of luteolin, the literature has no information on the exact mechanisms or molecular targets through which it deters cancer progression. This review discusses existing data on luteolin's anticancer activities and then offers possible explanations for and molecular targets of its cancer-preventive action. Luteolin prevents tumor development largely by inactivating several signals and transcription pathways essential for cancer cells. This review also offers insights into the molecular mechanisms and targets through which luteolin either prevents cancer or mediates cancer cell death. PMID- 25714654 TI - Efficient uranium capture by polysulfide/layered double hydroxide composites. AB - There is a need to develop highly selective and efficient materials for capturing uranium (normally as UO2(2+)) from nuclear waste and from seawater. We demonstrate the promising adsorption performance of S(x)-LDH composites (LDH is Mg/Al layered double hydroxide, [S(x)](2-) is polysulfide with x = 2, 4) for uranyl ions from a variety of aqueous solutions including seawater. We report high removal capacities (q(m) = 330 mg/g), large K(d)(U) values (10(4)-10(6) mL/g at 1-300 ppm U concentration), and high % removals (>95% at 1-100 ppm, or ~80% for ppb level seawater) for UO2(2+) species. The S(x)-LDHs are exceptionally efficient for selectively and rapidly capturing UO2(2+) both at high (ppm) and trace (ppb) quantities from the U-containing water including seawater. The maximum adsorption coeffcient value K(d)(U) of 3.4 * 10(6) mL/g (using a V/m ratio of 1000 mL/g) observed is among the highest reported for U adsorbents. In the presence of very high concentrations of competitive ions such as Ca(2+)/Na(+), S(x)-LDH exhibits superior selectivity for UO2(2+), over previously reported sorbents. Under low U concentrations, (S4)(2-) coordinates to UO2(2+) forming anionic complexes retaining in the LDH gallery. At high U concentrations, (S4)(2-) binds to UO2(2+) to generate neutral UO2S4 salts outside the gallery, with NO3(-) entering the interlayer to form NO3-LDH. In the presence of high Cl( ) concentration, Cl(-) preferentially replaces [S4](2-) and intercalates into LDH. Detailed comparison of U removal efficiency of S(x)-LDH with various known sorbents is reported. The excellent uranium adsorption ability along with the environmentally safe, low-cost constituents points to the high potential of S(x) LDH materials for selective uranium capture. PMID- 25714655 TI - Rickettsia rickettsii outer membrane protein YbgF induces protective immunity in C3H/HeN mice. AB - Rickettsia rickettsii is the etiological agent of Rocky Mountain spotted fever (RMSF). YbgF and TolC are outer membrane-associated proteins of R. rickettsii that play important roles in its interaction with host cells. We investigated the immunogenicity of YbgF and TolC for protection against RMSF. We immunized C3H/HeN mice with recombinant R. rickettsii YbgF (rYbgF) or TolC (rTolC). Rickettsial burden and impairment in the lungs, spleens, and livers of rYbgF-immunized mice were significantly lower than in rTolC-immunized mice. The ratio of IgG2a to IgG1 in rYbgF-immunized mice continued to increase over the course of our experiments, while that in rTolC-immunized mice was reduced. The proliferation and cytokine secretion of CD4(+) and CD8(+) T cells isolated from R. rickettsii-infected mice were analyzed following antigen stimulation. The results indicated that proliferation and interferon (IFN)-gamma secretion of CD4(+) or CD8(+) T cells in R. rickettsii-infected mice were significantly greater than in uninfected mice after stimulation with rYbgF. YbgF is a novel protective antigen of R. rickettsii. Protection conferred by YbgF is dependent upon IFN-gamma-producing CD4(+) and CD8(+) T cells and IgG2a, which act in synergy to control R. rickettsii infection. PMID- 25714656 TI - Synthetic control of composition and crystallite size of silver ferrite composites: profound electrochemistry impacts. AB - A paradigm for concomitant control of crystallite size and composition of bimetallic composites via co-precipitation is introduced. Direct preparation of composites of silver ferrite and amorphous maghemite via nonstoichiometric synthesis was demonstrated. Notable impact on electrochemistry was observed, with ~200% increase in reversible capacity for the small crystallite material. PMID- 25714657 TI - Effect of treatment of cystic fibrosis pulmonary exacerbations on systemic inflammation. AB - RATIONALE: In cystic fibrosis (CF), pulmonary exacerbations present an opportunity to define the effect of antibiotic therapy on systemic measures of inflammation. OBJECTIVES: Investigate whether plasma inflammatory proteins demonstrate and predict a clinical response to antibiotic therapy and determine which proteins are associated with measures of clinical improvement. METHODS: In this multicenter study, a panel of 15 plasma proteins was measured at the onset and end of treatment for pulmonary exacerbation and at a clinically stable visit in patients with CF who were 10 years of age or older. MEASUREMENTS AND MAIN RESULTS: Significant reductions in 10 plasma proteins were observed in 103 patients who had paired blood collections during antibiotic treatment for pulmonary exacerbations. Plasma C-reactive protein, serum amyloid A, calprotectin, and neutrophil elastase antiprotease complexes correlated most strongly with clinical measures at exacerbation onset. Reductions in C-reactive protein, serum amyloid A, IL-1ra, and haptoglobin were most associated with improvements in lung function with antibiotic therapy. Having higher IL-6, IL-8, and alpha1-antitrypsin (alpha1AT) levels at exacerbation onset were associated with an increased risk of being a nonresponder (i.e., failing to recover to baseline FEV1). Baseline IL-8, neutrophil elastase antiprotease complexes, and alpha1AT along with changes in several plasma proteins with antibiotic treatment, in combination with FEV1 at exacerbation onset, were predictive of being a treatment responder. CONCLUSIONS: Circulating inflammatory proteins demonstrate and predict a response to treatment of CF pulmonary exacerbations. A systemic biomarker panel could speed up drug discovery, leading to a quicker, more efficient drug development process for the CF community. PMID- 25714658 TI - Faulty analysis in study of robotic-assisted minimally invasive radical prostatectomy-reply. PMID- 25714659 TI - Boron nitride nanosheets as improved and reusable substrates for gold nanoparticles enabled surface enhanced Raman spectroscopy. AB - Atomically thin boron nitride (BN) nanosheets have been found to be excellent substrates for noble metal particles enabled surface enhanced Raman spectroscopy (SERS), thanks to their good adsorption of aromatic molecules, high thermal stability and weak Raman scattering. Faceted gold (Au) nanoparticles have been synthesized on BN nanosheets using a simple but controllable and reproducible sputtering and annealing method. The size and density of the Au particles can be controlled by sputtering time, current and annealing temperature etc. Under the same sputtering and annealing conditions, the Au particles on BN of different thicknesses show various sizes because the surface diffusion coefficients of Au depend on the thickness of BN. Intriguingly, decorated with similar morphology and distribution of Au particles, BN nanosheets exhibit better Raman enhancements than silicon substrates as well as bulk BN crystals. Additionally, BN nanosheets show no noticeable SERS signal and hence cause no interference to the Raman signal of the analyte. The Au/BN substrates can be reused by heating in air to remove the adsorbed analyte without loss of SERS enhancement. PMID- 25714661 TI - The impact of patent eligibility on biotech patents: A flow chart for determining patent eligibility and an immune therapy case study. AB - US common law recites a natural law, natural phenomenon or abstract idea as exceptions to the 4 statutory patentable categories to guard against the wholesale preemption of fundamental principles. The very recent evolutions of patent exceptions in the US may increase the difficulty of patenting and may create uncertainty in determining patent eligibility. To solve the thorny problem of eligibility, this study presents a flow chart based on the courts' decisions that can serve as a set of guidelines for determining patent eligibility. A case related to prostate cancer immune therapy is presented for discussion. PMID- 25714660 TI - Interferon-Beta, a Decisive Factor in Angiogenesis and Arteriogenesis. AB - In this review we discuss the current literature on the effects of type I interferons (IFN) and their downstream effectors on vascular growth in experimental models in vitro and in vivo. In addition to its well-documented role in angiogenesis, that is, the growth of new capillaries from existing vessels, we will also describe emerging evidence and mechanisms by which type I IFN may inhibit arteriogenesis, that is, the expansive remodeling of existing collateral arteries. Crucial in both processes is the common role of circulating monocytes, which are known to act as pivotal cellular modulators in revascularization through secreted chemokines, proteases, and growth factors. These secreted molecules, which are all modulated by IFN signaling, act via degradation of the extracellular matrix and by stimulating the proliferation of vascular smooth muscle cells and endothelial cells. Thus, next to the antiviral and immunomodulatory activities of type I IFNs, a potent role of IFN-beta as modulator of revascularization is now emerging and may be considered a potential clinical target for the stimulation of angiogenesis and arteriogenesis in ill perfused tissues. PMID- 25714662 TI - Mechanically stable thermally crosslinked poly(acrylic acid)/reduced graphene oxide aerogels. AB - Graphene oxide (GO) aerogels, high porosity (>99%) low density (~3-10 mg cm(-3)) porous materials with GO pore walls, are particularly attractive due to their lightweight, high surface area, and potential use in environmental remediation, superhydrophobic and superoleophilic materials, energy storage, etc. However, pure GO aerogels are generally weak and delicate which complicates their handling and potentially limits their commercial implementation. The focus of this work was to synthesize highly elastic, mechanically stable aerogels that are robust and easy to handle without substantially sacrificing their high porosity or low density. To overcome this challenge, a small amount of readily available and thermally cross-linkable poly(acrylic acid) (PAA) was intermixed with GO to enhance the mechanical integrity of the aerogel without disrupting other desirable characteristic properties. This method is a simple straightforward procedure that does not include multistep or complicated chemical reactions, and it produces aerogels with mass densities of about 4-6 mg cm(-3) and >99.6% porosity that can reversibly support up to 10,000 times their weight with full recovery of their original volume. Finally, pressure sensing capabilities were demonstrated and their oil absorption capacities were measured to be around 120 g oil per g aerogel(-1) which highlights their potential use in practical applications. PMID- 25714663 TI - Evaluation of an alpha synuclein sensitized dendritic cell based vaccine in a transgenic mouse model of Parkinson disease. AB - In order to develop a cell-based vaccine against the Parkinson disease (PD) associated protein alpha-synuclein (alpha-Syn) 3 peptides were synthesized based upon predicted B cell epitopes within the full length alpha-Syn protein sequence. These peptide fragments as well as the full length recombinant human alpha-Syn (rh- alpha-Syn) protein were used to sensitize mouse bone marrow-derived dendritic cells (DC) ex vivo, followed by intravenous delivery of these sensitized DCs into transgenic (Tg) mice expressing the human A53T variant of alpha-Syn. ELISA analysis and testing of behavioral locomotor function by rotometry were performed on all mice after the 5th vaccination as well as just prior to euthanasia. The results indicated that vaccination with peptide sensitized DCs (PSDC) as well as DCs sensitized by rh-alpha-Syn induced specific anti-alpha-Syn antibodies in all immunized mice. In terms of rotometry performance, a measure of locomotor activity correlated to brain dopamine levels, mice vaccinated with PSDC or rh- alpha-Syn sensitized DCs performed significantly better than non-vaccinated Tg control mice during the final assessment (i.e. at 17 months of age) before euthanasia. As well, measurement of levels of brain IL 1alpha, a cytokine hypothesized to be associated with neuroinflammation, demonstrated that this proinflammatory molecule was significantly reduced in the PSDC and rh- alpha-Syn sensitized DC vaccinated mice compared to the non vaccinated Tg control group. Overall, alpha-Syn antigen-sensitized DC vaccination was effective in generating specific anti- alpha-Syn antibodies and improved locomotor function without eliciting an apparent general inflammatory response, indicating that this strategy may be a safe and effective treatment for PD. PMID- 25714664 TI - Implementation of video telehealth to improve access to evidence-based psychotherapy for posttraumatic stress disorder. AB - BACKGROUND: Increasing access to psychotherapy for posttraumatic stress disorder (PTSD) is a primary focus of the Department of Veterans Affairs (VA) healthcare system. Delivery of treatment via video telehealth can expand availability of treatment and be equally effective as in-person treatment. Despite VA efforts, barriers to establishing telehealth services remain, including both provider acceptance and organizational obstacles. Thus, development of specific strategies is needed to implement video telehealth services in complex healthcare systems, like the VA. MATERIALS AND METHODS: This project was guided by the Promoting Action on Research Implementation in Health Services framework and used external facilitation to increase access to psychotherapy via video telehealth. The project was conducted at five VA Medical Centers and their associated community clinics across six states in the South Central United States. RESULTS: Over a 21 month period, 27 video telehealth clinics were established to provide greater access to evidence-based psychotherapies for PTSD. Examination of change scores showed that participating sites averaged a 3.2-fold increase in unique patients and a 6.5-fold increase in psychotherapy sessions via video telehealth for PTSD. Differences between participating and nonparticipating sites in both unique patients and encounters were significant (p=0.041 and p=0.009, respectively). Two groups emerged, separated by degree of engagement in the facilitation intervention. Facilitation was perceived as useful by providers. CONCLUSIONS: To our knowledge, this is the first prospective study of external facilitation as an implementation strategy for telehealth. Our findings suggest that external facilitation is an effective and acceptable strategy to support providers as they establish clinics and make complex practice changes, such as implementing video telehealth to deliver psychotherapy. PMID- 25714665 TI - Involvement of miR-133a and miR-326 in ADM resistance of HepG2 through modulating expression of ABCC1. AB - Recent studies have shown that a class of small, functional RNAs, named microRNAs, may regulate multidrug resistance-associated protein 1 (ABCC1). Since ABCC1 is an important efflux transporter responsible for cellular drug disposition, the discovery of microRNAs (miRNA) brings an idea that there may be some other unknown multidrug resistance (MDR) mechanisms exist. Using computational programs, we predicted that the 3'untranslated region (3'UTR) of ABCC1 contains a potential miRNA binding site for miR-133a and also two other for miR-326. These binding sites were confirmed by luciferase reporter assay. ABCC1 mRNA degradation was accelerated dramatically in cells transfected with miR-133a or miR-326 mimics using qRT-PCR, Furthermore, western blot analysis indicated that ABCC1 protein expression was significantly down-regulated in hepatocellular carcinoma cells line HepG2 after transfection with miR-133a or miR-326 mimics, suggesting the involvement of mRNA degradation and protein expression mechanism. The effects of the two miRNAs on adriamycin (ADM) sensitivity to HepG2 cells were determined by MTT assay. Compared with mock transfection, miR-133a or miR-326 mimics transfection sensitized these cells to ADM. These findings for the first time demonstrated that the involvement of miR-133a and miR-326 in MDR is mediated by ABCC1 in hepatocellular carcinoma cell line HepG2 and suggested that miR-133a and miR-326 may be efficient agents for preventing and reversing ADM resistance in cancer cells. PMID- 25714666 TI - Comparison of the diagnostic performance of H/M ratio between early and delayed phases for Lewy body disease. AB - OBJECTIVES: The aim of the study was to compare the diagnostic performance of early-phase I-metaiodobenzylguanidine (MIBG) scintigraphy with that of delayed phase imaging in Lewy body disease (LBD). METHODS: A retrospective cohort study of 123I-MIBG scintigraphy was carried out in 192 patients who were suspected of having LBD. Clinical diagnosis was obtained using the UK Parkinson's Disease Brain Bank Criteria in some cases or the third report of the Dementia with Lewy bodies Consortium in others. The participants consisted of 81 patients with LBD and 111 nondiseased patients. An injection of 111 MBq of 123I-MIBG was used. Planar images were obtained in an early phase and again in a delayed phase and the heart to mediastinum count ratio was calculated for both phases. Diagnostic performance was compared using a receiver-operator characteristic analysis. The cutoff value was chosen to maximize the Youden index. The sensitivity and specificity of each phase were calculated from the optimal cutoff value. RESULTS: The heart to mediastinum ratio of the LBD group (median 1.8 and 1.45 for early and delayed phases, respectively) was significantly lower than that of the nondiseased group (median 2.93 and 3.18 for early and delayed phases, respectively). The area under the receiver-operating characteristic curve was not significantly different between the early and delayed phases (0.871 vs. 0.893; P=0.0914). Sensitivity and specificity were 80.2 and 91% for early-phase imaging (cutoff value at 2.28) and 81.5 and 95.5% (cutoff value at 1.91) for delayed phase imaging, respectively. CONCLUSION: The diagnostic performance of 123I-MIBG scintigraphy was not significantly different between early-phase and delayed phase imaging. PMID- 25714667 TI - Factors influencing the success of radioiodine therapy in patients with Graves' disease. AB - OBJECTIVE: The first dose of radioiodine (I) does not always cure hyperthyroidism in patients with Graves' disease (GD). Our aim was to evaluate the factors influencing the success of I therapy. PATIENTS AND METHODS: We reviewed the medical records of 724 patients who were first diagnosed with GD between 2005 and 2009 and were subsequently treated with I in a fixed-dose manner considering the thyroid volume (TV). TSH, fT(4), and fT(3) were measured. TV was measured by means of ultrasonography. Successful therapy was followed by euthyroidism or hypothyroidism. RESULTS: Out of 724 patients, 656 (90.5%) were successfully (Group 1) and 69 (9.5%) were unsuccessfully (Group 2) treated with the first dose of (131)I. In Group 1, the applied dose of (131)I was lower than that in Group 2 [626+/-107, 95% confidence interval (CI) 618-634, and 709+/-140, 95% CI 675-742 MBq, respectively; P<0.001]. At presentation, patients in Group 1 were younger than those in Group 2 (45.5+/-14.9, 95% CI 44.4-46.6, and 50.1+/-15.8, 95% CI 46.3-53.9 years, respectively; P=0.031). They had a lower fT(4) (54.9+/-26.1, 95% CI 52.9-56.9, and 72.1+/-34.1, 95% CI 63.9-80.3 pmol/l, respectively; P<0.001), a lower fT3 (20.9+/-8.2, 95% CI 20.3-21.5, and 23.9+/-8.2, 95% CI 21.9-25.9 pmol/l, respectively; P<0.001), and a smaller TV (21.5+/-13.2, 95% CI 20.2-22.8, and 35.6+/-22.3, 95% CI 28.2-42.9 ml, respectively; P<0.001). Before I therapy, patients in Group 1 had a lower fT(3) (9.6+/-6.0, 95% CI 9.2-10.1, and 11.3+/ 7.6, 95% CI 9.5-13.2 pmol/l, respectively; P=0.038). CONCLUSION: Successfully treated GD patients were younger, less severely hyperthyroid, and had a smaller TV at presentation. They were also less severely hyperthyroid before I therapy. PMID- 25714668 TI - Comparison of gamma camera-based methods to measure glomerular filtration rate in potential kidney donors. AB - INTRODUCTION: The aim of this study was to compare two gamma camera-based methods (Gates' method and Inoue's method) for measuring glomerular filtration rate (GFR) with Russell's two plasma sample clearance method (2-PSC), which was taken as the gold standard. MATERIALS AND METHODS: In 94 healthy potential kidney donors (25 women and 69 men), GFR was measured by means of the 2-PSC method and was compared with Gates' and Inoue's methods of assessing GFR after technetium-99m-labeled diethylene triamine penta-acetic acid (99 mTc-DTPA) injection. RESULTS: Inoue's method showed no statistically significant difference (P=0.22) with the gold standard (2-PSC); there was good correlation (r=0.69) and least bias (-1.91 ml/min/1.73 m2, root mean squared error=11.85 ml/min/1.73 m2). Gates' method showed weak correlation (r=0.36) and tended to underestimate GFR by 21% with bias of 25 ml/min/1.73 m2 and root mean squared error of 29.97. CONCLUSION: For a normal healthy adult population, Inoue's method gives a better measure of GFR in contrast to Gates' method when compared with 2-PSC method of GFR calculation. PMID- 25714669 TI - A new visible-light-excitable ICT-CHEF-mediated fluorescence 'turn-on' probe for the selective detection of Cd(2+) in a mixed aqueous system with live-cell imaging. AB - A new quinoline based sensor was developed and applied for the selective detection of Cd(2+) both in vitro and in vivo. The designed probe displays a straightforward approach for the selective detection of Cd(2+) with a prominent fluorescence enhancement along with a large red shift (~38 nm), which may be because of the CHEF (chelation-enhanced fluorescence) and ICT (internal charge transfer) processes after interaction with Cd(2+). The interference from other biologically important competing metal ions, particularly Zn(2+), has not been observed. The visible-light excitability of the probe merits in the viewpoint of its biological application. The probe enables the detection of intracellular Cd(2+) with non-cytotoxic effects, which was demonstrated with the live RAW cells. The experimentally observed change in the structure and electronic properties of the sensor after the addition of Cd(2+) were modelled by the density functional theory (DFT) and time-dependent density functional theory (TDDFT) computational calculations, respectively. Moreover, the test strip experiment with this sensor exhibits both absorption and fluorescence color changes when exposed to Cd(2+) in a mixed aqueous solution, which also makes the probe more useful. The minimum limit of detection of Cd(2+) by the probe was in the range of 9.9 * 10(-8) M level. PMID- 25714671 TI - Liver protein profiles in insulin receptor-knockout mice reveal novel molecules involved in the diabetes pathophysiology. AB - Liver has a principal role in glucose regulation and lipids homeostasis. It is under a complex control by substrates such as hormones, nutrients, and neuronal impulses. Insulin promotes glycogen synthesis, lipogenesis, and lipoprotein synthesis and inhibits gluconeogenesis, glycogenolysis, and VLDL secretion by modifying the expression and enzymatic activity of specific molecules. To understand the pathophysiological mechanisms leading to metabolic liver disease, we analyzed liver protein patterns expressed in a mouse model of diabetes by proteomic approaches. We used insulin receptor-knockout (IR(-/-)) and heterozygous (IR(+/-)) mice as a murine model of liver metabolic dysfunction associated with diabetic ketoacidosis and insulin resistance. We evaluated liver fatty acid levels by microscopic examination and protein expression profiles by orthogonal experimental strategies using protein 2-DE MALDI-TOF/TOF and peptic nLC-MS/MS shotgun profiling. Identified proteins were then loaded into Ingenuity Pathways Analysis to find possible molecular networks. Twenty-eight proteins identified by 2-DE analysis and 24 identified by nLC-MS/MS shotgun were differentially expressed among the three genotypes. Bioinformatic analysis revealed a central role of high-mobility group box 1/2 and huntigtin never reported before in association with metabolic and related liver disease. A different modulation of these proteins in both blood and hepatic tissue further suggests their role in these processes. These results provide new insight into pathophysiology of insulin resistance and hepatic steatosis and could be useful in identifying novel biomarkers to predict risk for diabetes and its complications. PMID- 25714670 TI - Enhanced fatty acid oxidation in adipocytes and macrophages reduces lipid-induced triglyceride accumulation and inflammation. AB - Lipid overload in obesity and type 2 diabetes is associated with adipocyte dysfunction, inflammation, macrophage infiltration, and decreased fatty acid oxidation (FAO). Here, we report that the expression of carnitine palmitoyltransferase 1A (CPT1A), the rate-limiting enzyme in mitochondrial FAO, is higher in human adipose tissue macrophages than in adipocytes and that it is differentially expressed in visceral vs. subcutaneous adipose tissue in both an obese and a type 2 diabetes cohort. These observations led us to further investigate the potential role of CPT1A in adipocytes and macrophages. We expressed CPT1AM, a permanently active mutant form of CPT1A, in 3T3-L1 CARDelta1 adipocytes and RAW 264.7 macrophages through adenoviral infection. Enhanced FAO in palmitate-incubated adipocytes and macrophages reduced triglyceride content and inflammation, improved insulin sensitivity in adipocytes, and reduced endoplasmic reticulum stress and ROS damage in macrophages. We conclude that increasing FAO in adipocytes and macrophages improves palmitate-induced derangements. This indicates that enhancing FAO in metabolically relevant cells such as adipocytes and macrophages may be a promising strategy for the treatment of chronic inflammatory pathologies such as obesity and type 2 diabetes. PMID- 25714672 TI - Carbon monoxide reverses adipose tissue inflammation and insulin resistance upon loss of ovarian function. AB - We hypothesized that carbon monoxide (CO) might suppress chronic inflammation, which led to metabolic disturbances. Ovariectomy (OVX) was performed in mice to mimic chronic inflammation secondary to loss of ovarian function. OVX increased fat mass and the infiltration of highly inflammatory CD11c cells into adipose tissue (AT), resulting in a disturbance of glucose metabolism. Treatment of CO attenuated these; CO decreased recruitment of CD11c-expressing cells in AT and reduced expression of CD11c in bone marrow-derived macrophages, protecting them from M1 polarization. Upregulated cGMP and decreased reactive oxygen species were responsible for the inhibitory activity of CO on CD11c expression; knockdown of soluble guanylate cyclase or heme oxygenase-1 using small interfering RNAs reduced this inhibition substantially. Improved OVX-induced insulin resistance (IR) by CO was highly associated with its activity to attenuate AT inflammation. Our results suggest a therapeutic value of CO to treat postmenopausal IR by reducing AT inflammation. PMID- 25714674 TI - Pancreatic beta-cell dysfunction in polycystic ovary syndrome: role of hyperglycemia-induced nuclear factor-kappaB activation and systemic inflammation. AB - In polycystic ovary syndrome (PCOS), oxidative stress is implicated in the development of beta-cell dysfunction. However, the role of mononuclear cell (MNC) derived inflammation in this process is unclear. We determined the relationship between beta-cell function and MNC-derived nuclear factor-kappaB (NF-kappaB) activation and tumor necrosis factor-alpha (TNF-alpha) secretion in response to a 2-h 75-g oral glucose tolerance test (OGTT) in normoglycemic women with PCOS (15 lean, 15 obese) and controls (16 lean, 14 obese). First- and second-phase beta cell function was calculated as glucose-stimulated insulin secretion (insulin/glucose area under the curve for 0-30 and 60-120 min, respectively) * insulin sensitivity (Matsuda Index derived from the OGTT). Glucose-stimulated NF kappaB activation and TNF-alpha secretion from MNC, and fasting plasma thiobarbituric acid-reactive substances (TBARS) and high-sensitivity C-reactive protein (hs-CRP) were also assessed. In obese women with PCOS, first- and second phase beta-cell function was lower compared with lean and obese controls. Compared with lean controls, women with PCOS had greater change from baseline in NF-kappaB activation and TNF-alpha secretion, and higher plasma TBARS. beta-Cell function was inversely related to NF-kappaB activation (1st and 2nd) and TNF alpha secretion (1st), and plasma TBARS and hs-CRP (1st and 2nd). First- and second-phase beta-cell function also remained independently linked to NF-kappaB activation after adjustment for body fat percentage and TBARS. In conclusion, beta-cell dysfunction in PCOS is linked to hyperglycemia-induced NF-kappaB activation from MNC and systemic inflammation. These data suggest that in PCOS, inflammation may play a role in impairing insulin secretion before the development of overt hyperglycemia. PMID- 25714673 TI - Loss of survival factors and activation of inflammatory cascades in brain sympathetic centers in type 1 diabetic mice. AB - Neuroinflammation and neurodegeneration have been observed in the brain in type 1 diabetes (T1D). However, little is known about the mediators of these effects. In T1D mice with 12- and 35-wk duration of diabetes we examined two mechanisms of neurodegeneration, loss of the neuroprotective factors insulin-like growth factor I (IGF-I) and IGF-binding protein-3 (IGFBP-3) and changes in indoleamine 2,3 dioxygenase (IDO) expression in the brain, and compared the response to age matched controls. Furthermore, levels of matrix metalloproteinase-2 (MMP-2), nucleoside triphosphate diphosphohydrolase-1 (CD39), and ionized calcium-binding adaptor molecule 1 (Iba-1) were utilized to assess inflammatory changes in astrocytes, microglia, and blood vessels. In the diabetic hypothalamus (HYPO), we observed 20% reduction in neuronal soma diameter (P<0.05) and reduced neuronal expression of IGFBP-3 (-32%, P<0.05) and IGF-I (-15%, P<0.05) compared with controls at 35 wk. In diabetic HYPO, MMP-2 expression was increased in astrocytes (46%, P<0.01), and IDO+ cell density rose by (62%, P<0.05). CD39 expression dropped by 30% (P<0.05) in microglia and blood vessels. With 10 wk of systemic treatment using minocycline, an anti-inflammatory agent that crosses the blood brain barrier, MMP-2, IDO, and CD39 levels normalized (P<0.05). Our results suggest that increased IDO and early loss of CD39+ protective cells lead to activation of inflammation in sympathetic centers of the CNS. As a downstream effect, the loss of the neuronal survival factors IGFBP-3 and IGF-I and the neurotoxic products of the kynurenine pathway contribute to the loss of neuronal density observed in the HYPO in T1D. PMID- 25714675 TI - Analysis of the liver lipidome reveals insights into the protective effect of exercise on high-fat diet-induced hepatosteatosis in mice. AB - The accumulation of lipid at ectopic sites, including the skeletal muscle and liver, is a common consequence of obesity and is associated with tissue-specific and whole body insulin resistance. Exercise is well known to improve insulin resistance by mechanisms not completely understood. We performed lipidomic profiling via mass spectrometry in liver and skeletal muscle samples from exercise-trained mice to decipher the lipid changes associated with exercise induced improvements in whole body glucose metabolism. Obesity and insulin resistance were induced in C57BL/6J mice by high-fat feeding for 4 wk. Mice then underwent an exercise training program (treadmill running) 5 days/wk (Ex) for 4 wk or remained sedentary (Sed). Compared with Sed, Ex displayed improved (P < 0.01) whole body metabolism as measured via an oral glucose tolerance test. Deleterious lipid species such as diacylglycerol (P < 0.05) and cholesterol esters (P < 0.01) that accumulate with high-fat feeding were decreased in the liver of trained mice. Furthermore, the ratio of phosphatidylcholine (PC) to phosphatidylethanolamine (PE) (the PC/PE ratio), which is associated with membrane integrity and linked to hepatic disease progression, was increased by training (P < 0.05). These findings occurred without corresponding changes in the skeletal muscle lipidome. A concomitant decrease (P < 0.05) was observed for the fatty acid transporters CD36 and FATP4 in the liver, suggesting that exercise stimulates a coordinated reduction in fatty acid entry into hepatocytes. Given the important role of the liver in the regulation of whole body glucose homeostasis, hepatic lipid regression may be a key component by which exercise can improve metabolism. PMID- 25714678 TI - Distinct lipid effects on tBid and Bim activation of membrane permeabilization by pro-apoptotic Bax. AB - After exposure to stressful stimuli, apoptotic signals can be relayed to mitochondria by pro-apoptotic activator proteins, tBid (truncated Bid/p15) and Bim (Bcl-2 interacting mediator), which activate Bax (Bcl-2 associated X protein) and or Bak (Bcl-2 antagonist/killer) to induce mitochondrial outer membrane (MOM) permeabilization (MOMP). These protein-protein and protein-membrane interactions are critical for apoptosis regulation, since MOMP irreversibly leads to cell death. Whereas the distinct roles of tBid and Bim as sensors of different types of stress are well recognized, it is not known whether the molecular mechanisms whereby they initiate MOMP are the same. In the present study, we compare membrane permeabilization by Bax activated by either cBid [cleaved Bid (p7 and p15)] or Bim and we examine the role of membrane lipids in the recruitment and activation of these three Bcl-2 (B-cell lymphoma 2) pro-apoptotic proteins. We employ fluorescently-labelled proteins and liposomes to quantify the effects of specific lipids on each of the well-characterized steps in Bax-mediated membrane permeabilization. We show that high levels of cholesterol in the membrane inhibit permeabilization by categorically identifying the recruitment of Bax by the activators and Bax insertion in the membrane as the steps being hindered by cholesterol. Furthermore, we show that binding of both cBid and Bim to membranes is facilitated by electrostatic interactions with anionic phospholipids. However, whereas Bim does not require any particular anionic lipids, the conformational change in tBid depends on cardiolipin (CL). This suggests that CL can activate tBid in a similar manner to Mtch2 (mitochondrial carrier homologue 2). Thus, lipids modify multiple aspects of Bax-mediated membrane permeabilization. PMID- 25714679 TI - Correction to in vitro bioaccessibility of carotenoids, flavonoids, and vitamin C from differently processed oranges and orange juices [Citrus sinensis (L.) Osbeck]. PMID- 25714676 TI - Skeletal muscle dysfunction is associated with derangements in mitochondrial bioenergetics (but not UCP3) in a rodent model of sepsis. AB - Muscle dysfunction is a common feature of severe sepsis and multiorgan failure. Recent evidence implicates bioenergetic dysfunction and oxidative damage as important underlying pathophysiological mechanisms. Increased abundance of uncoupling protein-3 (UCP3) in sepsis suggests increased mitochondrial proton leak, which may reduce mitochondrial coupling efficiency but limit reactive oxygen species (ROS) production. Using a murine model, we examined metabolic, cardiovascular, and skeletal muscle contractile changes following induction of peritoneal sepsis in wild-type and Ucp3(-/-) mice. Mitochondrial membrane potential (Deltapsim) was measured using two-photon microscopy in living diaphragm, and contractile function was measured in diaphragm muscle strips. The kinetic relationship between membrane potential and oxygen consumption was determined using a modular kinetic approach in isolated mitochondria. Sepsis was associated with significant whole body metabolic suppression, hypothermia, and cardiovascular dysfunction. Maximal force generation was reduced and fatigue accelerated in ex vivo diaphragm muscle strips from septic mice. Deltapsim was lower in the isolated diaphragm from septic mice despite normal substrate oxidation kinetics and proton leak in skeletal muscle mitochondria. Even though wild-type mice exhibited an absolute 26 +/- 6% higher UCP3 protein abundance at 24 h, no differences were seen in whole animal or diaphragm physiology, nor in survival rates, between wild-type and Ucp3(-/-) mice. In conclusion, this murine sepsis model shows a hypometabolic phenotype with evidence of significant cardiovascular and muscle dysfunction. This was associated with lower Deltapsim and alterations in mitochondrial ATP turnover and the phosphorylation pathway. However, UCP3 does not play an important functional role, despite its upregulation. PMID- 25714677 TI - Peripheral insulin resistance in obese girls with hyperandrogenism is related to oxidative phosphorylation and elevated serum free fatty acids. AB - Hyperandrogenic syndrome (HAS) is associated with insulin resistance (IR) and type 2 diabetes. Muscle IR in type 2 diabetes is linked with defects in mitochondrial oxidative capacity. In vivo muscle mitochondrial function has not been studied in HAS, especially in youth, who are early in the disease process. Our goal was to measure muscle mitochondrial oxidative function and peripheral IR in obese youth with HAS. Obese girls without HAS [n = 22, age 15(13,17) yr, BMI Z score 2.05 +/- 0.37] and with HAS [n = 35, age 15(14,16) yr, BMI Z-score 2.18 +/- 0.30] were enrolled. Mitochondrial function was assessed with (31)phosphorus MR spectroscopy before, during, and after near-maximal isometric calf exercise, and peripheral IR was assessed with an 80 mU.m(-2).min(-1) hyperinsulinemic euglycemic clamp. Girls with HAS had higher androgens [free androgen index 7.9(6.6,15.5) vs. 3.5(3.0,4.0), P < 0.01] and more IR [glucose infusion rate 9.4(7.0, 12,2) vs. 14.5(13.2,15.8) mg.kg lean(-1).min(-1), P < 0.01]. HAS girls also had increased markers of inflammation including CRP, platelets, and white blood cell count and higher serum free fatty acids during hyperinsulinemia. Mitochondrial oxidative phosphorylation was lower in HAS [0.11(0.06,0.19) vs. 0.18(0.12,0.23) mmol/s, P < 0.05], although other spectroscopy markers of mitochondrial function were similar between groups. In multivariate analysis of the entire cohort, IR related to androgens, oxidative phosphorylation, and free fatty acid concentrations during hyperinsulinemia. These relationships were present in just the HAS cohort as well. Obese girls with HAS have significant peripheral IR, which is related to elevated androgens and free fatty acids and decreased mitochondrial oxidative phosphorylation. These may provide future options as targets for therapeutic intervention. PMID- 25714680 TI - Non-coding RNA: Circular RNAs promote transcription. PMID- 25714682 TI - Fanning the flames of CIN. PMID- 25714683 TI - gDNA Q-PCR for clinical monitoring of CML. PMID- 25714681 TI - Replication fork reversal in eukaryotes: from dead end to dynamic response. AB - The remodelling of replication forks into four-way junctions following replication perturbation, known as fork reversal, was hypothesized to promote DNA damage tolerance and repair during replication. Albeit conceptually attractive, for a long time fork reversal in vivo was found only in prokaryotes and specific yeast mutants, calling its evolutionary conservation and physiological relevance into question. Based on the recent visualization of replication forks in metazoans, fork reversal has emerged as a global, reversible and regulated process, with intriguing implications for replication completion, chromosome integrity and the DNA damage response. The study of the putative in vivo roles of recently identified eukaryotic factors in fork remodelling promises to shed new light on mechanisms of genome maintenance and to provide novel attractive targets for cancer therapy. PMID- 25714684 TI - Formation of N3(-) during interaction of NO with reduced ceria. AB - We show that the first stages of interaction between NO and reduced ceria comprise the formation of azides, N3(-), with simultaneous oxidation of Ce(3+) to Ce(4+). This finding imposes revision on some current views of catalytic NO conversion and may contribute to design of new deNOx materials and processes. PMID- 25714686 TI - Hemodynamic changes with two lipid emulsions for treatment of bupivacaine toxicity in swines. AB - PURPOSE: To compare the hemodynamic changes following two different lipid emulsion therapies after bupivacaine intoxication in swines. METHODS: Large White pigs were anesthetized with thiopental, tracheal intubation performed and mechanical ventilation instituted. Hemodynamic variables were recorded with invasive pressure monitoring and pulmonary artery catheterization (Swan-Ganz catheter). After a 30-minute resting period, 5 mg.kg-1 of bupivacaine by intravenous injection was administered and new hemodynamic measures were performed 1 minute later; the animals were than randomly divided into three groups and received 4 ml.kg-1 of one of the two different lipid emulsion with standard long-chaim triglyceride, or mixture of long and medium-chain triglyceride, or saline solution. Hemodynamic changes were then re-evaluated at 5, 10, 15, 20 and 30 minutes. RESULTS: Bupivacaine intoxication caused fall in arterial blood pressure, cardiac index, ventricular systolic work index mainly and no important changes in vascular resistances. Both emulsion improved arterial blood pressure mainly increasing vascular resistance since the cardiac index had no significant improvement. On the systemic circulation the hemodynamic results were similar with both lipid emulsions. CONCLUSION: Both lipid emulsions were efficient and similar options to reverse hypotension in cases of bupivacaine toxicity. PMID- 25714685 TI - ATPaseTb2, a unique membrane-bound FoF1-ATPase component, is essential in bloodstream and dyskinetoplastic trypanosomes. AB - In the infectious stage of Trypanosoma brucei, an important parasite of humans and livestock, the mitochondrial (mt) membrane potential (Deltapsim) is uniquely maintained by the ATP hydrolytic activity and subsequent proton pumping of the essential FoF1-ATPase. Intriguingly, this multiprotein complex contains several trypanosome-specific subunits of unknown function. Here, we demonstrate that one of the largest novel subunits, ATPaseTb2, is membrane-bound and localizes with monomeric and multimeric assemblies of the FoF1-ATPase. Moreover, RNAi silencing of ATPaseTb2 quickly leads to a significant decrease of the Deltapsim that manifests as a decreased growth phenotype, indicating that the FoF1-ATPase is impaired. To further explore the function of this protein, we employed a trypanosoma strain that lacks mtDNA (dyskinetoplastic, Dk) and thus subunit a, an essential component of the proton pore in the membrane Fo-moiety. These Dk cells generate the Deltapsim by combining the hydrolytic activity of the matrix-facing F1-ATPase and the electrogenic exchange of ATP4- for ADP3- by the ATP/ADP carrier (AAC). Surprisingly, in addition to the expected presence of F1-ATPase, the monomeric and multimeric FoF1-ATPase complexes were identified. In fact, the immunoprecipitation of a F1-ATPase subunit demonstrated that ATPaseTb2 was a component of these complexes. Furthermore, RNAi studies established that the membrane-bound ATPaseTb2 subunit is essential for maintaining normal growth and the Deltapsim of Dk cells. Thus, even in the absence of subunit a, a portion of the FoF1-ATPase is assembled in Dk cells. PMID- 25714687 TI - Low-level laser therapy modulates musculoskeletal loss in a skin burn model in rats. AB - PURPOSE: To investigate the effectiveness of low-level laser therapy (LLLT) on gastrocnemius muscle morphology and Myod immunoexpression in a model of dorsal burn in rats. METHODS: Sixteen male Wistar rats were distributed into two groups: control group (CG): rats submitted to scald burn injury without treatment and laser treated group (LG): rats submitted to scald burn injury and treated with laser therapy. Fourteen days post-surgery, gastrocnemius muscle was evaluated being the specimens stained with HE and morphometric data was evaluated. MyoD expression was assessed by immunohistochemistry. RESULTS: The results showed that laser treated animals presented more organized tissue morphology compared to the non-treated animals, with a higher number of nucleus in the fibers. Also, the cross sectional area of the fibers and the MyoD immunoexpression in the laser treated groups was higher. CONCLUSION: Low-level laser therapy had positive effects on gastrocnemius muscle, improving tissue muscle morphology, increasing cross sectional area and MyoD immunoexpression. PMID- 25714688 TI - Which is the best route of administration for cell therapy in experimental model of small-for size syndrome in rats? AB - PURPOSE: To evaluate which is the best route of administration for cell therapy in experimental rat model of small-for size syndrome. METHODS: A total of 40 rats underwent partial hepatectomy (70%) that induces the small-for-size syndrome and were divided into four groups of route administration: intravenous, intraperitoneal, enteral and tracheal. The small-for-size syndrome model was designed with extended partial hepatectomy (70%). The animals were divided into four groups of routes administration: intravenous (n=10) - intravenously through the dorsal vein of the penis; intraperitoneal (n=10) - intraperitoneally in the abdominal cavity; enteral (n=10) - oroenteral with the placement of a number 4 urethral probe and maintained at third duodenal portion; tracheal (n=10) - after tracheal intubation. We track the animals and monitor them for 21 days; during this follow-up we evaluated the result of cell therapy application tracking animals using ultrasound, radiography and PET-scan. Statistical analysis was performed using GraphPad Prism Software(r). Differences were considered significant with the p<0.05. Data are presented as the median and variation for continuous variables. Comparisons between groups were made using analysis of the imaging test by the researchers. RESULTS: All four groups underwent partial hepatectomy of 70% liver tissue targeting the same weight of resected liver. Initially the PET-scan tests showed similarity in administered cells by different routes. However, in few days the route of intravenous administration showed to be the most appropriated to lead cells to the liver followed by enteral. The tracheal and peritoneal routes were not as much successful for this goal. CONCLUSION: The intravenous route is the best one to cell therapy in experimental rat model of small-for size-syndrome. PMID- 25714689 TI - Preconditioning with mono and polyunsaturated fatty acids and low-intensity electrical stimulation. Effects on skin repair in rats. AB - PURPOSE: To evaluate the effects of preconditioning with oils mixes containing omega3/omega6/omega9 associated with micro-currents on skin repair in rats. METHODS: One-hundred and eight Wistar rats randomized into G-1, G-2 and G-3 groups were treated with saline (0.9%), mix 1 (corn+soybean oils) and mix 2 (olive+canola+flaxseed oils), respectively, in a single dose (0.01ml/g) by gavage. Next, each group was subdivided into sham and stimulated subgroups. Pulsed-wave microcurrents (0.5 uA, 0.5 Hz) were applied to stimulated subgroups for 20 min. One hour later anesthetized rats were subjected to surgery. A dorsal incision (6 cm long) was carried out and closed with interrupted nylon sutures. Samples (1 cm2) were harvested from the mid-portion of the incision on the 7, 14, 21 post-operative (P.O.) days. Variables were analyzed using Mann-Whitney/Dunn tests Significance level was set to 5 % (p<0.05). RESULTS: Micro-currents promoted increase of exudate and reduction of epithelialization on day 7 in G1 rats. Mixes 1/2 reduced vascularization on 7/14th days P.O. Both 1/2 mixes reduced fibrosis on day 14. Preconditioning with mix 1 led to increased expression of NF-kB on the 7th day. CONCLUSION: Preconditioning with microcurrents has pro-inflammatory effects while oil mixes 1 and 2 decrease fibrosis and vascularization in the proliferative phase of cicatrization. PMID- 25714690 TI - Pentoxifylline and prostaglandin E1 action on ischemia and reperfusion of small intestine tissue in rats. An immunohistochemical study. AB - PURPOSE: To investigate the action of pentoxifylline (PTX) and prostaglandin E1 (PGE1) on ischemia and reperfusion of small intestine tissue in rats, using immunohistochemical analysis. METHODS: Thirty-five Wistar rats were distributed as follows: group A (n=10): subjected to intestinal ischemia and reperfusion for 60 min, with no drugs; group B (n=10): PTX given during tissue ischemia and reperfusion; group C (n=10): PGE1 given during tissue ischemia and reperfusion; group D (n=5): sham. A segment of the small intestine was excised from each euthanized animal and subjected to immunohistochemical examination. RESULTS: Mean number of cells expressing anti-FAS ligand in the crypts was highest in Group A (78.9 +/- 17.3), followed by groups B (16.7 +/- 2.8), C (11.3 +/- 1.8), and D (2.5 +/- 0.9), with very significant differences between groups (p<0.0001). CONCLUSIONS: The use of pentoxifylline or prostaglandin E1 proved beneficial during tissue reperfusion. The immunohistochemical results demonstrated a decrease in apoptotic cells, while protecting other intestinal epithelium cells against death after reperfusion, allowing these cells to renew the epithelial tissue. PMID- 25714691 TI - Copaiba oil effect on experimental jaw defect in Wistar rats. AB - PURPOSE: To evaluate the effects of copaiba oil on jaw defects repair in Wistar rats treated with bioglass or adipose tissue. METHODS: A jaw defect was randomly created in forty-two rats and filled with bioglass or adipose tissue. The two groups (Gbio and Gcell) were subdivided in three subgroups with seven animals each according to gavage administration: control (distillated water), oil (copaiba oil) and melox (meloxicam). Euthanasia was performed after forty post operative days. The bone formation was analyzed regarding the histological aspects. RESULTS: The osteoclasts activity was observed only in four subgroups (p=0.78). Regarding the osteoblasts presence, it was very similar between the subgroups, the difference was due to Gcell-melox (p=0.009) that presented less osteoblastic activity. The inflammatory cells were more evident in Gcell-melox subgroup, however, there was no difference in comparison with the other subgroups (p=0.52). Bone formation was observed in all subgroups, just two animals showed no bone formation even after 40 days. More than 50% of bone matrix mineralization was observed in 56% (23 animals) of the analyzed areas. The bone matrix mineralization was not different between subgroups (p=0.60). CONCLUSIONS: The subgroups that received copaiba oil showed bone repair, although not statistically significant in comparison to subgroups treated with meloxicam or controls. Copaiba oil administered by gavage had no effect on bone repair in this experimental model. PMID- 25714692 TI - Effects of immunosuppression with tacrolimus and mycophenolate mofetil on renal histology and function in single kidney rats submitted to ischemia and reperfusion. AB - PURPOSE: To evaluate renal histological changes and renal function in single kidney rats submitted to renal ischemia-reperfusion and to immunosuppression with tacrolimus and mycophenolate-mofetil. METHODS: Experimental study with 80 Wistar rats distributed into control, Sham and six other groups treated with immunosuppressive drugs. Animals undergoing surgery, right nephrectomy and left renal clamping, killed on the 14th day and analyzed for renal histology, urea and creatinine. RESULTS: The group receiving tacrolimus at higher doses (T3) showed renal histological lesions indicative of early nephrotoxicity, and significant increase in urea and creatinine. The group M (mycophenolate-mofetil alone) and the group M2 (mycophenolate-mofetil combined with half the usual dose of tacrolimus) presented a slight rise in serum urea. The groups using mycophenolate mofetil alone or combined with tacrolimus showed creatinine levels similar to that of the group T3. CONCLUSIONS: Histologically, the association of injury by ischemia-reperfusion with the use of tacrolimus or mycophenolate-mofetil alone demonstrated a higher rate of renal changes typical of early nephrotoxicity. In laboratory, the combination of injury by ischemia-reperfusion with tacrolimus at higher doses proved to be nephrotoxic. PMID- 25714693 TI - Effects of blocking alphavbeta3 integrin by a recombinant RGD disintegrin on remodeling of wound healing after induction of incisional hernia in rats. AB - PURPOSE: To investigate the changes induced by DisBa-01 on repair of wound healing after induced incisional hernia (IH) in rats. METHODS: Thirty two male albino rats were submitted to IH and divided into four experimental groups: G1, placebo control; G2, DisBa-01-treated; G3, anti-alphavbeta3 antibodies-treated and G4, anti-alpha2 antibodies-treated. Histological, biochemical and extracellular matrix remodeling analysis of abdominal wall were evaluated. RESULTS: After 14 days, 100% of the G2 did not present hernia, and the hernia ring was closed by a thin membrane. In contrast, all groups maintained incisional hernia. DisBa-01 also increased the number macrophages and fibroblasts and induced the formation of new vessels. Additionally, MMP-2 was strongly activated only in G2 (p<0.05). Anti- alphavbeta3-integrin antibodies produced similar results than DisBa-01 but not anti-alpha2 integrin blocking antibodies. CONCLUSION: DisBa-01 has an important role in the control of wound healing and the blocking of this integrin may be an interesting therapeutically strategy in incisional hernia. PMID- 25714694 TI - Outcome of pigs with short gut syndrome submitted to orthotopic intestinal transplantation. AB - PURPOSE: To evaluate the current model of small bowel resection and intestinal transplantation in pigs. METHODS: Forty two Large White pigs were distributed in five groups: G1(n=6), G2(n=6) and G3(n=6) were submitted to 80%,100% and 100% plus right colon resection respectively and G4(n=7) and G5(n=5) to 100% SBR plus IT without and with immunosuppression based on Tacrolimus and Mycophenolic acid. Evaluation included weight control, clinical status, biochemical analysis and endoscopies for graft biopsies. Follow-up in G1 and 2 was 84 days, while in G3, four and five was +/- three weeks. RESULTS: G1 increased weight suggesting adaptation while G2 and 3 loused weight and inadequate adaptation. G4 and 5 died of acute cellular rejection (ACR) and sepses respectively. Overall survival in G1, 2, 3, 4 and 5 at 30 days was 100, 100, 0 and 20 %, respectively. Medium survival in G4 and 5 was 14 and 16 days. CONCLUSIONS: The resection of 80% of small intestine in pigs is not suitable for short bowel syndrome induction. Intestinal transplantation with the proposed immunosuppression protocol was effective in prevent the occurrence of severe acute rejection, but inappropriate to increase recipients survival. PMID- 25714695 TI - Study of the clinical and histopathological repercussions of the "omental band" in dogs' stomach. AB - PURPOSE: To evaluate the efficacy of the "omental band" as a bariatric surgical technique. METHODS: A sample of 35 dogs was studied. The Test Group was composed by 20 dogs. Of these, six were observed by 10 days, six were observed by 20 days and eight were observed by 30 days of post-operatory. The Control Group was composed by 15 dogs. Of these, five were observed by 10 days, five were observed by 20 days and five were observed by 30 days of post-operatory. The weight loose was the variable utilized to the evaluation of the efficacy of the surgical technique described in this study, once all of the dogs were weighted in precision balance before the surgical act and at the end of the post-operatory observation period. RESULTS: At the end of the study it was observed that the weight loose of the dogs submitted to the "omental band's" surgical technique was meaningfully higher in comparison with the dogs of the Control Group at the end of the post-operatory observation period. CONCLUSION: The surgical technique of the "omental band" showed effective in dogs, once has proposed a meaningfully weight loose. PMID- 25714696 TI - Portland cement versus MTA as a root-end filling material. A pilot study. AB - PURPOSE: To assess periradicular lesions clinically and by computed tomography (CT) after endodontic surgery using either Portland cement or mineral trioxide aggregate (MTA) as a root-end filling material. METHODS: Three patients diagnosed with periradicular lesions by cone-beam CT underwent endodontic surgery with root end filling. Patient A was treated with MTA as the root-end filling material, patient B was treated with Portland cement and patient C had two teeth treated, one with MTA and the other with Portland cement. Six months after surgery, the patients were assessed clinically and by CT scan and the obtained results were compared. RESULTS: Periradicular tissue regeneration was observed in all cases, with no significant differences in bone formation when comparing the use of MTA and Portland cement as root-end filling materials. CONCLUSION: Both mineral trioxide aggregate and Portland cement were successful in the treatment of periradicular lesions. PMID- 25714697 TI - Development of a flow method for the hydroboration/oxidation of olefins. AB - A method for the continuous preparation of alcohols by hydroboration/oxidation of olefins using flow techniques is described. The process allows the isolation of up to 120 mmol h(-1) of the desired alcohol in a very rapid manner with good functional group tolerance. The flow setup can be modified to perform a continuous extraction of the desired alcohol from the biphasic mixture produced by the reaction. PMID- 25714698 TI - A Pan-Cancer Review of ALK Mutations: Implications for Carcinogenesis and Therapy. AB - The anaplastic lymphoma kinase (ALK) is a druggable target for cancer therapy. By and large, the oncogenic activation of ALK in human tumors is known to occur by gene rearrangement (e.g. EML4-ALK, NMP-ALK, etc.). Clinical use of ALK inhibitors for "ALK-rearranged" lung cancers has remarkably improved patient survival. To date, much has been known about ALK gene rearrangement in human carcinogenesis and its drug sensitivity relationship. However, emerging genomic data from the Cancer Genome Atlas (TCGA, USA) are now revealing common ALK point mutations (~3.06%) in various cancer types other than lung cancer. Importantly, several recent studies have demonstrated that ALK point mutations, independent of ALK gene rearrangement, can be oncogenic. Thus, ALK mutations can be pathogenically and perhaps therapeutically important for various cancer types. Here, we summarized the latest ALK mutation frequencies and mutation patterns across 17 human cancer types stemming from TCGA. Unlike many other oncogenes with high frequency of hotspot mutations, ALK point mutations tend to span along the entire gene. Up till now, several recurrent mutations (G263, R401, R551, P968 and E1242) and mutation-rich cluster regions have been identified, but their functional effects remain unknown. We also conducted a comprehensive review of all ALK mutated human cancer cell lines (from the Cell Line Encyclopedia (CCLE) and the NCI-60 panel), which can be used as model systems for ALK mutation biology and drug screening studies. Lastly, we summarized both the preclinical and clinical findings of ALK mutations on carcinogenesis and drug sensitivity, which may provide important insight into new treatment strategies and prompt future ALK mutation studies in various cancer types. PMID- 25714699 TI - Combination Therapy of Intraperitoneal Rapamycin and Convection- Enhanced Delivery of Nanoliposomal CPT-11 in Rodent Orthotopic Brain Tumor Xenografts. AB - BACKGROUND: Glioblastoma multiforme (GBM) is the most malignant histological type of glioma. It exhibits an extremely aggressive action including invasion of large zones of brain parenchyma. Even after the application of surgery, radio and chemotherapy, the effect and survival for patients with GBM continue to be very poor. The PI3K/AKT/mTOR is a key pathway in the regulation of the proliferation of cancer cells. This is the reason to consider the mTOR inhibitors such as rapamycin analogs as an encouraging therapy for malignant glioma, but current investigations suggest that single inhibition of mTOR may be insufficient. For this reason, there is a need for the use of more than one agent rationally combined. METHODS: In this study, we have evaluated the therapeutic potential of the combination of two different drugs: intraperitoneal rapamycin and convection enhanced delivery of nanoliposomes containing the topoisomerase I inhibitor CPT 11. The effect was analyzed by flow cytometry, cell growth, immunocytochemistry and immunohistochemistry, and rodent orthotopic xenograft survival analysis. RESULTS: The combination presented remarkable efficacy in a survival study. We present an increase in survival of 6-fold in xenotransplanted animals without rise in toxicity. CONCLUSION: In summary, we propose a very powerful new combination therapy for glioma. PMID- 25714700 TI - MiRNA153 Reduces Effects of Chemotherapeutic Agents or Small Molecular Kinase Inhibitor in HCC Cells. AB - MicroRNA-153 (miR-153) is considered to be a tumor regulator. Silencing of miR 153 expression induced apoptosis in breast cancer cells. Data on mechanism suggest that up-regulation of miR- 153 level promotes cell proliferation via the down regulation of the expression of PTEN or FOXO1, which attenuates the proliferation of cancerous cells. This study aims to identify the effect of miR 153 on the activity of chemotherapeutic and targeted agents in HCC cells and to investigate the mechanisms involved. MTT, soft agar, trans-well and flow cytometry assays were performed to examine whether miR-153 down-regulated the activity of the chemotherapeutic and targeted drugs, Sorafenib, Etoposide and Paclitaxel in HCC cells. The rate of proliferation inhibition, relative survival rates and IC50 values of each drug were calculated. Western blot and luciferase assays were performed to assess whether miR-153 modulates the expression of important genes related to cell proliferation, apoptosis or survival. Results showed that miR-153 attenuated the effect of Etoposide, Paclitaxel and Sorafenib on HepG2 cells; the IC50 value increased from 0.25+/-0.01MUmol/L to 1.02+/ 0.14MUmol/L, 0.05+/-0.01MUmol/L to 0.14+/-0.02MUmol/L and from 1.09+/-0.15MUmol/L to 5.18+/-0.99MUmol/L, respectively. In addition, miR-153 also reduced the effect of these drugs on MHCC- 97H, MHCC-97 L and L-02 cells; and it also reduced the effects of Sorafenib, Etoposide and Paclitaxel on anchor-independent growth of HepG2 cells. Over-expression of miR-153 down-regulated the activity of Etoposide and Paclitaxel on cell cycle arrest of HepG2 cells and the effect of Sorafenib on the invasion and migration of HepG2 cells. Furthermore, overexpression of miR-153 also enhanced the growth of HepG2, MHCC-97H, MHCC-97 L and L-02 cells. Mechanisms data showed that overexpression of miR-153 down regulated the activity of luciferase reporters, p15-Luc and p21-Luc; and enhanced the protein level of pro survival or anti-apoptosis proteins Survivin and BCL-2. These results show that overexpression of miR-153 protects HepG2 cells against the effects of these drugs via multiple mechanisms, and miR-153 may be a novel target for HCC in future diagnostic and therapeutic interventions. PMID- 25714701 TI - Targeting microparticle biogenesis: a novel approach to the circumvention of cancer multidrug resistance. AB - Microparticles (MPs) are released from most eukaryotic cells after the vesiculation of the plasma membrane and serve as vectors of long and short-range signaling. MPs derived from multidrug resistant (MDR) cancer cells carry molecular components of the donor cell such as nucleic acids and proteins, and can alter the activity of drug-sensitive recipient cells through the transfer of their cargo. Given the substantial role of MPs in the acquisition and dissemination of MDR, we propose that the inhibition of MP release provides a novel therapeutic approach. This study characterises the effect of a panel of molecules known to act on MP-biosynthetic pathways. We demonstrate a differential effect by these molecules on MP inhibition that appear dependent on the release of intracellular calcium stores following activation with the calcium ionophore A23187. Calpain inhibitor, PD-150606; a selective inhibitor of Rho-associated, coiled-coil containing protein kinase (ROCK), Y-27632; and the vitamin B5 derivative pantethine, inhibited MP release only upon prior activation with A23187. Calpain inhibitor II showed significant inhibition in the absence of cell activation, whereas the vitamin B5 derivatives cystamine dihydrochloride and cysteamine hydrochloride showed no effect on MP inhibition under either condition. In contrast the classical pharmacological inhibitor of MDR, the calcium channel blocker Verapamil, showed an increase in MP formation on resting cells. These results suggest a potential role for calcium in the mechanism of action for PD-150606, Y-27632 and pantethine. These molecules, together with calpain inhibitor II have shown promise as modulators of MP release and warrant consideration as potential candidates for the development of an alternative therapeutic strategy for the prevention of MP-mediated MDR in cancer. PMID- 25714702 TI - Physicochemical and immunological assessment of engineered pure protein particles with different redox states. AB - The development of subunit antigen delivery formulations has become an important research endeavor, especially in cases where a whole cell vaccine approach has significant biosafety issues. Particle-based systems have shown particular efficacy due to their inherent immunogenicity. In some cases, fabrication techniques can lead to changes in the redox states of encapsulated protein antigens. By employing a uniform, well-characterized, single-protein system, it is possible to elucidate how the molecular details of particle-based protein antigens affect their induced immune responses. Using mesoporous silica templated, amide bond-stabilized ovalbumin particles, three types of particles were fabricated from native, reduced, and oxidized ovalbumin, resulting in particles with different physicochemical properties and immunogenicity. Phagocytosis, transcription factor activation, and cytokine secretion by a mouse macrophage cell line did not reveal significant differences between the three types of particles. Oxidation of the ovalbumin, however, was shown to inhibit the intracellular degradation of the particles compared with native and reduced ovalbumin particles. Slow intracellular degradation of the oxidized particles was correlated with inefficient antigen presentation and insignificant levels of T cell priming and antibody production in vivo. In contrast, particles fabricated from native and reduced ovalbumin were rapidly degraded after internalization by macrophages in vitro and resulted in significant T cell and B cell immune responses in vivo. Taken together, the current study demonstrates how the redox state of a protein antigen significantly impacts the immunogenicity of the particulate vaccine formulations. PMID- 25714704 TI - Enantioselective synthesis of dialkylated N-heterocycles by palladium-catalyzed allylic alkylation. AB - The enantioselective synthesis of alpha-disubstituted N-heterocyclic carbonyl compounds has been accomplished using palladium-catalyzed allylic alkylation. These catalytic conditions enable access to various heterocycles, such as morpholinone, thiomorpholinone, oxazolidin-4-one, 1,2-oxazepan-3-one, 1,3 oxazinan-4-one, and structurally related lactams, all bearing fully substituted alpha-positions. Broad functional group tolerance was explored at the alpha position in the morpholinone series. We demonstrate the utility of this method by performing various transformations on our useful products to readily access a number of enantioenriched compounds. PMID- 25714703 TI - Sleep and multisystem biological risk: a population-based study. AB - BACKGROUND: Short sleep and poor sleep quality are associated with risk of cardiovascular disease, diabetes, cancer, and mortality. This study examines the contribution of sleep duration and sleep quality on a multisystem biological risk index that is known to be associated with morbidity and mortality. METHODS: Analyses include a population-based sample from the Midlife Development in the United States survey recruited to the Biomarker substudy. A total of 1,023 participants aged 54.5 years (SD = 11.8), 56% female and 77.6% white, were included in the analyses. A multisystem biological risk index was derived from 22 biomarkers capturing cardiovascular, immune, lipid-metabolic, glucose-metabolic, sympathetic, parasympathetic, and hypothalamic-pituitary-adrenal systems. Self reported average sleep duration was categorized as short (<5 hrs), below normal (5 to <6.5 hrs), normal (6.5 to <8.5 hrs), and long sleepers (8.5+ hrs). Sleep quality was determined using the Pittsburgh Sleep Quality Index categorized as normal (<=5) and poor quality (>5) sleep. FINDINGS: Linear mixed effect models adjusting for age, gender, race, education, income, BMI, and health status were performed. As compared to normal sleepers, multisystem biological risk in both short (B(SE) = .38(.15), p<.01) and long sleepers (B(SE) = .28(.11), p<.01) were elevated. Poor quality sleep alone was associated with elevated multisystem biological risk (B(SE) = .15(.06), p = .01), but was not significant after adjustment for health status. All short sleepers reported poor sleep quality. However in the long sleepers, only those who reported poor sleep quality exhibited elevated multisystem biological risk (B(SE) = .93(.3), p = .002). CONCLUSIONS: Self-reported poor sleep quality with either short or long sleep duration is associated with dysregulation in physiological set points across regulatory systems, leading to elevated multisystem biological risk. Physicians should inquire about sleep health in the assessment of lifestyle factors related to disease risk, with evidence that healthy sleep is associated with lower multisystem biological risk. PMID- 25714705 TI - Neuronal expression of the human neuropeptide S receptor NPSR1 identifies NPS induced calcium signaling pathways. AB - The neuropeptide S (NPS) system was discovered as a novel neurotransmitter system a decade ago and has since been identified as a key player in the modulation of fear and anxiety. Genetic variations of the human NPS receptor (NPSR1) have been associated with pathologies like panic disorders. However, details on the molecular fundamentals of NPSR1 activity in neurons remained elusive. We expressed NPSR1 in primary hippocampal cultures. Using single-cell calcium imaging we found that NPSR1 stimulation induced calcium mobilization from the endoplasmic reticulum via activation of IP3 and ryanodine receptors. Store operated calcium channels were activated in a downstream process mediating entry of extracellular calcium. We provide the first detailed analysis of NPSR1 activity and the underlying intracellular pathways with respect to calcium mobilization in neurons. PMID- 25714706 TI - Noninvasive assessment of liver function. AB - PURPOSE OF REVIEW: It is our opinion that there is an unmet need in hepatology for a minimally or noninvasive test of liver function and physiology. Quantitative liver function tests define the severity and prognosis of liver disease by measuring the clearance of substrates whose uptake or metabolism is dependent upon liver perfusion or hepatocyte function. Substrates with high affinity hepatic transporters exhibit high 'first-pass' hepatic extraction and their clearance measures hepatic perfusion. In contrast, substrates metabolized by the liver have low first-pass extraction and their clearance measures specific drug metabolizing pathways. RECENT FINDINGS: We highlight one quantitative liver function test, the dual cholate test, and introduce the concept of a disease severity index linked to clinical outcome that quantifies the simultaneous processes of hepatocyte uptake, clearance from the systemic circulation, clearance from the portal circulation, and portal-systemic shunting. SUMMARY: It is our opinion that dual cholate is a relevant test for defining disease severity, monitoring the natural course of disease progression, and quantifying the response to therapy. PMID- 25714708 TI - The cellobiose sensor CebR is the gatekeeper of Streptomyces scabies pathogenicity. AB - A relatively small number of species in the large genus Streptomyces are pathogenic; the best characterized of these is Streptomyces scabies. The pathogenicity of S. scabies strains is dependent on the production of the nitrated diketopiperazine thaxtomin A, which is a potent plant cellulose synthesis inhibitor. Much is known about the genetic loci associated with plant virulence; however, the molecular mechanisms by which S. scabies triggers expression of thaxtomin biosynthetic genes, beyond the pathway-specific activator TxtR, are not well understood. In this study, we demonstrate that binding sites for the cellulose utilization repressor CebR occur and function within the thaxtomin biosynthetic cluster. This was an unexpected result, as CebR is devoted to primary metabolism and nutritive functions in nonpathogenic streptomycetes. In S. scabies, cellobiose and cellotriose inhibit the DNA-binding ability of CebR, leading to an increased expression of the thaxtomin biosynthetic and regulatory genes txtA, txtB, and txtR. Deletion of cebR results in constitutive thaxtomin A production and hypervirulence of S. scabies. The pathogenicity of S. scabies is thus under dual direct positive and negative transcriptional control where CebR is the cellobiose-sensing key that locks the expression of txtR, the key necessary to unlock the production of the phytotoxin. Interestingly, CebR-binding sites also lie upstream of and within the thaxtomin biosynthetic clusters in Streptomyces turgidiscabies and Streptomyces acidiscabies, suggesting that CebR is most likely an important regulator of virulence in these plant-pathogenic species as well. IMPORTANCE: What makes a microorganism pathogenic is not limited to the genes acquired for virulence. Using the main causative agent of scab lesions on root and tuber crops as an example, our work identified the subtle but essential genetic changes that generate the cis-acting elements necessary for proper timing of the expression of the cluster of genes responsible for the biosynthesis of thaxtomin A, the primary virulence factor in plant-pathogenic streptomycetes. These data illustrate a situation in which a regulator associated with primary metabolism in nonpathogens, CebR, has been coopted as a master regulator of virulence in pathogenic species. Furthermore, the manipulation of CebR-mediated control of thaxtomin production will facilitate overproduction of this natural and biodegradable herbicide for commercial purposes. Our work thus provides a concrete example of how a strictly theoretical and computational work was able to elucidate a regulatory mechanism associated with the virulence of a plant pathogen and to generate solutions to purely agro-industrial concerns. PMID- 25714707 TI - Novel pseudotaxis mechanisms improve migration of straight-swimming bacterial mutants through a porous environment. AB - Bacterial locomotion driven by flagella is given directionality by the chemotaxis signal transduction network. In the classic plate assays of migration in porous motility agar, efficient motility is compromised in chemotaxis mutants of diverse bacteria. Nonchemotactic mutants become trapped within the agar matrix. Suppressor mutations that prevent this entanglement but do not restore chemotaxis, a phenomenon designated pseudotaxis, were first reported to arise for Escherichia coli. In this study, novel mechanisms of pseudotaxis have been identified for the plant-pathogenic alphaproteobacterium Agrobacterium tumefaciens. Mutants with chemotaxis mutation suppressor (cms) mutations that impart enhanced migration in motility agar compared to that of their straight swimming, nonchemotactic parent were isolated. We find that pseudotaxis in A. tumefaciens occurs most commonly via mutations in the D1 domain of the flagellar hook protein, FlgE, but it can also be found less frequently to be due to mutations in the hook length regulator, FliK, or in the motor protein, MotA. Single-cell-tracking studies of cms mutants in bulk medium clearly reveal frequent changes in the direction of swimming, similar to the swimming of strains that are proficient for chemotaxis, but independent of a sensory mechanism. Our results suggest that the tumbling process can be tuned through mutation and evolution to optimize migration through complex, porous environments. IMPORTANCE: Chemotaxis sensory networks control direct bacterial motility by modulating flagellar rotary motion, alternating cellular movement between runs and tumbles. The straight-swimming phenotype of chemotaxis-deficient cells yields nonexpanding colonies in motility agar. Enhanced, chemotaxis-independent spreading, dubbed pseudotaxis, has been observed in Escherichia coli mutants. We have identified novel pseudotaxis mutations in Agrobacterium tumefaciens that alter the flagellar hook structure or motor, leading to randomly occurring reorientations observed in single-cell tracking studies in bulk medium. These directional changes allow the cells to migrate more efficiently than the parent strain through the agar matrix, independently of the chemotaxis process. These findings reveal that tumbling can be tuned for effective navigation in complex porous environments, analogous to the natural habitats for many bacteria, and provide evidence for the strong selective pressure exerted by the external environment on the basal pattern of motility, even in the absence of chemotaxis. PMID- 25714709 TI - Integrated microfluidic card with TaqMan probes and high-resolution melt analysis to detect tuberculosis drug resistance mutations across 10 genes. AB - Genotypic methods for drug susceptibility testing of Mycobacterium tuberculosis are desirable to speed the diagnosis and proper therapy of tuberculosis (TB). However, the numbers of genes and polymorphisms implicated in resistance have proliferated, challenging diagnostic design. We developed a microfluidic TaqMan array card (TAC) that utilizes both sequence-specific probes and high-resolution melt analysis (HRM), providing two layers of detection of mutations. Twenty-seven primer pairs and 40 probes were designed to interrogate 3,200 base pairs of critical regions of the inhA, katG, rpoB, embB, rpsL, rrs, eis, gyrA, gyrB, and pncA genes. The method was evaluated on 230 clinical M. tuberculosis isolates from around the world, and it yielded 96.1% accuracy (2,431/2,530) in comparison to that of Sanger sequencing and 87% accuracy in comparison to that of the slow culture-based susceptibility testing. This TAC-HRM method integrates assays for 10 genes to yield fast, comprehensive, and accurate drug susceptibility results for the 9 major antibiotics used to treat TB and could be deployed to improve treatment outcomes. IMPORTANCE: Multidrug-resistant tuberculosis threatens global tuberculosis control efforts. Optimal therapy utilizes susceptibility test results to guide individualized treatment regimens; however, the susceptibility testing methods in use are technically difficult and slow. We developed an integrated TaqMan array card method with high-resolution melt analysis that interrogates 10 genes to yield a fast, comprehensive, and accurate drug susceptibility result for the 9 major antituberculosis antibiotics. PMID- 25714711 TI - Positioning the flagellum at the center of a dividing cell to combine bacterial division with magnetic polarity. AB - Faithful replication of all structural features is a sine qua non condition for the success of bacterial reproduction by binary fission. For some species, a key challenge is to replicate and organize structures with multiple polarities. Polarly flagellated magnetotactic bacteria are the prime example of organisms dealing with such a dichotomy; they have the challenge of bequeathing two types of polarities to their daughter cells: magnetic and flagellar polarities. Indeed, these microorganisms align and move in the Earth's magnetic field using an intracellular chain of nano-magnets that imparts a magnetic dipole to the cell. The paradox is that, after division occurs in cells, if the new flagellum is positioned opposite to the old pole devoid of a flagellum during cell division, the two daughter cells will have opposite magnetic polarities with respect to the positions of their flagella. Here we show that magnetotactic bacteria of the class Gammaproteobacteria pragmatically solve this problem by synthesizing a new flagellum at the division site. In addition, we model this particular structural inheritance during cell division. This finding opens up new questions regarding the molecular aspects of the new division mechanism, the way other polarly flagellated magnetotactic bacteria control the rotational direction of their flagella, and the positioning of organelles. IMPORTANCE: Magnetotactic bacteria produce chains of magnetic nanoparticles that endow the cells with a magnetic dipole, a "compass" used for navigation. This feature, however, also drastically complicates cellular division in the case of polarly flagellated bacteria. In this case, the bacteria have to pass on to their daughter cells two types of cellular polarities simultaneously, their magnetic polarity and the polarity of their motility apparatus. We show here that magnetotactic bacteria of the Gammaproteobacteria class pragmatically solve this problem by synthesizing the new flagellum at the division site, a division scheme never observed so far in bacteria. Even though the molecular mechanisms behind this scheme cannot be resolved at the moment due to the lack of genetic tools, this discovery provides a new window into the organizational complexity of simple organisms. PMID- 25714710 TI - Toxoplasma gondii superinfection and virulence during secondary infection correlate with the exact ROP5/ROP18 allelic combination. AB - The intracellular parasite Toxoplasma gondii infects a wide variety of vertebrate species globally. Infection in most hosts causes a lifelong chronic infection and generates immunological memory responses that protect the host against new infections. In regions where the organism is endemic, multiple exposures to T. gondii likely occur with great frequency, yet little is known about the interaction between a chronically infected host and the parasite strains from these areas. A widely used model to explore secondary infection entails challenge of chronically infected or vaccinated mice with the highly virulent type I RH strain. Here, we show that although vaccinated or chronically infected C57BL/6 mice are protected against the type I RH strain, they are not protected against challenge with most strains prevalent in South America or another type I strain, GT1. Genetic and genomic analyses implicated the parasite-secreted rhoptry effectors ROP5 and ROP18, which antagonize the host's gamma interferon-induced immunity-regulated GTPases (IRGs), as primary requirements for virulence during secondary infection. ROP5 and ROP18 promoted parasite superinfection in the brains of challenged survivors. We hypothesize that superinfection may be an important mechanism to generate T. gondii strain diversity, simply because two parasite strains would be present in a single meal consumed by the feline definitive host. Superinfection may drive the genetic diversity of Toxoplasma strains in South America, where most isolates are IRG resistant, compared to North America, where most strains are IRG susceptible and are derived from a few clonal lineages. In summary, ROP5 and ROP18 promote Toxoplasma virulence during reinfection. IMPORTANCE: Toxoplasma gondii is a widespread parasite of warm blooded animals and currently infects one-third of the human population. A long standing assumption in the field is that prior exposure to this parasite protects the host from subsequent reexposure, due to the generation of protective immunological memory. However, this assumption is based on clinical data and mouse models that analyze infections with strains common to Europe infections with strains common to Europe and North America. In contrast, we found that the majority of strains sampled from around the world, in particular those from South America, were able to kill or reinfect the brains of hosts previously exposed to T. gondii. The T. gondii virulence factors ROP5 and ROP18, which inhibit key host effectors that mediate parasite killing, were required for these phenotypes. We speculate that these results underpin clinical observations that pregnant women previously exposed to Toxoplasma can develop congenital infection upon reexposure to South American strains. PMID- 25714712 TI - High-throughput analysis of gene essentiality and sporulation in Clostridium difficile. AB - Clostridium difficile is the most common cause of antibiotic-associated intestinal infections and a significant cause of morbidity and mortality. Infection with C. difficile requires disruption of the intestinal microbiota, most commonly by antibiotic usage. Therapeutic intervention largely relies on a small number of broad-spectrum antibiotics, which further exacerbate intestinal dysbiosis and leave the patient acutely sensitive to reinfection. Development of novel targeted therapeutic interventions will require a detailed knowledge of essential cellular processes, which represent attractive targets, and species specific processes, such as bacterial sporulation. Our knowledge of the genetic basis of C. difficile infection has been hampered by a lack of genetic tools, although recent developments have made some headway in addressing this limitation. Here we describe the development of a method for rapidly generating large numbers of transposon mutants in clinically important strains of C. difficile. We validated our transposon mutagenesis approach in a model strain of C. difficile and then generated a comprehensive transposon library in the highly virulent epidemic strain R20291 (027/BI/NAP1) containing more than 70,000 unique mutants. Using transposon-directed insertion site sequencing (TraDIS), we have identified a core set of 404 essential genes, required for growth in vitro. We then applied this technique to the process of sporulation, an absolute requirement for C. difficile transmission and pathogenesis, identifying 798 genes that are likely to impact spore production. The data generated in this study will form a valuable resource for the community and inform future research on this important human pathogen. IMPORTANCE: Clostridium difficile is a common cause of potentially fatal intestinal infections in hospital patients, particularly those who have been treated with antibiotics. Our knowledge of this bacterium has been hampered by a lack of tools for dissecting the organism. We have developed a method to study the function of every gene in the bacterium simultaneously. Using this tool, we have identified a set of 404 genes that are required for growth of the bacteria in the laboratory. C. difficile also produces a highly resistant spore that can survive in the environment for a long time and is a requirement for transmission of the bacteria between patients. We have applied our genetic tool to identify all of the genes required for production of a spore. All of these genes represent attractive targets for new drugs to treat infection. PMID- 25714713 TI - Transmitted/founder hepatitis C viruses induce cell-type- and genotype-specific differences in innate signaling within the liver. AB - Hepatitis C virus (HCV) infection leads to persistence in the majority of cases despite triggering complex innate immune responses within the liver. Although hepatocytes are the preferred site for HCV replication, nonparenchymal cells (NPCs) can also contribute to antiviral immunity. Recent innovations involving single-genome amplification (SGA), direct amplicon sequencing, and phylogenetic inference have identified full-length transmitted/founder (T/F) viruses. Here, we tested the effect of HCV T/F viral RNA (vRNA) on innate immune signaling within hepatocytes and NPCs, including the HepG2 and Huh 7.5.1 cell lines, a human liver endothelial cell line (TMNK-1), a plasmacytoid dendritic cell line (GEN2.2), and a monocytic cell line (THP-1). Transfection with hepatitis C T/F vRNA induced robust transcriptional upregulation of type I and III interferons (IFNs) within HepG2 and TMNK-1 cells. Both the THP-1 and GEN2.2 lines demonstrated higher type I and III IFN transcription with genotype 3a compared to genotype 1a or 1b. Supernatants from HCV T/F vRNA-transfected TMNK-1 cells demonstrated superior viral control. Primary human hepatocytes (PHH) transfected with genotype 3a induced canonical pathways that included chemokine and IFN genes, as well as overrepresentation of RIG-I (DDX58), STAT1, and a Toll-like receptor 3 (TLR3) network. Full-length molecular clones of HCV induce broad IFN responses within hepatocytes and NPCs, highlighting that signals imparted by the various cell types within the liver may lead to divergent outcomes of infection. In particular, the finding that HCV genotypes differentially induce antiviral responses in NPCs and PHH might account for relevant clinical-epidemiological observations (higher clearance but greater necroinflammation in persistence with genotype 3). IMPORTANCE: Hepatitis C virus (HCV) has become a major worldwide problem, and it is now the most common viral infection for which there is no vaccine. HCV infection often leads to persistence of the virus and is a leading cause of chronic hepatitis, liver cancer, and cirrhosis. There are multiple genotypes of the virus, and patients infected with different viral genotypes respond to traditional therapy differently. However, the immune response to the virus within the liver has not been fully elucidated. Here, we determined the responses to different genotypes of HCV in cell types of the liver. We found that the immune response varied according to both cell type and HCV genotype, leading to a more pronounced induction of inflammatory pathways after exposure to certain genotypes. Therefore, inflammatory pathways that are being robustly activated by certain HCV genotypes could lead to more severe damage to the liver, inducing diverse outcomes and responses to therapy. PMID- 25714715 TI - Pseudomonas aeruginosa-induced bleb-niche formation in epithelial cells is independent of actinomyosin contraction and enhanced by loss of cystic fibrosis transmembrane-conductance regulator osmoregulatory function. AB - The opportunistic pathogen Pseudomonas aeruginosa can infect almost any site in the body but most often targets epithelial cell-lined tissues such as the airways, skin, and the cornea of the eye. A common predisposing factor is cystic fibrosis (CF), caused by defects in the cystic fibrosis transmembrane-conductance regulator (CFTR). Previously, we showed that when P. aeruginosa enters epithelial cells it replicates intracellularly and occupies plasma membrane blebs. This phenotype is dependent on the type 3 secretion system (T3SS) effector ExoS, shown by others to induce host cell apoptosis. Here, we examined mechanisms for P. aeruginosa-induced bleb formation, focusing on its relationship to apoptosis and the CFTR. The data showed that P. aeruginosa-induced blebbing in epithelial cells is independent of actin contraction and is inhibited by hyperosmotic media (400 to 600 mOsM), distinguishing bacterially induced blebs from apoptotic blebs. Cells with defective CFTR displayed enhanced bleb formation upon infection, as demonstrated using bronchial epithelial cells from a patient with cystic fibrosis and a CFTR inhibitor, CFTR(Inh)-172. The defect was found to be correctable either by incubation in hyperosmotic media or by complementation with CFTR (pGFP CFTR), suggesting that the osmoregulatory function of CFTR counters P. aeruginosa induced bleb-niche formation. Accordingly, and despite their reduced capacity for bacterial internalization, CFTR-deficient cells showed greater bacterial occupation of blebs and enhanced intracellular replication. Together, these data suggest that P. aeruginosa bleb niches are distinct from apoptotic blebs, are driven by osmotic forces countered by CFTR, and could provide a novel mechanism for bacterial persistence in the host. IMPORTANCE: Pseudomonas aeruginosa is an opportunistic pathogen problematic in hospitalized patients and those with cystic fibrosis (CF). Previously, we showed that P. aeruginosa can enter epithelial cells and replicate within them and traffics to the membrane blebs that it induces. This "bleb-niche" formation requires ExoS, previously shown to cause apoptosis. Here, we show that the driving force for bleb-niche formation is osmotic pressure, differentiating P. aeruginosa-induced blebs from apoptotic blebs. Either CFTR inhibition or CFTR mutation (as seen in people with CF) causes P. aeruginosa to make more bleb niches and provides an osmotic driving force for blebbing. CFTR inhibition also enhances bacterial occupation of blebs and intracellular replication. Since CFTR is targeted for removal from the plasma membrane when P. aeruginosa invades a healthy cell, these findings could relate to pathogenesis in both CF and healthy patient populations. PMID- 25714716 TI - Chronic superantigen exposure induces systemic inflammation, elevated bloodstream endotoxin, and abnormal glucose tolerance in rabbits: possible role in diabetes. AB - Excessive weight and obesity are associated with the development of diabetes mellitus type 2 (DMII) in humans. They also pose high risks of Staphylococcus aureus colonization and overt infections. S. aureus causes a wide range of severe illnesses in both healthy and immunocompromised individuals. Among S. aureus virulence factors, superantigens are essential for pathogenicity. In this study, we show that rabbits that are chronically exposed to S. aureus superantigen toxic shock syndrome toxin-1 (TSST-1) experience impaired glucose tolerance, systemic inflammation, and elevated endotoxin levels in the bloodstream, all of which are common findings in DMII. Additionally, such DMII-associated findings are also seen through effects of TSST-1 on isolated adipocytes. Collectively, our findings suggest that chronic exposure to S. aureus superantigens facilitates the development of DMII, which may lead to therapeutic targeting of S. aureus and its superantigens. IMPORTANCE: Obesity has a strong correlation with type 2 diabetes, in which fatty tissue, containing adipocytes, contributes to the development of the illness through altered metabolism and chronic inflammation. The human microbiome changes in persons with obesity and type 2 diabetes, including increases in Staphylococcus aureus colonization and overt infections. While the microbiome is essential for human wellness, there is little understanding of the role of microbes in obesity or the development of diabetes. Here, we demonstrate that the S. aureus superantigen toxic shock syndrome toxin-1 (TSST-1), an essential exotoxin in pathogenesis, induces inflammation, lipolysis, and insulin resistance in adipocytes both in vitro and in vivo. Chronic stimulation of rabbits with TSST-1 results in impaired systemic glucose tolerance, the hallmark finding in type 2 diabetes in humans, suggesting a role of S. aureus and its superantigens in the progression to type 2 diabetes. PMID- 25714717 TI - Toxin synthesis by Clostridium difficile is regulated through quorum signaling. AB - Clostridium difficile infection (CDI) is dramatically increasing as a cause of antibiotic- and hospital-associated diarrhea worldwide. C. difficile, a multidrug resistant pathogen, flourishes in the colon after the gut microbiota has been altered by antibiotic therapy. Consequently, it produces toxins A and B that directly cause disease. Despite the enormous public health problem posed by this pathogen, the molecular mechanisms that regulate production of the toxins, which are directly responsible for disease, remained largely unknown until now. Here, we show that C. difficile toxin synthesis is regulated by an accessory gene regulator quorum-signaling system, which is mediated through a small (<1,000-Da) thiolactone that can be detected directly in stools of CDI patients. These findings provide direct evidence of the mechanism of regulation of C. difficile toxin synthesis and offer exciting new avenues both for rapid detection of C. difficile infection and development of quorum-signaling-based non-antibiotic therapies to combat this life-threatening emerging pathogen. IMPORTANCE: Clostridium difficile infection (CDI) is the most common definable cause of hospital-acquired and antibiotic-associated diarrhea in the United States, with the total cost of treatment estimated between 1 and 4.8 billion U.S. dollars annually. C. difficile, a Gram-positive, spore-forming anaerobe, flourishes in the colon after the gut microbiota has been altered by antibiotic therapy. As a result, there is an urgent need for non-antibiotic CDI treatments that preserve the colonic microbiota. C. difficile produces toxins A and B, which are directly responsible for disease. Here, we report that C. difficile regulates its toxin synthesis by quorum signaling, in which a novel signaling peptide activates transcription of the disease-causing toxin genes. This finding provides new therapeutic targets to be harnessed for novel nonantibiotic therapy for C. difficile infections. PMID- 25714718 TI - Sewage reflects the microbiomes of human populations. AB - Molecular characterizations of the gut microbiome from individual human stool samples have identified community patterns that correlate with age, disease, diet, and other human characteristics, but resources for marker gene studies that consider microbiome trends among human populations scale with the number of individuals sampled from each population. As an alternative strategy for sampling populations, we examined whether sewage accurately reflects the microbial community of a mixture of stool samples. We used oligotyping of high-throughput 16S rRNA gene sequence data to compare the bacterial distribution in a stool data set to a sewage influent data set from 71 U.S. cities. On average, only 15% of sewage sample sequence reads were attributed to human fecal origin, but sewage recaptured most (97%) human fecal oligotypes. The most common oligotypes in stool matched the most common and abundant in sewage. After informatically separating sequences of human fecal origin, sewage samples exhibited ~3* greater diversity than stool samples. Comparisons among municipal sewage communities revealed the ubiquitous and abundant occurrence of 27 human fecal oligotypes, representing an apparent core set of organisms in U.S. populations. The fecal community variability among U.S. populations was significantly lower than among individuals. It clustered into three primary community structures distinguished by oligotypes from either: Bacteroidaceae, Prevotellaceae, or Lachnospiraceae/Ruminococcaceae. These distribution patterns reflected human population variation and predicted whether samples represented lean or obese populations with 81 to 89% accuracy. Our findings demonstrate that sewage represents the fecal microbial community of human populations and captures population-level traits of the human microbiome. IMPORTANCE: The gut microbiota serves important functions in healthy humans. Numerous projects aim to define a healthy gut microbiome and its association with health states. However, financial considerations and privacy concerns limit the number of individuals who can be screened. By analyzing sewage from 71 cities, we demonstrate that geographically distributed U.S. populations share a small set of bacteria whose members represent various common community states within U.S. adults. Cities were differentiated by their sewage bacterial communities, and the community structures were good predictors of a city's estimated level of obesity. Our approach demonstrates the use of sewage as a means to sample the fecal microbiota from millions of people and its potential to elucidate microbiome patterns associated with human demographics. PMID- 25714719 TI - LytM proteins play a crucial role in cell separation, outer membrane composition, and pathogenesis in nontypeable Haemophilus influenzae. AB - LytM proteins belong to a family of bacterial metalloproteases. In Gram-negative bacteria, LytM factors are mainly reported to have a direct effect on cell division by influencing cleavage and remodeling of peptidoglycan. In this study, mining nontypeable Haemophilus influenzae (NTHI) genomes, three highly conserved open reading frames (ORFs) containing a LytM domain were identified, and the proteins encoded by the ORFs were named YebA, EnvC, and NlpD on the basis of their homology with the Escherichia coli proteins. Immunoblotting and confocal analysis showed that while NTHI NlpD is exposed on the bacterial surface, YebA and EnvC reside in the periplasm. NTHI DeltayebA and DeltanlpD deletion mutants revealed an aberrant division phenotype characterized by an altered cell architecture and extensive membrane blebbing. The morphology of the DeltaenvC deletion mutant was identical to that of the wild-type strain, but it showed a drastic reduction of periplasmic proteins, including the chaperones HtrA, SurA, and Skp, and an accumulation of beta-barrel-containing outer membrane proteins comprising the autotransporters Hap, IgA serine protease, and HMW2A, as observed by proteomic analysis. These data suggest that EnvC may influence the bacterial surface protein repertoire by facilitating the passage of the periplasmic chaperones through the peptidoglycan layer to the close vicinity of the inner face of the outer membrane. This hypothesis was further corroborated by the fact that an NTHI envC defective strain had an impaired capacity to adhere to epithelial cells and to form biofilm. Notably, this strain also showed a reduced serum resistance. These results suggest that LytM factors are not only important components of cell division but they may also influence NTHI physiology and pathogenesis by affecting membrane composition. IMPORTANCE: Nontypeable Haemophilus influenzae (NTHI) is an opportunistic pathogen that colonizes the human nasopharynx and can cause serious infections in children (acute otitis media) and adults (chronic obstructive pulmonary disease). Several virulence factors are well studied, but the complete scenario of NTHI pathogenesis is still unclear. We identified and characterized three NTHI LytM factors homologous to the Escherichia coli LytM proteins. Although LytM factors are reported to play a crucial role in the cell division process, in NTHI they are also involved in other bacterial functions. In particular, YebA and NlpD are fundamental for membrane stability: indeed, their absence causes an increased release of outer membrane vesicles (OMVs). On the other hand, our data suggest that EnvC could directly or indirectly affect peptidoglycan permeability and consequently, bacterial periplasmic and outer membrane protein distribution. Interestingly, by modulating the surface composition of virulence determinants, EnvC also has an impact on NTHI pathogenesis. PMID- 25714714 TI - Identification, molecular cloning, and analysis of full-length hepatitis C virus transmitted/founder genotypes 1, 3, and 4. AB - Hepatitis C virus (HCV) infection is characterized by persistent replication of a complex mixture of viruses termed a "quasispecies." Transmission is generally associated with a stringent population bottleneck characterized by infection by limited numbers of "transmitted/founder" (T/F) viruses. Characterization of T/F genomes of human immunodeficiency virus type 1 (HIV-1) has been integral to studies of transmission, immunopathogenesis, and vaccine development. Here, we describe the identification of complete T/F genomes of HCV by single-genome sequencing of plasma viral RNA from acutely infected subjects. A total of 2,739 single-genome-derived amplicons comprising 10,966,507 bp from 18 acute-phase and 11 chronically infected subjects were analyzed. Acute-phase sequences diversified essentially randomly, except for the poly(U/UC) tract, which was subject to polymerase slippage. Fourteen acute-phase subjects were productively infected by more than one genetically distinct virus, permitting assessment of recombination between replicating genomes. No evidence of recombination was found among 1,589 sequences analyzed. Envelope sequences of T/F genomes lacked transmission signatures that could distinguish them from chronic infection viruses. Among chronically infected subjects, higher nucleotide substitution rates were observed in the poly(U/UC) tract than in envelope hypervariable region 1. Fourteen full length molecular clones with variable poly(U/UC) sequences corresponding to seven genotype 1a, 1b, 3a, and 4a T/F viruses were generated. Like most unadapted HCV clones, T/F genomes did not replicate efficiently in Huh 7.5 cells, indicating that additional cellular factors or viral adaptations are necessary for in vitro replication. Full-length T/F HCV genomes and their progeny provide unique insights into virus transmission, virus evolution, and virus-host interactions associated with immunopathogenesis. IMPORTANCE: Hepatitis C virus (HCV) infects 2% to 3% of the world's population and exhibits extraordinary genetic diversity. This diversity is mirrored by HIV-1, where characterization of transmitted/founder (T/F) genomes has been instrumental in studies of virus transmission, immunopathogenesis, and vaccine development. Here, we show that despite major differences in genome organization, replication strategy, and natural history, HCV (like HIV-1) diversifies essentially randomly early in infection, and as a consequence, sequences of actual T/F viruses can be identified. This allowed us to capture by molecular cloning the full-length HCV genomes that are responsible for infecting the first hepatocytes and eliciting the initial immune responses, weeks before these events could be directly analyzed in human subjects. These findings represent an enabling experimental strategy, not only for HCV and HIV-1 research, but also for other RNA viruses of medical importance, including West Nile, chikungunya, dengue, Venezuelan encephalitis, and Ebola viruses. PMID- 25714722 TI - Essential oil of Croton zehntneri and its main constituent anethole block excitability of rat peripheral nerve. AB - Croton zehntneri is an aromatic plant native to Northeast Brazil and employed by local people to treat various diseases. The leaves of this plant have a rich content of essential oil. The essential oil of C. zehntneri samples, with anethole as the major constituent and anethole itself, have been reported to have several pharmacological activities such as antispasmodic, cardiovascular, and gastroprotective effects and inducing the blockade of neuromuscular transmission and antinociception. Since several works have demonstrated that essential oils and their constituents block cell excitability and in view of the multiple effects of C. zehntneri essential oil and anethole on biological tissues, we undertook this investigation aiming to characterize and compare the effects of this essential oil and its major constituent on nerve excitability. Sciatic nerves of Wistar rats were used. They were mounted in a moist chamber, and evoked compound action potentials were recorded. Nerves were exposed in vitro to the essential oil of C. zehntneri and anethole (0.1-1 mg/mL) up to 180 min, and alterations in excitability (rheobase and chronaxie) and conductibility (peak-to peak amplitude and conduction velocity) parameters of the compound action potentials were evaluated. The essential oil of C. zehntneri and anethole blocked, in a concentration-dependent manner with similar pharmacological potencies (IC50: 0.32 +/- 0.07 and 0.22 +/- 0.11 mg/mL, respectively), rat sciatic nerve compound action potentials. Strength-duration curves for both agents were shifted upward and to the right compared to the control curve, and the rheobase and chronaxie were increased following essential oil and anethole exposure. The time courses of the essential oil of C. zehntneri and anethole effects on peak-to-peak amplitude of compound action potentials followed an exponential decay and reached a steady state. The essential oil of C. zehntneri and anethole caused a similar reduction in conduction velocities of the compound action potential waves investigated. In conclusion, we demonstrated here that the essential oil of C. zehntneri blocks neuronal excitability and that this effect, which can be predominantly attributable to its major constituent, anethole, is important since these agents have several pharmacological effects likely related to the alteration of excitability. This finding is relevant due to the use of essential oils in aromatherapy and the low acute toxicity of this agent, which exhibits other effects of potential therapeutic usefulness. PMID- 25714720 TI - A new player at the flagellar motor: FliL controls both motor output and bias. AB - The bacterial flagellum is driven by a bidirectional rotary motor, which propels bacteria to swim through liquids or swarm over surfaces. While the functions of the major structural and regulatory components of the flagellum are known, the function of the well-conserved FliL protein is not. In Salmonella and Escherichia coli, the absence of FliL leads to a small defect in swimming but complete elimination of swarming. Here, we tracked single motors of these bacteria and found that absence of FliL decreases their speed as well as switching frequency. We demonstrate that FliL interacts strongly with itself, with the MS ring protein FliF, and with the stator proteins MotA and MotB and weakly with the rotor switch protein FliG. These and other experiments show that FliL increases motor output either by recruiting or stabilizing the stators or by increasing their efficiency and contributes additionally to torque generation at higher motor loads. The increased torque enabled by FliL explains why this protein is essential for swarming on an agar surface expected to offer increased resistance to bacterial movement. IMPORTANCE: FliL is a well-conserved bacterial flagellar protein whose absence leads to a variety of motility defects, ranging from moderate to complete inhibition of swimming in some bacterial species, inhibition of swarming in others, structural defects that break the flagellar rod during swarming in E. coli and Salmonella, and failure to eject the flagellar filament during the developmental transition of a swimmer to a stalk cell in Caulobacter crescentus. Despite these many phenotypes, a specific function for FliL has remained elusive. Here, we established a central role for FliL at the Salmonella and E. coli motors, where it interacts with both rotor and stator proteins, increases motor output, and contributes to the normal rotational bias of the motor. PMID- 25714723 TI - In vitro vasoactivity of zerumbone from Zingiber zerumbet. AB - The sesquiterpene zerumbone, isolated from the rhizome of Zingiber zerumbet Sm., besides its widespread use as a food flavouring and appetiser, is also recommended in traditional medicine for the treatment of several ailments. It has attracted great attention recently for its effective chemopreventive and therapeutic effects observed in various models of cancer. To assess the zerumbone safety profile, a pharmacology study designed to flag any potential adverse effect on vasculature was performed. Zerumbone was tested for vasorelaxing activity on rat aorta rings and for L-type Ba(2+) current blocking activity on single myocytes isolated from the rat-tail artery. The spasmolytic effect of zerumbone was more marked on rings stimulated with 60 mM than with 30 mM K(+) (IC50 values of 16 uM and 102 uM, respectively). In the presence of 60 mM K(+), zerumbone concentration-dependently inhibited the contraction induced by the cumulative additions of Ca(2+), this inhibition being inversely related to the Ca(2+) concentration. Phenylephrine-induced contraction was inhibited by the drug, though less efficiently and independently of the presence of an intact endothelium, without affecting Ca(2+) release from the intracellular stores. Zerumbone inhibited the L-type Ba(2+) current (estimated IC50 value of 458.7 uM) and accelerated the kinetics of current decay. In conclusion, zerumbone showed an overall weak in vitro vasodilating activity, partly attributable to the blocking of the L-type Ca(2+) channel, which does not seem to represent, however, a serious threat to its widespread use. PMID- 25714721 TI - The ferrous iron-responsive BqsRS two-component system activates genes that promote cationic stress tolerance. AB - The physiological resistance of pathogens to antimicrobial treatment is a severe problem in the context of chronic infections. For example, the mucus-filled lungs of cystic fibrosis (CF) patients are readily colonized by diverse antibiotic resistant microorganisms, including Pseudomonas aeruginosa. Previously, we showed that bioavailable ferrous iron [Fe(II)] is present in CF sputum at all stages of infection and constitutes a significant portion of the iron pool at advanced stages of lung function decline [R. C. Hunter et al., mBio 4(4):e00557-13, 2013]. P. aeruginosa, a dominant CF pathogen, senses Fe(II) using a two-component signal transduction system, BqsRS, which is transcriptionally active in CF sputum [R. C. Hunter et al., mBio 4(4):e00557-13, 2013; N. N. Kreamer, J. C. Wilks, J. J. Marlow, M. L. Coleman, and D. K. Newman, J Bacteriol 194:1195-1204, 2012]. Here, we show that an RExxE motif in BqsS is required for BqsRS activation. Once Fe(II) is sensed, BqsR binds a tandem repeat DNA sequence, activating transcription. The BqsR regulon--defined through iterative bioinformatic predictions and experimental validation--includes several genes whose products are known to drive antibiotic resistance to aminoglycosides and polymyxins. Among them are genes encoding predicted determinants of polyamine transport and biosynthesis. Compared to the wild type, bqsS and bqsR deletion mutants are sensitive to high levels of Fe(II), produce less spermidine in high Fe(II), and are more sensitive to tobramycin and polymyxin B but not arsenate, chromate, or cefsulodin. BqsRS thus mediates a physiological response to Fe(II) that guards the cell against positively charged molecules but not negatively charged stressors. These results suggest Fe(II) is an important environmental signal that, via BqsRS, bolsters tolerance of a variety of cationic stressors, including clinically important antimicrobial agents. IMPORTANCE: Clearing chronic infections is challenging due to the physiological resistance of opportunistic pathogens to antibiotics. Effective treatments are hindered by a lack of understanding of how these organisms survive in situ. Fe(II) is typically present at micromolar levels in soils and sedimentary habitats, as well as in CF sputum. All P. aeruginosa strains possess a two-component system, BqsRS, that specifically senses extracellular Fe(II) at low micromolar concentrations. Our work shows that BqsRS protects the cell against cationic perturbations to the cell envelope as well as low pH and reduction potential (Eh), conditions under which Fe(2+) is stable. Fe(II) can thus be understood as a proxy for a broader environmental state; the cellular response to its detection may help rationalize the resistance of P. aeruginosa to clinically important cationic antibiotics. This finding demonstrates the importance of considering environmental chemistry when exploring mechanisms of microbial survival in habitats that include the human body. PMID- 25714724 TI - Effectiveness and tolerability of a standardized extract from Ageratina pichinchensis in patients with diabetic foot ulcer: a randomized, controlled pilot study. AB - Previous works have shown that extracts obtained from Ageratina pichinchensis are capable of reducing the time needed for wounds to heal. By means of a randomized, double-blind pilot study, the objective of this work was to evaluate the effectiveness and tolerability of a phytopharmaceutical developed with a standardized extract (5 %, cream formulation) of A. pichinchensis, topically administered in patients with diabetic foot ulcer. Micronized silver sulfadiazine (1 %) was employed as a control treatment. Treatments were randomly assigned to each patient, and clinical evolution was evaluated weekly until complete healing of the wound. All patients who concluded the study achieved complete healing of their ulcers. After six weeks of treatment, patients in the experimental group exhibited a wound-healing process of 77.5 %, while that of patients in the control group was 69.8 %. A statistically significant difference was not found between groups. The average time needed for complete wound healing was 65.47 +/- 47.08 days for patients treated with the A. pichinchensis extract and 77.46 +/- 50.8 days for patients in the control group (p = 0.509). There was no case in either of the groups in which adverse side effects were identified. Thus, it was concluded that the A. pichinchensis extract showed the ability to improve the healing process in patients with diabetic foot ulcer; however, no statistically significant differences were observed when compared with results obtained in patients administered the control treatment (micronized silver sulfadiazine). Some limitations of this study must be addressed, such as small sample size. This work comprises a pilot study that could be useful in a future clinical trial with a greater number of patients. PMID- 25714725 TI - Suppression of inducible nitric oxide synthase pathway by 7-deacetylgedunin, a limonoid from Xylocarpus sp. AB - In this study, limonoids isolated from Xylocarpus plants were tested for their in vitro anti-inflammatory effects. The results demonstrated that only 7 deacetylgedunin (1), a gedunin-type limonoid, significantly inhibited lipopolysaccharide- and interferon-gamma-stimulated production of nitric oxide in murine macrophage RAW 264.7 cells. The suppression of nitric oxide production by 1 was correlated with the downregulation of mRNA and protein expression of inducible nitric oxide synthase. Mechanistic studies revealed that the transcriptional activity of nuclear factor-kappaB, IkappaBalpha degradation, and the activation of mitogen-activated protein kinases, stimulated with lipopolysaccharide and interferon-gamma, were suppressed by 1. PMID- 25714726 TI - Neurodifferentiating potential of 8-prenylnaringenin and related compounds in neural precursor cells and correlation with estrogen-like activity. AB - Neurodegenerative diseases are an increasing burden for our ageing societies; there is an as yet unmet need for the development of effective therapies. Neurogenesis, i.e., the generation of new neurons in the adult brain from neural stem cells, has received increasing attention since it offers the potential for endogenous brain repair and functional regeneration. Adult neurogenesis is partially under the control of sex hormones such as estradiol, and boosting neurogenesis with estradiol in animals correlates with cognitive improvement. 8 Prenylnaringenin imitates as highly potent phytoestrogen the effects of estradiol. Here, we studied the potential of 8-prenylnaringenin, 6 prenylnaringenin, and related compounds on differentiation induction in vitro using neural precursor cells transiently transfected with a doublecortin promoter luciferase construct, which was recently shown to indicate neuronal fate and differentiation. The flavanones 8-prenylnaringenin and 6-prenylnaringenin showed slight activity in this assay but significant activity by immunostaining. Although the estrogen-like activities of 8-prenylnaringenin and 6 prenylnaringenin are very different, the activity in differentiation induction is similar. Interestingly, also some prenylflavonoids with extended prenyl groups, e.g., a geranyl group, showed increased differentiation activity, while estrogen like activity is decreased. This allows the conclusion that estrogen-like activity of prenylflavanones does not correlate directly with the activity of differentiation induction in neural precursor cells. PMID- 25714727 TI - How to Valorize Biodiversity? Let's Go Hashing, Extracting, Filtering, Mining, Fishing. AB - Nature was and still is a prolific source of inspiration in pharmacy, cosmetics, and agro-food industries for the discovery of bioactive products. Informatics is now present in most human activities. Research in natural products is no exception. In silico tools may help in numerous cases when studying natural substances: in pharmacognosy, to store and structure the large and increasing number of data, and to facilitate or accelerate the analysis of natural products in regards to traditional uses of natural resources; in drug discovery, to rationally design libraries for screening natural compound mimetics and identification of biological activities for natural products. Here we review different aspects of in silico approaches applied to the research and development of bioactive substances and give examples of using nature-inspiring power and ultimately valorize biodiversity. PMID- 25714728 TI - Prospects of boswellic acids as potential pharmaceutics. AB - Boswellic acids have long been considered the main bioactive components of frankincense, and many studies in vitro and in animals as well as several clinical studies have confirmed their various bioactivities. In particular, a large number of mechanistic studies have confirmed their anti-inflammatory and antitumor activities. However, not every boswellic acid exhibits a satisfactory pharmacological performance, which depends on the chemical structure and functional groups of the acid. To enhance the pharmacological values of boswellic acids, derivatization has been specifically applied with the aim of discovering more active derivatives of BAs. In addition, the preliminary pharmacokinetic studies of these compounds using various standard methods show their poor bioavailability in humans and rodents, which has led to questions of their pharmacological relevance and potentially limits their use in clinical practice and pharmaceutical development. To improve these effects, some approaches have shown some improvements in effectiveness, and the new formula compatibility approach is considered a very reasonable method for improving the bioavailability of boswellic acids. PMID- 25714730 TI - Role of encapsulated metal cation in the reactivity and regioselectivity of the C60 Diels-Alder reaction. AB - Endohedral metallofullerene has novel properties because of the interaction between the encapsulated metal atom or cation and fullerene. Experiments have demonstrated that the insertion of Li(+) into C60 can greatly promote the reactivity of the Diels-Alder (DA) cycloaddition of cyclopentadiene (CpH) to C60. However, the reaction is sufficiently fast that its quantitative kinetic data cannot be obtained experimentally. In addition, knowledge regarding the effects of other alkali metal cations and metal cations with more charges on the reactivity and regioselectivity of C60 is almost nonexistent. In the current study, DA cycloadditions of CpH to M(+)@C60 (where M = Li, Na, K, Rb, and Cs) and Ca(2+)@C60 were investigated via density functional theory in the gas phase and in solvent. Via careful discussion and comparison with the results of C60, we concluded the following for the DA reaction of CpH to C60 and, more generally, for DA reactions of other fullerenes: (1) the encapsulated metal cations enhance the reactivity; (2) among alkali metal cations, Na(+) could be the best catalyst; (3) Ca(2+) is more favorable in promoting the reactivity than any alkali metal cation; (4) encapsulated metal cations with more positive charges enhance the reactivity of the 6-5 bond in C60, which is significant when the 6-5 adduct is the target product. PMID- 25714729 TI - Managing hypertension by polyphenols. AB - Some polyphenols, obtained from plants of broad use, induce a favorable endothelial response in hypertension and beneficial effects in the management of other metabolic cardiovascular risks. Previous studies in our laboratories using the calyces of Hibiscus sabdariffa as a source of polyphenols show that significant effects on hypertension are noticeable in humans only when provided in high amounts. Available data are suggestive in animal models and ex vivo experiments, but data in humans are difficult to acquire. Additionally, and despite the low bioavailability of polyphenols, intervention studies provide evidence for the protective effects of secondary plant metabolites. Assumptions on public health benefits are limited by the lack of scientific knowledge, robust data derived from large randomized clinical trials, and an accurate assessment of the bioactive components provided by common foodstuff. Because it is likely that clinical effects are the result of multiple interactions among different polyphenols rather than the isolated action of unique compounds, to provide polyphenol-rich botanical extracts as dietary supplements is a suggestive option. Unfortunately, the lack of patent perspectives for the pharmaceutical industries and the high cost of production and release for alimentary industries will hamper the performance of the necessary clinical trials. Here we briefly discuss whether and how such limitations may complicate the extensive use of plant-derived products in the management of hypertension and which steps are the necessary to deal with the predictable complexity in a possible clinical practice. PMID- 25714731 TI - Sectorial water use trends in the urbanizing Pearl River Delta, China. AB - Assessing and managing water use is crucial for supporting sustainable river basin management and regional development. The first consistent and comprehensive assessment of sectorial water use in the Pearl River Delta (PRD) is presented by analysing homogenized annual water use data from 2000 to 2010 in relation to socio economic statistics for the same period. An abstraction of water use, using the concept of water use intensity, and based on equations inspired by those used in global water resource models, is developed to explore the driving forces underlying water use changes in domestic, industrial and agricultural sectors. We do this at both the level of the region as a whole, as well as for the nine cities that constitute the PRD separately. We find that, despite strong population and economic growth, the PRD managed to stabilize its absolute water use by significant improvements in industrial water use intensities, and early stabilisation of domestic water use intensities. Results reveal large internal differentiation of sectorial water use among the cities in this region, with industrial water use intensity varying from -80 to +95% and domestic water use intensity by +/- 30% compared to the PRD average. In general, per capita water use is highest in the cities that industrialised first. Yet, all cities except Guangzhou are expected to approach a saturation value of per capita water use much below what is suggested in recent global studies. Therefore, existing global assessments probably have overestimated future domestic water use in developing countries. Although scarce and uncertain input data and model limitations lead to a high level of uncertainty, the presented conceptualization of water use is useful in exploring the underlying driving forces of water use trends. PMID- 25714732 TI - West Nile virus infection in Ogbomoso: serological evidence. AB - A seroepidemiological study for West Nile virus was carried out in an urban and rural settlements in Ogbomoso for its IgM and IgG. Human sera was obtained and West Nile virus IgM and IgG was determined using Enzyme Linked Immunosorbent Assay technique. Out of 93 subjects tested, 19.4% and 12.9% were positive for IgG and IgM, respectively. Among the urban dwellers, 23.40% were positive for both IgG and IgM, while the rural dwellers had 15.22% for IgG and 2.17% for IgM. Test for pure antibody to West Nile virus revealed that 23.7% had the virus while 8.6% had antibodies that cross reacted for other flaviviruses. Results show that West Nile virus is circulating in Ogbomoso and its environ which might have accounted for malaria like infection in the region. PMID- 25714734 TI - Biodistribution characteristics and SPECT imaging of (99m)Tc-RET and (99m)Tc-REG in human lung cancer xenografts. AB - OBJECTIVE: To investigate the biodistribution and single-photon emission computed tomography (SPECT) imaging of (99m)Tc-labeled arginine-glutamic acid-threonine (RET) and arginine-glutamic acid-glycine (REG) in nude mice bearing human lung cancer xenografts. MATERIALS AND METHODS: RET and REG were labeled directly with (99m)Tc and their binding efficiency to tumor cells was measured in human nonsmall cell lung cancer H1299 cells. After intravenously injecting (99m)Tc-RET and (99m)Tc-REG into normal mice and nude mice bearing human lung cancer xenografts, their biodistribution was measured at different postinjection times, and percentages of injected dose per gram tissue (% ID/g) of organs of interest were calculated. The mice bearing H1299 lung cancer xenografts were scanned by SPECT at different times following the (99m)Tc-RET or (99m)Tc-REG injection. RESULTS: The radiochemical purity of (99m)Tc-RET and (99m)Tc-REG was 93.15%+/ 2.02% and 92.90%+/-2.86%, respectively. The binding rate of (99m)Tc-RET and (99m)Tc-REG to H1299 cells was 3.56%+/-0.37% and 2.32%+/-0.31%, respectively. The uptake of (99m)Tc-RET and (99m)Tc-REG in tumor was 4.96+/-1.05% ID/g at 4 hours postinjection and 1.95+/-0.73% ID/g at 2 hours postinjection, respectively. Tumors in nude mice could be best imaged at 4.5-6 hours postinjection of (99m)Tc RET. CONCLUSION: (99m)Tc-RET has a higher binding rate to H1299 cells than (99m)Tc-REG and might be used as a potential lung cancer imaging agent. PMID- 25714733 TI - Non-invasive screening for Alzheimer's disease by sensing salivary sugar using Drosophila cells expressing gustatory receptor (Gr5a) immobilized on an extended gate ion-sensitive field-effect transistor (EG-ISFET) biosensor. AB - Body fluids are often used as specimens for medical diagnosis. With the advent of advanced analytical techniques in biotechnology, the diagnostic potential of saliva has been the focus of many studies. We recently reported the presence of excess salivary sugars, in patients with Alzheimer's disease (AD). In the present study, we developed a highly sensitive, cell-based biosensor to detect trehalose levels in patient saliva. The developed biosensor relies on the overexpression of sugar sensitive gustatory receptors (Gr5a) in Drosophila cells to detect the salivary trehalose. The cell-based biosensor was built on the foundation of an improved extended gate ion-sensitive field-effect transistor (EG-ISFET). Using an EG-ISFET, instead of a traditional ion-sensitive field-effect transistor (ISFET), resulted in an increase in the sensitivity and reliability of detection. The biosensor was designed with the gate terminals segregated from the conventional ISFET device. This design allows the construction of an independent reference and sensing region for simultaneous and accurate measurements of samples from controls and patients respectively. To investigate the efficacy of the cell-based biosensor for AD screening, we collected 20 saliva samples from each of the following groups: participants diagnosed with AD, participants diagnosed with Parkinson's disease (PD), and a control group composed of healthy individuals. We then studied the response generated from the interaction of the salivary trehalose of the saliva samples and the Gr5a in the immobilized cells on an EG ISFET sensor. The cell-based biosensor significantly distinguished salivary sugar, trehalose of the AD group from the PD and control groups. Based on these findings, we propose that salivary trehalose, might be a potential biomarker for AD and could be detected using our cell-based EG-ISFET biosensor. The cell-based EG-ISFET biosensor provides a sensitive and direct approach for salivary sugar detection and may be used in the future as a screening method for AD. PMID- 25714735 TI - Editorial: Capturing the dynamics of development and psychopathology: from neural circuits to global trends. PMID- 25714736 TI - Commentary: Should we move away from an attachment framework for understanding disinhibited social engagement disorder (DSED)? A commentary on Zeanah and Gleason (2015). PMID- 25714737 TI - Commentary: Developmental origins of autism and ADHD--a commentary on Johnson et al. (2015). PMID- 25714738 TI - Commentary: Insights from across diagnostic boundaries: ADHD in the RDoC era--a commentary on Scerif and Baker (2015). PMID- 25714739 TI - Commentary: We've only just begun: unravelling the underlying genetics of neurodevelopmental disorders--a commentary on Kiser et al. (2015). PMID- 25714740 TI - Commentary: Developmental connectomics to advance our understanding of typical and atypical brain development--a commentary on Vertes and Bullmore (2015). PMID- 25714741 TI - Commentary: Seeing the forest of knowledge for the trees of associations--a commentary on Costello and Maughan (2015). PMID- 25714742 TI - Commentary: 'Diseases of the world': from epidemiology to etiology of child and adolescent psychopathology--a commentary on Polanczyk et al. (2015). PMID- 25714743 TI - Commentary: Physical health outcomes and health care have improved so much, so why is child mental health getting worse? Or is it? A commentary on Collishaw (2015). PMID- 25714745 TI - Naked but not Hairless: the pitfalls of analyses of molecular adaptation based on few genome sequence comparisons. AB - The naked mole-rat (Heterocephalus glaber) is the only rodent species that naturally lacks fur. Genome sequencing of this atypical rodent species recently shed light on a number of its morphological and physiological adaptations. More specifically, its hairless phenotype has been traced back to a single amino acid change (C397W) in the hair growth associated (HR) protein (or Hairless). By considering the available species diversity, we show that this specific position is in fact variable across mammals, including in the horse that was misleadingly reported to have the ancestral Cysteine. Moreover, by sequencing the corresponding HR exon in additional rodent species, we demonstrate that the C397W substitution is actually not a peculiarity of the naked mole-rat. Instead, this specific amino acid substitution is present in all hystricognath rodents investigated, which are all fully furred, including the naked mole-rat closest relative, the Damaraland mole-rat (Fukomys damarensis). Overall, we found no statistical correlation between amino acid changes at position 397 of the HR protein and reduced pilosity across the mammalian phylogeny. This demonstrates that this single amino acid change does not explain the naked mole-rat hairless phenotype. Our case study calls for caution before making strong claims regarding the molecular basis of phenotypic adaptation based on the screening of specific amino acid substitutions using only few model species in genome sequence comparisons. It also exposes the more general problem of the dilution of essential information in the supplementary material of genome papers thereby increasing the probability that misleading results will escape the scrutiny of editors, reviewers, and ultimately readers. PMID- 25714744 TI - Two host clades, two bacterial arsenals: evolution through gene losses in facultative endosymbionts. AB - Bacterial endosymbiosis is an important evolutionary process in insects, which can harbor both obligate and facultative symbionts. The evolution of these symbionts is driven by evolutionary convergence, and they exhibit among the tiniest genomes in prokaryotes. The large host spectrum of facultative symbionts and the high diversity of strategies they use to infect new hosts probably impact the evolution of their genome and explain why they undergo less severe genomic erosion than obligate symbionts. Candidatus Hamiltonella defensa is suitable for the investigation of the genomic evolution of facultative symbionts because the bacteria are engaged in specific relationships in two clades of insects. In aphids, H. defensa is found in several species with an intermediate prevalence and confers protection against parasitoids. In whiteflies, H. defensa is almost fixed in some species of Bemisia tabaci, which suggests an important role of and a transition toward obligate symbiosis. In this study, comparisons of the genome of H. defensa present in two B. tabaci species (Middle East Asia Minor 1 and Mediterranean) and in the aphid Acyrthosiphon pisum revealed that they belong to two distinct clades and underwent specific gene losses. In aphids, it contains highly virulent factors that could allow protection and horizontal transfers. In whiteflies, the genome lost these factors and seems to have a limited ability to acquire genes. However it contains genes that could be involved in the production of essential nutrients, which is consistent with a primordial role for this symbiont. In conclusion, although both lineages of H. defensa have mutualistic interactions with their hosts, their genomes follow distinct evolutionary trajectories that reflect their phenotype and could have important consequences on their evolvability. PMID- 25714747 TI - Building the foundation for international conservation planning for breeding ducks across the U.S. and Canadian border. AB - We used publically available data on duck breeding distribution and recently compiled geospatial data on upland habitat and environmental conditions to develop a spatially explicit model of breeding duck populations across the entire Prairie Pothole Region (PPR). Our spatial population models were able to identify key areas for duck conservation across the PPR and predict between 62.1-79.1% (68.4% avg.) of the variation in duck counts by year from 2002-2010. The median difference in observed vs. predicted duck counts at a transect segment level was 4.6 ducks. Our models are the first seamless spatially explicit models of waterfowl abundance across the entire PPR and represent an initial step toward joint conservation planning between Prairie Pothole and Prairie Habitat Joint Ventures. Our work demonstrates that when spatial and temporal variation for highly mobile birds is incorporated into conservation planning it will likely increase the habitat area required to support defined population goals. A major goal of the current North American Waterfowl Management Plan and subsequent action plan is the linking of harvest and habitat management. We contend incorporation of spatial aspects will increase the likelihood of coherent joint harvest and habitat management decisions. Our results show at a minimum, it is possible to produce spatially explicit waterfowl abundance models that when summed across survey strata will produce similar strata level population estimates as the design-based Waterfowl Breeding Pair and Habitat Survey (r2 = 0.977). This is important because these design-based population estimates are currently used to set duck harvest regulations and to set duck population and habitat goals for the North American Waterfowl Management Plan. We hope this effort generates discussion on the important linkages between spatial and temporal variation in population size, and distribution relative to habitat quantity and quality when linking habitat and population goals across this important region. PMID- 25714748 TI - A "gleevec moment". PMID- 25714746 TI - P300 event-related potential as an indicator of inattentional deafness? AB - An analysis of airplane accidents reveals that pilots sometimes purely fail to react to critical auditory alerts. This inability of an auditory stimulus to reach consciousness has been coined under the term of inattentional deafness. Recent data from literature tends to show that tasks involving high cognitive load consume most of the attentional capacities, leaving little or none remaining for processing any unexpected information. In addition, there is a growing body of evidence for a shared attentional capacity between vision and hearing. In this context, the abundant information in modern cockpits is likely to produce inattentional deafness. We investigated this hypothesis by combining electroencephalographic (EEG) measurements with an ecological aviation task performed under contextual variation of the cognitive load (high or low), including an alarm detection task. Two different audio tones were played: standard tones and deviant tones. Participants were instructed to ignore standard tones and to report deviant tones using a response pad. More than 31% of the deviant tones were not detected in the high load condition. Analysis of the EEG measurements showed a drastic diminution of the auditory P300 amplitude concomitant with this behavioral effect, whereas the N100 component was not affected. We suggest that these behavioral and electrophysiological results provide new insights on explaining the trend of pilots' failure to react to critical auditory information. Relevant applications concern prevention of alarms omission, mental workload measurements and enhanced warning designs. PMID- 25714749 TI - Treatment of obesity in 2015. AB - Obesity is a major health priority in the United States, as well as globally. It is associated with multiple comorbidities and reduced life expectancy. Effective management of obesity involves producing an intervention plan tailored to the individual patient. Potential contributory factors to weight gain, including dietary habits, physical inactivity, associated medical conditions, and medications, should be identified and addressed. Lifestyle interventions comprising diet modification, physical activity, and behavior therapy are foundational to the management of obesity. Caloric restriction is the most important component in achieving weight loss through negative energy balance, whereas sustained physical activity is important in maintaining the weight loss. Adjunctive therapies in the form of pharmacotherapy and bariatric surgery are required in patients who do not achieve targeted weight loss and health goals with lifestyle interventions. Currently there are 3 drugs approved for long-term management of obesity, orlistat, phentermine/topiramate extended release, and lorcaserin, and there are 2 on the horizon, bupropion/naltrexone and liraglutide. Bariatric surgery is an effective strategy recognized to produce durable weight loss with amelioration of obesity-related comorbidities and should be considered a treatment option in eligible patients. PMID- 25714751 TI - Overlooked mountain rock pools in deserts are critical local hotspots of biodiversity. AB - BACKGROUND: The world is undergoing exceptional biodiversity loss. Most conservation efforts target biodiversity hotspots at large scales. Such approach overlooks small-sized local hotspots, which may be rich in endemic and highly threatened species. We explore the importance of mountain rock pools (gueltas) as local biodiversity hotspots in the Sahara-Sahel. Specifically, we considered how many vertebrates (total and endemics) use gueltas, what factors predict species richness, and which gueltas are of most priority for conservation. We expected to provide management recommendations, improve local biodiversity conservation, and simultaneously contribute with a framework for future enhancement of local communities' economy. The identification of local hotspots of biodiversity is important for revaluating global conservation priorities. METHODOLOGY/PRINCIPAL FINDINGS: We quantified the number of vertebrate species from each taxonomic group and endemics present in 69 gueltas in Mauritania, then compared these with species present in a surrounding area and recorded in the country. We evaluated the predictors of species number's present in each guelta through a multiple regression model. We ranked gueltas by their priority for conservation taking into account the percentage of endemics and threats to each guelta. Within a mere aggregate extent of 43 ha, gueltas hold about 32% and 78% of the total taxa analysed and endemics of Mauritania, respectively. The number of species present in each guelta increased with the primary productivity and area of gueltas and occurrence of permanent water. Droughts and human activities threaten gueltas, while 64% of them are currently unprotected. CONCLUSION/SIGNIFICANCE: Gueltas are crucial for local biodiversity conservation and human activities. They require urgent management plans in Mauritania's mountains. They could provide refugia under climate change being important for long-term conservation of Sahara-Sahel biodiversity. Given their disproportional importance in relation to their size, they are local hotspots of biodiversity deserving global attention. PMID- 25714752 TI - What drives academic data sharing? AB - Despite widespread support from policy makers, funding agencies, and scientific journals, academic researchers rarely make their research data available to others. At the same time, data sharing in research is attributed a vast potential for scientific progress. It allows the reproducibility of study results and the reuse of old data for new research questions. Based on a systematic review of 98 scholarly papers and an empirical survey among 603 secondary data users, we develop a conceptual framework that explains the process of data sharing from the primary researcher's point of view. We show that this process can be divided into six descriptive categories: Data donor, research organization, research community, norms, data infrastructure, and data recipients. Drawing from our findings, we discuss theoretical implications regarding knowledge creation and dissemination as well as research policy measures to foster academic collaboration. We conclude that research data cannot be regarded as knowledge commons, but research policies that better incentivise data sharing are needed to improve the quality of research results and foster scientific progress. PMID- 25714753 TI - Depth-dependent changes in collagen organization in the human peripapillary sclera. AB - PURPOSE: The collagen structure of the human peripapillary sclera plays a significant role in determining optic nerve head (ONH) biomechanics, and is therefore of interest in the study of glaucoma. The aim of the current work was to map the anisotropic collagen structure of the normal human peripapillary sclera as a function of tissue depth. METHODS: Wide-angle x-ray scattering was used to quantify collagen fibril orientation at 0.5 mm intervals across six 150 MUm-thick serial sections through the peripapillary sclera of eight normal European-derived human eyes. Two structural parameters were measured: 1) the relative number of fibrils preferentially aligned at a given angle within the tissue plane, 2) the degree of collagen alignment (anisotropy). RESULTS: The inner-most one-third of the peripapillary scleral stroma (nearest to the choroid) was characterised by collagen fibrils either randomly arranged or preferentially aligned radially with respect to the ONH. In contrast, the outer two-thirds of the tissue was dominated by a circumferential arrangement of collagen encircling the ONH. In all tissue regions the degree of collagen anisotropy peaked in the mid-stroma and progressively decreased towards the tissue surfaces, with the largest depth variations occurring in the inferior-nasal quadrant, and the smallest occurring in the superior-nasal quadrant. CONCLUSIONS: Significant, region-specific variations in collagen structure are present in the human peripapillary sclera as a function of depth. In normal eyes, the circumferential collagen fibril architecture is most prominent in the outer two-thirds of the stroma, possibly as a mechanical adaption to more effectively support the lamina cribrosa at the level of its insertion into the scleral canal wall. PMID- 25714754 TI - Sports practices related to alcohol and tobacco use among high school students. AB - OBJECTIVE: To examine the relationship between alcohol and tobacco use and sports in a national sample of secondary students. METHODS: This cross-sectional study enrolled a representative sample of secondary students from public and private schools from all 27 Brazilian state capitals. Students were assessed in 2010 by a self-report questionnaire including questions on drug use and sport activity in the last month (n=13,872). RESULTS: Subjects who played sports exhibited a higher frequency of alcohol use and heavy episodic drinking than their peers who did not play sports. Practices that were associated with higher odds of heavy episodic drinking in the last month included gym, weight training (adjusted odds ratio [aOR]: 2.0, 95% confidence interval [95%CI] 1.6-2.4), and soccer (aOR: 1.3, 95%CI 1.1-1.5). Fighting, martial arts, or capoeira were associated with smoking (aOR: 1.9, 95%CI 1.2-3.2). CONCLUSION: These results suggest a relationship between some sports preferences and a higher risk of alcohol or tobacco use among Brazilian secondary students. This relationship should be considered in preventive programs. PMID- 25714755 TI - Serum concentrations of brain-derived neurotrophic factor and mental disorders in imprisoned women. AB - OBJECTIVE: Mental disorders and early trauma are highly prevalent in female inmates. Brain-derived neurotrophic factor (BDNF) plays an important role in learning, memory processes, and mood regulation. The aim of this study was to evaluate the relationship between serum BDNF levels and mental disorders among imprisoned women as compared with age- and education-matched controls. METHODS: A consecutively recruited sample of 18 female prisoners with mental disorders was assessed for sociodemographic, criminal, and clinical variables using standardized instruments, the Mini International Neuropsychiatric Interview Plus (MINI Plus), and serum BDNF levels. RESULTS: High rates of childhood sexual abuse and posttraumatic stress disorder (PTSD) were found in the group of forensic patients. Serum BDNF levels in the forensic group did not differ from those of healthy controls, and were significantly higher when compared with those of women with mental disorders hospitalized in a general hospital. CONCLUSION: Elevated serum BDNF levels were found in imprisoned women. The results of this study may suggest neurobiological mechanisms similar to those seen in previous clinical and preclinical studies showing the involvement of BDNF in the pathophysiology of PTSD. PMID- 25714756 TI - In Search of a Proportionate Funding in Medicine. PMID- 25714757 TI - The diagnosis of CAD in women: addressing the unmet need - a report from the national expert roundtable meeting. AB - A multistakeholder panel comprising experts in the fields of clinical cardiology, medical technology innovation, women's health research and policy analysis, personalized medicine, payers (including self-insured employers), patient advocacy, and health economics was convened at the Heart House in Washington, DC. The following points emerged as key concepts: (1) Diagnostic challenges in the evaluation of women with symptoms suggestive of obstructive coronary artery disease (CAD) result from: (a) presentation with atypical symptoms and lower pretest probability of disease compared to men, (b) fatty tissue and breast tissue attenuation on cardiac imaging leading to false positive findings, and (c) the presence of microvascular CAD. (2) Diagnostic challenges lead to both over testing of low-risk women and under-testing of high-risk women. (3) Efforts should be directed toward increasing clinician, clinical professional society, and consumer awareness and understanding of sex-specific differences between men and women in the pathophysiology of CAD. (4) Multiple health care stakeholders should be made aware of new advances in genomic approaches to address the challenges of diagnosing obstructive CAD; specifically, the Corus CAD gene expression test, which was shown to have high sensitivity and negative predictive value in a recent clinical trial. As such, it has promise as a tool to help clinicians to rule out obstructive CAD as a cause of a patient's symptoms. (Population Health Management 2015;18:86-92). PMID- 25714758 TI - Establishment of the WHO 1st International Standard ADAMTS13, plasma (12/252): communication from the SSC of the ISTH. PMID- 25714759 TI - Urinary Lipid Peroxidation Byproducts: Are They Relevant for Predicting Neonatal Morbidity in Preterm Infants? AB - Preterm infants have an immature antioxidant system; however, they frequently require supplemental oxygen. Oxygen-free radicals cause both pulmonary and systemic inflammation, and they are associated with increased morbidity and mortality. Consequently, screening of metabolite profiles representing the amount of lipid peroxidation is considered of great relevance for the evaluation of in vivo oxidative stress and derived inflammation and damage. Ranges for total relative contents of isoprostanes (IsoPs), isofurans (IsoFs), neuroprostanes (NeuroPs), and neurofurans (NeuroFs) within targeted SpO2 ranges were determined in urine samples of 254 preterm infants<32 weeks of gestation within the frame of two randomized, controlled, and blinded clinical trials employing ultra performance liquid chromatography-tandem mass spectrometry. A total of 536 serial urine samples collected during the first 4 weeks after birth in recruited infants who did not develop free radical associated conditions were analyzed. A reference range for lipid peroxidation byproducts, including isoprostanes, isofurans, neuroprostanes, and neurofurans, was calculated and possible correlations with neonatal conditions were investigated. Urinary elimination of isofurans in the first 4 days after birth correlated with later development of bronchopulmonary dysplasia. Our observations lead to the hypothesis that early urinary determination of lipid peroxidation byproducts, especially isofurans, is relevant to predict development of chronic lung conditions. PMID- 25714761 TI - Beneficial effects of adjuvant intravitreal bevacizumab injection on outcomes of Ahmed glaucoma valve implantation in patients with neovascular glaucoma: systematic literature review. AB - PURPOSE: We evaluated the effects of adjuvant intravitreal bevacizumab injection on the outcomes of Ahmed glaucoma valve (AGV) implantation in patients with neovascular glaucoma (NVG) through a systematic literature review. METHODS: An extensive search of PubMed, EMBASE, and the Cochrane Library was performed in November 2014 for selection of relevant studies. The weighted mean difference of the percentage of intraocular pressure reduction (IOPR%) from baseline to endpoint was used as the primary efficacy estimate, and Mantel-Haenszel odds ratios and 95% confidence intervals (CIs) of the success rate were used as the secondary efficacy estimates. The incidence of adverse events was also documented through a review of the studies. RESULTS: Six studies involving 252 patients (256 eyes) were included in this systematic review. The differences in the means and 95% CIs of the IOPR% of 6 studies showed that adjuvant bevacizumab treatment tended to be more effective than AGV implantation alone. Comparison of the outcomes of AGV implantation only with those of AGV implantation+adjuvant bevacizumab showed a success rate in favor of AGV implantation+adjuvant bevacizumab. The incidence of bleeding-associated complications such as hyphema, vitreous hemorrhage, and suprachoroidal hemorrhage was lower in association with combination treatment than with AGV implantation only. Combination treatment seemed to be associated with a lower incidence of other adverse effects such as hypotony, flat chamber, choroidal detachment/effusion, tube-associated complications, and corneal decompensation. CONCLUSION: AGV implantation with adjuvant bevacizumab was more effective and had a higher success rate than surgery alone for lowering IOP in patients with NVG. The combined procedure tended to show a lower incidence of bleeding-associated complications, such as hyphema. PMID- 25714760 TI - PARK2-mediated mitophagy is involved in regulation of HBEC senescence in COPD pathogenesis. AB - Cigarette smoke (CS)-induced mitochondrial damage with increased reactive oxygen species (ROS) production has been implicated in COPD pathogenesis by accelerating senescence. Mitophagy may play a pivotal role for removal of CS-induced damaged mitochondria, and the PINK1 (PTEN-induced putative kinase 1)-PARK2 pathway has been proposed as a crucial mechanism for mitophagic degradation. Therefore, we sought to investigate to determine if PINK1-PARK2-mediated mitophagy is involved in the regulation of CS extract (CSE)-induced cell senescence and in COPD pathogenesis. Mitochondrial damage, ROS production, and cell senescence were evaluated in primary human bronchial epithelial cells (HBEC). Mitophagy was assessed in BEAS-2B cells stably expressing EGFP-LC3B, using confocal microscopy to measure colocalization between TOMM20-stained mitochondria and EGFP-LC3B dots as a representation of autophagosome formation. To elucidate the involvement of PINK1 and PARK2 in mitophagy, knockdown and overexpression experiments were performed. PINK1 and PARK2 protein levels in lungs from patients were evaluated by means of lung homogenate and immunohistochemistry. We demonstrated that CSE induced mitochondrial damage was accompanied by increased ROS production and HBEC senescence. CSE-induced mitophagy was inhibited by PINK1 and PARK2 knockdown, resulting in enhanced mitochondrial ROS production and cellular senescence in HBEC. Evaluation of protein levels demonstrated decreased PARK2 in COPD lungs compared with non-COPD lungs. These results suggest that PINK1-PARK2 pathway mediated mitophagy plays a key regulatory role in CSE-induced mitochondrial ROS production and cellular senescence in HBEC. Reduced PARK2 expression levels in COPD lung suggest that insufficient mitophagy is a part of the pathogenic sequence of COPD. PMID- 25714762 TI - [Three types of bias: distortion of research results and how that can be prevented]. AB - A systematic distortion of the relationship between a treatment, risk factor or exposure and clinical outcomes is denoted by the term 'bias'. Three types of bias can be distinguished: information bias, selection bias, and confounding. These three types of bias and their potential solutions are discussed using various examples. PMID- 25714763 TI - [Invasive pulmonary aspergillosis in influenza]. AB - BACKGROUND: Invasive pulmonary aspergillosis (IPA) is a life-threatening infection that occurs predominantly in severely immunocompromised patients. Recently, IPA is also increasingly seen in less severely immunocompromised patients, such as patients with COPD receiving glucocorticoids and patients on ventilation in an IC unit. CASE DESCRIPTION: Here we present the case of a 59 year-old male who died of influenza complicated by a superinfection with Aspergillus fumigatus. This patient had no known previous medical history, except schizophrenia. CONCLUSION: Since the 2009 influenza pandemic, IPA has been increasingly reported as a superinfection in patients with a severe influenza virus infection. This combined Aspergillus and influenza infection often has a fatal outcome. An Aspergillus sputum culture should be taken seriously in patients with severe influenza pneumonia, and treatment should be considered early in the disease course. PMID- 25714764 TI - [Ceftriaxone-induced immune haemolytic anaemia and multi-organ failure]. AB - BACKGROUND: Drug-induced immune haemolytic anaemia (DIIHA) is caused by various drugs or their metabolites. Cephalosporins are associated with haemolytic anaemia but multi-organ failure is rarely described. CASE DESCRIPTION: We report the case of a 57-year-old female who was diagnosed with neuroborreliosis and treated with ceftriaxone. The patient developed severe DIIHA. Massive intravascular haemolysis led to shock and acute renal failure, necessitating mechanical ventilation and dialysis. Treatment with ceftriaxone was discontinued and glucocorticoids were prescribed. The patient recovered slowly but fully. CONCLUSION: Ceftriaxone induced immune haemolytic anaemia is a rare but potentially fatal condition. PMID- 25714765 TI - [Assessment of euthanasia request by SCEN physicians]. AB - OBJECTIVE: To determine how uniformly Support and Consultation on Euthanasia in the Netherlands (SCEN) doctors assess a euthanasia request in patients not in the final stages of a terminal illness. DESIGN: Qualitative research. METHOD: Internal survey among SCEN doctors in the 'SCEN-Drenthe' peer group, who were asked to provide an opinion on the requirements of due care, items a to d, of the Termination of life on request and assisted suicide act (WTL) in three fictitious patients. RESULTS: Sixty assessments were received from 20 SCEN physicians. Half of the reviews were assessed as 'due care requirements not met". 45% of these were for a patient whose request was based on the grounds of a "completed life", 50% for a patient with Alzheimer's, and 55% for a patient with a reduced level of consciousness. Uncertainty about the place of Article 2.2 of the WTL, personal assessment of the unbearable nature of hopeless suffering and the rejection of alternative solutions were responsible for the heterogeneous assessments. CONCLUSION: Uniformity of assessment is important to avoid legal disparity in this patient group. We found no medical or ethical benchmarks for determining the unbearable nature of suffering. A verifying assessment by the SCEN physician can only provide an opinion regarding the presence of hopeless pain that is classified as "unbearable". A negative SCEN assessment undermines a person's sense of justice at a difficult time, while the hopeless suffering may well be accepted as unbearable in comparable cases. Adapting the KNMG "Guidelines on euthanasia for patients in a state of reduced consciousness" so that they are in line with the WTL could also contribute to greater uniformity. PMID- 25714766 TI - [Caesarean section in conflict with the patient's right to self-determination?]. AB - Competent patients have the right to refuse treatment and healthcare workers should acknowledge their wishes. In the Netherlands there are conflicting (constitutional) rights of the foetus and of mentally ill patients. This paper describes the legal and ethical problems in the case of a mentally ill patient at 37 weeks of pregnancy who refused an obstetric examination. The patient refused to cooperate and have her physical condition and mental status examined. Her refusal endangered the life of the foetus. The obstetrician decided to perform a caesarean section, even if this would be in conflict with the patient's right to self-determination. In these cases no legal framework exists for providing the best medical care. New legislation should be drawn up to prevent similar cases occurring in the future. If a caesarean section is in conflict with a patient's right to self-determination, it should always be performed as a last resort. PMID- 25714767 TI - [A girl with hyperkeratotic patches on the skin]. AB - A 5-year-old girl with generalized verrucous hyperkeratosis consulted the dermatologist for diagnosis and therapy. Further physical and mental development were normal. Gene analysis of keratin 1 and 10 was negative. According to the clinical findings, the diagnosis ichthyosis hystrix was made. Treatment with oral vitamin-A was suggested to the family. PMID- 25714768 TI - [The future of guidelines: an exploration based on the four perspectives of the PHSF-2014]. AB - In the Dutch Public Health Status and Foresight report (PHSF), the Dutch National Institute for Public Health and the Environment explores the future of public health and health care in the Netherlands up to 2040. In the first article of a short series on the PHSF 2014, we briefly explained the study and four normative perspectives on public health. In the second article, we described the most important future trends up to 2030. In this, the final article on the PHSF 2014, we use the four normative perspectives as a foresight of future guidelines. We make some recommendations in which normative diversity is taken into account. Our ultimate goal is to see our results and analyses also being put to use in other strategic discussions and determinations. PMID- 25714769 TI - [Optical diagnosis of colorectal polyps: electronic chromoendoscopy]. AB - Polyps of 1-5 mm are often detected during colonoscopy; these are only sporadically malignant. The removal, collection and pathological analysis of these polyps accounts for a significant part of the costs of a colonoscopy. The histologist's assessment is the gold standard and is endorsed in all guidelines for determination of the recommended interval for surveillance colonoscopy. If, however, it was possible to make a reliable endoscopic diagnosis of a polyp during colonoscopy the pathologist's assessment would not be needed. This strategy is known as optical diagnosis, and application would lead to cost savings in the Netherlands. Before this strategy can be safely applied in practice minimal requirements for precision have to be met, and these are not fulfilled during use of white-light endoscopy. The development of electronic chromoendoscopy will lead to improved accuracy in endoscopic diagnosis of polyps. PMID- 25714770 TI - [Clipping comparable to coiling in intracranial aneurysm]. AB - The 10-year follow-up results of the International Subarachnoid Aneurysm Trial essentially show the same results as the 5-year follow-up: no significant differences between endovascular coiling and neurosurgical clipping of ruptured intracranial aneurysms in terms of functional outcome (primary endpoint). The authors' statement that cumulative mortality rates still favour coiling did not hold up after modified intention-to-treat analysis had been performed. Moreover, the authors themselves show that survival between these treatment options is not significantly different. In the long term, coiling and clipping should therefore both be regarded viable treatment options. PMID- 25714771 TI - [A girl with a perioral rash]. AB - A 5-year-old girl consulted the general practitioner with perioral skin lesions. Dermatological findings were erythema and squamae with a sharp border, without vesicles or crusts. She had a habit of licking her lips frequently, which is causal for lip licking dermatitis. After stopping this habit, the skin healed, without application of dermal therapy. PMID- 25714772 TI - [The art of saying 'no': is it important inside or outside the consulting room?]. AB - This commentary discusses a report by the Health Council of the Netherlands on 'The art of saying no: factors contributing to the delivery of unnecessary health care'. In this report the Health Council identifies and discusses contributing factors in the areas of society, the organisation of health care and doctor patient consultations. In its recommendations the Health Council calls upon doctors to avoid delivering unnecessary care and to set boundaries by using risk communication and decision aids. Yet again, this commentary argues that the current complex health system as created by the government and health insurance companies severely restricts health professionals' ability to do so. PMID- 25714773 TI - [The fringes of the euthanasia law]. AB - A survey published in the Dutch Journal of Medicine (NTvG) shows that doctors asked to assess the suffering of patients making a request for euthanasia may give very different opinions. In this paper, I argue that this stems from the subjective character of the term 'unbearable' and that differences are bound to occur even more frequently in 'borderline' cases, such as those presented here. In my opinion, such differences do not justify a plea to abandon the assessment of unbearable suffering altogether. Rather, differences in assessment may serve as indications that the boundaries of the Dutch law on euthanasia and physician assisted suicide are within sight. Moreover, it is argued that advance directives can only be seen as euthanasia requests in a legal sense if, at the time of issue of the directive, the patient was informed about his or her diagnosis and had discussed different treatment options with the physician. Such a directive may never serve as a generic request which is valid under hypothetical conditions. PMID- 25714774 TI - Does the level of WT1 expression predict the outcome in Philadelphia-negative myeloproliferative neoplasms? AB - AIMS: Despite the clinical importance of the leukemic transformation of chronic myeloproliferative neoplasms (MPNs), very little is known about markers that predict leukemic transformation. We studied WT1 expression in 37 MPN patients diagnosed as bcr-abl negative and JAK2 (V617F) positive with a molecular genetic test, and 23 healthy controls. RESULTS: WT1 expression is higher in MPN patients compared with normal controls (p=0.002). According to the WT1 expression levels, patients were divided into two groups: high (>=0.205) and low (0-0.205) WT1 expression. Two out of six patients with a high WT1 expression level transformed to myelodysplastic syndrome at a 42- and 46-month follow-up, respectively. CONCLUSIONS: Our results suggest that the overexpression of WT1 may play an important role in the leukemic transformation of MPNs. PMID- 25714776 TI - X-ray spectroscopy as a probe for lithium polysulfide radicals. AB - The discharge mechanism in lithium sulfur batteries is still unknown and has been purported to involve significant concentrations of polysulfide radicals. Methods capable of quantifying these species in solution are therefore of paramount importance to revealing electrochemical pathways. Here we utilize DFT based X-ray Absorption Spectroscopy (XAS) simulations at the sulfur K-edge to obtain the spectra of polysulfide molecules in neutral, radical (-1) and dianionic (-2) charge states. Our calculations indicate that, contrary to recent propositions, the observed low energy, pre-edge feature in S K-edge XAS near 2470 eV is not exclusively due to radical species, but rather arises predominantly from core excitations of terminal atoms, at the ends of linear polysulfides, to sigma* orbitals, consistent with our previous results for the dianionic species. We do however find a spectral feature unique to radicals, lying 0.5-1 eV below the established pre-edge, that arises from 1s -> pi* transitions of the terminal atoms. Existing measurements on polysulfides show no evidence for such transitions. We predict that detection of linear radicals in polysulfide mixtures using XAS is limited to high mole fractions (>20%), due to the relatively weak XAS intensity of this pi* feature. PMID- 25714777 TI - 2-(2-Hydroxyphenyl)benzimidazole-based four-coordinate boron-containing materials with highly efficient deep-blue photoluminescence and electroluminescence. AB - Two novel four-coordinate boron-containing emitters 1 and 2 with deep-blue emissions were synthesized by refluxing a 2-(2-hydroxyphenyl)benzimidazole ligand with triphenylborane or bromodibenzoborole. The boron chelation produced a new pi conjugated skeleton, which rendered the synthesized boron materials with intense fluorescence, good thermal stability, and high carrier mobility. Both compounds displayed deep-blue emissions in solutions with very high fluorescence quantum yields (over 0.70). More importantly, the samples showed identical fluorescence in the solution and solid states, and the efficiency was maintained at a high level (approximately 0.50) because of the bulky substituents between the boron atom and the benzimidazole unit, which can effectively separate the flat luminescent units. In addition, neat thin films composed of 1 or 2 exhibited high electron and hole mobility in the same order of magnitude 10(-4), as determined by time-of-flight. The fabricated electroluminescent devices that employed 1 or 2 as emitting materials showed high-performance deep-blue emissions with Commission Internationale de L'Eclairage (CIE) coordinates of (X = 0.15, Y = 0.09) and (X = 0.16, Y = 0.08), respectively. Thus, the synthesized boron-containing materials are ideal candidates for fabricating high-performance deep-blue organic light emitting diodes. PMID- 25714778 TI - The autophagy sensor ITPR1 protects renal carcinoma cells from NK-mediated killing. AB - Clear cell renal cell carcinoma (ccRCC) is dominated by inactivating mutations in VHL (von Hippel-Lindau tumor suppressor, E3 ubiquitin protein ligase), leading to constitutive activation of the hypoxia-inducible factors (HIFs) and induction of a hypoxia response transcription signature. Our study demonstrated that VHL mutation results in the acquisition of ccRCC resistance to NK-mediated lysis by a mechanism involving EPAS1/HIF-2alpha stabilization. More importantly we identified ITPR1 (inositol 1,4,5-trisphosphate receptor, type 1) as a direct novel target of EPAS1 and as a potent regulator of NK-mediated killing through the activation of autophagy in target cells by a signal derived from NK cells. Therefore, it is conceivable to consider EPAS1 or the autophagy sensor ITPR1 as a potential target in future therapeutic protocols that aim to improve NK cell responses in patients with RCC and other solid malignancies. PMID- 25714775 TI - Mitochondrial genomes suggest rapid evolution of dwarf California Channel Islands foxes (Urocyon littoralis). AB - Island endemics are typically differentiated from their mainland progenitors in behavior, morphology, and genetics, often resulting from long-term evolutionary change. To examine mechanisms for the origins of island endemism, we present a phylogeographic analysis of whole mitochondrial genomes from the endangered island fox (Urocyon littoralis), endemic to California's Channel Islands, and mainland gray foxes (U. cinereoargenteus). Previous genetic studies suggested that foxes first appeared on the islands >16,000 years ago, before human arrival (~13,000 cal BP), while archaeological and paleontological data supported a colonization >7000 cal BP. Our results are consistent with initial fox colonization of the northern islands probably by rafting or human introduction ~9200-7100 years ago, followed quickly by human translocation of foxes from the northern to southern Channel Islands. Mitogenomes indicate that island foxes are monophyletic and most closely related to gray foxes from northern California that likely experienced a Holocene climate-induced range shift. Our data document rapid morphological evolution of island foxes (in ~2000 years or less). Despite evidence for bottlenecks, island foxes have generated and maintained multiple mitochondrial haplotypes. This study highlights the intertwined evolutionary history of island foxes and humans, and illustrates a new approach for investigating the evolutionary histories of other island endemics. PMID- 25714780 TI - Spermatozoa of Sminthopsis murina (Mammalia: Metatheria) exhibit an unusually high degree of chromatin stability in the absence of disulphide bonding in protamine 1. AB - Although all but a single genus (Planigale) of the metatheria so far examined contain no cysteine residues in protamine 1, we report a remarkable level of chromatin stability in the spermatozoa of the common dunnart, Sminthopsis murina. S. murina cauda epididymal spermatozoa and somatic epithelial cells were exposed to a combination of graded treatments to lyse sperm protein and induce sperm DNA damage via standard freeze-thaw protocols and post-thaw incubation at 37 degrees C for 48h, exposure to sodium nitroprusside (SNP) and the enzyme AluI restriction endonuclease. Sperm DNA fragmentation was assessed using the comet assay and sperm chromatin dispersal test. Although S. murina somatic cells showed DNA fragmentation following protein lysis and after treatment with all the protocols specifically designed to induce chromatin damage, sperm DNA fragmentation was only observed following moderate to severe proteolytic exposure and treatment with the restriction endonuclease; there was also an increase in the baseline halo of spermatozoa treated with an aggressive reducing agent, but no corresponding evidence of fragmented DNA, suggesting that cysteine residues may be functioning to conform tertiary and/or quaternary chromatin structure. Given that the protamine 1 of S. murina contains no cysteine, we suggest that the source of these residues is possibly the histone fraction of the chromatin and that the high level of stability is potentially related to prolonged sperm survival in the female's reproductive tract. PMID- 25714779 TI - Histidine 352 (His352) and tryptophan 355 (Trp355) are essential for flax UGT74S1 glucosylation activity toward secoisolariciresinol. AB - Flax secoisolariciresinol diglucoside (SDG) lignan is a natural phytoestrogen for which a positive role in metabolic diseases is emerging. Until recently however, much less was known about SDG and its monoglucoside (SMG) biosynthesis. Lately, flax UGT74S1 was identified and characterized as an enzyme sequentially glucosylating secoisolariciresinol (SECO) into SMG and SDG when expressed in yeast. However, the amino acids critical for UGT74S1 glucosyltransferase activity were unknown. A 3D structural modeling and docking, site-directed mutagenesis of five amino acids in the plant secondary product glycosyltransferase (PSPG) motif, and enzyme assays were conducted. UGT74S1 appeared to be structurally similar to the Arabidopsis thaliana UGT72B1 model. The ligand docking predicted Ser357 and Trp355 as binding to the phosphate and hydroxyl groups of UDP-glucose, whereas Cys335, Gln337 and Trp355 were predicted to bind the 7-OH, 2-OCH3 and 17-OCH3 of SECO. Site-directed mutagenesis of Cys335, Gln337, His352, Trp355 and Ser357, and enzyme assays revealed an alteration of these binding sites and a significant reduction of UGT74S1 glucosyltransferase catalytic activity towards SECO and UDP glucose in all mutants. A complete abolition of UGT74S1 activity was observed when Trp355 was substituted to Ala355 and Gly355 or when changing His352 to Asp352, and an altered metabolite profile was observed in Cys335Ala, Gln337Ala, and Ser357Ala mutants. This study provided for the first time evidence that Trp355 and His352 are critical for UGT74S1's glucosylation activity toward SECO and suggested the possibility for SMG production in vitro. PMID- 25714781 TI - Mn-salen catalysed benzylic C-H activation for the synthesis of aryl [(18)F]CF3 containing PET probes. AB - The development of a Mn-salen complex catalysed oxidative benzylic fluorination of non-activated C-H bonds using [(18)F]fluoride is described for installation of [(18)F]CHRF, [(18)F]CR2F and particularly [(18)F]CF3 containing groups in the presence of other functional groups. PMID- 25714782 TI - A top-notch viral oncogene. PMID- 25714783 TI - Cervical cancer epidemiology in foreign women in Northern Italy: role of human papillomavirus prevalence in country of origin. AB - This study compares the incidence and treatments of cervical neoplasia in foreigners from high migration countries and Italians in the Reggio Emilia province (Northern Italy) in 2002-2009. Standardized incidence ratios (SIRs) and 95% confidence intervals (95% CI) for cervical intraepithelial neoplasia grade 3 (CIN3) and cancer were calculated for foreigners versus Italian women; foreigners were also classified according to the prevalence of human papillomavirus (HPV) in their country of origin. The proportion of hysterectomies is presented as an indicator of inappropriate surgery in CIN3 and microinvasive cancers. A higher risk was observed in women from high human papillomavirus prevalence countries (HHPVC) both for cancer and for CIN3 (SIR=4.1, 95% CI=2.2-6.9; SIR=2.0, 95% CI 1.7-2.5, respectively), whereas in those from low human papillomavirus prevalence countries (LHPVC), no difference for cancer and a lower risk for CIN3 were observed (SIR=1.0, 95% CI 0.2-2.2; SIR=0.6, 95% CI 0.4-0.8, respectively). A lower CIN3/cancer ratio was found in women from HHPVC (2.6) and in women from LHPVC (3.6) than in Italians (7.4). The percentage of hysterectomies for CIN3 or microinvasive cancers was 3.4 in foreigners and 4.7 in Italians. A higher risk of cervical cancer was found in women from HHPVC compared with Italians and women from LHPVC, suggesting a role of HPV prevalence in the country of origin in the excess risk. The CIN3/cancer ratio was lower for both women from HHPVC and women from LHPVC, also suggesting a role of low screening uptake for cervical cancer incidence in immigrants. PMID- 25714784 TI - The protein kinase promiscuities in the cancer-preventive mechanisms of NSAIDs. AB - NSAIDs have been observed to have cancer-preventive properties, but the actual mechanism is elusive. We hypothesize that NSAIDs might have an effect through common pathways and targets of anticancer drugs by exploiting promiscuities of anticancer drug targets. Here, we have explored NSAIDs by their structural and pharmacophoric similarities with small anticancer molecules. In-silico analyses have shown a strong similarity between NSAIDs and protein kinase (PK) inhibitors. The calculated affinities of NSAIDs were found to be lower than the affinities of anticancer drugs, but higher than the affinities of compounds that are not specific to PKs. The competitive inhibition model suggests that PK might be inhibited by around 10%, which was confirmed by biochemical screening of some NSAIDs against PKs. NSAIDs did not affect all PKs universally, but had specificities for certain sets of PKs, which differed according to the NSAID. The study revealed potentially new features and mechanisms of NSAIDs that are useful in explaining their role in cancer prevention, which might lead to clinically significant breakthroughs in the future. PMID- 25714785 TI - Factors associated with delaying medical assessment of patients and impacting the prognosis of rectal cancer. AB - The aims of this study were (a) to compare the clinical presentations and outcomes of patients referred to the hospital from the emergency department (ED) and those referred from non-ED facilities in a Chinese population and (b) to identify the factors influencing delays in medical assessment and prognosis for patients with rectal cancer (RC). Eligible Chinese patients newly diagnosed with RC, admitted to the hospital from the ED, or referred from non-ED sources between 1 January 2008 and 31 December 2009 were enrolled in this prospective study. Associations between symptoms, symptom duration, tumor stage at diagnosis, and 3 year survival were proposed to identify factors associated with delay in the diagnosis of RC and emergency admission. Compared with patients in the non-ED group, patients in the ED group had a significantly longer hospital stay, greater in-hospital mortality, a higher proportion of advanced stage tumor, lower rate of undergoing potentially curative surgery, and a higher proportion of symptom duration longer than 1 month. There was a statistically significant difference in the 3-year overall survival between the patients who underwent emergency operation within 24 h of admission and the patients presenting as emergency who underwent an operation longer than 24 h from admission to operation. Patients who endured symptoms longer than 1 month had a significantly higher proportion of emergency admissions, higher proportion of advanced stage tumor, and lower rate of undergoing potentially curative surgery compared with patients whose symptom duration was less than 1 month. In conclusion, (a) ED referral patients endured significantly longer symptom duration before diagnosis. (b) Emergency operation within 24 h of admission was an independent prognostic indicator of overall survival in patients with RC. A two-stage approach for the management of patients with RC who presented as emergency could enable patients to be transferred to a specialist department of surgical oncology for a definitive radical oncological operation and improve the prognosis. PMID- 25714786 TI - A Perspective on Metabolic Syndrome and Nonalcoholic Fatty Liver Disease. AB - Nonalcoholic fatty liver disease (NAFLD) is increasingly being diagnosed worldwide and is strongly associated with the features of metabolic syndrome. In this brief review, we discuss two key questions relating to NAFLD and metabolic syndrome: (1) Does NAFLD predict the development of type 2 diabetes mellitus and metabolic syndrome, or is it simply an epiphenomenon? (2) Are there differences between metabolic syndrome-associated NAFLD and NAFLD associated with genetic variation in the patatin-like phospholipase domain-containing 3 (PNPLA3) gene? Accumulating evidence indicates that NAFLD is not simply the hepatic manifestation of the metabolic syndrome, but is a pathogenic determinant of the syndrome. Genetic variation within the PNPLA3 gene (e.g., I148M homozygosity) confers a higher risk of developing more severe histological features of NAFLD, but a lower risk of developing metabolic syndrome traits. We suggest that future research is now required to elucidate whether both metabolic syndrome-related NAFLD and PNPLA3-related NAFLD produce the same risk of developing extrahepatic complications. PMID- 25714787 TI - Vitamin D and cardiometabolic risk factors and diseases. AB - Obesity, type 2 diabetes, and cardiovascular disease (CVD) are the most common preventable causes of morbidity and mortality worldwide. Insulin resistance, which is a shared feature in these conditions, is also strongly linked to the development of polycystic ovary syndrome (PCOS), which is the most common endocrine disease in women of reproductive age and a major cause of infertility. Vitamin D deficiency has reached epidemic proportions worldwide, primarily due to the shift to sedentary, indoor lifestyles and sun avoidance behaviours to protect against skin cancer. In recent years, vitamin D deficiency has been implicated in the aetiology of type 2 diabetes, PCOS and CVD, and has been shown to be associated with their risk factors including obesity, insulin resistance, hypertension, as well as chronic low-grade inflammation. Treating vitamin D deficiency may offer a feasible and cost-effective means of reducing cardiometabolic risk factors at a population level in order to prevent the development of type 2 diabetes and CVD. However, not all intervention studies show that vitamin D supplementation alleviates these risk factors. Importantly, there is significant heterogeneity in existing studies with regards to doses and drug regimens used, populations studied (i.e. vitamin D deficient or sufficient), and the lengths of supplementation, and only few studies have directly examined the effect of vitamin D on insulin secretion and resistance with the use of clamp methods. Therefore, there is a need for well-designed large scale trials to clarify the role of vitamin D supplementation in the prevention of type 2 diabetes, PCOS, and CVD. PMID- 25714788 TI - Enterovirus d68. A focused review and clinical highlights from the 2014 U.S. Outbreak. AB - Enterovirus D68 (EV-D68), a member of the Picornaviridae family, was first identified in 1962 and is part of a group of small, nonenveloped RNA viruses. As a family, these viruses are among the most common causes of disease among humans. However, outbreaks of disease attributable to EV-D68 have been rarely reported in the previous 4 decades. Reports from a few localized outbreaks since 2008 describe severe lower respiratory tract infection in children. In the late summer of 2014, EV-D68 caused a geographically widespread outbreak of respiratory disease of unprecedented magnitude in the United States. The Centers for Disease Control and Prevention was first notified of increased respiratory viral activity by Children's Mercy Hospitals (CMH) in Kansas City, Missouri, and EV-D68 was identified in 50% of nasopharyngeal specimens initially tested. Between mid August and December 18, 2014, confirmed cases of lower respiratory tract infection caused by EV-D68 were reported in 1,152 people in 49 states and the District of Columbia. A focused review of EV-D68 respiratory disease and clinical highlights from the 2014 U.S. outbreak are presented here. PMID- 25714790 TI - Robustness of synthetic circadian clocks to multiple environmental changes. AB - A molecular network that mimics circadian clocks from cyanobacteria is constructed in silico. Simulating its oscillatory behaviour under variable conditions reveals its robustness relative to networks of alternative topologies. The principles for synthetic chemical circadian networks to work properly are consequently highlighted. PMID- 25714789 TI - A case study of the mechanism of alcohol-mediated Morita Baylis-Hillman reactions. The importance of experimental observations. AB - The mechanism of the Morita Baylis-Hillman reaction has been heavily studied in the literature, and a long series of computational studies have defined complete theoretical energy profiles in these reactions. We employ here a combination of mechanistic probes, including the observation of intermediates, the independent generation and partitioning of intermediates, thermodynamic and kinetic measurements on the main reaction and side reactions, isotopic incorporation from solvent, and kinetic isotope effects, to define the mechanism and an experimental mechanistic free-energy profile for a prototypical Morita Baylis-Hillman reaction in methanol. The results are then used to critically evaluate the ability of computations to predict the mechanism. The most notable prediction of the many computational studies, that of a proton-shuttle pathway, is refuted in favor of a simple but computationally intractable acid-base mechanism. Computational predictions vary vastly, and it is not clear that any significant accurate information that was not already apparent from experiment could have been garnered from computations. With care, entropy calculations are only a minor contributor to the larger computational error, while literature entropy correction processes lead to absurd free-energy predictions. The computations aid in interpreting observations but fail utterly as a replacement for experiment. PMID- 25714791 TI - Detection of influenza vaccine effectiveness among nursery school children: Lesson from a season with cocirculating respiratory syncytial virus. AB - In the winter influenza epidemic season, patients with respiratory illnesses including respiratory syncytial virus (RSV) infections increase among young children. Therefore, we evaluated the effectiveness of influenza vaccine against influenza-like illness (ILI) using a technique to identify outbreaks of RSV infection and to distinguish those patients from ILI patients. The study subjects were 101 children aged 12 to 84 months attending nursery school. We classified the cases into 6 levels based on the definitions of ILI for outcomes. We established observation periods according to information obtained from regional surveillance and rapid diagnostic tests among children. Multivariate odds ratios (ORs) for each case classification were obtained using a logistic regression model for each observation period. For the entire observation period, ORs for cases with fever plus respiratory symptoms were reduced marginally significantly. For the local influenza epidemic period, only the OR for the most serious cases was significantly decreased (0.20 [95%CI: 0.04-0.94]). During the influenza outbreak among the nursery school children, multivariate ORs for fever plus respiratory symptoms decreased significantly (>= 38.0 degrees C plus >= one symptoms: 0.23 [0.06-0.91), >= 38.0 degrees C plus >= 2 symptoms: 0.21 [0.05 0.85], >= 39.0 degrees C plus >= one symptoms: 0.18 [0.04-0.93] and >= 39.0 degrees C plus >= 2 symptoms: 0.16 [0.03-0.87]). These results suggest that confining observation to the peak influenza epidemic period and adoption of a strict case classification system can minimize outcome misclassification when evaluating the effectiveness of influenza vaccine against ILI, even if influenza and RSV cocirculate in the same season. PMID- 25714792 TI - An anti-fouling aptasensor for detection of thrombin by dual polarization interferometry. AB - An anti-fouling surface was designed to effectively resist nonspecific protein adsorption using dual polarization interferometry, based on which the aptasensor for detection of thrombin was fabricated according to the specific interaction between thrombin and its 15-mer aptamer. PMID- 25714793 TI - Pharmacologic sensitivity of paclitaxel to its delivery vehicles drives distinct clinical outcomes of paclitaxel formulations. AB - Paclitaxel, an effective antitumor agent, is formulated in various vehicles serving as carriers to deliver the hydrophobic paclitaxel to tissue. The approved formulations in the U.S. are paclitaxel formulated in Cremophor EL (currently known as Kolliphor EL) and nanoparticle albumin-bound paclitaxel (nab paclitaxel). Despite having the same active ingredient (paclitaxel), different formulations produce distinct products with unique efficacy and safety profiles. A semimechanistic model was developed to describe the pharmacologic sensitivity of paclitaxel under different formulations. Circulating paclitaxel concentration data from patients treated with nab-paclitaxel or Cremophor EL-paclitaxel were analyzed in NONMEM using a semimechanistic model with simultaneous disposition of paclitaxel-carrier complexes and the total paclitaxel released from the complexes. The key factors driving paclitaxel exposure in circulation and peripheral tissues were explored via sensitivity analysis. The rapid decline of total paclitaxel concentration following intravenous administration of nab paclitaxel and Cremophor EL-paclitaxel was attributed to rapid tissue distribution of the paclitaxel-carrier complexes, with minor contribution of free and protein-bound paclitaxel. Distribution of nab-paclitaxel to peripheral tissue was 4-fold faster and 10-fold more extensive than that of Cremophor EL-paclitaxel micelles, resulting in distinct tissue paclitaxel profiles. Sensitivity analyses showed the plasma paclitaxel-time profile was insensitive to the rapid rates of tissue distribution and decomposition of paclitaxel-carrier complexes but that the tissue distribution profile of paclitaxel was highly sensitive. Tissue distribution of paclitaxel is carrier complex system-dependent. Different delivery systems result in distinct tissue paclitaxel profiles but similar paclitaxel concentration-time profiles in plasma or blood, rendering the paclitaxel plasma profile a poor surrogate for its clinical outcome. PMID- 25714794 TI - Thirty-day postoperative mortality among individuals with HIV infection receiving antiretroviral therapy and procedure-matched, uninfected comparators. AB - IMPORTANCE: Antiretroviral therapy (ART) has converted human immunodeficiency virus (HIV) infection into a chronic condition, and patients now undergo a variety of surgical procedures, but current surgical outcomes are inadequately characterized. OBJECTIVE: To compare 30-day postoperative mortality in patients with HIV infection receiving ART with the rates in uninfected individuals. DESIGN, SETTING, AND PARTICIPANTS: Retrospective analysis of nationwide electronic medical record data from the US Veterans Health Administration Healthcare System, October 1, 1996, to September 30, 2010. Common inpatient surgical procedures were grouped using the Healthcare Cost and Utilization Project Clinical Classification System to match HIV-infected and uninfected patients in a 1:2 ratio. Data on 1641 patients with HIV infection receiving combination ART who were undergoing inpatient surgery were compared with data on 3282 procedure-matched, uninfected comparators. Poisson regression models of 30 day postoperative mortality were adjusted for procedure year, age, Charlson Comorbidity Index score, hemoglobin level, albumin level, HIV infection, CD4 cell count, and HIV-1 RNA level. MAIN OUTCOMES AND MEASURES: All-cause 30-day postoperative mortality. RESULTS: The most common procedures in both groups were cholecystectomy (10.5%), hip arthroplasty (10.5%), spine surgery (9.8%), herniorrhaphy (7.4%), and coronary artery bypass grafting (7.0%). In patients with HIV infection, CD4 cell distributions were 80.0% with 200/MUL or more, 16.3% with 50/MUL to 199/MUL, and 3.7% with less than 50/MUL; 74.1% of patients with HIV infection had undetectable HIV-1 RNA. Human immunodeficiency virus infection was associated with higher 30-day postoperative mortality compared with the mortality in uninfected patients (3.4% [56 patients]) vs 1.6% [53]); incidence rate ratio [IRR], 2.11; 95% CI, 1.41-3.17; P < .001). CD4 cell count was inversely associated with mortality, but HIV-1 RNA provided no additional information. After adjustment, patients with HIV infection had increased mortality compared with uninfected patients at all CD4 cell count strata (>=500/MUL: IRR, 1.92; 95% CI, 1.02-3.60; P = .04; 200-499/MUL: IRR, 1.89; 95% CI, 1.20-2.98; P = .01; 50-199/MUL: IRR, 2.66; 95% CI, 1.29-5.47; P = .01; and <50/MUL: IRR, 6.21; 95% CI, 3.55-10.85; P < .001). Hypoalbuminemia (IRR, 4.35; 95% CI, 2.78-6.81; P < .001) and age in decades (IRR, 1.47; 95% CI, 1.23-1.76; P < .001) were also strongly associated with mortality. CONCLUSIONS AND RELEVANCE: Current postoperative mortality rates among individuals with HIV infection who are receiving ART are low and are influenced as much by hypoalbuminemia and age as by CD4 cell status. Human immunodeficiency virus infection and CD4 cell count are only 2 of many factors associated with surgical outcomes that should be incorporated into surgical decision making. PMID- 25714796 TI - The combined use of cytokine-induced killer cells and cyclosporine a for the treatment of aplastic anemia in a mouse model. AB - In this study, we investigated the combined use of cytokine-induced killer (CIK) cells and cyclosporine A (CsA) to treat a mouse model of aplastic anemia (AA). CIK cells were cultured and injected alone or in combination with CsA into mice that had previously been induced into AA by busulfan and mouse interferon-gamma (IFN-gamma). The CIK cell-treated group had a survival rate of 55%, which was similar to the 60% survival rate observed in the CsA-treated group. The combination group showed a survival rate as high as 90%, while none of the mice in the no-treatment group survived to the end of the experiment. The CIK cells produced multiple cytokines, including several hematopoietic growth factors, which could promote the expansion of mouse bone marrow mononuclear cells in vitro. CsA reduced the proportion of CD4(+) T cells and the level of IFN-gamma. The combined CIK cell and CsA treatment exhibited the best curative effect, a finding that might be due to the influence of these factors on both hematopoiesis and immunity. These data suggest that the combination of CIK cells and immunosuppressive therapy might be a candidate therapy for AA in the future. PMID- 25714795 TI - beta-Amyloid and alpha-synuclein cooperate to block SNARE-dependent vesicle fusion. AB - Alzheimer's disease (AD) and Parkinson's disease (PD) are caused by beta-amyloid (Abeta) and alpha-synuclein (alphaS), respectively. Ample evidence suggests that these two pathogenic proteins are closely linked and have a synergistic effect on eliciting neurodegenerative disorders. However, the pathophysiological consequences of Abeta and alphaS coexistence are still elusive. Here, we show that large-sized alphaS oligomers, which are normally difficult to form, are readily generated by Abeta42-seeding and that these oligomers efficiently hamper neuronal SNARE-mediated vesicle fusion. The direct binding of the Abeta-seeded alphaS oligomers to the N-terminal domain of synaptobrevin-2, a vesicular SNARE protein, is responsible for the inhibition of fusion. In contrast, large-sized Abeta42 oligomers (or aggregates) or the products of alphaS incubated without Abeta42 have no effect on vesicle fusion. These results are confirmed by examining PC12 cell exocytosis. Our results suggest that Abeta and alphaS cooperate to escalate the production of toxic oligomers, whose main toxicity is the inhibition of vesicle fusion and consequently prompts synaptic dysfunction. PMID- 25714797 TI - Pyridine versus acetonitrile coordination in rhodium-N-heterocyclic carbene square-planar complexes. AB - Experimental and theoretical studies on the factors that control the coordination chemistry of N-donor ligands in square-planar complexes of the type RhCl(NHC)L(1)L(2) (NHC = N-heterocyclic carbene) are presented. The dinuclear complexes [Rh(MU-Cl)(IPr)(eta(2)-olefin)]2 {IPr = 1,3-bis-(2,6 diisopropylphenyl)imidazol-2-carbene} have been reacted with different combinations of ligands including pyridine, acetonitrile, 2-pyridylacetonitrile, triphenylphosphine, tricyclohexylphosphine, carbon monoxide or molecular oxygen. In addition, the reactivity of RhCl(IPr)(PPh3)2 has also been studied. Pyridine preferentially coordinates trans to the carbene ligand whereas pi-acceptor ligands (olefin, CO or PPh3) are prone to bind cis to IPr and trans to chlorido, unless steric bulk hinders the coordination of the ligand (PCy3). In contrast, acetonitrile is more labile than pyridine but is able to form complexes coordinated cis-to-IPr. Molecular dioxygen also displaces the labile cyclooctene ligand in RhCl(IPr)(eta(2)-coe)(py) to give a square-planar dioxygen adduct which can be transformed into a peroxo derivative by additional coordination of pyridine. Charge decomposition analysis (CDA) shows that sigma-donation values are similar for coordination at cis- or trans-IPr positions, whereas efficient pi backbonding is significantly observed at cis position being the favoured coordination site for pi-acceptor ligands. The Rh-IPr rotational barrier in a series of square-planar complexes has been analysed. It has been found that the main contribution is the steric hindrance of the ancillary ligand. The presence of a pi-donor ligand such as chlorido slows down the dynamic process. PMID- 25714798 TI - Safety and immunogenicity of 23-valent pneumococcal polysaccharide vaccine in 2 to 70 year old healthy people in China: A phase III double blind, randomized clinical trial. AB - To evaluate the safety and immunogenicity of 23-valent pneumococcal polysaccharide vaccine (PPV23), a randomized, double-blind and parallel controlled clinical trial was conducted in Yancheng, Jiangsu Province of China. There were 1200 subjects randomized into 2 groups with a 1:1 allocation. Subjects received 0.5 mL of tested PPV23 or control PPV23 by intramuscular injection in the deltoid, respectively. Results showed that seroconversion rates of all 23 types except type 3 were not significantly different between the 2 groups. The seroconversion rate of the Group T for type 3 (P = 0.0009) was significantly higher than the Group C. The post-vaccination GMCs of the Group T for types 1 (P = 0.0340), 3 (P = 0.0003), 9V (P = 0.0016), 11A (P = 0.0222) and 33F (P = 0.0344) were significantly higher than the Group C. The frequencies of local and general reactions were not significantly different and acceptable in both groups. In conclusion, The PPV23 showed a good immunogenicity and tolerability in 2 to 70 y old healthy people. PMID- 25714799 TI - Facial width-to-height ratio in a large sample of Commonwealth Games athletes. AB - Evidence that facial width-to-height ratio (FWHR) is a sexually dimorphic morphological measure is mixed. Research has also linked FWHR with aggression and other behavioral tendencies, at least in men. Again, other research has found no such relationship. Here, I tested for both possible relationships using a sample of 2,075 male and 1,406 female athletes from the Glasgow 2014 Commonwealth Games. Men showed significantly greater FWHRs than women, but this difference could be attributed to differences in body size. In addition, I found greater FWHRs in men who competed in sports involving physical contact and those stereotyped as more masculine. Again, these results could be attributed to differences in body size between categories. For women, no differences in FWHR were found regarding the amount of contact involved in a sport and how that sport was stereotyped. Finally, the FWHRs of athletes showed no relationship with the amount of aggression and related traits that were judged as required for success in those sports, although FWHRs did correlate with perceived endurance demands in women. Therefore, in a large sample of athletes, the sex difference in FWHR could be attributed to body size, and little support was found for the predicted links between this facial measure and behavior. PMID- 25714800 TI - Mixing of diphtheria, tetanus, and acellular pertussis (DTaP) vaccines in a population of children in managed care. AB - The Advisory Committee on Immunization Practices recommends administering diphtheria, tetanus and acellular pertussis (DTaP) vaccines to children at 2, 4, 6, 15-18 months, and 4-6 y of age; preferably with the same-brand vaccine for the whole series. We estimated age-appropriate DTaP dose completion and the proportion of children receiving a "mixed" DTaP vaccination series (ie, including DTaP vaccines from >= 2 brands) across the 3 milestones. Commercially-insured children born between 01/01/2003 and 04/30/2011 were identified from United States health insurance claims data and assigned to >= 1 of 3 study cohorts based on the duration of continuous health plan enrollment: 1) birth to <8 months; 2) birth to <20 months; 3) birth to <7 years. Dose completion and brand mixing of the first 3, first 4 or all 5 doses were measured in the respective cohorts. Administered DTaP vaccinations were identified in claims data and classified by brand (based on vaccine components and manufacturer). The analysis included children who received >= 2 DTaP vaccinations and had known brand information for all doses. Age-appropriate dose completion was 77% with 3 doses (<8 months cohort), 71% with 4 doses (<20 months cohort), and 85% with 5 doses (<7 years cohort). Mixed DTaP series were received by 4.7% (95% confidence interval [CI]: 4.6%-4.7%) in the <8 months cohort, 29.0% (95% CI: 28.6%-29.4%) in the <20 months cohort, and 39.0% (95% CI: 34.5, 43.6) in the <7 years cohort. DTaP mixing was just 4.7% for the first 3 doses but subsequently increased with the number of administered doses. PMID- 25714802 TI - Cytokine-induced monocyte MMP-1 is negatively regulated by GSK-3 through a p38 MAPK-mediated decrease in ERK1/2 MAPK activation. AB - Elucidation of the signal transduction events leading to the production of MMPs by monocytes/macrophages may provide insights into the mechanisms involved in the destruction of connective tissue associated with chronic inflammatory lesions. Here, we show that GSK-3 is a negative regulator of cytokine-induced MMP-1 production by monocytes. Inhibition of monocyte GSK-3 pharmacologically with SB216763 or GSK-3beta siRNA caused a significant enhancement of MMP-1 by TNF alpha- and GM-CSF-activated monocytes, indicating that induction of MMP-1 by TNF alpha and GM-CSF involved phosphorylation/inactivation of GSK-3. TNF-alpha- and GM-CSF-induced phosphorylation of GSK-3 and subsequent MMP-1 production was blocked with the PKC inhibitor Go6976 but not by the AKT1/2 inhibitor AKT VIII, showing that cytokine phosphorylation of GSK-3 occurs primarily through a PKC pathway. Inhibition of GSK-3 resulted in decreased phosphorylation of p38 MAPK with a corresponding increase in phosphorylation of ERK1/2 MAPK. Enhanced MMP-1 production by treatment with SB216763 was a result of increased ERK1/2 activation, as demonstrated by inhibition of MMP-1 by PD98059, a specific ERK1/2 inhibitor. Conversely, the p38 MAPK inhibitor SB203580 enhanced cytokine activation of ERK1/2 and the production of MMP-1 similar to that of SB216763. These findings demonstrate that the degree of cytokine-mediated phosphorylation/inhibition of GSK-3 determines the level of MMP-1 production through a mechanism involving decreased activation of p38 MAPK, a negative regulator of ERK1/2 required for cytokine-induced production of MMP-1 by monocytes. PMID- 25714801 TI - Neutrophils and inflammatory metabolism in antimicrobial functions of the mucosa. AB - In this mini-review, we will discuss recent findings that implicate neutrophil infiltration and function in establishing a metabolic environment to facilitate efficient pathogen clearance. For decades, neutrophils have been regarded as short lived, nonspecific granulocytes, equipped with toxic antimicrobial factors and a respiratory burst generating ROS. Recent findings demonstrate the importance of HIF signaling in leukocytes and surrounding tissues during inflammation. Here, we will review the potential mechanisms and outcomes of HIF stabilization within the intestinal mucosa. PMID- 25714804 TI - Store-operated calcium signaling in neutrophils. AB - Calcium signals in neutrophils are initiated by a variety of cell-surface receptors, including formyl peptide and other GPCRs, FcRs, and integrins. The predominant pathway by which calcium enters immune cells is termed SOCE, whereby plasma membrane CRAC channels allow influx of extracellular calcium into the cytoplasm when intracellular ER stores are depleted. The identification of 2 key families of SOCE regulators, STIM calcium "sensors" and ORAI calcium channels, has allowed for genetic manipulation of SOCE pathways and provided valuable insight into the molecular mechanism of calcium signaling in immune cells, including neutrophils. This review focuses on our current knowledge of the molecules involved in neutrophil SOCE and how study of these molecules has further informed our understanding of the role of calcium signaling in neutrophil activation. PMID- 25714803 TI - mTOR and metabolic regulation of conventional and regulatory T cells. AB - mTOR signaling links bioenergetic and biosynthetic metabolism to immune responses. mTOR is activated by diverse upstream stimuli, including immune signals, growth factors, and nutrients. Recent studies highlight crucial roles of mTOR signaling in immune functions mediated by conventional T cells and Tregs In this review, we discuss the regulation of mTOR signaling in T cells and the functional impacts of mTOR and metabolic pathways on T cell-mediated immune responses, with a particular focus on the differentiation and function of Tregs. PMID- 25714805 TI - Liver Transplantation for Hemoperitoneum Secondary to Huge Multiple Hemangiomatosis: A Case Report of a Tele-intensive Care Unit in Deceased-Donor Management. AB - BACKGROUND: Patients with growing and nonresectable liver hemangiomas should be followed up by a transplant center with extensive experience in complex liver disease. They could be treated on an emergency basis with orthotopic liver transplantation, with an expectation of good long-term results. MATERIALS AND METHODS: We describe the case of a 37-year-old woman with liver hemangiomatosis followed up for 8 years, who presented with bleeding requiring transfusions and developed hemodynamic instability. We listed her for emergency transplant before her sister's living donor work-up could be completed. A liver from a cadaveric donor became available at a small local hospital with no experience in organ donation. Tele-intensive care unit (tele-ICU) technology was used for providing clinical data electronically to physicians, nurses, and other critical care specialists, creating medication orders, and communicating with on-site caregivers to implement changes in donor care. RESULTS: The recipient was transplanted on an emergency basis with a specific customization and application of the telemedicine system in the management of the organ procurement by the recipient team. Tele-ICU technology was used for providing an effective intensive care unit service, managing and stabilizing the deceased donor and allowing the procurement to be carried out uneventfully. CONCLUSIONS: Tele-ICU technology could be a promising resource for emergency transplantation, reducing the urgent need for a living donation and allowing prompt recipient team management of the deceased donor. Our first tele-ICU case offers early confirmation of the feasibility of the telemedicine system in deceased-donor management. PMID- 25714806 TI - Glucose-corrected standardized uptake value in the differentiation of high-grade glioma versus post-treatment changes. AB - BACKGROUND: Standardized uptake values (SUVs) of fluorine-18 fluorodeoxyglucose PET ((18)F-FDG PET) are used widely to differentiate residual or recurrent high grade gliomas from post-treatment changes in patients with brain tumors. The aim of this study is to assess the accuracy of SUV corrected by blood glucose level (SUV(gluc)) compared with various quantitative methods in this role. MATERIALS AND METHODS: In 55 patients with dynamic F-FDG PET scans, there were 97 glioma lesions: glioblastoma (n=60), grade III gliomas (n=22), grade III or IV gliomas (n=6), grade I/II (n=7), and prebiopsy lesions (n=2). The final actual diagnosis was made on the basis of pathology (n=33) and clinical outcome (n=64). Dynamic F FDG PET scans were processed to generate parametric images of SUV(gluc), SUV(max), and glucose metabolic rate (GMR). Lesion to cerebellum ratios (SUV(Rc)) and contralateral white matter ratios (SUV(Rw)) were also measured. The SUV(gluc) was calculated as SUV(max)*blood glucose level/100. RESULTS: Using the thresholds of SUV(max)>4.6, SUV(Rc)>0.9, SUV(Rw)>1.8, SUV(gluc)>4.3, and GMR>12.2 MUmol/min/100 g to represent positivity for viable tumors, the accuracies were the same for the SUV(gluc) and SUV(Rw) (80%) and were higher than the conventional SUV(max) (72%). The area under the receiver operating characteristic curve for the SUV(gluc) (0.8933) was better than that for the SUV(max) (0.8266) (P<0.01) and was similar to those of the GMR (0.8622), SUV(Rc) (0.8606), and SUV(Rw) (0.8981). CONCLUSION: These results suggest that SUV(gluc) may aid in the differentiation of residual or recurrent high-grade tumor from post-treatment changes in patients with abnormal blood glucose levels. The simplicity of the SUV(gluc) avoids the complexity of kinetic analysis or the requirement of a reference tissue. PMID- 25714807 TI - Nuclear medicine technologist education and training in Europe: literature and web-based findings. AB - PURPOSE: The education and training of a nuclear medicine technologist (NMT) is not homogeneous among European countries, which leads to different scope of practices and, therefore, different technical skills are assigned. The goal of this research was to characterize the education and training of NMT in Europe. MATERIALS AND METHODS: This study was based on a literature research to characterize the education and training of NMT and support the historical evolution of this profession. It was divided into two different phases: the first phase included analysis of scientific articles and the second phase included research of curricula that allow health professionals to work as NMT in Europe. RESULTS: The majority of the countries [N=31 (89%)] offer the NMT curriculum integrated into the high education system and only in four (11%) countries the education is provided by professional schools. The duration in each education system is not equal, varying in professional schools (2-3 years) and high education level system (2-4 years), which means that different European Credit Transfer and Accumulation System, such as 240, 230, 222, 210 or 180 European Credit Transfer and Accumulation System, are attributed to the graduates. The professional title and scope of the practice of NMT are different in different countries in Europe. In most countries of Europe, nuclear medicine training is not specific and curriculum does not demonstrate the Nuclear Medicine competencies performed in clinical practice. CONCLUSION: The heterogeneity in education and training for NMT is an issue prevalent among European countries. For NMT professional development, there is a huge need to formalize and unify educational and training programmes in Europe. PMID- 25714808 TI - Prediction of femoral head collapse in osteonecrosis using 18F-fluoride positron emission tomography. AB - OBJECTIVE: We investigated the usefulness of (18)F-fluoride PET as a predictor of femoral head collapse in patients with osteonecrosis (ON) before radiographic changes occur. PATIENTS AND METHODS: Sixty-six hips of 42 patients diagnosed with ON of the femoral head were included in this study. We evaluated the relationship between the maximum standardized uptake value (SUV(max)) in (18)F-fluoride PET and the Ficat classification. We evaluated the relationship between SUV(max) and the presence of femoral head collapse on plain radiography at 12 months after (18)F-fluoride PET in 23 hips of 18 patients with Ficat classification stage 1 or 2. A receiver operating characteristic analysis was carried out to calculate the cut-off SUVmax for the prediction of femoral head collapse. We analyzed the relationship between SUV(max) and femoral head collapse on plain radiography in the 23 hips using a logistic regression model. RESULTS: SUV(max) increased according to the progression of the Ficat classification stage. The mean SUV(max) was 12.3+/-5.9 in the collapse group and 4.9+/-1.3 in the noncollapse group (P<0.01). The cut-off SUV(max) of 6.45 (sensitivity: 0.80, specificity: 0.92) was used for the prediction of femoral head collapse. In the univariate analysis, SUV(max), type classification, and ring sign were related significantly to femoral head collapse. CONCLUSION: We showed that the quantitative assessment of SUV(max) in (18)F-fluoride PET was useful to predict femoral head collapse in ON. (18)F-Fluoride PET might reflect accelerated bone metabolism because of microcollapse of the femoral head, which is undetectable on plain radiography. PMID- 25714809 TI - ULK1: a promising biomarker in predicting poor prognosis and therapeutic response in human nasopharygeal carcinoma. AB - Plenty of studies have established that dysregulation of autophagy plays an essential role in cancer progression. The autophagy-related proteins have been reported to be closely associated with human cancer patients' prognosis. We explored the expression dynamics and prognostic value of autophagy-related protein ULK1 by immunochemistry (IHC) method in two independent cohorts of nasopharygeal carcinoma (NPC) cases. The X-tile program was applied to determine the optimal cut-off value in the training cohort. This derived cutoff value was then subjected to analysis the association of ULK1 expression with patients' clinical characteristics and survival outcome in the validation cohort and overall cases. High ULK1 expression was closely associated with aggressive clinical feature of NPC patients. Furthermore, high expression of ULK1 was observed more frequently in therapeutic resistant group than that in therapeutic effective group. Our univariate and multivariate analysis also showed that higher ULK1 expression predicted inferior disease-specific survival (DSS) (P<0.05). Consequently, a new clinicopathologic prognostic model with 3 poor prognostic factors (ie, ULK1 expression, overall clinical stage and therapeutic response) could significantly stratify risk (low, intermediate and high) for DSS in NPC patients (P<0.001). These findings provide evidence that, the examination of ULK1 expression by IHC method, could serve as an effective additional tool for predicting therapeutic response and patients' survival outcome in NPC patients. PMID- 25714810 TI - Molecular cloning and characterization of anti-Mullerian hormone (AMH) from the Japanese wrinkled frog, Rana rugosa. AB - The role of anti-Mullerian hormone (AMH) during gonad development has been studied extensively in many species of mammal, bird, reptile, and fish but remains unresolved in amphibians. In male mammalian embryos, Sox9 activates AMH expression, which initiates regression of the Mullerian ducts. However, Sox9 (Sry related HMG box 9) is unlikely to initiate AMH in chicken, because AMH precedes Sox9 expression in this species. To clarify whether AMH is involved in testicular differentiation in amphibians, we cloned the full-length AMH cDNA from the Japanese wrinkled frog, Rana rugosa. The AMH gene, which appears to be autosomal, is exclusively expressed in the testis of adult frog among 8 different tissues examined; Sertoli cells are probably responsible for its expression. AMH expression was found in the undifferentiated gonad of both male and female tadpoles, increasing in the differentiating testis. Moreover, we observed consensus binding sites for Sox9 in the 5'-flanking region of the AMH gene. Sox9 stimulated statistically significant AMH expression in luciferase reporter assays when coexpressed in Xenopus kidney-derived A6 cells. However, Sox9 expression showed no sexual dimorphism when AMH expression was up-regulated in the developing testis. These results, taken together, suggest that AMH is probably involved in testicular differentiation in R. rugosa, although an additional, perhaps tissue-specific, transcription factor may be required for the regulation of AMH transcription. PMID- 25714811 TI - Elucidating the links between endocrine disruptors and neurodevelopment. AB - Recent data indicate that approximately 12% of children in the United States are affected by neurodevelopmental disorders, including attention deficit hyperactivity disorder, learning disorders, intellectual disabilities, and autism spectrum disorders. Accumulating evidence indicates a multifactorial etiology for these disorders, with social, physical, genetic susceptibility, nutritional factors, and chemical toxicants acting together to influence risk. Exposure to endocrine-disrupting chemicals during the early stages of life can disrupt normal patterns of development and thus alter brain function and disease susceptibility later in life. This article highlights research efforts and pinpoints approaches that could shed light on the possible associations between environmental chemicals that act on the endocrine system and compromised neurodevelopmental outcomes. PMID- 25714812 TI - rpS6 regulates blood-testis barrier dynamics through Arp3-mediated actin microfilament organization in rat sertoli cells. An in vitro study. AB - In the seminiferous epithelium of rat testes, preleptotene spermatocytes residing in the basal compartment are transported across the blood-testis barrier (BTB) to enter the adluminal compartment at stage VIII of the epithelial cycle. This process involves redistribution of tight junction (TJ) proteins via reorganization of actin cytoskeleton in Sertoli cells that serves as attachment site for adhesion protein complexes. Ribosomal protein S6 (rpS6), a downstream molecule of mTORC1 (mammalian target of rapamycin complex 1), participates in this process via a yet-to-be defined mechanism. Here, we constructed an rpS6 quadruple phosphomimetic mutant by converting Ser residues at 235, 236, 240, and 244 to Glu via site-directed mutagenesis, making this mutant constitutively active. When this rpS6 mutant was overexpressed in Sertoli cells cultured in vitro with an established TJ barrier mimicking the BTB in vivo, it perturbed the TJ permeability by down-regulating and redistributing TJ proteins at the cell cell interface. These changes are mediated by a reorganization of actin microfilaments, which was triggered by a redistribution of activated actin related protein 3 (Arp3) as well as changes in Arp3-neuronal Wiskott-Aldrich Syndrome protein (N-WASP) interaction. This in turn induced reorganization of actin microfilaments, converting them from a "bundled" to an "unbundled/branched" configuration, concomitant with a reduced actin bundling activity, thereby destabilizing the TJ-barrier function. These changes were mediated by Akt (transforming oncogene of v-akt), because an Akt knockdown by RNA interference was able to mimic the phenotypes of rpS6 mutant overexpression at the Sertoli cell BTB. In summary, this study illustrates a mechanism by which mTORC1 signal complex regulates BTB function through rpS6 downstream by modulating actin organization via the Arp2/3 complex, which may be applicable to other tissue barriers. PMID- 25714813 TI - Estrogen receptor 1 (ESR1; ERalpha), not ESR2 (ERbeta), modulates estrogen induced sex reversal in the American alligator, a species with temperature dependent sex determination. AB - All crocodilians and many turtles exhibit temperature-dependent sex determination where the temperature of the incubated egg, during a thermo-sensitive period (TSP), determines the sex of the offspring. Estrogens play a critical role in sex determination in crocodilians and turtles, as it likely does in most nonmammalian vertebrates. Indeed, administration of estrogens during the TSP induces male to female sex reversal at a male-producing temperature (MPT). However, it is not clear how estrogens override the influence of temperature during sex determination in these species. Most vertebrates have 2 forms of nuclear estrogen receptor (ESR): ESR1 (ERalpha) and ESR2 (ERbeta). However, there is no direct evidence concerning which ESR is involved in sex determination, because a specific agonist or antagonist for each ESR has not been tested in nonmammalian species. We identified specific pharmaceutical agonists for each ESR using an in vitro transactivation assay employing American alligator ESR1 and ESR2; these were 4,4',4''-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT) and 7-bromo-2 (4-hydroxyphenyl)-1,3-benzoxazol-5-ol (WAY 200070), respectively. Alligator eggs were exposed to PPT or WAY 200070 at a MPT just before the TSP, and their sex was examined at the last stage of embryonic development. Estradiol-17beta and PPT, but not WAY 200070, induced sex reversal at a MPT. PPT-exposed embryos exposed to the highest dose (5.0 MUg/g egg weight) exhibited enlargement and advanced differentiation of the Mullerian duct. These results indicate that ESR1 is likely the principal ESR involved in sex reversal as well as embryonic Mullerian duct survival and growth in American alligators. PMID- 25714814 TI - Mares prefer the voices of highly fertile stallions. AB - We investigated the possibility that stallion whinnies, known to encode caller size, also encoded information about caller arousal and fertility, and the reactions of mares in relation to type of voice. Voice acoustic features are correlated with arousal and reproduction success, the lower-pitched the stallion's voice, the slower his heart beat and the higher his fertility. Females from three study groups preferred playbacks of low-pitched voices. Hence, females are attracted by frequencies encoding for large male size, calmness and high fertility. More work is needed to explore the relative importance of morpho physiological features. Assortative mating may be involved as large females preferred voices of larger stallions. Our study contributes to basic and applied ongoing research on mammal reproduction, and questions the mechanisms used by females to detect males' fertility. PMID- 25714816 TI - Guide to the various phylogenetic classification schemes for Escherichia coli and the correspondence among schemes. AB - Numerous tools allowing the rapid and universal identification of the clones/clonal complexes/phylogroups of Escherichia coli have been developed, as it is a commensal of the vertebrate gut, a major pathogen in veterinary and human medicine, and a bacterial indicator of faecal contamination. The ability to identify clones/clonal complexes/phylogroups is crucial, as a strain's ecological niche, lifestyle and propensity to cause disease vary with its phylogenetic origins. There are currently three multi-locus sequence typing (MLST) schemes for E. coli, as well as several PCR-based assays for determining a strain's phylogroup or clonal complex. In this work, we present data that will enable investigators to determine the correspondence between the PCR-based assays and the three MLST schemes, and provide the means for assigning a sequence type (ST) to a phylogroup when no other data on the strain phylogroup membership are available. Such information will help the scientific community to accurately identify the E. coli clones reported in various publications. Although whole genome sequencing will replace classical MLST and most alternative PCR-based methods, the ST nomenclature of the MLST scheme hosted at the University of Warwick will largely persist. PMID- 25714815 TI - Retirement age and the age of onset of Alzheimer's disease: results from the ICTUS study. AB - OBJECTIVES: To test whether deferred retirement is associated with delayed onset of Alzheimer's disease (AD), and, if so, to determine whether retirement age still predicts the age at onset of AD when two potential biases are considered. METHODS: The study sample was gathered from the Impact of Cholinergic Treatment Use/Data Sharing Alzheimer cohort (ICTUS/DSA), a European study of 1,380 AD patients. Information regarding retirement age, onset of symptoms and covariates was collected at baseline whereas age at diagnosis was gathered from the patient's medical record prior to study entry. Linear mixed models, adjusted for gender, education, occupation, center, country, household income, depression and cardiovascular risk factors were conducted on 815 patients. RESULTS: (1) The global analyses (n = 815) revealed that later age at retirement was associated with later age at diagnosis (beta = 0.31, p < 0.0001); (2) once the selection bias was considered (n = 637), results showed that this association was weaker but remained significant (beta = 0.15, p = 0.004); (3) once the bias of the reverse causality (i.e., the possibility that subjects may have left the workforce due to prior cognitive impairment) was considered (n = 447), the effect was no longer significant (beta = 0.06, p = 0.18). CONCLUSION: The present study supports that there is an association between retirement age and age at onset of AD. However, the strength of this association appears to be overestimated due to the selection bias. Moreover, the causality issue remains unresolved. Further prospective investigations are mandatory in order to correctly address this question. PMID- 25714817 TI - Intraspecific variability in allelopathy of Heracleum mantegazzianum is linked to the metabolic profile of root exudates. AB - BACKGROUND AND AIMS: Allelopathy may drive invasions of some exotic plants, although empirical evidence for this theory remains largely inconclusive. This could be related to the large intraspecific variability of chemically mediated plant-plant interactions, which is poorly studied. This study addressed intraspecific variability in allelopathy of Heracleum mantegazzianum (giant hogweed), an invasive species with a considerable negative impact on native communities and ecosystems. METHODS: Bioassays were carried out to test the alleopathic effects of H. mantegazzianum root exudates on germination of Arabidopsis thaliana and Plantago lanceolata. Populations of H. mantegazzianum from the Czech Republic were sampled and variation in the phytotoxic effects of the exudates was partitioned between areas, populations within areas, and maternal lines. The composition of the root exudates was determined by metabolic profiling using ultra-high-performance liquid chromatography with time-of-flight mass spectrometry, and the relationships between the metabolic profiles and the effects observed in the bioassays were tested using orthogonal partial least squares analysis. KEY RESULTS: Variance partitioning indicated that the highest variance in phytotoxic effects was within populations. The inhibition of germination observed in the bioassay for the co-occurring native species P. lanceolata could be predicted by the metabolic profiles of the root exudates of particular maternal lines. Fifteen compounds associated with this inhibition were tentatively identified. CONCLUSIONS: The results present strong evidence that intraspecific variability needs to be considered in research on allelopathy, and suggest that metabolic profiling provides an efficient tool for studying chemically mediated plant-plant interactions whenever unknown metabolites are involved. PMID- 25714819 TI - How the American Heart Association helped change women's heart health. PMID- 25714818 TI - In vivo imaging of the S-locus receptor kinase, the female specificity determinant of self-incompatibility, in transgenic self-incompatible Arabidopsis thaliana. AB - BACKGROUND AND AIMS: The S-locus receptor kinase (SRK), which is expressed in stigma epidermal cells, is responsible for the recognition and inhibition of 'self' pollen in the self-incompatibility (SI) response of the Brassicaceae. The allele-specific interaction of SRK with its cognate pollen coat-localized ligand, the S-locus cysteine-rich (SCR) protein, is thought to trigger a signalling cascade within the stigma epidermal cell that leads to the arrest of 'self' pollen at the stigma surface. In addition to the full-length signalling SRK receptor, stigma epidermal cells express two other SRK protein species that lack the kinase domain and whose role in the SI response is not understood: a soluble version of the SRK ectodomain designated eSRK and a membrane-tethered form designated tSRK. The goal of this study was to describe the sub-cellular distribution of the various SRK protein species in stigma epidermal cells as a prelude to visualizing receptor dynamics in response to SCR binding. METHODS: The Arabidopsis lyrata SRKb variant was tagged with the Citrine variant of yellow fluorescent protein (cYFP) and expressed in A. thaliana plants of the C24 accession, which had been shown to exhibit a robust SI response upon transformation with the SRKb-SCRb gene pair. The transgenes used in this study were designed for differential production and visualization of the three SRK protein species in stigma epidermal cells. Transgenic stigmas were analysed by pollination assays and confocal microscopy. KEY RESULTS AND CONCLUSIONS: Pollination assays demonstrated that the cYFP-tagged SRK proteins are functional and that the eSRK is not required for SI. Confocal microscopic analysis of cYFP tagged SRK proteins in live stigma epidermal cells revealed the differential sub cellular localization of the three SRK protein species but showed no evidence for redistribution of these proteins subsequent to incompatible pollination. PMID- 25714820 TI - Characteristics and outcomes of women veterans undergoing cardiac catheterization in the Veterans Affairs Healthcare System: insights from the VA CART Program. AB - BACKGROUND: The number of women veterans is increasing, yet little is known about their cardiovascular risk factors, coronary anatomy, cardiac treatments, and outcomes after cardiac catheterization. Prior studies have shown that nonveteran women have more risk factors, receive less aggressive treatment, and have worse outcomes, despite having less obstructive coronary artery disease than men. Whether these differences exist among women veterans in the veterans affairs healthcare system is unknown. METHODS AND RESULTS: Data on 85 936 veterans (3181 women) undergoing initial cardiac catheterization between October 1, 2007, and September 30, 2012, were examined using the national veterans affairs Clinical Assessment Reporting and Tracking (CART) Program. Sex differences in demographics, indications, coronary anatomy, cardiac treatments, and outcomes were analyzed. Women veterans were younger (56.9 versus 63.0 years, P<0.0001) with fewer traditional cardiovascular risk factors, but with more obesity, depression, and posttraumatic stress disorder than men. Women had lower rates of obstructive coronary artery disease than men (22.6% versus 53.3%). Rates of procedural complications were similar in both genders. Adjusted outcomes at 1 year showed women had lower mortality (hazard ratio, 0.74; confidence interval, 0.60-0.92) and less all-cause rehospitalization (hazard ratio, 0.87; confidence interval, 0.82-0.93), but no difference in rates of unplanned percutaneous coronary intervention. CONCLUSIONS: Women veterans undergoing catheterization are younger, have more obesity, depression, and posttraumatic stress disorder, less obstructive coronary artery disease, and similar long-term outcomes, compared with men. These findings suggest a significant portion of women veterans may have chest pain not attributable to obstructive coronary artery disease. Further research into possible causes, such as endothelial dysfunction or concurrent psychological comorbidities, is needed. PMID- 25714821 TI - Cardiac resynchronization therapy in women versus men: observational comparative effectiveness study from the National Cardiovascular Data Registry. AB - BACKGROUND: Women have been under-represented in trials of cardiac resynchronization therapy-defibrillators (CRT-D). Previous studies suggest that women benefit from CRT-D at shorter QRS duration than men and that there may be no benefit of CRT-D in patients without left bundle branch block (LBBB) regardless of patient sex. METHODS AND RESULTS: We compared sex-specific death risk in 75 079 patients with New York Heart Association class III or IV heart failure, reduced left ventricular ejection fraction, and prolonged QRS duration (>=120 ms) receiving either CRT-D or implantable cardioverter defibrillator in subgroups according to QRS morphology and 10-ms increments in QRS duration. We applied propensity score weighting to control for differences between treatments. Among patients with LBBB, women receiving CRT-D had a lower relative death risk than those receiving an implantable cardioverter-defibrillator (absolute difference, 11%; hazard ratio=0.74 [95% confidence interval, 0.68-0.81]). In men, the lower mortality with CRT-D versus implantable cardioverter defibrillator was less pronounced (absolute difference, 9%; hazard ratio=0.84 [0.79-0.89]; sex*device interaction P=0.025). In those without LBBB, the mortality difference was modest and did not differ between women and men (absolute difference, 3%; hazard ratio=0.88 [0.79-0.97] in women and absolute difference, 2%; hazard ratio=0.95 [0.91-0.998] in men; interaction P=0.17). In subgroups according to QRS duration, CRT-D was associated with better survival in both sexes with LBBB and QRS >=130 ms, whereas there was no clear relation between QRS duration and survival in patients without LBBB regardless of patient sex. CONCLUSIONS: In a large real-world population CRT-D was associated with a lower mortality risk in both sexes with LBBB, although more pronounced among women. Only among those with LBBB, both sexes had better survival with longer QRS duration. The mortality differences in patients without LBBB were attenuated in both sexes. PMID- 25714822 TI - Difference or disparity: will big data improve our understanding of sex and cardiovascular disease? PMID- 25714823 TI - Plugging the leaking pipeline: why men have a stake in the recruitment and retention of women in cardiovascular medicine and research. PMID- 25714824 TI - "Frailty, thy name is woman": syndrome of women with heart failure with preserved ejection fraction. PMID- 25714825 TI - Sex differences in the care of patients with advanced heart failure. PMID- 25714826 TI - Symptom recognition and healthcare experiences of young women with acute myocardial infarction. AB - BACKGROUND: Prompt recognition of acute myocardial infarction symptoms and timely care-seeking behavior are critical to optimize acute medical therapies. Relatively little is known about the symptom presentation and care-seeking experiences of women aged <=55 years with acute myocardial infarction, a group shown to have increased mortality risk as compared with similarly aged men. Understanding symptom recognition and experiences engaging the healthcare system may provide opportunities to reduce delays and improve acute care for this population. METHODS AND RESULTS: We conducted a qualitative study using in-depth interviews with 30 women (aged 30-55 years) hospitalized with acute myocardial infarction to explore their experiences with prodromal symptoms and their decision-making process to seek medical care. Five themes characterized their experiences: (1) prodromal symptoms varied substantially in both nature and duration; (2) they inaccurately assessed personal risk of heart disease and commonly attributed symptoms to noncardiac causes; (3) competing and conflicting priorities influenced decisions about seeking acute care; (4) the healthcare system was not consistently responsive to them, resulting in delays in workup and diagnosis; and (5) they did not routinely access primary care, including preventive care for heart disease. CONCLUSIONS: Participants did not accurately assess their cardiovascular risk, reported poor preventive health behaviors, and delayed seeking care for symptoms, suggesting that differences in both prevention and acute care may be contributing to young women's elevated acute myocardial infarction mortality relative to men. Identifying factors that promote better cardiovascular knowledge, improved preventive health care, and prompt care seeking behaviors represent important target for this population. PMID- 25714827 TI - Women in clinical research: what we need for progress. PMID- 25714829 TI - Sex is associated with differences in individual trajectories of change in social health after implantable cardioverter-defibrillator. AB - BACKGROUND: Social health is a dimension of quality of life, and refers to people's involvement in, and satisfaction with social roles, responsibilities, and activities. The implantable cardioverter-defibrillator is associated with changes in overall quality of life, but little is known about sex differences in individual trajectories of change in social health. METHODS AND RESULTS: We prospectively measured changes in 3 subscales of the SF-36v2 generic health questionnaire (role physical, role emotional, and social functioning), 2 Patient Reported Outcomes Measurement Information System short forms (satisfaction with participation in social roles and satisfaction with participation in discretionary social activities), and the Florida Patient Acceptance Survey before and at 1, 2, and 6 months after implantation. Individual growth models of temporal change were estimated. The scores of the 6 indicators improved with time. The unconditional model demonstrated significant (fixed effects: P<0.05; covariance parameters: P<0.10) residual variability in the individual trajectories. In the conditional model, men and women differed significantly in their rates of change in the scores of 3 of the 6 measures. Although men's mean scores exceeded women's mean scores on all indicators at baseline (range of relative mean difference: 11.0% to 17.8%), the rate of women's change resulted in a reversal in relative standing at 6 months after implantation, with the mean scores of women exceeding the men's by 4.5% to 5.6%. CONCLUSIONS: Men and women differed in their trajectories of change in social health, both in terms of their starting points (ie, baseline scores) and their rates of change. PMID- 25714830 TI - Characterization of metabolically quiescent Leishmania parasites in murine lesions using heavy water labeling. AB - Information on the growth rate and metabolism of microbial pathogens that cause long-term chronic infections is limited, reflecting the absence of suitable tools for measuring these parameters in vivo. Here, we have measured the replication and physiological state of Leishmania mexicana parasites in murine inflammatory lesions using 2H2O labeling. Infected BALB/c mice were labeled with 2H2O for up to 4 months, and the turnover of parasite DNA, RNA, protein and membrane lipids estimated from the rate of deuterium enrichment in constituent pentose sugars, amino acids, and fatty acids, respectively. We show that the replication rate of parasite stages in these tissues is very slow (doubling time of ~12 days), but remarkably constant throughout lesion development. Lesion parasites also exhibit markedly lower rates of RNA synthesis, protein turnover and membrane lipid synthesis than parasite stages isolated from ex vivo infected macrophages or cultured in vitro, suggesting that formation of lesions induces parasites to enter a semi-quiescent physiological state. Significantly, the determined parasite growth rate accounts for the overall increase in parasite burden indicating that parasite death and turnover of infected host cells in these lesions is minimal. We propose that the Leishmania response to lesion formation is an important adaptive strategy that minimizes macrophage activation, providing a permissive environment that supports progressive expansion of parasite burden. This labeling approach can be used to measure the dynamics of other host-microbe interactions in situ. PMID- 25714831 TI - Disentangling the diversity of arboreal ant communities in tropical forest trees. AB - Tropical canopies are known for their high abundance and diversity of ants. However, the factors which enable coexistence of so many species in trees, and in particular, the role of foragers in determining local diversity, are not well understood. We censused nesting and foraging arboreal ant communities in two 0.32 ha plots of primary and secondary lowland rainforest in New Guinea and explored their species diversity and composition. Null models were used to test if the records of species foraging (but not nesting) in a tree were dependent on the spatial distribution of nests in surrounding trees. In total, 102 ant species from 389 trees occurred in the primary plot compared with only 50 species from 295 trees in the secondary forest plot. However, there was only a small difference in mean ant richness per tree between primary and secondary forest (3.8 and 3.3 sp. respectively) and considerably lower richness per tree was found only when nests were considered (1.5 sp. in both forests). About half of foraging individuals collected in a tree belonged to species which were not nesting in that tree. Null models showed that the ants foraging but not nesting in a tree are more likely to nest in nearby trees than would be expected at random. The effects of both forest stage and tree size traits were similar regardless of whether only foragers, only nests, or both datasets combined were considered. However, relative abundance distributions of species differed between foraging and nesting communities. The primary forest plot was dominated by native ant species, whereas invasive species were common in secondary forest. This study demonstrates the high contribution of foragers to arboreal ant diversity, indicating an important role of connectivity between trees, and also highlights the importance of primary vegetation for the conservation of native ant communities. PMID- 25714832 TI - Bone-breaking bite force of Basilosaurus isis (Mammalia, Cetacea) from the late Eocene of Egypt estimated by finite element analysis. AB - Bite marks suggest that the late Eocence archaeocete whale Basilosaurus isis (Birket Qarun Formation, Egypt) fed upon juveniles of the contemporary basilosaurid Dorudon atrox. Finite element analysis (FEA) of a nearly complete adult cranium of B. isis enables estimates of its bite force and tests the animal's capabilities for crushing bone. Two loadcases reflect different biting scenarios: 1) an intitial closing phase, with all adductors active and a full condylar reaction force; and 2) a shearing phase, with the posterior temporalis active and minimized condylar force. The latter is considered probable when the jaws were nearly closed because the preserved jaws do not articulate as the molariform teeth come into occulusion. Reaction forces with all muscles active indicate that B. isis maintained relatively greater bite force anteriorly than seen in large crocodilians, and exerted a maximum bite force of at least 16,400 N at its upper P3. Under the shearing scenario with minimized condylar forces, tooth reaction forces could exceed 20,000 N despite lower magnitudes of muscle force. These bite forces at the teeth are consistent with bone indentations on Dorudon crania, reatract-and-shear hypotheses of Basilosaurus bite function, and seizure of prey by anterior teeth as proposed for other archaeocetes. The whale's bite forces match those estimated for pliosaurus when skull lengths are equalized, suggesting similar tradeoffs of bite function and hydrodynamics. Reaction forces in B. isis were lower than maxima estimated for large crocodylians and carnivorous dinosaurs. However, comparison of force estimates from FEA and regression data indicate that B. isis exerted the largest bite forces yet estimated for any mammal, and greater force than expected from its skull width. Cephalic feeding biomechanics of Basilosaurus isis are thus consistent with habitual predation. PMID- 25714833 TI - Biotic stress shifted structure and abundance of Enterobacteriaceae in the lettuce microbiome. AB - Lettuce cultivars are not only amongst the most popular vegetables eaten raw, they are also involved in severe pathogen outbreaks world-wide. While outbreaks caused by Enterobacteriaceae species are well-studied, less is known about their occurrence in natural environments as well as the impact of biotic stress. Here, we studied the ecology of the human health-relevant bacterial family Enterobacteriaceae and assessed the impact of biotic disturbances by a soil-borne phytopathogenic fungus and Gastropoda on their structure and abundance in mesocosm and pot experiments. Using a polyphasic approach including network analyses of 16S rRNA gene amplicon libraries, quantitative PCR and complementary fluorescence in situ hybridization (FISH) microscopy we found substantial yet divergent Enterobacteriaceae communities. A similar spectrum of 14 genera was identified from rhizo- and phyllospheres but the abundance of Enterobacteriaceae was on average 3fold higher in phyllosphere samples. Both stress factors shifted the bacterial community of the leaf habitat, characterized by increases of species abundance and diversity. For the rhizosphere, we observed significant structural shifts of Enterobacteriaceae communities but also a high degree of resilience. These results could be confirmed by FISH microscopy but it was difficult to visualize phyllosphere communities. Additional inoculation experiments with Escherichia coli as model revealed their presence below the wax layer as well as in the endosphere of leaves. The observed presence influenced by stress factors and the endophytic life style of Enterobacteriaceae on lettuce can be an important aspect in relation to human health. PMID- 25714835 TI - Multifactorial analysis of conditional reprogramming of human keratinocytes. AB - Co-culture of human primary epithelial cells with irradiated 3T3 fibroblast feeder cells (J2 cells) and the Rho kinase inhibitor Y-27632 (Y) allows for the unrestricted growth of cells of epithelial origin by the process termed conditional reprogramming. To better understand the nature of the signaling processes associated with conditionally reprogrammed cells, the effect of the two critical components of the co-culture conditions, J2 cells and Y, on the growth of human foreskin keratinocytes (HFKs) was evaluated by gene expression profiling, reverse-phase protein arrays and siRNA screening. J2 cells and Y acted cooperatively to down-regulate differentiation, and upregulate proliferation and cell adhesion, including increased pT308Akt and pERK, and reduced TGF-beta pathway signaling. These findings establish a mechanistic basis for the unlimited growth potential of human epithelial cells that will be invaluable to assess the effect of genetic changes in pathologic tissues and their response to therapeutic agents. PMID- 25714836 TI - Musical minds: attentional blink reveals modality-specific restrictions. AB - BACKGROUND: Formal musical training is known to have positive effects on attentional and executive functioning, processing speed, and working memory. Consequently, one may expect to find differences in the dynamics of temporal attention between musicians and non-musicians. Here we address the question whether that is indeed the case, and whether any beneficial effects of musical training on temporal attention are modality specific or generalize across sensory modalities. METHODOLOGY/PRINCIPAL FINDINGS: When two targets are presented in close temporal succession, most people fail to report the second target, a phenomenon known as the attentional blink (AB). We measured and compared AB magnitude for musicians and non-musicians using auditory or visually presented letters and digits. Relative to non-musicians, the auditory AB was both attenuated and delayed in musicians, whereas the visual AB was larger. Non musicians with a large auditory AB tended to show a large visual AB. However, neither a positive nor negative correlation was found in musicians, suggesting that at least in musicians, attentional restrictions within each modality are completely separate. CONCLUSION/SIGNIFICANCE: AB magnitude within one modality can generalize to another modality, but this turns out not to be the case for every individual. Formal musical training seems to have a domain-general, but modality-specific beneficial effect on selective attention. The results fit with the idea that a major source of attentional restriction as reflected in the AB lies in modality-specific, independent sensory systems rather than a central amodal system. The findings demonstrate that individual differences in AB magnitude can provide important information about the modular structure of human cognition. PMID- 25714834 TI - Potential contribution of phenotypically modulated smooth muscle cells and related inflammation in the development of experimental obstructive pulmonary vasculopathy in rats. AB - We tested the hypothesis that phenotypically modulated smooth muscle cells (SMCs) and related inflammation are associated with the progression of experimental occlusive pulmonary vascular disease (PVD). Occlusive PVD was induced by combined exposure to a vascular endothelial growth factor receptor tyrosine kinase inhibitor Sugen 5416 and hypobaric hypoxia for 3 weeks in rats, which were then returned to ambient air. Hemodynamic, morphometric, and immunohistochemical studies, as well as gene expression analyses, were performed at 3, 5, 8, and 13 weeks after the initial treatment (n = 78). Experimental animals developed pulmonary hypertension and right ventricular hypertrophy, and exhibited a progressive increase in indices of PVD, including cellular intimal thickening and intimal fibrosis. Cellular intimal lesions comprised alpha smooth muscle actin (alpha SMA)+, SM1+, SM2+/-, vimentin+ immature SMCs that were covered by endothelial monolayers, while fibrous intimal lesions typically included alpha SMA+, SM1+, SM2+, vimentin+/- mature SMCs. Plexiform lesions comprised alpha SMA+, vimentin+, SM1-, SM2- myofibroblasts covered by endothelial monolayers. Immature SMC-rich intimal and plexiform lesions were proliferative and were infiltrated by macrophages, while fibrous intimal lesions were characterized by lower proliferative abilities and were infiltrated by few macrophages. Compared with controls, the number of perivascular macrophages was already higher at 3 weeks and progressively increased during the experimental period; gene expression of pulmonary hypertension-related inflammatory molecules, including IL6, MCP1, MMP9, cathepsin-S, and RANTES, was persistently or progressively up-regulated in lungs of experimental animals. We concluded that phenotypically modulated SMCs and related inflammation are potentially associated with the progression of experimental obstructive PVD. PMID- 25714837 TI - The effect of Insecticide Treated Nets (ITNs) on Plasmodium falciparum infection in rural and semi-urban communities in the south west region of Cameroon. AB - Insecticide Treated Nets (ITNs) have been shown to reduce morbidity and mortality, but coverage and proper utilization continues to be moderate in many parts of sub-Saharan Africa. The gains made through a nationwide free distribution were explored as well as the effect on malaria prevalence in semi urban and rural communities in south western Cameroon. A cross sectional survey was conducted between August and December 2013. Information on net possession, status and use were collected using a structured questionnaire while malaria parasitaemia was determined on Giemsa-stained blood smears by light microscopy. ITN ownership increased from 41.9% to 68.1% following the free distribution campaign, with 58.3% (466/799) reportedly sleeping under the net. ITN ownership was lower in rural settings (adjusted OR = 1.93, 95%CI = 1.36-2.74, p<0.001) and at lower altitude (adjusted OR = 1.79, 95%CI = 1.22-2.62, p = 0.003) compared to semi-urban settings and intermediate altitude respectively. Conversely, ITN usage was higher in semi-urban settings (p = 0.002) and at intermediate altitude (p = 0.002) compared with rural localities and low altitude. Malaria parasitaemia prevalence was higher in rural (adjusted OR = 1.63, 95%CI = 1.07-2.49) compared to semi-urban settings and in those below 15 years compared to those 15 years and above. Overall, participants who did not sleep under ITN were more susceptible to malaria parasitaemia (adjusted OR = 1.70, 95%CI = 1.14-2.54, p = 0.009). Despite the free distribution campaign, ITN ownership and usage, though improved, is still low. As children who reside in rural settings have greater disease burden (parasitemia) than children in semi-urban settings, the potential gains on both reducing inequities in ITN possession as well as disease burden might be substantial if equitable distribution strategies are adopted. PMID- 25714838 TI - When field experiments yield unexpected results: lessons learned from measuring selection in White Sands lizards. AB - Determining the adaptive significance of phenotypic traits is key for understanding evolution and diversification in natural populations. However, evolutionary biologists have an incomplete understanding of how specific traits affect fitness in most populations. The White Sands system provides an opportunity to study the adaptive significance of traits in an experimental context. Blanched color evolved recently in three species of lizards inhabiting the gypsum dunes of White Sands and is likely an adaptation to avoid predation. To determine whether there is a relationship between color and susceptibility to predation in White Sands lizards, we conducted enclosure experiments, quantifying survivorship of Holbrookia maculate exhibiting substrate-matched and substrate mismatched phenotypes. Lizards in our study experienced strong predation. Color did not have a significant effect on survival, but we found several unexpected relationships including variation in predation over small spatial and temporal scales. In addition, we detected a marginally significant interaction between sex and color, suggesting selection for substrate matching may be stronger for males than females. We use our results as a case study to examine six major challenges frequently encountered in field-based studies of natural selection, and suggest that insight into the complexities of selection often results when experiments turn out differently than expected. PMID- 25714839 TI - Caspase-1 activation by NLRP3 inflammasome dampens IL-33-dependent house dust mite-induced allergic lung inflammation. AB - The cysteine protease caspase-1 (Casp-1) contributes to innate immunity through the assembly of NLRP3, NLRC4, AIM2, and NLRP6 inflammasomes. Here we ask whether caspase-1 activation plays a regulatory role in house dust mite (HDM)-induced experimental allergic airway inflammation. We report enhanced airway inflammation in caspase-1-deficient mice exposed to HDM with a marked eosinophil recruitment, increased expression of IL-4, IL-5, IL-13, as well as full-length and bioactive IL-33. Furthermore, mice deficient for NLRP3 failed to control eosinophil influx in the airways and displayed augmented Th2 cytokine and chemokine levels, suggesting that the NLPR3 inflammasome complex controls HDM-induced inflammation. IL-33 neutralization by administration of soluble ST2 receptor inhibited the enhanced allergic inflammation, while administration of recombinant IL-33 during challenge phase enhanced allergic inflammation in caspase-1-deficient mice. Therefore, we show that caspase-1, NLRP3, and ASC, but not NLRC4, contribute to the upregulation of allergic lung inflammation. Moreover, we cannot exclude an effect of caspase-11, because caspase-1-deficient mice are deficient for both caspases. Mechanistically, absence of caspase-1 is associated with increased expression of IL-33, uric acid, and spleen tyrosine kinase (Syk) production. This study highlights a critical role of caspase-1 activation and NLPR3/ASC inflammasome complex in the down-modulation of IL-33 in vivo and in vitro, thereby regulating Th2 response in HDM-induced allergic lung inflammation. PMID- 25714840 TI - The effect of domestication on inhibitory control: wolves and dogs compared. AB - Inhibitory control i.e. blocking an impulsive or prepotent response in favour of a more appropriate alternative, has been suggested to play an important role in cooperative behaviour. Interestingly, while dogs and wolves show a similar social organization, they differ in their intraspecific cooperation tendencies in that wolves rely more heavily on group coordination in regard to hunting and pup rearing compared to dogs. Hence, based on the 'canine cooperation' hypothesis wolves should show better inhibitory control than dogs. On the other hand, through the domestication process, dogs may have been selected for cooperative tendencies towards humans and/or a less reactive temperament, which may in turn have affected their inhibitory control abilities. Hence, based on the latter hypothesis, we would expect dogs to show a higher performance in tasks requiring inhibitory control. To test the predictive value of these alternative hypotheses, in the current study two tasks; the 'cylinder task' and the 'detour task', which are designed to assess inhibitory control, were used to evaluate the performance of identically raised pack dogs and wolves. Results from the cylinder task showed a significantly poorer performance in wolves than identically-raised pack dogs (and showed that pack-dogs performed similarly to pet dogs with different training experiences), however contrary results emerged in the detour task, with wolves showing a shorter latency to success and less perseverative behaviour at the fence. Results are discussed in relation to previous studies using these paradigms and in terms of the validity of these two methods in assessing inhibitory control. PMID- 25714842 TI - Mechanisms of Sb(III) oxidation by pyrite-induced hydroxyl radicals and hydrogen peroxide. AB - Antimony (Sb) is an element of growing interest, and its toxicity and mobility are strongly influenced by redox processes. Sb(III) oxidation mechanisms in pyrite suspensions were comprehensively investigated by kinetic measurements in oxic and anoxic conditions and simulated sunlight. Sb(III) was oxidized to Sb(V) in both solution and on pyrite surfaces in oxic conditions; the oxidation efficiency of Sb(III) was gradually enhanced with the increase of pH. The pyrite induced hydroxyl radical (.OH) and hydrogen peroxide (H2O2) are the oxidants for Sb(III) oxidation. .OH is the oxidant for Sb(III) oxidation in acidic solutions, and H2O2 becomes the main oxidant in neutral and alkaline solutions. .OH and H2O2 can be generated by the reaction of previously existing FeIII(pyrite) and H2O on pyrite in anoxic conditions. The oxygen molecule is the crucial factor in continuously producing .OH and H2O2 for Sb(III) oxidation. The efficiency of Sb(III) oxidation was enhanced in surface-oxidized pyrite (SOP) suspension, more .OH formed through Fenton reaction in acidic solutions, but Fe(IV) and H2O2 were formed in neutral and alkaline solutions. Under the illumination of simulated sunlight, more .OH and H2O2 were produced in the pyrite suspension, and the oxidation efficiency of Sb(III) was remarkably enhanced. In conclusion, Sb(III) can be oxidized to Sb(V) in the presence of pyrite, which will greatly influence the fate of Sb(III) in the environment. PMID- 25714841 TI - Integrin mediated adhesion of osteoblasts to connective tissue growth factor (CTGF/CCN2) induces cytoskeleton reorganization and cell differentiation. AB - Pre-osteoblast adhesion and interaction with extracellular matrix (ECM) proteins through integrin receptors result in activation of signaling pathways regulating osteoblast differentiation. Connective tissue growth factor (CTGF/CCN2) is a matricellular protein secreted into the ECM. Prior studies in various cell types have shown that cell adhesion to CTGF via integrin receptors results in activation of specific signaling pathways that regulate cell functions, such as differentiation and cytoskeletal reorganization. To date, there are no studies that have examined whether CTGF can serve as an adhesive substrate for osteoblasts. In this study, we used the MC3T3-E1 cell line to demonstrate that CTGF serves as an adhesive matrix for osteoblasts. Anti-integrin blocking experiments and co-immunoprecipitation assays demonstrated that the integrin alphavbeta1 plays a key role in osteoblast adhesion to a CTGF matrix. Immunofluorescence staining of osteoblasts cultured on a CTGF matrix confirmed actin cytoskeletal reorganization, enhanced spreading, formation of focal adhesions, and activation of Rac1. Alkaline phosphatase (ALP) staining and activity assays, as well as Alizarin red staining demonstrated that osteoblast attachment to CTGF matrix enhanced maturation, bone nodule formation and matrix mineralization. To investigate whether the effect of CTGF on osteoblast differentiation involves integrin-mediated activation of specific signaling pathways, we performed Western blot, chromatin immunoprecipitation (ChIP) and qPCR assays. Osteoblasts cultured on a CTGF matrix showed increased total and phosphorylated (activated) forms of focal adhesion kinase (FAK) and extracellular signal-regulated kinase (ERK). Inhibition of ERK blocked osteogenic differentiation in cells cultured on a CTGF matrix. There was an increase in runt related transcription factor 2 (Runx2) binding to the osteocalcin gene promoter, and in the expression of osteogenic markers regulated by Runx2. Collectively, the results of this study are the first to demonstrate CTGF serves as a suitable matrix protein, enhancing osteoblast adhesion (via alphavbeta1 integrin) and promoting cell spreading via cytoskeletal reorganization and Rac1 activation. Furthermore, integrin-mediated activation of ERK signaling resulted in increased osteoblast differentiation accompanied by an increase in Runx2 binding to the osteocalcin promoter and in the expression of osteogenic markers. PMID- 25714844 TI - Letters. PMID- 25714843 TI - Antitumor RNases: killer's secrets. PMID- 25714847 TI - Intraosseous hibernoma: a case report and review of the literature. AB - STUDY DESIGN: A case report and a literature review are presented. OBJECTIVE: To describe and review the clinical presentation and characteristic imaging and pathology findings of intraosseous hibernoma. SUMMARY OF BACKGROUND DATA: Hibernomas are lesions of brown fat. Brown fat is typically found in newborn mammals and is rich in mitochondria, thus enabling its role in thermoregulation. It represents a small proportion of adult fat and is distinct from the more common "white fat." Rarely does a hibernoma occur within bone. To the authors' knowledge, 5 cases in all have been reported in the literature. METHODS: We report the first case to our knowledge of an intraosseous hibernoma occurring within the lumbar spine as well as a review of the literature. RESULTS: Characteristic findings from magnetic resonance studies include variable T1W signal relative to skeletal muscle and hyperintense signal on fluid-sensitive imaging. Computed tomography has consistently demonstrated a sclerotic lesion with variable definition. Pathologic findings include sheets of multivacuolated cells with centrally placed nuclei and numerous tiny surrounding cytoplasmic vacuoles overlying bony trabeculae. CONCLUSION: Our review of the literature demonstrates that intraosseous hibernoma is most likely an incidental finding with a predilection for the lower extremities in middle-aged females. LEVEL OF EVIDENCE: 4. PMID- 25714848 TI - Toward a specific outcome instrument for spinal trauma: how to measure function and health. AB - STUDY DESIGN: Validation study. OBJECTIVE: To investigate the most valid, reliable, and comprehensible response scale for spinal trauma patients to compare their current level of function and health with their preinjury state. SUMMARY OF BACKGROUND DATA: In the context of a main project of the AOSpine Knowledge Forum Trauma to develop a disease-specific outcome instrument for adult spinal trauma patients, the need to identify a response scale that uniquely reflects the degree to which a spine trauma patient has returned to his or her preinjury state is crucial. METHODS: In the first phase, 3 different question formats and 3 different response formats were investigated in a questionnaire, which was administered twice. Based on the results of the first phase, in the second phase, a modified questionnaire was administered once to a second group of patients to investigate 5 different response formats: 0-10 Numeric Rating Scale-11, 0-100 Numeric Rating Scale-101, Visual Analogue Scale, Verbal Rating Scale, and Adjective Scale. All patients were interviewed in a semistructured fashion to identify their preferences. Multiple statistical analyses were performed: test retest reliability, internal consistency, and discriminant validity. RESULTS: Twenty eligible patients were enrolled in the first phase and 59 in the second phase. The initial phase revealed the highest preference for 1 specific question format (60.0% and 86.7% after the first and second administration of the questionnaire, respectively). The second phase showed the Verbal Rating Scale as the most preferred response format (35.6%). The semistructured interviews revealed that overall, a subgroup of patients preferred a verbal response format (42.4%), and another group of patients preferred a numerical response format (49.1%). The statistical analysis showed good to excellent psychometric properties for all formats. CONCLUSION: The most preferred question and response formats were identified for use in a disease-specific outcome instrument for spinal trauma patients. LEVEL OF EVIDENCE: 3. PMID- 25714849 TI - Immediate Reduction of a Retro-odontoid Synovial Cyst Following Lateral Atlantoaxial Joint Puncture and Arthrography: A Case Report. AB - STUDY DESIGN: Case report. OBJECTIVE: We report on a case with a retro-odontoid synovial cyst, and the immediate reduction of the cyst was confirmed after lateral atlantoaxial joint puncture and arthrography. SUMMARY OF BACKGROUND DATA: Retro-odontoid synovial cysts are rare diseases located posteriorly to a dense axis. Because most reports have focused on surgical treatment, only a few have examined nonsurgical treatment. However, several months are required after nonsurgical treatment until cyst regression. METHODS: A 52-year-old female presented with atlantoaxial instability. She complained of neck pain and numbness in her hands. Magnetic resonance imaging revealed a retro-odontoid synovial cyst. Lateral atlantoaxial joint puncture and arthrography were performed. RESULTS: Two days after treatment, the patient showed significant improvement in the numbness of her hands, and a follow-up magnetic resonance imaging revealed an immediate reduction in the cyst. During a 4.5-year follow-up period, no recurrence of the clinical symptoms occurred. CONCLUSION: Lateral atlantoaxial joint puncture may immediately reduce retro-odontoid synovial cysts, and the lateral atlantoaxial joint has a communication channel with the retro-odontoid synovial cyst via the atlantodental joint. Once disappearance of the cyst is confirmed, an acceptable long-term outcome can be achieved with nonsurgical treatment even in cases with atlantoaxial instability. LEVEL OF EVIDENCE: N/A. PMID- 25714850 TI - Acute cauda equina syndrome caused by a disk herniation-is emergent surgery the correct option? Surgical decompression remains the standard of care. PMID- 25714851 TI - Lack of association between EPHX1 polymorphism and esophageal cancer risk: evidence from meta-analysis. AB - The microsomal epoxide hydrolase 1 (EPHX1) Tyr113His and His139Arg polymorphisms have been reported to be associated with esophageal cancer (EC) risk, yet the results of these previous results have been inconsistent or controversial. The objective of this study was to explore whether the EPHX1 Tyr113His and His139Arg polymorphisms confer risk to EC. The relevant studies were identified through a search of PubMed, Excerpta Medica Database (Embase), Elsevier Science Direct, and Chinese Biomedical Literature Database until May 2013. The association between the EPHX1 Tyr113His and His139Arg polymorphisms and EC risk was pooled by odds ratios (ORs) together with their 95% confidence intervals (95%CIs). A total of eight case-control studies with 1163 EC patients and 1868 controls (seven studies for both Tyr113His and His139Arg polymorphisms, one study only for Tyr113His polymorphism) were eventually identified. We found no association between EPHX1 Tyr113His and His139Arg polymorphisms and EC risk in overall population (For Tyr113His: His vs. Tyr: OR = 1.05, 95%CI = 0.95-1.15, P = 0.379; His/His vs. Tyr/Tyr: OR = 1.04, 95%CI = 0.88-1.22, P = 0.208; His/Tyr vs. Tyr/Tyr: OR = 0.96, 95%CI = 0.80-1.15, P = 0.577; His/His vs. His/Tyr + Tyr/Tyr: OR = 1.10, 95%CI = 0.96-1.26, P = 0.164; His/His + His/Tyr vs. Tyr/Tyr: OR = 1.01, 95%CI = 0.90 1.12, P = 0.543. For His139Arg: Arg vs. His: OR = 1.04, 95%CI = 0.94-1.14, P = 0.465; Arg/Arg vs. His/His: OR = 1.06, 95%CI = 0.91-1.24, P = 0.470; Arg/His vs. His/His: OR = 1.03, 95%CI = 0.91-1.16, P = 0.673; Arg/Arg vs. Arg/His + His/His: OR = 1.04, 95%CI = 0.85-1.27, P = 0.708; Arg/Arg + Arg/His vs. His/His: OR = 1.02, 95%CI = 0.93-1.13, P = 0.617). In subgroup analysis based on ethnicity, significant association has been found in neither EPHX1 Tyr113His nor His139Arg polymorphism. The current meta-analysis suggests no evidence of association between the EPHX1 polymorphism and EC risk. PMID- 25714852 TI - Risk factors for persistent pain and its influence on maternal wellbeing after cesarean section. AB - OBJECTIVES: To investigate the overall incidence and risk factors for persistent pain and its interference with daily life after cesarean section. DESIGN: Prospective long-term follow-up study. SETTING: Karolinska University Hospital, Stockholm, Sweden. POPULATION: 260 healthy women who underwent elective cesarean section. METHODS: Information on demographics, medical history, postoperative pain and analgesic requirements was collected. A questionnaire consisting of the Brief Pain Inventory was posted at 3, 6 and 12 months after surgery. Women rated pain intensity as well as interference with factors related to general function and quality of life. MAIN OUTCOME MEASURES: The overall incidence and risk factors for persistent postoperative pain at three time points. Persistent pain was considered a secondary outcome. RESULTS: At 3, 6 and 12 months respectively 40, 27 and 22% of patients reported pain in one or more locations, in the surgical site as well as in other areas. A psychological indication, as well as a first cesarean section, increased the risk for pain at 3 months. Severe postoperative pain in the immediate postoperative period or undergoing a first cesarean section were significant independent risk factors for the development of persistent pain up to 6 months after cesarean section. Parameters related to quality of life were significantly impaired in women with persistent pain. CONCLUSION: Several factors, including severe postoperative pain, were shown to influence the risk for persistent pain after cesarean section. Long-term pain markedly affected women's wellbeing. PMID- 25714854 TI - Direct ortho-thiolation of arenes and alkenes by nickel catalysis. AB - The direct thiolation of arenes and alkenes with diaryl disulfides was developed by nickel catalysis. The reaction displayed exceptional compatibility with a wide range of functional groups to regioselectively give the diaryl sulfides and alkenyl sulfides in high yields. PMID- 25714853 TI - Targeting multiple tyrosine kinase receptors with Dovitinib blocks invasion and the interaction between tumor cells and cancer-associated fibroblasts in breast cancer. AB - A constitutive and dynamic interaction between tumor cells and their surrounding stroma is a prerequisite for tumor invasion and metastasis. Fibroblasts and myofibroblasts (collectively called cancer associated fibroblasts, CAFs) often represent the major cellular components of tumor stroma. Tumor cells secret different growth factors which induce CAFs proliferation and differentiation, and, consequently, CAFs secrete different chemokines, cytokines or growth factors which induce tumor cell invasion and metastasis. In this study we showed here that CAFs from breast cancer surgical specimens significantly induced the invasion of breast cancer cells in vitro. Most interestingly, the novel multiple tyrosine kinase inhibitor Dovitinib significantly blocked the CAFs-induced invasion of breast cancer cells by, at least in part, inhibition of the expression and secretion of CCL2, CCL5 and VEGF in CAFs. Inhibition of PI3K/Akt/mTOR signaling could be responsible for the effects of Dovitinib, since Dovitinib antagonized the promoted phosphorylated Akt after treatment with PDGF, FGF or breast cancer cell-conditioned media. Treatment with Dovitinib in combination with PI3K/Akt/mTOR signaling inhibitors Ly294002 or RAD001 resulted in additive inhibition of cell invasion. This is the first in vitro study to show that the multiple tyrosine kinase inhibitor has therapeutic activities against breast cancer metastasis by targeting both tumor cells and CAFs. PMID- 25714855 TI - Syntheses, crystal structures, optical and theoretical studies of the actinide thiophosphates SrU(PS4)2, BaU(PS4)2, and SrTh(PS4)2. AB - Three new actinide thiophosphates, SrU(PS4)2, BaU(PS4)2, and SrTh(PS4)2, have been synthesized by high-temperature solid-state methods, and their crystal structures were determined from single-crystal X-ray diffraction studies. These three isostructural compounds crystallize in a new structure type in space group D4h13-P42/mbc of the tetragonal system. Their structure features infinite one dimensional chains of infinity1[An(PS4)2(2-)] anions (An = U or Th). Each An atom is coordinated by eight S atoms in a bicapped trigonal prism, and each P atom is tetrahedrally bonded to four S atoms. The compounds are readily charge balanced as Ak2+An4+(P5+(S2-)4)2. Optical studies on single crystals of SrU(PS4)2 and BaU(PS4)2 as well as ground single crystals of SrTh(PS4)2 revealed a direct band gap of 2.13(2) eV and an indirect band gap value of 1.99(2) eV for SrU(PS4)2 and a direct and indirect gap of about 2.28(2) eV for BaU(PS4)2. SrTh(PS4)2 has a relatively large band gap of 3.02(2) eV. DFT calculations for SrU(PS4)2 and BaU(PS4)2 using the HSE functional predict both compounds to be antiferromagnetic and have very similar electronic structures with band gaps of 2.7 eV. The band gap calculated for SrTh(PS4)2 is 3.2 eV. PMID- 25714857 TI - Catalytic Silylation of Unactivated C-H Bonds. PMID- 25714858 TI - Diagnosis and treatment of incidental venous thromboembolism in cancer patients: guidance from the SSC of the ISTH. PMID- 25714856 TI - The 'Maltreatment and Abuse Chronology of Exposure' (MACE) scale for the retrospective assessment of abuse and neglect during development. AB - There is increasing interest in childhood maltreatment as a potent stimulus that may alter trajectories of brain development, induce epigenetic modifications and enhance risk for medical and psychiatric disorders. Although a number of useful scales exist for retrospective assessment of abuse and neglect they have significant limitations. Moreover, they fail to provide detailed information on timing of exposure, which is critical for delineation of sensitive periods. The Maltreatment and Abuse Chronology of Exposure (MACE) scale was developed in a sample of 1051 participants using item response theory to gauge severity of exposure to ten types of maltreatment (emotional neglect, non-verbal emotional abuse, parental physical maltreatment, parental verbal abuse, peer emotional abuse, peer physical bullying, physical neglect, sexual abuse, witnessing interparental violence and witnessing violence to siblings) during each year of childhood. Items included in the subscales had acceptable psychometric properties based on infit and outfit mean square statistics, and each subscale passed Andersen's Likelihood ratio test. The MACE provides an overall severity score and multiplicity score (number of types of maltreatment experienced) with excellent test-retest reliability. Each type of maltreatment showed good reliability as did severity of exposure across each year of childhood. MACE Severity correlated 0.738 with Childhood Trauma Questionnaire (CTQ) score and MACE Multiplicity correlated 0.698 with the Adverse Childhood Experiences scale (ACE). However, MACE accounted for 2.00- and 2.07-fold more of the variance, on average, in psychiatric symptom ratings than CTQ or ACE, respectively, based on variance decomposition. Different types of maltreatment had distinct and often unique developmental patterns. The 52-item MACE, a simpler Maltreatment Abuse and Exposure Scale (MAES) that only assesses overall exposure and the original test instrument (MACE-X) with several additional items plus spreadsheets and R code for scoring are provided to facilitate use and to spur further development. PMID- 25714859 TI - The formation mechanism of fluorescent metal complexes at the Li(x)Ni(0.5)Mn(1.5)O(4-delta)/carbonate ester electrolyte interface. AB - Electrochemical oxidation of carbonate esters at the Li(x)Ni(0.5)Mn(1.5)O(4 delta)/electrolyte interface results in Ni/Mn dissolution and surface film formation, which negatively affect the electrochemical performance of Li-ion batteries. Ex situ X-ray absorption (XRF/XANES), Raman, and fluorescence spectroscopy, along with imaging of Li(x)Ni(0.5)Mn(1.5)O(4-delta) positive and graphite negative electrodes from tested Li-ion batteries, reveal the formation of a variety of Mn(II/III) and Ni(II) complexes with beta-diketonate ligands. These metal complexes, which are generated upon anodic oxidation of ethyl and diethyl carbonates at Li(x)Ni(0.5)Mn(1.5)O(4-delta), form a surface film that partially dissolves in the electrolyte. The dissolved Mn(III) complexes are reduced to their Mn(II) analogues, which are incorporated into the solid electrolyte interphase surface layer at the graphite negative electrode. This work elucidates possible reaction pathways and evaluates their implications for Li(+) transport kinetics in Li-ion batteries. PMID- 25714860 TI - Geoffrey Ling, MD, PhD, FAAN, FANA. PMID- 25714861 TI - Traumatic brain injury. PMID- 25714862 TI - Biophysical mechanisms of traumatic brain injuries. AB - Despite years of effort to prevent traumatic brain injuries (TBIs), the occurrence of TBI in the United States alone has reached epidemic proportions. When an external force is applied to the head, it is converted into stresses that must be absorbed into the brain or redirected by a helmet or other protective equipment. Complex interactions of the head, neck, and jaw kinematics result in strains in the brain. Even relatively mild mechanical trauma to these tissues can initiate a neurochemical cascade that leads to TBI. Civilians and warfighters can experience head injuries in both combat and noncombat situations from a variety of threats, including ballistic and blunt impact, acceleration, and blast. It is critical to understand the physics created by these threats to develop meaningful improvements to clinical care, injury prevention, and mitigation. Here the authors review the current state of understanding of the complex loading conditions that lead to TBI and characterize how these loads are transmitted through soft tissue, the skull and into the brain, resulting in TBI. In addition, gaps in knowledge and injury thresholds are reviewed, as these must be addressed to better design strategies that reduce TBI incidence and severity. PMID- 25714863 TI - Neuropathology of traumatic brain injury: comparison of penetrating, nonpenetrating direct impact and explosive blast etiologies. AB - The neuropathology of traumatic brain injury (TBI) from various causes in humans is not as yet fully understood. The authors review and compare the known neuropathology in humans with severe, moderate, and mild TBI (mTBI) from nonpenetrating closed head injury (CHI) from blunt impacts and explosive blasts, as well as penetrating head injury (PHI). Penetrating head injury and CHI that are moderate to severe are more likely than mTBI to cause gross disruption of the cerebral vasculature. Axonal injury is classically exhibited as diffuse axonal injury (DAI) in severe to moderate CHI. Diffuse axonal injury is also prevalent in PHI. It is less so in mTBI. There may be a unique pattern of periventricular axonal injury in explosive blast mTBI. Neuronal injury is more prevalent in PHI and moderate to severe CHI than mTBI. Astrocyte and microglial activation and proliferation are found in all forms of animal TBI models and in severe to moderate TBI in humans. Their activation in mTBI in the human brain has not yet been studied. PMID- 25714864 TI - Chronic traumatic encephalopathy: a neurodegenerative consequence of repetitive traumatic brain injury. AB - Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease that develops as a result of repetitive mild traumatic brain injury. Chronic traumatic encephalopathy is characterized by a unique pattern of accumulation of hyperphosphorylated tau in neurons and astrocytes. The tau abnormalities begin focally and perivascularly at the depths of the cerebral sulci, spread to the superficial layers of the adjacent cortex, and eventually become widespread throughout the medial temporal lobes, diencephalon, and brainstem. Abnormalities in 43 kDa TAR DNA-binding protein are also found in most cases of CTE. To date, CTE can only be diagnosed by postmortem neuropathological examination, although there are many ongoing research studies examining imaging techniques and biomarkers that might prove to have diagnostic utility. Currently, the incidence and prevalence of CTE are unknown, although great strides are being made to better understand the clinical symptoms and signs of CTE. Further research is critically needed to better identify the genetic and environmental risk factors for CTE as well as potential rehabilitation and therapeutic strategies. PMID- 25714865 TI - Diagnosis and management of acute concussion. AB - Mild traumatic brain injury (mTBI), or concussion, constitutes a significant percentage of the millions of TBIs sustained in the United States each year. Symptoms are typically short-lived, and may correlate to physiologic changes in the acute period after injury. There are many available tools that can be utilized on the sideline as well as in the clinical setting for assessment and diagnosis of concussion. It is important to use validated tests in conjunction with a thorough history and physical examination. Neurocognitive testing may be helpful in the subacute period. Management should begin with removal from risk if a concussion is suspected, and once diagnosis is made, education and reassurance should be provided. Once symptoms have resolved, a graded return-to-play protocol can be implemented with close supervision and observation for return of symptoms. Management should be tailored to the individual, and if symptoms are prolonged, further diagnostic evaluation may be necessary. PMID- 25714867 TI - Neurosurgical management in traumatic brain injury. AB - Severe traumatic brain injury (TBI) is one of the most complex and diverse pathologic medical conditions. Each year, approximately 100,000 patients require neurosurgical evacuation of an intracranial hematoma in the United States. It is essential, early in the clinical course, to distinguish those patients with severe TBI who require operative intervention from those who can be managed with only conservative measures. The surgical technique employed is determined primarily by the specific underlying pathology in conjunction with the patient's other comorbidities. PMID- 25714866 TI - Pathophysiology and clinical management of moderate and severe traumatic brain injury in the ICU. AB - Moderate and severe traumatic brain injury (TBI) is the leading cause of morbidity and mortality among young individuals in high-income countries. Its pathophysiology is divided into two major phases: the initial neuronal injury (or primary injury) followed by secondary insults (secondary injury). Multimodality monitoring now offers neurointensivists the ability to monitor multiple physiologic parameters that act as surrogates of brain ischemia and hypoxia, the major driving forces behind secondary brain injury. The heterogeneity of the pathophysiology of TBI makes it necessary to take into consideration these interacting physiologic factors when recommending for or against any therapies; it may also account for the failure of all the neuroprotective therapies studied so far. In this review, the authors focus on neuroclinicians and neurointensivists, and discuss the developments in therapeutic strategies aimed at optimizing intracranial pressure and cerebral perfusion pressure, and minimizing cerebral hypoxia. The management of moderate to severe TBI in the intensive care unit is moving away from a pure "threshold-based" treatment approach toward consideration of patient-specific characteristics, including the state of cerebral autoregulation. The authors also include a concise discussion on the management of medical and neurologic complications peculiar to TBI as well as an overview of prognostication. PMID- 25714868 TI - Clinical approach to posttraumatic epilepsy. AB - Traumatic brain injury (TBI) is one of the most common causes of acquired epilepsy, and posttraumatic epilepsy (PTE) results in significant somatic and psychosocial morbidity. The risk of developing PTE relates directly to TBI severity, but the latency to first seizure can be decades after the inciting trauma. Given this "silent period," much work has focused on identification of molecular and radiographic biomarkers for risk stratification and on development of therapies to prevent epileptogenesis. Clinical management requires vigilant neurologic surveillance and recognition of the heterogeneous endophenotypes associated with PTE. Appropriate treatment of patients who have or are at risk for seizures varies as a function of time after TBI, and the clinician's armamentarium includes an ever-expanding diversity of pharmacological and surgical options. Most recently, neuromodulation with implantable devices has emerged as a promising therapeutic strategy for some patients with refractory PTE. Here, we review the epidemiology, diagnostic considerations, and treatment options for PTE and develop a roadmap for providers encountering this challenging clinical entity. PMID- 25714869 TI - Neuropsychiatric disturbances associated with traumatic brain injury: a practical approach to evaluation and management. AB - Traumatic brain injury (TBI) causes a wide variety of neuropsychiatric disturbances associated with great functional impairments and low quality of life. These disturbances include disorders of mood, behavior, and cognition, and changes in personality. The diagnosis of specific neuropsychiatric disturbances can be difficult because there is significant symptom overlap. Systematic clinical evaluations are necessary to make the diagnosis and formulate a treatment plan that often requires a multipronged approach. Management of TBI associated neuropsychiatric disorders should always include nonpharmacological interventions, including education, family involvement, supportive and behavioral psychotherapies, and cognitive rehabilitation. Pharmacological treatments include antidepressants, anticonvulsants, antipsychotics, dopaminergic agents, and cholinesterase inhibitors. However, evidence-based treatments are extremely limited, and management relies on clinical empiricism and resemblance of TBI neuropsychiatric symptom profiles with those of idiopathic psychiatric disorders. Although the understanding of TBI-associated neuropsychiatric disorders has improved in the last decade, further research is needed including prospective, longitudinal studies to explore biomarkers that will assist with management and prognosis as well as randomized-controlled studies to validate pharmacological and nonpharmacological treatments. The current review summarizes the available literature in support of a structured, systematic evaluation approach and treatment options as well as recommendations for further research directions. PMID- 25714871 TI - AKT1 E17K in Colorectal Carcinoma Is Associated with BRAF V600E but Not MSI-H Status: A Clinicopathologic Comparison to PIK3CA Helical and Kinase Domain Mutants. AB - The PI3K/AKT/mTOR pathway is activated through multiple mechanisms in colorectal carcinoma. Here, the clinicopathologic and molecular features of AKT1 E17K mutated colorectal carcinoma in comparison with PIK3CA-mutated colorectal carcinoma are described in detail. Interestingly, in comparison with PIK3CA mutants, AKT1 E17K was significantly associated with mucinous morphology and concurrent BRAF V600E mutation. Among PIK3CA mutants, exon 21 mutations were significantly associated with BRAF V600E mutation, MSI-H status, and poor differentiation, while exon 10 mutations were associated with KRAS/NRAS mutations. Three of four AKT1 mutants with data from both primary and metastatic lesions had concordant AKT1 mutation status in both. Both AKT1- and PIK3CA-mutant colorectal carcinoma demonstrated frequent loss of PTEN expression (38% and 34%, respectively) and similar rates of p-PRAS 40 expression (63% and 50%, respectively). Both patients with AKT1 E17K alone had primary resistance to cetuximab, whereas 7 of 8 patients with PIK3CA mutation alone experienced tumor shrinkage or stability with anti-EGFR therapy. These results demonstrate that AKT1 E17K mutation in advanced colorectal carcinoma is associated with mucinous morphology, PIK3CA wild-type status, and concurrent RAS/RAF mutations with similar pattern to PIK3CA exon 21 mutants. Thus, AKT1 E17K mutations contribute to primary resistance to cetuximab and serve as an actionable alteration. IMPLICATIONS: This first systematic study of AKT1 and PIK3CA hotspot mutations and their association with cetuximab resistance and BRAF V600E mutation has important ramifications for the development of personalized medicine, particularly in identifying patient candidates for PI3K or AKT inhibitors. PMID- 25714872 TI - Effect of gonadal steroid receptors alterations on the pathophysiology of pelvic organ prolapse and urinary incontinence. AB - BACKGROUND: The aim of this study was to investigate the contribution of the gonadal steroid receptors expression to the pathophysiological pathways of pelvic organ prolapse (POP) and urodynamic stress urinary incontinence (USUI) after menopause. METHODS: This was a prospective closely-matched controlled clinicopathological study. Immunohistochemistry for estrogen receptor isoform alpha (ER-alpha) and beta (ER-beta), as well as for progesterone receptor (PR), was performed on formaline-fixed and paraffin-embedded sections of specimens coming from the pubocervical fascia of postmenopausal women who were allocated into three groups: patients with synchronous POP and USUI (Group A), patients diagnosed with only POP (Group B), and patients without POP or USUI who underwent gynecological surgery for another benign indication (control group, Group C). RESULTS: There was no statistically significant difference among the three groups for age, parity, body mass index, or smoking. The expression of ER-alpha receptors was found significantly reduced among samples of Group B when compared with control group. Statistically significant reduction not only for ER-alpha, but for ER-beta, as well, was noticed among samples of Group A, compared to the other two groups. No remarkable differences concerning the density of PR receptors were observed among the three groups. CONCLUSIONS: Alterations of ER alpha in the pubocervical fascia and around the urethra in postmenopausal women may play an important role in the pathophysiology of POP. In addition, the risk for developing USUI among POP patients seems to be strongly associated with the reduction of both estrogen receptors (ER-alpha and ER-beta) expression. PMID- 25714873 TI - Robotic nerve-sparing radical hysterectomy. AB - AIM: The aim of this paper was to describe the robotic nerve-sparing technique and review the most recent data in the literature on this surgical approach. METHODS: Presentation of anatomical aspects regarding the nerve-sparing technique, besides discussion of the surgical steps as performed in our institution. RESULTS: Robotic-assisted nerve-sparing radical hysterectomy is a feasible approach for the treatment of cervical cancer patients, with remarkable advantages in terms of ergonomy, articulated movements and image magnification. All these features contribute for identification and preservation of the pelvic innervation, reducing the risk of surgical sequelae. CONCLUSION: Robotic nerve sparing technique can be incorporated as a standard care without compromising radicality. PMID- 25714874 TI - Single-port approach to benign gynecologic pathology. A review. AB - Laparoscopy is the gold standard in gynecological surgery. Single-port laparoscopic surgery, has been developed in order to improve minimally invasive surgery. We analyzed single-port approach in benign gynecologic pathology and made a bibliographic research on Pubmed and Medline from January 2000 to January 2015. From what emerges from the papers taken into consideration, single-port laparoscopy can be used for salpingostomy or salpingectomy to treat tubal ectopic pregnancy, benign adnexal disease (ovarian cystectomy, salpingo-oophorectomy), and for hysterectomy. We do not have enough data for complex procedures like myomectomy or hysteropexy. Robotic single-port laparoscopy seems to be a very attractive perspective and its use in benign gynecology surgery is expanding. More and more ergonomic limitations of single-port laparoscopy are corrected by development of articulated or flexible instruments and camera. Beyond these preliminary results, more ample prospective studies with an adapted and standardized instrumentation are thus essential to highlight real profits. PMID- 25714875 TI - Clinical aspects and perinatal outcomes after cryopreservation of embryos and gametes. AB - Cryopreservation techniques play today a central role in assisted reproduction, as they enhance the overall efficacy of in vitro fertilization (IVF) treatments by allowing the banking of supernumerary embryos obtained in these treatments, and their later use. The transfer of frozen/thawed embryos was established nearly 30 years ago, and although it has been clinical routine for a long time, the importance of freezing embryos has been newly emphasized. As recognized downsides of IVF treatment include the high prevalence of perinatal complications due to multiple births, the recommended practice of transferring fewer embryos in the fresh IVF treatment cycle, with the goal of performing single embryo transfer and the cryostorage of remaining embryos for their later use in frozen-thawed cycles, one at a time, is currently the trend. Also of great importance, cryopreservation techniques for spermatozoa and oocytes have additionally permitted gamete storage for long-term and the implementation of several new treatment modalities for assisted reproduction. Most of these methods are applied today in clinical programs of fertility preservation and third-part reproduction, such as sperm- and egg donor programs. Use of frozen thawed sperm has been in clinical use for over 50 years and banking sperm has been routinely offered to men, usually before gonadotoxic treatments, but also in many cases, practised as a "safety policy" previously to a vasectomy. Freezing methods for women's egg have required a much longer time to achieve a comparable effective clinical standard. Only recently, with the development of vitrification of oocytes, the clinical standard was recognized and since 2013 when the label "experimental" was removed, the freezing of oocytes could be regarded as an established method, and its use extended into clinical practice for fertility preservation but also performed after personal requirements, so called, "social freezing". PMID- 25714870 TI - Emerging therapies in traumatic brain injury. AB - Despite decades of basic and clinical research, treatments to improve outcomes after traumatic brain injury (TBI) are limited. However, based on the recent recognition of the prevalence of mild TBI, and its potential link to neurodegenerative disease, many new and exciting secondary injury mechanisms have been identified and several new therapies are being evaluated targeting both classic and novel paradigms. This includes a robust increase in both preclinical and clinical investigations. Using a mechanism-based approach the authors define the targets and emerging therapies for TBI. They address putative new therapies for TBI across both the spectrum of injury severity and the continuum of care, from the field to rehabilitation. They discussTBI therapy using 11 categories, namely, (1) excitotoxicity and neuronal death, (2) brain edema, (3) mitochondria and oxidative stress, (4) axonal injury, (5) inflammation, (6) ischemia and cerebral blood flow dysregulation, (7) cognitive enhancement, (8) augmentation of endogenous neuroprotection, (9) cellular therapies, (10) combination therapy, and (11) TBI resuscitation. The current golden age of TBI research represents a special opportunity for the development of breakthroughs in the field. PMID- 25714876 TI - Intrafollicular nerve growth factor concentration in patients with polycystic ovary syndrome: a case-control study. AB - BACKGROUND: To evaluate the concentration of nerve growth factor (NGF) in follicular fluid of women affected by polycystic ovary syndrome (PCOS) undergoing to In Vitro Fertilization cycle. METHODS: In the context of an in-vivo study, a sample of 52 women was considered: 20 were without pathology (male infertility - control group) and 32 were affected by PCOS. All patients received a long stimulation protocol and the oocytes obtained by pick-up were fertilized with standard procedures of intracytoplasmic sperm injection (ICSI). Samples of follicular fluid (FF) were collected at oocyte pick-up. After centrifugation at 560 * g for 3 min, follicular fluid samples were frozen at -80 degrees C. After thawing the values of NGF in FF were determined by enzyme immunoassay ELISA using commercially available NGF enzyme-linked immunosorbent assay kits. The results of study were analyzed statistically with Student's t-test. RESULTS: The content of NGF was higher in FF of PCOS patients (2023.30+/-587.09 pg/mL) in comparison with control group (1704.09+/-326.8 pg/mL; P<0.05). The levels of serum estrogen (E2) were higher in patients with PCOS (1724.24+/-635.79 pg/mL) than in control group (1305.3+/-298.12 pg/mL; P<0.05). The number of retrieved oocytes was more in PCOS patients (9.7+/-4.6) than in control group (8+/-4.4), but oocytes in metaphase II were similar in two groups (6.2+/-2.4 vs. 6.09+/-4). CONCLUSIONS: The present results show that ovaries of PCOS patients produce more NGF than non-PCOS patients; it confirms that an excess of ovarian NGF might be an abnormality contributing to polycistic ovary morphology and PCOS. PMID- 25714878 TI - Expression of NR1I3 in mouse lung tumors induced by the tobacco-specific nitrosamine 4-(methylnitrosamino)-4-(3-pyridyl)-1-butanone. AB - Nuclear receptor subfamily 1, group I, member 3 (NR1I3) is reported to be a possible novel therapeutic target for some cancers, including lung, brain and hematopoietic tumors. Here, we characterized expression of NR1I3 in a mouse model of lung carcinogenesis induced by 4-(methylnitrosamino)-4-(3-pyridyl)-1-butanone (NNK), the most potent tobacco carcinogen. Lung tumors were collected from mice treated with NNK (400 mg/kg) and euthanized after 52 weeks. Benign and malignant lesions were formalin-fixed and paraffin-embedded for histology and immunohistochemistry, with samples snap-frozen for mRNA analysis. Immunohistochemically, we found that most macrophages and type I and II pneumocytes expressed NR1I3, whereas fibroblasts and endothelial cells were NR1I3 . Compared with benign lesions, malignant lesions had less NR1I3+ tumor cells. Gene expression analysis also showed an inverse correlation between NR1I3 mRNA expression and tumor size (P=0.0061), suggesting that bigger tumors expressed less NR1I3 transcripts, in accordance with our immunohistochemical NR1I3 tests. Our results indicate that NR1I3 expression decreased during progression of malignant lung tumors induced by NNK in mice. PMID- 25714877 TI - Autophagy plays an important role in protecting Pacific oysters from OsHV-1 and Vibrio aestuarianus infections. AB - Recent mass mortality outbreaks around the world in Pacific oysters, Crassostrea gigas, have seriously affected the aquaculture economy. Although the causes for these mortality outbreaks appear complex, infectious agents are involved. Two pathogens are associated with mass mortality outbreaks, the virus ostreid herpesvirus 1 (OsHV-1) and the bacterium Vibrio aestuarianus. Here we describe the interactions between these 2 pathogens and autophagy, a conserved intracellular pathway playing a key role in innate immunity. We show for the first time that autophagy pathway is present and functional in Pacific oysters and plays an important role to protect animals from infections. This study contributes to better understand the innate immune system of Pacific oysters. PMID- 25714879 TI - Effects of propofol on lipopolysaccharide-induced expression and release of HMGB1 in macrophages. AB - This study aimed to determine the effects of different concentrations of propofol (2,6-diisopropylphenol) on lipopolysaccharide (LPS)-induced expression and release of high-mobility group box 1 protein (HMGB1) in mouse macrophages. Mouse macrophage cell line RAW264.7 cells were randomly divided into 5 treatment groups. Expression levels of HMGB1 mRNA were detected using RT-PCR, and cell culture supernatant HMGB1 protein levels were detected using enzyme-linked immunosorbent assay (ELISA). Translocation of HMGB1 from the nucleus to the cytoplasm in macrophages was observed by Western blotting and activity of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) in the nucleus was detected using ELISA. HMGB1 mRNA expression levels increased significantly in the cell culture supernatant and in cells after 24 h of stimulating RAW264.7 cells with LPS (500 ng/mL). However, HMGB1 mRNA expression levels in the P2 and P3 groups, which received 500 ng/mL LPS with 25 or 50 MUmol/mL propofol, respectively, were significantly lower than those in the group receiving LPS stimulation (P<0.05). After stimulation by LPS, HMGB1 protein levels were reduced significantly in the nucleus but were increased in the cytoplasm (P<0.05). Simultaneously, the activity of NF-kappaB was enhanced significantly (P<0.05). After propofol intervention, HMGB1 translocation from the nucleus to the cytoplasm and NF-kappaB activity were inhibited significantly (each P<0.05). Thus, propofol can inhibit the LPS-induced expression and release of HMGB1 by inhibiting HMGB1 translocation and NF-kappaB activity in RAW264.7 cells, suggesting propofol may be protective in patients with sepsis. PMID- 25714828 TI - Does sex affect anticoagulant use for stroke prevention in nonvalvular atrial fibrillation? The prospective global anticoagulant registry in the FIELD-Atrial Fibrillation. AB - BACKGROUND: Among patients with atrial fibrillation (AF), women are at higher risk of stroke than men. Using prospective cohort data from a large global population of patients with nonvalvular AF, we sought to identify any differences in the use of anticoagulants for stroke prevention in women and men. METHODS AND RESULTS: This was a prospective multicenter observational registry with 858 randomly selected sites in 30 countries. A total of 17 184 patients with newly diagnosed (<=6 weeks) nonvalvular AF and >=1 additional investigator-defined stroke risk factor(s) were recruited (March 2010 to June 2013). The main outcome measure was the use of anticoagulants (vitamin K antagonists, factor Xa inhibitors, and direct thrombin inhibitors) for stroke prevention at AF diagnosis. Of 17 184 patients enrolled, 43.8% were women. More women than men were at moderate-to-high risk of stroke (CHADS2 score >=2: 65.1% versus 54.7%). Rates of anticoagulant use were not different overall (60.9% of men versus 60.8% of women) and in patients with a CHADS2 score >=2 (adjusted odds ratio for women versus men, 1.00; 95% confidence interval, 0.92-1.09). In patients at low risk (CHA2DS2-VASc of 0 in men and 1 in women), 41.8% of men and 41.1% of women received an anticoagulant. In patients at high risk (CHA2DS2-VASc score >=2), 35.4% of men and 38.4% of women did not receive an anticoagulant. CONCLUSIONS: These contemporary global data show that anticoagulant use for stroke prevention is no different in men and women with nonvalvular AF. Thromboprophylaxis was, however, suboptimal in substantial proportions of men and women, with underuse in those at moderate-to-high risk of stroke and overuse in those at low risk. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362. PMID- 25714880 TI - Effects of conventional vs high-dose rocuronium on the QTc interval during anesthesia induction and intubation in patients undergoing coronary artery surgery: a randomized, double-blind, parallel trial. AB - Myocardial ischemia, as well as the induction agents used in anesthesia, may cause corrected QT interval (QTc) prolongation. The objective of this randomized, double-blind trial was to determine the effects of high- vs conventional-dose bolus rocuronium on QTc duration and the incidence of dysrhythmias following anesthesia induction and intubation. Fifty patients about to undergo coronary artery surgery were randomly allocated to receive conventional-dose (0.6 mg/kg, group C, n=25) or high-dose (1.2 mg/kg, group H, n=25) rocuronium after induction with etomidate and fentanyl. QTc, heart rate, and mean arterial pressure were recorded before induction (T0), after induction (T1), after rocuronium (just before laryngoscopy; T2), 2 min after intubation (T3), and 5 min after intubation (T4). The occurrence of dysrhythmias was recorded. In both groups, QTc was significantly longer at T3 than at baseline [475 vs 429 ms in group C (P=0.001), and 459 vs 434 ms in group H (P=0.005)]. The incidence of dysrhythmias in group C (28%) and in group H (24%) was similar. The QTc after high-dose rocuronium was not significantly longer than after conventional-dose rocuronium in patients about to undergo coronary artery surgery who were induced with etomidate and fentanyl. In both groups, compared with baseline, QTc was most prolonged at 2 min after intubation, suggesting that QTc prolongation may be due to the nociceptive stimulus of intubation. PMID- 25714881 TI - Neuropeptide Y, substance P, and human bone morphogenetic protein 2 stimulate human osteoblast osteogenic activity by enhancing gap junction intercellular communication. AB - Bone homeostasis seems to be controlled by delicate and subtle "cross talk" between the nervous system and "osteo-neuromediators" that control bone remodeling. The purpose of this study was to evaluate the effect of interactions between neuropeptides and human bone morphogenetic protein 2 (hBMP2) on human osteoblasts. We also investigated the effects of neuropeptides and hBMP2 on gap junction intercellular communication (GJIC). Osteoblasts were treated with neuropeptide Y (NPY), substance P (SP), or hBMP2 at three concentrations. At various intervals after treatment, cell viability was measured by the MTT assay. In addition, cellular alkaline phosphatase (ALP) activity and osteocalcin were determined by colorimetric assay and radioimmunoassay, respectively. The effects of NPY, SP and hBMP on GJIC were determined by laser scanning confocal microscopy. The viability of cells treated with neuropeptides and hBMP2 increased significantly in a time-dependent manner, but was inversely associated with the concentration of the treatments. ALP activity and osteocalcin were both reduced in osteoblasts exposed to the combination of neuropeptides and hBMP2. The GJIC of osteoblasts was significantly increased by the neuropeptides and hBMP2. These results suggest that osteoblast activity is increased by neuropeptides and hBMP2 through increased GJIC. Identification of the GJIC-mediated signal transduction capable of modulating the cellular activities of bone cells represents a novel approach to studying the biology of skeletal innervation. PMID- 25714882 TI - Effect of L-carnitine on exercise performance in patients with mitochondrial myopathy. AB - Exercise intolerance due to impaired oxidative metabolism is a prominent symptom in patients with mitochondrial myopathy (MM), but it is still uncertain whether L carnitine supplementation is beneficial for patients with MM. The aim of our study was to investigate the effects of L-carnitine on exercise performance in MM. Twelve MM subjects (mean age+/-SD=35.4+/-10.8 years) with chronic progressive external ophthalmoplegia (CPEO) were first compared to 10 healthy controls (mean age+/-SD=29+/-7.8 years) before they were randomly assigned to receive L carnitine supplementation (3 g/daily) or placebo in a double-blind crossover design. Clinical status, body composition, respiratory function tests, peripheral muscle strength (isokinetic and isometric torque) and cardiopulmonary exercise tests (incremental to peak exercise and at 70% of maximal), constant work rate (CWR) exercise test, to the limit of tolerance [Tlim]) were assessed after 2 months of L-carnitine/placebo administration. Patients with MM presented with lower mean height, total body weight, fat-free mass, and peripheral muscle strength compared to controls in the pre-test evaluation. After L-carnitine supplementation, the patients with MM significantly improved their Tlim (14+/-1.9 vs 11+/-1.4 min) and oxygen consumption ( V O 2 ) at CWR exercise, both at isotime (1151+/-115 vs 1049+/-104 mL/min) and at Tlim (1223+/-114 vs 1060+/-108 mL/min). These results indicate that L-carnitine supplementation may improve aerobic capacity and exercise tolerance during high-intensity CWRs in MM patients with CPEO. PMID- 25714883 TI - IL-6 and TNF-alpha serum levels are associated with early death in community acquired pneumonia patients. AB - Community-acquired pneumonia (CAP) is amongst the leading causes of death worldwide. As inflammatory markers, cytokines can predict outcomes, if interpreted together with clinical data and scoring systems such as CURB-65, CRB, and Acute Physiology and Chronic Health Evaluation II (APACHE II). The aim of this study was to determine the impact of inflammatory biomarkers on the early mortality of hospitalized CAP patients. Twenty-seven CAP patients needing hospitalization were enrolled for the study and samples of interleukin-1 (IL-1) and interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), C-reactive protein (CRP), and homocystein were collected at the time of admission (day 1) as well as on the seventh day of the treatment. There was a significant reduction in the levels of IL-6 between the first and the second collections. Median IL-6 values decreased from 24 pg/mL (day 1) to 8 pg/mL (day 7) (P=0.016). The median levels of TNF-alpha were higher in patients: i) with acute kidney injury (AKI) (P=0.045), ii) requiring mechanical ventilation (P=0.040), iii) with short hospital stays (P=0.009), iv) admitted to the intensive care unit (ICU) (P=0.040), v) who died early (P=0.003), and vi) with worse CRB scores (P=0.013). In summary, IL-6 and TNF-alpha levels were associated with early mortality of CAP patients. Longer admission levels demonstrated greater likelihood of early death and overall mortality, necessity of mechanical ventilation, and AKI. PMID- 25714884 TI - Exercise training prevents increased intraocular pressure and sympathetic vascular modulation in an experimental model of metabolic syndrome. AB - The present study aimed to study the effects of exercise training (ET) performed by rats on a 10-week high-fructose diet on metabolic, hemodynamic, and autonomic changes, as well as intraocular pressure (IOP). Male Wistar rats receiving fructose overload in drinking water (100 g/L) were concomitantly trained on a treadmill for 10 weeks (FT group) or kept sedentary (F group), and a control group (C) was kept in normal laboratory conditions. The metabolic evaluation comprised the Lee index, glycemia, and insulin tolerance test (KITT). Arterial pressure (AP) was measured directly, and systolic AP variability was performed to determine peripheral autonomic modulation. ET attenuated impaired metabolic parameters, AP, IOP, and ocular perfusion pressure (OPP) induced by fructose overload (FT vs F). The increase in peripheral sympathetic modulation in F rats, demonstrated by systolic AP variance and low frequency (LF) band (F: 37+/-2, 6.6+/-0.3 vs C: 26+/-3, 3.6+/-0.5 mmHg2), was prevented by ET (FT: 29+/-3, 3.4+/ 0.7 mmHg2). Positive correlations were found between the LF band and right IOP (r=0.57, P=0.01) and left IOP (r=0.64, P=0.003). Negative correlations were noted between KITT values and right IOP (r=-0.55, P=0.01) and left IOP (r=-0.62, P=0.005). ET in rats effectively prevented metabolic abnormalities and AP and IOP increases promoted by a high-fructose diet. In addition, ocular benefits triggered by exercise training were associated with peripheral autonomic improvement. PMID- 25714885 TI - In vitro biological screening of the anticholinesterase and antiproliferative activities of medicinal plants belonging to Annonaceae. AB - The aim of this research was to investigate the antiproliferative and anticholinesterase activities of 11 extracts from 5 Annonaceae species in vitro. Antiproliferative activity was assessed using 10 human cancer cell lines. Thin layer chromatography and a microplate assay were used to screen the extracts for acetylcholinesterase (AchE) inhibitors using Ellman's reagent. The chemical compositions of the active extracts were investigated using high performance liquid chromatography. Eleven extracts obtained from five Annonaceae plant species were active and were particularly effective against the UA251, NCI-470 lung, HT-29, NCI/ADR, and K-562 cell lines with growth inhibition (GI50) values of 0.04-0.06, 0.02-0.50, 0.01-0.12, 0.10-0.27, and 0.02-0.04 ug/mL, respectively. In addition, the Annona crassiflora and A. coriacea seed extracts were the most active among the tested extracts and the most effective against the tumor cell lines, with GI50 values below 8.90 ug/mL. The A. cacans extract displayed the lowest activity. Based on the microplate assay, the percent AchE inhibition of the extracts ranged from 12 to 52%, and the A. coriacea seed extract resulted in the greatest inhibition (52%). Caffeic acid, sinapic acid, and rutin were present at higher concentrations in the A. crassiflora seed samples. The A. coriacea seeds contained ferulic and sinapic acid. Overall, the results indicated that A. crassiflora and A. coriacea extracts have antiproliferative and anticholinesterase properties, which opens up new possibilities for alternative pharmacotherapy drugs. PMID- 25714886 TI - Vagotomy ameliorates islet morphofunction and body metabolic homeostasis in MSG obese rats. AB - The parasympathetic nervous system is important for beta-cell secretion and mass regulation. Here, we characterized involvement of the vagus nerve in pancreatic beta-cell morphofunctional regulation and body nutrient homeostasis in 90-day-old monosodium glutamate (MSG)-obese rats. Male newborn Wistar rats received MSG (4 g/kg body weight) or saline [control (CTL) group] during the first 5 days of life. At 30 days of age, both groups of rats were submitted to sham-surgery (CTL and MSG groups) or subdiaphragmatic vagotomy (Cvag and Mvag groups). The 90-day old MSG rats presented obesity, hyperinsulinemia, insulin resistance, and hypertriglyceridemia. Their pancreatic islets hypersecreted insulin in response to glucose but did not increase insulin release upon carbachol (Cch) stimulus, despite a higher intracellular Ca(2+) mobilization. Furthermore, while the pancreas weight was 34% lower in MSG rats, no alteration in islet and beta-cell mass was observed. However, in the MSG pancreas, increases of 51% and 55% were observed in the total islet and beta-cell area/pancreas section, respectively. Also, the beta-cell number per beta-cell area was 19% higher in MSG rat pancreas than in CTL pancreas. Vagotomy prevented obesity, reducing 25% of body fat stores and ameliorated glucose homeostasis in Mvag rats. Mvag islets demonstrated partially reduced insulin secretion in response to 11.1 mM glucose and presented normalization of Cch-induced Ca(2+) mobilization and insulin release. All morphometric parameters were similar among Mvag and CTL rat pancreases. Therefore, the higher insulin release in MSG rats was associated with greater beta-cell/islet numbers and not due to hypertrophy. Vagotomy improved whole body nutrient homeostasis and endocrine pancreatic morphofunction in Mvag rats. PMID- 25714887 TI - The role of necroptosis in neurosurgical diseases. AB - Programmed necrosis or necroptosis is an alternative form of cell death that is executed through a caspase-independent pathway. Necroptosis has been implicated in many pathological conditions. Genetic or pharmacological inhibition of necroptotic signaling has been shown to confer neuroprotection after traumatic and ischemic brain injury. Therefore, the necroptotic pathway represents a potential target for neurological diseases that are managed by neurosurgeons. In this review, we summarize recent advances in the understanding of necroptotic signaling pathways and explore the role of necroptotic cell death in craniocerebral trauma, brain tumors, and cerebrovascular diseases. PMID- 25714888 TI - Intensity and physiological responses to the 6-minute walk test in middle-aged and older adults: a comparison with cardiopulmonary exercise testing. AB - The 6-minute walk test (6MWT) is a simple field test that is widely used in clinical settings to assess functional exercise capacity. However, studies with healthy subjects are scarce. We hypothesized that the 6MWT might be useful to assess exercise capacity in healthy subjects. The purpose of this study was to evaluate 6MWT intensity in middle-aged and older adults, as well as to develop a simple equation to predict oxygen uptake ( V O 2 ) from the 6-min walk distance (6MWD). Eighty-six participants, 40 men and 46 women, 40-74 years of age and with a mean body mass index of 28+/-6 kg/m2, performed the 6MWT according to American Thoracic Society guidelines. Physiological responses were evaluated during the 6MWT using a K4b2 Cosmed telemetry gas analyzer. On a different occasion, the subjects performed ramp protocol cardiopulmonary exercise testing (CPET) on a treadmill. Peak V O 2 in the 6MWT corresponded to 78+/-13% of the peak V O 2 during CPET, and the maximum heart rate corresponded to 80+/-23% of that obtained in CPET. Peak V O 2 in CPET was adequately predicted by the 6MWD by a linear regression equation: V O 2 mL.min-1.kg-1 = -2.863 + (0.0563*6MWDm) (R2=0.76). The 6MWT represents a moderate-to-high intensity activity in middle-aged and older adults and proved to be useful for predicting cardiorespiratory fitness in the present study. Our results suggest that the 6MWT may also be useful in asymptomatic individuals, and its use in walk-based conditioning programs should be encouraged. PMID- 25714889 TI - Dexamethasone and sodium carboxymethyl cellulose prevent postoperative intraperitoneal adhesions in rats. AB - We aimed to evaluate the effects of the barrier agent sodium carboxymethyl cellulose (SCMC) with and without dexamethasone for the prevention of postoperative adhesion formation in a rat model of postoperative peritoneal adhesion. A total of 160 three-month old male and female Wistar rats underwent a laparotomy, and adhesions were induced by ileocecal abrasion. Rats were randomly assigned to 4 groups (n=40 each): group A, untreated; group B, treated with SCMC only; group C1, treated with SCMC + 3 mg dexamethasone, and group C2, treated with SCMC + 8 mg dexamethasone. After 12 days, adhesion formation and histopathological changes were compared. In groups A, B, C1, and C2, the mortality rates were 10, 5, 5, and 5%, respectively. In groups C1 and C2, the adhesions were filmy and easy to dissect and were milder compared with those in groups A and B. The total adhesion score in group C1 (3.38+/-0.49) was significantly lower than that of group B (6.01+/-0.57; P<0.01) or group A (8.01+/ 0.67; P<0.05). There was no significant difference in adhesion formation between groups C1 and C2. Compared with groups A and B, groups C1 and C2 exhibited milder histopathological changes. SCMC in combination with dexamethasone can prevent adhesion formation and is a better barrier agent than SCMC alone. The safety and feasibility of SCMC in combination with dexamethasone to prevent adhesion formation after abdominal surgery warrants further clinical study. PMID- 25714890 TI - The superoxide anion donor, potassium superoxide, induces pain and inflammation in mice through production of reactive oxygen species and cyclooxygenase-2. AB - It is currently accepted that superoxide anion (O2*-) is an important mediator in pain and inflammation. The role of superoxide anion in pain and inflammation has been mainly determined indirectly by modulating its production and inactivation. Direct evidence using potassium superoxide (KO2), a superoxide anion donor, demonstrated that it induced thermal hyperalgesia, as assessed by the Hargreaves method. However, it remains to be determined whether KO2 is capable of inducing other inflammatory and nociceptive responses attributed to superoxide anion. Therefore, in the present study, we investigated the nociceptive and inflammatory effects of KO2. The KO2-induced inflammatory responses evaluated in mice were: mechanical hyperalgesia (electronic version of von Frey filaments), thermal hyperalgesia (hot plate), edema (caliper rule), myeloperoxidase activity (colorimetric assay), overt pain-like behaviors (flinches, time spent licking and writhing score), leukocyte recruitment, oxidative stress, and cyclooxygenase-2 mRNA expression (quantitative PCR). Administration of KO2 induced mechanical hyperalgesia, thermal hyperalgesia, paw edema, leukocyte recruitment, the writhing response, paw flinching, and paw licking in a dose-dependent manner. KO2 also induced time-dependent cyclooxygenase-2 mRNA expression in the paw skin. The nociceptive, inflammatory, and oxidative stress components of KO2-induced responses were responsive to morphine (analgesic opioid), quercetin (antioxidant flavonoid), and/or celecoxib (anti-inflammatory cyclooxygenase-2 inhibitor) treatment. In conclusion, the well-established superoxide anion donor KO2 is a valuable tool for studying the mechanisms and pharmacological susceptibilities of superoxide anion-triggered nociceptive and inflammatory responses ranging from mechanical and thermal hyperalgesia to overt pain-like behaviors, edema, and leukocyte recruitment. PMID- 25714891 TI - Sorafenib prevents liver fibrosis in a non-alcoholic steatohepatitis (NASH) rodent model. AB - Liver fibrosis occurring as an outcome of non-alcoholic steatohepatitis (NASH) can precede the development of cirrhosis. We investigated the effects of sorafenib in preventing liver fibrosis in a rodent model of NASH. Adult Sprague Dawley rats were fed a choline-deficient high-fat diet and exposed to diethylnitrosamine for 6 weeks. The NASH group (n=10) received vehicle and the sorafenib group (n=10) received 2.5 mg.kg(-1).day(-1) by gavage. A control group (n=4) received only standard diet and vehicle. Following treatment, animals were sacrificed and liver tissue was collected for histologic examination, mRNA isolation, and analysis of mitochondrial function. Genes related to fibrosis (MMP9, TIMP1, TIMP2), oxidative stress (HSP60, HSP90, GST), and mitochondrial biogenesis (PGC1alpha) were evaluated by real-time quantitative polymerase chain reaction (RT-qPCR). Liver mitochondrial oxidation activity was measured by a polarographic method, and cytokines by enzyme-linked immunosorbent assay (ELISA). Sorafenib treatment restored mitochondrial function and reduced collagen deposition by nearly 63% compared to the NASH group. Sorafenib upregulated PGC1alpha and MMP9 and reduced TIMP1 and TIMP2 mRNA and IL-6 and IL-10 protein expression. There were no differences in HSP60, HSP90 and GST expression. Sorafenib modulated PGC1alpha expression, improved mitochondrial respiration and prevented collagen deposition. It may, therefore, be useful in the treatment of liver fibrosis in NASH. PMID- 25714892 TI - Gene expression of estrogen and oxytocin receptors in the uterus of pregnant and parturient bitches. AB - In the canine species, the precise mechanisms of pregnancy maintenance and the initiation of parturition are not completely understood. The expression of genes encoding the receptors for estrogen (ERalpha mRNA) and oxytocin (OTR mRNA) was studied in the endometrium and myometrium during pregnancy and parturition in dogs. Real-time PCR was performed to quantify the levels of ERalpha mRNA and OTR mRNA in the uterus of bitches during early (up to 20 days of gestation), mid (20 to 40 days) and late pregnancy (41 to 60 days), and parturition (first stage of labor). All tissues expressed ERalpha and OTR mRNA, and are thus possibly able to respond to eventual estrogen and oxytocin hormonal stimuli. No statistically significant differences in the expression of ERalpha mRNA were verified in the endometrium and myometrium throughout pregnancy and parturition, but expression of OTR mRNA increased at both parturition and late pregnancy. We concluded that the increase of endometrial and myometrial OTR mRNA expression in dogs is not an event dependent on estrogenic stimulation. Moreover, the contractility response of the canine uterus to oxytocin begins during pregnancy and maintains myometrial activity. The expression of OTR mRNA in canine uterine tissues varied over time, which supports an interpretation that the sensitivity and response to hormone therapy varies during the course of pregnancy and labor. Further studies are needed to elucidate the factors underlying the synthesis of uterine oxytocin receptors and the possible role of ERbeta rather than ERalpha in the uterine tissues during pregnancy and parturition in dogs. PMID- 25714893 TI - Reduction of blood nitric oxide levels is associated with clinical improvement of the chronic pelvic pain related to endometriosis. AB - The objective of this prospective study was to determine the plasma levels of nitric oxide (NO) in women with chronic pelvic pain secondary to endometriosis (n=24) and abdominal myofascial pain syndrome (n=16). NO levels were measured in plasma collected before and 1 month after treatment. Pretreatment NO levels (MUM) were lower in healthy volunteers (47.0+/-12.7) than in women with myofascial pain (64.2+/-5.0, P=0.01) or endometriosis (99.5+/-12.9, P<0.0001). After treatment, plasma NO levels were reduced only in the endometriosis group (99.5+/-12.9 vs 61.6+/-5.9, P=0.002). A correlation between reduction of pain intensity and reduction of NO level was observed in the endometriosis group [correlation = 0.67 (95%CI = 0.35 to 0.85), P<0.0001]. Reduction of NO levels was associated with an increase of pain threshold in this group [correlation = -0.53 (-0.78 to -0.14), P<0.0001]. NO levels appeared elevated in women with chronic pelvic pain diagnosed as secondary to endometriosis, and were directly associated with reduction in pain intensity and increase in pain threshold after treatment. Further studies are needed to investigate the role of NO in the pathophysiology of pain in women with endometriosis and its eventual association with central sensitization. PMID- 25714894 TI - Interaction between affordance and handedness recognition: a chronometric study. AB - The visualization of tools and manipulable objects activates motor-related areas in the cortex, facilitating possible actions toward them. This pattern of activity may underlie the phenomenon of object affordance. Some cortical motor neurons are also covertly activated during the recognition of body parts such as hands. One hypothesis is that different subpopulations of motor neurons in the frontal cortex are activated in each motor program; for example, canonical neurons in the premotor cortex are responsible for the affordance of visual objects, while mirror neurons support motor imagery triggered during handedness recognition. However, the question remains whether these subpopulations work independently. This hypothesis can be tested with a manual reaction time (MRT) task with a priming paradigm to evaluate whether the view of a manipulable object interferes with the motor imagery of the subject's hand. The MRT provides a measure of the course of information processing in the brain and allows indirect evaluation of cognitive processes. Our results suggest that canonical and mirror neurons work together to create a motor plan involving hand movements to facilitate successful object manipulation. PMID- 25714895 TI - Synthesis of orotidine by intramolecular nucleosidation. AB - An intramolecular nucleosidation approach provides easy access to orotidine in high yields. Notably, orotate itself is used as a leaving group at the anomeric position. This method has the potential for facile access to derivatives of orotidine of therapeutic interest, with implications for prebiotic formation of nucleosides. PMID- 25714896 TI - The problem of substance abuse in people with schizophrenia. PMID- 25714897 TI - Starter unit flexibility for engineered product synthesis by the nonreducing polyketide synthase PksA. AB - Nonreducing polyketide synthases (NR-PKSs) are unique among PKSs in their domain structure, notably including a starter unit:acyl-carrier protein (ACP) transacylase (SAT) domain that selects an acyl group as the primer for biosynthesis, most commonly acetyl-CoA from central metabolism. This clan of mega enzymes resembles fatty acid synthases (FASs) by sharing both their central chain elongation steps and their capacity for iterative catalysis. In this mode of synthesis, catalytic domains involved in chain extension exhibit substrate plasticity to accommodate growing chains as small as two carbons to 20 or more. PksA is the NR-PKS central to the biosynthesis of the mycotoxin aflatoxin B1 whose SAT domain accepts an unusual hexanoyl starter from a dedicated yeast-like FAS. Explored in this paper is the ability of PksA to utilize a selection of potential starter units as substrates to initiate and sustain extension and cyclization to on-target, programmed polyketide synthesis. Most of these starter units were successfully accepted and properly processed by PksA to achieve biosynthesis of the predicted naphthopyrone product. Analysis of the on-target and derailment products revealed trends of tolerance by individual PksA domains to alternative starter units. In addition, natural and un-natural variants of the active site cysteine were examined and found to be capable of biosynthesis, suggesting possible direct loading of starter units onto the beta-ketoacyl synthase (KS) domain. In light of the data assembled here, the predictable synthesis of unnatural products by NR-PKSs is more fully defined. PMID- 25714899 TI - DMSO/Tf2O-mediated cross-coupling of tryptamine with substituted aniline to access C3a-N1'-linked pyrroloindoline alkaloids. AB - The cross-coupling of tryptamine with substituted aniline to access C3a-nitrogen linked pyrroloindolines has been developed via the consecutive cyclization of tryptamine with DMSO/Tf2O and the substitution of 3a-pyrroloindolylthionium intermediate with aniline. The use of 2,3-dihydrotryptamine instead of aniline enabled easy access to 3a-(1-indolyl)pyrroloindoline and the concise synthesis of C3a-N1'-linked pyrroloindoline alkaloid (+/-)-psychotriasine was accomplished. PMID- 25714898 TI - Securely measuring the overlap between private datasets with cryptosets. AB - Many scientific questions are best approached by sharing data--collected by different groups or across large collaborative networks--into a combined analysis. Unfortunately, some of the most interesting and powerful datasets--like health records, genetic data, and drug discovery data--cannot be freely shared because they contain sensitive information. In many situations, knowing if private datasets overlap determines if it is worthwhile to navigate the institutional, ethical, and legal barriers that govern access to sensitive, private data. We report the first method of publicly measuring the overlap between private datasets that is secure under a malicious model without relying on private protocols or message passing. This method uses a publicly shareable summary of a dataset's contents, its cryptoset, to estimate its overlap with other datasets. Cryptosets approach "information-theoretic" security, the strongest type of security possible in cryptography, which is not even crackable with infinite computing power. We empirically and theoretically assess both the accuracy of these estimates and the security of the approach, demonstrating that cryptosets are informative, with a stable accuracy, and secure. PMID- 25714902 TI - An in situ vapour phase hydrothermal surface doping approach for fabrication of high performance Co3O4 electrocatalysts with an exceptionally high S-doped active surface. AB - A facile in situ vapour phase hydrothermal (VPH) surface doping approach has been developed for fabrication of high performance S-doped Co3O4 electrocatalysts with an unprecedentedly high surface S content (>47%). The demonstrated VPH doping approach could be useful for enrichment of surface active sites for other metal oxide electrocatalysts. PMID- 25714900 TI - Eye contact perception in the West and East: a cross-cultural study. AB - This study investigated whether eye contact perception differs in people with different cultural backgrounds. Finnish (European) and Japanese (East Asian) participants were asked to determine whether Finnish and Japanese neutral faces with various gaze directions were looking at them. Further, participants rated the face stimuli for emotion and other affect-related dimensions. The results indicated that Finnish viewers had a smaller bias toward judging slightly averted gazes as directed at them when judging Finnish rather than Japanese faces, while the bias of Japanese viewers did not differ between faces from their own and other cultural backgrounds. This may be explained by Westerners experiencing more eye contact in their daily life leading to larger visual experience of gaze perception generally, and to more accurate perception of eye contact with people from their own cultural background particularly. The results also revealed cultural differences in the perception of emotion from neutral faces that could also contribute to the bias in eye contact perception. PMID- 25714903 TI - A decoy-free approach to the identification of peptides. AB - A growing number of proteogenomics and metaproteomics studies indicate potential limitations of the application of the "decoy" database paradigm used to separate correct peptide identifications from incorrect ones in traditional shotgun proteomics. We therefore propose a binary classifier called Nokoi that allows fast yet reliable decoy-free separation of correct from incorrect peptide-to spectrum matches (PSMs). Nokoi was trained on a very large collection of heterogeneous data using ranks supplied by the Mascot search engine to label correct and incorrect PSMs. We show that Nokoi outperforms Mascot and achieves a performance very close to that of Percolator at substantially higher processing speeds. PMID- 25714901 TI - Intranasal vaccination with a plant-derived H5 HA vaccine protects mice and ferrets against highly pathogenic avian influenza virus challenge. AB - Highly pathogenic avian influenza H5N1 infection remains a public health threat and vaccination is the best measure of limiting the impact of a potential pandemic. Mucosal vaccines have the advantage of eliciting immune responses at the site of viral entry, thereby preventing infection as well as further viral transmission. In this study, we assessed the protective efficacy of hemagglutinin (HA) from the A/Indonesia/05/05 (H5N1) strain of influenza virus that was produced by transient expression in plants. The plant-derived vaccine, in combination with the mucosal adjuvant (3',5')-cyclic dimeric guanylic acid (c-di GMP) was used for intranasal immunization of mice and ferrets, before challenge with a lethal dose of the A/Indonesia/05/05 (H5N1) virus. Mice vaccinated with 15 MUg or 5 MUg of adjuvanted HA survived the viral challenge, while all control mice died within 10 d of challenge. Vaccinated animals elicited serum hemagglutination inhibition, IgG and IgA antibody titers. In the ferret challenge study, all animals vaccinated with the adjuvanted plant vaccine survived the lethal viral challenge, while 50% of the control animals died. In both the mouse and ferret models, the vaccinated animals were better protected from weight loss and body temperature changes associated with H5N1 infection compared with the non vaccinated controls. Furthermore, the systemic spread of the virus was lower in the vaccinated animals compared with the controls. Results presented here suggest that the plant-produced HA-based influenza vaccine adjuvanted with c-di-GMP is a promising vaccine/adjuvant combination for the development of new mucosal influenza vaccines. PMID- 25714905 TI - Nanoelectronics aiming at cancer. PMID- 25714906 TI - Cost-Effectiveness of Global Endometrial Ablation vs. Hysterectomy for Treatment of Abnormal Uterine Bleeding: US Commercial and Medicaid Payer Perspectives. AB - Cost-effectiveness modeling studies of global endometrial ablation (GEA) for treatment of abnormal uterine bleeding (AUB) from a US perspective are lacking. The objective of this study was to model the cost-effectiveness of GEA vs. hysterectomy for treatment of AUB in the United States from both commercial and Medicaid payer perspectives. The study team developed a 1-, 3-, and 5-year semi Markov decision-analytic model to simulate 2 hypothetical patient cohorts of women with AUB-1 treated with GEA and the other with hysterectomy. Clinical and economic data (including treatment patterns, health care resource utilization, direct costs, and productivity costs) came from analyses of commercial and Medicaid claims databases. Analysis results show that cost savings with simultaneous reduction in treatment complications and fewer days lost from work are achieved with GEA versus hysterectomy over almost all time horizons and under both the commercial payer and Medicaid perspectives. Cost-effectiveness metrics also favor GEA over hysterectomy from both the commercial payer and Medicaid payer perspectives-evidence strongly supporting the clinical-economic value about GEA versus hysterectomy. Results will interest clinicians, health care payers, and self-insured employers striving for cost-effective AUB treatments. PMID- 25714907 TI - Translating Behavioral Interventions Onto mHealth Platforms: Developing Text Message Interventions for Smoking and Alcohol. AB - The development of mHealth applications is often driven by the investigators and developers with relatively little input from the targeted population. User input is commonly limited to "like/dislike" post- intervention consumer satisfaction ratings or device or application specific user analytics such as usability. However, to produce successful mHealth applications with lasting effects on health behaviors it is crucial to obtain user input from the start of each project and throughout development. The aim of this tutorial is to illustrate how qualitative methods in an iterative process of development have been used in two separate behavior change interventions (targeting smoking and alcohol) delivered through mobile technologies (ie, text messaging). A series of focus groups were conducted to assist in translating a face-to-face smoking cessation intervention onto a text message (short message service, SMS) delivered format. Both focus groups and an advisory panel were used to shape the delivery and content of a text message delivered intervention for alcohol risk reduction. An in vivo method of constructing message content was used to develop text message content that was consistent with the notion of texting as "fingered speech". Formative research conducted with the target population using a participatory framework led to important changes in our approach to intervention structure, content development, and delivery. Using qualitative methods and an iterative approach that blends consumer-driven and investigator-driven aims can produce paradigm-shifting, novel intervention applications that maximize the likelihood of use by the target audience and their potential impact on health behaviors. PMID- 25714909 TI - Correction: Ammonia oxidizers in a pilot-scale multilayer rapid infiltration system for domestic wastewater treatment. PMID- 25714908 TI - Correlations and functional connections in a population of grid cells. AB - We study the statistics of spike trains of simultaneously recorded grid cells in freely behaving rats. We evaluate pairwise correlations between these cells and, using a maximum entropy kinetic pairwise model (kinetic Ising model), study their functional connectivity. Even when we account for the covariations in firing rates due to overlapping fields, both the pairwise correlations and functional connections decay as a function of the shortest distance between the vertices of the spatial firing pattern of pairs of grid cells, i.e. their phase difference. They take positive values between cells with nearby phases and approach zero or negative values for larger phase differences. We find similar results also when, in addition to correlations due to overlapping fields, we account for correlations due to theta oscillations and head directional inputs. The inferred connections between neurons in the same module and those from different modules can be both negative and positive, with a mean close to zero, but with the strongest inferred connections found between cells of the same module. Taken together, our results suggest that grid cells in the same module do indeed form a local network of interconnected neurons with a functional connectivity that supports a role for attractor dynamics in the generation of grid pattern. PMID- 25714910 TI - The BAARA (Biological AutomAted RAdiotracking) system: a new approach in ecological field studies. AB - Radiotracking is an important and often the only possible method to explore specific habits and the behaviour of animals, but it has proven to be very demanding and time-consuming, especially when frequent positioning of a large group is required. Our aim was to address this issue by making the process partially automated, to mitigate the demands and related costs. This paper presents a novel automated tracking system that consists of a network of automated tracking stations deployed within the target area. Each station reads the signals from telemetry transmitters, estimates the bearing and distance of the tagged animals and records their position. The station is capable of tracking a theoretically unlimited number of transmitters on different frequency channels with the period of 5-15 seconds per single channel. An ordinary transmitter that fits within the supported frequency band might be used with BAARA (Biological AutomAted RAdiotracking); an extra option is the use of a custom-programmable transmitter with configurable operational parameters, such as the precise frequency channel or the transmission parameters. This new approach to a tracking system was tested for its applicability in a series of field and laboratory tests. BAARA has been tested within fieldwork explorations of Rousettus aegyptiacus during field trips to Dakhla oasis in Egypt. The results illustrate the novel perspective which automated radiotracking opens for the study of spatial behaviour, particularly in addressing topics in the domain of population ecology. PMID- 25714911 TI - Urine 8-isoprostane in relation to adiposity and insulin resistance in individuals at high cardiometabolic risk. AB - BACKGROUND: Oxidative stress has been implicated in the pathogenesis of many conditions, including insulin resistance and obesity. However, in vivo data concerning these relationships are scarce and conflicting. Therefore, the aim of this study was to investigate the association of oxidative stress with abdominal adiposity and insulin resistance in individuals at high cardiometabolic risk. METHODS: A total of 116 overweight/obese individuals participating in the HealthGrain and Etherpaths European Projects, having waist circumference (WC) and any other component of the metabolic syndrome, were included in this cross sectional evaluation. 8-Isoprostane concentrations in 24-hr urine were measured as marker of oxidative stress in vivo. Baseline anthropometric and metabolic parameters were analyzed according to quartiles of 8-isoprostanes. Linear regression (LR) analysis was used to assess clinical correlates of oxidative stress. RESULTS: Urinary 8-isoprostane levels were 52% higher in men than in women (P<0.001). Across the isoprostanes quartiles, there was a significant increase in WC and body weight [P for trend<0.001; analysis of variance (ANOVA) P<0.001] and fasting triglycerides (P for trend<0.05; ANOVA P<0.05), and a significant decrease in high-density lipoprotein cholesterol (P for trend<0.001; ANOVA P=0.001). No significant association between urinary isoprostane concentrations and insulin resistance [homeostasis model assessment of insulin resistance (HOMA-IR)] was found. WC circumference and body weight remained significant after adjustment for age and gender (P=0.023 and P=0.014, respectively) and independently associated with isoprostanes at LR (P<0.005 for both). CONCLUSIONS: Central obesity was independently associated with oxidative stress even in a population homogeneous for adiposity and cardiometabolic risk, whereas no relationship was observed between oxidative stress and insulin resistance. PMID- 25714912 TI - Activation of caspase-8 and caspase-9 are required for PC12 cells differentiation. AB - Nerve growth factor- (NGF) induced potent activation of caspase-8, and caspase-9 in PC12 cells in a time-dependent manner. Peptide inhibition of caspase activity led to a potent reduction in neurite outgrowth in NGF-treated cells. Although NGF treatment resulted in cell-cycle G0/G1 arrest as detected by FACS cell-cycle analysis, caspase inhibitors (caspase-8 and caspase-9 inhibitors) could block the G0/G1 arrest in PC12 cells. We demonstrated the unique caspase cascade, caspase 8, caspase-3, and caspase-9 to occur, in this order. In conclusion, present results confirm a unique role for the caspase-8 and caspase-9 mediated signal cascade in the differentiation of PC12 cells. PMID- 25714913 TI - Optically diffracting hydrogels for screening kinase activity in vitro and in cell lysate: impact of material and solution properties. AB - Optically diffracting films based on hydrogel-encapsulated crystalline colloidal arrays have considerable utility as sensors for detecting enzymaticphosphorylation and, thus, in screening small molecule modulators of kinases. In this work, we have investigated the impact of hydrogel properties, as well as the role of the ionic character of the surrounding environment, on the optical sensitivity of kinase responsive crystalline colloidal array-containing hydrogels. In agreement with a model of hydrogel swelling, the optical sensitivity of such materials increased as the shear modulus and the Flory Huggins interaction parameter between polymer and solvent decreased. Additionally, elimination of extraneous charges in the polymer backbone by exploiting azide-alkyne click chemistry to functionalize the hydrogels with a peptide substrate for protein kinase A further enhanced the sensitivity of the optically diffracting films. Increasing peptide concentration and, in turn, immobilized charge within the hydrogel network was shown to increase the optical response over a range of ionic strength conditions. Ultimately, we showed that, by tuning the hydrogel and solution properties, as little as 0.1 U/MUL protein kinase A could be detected in short reaction times (i.e., 2 h), which is comparable to conventional biochemical kinase assays. We further showed that this approach can be used to detect protein kinase A activity in lysate from HEK293 cells. The sensitivity of the resulting films, coupled with the advantages of photonic crystal based sensors (e.g., label free detection), makes this approach highly attractive for screening enzymatic phosphorylation. PMID- 25714915 TI - Dog's discrimination of human selfish and generous attitudes: the role of individual recognition, experience, and experimenters' gender. AB - Discrimination of and memory for others' generous and selfish behaviors could be adaptive abilities in social animals. Dogs have seemingly expressed such skills in both direct and indirect interactions with humans. However, recent studies suggest that their capacity may rely on cues other than people's individual characteristics, such as the place where the person stands. Thus, the conditions under which dogs recognize individual humans when solving cooperative tasks still remains unclear. With the aim of contributing to this problem, we made dogs interact with two human experimenters, one generous (pointed towards the food, gave ostensive cues, and allowed the dog to eat it) and the other selfish (pointed towards the food, but ate it before the dog could have it). Then subjects could choose between them (studies 1-3). In study 1, dogs took several training trials to learn the discrimination between the generous and the selfish experimenters when both were of the same gender. In study 2, the discrimination was learned faster when the experimenters were of different gender as evidenced both by dogs' latencies to approach the bowl in training trials as well as by their choices in preference tests. Nevertheless, dogs did not get confused by gender when the experimenters were changed in between the training and the choice phase in study 3. We conclude that dogs spontaneously used human gender as a cue to discriminate between more and less cooperative experimenters. They also relied on some other personal feature which let them avoid being confused by gender when demonstrators were changed. We discuss these results in terms of dogs' ability to recognize individuals and the potential advantage of this skill for their lives in human environments. PMID- 25714914 TI - Induction of indoleamine 2, 3-dioxygenase in human dendritic cells by a cholera toxin B subunit-proinsulin vaccine. AB - Dendritic cells (DC) interact with naive T cells to regulate the delicate balance between immunity and tolerance required to maintain immunological homeostasis. In this study, immature human dendritic cells (iDC) were inoculated with a chimeric fusion protein vaccine containing the pancreatic beta-cell auto-antigen proinsulin linked to a mucosal adjuvant the cholera toxin B subunit (CTB-INS). Proteomic analysis of vaccine inoculated DCs revealed strong up-regulation of the tryptophan catabolic enzyme indoleamine 2, 3-dioxygenase (IDO1). Increased biosynthesis of the immunosuppressive enzyme was detected in DCs inoculated with the CTB-INS fusion protein but not in DCs inoculated with proinsulin, CTB, or an unlinked combination of the two proteins. Immunoblot and PCR analyses of vaccine treated DCs detected IDO1mRNA by 3 hours and IDO1 protein synthesis by 6 hours after vaccine inoculation. Determination of IDO1 activity in vaccinated DCs by measurement of tryptophan degradation products (kynurenines) showed increased tryptophan cleavage into N-formyl kynurenine. Vaccination did not interfere with monocytes differentiation into DC, suggesting the vaccine can function safely in the human immune system. Treatment of vaccinated DCs with pharmacological NF kappaB inhibitors ACHP or DHMEQ significantly inhibited IDO1 biosynthesis, suggesting a role for NF-kappaB signaling in vaccine up-regulation of dendritic cell IDO1. Heat map analysis of the proteomic data revealed an overall down regulation of vaccinated DC functions, suggesting vaccine suppression of DC maturation. Together, our experimental data indicate that CTB-INS vaccine induction of IDO1 biosynthesis in human DCs may result in the inhibition of DC maturation generating a durable state of immunological tolerance. Understanding how CTB-INS modulates IDO1 activity in human DCs will facilitate vaccine efficacy and safety, moving this immunosuppressive strategy closer to clinical applications for prevention of type 1 diabetes autoimmunity. PMID- 25714917 TI - Performance enhancement of MC-CDMA system through novel sensitive bit algorithm aided turbo multi user detection. AB - Multi carrier code division multiple access (MC-CDMA) system is a promising multi carrier modulation (MCM) technique for high data rate wireless communication over frequency selective fading channels. MC-CDMA system is a combination of code division multiple access (CDMA) and orthogonal frequency division multiplexing (OFDM). The OFDM parts reduce multipath fading and inter symbol interference (ISI) and the CDMA part increases spectrum utilization. Advantages of this technique are its robustness in case of multipath propagation and improve security with the minimize ISI. Nevertheless, due to the loss of orthogonality at the receiver in a mobile environment, the multiple access interference (MAI) appears. The MAI is one of the factors that degrade the bit error rate (BER) performance of MC-CDMA system. The multiuser detection (MUD) and turbo coding are the two dominant techniques for enhancing the performance of the MC-CDMA systems in terms of BER as a solution of overcome to MAI effects. In this paper a low complexity iterative soft sensitive bits algorithm (SBA) aided logarithmic Maximum a-Posteriori algorithm (Log MAP) based turbo MUD is proposed. Simulation results show that the proposed method provides better BER performance with low complexity decoding, by mitigating the detrimental effects of MAI. PMID- 25714918 TI - A model-based dose-response meta-analysis of ocular hypotensive agents as a drug development tool to evaluate new therapies in glaucoma. AB - PURPOSE: To characterize dose and response for intraocular pressure (IOP) reduction and incidence of hyperemia using a model-based meta-analysis of IOP lowering monotherapy studies to evaluate new ocular antihypertensive therapies for glaucoma. METHODS: Published randomized controlled trials, regulatory documents, and sponsor reports of IOP-lowering monotherapies were used to develop dose-response models to characterize efficacy (IOP change from baseline) and safety (incidence of hyperemia) profiles. RESULTS: The meta-analysis for efficacy included 31 trials with 6,516 patients receiving bimatoprost, latanoprost, travoprost, timolol, or placebo. Estimated IOP reduction with placebo was -2.01 mmHg. Maximal IOP reduction was similar among the prostaglandin analogs (estimate, -6.27 mmHg; baseline, 25 mmHg). Estimated median effective IOP lowering dose (ED50) was 0.002%, 0.00098%, and 0.00063% daily with bimatoprost, latanoprost, and travoprost, respectively. The hyperemia (safety) analysis included 25 trials with 6,244 patients. Typical maximal estimated difference between drug and placebo was 43%, and estimated ED50 of 0.011%, 0.014%, and 0.0015% daily for bimatoprost, latanoprost, and travoprost, respectively. Latanoprost treatment was predicted to incur the lowest rate of hyperemia of the prostaglandins, for equivalent IOP reduction. CONCLUSIONS: Model-based meta analyses for IOP reduction and incidence of hyperemia among prostaglandin analogs are well described by maximal efficacy models and can provide a useful methodology for evaluating glaucoma therapies. PMID- 25714916 TI - A 60-year follow-up of the incidence and prevalence of multiple sclerosis in Hordaland County, Western Norway. AB - OBJECTIVE: Investigate the incidence of multiple sclerosis during 1953-2013 and estimate the prevalence rate of MS on 1 January 2003 and 2013 in Hordaland County, Western Norway. METHODS: All patients with onset of disease in Hordaland 1953-2013 were identified in files from previous studies until 2003 and from patient records at the departments of Neurology, Haukeland University Hospital and Haugesund Hospital during 2003-2013. 1558 patients were assessed and 1402 of these were included, of whom 1035 were alive and living in Hordaland at prevalence day 1 January 2013. Annual incidence rates were calculated for 1953 2013. RESULTS: On 1 January 2003, the crude prevalence rate was 191/100 000 population and on 1 January 2013, the crude prevalence rate was 211.4 (95% CI 198.3 to 224.2) per 100 000; 270.9 (95% CI 250.6 to 292.3) for women and 151.8 (95% CI 136.8 to 167.9) for men. Prevalence peaked at ages 55-59 years for women and 60-64 years for men. The annual incidence rate increased from 1.9 (95% CI 1.2 to 2.6) per 100 000 during 1953-1957 to 7.2 (95% CI 6.0 to 8.5) during 1978-1982 and to 8.5 (95% CI 7.3 to 9.7) during 2003-2007, thus indicating a stabilising incidence over the past 35 years. The female/male ratio ranged from 1.2:1 to 1.8:1 (p=0.381) during the period. CONCLUSIONS: Stabilising rather than increasing incidence combined with the stable female/male ratio are indicative of non-fluctuating environmental factors in a geographical area otherwise characterised by lack of vitamin D effective sun exposure. The rising prevalence of MS could result from improved survival and follow-up methodology. PMID- 25714919 TI - Mucosal contact points and paranasal sinus pneumatization: Does radiology predict headache causality? AB - OBJECTIVES/HYPOTHESIS: The goal of this study was to evaluate the prevalence of mucosal contact points (MCP), concha bullosa (CB), and variable paranasal sinus (PNS) volumes among patients sent for rhinogenic headache workup as compared with controls. STUDY DESIGN: Retrospective study with case and control groups. METHODS: Fifty-three adults with clear PNS computed tomography (CT) scans were included: 28 patients who have originally undergone PNS CT scan as part of sinus (rhinogenic) headache workup, and 25 controls in whom PNS CT scans were obtained for other purposes. All subjects were asked to report their symptoms using a headache scoring system. CT scans of all subjects were analyzed for presence of MCP, CB, as well as for volumes of maxillary, frontal, and sphenoid sinuses. RESULTS: MCP was found in 40% of controls, and in 50%, 50%, and 40% of mild, moderate, and severe headache groups, respectively. CB was found in 24% of controls, and in 33.3%, 58.3%, and 20%, of mild, moderate, and severe headache groups, respectively. Total volume of the measured PNS ranged from 23.9 to 81.4 cm(3) (mean +/- standard deviation [SD], 48.3 +/- 15.8) in the control group and from 5.31 to 87.4 cm(3) (mean +/- SD, 43.6 +/- 16) in the patient group. No statistically significant difference was found between groups regarding all studied variables. CONCLUSIONS: Radiological identification of MCP, CB, or hyperpneumatized sinuses does not seem to be a predictor of headache causality. Further studies are required to identify clinical scenarios in which these variations may contribute to pain symptoms. LEVEL OF EVIDENCE: 3b. PMID- 25714920 TI - Proximity effect: insight into the fundamental forces governing chemical reactivity of aromatic systems. AB - The analysis of different layers of proximity effect in ortho-substituted aromatic compounds, using a DFT-level study, is reported. Polar and steric components of the proximity effect have been partitioned by applying multivariate regression analysis to an unusual six-electron heteroelectrocyclic reaction of the ortho-substituted nitrosostyrenes. The two pathways, 1,5- and 1,6 cyclizations, emanating from these substrates result into zwitterionic five membered and neutral six-membered rings, respectively. The substituents at position 1, which are adjacent to the polar nitroso group, influenced the barrier primarily through electronic effect. Furthermore, a mechanistic shift from the 1,5 to 1,6 pathway, for certain substrates, is explained by the electronic repulsion. In contrast to position 1, the substituents on position 4 stereoelectronically interacted with a bulkier alkene moiety. Furthermore, unlike position 1, the position-4-substituted substrates are predicted to give only 1,5 products. A comparison of the two ortho positions with position 2, which is meta to the nitroso and para to the alkene, revealed an intriguing relationship between various electronic factors. PMID- 25714921 TI - Rituximab increases the cytotoxicities of vincristine and hydroxyurea through caspase-dependent and caspase-independent cell death, respectively. AB - In the treatment of B cell non-Hodgkin's lymphoma, rituximab is used in combination with different chemotherapeutics to improve its efficacy, but the mechanisms involved are not fully understood. The authors examined the mechanism by which rituximab combined with hydroxyurea or vincristine induces cell death in the human Burkitt's lymphoma Ramos cell line. Cell death was analyzed by phosphatidylserine exposure, caspase activation, and mitochondrial membrane changes. Their results indicate that the cell death initiated by the combination of rituximab and hydroxyurea is caspase-independent. In contrast, preincubation of the cells with the same concentrations of caspase inhibitors used with hydroxyurea eliminated the synergistic effect of the rituximab and vincristine combination. This was confirmed by the presence of the active fragment of caspase 3 in vincristine-treated cells. These preliminary results demonstrate that rituximab can activate different downstream signals to induce direct cell effects. Furthermore, the findings support the important role of mitochondria in the regulation of both pathways. PMID- 25714922 TI - Blood-stage immunity to Plasmodium chabaudi malaria following chemoprophylaxis and sporozoite immunization. AB - Protection against malaria in humans can be achieved by repeated exposure to infected mosquito bites during prophylactic chloroquine treatment (chemoprophylaxis and sporozoites (CPS)). We established a new mouse model of CPS immunization to investigate the stage and strain-specificity of malaria immunity. Immunization with Plasmodium chabaudi by mosquito bite under chloroquine cover does not generate pre-erythrocytic immunity, which is acquired only after immunization with high sporozoite doses. Instead, CPS immunization by bite elicits long-lived protection against blood-stage parasites. Blood-stage immunity is effective against a virulent, genetically distinct strain of P. chabaudi. Importantly, if exposure to blood-stage parasitemia is extended, blood-stage parasites induce cross-stage immunity targeting pre-erythrocytic stages. We therefore show that CPS immunization can induce robust, long-lived heterologous blood-stage immunity, in addition to protection against pre-erythrocytic parasites following high dose sporozoite immunization. Cross-stage immunity elicited by blood-stage parasites may further enhance efficacy of this immunization regimen. PMID- 25714924 TI - Graded Ca2+/calmodulin-dependent coupling of voltage-gated CaV1.2 channels. AB - In the heart, reliable activation of Ca(2+) release from the sarcoplasmic reticulum during the plateau of the ventricular action potential requires synchronous opening of multiple CaV1.2 channels. Yet the mechanisms that coordinate this simultaneous opening during every heartbeat are unclear. Here, we demonstrate that CaV1.2 channels form clusters that undergo dynamic, reciprocal, allosteric interactions. This 'functional coupling' facilitates Ca(2+) influx by increasing activation of adjoined channels and occurs through C-terminal-to-C terminal interactions. These interactions are initiated by binding of incoming Ca(2+) to calmodulin (CaM) and proceed through Ca(2+)/CaM binding to the CaV1.2 pre-IQ domain. Coupling fades as [Ca(2+)]i decreases, but persists longer than the current that evoked it, providing evidence for 'molecular memory'. Our findings suggest a model for CaV1.2 channel gating and Ca(2+)-influx amplification that unifies diverse observations about Ca(2+) signaling in the heart, and challenges the long-held view that voltage-gated channels open and close independently. PMID- 25714923 TI - Serotonergic neurons signal reward and punishment on multiple timescales. AB - Serotonin's function in the brain is unclear. One challenge in testing the numerous hypotheses about serotonin's function has been observing the activity of identified serotonergic neurons in animals engaged in behavioral tasks. We recorded the activity of dorsal raphe neurons while mice experienced a task in which rewards and punishments varied across blocks of trials. We 'tagged' serotonergic neurons with the light-sensitive protein channelrhodopsin-2 and identified them based on their responses to light. We found three main features of serotonergic neuron activity: (1) a large fraction of serotonergic neurons modulated their tonic firing rates over the course of minutes during reward vs punishment blocks; (2) most were phasically excited by punishments; and (3) a subset was phasically excited by reward-predicting cues. By contrast, dopaminergic neurons did not show firing rate changes across blocks of trials. These results suggest that serotonergic neurons signal information about reward and punishment on multiple timescales. PMID- 25714925 TI - Registered report: tumour vascularization via endothelial differentiation of glioblastoma stem-like cells. AB - The Nature in 2010 (Ricci-Vitiani et al., 2010). The experiments that will be replicated are those reported in Figure 4B and Supplementary Figure 10B (Ricci Vitiani et al., 2010), which demonstrate that glioblastoma stem-like cells can derive into endothelial cells, and can be selectively ablated to reduce tumor progression in vivo, and Supplementary Figures S10C and S10D (Ricci-Vitiani et al., 2010), which demonstrate that fully differentiated glioblastoma cells cannot form functionally relevant endothelium. The Reproducibility Project: Cancer Biology is a collaboration between the eLife. PMID- 25714927 TI - The genetic architecture of gene expression levels in wild baboons. AB - Primate evolution has been argued to result, in part, from changes in how genes are regulated. However, we still know little about gene regulation in natural primate populations. We conducted an RNA sequencing (RNA-seq)-based study of baboons from an intensively studied wild population. We performed complementary expression quantitative trait locus (eQTL) mapping and allele-specific expression analyses, discovering substantial evidence for, and surprising power to detect, genetic effects on gene expression levels in the baboons. eQTL were most likely to be identified for lineage-specific, rapidly evolving genes; interestingly, genes with eQTL significantly overlapped between baboons and a comparable human eQTL data set. Our results suggest that genes vary in their tolerance of genetic perturbation, and that this property may be conserved across species. Further, they establish the feasibility of eQTL mapping using RNA-seq data alone, and represent an important step towards understanding the genetic architecture of gene expression in primates. PMID- 25714928 TI - Role of transplantation in the treatment of benign solid tumors of the liver: a review of the United Network of Organ Sharing data set. AB - IMPORTANCE: The role of orthotopic liver transplantation for the treatment of benign solid liver tumors (BSLT) is not well defined. OBJECTIVE: To analyze outcomes in the United Network of Organ Sharing data set of patients with a diagnosis of BSLT who underwent transplantation. DESIGN, SETTING, AND PARTICIPANTS: A retrospective analysis of the United Network of Organ Sharing data set was performed for all (N = 87,280) patients who underwent transplantation for BSLT in the United States from October 1, 1988, through January 31, 2013. MAIN OUTCOMES AND MEASURES: Demographics, clinicopathological characteristics, distribution of the procedures by region and state, and overall survival rates. RESULTS: During the study period, 147 liver transplants (0.17%) were to treat BSLT. Sixty-two patients (42.2%) had adenomas, 29 (19.7%) had focal nodular hyperplasia, 25 (17.0%) had hemangiomas, 11 (7.5%) had hepatic epithelioid hemangioendotheliomas, and 20 (13.6%) were classified as having unknown benign tumors. The overall 1-, 3-, and 5-year survival rates were 90.9%, 85.2%, and 81.8%, respectively. Using multivariable analysis, we found that age was the only independent factor associated with patient survival. The overall 5 year survival rate for patients older than 50 years was 88% compared with 91% in younger individuals (95% CI, 148-384; P = .005). Region 3 (Alabama, Arkansas, Florida, Georgia, Louisiana, Mississippi, and Puerto Rico) contributed the maximum number (33 [22.4%]) of these transplants. CONCLUSIONS AND RELEVANCE: Although liver transplantation cannot be considered a first-line treatment, it is a valid therapeutic option in selected patients who are not amenable to resection. Only 0.17% of the transplants in the United States are performed for this indication, with satisfying long-term results. Age was an independent predictor of patient survival. Further studies are needed to better understand the role of liver transplantation in the treatment of BSLT. PMID- 25714929 TI - Structural basis for xyloglucan specificity and alpha-d-Xylp(1 -> 6)-D-Glcp recognition at the -1 subsite within the GH5 family. AB - GH5 is one of the largest glycoside hydrolase families, comprising at least 20 distinct activities within a common structural scaffold. However, the molecular basis for the functional differentiation among GH5 members is still not fully understood, principally for xyloglucan specificity. In this work, we elucidated the crystal structures of two novel GH5 xyloglucanases (XEGs) retrieved from a rumen microflora metagenomic library, in the native state and in complex with xyloglucan-derived oligosaccharides. These results provided insights into the structural determinants that differentiate GH5 XEGs from parental cellulases and a new mode of action within the GH5 family related to structural adaptations in the -1 subsite. The oligosaccharide found in the XEG5A complex, permitted the mapping, for the first time, of the positive subsites of a GH5 XEG, revealing the importance of the pocket-like topology of the +1 subsite in conferring the ability of some GH5 enzymes to attack xyloglucan. Complementarily, the XEG5B complex covered the negative subsites, completing the subsite mapping of GH5 XEGs at high resolution. Interestingly, XEG5B is, to date, the only GH5 member able to cleave XXXG into XX and XG, and in the light of these results, we propose that a modification in the -1 subsite enables the accommodation of a xylosyl side chain at this position. The stereochemical compatibility of the -1 subsite with a xylosyl moiety was also reported for other structurally nonrelated XEGs belonging to the GH74 family, indicating it to be an essential attribute for this mode of action. PMID- 25714926 TI - Angiopoietin-like proteins stimulate HSPC development through interaction with notch receptor signaling. AB - Angiopoietin-like proteins (angptls) are capable of ex vivo expansion of mouse and human hematopoietic stem and progenitor cells (HSPCs). Despite this intriguing ability, their mechanism is unknown. In this study, we show that angptl2 overexpression is sufficient to expand definitive HSPCs in zebrafish embryos. Angptl1/2 are required for definitive hematopoiesis and vascular specification of the hemogenic endothelium. The loss-of-function phenotype is reminiscent of the notch mutant mindbomb (mib), and a strong genetic interaction occurs between angptls and notch. Overexpressing angptl2 rescues mib while overexpressing notch rescues angptl1/2 morphants. Gene expression studies in ANGPTL2-stimulated CD34(+) cells showed a strong MYC activation signature and myc overexpression in angptl1/2 morphants or mib restored HSPCs formation. ANGPTL2 can increase NOTCH activation in cultured cells and ANGPTL receptor interacted with NOTCH to regulate NOTCH cleavage. Together our data provide insight to the angptl-mediated notch activation through receptor interaction and subsequent activation of myc targets. PMID- 25714930 TI - Drugs and cardiovascular risk in inflammatory arthritis: another case of glucocorticoid-bashing? PMID- 25714931 TI - Disease specificity of autoantibodies to cytosolic 5'-nucleotidase 1A in sporadic inclusion body myositis versus known autoimmune diseases. AB - OBJECTIVES: The diagnosis of inclusion body myositis (IBM) can be challenging as it can be difficult to clinically distinguish from other forms of myositis, particularly polymyositis (PM). Recent studies have shown frequent presence of autoantibodies directed against cytosolic 5'-nucleotidase 1A (cN-1A) in patients with IBM. We therefore, examined the autoantigenicity and disease specificity of major epitopes of cN-1A in patients with sporadic IBM compared with healthy and disease controls. METHODS: Serum samples obtained from patients with IBM (n=238), PM and dermatomyositis (DM) (n=185), other autoimmune diseases (n=246), other neuromuscular diseases (n=93) and healthy controls (n=35) were analysed for the presence of autoantibodies using immunodominant cN-1A peptide ELISAs. RESULTS: Autoantibodies directed against major epitopes of cN-1A were frequent in patients with IBM (37%) but not in PM, DM or non-autoimmune neuromuscular diseases (<5%). Anti-cN-1A reactivity was also observed in some other autoimmune diseases, particularly Sjogren's syndrome (SjS; 36%) and systemic lupus erythematosus (SLE; 20%). CONCLUSIONS: In summary, we found frequent anti-cN-1A autoantibodies in sera from patients with IBM. Heterogeneity in reactivity with the three immunodominant epitopes indicates that serological assays should not be limited to a distinct epitope region. The similar reactivities observed for SjS and SLE demonstrate the need to further investigate whether distinct IBM-specific epitopes exist. PMID- 25714933 TI - Ventricular arrhythmias in Chagas disease. AB - Sudden death is one of the most characteristic phenomena of Chagas disease, and approximately one-third of infected patients develop life-threatening heart disease, including malignant ventricular arrhythmias. Fibrotic lesions secondary to chronic cardiomyopathy produce arrhythmogenic substrates that lead to the appearance and maintenance of ventricular arrhythmias. The objective of this study is to discuss the main clinical and epidemiological aspects of ventricular arrhythmias in Chagas disease, the specific workups and treatments for these abnormalities, and the breakthroughs needed to determine a more effective approach to these arrhythmias. A literature review was performed via a search of the PubMed database from 1965 to May 31, 2014 for studies of patients with Chagas disease. Clinical management of patients with chronic Chagas disease begins with proper clinical stratification and the identification of individuals at a higher risk of sudden cardiac death. Once a patient develops malignant ventricular arrhythmia, the therapeutic approach aims to prevent the recurrence of arrhythmias and sudden cardiac death by the use of implantable cardioverter defibrillators, antiarrhythmic drugs, or both. In select cases, invasive ablation of the reentrant circuit causing tachycardia may be useful. Ventricular arrhythmias are important manifestations of Chagas cardiomyopathy. This review highlights the absence of high-quality evidence regarding the treatment of ventricular arrhythmias in Chagas disease. Recognizing high-risk patients who require specific therapies, especially invasive procedures such as the implantation of cardioverter defibrillators and ablative approaches, is a major challenge in clinical practice. PMID- 25714932 TI - Does MOVES move the needle? PMID- 25714934 TI - Yb7Ni4InGe12: a quaternary compound having mixed valent Yb atoms grown from indium flux. AB - The new intermetallic compound Yb7Ni4InGe12 was obtained as large silver needle shaped single crystals from reactive indium flux. Single crystal X-ray diffraction suggests that Yb7Ni4InGe12 crystallizes in the Yb7Co4InGe12 structure type, and tetragonal space group P4/m and lattice constants are a = b = 10.291(2) A and c = 4.1460(8) A. The crystal structure of Yb7Ni4InGe12 consists of columnar units of three different types of channels filled with the Yb atoms. The crystal structure of Yb7Ni4InGe12 is closely related to Yb5Ni4Ge10. The effective magnetic moment obtained from the magnetic susceptibility measurements in the temperature range 200-300 K is 3.66MUB/Yb suggests mixed/intermediate valence behavior of ytterbium atoms. X-ray absorption near edge spectroscopy (XANES) confirms that Yb7Ni4InGe12 exhibits mixed valence. PMID- 25714935 TI - Neglected Monteggia fracture dislocations in children: a systematic review. AB - Monteggia fractures are uncommon and frequently missed injuries in children. This article aims to study, in a systematic manner, the surgical management and complications of treatment of chronic radial head dislocations. After screening of relevant abstracts, a total of 28 studies were included in the systematic review. A narrative synthesis of various treatment modalities has been discussed. This article concludes that open reduction should be attempted unless dysmorphism of the radial head restricts it. Open reduction with ulnar osteotomy with or without annular ligament reconstruction is the most commonly performed procedure and is expected to result in reduced pain and elbow deformity. PMID- 25714937 TI - Histological differences between various methods of hemiepiphysiodesis: is guided growth really different? AB - Traditional systems of hemiepiphysiodesis are based on the application of asymmetrical compression to the physis to correct angular deformities. The guided growth method claims to act as a tension plate avoiding compression. The aim of this study was to confirm or refute this claim. Twenty-four White New Zealand rabbits were subjected to a proximal tibial hemiepiphysiodesis using either staples or a plate and two-screws method. Both methods succeeded in producing deformity. The initial existent histological differences between systems became less apparent after 6 weeks of hemiepiphysiodesis, when histological results were very similar. The findings suggest that the eight-plate system produces, like staples, compression of the physis, but the forces are applied more gradually. PMID- 25714936 TI - Macrophage activation syndrome or septic arthritis: a case of mistaken identity. AB - We present an interesting case of macrophage activation syndrome in a 2-year-old, with no previous rheumatological diagnoses, incorrectly diagnosed with septic arthritis, to highlight the diagnostic difficulties, especially in small hospital units. We aim to present the similarities between the two conditions and to summarize the clinical, radiological and epidemiological features of macrophage activation syndrome, an underdiagnosed condition. A review of the current literature was performed, and a diagnostic algorithm was created. No current set treatment regimen exists, but current recommendations have been included. We have demonstrated the pitfalls in diagnosis and the importance of immediate treatment in optimizing prognosis. PMID- 25714938 TI - Back pain in Duchenne muscular dystrophy: steroids are not always the culprit. AB - We report on a child with Duchenne muscular dystrophy on prolonged corticosteroid treatment who presented with back pain and was subsequently found to have a monostotic fibrous dysplasia lesion of the spine. It is the intent of this case report to emphasize the need to maintain a high index of suspicion for other potential causes of back pain in Duchenne muscular dystrophy besides vertebral compression fractures. PMID- 25714939 TI - Posterior shoulder dislocation with ipsilateral proximal humerus type 2 physeal fracture: case report. AB - In pediatric patients, proximal humeral physeal fractures are uncommon injuries compared with distal physeal fractures. Usually, the growth plate is the most vulnerable site of fracture in the proximal humerus. Proximal humeral physeal fractures accompanying posterior shoulder dislocation are very rare. There are few recent reports on the combination of glenohumeral dislocation and proximal humerus fractures. Here, we describe a case of posterior shoulder dislocation with ipsilateral proximal humerus type 2 physeal fracture in a 9-year-old boy. We treated the patient by closed reduction and percutaneous pinning under general anesthesia. PMID- 25714940 TI - The shaft fractures of the radius and ulna in children: current concepts. AB - The incidence of forearm shaft fractures in children has increased in recent years. They are challenging to treat and they can result in several long-lasting complications. The treatment of children's fractures needs to be individualized to their needs. Nonoperative care will be satisfactory for young, preschool children and it is primarily treatment in stable fractures of children at every age. Injury mechanism must be understood to perform appropriate closed reduction. Immobilization using a long-arm cast needs to be focused against the deforming muscle forces - in particular those that rotate - in the forearm, keeping the bones in alignment until bone healing. Operative stabilization by elastic stable intramedullary nailing is the primarily method of treatment in cases of unstable fractures, in particular, in children between preschool age and adolescence. For older children near to skeletal maturity, a rigid plate and screw fixation will be justified. The most common complication after closed treatment is worsening of the alignment and need for repetitive interventions. elastic stable intramedullary nailing results usually in good outcome, and range of forearm rotation is the main feature determining the clinical result. In this article, we report the current concept of paediatric shaft fractures in the radius and ulna. PMID- 25714941 TI - Temporary scaphocapitate fixation with or without radial shortening for adolescent Kienbock's disease. AB - We performed temporary scaphocapitate joint fixation with or without radial shortening osteotomy, depending on the ulnar variance, in adolescent Kienbock's disease. The aim of the current study was to evaluate the radiological and clinical results and compare our results with those of other previously reported methods. Temporary scaphocapitate fixation alone or fixation accompanied by radial shortening osteotomy has been performed in three patients since 2003. All six patients were males, and their mean age at surgery was 15.5 years. The fixation was performed using two Kirschner-wires in closed methods, and the shortening of the radius was performed using the volar approach and secured with a plate. Radial shortenings of 4, 2, and 7 mm were applied. Radiological findings of Kienbock's disease, including ulnar variance and carpal height ratio, were investigated at the final follow-up by simple radiography and MRI. Clinical results of pain, range of wrist motion, and grip strength were also evaluated. The mean age at the final follow-up of six patients was 22 years, and the follow up period was 6.8 years. Sclerosis or fragmentation of all the lunates in the simple radiographs improved, and the carpal height ratio increased to 0.5 at the final follow-up. The signal intensities on the final MRI were all normalized. The final visual analog scale scores decreased to 1.2, and wrist ranges of motion were all statistically significantly increased. In addition, grip strength increased to 69% of that of the normal side at the final follow-up. We suggest that temporary scaphocapitate joint fixation is a recommendable option with or without radial shortening, depending on the ulnar variance, in adolescent Kienbock's disease. PMID- 25714944 TI - From the editor. PMID- 25714945 TI - Guest editorial: health care industry. PMID- 25714942 TI - Antimalarial NADPH-Consuming Redox-Cyclers As Superior Glucose-6-Phosphate Dehydrogenase Deficiency Copycats. AB - AIMS: Early phagocytosis of glucose-6-phosphate dehydrogenase (G6PD)-deficient erythrocytes parasitized by Plasmodium falciparum were shown to protect G6PD deficient populations from severe malaria. Here, we investigated the mechanism of a novel antimalarial series, namely 3-[substituted-benzyl]-menadiones, to understand whether these NADPH-consuming redox-cyclers, which induce oxidative stress, mimic the natural protection of G6PD deficiency. RESULTS: We demonstrated that the key benzoylmenadione metabolite of the lead compound acts as an efficient redox-cycler in NADPH-dependent methaemoglobin reduction, leading to the continuous formation of reactive oxygen species, ferrylhaemoglobin, and subsequent haemichrome precipitation. Structure-activity relationships evidenced that both drug metabolites and haemoglobin catabolites contribute to potentiate drug effects and inhibit parasite development. Disruption of redox homeostasis by the lead benzylmenadione was specifically induced in Plasmodium falciparum parasitized erythrocytes and not in non-infected cells, and was visualized via changes in the glutathione redox potential of living parasite cytosols. Furthermore, the redox-cycler shows additive and synergistic effects in combination with compounds affecting the NADPH flux in vivo. INNOVATION: The lead benzylmenadione 1c is the first example of a novel redox-active agent that mimics the behavior of a falciparum parasite developing inside a G6PD-deficient red blood cell (RBC) giving rise to malaria protection, and it exerts specific additive effects that are inhibitory to parasite development, without harm for non-infected G6PD-sufficient or -deficient RBCs. CONCLUSION: This strategy offers an innovative perspective for the development of future antimalarial drugs for G6PD-sufficient and -deficient populations. PMID- 25714946 TI - Interview. PMID- 25714947 TI - Support for caring and resiliency among successful nurse leaders. AB - Health care practice settings are replete with competing priorities for nurse leaders who are responsible to the staff, the organization, and the patients and their families. In the midst of the competing priorities, there is a mandate for successful nursing leadership that is patient centered. To support the continuance of nurse leader success and avoid discouragement and attrition, a caring and resilient model for leadership may be necessary. This article considers the practices of nurse leaders that support caring, resiliency, and, ultimately, their success. Successful navigation toward patient-centered solutions through the intentional and inextricably linked living caring and resiliency was enhanced with practices of self-care, accountability, and reflection. Within each of the 3 intentional practices, a primary process emerged that revealed how nurse leaders actualize their caring and resiliency. The practices and mutually supportive processes are discussed. Useful questions are provided to guide any nurse leader who is contemplating practices of self-care, accountability, and reflection for supporting caring and resiliency. PMID- 25714948 TI - Nurse leader resilience: career defining moments. AB - Resilience is an essential component of effective nursing leadership. It is defined as the ability to survive and thrive in the face of adversity. Resilience can be developed and internalized as a measure to improve retention and reduce burnout. Nurse leaders at all levels should develop these competencies to survive and thrive in an increasingly complex health care environment. Building positive relationships, maintaining positivity, developing emotional insight, creating work-life balance, and reflecting on successes and challenges are effective strategies for resilience building. Nurse leaders have a professional obligation to develop resilience in themselves, the teams they supervise, and the organization as a whole. Additional benefits include reduced turnover, reduced cost, and improved quality outcomes through organizational mindfulness. PMID- 25714949 TI - The resilient nurse leader: reinvention after experiencing job loss. AB - The nurse executive has been especially vulnerable to unexpected job loss as a result of financial and other pressures in the health care environment. The nurse leader is often the one who holds the standards of quality and safety above those of cost. While there may be many reasons or factors that affect a sudden removal of a nurse leader, the problem is that the unexpected job loss is often a devastating and traumatic event to the individual affected. Twelve nurse executives who experienced unexpected job loss were interviewed in depth for this study. Stories collected illustrated deep personal and professional loss of identity and self-esteem as well as colleagues and friends. Their resilience and ability to get past this adversity aided the nurse leaders in their healing, recovery, and reinvention of their professional selves. Finally, following reflection, the participants offer strategies for averting unexpected job loss as well as preparing for transition. PMID- 25714950 TI - Nursing resilience: a nursing opportunity. AB - Resilience is a concept that has been explored in many other professions and cultures. Nurses experience many difficult and unanticipated adverse situations that can negatively impact them. Resilience can be cultivated to aid individual nurses and nursing work groups to bounce back from these situations and integrate them into context of their practice. Practices such as meditation and education can support development of resilience. PMID- 25714951 TI - The role of resilience in involuntary chief nursing officer job loss. AB - The purpose of this article is to discuss the role resilience plays for chief nursing officers who have experienced involuntary loss of their positions. Various definitions of resilience based on 3 stages of resilience inquiry that have evolved over time and the "Broaden-and-Build Theory" of positive emotions are presented. Based on this foundation, recommendations are presented to help these chief nursing officers develop or enhance their resilience to move forward to a successful future. PMID- 25714952 TI - Thoughts to thrive (or survive) professional transitions. AB - This article shares practical ideas on how to thrive or survive an unexpected professional transition. The ideas are based on the author's personal experience and years of listening to, and coaching, professional colleagues. The logistics of transitioning out of an organization are difficult enough when it is planned. The challenges of doing so when it is an unexpected transition can be daunting. Logistical considerations on how to leave an organization and begin to explore other opportunities are presented. Topics include strategies on how to be resilient, manage financial and benefit changes, communicate reasons for the job change, and tap into professional networks. In today's environment, these logistical considerations are worthy of proactive contemplation. Exceptional leaders have likely spent their professional lives leading with valor, and times of transition should be no exception. Thriving and surviving in transition calls for a sense of resilience, careful consideration of potentially unforeseen logistics related to exiting an organization, and a sense of inspiration to continue to lead with courage. PMID- 25714953 TI - Leading a multicultural work environment: reflections on the next frontier of nurse leadership. AB - Nurses face the challenge of leading in a diverse society. Is the cross section of present-day nurse leaders prepared to meet the needs of patients and a work environment represented by a broader range of social backgrounds, cultural traditions, and languages? Fundamental to leaders' ability to meet diverse needs is a new framework for understanding the meaning of leadership, in which the issue of diversity is paramount. This article explores how the word leadership expresses a more complex system, when responsibility to address human needs is emphasized, and care for multilingual and multiethnic patients by a diverse, committed work environment is a focus. Under the umbrella of diversity, the necessary knowledge to create such a work environment may lack depth or may even be absent. PMID- 25714954 TI - Fostering career resilience amid a hospital closure. AB - Resilience involves fostering a positive response or outcome when one faces adverse circumstances. This article provides a personal account of the closure of a public hospital and the resilience the nursing staff and chief nurse found to go forward in their nursing careers. Three major aspects are explored: professional identity, confidence/courage, and a sense of caring or concern. PMID- 25714955 TI - Transformation by design: nursing workforce innovation and reduction strategies in turbulent times of change. AB - The evolution of care delivery from an acute care and inpatient standard to the outpatient setting and health promotion model is generating the need for innovative workforce and infrastructure adjustments to meet the new paradigm of population health management. Successful transformation of the nursing workforce necessitates a positive style of thinking that addresses rational concerns during times of difficult transition. Nurse leaders are called to recognize and appreciate the strengths of the nursing workforce by involving them in the course of change through collaboration, planning, and discussion. One unique way to plan and develop new care delivery models is to adopt the framework used in health facility planning and design for new services, units, or hospitals. This framework is flexible and can be adjusted easily to meet the objectives of a small nursing workforce innovation project or expanded to encompass the needs of a large-scale hospital transformation. Structured questioning further helps the team to identify barriers to care and allows for the development of new concepts that are objective and in accord with evidence-based practice and data. This article explores the advantages and disadvantages of implementing innovative workforce redesign and workforce reduction strategies. PMID- 25714956 TI - Emotional intelligence (EI) and nursing leadership styles among nurse managers. AB - Less than 12.5% of nurses aspire to leadership roles, noting lack of support and stress as major factors in their decision not to pursue this area of practice. Psychological resiliency, described as the ability to properly adapt to stress and adversity, is key to successful nurse managers. Emotional intelligence (EI) is a related concept to resiliency and is another noteworthy predictor of leadership and management success. This study was undertaken to determine the level of and relationship between EI and leadership style of nurse managers employed in Wisconsin and Illinois facilities. A descriptive, exploratory study design was utilized, with a convenience sample of nurse managers working in 6 large Midwestern health systems. Nurse managers were invited to participate in the study by their employer, completing the online consent form and the demographic, Multifactor Leadership Questionnaire (MLQ) Form 5X and the Emotional Quotient Inventory (EQ-i 2.0) surveys. Statistically significant positive relationships were noted between EI and transformational leadership and the outcomes of leadership (extra effort, effectiveness, and satisfaction). No statistically significant relationships were noted between EI and transactional or laissez-faire leadership styles. PMID- 25714957 TI - Summary of the nursing informatics year in review 2014. PMID- 25714958 TI - Resilient regulatory processes. PMID- 25714959 TI - Research in nursing informatics 2014. AB - This article reflects the work done in the third year of the Nursing Informatics Year in Review project. This project seeks to search and analyze articles written by nurses as first author on the subject of nursing informatics, published August 2013-August 2014. Each year we also seek recommended articles from our American Medical Informatics Association-Nursing Informatics Work Group (AMIA-NIWG) members that meet the same criteria as the search and most influenced their thinking and scholarship. Twenty-seven articles emerged from the literature review, and our AMIA-NIWG members recommended 32 articles. We analyzed the articles by journal of publication, country of first author, source of funding, research method, research setting, and area of focus. The purpose of this article was to present the results of this project for 2014. PMID- 25714961 TI - Dendritic-cell-based technology landscape: Insights from patents and citation networks. AB - As the most potent antigen-presenting cells, dendritic cells (DCs) are pivotal players in regulating immune responses. DC-based technologies have generated a series of typical and promising therapeutic options, especially after the first DC-based cancer vaccine was approved by US. Food and Drug Administration (US. FDA). In this context, this paper employs patents and citation networks to conduct a fundamental analysis in order to show overall landscape of DC-based technologies. The results in this research can be used as references for decision making in developing efficacious DC therapeutic products. PMID- 25714960 TI - N-terminal pro-B-type natriuretic peptide variability in stable dialysis patients. AB - BACKGROUND AND OBJECTIVES: Monitoring N-terminal pro-B-type natriuretic peptide (NT-proBNP) may be useful for assessing cardiovascular risk in dialysis patients. However, its biologic variation is unknown, hindering the accurate interpretation of serial concentrations. The aims of this prospective cohort study were to estimate the within- and between-person coefficients of variation of NT-proBNP in stable dialysis patients, and derive the critical difference between measurements needed to exclude biologic and analytic variation. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Fifty-five prevalent hemodialysis and peritoneal dialysis patients attending two hospitals were assessed weekly for 5 weeks and then monthly for 4 months between October 2010 and April 2012. Assessments were conducted at the same time in the dialysis cycle and entailed NT-proBNP testing, clinical review, electrocardiography, and bioimpedance spectroscopy. Patients were excluded if they became unstable. RESULTS: This study analyzed 136 weekly and 113 monthly NT-proBNP measurements from 40 and 41 stable patients, respectively. Results showed that 22% had ischemic heart disease; 9% and 87% had left ventricular systolic and diastolic dysfunction, respectively. Respective between- and within-person coefficients of variation were 153% and 27% for weekly measurements, and 148% and 35% for monthly measurements. Within-person variation was unaffected by dialysis modality, hydration status, inflammation, or cardiac comorbidity. NT-proBNP concentrations measured at weekly intervals needed to increase by at least 46% or decrease by 84% to exclude change due to biologic and analytic variation alone with 90% certainty, whereas monthly measurements needed to increase by at least 119% or decrease by 54%. CONCLUSIONS: The between-person variation of NT-proBNP was large and markedly greater than within-person variation, indicating that NT-proBNP testing might better be applied in the dialysis population using a relative-change strategy. Serial NT-proBNP concentrations need to double or halve to confidently exclude change due to analytic and biologic variation alone. PMID- 25714963 TI - Changes in Serum Amino Acids in Migraine Patients without and with Aura and their Possible Usefulness in the Study of Migraine Pathogenesis. AB - BACKGROUND: Results of several studies suggest that serum amino acids monitoring in migraine might be useful as an objective measurement of the disease status. OBJECTIVE: The aim of the present work was to analyze the profile of aliphatic and aromatic amino acids in blood serum of migraine patients without and with aura between attacks. METHODS: A total number of 37 migraine patients (26 with migraine without aura and 11 with migraine with aura), mean age 39+/-12 years, and 40 age-matched healthy subjects as the control group, mean age 38+/-14 years, were included into the study. The levels of glutamic acid, glutamine, histidine (His), valine (Val), isoleucine, leucine (Leu), phenyloalanine, lysine were evaluated. RESULTS: The level of His was significantly higher in both groups of migraine patients (without and with aura) compared to the control group (F(2,74)=10.17, p=0.00). The levels of Val and Leu were significantly different in migraine without but not with aura, when compared with the control group (F(2,74)=4.70, p=0.01 and F(2,74)=4.39, p=0.02, respectively). CONCLUSION: We found higher level of His in migraine patients without and with aura and lower level of Val and Leu in patients with migraine without aura. PMID- 25714962 TI - Comparative effectiveness of different forms of telemedicine for individuals with heart failure (HF): a systematic review and network meta-analysis. AB - BACKGROUND: Previous studies on telemedicine have either focused on its role in the management of chronic diseases in general or examined its effectiveness in comparison to standard post-discharge care. Little has been done to determine the comparative impact of different telemedicine options for a specific population such as individuals with heart failure (HF). METHODS AND FINDINGS: Systematic reviews (SR) of randomized controlled trials (RCTs) that examined telephone support, telemonitoring, video monitoring or electrocardiographic monitoring for HF patients were identified using a comprehensive search of the following databases: MEDLINE, EMBASE, CINAHL and The Cochrane Library. Studies were included if they reported the primary outcome of mortality or any of the following secondary outcomes: all-cause hospitalization and heart failure hospitalization. Thirty RCTs (N = 10,193 patients) were included. Compared to usual care, structured telephone support was found to reduce the odds of mortality(Odds Ratio 0.80; 95% Credible Intervals [0.66 to 0.96]) and hospitalizations due to heart failure (0.69; [0.56 to 0.85]). Telemonitoring was also found to reduce the odds of mortality(0.53; [0.36 to 0.80]) and reduce hospitalizations related to heart failure (0.64; [0.39 to 0.95]) compared to usual post-discharge care. Interventions that involved ECG monitoring also reduced the odds of hospitalization due to heart failure (0.71; [0.52 to 0.98]). LIMITATIONS: Much of the evidence currently available has focused on the comparing either telephone support or telemonitoring with usual care. This has therefore limited our current understanding of how some of the less common forms of telemedicine compare to one another. CONCLUSIONS: Compared to usual care, structured telephone support and telemonitoring significantly reduced the odds of deaths and hospitalization due to heart failure. Despite being the most widely studied forms of telemedicine, little has been done to directly compare these two interventions against one another. Further research into their comparative cost effectiveness is also warranted. PMID- 25714964 TI - Cofilin rod formation in neurons impairs neuronal structure and function. AB - Cofilin-1 is a major actin depolymerizer in the central nervous system. It is a member of the ADF/cofilin family that regulates the dynamics of actin filaments. The activity of cofilin-1 is regulated by the modulation of phosphorylation at its Ser3 residue, and its proper function is crucial for the structure and proper function of neurons. Cofilin rods, pathological structures composed of cofilin and actin, form under stress conditions. A high cofilin/F-actin ratio, cofilin dephosphorylation and/or cofilin oxidation are three major mechanisms of cofilin rod formation. Cofilin rods can be divided into cytoplasmic rods and nuclear rods. Cytoplasmic rods have been proved to disrupt dendritic transportation, cause synaptic loss and impair synaptic function, which maybe associated with neurodegenerative diseases such as Alzheimer's disease. On the other hand, the role of nuclear rods remains largely unknown. Further studies are needed to investigate the relationship and the underlying mechanisms of cofilin rod formation during the progression of various neurological diseases. PMID- 25714965 TI - New kid on the block: does histamine get along with inflammation in amyotrophic lateral sclerosis? AB - Results from amyotrophic lateral sclerosis (ALS) patients and pre-clinical studies strongly suggest that systemic and CNS-intrinsic immune activation plays a central role in ALS pathogenesis. Microglial cells are emerging in this context as master regulators with a bi-functional role in the progression of the pathological response. They foster a pro-inflammatory setting through the production of cytotoxic cytokines and chemokines (M1 phenotype), after an aborted effort to sustain an anti-inflammatory environment for motor neurons through the release of beneficial cytokines and growth factors (M2 phenotype). In this review, we gather information meant to propose that histamine and ATP, which are released from mast cells, microglia and damaged neurons at sites of injury where they function as transmitters, have to be considered as new players in the ALS neuroinflammatory arena. After all, abnormal histamine and ATP signalling in the brain are already documented in neurodegenerative/neuroinflammatory conditions such as multiple sclerosis, Alzheimer and Parkinson's disease and, at present, histamine- as well as ATP-related compounds are in clinical trial for these same pathologies. Concerning ALS, while emerging data are now available about purinergic mechanisms, the involvement of histamine is basically unexplored. The circumstantial evidence that we present here thus constitutes a solid background for formulating novel hypotheses, stimulating a scientific debate and, most of all, inspiring future research. We deem that a new potential role of histamine in the setting of ALS neuroinflammation might find a fertile ground where to thrive. ALS is still a disease without a cure: why not to play with a new kid on the block? PMID- 25714966 TI - Individual differences and vulnerability to drug addiction: a focus on the endocannabinoid system. AB - Vulnerability to drug addiction depends upon the interactions between the biological makeup of the individual, the environment, and age. These interactions are complex and difficult to tease apart. Since dopamine is involved in the rewarding effects of drugs of abuse, it is postulated that innate differences in mesocorticolimbic pathway can influence the response to drug exposure. In particular, higher and lower expression of dopamine D2 receptors in the ventral striatum (i.e. a marker of dopamine function) has been considered a putative protective and a risk factor, respectively, that can influence one's susceptibility to continued drug abuse as well as the transition to addiction. This phenomenon, which is phylogenetically preserved, appears to be a compensatory change to increased impulse activity of midbrain dopamine neurons. Hence, dopamine neuronal excitability plays a fundamental role in the diverse stages of the drug addiction cycle. In this review, a framework for the evidence that modulation of dopamine neuronal activity plays in the context of vulnerability to drug addiction will be presented. Furthermore, since endogenous cannabinoids serve as retrograde messengers to shape afferent neuronal activity in a short- and long-lasting fashion, their role in individual differences and vulnerability to drug addiction will be discussed. PMID- 25714968 TI - Ca2+ -myristoyl switch in neuronal calcium sensor-1: a role of C-terminal segment. AB - NCS1 (neuronal calcium sensor-1) is a Ca(2+)-myristoyl switch protein of the NCS protein family involved in synaptic plasticity and neurotransmission via Ca(2+) dependent regulation of dopamine D2 receptor and associated Gprotein coupled receptor kinase (GRK)-2. Overexpression of NCS1 in synaptic terminals results in accumulation of membrane-bound protein and its redundant regulatory activity associated with neurological disorders. Here, we have demonstrated that bovine photoreceptors contain NCS1 that is capable of a partially irreversible interaction with isolated photoreceptor membranes and implicated in Ca(2+) dependent binding and regulation of GRK1 in vitro. Using NCS1- recoverin C terminal chimeric construct (NR), it was found that the Ca(2+)-myristoyl switch of NCS1 is affected by its C-terminal segment downstream the fourth EF-loop of the protein, which is variable within the NCS family. NR retains structural stability and sensitivity to Ca(2+), but interacts with photoreceptor membranes with lower affinity in a Ca(2+)- dependent fully reversible manner and displays altered GRK1 modulation. These data combined with fluorescent probing of surface hydrophobicity of NCS1, NR and recoverin suggest that the C-terminal segment of NCS1 regulates reuptake of myristoyl group under Ca(2+)-free conditions and participates in organization of the target-binding pocket of the protein. We point out a putative role of NCS1 in photoreceptors as a modulator of GRK activity and propose targeting of the C-terminal segment of NCS1 as an appropriate way for selective suppression of excessive membrane accumulation and aberrant activity of the protein in neurons associated with central nervous system dysfunctions. PMID- 25714967 TI - Current Update on Synopsis of miRNA Dysregulation in Neurological Disorders. AB - Aberrant expression of microRNAs (miRNAs) has been implicated in various neurological disorders (NDs) of the central nervous system such as Alzheimer disease, Parkinson's disease, Huntington disease, amyotrophic lateral sclerosis, schizophrenia and autism. If dysregulated miRNAs are identified in patients suffering from NDs, this may serve as a biomarker for the earlier diagnosis and monitoring of disease progression. Identifying the role of miRNAs in normal cellular processes and understanding how dysregulated miRNA expression is responsible for their neurological effects is also critical in the development of new therapeutic strategies for NDs. miRNAs hold great promise from a therapeutic point of view especially if it can be proved that a single miRNA has the ability to influence several target genes, making it possible for the researchers to potentially modify a whole disease phenotype by modulating a single miRNA molecule. Hence, better understanding of the mechanisms by which miRNA play a role in the pathogenesis of NDs may provide novel targets to scientists and researchers for innovative therapies. PMID- 25714969 TI - Gum-Chewing and Headache: An Underestimated Trigger of Headache Pain in Migraineurs? AB - Tension-type headache and migraine are currently considered the second and third most frequent human diseases. Since a variety of conditions that involve the temporomandibular joint and chewing muscles are frequent causes of orofacial pain, the aim of this article was to review current published evidence about the potential relationship between gum-chewing and headache. A systematic electronic search performed on Medline, Scopus and Web of Science using the keywords "headache" or "migraine" and "chewing" allowed to finally identify 1 cross sectional, 1 observational and 3 randomized studies, along with 3 case reports about the potential association between gum-chewing and headache. Despite the limited evidence, it seems reasonable to suggest that headache attacks may be triggered by gum-chewing in migraineurs and in patients with tension-type headache. Opposite results were obtained in non-migraineurs, since in none of these studies an increased prevalence of headache pain was reported after gum chewing. Although larger randomized studies will be necessary to definitely establish the relationship between gum-chewing and headache across different populations, it seems cautionary to suggest that subjects with migraine or tension-type headache should avoid or limit gum-chewing in their lifestyle. PMID- 25714970 TI - Co-Treatment with Anthocyanins and Vitamin C Ameliorates Ethanol- Induced Neurodegeneration via Modulation of GABAB Receptor Signaling in the Adult Rat Brain. AB - Chronic ethanol exposure is known to cause neuronal damage in both humans and experimental animal models. Ethanol treatment induces neurotoxicity via the generation of reactive oxygen species (ROS), while anthocyanins (extracted from black soybean) and ascorbic acid (vitamin C) are free radical scavengers that can be used as neuroprotective agents against ROS. In this study the underlying neuroprotective potential of black soybean anthocyanins and vitamin C was determined. For this purpose, adult rats were exposed to 10% (v/v) ethanol for 8 weeks, followed by co-treatment with anthocyanins (24 mg/kg) and vitamin C (100 mg/kg) during the last 4 weeks. Our results showed that ethanol administration increased the expression of gamma -aminobutyric acid B1 receptor (GABAB1R) and induced neuronal apoptosis via alterations to the Bax/Bcl-2 ratio, release of cytochrome C and activation of caspase-3 and caspase-9. Anthocyanins alone and supplementation with vitamin C showed an additive effect in reversing the trend of apoptotic signals induced by ethanol in the cortex and hippocampus. Consequently, anthocyanins also decreased the expression of poly (ADP ribose) polymerase-1 induced by ethanol and prevented DNA damage. Furthermore, anthocyanins and vitamin C reversed the ethanol-induced expression of GABAB1R and its downstream signaling molecule phospho-cAMP response element binding protein. Moreover, histopathology and immunohistochemistry results showed that anthocyanins and vitamin C significantly reduced ethanol-induced neuronal cell death. Our study revealed a neuroprotective role of anthocyanins and vitamin C via modulation of GABAB1R expression in the adult brain. Hence, we suggest that anthocyanins or co-treatment with anthocyanins and vitamin C may be a new and potentially effective neuroprotective agent for alcohol abuse. PMID- 25714971 TI - Low activity of plasminogen activator: a common feature of non- iatrogenic comorbidities of schizophrenia. AB - Understanding the pathogenesis of non-iatrogenic comorbidities of schizophrenia may provide insights into the pathogenesis of schizophrenia itself. First episode, drug-naive schizophrenia patients are at high risk of thromboembolic events, diseases related to substance abuse, sexual dysfunction, reproductive disorders, inflammatory and autoimmune diseases, as well as complications of hyperinsulinemia or hyperhomocysteinemia. This review focuses on the role of reduced plasminogen activator activity in non-iatrogenic comorbidity of schizophrenia. By preventing thrombus dissolution, low tissue plasminogen activator activity increases the risk of thrombotic events. Components of the plasminogen activator system also play a key role in reproduction. Both illicit drugs and tobacco increase plasminogen activator levels in the central nervous system, which seems to relieve symptoms of the mental disorder. Chronic alcoholism, sexual dysfunction, inflammatory and autoimmune disorders, and complications of hyperinsulinemia or hyperhomocysteinemia are somehow related to low plasminogen activator activity. Plasminogen activator mediates several neurochemical processes that seem to prevent or reverse gray-matter atrophy seen in first-episode schizophrenia patients. Such processes include cleavage of brain derived neurotrophic factor precursor to an anti-apoptotic neurotrophin and activation of N-methyl-D-aspartate receptor. Controlled, randomized studies are needed to determine if measures aimed at correcting plasminogen activator activity can improve the quality of life, reduce morbidity and mortality rates, and particularly improve the course of schizophrenia. PMID- 25714972 TI - Effects of Chronic Lamotrigine Administration on Maximal Electroshock- Induced Seizures in Mice. AB - The aim of the study was to determine anticonvulsant activity of lamotrigine (LTG) after acute and chronic treatment in four different protocols against maximal electroshock-induced seizures in mice. Such a knowledge seems to be valuable in view of the fact that all interactions between LTG and other drugs are evaluated in acute, not chronic, experiments. Electroconvulsions were produced by means of alternating current (50 Hz, 25 mA, 0.2 s) delivered via ear clip electrodes. Motor impairment and long-term memory deficits in animals were assessed in the chimney test and in passive avoidance task, respectively. Brain and plasma concentrations of LTG were measured by HPLC. Chronic treatment with LTG (2 injections for 14 days) significantly potentiated the anticonvulsant effects of this antiepileptic in the maximal electroshock test in mice, significantly decreasing ED50 value for this antiepileptic. No impairment in motor coordination or long-term memory after acute or chronic treatment with LTG was noted. Nevertheless, prolonged treatment aggravated toxicity of LTG assessed in the chimney test as TD50 value. Repeated administration of LTG significantly increased plasma and brain concentrations of the antiepileptic drug when compared to the control group (single drug application). In conclusion, anticonvulsant action of LTG in the maximal electroshock test in mice may change, depending on the length of therapy. Both acute and chronic protocols are necessary in preclinical assessment of the anticonvulsant effects of drugs and possible interactions between them. PMID- 25714973 TI - Protective Effect of Notoginsenoside R1 on an APP/PS1 Mouse Model of Alzheimer's Disease by Up-Regulating Insulin Degrading Enzyme and Inhibiting Abeta Accumulation. AB - Notoginsenoside R1 (NTR1) is the main active ingredient of the well-known traditional Chinese herbal medicine Panax notoginseng, the root of Panax notoginseng (Burk.) F. H. Chen. Studies demonstrated that NTR1 may have some neuronal protective effects. Alzheimer's disease (AD) is a neurodegenerative disease characterized by beta -amyloid protein (Abeta) deposition, neurofibrillary tangle formation and neuronal loss. This study was designed to explore the protective effect of NTR1 on an APP/PS1 double-transgenic mouse model of AD and investigate the possible mechanism. The 3-month-old mice were fed with 5 mg/(kg*d), 25 mg/(kg*d) NTR1 or vehicle via oral gavage for 3 months and changes in behavior, neuropathology, and amyloid pathology were investigated. The mice with NTR1 treatment showed significant amelioration in the cognitive function and increased choline acetyl transferase expression, as compared to the vehicle treated mice. NTR1 treatment inhibited Abeta accumulation and increased insulin degrading enzyme expression in both APP/PS1 mice and N2a-APP695sw cells, suggesting that of NTR1 may exert its protective effects through the enhancement of the Abeta degradation. Furthermore, our data showed that the increased level of peroxisome proliferator-activated receptor gamma (PPARgamma) and the up regulation of insulin degrading enzyme induced by NTR1 were inhibited by administration of GW9662 (a PPARgamma antagonist), indicating that the effect of NTR1 was mediated, at least in part, by PPARgamma. Thus, our findings provide the evidences that NTR1 has protective effect on AD mouse model and NTR1 may be a potential candidate for AD treatment. PMID- 25714974 TI - Neuropharmacological Aspects of Crocus sativus L.: A Review of Preclinical Studies and Ongoing Clinical Research. AB - Crocus sativus L. (Iridaceae) is an important member of the genus Crocus having high medicinal value. Its dried stigmas, known as "saffron" are being widely used form past many centuries as a food additive, coloring agent, flavoring agent and a potential source of traditional medicine. The stigmas along with other botanical parts of Crocus sativus are being extensively used in ethnomedical treatment of varied central nervous system diseases. In line with its ethnomedical importance, several preclinical studies have been carried out to validate its traditional uses, identify active principle(s), understand pharmacological basis of therapeutic action and explore novel medicinal uses. The bioactive components of Crocus sativus have been found to modulate several synaptic processes via direct/indirect interplay with neurotransmitter receptor functions, interaction with neuronal death/survival pathways and alteration in neuronal proteins expression. Many clinical studies proving beneficial effect of Crocus sativus in depressive disorders, Alzheimer's disease and some other neurological abnormalities have also been carried out. Based on the vast literature reports available, an attempt has been made to comprehend the fragmented information on neuropharmacological aspects, chemistry and safety of Crocus sativus. Although the plant has been well explored, but still a large scope of future preclinical and clinical research exist to explore its potential in neurological diseases, that has been discussed in depth in the present review. PMID- 25714975 TI - Cerebrovascular and blood-brain barrier morphology in spontaneously hypertensive rats: effect of treatment with choline alphoscerate. AB - Cholinergic precursors increasing choline availability and acetylcholine synthesis/release may represent a therapeutic approach for countering cognitive impairment occurring in adult-onset dementia disorders. Choline alphoscerate (alpha-gliceryl-phosphoryl-choline, GPC) is among cholinergic precursors the most effective in enhancing acetylcholine biosynthesis and release in animal models. This study was designed to assess if a long-term treatment with GPC modify cerebrovascular components [perivascular astrocytes, blood-brain barrier (BBB) and microvessels] and endothelial inflammatory markers expression in spontaneously hypertensive rats (SHR) used as a model of brain vascular injury. Male SHR aged 32 weeks and age-matched normotensive Wistar-Kyoto rats were treated for 4 weeks with GPC (150 mg/kg/day) or a vehicle. Intracerebral arteries of different brain areas, perivascular astrocytes, BBB and endothelial inflammatory markers were assessed by quantitative morphological and immunohistochemical techniques. No significant changes in the size of perivascular astrocytes were observed in SHR versus normotensive Wistar-Kyoto rats, whereas the expression of the BBB marker aquaporin-4 increased in SHR. This phenomenon was countered by GPC treatment. On the contrary, GPC has no vasodilator effect on brain micro-vessels. Endothelial markers and vascular adhesion molecules expression were not homogeneously affected by hypertension and GPC treatment in intracerebral vessels. The observation that treatment with GPC reversed BBB changes and countered to some extent micro-vessels changes occurring in SHR could explain data of clinical trials reporting an improvement of cognitive function in subjects suffering from cerebrovascular disorders and treated with GPC. These preclinical data suggest that the compound could have a cerebrovascular protective effect deserving a further characterization. PMID- 25714976 TI - TiO2-Nanowired Delivery of Mesenchymal Stem Cells Thwarts Diabetes- Induced Exacerbation of Brain Pathology in Heat Stroke: An Experimental Study in the Rat Using Morphological and Biochemical Approaches. AB - We have shown previously that heat stroke produced by whole body hyperthermia (WBH) for 4 h at 38 degrees C in diabetic rats exacerbates blood-brain barrier breakdown, brain edema formation and neuronal cell injury as compared to healthy animals after identical heat exposure. In this combination of diabetes and WBH, normal therapeutic measures do not induce sufficient neuroprotection. Thus, we investigated whether nanowired mesenchymal cells (MSCs) when delivered systemically may have better therapeutic effects on brain damage in diabetic rats after WBH. Diabetes induced by streptozotocin administration (75 mg/kg, i.p, daily for 3 days) in rats resulted in clinical symptoms of the disease within 4 to 6 weeks (blood glucose level 20 to 30 mmoles/l as compared to saline control groups (4 to 6 mmoles/l). When subjected to WBH, these diabetic rats showed a 4 to 6-fold exacerbation of blood-brain barrier breakdown to Evans blue and radioiodine, along with brain edema formation and neuronal cell injury. Intravenous administration of rat MSCs (1x10(6)) to diabetic rats one week before WBH slightly reduced brain pathology, whereas TiO2 nanowired MSCs administered in an identical manner resulted in almost complete neuroprotection. On the other hand, MSCs alone significantly reduced brain pathology in saline-treated rats after WBH. These observations indicate that nanowired delivery of stem cells has superior therapeutic potential in heat stroke with diabetes, pointing to novel clinical perspectives in the future. PMID- 25714977 TI - Fish oil prevents oxidative stress and exerts sustained antiamnesic effect after global cerebral ischemia. AB - Transient, global cerebral ischemia (TGCI) causes hippocampal/cortical damage and the persistent loss of welltrained, long-term memory (retrograde amnesia). Fish oil (FO), a rich source of omega-3 polyunsaturated fatty acids, abolishes such amnesia in the absence of neurohistological protection. The present study investigated whether FO prevents ischemia-induced oxidative stress and whether such an action contributes to the lasting effect of FO on memory recovery. In a first experiment, FO was administered for 4 days prior to ischemia, and antioxidant status was subsequently measured after 24 h of reperfusion. In another experiment, naive rats were trained in an eight-arm radial maze until they achieved asymptotic performance and then subjected to TGCI. One group of rats received FO as in the first experiment (i.e., 4 days prior to ischemia), whereas another group received FO for 4 days prior to ischemia plus 6 days postischemia. Retrograde memory performance was assessed 2-5 weeks after ischemia. TGCI depleted the level of antioxidant enzymes and increased the amount of protein carbonylation, indicating oxidative damage. Fish oil reversed oxidative damage to control levels. The same treatment that attenuated oxidative stress after 24 h of reperfusion also prevented retrograde amnesia assessed several weeks later. This antiamnesic effect afforded by short preischemia treatment was comparable to 10 days of treatment but not as consistent. These data indicate that an antioxidant action in the hyperacute phase of ischemia/reperfusion may contribute to the long-term, antiamnesic effect of FO. PMID- 25714978 TI - Inflammatory and cell death pathways in brain and peripheral blood in Parkinson's disease. AB - Evidence has been accumulated showing that inflammatory and cell death pathways are altered both in brain and periphery during Parkinson disease (PD). Neuronal loss in PD is associated with chronic neuroinflammation characterized by microglia activation through the release of reactive oxygen radicals, cytokines, and Prostaglandin E2. The release of these inflammatory mediators in addition to deprivation in growth factors and increase of calcium and dopamine seem implicated in triggering apoptosis. The interaction of leucine-rich repeat kinase and Fas- Associated protein with Death Domain has been implicated in the switching-on of the extrinsic apoptotic pathway via caspase-8 activation, while deficiency in PTEN induced putative kinase 1 has been shown to cause Ca2+ accumulation in mitochondria, increased generation of reactive oxygen species and intrinsic cell death. Autophagy/mitophagy appears to be impaired in the brain during PD; this impairment could be related to defective degradation of mutant alpha-synuclein and consequent apoptotic cell death. Regarding the peripheral blood, reduced amounts of dopamine, reduced levels of immunoreactivity for tyrosine hydroxylase and dopamine active transporter, and alterations of dopamine receptor expression have been detected in mononuclear cells from PD patients. In addition, mononuclear cells from PD patients show mitochondrial, ubiquitin proteasome system dysfunction and up-regulation of alpha-synuclein gene, associated to high expression of the Fas molecule, activation of caspase-3 and -9 and proneness to apoptosis. These and other observations reported in this mini review suggest that a better understanding of molecular dysfunctions in inflammatory and cell death/autophagy pathways, both in the brain and peripheral blood, could provide useful targets for future investigation on drug-discovery and biomarker identification in PD. PMID- 25714979 TI - The effect of acori graminei rhizoma and extract fractions on spatial memory and hippocampal neurogenesis in amyloid beta 1-42 injected mice. AB - Acori graminei Rhizoma (AGR), the dry rhizoma of Acorus gramineus Soland (Araceae), has been used as an Asian traditional herbal medicine against senile dementia, stroke, and cardiovascular disease. Previous studies have revealed neuroprotective effects of AGR on neuronal damage and learning impairment, while mostly focused on the effect of volatile oil fraction of AGR. This study aimed to investigate the neuroprotective effects of different extract fractions from AGR against Alzheimer disease-like symptoms induced by Amyloid Beta (Abeta) 1-42 intra-hippocampal injection. On day 7 after intra-hippocampal injection of saline or Abeta1-42, spatial memory was assessed by the first Morris water maze, followed by 3-week intra-gastric administration of saline or water extract, volatile oil fraction, or defatted decoction fraction of AGR respectively. Mice were subsequently subjected to the second Morris water maze task. Levels of Abeta1-42 and expressions of doublecortin and nestin in the hippocampus were examined using immunohistochemistry. Our results suggested that treatment with these different extract fractions from AGR could ameliorate cognitive impairment and down-regulate expressions of doublecortin and nestin in the hippocampus of Abeta1-42 injected mice, in which water extract and volatile oil fractions were more effective in spatial memory than defatted decoction fraction. PMID- 25714980 TI - Can topiramate induce pruritus? A case report and review of literature. AB - A 41-year-old woman with Major Depressive Disorder-Recurrent was treated with topiramate at 150 mg/day. After this administration, she developed intense pruritus and skin lesions due to scratching. Consequently, she was weaned off topiramate and the lesions regressed. Pruritus and cutaneous lesions are extremely rare side effects of topiramate, so we report an interesting case of skin reaction to this drug. PMID- 25714981 TI - Treatment of internet addiction in patient with panic disorder and obsessive compulsive disorder: a case report. AB - Problematic Internet use is a worldwide social issue and it can be found in any age, social, educational, or economic range. In some countries like China and South Korea internet addiction (IA) is considered a public health condition and this governments support research, education and treatment. Internet addiction has been associated with others psychiatric disorders. Panic disorder (PD) and Obsessive Compulsive Disorder (OCD) are anxiety disorders that involve a lot of damages in patient's life. We report a treatment of a patient with Panic Disorder and Obsessive Compulsive Disorder and internet addition involving pharmacotherapy and Cognitive Behavioral Therapy (CBT). The Cognitive Behavioral Therapy was conducted 1 time per week during 10 weeks and results suggest that the treatment was an effective treatment for the anxiety and for the internet addiction. PMID- 25714982 TI - Fluorescence-based detection of single-nucleotide changes in RNA using graphene oxide and DNAzyme. AB - We report a simple fluorometric method for detection of single-nucleotide changes in RNA using graphene oxide (GO) and RNA-cleaving DNAzyme. The fluorescent DNA probe (F-DNA) was annealed to RNA fragments generated by RNA cleavage with DNAzyme specific to mutant RNA. The F-DNA-RNA duplex attenuated the quenching of F-DNA fluorescence by GO. PMID- 25714984 TI - Frequency-dependent force fields for QMMM calculations. AB - We outline the construction of frequency-dependent polarizable force fields. The force fields are derived from analytic response theory for different frequencies using a generalization of the LoProp algorithm giving a decomposition of a molecular dynamical polarizability to localized atomic dynamical polarizabilities. These force fields can enter in a variety of applications - we focus on two such applications in this work: firstly, they can be incorporated in a physical, straightforward, way for current existing methods that use polarizable embeddings, and we can show, for the first time, the effect of the frequency dispersion within the classical environment of a quantum mechanics molecular mechanics (QMMM) method. Our methodology is here evaluated for some test cases comprising water clusters and organic residues. Secondly, together with a modified Silberstein-Applequist procedure for interacting inducible point dipoles, these frequency-dependent polarizable force fields can be used for a classical determination of frequency-dependent cluster polarizabilities. We evaluate this methodology by comparing with the corresponding results obtained from quantum mechanics or QMMM where the absolute mean [small alpha, Greek, macron] is determined with respect to the size of the QM and MM parts of the total system. PMID- 25714983 TI - IL-33 Enhances Humoral Immunity Against Chronic HBV Infection Through Activating CD4(+)CXCR5(+) TFH Cells. AB - This study aimed to investigate the potential effect of interleukin 33 (IL-33) on humoral responses to hepatitis B virus (HBV) and the possible mechanisms underlying the action of IL-33 in regulating follicular helper T (TFH) cells. The impact of IL-33 treatment on the levels of serum HBV DNA, HBsAg, HBeAg, HBsAb, and HBeAb, as well as the frequencies of CD4(+)CXCR5(+) TFH cells in wild-type HBV transgenic (HBV-Tg) mice and in a transwell coculture of HepG2.2.15 with IL 33-treated peripheral blood mononuclear cells (PBMCs) were determined. Furthermore, the gene transcription profiles in IL-33-treated TFH cells were determined by microarrays. IL-33 treatment significantly reduced the levels of serum HBV DNA, HBsAg, and HBeAg, but increased the levels of HBsAb and HBeAb in HBV-Tg mice, accompanied by increased frequency of splenic infiltrating CD4(+)CXCR5(+) TFH cells in HBV-Tg. Similarly, coculture of HepG2.2.15 cells with IL-33-treated PBMCs reduced the levels of HBV DNA, HBsAg, and HBeAg, but increased the levels of HBsAb and HBeAb. Microarray analyses indicated that IL-33 significantly modulated the transcription of many genes involved in regulating TFH activation and differentiation. Our findings suggest that IL-33 may activate TFH cells, promoting humoral responses to HBV during the pathogenic process. PMID- 25714985 TI - Quiltophagy--autophagy as folk art. AB - Over the years macroautophagy (hereafter autophagy) has been depicted artistically through painting, music, dance, videos, and poetry. A unifying idea behind these different aesthetic approaches is that people learn in different ways. Thus, some learners may be engaged by a detailed, but static, painting, whereas others may find insight through the dynamic visualization provided by a dance. While each of these formats has advantages, they also have a common weakness--whether delivered through watercolor on a canvas, words on a paper, or movement captured in a video, they are all 2-dimensional. Yet, some people are tactile learners. In this paper, a quilter describes a project she created with the goal of demonstrating autophagy using a 3-dimensional approach, in which different fiber textures could be used to elaborate certain parts of the process. PMID- 25714986 TI - A universal sensing platform based on the repair ligation-mediated light producing DNA machine. AB - The repair ligation-mediated light-producing DNA machine can produce light through transforming the repetitive DNA cleavage/ligation motions into optical energy without the requirement of either external reporting reagents or excitation light, and it can be applied for sensitive and selective detection of DNA, thrombin, adenosine, potassium ions (K(+)) and endonuclease even in human serum. PMID- 25714987 TI - Vaccine attitudes and practices among obstetric providers in New York State following the recommendation for pertussis vaccination during pregnancy. AB - To determine factors associated with obstetric provider recommendation of pertussis vaccine (Tdap) to their pregnant patients following the Advisory Committee on Immunization Practices (ACIP) recommendation that Tdap be given in the third trimester of each pregnancy. Obstetric providers across New York State anonymously completed a standard set of questions to assess vaccine recommendation knowledge and practice. STATISTICAL ANALYSIS: Descriptive statistical methods were used to define provider characteristics, knowledge and vaccine practices. Factors associated with recommendation were analyzed using odds ratios. 133 obstetric providers were included in the study. 11% and 13% expressed concern with pertussis vaccine safety and efficacy, respectively, in pregnant women. 92% of obstetric providers stated that they knew ACIP recommendations for Tdap during pregnancy, 80% recommended Tdap to all eligible patients, but only 67% provided Tdap vaccine in their office. Provider knowledge of recommendation (OR 23.33), routine provider recommendation of influenza vaccine (OR 12.5), and administration of pertussis vaccine in the office (OR 7.01) were all factors strongly associated with routine provider recommendation of Tdap vaccine to eligible pregnant women (P < 0.05). Providers expressed concerns with cost of Tdap, the need to administer Tdap with each pregnancy, vaccine safety, low incidence of pertussis in the area, and administration of pertussis vaccine at the hospital after delivery. Educational programs are needed to improve provider vaccine confidence and recommendation. PMID- 25714989 TI - Insights in peptide diffusion channels from the bacterial amyloid secretor CsgG. PMID- 25714988 TI - A theoretical justification for single molecule peptide sequencing. AB - The proteomes of cells, tissues, and organisms reflect active cellular processes and change continuously in response to intracellular and extracellular cues. Deep, quantitative profiling of the proteome, especially if combined with mRNA and metabolite measurements, should provide an unprecedented view of cell state, better revealing functions and interactions of cell components. Molecular diagnostics and biomarker discovery should benefit particularly from the accurate quantification of proteomes, since complex diseases like cancer change protein abundances and modifications. Currently, shotgun mass spectrometry is the primary technology for high-throughput protein identification and quantification; while powerful, it lacks high sensitivity and coverage. We draw parallels with next generation DNA sequencing and propose a strategy, termed fluorosequencing, for sequencing peptides in a complex protein sample at the level of single molecules. In the proposed approach, millions of individual fluorescently labeled peptides are visualized in parallel, monitoring changing patterns of fluorescence intensity as N-terminal amino acids are sequentially removed, and using the resulting fluorescence signatures (fluorosequences) to uniquely identify individual peptides. We introduce a theoretical foundation for fluorosequencing and, by using Monte Carlo computer simulations, we explore its feasibility, anticipate the most likely experimental errors, quantify their potential impact, and discuss the broad potential utility offered by a high-throughput peptide sequencing technology. PMID- 25714990 TI - Anti-VEGF Drugs in Eye Diseases: Local Therapy with Potential Systemic Effects. AB - Vascular endothelial growth factor (VEGF) is one of the main endogenous pro angiogenic cytokines. Inhibition of the VEGF signaling pathways is an effective treatment for cancer patients. In addition, local anti- VEGF therapy was developed and established to treat proliferative diabetic retinopathy, age related macular degeneration and retinal vein occlusion. For systemic administration of anti-VEGF drugs, serious side effects including hypertension or renal disorders have been observed. Evidence suggests that systemic effects might occur or develop in long-term treatment, despite limited resorption and minimal local side effects. Here, only limited data from clinical studies are available. The VEGF system is delicately balanced, and changes might result in deleterious effects. This review provides a brief overview of the VEGF-system, and summarizes its relevance in proliferative eye diseases. The anti-VEGF drugs locally used to treat different disease conditions are discussed with their local and systemic side effects. PMID- 25714991 TI - Combined imaging of oxidative stress and microscopic structure reveals new features in human atherosclerotic plaques. AB - Human atherosclerotic samples collected by carotid endarterectomy were investigated using electronic paramagnetic resonance imaging (EPRI) for visualization of reactive oxygen species, and nonlinear optical microscopy (NLOM) to study structural features. Regions of strong EPRI signal, indicating a higher concentration of reactive oxygen species and increased inflammation, were found to colocalize with regions dense in cholesterol crystals as revealed by NLOM. PMID- 25714992 TI - Enhanced resolution through thick tissue with structured illumination and adaptive optics. AB - Structured illumination microscopy provides twice the linear resolution of conventional fluorescence microscopy, but in thick samples, aberrations degrade the performance and limit the resolution. Here, we demonstrate structured illumination microscopy through 35 MUm of tissue using adaptive optics (AO) to correct aberrations resulting in images with a resolution of 140 nm. We report a 60% minimum improvement in the signal-to-noise ratio of the structured illumination reconstruction through thick tissue by correction with AO. PMID- 25714993 TI - Assessment of a government-subsidized supermarket in a high-need area on household food availability and children's dietary intakes. AB - OBJECTIVE: To assess the impact of a new government-subsidized supermarket in a high-need area on household food availability and dietary habits in children. DESIGN: A difference-in-difference study design was utilized. SETTING: Two neighbourhoods in the Bronx, New York City. Outcomes were collected in Morrisania, the target community where the new supermarket was opened, and Highbridge, the comparison community. SUBJECTS: Parents/caregivers of a child aged 3-10 years residing in Morrisania or Highbridge. Participants were recruited via street intercept at baseline (pre-supermarket opening) and at two follow-up periods (five weeks and one year post-supermarket opening). RESULTS: Analysis is based on 2172 street-intercept surveys and 363 dietary recalls from a sample of predominantly low-income minorities. While there were small, inconsistent changes over the time periods, there were no appreciable differences in availability of healthful or unhealthful foods at home, or in children's dietary intake as a result of the supermarket. CONCLUSIONS: The introduction of a government subsidized supermarket into an underserved neighbourhood in the Bronx did not result in significant changes in household food availability or children's dietary intake. Given the lack of healthful food options in underserved neighbourhoods and need for programmes that promote access, further research is needed to determine whether healthy food retail expansion, alone or with other strategies, can improve food choices of children and their families. PMID- 25714994 TI - Ziram and sodium N,N-dimethyldithiocarbamate inhibit ubiquitin activation through intracellular metal transport and increased oxidative stress in HEK293 cells. AB - Ubiquitin activating enzyme E1 plays a pivotal role in ubiquitin based protein signaling through regulating the initiating step of the cascade. Previous studies demonstrated that E1 is inhibited by covalent modification of reactive cysteines contained within the ubiquitin-binding groove and by conditions that increase oxidative stress and deplete cellular antioxidants. In this study, we determined the relative contribution of covalent adduction and oxidative stress to E1 inhibition produced by ziram and sodium N,N-dimethyldithiocarbamate (DMDC) in HEK293 cells. Although no dithiocarbamate-derived E1 adducts were identified on E1 using shotgun LC/MS/MS for either ziram or DMDC, both dithiocarbamates significantly decreased E1 activity, with ziram demonstrating greater potency. Ziram increased intracellular levels of zinc and copper, DMDC increased intracellular levels of only copper, and both dithiocarbamates enhanced oxidative injury evidenced by elevated levels of protein carbonyls and expression of heme oxygenase-1. To assess the contribution of intracellular copper transport to E1 inhibition, coincubations were performed with the copper chelator triethylenetetramine hydrochloride (TET). TET significantly protected E1 activity for both of the dithiocarbamates and decreased the associated oxidative injury in HEK293 cells as well as prevented dithiocarbamate-mediated lipid peroxidation assayed using an ethyl aracidonate micelle system. Because TET did not completely ameliorate intracellular transport of copper or zinc for ziram, TET apparently maintained E1 activity through its ability to diminish dithiocarbamate-mediated oxidative stress. Experiments to determine the relative contribution of elevated intracellular zinc and copper were performed using a metal free incubation system and showed that increases in either metal were sufficient to inhibit E1. To evaluate the utility of the HEK293 in vitro system for screening environmental agents, a series of additional pesticides and metals was assayed, and eight agents that produced a significant decrease and five that produced a significant increase in activated E1 were identified. These studies suggest that E1 is a sensitive redox sensor that can be modulated by exposure to environmental agents and can regulate downstream cellular processes. PMID- 25714995 TI - Validation of the fully automated Pangao PG-800B68 upper-arm device according to the European Society of Hypertension International Protocol revision 2010. AB - OBJECTIVE: This study aimed to validate the fully automated Pangao PG-800B68 upper-arm device according to the European Society of Hypertension International Protocol (ESH-IP) revision 2010. MATERIALS AND METHODS: Sequential measurements of systolic blood pressure (SBP) and diastolic blood pressure (DBP) were obtained in 33 participants using the standard mercury sphygmomanometer and the test device. The ESH-IP revision 2010 was followed precisely and 99 pairings of test device and reference blood pressure measurements were obtained for analysis. RESULTS: The number of blood pressure differences within 5, 10, and 15 mmHg was 76, 95, and 98, respectively, for SBP and 79, 96, and 99, respectively, for DBP. The device achieved all the required criteria of the ESH-IP revision 2010 with a device-observer difference of -0.03+/-4.64 mmHg for SBP and -0.64+/-4.50 mmHg for DBP. CONCLUSION: According to the validation results on the basis of the ESH-IP revision 2010, the Pangao PG-800B68 can be recommended for clinical use and self measurement in adults. PMID- 25714997 TI - The legacy of anatomical donation. PMID- 25714996 TI - Gprc5a-deficiency confers susceptibility to endotoxin-induced acute lung injury via NF-kappaB pathway. AB - Susceptibility to acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) varies greatly among patients in sepsis/septic shock. The genetic and biochemical reasons for the difference are not fully understood. G protein coupled receptor family C group 5 member A (GPRC5A), a retinoic acid target gene, is predominately expressed in the bronchioalveolar epithelium of lung. We hypothesized that Gprc5a is important in controlling the susceptibility to ALI or ARDS. In this study, we examined the susceptibility of wild-type and Gprc5a knockout (ko) mice to induced ALI. Administration of endotoxin LPS induced an increased pulmonary edema and injury in Gprc5a-ko mice, compared to wild-type counterparts. Consistently, LPS administration induced higher levels of inflammatory cytokines (IL-1beta and TNFalpha) and chemokine (KC) in Gprc5a-ko mouse lungs than in wild-type. The enhanced pulmonary inflammatory responses were associated with dysregulated NF-kappaB signaling in the bronchioalveolar epithelium of Gprc5a-ko mouse lungs. Importantly, selective inhibition of NF kappaB through expression of the super-repressor IkappaBalpha in the bronchioalveolar epithelium of Gprc5a-ko mouse lungs alleviated the LPS-induced pulmonary injury, and inflammatory response. Thus, Gprc5a is critical for lung homeostasis, and Gprc5a deficiency confers the susceptibility to endotoxin induced pulmonary edema and injury, mainly through NF-kappaB signaling in bronchioalveolar epithelium of lung. PMID- 25714998 TI - Reliability of a Noninvasive Measure of V./Q. Mismatch for Bronchopulmonary Dysplasia. AB - RATIONALE: Currently used definitions of bronchopulmonary dysplasia (BPD) lack a continuous measure of disease severity. OBJECTIVES: To determine if an indirect measure of V./Q. mismatch is reliable when simplified to facilitate more widespread use for grading disease severity in BPD at 36 weeks postmenstrual age. METHODS: We used prospectively collected data from 32 preterm infants undergoing an oxygen reduction test at 36 weeks postmenstrual age to perform a simplified indirect assessment of V./Q. mismatch for each infant. Independent raters applied the model, and interrater reliability for a quantitative measure of mismatch was measured by intraclass correlation coefficient. A receiver operating characteristic curve evaluated the impact of increasing degrees of V./Q. mismatch on diagnosing BPD as defined by oxygen reduction test failure. MEASUREMENTS AND MAIN RESULTS: Concordance for the quantitative measure of V./Q. mismatch between independent raters improved from 0.72 (confidence interval [CI], 0.48-0.86) to 0.93 (CI, 0.87-0.96) after refinement of instructions for applying the simplified model. Higher degrees of mismatch were increasingly predictive of oxygen reduction test failure, with a receiver operating characteristic curve analysis area under the curve of 0.83 (CI, 0.68-0.99; P = 0.03). CONCLUSIONS: A simplified indirect measure of V./Q. mismatch for diagnosing and grading disease severity in BPD has high reliability and can be performed with data obtained during a standard oxygen reduction test. This should facilitate more widespread investigation of this model as a technique for characterizing BPD severity. PMID- 25715000 TI - Erratum: Crystal structure of (E)-N-(3,4-di-meth-oxy-benzyl-idene)morpholin-4 amine. Corrigendum. AB - The list of authors in the paper by Celikesir et al. [Acta Cryst. (2014), E70, o935] is corrected.[This corrects the article DOI: 10.1107/S160053681401678X.]. PMID- 25715001 TI - Inside the tumor: p53 modulates calcium homeostasis. PMID- 25714999 TI - Integrative analysis of circadian transcriptome and metabolic network reveals the role of de novo purine synthesis in circadian control of cell cycle. AB - Metabolism is the major output of the circadian clock in many organisms. We developed a computational method to integrate both circadian gene expression and metabolic network. Applying this method to zebrafish circadian transcriptome, we have identified large clusters of metabolic genes containing mostly genes in purine and pyrimidine metabolism in the metabolic network showing similar circadian phases. Our metabolomics analysis found that the level of inosine 5' monophosphate (IMP), an intermediate metabolite in de novo purine synthesis, showed significant circadian oscillation in larval zebrafish. We focused on IMP dehydrogenase (impdh), a rate-limiting enzyme in de novo purine synthesis, with three circadian oscillating gene homologs: impdh1a, impdh1b and impdh2. Functional analysis revealed that impdh2 contributes to the daily rhythm of S phase in the cell cycle while impdh1a contributes to ocular development and pigment synthesis. The three zebrafish homologs of impdh are likely regulated by different circadian transcription factors. We propose that the circadian regulation of de novo purine synthesis that supplies crucial building blocks for DNA replication is an important mechanism conferring circadian rhythmicity on the cell cycle. Our method is widely applicable to study the impact of circadian transcriptome on metabolism in complex organisms. PMID- 25715002 TI - Knowledge bases, clinical decision support systems, and rapid learning in oncology. AB - One of the most important benefits of health information technology is to assist the cognitive process of the human mind in the face of vast amounts of health data, limited time for decision making, and the complexity of the patient with cancer. Clinical decision support tools are frequently cited as a technologic solution to this problem, but to date useful clinical decision support systems (CDSS) have been limited in utility and implementation. This article describes three unique sources of health data that underlie fundamentally different types of knowledge bases which feed into CDSS. CDSS themselves comprise a variety of models which are discussed. The relationship of knowledge bases and CDSS to rapid learning health systems design is critical as CDSS are essential drivers of rapid learning in clinical care. PMID- 25715003 TI - Factors affecting uptake of recommended immunizations among health care workers in South Australia. AB - Despite the benefits of vaccination for health care workers (HCWs), uptake of recommended vaccinations is low, particularly for seasonal influenza and pertussis. In addition, there is variation in uptake within hospitals. While all vaccinations recommended for HCWs are important, vaccination against influenza and pertussis are particularly imperative, given HCWs are at risk of occupationally acquired influenza and pertussis, and may be asymptomatic, acting as a reservoir to vulnerable patients in their care. This study aimed to determine predictors of uptake of these vaccinations and explore the reasons for variation in uptake by HCWs working in different hospital wards. HCWs from wards with high and low influenza vaccine uptake in a tertiary pediatric and obstetric hospital completed a questionnaire to assess knowledge of HCW recommended immunizations. Multiple logistic regression was used to determine predictors of influenza and pertussis vaccination uptake. Of 92 HCWs who responded, 9.8% were able to identify correctly the vaccines recommended for HCWs. Overall 80% of respondents reported they had previously received influenza vaccine and 50.5% had received pertussis vaccine. Independent predictors of pertussis vaccination included length of time employed in health sector (P < 0.001), previously receiving hepatitis B/MMR (measles, mumps, rubella) vaccine (P < 0.001), and a respondent being aware influenza infections could be severe in infants (p = 0.023). Independent predictors of seasonal influenza vaccination included younger age (P < 0.001), English as first language (P < 0.001), considering it important to be vaccinated to protect themselves (P < 0.001), protect patients (p = 0.012) or awareness influenza could be serious in immunocompromised patients (p = 0.030). Independent predictors for receiving both influenza and pertussis vaccinations included younger age (P < 0.001), time in area of work (P = 0.020), previously receiving hepatitis B vaccine (P = 0.006) and awareness influenza could be severe in infants (P < 0.001). A knowledge gap exists around HCW awareness of vaccination recommendations. Assessment of the risk/benefit value for HCWs and their patients, determines uptake of HCW immunization programs and should be considered in promotional HCW vaccination programs. PMID- 25715004 TI - Latanoprost-induced Cytokine and Chemokine Release From Human Tenon's Capsule Fibroblasts: Role of MAPK and NF-kappaB Signaling Pathways. AB - PURPOSE: Long-term topical antiglaucoma therapy is considered a significant risk factor for failure of trabeculectomy. We investigated the effects of antiglaucoma drugs on proinflammatory cytokine and chemokine release from cultured human Tenon's capsule fibroblasts (HTFs) as well as the signaling pathways that underlie such effects. MATERIALS AND METHODS: Release of the proinflammatory cytokine interleukin (IL)-6 and the chemokines IL-8 and monocyte chemotactic protein (MCP)-1 was measured with enzyme-linked immunosorbent assays. The phosphorylation (activation) of mitogen-activated protein kinases (MAPKs) as well as the phosphorylation and degradation of the nuclear factor-kappaB (NF-kappaB) inhibitor IkappaB-alpha were assessed by immunoblot analysis. RESULTS: Latanoprost stimulated the release of IL-6, IL-8, and MCP-1 from HTFs in a concentration-dependent and time-dependent manner, whereas timolol maleate and pilocarpine had no such effects. Latanoprost also activated the MAPKs extracellular signal-regulated kinase, p38, and c-Jun NH2-terminal kinase as well as induced the phosphorylation and degradation of IkappaB-alpha in these cells. The latanoprost-induced release of IL-6, IL-8, and MCP-1 was attenuated by inhibitors of MAPK (PD98059, SB203580, or JNK inhibitor II) or NF-kappaB (IkappaB kinase 2 inhibitor) signaling pathways. CONCLUSIONS: Latanoprost induced proinflammatory cytokine and chemokine release from HTFs in a manner dependent on MAPK and NF-kappaB signaling. These effects of latanoprost might influence bleb scarring after filtration surgery. PMID- 25715005 TI - Trabeculectomy in Patients With Glaucoma Over 80 Years of Age: Relatively Short term Outcomes. AB - PURPOSE: To compare the surgical outcomes of trabeculectomy performed in elderly patients (above 80 y) with those of younger controls. MATERIALS AND METHODS: We retrospectively reviewed the charts of patients who underwent trabeculectomy from January 1, 2009 through April 30, 2011 at the Wills Eye Hospital. Patients over 80 years of age were compared with younger controls. Outcome measures included intraocular pressure (IOP), visual acuity, number of glaucoma medications, surgical complications, and surgical failure. Surgical failure was defined as when IOP>21 mm Hg or <20% reduction below baseline or IOP<5 mm Hg or reoperation for glaucoma, or loss of light perception. RESULTS: Eighty-six eyes of patients over 80 years of age (range, 81 to 94 y) were compared with 86 eyes of younger controls (range, 22 to 79 y). Mean follow-up time was 23.9+/-8.0 and 25.1+/-8.0 months for each group, respectively. After 1 year, the failure rate was 31.3% in the elderly group, compared with 29.5% in the control group (P=0.98). At last follow-up visit, the rate of failure between the groups was similar (P=0.35). Postoperative complications were similar between the groups (P=0.25). CONCLUSIONS: The surgical outcomes of trabeculectomy in patients older than 80 years were found to be similar to those of younger controls. Taking into consideration elderly glaucoma patients' general health condition and life expectancy, age alone may not be a barrier to performing glaucoma filtration surgery. PMID- 25715006 TI - Circumcision and autism. PMID- 25715007 TI - Reaching a new milestone. PMID- 25715008 TI - Letter to the editor. PMID- 25715009 TI - Physician assistant students' attitudes towards a clinical doctoral degree. AB - PURPOSE: The introduction of clinical doctorate degrees in several health professions has fueled the debate about an entry-level clinical doctorate in the physician assistant profession. However, there is limited knowledge of the attitudes of physician assistant students toward obtaining a clinical doctorate. METHODS: All 147 accredited physician assistant programs in the United States were invited to participate in a Web-based survey conducted in January 2010; physician assistant students in any program year were eligible to participate. The survey examined physician assistant students' attitudes towards (a) enrolling in a clinical doctorate program, (b) additional schooling time, (c) monetary costs, and (d) perceived benefits of a clinical doctorate. Chi-square tests were conducted to examine differences in survey item responses and composite variables. RESULTS: From 37 states and 53 physician assistant programs, 1815 physician assistant students completed the survey and 1658 were included in this analysis. Nearly half (49.8%) of the responding physician assistant students overall had a positive attitude toward a clinical doctorate degree. More respondents favored than opposed enrolling in a clinical doctorate program if schooling time were an additional 12 months or less (55.5% vs 29.9%, P < .0001) and additional costs were between 20% and 29% of current expenditure (44.8% vs 36.4%, P < .0001). More than half (56.2%) of the physician assistant students considered perceived benefits (composite variable) as a reason to obtain a clinical doctorate. CONCLUSIONS: This large study comprising more than one-third of physician assistant programs and representing 80% of the US states with physician assistant programs finds that physician assistant students' interest in enrolling in a clinical doctorate program may be dependent on additional school time and monetary costs. PMID- 25715010 TI - Development and initial validation of a measure of intention to stay in academia for physician assistant faculty. AB - PURPOSE: The purpose of this research was to construct and validate a measure of "intention to stay in academia" for physician assistant faculty members. METHODS: The 70-item instrument was developed through a literature review, a qualitative investigation of how experienced physician assistant faculty members conceptualized "intention to stay in academia," and an expert review of survey items. The items were pilot tested on a convenience sample of 53 faculty members from 9 physician assistant programs; the revised survey was then administered to all 1002 physician assistant program faculty members in the United States with physician assistant credentials. Rasch analyses were conducted to examine psychometric properties of the measure and collect evidence of validity. RESULTS: The national survey had a 48% response rate, and participants were representative of all physician assistant faculty members. Although the overall instrument demonstrated acceptable construct coverage, good reliability estimates, and adequate fit statistics for the majority of the items, only 36.5% of the variance in the data could be explained by the measure. A subset of 19 items relating to a supportive academic environment ("Supportive Environment" scale) was extracted and met the expectations of the Rasch model. CONCLUSIONS: The Supportive Environment scale produced a meaningful progression of indicators of "intention to stay in academia" for physician assistant faculty members and demonstrated characteristics of a linear measure. Administrators can make valid inferences regarding physician assistant faculty intention to stay from the subscale analysis. PMID- 25715011 TI - Strategies and perceived barriers to recruitment of underrepresented minority students in physician assistant programs. AB - PURPOSE: The purpose of this descriptive cross-sectional study was to identify the characteristics and effectiveness of recruitment strategies for underrepresented minorities (URM) and barriers to URM applicants to physician assistant programs. METHODS: A 108-question survey was e-mailed to 168 physician assistant programs; 36 partial and 67 fully completed surveys were returned. The fully completed surveys were used in the data analysis. Participants were asked about the use of 20 recruitment strategies and the importance of 34 perceived barriers to enrollment of URM applicants. RESULTS: Of the 20 recruitment strategies, only 4 were used by close to 50% or more of programs: site visits (61.2%), preadmission counseling (58.2%), student loans (57.6%), and presentations targeted to minority students (47.8%). Only 9% of programs used enrichment courses, but this strategy was rated as most effective. Of the 34 barriers, the most frequent was low undergraduate grade point average (GPA) (82.5%). Self-reported success in recruitment was correlated with increased URM matriculation. Higher proportion of African American and Hispanic faculty on admissions committees was correlated with increased rates of URM matriculation. According to a similar survey, compared with medical schools, physician assistant programs use URM recruitment strategies less frequently and perceive financial barriers as a larger problem. CONCLUSIONS: The academically competitive physician assistant applicant pool decreases the need for recruitment of all students. Use of GPA and standardized test scores as sole criteria for admission and lack of recruitment of URM students lead to a decrease in diversity. If the physician assistant profession desires to improve student diversity in programs, they should consider using a more holistic approach for the admission process, which may allow for a more flexible and individualized review of applicants. PMID- 25715012 TI - Physician assistant program outreach to military service members as potential applicants. AB - Recent efforts to facilitate the career pathway for military veterans into the physician assistant profession include outreach to current service members that will make information about physician assistant education more readily accessible. This research article reviews several topics that physician assistant programs would need to consider before conducting outreach to this population and discusses methods for outreach activities. Physician assistant programs may choose to apply similar approaches as appropriate for their individual circumstances. Outcomes will be evaluated separately. PMID- 25715013 TI - A survey of knowledge and practices regarding prevention of unintended pregnancies. AB - PURPOSE: The purpose of this study was to identify the gaps in Kansas physician assistant practices and knowledge regarding prevention of unintended pregnancies with the aim of reducing the unintended pregnancy rate. METHODS: A survey targeting all licensed physician assistants in Kansas (N = 733) was developed based on a literature review of contraceptive behaviors, unintended pregnancy data, and providers' practices. RESULTS: The response rate was 22%. Most knowledge questions were answered incorrectly, with almost 60% of respondents underestimating the percent of both unintended pregnancies and abortions resulting from them. Eighty percent did not know that abstinence among teenagers is increasing. An average of only 28% of respondents frequently counseled teens to get contraception before their first intercourse, and counseling about highly effective reversible contraception beyond oral contraceptives was limited. Only 13% reported having been trained in intrauterine device (IUD) insertion. Of the physician assistant respondents who prescribe oral contraceptives, 42% reported ordering a 1-month supply for patients, despite risk of usage gaps. CONCLUSIONS: Areas where Kansas physician assistants could improve were identified. Increased counseling of teenagers about (a) highly effective methods of contraception and (b) contraception before their first intercourse is recommended. Training physician assistants in IUD insertion and prescribing oral contraceptives to dispense multiple months at once could result in fewer unintended pregnancies. PMID- 25715014 TI - Preceptors' and physician assistant students' views about the value of clinical site visits. AB - PURPOSE: To determine preceptor and student views about the value of clinical site visits. METHODS: An online survey of preceptors and students was conducted after completion of 1-year clerkships, during which each student received 2 visits from program faculty. An 11-question Likert scale (1 = strongly disagree, 5 = strongly agree) survey was administered to preceptors and students. Analysis was by descriptive statistics (percentage, mean +/- SD) and theme extraction. RESULTS: Response rate was 70% for preceptors and 77% for students. A majority of both groups agreed or strongly agreed that site visits met a need for clarifying the role of the clerkship, addressed expectations, and improved clinical experience; that visits were important, added value to education, and improved communication with the program. Visits increased preceptor self-reported confidence in faculty. Preceptor themes included "face-to-face validation," "personal touch," and "hands-on interaction." Student themes included "value of direct feedback from site visitor," "ability to improve skills between visits," and "connectedness to program." CONCLUSION: Preceptors and students agreed on the importance and value of site visits for improving communication, clinical skills, and quality of educational experience. PMID- 25715015 TI - Introduction of an interprofessional oral health curriculum. AB - PURPOSE: Physician assistants can incorporate a variety of oral health services into their practices, but many physician assistant programs do not dedicate adequate time to oral health education. Our goal was to develop a novel and interprofessional oral health education curriculum model for our physician assistant students that could be adopted by other physician assistant programs and dental schools in the United States. METHODS: Curricula were created collaboratively and taught by dental school faculty with a focus on the primary care setting. Prewritten and postwritten tests were administered along with a clinical skills examination. Student and faculty evaluations were administered for pedagogical evaluation. RESULTS: Pretests and posttests demonstrated a 25% increase in knowledge acquisition (paired t test: P < .001). Physical examination skills testing achieved a 95% completion rate. Student and faculty evaluations demonstrated high satisfaction rates with the curricula delivery. CONCLUSIONS: Initial evaluation of this novel interprofessional curriculum for physician assistant students demonstrates that it was successful. It was well-received by the students and the faculty members and resulted in measurable knowledge acquisition. This model could feasibly be reproduced in other institutions for oral health education. PMID- 25715016 TI - International clinical rotations and the duty to warn. PMID- 25715017 TI - A review of conveying confident conclusions: p values, confidence intervals, and forest plots. PMID- 25715018 TI - Human resources for health: a needs assessment of the Nepal health assistant - a physician assistant analogue? PMID- 25715019 TI - Stethoscope versus point-of-care ultrasound in the differential diagnosis of dyspnea: a randomized trial. AB - We aimed to determine the accuracies of point-of-care ultrasound (PoCUS) and stethoscopes as part of the physical examinations of patients with dyspnea. Three emergency medicine specialists in each of two groups of ultrasound and stethoscope performers underwent didactic and hands-on training on PoCUS and stethoscope usage. All the patients enrolled were randomized to one of two predetermined PoCUS or stethoscope groups. The diagnostic performance of ultrasonography was higher than that of the stethoscope in the diagnoses of heart failure (90 vs. 86%, 1.00 vs. 0.89, and 5.00 vs. 4.92, respectively) and pneumonia (90 vs. 86.7%, 0.75 vs. 0.73, and 16.50 vs. 13.82, respectively). No significant differences were observed in the utility parameters of these modalities in these diagnoses. Although some authors argue that it is time to abandon the 'archaic tools' of past centuries, we believe that it is too early to discontinue the use of the stethoscope. PMID- 25715020 TI - Education, exposure and experience of prehospital teams as quality indicators in regional trauma systems. AB - OBJECTIVE: Indicators to measure the quality of trauma care may be instrumental in benchmarking and improving trauma systems. This retrospective, observational study investigated whether data on three indicators for competencies of Dutch trauma teams (i.e. education, exposure, experience; agreed upon during a prior Delphi procedure) can be retrieved from existing registrations. The validity and distinctive power of these indicators were explored by analysing available data in four regions. METHODS: Data of all polytrauma patients treated by the Helicopter Emergency Medical Services were collected retrospectively over a 1 year period. During the Delphi procedure, a polytrauma patient was defined as one with a Glasgow Coma Scale of 9 or less or a Paediatric Coma Scale of 9 or less, together with a Revised Trauma Score of 10 or less. Information on education, exposure and experience of the Helicopter Emergency Medical Services physician and nurse were registered for each patient contact. RESULTS: Data on 442 polytrauma patients could be retrieved. Of these, according to the Delphi consensus, 220 were treated by a fully competent team (i.e. both the physician and the nurse fulfilled the three indicators for competency) and 22 patients were treated by a team not fulfilling all three indicators for competency. Across the four regions, patients were treated by teams with significant differences in competencies (P=0.002). CONCLUSION: The quality indicators of education, exposure and experience of prehospital physicians and nurses can be measured reliably, have a high level of usability and have distinctive power. PMID- 25715021 TI - A quantitative tool for measuring the quality of medical training in emergency medicine. AB - The most common method of assessing the quality of medical education is through a selection of qualitative assessments, usually as part of a programme evaluation. Common qualitative assessments include measurements of students' and teachers' participation, outcome measures such as assessment results, and qualitative assessments such as interviews and questionnaires of students and teachers. Programme evaluation can therefore be a process that is both laborious and subject to accusations of a lack of objectivity. As a result, the development of a quantitative tool that could be used alongside a programme evaluation may be both useful and desirable. A pragmatic scoring system, utilizing routinely collected quantitative data, termed as the Quality Assessment Tool, was developed during the 2013 academic year within the setting of an Emergency Medicine training programme in the UK. This tool was tested against the standard assessment currently used for this programme to establish whether the quantitative tool correlated with the programme evaluation. Second, the individual items within the tool were investigated to identify any correlations with the current assessment of quality established by the programme evaluation. The Quality Assessment Tool appears to be correlated to the quality of training delivered at individual training sites in a single specialty. It certainly identifies those centres delivering the highest quality of training and also identifies those centres whose training is consistently of a lower standard. The assessment tool is less accurate at ranking those training centres whose training is merely 'satisfactory'; whether this is a result of the imprecision of the tool itself or a reflection of the subjective nature of the current assessment (i.e. whether the current evaluation system lacks validity) cannot be stated. In summary, it appears to be possible to use a single quantitative tool to reliably, and with validity, measure the quality of training delivered at a postgraduate medical training centre. Although it is not envisaged that this would, or should, replace ongoing quality assurance systems such as programme evaluations, a validated tool can be derived for a given setting to usefully inform and augment current quality management systems in postgraduate medical education. PMID- 25715022 TI - Comparison of airway management techniques for different access in a simulated motor vehicle entrapment scenario. AB - BACKGROUND: Emergency airway management can be particularly challenging in patients entrapped in crashed cars because of limited access. The aim of this study was to analyse the feasibility of four different airway devices in various standardized settings utilized by paramedics and emergency physicians. METHODS: Twenty-five paramedics and 25 emergency physicians were asked to perform advanced airway management in a manikin entrapped in a car's left front seat, with access to the patient through the opened driver's door or access from the back seat. Available airway devices included Macintosh and Airtraq laryngoscopes, as well as laryngeal mask airway (LMA) Supreme and the Laryngeal Tube. The primary endpoints were successful placement, along with attempts needed to do so, and time for successful placement. The secondary endpoints included Cormack-Lehane grades and rating of the difficulty of the technique with the different devices. RESULTS: The overall intubation and placement success rates were equal for the Macintosh and Airtraq laryngoscopes as well as the LMA Supreme and Laryngeal Tube, with access from the back seat being superior in terms of placement time and ease of use. Supraglottic airway devices required half of the placement time and were easier to use compared with endotracheal tubes (with placement times almost >30 s). Paramedics and emergency physicians achieved equal overall successful placement rates for all devices. CONCLUSION: Both scenarios of securing the airway seem suitable in this manikin study, with access from the back seat being superior. Although all airway devices were applicable by both groups, paramedics and emergency physicians, supraglottic device placement was faster and always possible at the first attempt. Therefore, the LMA Supreme and the Laryngeal Tube are attractive alternatives for airway management in this context if endotracheal tube placement fails. Furthermore, supraglottic device placement, while the patient is still in the vehicle, followed by a definitive airway once the patient is extricated would be a worthwhile alternative course of action. PMID- 25715023 TI - Bradykinin-mediated angioedema: factors associated with admission to an intensive care unit, a multicenter study. AB - OBJECTIVE: Bradykinin-mediated angioedema is characterized by transient attacks of localized edema of subcutaneous or submucosal tissues and can be life threatening when involving the upper airways. The aim of this study was to determine the features of acute attacks that might be associated with admission to an ICU. PATIENTS AND METHODS: We carried out a retrospective, multicenter, observational study in consecutive patients attending one of six reference centers in France for acute bradykinin-mediated angioedema attacks. Patients had been hospitalized for an acute episode at least once previously. Acute attacks requiring ICU admission were compared with acute attacks that had not required ICU admission. RESULTS: Overall, 118 acute attacks in 31 patients were analyzed (10 patients with hereditary angioedema, 19 patients with angiotensin-converting enzyme inhibitor-induced angioedema, and two patients with acquired C1-inhibitor deficiency angioedema). In multivariate analysis, upper airway involvement, corticosteroid, and C1-inhibitor concentrate administration were associated with ICU admission. Seven episodes (18%) needed airway protection. The evolution was favorable in 38 of 39 attacks warranting ICU admission: patients were able to get out of the service (mean ICU stay 4+/-5 days). One death was observed by asphyxiation because of laryngeal swelling. CONCLUSION: Upper airway involvement is an independent risk factor for ICU admission. Corticosteroid use, which is an ineffective treatment, and C1-inhibitor concentrate use are factors for ICU admission. The presence of upper airway involvement should be a warning signal that the attack may be severe. PMID- 25715024 TI - Combination therapy with intravitreal bevacizumab and macular grid and scatter laser photocoagulation in patients with macular edema secondary to branch retinal vein occlusion. AB - PURPOSE: To assess the efficacy of combined intravitreal bevacizumab (IVB) and macular grid and scatter laser photocoagulation in the treatment of macular edema secondary to branch retinal vein occlusion (BRVO) over a 12-month period. METHODS: A prospective, interventional case series study was conducted in 20 patients. Patients were treated with 3 monthly IVB injections, followed by macular grid laser and scatter laser photocoagulation to nonperfused ischemic retina. Repeated IVB injections were performed on an as-needed basis when patients had recurrent macular edema. RESULTS: The best-corrected visual acuity of 20/40 or better was achieved in 17 eyes (85%) and a vision gain of 3 lines or more was noted in 12/20 eyes (60%). Mean visual acuity improved from 0.68 logMAR at baseline to 0.28 logMAR at 3 months, 0.26 logMAR at 6 months, and 0.26 logMAR at 12 months (P<0.01). The mean central macular thickness (CMT) was 442 MUm at baseline and decreased to 266, 264, 300, and 294 MUm at 1, 3, 6, and 12 months' follow-up, respectively (P<0.01). A mild rebound CMT increase was noted at 6 months, which was reduced after bevacizumab reinjection. Ten patients (50%) required repeated IVB injections. Fifteen eyes (75%) have complete edema resolution on optical coherence tomography scan at the 12-month return visit. Overall, patients received an average of 4 injections during the 12-month period. No adverse ocular or systemic events were observed following injections. CONCLUSIONS: Early IVB injections in combination with subsequent macular grid and scatter laser photocoagulation treatment significantly improved vision and reduced macular edema secondary to BRVO. Further studies are warranted to evaluate the long-term outcomes and safety. PMID- 25715025 TI - Word knowledge in the crowd: Measuring vocabulary size and word prevalence in a massive online experiment. AB - We use the results of a large online experiment on word knowledge in Dutch to investigate variables influencing vocabulary size in a large population and to examine the effect of word prevalence-the percentage of a population knowing a word-as a measure of word occurrence. Nearly 300,000 participants were presented with about 70 word stimuli (selected from a list of 53,000 words) in an adapted lexical decision task. We identify age, education, and multilingualism as the most important factors influencing vocabulary size. The results suggest that the accumulation of vocabulary throughout life and in multiple languages mirrors the logarithmic growth of number of types with number of tokens observed in text corpora (Herdan's law). Moreover, the vocabulary that multilinguals acquire in related languages seems to increase their first language (L1) vocabulary size and outweighs the loss caused by decreased exposure to L1. In addition, we show that corpus word frequency and prevalence are complementary measures of word occurrence covering a broad range of language experiences. Prevalence is shown to be the strongest independent predictor of word processing times in the Dutch Lexicon Project, making it an important variable for psycholinguistic research. PMID- 25715027 TI - Epidemiological factors involved in the development of bronchopulmonary dysplasia in very low birth-weight preterm infants. AB - BACKGROUND: In spite of the advances made in perinatal medicine, the incidence of bronchopulmonary dysplasia (BPD) has not decreased and the aetiopathogenesis of the "new" BPD is still a matter for debate. The objectives of the present study were to analyse the epidemiological factors and morbidity associated with the development of BPD in a cohort of very low birth-weight (VLBW) preterm infants. METHODS: This retrospective observational study included all the preterm infants with birth weight <=1500 g who were admitted to a tertiary-level hospital NICU from 2008 to 2011. A neurological follow-up was also carried out during the first two years of life. RESULTS: A total of 140 VLBW infants were analyzed: 28.4% presented oxygen dependence at 28 days, and 17.2% at 36 weeks adjusted gestational age. Predictive factors for the development of BPD were gestational age, birth weight, number of days of parenteral nutrition, number of days to achieve full enteral feeding, number of transfusions, duration of respiratory support and insulin administration, vasoactive drugs, diuretics, sedoanalgesia and postnatal corticosteroids. The neonatal morbidity associated with the development of BPD was late neonatal sepsis, patent ductus arteriosus, retinopathy of prematurity (ROP) and intraventricular hemorrhage. Non-significant associations with neurodevelopmental impairment were observed. CONCLUSIONS: Predictive factors for the development of BPD were respiratory support, feeding and different types of medication. Moreover, patients with BPD had a higher associated morbidity than those who did not develop BPD. PMID- 25715026 TI - Increased expression of HIF2alpha during iron deficiency-associated megakaryocytic differentiation. AB - BACKGROUND: Iron deficiency is associated with reactive thrombocytosis; however, the mechanisms driving this phenomenon remain unclear. We previously demonstrated that this occurs alongside enhanced megakaryopoiesis in iron-deficient rats, without alterations in the megakaryopoietic growth factors thrombopoietin, interleukin-6, or interleukin-11. OBJECTIVES: The aim of this study was to evaluate megakaryocyte differentiation under iron deficiency in an in vitro model and to investigate potential genes involved in this process. METHODS: Human erythroleukemia and megakaryoblastic leukemia cell lines, as well as cord-blood derived hematopoietic stem cells were cultured under iron deficiency. Cell morphology, ploidy, expression of CD41, CD61, and CD42b, and proplatelet formation were assessed in iron-deficient cultures. Polymerase chain reaction arrays were used to identify candidate genes that were verified using real-time polymerase chain reaction. Hypoxia-inducible factor 1, alpha subunit (HIF2alpha) protein expression was assessed in bone marrow sections from iron-deficient rats and vascular endothelial growth factor (VEGF)-A in culture supernatants. RESULTS AND CONCLUSIONS: Iron deficiency enhanced megakaryoid features in cell lines, increasing ploidy and initiating formation of proplatelet-like structures. In cord blood cell cultures, iron deficiency increased the percentage of cells expressing megakaryopoietic markers and enhanced proplatelet formation. HIF2alpha and VEGF were identified as potential pathways involved in this process. HIF2alpha protein expression was increased in megakaryocytes from iron-deficient rats, and VEGF-A concentration was higher in iron-deficient culture supernatants. Addition of VEGF-A to cell cultures increased percentage expression of megakaryocyte CD41. In conclusion, the data demonstrate that iron deficiency augments megakaryocytic differentiation and proplatelet formation and a potential role of HIF2alpha in megakaryopoiesis. PMID- 25715030 TI - Chiral crystallization and optical properties of three metal complexes based on two non-centrosymmetric tripodal ligands. AB - Chiral coordination polymers have attracted much attention due to their special properties and significant applications. In this work, we synthesized two non centrosymmetric ligands, N,N-bis(4-(1H-imidazol-1-yl)phenyl)-4-(pyridin-4 yl)aniline (DIMPPA) and N-(4-(1H-imidazol-1-yl)phenyl)-4-(pyridin-4-yl)-N-(4 (pyridin-4-yl)phenyl)aniline (MIDPPA), via structural modification of two reported centrosymmetric ligands; after that achiral -> chiral induction occurred in the construction of three coordination polymers namely {[Cd(DIMPPA)(5-OH bdc)](H2O)}n (1), {[Co(DIMPPA)(5-OH-bdc)](H2O)}n (2) and {[Cd2(MIDPPA)2(D ca)2(H2O)2](H2O)5}n (3), when replacing the reported centrosymmetric ligands with non-centrosymmetric ligands (5-OH-H2bdc = 5-hydroxyisophthalic acid, D-H2ca = D camphoric acid). Isostructural complexes 1 and 2 exhibit chiral 2D -> 3D frameworks with the coexistence of polyrotaxane and parallel polycatenation features. Complex 3 shows two-fold interpenetrating 3D chiral architecture with cds-type topology. The luminescence emissions of both complexes 1 and 3 are mostly assignable to the internal pi->pi* electron transition in DIMPPA and MIDPPA, respectively. Complex 3 can satisfy the fundamental requirement of second order nonlinear optical materials. PMID- 25715028 TI - BAX and BAK1 are dispensable for ABT-737-induced dissociation of the BCL2-BECN1 complex and autophagy. AB - Disruption of the complex of BECN1 with BCL2 or BCL2L1/BCL-XL is an essential switch that turns on cellular autophagy in response to environmental stress or treatment with BH3 peptidomimetics. Recently, it has been proposed that BCL2 and BCL2L1/BCL-XL may inhibit autophagy indirectly through a mechanism dependent on the proapoptotic BCL2 family members, BAX and BAK1. Here we report that the BH3 mimetic, ABT-737, induces autophagy in parallel with disruption of BCL2-BECN1 binding in 2 different apoptosis-deficient cell types lacking BAX and BAK1, namely in mouse embryonic fibroblasts cells and in human colon cancer HCT116 cells. We conclude that the BH3 mimetic ABT-737 induces autophagy through a BAX and BAK1-independent mechanism that likely involves disruption of BECN1 binding to antiapoptotic BCL2 family members. PMID- 25715031 TI - p-Benzoquinone adsorption-separation, sensing and its photoinduced transformation within a robust Cd(II)-MOF in a SC-SC fashion. AB - p-Benzoquinone (Q) adsorption-separation, sensing and its photoinduced transformation within a robust Cd(II)-MOF (1) is reported. All the adsorption, sensing and photochemical reactions are directly performed on the single-crystals of 1. PMID- 25715029 TI - Transhydrogenase promotes the robustness and evolvability of E. coli deficient in NADPH production. AB - Metabolic networks revolve around few metabolites recognized by diverse enzymes and involved in myriad reactions. Though hub metabolites are considered as stepping stones to facilitate the evolutionary expansion of biochemical pathways, changes in their production or consumption often impair cellular physiology through their system-wide connections. How does metabolism endure perturbations brought immediately by pathway modification and restore hub homeostasis in the long run? To address this question we studied laboratory evolution of pathway engineered Escherichia coli that underproduces the redox cofactor NADPH on glucose. Literature suggests multiple possibilities to restore NADPH homeostasis. Surprisingly, genetic dissection of isolates from our twelve evolved populations revealed merely two solutions: (1) modulating the expression of membrane-bound transhydrogenase (mTH) in every population; (2) simultaneously consuming glucose with acetate, an unfavored byproduct normally excreted during glucose catabolism, in two subpopulations. Notably, mTH displays broad phylogenetic distribution and has also played a predominant role in laboratory evolution of Methylobacterium extorquens deficient in NADPH production. Convergent evolution of two phylogenetically and metabolically distinct species suggests mTH as a conserved buffering mechanism that promotes the robustness and evolvability of metabolism. Moreover, adaptive diversification via evolving dual substrate consumption highlights the flexibility of physiological systems to exploit ecological opportunities. PMID- 25715032 TI - Titratable acidity of beverages influences salivary pH recovery. AB - A low pH and a high titratable acidity of juices and cola-based beverages are relevant factors that contribute to dental erosion, but the relative importance of these properties to maintain salivary pH at demineralizing levels for long periods of time after drinking is unknown. In this crossover study conducted in vivo, orange juice, a cola-based soft drink, and a 10% sucrose solution (negative control) were tested. These drinks differ in terms of their pH (3.5 +/- 0.04, 2.5 +/- 0.05, and 5.9 +/- 0.1, respectively) and titratable acidity (3.17 +/- 0.06, 0.57 +/- 0.04 and < 0.005 mmols OH- to reach pH 5.5, respectively). Eight volunteers with a normal salivary flow rate and buffering capacity kept 15 mL of each beverage in their mouth for 10 s, expectorated it, and their saliva was collected after 15, 30, 45, 60, 90, and 120 s. The salivary pH, determined using a mini pH electrode, returned to the baseline value at 30 s after expectoration of the cola-based soft drink, but only at 90 s after expectoration of the orange juice. The salivary pH increased to greater than 5.5 at 15 s after expectoration of the cola drink and at 30 s after expectoration of the orange juice. These findings suggest that the titratable acidity of a beverage influences salivary pH values after drinking acidic beverages more than the beverage pH. PMID- 25715033 TI - Patient satisfaction concerning implant-supported prostheses: an observational study. AB - The aim of this observational study was to assess the degree of patient satisfaction toward implant-supported prostheses. A questionnaire was used with two scales (one consisting of detailed adjectival and the other of numerical responses) regarding chewing, esthetics, speaking, comfort and overall satisfaction. The scales were administered to a sample of 147 patients treated with implants and prostheses. The data were submitted to the Kappa statistic and the Chi-square test to analyze the association between dependent and independent variables. High degrees of satisfaction (greater than 91%) were found for all categories evaluated, regardless of gender, age, number of implants or type of prosthesis. "Comfort" was associated significantly with the number of implants (p = 0.038), and "speaking" was associated significantly with the type of prosthesis (p = 0.029). Positive agreement was found between the scales for all categories evaluated, without statistically significant differences regarding respondent preference (p = 0.735). Patients treated with implant-supported prostheses were highly satisfied with the treatment. PMID- 25715034 TI - Vertical bone measurements from cone beam computed tomography images using different software packages. AB - This article aimed at comparing the accuracy of linear measurement tools of different commercial software packages. Eight fully edentulous dry mandibles were selected for this study. Incisor, canine, premolar, first molar and second molar regions were selected. Cone beam computed tomography (CBCT) images were obtained with i-CAT Next Generation. Linear bone measurements were performed by one observer on the cross-sectional images using three different software packages: XoranCat(r), OnDemand3D(r) and KDIS3D(r), all able to assess DICOM images. In addition, 25% of the sample was reevaluated for the purpose of reproducibility. The mandibles were sectioned to obtain the gold standard for each region. Intraclass coefficients (ICC) were calculated to examine the agreement between the two periods of evaluation; the one-way analysis of variance performed with the post-hoc Dunnett test was used to compare each of the software-derived measurements with the gold standard. The ICC values were excellent for all software packages. The least difference between the software-derived measurements and the gold standard was obtained with the OnDemand3D and KDIS3D (-0.11 and 0.14 mm, respectively), and the greatest, with the XoranCAT (+0.25 mm). However, there was no statistical significant difference between the measurements obtained with the different software packages and the gold standard (p> 0.05). In conclusion, linear bone measurements were not influenced by the software package used to reconstruct the image from CBCT DICOM data. PMID- 25715035 TI - Influence of 2% chlorhexidine on pH, calcium release and setting time of a resinous MTA-based root-end filling material. AB - The addition of chlorhexidine (CHX) to a resinous experimental Mineral Trioxide Aggregate (E-MTA) based root-end filling material is an alternative to boost its antimicrobial activity. However, the influence of chlorhexidine on the properties of this material is unclear. The aim of this study was to evaluate the influence of 2% chlorhexidine on the pH, calcium ion release and setting time of a Bisphenol A Ethoxylate Dimethacrylate/Mineral Trioxide Aggregate (Bis-EMA/MTA) based dual-cure experimental root-end filling material (E-MTA), in comparison with E-MTA without the addition of CHX and with conventional white MTA (W-MTA). The materials were placed in polyethylene tubes, and immersed in deionized water to determine pH (digital pH meter) and calcium ion release (atomic absorption spectrometry technique). The setting time of each material was analyzed using Gilmore needles. The data were statistically analyzed at a significance level of 5%. E-MTA + CHX showed an alkaline pH in the 3 h period of evaluation, the alkalinity of which decreased but remained as such for 15 days. The pH of E-MTA + CHX was higher than the other two materials after 7 days, and lower after 30 days (p < 0.05). All of the materials were found to release calcium ions throughout the 30 days of the study. The addition of CHX increased the calcium ion release of E-MTA to levels statistically similar to W-MTA. E-MTA showed shorter initial and final setting time, compared with W-MTA (p < 0.05). The addition of 2% CHX to MTA prevented setting of the material. The addition of CHX to E-MTA increased its pH and calcium ion release. However, it also prevented setting of the material. PMID- 25715036 TI - Perception of 'comprehensiveness of care': a qualitative study amongst dentists in the Brazilian Health System. AB - Comprehensiveness relates both to the scope of services offered and to a holistic clinical approach. The aim of this study was to identify the perception of Brazilian dentists regarding key concepts of comprehensiveness and its importance in primary health care oral health services performed in the public sector. Focus groups were conducted to explore three main concepts, 'patient welcoming', 'bonding' and 'quality of care', as well as their aspects. In total, there were four focus groups comprising seven general dentists, all of whom had at least two years of experience in primary care, from municipalities of varying sizes. Discussions of approximately 60 minutes were conducted, audio-recorded and transcribed. The data were analysed by qualitative thematic analysis, in line with the framework approach. The general dentists reported that they are aware that in the Brazilian Health System, the onset of patient care by primary health care services must happen through 'patient welcoming.' Nevertheless, they suggested that this action is often performed poorly due to the large volume of patients. Although they knew the importance of 'bonding', they realised that there is a lack of education preparing professionals to address interpersonal and social issues. They were aware that 'quality of care' is related to multiple factors. Comprehensiveness, as an approach in dental public health practices, needs to be enhanced, and there is evidence that primary care dentists are aware of the need for such an approach. PMID- 25715037 TI - Stability of antimicrobial activity of peracetic acid solutions used in the final disinfection process. AB - The instruments and materials used in health establishments are frequently exposed to microorganism contamination, and chemical products are used before sterilization to reduce occupational infection. We evaluated the antimicrobial effectiveness, physical stability, and corrosiveness of two commercial formulations of peracetic acid on experimentally contaminated specimens. Stainless steel specimens were contaminated with Staphylococcus aureus, Escherichia coli, Candida albicans, blood, and saliva and then immersed in a ready peracetic acid solution: 2% Sekusept Aktiv (SA) or 0.25% Proxitane Alpha (PA), for different times. Then, washes of these instruments were plated in culture medium and colony-forming units counted. This procedure was repeated six times per day over 24 non-consecutive days. The corrosion capacity was assessed with the mass loss test, and the concentration of peracetic acid and pH of the solutions were measured with indicator tapes. Both SA and PA significantly eliminated microorganisms; however, the SA solution was stable for only 4 days, whereas PA remained stable throughout the experiment. The concentration of peracetic acid in the SA solutions decreased over time until the chemical was undetectable, although the pH remained at 5. The PA solution had a concentration of 500-400 mg/L and a pH of 2-3. Neither formulation induced corrosion and both reduced the number of microorganisms (p = 0.0001). However, the differences observed in the performance of each product highlight the necessity of establishing a protocol for optimizing the use of each one. PMID- 25715038 TI - Computed tomography evaluation of rotary systems on the root canal transportation and centering ability. AB - The endodontic preparation of curved and narrow root canals is challenging, with a tendency for the prepared canal to deviate away from its natural axis. The aim of this study was to evaluate, by cone-beam computed tomography, the transportation and centering ability of curved mesiobuccal canals in maxillary molars after biomechanical preparation with different nickel-titanium (NiTi) rotary systems. Forty teeth with angles of curvature ranging from 20 degrees to 40 degrees and radii between 5.0 mm and 10.0 mm were selected and assigned into four groups (n = 10), according to the biomechanical preparative system used: Hero 642 (HR), Liberator (LB), ProTaper (PT), and Twisted File (TF). The specimens were inserted into an acrylic device and scanned with computed tomography prior to, and following, instrumentation at 3, 6 and 9 mm from the root apex. The canal degree of transportation and centering ability were calculated and analyzed using one-way ANOVA and Tukey's tests (alpha = 0.05). The results demonstrated no significant difference (p > 0.05) in shaping ability among the rotary systems. The mean canal transportation was: -0.049 +/- 0.083 mm (HR); -0.004 +/- 0.044 mm (LB); -0.003 +/- 0.064 mm (PT); -0.021 +/- 0.064 mm (TF). The mean canal centering ability was: -0.093 +/- 0.147 mm (HR); -0.001 +/- 0.100 mm (LB); -0.002 +/- 0.134 mm (PT); -0.033 +/- 0.133 mm (TF). Also, there was no significant difference among the root segments (p > 0.05). It was concluded that the Hero 642, Liberator, ProTaper, and Twisted File rotary systems could be safely used in curved canal instrumentation, resulting in satisfactory preservation of the original canal shape. PMID- 25715039 TI - Assessment of cephalometric characteristics in the elderly. AB - This cross-sectional study aimed at assessing the cephalometric characteristics in the elderly, taking into account differences between genders, age ranges, ethnic groups and dental aspects. The sample consisted of 250 elderly subjects of both genders (163 female, mean age: 68 yr.; 87 male: 70.4 yr.). Conventional lateral cephalograms for cephalometric analysis were scanned and analyzed by Dolphin Imaging software 11.5. The statistical treatment of the data evaluated the influence of gender and age range variables (independent t test), as well as ethnic group, facial profile, and dental characteristics (one-way ANOVA), on cephalometric measurements. A confidence interval of 95% and level of significance of 5% were considered for all the tests performed. The results revealed: 1) The cephalometric measurements evaluated showed significantly lower values for the female gender; 2) a significant decrease in the cephalometric values was observed in relation to the growth pattern, with the advancement of age; 3) significant cephalometric differences were observed between the ethnic groups and the facial profiles; 3) dentulous patients had greater absolute values for all the components evaluated, followed by the individuals with partial dental losses and by those who were edentulous. It may be concluded that the cephalometric alterations observed in this study are inherent to facial maturity, and that they represent specific characteristics regarding each of the variables evaluated. These modifications must be taken into account when planning the treatment for younger patients, to minimize the modifications arising from the natural aging process. PMID- 25715040 TI - Administrative and clinical denials by a large dental insurance provider. AB - The objective of this study was to assess the prevalence and the type of claim denials (administrative, clinical or both) made by a large dental insurance plan. This was a cross-sectional, observational study, which retrospectively collected data from the claims and denial reports of a dental insurance company. The sample consisted of the payment claims submitted by network dentists, based on their procedure reports, reviewed in the third trimester of 2012. The denials were classified and grouped into 'administrative', 'clinical' or 'both'. The data were tabulated and submitted to uni- and bivariate analyses. The confidence intervals were 95% and the level of significance was set at 5%. The overall frequency of denials was 8.2% of the total number of procedures performed. The frequency of administrative denials was 72.88%, whereas that of technical denials was 25.95% and that of both, 1.17% (p < 0.05). It was concluded that the overall prevalence of denials in the studied sample was low. Administrative denials were the most prevalent. This type of denial could be reduced if all dental insurance providers had unified clinical and administrative protocols, and if dentists submitted all of the required documentation in accordance with these protocols. PMID- 25715041 TI - Mechanical influence of thread pitch on orthodontic mini-implant stability. AB - The aim of this study was to evaluate the effect of pitch distance on the primary stability (PS) of orthodontic mini-implants (MIs) in artificial bone. Twenty experimental MIs were allocated to two groups, according to their geometric design: G1 (30o X 0.6 mm) and G2 (45o X 0.8 mm), and inserted into artificial bone of different densities: D1 (0.32 g/cm3) and D2 (0.64 g/cm3). The maximum insertion torque (IT) and removal torque (RT) values were recorded in N.cm. Loss of torque (LT) values were obtained by calculating the difference between the IT and RT. MI mobility was measured by means of a Periotest assessment. Normality and homogeneity were determined by means of the Kolmogorov-Smirnov and Shapiro Wilk tests, respectively. A two-way ANOVA was used to detect differences between the mini-implant design and density factors. The ANOVA/Tukey tests were used to determine the intergroup difference. Higher IT values were observed for G2 (p <= 0.05) in D2. No statistical difference for RT was observed between the groups, whereas G2 presented higher values only for LT (p <= 0.05). The Periotest values (PTV) were higher for G1, in comparison with G2, in D1. G1 presented better PS in D2 (IT, RT and LT), whereas G2 was found to be more stable in D1, after evaluation with Periotest. PMID- 25715042 TI - Esthetic perception of facial profile after treatment with the Thurow Appliance. AB - The objective of this article was to investigate the perception of esthetic changes in the facial profile of bilateral Class II patients treated with the Modified Thurow Appliance for extraoral treatment. Silhouettes were traced of profiles of patients who initially presented a bilateral Class II molar relationship and who, post-treatment, presented molars in a Class I relationship. Three groups were formed: the first composed of patients with maxillary protrusion (SNA >84 degrees ), the second with maxillary retrusion (SNA <80 degrees ), and the third with a well-positioned maxilla (SNA 80-84 degrees ). A panel of 200 lay evaluators judged the profile esthetics by a randomized drawing of the silhouettes. The multiple analysis results showed that the profile esthetic scores for the three positions of the maxilla were greatly influenced by significant interactions with the characteristics (like sex and age) of the evaluators: retrusive maxilla (Score *Age Group, p < 0.001), normal maxilla (Score *Sex, p = 0.024; Score *Age Group, p = 0.050) and protrusive maxilla (Score *Age Group, p < 0.001). It was observed that the profile of Class II patients with protrusion, normal relationship and retrusion of the maxilla, improved in their esthetic post-treatment result; however, the evaluators showed greater satisfaction with the groups of protrusion and normal position of the maxilla. The Modified Thurow Appliance provided significant improvements in the esthetics of the profile of patients who presented protrusion and normal position of the maxilla. However, its use was not the best treatment option for patients with maxillary retrusion. PMID- 25715045 TI - Causal estimation using semiparametric transformation models under prevalent sampling. AB - This article presents methods and inference for causal estimation in semiparametric transformation models for the prevalent survival data. Through the estimation of the transformation models and covariate distribution, we propose a few analytical procedures to estimate the causal survival function. As the data are observational, the unobserved potential outcome (survival time) may be associated with the treatment assignment, and therefore there may exist a systematic imbalance between the data observed from each treatment arm. Further, due to prevalent sampling, subjects are observed only if they have not experienced the failure event when data collection began, causing the prevalent sampling bias. We propose a unified approach, which simultaneously corrects the bias from the prevalent sampling and balances the systematic differences from the observational data. We illustrate in the simulation study that standard analysis without proper adjustment would result in biased causal inference. Large sample properties of the proposed estimation procedures are established by techniques of empirical processes and examined by simulation studies. The proposed methods are applied to the Surveillance, Epidemiology, and End Results (SEER) and Medicare linked data for women diagnosed with breast cancer. PMID- 25715044 TI - Role of radiology in central nervous system stimulation. AB - Central nervous system (CNS) stimulation is becoming increasingly prevalent. Deep brain stimulation (DBS) has been proven to be an invaluable treatment for movement disorders and is also useful in many other neurological conditions refractory to medical treatment, such as chronic pain and epilepsy. Neuroimaging plays an important role in operative planning, target localization and post operative follow-up. The use of imaging in determining the underlying mechanisms of DBS is increasing, and the dependence on imaging is likely to expand as deep brain targeting becomes more refined. This article will address the expanding role of radiology and highlight issues, including MRI safety concerns, that radiologists may encounter when confronted with a patient with CNS stimulation equipment in situ. PMID- 25715046 TI - Intraoperative dexmedetomidine reduces postoperative mechanical ventilation in infants after open heart surgery. AB - OBJECTIVE: The inclusion of dexmedetomidine in the operative and postoperative management of infants with congenital heart defects has lessened the need for opioids that may cause respiratory depression. Our objective was to show that a dexmedetomidine bolus at or about the time of sternal closure is associated with a decrease in the use of mechanical ventilation in the immediate postoperative period. DESIGN: Retrospective cohort study. SETTING: Single pediatric tertiary cardiac center. PATIENTS: Infants undergoing surgical intervention for congenital heart defects requiring cardiopulmonary bypass, age 30-365 days in a 5-year time period from June 1, 2008, to December 31, 2012. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 1,057 total encounters, 441 met inclusion criteria and were evenly distributed over the 5-year time period. Dexmedetomidine had been given at or about the time of sternal closure in 57% of patients. When the exposed and unexposed groups were compared in terms of mechanical ventilation immediately postoperative, there was a statistically significant effect of using dexmedetomidine on the odds of receiving mechanical ventilation (p = 0.0019). This difference remained significant after adjusting for covariates affecting the decision for mechanical ventilation, including year of the procedure, age and weight of subject, cardiopulmonary bypass time, the use of deep hypothermic circulatory arrest, intraoperative fentanyl dose, and the Risk Adjustment for Congenital Heart Surgery Score 1 (p = 0.0317). The odds of receiving mechanical ventilation are estimated to be two times higher for patients who did not receive dexmedetomidine than for patients who received dexmedetomidine after adjusting for variables. CONCLUSION: The use of dexmedetomidine bolus in the operating room at the time of sternal closure in infants undergoing open heart surgery is associated with reduced need for mechanical ventilation in the immediate postoperative period. PMID- 25715047 TI - Safety and efficacy of sodium nitroprusside during prolonged infusion in pediatric patients. AB - OBJECTIVE: Sodium nitroprusside is a direct-acting vasodilator used to lower blood pressure in the operating room and ICU. The efficacy of sodium nitroprusside has been analyzed in few pediatric randomized trials. This study assesses the efficacy and safety of sodium nitroprusside following at least 12 hours of IV infusion in children. DESIGN: Randomized, double-blind withdrawal to placebo study. SETTING: ICUs. PATIENTS: Pediatric patients younger than 17 years. INTERVENTIONS: Following 12-24 hours of open-label sodium nitroprusside titration, a blinded infusion of sodium nitroprusside or placebo was administered (at the stable rate used at the end of the open-label phase) for up to 30 minutes. MEASUREMENTS AND MAIN RESULTS: The primary efficacy measure was whether control of mean arterial blood pressure was lost, that is, increased above ambient baseline for two consecutive minutes during the blinded phase. The proportion of patients who lost mean arterial blood pressure control in the placebo group (15/19; 79%) was significantly different than those in the sodium nitroprusside group (9/20; 45%) (p = 0.048). Three patients experienced rebound hypertension during the blinded phase, and all were in the placebo group. Serious adverse event rates were low (7/52; 13%), and in only one patient was the serious adverse event determined to be related to sodium nitroprusside by the site investigator. Fourteen patients (27%) had whole blood cyanide levels above 0.5 MUg/mL, with high correlation (0.7) between infusion rate and cyanide levels, but there were few clinical signs of cyanide toxicity. CONCLUSIONS: Sodium nitroprusside is efficacious in maintaining mean arterial blood pressure control in children following a 12-hour infusion. Although a high proportion of patients were found to have elevated cyanide levels, toxicity was not observed. PMID- 25715049 TI - Essential thrombocythaemia. PMID- 25715051 TI - Development of an ELISA for the Pharmacokinetic Evaluation of a Murine Anti CD66 Monoclonal Antibody in Human Serum. AB - An enzyme-linked immunosorbent assay (ELISA) was needed to assist in the pharmacokinetic evaluation of the murine antibody conjugate CHX A" DTPA Besilesomab in serum samples in a clinical trial . A search failed to locate a validated assay that quantified murine antibodies in human serum so the purpose of this article was to develop a robust assay, validated against current guidelines. A detailed method for an ELISA to measure a murine antibody in human serum is described. The assay was validated as fit for purpose against the target values of coefficient of variation < 20% and accuracy +/- 20%. PMID- 25715048 TI - Vaccines for viral and bacterial pathogens causing acute gastroenteritis: Part I: Overview, vaccines for enteric viruses and Vibrio cholerae. AB - Efforts to develop vaccines for prevention of acute diarrhea have been going on for more than 40 y with partial success. The myriad of pathogens, more than 20, that have been identified as a cause of acute diarrhea throughout the years pose a significant challenge for selecting and further developing the most relevant vaccine candidates. Based on pathogen distribution as identified in epidemiological studies performed mostly in low-resource countries, rotavirus, Cryptosporidium, Shigella, diarrheogenic E. coli and V. cholerae are predominant, and thus the main targets for vaccine development and implementation. Vaccination against norovirus is most relevant in middle/high-income countries and possibly in resource-deprived countries, pending a more precise characterization of disease impact. Only a few licensed vaccines are currently available, of which rotavirus vaccines have been the most outstanding in demonstrating a significant impact in a short time period. This is a comprehensive review, divided into 2 articles, of nearly 50 vaccine candidates against the most relevant viral and bacterial pathogens that cause acute gastroenteritis. In order to facilitate reading, sections for each pathogen are organized as follows: i) a discussion of the main epidemiological and pathogenic features; and ii) a discussion of vaccines based on their stage of development, moving from current licensed vaccines to vaccines in advanced stage of development (in phase IIb or III trials) to vaccines in early stages of clinical development (in phase I/II) or preclinical development in animal models. In this first article we discuss rotavirus, norovirus and Vibrio cholerae. In the following article we will discuss Shigella, Salmonella (non-typhoidal), diarrheogenic E. coli (enterotoxigenic and enterohemorragic), and Campylobacter jejuni. PMID- 25715050 TI - The Extracellular IFI16 Protein Propagates Inflammation in Endothelial Cells Via p38 MAPK and NF-kappaB p65 Activation. AB - The nuclear interferon-inducible-16 (IFI16) protein acts as DNA sensor in inflammasome signaling and as viral restriction factor. Following Herpesvirus infection or UV-B treatment, IFI16 delocalizes from the nucleus to the cytoplasm and is eventually released into the extracellular milieu. Recently, our group has demonstrated the occurrence of IFI16 in sera of systemic-autoimmune patients that hampers biological activity of endothelia through high-affinity membrane binding. As a continuation, we studied the activity of endotoxin-free recombinant IFI16 (rIFI16) protein on primary endothelial cells. rIFI16 caused dose/time-dependent upregulation of IL-6, IL-8, CCL2, CCL5, CCL20, ICAM1, VCAM1, and TLR4, while secretion of IL-6 and IL-8 was amplified with lipopolysaccharide synergy. Overall, cytokine secretion was completely inhibited in MyD88-silenced cells and partially by TLR4-neutralizing antibodies. By screening downstream signaling pathways, we found that IFI16 activates p38, p44/42 MAP kinases, and NF-kB. In particular, activation of p38 is an early event required for subsequent p44/42 MAP kinases activity and cytokine induction indicating a key role of this kinase in IFI16 signaling. Altogether, our data conclude that extracellular IFI16 protein alone or by synergy with lipopolysaccharide acts like Damage-associated molecular patterns propagating "Danger Signal" through MyD88-dependent TLR pathway. PMID- 25715052 TI - A facile photopolymerization method for fabrication of pH and light dual reversible stimuli-responsive surfaces. AB - Dual reversible surfaces with pH and light responsive properties were prepared via two-stage photopolymerization by grafting dimethylaminoethyl methacrylate (DMAEMA) and 2-methyl-4-phenylazo acrylate (MPA-Azo) on a substrate. The wettability of the modified surface could be reversibly controlled because of the protonation and deprotonation of DMAEMA at different pH values and the photoisomerization of MPA-Azo under UV irradiation at different wavelengths. This facile two-stage photopolymerization method has potential applications in fabrication of various external stimuli-responsive surfaces in the future. PMID- 25715053 TI - The Recognition Process in Dermoscopy: Analytic Approach vs Heuristic Approach. PMID- 25715054 TI - Solvent jet desorption capillary photoionization-mass spectrometry. AB - A new ambient mass spectrometry method, solvent jet desorption capillary photoionization (DCPI), is described. The method uses a solvent jet generated by a coaxial nebulizer operated at ambient conditions with nitrogen as nebulizer gas. The solvent jet is directed onto a sample surface, from which analytes are extracted into the solvent and ejected from the surface in secondary droplets formed in collisions between the jet and the sample surface. The secondary droplets are directed into the heated capillary photoionization (CPI) device, where the droplets are vaporized and the gaseous analytes are ionized by 10 eV photons generated by a vacuum ultraviolet (VUV) krypton discharge lamp. As the CPI device is directly connected to the extended capillary inlet of the MS, high ion transfer efficiency to the vacuum of MS is achieved. The solvent jet DCPI provides several advantages: high sensitivity for nonpolar and polar compounds with limit of detection down to low fmol levels, capability of analyzing small and large molecules, and good spatial resolution (250 MUm). Two ionization mechanisms are involved in DCPI: atmospheric pressure photoionization, capable of ionizing polar and nonpolar compounds, and solvent assisted inlet ionization capable of ionizing larger molecules like peptides. The feasibility of DCPI was successfully tested in the analysis of polar and nonpolar compounds in sage leaves and chili pepper. PMID- 25715055 TI - Aryl hydrocarbon receptor activation and developmental toxicity in zebrafish in response to soil extracts containing unsubstituted and oxygenated PAHs. AB - Many industrial sites are polluted by complex mixtures of polycyclic aromatic compounds (PACs). Besides polycyclic aromatic hydrocarbons (PAHs), these mixtures often contain significant amounts of more polar PACs including oxygenated PAHs (oxy-PAHs). The effects of oxy-PAHs are, however, poorly known. Here we used zebrafish embryos to examine toxicities and transcriptional changes induced by PAC containing soil extracts from three different industrial sites: a gasworks (GAS), a former wood preservation site (WOOD), and a coke oven (COKE), and to PAH and oxy-PAH containing fractions of these. All extracts induced aryl hydrocarbon receptor (Ahr)-regulated mRNAs, malformations, and mortality. The WOOD extract was most toxic and the GAS extract least toxic. The extracts induced glutathione transferases and heat shock protein 70, suggesting that the toxicity also involved oxidative stress. With all extracts, Ahr2-knock-down reduced the toxicity, indicating a significant Ahr2-dependence on the effects. Ahr2-knock down was most effective with the PAH fraction of the WOOD extract and with the oxy-PAH fraction of the COKE extract. Our results indicate that oxy-PAH containing mixtures can be as potent Ahr activators and developmental toxicants as PAHs. In addition to Ahr activating potency, the profile of cytochrome P4501 inhibitors may also determine the toxic potency of the extracts. PMID- 25715056 TI - Catalytic enantioselective construction of quaternary stereocenters: assembly of key building blocks for the synthesis of biologically active molecules. AB - The ever-present demand for drugs with better efficacy and fewer side effects continually motivates scientists to explore the vast chemical space. Traditionally, medicinal chemists have focused much attention on achiral or so called "flat" molecules. More recently, attention has shifted toward molecules with stereogenic centers since their three-dimensional structures represent a much larger fraction of the chemical space and have a number of superior properties compared with flat aromatic compounds. Quaternary stereocenters, in particular, add greatly to the three-dimensionality and novelty of the molecule. Nevertheless, synthetic challenges in building quaternary stereocenters have largely prevented their implementation in drug discovery. The lack of effective and broadly general methods for enantioselective formation of quaternary stereocenters in simple molecular scaffolds has prompted us to investigate new chemistry and develop innovative tools and solutions. In this Account, we describe three approaches to constructing quaternary stereocenters: nucleophilic substitution of 3-halooxindoles, conjugate addition of boronic acids to cyclic enones, and allylic alkylation of enolates. In the first approach, malonic ester nucleophiles attack electrophilic 3-halooxindoles, mediated by a copper(II) bisoxazoline catalyst. A variety of oxindoles containing a benzylic quaternary stereocenter can be accessed through this method. However, it is only applicable to the specialized 3,3-disubstituted oxindole system. To access benzylic quaternary stereocenters in a more general context, we turned our attention to the enantioselective conjugate addition of carbon nucleophiles to alpha,beta unsaturated carbonyl acceptors. We discovered that in the presence of catalytic palladium-pyridinooxazoline complex, arylboronic acids add smoothly to beta substituted cyclic enones to furnish ketones with a beta-benzylic quaternary stereocenter in high yields and enantioselectivities. The reaction is compatible with a wide range of arylboronic acids, beta-substituents, and ring sizes. Aside from benzylic quaternary stereocenters, a more challenging motif is a quaternary stereocenter not adjacent to an aromatic group. Such centers represent more general structures in chemical space but are more difficult to form by asymmetric catalysis. To address this greater challenge, and motivated by the greater reward, we entered the field of palladium-catalyzed asymmetric allylic alkylation of prochiral enolate nucleophiles about a decade ago. On the basis of Tsuji's work, which solved the issue of positional selectivity for unsymmetrical ketones, we discovered that the phosphinooxazoline ligand effectively rendered this reaction enantioselective. Extensive investigations since then have revealed that the reaction exhibits broad scope and accepts a range of substrate classes, each with its unique advantage in synthetic applications. A diverse array of carbonyl compounds bearing alpha-quaternary stereocenters are obtained in excellent yields and enantioselectivities, and more possibilities have yet to be explored. As an alternative to palladium catalysis, we also studied iridium-catalyzed asymmetric allylic alkylations that generate vicinal quaternary and tertiary stereocenters in a single transformation. Overall, these methods provide access to small molecule building blocks with a single quaternary stereocenter, can be applied to various molecular scaffolds, and tolerate a wide range of functional groups. We envision that the chemistry reported in this Account will be increasingly useful in drug discovery and design. PMID- 25715057 TI - Signaling pathway involved in the immunomodulatory effect of Ganoderma atrum polysaccharide in spleen lymphocytes. AB - The aim of this study was to investigate the molecular mechanism underlying the immunomodulatory effect of Ganoderma atrum polysaccharide (PSG-1) in spleen lymphocytes. Our results showed that PSG-1 increased the intracellular Ca2+ concentration and calcineurin (CaN) activity. Moreover, PSG-1 was found to elevate nuclear factor of activated T cells (NFAT) activity, but this effect could be diminished by the treatment of CaN inhibitors (cyclosporin A and FK506). PSG-1-induced interleukin (IL)-2 production was also inhibited by cyclosporin A and FK506. In addition, PSG-1 was found to significantly enhance protein kinase C (PKC) activity. PKC was involved in induction of NFAT activity by PSG-1, as evidenced by abrogation of NFAT activity by PKC inhibitor calphostin C, which significantly decreased PSG-1-induced IL-2 production. On the basis of these results, we concluded that PSG-1 may induce activation of spleen lymphocytes at least in part via the Ca2+/CaN/NFAT/IL-2 signaling pathway and the PKC/NFAT/IL-2 signaling pathway cooperatively regulated PSG-1-induced activation of spleen lymphocytes. PMID- 25715058 TI - Bichromatic laser-induced quadrupole-dipole collisional energy transfer in Ca-Sr. AB - We consider the response of a laser-induced quadrupole-dipole collisional system driven by a strong dressing laser field with the aim of calculating the collisional cross section of a weak inducing laser probe. The addition of a second driving field to the traditional arrangement will cause magnitude changes of the spectra and modify the profile. The calculation results show that the bichromatic laser-induced collisional energy-transfer process can be an efficient way to probe Stark splitting of both the final state and intermediate state. The magnitude and position of the splitting spectral lines are strongly dependent on the intensity of the dressing laser field. The peak cross section almost reduces by a factor of 2 with the presence of the dressing laser. Also, in the antistatic wing, bright and dark lines are periodic, appearing with the increasing of the dressing laser intensity. PMID- 25715059 TI - The unusual suspects: Regulation of retinal calcium channels by somatostatin. PMID- 25715060 TI - Catalytic asymmetric dearomatizing redox cross coupling of ketones with aryl hydrazines giving 1,4-diketones. AB - An asymmetric Bronsted acid catalyzed dearomatizing redox cross coupling reaction has been realized, in which aryl hydrazines react with ketones to deliver 1,4 diketones, bearing an all-carbon quarternary stereocenter in high enantiopurity. PMID- 25715061 TI - DNA spontaneous mutation and its role in the evolution of GC-content: assessing the impact of the genetic sequence. AB - The structure of DNA is not constantly at its equilibrium point but evolves with time. It is generally accepted that evolution induces a decrease of the guanine cytosine (GC) content and a concomitant increase of the adenine-thymine (AT) ratio through a biased GC -> AT mutation process. Unfortunately, the mechanism behind this natural alteration of the stored genetic information is not fully understood. Here, we use a hybrid QM:QM' approach to assess the link between one of the sources of the spontaneous mutation, the so-called G*C* rare tautomers that arise from a double proton exchange between the bases, and the evolution of the GC-content. Our simulations indicate that the G*C* mutation is mainly accumulated in GC-rich regions rather than being randomly spread, and consequently the GC -> AT error tends to locate in coding fragments. That specific preference is indirectly induced by the base pairs containing the mutated point, as they tune the structure of the first hydration-shell that solvates the reactive base pair undergoing tautomerisation. The reorganisation of the explicit water molecules eventually modifies the energy barriers as well as the stability of the genetic error during the process. PMID- 25715062 TI - PYRROC: the first functionalized cycloalkyne that facilitates isomer-free generation of organic molecules by SPAAC. AB - We present the concept, synthesis, and kinetic characterization of PYRROC as the first functionalized cycloalkyne which cannot form isomers in the reaction with azides. In aqueous buffer, PYRROC displays unprecedented rate accelerations in SPAAC of three to four orders of magnitude, leading to rate constants exceeding 400 M(-1) s(-1). PMID- 25715063 TI - Luminescent lanthanide MOFs based on conjugated 1,1'-ethynebenzene-3,3',5,5' tetracarboxylate ligand: syntheses, structures and photoluminescent properties. AB - A family of novel lanthanide metal-organic frameworks (MOFs) with formula [Ln2(EBTC)1.5(CH3OH)4].6H2O [EBTC4- = 1,1'-ethynebenzene-3,3',5,5' tetracarboxylate, Ln = La (1), Ce (2), Pr (3), Nd (4), Sm (5), Eu (6), Gd (7), Tb (8) and Dy (9)], have been synthesized via solvothermal reaction. All compounds are isostructural, crystallized in the monoclinic space group P21/n, and show a three-dimensional (4,6)-connected network with Schlafli symbol of {310}. Photoluminescent measurements indicated that 1 and 7 emit the luminescence originating from the intraligand pi<-pi* transition, 2 shows the broadband emission due to allowed 4f-5d transitions, and 4-9 show the emission of typical lanthanide f-f transition via the ligand "antenna effect" in the solid state at ambient temperature. Interestingly, compounds 6 and 8 showed microsecond time scale fluorescence lifetimes with 0.84 ms for 6 and 0.39 ms for 8, respectively. Such unique spectroscopy features may have applications in biomacromolecule research. PMID- 25715065 TI - Quantification of aristolochic acid-RNA adducts in the urine of aristolochic acid treated rats by liquid chromatography-tandem mass spectrometry. AB - Balkan endemic nephropathy (BEN) is a peculiar renal disease affecting thousands of farmers living in the suburban areas of the Balkan countries. Emerging evidence suggested that BEN is an environmental disease caused by chronic food poisoning with aristolochic acid (AA). We have developed a sensitive liquid chromatography-tandem mass spectrometry method to detect urinary RNA-AA adducts. Results revealed high levels of RNA-AA adducts in the urine samples collected from AA-treated rats. To the best of our knowledge, this study is the first to report on the detection of urinary RNA-AA adducts. Compared with previous studies that quantified DNA-AA adducts, this method is more sensitive and user-friendly. PMID- 25715066 TI - Frequency and Risk of Marijuana Use among Substance-Using Health Care Patients in Colorado with and without Access to State Legalized Medical Marijuana. AB - With increasing use of state legalized medical marijuana across the country, health care providers need accurate information on patterns of marijuana and other substance use for patients with access to medical marijuana. This study compared frequency and severity of marijuana use, and use of other substances, for patients with and without state legal access to medical marijuana. Data were collected from 2,030 patients who screened positive for marijuana use when seeking health care services in a large, urban safety-net medical center. Patients were screened as part of a federally funded screening, brief intervention, and referral to treatment (SBIRT) initiative. Patients were asked at screening whether they had a state-issued medical marijuana card and about risky use of tobacco, alcohol, and other illicit substances. A total of 17.4% of marijuana users had a medical marijuana card. Patients with cards had higher frequency of marijuana use and were more likely to screen at moderate than low or high risk from marijuana use. Patients with cards also had lower use of other substances than patients without cards. Findings can inform health care providers of both the specific risks of frequent, long-term use and the more limited risks of other substance use faced by legal medical marijuana users. PMID- 25715064 TI - White matter structure in youth with behavioral and emotional dysregulation disorders: a probabilistic tractographic study. AB - IMPORTANCE: Psychiatric disorders in youth characterized by behavioral and emotional dysregulation are often comorbid and difficult to distinguish. An alternative approach to conceptualizing these disorders is to move toward a diagnostic system based on underlying pathophysiologic processes that may cut across conventionally defined diagnoses. Neuroimaging techniques have potentials for the identification of these processes. OBJECTIVE: To determine whether diffusion imaging, a neuroimaging technique examining white matter (WM) structure, can identify neural correlates of emotional dysregulation in a sample of youth with different psychiatric disorders characterized by behavioral and emotional dysregulation. DESIGN, SETTING, AND PARTICIPANTS: Using global probabilistic tractography, we examined relationships between WM structure in key tracts in emotional regulation circuitry (ie, cingulum, uncinate fasciculus, and forceps minor) and (1) broader diagnostic categories of behavioral and emotional dysregulation disorders (DDs) and (2) symptom dimensions cutting across conventional diagnoses in 120 youth with behavioral and/or emotional DDs, a referred sample of the Longitudinal Assessment of Manic Symptoms (LAM) study. Thirty age- and sex-matched typically developing youth (control participants) were included. Multivariate multiple regression models were used. The study was conducted from July 1, 2010, to February 28, 2014. MAIN OUTCOMES AND MEASURES: Fractional anisotropy as well as axial and radial diffusivity were estimated and imported into a well-established statistical package. We hypothesized that (1) youth with emotional DDs and those with both behavioral and emotional DDs would show significantly lower fractional anisotropy compared with youth with behavioral DDs in these WM tracts and (2) that there would be significant inverse relationships between dimensional measures of affective symptom severity and fractional anisotropy in these tracts across all participants. RESULTS: Multivariate multiple regression analyses revealed decreased fractional anisotropy and decreased axial diffusivity within the uncinate fasciculus in youth with emotional DDs vs those with behavioral DDs, those with both DDs, and the controls (F6,160 = 2.4; P = .032; all pairwise comparisons, P < .002). In the same model, greater severity of manic symptoms was positively associated with higher fractional anisotropy across all affected youth (F3,85 = 2.8; P = .044). CONCLUSIONS AND RELEVANCE: These findings suggest that abnormal uncinate fasciculus and cingulum WM structure may underlie emotional, but not behavioral, dysregulation in pediatric psychiatric disorders and that a different neural mechanism may exist for comorbid emotional and behavioral DDs. PMID- 25715067 TI - Stigma among California's Medical Marijuana Patients. AB - The enactment of California's Proposition 215 stipulates that patients may use marijuana for medical reasons, provided that it is recommended by a physician. Yet, medical marijuana patients risk being stigmatized for this practice. This article examines the way in which medical marijuana patients perceive and process stigma, and how it affects their interactions and experiences with others. Eighteen semi-structured interviews of medical marijuana patients were carried out using a semi-structured interview guide. Most patients circumvented their own physicians in obtaining a recommendation to use medicinal marijuana, and also used a host of strategies in order to justify their medical marijuana use to family, friends, and colleagues in order to stave off potential stigma. The stigmatization of medical marijuana thus has a profound effect on how patients seek treatment, and whether they seek medical marijuana treatment at all. PMID- 25715068 TI - Profiles of medicinal cannabis patients attending compassion centers in rhode island. AB - Little is understood regarding medicinal marijuana dispensary users. We sought to characterize socio-demographics and reasons for medicinal marijuana use among medical cannabis dispensary patients in Rhode Island. Participants (n=200) were recruited from one of two Compassion Centers in Rhode Island and asked to participate in a short survey, which included assessment of pain interference using the Brief Pain Inventory (BPI). The majority of participants were male (73%), Caucasian (80%), college educated (68%), and had health insurance (89%). The most common reason for medicinal marijuana use was determined to be chronic pain management. Participants were more likely to have BPI pain interference scores of > 5 if they were older (OR: 1.36, 95% CI: 1.04-1.78) or reported using cannabis as a substitute for prescription medications (OR: 2.47, 95% CI: 1.23 4.95), and were less likely to have interference scores of >5 if they had higher income levels (OR: 0.53, 95% CI: 0.40-0.70) or reported having ever received treatment for an alcohol use disorder. One-fifth of participants had a history of a drug or alcohol use disorder. Most participants report that medicinal cannabis improves their pain symptomology, and are interested in alternative treatment options to opioid-based treatment regimens. PMID- 25715069 TI - Application of the Passionate Attachment Model to Recreational Use of MDMA/Ecstasy. AB - Those who are not addicted to ecstasy, but who use it persistently over time, could be viewed as having a "passionate attachment" to a highly valued activity. To evaluate the associations of obsessive and harmonious passion with psychological and behavioral aspects of ecstasy consumption, we recruited a community sample of ecstasy users to complete a modified version of the Passion Scale (Vallerand et al. 2003) and other questionnaires assessing their substance use history, self-efficacy to refuse ecstasy, and use of ecstasy to cope with worries and problems. Both Obsessive and Harmonious passion scores were negatively correlated with self-efficacy to refuse ecstasy and positively correlated with using ecstasy to cope with worries and problems. The findings also provided partial support for our hypotheses that scores on the Obsessive Passion subscale would be associated with number of times participants had used ecstasy, the frequency of use, and the typical number of pills consumed. Participants agreed more strongly with statements indicative of Harmonious Passion to consume ecstasy, but Harmonious subscale scores were not associated with several measures of consumption. As a supplemental measure, the modified questionnaire could provide a more comprehensive picture of the psychology of one's ecstasy use. PMID- 25715070 TI - "Word of mouse": indigenous harm reduction and online consumerism of the synthetic compound methoxphenidine. AB - Methoxphenidine (MXP) was one of several NMDA antagonists marketed in 2013 to replace the recently controlled compound Methoxetamine (MXE). A steep rise in user interest was recorded, despite vendor cautioning of limited user feedback. The study presented a phenomenological analysis of MXP experiences amongst recreational drug users as posted on public Internet fora. Internet searches were carried out using specific key words; "methoxphenidine," "MXP" and in combination with "experience," "report," "forum," and "trip." Seven self-reported experiences and 28 thread discussions relating sole use of MXP were analyzed using the Empirical Phenomenological Psychological method. Five themes and 61 categories emerged. MXP is marketed as a legal replacement for MXE, diphenidine, and ketamine, with a dissociative and stimulant wave outcome often lasting for days. Harm reduction tactics, awareness of prior tolerance to dissociative and optimal settings for use are discussed. Acute side-effects relate to hypertension and seizures. Chronic long-term memory loss and limb numbness is reported. Sense of empowerment occurs in the afterglow experience. Internet drug fora fuel information exchange and informed consumerism of synthetic compounds, and offer viable mechanisms for pre- and post-purchase decision making and indigenous harm reduction. Continued surveillance of synthetic market entries and user trends is warranted. PMID- 25715072 TI - Substance Use among a National Sample of Asian/Pacific Islander Men Who Have Sex with Men in the U.S. AB - The objectives of this study were to describe drug use among Asian/Pacific Islander (API) men who have sex with men (MSM) and to examine how nativity (and acculturation as a secondary correlate) predicted such use. A total of 445 self identified API MSM from seven metropolitan cities participated in a national HIV serological testing and psychosocial and behavioral assessment study. Results indicate clubbing was significantly associated with higher levels of substance use. Additionally, participants who were U.S.-born were more likely to have reported marijuana use and those with higher levels of acculturation reported less marijuana use. Our bivariate findings suggest that foreign-born status and acculturation experience may provide a protective effect against marijuana use among API MSM. These associations largely did not hold in our multivariate models. Future research should more fully examine the role of acculturation and nativity in substance use behaviors. PMID- 25715071 TI - The Prevalence of Posttraumatic Stress Disorder Symptoms among Addiction Treatment Patients with Cocaine Use Disorders. AB - Co-occurring cocaine use and posttraumatic stress disorders are prevalent and associated with negative treatment, health and societal consequences. This study examined the relationships among PTSD symptoms, gender, and cocaine use problems. Within a cross-sectional design, we gathered archival point prevalence data on new admissions (n = 573) to three addiction treatment agencies. Demographic, substance use, and PTSD symptom information were collected across the three agencies. Logistic regression analyses revealed that patients with cocaine use disorders had a two-fold increased odds for a probable PTSD diagnosis, compared to patients without a cocaine use disorder (OR = 2.19, 95% CI = 1.49-3.22, p < 0.001). Among females with cocaine use disorder, multinomial regression yielded a significant increase in the risk of moderate (RRR = 2.12, 95% CI = 1.10-4.10, p < 0.05) and severe (RRR = 2.87, 95% CI = 1.33-6.21, p < 0.01) PTSD symptoms. Males with cocaine use disorders had a two-fold increase in the risk of moderate PTSD symptoms (RRR = 2.13, 95% CI = 1.23-3.68, p < 0.01), but had no increased risk of developing severe PTSD symptoms (RRR = 1.93, 95% CI = 0.85-4.39, p = 0.117). Cocaine use appears to impact the risk of PTSD symptoms, especially in females. Future research should explore the generalizability of these findings to more racially and ethnically diverse samples, as well as among persons with this comorbidity who are not engaged in treatment services. PMID- 25715073 TI - The Relationship Between the Accumulated Number of Role Transitions and Hard Drug Use among Hispanic Emerging Adults. AB - Emerging adults (ages 18 to 25) who experience multiple role transitions in a short period of time may engage in hard drug use as a maladaptive coping strategy to avoid negative emotions from stress. Given the collectivistic values Hispanics encounter growing up, they may experience additional role transitions due to their group-oriented cultural paradigm. This study examined whether those who experience many role transitions are at greater risk for hard drug use compared to those who experience few transitions among Hispanic emerging adults. Participants completed surveys indicating their hard drug use in emerging adulthood, role transitions in the past year of emerging adulthood, age, gender, and hard drug use in high school. Simulation analyses indicated that an increase in the number of role transitions, from 0 to 13, was associated with a 14% (95% CI, 4 to 29) higher probability of hard drug use. Specific role transitions were found to be associated with hard drug use, such as starting to date or experiencing a breakup. Intervention/prevention programs may benefit from acknowledging individual reactions to transitions in emerging adulthood, as these processes may be catalysts for personal growth where identities are consolidated and decisions regarding hard drug use are formed. PMID- 25715074 TI - Alcohol Screening among Opioid Agonist Patients in a Primary Care Clinic and an Opioid Treatment Program. AB - Problem alcohol use is associated with adverse health and economic outcomes, especially among people in opioid agonist treatment. Screening, brief intervention, and referral to treatment (SBIRT) are effective in reducing alcohol use; however, issues involved in SBIRT implementation among opioid agonist patients are unknown. To assess identification and treatment of alcohol use disorders, we reviewed clinical records of opioid agonist patients screened for an alcohol use disorder in a primary care clinic (n = 208) and in an opioid treatment program (n = 204) over a two-year period. In the primary care clinic, 193 (93%) buprenorphine patients completed an annual alcohol screening and six (3%) had elevated AUDIT scores. In the opioid treatment program, an alcohol abuse or dependence diagnosis was recorded for 54 (27%) methadone patients. Practitioner focus groups were completed in the primary care (n = 4 physicians) and the opioid treatment program (n = 11 counselors) to assess experience with and attitudes towards screening opioid agonist patients for alcohol use disorders. Focus groups suggested that organizational, structural, provider, patient, and community variables hindered or fostered alcohol screening. Alcohol screening is feasible among opioid agonist patients. Effective implementation, however, requires physician training and systematic changes in workflow. PMID- 25715075 TI - Women who inject drugs in the republic of georgia: in their own words. AB - This study describes the initiation and maintenance of illicit drug use, risky behaviors, and the substance use treatment experiences of women in Georgia. Qualitative interviews with 55 drug-using women (mean age 36 years; SD = 9.52), were conducted during April-September 2011. Participants presented diverse histories of drug use initiation and substance use, risky behaviors, and drug treatment participation. All participants reported concurrent use of different substances, including home-produced injection preparations. Women described their experiences of both the positive and negative effects (physical and psychological) that they attributed to their use of drugs. Findings enrich our understanding of the environment in which substance use is initiated and maintained in a female population in Georgia, and illustrate the importance of culture and the role of social factors in the development of injection drug use. Results can provide direction for tailoring the development of interventions for substance use disorders, public policy discussions regarding the treatment of women who use drugs, and future research on substance use among women in Georgia and other post-Soviet nations. PMID- 25715076 TI - A critical component of the continuum of care for substance use disorders: recovery homes in Philadelphia. AB - For many struggling with addiction, the ability to achieve stable recovery is often jeopardized by untenable housing or unsupportive living environments. Despite promising research on recovery residences, there are still significant gaps in the research on them. Using data collected from a stratified random sample of recovery homes in Philadelphia (N = 25), this study describes the organizational, operational, and programmatic characteristics of these homes and explores potential differences in these characteristics by funding source and gender of residents served. Although not licensed treatment providers, the majority of these homes operated in a recovery-oriented manner and offered a range of different services to their residents-all for a reasonable monthly fee (M = $340.40, SE = 18.60). Few differences emerged between homes that received funding from the Philadelphia Office of Addiction Services and those that did not or between those that served males as opposed to females. More research is needed to address resident outcomes and how Philadelphia recovery homes may compare with recovery residences in other parts of the country. PMID- 25715078 TI - Metal-organic frameworks for luminescence thermometry. AB - Metal-organic frameworks (MOFs) hold great promise for developing various types of luminescent sensors due to their remarkable structural diversity and tunable luminescence properties. In the last few years, utilizing luminescent MOFs to explore temperature sensing has gained intense attention. In this feature article, after the general description of luminescence thermometry, we have summarized the recent progress made in luminescent MOF thermometers, with particular emphasis on the dual-emitting MOFs that effectively illustrate the self-referencing temperature measurement based on the intensity ratios of two separate transitions. PMID- 25715077 TI - An efficient method for the preparation of styrene derivatives via Rh(III) catalyzed direct C-H vinylation. AB - The development of a method for the Rh(III)-catalyzed direct vinylation of an aromatic C-H bond to give functionalized styrenes in good yield, using vinyl acetate as a convenient and inexpensive vinyl source, is reported. High functional group tolerance is demonstrated for electronically distinct arenes as well as different directing groups. Mechanistic investigation resulted in the characterization of a novel rhodium-metallacycle, which represents the first X ray structure of a [1,2]-Rh(III)-alkenyl addition adduct. PMID- 25715079 TI - Multiple structural states exist throughout the helical nucleation sequence of the intrinsically disordered protein stathmin, as reported by electron paramagnetic resonance spectroscopy. AB - The intrinsically disordered protein (IDP) stathmin plays an important regulatory role in cytoskeletal maintenance through its helical binding to tubulin and microtubules. However, it lacks a stable fold in the absence of its binding partner. Although stathmin has been a focus of research over the past two decades, the solution-phase conformational dynamics of this IDP are poorly understood. It has been reported that stathmin is purely monomeric in solution and that it bears a short helical region of persistent foldedness, which may act to nucleate helical folding in the C-terminal direction. Here we report a comprehensive study of the structural equilibria local to this region in stathmin that contradicts these two claims. Using the technique of electron paramagnetic resonance (EPR) spectroscopy on spin-labeled stathmin mutants in the solution phase and when immobilized on Sepharose solid support, we show that all sites in the helical nucleation region of stathmin exhibit multiple spectral components that correspond to dynamic states of differing mobilities and stabilities. Importantly, a state with relatively low mobility dominates each spectrum with an average population greater than 50%, which we suggest corresponds to an oligomerized state of the protein. This is in contrast to a less populated, more mobile state, which likely represents a helically folded monomeric state of stathmin, and a highly mobile state, which we propose is the random coil conformer of the protein. Our interpretation of the EPR data is confirmed by further characterization of the protein using the techniques of native and SDS PAGE, gel filtration chromatography, and multiangle and dynamic light scattering, all of which show the presence of oligomeric stathmin in solution. Collectively, these data suggest that stathmin exists in a diverse equilibrium of states throughout the purported helical nucleation region and that this IDP exhibits a propensity toward oligomerization. PMID- 25715080 TI - Autologous Adipose Tissue-Derived Cells: Are We Talking About Adipose Derived Stem Cells, Stromal Vascular Fraction, or Coleman Fat Grafting? PMID- 25715081 TI - A pharmacist's perspective on metformin use and cancer outcomes. PMID- 25715082 TI - An oncologist's perspective on metformin use and acute lymphoblastic leukemia outcomes. PMID- 25715083 TI - Should pharmacokinetic safety challenges prevent metformin use in patients with cancer? PMID- 25715085 TI - Key articles and guidelines in the management of patients undergoing cardiac surgery. AB - Significant numbers of patients undergo cardiac surgery worldwide each year. A large evidence base exists regarding the optimal pre-, intra-, and postoperative mediation management for patients undergoing coronary artery bypass grafting (CABG) surgery, valve replacements or repairs, and mechanical circulatory support (MCS). Prevention and treatment of perioperative arrhythmias, perioperative antimicrobial prophylaxis, prevention of thrombosis, and bleeding through proper management of perioperative antiplatelet and anticoagulant therapies, and the use of pharmacotherapy to optimize both short- and long-term patient outcomes after cardiac surgery are the focus of this first compilation of guidelines and key articles in this patient population to be published in the Journal of Pharmacy Practice. PMID- 25715086 TI - Carvedilol-induced hyperkalemia in a patient with chronic kidney disease. AB - A 69-year-old male was admitted to the hospital with a chief complaint of abdominal pain, nausea, and vomiting. He had an extensive past medical history, including diabetes mellitus type 2 and chronic kidney disease stage III. Prior to admission, the patient was taking carvedilol 3.125 mg twice daily with no abnormality in his serum potassium. During hospitalization, his carvedilol was increased to 6.25 mg twice daily. The patient's serum potassium then rose from 4.8 to 6.7 mEq/L, with no improvement following administration of sodium polystyrene sulfonate. Nephrology concluded the carvedilol could be contributing to the hyperkalemia. The dose was decreased back to 3.125 mg twice daily, leading to the potassium normalizing to 4.4 mEq/L. The reported incidence of beta-blocker induced hyperkalemia is less than 5%. A literature search revealed several cases of beta-blocker-induced hyperkalemia, but to the authors' knowledge, this is the first case describing carvedilol specifically. Utilization of the Naranjo probability scale indicated a possible probability that the carvediol was the cause. PMID- 25715087 TI - President's Message: Advancing the Practice of Pharmacy in New York State. PMID- 25715088 TI - Validation of the Konsung QD217A for clinical use and self-measurement according to the European Society of Hypertension International Protocol. AB - OBJECTIVE: This study aimed to evaluate the accuracy of the automated oscillometric upper arm blood pressure (BP) monitor Konsung QD217A for home BP monitoring according to the European Society of Hypertension International Protocol revision 2010. METHODS: Three trained observers validated the performance of these devices by comparing the measurements obtained from these devices with those taken using a standard mercury sphygmomanometer. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were sequentially measured in 33 participants using a standard mercury sphygmomanometer and the Konsung QD217A device. A total of 99 pairs of comparisons were obtained from 33 participants. RESULTS: The QD217A device achieved the targets in part 1 of the validation study. The number of absolute differences between the device and the observers within a range of 5, 10 and 15 mmHg was 70/99, 92/99 and 96/99, respectively, for SBP and 80/99, 94/99 and 99/99, respectively, for DBP. The device also achieved the targets in part 2 of the validation study. A total of 27 and 31 participants for SBP and DBP, respectively, showed at least two of the three device-observers differences within 5 mmHg (required>=24). The number of participants without device-observer difference within 5 mmHg was one for SBP and one for DBP (required<=3). CONCLUSION: The Konsung upper arm BP monitor QD217A has passed the International Protocol requirements and it can be recommended for clinical use and self-measurement in adults. PMID- 25715089 TI - Cardiac remodeling in response to chronic iron deficiency: role of the erythropoietin receptor. AB - OBJECTIVE: Anemia is a common comorbidity of patients with heart failure, and iron deficiency is known as one of the causes of anemia in heart failure. Recent studies have shown that iron deficiency alone, without overt anemia, is associated with poor outcomes in patients with heart failure. Thus, to minimize the mortality in patients with heart failure, it is important to understand the link between iron deficiency and cardiac function. Chronic untreated iron deficiency results in cardiac remodeling, and we have previously reported that erythropoietin (Epo) and cardiac Epo receptor (EpoR) signaling may be associated with its remodeling. However, the link between EpoR signaling and its remodeling remains to be elucidated. Herein, we investigated the role of EpoR signaling on cardiac remodeling in response to chronic iron deficiency. METHODS: Wild-type mice and transgene-rescued EpoR-null mutant mice, which express EpoR only in the hematopoietic lineage (EpoR-restricted mice), were fed with either a normal or an iron-restricted diet, and the molecular mechanisms were investigated. RESULTS: Dietary iron restriction gradually induced anemia, Epo secretion, and cardiac hypertrophy in wild-type mice. In contrast, EpoR-restricted mice fed with an iron restricted diet exhibited anemia, left ventricular dilatation, and cardiac dysfunction compared with wild-type mice. Interestingly, altered cardiac mitochondrial biogenesis was observed in EpoR-restricted mice following iron deficiency. Moreover, cardiac p53 expression was increased in EpoR-restricted mice compared with wild-type mice following iron deficiency. CONCLUSION: These data indicate that EpoR signaling is associated with cardiac remodeling following chronic iron deficiency. PMID- 25715090 TI - Multiparametric carotid and cardiac ultrasound compared with clinical risk scores for the prediction of angiographic coronary artery disease: a multicenter prospective study. AB - OBJECTIVE: Cardiovascular risk prediction is deemed fundamental and the assessment of organ damage is emerging as a potentially 'downstream' picture of individual risk. Our aim was to assess the feasibility and value of prediction of coronaropathy [coronary artery disease (CAD)] of integrated cardiovascular ultrasound examination. METHODS: This multicenter study involved eight cardiology centers that enrolled 457 consecutive patients. Blood pressures, carotid intima media thickness (cIMT), carotid pulse wave velocity (cPWV), semiquantitative score of cardiac calcifications, global myocardial longitudinal strain (GLS), and rest Doppler flow velocity on the left anterior descending (LAD) coronary artery were measured. After coronary angiography, patients were divided in CAD, n = 273, at least one coronary stenosis higher than 50%, and no CAD, n = 184. RESULTS: CAD were older (65.9 +/- 10.7 versus 63.1 +/- 11.2 years, mean +/- standard deviation, P = 0.01), and had higher blood pressure (137.0 +/- 18.8/77.5 +/- 11.1 versus 130.2 +/- 17.4/75.1 +/- 9.7 mmHg, P < 0.02), cIMT (791.4 +/- 165.5 versus 712.0 +/- 141.5 mcm, P < 0.0001), cPWV (median: 9 versus 8.1 m/s, P < 0.01), score of calcium (median, 2 versus 1, P < 0.0001), LAD velocity (median, 38 versus 36, P < 0.07), and lower GLS (-17.6 +/- 4.3 versus -19.3 +/- 5.1, P < 0.05) than no CAD. Score of calcium was feasible in the totality of patients, cIMT in 97%, cPWV in 86%, GLS in 88%, and LAD in 84%. A combination of at least three variables was measurable in 80% of the patients. All ultrasound parameters significantly predicted CAD. However, in a stepwise logistic regression, the only combined predictors of obstructive CAD were score of calcium, cIMT, and LAD velocity. CONCLUSION: In Echo-Lab, Rome, Italy, the integrated cardiovascular ultrasound study is feasible in a high percentage of patients. The combination of three parameters, that is, score of calcium, cIMT, and LAD velocity, has incremental predictive value for obstructive CAD. PMID- 25715091 TI - Dietary and lifestyle patterns in relation to high blood pressure in children: the GRECO study. AB - OBJECTIVE: The objective of the present study was to investigate possible associations of dietary patterns with high blood pressure (BP) in a nationwide cross-sectional sample of 10-12 years old Greek schoolchildren. METHODS: Anthropometric measurements and information on dietary (by a semi-quantitative food frequency questionnaire) and physical activity habits were obtained from the children. BPs was measured in a single occasion using a standard protocol. Data from 2024 normal energy reporting children were included in the analysis. Principal component analysis was applied to identify dietary patterns. RESULTS: Seven dietary components (patterns) were extracted explaining 55% of the total variation in intake. Multiple logistic regression analysis revealed that predictors of high BP (75th percentile of SBP and/or DBP) were a pattern mainly characterized by the high consumption of cheese and red processed meat [odds ratio (OR) 1.15; 95% confidence intervals (CI) 1.03-1.30], being overweight (OR 2.10; 95% CI 1.61-2.73) or obese (OR 3.84; 95% CI 2.44-6.06) and breakfast frequency (OR 0.95; 95% CI 0.90-0.99). After controlling for sodium intake levels, the dietary pattern did not remain a significant predictor of high BP, indicating the potential mediating effect of sodium in the association. CONCLUSION: A dietary pattern that is characterized by high cheese and red processed meat consumption increases the likelihood of having high BP in children, probably through increasing dietary sodium intake. These findings could guide future interventions or public health initiatives to prevent the increasing rates of childhood elevated BP levels. PMID- 25715092 TI - Primary aldosteronism and its various clinical scenarios. AB - BACKGROUND: Primary aldosteronism is the most frequent endocrine cause of secondary hypertension. Aldosterone excess damages the cardiovascular system. OBJECTIVES: We compared biochemical; morphological, and cardiovascular risk differences among hypokalemic and normokalemic primary aldosteronism. We evaluated either both presentations correspond to two different entities or a unique disease in different evolutive stage. MATERIAL AND METHODS: This is a retrospective study including 157 patients with primary aldosteronism divided into two groups: typical presentation (serum potassium < 3.5 mmol/l, n = 87) and atypical presentation (serum potassium > 3.5 mmol/l, n = 70). RESULTS: The typical presentation group showed higher family background of ischemic heart disease (P = 0.028), plasmatic aldosterone levels (P = 0.001), and cardiovascular added risk (P = 0.013). Although kalemia was corrected in the hypokalemic group after specific treatment, typical presentation maintained lower levels. Predictors of typical presentation were the highest tertile of aldosterone level, baseline DBP, and a longer evolution of hypertension. Aldosterone serum levels increased along time in primary aldosteronism and it can be considered as the most discriminative factor for the type of presentation. CONCLUSION: Primary aldosteronism presentation along with normokalemia or hypokalemia could be the same disease at different evolution stages. Adequate detection of normokalemic primary aldosteronism deserves an early and intentional diagnostic attitude. PMID- 25715093 TI - Large artery stiffness and hypertension after antiangiogenic drugs: influence on cancer progression. AB - BACKGROUND: Systemic hypertension is a frequent side effect of antiangiogenic drugs (AADs) and may represent a marker of efficacy on cancer. We hypothesized that large artery properties are affected by AADs, and contribute to the rise of blood pressure and may be better related to cancer progression and mortality than hypertension. METHODS AND RESULTS: Participants were studied before AADs (V0), 10 days later (V1) and then every 2 weeks for 6 weeks (V1-V4). We included 57 consecutive patients in whom treatment with sorafenib (400 mg twice daily) or sunitinib (37.5-50 mg once daily) was indicated. The target dose could be adjusted according to tolerance and response. Aortic and carotid stiffness, brachial and central blood pressure and augmentation index were measured noninvasively at each visit. Data regarding cancer progression and mortality were collected at 6 months. Twenty-eight patients (49%) developed hypertension. Brachial SBP significantly increased during follow-up (V0-V1: +9.6 +/- 15.2 mmHg, P < 0.001; V0-V4: +6.0 +/- 17.8 mmHg, P = 0.04). Central BP, and aortic and carotid stiffness increased independently of brachial BP changes. Aortic and carotid stiffening were associated with cancer progression independently of BP changes [hazard risk 1.24 (1.01-1.51) and 1.34 (1.03-1.73), respectively; P < 0.05], but not with cancer mortality. Brachial SBP had no predictive value. CONCLUSION: Large arteries stiffen during AAD treatment partly independently of BP changes. Arterial mechanical properties are associated with BP rise. Arterial stiffening is related with the effects of AAD on cancer progression independently of BP changes. Large artery properties might help monitor AAD therapy in cancer patients. PMID- 25715094 TI - The mechanisms underlying fructose-induced hypertension: a review. AB - We are currently in the midst of an epidemic of metabolic disorders, which may, in part, be explained by excess fructose intake. This theory is supported by epidemiological observations as well as experimental studies in animals and humans. Rising consumption of fructose has been matched with growing rates of hypertension, leading to concern from public health experts. At this stage, the mechanisms underlying fructose-induced hypertension have not been fully characterized and the bulk of our knowledge is derived from animal models. Animal studies have shown that high-fructose diets up-regulate sodium and chloride transporters, resulting in a state of salt overload that increases blood pressure. Excess fructose has also been found to activate vasoconstrictors, inactivate vasodilators, and over-stimulate the sympathetic nervous system. Further work is required to determine the relevance of these findings to humans and to establish the level at which dietary fructose increases the risk of developing hypertension. PMID- 25715095 TI - The role of blood pressure, body weight and fat distribution on left ventricular mass, diastolic function and cardiac geometry in children. AB - BACKGROUND: Hypertension and obesity in childhood are related to early cardiac damage, as left ventricular hypertrophy. Few studies have analyzed the independent effects of hypertension and weight excess on diastolic function and left ventricular geometry. OBJECTIVE: We studied the effects of weight, waist circumference (as an index of fat distribution) and blood pressure on left ventricular mass index, the risk of left ventricular hypertrophy, diastolic function and left ventricular geometry in 526 children (237 girls, age range 6-15 years). METHODS: Children were divided into normotensive, prehypertensive and hypertensive (US Nomograms) groups, and into normal-weight, overweight, and obese (International Obesity Task Force classification) groups. Left ventricular mass index, diastolic function and left ventricular geometry were assessed. RESULTS: SBP z-scores and blood pressure categories significantly influenced cardiac mass (P < 0.001 and P = 0.02, respectively) and the prevalence of left ventricular hypertrophy (P < 0.001 and P < 0.05, respectively). Obesity, BMI, and waist circumference z-scores were significantly associated with an increment in E/Em ratio (P < 0.001, P < 0.01, and P < 0.01, respectively). Increasing blood pressure values and the presence of prehypertension (P < 0.05) and hypertension (P < 0.003), but not weight excess, were associated with concentric cardiac remodeling. In contrast, concentric hypertrophy was associated with hypertension (P < 0.01), obesity (P < 0.001), and increasing waist circumference (P < 001). CONCLUSIONS: Blood pressure values and hypertension are independently associated with an increase of cardiac mass and the presence of cardiac hypertrophy. Obesity and waist circumference, but not hypertension, are associated with a worsening of diastolic function, whereas only hypertensive children show high prevalence of concentric remodeling. Blood pressure and body weight and fat distribution have an independent and different impact on left ventricular structure and function in children. PMID- 25715098 TI - Eyes on new product development. PMID- 25715097 TI - PARK2/Parkin becomes critical when DNM1L/Drp1 is absent. AB - Maintaining mitochondrial dynamics and proper execution of mitophagy is crucial for sustaining cellular health. Defects in these processes have been linked to cardiovascular diseases and neurodegeneration. In a recent publication, we reported that the mitochondrial division dynamin protein DNM1L/Drp1 and the E3 ubiquitin ligase PARK2/Parkin work in a synergistic manner to maintain mitochondrial function and structural integrity in the mouse heart and brain. PMID- 25715099 TI - Variability in structure of university pulmonary/critical care fellowships and retention of fellows in academic medicine. AB - INTRODUCTION: Individual fellowship programs are challenged to find a format of training that not only meets the Accreditation Council for Graduate Medical Education requirements, but also grooms fellows to be trusted clinicians, and encourages them to enter academic careers. This study was undertaken as part of an internal effort to evaluate and revise the program structure of the pulmonary/critical care medicine fellowship at the Medical University of South Carolina. Our objectives were to characterize variation in the training structure and specifically research opportunities of university pulmonary/critical care medicine fellowship programs, and to identify factors associated with fellow retention in academic medicine and research. METHODS: A 30-item survey was developed through rigorous internal review and was administered via email. Descriptive statistics, Cronbach's alpha, correlations, Wilcoxon sign-rank test, and ANOVA were carried out. RESULTS: We had a response rate of 52%. Program directors reported that, within the past 5 years, 38% of their fellows remained in academic medicine and 20% remained in academics with significant research focus. We found a statistically significant association between obtaining a master's degree and remaining in academics (r = 0.559; P < 0.008). The survey also revealed statistically significant relationships between scholarly requirements (grant proposals, peer-reviewed original research projects) and the percent of fellows who graduated and remained in academics. CONCLUSIONS: This survey offers some insights that may be useful to fellowship program directors. In particular, advanced education in research and maximizing scholarly activities might be associated with increased academic retention among fellowship trainees. PMID- 25715100 TI - Corrigendum to "Molecular Characterization of a Fully Human Chimeric T-Cell Antigen Receptor for Tumor-Associated Antigen EpCAM". AB - [This corrects the article DOI: 10.1155/2012/853879.]. PMID- 25715096 TI - Vaccines for viral and bacterial pathogens causing acute gastroenteritis: Part II: Vaccines for Shigella, Salmonella, enterotoxigenic E. coli (ETEC) enterohemorragic E. coli (EHEC) and Campylobacter jejuni. AB - In Part II we discuss the following bacterial pathogens: Shigella, Salmonella (non-typhoidal), diarrheogenic E. coli (enterotoxigenic and enterohemorragic) and Campylobacter jejuni. In contrast to the enteric viruses and Vibrio cholerae discussed in Part I of this series, for the bacterial pathogens described here there is only one licensed vaccine, developed primarily for Vibrio cholerae and which provides moderate protection against enterotoxigenic E. coli (ETEC) (Dukoral((r))), as well as a few additional candidates in advanced stages of development for ETEC and one candidate for Shigella spp. Numerous vaccine candidates in earlier stages of development are discussed. PMID- 25715101 TI - The HLA-C*04: 01/KIR2DS4 gene combination and human leukocyte antigen alleles with high population frequency drive rate of HIV disease progression. AB - OBJECTIVE: The objective of this study is to identify human leukocyte antigen (HLA) class I and killer-cell immunoglobulin-like receptor (KIR) genotypes associated with different risks for HIV acquisition and HIV disease progression. DESIGN: A cross-sectional study of a cohort of 468 high-risk individuals (246 HIV positive and 222 HIV-negative) from outpatient clinics in Lima (Peru). METHODS: The cohort was high-resolution HLA and KIR-typed and analysed for potential differences in single-allele frequencies and allele combinations between HIV positive and HIV-negative individuals and for associations with HIV viral load and CD4 cell counts in infected individuals. RESULTS: HLA class I alleles associated with a lack of viral control had a significantly higher population frequency than relatively protective alleles (P = 0.0093), in line with a rare allele advantage. HLA-A02 : 01 and HLA-C04 : 01 were both associated with high viral loads (P = 0.0313 and 0.0001, respectively) and low CD4 cell counts (P = 0.0008 and 0.0087, respectively). Importantly, the association between HLA-C04 : 01 and poor viral control was not due to its linkage disequilibrium with other HLA alleles. Rather, the coexpression of its putative KIR ligand KIR2DS4f was critically linked to elevated viral loads. CONCLUSION: These results highlight the impact of population allele frequency on viral control and identify a novel association between HLA-C04 : 01 in combination with KIR2DS4f and uncontrolled HIV infection. Our data further support the importance of the interplay of markers of the adaptive and innate immune system in viral control. PMID- 25715102 TI - Low SAMHD1 expression following T-cell activation and proliferation renders CD4+ T cells susceptible to HIV-1. AB - OBJECTIVES: HIV-1 replication depends on the state of cell activation and division. It is established that SAMHD1 restricts HIV-1 infection of resting CD4 T cells. The modulation of SAMHD1 expression during T-cell activation and proliferation, however, remains unclear, as well as a role for SAMHD1 during HIV 1 pathogenesis. METHODS: SAMHD1 expression was assessed in CD4 T cells after their activation and in-vitro HIV-1 infection. We performed phenotype analyzes using flow cytometry on CD4 T cells from peripheral blood and lymph nodes from cohorts of HIV-1-infected individuals under antiretroviral treatment or not, and controls. RESULTS: We show that SAMHD1 expression decreased during CD4 T-cell proliferation in association with an increased susceptibility to in-vitro HIV-1 infection. Additionally, circulating memory CD4 T cells are enriched in cells with low levels of SAMHD1. These SAMHD1 cells are highly differentiated, exhibit a large proportion of Ki67 cycling cells and are enriched in T-helper 17 cells. Importantly, memory SAMHD1 cells were depleted from peripheral blood of HIV infected individuals. We also found that follicular helper T cells present in secondary lymphoid organs lacked the expression of SAMHD1, which was accompanied by a higher susceptibility to HIV-1 infection in vitro. CONCLUSION: We demonstrate that SAMHD1 expression is decreased during CD4 T-cell activation and proliferation. Also, CD4 T-cell subsets known to be more susceptible to HIV-1 infection, for example, T-helper 17 and follicular helper T cells, display lower levels of SAMHD1. These results pin point a role for SAMHD1 expression in HIV-1 infection and the concomitant depletion of CD4 T cells. PMID- 25715103 TI - Up-regulation of Tim-3 on T cells during acute simian immunodeficiency virus infection and on antigen specific responders. AB - OBJECTIVE: Understanding the role of T-cell immunoglobulin and mucin domain containing molecule 3 (Tim-3) on T cells and dendritic cells during the course of simian immunodeficiency virus (SIV) infection. DESIGN: Sequentially collected PBMCs from uninfected and SIVmac239-infected rhesus macaques were evaluated for Tim-3 expression by flow cytometry and antigen-specific responses. RESULTS: Blood innate immune cells (dendritic cells) and B cells showed high constitutive expression of Tim-3, whereas, compared to humans, only a minority of macaque T cells did. However, TIM-3 expression was transiently up-regulated on both CD4 and CD8 T cells during acute SIV infection, correlating with plasma viral loads, CD4 cell counts, and Ki67 expression up to 6 weeks postinfection and returned to baseline values by 8 weeks postinfection. Upon antigen-specific stimulation, most Tim-3 T cells produced various cytokines, suggesting that this marker is up regulated on effector antigen-specific T cells and not associated with T-cell exhaustion. Among myeloid dendritic cells (mDCs), a clear separation was seen between blood mDCs expressing Tim-3 and those expressing PD-L2 - a ligand for inhibitory receptor programmed death 1. CONCLUSION: Rhesus macaques show constitutive expression of Tim-3 primarily on innate immune cells, but markedly lower levels on T cells compared to humans. Nevertheless, Tim-3 expression on T cells is transiently up-regulated during acute, but not chronic, SIV infection, and appears to be a marker of antigen-specific effector cells. The exact role and contribution of Tim-3 to the modulation of antiviral responses in vivo will require additional investigation. PMID- 25715104 TI - Influence of lifelong cumulative HIV viremia on long-term recovery of CD4+ cell count and CD4+/CD8+ ratio among patients on combination antiretroviral therapy. AB - OBJECTIVE: We explored the impact of lifelong cumulative HIV viremia on immunological recovery during antiretroviral therapy, according to the timing of treatment initiation. METHODS: We estimated lifelong cumulative HIV viremia in patients followed in the ANRS PRIMO cohort since primary infection, including 244 patients who started treatment during PHI and had at least one treatment interruption, and 218 patients who started treatment later but with no interruptions. The impact of cumulative viremia on current immunological status was analysed using linear and logistic regression models. RESULTS: At the last visit on treatment, median CD4 cell count was 645 cells/MUl in the early/intermittent treatment group (median time from infection 9.5 years, 4.8 years of continuous treatment since last resumption), and 654 cells/MUl in the deferred/continuous treatment group (median time from infection 6.1 years, 3.0 years of continuous treatment). Only 36.1 and 39.8% of patients achieved a CD4/CD8 ratio of more than 1, respectively. Current CD4 cell count was not associated with cumulative HIV viremia in either group. In contrast, patients with high cumulative HIV viremia (>66th percentile vs. <33rd percentile) were less likely to achieve a CD4/CD8 ratio of more than 1 (26.8 vs. 43.3%, P = 0.003), even after controlling for the baseline CD4/CD8 ratio, treatment duration, sex and age. Much higher CD4 cell count and CD4/CD8 ratio were reached in early/continuous treatment, that is low viremia exposure group. CONCLUSION: Our results underline the critical need in early-treated patients to maintain adherence, in order to limit cumulative HIV viremia and optimize immunological recovery, notably the CD4/CD8 ratio. PMID- 25715105 TI - High HIV burden among people who inject drugs in 15 Indian cities. AB - BACKGROUND: Injecting drug use has historically been the principal driver of the HIV epidemic in the northeast states of India. However, recent data indicate growing numbers of people who inject drugs (PWIDs) in north and central Indian cities. METHODS: We conducted face-to-face surveys among PWIDs in seven northeast and eight north/central Indian cities using respondent-driven sampling. We used a rapid HIV-testing protocol to identify seropositive individuals and multiassay algorithm to identify those with recent infection. We used multilevel regression models that incorporated sampling weights and had random intercepts for site to assess risk factors for prevalent and incident (recent) HIV infection. RESULTS: We surveyed 14 481 PWIDs from 15 Indian cities between January and December 2013. Participants reported high rates of needle/syringe sharing. The median (site range) estimated HIV prevalence and incidence were 18.1% (5.9, 44.9) and 2.9 per 100 person-years (0, 12.4), respectively. HIV prevalence was higher in northeast sites, whereas HIV incidence was higher in north/central sites. The odds of prevalent HIV were over three-fold higher in women than in men. Other factors associated with HIV prevalence or incidence included duration since first injection, injection of pharmaceutical drugs, and needle/syringe sharing. CONCLUSIONS: The burden of HIV infection is high among PWIDs in India, and may be increasing in cities where injecting drug use is emerging. Women who inject drugs were at substantially higher risk for HIV than men - a situation that may be mediated by dual injection-related and sexual risks. PMID- 25715106 TI - Evaluating potential T-cell epitope peptides for detecting HIV-specific T cell responses in a highly diverse HIV-1 epidemic from Cameroon. AB - HIV genetic diversity is a major obstacle for vaccine development. To define whether potential T-cell epitope (PTE) peptide usage improves the detection of T cell responses in a highly diverse HIV-1 epidemic, we compared the magnitude, breadth and depth of group M PTE peptide responses to consensus M peptides in Gag and Nef proteins. Gag PTE responses were detected at a higher magnitude, more Nef PTE responses were detected at a cohort (but not individual) level and depth was detected in both Gag and Nef responses. PMID- 25715107 TI - Factors influencing healthy lifestyle changes: a qualitative look at low-income families engaged in treatment for overweight children. AB - BACKGROUND: Childhood obesity disproportionately affects low-income minority populations, yet there is a paucity of literature about effective interventions in this population. This study sought to understand the experience of low-income majority Hispanic families engaged in obesity treatment. METHODS: We conducted six focus groups (2=English, 4=Spanish) with families who completed a community based, family-oriented obesity treatment program, using standard qualitative focus group interview methods. Transcripts were recorded, transcribed, and analyzed for thematic content. Two coders using the software program ATLAS.ti (v.7.0; Scientific Software Development GmbH, Berlin, Germany) coded each transcript independently; reflexive team analysis with three study team members was used to reach a consensus. RESULTS: Participants (n=37) indicated high program satisfaction. Parents reported buying less junk/fast food, increased consumption of fruits and vegetables, preparing and eating more meals as a family, and increasing their families' physical activity (PA). Four barrier and facilitator themes emerged. Barrier themes were time and financial cost, parent's lack of time and energy, influence of family members, and challenges regarding physical environment. Facilitator themes were skill building around healthy eating and parenting, family involvement, and long-term health concerns. Unanticipated findings, parents reported, were that changes resulted in children sleeping better, feeling happier, and less irritability. CONCLUSIONS: Despite low income families experiencing barriers to lifestyle changes to manage obesity, they made positive dietary changes and increased PA by learning specific skills and including the whole family in those changes. Additionally, some unexpected benefits were noted, including improved sleep, less irritability, and children appearing happier. Future studies should consider using these parent-identified outcomes as secondary measures of program effectiveness. PMID- 25715108 TI - Promoting resiliency among palliative care clinicians: stressors, coping strategies, and training needs. AB - BACKGROUND: Palliative care clinicians (PCCs) are susceptible to burnout, as they regularly witness immense patient and family suffering; however, little is known about their specific challenges and training needs to enhance their long-term sustainability. OBJECTIVE: The purpose of this qualitative study was to explore common stressors, coping strategies, and training needs among PCCs in efforts to inform the development of a targeted Resiliency Program. METHODS: Utilizing a semistructured interview guide, we conducted a series of in-depth interviews with 15 PCCs at the Massachusetts General Hospital. RESULTS: Content analysis highlighted three main areas of stressors: (1) systematic challenges related to managing large, emotionally demanding caseloads within time constraints; (2) patient factors, such as addressing patients' mutable needs, managing family dynamics, and meeting patient and family demands and expectations; and (3) personal challenges of delineating emotional and professional boundaries. Engaging in healthy behaviors and hobbies and seeking emotional support from colleagues and friends were among the most common methods of coping with stressors. In terms of programmatic topics, PCCs desired training in mind-body skills (e.g., breathing, yoga, meditation), health education about the effects of stress, and cognitive strategies to help reduce ruminative thoughts and negative self-talk. A majority of clinicians stressed the need for brief strategies that could be readily integrated in the workplace. CONCLUSIONS: These results suggest that an intervention aimed to enhance PCC sustainability should focus on utilizing a skill-building approach to stress reduction that imparts strategies that can be readily utilized during work hours. PMID- 25715109 TI - The SMC loader Scc2 regulates gene expression. PMID- 25715110 TI - Bariatric surgery for metabolic syndrome in obesity. AB - Metabolic syndrome is closely associated with morbid obesity and leads to increased risk of cardiovascular diseases and related mortality. Bariatric surgery is considered an effective option for the management of this condition. We searched MEDLINE, Current Contents, and the Cochrane Library for papers published on bariatric surgery outcomes in English from January 1, 1990, to April 20, 2014. Bariatric surgery can significantly reduce body weight, resolve or cure many of the symptoms of metabolic syndrome, including type 2 diabetes, hypertension, hyperlipidemia, and improve long-term survival. Surgery, in addition to existing therapy, could therefore be considered as an optimal treatment for patients with metabolic syndrome and morbid obesity. PMID- 25715112 TI - Effect of the cation size on the framework structures of magnesium tungstate, A4Mg(WO4)3 (A = Na, K), R2Mg2(WO4)3 (R = Rb, Cs). AB - A series of alkali metal magnesium tungstates, A4Mg(WO4)3 (A = Na, K), R2Mg2(WO4)3 (R = Rb, Cs), were synthesized from a high temperature solution, and their structures were determined by single-crystal X-ray diffraction. Interestingly, Na4Mg(WO4)3 crystallizes in the monoclinic space group C2/c, while K4Mg(WO4)3 having an identical stoichiometry with Na4Mg(WO4)3, exhibits a different framework structure belonging to triclinic symmetry with the space group P1[combining macron]. Isostructural Rb2Mg2(WO4)3 and Cs2Mg2(WO4)3 crystallize in the space group P213 of cubic symmetry and reveal a three dimensional framework composed of isolated WO4 tetrahedra, MgO6 octahedra and RO12 (R = Rb, Cs) polyhedra. The effect of the alkali metal cation size on the framework structures of magnesium tungstate has been discussed in detail. In addition, the infrared spectra, as well as the UV-Vis-NIR diffuse reflectance spectroscopy data, are reported. The first-principles theoretical studies are also carried out to aid the understanding of electronic structures and linear optical properties. PMID- 25715111 TI - The yeast zeta-crystallin/NADPH:quinone oxidoreductase (Zta1p) is under nutritional control by the target of rapamycin pathway and is involved in the regulation of argininosuccinate lyase mRNA half-life. AB - The yeast zeta-crystallin (Zta1p) is a quinone oxidoreductase belonging to the zeta-crystallin family, with activity in the reduction of alkenal/alkenone compounds. Various biological functions have been ascribed to the members of this protein family, such as their ability to interact specifically with AU-rich sequences in mRNA, and thus they have been proposed to act as AU-rich element binding proteins (AREBPs). In this study, we evaluated the specificity of Zta1p for RNA versus DNA by means of a novel nonisotopic method for the in vitro quantitative detection of protein . RNA complexes. Through comparative transcriptomic analysis, we found that the lack of Zta1p negatively affects the expression of a group of genes involved in amino acid biosynthesis, the argininosuccinate lyase (ARG4) gene being one of them. Here, we propose that Zta1p participates in the post-transcriptional regulation of ARG4 expression by increasing the ARG4 mRNA half-life. In addition, expression of the zeta crystallin gene (ZTA1) is itself regulated by nutrient availability through the general amino acid control and target of rapamycin pathways. Our results shed new light on the zeta-crystallin family members from yeast to humans as stress response proteins with a bifunctional role in the detoxification of alkenal and alkenone compounds, and the regulation of gene expression. PMID- 25715113 TI - Agmatine attenuates lipopolysaccharide induced anorexia and sickness behavior in rats. AB - Sickness behavior is characterized by lethargy, reduced appetite, anhedonia and anxiety. It can be induced in experimental animals by bacterial endotoxin, lipopolysaccharide (LPS). We investigated the impact of intracerebroventricular agmatine injections (5-20MUg/rat, icv) on sickness behavior induced by LPS (100MUg/rat, ip) in rats. Rats challenged with LPS demonstrated hyperthermia, anorexia, anxiety, depression like phenomenon and reduction in body weights. Additionally, mediators of sickness behaviors, interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) level in LPS treated rat serum were also increased. The present study revealed that these LPS induced symptoms of sickness behavior including anorexia were normalized by pretreatment with agmatine. The IL 6 and TNF-alpha serum levels were also normalized in agmatine pretreated rats. It is anticipated that agmatine may suppress LPS induced sickness behavior by inhibiting proinflammatory pathway and/or activity circuitry in brain. This study suggests that agmatine may be an important therapeutic target in the treatment of anorexia and other neurological abnormalities associated with bacterial infection. PMID- 25715114 TI - Bioactive polymersomes self-assembled from amphiphilic PPO-glycopolypeptides: synthesis, characterization, and dual-dye encapsulation. AB - Glycopolypeptide-based polymersomes have promising applications as vehicles for targeted drug delivery because they are capable of encapsulating different pharmaceuticals of diverse polarity as well as interacting with specific cell surfaces due to their hollow structural morphology and bioactive surfaces. We have synthesized glycopolypeptide-b-poly(propylene oxide) by ROP of glyco-N carboxyanhydride (NCA) using the hydrophobic amine-terminated poly(propylene oxide) (PPO) as the initiator. This block copolymer is composed of an FDA approved PPO hydrophobic block in conjugation with hydrophilic glycopolypeptides which are expected to be biocompatible. We demonstrate the formation of glycopolypeptide-based polymersomes from the self-assembly of glycopolypeptide-b poly(propylene oxide) in which the presence of an ordered helical glycopolypeptide segment is required for their self-assembly into spherical nanoscale (~50 nm) polymersomes. The polymersomes were characterized in detail using a variety of techniques such as TEM, AFM, cryo-SEM, and light-scattering measurements. As a model for drugs, both hydrophobic (RBOE) and hydrophilic (calcein) dyes have been incorporated within the polymersomes from solution. To substantiate the simultaneous entrapment of the two dyes, spectrally resolved fluorescence microscopy was performed on the glycopeptide polymersomes cast on a glass substrate. We show that it is possible to visualize individual nanoscale polymersomes and effectively probe the dyes' colocalization and energy-transfer behaviors therein as well as investigate the variation in dual-dye encapsulation over a large number of single polymersomes. Finally, we show that the galactose moieties present on the surface can specifically recognize lectin RCA120, which reveals that the polymersomes' surface is indeed biologically active. PMID- 25715115 TI - Perception of the A/H1N1 influenza pandemic and acceptance of influenza vaccination by Universite Claude Bernard Lyon 1 staff: A descriptive study. AB - We assessed the perception and attitudes of university staff, including medical school and other science specialties, toward the 2009 A/H1N1 influenza pandemic and influenza vaccination program. A cross-sectional online survey was conducted among 4,529 university personnel on October 19-20, 2009. Seven hundred (15%) employees participated in the study. Only 18% were willing to be vaccinated, men more than women (29% versus 9%, P < 0.001), and professors/researchers more than administrative/technical staff (30% vs. 6%, P < 0.001). Intention to be vaccinated was insufficient. Additional efforts are needed to improve information dissemination among university staff. Medical university personnel should receive more information to increase vaccine coverage and protect them as well as patients. PMID- 25715117 TI - Photothermal synthesis of ultrafine Cu(x)O nanoparticles on carbon nanotubes for photosensitized degradation. AB - We exploit a facile strategy for photothermal synthesis (PTS) of CuxO nanoparticles (NPs) on carbon nanotubes (CNTs) suspended in solution, where the pulsed laser can penetrate through the liquid unimpeded and heat the CNTs selectively to a high temperature, thereafter, the hot CNTs trigger the chemical reactions to produce CuxO NPs directly on the CNT surface. PTS yields ultrafine NPs with sizes of 3-5 nm, which distribute evenly and connect tightly with CNTs. The CuxO-CNTs composite shows excellent photocatalytic properties due to its cascade energy structure, smooth electron transfer between NPs and CNTs, and elimination of structural defects in CNTs by laser heating. PMID- 25715116 TI - Telaprevir- and Boceprevir-based Triple Therapy for Hepatitis C in Liver Transplant Recipients With Advanced Recurrent Disease: A Multicenter Study. AB - BACKGROUND: Antiviral treatment with sustained virologic response (SVR) improves survival in liver transplant (LT) recipients, and is especially relevant to patients with advanced recurrent hepatitis C virus (HCV). We assessed the safety and efficacy of protease inhibitor-based triple therapy in patients with recurrent advanced fibrosis and cholestatic hepatitis. METHODS: The LT recipients with genotype 1 HCV and advanced fibrosis (F3-4/4) or cholestatic hepatitis treated with telaprevir- or boceprevir-based triple therapy at 6 centers (CRUSH-C consortium) were retrospectively assessed. The primary endpoints were SVR at 12 weeks (SVR12) and safety. RESULTS: Forty-five patients with advanced fibrosis and 9 with cholestatic hepatitis (74% men, 57% genotype 1a, 63% previous nonresponders) were included. SVR12 occurred in 51% with advanced fibrosis and 44% with cholestatic hepatitis. Extended rapid virologic response was highly predictive of SVR12. Hispanic ethnicity (odds ratio, 0.16; P = 0.03), previous null/partial response (0.24; P = 0.02), IL28B genotype CC (7.0; P = 0.02), albumin (3.87; P = 0.03), platelet count (1.01; P = 0.02), and steroid use (0.21; P = 0.03) were associated with SVR12. Six (11%) patients died, and hepatic decompensation occurred in 22% with advanced fibrosis and 33% with cholestatic hepatitis. Albumin (0.02; P = 0.001), encephalopathy (12.0; P = 0.04) and Hispanic ethnicity (odds ratio, 6.17; P = 0.01) were associated with death or decompensation. CONCLUSIONS: For LT recipients with recurrent advanced HCV and at greatest need of cure, protease inhibitor-based triple therapy achieved approximately 50% SVR12. However, there is significant risk of serious adverse events, arguing for earlier intervention. The availability of treatments with better efficacy and safety is of particular importance for posttransplant patients with advanced disease. PMID- 25715118 TI - New insights into mechanisms of glomerular injury and repair from the 10th International Podocyte Conference 2014. AB - Glomerular kidney diseases are a major cause of end-stage renal disease (ESRD). Thus, it comes as wonderful news that glomerular research is advancing at a remarkable pace. Researchers from around the world met at the 10th International Podocyte Conference in Freiburg, Germany, to discuss the latest developments and findings in this innovative field of kidney research. The meeting highlighted the tremendous progress in our understanding of podocyte-related disorders and promised a rapid transfer of this knowledge into novel treatment options for proteinuric kidney diseases. PMID- 25715119 TI - Lack of hyaluronidases exacerbates renal post-ischemic injury, inflammation, and fibrosis. AB - Renal ischemia-reperfusion injury (IRI) is a pathological process that may lead to acute renal failure and chronic dysfunction in renal allografts. During IRI, hyaluronan (HA) accumulates in the kidney, but suppression of HA accumulation during IRI protects the kidney from ischemic insults. Here we tested whether Hyal1-/- and Hyal2-/- mice display exacerbated renal damage following unilateral IRI due to a higher HA accumulation in the post-ischemic kidney compared with that in the kidney of wild-type mice. Two days after IRI in male mice there was accumulation of HA and CD44 in the kidney, marked tubular damage, infiltration, and increase creatininemia in wild-type mice. Knockout mice exhibited higher amounts of HA and higher creatininemia. Seven days after injury, wild-type mice had a significant decrease in renal damage, but knockout mice still displayed exacerbated inflammation. HA and CD44 together with alpha-smooth muscle actin and collagen types I and III expression were increased in knockout compared with wild type mice 30 days after IRI. Thus, both HA-degrading enzymes seem to be protective against IRI most likely by reducing HA accumulation in the post ischemic kidney and decreasing the inflammatory processes. Deficiency in either HYAL1 or HYAL2 leads to enhanced HA accumulation in the post-ischemic kidney and consequently worsened inflammatory response, increased tubular damage, and fibrosis. PMID- 25715121 TI - Spermidine on neurodegenerative diseases. PMID- 25715120 TI - Correlation of disease activity in proliferative glomerulonephritis with glomerular spleen tyrosine kinase expression. AB - Spleen tyrosine kinase (SYK) is an important component of the intracellular signaling pathway for various immunoreceptors. Inhibition of SYK has shown promise in preclinical models of autoimmune and glomerular disease. However, the description of SYK expression in human renal tissue, which would be desirable ahead of clinical studies, is lacking. Here we conducted immunohistochemical analysis for total and phosphorylated SYK in biopsy specimens from >120 patients with a spectrum of renal pathologies, including thin basement membrane lesion, minimal change disease, membranous nephropathy, IgA nephropathy, lupus nephritis, ANCA-associated glomerulonephritis, antiglomerular basement membrane disease, and acute tubular necrosis. We found significant SYK expression in proliferative glomerulonephritis and that glomerular expression levels correlated with presenting serum creatinine and histological features of disease activity that predict outcome in IgA nephropathy, lupus nephritis, ANCA-associated glomerulonephritis, and antiglomerular basement membrane disease. SYK was phosphorylated within pathological lesions, such as areas of extracapillary and endocapillary proliferation, and appeared to localize to both infiltrating leucocytes and to resident renal cells within diseased glomeruli. Thus SYK is associated with the pathogenesis of proliferative glomerulonephritides, suggesting that these conditions may respond to SYK inhibitor treatment. PMID- 25715122 TI - Flexible black phosphorus ambipolar transistors, circuits and AM demodulator. AB - High-mobility two-dimensional (2D) semiconductors are desirable for high performance mechanically flexible nanoelectronics. In this work, we report the first flexible black phosphorus (BP) field-effect transistors (FETs) with electron and hole mobilities superior to what has been previously achieved with other more studied flexible layered semiconducting transistors such as MoS2 and WSe2. Encapsulated bottom-gated BP ambipolar FETs on flexible polyimide afforded maximum carrier mobility of about 310 cm(2)/V.s with field-effect current modulation exceeding 3 orders of magnitude. The device ambipolar functionality and high-mobility were employed to realize essential circuits of electronic systems for flexible technology including ambipolar digital inverter, frequency doubler, and analog amplifiers featuring voltage gain higher than other reported layered semiconductor flexible amplifiers. In addition, we demonstrate the first flexible BP amplitude-modulated (AM) demodulator, an active stage useful for radio receivers, based on a single ambipolar BP transistor, which results in audible signals when connected to a loudspeaker or earphone. Moreover, the BP transistors feature mechanical robustness up to 2% uniaxial tensile strain and up to 5000 bending cycles. PMID- 25715124 TI - The challenge of production of knowledge on the Brazilian psychiatric reform process. PMID- 25715123 TI - VAV3 Overexpressed in Cancer Stem Cells Is a Poor Prognostic Indicator in Ovarian Cancer Patients. AB - Ovarian carcinoma is a highly lethal malignancy due to frequent relapse and drug resistance. Cancer stem cells (CSCs) are thought to contribute significantly to disease relapse and drug resistance. In this study, a subpopulation of CSCs of ovarian carcinoma was isolated and the genes differentially expressed in these cells were identified to characterize CSCs and to find candidate biomarkers. Ovarian carcinoma cells from patients were primarily cultured, and spheroid forming cells (SFCs) were isolated. The characteristic genes of SFCs were identified through cDNA microarray and validation by quantitative real-time polymerase chain reaction and immunohistochemistry, and the association of their expression with clinicopathologic parameters was analyzed. GSC (4.26-fold), VAV3 (7.05-fold), FOXA2 (12.06-fold), LEF1 (17.26-fold), COMP (21.33-fold), GRIN2A (9.36-fold), CD86 (23.14-fold), PYY (4.18-fold), NKX3-2 (10.35-fold), and PDK4 (74.26-fold) were significantly upregulated in SFCs compared with parental cancer cells. With validation for human ovarian carcinomas, LEF1, PYY, NKX3-2, and WNT3A were significantly upregulated in chemoresistant cancers compared with chemosensitive cancers. Overexpression of LEF1, VAV3, and NKX3-2 was significantly associated with distant metastasis by immunohistochemistry. VAV3 overexpression was an independent poor survival indicator (hazard ratio=15.27, P<0.05) by multivariate Cox analysis. The further functional assay revealed that VAV3 knockdown regulated CSC activation and ovarian cancer cell proliferation and sensitized paclitaxel (PTX)-resistant cancer cells to PTX treatment. Taken together, we identified by high-throughput analysis of CSCs that VAV3 overexpression is a novel biomarker for poor prognosis and survival in ovarian carcinoma. PMID- 25715125 TI - [The micropolitics of desire: the clinic of the individual in the mental health institution]. AB - The scope of this article is to discuss clinical practice issues in public mental health institutions, their predicaments and potential conditions, focusing especially on the practice "among others" of the psycho analyst in this clinic. The mental health field is a field in permanent revitalization, marked by the heterogeneity and plurality of guidelines, permeated by tensions between old models of care, new political objectives to redeem the minimum rights of a population traditionally excluded from social coexistence and proposals for a new clinical practice that concentrates on the individual. Based on clinical perceptions, I intend to approach the clinical treatment of the individual in a mental health institution, as well as the challenges of working in a team, bearing in mind the impositions of mental health policy arounnd which the services are structured. Our proposal is to think of the clinic as the micro politics of desire that sustains the daily work of monitoring the course of treatment for each individual. PMID- 25715126 TI - [The role of the pharmacist in dispensing medication in Adult Psychosocial Care Centers in the city of Sao Paulo, Capital of the State of Sao Paulo, Brazil]. AB - The objective of this study was to evaluate the role of the pharmacist in dispensing medication by conducting cross-sectional exploratory-descriptive research in eight Adult Psychosocial Care Centers (CAPS) in Sao Paulo. The pharmacists responsible for each of the dispensing units studied filled out a semi-structured questionnaire about the service provided. Two Adult CAPS units were selected from each of the North, South, Eastand West regions of Sao Paulo. The central region has no Adult CAPS, and was therefore not included in the study. Most of the respondents were aged between 35 and 40 years and were predominantly female. It was found that half of the respondents performed only 25% of dispensations and few conducted an analysis of all prescriptions before dispensing medication. All respondents contacted the prescriber if any medication related problems a rose. However, few pharmaceutical interventions were commonly performed. Furthermore, one respondent indicated that all his/her functions in the pharmacy could be delegated to another professional. These findings reveal the pressing need for actions that ensure the ongoing training of pharmacists to enable them to be clinically prepared to deal with patients with mental disorders. PMID- 25715127 TI - [Supply and demand in the meetings between mental health professionals and family members of people with mental disorders]. AB - This paper is a development of a doctoral thesis presented at the Federal University of Espirito Santo. It seeks to analyze the elucidation of needs, development of supply and demand in the provision of care and the relationship between mental health professionals and family members of people with mental disorders. A qualitative research approach was used as the method of choice to achieve the proposed objectives. Semi-structured interviews were conducted with mental health professionals from two psychosocial care centers (CAPS) in the city of Vitoria, Espirito Santo, and with family members of frequenters of these institutions. After thematic analysis of content, senses, meanings and values assigned to the needs, supplies and demands present in this relationship were revealed. It highlighted the disparity between supply and demand and the lack of awareness of the needs of family members and their demands related to the routines of mental institutions. Using ethics in the philosophy of Spinoza as a benchmark, the ramifications of this process are discussed in the meetings between mental health professionals and family members of people with mental disorders and the micropolitics of the provision of care in the context of these actors. PMID- 25715128 TI - [The clinical and psychosocial profile of inmates in psychiatric hospitals in the State of Ceara, Brazil]. AB - One of the most vexing problems in the context of psychiatric reform are the inmates of psychiatric hospitals institutionalized for one year or more. The long periods of hospitalization indicate that these inmates have been abandoned, which can aggravate their psychiatric disorders. This article seeks to trace a socio demographic and clinical profile of the inmates of psychiatric hospitals in the State of Ceara, Brazil. It is a cross-sectional study, based on reviews of medical registers, interviews and application of two scales: the Katz Index and the PANSS. Most of the 39 participants were men, single and of an economically active age. Information on education (69.2%) and religion (66.7%) were not known and for 12.8%, their marital status was unknown. Nearly 75% received no visits from friends or relatives. Two thirds maintained total independence to perform ADLs (Activities of Daily Living). The majority were admitted for primary psychotic disorder (76.8%). These manifested a marked negative syndrome in 96.7% of cases. The study highlights the situation of abandonment and loss of citizenship experienced by chronically institutionalized patients. It is questionable to what extent hospitals are prepared to offer the assistance that this population needs. PMID- 25715129 TI - From patient to clinical case: an ethnography with psychiatric inpatient care releases. AB - Social Science contributions to the understanding of psychiatric care have highlighted the passage from person to patient as being crucial to the moral career of the mentally ill. In this article another moment relevant to a discussion on illness and social identity is investigated, namely the passage from patient to clinical case. Socio-anthropological fieldwork was conducted between 2007 and 2010 with users of a care network after release from psychological internment, their relatives and neighbors. It highlighted not only the administrative categories that professionals in the network used to designate patients, but also those given by other villagers. Some villagers are considered doidos ("loonies") without having been admitted as "patients" to the local inpatient facility. Others are "users", registered at an outpatient service; or "clients", when they are frequent users. Some are called bonequeiros ("troublemakers"), "nervous", or barulhentos ("noisy crackpots") because of their behavior in public. Finally, by becoming the object of comments by people on the street, they also become "cases," which are eventually discussed at the mental care facilities, thus becoming "clinical cases." Mental disorders are as relevant to the management of a stigmatized social identity as surnames and nicknames. PMID- 25715130 TI - Building the mental health care network for children and adolescents: interventions in the territory. AB - Children with mental disorders may develop serious adverse effects in their functional performance. A structured care network may favor psychosocial components, such as self-confidence and problem solving capacity. This work seeks to identify the care network for children with mental disorders and develop interventions in the territory, highlighting changes achieved from these actions. This is a descriptive study based on the action research methood using an eco-Map for data presentation. The results indicate that the majority of children have stressful relationships within the family, and relationships of greater intensity and quality with the Community Health Workers, Primary Care and Education, with childcare, compared with specialist health services. The interventions were based on the guidelines of Family Health, Support Center and stressed the strengthening of family ties, and liaison with health services and schools/ daycare centers. PMID- 25715131 TI - [The perspective of professionals in primary health care on matrix support in mental health]. AB - The research investigates the matrix support in mental health in Primary Health Care in order to identify the guidelines, professional principles and values that permeate the process. The study used a qualitative approach with triangulation of techniques, and was performed with professionals from the Family Health Strategy. The results reveal a work process which is based on personalized relations, guided by the broadening of clinical practice and mediated by principles, such as inter-disciplinarity, bonding, comprehensiveness, accessibility, co responsibilization and longitudinality. The values that underpin the relationship with the specialist are organized around the bond, trust and honesty. Difficulties in taking patients to Psychosocial Care Centers arise as obstacles to networking. The bond with the specialist, the structure of Family Health teams and the exchange of experiences and knowledge are identified as facilitating factors. The conclusions drawn are that the networking and the systematic and longitudinal support by specialists are key to decentralization in mental health. PMID- 25715132 TI - The maze and the minotaur: mental health in primary health care. AB - The article aims to discuss the issue of integration of mental health in primary care by matrix support in mental health. We point out the main barriers in the use of this work method, as well as the facilitating factors of the matrix support of mental health in primary care. The first are within the scope of epistemological specificities, professional issues and management in the political and ideological dimensions. Among the second, we highlight: the care for people with mental disorders in the territory; the reduction of stigma and discrimination; the development of new skills for professionals in primary care; reduction of costs; simultaneous treatment of physical and mental illness, which often overlap; the possibility of incorporating mental health care in a perspective of extended clinical service using an inter/transdisciplinary approach. PMID- 25715133 TI - Unravelling the skein of care networks on drugs: a narrative review of the literature. AB - Heated debates on given models of treatment for drug users have raged in the halls of academia, in public policies, not to mention in the media. The care network on drugs is presented in this context as an important mechanism for users, but its construction turns out to be a challenge. Therefore, a critical analysis and narrative review of the scientific literature on the care network on drugs was conducted, seeking to pinpoint the challenges and opportunities for its consolidation. The results found include: a) a lack of specific studies on the care network on drugs; b) insufficient and disjointed coverage regarding the demand for treatment; c) the need to rethink the role of the Psychosocial Care Centers for Alcohol and other Drugs, seeking to strengthen, expand, structurally improve and readjust their practices; d) lack of critical analysis about the construction process of care models on drugs in public services; and e) the State's responsibility to provide better alternatives to the existing panorama revealed, making progress on strengthening intersectorial actions, structuring care and improving working conditions. PMID- 25715134 TI - [Anthropometric methods used in the evaluation of the postpartum weight retention: a systematic review]. AB - This paper is a systematic review of scientific papers that studied postpartum weight retention. The identification of the studies was conducted in the Medline, Lilacs and Digital Library of Theses and Dissertations databases between 2000 until 2013. The main information evaluated was: author, year of publication, sample size, year of data collection, losses and analysis thereof, age, follow-up time, weight in the baseline and in the postpartum, assessment methods of weight retention and main results. Twenty studies were selected, of which 25% (n = 5) were national. Regarding the mode of analysis, in some works the result was analyzed in different ways as continuous and categorical. Of the selected papers, 45% (n = 9) analyzed the retained weight only continuously, 5% (n = 1) only categorically and 40% (n = 8) both ways. One of the studies used distribution in percentiles and the other evaluated continuously, categorical and by indicators of absolute and relative weight reduction. In conclusion, the results found reveal a lack of well-defined information about the forms of anthropometric measurements of women after delivery, indicating the need for developing national proposals, consistent with the reality of our population. PMID- 25715135 TI - [The Mais Medicos program - a conceptual mistake]. AB - The Mais Medicos program (involving the influx of Cuban physicians) has been a topic of heated debate in the media, mainly due to the difference of opinion between the government and the medical profession. The population in general is left in a climate of anxiety and uncertainty. This paper discusses the misconceptions that have been misleading and confusing the actors involved in the conflict surrounding the program in question. PMID- 25715136 TI - [Samuel Barnsley Pessoa and the social determinants of rural endemic diseases]. AB - This article analyzes the main aspects of the trajectory, the ideas and the academic and political activism of Samuel Barnsley Pessoa (1898-1976). It reveals that Samuel Pessoa's activism must also be understood in the context of his communist militancy and highlights the fact that one of the original contributions of his work was the establishment of the relationship between agrarian structure and rural endemic diseases, between large and unproductive estates and disease and adherence to a project of transformation of Brazilian society. PMID- 25715137 TI - [Internationalization, science and health: global regenerative medicine and the parallel markets]. AB - Regenerative medicine involves a paradigm change due to organism regeneration at cellular and tissue level - a controversial contemporary issue and difficult to regulate. This article presents a summary of the main scientific, economic, social and regulatory global trends, analyzed according to relevant theoretical dilemmas in medical anthropology and in the sociology of science and health. This is especially true of the construction of a 'collective frame of reference' on the new biological and ontological entities, the shaping of biological citizenship, and governance through uncertainty. Empirical evidence is also presented on a key aspect in regulation and governance, namely the emergence of a new transnational demand in health research through the establishment of parallel markets for ova and experimental cellular therapies. Qualitative data collected for a broader research paper is analyzed, as well as journal reviews and information gathered during interviews with international leaders. The paper concludes with a discussion on the importance on international governance of clinical trials and on further exploration, towards a multilevel harmonization of a diversity of normative practices. PMID- 25715138 TI - [Sensitive female-specific hospitalization in primary care]. AB - The scope of this paper was to analyze female-specific sensitive hospitalization occurring in primary care conditions and factors that determine or affect the occurrence of such hospitalizations (social, economic and demographic factors; health control). Analysis was performed by surveys on hospital morbidity with a sample of 429 females attended in Unified Health System (SUS) contracted hospitals. The sensitive hospitalizations percentage in primary care reached 49.42% (n = 212), highlighting female-specific hospitalization at 19.35% (n = 83). Hospitalization risks comprised elderly people over sixty, low schooling, previous hospitalizations, normal health control, lack of association with the Family Health Strategy and pregnancy. Evident causes were related to conditions of pregnancy, childbirth, post-partum and inflammations of the female pelvic organs. Results suggested flaws in outpatient attendance that should be adequate and provide solutions in women's health. PMID- 25715139 TI - [Strategies for tackling absenteeism in dental appointments in the Family Health Units of a large municipality: action research]. AB - The aim of this study was to analyze the reasons for missed appointments in dental Family Health Units (FHU) and implement strategies to reduce same through action research. This is a study conducted in 12 FHUs in Piracicaba in the State of Sao Paulo from January, 1 to December, 31 2010. The sample was composed of 385 users of these health units who were interviewed over the phone and asked about the reasons for missing dental appointments, as well as 12 dentists and 12 nurses. Two workshops were staged with professionals: the first to assess the data collected in interviews and develop strategy, and the second for evaluation after 4 months. The primary cause for missed appointments was the opening hours of the units coinciding with the work schedule of the users. Among the strategies suggested were lectures on oral health, ongoing education in team meetings, training of Community Health Agents, participation in therapeutic groups and partnerships between Oral Health Teams and the social infrastructure of the community. The adoption of the single medical record was the strategy proposed by professionals. The strategies implemented led to a 66.6% reduction in missed appointments by the units and the motivating nature of the workshops elicited critical reflection to redirect health practices. PMID- 25715140 TI - [The perception of the young and long-lived elderly 'Gauchos' (from the State of Rio Grande do Sul, Brazil) about the public spaces they live in Resumo]. AB - By 2050, the number of Brazilians living in urban areas will be over 200 million and 29% of the population will be elderly. The long-lived elderly are 80 or more years old and the young elderly are between 60 and 79 years of age. The scope of this article was to verify the difference in perception between the young elderly and the long-lived elderly from Rio Grande do Sul (RS) about the urban environment they live in. This is a population-based, observational, descriptive, retrospective study with a quantitative analysis paradigm. Data was analyzed from Elderly Profile research in RS conducted by the Geriatric and Gerontological Institute of PUCRS in partnership with the RS School of Public Health. The sample consisted of 6913 questionnaires answered by the elderly from 59 cities. Data analysis was performed for each age group and independent variables were processed using the Chi-square test, with p under 0.05. Results showed that the perception of difficulties such as a lack of park benches and safety strips, short traffic light times for pedestrians, high steps and bad-smelling public toilets was greater among the young elderly. The long-lived elderly noticed these facts less, though they admitted that they frequent community environments less often. PMID- 25715141 TI - Family clustering of secondary chronic kidney disease with hypertension or diabetes mellitus. A case-control study. AB - In Brazil hypertension and type 2 diabetes mellitus are responsible for 60% of cases of end-stage renal disease in renal replacement therapy. In the United States studies have identified family clustering of chronic kidney disease, predominantly in African-Americans. A single Brazilian study observed family clustering among patients with chronic kidney disease when compared with hospitalized patients with normal renal function. This article aims to assess whether there is family clustering of chronic kidney disease in relatives of individuals in renal replacement therapy caused by hypertension and/or diabetes mellitus. A case-control study with 336 patients in renal replacement therapy with diabetes mellitus or hypertension for at least 5 years (cases) and a control matched sample group of individuals with hypertension or diabetes mellitus and normal renal function (n = 389). Individuals in renal replacement therapy (cases) had a ratio of 2.35 (95% CI 1.42-3.89, p < 0.001) versus the control group in having relatives with chronic renal disease, irrespective of race or causative illness. There is family clustering of chronic kidney disease in the sample studied, and this predisposition is irrespective of race and underlying disease (hypertension or diabetes mellitus). PMID- 25715143 TI - Disease burden in Brazil: an investigation into alcohol and non-viral cirrhosis. AB - Alcohol use/dependence are an important risk factor for cirrhosis of the liver. The article aims to describe and conduct a comparative analysis of Disability Adjusted Life Years (DALY), Years of Life Lost (YLL) and Years Lived with Disability (YLD) of alcohol use disorders and non-viral cirrhosis in Brazil in 2008. DALY was calculated as the sum of YLL and YLD. For YLL estimates, the mean number of deaths from 2007- 2009 in the country was considered. After revision of epidemiological data, prevalence of each disease was modelled with the DisMod tool, which generated incidence data for YLD estimates. Alcohol and non-viral cirrhosis were responsible for 3% and 1% of total DALYs, respectively. In both diseases, men contributed to a greater proportion of DALYs. Among the first ten causes of DALYs, alcohol use disorders occupied the second, third and sixth positions at the ages of 15-29, 30-44 and 45- 59, respectively. Non-viral cirrhosis was the eighth cause of DALY in the 30-44 age group in men; the fifth, in the 45-59 group and the eighth, in the 60-69 group. Age distribution suggests that interventions directed against alcohol use/dependence would have effects on the burden of alcoholic cirrhosis in the country. PMID- 25715142 TI - The association between cardiovascular risk factors and anthropometric obesity indicators in university students in Sao Luis in the State of Maranhao, Brazil. AB - The article aims to evaluate the relation between cardiovascular risk factors (CVRF) and anthropometric indicators in a sample of university students from Sao Luis-MA, Brazil. It is a cross-sectional study conducted with 968 university students, with median age of 22. Glycemia, triglycerides, HDL-c, smoking, alcohol consumption, physical inactivity, metabolic syndrome (Joint Interim Statement criteria) and insulin resistance (IR), were associated and correlated with anthropometric indicators such as BMI, WC, WHR and WHtR. Associations were found between TGL, SH, SM and higher values of all anthropometric variables. The RI was associated with higher BMI values and WHtR in men and women. The low HDL-c was associated with higher values of all anthropometric variables in women. Consumption of alcohol was associated with higher values of BMI and WC in women and WHR in men and WHtR. Smoking was associated with higher values of WHtR in both sexes. Physical inactivity was associated with higher values of WHR in men only. The highest correlations were established for women between TGL and BMI CC, WHR and WHtR. The indicators most associated with CVRF were BMI, WC and WHtR in females and WHR and WHtR in men. PMID- 25715144 TI - [The Brazilian Congresses of Social and Human Sciences in Health of Abrasco: a scientific field in dispute]. AB - Social knowledge in health is now being considered a scientific, political and proactive field in Brazil. Studying the texts of the Congresses of Social and Human Sciences in Health at Abrasco involves conducting a partial genealogical study of the area, learning how the constitution of this subfield emerged and developed, and also to map the current "state of the art" in this knowledge area. This article seeks to analyze the speeches of key informants on achievements of the Congresses. Thirteen interviews with presidents and coordinators of Social Sciences Commissions were recorded in different administrations between 1995 and 2011 when the Brazilian Congresses of Social and Human Sciences in health were staged. The speeches reveal three pivotal moments in the history of the Congresses. The first was in 1995 when the First Congress was held, which marked the coming of age of social science knowledge in health and the demarcation of the field. The second was at the Third Congress in 2005 seen as the consolidation of both the knowledge area and this scientific field. The third moment was at the Fifth Congress in 2011, which tabled the scientific agenda of social and human sciences in health within the context of Public Health in Brazil. PMID- 25715145 TI - Availability of hospital dental care services under sedation or general anesthesia for individuals with special needs in the Unified Health System for the State of Minas Gerais (SUS-MG), Brazil. AB - This study identified the demographic characteristics of individuals and dental treatment care under sedation/general anesthesia in a hospital environment in the Unified Health System in the State of Minas Gerais (SUS-MG). All Hospitalization Authorizations (AIHs) for Dental Treatment for Patients with Special Needs procedures were evaluated between July 2011 and June 2012. Demographic and health care variables for treatment were also assessed. Hospitalization rates per 10,000 inhabitants, and health care coverage provided in the state of Minas Gerais and in each of the Broader Health Regions were calculated. Descriptive analysis of data was carried out by calculating the central trend and variability frequency and measurements. All 1,063 AIHs paid during the study period were evaluated, which is equivalent to a rate of 0.54 hospitalizations per 10,000 individuals. The majority of the patients were adult, male, diagnosed with mental or behavioral disorders and resident in 27.7% of the municipalities in Minas Gerais. The procedures were performed in 39 municipalities and the care coverage was equal to 1.58%. The study reveals a classic demographic and clinical profile of patient attendance. Difficulties in establishing a network of dental care were identified. PMID- 25715146 TI - [Assessment of competencies of community health workers for epidemiological data collection]. AB - The scope of this study was to assess competencies in terms of reading, comprehension and problem-solving using educational material created for epidemiological research on people with disabilities. A form with twenty multiple choice questions was prepared and distributed to a sample of 348 community health workers (CHWs) in the State of Paraiba. The socioeconomic profile revealed that, within the sample, most of these CHWs are female, between 30-49 years of age, married or in a stable relationship, with two children and have graduated from high school. Over 98% of CHWs are government employees and more than half have been working for more than eight years in the same community, predominantly in the urban area. The score for overall performance evaluation ranged from 33 to 60 points, with the mean score of 53.44 +/- 4.88 points. This means that the CHWs were able to resolve over 65% of the questions properly. The overall performance was positively correlated with education and negatively with age, having children and the time taken to complete high school education. The overall results indicate the increasing professionalization and education of the CHWs and their potential role as collaborators in basic scientific research to make generalizations about public health. PMID- 25715147 TI - Health education or a shared therapeutic project? Health care goes beyond the pedagogical dimension. AB - The general objective of this research was to assess the possible contribution of homeopathy to the development of caregiving therapeutic projects in multidisciplinary workshops of permanent education in health, in the context of primary health care. The chosen points of analysis were the series of inconveniences expressed by health workers with respect to their work processes and it was the emergence of the theme of health education in the first meetings with the teams that led to the production of this article. This study discusses the existential territory of "being a health professional" as understood from a concept of education as a significant benchmark, and of a certain interventionist mission as a transcendent value. A progressive waning of the importance of health education was observed during the workshops, sometimes even disappearing from the discussions, as the caregiving therapeutic projects took shape. The conclusion reached is that this waning involved a process of moving towards a pact with the health system user, eventually considered to be a valid interlocutor; and that health care transcends any strictly pedagogical dimension. PMID- 25715148 TI - Quality of life of medical students at the State University of Rio de Janeiro (UERJ), measured using Whoqol-bref: a multivariate analysis. AB - UERJ allocates 45% of places as scholarships to socioeconomically-challenged students. Whoqol-bref was used to assess to what extent sociodemographic and health variables, the admission process and year of graduation simultaneously influence the quality of life (QOL) domains of medical students. 394 students with a mean age of 23 years participated in the study: 61% females, 43% scholarship holders and 20% with referred chronic morbidity (RCM). The lowest QOL scores were observed among women, with RCM, scholarship holders, economic class C and students in the 3rd and 6th years. Multiple linear regression analysis showed that all the independent variables analyzed had a negative association with QOL domains, and when assessed jointly contributed partly to its explanation, achieving 22% in the "environment" domain, influenced by their social class and the admission process. The presence of RCM had a negative influence on the physical, psychological and social relations domains. The last two domains were also influenced by the year of graduation. Variables with a positive influence on QOL need to be explored further. The data obtained are enough to serve as the base for care strategies for the most vulnerable students during medical training, giving special attention to scholarship students. PMID- 25715149 TI - Coverage by the public health services of medication and vaccines for the population with diabetes mellitus. AB - This study analyzed the coverage by the public health service of expenses with medication and vaccines for the adult population of Sao Paulo with self-reported diabetes mellitus in 2003 and the implications for access to medicines and vaccination campaigns programs. Data were collected by the Multicenter Health Survey of Sao Paulo. The Unified Health System (SUS) was widely used by the population for vaccination against influenza and pneumonia and there was significant private sector participation for coverage of expenses with medication, with an estimated coverage of 38% by SUS. There were no significant differences in the prevalence of use of public services for vaccination among the categories of variables studied, suggesting a universal distribution of vaccination by the public health service. Unlike vaccinations, in 2003 the coverage of medication expenses by the public health service was recent in Brazil, which may explain the low level of coverage. An analysis of coverage of vaccination and medication expenses in diabetes mellitus population since 2003 may contribute to be the basis for policies to broaden access of the population to health services. PMID- 25715150 TI - [Attitudes of dietitians in relation to obese individuals - an exploratory study]. AB - The scope of this study was to assess attitudes of dietitians in relation to obesity; involving beliefs about the characteristics attributed to obese people, the reasons that lead to obesity and obesity itself. Dietitians (N = 344; 97.1% women) were contacted via their professional council and filled out the online survey. The survey questions were translated and adapted from international studies on this subject and the responses were analyzed for concordance rate. The results pointed to strong stigmatization of obesity and prejudice against the obese, attributing characteristics such as greed (67.4%), unattractiveness (52.0%), ungainliness (55.1%), lack of willpower (43.6%) and laziness (42.3%). The most important causal factors were considered to be emotional and mood changes, food addiction and low self-esteem. Research on this topic should be enhanced since these attitudes can affect the efficacy of treatment and also to foster broad discussion and training regarding the significance of obesity and to ensure more individualized and humanized treatment for obese patients. PMID- 25715151 TI - [Rabies in the State of Rio de Janeiro, Brazil: analysis of surveillance and control actions in the municipal field]. AB - Rabies is an anthropozoonosis characterized by acute viral encephalitis with a lethality rate close to 100%, and it has undergone an epidemiologic transition in which the cycle involving chiroptera is increasing in importance. The scope of this research sought to analyze the rabies surveillance and control actions carried out in municipalities in the State of Rio de Janeiro. Questionnaires were distributed to a representative sample of zoonosis control service managers proportionately calculated in accordance with the Health Regions, according to the State Regionalization Guidance Plan. The data gathered was recorded and analyzed using descriptive statistical techniques. Based on the results attained, the conclusion reached is that the rabies surveillance and control actions were being unsatisfactorily conducted, especially for items related to the monitoring of vampire bat colonies, viral circulation surveillance, notification and monitoring of suspect or aggressive animals, quantification of dog population and population control of stray dogs. The surveillance and control of rabies was being neglected, and was not a priority in the health services in the municipalities evaluated. PMID- 25715152 TI - Induced abortion among Brazilian female sex workers: a qualitative study. AB - Prostitutes are vulnerable to unplanned pregnancies and abortions. In Brazil, abortion is a crime and there is no data about unsafe abortions for this population. The study describes how prostitutes perform illegal abortions and the health consequences thereof. Semi-structured interviews with 39 prostitutes from three cities in Brazil with previous induced abortion experience were conducted. Sixty-six abortions, with between one and eight occurrences per woman, were recorded. The majority of the cases resulted from sexual activity with clients. The inconsistent use of condoms with regular clients and the consumption of alcohol during work were indicated as the main causes of unplanned pregnancies. The main method to perform abortion was the intravaginal and oral use of misoprostol, acquired in pharmacies or on the black market. Invasive measures were less frequently reported, however with more serious health complications. The fear of complaint to the police meant that most women do not inform the health team regarding induced abortion. The majority of prostitutes aborted with the use of illegally-acquired misoprostol, ending abortion in a public hospital with infection and hemorrhagic complications. The data indicate the need for a public policy focusing on the reproductive health of prostitutes. PMID- 25715153 TI - Interdependence between government levels in Brazilian health policy: the implementation of Emergency Care Units in the State of Rio de Janeiro, Brazil. AB - This article addresses policymaking related to Emergency Care Units (ECU) in the State of Rio de Janeiro between 2007 and 2013, duly identifying the relationships between the various levels of government in this process. It prioritized the context of policy formulation, the factors that motivated the inclusion and maintenance of ECUs on the state agenda and the process of how the policy was implemented in the state. The study was based on the literature that defines the agenda and implementation of public policies and on contributions from historic institutionalism. The research involved analysis of documents, secondary data, and 51 interviews with people in positions of authority in state and municipal governments. The priority given to ECUs in the government agenda was the result of a confluence of historical, structural, political and institutional factors, as well as the current context. The results of this study indicate the existence of interdependence between levels of government, however federal coordination problems have prejudiced the integration of the various components of emergency health care in the state. PMID- 25715154 TI - The media-driven risk society, the anti-vaccination movement and risk of autismo. AB - Marked changes have been seen in the epidemiological profile of infectious diseases among middle-class families in industrialized countries due to beliefs related to the risks of vaccination. These beliefs are proliferating globally due to internet sites, blogs and the influence of celebrities in the mass communication media. Due to the complexity of a cultural phenomenon of this nature, contemporary concepts aligned to the idea of reflexivity in the risk society are analyzed. The concept of a receptive media-driven society in which the announcement of danger and protection in mutual reference and contradiction are also assessed. The frequent emergence of tensions derived from cycles of utterances and baseless comments construed as symbolic "biovalues" are discussed. The persistent effect of threatening biotechnological and fraudulent utterances has influenced virtual networks for almost three decades, supporting the debate about the connection between autism and vaccines. The conclusion reached is that the processes of production of significance interconnect at various levels in which representations circulate that support communication and group identity based on historical and cultural references. PMID- 25715158 TI - Implementing evidence-based palliative care. PMID- 25715159 TI - Why we need a national conversation about dying. PMID- 25715160 TI - Continuous subcutaneous infusion in palliative care: a review of current practice. AB - Syringe drivers are widely used in palliative care, and this article reviews the challenges and outstanding questions associated with their use. Misperceptions among the lay public and some health professionals can be addressed by sensitive communication with patients and families and clear thinking in clinical teams concerning the drugs and doses used, particularly in non-malignant disease. Good levels of knowledge concerning syringe driver use has been found among GPs and community nurses, although this is not the case in some nursing home teams. The advantages of newer devices, safety and efficacy of drug combinations, selection of diluent, and management of site reactions are discussed. PMID- 25715157 TI - Safety and immunogenicity of an investigational 4-component Staphylococcus aureus vaccine with or without AS03B adjuvant: Results of a randomized phase I trial. AB - We assessed the safety, reactogenicity and immunogenicity of a staphylococcal vaccine combining capsular polysaccharides types 5 and 8 (CPS5/8), conjugated to tetanus toxoid (TT), with mutated detoxified alpha-toxin (AT) and clumping factor A (ClfA). In this phase I, randomized, placebo-controlled, observer-blind trial (NCT01160172), 88 healthy 18- to 40-year-olds received CPS5-TT/CPS8-TT/AT/ClfA vaccine (5/5/10/10 MUg or 10/10/30/30 MUg dose, each with or without AS03B adjuvant) or saline, at months 0, 1, 6. Solicited and unsolicited adverse events (AEs) were recorded for 7 and 30 d post-vaccination, respectively; potential immune-mediated diseases (pIMDs) and serious AEs (SAEs) were recorded throughout the study. Humoral and antigen-specific CD4(+)/CD8(+) T-cell immunity were assessed from Day (D) 0 to D540 post-vaccination. The most frequently reported solicited local and general AEs were pain (78.6%-100% of subjects), fatigue (36.4%-93.3% of subjects post-dose 1-2) and headache (20%-44.4% of subjects post dose 3). Overall, 4 SAEs and 2 potential immune-mediated diseases (pIMDs) (none fatal or vaccine-related) were reported. For each antigen, pre-vaccination seropositivity rates were high (85.7%-100%) and geometric mean concentrations (GMCs) in vaccine recipients sharply increased from D0 to D14, then plateaued to study end. Exploratory group comparisons suggested higher GMCs with higher dosage, without AS03B effect. Vaccine-induced antibodies were functional (CPS5 opsonophagocytic assays, and AT/ClfA inhibition assays). AT- and ClfA-specific CD4(+) T-cells with Th0/Th1 cytokine profile were induced at low levels (median <0.05%) by each formulation (intracellular cytokine staining). In conclusion, no safety concerns were identified and each vaccine formulation induced robust humoral immune responses after the first vaccine dose. PMID- 25715161 TI - Bed care for patients in palliative settings: considering risks to caregivers and bed surfaces. AB - Ensuring patients are comfortable in bed is key to effective palliative care, but when moving and positioning patients in bed, health professionals face an occupational risk of injury. The turning and positioning (TAP) system is a new method of moving patients in bed, that evidence has shown to reduce the risk of injury to caregivers. Providing the correct bed surface is another aspect of bed care essential to the comfort of the palliative patient, and to aid wound prevention and treatment. It is important to take a patient-centred approach when considering the most appropriate bed surface patients. This article provides an overview and discussion of these two aspects of bed care for palliative patients. PMID- 25715162 TI - The person behind the patient: a feasibility study using the Patient Dignity Question for patients with palliative care needs in hospital. AB - OBJECTIVE: The purpose of this study was to assess the feasibility and acceptability of the Patient Dignity Question (PDQ) 'what do I need to know about you as a person to take the best care of you that I can?', as a person-centred intervention for patients with palliative needs in the acute hospital setting in Scotland, UK. METHOD: To test the feasibility of the research design, a purposive sample of nine patients and five health-care professionals (HCPs) were recruited from acute wards in the east of Scotland. Responses to the PDQ were assessed using a PDQ feedback questionnaire to gauge participant reaction to its use. A person-centred climate questionnaire (PCQ-P) was used to assess responses to the environment in relation to the person-centred approach. RESULTS: The results from responses to the PDQ feedback questionnaire indicate that it is feasible to carry out this type of study for people with palliative care needs in the acute care setting, and that participants found the PDQ acceptable. The PCQ-P was effective in determining the person-centred nature of the hospital climate. However, it was not possible to determine if the PDQ had a direct influence on this, without pre- and post-intervention data. CONCLUSIONS: The PDQ was feasible and acceptable for this group of participants as a means by which HCPs may enhance person-centred care for people with palliative needs in an acute hospital. Testing the implementation of the PDQ in a before-and-after study would be beneficial. PMID- 25715163 TI - Perinatal death: bereavement interventions used by US and Spanish nurses and midwives. AB - BACKGROUND: Little research has been published from a global perspective regarding needs of nurses and midwives related to perinatal bereavement. OBJECTIVE: To identify needs and concerns of US and Spanish nurses and midwives who have worked with perinatal death and to identify the bereavement interventions they use to help families with this experience. METHODS: A cross sectional study was conducted. Data were collected in 2011 from US (n=44) and Spanish (n=15) nurses and midwives via a questionnaire. RESULTS: Statistically significant differences between the nurses/midwives in each country were found regarding needs relating to knowledge, communication skills and managing personal feelings. Interventions of accompanying, listening, offering keepsakes, baptism discussion, and funeral planning were also found to be significantly different between the two groups. CONCLUSIONS: These findings demonstrate a continued need to increase the standard and consistency of perinatal bereavement care worldwide. Bereavement education in nursing curricula and practice settings in both cultures is essential to increase the standard of care. PMID- 25715164 TI - Development of a questionnaire to measure the key attributes of the community palliative care specialist nurse role. AB - BACKGROUND: Recent worldwide economic events have forced an examination of the nurse's contribution to high-quality, effective, person-centred care. Since the role of specialist nurses is considered one of the least understood or valued developments in nursing, specialist nurses must demonstrate their contribution to quality, person-centred health care. AIM: To develop a questionnaire which aims to measure the quality of care provided by palliative care specialist nurses from the patients' perspective and to undertake initial validation. METHOD: The process of questionnaire development involved six phases including systematic literature reviews, patient advisory groups and expert panel reviews, each of which contributed to the questionnaire face and content validity. Johnston's Expert Palliative Care Nurse Model (2002; 2005) provided an evidence-based framework for the development of the questionnaire, and enabled the identification of the key attributes of the palliative care specialist nurse role, thereby providing the themes on which to base the questionnaire. RESULTS: The Quality Measure for Palliative Nursing, a questionnaire, was developed. The themes identified in the questionnaire--personal characteristics, communication skills, knowledge, relationship with patient and providing comfort--aim to facilitate measurement of the quality of care provided by palliative care specialist nurses. Designed for use by palliative patients the Quality Measure for Palliative Nursing is a one-page questionnaire comprising of 15 questions. CONCLUSIONS: The Quality Measure for Palliative Nursing is unique since it aims to measure the quality of care provided by community palliative care specialist nurses, and could also be used to measure patient satisfaction with the quality of care provided. Further testing is recommended to ensure that this questionnaire can provide reliable and valid results. PMID- 25715165 TI - Developing a care model for hospice and palliative nurses. PMID- 25715169 TI - Photosensitizer conjugated iron oxide nanoparticles for simultaneous in vitro magneto-fluorescent imaging guided photodynamic therapy. AB - In this study, photosensitizer conjugated iron oxide nanoparticles were strategically designed and prepared for simultaneous PDT and dual-mode fluorescence/MR imaging. The MRI contrast agent Fe3O4 was modified by APTES to functionalize the surface and further to link with heparin-pheophorbide-A conjugates. PMID- 25715168 TI - Interferon-beta Mediates Signaling Pathways Uniquely Regulated in Hepatic Stellate Cells and Attenuates the Progression of Hepatic Fibrosis in a Dietary Mouse Model. AB - The results of clinical and experimental studies suggest that type I interferons (IFNs) may have direct antifibrotic activity in addition to their antiviral properties. However, the mechanisms are still unclear; in particular, little is known about the antifibrotic activity of IFN-beta and how its activity is distinct from that of IFN-alpha. Using DNA microarrays, we demonstrated that gene expression in TWNT-4 cells, an activated human hepatic stellate cell line, was remarkably altered by IFN-beta more than by IFN-alpha. Integrated pathway enrichment analyses revealed that a variety of IFN-beta-mediated signaling pathways are uniquely regulated in TWNT-4 cells, including those related to cell cycle and Toll-like receptor 4 (TLR4) signaling. To investigate the antifibrotic activity of IFN-beta and the involvement of TLR4 signaling in vivo, we used mice fed a choline-deficient l-amino acid-defined diet as a model of nonalcoholic steatohepatitis-related hepatic fibrosis. In this model, the administration of IFN-beta significantly attenuated augmentation of the area of liver fibrosis, with accompanying transcriptional downregulation of the TLR4 adaptor molecule MyD88. Our results provide important clues for understanding the mechanisms of the preferential antifibrotic activity of IFN-beta and suggest that IFN-beta itself, as well as being a modulator of its unique signaling pathway, may be a potential treatment for patients with hepatic fibrosis in a pathogenesis independent manner. PMID- 25715170 TI - Analysis using fluorescence labeling and mass spectrometry of disulfide-mediated interactions of soy protein when heated. AB - It is well-known that disulfide-mediated interactions are important when soy protein is heated, in which soy proteins are dissociated and rearranged to some new forms. In this study, the disulfide bond (SS) linked polymer, which was composed of the acidic (A) polypeptides of glycinin, basic (B) polypeptides of glycinin, and a small amount of alpha' and alpha of beta-conglycinin, was formed as the major product, accompanied by the formation of SS-linked dimer of B and monomer of A as minor products. The role of sulfhydryl (SH) of different subunits/polypeptides for forming intermolecular SS was investigated. The SH of B in glycinin (Cys298 of G1, Cys289 of G2, Cys440 of G4) was transformed into SS in polymer identified by mass spectrometry analysis. The SH content of polymer was lower than that of glycinin and beta-conglycinin subunits when heated. The SH content of B in polymer was lower than that in glycinin subunit, and both of them were decreased by heating. The SH content of A in polymer was increased and higher than that of B in polymer and A in glycinin subunit when heated. These results indicated that the SH of B in glycinin subunit was subjected to not only SH oxidation but also SH-SS exchange (with SS of A) for forming intermolecular SS of polymer. The SH oxidation and SH-SS exchange were proven by the change of SH content for the first time. The SH of B was suggested to be reactive for forming intermolecular SS of polymer. PMID- 25715171 TI - OPRM1 genotype and naltrexone response in depressed alcohol-dependent patients. AB - A functional polymorphism rs1799971 (A118G) in the MU-opioid receptor gene (OPRM1) produces an amino acid substitution Asn40Asp, which is believed to influence naltrexone response in nondepressed alcohol-dependent patients. In this study, patients with alcohol dependence and major depression (n=108) received open-label naltrexone and clinical case management for 12 weeks, and were randomized to citalopram or placebo. General linear mixed models examined the effect of the OPRM1 A118G genotype on alcohol outcomes during treatment. There was no evidence of any difference in the percentage of days abstinent, drinks per drinking day or percentage of heavy drinking days between Asp40 carriers and noncarriers during treatment. This study therefore failed to replicate the previous positive findings for this single nucleotide polymorphism in relation to naltrexone response, possibly indicating that the effect is not present in depressed patients. PMID- 25715172 TI - Enantioselective synthesis of 1,2-dihydronaphthalene-1-carbaldehydes by addition of boronates to isochromene acetals catalyzed by tartaric acid. AB - Tartaric acid is an ideal asymmetric catalyst as it is abundant, cheap, and environmentally friendly. (+)-Tartaric acid was found to catalyze a novel enantioselective [4 + 2] cycloaddition of isochromene acetals and vinylboronates. A variety of substituted isochromene acetals were tolerated, furnishing the desired dihydronaphthalenes and dihydrobenzofluorene products in good yields. High enantiomeric ratios (up to 98.5:1.5) and excellent diastereoselectivities (all >99:1) were observed employing 10 mol % of (+)-tartaric acid as the catalyst, in combination with 5 mol % of Ho(OTf)3. PMID- 25715173 TI - Direct and indirect effects of dispersion interactions on the electric properties of weakly bound complexes. AB - Direct (electronic) and indirect (geometrical) modifications of the molecular properties of weakly interacting complexes between the push-pull p-aminobenzoic acid (pABA) molecule and the nonpolar benzene (Bz) have been studied with a large panel of wave function (WF) and density functional theory (DFT) based methods using carefully selected atomic basis sets. For pABA, both the canonical (pABA-c) and zwitterionic (pABA-z) forms have been investigated. Owing to strongly distinct charge distributions, the two forms of pABA enable us to mimic different interaction modes with Bz. In this work, we assessed the performances of dispersion-corrected DFT methods, as well as of long-range corrected exchange correlation functionals. It follows from the SAPT analysis that both the structure and the interaction energy of the first complex (pABA-c...Bz) is mainly controlled by dispersion interactions whereas, in the second complex (pABA z...Bz), electrostatic and induction forces play also an important role. Our results suggest that the (non)linear electric properties of push-pull and zwitterionic molecules can be significantly reduced by the presence of a nonpolar compound. We also show that even for a complex with stability strongly determined by dispersion forces, the direct dispersion contributions to its electric properties can be small. Nevertheless, the intersystem distance is influenced by dispersion forces, which, in turn indirectly tune the induced properties. The zwitterionic derivative appears to be more challenging in the context of molecular properties. PMID- 25715174 TI - Novel ways to regulate T-type Ca(2+) channels. PMID- 25715175 TI - Correction to transition metal dichalcogenides and beyond: synthesis, properties, and applications of single- and few-layer nanosheets. PMID- 25715176 TI - Open-Label Trial of MABp1, a True Human Monoclonal Antibody Targeting Interleukin 1alpha, for the Treatment of Psoriasis. PMID- 25715177 TI - Branched-chain amino acids for people with hepatic encephalopathy. AB - BACKGROUND: Hepatic encephalopathy is a brain dysfunction with neurological and psychiatric changes associated with liver insufficiency or portal-systemic shunting. The severity ranges from minor symptoms to coma. A Cochrane systematic review including 11 randomised clinical trials on branched-chain amino acids (BCAA) versus control interventions has evaluated if BCAA may benefit people with hepatic encephalopathy. OBJECTIVES: To evaluate the beneficial and harmful effects of BCAA versus any control intervention for people with hepatic encephalopathy. SEARCH METHODS: We identified trials through manual and electronic searches in The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and Science Citation Index on 2 October 2014. SELECTION CRITERIA: We included randomised clinical trials, irrespective of the bias control, language, or publication status. DATA COLLECTION AND ANALYSIS: The authors independently extracted data based on published reports and collected data from the primary investigators. We changed our primary outcomes in this update of the review to include mortality (all cause), hepatic encephalopathy (number of people without improved manifestations of hepatic encephalopathy), and adverse events. The analyses included random-effects and fixed-effect meta-analyses. We performed subgroup, sensitivity, regression, and trial sequential analyses to evaluate sources of heterogeneity (including intervention, and participant and trial characteristics), bias (using The Cochrane Hepato-Biliary Group method), small study effects, and the robustness of the results after adjusting for sparse data and multiplicity. We graded the quality of the evidence using the GRADE approach. MAIN RESULTS: We found 16 randomised clinical trials including 827 participants with hepatic encephalopathy classed as overt (12 trials) or minimal (four trials). Eight trials assessed oral BCAA supplements and seven trials assessed intravenous BCAA. The control groups received placebo/no intervention (two trials), diets (10 trials), lactulose (two trials), or neomycin (two trials). In 15 trials, all participants had cirrhosis. Based on the combined Cochrane Hepato Biliary Group score, we classed seven trials as low risk of bias and nine trials as high risk of bias (mainly due to lack of blinding or for-profit funding). In a random-effects meta-analysis of mortality, we found no difference between BCAA and controls (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.69 to 1.11; 760 participants; 15 trials; moderate quality of evidence). We found no evidence of small-study effects. Sensitivity analyses of trials with a low risk of bias found no beneficial or detrimental effect of BCAA on mortality. Trial sequential analysis showed that the required information size was not reached, suggesting that additional evidence was needed. BCAA had a beneficial effect on hepatic encephalopathy (RR 0.73, 95% CI 0.61 to 0.88; 827 participants; 16 trials; high quality of evidence). We found no small-study effects and confirmed the beneficial effect of BCAA in a sensitivity analysis that only included trials with a low risk of bias (RR 0.71, 95% CI 0.52 to 0.96). The trial sequential analysis showed that firm evidence was reached. In a fixed-effect meta-analysis, we found that BCAA increased the risk of nausea and vomiting (RR 5.56; 2.93 to 10.55; moderate quality of evidence). We found no beneficial or detrimental effects of BCAA on nausea or vomiting in a random-effects meta-analysis or on quality of life or nutritional parameters. We did not identify predictors of the intervention effect in the subgroup, sensitivity, or meta-regression analyses. In sensitivity analyses that excluded trials with a lactulose or neomycin control, BCAA had a beneficial effect on hepatic encephalopathy (RR 0.76, 95% CI 0.63 to 0.92). Additional sensitivity analyses found no difference between BCAA and lactulose or neomycin (RR 0.66, 95% CI 0.34 to 1.30). AUTHORS' CONCLUSIONS: In this updated review, we included five additional trials. The analyses showed that BCAA had a beneficial effect on hepatic encephalopathy. We found no effect on mortality, quality of life, or nutritional parameters, but we need additional trials to evaluate these outcomes. Likewise, we need additional randomised clinical trials to determine the effect of BCAA compared with interventions such as non-absorbable disaccharides, rifaximin, or other antibiotics. PMID- 25715180 TI - Development of a New Attention Rating Scale for Children With Intellectual Disability: The Scale of Attention in Intellectual Disability (SAID). AB - Difficulties with attention, impulsivity, and hyperactivity are thought to be as common among children with intellectual disability (ID) as they are in children without ID. Despite this, there is a lack of scales to specifically assess ADHD symptomatology in children and adolescents with ID. This article describes the development and evaluation of a teacher-completed measure; the Scale of Attention in Intellectual Disability (SAID). A community survey of 176 teachers of children 5-13 years of age, with ID at all levels of impairment indicated that the T-SAID is a reliable and valid measure. Integrating this scale with neuropsychological and clinical research holds exciting promise for enhancing our understanding of the nature of attention difficulties within populations with ID. PMID- 25715181 TI - Taiwanese attitudes and affective reactions toward individuals and coworkers who have intellectual disabilities. AB - This study investigated the attitudes of Taiwanese employees toward individuals and their supported coworkers with intellectual disabilities (ID). The findings indicated that the general attitudes of Taiwanese employees toward individuals with ID and their affective reactions toward their coworkers with ID were positive. These discoveries were contrary to previous beliefs that Taiwanese people tended to have societal stigma toward people and coworkers with ID. The outcomes also showed that the participants who had longer work contact with their coworkers with ID tended to have more positive attitudes toward them. Therefore, promoting supported employment trainings and opportunities for qualified people with ID was recommended. PMID- 25715179 TI - Sirtuin inhibitor sirtinol is an intracellular iron chelator. AB - Sirtinol is a known inhibitor of sirtuin proteins, a family of deacetylases involved in the pathophysiology of aging. Spectroscopic and structural data reveal that this compound is also an iron chelator forming high-spin ferric species in vitro and in cultured leukemia cells. Interactions with the highly regulated iron pool therefore contribute to its overall intracellular agenda. PMID- 25715178 TI - Cognitive decline preceding the onset of psychosis in patients with 22q11.2 deletion syndrome. AB - IMPORTANCE: Patients with 22q11.2 deletion syndrome (22q11DS) have an elevated (25%) risk of developing schizophrenia. Recent reports have suggested that a subgroup of children with 22q11DS display a substantial decline in cognitive abilities starting at a young age. OBJECTIVE: To determine whether early cognitive decline is associated with risk of psychotic disorder in 22q11DS. DESIGN, SETTING, AND PARTICIPANTS: Prospective longitudinal cohort study. As part of an international research consortium initiative, we used the largest data set of intelligence (IQ) measurements in patients with 22q11DS reported to date to investigate longitudinal IQ trajectories and the risk of subsequent psychotic illness. A total of 829 patients with a confirmed hemizygous 22q11.2 deletion, recruited through 12 international clinical research sites, were included. Both psychiatric assessments and longitudinal IQ measurements were available for a subset of 411 patients (388 with >=1 assessment at age 8-24 years). MAIN OUTCOMES AND MEASURES: Diagnosis of a psychotic disorder, initial IQ, longitudinal IQ trajectory, and timing of the last psychiatric assessment with respect to the last IQ test. RESULTS: Among 411 patients with 22q11DS, 55 (13.4%) were diagnosed as having a psychotic disorder. The mean (SD) age at the most recent psychiatric assessment was 16.1 (6.2) years. The mean (SD) full-scale IQ at first cognitive assessment was lower in patients who developed a psychotic disorder (65.5 [12.0]) compared with those without a psychotic disorder (74.0 [14.0]). On average, children with 22q11DS showed a mild decline in IQ (full-scale IQ, 7.04 points) with increasing age, particularly in the domain of verbal IQ (9.02 points). In those who developed psychotic illness, this decline was significantly steeper (P < .001). Those with a negative deviation from the average cognitive trajectory observed in 22q11DS were at significantly increased risk for the development of a psychotic disorder (odds ratio = 2.49; 95% CI, 1.24-5.00; P = .01). The divergence of verbal IQ trajectories between those who subsequently developed a psychotic disorder and those who did not was distinguishable from age 11 years onward. CONCLUSIONS AND RELEVANCE: In 22q11DS, early cognitive decline is a robust indicator of the risk of developing a psychotic illness. These findings mirror those observed in idiopathic schizophrenia. The results provide further support for investigations of 22q11DS as a genetic model for elucidating neurobiological mechanisms underlying the development of psychosis. PMID- 25715183 TI - Cultural and child-related predictors of distress among Latina caregivers of children with intellectual disabilities. AB - The objective of this article is to examine associations among socioeconomic, cultural, and child factors and maternal distress among families of children with intellectual disabilities (ID). Latino and nonLatino White (NLW) mothers of children with and without ID (N = 192) reported on familism, language acculturation, maternal distress, child adaptive functioning, and child behavior problems. Among mothers of children with ID, higher levels of child behavior problems mediated the association between Latina ethnicity and elevated maternal distress. Associations between child behavior problems and maternal distress in Latina mothers of children with ID were moderated by single-parent marital status, higher familism, and lower English usage. Thus, child and cultural factors contribute to elevated distress among Latina mothers of children with ID. PMID- 25715182 TI - Language development in infants and toddlers with fragile X syndrome: change over time and the role of attention. AB - Fragile X syndrome (FXS) is associated with significant language and communication delays, as well as problems with attention. This study investigated early language abilities in infants and toddlers with FXS (n = 13) and considered visual attention as a predictor of those skills. We found that language abilities increased over the study period of 9 to 24 months, with moderate correlations among language assessments. In comparison to typically developing infants (n = 11), language skills were delayed beyond chronological age and developmental-level expectations. Aspects of early visual attention predicted later language ability. Atypical visual attention is an important aspect of the FXS phenotype with implications for early language development, particularly in the domain of vocabulary. PMID- 25715184 TI - Autism and families' financial burden: the association with health insurance coverage. AB - We examined the relationship between family financial burden and children's health insurance coverage in families (n = 316) raising children with autism spectrum disorders (ASD), using pooled 2000-2009 Medical Expenditure Panel Survey data. Measures of family financial burden included any out-of-pocket spending in the previous year, and spending as a percentage of families' income. Families spent an average of $9.70 per $1,000 of income on their child's health care costs. Families raising children with private insurance were more than 5 times as likely to have any out-of-pocket spending compared to publicly insured children. The most common out-of-pocket expenditure types were medications, outpatient services, and dental care. This study provides evidence of the relative inadequacy of private insurance in meeting the needs of children with ASD. PMID- 25715188 TI - Erratum. PMID- 25715185 TI - Impact of exposure to potentially traumatic events on individuals with intellectual disability. AB - This study explored the prevalence of posttraumatic symptomatology (PTS) and functional problems among Israeli individuals with intellectual disability (ID) who live in supported residential care settings and who have been exposed to political violence. The sample included 196 residents exposed to chronic missile attacks and 91 residents with ID who were not exposed. Results showed PTS and functional problems to be higher in the exposed group compared to the nonexposed one, although still low compared to the general exposed population. Exposure was found to be related to PTS and functioning problems suggested individuals with ID are reactive to political violence, though the underlying mechanisms are not clear. Implications for research, caretakers, and policy are discussed. PMID- 25715189 TI - Template free construction of a hollow Fe3O4 architecture embedded in an N-doped graphene matrix for lithium storage. AB - The rational design and fabrication of electrode materials is a significant, yet highly challenging task. In this work, mesoporous Fe3O4 nanostructures featuring 3D structured hollow nanoparticles decorated by N-doped graphene with an average size of 10 nm were synthesized by a combination of hydrothermal and post carbonization techniques, and were subsequently studied as an anode material for lithium ion batteries. This hollow nanoarchitecture anchored on N-doped graphene sheets, possessing a large specific surface area and enhanced volumetric capacity, offers maximum lithium storage, facilitates rapid electrochemical kinetics, buffers volume changes during the lithium ion insertion and extraction processes, and removes detrimental active sites due to N incorporation, which is important for improving the recycling ability of anode materials. High reversible capacities, excellent rate-capability and stable performance were continuously observed. Accordingly, graphene-based composites that intercalate hollow Fe3O4 nanocrystals into N-doped graphene sheets have been demonstrated to be promising electrode materials for energy storage. PMID- 25715190 TI - Comparison of photocatalytic and transport properties of TiO2 and ZnO nanostructures for solar-driven water splitting. AB - Titanium dioxide (TiO2) and zinc oxide (ZnO) nanostructures have been widely used as photo-catalysts due to their low-cost, high surface area, robustness, abundance and non-toxicity. In this work, four TiO2 and ZnO-based nanostructures, i.e. TiO2 nanoparticles (TiO2 NPs), TiO2 nanotubes (TiO2 NTs), ZnO nanowires (ZnO NWs) and ZnO@TiO2 core-shell structures, specifically prepared with a fixed thickness of about 1.5 MUm, are compared for the solar-driven water splitting reaction, under AM1.5G simulated sunlight. Complete characterization of these photo-electrodes in their structural and photo-electrochemical properties was carried out. Both TiO2 NPs and NTs showed photo-current saturation reaching 0.02 and 0.12 mA cm(-2), respectively, for potential values of about 0.3 and 0.6 V vs. RHE. In contrast, the ZnO NWs and the ZnO@TiO2 core-shell samples evidence a linear increase of the photocurrent with the applied potential, reaching 0.45 and 0.63 mA cm(-2) at 1.7 V vs. RHE, respectively. However, under concentrated light conditions, the TiO2 NTs demonstrate a higher increase of the performance with respect to the ZnO@TiO2 core-shells. Such material-dependent behaviours are discussed in relation with the different charge transport mechanisms and interfacial reaction kinetics, which were investigated through electrochemical impedance spectroscopy. The role of key parameters such as electronic properties, specific surface area and photo-catalytic activity in the performance of these materials is discussed. Moreover, proper optimization strategies are analysed in view of increasing the efficiency of the best performing TiO2 and ZnO-based nanostructures, toward their practical application in a solar water splitting device. PMID- 25715191 TI - Where occupation and environment overlap: US Forest Service worker exposure to Libby Amphibole fibers. AB - The National Institute for Occupational Safety and Health (NIOSH) conducted an evaluation of exposures to asbestiform amphibole, known as Libby Amphibole (LA), to personnel from the US Department of Agriculture-Forest Service (USFS) working in the Kootenai National Forest near a former vermiculite mine close to Libby, Montana. LA is associated with vermiculite that was obtained from this mine; mining and processing over many years have resulted in the spread of LA into the surrounding Kootenai Forest where it has been found in tree bark, soil, and forest floor litter. As a result of this and other contamination, Libby and surrounding areas have been designated a "Superfund" site by the US Environmental Protection Agency (EPA). This article describes the application of EPA methods for assessing cancer risks to NIOSH sampling results. Phase-contrast microscopy for airborne asbestos fiber evaluation was found to be less useful than transmission electron microscopy in the presence of interfering organic (plant) fibers. NIOSH Method 7402 was extended by examination of larger areas of the filter, but fiber counts remained low. There are differences between counting rules in NIOSH 7402 and the ISO method used by EPA but these are minor in the context of the uncertainty in concentration estimates from the low counts. Estimates for cancer risk are generally compatible with those previously estimated by the EPA. However, there are limitations to extrapolating these findings of low risk throughout the entire area and to tasks that were not evaluated. PMID- 25715192 TI - Female Rats Demonstrate Improved Locomotor Recovery and Greater Preservation of White and Gray Matter after Traumatic Spinal Cord Injury Compared to Males. AB - The possibility of a gender-related difference in recovery after spinal cord injury (SCI) remains a controversial subject. Current empirical animal research lacks sizable test groups to definitively determine whether significant differences exist. Evaluating locomotor recovery variances between sexes following a precise, clinically relevant spinal cord contusion model can provide valuable insight into a possible gender-related advantage in outcome post-SCI. In the current study, we hypothesized that by employing larger sample sizes in a reproducible contusive SCI paradigm, subtle distinctions in locomotor recovery between sexes, if they exist, would be elucidated through a broad range of behavioral tests. During 13 weeks of functional assessment after a thoracic (T8) contusive SCI in rat, significant differences owing to gender existed for the Basso, Beattie, and Bresnahan score and CatWalk hindlimb swing, support four, and single stance analyses. Significant differences in locomotor performance were noticeable as early as 4 weeks post-SCI. Stereological tissue-volume analysis determined that females, more so than males, also exhibited greater volumes of preserved gray and white matter within the injured cord segment as well as more spared ventral white matter area at the center of the lesion. The stereological tissue analysis differences favoring females directly correlated with the female rats' greater functional improvement observed at endpoint. PMID- 25715193 TI - Repair bond strength of composite resin to sandblasted and laser irradiated Y-TZP ceramic surfaces. AB - This study investigated the effects of different surface treatments on the repair bond strength of yttrium-stabilized tetragonal zirconia polycrystalline ceramic (Y-TZP) zirconia to a composite resin. Sixty Y-TZP zirconia specimens were prepared and randomly divided into six groups (n = 10) as follows: Group 1, surface grinding with Cimara grinding bur (control); Group 2, sandblasted with 30 um silica-coated alumina particles; Group 3, Nd:YAG laser irradiation; Group 4, Er,Cr:YSGG laser irradiation; Group 5, sandblasted + Nd:YAG laser irradiation; and Group 6, sandblasted + Er,Cr:YSGG laser irradiation. After surface treatments, the Cimara((r)) System was selected for the repair method and applied to all specimens. A composite resin was built-up on each zirconia surface using a cylindrical mold (5 * 3 mm) and incrementally filled. The repair bond strength was measured with a universal test machine. Data were analyzed using a one-way ANOVA and a Tukey HSD test (p = 0.05). Surface topography after treatments were evaluated by a scanning electron microscope (SEM). Shear bond strength mean values ranged from 15.896 to 18.875 MPa. There was a statistically significant difference between group 3 and the control group (p < 0.05). Also, a significant increase in bond strength values was noted in group 6 (p < 0.05). All surface treatment methods enhanced the repair bond strength of the composite to zirconia; however, there were no significant differences between treatment methods. The results revealed that Nd:YAG laser irradiation along with the combination of sandblasting and Er,Cr:YSGG laser irradiation provided a significant increase in bond strength between the zirconia and composite resin. PMID- 25715196 TI - Securing our place in history. PMID- 25715194 TI - Risperidone exacerbates Psychosis: A paradoxical phenomenon? PMID- 25715203 TI - Reconsidering contact precautions for MRSA and VRE. PMID- 25715197 TI - Communicating patient DNR status using color-coded wristbands. PMID- 25715198 TI - Retirement. PMID- 25715200 TI - Ethical issues. PMID- 25715199 TI - Ebola. PMID- 25715201 TI - CNAs in nursing homes. PMID- 25715195 TI - Detergent-type membrane fragmentation by MSI-78, MSI-367, MSI-594, and MSI-843 antimicrobial peptides and inhibition by cholesterol: a solid-state nuclear magnetic resonance study. AB - Multidrug resistance against the existing antibiotics is becoming a global threat, and any potential drug that can be designed using cationic antimicrobial peptides (AMP) could be an alternate solution to alleviate this existing problem. The mechanism of action of killing bacteria by an AMP differs drastically in comparison to that of small molecule antibiotics. The main target of AMPs is to interact with the lipid bilayer of the cell membrane and disrupt it to kill bacteria. Consequently, the modes of membrane interaction that lead to the selectivity of an AMP are very important to understand. Here, we have used different membrane compositions, such as negatively charged, zwitterionic, or mixed large unilamellar vesicles (LUVs), to study the interaction of four different synthetically designed cationic, linear antimicrobial peptides: MSI-78 (commercially known as pexiganan), MSI-367, MSI-594, and MSI-843. Our solid-state nuclear magnetic resonance (NMR) experiments confirmed that the MSI peptides fragmented LUVs through a detergent-like carpet mechanism depending on the amino acid sequence of the MSI peptide and/or the membrane composition of LUVs. Interestingly, the fragmented lipid aggregates such as SUVs or micelles are sufficiently small to produce an isotropic peak in the (31)P NMR spectrum. These fragmented lipid aggregates contain only MSI peptides bestowed with lipid molecules as confirmed by NMR in conjunction with circular dichroism spectroscopy. Our results also demonstrate that cholesterol, which is present only in the eukaryotic cell membrane, inhibits the MSI-induced fragmentation of LUVs, suggesting that the MSI peptides can discriminate the bacteria and the eukaryotic cell membranes, and this selectivity could be used for further development of novel antibiotics. PMID- 25715204 TI - New guidelines on HIV prevention in teens and adults. PMID- 25715205 TI - Cigarettes still cause a third of U.S. cancer deaths. PMID- 25715207 TI - Misuse of autoinjectors and inhalers. PMID- 25715212 TI - Moral distress in nursing. PMID- 25715213 TI - Physician vs. nonphysician anesthetists for surgical patients. PMID- 25715219 TI - Interprofessional collaboration and education. PMID- 25715220 TI - Conflict engagement: a new model for nurses. AB - This article is one in a series on conflict. It is part of an ongoing series on leadership coordinated by the American Organization of Nurse Executives (AONE), highlighting topics of interest to nurse managers and emerging nurse leaders. The AONE provides leadership, professional development, advocacy, and research to advance nursing practice and patient care, promote nursing leadership excellence, and shape public policy for health care. PMID- 25715225 TI - Advocacy for vulnerable patients: how grassroots organizations can influence health care policy. PMID- 25715227 TI - The impact of a comprehensive airway management training program for pulmonary and critical care medicine fellows. A three-year experience. AB - RATIONALE: Airway management in the intensive care unit (ICU) is challenging, as many patients have limited physiologic reserve and are at risk for clinical deterioration if the airway is not quickly secured. In academic medical centers, ICU intubations are often performed by trainees, making airway management education paramount for pulmonary and critical care trainees. OBJECTIVES: To improve airway management education for our trainees, we developed a comprehensive training program including an 11-month simulation-based curriculum. The curriculum emphasizes recognition of and preparation for potentially difficult intubations and procedural skills to maximize patient safety and increase the likelihood of first-attempt success. METHODS: Training is provided in small group sessions twice monthly using a high-fidelity simulation program under the guidance of a core group of two to three advanced providers. The curriculum is designed with progressively more difficult scenarios requiring critical planning and execution of airway management by the trainees. Trainees consider patient position, preoxygenation, optimization of hemodynamics, choice of induction agents, selection of appropriate devices for the scenario, anticipation of difficulties, back-up plans, and immediate postintubation management. Clinical performance is monitored through a continuous quality improvement program. MEASUREMENTS AND MAIN RESULTS: Sixteen fellows have completed the program since July 1, 2013. In the 18 months since the start of the curriculum (July 1, 2013-December 31, 2014), first-attempt success has improved from 74% (358/487) to 82% (305/374) compared with the 18 months before implementation (P = 0.006). During that time there were no serious complications related to airway management. Desaturation rates decreased from 26 to 17% (P = 0.002). Other complication rates are low, including aspiration (2.1%), esophageal intubation (2.7%), dental trauma (0.8%), and hypotension (8.3%). First-attempt success in a 6-month period after implementation (July 1, 2014-December 31, 2014) was significantly higher (82.1 compared with 70.9%, P = 0.03) than during a similar 6-month period before implementation (July 1, 2012-December 31, 2012). CONCLUSIONS: This comprehensive airway curriculum is associated with improved first-attempt success rate for intensive care unit intubations. Such a curriculum holds the potential to improve patient care. PMID- 25715228 TI - Day-to-day reliability of pressure pain threshold and pain ratings in college aged men. AB - The purpose of this study was to examine the reliability of pressure pain threshold (PPT) and pain tolerance assessment in the finger over three testing days. PPT was assessed in the middle finger at the mid-point between the proximal and distal interphalangel joints in 49 college-aged men on three occasions (day 1, day 2, day 3) each separated by 48 h. The pressure evoking PPT was subsequently applied for up to 120 s to assess pain tolerance, whereas pain intensity was rated every 15 s. PPTs were reduced from day 1 to day 2 (P<0.001; intraclass correlation coefficient=0.63), but demonstrated excellent reliability from day 2 to day 3 (P=0.62; intraclass correlation coefficient=0.89). No differences were observed in pain tolerance. Ratings of pressure pain intensity rose over time during the 120 s test (P<=0.002) and were reduced on testing day 3 compared with day 1 (P=0.029). Our results suggest the use of least one familiarization session would lead to significantly improved day-to-day reliability of PPT assessment in the finger. In addition, the application of the force eliciting PPT was a poor discriminator of pain tolerance because of the fact the majority of participants (146 out of 147 sessions) could tolerate the stimulus for the entire 120 s. PMID- 25715229 TI - Influence of finger amputation on grip strength and objectively measured hand function: a descriptive cross-sectional study. AB - Finger amputations are common and hands are essential for functioning, but studies on factors influencing functioning after finger amputation are lacking. Therefore, we aimed to explore the influence of the number and level of amputated fingers on hand function and grip strength. A prospective descriptive cross sectional study involving 69 patients with partial or complete amputation of one or more fingers of one hand was carried out. The function of both hands was assessed using the Southampton Hand Assessment Procedure test; grip strength was measured in 42 patients. We confirmed that finger amputation worsens hand function (especially tripod and tip pinch) and reduces grip strength, whereby the extent of the worsening depends on amputation type - it is the smallest after thumb amputation and the largest after amputation of the index finger and fingers III-V. However, because of the variety of amputation types, we recommend that future studies either involve very large samples or focus on specific amputations. PMID- 25715230 TI - Therapeutic exercise for rotator cuff tendinopathy: a systematic review of contextual factors and prescription parameters. AB - Exercise is widely regarded as an effective intervention for symptomatic rotator cuff tendinopathy but the prescription is diverse and the important components of such programmes are not well understood. The objective of this study was to systematically review the contextual factors and prescription parameters of published exercise programmes for rotator cuff tendinopathy, to generate recommendations based on current evidence. An electronic search of AMED, CiNAHL, CENTRAL, MEDLINE, PEDro and SPORTDiscus was undertaken from their inception to June 2014 and supplemented by hand searching. Eligible studies included randomized controlled trials evaluating the effectiveness of exercise in participants with rotator cuff tendinopathy. Included studies were appraised using the Cochrane risk of bias tool and synthesized narratively. Fourteen studies were included, and suggested that exercise programmes are widely applicable and can be successfully designed by physiotherapists with varying experience; whether the exercise is completed at home or within a clinic setting does not appear to matter and neither does pain production or pain avoidance during exercise; inclusion of some level of resistance does seem to matter although the optimal level is unclear, the optimal number of repetitions is also unclear but higher repetitions might confer superior outcomes; three sets of exercise are preferable to two or one set but the optimal frequency is unknown; most programmes should demonstrate clinically significant outcomes by 12 weeks. This systematic review has offered preliminary guidance in relation to contextual factors and prescription parameters to aid development and application of exercise programmes for rotator cuff tendinopathy. PMID- 25715231 TI - The Work Activity and Participation Outcomes Framework: a new look at work disability outcomes through the lens of the ICF. AB - Work disability is common among people with chronic conditions. The terminology in the field is variable and often used interchangeably and there is a lack of comprehensive frameworks to describe work as an outcome. Varied operationalization of work disability makes it difficult to establish precise estimates of the impact of chronic musculoskeletal conditions on work. A new conceptual framework was developed using the International Classification of Functioning, Disability and Health and was named 'Work Activity and Participation Outcome (Work APO) Framework' which clarified definitions in the field. Applying the framework to people at risk of work disability and evaluating their outcomes could advance the literature. PMID- 25715233 TI - Syndrome X (Metabolic Syndrome) for Generation Z! Why? PMID- 25715232 TI - Multifunctional roles of the autoimmune disease-associated tyrosine phosphatase PTPN22 in regulating T cell homeostasis. AB - The non-receptor tyrosine phosphatase PTPN22 has a vital function in inhibiting antigen-receptor signaling in T cells, while polymorphisms in the PTPN22 gene are important risk alleles in human autoimmune diseases. We recently reported that a key physiological function of PTPN22 was to prevent naive T cell activation and effector cell responses in response to low affinity antigens. PTPN22 also has a more general role in limiting T cell receptor-induced proliferation. Here we present new data emphasizing this dual function for PTPN22 in T cells. Furthermore, we show that T cell activation modulates the expression of PTPN22 and additional inhibitory phosphatases. We discuss the implication of these findings for our understanding of the roles of PTPN22 in regulating T cell responses and in autoimmunity. PMID- 25715234 TI - The effects of disease awareness on lifestyle changes and the use of preventive measures in asthma patients. AB - Reduction in asthma incidences and mortality, as well as improved quality of life, can be achieved via a wide use of prevention methods. A number of randomized cohort studies demonstrated the effectiveness of such management and the need for multiple treatments. Here, we evaluate whether asthma awareness influences the lifestyle and the use of prevention, as well as the effects of age, sex, economic status, and education on the use of prophylaxis. A total of 18,617 (53.8% female; 24.2% 6-7 years old, 25.4% 13-14 years old, and 50.4% 20-44 years old) were selected by a stratified cluster sampling method in eight cities and one rural area, each over 150,000 citizens. The sample was selected based on the methods and questionnaires of International Study of Asthma and Allergies in Childhood and European Community Respiratory Health Survey. Patients aware of asthma significantly less often (p < 0.05) reported owning asthma-inducing items and significantly more often reported behaviors minimizing the number of allergens (p < 0.05). Patients aware of asthma took all actions reducing their exposure to in-house allergens significantly more often than the healthy (p < 0.05) and individuals with symptoms only (p < 0.05). Allergy prevention was used more often in children (p < 0.0005), responders aware of diseases (p < 0.05), higher levels of education (p < 0.05), and higher household income (p < 0.05). The most common type of prophylaxis used is prophylactic actions, which are undertaken by patients diagnosed with asthma and who are aware of their disease. Adults do not use preventive measures as often as children or adolescents do. Higher rates of prevention-oriented behavior were observed in groups characterized by higher levels of education and higher household income. PMID- 25715235 TI - Serum high-sensitivity C-reactive protein can be an airway inflammation predictor in bronchial asthma. AB - It is controversial that the serum high-sensitivity C-reactive protein (hs-CRP) can be a useful marker of airway inflammation in bronchial asthma, because various factors have been reported to affect hs-CRP levels. We conducted a study in patients with mild bronchial asthma without complications to determine whether hs-CRP is a useful indicator of airway inflammation. The induced sputum cell differentiation, respiratory function tests, bronchial hyperresponsiveness tests, and hs-CRP measurement were performed in the subject population consisted of 40 healthy volunteers and 45 patients with bronchial asthma. The log-transformed (log) serum hs-CRP level was higher in asthmatic patients compared with healthy controls (2.49 +/- 0.41 versus 2.21 +/- 0.39; p = 0.002). A receiver-operating characteristic (ROC) analysis showed a sensitivity of 0.69 and specificity of 0.70 for a log serum hs-CPR of 2.3 to distinguish asthmatic patents from healthy controls. The log serum hs-CRP level negatively correlated with forced volume in 1 second (FEV1.0)%pred (r = -0.31, p = 0.04), positively correlated with sputum eosinophils (r = 0.34, p = 0.02), negatively correlated with sputum macrophages (r = -0.56, p < 0.001), and did not correlate with log 20% fall in FEV1.0 (PC20) (r = -0.09, p = 0.56). A multiple regression analysis revealed that the log serum hs-CRP concentration significantly correlated with eosinophils (p = 0.019) and neutrophils (p = 0.042) in the sputum, respectively. Serum hs-CRP may be a useful marker of airway inflammation in nonsmoking asthmatic patients without complications, such as heart disease, hypertension, hyperlipidemia, chronic obstructive pulmonary disease, or infection. PMID- 25715236 TI - Effect of TRPV1 gene mutation on bronchial asthma in children before and after treatment. AB - Bronchial asthma is a worldwide disease with high incidence. It not only harms children's physical and mental health, but it also brings a heavy burden to their families as well as the society. However, the trigger and pathogenesis of the disease remain unclear. This study aimed to analyze TRPV1 gene mutation and expression of cytokines in children with acute bronchial asthma before and after treatment, thus providing theoretical guidance for the diagnosis and treatment of bronchial asthma in children. Real-time quantitative polymerase chain reaction was adopted to detect TRPV1 mRNA expression level and enzyme-linked immuno sorbent assay was used to detect the serum total IgE level, eosinophil (EOS) number, IL-4, IL-5, and interferon (IFN) gamma levels in peripheral venous blood of children in the healthy control group and asthma group before and after treatment. Logistic regression analysis was applied to analyze the most essential factor inducing bronchial asthma in children. TRPV1 mRNA level of peripheral blood in the asthma group was higher than that in the control group before treatment (p < 0.01). The IL-4, IL-5, and EOS levels in serum were markedly higher than those in the control group (p < 0.01), whereas the IFN-gamma level was lower than that in the control group (p < 0.01). After conventional treatment, TRPV1 mRNA level increased significantly (p < 0.01). The levels of serum IL-4, IL-5, and EOS were significantly lower than those before treatment (p < 0.01), whereas, IFN-gamma level was higher than that before treatment (p < 0.01). Compared with that before treatment, the expression level of IgE showed a significant decrease after treatment (p < 0.01). The results of logistic regression analysis indicated that TRPV1 expression level, IL-4 level, and rs4790522 site mutation were the main risk factors inducing bronchial asthma in children. TRPV1 gene mutation was closely related to bronchial asthma in children, which provided a theoretical basis for the treatment and prognosis of children with bronchial asthma. PMID- 25715237 TI - Wheels within wheals: the burden of urticaria and angioedema. PMID- 25715238 TI - Selection of patients for sublingual immunotherapy (SLIT) versus subcutaneous immunotherapy (SCIT). AB - Allergy immunotherapy has been used to help alleviate symptoms of allergic diseases for over 100 years. In the setting of the recently approved sublingual immunotherapy, allergists are now faced with which therapeutic regimen to use in clinical practice, sublingual immunotherapy (SLIT) or subcutaneous immunotherapy (SCIT). Both SLIT and SCIT have been shown to be beneficial for the therapy of seasonal allergic rhinoconjunctivitis. Each therapeutic measure has its associated benefits. SLIT has a better safety profile with less systemic reactions and to date, no reported fatal reactions. SCIT, the primary method of allergen immunotherapy in the United States, has a slightly better efficacy profile and readily allows for treatment of polyallergic patients. This review focuses on how to incorporate SLIT into daily clinical practice and on how to choose SLIT versus SCIT. PMID- 25715239 TI - Effect of breastfeeding on lung function in asthmatic children. AB - Effect of breastfeeding on the protective effect on asthma has been studied extensively but remains controversial. Studies regarding the effect of breastfeeding on lung function have also been conflicting. The aim of this study was to determine the influence of breastfeeding on lung function in asthmatic children. We included 555 patients who visited Severance Children's Hospital Allergy Clinic with asthma. Pulmonary function, its bronchodilator response (BDR), fractional nitric oxide, and sputum eosinophils were measured. Parents completed questionnaires with information on feeding practices, family history of allergic disease, exposure to tobacco smoke, and presence of pets. Breastfeeding duration was categorized as not breastfed, breastfed <6 months, and breastfed >=6 months. Within the asthma group, we stratified by atopic sensitization. We also investigated whether exclusivity of breastfeeding had any modifying effect on lung function. In the asthma group, ratio of forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) significantly increased according to breastfeeding duration: 86.6 +/- 8.7 for not breastfed group, 87.2 +/- 8.6 for <6 months group, and 88.8 +/- 7.7 for >=6 months group. Within asthma group, only the nonatopic subjects showed a significant increase of FEV1/FVC, maximal midexpiratory flow, and decrease of maximal response to BD according to breastfeeding duration. Increase in FEV1/FVC was seen in the exclusive breastfeeding for >=6 months group compared with those partially breastfed but FVC was significantly lower in those exclusively breastfed <6 months group compared with those partially breastfed. BDR decreased with breastfeeding duration in the nonatopic asthma group. In conclusion, longer duration of breastfeeding appears to have a favorable effect on lung function in asthmatic children, especially in nonatopic subjects. PMID- 25715240 TI - Central serous chorioretinopathy secondary to corticosteroids in patients with atopic disease. AB - Central serous chorioretinopathy (CSCR) is of unknown etiology and is the most common cause of retinopathy after age-related macular degeneration, diabetic retinopathy, and retinal vein occlusion. Vision loss results from fluid leakage and serous detachment in the macula. Five percent of patients develop chronic CSCR. It is predominantly found in middle-aged men (age-adjusted rates per 100,000: 9.9 for men and 1.7 for women) and is usually unilateral and reversible. Three-quarters of CSCR patients resolve within 3 months but 45% have recurrences, usually with only minor visual acuity changes. Risk factors include type A personality, emotional stress, elevated catecholamines, hypertension, pregnancy, organ transplantation, increased levels of endogenous cortisol, psychopharmacologic medication, use of phosphodiesterase 5 inhibitors, obstructive sleep apnea, Helicobacter pylori infection, or treatment with corticosteroids. Five percent of patients develop chronic disease as a result of subretinal fibrin formation within the blister. CSCR is often bilateral, multifocal, and recurrent, and may be associated with subretinal fibrin formation within the blister. Permanent loss of vision may result from subretinal fibrin fibrosis with scarring of the macula. Corticosteroid-associated CSCR occurs bilaterally in 20% of patients. Steroid-associated therapy may begin days to years after therapy with any form of drug delivery. We present three atopic patients who presented at various times after oral, inhaled, intranasal, and topical corticosteroid therapy. One patient developed CSCR after three separate types of administration of corticosteroids, which, to our knowledge, has not been observed in the literature. PMID- 25715241 TI - Indoor determinants of dustborne allergens in Mexican homes. AB - Exposure to indoor allergens represents a significant risk factor for allergies and asthma in several parts of the world. In Mexico, few studies have evaluated indoor allergens, including cat, dog, and mouse allergens and the factors that predict their presence. This study evaluates the main environmental and household predictors of high prenatal allergen levels and multiple allergen exposures in a birth cohort from Mexico City. A cross-sectional study was conducted as part of a birth cohort study of 1094 infants recruited during pregnancy and followed until delivery. We collected dust samples in a subset of 264 homes and assessed environmental factors. Der p 1, Der f 1, dust mite group 2, Fel d 1, Can f 1, Rat n 1, Mus m 1, and Bla g 2 concentrations in dust samples were measured using immunoassays. To define detectable allergen levels, the lowest limits of detection for each allergen were taken as cutoff points. Overall allergen exposure was considered high when four or more allergens exceeded detectable levels in the same household. Logistic regression was used for predictive models. Eighty-five percent of homes had at least one allergen in dust over the detection limit, 52.1% had high exposure (four or more allergens above detectable limits), and 11.7% of homes had detectable levels for more than eight allergens. Der p 1, Der p 2, Mus m 1, and Fel d 1 were the most frequent allergens detected. Each allergen had both common and distinct predictors. The main predictors of a high multiple allergen index were the size of the home, pesticide use, mother's age, mother as homemaker, and season. Increased indoor environmental allergen exposure is mainly related to sociodemographic factors and household cleaning. PMID- 25715242 TI - Clinical-laboratory characteristics of ANA-positive chronic idiopathic urticaria. AB - Despite the established association between chronic idiopathic/spontaneous urticaria (CIU) and presence of antinuclear antibodies (ANAs), the prevalence of autoimmune comorbidities in this population has not been analyzed. Here, we aim to identify clinical and laboratory manifestations associated with ANA-positive CIU. ANA-positive patients were identified via electronic data capture from the electronic patient record database of Leumit Health care Services (LHS) of Israel. Patient characteristics, medical histories, and details of diagnostic workup, medical treatment, and follow-up were retrieved by performing a chart review of electronic patient records (EPRs). The prevalence of target diseases among ANA(+) CIU(+), ANA(+) CIU(-), and ANA(-) CIU(+) patients was calculated. A total of 91 ANA(+) CIU(+), 3131 ANA(+) CIU(-), and 478 ANA(-) CIU(+) patients were identified. The ANA(+) CIU(+) group was characterized by higher prevalence of Sjogren's syndrome (SS)-A 52 antibodies (Ab) (7.7% versus 2.4%; p = 0.008), SS A 60 Ab (11% versus 2.8%; p = < 0.001), and SS-B Ab (14.3% versus 3.2%; p < 0.001), compared with ANA(-) CIU(+) group. Additionally, ANA(+) CIU(+) patients were more likely to be diagnosed with thyroid autoimmune diseases, higher C reactive protein (6.4 +/- 10.3 versus 4.1 +/- 8.8 mg/L; p = 0.027), and more profound basopenia (0.04 +/- 0.09 versus 0.15 +/- 0.11 cell/mm(3); p < 0.001) than ANA(-) CIU patients. More ANA(+) CIU(+) patients were resistant to four-fold standard licensed doses of antihistamines than ANA(-) CIU(+) patients [11 (12.1%) versus 29 (6.1%); p = 0.046]. ANA-positive CIU is characterized by higher prevalence of SS-A 52, SS-A 60, and SS-B antibodies and poorer clinical response to antihistamine medications. PMID- 25715243 TI - Before and after, the impact of available on-demand treatment for HAE. AB - Availability of effective treatment for acute attacks is expected to transform the care of hereditary angioedema (HAE) patients. We felt that it would be of interest to test these assumptions by examining the perceptions of HAE patients regarding the impact that these therapies have had on their lives. Patients at a United States HAE Association summit meeting were asked to rate the burden of HAE currently and compare by recall with 2009 when these therapies were not available. Questions covered five domains: psychological/emotional status, ability to carry out daily activities, fear of suffocation, worry about their children inheriting HAE, and medication side effects. Data were analyzed using Wilcoxon signed-rank tests or analysis of variance. Responses were obtained from 134 self-identified HAE subjects: 85 type I, 21 type II, and 28 with normal C1 inhibitor (C1INH). Burden of disease showed significant improvement in all domains except worry about children inheriting HAE. With the introduction of newer therapies, subjects with the most severe burden of illness improved more than those with milder burdens. However, significant burden of illness remained. The availability of the current treatments has substantially improved the quality of life for HAE patients in the United States, similar to a survey of Danish HAE patients regarding the introduction of home treatment. Nevertheless, our study shows that a substantial burden of illness remains for HAE patients. PMID- 25715244 TI - Current characteristics associated with hereditary angioedema attacks and treatment: the home infusion based patient experience. AB - This article presents a current perspective on the characteristics of hereditary angioedema (HAE) attacks and treatment as captured by a home infusion service. Retrospective data on 158 HAE patients who were enrolled in this acute treatment program were analyzed for factors surrounding an attack. The majority of patients had a high level of disease severity at baseline (88%), with a higher than expected likelihood of having a positive family history (87.8%). The most likely times for patients to call for home treatment were just before and during working hours (6:00 A.M.-5:00 P.M.). Eighty-three percent had more than one alternate mode of medication. Factors associated with a severe attack included an overall severe rating of HAE attacks in the previous year, an abdominal attack alone or a combination of peripheral and abdominal attacks versus a peripheral attack alone, and the use of two doses rather than one for treatment of the current attack. Average time to relief onset was 43.5 minutes. One dose of ecallantide was sufficient to treat the majority of attacks, and a second dose was needed in 23.6% of patients experiencing a severe attack. However, patients who reported both a severe attack rating during the previous year and experiencing only a peripheral current attack were more likely to experience a severe current attack. Acute treatment paradigms for HAE remain diverse. Understanding factors driving these decisions could help alleviate the overall burden of this disease and help overcome some of the challenges faced by the patients and their caretakers and improve their quality of life. Enhanced capture and analysis of prodromal factors in future studies should help us further alleviate the burden of this disease. PMID- 25715245 TI - A 31-year-old pregnant woman with angioedema. AB - Angioedema is swelling of the deep layers of the dermis and subcutaneous tissue due to an increase in vascular permeability. Angioedema sometimes occurs concomitantly with urticaria and represents an allergic disease. In other cases, angioedema is not associated with an allergic condition. We present the case of a 31-year-old woman with new-onset angioedema in the setting of her first pregnancy. After detailed history, physical examination, and laboratory evaluation, a cause for her angioedema was found that had not been considered previously and had significant implications for future management, particularly in light of her current pregnancy. Because allergists are commonly called on to evaluate and treat angioedema, we should be aware of the many disease processes that can present with this symptom and be well-versed in the workup of new-onset angioedema. PMID- 25715246 TI - For the patient. PMID- 25715247 TI - BATEMANATER: a computer program to estimate and bootstrap mating system variables based on Bateman's principles. AB - Bateman's principles continue to play a major role in the characterization of genetic mating systems in natural populations. The modern manifestations of Bateman's ideas include the opportunity for sexual selection (i.e. I(s) - the variance in relative mating success), the opportunity for selection (i.e. I - the variance in relative reproductive success) and the Bateman gradient (i.e. beta(ss) - the slope of the least-squares regression of reproductive success on mating success). These variables serve as the foundation for one convenient approach for the quantification of mating systems. However, their estimation presents at least two challenges, which I address here with a new Windows-based computer software package called BATEMANATER. The first challenge is that confidence intervals for these variables are not easy to calculate. BATEMANATER solves this problem using a bootstrapping approach. The second, more serious, problem is that direct estimates of mating system variables from open populations will typically be biased if some potential progeny or adults are missing from the analysed sample. BATEMANATER addresses this problem using a maximum-likelihood approach to estimate mating system variables from incompletely sampled breeding populations. The current version of BATEMANATER addresses the problem for systems in which progeny can be collected in groups of half- or full-siblings, as would occur when eggs are laid in discrete masses or offspring occur in pregnant females. BATEMANATER has a user-friendly graphical interface and thus represents a new, convenient tool for the characterization and comparison of genetic mating systems. PMID- 25715248 TI - Glucagon-Like Peptide 1 Protects against Hyperglycemic-Induced Endothelial-to Mesenchymal Transition and Improves Myocardial Dysfunction by Suppressing Poly(ADP-Ribose) Polymerase 1 Activity. AB - Under high glucose conditions, endothelial cells respond by acquiring fibroblast characteristics, that is, endothelial-to-mesenchymal transition (EndMT), contributing to diabetic cardiac fibrosis. Glucagon-like peptide-1 (GLP-1) has cardioprotective properties independent of its glucose-lowering effect. However, the potential mechanism has not been fully clarified. Here we investigated whether GLP-1 inhibits myocardial EndMT in diabetic mice and whether this is mediated by suppressing poly(ADP-ribose) polymerase 1 (PARP-1). Streptozotocin diabetic C57BL/6 mice were treated with or without GLP-1 analog (24 nmol/kg daily) for 24 wks. Transthoracic echocardiography was performed to assess cardiac function. Human aortic endothelial cells (HAECs) were cultured in normal glucose (NG) (5.5 mmol/L) or high glucose (HG) (30 mmol/L) medium with or without GLP 1analog. Immunofluorescent staining and Western blot were performed to evaluate EndMT and PARP-1 activity. Diabetes mellitus attenuated cardiac function and increased cardiac fibrosis. Treatment with the GLP-1 analog improved diabetes mellitus-related cardiac dysfunction and cardiac fibrosis. Immunofluorescence staining revealed that hyperglycemia markedly increased the percentage of von Willebrand factor (vWF)(+)/alpha smooth muscle actin (alpha-SMA)(+) cells in total alpha-SMA(+) cells in diabetic hearts compared with controls, which was attenuated by GLP-1 analog treatment. In cultured HAECs, immunofluorescent staining and Western blot also showed that both GLP-1 analog and PARP-1 gene silencing could inhibit the HG-induced EndMT. In addition, GLP-1 analog could attenuate PARP-1 activation by decreasing the level of reactive oxygen species (ROS). Therefore, GLP-1 treatment could protect against the hyperglycemia-induced EndMT and myocardial dysfunction. This effect is mediated, at least partially, by suppressing PARP-1 activation. PMID- 25715249 TI - Cysteine Oxidation Targets Peroxiredoxins 1 and 2 for Exosomal Release through a Novel Mechanism of Redox-Dependent Secretion. AB - Nonclassical protein secretion is of major importance as a number of cytokines and inflammatory mediators are secreted via this route. Current evidence indicates that there are several mechanistically distinct methods of nonclassical secretion. We have shown recently that peroxiredoxin (Prdx) 1 and Prdx2 are released by various cells upon exposure to inflammatory stimuli such as lipopolysaccharide (LPS) or tumor necrosis factor alpha (TNF-alpha). The released Prdx then acts to induce production of inflammatory cytokines. However, Prdx1 and 2 do not have signal peptides and therefore must be secreted by alternative mechanisms, as has been postulated for the inflammatory mediators interleukin 1beta (IL-1beta) and high mobility group box-1 (HMGB1). We show here that circulating Prdx1 and 2 are present exclusively as disulfide-linked homodimers. Inflammatory stimuli also induce in vitro release of Prdx1 and 2 as disulfide linked homodimers. Mutation of cysteines Cys51 or Cys172 (but not Cys70) in Prdx2, and Cys52 or Cys173 (but not Cys71 or Cys83) in Prdx1 prevented dimer formation and this was associated with inhibition of their TNF-alpha-induced release. Thus, the presence and oxidation of key cysteine residues in these proteins are a prerequisite for their secretion in response to TNF-alpha, and this release can be induced with an oxidant. By contrast, the secretion of the nuclear-associated danger signal HMGB1 is independent of cysteine oxidation, as shown by experiments with a cysteine-free HMGB1 mutant. Release of Prdx1 and 2 is not prevented by inhibitors of the classical secretory pathway, instead, both Prdx1 and 2 are released in exosomes from both human embryonic kidney (HEK) cells and monocytic cells. Serum Prdx1 and 2 also are associated with the exosomes. These results describe a novel pathway of protein secretion mediated by cysteine oxidation that underlines the importance of redox-dependent signaling mechanisms in inflammation. PMID- 25715251 TI - Gastric cancer screening uptake trends in Korea: results for the National Cancer Screening Program from 2002 to 2011: a prospective cross-sectional study. AB - Although the effectiveness of mass screening for gastric cancer remains controversial, several countries with a high prevalence of gastric cancer have implemented nationwide gastric cancer screening programs. This study was conducted to assess trends in the use of either upper gastrointestinal series (UGIS) or endoscopy to screen for gastric cancer, as well as to assess factors strongly associated with changes therein, over a 10-year period. Data were obtained from the National Cancer Screening Program (NCSP) database from 2002 to 2011 in Korea. The NCSP provides biennial gastric cancer screening with either UGIS or endoscopy for men and women aged >=40 years. Using the NCSP database, overall screening rates for gastric cancer and percentages of endoscopy use among participants were analyzed from 2002 to 2011. To estimate changes in participation rates and endoscopy use over time, we assessed the average annual percentage change (APC) by comparing the rates from 2002 and 2011 as relative rates. Participation rates for gastric cancer screening increased 4.33% annually from 2002 to 2011. In terms of screening method, a substantial increase in endoscopy use was noted among the gastric cancer screening participants over the 10-year period. The percentage of participants who had undergone endoscopy test increased from 31.15% in 2002 to 72.55% in 2011, whereas the percentage of participants who underwent UGIS decreased tremendously. Increased endoscopy test use was greatest among participants aged 40 to 49 (APC = 4.83%) and Medical Aid Program recipients (APC = 5.73%). Overall, men, participants of ages 40 to 49 years, and National Health Insurance beneficiaries of higher socioeconomic status were more likely to undergo screening via endoscopy. This study of nationwide empirical data from 2002 to 2011 showed that endoscopy is increasingly being used for gastric cancer screening in Korea, compared with UGIS. Nevertheless, further study of the impact of endoscopy on gastric cancer mortality is needed, and future evaluations of screening methods should take into account both cost and any associated reduction in gastric cancer mortality. PMID- 25715250 TI - Estrogen supplementation to progesterone as luteal phase support in patients undergoing in vitro fertilization: systematic review and meta-analysis. AB - Meta-analyses have found conflicting results with respect to the use of progesterone or progesterone plus estrogen as luteal phase support for in vitro fertilization (IVF) protocols involving gonadotropins and/or gonadotropin releasing hormone analogs. The aim of the present study was to perform an updated meta-analysis on the efficacy of progesterone versus progesterone plus estrogen as luteal phase support. We searched the MEDLINE, Cochrane Library, and Google Scholar databases (up to March 18, 2014). The search terms were (estrogen OR estradiol OR oestradiol) AND (progesterone) AND (IVF OR in vitro fertilization) AND (randomized OR prospective). We did not limit the form of estrogen and included subjects who contributed more than 1 cycle to a study. The primary outcome was clinical pregnancy rate. Secondary outcomes were ongoing pregnancy rate, fertilization rate, implantation rate, and miscarriage rate. A total of 11 articles were included in the present analysis, with variable numbers of studies assessing each outcome measure. Results of statistical analyses indicated that progesterone plus estrogen treatment was more likely to result in clinical pregnancy than progesterone alone (pooled odds ratio 1.617, 95% confidence interval 1.059-2.471; P = 0.026). No significant difference between the 2 treatment regimens was found for the other outcome measures. Progesterone plus estrogen for luteal phase support is associated with a higher clinical pregnancy rate than progesterone alone in women undergoing IVF, but other outcomes such as ongoing pregnancy rate, fertilization rate, implantation rate, and miscarriage rate are the same for both treatments. PMID- 25715252 TI - High incidence of EGFR mutations in pneumonic-type non-small cell lung cancer. AB - To retrospectively identify computed tomography (CT) features that correlate with epidermal growth factor receptor (EGFR) mutation in surgically resected pneumonic type lung cancer (P-LC). A total of 953 consecutive patients with surgically resected lung cancer in the First Affiliated Hospital of Guangzhou Medical University from August 2011 to August 2013 were studied. The CT manifestations were reevaluated independently by 2 radiologists. The presence of pneumonic-type consolidation with pathological confirmed non-small lung cancer (NSCLC) was defined as P-LC. EGFR mutation was determined by direct DNA sequencing or amplification refractory mutation system-PCR. EGFR mutation rates as well as clinical and pathological manifestations between P-LC and control lung cancer patients were compared. P-LC was diagnosed in 85 patients. Among these patients, 82 were adenocarcinoma (including 78 cases of invasive adenocarcinoma and 4 cases of microinvasive adenocarcinoma), 2 were squamous carcinoma and 1 was other type. P-LC occurred more frequently in female (58.8% vs 37.1%, P < 0.01), nonsmoking (76.5% vs 56.5%, P = 0.001) and adenocarcinoma (58.8% vs 37.1%, P < 0.01) patients. Moreover, EGFR mutations were found in 39 of 52 P-LC patients (75%) and 263 of 542 non-P-LC NSCLC patients (48.5%). However, no difference was found on the mutation sites of EGFR. Histological type, sex, and radiological manifestations (P-LC vs non-P-LC) but not smoking or sequencing method can be served as the independent predictor of EGFR mutations. P-LC patients showed a significant higher incidence of EGFR mutations, which was independent of sex, histological type, and smoking history. The patients with imaging manifestation of pneumonic-type consolidation are highly suggested to perform EGFR mutation analysis to guide the sequential treatment. PMID- 25715253 TI - Assessment of risk for recurrent diverticulitis: a proposal of risk score for complicated recurrence. AB - Recurrence of acute diverticulitis is common, and--especially complicated recurrence--causes significant morbidity. To prevent recurrence, selected patients have been offered prophylactic sigmoid resection. However, as there is no tool to predict whose diverticulitis will recur and, in particular, who will have complicated recurrence, the indications for sigmoid resections have been variable. The objective of this study was to identify risk factors predicting recurrence of acute diverticulitis. This is a retrospective cohort study of patients presenting with computed tomography-confirmed acute diverticulitis and treated nonresectionally during 2006 to 2010. Risk factors for recurrence were identified using uni- and multivariate Cox regression. A total of 512 patients were included. History of diverticulitis was an independent risk factor predicting uncomplicated recurrence of diverticulitis (1-2 earlier diverticulitis HR 1.6, 3 or more--HR 3.2). History of diverticulitis (HR 3.3), abscess (HR 6.2), and corticosteroid medication (HR 16.1) were independent risk factors for complicated recurrence. Based on regression coefficients, risk scoring was created: 1 point for history of diverticulitis, 2 points for abscess, and 3 points for corticosteroid medication. The risk score was unable to predict uncomplicated recurrence (AUC 0.48), but was able to predict complicated recurrence (AUC 0.80). Patients were further divided into low-risk (0-2 points) and high-risk (>2 points) groups. Low-risk and high-risk groups had 3% and 43% 5 year complicated recurrence rates, respectively. Risk for complicated recurrence of acute diverticulitis can be assessed using risk scoring. The risk for uncomplicated recurrence increases along with increasing number of previous diverticulitis. PMID- 25715254 TI - The association between macular thickness and peripapillary retinal nerve fiber layer thickness in Chinese children. AB - To investigate the association between macular thickness and peripapillary retinal nerve fiber layer (RNFL) thickness in Chinese children. This cross sectional study recruited consecutive cases of healthy pediatric subjects aged 4 to 18 from Caritas Medical Centre in Hong Kong Special Administrative Region, China, from 2013 to 2014. Subjects with only eye, ocular tumors, congenital glaucoma, congenital cataract, congenital nystagmus, microphthalmos, optic nerve or retinal disease, active ocular infections, corneal scars, and severe visual impairment of any cause were excluded. Peripapillary RNFL thickness and macular thickness at 1-mm-diameter fovea center (C1), 3-mm-diameter temporal quadrant (T3), and 3-mm-diameter nasal quadrant (N3) were measured with optical coherence tomography. Best-corrected visual acuity, axial length, and cycloplegic refraction were also recorded. Spearman correlation was used to analyze the association between T3, C1, and N3 with each of the following: average and quadrant RNFL thickness, axial length, and spherical equivalent. In 179 subjects, the mean age was 7.9 +/- 3.6 years. There were 90 male and 89 female subjects, all of Chinese ethnicity. The mean spherical equivalent was -0.1 +/- 3.1 D and mean axial length was 22.9 +/- 1.4 mm. There were significant and positive correlations of the average (T3: r = 0.20, P = 0.04; N3: r = 0.2, P = 0.005), superior (T3: r = 0.20, P = 0.03; N3: r = 0.2, P = 0.03), and inferior (T3: r = 0.20, P = 0.02; N3: r = 0.2, P = 0.01) peripapillary RNFL thicknesses with the T3 and N3 macular thicknesses but not C1. The nasal peripapillary RNFL thickness was also positively correlated with T3 (r = 0.20, P = 0.01). There were no significant associations between the macular thickness (T3, C1, N3) with neither the spherical equivalent (P > 0.2) nor the axial length (P > 0.3). The macular thickness was positive correlated with the peripapillary RNFL thickness in a population of healthy Chinese children. PMID- 25715255 TI - Changes in disability levels among older adults experiencing adverse events in postacute rehabilitation care: a prospective observational study. AB - This study aimed to assess the relationship between adverse events (AEs) and changes in the levels of disability from admission to discharge during inpatient rehabilitation programs. A prospective cohort study was conducted among a cohort of inpatients (216 older adults) admitted to a rehabilitation unit. The occurrences of any AE were reported. The level of disability regarding mobility activities was estimated using the disability qualifiers from the International Classification of Functioning, Disability, and Health. Changes in the levels of disability between admission and discharge were assessed. Baseline-measured covariates were also selected. Regarding all 4 disability levels ("no limitation," "mild," "moderate," "severe," and "complete disability"), a total of 159 participants experienced an improvement at discharge (126 participants progressed 1 level, whereas 33 improved 2 disability levels), 56 made no change, and no participants experienced a decline. The occurrence of fall-related events and the diagnostic group (musculoskeletal system) are specific predictive factors of change in the level of disability. The odds of undergoing a change in any disability level between admission and discharge decreases by 68% (1-0.32) when patients experience fall-related events (odds ratio [OR] = 0.32, 95% confidence interval [CI] = 0.11-0.97, P = 0.041) and increases for individuals with musculoskeletal conditions (OR = 3.91, 95% CI = 1.34-11.38, P = 0.012). Our findings suggest that increased efforts to prevent the occurrence of these AEs, together with early interventions suited to the diagnosis of the affected system, may have a positive influence on the improvement of disability. Further studies should evaluate disability over time after discharge to obtain a better sense of how transient or permanent the associated disability may be. PMID- 25715256 TI - Effect of 3-hydroxy-3-methylglutaryl-coenzyme a reductase inhibitor on disease activity in patients with rheumatoid arthritis: a meta-analysis. AB - HMG-CoA reductase inhibitors (also known as statins) are widely used as lipid lowering agents in patients with rheumatoid arthritis (RA) to reduce their cardiovascular risk. However, whether they have an effect on RA disease activity is controversial. This study aimed to investigate the effect of statins on disease activity in RA patients. A systematic literature review was performed using the MEDLINE, EMBASE, Cochrane Library, ISI WEB of Knowledge, Scopus, and Clinical Trials Register databases. Only prospective randomized controlled trials or controlled clinical trials comparing the efficacy of statins with placebo on adult RA patients were included. The efficacy was measured according to the ACR criteria, EULAR criteria, DAS28, HAQ score, ESR, or CRP. The Jadad score was used for quality assessment. The inverse variance method was used to analyze continuous outcomes. A fixed-effects model was used when there was no significant heterogeneity; otherwise, a random-effects model was used. For stability of results, we performed leave-one-study-out sensitivity analysis by omitting individual studies one at a time from the meta-analysis. Publication bias was assessed using Egger test. A total 13 studies involving 737 patients were included in the meta-analysis; 11 studies were included in the meta-analysis based on DAS28, while the other 2 studies were only included in the meta-analysis based on ESR or CRP. The standardized mean difference (SMD) in DAS28 between the statin group and the placebo group was -0.55 (95% CI [-0.83, -0.26], P = 0.0002), with an I2 value of 68%. Subgroup analysis showed that patients with more active disease tended to benefit more from statin therapy (SMD -0.73, P = 0.01) than patients with moderate or low disease activity (SMD -0.38, P = 0.03). Statin therapy also significantly reduced tender joint counts, swollen joint counts, ESR, and CRP compared with placebo, but the reduction in HAQ score and VAS was not significant (P > 0.05). This meta-analysis suggested that statin therapy might be effective in the reduction of RA disease activity measured by DAS28, TJC, SJC, as well as ESR and CRP. PMID- 25715257 TI - N3 subclassification incorporated into the final pathologic staging of gastric cancer: a modified system based on current AJCC staging. AB - The seventh edition of the American Joint Committee on Cancer (AJCC) TNM classification system for gastric cancer (GC) was established in 2009. We assessed the unmet medical needs of patients with the N3 classification of the seventh TNM staging system by comparing survival according to the extent of nodal involvement, with a particular focus on the cutoff points for the number of involved nodes in the N3 classification. We retrospectively reviewed 3178 patients with GC who were registered in the GC database of the Department of General Surgery at the Chang Gung Memorial Hospital between 1994 and 2010. Among them, 884 patients undergoing curative intent resection had N3 lymph node involvement. The clinicopathological features and surgical outcomes were compared among all patients with GC and between the N3a and N3b groups. N3b might impose GC patients with poor clinical outcome. We proposed a modified staging system, based on AJCC seventh edition, accordingly. T1-3N3 might be not simply categorized into stage IIIA as seventh AJCC suggested. Taking N3a and N3b into consideration, T1-3N3 might be further categorized into stage IIIB and IIIC, respectively, as we proposed, based on survival analysis. In addition, T4bN3bM0 is as dismal as M1 disease. In our proposed staging system, good discriminations between different stages are still maintained. The N3 category should be subclassified as N3a or N3b due to the survival differences. Furthermore, T1 3N3aM0 could be categorized as stage IIIB, T1-3N3bM0 could be categorized as stage IIIC, T4aN3bM0 could be categorized as stage IIID, and T4bN3bM0 might be regarded as stage IV as we proposed. PMID- 25715258 TI - Association of comorbidities with postoperative in-hospital mortality: a retrospective cohort study. AB - The purpose of this article is to evaluate the American Society of Anesthesiologists Physical Status (ASA PS) and the Charlson comorbidity index (CCI) for the prediction of postoperative mortality. The ASA PS has been suggested to be equally good as the CCI in predicting postoperative outcome. However, these scores have never been compared in a broad surgical population. We conducted a retrospective cohort study in a German tertiary care university hospital. Predictive accuracy was compared using the area under the receiver operating characteristic curves (AUROC). In a post hoc approach, a regression model was fitted and cross-validated to estimate the association of comorbidities and intraoperative factors with mortality. This model was used to improve prediction by recalibrating the CCI for surgical patients (sCCIs) and constructing a new surgical mortality score (SMS). The data of 182,886 patients with surgical interventions were analyzed. The CCI was superior to the ASA PS in predicting postoperative mortality (AUROCCCI 0.865 vs AUROCASAPS 0.833, P < 0.001). Predictive quality further improved after recalibration of the sCCI and construction of the new SMS (AUROCSMS 0.928 vs AUROCsCCI 0.896, P < 0.001). The SMS predicted postoperative mortality especially well in patients never admitted to an intensive care unit. The newly constructed SMS provides a good estimate of patient's risk of death after surgery. It is capable of identifying those patients at especially high risk and may help reduce postoperative mortality. PMID- 25715259 TI - Reduced red blood cell count predicts poor survival after surgery in patients with primary liver cancer. AB - Currently, the optimal therapy of primary liver cancer (PLC) remains to be hepatic resection. For better management of the patients, we evaluated the prognostic predicting value of red blood cell (RBC) count, a routine laboratory parameter, on the long-term survival of patients who underwent surgical treatment. Clinical and laboratory data of 758 patients, who underwent surgical hepatic resection, were retrospectively studied by chi2 tests and logistic regression. All patients were enrolled at Henan Cancer Hospital, Zhengzhou, China, from February 2009 to July 2013, and none of them received any other treatments before surgery. Kaplan-Meier survival analysis and Cox proportional hazard models were used to examine the influence of RBC counts on patients' survival. The Cox univariate and multivariate analyses showed that preoperative RBC count was an independent risk factor of poor prognosis after surgical treatment. The Kaplan-Meier curves showed that the overall survival (OS) of patients without reduced preoperative RBC counts was significantly better than those patients with reduced preoperative RBC counts (P < 0.001). Concordantly, compared with the patients with either reduced preoperative and/or postoperative RBC counts, patients without reduced RBC counts preferred to be low Child-Pugh grades (P = 0.0065), which implies a better hepatic function. In addition, low RBC count was found to be significantly associated with patients of female (P = 0.003), younger age (P = < 0.001), and with higher AST/ALT ratio (P = 0.005). This study revealed that patients with preoperative RBC counts lower than normal had worse OS rates than those without reduced preoperative RBC counts, perhaps due to the significant correlation of reduced preoperative RBC count to patients' worse Child-Pugh grade that reflect the loss of liver functions. PMID- 25715260 TI - Use of RENAL nephrometry scores for predicting tumor upgrading between core biopsies and surgical specimens: a prospective ex vivo study. AB - Determination of Fuhrman grade (FG) on biopsies of renal masses is relatively inaccurate, being prone to underestimating the true grade as ascertained from surgical specimens. This study evaluated whether anatomical features of tumors could predict tumor upgrading between core biopsies and surgical specimens. We prospectively enrolled 249 patients undergoing surgical resection of solid renal masses at our institution from 2012 to 2013. Tumor anatomical features were defined using RENAL nephrometry scores. Two peripheral and 1 central ex vivo core biopsies were taken from surgical specimens with an F18-gauge needle. Logistic regression was used to assess associations between covariates and FG upgrading. A comprehensive nomogram was constructed to quantitate the probability of tumor upgrading. The median tumor size was 4.75 cm and FG upgrading occurred in 43.6% of cases. In tumors of low, intermediate, and high complexity, the risk of FG upgrading was 22.0%, 47.6%, and 50.6%, respectively. According to multivariate analyses, anatomical features R (radius) and L (location) scores correlated significantly with FG upgrading. A combination of anatomical features and core biopsy findings predicted tumor upgrading with an accuracy of 0.884. With a threshold of 30%, our nomogram identified 92.4% of cases with upgrading; however, it overrated 26.8% of patients without upgrading. This ex vivo prospective study demonstrated that RENAL nephrometry score can aid prediction of FG upgrading between core biopsies and surgical specimens. Our nomogram uses anatomical features to predict true FG from renal biopsies. PMID- 25715261 TI - Application of 3D rapid prototyping technology in posterior corrective surgery for Lenke 1 adolescent idiopathic scoliosis patients. AB - A retrospective study to evaluate the effectiveness of 3-dimensional rapid prototyping (3DRP) technology in corrective surgery for Lenke 1 adolescent idiopathic scoliosis (AIS) patients. 3DRP technology has been widely used in medical field; however, no study has been performed on the effectiveness of 3DRP technology in corrective surgery for Lenke 1 AIS patients. Lenke 1 AIS patients who were preparing to undergo posterior corrective surgery from a single center between January 2010 and January 2012 were included in this analysis. Patients were divided into 2 groups. In group A, 3-dimensional (3D) printing technology was used to create subject-specific spine models in the preoperative planning process. Group B underwent posterior corrective surgery as usual (by free hand without image guidance). Perioperative and postoperative clinical outcomes were compared between 2 groups, including operation time, perioperative blood loss, transfusion volume, postoperative hemoglobin (Hb), postoperative complications, and length of hospital stay. Radiological outcomes were also compared, including the assessment of screw placement, postoperative Cobb angle, coronal balance, sagittal vertical axis, thoracic kyphosis, and lumbar lordosis. Subgroup was also performed according to the preoperative Cobb angle: mean Cobb angle <50 degrees and mean Cobb angle >50 degrees . Besides, economic evaluation was also compared between 2 groups. A total of 126 patients were included in this study (group A, 50 and group B, 76). Group A had significantly shorter operation time, significantly less blood loss and transfusion volume, and higher postoperative Hb (all, P < 0.001). However, no significant differences were observed in complication rate, length of hospital stay, and postoperative radiological outcomes between 2 groups (all, P>0.05). There was also no significant difference in misplacement of screws in total populations (16.90% vs 18.82%, P = 0.305), whereas a low misplacement rate of pedicle screws was observed in patients whose mean Cobb angle was >50 degrees (9.15% vs 13.03%, P = 0.02). Besides, using 3DRP increased the economic burden of patients (157,000 +/- 9948.85 Ren Min Bi (RMB) vs 152,500 +/- 11,445.52 RMB, P = 0.03). Using the 3D printing technology before posterior corrective surgery might reduce the operation time, perioperative blood loss, and transfusion volume. There did not appear to be a benefit to using this technology with respect to complication rate and postoperative radiological outcomes; however, 3D technology could reduce the misplacement rate in patients whose preoperative mean Cobb angle was >50 degrees . Besides, it also increased the patients' hospital cost. Therefore, future prospective studies are needed to elucidate the efficacy of this emerging technology. PMID- 25715262 TI - Microbial contamination of glaucoma eyedrops used by patients compared with ocular medications used in the hospital. AB - The aim of this study was to compare the percentage of contamination of multiuse eyedrops applied by glaucoma patients at home and by the medical personnel at the outpatient department, the ward, and the operating room of our Department of Ophthalmology. Eyedrops were collected over a period of 11 months. Samples were taken from the dropper tip (smear), drops, and the residual fluid inside the bottle and cultivated on blood agar. Colony forming units were counted and identified by mass spectrometry. The percentage of contamination was significantly higher in eyedrops applied by the patients (29/119; 24.4%, P < 0.01), used in the ward (26/133; 19.5%, P < 0.01), and in the outpatient unit (6/35; 17.1%, P = 0.036) compared with that in the operating room (6/113; 5.3%). The median period of use was 1 week in the operating room compared with 4 weeks in the other groups (P < 0.01). Glaucoma medications were significantly more frequently contaminated than antibiotic and anesthetic eyedrops (P < 0.05). For eyedrops applied by the patients, the tip was more frequently contaminated than the drops and the residual internal fluid. For eyedrops from the ward, the opposite was true. Pathogenic strains (Pseudomonas aeruginosa, Serratia marcescens, Acinetobacter lwoffii, Stenotrophomonas maltophilia, and Staphylococcus aureus) were found only in 6 bottles (1.5%), whereas most of the detected microbes belonged to human or environmental flora. This study underlines the importance of hygienic handling of eyedrops and raises the question of whether single-use glaucoma medication might be preferred to reduce the risk of contamination. PMID- 25715264 TI - A case report of severe paraquat poisoning in an HIV-positive patient: an unexpected outcome and inspiration. AB - We described and analyzed the treatment process of an HIV-positive patient with severe paraquat (PQ) poisoning. A 34-year-old man ingested about 50 mL of a 20% solution of PQ in a suicide attempt. He was treated with gastric lavage, oral administration of adsorbent, and symptomatic treatments at the local hospital, and was transferred to our emergency department. Ten hours after the exposure, the concentration of plasma PQ was 2.17 mg/L and was substantially above the survival limits of the severity index for PQ poisoning (SIPP) curve (0.30 mg/L). The equation produced by Jones et al (Jones AL, Elton R, Flanagan R. Multiple logistic regression analysis of plasma paraquat concentrations as a predictor of outcome in 375 cases of paraquat poisoning. QJM. 1999:92;573-578) predicted a 20.5% probability of survival at admission. Unfortunately, the patient was diagnosed as HIV infected, and CD4 lymphocyte count also confirmed that the patient was in a state of mild suppression of immunological function. Immediately, the patient received normative immunosuppressive therapy and hemoperfusion (HP). On the 15th day after poisoning, the patient recovered well and was discharged. All along, the evolution of the patient's status was in accordance with the characteristics of PQ poisoning, but the extent and duration of damage was mismatching and drastically alleviative by the previous biological indices. The particular case of treatment may be indirectly supporting the effectiveness of immunosuppressive therapy in treating patients with PQ poisoning. PMID- 25715263 TI - The high prevalence of hypovitaminosis D in China: a multicenter vitamin D status survey. AB - Vitamin D deficiency, which is usually detected by using immunoassays or the more reliable liquid chromatography tandem mass spectrometry (LC-MS/MS) methods, has recently been considered a public health problem worldwide. However, the vitamin D status in Chinese populations, as measured using the LC-MS/MS method, is not available. The objective of this multicenter study was to determine the vitamin D status and prevalence of vitamin D deficiency by using a reliable method in 5 large cities in China. From May 1 to September 31, 2013, we conducted a multicenter study on 2173 apparently healthy adults who were recruited from 5 Chinese cities. The 25-hydroxyvitamin D 25OHD2 and 25OHD3 levels were measured using the LC-MS/MS method. Intact parathyroid hormone (iPTH), calcium, phosphorus, and alkaline phosphate levels were also measured using an automatic analyzer. The mean 25OHD level of all participants was 19.4 +/- 6.4 ng/mL (2.5 97.5%: 7.9-32.6 ng/mL), and only 109 (5.0%) participants had a 25OHD2 level >2.5 ng/mL (maximum, 22.4 ng/mL). In this study, the prevalence of severe vitamin D deficiency (<10 ng/mL), vitamin D deficiency (10-20 ng/mL), vitamin D insufficiency (20-30 ng/mL), and vitamin D sufficiency (>30 ng/mL) was 5.9%, 50.0%, 38.7%, and 5.4%, respectively. Women had a significant higher rate of deficiency than men (66.3% vs 45.3%, P < 0.01). Participants aged 18 to 39 years had a lower 25OHD level than elderly individuals (>59 years). Lifestyle may influence the 25OHD level more than the latitude, with participants in Dalian having the highest 25OHD level and the lowest deficiency rate. The serum iPTH level showed a significant negative correlation with the 25OHD level (r = -0.23, P < 0.01) after correcting for age and sex. In conclusion, the present study evaluated the vitamin D status using a reliable method, and our results indicate that vitamin D deficiency is prevalent among all age groups in China, especially among younger adults. We also observed significant differences in the 25OHD levels according to sex, age, and region among apparently healthy individuals. PMID- 25715265 TI - Factors associated with false-negative endoscopic biopsy results after neoadjuvant chemoradiotherapy in patients with esophageal squamous cell carcinoma. AB - The usefulness of endoscopic biopsy following neoadjuvant chemoradiotherapy (nCRT) is limited because of its high false-negative (FN) rates. However, data on the factors associated with FN biopsy results remain scarce. The purpose of this study was to investigate factors associated with FN results on endoscopic biopsies in patients with esophageal squamous cell carcinoma (ESCC) following nCRT. We retrospectively reviewed the records of ESCC patients who were treated at the Chang Gung Memorial Hospital, Taoyuan, Taiwan, between 1999 and 2013. Inclusion criteria were receiving nCRT as first-line treatment before esophagectomy and having been preoperatively submitted to an endoscopic biopsy. Endoscopic findings at the lesion site were classified into 6 distinct categories: stricture, tumor, ulcer, scar, other findings, or normal. Univariate and multivariate analyses were used to identify factors associated with FN biopsy findings. A total of 227 patients were selected, of which 92 (41.9%) had positive biopsy results. Among patients with negative biopsy findings (n = 135), 85 were found to have residual cancer on the resected esophagus. Multivariate analysis identified endoscopic findings as the only independent predictor of FN biopsy results. The negative predictive values were 77.8%, 61.9%, 52.6%, 30.3%, 23.1%, and 20.0% for the normal, scar, other findings, ulcer, stricture, and tumor categories, respectively (P < 0.001). In ESCC patients, the FN rate of endoscopic biopsy after nCRT is associated with the type of residual lesion. PMID- 25715266 TI - A novel endoscopic-assisted harvesting of pedicled freestyle fasciocutaneous flaps. AB - The endoscopy-assisted technique has been demonstrated in harvesting muscle flaps; however, for pedicled freestyle fasciocutaneous flaps, few studies have applied this technique. We present a surgical procedure utilizing endoscopic assisted method to identify the perforators of pedicled freestyle fasciocutaneous flaps for the reconstruction of soft tissue defects. From August to December 2012, 9 consecutive patients underwent endoscopic-assisted harvesting of fasciocutaneous flaps for the reconstruction of soft tissue defects. All of the defects were caused by trauma with tendon or bone exposure. Postoperatively, all patients were requested to return for outpatient follow-up visits for at least 3 months. The age of the 9 patients (8 men and 1 woman) ranged from 20 to 79 years (median 59 years). The defects ranged in size from 2 * 2 to 6 * 8 cm2. Two patients received anterolateral thigh transmuscular perforator flaps, 5 patients received fibular septocutaneous perforator flaps, and 2 patients received medial gastrocnemius transmuscular perforator flaps. The median incision length was 10 cm, and the median operative time was 120 minutes. None of the patients had intraoperative complications, and intraoperative bleeding was minimal (<50 mL). At the end of the 3-month follow-up period, none of the patients had any complications on either recipient or donor site, including total or partial necrosis of the flaps, flap dehiscence, hematomas, seromas, wound infections, or any conditions that indicated additional unplanned operative procedures. All of the patients had surviving flaps. Our results demonstrated that the endoscopic assisted method could be a valuable and reliable alternative in harvesting pedicled freestyle fasciocutaneous flaps. PMID- 25715267 TI - The predictive accuracy of PREDICT: a personalized decision-making tool for Southeast Asian women with breast cancer. AB - Web-based prognostication tools may provide a simple and economically feasible option to aid prognostication and selection of chemotherapy in early breast cancers. We validated PREDICT, a free online breast cancer prognostication and treatment benefit tool, in a resource-limited setting. All 1480 patients who underwent complete surgical treatment for stages I to III breast cancer from 1998 to 2006 were identified from the prospective breast cancer registry of University Malaya Medical Centre, Kuala Lumpur, Malaysia. Calibration was evaluated by comparing the model-predicted overall survival (OS) with patients' actual OS. Model discrimination was tested using receiver-operating characteristic (ROC) analysis. Median age at diagnosis was 50 years. The median tumor size at presentation was 3 cm and 54% of patients had lymph node-negative disease. About 55% of women had estrogen receptor-positive breast cancer. Overall, the model predicted 5 and 10-year OS was 86.3% and 77.5%, respectively, whereas the observed 5 and 10-year OS was 87.6% (difference: -1.3%) and 74.2% (difference: 3.3%), respectively; P values for goodness-of-fit test were 0.18 and 0.12, respectively. The program was accurate in most subgroups of patients, but significantly overestimated survival in patients aged <40 years, and in those receiving neoadjuvant chemotherapy. PREDICT performed well in terms of discrimination; areas under ROC curve were 0.78 (95% confidence interval [CI]: 0.74-0.81) and 0.73 (95% CI: 0.68-0.78) for 5 and 10-year OS, respectively. Based on its accurate performance in this study, PREDICT may be clinically useful in prognosticating women with breast cancer and personalizing breast cancer treatment in resource-limited settings. PMID- 25715268 TI - Incidence of subsequent cholangiocarcinomas after another malignancy: trends in a population-based study. AB - Cholangiocarcinoma (CCA) characterized by late diagnosis and poor outcomes represents the commonest malignancy of biliary tract. Understanding metachronous cancer associations may achieve earlier detection. We aimed to evaluate the risk of subsequent CCAs among common cancer survivors. The National Cancer Institute's Surveillance, Epidemiology, and End Results database (1973-2010) was reviewed for patients with 1 of the 25 primary cancers. Standardized incidence ratios (SIRs) were calculated as an approximation of relative risk for subsequent CCAs after primary malignancy. Data were stratified by age at primary cancer diagnosis, latency period, and application of radiation. A total of 1487 patients developed subsequent CCAs. For patients diagnosed with primary cancers between the ages 20 and 39 years, the risk was increased among colon (SIR 14.65), gallbladder (129.29), and uterus (7.29) cancer survivors. At ages of 40 to 59 years, oral cavity and pharynx (1.89), stomach (3.24), colon (1.76), gallbladder (11.78), and lung cancers (1.75) were associated with increased risk. We found persistently elevated SIRs after colon and gallbladder cancer between ages 60 and 79 years. The SIR remained significant among gallbladder cancer survivors diagnosed after 80 years. Gallbladder cancer showed elevated risk at all of the latency periods except first 6 to 11 months. Increased risk of lung cancer (1.66) was detected after 120 months. However, radiation therapy did not contribute to increased risk. This population-based study suggests that several initial cancers are associated with elevated risk of CCA. The increased risk may be due to shared genetic or environmental etiological factors between these malignancies. Lower threshold for CCA surveillance may be warranted in high-risk patients. PMID- 25715269 TI - Histochemical analysis of paraspinal rotator muscles from patients with adolescent idiopathic scoliosis: a cross-sectional study. AB - Morphological, biochemical, and histopathological alterations in the paraspinal skeletal muscle of patients with adolescent idiopathic scoliosis (AIS) have been extensively reported. We evaluated rotator muscle fibers from the apex vertebra of AIS patients through histological and immunohistochemical analysis. A population of 21 female AIS patients who underwent corrective surgery between 2010 and 2013 had biopsies taken from the paraspinal muscle in the convex and concave sides of the thoracic curve apical vertebra. Serial sections were stained following routine protocols for hematoxylin and eosin (HE), Sudan red, Gomori trichrome, NADH, ATPase, and cytochrome oxidase. We assessed muscular atrophy and hypertrophy, fatty proliferation, endomysial and perimysial fibrosis, the presence of hyaline fibers, mitochondrial proliferation, muscular necrosis, nuclear centralization, and inflammation. Two independent professionals evaluated the slices. The thoracic curves had an average Cobb angle of 68 degree. Comparative analysis of the concave and convex sides was performed with McNemar test at a significance level of 5%. Results showed significant differences in both endomysial and perimysial fibrosis and fatty involution between the two sides of the apex vertebra. Paraspinal muscles in the concave side of the scoliosis apex had significantly more fibrosis and fatty involution. However, both sides showed signs of myopathy, muscular atrophy due to necrosis, presence of hyaline fibers, and mitochondrial proliferation. PMID- 25715270 TI - Minimum energy paths of wetting transitions on grooved surfaces. AB - A method that computes minimum energy paths (MEPs) of wetting transitions is developed. The method couples the Cahn-Hilliard formulation of a modified phase field method with the simplified string method. Its main computational kernel is the fast Fourier transform that is efficiently performed on graphics processing units. The effectiveness of the proposed method is demonstrated on two types of transitions of droplets on grooved surfaces. The first is the transition from the Cassie-Baxter wetting state to the Wenzel state, where it is shown that it progresses in a sequential manner with the droplet wetting each groove successively. The second transition type is a lateral displacement of the droplet against the grooves, where the droplet successively detaches/attaches from/to the rear/front protrusion of the surface (a transition in the reverse order is also possible). The energy barriers of both the transitions are extracted from the MEP; they are useful for the evaluation of the robustness of superhydrophobic surfaces (resistance to the Cassie-Baxter to Wenzel transition) and the droplet mobility on those surfaces (high mobility/small resistance to lateral displacements). The relation of the MEP with the potential transition paths coming from the solution space mapping is discussed. PMID- 25715271 TI - Spontaneous emotion regulation: differential effects on evoked brain potentials and facial muscle activity. AB - Late positive potentials (LPPs) were found to be decreased during down-regulation and increased during up-regulation of positive and negative emotions. However, previous studies lack ecological validity, since they explicitly instructed their participants to use certain regulation strategies. The goal of our study was to test an ecologically more valid paradigm of emotion regulation. We therefore investigated the effects of freely chosen emotion regulation strategies on LPPs and additionally assessed facial EMG responses and valence and arousal ratings as control variables. Responses to positive IAPS pictures were marked by pleasant valence ratings and high activations of M. zygomaticus major, negative pictures elicited unpleasant valence ratings and high activations of M. corrugator supercilii, and both, positive and negative pictures, went along with increased arousal ratings and LPPs. Importantly, ratings and EMG activity were intensified through up-regulation and attenuated through down-regulation of emotions, while LPPs were increased through both up-and down-regulation. We conclude that LPPs in paradigms with free choice of emotion regulation strategies might be a marker of attentional resources required for the selection of adequate emotion up- and down regulation strategies, while LPP effects following emotion regulation with specific, instructed strategies reflect modulated arousal processes. PMID- 25715272 TI - Direct introduction of a naphthalene-1,8-diamino boryl [B(dan)] group by a Pd catalysed selective boryl transfer reaction. AB - A non-symmetrical diboron reagent, B(pin)-B(dan), has been utilised in the Pd catalysed borylation of aryl bromides and chlorides. Remarkably selective formation of aryl-B(dan) bonds is established. This represents a direct and efficient way to introduce masked boronic acids. The synthetic usefulness of this reaction is demonstrated in the preparation of boron-differentiated di- and polyboron compounds. PMID- 25715273 TI - Ovarian Fibroma Presenting With Meigs Syndrome. PMID- 25715274 TI - Microbiome engineering. PMID- 25715275 TI - Mental health: thinking from the gut. PMID- 25715276 TI - The diverse microbiome of the hunter-gatherer. PMID- 25715277 TI - The microbes within. PMID- 25715278 TI - Gut microbiome: the peacekeepers. PMID- 25715279 TI - Why microbiome treatments could pay off soon. PMID- 25715280 TI - The gene-microbe link. PMID- 25715281 TI - Your microbes at work: fiber fermenters keep us healthy. PMID- 25715282 TI - Effective cryopreservation of golden Syrian hamster embryos by open pulled straw vitrification. AB - Golden Syrian hamster embryos are difficult to cryopreserve due to their high sensitivity to cryoprotectants and in vitro handling. The objective of this study is to develop a robust open pulled straw (OPS) vitrification technique for cryopreserving hamster embryos at various developmental stages. We first systematically tested the concentrations of cryoprotectants and the exposure times of two-cell embryos to various vitrification solutions. We identified pretreatment of two-cell embryos with 10% (v/v) ethylene glycol (EG) + 10% (v/v) dimethylsulfoxide (DMSO) for 30 s followed by exposure in the vitrification solution, EDFS30 (containing 15% EG + 15% DMSO), for 30 s before plunging into liquid nitrogen (two-step exposure method) as the optimal OPS vitrification protocol. We then investigated the resourcefulness of this protocol for vitrifying hamster embryos at different developmental stages. The results showed that high blastocyst rates from embryos vitrified at two-cell, four-cell, eight cell, or morula stage (62%, 78%, 80%, or 72%, respectively), but not those verified at pronuclear (0%) or blastocyst stage (24%; P < 0.05), were achieved by this protocol. When embryos vitrified at the two-cell stage were recovered and then directly transferred to recipient females, 29% of them developed to term, a development rate not significantly different (P > 0.05) from the 40% birth rate of the unvitrified controls. In conclusion, we have developed an effective two step OPS vitrification protocol for hamster embryos. PMID- 25715283 TI - Rapid and Direct Encoding of Numerosity in the Visual Stream. AB - Humans are endowed with an intuitive number sense that allows us to perceive and estimate numerosity without relying on language. It is controversial, however, as to whether there is a neural mechanism for direct perception of numerosity or whether numerosity is perceived indirectly via other perceptual properties. In this study, we used a novel regression-based analytic method, which allowed an assessment of the unique contributions of visual properties, including numerosity, to explain visual evoked potentials of participants passively viewing dot arrays. We found that the human brain is uniquely sensitive to numerosity and more sensitive to changes in numerosity than to changes in other visual properties, starting extremely early in the visual stream: 75 ms over a medial occipital site and 180 ms over bilateral occipitoparietal sites. These findings provide strong evidence for the existence of a neural mechanism for rapidly and directly extracting numerosity information in the human visual pathway. PMID- 25715286 TI - Climate change, health, and penguins in Copacabana. PMID- 25715284 TI - Complementary Patterns of Direct Amygdala and Hippocampal Projections to the Macaque Prefrontal Cortex. AB - The projections from the amygdala and hippocampus (including subiculum and presubiculum) to prefrontal cortex were compared using anterograde tracers injected into macaque monkeys (Macaca fascicularis, Macaca mulatta). Almost all prefrontal areas were found to receive some amygdala inputs. These connections, which predominantly arose from the intermediate and magnocellular basal nucleus, were particularly dense in parts of the medial and orbital prefrontal cortex. Contralateral inputs were not, however, observed. The hippocampal projections to prefrontal areas were far more restricted, being confined to the ipsilateral medial and orbital prefrontal cortex (within areas 11, 13, 14, 24a, 32, and 25). These hippocampal projections principally arose from the subiculum, with the fornix providing the sole route. Thus, while the lateral prefrontal cortex essentially receives only amygdala inputs, the orbital prefrontal cortex receives both amygdala and hippocampal inputs, though these typically target different areas. Only in medial prefrontal cortex do direct inputs from both structures terminate in common sites. But, even when convergence occurs within an area, the projections predominantly terminate in different lamina (hippocampal inputs to layer III and amygdala inputs to layers I, II, and VI). The resulting segregation of prefrontal inputs could enable the parallel processing of different information types in prefrontal cortex. PMID- 25715287 TI - Challenges and perspectives for the promotion of adequate and healthy food in Brazil. PMID- 25715285 TI - The cyst nematode effector protein 10A07 targets and recruits host posttranslational machinery to mediate its nuclear trafficking and to promote parasitism in Arabidopsis. AB - Plant-parasitic cyst nematodes synthesize and secrete effector proteins that are essential for parasitism. One such protein is the 10A07 effector from the sugar beet cyst nematode, Heterodera schachtii, which is exclusively expressed in the nematode dorsal gland cell during all nematode parasitic stages. Overexpression of H. schachtii 10A07 in Arabidopsis thaliana produced a hypersusceptible phenotype in response to H. schachtii infection along with developmental changes reminiscent of auxin effects. The 10A07 protein physically associates with a plant kinase and the IAA16 transcription factor in the cytoplasm and nucleus, respectively. The interacting plant kinase (IPK) phosphorylates 10A07 at Ser-144 and Ser-231 and mediates its trafficking from the cytoplasm to the nucleus. Translocation to the nucleus is phosphorylation dependent since substitution of Ser-144 and Ser-231 by alanine resulted in exclusive cytoplasmic accumulation of 10A07. IPK and IAA16 are highly upregulated in the nematode-induced syncytium (feeding cells), and deliberate manipulations of their expression significantly alter plant susceptibility to H. schachtii in an additive fashion. An inactive variant of IPK functioned antagonistically to the wild-type IPK and caused a dominant-negative phenotype of reduced plant susceptibility. Thus, exploitation of host processes to the advantage of the parasites is one mechanism by which cyst nematodes promote parasitism of host plants. PMID- 25715288 TI - Satisfaction measurement instruments for healthcare service users: a systematic review. AB - Patient satisfaction surveys can be an interesting way to improve quality and discuss the concept of patient-centered care. This study aimed to conduct a systematic review of the validated patient satisfaction measurement instruments applied in healthcare. The systematic review searched the MEDLINE/PubMed, LILACS, SciELO, Scopus and Web of Knowledge. The search strategy used the terms: "Patient Satisfaction" AND "Patient centered care" AND "Healthcare survey OR Satisfaction questionnaire" AND "Psychometric properties". 37 studies were included and almost all studies showed that satisfaction is a multidimensional construct. In these studies, 34 different instruments were used and most surveys contained the dimension patient-healthcare professional interactions, physical environment and management process. The COSMIN score for methodological quality showed that most of them scored a good or fair average. We can conclude that there is not a gold standard instrument for patient satisfaction assessment but some dimensions are essential for this construct. PMID- 25715290 TI - [Data quality in surveys on alcohol consumption among university students]. AB - Different survey modalities have been developed to assess alcohol consumption and related problems. Research that compares data quality between survey modalities is scarce in Latin America. The aim of this study was to assess data quality in three survey modalities on alcohol consumption: self-administered online, self administered hard-copy, and face-to-face interviews. Data were obtained from three probabilistic samples of students (n = 60 each) from the National University of Mar del Plata, Argentina, using the same questionnaire. Data quality was measured for each modality by overall response rate, item response rate, and accuracy. Data accuracy was evaluated as the percentage of self reported binge drinking, positive results on AUDIT, and internal consistency of AUDIT for each modality. The overall and item response rates were lower in the online modality and similar between the other two. No differences were found between modalities in the accuracy of responses. PMID- 25715289 TI - [Meta analysis of the use of Bayesian networks in breast cancer diagnosis]. AB - The aim of this study was to determine the accuracy of Bayesian networks in supporting breast cancer diagnoses. Systematic review and meta-analysis were carried out, including articles and papers published between January 1990 and March 2013. We included prospective and retrospective cross-sectional studies of the accuracy of diagnoses of breast lesions (target conditions) made using Bayesian networks (index test). Four primary studies that included 1,223 breast lesions were analyzed, 89.52% (444/496) of the breast cancer cases and 6.33% (46/727) of the benign lesions were positive based on the Bayesian network analysis. The area under the curve (AUC) for the summary receiver operating characteristic curve (SROC) was 0.97, with a Q* value of 0.92. Using Bayesian networks to diagnose malignant lesions increased the pretest probability of a true positive from 40.03% to 90.05% and decreased the probability of a false negative to 6.44%. Therefore, our results demonstrated that Bayesian networks provide an accurate and non-invasive method to support breast cancer diagnosis. PMID- 25715291 TI - Multilevel analysis of self-perception in oral health and associated factors in Southern Brazilian adults: a cross-sectional study. AB - The aim of this study was to evaluate the association between individual and contextual variables related to self-perception in oral health among residents in the municipality of Sao Leopoldo, Rio Grande do Sul State, Brazil. The cross sectional design involved 1,100 adults in 38 census tracts. The self-perception was evaluated using the Oral Health Impact Profile (OHIP-14) tool. A logistic multilevel analysis was performed. The multivariate analysis revealed that those who are of the female gender, older, with lower scores of quality of life and less social support, with poor healthy eating habits, smokers and those living in low-income census tracts presented higher odds of reporting worse oral health self-perception (OHIP-1). We concluded that individual and contextual variables are associated with oral health self-perception. This is essential information for planning health services wishing to meet the health needs of the population. PMID- 25715292 TI - Medical therapeutic itineraries of women with breast cancer diagnosis affiliated to the People's Health Insurance in San Luis Potosi, central Mexico. AB - This study aims to describe the medical itineraries followed by breast cancer women affiliated to the People's Health Insurance in San Luis Potosi, central Mexico. We used an ethnographic approach based on oral histories of 12 women diagnosed with breast cancer in the year prior to the first meeting. Two face-to face sessions per participant lasting 60 minutes each were conducted followed by a telephone interview. Content and diachronic analyses were used. Three main itineraries were identified: (1) diagnostic process, (2) final diagnosis to treatment, and (3) cancer control and relapse. Findings suggested that infrastructure and human resources to adequately screen and timely diagnose breast cancer were scant and insufficiently trained, respectively. Deferral of medical assessment was related with lack of information about breast cancer consequences, with women being afraid of a positive result, and with economic constraints. The current screening program needs to be redesigned to prevent diagnostic delays, as these seem to explain the high frequency of advanced stages reported at the time of diagnosis. PMID- 25715293 TI - [Evaluation of women's health care programs in the main institutions of the Mexican health system]. AB - The aim of this study was to analyze the institutional capacity for provision of women's health care services in Mexico in accordance with prevailing regulations. A probabilistic national sample of health care institutions was used to compare performance rates according to services packages based on analysis of variance. No package showed outstanding performance. Adequate performance was seen in referral and counter-referral centers for uterine cervical cancer, childbirth care, breast cancer diagnosis, family planning counseling, and training in sexual and reproductive health. The lowest performance was seen in the prevention of uterine cervical cancer, obstetric urgencies, family and sexual violence, and promotion of family planning. All the institutions showed low performance in the prevention of breast cancer, promotion of family planning, and management of family and gender violence. The Ministry of Health's leadership needs to be strengthened in order to overcome resistance for the institutions to adhere to the prevailing regulations. PMID- 25715294 TI - [Building a "Smiling Brazil"? Implementation of the Brazilian National Oral Health Policy in a health region in the State of Sao Paulo]. AB - This paper is a case study on the implementation of the Brazilian National Oral Health Policy (PNSB), known as "Smiling Brazil", in the cities of the Regional Health Department of Araraquara (DRS III) in Sao Paulo State. A structured questionnaire was given to the municipal oral health coordinators, an interview with oral health care professionals and managers was conducted, and the official data provided by the Brazilian Ministry of Health were coded to assess the policy's scope: (i) expansion and qualification of actions; (ii) work conditions; (iii) care; (iv) access; and (v) planning and management. The quantitative and qualitative analyses were linked by methods triangulation. In terms of PNSB implementation, the majority of the cities (52.6%) were classified as "good", with 42.1% classified as "bad". Approximately 10 years after launching the PNSB, despite strides in oral health care and access to different levels of care, the cities still experience difficulties in implementing the policy's principles. PMID- 25715295 TI - [Association between psychosocial aspects of work and quality of life among motorcycle taxi drivers]. AB - This study aimed to evaluate the quality of life of motorcycle taxi drivers and the association with psychosocial characteristics of their work. This was a cross sectional epidemiological study with a sample of 400 motorcycle taxi drivers in Jequie, Bahia State, Brazil. The study used a form containing demographic and socioeconomic data, WHO Quality of Life-Bref Questionnaire (WHOQOL-Bref), and the Job Content Questionnaire (JCQ). Motorcycle taxi drivers with greater decision making control over their work showed better self-rated quality of life in the psychological domain; those with high psychological demands presented better self rated quality of life in the social relations and environmental domains; those with high strain and active work showed better self-rated quality of life in the social and environmental domains. The psychosocial work environment and especially decision-making autonomy were thus important determinants of self rated quality of life in this group of motorcycle taxi drivers. PMID- 25715296 TI - [Factors associated with geographic access to health services by TB patients in three State capitals in Northeast Brazil]. AB - The aim of this study was to identify factors associated with geographic access to health services by tuberculosis patients in three State capitals in Northeast Brazil. The sample consisted of new tuberculosis cases reported in 2007. The study used data from the Information System on Notifiable Diseases and the National Registry of Healthcare Organizations. Addresses of households and health services were geocoded, and difficult access was defined as a distance greater than 800 meters from the household to the health service. Crude prevalence ratios were estimated, as well as adjusted prevalence ratios using Poisson regression. After adjusting the study variables, the only variable that remained associated with difficult access was primary healthcare units in Salvador, Bahia State (PR = 0.75; 95%CI: 0.720-0.794) and in Recife, Pernambuco State (PR = 0.402; 95%CI: 0.318-0.508). The study concluded that decentralization of primary care can help improve access to health services. PMID- 25715297 TI - Morbidity and mortality associated with injuries: results of the Global Burden of Disease study in Brazil, 2008. AB - The aim of this study was to estimate the global burden of disease from external causes in 2008 in Brazil, based on DALYs (disability-adjusted life years). YLLs (years of life lost) were estimated according to the method proposed by Murray & Lopez (1996). Meanwhile, the method for estimating YLDs (years lived with disability) included methodological adjustments taking the Brazilian reality into account. The study showed a total of 195 DALYs per 100 thousand inhabitants, of which 19 DALYs were related to external causes. Among YLLs, 48% were from unintentional causes and 52% from intentional causes. Among YLDs, unintentional causes predominated, with 95%. The share of YLLs in DALYs was 90%. The cause with the highest proportion of YLLs was "homicide and violence" (43%), followed by "road traffic accidents" (31%). Falls accounted for the highest share of YLDs (36%). The sex ratio (male-to-female) was 4.8 for DALYs, and the predominant age bracket was 15-29 years. Since external causes are avoidable, the study provides potentially useful information for policymakers in public security and health. PMID- 25715298 TI - [The cost of meeting dietary guidelines for low-income Brazilian families]. AB - The objective was to identify the cost of meeting the Brazilian National Dietary Guidelines and analyze the impact on family budget. Data from the Brazilian Household Budget Survey for 2008 were used. Food purchases were recorded for seven days in 55,970 households. A subset of low-income families (<= BRL 415.00 per capita/month and <= US$ 1.00 per capita/day) was used for the analysis. We estimated per capita calorie availability, total food expenditures, and food prices aggregated in 8 food groups based on the Brazilian Guidelines. Each food group's share in total calories was estimated and compared to the recommendations. Actual purchases exceeded the recommendations for beans, oils/fats, sweets, and meat/eggs, and fell short for fruits, vegetables, dairy products, and grains. Meeting the recommendations would increase food expenditures by 58% among individuals with per capita income <= US$ 1.00/day and by 39% for those with per capita income <= BRL 415.00. Adoption of the recommendations would require 145% of total income. Meeting current recommendations would demand an increase in income or a policy to reduce food prices. PMID- 25715299 TI - [Hand hygiene: health professionals' knowledge and areas for improvement]. AB - The objective of this study was to analyze knowledge on hand hygiene among staff workers in the Andalusian Public Health System (Spain). This was a cross sectional study with surveys (2011) using the Hand Hygiene Knowledge Assessment Questionnaire for Healthcare Workers with the latent class analysis technique. The average number of questions answered correctly was 17.51+/-3.68. Questions with lower percentages of correct responses were those on hand hygiene for prevention of microorganism transmission to patients and those on hand- rubbing versus hand-washing. We obtained a model with 7 latent classes. Workers with lower knowledge tended to be younger, males, and non-healthcare workers. Having received previous training did not necessarily ensure excellent knowledge. The study concludes that hand hygiene training programs need to be revised in order to improve knowledge on conceptual characteristics involved in the transmission of microorganisms via the hands. PMID- 25715300 TI - Effect of physical intimate partner violence on body mass index in low-income adult women. AB - This study aimed to assess whether physical intimate partner violence affects the nutritional status of adult women with different levels of body mass index (BMI). This was a population-based cross-sectional study with 625 women selected through complex multistage cluster sampling. Information on physical intimate partner violence was obtained with the Revised Conflict Tactics Scales, and nutritional status was measured as BMI (kg/m2). A quantile regression model was used to assess the effect of physical intimate partner violence at all percentiles of BMI distribution. Physical intimate partner violence occurred in 27.6% of the women (95%CI: 20.0; 35.2). Mean BMI was 27.9kg/m2 (95%CI: 27.1; 28.7). The results showed that physical intimate partner violence was negatively associated with BMI between the 25th and 85th percentiles, corresponding to 22.9 and 31.2kg/m2. The findings support previous studies indicating that physical intimate partner violence can reduce BMI in low-income women. PMID- 25715301 TI - [The association between self-rated living environment and excess weight in a small Brazilian town]. AB - This population-based cross-sectional study examined the relationship between self-rated living environment and excess body weight in a sample of 216 adults from Itirapua, Sao Paulo State, Brazil. Logistic regression adjusted for gender and age showed that people living far from outdoor areas for physical exercise [OR = 2.05 (95%CI: 1.15; 3.66)] and primary schools [OR = 1.99 (95%CI: 1.13; 3.47)] had higher odds of excess weight. Satisfaction with the quality of available supermarkets [OR = 0.14 (95%CI: 0.03; 0.69) p = 0.02], adequate street lighting [OR = 0.37 (95%CI: 0.14; 0.96) p = 0.02], and pedestrians walking on sidewalks within one's line-of-sight [OR = 0.41 (95%CI: 0.18; 0.94) p = 0.03] were inversely associated with excess weight. The results suggest that small-town individuals' negative perceptions of their living environment are associated with excess weight. PMID- 25715302 TI - [The legitimacy of representation in forums with social participation: the case of the Bahia State Health Council, Brazil]. AB - The electoral representation model is insufficient and inadequate for new participatory roles such as those played by members of health councils. This article analyzes representation and representativeness in the Bahia State Health Council, Brazil. The study included interviews with 20 current or former members of the State Health Council, analysis of the council minutes and bylaws, and observation of plenary meetings. Discourse analysis technique was used to analyze interventions by members. The article discusses the results in four analytical lines: the process by which various organizations name representatives to the Council; the relationship between Council members and their constituencies; interest representation in the Council; and criteria used by the plenary to take positions. The study reveals various problems with the representativeness of the Bahia State Health Council and discusses the peculiarities of representation in social participation forums and the characteristics that give legitimacy to representatives. PMID- 25715303 TI - [Sick leave benefits for workers in the Brazilian meat and fish industries in 2008]. AB - This study aims to analyze factors associated with sick leave rates among workers in the meat, fish, and seafood industries in Brazil. The study analyzed all sick leave benefits granted by the country's social security system to workers in these industries in 2008. Incidence of sick leave per 10 thousand jobs was stratified by sex, age, diagnosis, job position, State, and nature and length of benefits. The study analyzed 31,913 sick leaves, with an annual incidence of 788.7. Meat processing and packaging showed the highest incidence, and fish and seafood processing and packaging showed the longest mean length of sick leave. Women showed a higher sick leave incidence, while men received longer average sick leaves. Injuries, musculoskeletal disorders, and mental disorders accounted for 67.2% of sick leaves. The most common diagnoses were lower back pain, first trimester bleeding in pregnancy, and depression. The data suggest poor job protection and adverse working conditions in these industries. PMID- 25715304 TI - The demand-control model for job strain: a commentary on different ways to operationalize the exposure variable. AB - Demand-control has been the most widely used model to study job strain in various countries. However, researchers have used the model differently, thus hindering the comparison of results. Such heterogeneity appears in both the study instrument used and in the definition of the main exposure variable - high strain. This cross-sectional study aimed to assess differences between various ways of operationalizing job strain through association with prevalent hypertension in a cohort of workers (Pro-Health Study). No difference in the association between high job strain and hypertension was found according to the different ways of operationalizing exposure, even though prevalence varied widely, according to the adopted form, from 19.6% for quadrants to 42% for subtraction tertile. The authors recommend further studies to define the cutoff for exposure variables using combined subjective and objective data. PMID- 25715308 TI - Trimetazidine Decreases Risk of Contrast-Induced Nephropathy in Patients With Chronic Kidney Disease: A Meta-Analysis of Randomized Controlled Trials. AB - OBJECTIVES: We sought to synthesize and analyze the available data from randomized controlled trials (RCTs) for trimetazidine (TMZ) in the prevention of contrast-induced nephropathy (CIN). BACKGROUND: Contrast-induced nephropathy after coronary angiography is associated with poor outcomes. Trimetazidine is an anti-ischemic drug that might reduce incidence of CIN, but current data are inconclusive. METHODS: We searched MEDLINE/PubMed, EMBASE, Scopus, Cochrane Library, Web of Science, and ScienceDirect electronic databases for RCTs comparing intravenous hydration with normal saline (NS) and/or N-acetyl cysteine (NAC) versus TMZ plus NS +/- NAC for prevention of CIN. We used RevMan 5.2 for statistical analysis with the fixed effects model. RESULTS: Of the 808 studies, 3 RCTs met criteria with 290 patients in the TMZ plus NS +/- NAC group and 292 patients in the NS +/- NAC group. The mean age of patients was 59.5 years, and baseline serum creatinine ranged from 1.3 to 2 mg/dL. Trimetazidine significantly reduced the incidence of CIN by 11% (risk difference 0.11; 95% confidence interval, 0.16-0.06; P < .01). There was no significant heterogeneity between the studies (I(2) statistic = 0). The number needed to treat to prevent 1 episode of CIN was 9. CONCLUSIONS: The addition of TMZ to NS +/- NAC significantly decreased the incidence of CIN in patients undergoing coronary angiography. In conclusion, TMZ could be considered as a potential tool for prevention of CIN in patients with renal dysfunction. PMID- 25715309 TI - Simulation is an adjunct to clinical training, not a replacement. PMID- 25715310 TI - On quality control and the importance of European postgraduate medical specialty assessments. PMID- 25715311 TI - Copper Bromide Laser vs Triple-Combination Cream for the Treatment of Melasma: A Randomized Clinical Trial. PMID- 25715312 TI - Suicidal ideation and suicide attempts among adults with psychotic experiences: data from the Collaborative Psychiatric Epidemiology Surveys. AB - IMPORTANCE: Suicide is a leading cause of preventable death, especially among individuals with psychotic disorders, and may also be common among nonclinical populations of adults with subthreshold psychotic experiences. Understanding this association has the potential to critically bolster suicide prevention efforts. OBJECTIVES: To examine the association between 12-month suicidality and 12-month psychotic experiences and to test the hypotheses that psychotic experiences are associated with increased prevalence of suicidal ideation and suicide attempts during the concurrent period and with greater severity of suicidal behavior. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional survey data were drawn from a large general population-based sample of households in the United States identified through the Collaborative Psychiatric Epidemiology Surveys (2001 2003). Adult household residents (n = 11,716) were selected using a clustered multistage sampling design with oversampling of racial/ethnic minority groups. Logistic regression models were adjusted for potential demographic confounders and co-occurring DSM-IV mental health conditions. EXPOSURES: Twelve-month psychotic experiences assessed with the Composite International Diagnostic Interview, version 3.0 psychosis screen. MAIN OUTCOMES AND MEASURES: Twelve-month suicidal ideation and suicide attempts. RESULTS: Respondents reporting psychotic experiences were more likely to report concurrent suicidal ideation (odds ratio [OR], 5.24; 95% CI, 2.85-9.62) and suicide attempts (OR, 9.48; 95% CI, 3.98 22.62). Most respondents with psychotic experiences (mean [SE], 65.2% [4.2%]) met criteria for a DSM-IV depressive, anxiety, or substance use disorder. Among respondents with suicidal ideation, those with psychotic experiences were likely to make an attempt during the concurrent 12-month period (OR, 3.49; 95% CI, 1.05 11.58) when adjusting for co-occurring psychiatric disorders. In contrast, depressive (OR, 1.67; 95% CI, 0.62-4.52), anxiety (OR, 1.57; 95% CI, 0.40-6.09), and substance use disorders (OR, 1.64; 95% CI, 0.24-11.17) did not reliably identify those at risk for attempts among respondents with suicidal ideation. The mean (SE) 12-month prevalence of suicide attempts among individuals reporting ideation and psychotic experiences and meeting criteria for any psychiatric disorder was 47.4% (10.9%) compared with 18.9% (4.8%) among those with just ideation and a disorder. Psychotic experiences were especially prevalent among individuals reporting severe attempts and may account for nearly one-third of attempts with intent to die (population attributable risk, 29.01%) in the United States annually. CONCLUSIONS AND RELEVANCE: Assessment of psychotic experiences among individuals with suicidal ideation has potential clinical and public health utility in reducing the prevalence of suicide attempts, particularly attempts with intent to die. PMID- 25715313 TI - Antioxidants and Biomarkers of Oxidative Stress in Preterm Infants with Symptomatic Patent Ductus Arteriosus. AB - OBJECTIVE: Immature antioxidant and oxygen-sensing mechanisms are involved in the pathogenesis of the patent ductus arteriosus (PDA). We conducted a prospective, observational, pilot study to test the hypothesis that antioxidant activity is low at birth in preterm infants at risk for symptomatic PDA. STUDY DESIGN: Blood and urine samples were collected within 24 to 48 hours of life in 53 preterm infants (<=32 weeks' gestation) who developed early PDA symptoms and in 30 term (>=37 weeks' gestation) control infants. Thirty preterm infants developed hemodynamically significant PDA (hsPDA) and required pharmacologic treatment and/or PDA ligation. For these infants, blood and urine samples were also collected at 24 hours posttreatment. Samples were analyzed for biomarkers of antioxidant activity, oxidative stress, and lipid peroxidation. RESULTS: At 24 to 48 hours after birth, plasma superoxide dismutase (SOD), urinary catalase, and plasma and urinary 8-isoPGF2alpha were significantly lower in preterm infants who developed hsPDA. Plasma 8-isoPGF2alpha levels rebounded post-PDA treatment, while urinary prostaglandin E2, plasma and urinary thromboxane B2, and plasma SOD declined. CONCLUSION: The antioxidant status is low in preterm infants at risk for developing hsPDA. SOD may be a key antioxidant regulating functional ductus arteriosus closure. Therefore, low levels may result in persistence of a hsPDA. PMID- 25715315 TI - Development and validation of the Proxy-Reported Pulmonary Outcomes Scale for premature infants. AB - OBJECTIVE: Test the feasibility of using a bedside nurse-reported tool (Proxy Reported Pulmonary Outcome Scale, PRPOS) for evaluating the severity of bronchopulmonary dysplasia (BPD) by assessing functional, disease-related measures. STUDY DESIGN: Bedside nurses tested the 26-item instrument by observing preterm infants (23-30 weeks at birth) at 36 to 37(4/7) weeks postmenstrual age before, during, and after a care time. We analyzed item reliability, validity, and model fit to determine the six items to include in the final measurement tool. RESULT: We completed assessments on 188 preterm infants. The frequency of an abnormal PRPOS item score increased with increasing National Institute of Child Health and Development (NICHD) BPD category. The six-candidate items produced an internally consistent scale. Addition of the NICHD BPD classification increased reliability moderately; addition of feeding items decreased reliability. The PRPOS score correlated with postmenstrual age at discharge. Infants discharged on oxygen or diuretics had higher median PRPOS scores than did infants who were not prescribed those therapies. CONCLUSION: The PRPOS is an internally consistent, proxy-reported measure of respiratory function in premature infants, based on observable, functional performance measures. Initial testing demonstrates known-groups validity and ongoing testing can assess predictive validity. PMID- 25715316 TI - Gadolinium-based nanoparticles for theranostic MRI-radiosensitization. AB - A rapid development of gadolinium-based nanoparticles is observed due to their attractive properties as MRI-positive contrast agents. Indeed, they display high relaxivity, adapted biodistribution and passive uptake in the tumor thanks to enhanced permeability and retention effect. In addition to these imaging properties, it has been recently shown that they can act as effective radiosensitizers under different types of irradiation (radiotherapy, neutron therapy or hadron therapy). These new therapeutic modalities pave the way to therapy guided by imaging and to personalized medicine. PMID- 25715317 TI - A simple and highly selective 2,2-diferrocenylpropane-based multi-channel ion pair receptor for Pb(2+) and HSO4(-). AB - A structurally simple, 2,2-diferrocenylpropane-based ion pair receptor 1 was synthesized and characterized by (1)H NMR, (13)C NMR, HRMS, elemental analyses, and single-crystal X-ray diffraction. The ion pair receptor 1 showed excellent selectivity and sensitivity towards Pb(2+) with multi-channel responses: a fluorescence enhancement (more than 42-fold), a notable color change from yellow to red, redox anodic shift (DeltaE1/2 = 151 mV), while HSO4(-) promoted fluorescence enhancement when Pb(2+) or Zn(2+) was bonded to the cation binding site. (1)H NMR titration and density functional theory were performed to reveal the sensing mechanism based on photo-induced electron transfer (PET). PMID- 25715314 TI - Management Practice and Mortality for Infants with Congenital Diaphragmatic Hernia. AB - OBJECTIVE: Congenital diaphragmatic hernia (CDH) is fatal in 20 to 40% of cases, largely due to pulmonary dysmaturity, lung hypoplasia, and persistent pulmonary hypertension. Evidence for survival benefit of inhaled nitric oxide (iNO), extracorporeal membrane oxygenation (ECMO), and other medical interventions targeting pulmonary hypertension is lacking. We assessed medical interventions and mortality over time in a large multicenter cohort of infants with CDH. STUDY DESIGN: We identified all infants >= 34 weeks' gestation with CDH discharged from 29 neonatal intensive care units between 1999 and 2012 with an average of >= 2 CDH admissions per year. We examined mortality and the proportion of infants exposed to medical interventions, comparing four periods of time: 1999-2001, 2002 2004, 2005-2007, and 2008-2012. RESULTS: We identified 760 infants with CDH. From 1999-2001 to 2008-2012, use of iNO increased from 20% of infants to 50%, sildenafil use increased from 0 to 14%, and milrinone use increased from 0 to 22% (p < 0.001). Overall mortality (28%) did not significantly change over time compared with the earliest time period. CONCLUSION: Despite changing use of iNO, sildenafil, and milrinone, CDH mortality has not significantly decreased in this population of infants. PMID- 25715319 TI - Construction of kinked heteronanorods modified by metal nanoparticles with enhanced catalytic performance. AB - Unique kinked semiconductor-metal Au-Ag2S-ZnS and Au-Ag2S-ZnS-Au heteronanorods have been synthesized for the first time by a seed-mediated growth method. A plausible mechanism for the formation of kinked heteronanorods is proposed. The catalytic activity of such novel kinked semiconductor-metal heteronanorods with selective deposition and uniform morphology is also investigated via a model reaction based on the reduction of 4-nitrophenol by NaBH4. PMID- 25715318 TI - The compatibility of inactivated-Enterovirus 71 vaccination with Coxsackievirus A16 and Poliovirus immunizations in humans and animals. AB - Enterovirus 71 (EV71) is the key pathogen for Hand, Foot, and Mouth Disease (HFMD) and can result in severe neurological complications and death among young children. Three inactivated-EV71 vaccines have gone through phase III clinical trials and have demonstrated good safety and efficacy. These vaccines will benefit young children under the threat of severe HFMD. However, the potential immunization-related compatibility for different enterovirus vaccines remains unclear, making it hard to include the EV71 vaccine in Expanded Program on Immunization (EPI). Here, we measured the neutralizing antibodies (NTAbs) against EV71, Coxsackievirus A16 (CA16) and Poliovirus from infants enrolled in those EV71 vaccine clinical trials. The results indicated that the levels of NTAb GMTs for EV71 increased significantly in all 3 vaccine groups (high, middle and low dosages, respectively) post-vaccination. Seroconversion ratios and Geometric mean fold increase were significantly higher in the vaccine groups (>= 7/9 and 8.9 ~ 228.1) than in the placebo group (<= 1/10 and 0.8 ~ 1.7, P < 0.05). But no similar NTAb response trends were found in CA16 and 3 types of Poliovirus. The decrease of 3 types of Poliovirus NTAb GMTs and an increase of CA16 GMTs post EV71-vaccination were found in vaccine and placebo groups. Further animal study on CA16 and poliovirus vaccine co-immunization or pre-immunization with EV71 vaccine in mice indicated that there was no NTAb cross-activity between EV71 and CA16/Poliovirus. Our research showed that inactivated-EV71 vaccine has good specific-neutralizing capacity and can be included in EPI. PMID- 25715320 TI - Microbial synthesis of plant oxylipins from gamma-linolenic acid through designed biotransformation pathways. AB - Secondary metabolites of plants are often difficult to synthesize in high yields because of the large complexity of the biosynthetic pathways and challenges encountered in the functional expression of the required biosynthetic enzymes in microbial cells. In this study, the biosynthesis of plant oxylipins--a family of oxygenated unsaturated carboxylic acids--was explored to enable a high-yield production through a designed microbial synthetic system harboring a set of microbial enzymes (i.e., fatty acid double-bond hydratases, alcohol dehydrogenases, Baeyer-Villiger monooxygenases, and esterases) to produce a variety of unsaturated carboxylic acids from gamma-linolenic acid. The whole cell system of the recombinant Escherichia coli efficiently produced (6Z,9Z)-12 hydroxydodeca-6,9-dienoic acid (7), (Z)-9-hydroxynon-6-enoic acid (15), (Z)-dec-4 enedioic acid (17), and (6Z,9Z)-13-hydroxyoctadeca-6,9-dienoic acid (2). This study demonstrated that various secondary metabolites of plants can be produced by implementing artificial biosynthetic pathways into whole-cell biocatalysis. PMID- 25715321 TI - Photophysical properties of beta-substituted free-base corroles. AB - Corroles are an emergent class of fluorophores that are finding an application and reaction chemistry to rival their porphyrin analogues. Despite a growing interest in the synthesis, reactivity, and functionalization of these macrocycles, their excited-state chemistry remains undeveloped. A systematic study of the photophysical properties of beta-substituted corroles was performed on a series of free-base beta-brominated derivatives as well as a beta-linked corrole dimer. The singlet and triplet electronic states of these compounds were examined with steady-state and time-resolved spectroscopic methods, which are complemented with density functional theory (DFT) and time-dependent DFT calculations to gain insight into the nature of the electronic structure. Selective bromination of a single molecular edge manifests in a splitting of the Soret band into x and y polarizations, which is a consequence of asymmetry of the molecular axes. A pronounced heavy atom effect is the primary determinant of the photophysical properties of these free-base corroles; bromination decreases the fluorescence quantum yield (from 15% to 0.47%) and lifetime (from 4 ns to 80 ps) by promoting enhanced intersystem crossing, as evidenced by a dramatic increase in knr with bromine substitution. The nonbrominated dimer exhibits absorption and emission features comparable to those of the tetrabrominated derivative, suggesting that oligomerization provides a means of red-shifting the spectral properties akin to bromination but without decreasing the fluorescence quantum yield. PMID- 25715322 TI - Parent binge eating and depressive symptoms as predictors of attrition in a family-based treatment for pediatric obesity. AB - BACKGROUND: Attrition is a significant problem in family-based treatment (FBT) for childhood obesity. Despite this, very few studies have examined factors associated with attrition. The current study examined parent symptoms of depression and binge eating as predictors of attrition in FBT. METHODS: Participants included 77 parents of overweight children enrolled in FBT for childhood obesity. Data were collected at baseline and post-treatment. Binary logistic regression was used to assess associations between parent binge eating symptoms, depressive symptoms, and attrition. RESULTS: Results showed that parent binge eating symptoms (p=0.02), but not depressive symptoms (p=0.07), were significantly associated with attrition, after controlling for parent BMI, treatment group assignment, and family income. CONCLUSIONS: Higher reported parent binge eating symptoms were significantly related to attrition in FBT. Assessment of parent binge eating may be important in identifying families at risk for dropping out of FBT. Further, FBT may need to be adapted for families with parents who have a high level of psychopathology. PMID- 25715323 TI - Remediating buildings damaged by dampness and mould for preventing or reducing respiratory tract symptoms, infections and asthma. AB - BACKGROUND: Dampness and mould in buildings have been associated with adverse respiratory symptoms, asthma and respiratory infections of inhabitants. Moisture damage is a very common problem in private houses, workplaces and public buildings such as schools. OBJECTIVES: To determine the effectiveness of repairing buildings damaged by dampness and mould in order to reduce or prevent respiratory tract symptoms, infections and symptoms of asthma. SEARCH METHODS: We searched CENTRAL (2014, Issue 10), MEDLINE (1951 to November week 1, 2014), EMBASE (1974 to November 2014), CINAHL (1982 to November 2014), Science Citation Index (1973 to November 2014), Biosis Previews (1989 to June 2011), NIOSHTIC (1930 to March 2014) and CISDOC (1974 to March 2014). SELECTION CRITERIA: Randomised controlled trials (RCTs), cluster-RCTs (cRCTs), interrupted time series studies and controlled before-after (CBA) studies of the effects of remediating dampness and mould in a building on respiratory symptoms, infections and asthma. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data and assessed the risk of bias in the included studies. MAIN RESULTS: We included 12 studies (8028 participants): two RCTs (294 participants), one cRCT (4407 participants) and nine CBA studies (3327 participants). The interventions varied from thorough renovation to cleaning only.Repairing houses decreased asthma-related symptoms in adults (among others, wheezing (odds ratio (OR) 0.64; 95% confidence interval (CI) 0.55 to 0.75) and respiratory infections (among others, rhinitis (OR 0.57; 95% CI 0.49 to 0.66), two studies, moderate-quality evidence). For children, we did not find a difference between repaired houses and receiving information only, in the number of asthma days or emergency department visits because of asthma (one study, moderate-quality evidence).One CBA study showed very low-quality evidence that after repairing a mould-damaged office building, asthma-related and other respiratory symptoms decreased. In another CBA study, there was no difference in symptoms between full or partial repair of houses.For children in schools, the evidence of an effect of mould remediation on respiratory symptoms was inconsistent and out of many symptom measures only respiratory infections might have decreased after the intervention. For staff in schools, there was very low-quality evidence that asthma-related and other respiratory symptoms in mould-damaged schools were similar to those of staff in non-damaged schools, both before and after intervention. AUTHORS' CONCLUSIONS: We found moderate to very low-quality evidence that repairing mould-damaged houses and offices decreases asthma-related symptoms and respiratory infections compared to no intervention in adults. There is very low-quality evidence that although repairing schools did not significantly change respiratory symptoms in staff, pupils' visits to physicians due to a common cold were less frequent after remediation of the school. Better research, preferably with a cRCT design and with more validated outcome measures, is needed. PMID- 25715324 TI - A set of robust fluorescent peptide probes for quantification of Cu(ii) binding affinities in the micromolar to femtomolar range. AB - Reliable quantification of copper binding affinities and identification of the binding sites provide a molecular basis for an understanding of the nutritional roles and toxic effects of copper ions. Sets of chromophoric probes are now available that can quantify Cu(i) binding affinities from nanomolar to attomolar concentrations on a unified scale under in vitro conditions. Equivalent probes for Cu(ii) are lacking. This work reports development of a set of four fluorescent dansyl peptide probes (DP1-4) that can quantify Cu(ii) binding affinities from micromolar to femtomolar concentrations, also on a unified scale. The probes were constructed by conjugation of a dansyl group to four short peptides of specific design. Each was characterised by its dissociation constant KD, its pH dependence and the nature of its binding site. One equivalent of Cu(ii) is bound by the individual probes that display different and well separated affinities at pH 7.4 (log KD = -8.1, -10.1, -12.3 and -14.1, respectively). Intense fluorescence is emitted at lambdamax ~ 550 nm upon excitation at ~330 nm. Binding of Cu(ii) quenches the fluorescence intensity linearly until one equivalent of Cu(ii) is bound. Multiple approaches and multiple affinity standards were employed to ensure reliability. Selected examples of application to well-characterised Cu(ii) binding peptides and proteins are presented. These include Abeta16 peptides, two naturally occurring Cu(ii)-chelating motifs in human serum and cerebrospinal fluid with sequences GHK and DAHK and two copper binding proteins, CopC from Pseudomonas syringae and PcoC from Escherichia coli. Previously reported affinities are reproduced, demonstrating that peptides DP1-4 form a set of robust and reliable probes for Cu(ii) binding to peptides and protein targets. PMID- 25715325 TI - New generations of targeted therapies fighting the resistance in solid tumors. AB - PURPOSE OF REVIEW: The identification of molecular alterations that drive tumor growth and spread of solid tumors has led to the development of multiple targeted therapies considered as first-generation agents that have improved clinical benefit. However, tumor cells are able to rapidly develop resistance to these agents. The growing understanding of the biology of the resistance mechanisms has spurred ongoing development of second-generation and third-generation targeted therapies aiming at new strategies to overcome resistance. RECENT FINDINGS: Several generations of targeted therapies have been developed in order to prevent, delay or overcome tumor resistance. Some agents have already been approved, and others are currently under active clinical investigation in several cancer subtypes, including breast cancer, nonsmall cell lung cancer, head and neck squamous cell cancer and colorectal cancer. SUMMARY: In the present review, we will discuss in solid tumors, the recent development of next generation anticancer-targeted therapies and new strategies including combination agents currently under active clinical investigation. PMID- 25715326 TI - Advances in imaging modalities in prostate cancer. AB - PURPOSE OF REVIEW: Imaging plays an important role in the clinical management of prostate cancer (PCa). Thus, much effort has gone into improving imaging modalities in PCa. This review focuses on the recent advancements in transrectal ultrasound, MRI and PET during the past year. RECENT FINDINGS: Contrast-enhanced transrectal ultrasound with microbubbles may be useful in PCa, but needs further evaluation before more widespread use. Multiparametric MRI has emerged as a valuable tool to assist clinical management of PCa, and great progress has been made in the past year. Several radionuclides for PET/computed tomography have been tested in clinical trials; most of the studies have used radiolabeled choline. However, new PET tracers such as (18)F-1-amino-3-fluorine 18 fluorocyclobutane-1-carboxylic acid and (68)Ga-labeled prostate-specific membrane antigen ligands are demonstrating promising results. PET/MRI may further improve imaging in PCa, but this imaging modality needs to be evaluated further. SUMMARY: Several advances in the imaging of PCa have been made during the past year. In particular, important clinical developments have been reported in multiparametric MRI, PET/computed tomography, and PET/MRI. The continuing development of imaging techniques in PCa has the potential to optimize treatment of PCa. However, the optimal imaging strategies for each of the major clinical scenarios in PCa have not yet been identified. PMID- 25715327 TI - A Case of Reversible Cardiomyopathy Managed Successfully. AB - Cardiomyopathy accounts for 0.7% of cardiac deaths in the United States. Dilated cardiomyopathy as the primary manifestation of hyperthyroidism is a rare phenomenon. Presenting the case of a middle-aged African American woman with a history of hypertension and asthma, who experienced progressive shortness of breath. Extensive work-up revealed dilated cardiomyopathy with hyperfunctioning thyroid gland that responded well to antithyroid therapy. An interval echocardiogram showed significant reversal of cardiac dysfunction. The reversible nature of this disease entity was again proven when the patient was successfully treated for heart failure for the second time a few months later and was again found to have normalization of cardiomyopathic changes. PMID- 25715328 TI - Granulomatous Mastitis in a Hispanic Woman. AB - A 33-year-old mother of 2 healthy children presented with bilateral recurrent breast infections despite successful treatment of each episode of an infection. With a negative rheumatologic medical history as well as a negative review of systems, she continued to have these infections frequently. Hence, a breast biopsy was performed after the treatment with a course of antimicrobials, which revealed changes suggestive of granulomatous mastitis. She was started on methotrexate (MTX) with a good response. But, due to persistent nodularity, corticosteroids were added to the regimen with MTX dose escalation. Patient remained disease free thereafter without any adverse effects. PMID- 25715329 TI - Surgical Revascularization for Ischemic Cardiomyopathy in the Post-STICH Era. AB - Coronary artery disease (CAD) accounts for significant morbidity and mortality in the United States and most developed countries. Patients with heart failure secondary to CAD have demonstrable poorer outcomes compared with those patients with heart failure because of other causes. Even when the causative relationship between CAD and systolic dysfunction can be unequivocally established, the controversy of revascularization in patients with ischemic cardiomyopathy continues to challenge clinicians. The potential benefit of revascularization has to be weighed against the higher operative and postoperative mortality of coronary artery bypass graft surgery in patients with very low ejection fraction and the possible futility of a high-risk intervention in certain patients. This review focuses on the role of surgical revascularization in patients with ischemic cardiomyopathy in light of data emerging from the original Surgical Treatment for Ischemic Heart Failure trial and its substudies, with an emphasis on the clinical implications for patient selection. PMID- 25715330 TI - Reexamination of the origin of the pseudo Jahn-Teller puckering instability in silicene. AB - Silicene, the graphene-like crystal formed by the Si hexagonal lattice, presents a periodic buckled structure whose origin is due to the pseudo Jahn-Teller instability on each of its planar six membered rings. This has been attributed to the coupling of the planar D6h ground state with the first b2g excited state through a b2g vibrational mode. Here we show, by explicitly calculating the vibronic coupling constants through a complete study of the PJT effect, that the vibronic coupling of the ground state with only one excited state to explain the planar instability is inconsistent with the linear multilevel PJT effect theory. It is also shown that in order to have consistency, the PJT model should include the next excited state, which is symmetry compatible coupled to the puckering mode. This is done by the analysis, based on DFT and TDDFT calculations, of the vibronic instability of the ground state of hexasilabenzene, the basic silicon hydrogenated hexagonal ring unit defining silicene. PMID- 25715331 TI - Force-control at cellular membranes. AB - Force-regulation at cellular membranes relies on dynamic molecular platforms that integrate intra- and extracellular signals to control cell shape and function. To correctly respond to a continuously changing environment, activity of these platforms needs to be tightly controlled in space and time. Over the last few years, curvature-dependent mechano-chemical signal translation-a receptor independent signaling mechanism where physical forces at the plasma membrane trigger nanoscale membrane deformations that are then translated into chemical signal transduction cascades-has emerged as a new signaling principle that cells use to regulate forces at the membrane. However, until recently, technical limitations have precluded studies of this force-induced curvature-dependent signaling at the physiological scale. Here, we comment on recent advancements that allow studying curvature-dependent signaling at membranes, and discuss processes where it may be involved in. Considering its general impact on cell function, a particular focus will be put on the curvature-dependence of feedback loops that control actin-based forces at cellular membranes. PMID- 25715332 TI - Endoscopic excision of synchronous large bowel polyps in the presence of colorectal carcinoma: is the fear of malignant cell implantation justified? A systematic review of the literature. AB - AIM: A systematic review of the literature was performed to establish evidence to support the practice that in the presence of a colonoscopically diagnosed colorectal cancer immediate endoscopic excision of synchronous polyps should not be performed due to the risk of malignant cell implantation at the polypectomy site. METHOD: A systematic literature search was performed using Medline, Embase and the Cochrane Central Register of Controlled Trials to identify studies comparing the rate of implantation of colorectal cancer cells in normal and damaged colonic mucosa and reports of colorectal cancer cells seeding into sites of damaged mucosa after polypectomy. RESULTS: No randomized controlled trials were identified. Three studies involving mammalian models of colonic mucosal damage were included. Pooling relevant results revealed that out of 59 exposed mammals only one developed tumour cell implantation at a site of colonic mucosal damage. This equates to a mammalian in vivo experimental risk of malignant cell implantation of 1.6%. CONCLUSION: The topic of colorectal cancer seeding following endoscopic procedures has received little attention. This review suggests that in the presence of a proximal colonic carcinoma there is a negligible risk of malignant implantation if a more distal polyp is endoscopically excised. PMID- 25715334 TI - Peer mentoring for core medical trainees: uptake and impact. AB - OBJECTIVE: To assess the uptake and impact of a peer mentoring scheme for core medical trainees on both mentors and mentees. METHOD: All second year core medical trainees in the Southwest London Training programme in September 2012 were invited to mentor a first year core medical trainee. In parallel, all first year core medical trainees were invited to be mentored. Both potential mentors and mentees were asked to submit personal statements, to attend a three-session mentoring training programme and to be matched into mentoring pairs. The impact of the mentoring scheme on trainees' behaviour and outlook was assessed through questionnaires distributed at the start and at the end of the year. RESULTS: 31 of 72 (43%) core medical trainees submitted personal statements and 40 of 72 (56%) attended training sessions. 42 trainees (58%) participated in the scheme (21 mentor/mentee pairs were established). Of the trainees who participated, 23 of 42 (55%) completed the end of year questionnaire. Participating trainees viewed the scheme positively. Reported benefits included changes in their behaviour and acquiring transferable skills that might help them in later career roles, such as an educational supervisor. The end of year questionnaire was sent to all trainees and 10 responded who had not participated. They were asked why they had not participated and their reasons included lack of time, lack of inclination and a desire for more senior mentors. Their suggestions for improvement included more structured sessions to allow the mentor/mentee pairs to meet. CONCLUSIONS: This simple peer mentoring scheme was popular despite busy workloads and benefited all concerned. It is a simple effective way of supporting doctors. More work is needed to improve training for mentors and to improve access to mentoring. PMID- 25715333 TI - Postoral glucose sensing, not caloric content, determines sugar reward in C57BL/6J mice. AB - Recent studies suggest that because of their energy value, sugars are more rewarding than non-caloric sweeteners. However, intragastric infusion data indicate that sugars differ in their postoral appetite-stimulating effects. We therefore compared the preference for isocaloric 8% sucrose, glucose, and fructose solutions with that of a non-caloric sweetener solution (0.8% sucralose) in C57BL/6J mice. Brief 2-bottle tests indicated that sucralose was isopreferred to sucrose but more preferred than glucose or fructose. Yet, in long-term tests, the mice preferred sucrose and glucose, but not fructose to sucralose. Additional experiments were conducted with a non-caloric 0.1% sucralose + 0.1% saccharin mixture (S + S), which does not have the postoral inhibitory effects of 0.8% sucralose. The S + S was preferred to fructose in brief and long-term choice tests. S + S was also preferred to glucose and sucrose in brief tests, but the sugars were preferred in long-term tests. In progressive ratio tests, non deprived and food-deprived mice licked more for glucose but not fructose than for S + S. These findings demonstrate that the nutrient-specific postoral actions, not calories per se, determine the avidity for sugar versus non-caloric sweeteners. Furthermore, sweet taste intensity and potential postoral inhibitory actions must be considered in comparing non-caloric and caloric sweeteners. PMID- 25715335 TI - Assessing Organizational Readiness for a Participatory Occupational Health/Health Promotion Intervention in Skilled Nursing Facilities. AB - The long-term care sector is characterized by high morbidity and employee turnover, along with associated costs. Effective health protection and health promotion are important to improve physical and psychosocial well-being of caregivers. Assessment of organizational readiness for change is an essential precursor to the successful implementation of workplace programs addressing work climate, structure of tasks and relationships, and other issues that may be perceived as challenging by some within the institution. This study qualitatively assessed readiness of five skilled nursing facilities for a participatory occupational health/health promotion intervention. Selection criteria were developed to screen for program feasibility and ability to conduct prospective evaluations, and information was collected from managers and employees (interviews and focus groups). Three centers were selected for the program, and the first year of formative evaluation and intervention experience was then reviewed to evaluate and modify our selection criteria after the fact. Lessons learned include adding assessment of communication and the structure of problem solving to our selection criteria, improving methods to assess management support in a concrete (potentially nonverbal) form, and obtaining a stated financial commitment and resources to enable the team to function. Assessment of organizational readiness for change is challenging, although necessary to implement effective and sustainable health promotion programs in specific organizations. PMID- 25715338 TI - Improving myocardial injury, infarct size, and myocardial salvage in the era of primary PCI for STEMI. AB - ST-segment elevation myocardial infarction (STEMI) is a major cause of mortality and disability worldwide. Reperfusion therapy by thrombolysis or primary percutaneous coronary intervention (PPCI) improves survival and quality of life in patients with STEMI. Despite the proven efficacy of timely reperfusion, mortality from STEMI remains high, particularly among patients with suboptimal reperfusion. Reperfusion injury following opening of occluded coronary arteries mitigates the efficacy of PPCI by further accentuating ischemic damage and increasing infarct size (IS). On the basis of experimental studies, it is assumed that nearly 50% of the final IS is because of the reperfusion injury. IS is a marker of ischemic damage and adequacy of reperfusion that is strongly related to mortality in reperfused patients with STEMI. Many therapeutic strategies including pharmacological and conditioning agents have been proven effective in reducing reperfusion injury and IS in preclinical research. Mechanistically, these agents act either by inhibiting reperfusion injury cascades or by activating cellular prosurvival pathways. Although most of these agents/strategies are at the experimental stage, some of them have been tested clinically in patients with STEMI. This review provides an update on key pharmacological agents and postconditioning used in the setting of PPCI to reduce reperfusion injury and IS. Despite intensive research, no strategy or intervention has been shown to prevent reperfusion injury or enhance myocardial salvage in a consistent manner in a clinical setting. A number of novel therapeutic strategies to reduce reperfusion injury in the setting of PPCI in patients with STEMI are currently under investigation. They will lead to a better understanding of reperfusion injury and to more efficient strategies for its prevention. PMID- 25715336 TI - Protein-Binding Function of RNA-Dependent Protein Kinase Promotes Proliferation through TRAF2/RIP1/NF-kappaB/c-Myc Pathway in Pancreatic beta cells. AB - Double-stranded RNA-dependent protein kinase (PKR), an intracellular pathogen recognition receptor, is involved both in insulin resistance in peripheral tissues and in downregulation of pancreatic beta-cell function in a kinase dependent manner, indicating PKR as a core component in the progression of type 2 diabetes. PKR also acts as an adaptor protein via its protein-binding domain. Here, the PKR protein-binding function promoted beta-cell proliferation without its kinase activity, which is associated with enhanced physical interaction with tumor necrosis factor receptor-associated factor 2 (TRAF2) and TRAF6. In addition, the transcription of the nuclear factor kappa-light-chain-enhancer of activated B cell (NF-kappaB)-dependent survival gene c-Myc was upregulated significantly and is necessary for proliferation. Upregulation of the PKR protein binding function induced the NF-kappaB pathway, as observed by dose-dependent degradation of IkappaBalpha, induced nuclear translocation of p65 and elevated NF kappaB-dependent reporter gene expression. NF-kappaB-dependent reporter activity and beta-cell proliferation both were suppressed by TRAF2-siRNA, but not by TRAF6 siRNA. TRAF2-siRNA blocked the ubiquitination of receptor-interacting serine/threonine-protein kinase 1 (RIP1) induced by PKR protein binding. Furthermore, RIP1-siRNA inhibited beta-cell proliferation. Proinflammatory cytokines (TNFalpha) and glucolipitoxicity also promoted the physical interaction of PKR with TRAF2. Collectively, these data indicate a pivotal role for PKR's protein-binding function on the proliferation of pancreatic beta cells through TRAF2/RIP1/NF-kappaB/c-Myc pathways. Therapeutic opportunities for type 2 diabetes may arise when its kinase catalytic function, but not its protein binding function, is downregulated. PMID- 25715339 TI - Long-term effect of second-generation drug-eluting stents for coronary artery disease, everolimus-eluting versus zotarolimus-eluting stents: a meta-analysis. AB - BACKGROUND: Compared with the zotarolimus-eluting stent (ZES), the everolimus eluting stent (EES) has reduced the risk of stent restenosis and thrombosis as found in a number of randomized-controlled trials (RCTs). However, the benefits have been variable. MATERIALS AND METHODS: We evaluate the long-term effect of EES and ZES on the risk of stent thrombosis and target lesion revascularization in patients receiving PCI. We identified RCTs by a systematic search of MEDLINE, EMBASE, and Cochrane Database. RESULTS: Five RCTs (9853 patients) were included. Overall, EES significantly reduced the risk of target lesion revascularization [odds ratio (OR), 0.77; 95% confidence interval (CI), 0.62-0.95; P=0.01] compared with ZES therapy. However, there was no difference in the risk of target vessel revascularization (OR, 0.93; 95% CI, 0.78-1.10; P=0.38) and definite/probable stent thrombosis (OR, 0.83; 95% CI, 0.56-1.25; P=0.37) between the two groups. Furthermore, the risk of mortality (OR, 1.04; 95% CI, 0.84-1.27; P=0.73), myocardial infarction (OR, 0.95; 95% CI, 0.74-1.23; P=0.70), and major adverse cardiac event (OR, 0.96; 95% CI, 0.84-1.10; P=0.53) was similar between the two groups. CONCLUSION: The new-generation Resolute-ZES and EES have a similar long term safety and efficacy profile. PMID- 25715337 TI - Regulation of Vascular Tone, Angiogenesis and Cellular Bioenergetics by the 3 Mercaptopyruvate Sulfurtransferase/H2S Pathway: Functional Impairment by Hyperglycemia and Restoration by DL-alpha-Lipoic Acid. AB - Hydrogen sulfide (H2S), as a reducing agent and an antioxidant molecule, exerts protective effects against hyperglycemic stress in the vascular endothelium. The mitochondrial enzyme 3-mercaptopyruvate sulfurtransferase (3-MST) is an important biological source of H2S. We have recently demonstrated that 3-MST activity is inhibited by oxidative stress in vitro and speculated that this may have an adverse effect on cellular homeostasis. In the current study, given the importance of H2S as a vasorelaxant, angiogenesis stimulator and cellular bioenergetic mediator, we first determined whether the 3-MST/H2S system plays a physiological regulatory role in endothelial cells. Next, we tested whether a dysfunction of this pathway develops during the development of hyperglycemia and MUmol/L to diabetes-associated vascular complications. Intraperitoneal (IP) 3-MP (1 mg/kg) raised plasma H2S levels in rats. 3-MP (10 1 mmol/L) promoted angiogenesis in vitro in bEnd3 microvascular endothelial cells and in vivo in a Matrigel assay in mice (0.3-1 mg/kg). In vitro studies with bEnd3 cell homogenates demonstrated that the 3-MP-induced increases in H2S production depended on enzymatic activity, although at higher concentrations (1-3 mmol/L) there was also evidence for an additional nonenzymatic H2S production by 3-MP. In vivo, 3-MP facilitated wound healing in rats, induced the relaxation of dermal microvessels and increased mitochondrial bioenergetic function. In vitro hyperglycemia or in vivo streptozotocin diabetes impaired angiogenesis, attenuated mitochondrial function and delayed wound healing; all of these responses were associated with an impairment of the proangiogenic and bioenergetic effects of 3-MP. The antioxidants DL-alpha-lipoic acid (LA) in vivo, or dihydrolipoic acid (DHLA) in vitro restored the ability of 3-MP to stimulate angiogenesis, cellular bioenergetics and wound healing in hyperglycemia and diabetes. We conclude that diabetes leads to an impairment of the 3-MST/H2S pathway, and speculate that this may contribute to the pathogenesis of hyperglycemic endothelial cell dysfunction. We also suggest that therapy with H2S donors, or treatment with the combination of 3-MP and lipoic acid may be beneficial in improving angiogenesis and bioenergetics in hyperglycemia. PMID- 25715340 TI - Hemichorea-hemiballism: a case report. AB - A 55-year-old woman with type 2 diabetes mellitus presented with abnormal left sided movements of her arm and leg. Her initial CT scan of head showed a hyperintensity in the right basal ganglia. A 3 T MR scan of brain showed changes consistent with right basal ganglia haemorrhage. We diagnosed hemichorea hemiballism syndrome. We treated her movement disorder with tetrabenazine and sulpiride and improved her glucose control. After 4 months, she still has mildly abnormal left-sided movements but can function independently again. In this article, we discuss her imaging and review the literature on hemichorea hemiballism. PMID- 25715341 TI - Violent Victimization in the Prison Context: An Examination of the Gendered Contexts of Prison. AB - Currently there are few published, multilevel studies of physical assault victimization of prisoners. This study builds on the extant research by utilizing a nationally representative sample of correctional facilities (n = 326) and inmates (n = 17,640) to examine the impacts of a large set of theoretically and empirically derived individual- and contextual-level variables on prison victimization, including how the gendered context of prison impacts victimization. Results support the lifestyles/routine activities approach. Inmates who were charged with a violent offense, were previously victimized, were smaller in size, were not married, were without a work assignment, misbehaved, did not participate in programs, used alcohol or drugs, and those who had a depression or personality disorder were more likely to be victimized. In addition, the data suggest that 8% of the variance in victimization is due to the prison context. Prisons with high proportions of violent offenders, males, inmates from multiracial backgrounds, and inmates with major infractions had increased odds of victimization. Moreover, the sex-composition of the prison has significant main and interactive effects predicting victimization. Specifically, we find that the effects of being convicted of a drug crime, drug use, military service, major infractions, and diagnosed personality disorders are all gendered in their impacts on victimization. PMID- 25715342 TI - Primary peritoneal clear cell carcinoma versus ovarian carcinoma versus malignant transformation of endometriosis: a vexing issue. AB - Peritoneum is a site for both primary and secondary tumors. Primary peritoneal tumors are fairly rare. The most common primary tumors of the peritoneum are malignant mesothelioma and serous papillary adenocarcinoma. Clear cell carcinoma of the peritoneum is extremely rare and often misdiagnosed as mesothelioma, serous carcinoma, or metastatic adenocarcinoma, so it represents a diagnostic challenge for both clinicians and pathologists. Up to date, to the best of our knowledge, only 11 cases of primary peritoneal clear cell carcinoma have been reported in the English literature. Distinguishing this tumor of the peritoneum versus ovarian carcinoma can be problematic. Herein, we report a rare case of primary peritoneal clear cell carcinoma occurring in a 49-year-old woman, along with a review of the literature. PMID- 25715344 TI - Glucosylceramide synthase inhibitors differentially affect expression of glycosphingolipids. AB - Glucosylceramide synthase (GCS) catalyzes the first committed step in the biosynthesis of glucosylceramide (GlcCer)-related glycosphingolipids (GSLs). Although inhibitors of GCS, PPMP and PDMP have been widely used to elucidate their biological function and relevance, our comprehensive literature review revealed that the available data are ambiguous. We therefore investigated whether and to what extent GCS inhibitors affect the expression of lactosylceramide (LacCer), neolacto (nLc4 and P1), ganglio (GM1 and GD3) and globo (Gb3 and SSEA3) series GSLs in a panel of human cancer cell lines using flow cytometry, a commonly applied method investigating cell-surface GSLs after GCS inhibition. Their cell-surface GSL expression considerably varied among cell lines and more importantly, sublethal concentrations (IC10) of both inhibitors preferentially and significantly reduced the expression of Gb3 in the cancer cell lines IGROV1, BG1, HT29 and T47D, whereas SSEA3 was only reduced in BG1. Unexpectedly, the neolacto and ganglio series was not affected. LacCer, the precursor of all GlcCer related GSL, was significantly reduced only in BG1 cells treated with PPMP. Future research questions addressing particular GSLs require careful consideration; our results indicate that the extent to which there is a decrease in the expression of one or more particular GSLs is dependent on the cell line under investigation, the type of GCS inhibitor and exposure duration. PMID- 25715345 TI - Erratum: UDP-N-acetyl-alpha-D-galactosamine: polypeptide N acetylgalactosaminyltransferases: completion of the family tree. PMID- 25715346 TI - Seven Ventilators Challenged With Leaks During Neonatal Nasal CPAP: An Experimental Pilot Study. AB - BACKGROUND: Nasal CPAP is the most common respiratory support for neonates. Several factors are considered important for effective treatment, including leaks at the patient interface and the delivery of pressure-stable CPAP. Investigations of pressure stability during leaks should include both the change in the mean delivered CPAP and the pressure variation during each breath. The aim of this study was to examine the response of ventilators delivering nasal CPAP when challenged with leaks at the patient interface. METHODS: Seven ventilators providing nasal CPAP at 4 cm H2O were challenged with leaks during simulated neonatal breathing. Leak was applied for 15 consecutive breaths at a constant level (1-4 L/min). RESULTS: The 2 aspects of pressure stability were evaluated by measuring the mean delivered CPAP and the amplitude of pressure swings before, during, and after leaks. The ability to maintain the delivered CPAP and the amplitude of pressure swings varied greatly among the 7 ventilators before, during, and after leaks. Four of the ventilators tested have built-in leak compensation. CONCLUSIONS: There was no simple relationship between maintaining delivered CPAP during leaks and providing CPAP with low pressure swing amplitude. Maintaining the delivered CPAP and providing this without pressure swings are 2 separate aspects of pressure stability, and investigations concerning the clinical importance of pressure stability should address both aspects. This study also shows that compensation for leaks does not necessarily provide pressure stable CPAP. PMID- 25715347 TI - Association Between Vitamin D Status and Weaning From Prolonged Mechanical Ventilation in Survivors of Critical Illness. AB - BACKGROUND: In this study, we examined the association between 25-hydroxyvitamin D (25(OH)D) concentration and successful weaning from mechanical ventilation in a cohort of ICU survivors requiring prolonged mechanical ventilation. METHODS: This was a retrospective cohort study of ICU survivors admitted to a long-term acute care hospital. Demographic data were extracted from medical records, including 25(OH)D concentrations drawn on admission. Subjects were divided into 2 groups based on their 25(OH)D concentrations (deficient, < 20 ng/mL; not deficient, >= 20 ng/mL), and associations between 25(OH)D concentration and successful weaning were calculated. RESULTS: A total of 183 subjects were studied. A high prevalence of 25(OH)D deficiency was found (61%, 111/183). No association was found between 25(OH)D concentration and weaning from mechanical ventilation. Increased comorbidity burden (Charlson comorbidity index) was associated with decreased odds of weaning (odds ratio of 0.50, 95% CI 0.25-0.99, P = .05). CONCLUSIONS: Vitamin D deficiency is common in ICU survivors requiring prolonged mechanical ventilation. Surprisingly, there was no significant relationship between 25(OH)D concentration and successful weaning. This finding may be due to the low 25(OH)D concentrations seen in our subjects. Given what is known about vitamin D and lung function and given the low vitamin D concentrations seen in patients requiring long-term ventilatory support, interventional studies assessing the effects of 25(OH)D supplementation in these patients are needed. PMID- 25715348 TI - T1 glottic carcinoma: do comorbidities, facility characteristics, and sociodemographics explain survival differences across treatment? AB - OBJECTIVE: Recent large-scale studies have observed differences in survival following treatment for early laryngeal carcinoma depending on treatment type but were not able to take sociodemographic, comorbidity, and facility data into account. The objective of this study was to determine whether survival differences across treatment types persist when these factors are included in the analysis. STUDY DESIGN: Retrospective cohort analysis. SETTING: Linked Surveillance, Epidemiology, and End Results (SEER)-Medicare data files. SUBJECTS AND METHODS: Medicare beneficiaries who were identified through the SEER registries (1991-2009) as having T1 glottic squamous cell carcinoma (scca) and a known treatment type were included. RESULTS: A total of 2338 patients with incident T1 glottic scca were identified. Most were white and male. Treatment type was radiation only in 47%, local surgery and radiation in 39%, and local surgery only in 14%. Black race and increased comorbidities were associated with worse survival. When sociodemographics, comorbidities, and facility characteristics were taken into account, survival differences were observed across treatment types, with those receiving local surgery demonstrating better overall and cancer-specific survival. CONCLUSION: These results suggest that following treatment of T1 glottic scca, there may be survival differences across treatment types beyond those explained by sociodemographic, comorbidity, and facility characteristics. PMID- 25715349 TI - State of otolaryngology match: has competition increased since the "early" match? AB - OBJECTIVE: To examine fluctuations in supply and demand of otolaryngology residency positions after the shift from an "early match" coordinated by the San Francisco match to a "conventional" matching process through the National Residency Matching Program (NRMP). To determine whether competition among otolaryngology residency positions have changed during this time frame. DESIGN: Database analysis. SUBJECTS AND METHODS: Matching statistics from 1998 to 2013 were obtained for all first-year residency positions through the NRMP. Matching statistics from 1998 to 2005 were obtained for otolaryngology residency positions through the San Francisco match. Univariate analysis was performed, with a P value less than .05 determined as significant. RESULTS: The number of otolaryngology positions and applicants remained proportional to the overall number of positions and applicants in the NRMP match. Otolaryngology applicants per position and the matching rate of all applicants did not change between the 2 time periods studied. The overall match rate of US seniors applying to otolaryngology did not change, while the match rate of non-US seniors decreased significantly following initiation of the conventional match. There was no significant change in United States Medical Licensing Exam step 1 scores or percentage of unfilled otolaryngology residency positions between the 2 time periods. CONCLUSIONS: When comparing the early versus conventional otolaryngology match time periods, the only major change was the decreased percentage of matching among non-US senior applicants. Despite a significant shift in match timing after 2006, the supply, demand, and competitiveness of otolaryngology residency positions have not changed significantly. PMID- 25715351 TI - Nasoseptal flap reconstruction of pediatric sellar defects: a radiographic feasibility study and case series. AB - OBJECTIVES: In this study, we used computed tomography measurements to investigate the feasibility of nasoseptal flap reconstruction of sellar defects in children, and we reviewed our institutional experience with the procedure. STUDY DESIGN: Cross-sectional and case series. SETTING: Pediatric tertiary care facility. METHODS: We obtained 10 normal maxillofacial scans for each year of age from birth to 18. Computer-assisted nasal and skull-base measurements were performed. Patients with incomplete pneumatization were excluded from analysis. Reconstruction was presumed feasible if the ratio of nasoseptal flap length to associated sellar defect length was greater than 1. Chart review identified surgical patients. RESULTS: Of 190 scans, 125 had complete pneumatization. Of these, 120 (96%) displayed a ratio of nasoseptal flap length to sellar defect length greater than 1, suggesting that reconstruction would be feasible. Mean ratio of flap length to defect length for all subjects was 1.47 (SD 0.33; 95% CI, 1.41-1.53). Only 5 of 125 patients (4%) had a ratio less than 1; the median age for these patients was 15 years, which is older than the median age of 12 years for subjects with a ratio greater than 1 (P = .02). An inverse relationship was identified between age and ratio of flap length to defect length (r = -0.49, P < .001). Case series identified 6 children, ages 5 to 17; flap length was never described as a limitation. CONCLUSIONS: Nasoseptal flap length is not a limiting factor for reconstruction of pediatric sellar defects. When compared with older patients, younger patients tend to have greater nasoseptal flap length relative to sellar defect length. PMID- 25715350 TI - Effects of mindfulness based stress reduction therapy on subjective bother and neural connectivity in chronic tinnitus. AB - OBJECTIVE: To evaluate the impact of a Mindfulness Based Stress Reduction (MBSR) program in patients with chronic bothersome tinnitus on the (1) severity of symptoms of tinnitus and (2) functional connectivity in neural attention networks. STUDY DESIGN: Open-label interventional pilot study. SETTING: Outpatient academic medical center. SUBJECTS: A total of 13 adult participants with a median age of 55 years, suffering from bothersome tinnitus. METHODS: An 8 week MBSR program was conducted by a trained MBSR instructor. The primary outcome measure was the difference in patient-reported tinnitus symptoms using the Tinnitus Handicap Index (THI) and Tinnitus Functional Index (TFI) between pre intervention, post-MBSR, and 4-week post-MBSR assessments. Secondary outcomes included change in measurements of depression, anxiety, mindfulness, and cognitive abilities. Functional connectivity magnetic resonance imaging (MRI) was performed at pre- and post-MBSR intervention time points to serve as a neuroimaging biomarker of critical cortical networks. RESULTS: Scores on the THI and TFI showed statistically significant and clinically meaningful improvement over the course of the study with a median DeltaTHI of -16 and median DeltaTFI of -14.8 between baseline and 4-week follow-up scores. Except for depression, there was no significant change in any of the secondary outcome measures. Analysis of the resting state functional connectivity MRI (rs-fcMRI) data showed increased connectivity in the post-MBSR group in attention networks but not the default network. CONCLUSION: Participation in an MBSR program is associated with decreased severity in tinnitus symptoms and depression and connectivity changes in neural attention networks. MBSR is a promising treatment option for chronic bothersome tinnitus that is both noninvasive and inexpensive. PMID- 25715352 TI - Minimally Invasive Surgery for Osseointegrated Auditory Implants: A Comparison of Linear versus Punch Techniques. AB - OBJECTIVES: (1) To describe the benefits of the minimally invasive punch technique without soft tissue reduction (PT) for the placement of percutaneous osseointegrated auditory implants. (2) To compare and contrast techniques and outcomes from PT with the linear technique with soft tissue reduction (LT). STUDY DESIGN: Case series with chart review SETTING: Performed at a tertiary otology practice at an academic medical center. SUBJECTS AND METHODS: LT was used until 2012 when a switch was made for all patients to PT. Preoperative variables recorded included age, sex, BMI, smoking status, indication, device selected, and abutment length. Outcomes measures included surgical time, skin reaction grading by Holgers score at 1 week and at most recent follow-up, and any other complications. Two-sample t test and chi(2) was used to compare. RESULTS: A total of 51 patients (34 LT, 17 PT) were identified. Surgical time was found to be significantly shorter for the PT group (LT, 49.2 min; PT, 13.4 min; P < .001). There were no statistically significant differences between LT and PT for mean Holgers at first (LT, 0.24; PT, 0.47; P = .87) or final follow-up (LT, 0.62; PT, 0.41; P = .22). CONCLUSIONS: The punch technique offers several potential surgical and cosmetic advantages over the linear technique without compromising skin-reactivity outcomes. This study supports a growing trend toward minimally invasive percutaneous auditory implant surgery. PMID- 25715353 TI - Medical treatment of traumatic anosmia. AB - OBJECTIVES: To study the effects of zinc and steroid in the treatment of traumatic anosmia. STUDY DESIGN: A prospective, randomized study. SETTING: Academic medical center. SUBJECTS AND METHODS: Patients with a clear history of loss of smell after head injury and whose thresholds were -1 measured by the phenyl ethyl alcohol threshold test were included in this study from January 2010 to May 2013. They were randomly divided into 4 groups. Patients in group 1 were treated with zinc gluconate for a month and high-dose prednisolone with tapering for 2 weeks. Those in group 2 took only zinc gluconate, and those in group 3 took only prednisolone. Patients in group 4 did not take any medicine. All patients were followed up by phenyl ethyl alcohol threshold testing, and magnetic resonance imaging was performed to measure the volume of olfactory bulbs. RESULTS: Thirty-nine patients in group 1, 35 in group 2, 34 in group 3, and 37 in group 4 completed the study. The recovery of olfactory function was observed in 11 patients (28.2%) in group 1, in 9 (25.7%) in group 2, in 4 (11.8%) in group 3, and in 1 (2.7%) in group 4. The recovery rates of olfactory function of groups 1 and 2 were significantly higher than the recovery rate of group 4. The volume of olfactory bulbs was not significantly different between those with and without improved olfactory function. CONCLUSION: Our results show that zinc gluconate has a promising effect in treating traumatic anosmia. PMID- 25715354 TI - Correlation between sleep disruption on postoperative pain. AB - OBJECTIVES: To identify the amount of sleep disruption that occurs in the postoperative inpatient hospital setting, determine the relationship between sleep disruption and the quantity of narcotics taken for postoperative pain, and determine if hospital length of stay is related to sleep disruption. STUDY DESIGN: Prospective cohort study. SETTING: Single tertiary care academic institution. SUBJECTS AND METHODS: Fifty patients undergoing total hip or knee arthroplasty at Henry Ford Hospital in Detroit, Michigan, between January 2013 and November 2013 were asked to wear an actigraph during their postoperative hospital stay. Total sleep time, sleep efficiency, awake index, total narcotic use, visual analog pain scores, and postoperative complications were analyzed. RESULTS: Overall sleep efficiency was 61.2% and 66.5% with an awake index of 5.5 and 5.4 for each of the postoperative nights measured. A significant correlation was found between increased self-reported pain scores and decreased total sleep time (r = -0.31; P = .03). Spearman correlations between total sleep time, sleep efficiency, and awake index were made with narcotic use on postoperative day (POD) 0 and 1. Longer hospital length of stay was significantly correlated with decreased sleep efficiency (r = -0.35, P = .01). Complication rates were not statistically different compared with sleep parameters. CONCLUSION: Better control of a patient's pain is associated with greater sleep efficiency and total sleep time. Improvements in sleep efficiency in hospitalized patients may be associated with a decrease in length of stay. PMID- 25715356 TI - Noninvasive prenatal testing and fetal sonographic screening: roundtable discussion. PMID- 25715357 TI - Reliability and precision of stress sonography of the ulnar collateral ligament. AB - OBJECTIVES: Musculoskeletal sonography has emerged as an additional diagnostic tool that can be used to assess medial elbow pain and laxity in overhead throwers. It provides a dynamic, rapid, and noninvasive modality in the evaluation of ligamentous structural integrity. Many studies have demonstrated the utility of dynamic sonography for medial elbow and ulnar collateral ligament (UCL) integrity. However, evaluating the reliabilityand precision of these measurements is critical if sonography is ultimately used as a clinical diagnostic tool. The purpose of this study was to evaluate the reliability and precision of stress sonography applied to the medial elbow. METHODS: We conducted a cross-sectional study during the 2011 baseball off-season. Eighteen National Collegiate Athletic Association Division I pitchers were enrolled, and 36 elbows were studied. Using sonography, the medial elbow was assessed, and measurements of the UCL length and ulnohumeral joint gapping were performed twice under two conditions (unloaded and loaded) and bilaterally. RESULTS: Intraclass correlation coefficients (0.72-0.94) and standard errors of measurements (0.3-0.9 mm) for UCL length and ulnohumeral joint gapping were good to excellent. Mean differences between unloaded and loaded conditions for the dominant arms were 1.3 mm (gapping; P < .001) and 1.4 mm (UCL length; P < .001). CONCLUSIONS: Medial elbow stress sonography is a reliable and precise method for detecting changes in ulnohumeral joint gapping and UCL lengthening. Ultimately, this method may provide clinicians valuable information regarding the medial elbow's response to valgus loading and may help guide treatment options. PMID- 25715355 TI - Developing in vitro expanded CD45RA+ regulatory T cells as an adoptive cell therapy for Crohn's disease. AB - BACKGROUND AND AIM: Thymus-derived regulatory T cells (Tregs) mediate dominant peripheral tolerance and treat experimental colitis. Tregs can be expanded from patient blood and were safely used in recent phase 1 studies in graft versus host disease and type 1 diabetes. Treg cell therapy is also conceptually attractive for Crohn's disease (CD). However, barriers exist to this approach. The stability of Tregs expanded from Crohn's blood is unknown. The potential for adoptively transferred Tregs to express interleukin-17 and exacerbate Crohn's lesions is of concern. Mucosal T cells are resistant to Treg-mediated suppression in active CD. The capacity for expanded Tregs to home to gut and lymphoid tissue is unknown. METHODS: To define the optimum population for Treg cell therapy in CD, CD4(+)CD25(+)CD127(lo)CD45RA(+) and CD4(+)CD25(+)CD127(lo)CD45RA(-) Treg subsets were isolated from patients' blood and expanded in vitro using a workflow that can be readily transferred to a good manufacturing practice background. RESULTS: Tregs can be expanded from the blood of patients with CD to potential target dose within 22-24 days. Expanded CD45RA(+) Tregs have an epigenetically stable FOXP3 locus and do not convert to a Th17 phenotype in vitro, in contrast to CD45RA(-) Tregs. CD45RA(+) Tregs highly express alpha4beta7 integrin, CD62L and CC motif receptor 7 (CCR7). CD45RA(+) Tregs also home to human small bowel in a C.B-17 severe combined immune deficiency (SCID) xenotransplant model. Importantly, in vitro expansion enhances the suppressive ability of CD45RA(+) Tregs. These cells also suppress activation of lamina propria and mesenteric lymph node lymphocytes isolated from inflamed Crohn's mucosa. CONCLUSIONS: CD4(+)CD25(+)CD127(lo)CD45RA(+) Tregs may be the most appropriate population from which to expand Tregs for autologous Treg therapy for CD, paving the way for future clinical trials. PMID- 25715358 TI - A sonographic technique to evaluate the anterior bundle of the ulnar collateral ligament of the elbow: imaging features and anatomic correlation. AB - OBJECTIVES: The aim of this study was to test a sonographic technique used to view the anterior bundle of the ulnar collateral ligament (UCL), describe its sonographic characteristics in healthy volunteers, and verify these characteristics by determining interobserver variability and their correlations in cadavers. METHODS: Sonographic studies of the anterior bundle of the UCL were performed on 48 elbows of asymptomatic healthy volunteers. The participants were examined by 3 experts, who identified the insertion sites of the anterior bundle and subjectively evaluated its echogenicity and echo texture. A sonographic examination of the anterior bundle of the UCL in a cadaveric elbow was performed, and the same aspects were evaluated. RESULTS: In all cases, the anterior bundle of the UCL appeared as a triangular structure in the coronal plane and had a hyperechoic homogeneous echo texture in most of these cases. The cadaveric elbow had the same sonographic characteristics as the volunteers. CONCLUSIONS: As shown by examining the interobserver variability and determining the correlation with cadaveric tissue, sonography proved to be a reliable tool for evaluating the normal aspects of the anterior bundle of the UCL. PMID- 25715359 TI - Sonography of cat scratch disease. AB - OBJECTIVES: To characterize the sonographic features of cat scratch disease and to identify features that allow differentiation from other causes of medial epitrochlear masses. METHODS: After Institutional Review Board approval was obtained, patients who underwent sonography for a medial epitrochlear mass or lymph node were identified via the radiology information system. Patients were divided into 2 groups: cat scratch disease and non-cat scratch disease, based on pathologic results and clinical information. Sonograms were retrospectively reviewed and characterized with respect to dimension, shape (round, oval, or lobular), symmetry, location (subcutaneous or intramuscular), multiplicity, echogenicity (anechoic, hypoechoic, isoechoic, hyperechoic, or mixed), hyperechoic hilum (present or absent), adjacent anechoic or hypoechoic area, hyperemia (present or absent), pattern of hyperemia if present (central, peripheral, or mixed), increased posterior through-transmission (present or absent), and shadowing (present or absent). Sonographic findings were compared between the patients with and without cat scratch disease. RESULTS: The final patient group consisted of 5 cases of cat scratch disease and 16 cases of other causes of medial epitrochlear masses. The 2 sonographic findings that were significantly different between the cat scratch disease and non-cat scratch disease cases included mass asymmetry (P = .0062) and the presence of a hyperechoic hilum (P = .0075). The other sonographic findings showed no significant differences between the groups. CONCLUSIONS: The sonographic finding of an epitrochlear mass due to cat scratch disease most commonly is that of a hypoechoic lobular or oval mass with central hyperemia and a possible adjacent fluid collection; however, the presence of asymmetry and a hyperechoic hilum differentiate cat scratch disease from other etiologies. PMID- 25715360 TI - Influence of various breast factors on the quality of strain elastograms. AB - OBJECTIVES: To determine the influence of the depth and size of breast lesions, the thickness of the adipose layer, and the thickness of the breast on the quality of strain elastograms obtained from Chinese women. METHODS: Ultrasound elastography was conducted on 326 breast lesions in 272 women. The quality of the images was evaluated according to criteria for satisfactory and unsatisfactory elastograms. Univariate and multivariate logistic regression analyses were conducted to determine the relationship between measured factors and image quality. RESULTS: Among the 326 lesions, 300 (92%) had satisfactory images, and 26 (8%) had unsatisfactory images. Univariate analyses indicated that all of the data from the unsatisfactory group were higher than the data from the satisfactory group in terms of the distance from the deep and superficial edges of the lesion to the skin, the thickness of the adipose layer anterior to the lesion, and the breast thickness at the location of the lesion (all P < .05 ). Lesions in the unsatisfactory group were larger than those in the satisfactory group when the distance from the deep edge of the lesion to the skin was between 2.1 and 2.5 cm and the distance from the superficial edge of the lesion to the skin was between 1.6 and 2.3 cm (all P< .05). Multivariate logistic regression analysis revealed that both the distance from the superficial edge of the lesion to the skin (odds ratio, 18.335; P = .029) and the breast thickness at the location of the lesion (odds ratio, 20.447; P < .001) were the independent influencing factors that affected the quality of elastograms. CONCLUSIONS: Satisfactory images are more easily acquired if the lesion is relatively superficial or located in areas of thinner breast thickness. Furthermore, among deeper lesions, satisfactory images are more common in large lesions. PMID- 25715361 TI - Noninvasive evaluation of liver fibrosis using real-time tissue elastography and transient elastography (FibroScan). AB - OBJECTIVES: The purpose of this study was to assess liver fibrosis with real-time tissue elastography and to compare the results with those of transient elastographic (FibroScan; Echosens, Paris, France) measurements by using liver biopsy as the reference standard. METHODS: Real-time tissue elastography and percutaneous liver biopsy were performed in 166 patients with chronic hepatitis B (estimation group). The relationship between the parameters obtained via real time tissue elastography and the hepatic fibrosis stage was evaluated by a stepwise multiple linear regression, and the regression equation was used to calculate the liver fibrosis index. The diagnostic performance of the liver fibrosis index was validated and compared with FibroScan in 121 other patients with chronic hepatitis B (validation group). RESULTS: The liver fibrosis index was calculated as follows: liver fibrosis index = 0.043 low-strain area ratio + 4.520 skewness + 0.033 mean - 1.002 kurtosis. The liver fibrosis index and liver stiffness measured by FibroScan were both significantly associated with the fibrosis stage in the validation group (r= 0.667 and 0.664, respectively; both P< .001). The areas under the receiver operating characteristic curves for the liver fibrosis index and liver stiffness were 0.880 and 0.909 for predicting substantial fibrosis (scores >=F2), 0.868 and 0.874 for predicting severe fibrosis (>=F3), and 0.752 and 0.815 for predicting cirrhosis (F4), respectively. CONCLUSIONS: Real-time tissue elastography is an effective method for assessing liver fibrosis, with diagnostic performance similar to that of transient elastography. PMID- 25715362 TI - Real-time contrast-enhanced sonographically guided biopsy or radiofrequency ablation of focal liver lesions using perflurobutane microbubbles (sonazoid): value of Kupffer-phase imaging. AB - OBJECTIVES: To evaluate the utility of Kupffer-phase imaging by real-time contrast-enhanced sonography using the perflurobutane microbubble contrast agent Sonazoid (GE Healthcare, Oslo, Norway) in guiding biopsy or radiofrequency (RF) ablation of focal liver lesions. METHODS: A total of 75 patients (mean age, 59.7 years) who were referred for percutaneous biopsy (n = 42) or RF ablation (n = 33) were included in the study. Grayscale sonography and contrast-enhanced sonography using Sonazoid were performed in all patients before the procedure. The conspicuity of each targeted liver lesion on grayscale sonography, vascular-phase contrast-enhanced sonography, and Kupffer-phase contrast-enhanced sonography was graded using a 5-point scale. Lesion detection rates were calculated, and the conspicuity of the lesions among the imaging modalities was compared. The technical success of the procedures was also assessed. RESULTS: The procedures were conducted in 66 patients (biopsy in 41 and RF ablation in 25) under real time guidance by Kupffer-phase contrast-enhanced sonography. Lesion detection rates were 77.3% (58 of 75), 84.0% (63 of 75), and 92.0% (69 of 75) on grayscale sonography, vascular-phase contrast-enhanced sonography, and Kupffer-phase contrast-enhanced sonography, respectively, and were significantly different among the 3 modalities (P= .034). Overall, lesion conspicuity was significantly increased on vascular-phase and Kupffer-phase contrast-enhanced sonography compared to grayscale sonography (P < .001). Technical success rates for the procedures were 95.2% (40 of 42) for biopsy and 69.7% (23 of 33) for RF ablation. CONCLUSIONS: Kupffer-phase imaging by contrast-enhanced sonography using Sonazoid increases the conspicuity of the liver lesions compared to grayscale sonography, and it is useful for real-time guidance of percutaneous biopsy or RF ablation of focal liver lesions. PMID- 25715363 TI - Diagnosis of hepatocellular carcinoma nodules in patients with chronic liver disease using contrast-enhanced sonography: usefulness of the combination of arterial- and kupffer-phase enhancement patterns. AB - OBJECTIVES: To determine the usefulness of contrast-enhanced sonography using the perfluorobutane contrast agent Sonazoid (Daiichi-Sankyo, Tokyo, Japan) for establishing the diagnosis and cellular differentiation of hepatocellular carcinoma in patients with chronic liver disease. METHODS: Patients with chronic liver disease in whom hepatic nodules were detected during screening for hepatocellular carcinoma were examined by imaging modalities, including contrast enhanced computed tomography (CT), contrast-enhanced sonography, and contrast enhanced magnetic resonance imaging. Nodules with negative imaging findings were further investigated with core biopsy or followed at our hospital. Between April 2007 and March 2011, all patients with hepatic nodules who underwent core biopsy of the nodules or hepatic resection for hepatocellular carcinoma were reviewed. Fifty-nine nodules from 47 patients with 42 contrast-enhanced sonographic findings and 41 contrast-enhanced CT findings were examined. Arterial- and Kupffer-phase enhancement patterns of the nodules on contrast-enhanced sonography were compared with the diagnosis and cellular differentiation of hepatocellular carcinoma. Arterial- and late-phase enhancement patterns on contrast-enhanced CT were also compared with histologic findings. RESULTS: The combination of hyperenhancement in the arterial phase and hypoenhancement in the Kupffer phase on contrast-enhanced sonography (n = 11) correlated with moderately differentiated hepatocellular carcinoma (P = .0028, Fisher exact test). The combination of hypoenhancement in the arterial phase and isoenhancement in the Kupffer phase on contrast-enhanced sonography (n = 14) correlated with well differentiated hepatocellular carcinoma (P = .0006, Fisher exact test). The combination of high density in the arterial phase and low density in the late phase on contrast-enhanced CT (n = 21) correlated with moderately differentiated hepatocellular carcinoma (P = .0059, Fisher exact test), but no enhancement pattern combination on contrast-enhanced CT correlated with well-differentiated hepatocellular carcinoma. CONCLUSIONS: Sonazoid contrast-enhanced sonography is useful for diagnosis of well-differentiated hepatocellular carcinoma. PMID- 25715364 TI - Effects of high-intensity focused ultrasound for treatment of abdominal lymph node metastasis from gastric cancer. AB - OBJECTIVES: This retrospective study aimed to compare the efficacy and safety of combination treatment with high-intensity focused ultrasound (HIFU) and chemotherapy to those of chemotherapy alone for treatment of the abdominal lymph node metastasis from gastric cancer. METHODS: A total of 185 patients with gastric cancer and abdominal lymph node metastasis were enrolled and divided into 2 groups: group A received chemotherapy alone (n = 102); group B received HIFU combined with chemotherapy (n = 83). The clinical efficacy and safety of the groups were then analyzed. RESULTS: The overall response rates of groups A and B were 34.3% and 47.0%, respectively (P = .046). The pain relief rates in groups A and B were 51.6% and 75.0% (P = .039). At the data cutoff, the median survival times of groups A and B were 8.6 and 11.9 months (P < .05). The adverse reactions in the groups did not show significant differences (P > .05). Among the patients treated with HIFU and chemotherapy, those with small abdominal lymph nodes (diameter <3 cm) had a better prognosis than those with large nodes (diameter >=3 cm). CONCLUSIONS: In patients with gastric cancer and abdominal lymph node metastasis, the combination of HIFU and chemotherapy can provide clinical benefits. High-intensity focused ultrasound could effectively facilitate treatment of abdominal lymph node metastasis from gastric cancer. PMID- 25715365 TI - Sonographic assessment of spleen stiffness before and after transjugular intrahepatic portosystemic shunt placement with or without concurrent embolization of portal systemic collateral veins in patients with cirrhosis and portal hypertension: a feasibility study. AB - OBJECTIVES: To determine the feasibility of spleen stiffness measurement in the evaluation of portal hemodynamics in patients undergoing transjugular intrahepatic portosystemic shunt (TIPS) placement. METHODS: We prospectively correlated the spleen stiffness as measured by the shear wave velocity with the portal pressure and portosystemic gradient in patients undergoing TIPS procedures. Twenty-three consecutive patients referred for placement of a TIPS were enrolled. Included in our study were 19 patients in whom a spleen stiffness measurement was obtained before, immediately after, and 1 to 3 days after placement. Spleen stiffness was measured by calculating the Young modulus estimated from the shear wave velocity. A 2-tailed nonparametric Mann-Whitney U test was used to assess statistically significant differences in spleen stiffness measurement after TIPS placement, and regression analysis was used to correlate spleen stiffness measurement with portal pressure. RESULTS: After TIPS placement, the spleen stiffness measurement increased, with a mean increase in the Young modulus +/- SD of 6.54 +/- 6.29 kPa in 42% of patients (8 of 19). In the remaining 58% (11 of 19), the spleens became softer after TIPS placement (Young modulus decreased by 9.57 +/- 8.82 kPa). Eight patients, including 5 with concurrent embolization or thrombosis of competitive shunts, had increased spleen stiffness. The mean change in the median spleen stiffness before and after TIPS placement between the patients with and without competitive shunts was statistically significantly different (P < .04, nonparametric Mann-Whitney U test). There was no measurable correlation between spleen stiffness measurement and portal pressure before and after TIPS placement. CONCLUSIONS: This study demonstrates the feasibility of a noninvasive spleen stiffness measurement, which could complement conventional sonography with additional functional information in patients undergoing TIPS procedures. PMID- 25715366 TI - External ultrasound for carotid atherosclerotic plaque treatment. AB - OBJECTIVES: The purpose of this study was to evaluate the efficacy of external ultrasound in the treatment of carotid atherosclerotic plaques. METHODS: In the prospective study, 357 patients with 363 carotid atherosclerotic plaques were divided into an ultrasound treatment group and a control group. For 30 days, conventional medical treatment was conducted on 54 plaques in the control group, whereas irradiation therapy in addition to conventional medical treatment was conducted on 309 plaques in the ultrasound group. Carotid sonography was conducted before and after treatment, and the maximum plaque thickness and area were measured in a longitudinal section. RESULTS: No patients withdrew from the treatment because of related side effects. After treatment, the maximum thickness and area of 79.94% of the plaques in the ultrasound group were reduced, whereas in the control group, the thickness and area of 18.52% were reduced. The mean changes in plaque thickness and area +/- SD in the ultrasound and control groups were 0.22 +/- 0.19 mm (7.61% +/- 5.67%) versus 0.02 +/- 0.05 mm (0.74% +/- 1.64%) and 0.047 +/- 0.039 cm(2) (13.28% +/- 9.8%) versus 0.0044 +/- 0.0102 cm(2) (1.1% +/- 2.46%), respectively. Changes in both plaque thickness and area in the ultrasound group were significantly greater than those in the control group (P< .0001). Furthermore, the plaque echo type was another prognostic factor affecting efficacy (P < .05). CONCLUSIONS: External ultrasound treatment is safe and effective for carotid atherosclerotic plaques and is worthy of further research and applications. The efficacy in anechoic/hypoechoic plaques is significantly higher than that in mixed echoic and calcified echoic plaques. PMID- 25715367 TI - Association of common carotid artery Doppler-determined dicrotic notch velocity with the left ventricular ejection fraction. AB - OBJECTIVES: The appearance of the dicrotic notch on blood pressure tracings is associated with impaired cardiac function. Common carotid artery waveforms have similar fiduciary markers, yet they have not been related to cardiac function. We studied associations of common carotid artery dicrotic notch velocities with the left ventricular ejection fraction (LVEF) determined by echocardiography. METHODS: We conducted a retrospective study of 37 patients who had cardiac echocardiography and carotid Doppler evaluations within 1 day of each other. The LVEF was determined by the biplane modified Simpson rule. Doppler parameters were measured from tracings of the left common carotid artery 4 cm from the flow divider. Linear regression and stepwise multivariable linear regression models were used to evaluate any association between the LVEF and the following variables: age, sex, peak systolic velocity (PSV), end-diastolic velocity (EDV), dicrotic notch velocity, rise time (EDV to PSV), resistive index, and cardiac cycle length. RESULTS: The dicrotic notch velocity was the only variable associated with the LVEF (P = .028) in a bivariate analyses. A backward selection stepwise multivariable equation predicting the LVEF had the dicrotic notch (P = .001) and resistive index (P = .01) as significant predictors, whereas the cardiac cycle length (P = .08) and PSV (P = .08) were borderline not significant. Model goodness of fit was R(2) = 0.37 (P = .004). CONCLUSIONS: Dicrotic notch velocities measured from common carotid artery Doppler waveforms are associated with the LVEF and might offer some clinical value in selected cases. PMID- 25715368 TI - Shape-based approach for coronary calcium lesion volume measurement on intravascular ultrasound imaging and its association with carotid intima-media thickness. AB - OBJECTIVES: Coronary calcification plays an important role in diagnostic classification of lesion subsets. According to histopathologic studies, vulnerable atherosclerotic plaque contains calcified deposits, and there can be considerable variation in the extent and degree of calcification. Intravascular ultrasound (IVUS) has demonstrated its role in imaging coronary arteries, thereby displaying calcium lesions. The aim of this work was to develop a fully automated system for detection, area and volume measurement, and characterization of the largest calcium deposits in coronary arteries. Furthermore, we demonstrate the correlation between the coronary calcium IVUS volume and the neurologic risk biomarker B-mode carotid intima-media thickness (IMT). METHODS: Our system automatically detects the frames with calcium, identifies the largest calcium region, and performs shape-based volume measurements. The carotid IMT is measured by using AtheroEdge software (AtheroPoint, LLC) on B-mode ultrasound imaging. RESULTS: Our database consists of low-contrast IVUS videos and corresponding B mode images from 100 patients. Our experiments showed that the correlation between calcium volumes and carotid IMT was higher for the left carotid artery compared to the right carotid artery (r = 0.066 for the left carotid artery and 0.121 for the right carotid artery). We obtained 97% accuracy for automated calcium detection compared against the scoring given by our expert radiologists. Furthermore, we benchmarked shape-based volume measurement against the conventional method, which used integration of regions and showed a correlation of 84%. CONCLUSIONS: Since carotid IMT is an independent prognostic factor for myocardial infarction, and calcium lesions are correlated with stroke risk, we believe that this automated system for calcium volume measurement could be useful for assessing patients' cardiovascular risk. PMID- 25715369 TI - Characterization of coronary flow reserve and left ventricular remodeling in a mouse model of chronic aortic regurgitation with carvedilol intervention. AB - OBJECTIVES: We hypothesized that left ventricular (LV) remodeling might be exaggerated by an impaired coronary flow reserve in mice with chronic severe aortic regurgitation, and carvedilol, a beta-adrenoceptor blocker, could regress the course. METHODS: Severe aortic regurgitation was induced by retrograde puncture of the aortic valve leaflets under sonographic guidance in 12-week-old male C57BL/6J mice. Four weeks after regurgitation, the mice were treated with carvedilol (30 mg/kg/d) or not treated (control). Before and 4 weeks after carvedilol treatment, the coronary flow reserve and LV structure and function were evaluated by echocardiography. Cardiomyocytes and fibrosis were validated by histologic analysis. RESULTS: Four-week aortic regurgitation caused a decreased LV ejection fraction and an increased LV end-systolic volume index. Regurgitation also impaired the coronary flow reserve due to an increase in the basal coronary peak diastolic velocity and velocity-time integral combined with the absence of substantial changes in the hyperemic coronary peak diastolic velocity and velocity-time integral. Four more weeks of regurgitation further deteriorated LV remodeling and coronary perfusion in the control group. In contrast, the carvedilol-treated group showed attenuated LV remodeling and a higher coronary flow reserve by decreasing the basal peak diastolic velocity and velocity-time integral without substantial changes in the hyperemic peak diastolic velocity and velocity-time integral. The coronary flow reserve and its pretreatment versus posttreatment difference were positively correlated with the pretreatment versus posttreatment LV ejection fraction and end-systolic volume index differences. In the carvedilol-treated group, subendocardial fibrosis was significantly reduced (P < .05), and the cardiomyocyte cross-sectional area tended to be smaller. CONCLUSIONS: In mice with chronic severe aortic regurgitation, carvedilol therapy significantly improves the impaired coronary flow reserve and sufficiently attenuates adverse LV remodeling. Sustained coronary flow reserve impairment indicates progressive LV remodeling. PMID- 25715371 TI - Sonography of the scrotum: from appendages to scrotolithiasis. AB - In this pictorial essay, we review and discuss the varying morphologic characteristics of scrotal appendages and calculi. Characteristic sonograms obtained from patients with coexisting hydrocele are presented, and recent literature is included. Hydrocele greatly facilitates the imaging of these intrascrotal structures, as it acts as a "water path". On the one hand, torsion of a scrotal appendage should always be included in the differential diagnosis of acute scrotum, especially in children. On the other hand, scrotolithiasis may occasionally cause mild discomfort. As a consequence, and given the widespread use of sonography for the evaluation of both acute and chronic conditions of the scrotum, radiologists should be familiar with these entities. PMID- 25715370 TI - Scrotal swelling in the neonate. AB - Discovery of scrotal swelling in a neonate can be a source of anxiety for parents, clinicians, and sonologists alike. This pictorial essay provides a focused review of commonly encountered scrotal masses and mimics specific to the neonatal setting. Although malignancy is a concern, it is very uncommon, as most neonatal scrotal masses are benign. Key discriminating features and management options are highlighted to improve the radiologist's ability to diagnose neonatal scrotal conditions and guide treatment decisions. Neonatal scrotal processes ranging from common to uncommon will be discussed. PMID- 25715372 TI - Quantitative evaluation of sonophoresis efficiency and its dependence on sonication parameters and particle size. AB - Transdermal drug delivery makes a critical contribution to medical practice and some advantages over conventional oral administration and hypodermic injection. Enhancement of percutaneous absorption or penetration of therapeutic agents (ie, drugs and macromolecules) by ultrasound, termed sonophoresis, has been applied and studied for decades. In this study, the penetration percentage through porcine ear skin specimens was determined quantitatively by measuring the fluorescence from nanoparticles of 60, 220, and 840 nm in size in a receptor chamber at different sonication parameters (ie, duty cycle, 20%-100%; acoustic intensity, 0.3-1.0 W/cm(2); duration, 7-30 minutes; and frequency, 1 MHz). In general, the sonophoresis efficiency increased with the acoustic intensity, duty cycle, and sonication duration but decreased with the particle size (mean +/- SD, 62.6% +/- 5.4% for 60-nm versus 11.9% +/- 1.1% for 840-nm polystyrene nanospheres after 30 minutes of sonication at 0.5 W/cm(2) and a 100% duty cycle; P < .05). On scanning electron microscopy the pore size remained the same (~100 MUm), but more flakes were observed with the progress of sonication. In summary, sonophoresis efficiency is dependent on the ultrasound parameters and particle size. Sufficient sonication would lead to satisfactory penetration of even submicrometer objects through the pores. PMID- 25715373 TI - Two cases of heterotopic pregnancy: review of the literature and sonographic diagnosis in the emergency department. AB - We present 2 recent cases of heterotopic pregnancy in which bedside sonography performed by the treating emergency physician was used to identify the heterotopic pregnancy and facilitate prompt gynecologic intervention. The cases, the sonographic approach to the diagnosis of heterotopic pregnancy, and a review of the literature are presented. PMID- 25715374 TI - Prenatal sonographic diagnosis of premature constriction of the fetal ductus arteriosus after maternal self-medication with benzydamine hydrochloride: report of 3 cases and review of the literature. AB - We report 3 cases of prenatal diagnosis of premature constriction of the ductus arteriosus after maternal benzydamine hydrochloride therapy (3-mg lozenges) in third-trimester pregnancies. In each case, fetal echocardiography revealed a dilated, hypocontractile right ventricle with severe tricuspid regurgitation and constriction of the ductus arteriosus. Although the effect of indomethacin and other nonsteroidal anti-inflammatory drugs on prenatal ductal constriction is well known, readily available over-the-counter nonsteroidal anti-inflammatory drugs such as benzydamine can have an equally deleterious effect and are best avoided in the third trimester of pregnancy. PMID- 25715375 TI - Deep infiltrating endometriosis of the bowel wall: the comet sign. AB - The purpose of this study was to evaluate the appearance of deep infiltrating endometriosis of the bowel wall in the cul-de-sac and determine the characteristic appearance of these lesions. We searched our database between January 1, 2011, and December 31, 2013, for all patients who had sonographic findings of suspected deep infiltrating endometriosis of the bowel with obliteration of the cul-de-sac. The medical record of each patient was examined retrospectively for evidence of surgical confirmation of disease. The sonographic appearance, shape, and size of the bowel wall lesions were evaluated to develop criteria for deep infiltrating endometriosis of the rectosigmoid and cul-de-sac. The search of our database revealed 35 patients with sonographic findings of pelvic bowel wall endometriosis associated with obliteration of the cul-de-sac. Ten of these patients had surgical confirmation of bowel wall endometriosis after the scan, and another 4 patients had surgical evidence of endometriosis from prior surgery. All of the patients who underwent surgery subsequent to sonography had confirmation of their bowel wall infiltrative endometriosis. Sonographically, the bowel lesions were solid, focal, and tubular with slightly irregular margins and in most cases a thinner section or a "tail" at one end, resembling a comet. This study confirms that bowel wall implants have a very characteristic appearance, and extending the transvaginal examination to include an evaluation of the rectosigmoid seeking these bowel lesions is valuable, especially in any patient presenting with a history of pelvic pain. PMID- 25715376 TI - Anomalous origin of both coronary arteries from the pulmonary artery in hypoplastic left heart syndrome. PMID- 25715377 TI - Sonographic evaluation of trigger finger at the wrist and carpal tunnel syndrome resulting from a deep soft tissue leiomyoma. PMID- 25715379 TI - Enamel Hypomineralization and Structural Defects in Amelotin-deficient Mice. AB - Amelotin (AMTN) is a relatively recently discovered enamel protein that is predominantly expressed by ameloblasts during the maturation stage of amelogenesis and is present at lower levels in the junctional epithelium of erupted teeth. Previous studies have suggested a function of this protein in enamel mineralization and cell attachment. Genetic mouse models have been instrumental in defining the role of many enamel-related proteins, but a genetic mouse model lacking the Amtn gene has not been reported. Here, we describe the generation of amelotin-deficient mice and the analysis of their enamel phenotype in comparison with that of wild-type animals. Ablation of AMTN expression resulted in mechanically inferior enamel of mandibular incisors that showed chipping and fractures at the incisal edge. Enamel mineralization was delayed, resulting in hypomineralized inner enamel and structural defects in the outer enamel. Erupted enamel close to the gingival margin showed increased surface roughness. The expression levels of the enamel matrix proteins AMEL, AMBN, ENAM, and ODAM and the enamel proteases MMP-20 and KLK-4 were not significantly altered, although the expression of KLK-4 was delayed. The morphology of ameloblasts showing prominent Tomes' processes during the secretory stage was not altered, and there was no indication of disruption of cell structures or activities, but a residual layer, presumably consisting of organic material, remained at the enamel surface close to the gingival margin. The integrity of the dentogingival attachment at the junctional epithelium appeared unaffected by AMTN deficiency. These observations indicate that AMTN plays a subtle yet critical role in enamel biomineralization, particularly during the establishment of the outer and surface enamel layers. This role appears to be largely independent of other enamel proteins. PMID- 25715380 TI - Investigating the fetal and postnatal effects of paternal alcohol exposure in mouse offspring: a review. AB - To further elucidate the possible effects of paternal alcohol exposure on fetal and post-natal development, Lee et al. conducted an experimental animal study from which potential transgenerational consequences of paternal alcohol exposure on mouse offspring were explored. The authors concluded that paternal alcohol consumption likely poses some risk to those developing offspring. However, the authors' analysis of the incidence of fetal abnormalities may be misleading. The incidence of abnormality for each treatment group was calculated by dividing the number of abnormalities by the total number of dames. This approach to presenting the data is misrepresentative, because if a dame were carrying one abnormally developed fetus out of a litter of, say, 16, the entire litter would be captured as an "abnormality" in the calculation of incidence. PMID- 25715378 TI - Effect of antibacterial dental adhesive on multispecies biofilms formation. AB - Antibacterial adhesives have favorable prospects to inhibit biofilms and secondary caries. The objectives of this study were to investigate the antibacterial effect of dental adhesives containing dimethylaminododecyl methacrylate (DMADDM) on different bacteria in controlled multispecies biofilms and its regulating effect on development of biofilm for the first time. Antibacterial material was synthesized, and Streptococcus mutans, Streptococcus gordonii, and Streptococcus sanguinis were chosen to form multispecies biofilms. Lactic acid assay and pH measurement were conducted to study the acid production of controlled multispecies biofilms. Anthrone method and exopolysaccharide (EPS):bacteria volume ratio measured by confocal laser scanning microscopy were performed to determine the EPS production of biofilms. The colony-forming unit counts, scanning electron microscope imaging, and dead:live volume ratio decided by confocal laser scanning microscopy were used to study the biomass change of controlled multispecies biofilms. The TaqMan real-time polymerase chain reaction and fluorescent in situ hybridization imaging were used to study the proportion change in multispecies biofilms of different groups. The results showed that DMADDM-containing adhesive groups slowed the pH drop and decreased the lactic acid production noticeably, especially lactic acid production in the 5% DMADDM group, which decreased 10- to 30-fold compared with control group (P < 0.05). EPS was reduced significantly in 5% DMADDM group (P < 0.05). The DMADDM groups reduced the colony-forming unit counts significantly (P < 0.05) and had higher dead:live volume ratio in biofilms compared with control group (P < 0.05). The proportion of S. mutans decreased steadily in DMADDM-containing groups and continually increased in control group, and the biofilm had a more healthy development tendency after the regulation of DMADDM. In conclusion, the adhesives containing DMADDM had remarkable antimicrobial properties to serve as "bioactive" adhesive materials and revealed its potential value for antibiofilm and anticaries clinical applications. PMID- 25715381 TI - Gait adaptations of transfemoral prosthesis users across multiple walking tasks. AB - BACKGROUND: For people with lower extremity amputations, the decreased confidence and suboptimal gait associated with dynamic instability can negatively affect mobility and quality of life. Quantifying dynamic instability could enhance clinical decision making related to lower extremity prosthetics and inform future prosthetic research. OBJECTIVE: To quantitatively examine gait adaptations in transfemoral amputees across various walking conditions. STUDY DESIGN: Cross sectional study. METHODS: Plantar-pressure data were collected from 11 individuals with unilateral transfemoral amputations using an in-shoe plantar pressure measurement system while navigating rigid and soft ground, ramp, and stair conditions. Six parameters were examined: anterior-posterior and medial lateral center-of-pressure direction changes, sensor cell loading frequency (cell triggering), maximum lateral force position, double support time, and stride time. Paired t-tests and analyses of variance were used to examine differences between limbs and walking conditions, respectively. RESULTS: Values for medial lateral center-of-pressure direction change, sensor cell loading frequency, and double support time were significantly greater on the intact limb than the prosthetic limb. Significant differences between conditions occurred only for anterior-posterior center-of-pressure direction change and double support time on the prosthetic limb. CONCLUSION: Higher values on the intact limb suggest that it plays a key role in maintaining stability and optimizing body progression during different tasks. Differences between participants, limbs, and walking condition indicate parameter sensitivity to adaptive gait strategies. CLINICAL RELEVANCE: This plantar-pressure-based approach is a viable option for point-of-care evaluation of locomotor performance, across common various mobility tasks and activities of daily living. The information obtained could be valuable for prosthetic prescription and optimization of prosthetic fit and alignment, potentially improving mobility for prosthetic users with dynamic stability deficits. PMID- 25715382 TI - Medications used in the treatment of disruptive behavior in children with FASD--a guide. AB - The majority of children with FASD suffer from disruptive behaviors and most of them need medications to modify these behaviors. The objective of this review is to familiarize professionals caring for children with FASD with stimulants and other drugs for ADHD, and the second generation antipsychotic risperidone - for aggressive and defiant behaviors. PMID- 25715383 TI - Developing a multi-criteria approach for drug reimbursement decision making: an initial step forward. AB - BACKGROUND: Coverage decisions for a new drug revolve around the balance between perceived value and price. But what is the perceived value of a new drug? Traditionally, the assessment of such value has largely revolved around the estimation of cost-effectiveness. However, very few will argue that the cost effectiveness ratio presents a fulsome picture of 'value'. Multi-criteria decision analysis (MCDA) has been advocated as an alternative to cost effectiveness analysis and it has been argued that it better reflects real world decision-making. OBJECTIVE: The objective of this project was to address the issue of the lack of a satisfactory methodology to measure value for drugs by developing a framework to operationalize an MCDA approach incorporating societal values as they pertain to the value of drugs. METHODS: Two workshops were held, one in Toronto in conjunction with the CAPT annual conference, and one in Ottawa, as part of the annual CADTH Symposium. Notes were taken at both workshops and the data collected was analyzed using a grounded theory approach. The intent was to reflect, as accurately as possible, what was said at the workshops, without normative judgement. RESULTS: Results to date are a set of guiding principles and criteria. There are currently ten criteria: Comparative effectiveness, Adoption feasibility, Risks of adverse events, Patient autonomy, Societal benefit, Equity, Strength of evidence, Incidence/prevalence/severity of condition, Innovation, and Disease prevention/ health promotion. CONCLUSION: Much progress has been made and it is now time to share the results. Feedback will determine the final shape of the framework proposed. PMID- 25715384 TI - Harmonization of HTA--based reimbursement and regulatory approval activities: a qualitative study. AB - BACKGROUND: Regulatory approval and reimbursement are necessary to bring health technologies to market. As both are distinct processes, the lack of interaction between regulators and payers has been criticized for resulting in health system inefficiencies. OBJECTIVES: This study describes the experiences of health system stakeholders on the development and implementation of initiatives to better harmonize HTA-reimbursement and regulatory activities, as well as Canadian perceptions on such initiatives. METHODS: Thematic analysis of semi-structured interviews was conducted. Participants represented those whom have published or worked actively in this area or who held positions in HTA and/or reimbursement agencies that gave them insight into the Canadian healthcare system. Interviews were recorded, transcribed and analyzed to identify emerging themes and relationships. RESULTS: Fourteen individuals from twelve organizations participated, including representatives from Canada, US, UK and Netherlands. Harmonization was identified as either a means to: (i) develop economies of scale in the generation of clinical data; and/or (ii) align the lifecycle of a health technology. For such initiatives to be successfully implemented, the following key issues emerged: (i) fostering healthy relationships; (ii) promoting well intentions; (iii) defining governance and leadership clearly; and (iv) securing organizational infrastructure. CONCLUSIONS: Attempts to harmonize reimbursement and regulatory activities is in its infancy; although, much can be learned from current Canadian and international experiences. Within Canada there is much interest, although concerns have been raised on the extent to which harmonization is possible. Successful policy implementation would require inter-agency collaborations, with particular attention towards capacity building and strong leadership. PMID- 25715385 TI - Patterns of oral anticoagulants use in atrial fibrillation. AB - BACKGROUND: Novel oral anticoagulants are available for the management of atrial fibrillation and are considered more convenient to use than warfarin. OBJECTIVE: The main objective of this study was to describe patterns of oral anticoagulant use in the 6 months period following the availability of dabigatran at our hospital. METHODS: A cross-sectional study was conducted in a single University hospital in the province of Quebec, Canada. Medical records of subjects on oral anticoagulants for atrial fibrillation that were hospitalized between October 1st, 2011 and March 31th, 2012 were reviewed. Type of use (prevalent, incident and switch) and patient's characteristics of warfarin and dabigatran users were compared using Chi-squared and T-tests. RESULTS: In the 6-month period following dabigatran availability in the hospital, 59 patients (13%) were on dabigatran and 388 (87%) on warfarin. Mean CHADS2 score, mean age and mean number of chronic medications were lower in the dabigatran group. The percentage of patients with coronary artery disease was lower and renal function was higher in the dabigatran group. CONCLUSION: Dabigatran use remained low in the first 6 months period following the approval of dabigatran at our hospital, which could be explained by limited data on the efficacy and safety of this agent in subjects with multiple comorbidities. PMID- 25715386 TI - Electrogustometry and contact endoscopy findings in patients with head and neck malignancies treated with chemotherapy, radiotherapy, or radiochemotherapy. AB - This study aimed to investigate in parallel changes in gustatory function, changes in morphology of the fungiform papillae, as well as changes in the shape and density of the vessels of the tip of the tongue in patients treated with chemotherapy, radiotherapy, or radiochemotherapy. Twenty patients (7 females and 13 males; age range: 42-78 years) with head and neck malignancies (hypopharynx, larynx, oropharynx, and parotid) treated with radiochemotherapy (n = 8), chemotherapy (n = 8), or radiotherapy (n = 4) were prospectively studied. In all patients, electrogustometry and contact endoscopy were performed. Radiotherapy treated patients exhibited higher electrogustometry thresholds and greater alterations in the morphology and vascularization of the fungiform papillae than the other two groups. Radiochemotherapy patients had less pronounced changes of the electrogustometry threshold and fungiform papillae structure compared with radiotherapy patients. Chemotherapy alone caused less severe change in both electrogustometry threshold and fungiform papillae structure than radiotherapy or radiochemotherapy. Radiotherapy alone caused greater disorders of taste-related anatomic parameters and electrogustometry thresholds compared with chemotherapy and combined radiochemotherapy. PMID- 25715391 TI - Estimation of causal effects of binary treatments in unconfounded studies with one continuous covariate. AB - The estimation of causal effects in nonrandomized studies should comprise two distinct phases: design, with no outcome data available; and analysis of the outcome data according to a specified protocol. Here, we review and compare point and interval estimates of common statistical procedures for estimating causal effects (i.e. matching, subclassification, weighting, and model-based adjustment) with a scalar continuous covariate and a scalar continuous outcome. We show, using an extensive simulation, that some highly advocated methods have poor operating characteristics. In many conditions, matching for the point estimate combined with within-group matching for sampling variance estimation, with or without covariance adjustment, appears to be the most efficient valid method of those evaluated. These results provide new conclusions and advice regarding the merits of currently used procedures. PMID- 25715392 TI - Neural development and regeneration: it's all in your spinal cord. AB - The spinal cord constitutes an excellent model system for studying development and regeneration of a functional nervous system, from specification of its precursors to circuit formation. The latest advances in the field of spinal cord development and its regeneration following damage were discussed at a recent EMBO workshop 'Spinal cord development and regeneration' in Sitges, Spain (October, 2014), highlighting the use of direct visualization of cellular processes, genome wide molecular techniques and the development of methods for directed stem cell differentiation and regeneration. PMID- 25715394 TI - Bicaudal C1 promotes pancreatic NEUROG3+ endocrine progenitor differentiation and ductal morphogenesis. AB - In human, mutations in bicaudal C1 (BICC1), an RNA binding protein, have been identified in patients with kidney dysplasia. Deletion of Bicc1 in mouse leads to left-right asymmetry randomization and renal cysts. Here, we show that BICC1 is also expressed in both the pancreatic progenitor cells that line the ducts during development, and in the ducts after birth, but not in differentiated endocrine or acinar cells. Genetic inactivation of Bicc1 leads to ductal cell over proliferation and cyst formation. Transcriptome comparison between WT and Bicc1 KO pancreata, before the phenotype onset, reveals that PKD2 functions downstream of BICC1 in preventing cyst formation in the pancreas. Moreover, the analysis highlights immune cell infiltration and stromal reaction developing early in the pancreas of Bicc1 knockout mice. In addition to these functions in duct morphogenesis, BICC1 regulates NEUROG3(+) endocrine progenitor production. Its deletion leads to a late but sustained endocrine progenitor decrease, resulting in a 50% reduction of endocrine cells. We show that BICC1 functions downstream of ONECUT1 in the pathway controlling both NEUROG3(+) endocrine cell production and ductal morphogenesis, and suggest a new candidate gene for syndromes associating kidney dysplasia with pancreatic disorders, including diabetes. PMID- 25715393 TI - A pathway to bone: signaling molecules and transcription factors involved in chondrocyte development and maturation. AB - Decades of work have identified the signaling pathways that regulate the differentiation of chondrocytes during bone formation, from their initial induction from mesenchymal progenitor cells to their terminal maturation into hypertrophic chondrocytes. Here, we review how multiple signaling molecules, mechanical signals and morphological cell features are integrated to activate a set of key transcription factors that determine and regulate the genetic program that induces chondrogenesis and chondrocyte differentiation. Moreover, we describe recent findings regarding the roles of several signaling pathways in modulating the proliferation and maturation of chondrocytes in the growth plate, which is the 'engine' of bone elongation. PMID- 25715395 TI - Hnf1b controls pancreas morphogenesis and the generation of Ngn3+ endocrine progenitors. AB - Heterozygous mutations in the human HNF1B gene are associated with maturity-onset diabetes of the young type 5 (MODY5) and pancreas hypoplasia. In mouse, Hnf1b heterozygous mutants do not exhibit any phenotype, whereas the homozygous deletion in the entire epiblast leads to pancreas agenesis associated with abnormal gut regionalization. Here, we examine the specific role of Hnf1b during pancreas development, using constitutive and inducible conditional inactivation approaches at key developmental stages. Hnf1b early deletion leads to a reduced pool of pancreatic multipotent progenitor cells (MPCs) due to decreased proliferation and increased apoptosis. Lack of Hnf1b either during the first or the secondary transitions is associated with cystic ducts. Ductal cells exhibit aberrant polarity and decreased expression of several cystic disease genes, some of which we identified as novel Hnf1b targets. Notably, we show that Glis3, a transcription factor involved in duct morphogenesis and endocrine cell development, is downstream Hnf1b. In addition, a loss and abnormal differentiation of acinar cells are observed. Strikingly, inactivation of Hnf1b at different time points results in the absence of Ngn3(+) endocrine precursors throughout embryogenesis. We further show that Hnf1b occupies novel Ngn3 putative regulatory sequences in vivo. Thus, Hnf1b plays a crucial role in the regulatory networks that control pancreatic MPC expansion, acinar cell identity, duct morphogenesis and generation of endocrine precursors. Our results uncover an unappreciated requirement of Hnf1b in endocrine cell specification and suggest a mechanistic explanation of diabetes onset in individuals with MODY5. PMID- 25715396 TI - A MEIG1/PACRG complex in the manchette is essential for building the sperm flagella. AB - A key event in the process of spermiogenesis is the formation of the flagella, which enables sperm to reach eggs for fertilization. Yeast two-hybrid studies revealed that meiosis-expressed gene 1 (MEIG1) and Parkin co-regulated gene (PACRG) interact, and that sperm-associated antigen 16, which encodes an axoneme central apparatus protein, is also a binding partner of MEIG1. In spermatocytes of wild-type mice, MEIG1 is expressed in the whole germ cell bodies, but the protein migrates to the manchette, a unique structure at the base of elongating spermatid that directs formation of the flagella. In the elongating spermatids of wild-type mice, PACRG colocalizes with alpha-tubulin, a marker for the manchette, whereas this localization was not changed in the few remaining elongating spermatids of Meig1-deficient mice. In addition, MEIG1 no longer localizes to the manchette in the remaining elongating spermatids of Pacrg-deficient mice, indicating that PACRG recruits MEIG1 to the manchette. PACRG is not stable in mammalian cells, but can be stabilized by MEIG1 or by inhibition of proteasome function. SPAG16L is present in the spermatocyte cytoplasm of wild-type mice, and in the manchette of elongating spermatids, but in the Meig1 or Pacrg-deficient mice, SPAG16L no longer localizes to the manchette. By contrast, MEIG1 and PACRG are still present in the manchette of Spag16L-deficient mice, indicating that SPAG16L is a downstream partner of these two proteins. Together, our studies demonstrate that MEIG1/PACRG forms a complex in the manchette and that this complex is necessary to transport cargos, such as SPAG16L, to build the sperm flagella. PMID- 25715397 TI - Wnt ligands from the embryonic surface ectoderm regulate 'bimetallic strip' optic cup morphogenesis in mouse. AB - The Wnt/beta-catenin response pathway is central to many developmental processes. Here, we assessed the role of Wnt signaling in early eye development using the mouse as a model system. We showed that the surface ectoderm region that includes the lens placode expressed 12 out of 19 possible Wnt ligands. When these activities were suppressed by conditional deletion of wntless (Le-cre; Wls(fl/fl)) there were dramatic consequences that included a saucer-shaped optic cup, ventral coloboma, and a deficiency of periocular mesenchyme. This phenotype shared features with that produced when the Wnt/beta-catenin pathway co-receptor Lrp6 is mutated or when retinoic acid (RA) signaling in the eye is compromised. Consistent with this, microarray and cell fate marker analysis identified a series of expression changes in genes known to be regulated by RA or by the Wnt/beta-catenin pathway. Using pathway reporters, we showed that Wnt ligands from the surface ectoderm directly or indirectly elicit a Wnt/beta-catenin response in retinal pigment epithelium (RPE) progenitors near the optic cup rim. In Le-cre; Wls(fl/fl) mice, the numbers of RPE cells are reduced and this can explain, using the principle of the bimetallic strip, the curvature of the optic cup. These data thus establish a novel hypothesis to explain how differential cell numbers in a bilayered epithelium can lead to shape change. PMID- 25715398 TI - Muscle composition is regulated by a Lox-TGFbeta feedback loop. AB - Muscle is an integrated tissue composed of distinct cell types and extracellular matrix. While much emphasis has been placed on the factors required for the specification of the cells that comprise muscle, little is known about the crosstalk between them that enables the development of a patterned and functional tissue. We find in mice that deletion of lysyl oxidase (Lox), an extracellular enzyme regulating collagen maturation and organization, uncouples the balance between the amount of myofibers and that of muscle connective tissue (MCT). We show that Lox secreted from the myofibers attenuates TGFbeta signaling, an inhibitor of myofiber differentiation and promoter of MCT development. We further demonstrate that a TGFbeta-Lox feedback loop between the MCT and myofibers maintains the dynamic developmental homeostasis between muscle components while also regulating MCT organization. Our results allow a better understanding of diseases such as Duchenne muscular dystrophy, in which LOX and TGFbeta signaling have been implicated and the balance between muscle constituents is disturbed. PMID- 25715399 TI - Drosophila small heat shock protein CryAB ensures structural integrity of developing muscles, and proper muscle and heart performance. AB - Molecular chaperones, such as the small heat shock proteins (sHsps), maintain normal cellular function by controlling protein homeostasis in stress conditions. However, sHsps are not only activated in response to environmental insults, but also exert developmental and tissue-specific functions that are much less known. Here, we show that during normal development the Drosophila sHsp CryAB [L(2)efl] is specifically expressed in larval body wall muscles and accumulates at the level of Z-bands and around myonuclei. CryAB features a conserved actin-binding domain and, when attenuated, leads to clustering of myonuclei and an altered pattern of sarcomeric actin and the Z-band-associated actin crosslinker Cheerio (filamin). Our data suggest that CryAB and Cheerio form a complex essential for muscle integrity: CryAB colocalizes with Cheerio and, as revealed by mass spectrometry and co-immunoprecipitation experiments, binds to Cheerio, and the muscle-specific attenuation of cheerio leads to CryAB-like sarcomeric phenotypes. Furthermore, muscle-targeted expression of CryAB(R120G), which carries a mutation associated with desmin-related myopathy (DRM), results in an altered sarcomeric actin pattern, in affected myofibrillar integrity and in Z-band breaks, leading to reduced muscle performance and to marked cardiac arrhythmia. Taken together, we demonstrate that CryAB ensures myofibrillar integrity in Drosophila muscles during development and propose that it does so by interacting with the actin crosslinker Cheerio. The evidence that a DRM-causing mutation affects CryAB muscle function and leads to DRM-like phenotypes in the fly reveals a conserved stress-independent role of CryAB in maintaining muscle cell cytoarchitecture. PMID- 25715401 TI - Correction: the NAV2 homolog Sickie regulates F-actin-mediated axonal growth in Drosophila mushroom body neurons via the non-canonical Rac-Cofilin pathway. PMID- 25715402 TI - Correction: Arabidopsis AIP1-2 restricted by WER-mediated patterning modulates planar polarity. PMID- 25715400 TI - Extramacrochaetae functions in dorsal-ventral patterning of Drosophila imaginal discs. AB - One of the seminal events in the history of a tissue is the establishment of the anterior-posterior, dorsal-ventral (D/V) and proximal-distal axes. Axis formation is important for the regional specification of a tissue and allows cells along the different axes to obtain directional and positional information. Within the Drosophila retina, D/V axis formation is essential to ensure that each unit eye first adopts the proper chiral form and then rotates precisely 90 degrees in the correct direction. These two steps are important because the photoreceptor array must be correctly aligned with the neurons of the optic lobe. Defects in chirality and/or ommatidial rotation will lead to disorganization of the photoreceptor array, misalignment of retinal and optic lobe neurons, and loss of visual acuity. Loss of the helix-loop-helix protein Extramacrochaetae (Emc) leads to defects in both ommatidial chirality and rotation. Here, we describe a new role for emc in eye development in patterning the D/V axis. We show that the juxtaposition of dorsal and ventral fated tissue in the eye leads to an enrichment of emc expression at the D/V midline. emc expression at the midline can be eliminated when D/V patterning is disrupted and can be induced in situations in which ectopic boundaries are artificially generated. We also show that emc functions downstream of Notch signaling to maintain the expression of four-jointed along the midline. PMID- 25715403 TI - Failure-free survival in a prospective cohort of patients with chronic graft versus-host disease. AB - Failure-free survival, defined as the absence of relapse, non-relapse mortality or addition of another systemic therapy, has been proposed as a potential endpoint for clinical trials, but its use has only been reported for single center studies. We measured failure-free survival in a prospective observational cohort of patients (n=575) with both newly diagnosed and existing chronic graft versus-host disease from nine centers. Failure was observed in 389 (68%) patients during the observation period. The median follow up of all patients was 30.9 months, and the median failure-free survival was 9.8 months (63% at 6 months, 45% at 1 year, and 29% at 2 years). Of the variables measured at enrollment, ten were associated with shorter failure-free survival: higher National Institutes of Health 0-3 skin score, higher National Institutes of Health 0-3 gastrointestinal score, worse range of motion summary score, lower forced vital capacity (%), bronchiolitis obliterans syndrome, worse quality of life, moderate to severe hepatic dysfunction, absence of treatment for gastric acid, female donor for male recipient, and prior grade II-IV acute graft-versus-host disease. Addition of a new systemic treatment, the major cause of failure, was associated with an increased risk of subsequent non-relapse mortality (hazard ratio=2.06, 95% confidence interval: 1.29-3.32; P<0.003) and decreased survival (hazard ratio=1.51, 95% confidence interval: 1.04-2.18; P<0.03). These results show that fewer than half of patients on systemic treatment will be failure-free survivors at 1 year, and fewer than a third will reach 2 years without experiencing failure. Better treatments are needed for chronic graft-versus-host disease. Clinicaltrials.gov identifier: NCT00637689. PMID- 25715404 TI - Dasatinib in high-risk core binding factor acute myeloid leukemia in first complete remission: a French Acute Myeloid Leukemia Intergroup trial. AB - Core-binding factor acute myeloid leukemia is a favorable acute myeloid leukemia subset cytogenetically defined by t(8;21) or inv(16)/t(16;16) rearrangements, disrupting RUNX1 (previously CBFA/AML1) or CBFB transcription factor functions. The receptor tyrosine kinase KIT is expressed in the vast majority of these acute myeloid leukemias and frequent activating KIT gene mutations have been associated with a higher risk of relapse. This phase II study aimed to evaluate dasatinib as maintenance therapy in patients with core-binding factor acute myeloid leukemia in first hematologic complete remission, but at higher risk of relapse due to molecular disease persistence or recurrence. A total of 26 patients aged 18-60 years old previously included in the CBF-2006 trial were eligible to receive dasatinib 140 mg daily if they had a poor initial molecular response (n=18) or a molecular recurrence (n=8). The tolerance of dasatinib as maintenance therapy was satisfactory. The 2-year disease-free survival in this high-risk population of patients was 25.7%. All but one patient with molecular recurrence presented subsequent hematologic relapse. Patients with slow initial molecular response had a similar disease-free survival when treated with dasatinib (40.2% at 2 years) or without any maintenance (50.0% at 2 years). The disappearance of KIT gene mutations at relapse suggests that clonal devolution may in part explain the absence of efficacy observed with single-agent dasatinib in these patients (n. EudraCT: 2006-006555-12). PMID- 25715405 TI - Chronic exposure to IFNalpha drives medullar lymphopoiesis towards T-cell differentiation in mice. AB - Interferon-alpha is a potent antiviral agent and a vigorous adjuvant in the induction of T-cell responses but its use is limited by hematologic toxicity. Interferon-alpha alters hematopoietic stem cell dormancy and impairs myelocytic and erythrocytic/megakaryocytic differentiation from hematopoietic progenitors. However, the effect of chronic interferon-alpha exposure on hematopoietic precursors has still not been well characterized. Here, we transduced the liver of mice with an adenoassociated vector encoding interferon-alpha to achieve sustained high serum levels of the cytokine. The bone marrow of these animals showed diminished long-term and short-term hematopoietic stem cells, reduction of multipotent progenitor cells, and marked decrease of B cells, but significant increase in the proportion of CD8(+) and CD4(+)CD8(+) T cells. Upon adoptive transfer to RAG(-/-) mice, bone marrow cells from interferon-alpha-treated animals generated CD4(+) and CD8(+) T cells while CD19(+), CD11b(+) and NK1.1(+) lineages failed to develop. These effects are associated with the transcriptional downregulation of transcription factors involved in B-cell differentiation and modulation of key factors for T-cell development. Thus, sustained interferon alpha exposure causes hematopoietic stem cells exhaustion and drives common lymphoid progenitors towards T-cell generation. PMID- 25715409 TI - Responding to the challenges of primary diabetes care through the national diabetes education program. PMID- 25715406 TI - Erythroblast apoptosis and microenvironmental iron restriction trigger anemia in the VK*MYC model of multiple myeloma. AB - Multiple myeloma is a malignant disorder characterized by bone marrow proliferation of plasma cells and by overproduction of monoclonal immunoglobulin detectable in the sera (M-spike). Anemia is a common complication of multiple myeloma, but the underlying pathophysiological mechanisms have not been completely elucidated. We aimed to identify the different determinants of anemia using the Vk*MYC mouse, which spontaneously develops an indolent bone marrow localized disease with aging. Affected Vk*MYC mice develop a mild normochromic normocytic anemia. We excluded the possibility that anemia results from defective erythropoietin production, inflammation or increased hepcidin expression. Mature erythroid precursors are reduced in Vk*MYC bone marrow compared with wild-type. Malignant plasma cells express the apoptogenic receptor Fas ligand and, accordingly, active caspase 8 is detected in maturing erythroblasts. Systemic iron homeostasis is not compromised in Vk*MYC animals, but high expression of the iron importer CD71 by bone marrow plasma cells and iron accumulation in bone marrow macrophages suggest that iron competition takes place in the local multiple myeloma microenvironment, which might contribute to anemia. In conclusion, the mild anemia of the Vk*MYC model is mainly related to the local effect of the bone marrow malignant clone in the absence of an overt inflammatory status. We suggest that this reproduces the initial events triggering anemia in patients. PMID- 25715410 TI - Gestational diabetes mellitus and the offspring--Jack and Jill are different still. PMID- 25715411 TI - Saul Genuth, MD: clinical researcher and leader in developing modern diabetes treatment. PMID- 25715412 TI - SGLT2 inhibitors: the latest "new kids on the block"! PMID- 25715413 TI - Where does combination therapy with an SGLT2 inhibitor plus a DPP-4 inhibitor fit in the management of type 2 diabetes? PMID- 25715414 TI - Blood pressure reduction: an added benefit of sodium-glucose cotransporter 2 inhibitors in patients with type 2 diabetes. PMID- 25715415 TI - Sleep duration and risk of type 2 diabetes: a meta-analysis of prospective studies. AB - OBJECTIVE: It remains unclear how many hours of sleep are associated with the lowest risk of type 2 diabetes. This meta-analysis was performed to assess the dose-response relationship between sleep duration and risk of type 2 diabetes. RESEARCH DESIGN AND METHODS: PubMed and Embase were searched up to 20 March 2014 for prospective observational studies that assessed the relationship of sleep duration and risk of type 2 diabetes. Both semiparametric and parametric methods were used. RESULTS: Ten articles with 11 reports were eligible for inclusion in the meta-analysis. A total of 18,443 incident cases of type 2 diabetes were ascertained among 482,502 participants with follow-up periods ranging from 2.5 to 16 years. A U-shaped dose-response relationship was observed between sleep duration and risk of type 2 diabetes, with the lowest risk observed at a sleep duration category of 7-8 h per day. Compared with 7-h sleep duration per day, the pooled relative risks for type 2 diabetes were 1.09 (95% CI 1.04-1.15) for each 1 h shorter sleep duration among individuals who slept <7 h per day and 1.14 (1.03 1.26) for each 1-h increment of sleep duration among individuals with longer sleep duration. CONCLUSIONS: Our dose-response meta-analysis of prospective studies shows a U-shaped relationship between sleep duration and risk of type 2 diabetes, with the lowest type 2 diabetes risk at 7-8 h per day of sleep duration. Both short and long sleep duration are associated with a significantly increased risk of type 2 diabetes, underscoring the importance of appropriate sleep duration in the delay or prevention of type 2 diabetes. PMID- 25715416 TI - Erratum: efficacy and safety of dulaglutide versus sitagliptin after 52 weeks in type 2 diabetes in a randomized controlled trial (AWARD-5). Diabetes Care 2014;37:2149-2158. PMID- 25715418 TI - Effect of bariatric surgery versus intensive medical management on diabetic ophthalmic outcomes. PMID- 25715419 TI - Blinded continuous glucose monitoring during Yom Kippur fasting in patients with type 1 diabetes on continuous subcutaneous insulin infusion therapy. PMID- 25715420 TI - Retinal thinning as a marker of disease progression in patients with Wolfram syndrome. PMID- 25715421 TI - Remission of severe neonatal diabetes with very early sulfonylurea treatment. PMID- 25715422 TI - Comment on Duran et al. Introduction of IADPSG criteria for the screening and diagnosis of gestational diabetes mellitus results in improved pregnancy outcomes at a lower cost in a large cohort of pregnant women: the St. Carlos Gestational Diabetes Study. Diabetes Care 2014;37:2442-2450. PMID- 25715423 TI - Response to Comment on Duran et al. Introduction of IADPSG criteria for the screening and diagnosis of gestational diabetes mellitus results in improved pregnancy outcomes at a lower cost in a large cohort of pregnant women: the St. Carlos Gestational Diabetes Study. Diabetes Care 2014;37:2442-2450. PMID- 25715424 TI - Comment on Liu et al. Latent autoimmune diabetes in adults with low-titer GAD antibodies: similar disease progression with type 2 diabetes: a nationwide, multicenter prospective study (LADA China Study 3). Diabetes Care 2015;38:16-21. PMID- 25715425 TI - Response to comment on Liu et al. Latent autoimmune diabetes in adults with low titer GAD antibodies: similar disease progression with type 2 diabetes: a nationwide, multicenter prospective study (LADA China Study 3). Diabetes Care 2015;38:16-21. PMID- 25715426 TI - Comment on O'Connor et Al. Randomized trial of telephone outreach to improve medication adherence and metabolic control in adults with diabetes. Diabetes care 2014;37:3317-3324. PMID- 25715427 TI - Response to comment on O'Connor et al. Randomized trial of telephone outreach to improve medication adherence and metabolic control in adults with diabetes. Diabetes care 2014;37:3317-3324. PMID- 25715428 TI - Comment on steck et al. Early hyperglycemia detected by continuous glucose monitoring in children at risk for type 1 diabetes. Diabetes care 2014;37:2031 2033. PMID- 25715429 TI - Response to comment on Steck et al. Early hyperglycemia detected by continuous glucose monitoring in children at risk for type 1 diabetes. Diabetes care 2014;37:2031-2033. PMID- 25715430 TI - Comment on Tovote et al. Individual mindfulness-based cognitive therapy and cognitive behavior therapy for treating depressive symptoms in patients with diabetes: results of a randomized controlled trial. Diabetes care 2014;37:2427 2434. PMID- 25715431 TI - Aortic remodelling in aortic dissection after frozen elephant trunk?. AB - OBJECTIVES: Frozen elephant trunk (FET) can be used for continuous downstream aorta treatment in acute aortic dissection (AAD) and chronic aortic dissection (CAD). The study reports the changes in the lumen volumes along the downstream aorta towards remodelling. METHODS: In 70 patients (22 CAD, 48 AAD), pre-, postoperative and at least the 1-year follow-up aortic imaging was available. Volume changes of aortic lumen (AL) and true lumen (TL) between examinations along the stent graft aortic segment (A), downstream to coeliac trunk (B) and distally to bifurcation (C) were used for quantification. TL increase >10% with stable AL or AL decrease >10% with stable TL were classified as positive, changes within a 10% threshold as stable, and all other changes as negative remodelling. RESULTS: In AAD, positive or stable remodelling occurred in A (90%), B (65%), C (58%) within 1 year, thereafter in 26 patients (follow-up: 47 +/- 21 months) in A (92%), B (65%), C (62%). Negative remodelling in >=2 segments was found in 5/26 (19%) patients. In CAD, positive or stable remodelling occurred in A (100%), B (86%), C (77%) within 1 year, thereafter in 16 patients (follow-up: 46 +/- 20 months) in A (75%), B (44%), C (38%). Negative remodelling in >=2 segments was found in 7/16 (43%) patients, 5 underwent reintervention, and stabilized thereafter. CONCLUSIONS: FET facilitates positive remodelling in AAD and CAD down to stent graft level. Distally, 20% AAD and 40% CAD patients remain at risk for secondary reintervention, and can be identified by negative remodelling in >=2 segments in the follow-up examinations. PMID- 25715432 TI - The effects of age and resveratrol on the hypoxic preconditioning protection against hypoxia-reperfusion injury: studies in rat hearts and human cardiomyocytes. AB - OBJECTIVES: The loss of effectiveness of ischaemic preconditioning in protecting old hearts from ischaemia/reperfusion damage is thought to be due to low sirtuin 1 levels in old hearts. We sought to determine whether resveratrol (RES), an activator of sirtuin 1, would restore this protection to that seen with ischaemic preconditioning in young hearts. METHODS: A Langendorff heart perfusion model was established in 80 old and 80 adult rats to test the effects of hypoxic preconditioning (HPC) and/or RES on preventing hypoxia-reperfusion (H/R) injury. The effects were further tested by comparing the effects of HPC and RES on cell survival rate and lactate dehydrogenase (LDH) in cardiomyocytes from 15 old and 15 young humans. RESULTS: The HPC + RES group performed better in both adult and old groups than the corresponding H/R, HPC and RES groups, causing ~50% in the adult and 40% in the old group restoration of left ventricular developed pressure and ~90% in the adult and 80% in the old group restoration of dp/dtmax. HPC and RES each reduced apoptosis in both groups. The HPC + RES treatment showed an additive benefit in reducing apoptosis in the adult group but not in the old group. In H/R-treated young and old human cardiomyocytes, cell survival and LDH level were significantly improved in the RES + HPC group compared with the HPC group. CONCLUSIONS: This study showed that RES lessened the ageing effect and enhanced the cardioprotective effect of HPC in older individuals. PMID- 25715434 TI - [Functional imaging--static & more dynamic]. PMID- 25715433 TI - [Bibliography of the Pomeranian Medical University in Szczecin for the year 2010]. PMID- 25715435 TI - [Median approach for excision of the remaining left pulmonary lobe (use of the transverse pericardial sinus)]. PMID- 25715436 TI - Response: re: promotion of family-centered birth with gentle cesarean delivery. PMID- 25715437 TI - Response: re: family physicians' knowledge of commonly overused treatments and tests. PMID- 25715438 TI - This special issue includes a selection of papers presented at the 2nd IEEE International Conference. Introduction. PMID- 25715439 TI - Are cannabinoids effective for orofacial pain states? PMID- 25715440 TI - [Quorum sensing regulation in bacteria of the family Enterobacteriaceae]. AB - Bacteria are able to sense an increase in population density and can respond to it by coordinated regulation of the expression of certain sets of genes in the total population of bacteria. This specific mode of regulation is known as Quorum Sensing (QS). The QS systems include low-molecular-weight signaling molecules of different chemical natures and the regulatory proteins that interact with the signaling molecules. The QS systems are global regulators of bacterial gene expression. They play an important role in controlling metabolic processes in bacteria. This review describes QS systems in members of the bacterial family Enterobacteriaceae functioning with the involvement of various signaling molecules, including N-acyl-homoserine lactones, AI-2, AI-3, peptides, and indole. The differences of the QS system in these bacteria from those in other taxonomic groups of bacteria are discussed. Data on the role of different types of QS systems in the regulation of different cellular processes in bacteria, i.e., their virulence, the synthesis of enzymes and antibiotics, biofilm formation, apoptosis, etc. are presented. PMID- 25715441 TI - [Organization of the Drosophila melanogaster SF1 insulator and its role in transcription regulation in transgenic lines]. AB - The SF1 insulator was found to contain a polyadenylation signal, which corresponded to the functional polyadenylation signal in embryonic S2 cells and the transgenic lines of Drosophila and bi-directional promoter that functioned in S2 cells. The studies performed did not confirm the ability of the SF1 insulator to protect expression of reporter gene white from the chromosome position effect in transgenic lines. PMID- 25715442 TI - [ITS-polymorphism of salt-tolerant and salt-sensitive native isolates of Sinorhizoblum meliloti--symbionts of alfalfa, clover and fenugreek plants]. AB - Polymorphism of rrs-rrl sequence of ribosomal operons (intergenic sequence, ITS) was studied among 81 isolates of Sinorhizobium meliloti (AK001-AK210) derived from the collection of alfalfa nodulating bacteria of the Laboratory of genetics of ARRIAM, by using species-specific primers FGPS 1490/FGPL132VM. Isolates were obtained from nodules of different species of wild host plants from Medicago, Melilotus and Trigonella genera grown in salinized North-Western region of Kazakhstan. The typical structure of ITS, similar to that of test strain Rm1021, was dominant in native rhizobia population, while in one third of the isolates (33.3%) this sequence was divergent. Among the latter, the ITS type of strain AK83 (RCAM00182) was dominant. Here, we show for the first time that isolates with reduced level of salt-tolerance had more diverse intergenic sequences of rrn operons. No phylogenetic separation was observed between isolates grouped on the basis of their tolerance or sensitivity towards 0.6 M NaCl. However, the frequency of divergent ITS types within the two groups of rhizobia depended on the host symbiotic preference observed in natural environment, allowing to speculate about the existence of a chromosome types specific for S. meliloti isolates with differential salt tolerance. In conclusion, we propose that in the area subjected to secondary salinization, which are also the centre of introgressive hybridization of alfalfa, micro-evolutionary processes, affecting rrn-operons and associated with salt adaptation, are also occurring in symbiotic root nodule bacteria populations. PMID- 25715443 TI - [Generation and study of the strains of streptomycetes--heterologous hosts for the production of moenomycin]. AB - In this paper, we report the generation of a number of novel heterologous streptomycete hosts producing nosokomycin A2 (one of the members of Mm family) and determine their potential for antibiotic production. The rpoB point mutation in the model strain of Streptomyces coelicolor (strain M1152) significantly improved nosokomycin A2 production compared to parental strains (M145 and M512), while double rpoBrpsL mutation in the same species (strain M1154) decreased it. Our results point to the previously unanticipated epistatic interactions between mutations that individually are known to be highly beneficial for antibiotic production. We also showed for the first time that facultative chemolitotrophic streptomycete S. thermospinosisporus and chloramphenicol producer S. venezuelae can be used as the hosts for moe genes. PMID- 25715444 TI - [Mitochondrial DNA variation and reticulate evolution of the genus Abies]. AB - The sequences of three regions of mitochondrial DNA (mtDNA) of a total length of 5226 bp were used to study the phylogeography of the genus Abies. The mtDNA haplotype network, comprising 36 studied Abies taxa, consisted of two branches: the first represented all American species plus two Asian, and the second included the remaining Eurasian species. Within these clusters, the haplotypes formed nine major groups, generally corresponding to the clades of the previously obtained phylogeny based on chloroplast DNA (cpDNA), but the relationships of these groups were significantly different: species assignment to the particular mtDNA haplotype group was more in line with its geographical distribution. In addition, the mtDNA haplotype network contains cycles indicating the recombination. It is assumed that the incongruence of cpDNA and mtDNA phylogenies is caused by the introgression capture of alien mtDNA during species hybridization and thus contains information about past migrations. The cases of incongruence of mitochondrial and chloroplast DNA suggesting a migration of Abies between Asia and North America are discussed. PMID- 25715445 TI - [Natural nucleotide polymorphism of the Srlk gene that determines salt stress tolerance in alfalfa (Medicago sativa L)]. AB - Based on legume genome syntheny, the nucleotide sequence of Srlk gene, key role of which in response to salt stress was demonstrated for the model species Medicago truncatula, was identified in the major forage and siderate crop alfalfa (Medicago sativa). In twelve alfalfa samples originating from regions with contrasting growing conditions, 19 SNPs were revealed in the Srlk gene. For two nonsynonymous SNPs, molecular markers were designed that could be further used to analyze the association between Srlk gene nucleotide polymorphism and the variability in salt stress tolerance among alfalfa cultivars. PMID- 25715446 TI - [Chromosomal structure of the hybrids between Allium cepa L. and Allium fistulosum L. with relative resistance to downy mildew based on in situ hybridization]. AB - Genomic in situ hybridization (GISH) was used for a chromosomal composition study of the later generations of interspecific hybrids between A. cepa L. and A. fistulosum L., which are relatively resistant to downy mildew (peronosporosis). GISH revealed that F2 hybrids, which did not produce seeds, were triploids (2n = 3x = 24) with 24 chromosomes and possessed in their compliments 16 chromosomes of A. fistulosum L. and eight chromosomes of A. cepa L. or eight chromosomes of A. fistulosum L. and 16 chromosomes of A. cepa L. The advanced F5 hybrid, which produced few seeds, was amphidiploid with 32 chromosomes. BC1F5 hybrid was triploid with eight chromosomes of A. fistulosum L. and 16 chromosomes of A. cepa L., which did not produce seeds. BC2 (BC1F5) plant was amphidiploid that possessed 4 recombinant chromosomes and produced few seeds. GISH results point to 2n-gametes formation in macro- and microsporogenesis of the hybrids. The mechanism of 2n-gametes formation and the possibility of apomixes events in the backcrossing progeny are discussed. PMID- 25715447 TI - [Molecular genetic analysis of the shantar summer group of bowhead whales (Balaena mysticetus L.) in the Okhotsk Sea]. AB - The results of molecular genetic analysis (full-length sequences of the cytochrome b gene and mtDNA control region and the allelic composition of 14 microsatellite loci) of 65 tissue samples from the endangered bowhead whale (Balaena mysticetus) population in the Sea of Okhotsk are presented. The data obtained enable the suggestion that the current state of the Sea of Okhotsk bowhead whale population is rather stable. PMID- 25715448 TI - [Linkage disequilibrium analysis for microsatellite loci in six cattle breeds]. AB - Autosomal microsatellites are valuable tools for investigating genetic diversity and population structure and making conservation decisions to preserve valuable breeds of domestic animals. We carried out a linkage disequilibrium analysis using 29 microsatellite markers in six cattle populations: Suksun, Istoben, Yaroslavl, Kholmogory, Grey Ukrainian and Pechora type Kholmogory breeds. We discovered a significant linkage between microsatellites INRA037 and CSRM60 in Grey Ukrainian breed. PMID- 25715449 TI - [New recurrent extended deletion, including GJB2 and GJB6 genes, results in isolated sensorineural hearing impairment with autosomal recessive type of inheritance]. AB - Hereditary hearing loss with the autosomal recessive type of inheritance of the DFNB 1 genetic type, caused by mutations in the GJB2 gene, is the main reason of innate non-syndromal hearing impairment in most developed countries of the world (including Russia). Intragenic point mutations prevail among the GJB2 gene defectors; however, extended deletions in the DFNB1 locus are also found with considerable frequency in some populations (for example, Spain, Great Britain, France, United States, and Brazil). Among the four known extended deletions, only one deletion affects directly the GJB2 gene sequence and was described in a single family. A new extended deletion in the GJB2 and GJB6 gene sequences (approximately 101 kb in size; NC_000013.10:g.20,757,021_20,858,394del), detected in three unrelated Russian patients, was described and characterized. Ingush origin of this mutation is assumed. If the new deletion is frequent, its detection is very important for the genetic consulting of families with hereditary hearing impairment. PMID- 25715450 TI - [DNA repair XRCC1, XPD genes polymorphism as associated with the development of bladder cancer and renal cell carcinoma]. AB - We examined the correlations between the polymorphic alleles of the DNA repair genes XRCC1 (c.839G> A, rs25489; and c.1196A> G, rs25487), XPA (c.-4A> G, rs1800975), and XPD (c.2251A> C, rs13181) and the progression and severity of neoplasias in the bladder and kidney in patients of three distinct ethnic groups, Bashkir, Russians, and Tatar, residing in the Republic of Bashkorostan. The study enrolled 468 cancer patients and 351 healthy individuals. Genotyping for polymorphic alleles was carried out using the PCR-RFLP method. We identified a correlation between allele A of the c.839 G>A locus of the XRCC1 gene and the incidence of the bladder cancer (BC) and kidney cancer (KC) in the Tatar study group, using the additive genetic effects model (Odds Ratio (OR) = 5.23 and OR = 3.90). In turn, the heterozygous G/A genotype was present at a significantly higher frequency in the KC patients of Bashkir ethnic origin, compared with the control group (p = 0.0061, OR= 4.72). Additional analysis with consideration of participants' smoking status showed that the G/A genotype is significantly more frequent in smokers with BC (OR = 1.96, p = 0.05) then in healthy smokers. We also determined, using the recessive genetic model, that the genotype A/A of the c. 1196A>G locus of the XRCC1 gene was correlated with a higher risk of BC in the Russian cohort (OR = 2.29, p = 0.0082) and an increased incidence of KC in the Bashkir group (OR = 4.06, p = 0.05). A similar correlation was obtained for smokers. In contrast, the allele c.2251 A>C in the XPD gene correlated with a lower risk for BC and KC in the Tatars (p = 0.0003, OR = 0.48 and p < 0.0001, OR = 0.37) in the additive model and in the Bashkirs (p = 0.0083, OR = 0.12) and Russians (p = 0.0001, OR = 0.14) in the recessive model. Further, we uncovered that polymorphism c.839 G>A in the XRCC1 gene contributes to the progression of noninvasive and invasive BC and promotes KC at early and advanced stages of the disease. Thus, we identified similar correlations between DNA repair gene polymorphism and the incidence and progression of BC and KC. We propose that this result points to the involvement of common pathogenetic mechanisms in the initiation and progression of the urinary neoplasias. PMID- 25715451 TI - [A method of quantitative assessment of cytokine gene mRNA expression levels using real-time PCR in homogenous low cell number populations]. AB - We propose a method of quantitative functional activity assessment in cells isolated via sorting on a flow cytometer. We show that cell populations vary in the mRNA expression of cytokine genes immediately after isolation and sorting, while the maintenance of homogenous populations in culture without stimulation results in an increase in these gene mRNA expression. Using the original system, it is now possible to detect mRNA cytokine genes with high sensitivity, starting from 90 cells per specimen. This approach permits genetic and immunogenetic analysis of gene expression with the goal of determining their functions in the in vitro studies. PMID- 25715452 TI - [Molecular variability in geographically distant populations of Drosophila melanogaster at the Lim3 gene regulating nervous system development]. AB - In this study, we compare the variability of the regulatory region of the Lim3 gene, which plays a key role in the development of the nervous system, in two populations of Drosophila melanogaster inhabiting the cities of Aleksandrov (Russia) and Raleigh (United States). The two population areas are located in different geographic regions and differ in their ecology. A comparison of nucleotide sequences of 16 (2010) and 20 (2011) alleles from the Alexandrov population showed that in both cases the variability level of the untranslated Lim3 region was considerably lower than that of the 5' regulatory region adjacent to the transcription start site. According to quantitative and quantitative parameters of the variability, there was no difference between samples of different years, which indicates the stability of the population inhabiting the northern border of the species areal. The patterns of polymorphic sites are similar in both populations, which suggest a neutral character of the variability found with respect to environmental factors, as well as the importance of nucleotide substitutions in a number of sites of the Lim3 regulatory region with respect to the control of this gene expression. PMID- 25715453 TI - Inversion polymorphism in two Serbian natural populations of Drosophila subobscura: analysis of long-term changes. AB - To study whether inversions (or arrangements) by themselves or karyotypes are the main global warming adaptive target of natural selection, two Drosophila subobscura Serbian populations (Apatin and Petnica) were re-analyzed using different statistical approaches. Both populations were sampled in an approximately 15 years period: Apatin in 1994 and 2008 + 2009 and Petnica in 1995 and 2010. For all chromosomes, the four collections studied were in Hardy Weinberg equilibrium. Thus, it seems that inversions (or arrangements) combined at random to constitute populations' karyotypes. However, there were differences in karyotypic frequencies along the years, although they were significant only for Apatin population. It is possible to conclude that inversions (or arrangements) are likely the target of natural selection, because they presented long-term changes, but combine at random to generate the corresponding karyotypic combinations. As a consequence, the frequencies of karyotypes also change along time. PMID- 25715454 TI - [Genes for biosynthesis of butenolide-like signalling molecules in Streptomyces ghanaensis, their role in moenomycin production]. AB - Moenomycins (Mm)--phosphoglycolipid compounds produced by Streptomyces ghanaensis ATCC14672--are considered a promising model for development of novel-class of antibiotics. In this regard it is important to generate Mm overproducing strains which would be a basis for economically justified production of this antibiotic. In this work a set of genes for synthesis and reception of low-molecularweight signaling molecules (LSM) in ATCC14672 were described and their significance for Mm production was studied. The ATCC 14672 genome carries structural and regulatory genes for production of LSMs of avenolide and gamma-butyrolacone families. Additional copies of LSM biosynthetic genes ssfg_07848 and ssfg_07725 did not alter the Mm production level. ATCC14672 LSMs are not capable of restoring the sporulation of butyrolactone-nonpro-ucing mutant ofS . griseus. Likewise, while the heterologous host S. lividans 1326 produced Mm, its mutant M707 (deficient in the butyrolactone synthase gene scbA) did not. Thus, while the natural level of LSMs pro-uction by ATCC 14672 does not limit Mm synthesis, the former is essential for the synthesis of moenomycins. PMID- 25715455 TI - [Expression of the Drosophila melanogaster limk1 gene 3'-UTRs mRNA in Yeast Saccharomyces cerevisiae]. AB - The stability of mRNA and its translation efficacy in higher eukaryotes are influenced by the interaction of 3'-untranscribed regions (3'-UTRs) with microRNAs and RNA-binding proteins. Since Saccharomyces cerevisiae lack microRNAs, it is possible to evaluate the contribution of only 3'-UTRs' and RNA binding proteins' interaction in post-transcriptional regulation. For this, the post-transcriptional regulation of Drosophila limk1 gene encoding for the key enzyme of actin remodeling was studied in yeast. Analysis of limkl mRNA 3'-UTRs revealed the potential sites of yeast transcriptional termination. Computer remodeling demonstrated the possibility of secondary structure formation in limkl mRNA 3'-UTRs. For an evaluation of the functional activity of Drosophila 3'-UTRs in yeast, the reporter gene PHO5 encoding for yeast acid phosphatase (AP) fused to different variants of Drosophila limk1 mRNA 3'-UTRs (513, 1075, 1554 bp) was used. Assessments of AP activity and RT-PCR demonstrated that Drosophila limkl gene 3'-UTRs were functionally active and recognized in yeast. Therefore, yeast might be used as an appropriate model system for studies of 3'-UTR's role in post transcriptional regulation. PMID- 25715456 TI - [Microsatellite Loci polymorphism of chloroplast DNA of the pine tree (Pinus sylvestris L.) in Asia and Eastern Europe]. AB - The variability of four microsatellite loci of chloroplast DNA was studied in 38 populations of Pinus sylvestris in the European part of Russia, Siberia, Kazakhstan, Transbaikalia and Mongolia. High variability was observed in all regions. In total, 152 haplotypes were identified. The level of population differentiation R(ST) was 2.1%. The differentiation of three geographical groups of populations (European, Siberian-Kazakhstan and Transbaikalian-Mongolian) was insignificant (R(CT) = 0.004%). At the same time, some rare haplotypes were found to be specific for a certain geographical region. Distribution of the rare haplotypes, which differentiated European populations from Asian populations and Mongolian and Transbaikalian populations from the Siberian, showed the independence of the history of these regions. This corresponds more to the hypothesis that the modern areal of Pinus sylvestris originated via settlement from many origins than to the hypothesized single center of the post-boulder period of recolonization. The distribution of the pair differences between the individual specimens corresponded to the model of sudden population growth. The assessments of the age of this event for Pinus sylvestris (4.5-4.7 million years), which were obtained on the basis of this model, significantly exceeded the age of the quaternary period. Therefore, the revealed growth of populations is hardly due to the changes in flora related with the boulder-period, but rather mirrors the moment of the species formation. PMID- 25715457 TI - [Chromosomal organization of centromeric Ty3/gypsy retrotransposons in Allium cepa L. and Allium fistulosum L]. AB - This is the first report on the presence of Ty3/gypsy-like retrotransposons in the centromeric region of Allium cepa and Allium fistulosum. The paper identifies the putative Ty3/gypsy centromeric retrotransposons (CR) among the DNA sequences of A. cepa present in the NCBI database and evaluates their copy number in the genomes of Allium cepa and Allium fistulosum. The putative copy number of Ty3/gypsy CR constituted about 26000 for A. cepa and about 7000 for A. fistulosum. The chromosomal organization of Ty3/gypsy CR was analyzed with the help of fluorescent in situ hybridization (FISH). The 300-bp PCR products synthesized with genomic DNA of Allium cepa and Allium fistulosum and primers designed for the sequence ET645811 of A. cepa (Genome Survey Sequence database), displaying similarity to the reverse transcriptase of the CR Ty3/gypsy family, served as FISH hybridization probes. On the chromosomes of A. cepa, hybridization signals were mainly localized in the centromeric region. On the chromosomes of A. fistulosum the signals were less expressed in the centromeric regions, though they were abundant in other chromosomal regions. The pathways of evolution in these closely related species are discussed. PMID- 25715458 TI - [Intraspecific polymorphism of the sucrose synthase genes in Russian and Kazakhstan potato cultivars]. AB - In 12 different Russian and Kazakhstan potato cultivars, the polymorphism of the glycosyltransferase domain of the sucrose synthase gene was first examined, as well as the polymorphism of the sucrose synthase domain fragment of the same gene in the potato cultivars of Kazakhstan breed. It was demonstrated that the examined sequences contained point mutations, as well as insertions and deletions, including those not described earlier. Amino acid substitutions specific to heat- and drought-tolerant varieties were also identified and could be associated with the development of abiotic stress resistance. PMID- 25715459 TI - [Regulation of somatic embryogenesis in Panax ginseng C. A. Meyer cell cultures by PgCDPK2DS1]. AB - We isolated the full-length cDNA of PgCDPK2DS1 gene, the expression of which was significantly increased at early stages of embryo development in cell cultures of ginseng P. ginseng 2c3. Interest in this gene also was supported by its nonstandard structure: the amino acid sequence of the PgCDPK2DS1 gene contained only the N-terminal domain and 80% of the kinase domain. Overexpression of the PgCDPK2DS1 gene in nonembryonic calli 1c resulted in the appearance of embryonic structures in the PgCDPK2DS1-transgenic ginseng cell culture 1c-2d. Also, expression of the plant embryogenesis marker genes WUS and SERK significantly increased in cell culture 1c-2d. The observed embryo-like structures were at early stages of embryo development; attempts to obtain an adult plant from these embryo-like structures were unsuccessful. Overexpression of PgCDPK2DS1 gene in the embryonic cell culture PG resulted in a decrease of embryonic structures in the PgCDPK2DS1-transgenic ginseng cell culture PG-2d. Moreover, expression of the plant embryogenesis marker genes WUS and SERK and expression of the endogenous PgCDPK2DS1 significantly decreased in the cell culture PG-2d. Thus, for the first time it was shown that the PgCDPK2DS1 gene is involved in the regulation of somatic embryogenesis in P. ginseng cell cultures. PMID- 25715460 TI - Development of 5Ns chromosome-specific SCAR markers for utilization in future wheat breeding programs. AB - In previous studies, we developed a wheat-Psathyrostachys huashanica Keng disomic addition line 3-8-10-2, which exhibited high stripe rust resistance and could be used as a donor source for introducing novel disease resistance gene(s) into wheat in future breeding programs. It was identified using cytology, genomic in situ hybridization (GISH), EST-SSR, EST-STS and morphological analyses. However, these techniques are not suitable for breeding programs that require the rapid screening of large numbers of genotypes because they are highly technical and time-consuming. In this study, three Ns genome-specific SCAR markers were developed via random amplified polymorphic DNA (RAPD) markers. These SCAR markers were further validated using a complete set of wheat-P. huashanica disomic addition lines, which segregated the 5Ns disomic addition line individuals. Our results indicated that the SCAR markers associated with the 5Ns chromosome of P. huashanica and they provide a low cost, high efficiency, alternative tool for screening 5Ns chromosomes in a wheat background. These newly developed SCAR markers that species-specificity of the markers was proved by analysis of a wide range of cereal species, and specific for 5Ns chromosome, which should be useful in marker-assisted selection for wheat breeders who want to screen genotypes that may contain 5Ns chromatin. PMID- 25715461 TI - [Genetic and morphological variety in Lepidoptera: evidence from monomorphic Panolis flammea L. and polymorphic Archips podana Scop]. AB - The variability of the mtDNA locus COI and morphology of male reproductive structures were analyzed in a monomorphic (Panolis flammea) and a polymorphic (Archipspodana) moth species. The level of population heterogeneity was related to reproductive behavior and the feeding range. In P. flammea, in contrast to A. podana, copulation does not depend on particular guiding structures. The continuous character of variation in the number and size of prongs on the aedeagus indicates that P. flammea is monomorphic by these traits. The level of nucleotide variation in the COI locus of mtDNA was also higher in the polymorphic A. podana than in the monomorphic P. flammea, possibly correlating with morphological intraspecies variation. PMID- 25715462 TI - [Antimutagenic effect of chemosignals from isolated female house mouse on male germ cells (Mus musculus L)]. AB - The influence of chemosignals from isolated mature females of the CBA line on level of spontaneous and radiation-induced meiotic disturbances in spermatocytes I of males of the same line was studied. Using an ana-telophase method, 24-hour exposure of males to soiled bedding containing isolated females chemosignals was shown to lead to a significantly lower frequency of chromosomal aberrations and other meiotic disturbances in spermatocytes I as compared to males kept on clean bedding. The same effect of female chemosignals was found in the reproductive cells of irradiated males (4 Gr). The mechanisms and importance of the revealed antimutagenic effect of mouse female chemosignals on the male reproductive cells in the reproduction process are discussed. PMID- 25715463 TI - [Analysis of genetic diversity of Russian regional populations based on common STR markers used in DNA identification]. AB - We conducted the first genetic analysis of a wide a range of rural Russian populations in European Russia with a panel of common DNA markers commonly used in criminalistics genetic identification. We examined a total of 647 samples from indigenous ethnic Russian populations in Arkhangelsk, Belgorod, Voronezh, Kursk, Rostov, Ryazan, and Orel regions. We employed a multiplex genotyping kit, COrDIS Plus, to genotype Short Tandem Repeat (STR) loci, which included the genetic marker panel officially recommended for DNA identification in the Russian Federation, the United States, and the European Union. In the course of our study, we created a database of allelic frequencies, examined the distribution of alleles and genotypes in seven rural Russian populations, and defined the genetic relationships between these populations. We found that, although multidimensional analysis indicated a difference between the Northern gene pool and the rest of the Russian European populations, a pairwise comparison using 19 STR markers among all populations did not reveal significant differences. This is in concordance with previous studies, which examined up to 12 STR markers of urban Russian populations. Therefore, the database of allelic frequencies created in this study can be applied for forensic examinations and DNA identification among the ethnic Russian population over European Russia. We also noted a decrease in the levels of heterozygosity in the northern Russian population compared to ethnic populations in southern and central Russia, which is consistent with trends identified previously using classical gene markers and analysis of mitochondrial DNA. PMID- 25715464 TI - [Association of kynurenine-3-monooxygenase gene with schizophrenia]. AB - Neurotoxic products produced during tryptophan metabolism via the kynurenine pathway could be involved in schizophrenia pathogenesis. It has been shown that kynurenine-3-monooxygenase (KMO) is indirectly involved in these products' formation. KMO polymorphic loci rs2275163 (C/T) and rs1053230 (A/G) were examined in 187 schizophrenia patients and 229 healthy subjects. A genetic combination of allele T and genotype GG was observed more often in a patient group compared with healthy controls (p = 0.003, OR 2.0 (95% CI 1.2-2.9). In the latter group, this combination was associated with schizophrenia endophenotype (p = 0.04), which manifested in a higher expression of schizotypal personality traits assessed using the MMPI test. PMID- 25715465 TI - [Polymorphism of mitochondrial DNA in old believers from Siberia]. AB - The polymorphism of mtDNA was examined in populations of Old Believers (n = 104) and Russians from Novosibirsk oblast (n = 270). Most of the haplogroups identified belonged to West Eurasian lineages. The frequencies of these haplogroups constituted 96.6% in Russians from Novosibirsk and 93.2% in Old Believers from Tyumen oblast. The populations examined were characterized by a high mtDNA diversity level (h = 0.98) compared to other population samples of Russians from Russia. Among the West Eurasian haplogroups, the most common (a frequency of more than 10%) were haplogroups H, U, J, and T, the proportion of which constituted 77.9% in Old Believers and 83.1% in Russians from Novosibirsk. The Mongoloid admixture in Russians (3.3%) and Old Believers (6.7%) was represented by haplogroups A, D, Z, and C, D, M*, respectively. Statistically significant differences (P < 0.05) were revealed between the Old Believers examined and Bosnians, Czechs, Slovenes, and Russians from the cities of Nizhny Novgorod and Tula. The data obtained confirm the earlier hypothesized influence of the Finno-Ugric component on the East Slavic populations. PMID- 25715466 TI - [Cytogenetics of recurrent pregnancy loss]. AB - The contribution of chromosomal abnormalities to recurrent pregnancy loss (RLP) is reviewed in the paper. Data from conventional cytogenetic analysis of the karyotype of parents and spontaneous abortions, as well as the results of molecular cytogenetic investigations and preimplantation genetic diagnostics, are discussed. Information about the significance of epigenetic impairments (abnormalities of imprinting and X-chromosome inactivation) for recurrent pregnancy loss is also considered. Cytogenetic analysis of products of conception enables ascertainment of the causes of embryonic death in a large proportion of families, more accurate estimation of the therapeutic efficiency of treatment and drugs (when women with abnormal embryos were excluded), and a statistically valid prognosis about the next pregnancy outcome. PMID- 25715467 TI - [Induction of transpositions of hobo-elements in chronically irradiated cells of dysgenetic and non-dysgenetic individuals of Drosophila melanogaster]. AB - This paper studies the effect of chronic gamma-radiation of different intensities on the induction of hobo-elements in cells ofdysgenetic and non-dysgenetic drosophila species. The level of gonadal atrophy, DNA damage, and mutability of the mini-white locus is estimated. It is shown that the frequency of displacements of the hobo-elements increases with the increase in the chronic irradiation dose, where an essential role belongs to the maternal effect. The level of DNA damage in the cells of embryos and larvae varies and depends on the conditions of induction of hobo-transposons. Analysis of the PCR products showed that chronic irradiation in a certain range of accumulated doses is able to induce formation of new copies of the hobo-elements. At the same time, the structure of deleted hobo-sequences may vary in response to higher doses of irradiation. PMID- 25715468 TI - [Genetic basis of the variability of nitrate reduction trait in Yersinia pestis strains]. AB - The genetic basis of the varying ability to reduce nitrate in strains belonging to different biovars and subspecies of plague-causing microbe has been investigated and the inability to reduce nitrate observed in different intraspecies groups of Yersinia pestis has been shown to stem from mutations in different genes involved in the expression of this trait. The absence of denitrifying activity in strains of altaica and hissarica subspecies was not due to a mutation at position 613 of the periplasmic reductase napA observed in the strains of the biovar medievalis of the main subspecies, but rather was due to a mutation in the sequence encoding the nitrate-binding domain of the ABC transporter protein SsuA; a thymine insertion (+T) was detected at position 302 from the start of the ssuA gene. Five strains of biovar antiqua isolated at different times in Mongolia, China, and Africa were shown to lack the ability to reduce nitrate. A PCR test targeting two chromosomal regions containing deletions of 19 and 24 bp in size has been developed for the identification of strains of the biovar medievalis. This test can be combined with the test for the marker mutation in the napA gene for a more reliable detection of Y. pestis strains belonging to this biovar. PMID- 25715469 TI - [Carbohydrate-binding sequences of the lectin genes in leguminous plants from the Galegeae and Hedysareae tribes]. AB - The carbohydrate-binding sequences (CBS) of the lectin genes from legume plants of the genera Astragalus Lam., Oxytropis DC., and Hedysarum L. were determined. Computer-assisted analysis of nucleotide and predicted amino acid sequences of the lectin gene fragments examined revealed a high homology level between their CBS. At the same time, the CBS of Astragalus and Oxytropis were considerably different from the lectin gene CBS in the earlier examined representatives of the tribe Galegeae, Caragana frutex and C. arborescens. This fact probably points to the differences in the carbohydrate-binding specificity of the proteins examined, which can eventually affect their functional activity. PMID- 25715470 TI - [Distribution of the genetic diversity of the Siberian stone pine, Pinus sibirica Du Tour, along the latitudinal and longitudinal profiles]. AB - The Siberian stone pine (Pinus sibirica Du Tour) is one of the main forest forming coniferous species of the boreal ecosystems of Western Siberia. We used the isozyme method to analyze 11 ecotypes representing the latitudinal and longitudinal profiles within the species range, including samples from the geographic boundaries of the distribution. The genetic structure of the ecotypes is described on the basis of the variability for 26 isozyme loci encoding for 16 enzyme systems. The greatest genetic diversity was observed in the taiga ecotypes in the central part of the studied area, while the ecotypes along the species range boundaries were shown to be genetically depauperized. Approximately 8.1% of the observed genetic diversity is attributed to differences between the studied ecotypes. We detected high levels of genetic diversity for the Fest_2, Pgm_1, Sod_4, and a few otherloci, as well as a correlation between allele frequencies and geographical locations of the populations. The results of multivariate analysis of allelic frequencies as well as cluster analysis allowed us to discriminate three major groups of ecotypes: north-eastern, central and south western. In view of our results, we compare two hypotheses: one which attributes the spatial distribution of genetic variations to the selectivity for some of the polymorphic allozyme loci, and the other based in the history of the formation of the range of the Siberian stone pine. PMID- 25715471 TI - [Genetic diversity of modern Russian durum wheat cultivars at the gliadin-coding loci]. AB - The allelic diversity at four gliadin-coding loci was examined in modern cultivars of the spring and winter durum wheat Triticum durum Desf. Comparative analysis of the allelic diversity showed that the gene pools of these two types of durum wheat, having different life styles, were considerably different. For the modern spring durum wheat cultivars, a certain reduction of the genetic diversity was observed compared to the cultivars bred in the 20th century. PMID- 25715472 TI - [Role of the expansin genes NtEXPA1 and NtEXPA4 in the regulation of cell extension during tobacco leaf growth]. AB - The tobacco plant genes NtEXPA1 and NtEXPA4 encode the alpha-expansin proteins involved in the regulation of cell growth and extension. We examined the levels of expression of these genes in various plant organs and under the effect of exogenous phytohormones. The highest levels of NtEXPA1 expression were registered in the terminal bud and in the young growing leaves and flowers. NtEXPA1 expression ceased once the leaves stopped growing. The NtEXPA4 gene showed a similar expression profile, except for higher levels of mRNA in the leaves. In young leaves located near the terminal bud, high levels of NtEXPA1 and NtEXPA4 are induced by auxins. In the lower leaves, expansin expression is differentially regulated by brassinosteroids, which inhibit NtEXPA1 and upregulate NtEXPA4. We further showed that expression of the transgenic ARGOS-LIKE results in upregulation of NtEXPA1 and a reduction in the NtEXPA4 mRNA. In turn, overexpression of NtEXPA1 resulted in an increased size of the leaves and stems because of the larger size of the individual cells. PMID- 25715473 TI - Estimation of genetic diversity using SSR markers in sunflower. AB - Microsatellites or simple sequence repeats (SSRs) were used for the estimation of genetic diversity among a group of 40 sunflower lines developed at the research area of Department of Plant Breeding and Genetics, University of Agriculture, Faisalabad. Total numbers of alleles amplified by 22 polymorphic primers were 135 with an average of 6.13 alleles per locus, suggesting that SSR is a powerful technique for assessment of genetic diversity at molecular level. The expected heterozygosity (PIC) ranged from 0.17 to 0.89. The highest PIC value was observed at the locus C1779. The genetic distances ranged from 9 to 37%. The highest genetic distance was observed between the lines L50 and V3. Genetic distances were low showing lesser amount of genetic diversity among the sunflower lines. PMID- 25715474 TI - [Genetic variability of sable Martes zibellina L., pine marten M. martes L., and their hybrids in Western Siberia: protein and DNA polymorphism]. AB - Using four types of markers, the genetic variability of sable and pine marten inhabiting Western Siberia was examined. Izoenzyme and restriction endonuclease analysis of the mtDNA cytochrome b gene fragment, as well as the ISSR-PCR and analysis of microsatellite variation, revealed a low differentiation level of sable and pine marten and confirmed the hybrid origin of atypical representatives of these species. The hybrids were characterized by an increased heterozygosity level and were genetically closer to sable than to pine marten. In atypical martens, the presence of mtDNA haplotypes of eastern sable was identified. This could be the consequence of the reintroduction of the Barguzin sable in the 20th century. In Western Siberia, the introgression of genes between sable and pine marten was massive and symmetrical. It apparently occurred in the past and continues in the present. PMID- 25715475 TI - [Experimental approach to the gene therapy of motor neuron disease with the use of genes hypoxia-inducible factors]. AB - Motor neuron disease (MND), or amyotrophic lateral sclerosis, is a fatal neurodegenerative disorder characterized by a progressive loss of motor neurons in the spinal cord and the brain. Several angiogenic and neurogenic growth factors, such as the vascular endothelial growth factor (VEGF), angiogenin (ANG), insulin-like growth factor (IGF) and others, have been shown to promote survival of the spinal motor neurons during ischemia. We constructed recombinant vectors using human adenovirus 5 (Ad5) carrying the VEGF, ANG or IGF genes under the control of the cytomegalovirus promoter. As a model for MND, we employed a transgenic mice strain, B6SJL-Tg (SOD1*G93A)d11 Gur/J that develops a progressive degeneration of the spinal motor neurons caused by the expression of a mutated Cu/Zn superoxide dismutase gene SOD1. Delivery of the therapeutic genes to the spinal motor neurons was done using the effect of the retrograde axonal transport after multiple injections of the Ad5-VEGF, Ad5-ANG and Ad5-IGF vectors and their combinations into the limbs and back muscles of the SOD1(G93A) mice. Viral transgene expression in the spinal cord motor neurons was confirmed by immunocytochemistry and RT-RCR. We assessed the neurological status, motor activity and lifespan of experimental and control animal groups. We discovered that SOD1(G93A) mice injected with the Ad5-VEGF + Ad5-ANG combination showed a 2 3 week delay in manifestation of the disease, higher motor activity at the advanced stages of the disease, and at least a 10% increase in the lifespan compared to the control and other experimental groups. These results support the safety and therapeutic efficacy of the tested recombinant treatment. We propose that the developed experimental MND treatment based on viral delivery of VEGF + ANG can be used as a basis for gene therapy drug development and testing in the preclinical and clinical trials of the MND. PMID- 25715476 TI - [Genetic and clinical characteristics of 22q11.2 deletion syndrome]. AB - In a group of 140 patients with typical phenotype, the 22q11.2 microdeletion was detected in 43 patients (32%) using FISH and MLPA methods. There were no deletions of other chromosomal loci leading to phenotypes similar to the 22q11.2 deletion syndrome (22q11.2DS). Sequencing of the TBX1 gene did not detect any mutations, except for some common neutral polymorphisms. For the first time in the Russian Federation, the diagnostic efficiency of 22q11.2DS appeared to be 32%, as a result of the application of a combination of genetic approaches for a large group of patients with suspected 22q11.2DS. PMID- 25715477 TI - [Examination of structural changes in the transforming growth factor beta receptor 1 (TGFbetaR1) gene in patients with chronic heart failure]. AB - We examined nine exons of transforming growth factor beta receptor type 1 (TGFbetaR1) gene in patients with chronic heart failure with different types of heart remodelling. We identified two missense mutations (c.457G>A (p.V1531) and c.1285A>C (p.Y229S)) and two synonym substitutions (c.1125A>C (p.Y377Y) and c.516A>G (p.S172S)), as well as polymorphisms at splicing site c.1024+24G>A (rs334354). Substitutions c.1285A>C (p.Y229S) and c.516A>G (p.S172S) were not previously described. PMID- 25715478 TI - [Results of the population and genetic study in the Republic of Tatarstan]. AB - Using data on the distribution of frequent surnames, the Crow index and its components, and nine polymorphic DNA loci, it was shown that the Tatar population of the Republic of Tatarstan is divided into subethnic groups (Mishars, Teptyars, and Kazan Tatars). No subdivision within each of these groups was found. PMID- 25715479 TI - [Let sleeping dogs lie ..., but bail out your friend]. AB - In 2013, 80,000 new cases of infection caused by human immunodeficiency virus (HIV) (HIV infection) were registered in Russia; there have been a total of as many as 850,000 notified HIV-infected cases in this country, which suggests that the HIV/AIDS epidemic becomes generalized. Of them, 150,000 people have died, most (22,000) cases in 2013, predominantly due to the late diagnosis of HIV infection and its delayed treatment initiation. The rise of new cases denotes that counteraction against the spread of HIV is inadequately effective; in this connection a further increase in morbidity and mortality rates should be forthcoming. However, the medical community has proved to be poorly trained to fight the epidemic; there is a lower awareness and knowledge about HIV infection among healthcare workers. To overcome the epidemic and its imminent negative implications, it is necessary to improve an epidemiological surveillance system, to introduce proven effective methods for the prevention of the disease, to increase patient access to current treatments, which will require not only higher direct expenditures on preventive measures, the creation of an infrastructure, and the purchase of medicaments and diagnostic agents, but also on the training and retraining of a large number of healthcare workers. PMID- 25715480 TI - [Primary immunodeficiencies are a topical problem of modern medicine]. AB - AIM: To analyze the incidence of primary immunodeficiencies (PIDs), to reveal the specific features of the course of this condition at the present stage, and to estimate the quality of health care to patients with PIDs. SUBJECTS AND METHODS: An open-label prospective trial was performed in 94 patients with different forms of PIDs (63 with selective immunoglobulin A (IgA) deficiency and 31 with other more severe primary immunodeficiencies) who had been permanent residents in the Perm Territory in the period 1990 to 2012. RESULTS: The registered PID cases were noted to be lower than the estimated ones. Over 22 years of follow-ups, the death rates for this group of patients with these diseases were 11%, and the disability rates were 27%. In severe PIDs (exclusive of selective IgA deficiency), these rates were as high as 35.5 and 96%, respectively. The rate of untimely diagnosis of severe PIDs was high (43%). Molecular genetic studies were conducted in only one tenth of the patents with this disease. PID treatment generally complied with the accepted medical standards. However, all patients with X-linked agammaglobulinemia were observed to have periodic irregularities of replacement therapy with intravenous immunoglobulins, which was a cause of death in 2 patients. Adult patients with common variable immune deficiency received no adequate replacement therapy. Timely diagnosis and adequate therapy could not only preserve the life of many patients with severe PIDs (64.5% survived), but could achieve its relatively satisfactory quality. CONCLUSION: As of now, PIDs ceased to be fatal diseases. To improve the quality of health care to patients with this pathology, there is a need to increase the awareness of the diagnosis and treatment of immunodeficiencies among physicians of different specialties, to extend the application of molecular genetic techniques, including those for prenatal diagnosis, and to continuously provide patients with essential drugs. PMID- 25715481 TI - [Awareness of the issues of HIV infection in the dwellers of the Central Administrative District of Moscow]. AB - AIM: To study the awareness of HIV infection in the dwellers of the Central Administrative District of Moscow. SUBJECTS AND METHODS: A continuous cross sectional survey was made in all the citizens who applied to the V.A. Gilyarovsky Mental Hospital Three, Branch Four, for information on the day of the survey and gave their consent to participate in this survey that was performed in 4 steps; a total of 414 persons were questioned. Their knowledge and ideas were anonymously assessed using a specially developed questionnaire. After analyzing their replies, the respondents were divided into 3 groups: 1) representatives of the so called general population; 2) draft-age youngsters; 3) health care workers. RESULTS: The draftees (34%) gave the largest number of wrong answers to the question whether human immunodeficiency virus (HIV) could be transmitted through mosquito bites (p=0.0001). Among the healthcare workers, 81% of the respondents indicated that HIV could not be transmitted through mosquito bites; the proportion of right answers among the general population was 64.3%. The statement that a condom reliably protects against HIV infection was considered to be true by 52.4% of the health care workers, 56% of the draftees, and 62.2% of the representatives of the general population. The HIV/AIDS topic was not relevant for 43.4% of the general population and 58.3% of the health care workers; 98.7% of the respondents of the general population pointed that blood should be sampled for testing for HIV antibodies to find out whether a person had HIV (AIDS); this answer was chosen by 87.5% of the surveyed health care workers. CONCLUSION: Low knowledge about HIV infection particularly among the draft-age youngsters is evidence for the insufficient efficiency of performed preventive measures among both the general population and the organized young people. Attention is drawn to the opinion of the respondent health care workers as to the reliability of using the condom to prevent HIV transmission. The findings will be kept in mind when elaborating the teaching programs. PMID- 25715482 TI - [The duration of an HIV infection course and its influencing factors]. AB - AIM: To study the duration of the natural course of HIV infection and to identify its influencing factors. SUBJECTS AND METHODS: 938 outpatient case histories of adult HIV-positive patients registered at the dispensary and the data of 3403 AIDS patients registered in the computer base, including those on 2588 dead people, were retrospectively analyzed. Kaplan-Meier survival analysis and Cox regression model were used. Gender, age, and route of infection were regarded as potential factors influencing the natural course of HIV infection. RESULTS: In Russia before the mass use of antiretroviral therapy (ART), the median survival from infection to death in the HIV-infected was 11.8 years; that from infection to establishment of AIDS was 11.6 years; the life expectancy following its diagnosis was 1.9 months. Patient age was a main factor influencing the course of HIV infection: in persons who had been infected with HIV at an age of over 35 years, lower CD4 lymphocyte counts and clinical progression occurred more rapidly than in those infected at a younger age. Less than 50% of the patients needed ART 5 years after HIV infection. CONCLUSION: An HIV-infected patient without ART survives almost twice less. It is necessary to detect HIV infection as early as possible and to regularly follow up patients regardless of the duration of infection in order to timely initiate its treatment. PMID- 25715483 TI - [Location of foci in cerebral toxoplasmosis in HIV-infected patients]. AB - AIM: To analyze the data of magnetic resonance imaging (MRI) of the brain in its toxoplasmosis in HIV-infected patients. SUBJECT AND METHODS: The clinical picture of cerebral toxoplasmosis was studied in 207 patients aged 18-76 years with Stage 4B HIV infection concurrent with the disease. Brain MRI using an Obraz-1 low field (0.12 T) MRI scanner (Russia) was carried out in 115 (55.5%) patients. This investigation was conducted in 74 (65%) treated patients over time. RESULTS: Brain T2-weighted and FLAR MRI scans most frequently revealed higher-signal polymorphic foci and T1-weighted MRI scans showed lower-signal ones predominantly involving the white matter or white-grey matter border. Perifocal edema was often recorded. Intravenous gadolinium contrast study indicated that these foci accumulated the contrast agent around the periphery following the target patterns. Sixty-four (86.5%) patients were observed to have significant positive changes: reductions in the number and sizes of foci and the area of perifocal edema; in 29 patients, the inflammatory foci changed into cysts as a favorable outcome of necrotizing encephalitis. The foci resolved completely only in 7% of the patients. CONCLUSION: MRI is of great importance in intensive care, neurology, or neurosurgery units where patients with cerebral toxoplasmosis mimicking an acute cerebrovascular accident or a brain tumor are particularly frequently admitted to. PMID- 25715484 TI - [Results of a comparative study of the efficacy of once daily darunavir/atazanavir in treatment-naive patients with HIV infection]. AB - AIM: To evaluate the efficacy of boosted darunavir and atazanavir used in antiretroviral therapy (ARVT) regimens for treatment-naive HIV-infected patients with low baseline immune parameters and a high viral load. MATERIALS AND METHODS: The investigators evaluated the clinical, immunological, and virological efficiency of treatment: the time course of changes in CD4+ lymphocyte levels and viral load at the beginning and at 12, 24, 48, 72, and 96 weeks of antiviral therapy, as well as adverse reactions. RESULTS: The virological effect of once daily darunavir/ritonavir 800/100 mg was highly competitive with that of atazanavir/ritonavir: at 96 weeks of treatment, HIV RNA <120 copies/ml was achieved in 95% of the patients in both treatment groups. A combination of once daily darunavir/ritonavir 800/100 mg ensured a more marked immunological improvement: a difference in the increment (77.1 in 1 MUl) of CD4+ lymphocyte count in patients who took darunavir (362.2 in MUl) and in those who used atazanavir (285.1 in MUl). In the patients who received darunavir, diarrhea, nausea, and headache were observed at the same frequency as in those who had atazanavir. CONCLUSION: The use of the test agents used in the ARVT has shown their efficacy and good tolerability. PMID- 25715485 TI - [The efficacy and safety of a therapy regimen including raltegravir and a fixed dose combination of lamivudine and abacavir in previously rifabutin-treated patients with tuberculosis and HIV infection]. AB - AIM: To evaluate the efficiency and safety of using raltegravir (RAL) twice daily in conjunction with a once-daily fixed dose combination of abacavir (ABC)/lamivudine (3TC) in patients with HIV infection and active tuberculosis who have not previously received antiretroviral therapy (ART) and have taken rifabutin as antituberculosis therapy (ATT). SUBJECTS AND METHODS: The efficiency of ART was evaluated in 28 patients from a change in HIV RNA levels and from an increase in CD4+ lymphocyte counts during 48-week treatment that had been completed by 15 (53.6%) patients. The main reason for therapy discontinuation was that the patients returned to the use psychoactive agents. RESULTS: After 24 and 48 weeks of ART, the level of HIV RNA reached the undetectable values (less than 50 copies/ml) in 81.25 and 75% of the patients, respectively (according to an analysis including the patients who had completed the study in conformity with the requirements of the protocol). In only 2 patients, the virological therapy proved to be ineffective, which was likely to be associated with noncompliance with drug therapy. Following 24- and 48-week therapy, the increase in median CD4+ lymphocyte counts was 70 and 208.5 per MUl, respectively. The concurrent use of ART and ATT caused positive changes in the lung skiagraphic pattern in 92.9% of the patients and complete resolution of lung tissue infiltration in 71.4%. Mixed infection ended in a fatal outcome caused by a progressive tuberculous process in 3 (10.7%) patients, in 2 of them within the first 8 weeks of treatment. The concomitant use of ATT including rifabutin and an ART (RAL + ABC/3TC) regimen was safe since one patient was noted to have a RAL-related adverse event (AE) (an allergic reaction) and caused the patient to discontinue therapy. ATT was not discontinued because of AE in any case. CONCLUSION: The ART regimen containing RAL and a fixed dose combination of ABC/3TC for adult patients with tuberculosis concurrent with HIV infection who are on combined therapy using rifabutin for tuberculosis may be recommended for the treatment of this category of patients. PMID- 25715487 TI - [The clinical and hemostasiological features of chronic hepatitides of different genesis]. AB - AIM: To comparatively characterize clinical, biochemical, and hemostasiological parameters in patients with chronic alcoholic hepatitis (CAH) and chronic mixed hepatitis (CMH), i.e. CAH + chronic hepatitis C. SUBJECTS AND METHODS: Sixty three patients (mean age 39.05+/-4.95 years) with chronic hepatitides of different etiology, who underwent general clinical, biochemical, and hemostasiological studies, were examined. RESULTS: The frequency and duration of major clinical symptoms were maximally pronounced in the patients with CMH. Aspartate aminotransferase concentrations were significantly decreased only in the patients with CAH, remaining at higher levels in CMH. The activity of gamma glutamyl transpeptidase was twice higher in CAH. In the patients of both groups, the total concentration of nitrates and nitrites was recorded within the normal range and the activity of von Willebrand factor was significantly higher than normal. The aggregation of platelets and erythrocytes in the patients of all the groups was significantly lower than that in the healthy individuals, but differed at different disease stages. CONCLUSION: CMH was ascertained to have a more severe course. The hemostatic system did not significantly depend on the etiology of hepatitis, but was variable in different periods of various hepatitides. PMID- 25715486 TI - [Tuberculosis in patients with lymphoproliferative diseases]. AB - AIM: To study the clinical manifestations, diagnosis, and treatment of lymphoproliferative diseases (LPD) concurrent with tuberculosis. SUBJECTS AND METHODS: In 1990 to 2013, the Hematology Research Center, Ministry of Health of Russia, followed up 4422 patients with LPD. Lymphomas and leukemias were diagnosed using the universally protocols. Tuberculosis was verified by the results of a comprehensive examination involving the histological study of biopsy specimens. RESULTS: Tuberculosis was identified in 85 (2%) patients with LPD. According to the nosological entity, the tuberculosis detection rates were 3% (40/1350) in Hodgkin lymphoma (HL), 1.2% (20/1627) in aggressive lymphomas, 1.4% (16/1136) in mature cell lymphomas and chronic lymphocytic leukemia, and 2.9% (9/309) in hairy cell leukemia. In accordance with its site, pulmonary tuberculosis was 73%; extrapulmonary tuberculosis, 14%; generalized tuberculosis, 12%. In pulmonary tuberculosis, its disseminated and focal involvements were found in 71 and 18% of cases, respectively. Tuberculosis was detected in 43% of the patients with HL in remission; it occurred only in other hemoblastoses in its active phase. When tuberculosis and LPD were simultaneously found, both diseases were concurrently treated. If the chemotherapy of LPD was effective, tuberculosis was cured in all the patients. CONCLUSION: Patients with LPD are a group at increased risk for tuberculosis. The diagnosis of recurrent LPD must be histologically proven. When tuberculosis and LPD are simultaneously found, both diseases should be concurrently treated. PMID- 25715488 TI - [Adenovirus pneumonia with a fatal outcome in adults]. AB - AIM: To retrospectively analyze the medical records of patients who have died from complications of community-acquired pneumonia (CAP) caused by adenovirus serotype 7. SUBJECTS AND METHODS: CAP was diagnosed in patients (6 men aged 19-24 years and 1 woman aged 49 years) on the basis of clinical, laboratory, and radiological findings. Adenoviral pneumonia was established by real-time polymerase chain reaction (PCR). Adenovirus DNA was detected in the patients' autopsy samples (lungs, brain, spleen, liver, blood). The adenoviruses were referred to as B1 serotype 7 on the basis of hexone gene sequencing results. Other potential causative agents of pneumonia were excluded by a battery of molecular genetic tests for a wide range of viral and bacterial pathogens of acute respiratory tract infections. RESULTS: In all cases, the disease began acutely with fever (37.8 to 39 degrees C), weakness, headache, a sore throat, a dry, unproductive cough or runny nose. Clinical deterioration during symptomatic therapy led to hospital admission for CAP on disease days 2-11. The patients continued to feel worse during massive antibiotic therapy, by switching a drug one to six times and by simultaneously using 2-4 antibiotics and intensive therapy. Death occurred on disease days 10-24. Postmortem examination of all the patients revealed acute respiratory distress syndrome and multiple organ failure. CONCLUSION: Adenovirus pneumonia causes diagnostic and therapeutic problems for clinicians. The clinical introduction of PCR methods for the diagnosis of viral infections allow the clinicians to elaborate and timely use effective management tactics in patients with adenoviral pneumonia and to prevent their death. It is necessary to design etiotropic therapy agents and to introduce the specific prevention of adenovirus infection in risk groups. PMID- 25715490 TI - [Evaluation of the efficiency of diagnostic regimens for enterohemorrhagic escherichiasis. Etiological verification of hemolytic uremic syndrome in the Russian Federation]. AB - AIM: To evaluate the practical efficiency of the diagnostic algorithms for enterohemorrhagic escherichiasis, which are laid down by the current normative documents of the Russian Federation. SUBJECTS AND METHODS: The investigators estimated the prevalence of enterohemorrhagic Escherichia coli (EHEC) infection in children with the symptoms of acute enteric infections (AEI) (archival samples) and in those aged less than 5 years with fatal evolution and a history of diarrhea and hemolytic uremic syndrome (HUS), evaluated the efficiency of bacteriological tests in HUS patients with acute EHEC infection, and comparatively analyzed the documents regulating EHEC surveillance in the Russian Federation and other countries. RESULTS: Nucleic acid amplification assay showed that the prevalence of EHEC among the hospitalized children was 1.2% (27/1269), the anamnestic registration rate for HUS among the children with fatal outcomes in AEI was 20% (5/25). The efficiency of the bacteriological diagnosis of enterohemorrhagic escherichiasis in the archival samples corresponding to the early stages of the disease in the presence of diarrhea and at the HUS development stage was 48.1% (13/27) and 6.1% (2/33), respectively. There was a potential to enhance the efficiency of the normative documents regulating the etiological diagnosis of EHEC infection in the Russian Federation. CONCLUSION: The given data substantiate the necessity of including the etiological diagnosis of EHEC infection in the list of mandatory screening studies in children with sporadic cases of hemocolitis at the early stages of the disease. PMID- 25715489 TI - [Pneumocystis pneumonia in patients with Hodgkin lymphoma]. AB - AIM: To assess the results of diagnosing and treating Pneumocystis pneumonia (PP) in patients with Hodgkin lymphoma (HL) over 15 years. SUBJECTS AND METHODS: In 1999 to 2013, PP occurred in 22 (3%) of 741 HL patients receiving programmed polychemotherapy (PCT). The male/female ratio was 1:1.1; median age was 32 (18 65) years. Advanced stages (IIB-IV) of the disease were seen in 82% of the patients. The diagnosis of PP was established when Pneumocystis (more than 5 cysts in the specimen) was detected in the lavage fluid by indirect immunofluorescence assay. RESULTS: PP developed after 4 or more cycles of PCT. Along with Pneumocystis, all the cases were found to have additional pathogens: herpes virus in 72% and bacteria and fungi in 33%. All the patients received combined antimicrobial therapy using high doses of intravenous trimethoprim sulfamethoxazole. Ten (45%) patients required mechanical ventilation (MV). The total mortality in PP was 32% (7 patients died); moreover, none of the patients without MV died whereas the mortality among those who had MV was 70% (7 of the 10 patients died). High death rates (80%) were noted among the patients with recurrent and resistant HL. CONCLUSION: PP should be prevented with trimethoprim sulfamethoxazole in patients with LH during PCT. If respiratory failure and X-ray signs of interstitial pneumonia appear, there is a need for fibrobronchoscopy with bronchoalveolar lavage and comprehensive microbiological testing of lavage fluid. PMID- 25715491 TI - [Some features of primary facial erysipelas under the present conditions]. AB - AIM: To establish the features of clinical and laboratory changes in facial erysipelas in relation to its form. SUBJECTS AND METHODS: Twenty-three patients (15 women and 8 men) aged 31 to 78 years who were diagnosed with moderate facial erysipelas, primary facial erysipelas being present in 91% of cases were examined. The investigators studied the biochemical substrates and enzymes and composition of proteins in the serum by an electrophoretic method, the aggregation activity of red blood cells and platelets, plasma hemostasis (a coagulogram, levels of fibrinogen, antithrombin III, and D-dimer), and von Willebrand factor, a marker of vessel wall injury, on hospital admission at disease onset (days 1-3), over time (days 4-6, 7-9), and in convalescence (days 10-12), by obligatorily using control materials. CONCLUSION: Bleeding disorders in facial erysipelas correspond to the vasculite purpuric type of hemorrhagic diathesis (according to the classification developed by Z. S. Barkagan) with the laboratory signs of evolving disseminated intravascular coagulation: impairments in erythrocyte hemostasis and blood vessel endothelium. The changes in the functional properties of red blood cells match with the suppression of metabolic processes. And if the neuraminidase effect of beta-hemolytic streptococcus is shown at the level of the red blood cell membrane, the activity of NADase blocks processes in the entire macroenergetics. In the presence of a high fever reaction, the low levels of transaminases (aspartate aminotransferase, alanine aminotransferase) and membrane enzymes (alkaline phosphatase, creatinine phosphokinase) decrease the detoxification capacities of serum and increase a load on blood albumin and erythrocyte barriers. Rapid normalization of C-reactive protein levels enables one to use this simple and highly sensitive test to monitor the involution of erysipelatous inflammation and the efficiency of treatment. The changes in the hemostatic system and metabolic tests are less pronounced in patients with facial erysipelas than in those with lower-extremity erysipelas. PMID- 25715492 TI - [Clinical features of pertussis in adults]. AB - AIM: To study the clinical features of pertussis in adults. SUBJECTS AND METHODS: The clinical manifestations of pertussis in adults were analyzed in 62 patients treated in the Core Unit and Obstetric Unit, Clinical Infectious Diseases Hospital One, Moscow Healthcare Department, in 2011-2013. RESULTS: Investigations conducted in the familial foci of pertussis showed that its incidence rate was 23.7 and 10% in adults and in pediatric institutions, respectively. The source of infant infection was adults in almost one third of cases, mothers in 72% and fathers in 27.7%. Assessment of the symptom complex of pertussis in the sick mothers in the observed period ascertained that 94+/-3% had experienced the typical form of whooping cough: 72.0+/-5.7 and 22.0+/-5.3% had its mild and moderate forms, respectively. The disease had run a latent course in 6+/-3% of the patients. The paper describes cases of pertussis in 5 pregnant women admitted to the obstetric unit for complaints of persistent cough. The diagnosis of whooping cough in all the cases was based on clinical and epidemiological findings and serological tests showing specific IgA and IgG antibodies. Three and two patients experienced moderate and mild pertussis, respectively. CONCLUSION: Pertussis now remains one of the infectious diseases relevant not only to a pediatric population, but also to an adult one. Adult pertussis maintains the main clinical features typical for this infection with a predominance of its mild forms, which makes its diagnosis difficult. A serological test (enzyme immunoassay) is of high diagnostic value for verifying whooping cough in adults under the present conditions. PMID- 25715493 TI - [South African tick bite fever in a group of Russian tourists]. AB - The paper describes a clinical case of South African tick bite fever in a group of Russian tourists. The group of 5 people who had been ill with this disease after a tourist trip to the South African Republic (the Kruger National Park in the north-eastern province of Mpumalanga) were followed up. During their trip, all of them were bitten by different insects many times. The disease exhibited different clinical presentations; however, all the patients were noted to have a fever with slight intoxication and a maculopapular rash at different sites of the body; 3 had lymphadenopathy and one had a primary effect at the site of tick sticking. The diagnosis was verified by indirect immunofluorescence for the detection of high titers to Rickettsia conorii. The course of the disease was favorable in all the patients treated with antibiotics (doxycycline or ceftriaxone). PMID- 25715494 TI - [A case of acute opisthorchiasis concurrent with chronic hereditary hemolytic anemia]. AB - The paper analyzes the clinical and laboratory manifestations of acute Opisthorchis invasion concurrent with chronic hereditary hemolytic anemia before and after antihelminthic therapy. It gives the results of direct clinical observation of a patient in the acute phase of opisthorchiasis in the presence of Minkowsky-Shauffard disease. His examination encompassed conventional laboratory and instrumental studies used in hepatology, such as physical, biochemical, and immunological examinations (tests for viral hepatitismarkers and autoimmune liver diseases), and abdominal ultrasound scanning and magnetic resonance imaging. The patient with acute opisthorchiasis concurrent with hemolytic anemia was found to have a preponderance of clinical and laboratory manifestations of hepatocholangitis in the early stages of the disease and a prevalence of subfebrility with progressive eosinophilia in the presence of regressive symptoms. The clinical and laboratory signs of hereditary microspherocytosis suggest that the process is decompensated. The found clinical and laboratory changes correspond to the natural course of the diseases. The magnitude of changes in laboratory parameters suggests that there is an intercurrent interaction of infectious and somatic diseases, but does not hinder dehelminthization. PMID- 25715495 TI - [Pulmonary vasculitis as a clinical mask of HCV infection: efficiency of interferon-free antiviral therapy]. AB - The paper describes a clinical case of pulmonary vasculitis caused by hepatitis C virus (HCV). Its diagnosis was established on the basis of in-depth laboratory testing and an investigation of the molecular biological markers of viremia (polymerase chain reaction--PCR--HCV RNA) in peripheral blood mononuclear cells. By taking into account of extrahepatic HCV replication and contraindications to interferon therapy, the female patient was given an interferon-free antiviral therapy cycle using an interferonogenic inductor in combination with ribavirin. Pathogenic therapy (methylpred and ursodeoxycholic acid) was additionally performed. An interferon-free regimen of cycloferon + ribavirin led to sustained remission of HCV infection running with its systemic manifestations. The therapy could improve the function of not only the liver, but also the lung. In suspected extrahepatic HCV infections, an investigation of molecular biological markers for viremia (HCV RNA PCR) in the peripheral blood mononuclear cells is an essential diagnostic technique. Interferonogenic inductors, cycloferon in particular, should be used in combination with ribavirin when a chronic hepatitis C patient with the extrahepatic manifestations of HCV infection has contraindications to conventional therapy with recombinant interferon-alpha. PMID- 25715496 TI - [Herpes zoster-induced neuralgia (neuropathy)]. AB - Neuralgia (neuropathy) is the most common manifestation of herpes zoster (HZ). In spinal and cranial neuralgia, there are 3 types of pain: 1) spontaneous, persistent, burning pain; 2) intermittent sharp pain; 3) pain occurring with nonpainful stimulation. The skin exhibits areas of hypesthesia, anesthesia, and dysesthesia. Ophthalmic neuralgia (of the first branch of the trigeminal nerve) is encountered in 20% of HZ cases. HZ of the auricle and external auditory meatus concurrent with facial and vestibulocochlear neuropathy is diagnosed as Ramsay Hunt syndrome. Postherpetic neuralgia (neuropathy) is characterized by pain present for 3 months or more after the appearance of herpetic eruptions. Combined therapy involving the earlier use of antiviral agents, tricyclic antidepressants, analgesics, and neuromidine is the most effective option for HZ-induced neuralgia (neuropathy). PMID- 25715497 TI - [Entecavir in the treatment of chronic hepatitis B: multicenter randomized trials and real clinical practice]. AB - The goal of treatment for chronic hepatitis B (CHB) is now to improve quality of life and to prevent the poor outcomes of the disease rather than to eliminate the virus from the body. This goal may be achieved via the long-term maintenance of aviremia. According to the International and Russian clinical guidelines, entecavir is the first-line drug of choice to treat patients with CHB. For almost 10 years of world clinical practice there has been evidence that entecavir has a high efficacy and a favorable safety profile in a number of randomized clinical trials and in real medical practice worldwide, in Russia in particular. For instance, the BRAVR (Baraclude Russian Analysis of Virological Response) trial of 147 CHB patients from 10 Russian cities indicated that the rate of aviremia was 85.8% (n=147), 89.9% (n=138), 89.4% (n=97), and 93.5% (n=81) at 1, 2, 3, and 4 years, respectively. In addition to its virological, immunological, and biochemical efficacies, entecavir also proved to be effective in achieving the regression of histological changes and in preventing the decompensation of cirrhosis and the development of carcinoma. The given data permit the use of entecavir for the long-term therapy of CHB with confidence. PMID- 25715498 TI - [Simeprevir in combination with pegylated interferon-alpha and ribavirin in the treatment of naive patients with genotype 1 chronic hepatitis C]. AB - Triple therapy with pegylated interferon-alpha, ribavirin, and simeprevir is now optimal among the antiviral treatment options available in the Russian Federation for patients with chronic hepatitis C (CHC), including inthe compensated stage of liver cirrhosis. The optimality of this combination is determined by its high efficacy--the given combination of antiviral agents allows one to predict that more than 90% of naive patients with CHC will achieve a sustained virological response as 97-99% of the Russian population patients is infected with hepatitis C virus subgenotype 1b. The second important aspect that can recognize the triple therapy incorporating simeprevir to be most rational now is its safety similar to that of double therapy with pegylated interferon-alpha and ribavirin. In addition, the absolute advantages of the triple therapy including simeprevir are shorter treatment duration (for a total of 24 weeks) for all naive patients with CHC, including those in the compensated stage of cirrhosis, and simeprevir taken as one capsule once daily. PMID- 25715499 TI - [Acute respiratory distress syndrome: how to optimize oxygen transport and to improve prognosis]. AB - The paper reviews the state-of-the-art of acute respiratory distress syndrome (ARDS) and current approaches to correcting respiratory failure. It highlights the historical and present-day data on the efficiency of extracorporeal membrane hemoxygenation, high-frequency ventilation, surfactant and inhaled nitric oxide therapy, and prone ventilation. The examinations have shown that ventilation in the prone position and extracorporeal membrane hemoxygenation not only improve gas exchange, but have a positive prognostic impact. The use of inhaled nitric oxide and surfactant achieves improved oxygenation for a while, but has no substantial effect on prognosis. The place of high-frequency oscillatory ventilation in the treatment of patients with ARDS has not been fully determined as some examinations have indicated a positive prognostic impact and other examinations have shown none or a negative impact. PMID- 25715500 TI - [Use of nonsteroidal anti-inflammatory drugs in case of ankylosing spondylitis: long and persistently!]. AB - Nonsteroidal anti-inflammatory drugs (NSAIDs) are extensively used in the treatment of rheumatic diseases to relieve pain and signs of inflammation. However, when treated for ankylosing spondylosis (AS), NSAIDS exert both symptomatic and structure-modifying effects, by slowing down the development of vertebral ankylosis. The effect of these drugs, which underlines the formation of syndesmophytes, may be associated with their anti-inflammatory activity and ability to suppress abnormal bone proliferation. There is convincing evidence to support the capacity of NSAIDs, when long and continuously used, to reduce the rates of X-ray progression of AS. So the continuous use of NSAIDs must be now considered to be a mandatory component of pharmacotherapy for this disease. Their use should be continued even after achieving a marked clinical improvement. At the same time, this situation requires that the development of adverse reactions as structural and functional diseases of the gastrointestinal tract and cardiovascular system be thoroughly controlled in this situation. The danger of these complications determines the need for a physician's attention, obligatory consideration of risk factors, and rational choice of the safest NSAIDs. PMID- 25715501 TI - [Cognitive impairments as a universal clinical syndrome in a therapist's practice]. AB - The problem of cognitive dysfunctions in patients with somatic diseases occupies a prominent place now since they are one of the most common manifestations of organic brain lesions. The early detection of potentially cured cognitive impairments is one of the important tasks of a present-day therapist, cardiologist, endocrinologist, and family doctor as the patients with early-stage cognitive impairments constitute the majority of those who have sought medical advice. In the modern world, primary health care physicians' actions are decisive in predicting the development of dementia since the detection of early non dementia forms of cognitive impairments and neuroprotective therapy with mexidol in particular are frequently quite sufficient to considerably reduce the degree of the impairments and to improve the prognosis of dementia. PMID- 25715502 TI - [Detection of cognitive deficit in a therapist's practice: review of screening scales]. AB - Acute and chronic cognitive impairments quite often complicate visceral diseases. In this connection, it is important for a therapist to know brief scales to screen for cognitive impairments. Tests, such as a six-component screener, a short orientation-memory-concentration test, a short portable mental status questionnaire, Hodkinson's abbreviated mental test (AMT) (AMT-4 and AMT-10), a clock drawing test, and 4 'A's Test (4AT) may be used for the primary assessment of cognitive functions. Mini-Mental Status Examination may be further used if dementia is suspected; the Montreal Cognitive Assessment may be applied to identify moderate cognitive impairments. Special scales, such as the confusion assessment method for the intensive care unit, are employed to diagnose acute cognitive dysfunction. PMID- 25715503 TI - Managing change in medicine. PMID- 25715504 TI - MedChi offers tools for a changing healthcare environment. PMID- 25715505 TI - Looking in all the wrong places. PMID- 25715506 TI - Introduction. PMID- 25715507 TI - MedChi accomplishments during the 2014 Maryland Legislative Session. PMID- 25715508 TI - Margin of error. PMID- 25715509 TI - VA health care system: increasing all veterans' access to end-of-life care. PMID- 25715510 TI - When cure is not possible: the role of palliative care. PMID- 25715511 TI - Thinking about what we do and how we care for people: the physician difference. PMID- 25715512 TI - Boiler plates and jerkwater towns. PMID- 25715514 TI - 2013 healthcare: the rest of the story. PMID- 25715513 TI - The Medical & Chirurgical Faculty of Maryland and the War of 1812. PMID- 25715515 TI - Insurance reforms needed to curb costs. PMID- 25715516 TI - Communication and myths. PMID- 25715517 TI - Introduction: Global health for Maryland physicians: why you should read these articles. PMID- 25715518 TI - Why practicing physicians should care about global health. PMID- 25715519 TI - Overview of international emergency medicine. PMID- 25715520 TI - Transitioning from a practicing physician to a mission director: addressing safety issues. PMID- 25715521 TI - Global aging, local solutions: Maryland physicians as the agents of change. PMID- 25715522 TI - The global challenge of non-communicable diseases in an age of austerity: why physicians should contribute to the global policy discussion. PMID- 25715523 TI - Reverse foreign aid to Maryland revisited again. PMID- 25715524 TI - Resource availability and utilization: local versus international needs. PMID- 25715525 TI - Tuberculosis in Maryland: global and historical perspectives. PMID- 25715527 TI - Awards. PMID- 25715526 TI - The changing face of medicine. PMID- 25715528 TI - Criminalising research fraud. AB - The incidence of research fraud has reached troubling levels. Too often peer review has failed to prevent it. The harm caused by such conduct extends to patients, co-authors, supervisors, employing institutions, funders, journals, publishers, and importantly the area and direction of the research itself and its potential influence are tarnished. A number of commentators have raised the option of criminal charges being preferred against those responsible for such fraud. This has occurred in the United States, in particular, but also in the United Kingdom, Korea and Australia in high-profile cases. There is much to be said for this form of prosecutorial response to the phenomenon of research fraud given its multi-level ramifications, the considered nature of the conduct, and the fact that it is engaged in by persons well positioned to appreciate the harm that their deceit may cause. The involvement of the criminal law enhances the potential for deterrence from yielding to the temptation and opportunity to engage in research fraud. PMID- 25715529 TI - Disciplinary proceedings for inappropriate prescription of opioid medications by medical practitioners in Australia (2010-2014). AB - An analysis of 32 cases reported between July 2010 and September 2014 by professional disciplinary tribunals in New South Wales and Victoria against medical practitioners found guilty of inappropriately prescribing Sch 8 medications (mainly opioids) and Sch 4 drugs (mainly benzodiazepines) demonstrated, among others, a lengthy delay between the occurrence of the miscreant conduct and the conclusion of disciplinary proceedings. The study also raised questions about the appropriateness of utilising common criminal law theories of punishment and deterrence by non-judicial tribunals. PMID- 25715530 TI - Legal liability for psychiatrists' decisions about involuntary inpatient status for mental health patients. AB - The decisions by the High Court in Hunter and New England Local Health District v McKenna [2014] HCA 44 and by the majority of the New South Wales Court of Appeal in Hunter Area Health Service v Presland (2005) 63 NSWLR 22 create a high level of immunity for psychiatrists and the institutions in which they provide services from tortious liability for failure to impose involuntary detention or maintain involuntary detention of persons who, after release, engage in violent conduct. This column scrutinises the development of Australian law in such matters, including the public policy issues. It argues that the law has gone too far in denying a duty of care on the basis of both the least restrictive principle that is inherent in the power (as against duty) to detain involuntarily and in seeking to avoid the creation of a defensive mindset in psychiatrists or a distortive influence upon their decision-making. PMID- 25715531 TI - Is a cleft lip and palate a serious "handicap"? Jepson v Chief Constable of West Mercia--a legal and ethical critique. AB - This column considers the legal and ethical dimensions of the controversial case of Jepson v Chief Constable of West Mercia. The purpose of bringing legal proceedings was to judicially review the notion that a cleft lip and palate should be regarded as a serious "handicap" for the purposes of s 1(1)(d) of the Abortion Act 1967 (UK). The Column argues that while Parliament failed to provide a sufficiently precise definition of "seriously handicapped", it is clear that it never intended and positively rejected the notion that a cleft lip and palate was a serious enough condition to warrant the lawful termination of a pregnancy. In determining what constitutes a sufficiently serious disability, the column critiques the medical model of disability and proposes a remedy model in its place. Finally, it argues that an attentive and responsive moral framework is fundamental to any substantial narrative ethics, and it suggests that a life with a disability can generate meaningful stories and that when there is a network of support and relationships around the person living that life, that human life is not only viable but also, in its own way, fulfilling, even if not ordinary. PMID- 25715532 TI - Nursing documentation: a valuable clinical activity. AB - Professional codes and guidelines in combination with organisational and institutional policies and procedures identify and benchmark the standards of good documentation practices within a health care context. The Nursing and Midwifery Board of Australia has adopted, as part of the regulatory framework for nursing and midwifery practice, the principles essential for good documentation. Although these principles have remained unchanged for decades, issues based on poor documentation practices continue to be raised in courts and tribunals. This column seeks to highlight the importance of recognising documentation as a valuable clinical activity and therefore deserving of closer attention and adherence. PMID- 25715533 TI - Crimes amendment (Zoe's law) Bill 2013 (No 2): paradoxical commercial impacts of the conservative agenda on fetal rights. AB - In 2013, Liberal MP Chris Spence introduced a Private Member's Bill to the New South Wales Parliament, reinvigorating an earlier Bill introduced by Christian Democrat MP Fred Nile. If passed, the Bill would have bestowed legal personhood on fetuses of 20 weeks or more for the purpose of grievous bodily harm offences in the Crimes Act 1900 (NSW). The Bill had the potential to undermine freedom of choice for women in relation to abortions prior to the point of viability (capacity for fetal existence outside the womb) as well as other decisions concerning pregnancy and childbirth. One hypothesis is that legislative measures such as this that support the rights of the fetus are well intentioned initiatives by those for whom the fetus is an essentially independent entity or symbol of innocence and moral purity whose existence must be protected over and above the interests and independent decision-making capacity of the mother. This column explores this hypothesis in the context of the paradoxical negative commercial implications of such legislation on multiple areas involving fetal maternal interaction including surrogacy. PMID- 25715534 TI - Response to article: Jammal W, StewarT C and Parker M, "'CAM-creep': medical practitioners, professional discipline and integrative medicine" (2014) 22 JLM 221. PMID- 25715536 TI - The standard of medical care under the Australian Civil Liability Acts: ten years on. AB - It has been more than a decade since the modified Bolam test was legislatively enacted.by the Australian States following the medical indemnity crisis. Since its implementation, the modified Bolam test has been configured by judges as a defence to the common law standard of care in medical diagnosis and treatment. The article argues against this interpretation and suggests an alternative way of implementing this statutory test. It is proposed that the modified Bolam test ought to have been applied as a single yardstick to determine the required standard of care in diagnosis and treatment. Changes are also recommended to reform the test with a view to striking a balance between the interests of patients and doctors in medical disputes, and strengthening judicial supervision of the medical profession. These proposed reforms could resolve the shortcomings of the common law more effectively. They may also enhance the standard of medical care in Australia in the long run. PMID- 25715535 TI - The bereavement gap: grief, human dignity and legal personhood in the debate over Zoe's law. AB - A Bill before the New South Wales Parliament attempted to re-frame harm to late term fetuses as grievous bodily harm to the fetus itself rather than (under the existing law) grievous bodily harm to the mother. To achieve this, the Bill extended legal personhood to the fetus for a limited number of offences. The Bill was brought on behalf of Brodie Donegan, who lost her daughter Zoe at 32 weeks' gestation when Donegan was hit by a drug-affected driver. This article asks what the perspective of a grieving mother can bring to the debate, in terms of helping the criminal law accurately come to grips with the complexity of pregnancy and the specific harm of fetal loss. It assesses the likely impacts of a change to fetal personhood and suggests an alternative legislative approach which is less likely to result in an erosion of bodily autonomy for pregnant women. PMID- 25715537 TI - Holding unregistered health practitioners to account: an analysis of current regulatory and legislative approaches. AB - An increasingly large part of health care delivery in Australia is provided by unregistered health practitioners, who have not been historically subject to formal regulatory arrangements and instead have been held to account via a milieu of non-specific regulatory and legislative obligations. This article explores current trends in the regulation of unregistered practitioners in civil law, criminal law and in the development of new regulatory tools such as "negative licensing". In addition, this article conducts an empirical analysis of the favoured model for extending accountability to unregistered health practitioners (negative licensing) by examining its application in New South Wales. Based on this analysis, it is argued that although negative licensing offers greater protections than previous models, it should not be viewed as a replacement for extension of statutory registration to new health disciplines, and instead should be viewed as a complementary measure to existing and new statutory registration arrangements. PMID- 25715539 TI - Confusing criminal and civil law: when may a hospital refuse to release a dead body? AB - A United Kingdom bereavement advice group has expressed concern that hospitals in Britain may be acting "illegally" in refusing to release dead bodies to relatives unless they provide evidence that funeral arrangements have been made. In some cases, hospitals may have refused to release a body to anyone other than an undertaker. The charity argues that this behaviour constitutes the common law offence of preventing the lawful burial of a body. This article considers the confusion that may occur between this offence and interference with the right to possession of a body for lawful burial. The conclusion is that it is extremely unlikely a hospital or its employees would fall foul of the criminal law in refusing to release a dead body and may be liable in the civil courts if they release a body to someone who does not have the duty and consequent right to possession of the body for lawful burial. PMID- 25715538 TI - Voluntary palliated starvation: a lawful and ethical way to die? AB - Increasingly, individuals want control over their own destiny. This includes the way in which they die and the timing of their death. The desire for self determination at the end of life is one of the drivers for the ever-increasing number of jurisdictions overseas that are legalising voluntary euthanasia and/or assisted suicide, and for the continuous attempts to reform State and Territory law in Australia. Despite public support for law reform in this field, legislative change in Australia is unlikely in the near future given the current political landscape. This article argues that there may be another solution which provides competent adults with control over their death and to have any pain and symptoms managed by doctors, but which is currently lawful and consistent with prevailing ethical principles. "Voluntary palliated starvation" refers to the process which occurs when a competent individual chooses to stop eating and drinking, and receives palliative care to address pain, suffering and symptoms that may be experienced by the individual as he or she approaches death. The article argues that, at least in some circumstances, such a death would be lawful for the individual and doctors involved, and consistent with principles of medical ethics. PMID- 25715540 TI - A right to choose how to live: the Australian common law position on refusals of care. AB - There has been limited examination of the Australian common law position regarding contemporaneous refusals of care or medical treatment by competent adults since the first two Australian cases to adjudicate on refusals of this type: H Ltd v J and Brightwater Care Group (Inc) v Rossiter. This article maps the legal position in Australia in light of the two cases with particular emphasis on the finding in H Ltd v J that self-starvation is not suicide at common law. Finally, this article highlights the broader relevance of this area of the law and its capacity to inform debates as disparate as whether to legalise voluntary euthanasia and the possible implications for the autonomy of pregnant women of proposed laws giving legal status to fetuses (particularly Zoe's Law). PMID- 25715541 TI - New Zealand's Mental Health District Inspector in historical context: "the impartial scrutiny of a citizen of standing". AB - The Mental Health (Compulsory Assessment and Treatment) Act 1992 (NZ) legislates for District Inspectors who ensure that mental health consumers held under the Act are aware of their legal rights. The New Zealand District Inspector role first appeared in 19th century legislation. Its historical longevity does not, however, denote that this role has been consistent since its inception. This article looks at the historical development of the District Inspector and its companion role, the Official Visitor, focusing in particular on the period 1969 1992, when the purpose and scope of the roles was part of a Mental Health Act 1969 review. This was a time of fundamental social and professional change, shifting ideas of psychiatric practice, new locations of treatment, and growing emphasis on patient/consumer rights. The sometimes heated debates surrounding the roles reflect these changing ideas. An historical analysis of the District Inspector and Official Visitor roles aids understanding of how the social and political contexts affect mental health issues; this has relevance for current mental health law. PMID- 25715542 TI - Wrongful life claims and negligent selection of gametes or embryos in infertility treatments: a quest for coherence. AB - This article discusses an anomaly in the English law of reproductive liability: that is, an inconsistency between the law's approach to wrongful life claims and its approach to cases of negligent selection of gametes or embryos in infertility treatments (the selection cases). The article begins with an account of the legal position, which brings into view the relevant inconsistency: while the law treats wrongful life claims as non-actionable, it recognises a cause of action in the selection cases, although the selection cases bear a relevant resemblance to wrongful life claims. The article then considers arguments that may be invoked in an attempt to reconcile the above two strands of the law. Three of these counterarguments consist in attempts to distinguish the selection cases from wrongful life claims. It is argued that these attempts fail to reveal a valid basis for treating these situations differently. A fourth possible counterargument levels against the present analysis a charge of reductio ad absurdum. It is shown that this argument suffers from a fundamental flaw caused by confusion between different senses of the term "identity". Finally, the article discusses possible changes to the legal position that could rectify the problem. It argues that one of these changes, which focuses on legal redress for violation of personal autonomy, is particularly apt to resolve the problem at hand, but also highlights the need for further inquiry into the broader implications of introducing this form of redress into the law of torts. PMID- 25715543 TI - Young people and medical procedures: whether or not young people can be competent to make medical decisions in their own interests. AB - Young people, as they grow older, gain increasing competency to make their own decisions--this is reflected in many areas of their lives. Yet, in relation to medical procedures, the case law both in Australia and in England suggests that the area remains uncertain, with courts often resorting to tests of best interests in lieu of personal autonomy particularly where the medical procedure increases in complexity and/or urgency. In fact, at common law, young people must prove themselves to be more competent than adults in order to have their ethical autonomy respected. Legislation in two States in Australia has addressed the issue. However, reform is needed to prescribe an age at which competency of a young person may be presumed for both consent and refusal of medical treatment. Further, the adoption into legislation of the test of Gillick competency would provide for determinations below the age of presumption, and restrict the practice of courts imposing best interests over a young person's own interests. PMID- 25715544 TI - We didn't start this fireless vapour: e-cigarette legislation in Australia. AB - Electronic cigarettes (or e-cigarettes) are devices that heat a cartridge containing a solution that becomes a vapour for the user to inhale. The vapour may or may not contain nicotine. E-cigarettes do not contain tar and other toxins, which traditional cigarettes do, so they may be less damaging to people's health than smoking traditional cigarettes. However, no studies exist about the long-term effects of using e-cigarettes yet. It is illegal to sell e-cigarettes with nicotine in Australia, though Australians may import a three-month supply from overseas. It is legal to sell e-cigarettes with nicotine in some other jurisdictions, such as the United Kingdom and the European Union. This article argues that the Australian government should consider legalising the sale of e cigarettes with nicotine in Australia for health, safety and economic reasons and to protect youth. If the sale of e-cigarettes with nicotine becomes legal, the Australian government must strictly regulate it. PMID- 25715545 TI - ["Vestnik oftalmologii" in Russian medical and social life (for the 130th anniversary of the journal)]. PMID- 25715546 TI - [Eye care management in Russian Federation]. AB - The article presents an analysis of Russian eye care performance indicators based on federal and sector statistics over the recent years provided by the Ministry of Health of the Russian Federation, that is the incidence of eye diseases, eye care equipment provision, inpatient and outpatient volumes. Legal acts of the Russian Federation on health system in general and eye care in particular were taken into consideration when preparing the section on organizational matters. Problems of human resources, efficiency of specialists' time management, hospital beds use, and administrative issues in particular regions and Russia as a whole are discussed. PMID- 25715547 TI - [Ophthalmic oncology: achievements over the last two decades]. AB - The article describes current trends in scientific research, especially those that concern treatment of the most common cancers. The latter include malignant eyelid and conjunctiva tumors, retinoblastoma and choroidal melanoma. Relevant publications in Russian and foreign journals demonstrate a progressive advance in treatment approaches: from radical methods associated with surrounding tissue damage to local tumor destruction. Comparative analysis of the methods and their effectiveness suggest that Russian ophthalmic oncology meets state-of-the-art international criteria. PMID- 25715548 TI - [Historical and modern perspective on neuro-ophthalmology]. PMID- 25715550 TI - [Fundamental ophthalmology: the role of electrophysiological studies]. AB - Studying of functional aspects of eye disease pathogenesis by electrophysiological methods is widely demanded in fundamental ophthalmology. Introduction of modern methods of functional assessment into experimental and clinical projects significantly broadens knowledge of normal and pathological functioning of the visual system and is the basis for further development of new strategies of pathogenetic treatment, diagnostics and expert evaluation. Some problems of ophthalmology, including those that concern age-related macular degeneration, glaucoma, diabetic retinopathy, and other diseases, are considered in the context of how much electrophysiology contributes to their solution. The role of functional examinations of the retina in studying pathophysiology of neurodegenerative brain diseases, such as Alzheimer's and Parkinson's, is also discussed. PMID- 25715549 TI - [Modern perspective on the problem of retinopathy of prematurity]. AB - The article contains an analysis of the current state of the problem of retinopathy of prematurity (RP). Advances of international and Russian ophthalmology in understanding the pathogenesis, clinical presentation of both active and regressive RP, results of multicentre studies on RP treatment and prognosis were taken into consideration. There is a tendency towards a considerable change in the range of survived premature newborns and a growing need for development of new treatment approaches on the basis of pathogenetic studies. A wide range of RP outcomes, late complications, and concomitant pathology, which determine functional prognosis and quality of life in patients who have had RP, is discussed. PMID- 25715551 TI - [Keratoconus: modern approaches to pathogenetic studies, diagnosis, optical correction, and treatment]. AB - OBJECTIVE: To evaluate modern approaches to pathogenetic studies, diagnosis, optical correction, and treatment of keratoconus (KC). MATERIAL AND METHODS: Research results over the recent years obtained with up-to-date methods of pathogenetic studying, diagnosis, correction, and treatment of KC are presented. RESULTS: Modern approaches to KC consist in analysis of corneal composition and trace elements migration as well as influencing factors. Topographic keratometry and pachymetry proved effective in early detection of KC. Results of intrastromal corneal segments implantation and corneal collagen cross-linking for optical correction and prevention of progression of KC are presented. The use of contact lenses and penetrative keratoplasty for optical correction in KC is comparatively analyzed. A new technique of complete corneal stromoplasty with viscoablation, which does not require anterior corneal stroma pre-separation and removal over the whole area of transplantation and ensures good visual control of Descemet's membrane separation, is suggested. Combined eximer laser photorefractive and phototherapeutic keratectomy for early keratoconus is theoretically substantiated. CONCLUSION: In most patients the discussed methods ensure prevention of progression of keratoconus, optical correction, and treatment. Prospects of further improvement of early diagnosis and treatment are associated with profound studying of the disease pathogenesis. PMID- 25715552 TI - [Peripheral refraction and retinal contour in children with myopia by results of refractometry and partial coherence interferometry]. AB - OBJECTIVE: To determine the posterior pole contour of the eye based on the relative peripheral refractive error and relative eye length. MATERIAL AND METHODS: A parallel study was performed, which enrolled 38 children (76 eyes) with myopia from -1.25 to -10.82 diopters. The patients underwent peripheral refraction assessment with WR-5100K Binocular Auto Refractometer ("Grand Seiko", Japan) and partial coherence tomography with IOLMaster ("Carl Zeiss", Germany) for the relative eye length in areas located 15 and 30 degrees nasal and temporal from the central fovea along the horizontal meridian. RESULTS: In general, refractometry and interferometry showed high coincidence of defocus signs and values for the areas located 15 and 30 degrees nasal as well as 15 degrees temporal from the fovea. However, in 41% of patients defocus signs determined by the two methods mismatched in one or more areas. Most of the mismatch cases were mild myopia. CONCLUSION: We suppose that such a mismatch is caused by optical peculiarities of the anterior eye segment that have an impact on refractometry results. PMID- 25715553 TI - [Modern aspects of reconstructive surgery for orbital trauma]. AB - The article describes the symptoms of an indirect orbital injury. Special attention is paid to clinical manifestations of muscle entrapment after trapdoor fractures in pediatric patients. Advantages of an original method of functional MSCT for orbital trauma are specified. Indications for orbital wall reconstruction, surgical approaches, the range of modern materials for orbital implantation, and problems of isolated orbital fractures repaired by craniofacial surgeons are considered from the ophthalmologist point of view. PMID- 25715554 TI - [Age-related macular degeneration]. AB - The review provides an update on the pathogenesis and new treatment modalities for neovascular age-related macular degeneration (AMD). The impact of polymorphism in particular genes, including complement factor H (CFH), age related maculopathy susceptibility 2 (ARMS2/LOC387715), and serine peptidase (HTRA1), on AMD development is discussed. Clinical presentations of different forms of exudative AMD, that is classic, occult, or more often mixed choroidal neovascularization, retinal angiomatous proliferation, and choroidal polypoidal vasculopathy, are described. Particular attention is paid to the results of recent clinical trials and safety issues around the therapy. PMID- 25715555 TI - [Modern opportunities and prospects for studying pathogenesis, diagnosing and treating hereditary optic neuropathies]. AB - OBJECTIVE: To evaluate modern opportunities and prospects for studying pathogenesis and improving diagnostics and treatment of hereditary optic neuropathies (HON). MATERIAL AND METHODS: The article presents summarized data on the pathogenesis, diagnostics, and treatment of HON based on modern methods of assessment. RESULTS: The results of long-term worldwide studies and those performed in the Research Institute of Eye Diseases in collaboration with several other institutions are presented. Genetic testing for mitochondrial and nucleus DNA mutations that have a known association with Leber's hereditary optic neuropathy (LHON) and autosomal dominant optic neuropathy (ADON) allow verification only in half of the cases. Particular features of hereditary diseases, such as incomplete penentrance, variable expression, clinical polymorphism, difficulties in detection of hereditary sings, and genetic heterogeneity, are shown to complicate the diagnosis of HON. Spectral retinal tomography revealed characteristic morphometric changes in the macular region and peripapillary nerve fiber layer in the acute stage of LHON. Hereditary optic neuropathies result from a genetically determined decrease in mitochondrial respiratory chain complexes activity, which is associated with a decrease in ATP production. From that standpoint, studying of mitochondrial oxidative phosphorylation biochemical defects in LHON and ADON is an option for detection of mitochondrial dysfunction. Results of a newly proposed method of mitochondrial membrane potential assessment in skin fibroblasts, which can be used for differential diagnosis of mitochondrial optic nerve diseases, are presented. Possible therapeutic measures for HON are discussed. CONCLUSION: In the prevailing number of cases the described clinical, molecular genetic, and cytological methods ensure proper diagnosis of hereditary optic neuropathies. Prospects of HON treatment, rather ambiguous, are associated with further studying of pathogenesis, development of drugs and gene therapy. PMID- 25715557 TI - [State-of-the-art cataract surgery and intraocular optical correction]. AB - The paper provides current knowledge on cataract epidemiology worldwide and in the Russian Federation, including issues of cataractogenesis and prevention. An overview of medical equipment for preoperative and intraoperative diagnostics is provided. Key aspects of the conventional ultrasonic phacoemulsification method as well as the most marked trends in correction of aphakia with intraocular lenses and in design of the latter are presented. Major laser-assisted techniques, including those that imply the use of femtosecond laser systems, and results that they yielded to date are discussed in detail. PMID- 25715556 TI - [The upper limit of individual normal range of intraocular pressure--a personalized criterion for IOP evaluation]. AB - OBJECTIVE: To determine clinical value of the use of the upper limit of individual normal range of intraocular pressure (IOP) in glaucoma diagnosing. MATERIAL AND METHODS: The study enrolled 229 conditionally healthy participants (229 eyes) with no ocular complaints after a basic ophthalmic assessment. Ocular blood flow and IOP were measured with Ocular Blood Flow Analyzer (Paradigm Medical Industries). An original formula was further used for calculation of the upper limit of normal range of IOP. All patients were divided into two groups depending on whether or not their IOP fell within the statistically normal range, i.e. was less than 21 mmHg. Thus, group 1 included 193 patients (193 eyes) with IOP from 6.7 to 21.0 mmHg, group 2 -36 patients (36 eyes) with IOP from 21.7 to 30.8 mmHg. Glaucoma diagnosis was made from automated perimetry (Humphrey Visual Field Analyzer) and retinal tomography (HRT3, Cirrus HD-OCT) findings. RESULTS: In group 1, the IOP was found to exceed the upper limit of individual normal range in 38 eyes, thus indicating the probability of glaucoma; of them, in 23 patients (60.5%) the diagnosis was confirmed by further examinations. In the rest 155 eyes from group 1 the IOP matched the individual normal range; of them, glaucoma was ruled out in 154 eyes (99.35%). In group 2, a risk of glaucoma was determined in 27 eyes, of which 24 (88.9%) were further diagnosed. In 9 eyes the IOP exceeded the statistically normal values and yet was within the individual normal range. In none of those 9 cases glaucoma was found. CONCLUSION: The upper limit of individual normal range of IOP is a personalized diagnostic criterion, which is more significant for evaluation of the risk of having or developing glaucoma than the upper limit of statistically normal range (21 mmHg). PMID- 25715558 TI - [Minimally invasive surgery for dacryostenosis: modern trends]. AB - The article presents the results of a monocentric randomized open prospective study conducted from 2008 to 2013. Lacrimal intubation with Mini-Monoka and Monoka silicone stents (mono- or bicanalicular) or with SRS and Ritleng ("FCI", France) stents for dacryostenosis of different localization was performed in 151 patients (203 eyes). The follow-up period was 12 months after the extubation. Patient examination and monitoring included collection of subjective Munk scores for epiphora, lacrimal scintigraphy and bulbar hyperemia evaluation. Though all interventions were proved to be effective, the authors came to the conclusion that, bicanalicular Mini-Monoka and Monoka stents were associated with fewer complications as compared with bicanalicular SRS and Ritleng stents. PMID- 25715560 TI - [Once again on the term "ocular surface"]. PMID- 25715559 TI - [On pathogenesis of primary open-angle glaucoma]. AB - The article comprises data on the pathogenesis of primary open-angle glaucoma. Accepted theories and risk factors of glaucoma development are considered from a historical perspective as well as in the light of modern understanding of the essence of glaucomatous optic neuropathy. The impact of different independent factors on particular pathogenetic events and their interrelation is shown. Data on possible mechanisms involved in the neurogenerative process that yet lack substantiation are presented. PMID- 25715561 TI - [On some terms used in ophthalmology]. PMID- 25715562 TI - ["Ocular surface" and other terms]. PMID- 25715563 TI - [On the term "ocular surface"]. PMID- 25715564 TI - [For the discussion of the term "ocular surface"]. PMID- 25715565 TI - Patient' page. Why you should schedule a dental appointment before a vacation. PMID- 25715568 TI - Social media is more social than media. PMID- 25715567 TI - Medicaid dental program: compliance audits. PMID- 25715569 TI - [New directions in the therapy of pulmonary arterial hypertension]. AB - Recent years are the time of dynamic development of pulmonary arterial pressure pharmacotherapy. By introducing the goal oriented therapy the survival in this group of patients has significantly increased. Apart from the pharmacotherapy used according to the ESC guidelines, new attempts of interventional treatment based on denervation of pulmonary artery have also been taken. Constantly, the new clinical trials (tests?) of drugs acting via new metabolic pathways have been conducted. They include for example: soluble guanylate cyclase stimulators, tyrosine kinase inhibitors, serotonin receptors inhibitors, Rhokinase inhibitors, VIP analogues. One of the newmedicines is riociguat, the effectiveness and safety of which have been confirmed in the PATENT and CHEST study. However, the small number and clinical diversity in the group of the PAH patients cause significant difficulties with the extrapolation of the results of trials according to the guidelines of the therapy. PMID- 25715570 TI - The influence of prostaglandin PGE1 and PGF2alpha analogues on autonomic nervous system activity, estimated with heart rate variability, in cyclophosphamide induced hemorrhagic cystitis in rats. AB - The cyclophosphamide-induced hemorrhagic cystitis (CP-HC) is a common consequence of cyclophosphamide treatment with complex pathophysiology involving several inflammatory mechanisms and autonomic nervous system dysregulation. THE AIM OF THIS STUDY: To determine effects of prostaglandin PGE1 and PGF2alpha analogues on the activity of the autonomic nervous system (ANS), estimatedindirectly on the basis of heart rate variability (HRV), in an experimental model of cyclophosphamide-induced hemorrhagic cystitis (CP-HC). Moreover we verified if potential changes in autonomic regulation can contribute to uroprotective role of prostaglandins. MATERIAL AND METHODS: The study included three groups of rats with experimentally induced CP-HC. The animals from group 2 and 3 were administered PGE1 and PGF2a analogues, respectively, and the rats from group 1 (controls) did not receive any treatment. The HRV of animals from all the groups was analyzed after seven days of the experiment. RESULTS: Administration of both PGF2alpha and PGE1 was associated with an increase in the power of VLF component and total power on frequency-domain analysis. Moreover, a significant increase in the power of non-normalized components, LH and HF, and two parameters of time domain analysis, SDN-N and rMSSD, was documented in PGF2alpha-administered animals. Both prostaglandin-treated groups did not differ significantly from the controls in terms of the values of normalized parameters, nLF and nHF. CONCLUSIONS: The analyzed prostaglandin analogues increased total autonomic activity but did not induced preferential changes in sympathetic or parasympathetic activity. Nevertheless, the VLF changes documented on HRV analysis may reflect a decrease in the level of certain pro-inflammatory mediators, thus pointing to, previously postulated in literature, potential beneficial uroprotective effect of prostaglandins in CP-HC. PMID- 25715571 TI - [Comparison of the effects of rehabilitation in stroke patients rehabilitated in stationary conditions and the home]. AB - Rehabilitation after stroke is to help the patient recover optimal physical condition, psychosocial and vocational. Standard of care is to ensure comprehensiveness and continuity of the rehabilitation process. THE AIM OF THE STUDY: Was to compare the effects of rehabilitation in stroke patients rehabilitated in the hospital and at home. MATERIAL AND METHODS: The 90 patients after ischemic stroke were examined. The first examined group (45 people) consisted ofpatients rehabilitated at the Department of Rehabilitation and Physical Medicine of the WAM University Hospital in Lodz. The second examined group number (45 people) consisted of patients waiting for admission to the Department of Rehabilitation, who were rehabilitated in environmental conditions. The patients were examined twice: first before the rehabilitation (study I) and then at the end of rehabilitation program (study II). Functional status was examined with the Barthel ADL Index and the Brunnstrom scale. RESULTS: Both individuals after stroke rehabilitated in hospital and those rehabilitated in environmental conditions achieved a significant improvement in functional of paretic limbs and improving independence in activities of daily living. However, the improvement observed in the hospital group was significantly higher. Better positive effects in patients included hospital rehabilitation is achieved through the implementation of comprehensive treatment of the involvement in the therapeutic process the entire interdisciplinary team. CONCLUSIONS: The comprehensive stationary rehabilitation significantly affected on improving the functional ability of stroke compared to those rehabilitated in environmental conditions. Rehabilitation at home, even though it is associated with certain restrictions is an important element in the overall process of rehabilitation. PMID- 25715572 TI - [The effect of selected physical procedures on mobility in women with rheumatoid arthritis]. AB - Electrotherapy, including iontophoresis and magnetic field, is one of the most commonly used physical procedures in the treatment of rheumatoid arthritis (RS). THE AIM OF THE PAPER: To evaluate the effect of iontophoresis and magnetic field procedures on the intensity and frequency of pain sensation, administration of analgesics, limitation of knee joint mobility and comparative evaluation of analgesic effect s of the applied procedures. MATERIAL AND METHODS: The study included a group of 60 female patients affected by RS with knee joint pain. Patients were randomly assigned to 3 equally-numbered groups. Group I was subjected to 20 iontophoresis procedures. Group II underwent 20 procedures with magnetic field. Group III was treated with 20 procedures combining both iontophoresis and magnetic field. Each iontophoresis procedure lasted 20 minutes, whereas the magnetic field procedure took 30 minutes. All study participants were evaluated in relation to pain sensation after and before the treatment with VAS (Visual Analogue Scale) and Latinen scale. RESULTS: After a 4-week therapy in all the three groups there was a statistically significant decrease in pain perception with VAS scale and with all domains of Laitinen scale excluding the limitation of physical activity criterion. The comparative evaluation of statistically important differences after the therapy between the groups revealed marked decrease of pain perception in groups I and II comparing to group II. There were no significant differences between groups I and III. CONCLUSIONS: Iontophoresis and magnetic field treatments demonstrate effective analgesic property in female patients with rheumatoid arthritis. The conducted studies showed the highest analgesic effects for both treatments used. PMID- 25715573 TI - [The duration of the symptoms of carpal tunnel syndrome to the diagnosis]. AB - Carpal tunnel syndrome (CTS) is the most common entrapment neuropathy. Efficacy of the surgical treatment is dependent on the severity of median nerve injury. THE AIM OF STUDY: To determine the average duration of symptoms to diagnosis CTS. MATERIAL AND METHODS: Survey study conceming the duration of symptoms of CTS to establishing the diagnosis was conducted between 192 consecutive patients with CTS referred to the Electrophysiology Laboratory of the Military Institute of Medicine for the confirmatory EMG testing. The questionnaire included question concerning the duration of symptoms of neuropathy of the median nerve and the selected epidemiological data, i.e., gender, age, place of residence, profession, comorbidities, specialization of referring physician. Nerve conduction parameters of median and ulnarnerves were assessed by means of study ENG/EMG (amplitude, conduction velocity and final latency in motor fibers). Some of the patients had performed comparative tests of the median nerve and ulnar or radial nerves. On the basis of these values the severity of carpal tunnel syndrome was determined according to the Padua's classification. RESULTS: In the group of women surveyed duration of symptoms until diagnosis was on average 39,6 months (from 1 month to 20 years), while in men this time was on average 37.4 months (from I month to 7 years). CONCLUSIONS: The results of this study indicate that the average duration of symptoms CTS until diagnosis is long and can have a negative impact on the results of treatment. PMID- 25715574 TI - [A positive test QuantiFERON-TB Gold In-Tube in a patient treated with continuous ambulatory peritoneal dialysis]. AB - Patients undergoing renal replacement therapy have a higher risk of developing tuberculosis (TBC) in comparison with normal renal function population. The anergy to the tuberculin skin test, the lack of characteristic clinical symptoms of TBC and typical radiographic signs, and high prevalence of extrapulmonary TBC make the diagnosis in dialysis patients difficult and often delay the treatment. In contrast to the active TBC, latent TBC infection (LTBI) is asymptomatic and is not a direct epidemiological problem. However, in patients with end-stage renal disease prepared for renal transplantation, it is an obstacle to qualifying for immunosuppressive therapy. Treatment of LTBI patients with antimycobacterial medication decreases about 90% risk of developing active TB. Therefore, the possibility of a fast and easy identification of LTBI in this group of patients is extremely important. Test QuantiFERON-TB Gold In-Tube (QFT-G) is a new, simple and rapid diagnostic tool in LTBI and active tuberculosis infection (in conjunction with previously used clinical and microbiological methods). This test has been approved and is used in many European countries and in the USA. In a 65 year old patient, treated for 5 years with continuous ambulatory peritoneal dialysis, positive QFT-G results were shownin the course of diagnosis before reporting to the transplant program. After conducting an extensive diagnosis for tuberculosis infection (epidemiological interview, clinical examination, imaging studies, cultures by MB/BacT and the conventional method, consultations with a pulmonologist), latent form of tuberculosis was diagnosed with unspecified location. Due to the positive QFT-G and the need for future immunosuppressive treatment after kidney transplantation, a three-month prophylactic treatment with Rifamazyd 450 mg per day was included. After treatment, the patient entered the waiting list for a kidney transplant. Test QFT-G, in conjunction with other conventional methods is a good and rapid diagnostic tool in the identification of LTBI. PMID- 25715575 TI - [Necrotizing gastritis in a patient in severe neutropenia]. AB - One extremely rare complication of chemotherapy for hematologic malignancies that is burdened with a high mortality rate (50%-80%) is necrotizing gastritis and gastric gangrene as result of poor clinical outcome of neutropenic gastritis (NG). We present a unique case of a neutropenic patient with necrotizing full thickness gastritis due to bacterial and fungal infection. Up to date only few such cases have been reported in world literature. A 28-year-old patient was subjected to dose-escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone), (chemotherapy regimen) for Hodgkin lymphoma. In neutropenic patient abdominal pain, bleeding from the alimentary tract was observed. Hemorrhagic gastritis was recognized at endoscopy and CT demonstrated marked gastric wall thickness. Following NG diagnosis intensive treatment was initiated. On day 2 the patient's condition deteriorated (septic shock, multiple organ failure). Repeat endoscopy revealed gastric necrosis and laparotomy was performed. As consequence of cardiac arrest and cardiopulmonary resuscitation the surgical procedure was limited to total gastrectomy, feeding jejustomy and esophageal drainage through nasoesophageal catherization. Roux-loop esophagojejunostomy was performed on day 22 and supplemented 4 days later by endoscopic placement of covered self-expandable stent due to anastomosis leak. The procedure proved successful and oral feeding was well-tolerated. The patient was discharged in 32 days following recognition of gastric necrosis. Chemotherapy complications in neutropenic patients are life threatening conditions. Immediate pharmacological treatment usually leads to improvement. Surgical management usually the resection of necrotic zones is restricted to cases of poor prognosis or deterioration of patient's condition and complications. PMID- 25715576 TI - [Diagnostic role of galectin-3]. AB - The meaning of galectin-3 role in the diagnostics of different diseases was disscused in the paper. Galectin-3 is endogenous, soluble beta- galactoside binding lectin, which occur in the cell nucleus, the cytoplasm and on the surface of certain cells. Galectin-3 controls cell cycle, modulates adhesion, affects the mRNA splicing, extracellular matrix interactions and cellular differentiation. Galectin-3, also affects to procollagen I which irreversibly crosslinks to form collagen and results in parenchymal organs fibrosis. Taking into account numerous research and knowledge of action mechanism of galectin-3 there were presented changes in its activity in the pathological processes of the human body, including: heart failure, liver fibrosis and tumors. The results of published clinical studies have shown its high diagnostic sensitivity, which probably enables to application in laboratory diagnosis. PMID- 25715577 TI - [Microbial translocation in HIV infection]. AB - Contemporary antiretroviral therapy has significantly improved the prognosis of human immunodeficiency virus (HIV) infected individuals. However, treated individuals manifest increased mortality, compared to general population. This increased mortality seems to be associated with chronic immune activation which persist despite decrease of plasma HIV viremia levels. Recently, translocation of bacterial products from the gastrointestinal tract has been proposed as a major cause of pathological immune activation. PMID- 25715578 TI - [Evaluation of prostate cancer progression]. AB - Prostate cancer occures in male, especially over 65 year old. It develops usually in the peripheral zone, less commonly in central or transitional ones. The neoplasm screening bases on clinical digital rectal examination and serum level of prostate-specific antigen (PSA). Among patients with increase PSA concentration, transrectal ultrasound usually with multiple core biopsies is performed. The obtained bioptates are histologically evaluated using Gleason's grading system. However, the method of choice to examine the entire pelvis is a magnetic resonance. According to current principles, the obtained images are evaluated using five-step PI-RADS classification based on T2-weithed, diffusion weighted and dynamic contrast enhancement images. Spectroscopy is also suggested especially in case of prostatic carcinoma. Such procedures allow precise evaluation of cancer progression, and is helpful in treatment planning and response monitoring. PMID- 25715579 TI - [About the genesis of the first Polish local research ethics committee]. AB - From the moment in which the development of medicine became necessary experimental research involving human subjects, the question arose about the ethical limits and limitations of the experiment. The turning point was the year 1947. The Nuremberg Code was formulated after the disclosure of pseudo-medical experiments involving human subjects during the Second World War. In 1964, the medical world accepted the Declaration of Helsinki, which, however, did not prevent abuses and it became necessary to appoint independent ethics committees supervising and enforcing the application of ethics in biomedical experiments. In Poland in the 60's and 70's started a discussion on the ethical rules related to conduct of research involving humans. The initiators of the appointment of bioethics committees were professors of medicine, inspiring experiences of their Western colleagues. It was difficult for reasons of political ideologies to convince the authorities to use the best of western solutions. This paper attempts to describe the circumstances connected with the appointment in 1979 at the Medical University of Gdansk, the first Polish bioethics committee. PMID- 25715580 TI - [The use of nanotechnology in medicinal products in the light of European Union law]. AB - The purpose of EU regulations in relation to nanotechnology, according to the European Commission's Communication "Regulatory aspects of nanomaterials", is to allow the public to use innovative applications of nanotechnology while ensuring a high level of safety, health care and environmental protection. This article characterizes and comments on EU legislation in respect of medicinal products containing nanomaterials. Medicinal products manufactured using nanotechnology are subject to the optional centralized authorization procedure by the European Commission authorizations for the placing on the market throughout the EU; advanced therapy medicinal products containing nanomaterials are covered by the mandatory centralized procedure. Evaluation of medicines in centralized authorization mode for the marketing of medicinal products, including those containing nanomaterials, is carried out by the Committee on Medicinal Products for Human Use (CHMP) subject to the European Medicines Agency (EMA). PMID- 25715581 TI - [Forming the nanosized molecular assemblies (nanoassociates) is a key to understand the properties of highly diluted aqueous solutions]. AB - In the present study it was shown that biological effects of highly diluted aqueous solutions were due to the formation of nano-sized (up to 400 nm) molecular assemblies, called nanoassociates mainly consisting of aqueous molecules (up to 500 million) under the influence of two effectors: solute and external electromagnetic fields. PMID- 25715582 TI - [Calculation of the amount of free water molecules in aqueous solutions by means of spectral parameters from the terahertz frequency domain taking into account processes of screening]. AB - In this paper we derive a formula to calculate the amount of free water molecules in solution. Physical values in this formula may be obtained by analyzing the spectra of aqueous solutions in the terahertz frequency range. Formula is derived on the basis of considering water polarization process in electric field. It is shown that without processes of shielding the electric field in the water calculations lead to very high estimation of a share of free water molecule. PMID- 25715583 TI - [Partitioning of taxifolin-iron ions complexes in octanol-water system]. AB - The composition of taxifolin-iron ions complexes in an octanol-water biphasic system was studied using the method of absorption spectrophotometry. It was found that at pH 5.0 in an aqueous biphasic system the complex of [Tf2 x Fe x (OH)k(H2O)8-k] is present, but at pH 7.0 and 9.0 the complexes of [Tf2 x Fe x (OH)k(H2O)2-k] and [Tf x Fe x OH)k(H2O)4-k] are predominantly observed. The formation of a stable [Tf3 x Fe] complex occurred in octanol phase. The charged iron ion of this complex is surrounded by taxifolin molecules, which shield the iron ion from lipophilic solvent. During transition from water to octanol phase the changes of the composition of complexes are accompanied by reciprocal changes in portion of taxifolin and iron ions in these phases. It was shown that the portion of taxifolin in aqueous solution in the presence of iron ions is increased at high pH values, and the portion of iron ions is minimal at pH 7.0. In addition, the parameters of solubility limits of taxifolin-iron ions complexes in an aqueous solution were determined. The data obtained gain a better understanding of the role of complexation of polyphenol with metal of variable valency in passive transport of flavonoids and metal ions across lipid membranes. PMID- 25715584 TI - [Structure and radioprotective properties of a non-toxic polysaccharide from Heliantnus tuberosus L]. AB - The data confirming non-toxicity of polysaccharide from Heliantnus tuberosus L. were gained in experimental studies on acute toxicity, the mass and cellularity of the immune system and cell viability of the lymphoid organs. The assumption of the absence of allergenicity was confirmed in the experiment of delayed-type hypersensitivity reaction . Dose reduction factor was specified in the experiment of absolute survival rates. The effectiveness of the substance as a radioprotector was confirmed. NMR spectrum was established, with the use of it a presumptive structure of a matter is restored. PMID- 25715585 TI - [Statistical analysis of big data: an approach based on support vector machines for classification and regression problems]. AB - A new type of learning algorithms with the supervisor for estimating multidimensional functions is considered. These methods based on Support Vector Machines are widely used due to their ability to deal with high-dimensional and large datasets, and their flexibility in modeling diverse sources of data. Support vector machines and related kernel methods are extremely good at solving prediction problems in computational biology. A background about statistical learning theory and kernel feature spaces is given including practical and algorithmic considerations. PMID- 25715586 TI - [The effect of phenols on the parameters of chlorophyll fluorescence and reaction of P700 in the green algae Scenedesmus quadricauda]. AB - The effect of phenols, present in drains of the tsellyulozo-paper industry, on photosynthesis of the microalgae Scenedesmus quadricauda has been studied. The analysis of induction curves of the slowed-down fluorescence and light curves of non-photochemical quenching of chlorophyll fluorescence of microalgae Scenedesmus quadricauda is carried out. It was observed that energization of photosynthetic membranes was inhibited at low concentration of phenol and pyrocatechin (0.1 mM). At higher concentrations phenol and pyrocatechin inhibited electron transport in FSII and increased a share of QB not restoring centers. As a result of it the rate of P700 pigment regeneration slowed down. The results obtained indicate that parameters of induction curves of the fast and slowed-down fluorescence can be used for detecting phenol and pyrocatechin in the environment at early stages of toxic effects. PMID- 25715587 TI - [Silver nanoparticles induce lipid peroxidation and morphological changes in human lymphocytes surface]. AB - To evaluate toxicity of silver nanoparticles synthesized by using the reverse micelle formation method, the effects of nanoparticles on lipid peroxidation and morphological changes of cell membranes in human lymphocytes were studied. It was found that under the influence of nanoparticles a reduction in cell viability and formation of excessive levels of reactive oxygen species were observed. Silver nanoparticles at different concentrations activate the processes of lipid peroxidation and, as a consequence, led to morphological changes in human lymphocytes. PMID- 25715588 TI - [Permeability of isolated rat hepatocyte plasma membranes for molecules of dimethyl sulfoxide]. AB - We have studied permeability of isolated rat hepatocyte membranes for molecules of dimethyl sulfoxide (DMSO) at different hypertonicity of a cryoprotective medium. The permeability coefficient of hepatocyte membranes kappa1 for DMSO molecules was shown to be the differential function of osmotic pressure between a cell and an extracellular medium. Ten-fold augmentation of DMSO concentration in the cryoprotective medium causes the decrease of permeability coefficients kappa1 probably associated with the increased viscosity in membrane-adjacent liquid layers as well as partial limitations appeared as a result of change in cell membrane shape after hepatocyte dehydration. We have found out that in aqueous solutions of NaCl (2246 mOsm/l) and DMSO (2250 mOsm/l) the filtration coefficient L(p) in the presence of a penetrating cryoprotectant (L(pDMSO) = (4.45 +/- 0.04) x 10(-14) m3/Ns) is 3 orders lower compared to the case with electrolyte (L(pNaCl) = (2.25 +/- 0.25) x 10(-11) m3/Ns). This phenomenon is stipulated by the cross impact of flows of a cryoprotectant and water at the stage of cell dehydration. Pronounced lipophilicity of DMSO, geometric parameters of its molecule as well as the presence of large aqueous pores in rat hepatocyte membranes allow of suggesting the availability of two ways of penetrating this cryoprotectant into the cells by non-specific diffusion through membrane lipid areas and hydrophilic channels. PMID- 25715589 TI - [Investigation of membrane permeability of carp spermatozoa for water molecules]. AB - The fundamentals of a photometry method for determination of membrane permeability of some fish spermatozoa for water molecules are presented. Osmotic tolerance of carp spermatozoa membranes was studied using EPR-spectroscopy and photometric analysis methods. It was shown that carp spermatozoa look like the ideal osmometers in their reaction on media of different osmolarity. The value of membrane permeability of carp spermatozoa for water molecules was determined. Data obtained can be used in cryobiology for creating cryoprotective media and regimes of fish sperm cryopreservation. PMID- 25715590 TI - [Effect of adenosine on the shape, aggregates morphology and aggregability of ATP depleted erythrocytes]. AB - The effect of adenosine on the shape, aggregate morphology and aggregability of ATP-depleted erythrocytes was studied. It is shown that the ATP-depletion of erythrocyte leads to the change in their shape: diskocytes transform to echinocytes. It is found that the aggregability of such cells in autoplasma significantly decreased. Incubation of echinocytes with adenosine largely restored discoid shape and erythrocyte aggregability. PMID- 25715591 TI - [Clusters of nonsolvent water in partially destroyed Saccharomyces cerevisiae yeast cells]. AB - The state of water in partially destroyed dry yeast cells has been studied using low-temperature 1H NMR spectroscopy. It has been shown that the residual water is in the form of clusters of strongly and weakly associated water (SAW and WAW, respectively). Three or more types of SAW different in the chemical shift values have been found. It has been established that the interfacial water poorly dissolves hydrochloric and trifluoroacetic acids as well as DMSO and CD3CN. Hydrochloric acid on a surface of biomaterials can be separated into HCl and water. This process is stabilized by polar co-solvents (DMSO and CD3CN) added to the CDCl3 dispersion medium. PMID- 25715592 TI - [Study of some aspects of the mechanism of bacterial synthesis of silver sulfide nanoparticles by mMetal-reducing bacteria Shewanella oneidensis MR-1]. AB - In the present work it was shown that biosynthesis of silver sulfide nanoparticles from silver nitrate and sodium thiosulfate solutions of millimolar concentration occurs efficiently by living Shewanella oneidensis MR-1 cells, as well as by ultrasonically-disrupted cells and by the membrane fraction of the cells. The size of nanoparticles synthesized in the presence of living cells was 7.8 +/- 1.5 nm, while in the presence of ultrasonically-disrupted cells--it was 6.52 nm. The shape of nanoparticles in both cases was close to spherical. It was also shown, that synthesis of nanoparticles occurs in a cell-free solution of sodium thiosulfate that has been incubated with cells previously and to which then a silver nitrate solution was added. In this case the nanoparticles were of elongated shape and their size was (11 +/- 4) x (24 +/- 6) nm. In the control experiment, when only silver nitrate and sodium thiosulfate solutions not incubated with cells were used, the nanoparticles were not detected. It was shown that biosynthesis of nanoparticles occurs both in aerobic and anaerobic conditions. Nanoparticles are not formed by using thermally inactivated cells as it was shown by us previously. The results show the important role of the native structures of cells for the nanoparticles formation. PMID- 25715593 TI - [Anti-tumour activity of dinitrosyl iron complexes with glutathione]. AB - The anti-tumour dose-dependent effect of binuclear dinitrosyl iron complexes with glutathione as NO donors on solid tumour in the mouse Lewis lung carcinome was detected. The complexes being injected at the doses of 21, 42, 105 mg/kg daily during 10 days blocked completely the development of the tumour for the first week after tumour cell implantation into animals. After that, the part of tumour cells which remained in intact alive state began to grow at the rate equal to that for control animals. The effect was proposed to be caused via the formation of the anti-nitrosative defense system in the cells as a response to NO attack to cells. It was also hypothesized that this system can be inactivated by higher doses of dinitrosyl iron complexes. The data were obtained which were in line with the hypothesis. PMID- 25715594 TI - [The heavy ion irradiation influence on the thermodynamic parameters of liquids in human body]. AB - In this manuscript a theoretical model describing the influence of the heavy ion radiotherapy on the liquid matter in the human body is suggested. Based on the fundamental equations of Bogoliubov chain the effective temperatures in the case of constant particles fluent are found in the context of single component model. An existence of such temperatures allows the use of equilibrium thermodynamics formalism to nonequilibrium stationary state. The obtained results provide the possibility of predicting the liquid matter structural changes in the biological systems in the area influenced by the heavy ion beams. PMID- 25715595 TI - [EPR study of iron status in human body during intensive physical activity]. AB - The iron metabolism was studied in serum blood samples collected from 26 professional sportsmen undergoing intensive physical exercises using EPR combined with haematological and biochemical laboratory tests. Only 23% of EPR spectra (n = 6) were practically normal while in the rest spectra additional abnormal absorption lines were detected. Presumably, the significant portion of new signals may be caused by different cytochromes. Moreover, the anisotropic signals with g1 approximately equal to 2.02; g2 approximately equal to 1.94 and g3 approximately equal to 1.86 registered in some spectra pointed to the sulfur-iron centers. There was nearly linear correlation between the concentration of Fe3+ in transfferin (Fe(3+)-Tf) obtained from the EPR spectra and the serum iron concentration measured by absorption photometry both for sportsmen and controls (healthy individuals and patients with different diseases). At equal serum iron concentrations the Fe(3+)-Tf level was higher in sportsmen than that in controls. The Pearson correlation coefficient (r) for Fe(3+)-Tf and serum iron values was equal to 0.89 in sportsmen versus r = 0.97 in controls. Additional new lines in serum EPR spectra of professional sportsmen prove the suitability of EPR assay for scheduled medical exams since routinebiochemical and haematological tests are insufficient to discover all abnormalities in iron metabolism under intensive physical exercises. PMID- 25715596 TI - [Mutagenic activation and carcinogenicity of aminoazo dyes of ortho aminoazotoluene and 3'-methyl-4-dimethylaminoazobenzene in experiments on suckling mice]. AB - It is found that after administration of 3'-methyl-4-dimethylaminoazobenzene (3' Me-DAB,) which was hepatocarcinogenic to rats, in suckling mice, the number of neoplastic lesions in the liver of mice was 3 times higher than after analogous administration of equimolar dose of ortho-aminoazotoluene (OAT)). However, in the Ames test (TA-98 strain of Salmonella typhimurium) with activation by hepatic enzymes (S-9 fraction) of both intact and Aroclor-1254-induced mice and rats OAT contributed by an order of magnitude to revertant colonies compared to 3'-Me-DAB. In vivo inhibition of sulfotransferase activity, the enzyme which catalyzes the final stage of the mutagenic activation of aminoazo dyes, had no effect on carcinogenicity of 3'-Me-DAB but more than 4 times elevated that of OAT. It was concluded that the mechanism of carcinogenic action of aminoazo dyes studied is not genotoxic and that the carcinogenic potential of OAT is lost in the process of mutagenic activation. PMID- 25715597 TI - [Reparative and neoplastic spheroid cellular structures and their mathematical model]. AB - Spheroid cell structures in the cell cultures have been described and are used for studying cell-cell and cell- matrix interactions. At the same time, spheroid cell structure participation in the repair and development of cancer in vivo remains unexplored. The aim of this study was to investigate the cellular composition of spherical structures and their functional significance in the repair of squamous epithelium in human papilloma virus-associated cervical pathology--chronic cervicitis and cervical intraepithelial neoplasia 1-3 degree, and also construct a mathematical model to explain the development and behavior of such spheroid cell structure. PMID- 25715598 TI - [Frequency-decrement electroencephalogram analysis by model of rhythmic processes of bioelectrical activity of the cerebral cortex]. AB - The results obtained earlier showed that the electroencephalogram is represented as convolution of harmonic functions having negative decrements with discrete evenly discontinuous white Gaussian noise. The method of EEG decrements calculation has been proposed and tested on model processes with set-up parameters and on real rat encephalograms. Studies of decrement characteristics along with amplitude-frequency characteristics of encephalograms in different functional states of animals will extend the possibilities of the mathematical processing of brain signals. PMID- 25715599 TI - [Acoustic thermometry of the patient brain with traumatic brain injury]. AB - Non-invasive deep brain acoustic thermometry is carried out for two patients at Burdenko Neurosurgery Institute. This method is based on the measurements of the own thermal acoustic radiation of the investigated object. These two patients have got the brain injury. Some of their skull bones are absent. Infrared thermometry was also used to measure the surface temperature of the forehead skin. On the basis of the experimental data the temperatures deep within the brain were reconstructed. The values for the two patients are equal to 37.3 0.7 and 37.0 0.3 degrees C. PMID- 25715600 TI - [A role of some intracellular signaling cascades in planarian regeneration activated under irradiation with low-temperature argon plasma]. AB - Using inhibitory analysis the role of some intracellular signaling pathways in activation of planarian regeneration under the influence of low-temperature argon plasma (LTAP) has been investigated. Inactivation of specific inhibitors of intracellular signaling enzymes such as the receptor tyrosine kinase (EGFR), TGF beta receptor, calmodulin, adenylate cyclase, phospholipase A2, phospholipase C, cyclin-dependent protein kinase, JAK2-protein kinase, JNK-protein kinase MEK protein kinase led to inhibition of the head growth during its regeneration in planarians. Pretreatment with LTAP irradiation provided no inhibitory action of some cascades regulating proliferation. However, the inhibitors of the key regulators of regeneration: TGF beta receptor, calmodulin and MEK-protein kinase completely suppressed the activating effect of plasma. Thus, by the example of regenerating planarians it is shown, that biological activity of low-temperature argon plasma LTAP is caused by modulation of a plurality of cellular signaling systems. PMID- 25715601 TI - [Terahertz radiation influence on stressed Drosophila life span]. AB - Virgin fruit fly females and males were stressed by placement into a confined space without food for 3 hours. Part of stressed flies were subjected to terahertz irradiation (0.1-2.2 THz) during 30 min. Life span of individual flies was evaluated. Terahertz radiation had some positive influence on male survival during the stage of monotonic decrease in flies number and negative effect during the stage of relatively stable number of flies. The survival of irradiated females on the stage of sharp decline in the number of flies was higher than in stressed and control females. Authors propose that terahertz radiation has an indirect effect on gene expression and signaling pathways which control the survival and life span of Drosophila. PMID- 25715602 TI - [Modeling the occurrence of shellfish poisoning outbreaks caused by Gymnodinium catenatum (Dinophyceae) through electromagnetic signal triggering]. AB - Accumulation of paralytic shellfish poisoning toxins (PSTs) in bivalves attributed to Gymnodinium catenatum blooms at the NW Portuguese coast was previously associated with periods of low solar activity (measured by the radio flux [R]), or low geomagnetic A(a) index. It was also observed that reduction of R preceded the occurrence of toxin accumulation, while A(a) index increase could be related to its absence during periods of low activity. For modeling toxin accumulation, the monthly decrease in R was studied along the decade 2003-2012. A match that helped explaining the highly toxic years of 2007 and 2008 was obtained by plotting the formula: DeltaR = (R(n-1) - R(n))/(R(n) - 65)2, where 65 represented the lowest radio activity known to date. The complex denominator was required to take into account the sunspot cycle. A 1-2 month lag was observed between maximal relative decline and maximal PSTs accumulation. PSTs in bivalves from the Portuguese south coast were related with natural electromagnetic cycles for the first time, and were not statistically associated with low R. A statistically significant association with low A(a) index also was not achieved, due to the low number of occurrences, although the 25-75 percentile was restricted to low Aa indexes in a similar way to that found for the NW coast. PSTs accumulation outside solar minima could be triggered by a steep decline in the A(a) index (DeltaA), but no lag was observed in this case. While DeltaR amplitude helped explaining the highly toxic years of 2007 and 2008 at the NW coast, the amplitude of DeltaA was not related to the severity of the accumulation. Other kind of local electromagnetic signaling was investigated resorting to the occurrence of seismologic phenomena, because these events can trigger electric activities. No statistical association was found between seism number or magnitude and PSTs at the south coast, located near the boundary between the African and Eurasian plates, and marked by moderate seismicity. PMID- 25715603 TI - [Mechanisms of sound reception and conduction in a dolphin]. AB - Morphology of a lower jaw, model and behavioral experiments are discussed with the aim of exploring the mechanisms of sound reception and conduction to the dolphin's lower jaw canals taking into account known concepts of acoustics and a theory of group antennas. It is shown that the left and right row of mental foramens with the respective mandibular canal and tissues of the canals are forming the new outer ear and the new external auditory canal by which the sound (in frequency band of 0.1-160 kHz) is transmitted into the middle ear, in contrast to the dolphin's non-functional outer ear. This new external ear is created by nature as a receiving array of the traveling wave antenna located in the throat of the acoustical horn (a corresponding mandibular canal). The results give reason to assume the presence of similar new outer ear in Odontoceti. PMID- 25715604 TI - [On selection criteria in spatially distributed models of competition]. AB - Discrete models of competitors (initial population and mutants) are considered in which reproduction is set by increasing and concave function, and migration in the space consisting of a set of areas, is described by a Markov matrix. This allows the use of the theory of monotonous operators to study problems of selection, coexistence and stability. It is shown that the higher is the number of areas, more and more severe constraints of selective advantage to initial population are required. PMID- 25715605 TI - [Basic phenomena of "macroscopic fluctuations" are repeated on light beams generated by lasers or light-emitting diodes]. AB - Basic phenomena of the "macroscopic fluctuations are repeated on the light beams generated by lasers or light-emitting diodes. Study of the light beams fluctuations look promissory. PMID- 25715606 TI - [A new hypothesis about the role of water in the mechanisms of morbid obesity formation]. AB - For the first time a comparative analysis is performed for water and fat metabolism in human bodies. In light of known data from the scientific literature on the interconnection of biosynthesis processes of water and palmitic acid, a hypothesis on water and fat mutual circulation in the human body is discussed. It is suggested that one of the possible reasons of morbid obesity may lie in the excessive activation of a system of the endogenous water biosynthesis (that results in the excessive enhancement of the fatty acids biosynthesis) owing to the chronic shortage of the water introduced from the outside. An assumption that the adult morbid obesity can arise as a delayed consequence of the pathological situation of shortage of liquid occurring in early childhood is discussed. PMID- 25715607 TI - [Analysis of mechanism of formation of epidemic variant of disease activator]. AB - Pre-epidemic circulation of a multivariate agent is simulated. An assumption on the possibility of forming a new variant as a combination of properties of circulating variants is examined. PMID- 25715608 TI - [Molecular characteristics and prediction of the reactive properties of the N chlorotaurine analogs]. AB - A number of molecular characteristics for the N-chlorotaurine structural analogs, amino acid chloramines and relative compounds have been computed by the ab initio method B3LYP/6-31G. In particular, the characteristics were the Mulliken atomic charges for the chloramine part and its adjacent atoms. A quantitative measure of the capabilities of the chloramines to react with the methionine sulfide group or sulfhydryl group of reduced glutathione was their reaction rate constants. The constants available in literature and determined in own experiments have been depicted with an exponential equation of multiple correlation. In the case of a reaction with methionine, the high determination coefficient (R2) was obtained with five independent variables. They were the charges of active chlorine, nitrogen, carbon bonded with nitrogen, a bond length between nitrogen and carbon atoms, and also molecular mass. The equation has been used to predict the rate constant values for the reaction between compounds that contain active chlorine and methionine. The prediction has showed that structural analogs of N chlorotaurine bearing two methyl groups at beta-carbon of taurine are remarkable for the low value of the discussed rate constant. PMID- 25715609 TI - [Photophysical properties and photodynamic activity of nanostructured aluminium phthalocyanines]. AB - We developed water-soluble supramolecular complexes of aluminium phthalocyanine based on mesoporous silica nanoparticles and polyvinylpirrolidone containing rare photoactive nanoaggregates. Radiative lifetimes, extinction coefficients and energy of electronic transitions of isolated and associated metal phthalocyanine complexes were calculated. Nontoxic concentrations of synthesized nanocomposite photosensibilizers were in vitro determined. In present study we compared photodynamic treatment efficacy using different modifications of aluminium phthalocyanine (Photosens(r), AlPc-nSiO2 and AlPc-PVP). Mesenchymal stromal cells were used as a model for photodynamic treatment. Intracellular accumulation of aluminium phthalocyanine based on mesoporous silica nanoparticles AlPc-nSiO2 was the most efficient. Illumination of phthalocyanine-loaded cells led to reactive oxygen species generation and subsequent apoptotic cell death. Silica nanoparticles provided a significant decrease of effective phthalocyanine concentration and enhanced cytotoxicity of photodynamic treatment. PMID- 25715610 TI - [Modeling of mechanochemical DNA cleavage by action of ultrasound]. AB - This study offers a simulation of the stretching dynamics of a double-stranded DNA fragment in the high-gradient flow of fluid near collapsing cavitation bubbles. Calculated profiles of elastic tension along the model of a polymer fragment were used to estimate the rates of mechanochemical cleavage at different positions of DNA restriction fragments. The resulting cleavage rate profiles are qualitatively consistent with the experimentally observed profiles of ultrasonic cleavage rates of DNA restriction fragments, which are position-dependent. The proposed model also relates the sequence specificity of ultrasonic DNA cleavage, which was experimentally detected earlier, to the peculiarities of sequence specific conformational dynamics of beta-D-deoxyribose in the B-form double helix. A quantitative assessment of the ultrasonic DNA cleavage rates for different conformational states of beta-D-deoxyribose derived from the proposed model qualitatively agrees with the experimental data. PMID- 25715611 TI - [Distribution of internal parameters of protein hydration shell structure]. AB - Valence and torsion angles distribution was obtained by computer simulation for protein hydration shell and bulk water. These distributions were analyzed. Hydration shell and bulk water have different distributions and we explain it in terms of topology. PMID- 25715612 TI - [Experimental observation of synergetic regular change of chirality sign in the hierarchy of biomimetic structures]. AB - Having investigated chiroptical characteristics of homochiral solutions of biomimetics the rule of changing a chirality sign in spontaneous formation of supramolecular helical structures was experimentally substantiated. This self organization presents evidence of a fundamental synergetic law of changing the chirality sign during the transition to a higher hierarchical level, being of common for modular prebiotic homochiral systems and basic molecular biological systems. PMID- 25715613 TI - [Dynamics of biomacromolecules in coherent electromagnetic radiation field]. AB - It is shown that induced oscillations and periodic displacements of the equilibrium positions occur in biomacromolecules in the absence of electromagnetic radiation absorption, due to modulation of interaction potential between atoms and groups of atoms forming the non-valence bonds in macromolecules by the external electromagnetic field. Such "hyperoscillation" state causes inevitably the changes in biochemical properties of macromolecules and conformational transformation times. PMID- 25715614 TI - [Insulin-like growth factor 1-induced changes in hemoporphyrin conformation in hemoglobin and NO-transporting function in human erythrocytes]. AB - The evidence on the effect of different insulin-like growth factor concentrations on a state of human erythrocytes is provided. Activation of the insulin-like growth factor receptors led to changes in the conformation of hemoglobin, NO transporting function in erythrocytes and also in micro-viscosity of the cell membrane. It was shown for the first time that at the binding of the insulin-like growth factor to a cell surface, hemoglobin of erythrocytes alters its conformations and affinity to ligands. PMID- 25715615 TI - [Analysis of thermal phenomena in erythrocytes from scorpionfish (Scorpaena porcus L.)]. AB - The ability of erythrocytes from marine teleost scorpionfish (S. porcus L.) to produce heat was investigated in vitro with the help of a special designed cell, built with a sensitive temperature sensor HEL-700. It is shown that a suspension of washed red blood cells produced heat for a long time, but with the addition of extracellular ATP the phenomenon of thermal spike was observed. It is assumed that the observed effect is provided by ATP cleavage with generation of heat by ecto-ATPase of the plasma membrane of red blood cells of fish. PMID- 25715616 TI - [Changes in lymphocytes under influence of oxidative substrates]. AB - Blood lymphocytes of children with oncology diseases were studied in smears compared with healthy ones examined from the closely selected group. The following two methods were used: the traditional in hematology method of smear staining for detection of blood formula and lymphocyte indices and the staining with novel cytobiochemical method including 60-min incubation in biochemical medium for estimation of the activity of succinate dehydrogenase, lactate dehydrogenase and their ratio, that can serve as a measure of respiration and glycolysis--Warburg effect, typical of tumor. The great increase in lymphocyte size by addition of lactate was found in blood smears of patients with tumors. This effect was not pronounced by addition of succinate and in cells of healthy persons. Changes in the structure of the cells in patients were also related to the changes in the activity of enzymes studied. These changes can be considered as transition of metabolism and the structure of cells to the state in tumor. Cytobiochemical method allows for higher diagnostic sensitivity of patient examination and efficiency of medical care of patients with oncological diseases. PMID- 25715617 TI - [Effect of magnesium, acetylsalicilic acid and emoxypine on aggregation of platelets]. AB - The thrombin-induced platelet aggregation was studied in the absence and presence of magnesium sulfate, acetylsalicylic acid and emoxypine. It was found that all the preparations studied were able separately to decrease platelet aggregation. In contrast, their joint action was not able to affect the aggregation of platelets. The data obtained can be used to choose the treatment strategy for patients with ischemic stroke. PMID- 25715618 TI - [On specific properties of the mitochondrial oxidative phosphorylation system operating as a supercomplex]. AB - This paper represents the study of endogenous and exogenous fatty acids affecting the mitochondrial phosphorylation system effectiveness depending on temperature. The experiment was set up under conditions in which the oxidative phosphorylation system operates as a supercomplex. Rat liver mitochondria were isolated without purposive fatty acids removal from membranes, then studied in hypotonic medium (120 mOsm). We managed to detect a very narrow interval 19 +/- 1 degrees C where the fatty acid uncoupling effect is weak up to disappearing. At the same small temperature range, a structural rearrangement that takes place in the enzyme system is accompanied with denser packing of membrane protein complexes. Thus, at the temperatures close to 19 degrees C the supercomplex works in the specific regime protected (or partially protected) from the uncoupling effect of fatty acids. Here we also discuss a physiological significance of the increased ATP synthesis effectiveness at lower temperatures and the most probable character of structural rearrangement taking place at 19 degrees C in the enzymes in the mitochondrial membrane. PMID- 25715619 TI - [On efficient in vitro purification of cell suspensions containing malignant cells]. AB - We propose a method for magnetic sorting of cell suspensions able to differentiate not only cells with single specific antigen on their surface, but also cells with a group of pre-defined antigens. Individually, each antigen of this group may be present on surfaces of non-selected cells. However, only the simultaneous presence of all given antigens on the cell surface means that such a cell should be separated. The method is of interest, for purification of cell suspensions from malignant cells, in particular, for purification of bone marrow material for autologous transplantation in leukemia. PMID- 25715620 TI - [The process of heme synthesis in bone marrow mesenchymal stem cells cultured under fibroblast growth factor bFGF and hypoxic conditions]. AB - It was demonstrated that fibroblast growth factor bFGF influences the process of heme synthesis, the proliferation activity and viability of bone marrow mesenchymal stem cells in culture under hypoxic conditions. The addition of fibroblast growth factor bFGF (7 ng/ml) to the medium under above conditions led to the accumulation of aminolevulinic acid--an early porphyrin and heme precursor, an increase in CD 71 expression--a transferrin receptor, and also a decrease in porphyrin pigments and heme contents--a late precursor and end products of heme synthesis, respectively. It was found that cultivation of the cells under hypoxic conditions and bFGF is an optimum to maintain high viability and proliferation capacity of the mesenchymal stem cells. PMID- 25715621 TI - [Relation of hydrophobicity index of microbial cells to their biofilm-forming ability]. AB - By examining cell adhesion to n-hexadecane the hydrophobicity index of S. aureus, E. coli and P. aeruginosa was measured. It has been established that the increase in the hydrophobicity of the microbial cells reduces their ability to form a biofilm. It is shown that the divalent metal ions are capable of increasing the hydrophobicity index of microbial cells and reducing biofilm formation. It is concluded that it is necessary to use materials with a negatively charged surface for biofilm preventive measures. PMID- 25715622 TI - [Comparative analysis of syngeneic and allogeneic transplantation without irradiation of the EGFP+ mice bone marrow cells with microspectral fluorescence method]. AB - The experimental results on syngeneic and allogeneic transplantation of whole fraction of mice bone marrow cells without irradiation have been presented. Data on the dynamics of the donor cell colonization of bone marrow, spleen, thymus and blood of the recipient mice were obtained. The degree of immunogenicity of donor cells with syngeneic and allogeneic bone marrow transplantation based on the microspectral fluorescence method was evaluated. Within the framework of the experiment a low degree of immunogenicity of donor cells with syngeneic and allogeneic transplantation is shown. Importantly, allogeneic bone marrow transplantation did not cause any reduction in the mean life span of mice. These data and the results of our previous studies, demonstrating the mean life span increased by 34% with syngeneic transplantation in line C57BL/6 EGFP+, allow for developing different methods of cell therapy with no risk of fatal consequences of the immunological incompatibility between donor and recipient. PMID- 25715624 TI - [The behavior of male Danio rerio after exposure of fish embryos to a simulated geomagnetic storm]. AB - Embryos of the zebrafish, Danio rerio, were exposed to a simulated geomagnetic storm during 24 hours. Fish, developed from these embryos, left a start chamber to an aquarium more readily in comparison to those reared in a normal geomagnetic field. On the other hand, general locomotor activity in fish was not essentially different between the two groups. We hypothesize that an exposure to a geomagnetic storm during embryonic period results in enhanced tolerance to stress caused by a novel environment. A low level stress is in turn a subject to further exploration. PMID- 25715623 TI - [Spectral analysis of self-oscillating motility in isolated plasmodial strand of Physarum polycephalum]. AB - In this study the experimental dependencies of the velocity of shuttle endoplasmic motion in the isolated plasmodial strand of Physarum polycephalum obtained by laser Doppler microscopy are presented. The spectral analysis of the time dependencies of the endoplasm allows obtaining two distinct harmonic components. Influence of KCN and SHAM--inhibitors of cellular respiration--leads to a complete cessation of endoplasmic motion in the strand. After removal of the inhibitors the respiratory system becomes normal, gradually restoring the activity of both harmonic oscillation sources. Based on the spectral analysis the simulated time-dependent velocity of the endoplasmic motion is rather good consistent with experimental data. PMID- 25715625 TI - [Modulating effect of weak combined magnetic fields on duration of mealworm beetle Tenebrio molitor metamorphosis stage]. AB - It is shown that an exposure of pupae of the mealworm beetle Tenebrio molitor to the combined static (42 MUT) and very weak alternating (250 nT) magnetic fields exerts different influence, depending on the frequency of the alternating magnetic field, on duration of metamorphosis processes in these insects. For instance, an exposure of pupae to weak combined magnetic fields, adjusted to the frequency of ion cyclotron resonance for glutaminic acid (4,4 Hz), stimulates metamorphosis process--a transitional stage from pupae to imago lasts shorter. An inhibiting effect was observed when adjusted to the frequency of ion cyclotron resonance for Ca2 (32,2 Hz). At some frequencies this effect is not seen. For instance, an exposure at a frequency of ion cyclotron resonance for K+ (16,5 Hz) exerts no noticeable effect on the duration of the pupal metamorphosis stage. PMID- 25715626 TI - [Antitumor action and other regulatory effects of low intensity electromagnetic and chemical factors in experiment]. AB - This paper presents a brief overview of the results of the original researches of biological responses induced by agents of cytostatic and regulatory actions in small doses, as well as weak electromagnetic radiation of different frequency bands. The possibility of obtaining the expressed antitumor, antistress and geroprotective effects has been shown. The question of the relation of system mechanisms of realization of these effects with structural rearrangements in biological fluids, as well as the promising directions for optimizing the therapeutic properties of the informational impacts are discussed. PMID- 25715627 TI - [Influence of dinitrosyl iron complexes on blood metabolism in rats with thermal trauma]. AB - The dynamics in the oxidative and energy metabolism and enzyme systems of blood detoxification in animals with thermal trauma injected with dinitrosyl iron complexes was explored. The positive effect of dinitrosyl iron complexes on the state of blood pro- and antioxidant systems in animals with experimental thermal injury having profound oxidative stress is shown. This effect is observed as a considerable reduction of the intensity (normalization) of lipid peroxidation processes against significant elevation of antioxidant potential of blood plasma. This tendency was also fixed in erythrocyte membranes. It is also stated, that dinitrosyl iron complexes clearly normalized erythrocyte energy metabolism already by the 3rd day after trauma. In addition, infusions of dinitrosyl iron complexes caused marked stimulation of aldehyde dehydrogenase catalytic activity in burned rats via mechanism, associated with enzyme detoxification properties. PMID- 25715628 TI - [Computer modeling of parametric stability of heart rate dynamics during atrial fibrillation]. AB - Parametric stability of heart rate dynamics during atrial fibrillation was estimated in relation to the change in the parameter of the curvature of delay function in the atrioventricular node. The study was conducted by the method of computer modeling. We investigated the dependence of characteristics of stability of heart rate dynamics from the number of independent ectopic sources in the atrium during fibrillation. The results show that the stability of heart rate dynamics decreases as the number of independent ectopic sources in the atrium and the parameter of the curvature of delay function in the atrioventricular node increase. PMID- 25715629 TI - [Synchronization in human heart rate dynamics and Pc5 geomagnetic pulsations at different latitudes]. AB - Eight experiments were conducted in synchronized monitoring of cardiac indices in six healthy women at rest simultaneously in three geographic locations--Sofia, Moscow and Arkhangelsk. Comparing spectra of the dynamic time series of the pulse and variations in the horizontal component of the geomagnetic field vector in the frequency range of Pc5 geomagnetic pulsations showed that the main oscillation periods represented in physiological and geophysical time series at each time moment largely coincide. This effect was observed roughly to an equal extent for volunteers who underwent the measurements in all three geographic locations. PMID- 25715630 TI - [Quasi-periodic behavior of intermolecular interactions in water]. AB - We investigated the dynamics of physical characteristics of water by applying various methods of molecular structural analysis: IR spectroscopy, Raman spectroscopy, microwave radiometry and NMR. It was established that the changes in the physical characteristics of water are subject to certain laws. In all experiments, the periods of oscillations of the measured values showed good similarity and reproducibility, regardless of the method of analysis. The values of these periods are as follows: 1-3, 5-9, 10-13, 14-18, 21-29, 30-39, 41-55 and ~60 minutes. The amplitudes of these oscillations vary up to 10%. Based on the two-structure water model the observed quasi-periodic intermolecular interactions can be associated with the dynamics of mutual transitions between local structural inhomogeneities of water. The observed periodic character of intermolecular interactions can presumably be linked to the change in the ratio between the spin isomers of water molecules. The article discusses the connections between variations of the physical properties of water and biorhythms. PMID- 25715631 TI - [H2O ortho-para spin conversion in aqueous solutions as a quantum factor of Konovalov paradox]. AB - Recently academician Konovalov and co-workers observed an increase in electroconductivity and biological activity simultaneously with diffusion slowing (or nanoobject diameter increasing) and extremes of other parameters (zeta potential, surface tension, pH, optical activity) in low concentration aqueous solutions. This phenomenon completely disappeared when samples were shielded against external electromagnetic fields by a Faraday cage. A conventional theory of water and water solutions couldn't explain "Konovalov paradox" observed in numerous experiments (representative sampling about 60 samples and 7 parameters). The new approach was suggested to describe the physics of water and explain "Konovalov paradox". The proposed concept takes into account the quantum differences of ortho-para spin isomers of H2O in bulk water (rotational spin selectivity upon hydration and spontaneous formation of ice-like structures, quantum beats and spin conversion induced in the presence of a resonant electromagnetic radiation). A size-dependent self-assembly of amorphous complexes of H2O molecules more than 275 leading to the ice Ih structure observed in the previous experiments supports this concept. PMID- 25715632 TI - [A long-liver and a knight of science B. I. Hodorov (17.01.1922-05.07.2014)]. PMID- 25715633 TI - Specific role of dopamine in striatum during instrumental learning. AB - Research of dopamine's role in behavior is seemingly in a state of permanent controversy over all major topics. The notion of 'prediction error' is a central component of current reward leaning models, but there are many caveats and contradictions in supporting data. In this paper we propose that the same dopamine signal can promote action and reinforce this action, and outline novel model of reward learning in which dopamine provides a kind of teaching signal with DA release starting well before and persisting beyond the to-be reinforced action. The post-response signal that provides the true excitatory drive for LTP comes from intralaminar thalamus. The main part of hypothesized mechanism constitutes the direct pathway of striatal projection neurons and there are reasons to believe that the indirect pathway has the essential possibility to modulate the direct pathway, thus providing behavioral flexibility. PMID- 25715634 TI - [Neuroimmunological aspects of the pathogenesis of epilepsy]. AB - The review is devoted to the analysis of neuroimmunological aspects of the pathogenesis of epilepsy. Discuss the pathogenetic role of proinflammatory cytokines, antibodies to antigens of the nervous tissue and neurotransmitters, such as dopamine, serotonin, glutamate and GABA in the pathogenesis of epilepsy. The focus of the review is given to clinical research, devoted to the interrelation of the severity of the disease and changes of immunological indices. Disorders of the immune system are most pronounced in drug-resistant forms of epilepsy. Describes the clinical and experimental research, which shows that the use of antiepileptic drugs improves immunity. The use of immunotherapy in combination with anti-epileptics drugs leads to positive results. Thus, the analysis of the immune status of patients with epilepsy can serve as an important criterion for determining the severity of the disease and the appointment of adequate treatment. The authors analyze their own data of anticonvulsant activity of antibodies to glutamate and opposite proconvulsant effect of antibodies to GABA. PMID- 25715635 TI - [Animal experiments and the major achievements in the history of biomedicine]. AB - It is shown that major achievements in the history of biomedicine, obtained in experiments on animals: the discovery of blood circulation, the achievements of microbiology and development of the concept of immunity, the discovery of reflex and the doctrine of higher nervous activity, achievements of genetics, formation of modeling methods on animals and drug testing. It is stressed that the benefits for science and medicine, obtained through experimentation on animals, does not relieve scientists from responsibility. PMID- 25715636 TI - [Involvement of the dopaminergic system in the mechanisms of immunomodulation]. AB - This review considers functional organization of the brain dopaminergic (DAergic) system--DA-metabolism, major DA-pathways, classification and functions of DA receptors. Involvement of the DAergic system including D1- and D2-receptors in the mechanisms of immunostimulation, ways of the realization and intraimmune mechanisms underlying DAergic immunomodulation also discussed. PMID- 25715637 TI - Overexpression of toll-like receptor 2 in glomerular endothelial cells and podocytes in septic acute kidney injury mouse model. AB - Acute kidney injury (AKI) is one of the most common complications in patients with severe sepsis. The development of septic AKI increases patients' mobility and even mortality. Toll-like receptor 2 (TLR2), as a membrane surface receptor for bacterial, fungal, viral and certain endogenous substances, has been described to contribute to the development of septic AKI; however, the renal cell types associating TLR2 overactivation in septic AKI has not been described. In the current study, we investigated the TLR2 activation patterns in the kidney of lipopolysaccharide-induced septic AKI mice. Our results demonstrated that mRNA level of TLR2 significantly increased in the kidney of lipopolysaccharide-treated mice. Immunohistochemistry revealed the overactivation of TLR2 in the glomeruli. Double immunofluorescence analysis shows the precise distribution of TLR2 by showing the colocalization of TLR2 in glomeruli with synaptopodin, a podocyte marker, and Tie2, an endothelial marker. In addition, proapoptotic molecules Bax and Caspase-3 were increased in the glomeruli of lipopolysaccharide-treated mice. Together, the current study indicates that TLR2 is overactivated in the glomerular endothelial cells and podocytes in septic AKI mice, while the abundance of Bax and Caspase-3 were increased in the glomeruli of these mice, it may supply a clue that TLR2 induced these cell apoptosis in AKI. This finding provides an alternative mechanism to understand AKI development and potential targets for treatment. PMID- 25715638 TI - Individualized scheme of immunoadsorption for the recurrence of idiopathic focal segmental glomerulosclerosis in the graft: a single center experience. AB - OBJECTIVES: To explore the role of immunoadsorption (IA) for the treatment of idiopathic focal segmental glomerulosclerosis (FSGS) recurrence in the renal allograft, if applied in a personalized manner. METHODS: We studied patients with end-stage renal disease (ESRD) due to idiopathic FSGS, transplanted between 2001 and 2010. Patients with FSGS recurrence were treated with daily sessions of IA for the first week, followed by an every other day scheme and then individualized tapering until discontinuation. Complete remission was defined as a reduction of 24-h proteinuria to <= 0.5 g/day and partial remission as a reduction of 24-h proteinuria to 50% or more from baseline. RESULTS: Of the 18 renal transplant recipients with ESRD due to idiopathic FSGS, 12 (66.7%) experienced disease recurrence in a mean time of 0.75 months post-transplantation (KTx), with a mean proteinuria of 8.9 g/day at the time of recurrence. The mean recipient age was 30.8 years; the mean donor age was 47.4 years, while living related donors provided the allograft in seven cases. Four of the patients received therapy with rituximab in addition to IA. During a mean time of follow-up of 48.3 months, seven patients (58.3%) achieved complete remission, and five (41.7%) partial remission. At the end of follow-up, eight patients (66.7%) had functioning grafts, being in sustained remission, in contrast to four patients (33.3%), who ended up in ESRD because of FSGS recurrence. CONCLUSIONS: IA was shown efficacious in a small series of patients with recurrent FSGS in the graft. Renal function remained stable in eight of the 12 patients with FSGS recurrence. PMID- 25715639 TI - Mood and illness experiences of adults with cystinosis. AB - BACKGROUND: Cystinosis is an autosomal recessive disorder with an estimated incidence of 1/100,000-200,000 live births. The main complications are renal disease, visual impairment, endocrine abnormalities and growth retardation. OBJECTIVE: Our aim was to describe the mood and illness experiences of adults with cystinosis. METHODS: Twenty-three patients attending the adult cystinosis clinic at Guy's Hospital, London were asked to complete the Hospital Anxiety and Depression Scale (HADS) questionnaire anonymously. Eighteen months later, 21 patients who were still alive were invited to participate in a semi-structured interview aimed at exploring illness experience. RESULTS: Eighteen patients completed the HADS questionnaire (means: depression = 7.2; anxiety = 9.2), and 12 participated in the interviews. Three significant themes emerged: (i) the main physical complaints were tiredness, the impact of short stature and side effects of cysteamine medication, especially halitosis, poor taste and nausea. (ii) Cystinosis has a major impact on relationships, autonomy and social life, including reliance on families for support to self-manage, distress at dependence, social anxiety, reduced social involvement and some positive effects on family cohesiveness. (iii) Patients use a range of individual coping strategies to deal with their illness and medication. CONCLUSIONS: Adult cystinosis patients reported comparatively high-anxiety and depression scores. Common complaints related to the complications of cystinosis and the side-effects of cysteamine, which impacted on relationships, autonomy and social life. Patients described a wide range of strategies, including benefit finding, for coping with cystinosis. PMID- 25715640 TI - Effect of oxygen on neuronal excitability measured by critical flicker fusion frequency is dose dependent. AB - INTRODUCTION: Reactive oxygen species are involved in the functional changes necessary for synaptic plasticity, memory, and cognitive function. It is far from clear whether the increased excitability, and which forms of neuronal excitability, should be considered a part of the learning process or, rather, cellular manifestation of neuronal oxygen poisoning. It is yet to be elucidated whether oxygen (O2)-induced learning and poisoning use the same or distinct cellular pathways. PURPOSE: We hypothesized that O2-induced neuronal excitability might use the same or an intertwined signaling cascade as the poisoning cellular pathway. METHOD: Eighty-one healthy, young males, mean age 27.7 +/- 4.1 (SD) years, were exposed in the hyperbaric chamber to 0.7 atmosphere absolute (ATA) O2, 1.4 ATA O2, and 2.8 ATA O2. The critical flicker fusion frequency (CFFF), oxyhemoglobin saturation (SiO2), and heart rate (HR) were measured before exposure, after 30 min of oxygen breathing while still at pressure and then after exposure. RESULTS: Normobaric (0.7 ATA) O2 exposure did not affect CFFF and HR. Medium hyperbaric O2 exposure (1.4 ATA) decreased CFFF but HR remained unchanged. High hyperbaric O2 exposure (2.8 ATA) increased CFFF and diminished HR. SiO2 was similar in all investigated groups. A correlation between CFFF, HR, and SiO2 was observed only at low oxygen (0.7 ATA). CONCLUSIONS: The effect of O2 on neuronal excitability measured by CFFF in young healthy men was dose dependent: 0.7 ATA O2 did not affect CFFF; CFFF were significantly jeopardized at 1.4 ATA O2, while CFFF recovered at 2.8 ATA. With 2.8 ATA O2, the CFFF and oxygen poisoning transduction pathways seemed to be intertwined. PMID- 25715641 TI - Sleep during the third trimester of pregnancy: the role of depression and anxiety. AB - Depression has been associated with sleep disturbances in pregnancy; however, no previous research has controlled the possible confounding effect of anxiety on this association. This study aims to analyze the effect of depression on sleep during the third trimester of pregnancy controlling for anxiety. The sample was composed by 143 depressed (n = 77) and non-depressed (n = 66) pregnant women who completed measures of depression, anxiety, and sleep. Differences between groups in sleep controlling for anxiety were found. Depressed pregnant women present higher number of nocturnal awakenings and spent more hours trying falling asleep during the night and the entire 24 h period. Present findings point out the effect of depression on sleep in late pregnancy, after controlling for anxiety. PMID- 25715642 TI - [Canaloplasty and other non-penetrating glaucoma operations]. PMID- 25715643 TI - [Canaloplasty after trabeculectomy]. AB - BACKGROUND: Canaloplasty after failed trabeculectomy is an operation with differing individual surgical situations, which depend on the extent of scarring in the preexisting bleb area and on the site of the fistula in the chamber angle itself. OBJECTIVE: The results of 18 cases and the surgical technique are presented. PMID- 25715646 TI - Left lateral liver lobe torsion in a cat with moderate pectus excavatum. AB - A 6-year-old neutered female domestic shorthair cat weighing 3.1 kg was referred to the clinic owing to a 2 day history of anorexia. On physical examination, a pectus excavatum (PE) was apparent, and a cranial abdominal mass was palpated. Serum biochemical analysis showed severely elevated liver enzymes. On radiography, the PE was graded as moderate, and a 5 * 3 cm soft tissue density mass was detected in the cranial abdomen. Using duplex ultrasonography, the mass was identified as an enlarged liver lobe with vascular thrombosis. The diagnosis of liver lobe torsion (LLT) was confirmed surgically, and the affected left lateral lobe was resected. On follow-up, performed 1 and 6 months postoperatively, no further abnormalities were found on clinical examination or serum biochemical analysis. At follow-up examination, the PE did not appear to cause any additional clinical signs, indicating that treatment of moderate PE in older animals is not obligatory. This is the first reported case of LLT with concurrent PE, and the second feline case of LLT treated surgically. Animals with anatomical malformation of the diaphragm caused by PE may be at higher risk of developing LLT. Early diagnosis and surgical intervention of LLT can produce a good clinical outcome without further repercussions. PMID- 25715645 TI - Fatigue and self-care in patients with chronic heart failure. AB - BACKGROUND: Fatigue is a debilitating and highly prevalent symptom in patients with chronic heart failure (HF) possibly complicating HF self-care behaviour which is crucial for maintaining health. AIMS: The purpose of this study was to examine whether general and exertion fatigue are distinctively associated with self-care in patients with chronic HF. METHODS: In total, 545 outpatients with chronic HF (mean age=66.2 years; 75% male) completed measures of general fatigue (i.e. a sustained sense of exhaustion including mental efforts), exertion fatigue (i.e. fatigue directly related to physical activity), sleep problems, mood symptoms and HF self-care behaviour at baseline, 12-, and 18-month follow-up. RESULTS: Linear mixed modelling results showed that general and exertion fatigue were significantly associated with poor HF self-care (estimate=0.10, p=0.004; estimate=0.06, p=0.01, respectively) and poor consulting behaviour (estimate=0.05, p=0.04; estimate=0.04, p=0.007, respectively) over time, independent of sleep and mood problems, and other clinical covariates. Exertion fatigue was associated with supplementary determinants. CONCLUSION: This is the first prospective study demonstrating that general and exertion fatigue were both associated with poor HF self-care, which could not be explained by sleep problems or mood symptoms, and was independent of clinical indicators of disease severity. Treatment of fatigue problems may improve HF self-care skills and ultimately quality of life and cardiovascular outcomes. Further research is needed to examine this potential causal relationship. PMID- 25715644 TI - Human infections with Sarcocystis species. AB - Recurrent outbreaks of muscular sarcocystosis among tourists visiting islands in Malaysia have focused international attention on sarcocystosis, a disease once considered rare in humans. Sarcocystis species require two hosts, definitive and intermediate, to complete their life cycle. Humans can serve as definitive hosts, with intestinal sarcocystosis for two species acquired from eating undercooked meat: Sarcocystis hominis, from beef, and Sarcocystis suihominis, from pork. Symptoms such as nausea, stomachache, and diarrhea vary widely depending on the number of cysts ingested but appear more severe with pork than with beef. Humans serve as intermediate hosts for Sarcocystis nesbitti, a species with a reptilian definitive host, and possibly other unidentified species, acquired by ingesting sporocysts from feces-contaminated food or water and the environment; infections have an early phase of development in vascular endothelium, with illness that is difficult to diagnose; clinical signs include fever, headache, and myalgia. Subsequent development of intramuscular cysts is characterized by myositis. Presumptive diagnosis based on travel history to tropical regions, elevated serum enzyme levels, and eosinophilia is confirmed by finding sarcocysts in muscle biopsy specimens. There is no vaccine or confirmed effective antiparasitic drug for muscular sarcocystosis, but anti-inflammatory drugs may reduce symptoms. Prevention strategies are also discussed. PMID- 25715647 TI - Use of HIV point-of-care testing within a Queensland clinical setting. PMID- 25715648 TI - Procedural sedation in the emergency department. AB - Procedural sedation options in the emergency department now allow for more effective and safer care and facilitate the delivery of orthopaedic care that would otherwise require operating room anesthesia. Traditional sedation agents, such as nitrous oxide, midazolam, fentanyl, and ketamine, have a persistent role. Etomidate and propofol are relatively recent additions that are highly effective. Combination regimens, such as ketamine-midazolam and ketamine-propofol, may be superior because they benefit from synergistic traits. Despite these sedation regimens, use of local blocks in adults continues to be effective, and intranasal delivery in children has emerged as a viable option. Orthopaedic surgeons should be aware of the appropriateness of different sedation regimens and other options for specific clinical scenarios. PMID- 25715650 TI - Hyperferritinemia is associated with short survival time in dogs with multicentric lymphoma. AB - In the present study, we examined the relationship between serum ferritin concentration before treatment and survival time in dogs with multicentric lymphoma. Eighteen dogs with multicentric lymphoma were enrolled in the study. When the dogs were classified into high and low ferritin groups on the basis of their serum ferritin concentration (3,000 ng/ml cut-off value), the median survival time of dogs with high concentrations (>=3,000 ng/ml, n=7) was 40 days, whereas it was 360 days among dogs with low concentrations (<3,000 ng/ml, n=11). This difference was statistically significant (P=0.001). This finding suggests that the initial high level of serum ferritin indicates short survival time in dogs with multicentric lymphoma. Large-scale research is necessary to confirm this finding. PMID- 25715649 TI - Let-7 and miR-125 cooperate to prime progenitors for astrogliogenesis. AB - The molecular basis of astrocyte differentiation and maturation is poorly understood. As microRNAs have important roles in cell fate transitions, we set out to study their function during the glial progenitor cell (GPC) to astrocyte transition. Inducible deletion of all canonical microRNAs in GPCs in vitro led to a block in the differentiation to astrocytes. In an unbiased screen, the reintroduction of let-7 and miR-125 families of microRNAs rescued differentiation. Let-7 and miR-125 shared many targets and functioned in parallel to JAK-STAT signaling, a known regulator of astrogliogenesis. While individual knockdown of shared targets did not rescue the differentiation phenotype in microRNA-deficient GPCs, overexpression of these targets in wild-type GPCs blocked differentiation. This finding supports the idea that microRNAs simultaneously suppress multiple mRNAs that inhibit differentiation. MicroRNA regulated transcripts exhibited concordant changes during in vivo differentiation and were enriched for a gene set upregulated in glioblastomas, consistent with validity of using the in vitro model to study in vivo events. These findings provide insight into the microRNAs and the genes they regulate in this important cell fate transition. PMID- 25715651 TI - CCL2 induces neural stem cell proliferation and neuronal differentiation in Niemann-Pick type C mice. AB - Niemann-Pick type C disease (NP-C) is a rare and ultimately fatal lysosomal storage disorder with variable neurologic symptoms. Loss of neuronal function and neuronal cell death occur in the NP-C brain, similar to the findings for other neurodegenerative diseases. Targeting of neuronal cells in the brain therefore represents a potential clinical intervention strategy to reduce the rate of disease progression and improve the quality of life. We previously reported that bone marrow stem cells show a neurogenic effect through CCL2 (also known as monocyte chemoattractant protein-1, MCP-1) secretion in the brains of NP-C mice. However, the direct effect of CCL2 on neurogenesis has not been ascertained. Here, to define neurogenic effects of CCL2 in NP-C, we applied human recombinant CCL2 to neural stem cells (NSCs) derived from NP-C mice. CCL2-treated NSCs showed significantly increased capacity for self-renewal, proliferation and neuronal differentiation. Similar results were observed in the subventricular zone of NP-C mice after CCL2 treatment. Furthermore, infusion of CCL2 into the NP-C mouse brain resulted in reduction of neuroinflammation. Taken together, our results demonstrate that CCL2 is a potential new therapeutic agent for NP-C. PMID- 25715652 TI - Acetazolamide-induced myokymia. PMID- 25715654 TI - People with depression are more likely to commit violent crime, study concludes. PMID- 25715653 TI - Genome-Wide Profiling of TRACK Kidneys Shows Similarity to the Human ccRCC Transcriptome. AB - Renal cell carcinoma (RCC) is the most common cancer arising from the kidney in adults, with clear cell RCC (ccRCC) representing the majority of all RCCs. Expression of a human HIF1alpha triple-mutant (P402A, P564A, and N803A) construct in the proximal tubule cells of C57BL/6 mice [TRAnsgenic model of Cancer of the Kidney (TRACK); ref. 1] mimics the histologic changes found in early stage human ccRCC. To better understand the genomic landscape, a high-throughput sequence analysis was performed with cDNA libraries (RNAseq) derived from TRACK transgenic positive (TG(+)) kidney cortex along with human ccRCC transcripts from the Oncomine and The Cancer Genome Atlas databases. Importantly, the expression profiles of TRACK TG(+) kidneys show significant similarities with those observed in human ccRCC, including increased expression of genes involved in glycolysis and the tricarboxylic acid cycle. Some of the transcripts overexpressed in both the TRACK mouse model and human ccRCC include ANKRD37, CA9, EGLN3, HK2, NDUFA4L2, and SLC16A3. These data suggest that constitutive activation of HIF1alpha in kidney proximal tubule cells transcriptionally reprograms the regulation of metabolic pathways in the kidney and that HIF1alpha is a major contributor to the altered metabolism observed in human ccRCC. IMPLICATIONS: TRACK (GGT-HIF1alphaM3) kidney mRNA profiles show similarities to human ccRCC transcriptome and phenotypes associated with the Warburg effect. PMID- 25715655 TI - Rate-dependent phase transitions in Li2FeSiO4 cathode nanocrystals. AB - Nanostructured lithium metal orthosilicate materials hold a lot of promise as next generation cathodes but their full potential realization is hampered by complex crystal and electrochemical behavior. In this work Li2FeSiO4 crystals are synthesized using organic-assisted precipitation method. By varying the annealing temperature different structures are obtained, namely the monoclinic phase at 400 degrees C, the orthorhombic phase at 900 degrees C, and a mixed phase at 700 degrees C. The three Li2FeSiO4 crystal phases exhibit totally different charge/discharge profiles upon delithiation/lithiation. Thus the 400 degrees C monoclinic nanocrystals exhibit initially one Li extraction via typical solid solution reaction, while the 900 degrees C orthorhombic crystals are characterized by unacceptably high cell polarization. In the meantime the mixed phase Li2FeSiO4 crystals reveal a mixed cycling profile. We have found that the monoclinic nanocrystals undergo phase transition to orthorhombic structure resulting in significant progressive deterioration of the material's Li storage capability. By contrast, we discovered when the monoclinic nanocrystals are cycled initially at higher rate (C/20) and subsequently subjected to low rate (C/50) cycling the material's intercalation performance is stabilized. The discovered rate-dependent electrochemically-induced phase transition and stabilization of lithium metal silicate structure provides a novel and potentially rewarding avenue towards the development of high capacity Li-ion cathodes. PMID- 25715656 TI - Physical activity and the risk of Barrett's esophagus. AB - Physical activity either directly or through influencing body fat may affect the risk of Barrett's esophagus (BE). However, the effect of physical activity on the risk of developing BE has not been examined. We conducted a case-control study among consecutive eligible patients either scheduled for elective endoscopy or recruited from primary care clinics to undergo a study endoscopy. Study participants completed the International Physical Activity Questionnaire (IPAQ) short form that measures physical activity during the past 7 days. We categorized level of physical activity by low, moderate, or high and estimated metabolic equivalent minutes per week (MET min/week). We calculated odds ratios (ORs) using logistic regression models and adjusted for age, sex, race, gastroesophageal reflux disease symptoms, Helicobacter pylori infection, body mass index, and waist-to-hip ratio. There were 307 cases with BE and 1724 controls (1262 from endoscopy and 462 from the primary care clinic) with IPAQ information. BE cases were more likely to be in the high-category physical activity category than controls (14.3% vs. 11.5% P = 0.08). However, there were no differences in the overall average MET min/week for walking between BE cases and controls (909 vs. 561; P = 0.16), with similar findings among those with moderate activity (1094 vs. 755, P = 0.18) or vigorous activity (784 vs. 826, P = 0.93). In multivariable logistic regression, physical activity level was not significantly associated with BE (OR = 1.19, 95% confidence interval: 0.82-1.73). Recent amount and intensity of physical activity are not associated with a reduction in the risk of BE. Studies are required to examine the long-term effects of physical activity. PMID- 25715657 TI - People in sub-Saharan Africa rate their health and health care among the lowest in the world. AB - The health of people in sub-Saharan Africa is a major global concern. However, data are weak, and little is known about how people in the region perceive their health or their health care. We used data from the Gallup World Poll in 2012 to document sub-Saharan Africans' perceived health status, their satisfaction with health care, their contact with medical professionals, and the priority they attach to health care. In comparison to other regions of the world, sub-Saharan Africa has the lowest ratings for well-being and the lowest satisfaction with health care. It also has the second-lowest perception of personal health, after only the former Soviet Union and its Eastern European satellites. HIV prevalence is positively correlated with perceived improvements in health care in countries with high prevalence. This is consistent with an improvement in at least some health care services as a result of the largely aid-funded rollout of antiretroviral treatment. Even so, sub-Saharan Africans do not prioritize health care as a matter of policy, although donors are increasingly shifting their aid efforts in the region toward health. PMID- 25715658 TI - Receptor-targeted lentiviral vectors are exceptionally sensitive toward the biophysical properties of the displayed single-chain Fv. AB - An increasing number of applications require the expression of single-chain variable fragments (scFv) fusion proteins in mammalian cells at the cell surface membrane. Here we assessed the CD30-specific scFv HRS3, which is used in immunotherapy, for its ability to retarget lentiviral vectors (LVs) to CD30 and to mediate selective gene transfer into CD30-positive cells. Fused to the C terminus of the type-II transmembrane protein hemagglutinin (H) of measles virus and expressed in LV packaging cells, gene transfer mediated by the released LV particles was inefficient. A series of point mutations in the scFv framework regions addressing its biophysical properties, which substantially improved production and increased the melting temperature without impairing its kinetic binding behavior to CD30, also improved the performance of LV particles. Gene transfer into CD30-positive cells increased ~100-fold due to improved transport of the H-scFv protein to the plasma membrane. Concomitantly, LV particle aggregation and syncytia formation in packaging cells were substantially reduced. The data suggest that syncytia formation can be triggered by trans-cellular dimerization of H-scFv proteins displayed on adjacent cells. Taken together, we show that the biophysical properties of the targeting ligand have a decisive role for the gene transfer efficiency of receptor-targeted LVs. PMID- 25715659 TI - Large area synthesis of a nanoporous two-dimensional polymer at the air/water interface. AB - We present the synthesis of a two-dimensional polymer at the air/water interface and its nm-resolution imaging. Trigonal star, amphiphilic monomers bearing three anthraceno groups on a central triptycene core are confined at the air/water interface. Compression followed by photopolymerization on the interface provides the two-dimensional polymer. Analysis by scanning tunneling microscopy suggests that the polymer is periodic with ultrahigh pore density. PMID- 25715660 TI - Hepatoprotective effects of soluble rice protein in primary hepatocytes and in mice. AB - BACKGROUND: The production of rice-derived by-products has increased owing to the growing use of processed rice products. The objective of this study was to isolate highly purified proteins from a rice by-product, rice syrup meal, and to examine their hepatoprotective effects in vitro and in vivo. RESULTS: Soluble rice protein (SRP70) was obtained via enzymatic processing of rice syrup meal using Termamyl SC and Alcalase. Mass spectrometry analysis showed that SRP70 contained low-molecular-weight (<600 Da) peptides. SRP70 did not affect the viability of rat primary hepatocytes and ameliorated tert-butyl hydroperoxide (t BHP)-induced cytotoxicity. t-BHP-induced elevations in hepatocyte alanine aminotransferase, aspartate aminotransferase and lactate dehydrogenase activities were reduced by SRP70 in a dose-dependent manner. In addition, t-BHP exposure increased the level of malondialdehyde, a toxic reactive aldehyde, which was dose dependently decreased by SRP70 treatment. These SRP70-induced decreases in biochemical parameters were also observed in vivo in mice. In particular, SRP70 increased the activities of liver antioxidant enzymes in t-BHP-treated mice, including catalase and glutathione peroxidase, as well as increasing the level of glutathione, an antioxidant peptide. SRP70-mediated activation of antioxidant enzymes was shown to be due to the up-regulation in their gene expressions, while nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) oxidase 4 (NOX4), a pro-oxidant enzyme, was down-regulated by SRP70. Hematoxylin and eosin staining also showed that SRP70 protected the liver from histopathological changes induced by t-BHP. CONCLUSION: Taken together, these data showed that SRP70, which is derived from a rice-processing by-product, had hepatoprotective effects in vitro and in vivo. PMID- 25715661 TI - Validation of a GPU-based Monte Carlo code (gPMC) for proton radiation therapy: clinical cases study. AB - Monte Carlo (MC) methods are recognized as the gold-standard for dose calculation, however they have not replaced analytical methods up to now due to their lengthy calculation times. GPU-based applications allow MC dose calculations to be performed on time scales comparable to conventional analytical algorithms. This study focuses on validating our GPU-based MC code for proton dose calculation (gPMC) using an experimentally validated multi-purpose MC code (TOPAS) and compare their performance for clinical patient cases. Clinical cases from five treatment sites were selected covering the full range from very homogeneous patient geometries (liver) to patients with high geometrical complexity (air cavities and density heterogeneities in head-and-neck and lung patients) and from short beam range (breast) to large beam range (prostate). Both gPMC and TOPAS were used to calculate 3D dose distributions for all patients. Comparisons were performed based on target coverage indices (mean dose, V95, D98, D50, D02) and gamma index distributions. Dosimetric indices differed less than 2% between TOPAS and gPMC dose distributions for most cases. Gamma index analysis with 1%/1 mm criterion resulted in a passing rate of more than 94% of all patient voxels receiving more than 10% of the mean target dose, for all patients except for prostate cases. Although clinically insignificant, gPMC resulted in systematic underestimation of target dose for prostate cases by 1-2% compared to TOPAS. Correspondingly the gamma index analysis with 1%/1 mm criterion failed for most beams for this site, while for 2%/1 mm criterion passing rates of more than 94.6% of all patient voxels were observed. For the same initial number of simulated particles, calculation time for a single beam for a typical head and neck patient plan decreased from 4 CPU hours per million particles (2.8-2.9 GHz Intel X5600) for TOPAS to 2.4 s per million particles (NVIDIA TESLA C2075) for gPMC. Excellent agreement was demonstrated between our fast GPU-based MC code (gPMC) and a previously extensively validated multi-purpose MC code (TOPAS) for a comprehensive set of clinical patient cases. This shows that MC dose calculations in proton therapy can be performed on time scales comparable to analytical algorithms with accuracy comparable to state-of-the-art CPU-based MC codes. PMID- 25715662 TI - The role of contrast-enhanced ultrasound (CEUS) in visualizing atherosclerotic carotid plaque vulnerability: which injection protocol? Which scanning technique? AB - PURPOSE: To correlate the degree of plaque vulnerability as determined by contrast-enhanced ultrasound (CEUS) with histological findings. Secondary objectives were to optimize the CEUS acquisition technique and image evaluation methods. MATERIALS AND METHODS: Fifty consecutive patients, either symptomatic and asymptomatic referring to our department in order to perform carotid endarterectomy (TEA), were enrolled. Each patient provided informed consent before undergoing CEUS. Ultrasound examination was performed using high-frequency (8-14 MHz) linear probe and a non-linear pulse inversion technique (mechanical index: 0.09-1.3). A double contrast media injection (Sonovue, 2 mL and 4 mL; Bracco, Italy) was performed. Two videotapes were recorded for every injection: early "dynamic" phase and late "flash" phase, performed with 6 high mechanical index impulses. Movies were quantitatively and qualitatively evaluated. Qualitative and quantitative evaluation were statistically compared to immunohistological diagnosis of vulnerable plaque, considered as gold standard. RESULTS: Qualitative CEUS evaluation obtained high statistical results when compared to immunohistological results, with values of sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and diagnostic accuracy of 94%, 68%, 87%, 85% and 86%, respectively, which became higher if considering only asymptomatic patient, with a NPV of 91%. Nevertheless, quantitative software evaluation proved less effective and could not reach similar results. CONCLUSION: Carotid plaque enhancement assessed with CEUS well correlates with histological assessment of plaque instability. CEUS may provide valuable information for plaque risk stratification and may play a role in the indication to treatment of patients with carotid stenoses, particularly in asymptomatic population. PMID- 25715663 TI - Supine spinal magnetic resonance imaging with straightened lower extremities in spondylolisthesis: a comparison with the conventional technique. AB - OBJECTIVES: To compare the degree of slip in spondylolisthesis on supine magnetic resonance (MR) images obtained with flexed and straightened lower extremities. METHODS: Supine spinal MR studies were performed in 100 cases of symptomatic spondylolisthesis with flexed and then straightened lower extremities. The angle of lumbar lordosis (by Cobb's method) and the degree of slip (by Taillard's method) were compared between the two sets of images. RESULTS: The mean angle of lumbar lordosis increased from 51.65+/-8.57 degrees on MR images with flexed lower limbs to 57.39+/-9.05 degrees on MR images with straightened lower limbs (p<0.001; mean percent increase: 11.51%). Similar change was also observed for the mean degree of slip (from 25.80+/-7.74% to 28.68+/-7.93%, p<0.001; mean percent increase: 12.60%). After MR imaging with straightened lower extremities 22 out of 54 initially grade I cases had grade II disease (p<0.001). CONCLUSIONS: Supine magnetic resonance imaging with straightened lower extremities detects higher degree of slippage in symptomatic patients with spondylolisthesis compared to conventional MRI with flexed lower extremities. PMID- 25715665 TI - Origin of the metastable stability in flavylium multistate systems. AB - Metastable states regarding the network of chemical reactions involving flavylium compounds were investigated as well as the role they may play in models for optical memories capable of write-read-erase. A necessary requirement to achieve metastable states in flavylium systems is the existence of a high cis-trans isomerization barrier, as in 4'-hydroxyflavylium described through this paper. In an optical memory, the metastable state could be the signal to be detected upon the write step. In that case the autoerase is prevented by the metastable state. Conversely, the metastable state may be the initial state and prevents the auto and unwanted write step. The compound 4'-hydroxyflavylium offers the possibility of achieving both of these two situations, depending on the sequence of the pH stimuli prior to light absorption. In this work the pH dependent distribution of the flavylium species of the network in the presence of beta-cyclodextrin was calculated. Improvement of the performance of the photochromic system in the presence of beta-cyclodextrin was observed. PMID- 25715664 TI - Pelvic X-ray examinations in follow-up of hip arthroplasty or femoral osteosynthesis--dose reduction and quality criteria. AB - OBJECTIVE: Digital plain radiographs of the pelvis are frequently performed in follow-up examinations of patients who received total hip arthroplasty (THA) or osteosynthesis (OS). Thus, the purpose was to reduce the radiation dose and to determine objective quality control criteria to ensure accurate assessment. MATERIALS AND METHODS: Institutional review board approval was obtained. In this prospective randomized study, 289 patients underwent X-ray examination of the pelvis as follow up after receiving THA or OS with standard and reduced dose. The evaluation of the plain radiographs was conducted using the following criteria: bone-implant interface, implant-implant discrimination, implant-surface character and periarticular heterotopic ossification. Two radiologists evaluated these criteria using a score ranging from 1 (definitely assessable) to 4 (not assessable). If a single criterion had been evaluated with a score of 3 or more or more than 2 criteria with 2 points, the radiograph was scored as "not assessable". The study was designed as non-inferiority-trial. RESULTS: Seven (2.4%) examined X-rays were scored as not assessable. There was no statistical inferiority between the examinations with standard (0.365 mSv) or reduced dose (0.211 mSv). Reduced dose only led to limitations in the evaluation of ceramic components with low clinical impact in most scenarios. CONCLUSION: Plain radiography of the pelvis in patients with THA or OS can be performed with a dose reduction of about 42% without a loss of important information. The obtained quality control criteria were clinically applicable. PMID- 25715666 TI - DNA polymerases beta and lambda and their roles in cell. AB - Among the set of mammalian DNA polymerases, DNA polymerases belonging to the X and Y families have a special place. The majority of these enzymes are involved in repair, including base excision repair and non-homologous end joining. Some of them play a crucial role during the specific process which is referred to as translesion synthesis (TLS). TLS intends for the cell surviving during the replication of damaged DNA templates. Additionally, specific activities of TLS polymerases have to be useful for repair of double-stranded clustered lesions: if the synthesis is proceeded via base excision repair process, the role of DNA polymerases beta or lambda will be important. In this review we discussed the biochemical properties and functional relevance of X family DNA polymerases beta and lambda. PMID- 25715667 TI - Effect of cerebral ischemia on redox status of plasma aminothiols. AB - We measured the content of reduced aminothiols (cysteine, homocysteine, and glutathione) after mechanical occlusion of the middle cerebral artery in rats. During acute period of ischemia (3 h), these parameters decreased by ~10 times. In 7 days, the content of reduced aminothiols in some animals remained low, but in the others surpassed the initial levels. These results indicate significant impairment of the redox status of the circulating aminothiol pool apparently caused by oxidative stress of the peripheral vascular endothelial occurring as a response to cerebral ischemia. Thus, the total amount of homocysteine is considered a risk factor for stroke, while its reduced fraction can reflect the post stroke state. PMID- 25715668 TI - Hydrogen bonding and molecular orientation at the liquid-vapour interface of water. AB - We determine the molecular structure and orientation at the liquid-vapour interface of water using an electronically coarse grained model constructed to include all long-range electronic responses within Gaussian statistics. The model, fit to the properties of the isolated monomer and dimer, is sufficiently responsive to generate the temperature dependence of the surface tension from ambient conditions to the critical point. Acceptor hydrogen bonds are shown to be preferentially truncated at the free surface under ambient conditions and a related asymmetry in hydrogen bonding preference is identified in bulk water. We speculate that this bonding asymmetry in bulk water is the microscopic origin of the observed surface structure. PMID- 25715669 TI - Chrousos syndrome: from molecular pathogenesis to therapeutic management. AB - BACKGROUND: Primary Generalized Glucocorticoid Resistance or Chrousos syndrome is a rare genetic condition characterized by end-organ insensitivity to glucocorticoids owing to inactivating mutations of the NR3C1 gene. MATERIALS AND METHODS: We conducted a systematic review of the published, peer-reviewed medical literature using MEDLINE (1975 through November 2014) to identify original articles and reviews on this topic. The search terms included 'primary generalized glucocorticoid resistance', 'Chrousos syndrome', 'glucocorticoid receptor gene' and 'glucocorticoid receptor mutations'. RESULTS: Only a few cases of Chrousos syndrome have been described to date, ranging from asymptomatic to severe forms of mineralocorticoid and/or androgen excess. All reported cases have been associated with point mutations or deletions in the NR3C1 gene. The tremendous progress of molecular biology has enabled us to apply standard methods to investigate the molecular mechanisms of action of the mutant glucocorticoid receptors (GRs). We and others have identified and functionally characterized novel mutations causing Chrousos syndrome, while structural biology has enabled us to have a better understanding of how conformational changes of the receptor cause glucocorticoid resistance. In this review, we also present our results of the functional characterization of two recently described mutations, and we discuss the diagnostic approaches and therapeutic management of patients with Chrousos syndrome. CONCLUSIONS: Although Chrousos syndrome is a rare condition, many clinical cases remain unrecognized for a long time. We recommend determination of the 24-h urinary free cortisol excretion and sequencing of the NR3C1 gene in patients with hyperandrogenism and/or hypertension of unknown origin. PMID- 25715670 TI - Yeast Hmt1 catalyses asymmetric dimethylation of histone H3 arginine 2 in vitro. AB - Protein arginine methyltransferases (PRMTs) are a family of enzymes that can methylate protein arginine residues. PRMTs' substrates include histones and a variety of non-histone proteins. Previous studies have shown that yeast Hmt1 is a type I PRMT and methylates histone H4 arginine 3 and several mRNA-binding proteins. Hmt1 forms dimers or oligomers, but how dimerization or oligomerization affects its activity remains largely unknown. We now report that Hmt1 can methylate histone H3 arginine 2 (H3R2) in vitro. The dimerization but not hexamerization is essential for Hmt1's activity. Interestingly, the methyltransferase activity of Hmt1 on histone H3R2 requires reciprocal contributions from two Hmt1 molecules. Our results suggest an intermolecular trans-complementary mechanism by which Hmt1 dimer methylates its substrates. PMID- 25715672 TI - Verrucous hyperplasia associated with neuropathy from schistorrhachis. PMID- 25715671 TI - The effects analysis of two neonicotinoid insecticides on in vitro maturation of porcine oocytes using hanging drop monoculture method. AB - Acetamiprid (ACE) and imidacroprid (IMI) are known neonicotinoid insecticides with strong affinities for the insect-selective nicotinic acetylcholine receptor. These provide insect control by hyperstimulating insect nerves and are used for agricultural pest management. However, it has also been reported that ACE and IMI affect mammalian reproductive function. We determined the effects of ACE and IMI on the in vitro maturation of porcine oocytes. Significant decreases in nuclear maturation rates were observed in the ACE or IMI-exposed groups. Also, in matured oocytes from the ACE or IMI-exposed groups, irregular chromosomes were observed. Our results suggest that ACE and IMI exposure was detrimental to porcine oocytes and the extent of the effects depends on the concentration of exposure. PMID- 25715673 TI - Acquiring, recording, and analyzing pathology data from experimental mice: an overview. AB - Pathology is often underutilized as an end point in mouse studies in academic research because of a lack of experience and expertise. The use of traditional pathology techniques including necropsy and microscopic analysis can be useful in identifying the basic processes underlying a phenotype and facilitating comparison with equivalent human diseases. This overview aims to provide a guide and reference to the acquisition, recording, and analysis of high-quality pathology data from experimental mice in an academic research setting. PMID- 25715674 TI - Synthetic polymer as an adjuvant in collagen-induced arthritis. AB - Collagen-induced arthritis (CIA), the classical animal model for experimental arthritis, resembles human rheumatoid arthritis in several aspects. However, the most widely used method of inducing CIA utilizes Freund's adjuvants, which can skew the elicited immune responses and also pose toxicity problems. This unit describes a new method of inducing CIA using a well defined stimuli-responsive synthetic polymer, poly-N-isopropylacrylamide-based adjuvant, mixed with the joint cartilage protein collagen type II (CII). PNiPAAm as an adjuvant is biodegradable and biocompatible, and does not skew immune responses. Thus, it is helpful in the development of arthritis models for studying antigen and tissue specific autoimmune responses in an unbiased manner. This model is valuable for analyzing disease pathways, positional identification of genes regulating arthritis, validation of existing therapies, and exploring new therapeutic targets. Furthermore, this newly developed PNiPAAm adjuvant allows investigation of disease induction using specific autoantigens in several autoimmune diseases independently of toll-like receptors, as well as optimization of vaccine delivery systems for infectious diseases. PMID- 25715675 TI - Ethnic variations in immigrant poverty exit and female employment: the missing link. AB - Despite widespread interest in poverty among recent immigrants and female immigrant employment, research on the link between the two is limited. This study evaluates the effect of recently arrived immigrant women's employment on the exit from family poverty and considers the implications for ethnic differences in poverty exit. It uses the bivariate probit model and the Fairlie decomposition technique to analyze data from the Longitudinal Survey of Immigrants to Canada (LSIC), a nationally representative survey of immigrants arriving in Canada, 2000 2001. Results show that the employment of recently arrived immigrant women makes a notable contribution to lifting families out of poverty. Moreover, the wide ethnic variations in the probability of exit from poverty between European and non-European groups are partially explained by the lower employment rates among non-European women. The results suggest that the equal earner/female breadwinner model applies to low-income recent immigrant families in general, but the male breadwinner model explains the low probability of poverty exit among select non European groups whose female employment rates are notably low. PMID- 25715676 TI - Disease incidence and mortality among older Americans and Europeans. AB - Recent research has shown a widening gap in life expectancy at age 50 between the United States and Europe as well as large differences in the prevalence of diseases at older ages. Little is known about the processes determining international differences in the prevalence of chronic diseases. Higher prevalence of disease could result from either higher incidence or longer disease specific survival. This article uses comparable longitudinal data from 2004 and 2006 for populations aged 50 to 79 from the United States and from a selected group of European countries to examine age-specific differences in prevalence and incidence of heart disease, stroke, lung disease, diabetes, hypertension, and cancer as well as mortality associated with each disease. Not surprisingly, we find that Americans have higher disease prevalence. For heart disease, diabetes, and cancer, incidence is lower in Europe when we control for sociodemographic and health behavior differences in risk, and these differences explain much of the prevalence gap at older ages. On the other hand, incidence is higher in Europe for lung disease and not different between Europe and the United States for hypertension and stroke. Our findings do not suggest a survival advantage conditional on disease in Europe compared with the United States. Therefore, the origin of the higher disease prevalence at older ages in the United States is to be found in higher prevalence earlier in the life course and, for some conditions, higher incidence between ages 50 and 79. PMID- 25715677 TI - Integrin-beta1 regulates chondrocyte proliferation and apoptosis through the upregulation of GIT1 expression. AB - Chondrocytes play a critical role in the repair process of osteoarthritis, which is also known as degenerative arthritis. Integrins, as the key family of cell surface receptors, are responsible for the regulation of chondrocyte proliferation, differentiation, survival and apoptosis through the recruitment and activation of downstream adaptor proteins. Moreover, G-protein-coupled receptor kinase interacting protein-1 (GIT1) exerts its effects on cell proliferation and migration through interaction with various cytokines. It has been previously suggested that GIT1 acts as a vital protein downstream of the integrin-mediated pathway. In the present study, we investigated the effects of integrin-beta1 on cell proliferation and apoptosis, as well as the underlying mechanisms in chondrocytes in vitro. Following transfection with a vector expressing integrin-beta1, our results revealed that the overexpression of integrin-beta1 enhanced GIT1 expression, whereas the knockdown of integrin-beta1 by siRNA suppressed GIT1 expression. However, no significant effect was observed on integrin-beta1 expression following the enforced overexpression of GIT1, which suggests that GIT1 is localized downstream of integrin-beta1. In other words, integrin-beta1 regulates the expression of GIT1. Furthermore, this study demonstrated that integrin-beta1 and GIT1 increased the expression levels of aggrecan and type II collagen, thus promoting chondrocyte proliferation; however, they inhibited chondrocyte apoptosis. Taken together, our data demonstrate that integrin-beta1 plays a vital role in chondrocyte proliferation, differentiation and apoptosis. GIT1 exerts effects similar to those of integrin-beta1 and is a downstream target of integrin-beta1. PMID- 25715679 TI - Timing of gaze alone tells us nothing about visit quality and EHR design. PMID- 25715678 TI - Dynamic changes of nuclear RNA foci in proliferating DM1 cells. AB - Nuclear RNA foci are molecular hallmarks of myotonic dystrophy type 1 (DM1). However, no designated study has investigated their formation and changes in proliferating cells. Proliferating cells, as stem cells, consist of an important cellular pool in the human body. The revelation of foci changes in these cells might shed light on the effects of the mutation on these specific cells and tissues. In this study, we used human DM1 iPS-cell-derived neural stem cells (NSCs) as cellular models to investigate the formation and dynamic changes of RNA foci in proliferating cells. Human DM1 NSCs derived from human DM1 iPS cells were cultured under proliferation conditions and nonproliferation conditions following mitomycin C treatment. The dynamic changes of foci during the cell cycle were investigated by fluorescence in situ hybridization. We found RNA foci formed and dissociated during the cell cycle. Nuclear RNA foci were most prominent in number and size just prior to entering mitosis (early prophase). During mitosis, most foci disappeared. After entering interphase, RNA foci accumulated again in the nuclei. After stopping cell dividing by treatment of mitomycin C, the number of nuclear RNA foci increased significantly. In summary, DM1 NSC nuclear RNA foci undergo dynamic changes during cell cycle, and mitosis is a mechanism to decrease foci load in the nuclei, which may explain why dividing cells are less affected by the mutation. The dynamic changes need to be considered when using foci as a marker to monitor the effects of therapeutic drugs. PMID- 25715680 TI - Validity of the Nintendo Wii Balance Board to assess weight bearing asymmetry during sit-to-stand and return-to-sit task. AB - Weight bearing asymmetry is common in patients with unilateral lower limb musculoskeletal pathologies. The Nintendo Wii Balance Board (WBB) has been suggested as a low-cost and widely-available tool to measure weight bearing asymmetry in a clinical environment; however no study has evaluated the validity of this tool during dynamic tasks. Therefore, the purpose of this study was to determine the concurrent validity of force measurements acquired from the WBB as compared to laboratory force plates. Thirty-five individuals before, or within 1 year of total joint arthroplasty performed a sit-to-stand and return-to-sit task in two conditions. First, subjects performed the task with both feet placed on a single WBB. Second, the task was repeated with each foot placed on an individual laboratory force plate. Peak vertical ground reaction force (VGRF) under each foot and the inter-limb symmetry ratio were calculated. Validity was examined using Intraclass Correlation Coefficients (ICC), regression analysis, 95% limits of agreement and Bland-Altman plots. Force plates and the WBB exhibited excellent agreement for all outcome measurements (ICC=0.83-0.99). Bland-Altman plots showed no obvious relationship between the difference and the mean for the peak VGRF, but there was a consistent trend in which VGRF on the unaffected side was lower and VGRF on the affected side was higher when using the WBB. However, these consistent biases can be adjusted for by utilizing regression equations that estimate the force plate values based on the WBB force. The WBB may serve as a valid, suitable, and low-cost alternative to expensive, laboratory force plates for measuring weight bearing asymmetry in clinical settings. PMID- 25715682 TI - Mechanistic insights into the lipid interaction of an ancient saposin-like protein. AB - The members of the expanding family of saposin-like proteins (SAPLIPs) have various biological functions in plants, animals, and humans. In addition to a similar protein backbone, these proteins have in common the fact that they interact with lipid membranes. According to their phylogenetic position, it has long been thought that amoeboid protozoans produce archetypes of SAPLIPs and that these are lytic proteins that can perforate membranes of prokaryotic and eukaryotic target cells. Here, we show that an amoebic SAPLIP from Entamoeba invadens does not form lytic pores in membranes but displays several characteristics that are known from human saposins. The protein named invaposin changes the conformation from a closed to an open form in the presence of lipid membranes, acts in a pH-dependent manner, selectively binds anionic lipids, aggregates lipid vesicles of the preferred composition, and dimerizes upon acidification. Our data indicate that the principal features of the lipid-binding saposins evolved long before the appearance of the vertebrate lineage and push the origin of saposins even deeper down the phylogenetic tree to unicellular organisms. PMID- 25715681 TI - Endocannabinoid Catabolic Enzymes Play Differential Roles in Thermal Homeostasis in Response to Environmental or Immune Challenge. AB - Cannabinoid receptor agonists, such as Delta(9)-THC, the primary active constituent of Cannabis sativa, have anti-pyrogenic effects in a variety of assays. Recently, attention has turned to the endogenous cannabinoid system and how endocannabinoids, including 2-arachidonoylglycerol (2-AG) and anandamide, regulate multiple homeostatic processes, including thermoregulation. Inhibiting endocannabinoid catabolic enzymes, monoacylglycerol lipase (MAGL) or fatty acid amide hydrolase (FAAH), elevates levels of 2-AG or anandamide in vivo, respectively. The purpose of this experiment was to test the hypothesis that endocannabinoid catabolic enzymes function to maintain thermal homeostasis in response to hypothermic challenge. In separate experiments, male C57BL/6J mice were administered a MAGL or FAAH inhibitor, and then challenged with the bacterial endotoxin lipopolysaccharide (LPS; 2 mg/kg ip) or a cold (4 degrees C) ambient environment. Systemic LPS administration caused a significant decrease in core body temperature after 6 h, and this hypothermia persisted for at least 12 h. Similarly, cold environment induced mild hypothermia that resolved within 30 min. JZL184 exacerbated hypothermia induced by either LPS or cold challenge, both of which effects were blocked by rimonabant, but not SR144528, indicating a CB1 cannabinoid receptor mechanism of action. In contrast, the FAAH inhibitor, PF 3845, had no effect on either LPS-induced or cold-induced hypothermia. These data indicate that unlike direct acting cannabinoid receptor agonists, which elicit profound hypothermic responses on their own, neither MAGL nor FAAH inhibitors affect normal body temperature. However, these endocannabinoid catabolic enzymes play distinct roles in thermoregulation following hypothermic challenges. PMID- 25715683 TI - Peanut rust (Puccinia arachidis Speg.) disease: its background and recent accomplishments towards disease resistance breeding. AB - The peanut rust disease is an economically important biotic stress that significantly reduces the pod and fodder yield and oil quality. It is caused by the basidiomycete fungus Puccinia arachidis Speg. which belongs to class Pucciniomycetes like other rust fungus but has fewer occurrences in teliospore form. The P. arachidis predominantly spreads by the repeated cycle of uredospores in the field. The disease is prevalent in most of the countries where peanut is cultivated and favored by warm and humid climatic conditions. Despite its economic importance, very limited work has been carried out on host-fungus interaction, fungal genetic diversity, and physiological specialization. The present review describes different aspects of P. arachidis especially its symptomatology, cell biological aspects of pathogenesis, epidemiology, and physiology of resistance as well as developments on genetics and genomics of host resistance, and resistance breeding. The review will help to understand the behavior of this causal organism and the host resistance and subsequently design the breeding approaches to check the spread of the disease. PMID- 25715685 TI - The Impact of Ripening Time on Technological Quality Traits, Chemical Change and Sensory Characteristics of Dry-cured Loin. AB - The effect of ripening time on the technological quality traits, fatty acid compositions and sensory characteristics of dry-cured loin was studied. Pork loins (n = 102) at 24 h post-mortem were used to produce dry-cured loins. The dry cured loins were assessed at 30, 60, and 90 days of ripening for the aforementioned characteristics. Our results showed that the water activity (aw) decreased (p<0.05) up to 60 days and did not change thereafter. The lipid oxidation and weight loss levels significantly (p<0.05) increased with increased ripening time. The Commission Internationale de l'Eclairage (CIE) L* decreased for 90 days while CIE a* increased for 60 days and did not increase thereafter. More noticeably, the levels of most of unsaturated fatty acids and total polyunsaturated fatty acids significantly decreased as increasing ripening time up to 90 days. The 30 days-ripened loins had lower (p<0.05) color, flavor and overall acceptability scores than the loins ripened for 60 and 90 days, however, no differences in sensory traits occurred between the 60 and 90 day-ripened samples. Based on the results obtained in the present study, it is suggested that the ripening duration between 30 and 60 days could be more appropriate for producing dry-cured loin product with higher quality and economic benefits. PMID- 25715686 TI - Characteristics of Wet and Dried Distillers Grains on In vitro Ruminal Fermentation and Effects of Dietary Wet Distillers Grains on Performance of Hanwoo Steers. AB - Two experiments were conducted to evaluate the nutrient composition, in vitro dry matter disappearance (IVDMD) and organic matter disappearance (IVOMD) of three kinds of distillers grains (DG); i) wet distillers grains (WDG, KRW 25/kg), ii) dried distillers grains (DDG, KRW 280/kg), iii) dried distillers grains with solubles (DDGS, KRW 270/kg) produced from tapioca 70% and rice 30%, and to evaluate dietary effects of WDG on the performance of Hanwoo steers. In Exp. 1, twelve-WDG, four-DDG and one-DDGS were collected from seven ethanol plants. Average crude protein, crude fiber, neutral detergent fiber, and acid detergent fiber of WDG, DDG, and DDGS were: 32.6%, 17.8%, 57.5%, and 30.2% for WDG, 36.7%, 13.9%, 51.4%, and 30.5% for DDG, and 31.0%, 11.9%, 40.3%, and 21.2% for DDGS (DM basis), respectively. The DDGS had a higher quantity of water-soluble fraction than WDG and DDG and showed the highest IVDMD (p<0.05) in comparison to others during the whole experimental time. The IVDMD at 0 to 12 h incubation were higher (p<0.05) in DDG than WDG, but did not show significant differences from 24 to 72 h. The same tendency was observed in IVOMD, showing that DG made from tapioca and rice (7:3) can be used as a feed ingredient for ruminants. Considering the price, WDG is a more useful feed ingredient than DDG and DDGS. In Exp. 2, 36 Hanwoo steers of 21 months (495.1+/-91 kg) were randomly assigned to one of three dietary treatments for 85 days; i) Control (total mixed ration, TMR), ii) WDG 10% (TMR containing 10% of WDG, as fed basis), and iii) WDG 20% (TMR containing 20% of WDG, as fed basis). With respect to body weight and average daily gain, there were no differences between control and WDG treatments during the whole experimental period. Dry matter intake of control (9.34 kg), WDG 10% (9.21 kg) and 20% (8.86 kg) and feed conversion ratio of control (13.0), WDG 10% (13.2) and 20% (12.1) did not show differences between control and WDG treatments. Thus, the use of WDG up to 20% in TMR did not show any negative effect on the performance of Hanwoo steers. PMID- 25715684 TI - Associations of prostate cancer risk variants with disease aggressiveness: results of the NCI-SPORE Genetics Working Group analysis of 18,343 cases. AB - Genetic studies have identified single nucleotide polymorphisms (SNPs) associated with the risk of prostate cancer (PC). It remains unclear whether such genetic variants are associated with disease aggressiveness. The NCI-SPORE Genetics Working Group retrospectively collected clinicopathologic information and genotype data for 36 SNPs which at the time had been validated to be associated with PC risk from 25,674 cases with PC. Cases were grouped according to race, Gleason score (Gleason <= 6, 7, >= 8) and aggressiveness (non-aggressive, intermediate, and aggressive disease). Statistical analyses were used to compare the frequency of the SNPs between different disease cohorts. After adjusting for multiple testing, only PC-risk SNP rs2735839 (G) was significantly and inversely associated with aggressive (OR = 0.77; 95 % CI 0.69-0.87) and high-grade disease (OR = 0.77; 95 % CI 0.68-0.86) in European men. Similar associations with aggressive (OR = 0.72; 95 % CI 0.58-0.89) and high-grade disease (OR = 0.69; 95 % CI 0.54-0.87) were documented in African-American subjects. The G allele of rs2735839 was associated with disease aggressiveness even at low PSA levels (<4.0 ng/mL) in both European and African-American men. Our results provide further support that a PC-risk SNP rs2735839 near the KLK3 gene on chromosome 19q13 may be associated with aggressive and high-grade PC. Future prospectively designed, case-case GWAS are needed to identify additional SNPs associated with PC aggressiveness. PMID- 25715687 TI - Effects of Feeding Barley Naturally Contaminated with Fusarium Mycotoxins on Growth Performance, Nutrient Digestibility, and Blood Chemistry of Gilts and Growth Recoveries by Feeding a Non-contaminated Diet. AB - The objectives of this study were to investigate the effects of feeding barley naturally contaminated with Fusarium mycotoxins on growth performance, vulva swelling, and digestibility of dry matter, organic matter, and crude protein of gilts and the recovery of gilts fed normal diets immediately after the exposure to contaminated diets by measuring growth performance and vulva swelling. In Exp. 1, four diets were prepared to contain 0%, 15%, 30%, or 45% contaminated barley containing 25.7 mg/kg deoxynivalenol and 26.0 MUg/kg zearalenone. Sixteen gilts with an initial body weight (BW) of 33.3 kg (standard deviation = 3.0) were individually housed in a metabolism crate and assigned to 4 diets with 4 replicates in a randomized complete block design based on BW. During the 14-d feeding trial, individual BW and feed consumption were measured weekly and the vertical and horizontal lengths of vulva were measured every 3 d. From d 10, feces were collected by the maker-to-marker method for 4 d. Blood samples were collected on d 14. During the overall period, the average daily gain, average daily feed intake, and gain:feed of pigs linearly decreased (p<0.01) as the dietary concentration of contaminated barley increased. However, the digestibility of crude protein was linearly increased (p = 0.011) with the increasing amounts of contaminated barley. Increasing dietary Fusarium mycotoxin concentrations did not influence vulva size, blood characteristic as well as immunoglobulin level of pigs. In the Exp. 2, a corn-soybean meal-based diet was formulated as a recovery diet. Pigs were fed the recovery diet immediately after completion of the Exp. 1. During the 14-d of recovery period, the individual BW and feed consumption were measured weekly and the vertical and horizontal length of vulva were measured every 3 d from d 0. On d 7, the feed intake of pigs previously fed contaminated diets already reached that of pigs fed a diet with 0% contaminated barley and no significant difference in growth performance among treatments was observed during d 7 to 14 of the recovery period. In conclusion, increasing levels of mycotoxins in diets linearly decreased the growth performance of pigs, and these damages can be recovered in 7 d after the diet was replaced with a normal diet. The vulva size, blood characteristic, immune responses were not affected by increasing level of contaminated barley in the diets fed to pigs. PMID- 25715688 TI - Animal Performance and Carcass Characteristics of Bulls (1/2 Puruna vs 1/2 Canchim) Slaughtered at 16 and 22 Months Old, and Three Different Weights. AB - Current study aimed to evaluate the performance of bulls (1/2 Puruna vs 1/2 Canchim) slaughtered at two ages and three different weights. One hundred and thirteen bulls were divided into two slaughter ages (16 and 22 months) and three different slaughter weights (light, 422 kg; medium, 470 kg; and heavy, 550 kg). The body weight was higher for bulls slaughtered at 16 months. Daily gain, carcass weight and dressing were higher for bulls slaughtered at 16 months. Feed intake was higher for bulls slaughtered at 22 months although feed efficiency was better for bulls slaughtered at 16 months. Carcass characteristics were better for bulls slaughtered at 16 months. The percentages of muscle, fat and bone and meat characteristics were similar between two slaughter ages. Feed intake and animal performance was lower for lighter animals. Feed conversion and carcass dressing were similar in the three slaughter weights. Muscle percentage was higher for heavier animals but fat and bone percentages were lower. Slaughter weight had no effect on meat characteristics. PMID- 25715689 TI - Angiotensin I-converting enzyme inhibitor activity on egg albumen fermentation. AB - Lactobacillus plantarum is used for fermentation of fish products, meat and milk. However, the utilization of these bacteria in egg processing has not been done. This study was designed to evaluate the potential of fermented egg albumen as a functional food that is rich in angiotensin I-converting enzyme inhibitors activity (ACE-inhibitor activity) and is antihypertensive. A completely randomized design was used in this study with six durations of fermentation (6, 12, 18, 24, 30, and 36 h) as treatments. Six hundred eggs obtained from the same chicken farm were used in the experiment as sources of egg albumen. Bacteria L. plantarum FNCC 0027 used in the fermentation was isolated from cow's milk. The parameters measured were the total bacteria, dissolved protein, pH, total acid and the activity of ACE-inhibitors. The results showed that there were significant effects of fermentation time on the parameters tested. Total bacteria increased significantly during fermentation for 6, 12, 18, and 24 h and then decreased with the increasing time of fermentation to 30 and 36 h. Soluble protein increased significantly during fermentation to 18 h and then subsequently decreased during of fermentation to 24, 30, and 36 h. The pH value decreased markedly during fermentation. The activities of ACE-inhibitor in fermented egg albumen increased during fermentation to 18 h and then decreased with the increasing of the duration of fermentation to 24, 30, and 36 h. The egg albumen which was fermented for 18 h resulted in a functional food that was rich in ACE inhibitor activity. PMID- 25715690 TI - Life Cycle Assessment of Biogas Production in Small-scale Household Digesters in Vietnam. AB - Small-scale household digesters have been promoted across Asia as a sustainable way of handling manure. The major advantages are that they produce biogas and reduce odor. However their disadvantages include the low recycling of nutrients, because digestate is dilute and therefore difficult to transport, and the loss of biogas as a result of cracks and the intentional release of excess biogas. In this study, life cycle assessment (LCA) methodology was used to assess the environmental impacts associated with biogas digesters in Vietnam. Handling 1,000 kg of liquid manure and 100 kg of solid manure in a system with a biogas digester reduced the impact potential from 4.4 kg carbon dioxide (CO2) equivalents to 3.2 kg CO2 equivalents compared with traditional manure management. However, this advantage could easily be compromised if digester construction is considered in the LCA or in situations where there is an excess of biogas which is intentionally released. A sensitivity analysis showed that biogas digesters could be a means of reducing global warming if methane emissions can be kept low. In terms of eutrophication, farms with biogas digesters had 3 to 4 times greater impacts. In order to make biogas digesters sustainable, methods for recycling digestates are urgently required. PMID- 25715691 TI - Selection for Duration of Fertility and Mule Duck White Plumage Colour in a Synthetic Strain of Ducks (Anas platyrhynchos). AB - A synthetic strain of ducks (Anas platyrhynchos) was developed by introducing genes for long duration of fertility to be used as mother of mule ducklings and a seven-generation selection experiment was conducted to increase the number of fertile eggs after a single artificial insemination (AI) with pooled Muscovy semen. Reciprocal crossbreeding between Brown Tsaiya LRI-2 (with long duration of fertility) and Pekin L-201 (with white plumage mule ducklings) ducks produced the G0. Then G1 were intercrossed to produce G2 and so on for the following generations. Each female duck was inseminated 3 times, at 26, 29, and 32 weeks of age. The eggs were collected for 14 days from day 2 after AI. Individual data regarding the number of incubated eggs (Ie), the number of fertile eggs at candling at day 7 of incubation (F), the total number of dead embryos (M), the maximum duration of fertility (Dm) and the number of hatched mule ducklings (H) with plumage colour were recorded. The selection criterion was the breeding values of the best linear unbiased prediction animal model for F. The results show high percentage of exhibited heterosis in G2 for traits to improve (19.1% for F and 12.9% for H); F with a value of 5.92 (vs 3.74 in the Pekin L-201) was improved in the G2. Heritabilities were found to be low for Ie (h (2) = 0.07+/ 0.03) and M (h (2) = 0.07+/-0.01), moderately low for Dm (h (2) = 0.13+/-0.02), of medium values for H (h (2) = 0.20+/-0.03) and F (h (2) = 0.23+/-0.03). High and favourable genetic correlations existed between F and Dm (rg = 0.93), between F and H (rg = 0.97) and between Dm and H (rg = 0.90). The selection experiment showed a positive trend for phenotypic values of F (6.38 fertile eggs in G10 of synthetic strain vs 5.59 eggs in G4, and 3.74 eggs in Pekin L-201), with correlated response for increasing H (5.73 ducklings in G10 vs 4.86 in G4, and 3.09 ducklings in Pekin L-201) and maximum duration of the fertile period without increasing the embryo mortality rate. The average predicted genetic response for F was 40% of genetic standard deviation per generation of selection. The mule ducklings' feather colour also was improved. It was concluded that this study provided results for a better understanding of the genetics of the duration of fertility traits in the common female duck bred for mule and that the selection of a synthetic strain was effective method of improvement. PMID- 25715692 TI - Validating skinfold thickness as a proxy to estimate total body fat in wild toque macaques (Macaca sinica) using the mass of dissected adipose tissue. AB - Skinfold thickness (SFT) has been used often in non-human primates and humans as a proxy to estimate fatness (% body fat). We intended to validate the relation between SFT (in recently deceased specimens) and the mass of adipose tissue as determined from dissection of fresh carcasses of wild toque macaques (Macaca sinica). In adult male and female toque macaques body composition is normally 2% adipose tissue. Calipers for measuring SFT were suitable for measuring only some subcutaneous deposits of adipose tissue but were not suitable for measuring large fat deposits within the body cavity or minor intermuscular ones. The anatomical distribution of 13 different adipose deposits, in different body regions (subcutaneous, intra-abdominal and intermuscular) and their proportional size differences, were consistent in this species (as in other primates), though varying in total mass among individuals. These consistent allometric relationships were fundamental for estimating fatness of different body regions based on SFT. The best fit statistically significant correlations and regressions with the known masses of dissectible adipose tissue were evident between the SFT means of the seven sites measured, as well as with a single point on the abdomen anterior to the umbilicus. SFT related to total fat mass and intra-abdominal fat mass in curvilinear regressions and to subcutaneous fat mass in a linear relationship. To adjust for differences in body size among individuals, and to circumvent intangible variations in total body mass allocated, for example to the gastro-intestinal contents, dissected fat mass was estimated per unit body size (length of crown-rump)(3). SFT had greater coefficients of correlation and regressions with this Fat Mass Index (g/dm(3)) than with Percent Body Fat. PMID- 25715693 TI - Mesenchymal condensation-dependent accumulation of collagen VI stabilizes organ specific cell fates during embryonic tooth formation. AB - BACKGROUND: Mechanical compression of cells during mesenchymal condensation triggers cells to undergo odontogenic differentiation during tooth organ formation in the embryo. However, the mechanism by which cell compaction is stabilized over time to ensure correct organ-specific cell fate switching remains unknown. RESULTS: Here, we show that mesenchymal cell compaction induces accumulation of collagen VI in the extracellular matrix (ECM), which physically stabilizes compressed mesenchymal cell shapes and ensures efficient organ specific cell fate switching during tooth organ development. Mechanical induction of collagen VI deposition is mediated by signaling through the actin-p38MAPK-SP1 pathway, and the ECM scaffold is stabilized by lysyl oxidase in the condensing mesenchyme. Moreover, perturbation of synthesis or cross-linking of collagen VI alters the size of the condensation in vivo. CONCLUSIONS: These findings suggest that the odontogenic differentiation process that is induced by cell compaction during mesenchymal condensation is stabilized and sustained through mechanically regulated production of collagen VI within the mesenchymal ECM. PMID- 25715694 TI - Serum tocopherol levels and vitamin E intake are associated with lung function in the normative aging study. AB - BACKGROUND & AIMS: The results of studies assessing relationships between vitamin E intake and status and lung function are conflicting. This study aimed to evaluate the effect of vitamin E intake and serum levels of tocopherol isoforms on lung function in a cross-sectional sample of 580 men from the Normative Aging Study, a longitudinal aging study. METHODS: Regression models were used to look at associations of serum tocopherol isoform levels and vitamin E intake with lung function parameters after adjustment for confounders. Vitamin E intake was measured using a food frequency questionnaire and serum levels of gamma, alpha, and delta-tocopherol levels were measured using high-performance liquid chromatography. RESULTS: After adjustment for potential confounders, serum gamma tocopherol had a significant inverse association with forced vital capacity (beta = -0.10, p = 0.05). Alpha and delta-tocopherol were not associated with any lung function parameter. After classifying COPD status according to Global Initiative for Obstructive Lung Disease (GOLD) stage criteria, serum levels of delta tocopherol were lower in participants with more severe COPD (p = 0.01). Serum levels of delta-tocopherol were also lower in participants with greater levels of smoking (p = 0.02). Both vitamin E intake (beta = 0.03, p = 0.02; beta = 0.03, p = 0.01) and use of vitamin E supplements (beta = 0.05, p = 0.03; beta = 0.06. p = 0.02) were positively associated with FEV1 and FVC, after adjusting for confounders. Subjects who took vitamin E supplements had significantly higher alpha-tocopherol levels (p < 0.0001) and lower gamma-tocopherol levels (p < 0.0001) than non-users. CONCLUSION: In this study, there is a positive association between dietary vitamin E intake and lung function, and evidence of an inverse relationship between serum levels of gamma-tocopherol and lung function. PMID- 25715695 TI - Quantitative Evaluation of mMate1 Function Based on Minimally Invasive Measurement of Tissue Concentration Using PET with [(11)C]Metformin in Mouse. AB - PURPOSE: To evaluate the function of multidrug and toxin extrusion proteins (MATEs) using (11)C-labeled metformin ([(11)C]metformin) by positron emission tomography (PET). METHODS: PET was performed by intravenous bolus injection of [(11)C]metformin. Pyrimethamine at 0.5 and 5 mg/kg was intravenously administered to mice 30 min prior to the scan. Integration plot analysis was conducted for calculating liver (CLuptake,liver), kidney (CLuptake,kidney) tissue uptake, intrinsic biliary (CLint,bile) and urinary (CLint,urine) excretion clearances of [(11)C]metformin. RESULTS: Visualization by PET showed that pyrimethamine increased concentrations of [(11)C]metformin in the liver and kidneys, and decreased the concentrations in the urinary bladder without changing the blood profiles. Pyrimethamine had no effect on the CLuptake,liver and CLuptake,kidney, which were similar to the blood-flow rate. CLint,bile with regard to the liver concentration was unable to be determined, but administration of 0.5 and 5 mg/kg of pyrimethamine increased the liver-to-blood ratio to 1.6 and 2.3-fold, respectively, indicating that pyrimethamine inhibited the efflux of [(11)C]metformin from the liver. CLint,urine with regard to the corticomedullary region concentrations was decreased 37 and 68% of the control by administration of 0.5 and 5 mg/kg of pyrimethamine, respectively (P < 0.05). CONCLUSIONS: Tissue concentration based investigations using [(11)C]metformin by PET enables the functional analysis of MATEs in the liver and kidneys. PMID- 25715696 TI - A Novel Approach for Analyzing the Dissolution Mechanism of Solid Dispersions. AB - PURPOSE: To analyze the dissolution mechanism of solid dispersions of poorly water-soluble active pharmaceutical ingredients (APIs), to predict the dissolution profiles of the APIs and to find appropriate ways to improve their dissolution rate. METHODS: The dissolution profiles of indomethacin and naproxen from solid dispersions in PVP K25 were measured in vitro using a rotating-disk system (USP II). A chemical-potential-gradient model combined with the thermodynamic model PC-SAFT was developed to investigate the dissolution mechanism of indomethacin and naproxen from their solid dispersions at different conditions and to predict the dissolution profiles of these APIs. RESULTS: The results show that the dissolution of the investigated solid dispersions is controlled by dissolution of both, API and PVP K25 as they codissolve according to the initial API loading. Moreover, the dissolution of indomethacin and naproxen was improved by decreasing the API loading in polymer (leading to amorphous solid dispersions) and increasing stirring speed, temperature and pH of the dissolution medium. The dissolution of indomethacin and naproxen from their amorphous solid dispersions is mainly controlled by the surface reaction, which implies that indomethacin and naproxen dissolution can be effectively improved by formulation design and by improving their solvation performance. CONCLUSIONS: The chemical-potential-gradient model combined with PC-SAFT can be used to analyze the dissolution mechanism of solid dispersions and to describe and predict the dissolution profiles of API as function of stirring speed, temperature and pH value of the medium. This work helps to find appropriate ways to improve the dissolution rate of poorly-soluble APIs. PMID- 25715697 TI - Improvement of Oral Bioavailability of N-251, a Novel Antimalarial Drug, by Increasing Lymphatic Transport with Long-Chain Fatty Acid-Based Self Nanoemulsifying Drug Delivery System. AB - PURPOSE: The objective of this study was to improve the absorption behavior of N 251, a novel antimalarial drug, by preparing an appropriate self-nanoemulsifying drug delivery system (SNEDDS). METHODS: Two different types of SNEDDS formulations, medium-chain fatty acid-based SNEDDS (MC-SNEDDS) and long-chain fatty acid-based SNEDDS (LC-SNEDDS), were prepared based on pseudo-ternary phase diagram, and examined for their in vivo oral absorption behavior in rats. RESULTS: Oral dosing of MC-SNEDDS formulations significantly improved the bioavailability (BA) of N-251 compared with N-251 powders. However, its high hepatic extraction limited the BA of N-251 to only 0.49 for MC-SNEDDS B, the best formulation of MC-SNEDDS. LC-SNEDDS formulations, especially LC-SNEDDS F provided the highest BA, 0.65, and successfully attenuated the inter-individual difference in the absorption behavior. Furthermore, it was confirmed that lymphatic transport of N-251 for LC-SNEDDS F was significantly increased up to around 3.19 times larger than that for MC-SNEDDS B. Simulation study suggested that 20 to 39% of N-251 uptaken by the small intestine would be delivered to lymphatic system after oral administration of LC-SNEDDS F. CONCLUSIONS: SNEDDS formulations significantly improved the absorption behavior of N-251 and long-chain fatty acid based lipid further improved it by avoiding the hepatic first-pass elimination. PMID- 25715698 TI - Overexpressed Macrophage Mannose Receptor Targeted Nanocapsules- Mediated Cargo Delivery Approach for Eradication of Resident Parasite: In Vitro and In Vivo Studies. AB - PURPOSE: Since, Leishmania protozoans are obligate intracellular parasites of macrophages, an immunopotentiating macrophage-specific Amphotericin B (AB) delivery system would be ideally appropriate to increase its superiority for leishmaniasis treatment and to eliminate undesirable toxicity. Herein, we report AB entrapped mannose grafted chitosan nanocapsules (MnosCNc-AB) that results in effective treatment of visceral leishmaniasis, while also enhancing L. donovani specific T-cell immune responses in infected host. METHODS: MnosCNc-AB were prepared via synthesized mannosylated chitosan deposition on interface of oil/water nanoemulsion intermediate and were characterized. J774A.1 macrophage uptake potential, antileishmanial activity and immunomodulatory profile were evaluated in hamster. Tissue localization, biodistribution and toxicity profile were also investigated. RESULTS: MnosCNc-AB had nanometric size (197.8 +/- 8.84 nm), unimodal distribution (0.115 +/- 0.04), positive zeta potential (+31.7 +/- 1.03 mV) and 97.5 +/- 1.13% cargo encapsulation efficiency. Superior macrophage internalization of mannosylated chitosan nanocapsules compared to unmodified chitosan nanocapsules was observed by fluorescence-based assessment, further confirmed by rapid blood clearance and, greater localization and higher accumulation in macrophage rich liver and spleen. While, MnosCNc-AB mediated cargo distribution to kidney decreased. Augmented in vitro antileishmanial activity and in vivo pro-inflammatory mediator's expression were observed with MnosCNc-AB, led to significant reduction (~90%) in splenic parasite burden. CONCLUSIONS: Results demonstrated that mannose ligand grafted chitosan nanocapsules could improve selective delivery of AB into macrophages via interactions with overexpressed mannose receptors thus reduce undesirable toxicity. Study provides evidence for MnosCNc-AB potential to leishmaniasis therapeutics and presents valuable therapeutic strategies for combating chronic macrophage-resident microbial infections. PMID- 25715699 TI - Leptin induces fasting hypoglycaemia in a mouse model of diabetes through the depletion of glycerol. AB - AIMS/HYPOTHESIS: Leptin has profound glucose-lowering effects in rodent models of type 1 diabetes, and is currently being tested clinically to treat this disease. In addition to reversing hyperglycaemia, leptin therapy corrects multiple lipid, energy and neuroendocrine imbalances in rodent models of type 1 diabetes, yet the precise mechanism has not been fully defined. Thus, we performed metabolic analyses to delineate the downstream metabolic pathway mediating leptin-induced glucose lowering in diabetic mice. METHODS: Mice were injected with streptozotocin (STZ) to induce insulin-deficient diabetes, and were subsequently treated with 20 MUg/day recombinant murine leptin or vehicle for 5 to 14 days. Energy-yielding substrates were measured in the liver and plasma, and endogenous glucose production was assessed by tolerance to extended fasting. RESULTS: STZ leptin-treated mice developed severe hypoketotic hypoglycaemia during prolonged fasting, indicative of suppressed endogenous ketone and glucose production. STZ leptin mice displayed normal gluconeogenic and glycogenolytic capacity, but had depleted circulating glycerol and NEFA. The depletion of glycerol and NEFA correlated tightly with the kinetics of glucose lowering in response to chronic leptin administration, and was not mimicked by single leptin injection. Administration of glycerol acutely reversed fasting-induced hypoglycaemia in leptin-treated mice. CONCLUSIONS/INTERPRETATION: The findings of this study suggest that the diminution of circulating glycerol reduces endogenous glucose production, contributing to severe fasting-induced hypoglycaemia in leptin treated rodent models of type 1 diabetes, and support that depletion of glycerol contributes to the glucose-lowering action of leptin. PMID- 25715700 TI - A case of an additional right external iliac vein surrounding the right external iliac artery and lacking the right common iliac vein. AB - A case of an additional right external iliac vein lacking a right common iliac vein was found in an 84-year-old female cadaver during a dissection course at Aichi Medical University in 2014. The findings are reported and discussed from the embryological and clinical viewpoints. The right and left iliac venous systems were macroscopically observed with attention to the homonymous arteries and the inferior vena cava. In this cadaver, a preaortic external iliac vein originated from a right external iliac vein and drained directly into the inferior vena cava. The preaortic and right external iliac veins surrounded the right external iliac artery. In addition, the right internal iliac vein drained into the left common iliac vein, and the right obturator vein drained into the right external iliac vein. Our findings suggested that normal external iliac veins developed from the ventral limb of the iliac venous system in this case. Our case has clinical importance for surgical complications such as hemorrhages in pelvic operations, phlebography, and especially central venous cauterization of the right femoral vein. PMID- 25715701 TI - An A/C germline single-nucleotide polymorphism in the TNFAIP3 gene is associated with advanced disease stage and survival in only surgically treated esophageal cancer. PMID- 25715702 TI - Caffeine inhibits glucose transport by binding at the GLUT1 nucleotide-binding site. AB - Glucose transporter 1 (GLUT1) is the primary glucose transport protein of the cardiovascular system and astroglia. A recent study proposes that caffeine uncompetitive inhibition of GLUT1 results from interactions at an exofacial GLUT1 site. Intracellular ATP is also an uncompetitive GLUT1 inhibitor and shares structural similarities with caffeine, suggesting that caffeine acts at the previously characterized endofacial GLUT1 nucleotide-binding site. We tested this by confirming that caffeine uncompetitively inhibits GLUT1-mediated 3-O methylglucose uptake in human erythrocytes [Vmax and Km for transport are reduced fourfold; Ki(app) = 3.5 mM caffeine]. ATP and AMP antagonize caffeine inhibition of 3-O-methylglucose uptake in erythrocyte ghosts by increasing Ki(app) for caffeine inhibition of transport from 0.9 +/- 0.3 mM in the absence of intracellular nucleotides to 2.6 +/- 0.6 and 2.4 +/- 0.5 mM in the presence of 5 mM intracellular ATP or AMP, respectively. Extracellular ATP has no effect on sugar uptake or its inhibition by caffeine. Caffeine and ATP displace the fluorescent ATP derivative, trinitrophenyl-ATP, from the GLUT1 nucleotide-binding site, but d-glucose and the transport inhibitor cytochalasin B do not. Caffeine, but not ATP, inhibits cytochalasin B binding to GLUT1. Like ATP, caffeine renders the GLUT1 carboxy-terminus less accessible to peptide-directed antibodies, but cytochalasin B and d-glucose do not. These results suggest that the caffeine binding site bridges two nonoverlapping GLUT1 endofacial sites-the regulatory, nucleotide-binding site and the cytochalasin B-binding site. Caffeine binding to GLUT1 mimics the action of ATP but not cytochalasin B on sugar transport. Molecular docking studies support this hypothesis. PMID- 25715703 TI - Regulation of basal promoter activity of the human thiamine pyrophosphate transporter SLC44A4 in human intestinal epithelial cells. AB - Microbiota of the large intestine synthesize considerable amount of vitamin B1 in the form of thiamine pyrophosphate (TPP). There is a specific high-affinity regulated carrier-mediated uptake system for TPP in human colonocytes (product of the SLC44A4 gene). The mechanisms of regulation of SLC44A4 gene expression are currently unknown. In this study, we characterized the SLC44A4 minimal promoter region and identified transcription factors important for basal promoter activity in colonic epithelial cells. The 5'-regulatory region of the SLC44A4 gene (1,022 bp) was cloned and showed promoter activity upon transient transfection into human colonic epithelial NCM460 cells. With the use of a series of 5'- and 3' deletion luciferase reporter constructs, the minimal genomic region that required basal transcription of the SLC44A4 gene expression was mapped between nucleotides -178 and +88 (using the distal transcriptional start site as +1). Mutational analysis performed on putative cis-regulatory elements established the involvement of ETS/ELF3 [E26 transformation-specific sequence (ETS) proteins], cAMP-responsive element (CRE), and SP1/GC-box sequence motifs in basal SLC44A4 promoter activity. By means of EMSA, binding of ELF3 and CRE-binding protein-1 (CREB-1) transcription factors to the SLC44A4 minimal promoter was shown. Contribution of CREB into SLC44A4 promoter activity was confirmed using NCM460 cells overexpressing CREB. We also found high expression of ELF3 and CREB-1 in colonic (NCM460) compared with noncolonic (ARPE19) cells, suggesting their possible contribution to colon-specific pattern of SLC44A4 expression. This study represents the first characterization of the SLC44A4 promoter and reports the importance of both ELF3 and CREB-1 transcription factors in the maintenance of basal promoter activity in colonic epithelial cells. PMID- 25715704 TI - Nonsynonymous single nucleotide polymorphisms of NHE3 differentially decrease NHE3 transporter activity. AB - Genetic determinants appear to play a role in susceptibility to chronic diarrhea, but the genetic abnormalities involved have only been identified in a few conditions. The Na+/H+ exchanger 3 (NHE3) accounts for a large fraction of physiologic intestinal Na+ absorption. It is highly regulated through effects on its intracellular COOH-terminal regulatory domain. The impact of genetic variation in the NHE3 gene, such as single nucleotide polymorphisms (SNPs), on transporter activity remains unexplored. From a total of 458 SNPs identified in the entire NHE3 gene, we identified three nonsynonymous mutations (R474Q, V567M, and R799C), which were all in the protein's intracellular COOH-terminal domain. Here we evaluated whether these SNPs affect NHE3 activity by expressing them in a mammalian cell line that is null for all plasma membrane NHEs. These variants significantly reduced basal NHE3 transporter activity through a reduction in intrinsic NHE3 function in variant R474Q, abnormal trafficking in variant V567M, or defects in both intrinsic NHE3 function and trafficking in variant R799C. In addition, variants NHE3 R474Q and R799C failed to respond to acute dexamethasone stimulation, suggesting cells with these mutant proteins might be defective in NHE3 function during postprandial stimulation and perhaps under stressful conditions. Finally, variant R474Q was shown to exhibit an aberrant interaction with calcineurin B homologous protein (CHP), an NHE3 regulatory protein required for basal NHE3 activity. Taken together, these results demonstrate decreased transport activity in three SNPs of NHE3 and provide mechanistic insight into how these SNPs impact NHE3 function. PMID- 25715705 TI - A comparative study of the effects of 4-META/MMA-TBB resin and cyanoacrylate on wound healing of skin defects. AB - The purpose of this study was to investigate the healing process of wounded skin following the application of cyanoacrylate or a 4-(2-methacryloxyethyl) trimellitic anhydride/methyl methacrylate-tributylborane resin (4-META resin). Those materials were applied to skin wound areas in rats, and the regenerating tissues were biopsied and examined at days 1, 3, 5, 7, and 14. Paraffin-embedded specimens were sectioned and stained with hematoxylin and eosin or with Azan Mallory stain. Sections were also immunohistochemically stained with Pan cytokeratin and CD68 antibodies. In cyanoacrylate-treated wounds, CD68-positive cells were observed in the connective tissue and their number increased up to day 5. The wound surface was completely covered by epithelial tissue at day 14. In 4 META resin-treated wounds, CD68-positive cells appeared in the soft-tissue hybrid layer (STHL) and epithelial tissue had migrated under the STHL by day 5. The wound surface was completely covered by epithelial tissue at day 7. CD68-positive cells were distributed over the entire area of the cyanoacrylate-treated wounds, but accumulated under the STHL in the 4-META resin-treated wounds. In conclusion, the results suggest that covering skin defects with a 4-META resin is an effective strategy to promote wound healing compared to cyanoacrylate. PMID- 25715706 TI - Dynamic combinatorial chemistry on a monolayer protected gold nanoparticle. AB - Here, we show that the addition of Hg(2+) or Ag(+) metal ions to a dynamic system composed of monolayer protected gold nanoparticles (Au NPs) and a mixture of four nucleotides (dGMP, dAMP, TMP, and dCMP) leads to the self-selection of TMP or dGMP, respectively, on the monolayer surface. PMID- 25715707 TI - Effect of ovarian hormones on maturation of dendritic cells from peripheral blood monocytes in dogs. AB - Previously, we reported that ovarian hormones affect the immune response against E. coli isolated from the dogs affected with pyometra. In order to investigate mechanisms underlying the immune modulation, we examined the effects of ovarian hormones on the generation of dendritic cells (DCs), the most potent antigen presenting cell. DCs were differentiated from peripheral blood monocytes (PBMOs) using a cytokine cocktail. Both estrogen receptor and progesterone receptors were expressed by the PBMOs and immature DCs. When various ovarian hormones were added to the culture for the DC differentiation, progesterone significantly decreased the expression of DC maturation markers, such as CD1a, CD80 and CD86, on mature DCs. Conversely, the addition of estrogen to the cultures increased the expression of CD86, but not other maturation makers. Furthermore, DCs differentiated in the presence of progesterone did not stimulate allogeneic mononuclear cells in PB. Taken together, these results indicate that progesterone diminishes the maturation of DCs, leading to decreased immune responses against invading pathogens. PMID- 25715709 TI - Imaging of the elbow in children with wrist fracture: an unnecessary source of radiation and use of resources? AB - BACKGROUND: Anecdotally accepted practice for evaluation of children with clinically suspected or radiographically proven wrist fracture in many urgent care and primary care settings is concurrent imaging of the forearm and elbow, despite the lack of evidence to support additional images. These additional radiographs may be an unnecessary source of radiation and use of health care resources. OBJECTIVE: Our study assesses the necessity of additional radiographs of the forearm and elbow in children with wrist injury. MATERIALS AND METHODS: We reviewed electronic medical records of children 17 and younger in whom wrist fracture was diagnosed in the emergency department. We identified the frequency with which additional radiographs of the proximal forearm and distal humerus demonstrated another site of acute injury. RESULTS: We identified 214 children with wrist fracture. Of those, 129 received additional radiographs of the elbow. Physical examination findings proximal to the wrist were documented in only 16 (12%) of these 129 children. A second injury proximal to the wrist fracture was present in 4 (3%) of these 129 children, all of whom exhibited physical examination findings at the elbow. No fractures were documented in children with a negative physical examination of the elbow. CONCLUSION: Although elbow fractures occasionally complicate distal forearm fractures in children, our findings indicate that a careful physical evaluation of the elbow is sufficient to guide further radiographic investigation. Routine radiographs of both the wrist and elbow in children with distal forearm fracture appear to be unnecessary when an appropriate physical examination is performed. PMID- 25715708 TI - Expression profiling analysis of the microRNA response of Cynoglossus semilaevis to Vibrio anguillarum and other stimuli. AB - To investigate the roles of microRNAs (miRNA) of Cynoglossus semilaevis in response to Vibrio anguillarum that were previously identified using high throughput sequencing, microarray analyses was performed on three small RNA libraries (CG, NOSG, and HOSG) prepared from C. semilaevis immune tissues. In total, of 1279 designed probes, 739 (57.78 %) were detectable. The expression levels of these miRNAs were analyzed using pairwise comparisons among the three libraries, and a total of 99 miRNAs were observed to be significantly differentially expressed. The expression patterns of 10 differentially expressed miRNAs were validated by real-time quantitative PCR (RT-qPCR). In addition, expression of miR-142-5p, miR-223, and miR-181a in response to V. anguillarum at numerous time-points in four tissues, as well as the responses to lipopolysaccharide (LPS), polyinosinic:polycytidylic acid (poly I:C), peptidoglycan (PGN), and red-spotted grouper nervous necrosis virus (RGNNV) in head kidney cells, were studied by qRT-PCR. Taken together, all of the expression profiles showed significant differences compared to the control group; both similarities and differences in the expression responses to the same pathogen were observed. Collectively, these findings highlighted the putative roles for miRNAs in the context of the innate immune response of C. semilaevis exposing to pathogens and that further studies are needed to understand the molecular mechanisms of miRNA regulation in C. semilaevis host-pathogen interactions. PMID- 25715711 TI - Marijuana: a time-honored but untested treatment for epilepsy. AB - The biology of the endocannabinoid system in the brain provides a possible basis for a beneficial pharmacological effect of marijuana on seizures. However, evidence for efficacy of cannabis treatment of epilepsy is anecdotal because no acceptable randomized controlled trials have been done. Proper dosage and means of administration remain unknown. Cannabis is safer than other controlled substances, including tobacco or alcohol, and appears to be relatively safe compared with most pharmaceuticals used to treat epilepsy. This is a review of this topic from a Canadian perspective. PMID- 25715710 TI - Responses of solid tumor cells in DMEM to reactive oxygen species generated by non-thermal plasma and chemically induced ROS systems. AB - In this study, we assessed the role of different reactive oxygen species (ROS) generated by soft jet plasma and chemical-induced ROS systems with regard to cell death in T98G, A549, HEK293 and MRC5 cell lines. For a comparison with plasma, we generated superoxide anion (O2(-)), hydroxyl radical (HO.), and hydrogen peroxide (H2O2) with chemicals inside an in vitro cell culture. Our data revealed that plasma decreased the viability and intracellular ATP values of cells and increased the apoptotic population via a caspase activation mechanism. Plasma altered the mitochondrial membrane potential and eventually up-regulated the mRNA expression levels of BAX, BAK1 and H2AX gene but simultaneously down-regulated the levels of Bcl-2 in solid tumor cells. Moreover, a western blot analysis confirmed that plasma also altered phosphorylated ERK1/2/MAPK protein levels. At the same time, using ROS scavengers with plasma, we observed that scavengers of HO. (mannitol) and H2O2 (catalase and sodium pyruvate) attenuated the activity of plasma on cells to a large extent. In contrast, radicals generated by specific chemical systems enhanced cell death drastically in cancer as well as normal cell lines in a dose-dependent fashion but not specific with regard to the cell type as compared to plasma. PMID- 25715712 TI - When the mean is an empty plate for clinicians and scientists, and a full plate for politicians and writers. PMID- 25715713 TI - Extreme root resorption associated with induced tooth movement: a protocol for clinical management. AB - Cases in which teeth have only the cervical third remaining from orthodontically induced external root resorption, cast the following doubts: 1) What care should be taken to keep these teeth in mouth with the least risk possible? 2) What care should be taken with regards to reading of imaging exams, particularly in terms of accurately determining cervical root and bone loss? 3) Why is not endodontic treatment recommended in these cases? The present study aims at shedding light on the aforementioned topics so as to induce new insights into the theme. PMID- 25715714 TI - What is gold standard and what is ground truth? PMID- 25715715 TI - An interview with Arno Locks. PMID- 25715716 TI - Measurement accuracy and reliability of tooth length on conventional and CBCT reconstructed panoramic radiographs. AB - INTRODUCTION: This in vivo study assessed accuracy and reliability of tooth length measurements obtained from conventional panoramic radiographs and CBCT panoramic reconstructions to that of a digital caliper (gold standard). METHODS: The sample consisted of subjects who had CBCT and conventional panoramic radiographic imaging and who required maxillary premolar extraction for routine orthodontic treatment. A total of 48 teeth extracted from 26 subjects were measured directly with digital calipers. Radiographic images were scanned and digitally measured in Dolphin 3D software. Accuracy of tooth length measurements made by CBCT panoramic reconstructions, conventional panoramic radiographs and digital caliper (gold standard) were compared to each other by repeated measures one-way ANOVA with Bonferroni correction and by single measures intraclass correlation coefficient. RESULTS: Repeated root length measures with digital calipers, panoramic radiographs and CBCT constructed panoramic-like images were all individually highly reliable. Compared to the caliper (gold standard), tooth measurements obtained from conventional panoramic radiographs were on average 6.3 mm (SD = 2.0 mm) longer, while tooth measurements from CBCT panoramic reconstructions were an average of 1.7 mm (SD = 1.2 mm) shorter. CONCLUSIONS: In comparison to actual tooth lengths, conventional panoramic radiographs were relatively inaccurate, overestimating the lengths by 29%, while CBCT panoramic reconstructions underestimated the lengths by 4%. PMID- 25715717 TI - Facial height in Japanese-Brazilian descendants with normal occlusion. AB - OBJECTIVE: The aim of this study was to determine the standards of facial height in 30 young (14-year-old) Japanese-Brazilian descendants with normal occlusion, and assess whether sexual dimorphism is evident. METHODS: The cephalometric measurements used followed the analyses by Wylie-Johnson, Siriwat-Jarabak, Gebeck, Merrifield and Horn. RESULTS: Results showed dimorphism for total anterior facial height (TAFH), lower anterior facial height (LAFH), anterior facial height (AFH), total posterior facial height (TPFH) and upper posterior facial height (UPFH) measurements. CONCLUSIONS: The standards of facial heights in young Japanese-Brazilian descendants with normal occlusion were observed. Sexual dimorphism was identified in five out of thirteen evaluated variables at this age range. PMID- 25715718 TI - Bruxism in children and transverse plane of occlusion: is there a relationship or not? AB - OBJECTIVE: To assess the occurrence of bruxism in deciduous dentition and a potential association between the habit and the presence or absence of posterior crossbite. METHODS: A total of 940 patient files were assessed. They were gathered from the archives of University of Sao Paulo City--UNICID; however, 67 patient files were dismissed for not meeting the inclusion criteria. Therefore, 873 children, males and females, comprised the study sample. They were aged between 2-6 years old and came from six different public primary schools from the east of the city of Sao Paulo. Data were collected through questionnaires answered by parents/guardians and by clinical examinations carried out in the school environment in order to obtain the occlusal characteristics in the transverse direction. First, a descriptive statistical analysis of all variables was performed (age, sex, race, posterior crossbite, bruxism, headache and restless sleep); then, the samples were tested by means of chi-square test with significance level set at 0.05%. A logistic regression model was applied to identify the presence of bruxism. RESULTS: The prevalence of this parafunctional habit was of 28.8%, with 84.5% of patients showing no posterior crossbite. Regarding the association of bruxism with crossbite, significant results were not found. Children with restless sleep have 2.1 times more chances of developing bruxism, whereas children with headache have 1.5 more chances. CONCLUSION: Transverse plane of occlusion was not associated with the habit of bruxism. PMID- 25715719 TI - Photoelastic analysis of stress generated by wires when conventional and self ligating brackets are used: a pilot study. AB - OBJECTIVE: By means of a photoelastic model, this study analyzed the stress caused on conventional and self-ligating brackets with expanded arch wires. METHOD: Standard brackets were adhered to artificial teeth and a photoelastic model was prepared using the Interlandi 19/12 diagram as base. Successive activations were made with 0.014-in and 0.018-in rounded cross section Nickel Titanium wires (NiTi) and 0.019 x 0.025-in rectangular stainless steel wires all of which made on 22/14 Interlandi diagram. The model was observed on a plane polariscope--in a dark field microscope configuration--and photographed at each exchange of wire. Then, they were replaced by self-ligating brackets and the process was repeated. Analysis was qualitative and observed stress location and pattern on both models analyzed. CONCLUSIONS: Results identified greater stress on the region of the apex of premolars in both analyzed models. Upon comparing the stress between models, a greater amount of stress was found in the model with conventional brackets in all of its wires. Therefore, the present pilot study revealed that alignment of wires in self-ligating brackets produced lower stress in periodontal tissues in expansive mechanics. PMID- 25715720 TI - Transverse effects on the nasomaxillary complex one year after rapid maxillary expansion as the only intervention: a controlled study. AB - The aim of this study was to assess by means of cone-beam computed tomography (CBCT) scans the transverse effects on the nasomaxillary complex in patients submitted to rapid maxillary expansion (RME) using Haas expander in comparison to untreated individuals. This prospective controlled clinical study assessed 30 subjects (18 boys and 12 girls) with mixed dentition and during pubertal growth. The treated group was submitted to RME with Haas expander, retention for six months and a six-month follow-up after removal. The control group matched the treated group in terms of age and sex distribution. CBCT scans were taken at treatment onset and one year after the expander was activated. Maxillary first molars (U6) width, right and left U6 angulation, maxillary alveolar width, maxillary basal width, palatal alveolar width, palatal base width, right and left alveolar angulation, palatal area, nasal base width, nasal cavity width and inferior nasal cavity area on the posterior, middle and anterior coronal slices were measured with Dolphin Imaging Software(r) 11.5, except for the first two variables which were performed only on the posterior slice. All transverse dimensions increased significantly (P < 0.05) in the treated group in comparison to the control, except for alveolar angulation and inferior nasal cavity area (P > 0.05). Results suggest that increase of molar, maxillary, palatal and nasal transverse dimensions was stable in comparison to the control group one year after treatment with RME. PMID- 25715721 TI - Rapid maxillary expansion effects: an alternative assessment method by means of cone-beam tomography. AB - INTRODUCTION: This study aims to develop a method to assess the changes in palatal and lingual cross-sectional areas in patients submitted to rapid maxillary expansion (RME). METHODS: The sample comprised 31 Class I malocclusion individuals submitted to RME and divided into two groups treated with Haas (17 patients) and Hyrax (14 patients) expanders. Cone-beam computed tomography scans were acquired at T0 (before expansion ) and T1 (six months after screw stabilization). Maxillary and mandibular cross-sectional areas were assessed at first permanent molars and first premolars regions and compared at T0 and T1. Mandibular occlusal area was also analyzed. RESULTS: Maxillary cross-sectional areas increased in 56.18 mm2 and 44.32 mm2 for the posterior and anterior regions. These values were smaller for the mandible, representing augmentation of 40.32 mm2 and 39.91 mm2 for posterior and anterior sections. No differences were found when comparing both expanders. Mandibular occlusal area increased 43.99mm2 and mandibular incisors proclined. Increments of 1.74 mm and 1.7 mm occurred in mandibular intermolar and interpremolar distances. These same distances presented increments of 5.5 mm and 5.57 mm for the maxillary arch. CONCLUSION: Occlusal and cross-sectional areas increased significantly after RME. The method described seems to be reliable and precise to assess intraoral area changes. PMID- 25715722 TI - Analysis of correlation between initial alveolar bone density and apical root resorption after 12 months of orthodontic treatment without extraction. AB - OBJECTIVE: The aim of the present study was to investigate the correlation between initial alveolar bone density of upper central incisors (ABD-UI) and external apical root resorption (EARR) after 12 months of orthodontic movement in cases without extraction. METHODS: A total of 47 orthodontic patients 11 years old or older were submitted to periapical radiography of upper incisors prior to treatment (T1) and after 12 months of treatment (T2). ABD-UI and EARR were measured by means of densitometry. RESULTS: No statistically significant correlation was found between initial ABD-UI and EARR at T2 (r = 0.149; p = 0.157). CONCLUSION: Based on the present findings, alveolar density assessed through periapical radiography is not predictive of root resorption after 12 months of orthodontic treatment in cases without extraction. PMID- 25715723 TI - Factors associated with the prevalence of anterior open bite among preschool children: a population-based study in Brazil. AB - INTRODUCTION: The aim of this study was to identify factors associated with the prevalence of anterior open bite among five-year-old Brazilian children. METHODS: A cross-sectional study was undertaken using data from the National Survey of Oral Health (SB Brazil 2010). The outcome variable was anterior open bite classified as present or absent. The independent variables were classified by individual, sociodemographic and clinical factors. Data were analyzed through bivariate and multivariate analysis using SPSS statistical software (version 18.0) with a 95% level of significance. RESULTS: The prevalence of anterior open bite was 12.1%. Multivariate analysis showed that preschool children living in Southern Brazil had an increased chance of 1.8 more times of having anterior open bite (CI 95%: 1.16-3.02). Children identified with alterations in overjet had 14.6 times greater chances of having anterior open bite (CI 95%: 8.98-24.03). CONCLUSION: There was a significant association between anterior open bite and the region of Brazil where the children lived, the presence of altered overjet and the prevalence of posterior crossbite. PMID- 25715724 TI - Brazilian primary school teachers' knowledge about immediate management of dental trauma. AB - OBJECTIVE: To assess the level of knowledge of primary school teachers in the public school network of Northeastern Brazil with respect to management of dental trauma and its relationship with prognosis. METHODS: A questionnaire was applied to 195 school teachers of public schools in Northeastern Brazil. The questionnaire comprised 12 objective questions about dental trauma and methods for its prevention and management. Data were submitted to chi-square test and Poisson regression test (P > 0.05). RESULTS: Out of the 141 teachers who responded the questionnaires, the majority were women (70.2%) and most of them had experienced previous dental accidents involving a child (53.2%). The majority (84.4%) had incomplete college education and few were given some training on how to deal with emergency situations during their undergraduate course (13.5%) or after it (38.3%). Their level of knowledge about dental trauma and emergency protocols showed that unsatisfactory knowledge level was associated with the male sex: 46% higher for men in comparison to women (P = 0.025). CONCLUSIONS: Approximately half of teachers evaluated had unsatisfactory knowledge about dental trauma and emergency protocols, with female teachers showing more knowledge than men. PMID- 25715725 TI - Determining shapes and dimensions of dental arches for the use of straight-wire arches in lingual technique. AB - INTRODUCTION: This study aims to determine the shape and dimension of dental arches from a lingual perspective, and determine shape and size of a straight archwire used for lingual Orthodontics. METHODS: The study sample comprised 70 Caucasian Brazilian individuals with normal occlusion and at least four of Andrew's six keys. Maxillary and mandibular dental casts were digitized (3D) and the images were analyzed by Delcam Power SHAPET 2010 software. Landmarks on the lingual surface of teeth were selected and 14 measurements were calculated to determine the shape and size of dental arches. RESULTS: Shapiro-Wilk test determined small arch shape by means of 25th percentile (P25%)--an average percentile for the medium arch; and a large one determined by means of 75th percentile (P75%). T-test revealed differences between males and females in the size of 12 dental arches. CONCLUSION: The straight-wire arch shape used in the lingual straight wire technique is a parabolic-shaped arch, slightly flattened on its anterior portion. Due to similarity among dental arch sizes shown by males and females, a more simplified diagram chart was designed. PMID- 25715726 TI - Class III treatment using facial mask: stability after 10 years. AB - Early Class III malocclusion treatment may not have long-term stability due to mandibular growth. Although some features of this malocclusion point to a better prognosis, it is practically impossible for the orthodontist to foresee cases that require new intervention. Many patients need retreatment, whether compensatory or orthodontic-surgical. The present study reports the case of a Class III patient treated at the end of the mixed dentition with the use of a face mask followed by conventional fixed appliances. The case remains stable 10 years after treatment completion. It was presented to the Brazilian Board of Orthodontics and Dentofacial Orthopedics (BBO) as a requirement for the title of certified by the BBO. PMID- 25715729 TI - Retraction Note to: Inhibition of Lipopolysaccharide (LPS)-Induced Inflammatory Responses by Selenium in Bovine Mammary Epithelial Cells in Primary Culture. PMID- 25715727 TI - Is there a consensus for CBCT use in Orthodontics? AB - This article aims to discuss current evidence and recommendations for cone-beam computed tomography (CBCT) in Orthodontics. In comparison to conventional radiograph, CBCT has higher radiation doses and, for this reason, is not a standard method of diagnosis in Orthodontics. Routine use of CBCT in substitution to conventional radiograph is considered an unaccepted practice. CBCT should be indicated with criteria only after clinical examination has been performed and when the benefits for diagnosis and treatment planning exceed the risks of a greater radiation dose. It should be requested only when there is a potential to provide new information not demonstrated by conventional scans, when it modifies treatment plan or favors treatment execution. The most frequent indication of CBCT in Orthodontics, with some evidence on its clinical efficacy, includes retained/impacted permanent teeth; severe craniofacial anomalies; severe facial discrepancies with indication of orthodontic-surgical treatment; and bone irregularities or malformation of TMJ accompanied by signs and symptoms. In exceptional cases of adult patients when critical tooth movement are planned in regions with deficient buccolingual thickness of the alveolar ridge, CBCT can be indicated provided that there is a perspective of changes in orthodontic treatment planning. PMID- 25715730 TI - dPob/EMC is essential for biosynthesis of rhodopsin and other multi-pass membrane proteins in Drosophila photoreceptors. AB - In eukaryotes, most integral membrane proteins are synthesized, integrated into the membrane, and folded properly in the endoplasmic reticulum (ER). We screened the mutants affecting rhabdomeric expression of rhodopsin 1 (Rh1) in the Drosophila photoreceptors and found that dPob/EMC3, EMC1, and EMC8/9, Drosophila homologs of subunits of ER membrane protein complex (EMC), are essential for stabilization of immature Rh1 in an earlier step than that at which another Rh1 specific chaperone (NinaA) acts. dPob/EMC3 localizes to the ER and associates with EMC1 and calnexin. Moreover, EMC is required for the stable expression of other multi-pass transmembrane proteins such as minor rhodopsins Rh3 and Rh4, transient receptor potential, and Na(+)K(+)-ATPase, but not for a secreted protein or type I single-pass transmembrane proteins. Furthermore, we found that dPob/EMC3 deficiency induces rhabdomere degeneration in a light-independent manner. These results collectively indicate that EMC is a key factor in the biogenesis of multi-pass transmembrane proteins, including Rh1, and its loss causes retinal degeneration. PMID- 25715731 TI - Macrocyclic dinuclear, helical, layered and 3-D Ag(I) complexes constructed from AgX (X = NO3(-) and ClO4(-)) and flexible bis(pyridyl) ligands with a chelating spacer: syntheses, structures and photoluminescence properties. AB - Reaction of AgX (X = NO3- and ClO4-) and three flexible bis(pyridyl) ligands with a chelating spacer leads to the formation of eight novel Ag(I)-bis(pyridyl) coordination complexes: {[Ag2L1(NO3)2]n.2nH2O} (1), {[AgL1]n.nClO4} (2), {[AgL2]n.nNO3} (3), {[AgL2]n.nClO4} (4), [Ag2(H2L2)2].6ClO4.9H2O (5), {[AgL3]n.nNO3.nH2O} (6), {[AgL3]n.nClO4.nH2O} (7), and {[Ag3(L3)2(ClO4)]n.2nClO4} (8) (L1 = N,N'-bis(pyridin-2-ylmethyl)propane-1,3-diamine, L2 = N,N'-bis(pyridin 3-ylmethyl)propane-1,3-diamine, L3 = N,N'-bis(pyridin-4-ylmethyl)propane-1,3 diamine), which have been characterized by elemental analysis, IR, TG, UV-Vis DRS, PL, powder and single-crystal X-ray diffraction. Complex 1 presents a (4,4) layered motif which is furnished by the bridging of L1 molecules and nitrate anions in MU4 (kappa1N1:kappa1N2:kappa1N3:kappa1N4) and MU2 (kappa1O4:kappa1O6) modes. With a different MU2 (kappa1N1:kappa1N2:kappa1N3:kappa1N4) mode, L1 molecules in complex 2 join the adjacent Ag(I) cations to form a helical chain structure. Complexes 3 and 4 also show helical chain structures with the L2 molecules displaying the same MU3 (kappa1N1:kappa1N2:kappa1N3:kappa1N4) mode. The protonation of -NH- groups in the chelating spacer leads to the formation of H2L22+ cations which further results in a macrocyclic dinuclear motif in complex 5. Complexes 6 and 7 are 3-D svi-x nets with the counter-anions and lattice water molecules being encapsulated in the 1-D channels. Complex 8 exhibits a snake shaped chain with the L3 molecules presenting MU3 (kappa1N:kappa1N':kappa1N":kappa1N) mode. The structural diversities of complexes 1-8 can be attributed to the coordination modes and conformations of L1-L3. The photoluminescence properties demonstrate that complexes 1, 2 and 5 exhibit ligand based blue emission maxima from 455 to 462 nm at room temperature in the solid state. PMID- 25715732 TI - Effects of tissue stiffness, ultrasound frequency, and pressure on histotripsy induced cavitation bubble behavior. AB - Histotripsy is an ultrasound ablation method that controls cavitation to fractionate soft tissue. In order to effectively fractionate tissue, histotripsy requires cavitation bubbles to rapidly expand from nanometer-sized initial nuclei into bubbles often larger than 50 um. Using a negative pressure high enough to initiate a bubble cloud and expand bubbles to a sufficient size, histotripsy has been shown capable of completely fractionating soft tissue into acelluar debris resulting in effective tissue removal. Previous work has shown that the histotripsy process is affected by tissue mechanical properties with stiffer tissues showing increased resistance to histotripsy fractionation, which we hypothesize to be caused by impeded bubble expansion in stiffer tissues. In this study, the hypothesis that increases in tissue stiffness cause a reduction in bubble expansion was investigated both theoretically and experimentally. High speed optical imaging was used to capture a series of time delayed images of bubbles produced inside mechanically tunable agarose tissue phantoms using histotripsy pulses produced by 345 kHz, 500 kHz, 1.5 MHz, and 3 MHz histotripsy transducers. The results demonstrated a significant decrease in maximum bubble radius (Rmax) and collapse time (tc) with both increasing Young's modulus and increasing frequency. Furthermore, results showed that Rmax was not increased by raising the pressure above the intrinsic threshold. Finally, this work demonstrated the potential of using a dual-frequency strategy to modulate the expansion of histotripsy bubbles. Overall, the results of this study improve our understanding of how tissue stiffness and ultrasound parameters affect histotripsy-induced bubble behavior and provide a rational basis to tailor acoustic parameters for treatment of the specific tissues of interest. PMID- 25715733 TI - Investigating Treatment Outcomes Across OCD Symptom Dimensions in a Clinical Sample of OCD Patients. AB - Despite the heterogeneous nature of obsessive-compulsive disorder (OCD), many self-report assessments do not adequately capture the clinical picture presenting within each symptom dimension, particularly unacceptable thoughts (UTs). In addition, obsessions and ordering/arranging compulsions are often underrepresented in samples of treatment outcome studies for OCD. Such methodological discrepancies may obscure research findings comparing treatment outcomes across OCD symptom dimensions. This study aimed to improve upon previous research by investigating treatment outcomes across OCD symptom dimensions using the Dimensional Obsessive-Compulsive Scale, which offers a more comprehensive assessment of UTs. The study included a primarily residential sample of 134 OCD patients. Results indicated that there were no significant differences in treatment outcomes across symptom dimensions. However, the severity of UTs remained significantly greater than other symptom dimensions at both admission and discharge. Thus, it is possible that UTs may exhibit uniquely impairing features, compared with other symptom dimensions. It is also possible that these findings may reflect the characteristics of the residential OCD samples. These speculations as well as implications for OCD treatment and future research are discussed. PMID- 25715734 TI - Isolation and characterization of arylacetamide deacetylase in cynomolgus macaques. AB - Arylacetamide deacetylase (AADAC), a microsomal serine esterase, hydrolyzes drugs, such as flutamide, phenacetin and rifampicin. Because AADAC has not been fully investigated at molecular levels in cynomolgus macaques, the non-human primate species widely used in drug metabolism studies, cynomolgus AADAC cDNA was isolated and characterized. The deduced amino acid sequence, highly homologous (92%) to human AADAC, was more closely clustered with human AADAC than the dog, rat or mouse ortholog in a phylogenetic tree. AADAC was flanked by AADACL2 and SUCNR1 in the cynomolgus and human genomes. Moreover, relatively abundant expression of AADAC mRNA was found in liver and jejunum, the drug-metabolizing organs, in cynomolgus macaques, similar to humans. The results suggest molecular similarities of AADAC between cynomolgus macaques and humans. PMID- 25715735 TI - Validity of parent's self-reported responses to home safety questions. AB - The aim of the study was to describe the validity of parent's self-reported responses to questions on home safety practices for children of 2-4 years. A cross-sectional validation study compared parent's self-administered responses to items in the Home Injury Prevention Survey with home observations undertaken by trained researchers. The relationship between the questionnaire and observation results was assessed using percentage agreement, sensitivity, specificity, positive predictive value, negative predictive value and intraclass correlation coefficients. Percentage agreements ranged from 44% to 100% with 40 of the total 45 items scoring higher than 70%. Sensitivities ranged from 0% to 100%, with 27 items scoring at least 70%. Specificities also ranged from 0% to 100%, with 33 items scoring at least 70%. As such, the study identified a series of self administered home safety questions that have sensitivities, specificities and predictive values sufficiently high to allow the information to be useful in research and injury prevention practice. PMID- 25715736 TI - Extracorporeal treatment for theophylline poisoning: systematic review and recommendations from the EXTRIP workgroup. AB - BACKGROUND: The Extracorporeal Treatments in Poisoning workgroup was created to provide evidence-based recommendations on the use of extracorporeal treatments (ECTRs) in poisoning. Here, the workgroup presents its systematic review and recommendations for theophylline. METHODS: After a systematic review of the literature, a subgroup reviewed articles, extracted data, summarized findings, and proposed structured voting statements following a pre-determined format. A two-round modified Delphi method was chosen to reach a consensus on voting statements and the RAND/UCLA Appropriateness Method was used to quantify disagreement. Anonymous votes were compiled, returned, and discussed. A second vote determined the final recommendations. RESULTS: 141 articles were included: 6 in vitro studies, 4 animal studies, 101 case reports/case series, 7 descriptive cohorts, 4 observational studies, and 19 pharmacokinetic studies, yielding a low to-very-low quality of evidence for all recommendations. Data on 143 patients were reviewed, including 10 deaths. The workgroup concluded that theophylline is dialyzable (level of evidence = A) and made the following recommendations: ECTR is recommended in severe theophylline poisoning (1C). Specific recommendations for ECTR include a theophylline concentration [theophylline] > 100 mg/L (555 MUmol/L) in acute exposure (1C), the presence of seizures (1D), life-threatening dysrhythmias (1D) or shock (1D), a rising [theophylline] despite optimal therapy (1D), and clinical deterioration despite optimal care (1D). In chronic poisoning, ECTR is suggested if [theophylline] > 60 mg/L (333 MUmol/L) (2D) or if the [theophylline] > 50 mg/L (278 MUmol/L) and the patient is either less than 6 months of age or older than 60 years of age (2D). ECTR is also suggested if gastrointestinal decontamination cannot be administered (2D). ECTR should be continued until clinical improvement is apparent or the [theophylline] is < 15 mg/L (83 MUmol/L) (1D). Following the cessation of ECTR, patients should be closely monitored. Intermittent hemodialysis is the preferred method of ECTR (1C). If intermittent hemodialysis is unavailable, hemoperfusion (1C) or continuous renal replacement therapies may be considered (3D). Exchange transfusion is an adequate alternative to hemodialysis in neonates (2D). Multi dose activated charcoal should be continued during ECTR (1D). CONCLUSION: Theophylline poisoning is amenable to ECTRs. The workgroup recommended extracorporeal removal in the case of severe theophylline poisoning. PMID- 25715738 TI - Notch ligand delta-like1: X-ray crystal structure and binding affinity. AB - The Notch pathway is a fundamental signalling system in most multicellular animals. We have determined the X-ray crystal structure of the extracellular domain of the Notch ligand delta-like ligand-1 (Dll-1). The structure incorporates the N-terminal C2 domain, receptor-binding DSL domain and the first six (of eight) EGF (epidermal growth factor)-like repeats, which form a highly extended conformation, confirmed by analytical ultracentrifugation. Comparison of our structure with a fragment of Jagged1 ligand allows us to dissect the similarities and differences between the ligand families. Differences in the C2 domains of Dll-1 and Jagged1 suggest their lipid-binding properties are likely to differ. A conserved hydrophobic patch on the surface of both Dll-1 and Jagged1 provides a likely receptor-interaction site that is common to both ligands. We also explore the binding affinity of Dll-1 for a fragment of Notch1 using different techniques. Apparent binding affinities vary when different techniques are used, explaining discrepancies in the literature. Using analytical ultracentrifugation, we perform for the first time binding analyses where both receptor and ligand are in solution, which confirms a Kd of 10 MUM for this interaction. PMID- 25715737 TI - Defining the gene repertoire and spatiotemporal expression profiles of adhesion G protein-coupled receptors in zebrafish. AB - BACKGROUND: Adhesion G protein-coupled receptors (aGPCRs) are the second largest of the five GPCR families and are essential for a wide variety of physiological processes. Zebrafish have proven to be a very effective model for studying the biological functions of aGPCRs in both developmental and adult contexts. However, aGPCR repertoires have not been defined in any fish species, nor are aGPCR expression profiles in adult tissues known. Additionally, the expression profiles of the aGPCR family have never been extensively characterized over a developmental time-course in any species. RESULTS: Here, we report that there are at least 59 aGPCRs in zebrafish that represent homologs of 24 of the 33 aGPCRs found in humans; compared to humans, zebrafish lack clear homologs of GPR110, GPR111, GPR114, GPR115, GPR116, EMR1, EMR2, EMR3, and EMR4. We find that several aGPCRs in zebrafish have multiple paralogs, in line with the teleost-specific genome duplication. Phylogenetic analysis suggests that most zebrafish aGPCRs cluster closely with their mammalian homologs, with the exception of three zebrafish-specific expansion events in Groups II, VI, and VIII. Using quantitative real-time PCR, we have defined the expression profiles of 59 zebrafish aGPCRs at 12 developmental time points and 10 adult tissues representing every major organ system. Importantly, expression profiles of zebrafish aGPCRs in adult tissues are similar to those previously reported in mouse, rat, and human, underscoring the evolutionary conservation of this family, and therefore the utility of the zebrafish for studying aGPCR biology. CONCLUSIONS: Our results support the notion that zebrafish are a potentially useful model to study the biology of aGPCRs from a functional perspective. The zebrafish aGPCR repertoire, classification, and nomenclature, together with their expression profiles during development and in adult tissues, provides a crucial foundation for elucidating aGPCR functions and pursuing aGPCRs as therapeutic targets. PMID- 25715739 TI - HIV-associated pulmonary arterial hypertension: from bedside to the future. AB - Pulmonary arterial hypertension (PAH) is a life-threatening complication of HIV infection. The prevalence of HIV-associated PAH (HIV-PAH) seems not to be changed over time, regardless of the introduction of highly active antiretroviral therapy (HAART). In comparison with the incidence of idiopathic PAH in the general population (1-2 per million), HIV-infected patients have a 2500-fold increased risk of developing PAH. HIV-PAH treatment is similar to that for all PAH conditions and includes lifestyle changes, general treatments and specific treatments. PMID- 25715740 TI - Measles outbreaks in Australia: obstacles to vaccination. PMID- 25715741 TI - Mononuclear phagocyte-mediated antifungal immunity: the role of chemotactic receptors and ligands. AB - Over the past two decades, fungal infections have emerged as significant causes of morbidity and mortality in patients with hematological malignancies, hematopoietic stem cell or solid organ transplantation and acquired immunodeficiency syndrome. Besides neutrophils and CD4(+) T lymphocytes, which have long been known to play an indispensable role in promoting protective antifungal immunity, mononuclear phagocytes are now being increasingly recognized as critical mediators of host defense against fungi. Thus, a recent surge of research studies has focused on understanding the mechanisms by which resident and recruited monocytes, macrophages and dendritic cells accumulate and become activated at the sites of fungal infection. Herein, we critically review how a variety of G-protein coupled chemoattractant receptors and their ligands mediate mononuclear phagocyte recruitment and effector function during infection by the most common human fungal pathogens. PMID- 25715742 TI - The role of FcepsilonRI expressed in dendritic cells and monocytes. AB - Early studies regarding the function of FcepsilonRI in dendritic cells (DCs) and monocytes have focused on its role in mediating inflammatory signaling and enhancing T cell immunity. It has been the case in part because FcepsilonRI is the major receptor that mediates allergic inflammatory signaling in mast cells and basophils and because DCs and monocytes are antigen presenting cells capable of activating naive and/or effector T cells. These studies have led to the general belief that FcepsilonRI-mediated DC signaling and antigen presentation promote development and activation of Th2 cells and contribute to allergic inflammatory diseases. However, this belief has long suffered from a lack of evidence. Recently, studies have emerged that provide evidence supporting an opposing role: that FcepsilonRI on DCs instead promotes immune homeostasis and regulation. In this review, we will update the current status of our understanding of FcepsilonRI biology and function, with a specific focus on DCs and monocytes. PMID- 25715745 TI - Trap-assisted photomultiplication polymer photodetectors obtaining an external quantum efficiency of 37,500%. AB - A smart strategy is reported to obtain photomultiplication (PM) type polymer photodetectors (PPDs) based on poly(3-hexylthiophene) (P3HT) and [6,6]-phenyl-C61 butyric acid methyl ester (PC61BM) which are commonly used in polymer solar cells. The PPDs with 1 wt % PC61BM exhibit a champion EQE of 37,500% under 625 nm illumination with an intensity of 8.87 MUW cm(-2) at -19 V bias. The PM phenomenon of PPDs with rather low PC61BM doping ratios should be attributed to the enhanced hole tunneling injection assisted by trapped electrons in PC61BM near the Al cathode, which can be completely demonstrated from (i) turning distribution of electron traps by changing P3HT:PC61BM doping weight ratios from 200:1 to 1:1; (ii) adjusting interfacial barrier width by inserting LiF layer between the active layer and the Al cathode. PMID- 25715744 TI - Direct identification of mycobacteria from clinical specimens by multiplex real time PCR. AB - AIMS: To directly identify clinically relevant mycobacteria from clinical specimens, we have developed a multiplex real-time PCR assay with hydrolysis probes that can identify 20 mycobacterial species. METHODS AND RESULTS: The assay was initially evaluated using 248 strains, including both reference strains and clinical isolates. Then, the assay was implemented according to a scheme in our laboratory. The scheme based on the clinical differences between the Mycobacterium tuberculosis complex (MTC) and nontuberculous mycobacteria (NTM) consisted of three stepwise PCRs. MTC and NTM were differentially detected in the step 1 PCR, and the NTM species were identified in the step 2 and step 3 PCRs. During a 2.5-year period, 1877 isolates of MTC (1142 directly recovered from clinical specimens) and 596 isolates of NTM (143 directly recovered from clinical specimens) were detected, and the species of 590 (99.0%) of the 596 NTM isolates were identified. CONCLUSIONS: Our experience shows that this is a new paradigm for rapidly and accurately identifying clinically relevant mycobacteria, in which a multiplex real-time PCR assay is directly applied to clinical specimens in a stepwise fashion. SIGNIFICANCE AND IMPACT OF THE STUDY: This study is the first report of a multiplex real-time PCR assay for identifying clinically important mycobacterial species directly from clinical specimens and its application in a clinical microbiology laboratory. PMID- 25715746 TI - Natural history of bleeding risk in colonic diverticulosis patients: a long-term colonoscopy-based cohort study. AB - BACKGROUND: The natural history of bleeding risk from colonic diverticulosis remains unclear. AIM: To identify the incidence of bleeding in colonic diverticulosis patients and associated risk factors. METHODS: A cohort of 1514 patients with colonoscopy-confirmed asymptomatic diverticulosis was selected between 2001 and 2013. Age, sex and location of colonic diverticulosis (right or left side, or bilateral) were assessed. The endpoint was a bleeding event, and data were censored at the time of last colonoscopy. The cumulative and overall incidences of bleeding were estimated using the Kaplan-Meier and person-years methods. The Cox proportional hazards model was used to estimate age- and sex adjusted hazard ratios (aHRs). RESULTS: The median follow-up period was 46 months. Bleeding events occurred in 35 patients, and the median time-to-event interval was 50 months. Kaplan-Meier analysis showed that the cumulative incidence of diverticular bleeding was 0.21% at 12 months, 2.2% at 60 months and 9.5% at 120 months. By the person-years method, the overall incidence rate of bleeding was 0.46 per 1000 patient-years. On multivariate analysis, age >=70 (aHR. 3.7) and bilateral diverticulosis (aHR, 2.4) were significant risk factors for bleeding. CONCLUSIONS: This long-term follow-up study demonstrated that the cumulative incidence of bleeding from diverticulosis was approximately 2% at 5 years and 10% at 10 years, and the overall incidence was 0.46 per 1000 patient years. Bilateral diverticulosis increased the risk of bleeding. PMID- 25715747 TI - The clinical characteristics and manifestations of cytomegalovirus esophagitis. AB - Esophagitis is the second most common gastrointestinal manifestation of cytomegalovirus (CMV) infection after colitis. CMV esophagitis has been reported in patients who have undergone transplantation, are on long-term renal dialysis, or who have the human immunodeficiency virus infection. This study aimed to investigate the clinical characteristics and manifestations of CMV esophagitis in patients who underwent diagnostic endoscopy. A total of 16 patients with histologically proven CMV infection were identified from 1539 patients with esophageal ulcers and analyzed retrospectively (January 2006 to December 2013). Patients' personal data (age, smoking, and alcohol consumption), underlying systemic diseases (diabetes mellitus, end-stage renal disease, and chronic obstructive pulmonary disease), malignancy, indication for esophagogastroduodenoscopy, endoscopic characteristics, and diagnostic methods (pathological or serological findings) were collected for further analysis. Among the patients with CMV esophagitis, the mean age was 59.94 years (range, 23-84 years). The male : female ratio was 1.67:1. Odynophagia and epigastralgia were common symptoms. Of the 16 patients, 3 (18.75%) were infected with the human immunodeficiency virus and 9 (56.25%) had an underlying malignancy, including lung cancer (6 patients), esophageal cancer (2 patients), gastric cancer (1 patient), ampulla of Vater cancer (1 patient), and lymphoma (1 patient). Six of the 9 patients (66.7%) with malignancy had been administered concurrent chemoradiotherapy (CCRT). In this study, patients with malignancy who had been administered CCRT were at increased risk for CMV esophagitis, which had not been reported before in the literature. CMV esophagitis should be considered as a potential treatment-related complication of CCRT. PMID- 25715743 TI - Eukaryotic enhancers: common features, regulation, and participation in diseases. AB - Enhancers are positive DNA regulatory sequences controlling temporal and tissue specific gene expression. These elements act independently of their orientation and distance relative to the promoters of target genes. Enhancers act through a variety of transcription factors that ensure their correct match with target promoters and consequent gene activation. There is a growing body of evidence on association of enhancers with transcription factors, co-activators, histone chromatin marks, and lncRNAs. Alterations in enhancers lead to misregulation of gene expression, causing a number of human diseases. In this review, we focus on the common characteristics of enhancers required for transcription stimulation. PMID- 25715748 TI - Paediatric cutaneous lymphomas: a review and comparison with adult counterparts. AB - Primary cutaneous lymphomas (CL) in children is rare. Only a few studies focused specifically on paediatric CL and therefore little is known whether primary CL in children are similar to or different from their adult counterparts with respect to the clinicopathological presentation, behaviour and prognosis. An extensive literature search using PubMed/MEDLINE from January 1995 through July 2014 was undertaken for articles reporting cases of paediatric CL. In addition, we identified 31 children with CL in our institutions. Mycosis fungoides and lymphomatoid papulosis are the two most prevalent lymphoma forms in children. A few entities of cutaneous lymphomas such as cutaneous diffuse large B-cell lymphoma leg type, and Sezary syndrome have not been reported so far in children. Other lymphoma entities such as hydroa vacciniforme-like lymphoma are mostly seen in certain geographic areas (Asia, Central and South America). In the paediatric population, low-malignant indolent forms such as primary cutaneous marginal zone lymphoma and primary cutaneous follicle centre lymphoma are very rare, whereas the more aggressive forms of B-cell lymphomas, precursor lymphoblastic lymphomas, and blastic plasmacytoid dendritic cell neoplasm are the most common forms in children, mostly involving the skin secondarily. Most paediatric lymphomas have similar clinicopathological features and course as their adults counterparts, particularly in the group of cutaneous T-cell lymphomas. The spectrum of cutaneous B-cell lymphomas in children significantly differs from the one in adults. Diagnostic work-up and treatment of paediatric patients with lymphomas are best achieved in close collaboration with paediatric haematopathologists and oncologists. PMID- 25715749 TI - Experimental Peri-Implantitis around Different Types of Implants - A Clinical and Radiographic Study in Dogs. AB - BACKGROUND: The influence of the implant micro and macrostructure on peri implantitis is not fully understood. PURPOSE: To determine the effect of ligature induced peri-implantitis on three commercially available implant types. MATERIALS AND METHODS: Five beagle dogs were used. Two months following tooth extraction, three different implant types (BIOMET 3i T3, BIOMET 3i, Palm Beach Gardens, FL, USA; Straumann Bone Level, Straumann GmbH, Basel, Switzerland; Nobel Replace Tapered, Nobel Biocare, Gothenburg, Sweden) were placed in a randomized fashion in each hemi-mandible. Peri-implantitis was initiated by ligature placement and soft diet. Ligatures were added every 2 weeks for a total of four ligature advancements. After 2 weeks, the ligatures were removed, oral hygiene measures initiated for 3 weeks, and clinical (probing depth, mucosal recession, bleeding on probing), intrasurgical (intrasurgical defect depth, intrasurgical defect width), and radiographic (radiographic bone level) parameters assessed. RESULTS: Nobel Replace Tapered implants showed significantly higher intrasurgical defect depth, intrasurgical defect width, probing depths, and radiographic bone level when compared to BIOMET 3i T3 or Straumann Bone Level implants. Straumann Bone Level implants showed largely similar clinical outcomes to BIOMET 3i T3. No significant differences between the groups were observed for mean mucosal recession. CONCLUSION: In an experimental peri-implantitis model, Nobel Replace Tapered implants are associated with pronounced tissue loss. PMID- 25715750 TI - Partial Brown-Sequard syndrome due to presumed fibrocartilaginous embolism. PMID- 25715751 TI - Focal persistent inflammation of atopic myelitis: a radiological demonstration. PMID- 25715752 TI - Bilateral middle cranial fossa arachnoidal cysts with temporal lobe agenesis associated with astrocytoma: fortuitous finding. PMID- 25715753 TI - Effects of endothelium, stent design and deployment on the nitric oxide transport in stented artery: a potential role in stent restenosis and thrombosis. AB - Extrinsic factors such as stent design, deployment and damage to endothelium are associated with stent restenosis and thrombosis. We hypothesize that these extrinsic factors can affect nitric oxide (NO) concentration and disturb its distribution in the stented artery, hence contributing to stent restenosis and thrombosis. We numerically investigated the effects of different endothelium coverage and high-risk factors including thicker strut, stent malapposition and overlapping on the NO distribution in the stented artery. The decrease in the endothelium coverage would greatly reduce the NO concentration, and the location of the coverage relative to the strut significantly affected its distribution. Strut protrusion and thicker strut would induce flow disruption, which not only decreases NO concentration but also greatly changes NO distribution, leading to very low NO concentration near the strut, especially the distal region. Likewise, strut malapposition and overlap would both diminish the NO concentration. However, the distribution of NO for relatively large malapposition was much evener than that for small malapposition. Moreover, proper deployment of the overlapping strut would result in relatively high and uniform NO concentration. In conclusion, less endothelium coverage, thicker struts and improper stent deployment may decrease NO concentration and lead to relatively low NO concentration near the strut. PMID- 25715754 TI - With the help of kin? Household composition and reproduction in the Netherlands, 1842-1920. AB - Relatives play an important role in human reproduction according to evolutionary theories of reproductive behavior, but previous empirical studies show large differences in the effects of kin on fertility outcomes. In our paper we examine the effect of co-resident kin and non-kin on the length of birth intervals over the reproductive life course of Dutch women born between 1842 and 1920. We estimate Cox proportional hazard models for parity progression based on the presence of kin and non-kin in the household while controlling for a large number of individual and community-level characteristics. We find that couples living with their brothers experienced shorter birth intervals whereas couples residing with a widowed father had relatively longer birth intervals. The effects of these types of kin on reproduction were most pronounced up to the birth of the fifth child, but not thereafter. We found no effect for mothers or other types of kin. PMID- 25715755 TI - Genetics of wellbeing and its components satisfaction with life, happiness, and quality of life: a review and meta-analysis of heritability studies. AB - Wellbeing is a major topic of research across several disciplines, reflecting the increasing recognition of its strong value across major domains in life. Previous twin-family studies have revealed that individual differences in wellbeing are accounted for by both genetic as well as environmental factors. A systematic literature search identified 30 twin-family studies on wellbeing or a related measure such as satisfaction with life or happiness. Review of these studies showed considerable variation in heritability estimates (ranging from 0 to 64 %), which makes it difficult to draw firm conclusions regarding the genetic influences on wellbeing. For overall wellbeing twelve heritability estimates, from 10 independent studies, were meta-analyzed by computing a sample size weighted average heritability. Ten heritability estimates, derived from 9 independent samples, were used for the meta-analysis of satisfaction with life. The weighted average heritability of wellbeing, based on a sample size of 55,974 individuals, was 36 % (34-38), while the weighted average heritability for satisfaction with life was 32 % (29-35) (n = 47,750). With this result a more robust estimate of the relative influence of genetic effects on wellbeing is provided. PMID- 25715756 TI - Stereoselective synthesis of unsaturated alpha-amino acids. AB - Stereoselective synthesis of unsaturated alpha-amino acids was performed by asymmetric alkylation. Two methods were investigated and their enantiomeric excess measured and compared. The first route consisted of an enantioselective approach induced by the Corey-Lygo catalyst under chiral phase transfer conditions while the second one involved the hydroxypinanone chiral auxiliary, both implicating Schiff bases as substrate. In all cases, the use of a prochiral Schiff base gave higher enantiomeric excess and yield in the final desired amino acid. PMID- 25715757 TI - New insights into novel inhibitors against deoxyhypusine hydroxylase from plasmodium falciparum: compounds with an iron chelating potential. AB - Deoxyhypusine hydroxylase (DOHH) is a dinuclear iron enzyme required for hydroxylation of the aminobutyl side chain of deoxyhypusine in eukaryotic translation initiation factor 5A (eIF-5A), the second step in hypusine biosynthesis. DOHH has been recently identified in P. falciparum and P. vivax. Both enzymes have very peculiar features including E-Z type HEAT-like repeats and a diiron centre in their active site. Both proteins share only 26 % amino acid identity to the human paralogue. Hitherto, no X-ray structure exists from either enzyme. However, structural predictions based on the amino acid sequence of the active site in comparison to the human enzyme show that four conserved histidine and glutamate residues provide the coordination sites for chelating the ferrous iron ions. Recently, we showed that P. vivax DOHH is inhibited by zileuton (N-[1 (1-benzothien-2-yl)ethyl]-N-hydroxyurea), a drug that is known for inhibiting human 5-lipoygenase (5-LOX) by the complexation of ferrous iron. A novel discovery program was launched to identify inhibitors of the P. falciparum DOHH from the Malaria Box, consisting of 400 chemical compounds, which are highly active in the erythrocytic stages of Malaria infections. In a first visual selection for potential ligands of ferrous iron, three compounds from different scaffold classes namely the diazonapthyl benzimidazole MMV666023 (Malaria Box plate A, position A03), the bis-benzimidazole MMV007384 (plate A, position B08), and a 1,2,5,-oxadiazole MMV665805 (plate A, position C03) were selected and subsequently evaluated in silico for their potential to complex iron ions. As a proof of principle, a bioanalytical assay was performed and the inhibition of hypusine biosynthesis was determined by GC-MS. All tested compounds proved to be active in this assay and MMV665805 exhibited the strongest inhibitory effect. Notably, the results were in accordance with the preliminary quantum-mechanical calculations suggesting the strongest iron complexation capacity for MMV665805. This compound might be a useful tool as well as a novel lead structure for inhibitors of P. falciparum DOHH. PMID- 25715758 TI - Photoreceptor projections and receptive fields in the dorsal rim area and main retina of the locust eye. AB - In many insect species, photoreceptors of a small dorsal rim area of the eye are specialized for sensitivity to the oscillation plane of polarized skylight and, thus, serve a role in sky compass orientation. To further understand peripheral mechanisms of polarized-light processing in the optic lobe, we have studied the projections of photoreceptors and their receptive fields in the main eye and dorsal rim area of the desert locust, a model system for polarization vision analysis. In both eye regions, one photoreceptor per ommatidium, R7, has a long visual fiber projecting through the lamina to the medulla. Axonal fibers from R7 receptors of the dorsal rim area have short side branches throughout the depth of the dorsal lamina and maintain retinotopic projections to the dorsal medulla following the first optic chiasma. Receptive fields of dorsal rim photoreceptors are considerably larger (average acceptance angle 33 degrees ) than those of the main eye (average acceptance angle 2.04 degrees ) and, taken together, cover almost the entire sky. The data challenge previous reports of two long visual fibers per ommatidium in the main eye of the locust and provide data for future analysis of peripheral networks underlying polarization opponency in the locust brain. PMID- 25715759 TI - Regulatory effect of chemokines in bone marrow niche. AB - Chemokines secreted from different cellular components of bone marrow (BM) play an important role in the formation of the BM niche system. The hematopoietic stem cell (HSC) pool located in specialized anatomical sites within the BM is subjected to a complex network of chemokines, such that the produced chemokines affect the fate of these cells. Expression of different chemokine receptors on leukemic stem cells (LSCs) uncovers the critical role of chemokines in the maintenance, survival and fate of these cells in the leukemic niche. As a pre metastatic niche rich in a variety of chemokines, the BM niche is turned into a locus of tumor cell development and division. The chemokine receptors expressed on the surface of metastatic cells lead to their metastasis and homing to the BM niche. Knowledge of chemokines and their receptors leads to the production of various therapeutic antagonists at chemokine receptors expressed on leukemic and tumor cells, enabling interference with chemokine function as a therapeutic tool. New findings suggest that miRNAs, with their specific inhibitory function, affect the ability of producing and expressing chemokines and chemokine receptors. This review focuses on the emerging role of chemokines and their receptors in normal and pathologic conditions of the BM niche, and also discusses the new therapeutic methods with this background. PMID- 25715760 TI - Ferritin H subunit gene is specifically expressed in melanophore precursor derived white pigment cells in which reflecting platelets are formed from stage II melanosomes in the periodic albino mutant of Xenopus laevis. AB - "White pigment cells" are derived from melanophore precursors and contain both melanophore-specific and iridophore-specific pigment organelles. Whereas melanophores differentiate in the wild type regenerating tail, white pigment cells appear in the regenerating tail in the periodic albino mutant (a(p)/a(p)) of Xenopus laevis. The localization and density of white pigment cells in the mutant regenerating tail are similar to those of melanophores in the wild type regenerating tail. Here, white pigment cells in the mutant regenerating tail have been compared with melanophores in the wild type regenerating tail in the presence of phenylthiourea (PTU), which inhibits melanosome maturation in melanophores but does not affect reflecting platelet formation in white pigment cells. Ultrastructural analysis shows that reflecting platelet formation in white pigment cells is different from that in iridophores. Reflecting platelets in iridophores are formed from spherical vesicles with electron-dense material, whereas they are formed from stage II melanosomes characteristic of melanophore precursors in white pigment cells. Ultrastructural features of pigment organelles, except reflecting platelets, are similar between mutant melanophores and white pigment cells. In an attempt to identify specific genes in white pigment cells, a subtracted cDNA library enriched for mutant cDNAs has been prepared. Subtracted cDNA fragments have been cloned and selected by whole mount in situ hybridization. Among cDNA fragments examined so far, the ferritin H subunit gene is specifically expressed in white pigment cells, but not in melanophores. Pigment organellogenesis and specific gene expression in white pigment cells are also discussed. PMID- 25715761 TI - Proteoglycans as potential microenvironmental biomarkers for colon cancer. AB - Glycosylation changes occur widely in colon tumours, suggesting glycosylated molecules as potential biomarkers for colon cancer diagnostics. In this study, proteoglycans (PGs) expression levels and their transcriptional patterns are investigated in human colon tumours in vivo and carcinoma cells in vitro. According to RT-PCR analysis, normal and cancer colon tissues expressed a specific set of PGs (syndecan-1, perlecan, decorin, biglycan, versican, NG2/CSPG4, serglycin, lumican, CD44), while the expression of glypican-1, brevican and aggrecan was almost undetectable. Overall transcriptional activity of the PGs in normal and cancer tissues was similar, although expression patterns were different. Expression of decorin and perlecan was down-regulated 2-fold in colon tumours, while biglycan and versican expression was significantly up regulated (6-fold and 3-fold, respectively). Expression of collagen1A1 was also increased 6-fold in colon tumours. However, conventional HCT-116 colon carcinoma and AG2 colon cancer-initiating cells did not express biglycan and decorin and were versican-positive and -negative, respectively, demonstrating an extracellular origin of the PGs in cancer tissue. Selective expression of heparan sulfate (HS) proteoglycans syndecan-1 and perlecan in the AG2 colon cancer initiating cell line suggests these PGs as potential biomarkers for cancer stem cells. Overall transcriptional activity of the HS biosynthetic system was similar in normal and cancer tissues, although significant up-regulation of extracellular sulfatases SULF1/2 argues for a possible distortion of HS sulfation patterns in colon tumours. Taken together, the obtained results suggest versican, biglycan, collagen1A1 and SULF1/2 expression as potential microenvironmental biomarkers and/or targets for colon cancer diagnostics and treatment. PMID- 25715762 TI - A Unique Case of Erdheim-Chester Disease with Axial Skeleton, Lymph Node, and Bone Marrow Involvement. AB - Erdheim-Chester disease is a rare non-Langerhans-cell histiocytosis with bone and organ involvement. A 76-year-old man presented with low back pain and a history of visits for exertional dyspnea. We diagnosed him with anemia of chronic disease, cytopenia related to chronic illness, chronic renal failure due to hypertension, and hypothyroidism. However, we could not determine a definite cause or explanation for the cytopenia. Multiple osteosclerotic axial skeleton lesions and axillary lymph node enlargement were detected by computed tomography. Bone marrow biopsy revealed histiocytic infiltration, which was CD68-positive and CD1a-negative. This report describes an unusual presentation of Erdheim-Chester disease involving the bone marrow, axial skeleton, and lymph nodes. PMID- 25715763 TI - Phase I Study of OPB-31121, an Oral STAT3 Inhibitor, in Patients with Advanced Solid Tumors. AB - PURPOSE: OPB-31121 is an oral STAT3 inhibitor with a good preclinical antitumor activity. This phase I dose-escalation study of OPB-31121 was conducted to determine maximum-tolerated dose (MTD), safety, pharmacokinetics, and preliminary antitumor efficacy in patients with advanced solid tumors. MATERIALS AND METHODS: Patients received OPB-31121 once daily for 28 days of each cycle followed by 2 weeks rest. A standard 3+3 design was used for dose-escalation. Safety and response were evaluated by the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) ver. 3.0 and Response Evaluation Criteria in Solid Tumor (RECIST) ver. 1.0, respectively. RESULTS: Twenty-five patients were treated with OPB-31121 at five dose levels: 100 mg (n=4), 200 mg (n=3), 400 mg (n=3), 600 mg (n=7), and 800 mg (n=8). Seven patients discontinued treatment during cycle 1 for various reasons other than study drug-related adverse events. Among 18 patients who were evaluable for dose-limiting toxicity (DLT), three DLTs were observed: one DLT (grade 3 vomiting) at 600 mg and two DLTs (grade 3 vomiting, grade 3 diarrhea) at 800 mg. The MTD was determined as 800 mg/day. Common adverse events were gastrointestinal adverse event including nausea (84%), vomiting (80%), and diarrhea (72%). Pharmacokinetics did not demonstrate dose proportionality of OPB-31121. Eight patients had stable disease and 10 patients had disease progression. Two patients (1 colon cancer, 1 rectal cancer) showed tumor shrinkage. One gastric cancer patient continued treatment up to cycle 13 before disease progression. CONCLUSION: This study demonstrates feasibility of STAT3 inhibition in patients with advanced solid tumor. OPB-31121, at the MTD of 800 mg/day, was safe and relatively well tolerated, and has a preliminary antitumor activity. PMID- 25715764 TI - Prognostic Significance of Defining L-Cell Type on the Biologic Behavior of Rectal Neuroendocrine Tumors in Relation with Pathological Parameters. AB - PURPOSE: In 2010, the World Health Organization categorized L-cell type neuroendocrine tumors (NETs) as tumors of uncertain malignancy, while all others were classified as malignant. However, the diagnostic necessity of L-cell immunophenotyping is unclear, as are tumor stage and grade that may guide diagnosis and management. To clarify the predictive markers of rectal neuroendocrine neoplasms (NENs), 5- and 10-year overall survival (OS) was analyzed by pathological parameters including L-cell phenotype. MATERIALS AND METHODS: A total of 2,385 rectal NENs were analyzed from our previous multicenter study and a subset of 170 rectal NENs was immunophenotyped. RESULTS: In univariate survival analysis, tumor grade (p < 0.0001), extent (p < 0.0001), size (p < 0.0001), lymph node metastasis (p=0.0063), and L-cell phenotype (p < 0.0001) showed significant correlation with the prognosis of rectal NENs; however, none of these markers achieved independent significance in multivariate analysis. The 10-year OS of tumors of NET grade 1, < 10 mm, the mucosa/submucosa was 97.58%, 99.47%, and 99.03%, respectively. L-Cell marker, glucagon II (GLP-1&2), with a cut off score of > 10, is useful in defining L-Cell type. In this study, an L cell immunophenotype was found in 83.5% of all rectal NENs and most, but not all L-cell type tumors were NET G1, small (< 10 mm) and confined to the mucosa/submucosa. CONCLUSION: From these results, the biological behavior of rectal NENs does not appear to be determined by L-cell type alone but instead by a combination of pathological parameters. PMID- 25715765 TI - Effective Treatment of Solitary Pituitary Metastasis with Panhypopituitarism in HER2-Positive Breast Cancer by Lapatinib. AB - Brain metastasis affects one third of patients with HER2-positive breast cancer after treatment with trastuzumab. Surgical resection and radiation therapy are often unsuccessful at accomplishing complete control of metastasis. Lapatinib is presumed to cross the blood-brain barrier, and exhibits clinical activities for treatment of HER2-positive breast cancer. A 43-year-old woman was treated for early breast carcinoma with total mastectomy, axillary lymph-node dissection, and adjuvant chemotherapy with cyclophosphamide plus doxorubicin. After the end of adjuvant trastuzumab therapy, she was diagnosed with panhypopituitarism due to pituitary metastasis. Surgical removal and whole brain radiation therapy were performed, but a portion of viable tumor remained. Only taking lapatinib, the size of the metastatic lesion began to shrink. Trastuzumab may have controlled the micro-metastasis of breast cancer, but it was unable to control its progression to the central nervous system. Lapatinib is a possible option for HER2-positive metastatic breast cancer patients with brain metastasis. PMID- 25715766 TI - A Clinicopathological Review of Pulmonary Metastasis from Uterine Cervical Cancer. AB - PURPOSE: The purpose of this study was to investigate the clinicopathological features of pulmonary metastasis from cervical cancer. MATERIALS AND METHODS: We reviewed the medical records of 56 patients with cervical cancer who developed pulmonary metastasis after radical hysterectomy, postoperative concurrent chemoradiation or systemic chemotherapy between January 1990 and March 2014. RESULTS: Fifty-six patients were diagnosed with pulmonary metastasis from cervical cancer. The prevalence of pulmonary metastasis was 3.6%. The mean event free duration was 12 months. Twelve patients underwent surgical removal of metastatic lesions. The overall survival (OS) of patients with <= 3 metastatic lung lesions was 40.7 months, longer than those with > 4 lesions (25 months, p=0.034). The OS of patients who underwent surgical resection was 53.8 months, longer than that of those who did not (p=0.006). In addition, the OS of patients with adjuvant platinum-based chemotherapy was 32.6 months (p=0.027). CONCLUSION: In this study, we found that the number of metastatic nodules, surgical resection, and postoperative platinum-based chemotherapy can influence clinical outcome. Further studies on prognostic factors and successful treatment modalities are warranted. PMID- 25715768 TI - Peptide Nucleic Acid Clamping Versus Direct Sequencing for the Detection of EGFR Gene Mutation in Patients with Non-small Cell Lung Cancer. AB - PURPOSE: Direct sequencing (DS) is the standard method for detection of epidermal growth factor receptor (EGFR) gene mutation in non-small cell lung cancer (NSCLC); however, low detection sensitivity is a problem. The aim of this study is to demonstrate higher detection rate of EGFR gene mutation with peptide nucleic acid (PNA) clamping compared with DS. MATERIALS AND METHODS: This is a single arm, prospective study for patients with stage IIIB/IV or relapsed NSCLC. Using tumor DNA from 138 patients, both DS and PNA clamping for EGFR gene in exon 18, 19, 20, and 21 were performed. Discrepant results between the two methods were verified using Cobas and a mutant enrichment based next generation sequencing (NGS). Patients with activating mutations were treated with EGFR tyrosine kinase inhibitor (EGFR-TKI, gefitinib, or erlotinib) as first line treatment. RESULTS: Of 138 paired test sets, 24 (17.4%) and 45 (32.6%) cases with activating mutations were detected by DS and PNA clamping, respectively. The difference of detection rate between the two methods was 15.2% (95% confidence interval, 8.7% to 17.8%; p < 0.001). Between the two methods, 25 cases showed discrepant results (n=23, PNA+/DS-; n=2, PNA-/DS+). Mutations were confirmed by Cobas or NGS in 22 of 23 PNA+/DS- cases. The response rates to EGFR-TKI were 72.2% in the PNA+/DS+ group and 85.0% in the PNA+/DS- group. CONCLUSION: PNA clamping showed a significantly higher detection rate of EGFR gene mutation compared with DS. Higher sensitivity of PNA clamping was not compromised by the loss of predictive power of response to EGFR-TKI. PMID- 25715767 TI - Phase I Study of CKD-516, a Novel Vascular Disrupting Agent, in Patients with Advanced Solid Tumors. AB - PURPOSE: CKD-516 is a newly developed vascular disrupting agent. This phase I dose-escalation study of CKD-516 was conducted to determine maximum-tolerated dose (MTD), safety, pharmacokinetics, and preliminary antitumor efficacy in patients with advanced solid tumors. MATERIALS AND METHODS: Patients received CKD 516 intravenously on D1 and D8 every 3 weeks, in a standard 3+3 design. Safety was evaluated by National Cancer Institute Common Terminology Criteria for Adverse Events ver. 4.02 and response was assessed by Response Evaluation Criteria in Solid Tumor ver. 1.1. RESULTS: Twenty-three patients were treated with CKD-516 at seven dosing levels: 1 mg/m(2)/day (n=3), 2 mg/m(2)/day (n=3), 3.3 mg/m(2)/day (n=3), 5 mg/m(2)/day (n=3), 7 mg/m(2)/day (n=3), 9 mg/m(2)/day (n=6), and 12 mg/m(2)/day (n=2). Mean age was 54 and 56.5% of patients were male. Two dose-limiting toxicities, which were both grade 3 hypertension, were observed in two patients at 12 mg/m(2)/day. The MTD was determined as 12 mg/m(2)/day. Most common adverse events were gastrointestinal adverse events (diarrhea, 34.8% [30.4% grade 1/2, 13.0% grade 3]; nausea, 21.7% [all grade 1/2]; vomiting, 21.7% [all grade 1/2]), myalgia (17.4%, all grade 1/2), and abdominal pain (21.7% [21.7% grade 1/2, 4.3% grade 3]). The pharmacokinetic study showed the dose linearity of all dosing levels. Among 23 patients, six patients (26.1%) showed stable disease. Median progression-free survival was 39 days (95% confidence interval, 37 to 41 days). CONCLUSION: This study demonstrates feasibility of CKD 516, novel vascular disrupting agent, in patients with advanced solid tumor. MTD of CKD-516 was defined as 12 mg/m(2)/day on D1 and D8 every 3 weeks. PMID- 25715769 TI - A Case of von Hippel-Lindau Disease with Colorectal Adenocarcinoma, Renal Cell Carcinoma and Hemangioblastomas. AB - von Hippel-Lindau (VHL) disease is an autosomal dominant inherited tumor syndrome associated with mutations of the VHL tumor suppressor gene located on chromosome 3p25. The loss of functional VHL protein contributes to tumorigenesis. This condition is characterized by development of benign and malignant tumors in the central nervous system (CNS) and the internal organs, including kidney, adrenal gland, and pancreas. We herein describe the case of a 74-year-old man carrying the VHL gene mutation who was affected by simultaneous colorectal adenocarcinoma, renal clear cell carcinoma, and hemangioblastomas of CNS. PMID- 25715770 TI - A Case of Metastatic Low-Grade Endometrial Stromal Sarcoma Treated with Letrozole after Ovarian Ablation by Radiotherapy. AB - A 50-year-old woman was admitted to our hospital due to multiple lung nodules detected incidentally on a chest X-ray. A video-assisted thoracoscopic lung biopsy revealed low-grade endometrial stromal sarcoma (LG-ESS). She had undergone a simple hysterectomy 1 year earlier owing to a diagnosis of adenomyosis. A review of her previous hysterectomy specimen showed not endometriosis but LG-ESS. According to the patient's levels of serum follicle stimulating hormone and estradiol, she was in the premenopausal state with retained and normally functioning ovaries. She then underwent ovarian ablation by radiotherapy, after which she was administered 2.5 mg of letrozole once per day. Three months later, the size of the metastatic nodules in both lungs had decreased. The patient was followed up for 24 months while continuing on letrozole, and maintained a partial remission. We report herein on a case of metastatic LG-ESS treated with letrozole after ovarian ablation by radiotherapy. PMID- 25715771 TI - SEC31A-ALK Fusion Gene in Lung Adenocarcinoma. AB - Anaplastic lymphoma kinase (ALK) fusion is a common mechanism underlying pathogenesis of non-small cell lung carcinoma (NSCLC) where these rearrangements represent important diagnostic and therapeutic targets. In this study, we found a new ALK fusion gene, SEC31A-ALK, in lung carcinoma from a 53-year-old Korean man. The conjoined region in the fusion transcript was generated by the fusion of SEC31A exon 21 and ALK exon 20 by genomic rearrangement, which contributed to generation of an intact, in-frame open reading frame. SEC31A-ALK encodes a predicted fusion protein of 1,438 amino acids comprising the WD40 domain of SEC31A at the N-terminus and ALK kinase domain at the C-terminus. Fluorescence in situ hybridization studies suggested that SEC31A-ALK was generated by an unbalanced genomic rearrangement associated with loss of the 3'-end of SEC31A. This is the first report of SEC31A-ALK fusion transcript in clinical NSCLC, which could be a novel diagnostic and therapeutic target for patients with NSCLC. PMID- 25715772 TI - Pazopanib for Non-small Cell Lung Cancer: The First Case Report in Korea. AB - Pazopanib is a potent multitargeted tyrosine kinase inhibitor that has been shown to have good efficacy in patients with renal cell carcinoma. A previous phase II trial demonstrated that short-term pazopanib administration was generally well tolerated and showed antitumor activity in patients with early-stage non-small cell lung cancer. Herein, we report on the case of a 66-year-old man with simultaneous metastatic squamous cell carcinoma of the lung and renal cell carcinoma who was treated with pazopanib. The patient showed an unexpected partial response and experienced a 10-month progression-free survival without significant toxicity. To the best of the authors' knowledge, this is the first report of pazopanib treatment in a non-small cell lung cancer patient in Korea. The results in this patient suggest that pazopanib may be a valid treatment option for advanced non-small cell lung cancer. PMID- 25715773 TI - Predicting mortality following hip fracture: an analysis of comorbidities and complications. AB - BACKGROUND: Hip fracture is common in the geriatric population. These patients have multiple comorbidities that complicate treatment and recovery such that poor functional outcomes often result. Since functional outcomes are associated with comorbidities and complications it is important to define the contributing factors. AIMS: To describe comorbidities common to geriatric hip fracture patients and determine predictability of complications and mortality based on comorbidities. METHODS: Data in this study were sourced from information prospectively collected for evaluation of a new orthogeriatric service established at a University Teaching Hospital over the period of 1 year. RESULTS: The median age was 82 years (range 54-100) and 73 % were female (N = 206). Common comorbidities included hypertension (51 %), dementia (28 %), osteoporosis (19 %), ischaemic heart disease (IHD) (15 %) and chronic obstructive pulmonary disease (15 %). In predicting 1-year mortality based on comorbidities, the final model included age, IHD, delay to surgery and explained 26 % of the variability in mortality. Predicting 1-year mortality based on complications, the final model included age and respiratory complications and explained 26 % of the variability in mortality. There was a significant association between having respiratory complications and chronic obstructive pulmonary disease (p < 0.001) with 63 % of those with respiratory complications having chronic obstructive pulmonary disease. CONCLUSIONS: This study highlights specific patient comorbidities and medical complications that could be used to guide clinical assessment, management and targeted interventions that improve outcomes in this patient group. PMID- 25715775 TI - Puppies on the doorstep. PMID- 25715774 TI - [Experiences with PMMA cement as a stand-alone intervertebral spacer. Percutaneous cement discoplasty in the case of vacuum phenomenon within lumbar intervertebral discs]. AB - BACKGROUND: The treatment of symptomatic degenerative disc disease of the lumbar spine in elderly patients by standard surgical methods is often limited due to severe comorbidities (e.g., cardiopulmonary disease, hypertonia, diabetes). Minimally invasive procedures are more acceptable in this population, since they reduce surgical morbidity and the risk of complications. The percutaneous cement discoplasty (PCD) technique was introduced by the authors to treat dynamic (and angular) instability of the symptomatic lumbar segment by injecting bone cement (polymethylmethacrylate, PMMA) into the disc spaces showing vacuum phenomena via a posterolaterally positioned Jamshidi needle. The aim of this article is to describe the indication, method, and clinical results of PCD. METHOD: A total of 81 patients were treated with PCD in a tertiary care referral center over a 6 year period. The current study includes the first group of 47 consecutive patients to complete a pre- and postoperative questionnaire booklet regarding leg and back pain using the visual analog scale (VAS) and the Oswestry disability index (ODI) questionnaire. RESULTS: A total of 130 discs in these 47 patients were treated with PCD. The majority of patients reported a reduction in their lower back and leg pain (69 and 66 %, respectively; p < 0.02) postoperatively. At 6-month follow-up, 61 % of patients had a minimum 10-point reduction in their ODI scores (p < 0.01). CONCLUSION: Elderly patients with symptomatic dynamic foraminal stenosis and vacuum phenomenon in the intervertebral disc are suitable candidates for PCD, particularly if they represent high-risk patients for open surgery. PMID- 25715776 TI - Non-metastatic squamous cell carcinoma within a Rathke's cleft cyst. AB - INTRODUCTION: Primary intracranial and sellar squamous cell carcinoma is an extremely rare entity, usually caused by malignant transformation of epidermoid cysts, or very rarely other non-malignant epithelial cysts. Malignant transformation of a Rathke's cleft cyst has never been described. CASE DESCRIPTION: We present a 49-year-old male patient who presented with a 3-month history of progressive frontotemporal headaches. Imaging revealed a 1.2 cm cystic pituitary mass consistent with a hemorrhagic Rathke's cleft cyst. The patient underwent trans-sphenoidal resection of the pituitary cyst, and pathologic analysis revealed a squamous cell carcinoma lining a Rathke's cleft cyst. Extensive imaging and otorhinolaryngologic evaluation revealed no primary source for metastasis. CONCLUSIONS: We feel this represents the first case of a patient with a pituitary lesion in which presentation and MRI imaging were consistent with Rathke's cleft cyst, yet histology revealed squamous cell carcinoma in situ. PMID- 25715777 TI - Aging-induced changes in sex-steroidogenic enzymes and sex-steroid receptors in the cortex, hypothalamus and cerebellum. AB - We investigated age-induced changes in mRNA expression profiles of sex steroidogenic enzymes and sex-steroid receptors in 3-, 12-, and 24-month-old male rat brain subregions [cerebral cortex (CC), hypothalamus (Hy) and cerebellum (CL)]. In many cases, the expression levels of mRNA decreased with age for androgen synthesis enzyme systems, including Cyp17a1, Hsd17b and Srd5a in the CC and CL, but not in the Hy. Estradiol synthase Cyp19a1 did not show age-induced decline in the Hy, and nearly no expression of Cyp19a1 was observed in the CC and CL over 3-24 m. Androgen receptor Ar increased in the Hy but decreased in the CC with age. Estrogen receptor Esr1 increased in the CC and Hy, and did not change in the CL with age. Esr2 did not change in the CC and Hy, but decreased in the CL with age. As a comparison, age-induced changes of brain-derived neurotrophic factor mRNA were also investigated. PMID- 25715779 TI - Resistance phenotypes and genotypes among multiple-antimicrobial-resistant Salmonella enterica subspecies enterica serovar Choleraesuis strains isolated between 2008 and 2012 from slaughter pigs in Okinawa Prefecture, Japan. AB - A total of 349 Salmonella enterica subspecies enterica serovar Choleraesuis (S. Choleraesuis) strains, which were isolated between 2008 and 2012 from 349 pigs at two slaughterhouses in Okinawa Prefecture, Japan, were investigated for antimicrobial susceptibility and the presence of antimicrobial resistance genes. All isolates were resistant to at least four antimicrobial agents. The antimicrobial agents for which isolates showed a high incidence of resistance were as follows: ampicillin (100%) and streptomycin (100%), followed by gentamicin (99.7%), oxytetracycline (99.7%), sulfamethoxazole/trimethoprim (99.4%), nalidixic acid (40.1%) and oxolinic acid (40.1%). All isolates were sensitive to cefuroxime, ceftiofur, colistin, fosfomycin, enrofloxacin, orbifloxacin and danofloxacin. The predominant resistance phenotypes and genotypes were: resistance to ampicillin, streptomycin, gentamicin, oxytetracycline and sulfamethoxazole/trimethoprim (58.5%, 204/349) and blaTEM strA-strB-aadA1-aadA2-aacC2-tet (B)-sul1-sul2-dhfrXII-dhfrXIII (36.1%, 126/349). The quinolone resistance-determining regions (QRDRs) of gyrA, gyrB, parC and parE of the quinolone-resistant isolates (n=12) showed amino acid substitutions of Ser 83->Phe or Asp-87->Tyr in GyrA and Ser-107->Ala in ParC. To our knowledge, this is the first report on the molecular characterization of antimicrobial resistance among S. Choleraesuis strains in Japan. PMID- 25715778 TI - Evaluation of the drug sensitivity and expression of 16 drug resistance-related genes in canine histiocytic sarcoma cell lines. AB - Canine histiocytic sarcoma (HS) is an aggressive tumor type originating from histiocytic cell lineages. This disease is characterized by poor response to chemotherapy and short survival time. Therefore, it is of critical importance to identify and develop effective antitumor drugs against HS. The objectives of this study were to examine the drug sensitivities of 10 antitumor drugs. Using a real time RT-PCR system, the mRNA expression levels of 16 genes related to drug resistance in 4 canine HS cell lines established from dogs with disseminated HS were determined and compared to 2 canine lymphoma cell lines (B-cell and T-cell). These 4 canine HS cell lines showed sensitivities toward microtubule inhibitors (vincristine, vinblastine and paclitaxel), comparable to those in the canine B cell lymphoma cell line. Moreover, it was shown that P-gp in the HS cell lines used in this study did not have enough function to efflux its substrate. Sensitivities to melphalan, nimustine, methotrexate, cytarabine, doxorubicin and etoposide were lower in the 4 HS cell lines than in the 2 canine lymphoma cell lines. The data obtained in this study using cultured cell lines could prove helpful in the developing of advanced and effective chemotherapies for treating dogs that are suffering from HS. PMID- 25715780 TI - Biodegradation of fat, oil and grease (FOG) deposits under various redox conditions relevant to sewer environment. AB - Fat, oil and, grease (FOG) deposits are one primary cause of sanitary sewer overflows (SSOs). While numerous studies have examined the formation of FOG deposits in sewer pipes, little is known about their biodegradation under sewer environments. In this study, FOG deposit biodegradation potential was determined by studying the biodegradation of calcium palmitate in laboratory under aerobic, nitrate-reducing, sulfate-reducing, and methanogenic conditions. Over 110 days of observation, calcium palmitate was biodegraded to CO2 under aerobic and nitrate reducing conditions. An approximate 13 times higher CO2 production rate was observed under aerobic condition than under nitrate-reducing condition. Under sulfate-reducing condition, calcium palmitate was recalcitrant to biodegradation as evidenced by small reduction in sulfate. No evidence was found to support calcium palmitate degradation under methanogenic condition in the simulated sewer environment. Dominant microbial populations in the aerobic and nitrate-reducing microcosms were identified by Illumina seqeuncing, which may contain the capability to degrade calcium palmitate under both aerobic and nitrate-reducing conditions. Further study on these populations and their functional genes could shed more light on this microbial process and eventually help develop engineering solutions for SSOs control in the future. PMID- 25715781 TI - Denitrification potential under different fertilization regimes is closely coupled with changes in the denitrifying community in a black soil. AB - Preferable inorganic fertilization over the last decades has led to fertility degradation of black soil in Northeast China. However, how fertilization regimes impact denitrification and its related bacterial community in this soil type is still unclear. Here, taking advantage of a suit of molecular ecological tools in combination of assaying the potential denitrification (DP), we explored the variation of activity, community structure, and abundance of nirS and nirK denitrifiers under four different fertilization regimes, namely no fertilization control (N0M0), organic pig manure (N0M1), inorganic fertilization (N1M0), and combination of inorganic fertilizer and pig manure (N1M1). The results indicated that organic fertilization increased DP, but inorganic fertilization had no impacts. The increase of DP was mirrored by the shift of nirS denitrifiers' community structure but not by that of nirK denitrifiers'. Furthermore, the change of DP coincided with the variation of abundances of both denitrifiers. Shifts of community structure and abundance of nirS and nirK denitrifiers were correlated with the change of soil pH, total nitrogen (TN), organic matter (OM), C:P, total phosphorus (TP), and available phosphorus (Olsen P). Our results suggest that the change of DP under these four fertilization regimes was closely related to the shift of denitrifying bacteria communities resulting from the variation of properties in the black soil tested. PMID- 25715782 TI - Experimental design-aided systematic pathway optimization of glucose uptake and deoxyxylulose phosphate pathway for improved amorphadiene production. AB - Artemisinin is a potent antimalarial drug; however, it suffers from unstable and insufficient supply from plant source. Here, we established a novel multivariate modular approach based on experimental design for systematic pathway optimization that succeeded in improving the production of amorphadiene (AD), the precursor of artemisinin, in Escherichia coli. It was initially found that the AD production was limited by the imbalance of glyceraldehyde 3-phosphate (GAP) and pyruvate (PYR), the two precursors of the 1-deoxy-D-xylulose-5-phosphate (DXP) pathway. Furthermore, it was identified that GAP and PYR could be balanced by replacing the phosphoenolpyruvate (PEP)-dependent phosphotransferase system (PTS) with the ATP-dependent galactose permease and glucose kinase system (GGS) and this resulted in fivefold increase in AD titer (11 to 60 mg/L). Subsequently, the experimental design-aided systematic pathway optimization (EDASPO) method was applied to systematically optimize the transcriptional expressions of eight critical genes in the glucose uptake and the DXP and AD synthesis pathways. These genes were classified into four modules and simultaneously controlled by T7 promoter or its variants. A regression model was generated using the four-module experimental data and predicted the optimal expression ratios among these modules, resulting in another threefold increase in AD titer (60 to 201 mg/L). This EDASPO method may be useful for the optimization of other pathways and products beyond the scope of this study. PMID- 25715783 TI - The distribution pattern of DNA and protoxin in Bacillus thuringiensis as revealed by laser confocal microscopy analysis. AB - It was reported that the parasporal crystal from Bacillus thuringiensis contained DNA fragments. To investigate the distribution of protoxin and DNA in B. thuringiensis cells at different growth stages, a cry1Ac-gfp fusion gene was constructed and expressed in an acrystalliferous B. thuringiensis strain, in which the localization of DNA and protoxin were indicated by DNA-specific dye and green fluorescent protein, respectively. When the recombinant cells were at the vegetative growth stage, the Cry1Ac-GFP fusion protein was not expressed and the DNA fluorescent signal was evenly distributed throughout the cell. At the initial stage of sporulation, the Cry1Ac-GFP fusion protein was expressed and accumulated as inclusion body, while two condensed DNA signals existed at each pole of the cell. With the extension of culture time, it seemed that the DNA fluorescence from the region of spore development gradually became faint or vanishing, while the DNA signal was still present in the other pole or the remaining area of the mother cell. Interestingly and unexpectedly, there was no DNA fluorescence signal in the region of the growing and mature inclusion body of Cry1Ac-GFP in B. thuringiensis cell, which might indicate that the DNA embodied in the inclusion body was not accessible to the DNA-specific dye. This was the first investigation devoted exclusively to the in vivo distribution of protoxin and DNA in B. thuringiensis at different growth stages. These data shed light on deeply understanding the process of sporulation and parasporal crystal formation as well as further exploring the interaction of DNA and protoxin in B. thuringiensis. PMID- 25715784 TI - Pathway-specific regulation revisited: cross-regulation of multiple disparate gene clusters by PAS-LuxR transcriptional regulators. AB - PAS-LuxR regulators are highly conserved proteins devoted to the control of antifungal production by binding to operators located in given promoters of polyene biosynthetic genes. The canonical operator of PimM, archetype of this class of regulators, has been used here to search for putative targets of orthologous protein PteF in the genome of Streptomyces avermitilis, finding 97 putative operators outside the pentaene filipin gene cluster (pte). The processes putatively affected included genetic information processing; energy, carbohydrate, and lipid metabolism; DNA replication and repair; morphological differentiation; secondary metabolite biosynthesis; and transcriptional regulation, among others. Seventeen of these operators were selected, and their binding to PimM DNA-binding domain was assessed by electrophoretic mobility shift assays. Strikingly, the protein bound all predicted operators suggesting a direct control over targeted processes. As a proof of concept, we studied the biosynthesis of the ATP-synthase inhibitor oligomycin whose gene cluster included two operators. Regulator mutants showed a severe loss of oligomycin production, whereas gene complementation of the mutant restored phenotype, and gene duplication in the wild-type strain boosted oligomycin production. Comparative gene expression analyses in parental and mutant strains by reverse transcription quantitative polymerase chain reaction of selected olm genes corroborated production results. These results demonstrate that PteF is able to cross-regulate the biosynthesis of two related secondary metabolites, filipin and oligomycin, but might be extended to all the processes indicated above. This study highlights the complexity of the network of interactions in which PAS-LuxR regulators are involved and opens new possibilities for the manipulation of metabolite production in Streptomycetes. PMID- 25715785 TI - Structural insights into the substrate stereospecificity of D-threo-3 hydroxyaspartate dehydratase from Delftia sp. HT23: a useful enzyme for the synthesis of optically pure L-threo- and D-erythro-3-hydroxyaspartate. AB - D-threo-3-Hydroxyaspartate dehydratase (D-THA DH) is a fold-type III pyridoxal 5' phosphate-dependent enzyme, isolated from a soil bacterium of Delftia sp. HT23. It catalyzes the dehydration of D-threo-3-hydroxyaspartate (D-THA) and L-erythro 3-hydroxyaspartate (L-EHA). To elucidate the mechanism of substrate stereospecificity, crystal structures of D-THA DH were determined in complex with various ligands, such as an inhibitor (D-erythro-3-hydroxyaspartate (D-EHA)), a substrate (L-EHA), and the reaction intermediate (2-amino maleic acid). The C (beta) -OH of L-EHA occupied a position close to the active-site Mg(2+), clearly indicating a possibility of metal-assisted C (beta) -OH elimination from the substrate. In contrast, the C (beta) -OH of an inhibitor was bound far from the active-site Mg(2+). This suggests that the substrate specificity of D-THA DH is determined by the orientation of the C (beta) -OH at the active site, whose spatial arrangement is compatible with the 3R configuration of 3 hydroxyaspartate. We also report an optically pure synthesis of L-threo-3 hydroxyaspartate (L-THA) and D-EHA, promising intermediates for the synthesis of beta-benzyloxyaspartate, by using a purified D-THA DH as a biocatalyst for the resolution of racemic DL-threo-3-hydroxyaspartate (DL-THA) and DL-erythro-3 hydroxyaspartate (DL-EHA). Considering 50 % of the theoretical maximum, efficient yields of L-THA (38.9 %) and D-EHA (48.9 %) as isolated crystals were achieved with >99 % enantiomeric excess (e.e.). The results of nuclear magnetic resonance signals verified the chemical purity of the products. We were directly able to isolate analytically pure compounds by the recrystallization of acidified reaction mixtures (pH 2.0) and thus avoiding the use of environmentally harmful organic solvents for the chromatographic purification. PMID- 25715786 TI - Impact of analgesic modality on stress response following laparoscopic colorectal surgery: a post-hoc analysis of a randomised controlled trial. AB - BACKGROUND: Epidural analgesia is perceived to modulate the stress response after open surgery. This study aimed to explore the feasibility and impact of measuring the stress response attenuation by post-operative analgesic modalities following laparoscopic colorectal surgery within an enhanced recovery after surgery (ERAS) protocol. METHODS: Data were collected as part of a double-blinded randomised controlled pilot trial at two UK sites. Patients undergoing elective laparoscopic colorectal resection were randomised to receive either thoracic epidural analgesia (TEA) or continuous local anaesthetic infusion to the extraction site via wound infusion catheter (WIC) post-operatively. The aim of this study was to measure the stress response to the analgesic modality by measuring peripheral venous blood samples analysed for serum concentrations of insulin, cortisol, epinephrine and interleukin-6 at induction of anaesthesia, at 3, 6, 12 and 24 h after the start of operation. Secondary endpoints included mean pain score in the first 48 h, length of hospital stay, post-operative complications and 30-day re admission rates. RESULTS: There was a difference between the TEA and WIC groups that varies across time. In the TEA group, there was significant but transient reduced level of serum epinephrine and a higher level of insulin at 3 and 6 h. In the WIC, there was a significant reduction of interleukin-6 values, especially at 12 h. There was no significant difference observed in the other endpoints. CONCLUSIONS: There is a significant transient attenuating effect of TEA on stress response following laparoscopic colorectal surgery and within ERAS as expressed by serum epinephrine and insulin levels. Continuous wound infusion with local anaesthetic, however, attenuates cytokine response as expressed by interleukin-6. PMID- 25715787 TI - Robotic-assisted resection of presacral sclerosing epithelioid fibrosarcoma. AB - PURPOSE: To demonstrate the utility of robotic approach to resect a large presacral mass. METHODS: The patient is a 76-year-old male with a large, 8 * 7 cm presacral mass identified on a CT scan. On patient history analysis, he denied any changes in bowel habits, abdominal pain, or any other obstructive symptoms. After discussing the possible surgical options, the patient was taken to operating room for a robotic resection of the mass. RESULTS: For resection, a 12 mm camera port was placed at the umbilicus, and three 8-mm robotic ports and an additional two 5-mm were utilized for dissection and retraction. The peritoneal reflection on the right was incised and the retroperitoneal space entered. Once the posterior dissection was completed, the dissection was carried down both sides bilaterally, with attention paid to not injure the superior rectal artery or any mesorectal vessels. The pseudocapsule of the mass was surrounded during this dissection. The rectum was pushed forward and was thinned out from the constant mass effect. At this point, the mass was fairly mobile, the robot was undocked, a 7.5-cm Pfannenstiel incision was made, and the mass was extracted. A leak test was performed which was negative. Ultimately, the decision was made, for functional purposes, to give the patient a diverting loop ileostomy. CONCLUSIONS: This case demonstrates the feasibility of the robot in the resection of presacral masses. It is useful especially in narrow, difficult, male pelvises. PMID- 25715788 TI - The OTSC((r)) proctology clip system for the closure of refractory anal fistulas. AB - BACKGROUND: To evaluate the efficacy of the over-the-scope clip (OTSC((r))) proctology set for the closure of refractory anal fistulas. METHODS: This retrospective single-center study included all consecutive patients undergoing an OTSC((r)) proctology closure of anal fistulas between October 2012 and June 2014. The OTSC((r)) was only used in refractory cases after previous fistula surgery, including patients with Crohn's disease, or multiple previous surgical approaches. RESULTS: There were ten patients (five males and five females) with a median age of 41 years (range 26-69 years). The etiology of the fistula was cryptoglandular in four patients, and perianal Crohn's disease in six patients (including one patient with an anovaginal fistula). The surgical procedure was technically successful in all patients. Permanent fistula closure was achieved in seven out of ten patients (70 %) within a median time of 72 days (range 31-109 days). Median total follow-up time was 230.5 days (range 156-523 days). There were three failures (30 %), including two cryptoglandular and one Crohn's disease associated fistula. In all three cases, the OTSC((r)) was lost spontaneously on days 22, 23, and 40, respectively. In three of the seven patients with successful closure, the OTSC((r)) was removed after complete healing of the fistula. CONCLUSIONS: The novel OTSC((r)) proctology system is a safe and effective method for the closure of even complex and recurrent fistulas. PMID- 25715789 TI - Quantification of the effects of Mandarin dialect differences on the use of norm referenced speech perception tests. AB - OBJECTIVE: Determine the effects of Chinese dialects on results for the Mandarin HINT recorded with a talker speaking Standard Mandarin (Putonghua). DESIGN: Normally-hearing subjects with different dialect exposure histories and usage preferences were administered the Mandarin HINT, and results were compared with published norms. Additional published measures of the intelligibility and mutual intelligibility of Chinese dialects were used to identify dialects for which Putonghua is highly intelligible. STUDY SAMPLE: One sample (N = 19) was exposed to a variety of dialects throughout China during childhood, and used Putonghua as adults. A second sample (N = 22) was exposed to Sichuanhua (the dialect found in Sichuan province) during childhood, and used Sichuanhua as adults. RESULTS: The average difference in SRTs for the Putonghua and Sichuanhua groups was 0.66 dB, with the Sichuanhua group's SRTs slightly higher. Means for neither group fell outside the confidence intervals for the norms. Putonghua is intelligible for 98% of Sichuanhua dialect users, and for over 90% of the users of two-thirds of the remaining Chinese regional dialects. CONCLUSIONS: Norm-referenced speech perception tests, such as the Mandarin HINT, can be used with speakers of Chinese regional dialects for whom Putonghua is highly intelligible. Small differences in dialect-specific norms are not clinically significant. PMID- 25715790 TI - Effect of Linolenic acid during in vitro maturation of ovine oocytes: embryonic developmental potential and mRNA abundances of genes involved in apoptosis. AB - PURPOSE: To study the effect of alpha-linolenic acid (ALA) on meiotic maturation, mRNA abundance of apoptosis-related (Bax and Bcl-2) molecules, and blastocyst formation in ovine oocytes. METHODS: A preliminary experiment was conducted to analyze the concentration of ALA in "small" (<=2 mm) and "large" (>=6 mm) follicles using gas chromatography/mass spectrometry analysis. The concentration of ALA in small and large follicles was determined to be in a range of 75.4 to 125.7 MUM, respectively. In vitro maturation (IVM) of oocyte was then performed in presence of 0 (control), 10 (ALA-10), 50 (ALA-50), 100 (ALA-100), and 200 (ALA 200) MUM of ALA. Meiotic maturation and mRNA abundance of Bax, and Bcl-2 genes was evaluated after 24 h of IVM. The embryonic cleavage and blastocyst formation following parthenogenetic activation were also determined for each group. RESULTS: The highest concentration of ALA (ALA-200) decreased the oocyte maturation rate compared with the control group. Analysis of apoptosis-related genes in oocytes after IVM revealed lesser transcript abundances for Bax gene, and higher transcript abundances for Bcl-2 gene in ALA-treated oocytes as compared with the control oocytes. In term of cleavage rate (considered as 2-cell progression), we did not observe any differences among the groups. However, ALA 100 group promoted more blastocyst formation as compared with the control group. CONCLUSION: Our results suggested that ALA treatment during IVM had a beneficial effect on developmental competence of ovine oocytes by increasing the blastocyst formation and this might be due to the altered abundance of apoptosis-regulatory genes. PMID- 25715791 TI - Cysteine analogs with a free thiol group promote fertilization by reducing disulfide bonds in the zona pellucida of mice. AB - Archives of cryopreserved sperm harvested from genetically engineered mice, in mouse resource centers, are a readily accessible genetic resource for the scientific community. We previously reported that exposure of oocytes to reduced glutathione (GSH) greatly improves the fertilization rate of frozen-thawed mouse sperm. Application of GSH to in vitro fertilization techniques is widely accepted as a standard protocol to produce sufficient numbers of mice from cryopreserved sperm. However, the detailed mechanism of the enhancement of fertilization mediated by GSH in vitro is not fully understood. Here we focused on the chemical by determining the effects of its amino acid constituents and cysteine analogs on the fertilization of oocytes by frozen-thawed sperm. Furthermore, we determined the stability of these compounds in aqueous solution. We show here that l cysteine (l-Cys), d-cysteine (d-Cys), or N-acetyl-l-cysteine (NAC) increased the rate of fertilization when added to the medium but did not adversely affect embryo development in vitro or in vivo. The levels of thiol groups of proteins in the zona pellucida (ZP) and the expansion of the ZP were increased by l-Cys, d Cys, and NAC. These effects were abrogated by the methylation of the thiol group of l-Cys. NAC was the most stable of these compounds in the fertilization medium at 4 degrees C. These results suggest that the thiol groups of cysteine analogs markedly enhance the fertilization rate of mouse oocytes. PMID- 25715792 TI - Emerging methods to generate artificial germ cells from stem cells. AB - Germ cells are responsible for the transmission of genetic and epigenetic information across generations. At present, the number of infertile couples is increasing worldwide; these infertility problems can be traced to environmental pollutions, infectious diseases, cancer, psychological or work-related stress, and other factors, such as lifestyle and genetics. Notably, lack of germ cells and germ cell loss present real obstacles in infertility treatment. Recent research aimed at producing gametes through artificial germ cell generation from stem cells may offer great hope for affected couples to treat infertility in the future. Therefore, this rapidly emerging area of artificial germ cell generation from nongermline cells has gained considerable attention from basic and clinical research in the fields of stem cell biology, developmental biology, and reproductive biology. Here, we review the state of the art in artificial germ cell generation. PMID- 25715794 TI - Endometrial CRISP3 is regulated throughout the mouse estrous and human menstrual cycle and facilitates adhesion and proliferation of endometrial epithelial cells. AB - The endometrium (the mucosal lining of the uterus) is a dynamic tissue that undergoes extensive remodeling, secretory transformation in preparation for implantation of an embryo, inflammatory and proteolytic activity during menstruation, and rapid postmenstrual repair. A plethora of local factors influence these processes. Recently, a cysteine-rich protein, CRISP3, a clade of the CRISP, antigen 5, pathogenesis-related (CAP) protein superfamily, has been implicated in uterine function. The localization, regulation, and potential function of CRISP3 in both the human and mouse endometrium is described. CRISP3 localizes to the luminal and glandular epithelium of the endometrium within both species, with increased immunoreactivity during the proliferative phase of the human cycle. CRISP3 also localizes to neutrophils, particularly within the premenstrual human endometrium and during the postbreakdown repair phase of a mouse model of endometrial breakdown and repair. Endometrial CRISP3 is produced by primary human endometrial epithelial cells and secreted in vivo to accumulate in the uterine cavity. Secreted CRISP3 is more abundant in uterine lavage fluid during the proliferative phase of the menstrual cycle. Human endometrial epithelial CRISP3 is present in both a glycosylated and a nonglycosylated form in vitro and in vivo. Treatment of endometrial epithelial cells in vitro with recombinant CRISP3 enhances both adhesion and proliferation. These data suggest roles for epithelial and neutrophil-derived CRISP3 in postmenstrual endometrial repair and regeneration. PMID- 25715793 TI - Porcine sertoli cell proliferation after androgen receptor inactivation. AB - Sertoli cell proliferation in neonatal boars is potentially androgen dependent. Hence, the immediate objective was to evaluate effects of androgen receptor mediated signaling on the first wave of Sertoli cell proliferation. The experimental design employed littermate pairs of boars with one member assigned to receive a daily oral dose of flutamide, an androgen receptor antagonist, beginning at 1 wk of age and the littermate the canola oil vehicle. Experiment 1 examined the response at 6.5 wk of age after completion of the first wave of Sertoli cell proliferation, and experiment 2 examined the response at 11 wk of age after initiation of the second wave of Sertoli cell proliferation. Experiment 3 was designed to evaluate initial responses at 2, 3, or 4 wk of age. Additional littermates from four of the litters evaluated at 2 wk of age were hemicastrated at 8 days of age. Testis weight increased approximately 50% in the flutamide treated boars compared with vehicle-treated littermates (P = 0.01) by 6.5 wk of age. Approximately 80% more Sertoli cells/testis were present in flutamide treated boars at 6.5 wk of age compared with their vehicle-treated littermates (P < 0.01). Animals that were hemicastrated at 8 days of age had more Sertoli cells/testis than their intact littermates at 2 wk of age (P < 0.01), but flutamide inhibited the hemicastration response. Androgen receptor antagonism during postnatal Sertoli cell proliferation increases Sertoli cell numbers, as does hemicastration, but receptor antagonism initially inhibits Sertoli cell proliferation induced by hemicastration. PMID- 25715795 TI - Conditional deletion of the relaxin receptor gene in cells of smooth muscle lineage affects lower reproductive tract in pregnant mice. AB - Relaxin hormone secreted into the circulation during pregnancy was discovered through its effects on pubic symphysis relaxation and parturition. Genetic inactivation of the relaxin gene or its cognate relaxin family peptide receptor 1 (RXFP1) in mice caused failure of parturition and mammary nipple enlargement, as well as increased collagen fiber density in the cervix and vagina. However, the relaxin effect on discrete cells and tissues has yet to be determined. Using transgenic mice with a knockin LacZ reporter in the Rxfp1 allele, we showed strong expression of this gene in vaginal and cervical stromal cells, as well as pubic ligament cells. We produced a floxed Rxfp1 allele that was used in combination with the Tagln-cre transgene to generate mice with a smooth muscle specific gene knockout. In pregnant females, the ROSA26 reporter activated by Tagln-cre was detected in smooth muscle cells of the cervix, vagina, uterine artery, and in cells of the pubic symphysis. In late pregnant females with conditional gene ablation, the length of pubic symphysis was significantly reduced compared with wild-type or heterozygous Rxfp1(+/-) females. Denser collagen content was revealed by Masson trichrome staining in reproductive tract organs, uterine artery, and pubic symphysis. The cervical and vaginal epithelium was less developed than in heterozygous or wild-type females, although nipple size was normal and the dams were able to nurse their pups. In summary, our data indicate that relaxin/RXFP1 signaling in smooth muscle cells is important for normal collagen turnover and relaxation of the pubic symphysis during pregnancy. PMID- 25715796 TI - Reduction of Mitochondrial Function by FCCP During Mouse Cleavage Stage Embryo Culture Reduces Birth Weight and Impairs the Metabolic Health of Offspring. AB - The periconceptual environment represents a critical window for programming fetal growth trajectories and susceptibility to disease; however, the underlying mechanism responsible for programming remains elusive. This study demonstrates a causal link between reduction of precompaction embryonic mitochondrial function and perturbed offspring growth trajectories and subsequent metabolic dysfunction. Incubation of embryos with carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (FCCP), which uncouples mitochondrial oxidative phosphorylation, significantly reduced mitochondrial membrane potential and ATP production in 8-cell embryos and the number of inner cell mass cells within blastocysts; however, blastocyst development was unchanged. This perturbed embryonic mitochondrial function was concomitant with reduced birth weight in female offspring following embryo transfer, which persisted until weaning. FCCP-treated females also exhibited increased adiposity at 4 wk, increased adiposity gain between 4 and 14 wk, glucose intolerance at 8 wk, and insulin resistance at 14 wk. Although FCCP treated males also exhibited reduced glucose tolerance, but their insulin sensitivity and adiposity gain between 4 and 14 wk was unchanged. To our knowledge, this is one of the first studies to demonstrate that reducing mitochondrial function and, thus, decreasing ATP output in the precompacting embryo can influence offspring phenotype. This is of great significance as a large proportion of patients requiring assisted reproductive technologies are of advanced maternal age or have a high body mass index, both of which have been independently linked with perturbed early embryonic mitochondrial function. PMID- 25715798 TI - Parametric imaging of viscoelasticity using optical coherence elastography. AB - We demonstrate imaging of soft tissue viscoelasticity using optical coherence elastography. Viscoelastic creep deformation is induced in tissue using step-like compressive loading and the resulting time-varying deformation is measured using phase-sensitive optical coherence tomography. From a series of co-located B scans, we estimate the local strain rate as a function of time, and parameterize it using a four-parameter Kelvin-Voigt model of viscoelastic creep. The estimated viscoelastic strain and time constant are used to visualize viscoelastic creep in 2D, dual-parameter viscoelastograms. We demonstrate our technique on six silicone tissue-simulating phantoms spanning a range of viscoelastic parameters. As an example in soft tissue, we report viscoelastic contrast between muscle and connective tissue in fresh, ex vivo rat gastrocnemius muscle and mouse abdominal transection. Imaging viscoelastic creep deformation has the potential to provide complementary contrast to existing imaging modalities, and may provide greater insight into disease pathology. PMID- 25715797 TI - EP2 Receptor Signaling Regulates Microglia Death. AB - The timely resolution of inflammation prevents continued tissue damage after an initial insult. In the brain, the death of activated microglia by apoptosis has been proposed as one mechanism to resolve brain inflammation. How microglial death is regulated after activation is still unclear. We reported that exposure to lipopolysaccharide (LPS) and interleukin (IL)-13 together initially activates and then kills rat microglia in culture by a mechanism dependent on cyclooxygenase-2 (COX-2). We show here that activation of the E prostanoid receptor 2 (EP2, PTGER2) for prostaglandin E2 mediates microglial death induced by LPS/IL-13, and that EP2 activation by agonist alone kills microglia. Both EP2 antagonists and reactive oxygen scavengers block microglial death induced by either LPS/IL-13 or EP2 activation. By contrast, the homeostatic induction of heme oxygenase 1 (Hmox1) by LPS/IL-13 or EP2 activation protects microglia. Both the Hmox1 inducer cobalt protoporphyrin and a compound that releases the Hmox1 product carbon monoxide (CO) attenuated microglial death produced by LPS/IL-13. Whereas CO reduced COX-2 protein expression, EP2 activation increased Hmox1 and COX-2 expression at both the mRNA and protein level. Interestingly, caspase-1 inhibition prevented microglial death induced by either LPS/IL-13 or low (but not high) concentrations of butaprost, suggestive of a predominantly pyroptotic mode of death. Butaprost also caused the expression of activated caspase-3 in microglia, pointing to apoptosis. These results indicate that EP2 activation, which initially promotes microglial activation, later causes delayed death of activated microglia, potentially contributing to the resolution phase of neuroinflammation. PMID- 25715799 TI - Human factors and ergonomics and quality improvement science: integrating approaches for safety in healthcare. PMID- 25715800 TI - Telling stories with images. PMID- 25715801 TI - Examining an Australian physical activity and nutrition intervention using RE AIM. AB - Translating evidence-based interventions into community practice is vital to health promotion. This study used the RE-AIM framework to evaluate the larger dissemination of the ManUp intervention, an intervention which utilized interactive web-based technologies to improve the physical activity and nutrition behaviors of residents in Central Queensland, Australia. Data were collected for each RE-AIM measure (Reach, Effectiveness, Adoption, Implementation, Maintenance) using (i) computer-assisted telephone interview survey (N = 312) with adults (18 years and over) from Central Queensland, (ii) interviews with key stakeholders from local organizations (n = 12) and (iii) examination of project-related statistics and findings. In terms of Reach, 47% of participants were aware of the intervention; Effectiveness, there were no significant differences between physical activity and healthy nutrition levels in those aware and unaware; Adoption, 73 participants registered for the intervention and 25% of organizations adopted some part of the intervention; Implementation, 26% of participants initially logged onto the website, 29 and 17% started the web-based physical activity and nutrition challenges, 33% of organizations implemented the intervention, 42% considered implementation and 25% reported difficulties; Maintenance, an average of 0.57 logins and 1.35 entries per week during the 12 week dissemination and 0.27 logins and 0.63 entries per week during the 9-month follow-up were achieved, 22 and 0% of participants completed the web-based physical activity and nutrition challenges and 33.3% of organizations intended to continue utilizing components of the intervention. While this intervention demonstrated good reach, effectiveness, adoption and implementation warrant further investigation. PMID- 25715802 TI - Glomus tumor of the liver in a cow. AB - An 11-year-old Holstein-Friesian cow exhibited anorexia and jaundice. A large mass was found in the liver during necropsy. Macroscopically, the mass was composed of dark red multilobular tissue and a centrally located abscess, which was connected to the hepatic duct. Histologically, the mass consisted of proliferation of small neoplastic cells and was demarcated from the hepatic parenchyma by a thick region of granulation tissue. The neoplastic cells were predominantly arranged in solid sheets, but they also formed blood-filled cancellous structures, and proliferating foci were seen around blood vessels. Periodic acid-Schiff reaction demonstrated that a fine basement membrane-like structure surrounded the neoplastic cells. Immunohistochemically, the neoplastic cells were positive for vimentin and alpha smooth muscle actin and negative for cytokeratin, factor VIII-related antigen, chromogranin and desmin. Based on its histopathological features, the hepatic neoplasm was diagnosed as a primary glomus tumor. This is the first report about a primary glomus tumor of the liver in a cow. PMID- 25715803 TI - Sexing murine embryos with an indirect immunofluorescence assay using phage antibody B9-Fab against SDM antigen. AB - The use of serologically detectable male (SDM; also called H-Y) antigens to identify male embryos may be limited by the source of anti-SDM antibody. In the present study, novel anti-SDM B9-Fab recombinant clones (obtained by chain shuffling of an A8 original clone) were used to detect SDM antigens on murine embryos. Murine morulae and blastocysts (n=138) were flushed from the oviducts of Kunming mice and incubated with anti-SDM B9-Fab for 30 min at 37 degrees C. With an indirect immunofluorescence assay, the membrane and inner cell mass had bright green fluorescence (presumptive males). Overall, 43.5% (60/138) were classified as presumptive males and 56.5% (78/138) as presumptive females, with 85.0 and 88.5% of these, respectively, confirmed as correct predictions (based on PCR analysis of a male-specific [Sry] sequence). We concluded that the anti-SDM B9 Fab molecule had potential for non-invasive, technically simple immunological sexing of mammalian embryos. PMID- 25715804 TI - In vivo generation of a mature and functional artificial skeletal muscle. AB - Extensive loss of skeletal muscle tissue results in mutilations and severe loss of function. In vitro-generated artificial muscles undergo necrosis when transplanted in vivo before host angiogenesis may provide oxygen for fibre survival. Here, we report a novel strategy based upon the use of mouse or human mesoangioblasts encapsulated inside PEG-fibrinogen hydrogel. Once engineered to express placental-derived growth factor, mesoangioblasts attract host vessels and nerves, contributing to in vivo survival and maturation of newly formed myofibres. When the graft was implanted underneath the skin on the surface of the tibialis anterior, mature and aligned myofibres formed within several weeks as a complete and functional extra muscle. Moreover, replacing the ablated tibialis anterior with PEG-fibrinogen-embedded mesoangioblasts also resulted in an artificial muscle very similar to a normal tibialis anterior. This strategy opens the possibility for patient-specific muscle creation for a large number of pathological conditions involving muscle tissue wasting. PMID- 25715806 TI - The impact of healthcare-associated methicillin-resistant Staphylococcus aureus infections on post-discharge healthcare costs and utilization. AB - OBJECTIVE: Healthcare-associated methicillin-resistant Staphylococcus aureus (MRSA) infections are a major cause of morbidity, mortality, and cost among hospitalized patients. Little is known about their impact on post-discharge resource utilization. The purpose of this study was to estimate post-discharge healthcare costs and utilization attributable to positive MRSA cultures during a hospitalization. METHODS: Our study cohort consisted of patients with an inpatient admission lasting longer than 48 hours within the US Department of Veterans Affairs (VA) system between October 1, 2007, and November 30, 2010. Of these patients, we identified those with a positive MRSA culture from microbiology reports in the VA electronic medical record. We used propensity score matching and multivariable regression models to assess the impact of positive culture on post-discharge outpatient, inpatient, and pharmacy costs and utilization in the 365 days following discharge. RESULTS: Our full cohort included 369,743 inpatients, of whom, 3,599 (1.0%) had positive MRSA cultures. Our final analysis sample included 3,592 matched patients with and without positive cultures. We found that, in the 12 months following hospital discharge, having a positive culture resulted in increases in post-discharge pharmacy costs ($776, P<.0001) and inpatient costs ($12,167, P<.0001). Likewise, having a positive culture increased the risk of a readmission (odds ratio [OR]=1.396, P<.0001), the number of prescriptions (incidence rate ratio [IRR], 1.138; P<.0001) and the number of inpatient days (IRR, 1.204; P<.0001,) but decreased the number of subsequent outpatient encounters (IRR, 0.941; P<.008). CONCLUSIONS: The results of this study indicate that MRSA infections are associated with higher levels of post-discharge healthcare cost and utilization. These findings indicate that financial benefits resulting from infection prevention efforts may extend beyond the initial hospital stay. PMID- 25715807 TI - Nanotransfersomes of carvedilol for intranasal delivery: formulation, characterization and in vivo evaluation. AB - CONTEXT: Development of carvedilol-loaded transfersomes for intranasal administration to overcome poor nasal permeability and hepatic first pass effect so as to enhance its bioavailability. OBJECTIVE: The purpose of this study was to develop carvedilol-loaded transfersomes containing different edge activators (EAs) then evaluating the in vivo behavior of the optimized formula in rabbits. METHODS: The vesicles were prepared by incorporating different EAs including Span 20, Span 60, Tween 20, Tween 80, and sodium deoxycholate (SDC) in the lipid bilayer and each EA was used in three different ratios with respect to phosphatidylcholine (PC) including 95:5%, 85:15%, and 75:25% w/w (PC:EA). Evaluation of transfersomes was carried out in terms of shape, size, entrapment efficiency (EE), in vitro release, ex vivo permeation, confocal laser scanning microscopy (CLSM), and stability studies. The pharmacokinetic study of the optimized formula was conducted in rabbits. RESULTS: The mean diameter of the vesicles was in the range of 295-443 nm. Transfersomes prepared with 95:5% (w/w) (PC:EA) ratio showed highest EE% where Span 60 gave the highest values. Whereas those prepared using 85:15% w/w ratio showed highest percentages of drug release where SDC was superior to other EAs. The developed transfersomes exhibited significantly higher amounts of carvedilol permeated through nasal mucosa. CLSM of formula T14 containing SDC with 85:15% (w/w) (PC:EA) ratio revealed high permeation across the nasal mucosa. CONCLUSION: The nanotransfersomal vesicles were significantly more efficient in nasal delivery of carvedilol with absolute bioavailability of 63.4%. PMID- 25715808 TI - Folic acid-conjugated superparamagnetic iron oxide nanoparticles for tumor targeting MR imaging. AB - Superparamagnetic iron oxide nanoparticles (SPIONs) have been the subject of extensive research due to their potential biomedical applications. In the present investigation, superparamagnetic FA-PEI-Fe3O4 were successfully prepared and evaluated as a targeted MRI contrast agent. FTIR characteristics, TGA, VSM, and MR imaging confirmed the composition and magnetic properties of the synthesized nanoparticles. TEM showed that FA-PEI-Fe3O4 were spherical in shape and well dispersed. The nanoparticles were superparamagnetic at room temperature with a saturation magnetization value of 67.1 emu/g. The nanoparticles showed higher uptake efficiency due to receptor-mediated endocytosis. Moreover, specificity of FA-PEI-Fe3O4 to target tumor cells was demonstrated by the increased nanoparticle uptake and significant contrast enhancement of KB cells over MCF7 cells. The competitive inhibition of FA-PEI-Fe3O4 by free FA further confirmed the specific interaction of this conjugate with FA receptors. In vivo MR imaging studies showed a decreased signal intensity and enhanced tumor contrast post-injection of FA-PEI-Fe3O4. These results indicate that FA-PEI-Fe3O4 can be used as a promising tumor-targeting agent as well as a T2 negative-contrast agent in MR imaging applications. PMID- 25715809 TI - Methacrylate micro/nano particles prepared by spray drying: a preliminary in vitro/in vivo study. AB - Delivery systems controlling drug release only in the colon holds great promises since they improve utilization of drug and decrease the dosing times comparison with conventional forms. The aim of the present study was to prepare polymeric microparticles on the basis of Ciprofloxacin via oral route for the treatment of inflammatory bowel disease. Ciprofloxacin was selected because of its extensive coverage for intestinal flora, relatively favorable side-effect profile and preliminary data suggesting its efficacy in the treatment of active Crohn's Disease. Microparticles were prepared using different acrylic compounds, namely Eudragit(r) RL (PO) and RS (PO) and a mixture of both. Spray-drying was used as a preparation method of Ciprofloxacin/Eudragit(r) microparticles using a Mini Spray Dryer B-290 (Buchi, Postfach, Switzerland). In vitro dissolution studies were performed to choose the best formulation and selected microparticles were characterized by size and morphology by environmental scanning electron microscopy. Yield and encapsulation efficiency were calculated and in vivo/ex vivo experiments were investigated both of which suggest that selected microparticles can be used for colon targeting of drugs increasing residence time of the drug in the affected area. PMID- 25715810 TI - A nanoparticulate drug-delivery system for glaucocalyxin A: formulation, characterization, increased in vitro, and vivo antitumor activity. AB - Glaucocalyxin A (GLA) is a phytochemical component with multiple pharmacological activities; however, glaucocalyxin A's wider use has been restricted by its poor solubility. In this study, GLA nanosuspensions were prepared with precipitation combined ultrasonication and were characterized by dynamic light scattering (DLS), transmission electron microscope (TEM), and differential scanning calorimetry (DSC). The GLA nanosuspensions were spherical with a smooth surface and a small size of 143 nm, the drug payload achieved 8.95%, and the maximum GLA concentration reached 1 mg/mL. The lyophilized powders for the GLA nanosuspensions were amorphous and displayed a biphasic drug release pattern with an initial burst release and a consequent sustained release. In contrast to the free drug solution, GLA nanosuspensions showed higher in vitro antitumor activity against HepG2 cells (IC50 value of 1.793 versus 2.884 MUg/mL at 24 h, p < 0.01). Meanwhile, nanosuspensions displayed better anticancer efficacy than free GLA on H22 bearing mice (54.11% versus 36.02% tumor inhibition rate). These results indicate that GLA nanosuspensions have great potential for the treatment of hepatic cancer. PMID- 25715811 TI - Current landscape for treatment of advanced basal cell carcinoma. AB - Basal cell carcinomas (BCCs) account for around 80% of non-melanoma skin cancer. Australia has the highest incidence of BCC globally and the rates continue to increase in both Australia and New Zealand. BCC causes significant morbidity, placing an enormous burden on the healthcare system. Treatment of patients with advanced BCC can be particularly challenging. A panel of UK experts recently defined advanced disease as BCC that in which current treatment modalities are considered potentially contraindicated by clinical or patient-driven factors. Research has found that mutations in the hedgehog signalling pathway underpin the pathogenesis of the vast majority of sporadic BCC, as well as Gorlin syndrome. The first-in-class oral small molecule hedgehog pathway inhibitor - vismodegib-is now approved in a number of countries for use in locally-advanced and metastatic BCC and has resulted in improved outcomes in the majority of patients treated. With a number of similar agents in the pipeline, research is now focusing on identifying mechanisms that may contribute to resistance to this agent in some lesions. PMID- 25715812 TI - Estimating service demand for respite care among informal carers of people with psychological disabilities in Australia. AB - OBJECTIVE: To estimate service demand (willingness to seek or use services) for respite care among informal, primary carers of people with a psychological disability and to describe their characteristics. METHODS: Analysis of data from the household component of the 2009 Survey of Disability Ageing and Carers (n=64,213 persons). RESULTS: In Australia in 2009, 1.0% of people aged 15 years or over (177,900 persons) provided informal, primary care to a co-resident with a psychological disability. One-quarter (27.2%) of these carers reported service demand for respite care, of whom one-third had used respite services in the past three months and four-fifths had an unmet need for any or more respite care. A significantly greater percentages of carers with service demand for respite care spent 40 or more hours per week on caregiving, provided care to a person with profound activity restrictions and reported unmet support needs, compared to carers without service demand. Lack of suitable, available respite care models was a barrier to utilisation. CONCLUSIONS: Findings confirm significant service demand for, and under-utilisation of, respite care among mental health carers. IMPLICATIONS: Increased coverage of respite services, more flexible service delivery models matched to carers' needs and better integration with other support services are indicated. PMID- 25715813 TI - [Echocardiographic evaluation of systolic left ventricular function in heart failure: value of alternative parameters for determination of ejection fraction]. AB - Assessment of the left ventricular ejection fraction plays a key role in the echocardiographic diagnosis of heart failure. The parameter most commonly used is the ejection fraction computed with the biplane disc summation method of Simpson; however, there are numerous limitations to this method, such as the assumption of geometrical symmetry, a substantial intraobserver and interobserver variability, foreshortening of the left ventricle and insufficient image quality for endocardial tracking. Alternative parameters for the evaluation of left ventricular function should be taken into consideration. Speckle tracking echocardiography has proven to be a reliable prognostic factor and a good tool for differentiating cardiomyopathies. Simple measurements, which are also feasible with poor image quality, are mitral annular plane systolic excursion (MAPSE) and the velocity of mitral annular movement (Sm or S'). In mitral regurgitation, left ventricular dP/dt represents the time to build up a certain pressure gradient and is therefore a measure of the contractile force exerted. Three-dimensional echocardiography has proven to be an important tool not only for three-dimensional measurement of the left ventricular ejection fraction but also for multivectoral speckle tracking analysis. PMID- 25715814 TI - [Exercise training as a key component of heart failure therapy]. AB - Physical exercise has been recognized as a standard therapy in the guidelines for secondary prevention of chronic heart failure. In clinical practice its benefits are widely underestimated. It is still too rarely applied as a therapeutic component, despite overwhelming scientific evidence, including meta-analyses illustrating the positive effect on exercise capacity, quality of life and hospitalization. It is crucial that patients undergo a thorough clinical investigation, including exercise testing and are in a clinically stable condition for at least 6 weeks under optimal guideline-conform medicinal therapy before exercise training is initiated. Moreover, it is important that only approved exercise regimens should be prescribed and exercise sessions should be appropriately monitored. Both moderate continuous endurance training and recently developed interval training have been shown to be safe and effective in chronic heart failure. Ideally, endurance training should be combined with moderate resistance training. Current evidence clearly demonstrates a dose-response relationship in the way that beneficial effects of exercise training are strongly related to factors such as exercise duration and intensity. Development of strategies that support long-term adherence to exercise training are a crucial challenge for both daily practice and future research. PMID- 25715816 TI - Uncertainty Assessment in the Quantification of Risk Rates of Occupational Accidents. AB - Occupational risk rates per hour of exposure have been quantified for 63 occupational accident types for the Dutch working population. Data were obtained from the analysis of more than 9,000 accidents that occurred over a period of six years in the Netherlands and resulted in three types of reportable consequences under Dutch law: (a) fatal injury, (b) permanent injury, and (c) serious recoverable injury requiring at least one day of hospitalization. A Bayesian uncertainty assessment on the value of the risk rates has been performed. Annual risks for each of the 63 occupational accident types have been calculated, including the variability in the annual exposure of the working population to the corresponding hazards. The suitability of three risk measures-individual risk rates, individual annual risk, and number of accidents-is examined and discussed. PMID- 25715815 TI - Significance of the interval between first and second transurethral resection on recurrence and progression rates in patients with high-risk non-muscle-invasive bladder cancer treated with maintenance intravesical Bacillus Calmette-Guerin. AB - OBJECTIVES: To evaluate the effect of the interval between the initial and second transurethral resection (TUR) on the outcome of patients with high-risk non muscle-invasive bladder cancer (NMIBC) treated with maintenance intravesical Bacillus Calmette-Guerin (BCG) therapy. PATIENTS AND METHODS: We reviewed the data of patients from 10 centres treated for high-risk NMIBC between 2005 and 2012. Patients without a diagnosis of muscle-invasive cancer on second TUR performed <=90 days after a complete first TUR, and received at least 1 year of maintenance BCG were included in this study. The interval between first and second TUR in addition to other parameters were recorded. Multivariate logistic regression analysis was used to identify predictors of recurrence and progression. RESULTS: In all, 242 patients were included. The mean (sd, range) follow-up was 29.4 (22.2, 12-96) months. The 3-year recurrence- and progression free survival rates of patients who underwent second TUR between 14 and 42 days and 43-90 days were 73.6% vs 46.2% (P < 0.001) and 89.1% vs 79.1% (P = 0.006), respectively. On multivariate analysis, the interval to second TUR was found to be a predictor of both recurrence [odds ratio (OR) 3.598, 95% confidence interval (CI) 1.885-8.137; P = 0.001] and progression (OR 2.144, 95% CI 1.447-5.137; P = 0.003). CONCLUSIONS: The interval between first and second TUR should be <=42 days in order to attain lower recurrence and progression rates. To our knowledge, this is the first study demonstrating the effect of the interval between first and second TUR on patient outcomes. PMID- 25715817 TI - Successful treatment of lichen amyloidosus with oral alitretinoin. PMID- 25715818 TI - Multinucleated histiocytes in esophageal squamous mucosa secondary to gastroesophageal reflux disease in a patient with esophageal stricture. AB - We present a novel finding of multinucleated histiocytes associated with acute and chronic inflammation secondary to gastroesophageal reflux in a patient with a history of esophageal stricture, representing the first documented case after a review of the literature. Multinucleated squamous cells, while rare, are a more common finding in association with reactive and inflammatory conditions and have been reported in other areas of the body, such as the vulva, skin, and colon. Esophageal involvement with multinucleated epithelial giant cells appears to be a much less frequently encountered occurrence with only one previous report in the literature. We add to this series an interesting case of esophageal multinucleated giant cells that are histiocytes rather than epithelial cells, supported with positive CD68 immunohistochemical staining. Our patient had severe esophageal dysphagia with stricture with history of food impaction, requiring several dilation sessions to achieve an esophageal luminal diameter of 17 mm. There was marked clinical and endoscopic improvement with proton pump inhibitor and endoscopic therapy. The multinucleated mucosal histiocytes at the time of biopsy were likely due to reactive changes from chronic injury due to food stasis and reflux. PMID- 25715820 TI - Multicenter survey of attitudes and perceptions of pain medicine fellows toward the use of lateral versus contralateral-oblique fluoroscopic view for interlaminar cervical epidural injection. AB - OBJECTIVE: For interlaminar cervical epidural steroid injections (CESI) the lateral fluoroscopic view (LAT) is often considered to improve needle localization. However, the contralateral-oblique view (CLO) is a useful alternative with potential advantages to improve identification of cervical anatomy and needle depth assessment. The authors explored the attitudes and perceptions of pain medicine fellows currently training in two ACGME-accredited pain medicine fellowship programs regarding the use of these two types of fluoroscopic views. METHODS: The survey was conducted online following a request by e-mail. Of a total of 20 fellows who were contacted, there were 17 respondents who had experience with both techniques, and they were included for analysis. RESULTS: The response rate for participation was 95%. Whereas 70.6% respondents reported they were very certain about the assessment of anatomy with the CLO view, only 17.6% felt very certain with the LAT view. Compared with learning to perform interlaminar CESI using the LAT view only, the majority of fellows thought that using the CLO technique was easier to learn (P < 0.01) and offered better visualization of contrast dye spread pattern to confirm the cervical epidural space (P = 0.013). All respondents perceived that the likelihood of interlaminar CESI complications would be lower with CLO technique. Overall, 82.4% of respondents considered CLO visualization as a preferred technique for interlaminar CESI. Respondents stated that the likelihood of using the CLO technique as an independent physician was significantly higher than using only the LAT technique (P < 0.001), particularly for patients who are obese and have short necks. CONCLUSIONS: For interlaminar CESI, using the CLO is perceived to provide better definition of anatomy and yet is easier to learn. Trainees may become more confident in performing interlaminar CESI with the CLO. We encourage all fellowship programs to include the CLO technique for interlaminar CESI as part of the training. PMID- 25715819 TI - Ion-pair amphiphile: a neoteric substitute that modulates the physicochemical properties of biomimetic membranes. AB - Ion-pair amphiphiles (IPAs) are neoteric pseudo-double-tailed compounds with potential as a novel substitute of phospholipid. IPA, synthesized by stoichiometric/equimolar mixing of aqueous solution of hexadecyltrimethylammonium bromide (HTMAB) and sodium dodecyl sulfate (SDS), was used as a potential substituent of naturally occurring phospholipid, soylecithin (SLC). Vesicles were prepared using SLC and IPA in different ratios along with cholesterol. The impact of IPA on SLC was examined by way of surface pressure (pi)-area (A) measurements. Associated thermodynamic parameters were evaluated; interfacial miscibility between the components was found to depend on SLC/IPA ratio. Solution behavior of the bilayers, in the form of vesicles, was investigated by monitoring the hydrodynamic diameter, zeta potential, and polydispersity index over a period of 100 days. Size and morphology of the vesicles were also investigated by electron microscopic studies. Systems comprising 20 and 40 mol % IPA exhibited anomalous behavior. Thermal behavior of the vesicles, as scrutinized by differential scanning calorimetry, was correlated with the hydrocarbon chain as well as the headgroup packing. Entrapment efficiency (EE) of the vesicles toward the cationic dye methylene blue (MB) was also evaluated. Vesicles were smart enough to entrap the dye, and the efficiency was found to vary with IPA concentration. EE was found to be well above 80% for some stable dispersions. Such formulations thus could be considered to have potential as novel drug delivery systems. PMID- 25715821 TI - [Neuropsychoanalysis - modern fad or return to Freud's original concepts?].